PMID- 27451496 TI - [PESTIVIRUSES IN RUMINANTS]. AB - The genus Pestivirus includes four species: bovine viral diarrhea virus 1, bovine viral diarrhea virus 2, classical swine fever disease virus, and ovine border disease virus. Pestiviruses infect many species of domestic and wild animals. Bovine viral diarrhea virus is a prototypical representative of the pestiviruses of ruminant animals. Recently, new candidates appeared for including in this genus: two viruses of the wild ruminant animals that have not been officially classified and one HoBi-like virus discovered for the first time in the bovine fetal serum. The circulation of the ruminant animal pestiviruses within population of domestic and wild animals, the presence of these viruses in bioproducts stimulates studies of the infection reservoirs and their influence on the effect of the bovine viral diarrhea control programs. PMID- 27451497 TI - [QUANTITATIVE DNA EVALUATION OF THE HIGH CARCINOGENIC RISK OF HUMAN PAPILLOMA VIRUSES AND HUMAN HERPES VIRUSES IN MALES WITH FERTILITY DISORDERS]. AB - Infertility is an actual medical and social problem. In 50% of couples it is associated with the male factor and in more than 50% of cases the etiology of the infertility remains insufficiently understood. The goal of this work was to study the prevalence and to perform quantitative analysis of the human herpes viruses (HHV) and high carcinogenic risk papilloma viruses (HR HPV) in males with infertility, as well as to assess the impact of these infections on sperm parameters. Ejaculate samples obtained from 196 males fall into 3 groups. Group 1 included men with the infertility of unknown etiology (n = 112); group 2, patients who had female partners with the history of spontaneous abortion (n = 63); group 3 (control), healthy men (n = 21). HHV and HR HPV DNA in the ejaculates were detected in a total of 42/196 (21.4%) males: in 31 and 11 patients in groups 1 and 2, respectively (p > 0.05) and in none of healthy males. HHV were detected in 24/42; HR HPV, in 18/42 males (p > 0.05) without significant difference between the groups. Among HR HPV genotypes of the clade A9 in ejaculate were more frequent (14/18, p = 0.04). Comparative analysis of the sperm parameters showed that in the ejaculates of the infected patients sperm motility as well as the number of morphologically normal cells were significantly reduced compared with the healthy men. The quantification of the viral DNA revealed that in 31% of the male ejaculates the viral load was high: > 3 Ig10/100000 cells. Conclusion. The detection of HHV and HR HPV in the ejaculate is associated with male infertility. Quantification of the viral DNA in the ejaculate is a useful indicator for monitoring viral infections in infertility and for decision to start therapy. PMID- 27451498 TI - [EVALUATION OF THE HUMAN SENSITIVITY TO SMALLPOX VIRUS BY THE PRIMARY CULTURES OF THE MONOCYTE-MACROPHAGES]. AB - Studies of the primary cultures of granulocytes, mononuclear, and monocyte macrophage cells derived from human blood were performed using variola virus (VARV) in the doses of 0.001-0.021 PFU/cell (plaques-forming units per cell). Positive dynamics of the virus accumulation was observed only in the monocyte macrophages with maximum values of virus concentration (5.0-5.5 Ig PFU/ml) mainly within six days after the infection. The fact of VARV replication in the monocyte macrophages was confirmed by the data of electron microscopy. At the same time, virus vaccines when tested in doses 3.3 and 4.2 Ig PFU/ml did not show the ability to reproduce in these human cells. The people sensitivity to VARV as assessed from the data obtained on human monocyte-macrophages corresponded to -1 PFU (taking into account the smooth interaction of the virus in the body to the cells of this type), which is consistent to previously found theoretical data on the virus sensitivity. The human susceptibility to VARV assessed experimentally can be used to predict the adequacy of developed smallpox models (in vivo) based on susceptible animals. This is necessary for reliable assessment of the efficiency of development of drugs for treatment and prophylaxis of the smallpox. PMID- 27451499 TI - [HUMAN CYTOMEGALOVIRUS INFECTION AND SPONTANEOUS ABORTION IN PREGNANT WOMEN OF I AND II TRIMESTER]. AB - The goal of this work was the evaluation of the frequency of human CMV infection among the women, whose pregnancy ended in miscarriage, detection of active forms of infection and treatment before pregnancy. Virological and sero-immunological techniques were used. A total of 116 women who had miscarriages before the 28 week of pregnancy were submitted to the CMV test. 109 women (94.0%) demonstrated positive results. 49 women (42.2%) had active form of the cytomegalovirus infection. 13 women (26.5%) had the recurrent form and 36 patients (73.5%) had the persistent form of CMV infection (stage of productive replication). All the women with active CMVI were treated before the next pregnancy. Immunomodulatory therapy for the treatment was used. PMID- 27451500 TI - [THE USE OF THE MODEL MOUSE ICR--VARIOLA VIRUS FOR EVALUATION OF ANTIVIRAL DRUG EFFICACY]. AB - Mice of the ICR outbred population were infected intranasally (i/n) with the variola virus (VARV, strain Ind-3a). Clinical signs of the disease did not appear even at the maximum possible dose of the virus 5.2 lg PFU/head (plaque-forming units per head). In this case, 50% infective dose (ID50) of VARV estimated by the presence or absence of the virus in the lungs three days after infection (p.i.) was equal to 2.7 +/- 0.4 lg PFU/head. Taking into account the 10% application of the virus in the lungs during the intranasal infection of the mice, it was adequate to 1.7 lg PFU/lungs. This indicates a high infectivity of the VARV for mice comparable to its infectivity for humans. After the i/n infection of mice with the VARV at a dose 30 ID50/ head the highest concentration of the virus detected in the lungs (4.9 +/- 0.0 lg PFU/ml of homogenate) and in nasal cavity tissues (4.8 +/- 0.0 lg PFU/ml) were observed. The pathomorphological changes in the respiratory organs of the mice infected with the VARV appeared at 3-5 days p.i., and the VARV reproduction noted in the epithelial cells and macrophages were noticed. When the preparations ST-246 and NIOCH-14 were administered orally at a dose of 60 MUg/g of mouse weight up to one day before infection, after 2 hours, 1 and 2 days p.i., the VARV reproduction in the lungs after 3 days p.i. decreased by an order of magnitude. Thus, outbred ICR mice infected with the VARV can be used as a laboratory model of the smallpox when evaluating the therapeutic and prophylactic efficacy of the antismallpox drugs. PMID- 27451501 TI - [THE PROOF OF VERTICAL TRANSMISSION OF THE NUCLEOPOLYHEDROVIRUS IN MANY GENERATIONS OF THE GYPSY MOTH LYMANTRIA DISPAR L]. AB - INTRODUCTION: Insect viruses can play an important role in population dynamics of their hosts. That is why the problem of permanent viral infection support among virus-positive insects is associated with one of the intriguing problems of general biology and virology. MATERIALS AND METHODS: Under laboratory conditions, the modeling of the vertical transmission of the nucleopolyhedrovirus (NPV) gypsy moth was implemented at relatively high level of mortality among insects of parental generation (60%). The diagnostics of the occult virus was executed by the PCR method among insects before their infection under laboratory conditions, as well as among insects that survived after inoculation. RESULTS: The NPV-caused mortality among insects that survived after infection in generations F1, F2, and F3 was 14 +/- 4%, 10 +/- 4%, and 5 +/- 0.5%, respectively. In the following three generations NPV-induced mortality was not noticed. DISCUSSION: The level of the virus-positive individuals among the gypsy moth embryos in all occasions was higher than the NPV-induced mortality of insects. Thus, the given results show that the presence of virus among insect does not mean inevitable mortality of their hosts. Perhaps, the viral DNA can completely or partly lose its infectivity but may exist in the analyzed insect samples. CONCLUSIONS: The viral infection can be formed among progeny surviving after inoculation of insects. It can be actuated during three generations of the gypsy moth. The level of the virus positive individuals among the gypsy moth embryos determined by the PCR method in daughter generations was higher than the NPV- induced mortality of insects. PMID- 27451503 TI - What an Honor.... PMID- 27451502 TI - [UNIFICATION OF THE MOLECULAR EPIDEMIOLOGICAL RESEARCH OF THE TICK-BORNE ENCEPHALITIS]. AB - Molecular genetic techniques and approaches in epidemiological studies were breakthrough in the understanding of the laws, ways, and mechanisms of the spread of the pathogens. However, lack of standard methods makes it difficult to compare results obtained by different scientific groups. In this work we propose to choose one fragment of the TBEV genome as a genetic marker whose sequencing would be both obligatory and sufficient for the molecular epidemiological studies. The best candidate for this purpose may be a fragment of the gene E of 454 nucleotides in length. The deduced amino acid sequence of this fragment was a basis for a new approach for the TBEV differentiation with clusteron being a structural unit (Kovalev and Mukhacheva, 2013). The clusteron approach was proved to be informative for studying the genetic structure of the TBEV-Sib population in the Middle Urals. TBE foci were shown to be unique in both quantitative and qualitative composition of the clusterons. The greatest clusteron diversity in the south of the Middle Urals, through the Trans-Siberian way, may reflect the history of the colonization, closely associated with the roads between Siberia and the European part of Russia. The age of three clusterons did not exceed 50 years, which may indicate an ongoing evolutionary process taking place in the TBEV-Sib populations. In turn, their spatial distribution indicates the crucial role of human factors in the spread of the TBEV (Kovalev & Mukhacheva, 2014). The clusteron approach provides formalization of ideas about the structure of the viral populations and could be used not only by researchers but also by epidemiological surveillance services. Unification of the studies of the TBEV on the basis of a standard genetic marker would consolidate the efforts of researchers from different regions of Russia and other countries. PMID- 27451504 TI - Why Reading and Understanding Your Contracts Is So Important. PMID- 27451505 TI - Healthy Debate or Risky Territory: Discussing Politics in the Workplace. PMID- 27451506 TI - Introducing a New, Non-disciplinary Option for Peer Review. PMID- 27451508 TI - Outgoing, Incoming Boards Meet Following April's House of Delegates. PMID- 27451507 TI - Registered Dental Assistants Are in Demand! PMID- 27451509 TI - [Not Available]. PMID- 27451510 TI - [Tuberculosis screening in school health services in Geneva, Switzerland]. AB - Recent immigrantyouth have multiple health needs that need to be adapted to the context of migration. School health services provide a systematic health check to allyoung immigrants starting school in Geneva, including a tuberculin skin test if coming from a middle or high incidence country. Positive tests are confirmed with Interferon Gamma Release Assay (IGRA) and if indicated, offered treatment of latent tuberculosis even in the absence of clear guidelines. Collective and individual benefits outweigh the difficult logistics: reducing risk of reactivation of latent tuberculosis for populations living in promiscuity, effective collaboration between primary care and school health services to answer the needs of these underserved youth. PMID- 27451511 TI - [Somatic care and complications of anorexia nervosa in adolescent girls]. AB - Anorexia nervosa is a frequent condition that appears mainly during adolescence and may persist until adulthood. It can have serious consequences, which is why it must be quickly detected and treated. In this article, we describe the parameters to be followed in outpatient clinic, complications not to be missed and when a hospital treatment becomes necessary. PMID- 27451512 TI - [Assess spirituality with adolescent outpatients: taboo or necessity?]. AB - Spirituality affects adolescents' as well as adults' daily life. It is usually considered to be a protective factor in physical and psychological health outcomes, but might also be a cause of suffering. In the perspective of an holistic approach, health professional should assess this subject with tact and sensitivity. Until there is a suitable instrument adapted to this age group and European culture, the exploration of spirituality and religious practices can be evaluated while taking the clinical history. Nevertheless, resistance which is common in health professionals, could be overcome by appropriate training. PMID- 27451513 TI - [Sexual health in adolescents: how to approach it in consultation?]. AB - Adolescent's sexual health, in particular the risk of unwanted pregnancies and sexually transmitted infections (STIs), is a complex topic that deserves special attention. Confidential care and non-stigmatizing attitude as well as working with sexual health counsellors are strongly recommended. If an adolescent consults with an adult, it is beneficial to proceed stepwise in order to promote patient's autonomy and to build a relationship of trust with both of them. A focused approach of the teenager, adapted to its needs, as well as techniques such as Quick start and bridging, can improve compliance to contraception. Regarding the risk of STIs, primary prevention remains essential. The most effective prevention currently consists in systematic condom use. PMID- 27451514 TI - [Not without my family! The importance of the entourage in primary care medicine with youth]. AB - At the doctor's office primary care, symptomatology of young is often vague or nonspecific. Faced with such symptoms, via the analysis of a clinical case, significant in many clinical situations, we show the importance of considering the significant members of the entourage and invite them to the surgery. A therapeutic alliance better weaves between the youth and his doctor if the environment is taken into account and will lead to better therapeutic response. PMID- 27451515 TI - [Adolescent and physical activity: addi(c)tive excesses]. AB - Benefits of physical activity during adolescence have widely been demonstrated. Yet, raising awareness among young athletes and their surrounding about risks associated with too early specialization or energy deficit--with or without eating disorder--is of outmost importance. Such behaviours can affect adolescents' physical or psychological development as well as compromise their athletic career not to mention the potential negative impact on their athletic performance. Primary care practitioners play an important role in early detection and prevention of overuse injuries as well as psychological distress associated with intense physical activity. Such situations need the intervention of an interdisciplinary team in order to prevent long-term complications. PMID- 27451516 TI - [Assertive community treatment: promoting engagement with care of people suffering severe addiction]. AB - Despite the increasing number of specialized addiction services and the constant deployment of health care resources, a coordinated needs-based treatment is not always available for people with severe drugs and/or alcohol problems. Too often the involved health care professionals feel helpless and overwhelmed by the complexity of the situation. In order to promote the treatment engagement of the hard-to-reach substance users, a multidisciplinary mobile team project for addiction (SIMA) was developed in Lausanne, Switzerland, in 20174. This paper describes the model of intervention, the profile of the population followed during the first year of intervention and illustrates, through two clinical cases, the advantages of this approach. PMID- 27451517 TI - [Not Available]. PMID- 27451518 TI - [Not Available]. PMID- 27451519 TI - [Not Available]. PMID- 27451520 TI - [Not Available]. PMID- 27451521 TI - [Not Available]. PMID- 27451522 TI - [Not Available]. PMID- 27451523 TI - [Not Available]. PMID- 27451524 TI - [Not Available]. PMID- 27451525 TI - Proficiency testing program providers respond to client concerns. PMID- 27451526 TI - The laboratory's role in combating sepsis. PMID- 27451527 TI - Applications of nucleic acid testing in diagnosis and therapy. PMID- 27451528 TI - Laboratory Information Systems: Industry experts look ahead. PMID- 27451529 TI - Phenotypic analysis of bacterial virulence using electric cell-substrate impedance sensing. PMID- 27451530 TI - An update on Vitamin D testing: What is right for your laboratory? PMID- 27451531 TI - ACLA represents the interests of the clinical lab in an uncertain regulatory climate. PMID- 27451532 TI - Despite changes, our future holds promise. PMID- 27451533 TI - Opioids. PMID- 27451534 TI - No one wants 'Dr. J-Dubs' to examine them. PMID- 27451535 TI - Be prepared for medical emergencies. PMID- 27451536 TI - How would you like to give back? PMID- 27451537 TI - How is the Illinois budget impasse affecting dentists? PMID- 27451538 TI - Alvaro Figueroa has a mission. PMID- 27451539 TI - Happy Birthday, Code of Ethics. PMID- 27451540 TI - Free-Range, Gluten-Free, Eco-Friendly Advertising. PMID- 27451541 TI - P. Gingivalis May Increase Pancreatic Cancer Risk. PMID- 27451542 TI - The Dental Care System in California: An Analysis. PMID- 27451543 TI - Dentist Workforce Projections--California. PMID- 27451544 TI - Getting More Dentists to Participate in Medi-Cal: Insights From an Innovative Statewide Survey. PMID- 27451545 TI - Dental Care Service Delivery Within Federally Qualified Health Centers in California. PMID- 27451546 TI - The Impact of Risk-Based Care on Early Childhood and Youth Populations. AB - This quality improvement project explored dental caries risk among children residing in El Monte, Calif., a low-income area 16 miles east of Los Angeles. In an attempt to decrease oral health disparities, Western University of Health Sciences, College of Dental Medicine established school-based oral health centers in El Monte and implemented a modified caries risk assessment protocol. Results showed a statistically significant decrease in caries risk following disease management interventions. PMID- 27451547 TI - Follow-Up Protocol: When Office Staff Inadvertently Give Treatment Advice. PMID- 27451548 TI - Evaluating an Infection Control Breach. PMID- 27451550 TI - Improving health care through the supply chain. PMID- 27451549 TI - Replanted immature avulsed teeth. PMID- 27451551 TI - App enables compliant communication. PMID- 27451552 TI - Internet of Things. How can smarter technologies improve operations? PMID- 27451553 TI - The ROI of SUSTAINABILITY. Financial benefits are just the beginning. PMID- 27451554 TI - Green flooring gains ground. Sustainable materials offer numerous benefits. PMID- 27451555 TI - CRITICAL WATER DELIVERY. Designing and maintaining plumbing infrastructure. PMID- 27451556 TI - Lighting the way. LED continues to shine for design and efficiency. PMID- 27451557 TI - A look at multidrug-resistant organisms. Common superbugs and prevention strategies for health care facilities. PMID- 27451558 TI - Creating a sea change. PMID- 27451559 TI - CMS and Joint Commission Adopt 2012 Life Safety Code. PMID- 27451560 TI - Revisions Announced for Advanced Certification for Heart Failure Program. PMID- 27451561 TI - Statement on Pain Management: Understanding How Joint Commission Standards Address Pain. PMID- 27451562 TI - Testing and Maintaining Hoses, Dampers, Doors, and Other Fire Safety Equipment. A Further Examination into EC.02.03.05. PMID- 27451563 TI - Transforming the Disbursement Cycle: Four Steps for Selecting a Diversified Payment Strategy. PMID- 27451564 TI - An evolving DSH payment. AB - Updates to the Medicare inpatient prospective payment system (IPPS) will change disproportionate share hospital (DSH) payments for coming fiscal years. In FY17, changes to the calculation of Factor 2 will lower the uncompensated care DSH available for allocation. In FY18, the Centers for Medicare & Medicaid Services (CMS) will begin using uncompensated care expenses to determine a hospital's share of payments from the uncompensated care DSH pool. PMID- 27451566 TI - Thrive. PMID- 27451565 TI - Hospital inventory: the big little risk. AB - Pharmaceutical inventory management as an ancillary concern presents a risk for hospitals and health systems. Healthcare leaders should look to prevent fraud as well as legal noncompliance. Leaders should consider not only how much inventory they need but also how to store it and who to assign to handling it. PMID- 27451567 TI - The path to cost transformation. AB - A healthcare organization's efforts to strategically transform its cost structure in preparation for value-based payment invariably must begin with a systemwide assessment of cost and quality. Such an assessment should focus on three categories of performance improvement activities: margin improvement, business restructuring, and clinical transformation. A work-team approach is recommended, where teams with multidisciplinary representation assume responsibility for assessing specific areas (e.g., acute care enterprise, physician enterprise, business restructuring). PMID- 27451568 TI - Improving ED efficiency to capture additional revenue. AB - An increase in the number of patients visiting emergency departments (EDs) presents an opportunity for additional revenue if hospitals take four steps to optimize resources: Streamline the patient pathway and reduce the amount of time each patient occupies a bed in the ED. Schedule staff according to the busy and light times for patient arrivals. Perform registration and triage bedside, reducing initial wait times. Create an area for patients to wait for test results so beds can be freed up for new arrivals. PMID- 27451569 TI - The value journey: improving cost structure through performance improvement. AB - A performance improvement project helped Bronx-Lebanon Hospital Center in New York, which serves a highly indigent population, to increase efficiencies and cost savings as it moved toward value-based health care. Specific initiatives included in-depth analyses of provider and employee productivity, performed by focus teams led by executive sponsors and the department directors or managers. Through two broad phases, focusing on nonlabor and labor areas, the organization was able to realize savings amounting to more than $20 million. PMID- 27451570 TI - Optimizing revenue cycle performance before, during, and after an EHR implementation. AB - An electronic health record implementation brings risks of adverse revenue cycle activity. Hospitals and health systems can mitigate that risk by taking aproactive, three-phase approach: Identify potential issues prior to implementation. Create teams to oversee operations during implementation. Hold regular meetings after implementation to ensure the system is running smoothly. PMID- 27451571 TI - Rolling capital: managing investments in a value-based care world. AB - The importance of capital planning is increasing as the healthcare industry moves toward value-based care. Replacing unwieldy and inflexible traditional capital planning processes with a rolling capital planning approach can result in: Greater standardization, facilitating better strategic planning across the whole system. Reduced labor intensity in the planning and budgeting process. Reduced costs through being able to plan better for replacement purchases and take advantage of group purchasing and bundling opportunities. Increased transparency in the decision-making process. PMID- 27451572 TI - The right time and place for affiliating. PMID- 27451574 TI - Assessing regional differences in costs for key hospital costs centers. PMID- 27451573 TI - The CPC+ model: a grassroots approach to value-based care. PMID- 27451575 TI - House of Delegates Inaugural Address. PMID- 27451576 TI - Testifying at MAG's House of Delegates. PMID- 27451578 TI - MAG ready to get back to "job one" during the 2016 legislative session. PMID- 27451577 TI - House of Delegates Executive Director's Report. PMID- 27451579 TI - How to comply with the Physician Self-Referral Law (Stark). PMID- 27451580 TI - My renaissance. PMID- 27451581 TI - My experience with medical scribes. PMID- 27451582 TI - Code blue 309W: A student's first look at death. PMID- 27451583 TI - Lawsuits arising out of care in the ER--10 years after tort reform in Georgia. PMID- 27451584 TI - Avoiding the Medicare Advantage/Medicaid "payment gap". PMID- 27451585 TI - CMS updates Stark in important ways. PMID- 27451587 TI - Life lessons: continued. PMID- 27451586 TI - Misdiagnosed ectopic pregnancy: Another example of cognitive bias? PMID- 27451588 TI - Respiratory tuberculosis in children and adolescents: Assessment of radiological severity pattern and age-related changes within two decades. AB - INTRODUCTION: Despite the global decline of tuberculosis (TB), the annual risk of TB infection in children from developing countries remains high. Giving the global and regional epidemiological context in the past 20 years and a recent classification, dividing childhood TB into severe and non-severe disease, our aim was to find possible differences regarding disease severity in the pediatric population, as assessed by chest radiography (CXR) over 2 decades. MATERIALS AND METHOD: A retrospective analysis of CXRs from newly confirmed respiratory TB patients was performed at the Pediatric Pulmonology Department of a tertiary-care university hospital that acts as a referral TB center in Transylvania. CXRs were reviewed for all patients suffering from respiratory TB in 1994-1999 (Group A) and all respective cases from 2008-2013 (Group B). RESULTS: In the 110 respiratory TB cases identified in group A and 73 respective cases found in group B, the male:female distribution was similar, 56%-44%. In group A a severe pattern was present in 34% of patients, while in group B there were 43% of respective cases. The median age for severe disease in group A was 10 years, and 15 years in group B (p < 0.05). Furthermore, in group B there was less mediastinal lymphadenopathy (55% vs. 68% in group A), more cavities (11% vs. 6% in group A) and a significantly higher number of consolidation, 38% vs. 25% (p = 0.04). CONCLUSION: CXR findings in the pediatric population have evolved from a mainly nonsevere TB pattern to an increased prevalence of severe disease, found mostly in the adolescents. PMID- 27451589 TI - Respiratory rehabilitation in healing depression and anxiety in COPD patients. AB - Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory affection of the whole lung, characterized by an accelerated loss of the pulmonary functions, that reduces the patients' independence and stops them from having a normal, active life. The medical rehabilitation is considered "Third class rehabilitation", after preventive medicine and pharmaceutical medicine, and the respiratory rehabilitation recovery represents a complex structure of service addressing to patients with chronic pulmonary illnesses whose aim is to optimize the physical performances, psycho-social and autonomy. AIM AND OBJECTIVES: The main objective of this study is to show the importance of respiratory rehabilitation that is correctly and timely made, based on the gravity and stage of the illness, the COPD patient's associated illnesses and their importance in improving the patient's mental and physical quality of life. Patients from the study were assigned a complex pulmonary rehabilitation regimen consisting of 10 physical exercise sessions and 10 educational sessions, for two weeks, followed by 3 physical education sessions and medical education per week, for six weeks. MATERIAL AND METHOD; The research included 35 COPD patients from the 5th medical Geriatric and Gerontology. Clinic during 1.03.2014-30.11.2014. Patients from the study were assigned a complex pulmonary rehabilitation regimen consisting of 10 physical exercise sessions and 10 educational session for two weeks, followed by 3 sessions a week for 6 weeks. The dyspnea evaluation was made by BORG and MRC dyspnea scales, the quality of life was measured by St. George and CAT questionnaires, and anxiety and anxiety and depression were quantified by Hamilton Anxiety Rating Scale (HARS) and Hamilton Depression Rating Scale (HDRS). RESULTS: The gradation of dyspnea on BORG scale was correlated with the variation of the expiratory capacity that varied at COPD patients, suggesting that hyperinflation has a major role in producing the dyspnea. The average score measurement was about 75.25 +/- 5.9. the positive effects of rehab were validated by decreasing the St. George score by 16% to the initial value. Respiratory rehab was an important way of treatment due to effort tolerance increasing and the patient's independence. Depression was significantly more pronounced in women (Z = -1.876: p = 0.039). The little value of maximum respiratory volume per second (VEMS) was correlated to a bigger HARS and HDRS score. CONCLUSIONS: The prevalence and importance of symptoms of anxiety and depression in COPD patients requires a specific questionnaire as routine screening procedure, for detecting early symptoms and preventing their progress. PMID- 27451590 TI - Predictors of daytime sleepiness in patients with obstructive sleep apnea. AB - BACKGROUND: The main symptomatic criterion to diagnose obstructive sleep apnea (OSA) is the level of daytime sleepiness. The Epworth Sleepiness Scale is a simple, self-administered questionnaire which provides a measurement of the subject's general level of daytime sleepiness. The aim of this study was to investigate the factors that can predict daytime sleepiness in patients with sleep apnea. METHODS: 50 consecutive patients with obstructive sleep apnea were enrolled into the study. Age, gender, anthropometric and polygraphic data were thoroughly analyzed. In all subjects daily sleepiness was assessed by Epworth Sleepiness Scale. RESULTS: The mean age of the subjects was 54.7 +/- 12.8 years, 82% males. The mean BMI was 31.9 +/- 6 kg/m2. Pearson correlation coefficient analysis demonstrates a significant positive correlation between the Epworth Sleepiness Scale and the desaturation index (r = 0.31, p < 0.01) and arterial hypertension (r = 0.32, p < 0.01). The forward stepwise regression analysis shows that the apnea hypopnea index and desaturation index are important predictors of daytime sleepiness in patients with obstructive sleep apnea which explains 40% of the Epworth Sleepiness Scale score. CONCLUSION: The desaturation index showed the strongest correlation with the Epworth scale. According to the results of the backward stepwise multiple regression and logistic regression, the predictors for the level of daytime sleepiness are oAHI and index of desaturation. According to the analysis of the ROC curve, desaturation index is a predictor of a high specificity. PMID- 27451591 TI - Surgical and Anatomical Particularities and Difficulties in Histopathological Sampling for Superior Vena Cava Syndrome. AB - The superior vena cava syndrome is due to the increased venous pressure in the upper torso, neck and head, caused by the obstruction of the superior vena cava. Both external and internal factors cause obstruction (95% are malign causes), and the most severe manifestation is represented by cerebral edema that can even lead to coma. The diagnostic algorithm for the superior vena cava syndrome is widely known. There are many controversies and discussions about the safety of histopathological sampling. The purpose of this paper is to assess such risks, the complication rate and the diagnostic yield of surgical sampling, by analyzing the 26 interventions performed in our clinic. Although the complication rate was higher than that observed in the absence of the superior vena cava syndrome, surgery remains mandatory for a rapid histopathological diagnosis, therefore demanding a protocol that must include a mandatory extemporaneous exam of the biopsy. PMID- 27451592 TI - Asthma-like symptoms in a patient with rheumatoid arthritis and Adalimumab treatment. AB - After the introduction of anti-TNFalpha medication for treatment of autoimmune conditions, clinicians have investigated not only other possible uses for the drugs, but also less common side-effects and interactions with other pathologies. Despite some succes registered with Adalimumab as an antiinflammatory agent in severe asthma, there have been case reports of patients developing asthma or asthma-like symptoms following anti-TNFalpha therapy. The case presents a patient without previous family or personal history of respiratory or atopic conditions that developed bronchospasm immediately after the initiation of Adalimumab and Methotrexate treatment for rheumatoid arthritis. Despite the patient presenting asthma characteristics (expiratory wheezing, dry cough, partial reversibility at post bronchodilator test) and asthma medication alleviating simtomathology, biological markers (eosenophil granulocytes in sputum, serum IgE) for asthma are absent. The relationship between bronchospasm and medication and other possible causes for her respiratory symptoms are discussed. PMID- 27451593 TI - Immune reconstitution inflammatory syndrome in central nervous system tuberculosis. AB - BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) related to tuberculosis (TB) is an exacerbation of an inflammatory response that most often occurs in HIV-infected patients but it has also been observed in non-HIV immunocompromised hosts. We describe two cases of TB associated IRIS with CNS involvement, one in a patient diagnosed with HIV infection and the other in a patient with immunosuppression due to anti tumor necrosis factor treatment. CASE REPORT; The first case was a 40-year-old man, newly diagnosed with HIV infection, who developed right hemiplegia and expressive aphasia. Lumbar puncture and MRI sustained the diagnosis of TB meningoencephalitis. He initially improved understandard antituberculous therapy (ATT). After 6 weeks of ATT antiretroviral treatment (ART) was initiated and one week later the patient experienced worsening of his symptoms (left hemiparesis and mixed aphasia), of CSF and MRI changes. He improved after he was starting on corticosteroids in tapering doses, with clinical deterioration at lower doses over a 5-month period. The second case was a 56-year-old male, treated for 3 years with Infliximab for ankylosing spondylitis. He was diagnosed with disseminated TB (CNS tuberculomas and pulmonary TB), histological and bacteriological confirmed the diagnosis. His neurological symptoms improved after starting ATT but after 2 weeks of therapy he presented with diplopia and generalized tonic-clonic seizures. These symptoms improved only after corticosteroids were added (tapering doses during the next 6 months). CONCLUSION: TB-associated IRIS with CNS involvement is potentially life threatening. Corticosteroids should be used to control the IRIS symptoms in those patients. The dosing and duration should be tailored to each patient. PMID- 27451594 TI - Haemoptysis as a primary manifestation of cryptogenic organizing pneumonia (COP). AB - Cryptogenic organizing pneumonia (COP), previously called bronchiolitis obliterans organizing pneumonia (BOOP) is a clinicopathological disorder of unknown aetiology but increasingly reported. It usually presents with symptoms of dyspnea, cough, fever, weight loss accompanied by the presence of alveolar opacities on chest radiograph. Haemoptysis, described as blood streaking has only rarely been reported as primary presentation of COP. Herein, we report a case of COP in which submassive haemoptysis was the main clinical manifestation. The clinical, radiological, pathological, and therapeutic aspects of the disease are briefly discussed. Cryptogenic organizing pneumonia should be taken into consideration in the differential diagnosis of severe haemoptysis. PMID- 27451595 TI - The efficiency of continuous positive airway pressure therapy in reducing cardiovascular dysfunction in a patient with arterial hypertension and obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) has been included by European and American hypertension therapy guidelines as a common cause of high blood pressure. Recent studies have demonstrated a strong link between OSA and HBP and the treatment thereof should consist of combination therapy, especially in patients with refractory AHT and a non-dipping profile. We present the case of a patient with high grade hypertension, with secondary organ damage and severe OSA. The ultimate method for controlling blood pressure and reversing subclinical cardiac and cerebrovascular dysfunction of this patient was the specific therapy with continuous positive airway pressure (cPAP). PMID- 27451596 TI - Pneumologia's workshops: how to write a scientific article. PMID- 27451597 TI - First National Conference on Interstitial Lung Diseases. Timisoara, October 9-10. PMID- 27451598 TI - PbBr-Based Layered Perovskite Organic-Inorganic Superlattice Having Carbazole Chromophore; Hole-Mobility and Quantum Mechanical Calculation. AB - We have successfully evaluated hole mobility in a spin-coated film of a lead bromide based layered perovskite having carbazole chromophore-linked ammonium molecules as organic layer by using FET measurement. The values of hole mobility, threshold voltage and on/off ratio at room temperature were evaluated.to.be 1.7 x 10(-6) cm2 V-1 s-1, 27 V and 28 V, respectively. However, the spin-coated films on Si substrates were not so uniform compared with those on fused quartz substrates. To improve the film uniformity, we examined the relationship between substrate temperature during spin-coating and film morphology in the layered perovskite spin-coated films. The mean roughness of the spin-coated films on Si substrates was dependent on the substrate temperature. At 353 K, the mean roughness was minimized and the carrier mobility was enhanced by one order of magnitude; the values of hole mobility and threshold voltage were .estimated to be 3.4 x 10(-5) cm2 V-1 s-1, and 22 V at room temperature in a preliminary FET evaluation, respectively. In addition, we determined a crystal structure of the layered perovskite by X-ray diffraction analysis. To gain a better understanding of the observed hole transports, we conducted quantum mechanical calculations using the obtained crystal structure information. The calculated band structure of the layered organic perovskite showed that the valence band is composed of the organic carbazole layer, which confirms that.the measured hole mobility is mainly derived from the organic part of the layered perovskite. Band and hopping transport mechanisms were discussed by calculating the effective masses and transfer integrals for the 2D periodic system of the organic layer in isolation. PMID- 27451599 TI - Physical Property Evaluation of ZnO Thin Film Fabricated by Low-Temperature Process for Flexible Transparent TFT. AB - The usual silicon-based display back planes require fairly high process temperature and thus the development of a low temperature process is needed on flexible plastic substrates. A new type of flexible organic light emitting transistor (OLET) had been proposed and investigated in the previous work. By using ultraviolet/ozone (UV/O3) assisted thermal treatments on wet processed zinc oxide field effect transistor (ZnO-FET), through low-process temperature, ZnO FETs were fabricated which succeeded to achieve target drain current value and mobility. In this study, physical property evaluation of ZnO was conducted in term of their crystallinity, the increase composition of ZnO formed inside the thin film and the decrease of the carbon impurities originated from aqueous solution of the ZnO itself. The X-ray diffraction (XRD) evaluation showed UV/03 assisted thermal treatment has no obvious effect towards crystallinity of ZnO in the range of low process temperature. Moreover, through X-ray photoelectron spectroscopy (XPS) evaluation and Fourier transform infrared (FT-IR) spectroscopy evaluation, more carbon impurities disappeared from the ZnO thin film and the increase of composition amount of ZnO, when the thin film was subjected to UV/O3 assisted thermal treatment. Therefore, UV/O3 assisted thermal treatment contributed in carbon impurities elimination and accelerate ZnO formation in ZnO thin film, which led to the improvement in the electrical property of ZnO-FET in the low-process temperature. PMID- 27451600 TI - Effect of Morphology Control of Light Absorbing Layer on CH3NH3PbI3 Perovskite Solar Cells. AB - As one of the most significant components of perovskite solar cells, the perovskite light absorbing layer demands high quality to guarantee extraordinary power conversion efficiency (PCE). We have fabricated series of CH3NH3PbI3 perovskite solar cells by virtue of gas-flowing assisting (GFA), spin coating twice for the Pbl2 layer and dipping the semi-samples in a thermal CH3NH3I solution, by which some undesirable perovskite morphologies can be effectively avoided. The modified conductions have also dramatically improved the perovskite layer and elevated the coverage ratio from 53.6% to 79.5%. All the fabrication processes, except the steps for deposition of the hole transport material (HTM) and back gold electrode, have been conducted in air and an average PCE of 6.6% has been achieved by initiatively applying N,N'-bis(1-naphtyl)-N,N'-diphenyl-1,1' biphenyl-4,4'-diamine (alpha-NPD) doped by MoO3 as HTM. The CH3NH3PbI3 perovskite's morphology and its coverage ratio to the underneath TiO2 mesoporic layer are evaluated to account for the cells' performance. It has demonstrated that higher homogeneity and coverage ratio of the CH3NH3PbI3 layer have most significantly contributed to the solar cells' light conversion efficiency. Keywords: Perovskite, Solar Cell, Morphology, Coverage Ratio, Hole Transport Material. PMID- 27451601 TI - Indoor Light Performance of Coil Type Cylindrical Dye Sensitized Solar Cells. AB - A very good performance under low/diffused light intensities is one of the application areas in which dye-sensitized solar cells (DSSCs) can be utilized effectively compared to their inorganic silicon solar cell counterparts. In this article, we have investigated the 1 SUN and low intensity fluorescent light performance of Titanium (Ti)-coil based cylindrical DSSC (C-DSSC) using ruthenium based N719 dye and organic dyes such as D205 and Y123. Electrochemical impedance spectroscopic results were analyzed for variable solar cell performances. Reflecting mirror with parabolic geometry as concentrator was also utilized to tap diffused light for indoor applications. Fluorescent light at relatively lower illumination intensities (0.2 mW/cm2 to 0.5 mW/cm2) were used for the investigation of TCO-less C-DSSC performance with and without reflector geometry. Furthermore, the DSSC performances were analyzed and compared with the commercially available amorphous silicon based solar cell for indoor applications. PMID- 27451602 TI - Influence of Pentacene Interface Layer in ITO/alpha-NPD/Alq3/Al Organic Light Emitting Diodes by Time-Resolved Electric-Field-Induced Optical Second-Harmonic Generation Measurement. AB - By using I-V, EL-V, displacement current measurement (DCM) and time-resolved electric-field-induced optical second-harmonic generation (TR-EFISHG) measurement, we studied the influence of interface pentacene layer inserted between ITO and a-NPD layers in ITO/alpha-NPD/Alq3/Al OLEDs. All experiments were carried out for the OLEDs with and without a pentacene interface layer. The I-V and EL-V measurements showed the decrease of operating voltage of EL, the DCM showed the lowering of inception voltage of carrier injection by inserting a pentacene interface layer. The TR-EFISHG measurement showed the faster accumulation of holes at the interface between the a-NPD and Alq3 layers, which resulted in the relaxation of electric field of a-NPD layer accomplished by the increase of the conductivity and the increase of the electric field in the Alq3 layer. We conclude that TR-EFISHG measurement is helpful for understanding I-V and EL-V characteristics, and can be combined with other methods to give significant information which are impacted by the interface layer. PMID- 27451603 TI - Organic Light-Emitting Diodes with Heterojunction of Thiophene/Phenylene Co Oligomer Derivatives. AB - Organic light-emitting diodes are fabricated by heterojunction of thiophene/phenylene co-oligomer films using biphenyl-capped bithiophene (BP2T) and its cyano-substituted derivative (BP2T-CN). Strong electron-withdrawing cyano groups in BP2T-CN transform the p-type BP2T into n-type. Photoluminescence and electroluminescence from their bilayered films dominantly result from the BP2T-CN layer since the lying molecular orientation of BP2T-CN facilitates surface emission while the standing orientation of BP2T is not suitable for the device configuration. The current density and electroluminescence intensity are considerably increased by carrier doping with MoO3 and Cs2CO3 into the BP2T and BP2T-CN films, respectively. PMID- 27451604 TI - Amplified Emission and Field-Effect Transistor Characteristics of One Dimensionally Structured 2,5-Bis(4-biphenylyl)thiophene Crystals. AB - One-dimensional (1D) structures of 2,5-bis(4-biphenylyl)thiophene (BP1T) crystals are fabricated for light amplification and field-effect transistor (FET) measurements. A strip-shaped 1D structure (10 um width) made by photolitography of a vapor-deposited polycrystalline film shows amplified spontaneous emission and lasing oscillations under optical pumping. An FET fabricated with this 1D structure exhibits hole-conduction with a mobility of uh = 8.0 x 10(-3) cm2/Vs. Another 1 D-structured FET is fabricated with epitaxially grown needle-like crystals of BP1T. This needle-crystal FET exhibits higher mobility of uh = 0.34 cm2/Vs. This improved hole mobility is attributed to the single-crystal channel of epitaxial needles while the grain boudaries in the polycrystalline 1 D structure decrease the carrier transport. PMID- 27451605 TI - Enhanced Photocurrent Generation from Bacteriorhodopsin Photocells Using Grating Structured Transparent Conductive Oxide Electrodes. AB - We fabricated a grating-structured electrode made of indium-doped zinc oxide (IZO) with a high refractive index (approximately 2) for a bacteriorhodopsin (bR) photocell. We investigated the photocurrent characteristics of the bR photocell and demonstrated that the photocurrent values from the bR/IZO electrode with the grating structure with a grating period of 340 nm were more than 3.5-4 times larger than those without the grating structure. The photocurrent enhancement was attributed to the resonance effect due to light coupling to the grating structure as well as the scattering effect based on the experimental results and analysis using the photonic band structure determined using finite-difference time-domain (FDTD) simulations. The refractive index of the bR film in electrolyte solution (1.40) used in the FDTD simulations was estimated by analyzing the extinction peak wavelength of 20-nm gold colloids in the bR film. Our results indicate that the grating- or photonic-crystal-structured transparent conductive oxide (TCO) electrodes can increase the light use efficiency of various bR devices such as artificial photosynthetic devices, solar cells, and light-sensing devices. PMID- 27451606 TI - N-Type Conductive Polymer Having a Concept of Self-Dope: --Poly(P methylpyridinium vinylene)--. AB - Novel self-doped n-type conducting polymer, poly(p-methylpyridinium vinylene), PMePyV were synthesized by using the quaternization of poly(p-pyridyl vinylene), PPyV and several regiochemical consequences in this polymer were proposed. The electrical, optical, and, electrochemical properties of self-doped n-type conductive polymer were observed. In addition, a possibility of a variety of functional applications of self-doped n-type conductive polymer was indicated. PMID- 27451607 TI - Temperature Dependence of Field-Effect Mobility in Organic Thin-Film Transistors: Similarity to Inorganic Transistors. AB - Carrier transport in solution-processed organic thin-film transistors (OTFTs) based on dioctylbenzothienobenzothiophene (C8-BTBT) has been investigated in a wide temperature range from 296 to 10 K. The field-effect mobility shows thermally activated behavior whose activation energy becomes smaller with decreasing temperature. The temperature dependence of field-effect mobility found in C8-BTBT is similar to that of others materials: organic semiconducting polymers, amorphous oxide semiconductors and hydrogenated amorphous silicon. These results indicate that hopping transport between isoenergetic localized states becomes dominated in a low temperature regime in these materials. PMID- 27451608 TI - Chemical Vapor Deposition of MoS2: Insight Into the Growth Mechanism by Separated Gas Flow Experiments. AB - We report detailed experiments on chemical vapor deposition of an atomic' layer semiconductor MoS2. We developed a new type of CVD system in which MoO3 and S sources are separately supplied to the substrates. It has become possible to precisely control the supply of the materials separately in the order of seconds. Raman and XPS analysis of the films grown under various conditions revealed that the initially obtained films are S-deficient and complete stoichiometry is reached after several minutes under S vapor flow. PMID- 27451609 TI - Printable Organic Light-Emitting Devices and Application for Optical Signal Transmission. AB - Organic light emitting devices, in particular, properties of polymer light emitting transistors with printed electrodes and bilayer printed devices with in plane emission have been investigated and discussed. The semitransparent device based on poly(9,9-dioctylfluorene-co-benzothiadiazole) (F8BT) with Ag-nanowire source/drain and transparent carbon nanotube gate electrodes exhibits ambipolar and light-emitting characteristics. For the devices with oriented poly(9,9 dioctylfluorene) (F8) films, enhanced electron and hole field-effect mobilities have been achieved by aligning the polymer chains parallel to the transport direction. The bilayer device using F8BT lower layer and oriented F8 upper layer with the channel direction parallel to the polymer orientation exhibits improved EL intensity and higher external quantum efficiency than that with the channel direction perpendicular to the polymer chains orientation. The optical pulses of more than 100 Hz frequency are generated by directly modulating a bilayer device with an in-plane emission pattern. PMID- 27451610 TI - Optical Degradation of Colloidal Eu-Complex Embedded in Silica Glass Film Using Reprecipitation and Sol-Gel Methods. AB - A reprecipitation method has been investigated for fabricating colloidal nanoparticles using Eu-complex. Herein, we investigated optical degradation characteristics of (1,10-phenanthroline)tris [4,4,4-trifluoro-1-(2-thienyl)-1,3 butanedionato]europium(III) colloidal nanoparticles, which were embedded into a silica glass film fabricated by a conventional sol-gel process. At first, we tried several types of good solvents for the reprecipitation method, and dimethyl sulfoxide (DMSO) is found to be a suitable solvent for realizing the small diameter and the high long-term stability against the ultraviolet irradiation even though the boing point of DMSO is higher than that of water used as a poor solvent. By optimizing the good solvent and the concentration of Eu-complex, the relative photoluminescence intensity of 0.96 was achieved even though the ultraviolet light was continuously irradiated for 90 min. In addition, the average diameter of 106 nm was achieved when DMSO was used as a good solvent, resulting in the high transmittance at a visible wavelength region. Therefore, we can achieve the transparent emissive thin film with a center wavelength of 612 nm, and the optical degradation was drastically reduced by forming nanoparticles. PMID- 27451611 TI - Investigating the Influence of Alkyl Chain Length in Poly(3-alkylthiophene)s Over the Thin Film Morphology by Optical and Electrical Characterization. AB - This paper studies the influence of alkyl-chain length in poly(3-alkylthiophene)s over the morphology of thin films and electrical parameters of the devices based on it. Regioregular poly(3-hexylthiophene) and poly(3-octylthiophene) were chosen as the semiconducting materials for the study. The morphological variations were studied by absorption spectroscopy, photoluminescence spectroscopy and X-ray diffraction study. The absorption and photoluminescence showed decreased coplanarity of main chain in poly(3-octylthiophene) over poly(3-hexylthiophene) and which was later confirmed using X-ray diffraction studies which clearly showed increased interchain spacing in case of poly(3-octylthiophene). The schottky diodes fabricated using these materials showed decreased mobility in poly(3-octylthiophene) based diodes as measured by space-charge limiting current method and photo-induced charge carrier extraction by linearly increasing voltage technique. Moreover, we observed a negative field dependence of mobility at room temperature in both the devices and attributed this to the presence of dominant positional disorder in poly(3-alkylthiophene)s. Furthermore, the photocurrent dependence on electric field too showed inferior mobility of poly(3 octylthiophene) based diodes. PMID- 27451612 TI - Interfacial Energy Alignment at the ITO/Ultra-Thin Electron Selective Dielectric Layer Interface and Its Effect on the Efficiency of Bulk-Heterojunction Organic Solar Cells. AB - We have investigated the photovoltaic properties of an inverted bulk heterojunction (BHJ) cell in a device with an indium-tin-oxide (ITO)/electron selective layer (ESL)/P3HT:PCBM active layer/MoOx/Ag multilayered structure. The insertion of only single layer of poly(diallyl-dimethyl-ammonium chloride) (PDDA) cationic polymer film (or poly(ethyleneimine) (PEI) polymeric interfacial dipole layer) and titanium oxide nanosheet (TN) films as an ESL effectively improved cell performance. Abnormal S-shaped curves were observed in the inverted BHJ cells owing to the contact resistance across the ITO/active layer interface and the ITO/PDDA/TN/active layer interface. The series resistance across the ITO/ESL interface in the inverted BHJ cell was successfully reduced using an interfacial layer with a positively charged surface potential with respect to ITO base electrode. The positive dipole in PEI and the electronic charge phenomena at the electrophoretic deposited TN (ED-TN) films on ITO contributed to the reduction of the contact resistance at the electrode interface. The surface potential measurement revealed that the energy alignment by the transfer of electronic charges from the ED-TN to the base electrodes. The insertion of the ESL with a large positive surface potential reduced the potential barrier for the electron injection at ITO/TN interface and it improved the photovoltaic properties of the inverted cell with an ITO/TN/active layer/MoOx/Ag structure. PMID- 27451613 TI - Influence of Parametric Variations on Hydrothermal Growth of ZnO Nanostructures for Hybrid Polymer/ZnO Based Photodetector. AB - Dumbbell and flower like ZnO nano-crystals were grown via hydrothermal process. The as-prepared dumbbells, with length of 0.8-10 um and edge length of 0.3-0.8 um possess a hexagonal structure, while flowers with lengths ranging from 1-6 um with hexagonal structure have been synthesized. The effect of temperature, solution concentration and growth time on the size and shapes of the ZnO nanostructures has been studied using Field emission scanning electron microscope (FESEM) and X-ray diffractometer (XRD). Further the optical properties of nanostructures were investigated by Photoluminescence (PL) spectroscopy, which shows emission in UV and visible regions. From Diffused reflectance spectroscopic analysis (DRA) it was observed that ZnO nanodumbbells and nanoflowers have a direct band gap of 3.27 eV and 3.25 eV respectively. The I-V plot showed dependence of current values under dark and illumination over the annealing temperature during the growth stage. Thus we report a control over the shape and dimension of nanostructures by varying various parameters having implications for (opto)electronic devices. PMID- 27451614 TI - Emission Behavior of Crystalline 1,4-Bis(4-phenylthiophene-2-yl)benzene Film Under Optical Excitation with Ultra Short Pulses. AB - We evaluated emission behaviors of crystallized films of 1,4-bis(5 phenylthiophene-2-yl)benzene (AC5) in detail which was a representative thiophene/phenylene co-oligomer. The crystallized AC5 films were prepared by vapor deposition onto a substrate and thermal treatment. The AC5 films consisted of a crystalline domain with the size of several tens of micrometers. We used femtosecond laser pulses for the excitation of the AC5 films. As a result, the femtosecond laser pulses did not induce re-absorption above excitation energy densities of their laser threshold. The obtained gain value for AC5 crystallized film was large, over 150 cm-1. Furthermore, the emission cross section of the crystallized AC5 film was nearly 10(-16) cm2. PMID- 27451615 TI - Partial Dissolution of Charge Order Phase Observed in beta-(BEDT-TTF)2PF6 Single Crystal Field Effect Transistor. AB - The effect of an applied gate electric field on the charge-order phase in beta (BEDT-TTF)2PF6 single-crystal field-effect transistor structure was observed at around room temperature by technical improvement with respect to sample preparation and electrical measurements. A relatively slight but systematic increase of the electrical conductance induced by the applied gate electric field and its temperature dependence was observed at around the metal-insulator transition temperature (TMI). The temperature dependence of the modulated electrical conductance demonstrated that TMI was shifted toward the lower side by application of a gate electric field, which corresponds to partial dissolution of the charge-order phase. The thickness of the partially dissolved charge order region was estimated to be several score times larger than the charge accumulation region. PMID- 27451616 TI - High-Mobility 6,13-Bis(triisopropylsilylethynyl) Pentacene Transistors Using Solution-Processed Polysilsesquioxane Gate Dielectric Layers. AB - Polysilsesquioxane (PSQ) is a low-temperature curable polymer that is compatible with low-cost plastic substrates. We cured PSQ gate dielectric layers by irradiation with ultraviolet light at ~60 degrees C, and used them for 6,13 bis(triisopropylsilylethynyl) pentacene (TIPS-pentacene) thin film transistors (TFTs). The fabricated TFTs have shown the maximum and average hole mobility of 1.3 and 0.78 +/- 0.3 cm2V-1s-1, which are comparable to those of the previously reported transistors using single-crystalline TIPS-pentacene micro-ribbons for their active layers and thermally oxidized SiO2 for their gate dielectric layers. Itis therefore demonstrated that PSQ is a promising polymer gate dielectric material for low-cost organic TFTs. PMID- 27451617 TI - Influence of Temperature Variation on Field Effect Transistor Properties Using a Solution-Processed Liquid Crystalline Semiconductor, 8TNAT8. AB - In this study, we used a liquid crystalline (LC) semiconductor, 8TNAT8, solution (e.g., 0.1 wt% in toluene) for forming an organic semiconductor layer by solution casting method, and fabricated bottom-gate/bottom-contact type field effect transistors (FETs). These LC semiconductors show FET characteristic properties and have high carrier mobility of 0.01 cm2 V-1 s-1. We have investigated the surface morphology and the influence of temperature variation on LC FET properties across the phase transition from crystal to mesophase of a LC semiconductor, 8TNAT8. In the most cases, FET mobility was irreversibly decreased after. temperature heat stress above the melting point of 8TNAT8, owing to the morphological change of LC layer. PMID- 27451618 TI - Design of Far-Red Sensitizing Squaraine Dyes Aiming Towards the Fine Tuning of Dye Molecular Structure. AB - Model squaraine dyes having sharp and narrow absorptions mainly in the far-red wavelength region has been logically designed, synthesized and used for their application as sensitizer in the dyesensitized solar cells (DSSC). In order to have fine control on energetics, dyes having same mother core and alkyl chain length varying only in molecular symmetry and position of substituent were designed. It has been found that even keeping all other structural factor constant, only positional variation of substituent leads to not only in the variation of energetics by 0.1 eV but affects the photovoltaic characteristics also. Optimum concentration of dye de-aggregating agent was found to be 100 times with respect to the sensitizing dye concentration. Amongst dyes utilized in this work best performance was obtained for unsymmetrical dye SQ-40 giving a photoconversion efficiency of 4.01% under simulated solar irradiation at global AM 1.5. PMID- 27451619 TI - Synthesis of Vertically-Aligned Carbon Nanotubes from Langmuir-Blodgett Films Deposited Fe Nanoparticles on Al2O3/Al/SiO2/Si Substrate. AB - In order to apply vertically-aligned carbon nanotubes (VA-CNTs) to a new Pt supporting material of polymer electrolyte fuel cell (PEFC), number density and outer diameter of CNTs must be controlled independently. So, we employed Langmuir Blodgett (LB) technique for depositing CNT growth catalysts. A Fe nanoparticle (NP) was used as a CNT growth catalyst. In this study, we tried to thicken VA-CNT carpet height and inhibit thermal aggregation of Fe NPs by using Al2O3/Al/SiO2/Si substrate. Fe NP LB films were deposited on three typed of substrates, SiO2/Si, as-deposited Al2O3/Al/SiO2/Si and annealed Al2O3/Al/SiO2/Si at 923 K in Ar atmosphere of 16 Pa. It is known that Al2O3/Al catalyzes hydrocarbon reforming, inhibits thermal aggregation of CNT growth catalysts and reduces CNT growth catalysts. It was found that annealed Al2O3/Al/SiO2/Si exerted three effects more strongly than as-deposited Al2O3/Al/SiO2/Si. VA-CNTs were synthesized from Fe NPs C16 LB films by thermal chemical vapor deposition (CVD) method. As a result, at the distance between two nearest CNTs 28 nm or less, VA-CNT carpet height on annealed Al2O3/Al/SiO2/Si was about twice and ten times thicker than that on SiO2/Si and that on as-deposited Al2O3/Al/SiO2/Si, respectively. Moreover, distribution of CNT outer diameter on annealed Al2O3/Al/SiO2/Si was inhibited compared to that on SiO2/Si. These results suggest that since thermal aggregation of Fe NPs is inhibited, catalyst activity increases and distribution of Fe NP size is inhibited. PMID- 27451620 TI - Wettability Control of Gold Surfaces Modified with Benzenethiol Derivatives: Water Contact Angle and Thermal Stability. AB - The water wettability of Au surfaces has been controlled using various benzenethiol derivatives including 4-methylbenzenethiol, pentafluorobenzenethiol, 4-flubrobenzenethiol, 4-methoxy-benzenethiol, 4-nitrobenzenethiol, and 4 hydroxybenzenethiol. The water contact angle of the Au surface modified with the benzenethiol derivative was found to vary in the wide range of 30.9 degrees to 88.3 degrees . The contact angle of the modified Au films annealed was also measured in order to investigate their thermal stability. The change in the contact angle indicated that the modified surface is stable at temperatures below about 400 K. Meanwhile, the activation energy of desorption from the modified surface was estimated from the change in the contact angle. The modified Au surface was also examined using X-ray photoelectron spectroscopy. PMID- 27451621 TI - Effect of Addition of KI on the Hydrothermal Growth of ZnO Nanostructures Towards Hybrid Optoelectronic Device Applications. AB - We report the structural and optoelectronic properties of Zinc oxide (ZnO) nanostructures prepared by hydrothermal method. The morphological, structural and optical properties of the grown ZnO nanostructures were investigated using X-ray diffraction (XRD), scanning electron microscope (SEM) and photoluminescence spectroscopy (PL) respectively. Upon addition of relatively small amount of KI during the in-situ hydrothermal growth the nanorods were formed, further increasing the concentration led to increased diameter of these nanorods and finally at relatively higher concentration of KI, ZnO nanosheets were formed. Later these structures were used to fabricate bi-layer ZnO/P3HT based hybrid photodiode. Subsequent hybrid photodiode measurement with ZnO nanorods and ZnO nanosheets indicated that the nanosheets exhibited improved photodiode response. Compared to the ZnO nanorod/P3HT devices, the optimized photodiode with the dense ZnO nanosheets/P3HT have shown significant increase in the rectification ratio and the photosenstivity from 3.21 to 1420 and from 5.85 to 1330 respectively. The enhanced photodiode response of bi-layered devices consisting of ZnO nanosheets indicated that optimizing the shape and size of ZnO nanostructures had a significant influence on the overall photocurrent and the observed results have been explained on the basis of reduction in the defect density with pronounced absorption in the UV region, thus leading to improved transmission of light in the visible range through these layers. PMID- 27451622 TI - Fabrication of Vertical Molecular Junction Devices with Conductive Polymer Contacts Using a Peeling Method. AB - We present a simple technique for patterning Au top electrodes in vertical molecular junction devices that have the conductive polymer, poly(3,4-ethylene dioxythiophene)-poly(4-styrene sulfonate) ( PEDOT: PSS), as a contact layer between the self-assembled monolayer and the Au top electrode. In this method, a thermally curable photoresist of SU-8 is used to define the areas where the top electrodes are formed. The hydrophobicity and low surface energy of the cured SU 8 facilitates selective deposition of PEDOT: PSS onto the defined top electrode areas of the device through solution dewetting, and also enables the physical peeling of the Au top electrodes deposited on the SU-8 layers using an adhesion tape. Through this approach, vertical molecular junctions with patterned Au top electrodes can be fabricated without employing the shadow mask evaporation process used in the conventional approach. We processed vertical molecular tunneling devices based on self-assembled alkanedithiol monolayers with an active area of 100 um2. PMID- 27451623 TI - Spectrally-Narrowed Emissions from Organic Crystals Having a One-Dimensional Grating on Their Surface. AB - We have succeeded in directly engraving one-dimensional diffraction gratings on the surface of organic semiconducting oligomer crystals by using focused ion beam (FIB) lithography and laser ablation (LA) methods. The FIB method enabled us to shape the gratings with varying periods down to ~150 nm. With the LA method a large-area grating with a ~500-nm period was readily accessible. All the above crystals indicated spectrally-narrowed emission (SNE) lines even in the case of shallow groove depths ~2-4 nm. In particular, we definitively observed the SNE pertinent to the first-order diffraction with the crystal having the diffraction grating of a 148.3-nm average period. The present results indicate utility of the built-in gratings that can directly be fabricated on the surface of the crystals. PMID- 27451624 TI - Molecular Packing Structure of Mesogenic Octa-Hexyl Substituted Phthalocyanine Thin Film by X-ray Diffraction Analysis. AB - The molecular packing structure in a thin film of the liquid crystalline phthalocyanine, 1,4,8,11,15,18,22,25-octahexylphthalocyanine (C6PcH2), which is a promising small-molecular material for solution-processable organic thin-film solar cells, has been investigated by X-ray diffraction (XRD) measurement. The crystal structure of C6PcH2 in the spin-coated film was determined to be a centered rectangular structure (a = 36.4 A, b = 20.3 A). The tilt angle of the phthalocyanine core normal vector was 34-39 degrees from the column axis, and the shortest intermolecular distance was 3.9-4.0 A. The crystal structure determined by XRD analysis was ascertained to be consistent with that calculated by Fourier analvsis. PMID- 27451625 TI - Effects of Bimolecular Recombination on Impedance Spectra in Organic Semiconductors: Analytical Approach. AB - An analytical expression for impedance spectra in the case of double injection (both electrons and holes are injected into an organic semiconductor thin film) has been derived from the basic transport equations (the current density equation, the continuity equation and the Possion's equation). Capacitance frequency characteristics calculated from the analytical expression have been examined at different recombination constants and different values of mobility balance defined by a ratio of electron mobility to hole mobility. Negative capacitance appears when the recombination constant is lower than the Langevin recombination constant and when the value of the mobility balance approaches unity. These results are consistent with the numerical results obtained by a device simulator (Atlas, Silvaco). PMID- 27451626 TI - Investigation of Ultraviolet Light Curable Polysilsesquioxane Gate Dielectric Layers for Pentacene Thin Film Transistors. AB - Polysilsesquioxane (PSQ) comprising 3-methacryloxypropyl groups was investigated as an ultraviolet (UV)-light curable gate dielectric-material for pentacene thin film transistors (TFTs). The surface of UV-light cured PSQ films was smoother than that of thermally cured ones, and the pentacene layers deposited on the UV Iight cured PSQ films consisted of larger grains. However, carrier mobility of the TFTs using the UV-light cured PSQ films was lower than that of the TFTs using the thermally cured ones. It was shown that the cross-linker molecules, which were only added to the UV-light cured PSQ films, worked as a major mobility limiting factor for the TFTs. PMID- 27451627 TI - Catalytic Improvement on Counter Electrode of Dye-Sensitized Solar Cells Using Electrospun Pt Nano-Fibers. AB - A dye-sensitized solar cell is one of cost-competitive photovoltaic devices. For higher performance, all components have been actively studied and improved. However, Pt is still a dominant catalyst since first development although some catalytic materials were studied so far. Catalytic materials of counter electrode play an important role in the performance because it supplies electrons from counter electrode to electrolyte. Therefore, the catalytic activation of counter electrode is closely connected with the performance enhancement. In this work, Pt nano-fiber was fabricated by electrospinning and applied for the counter electrode. Its wide surface area is advantageous for good conductivity and catalytic activation. Morphological characteristics of nano-fibers were analyzed according to electrospinning conditions. Photovoltaic properties, cyclic voltammetry, impedance analysis verified the catalytic activation. Consequently, dye-sensitized solar cell with Pt nano-fiber electrospun at 5.0 kV of applied voltage had higher performance than conventional dye-sensitized solar cell with Pt thin film. This work is significant for related researches because all nano fibers counter electrode material proposed so far never exceeded the performance of conventional Pt counter electrode. PMID- 27451628 TI - Enhancement of Exciton Emission in Lead Halide-Based Layered Perovskites by Cation Mixing. AB - Spin-coated films of a lead halide, PbX: X = I and Br, layered perovskites having cyclohexenylethyl ammonium molecule as an organic layer, which were mixed with other metal halide-based layered perovskites consisting of various divalent metal halides (for example, Ca2, Cdl2, FeI2, SnBr2 and so on), were prepared. The results of X-ray diffraction measurements exhibited that solid solution formation between PbX-based layered perovskite and other divalent metal halide-based layered perovskites was observed up to very high molar concentration of 50 molar% in the mixed film samples when divalent cations having ionic radius close to that of Pb2+ were employed. In the solid solution films, the exciton emission was much enhanced at room temperature. Exciton emission intensity of Pbl-based layered perovskite mixed with Cal-based layered perovskite (20 molar%) is about 5 times large that of the pristine Pbl-based layered perovskite, and that of PbBr-based layered perovskite mixed with SnBr-based layered perovskite (20 molar%) was also about 5 times large that of the pristine PbBr-based layered perovskite at room temperature. PMID- 27451629 TI - Actuation Behavior of Polylactic Acid Fiber Films Prepared by Electrospinning. AB - A poly-DL-lactide (PLA) fiber film was prepared using the electrospinning method. This film consisted of randomly oriented PLA nanofibers. Consequently, it had sponge-like structure and was quite soft compared to PLA films prepared by spin coating. The average diameter of the fibers and the density of the film were 730 nm and 20%, respectively. By applying a voltage, the PLA film was subjected to electric-field-induced strain: expansion and compression in the thickness direction. When a voltage of -200 V was applied to the film, its thickness shrank from 13.5 um to 10.0 um (a 26% reduction). Electric-field-induced strain can occur via two different mechanisms: The first is electrostrictive behavior. That. is, in a highly electric field region, a change of film thickness occurs (compression only) from the electrostatic force between electrodes. The second mechanism is piezoelectric-like behavior that occurs in racemic PLA, wherein a PLA nanofiber is expanded and compressed by applying positive and negative voltage. Such piezoelectric-like behavior was not observed in spin-coated PLA films. PMID- 27451630 TI - Simple Calculation of Power Conversion Efficiency of PC61BM and PC71 BM Based Organic Solar Cells--Good Agreement with Experiments in Donor Materials with Different Band Gap Energies. AB - The power conversion efficiencies (PCEs) as a function of band gap energies and the lowest unoccupied molecular orbital (LUMO) levels of donor materials are studied in bulk-heterojunction organic solar cells (OSCs) fabricated from donor materials and fullerene acceptors. The PCEs of [6,6]-pheynl-C61-butyric acid methyl ester (PC61BM) and [6,6]-pheynl-C71-butyric acid methyl ester (PC71 BM) based OSCs blended with donor materials under the Air Mass 1.5 (AM1.5) spectrum are calculated. In the calculation, the short circuit current densities are determined by band gap energies of donor materials and the open circuit voltages are derived from the difference between the highest occupied molecular orbital (HOMO) levels of donor materials and LUMO levels of PC61BM and PC71 BM. The calculation is in good agreement with the experiments. The PCEs under a fluorescent lamp are also calculated. The calculated PCEs of PC71 BM based OSCs under a fluorescent lamp are higher than those under the AM1.5 spectrum by a factor of 2. The PCEs of thieno [3,4-b] thiophene and benzodithiophene (PTB7):PC71BM based OSCs are studied under the AM1.5 spectrum and a fluorescent lamp spectrum and are consistent with the calculation. PMID- 27451631 TI - Transport Characteristics of the Organic Field-Effect Transistors Based on Charge Transfer Complex as Semiconductors. AB - The n-type organic field-effect transistors are fabricated with using four kinds of charge transfer (CT) complexes with PXX (peri-xanthenoxanthene) as a donor component. The CT complexes with four kinds of acceptors form mixed-stack type one-dimentional columns with different PXX-acceptor overlaps. Comparison of the field-effect properties reveals the correlation between the device performance and intermolecular interaction in the semiconducting CT complexes. PMID- 27451632 TI - Opportunities for Low Cost Processing of Erbium 8-Quinolinolates for Active Integrated Photonic Applications. AB - Erbium-doped organic emitters are promising active materials for Photonic Integrated Circuits (PICs) due to their emission shown at 1550 nm combined to the potential low cost processing. In particular, Erbium Quinoline (ErQ) gained a strong interest in the last decade for the good emission efficiency. This contribution reports the results derived from the application of ErQ as active core material within a buried optical waveguide, following the development of a purposed optical process to control the refractive index of ErQ and then to define a patterned structure from a single thin film deposition step. The reported results show the potential of Er-doped organic materials for low cost processing and application to planar PICs. PMID- 27451633 TI - Study of Electrical Conduction Mechanism of Organic Double-Layer Diode Using Electric Field Induced Optical Second Harmonic Generation Measurement. AB - By using electric field induced optical second harmonic generation (EFISHG) and current voltage (I-V) measurements, we studied the electrical transport mechanism of organic double-layer diodes with a structure of Au/N, N'-di-[(1-naphthyl)-N, N'-diphenyl]-(1,1'-biphenyl)-4,4'-diamine (a-NPD)/poly(methyl methacrylate) (PMMA)/indium zinc oxide (IZO). Here the alpha-NPD is a carrier transport layer and the PMMA is an electrical insulating layer. The current level was very low, but the I-V characteristics showed a rectifying behavior. The EFISHG measurement selectively and directly probed the electric field across the alpha-NPD layer, and showed that the electric field across the a-NPD layer is completely relaxed owing to the charge accumulation at the a-NPD/PMMA interface in the region V > 0, whereas the carrier accumulation was not significant in the region V < 0. On the basis of these experimental results, we proposed a model of the rectification. Further, by coupling the I-V characteristics with the EFISHG measurement, the I-V characteristics of the diodes were well converted into the current-electric field (I-E) characteristics of the alpha-NPD layer and the PMMA layer. The I-E characteristics suggested the Schottky-type conduction governs the carrier transport. We conclude that the I-V measurement coupled with the EFISHG measurement is very useful to study carrier transport mechanism of the organic double-layer diodes. PMID- 27451634 TI - Degradation of Bilayer Organic Light-Emitting Diodes Studied by Impedance Spectroscopy. AB - The degradation of bilayer organic light-emitting diodes (OLEDs) with a device structure of N,N'-di(1-naphthyl)-N,N'-diphenylbenzidine (alpha-NPD) (hole transport layer) and tris-(8-hydroxyquinolate)aluminum (Alq3) (emissive layer and electron transport layer) has been studied by impedance spectroscopy and device simulation. Two modulus peaks are found in the modulus spectra of the OLEDs below the electroluminescence threshold. After aging of the OLEDs, the intensity of electroluminescence is degraded and the modulus peak due to the Alq3 layer is shifted to lower frequency, indicating that the resistance of the Alq3 layer is increased. Device simulation reveals that the increase in the resistance of the Alq3 layer is due to the decrease in the electron mobility in the Alq3 layer. PMID- 27451635 TI - Cytocompatibility of HeLa Cells to Nano-Sized Ceramics Particles. AB - In this study, we investigated the behaviors and cytocompatibility response of human cervical carcinoma (HeLa) cells expose to nano-sized particles. Cultivated cells exposed to titanium oxide and indium oxide nanoparticles remained highly viable. In the presence of copper oxide (CuO); however, the cells became seriously inflamed. To understand the mechanism by which CuO causes cell death, we evaluated cell death and apoptosis cytometry. CuO induced cells apoptosis more strongly than exposure to titania nanoparticles. Confocal fluorescence microscopy revealed that the nano-sized particles penetrate the cells. PMID- 27451636 TI - Evaluation of Thermal Stability of Organic Electro-Optic Device by Using Thermally Stimulated Current. AB - Thermally stimulated current (TSC) measurement was employed to study the thermal stability of electro-optic (EO) polymers, i.e., guest/host polymer DR1/PMMA and side-chain polymer PMMA-co-DR1. Here the isothermal relaxation test showed that the relaxation time tau (85 degrees C) of side-chain polymer PMMA-co-DR1 is longer than that of guest/host polymer DR1/PMMA. TSC peaks appeared symmetrically in proportion to the poling electric field Ep, indicating that DR1 molecules make a dominant contribution to dipolar depolarization. Thermal sampling (TS) method showed that the activation energy of the DR1/PMMA is around 1 eV, while that of the PMMA-co-DR1 is distributed >1 eV. Results suggested that side-chain polymer is preferable to the guest/host polymer in the thermal stability. TSC measurement is helpful as a conventional method for studying the life time of EO polymers in terms of dipolar motion. PMID- 27451637 TI - Scanning Electron Microscopy Observation of Interface Between Single Neurons and Conductive Surfaces. AB - Interfaces between single neurons and conductive substrates were investigated using focused ion beam (FIB) milling and subsequent scanning electron microscopy (SEM) observation. The interfaces play an important role in controlling neuronal growth when we fabricate neuron-nanostructure integrated devices. Cross sectional images of cultivated neurons obtained with an FIB/SEM dual system show the clear affinity of the neurons for the substrates. Very few neurons attached themselves to indium tin oxide (ITO) and this repulsion yielded a wide interspace at the neuron-ITO interface. A neuron-gold interface exhibited partial adhesion. On the other hand, a neuron-titanium interface showed good adhesion and small interspaces were observed. These results are consistent with an assessment made using fluorescence microscopy. We expect the much higher spatial resolution of SEM images to provide us with more detailed information. Our study shows that the interface between a single neuron and a substrate offers useful information as regards improving surface properties and establishing neuron-nanostructure integrated devices. PMID- 27451638 TI - Carrier Transport Mechanism in Single Crystalline Organic Semiconductor Thin Film Elucidated by Visualized Carrier Motion. AB - Time-resolved microscopic second harmonic generation (TRM-SHG) measurement was conducted to evaluate temperature dependence of the anisotropic carrier transport process in 6,13-Bis(triisopropylsilylethynyl) (TIPS) pentacene single crystalline domains for two orthogonal directions. Enhancement of the electric field induced SHG (EFI-SHG) signal at the electrode edge at low temperature suggests the presence of potential drop in the injection process. We directly evaluated temperature dependence of the carrier mobility by taking into account the potential drop, and concluded that the Marcus theory is appropriate to interpret the carrier transport in anisotropic TIPS pentacene thin film. TRM-SHG method is a facile and effective way to directly visualize transport process in anisotropic materials and to evaluate injection and transport processes simultaneously. PMID- 27451639 TI - Preparation of Chiral Polydiacetylene Films by Using Three-Photon Polymerization. AB - Asymmetric polymerization of polydiacetylene (PDA) from commercially available achiral derivative of diacetylene monomer using circularly polarized pulse laser is demonstrated. Chiral source was only circularly polarized laser, and irradiation of left- and right-circularly polarized light effectively promoted the polymerization of chiral PDAs with opposite handedness. Difference between the laser wavelength and the absorption peak of monomer suggested the contribution of the multiphoton excitation to the photo-polymerization. Laser power dependence of the polymerization rate indicated the possibility of three photon polymerization. PMID- 27451640 TI - Fabrication and Measurement of Electroluminescence and Electrical Properties of Organic Light-Emitting Diodes Containing Mott Insulator Nanocrystals. AB - By using the short-time electrocrystallization technique, phthalocyanine (Pc) based Mott insulator Co(Pc)(CN)2 . 2CHCl3 nanocrystals were fabricated and applied to organic light-emiting diodes (OLEDs). The fabricated device having the configuration ITO/Co(Pc)(CN)2 . 2CHCl3/Alq3/Al, in which ITO is indium-tin oxide and Alq3 is tris(8-hydroxyquinolinato)aluminum, showed clear emission from Alq3, suggesting the Mott insulator Co(Pc)(CN)2 . 2CHCl3 can work as useful hole injection and transport material in OLEDs. PMID- 27451641 TI - Hybrid Organic-Inorganic Solar Cells with Electrodeposited Al-Doped Zinc Oxide. AB - Hybrid solar cells were fabricated using aluminum-doped zinc oxide (AZO) grown by electrochemical deposition from chloride electrolyte solutions with Al/Zn molar ratios of 0.5, 2.5, and 5.0%. The substrates were AZO- and ZnO-seeded ITO. Ordered nanorod structures with high optical transmittance were grown at 0.5% Al/Zn ratio while interconnected micron-sized flakes were grown at 2.5% and 5.0%. The estimated band gap energies increase for higher Al dopant content, showing Burstein-Moss effect. EDX analysis detected high aluminum content in the 5.0% samples suggesting that insulating aluminum oxide phases were formed thus causing reduced solar cell efficiencies. The highest power conversion efficiency of 1.71%, from the 0.5% sample grown on ZnO-seeded ITO, can be attributed to the presence of AZO nanorods which provide a large interfacial area and effective charge transport. PMID- 27451642 TI - Effect of Reactive Self-Assembled Monolayer at the Anode Interface of Organic Light-Emitting Diode. AB - Organic light-emitting diodes (OLEDs) were prepared on-indium-tin oxide (ITO) substrates that were modified with various self-assembled monolayers (SAMs) including those which have reactive terminal units. The OLED performance was analyzed in terms of molecular length, dipole moment and HOMO level of SAM molecules estimated by the density functional theory calculation. It was suggested that the current efficiency of OLED is partly improved by controlling the carrier balance, interfacial dipole moment, and electron energy level by SAM modification. More importantly, remarkable improvement in OLED efficiency was achieved by chemically tethering the inorganic/organic interface via benzophenone terminated SAM. The reactive SAM having benzophenone terminal group can be a promising tool to control the inorganic/organic interface for organic devices. PMID- 27451643 TI - Organic Position-Sensitive Detectors Based on ZnO:Al and CuPc:C60. AB - Organic position-sensitive detector (OPSD) based on copper phthalocyanine CuPc:fullerene C60 bulk-heterojunction with an inverted structure have been fabricated using aluminum doped ZnO (ZnO:Al) as a resistive layer, which is prepared by sol-gel method. The resistance length of the one-dimensional PSD is fixed at 5 mm, and the Ag common electrode is fabricated by vacuum evaporation within the 100-um width. The current density-voltage characteristics with different structures of photodetector, the influence of ZnO:Al resistivity on the thickness and the position characteristics of PSDs are investigated. The experimental results indicate that the architecture, which uses an inverted structure, increases sensitivity under red light illumination compared to the conventional structure. In addition, the thickness of the ZnO:Al has influence on the position characteristics. The resistivity of ZnO:A film with Al doping concentration of 2 mol% prepared in this study is around 150 Omegacm and it increases from less than approximately 400 nm-thickness. These characteristics seem to be correlated with the properties of ZnO:AI resistive layer. For a device with a 620 nm-thick ZnO:Al layer, the measured position values obtained from the output photocurrent agree with the actual position values under red laser light illumination. CuPc:C60 OPSD with an inverted structure exhibits red light sensitivity, high incident-photon-to-current conversion efficiency of above 80% at -3 V and linearity error of 5.9% at -2 V. PMID- 27451644 TI - Development of UV Light Irradiation Patterning of Bacteriorhodopsin Thin Films for Biomimetic Functional Devices. AB - We developed a new patterning method for bacteriorhodopsin (bR) thin films using UV light irradiation. The proton pump function of bR thin films can be deactivated with UV light irradiation. Inactivation of the proton pump function of bR is related to structural changes or photo-bleaching of the retinal in bR using UV light exposure, which was confirmed with absorption and Raman spectroscopy measurements. Utilizing inactivation of the proton pump function with UV light irradiation, we prepared a bR photocell with a stripe-patterned bR thin film and measured its photocurrent response. The new patterning method is applicable to complicated patterning and patterning with a higher spatial resolution, which extends the application of bR thin films as sensor devices. PMID- 27451645 TI - Self-Spreading of Lipid Bilayer on a Hydrophobic Surface Made by Self-Assembled Monolayer with Short Alkyl Chain. AB - Behaviors of self-spreading of lipid bilayer membrane on a glass surface modified with self-assembled monolayer (SAM) with short alkyl chain were observed with fluorescence microscopy. Hydrophobic surface made by SAM was found to hamper the self-spreading phenomenon but the lipid bilayer spread on a hydrophilic one where SAM was decomposed by oxidation. On a binary surface having a hydrophobic region and a hydrophilic one, the lipid bilayer spread on the hydrophilic region but it stopped at the boundary of the hydrophobic region. PMID- 27451646 TI - Rate Constant Change of Photo Reaction of Bacteriorhodopsin Observed in Trimeric Molecular System. AB - To elucidate the time evolution of photo reaction of bacteriorhodopsin in glycerol mixed purple membrane at around 196 K under irradiation by red light, a kinetic model was constructed. The change of absorption with irradiation at times of 560 nm and 412 nm was analyzed for the purpose of determining reaction rates of photo reaction of bacteriorhodopsin and its product M intermediate. In this study it is shown that reaction rates of conversion from bacteriorhodopsin to the M intermediate can be explained by a set of linear differential equations. This model analysis concludes that bacteriorhodopsin in which constitutes a trimer unit with other two bacteriorhodopsin molecules changes into M intermediates in the 1.73 of reaction rate, in the initial step, and according to the number of M intermediate in a trimer unit, from three to one, the reaction rate of bacteriorhodopsin into M intermediates smaller as 1.73, 0.80, 0.19 which caused by influence of inter-molecular interaction between bacteriorhodopsin. PMID- 27451647 TI - A Special Section on Luminescence Nanomaterials. PMID- 27451648 TI - Activities of Combined TiO2 Semiconductor Nanocatalysts Under Solar Light on the Reduction of CO2. AB - The materials based on TiO2 semiconductors are a promising option for electro photocatalytic systems working as solar energy low-carbon fuels exchanger. These materials' structures are modified by doping metals and metal oxides, by metal sulfides sensitization, or by graphene supported membrane, enhancing their catalytic activity. The basic phenomenon of CO2 reduction to CH4 on Pd modified TiO2 under UV irradiation could be enhanced by Pd, or RuO2 co-doped TiO2. Sensitization with metal sulfide QDs is effective by moving of photo-excited electron from QDs to TiO2 particles. Based on characteristics of the catalysts various combinations of catalysts are proposed in order to creat catalyst systems with good CO2 reduction efficiency. From this critical review of the CO2 reduction to organic compounds by converting solar light and CO2 to storable fuels it is clear that more studies are still attractive and needed. PMID- 27451649 TI - Influence of H, H2, O and O2 on Armchair SiGe Nanotubes: A Theoretical Study. AB - A systematic, hybrid density functional theory study of interaction between SiGe nanotubes (SiGeNTs) and X (X = H, O, H2 and 02) have been performed using the hybrid functional B3LYP and an all electron 3-21G* basis set implemented in GAUSSIAN 09 suite of software. All possible internal. and external adsorption sites were considered, and it was found that H prefers to move onto top of an atom site while O prefers to incorporate into NT wall by breaking the bonds. Adsorption energies for H is ~2.0 eV and for O it is ~5.0 eV. Controlled adsorption of atomic H and several molecular O give rises to defect density states in the frontier orbital region. H rich adsorptions predict the difference between highest occupied molecular orbital (HOMO) energy and the lowest unoccupied molecular orbital (LUMO) energy increase while O rich adsorptions predict the decrease in HOMO-LUMO energy gap. O and O2 adsorptions predict definite ionic bonding character while H atomic adsorptions predict covalent bonding. H2 is very neutral towards the adsorption into SiGeNTs and clealy shows the physisorption adsorption. Considering the all adsorptions, the adsorptions happened within the Si vicinity of the SiGeNT shows the most stable and preferred adsorption region. PMID- 27451650 TI - Synthesis, Photoluminescence and Bio-Targeting Applications of Blue Graphene Quantum Dots. AB - Chemical derived graphene oxide, an atomically thin sheet of graphite with two dimensional construction, offers interesting physical, electronic, thermal, chemical, and mechanical properties that are currently being explored for advanced physics electronics, membranes, and composites. Herein, we study graphene quantum dots (GQD) with the blue photoluminescence under various parameters. The GQD samples were prepared at different temperatures, and the blue photoluminescence intensity of the solution improved radically as the heating temperatures increased. Concerning PL peak and intensity of the quantum dots, the results demonstrated dependence on time under heating, temperature of heating, and pH adjusted by the addition of sodium hydroxide. After hydrothermal synthesis routes, the functional groups of graphene oxide were altered the morphology showed the stacking configuration, and self-assembled structure of the graphene sheets with obvious wrinkles appeared at the edge structures. In addition, absorption, PL, and PLE spectra of the graphene quantum dots increase with different quantities of sodium hydroxide added. Finally, using GQD to target PNTIA cells was carried out successfully. High uptake efficiency and no cytotoxic effects indicate graphene quantum dots can be suitable for bio-targeting. PMID- 27451651 TI - Synthesis and Luminescent Properties of Eu2+ Doped Sr5SiO4Cl6 Phosphor by Sol-Gel Method. AB - The paper discusses preparation and luminescent properties of Sr5SiO4Cl6:Eu2+ blue phosphor, which was synthesized by sol-gel method. The emission and excitation spectra, SEM, XRD and diffuse reflection of the fluorescent powder were measured. It was shown that the samples were single phase of Sr5SiO4Cl6 by the XRD patterns. The photoluminescence and excitation spectra of this phosphor were investigated. The phosphor excited by 278 nm light showed an asymmetric spectrum. The emission spectra can be separated into three distinct peaks located at 450, 480 and 540 nm, respectively. The influences of Eu2+ ions concentration on the emission intensity of Sr5SiO4Cl6:Eu2+ phosphors were studied in detail. The influences of different sintering temperature on the emission intensity were also investigated. The optimal sintering temperature was 750 degrees C. Effects of the amount of complexing agent were studied and a ratio of 1~1.1 to that of the cation was the best. The particle diameter of the phosphor was studied by SEM. The potential applications were also discussed. PMID- 27451652 TI - Hydrothermal Synthesis and Luminescent Properties of Eu3+ Doped Sr3Al2O6 Phosphor for White LED. AB - Eu3+ ions doped Sr3Al2O6 phosphors were successfully synthesized via a hydrothermal method. The precursor was prepared by low temperature hydrothermal method using ammonia as both alkaline source and precipitator. Then the final product was obtained by high temperature sintering. In addition, the structures, morphologies, and luminescent properties of as-prepared products were thoroughly characterized by X-ray powder diffraction (XRD), Scanning electron microscopy (SEM), Fluorescence spectroscopy (PL). XRD shown a single phase Sr3Al2O6 prepared by a facile hydrothermal method at 250 degrees C for 10 h. In the PL spectra of as-prepared samples, the optimal value of Eu3+ concentration is 2 mol%. From the fluorescent spectra, the emission peaks of Sr3Al2O6: Eul+ phosphors are centered at around 591 nm, and the excitation peaks are centered at around 233 nm, 323 nm, 394 nm, and 468 nm, respectively, which were assigned to the characteristic transition of Eu3+ ions. The influence of ammonia, and the synthesis temperature on the luminescent properties of Sr3Al206: Eu3+ phosphors were studied in detail. The alkaline earth aluminates luminescent materials activated by rare earth ions have good prospects in the field of new-generation light sources. PMID- 27451653 TI - Photoluminescence Properties Research on Graphene Quantum Dots/Silver Composites. AB - Graphene quantum dots (GQDs) possess unique properties of graphene and exhibit a series of new phenomena of 0 dimension (D) carbon materials. Thus, GQDs have attracted much attention from researchers and have shown great promise for many applications. Recently, many works focus on GQDs-metal ions and metal nanoparticles (NPs). Although, many researches point out that metal ions and metal NPs have significant effect on photoluminescence (PL) feature of GQDs, mainly focus on PL intensity. Here, for the first time, we reported that metal NPs also affected PL peak position which was dependent on the mix mechanism of metal and GQDs. When GQDs-silver (Ag) composite mixed by physical method and excited at a wavelength of 320 nm, PL peak position of composites first showed blue-shifted then red-shifted with increasing of Ag content. However, if GQDs-Ag composite prepared by chemical method, PL peak position of the composites blue shifted. Furthermore, the shift of PL peak position of GQDs-Ag prepared both for physical and chemical method displayed excitation-dependent feature. When the excitation wavelength approached to Ag SPR peaks, no obvious PL shift was observed. The mechanism for different PL shifts and the phenomenon of excitation dependent PL shift as well as the formation mechanism of GQDs-Ag composite by chemical method are discussed in detail in this paper. PMID- 27451654 TI - Luminescence Properties and Synthesis of SrMgAl10O17:Mn4+ Red Phosphor for White Light-Emitting Diodes. AB - A series of Mn4+ doped SrMgAl10O17 phosphors are synthesized by a conventional solid-state reaction method in air, and their crystal structure, morphology, and fluorescence properties are investigated. The luminescence properties show clearly that SrMgAl10O17:Mn4+ phosphor can be excited by UV (200-380 nm), near UV (380-420 nm), and blue (420-480 nm) bands of LEDs chip, and emits red light in the range of 600 nm to 750 nm with satisfying CIE chromaticity coordinates (0.7207, 0.2793). The optimal doping concentration of Mn4+ ion is ~1 mol%, and its lifetime is ~1.15 ms. The possible luminous mechanism of Mn4+ ion is discussed by Tanabe-Sugano diagram. These experiment results indicate that Mn4+ doped SrMgAl10O17 phosphors can be a potential application as a red-emitting phosphor candidate in white LEDs. PMID- 27451655 TI - Near-Infrared Quantum Cutting in Yb3+ Doped SrMoO4 Phosphors. AB - Efficient near-infrared (NIR) quantum cutting (QC) has been demonstrated in Yb3+ doped SrMoO4 phosphors synthesized by the high-temperature solid-state reaction method. The obtained SrMoO4:Yb3+ phosphors were characterized by X-ray diffraction (XRD), diffuse reflectance spectra, photoluminescence (PL) spectra and decay lifetime to understand the observed near-infrared quantum cutting phenomena. The XRD results show that all the prepared phosphors can be readily indexed to the pure tetragonal phase of SrMoO4 and exhibit good crystallinity. The experimental results showed that the strong visible molybdate (MoO2-(4)) emission around 493 nm and near-infrared (NIR) emission around 1000 nm from Yb3+(2F(5/2)-->2F(7/2)) of SrMoO4:Yb3+ phosphors were observed under ultraviolet (290 nm) excitation. The Yb + concentration dependence of luminescent properties and lifetimes of both the visible and NIR emissions have also been investigated. The quenching concentration of Yb3+ ions approaches as high as 10 mol%. The cooperative energy transfer (CET) mechanism was also discussed in detail. The broadband NIR QC phosphors may possibly have potential application in enhancing the conversion efficiency of solar cells. PMID- 27451656 TI - Preparation and Luminescent Properties of Sm3+-Doped High Thermal Stable Sodium Yttrium Orthosilicate Phosphor. AB - Orange-red-emitting sodium yttrium orthosilicate NaYSiO4:xSm3+ (x = 0.005, 0.01, 0.02, 0.05, 0.10, 0.15, and 0.20) were synthesized. The phase structure and photoluminescence properties of these phosphors were investigated. The emission spectrum obtained by excitation into 406 nm contains exclusively the characteristic emissions of Sm3+ at 571 nm, 602 nm, 648 nm, and 710 nm, which correspond to the transitions from 4G5/2 to 6H5/2, 6H7/2, 6H9/2, and 6H11/2 of Sm3+, respectively. The strongest one is located at 602 nm due to the 4G5/2 --> 6H7/2 transition of Sm3+, generating bright orange-red light. The optimum dopant concentration of Sm3+ ions in NaYSiO4:xSm3+ is around 2 mol%, and the critical transfer distance of Sm3+ is calculated as 23 A. The thermal quenching temperature is above 500 K. The fluorescence lifetime of Sm3+ in NaYSiO4:0.02Sm3+ is 1.83 ms. The NaYSiO4:Sm3+ phosphors may be potentially used as red phosphors for white light emitting diodes. PMID- 27451657 TI - A New Blue-Emitting Mg2Al4Si5O18:Ce3+ Phosphor for White Light Emitting Diodes. AB - A series of blue-emitting Mg2Al4Si5O18:Ce3+ phosphors were prepared via the conventional high temperature solid-state reaction method. The phase structure, photoluminescence (PL) properties, PL thermal stability, and fluorescence decay curves of the samples were investigated for the first time. Under excitation at 365 nm, the phosphor exhibited a broad band blue emission with peak at 440 nm, which was ascribed to the 4f --> 5d transition of Ce3+, and the color coordinate was (0.1602, 0.0849). When the temperature increased to 150 degrees C, the luminescence intensity of the Mg2Al4Si5O18:0.06Ce3+ phosphor was 55.73% of the initial value at room temperature. The activation energy DeltaE was calculated to be 0.25 eV, which proved the good thermal stability of the sample. The energy transfer critical distance between Ce3+ ions in Mg2Al4Si5O18 host were also calculated. The above results indicate that the Mg2Al4Si5O18:Ce3+ is a promising candidate as a blue-emitting near ultraviolet convertible phosphor for application in white light emitting diodes (WLEDs). PMID- 27451658 TI - Near-infrared Downconversion in LuPO4: Tm3+, Yb3+ Phosphors. AB - Tm3+ and Yb3+ codoped LuPO4 phosphors were synthesized by the reverse-strike co precipitation method. The obtained LuPO4:Tm3+,Yb3+ phosphors were characterized by X-ray diffraction (XRD), diffuse reflectance spectra, photoluminescence (PL) spectra, and decay lifetime to understand the observed near-infrared downconversion (DC) phenomena. The XRD results show that all the prepared phosphors can be readily indexed to the pure tetragonal phase of LuPO4 and exhibit good crystallinity. The experimental results showed that the strong visible emission around 649 nm from Tm3+(1G4 --> 3F4) and near-infrared (NIR) emission around 1003 nm from Yb3+(2F5/2 --> 2F7/2) of LuPO4:Tm3+,Yb3+ phosphors were observed under 468 nm excitation, respectively. The Yb3+ concentration dependence of luminescent properties and lifetimes of both the visible and NIR emissions have also been investigated. The quenching concentration of Yb3+ ions approaches 30 mol%. The DC mechanism is also discussed in detail. PMID- 27451659 TI - Effect of Gallium and Indium Co-Substituting on Upconversion Properties of Er/Yb:Yttrium Aluminum Garnet Powders Prepared by the Co-Precipitation Method. AB - Gallium and Indium co-substituted Yb, Er:YAG was fabricated through the chemical co-precipitation method. The formation process and structure of the Ga3+ and In3+ substituted phosphor powders were characterized by the X-ray diffraction, thermo gravimetry analyzer, infrared spectra, and X-ray photoelectron spectroscopy, and the effects of Ga3+ and In3+ concentration on the luminescence properties were investigated by spectrum. The results showed that the blue shift occurred after the substitution of Ga3+ and In3+ for Al3+ in matrix, and the intensity of emission spectrum was affected by the concentration of Ga3+ and In3+. PMID- 27451660 TI - Synthesis, Characterization and Novel Photoluminescence of SrWO4:Ln3+ Nanocrystals. AB - SrWO4:Ln3+ (Ln = Eu, Ce, and Tb) nanocrystals were successfully synthesized by a hydrothermal method, and were characterized by X-ray diffraction, transmission electron microscopy, and scanning electron microscopy. The results indicated that the crystalline size of nanocrystals decreases with increasing Eu3+ concentrations and increases with increasing annealing temperature, gradually. The photoluminescence properties of SrWO4:Ln3+ were investigated in detail. In the emission spectra of SrWO4:Eu3+, the luminescence was dominated by 5D0--> 7F2 transition, indicating that Eu3+ occupied a site lacking inversion symmetry. The concentration quenching effect hardly occurs. In the excitation spectra of SrWO4:Eu3+ nanocrystals monitored at 619 nm, the most intense peak is centered at 467 nm when the Eu3+ concentration was less than 10%, while the most intense peak is centered at 396 nm when the Eu3+ concentration was 15%. In the normalized emission spectra of SrWO4:Ce3+/Tb3+ nanocrystals excited at 254 nm, the intensity ratio of the sharp emission peaks from Tb3+ ions to the broad emission band from Ce3+ ions increased with increasing Tb3+ concentration. PMID- 27451661 TI - Electrochemical Tuning of Amorphous Carbon Amount and Surface Oxidation Degree of Graphitic Quantum Dots. AB - Graphitic quantum dots (GQDs) have attracted much interesting of researchers because of its amazing optical properties and its ability to be used for many applications. Now, there are various methods have been reported for preparation of GQDs. Among them electrochemical method is simple technology, while it can afford various conditions to realize controllable prepared of GQDs. In this study, we tuned the PH values of electrolyte to probe the relationship of electrolyte environment and GQDs' optical properties as well as to seek the effective controllable condition for GQDs' preparation. It is found that the density of oxygen-related functional groups and the amount of amorphous carbon of GQDs were related to the PH values of electrolyte. The amount of amorphous carbon decreased as the PH values increased in the region of 6.6 to 7.1. Although, the positions of photoluminescence (PL) peak almost no changed of GQDs with different density of oxygen-related functional groups, GQDs with the lowest amount of amorphous carbon achieved the maximum PL intensity. Therefore, controlling amorphous carbon's amount by electrochemical method may afford a new direction to improve the fluorescence (FL) emission of GQDs. PMID- 27451662 TI - Concentration-Dominated Temperature-Dependence of Upconversion Luminescence in Gd6WO12 Nanophosphor Co-Doped with Er3+ and Yb3+. AB - Nanosized Gd6WO12 phosphors containing various Er3+ concentrations and fixed Yb3+ concentration were synthesized by a co-precipitation method. The crystal structure and microscopic morphology of the obtained nanophosphors were characterized by means of X-ray diffraction (XRD) and field emission scanning electron microscopy (FE-SEM). Two-photon processes for both the green and red upconversion (UC) emissions were confirmed by analyzing the dependence of UC intensities on 980 nm laser working current. UC emission intensity changing with temperature displays different trends for the samples with different Er3+ concentrations. The experimental results indicated that thermal quenching behavior of UC luminescence could not be simply explained by crossover mechanism. The enhancement for green UC emission in the sample with higher Er3+ concentration was discussed. Finally, the ErS+ concentration dependence of UC luminescence was experimentally observed, and its mechanisms were analyzed. PMID- 27451663 TI - Structure and Optical Thermometry Characterization of Er3+/Yb3+ Co-Doped BaGd2CuO5. AB - Er3+/Yb3+ co-doped BaGd2CuO5 upconversion luminescent materials are obtained by solid phase method. Rietveld refinement on X-ray diffraction data indicates that Er3+/Yb3+ ions are inclined to occupy the Gd(1) site in the structure of BaGd2CuO5 (green phase). Two green emission peaks located at 523 nm and 547 nm have been produced by the excitation of 971 nm LD. The fluorescence intensity ratio (FIR) of the two green emission peaks have been investigated in the temperature range of 290 K-594 K. The maximum sensitivity derived from the FIR technique of the green upconversion emission is approximately 0.0038 K-1, and it has a high transmission power at low excitation density. This result implies that the Er3+/Yb3+ co-doped BaGd2CuO5 phosphors can play an important role in temperature measurements with a better sensitivity. PMID- 27451664 TI - A Green Route to Hexagonal and Monoclinic BiPO4:Ln3+ (Ln = Sm, Eu, Tb, Dy) Nanocrystallites for Tailoring Luminescent Performance. AB - Selective synthesis of specific phased nanomaterials via a green route is a promising yet challeng- ing task. In the present work, the hexagonal and monoclinic phases of BiPO4:Ln3+ (Ln = Sm, Eu, Tb, Dy) were prepared via room temperature co-precipitation method. For adjusting the phase of the products, the prepared mediums selected were the most common solvents, i.e., water and ethanol. It was very important that the prepared mediums could be easily recycled and reused by evapo- rating the filtrate. The formation mechanisms of hexagonal in water and monoclinic in ethanol were investigated. Interestingly, the growth behaviors of these phases were quite distinct and thus gave rise to distinct morphology and particle size. The hexagonal phase possesses a rod-like morphol- ogy with diameters of 50-160 nm and lengths of 65-400 nm while the monoclinic phase consists of almost entirely irregular nanoparticles. Also, it was found that the bending and stretching vibrations of O-H and PO4 tetrahedra were quite different for the products prepared in water and ethanol. Moreover, it was found that the luminescence properties, including emission intensity, lifetime, quan- tum efficiency, and color, could be readily tailored through controlling the phase structures and microstructures. The results showed that the monoclinic phase exhibited superior luminescent per- formance to the hexagonal phase. The methodologies reported in this work were fundamentally important, which could be easily extended to large-scale synthesis of other phased nanomaterials for potential applications as electroluminescent devices, optical integrated circuits, or biomarkers. PMID- 27451665 TI - Facile Synthesis of r-GO@Pd/TiO2 Nanocomposites and Its Photocatalytic Activity Under Visible Light. AB - Reduced Graphene Oxide Wrapped Pd/TiO2 (r-GO@Pd/TiO2) which exhibited high photocatalytic activity under visible light was synthesized from commercial chemicals. The classic sol-gel method and the Ar gas bubbling composition was used in the preparation of the catalyst. Furthermore, the best Pd-doping concentration in crystals, the wrapping concentration of r-GO over nanoparticles, and the optimal calcination temperature were investigated to enhance the photocatalytic activity of the hybrid catalyst. The experimental results showed that the catalytic efficiency of r-GO@Pd/TiO2 reached maximum value at the optimum synthesis conditions: 0.7 wt% Pd-doped TiO2 by sol-gel process, calcination temperature of 550 degrees C, 1 mg of GO for 100 .gram wrapped Pd/TiO2. X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), and Transmission Electron Microscopy (TEM) techniques were conducted to determine the nanostructure of the catalysts. The average crystallite size of nanoparticles was 14 nm with perfect dispersion of Pd dots and wraps of r-GO membrane. Methyl Blue was used as an organic dye model to test the ability in wastewater treatment of the catalysts. A comparison between different catalysts' characteristics was also studied. The r-GO@Pd/TiO2 showed a higher photocatalytic activity compared to Pd/TiO2 and commercial P25. Additionally, the complete dye reduction under visible light excitation indicated that wrapping r-GO round Pd/TiO2 improved the photocatalytic activity of catalysts. The determination of the stability of r GO@Pd/TiO2 showed that its photocatalysis was persistent over several times of recycling examination. Therefore, r-GO@ Pd/TiO2 in wastewater treatment. PMID- 27451666 TI - Gain Characteristics of Polymer Waveguide Amplifiers Based on NaYF4:Ybl+, Er3+ Nanocrystals at 0.54 um Wavelength. AB - Gain characteristics of polymer waveguide amplifiers based on NaYF4:Yb3+, Er3+ nanocrystals (NCs) at 0.54 um wavelength were investigated through numerical simulations. NaYF4:18%Yb3+, 1 0%Er3+ NCs were doped into SU-8 2005 polymer matrix as the core of a polymer waveguide. The absorption spectrum and photoluminescence spectrum of the NCs were recorded and analyzed. The Judd-Ofelt parameters were achieved by means of Judd-Ofelt theory: Omega2 = 6.302 x 10(-20) cm2, Omega4 = 0.69 x 10(-20) cm2, Omega6 =7.572 x 10(-20) cm2. We simulated the gain characteristics of the waveguide amplifier at 0.54 um wavelength by combining the atomic rate equations with power propaga- tion equations. The gain curves had the saturation effects. A maximum gain -4.3 dB for the 5 cm waveguide with the Er3+ concentration of ~7.5 x 1025 m-3 was obtained. PMID- 27451667 TI - Influence of Pt and Pd Modification on the Visible Light Photocatalytic Activity of N-Doped Titania Photocatalysts. AB - Pd and Pt modified N-doped titania nanoparticle powders were prepared by a facile sol-gel method. Nitrogen doping and metal modification were carried out simultaneously during the preparation pro- cess. The as-prepared samples were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), diffuse reflectance spectroscopy (DRS), photoluminescence (PL) spectroscopy and X ray photoelectron spectroscopy (XPS). The visible light photocatalytic activities of the as prepared samples were evaluated by analyzing their effect on the photocatalytic decomposition of methyl orange (MO). The chemical state of the metal is the key factor determining the performance of metal modified N-doped titania. The Pd used to modify the N-doped titania (Pd-NT) in our study was of the PdOx(x<=2) species, which increased the absorbance in the visible light region, decreased the recombination of photo-generated electron-hole pairs, and resulted in a significant enhancement in the visible light photocatalytic activity. The Pt species used to modify the N-doped titania (Pt-NT) was mainly in the metallic state, which resulted in a decrease in the absorbance in the visible light region, and an increase in the recombination of photo-generated electron hole pairs. Pt modification led to a deterioration in the visible light photocatalytic activity of the material. PMID- 27451668 TI - Near Infrared Quantum Cutting of Tb3+-Yb3+ Co-Doped CeF3 Nanophosphors. AB - In this paper, Tb3+-Yb3+ Co-doped CeF3 nanophosphors were synthesized using the microwave-assisted heating hydrothermal method (M-H). The excitation and emission spectra of the samples at room temperature show that the samples absorb ultraviolet light from 250 nm to 280 nm, and emit light at 300 nm. This corresponds to the transitions from 5D to 4F of Ce3+, 480 nm, 540 nm, 583 nm, 620 nm which correspond to the transitions from 5D4 to 7F6,5,4,3 of Tb3+, 973 nm which corresponds to the transitions from 2F5/2-2F7/2 of Yb3+. In the emission spectra, it is clear that the emission intensity of Ce3+ and Tb3+ decreases, and Yb3+ increases with increasing Yb3+. This suggests that energy transfer from Ce3+ to Yb3+, and Ce3+ to Tb3+ to Yb3+ may occur. In the near infrared emission area, it is noted that a distinct emission centered at 973 nm was observed under 260 nm excitation. This is due to transitions among the different Stark levels of 2FJ(J=5/2,7/2) Yb3+ ions. This also suggests an energy transfer from Ce3+ ions to Tb3+ and then to Yb3+. The energy transfers from Tb3+-Yb3+ Co-doped CeF3 nanophosphors, which lead to intense NIR emissions at 900-1050 nm, match the energy of Si band gaps of Si-based solar cells. Therefore, these kinds of materials are promising candidates for applications that require modifying if solar spectrums and enhancement of conversion efficiency of Si-based solar cells. PMID- 27451669 TI - Research Based on Optical Non-Destructive Testing of Pigment Identification. AB - Optical Non-Destructive Testing (ONDT) can be applied as penetrating elemental and structure analysis technology in the Pigments identification field. Three dimensional video microscopy, Raman microscopy and energy dispersive X-ray fluorescence spectroscopy are employed to measure the materials based on a Qing Dynasty meticulous painting. The results revealed that the dark yellow area within the decorative patterns was presented due to the interaction of Emerald green and hematite, and the bright yellow edge area was delineated by Cu-Zn-Pb composition. The interesting thing is that an artificial synthetic ultramarine blue was checked in the painting. According to the first synthesized time of ultramarine blue and Paris green, the time limit of the painting completion can be identified. The principle of Pigment subtractive colorant and nitikaset method were employed to interpreting the results. Optical testing combined with the area of cultural relic identification can be a potential method to build an expert identification system successfully. This work also help lay the optical method groundwork for further cultural relic identification, sterilization, and preservation. PMID- 27451670 TI - Decorated TiO2 Nanoparticles with La and Ag Elements to Improve Photocatalytic Activity Under Visible Light for the Degradation of MO. AB - Visible-light photocatalyst of TiO2/La/Ag nanocomposites were successfully synthesized via the conventional sol-gel method and reducing agent of Ag+. The photocatalytic activities were evaluated by methyl orange (MO) degradation. They have remarkable photocatalytic activities compared to TiO2-Anatase, which is thanks to the separation of electron-hole pairs by Ag nanoparticles and lanthanum. The products were characterized by a series of techniques such as X ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), and Uv-vis. The results show that spherical nanocomposites have been prepared with the size 300 nm and Ag nanoparticles (~10 nm) are dispersed uniformly onto the surface of TiO2/La, which forms TiO2/La/Ag nanocomposites. TiO2/La/Ag nanocomposites have good absorption in the visible region (700 nm > lambda > 400 nm). The reasons are as follows: (1) the efficient separation of photogenerated electrons and holes of the photocatalysts on the surface of TiO2/La/Ag nanocomposites and (2) a wide visible-light photoabsorption range (700 nm > lambda > 400 nm). Therefore, this study may provide some new idea for the rational design and the facile synthesis of composite catalysts with a green, efficient pathway. PMID- 27451671 TI - Microstructure and Luminescence Properties of Tb3+ Doped ZnO Quantum Dots. AB - In order to increase the exchange efficiency of solar cells by down-conversion, Tb3+ doped ZnO quantum dots (QDs) were successfully synthesized by sol-gel process. The X-ray diffraction (XRD) results indicate that ZnO QDs have hexagonal wurtzite structure. ZnO QDs have a spherical shape and diameter around 5 nm, which was confirmed by high-resolution transmission electron microscopy (HRTEM). The intensity of visible light emission peaks becomes strengthened and then weakened with the increase of Tb3+ doping concentration. When the concentration is more than 1%, because of the decrease of surface defects and concentration quenching effect, the emissive intensity is weakened. The enhancement of the PL emission peaks at 542 nm, 582 nm, and 619 nm was assigned to energy transfer between TbS+ ions and ZnO QDs host. Moreover, the absorption spectra also demonstrates energy transfers from Tb3+ ions to ZnO QDs. PMID- 27451672 TI - Luminescence Properties of Sm3+/Eu3+ Co-Doped ZnO Quantum Dots. AB - In order to improve luminescence properties of semiconductor ZnO quantum dots (QDs), Sm3+/Eu3+ co-doped ZnO QDs have been controllably synthesized by sol-gel method in this paper. ZnO QDs have a spherical shape with mean diameter at about 5-6 nm, which was characterized by high-resolution transmission electron microscopy (HRTEM). ZnO QDs have hexagonal wurtzite structure with parts of Sm3+ and Eu3+ incorporated into the lattice, which was demonstrated by X-ray Diffraction (XRD). Luminescence properties at room temperature (RT) of different amount of Sm3+ and 2 mol% Eu3+ doped ZnO QDs were examined in-depth by optical spectra. In contrast to the Pr3+/Eu3+ co-doped fluorescent performance researched in our previous study, the photoluminescence (PL) spectra indicates the unique luminescence properties of Sm3+/Eu3+ co-doped ZnO QDs. In addition, fluorescence lifetimes were obtained to illustrate the luminous mechanism. PMID- 27451673 TI - Preparation of Fluorescent Dye-Doped Biocompatible Nanoparticles for Cell Labeling. AB - In this paper, we report a series of fluorescent biocompatible nanoparticles (NPs), prepared by a facile reprecipitation-encapsulation method, for cellular labeling. The as-prepared NPs exhibit a narrow size distribution of 70-110 nm, and a core-shell structure comprised of a hybrid core doped with different dyes and a poly-L-lysine (PLL) shell. With coumarin 6, nile red, and meso- tetraphenylporphyrin as the imaging agents, the fluorescent NPs gave green, orange, and red emissions respectively. Due to the positively charged PLL shell, the fluorescent NPs exhibit neglected cytotoxicity and efficient cellular uptake. After incubation with living cells, the results obtained by laser confocal microscope from green, orange, and red channels all clearly show that the fluores cent NPs are inhomogenously localized inside the cytoplasm without penetrating into the nucleus. Since such PLL-modified NPs can encapsulate other hydrophobic dyes, a wide spectrum of nanoimaging agents is thus expected. Furthermore, the surface amino groups on the PLL shell afford an anchoring site for further bioconjugation, and targeted imaging is also very promising. PMID- 27451674 TI - Enhancement of Photoluminescence in BaSi2O2N2:Eu2+ by Partial Ge4+ Substitution for Si4+. AB - Ge4+-doped BaSi2O2N2: Eu2+ phosphors were prepared by a high temperature solid state reaction method. The phase structure, photoluminescence (PL) properties and PL thermal stability of the as-synthesized samples were investigated. The emission intensity of the Ba(Si0.99Ge0.01)2O2N2: 0.05Eu2+ phosphor was 41.7% greater than that of BaSi2O2N2:0.05Eu2+. When the temperature increased to 150 degrees C, the emission intensity of Ba(Si0.99Ge0.01)2O2N2:0.05Eu2+ phosphor was 67.0% of the initial value at room temperature. This value was 22.9% greater than that of BaSi2O2N2:0.05Eu2+. The related mechanism has also been explained through the crystal field theory. All these results indicated that the Ge4+-doped BaSi2O2N2:0.05Eu2+ phosphor is a promising material for application in white light emitting diodes. PMID- 27451675 TI - Laser Spectroscopy of GdPO4 . nH2O:Eu Nanomaterials. AB - One-dimensional GdPO4 . nH2O:Eu nanowires and nanorods of different sizes and the same structure were synthesized by hydrothermal method. Nanowire and nanorods had width and length of about 10 nm/50 nm and 80 nm/1 um, respectively. Adjusting reaction system PH value by adding alkali metal NaOH, the size and shape of the product can be tuned. The high resolution spectra, excitation spectra, and laser selective excitation spectra at low temperature were determined. Nanorod compared with nanowire, photoluminescence was enhanced, and the excitation spectrum and laser selective excitation spectra were broadened. These results suggest that Eu3+ in GdPO4 . nH20 nanorod and nanowire were located in different local environments. PMID- 27451676 TI - Synthesis and Photoluminescence of Rhombic NaLa(MoO4)2:Ln3+ Nanocrystals. AB - Rhombic NaLa(MoO4)2:Ln3+ (Ln = Eu and Tb) nanocrystals were synthesized by a hydrothermal method. The structures and morphologies of the nanocrystals were characterized by X-ray diffraction, Raman spectroscopy, and scanning electron microscopy. The results indicated that the crystalline size increased with increasing Na2MoO4 content. The photoluminescence properties of NaLa(MoO4)2:Ln3+ nanocrystals were investigated in detail. In the emission spectra of NaLa(MoO4)2:Eu3+ nanocrystals, the 5D0 --> 7F2 is dominant, and the peak positions and spectral shapes of emissions were independent of Eu3+ concentration. The luminescence intensity increased with increasing Eu3+ concentration, up to about 10 mol%, and then decreased. In the emission spectra of NaLa(MoO4)2:Tb3+ nanocrystals, the 5D4 --> 7F5 is dominant. The sample with a dopant concentration of 20 mol% showed the highest emission intensity. PMID- 27451677 TI - Preparation and Photovoltaic Properties of Dye Sensitized Solar Cells Using ZnO Nanorods Stacking Films on AZO Substrate as Photoanode. AB - Three-dimensional stacking of ZnO nanorods on conducting aluminum-doped ZnO (AZO) glass were studied as efficient photoanodes of dye sensitized solar cells (DSSCs). By changing hydrothermal growth time and cycle times, the thickness of ZnO nanorods stacking films varied from 30 um to 64 um, and its influence on the energetic conversion efficiency of the DSSCs based on the stacking films photoanodes was investigated. The loading density of N719 on the surface of ZnO nanorods was studied to increase the efficiency of the cells. Annealing experiments showed that the AZO substrates remained good conductors until heated above 350 degrees C. A photoelectric conversion efficiency as high as ~2.0% together with ISC of ~9.5 mA/cm2, VOC of ~0.5 V and FF of ~41.4% was achieved for the DSSC using 50 um-thick film stacking by ZnO nanorods as photoanode and N719 as sensitizer under illumination of AM1.5G solar light (power density of 100 mW/cm2). A charge separation and transfer mechanism was proposed for the ZnO nanorods stacking electrode-based DSSCs. PMID- 27451678 TI - Synthesis and Characterization of alpha-ZrP@CHI Drug Deliver System. AB - This paper described the controlled synthesis and release properties of a new kind of multifunctional drug-release system which was prepared by encapsulation of zirconium bis-(monohydrogen orthophosphate) monohydrate (alpha-ZrP) with chitosan (CHI). As obtained the alpha-ZrP@CHI nanocomposites were found to possess the structural features of both alpha-ZrP and CHI. The release properties of the alpha-ZrP@CHI nanocomposites were evaluated using Gentamicin sulfate as the model drug. And alpha-ZrP@CHI composites showed a prolonged drug release time compared with alpha-ZrP, which can be attributed to the unique lamellar structure and the encapsulation with CHI. The controlled synthesis of alpha-ZrP@CHI nanocomposite thus provided a new opportunity for future development of delivery vehicles. PMID- 27451679 TI - Optical Limiting Properties of Graphene/Polymer Composites. AB - Graphene oxide (GO) was doped into four polymers films: Poly(methyl methacrylate) (PMMA), polystyrene (PS), polycarbonate (PC), and polyacrylonitrile (PAN). Following that, their optical limiting properties were investigated at 532 nm. In order to make GO hydrophobic, the lipophilic alkyl chains were connected to GO. The results showed that GO/PAN composite possesses better non-linear response than the other three composites at the same transmission (T ~ 59%). The reason were attributed to the thermal effect coming from high input fluence of laser, which improved the cross link density of PAN and further enhanced the interaction between the GO-ODA and PAN. Meanwhile, GO/PC and GO/PS had similar optical limiting property and GO/PMMA film gave the weakest optical limiting effect in our experiment. PMID- 27451680 TI - Citrate-Complexation Synthesis and Photoluminescence Properties of Y6MoO12:Eu Nanocrystalline. AB - Y6MoO12 doped with Eu3+ was synthesized using a citrate-complexation route, and was calcined at 800 degrees C and 1400 degrees C, respectively. The structure, morphology and photoluminescence (PL) properties of the samples, and their dependence on the crystallite size were investigated. XRD patterns indicate that the Y6MoO12:Eu3+ powder was obtained at both calcination temperatures, and had a cubic structure. The results also suggest that Y6MoO12:Eu3+ calcined at 800 degrees C was in the nanocrystalline phase, which was confirmed by the SEM microimage. The crystalline size was about 140 nm. Both phosphors could be excited via three channels: f-f excitation of Eu3+ by blue light, MoO groups excitation by near-UV light, and charge transfer state excitation of Eu3+ by UV light. Both samples yielded red light emissions dominated by the 5D0-7F2 transition at 613 nm. The excitation efficient of the three channels depended on the calcination temperature. The energy transfer from the MoO groups to the Eu3+ ions was more effective in the nanocrystalline phase. The temporal decay feature of the phosphor was also characterized. PMID- 27451681 TI - Optical Temperature Sensor Based on Infrared Excited Green Upconversion Emission in Hexagonal Phase NaLuF4:Yb3+/Er3+ Nanorods. AB - Hexagonal phase NaLuF4:Yb3+/Er3+ nanorods were synthesized hydrothermally. An analysis of the intense green upconversion emissions at 525 nm and 550 nm in hexagonal phase NaLuF4:Yb3/+Er3+ nanorods under excitation power density of 4.2 W/cm2 available from a diode laser emitting at 976 nm, have been undertaken. Fluorescence intensity ratio (FIR) variation of temperature-sensitive green upconversion emissions at 525 nm and 550 nm in this material was recorded in the physiological range from 295 to 343 K. The maximum sensitivity derived from the FIR technique of the green upconversion emissions is approximately 0.0044 K-1. Experimental results implied that hexagonal phase NaLuF4:Yb3/+Er3+ nanorods was a potential candidate for optical temperature sensor. PMID- 27451682 TI - Improving the Fluorescence Concentration Quenching of Porphyrin Potassium Salt by Ag Nano Colloids. AB - Silver nanoparticles (NPs) with diameters less than 25 nm, and 5, 10, 15, 20 tetrakis(4-carboxyphenyl) porphyrin potassium salt (K4TCPPS) was synthesized. By adding silver colloids into the K4TCPPS solutions, the fluorescence concentration quenching of the K4TCPPS solutions was improved between 1 x 10(-6) - 5 x 10(-4) M, depending on the size of the Ag NPs, the concentration of the K4TCPPS and the excitation wavelength. Under excitation wavelengths of 360 and 414 nm, the enhancement was in the range of 0.34-22.8, and 0.71-82.46, respectively. The enhancement increased with decreasing size of the Ag NPs. At the two highest enhancements, the concentrations of the K4TCPPS solutions were 1 x 10(-4) and 1 x 10(-5) M respectively, and the size of the Ag NPs was about 5 nm. The main reasons for the fluorescence enhancing effect are due to fluorescence resonance energy transfer (FRET) between K4TCPPS molecules and Ag NPs, and decreased collision quenching between free K4TCPPS molecules, and free K4TCPPS molecules with Ag NPs. Our results showed that Ag NPs with sizes of about 5 nm can effectively improve the fluorescence concentration quenching of K4TCPPS solutions. This result also suggests that it is possible to use noble metal NPs to improve fluorescence concentration quenching. PMID- 27451683 TI - Mechanism of Biological Compatibility of Water-Soluble Yb3+, Er3+ Codoped NaYF4 Nanoparticles. AB - Water soluble NaYF4 nanocrystals codoped with 20 mol% Yb3+, 2 mol% Er3+ were prepared by a facile solvothermal approach using polyvinylpyrrolidone (PVP) as a surfactant. As a potential material for luminescent probes, in votroeffects of upconversion nanoparticles (UCNPs) on human aenocarcinoma (SGC-7901) cells with different concentrations were observed. These effects range from cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, AnnexinV-FITC-propidium iodide (PI) apoptosis detection, and cell cycles. Our results demonstrated that the cells treated with UCNPs showed a decrease in cell viability accompanied the decreased MMP and the release of ROS. When treated with 400 ug/mL UCNPs, AnnexinV-FITC-PI apoptosis detection showed the UCNPs induced apoptosis, the cell cycle indicated the UCNPs suppressor cells in the G1 phase obviously, thereby reducing cell activity. PMID- 27451684 TI - Improved Mobility and Bias Stability of Thin Film Transistors Using the Double Layer a-InGaZnO/a-InGaZnO:N Channel. AB - The amorphous indium-gallium-zinc oxide (a-IGZO) thin film transistors (TFTs) were demonstrated based on a double-layer channel structure, where the channel is composed of an ultrathin nitro-genated a-IGZO (a-IGZO:N) layer and an undoped a IGZO layer. The double-layer channel device showed higher saturation mobility and lower threshold-voltage shift (5.74 cm2/Vs, 2.6 V) compared to its single-layer counterpart (0.17 cm2/Vs, 7.23 V). The improvement can be attributed to three aspects: (1) improved carrier transport properties of the channel by the a-IGZO:N layer with high carrier mobility and the a-IGZO layer with high carrier concentration, (2) reduced interfacial trap density between the active channel and the gate insulator, and (3) higher surface flatness of the double-layer channel. Our study reveals key insights into double-layer channel, involving selecting more suitable electrical property for back-channel layer and more suitable interface modification for active layer. Meanwhile, room temperature fabrication amorphous TFTs offer certain advantages on better flexibility and higher uniformity over a large area. PMID- 27451685 TI - Improved Near-Infrared Up-Conversion Emission of Tm3+ Sensitized by Yb3+ and Ho3+ in LuF3 Nanocrystals. AB - In the present work, mono-disperse and uniform orthorhombic lutetium fluoride (LuF3) nanocrystals with an average size of about 35 nm have been successfully synthesized by a simple ionothermal method without any template. The infrared (IR) to visible up-conversion (UC) photoluminescence of LuF3 doped with Yb3+, Tm3+, and Ho3+ under 980 nm excitation was systemically studied. The intensity of near infrared (NIR) to visible up-conversion emission of Tm3+ was improved efficiently by adding Yb3+ and Ho3+ in LuF3, especially for the broad NIR emission band located at 812 nm. Meanwhile, compared to the Yb3+ and Tm3+ co doped LuF3, the ratio of red to green emission in the Yb3+, TmS+, and HoS+ co doped LuF3 changed greatly, and a bright yellowish-green emission was observed under 980 nm laser excitation. It shows that Yb3+, Tm3+ and Ho3+ co-doped LuF3 nanocrystals provided a potential application in vitro and in vivo bio-imaging, color displays and optical storage. PMID- 27451686 TI - Growth and Properties of Cl- Incorporated ZnO Nanofilms Grown by Ultrasonic Spray Assisted Chemical Vapor Deposition. AB - Pure and Cl- incorporated ZnO nanofilms were grown by the ultrasonic spray assisted chemical vapor deposition (CVD) method. The properties of the nanofilms were investigated. The effects of growth temperature and Cl- concentration on the crystal structure, morphology, and optical properties of the nanofilms were studied. Temperature plays an important role in the growth mode and morphology of the pure nanofilms. Preferential growth along the c-axis occurs only at modulating temperature. Lower temperature suppresses the preferential growth, and higher temperature suppresses the growth of the nanofilms. The morphologies of the nanofilms change from lamellar and spherical structures into hexagonal platelets, then into separated nanoparticles with an increase in the temperature. Incorporating Cl- results in the lattice contracting gradually along with c-axis. Grains composing the nanofilms refine, and the optical gap broadens with increasing of Cl- concentration in growth precursor. Incorporating Cl- could reduce oxygen vacancies and passivate the non-irradiated centers, thus enhancing the UV emission and suppressing the visible emission of ZnO nanofilms. PMID- 27451687 TI - An Electrostatically Self-Assembled Thin Film Made of Zn-Substituted Tungstoborate and Rhodamine B with Photoelectrochemical Properties. AB - An electrostatically self-assembled multilayer thin film consisting of alternating layers of Keggin polyoxometalate of Zn-substituted tungstoborate (BW11Zn) and Rhodamine B (RhB) has successfully been prepared on a quartz and indium-tin oxide (ITO) glass substrate. The ultraviolet-visible (UV-vis) absorption spectra demonstrated that the electrostatically self-assembled film of (BW11Zn/RhB)n was uniformly deposited layer by layer, and the RhB molecules in the film formed the J-aggregation. The photoelectrochemical investigations showed that the films generated stable cathodic photocurrents that originated from RhB, and the maximal cathodic photocurrent density generated by an eight-layer film was 4.9 uA/cm2 while the film was irradiated with 100 mW/cm2 polychromatic light of 730 nm > lambda > 325 nm at an applied potential of 0 V versus a saturated calomel electrode. PMID- 27451688 TI - Near-infrared Quantum Cutting for Solar Cells in Ce3+-Yb3+ Co-Doped CaF2 Nanoparticles. AB - A series of Ce3+-Yb3+ co-doped CaF2 nanoparticles were prepared by a hydrothermal synthesis method. The structure, morphology, photoluminescence properties, and fluorescence dynamics were studied systemically. Under the excitation of the 5d level of Ce3+, an efficient energy transfer from Ce3+ to Yb3+ occurred, and the efficient near-infrared emission at 900-1050 nm matching to the energy of Si band gap of Si-based solar cells was observed. The lifetime of Ce3+ decreased, and the inner quantum efficiency increased with increasing Yb3+ concentration. The quantum efficiency dependent on Yb3+ concentration was calculated, and the maximum efficiency approached 186%. As a down-conversion luminescent convertor, this kind of material can be used in front of Si-based solar cells to reduce thermalization loss and enhance conversion efficiency of solar cells. PMID- 27451689 TI - Luminescence Properties of Self-Activated Mm(VO4)2 (M = Mg, Ca, Sr, and Ba) Phosphors Synthesized by Solid-State Reaction Method. AB - In this paper, M3(VO4)2 (M = Mg, Ca, Sr, and Ba) self-activated phosphors were prepared by a solid-state reaction method at 1,000 degrees C for 5 h. The phase formation and micrographs were analyzed by X-ray diffraction and scanning electron microscopy. The Ca3(VO4)2 phosphor does not show any emission peaks under excitation with ultraviolet (UV) light. However, the M3(VO4)2 (M = Mg, Sr, and Ba) samples are effectively excited by UV light chips ranging from 200 nm to 400 nm and exhibit broad emission bands due to the charge transfer from the oxygen 2p orbital to the vacant 3d orbital of the vanadium in the VO4. The color of these phosphors changes from yellow to light blue via blue-green with increasing ionic radius from Mg to Sr to Ba. The luminescence lifetimes and quantum yield decrease with the increasing unit cell volume and V-V distance, in the order of Mg3(VO4)2 to Sr3(VO4)2 to Ba3(VO4)2. The emission intensity decreases with the increase of temperatures, but presents no color shift. This confirms that these self-activated M3(VO4)2 phosphors can be suggested as candidates of the single-phase phosphors for light using UV light emitting diodes (LEDs). PMID- 27451690 TI - Upconversion Luminescence Properties of Er3+ Doped Yb2Ti20 Nanophosphor by Gd3+ Codoping. AB - Er3+ doped Yb2Ti207 nanophosphors by Gd3+ codoping with nominal composition of (Er0.05Yb0.95-xGd3+)2Ti2O7 (x = 0, 0.2, 0.4, 0.6, 0.8, and 0.95) have been prepared by sol-gel method. Er3+-Gd3+ codoped Yb2Ti2O7 was characteristic of a typical face-centered cubic crystal phase, and the unit cell parameter increased linearly with the increase of Gd3+ concentration. Under a 976 nm laser diode excitation, both green and red upconversion emissions were observed and the upconversion emissions were enhanced significantly by Gd3+ codoping, showing the strongest green and red emissions at 80 mol% Gd3+ codoping. The intensity ratio of green to red emissions (Igreen/Ired) increased monotonously with the increase of Gd3+ concentration. The energy transfer between Yb3+ and Er3+ and the variation of local crystal field symmetry of Er3+ by the substitution of Yb3+ by Gd3+ ions led to the improvement of upconversion properties of Er3+-Gd3+ codoped Yb2TiO7 nanophosphors. PMID- 27451691 TI - Synthesis and Luminescence Studies of Sm3+ Doped Ca9Y(PO4)7 Orange-Red-Emitting Phosphor. AB - Ca9Y(PO4)7:Sm3+ phosphor was prepared via solid state reaction. The crystal structure of the phosphor was characterized by X-ray powder diffraction (XRD). The photoluminescence (PL) properties of CagY(PO4)7:Sm3+ were investigated. The emission of the Ca9Y(PO4)7:Sm3+ phosphor consisted of some sharp emission peaks of Sm3+ centered at 563 nm, 600 nm, and 647 nm. The strongest one is located at 600 nm due to the 4G5/2-6H7/2 transition of Sm3+. The critical distance was calculated to be 10.5 A. The chromatic properties of the sample Ca9Y(PO4)7:Sm3+ phosphor were located in the orange reddish region. The CagY(PO4)7:Sm3+ phosphor may be potentially used as red phosphor for white light-emitting diodes (WLED). PMID- 27451692 TI - Self-Assembled NaTb1-xEux(MoO4)2: Synthesis and Luminescence Properties. AB - Novel 3D Eu3+ doped NaTb(MoO4)2 composites were successfully self-assembled by a facile hydrothermal treatment. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and photoluminescence (PL) spectra were used to characterize the structures, morphologies and the luminescent properties of as-prepared products. Emission and excitation spectra showed that the phosphor exhibits a dominant red emission at 615 nm with excitation wavelength of 465 nm at room temperature. The emission intensity increased with the increase of Eu3+ concentrations for the investigated range of 2-10 mol% Eu3+ doping in NaTb(MoO4)2. The doping of Eu3+ results in a distorted Eu-0. cluster and enhanced luminescence intensity. PMID- 27451693 TI - Uniform Cerium-Based Coordination Polymer Microsnheres: Preoaration and Upconversion Emission. AB - Homogeneously doped Yb3+ and Er3+ cerium-based coordination polymer (CP) microspheres have been successfully synthesized on a large scale through a simple solvothermal route with 2,5-pyridinedicarboxylic acid (2,5-H2PDC) as the organic linker. CeO2: Yb3+, Er3+ porous microspheres were obtained by annealing the corresponding CP microspheres at 600 degrees C for 4 h under atmospheric pressure. These as-prepared products were characterized by Powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), energy dispersion X-ray (EDX) spectroscopy, Thermogravimetric (TG) and derivative thermogravimetric (DTG) analysis. The room temperature upconversion luminescent spectra of the as-prepared microspheres were carried out by 980 nm NIR light excitation. Interestingly, Yb3+ and Er3+ codoped CP microspheres give a single band emission centered at 673 nm, while the CeO2: Yb3+, Er3+ microspheres give emission in green and red region, with red being the dominant emission. The emission intensity of the CeO2: Yb3+, Er3+ microspheres were much stronger than that of the Yb3+ and Er3+ codoped CP microspheres. PMID- 27451694 TI - Morphology Controllable Synthesis of ScF3:Er3+, Yb3+ Nano/Sub-Microncrystals by Hydrothermal/Solvothermal Process. AB - In this paper, red phosphors Yb3+-Er3+ co-doped ScF3 nano/microcrystals were successfully prepared by a facile hydrothermal/solvothermal route using the sodium dodecyl benzene sulfonate (SDBS) as the surfactant. The structure, morphologies and up-conversion (UC) photoluminescence properties of the as prepared products were well characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and photoluminescence (PL) spectra, respectively. The SEM images show that the obtained samples are the uniform cubic and cuboid crystals. With the increase of the surfactant SDBS or the change in the solvent types, the sample change their size from nanometer to submicron. Upon the 980 nm laser diode excitation, the ScF3:Era+, Yb3+ nanocrystals exhibit red emission which can be assigned to the characteristic 4F9/2/4I15/2 transition of Er3+. In order to understand the emission mechanisms of ScF3:ErS+, Yb3+ nanocrystals, the dependence of UC luminescence intensity on the 980 nm excitation power was measured, suggesting that the UC phenomenon results from a two-photon process. Meanwhile, the emission intensities of the YbS+-Er3+ codoped ScF3 nano/sub-micro crystals with different solution composition show an obvious change under the 980 nm laser excitation. Therefore, the phosphors Yb3+-Er3+ co-doped ScF3 possibly have a potential application in the biological applications. PMID- 27451695 TI - The Upconversion Luminescence Properties of Er3+/Tm3+, Yb3+-Codoped Cubic BaLiF3. AB - Cubic BaLiF3 samples were prepared using a facile surfactant-assisted hydrothermal-microemulsion method. The samples were characterized by X-ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). The upconversion luminescence (UCL) properties of the Er3+/Tm3+, Yb3+- codoped BaLiF3 samples were measured under a 980 nm excitation wavelength. Moreover, the effects of varying the concentration of Li+ ions on the luminescence properties of Er3+, Yb3+ codoped BaLiF3 were also investigated. The Tm3+, Yb3+ codoped BaLiF3 samples displayed multi-color emissions. This behavior can be explained by the pump power dependence of the upconversion emissions and the energy levels diagram. PMID- 27451696 TI - Temperature-Dependent Photoluminescence of Zn-Cu-In-S Quaternary Nanocrystals with Different Reaction Time. AB - Non-toxic, environment-benign colloidal ZnCulnS Nanocrystals (ZCIS NCs) were synthesized and the temperature dependence of the photoluminescence (PL) energy, line width, and intensity for the ZCIS NCs with different reaction time were studied in the temperature range from 50 to 280 K. Generally, for typical ZCIS NCs ensemble, it has been constantly observed that the PL peaks energy decrease with the experimental temperature raising and the value of Eg(0) decrease with the increase of reaction time. Furthermore, the full width at half maximums (FWHM) of the PL spectra increased with the experimental temperature raising. It was found that the temperature dependence of the integrated PL intensity of ZCIS NCs decrease with the experimental temperature raising and the intensity decrease much with increasing reaction time. PMID- 27451697 TI - Correlated Color Temperature Tunable White Electroluminescence from Cadmium-Free ZnS Quantum Dots. AB - We propose correlated color temperature tunable white light-emitting from different sizes cadmium-free quantum dots (QDs) without organic ligand modulation. A size series of free-standing ZnS QDs were prepared by coprecipitation method. Experimental results show that the broad electroluminescences (EL) spectra from all samples cover almost the entire visible region and the electroluminescence peak is significantly redshifted from 489 to 580 nm with ZnS QDs sizes increasing from 1.1 to 4 nm. Moreover, the chromaticity coordinates calculated from EL spectra are (0.27, 0.36), (0.36, 0.42) and (0.42, 0.46) for QDs with average sizes 1.1, 2 and 4 nm drived at 15 V respectively, correspondingly, white EL spectra with a continuously tunable color changes from bluish white (CCT = 12400 K) to yellowish white (CCT = 3700 K). The differences between the photoluminescence (PL) and EL spectra were observed. Furthermore, the comparison between EL and PL spectra and active defect-levels of ZnS QDs with various sizes are discussed to understand the mechanism of the tunable spectra. The results offer that a convenience method to obtain tunable EL spectra in white color from ZnS QDs defects by controlling the size of the QDs. PMID- 27451698 TI - Preparation of LaF3:Eu3+ Based Inorganic-Organic Hybrid Nanostructures via an Ion Exchange Method and Their Strong Luminescence. AB - Lanthanide doped inorganic-organic hybrid nanostructures have received much attention in recent years due to their strong luminescence sensitized by organic ligands via an energy transfer route. In this work, an ion exchange method was used to prepare Eu3+ doped LaF3 based inorganic-organic hybrid nanostructures with organic ligands. The undoped LaF3 nanoparticles were first synthesized by a hydrothermal method, and Eu3+ ions were then ion exchanged into these LaF. nanoparticles to form the Eu3+ doped LaF3 nanoparticles, which were then used to prepare the inorganic-organic hybrid nanostructures with benzoic acid and 2 thenoyltrifluoroacetone. As a result of the luminescence sensitization, strong luminescence was observed in these inorganic-organic hybrid nanostructures, and the luminescence enhancement was over 40 times. Dependence of the luminescence of the hybrid nanostructures on the doping concentration and amount of organic ligands was studied in detail, and optimization was conducted to obtain the maximum luminescence for the hybrid nanostructures. PMID- 27451699 TI - Enhanced Photoluminescence Properties of Carbon Dots by Doping with Europium. AB - Europium (Eu) doped carbon dots (CDs) were synthesized via a rapid and simple microwave medi- ated method using polyethylene glycol (PEG) as a precursor, and characterized in detail. The results were that these as-prepared CDs showed a uniform and small particle size, and exhibit good pho- tostability and high photoluminescence quantum yields. Additionally, it also found that the doped Eu would change the fluorescence properties, which indicates potential applications in the field of biolabeling. PMID- 27451700 TI - Color Tunable and Upconversion Luminescence in Yb-Tm Co-Doped Yttrium Phosphate Inverse Opal Photonic Crystals. AB - For this paper, YPO4: Tm, Yb inverse opals with the photonic band gaps at 475 nm and 655 nm were prepared by polystyrene colloidal crystal templates. We investigated the influence of photonic band gaps on the Tm-Yb upconversion emission which was in the YPO4: Tm Yb inverse opal photonic crystals. Comparing with the reference sample, significant suppression of both the blue and red upconversion luminescence of Tm3+ ions were observed in the inverse opals. The color purity of the blue emission was improved in the inverse opal by the suppression of red upconversion emission. Additionally, mechanism of upconversion emission in the inverse opal was discussed. We believe that the present work will be valuable for not only the foundational study of upconversion emission modification but also the development of new optical devices in upconversion lighting and display. PMID- 27451701 TI - Upconversion Luminescence Properties of NaYF4 Nanocrystals Precipitated Nd3+/Nb3+/Ho3+ Tri-Doped Oxyfluoride Glass Ceramics. AB - Transparent oxyflouride glass ceramics composed of SiO2-Al2O3-Na2O-NaF-YF3 tri coped with Nd3+/Yb3+/Ho3+ were prepared by thermal treatment. Segregation of NaYF4 nanocrystals in the matrix was confirmed from structural analysis by means of X-ray diffraction and transmission electron microscopy. Compared with glass samples, very strong green upconversion (UC) luminescence due to the Ho3+: (4F5, 5S2) --> 51(8) transition was observed in the glass ceramics under 808 nm excitation. It was found that upconversion intensity of Ho3+ strongly depends on the Nd3+ concentration, and the energy transfer process from Nd3+ to Ho3+ via Yb3+ was proposed. PMID- 27451702 TI - Effect of Ce3+ Concentration on the Luminescence Properties of Ce3+/Er3+Nb3+ Tri Doped NaYF4 Nanocrystals. AB - In order to investigate the effect of Ce3+ concentration on the emission properties of ErS+/y3+ codoped NaYF4 nanocrystals, Ce3+/Er3+/Yb3+ tri-doped NaYF4 nanocrystals were prepared through a facile EDTA-assisted hydrothermal method. The upconversion .(UC) and the near infrared (NIR) emission properties of Er3+ ions were systematically investigated in the NaYF4:Ce3+/Er3+/Yb3+ nanocrystals. Under 980 nm excitation, with the increasing of Ce3+ concentration, the emission intensity of Er3+ at 1550 nm (4I13/2 --> 4I15/2) band increases initially and then decreases. The increase of the fluorescence intensity of 1550 nm is due to the energy transfer between Er+ and Ce3+ ions: Er3+:4(11/2)+Ce3+:2F5/2 --> Er3+:4I13/2 +Ce3+:2F7/2. But when Ce3+ doping concentration is 2.0%, the cross relaxation:Er3+:4I13/2+ Ce3+:2F5/2 --> Er3+:4I15/2+Ce3+:2F7/2 happens, which depopulates the 4113/2 level of Er3+ and results in the decrease of the emission intensity of Er3+ at 1550 nm band. Meanwhile, incorporation of Ce3+ dramatically decreases the visible UC emission intensity. A possible emission mechanism was proposed. PMID- 27451703 TI - Tuning Upconversion Emission of beta-NaGdF4:Yb+/Ho3+ Nanorods Through Yb3+. AB - Yb3+/Ho3+ doped hexagonal NaGdF4 nanocrystals are synthesized through solvothermal method, for which pure hexagonal phased nanorods are presented. The concentration influence of Yb3+ ions on the sample morphology and fluorescence emission of Ho3+ is investigated. It is found that the sample size is changed from 25 nm to 125 nm and the upconversion emission is tuned from green to yellow when the concentration of Yb3+ ions is increased from 5.0 mol% to 50.0 mol%. The possible upconversion mechanism and the improvement of crystallinity are carefully investigated. It is suggested that the cross-relaxation process between Ho3+ ions promotes the red emission and quenches the green emission. PMID- 27451704 TI - Ag@SiO2/LaF3:Eu3+ Composite Nanostructure and Its Surface Enhanced Luminescence Effect. AB - Ag@SiO2/LaF3:Eu3+ core-shell nanostructure was synthesized with a wet chemical method in which the SiO2 layer functioned as a separation layer between Ag-core and LaF3:Eu3+ luminescence material. With this system, surface enhanced luminescene of LaF3:Eu3+ with Ag substrate was investigated, and an obvious enhancement effect was observed. The dependence of the luminescence enhancement on the distance between the luminescence shell and the metallic core was studied too. It is believed that the enhancement effect presented by the current hybrid nanostructure system has great potential in the development of photovoltaic cells. PMID- 27451705 TI - A New Kind of Blue Hybrid Electroluminescent Device. AB - Bright blue Electroluminescence come from a ITO/BBOT doped silica (6 x 10(-3) M) made by a sol-gel method/Al driven by AC with 500 Hz at different voltages and Gaussian analysis under 55 V showed that blue emission coincidenced with typical triple emission from BBOT. This kind of device take advantage of organics (BBOT) and inorganics (silica). Electroluminescence from a single-layered sandwiched device consisting of blue fluorescent dye 2,5-bis (5-tert-butyl-2-benzoxazolyl) thiophene (BBOT) doped silica made by sol-gel method was investigated. A number of concentrations of hybrid devices were prepared and the maxium concentration was 6 x 10(-3) M. Blue electroluminescent (EL) always occurred above a threshold field 8.57 x 10(5) V/cm (30 V) at alternating voltage at 500 HZ. The luminance of the devices increased with the concentration of doped BBOT, but electroluminescence characteristics were different from a single molecule's photoluminescence properties of triple peaks. When analyzing in detail direct current electroluminescence devices of pure BBOT, a single peak centered at 2.82 eV appeared with the driven voltage increase, which is similar to the hybrid devices. Comparing Gaussian decomposition date between two kinds of devices, the triple peak characteristic of BBOT was consistent. It is inferred that BBOT contributed EL of the hybrid devices mainly and silica may account for a very small part. Meanwhile the thermal stability of matrix silica was measured by Thermal Gravity-Mass Spectroscopy (TG-MS). There is 12 percent weight loss from room temperature to 1000 degrees C and silica has about 95% transmittance. So the matric silica played an important role in thermal stability and optical stability for BBOT. In addition, this kind of blue electroluminescence device can take advantages of organic materials BBOT and inorganic materials silica. This is a promising way to enrich EL devices, especially enriching inorganic EL color at a low cost. PMID- 27451706 TI - Optical Temperature Sensing Behavior Through Stark Sublevels Transitions of Green and Red Upconversion Emissions for Er3+-Yb3+-Li+ Codoped TiO2 Phosphors. AB - The Er3+-Yb3+-Li+ codoped TiO2 phosphors have been prepared by sol-gel method. The green and red upconversion emissions were observed under a 976 nm laser diode excitation, which were ascribed to 2H11/2 --> 4I15/2, 4S3/2(I)/4S3/2(II) - >4I15/2, and 4F9/2(I)/4F9/2(II) -->4I15/2 transitions of Er3+ Stark sublevels. The fluorescence intensity ratios (FIR), which are corresponding to the transitions of 2H11/2/(4S3/2(I)+4S3/2(II))--> 4I5/2, 4S3/2(I)/4S3/2(II) - >4I15/2, and 4F9/2(II)/4F9/2(II) -->4I15/2, have been studied as a function of temperature in the range of 303 673 K. The temperature sensitivities have been calculated at the maximum value of 0.0020 K-1, 0.0015 K-1, and 0.0011 K-1 at the temperatures of 427 K, 350 K, and 273 K for the three coupled energy level transitions, respectively. The Er3+-Yb3+-Li+ codoped Ti02 phosphor with different temperature sensitivities by Stark sublevels indicated that it is a promising material for application in optical temperature sensing at a wide range of temperature. PMID- 27451707 TI - The Size Confinement Effect for Eu3+ Concentration Quenching and Energy Transfer in YVO4 Nanocrystal. AB - YVO4: Eu3+ nanocrystal powders (~30 nm) with different doping concentrations were prepared using a precipitation method. Bulky powders (~500 nm) were obtained by annealing the nanopowders at high temperature. The concentration quenching of luminescent centers and energy transfer in YVO4: Eu3+ powders were investigated. It was found that quenching concentration for Eu3+ 5D0--> 7F2 transition emission in nanopowders is distinctly higher than that in bulk powders. The type of energy transfer that caused concentration quenching was identified to be electric dipole dipole interaction in bulk powders and exchange interaction in nanopowders. The electric dipole-dipole interaction is a long-range interaction (operating range of several nanometers). The size confinement effect of boundary in nanoparticles has obvious inhibitory effect on electric dipole-dipole interaction, and hardly affect the exchange interaction which is a short-range interaction (operating range several angstroms). The electric dipole-dipole interaction is restrained by particle boundary in nanopowders. So energy transfer of Eu3+ ions in nanomaterials is dominated by exchange interaction, and quenching concentration of nanomaterials is higher than in bulky materials. PMID- 27451708 TI - Effect of Tourmaline-Doped on the Far Infrared Emission of Iron Ore Tailings Ceramics. AB - Iron ore tailings as secondary resources have been of great importance to many countries in the world. Their compositions are similar to that of infrared emission ceramics, but there are few reports about it. In addition, tourmaline has high infrared emission properties due to its unique structure. With the purpose of expanding functional utilization of iron ore tailings, as well as reducing the production cost of far infrared ceramics, a new kind of far infrared emission ceramics was prepared by using iron ore tailings, calcium carbonate, silica, and natural tourmaline. The ceramics powders were characterized by Fourier transform infrared spectroscope, X-ray diffraction and scanning electron microscopy, respectively. The results show that after being sintered at 1065 degrees C, the percentage of pseudobrookite and lattice strain of samples increased with increasing the elbaite content. Furthermore, the added tourmaline was conducive to the densification sintering of ceramics. The appearance of Li-O vibration at 734.73 cm-1, as well as the strengthened Fe-O vibration at 987.68 cm 1 were attributed to the formation of Li0.375Fe1.23Ti1.4O5 solid solution, which led the average far infrared emissivity of ceramics increase from 0.861 to 0.906 within 8-14 um. PMID- 27451709 TI - Photoluminescence and Photocatalytic Activity of Bi2MoO6:Ln3+ Nanocrystals. AB - Sheet-like Bi2MoO6:Ln3+ nanocrystals were synthesized by a hydrothermal method. The crystalline size of Bi2MoO6:Ln3+ (Ln = Eu and Gd) nanocrystals changes gradually with the increasing of Ln3+ content in the reaction solutions. The photoluminescence properties of Bi2MoO6:Ln3+ nanocrystals were investigated in detail. In the emission spectra of Bi2MoO6:Eu3+ nanocrystals the 5D0-->7F2 is much stronger than the 5D0 --> 7F1 and is the strongest when the excitation is performed at 467 nm. The relative intensity of the transitions from Eu3+ increased with increasing Eu3+ concentrations, up to about 50 mol%, and then decreased abruptly. In the excitation spectra of Bi2MoOI:Eul+ (30%)/Gd3+ monitored at 618 nm, the 7F0 --> 5D2 (~467 nm) transition is dominating when the Gd3+ concentrations were 10% or 20%. When the Gd3+ concentration was 30%, the 7FO -> D1 (~538 nm) transition is dominating. In addition, the photocatalytic activity of Bi2MoO6:Eu3+ was evaluated by the degradation of rhodamine B (RhB) aqueous solution under simulated solar light. The best photocatalytic performance was observed when the Eu3+ concentration was 1%. PMID- 27451710 TI - Structure and Optimum Luminescence for Nearly Block-Like LaOCl:Eu3+ Nanoparticles. AB - In this work, we report a simple method for the synthesis of block-like Eu3+ doping LaOCl nanophosphors with different doping content. It was found that the average grain diameter of Eu3+ doping LaOCl samples decreased with increasing Eu3+ doping concentration. The lattice volume shrinked due to different response for different axial under high pressure that led to lower lattice symmetry of LaOCl:Eu3+. The emission of LaOCI:Eu3+ increased with the increasing Eu3+ concentration due to the lower local symmetry, which also led to a gradual reduction in lifetime. PMID- 27451711 TI - Synthesis and Characteristic of the NaYF4/Fe3O4@SiO2@Tb(DBM)3 . 2H2O/SiO2 Luminomagnetic Microspheres with Core-Shell Structure. AB - The structure and properties of the multifunctional nanoparticles were characterized by X-ray diffraction (XRD), Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), Photoluminescence spectra and Vibrating sample magnetometer (VSM). The experimental results show that the microsphere has the magnetic core and silica shell bonded with terbium complex. These multifunctional nanoparticles exhibit strong visible emission and up conversion emission, which is based on the use of up-converting nanoparticles (UCNPs) of the NaYF4:Yb3+, Er3+/Tm3+ type that can be excited with 980 nm laser light to give a green and red luminescence, moreover, nanoparticles possess magnetism with a saturation magnetization of 18.48 emu/g and paramagnetism at room temperature. PMID- 27451712 TI - SiC Nanowire Film Photodetectors: A Promising Candidate Toward High Temperature Photodetectors. AB - In this study, UV photodetectors (PDs) based on SiC nanowire films have been successfully prepared by a simple and low-cost drip-coating method followed by sintering at 500 degrees C. The corresponding electrical characterizations clearly demonstrate that the SiC nanowire based PD devices can be regarded as a promising candidate for UV PDs. The PDs can exhibit the excellent performances of fast, high sensitivity, linearity, and stable response, which can thus achieve on line monitoring of weak UV light. Furthermore, the SiC nanowire-based PDs enable us to fabricate detectors working under high temperature as high as 150 degrees C. The high photosensitivity and rapid photoresponse for the PDs can be attributed to the superior single crystalline quality of SiC nanowires and the ohmic contact between the electrodes and nanowires. PMID- 27451713 TI - Synthesis and Upconversion Luminescence of High-Quality Water-Soluble NaYF4:Yb3+,Er3+ Nanoclusters. AB - Hexagonal phase NaYF4:Yb3+,Er3+ nanoclusters were prepared using a facile solvothermal method. The structures and morphologies of the products were investigated using an X-ray powder diffractometer and a transmission electron microscope. Modified by the capping agent of poly(acrylic acid), the as-prepared NaYF4 NCs show excellent water solubility. Under 980-nm excitation, the aqueous solution of the sample displayed a bright green upconversion (UC) fluorescence. The luminescence dynamics were further studied based on the UC excitation pathways and the emission processes. Such water soluble UC samples may find application in the field of biological imaging. PMID- 27451714 TI - Hydrothermal Synthesis and Aspect Ratio Dependent Upconversion Luminescence of NaYF4:Yb3+/Er3+ Microcrystals. AB - beta-NaYF4:Yb3+,Er3+ microcrystals of good shape and with various aspect ratios were successfully prepared using a facile hydrothermal method. Field emission scanning electron microscope images and X-ray diffraction patterns were used to characterize the resulting samples. The upconversion luminescence (UCL) properties of the products were investigated as a function of their aspect ratios. It was found that the proportion of green to red emission intensities increased from 0.8 to 1.4 in the range of aspect ratios 0.04 to 0.9. This study demonstrates a new strategy for the synthesis of UCL materials with different spectral properties simply by changing their aspect ratios. PMID- 27451715 TI - Highly Stable Transparent Electrodes Made from Copper Nanotrough Coated with AZO/Al2O3. AB - Due to their high flexibility, high conductivity and high transparency in a wide spectrum range, metal nanowires and meshes are considered to be two of the most promising candidates to replace the traditional transparent conducting films, such as tin doped indium oxide. In this paper, transparent conducting films made from copper nanotroughs are prepared by the electrospinning of polymer fibers and subsequent thermal evaporation of copper. The advantages of the technique include low junction resistance, low cost and low preparation temperature. Although the copper nanotrough transparent conducting films exhibited a low sheet resistance (19.2 Omega/sq), with a high transmittance (88% at 550 nm), the instability of copper in harsh environments seriously hinders its applications. In order to improve the stability of the metal transparent conducting films, copper nanotroughs were coated with 39 nm thick aluminum-doped zinc oxide and 1 nm thick aluminum oxide films by atomic layer deposition. The optical and electrical measurements show that coating copper nanotrough with oxides barely reduces the transparency of the films. It is worth noting that conductive oxide coating can effectively protect copper nanotroughs from thermal oxidation or acidic corrosion, whilst maintaining the same flexibility as copper nanotroughs on its own. PMID- 27451716 TI - Effects of Cu Dopant on Lattice and Optical Properties of ZnS Quantum Dots. AB - Doped and undoped ZnS colloidal nanocrystals have drawn much attention due to their versatile applications in the fields of optoelectronics and biotechnology. In this paper, Cu doped ZnS quantum dots were synthesized via the simple thermolysis of ethylxanthate salts. The lattice and optical properties of the nanocrystals were then studied in detail. The quantum dot lattice contracted linearly between Cu concentrations of 0.2-2%, while it continued to contract more gradually as Cu concentrations were further increased from 4 to 6%, due in part to the Cu ions located on the surface of the ZnS lattice. Cu incorporation induces a long tail in absorption at long wavelengths. The PL spectrum shows a red shift at first, and then a blue shift with increases in Cu concentration. Cu doped at low concentrations (0.2-1%) enhanced the emission, while high Cu concentrations (2-6%) quenched emissions. PMID- 27451717 TI - Synthesis of Au-SiO2 Composite Nanospheres and Their Catalytic Activity. AB - We report a simple and environmentally friendly approach to the synthesis of Au SiC2 composite nanospheres. Our method presents a route for the decoration of preformed amine functionalized SiO2 nanospheres by in situ formation of Au nanoparticles at three different concentrations of Au precursor (HAuCl4). Herein, the silane coupling agent (KH-550) is used as an intermediary to connect the Au nanoparticles to the surfaces of the SiO2 nanospheres, which helps avoid the aggregation of Au nanoparticles. The crystal structure, chemical elements, morphology and catalytic properties of the Au-SiO2 composite nanospheres were analyzed by transmission electron microscopy (TEM), X-Ray powder diffraction (XRD), UV-vis-spectrophotometer (UV-vis) and X-ray photoelectron spectroscopy (XPS). The analytical results demonstrate that the Au nanoparticles (4-9 nm) were homogeneously distributed on the surface of the SiO2 nanospheres, which had a good FCC crystal structure. Moreover, the Au-SiO2 composite nanospheres exhibited good catalytic properties, measured by their ability to reduce organic dyes. The Au-SiO2 composite nanospheres are promising candidates for applications in catalysis and wastewater treatment. PMID- 27451718 TI - Hydrothermal Synthesis and Luminescence Property of Nanoscaled BiPO4:Eu3+ Powders. AB - A series of Bi1-xPO4:xEu3+ phosphors were prepared using a simple hydrothermal method. The effects of pH and Eu3+ doping on the structure, morphology and luminescence properties of BiPO4:Eu3+ were investigated systematically. X-ray diffraction (XRD) and field emission scanning electron microscope (FE-SEM) results reveal that the as-prepared BiPO4 crystals are in a low temperature monoclinic phase (LTMP), and have a rod-like structure with a size in the range of 1-5 um at pH 1. Increasing the pH to 2 transforms the BiPO4 to its hexagonal phase (HP), with peanut-like structures ranging from 50 to 150 nm. At pH 1, when the doping level is increased to 0.07, the phase transformation from LTMP to HP occurs, meaning that the amount of HP components increase with increasing Eu3+ doping. Furthermore, all the diffraction peaks of the Bi1-xPO4:xEu3+ can be fitted very well to HP when x = 0.11. The photoluminescence (PL) spectra suggest that orange-red luminescence can be observed in the series of BiPO4:Eu3+ phosphors, and that concentration quenching occurs when x = 0.07. PMID- 27451719 TI - Performance Enhancement of Small Molecular Solar Cells by Bilayer Cathode Buffer. AB - An effective composite bilayer cathode buffer structure is proposed for use in small molecular solar cells. CsF was doped in Alq3 to form the first cathode buffer, leading to small serial resistances. BCP was used as the second cathode buffer to block the holes to the electrode. The optimized bilayer cathode buffer significantly increased the short circuit and fill factor of devices. By integrating this bilayer cathode buffer, the CuPc/C60 small molecular heterojunction cell exhibited a power conversion efficiency of up to 0.8%, which was an improvement of 56% compared to a device with only the Alq3 cathode buffer. Meanwhile, the bilayer cathode buffer still has a good protective effect on the performance of the device. PMID- 27451720 TI - Modification of Multilayer Carbon Nanotubes for the Removal of Arsenate. AB - The aim of this study was to explore a new nano-composite carbon adsorbent material for the removal of arsenic from water. The multilayer carbon nanotubes (MCNTs) were treated with different acids and/or modified with iron to create more surface COOH sites or Fe-impregnated MCNTs for the enhanced uptake of As(V). Tests were conducted as a function of initial As(V) concentrations, contact time, and solution pH. The coverage of ferric hydroxides on MCNTs and the uptake of As on Fe-MCNTs were independently confirmed by field emission scanning electron microscope and energy dispersive X-ray spectroscopy analyses. With an As(V) uptake capacities of 27 mg/g on Fe-MCNTs and 14 mg/g on acid-MCNTs, the material showed superior performance for As(V) removal. PMID- 27451721 TI - Raising the Thermoelectric Performance of Fe3CoSb12 Skutterudites via Nd Filling and In-Situ Nanostructuring. AB - p-type skutterudites NdxFe3CoSb12 with x equaling 0.8, 0.85, 0.9, 0.95, 1.0 have been synthesized by solid state reaction followed by spark plasma sintering. The influence of Nd filling on electrical and thermal transport properties has been investigated in the Nd-filled skutterudite compounds in the temperature range from room temperature to 800 K. It was found that the Seebeck coefficient is drastically enhanced via filling Nd in p-Type skutterudites as well as the corresponding power factor although electrical conductivity is reduced. In addition, a large reduction in thermal conductivity is achieved by Nd fillers through rattling effect along with the in-situ nanostructured precipitate through scattering phonons with much wider frequency. These concomitant effects result in an enhanced thermoelectric performance with the dimensionless figure of merit ZT. These observations demonstrate an exciting scientific opportunity to raise the figure-of-merit of p-type skutterudites. PMID- 27451722 TI - Synthesis and Characterization of Eu3+-Doped CdS Quantum Dots by a Single-Step Aqueous Method. AB - Eu3+-doped CdS quantum dots (QDs) are successfully synthesized through a straightforward single-pot process in aqueous solution using thioglycolic acid as the capping ligand. The structure, shape, and spectral properties of the QDs are investigated. The obtained CdS:Eu3+ QDs exhibit cubic structures with good crystallinity and approximately sphere-like shapes about 4 nm in diameter. The CdS QDs manifest a broadband emission peak at 600 nm and enhanced Photoluminescence (PL) emission intensity after doping with Eu3+ ions. Given the strong PL intensity and good chromaticity of the sulfide-based QDs, they have potential use in doping rare-earth ions. PMID- 27451723 TI - Synthesis and Luminescence Properties of La2W2O9:Eu3+ Micron-Crystals. AB - La2W2O9:2%Eu3+ phosphors were synthesized by a typical hydrothermal procedure. The samples were characterized by X-ray diffraction and scanning electron microscope (SEM). X-ray diffraction analysis showed that a stock solution pH value equal to 9 is the ideal value, while the crystallization of the hydroxyl sodium yttrium tungstate crystal is improved by increasing the PH values of stock solution within limits. Meanwhile, SEMs of different pH values were recorded. Additionally, photo-luminescence excitation (PLE) and emission (PL) spectra were measured. It was found that this phosphor can be effectively excited by C-T band (266 nm) and ultraviolet light 342 nm. The wave-lengths at 342 nm fit in nicely with the whole visible region, thus the La2W2O9:2%Eu3+ phosphors emit white light. Furthermore, the annealing temperature's impact on PLE and PL spectra was also studied. The Eu3+-doped La2W2O9 phosphor may be a better candidate than current method for solid-state lighting applications. PMID- 27451724 TI - Synthesis and Optical Properties of Eu3+ Doped NaYF4 and KYF4 Micro/Nanocrystals. AB - Through a hydrothermal method, 1 mol% Eu3+ doped NaYF4 and KYF4 micro/nanocrystals have been synthesized. The materials were characterized by X ray diffraction (XRD) patterns, field emission scanning electron microscopy (FE SEM) images, room temperature photoluminescence (PL) excitation and emission spectra, and luminescent dynamic decay curves. The XRD analysis suggested the crystalline structures of the obtained samples. The FE-SEM images indicated the morphology and size of the obtained samples. The PL spectra illustrate the optical properties of Eu3+ in the two samples. Since it is sensitive to the local environment of the ion, the Eu3+ presents different optical properties in the NaYF4 and KYF4 materials. PMID- 27451725 TI - A Novel Blue-Green-Emitting Phosphor Gd4.67SiO13:Tb3+. AB - A novel blue-green-emitting phosphor Gd4.67SiO13:Tb3+ has been synthesized by a conventional high temperature solid-state method at 1350 degrees C for 6 h. X ray diffraction and photoluminescence spectra were used to characterize the as synthesized phosphor. The excitation spectrum is composed of a broadband and two sharp peaks, at 274 nm, and 311 nm, respectively. The emission spectrum is composed of multiple sharp peaks, of which the strongest peak is at 544 nm (5D4 - >7F5). The critical doping content of Tb3+ is 5%, with the emission intensity increasing proportionally with Tb3+ concentration increase until it reaches 5%. As doping concentration from 5% to 7%, the luminescence intensity gradually reduces. Concentration quenching mechanism for Tb3+ is demonstrated to be dipole dipole interaction. The Commission Internationale de L'Eclairage (CIE) coordinates are also investigated in this work. The CIE coordinates of the Gd4.67SiO13:0.03Tb3+ phosphor upon 311 nm excitation are (0.242, 0.323). All the results indicate that the blue-green-emitting phosphor Gd4.67SiO13:Tb3+ has potential research value. PMID- 27451726 TI - Synthesis and Luminescent Properties of CaSnO3:Eu Nanopowder Prepared by a Sol Gel Route. AB - Luminescent properties of nanocrystalline CaSnO3:1%Eu have been investigated in order to develop novel red phosphors. The results indicate that high-quality nanoparticles with controlled stoichiometry and microstructure were prepared by a sol-gel method using citric acid and EDTA as complexes. There are two broad excitation bands located at 240 and 270 nm existing in the excitation spectrum in addition to the characteristic excitation peaks of Eu3+. Further investigations show that the excitation band located at 240 nm can be assigned to the host absorption while the Eu-O charge transfer is responsible for the 270 nm excitation band. These results indicate that the host can efficiently transfer energy to the Eu3+ ions. The more important is that since the symmetry of Eu3+ ions is lower, the pure red emission (5D9 --> 7F2 transition located at 618 nm) is predominant over all the emission. This means CaSnO3:Eu is a potential candidate for red luminescent materials. PMID- 27451727 TI - Crystal Growth and Photoluminescence Properties of Truncated Cubic BaMgAl10O17:Eu2+ Phosphors for Three-Dimensional Plasma Display Panels. AB - Monodispersed, truncated cube BaMgAl10O17:Eu2+ phosphors were synthesized by the sol-gel process. Scanning electron microscope (SEM), photoluminescence spectrum, powder X-ray diffraction and decay curves were used to evaluate the truncated cubic BaMgAl10O17:Eu2+ phosphors. The crystal growth process and photoluminescence properties were discussed in detail. The results showed that this truncated cubic morphology can be achieved via a simple sinter process. These truncated cubic BaMgAl10O17:Eu2+ phosphors showed acceptable emission intensity and better thermal properties. This result indicates truncated cubic BaMgAl10O17:Eu2+ phosphors would meet the requirements of plasma display panels (PDPs). PMID- 27451728 TI - Local Environment Study of Eu3+ Doped KGd2F7 by Site-Selective Spectroscopy. AB - The site-selective spectra and decay curves at 20 K of Eu3+ ions doped KGd2F7 were measured to study the local environment of the Eu3+ sites. The experimental results show that Eu3+ ions occupy three types of sites in the KGd2F7 host. And Eu3+ ions in different types of sites exhibit quite distinct emission spectra and have remarkably different 5D0 level decay lifetimes. Based on the intensity ratio of 5D0--> 7F2,1 transitions of Eu3+ and the 5D0 decay lifetimes in different types of sites, the correlation between the luminescent properties and the site symmetry is discussed. PMID- 27451729 TI - Intracellular Temperature Imaging in Gold Nanorod-Assisted Photothermal Therapy with Luminescent Eu(III) Chelate Nanoparticles. AB - Eu-tris(dinaphthoylmethane)-bis-(trioctylphosphine oxide) (Eu-DT) molecules encapsulated by Polystyrene and bis(trimethoxysilyl)decane nanoparticles were prepared via a modified encapsulation-reprecipitation method and show a high sensitivity to sense temperature. After surface modification with poly-L-lysine, the fluorescent nanoparticles obtained a well biocompatibility and low toxicity at a certain concentration. In the physiological temperature range (25-45 degrees C), the fluorescence of the nanoparticles is rather sensitive to temperature with a sensitivity of -2.6%/ degrees C. The temperature nanosensors and gold nanorods were internalized into living HepG2 cells. The fluorescence intensity of phagocytic nanoparticles decreased with the irradiation of 808-nm laser, which were captured by Epi-fluorescence microscope. PMID- 27451730 TI - Improved Upconversion Luminescence in Water-Soluble Yb3+/Er3+ Codoped LaF3 Nanoparticles Through Ca2+ Doping. AB - Monodisperse water-soluble LaF3: Yb3+/Er3+ nanocrystals (NCs) have been successfully fabricated via a fast, facile, and environmentally-friendly polyol process with polyvinylpyrrolidone (PVP) as an amphiphilic surfactant. The obtained NCs with a small size of 18 nm can be well dispersed in hydrophilic solutions. Meanwhile, their upconversion (UC) luminescence intensity was increased through Ca2+ doping due to the decrease of symmetry around rare earth ions. PMID- 27451731 TI - Preparation and Optical Properties of Y2O3:Tb3+ Nanoballs. AB - Y2O3:Tb3+ nanoballs were synthesized via the urea homogeneous precipitation method (UPM). The resulting Y2O3:Tb3+ phosphors were characterized by X-ray diffraction (XRD), scanning electron microscopy, ultraviolet-visible (UV-vis) absorption spectra, and general photoluminescence spectra. The particle sizes estimated using X-ray diffractometry and scanning electron microcopy were about 50-200 nm. The emission intensity of the Y2O3:Tb3+ was low when the doping concentra- tions of Tb3+ were higher. The optimum concentration of Tb3+ for synthesis of Y2O3:Tb3+ nanocrystals is 1%. PMID- 27451732 TI - Facile Synthesis and Growth Mechanism of SiO2 Nanotubes with ZnS Nanowires as Intermediates. AB - SiO2 nanotubes with good chemical purity and well defined morphology were synthesized successfully in a one-step gas phase condensation process using gold catalyst. The as-synthesized products were characterized by transmission electron microscopy and nanoprobe X-ray energy dispersive. In the observations, a growth mechanism of the nanotubes is suggested. The new synthetic route to prepare SiO2 nanotubes is favorable to satisfy the special needs in commercial and industrial application and can be easily applied to other semiconductor materials. PMID- 27451733 TI - Study on Nonlinear Absorption Effect of Nanosecond Pulse Laser Irradiation for GaAs. AB - In order to research nonlinear absorption effect of pulse laser irradiation for GaAs, a physical model of Gaussian distribution pulse laser irradiation for semiconductor material was established by software COMSOL Multiphysics. The thermal effects of semiconductor material GaAs was analyzed under irradiation of nanosecond pulse laser with wavelength of 1064 nm. The radial and transverse temperature distribution of semiconductor material GaAs was calculated under irradiation of nanosecond pulse laser with different power density by solving the thermal conduction equations. The contribution of one-photon absorption, two photon absorption and free carrier absorption to temperature of GaAs material were discussed. The results show that when the pulse laser power density rises to 10(10) W/cm2, free carrier absorption played a leading role and it was more than that of one-photon absorption of material. The temperature contribution of two photon absorption and free carrier absorption could be ignored at laser power density lower than 10(8) W/cm2. The result is basically consistent with relevant experiments, which shows that physical model constructed is valid. PMID- 27451734 TI - Effect of the Dosage of Tourmaline on Far Infrared Emission Properties of Tourmaline/Glass Composite Materials. AB - Tourmaline/glass composite materials were prepared by sintering at 600 degrees C using micron-size tourmaline mineral and glass powders as raw materials. The glass has lower melting point than the transition temperature of tourmaline. The Fourier transform infrared spectroscopy showed that the far infrared emissivity of composite was significantly higher than that of either tourmaline or glass powders. A highest far infrared emissivity of 0.925 was obtained when the dosage of tourmaline was 10 wt%. The effects of the amount of tourmaline on the far infrared emission properties of composite was also systematically studied by field emission scanning electron microscope and X-ray diffraction. The tourmaline phase was observed in the composite, showing a particle size of about 70 nm. This meant that the tourmaline particles showed nanocrystallization. They distributed homogenous in the glass matrix when the dosage of tourmaline was not more than 20 wt%. Two reasons were attributed to the improved far infrared emission properties of composite: the particle size of tourmaline-doped was nanocrystallized and the oxidation of Fe2+ (0.076 nm in radius) to Fe3+ (0.064 nm in radius) took place inside the tourmaline-doped. This resulted in the shrinkage of unit cell of the tourmaline in the composite. PMID- 27451735 TI - PbS Quantum Dots Sensitized TiO2 Solar Cells Prepared by Successive Ionic Layer Absorption and Reaction with Different Adsorption Layers. AB - Lead sulfide (PbS) quantum dots (QDs) have been synthesized via successive ionic layer adsorption and reaction (SILAR) on a titanium dioxide (TiO2) nanoporous film for the fabrication of quantum dot-sensitized solar cells (QDSCs). The reaction is environmental friendly and energy saving. The green synthesized PbS QDs match the maximum remittance region of the solar spectrum and are suitable as sensitizers for TiO2 electrodes for cell devices application. PbS QDs were adsorbed in different adsorption layers in order to improve the solar cell performance. The optical properties of PbS sensitized TiO2 films were studied by scanning electron microscopy and UV-Vis absorbance spectroscopy. The photovoltaic characteristics of the PbS QDSCs were analyzed by I-V characteristics and electrochemical impedance spectroscopy. As a result, the light harvesting was enhanced with increasing SILAR adsorption layers. The maximum photovoltaic conversion efficiency of the PbS QDSCs (3.14%) was obtained at the 12 adsorption layers with the highest short circuit current density and lowest charge transfer resistance. PMID- 27451736 TI - Charge and Energy Transfer Between CdSe Quantum Dots and Polyaniline. AB - CdSe quantum dots (QDs) and polyaniline (PAni) were mixed to prepare CdSe QDs/PAni complex. PAni can quench the fluorescence of CdSe QDs. Fluorescence intensity of CdSe QDs/PAni complex is related to the size of CdSe QDs and the concentration of PAni. UV-Vis absorption spectra, fluorescence spectra, time resolved fluorescence spectroscopy were used to analys the quenching phenomenon. The mechanism of fluorescence quenching is dependent on two factors: on one hand, the Forster resonance energy transfer from CdSe to PAni; on the other hand, PAni can intercept the charge relaxation process of CdSe and lead to the interruption of radiative recombination. PMID- 27451737 TI - Synthesis and Characterization of SiO2@Y2MoO6:Eu3+ Core-Shell Structured Spherical Phosphors by Sol-Gel Process. AB - SiO2@Y2MoO6:Eu3+ core-shell phosphors were prepared by the sol-gel process. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectra (EDS), transmission electron microscopy (TEM), photoluminescence (PL) spectra as well as kinetic decays were used to characterize the resulting SiO2@Y2MoO6:Eu3+ core-shell phosphors. The XRD results demonstrated that the Y2MoO6:Eu3+ layers on the SiO2 spheres crystallized after being annealed at 700 degrees C and the crystallinity increased with raising the annealing temperature. The obtained core shell phosphors have spherical shape with narrow size distribution (average size ca. 640 nm), non-agglomeration, and smooth surface. The thickness of the Y2MoO6:Eu3+ shells on the SiO2 cores could be easily tailored by varying the number of deposition cycles (70 nm for four deposition cycles). The Eul+ shows a strong PL emission (dominated by 5D0-7F2 red emission at 614 nm) under the excitation of 347 nm UV light. The PL intensity of Eu3+ increases with increasing the annealing temperature and the number of coating cycles. PMID- 27451738 TI - Hydrothermal Synthesis and Multicolor Upconversion Fluorescence of Novel LiLuF4:Yb3+,Tm3+ Microcrystals. AB - LiLuF4:Yb3+,Tm3+ upconversion luminescence materials were synthesized by a hydrothermal method, in which NaF and NaBF4 were used as fluorine sources (labeled as sample A and B, respectively). Their morphologies, XRD patterns and UC emission properties were compared. The synthesized crystallites consist of regular octahedrons of several micrometers and aggregates. The XRD patterns indicate that they belong to tetragonal crystal system with 141/a space group. These microcrystals emit strong UC violet, visible and near infrared light under the excitation of 980 nm laser diode. The multicolor UC emissions from sample B are much stronger than those from sample A. The strong emission intensity is ascribed to good crystal quality of sample B. PMID- 27451739 TI - Study of Ac Dielectrophoretic Process of SiC Nanowires: A Universal Method for Alignment of Semiconductor Nanowires. AB - In this study, the dielectrophoretic processes of SiC nanowires suspended in three typical solvents, (highly purified water, ethanol and isopropanol) were systematically investigated. Optical microscope and SEM characterizations were used to observe the order of SiC nanowires on the surface of gold microchannels. The gold microchannels were induced by Ac dielectrophoresis of the corresponding dispersion solutions of SiC nanowires, with a concentration of 0.1 mg/mL. The study shows that the dielectrophoresis process is an effective way of synthesizing highly oriented SiC nanoarrays using isopropanol solution. The results also show that the arrangement of SiC nanowires on the interdigital electrode configuration not only depend on the kind of solvent used, but also on the applied frequency (1000 Hz~1 MHz) and voltage (1 V~20 V). PMID- 27451740 TI - Surfactant Effect on Formation of CaWO4:Eu3+ Crystals with Distinguished Morphologies in Hydrothermal Ambient. AB - Metal tungstates, expressed by the general formula of MWO4, have important properties and applications in photoluminescence, microwave applications, optical fibers, scintillator materials, humidity sensors, magnetic properties, and catalysts. In this paper, we report a successful synthesis of CaWO4:Eul+ crystals with various morphologies in mild hydrothermal conditions with surfacntant including sodium citrate, CTAB, PEG and citrate acid (CA). The formation of the crystals are strongly dependent on the employment of surfactant. The surfactant concentration has been found significant influence in the resulting morphologies due to different properties of each one. Extensive characterization have been performed by using X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM) in search of the formation mechanism of multi-morphological CaWO4:Eu3+ crystals. The growth mechanism of monodispersed CaWO4:EuS+ crystal are proposed. And the photoluminescence properties were investigated. PMID- 27451741 TI - Investigation on the Synthesis and Photoluminescence of CaMoO4:Eu3+ Microspheres. AB - Eu3+ doped CaMoO4 microspheres were synthesized via a facile hydrothermal method assisted by the citric acid additive. The structure and morphology of the samples were examined by X-ray diffractometer (XRD) and scanning electron microscopy (SEM), and the properties of the photoluminescence emission from the samples were investigated with spectroscopic technique. The XRD results revealed that the hydrothermally formed CaMoO4:Eu3+ phosphor has single-phase scheelite-type tetragonal structure. The SEM observation demonstrated that the samples have sphere-like morphologies and their diameters were about 3-4 um. Meanwhile, the influence of the citric acid on the formation of CaMoO4:Eu3+ was also investigated. The formation mechanism of CaMoO4:Eu3+ microspheres was explored based on the time-dependent experimental observation. The study on the luminescence spectra showed that CaMoO4:Eu3+ microspheres can be effectively excited at 395 nm, and good luminescence emission can be obtained at around 614 nm, which is attributed to the transition of 5D0 --> 7F2 from Eu3+. The current study suggests that CaMoO4:Eu3+ red phosphor is a potential candidate for white light-emitting diodes (WLEDs) application. PMID- 27451742 TI - Synthesis and Near-infrared Luminescent Properties of NaGdF4:Nd3+@NaGdF4 Core/Shell Nanocrystals with Different Shell Thickness. AB - The near-infrared to near-infrared (NIR-to-NIR) photoluminescence of nanocrystals has outstanding advantages in biological imaging. NaGdF4:Nd3+ core nanocrystals and NaGdF4:Nd3+@NaGdF4 core/shell nanocrystals with different shell thicknesses were synthesized by a simple solvothermal method. The obtained nanocrystals were characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD) analysis. The phase of all nanocrystals is hexagonal. NaGdF4:Nd3+ core nanocrystals have an average size of 6 nm. By controlling core-shell ratio for 1:2 and 1:3, we obtained NaGdF4:Nd3+@NaGdF4 core/shell nanocrystals with average sizes of 10 nm and 11 nm, respectively. When excited at 808 nm, strong NIR emission was observed. The emission peaks at -860 nm, -1060 nm and -1330 nm correspond to the transitions from the 4F3/2 state to the 4I9/2, 4I1/2 and 4I13/2 state of Nd3+ ions, respectively. The emission intensity of NaGdF4:Nd3+@NaGdF4 core/shell nanocrystals is stronger than that of the core. The intensity increases with the increase of shell thickness. The shell improves the luminous efficiency by reducing surface defects. The decay time of Nd3+ emission in NaGdF4:Nd3+@NaGdF4 core/shell nanocrystal is longer than that in NaGdF4:Nd3+ core, indicating that the shell isolates effectively the emitting ions (Nd3+) from the quenching defects. With the increase of shell thickness, the decay time becomes longer. Within a certain range of shell thickness, thicker shell can protect the emitting Nd3+ ions on the surface of core nanocrystals more effectively. PMID- 27451743 TI - Study on Fabrication and UV Photoelectric Property of TiO2 Nanotube Array Electrodes. AB - Highly ordered TiO2 nanotube array electrodes were successfully fabricated by a two-step anodization method on Ti sheet substrates in an electrolyte composed of ammonium fluoride, deionized water, and glycol. The tube wall was smooth, and the average internal and external diameters, wall thickness, and tube length achieved were 80 nm, 90 nm, 10 nm, and 9 um, respectively. X-ray diffraction and field emission scanning electron microscopy results revealed that the TiO2 nanotube arrays presented an amorphous structure. When calcined at 300 degrees C, the arrays crystallized into the anatase phase, and the crystallization degree of the oxide layer increased as the temperature rose. Calcinating at 400 degrees C did not obviously disrupt the porous structure of the highly ordered arrays. However, higher temperature enlarged the diameter of the nanotube array and roughened the tube wall. When the temperature reached 600 degrees C, the nanotube mouth broke because of the excessive stress, causing the oxide layer's thinness and nanotube mouth clogging. The photoelectric test showed that the electrode presented obvious photoresponse under 300-400 nm UV excitation (maximized at 360 nm). The degree of crystallization and the micro-structure of the oxide layer can significantly affect the photoelectric properties of the electrode. After calcination at 400 degrees C, the TiO2 nanotube arrays, with highly ordered tubular structure directly connected to the Ti substrate, can ensure the rapid transportation of photo-induced electrons to the Ti substrate, while the high crystallinity of the arrays can help reduce the defect density of the nanotube and extend the lifetime of the photo-induced carriers. The electrode showed the best photoelectric property, and the photocurrent intensity was maximized (29.6 uA). However, the calcination process with over-temperature resulted in substantial loss of the TiO2 oxide layer, mouth clogging, and a severe decline in the photoelectric properties. PMID- 27451744 TI - Preparation of Highly Crystallized Yttrium Oxysulfide Suspension via a Novel Colloidal Processing. AB - High-crystallized Y2O2S suspension was synthesized by a novel two-step method of high temperature solid-state reaction and subsequent colloidal processing. The synthesis method proposed in this study retains all advantages of the high temperature solid-state reaction method. The obtained data agrees with that of the PDF card, which indicates the product is pure Y2O2S crystals. The results show that the prepared Y2O2S particles are highly crystallized without any significant defects. The fine smooth particles were almost regular, exhibiting an approximately subspherical shape. Quantitative image analysis of particles suggests a mean particle size of 120+/-34 nm. That is to say, the yttrium oxysulfide colloid prepared by this method have a very narrow size distribution. The obtained ethanol suspension shows Tyndall effect when irradiated with laser of wavelength 532 nm. In addition, the particles exhibit excellent dispersibility in ethanol solution. This is rarely observed for the covalent compounds, which generally present poor dispersibility in solution. As is known to all, the state of the dispersion depends on the acid leaching process. The acid leaching process facilitates the adsorption of ethanol molecules on the surface of the particles. The electrostatic repulsive force among colloidal particles will improve their rheological properties and dispersibility in solution. In this study, the particles can be dispersed well in ethanol after acid leaching. The method'proposed in this study can be extended for the preparation of mono dispersed oxysulfide nanophosphors and may provide an efficient way for the preparation of stable covalent compound dispersions. PMID- 27451745 TI - Ce3+ and Ln3+ (Ln = Dy, Eu, Sm, Tb) Codoped SrF2 Nanoparticles: Synthesis and Multicolor Light Emission. AB - For optically active Ln3+ ions, fluoride is a very good luminescent substrate that has been used in the field of lasers, solid-phase optical transmitters, optical communications, up/down conversion. This work reports a systematic study on bridging between structure and tunable luminescence for SrF2:Ce3+/Ln3+ (Ln = Dy, Eu, Sm, Tb) nanoparticles. Regardless of the dopant level, all nano-crystals crystallized in a single cubic phase with the diameter of ~20-30 nm. It was found that SrF2:Ce3+ exhibited intense ultraviolet emission under 288 nm excitation which can be attributed to the typical 4f-5d transition of Ce3+ ions. After the incorporation of Ln3+ ions, multicolor emission can be achieved when excited by the 4f-5d transition of Ce3+. This result gave an evidence that the excitation energy of Ce3+ can be transferred to Ln3+ leading to multicolor emission. The findings reported in this work may provide useful information in designing novel luminescent materials for tailored performances. PMID- 27451746 TI - Enhanced Red Upconversion Luminescence in Yb-Er Codoped NaYF4 Nanocrystals. AB - In this work the effects of NaYF4:Yb,Er (NYE) structure on the enhanced red upconversion luminescence (UC) was investigated. alpha-NYE nanocrystals (NCs) and beta-NYE NCs were fabricated by a high temperature decomposition reaction method. The prepared NCs were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), and photoluminescence (PL) spectroscopy. The results show that the red UC luminescence of alpha-NYE NCs is significantly enhanced compared with that of beta-NYE. Furthermore, a possible energy transfer mechanism was proposed on the basis of our experimental results. PMID- 27451747 TI - The Effect of Phase Structures on the Enhanced Red Upconversion Luminescence in NaLuF4:Yb-Er Nanocrystals. AB - In this work, alpha-NaLuF4:Yb,Er (NLF) nanocomposites (NCs) and beta-NLF NCs with diameter about ~13 nm were fabricated by a high temperature decomposition reaction method. The effects of NLF structure on the enhanced red upconversion luminescence performance were investigated. Under 980 nm excitation from a laser diode, the alpha-NLF emitted dominant red UC emission. Furthermore, the possible energy transfer mechanism was proposed on the basis of our experimental results. PMID- 27451748 TI - Development of Biogenic Silver Nanoparticle Using Rosa Chinensis Flower Extract and Its Antibacterial Property. AB - In the present study, biosynthesis of silver nanoparticles was carried out using Rosa chinensis flower extract as reducing agent. The characterization of silver nanoparticles was done by UV-VIS spectrum. The morphology and size of silver nanoparticles were determined by transmission electron microscope (TEM) image. The crystallization of silver nanoparticles was confirmed by X-ray diffraction (XRD) measurements. The Fourier transform infrared (FT-IR) analysis was used to confirm the possible involvement in the formation and stabilization of synthesized silver nanoparticles by the extract of Rosa chinensis flower. Antibacterial activity of silver nanoparticles was studied against Gram positive Staphycoccus aureus and Gram negative Escherichia coil. PMID- 27451749 TI - Synthesis and Photoluminescence Characteristics of CaIn2O4:Dy3+ Phosphors Co Doped with Gd3+, Zn2+ or AI3+ Ions. AB - Novel warm-white emitting phosphors CaIn2O4:Dy3+ co-doped with Gd3+, Zn2+, or Al3+ ions were prepared by solid state reaction. In this paper, a strategy of co doping with different ions was used with the aim of affecting the luminescence properties of CaIn204:0.6%Dy3+ under NUV excitation. The luminescence intensities of CaIn2O4:0.6%Dy3+ were enhanced by 0.2% Gd3+ or 0.2% Zn2+ ions co-doping under 367 nm excitation, but lowered by co-doping with 0.2% Al3+ ions. Furthermore, the chromaticity coordinates of CaIn2O4:0.6%Dy3+ can be tuned from the cold-white region to warm-white region with Gd3+ or Zn2+ ions co-doping. These findings show that CaIn2O4:0.6%Dy3+,0.2% Gd3+, and CaIn2O4:0.6%Dy3+,0.2% Zn2+ have potential application value as new warm-white LED phosphors. PMID- 27451750 TI - Influence of Water Activated by Far infrared Porous Ceramics on Nitrogen Absorption in the Pig Feed. AB - Under modern and, intensive feeding livestock and poultry density has increased, and brought a deterioration of the farm environment. The livestock and their excrement generate harmful gases such as ammonia, etc. which restricted the sustainable development and improvement of production efficiency of animal husbandry. In this paper, a new kind of far infrared porous ceramics was prepared to activate, the animal drinking water. The activated water and common water were then supplied to pigs, and the fresh pig feces of experimental group and:control group were collected on a regular basis. The residual protein content in feces was tested by Kjeldahl nitrogen method to study the influence law of the porous ceramics on absorbing nitrogen element in animal feces. The results showed that compared with the control group, the protein content in the experimental group decreased on average by 39.2%. The activated drinking water was conducive to the absorption of nitrogen in pig feed. The clusters of water molecules became smaller under the action of the porous ceramics. Hence, they were easy to pass through the water protein channel on the cell membrane for speeding up the metabolism. PMID- 27451751 TI - Synthesis and Upconversion Luminescence of Water-Soluble of GdF3:Yb3+/Er3+ Nanoparticles. AB - Water-soluble Yb3+/Er3+ doped GdF3 nanocrystals were prepared using a thermal decomposition synthesis route. The crystal structure, morphology and up conversion spectra of the samples were characterized using X-ray powder diffractometry, transmission electron microscopy and a fluorescence spectrophotometer with single-wavelength diode laser of 980 nm. In Yb3+- and Er3+ codoped GdF3 nanocrystals, the relative intensity of green emission became stronger as the sample changed from water-soluble nanoparticles to hexane dispersed nanoparticles. The synthesis of such monidisperse, water-soluble, lanthanide-doped upconvertion particles will open new opportunities in targeting and drug delivery applications. PMID- 27451752 TI - Preparation and Properties of Ce3+:BaF2 Transparent Ceramics by Vacuum Sintering. AB - Ce0.001Ba0.999F2.001 powders were prepared by a chemical coprecipitation method using Ba(N03)2, KF.2H2O and Ce(NO3)3 6H20 as raw materials. Ce0.001Ba0.999F2.001 transparent ceramics were prepared by vacuum sintering. The results show that the Ce0.001Ba0.999F2.001 powders were blocky, and both powdered and sintered transparent ceramics were composed of BaF2 phases without the secondary phase. The maximum light transmittance of the Ce0.001Ba0.999F2.001 transparent ceramics reached 55%. The fracture morphology shows a cleavage fracture with a few micropores. The fluorescence spectra show that the Ce0.1Ba0.999F2.001 powders displayed emissions at 410 nm, 480 nm and 620 nm under 275 nm excitation. The Ce0.1Ba0.9F2.1 transparent ceramics displayed0emissions at 450 nm and 620 nm under 294 nm excitation. PMID- 27451753 TI - The Influence Mechanism of Halogen Ion on the Temperature Quenching Performance of Sr2SiO4:Eu Phosphors. AB - The luminescent properties of Sr2SiO4:Eu phosphors synthesized with and without flux have been investigated. With the co-dopation of NH4CI, the luminescent intensity of Sr2SiO4:Eu is increased and the temperature quenching property is improved. The effect of NH4Cl is analyzed not only from the crystallinity of the Sr2SiO4 crystal but also the band structure of Sr2SiO4 host, which is calculated by density functional method with the local density approximation. PMID- 27451754 TI - Photoluminescence Properties and Energy Transfer in a Novel Yellow Emitting Phosphor GdTaO4: Dy3+. AB - The phosphor Dy3+ doped M type gadolinium orthotantalate GdTaO4 was prepared successfully by traditional solid state reaction and the photoluminescence of GdTaO4: xDy3+ (0.01 <= x <= 0.10) has been investigated under ultraviolet and vacuum ultraviolet excitation. In the excitation spectra of GdTaO4: Dy3+, the overlap appears between the host lattice excitation, the excitation lines of Gd3+ and the f-f transitions of Dy3+, which indicates that the energy transfer could occur from the host to the Dy3+ ions. In the emission spectra of the samples, the intense emissions of Dy3+ have been expectably revealed both upon excitation at 365 nm and 147 nm. And the chromaticity coordinates of GdTaO4: xDy3+ have been correspondingly calculated. The results indicate that GdTaO4: Dy3+ would be a novel yellow emitting phosphor applied in light emitting diodes (LEDs), plasma display panels (PDPs) and mercury-free fluorescent tubes. PMID- 27451755 TI - Effects of Ti4+ Ions on Fluorescence Properties of Sr2CeO4:Sm3+ Phosphors. AB - Ti4+-doped Sr2CeO4:Sm3+ phosphors were synthesized with the solid-state reaction method and the effects of doping Ti4+ on the photoluminescence properties were investigated in detail. A broad excitation band ascribed to the O2- -Ce4+ transition was observed in the range of 200 to 400 nm and with doping Ti4+ nto Ce4+ sites, the intensity of charge transfer band of O2- --> Ce4+ (300-370 nm) was significantly broaden and enhanced. As a result, the emission intensity of Sr2Ce1-xTixO4 has improved about 85% by doping 0.01 mol Ti4+. White emission of Sr2-yCe0.99Ti0.01O4:ySm3+ at y < 0.03 is due the co-existence of Ce4+ --> O2- CT emission and 4G5/2-6HJ Sm3+ transitions whereas only the Sm3+ red emission prevails for 0.03 < y <= 0.15. The Sr1.99Ce0.99Ti0.01O4:0.01 Sm3+ phosphor exhibited excellent color purity. Its chromaticity coordinate is measured to be (0.326, 0.322), which is close to the pure white (0.33, 0.33). The results showed that Sr1.99Ce0.99Ti0.01O4: 0.01 Sm3+ phosphors could be considered as a potential single-phase white-emitting phosphor for white light-emitting diodes. PMID- 27451756 TI - Upconversion Luminescence Properties of Y2Mo4O15: Yb3+, Er3+ by Solid State Combustion Method. AB - The Yb3+ and Er3+ co-doped yttrium molybdenum oxide upconversion phosphors were prepared by the solid state combustion method using urea as fuel at ignition temperature of 550 degrees C. The upconversion phosphors were characterized by X ray diffraction (XRD), scanning electronic microscope (SEM), and photoluminescence spectra XRD results revealed the samples were pure monoclinic Y2Mo4O15 phases when the sintering temperature was 700 degrees C. SEM micrographs illustrated particle size distribution was almost uniform with an average particle diameter of about 0.5-1.0 um. The obtained Y2MO4O15: Yb3+, Er3+ presents bright and pure green upconversion luminescence during daylight pumping under 980 nm LD. According to the analysis of upconversion luminescent mechanism, the cross relaxation processes of Er3+ ions restrained the electron population of red emission energy level, which not only increased the green light upconversion emissions fluorescent branching ratio (IGIR = 153:1) but also enhanced the efficiency and purity of green light emissions. PMID- 27451757 TI - Research on the Luminescence and Temperature Quenching Properties of BaSi2O2N2:Eu2+ Phosphor. AB - The BaSi2O2N2:Eu2+ phosphor is synthesized by solid state reaction. The luminescent properties and temperature quenching performance of BaSi2O2N2:Eu2+ phosphor are measured. It has been demonstrated that the Eu2+ doped BaSi2O2N2 phosphor shows efficient green emission with peak at around 492 nm. With the incorporation of La3+ and Y3+, the quantum efficiency of BaSi2O2N2:Eu2+ and the temperature quenching performance of BaSi2O2N2:Eu2+ is changed, which is explained from the electronic structure view. PMID- 27451758 TI - Synthesis, Characterization and Luminescence Properties of Rod-Like LaPO4:Eu3+ Nanostructures. AB - Large-scale, rod-like nanostructures of LaPO4:Eu3+ phosphors were synthesized using a simple hydrothermal method. The phase composition, structure and morphology of the final products were characterized by XRD, FE-SEM and TEM. Highly crystalline material was obtained as confirmed by X-ray powder diffraction measurements. The FE-SEM and TEM observations indicate that the obtained LaPO4:Eu3+ nanorods have a diameter of about 10-20 nm, and a length of about 100 600 nm. Meanwhile, the excitation and emission spectra of the products at room temperature were measured using a fluorescence spectrometer. The effects of pH and Eu3+-doping on the morphology and luminescence properties of the as-prepared powders were investigated. The photoluminescence (PL) spectra show that the emission intensity of the LaPO4:Eu3+ phosphors improved with increases in concentrations of Eu3+ from 3 mol% to 14 mol%, and then decreased for higher concentrations. PMID- 27451759 TI - "Secondary Growth" in Hydrothermal Synthesis of Aligned ZnO Nanostructures and Its Application in Dye-Sensitized Solar Cells. AB - One-dimensional (1D) aligned ZnO nanostructures were prepared on ZnO film seeded substrates using a low-temperature hydrothermal method, and zinc nitrate and hexamethylenetetramine (HMT) precursors. It was observed that increasing the concentration ratio of Zn2+/HMT from 1 to 100 led to a "secondary growth," and a change in the morphologies of the ZnO nanostructures from arrays of thick nanorods to arrays of thin nanorod-step-thick nanorods. The morphological evolution of ZnO nanostructures with increased growth time at high Zn2+/HMT concentration ratios showed the same transformation. Dye-sensitized solar cells (DSSCs) were fabricated using ZnO nanostructures as the photoanodes, and the electron transport properties were determined by electrochemical impedance spectroscopy (EIS). Although the DSSCs showed low power conversion efficiencies due to the short lengths, the arrays of the thin nanorods demonstrated excellent electron transport with an electron diffusion coefficient (Dn) of 1.57 x 10(-3) cm2/s, and an effective diffusion length (L) of 140 um. PMID- 27451760 TI - Temperature and Oxygen Sensing Properties of Ru(II) Covalently-Grafted Sol-Gel Derived Ormosil Hybrid Materials. AB - In this article, oxygen and temperature-sensing hybrid materials consisting of [Ru(Phen)3]2+ portions covalently-grafted onto the sol-gel derived ormosil network were prepared by co-condensation of tetraethoxysilane (TEOS) using n octyltriethoxysilane as the network modifier. For comparison purposes, the hybrid materials in which [Ru(Phen)3]2+ were conventionally physically-incorporated into the matrix were also prepared. The obtained hybrid materials were characterized by Fourier transform infrared (FT-IR), luminescence intensity oxygen quenching Stern-Volmer plots, temperature quenching plots and excited-state lifetime. The near linear Stern-Volmer plots can be attributed to the approximate heterogeneous environment of the luminophore within the ormosil materials. The results reveal that the. covalently-grafted sample is more sensitive to 02, and has a higher sensing sensitivity and a higher thermal activation energy compared to the physically-incorporated one, since these Ru(II) molecules are strongly covalently grafted onto the Si-O network via the CH2-Si bonds and less -OH group. PMID- 27451761 TI - Synthesis, Morphology Control and Luminescent Properties of Rare Earth Ion-Doped CaWO4 Microstructures. AB - Rare earth ions (Tb3+, Eu3+) doped CaWO4 microstructures were synthesized by a facile hydrothermal route without using any templates and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and photoluminescence (PL) spectrum. The results indicate that the asprepared samples are well crystallized with scheelite structure of CaWO4, and the average diameter of the microstructures is 2~4 um. The morphology of CaWO4:Eu3+ microstructures can be controllably changed from microspheres to microflowers through altering the doping concentration of Eul+ from 3% to 35%, and the microflowers are constructed by a number of CaWO4:Eu3+ nanoflakes. Under the excitation of UV light, the emission spectrum of CaWO4:Eu3+ is composed of the characteristics emission of Eu3+ 5D0-7FJ (J = 1, 2, 3, 4) transitions, and that of CaWO4:Tb3+ is composed of Tb3+ 5D4-7FJ (J= 6, 5, 4, 3) transitions. Both of the optimal doping concentrations of Tb3+ and Eu3+ in CaWO4 microstructures are about 5%. PMID- 27451762 TI - Charge Effect on the Quantum Dots-Peptide Self-Assembly Using Fluorescence Coupled Capillary Electrophoresis. AB - We present a molecular characterization of metal-affinity driven self-assembly between CdSe-ZnS quantum dots and a series of hexahistidine peptides with different charges. In particular, we uti- lized fluorescence coupled capillary electrophoresis to test the self-assembly process of quantum dots with peptides in solution. Four peptides with different charges can be efficiently separated by fluorescence coupled capillary electrophoresis. The migration time appeared to be influenced by the charges of the peptide. In addition, the kinetics of self assembly process of quantum dots with one of the peptides manifested a bi-phasic kinetics followed by a saturating stage. This work revealed that there exist two types of binding sites on the surface of quantum dots for peptide 1: one type termed "high priority" binding site and a "low priority" site which is occupied after the first binding sites are fully occupied. The total self-assembly process finishes in solution within 80 s. Our work represents the systematic investigation of the details of self-assembly kinetics utilizing high-resolution fluorescence coupled capillary electrophoresis. The charge effect of peptide coating quantum dots provides a new way of preparing bioprobes. PMID- 27451763 TI - The Experiment and Simulation Method to Calibrate the Shear Modulus of Individual ZnO Nanorod. AB - A general method is presented to directly measure the shear modulus of an individual nanorod using atomic force microscope (AFM). To obtain shear modulus with less experiment error, finite element simulation is employed to simulate the twisting process of a ZnO nanorod. Based on the experimental measurements, the shear modulus of ZnO nanorod with 4 um in length and 166 nm in radius is characterized to be 9.1 +/- 0.2 GPa, which is obviously more accurate than the simple averaged experimental result. PMID- 27451764 TI - Exploring Nanoscale Electrical Properties of CuO-Graphene Based Hybrid Interfaced Memory Device by Conductive Atomic Force Microscopy. AB - The phenomenon of resistive switching is based on nanoscale changes in the electrical properties of the interface. In the present study, conductive atomic force microscope based nanoscale measurements of copper oxide (CuO-multilayer graphene (MLG) hybrid interface based devices have been carried out to understand changes in the electrical properties during resistive switching of the Ti-CuO/MLG Cu memory cells having different dimensions fabricated on the same substrate using stencil lithography technique. The dependence of resistive switching characteristics in LRS and HRS and current level of the conductive filaments (CF) on the electrode area have been studied. As the device dimension is reduced, the filamentary contribution is enhanced in comparison to the background contribution, resulting in'an increase in the current density ratio between LRS and HRS. It is also observed that as the device dimension is decreased from 150 to 25 um, the filament size decreases from 95 nm to 20 nm, respectively, which causes a decrease in the reset current and reset voltage. The results of the nanoscale CAFM measurements have shown a good correlation with the switching parameters obtained by the macroscale pad I-V measurements, thereby, suggesting the origin of resistive switching is due to the formation and rupture of an entity called filament, whose dimension is in nanorange. It is observed that changes in the electrical properties of the overall interface layer along with changes in the electrical conductivity of these filaments contribute towards resistive switching phenomenon. This study suggests that a significant reduction of reset current can be achieved by decreasing the memory device dimensions. PMID- 27451765 TI - Investigation of Photoluminescence Mechanisms from SiO2/Si:SiO2/SiO2 Structures in Weak Quantum Confined Regime by Deconvolution of Photoluminescence Spectra. AB - Si nanocrystals embedded in SiO2 matrix were prepared by co-sputtering method followed by a post annealing process in N2 ambient. By fixing sputtering parameters, the effects of annealing time and annealing temperature on the optical properties of Si nanocrystals are investigated. Origin and evolution of the photoluminescence (PL) in weak quantum confinement regime are discussed in the light of X-ray diffraction, Fourier transform infrared, and temperature dependent photoluminescence measurements. For all samples, the PL peaks tend to decompose to four Gaussian peaks in which attributed to the radiative defects in SiO2 matrix, nc-Si/SiO2 interface related localized defects, localized states in the amorphous Si band gap and quantum confinement of excitons in smaller nanocrystals. Considering the observation of luminescence and its decomposition tendency in nanocrystals with average sizes larger than exciton's Bohr radius the necessity to distinguish between the role of smaller and larger nanocrystals in the PL mechanisms is discussed. Furthermore, possible origin of the interface related localized states in particular Si=O double bonds in the nc-Si/SiO2 interface and that of radiative defects in SiO2 matrix are discussed. PMID- 27451766 TI - Spectral Dependent Photoelectrochemical Behaviors of CdS Sensitized ZnO Nanorods. AB - CdS decorated ZnO nanorods have been grown by a combination of hydrothermal method and successive ion layer absorption and reaction (SILAR) method. Optical absorption and emission properties of ZnO nanorods have been studied after sensitization with CdS nanoparticles. Current-voltage characteristics of ZnO nanorods and CdS sensitized ZnO nanorods have been studied in an electrochemical cell. The spectral dependent photocurrent and photopotential behaviors of ZnO nanorods and CdS sensitized ZnO nanorods have been investigated using monochromatic light of wavelength 300-700 nm. The photopotential recovery time have been estimated for CdS sensitized nanorods and pristine nanorods. PMID- 27451767 TI - Tuning the Size of Palladium Nanoparticles in Organic and Aqueous Solutions: Influence of Aminated and Thiolated Ligands. AB - Highly monodispersed palladium nanoparticles have been synthesized by a two-phase reduction method using two different capping agents, alkylamines and alkanethiols. The influence of ligand type in the properties of palladium nanoparticles have been analyzed in detail by means of several techniques as Infrared and Ultraviolet-Visible Spectroscopy, X-ray Diffraction and Transmission Electron Microscopy. It is shown how the size can be tuned easily between 2 and 4 nm by using alkylamines ligands with carbon chains of different lengths, while keeping up high purity and crystallinity. The transfer of these nanoparticles to water phase has been achieved by the ligand exchange process. In contrast, when alkanethiols are used as stabilizers no correlation between carbon chain length and size has been observed. This distinct chemical reactivity between palladium and mentioned ligands produces some particular electronic and magnetic properties that are analyzed by Electron Magnetic Resonance. The presence of free radicals associated with palladium and capping agent bond has been confirmed. No evidences of ferromagnetic behavior coming from Palladium nanoparticles have been found out in any of the studied samples. PMID- 27451768 TI - Hierarchically Assembled Nanofibers Created by a Layer-by-Layer Self-Assembly. AB - We report the hierarchically assembled nanofibers created by LbL self-assembly depending on the PSS-PAA fraction in the blend solutions and pH during bulid-up of the PAH/(PSS-PAA) multilayer films. The multilayer [(PEI/blend)/(PAH/blend)4] films with rhoPAA (PSS-PAA fraction in the blend solutions) = 0.0 in the blend solution exhibited surface morphologies of randomly isolated globular clusters, while at rhoPAA = 0.75, worm-like morphologies were observed. Interestingly, the multilayer [(PEI/blend)/(PAH/blend)4 films with rhoPAA = 0.9 exhibited unique fibrous morphologies with the diameter of about 50 nm at narrower pH range from 3.5 to 4.2, but also the fiber diameter distribution was narrower. Based on the thickness from the X-ray reflectivity, the thickness of the one bilayer multilayer film seemed to be 8.6 nm. The 3 bilayers multilayer film seemed to be formed as islands with very large roughness. The crystal sizes of the 3 bilayers and 5 bilayers multilayer films were about 71 nm and 123 nm, respectively. The resultant films were characterized using atomic force microscopy (AFM) and real time in situ X-ray scattering measurements. PMID- 27451769 TI - Synthesis and Photoluminescence of Single-Crystalline Fe(III)-Doped CdS Nanobelts. AB - In this paper, we report the synthesis and optical properties of Fe(III) doped CdS nanobelts (NBs) via simple Chemical Vapor Deposition (CVD) technique to explore their potential in nano-optics. The energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD) analysis manifested the presence of Fe(III) ions in the NBs subsequently confirmed by the peak shifting to lower phonon energies as recorded by Raman spectra and shorter lifetime in ns. Photoluminescence (PL) spectrum investigations of the single Fe(III)-doped CdS NBs depicted an additional PL peak centered at 573 nm (orange emission) in addition to the bandedge(BE) emission. The redshift and decrease in the BE intensity of the PL peaks, as compared to the bulk CdS, confirmed the quenching of spectra upon Fe doping. The synthesis and orange emission for Fe-doped CdS NBs have been observed for the first time and point out their potential in nanoscale devices. PMID- 27451770 TI - Synthesis, Characterization and Exploration of Multiferroic Properties in Nano Crystalline Tb1-xYxMnO3 (0 <= x <= 0.4). AB - We report the synthesis and electric properties of nano-crystalline Tb1-xYxMnO3 (x = 0, 0.1, 0.2, 0.3 and 0.4) compounds prepared by gel-combustion method. These samples were characterized by a number of techniques including X-ray diffraction (XRD), Raman spectroscopy, specific-heat measurement, neutron diffraction, and magnetic field dependent pyrocurrent measurement. All the samples crystallize in the orthorhombic structure with space group Pnma at room temperature. Anomalies were observed in low temperature specific-heat measurement corresponding to magnetic and electric phase transitions. The magnetic phase transitions occurred at ~35, ~22-28 and ~7 K for all the samples. Signatures of coupling between magnetic and electric order parameters were revealed by pyrocurrent measurements carried out in presence of magnetic fields. PMID- 27451771 TI - Biomimetic Modification and In Vivo Safety Assessment of Superparamagnetic Iron Oxide Nanoparticles. AB - The efficacy of superparamagnetic iron oxide nanoparticles (SPIONs) for biomedical applications depends on the magnetic properties, long time stability in biological fluids, and specific targeting capacity. The properties of SPIONs were generally improved by surface modification, but common modification technologies were usually conducted with multi-steps under rigid conditions. In this work, a facile and simple approach to synthesize functionalized SPIONs contrast agents was set up. First of all, SPIONs were prepared by an improved ultrasonic co-precipitation method. Then the surfaces of these SPIONs were modified biomimeticly by dopamine (DA) with strong adhesion. At last, the c(RGDyK), a biomolecule with the capacity of specific targeting capacity towards liver tumor cells, were coupled with DA on SPIONs via Mannich reaction. Thus the novel magnetic composite nanoparticles (abbreviated as c(RGDyK)-PDA-SPIONs) were successfully prepared. The as-synthesized nanoparticles were characterized by scanning electron microscope (SEM), dynamic light scattering, magnetic hysteresis loop measuring instrument. As a result, that the c(RGDyK)-PDA-SPIONs had an average size of about 50 nm and uniform distribution, and had superparamagnetic properties, good water dispersion stability. The acute toxicity test of the assynthesized c(RGDyK)-PDA-SPIONs to mice was also investigated. It was observed that LD50 of c(RGDyK)-PDA-SPIONs was 4.38 g/kg, with a 95% confidence interval ranging from 3.49 g/kg to 5.87 g/kg. These results indicated the novel c(RGDyK) PDA-SPIONs had excellent biocompatibility, which was endowed with a potential capacity to serve as MRI contrast agents in diagnosis and treatment of the liver tumor. PMID- 27451772 TI - Adsorption of Methyl Blue on Mesoporous Materials Using Rice Husk Ash as Silica Source. AB - It is recognized that recycling and reuse of waste can result in significant savings in materials and energy. In this research, the adsorption of methyl blue (MB) using waste rice husk ash (Rha) and mesoporous silica materials made from Rha (R-MCM) were analyzed. Mesoporous silica materials were synthesized using cetyltrimethyl ammonium bromide (CTAB) as a cationic surfactant and Rha as the silica source. The prepared samples were characterized by Brunnaur-Emmet-Teller (BET) adsorption isotherm analyzer and transmission electron microscope (TEM) analysis. The results showed the surface area of R-MCM materials was 1347 m2g-1 and the pore volume was 0.906 cm3g-1. TEM analysis showed that the mesoporous materials generally exhibited ordered hexagonal arrays of mesopores with a uniform pore size. The effects on adsorption performance under different initial dye concentrations, different pH values and different dosages of adsorbent were also studied. Both Langmuir and Freundlich adsorption models were applied to describe the equilibrium isotherms. The results show that the maximum removal efficiency of MB more than 99%. PMID- 27451773 TI - Preparation and Characterization of SnO2/Ag Hollow Microsphere via a Convenient Hydrothermal Route. AB - SnO2/Ag hollow microsphere, assembled form SnO2 and Ag nanoparticles, was synthesized via a facile one-step hydrothermal synthesis method using Na2SnO3.3H2O, CO(NH2)2 and AgNO3 as raw materials. XRD, SEM, and TEM results revealed that the obtained SnO2/Ag hollow microsphere with diameters of ca.3-5 um was built from uniformly distributed rutile SnO2 and cubic Ag nanoparticles. Moreover, XPS results indicate the existence of strong interaction between Ag and SnO2 nanoparticles, rather than simply physical contact, endowing the SnO2/Ag hollow microspheres with excellent photocatalytic performance in the degradation of RhB solution under visible light irradiation. PMID- 27451774 TI - Viewing the Interaction Between Double Strand Deoxyribonucleic Acid and Graphene Oxide via Atomic Force Microscopy. AB - The interaction between DNA and graphene-oxide (GO) is fundamental and of significance to a number of biomedical applications. It is fairly clear that pi pi stacking effect accounts for the strong interaction between ssDNA and GO, while little is known on the mechanics of the relative weak interaction between dsDNA and GO. Here we employ AFM to investigate the coupling behavior of dsDNA-GO duplex and reveal preference adsorption of DNAon GO. The results show that dsDNA tends to aggregate on GO surface. Additionally, it is observed that GO also tend to stack into multi-layer structure in the presence of dsDNA, indicating dsDNA can simultaneously interact with two sides of the GO sheet. Such a structure is, however, unstable and can easily collapse by rinsing or heating. PMID- 27451775 TI - Growth and Detachment of 5 Helix DNA Ribbons. AB - We report on the concentration-dependent surface-assisted growth and time temperature-dependent detachment of one-dimensional 5 helix DNA ribbons (5HR) on a mica substrate. The growth coverage ratio was determined by varying the concentration of the 5HR strands in a test tube, and the detachment rate of 5HR on mica was determined by varying the incubation time at a fixed temperature on a heat block. The topological changes in the concentration-dependent attachment and the time-temperature-dependent detachment for 5HR on mica were observed via atomic force microscopy. The observations indicate that 5HR started to grow on mica at ~10 nM and provided full coverage at ~50 nM. In contrast, 5HR at 65 degrees C started to detach from mica after 5 min and was completely removed after 10 min. The growth and detachment coverage show a sinusoidal variation in the growth ratio and a linear variation with a rate of detachment of 20%/min, respectively. The physical parameters that control the stability of the DNA structures on a given substrate should be studied to successfully integrate DNA structures for physical and chemical applications. PMID- 27451776 TI - Tungsten Trioxide (WO3) Nanoparticles as a New Anode Material for Sodium-Ion Batteries. AB - Tungsten trioxide (WO3) is investigated for the first time as an anode material for sodium-ion batteries. Pristine WO3 displays a discharge potential plateau at 1 V and exhibits a 1st discharge cycle sodium storage capacity of 640 mAh g-1. Electronic wiring of WO3 with graphene oxide (GO, 1% by weight) led to a significant increase in the storage capacity and cyclability of WO3. As a result, the discharge capacity of 1% GO-WO3 is enhanced to 927 mAh g-1 in the 1st discharge cycle. The electrochemical intercalation of Na in to WO3 and (1%) GO WO3 as obtained from galvanostatic charge/discharge cycling is also supported by cyclic voltammetry. PMID- 27451777 TI - SnO2/Reduced Graphene Oxide Nanocomposite as Anode Material for Lithium-Ion Batteries with Enhanced Cyclability. AB - SnO2 is considered as one of the most promising anode materials for next generation lithium-ion batteries, however, how to build energetic SnO2-based electrode architectures has still remained a big challenge. In this article, we developed a facile method to prepare SnO2/reduced graphene oxide (RGO) nanocomposite for an anode material of lithium-ion batteries. It is shown that, at the current density of 0.25 A.g-1, SnO2/RGO has a high initial capacity of 1705 mAh.g-1 and a capacity retention of 500 mAh . g-1 after 50 cycles. The total specific capacity of SnO2/RGO is higher than the sum of their pure counterparts, indicating a positive synergistic effect on the electrochemical performance. PMID- 27451778 TI - Towards Acid-Tolerated Ethanol Dehydration: Chitosan-Based Mixed Matrix Membranes Containing Cyano-Bridged Coordination Polymer Nanoparticles. AB - Prussian blue (PB) nanoparticles, one of many cyano-bridged coordination polymers, are successfully incorporated into chitosan (CS) polymer to prepare PB/CS mixed matrix membranes (MMMs). The PB nanoparticles are uniformly distributed in the MMMs without the collapse of the original PB structure. As prepared PB/CS MMMs are used for ethanol dehydration at 25 degrees C in the pervaporation process. The effect of loading PB in CS matrix on pervaporation performance is carefully investigated. The PB/CS membrane with 30 wt% PB loading shows the best performance with a permeate flux of 614 g. m-2 . h-1 and a separation factor of 1472. The pervaporation using our PB/CS membranes exhibits outstanding performance in comparison with the previously reported CS-based membranes and MMMs. Furthermore, the addition of PB allows PB/CS MMMs to be tolerant of acidic environment. The present work demonstrates good pervaporation performance of PB/CS MMMs for the separation of an ethanol/water (90:10 in wt%) solution. Our new system provides an opportunity for dehydration of bioethanol in the future. PMID- 27451779 TI - Dynamic Mechanical Properties, Crystallization Behavior and Morphology of Nanoscale Tin Fluorophosphate Glass/Polyamide 66 Hybrid Materials. AB - The dynamic mechanical properties, crystallization behavior and morphology of nanoscale Tg tin fluorophosphate glass (TFP glass)/polyamide 66 (PA66) hybrid materials were investigated by XRD, DSC and SEM. The experimental results showed that the Tg of TFP/PA66 hybrid decreased and the third relaxation in the highly filled hybrid appeared due to the interaction between the TFP glass and amide groups of PA66. The storage modulus of the hybrid materials increased with increase in the content of TFP at low temperatures but had little effect at high temperatures. This result was attributed to the stiffness depression of the TFP glass when the temperature rose above its Tg and the similar elasticity of the two phases because of the interaction between the components. The degree of crystallinity and a, y crystal content of PA66 both decreased due to the interaction between the two phases. In addition, the phase defect, the size distribution and the compatibility of TFP in the PA66 matrix were discussed by SEM, the results showed that the TFP appeared aggregation partly, but had the favorable compatibility in the PA66 matrix. PMID- 27451780 TI - Mn-Doping in NiO Nanoparticles: Defects-Modifications and Associated Effects Investigated Through Positron Annihilation Spectroscopy. AB - Manganese-doped nickel oxide (Ni1-xMnxO) nanoparticulate samples with x in the range 0 (undoped sample) to 0.35 were synthesized by sol-gel method involving chemical reactions between the solutions of nickel nitrate hexahydrate and manganese acetate tetrahydrate. The nanocrystallites obtained after annealing of the precipitates for different durations were characterized by X-ray diffraction and high resolution transmission electron microscopy. The samples showed high degree of purity with no secondary phase up to 35 at.% (x = 0.35) of Mn-doping. At the initial doping concentrations, the crystallite sizes increased due to vacancy type defects being recombined with some of the doped Mn2+ ions. However, substitution-induced strain soon overtook the crystallite dynamics and the sizes rapidly started reducing again as an indirect consequence of the necessity to accommodate majority of the doped cations on the surfaces of the nanocrystallites. There was conspicuous changes in the lattice parameter too which could again be attributed to the strain and charge effects. The average sizes of the crystallites were obtained in the range 5.5 nm to 13.1 nm for the different samples. UV-Vis absorption studies indicated the formation of excitonic states in NiO on Mn-doping. The band gap energy (Eg) derived from the optical absorption spectra showed a continuous increase with increase of Mn-doping of the samples. Positron lifetime and Doppler broadening spectroscopic studies were carried out on those samples to characterize the vacancy type defects and defect clusters/complexes. There were also indications to suggest positron annihilation at the crystallite surfaces owing to their sizes of nanometer order. Positron lifetimes decreased upon increase of Mn-doping. The coincidence Doppler broadened ratio curves indicated definite shifts of the prominent oxygen-electron annihilation peak and the variation of the lineshape parameter S also indicated clearly the effects of Mn-doping. PMID- 27451781 TI - Co9S8 Nano/Microspheres: Characterization and Magnetic Properties. AB - Co9S8 microspheres were synthesised by a simple solvothermal route in a binary solution of triethylenetetramine (TETA) and high-purity water (W). Among all the factors that may influence the samples morphologies, volume ratio of TETA and high-purity water are of extreme importance. SEM images show that the microspheres surfaces are coarse with a mean diameter of about 3-5 um. Their crystallinity can be improved by high temperature annealing. To determine the crystallinity and composition of samples, XRD, EDS and TEM tests were carried out. It can be inferred that these nano/microspheres are amorphous before annealing and crystallized after annealing. Meanwhile a higher element ratio of S:Co can be detected from the annealed samples on EDS results. In the case of magnetism, Co9S8 microspheres turn out to be paramagnetic at room temperature. PMID- 27451782 TI - Hierarchical NiO Nanoflake Arrays on Nickel Foam as a Supercapacitor Electrode with High Capacitance and High Rate Capability. AB - In this paper, we report a simple and cost-effective method for fabricating hierarchical NiO nanoflake arrays on nickel foam. X-ray diffraction, scanning electron microscope and transmission electron microscope are employed to study the morphology and structure of the as-synthesized NiO materials. Galvanostatic charge/discharge measurements demonstrate that the hierarchical NiO nanocomposite displays excellent capacitive behavior between the potential range of -0.1-0.5 V, and a maximum specific capacitance as high as 823 F g-1 can be achieved at a charge/discharge current density of 4 A g-1, and it only decreases by 20% when the current density increases to 12 A g-1. The remarkable electrochemical performance of this hierarchical NiO nanocomposite indicates the areat application potential in supercapacitors. PMID- 27451783 TI - Radiolabeled D-Penicillamine Magnetic Nanocarriers for Targeted Purposes. AB - The aim of this study is to synthesize D-Penicillamine (D-PA) conjugated magnetic nanocarriers for targeted purposes. Magnetic nanoparticles were prepared by partial reduction method and surface modification was done with an amino silane coupling agent's (structural properties), AEAPS, the particles were characterized by Scanning Electron Microscope (SEM), X-ray Diffraction (XRD). After that D-PA was linked with the magnetic nanoparticles (MNPs) and has been radiolabeled with [99mTc(CO)3]+ core. Quality controls of [99mTc(CO)3-MNP-D-PA] were established by Cd(Te) detector. The radiolabeling efficiency of magnetic nanoparticles ([99mTc(CO)3-MNP-D-PA]) was about 97.05% with good in vitro stability during the 24 hour period. As a parallel study, radiolabeled D-PA complex ([99mTc(CO)3-D PA]) was prepared with a radiolabeling yield of 97.93%. At the end, biologic activities of binding complexes were investigated on MCF7 human breast cancer cells. Our results show that, radiolabeled magnetic nanoparticles with core [99mTc(CO)3]+ ([99mTc(CO)3-MNP-D-PA]) showed the highest uptake on MCF7 cells which were applied magnetic field in the wells. In that case, result of this study emphasizes that radiolabeled magnetic nanoparticles with core [99mTc(CO)3]+ would support new occurrences of new agents. PMID- 27451784 TI - Synergistic Chemotherapeutic Activity of Curcumin Bearing Methoxypolyethylene Glycol-g-Linoleic Acid Based Micelles on Breast Cancer Cells. AB - Although curcumin (Cur), has been poised to be an anticancer boon for quite some, its progress from bench to bed has been strained due to various pharmaceutical hurdles. Consequently curcumin has been entrapped in methoxy poly ethylene glycol and linoleic acid conjugated polymeric micelles (PMs) to not only tackle the routine issues but to also provide a synergetic effect against MCF-7 breast cancer cells. Optimized PMs of Cur had size 186.53 +/- 12.10 nm with polydispersity index 0.143 +/- 0.031 and zeta potential -30.1 +/- 3.2 mV. Developed formulation (Mpeg-Cla-Cur PMs) was hemocompatible and had high cytotoxicity (IC50 55.80 +/- 4.63 u/mL) against MCF-7 cells in comparison to pure Cur suspension (IC50 75.05 +/- 5.75 ug/mL). As postulated cell cycle arrest and apoptosis studies revealed synergetic effect of Mpeg-Cla-Cur PMs with higher cell population in G1 phase in addition to high apoptosis of MCF-7 cells as compared to pure Cur suspension and con- trol group. Pharmacokinetic studies also show PMs enhanced MRT and T1/2 of Cur indicating its longer retention time in body. Mpeg Cla-Cur PMs might become as an excellent chemotherapeutic alternative candidate for treatment of breast cancer with higher commercial value. PMID- 27451785 TI - Preparation of Reduced-Graphene Nanoribbons via One-Step Solvothermal Process. AB - Carbon nanotubes were unzipped to become reduced-graphene nanoribbons via one step solvothermal process in a Teflon-lined autoclave. The samples were characterized by X-ray diffraction, thermo-gravimetric analysis and transmission electrical microscopy, respectively. Results showed that the solvothermal reaction temperature played an important role in the structure of the samples. When it was 75 degrees C, carbon nanotubes were completely cutted into graphene oxide nanoribbons. Moreover, when it was 155 degrees C, they were become reduced graphene nanoribbons. Furthermore, the as-prepared reduced-graphene nanoribbons could improve mechanical strength of the phenolic resin/hollow glass beads foamed composites. When the reduced-graphene nanoribbons loading was 0.4 wt%, the tensile and compressive strength of the composites were increased by 19.7% and 21.3%, respectively. PMID- 27451786 TI - Magnetic Field-Induced Accentuation of Drug Release from Core/Shell Magnetic Mesoporous Silica Nanoparticles for Anticancer Treatment. AB - Drug (9-aminoacridine) loaded core/shell magnetic iron oxide-containing mesoporous silica nanoparticles (MMSN) were treated with HeLa cells and the drug carriers were agitated by expo- sure to magnetic field. Viability studies show the applicability of drug loaded magnetic material for anticancer treatment, which is enhanced upon stimulation with magnetic field. Confocal micrographs of fluorescein grafted MMSN-treated HeLa cells confirmed the ability of magnetic field to concentrate the synthesized material in the exposed area of the cells. The synthesized material and the applied drug delivery method may find application in magnetic field-responsive targeted treatment of cancer. PMID- 27451787 TI - Hydrogels Containing Prussian Blue Nanoparticles Toward Removal of Radioactive Cesium Ions. AB - Recent reports have demonstrated the practical application of Prussian blue (PB) nanoparticles toward environmental clean-up of radionuclide 173Cs. Herein, we prepared a large amount of PB nanoparticles by mixing both iron(III) chloride and sodium ferrocyanide hydrate as starting precursors. The obtained PB nanoparticles show a high surface area (440 m2. g-1) and consequently an excellent uptake ability of Cs ions from aqueous solutions. The uptake ability of Cs ions into poly(N-isopropylacrylamide (PNIPA) hydrogel is drastically increased up to 156.7 m2. g-1 after incorporating our PB nanoparticles, compared to 30.2 m2 . g-1 after using commercially available PB. Thus, our PB-containing PNIPA hydrogel can be considered as an excellent candidate for the removal of Cs ions from aqueous solutions, which will be useful for the remediation of the nuclear waste. PMID- 27451788 TI - Graphene Oxide Modulates B Cell Surface Phenotype and Impairs Immunoglobulin Secretion in Plasma Cell. AB - Since discovery, graphene oxide (GO) has been used in all aspects of human life and revealed promising applications in biomedicine. Nevertheless, the potential risks of GO were always being revealed. Although GO was found to induce immune cell death and innate immune response, little is known regarding its toxicity to the specific adaptive immune system that is crucial for protecting against exotic invasion. The B-cell mediated adaptive immune system, which composed of highly specialized cells (B and plasma cell) and specific immune response (antibody response) is the focus in our present study. Using diverse standard immunological techniques, we found that GO modulated B cell surface phenotype, both costimulatory molecules (CD80, CD86 and especially CD40) and antigen presenting molecules (both classical and nonclassical) under the condition without causing cell death. Meanwhile, the terminal differentiated immunoglobulin (Ig) secreting plasma cell was affected by GO, which displayed a less secretion of Ig and more severe ER stress caused by the retention of the secreted form of Ig in cell compartment. The combined data reveal that GO has a particular adverse effect to B cell and the humoral immunity, directly demonstrating the potential risk of GO to the specific adaptive immunity. PMID- 27451789 TI - Preparation of Graphene Oxide and Its Mechanism in Promoting Tomato Roots Growth. AB - Graphene oxide is a new kind of nanomaterial. The graphene oxide was prepared and its quality detected by atomic force microscopy (AFM) and transmission electron microscopy (TEM), for better understanding of effects of the nanomaterial on plants. Wild type. (WT) tomato (Solanum lycopersicum) germplasm 'New Yorker' and corresponding transgenic plants (Prd29A::LeNCED1) were treated with prepared graphene oxide. 9-cis-epoxycarotenoid dioxygenase (NCED) is a key gene for ABA biosynthesis and overexpression of the NCED resulted in ABA accumulation and higher drought tolerance. Seminal root length in the WT tomato was longer than that in the control samples when the seedlings were treated with 20 mg/L graphene oxide for 15 days. In contrast, the same treatment resulted in shorter seminal root length in the transgenic plants compared with control samples. The graphene oxide treatments led to lower Superoxide Dismutase (SOD), Peroxidase (POD), Catalase (CAT) activity and Malondialdehyde (MDA) content in the WT and transgenic plants. 20 mg/L graphene oxide treatment also affected the transcript levels of IAA7, IAA4 and IAA10 but the effect on the wild type and corresponding transgenic plants was different. IAA4 transcription level decreased both in the WT and Prd29A::LeNCED1 transgenic plants while the IAA7 transcription level decreased in the transgenic plants and increased in the WT tomato. The IAA10 transcription level decreased in the WT tomato and increased in the Prd29A::LeNCED1 transgenic plants. Graphene oxide treatments resulted in higher transcription level of ABCG25 and ABCG40 in the WT plants but had no significant effect on transgenic plants. The transcription level of NCED in the WT and Prd29A::LeNCED1 transgenic plants treated with graphene oxide increased significantly, however, it was higher in the transgenic plants than in the WT tomato after 15 d treatment, indicating that the graphene oxide activated the rd29A promoter as does drought and salt. The HD-ZIP transcription level only decreased significantly in the treated Prd29A::LeNCED1 transgenic plants. All these results suggested that there was a crosstalk between ABA and graphene oxide and the graphene oxide affected plant growth through the ABA and IAA pathway. PMID- 27451790 TI - Investigation of Surfactant Type, Dosage and Ultrasonication Temperature Control on Dispersity of Metal-Coated Multi-Walled Carbon Nanotubes. AB - We studied the dispersity of multi-walled carbon nanotubes (MWNTs) combined with different metal- lic particles (Ni and Fe). An ultrasonic-assisted water-bath dispersion process was used to dis- perse the metal-coated MWNTs in different solutions and the dispersity was measured using an ultraviolet-visible spectrophotometer. The dispersity and morphology of the MWNTs were characterized using field-emission scanning electron microscopy (FE-SEM) together with digital image processing technology. Effects of dispersant type (sodium dodecyl benzene sulfonate (SDBS), oleic acid, and polymer (TNEDIS)) and surfactant dosage on the dispersity of the metal-coated MWNTs were investigated under controlled and uncontrolled temperatures and results were compared with those from the untreated MWNTs. The results showed that the negative effects of temperature on the ultrasonic dispersion process could be eliminated through a temperature controlled system. Moreover, the TNEDIS, SDBS, and oleic acid were arranged in the descending order of the dispersion effect degree. The untreated MWNTs, Ni coated MWNTs, and Fe-coated MWNTs were arranged in the descending degree of dispersity order. Since the metal coating makes the MWNTs harder and more fragile, the metal-coated MWNTs are more likely to fracture during the ultrasonic dispersion process. PMID- 27451791 TI - Preparation of La-TiO2/Bentonite and Its Photodegradation Properties to Cyanide. AB - The photocatalytic materials were prepared by sol-gel method: the main raw materials were tetrabutyltitanate and the lanthanum nitrate hexahydrate, bentonite was the carrier to support TiO2. The properties of the composites were characterized by specific surface area (BET), X-ray diffraction (XRD), fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and thermogravimetric analysis (TG). The photocatalytic degradation of cyanide waste water was used to assess the photocatalytic activity of the materials. The experimental results showed that the suitable content of lanthanum and roasted temperature could improve the photocatalytic activity. When the composites were roasted at 400 degrees C and the molar ratio of La to Ti was 1%, the photocatalyst reached optimal performance. PMID- 27451792 TI - Synthesis of Cationic Amphiphilic Block Copolymers Poly(4 vinylbenzyltriethylammonium chloride)-b-Poly(styrene) and Their Self-Assembly in Aqueous Solution. AB - Well defined two kinds of cationic amphiphilic block copolymers Poly(4 vinylbenzyltriethylammonium chloride)-b-Poly(styrene) are synthesized by combining reversible addition fragmentation chain transfer polymerizations and post-polymerization quaternization. Block copolymers are characterized by GPC and IHNMR. The self-assembly behaviors of the block copolymers are studied, which are characterized by TEM. For Poly(4-vinylbenzyltriethylammoniurn chloride)13-b Poly(styrene)136, crew-cut spherical micelles are obtained by using DMF as the initial common solvent, and the majority of the pearl series aggregates and a small-amount of rod-like aggregates are all observed by using the mixture of DMF and THF as the initial common solvent. The formation process of rod-like aggregates is proposed in three steps: the micellization of copolymer chains, the formation of pearl series aggregates from the collision and fusion of individual initial spherical micelles, and the transformation from pearl series aggregates to rod-like aggregates. For Poly(4- vinylbenzyltriethylammonium chloride)18-b Poly(styrene)370, large compound micelles and complicated spherical aggregates and small vesicles are all,obtained. The formation process of small vesicles is also proposed in three steps: the formation of initial spherical micelles with some hydrophilic block Poly(4-vinylbenzyltriethylammonium chloride) embedded in the core, the removing of the outer layer common solvent, and solvent nucleation in the center. It should be noted that solvent nucleation is critical, because of the hydrophilic block Poly(4-vinylbenzyltriethylammonium chloride) and the common solvent and water embedded in the core of the initial spherical micelles. PMID- 27451793 TI - Enhanced Activity of Nanocrystalline Beta Zeolite for Acylation of Veratrole with Acetic Anhydride. AB - Friedel-Craft acylation of veratrole using homogeneous acid catalysts such as AlCl3, FeCl3, ZnCl2, and HF etc. produces acetoveratrone, (3',4' dimethoxyacetophenone), which is the intermediate for synthesis of papavarine alkaloids. The problems associated with these homogeneous catalysts can be overcome by using heterogeneous solid catalysts. Since acetoveratrone is a larger molecule, large pore Beta zeolites with smaller particle sizes are beneficial for the liquid-phase acylation of veratrole, for easy diffusion of reactants and products. The present study aims in the acylation of veratrole with acetic anhydride using nanocrystalline Beta Zeolite catalyst. A systematic investigation of the effects of various reaction parameters was done. The catalysts were characterized for their structural features by using XRD, TEM and DLS analyses. The catalytic activity of nanocrystalline Beta zeolite was compared with commercial Beta zeolite for the acylation and was found that nanocrystalline Beta zeolite possessed superior activity. PMID- 27451794 TI - I Am TNA. PMID- 27451795 TI - TNA Legislative Summit Educates Future Nurses and Renews Spirit of Current RNs. PMID- 27451797 TI - From the President. PMID- 27451796 TI - An Angel Among Us. PMID- 27451798 TI - The Garden. PMID- 27451799 TI - Through the Eyes of Students. PMID- 27451800 TI - TNA Executive Director Honored at the Nashville Medical News' Women to Watch Class of 2016 Celebration. PMID- 27451801 TI - Emerging Nurse Leader Seminar Provides Inspirational Topics Related To Leadership. PMID- 27451802 TI - A Good Story on the Power of Stories. PMID- 27451803 TI - Spotlight on Practice. PMID- 27451804 TI - Especially a Nurse: Find Power in your Practice. PMID- 27451805 TI - Nurse Leadership Through Board Service. PMID- 27451806 TI - Nurses Rank as Most Honest, Ethical Profession for 14th Straight Year. PMID- 27451807 TI - Student Forum. PMID- 27451808 TI - The evaluation of possible role of endocrine disruptors in central and peripheral precocious puberty. AB - Exposure to environmental chemicals can affect genetic and epigenetic molecular pathways and may cause altered growth and development. Among those exposures, endocrine-disrupting chemicals (EDCs) are of particular concern as humans are abundantly exposed to these chemicals by various means in every period of life. Several well-known environmental chemicals, including phthalates and bisphenol A (BPA), are classified as EDCs. These EDCs are suggested to play roles in early onset of puberty in girls. The aim of this study is to determine plasma phthalate (di(2-ethylhexyl)phthalate [DEHP] and its main metabolite mono(2 ethylhexyl)phthalate [MEHP]) and urinary BPA levels in girls with idiopathic central precocious puberty (CPP) and peripheral precocious puberty (PPP). This study was performed on newly diagnosed idiopathic central precocious puberty (CPP) patients (n = 42) and peripheral precocious puberty (PPP) (n = 42) patients, who were admitted to Kecioren Training and Research Hospital, Clinic of Pediatric Endocrinology between August 2012 and -July 2013. Nonobese healthy girls (n = 50) were used as the control group. Urinary BPA levels were not statistically different in control, PPP and CPP groups (medians 10.91, 10.63 and 10.15 MUg/g creatinine, respectively; p > 0.05). Plasma DEHP levels were significantly higher in PPP group when compared to control. Plasma MEHP levels were not significantly different in control and PPP groups (p > 0.05). However, in CPP group, both plasma DEHP and MEHP levels were significantly higher than control and PPP groups. This study showed that phthalates might play a role in the occurence of CPP in girls. PMID- 27451809 TI - Utility of Novel Plasma Metabolic Markers in the Diagnosis of Pediatric Tuberculosis: A Classification and Regression Tree Analysis Approach. AB - Although tuberculosis (TB) has been the greatest killer due to a single infectious disease, pediatric TB is still hard to diagnose because of the lack of sensitive biomarkers. Metabolomics is increasingly being applied in infectious diseases. But little is known regarding metabolic biomarkers in children with TB. A combination of a NMR-based plasma metabolic method and classification and regression tree (CART) analysis was used to provide a broader range of applications in TB diagnosis in our study. Plasma samples obtained from 28 active TB children and 37 non-TB controls (including 21 RTIs and 16 healthy children) were analyzed by an orthogonal partial least-squares discriminant analysis (OPLS DA) model, and 17 metabolites were identified that can separate children with TB from non-TB controls. CART analysis was then used to choose 3 of the markers, l valine, pyruvic acid, and betaine, with the least error. The sensitivity, specificity, and area under the curve (AUC) of the 3 metabolites is 85.7% (24/28, 95% CI, 66.4%, 95.3%), 94.6% (35/37, 95% CI, 80.5%, 99.1%), and 0.984(95% CI, 0.917, 1.000), respectively. The 3 metabolites demonstrated sensitivity of 82.4% (14/17, 95% CI, 55.8%, 95.3%) and specificity of 83.9% (26/31, 95% CI, 65.5%, 93.9%), respectively, in 48 blinded subjects in an independent cohort. Taken together, the novel plasma metabolites are potentially useful for diagnosis of pediatric TB and would provide insights into the disease mechanism. PMID- 27451810 TI - Comment on "Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study". PMID- 27451811 TI - Challenges in the diagnosis of extrapulmonary tuberculosis. PMID- 27451812 TI - Based on speech delivered during 3rd Conference of South East Asia Region of The Union 26th and 27th May, 2016 Kathmandu (Nepal). PMID- 27451813 TI - A cross sectional study in patients with confirmed spinal tuberculosis in central Taiwan: Analysis of preliminary clinical presentation and neuroradiological findings. AB - Spinal tuberculosis (STB) can cause significant functional impairment. The purpose of the present study was to analyze the factors at preliminary presentation and the neuroradiological findings in STB patients. We performed a retrospective cross-sectional analysis of cases with a definitive diagnosis of STB. Four patients with confirmed mycobacterial infection and histopathological findings confirming TB were identified. We noted two key clinical indicators. We also identified seven key neuroradiological findings associated with STB lesions. A high degree of clinical suspicion along with nine neuroradiological findings described in this study are important for STB diagnosis and for starting treatment with antituberculosis agents. PMID- 27451814 TI - Radiographic chest findings and immunological status in HIV-positive patients with tuberculosis coinfection in a sub-urban Nigerian tertiary hospital. AB - INTRODUCTION: The study was undertaken to assess chest radiographic features and lymphocyte counts among HIV-positive patients with TB coinfection. MATERIALS AND METHOD: We reviewed the chest radiographs of all newly diagnosed, treatment-naive HIV-positive patients attending the Treatment Centre at the Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria. The radiographs were examined for presence or absence of features of tuberculosis and pneumonia. Those with tuberculosis were further evaluated for presence of cavities and milliary appearance. The demographic characteristics of the patients were recorded. RESULTS: Two hundred and ninety-five radiographs were reviewed, consisting of 192 females, 103 males with mean ages of 33.6+/-11.65 and 37.85+/-13.54 years, respectively. Normal radiographs were found in 68.5% patients, features of tuberculosis in 27.8%, and pneumonia in 2.7%. The percentages of males and females with tuberculosis were 35% and 25%, respectively. Patients with milliary TB were from the youngest age group and those with cavities had CD4 cell count below 200cells/mm(3). Cavities occurred most frequently in the lower zones. WBC and counts were highest in patients with pneumonia. CONCLUSION: Normal chest radiographs were associated with mild clinical course. Males were more frequently involved in TB coinfection. Cavities were associated with lowest CD4 cell count and occurred more in lower zones. Patients with HIV/PTB coinfection had the most severe weight loss. There was no statistically significant difference in absolute lymphocyte count between patients with or without tuberculosis. Chest radiograph remains a veritable tool for identifying HIV/AIDS patients with tuberculosis whether sputum is positive or negative. PMID- 27451815 TI - Immunotherapy for non-responders among patients of spinal tuberculosis. AB - BACKGROUND: Combined chemo- and immunotherapy are the major advancement in the treatment of tuberculosis. Immunotherapy supposedly increases cure rate while reducing the duration of treatment and tissue damage. Non-responders are those patients of tuberculosis who do not respond to anti-tubercular therapy (ATT) in the desired manner despite the mycobacteria showing sensitivity to the given drugs. The role of immunotherapy in the treatment of this particular subset of patients has been investigated scarcely. METHODS: The present study included a retrospective review of prospectively collected clinico-radiological data of 14 non-responder patients who were taking ATT for spinal tuberculosis for a mean duration of 10.3 months. An immunotherapeutic regime comprising of single intramuscular injection of vitamin D 600,000IU, 3 days course of oral albendazole 200mg daily, salmonella vaccine 0.5ml intramuscular and influenza vaccine 0.5ml intramuscular were added to ATT. The vaccines and the course of oral albendazole were repeated after a month. RESULTS: Before immunotherapy, seven patients were partially dependent while other seven were completely dependent on others for activities of daily living. All except one patient after treatment became independent till last follow-up (p value <0.01). Post immunotherapy, ATT was continued for mean duration of 4.9 months with mean follow-up of 22.4 months. All patients showed good clinical response within 2-6 weeks after the initiation of immunotherapy. CONCLUSIONS: The crux to success of the immunotherapy regime is its potential to restore the existing Th1 Th2 imbalance and to provide substitute to the anergic and dysfunctional immune cells. PMID- 27451816 TI - Patients' perceptions about the implementation of Revised National Tuberculosis Control Programme of India. AB - INTRODUCTION: Revised National Tuberculosis Control Programme (RNTCP) was launched by the Government of India in 1993. The present study has attempted to analyze the perceptions of patients regarding the implementation of RNTCP. MATERIALS AND METHODS: The present study was done in a teaching hospital in North India. All patients attending the hospital between March 2014 and July 2014 were included. The study design was cross-sectional using a pre-designed and tested questionnaire. The patients were questioned by personal interviews after obtaining an informed verbal consent. RESULTS: 74.5% patients were not aware about the kind of disease they were suffering from. 80% patients said that they were not talked in detail about their disease. 64.79% patients said that their doctor was the source of knowledge regarding DOTS prior to treatment. Despite an average distance of 4.75km between their home and DOTS centre, 90.5% patients said that they did not have any problem in travelling to the DOTS centre for medications. 91.5% and 93.5% patients felt the DOT provider behaviour was supportive and satisfactory respectively. CONCLUSION: 64% patients said that they were completely satisfied with the treatment under DOTS, 28.5% were partially satisfied and 7.5% were not satisfied with the treatment. PMID- 27451817 TI - Epidemiological features of skeletal tuberculosis at an urban district tuberculosis centre. AB - Skeletal tuberculosis is an important component of extra-pulmonary tuberculosis. It can lead to substantial morbidity and poses serious occupational and economic problem. We conducted a study in an urban District Tuberculosis Centre (DTC) to assess the burden and distribution of skeletal tuberculosis in the community. Our centre was catering to a population of 6-7 lakhs between 2007 and 2012. During this period, we treated 11,274 cases of tuberculosis. Out of these, 3086 (27.3%) were cases of extrapulmonary tuberculosis and 219 (1.94%) were cases of skeletal tuberculosis. Skeletal TB predominantly affects the young Indian population with incidence peaking in the second and third decades of life. 172 patients (78.5%) in our study were new cases. There were no drugs resistant (DRTB) skeletal TB cases till we concluded our study. Tuberculosis commonly involves joints more than long bones. The spinal column was the most commonly involved skeletal site affecting 62.6% of all cases. The rate of spinal TB in our study is much higher than that reported in literature. The high number of patients calls for close co ordination between managing orthopaedic surgeons, treating physicians and DOT providers to ensure adequate patient care. PMID- 27451818 TI - Add-on prednisolone in the management of cervical lymph node tuberculosis. AB - Studies defining role of systemic steroids in routine management of cervical lymph node tuberculosis (CLNTB) are too few and inconclusive. The present study was carried out to define the role of add-on prednisolone in the management of CLNTB. Patients of CLNTB were randomized into two groups. Group I patients received DOTS Category I treatment along with prednisolone 1mg/kg for first 4 weeks and then tapered down. Group II patients received DOTS Category I treatment along with placebo. Patients were kept under close follow up for 6 months. Response to therapy and adverse drug reactions, if any, were recorded. A total of 120 patients completed the study protocol. The two groups were similar with respect to age, sex, smoking, alcoholism, and clinical profile (p>0.5). At 2 months, 54 out of 60 patients in Group I showed symptom relief when compared with 44 out of 60 patients in Group II (p<0.001). Abscess, sinus, and/or appearance of new lymph node/s were noted in 3 and 13 patients in Group I and Group II, respectively (p<0.001). Complete resolution was seen in 57 patients in Group I when compared with only 40 patients of Group II and sequel in form of residual LN was noted in three patients of Group I when compared with 20 in Group II (p<0.001). Gastrointestinal side effects were reported by higher number of patients in Group I but skin rashes and joint pain were fewer when compared with Group II (p>0.05). All the adverse reactions were transient and amenable to symptomatic treatment. PMID- 27451819 TI - Tuberculosis mortality in a rural population from South India. AB - BACKGROUND: General mortality rate (GMR) is an essential indicator for assessing the health status of a community. Tuberculosis (TB) mortality is an indicator for the Millennium Development Goal for 2015. METHODS: This community-based retrospective survey was conducted in 2007-2008 on a sample of 114,605 rural populations living in 56 villages randomly selected from 218 villages in Tiruvallur district, South India, where the DOTS strategy was implemented in 1999. All the permanent residents of the households were registered and information on occurrence of death was recorded. All the deaths were investigated by verbal autopsy (VA) using standardized methods. RESULTS: A total of 719 deaths were registered. The GMR and tuberculosis mortality rate (TMR) were 648 (95% CI: 568-727) and 39 (95% CI: 25-52) per 100,000 p-yrs, respectively. The GMR increased with age, and was higher in males than females at all ages. The TMR was higher in males than females and the overall male:female ratio was 5:1. CONCLUSION: TB was the 6th leading cause of death overall and the 2nd leading cause among men in this area. Strategies to reduce TB death should be implemented and the impact should be monitored by repeat VA studies. PMID- 27451820 TI - Frequency of adverse events observed with second-line drugs among patients treated for multidrug-resistant tuberculosis. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is considered to be a worldwide problem with notoriously difficult and challenging treatment. Adverse events associated with second-line drugs (SLDs) can have severe impact on efficient management. OBJECTIVE: To know the frequency of adverse events due to SLDs in patients of MDR-TB. DESIGN: A prospective cohort analysis of 98 MDR-TB patients enrolled between June 2009 to February 2010 was conducted in Department of Pulmonary Medicine, King George Medical University, Lucknow, India. All the patients were provided standardized regimen. Adverse events associated with treatment were recognized primarily by clinical evidence and/or laboratory investigations that were advised at baseline and whenever clinically indicated during course of treatment. Adverse events were considered major if required permanent discontinuation or substitution of drugs. RESULTS: 119 adverse events were reported in 46 (46.9%) patients. The grouped adverse events were most commonly gastrointestinal that was observed with a frequency of 48 (40.3%) followed by ototoxicity in 28 (23.6%), and neurological in 21 (17.6%). 17 (17.4%) patients had major adverse events requiring permanent discontinuation or substitution of drugs that included deafness and tinnitus in 5 (5.1%) followed by psychosis in 4 (4.1%). None of the patients stopped complete regimen due to adverse events. The treatment success rate was observed to be 71 (72.4%). CONCLUSIONS: MDR-TB can be cured successfully with appropriate combination of drugs if adverse events associated with them can be managed aggressively and timely. Newer and less toxic drugs are urgently needed to treat MDR-TB patients. PMID- 27451821 TI - Lung health and heart rate variability changes in salt workers. AB - BACKGROUND: India is the third largest salt producing country in the World, with a global annual production of 230 million tonnes. Large number of salt workers get employed in these salt milling plants risking their life from the effects of salt. Recent foreign evidences reported that these salt workers are exposed to aerosol salt particles that disturb their lung and cardiovascular autonomic control. OBJECTIVES: To compare the status of lung health, cardiovascular autonomic control and biochemical changes in a group of salt industry workers with that of the age-matched normal subjects. METHODOLOGY: Volunteers of both sexes (25-35 years) were divided into Group I (n=10) controls and Group II (n=10) non-brine salt workers in salt milling plants. From fasting blood sample, complete blood count, plasma electrolyte and lipid profile estimation were done. After resting for 15min, blood pressure and lead II ECG were recorded. Spirometry was done using RMS Helios spirometer. Data collected were later analysed using GraphPad Prism 5.0 with statistical significance set at p<0.05. RESULTS: Blood pressure recorded showed a slight elevation in the subjects than that in the controls. Significant rise of plasma sodium (141.9+/-0.4, 138.7+/-1.0, p<0.008) and chloride (113.9+/-1.3, 107.7+/-1.4, p<0.005). Spirometric tests showed mild obstructive airway disease in the subjects with FEV1 and FEV1/FVC significantly lower than the controls (81.11+/-3.8, 92.0+/-3.3, p<0.049), (37.4+/-4.0, 112.8+/ 1.7, p<0.0001), FEF25-75% (123.3+/-5.6, 101.0+/-5.6, p<0.01). Heart rate variability parameters also showed statistically significant variation. CONCLUSION: Exposure to salt aerosols by the workers in the salt industry has shown a little or no impact on the respiratory system, however there are changes in the blood and cardiovascular system, which need to be further studied to understand the long-term influences of salt in this population. PMID- 27451822 TI - Drug susceptibility testing of rapidly growing mycobacteria in extrapulmonary tuberculosis. AB - There has been an increasing awareness of the rapidly growing mycobacteria (RGM), of which numerous species and phylogenetic groups are clearly established human pathogens. It is important to appropriately distinguish RGM from other mycobacteria, as first-line antituberculous drugs are ineffective for their treatment. Variability in susceptibility of RGM is seen in relation to species, different geographical areas, and time. Therefore, we conducted a study to speciate the isolates of RGM and perform antimicrobial susceptibility testing. The study was carried out in the department of microbiology of a tertiary care hospital. This study included 40 isolates of RGM obtained from clinical specimens from suspected cases of extrapulmonary tuberculosis. Forty isolates of RGM were speciated by phenotypic methods and drug susceptibility testing was done by broth microdilution method. Of the 40 isolates of RGM, 55% belonged to Mycobacterium fortuitum group, 35% were M. smegmatis group, and 10% were M. chelonae-abscessus group. In M. fortuitum group, sensitivity was seen to amikacin (13.63%), cefoxitin (18.18%), imipenem (31.81%), ceftriaxone (22.72%), and cotrimoxazole (31.81%). Only 14.28% and 7.14% of M. smegmatis were sensitive to cotrimoxazole and amikacin, respectively. M. chelonae-abscessus group was resistant to all the antibiotics tested and showed only intermediate sensitivity to amoxicillin clavulanic acid (50%) and gatifloxacin (25%). A variability in sensitivity to different antimicrobials exists in all groups. Hence, it is advisable to perform antimicrobial susceptibility test before commencement of therapy. PMID- 27451823 TI - Non-communicable disease comorbidities and risk factors among tuberculosis patients, Meghalaya, India. AB - We did cross-sectional study to estimate the prevalence of tobacco, alcohol use, hypertension and diabetes among tuberculosis (TB) patients in comparison to the non-TB patients in East Garo Hills District, Meghalaya, India. We surveyed 110 TB patients attending outpatient TB clinic and 110 age/sex matched non-TB subjects from the general outpatient department as comparison group. Prevalence of ever smoking was 74.5% and 55.4%; alcohol consumption 31.0% and 22.3%; hypertension 24.5% and 17.3%; diabetes 7.5%, 4.5% among TB patients and non-TB subjects, respectively. NCD and TB programmes need integration in the primary care for screening, counselling and treatment of NCD comorbidities. PMID- 27451824 TI - Multiple lumps in the breast due to Mycobacterium fortuitum. AB - Although breast tissue is the most resistant to tuberculosis, its incidence is increasing worldwide. High incidence of breast tuberculosis is presumed in India. The rapidly growing nontubercular mycobacteria, such as Mycobacterium fortuitum and Mycobacterium chelonae, are of increasing clinical importance because infections due to these organisms are often hospital acquired. The true incidence of M. fortuitum is unknown but it has been estimated to be between 4 and 6 cases per one million people. It causes skin or soft tissue infections following trauma or surgery. Breast infection with M. fortuitum is very uncommon. The most common clinical presentation of breast tuberculosis is a painless lump. Multiple lumps are rarely reported. The culture and molecular studies are the keystone for differentiation of various mycobacterium species. We report one such case of a 25 year-old female presenting with multiple painless lumps due to M. fortuitum infection in the left breast. PMID- 27451825 TI - An outbreak of multidrug-resistant tuberculosis among a family. AB - Tuberculosis is a major public health problem and it may be complicated by multidrug-resistant tuberculosis (MDR-TB). Wide transmission among immunocompetent contacts of the index case is possible. If you detect tuberculosis in two contacts of the index case, it is called an outbreak. The aim of our paper is to evaluate the characteristics of a MDR-TB outbreak affecting 7 people in a family treated during 2012-2014 in Istanbul Yedikule Training and Research Hospital for Chest Disease and Thoracic Surgery, Turkey. The cultures, spoligotyping, and DNA fingerprinting revealed the same Mycobacterium tuberculosis species as T1 genotype and ST53 subtype. All patients were negative for human immunodeficiency virus and free of other underlying diseases. PMID- 27451826 TI - "Cryptic" mediastinal tuberculosis with myasthenia-thymoma complex. AB - Mediastinal tuberculosis, although common in endemic areas, is rare in association with myasthenia-thymoma complex. Immunosuppressive therapy for myasthenia with thymoma might increase the susceptibility for mediastinal tuberculosis. Previous reports suggest aggravation of myasthenic symptoms with this association. This rare combination of pathologies adds to the diagnostic dilemma of the surgeon. Further research is warranted in the management aspects of this combination as regards to the timing of radiotherapy, weaning of immunosuppression and anti-tubercular therapy after maximal thymectomy. This case report emphasises the possibility of mediastinal tuberculosis as a differential diagnosis for mediastinal lymphadenopathy in the setting of a preoperative diagnosis of invasive thymoma. PMID- 27451827 TI - Clinical Relevance of Computed Tomography Pulmonary Venography. AB - BACKGROUND: In clinical routine, the pulmonary contrast-enhanced chest computer tomography (CT) is usually focussed on the pulmonary arteries. The purpose of this pictorial essay is to raise the clinicians' awareness for the clinical relevance of CT pulmonary venography. CASE PRESENTATION: A pictorial case series illustrates the clinical consequences of different pulmonary venous pathologies on systemic, pulmonary and bronchial circulation. CONCLUSION: Computed tomography pulmonary venography must be considered before atrial septal defect (ASD) closure and pulmonary lobectomy. Computed tomography pulmonary venography should be considered for patients with right ventricular overload and pulmonary hypertension, as well as for patients with unclear recurrent pulmonary infections, progressive dyspnoea, pleural effusions, haemoptysis, and for patients with respiratory distress after lung-transplantation. PMID- 27451828 TI - Prognosis of 908 patients with intracerebral hemorrhage in Chengdu, Southwest of China. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is the deadliest, most disable and least treatable form of acute cerebral accident. Prognostic risk factors of ICH are not yet fully identified. This study investigated the possible clinical factors leading to poor outcomes in patients with ICH, which can be used to guide clinical treatment and predict prognosis. METHODS: We prospectively enrolled patients with ICH who were admitted within 7 d of stroke onset from January 2012 to April 2014. The prognostic factors of patients with ICH were analyzed in univariate analyses and logistic regression analyses. RESULTS: A total of 908 consecutive patients with ICH (mean age, 57.87 +/- 13.92 years) were finally included, of which 616 patients (67.8%) were male. 59.5%, 54.5% and 52.2% patients with ICH had poor outcomes (death/disability) at 3, 6 and 12 months, respectively. Stroke severity and stroke-related complications during hospitalization were independently associated with poor outcomes both at 3 and 12 months. In addition, hyperglycemia, hematocrit and blood urea nitrogen on admission were independently associated with poor outcomes at three months. CONCLUSION: This study found that severity of ICH and stroke-related complications were independent predictors of poor outcomes at three months and one year after ICH. Thereby, it highlights the importance of understanding the role of clinical features in ICH prognostic evaluation. PMID- 27451829 TI - Scanning sports. PMID- 27451830 TI - Sportsmedicine forum. AB - A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Sportsmedicine Forum, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27451831 TI - Fitness Gomes to Harvard. PMID- 27451834 TI - The Average Child Deserves More Fitness Programs. PMID- 27451836 TI - Coming in sportsmedicine. PMID- 27451837 TI - Noteworthy. PMID- 27451839 TI - Acne Vulgaris in the Athlete. AB - In brief: The treatment of acne is basically the same for athletes and nonathletes. However, certain aspects of sports can affect acne adversely, and in some cases treating athletes may require a cautious approach. The best treatments are topical tretinoin for comedonal acne, benzoyl peroxide or topical antibiotics and tretinoin for comedonal and mild pustular acne, and a combination of oral antibiotics and long-term benzoyl peroxide or topical antibiotics (with the eventual aim of stopping the oral antibiotics in three to five months) for moderate to severe pustular acne. For severe cystic/nodular acne, highdose oral antibiotics and intralesional steroid injections or oral isotretinoin should be considered. PMID- 27451840 TI - Weight Lifting as a Cause of Bilateral Upper Extremity Compartment Syndrome. AB - In brief: Compartment syndrome caused by weight lifting occurs only rarely. In the case presented here, bilateral upper extremity compartment syndrome with rhabdomyolysis developed in a 30-year-old man who was an experienced weight lifter. Compartment pressure of 31 mm Hg in his right and left biceps, combined with other clinical findings, indicated that fasciotomy was necessary. Bilateral fasciotomies were performed from the mid-deltoid muscle to the distal forearm. Six weeks later the patient had good muscle strength and full range of motion in both arms. In addition to the case report, the authors discuss the clinical findings that suggest the presence of compartment syndrome. PMID- 27451841 TI - Hyponatremia in a Marathoner. AB - In brief: Hyponatremia is known to occur in athletes competing in endurance running events greater than marathon distances; it has also stricken participants in the Ironman Triathalon. This article describes a case of hyponatremia associated with altered mental status, increased intracranial pressure, and pulmonary edema in a 21-year-old man who had completed his first marathon. Salt loss from sweat and retention of hypotonic fluids are the most likely causes. This is the first reported case of this syndrome occurring at a marathon distance. PMID- 27451842 TI - Exercise Medicine in Medical Education in the United States. AB - In brief: A review of 92 US medical school bulletins showed that only four schools (4%) offer exercise medicine as part of required undergraduate course work. In 31 schools (34%) exercise information is offered on an elective basis; 57 schools (62%) offer no formal instruction of this type. Despite both the increasing study of the health aspects of cardiorespiratory fitness and the public's growing awareness of these benefits, medical schools continue to place little emphasis on this important component of preventive medicine. The authors recommend that medical students be required to take at least a short course in exercise medicine that emphasizes cardiorespiratory fitness. PMID- 27451843 TI - Legal Aspects of Cardiac Rehabilitation Exercise Programs. AB - In brief: Cardiac rehabilitation as a distinct c health care service is of fairly recent origin, and existing programs are rather broad and nonstandardized. Consequently, the malpractice crisis that has engulfed the medical profession may well affect professionals who practice cardiac rehabilitation. Various legal issues and concerns face cardiac rehabilitation programs, as they do any other health care provider group. The adoption of written program policies and procedures, set in accordance with national standards of practice, can address the legal and practical problems. Obtaining effective informed consent from patients and using various risk management techniques can also assist in the operation of safe and legally defensible cardiac rehabilitation programs. PMID- 27451844 TI - Rehabilitation of Football Players With Lumbar Spine Injury (Part 2 of 2). AB - In brief: Football is a collision sport that places tremendous demands on the lumbar spine. With a thorough, rational rehabilitation program, players who sustain injuries to the lumbar spine can return to competition. Part 1 of this article discussed the pain-control phase of the rehabilitation plan for football players with low back pain. In this concluding article, the author discusses the second phase of rehabilitation-the training phase-which emphasizes movement training and exercises for strengthening the abdominal muscles, in order to stabilize the lumbar spine. PMID- 27451845 TI - Preparticipation Screening for Sudden Cardiac Death in High School and College Athletes. AB - In brief: Sudden cardiac death in high school and college athletes is uncommon. When it does occur, its most common causes include hypertrophic cardiomyopathy, aortic rupture associated with Marian's syndrome, congenital coronary artery anomalies, and atherosclerotic coronary artery disease. A screening cardiovascular examination may help identify athletes who are at risk for sudden death. Echocardiography can be a useful tool for identifying previously undetected cardiovascular disease in young athletes, However, including it routinely in preparticipation evaluations is financially, logistically, and legally impractical. A brief but thorough screening history and physical examination should identify individuals who would benefit from a more extensive evaluation, which might include an echocardiogram and other tests. The authors discuss typical findings in individuals who should be evaluated further. PMID- 27451846 TI - Is There a Crisis in Youth Fitness-or Fatness? PMID- 27451847 TI - Are American Children Really Unfit? (Part 1 of 2). AB - Although many fitness experts and most members of the public believe American children are unfit, the evidence is inconclusive. Only in terms of body composition are children today known to be less fit than children 20 years ago. PMID- 27451848 TI - Sports Medicine Fellowships for Primary Care Physicians. PMID- 27451849 TI - Athletes' Headaches: Not Necessarily 'Little' Problems. AB - Although it's not clear why the exertion, effort, or trauma of certain sports causes headaches in some athletes, experts recommend thorough evaluations to rule out aneurysms, subdural hematomas, or ischemia. PMID- 27451850 TI - Perceived Exertion: An Old Exercise Tool Finds New Applications. AB - Rating scales of perceived exertion, which rely on an individual's subjective perceptions to determine energy output, may have uses beyond the clinic and laboratory-maybe even in everyday life. PMID- 27451851 TI - Strength and Endurance of the Upper Arm Muscles. PMID- 27451853 TI - Lower levels of maternal capital in early life predict offspring obesity in adulthood. AB - BACKGROUND: As of 2013, 65% of the world's population lived in countries where overweight/obesity kills more people than being underweight. Evolutionary perspectives provide a holistic understanding of both how and why obesity develops and its long-term implications. AIM: To test whether the maternal capital hypothesis, an evolutionary perspective, is viable for explaining the development of obesity in adulthood. SUBJECTS AND METHODS: Restricted-use data from the National Longitudinal Study of Adolescent Health (Add Health; n = 11 403) was analysed using logistic regressions. The sample included adolescents and their biological mothers. RESULTS: The odds of obesity in adulthood increased by 22% for every standard deviation increase in lack of maternal capital (Exp (B) = 1.22, p < .001). That is, individuals whose mothers were young, of an ethnic minority and had short breastfeeding durations were more likely to be obese in adulthood, even after controlling for other factors in infancy, adolescence and adulthood. The results showed that those whose mothers had lower capital were more prone to later life disease (specifically, obesity). CONCLUSION: The maternal capital perspective is useful for explaining how and why early life characteristics (including maternal resources) predict obesity in adulthood. Implications of the findings are discussed. PMID- 27451854 TI - Auricular acupuncture for substance use: a randomized controlled trial of effects on anxiety, sleep, drug use and use of addiction treatment services. AB - BACKGROUND: A common alternative treatment for substance abuse is auricular acupuncture. The aim of the study was to evaluate the short and long-term effect of auricular acupuncture on anxiety, sleep, drug use and addiction treatment utilization in adults with substance abuse. METHOD: Of the patients included, 280 adults with substance abuse and psychiatric comorbidity, 80 were randomly assigned to auricular acupuncture according to the NADA protocol, 80 to auricular acupuncture according to a local protocol (LP), and 120 to relaxation (controls). The primary outcomes anxiety (Beck Anxiety Inventory; BAI) and insomnia (Insomnia Severity Index; ISI) were measured at baseline and at follow-ups 5 weeks and 3 months after the baseline assessment. Secondary outcomes were drug use and addiction service utilization. Complete datasets regarding BAI/ISI were obtained from 37/34 subjects in the NADA group, 28/28 in the LP group and 36/35 controls. Data were analyzed using Chi-square, Analysis of Variance, Kruskal Wallis, Repeated Measures Analysis of Variance, Eta square (eta(2)), and Wilcoxon Signed Ranks tests. RESULTS: Participants in NADA, LP and control group improved significantly on the ISI and BAI. There was no significant difference in change over time between the three groups in any of the primary (effect size: BAI, eta(2) = 0.03, ISI, eta(2) = 0.05) or secondary outcomes. Neither of the two acupuncture treatments resulted in differences in sleep, anxiety or drug use from the control group at 5 weeks or 3 months. CONCLUSION: No evidence was found that acupuncture as delivered in this study is more effective than relaxation for problems with anxiety, sleep or substance use or in reducing the need for further addiction treatment in patients with substance use problems and comorbid psychiatric disorders. The substantial attrition at follow-up is a main limitation of the study. TRIAL REGISTRATION: Clinical Trials NCT02604706 (retrospectively registered). PMID- 27451855 TI - Rapid and accurate detection of carbapenemase genes in Enterobacteriaceae with the Cepheid Xpert Carba-R assay. AB - Rapid and accurate detection of carbapenemase-producing Enterobacteriaceae is pivotal for adequate antibiotic therapy and infection control. The Cepheid Xpert Carba-R assay detects and identifies the most prevalent carbapenemases (KPC, VIM, IMP, NDM and OXA-48), using automated real-time PCR. The test performance of the Xpert Carba-R was evaluated with 129 well-characterized non-repeat Enterobacteriaceae isolates, suspected for carbapenemase production, i.e. with meropenem MICs >0.25 mg l-1. The isolate collection contained 100 carbapenemase producing isolates (36 KPC-2 or KPC-3, 20 VIM-1, 4 KPC-2 plus VIM-1, 5 NDM-1, 2 IMP-1, 1 IMP-28, 1 IMP-1 plus VIM-1 and 31 OXA-48 like) and 29 negative control isolates producing extended-spectrum beta-lactamase and/or AmpC beta-lactamases. PCR and sequencing of beta-lactamase genes were used as reference tests. The sensitivity of the Xpert Carba-R was 100 % (100/100), with a 100 % (29/29) specificity. The time to result was approximately 55 min with a hands-on time of only 1 min per isolate. In conclusion, the Carba-R assay is a rapid and accurate instrument for the confirmation and identification of the blaKPC, blaVIM, blaIMP, blaNDM and blaOXA-48 genes. PMID- 27451856 TI - Antibacterial activity of resazurin-based compounds against Neisseria gonorrhoeae in vitro and in vivo. AB - Neisseria gonorrhoeae is the cause of the second most common sexually transmitted bacterial infection, with ca. 80 million new cases of gonorrhoea reported annually. The recent emergence of clinical isolates resistant to the last monotherapy against this bacterium, the cephalosporins, illustrates the need for new antigonococcal agents. Here we have characterised a new group of antimicrobials based on the compound resazurin that exhibits robust activity against N. gonorrhoeae in vitro. Resazurin inhibits the growth of a broad range of N. gonorrhoeae isolates, including those resistant to multiple antibiotics. Furthermore, treatment of human endometrial cells infected with N. gonorrhoeae with resazurin significantly reduces the number of intracellular bacteria. Whilst resazurin exhibited potent in vitro antimicrobial activity, in vivo resazurin did not limit the colonisation of mice with N. gonorrhoeae following vaginal infection. The ineffectiveness of resazurin in vivo is likely due to its interaction with serum albumin, which completely diminishes its antimicrobial activity. However, treatment of mice with a resazurin analogue (resorufin pentyl ether) that maintains its antimicrobial activity in the presence of serum albumin approached a significant decrease in the percentage of mice vaginally colonised. This treatment also decreased vaginal colonisation by N. gonorrhoeae over time. Together, these data suggest that resazurin derivatives have potential for the treatment of gonorrhoea. PMID- 27451857 TI - Development of potent chemical antituberculosis agents targeting Mycobacterium tuberculosis acetohydroxyacid synthase. AB - Mycobacterium tuberculosis acetohydroxyacid synthase (MTB-AHAS) has been suggested as a crucial target for antibacterial agents. High-throughput screening of a chemical library was performed to identify potent new inhibitors of MTB AHAS. Among the 6800 tested compounds, 15 were identified as potent inhibitors, exhibiting >80-90% inhibition of in vitro MTB-AHAS activity at a fixed concentration of 20 uM. Five compounds belonging to the triazolopyrimidine structural class showed greater inhibition potency, with a half-maximum inhibition concentration (IC50 value) in the low micromolar range (0.4-1.24 uM). Furthermore, potent inhibitors demonstrated non-competitive, uncompetitive or mixed-competitive inhibition. Molecular docking experiments with these potent chemicals using a homology model of MTB-AHAS indicated hydrophobic and hydrogen bond interactions with some key herbicide binding site residues with binding energies (DeltaG) of -8.04 to -10.68 Kcal/mol, respectively. The binding modes were consistent with inhibition mechanisms, as the chemicals were oriented outside the active site. Importantly, these potent inhibitors demonstrated significant growth inhibition of various clinically isolated multidrug-resistant and extensively drug-resistant M. tuberculosis strains, with 50% minimum inhibitory concentrations (MIC50 values) ranging from 0.2 ug/mL to 0.8 ug/mL, which resemble the MICs of conventional drugs for tuberculosis (isoniazid, 0.1 ug/mL; rifampicin, 0.4 ug/mL). Thus, the identified potent inhibitors show potential as scaffolds for further in vivo studies and might provide an impetus for the development of strong antituberculosis agents targeting MTB-AHAS. PMID- 27451859 TI - Women's Understanding of the Term 'Pap smear': A Comparison of Spanish-Speaking Versus English-Speaking Women. AB - Objective To compare the understanding of the term 'Pap smear' among Spanish speaking women, as compared to their English-speaking counterparts. Methods Surveys were distributed to English and Spanish speaking female patients in an urban Obstetrics and Gynecology clinic. Patients were at least 18 years old or they were less than 18 years old and pregnant. Results A majority of participants (77.3 % English-speaking vs. 74.1 % Spanish-speaking, respectively) were able to identify at least one correct descriptor for the term Pap smear. However, Spanish speaking women were significantly less likely to choose incorrect descriptors. Spanish-speaking women were much less likely to say that a Pap smear was the same as a Pelvic exam (45.7 vs. 78.8 %; p = 0.001), or a test for a sexually transmitted disease (25 vs. 60.6 %; p = 0.001). Conclusions for Practice Compared to English-speaking women, Spanish-speaking women are much less likely to conflate a pelvic exam with a Pap smear. Overall understanding was suboptimal, regardless of primary language, indicating that major efforts are still needed to improve functional health literacy with respect to cervical cancer screening. PMID- 27451860 TI - Use of digital health kits to reduce readmission after cardiac surgery. AB - BACKGROUND: Unintended rehospitalizations after surgical procedures represent a large percentage of readmissions and have been associated with increased morbidity and cost of care. Beginning in 2017, Medicare will expand diagnostic categories subject to financial penalties for excess postoperative readmissions to include coronary revascularization procedures. Arrhythmias and pulmonary complications comprise the largest categories for readmission after cardiac surgery. Technologic advances in remote monitoring have led to the use of web based digital health kits (DHK) aimed at reducing readmissions and improving postoperative outcomes. The present study was performed to determine the added benefit of incorporating DHK's into a formal readmissions reduction program (RRP) in preventing 30-d readmissions and to evaluate patient and provider satisfaction with the use of these devices. MATERIALS AND METHODS: This was a prospective study of all adult patients who underwent cardiac surgery at our institution from March 2014 to June 2015. During the study period, 443 adult patients (mean age, 65 +/- 14, 33% female) were identified and participated in the formal RRP, 27 of whom also received a DHK after discharge (416 control group). In addition to providing a live video link to a provider specializing in cardiac surgery, the DHK also allowed for automatic daily transmission of weight, oxygen saturation, heart rate, and blood pressure. Patients also completed a daily health survey targeting symptoms concerning for heart failure, poor wound healing, poor ambulation, and nonadherence to medications. Abnormal vitals or survey responses triggered automatic notifications to the healthcare team. Satisfaction surveys were administered to participants and members of the healthcare team. Pearson chi(2) test and the Welch's t-test were used to assess statistical differences in baseline characteristics and outcome variables. RESULTS: During the study period, the readmission rate for the DHK and control groups were similar (7.4% versus 9.9%, P = 0.65). The use of DHKs led to 1649 alerts and 144 interventions, with the highest number of alerts occurring during d 5-9. The majority of alerts (64%) were prompted by abnormal biometric measurements, and a significant correlation was noted between abnormal biometrics and required intervention (r = 0.62, P < 0.001). No correlation was seen between alerts because of health survey responses (r = 0.07, P = 0.71) or missed check-ins (r = 0.06, P = 0.76) and required interventions. Poststudy satisfaction surveys showed an overall satisfaction rating of 4.9 +/- 0.5 for DHK patients and 4.9 +/- 0.2 for members of the care team (scale 1-5, 5 = agree). CONCLUSIONS: In our study, adding DHKs to a formal RRP was not associated with a significant decrease in 30-d readmission rates. We also found that notifications because of abnormal biometric measures were significantly correlated with required interventions. In contrast, notifications due to abnormal health survey responses were not associated with increased interventions. Both patients and members of the healthcare team were highly satisfied with this technology. DHKs appear to extend care beyond the inpatient period and provide a portal for telemonitoring of surgical patients. However, this modality is highly resource intensive and may not significantly reduce readmissions. Further studies are warranted to evaluate the efficacy of such kits in reducing readmissions and costs of care. PMID- 27451861 TI - A policy of omitting an intensive care unit stay after robotic pancreaticoduodenectomy is safe and cost-effective. AB - BACKGROUND: Immediate postoperative admission to the intensive care unit (ICU) after pancreaticoduodenectomy (PD) is still a standard practice at many institutions. Our aim was to examine whether omission of an immediate postoperative ICU admission would be safe and result in improved outcomes and cost after robotic pancreaticoduodenectomy (RPD). METHODS: In December 2014, a non-ICU admission policy was implemented for patients undergoing RPD. Before this date, all RPDs were routinely admitted to the ICU on post operative day = 0. Using a prospective database, outcomes of the patients in the no-ICU cohort were compared with those of the patients routinely admitted to the ICU before implementation of this policy. RESULTS: The ICU (n = 49) and no-ICU cohorts (n = 47) were comparable in age, gender, body mass index, Charlson comorbidity index and American Society of Anesthesiologists scores, receipt of neoadjuvant therapy, operative time, estimated blood loss, tumor size, and pathologic diagnosis (all P values = NS). Clavien complications, pancreatic leak, reoperation, readmission, and mortality were similar between both the groups (all P values = NS). Hospital length of stay (LOS) was shorter for the no-ICU group (median 6.8 versus 7.7 d, P = 0.01). This reduced LOS and omission of routine postoperative ICU admission translated into a cost reduction from $23,933 (interquartile range $19,833 $28,991) in the ICU group to $19,516 (interquartile range $17,046-$23,893) in the no-ICU group, P = 0.004. The reduction in LOS and cost remained significant after adjusting for all related demographics and perioperative characteristics. CONCLUSIONS: A standard policy of omitting a postoperative ICU admission on post operative day 0 after RPD is safe and can result in reduced LOS and overall savings in total hospital cost. PMID- 27451863 TI - The effect of hospital volume on resection margins in rectal cancer surgery. AB - BACKGROUND: We hypothesized that after controlling for case-mix differences, the rates of positive resection margin after rectal cancer surgery vary substantially in the United States and that high-volume hospitals have lower margin positivity rates. MATERIALS AND METHODS: Patients treated with oncologic resection for stage I-III rectal cancer were selected from the 1998-2010 National Cancer Data Base. Hierarchical regression models were used to calculate risk- and reliability adjusted positive margin rates and hospital level variability in positive margin rates using Empirical Bayes techniques. RESULTS: A total of 113,113 patients were treated at 1446 hospitals. The mean overall risk- and reliability-adjusted positive margin rate was 7.3%. High-volume hospitals did not have a lower rate of adjusted margin positivity (7.4%, P = 0.75). When both case mix and hospital volume differences were factored into the model, variability in margin positivity rates increased by 9.8%, implying that referral to high-volume hospitals alone would not improve margin positivity rates. CONCLUSIONS: Rectal cancer margin positivity rates vary substantially in the United States, despite adjusting for differences in case mix. These results support standardization of surgical technique and pathologic assessment as part of a broader initiative that identifies and refers patients to higher performing hospitals rather than simply to higher volume hospitals. PMID- 27451862 TI - Hospital resources are associated with value-based surgical performance. AB - BACKGROUND: We have previously shown that inferior outcomes at safety-net hospitals are largely dependent on hospital factors. We hypothesized that hospitals providing "high value" care (low cost and better outcomes) would have advantages in human and financial resources. METHODS: The University HealthSystems Consortium Clinical Database and the American Hospital Association Annual Survey were used to examine hospitals performing eight complex surgical procedures from 2009 to 2013. Hospitals in the lowest quartiles of both mortality rate and cost were characterized as high value (n = 45), whereas those in the highest quartiles of both cost and mortality were low value (n = 45). Hospital size, staffing, and financial characteristics were compared between these two groups. RESULTS: On average, high-value hospitals had lower proportions of Medicaid patient days (17% versus 30%; P < 0.01), higher proportions of outpatient surgery (63% versus 53%; P < 0.01), and spent more on capital expenditures per bed ($155,710 versus $62,434; P < 0.05). Also, high-value hospitals employed more hospitalists (0.08 versus 0.04 per bed; P < 0.01), had more privileged physicians (2.04 versus 1.25 per bed; P < 0.01), and had more full-time equivalent personnel (8.48 versus 6.79 per bed; all P < 0.05). As a result, these hospitals appeared to be more efficient; high-value hospitals had more total admissions per bed (46 versus 38; P < 0.01), fewer days per admission (5.20 versus 5.77; P < 0.01), and more inpatient surgeries per bed (15.7 versus 12.6; all P < 0.05). CONCLUSIONS: Hospitals that invest in more human resources and demonstrate increased throughput perform complex surgery at higher "value" (i.e., lower costs and mortality). Value-based purchasing initiatives that link hospital reimbursement to unadjusted surgical outcomes may exacerbate, rather than improve, disparities in surgical care that currently exist. PMID- 27451864 TI - The utility of intraoperative nerve monitoring during thyroid surgery. AB - BACKGROUND: Damage to the recurrent laryngeal nerve (RLN) can lead to vocal cord paralysis, resulting in hoarseness, aspiration, stridor, and respiratory distress. The purpose of this study was to examine the impact of intraoperative nerve monitoring (IONM) on RLN injury during thyroidectomy when it is used as an adjunct to confirm the functional integrity of the RLN during delineation of its anatomic course after it has been visually identified. METHODS: A retrospective cohort study was performed comparing the rate of RLN injury in patients undergoing thyroidectomy with IONM, which was implemented in 2012, to patients who underwent thyroidectomy without IONM during the 3-year period immediately before IONM. Secondary analysis was performed to determine if there was a relationship between RLN injury and patient age, sex, substernal extension, central neck dissection, prior neck surgery, nodule size, gland weight, or pathology. RESULTS: A total of 627 patients underwent thyroidectomy, 315 with IONM and 312 without IONM. Of the 531 nerves at risk in the cohort with IONM, 4 (0.75%) were injured compared to 3 (0.58%) among the 517 nerves at risk in the cohort without IONM (P > 0.05). No secondary factor had a significant impact on RLN injury. CONCLUSIONS: The use of IONM had no impact on the rate of permanent RLN injury during thyroidectomy. Because of the low rate of RLN injury, a much larger sample size is needed to determine if IONM will a valuable adjunct in thyroid surgery, especially in specific high-risk subgroups. PMID- 27451865 TI - Outcome assessment of renal replacement therapy in neonates. AB - BACKGROUND: Recent advances in renal replacement therapy (RRT) have brought about a proliferation of dialysis in neonates (<30 d). This study aimed to assess morbidity and mortality after RRT initiation in this population. METHODS: Retrospective chart review of all patients between 2006 and 2014 requiring RRT initiated in the first 30 d of life was performed. RESULTS: A total of 49 patients were identified, of which 39 were boys and 10 were girls. Thirty-two patients (65%) had end-stage renal disease, 11 (22%) had errors of metabolism, and six (12%) required RRT for other pathologies. Median age and weight at RRT onset were 6 (4-14) d and 3.1 (2.7-4.0) kg, respectively. A total of 201 surgeries were performed. Excluding catheter revisions, 83 new hemodialysis (HD) and 28 new peritoneal dialysis lines were placed, with maximum of six HD and four peritoneal catheters placed in single patient. Catheter-associated morbidities occurred in 100% of patients. Most common complications for HD included circuit clotting (87%), bleeding (68%), and bacteremia (50%). Peritoneal dialysis complications included peritonitis (83%), malpositioned catheters (72%), and leaks (55%). Overall mortality was 65.3%, with 56% of all deaths occurring within first month of life and 94% occurring within first year. Among long-term survivors (median follow-up of 5.3 y), 44% were severely and 22% moderately developmentally delayed. CONCLUSIONS: Although RRT is becoming more technically feasible for neonates with renal and metabolic diseases, it remains associated with significant morbidity and mortality. Pediatric surgeons must be aware of the challenges, taking them into account when considering the care of these critically ill children. PMID- 27451866 TI - Surface microdialysis on small bowel serosa in monitoring of ischemia. AB - BACKGROUND: Ischemic injury of an organ causes metabolic change from aerobic to anaerobic metabolism. It has been shown in experimental studies on the heart and liver that such conversion may be detected by conventional microdialysis probes placed intra-parenchymatously, as well as on organ surfaces, by assaying lactate, pyruvate, glucose, and glycerol in dialysate. We developed a microdialysis probe (S-MUD) intended for use solely on organ surfaces. The aim of this study was to assess whether the newly developed S-MUD probe could be used for detection and monitoring of small bowel ischemia. METHODS: In anesthetized normoventilated pigs, a control S-MUD probe was applied on the jejunal serosa 50 cm downstream from the duodenojejunal junction (DJJ). Starting 100 cm from DJJ, a 100-cm long ischemic segment was created by division of all mesenteric vessels. S-MUDs were applied at 2.5, 5, 20, and 50 cm from the starting point of ischemia by serosal sutures. A standard MUD probe was placed in the abdominal cavity as a further control. Dialysate was harvested before inducing ischemia and subsequently every 20 min for 4 h. Central venous blood was drawn every hour to monitor systemic lactate, C-reactive protein, and white blood cell count. RESULTS: Microdialysis lactate levels were significantly higher than baseline from 20 min on into protocol time in the ischemic segment and in the control S-MUD probe. The peritoneal cavity probe showed no significant elevation. Lactate levels from the ischemic segment reached a plateau at 60 min. Courses of pyruvate, glucose, and glycerol levels were in accordance with transition from an aerobic to anaerobic metabolism in the bowel wall. No statistically significant changes in hemoglobin, white blood cell count, or lactate values in central venous blood were recorded. CONCLUSIONS: Assaying the aforementioned compounds in dialysate, harvested by the newly developed S-MUD probe, allowed detection and monitoring of small bowel ischemia from 20 min on following its onset. PMID- 27451868 TI - Risk factors for complications and recurrence after the Karydakis flap. AB - BACKGROUND: This study describes risk factors leading to the development of various postoperative complications and recurrence after the Karydakis procedure. MATERIALS AND METHODS: In this prospective analytic cohort study, 179 patients with sacrococcygeal pilonidal disease underwent Karydakis procedure. Characteristics of the pilonidal disease and excised ellipse were measured as possible risk factors. Postoperative complications and recurrence were recorded as outcomes. RESULTS: Multivariate analysis showed that the distance between the last caudal pit and anal verge and length of excised part are independent factors predicting limited superficial skin disruption and infection, respectively. Delayed wound healing was associated with the distance between the last caudal pit and anal verge and history of previous pilonidal surgery. The length of excised part was the only predictor of future recurrence. CONCLUSIONS: Patients with no history of previous pilonidal surgery, a short length of extracted part, and long distance of caudal pit from anal verge are best candidates for the Karydakis flap procedure. PMID- 27451867 TI - Indole-3-carbinol induces tumor cell death: function follows form. AB - BACKGROUND: Even with colonoscopy screening and preventive measures becoming more commonplace, colorectal cancer (CRC) remains the third leading cause of oncologic death in the United States as of 2014. Many chemotherapeutics exist for the treatment of colorectal cancer, though they often come with significant side effect profiles or narrow efficacy ranges in terms of patient profile. Dietary phytochemicals such as glucobrassicin and its metabolite indole-3-carbinol (I3C) have been implicated in tumor prevention in many preclinical models across a variety of gastrointestinal tumors and represent an intriguing new class of natural chemotherapeutics for CRC. I3C has been identified as a ligand of the aryl hydrocarbon receptor (AHR), and we aimed to characterize this AHR activation in relation to its cytotoxic properties. METHODS: Human colorectal cancer cell lines DLD1, HCT116, HT-29, LS513, and RKO were treated with indole-3-carbinol or vehicle. Cell viability was assessed via a fluorescent product assay, and apoptotic activity was assessed via a luminescent signal tied to a ratio of caspase-3 and caspase-7 activity. Gene expression of AHR and CYP1A1 messenger ribonucleic acid (mRNA) was measured using quantitative real-time polymerase chain reaction. Small interfering RNA stable expression lines were established on a HCT116 background using a laboratory-developed transfection protocol as published elsewhere. RESULTS: Multiple colorectal cancer cell types express increased CYP1A1 mRNA levels (a specific marker of AHR-driven activity) after treatment with I3C, characterizing I3C treatment as agonistic of this pathway. Also, I3C induced a dose-dependent decrease in cell viability as well as inducing apoptosis. Furthermore, using small interfering RNA interference to knockdown AHR responsiveness generated a significant resistance to the chemotherapeutic actions of indole-3-carbinol regarding both cell viability and apoptotic activity. CONCLUSIONS: Some degree of the cytotoxic and proapoptotic effects of indole-3 carbinol on colon cancer cells is dependent on activation of the aryl hydrocarbon receptor. This represents a novel mechanism for the molecular action of indole-3 carbinol and enhances our understanding of its effects in the context of colorectal cancer. Continued preclinical study of both indole-3-carbinol and the aryl hydrocarbon receptor pathway is warranted, which may one day lead to novel diet-derived colon cancer treatments that enlist the AHR. PMID- 27451869 TI - Clinical breast examination screening by trained laywomen in Malawi integrated with other health services. AB - BACKGROUND: Breast cancer awareness and early detection are limited in sub Saharan Africa. Resource limitations make screening mammography or clinical breast examination (CBE) by physicians or nurses impractical in many settings. We aimed to assess feasibility and performance of CBE by laywomen in urban health clinics in Malawi. METHODS: Four laywomen were trained to deliver breast cancer educational talks and conduct CBE. After training, screening was implemented in diverse urban health clinics. Eligible women were >=30 y, with no prior breast cancer or breast surgery, and clinic attendance for reasons other than a breast concern. Women with abnormal CBE were referred to a study surgeon. All palpable masses confirmed by surgeon examination were pathologically sampled. Patients with abnormal screening CBE but normal surgeon examination underwent breast ultrasound confirmation. In addition, 50 randomly selected women with normal screening CBE underwent breast ultrasound, and 45 different women with normal CBE were randomly assigned to surgeon examination. RESULTS: Among 1220 eligible women, 1000 (82%) agreed to CBE. Lack of time (69%) was the commonest reason for refusal. Educational talk attendance was associated with higher CBE participation (83% versus 77%, P = 0.012). Among 1000 women screened, 7% had abnormal CBE. Of 45 women with normal CBE randomized to physician examination, 43 had normal examinations and two had axillary lymphadenopathy not detected by CBE. Sixty of 67 women (90%) with abnormal CBE attended the referral visit. Of these, 29 (48%) had concordant abnormal physician examination. Thirty-one women (52%) had discordant normal physician examination, all of whom also had normal breast ultrasounds. Compared with physician examination, sensitivity for CBE by laywomen was 94% (confidence interval [CI] 79%-99%), specificity 58% (CI, 46%-70%), positive predictive value 48% (CI, 35%-62%), and negative predictive value 96% (CI, 85%-100%). Of 13 women who underwent recommended pathologic sampling of a breast lesion, two had cytologic dysplasia and all others benign results. CONCLUSIONS: CBE uptake in Lilongwe clinics was high. CBE by laywomen compared favorably with physician examination and follow-up was good. Our intervention can serve as a model for wider implementation. Performance in rural areas, effects on cancer stage and mortality, and cost effectiveness require evaluation. PMID- 27451870 TI - Digital subtraction angiography-guided esophagography, intraluminal drainage, and endoscopic clipping-complex managements for intrathoracic esophagogastric anastomotic leak. AB - BACKGROUND: Intrathoracic esophagogastric anastomotic leak is a critical complication after esophagectomy. Recently, novel complex diagnostic and therapeutic managements for intrathoracic esophagogastric anastomotic leak have been performed at our institution. MATERIALS AND METHODS: Sixty-seven consecutive patients with intrathoracic esophagogastric anastomotic leak after esophagectomy from January 2009 to May 2015 at our institution were reviewed. Thirty-nine patients received conventional managements (conventional group), in which they were diagnosed via contrast swallow when there was a suspicion of anastomotic leak and were subsequently treated with a metallic stent. Twenty-eight patients received complex managements (complex group), in which they were diagnosed using digital subtraction angiography, an intraluminal drainage tube was placed, and clips were subsequently performed under an endoscope. The outcomes of the two groups were retrospectively analyzed. RESULTS: There were no significant differences (P > 0.05) between the two groups in the preoperative general clinical data, whereas the postoperative data exhibited some differences. Compared with the conventional group, the confirmation time and recovery time are significantly decreased in the complex group (P < 0.01 and P < 0.01, respectively), and the incidence of severe complications is also lower (P < 0.01); however, there were no significant differences in the mortality rate between the two groups (P > 0.05). CONCLUSIONS: Complex managements may represent a useful therapeutic option for postoperative esophagogastric anastomotic leak. PMID- 27451871 TI - A reliable scoring system after major liver resection in mice. AB - BACKGROUND: Posthepatectomy liver failure and its transplant counterpart, small for-size syndrome, remain significant limitations for liver resections and segmental liver transplantation. Partial hepatectomy in mice is one of the most commonly used models to study liver regeneration, but blood and tissue sampling necessary to collect data can affect outcomes or even require euthanasia. We therefore developed a quantitative observational system to predict death from hepatectomy during the first 24 postoperative hours. MATERIALS AND METHODS: A total of 100 female, 10 to 12-week-old C57BL/6 mice underwent two-thirds hepatectomy and were monitored for up to 7 d. Our scoring system was based on five categories, each assigned 0-2 points: activity level, body posture, fur condition, respiratory status, and eye appearance. Seventy-five mice were scored 6 h, 12 h, 24 h, 2 d, 3 d, 5 d, and 7 d after surgery. The remaining 25 mice were scored similarly, but underwent, in addition, blood sampling for serum alanine aminotransferase, total bilirubin, interleukin-6, tumor necrosis factor-alpha, or euthanasia with liver sampling for conventional hematoxylin-eosin and Ki-67 staining. RESULTS: Retrospective analysis indicated that body condition scores <=5 on two consecutive time points within the first 24 postoperative hours accurately predicted eventual death. Animals in the low scoring group also had significantly higher serum alanine aminotransferase, total bilirubin, interleukin 6, tumor necrosis factor-alpha, more hepatocyte necrosis in hematoxylin-eosin, and fewer Ki-67 positive hepatocytes. CONCLUSIONS: Our scoring system accurately predicts survival, hepatocyte damage, liver regeneration, and systemic inflammation in a mouse hepatectomy model, within the first 24 hours of surgery. This could be useful in evaluating posthepatectomy interventions for their effect on survival and liver regeneration. PMID- 27451872 TI - Short-term outcomes of minimally invasive versus open colectomy for colon cancer. AB - BACKGROUND: Laparoscopic and open approaches to colon resection have equivalent long-term outcomes and oncologic integrity for the treatment of colon cancer. Differences in short-term outcomes should therefore help to guide surgeons in their choice of operation. We hypothesized that minimally invasive colectomy is associated with superior short-term outcomes compared to traditional open colectomy in the setting of colon cancer. MATERIALS AND METHODS: Patients undergoing nonemergent colectomy for colon cancer in 2012 and 2013 were selected from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) targeted colectomy participant use file. Patients were divided into two cohorts based on operative approach-open versus minimally invasive surgery (MIS). Univariate, multivariate, and propensity-adjusted multivariate analyses were performed to compare postoperative outcomes between the two groups. RESULTS: A total of 11,031 patients were identified for inclusion in the study, with an overall MIS rate of 65.3% (n = 7200). On both univariate and multivariate analysis, MIS approach was associated with fewer postoperative complications and lower mortality. In the risk-adjusted multivariate analysis, MIS approach was associated with an odds ratio of 0.598 for any postoperative morbidity compared to open (P < 0.001). CONCLUSIONS: This retrospective study of patients undergoing colectomy for colon cancer demonstrates significantly improved outcomes associated with a MIS approach, even when controlling for baseline differences in illness severity. When feasible, minimally invasive colectomy should be considered gold standard for the surgical treatment of colon cancer. PMID- 27451873 TI - Should vitamin D deficiency be corrected before parathyroidectomy? AB - BACKGROUND: Vitamin D deficiency is common in patients with hyperparathyroidism, but the importance of replacement before surgery is controversial. We aimed to evaluate the impact of vitamin D deficiency on the extent of resection and risk of postoperative hypocalcemia for patients undergoing parathyroidectomy for primary hyperparathyroidism. METHODS: We identified patients with primary hyperparathyroidism undergoing parathyroid surgery between 2000 and 2015 using a prospectively maintained database. Patients with normal (>=30 ng/mL) vitamin D were compared to those with levels less than 30 ng/mL. RESULTS: There were 1015 (54%) patients with normal vitamin D and 872 (46%) patients with vitamin D deficiency undergoing parathyroidectomy for primary hyperparathyroidism. Vitamin D deficiency was associated with higher preoperative parathyroid hormone (median 90 versus 77 pg/mL, P < 0.001) and calcium (median 10.5 versus 10.4 mg/dL, P < 0.001) compared with normal vitamin D. To achieve similar cure rates, patients with vitamin D deficiency were less likely to require removal of more than one gland (20% versus 30%, P < 0.001) than patients with normal vitamin D. Patients with vitamin D deficiency had similar rates of persistent (1.5% versus 2.0%, P = 0.43) and recurrent (1.7% versus 2.6%, P = 0.21) hyperparathyroidism. Postoperatively, both groups had equivalent rates of transient (2.3% versus 2.3%, P = 0.97) and permanent (0.2% versus 0.4%, P = 0.52) hypocalcemia. CONCLUSIONS: Restoring vitamin D in deficient patients should not delay the appropriate surgical treatment of primary hyperparathyroidism. Deficient patients are more likely to be cured with the excision of a single adenoma and no more likely to suffer persistence, recurrence, or hypocalcemia than patients with normal vitamin D. PMID- 27451874 TI - Transversus abdominis plane blocks: pilot of feasibility and the learning curve. AB - BACKGROUND: Our goal was to evaluate the learning curve for transversus abdominis plane (TAP) block placement and identify issues that impede successful placement. METHODS: Three novices were prospectively evaluated performing ultrasound-guided TAP blocks in 10 consecutive patients. Operators were assessed on medication knowledge, setup/placement, procedural steps, and performance time. Times were compared to an expert for efficiency and competence. The main outcome measures were procedures needed for competence and variables associated with increased coaching/procedure time. RESULTS: In the 30 patient sample, the mean body mass index (BMI) was 30.9 (standard deviation [SD], 5.79). Fifteen patients were obese (BMI > 30), seven (23.3%) super obese (BMI > 35), and 15 had prior abdominal surgery. The mean setup time was 107.5 s (SD, 87), right-side placement was 131.8 s (SD, 60.3), left-side placement 114.8 s (SD, 40.5), and total time 354 s (SD, 111). By the second attempt, all operators were fluent in the medication and setup. At block 3, operators 1 and 3 reached competence in performance time; by block 4, all three operators reached time competence. After reaching competence, outliers in procedure times were only experienced for extremes in BMI (<20 and >35). Additional coaching was needed in four patients with prior abdominal surgery to decipher the correct planes. CONCLUSIONS: Based on our pilot, by four attempts, novices reach appropriate speeds with progressively less coaching to safely and efficiently place TAP blocks. Extremes of BMI and prior abdominal surgery impact procedural time and may required additional coaching to facilitate placement. Given the promising results, further work on developing best practices for education and implementation is warranted. PMID- 27451875 TI - The clinical management and outcomes of cervical neuroblastic tumors. AB - BACKGROUND: Although patients with peripheral neuroblastoma (NB; pelvic and thoracic) typically have better outcomes and less aggressive disease compared with patients with abdominal disease, little has been published with regard to the management and outcomes of patients with cervical NB. Herein, we sought to determine the characteristics of cervical neuroblastic tumors and the effect of extent of resection on survival and outcomes. METHODS: We performed a retrospective review of 325 children with neuroblastic tumors at Children's Hospital Los Angeles over a 15-y period (January 1990-February 2015). Data collected from the medical record included location of tumor, age at diagnosis, age at resection, extent of resection, chemotherapy course, International Neuroblastoma Staging System stage, histologic International Neuroblastoma Pathology Classification, and MYCN amplification, a poor prognostic marker. Outcome variables included postoperative complications and overall survival. RESULTS: Twelve patients (3.6%) were found to have cervical neuroblastic tumors (nine NBs, one ganglioneuroblastoma, and two ganglioneuromas). All had favorable histology, and none (0/12) had MYCN amplification. Of the NB patients, four of nine patients underwent resection, whereas the other five underwent biopsy followed by chemotherapy or observation alone. Of the 12 total patients, six underwent gross total resection, four (67%) of which developed complications. At a median follow-up of 4.4 y, there were no recurrences or deaths. CONCLUSIONS: Cervical neuroblastic tumors represent favorable lesions with good outcomes similar to other peripheral neuroblastic tumors. In our study, survival was excellent regardless of extent of tumor resection. Based on our data, we recommend a minimally aggressive surgical approach in managing children with cervical neuroblastic tumors. PMID- 27451876 TI - Medical student hand preference, perceived dexterity, and impact of handedness on training. AB - BACKGROUND: The ubiquity of right-handed instruments and a predominance of right handed surgical faculty present a challenge to left-handed trainees. Little is known about hand preference and its impact on specialty selection. We sought to evaluate hand preference, perceived dexterity, and impact of handedness on training among medical students. MATERIALS AND METHODS: A survey was distributed to third and fourth year medical students. Hand preference was queried for various activities. A Likert scale was used to assess perceived dexterity and impact of handedness on training. Fisher's exact test was used to compare groups. RESULTS: Of those queried, 131 (37%) responded. Handedness was defined by writing preference: right (80%), left (18%), other (2%). Left-handed students were more likely to perceive themselves to be ambidextrous (50% versus 15%; P < 0.001) and prefer their contralateral hand for at least one other activity (50% versus 4%; P < 0.001). Left-handed students were significantly more likely to report that handedness affected their specialty selection (33% versus 10%; P < 0.01) and training (58% versus 6%; P < 0.001). In addition, they reported that they would benefit from additional training with right-handed instruments (61% versus 31%; P < 0.01), availability of left-handed instruments (63% versus 8%; P < 0.001), and trainers who adapted to their handedness (70% versus 14%; P < 0.001). CONCLUSIONS: Left-handed medical students reported greater ambidexterity and adverse impact of handedness on training. These results provide a contemporary snapshot of hand preference in medical students and an argument for improving and adapting surgical training for left-handed individuals. PMID- 27451877 TI - Ultrasonographic measurements of the inferior vena cava variation as a predictor of fluid responsiveness in patients undergoing anesthesia for surgery. AB - BACKGROUND: Both hypovolemia and hypervolemia are connected with increased morbidity and mortality in the treatment and prognosis of patients. An accurate assessment of volume state allows the optimization of organ perfusion and oxygen supply. Recently, ultrasonography has been used to detect hypovolemia in critically ill patients and perioperative patients. The objective of our study was to assess the correlation between inferior vena cava (IVC) variation obtained with ultrasound and stroke volume variation (SVV) measured by the Vigileo/FloTrac monitor, as fluid responsiveness indicators, in patients undergoing anesthesia for surgery. METHODS: Forty patients (American Society of Anesthesiologists grades I and II) scheduled for elective gastrointestinal surgery were enrolled in our study. After anesthesia induction, 6% hydroxyethyl starch solution was administered to patients as an intravenous (IV) fluid. The IVC diameters were measured with ultrasonography. SVV and stroke volume index (SVI) were obtained from the Vigileo monitor. All data were collected both before and after fluid challenge. RESULTS: Forty patients underwent IVC sonographic measurements and SVV calculation. After fluid challenge, mean arterial pressure, central venous pressure, SVI, and IVC diameters increased significantly, whereas SVV decreased markedly. The correlation coefficient between the increase in SVI and the baseline of IVC variation after an IV fluid was 0.710, and receiver operating characteristic (ROC) curve was 0.85. The correlation coefficient between the increase in SVI and the baseline of SVV was 0.803 with an ROC curve of 0.93. Central venous pressure had no significant correlation with SVI. CONCLUSIONS: Our data show that IVC variation and SVV proved to be reliable predictors of fluid responsiveness in patients undergoing anesthesia for surgery with mechanical ventilation. PMID- 27451878 TI - Impaired outcome colitis-associated rectal cancer versus sporadic cancer. AB - BACKGROUND: The surgical management of colitis-associated rectal cancer (CARC) is not well defined. This study determines outcomes after surgery for CARC compared with sporadic rectal cancer. MATERIALS AND METHODS: This is a retrospective cohort study comparing 27 patients with CARC with 54 matched patients with sporadic cancer. Matching criteria included age, gender, neoadjuvant chemoradiation, and American Joint Committee on Cancer stage. Outcome measures were disease-free and overall survival, tumor characteristics, and postoperative morbidity. RESULTS: Compared to those with sporadic rectal cancer, patients with CARC underwent proctocolectomy more frequently (21 [78%] versus 6 [22%] P < 0.001) and were more likely to have mucinous tumors (11 [40.7%] versus 12 [22.3%] P = 0.03). Overall 3-y survival was significantly reduced in CARC patients compared with patients with sporadic rectal cancer. Those with CARC undergoing segmental proctectomy only demonstrated reduced overall and disease-free survival compared to patients with sporadic rectal cancer and to colitis patients undergoing proctocolectomy (P = 0.002). CONCLUSIONS: Patients with CARC undergoing proctectomy demonstrate reduced disease-free survival versus those undergoing proctocolectomy, and versus patients with sporadic rectal cancer undergoing proctectomy. These findings warrant further study and suggest that proctocolectomy should be considered the preferred surgical approach for CARC. PMID- 27451879 TI - The effects of rikkunshito on body weight loss after esophagectomy. AB - BACKGROUND: After esophagectomy, esophageal cancer patients suffer from malnutrition, anorexia, and dysfunction of digestion and absorption. Rikkunshito, a traditional Japanese herbal medicine, reportedly attenuates gastrointestinal symptoms and appetite loss after gastrointestinal surgery. We evaluated the clinical effect of rikkunshito and its relationship with ghrelin in esophageal cancer patients after esophagectomy. METHODS: This prospective nonrandomized study included 40 patients with esophageal cancer who underwent esophagectomy at Wakayama Medical University Hospital. They were assigned to either the control group (n = 20, April 2011-January 2012) or the rikkunshito group (n = 20, January 2012-August 2012). Patients in the rikkunshito group received 2.5 g of rikkunshito before every meal for 48 wk beginning 4 wk after surgery. During the 48-week treatment, we assessed body weight loss, nutritional parameters, and quality of life (Functional Assessment of Cancer Therapy-Esophageal scale). The primary end point was the rate of body weight loss in two groups after the 48 week treatments. RESULTS: The rate of body weight loss was significantly less in the rikkunshito group than in the control group (P = 0.016). The acyl ghrelin level after the 48-week treatments was significantly higher in the rikkunshito group (131.7% +/- 74.5%) than in the control group (75.6% +/- 47.5%, P = 0.039). For the Functional Assessment of Cancer Therapy-Esophageal symptom scale, satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (P = 0.031). CONCLUSIONS: For esophageal cancer patients after esophagectomy, rikkunshito is useful for improving body weight loss in connection with an increase in plasma acyl ghrelin levels. PMID- 27451880 TI - Lactate predicts massive transfusion in hemodynamically normal patients. AB - BACKGROUND: Trauma patients at risk of deterioration because of occult injury may be hemodynamically normal on arrival. Early identification of these patients may improve care, especially for those who require massive transfusion (MT). We hypothesized that elevated admission lactate would predict the need for MT in hemodynamically normal patients. MATERIALS AND METHODS: All trauma patients treated at our university-based urban center over a 5-year period were reviewed. We included hemodynamically normal patients who had an admission lactate performed. First, a receiver-operating curve was used to determine the threshold lactate value. Subsequent analyses were then based on this value. Variables were analyzed using chi-square and unpaired t-tests, and univariable and multivariable regressions. RESULTS: There were 3468 hemodynamically normal patients with an admission lactate. Those who received MT (n = 19) had higher lactate than those who did not (n = 3449; 5.6 versus 2.6 mmol/L, P <= 0.001). Receiver-operating curve curve analysis revealed a threshold lactate value of 4 mmol/L with an area under the curve of 0.71. Patients with a lactate of >4 mmol/L had increased mortality (8% versus 2%), longer hospital length of stay (LOS, 6 versus 3 days), longer intensive care unit (ICU) LOS (6 versus 3 days), greater need for MT (2.8% versus 0.3%), and greater blood requirement (219 versus 38 mL; all P values < 0.001). After controlling for confounding variables, the predictive value of admission lactate >4 remained strong (odds ratio, 5.2; 95% confidence interval, 1.87-14.2). CONCLUSIONS: In hemodynamically normal trauma patients, the admission lactate of >4 mmol/L is a robust predictor of MT requirement and associated with poor outcomes. PMID- 27451881 TI - TNF-alpha stimulates colonic myofibroblast migration via COX-2 and Hsp27. AB - BACKROUND: Crohn's disease (CD) is a chronic inflammatory enteropathy characterized by fibrotic strictures. Myofibroblasts (MFBs) are stromal cells of the gastrointestinal tract found in increased numbers in patients with CD and represent the key effector cells involved in pathologic fibrosis. MFB is a known target of tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine strongly implicated in the pathophysiology of CD. However, the precise mechanisms through which TNF-alpha contributes to fibrosis remain incompletely understood. Here, we demonstrate for the first time that TNF-alpha increases MFB migration through the cyclooxygenase 2 (COX-2) and heat-shock protein 27 (Hsp27) pathways. MATERIALS AND METHODS: The human colonic MFB cell line 18Co was grown to confluence on 35 * 10 mm cell culture dishes and used from passages 8-14. An in vitro scratch assay assessed the effect of TNF-alpha (10 ng/mL) on MFB migration over 24 h in the presence or absence of several inhibitors (NS398, SB203580, Hsp27 siRNA). RESULTS: TNF-alpha significantly increased MFB migration over 24 h. TNF-alpha also led to the increased expression of COX-2 and stimulated rapid phosphorylation of Hsp27 at serine 82. TNF-alpha-induced COX-2 expression, Hsp27 phosphorylation, and MFB migration were all significantly inhibited by the P38 MAPK inhibitor SB203580 (P < 0.05). TNF-alpha-induced MFB migration was also significantly inhibited by NS398 (P < 0.05), a direct inhibitor of COX-2, and by siRNA targeting Hsp27 (P < 0.05). CONCLUSIONS: TNF-alpha stimulates colonic MFB migration through P38 MAPK-mediated activation of COX-2 and Hsp27. Further elucidating these inflammatory signaling pathways may lead to novel therapeutic targets for the treatment of CD-related fibrosis and strictures. PMID- 27451882 TI - Thromboxane A synthase enhances blood flow recovery from hindlimb ischemia. AB - BACKGROUND: Thromboxane A synthase (TXAS) is the enzyme that converts the arachidonic acid derivative prostaglandin H2 to thromboxane A2 (TXA2). TXA2 induces platelet aggregation, vasoconstriction, and proliferation. TXAS and TXA2 receptors or thromboxane prostanoid (TP) receptors are elevated in numerous cardiovascular and inflammatory diseases. Platelets contain numerous angiogenesis stimulating factors. However, the involvement of TXAS on recovery from an ischemic condition is not well understood. We hypothesized that the TXAS-TXA2-TP receptor axis would induce blood flow recovery by platelet activation. MATERIAL AND METHODS: The model of hindlimb ischemia was made by the right femoral artery ligation. The blood flow was estimated by laser Doppler images. Angiogenesis was estimated by the plasma level of the vascular endothelial growth factor and the stromal cell-derived factor-1 and by immunofluorescence analysis against CD31 and P-selectin glycoprotein ligand-1 (PSGL-1). RESULTS: In wild-type mice, blood flow recovery was enhanced by treatment with murine TXAS-overexpressing fibroblasts (C57-mTXAS) compared with empty vector- (EV) treated fibroblasts (C57-EV). Compared with C57-EV-treated mice, activated platelets (P-selectin(+) platelets) and plasma levels of vascular endothelial growth factor and stromal cell-derived factor-1 were increased in C57-mTXAS-treated mice. The enhanced-blood flow recovery by C57-mTXAS treatment was suppressed in the TP knockout mice (TP(-/-)). The expression of PSGL-1 in endothelial cells around the ischemic area was enhanced by C57-mTXAS treatment in wild-type but not in TP(-/-). CONCLUSIONS: These results indicated that local administration of C57-mTXAS-induced angiogenesis by activated platelets that bind to PSGL-1 on ischemic endothelial cells. PMID- 27451883 TI - Production of tissue-engineered intestine from expanded enteroids. AB - BACKGROUND: Short bowel syndrome is a life-threatening condition with few solutions. Tissue-engineered intestine (TEI) is a potential treatment, but donor intestine is a limiting factor. Expanded epithelial surrogates termed enteroids may serve as a potential donor source. MATERIALS AND METHODS: To produce TEI from enteroids, crypts were harvested from mice and enteroid cultures established. Enteroids were seeded onto polymer scaffolds using Matrigel or culture medium and implanted in immunosuppressed mice for 4 wk. Histology was analyzed using Periodic acid-Schiff staining and immunofluorescence. Neomucosa was quantified using ImageJ software. To determine whether TEI could be produced from enteroids established from small intestinal biopsies, 2 * 2-mm pieces of jejunum were processed for enteroid culture, enteroids were expanded and seeded onto scaffolds, and scaffolds implanted for 4 wk. RESULTS: Enteroids in Matrigel produced TEI in 15 of 15 scaffolds, whereas enteroids in medium produced TEI in 9 of 15 scaffolds. Use of Matrigel led to more neomucosal surface area compared to media (10,520 +/- 2905 MUm versus 450 +/- 127 MUm, P < 0.05). Histologic examination confirmed the presence of crypts and blunted villi, normal intestinal epithelial lineages, intestinal subepithelial myofibroblasts, and smooth muscle cells. Crypts obtained from biopsies produced an average of 192 +/- 71 enteroids. A single passage produced 685 +/- 58 enteroids, which was adequate for scaffold seeding. TEI was produced in 8 of 9 scaffolds seeded with expanded enteroids. CONCLUSIONS: Enteroids can be obtained from minimal starting material, expanded ex vivo, and implanted to produce TEI. This method shows promise as a solution to the limited donor intestine available for TEI production in patients with short bowel syndrome. PMID- 27451884 TI - Trauma team size and task performance in adult trauma resuscitations. AB - BACKGROUND: The initial evaluation of a trauma patient involves multiple personnel from various disciplines. Whereas this approach can expedite care, an increasing number of personnel can also create chaos and hinder efficiency. We sought to determine the optimal number of persons associated with an expedient primary survey. METHODS: Audio and/or video recordings of all consecutive adult trauma evaluations at a level 1 trauma center were reviewed for a 1-month period. A 20-task checklist was developed based on Advanced Trauma Life Support principles. The number of practitioners present (TeamN) and tasks completed at 2 and 5 min (Task2, Task5) were recorded. The association between TeamN, demographics, presence of attending surgeon, and team leader engagement and Task2/Task5 was measured the using chi square test and Spearman correlation. A multivariate regression model was developed. RESULTS: A total of 170 cases were reviewed, 44 of which were top-tier activations. Average TeamN was 6 +/- 2 persons. Task2 and Task5 were significantly positively correlated with TeamN (r = 0.34, P < 0.0001; r = 0.22, P = 0.004, respectively) and leader engagement (r = 0.27, P < 0.01; r = 0.16, P < 0.05, respectively). There was a significant positive correlation between TeamN and Task2 and Task5. Only TeamN had a significant, independent association with Task2 and Task5 (P = 0.005). We did not find a size that was negatively associated with task completion. Only assessment of breath sounds was negatively associated with increasing team size. CONCLUSIONS: TeamN is significantly associated with efficiency of trauma evaluation. Studies evaluating reasons for this and the effect of maximal team size are needed to determine optimal trauma team staffing. PMID- 27451885 TI - Hepatorenal protection in renal ischemia/reperfusion by celecoxib and pentoxifylline. AB - BACKGROUND: Renal ischemia/reperfusion (I/R) is a major clinical problem. Its pathogenesis is multifactorial involving oxidative stress, cytokine overproduction, and inflammatory responses in the kidney and remote organs. This study was performed to evaluate the effects of celecoxib (CEB) and pentoxifylline (PTX) on kidney and liver changes after renal I/R in rats. MATERIALS AND METHODS: Renal ischemia was induced by clamping renal pedicles for 1 h followed by reperfusion for another 1 h. The rats were assigned to five groups: sham control, untreated I/R, CEB + I/R, PTX + I/R, and (CEB + PTX)+I/R. Drug treatment was given for 7 d before I/R. Serum and tissue biochemical and histomorphologic changes were evaluated after reperfusion. RESULTS: Renal I/R caused changes in kidney and liver histology with a significant reduction in the function of both organs. An increase in tumor necrosis factor-alpha, myeloperoxidase, and malondialdehyde levels with a decrease in glutathione content and superoxide dismutase activity was observed in kidney and liver tissues. Pretreatment with CEB, PTX, or CEB + PTX attenuated all these changes and the extent of improvement was similar in all drug-treated groups. CONCLUSIONS: This study is the first experimental work demonstrating the simultaneous nephroprotective and hepatoprotective effects of CEB and PTX after renal I/R. It seems likely that both drugs protect the kidney and liver by reducing oxidative stress, attenuating tumor necrosis factor-alpha production and inhibiting neutrophil tissue infiltration. No additive protective effects were observed in rats received the combined treatment. Thus, our results may imply a promising therapeutic approach by using CEB or PTX to protect the kidney and liver against the hazardous consequences of renal I/R. PMID- 27451886 TI - Blood pressure-targeted stepwise resuscitation of hemorrhagic shock in a swine model. AB - BACKGROUND: Prolonged hemorrhagic shock and subsequent resuscitation frequently results in hemodynamic compromise. This study was designed to investigate the hemodynamic effect of the stepwise increase of blood pressure during initial resuscitation. MATERIALS AND METHODS: Fifteen anesthetized male pigs (35 +/- 5 kg) were used. Hemorrhagic shock was induced by losing 40% of estimated blood volume over 40 min and 10% of estimated blood volume over 20 min through the femoral artery and was maintained at a mean arterial pressure (MAP) of 30 +/- 3 mm Hg for 2.5 h. The resuscitation of the rapid resuscitation (RR) group was targeted to reach MAP of 70 +/- 5 mm Hg immediately by transfusion of shed blood via the femoral artery. The resuscitation of the pressure-targeted stepwise resuscitation (PSR) group was targeted to increase MAP by 10 mm Hg every 10 min up to 70 mm Hg, and then, the MAP was maintained at 70 +/- 5 mm Hg until transfusion of the entire shed blood. RESULTS: During the initial resuscitation period of 30 min, the heart rate was significantly lower in the RR group than in the PSR group (P < 0.05), and mixed venous oxygen saturation was significantly higher in the RR group than in the PSR group during the 30 min of initial resuscitation (P < 0.05). After 2 h of resuscitation, cardiac output and stroke volume were significantly higher in the PSR group than in the RR group (P < 0.05), and the systemic vascular resistance was significantly lower in the PSR group than in the RR group (P < 0.05). CONCLUSIONS: A stepwise increase of blood pressure compared with rapid normalization improves hemodynamic parameters in the swine hemorrhagic shock model. PMID- 27451887 TI - A dual-stage approach to contaminated, high-risk ventral hernia repairs. AB - BACKGROUND: The Modified Hernia Grading System (MHGS) was developed to risk stratify complex ventral hernia repairs (VHRs). MHGS grade 3 patients have mesh infections, dirty or contaminated fields, and/or violation of the alimentary tract. Reported surgical site infection (SSI) rates are over 40% after single stage VHR in contaminated fields. In an attempt to decrease the SSI rate in MHGS grade 3 patients, we developed a dual-stage VHR (DSVHR) approach. METHODS: We reviewed adult general surgery patients undergoing DSVHR between January 2010 and June 2014. All patients were MHGS grade 3. Primary end point was 30-d superficial and deep SSI. Secondary end points included other surgical site occurrences, 6-mo recurrence, and mesh excision rates. RESULTS: Fifteen patients underwent DSVHR. Mean age was 56 y, and median body mass index was 38.3 kg/m(2). Operative indication included enterocutaneous fistulas (ECF; n = 6), ECF with infected mesh (n = 2), infected mesh (n = 2), and VHR requiring bowel resection (n = 5). Thirty one operative procedures were performed with median of 2.5 d between procedures. Fascial closure was re-established in 12 patients; five patients had underlay biologic mesh placement; seven underwent component separation with retrorectus mesh placement (synthetic [n = 2], biologic [n = 5]). The remaining patients underwent bridging repair with biologic mesh. One patient developed a recurrence after 6 mo, whereas a single patient had a recurrence of their ECF. Four (27%) patients developed a SSI, with an additional four (27%) experiencing a surgical site occurrence. There were no postoperative mesh infections. CONCLUSIONS: DSVHR in MHGS grade 3 patients is associated with a lower SSI rate than previously reported for those undergoing single-stage repairs. PMID- 27451888 TI - A comparison of preemptive versus standard renal replacement therapy for acute kidney injury after cardiac surgery. AB - BACKGROUND: The optimal timing of renal replacement therapy (RRT) initiation in patients undergoing cardiac surgery remains controversial. This study aimed to determine whether preemptive RRT or standard RRT was associated with hospital mortality in cardiac surgical patients with acute kidney injury (AKI). METHODS: Data were retrospectively collected from patients who underwent cardiac surgery and experienced postoperative AKI requiring RRT at Zhongshan Hospital of Fudan University from September 1, 2006 to December 31, 2013. The patients were divided into two groups according to the RRT strategy applied. RESULTS: A total of 213 patients were enrolled in this study; 59 patients were categorized into the preemptive RRT group and 154 into the standard RRT group. The preemptive RRT group exhibited significantly lower mortality (33.90% versus 51.95%, P = 0.018) and time to recovery of renal function than the standard RRT group (15.34 +/- 14.46 versus 22.88 +/- 14.08 d, P = 0.022). Moreover, the preemptive RRT group showed significantly lower serum creatinine levels and higher proportions of recovery of renal function and weaning from RRT at death or discharge than the standard RRT group. There was no significant difference in the duration of mechanical ventilation, RRT, intensive care unit stay, or hospital stay between the two groups. CONCLUSIONS: In patients after cardiac surgery, preemptive RRT was associated with lower hospital mortality and faster and more frequent recovery of renal function than standard RRT. However, preemptive RRT did not affect other patient-centered outcomes including mechanical ventilation time, RRT time, or length of intensive care unit or hospital stay. PMID- 27451889 TI - Indications, techniques, and clinical outcomes of thoracic duct interventions in patients: a forgotten literature? AB - BACKGROUND: The evolution of the "gut-lymph concept" has promoted thoracic duct (TD) lymph drainage as a possible treatment to reduce systemic inflammation and end-organ dysfunction in acute illness. The aim was to review the published experience of thoracic duct interventions (TDIs) aimed at improving clinical outcomes. METHODS: A search of three databases (MEDLINE, EMBASE, and EMBASE CLASSIC) over the last 60 y. The indications for intervention, the technique, and clinical outcomes were reviewed. RESULTS: There were a wide range of indications for TDI. These included reducing rejection after transplantation, treating inflammatory diseases, and reducing chronic failure of the liver, kidney, and heart. The techniques included TD cannulation and lymphovenuous fistula. The outcomes were variable and often equivocal, and this appears to reflect poor design quality. There is clinical equipoise regarding a therapeutic role of (TD lymph drainage in acute pancreatitis, and probably other acute diseases. CONCLUSIONS: Until well-designed clinical trials are undertaken, the clinical benefits of TDIs will remain promising, but uncertain. PMID- 27451890 TI - Vacca pox to pexa vec: John Hunter's and Edward Jenner's contribution to oncolytic virotherapy. PMID- 27451891 TI - Pancreaticoduodenectomy outcomes in the pediatric, adolescent, and young adult population. AB - BACKGROUND: Pancreatic malignancy and chronic pancreatitis are rare in the pediatric, adolescent, and young adult (AYA) population, making pancreas resections an infrequent procedure in this demographic. Only case reports and small case series exist in the literature describing surgical outcomes and complications in this population. The aim of this study was to review the surgical outcomes of pediatric/AYA patients undergoing pancreaticoduodenectomy (PD) at our institution. METHODS: All pediatric/AYA adult patients (<=30 years) undergoing PD over a 15-year period (1998-2013) from a large academic institution were included. We provide adult (>30 years) data from our same institution for observational comparison. Retrospective chart review was performed to identify pertinent preoperative, perioperative, and postoperative data. RESULTS: Twenty two patients with a median age of 25 years (range, 11-30 years) underwent PD. The most common postoperative histologic diagnoses were chronic pancreatitis (6, 27.3%), solid pseudopapillary neoplasm (5, 22.7%), and adenocarcinoma (4, 18.2%). Complications were 31.8% in the pediatric/AYA cohort and 58.6% in the adult cohort. The most common postoperative complication was intraabdominal abscess, which occurred in three patients (13.6%). Thirty-day mortality was 0% for pediatric/AYA patients. There were no recurrences or disease-related deaths in patients with solid pseudopapillary neoplasm. Pediatric patients with adenocarcinoma had a median survival of 10.2 mo (interquartile range, 9-21), in contrast to adults of 57.8 mo (interquartile range, 11-132). CONCLUSIONS: This is the largest series of PD procedures reported in the pediatric/AYA population. The procedure appears to be safe, with no 30-day mortalities and an acceptable complication rate. PMID- 27451892 TI - Predictive value of axillary nodal imaging by magnetic resonance imaging based on breast cancer subtype after neoadjuvant chemotherapy. AB - BACKGROUND: Magnetic resonance imaging (MRI) is commonly used to determine residual breast disease after neoadjuvant chemotherapy (NCT) for cancer. Few studies have assessed its role in predicting nodal response, by cancer subtype. METHODS: A retrospective review was completed using our institutional cancer registry. Patients who started NCT from 2005 to 2010 with clinically node positive disease were evaluated. Those who underwent post-NCT breast MRI were selected. Radiologic response was determined by an independent review. Nodal involvement was confirmed pathologically after surgery. RESULTS: A total of 135 patients underwent post-NCT breast MRI. The positive and negative predictive values of MRI are 93% and 26%, respectively. A subset analysis by cancer phenotype demonstrates triple negative cancers have the highest sensitivity (68%) and luminal cancers have the highest positive predictive value (100%). CONCLUSIONS: This study demonstrates that MRI post-NCT, even by cancer subtype, cannot reliably predict residual nodal disease because of high false-negative rates (low negative-predictive value). PMID- 27451893 TI - Barriers and facilitators of surgical care in rural Uganda: a mixed methods study. AB - BACKGROUND: Surgical care delivery is poorly understood in resource-limited settings. To effectively move toward universal health coverage, there is a critical need to understand surgical care delivery in developing countries. This study aims to identify the barriers and facilitators of surgical care delivery at Soroti Regional Referral Hospital in Uganda. METHODS: In this mixed methods study, we (1) applied the Surgeons OverSeas' Personnel, Infrastructure, Procedures, Equipment, and Supplies tool to assess surgical capacity; (2) retrospectively reviewed inpatient records; (3) conducted four semistructured focus group discussions with 18 purposively sampled providers involved in perioperative care; and (4) observed the perioperative process of care using a time and motion approach. Descriptive statistics were generated from quantitative data. Qualitative data were thematically analyzed. RESULTS: The Personnel, Infrastructure, Procedures, Equipment, and Supplies survey revealed severe deficiencies in workforce (P-score = 14) and infrastructure (I-score = 5). Equipment, supplies, and procedures were generally available. Male and female wards were overbooked 83% and 60% of the time, respectively. Providers identified lack of space, patient overload, and superfluous patients' attendants as barriers to surgical care. Workforce challenges were tackled using teamwork and task sharing. Inadequate equipment and processes were addressed using improvisations. All observed subjects (n = 31) received interventions. The median decision-to intervention time was 2.5 h (Interquartile Range [IQR], 0.4, 21.4). However, 48% of subjects experienced delays. Median decision-to-intervention delay was 14.8 h (IQR, 0.9, 26.6). CONCLUSIONS: Despite severe workforce and physical infrastructural deficiencies at Soroti Regional Referral Hospital, providers are adjusting and innovating to deliver surgical care. PMID- 27451894 TI - Sporadic early-onset colon cancer expresses unique molecular features. AB - BACKGROUND: The overall incidence of colon cancer (CC) has steadily declined in the last decades but has increased in patients under age 50 y. The etiology of early-onset (EO) CC is not understood. The aim of this study was to elucidate gene expression patterns in EOCC and show its uniqueness compared to late-onset (LO) disease. METHODS: Two cohorts of patients with sporadic CC were identified. Tumors and matching noninvolved tissues from six EOCC patients (<50) and six late onset colon cancers (LOCC) patients (>65) were obtained from pathology archives. De-paraffinized tissues were macrodissected from FFPE sections, RNA isolated, and used for expression profiling of 770 cancer-related genes representing 13 canonical pathways. RESULTS: Among 770 genes assayed, changes in expression levels of 93 genes were statistically significant between EOCC and matching noninvolved tissues. There were also significant differences in expression levels of 118 genes between LOCC and matching noninvolved tissues. Detailed comparative gene expression analysis between EOCC and LOCC normalized to their matching noninvolved tissues revealed that changes in expression of 88 genes were unique to EOCC using the cutoff criteria of expression levels difference >2 fold and P value <0.01. From these differentially expressed genes specific to EOCC, 28 genes were upregulated and 60 genes downregulated. At the pathway level, RAS, MAPK, WNT, and DNARepair pathways were similarly deregulated in both age groups, whereas PI3K-AKT signaling was more specific to EOCC and cell cycle pathway to LOCC. CONCLUSIONS: These results suggest that sporadic EOCC is characterized by distinct molecular events compared to LOCC. PMID- 27451895 TI - Risk factors for recurrent violent injury among black men. AB - BACKGROUND: Black men are disproportionately overrepresented among victims of repeat violent injury. However, little is known about the risk factors that influence violent trauma recidivism among black men. We hypothesize that the following risk factors would be significant among black male victims of repeat violent injury: disrespect; being under the influence; being in a fight and using a weapon in the past year; and previous incarceration when comparing trauma recidivists versus nonrecidivists. METHODS: Using secondary data analysis, we identified a sample of 191 (n = 191) urban low-income black men treated by a level I trauma unit in Baltimore for violent injury (e.g., gunshot wound, stabbing, or assault) who participated in a hospital-based violence intervention program from 1998 to 2011. Participants in the program completed a risk factor for violent injury questionnaire to assess: exposure to chronic violence, criminal justice involvement, substance abuse, and disrespect (code of the street). RESULTS: We found that 58% of the sample is characterized as trauma recidivists (defined as hospitalization two or more times for violent injury). Black male patients of violent injury who engage in the following: substance abuse; had previously been in a fight or used a weapon in the past year; perceived disrespect as a precursor to violence; and experienced a previous incarceration were more likely to have multiple hospitalizations for violent injury. CONCLUSIONS: Trauma recidivism among urban black male victims of violent injury is a major public health issue. Hospital-based violence intervention programs should be engaged in reducing trauma recidivism among this population. PMID- 27451896 TI - With gratitude and anticipation. PMID- 27451897 TI - Increasing Nitrogen Fixation and Seed Development in Soybean Requires Complex Adjustments of Nodule Nitrogen Metabolism and Partitioning Processes. AB - Legumes are able to access atmospheric di-nitrogen (N2) through a symbiotic relationship with rhizobia that reside within root nodules. In soybean, following N2 fixation by the bacteroids, ammonia is finally reduced in uninfected cells to allantoin and allantoic acid [1]. These ureides present the primary long-distance transport forms of nitrogen (N), and are exported from nodules via the xylem for shoot N supply. Transport of allantoin and allantoic acid out of nodules requires the function of ureide permeases (UPS1) located in cells adjacent to the vasculature [2, 3]. We expressed a common bean UPS1 transporter in cortex and endodermis cells of soybean nodules and found that delivery of N from nodules to shoot, as well as seed set, was significantly increased. In addition, the number of transgenic nodules was increased and symbiotic N2 fixation per nodule was elevated, indicating that transporter function in nodule N export is a limiting step in bacterial N acquisition. Further, the transgenic nodules showed considerable increases in nodule N assimilation, ureide synthesis, and metabolite levels. This suggests complex adjustments of nodule N metabolism and partitioning processes in support of symbiotic N2 fixation. We propose that the transgenic UPS1 plants display metabolic and allocation plasticity to overcome N2 fixation and seed yield limitations. Overall, it is demonstrated that transporter function in N export from nodules is a key step for enhancing atmospheric N2 fixation and nodule function and for improving shoot N nutrition and seed development in legumes. PMID- 27451899 TI - Arabidopsis NAP1 Regulates the Formation of Autophagosomes. AB - The SCAR/WAVE complex is required for ARP2/3-mediated actin nucleation, and these complexes are highly conserved in plants and animals [1, 2]. Proteins from the SCAR/WAVE complex have been found to be membrane associated in plants [3]. Using fluorescent protein fusions, we have found that NAP1 [4], a component of the SCAR/WAVE complex, locates to vesicles or puncta that appear upon applied pressure. These NAP1 vesicles can be endoplasmic reticulum (ER)-associated, can co-align with the cytoskeleton, and fuse to each other homotypically. More interestingly, the majority co-localizes with the autophagosome marker ATG8, and anti-NAP1 identifies autophagosomes in immuno-TEM. Macroautophagy (hereafter referred to as autophagy) is enhanced under certain stress conditions such as nitrogen starvation and salt stress. We show that fewer autophagosomes are generated in the NAP1 knockout mutant during starvation stress. The nap1 mutant (and KO mutants of other components of the SCAR/WAVE and ARP2/3 complexes) is more susceptible to nitrogen starvation and is less salt tolerant, indicating defective autophagy. In conclusion, our data show that NAP1 has another function in plant cells, and that is as a regulator of autophagy. PMID- 27451898 TI - MRCK-1 Drives Apical Constriction in C. elegans by Linking Developmental Patterning to Force Generation. AB - Apical constriction is a change in cell shape that drives key morphogenetic events including gastrulation and neural tube formation. Apical force-producing actomyosin networks drive apical constriction by contracting while connected to cell-cell junctions. The mechanisms by which developmental patterning regulates these actomyosin networks and associated junctions with spatial precision are not fully understood. Here we identify a myosin light-chain kinase MRCK-1 as a key regulator of C. elegans gastrulation that integrates spatial and developmental patterning information. We show that MRCK-1 is required for activation of contractile actomyosin dynamics and elevated cortical tension in the apical cell cortex of endoderm precursor cells. MRCK-1 is apically localized by active Cdc42 at the external, cell-cell contact-free surfaces of apically constricting cells, downstream of cell fate determination mechanisms. We establish that the junctional components alpha-catenin, beta-catenin, and cadherin become highly enriched at the apical junctions of apically constricting cells and that MRCK-1 and myosin activity are required in vivo for this enrichment. Taken together, our results define mechanisms that position a myosin activator to a specific cell surface where it both locally increases cortical tension and locally enriches junctional components to facilitate apical constriction. These results reveal crucial links that can tie spatial information to local force generation to drive morphogenesis. PMID- 27451900 TI - Networks of Food Sharing Reveal the Functional Significance of Multilevel Sociality in Two Hunter-Gatherer Groups. AB - Like many other mammalian and primate societies [1-4], humans are said to live in multilevel social groups, with individuals situated in a series of hierarchically structured sub-groups [5, 6]. Although this multilevel social organization has been described among contemporary hunter-gatherers [5], questions remain as to the benefits that individuals derive from living in such groups. Here, we show that food sharing among two populations of contemporary hunter-gatherers-the Palanan Agta (Philippines) and Mbendjele BaYaka (Republic of Congo)-reveals similar multilevel social structures, with individuals situated in households, within sharing clusters of 3-4 households, within the wider residential camps, which vary in size. We suggest that these groupings serve to facilitate inter sexual provisioning, kin provisioning, and risk reduction reciprocity, three levels of cooperation argued to be fundamental in human societies [7, 8]. Humans have a suite of derived life history characteristics including a long childhood and short inter-birth intervals that make offspring energetically demanding [9] and have moved to a dietary niche that often involves the exploitation of difficult to acquire foods with highly variable return rates [10-12]. This means that human foragers face both day-to-day and more long-term energetic deficits that conspire to make humans energetically interdependent. We suggest that a multilevel social organization allows individuals access to both the food sharing partners required to buffer themselves against energetic shortfalls and the cooperative partners required for skill-based tasks such as cooperative foraging. PMID- 27451902 TI - The Nuclear Hormone Receptor NHR-40 Acts Downstream of the Sulfatase EUD-1 as Part of a Developmental Plasticity Switch in Pristionchus. AB - Developmental plasticity, the ability of one genotype to produce distinct phenotypes in different environments, has been suggested to facilitate phenotypic diversification, and several examples in plants and animals support its macroevolutionary potential [1-8]. However, little is known about associated molecular mechanisms, because environmental effects on development are difficult to study by laboratory approaches. One promising system is the mouth dimorphism of the nematode Pristionchus pacificus [9-12]. Following an irreversible decision in larval development, these nematodes form moveable teeth that occur in either of two discrete morphs. The "eurystomatous" (Eu) form has a wide mouth and two teeth, allowing predatory feeding on other nematodes. In contrast, the alternative ("stenostomatous"; St) form has diminutive mouthparts that largely constrain its diet to microbes. The sulfatase EUD-1 was previously discovered to execute a polyphenism switch based on dosage of functional alleles [13] and confirmed a prediction of evolutionary theory about how developmental switches control plasticity [1, 3]. However, the genetic context of this single gene, and hence the molecular complexity of switch mechanisms, was previously unknown. Here we use a suppressor screen to identify factors downstream of eud-1 in mouth-form regulation. We isolated three dominant, X-linked mutants in the nuclear hormone receptor gene nhr-40 that are haploinsufficient. Both eud-1 nhr-40 double and nhr 40 single mutants are all Eu, whereas transgenic overexpression of nhr-40 does not restore the wild-type phenotype but instead results in nearly all-St lines. Thus, NHR-40 is part of a developmental switch, suggesting that switch mechanisms controlling plasticity consist of multi-component hormonal signaling systems. PMID- 27451901 TI - Muscle- and Skin-Derived Cues Jointly Orchestrate Patterning of Somatosensory Dendrites. AB - Sensory dendrite arbors are patterned through cell-autonomously and non-cell autonomously functioning factors [1-3]. Yet, only a few non-cell-autonomously acting proteins have been identified, including semaphorins [4, 5], brain-derived neurotrophic factors (BDNFs) [6], UNC-6/Netrin [7], and the conserved MNR 1/Menorin-SAX-7/L1CAM cell adhesion complex [8, 9]. This complex acts from the skin to pattern the stereotypic dendritic arbors of PVD and FLP somatosensory neurons in Caenorhabditis elegans through the leucine-rich transmembrane receptor DMA-1/LRR-TM expressed on PVD neurons [8, 9]. Here we describe a role for the diffusible C. elegans protein LECT-2, which is homologous to vertebrate leukocyte cell-derived chemotaxin 2 (LECT2)/Chondromodulin II. LECT2/Chondromodulin II has been implicated in a variety of pathological conditions [10-13], but the developmental functions of LECT2 have remained elusive. We find that LECT 2/Chondromodulin II is required for development of PVD and FLP dendritic arbors and can act as a diffusible cue from a distance to shape dendritic arbors. Expressed in body-wall muscles, LECT-2 decorates neuronal processes and hypodermal cells in a pattern similar to the cell adhesion molecule SAX-7/L1CAM. LECT-2 functions genetically downstream of the MNR-1/Menorin-SAX-7/L1CAM adhesion complex and upstream of the DMA-1 receptor. LECT-2 localization is dependent on SAX-7/L1CAM, but not on MNR-1/Menorin or DMA-1/LRR-TM, suggesting that LECT-2 functions as part of the skin-derived MNR-1/Menorin-SAX-7/L1CAM adhesion complex. Collectively, our findings suggest that LECT-2/Chondromodulin II acts as a muscle derived, diffusible cofactor together with a skin-derived cell adhesion complex to orchestrate the molecular interactions of three tissues during patterning of somatosensory dendrites. PMID- 27451903 TI - Reciprocal Exchange Patterned by Market Forces Helps Explain Cooperation in a Small-Scale Society. AB - Social organisms sometimes depend on help from reciprocating partners to solve adaptive problems [1], and individual cooperation strategies should aim to offer high supply commodities at low cost to the donor in exchange for high-demand commodities with large return benefits [2, 3]. Although such market dynamics have been documented in some animals [4-7], naturalistic studies of human cooperation are often limited by focusing on single commodities [8]. We analyzed cooperation in five domains (meat sharing, produce sharing, field labor, childcare, and sick care) among 2,161 household dyads of Tsimane' horticulturalists, using Bayesian multilevel models and information-theoretic model comparison. Across domains, the best-fit models included kinship and residential proximity, exchanges in kind and across domains, measures of supply and demand and their interactions with exchange, and household-specific exchange slopes. In these best models, giving, receiving, and reciprocating were to some extent shaped by market forces, and reciprocal exchange across domains had a strong partial effect on cooperation independent of more exogenous factors like kinship and proximity. Our results support the view that reciprocal exchange can provide a reliable solution to adaptive problems [8-11]. Although individual strategies patterned by market forces may generate gains from trade in any species [3], humans' slow life history and skill-intensive foraging niche favor specialization and create interdependence [12, 13], thus stabilizing cooperation and fostering divisions of labor even in informal economies [14, 15]. PMID- 27451904 TI - Transient Tissue-Scale Deformation Coordinates Alignment of Planar Cell Polarity Junctions in the Mammalian Skin. AB - Planar cell polarity (PCP) refers to the collective alignment of polarity along the tissue plane. In skin, the largest mammalian organ, PCP aligns over extremely long distances, but the global cues that orient tissue polarity are unknown. Here, we show that Celsr1 asymmetry arises concomitant with a gradient of tissue deformation oriented along the medial-lateral axis. This uniaxial tissue tension, whose origin remains unknown, transiently transforms basal epithelial cells from initially isotropic and disordered states into highly elongated and aligned morphologies. Reorienting tissue deformation is sufficient to shift the global axis of polarity, suggesting that uniaxial tissue strain can act as a long-range polarizing cue. Observations both in vivo and in vitro suggest that the effect of tissue anisotropy on Celsr1 polarity is not a direct consequence of cell shape but rather reflects the restructuring of cell-cell interfaces during oriented cell divisions and cell rearrangements that serve to relax tissue strain. We demonstrate that cell intercalations remodel intercellular junctions predominantly between the mediolateral interfaces of neighboring cells. This restructuring of the cell surface polarizes Celsr1, which is slow to accumulate at nascent junctions yet stably associates with persistent junctions. We propose that tissue anisotropy globally aligns Celsr1 polarity by creating a directional bias in the formation of new cell interfaces while simultaneously aligning the persistent interfaces at which Celsr1 prefers to accumulate. PMID- 27451905 TI - Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding. AB - Defective RNA metabolism and transport are implicated in aging and degeneration [1, 2], but the underlying mechanisms remain poorly understood. A prevalent feature of aging is mitochondrial deterioration [3]. Here, we link a novel mechanism for RNA export through nuclear envelope (NE) budding [4, 5] that requires A-type lamin, an inner nuclear membrane-associated protein, to accelerated aging observed in Drosophila LaminC (LamC) mutations. These LamC mutations were modeled after A-lamin (LMNA) mutations causing progeroid syndromes (PSs) in humans. We identified mitochondrial assembly regulatory factor (Marf), a mitochondrial fusion factor (mitofusin), as well as other transcripts required for mitochondrial integrity and function, in a screen for RNAs that exit the nucleus through NE budding. PS-modeled LamC mutations induced premature aging in adult flight muscles, including decreased levels of specific mitochondrial protein transcripts (RNA) and progressive mitochondrial degradation. PS-modeled LamC mutations also induced the accelerated appearance of other phenotypes associated with aging, including a progressive accumulation of polyubiquitin aggregates [6, 7] and myofibril disorganization [8, 9]. Consistent with these observations, the mutants had progressive jumping and flight defects. Downregulating marf alone induced the above aging defects. Nevertheless, restoring marf was insufficient for rescuing the aging phenotypes in PS-modeled LamC mutations, as other mitochondrial RNAs are affected by inhibition of NE budding. Analysis of NE budding in dominant and recessive PS-modeled LamC mutations suggests a mechanism by which abnormal lamina organization prevents the egress of these RNAs via NE budding. These studies connect defects in RNA export through NE budding to progressive loss of mitochondrial integrity and premature aging. PMID- 27451906 TI - Tumor markers in the early detection of tumor recurrence in breast cancer patients: CA 125, CYFRA 21-1, HER2 shed antigen, LDH and CRP in combination with CEA and CA 15-3. AB - BACKGROUND: Kinetics of CA 15-3 and CEA have a high specificity in the early detection of metastatic breast cancer (MBC). However, this high specificity is associated with a lack of sensitivity. To decrease the number of false negative patients, the additional diagnostic potential of an extended panel of biomarkers was evaluated. METHODS: This analysis was performed as part of a large follow-up study (1998-2010) evaluating 813 patients with a median follow-up of 63months. After primary therapy, all patients underwent tumor marker monitoring for CEA and CA 15-3 at 6-week intervals. A reproducible previously defined increase (>=100%) based on the individual baseline value of each patient was considered as a strong indicator of MBC. For the present analysis, we retrospectively evaluated 1011 blood samples from 95 patients. Forty-seven of these had metastatic disease for the first time at the time of this evaluation, while the remaining 48 patients showed no evidence of disease. The sera of these patients were additionally assessed for the following parameters: cancer antigen (CA) 125, cytokeratin-19 soluble fragment (CYFRA 21-1), HER2 shed antigen, lactate-dehydrogenase (LDH) and C-reactive protein (CRP). RESULTS: 26 of 47 patients with MBC showed a reproducible tumor marker increase of at least CEA and/or CA 15-3 (55.3%, true positive). The remaining 21 patients with MBC showed no increase in CEA or CA 15 3 (44.7%, false negative, FN). By combining all markers mentioned above, 41 of 47 patients with MBC showed a reproducible marker increase with a sensitivity of 87.2% and specificity of 100%. CONCLUSION: This retrospective analysis indicates that a panel of biomarkers can increase the sensitivity of the CA 15-3/CEA combination without loss of specificity. The combined use is therefore helpful for early detection of MBC. PMID- 27451908 TI - Alkynyl Acylammoniums as Electrophilic 3C Synthons in a Formal [3 + 3] Annulation: Access to Functionalized 4H-Pyran-4-ones. AB - Alkynyl acylammoniums generated in situ from alkynyl acids are first used as electrophilic 3C synthons in a formal [3 + 3] annulation with 1,3-dicarbonyl compounds for regioselective synthesis of functionalized 4H-pyran-4-ones via a 4 (dimethylamino)pyridine/Lewis acid dual-activation strategy. This protocol paves the way for further investigation of alkynyl acylammoniums as 3C synthons for construction of diverse heterocyclic skeletons. PMID- 27451909 TI - The Art of the Radiology Report: Practical and Stylistic Guidelines for Perfecting the Conveyance of Imaging Findings. AB - The radiology report is the culmination of image acquisition, meticulous interpretation, and the generation of deliberate and thoughtful recommendations. It is essentially a translation of images into words, and as such must convey as much pertinent detail needed by the clinician in as concise a format as possible. Several important factors affect the overall quality of the finished report. Active voice helps to convey information more confidently, and in a manner that is easier to read and understand. The use of several words and phrases is frowned upon, as it makes the radiologist sound uncertain. The manner in which the impression is stated can significantly influence the ordering physician's decision as to whether to follow the radiologist's recommendations. Critical findings must be promptly communicated to the appropriate health care provider, and documented in the final report. By following the guidelines illustrated in this article, radiologists will learn how to create a perfected report, which will be concise, convey important findings while answering the clinical question posed, and will be favorably viewed by the requesting physician. PMID- 27451907 TI - PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kalpha Inhibition. AB - PIK3CA, which encodes the p110alpha subunit of PI3K, is frequently mutated and oncogenic in breast cancer. PI3Kalpha inhibitors are in clinical development and despite promising early clinical activity, intrinsic resistance is frequent among patients. We have previously reported that residual downstream mTORC1 activity upon treatment with PI3Kalpha inhibitors drives resistance to these agents. However, the mechanism underlying this phenotype is not fully understood. Here we show that in cancer cells resistant to PI3Kalpha inhibition, PDK1 blockade restores sensitivity to these therapies. SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2. Targeting either PDK1 or SGK1 prevents mTORC1 activation, restoring the antitumoral effects of PI3Kalpha inhibition in resistant cells. PMID- 27451910 TI - Detection Rate, Recall Rate, and Positive Predictive Value of Digital Compared to Screen-Film Mammography in the Quebec Population-Based Breast Cancer Screening Program. AB - PURPOSE: The study sought to compare performance indicators of computed radiography (CR) using different plate readers, digital direct radiography (DR), and screen-film mammography (SFM) in a population-based screening program. METHODS: This analysis involved women 50-69 years of age who participated in the breast screening program of Quebec (Canada) and who had screening mammogram between January 1, 2007, and September 30, 2012. The detection rate, recall rate, and positive predictive value of CR (n = 672,125 mammograms) and DR (n = 60,023) were compared to SFM (n = 782,894) using mixed-effect logistic regression, adjusting for potential confounders. No institutional review board approval was required. RESULTS: CR was not associated with change in cancer detection rate (odds ratio [OR]: 0.95; 95% confidence interval [CI]: 0.88-1.03), but with a small increase in recall rate (OR: 1.03; 95% CI: 1.01-1.06) compared to SFM. The association of CR with recall rate varies with the CR plate reader manufacturer (P < .0001). DR was not associated with change in detection rate (OR: 1.06; 95% CI: 0.89-1.25), but with an increase in the recall rate (OR: 1.25; 95% CI: 1.19 1.30) compared to SFM. CONCLUSIONS: In our screening program, digital mammograms gave detection rates equivalent to those of SFM, but with an increase of recall rate, particularly for DR. If this situation persists, the adoption of DR may increase the adverse effects of screening with little or no benefit for women. PMID- 27451911 TI - Milkweed control by food imprinted rabbits. AB - Many species of invasive plants are spreading out rapidly in Europe. The common milkweed occupies increasingly more area. Being poisonous, most animals will not graze on it however rabbits would be an effective organism for the biological control of milkweed. Rabbit kittens can learn the maternal diet in various ways. They prefer aromatic foods which their mother had eaten during pregnancy or lactation period, -even if it is poisonous- but they can also learn the maternal diet from the fecal pellets deposited by the mother into the nest during the nursing events. The present study was aimed to investigate if rabbit kittens can learn that the common milkweed is a potential food also. In the first 10days of their lives kits got fecal pellets originating from individuals having fed on common milkweed previously. When weaned on day 28 postpartum, these pups preferred the milkweed in the 3-way food choice test, opposite to the control group. Most surprisingly in a second experiment it was also shown that the common milkweed was also preferred by the kittens if their mother ate it not during, but one month before pregnancy. PMID- 27451912 TI - Primary prevention of sudden cardiac death in Prinzmetal angina: The role of electrophysiology study in risk stratification. PMID- 27451913 TI - Environment and cardiovascular disease: rationale of the Corinthia study. AB - Environmental factors constitute an important but underappreciated risk factor towards the development and progression of cardiovascular disease (CVD). Environmental exposure to variable pollutants is implicated in the derangement or propagation of adverse pathophysiological processes linked with atherosclerosis, including genetic, hemodynamic, metabolic, oxidative and inflammation parameters. However, no data exist on environmental pollution in rural or semi-rural areas. Therefore, the purpose of the "Corinthia" study is to examine the impact of environmental pollution in indices of cardiovascular morbidity and mortality in a cross-sectional and longitudinal design. The Corinthia study began in October 2015 and is planned to recruit 1,500 individuals from different regions of Corinthia country with different environmental exposures to pollutants and different patterns of soil/ground and/or air pollution until December 2016. Baseline measurements will include lifestyle measurements, anthropometric characteristics and a comprehensive cardiovascular examination. The follow-up is planned to extend prospectively up to 10 years and this study is anticipated to provide valuable data on the distinct impact of soil and air pollution on early markers of atherosclerosis and cardiovascular disease and on the overall impact of environment pollution to cardiovascular morbidity and mortality. PMID- 27451915 TI - Percutaneous transcatheter closure of aorto-right ventricular fistula using the Amplatzer duct occluder. AB - The occurrence of aorto-right ventricular fistula after an aortic valve replacement is rare. If it remains untreated, this condition can result in heart failure and could thus significantly compromise patient survival. Surgical closure is the treatment of choice; however, transcatheter closure has been attempted with relatively acceptable results. Here, we report on a patient who presented with heart failure with an aorto-right ventricular fistula that was present for nine years following aortic valve replacement. Successful transcatheter closure of the fistula with the use of the Amplatzer duct occluder was performed, suggesting that the percutaneous approach is an efficient technique for the treatment of such fistulae. PMID- 27451914 TI - Epidemiological characteristics, management and early outcomes of acute coronary syndromes in Greece: The PHAETHON study. AB - INTRODUCTION: In view of recent therapeutic breakthroughs in acute coronary syndromes (ACS) and essential demographic and socioeconomic changes in Greece, we conducted the prospective, multi-center, nationwide PHAETHON study (An Epidemiological Cohort Study of Acute Coronary Syndromes in the Greek Population) that aimed to recruit a representative cohort of ACS patients and examine current management practices and patient prognosis. METHODS: The PHAETHON study was conducted from May 2012 to February 2014. We enrolled 800 consecutive ACS patients from 37 hospitals with a proportional representation of all types of hospitals and geographical areas. Patients were followed for a median period of 189 days. Outcome was assessed with a composite endpoint of death, myocardial infarction, stroke, urgent revascularization and urgent hospitalization for cardiovascular causes. RESULTS: The mean age of patients was 62.7 years (78% males). The majority of patients (n=411, 51%) presented with ST-elevation myocardial infarction (STEMI), whereas 389 patients presented with NSTEMI (n=303, 38%) or UA (n=86, 11%). Overall, 58.8% of the patients had hypertension, 26.5% were diabetic, 52.5% had dyslipidemia, 71.1% had a smoking history (current or past), 25.8% had a family history of coronary artery disease (CAD) and 24.1% had a prior history of CAD. In STEMI patients, 44.5% of patients were treated with thrombolysis, 38.9% underwent a coronary angiogram (34.1% were treated with primary percutaneous coronary intervention) and 16.5% did not receive urgent treatment. The pain-to-door time was 169 minutes. During hospitalization, 301 (38%) patients presented one or more complications, and 13 died (1.6%). During follow-up, 99 (12.6%) patients experienced the composite endpoint, and 21 died (2.7%). CONCLUSIONS: The PHAETHON study provided valuable insights into the epidemiology, management and outcome of ACS patients in Greece. Management of ACS resembles the management observed in other European countries. However, several issues still to be addressed by public authorities for the timely and proper management of ACS. PMID- 27451916 TI - Influence of gestational age on serum incretin levels in preterm infants. AB - Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones secreted from the intestine in response to enteral feeding to stimulate insulin secretion. We investigated the relationship serum GIP and GLP-1 levels with gestational age, and insulin secretion in preterm infants. Serum GIP and GLP-1 levels were measured at birth and at 1, 2 and 4 weeks after birth in 30 infants, including 12 born before 30th week of gestation (early group) and 18 born after 30th week of gestation (late group). Blood glucose and serum insulin levels were measured, and the quantitative insulin sensitivity check index (QUICKI) was also calculated. The levels of GLP-1 at 2 and 4 weeks were significantly higher in the early group than those in the late group. The levels of GIP were not significantly different between two groups. At 4 weeks, serum insulin level was significantly higher and QUICKI was significantly lower in the early group. Furthermore, GLP-1 levels were significantly correlated with QUICKI and the serum insulin levels in all infants at 4 weeks. In preterm infants, enteral feeding to premature intestine may be associated with GLP-1 secretion. GLP-1 is also related to stimulated insulin secretion in early postnatal period. PMID- 27451917 TI - Connectivity of the anterior insula differentiates participants with first episode schizophrenia spectrum disorders from controls: a machine-learning study. AB - BACKGROUND: Early diagnosis of schizophrenia could improve the outcomes and limit the negative effects of untreated illness. Although participants with schizophrenia show aberrant functional connectivity in brain networks, these between-group differences have a limited diagnostic utility. Novel methods of magnetic resonance imaging (MRI) analyses, such as machine learning (ML), may help bring neuroimaging from the bench to the bedside. Here, we used ML to differentiate participants with a first episode of schizophrenia-spectrum disorder (FES) from healthy controls based on resting-state functional connectivity (rsFC). METHOD: We acquired resting-state functional MRI data from 63 patients with FES who were individually matched by age and sex to 63 healthy controls. We applied linear kernel support vector machines (SVM) to rsFC within the default mode network, the salience network and the central executive network. RESULTS: The SVM applied to the rsFC within the salience network distinguished the FES from the control participants with an accuracy of 73.0% (p = 0.001), specificity of 71.4% and sensitivity of 74.6%. The classification accuracy was not significantly affected by medication dose, or by the presence of psychotic symptoms. The functional connectivity within the default mode or the central executive networks did not yield classification accuracies above chance level. CONCLUSIONS: Seed-based functional connectivity maps can be utilized for diagnostic classification, even early in the course of schizophrenia. The classification was probably based on trait rather than state markers, as symptoms or medications were not significantly associated with classification accuracy. Our results support the role of the anterior insula/salience network in the pathophysiology of FES. PMID- 27451918 TI - The Reply. PMID- 27451919 TI - Hereditary Angioedema: How Long Should We Treat? PMID- 27451920 TI - Effects of early intervention on dietary intake and its mediating role on cognitive functioning: a randomised controlled trial. AB - OBJECTIVE: To investigate the impact of an early intervention programme, Preparing for Life, on dietary intake between 12 and 36 months of age, and the mediating role played by diet on cognitive functioning. DESIGN: A randomised controlled trial evaluation of a community-based home visiting programme. The intervention involved biweekly visits from mentors from pregnancy until age 5 years and parent training at age 2 years. Dietary intake was assessed at 12, 18, 24 and 36 months using an FFQ to calculate the proportion meeting dietary recommendations. Cognitive functioning was measured at 24 and 36 months. Treatment effects were estimated using conventional chi 2 tests, permutation testing, inverse probability weighting and the stepdown procedure. Mediation analysis examined the indirect effect of the intervention on cognitive functioning via its effect on dietary intake. SETTING: Socio-economically disadvantaged communities in Dublin, Republic of Ireland. SUBJECTS: Pregnant women (n 233) were assigned to the intervention (n 115) or control (n 118) group using an unconditional probability randomisation strategy. RESULTS: Positive treatment effects were observed for meeting dietary recommendations for protein foods at 24 (OR=2.52) and 36 (OR=2.42) months, and all food groups at 24 (OR=3.92) months. There were no effects on grain, dairy, fruit and vegetable, or fatty/sugary food recommendations in most models. The conventional and more novel methods yielded similar results. Mediation analysis indicated that 13 % of the intervention's effect on cognitive functioning was mediated by 36-month protein food consumption. CONCLUSIONS: The study demonstrates some potential to alter early childhood dietary patterns through community-based intervention programmes. PMID- 27451922 TI - Radiofrequency ablation of bilateral nevoid hyperkeratosis of nipple and areola. PMID- 27451921 TI - A novel algorithm for detecting multiple covariance and clustering of biological sequences. AB - Single genetic mutations are always followed by a set of compensatory mutations. Thus, multiple changes commonly occur in biological sequences and play crucial roles in maintaining conformational and functional stability. Although many methods are available to detect single mutations or covariant pairs, detecting non-synchronous multiple changes at different sites in sequences remains challenging. Here, we develop a novel algorithm, named Fastcov, to identify multiple correlated changes in biological sequences using an independent pair model followed by a tandem model of site-residue elements based on inter restriction thinking. Fastcov performed exceptionally well at harvesting co-pairs and detecting multiple covariant patterns. By 10-fold cross-validation using datasets of different scales, the characteristic patterns successfully classified the sequences into target groups with an accuracy of greater than 98%. Moreover, we demonstrated that the multiple covariant patterns represent co-evolutionary modes corresponding to the phylogenetic tree, and provide a new understanding of protein structural stability. In contrast to other methods, Fastcov provides not only a reliable and effective approach to identify covariant pairs but also more powerful functions, including multiple covariance detection and sequence classification, that are most useful for studying the point and compensatory mutations caused by natural selection, drug induction, environmental pressure, etc. PMID- 27451923 TI - Recurrent ulcers in the flexures of a 48-year-old woman. PMID- 27451924 TI - Psoriasis and risk of incident atrial fibrillation: A systematic review and meta analysis. AB - BACKGROUND AND OBJECTIVES: Patients with psoriasis might have a higher risk of developing atrial fibrillation as a result of chronic inflammation. This study aimed to investigate this association by comprehensively reviewing all available evidence. METHODS: We conducted a systematic review and meta-analysis of cohort studies that reported relative risk, hazard ratio, incidence ratio or standardized incidence ratio with 95% confidence intervals comparing the risk of incident atrial fibrillation in patients with psoriasis versus participants without psoriasis. Both retrospective and prospective cohort studies were eligible. Pooled risk ratio and 95% confidence intervals were calculated using random-effect, generic inverse variance methods of DerSimonian and Laird. RESULTS: Three retrospective studies with 110,568 cases of psoriasis and 5,352,817 participants without psoriasis were included in this meta-analysis. The pooled risk ratio of subsequent development of atrial fibrillation in patients with psoriasis versus participants without psoriasis was 1.21 (95% confidence interval, 1.14-1.29). The statistical heterogeneity was low with an I2 of 29%. LIMITATIONS: Coding-based design of the primary studies that had limited accuracy. CONCLUSIONS: Our meta-analysis demonstrated a statistically significant increase in the risk of incident atrial fibrillation among patients with psoriasis. PMID- 27451925 TI - Giant, mutilating facial lupus vulgaris due to long-term misdiagnosis. PMID- 27451926 TI - Pigmented oral lesion in a patient with metastatic melanoma. PMID- 27451927 TI - Phototherapeutic modalities pose no significantly increased risk of oxidative damage to DNA in dark skinned individuals. AB - BACKGROUND: 8-oxoguanine, a major product of DNA oxidation, is considered a key parameter in measuring the carcinogenic effects of ultraviolet radiation. OBJECTIVE: To assess and compare the carcinogenic potential of different photo (chemo) therapeutic modalities in photoresponsive skin diseases by measuring the levels of 8-oxoguanine in dark-skinned individuals before and after photo (chemo) therapy. METHODS: A prospective, randomized controlled pilot study was conducted in 63 patients of skin types III-V with photo-responsive dermatoses including vitiligo, psoriasis and mycosis fungoides. Patients were divided into three groups; Group 1 (received narrowband ultraviolet-B), Group 2 (received psoralen plus ultraviolet-A) and Group 3 (received broadband ultraviolet-A). Biopsies were taken before and after phototherapy to measure 8-oxoguanine levels using enzyme linked immunosorbent assay. Biopsies were also taken from the sun-protected skin in 21 controls subjects who had no dermatological disease. RESULTS: Regardless of the disease, a significantly higher level of 8-oxoguanine was found after treatment when compared to the pre-treatment baseline levels; however, these levels were comparable to those in control subjects. A weakly significant positive correlation was found between cumulative dose and 8-oxoguanine levels following psoralen plus ultraviolet-A therapy. In controls, comparing the 8 oxoguanine levels between skin types III and IV showed significantly lower 8 oxoguanine in skin type IV. CONCLUSION: Therapeutic doses of ultraviolet radiation are relatively safe in dark skinned patients; however, minimizing the cumulative dose of phototherapeutic modalities (particularly psoralen plus ultraviolet-A) is recommended. PMID- 27451928 TI - Anagen effluvium secondary to Gloriosa superba ingestion. AB - Anagen effluvium, the shedding of anagen hair, leads to diffuse non-scarring alopecia. We report two cases of anagen effluvium in the same family secondary to the ingestion of tubers of Gloriosa superba, which contains the antimitotic alkaloid colchicine. Both patients developed anagen effluvium and gastroenteritis 1-2 weeks after consuming the tubers. In addition, one of them had bicytopenia, pleural effusion, hematuria and altered liver function tests. Both were managed conservatively and counseled regarding the reversible nature of the hair loss. Follow-up at 3 months showed regrowth of hair in both the cases. PMID- 27451929 TI - Patch tests with commercial hair dye products in patients with allergic contact dermatitis to para-phenylenediamine. AB - BACKGROUND: Hair dye is one of the most common causes of allergic contact dermatitis. The main allergen has been identified as para-phenylenediamine. To prevent the recurrence of contact dermatitis to para-phenylenediamine, patients should discontinue the use of para-phenylenediamine-containing hair dye products. However, many patients are unable to discontinue their use for cosmetic or social reasons. Sometimes, they continue to have symptoms even after switching to so called "less allergenic" hair dyes. OBJECTIVES: To evaluate the safety of 15 commercially available hair dye products in patients with allergic contact dermatitis due to para-phenylenediamine. METHODS: We performed patch tests using 15 hair dyes that were advertised as "hypoallergenic," "no para-phenylenediamine" and "non-allergenic" products in the market. RESULTS: Twenty three patients completed the study and 20 (87.0%) patients had a positive patch test reaction to at least one product. While four (26.7%) hair dye products contained para phenylenediamine, 10 (66.7%) out of 15 contained m- aminophenol and 7 (46.7%) contained toluene-2,5-diamine sulfate. Only one product did not elicit a positive reaction in any patient. LIMITATIONS: Small sample size and possibility of false positive reactions. CONCLUSIONS: Dermatologists should educate patients with allergic contact dermatitis to para-phenylenediamine about the importance of performing sensitivity testing prior to the actual use of any hair dye product, irrespective of how it is advertised or labelled. PMID- 27451930 TI - Intralesional methotrexate as an adjuvant treatment for pyoderma gangrenosum: A case report. PMID- 27451931 TI - Tumor necrosis factor-alpha inhibitors for the treatment of psoriasis patients with liver cirrhosis: A report of four cases with a literature review. AB - Patients with psoriasis are at an increased risk of developing liver disease due to various factors. The existing data regarding the treatment of psoriasis patients with associated liver cirrhosis is limited. We report four patients of psoriasis with liver cirrhosis who were treated with TNF-alpha inhibitors for a mean duration of 35.4 months. Two patients were treated with etanercept, one with adalimumab and one was treated with both infliximab and etanercept. Three patients tolerated the treatment well without any deterioration of liver disease whereas one died of progressive liver disease. Although large-scale, controlled studies are needed, this case series provides insights regarding the long-term safety of TNF-alpha inhibitors in patients with psoriasis and liver cirrhosis. PMID- 27451932 TI - Topical peptides as cosmeceuticals. AB - Peptides are known to have diverse biological roles, most prominently as signaling/regulatory molecules in a broad variety of physiological processes including defense, immunity, stress, growth, homeostasis and reproduction. These aspects have been used in the field of dermatology and cosmetology to produce short, stable and synthetic peptides for extracellular matrix synthesis, pigmentation, innate immunity and inflammation. The evolution of peptides over the century, which started with the discovery of penicillin, has now extended to their usage as cosmeceuticals in recent years. Cosmeceutical peptides may act as signal modulators of the extracellular matrix component, as structural peptides, carrier peptides and neurotransmitter function modulators. Transdermal delivery of peptides can be made more effective by penetration enhancers, chemical modification or encapsulation of peptides. The advantages of using peptides as cosmeceuticals include their involvement in many physiological functions of the skin, their selectivity, their lack of immunogenicity and absence of premarket regulatory requirements for their use. However, there are disadvantages: clinical evidence for efficacy is often weak, absorption may be poor due to low lipophilicity, high molecular weight and binding to other ingredients, and prices can be quite high. PMID- 27451933 TI - Sexual behavior and condom use among a population of men who have sex with men attending a dermatology-sexually transmitted infection clinic in Beirut-Lebanon. PMID- 27451935 TI - Nonlinear force dependence on optically bound micro-particle arrays in the evanescent fields of fundamental and higher order microfibre modes. AB - Particles trapped in the evanescent field of an ultrathin optical fibre interact over very long distances via multiple scattering of the fibre-guided fields. In ultrathin fibres that support higher order modes, these interactions are stronger and exhibit qualitatively new behaviour due to the coupling of different fibre modes, which have different propagation wave-vectors, by the particles. Here, we study one dimensional longitudinal optical binding interactions of chains of 3 MUm polystyrene spheres under the influence of the evanescent fields of a two mode microfibre. The observation of long-range interactions, self-ordering and speed variation of particle chains reveals strong optical binding effects between the particles that can be modelled well by a tritter scattering-matrix approach. The optical forces, optical binding interactions and the velocity of bounded particle chains are calculated using this method. Results show good agreement with finite element numerical simulations. Experimental data and theoretical analysis show that higher order modes in a microfibre offer a promising method to not only obtain stable, multiple particle trapping or faster particle propulsion speeds, but that they also allow for better control over each individual trapped object in particle ensembles near the microfibre surface. PMID- 27451934 TI - Making use of longitudinal information in pattern recognition. AB - Longitudinal designs are widely used in medical studies as a means of observing within-subject changes over time in groups of subjects, thereby aiming to improve sensitivity for detecting disease effects. Paralleling an increased use of such studies in neuroimaging has been the adoption of pattern recognition algorithms for making individualized predictions of disease. However, at present few pattern recognition methods exist to make full use of neuroimaging data that have been collected longitudinally, with most methods relying instead on cross-sectional style analysis. This article presents a principal component analysis-based feature construction method that uses longitudinal high-dimensional data to improve predictive performance of pattern recognition algorithms. The method can be applied to data from a wide range of longitudinal study designs and permits an arbitrary number of time-points per subject. We apply the method to two longitudinal datasets, one containing subjects with mild cognitive impairment along with healthy controls, the other with early dementia subjects and healthy controls. Across both datasets, we show improvements in predictive accuracy relative to cross-sectional classifiers for discriminating disease subjects from healthy controls on the basis of whole-brain structural magnetic resonance image based voxels. In addition, we can transfer longitudinal information from one set of subjects to make disease predictions in another set of subjects. The proposed method is simple and, as a feature construction method, flexible with respect to the choice of classifier and image registration algorithm. Hum Brain Mapp 37:4385 4404, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27451937 TI - Erratum. PMID- 27451936 TI - Protective effects of physical exercise on MDMA-induced cognitive and mitochondrial impairment. AB - Debate continues about the effect of 3, 4-methylenedioxymethamphetamine (MDMA) on cognitive and mitochondrial function through the CNS. It has been shown that physical exercise has an important protective effect on cellular damage and death. Therefore, we investigated the effect of physical exercise on MDMA-induced impairments of spatial learning and memory as well as MDMA effects on brain mitochondrial function in rats. Male wistar rats underwent short-term (2 weeks) or long-term (4 weeks) treadmill exercise. After completion of exercise duration, acquisition and retention of spatial memory were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally (I.P) injected with MDMA (5, 10, and 15mg/kg) 30min before the first training trial in 4 training days of MWM. Different parameters of brain mitochondrial function were measured including the level of ROS production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outermembrane damage, the amount of cytochrome c release from the mitochondria, and ADP/ATP ratio. MDMA damaged the spatial learning and memory in a dose-dependent manner. Brain mitochondria isolated from the rats treated with MDMA showed significant increase in ROS formation, collapse of MMP, mitochondrial swelling, and outer membrane damage, cytochrome c release from the mitochondria, and finally increased ADP/ATP ratio. This study also found that physical exercise significantly decreased the MDMA-induced impairments of spatial learning and memory and also mitochondrial dysfunction. The results indicated that MDMA-induced neurotoxicity leads to brain mitochondrial dysfunction and subsequent oxidative stress is followed by cognitive impairments. However, physical exercise could reduce these deleterious effects of MDMA through protective effects on brain mitochondrial function. PMID- 27451938 TI - A comprehensive theoretical framework for the implementation and evaluation of opt-out HIV testing. AB - Opt-out HIV testing (in which patients are offered HIV testing as a default) is a potentially powerful strategy for increasing the number of people who know their HIV status and thus limiting viral transmission. Like any change in clinical practice, implementation of opt-out HIV testing in a health service requires a change management strategy, which should have theoretical support. This paper considers the application of three theories to the implementation and evaluation of an opt-out HIV testing programme: Behavioural Economics, the Health Belief Model and Normalisation Process Theory. An awareness, understanding and integration of these theories may motivate health care providers to order HIV tests that they may not routinely order, influence their beliefs about who should be tested for HIV and inform the operational aspects of opt-out HIV testing. Ongoing process evaluation of opt-out HIV testing programmes (based on these theories) will help to achieve individual health care provider self-efficacy and group collective action, thereby improving testing rates and health outcomes. PMID- 27451939 TI - Evolution of the incidence of hepatitis B virus infection and immunization rates in a large French cohort born between 1960 and 1994. AB - In France, several successive changes in anti-hepatitis B virus (HBV) vaccination policies occurred since 1982. We estimated the incidence and prevalence of HBV infection according to years of birth 1960 to 1994 in a large sentinel cohort to evaluate the epidemiology of HBV during vaccination policy changes. A retrospective cohort study included data from all HIV, HBV and hepatitis C virus (HCV) screening facilities in Grand Lyon. From 2005 to 2010, all 57113 individuals with complete HBV serologic status were enrolled. Survival analyses modeled separately various ages in each birth cohort. The proportion of immunized individuals increased in birth cohorts 1978 to 1984 (up to 58.3% (95% confidence interval (CI), 43.3-68.2 at age 15). In post-1985 birth cohorts, this proportion decreased to 19.5% (95% CI, 15.5-24) in birth cohort 1987 at age 15. Probability of past or current HBV infection increased constantly in birth cohorts 1960 to 1967, up to 12% (95% CI, 10.4-14) at age 30, then decreased gradually in birth cohorts 1968 to 1991, down to 0.9% (95% CI, 0.7-1.2) at age 17.5. In post-1991 cohorts, the probability of HBV infection increased again, up to 2.5% (95% CI, 1.7-3.6) at age 17.5. HBV incidence fluctuated between 5 and 8 per 1000 person years in pre-1986 birth cohorts, decreased to 2.1 (95% CI, 1.5-2.7) in birth cohorts 1986 to 1991 but rebounded to 5 (95% CI, 3.5-7.1) in post-1991 birth cohorts. HBV incidence was remarkably high in young adults with noticeable variations concomitantly to vaccination policy changes. A dramatic decline in immunization rate was temporally associated with a sharp rebound of infection after withdrawal of systematic adolescent vaccination in 1998. PMID- 27451940 TI - The history of Helicobacter pylori: from phylogeography to paleomicrobiology. AB - The study of the gastric pathogen Helicobacter pylori brought us interesting data on the history of mankind. Based on multi-locus sequence typing, it was possible to trace the migration of Homo sapiens all around the world, and to infer the time when he went Out of Africa. Beside these phylogeographic aspects, paleomicrobiology gave us important information on life in the Neolithic period, following the discovery of Otzi, the Iceman, who was living in the Tyrolean Alps 5200 years ago, and from whom a Helicobacter pylori genome was sequenced. This review presents the data accumulated in these different fields. PMID- 27451941 TI - Impact of a targeted isolation strategy at intensive-care-unit-admission on intensive-care-unit-acquired infection related to multidrug-resistant bacteria: a prospective uncontrolled before-after study. AB - Isolation of patients with multidrug resistant (MDR) bacteria is recommended to reduce cross-transmission of these bacteria. However, isolation of critically ill patients has several negative side effects. Therefore, we hypothesized that a targeted isolation strategy, based on the presence of at least one risk factor for MDR bacteria, would be not inferior to a systematic isolation strategy at intensive-care unit (ICU) admission. This prospective before-after study was conducted in a mixed ICU, during two 12-month periods, separated by a 1-month 'wash-out' period. During the before period, isolation was systematically performed in all patients at admission. During the after period, isolation was only performed in patients with at least one risk factor for MDR bacteria at admission. During the two periods, routine screening for MDR bacteria was performed at ICU admission, and isolation prescription was modified after receipt of screening result. Primary outcome was the percentage of patients with ICU acquired infection (ICUAI) related to MDR bacteria, measured from ICU admission until ICU discharge or day 28, whatever happens first. A total of 1221 patients were included. No significant difference was found in ICUAI related to MDR bacteria (85 of 585 (14.5%) vs. 84 of 636 (13.2%) patients, risk difference, 1.3%, 95% confidence interval [-5.2 to 2.6%]) between the two periods, confirming the non-inferiority hypothesis. Our results suggest that targeted isolation of patients at ICU admission is not inferior to systematic isolation, regarding the percentage of patients with ICUAI related to MDR bacteria. Further randomized controlled multicentre studies are needed to confirm our results. PMID- 27451942 TI - Recombinant fusion ESAT6-CFP10 immunogen as a skin test reagent for tuberculosis diagnosis: an open-label, randomized, two-centre phase 2a clinical trial. AB - We sought to assess the accuracy and safety of the ESAT6-CFP10 reagent in diagnosing tuberculosis (TB) disease. An open-label, randomized phase 2a trial was conducted in 56 healthy adults and 88 TB patients at one medical centre and one teaching hospital in China. All participants received 0.1, 0.5, 1 or 2 MUg ESAT6-CFP10 in their right forearm. Moreover, 56 healthy volunteers and 56 patients were given tuberculin-purified protein derivative (TB-PPD) in their left forearm. The remaining 32 patients were administered placebo. The main outcome measure was induration diameter. An enzyme-linked immunospot (ELISPOT) assay was conducted before the skin test. The ESAT6-CFP10 test caused a higher positivity rate than placebo (81.2% (26/32) vs. 3.1% (1/32); p <0.001). The median maximum induration diameter after ESAT6-CFP10 injection was 17.0 (interquartile range (IQR), 14.0-21.7) mm, similar to that for TB-PPD (17.5 (IQR, 7.0-30.5) mm). The diagnostic accuracy of ESAT6-CFP10 was superior to that of TB-PPD (area under the receiver operating characteristic curve (AUC), 0.870 (95% confidence interval (CI), 0.796-0.944) vs. 0.686 (95% CI, 0.585-0.786); p <0.001). When analysed in all participants, ESAT6-CFP10 had comparable AUC values to the ELISPOT assay (0.849 (95% CI, 0.835-0.952) vs. 0.908 (95% CI, 0.852-0.965)). Local itching (12/144, 8.3%) and pain (26/144, 18.1%) were the main side effects of ESAT6 CFP10. No serious adverse events were reported. The ESAT6-CFP10 skin test appears to be a safe and promising tool; further testing will confirm its efficacy in identifying TB disease. PMID- 27451943 TI - Memory window engineering of Ta2O5-x oxide-based resistive switches via incorporation of various insulating frames. AB - Three-dimensional (3D) stackable memory frames, including nano-scaled crossbar arrays, are one of the most reliable building blocks to meet the demand of high density non-volatile memory electronics. However, their utilization has the disadvantage of introducing issues related to sneak paths, which can negatively impact device performance. We address the enhancement of complementary resistive switching (CRS) features via the incorporation of insulating frames as a generic approach to extend their use; here, a Pt/Ta2O5-x/Ta/Ta2O5-x/Pt frame is chosen as the basic CRS cell. The incorporation of Ta/Ta2O5-x/Ta or Pt/amorphous TaN/Pt insulting frames into the basic CRS cell ensures the appreciably advanced memory features of CRS cells including higher on/off ratios, improved read margins, and increased selectivity without reliability degradation. Experimental observations identified that a suitable insulating frame is crucial for adjusting the abrupt reset events of the switching element, thereby facilitating the enhanced electrical characteristics of CRS cells that are suitable for practical applications. PMID- 27451944 TI - Strain differences in toxicity of oral cadmium intake in rats. AB - Influence of genetic background on toxicity of oral cadmium (Cd) administration (30 days, in drinking water; 5 ppm and 50 ppm of cadmium) was examined in Albino Oxford (AO) and Dark Agouti (DA) rats. Similar cadmium deposition was noted in gut and draining mesenteric lymph nodes (MLN) of both strains but intensity and/or the pattern of responses to cadmium in these tissues differ. Less intense intestinal damage and leukocyte infiltration was observed in gut of cadmium exposed AO rats. While gut-associated lymph node cells of DA rats responded to cadmium with an increase of cell proliferation, oxidative activity, IFN-gamma, IL 17 production and expression, no changes of these activities of MLN cells of cadmium-treated AO rats were observed. Spleen, which accumulated cadmium comparable to MLN, responded to metal by drop in cell viability and by reduced responsiveness of proliferation and cytokine production to stimulation in DA rats solely, which suggest tissue dependence of cadmium effects. More pronounced cadmium effects on MLN and spleen cells of DA rats (which accumulated similar cadmium doses as AO rats), showed greater susceptibility of this strain to cadmium. The results presented, for the first time, depict the influence of genetic background to effects of oral cadmium administration. PMID- 27451945 TI - ClC-3 Chloride Channel Proteins Regulate the Cell Cycle by Up-regulating cyclin D1-CDK4/6 through Suppressing p21/p27 Expression in Nasopharyngeal Carcinoma Cells. AB - It was shown in this study that knockdown of ClC-3 expression by ClC-3 siRNA prevented the activation of hypotonicity-induced chloride currents, and arrested cells at the G0/G1 phase in nasopharyngeal carcinoma CNE-2Z cells. Reconstitution of ClC-3 expression with ClC-3 expression plasmids could rescue the cells from the cell cycle arrest caused by ClC-3 siRNA treatments. Transfection of cells with ClC-3 siRNA decreased the expression of cyclin D1, cyclin dependent kinase 4 and 6, and increased the expression of cyclin dependent kinase inhibitors (CDKIs), p21 and p27. Pretreatments of cells with p21 and p27 siRNAs depleted the inhibitory effects of ClC-3 siRNA on the expression of CDK4 and CDK6, but not on that of cyclin D1, indicating the requirement of p21 and p27 for the inhibitory effects of ClC-3 siRNA on CDK4 and CDK6 expression. ClC-3 siRNA inhibited cells to progress from the G1 phase to the S phase, but pretreatments of cells with p21 and p27 siRNAs abolished the inhibitory effects of ClC-3 siRNA on the cell cycle progress. Our data suggest that ClC-3 may regulate cell cycle transition between G0/G1 and S phases by up-regulation of the expression of CDK4 and CDK6 through suppression of p21 and p27 expression. PMID- 27451946 TI - Potential Benefit of the Charge-Stabilized Nanostructure Saline RNS60 for Myelin Maintenance and Repair. AB - Myelin injury in multiple sclerosis (MS) has been attributed both to "outside-in" primary immune mediated and "inside-out" metabolic stress of oligodendrocyte (OL) related mechanisms. Subsequent remyelination is dependent on recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). RNS60 is a physically modified saline containing charge-stabilized nanobubbles generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. Administration of RNS60 has been shown to reduce the severity of EAE by dampening the immune response and myelin loss. Additionally, RNS60 has been demonstrated to enhance mitochondrial ATP synthesis in neurons. Here, we used post-natal rat derived OLs and OPCs to assess the impact of RNS60 on the response of OLs to metabolic stress in vitro (glucose-nutrient deprivation, referred to as 'NG') and on OPC differentiation capacity. Under the NG condition, our findings indicate that RNS60 decreases caspases 3/7 activation. Respirometric analyses revealed that RNS60 increased spare glycolytic capacity (SGC) under normal culture conditions. However, RNS60 enhanced OL spare respiratory capacity (SRC) when a metabolic stress was present. Furthermore, we show that RNS60 promotes OPC differentiation under physiological conditions. Our findings provide evidence for the potential therapeutic efficacy of RNS60 through the promotion of OL survival and OPC differentiation. PMID- 27451947 TI - An alphabaculovirus isolated from dead Lymantria dispar larvae shows high genetic similarity to baculovirus previously isolated from Lymantria monacha - An example of adaptation to a new host. AB - A new isolate of baculovirus, Lymantria dispar multiple nucleopolyhedrovirus-BNP (LdMNPV-BNP), was found in dead gypsy moth (L. dispar) caterpillars collected in the Biebrzanski National Park in Poland. Here, we examined its biological activity, structure, genetic content and phylogeny. Multiple nucleocapsids of LdMNPV-BNP are enveloped together in 2-26 virions embedded in occluded bodies (OBs) very similar to the OBs previously described in viruses infecting Lymantriinae. This isolate kills pest larvae in a relatively short time (LT50 of approximately 9days for a dose of 2*10(7)OBs/ml), highlighting the possibility for its use as a biopesticide. Next-generation sequencing of LdMNPV-BNP revealed gene content (e.g. DNA photolyase) that is not present in any LdMNPV isolate sequenced to date. The genome is 157,270 base pairs long and has a notably lower G+C content in comparison to other LdMNPVs (50.3% G+C content compared to an average of 57.4% among other LdMNPVs). According to our phylogenetic analysis based on 37 core genes, LdMNPV-BNP is a member of group II alphabaculoviruses, which are closely related to LdMNPV and LyxyMNPV (Lymantria xylina multiple nucleopolyhedrovirus). Molecular evolution inference based on the partial sequence of lef-8, lef-9 and polh genes shows that LdMNPV-BNP and isolates of Lymantria monacha nucleopolyhedrovirus (LymoNPV) may share a very recent common ancestor or be isolates of the same virus species. LdMNPV-BNP, like other baculoviruses, could be beneficial as an active component of biopesticides that can be used during forest integrated pest management. PMID- 27451949 TI - Subclinical hypothyroidism and gestational hypertension: causal or coincidence? PMID- 27451948 TI - Human breast cancer-derived soluble factors facilitate CCL19-induced chemotaxis of human dendritic cells. AB - Breast cancer remains as a challenging disease with high mortality in women. Increasing evidence points the importance of understanding a crosstalk between breast cancers and immune cells, but little is known about the effect of breast cancer-derived factors on the migratory properties of dendritic cells (DCs) and their consequent capability in inducing T cell immune responses. Utilizing a unique 3D microfluidic device, we here showed that breast cancers (MCF-7, MDA-MB 231, MDA-MB-436 and SK-BR-3)-derived soluble factors increase the migration of DCs toward CCL19. The enhanced migration of DCs was mainly mediated via the highly activated JNK/c-Jun signaling pathway, increasing their directional persistence, while the velocity of DCs was not influenced, particularly when they were co-cultured with triple negative breast cancer cells (TNBCs or MDA-MB-231 and MDA-MB-436). The DCs up-regulated inflammatory cytokines IL-1beta and IL-6 and induced T cells more proliferative and resistant against activation-induced cell death (AICD), which secret high levels of inflammatory cytokines IL-1beta, IL-6 and IFN-gamma. This study demonstrated new possible evasion strategy of TNBCs utilizing their soluble factors that exploit the directionality of DCs toward chemokine responses, leading to the building of inflammatory milieu which may support their own growth. PMID- 27451950 TI - Hypotension based on office and ambulatory monitoring blood pressure. Prevalence and clinical profile among a cohort of 70,997 treated hypertensives. AB - We aimed to determine the prevalence of hypotension and factors associated with the presence of this condition in treated hypertensive patients undergoing ambulatory blood pressure monitoring (ABPM). Data were taken from the Spanish ABPM Registry. Office blood pressure (BP) and ABPM were determined using validated devices under standardized conditions. Based on previous studies, hypotension was defined as office systolic/diastolic BP <110 and/or 70 mm Hg, daytime ABPM <105 and/or 65 mm Hg, nighttime ABPM <90 and/or 50 mm Hg, and 24 hour ABPM <100 and/or 60 mm Hg. Multivariable logistic regression was performed to determine the variables associated with the presence of hypotension. A total of 70,997 hypertensive patients on treatment (mean age 61.8 years, 52.5% men) were included in the study. The prevalence of hypotension was 8.2% with office BP, 12.2% with daytime ABPM, 3.9% with nighttime ABPM, and 6.8% with 24-hour ABPM. Low diastolic BP values were responsible for the majority of cases of hypotension. Some 68% of the hypotension cases detected by daytime ABPM did not correspond to hypotension according to office BP. The variables independently and consistently associated with higher likelihood of office, daytime, and 24 hour based hypotension were age, female gender, history of ischemic heart disease, and body mass index <30 kg/m(2) (P < .05). In conclusion, in this large cohort of patients in usual daily practice, one in eight treated hypertensive patients are at risk of hypotension according to daytime BP. Two-thirds of them are not adequately identified with office BP. ABPM could be especially helpful for identifying ambulatory hypotension, in particular in patients who are older, women, or with previous ischemic heart disease where antihypertensive treatment should be especially individualized and cautious. PMID- 27451951 TI - DNA-HMGB1 interaction: The nuclear aggregates of polyamine mediation. AB - Nuclear aggregates of polyamines (NAPs) are supramolecular compounds generated by the self-assembly of protonated nuclear polyamines (spermine, spermidine and putrescine) and phosphate ions. In the presence of genomic DNA, the hierarchical process of self-structuring ultimately produces nanotube-like polymers that envelop the double helix. Because of their modular nature and their aggregation disaggregation dynamics, NAPs confer plasticity and flexibility to DNA. Through the disposition of charges, NAPs also enable a bidirectional stream of information between the genome and interacting moieties. High mobility group (HMG) B1 is a non-histone chromosomal protein that binds to DNA and that influences multiple nuclear processes. Because genomic DNA binds to either NAPs or HMGB1 protein, we explored the ability of in vitro self-assembled NAPs (ivNAPs) to mediate the DNA-HMGB1 interaction. To this end, we structured DNA NAPs-HMGB1 and DNA-HMGB1-NAPs ternary complexes in vitro through opportune sequential incubations. Mobility shift electrophoresis and atomic force microscopy showed that the DNA-ivNAPs-HGMB1 complex had conformational assets supposedly more suitable those of the DNA-HGMB1-ivNAPs to comply with the physiological and functional requirements of DNA. Our findings indicated that ivNAPs act as mediators of the DNA-HMGB1 interaction. PMID- 27451952 TI - Structure of a plant beta-galactosidase C-terminal domain. AB - Most plant beta-galactosidases, which belong to glycoside hydrolase family 35, have a C-terminal domain homologous to animal galactose and rhamnose-binding lectins. To investigate the structure and function of this domain, the C-terminal domain of the rice (Oryza sativa L.) beta-galactosidase 1 (OsBGal1 Cter) was expressed in Escherichia coli and purified to homogeneity. The free OsBGal1 Cter is monomeric with a native molecular weight of 15kDa. NMR spectroscopy indicated that OsBGal1 Cter comprises five beta-strands and one alpha-helix. The structure of this domain is similar to lectin domains from animals, but loops A and C of OsBGal1 Cter are longer than the corresponding loops from related animal lectins with known structures. In addition, loop A of OsBGal1 Cter was not well defined, suggesting it is flexible. Although OsBGal1 Cter was predicted to be a galactose/rhamnose-binding domain, binding with rhamnose, galactose, glucose, beta-1,4-d-galactobiose and raffinose could not be observed in NMR experiments. PMID- 27451953 TI - First report of Fusarium oxysporum species complex infection in zebrafish culturing system. AB - Fusarium oxysporum species complex (FOSC) is a highly diverse fungus. Recently, F. oxysporum infection was identified from zebrafish (Danio rerio) culturing system in Korea. Initially, a rapid whitish smudge was appeared in the water with the fungal blooming on walls of fish tanks. Microscopic studies were conducted on fungal hyphae, colony pigmentation and chlamydospore formation and the presence of macro- and microspores confirmed that the isolated fungus as F. oxysporum. Furthermore, isolated F. oxysporum was confirmed by internal transcribed spacer sequencing which matched (100%) to nine F. oxysporum sequences available in GenBank. Experimental hypodermic injection of F. oxysporum into adult zebrafish showed the development of fungal mycelium and pathogenicity similar to signs observed. Histopathologic results revealed a presence of F. oxysporum hyphae in zebrafish muscle. Fusarium oxysporum growth was increased with sea salt in a concentration-dependent manner. Antifungal susceptibility results revealed that F. oxysporum is resistant to copper sulphate (up to 200 MUg mL-1 ) and sensitive to nystatin (up to 40 MUg mL-1 ). This is the first report of FOSC from zebrafish culture system, suggesting it appears as an emerging pathogen, thus posing a significant risk on zebrafish facilities in the world. PMID- 27451954 TI - Effect of crowding, temperature and age on glia activation and dopaminergic neurotoxicity induced by MDMA in the mouse brain. AB - 3,4-methylenedyoxymethamphetamine (MDMA or "ecstasy"), a recreational drug of abuse, can induce glia activation and dopaminergic neurotoxicity. Since MDMA is often consumed in crowded environments featuring high temperatures, we studied how these factors influenced glia activation and dopaminergic neurotoxicity induced by MDMA. C57BL/6J adolescent (4 weeks old) and adult (12 weeks old) mice received MDMA (4*20mg/kg) in different conditions: 1) while kept 1, 5, or 10*cage at room temperature (21 degrees C); 2) while kept 5*cage at either room (21 degrees C) or high (27 degrees C) temperature. After the last MDMA administration, immunohistochemistry was performed in the caudate-putamen for CD11b and GFAP, to mark microglia and astroglia, and in the substantia nigra pars compacta for tyrosine hydroxylase, to mark dopaminergic neurons. MDMA induced glia activation and dopaminergic neurotoxicity, compared with vehicle administration. Crowding (5 or 10 mice*cage) amplified MDMA-induced glia activation (in adult and adolescent mice) and dopaminergic neurotoxicity (in adolescent mice). Conversely, exposure to a high environmental temperature (27 degrees C) potentiated MDMA-induced glia activation in adult and adolescent mice kept 5*cage, but not dopaminergic neurotoxicity. Crowding and exposure to a high environmental temperature amplified MDMA-induced hyperthermia, and a positive correlation between body temperature and activation of either microglia or astroglia was found in adult and adolescent mice. These results provide further evidence that the administration setting influences the noxious effects of MDMA in the mouse brain. However, while crowding amplifies both glia activation and dopaminergic neurotoxicity, a high environmental temperature exacerbates glia activation only. PMID- 27451955 TI - Pancreatic cancer: Dodging immunosuppression. PMID- 27451957 TI - Proposed pathophysiologic framework to explain some excess cardiovascular death associated with ambient air particle pollution: Insights for public health translation. AB - The paper proposes a pathophysiologic framework to explain the well-established epidemiological association between exposure to ambient air particle pollution and premature cardiovascular mortality, and offers insights into public health solutions that extend beyond regulatory environmental protections to actions that can be taken by individuals, public health officials, healthcare professionals, city and regional planners, local and state governmental officials and all those who possess the capacity to improve cardiovascular health within the population. The foundation of the framework rests on the contribution of traditional cardiovascular risk factors acting alone and in concert with long-term exposures to air pollutants to create a conditional susceptibility for clinical vascular events, such as myocardial ischemia and infarction; stroke and lethal ventricular arrhythmias. The conceptual framework focuses on the fact that short-term exposures to ambient air particulate matter (PM) are associated with vascular thrombosis (acute coronary syndrome, stroke, deep venous thrombosis, and pulmonary embolism) and electrical dysfunction (ventricular arrhythmia); and that individuals having prevalent heart disease are at greatest risk. Moreover, exposure is concomitant with changes in autonomic nervous system balance, systemic inflammation, and prothrombotic/anti-thrombotic and profibrinolytic antifibrinolytic balance. Thus, a comprehensive solution to the problem of premature mortality triggered by air pollutant exposure will require compliance with regulations to control ambient air particle pollution levels, minimize exposures to air pollutants, as well as a concerted effort to decrease the number of people at-risk for serious clinical cardiovascular events triggered by air pollutant exposure by improving the overall state of cardiovascular health in the population. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. PMID- 27451958 TI - Mechanisms of the acute effects of inhaled ozone in humans. AB - Ambient air ozone (O3) is generated photochemically from oxides of nitrogen and volatile hydrocarbons. Inhaled O3 causes remarkably reversible acute lung function changes and inflammation. Approximately 80% of inhaled O3 is deposited on the airways. O3 reacts rapidly with CC double bonds in hydrophobic airway and alveolar surfactant-associated phospholipids and cholesterol. Resultant primary ozonides further react to generate bioactive hydrophilic products that also initiate lipid peroxidation leading to eicosanoids and isoprostanes of varying electrophilicity. Airway surface liquid ascorbate and urate also scavenge O3. Thus, inhaled O3 may not interact directly with epithelial cells. Acute O3 induced lung function changes are dominated by involuntary inhibition of inspiration (rather than bronchoconstriction), mediated by stimulation of intraepithelial nociceptive vagal C-fibers via activation of transient receptor potential (TRP) A1 cation channels by electrophile (e.g., 4-oxo-nonenal) adduction of TRPA1 thiolates enhanced by PGE2-stimulated sensitization. Acute O3 induced neutrophilic airways inflammation develops more slowly than the lung function changes. Surface macrophages and epithelial cells are involved in the activation of epithelial NFkB and generation of proinflammatory mediators such as IL-6, IL-8, TNFa, IL-1b, ICAM-1, E-selectin and PGE2. O3-induced partial depolymerization of hyaluronic acid and the release of peroxiredoxin-1 activate macrophage TLR4 while oxidative epithelial cell release of EGFR ligands such as TGFa or EGFR transactivation by activated Src may also be involved. The ability of lipid ozonation to generate potent electrophiles also provides pathways for Nrf2 activation and inhibition of canonical NFkB activation. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. PMID- 27451959 TI - Stress, Pregnancy, and Motherhood: Implications for Birth Weights in the Borderlands of Texas. AB - We argue that changes over time in how ideas of stress are incorporated into understandings of pregnancy and motherhood among Mexican immigrant women living in the United States may affect the documented increase of low birth weight infants born to those women. Stress has consistently been linked to low birth weight, and pregnant Mexican American and Mexican immigrant women differ in levels of perceived social stress. What is lacking is an explanation for these differences. We utilize a subset of 36 ethnographic interviews with pregnant immigrant women from northern Mexico and Mexican Americans living in south Texas to demonstrate how meanings of pregnancy and motherhood increasingly integrate notions of stress the longer immigrant Mexican women live in the United States. We situate our results within anthropological and sociological research on motherhood in the United States and Mexico, anthropological research in the U.S. Mexico borderlands, and interdisciplinary research on Hispanic rates of low birth weight. PMID- 27451960 TI - Estradiol-tethered micropatterned surfaces for the study of estrogenic non genomic pathways. AB - Besides its well-known hormonal effects initiated in the nucleus, estradiol (E2) also activates non-nuclear pathways through interactions with receptors located on the cell plasma membrane. Micropatterned substrates consisting of gold dots bearing tethered E2 distributed on a cell-adhesive substrate were prepared and shown to trigger specifically E2 non-genomic effects in cells grown on the substrates. PMID- 27451956 TI - The genetics and mechanisms of T cell acute lymphoblastic leukaemia. AB - T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened opportunities for the development of targeted therapies for the treatment of this disease. In this Review we examine our current understanding of the molecular mechanisms of T-ALL and recent developments in the translation of these results to the clinic. PMID- 27451961 TI - The CD147/MMP-2 signaling pathway may regulate early stage cardiac remodelling in spontaneously hypertensive rats. AB - Previous studies have reported that decreased matrix metalloproteinase-2 (MMP-2) is associated with early stage (age 8-16 weeks) ventricular remodelling in spontaneously hypertensive rats (SHR). We hypothesized that inhibited CD147/MMP-2 signalling might down-regulate MMP-2 expression and augment remodelling in spontaneously hypertensive rats. Twenty-nine male SHR (8 weeks) were randomly assigned to SHR, CD147, and CD147+DOX groups. The control group included eight age-matched WKY rats. CD147 and CD147+DOX groups received recombinant human CD147 (600 ng/kg in 1.5 mL saline, weekly). The SHR and WKY groups received the vehicle. The CD147+DOX group also received doxycycline, an inhibitor of MMPs (daily, 30 mg/kg in 1.5 mL saline, iG). On day 56 echocardiography and left ventricular mass index (LVWI) measurements were collected and histological sections were stained for cell and collagen content. Myocardium MMP-2, TIMP-1, CD147, and collagens types I and III were estimated by western blot. CD147 and the ratio of MMP-2/TIMP-1 were lower in SHR than WKY rats (P<.05). Myocyte hypertrophy, partial fibre breaks, plasmolysis, necrosis and collagen content (collagen volume fraction [CVF], I and III) in SHR were above control levels (P<.05). CD147 rats showed CD147, MMP-2 and MMP-2/TIMP-1 were increased (P<.05), CVF, LVWI, and collagen I and III were decreased (P<.05) and myocyte morphology was improved. CD147 levels did not differ between CD147+DOX and CD147 groups, CVF, collagens type I and III and partial fiber breaks were more abundant in CD147+DOX (P<.05). In summary, an inhibited CD147/MMP-2 pathway was associated with early stage cardiac remodelling, and CD147 supplementation may attenuate this response. PMID- 27451962 TI - Electronegativity and redox reactions. AB - Using the maximum hardness principle, we show that the oxidation potential of a molecule increases as its electronegativity increases and also increases as its electronegativity in its oxidized state increases. This insight can be used to construct a linear free energy relation for the oxidation potential, which we train on a set of 31 organic redox couples and test on a set of 10 different redox reactions. Better results are obtained when the electronegativity of the oxidized/reduced reagents are adjusted to account for the reagents' interaction with their chemical environment. PMID- 27451963 TI - Molecular mechanism of (18)F-FDG uptake reduction induced by genipin in T47D cancer cell and role of uncoupling protein-2 in cancer cell glucose metabolism. AB - INTRODUCTION: Compounds that modulate cancer cell glucose metabolism could open new opportunities for antitumor therapy and for monitoring response using (18)F FDG PET. Genipin, a natural dietary compound that blocks uncoupling protein 2 (UCP2)-mediated mitochondrial proton leakage, is a potential anticancer agent. We investigated the effect of genipin on glucose metabolism and the mitochondrial function of cancer cells. METHODS: Breast and colon cancer cells were assessed for effects of genipin on (18)F-FDG uptake. T47D breast cancer cells were further evaluated for time-dependent and dose-dependent effects on (18)F-FDG uptake, lactate release, oxygen consumption rate (OCR), reactive oxygen species (ROS) production, and mitochondrial membrane potential. The effects of UCP2 knockdown were evaluated using specific siRNA. RESULTS: Cancer cells displayed significant reductions in (18)F-FDG uptake by genipin. T47D cells showed the greatest reduction to 32.6+/-1.0% of controls by 250MUM genipin. The effect occurred rapidly, reaching a plateau by 1h that lasted up to 24h. The effect was dose dependent with a half-inhibitory concentration of 60.8MUM. An accompanying decrease in lactate release was consistent with reduced glycolytic flux. OCR was significantly decreased by genipin to 82.2+/-11.4% of controls, and ROS generation was increased to 156.7+/-16.0%. These effects were largely reproduced by UCP2 knockdown with specific siRNA. CONCLUSIONS: Genipin decreased cancer cell (18)F-FDG uptake by reducing both glycolytic flux and mitochondrial oxidative respiration. This effect appeared to occur by blocking the ability of UCP2 to dissipate energy and restrict ROS production through proton leakage. PMID- 27451964 TI - Response to Dr. Gerald M Reaven: good news for patients with familial hypercholesterolaemia: statins are not diabetogenic in this disease. PMID- 27451965 TI - Deoxyribonucleic acid telomere length shortening can predict the incidence of non alcoholic fatty liver disease in patients with type 2 diabetes mellitus. AB - AIMS/INTRODUCTION: To investigate the effect of telomere shortening and other predictive factors of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus patients in a 6-year prospective cohort study. MATERIALS AND METHODS: A total of 70 type 2 diabetes mellitus (mean age 57.8 +/- 6.7 years) patients without NAFLD were included in the study, and 64 of them were successfully followed up 6 years later, excluding four cases with significant alcohol consumption. NAFLD was diagnosed by the hepatorenal ratio obtained by a quantitative ultrasound method using NIH image analysis software. The 39 individuals that developed NAFLD were allocated to group A, and the 21 individuals that did not develop NAFLD were allocated to group B. Fluorescent real-time quantitative polymerase chain reaction was used to measure telomere length. RESULTS: There was no significant difference between the two groups in baseline telomere length; however, at the end of the 6th year, telomere length had become shorter in group A compared with group B. There were significant differences between these two groups in baseline body mass index, waistline, systolic blood pressure, glycated hemoglobin and fasting C-peptide level. In addition, the estimated indices of baseline insulin resistance increased in group A. Fasting insulin level, body mass index, systolic blood pressure at baseline and the shortening of telomere length were independent risk factors of NAFLD in type 2 diabetes mellitus patients. CONCLUSIONS: Telomere length became shorter in type 2 diabetes mellitus patients who developed NAFLD over the course of 6 years. Type 2 diabetes mellitus patients who developed NAFLD had more serious insulin resistance compared with those who did not develop NAFLD a long time ago. PMID- 27451966 TI - Calorie Labeling in Chain Restaurants and Body Weight: Evidence from New York. AB - This study analyzes the impact of local mandatory calorie labeling laws implemented by New York jurisdictions on body weight. The analysis indicates that on average the point-of-purchase provision of calorie information on chain restaurant menus reduced body mass index (BMI) by 1.5% and lowered the risk of obesity by 12%. Quantile regression results indicate that calorie labeling has similar impacts across the BMI distribution. An analysis of heterogeneity suggests that calorie labeling has a larger impact on the body weight of lower income individuals, especially lower income minorities. The estimated impacts of calorie labeling on physical activity, smoking, and the consumption of alcoholic beverages, fruits, and vegetables are small in magnitude, which suggests that other margins of adjustment drive the body-weight impacts estimated here. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27451967 TI - The prognostic value of fluorodeoxyglucose positron emission tomography metabolic tumor volume in solitary colorectal liver metastasis. AB - BACKGROUND: Management of colorectal liver metastasis (CRLM) is evolving but surgery remains the most effective treatment in improving survival. Optimal preoperative patient selection is important and semiquantitative F-18 fluorodeoxyglucose positron emission tomography (PET) parameters may provide valuable prognostic information. METHODS: Sixty-one patients with solitary CRLM as first site of distant dissemination and preoperatively staged with PET were retrospectively studied. Various semiquantitative PET parameters, pathological size of the hepatic lesion and clinical variables were correlated with survival outcome. The data were analyzed with nonparametric Kruskal-Wallis test and univariate Cox regression. Kaplan-Meier estimates of overall survival and disease free survival (DFS) were log-rank tested. RESULTS: Mean follow-up for the 61 subjects was 48 months. The 1- and 3-year survival rates were 98.7% and 72.2%. The median DFS was 16 months with recurrence in 10 (16.4%) patients following surgery. Univariate analysis found a statistically significant increased risk of death for higher mean PET tumor diameter (hazard ratio [HR] 2.95, P = 0.014), mean metabolic tumor volume (HR 3.0, P = 0.009) and median pathological size of hepatic lesion (HR 2.97, P = 0.022). Maximum standardized uptake value of the liver metastasis and calculated standardized uptake value ratio between tumor and normal liver parenchyma (tumor background ratio) were not predictive of overall survival. None of the PET parameters or clincopathological variables statistically correlated with DFS. CONCLUSION: Semiquantitative PET variables are potentially valuable prognostic biomarkers in CRLM. Volumetric data like metabolic tumor volume enable better estimation of tumor burden and its utility may improve preoperative risk stratification and optimize outcome. PMID- 27451969 TI - Optimizing the electric field around solid and core-shell alloy nanostructures for near-field applications. AB - The near electric field enhancement around plasmonic nanoparticles (NPs) is very important for applications like surface enhanced spectroscopies, plasmonic dye sensitized solar cells and plasmon-enhanced OLEDs, where the interactions occur close to the surface of the NPs. In this work we have calculated the near-field enhancement around solid and core-shell alloy NPs as a function of their geometrical parameters and composition. We have found that the field enhancement is lower in the AuxAg1-x alloys with respect to pure Ag NPs, but it is still high enough for most near-field applications. The higher order modes have a stronger influence over the near-field due to a sharper spatial decay of the near electric field with the increase of the order of multipolar modes. For the same reason, in AuxAg1-x@SiO2 core-shell structures, the quadrupolar mode is dominant around the core, whereas the dipolar mode is predominant around the shell. The LSPR modes can have different behaviours in the near- and the far-field, particularly for larger particles with high Ag contents, which indicates that caution must be exercised for designing plasmonic nanostructures for near-field applications, as the variations of the LSPR in the near-field cannot be inferred from those observed in the far-field. These results have important implications for the application of gold-silver alloy NPs in surface enhanced spectroscopies and in the fabrication of plasmon-based optoelectronic devices, like dye-sensitized solar cells and plasmon-enhanced organic light-emitting diodes. PMID- 27451968 TI - Impact of State Reporting Laws on Central Line-Associated Bloodstream Infection Rates in U.S. Adult Intensive Care Units. AB - OBJECTIVE: To examine the effect of mandated state health care-associated infection (HAI) reporting laws on central line-associated bloodstream infection (CLABSI) rates in adult intensive care units (ICUs). DATA SOURCES: We analyzed 2006-2012 adult ICU CLABSI and hospital annual survey data from the National Healthcare Safety Network. The final analytic sample included 244 hospitals, 947 hospital years, 475 ICUs, 1,902 ICU years, and 16,996 ICU months. STUDY DESIGN: We used a quasi-experimental study design to identify the effect of state mandatory reporting laws. Several secondary models were conducted to explore potential explanations for the plausible effects of HAI laws. PRINCIPAL FINDINGS: Controlling for the overall time trend, ICUs in states with laws had lower CLABSI rates beginning approximately 6 months prior to the law's effective date (incidence rate ratio = 0.66; p < .001); this effect persisted for more than 6 1/2 years after the law's effective date. These findings were robust in secondary models and are likely to be attributed to changes in central line usage and/or resources dedicated to infection control. CONCLUSIONS: Our results provide valuable evidence that state reporting requirements for HAIs improved care. Additional studies are needed to further explore why and how mandatory HAI reporting laws decreased CLABSI rates. PMID- 27451970 TI - Investigation of Rotavirus with Various Methods in Children with Acute Gastroenteritis and Determination of Its Molecular Epidemiology in Kayseri Province, Turkey. AB - BACKGROUND: In this study, the fresh stool samples from 254 children under 5 years of age with acute gastroenteritis which were delivered between October 2012 and December 2013 were collected. METHODS: In the stool samples, rotavirus antigens were investigated using two different immunochromatographic methods which are routinely used at different times, namely the RIDA(r) QUICK Rotavirus/Adenovirus Combi Test (R-Biopharm AG, Germany) and the Genx(r) Rotavirus Test (Diamed-Lab, Turkey), in addition to the Rotavirus Ag (Stool) ELISA (DRG, Germany) kit. The results were compared with reverse transcriptase PCR (RT-PCR). RESULTS: When the Genx(r) Rotavirus Test and RIDA(r) QUICK Rotavirus/Adenovirus Combi Test immunochromatographic methods were compared with RT-PCR, their sensitivity and specificity were found as 97.1%, 100%, and 80.4%, 72%, respectively. As to the Rotavirus Ag (Stool) ELISA method, on the other hand, its sensitivity was found to be 95.1% and its specificity was 86.5%. The most common genotype was G9P[8] (40%), which was followed by the G1P[8] (18.7%) and G3P[8] (9.6%) genotypes. CONCLUSION: Consequently, it was revealed that the sensitivity of ELISA and immunochromatographic methods, which provide results in a short time and are used in the investigation of rotavirus antigen, was high and their specificity was low; further studies to determine the distribution of G and P genotypes will contribute to establishing strategies for vaccine development for rotavirus in the world. PMID- 27451971 TI - Hepatic Overexpression of Hemopexin Inhibits Inflammation and Vascular Stasis in Murine Models of Sickle Cell Disease. AB - Sickle cell disease (SCD) patients have low serum hemopexin (Hpx) levels due to chronic hemolysis. We hypothesize that in SCD mice, hepatic overexpression of hemopexin will scavenge the proximal mediator of vascular activation, heme, and will inhibit inflammation and microvascular stasis. To examine the protective role of Hpx in SCD, we transplanted bone marrow from NY1DD SCD mice into HpxTM/TM or Hpx+/+ C57BL/6 mice. Dorsal skin fold chambers were implanted in week 13 post transplant and microvascular stasis (% non-flowing venules) evaluated in response to heme infusion. HpxTM/TM sickle mice had significantly greater microvascular stasis in response to heme infusion than Hpx+/+ sickle mice (p<0.05), demonstrating the protective effect of Hpx in SCD. We utilized Sleeping Beauty (SB) transposon-mediated gene transfer to overexpress wild-type rat Hpx (wt-Hpx) in NY1DD and Townes-SS SCD mice. Control SCD mice were treated with lactated Ringer's solution (LRS) or a luciferase (Luc) plasmid. Plasma and hepatic Hpx were significantly increased compared to LRS and Luc controls. Microvascular stasis in response to heme infusion in NY1DD and Townes-SS mice overexpressing wt Hpx had significantly less stasis than controls (p<0.05). Wt-Hpx overexpression markedly increased hepatic nuclear Nrf2 expression, HO-1 activity and protein, the heme-Hpx binding protein and scavenger receptor, CD91/LRP1 and decreased NF kappaB activation. Two missense (ms)-Hpx SB-constructs that bound neither heme nor the Hpx receptor, CD91/LRP1, did not prevent heme-induced stasis. In conclusion, increasing Hpx levels in transgenic sickle mice via gene transfer activates the Nrf2/HO-1 anti-oxidant axis and ameliorates inflammation and vaso occlusion. PMID- 27451972 TI - Supporting same-sex mothers in the Nordic child health field: a systematic literature review and meta-synthesis of the most gender equal countries. AB - AIMS AND OBJECTIVES: To explore the needs of and support given to lesbian, gay, bisexual, transgendered and inter-sex parents within the Nordic child health field. BACKGROUND: The number of lesbian, gay, bisexual, transgendered and inter sex parents is growing around the world. However, they face fear, discrimination and heteronormativity within the child health field. The Nordic countries (Sweden, Norway, Denmark, Finland and Iceland) rank as the most gender equal countries in the world; therefore, they may support lesbian, gay, bisexual, transgendered and inter-sex parents to a greater extent. DESIGN: Systematic literature review and meta-synthesis. METHOD: A systematic search was conducted for lesbian, gay, bisexual, transgendered and inter-sex parents' experiences in the child health field, which consists of prenatal, labour and birth, postnatal and child health clinics, using PubMed, PsychInfo, Sociological Abstracts and CINAHL, as well as searching the grey literature, from 2000-2015. Ten articles were included. A quality assessment and a meta-synthesis of the articles were performed. RESULTS: Nearly all studies were qualitative, and most articles had at least one area of insufficient reporting. Only two countries, Sweden and Norway, had lesbian, gay, bisexual, transgendered and inter-sex parents reporting on the child health field. However, gay, bisexual, transgender and inter-sex parents' perspectives were nonexistent in the literature; therefore, the results all relate to same-sex mothers. Five themes were found: Acceptance of Same-sex Mothers, Disclosing Sexual Orientation, Heteronormative Obstacles, Co-mothers are Not Fathers, and Being the Other Parent. CONCLUSIONS: Same-sex mothers are generally accepted within the Nordic child health field, but they still face overt and covert heteronormative obstacles, resulting in forms of discrimination and fear. Co-mothers feel invisible and secondary if they are not treated like an equal parent, but feel noticed and important when they are given equal support. RELEVANCE TO CLINICAL PRACTICE: Changes at the organisational and personnel levels can be made to better support same-sex mothers and co-mothers. Recognising both parents benefits the whole family. PMID- 27451973 TI - A novel slug-containing negative-feedback loop regulates SCF/c-Kit-mediated hematopoietic stem cell self-renewal. AB - The stem cell factor (SCF)/c-Kit pathway has crucial roles in controlling hematopoietic stem cell (HSC) renewal. However, little is known about the intracellular regulation of the SCF/c-Kit pathway in HSCs. We report here that Slug, a zinc-finger transcription repressor, functions as a direct transcriptional repressor of c-Kit in HSCs. Conversely, SCF/c-Kit signaling positively regulates Slug through downstream c-Myc and FoxM1 transcription factors. Intriguingly, c-Kit expression is induced by SCF/c-Kit signaling in Slug deficient HSCs. The balance between Slug and c-Kit is critical for maintaining HSC repopulating potential in vivo. Together, our studies demonstrate that Slug functions in a novel negative-feedback regulatory loop in the SCF/c-Kit signaling pathway in HSCs. PMID- 27451974 TI - Concurrent PI3K and NF-kappaB activation drives B-cell lymphomagenesis. PMID- 27451976 TI - The prognostic significance of trisomy 4 in acute myeloid leukaemia is dependent on age and additional abnormalities. PMID- 27451975 TI - Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1. AB - As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from chronic myeloid leukemia and acute myeloid leukemia patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (reverse transcriptase polymerase chain reaction) and protein level (fluorescence-activated cell sorting), and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPK), and protein kinase B (PKB/AKT). We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells, and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (for example, as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK-HO-1 dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating cell migration-mediated expansion of leukemia/lymphoma cells when the ComC becomes activated. PMID- 27451977 TI - Standardization of molecular monitoring for chronic myeloid leukemia in Latin America using locally produced secondary cellular calibrators. PMID- 27451979 TI - Thermodynamics of the multi-stage self-assembly of pH-sensitive gradient copolymers in aqueous solutions. AB - The self-assembly thermodynamics of pH-sensitive di-block and tri-block gradient copolymers of acrylic acid and styrene was studied for the first time using isothermal titration calorimetry (ITC) and dynamic light scattering (DLS) performed at varying pH. We were able to monitor each step of micellization as a function of decreasing pH. The growth of micelles is a multi-stage process that is pH dependent with several exothermic and endothermic components. The first step of protonation of the acrylic acid monomer units was accompanied mainly by conformational changes and the beginning of self-assembly. In the second stage of self-assembly, the micelles become larger and the number of micelles becomes smaller. While solution acidity increases, the isothermal calorimetry data show a broad deep minimum corresponding to an exothermic process attributed to an increase in the size of hydrophobic domains and an increase in the structure's hydrophobicity. The minor change in heat capacity (DeltaCp) confirms the structural changes during this exothermic process. The exothermic process terminates deionization of acrylic acid. The pH-dependence of the zeta-potential of the block gradient copolymer micelles exhibits a plateau in the regime corresponding to the pH-controlled variation of the micellar dimensions. The onset of micelle formation and the solubility of the gradient copolymers were found to be dependent on the length of the gradient block. PMID- 27451978 TI - Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. AB - Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence=6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting >72 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P=0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P=5.8 * 10-7; odds ratio (OR)=6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P=0.015) and had lower risk of AAP-related complications (15% vs 43%; P=0.13) compared with cases without this variant. Among 45 cases and 517 controls <10 years, the strongest associations with AAP were found for RGS6 variant rs17179470 (P=9.8 * 10-9; OR=7.3). Rs281366 is located in the ULK2 gene involved in autophagy, and RGS6 regulates G-protein signaling regulating cell dynamics. More than 50% of AAP cases <10 years carried one or both risk alleles. PMID- 27451981 TI - Decelerating and Trapping Large Polar Molecules. AB - Manipulating the motion of large polyatomic molecules, such as benzonitrile (C6 H5 CN), presents significant difficulties compared to the manipulation of diatomic molecules. Although recent impressive results have demonstrated manipulation, trapping, and cooling of molecules as large as CH3 F, no general technique for trapping such molecules has been demonstrated, and cold neutral molecules larger than 5 atoms have not been trapped (M. Zeppenfeld, B. G. U. Englert, R. Glockner, A. Prehn, M. Mielenz, C. Sommer, L. D. van Buuren, M. Motsch, G. Rempe, Nature 2012, 491, 570-573). In particular, extending Stark deceleration and electrostatic trapping to such species remains challenging. Here, we propose to combine a novel "asymmetric doublet state" Stark decelerator with recently demonstrated slow, cold, buffer-gas-cooled beams of closed-shell volatile molecules to realize a general system for decelerating and trapping samples of a broad range of volatile neutral polar prolate asymmetric top molecules. The technique is applicable to most stable volatile molecules in the 100-500 AMU range, and would be capable of producing trapped samples in a single rotational state and at a motional temperature of hundreds of mK. Such samples would immediately allow for spectroscopy of unprecedented resolution, and extensions would allow for further cooling and direct observation of slow intramolecular processes such as vibrational relaxation and Hertz-level tunneling dynamics. PMID- 27451980 TI - Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies. AB - Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib >= 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies. PMID- 27451982 TI - Effect of aeration and agitation on extractive fermentation of clavulanic acid by using aqueous two-phase system. AB - In this work, the effects of agitation and aeration rates on aqueous two-phase system (ATPS)-based extractive fermentation of clavulanic acid (CA) by Streptomyces variabilis DAUFPE 3060 were investigated through a 22 full factorial design, where oxygen transfer rate (OTR) and oxygen uptake rate (OUR) were selected as the responses. Aeration rates significantly influenced cell growth, OUR, and CA yield, while OTR was practically the same in all the runs. Under the intermediate agitation (950 rpm) and aeration conditions (3.5 vvm) of the central point runs, it was achieved OTR of 1.617 +/- 0.049 mmol L-1 h-1 , OUR of 0.132 +/- 0.030 mmol L-1 h-1 , maximum CA production of 434 +/- 4 mg L-1 , oxygen mass transfer coefficient of 33.40 +/- 2.01 s-1 , partition coefficient of 66.5 +/- 1.5, CA yield in the top and bottom phases of 75% +/- 2% and 19% +/- 1%, respectively, mass balance of 95% +/- 4% and purification factor of 3.8 +/- 0.1. These results not only confirmed the paramount role of O2 supply, broth composition and operational conditions in CA ATPS-extractive fermentation, but also demonstrated the possibility of effectively using this technology as a cheap tool to simultaneously produce and recover CA. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1444-1452, 2016. PMID- 27451983 TI - Healthy and unhealthy dietary patterns are related to pre-diabetes: a case control study. AB - Pre-diabetes increases the risk of diabetes and CVD. Several studies have investigated the relationship between food intake and pre-diabetes morbidity, but the dietary patterns of pre-diabetes subjects were not taken into consideration. The aim of this study was to determine the relationship between dietary patterns and pre-diabetes. In this regard, 150 pre-diabetic subjects and 150 healthy controls, who attended the diabetes screening centre in Shahreza, Iran, were matched for age group and sex. The weight, height, waist circumference, physical activity, systolic and diastolic blood pressures, and blood glucose levels of all participants were measured. Dietary information was collected using a semi quantitative FFQ. Using factor analysis, two dietary patterns were identified: the vegetables, fruits and legumes (VFL) dietary pattern and the sweet, solid fat, meat and mayonnaise (SSMM) dietary pattern. Multivariate logistic regression was used to assess the relationship between pre-diabetes and dietary patterns. After adjusting for age, education, physical activity, BMI and energy intake, the VFL dietary pattern was found to be negatively associated with lower pre-diabetes (OR 0.16; 95 % CI 0.10, 0.26). Furthermore, the SSMM dietary pattern was positively associated with pre-diabetes (OR 5.45; 95 % CI 3.22, 9.23). In conclusion, the VFL dietary pattern is inversely related to pre-diabetes, whereas the SSMM dietary pattern is associated with increased risk of pre-diabetes. PMID- 27451984 TI - The influence of funding models on collaboration in Australian general practice. AB - Despite more nurses working in Australian general practice, there has been limited investigation exploring ways that general practitioners and registered nurses work together to deliver clinical care. However, it has been postulated that the small business structure, common in Australian general practices, might influence collaboration between these two groups of health professionals. This paper presents one theme from a larger qualitative study. Eight general practitioners and fourteen registered nurses working in general practice participated in semistructured face-to-face interviews between February and May 2015. Naturalistic inquiry was adopted to elicit and explore the narrative accounts of participants about working together in general practice. An inductive process of thematic analysis was used to identify, analyse and report patterns and themes. Ancillary costs associated with the employment of registered nurses in general practice and the time registered nurses took to undertake procedural services were a concern for general practitioners. Registered nurses did not always work to their full scope of practice and many felt that their expertise was not appropriately remunerated. Findings suggested that fee for service funding models can negatively influence collaboration between general practitioners and registered nurses working in general practice. PMID- 27451985 TI - Ecological characteristics and in situ genetic associations for yield-component traits of wild Miscanthus from eastern Russia. AB - BACKGROUND AND AIMS: Miscanthus is a genus of perennial C4 grasses native to East Asia. It includes the emerging ligno-cellulosic biomass crop M. *giganteus, a hybrid between M. sinensis and M. sacchariflorus Biomass yield and cold tolerance are of particular interest in Miscanthus, given that this crop is more temperate adapted than its C4 relatives maize, sorghum and sugarcane. METHODS: A plant exploration was conducted in eastern Russia, at the northern extreme of the native range for Miscanthus, with collections including 174 clonal germplasm accessions (160 M. sacchariflorus and 14 M. sinensis) from 47 sites. Accessions were genotyped by restriction site-associated DNA sequencing (RAD-seq) and plastid microsatellites. KEY RESULTS: Miscanthus sinensis was found in maritime climates near Vladivostok (43.6 degrees N) and on southern Sakhalin Island (46.6 degrees N). Miscanthus sacchariflorus was found inland at latitudes as high as 49.3 degrees N, where M. sinensis was absent. Most M. sacchariflorus accessions were diploid, but approx. 2 % were tetraploids. Molecular markers revealed little population structure (Jost's D < 0.007 among diploid groups) but high genetic diversity (expected heterozygosity = 0.14) within the collection of Russian M. sacchariflorus Genome-wide association (GWA) analysis for traits measured at the collection sites revealed three M. sacchariflorus single nucleotide polymorphisms (SNPs) significantly associated with the number of stems per unit area, one with height and one with basal stem diameter; three were near or within previously described sorghum quantitative trait loci for related traits. CONCLUSIONS: This new Miscanthus germplasm collection from eastern Russia will be useful for breeding Miscanthus and sugarcane cultivars with improved adaptation to cold. Moreover, a strategy is proposed to facilitate the rapid utilization of new germplasm collections: by implementing low-cost SNP genotyping to conduct GWA studies of phenotypic data obtained at collection sites, plant breeders can be provided with actionable information on which accessions have desirable traits and alleles. PMID- 27451986 TI - Circadian rhythm of a Silene species favours nocturnal pollination and constrains diurnal visitation. AB - BACKGROUND AND AIMS: Traits related to flower advertisement and reward sometimes vary in a circadian way, reflecting phenotypic specialization. However, specialized flowers are not necessarily restricted to specialized pollinators. This is the case of most Silene species, typically associated with diurnal or nocturnal syndromes of pollination but usually showing complex suites of pollinators. METHODS: A Silene species with mixed floral features between diurnal and nocturnal syndromes was used to test how petal opening, nectar production, scent emission and pollination success correlate in a circadian rhythm, and whether this is influenced by environmental conditions. The effect of diurnal and nocturnal visitation rates on plant reproductive success is also explored in three populations, including the effect of the pollinating seed predator Hadena sancta KEY RESULTS: The result showed that repeated petal opening at dusk was correlated with nectar secretion and higher scent production during the night. However, depending on environmental conditions, petals remain opened for a while in the morning, when nectar and pollen still were available. Pollen deposition was similarly effective at night and in the morning, but less effective in the afternoon. These results were consistent with field studies. CONCLUSIONS: The circadian rhythm regulating floral attractiveness and reward in S. colorata is predominantly adapted to nocturnal flower visitors. However, favourable environmental conditions lengthen the optimal daily period of flower attraction and pollination towards morning. This allows the complementarity of day and night pollination. Diurnal pollination may help to compensate the plant reproductive success when nocturnal pollinators are scarce and when the net outcome of H. sancta shifts from mutualism to parasitism. These results suggest a functional mechanism explaining why the supposed nocturnal syndrome of many Silene species does not successfully predict their pollinator guilds. PMID- 27451987 TI - Plant family identity distinguishes patterns of carbon and nitrogen stable isotope abundance and nitrogen concentration in mycoheterotrophic plants associated with ectomycorrhizal fungi. AB - BACKGROUND AND AIMS: Mycoheterotrophy entails plants meeting all or a portion of their carbon (C) demands via symbiotic interactions with root-inhabiting mycorrhizal fungi. Ecophysiological traits of mycoheterotrophs, such as their C stable isotope abundances, strongly correlate with the degree of species' dependency on fungal C gains relative to C gains via photosynthesis. Less explored is the relationship between plant evolutionary history and mycoheterotrophic plant ecophysiology. We hypothesized that the C and nitrogen (N) stable isotope compositions, and N concentrations of fully and partially mycoheterotrophic species differentiate them from autotrophs, and that plant family identity would be an additional and significant explanatory factor for differences in these traits among species. We focused on mycoheterotrophic species that associate with ectomycorrhizal fungi from plant families Ericaceae and Orchidaceae. METHODS: Published and unpublished data were compiled on the N concentrations, C and N stable isotope abundances (delta(13)C and delta(15)N) of fully (n = 18) and partially (n = 22) mycoheterotrophic species from each plant family as well as corresponding autotrophic reference species (n = 156). These data were used to calculate site-independent C and N stable isotope enrichment factors (epsilon). Then we tested for differences in N concentration, (13)C and (15)N enrichment among plant families and trophic strategies. KEY RESULTS: We found that in addition to differentiating partially and fully mycoheterotrophic species from each other and from autotrophs, C and N stable isotope enrichment also differentiates plant species based on familial identity. Differences in N concentrations clustered at the plant family level rather than the degree of dependency on mycoheterotrophy. CONCLUSIONS: We posit that differences in stable isotope composition and N concentrations are related to plant family-specific physiological interactions with fungi and their environments. PMID- 27451994 TI - Annexins A2 and A8 in endothelial cell exocytosis and the control of vascular homeostasis. AB - Blood vessel homeostasis is controlled by a variety of regulatory circuits that involve both the vessel-lining endothelial cells as well as the circulating blood cells and products thereof. One important feature is the control exerted by endothelial cells through regulated exocytosis of factors affecting blood coagulation and local inflammatory processes. These factors include two important adhesion proteins: the leukocyte receptor P-selectin and the pro-coagulant von Willebrand factor (VWF) that binds platelets and is involved in the formation of a platelet plug at sites of blood vessel injury. Failure to correctly produce and secrete P-selectin and VWF leads to pathologies such as von Willebrand disease, the most common inherited bleeding disorder. P-selectin and VWF are stored in unique secretory granules, the Weibel-Palade bodies (WPB), that undergo a complex maturation process and are acutely secreted following endothelial stimulation, e.g. in the course of inflammation or following blood vessel injury. Two annexins have been shown to be involved in different aspects of WPB biology: annexin A8 is required for proper WPB maturation and annexin A2 participates in late steps of WPB exocytosis. Thus, by affecting the stimulated release of P-selectin and VWF from endothelial cells, annexins fulfil important functions in the control of vascular homeostasis and could be considered as targets for influencing P selectin- and VWF-dependent processes/pathologies. PMID- 27451995 TI - The power, pitfalls and potential of the nanodisc system for NMR-based studies. AB - The choice of a suitable membrane mimicking environment is of fundamental importance for the characterization of structure and function of membrane proteins. In this respect, usage of the lipid bilayer nanodisc technology provides a unique potential for nuclear magnetic resonance (NMR)-based studies. This review summarizes the recent advances in this field, focusing on (i) the strengths of the system, (ii) the bottlenecks that may be faced, and (iii) promising capabilities that may be explored in future studies. PMID- 27451996 TI - Medical student attitudes towards complementary and alternative medicine (CAM) in medical education: a critical review. AB - Background This paper aims to remedy a gap in the knowledge by presenting the first critical review of the literature on major themes relating to medical students perceptions and attitudes towards the exponentially growing field of complementary and alternative medicine (CAM). MethodsAfter a comprehensive database search of the literature, 21 papers were chosen as suitable for the review. The results from these papers were tabled and discussed. ResultsThe results indicated that medical students lacked knowledge of CAM and are generally positive towards CAM education (especially in the preclinical years, if it provided evidence of efficacy and post-placement). Medical students thought that CAM should generally be incorporated into the medical curriculum mainly so they can confidently undertake referral to CAM practitioners. Being able to communicate with future patients about their CAM use was a major motivation for medical students to learn about CAM and a factor for medical student support of further incorporation of CAM content in the medical curricula. Educational exposure to CAM in many forms and in many papers was shown to significantly affect medical student attitudes to CAM. This may be reflective of the fact that, outside direct CAM training, there may be limited accessible opportunities for medical students and if integration is to occur, educational exposure is most important. ConclusionsThe rise of CAM as a social and clinical phenomenon necessitates consideration of further inclusion of these topics in the medical curriculum, if future physicians are to be able to fully discharge their role as care providers in an increasingly medically pluralistic world. However, the inclusion of CAM needs to be done in an objective and critical manner, which is relevant to the learner. PMID- 27451997 TI - DLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa, in type-2 diabetes mellitus patients inadequately controlled by metformin and other oral antidiabetic agents. AB - BackgroundDLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa, has preclinically demonstrated its beneficial effects on glucose and lipid metabolism through the upregulation of insulin-signal transduction. This study evaluated the clinical efficacy of an add-on therapy with DLBS3233 in type-2 diabetes mellitus subjects inadequately controlled by metformin and other oral antidiabetes. MethodsThis was an open and prospective clinical study for 12 weeks of therapy, involving type-2 diabetes mellitus patients who had been treated with two oral antidiabetic agents for at least 3 months prior to screening, yet, with HbA1c level was still beyond 7.0 %. DLBS3233 was given orally at the dose of 100 mg once daily in addition to their baseline oral antidiabetes medication. The primary end point was the reduction of HbA1c level; and the secondary end points were changes of fasting and 1-h postprandial glucose, homeostatic model assessment-insulin resistance, adiponectin, and lipid profile, from their respective baseline. Results After 12 weeks of treatment, the HbA1c level was reduced by 0.65+/-1.58 % (p=0.001) from baseline (9.67+/-2.11 %); while the 1-h-PG level was reduced by -1.45+/-3.89 mmol/L (p=0.021) from baseline (15.29+/-4.49 mmol/L). Insulin sensitivity, lipid profile and adiponectin level were improved to a considerable extent. DLBS3233 did not adversely affect body weight, liver, and renal function. Most adverse events observed were tolerably mild and they all had been resolved by the end of the study. ConclusionsThe add on oral antidiabetes therapy with DLBS3233 at the dose of 100 mg once daily helped type-2 diabetes mellitus patients to improve their glycemic control, enhance insulin sensitivity, lipid profile, and adiponectin level. In addition, DLBS3233 treatment concomitantly with other oral antidiabetic agents was proven safe and tolerable in type-2 diabetes subjects. PMID- 27451998 TI - Enhanced Acquisition Rates of 'Candidatus Liberibacter asiaticus' by the Asian Citrus Psyllid (Hemiptera: Liviidae) in the Presence of Vegetative Flush Growth in Citrus. AB - The Asian citrus psyllid preferentially feeds and exclusively reproduces on young, newly emerged flush shoots of citrus. Asian citrus psyllid nymphs feed and complete their life stages on these flush shoots. Recent studies conducted under greenhouse conditions have shown that the transmission rates of 'Candidatus Liberibacter asiaticus' (CLas), the putative causal agent of huanglongbing disease of citrus, are enhanced when flush shoots are present. However, it is unclear if CLas acquisition by migrant adult Asian citrus psyllids is similarly enhanced. To address this knowledge gap, cohorts of Asian citrus psyllid adults were allowed 1-wk acquisition access period (AAP) on flushing and nonflushing shoots of qPCR-tested symptomatic (CLas+) and asymptomatic (CLas-) 10-yr-old sweet orange trees under field conditions. After the AAP, they were tested for CLas by qPCR. Progeny Asian citrus psyllid adults that emerged 4 wk post-AAP were similarly retrieved and tested. Eighty percent of flushing and 30% of nonflushing CLas+ trees produced infective Asian citrus psyllid adults, indicating that flush shoots have greater potential to be inoculum sources for CLas acquisition. Concomitantly, 21.1% and 6.0% infective adults were retrieved, respectively, from flushing and nonflushing CLas+ trees, indicating that Asian citrus psyllid adults acquire CLas more efficiently from flush shoots relative to mature shoots. In addition, 12.1% of infective Asian citrus psyllid adult progeny were obtained from 70% of flushing CLas+ trees. Significantly lower mean Ct values were also obtained from infective adults retrieved from flushing relative to nonflushing trees. The results underscore the role of flush shoots in CLas acquisition and the need to protect citrus trees from Asian citrus psyllid infestations during flush cycles. PMID- 27451999 TI - Time-Mortality Relationships to Control Tyrophagus putrescentiae (Sarcoptiformes: Acaridae) Exposed to High and Low Temperatures. AB - Tyrophagus putrescentiae (Schrank) (Sarcoptiformes: Acaridae) is a widely distributed pest species that is of significant economic importance for dry-cured country hams. Methyl bromide was used for decades in country ham plants to control this pest, but now this fumigant is recognized as an atmospheric ozone depleting compound and will be phased out for all uses in the near future. Of various chemical and nonchemical alternatives to methyl bromide, extreme temperatures are viable and straightforward nonchemical methods to control pests. This study evaluated the efficacy of high and low temperatures on mortality of mold mite in the laboratory. Ten eggs and a mixture of 40 adults and nymphs were separately exposed to different high and low temperatures, ranging from +35 to 45 degrees C and from -20 to +5 degrees C, for several periods of time. Mortality was assessed after a recovery period for each life stage. Tyrophagus putrescentiae eggs were found to be more tolerant to both high and low temperatures than were the mobile stages. Results showed that high temperatures from 40-45 degrees C killed all mites within 4 to 1 d, respectively, while -10 degrees C or lower killed all mites in less than 1 d. Regression analyses of mortality data as a function of exposure predicted times for achieving desired levels of mite mortality. This study suggests that extreme temperature treatment can play an important role in integrated pest management programs for dry-cured ham as an alternative to methyl bromide or other chemical treatments. PMID- 27452000 TI - Estimating E-Race European Corn Borer (Lepidoptera: Crambidae) Adult Activity in Snap Bean Fields Based on Corn Planting Intensity and Their Activity in Corn in New York Agroecosystems. AB - European corn borer, Ostrinia nubilalis (Hubner), is a major pest of processing snap bean because larvae are contaminants in pods. The incidence of O. nubilalis contaminated beans has become uncommon in New York, possibly because widespread adoption of Bt field corn has suppressed populations. Snap bean fields located where Bt corn has been intensively grown in space and time may be at lower risk for O. nubilalis than fields located where Bt corn is not common. To manage O. nubilalis infestation risk, growers determine insecticide application frequency in snap bean based on pheromone-trapping information in nearby sweet corn fields; adult activity is presumed equivalent in both crops. Our goal was to determine if corn planting intensity and adult activity in sweet corn could be used to estimate O. nubilalis populations in snap bean in New York in 2014-2015. Numbers of O nubilalis adults captured in pheromone-baited traps located in snap bean fields where corn was and was not intensively grown were similar, suggesting that O. nubilalis does not respond to local levels of Bt corn in the landscape. Numbers of Ostrinia nubilalis captured in pheromone-baited traps placed by snap bean fields and proximal sweet corn fields were not related, indicating that snap bean growers should no longer make control decisions based on adult activity in sweet corn. Our results also suggest that the risk of O. nubilalis infestations in snap bean is low (~80% of the traps caught zero moths) and insecticide applications targeting this pest should be reduced or eliminated. PMID- 27452001 TI - Mapping Global Potential Risk of Establishment of Rhagoletis pomonella (Diptera: Tephritidae) Using MaxEnt and CLIMEX Niche Models. AB - The apple maggot, Rhagoletis pomonella (Walsh) (Diptera: Tephritidae), is a major quarantine pest of apples (Malus domestica Borkhausen) in the United States. Apple maggot is found only in North America and negatively impacts the apple industry in the western United States by reducing grower access to export markets. To reduce the threat of apple maggot to export countries and to facilitate the movement of commercial apples, an assessment of potential risk of establishment of apple maggot is needed to predict which regions are suitable or unsuitable for the fly. We used a correlative niche model MaxEnt and a mechanistic model CLIMEX to model global potential risk of establishment of apple maggot. The MaxEnt model was developed by integrating apple maggot occurrences with global climatic variables. Apple (a major host of apple maggot) climatic suitability was used as an additional variable to include species interactions in the MaxEnt model. The CLIMEX model was developed using published apple maggot physiological tolerance thresholds. Both the MaxEnt and CLIMEX models correctly predicted the known distribution of apple maggot in North America, met biological expectations when projected to the world, and mostly agreed on climatic suitability worldwide for the fly. Degree-days at 6.7 degrees C, elevation, precipitation seasonality, and apple climatic suitability were the most important predictors associated with apple maggot distribution in North America. Our results can be used to make science-based international trade decisions by policy makers, and for monitoring apple maggot potential introductions in countries where it currently does not occur. PMID- 27452002 TI - Response to: 'Pharmacokinetic/pharmacodynamic properties and efficacy/safety of U 500R from randomized clinical studies'. PMID- 27452004 TI - American College of Surgeons: Southern California Chapter Neurosurgical Section. PMID- 27452003 TI - Interpretation of serological tests in the diagnosis of celiac disease: Anti deamidated gliadin peptide antibodies revisited. AB - Algorithms for celiac disease diagnosis provided by guidelines are based primarily on anti-tissue transglutaminase 2 (TG2) antibodies and/or anti endomysium antibodies. The place of anti-deamidated gliadin peptide (DGP) antibodies is less well established. This study was designed to assess the clinical relevance of anti-DGP antibodies. Two thousand and twenty-six consecutive unselected patients systematically tested for anti-TG2, endomysium, gliadin, DGP antibodies and IgA dosage were investigated. The serological interpretation was assessed by analyzing the medical records of patients. From the 1984 newly investigated patients suspected of celiac disease, 10% had at least one celiac marker. Anti-TG2, anti-endomysium, anti-gliadin and anti-DGP antibodies were found in 1.1%, 0.6%, 6.8% and 4.1% of cases respectively, with different combinations. The diagnosis of celiac disease was retained in 0.45% of patients. When using the duodenal biopsies as a gold standard, analysis of the anti-DGP diagnosis performance showed that the specificity and the predictive positive value (PPV) were lower than that of the anti-TG2 assay. The combined detection of anti-TG2 and anti-DGP antibodies had a lower PPV than that of anti TG2 and anti-endomysium antibodies (p = 0.04). When analyzing the contribution of anti-DGP antibodies as an additional marker to both anti-TG2 and anti-endomysium antibodies, the PPV of the three associated antibodies was shown to be significantly lower than the PPV of the both anti-TG2 and anti-endomysium antibodies (p = 0.04). As a conclusion, anti-DGP antibodies may not have the diagnosis value required as an additional screening test to anti-TG2 antibodies for identifying celiac disease patients in medical centers where anti-endomysium detection is available. PMID- 27452005 TI - The Eighth International Symposium on Microsurgical Anastomoses for Cerebral Ischaemia: Florence, Italy, 14-17 September, 1986. PMID- 27452007 TI - Editor's notes. PMID- 27452009 TI - Scanning sports. PMID- 27452013 TI - Coming in sportsmedicine. PMID- 27452012 TI - High School Kids: Looking Better, Living Worse? PMID- 27452014 TI - Sportsmedicine forum. PMID- 27452016 TI - Heel Pain in Recreational Runners. AB - In brief: Recreational runners are prone to a variety of lower extremity injuries; one of the most common is pain in the heel and sole of the foot. Among the most frequent problems are plantar fasciitis, Achilles tendinitis, and calcaneal stress fractures. Management may be challenging, since an underlying biomechanical problem often must be corrected in addition to treatment of symptoms. The authors describe the signs, symptoms, and management of heel pain and include several exercises to prevent it. PMID- 27452017 TI - Medical Concerns Among Wheelchair Road Racers. AB - In brief: Before participating in the 1987 Peachtree Road Race in Atlanta, 43 wheelchair athletes completed a questionnaire about their training methods, injuries, and medical concerns. The injuries reported most frequently were abrasions and musculoskeletal syndromes of the upper extremities. Of particular interest in the study were the types of residual neurologic deficits and autonomic dysfunction among athletes with spinal cord injury. These deficits included altered temperature regulatory mechanisms, neurogenic bladder and bowel, spasticity, and autonomic dysreflexia. Athletes also reported the medications they used; several medications used frequently by this group of athletes may have an adverse effect on performance. PMID- 27452018 TI - ECG Monitoring in Cardiac Rehabilitation: Is It Needed? AB - In brief: The need for expert supervision in cardiac rehabilitation exercise programs is generally accepted, but the use of ECG monitoring as a safety measure in such programs is controversial. No randomized controlled studies of monitoring vs supervision alone have been performed. Consequently, there is no uniform approach to the role of ECG monitoring in cardiac exercise programs. In addition, considerable expense for labor and equipment would be required to monitor all participants continuously for the duration of a program, which typically lasts 12 weeks. The data indicate that administrators of such a program would spend approximately $1 million on ECG monitoring over eight years in the hope of preventing one serious cardiac event. PMID- 27452019 TI - Physiologic Responses to Treadmill and Water Running. AB - In brief: The physiologic responses to running on a treadmill and to running in water while wearing a buoyant vest were compared in seven uninjured runners. Ventilation, oxygen uptake, and respiratory quotient were significantly higher during treadmill running, whereas heart rate and perceived exertion were not significantly different for the two forms of exercise. Water running elicited a 36% lower metabolic cost than treadmill running despite the athletes' efforts to maintain a similar level of exertion. The results suggest that water running may help lessen the rate of deconditioning of injured athletes who must suspend their regular forms of exercise, but they fail to show that the metabolic cost of water running is significantly greater than that of treadmill running. PMID- 27452020 TI - Women in the Military Academies: US Navy (Part 1 of 3). AB - In brief: Women were admitted to the US Naval Academy in Annapolis, Maryland, a little more than a decade ago. To compensate for differences between men and women, some modifications were made in the physical training program, which originally had been designed for men. For example, the personal defense requirement includes judo, boxing, and wrestling for men and judo, hand-to-hand defense, and fencing for women; all these activities are believed to develop poise, fortitude, and combat strategy. The authors point out that athletic women have more success than nonathletes at the academy, probably because athletes tend to possess the stamina, strength, and self-discipline required to survive the academy's tough, uncompromising physical environment. PMID- 27452021 TI - Sports Injury to the Larynx and Trachea. AB - In brief: Athletes in contact sports frequently sustain trauma to the upper aerodigestive system. However, because of the slow progression and/or lack of symptoms relating to injuries of the larynx and associated structures, an early diagnosis is often not made. Complications may follow shortly after such injuries or later, so athletes, coaches, and team physicians should have a working knowledge of the pathophysiology of these injuries. This article discusses the anatomy of this part of the body, as well as the diagnosis and treatment of injuries to the larynx and upper aerodigestive system. Principles of treatment of upper airway trauma in general and of specific injuries are also addressed. PMID- 27452022 TI - Arthritis and Aerobic Exercise: A Review. AB - In brief: Despite increasing evidence that regular aerobic exercise yields many benefits for patients with arthritis, patients often are advised to curtail physical activity. Findings from studies of patients with either rheumatoid arthritis or osteoarthritis who participated in an aerobic exercise program show that the subjects made significant gains in aerobic capacity, functional status, muscle strength, and other aspects of performance. In addition, they improved in subjective aspects that might have a positive impact on quality of life, including pain tolerance, joint pain, mood, and social activity. The authors discuss some questions that remain unanswered and present guidelines for physicians who wish to prescribe aerobic exercise for their arthritis patients. PMID- 27452023 TI - How I Manage Mallet Finger. AB - In brief: Mallet finger is common among athletes who play contact sports. This deformity results from the loss of extensor function of the distal interphalangeal joint. Most sports injuries of this type can be treated conservatively by splinting. Patients usually wear the splint for eight weeks or more; they must remove it to clean the finger every few days, making sure that the finger does not bend while the splint is off. Surgery should be reserved for deformities resulting from a fracture with a subluxated palmar fragment, and then only when conservative treatment has I failed. PMID- 27452024 TI - Cluster Headache Among Athletes. AB - A group of experts met to discuss a case from the University of California, San Diego, School of Medicine. This case conference is part of a series featuring a variety of sports medicine topics. PMID- 27452026 TI - King vs Arthritis: Advantage, King. AB - As a pro, Billie Jean King used a vigorous exercise program to help control arthritis in her knees. The results speak for themselves. PMID- 27452025 TI - Topical Analgesics: How Effective Are They? AB - Athletes may use topical analgesics to warm the muscles or to relieve exercise induced aches and pains. But researchers question how much these substances actually do what athletes think they do. PMID- 27452027 TI - Does Steroid Abuse Cause-or Excuse-Violence? AB - Some researchers claim that the psychiatric effects of steroid abuse, such as violent aggressiveness, pose a significant threat to society. Ironically, some lawyers see such abuse as opening the door to an insanity plea. PMID- 27452028 TI - Is Sports Medicine Hampered by Cost Containment? AB - Most sports medicine physicians are affected in some way by the multitude of HMOs and PPOs that have sprung up nationwide. Some have welcomed the patients and the assured payments these organizations bring. Others say these plans have interfered with medical care and have stunted innovation in sports medicine. PMID- 27452029 TI - Certification for Sports Physicians Gathers Momentum. AB - Several physician groups now offer tests for certificates of special qualification in sports medicine, and other groups are considering establishing such tests or are adding training programs. PMID- 27452032 TI - Strengthening the Gluteus Maximus. PMID- 27452030 TI - Is Fitness Reaching Only the Wealthy? AB - Poor Americans bear a disproportionately large burden of chronic disease, which researchers blame on health habits that wealthier Americans have abandoned. Many researchers are looking for ways to bring the health movement to those who now need it most. PMID- 27452033 TI - A novel Arg H52/Tyr H33 conservative motif in antibodies: A correlation between sequence of antibodies and antigen binding. AB - Antibodies are the family of proteins, which are responsible for antigen recognition. The computational modeling of interaction between an antigen and an antibody is very important when crystallographic structure is unavailable. In this research, we have discovered the correlation between the amino acid sequence of antibody and its specific binding characteristics on the example of the novel conservative binding motif, which consists of four residues: Arg H52, Tyr H33, Thr H59, and Glu H61. These residues are specifically oriented in the binding site and interact with each other in a specific manner. The residues of the binding motif are involved in interaction strictly with negatively charged groups of antigens, and form a binding complex. Mechanism of interaction and characteristics of the complex were also discovered. The results of this research can be used to increase the accuracy of computational antibody-antigen interaction modeling and for post-modeling quality control of the modeled structures. PMID- 27452034 TI - Enantioselective Total Synthesis of (+)-Psiguadial B. AB - The first enantioselective total synthesis of the cytotoxic natural product (+) psiguadial B is reported. Key features of the synthesis include (1) the enantioselective preparation of a key cyclobutane intermediate by a tandem Wolff rearrangement/asymmetric ketene addition, (2) a directed C(sp(3))-H alkenylation reaction to strategically forge the C1-C2 bond, and (3) a ring-closing metathesis to build the bridging bicyclo[4.3.1]decane terpene framework. PMID- 27452035 TI - On the Statistical Significance of Compressed Ratios in Isobaric Labeling: A Cross-Platform Comparison. AB - Isobaric labeling is gaining popularity in proteomics due to its multiplexing capacity. However, copeptide fragmentation introduces a bias that undermines its accuracy. Several strategies have been shown to partially and, in some cases, completely solve this issue. However, it is still not clear how ratio compression affects the ability to identify a protein's change of abundance as statistically significant. Here, by using the "two proteomes" approach (E. coli lysates with fixed 2.5 ratios in the presence or absence of human lysates acting as the background interference) and manipulating isolation width values, we were able to model isobaric data with different levels of accuracy and precision in three types of mass spectrometers: LTQ Orbitrap Velos, Impact, and Q Exactive. We determined the influence of these variables on the statistical significance of the distorted ratios and compared them to the ratios measured without impurities. Our results confirm previous findings1-4 regarding the importance of optimizing acquisition parameters in each instrument in order to minimize interference without compromising precision and identification. We also show that, under these experimental conditions, the inclusion of a second replicate increases statistical sensitivity 2-3-fold and counterbalances to a large extent the issue of ratio compression. PMID- 27452036 TI - Unprotected Amino Acids as Stable Radical Precursors for Heterocycle C-H Functionalization. AB - An efficient and general method for the C-H alkylation of heteroarenes using unprotected amino acids as stable alkyl radical precursors is reported. This one pot procedure is performed open to air under aqueous conditions and is effective for several natural and unnatural amino acids. Heterocycles of varying structure are suitably functionalized, and reactivity trends reflect the nucleophilic character of the radical species generated. PMID- 27452037 TI - Band Alignment Engineering at Cu2O/ZnO Heterointerfaces. AB - Energy band alignments at heterointerfaces play a crucial role in defining the functionality of semiconductor devices, yet the search for material combinations with suitable band alignments remains a challenge for numerous applications. In this work, we demonstrate how changes in deposition conditions can dramatically influence the functional properties of an interface, even within the same material system. The energy band alignment at the heterointerface between Cu2O and ZnO was studied using photoelectron spectroscopy with stepwise deposition of ZnO onto Cu2O and vice versa. A large variation of energy band alignment depending on the deposition conditions of the substrate and the film is observed, with valence band offsets in the range DeltaEVB = 1.45-2.7 eV. The variation of band alignment is accompanied by the occurrence or absence of band bending in either material. It can therefore be ascribed to a pinning of the Fermi level in ZnO and Cu2O, which can be traced back to oxygen vacancies in ZnO and to metallic precipitates in Cu2O. The intrinsic valence band offset for the interface, which is not modified by Fermi level pinning, is derived as DeltaEVB ~ 1.5 eV, being favorable for solar cell applications. PMID- 27452039 TI - Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis. AB - The classic toxicity of carbon tetrachloride (CCl4) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl4-induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl4 in liver fibrosis. Wistar rats were treated with CCl4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl4-treated group were significantly higher than that of CCl4-untreated group. CCl4-treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change >= 1.5, P < 0.05) and 1412 proteins (fold change >= 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl4 treatment. Therefore, the toxicological mechanisms of CCl4-induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl4 detoxication in the liver. PMID- 27452040 TI - Development of a multiplex MethyLight assay for the detection of DAPK1 and SOX1 methylation in epithelial ovarian cancer in a north Indian population. AB - Ovarian cancer is the fourth most common cancer in women worldwide. It is very heterogeneous at the clinical, histopathological and molecular levels and is caused by the accumulation of genetic and epigenetic changes in regulatory genes. More than 90% of ovarian cancers are epithelial in origin. Ovarian cancer is typically asymptomatic in its early stages, and, due to difficulties in early detection, most ovarian cancers are diagnosed at an advanced stage. The positive predictive value of CA-125, a routinely used serum protein marker, is < 30%; therefore, for effective screening, there is a need to develop a marker with high sensitivity for early detection. Development of blood-based biomarkers that detect DNA methylation in cell-free tumor-specific DNA is now being considered as a potential approach for the early diagnosis of cancer. Our objective in this study was to develop an absolute quantitative method, the MethyLight assay, to detect the promoter methylation status of two tumor suppressor genes. We analyzed the methylation level of the promoter regions of these genes in 42 tumor samples using the MethyLight assay. SOX1 promoter methylation was significantly higher in cancer samples than in normal samples (P = 0.011), whereas this difference between cancer and normal samples was not significant for DAPK1 promoter methylation (P = 0.18), when analyzed separately in a singleplex assay, whereas the detection frequency and significance level increased several-fold when these genes were analyzed together in a multiplex assay (P = 0.0004). The sensitivity was found to be 62% and 83% for DAPK1 and SOX1, respectively, when analyzed separately in the singleplex assay, but increased to 90% in the multiplex assay when either or both of the SOX1 and the DAPK1 gene promoters showed methylation. PMID- 27452038 TI - Tetramethylpyrazine Nitrone Improves Neurobehavioral Functions and Confers Neuroprotection on Rats with Traumatic Brain Injury. AB - Oxidative stress is one of the major secondary injury mechanisms after traumatic brain injury (TBI). 2-[[(1,1-Dimethylethyl)oxidoimino]-methyl]-3,5,6 trimethylpyrazine (TBN), a derivative of the clinically used anti-stroke drug tetramethylpyrazine armed with a powerful free radical-scavenging nitrone moiety, has been demonstrated promising therapeutic efficacy in ischemic stroke and Parkinson's models. The present study aims to investigate the effects of TBN on behavioral function and neuroprotection in rats subjected to TBI. TBN (90 mg/kg) was administered twice daily for 7 days by intravenous injection following TBI. TBN improved neuronal behavior functions after brain injury, including rotarod test and adhesive paper removal test. Compared with the TBI model group, TBN treatment significantly protected NeuN-positive neurons, while decreased glial fibrillary acidic protein (GFAP)-positive cells. The number of 4-hydroxynonenal (4-HNE)-positive and 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells around the damaged area after TBI were significantly decreased in the TBN treatment group. In addition, TBN effectively reversed the altered expression of Bcl-2, Bax and caspase 3, and the down-regulation of nuclear factor erythroid-derived 2-like 2 (Nrf-2) and hemeoxygenase-1 (HO-1) proteins expression stimulated by TBI. In conclusion, TBN improves neurobehavioral functions and protects neurons against TBI. This protective effect may be achieved by anti-neuronal apoptosis, alleviating oxidative stress damage and up-regulating Nrf-2 and HO-1 expression. PMID- 27452041 TI - AMAP: A pipeline for whole-genome mutation detection in Arabidopsis thaliana. AB - Detection of mutations at the whole-genome level is now possible by the use of high-throughput sequencing. However, determining mutations is a time-consuming process due to the number of false positives provided by mutation-detecting programs. AMAP (automated mutation analysis pipeline) was developed to overcome this issue. AMAP integrates a set of well-validated programs for mapping (BWA), removal of potential PCR duplicates (Picard), realignment (GATK) and detection of mutations (SAMtools, GATK, Pindel, BreakDancer and CNVnator). Thus, all types of mutations such as base substitution, deletion, insertion, translocation and chromosomal rearrangement can be detected by AMAP. In addition, AMAP automatically distinguishes false positives by comparing lists of candidate mutations in sequenced mutants. We tested AMAP by inputting already analyzed read data derived from three individual Arabidopsis thaliana mutants and confirmed that all true mutations were included in the list of candidate mutations. The result showed that the number of false positives was reduced to 12% of that obtained in a previous analysis that lacked a process of reducing false positives. Thus, AMAP will accelerate not only the analysis of mutation induction by individual mutagens but also the process of forward genetics. PMID- 27452042 TI - Inter- and intra-specific genetic divergence of Asian tiger frogs (genus Hoplobatrachus), with special reference to the population structure of H. tigerinus in Bangladesh. AB - The five frog species of the genus Hoplobatrachus are widely distributed in Asia and Africa, with Asia being considered the genus' origin. However, the evolutionary relationships of Asian Hoplobatrachus species remain ambiguous. Additionally, genetic diversity and fundamental differentiation processes within species have not been studied. We conducted molecular phylogenetic analysis on Asian Hoplobatrachus frogs and population genetic analysis on H. tigerinus in Bangladesh using the mitochondrial CYTB gene and 21 microsatellite markers. The resultant phylogenetic tree revealed monophyly in each species, notwithstanding the involvement of cryptic species in H. chinensis and H. tigerinus, which are evident from the higher genetic divergence between populations. Bayesian inference of population structure revealed genetic divergence between western and eastern H. tigerinus populations in Bangladesh, suggesting restricted gene flow caused by barriers posed by major rivers. However, genetic distances among populations were generally low. A discrete population is located in the low riverine delta region, which likely reflects long-distance dispersal. These results strongly suggest that the environment specific to this river system has maintained the population structure of H. tigerinus in this region. PMID- 27452043 TI - Hierarchical architecture of sponge spicules: biocatalytic and structure directing activity of silicatein proteins as model for bioinspired applications. AB - Since the first description of the silicateins, a group of enzymes that mediate the formation of the amorphous, hydrated biosilica of the skeleton of the siliceous sponges, much progress has been achieved in the understanding of this biomineralization process. These discoveries include, beside the proof of the enzymatic nature of the sponge biosilica formation, the dual property of the enzyme, to act both as a structure-forming and structure-guiding protein, and the demonstration that the initial product of silicatein is a soft, gel-like material that has to undergo a maturation process during which it achieves its favorable physical-chemical properties allowing the development of various technological or medical applications. This process comprises the hardening of the material by the removal of water and ions, its cast-molding to specific morphologies, as well as the fusion of the biosilica nanoparticles through a biosintering mechanism. The discovery that the enzymatically formed biosilica is morphogenetically active and printable also opens new applications in rapid prototyping and three-dimensional bioprinting of customized scaffolds/implants for biomedical use. PMID- 27452045 TI - Private prayer associations with depression, anxiety and other health conditions: an analytical review of clinical studies. AB - OBJECTIVES: To critically analyze appropriate clinical studies to assess the relationship between health conditions and the frequency of private prayer. Private prayer is defined as individuals praying for themselves. METHODS: Using PubMed and other search engines, we identified over 300 articles reporting relationships between prayer and health conditions. We identified 41 observational clinical studies that evaluated the relationship between private prayer and health conditions. Prayer scores of 5 to 1 were assigned to studies, with 5 being private prayer for health and 1 being prayer in combination with meditation or Bible study. Frequency scores ranged from 3 to 1 with 3 being twice daily or more and 0 when frequency was not assessed. Studies were ranked from 8 to 1 based on the sum of Prayer and Frequency Scores. RESULTS: Twenty-one studies had Prayer-Frequency scores of 5 to 8, indicating that they evaluated private prayer (praying for one's own health) of suitable frequency in association with health conditions. Nine of 11 studies indicated that private prayer was associated with a significantly lower prevalence of depression (P value, <0.01). Optimism as well as coping were significantly improved by prayer in four studies (P value, P < 0.01). In 10 studies of mental health conditions-including anxiety and confusion-there was a significant benefit associated with prayer (P < 0.01), In the reviewed studies, prayer did not have a significant effect on physical health or blood pressure. CONCLUSION: The reported observational studies suggest that frequent private prayer is associated with a significant benefit for depression, optimism, coping, and other mental health conditions such as anxiety. Controlled clinical trials are required to critically assess the associations of private prayer and health conditions. PMID- 27452046 TI - Run or Golf-Do Something. PMID- 27452044 TI - alpha-Linoleic acid enhances the capacity of alpha-1 antitrypsin to inhibit lipopolysaccharide induced IL-1beta in human blood neutrophils. AB - Alpha1-antitrypsin (A1AT, SERPINA1), a major circulating inhibitor of neutrophil elastase (NE) and proteinase-3 (PR3), has been proposed to reduce the processing and release of IL-1beta. Since the anti-inflammatory properties of A1AT are influenced by the presence of polyunsaturated fatty acids, we compared effects of fatty acid-free (A1AT-0) and alpha-linoleic acid bound (A1AT-LA) forms of A1AT on lipopolysaccharide (LPS)-induced synthesis of IL-1beta precursor and the release of IL-1beta from human blood neutrophils. The presence of A1AT-LA or A1AT-0 significantly reduced LPS induced release of mature IL-1beta. However, only A1AT LA reduced both steady state mRNA levels of IL-1beta and the secretion of mature IL-1beta. In LPS-stimulated neutrophils, mRNA levels of TLR2/4, NFKBIA, P2RX7, NLRP3, and CASP1 decreased significantly in the presence of A1AT-LA but not A1AT 0. A1AT-0 and A1AT-LA did not inhibit the direct enzymatic activity of caspase-1, but we observed complexes of either form of A1AT with NE and PR3. Consistent with the effect on TLR and IL-1beta gene expression, only A1AT-LA inhibited LPS induced gene expression of NE and PR3. Increased gene expression of PPAR-gamma was observed in A1AT-LA treated neutrophils without of LPS stimulation, and the selective PPAR-gamma antagonist (GW9662) prevented the reduction in IL-1beta by A1AT-LA. We conclude from our data, that the ability of A1AT to reduce TLR and IL 1beta gene expression depends on its association with LA. Moreover, the anti inflammatory properties of A1AT-LA are likely to be mediated by the activation of PPAR-gamma. PMID- 27452047 TI - Forum. AB - A Forum for Our Readers Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Forum, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27452048 TI - Wrap-ups. PMID- 27452049 TI - Fiber Facts. PMID- 27452051 TI - Scanning sports. AB - The following information was presented in July at the Family Physician in Sports Medicine meeting in Minneapolis sponsored by the American Academy of Family Physicians. PMID- 27452052 TI - QuikQuiz. PMID- 27452053 TI - Coming in sportsmedicine. PMID- 27452055 TI - Children, Sports, and Chronic Disease. AB - In brief Chronic disease afflicts several million children in the United States, many of whom face the additional burden of having their physical activities unnecessarily restricted. Yet sports and exercise can alleviate symptoms as well as improve a child's psychosocial development and quality of life. Physicians should consider prescribing exercise programs for children with cystic fibrosis, congenital heart disease, juvenile rheumatoid arthritis, and asthma. They should also strongly advocate these children's right to engage in whatever levels of physical activity will allow them to reach their potential. PMID- 27452056 TI - Sports-Related Nasal Injuries. AB - In brief Nasal injuries occur frequently in sports, but most are minor abrasions and contusions. Protective headgear has reduced but not eliminated more serious injuries, such as fractures. Nasal fractures can cause cumulative damage that is both functional and cosmetic. This is particularly significant during adolescence when the nose is growing. A thorough initial examination of the external and internal nose is important because many nasal injuries are underdiagnosed. When treatment of wounds or fractures is based on a sound understanding of the cartilaginous and bony structures of the nose, late complications and reoperation can be avoided. PMID- 27452057 TI - The Benefits of Walking the Golf Course. AB - In brief Leisure-time physical activity is associated with a decreased risk of coronary artery disease. This study evaluated the effect of walking the golf course on total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) levels, and the ratio of TC to HDL-C. Twenty-eight male golfers and 16 male nongolfing controls underwent lipoprotein analysis at the beginning and end of the golf season. The study demonstrates that golf lowers TC and LDL-C levels and improves risk ratios. PMID- 27452058 TI - Chronic Shoulder Pain in a Volleyball Player. AB - In brief A high school girl had pain in her right shoulder when she played volleyball. X-rays revealed the cause: diffuse multiple loose calcifications throughout the synovium of the shoulder. The calcifications were removed arthroscopically, and a partial synovectomy of the shoulder joint was performed. The patient's prognosis was considered fair because this disorder can recur; however, it sometimes resolves with no further problems. This disorder-synovial chrondomatosis-is especially rare in young athletes, occurring primarily in middle-aged men, with 60% of cases occurring in the knee. PMID- 27452060 TI - Shoulder Instability-A New Surgical Approach. AB - Orthopedists have long debated the best surgical treatment for shoulder instability. Now, new information about the inferior glenohumeral ligament complex has led to improved surgical results for both anterior and posterior instability. PMID- 27452059 TI - Sports and the Male Genitourinary System. AB - In brief Most injuries to the penis and scrotum in sports result from direct blows and require prompt evaluation. Bicycler's penis is a paresthesia and numbness in the perineum and phallus that resolve spontaneously. A direct blow to the scrotum usually causes a testicular contusion that responds to elevation of the scrotum and bed rest. Athletes wear athletic supporters and plastic cups for scrotal protection. Sexually transmitted diseases-nongonococcal urethritis, condyloma acuminatum, and herpes progenitalis-are common urologic problems in athletes. Patients should use condoms or abstain from sexual activity until the condition resolves. PMID- 27452061 TI - When a Knee Injury Became a Head Injury. PMID- 27452062 TI - The Winning Ways of Joe Paterno. AB - College football has changed dramatically during Joe Pater-no's 41-year tenure. One major difference is the role played by the team physician. PMID- 27452063 TI - Triathlons-Not Just for Ironmen. AB - Although they seem to call for inhuman strength and endurance, triathlons are not just for Ironmen: Women and seniors are also competitors in the event. But as the remarkably high completion rate of the Iron-man Triathlon World Championship would suggest, there may be something in the event itself that increases the likelihood of success. PMID- 27452065 TI - Flexibility for the Elbow and Forearm. PMID- 27452066 TI - 'Essential but not always available when needed' - an interview study of physicians' experiences and views regarding use of obstetric ultrasound in Tanzania. AB - BACKGROUND: The value of obstetric ultrasound in high-income countries has been extensively explored but evidence is still lacking regarding the role of obstetric ultrasound in low-income countries. OBJECTIVE: We aimed to explore experiences and views among physicians working in obstetric care in Tanzania, on the role of obstetric ultrasound in relation to clinical management. DESIGN: A qualitative study design was applied. Data were collected in 2015, through 16 individual interviews with physicians practicing in obstetric care at hospitals in an urban setting in Tanzania. Data were analyzed using qualitative content analysis. RESULTS: Use of obstetric ultrasound in the management of complicated pregnancy was much appreciated by participating physicians, although they expressed considerable concern about the lack of ultrasound equipment and staff able to conduct the examinations. These limitations were recognized as restricting physicians' ability to manage complications adequately during pregnancy and birth. Better availability of ultrasound was requested to improve obstetric management. Concerns were also raised regarding pregnant women's lack of knowledge and understanding of medical issues which could make counseling in relation to obstetric ultrasound difficult. Although the physicians perceived a positive attitude toward ultrasound among most pregnant women, occasionally they came across women who feared that ultrasound might harm the fetus. CONCLUSIONS: There seems to be a need to provide more physicians in antenatal care in Tanzania with ultrasound training to enable them to conduct obstetric ultrasound examinations and interpret the results themselves. Physicians also need to acquire adequate counseling skills as counseling can be especially challenging in this setting where many expectant parents have low levels of education. Providers of obstetric care and policy makers in Tanzania will need to take measures to ensure appropriate use of the scarce resources in the Tanzanian health care system and prevent the potential risk of overuse of ultrasound in pregnancy. PMID- 27452067 TI - [New insights of myositis-specific and -associated autoantibodies in juvenile and adult type myositis]. AB - Myositis, which means inflammation of the muscles, is a general term used for inflammatory myopathies. Myositis is a rare idiopathic autoimmune disease. It is believed that environmental factors such as virus, bacteria, parasites, direct injuries, drugs side effect can trigger the immune system of genetically susceptible individuals to act against muscle tissues. There are several types of myositis with the same systemic symptoms such as muscle weakness, fatigue, muscle pain and inflammation. These include dermatomyositis, juvenile dermatomyositis, inclusion-body myositis, polymyositis, orbital myositis and myositis ossificans. Juvenile and adult dermatomyositis are chronic, immune-mediated inflammatory myopathies characterized by progressive proximal muscle weakness and typical skin symptoms. The aim of the authors was to compare the symptoms, laboratory and serological findings and disease course in children and adult patients with idiopathic inflammatory myopathy. Early diagnosis and aggressive immunosuppressive treatment improve the mortality of these patients. Myositis specific autoantibodies have predictive and prognostic values regarding the associated overlap disease, response to treatment and disease course. The authors intend to lighten the clinical and pathogenetic significance of the new target autoantigens. Orv. Hetil., 2016, 157(29), 1179-1184. PMID- 27452068 TI - [Biological role of heterogeneous glycoprotein structures]. AB - Carbohydrate molecules connected mostly with covalent junctions to protein chains are called glycoproteins. These carbohydrate molecules are attached to the protein core in different qualities and order. When the protein core is connected with acidic components such as uronic acid or SO4 radicals, they are called proteoglycans. The currently used name "glycosaminoglycan" in this case is not entirely correct. In the living world polymannane structures occur, too. Glycoproteins do not only exceptionally hold acidic groups but they have neuraminic acid derivatives. Tissue, cellular and matrix structures, and mostly all serum "proteins" are mainly glycoproteins. In the everyday clinical practice glycoproteins are mentioned as proteins. Nevertheless, the inadequate use of the concept may cause errors in the attitudes, too. This paper aims to correct this notion, because the term of "glycobiology" has already been expanded to be an independent scientific field. The practical clinical consequences of recent knowledge in this field are also summarized including novel findings on glycoprotein structures and functions. The importance of the quantity of carbohydrates, and their structural arrangements are also presented. In short, significance of glycoprotein-carbohydrate structures, as well as their physiological and pathological roles are reviewed in order to introduce the field of "glycobiology". Orosomucoid and immunoglobulins are discussed separately. Orv. Hetil., 2016, 157(30), 1185-1192. PMID- 27452069 TI - [Neoadjuvant treatment as a limiting factor to rectal ultrasonography]. AB - INTRODUCTION: Rectal ultrasonography is a basic method for staging rectal cancer. Tissue changes after neoadjuvant treatment alter the accuracy of the method. AIM: The aim of the authors was to assess the accuracy of rectal ultrasonography after preoperative chemo-radiotherapy compared to the initial staging accuracy. METHOD: Rectal ultrasounds performed between 2006 and 2014 were assessed retrospectively. Ultrasonographic and pathological T and N stages were compared both in case of initial staging (control group) and re-staging. RESULTS: T staging was accurate in 70% in the control group and in 61% in re-staging. Rate of overstaging was 31% after neoadjuvant treatment. None of the ypT0 cases were identified. N staging accuracy was 64% in the control group and 61% in re-staging. CONCLUSIONS: Neoadjuvant treatment impairs the accuracy of rectal ultrasound. The role of re staging with rectal ultrasonography is debatable in the assessment of the efficacy of oncological treatment and surgical planning. Orv. Hetil., 2016, 157(30), 1193-1197. PMID- 27452070 TI - [Health behaviour of doctors]. AB - INTRODUCTION: Health behaviour involves maintaining, improving and restoration of health. AIM: The aim of the author was to assess correlations of health behaviour with age, gender, job type and overtime. METHOD: A quantitative cross-sectional study was conducted using an online questionnaire (N = 186). Data were analyzed with chi-square, Kolmogorov-Smirnov, Mann-Whitney and Kruskal-Wallis tests. RESULTS: Doctors working in in-patient care drink more coffee (p = 0.034) and energy drinks (p = 0.018); they eat undisturbed only on weekends at home (p = 0.032). Men consume more alcohol (p = 0.003), red meats (p<0.001) and hot meals (p = 0.018) and their daily fluid consumption exceeds 2 litres (p = 0.005); their body mass index values are higher compared to women (p<0.001; U = 2289.0). Doctors in primary care eat more hot meals (p = 0.005), and those under the age of 30 consume more crisps, fast food (p = 0.001) and energy drinks (p = 0.005), while they are more active (p = 0.010). CONCLUSIONS: Dietary habits of doctors are not ideal and their physical activity is diminished compared to international trends. Orv. Hetil., 2016, 157(30), 1198-1206. PMID- 27452071 TI - [Cerebral manifestations of thromboangiitis obliterans. Case report]. AB - Thromboangiits obliterans (Buerger's disease) is a non-atherosclerotic, segmental inflammatory and obliterative disease affecting small and medium sized arteries and veins. The etiology is still unknown, but it is in close relationship with tobacco use. Symptoms begin under the age of 45 years and the undulating course is typical. Patients usually present with acute and chronic ischemic or infectious acral lesions. Diagnosis is usually based on clinical and angiographic criteria and it is important to exclude autoimmune disease, thrombophilia, diabetes, and proximal embolic sources. Even though Buerger's disease most commonly involves the arteries of the extremities, the pathologic findings sometimes affect the cerebral, coronary and internal thoracic, renal and mesenteric arteries as well. The authors present the history of a patient with known Buerger's disease and acute ischemic stroke. Brain imaging detected acute and chronic ischemic lesions caused by middle cerebral non-atherosclerotic arteriopathy on the symptomatic side. Other etiology was excluded by detailed investigations. Orv. Hetil., 2016, 157(30), 1207-1211. PMID- 27452072 TI - [Pieces of personal records to the history of the 50-year-old Hungarian Society of Endocrinology and Metabolism]. PMID- 27452073 TI - [Miscellaneous]. PMID- 27452074 TI - Gold Nanoplate-Based 3D Hierarchical Microparticles: A Single Particle with High Surface-Enhanced Raman Scattering Enhancement. AB - Formation of intended nano- and microstructures with regular building blocks has attracted much attention because of their potential applications in the fields of optics, electronics, and catalysis. Herein, we report a novel strategy to spontaneously grow three-dimensional (3D) hierarchical cabbagelike microparticles (CLMPs) constructed by individual Au nanoplates. By reducing gold precursor to gold atoms, N-(3-amidino)-aniline (NAAN) itself was oxidized to form poly(N-(3 amidino)-aniline) (PNAAN), which specifically binds on Au(111) facet as a capping agent and which leads to the formation of gold nanoplates. Because of the incomplete coverage of Au(111) facet, new gold nanoplate growth sites were spontaneously generated from the crystal plane of existing Au nanoplates for the growth of other nanoplates. This process continued until the nanoplate density reached its maximum range, eventually resulting in CLMPs with well-controlled structures. This opens a new avenue to utilize the imperfection during nanoparticle (NP) growth for the construction of microstructures. The individual CLMP shows excellent surface-enhanced Raman scattering (SERS) performance with high enhancement factor (EF) and good reproducibility as it integrates the SERS enhancement effects of individual Au nanoplate and the nanogaps formed by the uniform and hierarchical structures. PMID- 27452075 TI - Highly Efficient Nondoped Organic Light Emitting Diodes Based on Thermally Activated Delayed Fluorescence Emitter with Quantum-Well Structure. AB - Highly efficiency nondoped thermally activated delayed fluorescence (TADF) organic light emitting diodes (OLEDs) with multiquantum wells structure were demonstrated. By using an emitting layer with seven quantum wells, the nondoped TADF OLEDs exhibit high efficiency with EQE of 22.6%, a current efficiency of 69 cd/A, and a power efficiency of 50 lm/W, which are higher than those of the conventional doped OLED and among the best of the TADF OLEDs. The high performance of the devices can be ascribed to effective confinement of the charges and excitons in the emission layer by the quantum well structure. The emission layer with multiquantum well structure is demonstrated to be cost effective for highly efficient nondoped TADF OLEDs and holds great potential for organic electronics. PMID- 27452076 TI - Effector Roles of Putidaredoxin on Cytochrome P450cam Conformational States. AB - In this study, the effector role of Pdx (putidaredoxin) on cytochrome P450cam conformation is refined by attaching two different spin labels, MTSL or BSL (bifunctional spin-label) onto the F or G helices and using DEER (double electron electron resonance) to measure the distance between labels. Recent EPR and crystallographic studies have observed that oxidized Pdx induces substrate-bound P450cam to change from the closed to the open state. However, this change was not observed by DEER in the reduced Pdx complex with carbon-monoxide-bound P450cam (Fe(2+)CO). In addition, recent NMR studies have failed to observe a change in P450cam conformation upon binding Pdx. Hence, resolving these issues is important for a full understanding the effector role of Pdx. Here we show that oxidized Pdx induces camphor-bound P450cam to shift from the closed to the open conformation when labeled on either the F or G helices with MTSL. BSL at these sites can either narrow the distance distribution widths dramatically or alter the extent of the conformational change. In addition, we report DEER spectra on a mixed oxidation state containing oxidized Pdx and ferrous CO-bound P450cam, showing that P450cam remains closed. This indicates that CO binding to the heme prevents P450cam from opening, overriding the influence exerted by Pdx binding. Finally, we report the open form P450cam crystal structure with substrate bound, which suggests that crystal packing effects may prevent conformational conversion. Using multiple labeling approaches, DEER provides a unique perspective to resolve how the conformation of P450cam depends on Pdx and ligand states. PMID- 27452077 TI - CORRIGENDUM: Silent Cerebral Ischemic Lesions After Catheter Ablation of Atrial Fibrillation in Patients on 5 Types of Periprocedural Oral Anticoagulation - Predictors of Diffusion-Weighted Imaging-Positive Lesions and Follow-up Magnetic Resonance Imaging. PMID- 27452080 TI - Risk factors and biomarkers for the recurrence of ovarian endometrioma: about the immunoreactivity of progesterone receptor isoform B and nuclear factor kappa B. AB - Ovarian endometrioma is one of the important causes of poor ovarian reserve and up to half of them have been recurred. However, the treatment for recurrence prevention has limited efficiency and repeated surgery makes worsen the ovarian reserve. To find better management for recurrence prevention, we investigated risk factors and biomarkers for the recurrent endometriomas. The medical records of women with history of surgical dissection for ovarian endometrioma were collected. After exclusion of the cases with concurrent hysterectomy, been menopaused during follow-up, incomplete medical record, and loss of follow-up, a total of 134 women were enrolled. Immunohistochemical staining for progesterone receptor isoform B (PR-B) and nuclear factor kappa B (NFkappaB) was done with the fixed tissue blocks of their endometriomas which were collected at the time of surgery. Severity of dysmenorrhea and co-existence of adenomyosis had significant correlation with recurrence of endometrioma. Serum CA-125 level at the time of recurrence was higher than the highest level of CA-125 during follow-up in non recurred group (55.6 versus 21.3 U/mL, p = 0.014). Increased PR-B (p = 0.041) and decreased NFkappaB (p = 0.036) immunoreactivity were found in recurrent group. However, to determine the possibility of immunoreactivity of PR-B and NFkappaB as biomarkers for recurrent endometrioma, further studies of various races and large numbers with prospective design are needed. PMID- 27452081 TI - A Case of Malignant PEComa of the Uterus Associated with Intramural Leiomyoma and Endometrial Carcinoma. AB - Perivascular epithelioid cell tumors (PEComas) refers to a family of mesenchymal neoplasms composed of angiomyolipomas, clear cell "sugar" tumors of the lung, and lymphangioleiomyomatoses. These tumors have a distinctive and common component of perivascular epithelioid cells that show an association with blood vessel walls and immunohistochemically display myomelanocytic differentiation. The unique neoplasms have been shown to have an expanded range through a variety of case reports, including visceral, intra-abdominal, soft tissue, and bone tumors. The retroperitoneum, abdominopelvic region, and uterus have been reported to be the most common sites. Most PEComas follow a benign course. However, reports of malignant PEComas are increasing. Many papers have described uterine PEComas, but to our knowledge, there have not yet been any reports of a malignant PEComa arising concomitant with another epithelial tumor and mesenchymal tumor. We report herein the case of a 67-year-old woman who experienced a malignant uterine PEComa infiltrating a preexisting intramural leiomyoma with synchronous well differentiated endometrial carcinoma and multiple liver and lung metastases. PMID- 27452082 TI - Survey on Disaster Relief Activities to the Pharmacists Belonging to Kobe-city Pharmaceutical Organization. AB - In 2014, there were about 160 thousands community pharmacists in Japan. Community pharmacists are health care workers who help victims in a disaster and are potential resources who can provide disaster relief. However, currently the disaster relief activities of community pharmacists are merely a resourceful and flexible demonstration of their professional abilities and not a specifically organized activity. Therefore, disaster relief education programs for community pharmacists are being explored and studies are still in the nascent stage. In this study, pharmacists of a pharmaceutical organization in Kobe City were asked to reply to a questionnaire survey so that their hopes and ideas about the disaster relief activities that they carry out can help build effective educational programs to enhance relief activities. Finally, 8 factors (cumulative contribution rate: 90.9%) were extracted by factor analysis (maximum likelihood method, the diagonal elements: squared multiple correlation, quartimin rotation) of the 25 questions. In addition, a hierarchical cluster analysis (Ward method) by the factor scores of the extracted 8 factors resulted in 7 groups. The findings revealed the groups into which the community pharmacists were divided and their hopes and ideas about disaster relief. We expect that these results could bring awareness about the disaster relief activities suitable for each community pharmacist, provide appropriate training opportunities for those who volunteer, and motivate daily studies and preparations for disaster relief activities among community pharmacists. PMID- 27452083 TI - Proteomics of hot-wet and cold-dry temperaments proposed in Iranian traditional medicine: a Network-based Study. AB - Lack of molecular biology evidence has led clinical success of alternative and complementary medicine (CAM) to be marginalized. In turn, a large portion of life Science researchers could not communicate and help to develop therapeutic potential laid in these therapeutic approaches. In this study, we began to quantify descriptive classification theory in one of the CAM branches i.e. Iranian traditional medicine (ITM). Using proteomic tools and network analysis, the expressed proteins and their relationships were studied in mitochondrial lysate isolated from PBMCs from two different temperaments i.e. Hot-wet (HW) and Cold-dry (CD). The 82% of the identified proteins are over- or under-represented in distinct temperaments. Also, our result showed the different protein-protein interaction networks (PPIN) represented in these two temperaments using centrality and module finding analysis. Following the gene ontology and pathway enrichment analysis, we have found enriched biological terms in each group which are in conformity with the physiologically known evidence in ITM. In conclusion, we argued that the network biology which naturally consider life at the system level along with the different omics data will pave the way toward explicit delineation of the CAM activities. PMID- 27452084 TI - Chemical Synthesis of the Galacturonic Acid Containing Pentasaccharide Antigen of the O-Specific Polysaccharide of Vibrio cholerae O139 and Its Five Fragments. AB - Three pentasaccharides, two tetrasaccharides, and a trisaccharide fragment of the O-specific antigen of Vibrio cholerae O139 were synthesized by applying 1 + 1, 2 + 1, 3 + 1, and 4 + 1 coupling strategies. The most challenging tasks involved were the synthesis of the 1,2-cis-glycosidic linkage between galactose and the linker (spacer) molecule and final purification of the target multicharged substances. Difficulties with final deprotection by hydrogenation/hydrogenolysis caused by the presence of galacturonic acid were overcome by protecting the acid with a group inert to the treatment with hydrogen. Some intermediates described previously as incompletely characterized amorphous materials were obtained in the crystalline condition and were fully characterized for the first time. PMID- 27452086 TI - QuikQuiz. PMID- 27452085 TI - Editor's notes. PMID- 27452087 TI - Scanning Sports. PMID- 27452088 TI - Wrap-up. PMID- 27452091 TI - Forum. AB - A Forum for Our Readers Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Forum, The Physician and Sportsmedicine, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27452093 TI - Nutrition and fitness. PMID- 27452094 TI - In my experience. PMID- 27452095 TI - Coming in sportsmedicine. PMID- 27452096 TI - Tennis Elbow: What's the Best Treatment? AB - In brief: Tennis elbow is not exclusively the bailiwick of tennis players. For example, pianists and anyone wielding a hammer are prone to the ailment. But regardless of the cause, the first step in treatment is to relieve pain and decrease inflammation. Then rehabilitation exercises can begin. Alterations in equipment and techniques that contribute to the problem are often key to recovery and prevention. PMID- 27452097 TI - Effort Thrombosis in a Runner. AB - In brief: Using hand weights during aerobic exercise has been recommended for increasing upper-body strength and calorie expenditure, but this practice can lead to a rare complication-effort thrombosis, as discussed in this case report. Physicians need to consider this complication when a runner complains of muscle strain. The patient history is important; physical examination should include arm measurement comparisons and neurologic, vascular, and musculoskeletal evaluations. PMID- 27452098 TI - Minimizing Corns and Calluses. AB - In brief: Calluses can be advantageous to some athletes but painful to others, while corns are characteristically painful. Corns and calluses, which may be confused with plantar warts, can be differentiated by gentle paring with a scalpel. This will reveal soft, granular, elongated mounds of dermis projecting up into the epidermis if the abnormality is a wart. Treatment of corns and calluses includes relieving the cause of pressure or friction. Properly fitting shoes and corn/callus pads can help prevent or minimize these common skin disorders. PMID- 27452099 TI - Can Regular Sports Participation Slow the Aging Process? Data on Masters Athletes. AB - In brief: Even moderate sports participation is associated with enhanced functional capacity, according to data collected on 554 men and 202 women who underwent maximal exercise testing during the 1985 World Masters Games in Toronto. Their training was modest relative to elite competitors. Nevertheless, their peak power output during cycle ergometry and peak oxygen intake were above the norm for nonathletes of the same age, resembling the values of sedentary 25 year-olds. Such gains have major implications for maintaining independence in the later years of life. Thus encouraging older people to increase their physical activity would seem an important public health measure. PMID- 27452101 TI - exercise adviser. PMID- 27452100 TI - Preparticipation Screening of College Athletes: Value of the Complete Blood Cell Count. AB - In brief: A retrospective study of 1,067 college athletes was done to determine the prevalence of certain abnormalities in their preseason complete blood cell count. The authors analyzed the values for white blood cell count, hemoglobin, mean corpuscular volume, and platelet count. In addition, they reviewed the literature to determine if an abnormality in any of these parameters alters athletic performance. Their conclusion: Only a hemoglobin level is useful in preseason evaluations. PMID- 27452102 TI - Common Concerns About the Common Cold. AB - Intense exercise may reduce healthy athletes' immunity or open the door to serious illness in athletes who already have a cold. Generally however, your patients can safely exercise with colds-and may even feel better-if some commonsense rules are followed. PMID- 27452103 TI - Stair Machines: The Truth About This Fitness Fad. AB - A person can burn an impressive amount of energy in a few minutes on a stair climbing machine, though there's nothing magical about this latest fitness craze. Observers say the same effect can come through such mundane tasks as ... well, climbing stairs. PMID- 27452104 TI - Parent-Infant Workouts: More Harm Than Help? AB - The fitness craze has spread far and wide, gathering new recruits of every age, size, and shape. But some physicians say its invasion into infancy is going a step too far. PMID- 27452105 TI - Exercise adviser. PMID- 27452107 TI - Mapping two-dimensional polar active fluids to two-dimensional soap and one dimensional sandblasting. AB - Active fluids and growing interfaces are two well-studied but very different non equilibrium systems. Each exhibits non-equilibrium behaviour distinct from that of their equilibrium counterparts. Here we demonstrate a surprising connection between these two: the ordered phase of incompressible polar active fluids in two spatial dimensions without momentum conservation, and growing one-dimensional interfaces (that is, the 1+1-dimensional Kardar-Parisi-Zhang equation), in fact belong to the same universality class. This universality class also includes two equilibrium systems: two-dimensional smectic liquid crystals, and a peculiar kind of constrained two-dimensional ferromagnet. We use these connections to show that two-dimensional incompressible flocks are robust against fluctuations, and exhibit universal long-ranged, anisotropic spatio-temporal correlations of those fluctuations. We also thereby determine the exact values of the anisotropy exponent zeta and the roughness exponents chix,y that characterize these correlations. PMID- 27452108 TI - Letter to the Editor: Disentangling cause and effect in the relationship between cannabis and psychosis: are we there yet? PMID- 27452110 TI - Evolutionary genetics: Knowing when to stop. PMID- 27452109 TI - Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis. AB - SIGNIFICANCE: Nonalcoholic fatty liver disease (NAFLD), characterized by liver triacylglycerol build-up, has been growing in the global world in concert with the raised prevalence of cardiometabolic disorders, including obesity, diabetes, and hyperlipemia. Redox imbalance has been suggested to be highly relevant to NAFLD pathogenesis. Recent Advances: As a major health problem, NAFLD progresses to the more severe nonalcoholic steatohepatitis (NASH) condition and predisposes susceptible individuals to liver and cardiovascular disease. Although NAFLD represents the predominant cause of chronic liver disorders, the mechanisms of its development and progression remain incompletely understood, even if various scientific groups ascribed them to the occurrence of insulin resistance, dyslipidemia, inflammation, and apoptosis. Nevertheless, oxidative stress (OxS) more and more appears as the most important pathological event during NAFLD development and the hallmark between simple steatosis and NASH manifestation. CRITICAL ISSUES: The purpose of this article is to summarize recent developments in the understanding of NAFLD, essentially focusing on OxS as a major pathogenetic mechanism. Various attempts to translate reactive oxygen species (ROS) scavenging by antioxidants into experimental and clinical studies have yielded mostly encouraging results. FUTURE DIRECTIONS: Although augmented concentrations of ROS and faulty antioxidant defense have been associated to NAFLD and related complications, mechanisms of action and proofs of principle should be highlighted to support the causative role of OxS and to translate its concept into the clinic. Antioxid. Redox Signal. 26, 519-541. PMID- 27452111 TI - Chromatin: Chromatin variation underLINEd. PMID- 27452113 TI - Plant genomics: 1001 genomes and epigenomes. PMID- 27452112 TI - Open questions in the study of de novo genes: what, how and why. AB - The study of de novo protein-coding genes is maturing from the ad hoc reporting of individual cases to the systematic analysis of extensive genomic data from several species. We identify three key challenges for this emerging field: understanding how best to identify de novo genes, how they arise and why they spread. We highlight the intellectual challenges of understanding how a de novo gene becomes integrated into pre-existing functions and becomes essential. We suggest that, as with protein sequence evolution, antagonistic co-evolution may be key to de novo gene evolution, particularly for new essential genes and new cancer-associated genes. PMID- 27452114 TI - Effect of Oxygen-deficiencies on Resistance Switching in Amorphous YFe0.5Cr0.5O3 d films. AB - Herein, we demonstrate the contribution of the oxygen-deficiencies on the bipolar resistance switching (RS) properties of amorphous-YFe0.5Cr0.5O3-d (a-YFCO) films. The a-YFCO films were prepared under various oxygen pressures to tune the concentration of oxygen-deficiencies in the films. The XPS data verify that the oxygen-deficiencies increase with decreasing oxygen pressure. The RS property becomes more pronounced with more oxygen-deficiencies in a-YFCO films. Based on the Ohmic conduction measurements in the low resistance state, we confirm that the RS mechanism is related to the migration of oxygen-deficiencies. The enhanced RS and long retention in a-YFCO suggest a great potential for applications in nonvolatile memory devices. PMID- 27452115 TI - Nano-Wilhelmy investigation of dynamic wetting properties of AFM tips through tip nanobubble interaction. AB - The dynamic wetting properties of atomic force microscopy (AFM) tips are of much concern in many AFM-related measurement, fabrication, and manipulation applications. In this study, the wetting properties of silicon and silicon nitride AFM tips are investigated through dynamic contact angle measurement using a nano-Wilhelmy balance based method. This is done by capillary force measurement during extension and retraction motion of AFM tips relative to interfacial nanobubbles. The working principle of the proposed method and mathematic models for dynamic contact angle measurement are presented. Geometric models of AFM tips were constructed using scanning electronic microscopy (SEM) images taken from different view directions. The detailed process of tip-nanobubble interaction was investigated using force-distance curves of AFM on nanobubbles. Several parameters including nanobubble height, adhesion and capillary force between tip and nanobubbles are extracted. The variation of these parameters was studied over nanobubble surfaces. The dynamic contact angles of the AFM tips were calculated from the capillary force measurements. The proposed method provides direct measurement of dynamic contact angles for AFM tips and can also be taken as a general approach for nanoscale dynamic wetting property investigation. PMID- 27452116 TI - Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers. AB - Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-alpha were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis. PMID- 27452117 TI - Lysine Acetylation and Succinylation in HeLa Cells and their Essential Roles in Response to UV-induced Stress. AB - Lysine acetylation and succinylation are major types of protein acylation that are important in many cellular processes including gene transcription, cellular metabolism, DNA damage response. Malfunctions in these post-translational modifications are associated with genome instability and disease in higher organisms. In this study, we used high-resolution nano liquid chromatography tandem mass spectrometry combined with affinity purification to quantify the dynamic changes of protein acetylation and succinylation in response to ultraviolet (UV)-induced cell stress. A total of 3345 acetylation sites in 1440 proteins and 567 succinylation sites in 246 proteins were identified, many of which have not been reported previously. Bioinformatics analysis revealed that these proteins are involved in many important biological processes, including cell signalling transduction, protein localization and cell metabolism. Crosstalk analysis between these two modifications indicated that modification switches might regulate protein function in response to UV-induced DNA damage. We further illustrated that FEN1 acetylation at different sites could lead to different cellular phenotypes, suggesting the multiple function involvement of FEN1 acetylation under DNA damage stress. These systematic analyses provided valuable resources and new insight into the potential role of lysine acetylation and succinylation under physiological and pathological conditions. PMID- 27452118 TI - One-Pot Synthesis of Hydrophilic and Hydrophobic N-Doped Graphene Quantum Dots via Exfoliating and Disintegrating Graphite Flakes. AB - Graphene quantum dots (GQDs) have drawn tremendous attention on account of their numerous alluring properties and a wide range of application potentials. Here, we report that hydrophilic and hydrophobic N-doped GQDs can be prepared via exfoliating and disintegrating graphite flakes. Various spectroscopic characterizations including TEM, AFM, FTIR, PL, XPS, and Raman spectroscopy demonstrated that the hydrophilic N-doped GQDs (IN-GQDs) and the hydrophobic N doped GQDs (ON-GQDs) are mono-layered and multi-layered, respectively. In terms of practical aspects, the supercapacitor of an ON-GQDs/SWCNTs composite paper electrode was fabricated and exhibited an areal capacitance of 114 mF/cm(2), which is more than 250% higher than the best reported value to date for a GQDs/carbon nanotube hybrid composite. For IN-GQDs applications, bio-memristor devices of IN-GQDs-albumen combination exhibited on/off current ratios in excess of 10(4) accompanied by stable switching endurance of over 250 cycles. The resistance stability of the high resistance state and the low resistance state could be maintained for over 10(4) s. Moreover, the IN-GQDs exhibited a superior quantum yield (34%), excellent stability of cellular imaging, and no cytotoxicity. Hence, the solution-based method for synchronized production of IN GQDs and ON-GQDs is a facile and processable route that will bring GQDs-based electronics and composites closer to actualization. PMID- 27452119 TI - Minimal short-term effect of dietary 2'-fucosyllactose on bacterial colonisation, intestinal function and necrotising enterocolitis in preterm pigs. AB - Human milk decreases the risk of necrotising enterocolitis (NEC), a severe gastrointestinal disease that occurs in 5-10 % of preterm infants. The prebiotic and immune-modulatory effects of milk oligosaccharides may contribute to this protection. Preterm pigs were used to test whether infant formula enriched with alpha1,2-fucosyllactose (2'-FL, the most abundant oligosaccharide in human milk) would benefit gut microbial colonisation and NEC resistance after preterm birth. Caesarean-delivered preterm pigs were fed formula (Controls, n 17) or formula with 5 g/l 2'-FL (2'-FL, n 16) for 5 d; eight 2'-FL pigs (50 %) and twelve Controls (71 %) developed NEC, with no difference in lesion scores (P=0.35); 2' FL pigs tended to have less anaerobic bacteria in caecal contents (P=0.22), but no difference in gut microbiota between groups were observed by fluorescence in situ hybridisation and 454 pyrosequencing. Abundant alpha1,2-fucose was detected in the intestine with no difference between groups, and intestinal structure (villus height, permeability) and digestive function (hexose absorption, brush border enzyme activities) were not affected by 2'-FL. Formula enrichment with 2' FL does not affect gut microbiology, digestive function or NEC sensitivity in pigs within the first few days after preterm birth. Milk 2'-FL may not be critical in the immediate postnatal period of preterm neonates when gut colonisation and intestinal immunity are still immature. PMID- 27452120 TI - Expression characteristics of sulfur dioxygenase and its function adaption to sulfide in echiuran worm Urechis unicinctus. AB - Animals living in coastal burrows are periodically exposed to the sulfide, a mixture of H2S, HS(-) and S(2-), during low tide. Mitochondrial sulfide oxidation is an important strategy that allows organisms to avoid injury from sulfide exposure, and sulfur dioxygenase (SDO) plays an essential role. In this study, we characterized the SDO expression and the total SDO-specific activity (T-SDO SA) in different organs of Urechis unicinctus, which inhabitU-shaped burrows in intertidal and subtidal mudflats. The SDO expressions at both mRNA and protein levels were highest in the anal sac, followed by the midgut, and were extraordinarily low in the body wall and hindgut; SDO was located mainly in the epithelial cells of all organs by immunohistochemistry. Moreover, the T-SDO SA was different in the detected organs, but with no significant differences and SDO SAs were strong positive correlation with GSH contents. Furthermore, we investigated the responses of the SDO in the midgut and hindgut of U. unicinctus during sulfide exposure. The SDO contents increased significantly at 48h and 72h, respectively, in both the midgut and hindgut when the worms were exposed to 50 and 150MUM sulfide. However, the T-SDO SA was no significantly different in the midgut except that at 72h for 150MUM sulfide treatment, meanwhile in the hindgut, the T-SDO SA increased significantly after 24h exposure for 50 and 150MUM sulfide treatments. We concluded that the hindgut plays more important role than the midgut in sulfide tolerance for U. unicinctus. PMID- 27452121 TI - Cry1Ab-expressing rice did not influence expression of fecundity-related genes in the wolf spider Pardosa pseudoannulata. AB - The impact of Bacillus thuringiensis (Bt) toxin proteins on non-target predatory arthropods is not well understood at the cellular and molecular levels. Here, we investigated the potential effects of Cry1Ab expressing rice on fecundity of the wolf spider, Pardosa pseudoannulata, and some of the underlying molecular mechanisms. The results indicated that brown planthoppers (BPHs) reared on Cry1Ab expressing rice accumulated the Cry toxin and that reproductive parameters (pre oviposition period, post-oviposition stage, number of eggs, and egg hatching rate) of the spiders that consumed BPHs reared on Bt rice were not different from those that consumed BPHs reared on the non-Bt control rice. The accumulated Cry1Ab did not influence several vitellin (Vt) parameters, including stored energy and amino acid composition, during one generation. We considered the possibility that the Cry toxins exert their influence on beneficial predators via more subtle effects detectable at the molecular level in terms of gene expression. This led us to transcriptome analysis to detect differentially expressed genes in the ovaries of spiders exposed to dietary Cry1Ab and their counterpart control spiders. Eight genes, associated with vitellogenesis, vitellogenin receptor activity, and vitellin membrane formation were not differentially expressed between ovaries from the treated and control spiders, confirmed by qPCR analysis. We infer that dietary Cry1Ab expressing rice does not influence fecundity, nor expression levels of Vt-associated genes in P. pseudoannulata. PMID- 27452122 TI - HGSNAT has a TATA-less promoter with multiple starts of transcription. AB - Acetyl-CoA:alpha-glucosaminide N-acetyltransferase (N-acetyltransferase) is a lysosomal membrane enzyme that catalyzes a key step in the lysosomal degradation of heparan sulfate. Its deficiency causes Sanfilippo syndrome type IIIC (Mucopolysaccharidosis type IIIC, MPS IIIC). Here we characterize the promoter region of HGSNAT, the gene encoding N-acetyltransferase, which is located in the pericentromeric region of chromosome 8. We show that HGSNAT transcription is driven by a TATA-less promoter whose key elements are contained within the 1054bp region upstream of exon 1. About 400 bases of the region's 3'-prime end overlap with an unmethylated CpG island. Reduced reporter activities from promoter serial deletion constructs suggested strong regulatory elements at positions -101 to 20bp and -1073 to -716bp of the downstream initiation codon (DS-ATG). Targeted mutagenesis of the first Specificity protein 1-A (Sp1-A) of the six in silico predicted Sp1 sites in the region flanking the major transcription start sites (TSSs, +50/-101) led to a 55% decrease of reporter activity, while inactivation of each of Sp1-B and Sp1-C resulted in its almost two-fold increase. The binding of Sp1 to the region was confirmed by chromatin immunoprecipitation (ChIP). Overall, this confirms that Sp1 is important for regulation of the HGSNAT promoter. Promoter fragments in antisense orientation (constructs pGL4 -20/-1305 and pGL4 +50/-1305) led to reporter activities of about 50% of the pGL4 -1305/-20 activity, implying divergent initiation of transcription at the promoter. We identified two main TSSs at positions +1 and -15 from DS-ATG using Rapid amplification of cDNA ends (5'RACE). Transcripts initiating at the TSSs thus contain only DS-ATG. Five patients from our MPS IIIC cohort (n=23) carried the rs4523300 promoter variant and one the rs149596192 promoter variant. Both variants lowered the expression of the reporter down to 68% and 59%, respectively. However, white blood cell (WBC) N-acetyltransferase activities in individuals carrying the variants did not significantly differ from homozygotes for the wild-type alleles, suggesting only a partial impact of transcriptional regulation on N-acetyltransferase activities in vivo. PMID- 27452123 TI - Spatial Resolution in Scanning Electron Microscopy and Scanning Transmission Electron Microscopy Without a Specimen Vacuum Chamber. AB - A long-standing goal of electron microscopy has been the high-resolution characterization of specimens in their native environment. However, electron optics require high vacuum to maintain an unscattered and focused probe, a challenge for specimens requiring atmospheric or liquid environments. Here, we use an electron-transparent window at the base of a scanning electron microscope's objective lens to separate column vacuum from the specimen, enabling imaging under ambient conditions, without a specimen vacuum chamber. We demonstrate in-air imaging of specimens at nanoscale resolution using backscattered scanning electron microscopy (airSEM) and scanning transmission electron microscopy. We explore resolution and contrast using Monte Carlo simulations and analytical models. We find that nanometer-scale resolution can be obtained at gas path lengths up to 400 MUm, although contrast drops with increasing gas path length. As the electron-transparent window scatters considerably more than gas at our operating conditions, we observe that the densities and thicknesses of the electron-transparent window are the dominant limiting factors for image contrast at lower operating voltages. By enabling a variety of detector configurations, the airSEM is applicable to a wide range of environmental experiments including the imaging of hydrated biological specimens and in situ chemical and electrochemical processes. PMID- 27452124 TI - Therapeutic developments for autoimmune demyelinating diseases: Musings from an MD (mouse doctor). AB - This paper is a summary of the lecture given by Dr. Racke at a meeting celebrating the 40th anniversary of the Neuroimmunology Branch (NIB). This talk was the keynote address given at the end of the first day of lectures after a toast given by Cedric Raine, Dale McFarlin's "brother from another mother". Several speakers during the day gave their own musings on the reasons for the success of the NIB, and this lecture attempted to give a sense to those present of the speaker's view for the reason of this success. PMID- 27452125 TI - Population-based trends in outcomes in adenoid cystic carcinoma of the oral cavity. AB - PURPOSE: Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm of secretory glands of the upper aerodigestive tract. It accounts for 3-5% of head and neck malignancies and most commonly arises from the minor salivary glands of the oral cavity. The clinical behavior of ACC from specific anatomic subsites, including the oral cavity, is not well described in the literature. We aim to elucidate patient demographics, clinicopathologic features, incidence, and survival trends for oral cavity ACC (OCACC). METHODS: Retrospective population based analysis of OCACC in the SEER database between 1973 and 2012. RESULTS: 1066 OCACC patients were identified, of which 57.7% were female (P<0.0001). Incidence was 0.049 per 100,000. Whites were most commonly affected (81.1%). The hard palate was the most commonly involved subsite (44.1%). Nodal involvement was seen in 8.4% of cases and distant metastasis was present in 6.2% of cases at the time of presentation. Disease-specific survival (DSS) rates at 1, 5, 10, 15, and 20years were 97.4%, 83.9%, 69.9%, 57.6%, and 46.2%, respectively. Females had a higher 5-year DSS (87.8%) than males (78.4%, P=0.0004). Cases treated with surgery had a favorable prognosis regardless of whether they received radiotherapy (P<0.0001). Nodal involvement reduced 5-year DSS by 51.6% (P<0.0001), while distant metastasis reduced 5-year DSS by 46.4% (P<0.0001). CONCLUSIONS: OCACC is a rare malignancy with females and whites being more commonly affected. At presentation, regional and distant metastases are uncommon. Poor prognostic indicators include male gender, nonsurgical therapy, nodal involvement, and distant metastasis. PMID- 27452126 TI - Terson's syndrome - Pathophysiologic considerations of an underestimated concomitant disease in aneurysmal subarachnoid hemorrhage. AB - Terson syndrome (TS) is a common and underestimated concomitant disease in patients suffering from subarachnoid hemorrhage (SAH). Aim of this study was to evaluate the influence of an initial unconsciousness and raised intracranial pressure (ICP) on the development of TS. We performed a retrospective analysis of 213 prospective collected SAH patients screened for TS to investigate the impact of an initial unconsciousness and raised ICP on the development of TS. A univariate analysis followed by a multivariate logistic regression model was performed to identify risk factors that are associated with TS. The findings are all discussed and correlated with the present pathophysiologic considerations of TS. The rate of TS in this study was 23.9%. A higher risk of TS in the univariate analysis was associated with a Glasgow Coma scale?7 (p=0.001), higher Hunt and Hess grade (p=0.001), Fisher grade IV (p=0.002), intracerebral hemorrhage (p=0.011), initial unconsciousness (p=0.013) and an ICP of ?25mmHg (p<0.001). An ICP of ?25mmHg was the only independent predictor for TS in the multivariate analysis (p=0.007). TS patients had a higher mortality (p=0.012) and a higher risk for a worse long-term outcome (p=0.002). Notable that 5 of 51 TS patients (9.8%) in this study developed TS with no raised ICP or initial unconsciousness. Terson syndrome is a common concomitant disease in SAH patients. The pathomechanism leading to TS is not exclusively related to raised ICP levels and/or unconsciousness. However, these factors may be associated with a high percentage of TS. PMID- 27452127 TI - Intravenous tissue plasminogen activator in acute branch atheromatous disease: Does it prevent early neurological deterioration? AB - Early neurological deterioration (END) and poor outcome frequently occur in lenticulostriate artery (LSA) infarction due to branch atheromatous disease (BAD). We evaluate whether the tissue plasminogen activator (tPA) can prevent END and improve the outcome by comparing with anti-platelet treatment in LSA infarction due to BAD. We enrolled the patients with LSA infarction due to BAD who arrived at the hospital within 24h from onset, and divided those into two groups by whether tPA was given or not. END and good outcome (modified Rankin score: 0-1) at 3months were examined between two groups. Consecutive 35 patients of LSA infarction due to BAD enrolled in this study. Nine patients were given tPA (tPA group) and 26 patients antiplatelets only (non-tPA group). Patients in tPA group showed no symptomatic hemorrhage. END occurred in 68.6% (24/35) of all patients, 66.7% (6/9) of tPA group and 69.2% (18/26) of non-tPA group (p=0.886). The proportion of good outcome at 3months were 25.7% in all patients, 22.2% (2/9) in tPA group and 26.9% (7/26) in non-tPA (p=0.781). tPA did not adequately prevent END, and did not show better outcome in LSA infarction due to BAD compared with antiplatelet therapy only. More effective treatment strategies are needed for prevention of END and favourable outcome in BAD. PMID- 27452128 TI - Glioblastoma multiforme targeted therapy: The Chlorotoxin story. AB - Glioblastoma multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival of <24months. Scorpion toxins are considered promising cancer drug candidates, primarily due to the discovery of hlorotoxin, derived from the venom of the Israeli yellow scorpion. This intriguing short peptide of only 36 amino-acids length and tight configuration, possess the ability to bind to GBM cells in a grade-related manner with ~100% of GBM cells staining positive and no cross reactivity to normal brain. Chlorotoxin has an anti-angiogenic effect as well. Molecular targets for Chlorotoxin include voltage gated chloride channels (GCC), calcium-dependent phospholipid-binding protein Annexin-2, and the inducible extracellular enzyme Matrix Metalloproteinase-2 (MMP-2). Of all its targets, MMP-2 seems to bear the most anti-neoplastic potential. Chlorotoxin is a promising tumortargeting peptide. Its small size and compact shape are convenient for intracranial delivery. We present a short discussion on Chlorotoxin. The structure, biological activity, molecular targets and possible clinical role of Chlorotoxin are discussed. Chlorotoxin can be utilized as a targeting domain as well, attaching different effector functions to it. Clinical applications in GBM therapy, intraoperative imaging, nano-probes and nano-vectors based technology; targeted chemotherapy and immunotherapy are discussed as well. Chlorotoxin is likely to play a significant role in effective GBM immunotherapy in the future. PMID- 27452129 TI - Quantitative analysis of brain edema in patients with malignant glioma treated with BCNU wafers. AB - BCNU wafers are a form of interstitial chemotherapy that is expected to improve the survival of patients with malignant glioma. However, their adverse events, especially brain edema, sometimes cause significant clinical symptoms. In this study, we performed a volumetric analysis of brain edema after the implantation of BCNU wafers and reported on the clinical course, and exacerbation factors of brain edema. Twelve patients who underwent surgical resection of supratentorial malignant glioma and BCNU wafer implantation, were enrolled. Radiographic quantitative analysis was conducted and compared with a historical control. The volume change in brain edema was divided into three groups and correlation with clinical symptoms was then evaluated. Compared with the control group, the brain edema in the BCNU wafer implantation group was significantly prolonged after surgery. Radiographic volumetric analysis revealed an increase of more than 25% at any time after surgery in four patients (33%) and a reduction of less than 25%, 1month after surgery in three patients (25%). Grade 3 clinical deterioration related to brain edema occurred in two patients and Grade 2 in one patient. Univariate analysis revealed that the radiographic deterioration of brain edema had no correlation with age, sex, diagnosis, tumor grade, preoperative volume of brain edema and tumor, residual tumor volume, or number of BCNU wafers. Radiographic quantitative analysis of brain edema indicated that BCNU wafer implantation may induce the prolongation and enlargement of brain edema with or without neurological deterioration. Brain edema may be controlled by intensive perioperative treatment with diuretics and corticosteroids. PMID- 27452130 TI - Biopsy proven pituitary sarcoidosis presenting as a possible adenoma. AB - Sarcoidosis is a well-recognized systemic granulomatous process which involves the central nervous system in 5-15% of patients. One of the more frequent sites of central nervous system involvement is the pituitary and hypothalamic region. Involvement of the sellar region by sarcoidosis is overall an infrequent occurrence, comprising less than 1% of all intrasellar lesions. Patients typically present with an infiltrative lesion on imaging studies and clinically with symptoms related to diabetes insipidus or hyperprolactinemia. This report describes a 38-year-old woman who initially presented with a variety of symptoms including headaches, light sensitivity, nausea and vomiting, acute visual changes, cold intolerance, amenorrhea, decreased libido, fatigue and galactorrhea. She had an elevated serum prolactin level and evidence of oligoclonal bands in the cerebrospinal fluid. Imaging studies discovered a 1.8cm mass involving the pituitary gland and compressing the optic chiasm. The lesion was excised and microscopically was marked by a chronic inflammatory cell infiltrate and scattered nonnecrotizing granulomas. Stains and microbiologic cultures failed to demonstrate microorganisms. There was no evidence of other organ involvement on postoperative imaging. She was treated with prednisone with improvement of symptoms and subsequently required methotrexate to treat left eye pain and blurred vision, 29months after her surgery. Achieving treatment control in patients with pituitary and hypothalamic improvement in sarcoidosis still remains a challenge. PMID- 27452131 TI - Anterior cervical discectomy and interbody fusion with porous tantalum implant. Results in a series with long-term follow-up. AB - Few papers have been published about the anterior cervical discectomy and fusion (ACDF) with implant of porous tantalum cages. These studies included patients submitted to operation at a single level. To our knowledge, we report the results of the largest series of ACDF with implant of porous tantalum cages. Our series included patients operated at a single or double level with a long follow-up (FU). We also discuss the pertinent literature. Clinical and outcome data of 99 consecutive patients (47 men, 52 women) submitted to ACDF with implant of porous tantalum cages (Trabecular Metal TM-S Cervical Fusion Device, Zimmer Spine, Minneapolis, MN) from June 2007 to September 2012, were retrospectively reviewed. Mean FU was 67.47+/-19.63months. The changes in pain were assessed using the Visual Analogue Scale (VAS). Patients were evaluated pre-operatively and at FU with the Short Form-36 Score Health Survey Version 2.0 (SF-36v2) for Physical Health and Mental Health Scores and the Neck Disability Index. We globally found a statistically significant improvement of all evaluated scores. Patients operated at two levels experienced a statistically significant improvement of all scores, with no statistical difference compared to patients operated at one level. No major complications occurred post-operatively and at FU. Only one patient (operated at two level) experienced an infection during FU. We conclude that ACDF with porous tantalum cages is a safe procedure, with long term clinical benefits (also in patients operated at two levels) and a very low rate of complications. PMID- 27452132 TI - Microscopic tubular discectomy for far lateral lumbar disc herniation. AB - Microscopic tubular discectomy (MTD) reduces muscle trauma associated with treatment of far lateral lumbar disc herniation (FLDH), but data from randomised controlled studies concerning its efficacy on posterolateral disc herniation, has failed to demonstrate its superiority over standard open techniques. Importantly concerns have been raised that it may be inferior in terms of relief of leg and back pain. Although several FLDH series show that MTD can deliver excellent outcomes, the volume of literature in this field has remained small and evidence based on health-related quality of life (HRQOL) measures, scarce. In this study we therefore evaluated the role of MTD for FLDH through analysing multiple HRQOL scores collected in a prospective database. We identified 24 patients who underwent MTD through a caudal approach, targeting directly the disc space to minimise traction on the dorsal root ganglion implicated in causing iatrogenic neuralgia. With a mean follow-up of 9.2months, the improvement in Oswestry Disability Index and Short Form 36 physical functioning and bodily pain scores was 32, (95% confidence interval [CI]: 21-43), 40 (95% CI: 30-51) and 35 (95% CI: 26-43) respectively. The improvement on the Visual Analogue Scale was 38mm (95% CI: 23-54) and 35mm (95% CI: 21-48) for leg pain and back pain respectively. There was no postoperative neuralgia noted and no reoperation required. Our data demonstrated clinically meaningful treatment effects and compare favourably with HRQOL surgical outcomes established for posterolateral disc herniation, supporting MTD as a valid treatment option for FLDH. PMID- 27452133 TI - Factors influencing local tumor control after Gamma Knife radiosurgery for intracranial metastases from breast cancer. AB - Because evaluation of Gamma Knife radiosurgery (GKRS) for brain metastases (METs) has mainly been based on overall or progression-free survival rates, that is, patients' general condition and control of the primary disease, we focused on factors influencing local tumor control after GKRS for METs from breast cancer. Data were retrospectively collected from our institution's records of patients who had undergone GKRS twice or more for METs from breast cancer. Failed GKRS was defined as a tumor needing re-treatment by further GKRS or having already been treated by other modalities prior to later GKRS procedures. Influences of various factors on local tumor control were examined. GKRS was performed on 623 tumors in 123 sessions in 90 patients. Median follow up was 9months (range 1-41months). According to multivariate analysis, use of HER2-targeting agents, (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.18-0.99, p=0.049), five or more lesions (HR 0.24, 95% CI 0.11-0.51, p<0.001), volume >1.2cm3 (HR 3.12, 95% CI 1.62-6.02, p<0.001), use of GK model B (HR 2.53, 95% CI 1.28-4.98, p=0.0076), and prescribed dosage ?18Gy (HR 0.19, 95% CI 0.01-0.51, p<0.001) were predictors of failed GKRS. Patients with METs from breast cancer with HER2-positive tumors, five or more lesions, and tumors of volume ?1.2cm3 are good candidates for GKRS. GK model C and Perfexion achieve better local tumor control than does GK model B. The recommended dosage is ?18Gy. PMID- 27452134 TI - Pleomorphic xanthoastrocytoma arising from the suprasellar region: A report of two cases. AB - Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm that usually arises in children and young adults. Typically, lesions of PXA are superficially located in the cerebral hemispheres. Herein, we report two extremely rare patients with PXA arising from suprasellar regions. One of the patients is a 29 year-old man admitted to our hospital with a history of progressive headache for 1month. The patient's brain MRI revealed a large tumor arising from the suprasellar cistern of the third ventricle. The second patient, a 52-year-old woman, presented with progressive dizziness and visual disturbance that had developed over the course of 1year. The MRI revealed a well-enhanced suprasellar solid mass measuring 1.4*1.2*1.4cm. Both patients underwent surgical removal of their tumors, and both patients showed similar microscopic structures and immunohistochemical phenotypes: the tumor cells were pleomorphic with mixtures of spindle-shaped, and multinuclear giant cells. In addition, eosinophilic granular bodies and xanthomatous cells were seen on section. Immunohistochemistry was positive for GFAP, S-100, and CD34, and was negative for IDH 1, CK, and Syn. The Ki-67 proliferation index was less than 1%. Silver impregnation revealed reticulin fibers surrounding the individual tumor cells, and small cell groups. Based on these findings, the two patients were diagnosed with PXA in the suprasellar region. To date, only five such patients have been reported in the literature. PXA should be included in the differential diagnosis for tumors arising in the sellar region. PMID- 27452135 TI - Ventilation tubes in middle ear effusion post-nasopharyngeal carcinoma radiation: To insert or not? PMID- 27452136 TI - Survivorship Between 2 Different Ceramic-on-Ceramic Total Hip Arthroplasty With or Without a Metal-Backed Titanium Sleeve Bearing: A 5- to 14-Year Follow-Up Study. AB - BACKGROUND: The aim of the study was to compare the clinical and radiographic results of consecutive ceramic-on-ceramic bearings with and without a metal backed titanium sleeve in patients undergoing total hip arthroplasty. METHODS: Eighty-five patients (64 women and 21 men; average age 55.2 years) were included in the A group without sleeve while 147 patients (116 women and 31 men; average age 54.2 years) were included in the B group with sleeve. Clinical and radiologic measurements at follow-up (range, 5-14 years; average, 8.1 years) were analyzed. RESULTS: The mean latest postoperative Harris Hip Score was 89.1 for patients from both groups. One joint (1.2%) in the A group displayed ceramic liner fracture, while no incidences of liner fracture occurred in the B group. Audible squeaking was observed in 1 joint (1.2%) in the A group and 1 (0.7%) in the B group. The mean annual liner rate of wear was 0.0049 and 0.0046 mm/y for the A group and B group, respectively. Three joints in the A group (3.5%) required revision total hip arthroplasty because of individual episodes of aseptic cup loosening, ceramic liner fracture, and infection. One joint in the B group (0.7%) required revision because of progressive osteolysis of the proximal femur. Ten year Kaplan-Meier survivorship, based on an end point of component loosening and bearing failure, was 97.6% for the A group and 99.3% for the B group. CONCLUSION: There were no clinical, radiographic, or survivorship differences between groups. PMID- 27452137 TI - The Prevalence of Diabetes Mellitus and Routine Hemoglobin A1c Screening in Elective Total Joint Arthroplasty Patients. AB - BACKGROUND: Diabetes mellitus has been associated with significant perioperative complications in joint arthroplasty. In addition, many patients are unaware of their dysglycemic status, and the prevalence of undiagnosed dysglycemia in joint arthroplasty patients is unknown. METHODS: Several years ago, we began routine hemoglobin A1c (HbA1c) level screening in all our patients planning to undergo elective total hip and total knee arthroplasties. We retrospectively reviewed the HbA1c levels in our initial 663 patients. RESULTS: Forty-eight percent of these patients were found to be nondiabetic; 19% percent had a previous history of some level of dysglycemia. Most significantly, over one third, 33.6% of these patients were previously undiagnosed dysglycemic patients; 31% were diagnosed as prediabetic and 2.6% as diabetic. CONCLUSION: Owing to the high prevalence of prediabetic patients who go on to develop diabetes and to the high correlation of poor glucose control with perioperative complications, we feel that it is imperative to identify this large number of previously undiagnosed dysglycemic patients. We recommend the routine screening of all patients planning to undergo major orthopedic procedures. Likewise, we recommend that identified patients be referred for diabetic counseling. We also recommend that patients with markedly elevated HbA1c levels have their elective surgery postponed until better glycemic control can be achieved. PMID- 27452138 TI - Functional Outcomes After Total Knee Arthroplasty Correlate With Spine Disability. AB - BACKGROUND: Despite pain resolution in most patients after total knee arthroplasty (TKA), poor function persists in approximately 20% of patients and frequently is associated with patient dissatisfaction. Lumbar spine problems are a leading cause of functional disability. This study sought to determine the association between lower knee function scores and history of spine disability. METHODS: Prospective demographic, health, and knee-specific data were collected for 1156 consecutive TKAs from July 2010 to July 2012. A spine questionnaire and Oswestry Disability Index (ODI) score were obtained from 691 knees. RESULTS: Of 691 patients, 371 (54%) with TKA had daily back pain or back pain that limited activity. Oxford Knee Score was significantly worse in patients with vs without back problems preoperatively (36.9/34.8; P = .0006) and postoperatively (20.2/17.0; P < .0001), but not for improvement (16.7/17.8; P = .10). Knee Society (KS) pain scores were similar regardless of spine history. KS function scores were lower in patients with vs without back problems preoperatively (42.3/47.0; P = .0005), postoperatively (69.0/79.8; P < .0001), and for improvement (25.8/32.9; P < .0001). Lower KS function was associated with female gender, age, health, preoperative function, and ODI. ODI was associated with Oxford Knee Score (R = 0.57) and KS function score (R = 0.54). CONCLUSION: Knee function scores were significantly worse in patients with a history of back problems and directly associated with ODI score. KS function scores indicated that TKA patients with back problems had worse function before and after TKA with less improvement. Poor TKA outcomes and dissatisfaction may reflect poor knee function, spine disability, or both. Awareness of coexisting spine disability should guide patient expectations and evaluation of TKA outcomes. PMID- 27452139 TI - Articulation of Native Cartilage Against Different Femoral Component Materials. Oxidized Zirconium Damages Cartilage Less Than Cobalt-Chrome. AB - BACKGROUND: Oxidized zirconium (OxZr) is produced by thermally driven oxidization creating an oxidized surface with the properties of a ceramic at the top of the Zr metal substrate. OxZr is much harder and has a lower coefficient of friction than cobalt-chrome (CoCr), both leading to better wear characteristics. We evaluated and compared damage to the cartilage of porcine patella plugs, articulating against OxZr vs CoCr. Our hypothesis was that, owing to its better wear properties, OxZr would damage cartilage less than CoCr. If this is true, OxZr might be a better material for the femoral component during total knee arthroplasty if the patella is not resurfaced. METHODS: Twenty-one plugs from porcine patellae were prepared and tested in a reciprocating pin-on-disk machine while lubricated with bovine serum and under a constant load. Three different configurations were tested: cartilage-cartilage as the control group, cartilage OxZr, and cartilage-CoCr. Macroscopic appearance, cartilage thickness, and the modified Mankin score were evaluated after 400,000 wear cycles. RESULTS: The control group showed statistically significant less damage than plugs articulating against both other materials. Cartilage plugs articulating against OxZr were statistically significantly less damaged than those articulating against CoCr. CONCLUSION: Although replacing cartilage by an implant always leads to deterioration of the cartilage counterface, OxZr results in less damage than CoCr. The use of OxZr might thus be preferable to CoCr in case of total knee arthroplasty without patella resurfacing. PMID- 27452140 TI - 9th International Conference on Head and Neck Cancer. PMID- 27452141 TI - Ipilimumab for relapse after allogeneic transplantation. PMID- 27452142 TI - IVF treatment not linked to breast cancer. PMID- 27452143 TI - Resistance to PD-1 blockade in melanoma. PMID- 27452144 TI - Mental disorder diagnoses among children and adolescents who use antipsychotic drugs. AB - Antipsychotic drugs are used increasingly by children and adolescents and there is concern about off-label use. We aimed to study which substances, and for which mental disorder diagnoses, antipsychotic drugs were prescribed to 0-18-year-old boys and girls in Norway. Linked data from the national health registry for prescription drugs in 2010 and mental disorder diagnoses in 2008-2012 were used to study the prevalence of antipsychotic drug use, the type of antipsychotic drug substances used, mental disorder diagnoses in users and distribution of drugs per diagnostic category across gender. In total, 0.18% of Norwegian children and adolescents were prescribed antipsychotic drugs during 2010, of which there were more boys (0.23%) than girls (0.13%). Risperidone was the most frequently used substance among boys (57.4%) and girls (32.3%), followed by aripiprazole (19.4%) in boys and quetiapine (27.4%) in girls. The most common mental disorder diagnoses among male users were hyperkinetic (49.9%) and autism spectrum disorder (27.1%), while anxiety disorders (41.5%) and depressive illness (33.6%) were most common among female users. A schizophrenia-like psychosis diagnosis was given to 11.1% of the male and 18.2% of the female users. A hyperkinetic disorder was diagnosed among 56.9% and 52.4% of the male risperidone and aripiprazole users, respectively. Among female quetiapine users, 57.1% were diagnosed with anxiety disorders and 52.4% with depressive illness. These results demonstrate that children and adolescents who use antipsychotic drugs are predominantly diagnosed with non-psychotic mental disorders such as hyperkinetic disorder among boys and anxiety disorder or depressive illness among girls. PMID- 27452145 TI - Metabolic Precision Medicines: Curing POMC Deficiency. AB - Pro-opiomelanocortin deficiency is a rare cause of severe intractable obesity. Two patients have experienced dramatic weight loss in response to setmelanotide, a melanocortin-4 receptor activator. The drug has potential in broader populations, but caution is warranted as it may act at other melanocortin receptors. PMID- 27452147 TI - What should we do to promote a social perspective in psychiatry? PMID- 27452148 TI - Ultra-high performance supercritical fluid chromatography of lignin-derived phenols from alkaline cupric oxide oxidation. AB - Traditional chromatographic methods for the analysis of lignin-derived phenolic compounds in environmental samples are generally time consuming. In this work, an ultra-high performance supercritical fluid chromatography method with a diode array detector for the analysis of major lignin-derived phenolic compounds produced by alkaline cupric oxide oxidation was developed. In an analysis of a collection of 11 representative monomeric lignin phenolic compounds, all compounds were clearly separated within 6 min with excellent peak shapes, with a limit of detection of 0.5-2.5 MUM, a limit of quantification of 2.5-5.0 MUM, and a dynamic range of 5.0-2.0 mM (R(2) > 0.997). The new ultra-high performance supercritical fluid chromatography method was also applied for the qualitative and quantitative analysis of lignin-derived phenolic compounds obtained upon alkaline cupric oxide oxidation of a commercial humic acid. Ten out of the previous eleven model compounds could be quantified in the oxidized humic acid sample. The high separation power and short analysis time obtained demonstrate for the first time that supercritical fluid chromatography is a fast and reliable technique for the analysis of lignin-derived phenols in complex environmental samples. PMID- 27452146 TI - Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose. AB - The arrangement of beta cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual beta cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the beta cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread beta cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus. PMID- 27452149 TI - [Depressive symptoms during anorexia nervosa: State of the art and consequences for an appropriate use of antidepressants]. AB - OBJECTIVE: Depressive comorbidity is often associated with anorexia nervosa (AN), and antidepressant medication is widely used although it does not rely on any convincing data in the scientific literature. Our objectives were: to summarize the epidemiological, physiological, psychopathological literature about the relation between AN and manifestations of depression, and to focus on the clinical trial data assessing the use of antidepressant medication in AN in order to clarify the strategy for the use of antidepressant in AN during adolescence. METHOD: A manual computerised search (Medline) was performed for relevant published studies assessing the association between depressive signs or Major Depressive Disorder (MDD) and AN. Another manual computerised search (Medline) listed clinical trials assessing antidepressant in AN. RESULTS: On the one hand, depressive symptoms are common during the course of AN and could have different meaning. Indeed, firstly, we can distinguish symptoms that are inherent to AN and which can be mistaken for depressive signs (for instance: low self-esteem, reduced social contacts). Secondly, long-term undernourishment can be held responsible for numerous psychological distortions, including anxiety and depression symptoms such as insomnia, impaired concentration, or social isolation. Thirdly, the natural course of AN can also lead to "depressive moments", in particular when switching to a "purging type" AN, or when recovery mobilizes control and narcissistic issues. On the other hand, MDD is also highly prevalent among AN patients and is a negative prognosis factor. Thus, it is complex to differentiate MDD from isolated depressive symptoms that could be inherent of the AN symptomatology which raises the question of the role of antidepressant medication in treatment of depression in AN. No significant benefit of antidepressant medication in AN has been shown in clinical trials, and according to international guidelines it should be prescribed only as a second line treatment, after appropriate refeeding, and in case of an authentic depressive disorder. Those data appear to be in contradiction with the frequent use of those drugs in clinical practice. DISCUSSION: Nevertheless, clinical trials assessing antidepressant treatment in AN suffer from methodological weakness concerning the size of the sample, the choice of the population or the evaluation criterion. This lack of proof must raise our vigilance concerning antidepressant medication in AN but should not categorically prevent the clinician from using it when necessary. We do believe that there are some indications for prescribing antidepressant in patients with AN. The clinical challenge lies in the differentiation of the depressive symptoms that are transitory and likely to improve without medication from those that signal the presence of an MDD. Three criterion could be indicative of MDD: familial history of mood disorder, as it is a major risk factor for MDD among relatives; the chronology of appearance of both disorders, when MDD pre-exists AN; a few specific symptoms cannot be attributed to undernourishment or reactive depressive signs, such as morning insomnia, daily variation of depressive symptoms, suicidal attempts or ideation and guilt ideation. Thus, in integrating the data from the literature review, we propose a pragmatic therapeutic strategy for the use of an antidepressant in AN during adolescence that lies in 3 main categories for depressive manifestations in AN: therapeutic emergencies: when an obvious and severe MDD is comorbid to AN, immediate antidepressant would be required; isolated and non-specific depressive sign: no medication would be relevant as they are supposed to improve with refeeding and psychotherapeutic support; intermediary patterns which is probably the most frequent situation. In the last case, it would be relevant to abstain from prescribing medication in first line, but an antidepressant medication should be quickly considered in the presence of one (or several) criterion listed above and its persistence despite refeeding. The general medical state of this fragile population of patients should be evaluated (standard blood test, ECG) before and during treatment. PMID- 27452150 TI - A Comprehensive Review of Common Respiratory Infections Encountered in Urgent and Primary Care: A Reference Guide for Judicious Antibiotic Use with Complementary Therapies. PMID- 27452152 TI - Effect of maternal body mass index and weight gain in women with gestational diabetes on the incidence of large-for-gestational-age infants. PMID- 27452153 TI - Combined maximum-quantum and DOSY 3D experiments provide enhanced resolution for small molecules in mixtures. AB - We illustrate here as the combination of high-order maximum-quantum (MaxQ) and Diffusion-Ordered SpectroscopY (DOSY) NMR experiments in a 3D layout allows superior resolution for crowded NMR spectra. Non-uniform sampling (NUS) allows compressing the experimental time effectively to reasonable durations. Because diffusion effects were encoded within multiple-quantum coherences, increased sensitivity to magnetic field gradients is observed, requiring compensation for convection effects. The experiment was demonstrated on the spectra of a mix of small polyaromatic molecules. Specifically, in the case analyzed, the experiment provided an extreme simplification through the MaxQDOSY-MaxQ projection plane that presents one peak per molecule. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27452151 TI - Altered anterior-posterior connectivity through the arcuate fasciculus in temporal lobe epilepsy. AB - How the interactions between cortices through a specific white matter pathway change during cognitive processing in patients with epilepsy remains unclear. Here, we used surface-based structural connectivity analysis to examine the change in structural connectivity with Broca's area/the right Broca's homologue in the lateral temporal and inferior parietal cortices through the arcuate fasciculus (AF) in 17 patients with left temporal lobe epilepsy (TLE) compared with 17 healthy controls. Then, we investigated its functional relevance to the changes in task-related responses and task-modulated functional connectivity with Broca's area/the right Broca's homologue during a semantic classification task of a single word. The structural connectivity through the AF pathway and task modulated functional connectivity with Broca's area decreased in the left midtemporal cortex. Furthermore, task-related response decreased in the left mid temporal cortex that overlapped with the region showing a decrease in the structural connectivity. In contrast, the region showing an increase in the structural connectivity through the AF overlapped with the regions showing an increase in task-modulated functional connectivity in the left inferior parietal cortex. These structural and functional changes in the overlapping regions were correlated. The results suggest that the change in the structural connectivity through the left frontal-temporal AF pathway underlies the altered functional networks between the frontal and temporal cortices during the language-related processing in patients with left TLE. The left frontal-parietal AF pathway might be employed to connect anterior and posterior brain regions during language processing and compensate for the compromised left frontal-temporal AF pathway. Hum Brain Mapp 37:4425-4438, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27452154 TI - Separation of motile sperm for in vitro fertilization from frozen-thawed bull semen using progesterone induction on a microchip. AB - This study presents a novel method for the separation of motile sperm from non progressive motile and immotile sperm and in vitro Fertilization (IVF). This separation of bull sperm was accomplished by inducing chemotaxis along a progesterone release agent in a 7.5-mm microchannel microchip composed of a biocompatible polydimethysiloxane layer and a glass gradient. The selected sperm was applied directly for IVF. In the first experiment, we tested the effect of different lengths of microchannnel (5mm, 7.5mm and 10mm) on quality parameter of separated sperm. The results showed that separated sperm using 7.5-mm microchannel chip were improved in sperm motility, swimming velocity, and beat frequency compared with other groups. In the second experiment, a medium containing sperm from swim-up method and outlet reservoir of our 7.5-mm microchannel chip was collected and mitochondrial activity of the sperm was determined by fluorescence microscopy. The sperm from the microchip had higher mitochondria activity (47.6%+/-6.0%) than the sperm from the swim-up method (23.6%+/-4.7%) (P<0.05). There were significant differences in rate of acrosome intactness between the swim-up method and the microchip (36.0%+/-4.1% vs. 66.8+/ 2.1%, respectively, P<0.05). In the third experiment, we compared sperm penetration in the microchip-IVF system with a standard IVF method (droplet-IVF). The microchip-IVF group had the highest percentages of oocytes penetrated (82.2%+/-1.6% vs. 63.5%+/-2.4%) and monospermic oocytes (67.8%+/-3.4% vs. 42.4%+/ 1.5%). In addition, early developmental competence of oocytes to the blastocyst stage was higher when the oocytes were inseminated in the microchip-IVF system compared with those inseminated in a standard droplet-IVF system. These results demonstrate that our microchip based on a sperm chemotaxis system is useful for motile sperm separation from frozen-thawed bull semen for IVF. Therefore, the optimized microchip system provides a good opportunity to sort motile bull sperm for IVF. PMID- 27452155 TI - Emodin ameliorates acute lung injury induced by severe acute pancreatitis through the up-regulated expressions of AQP1 and AQP5 in lung. AB - The present study investigates the ameliorating effects of emodin on acute lung injury (ALI) induced by severe acute pancreatitis (SAP). An ALI rat model was constructed by sodium ursodeoxycholate and they were divided into four groups: SHAM, ALI, emodin and dexamethasone (DEX) (n=24 per group). Blood samples and lung tissues were collected 6, 12 and 24 hours after the induction of SAP associated ALI. Lung wet/dry ratio, blood gases, serum amylase and tumor necrosis factor-alpha (TNF-alpha) were measured at each time point. The expressions of AQP1 and AQP5 in lung tissue were detected by immunohistochemical staining, western blotting and real-time PCR. As the results show, there were no statistical differences in the levels of serum amylase, lung wet/dry ratio, blood gases indexes, serum TNF-alpha and pathological changes between emodin and DEX groups. However, significant differences were observed when compared with the ALI group. AQP1 and AQP5 expressions were significantly increased and lung oedemas were alleviated with the treatment of emodin and DEX. The expressions of AQP1 and AQP5 were significantly decreased in SAP-associated ALI rats. Emodin up-regulated the expression of AQP1 and AQP5, it could reduce pulmonary oedema and ameliorate SAP-induced ALI. Regulations on AQP1 and AQP5 expression had a great value in clinical application. PMID- 27452156 TI - Assessment of the antibacterial, cytotoxic and mutagenic potential of the phenolic-rich hydroalcoholic extract from Copaifera trapezifolia Hayne leaves. AB - Copaifera trapezifolia Hayne occurs in the Atlantic Rainforest, which is considered one of the most important and endangered tropical forests on the planet. Although literature works have described many Copaifera spp., their biological activities remain little known. In the present study, we aimed to evaluate (1) the potential of the hydroalcoholic extract from C. trapezifolia leaves (CTE) to act against the causative agents of tooth decay and apical periodontitis and (2) the cytotoxicity and mutagenicity of CTE to ensure that it is safe for subsequent application. Concerning the tested bacteria, the MIC and the minimum bactericidal concentration of CTE varied between 100 and 400 ug ml-1. The time-kill assay conducted at a CTE concentration of 100 ug ml-1 evidenced bactericidal activity against Porphyromonas gingivalis (ATCC 33277) and Peptostreptococcus micros (clinical isolate) within 72 h. CTE at 200 ug ml-1 inhibited Porphyromonas gingivalis and Peptostreptococcus micros biofilm formation by at least 50 %. A combination of CTE with chlorhexidine dichlorohydrate did not prompt any synergistic effects. The colony-forming assay conducted on V79 cells showed that CTE was cytotoxic at concentrations above 156 ug ml-1. CTE exerted mutagenic effect on V79 cells, but the micronucleus test conducted on Swiss mice and the Ames test did not reveal any mutagenicity. Therefore, the use of standardized and safe extracts could be an important strategy to develop novel oral care products with antibacterial action. These extracts could also serve as a source of compounds for the discovery of new promising biomolecules. PMID- 27452157 TI - Functional protein-based nanomaterial produced in microorganisms recognized as safe: A new platform for biotechnology. AB - Inclusion bodies (IBs) are protein-based nanoparticles formed in Escherichia coli through stereospecific aggregation processes during the overexpression of recombinant proteins. In the last years, it has been shown that IBs can be used as nanostructured biomaterials to stimulate mammalian cell attachment, proliferation, and differentiation. In addition, these nanoparticles have also been explored as natural delivery systems for protein replacement therapies. Although the production of these protein-based nanomaterials in E. coli is economically viable, important safety concerns related to the presence of endotoxins in the products derived from this microorganism need to be addressed. Lactic acid bacteria (LAB) are a group of food-grade microorganisms that have been classified as safe by biologically regulatory agencies. In this context, we have demonstrated herein, for the first time, the production of fully functional, IB-like protein nanoparticles in LAB. These nanoparticles have been fully characterized using a wide range of techniques, including field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR) spectroscopy, zymography, cytometry, confocal microscopy, and wettability and cell coverage measurements. Our results allow us to conclude that these materials share the main physico-chemical characteristics with IBs from E. coli and moreover are devoid of any harmful endotoxin contaminant. These findings reveal a new platform for the production of protein-based safe products with high pharmaceutical interest. STATEMENT OF SIGNIFICANCE: The development of both natural and synthetic biomaterials for biomedical applications is a field in constant development. In this context, E. coli is a bacteria that has been widely studied for its ability to naturally produce functional biomaterials with broad biomedical uses. Despite being effective, products derived from this species contain membrane residues able to trigger a non-desired immunogenic responses. Accordingly, exploring alternative bacteria able to synthesize such biomaterials in a safe molecular environment is becoming a challenge. Thus, the present study describes a new type of functional protein-based nanomaterial free of toxic contaminants with a wide range of applications in both human and veterinary medicine. PMID- 27452158 TI - Pharmacist-physician collaborative care model for patients with uncontrolled type 2 diabetes in Brazil: results from a randomized controlled trial. AB - RATIONALE, AIMS AND OBJECTIVES: This study aimed to evaluate the effect of a pharmacist-physician collaborative care model on clinical outcomes in patients with uncontrolled type 2 diabetes and determine characteristics that influence this effect. METHODS: A randomized controlled trial was conducted in a secondary care clinic for 80 patients with type 2 diabetes, aged 40-79 years and glycosylated haemoglobin (A1C) level >= 7.0%. The intervention group received individual, face-to-face pharmaceutical consultations and remote telephone support after a routine visit. The main measures were clinical outcomes (A1C, blood pressure, LDL cholesterol) and process indicators (medication adherence, medication regimen complexity, use of medicines). Multiple regression models were used to determine the variables that could explain the reduction and individualized control of A1C. RESULTS: From the initial sample of 80 patients, 73 completed this study. Compared with usual care, patients in the intervention group showed greater reduction in A1C (-0.79 vs. -0.16; P = 0.010); and an increase in the percentage of patients achieving the individualized goal of A1C (25.0% vs. 5.4%; P = 0.020). In addition, there was an increase in the percentage of adherent patients and in the average scores of medication adherence. Participation in the intervention group, higher baseline A1C levels and greater change in medication adherence were all significant predictors of improvement in A1C levels. CONCLUSIONS: The results suggest that the collaborative care model proposed is feasible and more effective than the usual care in the reduction and individualized control of A1C levels in patients with uncontrolled type 2 diabetes. PMID- 27452159 TI - Statins, familial hypercholesterolemia, and type 2 diabetes. PMID- 27452160 TI - Heavy metals, metalloids and other hazardous elements in marine plastic litter. AB - Plastics, foams and ropes collected from beaches in SW England have been analysed for As, Ba, Br, Cd, Cl, Cr, Cu, Hg, Ni, Pb, Sb, Se, Sn and Zn by field-portable-x ray fluorescence spectrometry. High concentrations of Cl in foams that were not PVC-based were attributed to the presence of chlorinated flame retardants. Likewise, high concentrations of Br among both foams and plastics were attributed to the presence of brominated flame retardants. Regarding heavy metals and metalloids, Cd and Pb were of greatest concern from an environmental perspective. Lead was encountered in plastics, foams and ropes and up to concentrations of 17,500MUgg(-1) due to its historical use in stabilisers, colourants and catalysts in the plastics industry. Detectable Cd was restricted to plastics, where its concentration often exceeded 1000MUgg(-1); its occurrence is attributed to the use of both Cd-based stabilisers and colourants in a variety of products. PMID- 27452161 TI - Treatment of endotoxaemia and septicaemia in the equine patient. AB - Endotoxins, constituents of the cell wall of gram-positive and gram-negative bacteria, regularly result in severe illness and death in horses. In endotoxaemia, these constituents are present in the systemic circulation; in septicaemia, whole microbes invade normally sterile parts of the body. Interaction of these endotoxins with pathogen recognition receptors leads to an inflammatory response that cannot always be sufficiently contained and hence needs direct treatment. Over the last decennia, our understanding of the pathophysiology of endotoxaemia and septicaemia has significantly increased. Based on improved understanding of the interaction between receptors and endotoxins as well as the subsequent downstream signalling pathways, new therapeutic targets have been identified in laboratory animal species and humans. Important species differences in the recognition of endotoxins and pathogens by their receptors as well as the inflammatory response to receptor activation hamper extrapolation of this information to the horse (and other species). Historically, horses with endotoxaemia and septicaemia have been treated mainly symptomatically and supportively. Based on the identified therapeutic targets, this review describes the current knowledge of the treatment for endotoxaemia and septicaemia in the horse with reference to the findings in other animal species and humans. PMID- 27452162 TI - Increased levels of inflammatory mediators and proinflammatory monocytes in patients with type I diabetes mellitus and nephropathy. AB - AIMS: To investigate and describe the relationship between diabetic nephropathy and systemic inflammation in patients with type 1 diabetes mellitus (T1DM). METHODS: Patients with T1DM, with or without reduced renal function due to diabetic nephropathy, were included. Differences in inflammatory mediators, adhesion molecules, markers of endothelial dysfunction and subsets of monocytes were studied in patients with mean disease duration of 31years. RESULTS: Patients with T1DM with and without renal failure were compared. Patients with nephropathy had increased plasma levels of proinflammatory monocytes, as well as circulatory PAI-1, syndecan-1, VEGF, IL-1beta, IL-1Ra and CCL4. Peripheral blood mononuclear cells from patients with nephropathy numerically increased soluble ICAM and PAI-1 in co-culture with primary endothelial cells compared to cells from patients without nephropathy. CONCLUSIONS: T1DM patients with kidney failure have higher levels of proinflammatory monocytes and circulatory inflammatory mediators compared to patients with T1DM alone. The results highlight the importance of inflammation and endothelial dysfunction in diabetic nephropathy with reduced GFR. PMID- 27452163 TI - Metagenomics-Guided Mining of Commercially Useful Biocatalysts from Marine Microorganisms. AB - Marine microorganisms are a rich reservoir of highly diverse and unique biocatalysts that offer potential applications in food, pharmaceutical, fuel, and cosmetic industries. The fact that only less than 1% of microbes in any marine habitats can be cultured under standard laboratory conditions has hampered access to their extraordinary biocatalytic potential. Metagenomics has recently emerged as a powerful and well-established tool to investigate the vast majority of hidden uncultured microbial diversity for the discovery of novel industrially relevant enzymes from different types of environmental samples, such as seawater, marine sediment, and symbiotic microbial consortia. We discuss here in this review about approaches and methods in metagenomics that have been used and can potentially be used to mine commercially useful biocatalysts from uncultured marine microbes. PMID- 27452164 TI - Utilization of Chitinaceous Wastes for the Production of Chitinase. AB - Marine environment is the most abundant source of chitin. Several marine organisms possess chitin in their structural components. Hence, a huge amount of chitin wastes is deposited in marine environment when such organisms shed their outer skeleton and also after their demise. Waste chitins are potential nutrient source of certain microbes. These microbes produce chitinases that hydrolyze waste chitins. These organisms thus play an important role to remove the chitin wastes from marine environment. In connection with this, chitinases are found to be most important biocatalyst for the utilization of chitin wastes. Therefore, use of chitin for chitinase production is one of the useful tools for different types of bioprocesses. PMID- 27452165 TI - Enzymes from Seafood Processing Waste and Their Applications in Seafood Processing. AB - Commercial fishery processing results in discards up to 50% of the raw material, consisting of scales, shells, frames, backbones, viscera, head, liver, skin, belly flaps, dark muscle, roe, etc. Besides, fishing operations targeted at popular fish and shellfish species also result in landing of sizeable quantity of by-catch, which are not of commercial value because of their poor consumer appeal. Sensitivity to rapid putrefaction of fishery waste has serious adverse impact on the environment, which needs remedial measures. Secondary processing of the wastes has potential to generate a number of valuable by-products such as proteins, enzymes, carotenoids, fat, and minerals, besides addressing environmental hazards. Fishery wastes constitute good sources of enzymes such as proteases, lipases, chitinase, alkaline phosphatase, transglutaminase, hyaluronidase, acetyl glycosaminidase, among others. These enzymes can have diverse applications in the seafood industry, which encompass isolation and modification of proteins and marine oils, production of bioactive peptides, acceleration of traditional fermentation, peeling and deveining of shellfish, scaling of finfish, removal of membranes from fish roe, extraction of flavors, shelf life extension, texture modification, removal of off-odors, and for quality control either directly or as components of biosensors. Enzymes from fish and shellfish from cold habitats are particularly useful since they can function comparatively at lower temperatures thereby saving energy and protecting the food products. Potentials of these applications are briefly discussed. PMID- 27452166 TI - Marine Fungal and Bacterial Isolates for Lipase Production: A Comparative Study. AB - Lipases, belonging to the class of enzymes called hydrolases, can catalyze triglycerides to fatty acids and glycerol. They are produced by microbes of plant and animal origin, and also by marine organisms. As marine microorganisms thrive in extreme conditions, lipases isolated from their origin possess characteristics of extremozymes, retain its activity in extreme conditions and can catalyze few chemical reactions which are impossible otherwise relative to the lipase produced from terrestrial microorganisms. Lipases are useful in many industries like detergent, food, leather, pharmaceutical, diary, etc. Few commercial enzymes have been developed and the use of them in certain industries like dairy, soaps are proved to be beneficial. There are few research papers reporting the production of lipase from marine bacteria and fungi. Lipase production involves two types of fermentation processes-solid-state fermentation (SSF) and submerged fermentation (SmF). Although SmF process is used conventionally, SSF process produces lipase in higher amounts. The production is also influenced by the composition of the medium, physiochemical parameters like temperature, pH, carbon, and nitrogen sources. PMID- 27452167 TI - Sequential Optimization Methods for Augmentation of Marine Enzymes Production in Solid-State Fermentation: l-Glutaminase Production a Case Study. AB - There is an increased l-glutaminase market worldwide due to its relevant industrial applications. Salt tolerance l-glutaminases play a vital role in the increase of flavor of different types of foods like soya sauce and tofu. This chapter is presenting the economically viable l-glutaminases production in solid state fermentation (SSF) by Aspergillus flavus MTCC 9972 as a case study. The enzyme production was improved following a three step optimization process. Initially mixture design (MD) (augmented simplex lattice design) was employed to optimize the solid substrate mixture. Such solid substrate mixture consisted of 59:41 of wheat bran and Bengal gram husk has given higher amounts of l glutaminase. Glucose and l-glutamine were screened as a finest additional carbon and nitrogen sources for l-glutaminase production with help of Plackett-Burman Design (PBD). l-Glutamine also acting as a nitrogen source as well as inducer for secretion of l-glutaminase from A. flavus MTCC 9972. In the final step of optimization various environmental and nutritive parameters such as pH, temperature, moisture content, inoculum concentration, glucose, and l-glutamine levels were optimized through the use of hybrid feed forward neural networks (FFNNs) and genetic algorithm (GA). Through sequential optimization methods MD PBD-FFNN-GA, the l-glutaminase production in SSF could be improved by 2.7-fold (453-1690U/g). PMID- 27452168 TI - Solid-State Fermentation vs Submerged Fermentation for the Production of l Asparaginase. AB - l-Asparaginase, an enzyme that catalyzes l-asparagine into aspartic acid and ammonia, has relevant applications in the pharmaceutical and food industry. So, this enzyme is used in the treatment of acute lymphoblastic leukemia, a malignant disorder in children. This enzyme is also able to reduce the amount of acrylamide found in carbohydrate-rich fried and baked foods which is carcinogenic to humans. The concentration of acrylamide in food can be reduced by deamination of asparagine using l-Asparaginase. l-Asparaginase is present in plants, animals, and microbes. Various microorganisms such as bacteria, yeast, and fungi are generally used for the production of l-Asparaginase as it is difficult to obtain the same from plants and animals. l-Asparaginase from bacteria causes anaphylaxis and other abnormal sensitive reactions. To overcome this, eukaryotic organisms such as fungi can be used for the production of l-Asparaginase. l-Asparaginase can be produced either by solid-state fermentation (SSF) or by submerged fermentation (SmF). SSF is preferred over SmF as it is cost effective, eco friendly and it delivers high yield of enzyme. SSF process utilizes agricultural and industrial wastes as solid substrate. The contamination level is substantially reduced in SSF through low moisture content. Current chapter will discuss in detail the chemistry and applications of l-Asparaginase enzyme and various methods available for the production of the enzyme, especially focusing on the advantages and limitations of SSF and SmF processes. PMID- 27452169 TI - Production of Enzymes from Marine Actinobacteria. AB - Marine actinobacteria are well recognized for their capabilities to produce valuable natural products, which have great potential for applications in medical, agricultural, and fine chemical industries. In addition to producing unique enzymes responsible for biosynthesis of natural products, many marine actinobacteria also produce hydrolytic enzymes which are able to degrade various biopolymers, such as cellulose, xylan, and chitin. These enzymes are important to produce biofuels and biochemicals of interest from renewable biomass. In this chapter, the recent reports of novel enzymes produced by marine actinobacteria are reviewed, and advanced technologies that can be applied to search for novel marine enzymes as well as for improved enzyme production by marine actinobacteria are summarized, which include ribosome engineering, genome mining, as well as synthetic biology studies. PMID- 27452170 TI - Recent Advances in Marine Enzymes for Biotechnological Processes. AB - In the last decade, new trends in the food and pharmaceutical industries have increased concern for the quality and safety of products. The use of biocatalytic processes using marine enzymes has become an important and useful natural product for biotechnological applications. Bioprocesses using biocatalysts like marine enzymes (fungi, bacteria, plants, animals, algae, etc.) offer hyperthermostability, salt tolerance, barophilicity, cold adaptability, chemoselectivity, regioselectivity, and stereoselectivity. Currently, enzymatic methods are used to produce a large variety of products that humans consume, and the specific nature of the enzymes including processing under mild pH and temperature conditions result in fewer unwanted side-effects and by-products. This offers high selectivity in industrial processes. The marine habitat has been become increasingly studied because it represents a huge source potential biocatalysts. Enzymes include oxidoreductases, hydrolases, transferases, isomerases, ligases, and lyases that can be used in food and pharmaceutical applications. Finally, recent advances in biotechnological processes using enzymes of marine organisms (bacterial, fungi, algal, and sponges) are described and also our work on marine organisms from South America, especially marine derived fungi and bacteria involved in biotransformations and biodegradation of organic compounds. PMID- 27452171 TI - Preface. PMID- 27452172 TI - Clinical and pathogenic analysis of 507 children with bacterial meningitis in Beijing, 2010-2014. AB - OBJECTIVES: To explore the clinical characteristics and analyze the pathogens of bacterial meningitis in children. METHODS: Bacterial meningitis cases occurring from January 2010 through December 2014 at Beijing Children's Hospital were reviewed retrospectively. The records of all patients, including data on clinical features and laboratory information, were obtained and analyzed. RESULTS: In total, the cases of 507 pediatric patients seen over a 5-year period were analyzed; 220 of these cases were etiologically confirmed. These patients were classified into four age groups: 29 days to 1 year (n=373, 73.6%), 1-3 years (n=61, 12.0%), 3-6 years (n=41, 8.1%), and >6 years (n=32, 6.3%). The main pathogens identified in this study were Streptococcus pneumoniae (n=73, 33.2%), Escherichia coli (n=24, 10.9%), Enterococcus (n=22, 10.0%), and group B Streptococcus (n=18, 8.2%). All Gram-positive bacteria were sensitive to vancomycin and linezolid. All Gram-negative bacteria were sensitive to meropenem. The total non-susceptibility rate of S. pneumoniae to penicillin was 47.6% (20/42). The resistance rates to ceftriaxone, cefepime, and ceftazidime were 75% (9/12), 55.6% (5/9), and 40% (4/10), respectively. CONCLUSIONS: The main pathogen of bacterial meningitis in this study was S. pneumoniae. The antibiotic resistance rates among children with bacterial meningitis are of serious concern. PMID- 27452173 TI - Age-Dependent Niche Signals from the Choroid Plexus Regulate Adult Neural Stem Cells. AB - Specialized niches support the lifelong maintenance and function of tissue specific stem cells. Adult neural stem cells in the ventricular-subventricular zone (V-SVZ) contact the cerebrospinal fluid (CSF), which flows through the lateral ventricles. A largely ignored component of the V-SVZ stem cell niche is the lateral ventricle choroid plexus (LVCP), a primary producer of CSF. Here we show that the LVCP, in addition to performing important homeostatic support functions, secretes factors that promote colony formation and proliferation of purified quiescent and activated V-SVZ stem cells and transit-amplifying cells. The functional effect of the LVCP secretome changes throughout the lifespan, with activated neural stem cells being especially sensitive to age-related changes. Transcriptome analysis identified multiple factors that recruit colony formation and highlights novel facets of LVCP function. Thus, the LVCP is a key niche compartment that translates physiological changes into molecular signals directly affecting neural stem cell behavior. PMID- 27452174 TI - Molecular Obstacles to Clinical Translation of iPSCs. AB - The ability to reprogram somatic cells into induced pluripotent stem cells (iPSCs) using defined factors provides new tools for biomedical research. However, some iPSC clones display tumorigenic and immunogenic potential, thus raising concerns about their utility and safety in the clinical setting. Furthermore, variability in iPSC differentiation potential has also been described. Here we discuss whether these therapeutic obstacles are specific to transcription-factor-mediated reprogramming or inherent to every cellular reprogramming method. Finally, we address whether a better understanding of the mechanism underlying the reprogramming process might improve the fidelity of reprogramming and, therefore, the iPSC quality. PMID- 27452175 TI - Tissue Mechanics Orchestrate Wnt-Dependent Human Embryonic Stem Cell Differentiation. AB - Regenerative medicine is predicated on understanding the mechanisms regulating development and applying these conditions to direct stem cell fate. Embryogenesis is guided by cell-cell and cell-matrix interactions, but it is unclear how these physical cues influence stem cells in culture. We used human embryonic stem cells (hESCs) to examine whether mechanical features of the extracellular microenvironment could differentially modulate mesoderm specification. We found that, on a hydrogel-based compliant matrix, hESCs accumulate beta-catenin at cell cell adhesions and show enhanced Wnt-dependent mesoderm differentiation. Mechanistically, Src-driven ubiquitination of E-cadherin by Cbl-like ubiquitin ligase releases P120-catenin to facilitate transcriptional activity of beta catenin, which initiates and reinforces mesoderm differentiation. By contrast, on a stiff hydrogel matrix, hESCs show elevated integrin-dependent GSK3 and Src activity that promotes beta-catenin degradation and inhibits differentiation. Thus, we found that mechanical features of the microenvironmental matrix influence tissue-specific differentiation of hESCs by altering the cellular response to morphogens. PMID- 27452177 TI - Gold-catalysed cross-coupling between aryldiazonium salts and arylboronic acids: probing the usefulness of photoredox conditions. AB - The synthesis of biaryl compounds from aryldiazonium salts and arylboronic acids was achieved using PPh3AuCl as catalyst, CsF as base and acetonitrile as solvent. Combined to photosensitizers, irradiation by blue LEDs allowed accelerating the reaction and expanding its scope. Various functional groups were compatible including bromoaryls, iodoaryls, aldehydes and alcohols. A 2-iodobenzyl alcohol moiety was smoothly introduced by this method, enabling its consecutive isotopic labelling by a Pd-catalysed alkoxycarbonylation. PMID- 27452176 TI - Conversion of Human Gastric Epithelial Cells to Multipotent Endodermal Progenitors using Defined Small Molecules. AB - Endodermal stem/progenitor cells have diverse potential applications in research and regenerative medicine, so a readily available source could have widespread uses. Here we describe derivation of human induced endodermal progenitor cells (hiEndoPCs) from gastrointestinal epithelial cells using a cocktail of defined small molecules along with support from tissue-specific mesenchymal feeders. The hiEndoPCs show clonal expansion in culture and give rise to hepatocytes, pancreatic endocrine cells, and intestinal epithelial cells when treated with defined soluble molecules directing differentiation. The hiEndoPC-derived hepatocytes are able to rescue liver failure in Fah-/-Rag2-/- mice after transplantation, and, unlike hESCs, transplanted hiEndoPCs do not give rise to teratomas. Since human gastric epithelial cells are readily available from donors of many ages, this conversion strategy can generate clonally expandable cell populations with a variety of potential applications, including personalized drug screening and therapeutic strategies for liver failure and diabetes. PMID- 27452178 TI - Comparison of symmetric dimethylarginine with creatinine, cystatin C and their eGFR equations as markers of kidney function. AB - OBJECTIVES: Symmetric dimethylarginine (SDMA) is a catabolic product of arginine methylated proteins and is an emerging biomarker for kidney function. A limited number of studies in selected populations have shown good correlation between SDMA and a few known markers of glomerular filtration rate (GFR). However, a comprehensive comparison of SDMA with all existing serum endogenous markers in a population with varied kidney function and against measured GFR is lacking. The objective of this study was to compare the correlations of SDMA, creatinine, cystatin C and their eGFR equations against GFR measured by iothalamate clearance in an adult population with varied kidney function. DESIGN & METHODS: Left-over serum and plasma specimens were collected from 40 adults with normal and reduced kidney function. GFR was measured using a radioactive iothalamate procedure. Creatinine and cystatin C were measured on Roche Cobas 8000. SDMA was measured by a published liquid chromatography-tandem mass spectrometry method. RESULTS: SDMA correlated highly with measured GFR (r=-0.84), which was better than creatinine (r=-0.70) but equivalent to cystatin C (r=-0.86) and the eGFR equations [MDRD and CKD-EPI (separate and combined)]. CONCLUSIONS: SDMA is a strong marker of kidney function and further studies are needed to establish an eGFR formula that includes it for widespread clinical use. PMID- 27452179 TI - Verification of out-of-control situations detected by "average of normal" approach. AB - OBJECTIVES: "Average of normal" (AoN) or "moving average" is increasingly used as an adjunct quality control tool in laboratory practice. Little guidance exists on how to verify if an out-of-control situation in the AoN chart is due to a shift in analytical performance, or underlying patient characteristics. DESIGN AND METHODS: Through simulation based on clinical data, we examined 1) the location of the last apparently stable period in the AoN control chart after an analytical shift, and 2) an approach to verify if the observed shift is related to an analytical shift by repeat testing of archived patient samples from the stable period for 21 common analytes. RESULTS: The number of blocks of results to look back for the stable period increased with the duration of the analytical shift, and was larger when smaller AoN block sizes were used. To verify an analytical shift, 3 archived samples from the analytically stable period should be retested. In particular, the process is deemed to have shifted if a difference of >2 analytical standard deviations (i.e. 1:2s rejection rule) between the original and retested results are observed in any of the 3 samples produced. The probability of Type-1 error (i.e., false rejection) and power (i.e., detecting true analytical shift) of this rule are <0.1 and >0.9, respectively. CONCLUSIONS: The use of appropriately archived patient samples to verify an apparent analytical shift is preferred to quality control materials. Nonetheless, the above findings may also apply to quality control materials, barring matrix effects. PMID- 27452180 TI - Recent advances of liquid chromatography-(tandem) mass spectrometry in clinical and forensic toxicology - An update. AB - Liquid chromatography (LC) coupled to mass spectrometry (MS) or tandem mass spectrometry (MS/MS) is a well-established and widely used technique in clinical and forensic toxicology as well as doping control especially for quantitative analysis. In recent years, many applications for so-called multi-target screening and/or quantification of drugs, poisons, and or their metabolites in biological matrices have been developed. Such methods have proven particularly useful for analysis of so-called new psychoactive substances that have appeared on recreational drug markets throughout the world. Moreover, the evolvement of high resolution MS techniques and the development of data-independent detection modes have opened new possibilities for applications of LC-(MS/MS) in systematic toxicological screening analysis in the so called general unknown setting. The present paper will provide an overview and discuss these recent developments focusing on the literature published after 2010. PMID- 27452181 TI - Clinical chemistry in higher dimensions: Machine-learning and enhanced prediction from routine clinical chemistry data. AB - Big Data is having an impact on many areas of research, not the least of which is biomedical science. In this review paper, big data and machine learning are defined in terms accessible to the clinical chemistry community. Seven myths associated with machine learning and big data are then presented, with the aim of managing expectation of machine learning amongst clinical chemists. The myths are illustrated with four examples investigating the relationship between biomarkers in liver function tests, enhanced laboratory prediction of hepatitis virus infection, the relationship between bilirubin and white cell count, and the relationship between red cell distribution width and laboratory prediction of anaemia. PMID- 27452182 TI - Soluble E-cadherin as a serum biomarker in patients with HBV-related liver diseases. AB - OBJECTIVE: Substantial evidence indicates that serum sE-cadherin is a pivotal regulator that contributes to the initiation and development of various types of diseases. However, very little is known about the relationship between levels of serum sE-cadherin and HBV-related disorders. The overall goal of the study is to get a better insight into whether or not serum sE-cadherin is involved in HBV related diseases. DESIGN AND METHODS: Serum levels of sE-cadherin and IFN-gamma, from 113 patients with chronic hepatitis B, 101 patients with HBV-related cirrhosis, 75 patients with hepatocellular carcinoma and 125 healthy individuals were measured with commercial available sandwich ELISA kits. RESULTS: sE-cadherin values were significantly higher in patients compared to healthy control (p<0.0001). The levels of serum sE-cadherin were significantly positively correlated with the serum levels of IFN-gamma, alanine transaminase and aspartate aminotransferase in chronic hepatitis B and cirrhosis patients. In hepatocellular carcinoma patients, serum sE-cadherin concentrations were only significantly positively correlated with the serum levels of ALT and AST. CONCLUSIONS: Serum sE cadherin levels maybe an important indicator of the pathogenesis of progression of HBV-related disorders. PMID- 27452183 TI - Disparities in psychosocial cancer care: a report from the International Federation of Psycho-oncology Societies. AB - BACKGROUND: The aim of the study was to understand the characteristics of the International Federation of Psycho-oncology Societies (FPOS) and possible disparities in providing psychosocial care in countries where psycho-oncology societies exist. METHOD: A survey was conducted among 29 leaders of 28 countries represented within the FPOS by using a questionnaire covering (i) characteristics of the society; (ii) characteristics of the national health care system; (iii) level of implementation of psycho-oncology; and (iv) main problems of psycho oncology in the country. RESULTS: Twenty-six (90%) FPOS returned the questionnaires. One-third reported to have links with and support from their government, while almost all had links with other scientific societies. The FPOS varied in their composition of members' professions. Psychosocial care provision was covered by state-funded health services in a minority of countries. Disparities between countries arose from different causes and were problematic in some parts of the world (eg, Africa and SE Asia). Elsewhere (eg, Southern Europe and Eastern Europe), austerity policies were reportedly responsible for resource shortages with negative consequences on psychosocial cancer care. Half of FPOS rated themselves to be integrated into mainstream provision of care, although lack of funding was the most common complain. CONCLUSIONS: The development and implementation of psycho-oncology is fragmented and undeveloped, particularly in some parts of the world. More effort is needed at national level by strong coalitions with oncology societies, better national research initiatives, cancer plans, and patient advocacy, as well as by stronger partnership with international organizations (eg, World Health Organization and Union for International Cancer Control). PMID- 27452184 TI - Adsorption of flexible polyelectrolytes on charged surfaces. AB - Adsorption of weakly charged polyelectrolyte (PE) chains from dilute solution on an oppositely charged surface is studied using the self-consistent mean-field approach. The structure of the adsorbed polymer layer and its excess charge are analyzed in the most important asymptotic and intermediate regimes both analytically and numerically. Different regimes of surface charge compensation by PE chains including partial and full charge inversion are identified and discussed in terms of physical parameters like the magnitude of specific short range interactions of PE segments with the surface, solvent quality and ionic strength. The effect of excluded-volume monomer interactions is considered quantitatively both in the marginally good and poor solvent regimes. PMID- 27452185 TI - Predicting the binding free energy of the inclusion process of 2-hydroxypropyl beta-cyclodextrin and small molecules by means of the MM/3D-RISM method. AB - A protocol to calculate the binding free energy of a host-guest system is proposed based on the MM/3D-RISM method, taking cyclodextrin derivatives and their ligands as model systems. The protocol involves the procedure to identify the most probable binding mode (MPBM) of receptors and ligands by means of the umbrella sampling method. The binding free energies calculated by the MM/3D-RISM method for the complexes of the seven ligands with the MPBM of the cyclodextrin, and with the fluctuated structures around it, are in agreement with the corresponding experimental data in a semi-quantitative manner. It suggests that the protocol proposed here is promising for predicting the binding affinity of a small ligand to a relatively rigid receptor such as cyclodextrin. PMID- 27452186 TI - Erratum: Proton solvation in protic and aprotic solvents [J. Comput. Chem. 2015, 37, 1082-1091]. PMID- 27452187 TI - A negative urinalysis is associated with a low likelihood of intra-abdominal injury after blunt abdominal trauma. AB - BACKGROUND: The utility of urinalysis (UA) to diagnose intra-abdominal (IA) or genitourinary (GU) injury after blunt trauma remains controversial. The purpose of this study was to determine the significance of UA in the blunt trauma patient. METHODS: A retrospective review of patients admitted for blunt abdominal trauma from 2011 to 2013. RESULTS: A total of 1,795 patients sustained blunt abdominal trauma: mean age of 44 +/- 21 years; mean Injury Severity Score of 13 +/- 10. Overall 810 patients had a negative UA (45%). Two patients (2/810 and .2%) had a GU injury and neither required intervention. Thirty-two patients (32/810 and 4.0%) had an IA injury, and 2 (2/810 and .02%) required intervention. The sensitivity for predicting GU injury requiring intervention was 1, and IA injury requiring intervention was .96. Negative predictive values were 1 and .99. CONCLUSIONS: A negative UA correlates with a low risk for GU and IA injury after blunt abdominal trauma. A negative UA should be evaluated prospectively as part of a clinical prediction score to rule out injury and avoid unnecessary radiation exposure from computed tomography imaging. PMID- 27452188 TI - Rapid Imaging of Latent Fingerprints Using Biocompatible Fluorescent Silica Nanoparticles. AB - Fluorescent silica nanoparticles (FSNPs) are synthesized through the Stober method by incorporating silane-modified organic dye molecules. The modified fluorescent organic dye molecule is able to be prepared by allylation and hydrosilylation reactions. The optical properties of as-prepared FSNPs are shown the similar optical properties of PR254A (allylated Pigment Red 254) and have outstanding photostability. The polyvinylpyrrolidone (PVP) is introduced onto the surface of FSNP to enhance the binding affinity of PVP-coated FSNP for latent fingerprints (LFPs) detection. The simple preparation and easy control of surface properties of FSNPs show potential as a fluorescent labeling material for enhanced latent fingerprint detection on hydrophilic and hydrophobic substrates in forensic science for individual identification. PMID- 27452189 TI - Determining the cost-effectiveness of endoscopic surveillance for gastric cancer in patients with precancerous lesions. AB - AIM: To identify the optimal strategy for gastric cancer (GC) prevention by evaluating the cost-effectiveness of esophagogastroduodenoscopy (EGD)-based preventive strategies. METHODS: We conducted a model-based cost-effectiveness analysis. Adopting a healthcare payer's perspective, Markov models simulated the clinical experience of the target population (Singaporean Chinese 50-69 years old) undergoing endoscopic screening, endoscopic surveillance and usual care of do-nothing. The screening strategy examined the cohort every alternate year whereas the surveillance strategy provided annual EGD only to people with precancerous lesions. For each strategy, discounted lifetime costs ($) and quality adjusted life years (QALY) were estimated and compared to generate incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analysis was conducted to identify influential parameters and quantify the impact of model uncertainties. RESULTS: Annual EGD surveillance with an ICER of $34 200/QALY was deemed cost-effective for GC prevention within the Singapore healthcare system. To inform implementation, the models identified six influential factors and their respective thresholds, namely discount rate (<4.20%), age of starting surveillance (>51.6 years), proportion of program cost in delivering endoscopy (<65%), cost of follow-up EGD (<$484), utility of stage 1 GC patients (>0.72) and odds ratio of GC for high-risk subjects (>3.93). The likelihood that surveillance is the most cost-effective strategy is 69.5% accounting for model uncertainties. CONCLUSION: Endoscopic surveillance of gastric premalignancies can be a cost-effective strategy for GC prevention. Its implementation requires careful assessment on factors influencing the actual cost effectiveness. PMID- 27452190 TI - Alcohol and suicide in the Nenets Autonomous Okrug and Arkhangelsk Oblast, Russia. AB - BACKGROUND: High suicide rates in the Russian North are coupled with high alcohol consumption in the described populations. OBJECTIVE: To investigate the potential role of alcohol consumption on suicides in the Nenets Autonomous Okrug (NAO) in 2002-2012 and to compare this information with corresponding data from the neighboring Arkhangelsk Oblast (AO). DESIGN: Retrospective population-based mortality study. METHODS: Data from autopsy reports were used to identify 252 cases of suicide in the NAO and 1,198 cases in the AO in the period 2002-2012. Postmortem blood alcohol content (BAC) was available for 228 cases in the NAO and 1,185 cases in the AO. BAC as well as other selected variables were compared between the NAO and the AO among women and men, different age groups, ethnic groups, and selected variables of suicide. RESULTS: Alcohol was present in the blood of 74.1% of male and 82.9% of female suicide cases in the NAO, which was significantly higher than the proportions found in the AO (59.3% of male and 46.6% female cases). BAC<1.00/00 and between 2.0 and 3.00/00 were more frequently found among suicide cases in the NAO than those in the AO. CONCLUSIONS: Our findings specify that alcohol drinking may be an essential risk factor for suicide in the NAO, and that this factor may be of greater importance in the indigenous population of the NAO than among Russians in the AO. PMID- 27452191 TI - Creating Unidimensional Global Measures of Physician Practice Quality Based on Health Insurance Claims Data. AB - OBJECTIVE: To explore the extent to which commonly used claims-based process quality indicators can be used to create an internally valid global composite measure of physician practice quality. DATA SOURCES: Health insurance claims data (October 2007-May 2010) from 134 physician practices in Seattle, WA. STUDY DESIGN: We use confirmatory and exploratory factor analysis to develop theory- and empirically driven internally valid composite measures based on 19 quality indicators. DATA COLLECTION METHODS: Health insurance claims data from nine insurance companies and self-funded employers were collected and aggregated by third-party organization. PRINCIPAL FINDINGS: Our results did not support a single global measure using the entire set of quality indicators. We did identify an acceptable multidimensional model (RMSEA = 0.059; CFI = 0.934; TLI = 0.910). The four dimensions in our data were diabetes, depression, preventive care, and generic drug prescribing. CONCLUSIONS: Our study demonstrates that commonly used process indicators can be used to create a small set of useful composite measures. However, the lack of an internally valid single unidimensional global measure has important implications for policy approaches meant to improve quality by rewarding "high-quality physicians." PMID- 27452192 TI - Guideline panels should seldom make good practice statements: guidance from the GRADE Working Group. PMID- 27452193 TI - Sex-specific effects of low-dose gestational estradiol-17beta exposure on bone development in porcine offspring. AB - Estrogens are important for the bone development and health. Exposure to endocrine disrupting chemicals during the early development has been shown to affect the bone phenotype later in life. Several studies have been performed in rodents, while in larger animals that are important to bridge the gap to humans there is a paucity of data. To this end, the pig as large animal model was used in the present study to assess the influence of gestational estradiol-17beta (E2) exposure on the bone development of the prepubertal and adult offspring. Two low doses (0.05 and 10MUg E2/kg body weight) referring to the 'acceptable daily intake' (ADI) and the 'no observed effect level' (NOEL) as stated for humans, and a high-dose (1000MUg E2/kg body weight), respectively, were fed to the sows every day from insemination until delivery. In the male prepubertal offspring, the ADI dose group had a lower strength strain index (p=0.002) at the proximal tibia compared to controls, which was determined by peripheral quantitative computed tomography. Prepubertal females were not significantly affected. However, there was a higher cortical cross-sectional area (CSA) (p=0.03) and total CSA (p=0.02) at the femur midpoint in the adult female offspring of the NOEL dose group as measured by computed tomography. These effects were independent from plasma hormone concentrations (leptin, IGF1, estrogens), which remained unaltered. Overall, sex-specific effects on bone development and non-monotonic dose responses were observed. These results substantiate the high sensitivity of developing organisms to exogenous estrogens. PMID- 27452194 TI - Involvement of COX-2 in nickel elution from a wire implanted subcutaneously in mice. AB - Many types of medical alloys include nickel (Ni), and the elution of Ni ions from these materials causes toxicities and inflammation. We have previously reported that inflammation enhances Ni elution, although the molecular mechanisms underlying this effect remain unclear. In this study, we investigated how inflammatory responses enhanced Ni elution in a wire-implantation mouse model. Subcutaneous implantation of Ni wire induced the expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) mRNA in the surrounding tissues. Immunostaining analysis showed that cells expressing COX-2 were mainly fibroblast-like cells 8h after implantation of a Ni wire, but were mainly infiltrated leukocytes at 24h. NiCl2 induced the expression of COX-2 mRNA in primary fibroblasts, neutrophils, RAW 264 cells, and THP-1 cells, indicating that Ni ions can induce COX-2 expression in various types of cells. The elution of Ni ions from the implanted Ni wire at 8h was reduced by dexamethasone (Dex), indomethacin (Ind), or celecoxib (Cel) treatment. Ni wire implantation induced an increase in mRNA levels for anaerobic glycolytic pathway components glucose transporter 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4); the expression of these genes was also inhibited by Dex, Ind, and Cel. In primary fibroblasts, the expression of these mRNAs and the production of lactate were induced by NiCl2 and further potentiated by PGE2. Furthermore, Ni wire-induced infiltration of inflammatory leukocytes was significantly reduced by Dex, Ind, or Cel. Depletion of neutrophils with a specific antibody caused reduction of both leukocyte infiltration and Ni elution. These results indicate that Ni ions eluted from wire induced COX-2 expression, which further promoted elution of Ni ions by increasing lactate production and leukocyte infiltration. Since COX inhibitors and Dex reduced the elution of Ni ions, these drugs may be useful for prevention of metal-related inflammation and allergy. PMID- 27452195 TI - First report of Candida auris in America: Clinical and microbiological aspects of 18 episodes of candidemia. AB - OBJECTIVES: Characterization of a hospital outbreak of Candida auris candidemia that involved 18 critically ill patients in Venezuela. METHOD: Bloodstream isolates of C. auris obtained from 18 patients admitted at a medical center in Maracaibo, between March, 2012 and July, 2013 were included. Species identification was confirmed by ITS rDNA sequencing. Isolates were subsequently typed by amplified fragment length polymorphism fingerprinting (AFLP). Susceptibility testing was performed according to CLSI. Clinical data were collected from all cases by using a standard clinical form. RESULTS: A total of 13 critically ill pediatric and 5 adult patients, with a median age of 26 days, were included. All were previously exposed to antibiotics and multiple invasive medical procedures. Clinical management included prompt catheter removal and antifungal therapy. Thirteen patients (72%) survived up to 30 days after onset of candidemia. AFLP fingerprinting of all C. auris isolates suggested a clonal outbreak. The isolates were considered resistant to azoles, but susceptible to anidulafungin and 50% of isolates exhibited amphotericin B MIC values of >1 MUg/ml. CONCLUSIONS: The study demonstrated that C. auris is a multiresistant yeast pathogen that can be a source of health-care associated infections in tertiary care hospitals with a high potential for nosocomial horizontal transmission. PMID- 27452196 TI - Detection of beta-D-glucan for the diagnosis of invasive fungal infection in children with hematological malignancy. AB - OBJECTIVES: The beta-D-glucan assay (BDG) has been added to the EORTC/MSG criteria for the diagnosis of invasive fungal infections (IFI), but data from pediatric populations is scarce. The aim of this study was to evaluate performance of BDG in a cohort of hemato-oncological children with hematological malignancy at risk for IFI. METHODS: 113 patients were included through an 18 month period. In addition to routine IFI screening, BDG was assayed once a week. IFIs were classified using EORTC/MSG criteria without including the BDG results. Performances were assessed after a ROC analysis for optimization and multivariate analysis to detect the causes of false positivity. RESULTS: 8 proven and 4 probable IFIs, and 7 possible IFIs were diagnosed in 9 and 7 patients, respectively. Sensitivity and specificity increased from 75% and 56% to 100% and 91.1%, respectively when considering the whole population and patients not having received any antifungals prior to the test. Multivariate analysis revealed that being younger than 7, severe colitis/mucositis, recent administration of polyvalent immunoglobulins and digestive colonization with Enterococcus sp were independent risk factors for false positivity. CONCLUSIONS: BDG is a valuable test to detect IFI in pediatric patients not previously treated with antifungals and to detect the occurrence of chronic infection. PMID- 27452197 TI - Circulating cell-free DNA is elevated in community-acquired bacterial pneumonia and predicts short-term outcome. PMID- 27452198 TI - Effect of Fenoldopam Continuous Infusion on Glomerular Filtration Rate and Fractional Excretion of Sodium in Healthy Dogs. AB - BACKGROUND: Acute kidney injury (AKI) is a common problem in small-animal patients and carries a guarded prognosis with substantial morbidity and mortality, particularly in oligoanuric dogs. Fenoldopam, a selective dopamine agonist, has been shown to increase urine output in healthy dogs and cats; however, the mechanism of action is unknown. HYPOTHESIS/OBJECTIVES: To evaluate the effect of fenoldopam infusion on glomerular filtration rate (GFR) and fractional excretion of sodium (FeNa) in healthy dogs. ANIMALS: Ten healthy, privately owned dogs. METHODS: Randomized, crossover design with negative control. Ten healthy dogs were given fenoldopam diluted in 5% dextrose (D5W) as a continuous IV infusion of 0.8 MUg/kg/min for 5 hours and a control infusion of D5W alone, 7 days apart. Glomerular filtration rate was measured by exogenous iohexol clearance, beginning 1 hour after the start of the fenoldopam infusion. Fractional excretion of sodium (FeNa) was measured before and after the infusion. Glomerular filtration rate and change in FeNa were compared between treatment days. RESULTS: Fenoldopam infusion resulted in a significantly increased (P = .0166) GFR (median GFR, 3.33 mL/min/kg) in healthy dogs compared with D5W infusion (median GFR, 2.71 mL/kg/min). Fenoldopam also resulted in a significantly increased (P = .0148) FeNa (mean change, 0.106), whereas infusion of D5W alone did not (mean change, 0.016). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy dogs, fenoldopam significantly increased GFR and FeNa compared with infusion of D5W alone. No adverse effects were seen. PMID- 27452199 TI - Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Associated With Ryanodine Receptor (RyR2) Gene Mutations - Long-Term Prognosis After Initiation of Medical Treatment. AB - BACKGROUND: The long-term prognosis of cardiac ryanodine receptor (RyR2) positive catecholaminergic polymorphic ventricular tachycardia (CPVT) patients after initiation of medical therapy has not been well investigated. This study aimed to assess the recurrence of fatal cardiac event after initiation of medical therapy inRyR2-positive CPVT patients. METHODS AND RESULTS: Thirty-fourRyR2-positive CPVT patients with a history of cardiac events were enrolled. All patients had medical treatment initiated after the first symptom or diagnosis. Exercise stress tests (ESTs) were performed to evaluate the efficacy of the medical therapy. Even after the initiation of medical therapy, high-risk ventricular arrhythmias (VAs), including premature ventricular contraction couplets, bigeminy, and ventricular tachycardia, were still induced in the majority of patients (80.6%). During 7.4 years of follow-up after the diagnosis, 7 of the 34 (20.6%) patients developed fatal cardiac events. Among those 7 patients, 6 (85.7%) were not compliant with either exercise restriction or medication therapy at the time of the events. CONCLUSIONS: Even after initiation of medical treatment, high-risk VAs were induced during EST in mostRyR2-positive CPVT patients. Most fatal recurrent cardiac events occurred in patients who were noncompliant with exercise restriction and/or medical therapy. Medical management including strict exercise restriction should be emphasized to prevent recurrent cardiac event in mostRyR2 positive CPVT patients. (Circ J 2016; 80: 1907-1915). PMID- 27452200 TI - Temporal Trends in Stroke Severity and Prior Antithrombotic Use Among Acute Ischemic Stroke Patients in Japan. AB - BACKGROUND: Few existing stroke registries allow for evaluation of stroke severity, stroke subtype and antithrombotic usage prior to stroke onset over a given time period. The present study aimed to elucidate temporal trends in initial presenting stroke severity, stroke subtype and prior antithrombotic use over a 12-year period in a Japanese multicenter stroke registry. METHODS AND RESULTS: We included 71,017 acute ischemic stroke patients (72+/-12 years old; 27,445 women) from the Japan Standard Stroke Registry Study (JSSRS) who were admitted to 94 hospitals between 2001 and 2012. The mean age of stroke onset increased gradually over time (P<0.001). Cardioembolic stroke patients (n=19,247) exhibited more severe NIHSS scores when compared with those with non cardioembolic stroke (n=50,427). The proportion of cardioembolic stroke patients tended to increase over time, rising from 25.9% in 2001-2002 to 30.2% in 2011 2012 (P<0.001). Among the cardioembolic stroke patients, the frequency of prior anticoagulant use significantly increased from 15.6% in 2001-2002 to 24.8% in 2011-2012 (P<0.001). The frequency of prior antiplatelet use increased from 2001 2002 to 2007-2008 but decreased after 2007-2008. Among both cardioembolic and non cardioembolic stroke patients, initial stroke severity at admission decreased over time, particularly after 2008. CONCLUSIONS: In this Japanese study, the mean age of ischemic stroke onset increased, while the initial neurological severity at presentation decreased, over a 12-year period. (Circ J 2016; 80: 2033-2036). PMID- 27452201 TI - Partial Anomalous Pulmonary Venous Connection With Left Atrial Drainage of the Superior Vena Cava. PMID- 27452202 TI - Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins - ODYSSEY JAPAN Randomized Controlled Trial. AB - BACKGROUND: The ODYSSEY Japan study was designed to demonstrate the reduction in low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on to existing lipid-lowering therapy in Japanese patients with heterozygous familial hypercholesterolemia (heFH) or non-FH at high cardiovascular risk who require additional pharmacological management to achieve their LDL-C treatment goal (<2.6 or <3.1 mmol/L, depending on risk category). METHODS AND RESULTS: This randomized, double-blind, parallel-group, 52-week study was conducted in Japan. Patients (n=216) with heFH, non-FH at high cardiovascular risk with coronary disease, or classified as category III were enrolled. The prespecified safety analysis was done after the last patient completed 52 weeks. Patients were randomized (2:1, alirocumab:placebo) with stratification for heFH to s.c. alirocumab (75 mg every 2 weeks [Q2 W] with increase to 150 mg if week 8 LDL-C >=2.6/3.1 mmol/L) or placebo for 52 weeks plus stable statin therapy. At week 24, mean+/-SE change in LDL-C from baseline was -62.5+/-1.3% in the alirocumab group and 1.6+/-1.8% in the placebo group (difference, -64.1+/-2.2%; P<0.0001); the reduction was sustained to week 52 (alirocumab, -62.5+/-1.4%; placebo, -3.6+/ 1.9%). No patterns were evident between treatment groups for adverse events at 52 weeks. CONCLUSIONS: In high-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab markedly reduced LDL-C vs. placebo and was well tolerated over 52 weeks. (Circ J 2016; 80: 1980-1987). PMID- 27452203 TI - Has the Safety of Edoxaban 60 mg Among East Asian Atrial Fibrillation Patients Been Truly Proven by the ENGAGE AF-TIMI 48 Subanalysis? PMID- 27452204 TI - Has the Safety of Edoxaban 60 mg Among East Asian Atrial Fibrillation Patients Been Truly Proven by the ENGAGE AF-TIMI 48 Subanalysis? - Reply. PMID- 27452205 TI - An in vitro-in silico interface platform for spatiotemporal analysis of pattern formation in collective epithelial cells. AB - A multicellular organization is a complex resulting from the coordinated migration of cells to form a specific pattern. The directionality of migration is governed by the mechanical and molecular dynamics of factors secreted from the cells. The mechanism underlying pattern formation is too complex to unveil by culture experiments alone. A mathematical model could provide a powerful tool for elucidating the mechanism of pattern formation by computing the molecular dynamics, which are difficult to visualize by culture experiments. However, there tends to be a gap between mathematical models and experimental research due to incongruity between the idealized conditions of the model and the experimental results. This paper presents an in vitro-in silico interface platform for elucidating the logic of multicellular pattern formation. Two-dimensional collective cell pattern formation was developed using normal human bronchial epithelial cells. Then, geometrical control of collective cells followed by feedback iteration was used to bridge the gap between the mathematical model and in vitro experiments. The mechanisms underlying the pattern formation of bronchial epithelial cells were evaluated using a reaction-diffusion model. The results indicated that differences in the diffusion rates of the activator and inhibitor determine the direction of collective cell migration to form a specific pattern. PMID- 27452206 TI - The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. AB - Progesterone receptor membrane component 1 (PGRMC1) is a multi-functional protein with a heme-binding moiety related to that of cytochrome b5, which is a putative progesterone receptor. The recently solved PGRMC1 structure revealed that heme binding involves coordination by a tyrosinate ion at Y113, and induces dimerization which is stabilized by hydrophobic stacking of heme on adjacent monomers. Dimerization is required for association with cytochrome P450 (cyP450) enzymes, which mediates chemoresistance to doxorubicin and may be responsible for PGRMC1's anti-apoptotic activity. Here we review the multiple attested involvement of PGRMC1 in diverse functions, including regulation of cytochrome P450, steroidogenesis, vesicle trafficking, progesterone signaling and mitotic spindle and cell cycle regulation. Its wide range of biological functions is attested to particularly by its emerging association with cancer and progesterone responsive female reproductive tissues. PGRMC1 exhibits all the hallmarks of a higher order nexus signal integration hub protein. It appears capable of acting as a detector that integrates information from kinase/phosphatase pathways with heme and CO levels and probably redox status. PMID- 27452207 TI - Evidence-based recommendations for the diagnosis and management of rheumatoid arthritis for non-rheumatologists: Integrating systematic literature research and expert opinion of the Thai Rheumatism Association. AB - AIM: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease leading to joint damage, functional disability, poor quality of life and shortened life expectancy. Early diagnosis and aggressive treatment are a principal strategy to improve outcomes. To provide best practices in the diagnosis and management of patients with RA, the Thai Rheumatism Association (TRA) developed scientifically sound and clinically relevant evidence-based recommendations for general practitioners, internists, orthopedists, and physiatrists. METHODS: Thirty-seven rheumatologists from across Thailand formulated 18 clinically relevant questions: three for diagnosis, 10 for treatments, four for monitoring, and one for referral. A bibliographic team systematically reviewed the relevant literature on these topics up to December 2013. A set of recommendations was proposed based on the results of systematic reviews combined with expert opinions. Group consensus was achieved for all statements and recommendations using the nominal group technique. RESULTS: A set of recommendations was proposed. For diagnosis, either American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism 2010 classification criteria can be applied. For treatment, nonsteroidal anti-inflammatory drugs, glucocorticoid, and disease-modifying antirheumatic drugs, including antimalarials, methotrexate and sulfasalazine are recommended. Physiotherapy should be suggested to all patients. Tight control strategy and monitoring for efficacy and side effects of treatments, as well as indications for referral to a rheumatologist are provided. CONCLUSIONS: These evidence-based recommendations provide practical guidance for diagnosis, fundamental management and referral of patients with RA for non-rheumatologists. However, it should be incorporated with clinical judgments and decisions about care for each individual patient. PMID- 27452208 TI - Identification of the novel B*27:144 allele in an Irish Individual. AB - The sequence of HLA-B*27:144 differs from HLA-B*27:05:02 by one nucleotide change at position 506. PMID- 27452209 TI - Self-assembly of core-polyethylene glycol-lipid shell (CPLS) nanoparticles and their potential as drug delivery vehicles. AB - Herein a new multifunctional formulation, referred to as a core-polyethylene glycol-lipid shell (CPLS) nanoparticle, has been proposed and studied in silico via large scale coarse-grained molecular dynamics simulations. A PEGylated core with surface tethered polyethylene glycol (PEG) chains is used as the starting configuration, where the free ends of the PEG chains are covalently bonded with lipid molecules (lipid heads). A complete lipid bilayer is formed at the surface of the PEGylated particle core upon addition of free lipids, driven by the hydrophobic properties of the lipid tails, leading to the formation of a CPLS nanoparticle. The self-assembly process is found to be sensitive to the grafting density and molecular weight of the tethered PEG chains, as well as the amount of free lipids added. At low grafting densities the assembly of CPLS nanoparticles cannot be accomplished. As demonstrated by simulations, a lipid bud/vesicle can be formed on the surface when an excess amount of free lipids is added at high grafting density. Therefore, the CPLS nanoparticles can only be formed under appropriate conditions of both PEG and free lipids. The CPLS nanoparticle has been recognized to be able to store a large quantity of water molecules, particularly with high molecular weight of PEG chains, indicating its capacity for carrying hydrophilic molecules such as therapeutic biomolecules or imaging agents. Under identical size and surface chemistry conditions of a liposome, it has been observed that the CPLS particle can be more efficiently wrapped by the lipid membrane, indicating its potential for a greater efficiency in delivering its hydrophilic cargo. As a proof-of-concept, the experimental realization of CPLS nanoparticles is explicitly demonstrated in this study. To test the capacity of the CPLS to store small molecule cargo a hydrophilic dye was successfully encapsulated in the particles' water soluble layer. The results of this study show the power and potential of simulation-driven approaches for guiding the design of more efficient nanomaterial delivery platforms. PMID- 27452211 TI - Physician-at-large. PMID- 27452212 TI - Problems solutions. PMID- 27452213 TI - The medical bookshelf. PMID- 27452215 TI - Introduction. AB - The signs which one ordinarily associates with gout, such as subcutaneous nodules, podagra, arthritis, and elevation of blood uric acid level, do not necessarily make for a diagnosis of that condition, as Dr Talbott and his associates explain. Gout is still frequently misdiagnosed, in spite of renewed interest in it, because of ignorance of its many facets, which are described in this symposium. One of the most important of these may be the "gouty diathesis" which appears to be associated with significant disease, particularly coronary heart disease. PMID- 27452216 TI - Cme credit quiz. PMID- 27452217 TI - Pregnancy testing. AB - Immunoassays have virtually replaced bioassays for detection of pregnancy. Slide and tube tests are applicable in most clinical situations. Because of its sensitivity, radioimmunoassay is ideal for diagnosis of early and ectopic pregnancies. PMID- 27452219 TI - Therapeutic index. PMID- 27452210 TI - Prospects of modeling poststroke epileptogenesis. AB - This Review describes the current status of poststroke epilepsy (PSE) with an emphasis on poststroke epileptogenesis modeling for testing new therapeutic agents. Stroke is a leading cause of epilepsy in an aging population. Late-onset "epileptic" seizures have been reported in up to 30% cases after stroke. Nevertheless, the overall prevalence of PSE is 2-4%. Rodent models of stroke have contributed to our understanding of the relationship between seizures and the underlying ischemic damage to neurons. To understand whether acutely generated stroke events lead to a chronic phenotype more closely resembling PSE with recurrent seizures, a limited variety of approaches emerged in early 2000s. These limited methods of causing an occlusion in mice and rats show different infarct size and neurological deficits. The most often employed procedure for inducing focal ischemia is the middle cerebral artery occlusion. This mimics the pathophysiology seen in humans in terms of extent of damage to cortex and striatum. Photothrombosis and endothelin-1 models can similarly evoke episodes of ischemic stroke. These models are well suited to studying mechanisms and biomarkers of epileptogenesis or optimizing novel drug discoveries. However, modeling of PSE is tedious, is highly variable, and lacks validity; therefore, it is not widely implemented in epilepsy research. Moreover, the relevance of ischemic models to specific forms of human stroke remains unclear. Stroke modeling in young male rodents lacks clinical relevance to elderly populations and especially to women, likely as a result of sex differences. Nevertheless, because of the neuronal damage and epileptogenic insult that these models trigger, they are helpful tools in studying acquired epilepsy and prophylactic drug therapy. (c) 2016 Wiley Periodicals, Inc. PMID- 27452220 TI - MicroRNA-203 Inversely Correlates with Differentiation Grade, Targets c-MYC, and Functions as a Tumor Suppressor in cSCC. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer and a leading cause of cancer mortality among solid organ transplant recipients. MicroRNAs (miR) are short RNAs that regulate gene expression and cellular functions. Here, we show a negative correlation between miR-203 expression and the differentiation grade of cSCC. Functionally, miR-203 suppressed cell proliferation, cell motility, and the angiogenesis-inducing capacity of cSCC cells in vitro and reduced xenograft tumor volume and angiogenesis in vivo. Transcriptomic analysis of cSCC cells with ectopic overexpression of miR-203 showed dramatic changes in gene networks related to cell cycle and proliferation. Transcription factor enrichment analysis identified c-MYC as a hub of miR-203 induced transcriptomic changes in squamous cell carcinoma. We identified c-MYC as a direct target of miR-203. Overexpression of c-MYC in rescue experiments reversed miR-203-induced growth arrest in cSCC, which highlights the importance of c-MYC within the miR-203-regulated gene network. Together, miR-203 acts as a tumor suppressor in cSCC, and its low expression can be a marker for poorly differentiated tumors. Restoration of miR-203 expression may provide a therapeutic benefit, particularly in poorly differentiated cSCC. PMID- 27452221 TI - Essential Role of Polarity Protein Par3 for Epidermal Homeostasis through Regulation of Barrier Function, Keratinocyte Differentiation, and Stem Cell Maintenance. AB - Partitioning-defective (Par) proteins contribute to multiprotein complexes that drive cell polarity and fate in invertebrates. Of these, the ternary Par3 atypical protein kinase C-Par6 polarity complex mediates asymmetry in various systems, whereas Par3 and aPKC/Par6 can also act independently. aPKC-lambda has recently been implicated in epidermal differentiation and stem cell fate; however, whether Par3 contributes to the homeostasis of adult stratified epithelia is currently unknown. Here, we provide functional evidence that epidermal Par3 loss disturbed the inside-out skin barrier, coinciding with altered expression and localization of principle tight junction components, and that epidermal differentiation and thickness were increased. Moreover, Par3 inactivation caused an initial expansion and later decline of hair follicle bulge stem cells, accompanied by an enrichment of committed progenitors, formation of hypertrophic sebaceous glands, and increased epidermal differentiation, suggesting aberrant cell fate decisions. Importantly, and opposite to aPKClambda deletion, Par3 loss did not enhance perpendicular cell divisions. Instead, in Par3-deficient hair follicles, spindles were shifted toward planar orientation, indicating that abnormal differentiation after Par3 inactivation is unlikely to be attributed to increased perpendicular spindle orientation. Collectively, mammalian Par3 controls the epidermal barrier, differentiation, and stem cell maintenance in the pilosebaceous unit, which are all essential for the homeostasis of an important barrier-forming epithelium. PMID- 27452222 TI - Macular disease genetics and supplementation: the evidence for choosing wisely. PMID- 27452223 TI - Quantification of the filtering bleb's structure with anterior segment optical coherence tomography. AB - BACKGROUND: The aim of the study is to determine the relationship between post trabeculectomy bleb structure evaluated using anterior segment optical coherence tomography (AS-OCT) and postoperative intraocular pressure (IOP). DESIGN: Rretrospective is showed for the design of this study. PARTICIPANTS: There are twenty-seven eyes of 27 trabeculectomy patients. METHODS: We drew contour lines for the bleb and cleft on 8-radius-scanned AS-OCT images, and determined correlations of AS-OCT measurements to postoperative IOP at 6 months. MAIN OUTCOME MEASURES: The parameter used in this study is an anterior segment optical coherence tomography measurements of bleb structure, including cleft volume, wall volume, and the brightness of the bleb wall. RESULTS: We found significant correlations between postoperative IOP at 6 months and cleft volume at 3 and 6 months (r = -0.56, P = 0.007 and r = -0.82, P <0.001), bleb wall volume at 6 months (r = -0.48, P = 0.042), bleb vertical brightness at 3 and 6 months (r = 0.73, P < 0.001 and r = 0.49, P = 0.040), and bleb horizontal brightness at 1 week, 2 weeks, 3 months and 6 months (r = 0.49, P = 0.016, r = 0.65, P < 0.001, r = 0.52, P = 0.013 and r = 0.71, P = 0.001). A stepwise multiple regression analysis of bleb structural measurements made <=2 weeks postoperatively showed that the strongest independent factor indicating postoperative IOP at 6 months was bleb horizontal brightness at 2 weeks (beta = 0.50, P = 0.006). CONCLUSIONS: Early postoperative AS-OCT measurements of blebs, especially horizontal brightness of the bleb wall, were associated with postoperative IOP at 6 months. AS-OCT measurements of blebs may be useful predictors of trabeculectomy outcomes. PMID- 27452225 TI - Continuing Professional Development. PMID- 27452224 TI - Blood culture bottles are superior to conventional media for vitreous culture. AB - BACKGROUND: To compare blood culture bottles and conventional media for the vitreous culture in patients with clinically suspected infectious endophthalmitis. DESIGN: Retrospective comparative study at KKU Eye Center, Khon Kaen University. PARTICIPANTS: There were 342 patients with clinically suspected infectious endophthalmitis participated in the study. METHODS: The vitreous specimens were inoculated in both blood culture bottles and on conventional culture media (blood agar, MacConkey agar, chocolate agar, Sabouraud dextrose agar and thioglycolate broth). MAIN OUTCOME MEASURES: The number of positive culture yields in both blood culture bottles and conventional media. RESULTS: Positive culture yields in both methods were found in 151 eyes (49.5%). There were 136 of 151 eyes (90.1%) with positive culture in blood culture bottles, whereas 99 of 151 eyes (65.6%) yielded positive cultures in conventional media. These findings were different with a statistical significance (P < 0.00001) and an odds ratio of 3.47 (95% confidence interval 1.92, 6.63). A combination of blood culture bottles and conventional media improved the yield. CONCLUSIONS: Blood culture bottles are superior to conventional media for vitreous culture in clinically suspected infectious endophthalmitis. Vitreous culture using blood culture bottles should be recommended as the primary method for microbiological diagnosis. A combination of both methods further improves the positive culture yield. PMID- 27452226 TI - A Epidemiological Investigation of a Nosocomial Outbreak of Multidrug-Resistant Acinetobacter baumannii in a Critical Care Center in Japan, 2011-2012. AB - Volume 69, no. 2, p. 143-148, 2016. Page 143, Title should appear as shown below.An Epidemiological Investigation of a Nosocomial Outbreak of Multidrug Resistant Acinetobacter baumannii in a Critical Care Center in Japan, 2011-2012. PMID- 27452227 TI - Bacterial genetics: A new class of Hfq-like sRNA chaperones? PMID- 27452228 TI - Comment on Tocheva et al. "Sporulation, bacterial cell envelopes and the origin of life". PMID- 27452229 TI - Bacterial pathogenesis: Gut bugs in the lung link sepsis to ARDS. PMID- 27452231 TI - Microbiome: Microbial mobilomes differ between societies. PMID- 27452232 TI - Author's reply. PMID- 27452233 TI - Direct C-C Coupling of CO2 and the Methyl Group from CH4 Activation through Facile Insertion of CO2 into Zn-CH3 sigma-Bond. AB - Conversion of CO2 and CH4 to value-added products will contribute to alleviating the green-house gas effect but is a challenge both scientifically and practically. Stabilization of the methyl group through CH4 activation and facile CO2 insertion ensure the realization of C-C coupling. In the present study, we demonstrate the ready C-C coupling reaction on a Zn-doped ceria catalyst. The detailed mechanism of this direct C-C coupling reaction was examined based on the results from density functional theory calculations. The results show that the Zn dopant stabilizes the methyl group by forming a Zn-C bond, thus hindering subsequent dehydrogenation of CH4. CO2 can be inserted into the Zn-C bond in an activated bent configuration, with the transition state in the form of a three centered Zn-C-C moiety and an activation barrier of 0.51 eV. The C-C coupling reaction resulted in the acetate species, which could desorb as acetic acid by combining with a surface proton. The formation of acetic acid from CO2 and CH4 is a reaction with 100% atom economy, and the implementation of the reaction on a heterogeneous catalyst is of great importance to the utilization of the greenhouse gases. We tested other possible dopants including Al, Ga, Cd, In, and Ni and found a positive correlation between the activation barrier of C-C coupling and the electronegativity of the dopant, although C-H bond activation is likely the dominant reaction on the Ni-doped ceria catalyst. PMID- 27452230 TI - Spatial structure, cooperation and competition in biofilms. AB - Bacteria often live within matrix-embedded communities, termed biofilms, which are now understood to be a major mode of microbial life. The study of biofilms has revealed their vast complexity both in terms of resident species composition and phenotypic diversity. Despite this complexity, theoretical and experimental work in the past decade has identified common principles for understanding microbial biofilms. In this Review, we discuss how the spatial arrangement of genotypes within a community influences the cooperative and competitive cell-cell interactions that define biofilm form and function. Furthermore, we argue that a perspective rooted in ecology and evolution is fundamental to progress in microbiology. PMID- 27452234 TI - Algorithm for Designing Nanoscale Supramolecular Therapeutics with Increased Anticancer Efficacy. AB - In the chemical world, evolution is mirrored in the origin of nanoscale supramolecular structures from molecular subunits. The complexity of function acquired in a supramolecular system over a molecular subunit can be harnessed in the treatment of cancer. However, the design of supramolecular nanostructures is hindered by a limited atomistic level understanding of interactions between building blocks. Here, we report the development of a computational algorithm, which we term Volvox after the first multicellular organism, that sequentially integrates quantum mechanical energy-state- and force-field-based models with large-scale all-atomistic explicit water molecular dynamics simulations to design stable nanoscale lipidic supramolecular structures. In one example, we demonstrate that Volvox enables the design of a nanoscale taxane supramolecular therapeutic. In another example, we demonstrate that Volvox can be extended to optimizing the ratio of excipients to form a stable nanoscale supramolecular therapeutic. The nanoscale taxane supramolecular therapeutic exerts greater antitumor efficacy than a clinically used taxane in vivo. Volvox can emerge as a powerful tool in the design of nanoscale supramolecular therapeutics for effective treatment of cancer. PMID- 27452235 TI - Electrochemical construction of three-dimensional porous Mn3O4 nanosheet arrays as an anode for the lithium ion battery. AB - Three-dimensional (3D) porous Mn3O4 nanosheet arrays were constructed via an electrodeposition followed by high temperature annealing using 3D porous Cu, prepared by a facile electroless plating method, as the substrate. The 3D pores and voids between the nanosheet arrays were able to provide rapid ion transfer channels, as well as accommodating the volumetric changes of Mn3O4 during the electrochemical cycling. Electrons can directly exchange between the substrate and the nanosheet units, avoiding curving and the long transfer distance in conventional electrodes constructed using casting technology. Furthermore, the nanosheets were transformed into the architecture with smaller sub-nanosheets on the pristine nanosheets after 1 cycle, facilitating ion transferring, and were thoroughly transformed into smaller sub-nanosheets after 1000 cycles but without obvious exfoliation, assuring good electrical contact between the active particles and substrate. Based on the above unique characteristics, the 3D porous Mn3O4 nanosheet arrays could be directly used as a binder-free and conductive agent-free electrode to deliver ultrahigh electrochemical performance that is much better than achieved in previous reports. The first reversible capacity was 1166.3 mA h g(-1) and remained 667.9 mA h g(-1) after 1000 cycles at 1.0 A g(-1). Also, the reversible capacities at high current densities of 10.0 A g(-1) and 20.0 A g(-1) remained high at 416.1 and 216.7 mA h g(-1), respectively. PMID- 27452237 TI - High concentration biotherapeutic formulation and ultrafiltration: Part 1 pressure limits. AB - High therapeutic dosage requirements and the desire for ease of administration drive the trend to subcutaneous administration using delivery systems such as subcutaneous pumps and prefilled syringes. Because of dosage volume limits, prefilled syringe administration requires higher concentration liquid formulations, limited to about 30 cP or roughly 100-300 g L-1 for mAb's. Ultrafiltration (UF) processes are routinely used to formulate biological therapeutics. This article considers pressure constraints on the UF process that may limit its ability to achieve high final product concentrations. A system hardware analysis shows that the ultrafiltration cassette pressure drop is the major factor limiting UF systems. Additional system design recommendations are also provided. The design and performance of a new cassette with a lower feed channel flow resistance is described along with 3D modeling of feed channel pressure drop. The implications of variations in cassette flow channel resistance for scaling up and setting specifications are considered. A recommendation for a maximum pressure specification is provided. A review of viscosity data and theory shows that molecular engineering, temperature, and the use of viscosity modifying excipients including pH adjustment can be used to achieve higher concentrations. The combined use of a low pressure drop cassette with excipients further increased final concentrations by 35%. Guidance is provided on system operation to control hydraulics during final concentration. These recommendations should allow one to design and operate systems to routinely achieve the 30 cP target final viscosity capable of delivery using a pre-filled syringe. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:113-124, 2017. PMID- 27452239 TI - Is My Time Your Time? PMID- 27452236 TI - A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours. AB - Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumours and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. Here we report that the Salmonella type III secretion effector, SipA, is responsible for P-gp modulation through a pathway involving caspase-3. Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin). On the basis of our finding that the SipA Salmonella effector is fundamental for functionally decreasing P-gp, we engineered a nanoparticle mimic that both overcomes multidrug resistance in cancer cells and increases tumour sensitivity to conventional chemotherapeutics. PMID- 27452238 TI - Multifaceted impairments in impulsivity and brain structural abnormalities in opioid dependence and abstinence. AB - BACKGROUND: Chronic opioid exposure, as a treatment for a variety of disorders or as drug of misuse, is common worldwide, but behavioural and brain abnormalities remain under-investigated. Only a small percentage of patients who receive methadone maintenance treatment (MMT) for previous heroin misuse eventually achieve abstinence and studies on such patients are rare. METHOD: The Cambridge Neuropsychological Test Automated Battery and T1 weighted magnetic resonance imaging (MRI) were used to study a cohort of 122 male individuals: a clinically stable opioid-dependent patient group receiving MMT (n = 48), an abstinent previously MMT maintained group (ABS) (n = 24) and healthy controls (n = 50). RESULTS: Stable MMT participants deliberated longer and placed higher bets earlier in the Cambridge Gambling Task (CGT) and showed impaired strategic planning compared with healthy controls. In contrast, ABS participants showed impairment in choosing the least likely outcome, delay aversion and risk adjustment on the CGT, and exhibited non-planning impulsivity compared with controls. MMT patients had widespread grey matter reductions in the orbitomedial prefrontal cortex, caudate, putamen and globus pallidus. In contrast, ABS participants showed midbrain-thalamic grey matter reductions. A higher methadone dose at the time of scanning was associated with a smaller globus pallidus in the MMT group. CONCLUSIONS: Our findings support an interpretation of heightened impulsivity in patients receiving MMT. Widespread structural brain abnormalities in the MMT group and reduced brain structural abnormality with abstinence suggest benefit of cessation of methadone intake. We suggest that a longitudinal study is required to determine whether abstinence improves abnormalities, or patients who achieve abstinence have reduced abnormalities before methadone cessation. PMID- 27452240 TI - Letters. PMID- 27452241 TI - Brief reports. PMID- 27452242 TI - Nocturnal Erythromelalgia. PMID- 27452245 TI - Quantity and Quality of Exercise for Developing and Maintaining Fitness in Healthy Adults. PMID- 27452246 TI - Inspiration Precedes Perspiration. PMID- 27452247 TI - Shinsplints:An Update. PMID- 27452249 TI - Cme credit quiz. PMID- 27452248 TI - Shinsplints:An Update. AB - Although shinsplints can be prevented with proper training techniques, athletes sometimes develop pain that does not respond to the trainer's usual treatments. The physician's specific diagnosis and treatment are important in these cases. PMID- 27452250 TI - Sportsmedicine History. AB - Although injuries have plagued man since he started engaging in sports, sportsmedicine is a relatively new field. Surprisingly, two of its earliest pioneers advocated treatments that are still used today. PMID- 27452251 TI - Heart Rates of Basketball Coaches. AB - Head and assistant basketball coaches have similar increases in their heart rates during games, but the head coaches-the decision makers-consistently have significantly higher heart rates. PMID- 27452252 TI - High School Injuries Basketball. AB - Poor conditioning takes its toll in girls' high school basketball. An Oklahoma City girls' varsity team incurred over four times as many injuries per player as a boys' varsity team. PMID- 27452253 TI - Exercise for the Older Adult. AB - Exercise at my age? This report provides ammunition to help physicians convince themselves and their patients that exercise for the older adult is healthy and necessary. PMID- 27452254 TI - Osteitis Pubis in Sports Activities. AB - Shear forces transmitted to the pubic symphysis in running and kicking sports may produce osteitis pubis. It could be confused with muscle strain, inguinal hernia, prostatitis, orchitis, or urolithiasis. PMID- 27452255 TI - Physical Education: Model Programs Point the Way. AB - Model programs for high school physical education do exist in this country, and their success makes them worth emulating. A report on the programs in two California schools tells how they do it, and how legislative changes may affect their future. PMID- 27452256 TI - Maturity Sorting: New Balance for Young Athletes. AB - Differences in physical maturity often lead to unfair competition in secondary school athletic programs. In New York State, competition is based on maturity levels-and the program is expanding. PMID- 27452258 TI - Scanning sports. PMID- 27452257 TI - Developing and Testing Flexibility. PMID- 27452260 TI - Diffusion-weighted magnetic resonance imaging in differentiating acute infectious spondylitis from degenerative Modic type 1 change; the role of b-value, apparent diffusion coefficient, claw sign and amorphous increased signal. AB - OBJECTIVE: To examine the effect of using different b-values on the utility of diffusion-weighted (DW) MRI in differentiating acute infectious spondylitis from Modic type 1 and the discriminative accuracy of related apparent diffusion coefficient (ADC), claw-sign and amorphous increased signal. METHODS: 43 patients with equivocal diagnosis of acute infectious spondylitis/Modic type 1 by using MR images were prospectively studied. The discriminative accuracy of DW MRI using three b-values of 50, 400, 800 s mm(-2), ADC, claw sign and amorphous increased signal was examined. RESULTS: DW MRI differentiated infectious spondylitis from Modic type 1 change most accurately when a b-value of 800 s mm(-2) was chosen [sensitivity, 91.7%; specificity, 96.8%; positive-predictive value (PPV), 91.7%; negative-predictive value (NPV), 96.8%; and accuracy, 95.3%]. The optimal cut-off ADC value was 1.52 * 10(-3) mm(2) s(-1) (sensitivity, 91.7%; specificity, 100%; PPV, 100%; NPV, 96.9%; and accuracy, 97.7%). Best visualized at a b-value of 50 s mm(-2), claw sign (for degeneration) and amorphous increased signal (for infection) were 100% accurate. CONCLUSION: Should DW MRI be used in differentiating acute infectious spondylitis from degeneration, large b-values are required. With low b-values, however, claw sign and amorphous increased signal are very accurate in this regard. ADVANCES IN KNOWLEDGE: DW MRI using large b-values could be used in differentiating acute infectious spondylitis from Modic type I. PMID- 27452261 TI - Absorbed organ and effective doses from digital intra-oral and panoramic radiography applying the ICRP 103 recommendations for effective dose estimations. AB - OBJECTIVE: During dental radiography, the salivary and thyroid glands are at radiation risk. In 2007, the International Commission on Radiological Protection (ICRP) updated the methodology for determining the effective dose, and the salivary glands were assigned tissue-specific weighting factors for the first time. The aims of this study were to determine the absorbed dose to the organs and to calculate, applying the ICRP publication 103 tissue-weighting factors, the effective doses delivered during digital intraoral and panoramic radiography. METHODS: Thermoluminescent dosemeter measurements were performed on an anthropomorphic head and neck phantom. The organ-absorbed doses were measured at 30 locations, representing different radiosensitive organs in the head and neck, and the effective dose was calculated according to the ICRP recommendations. RESULTS: The salivary glands and the oral mucosa received the highest absorbed doses from both intraoral and panoramic radiography. The effective dose from a full-mouth intraoral examination was 15 MUSv and for panoramic radiography, the effective dose was in the range of 19-75 MUSv, depending on the panoramic equipment used. CONCLUSION: The effective dose from a full-mouth intraoral examination is lower and that from panoramic radiography is higher than previously reported. Clinicians should be aware of the higher effective dose delivered during panoramic radiography and the risk-benefit profile of this technique must be assessed for the individual patient. ADVANCES IN KNOWLEDGE: The effective dose of radiation from panoramic radiography is higher than previously reported and there is large variability in the delivered radiation dosage among the different types of equipment used. PMID- 27452262 TI - Comparing the sensitivity of linear and volumetric MRI measurements to detect changes in the size of vestibular schwannomas in patients with neurofibromatosis type 2 on bevacizumab treatment. AB - OBJECTIVE: To compare the sensitivity of linear and volumetric measurements on MRI in detecting schwannoma progression in patients with neurofibromatosis type 2 on bevacizumab treatment as well as the extent to which this depends on the size of the tumour. METHODS: We compared retrospectively, changes in linear tumour dimensions at a range of thresholds to volumetric tumour measurements performed using Brainlab iPlan((r)) software (Feldkirchen, Germany) and classified for tumour progression according to the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. RESULTS: Assessment of 61 schwannomas in 46 patients with a median follow-up of 20 months (range 3-43 months) was performed. There was a mean of 7 time points per tumour (range 2-12 time points). Using the volumetric REiNS criteria as the gold standard, a sensitivity of 86% was achieved for linear measurement using a 2-mm threshold to define progression. CONCLUSION: We propose that a change in linear measurement by 2 mm (particularly in tumours with starting diameters 20-30 mm, the majority of this cohort) could be used as a filter to identify cases of possible progression requiring volumetric analysis. This pragmatic approach can be used if stabilization of a previously growing schwannoma is sufficient for a patient to continue treatment in such a circumstance. ADVANCES IN KNOWLEDGE: We demonstrate the real-world limitations of linear vs volumetric measurement in tumour response assessment and identify limited circumstances where linear measurements can be used to determine which patients require the more resource-intensive volumetric measurements. PMID- 27452263 TI - Mammography in females with an implanted medical device: impact on image quality, pain and anxiety. AB - OBJECTIVE: To assess the image quality of mammograms in females with an implanted medical device (IMD), to evaluate pain and anxiety during mammography in these females and to investigate the experience of radiographers. METHODS: Image quality was evaluated by two radiographers and one radiologist in the images of females with an IMD participating in the Dutch screening programme (clients). Pain and anxiety were scored using a Numeric Rating Scale in both clients visiting a screening organization and patients from the Isala Hospital, Zwolle. Experience of screening radiographers was collected with a questionnaire. RESULTS: Images of the breast with IMD showed reduced contrast in craniocaudal (CC) and mediolateral-oblique (MLO) views [by both the radiographers and radiologist (range: 11-29%)], less projected breast tissue [only radiographers; CC lateral side: 25.5%, 95% confidence interval (CI): 18.7-32.2] and reduced projection of the pectoral muscle (only radiographers; MLO width pectoral muscle: 31.5%, 95% CI: 24.4-38.7). Clients experienced more pain and anxiety during mammography in the breast with IMD compared to the breast without IMD in the breast (pain difference CC: 0.48 +/- 0.16, p = 0.003; pain difference MLO: 0.46 +/- 0.16, p = 0.004; anxiety difference 1.30 +/- 0.22; p < 0.001). Patients experienced more pain (1.05 +/- 0.12; p < 0.001) and anxiety (1.22 +/- 0.15; p < 0.001) after placement of IMD. Radiographers are more cautious, more anxious and use less compression during mammography of breasts with IMD. CONCLUSION: Image quality in a breast with an IMD could be improved by projecting more breast tissue on the mammogram, thereby including (part of) the IMD between the paddles, if required. In addition, radiographers should pay sufficient attention to reducing discomfort both before and during the screening examination. ADVANCES IN KNOWLEDGE: Little is known about the quality of mammography in females with an IMD or how these females and radiographers experience the screening examination. The results of our study showed that having an IMD could result in a suboptimal mammogram and increased discomfort. PMID- 27452264 TI - Volumetric breast density measurement: sensitivity analysis of a relative physics approach. AB - OBJECTIVE: To investigate the sensitivity and robustness of a volumetric breast density (VBD) measurement system to errors in the imaging physics parameters including compressed breast thickness (CBT), tube voltage (kVp), filter thickness, tube current-exposure time product (mAs), detector gain, detector offset and image noise. METHODS: 3317 raw digital mammograms were processed with Volpara((r)) (Matakina Technology Ltd, Wellington, New Zealand) to obtain fibroglandular tissue volume (FGV), breast volume (BV) and VBD. Errors in parameters including CBT, kVp, filter thickness and mAs were simulated by varying them in the Digital Imaging and Communications in Medicine (DICOM) tags of the images up to +/-10% of the original values. Errors in detector gain and offset were simulated by varying them in the Volpara configuration file up to +/-10% from their default values. For image noise, Gaussian noise was generated and introduced into the original images. RESULTS: Errors in filter thickness, mAs, detector gain and offset had limited effects on FGV, BV and VBD. Significant effects in VBD were observed when CBT, kVp, detector offset and image noise were varied (p < 0.0001). Maximum shifts in the mean (1.2%) and median (1.1%) VBD of the study population occurred when CBT was varied. CONCLUSION: Volpara was robust to expected clinical variations, with errors in most investigated parameters giving limited changes in results, although extreme variations in CBT and kVp could lead to greater errors. ADVANCES IN KNOWLEDGE: Despite Volpara's robustness, rigorous quality control is essential to keep the parameter errors within reasonable bounds. Volpara appears robust within those bounds, albeit for more advanced applications such as tracking density change over time, it remains to be seen how accurate the measures need to be. PMID- 27452266 TI - Adding the power of iodinated contrast media to the credibility of mammography in breast cancer diagnosis. AB - Dual-energy contrast-enhanced spectral mammography (CESM) represents a relatively new diagnostic tool adjunct to mammography. The aim of this study was to strengthen the breast imaging-reporting and data system (BIRADS) classification score in order to improve early breast cancer diagnosis. For this reason, we propose a sum score, termed malignancy potential score (MPS), incorporating the standard BIRADS score and our proposed CESM score. From September 2014 to September 2015, 216 females (age range, 26-85 years; mean age 54.6 years) underwent CESM evaluation of mammographic findings that were primarily assessed as BIRADS 2-5. 10 of these patients had bilateral findings; a total of 226 lesions were examined. High-energy image evaluation was based on the intensity of contrast enhancement of the lesion compared with background enhancement, categorized as Type -1, 0, 1 or 2 enhancement. Histopathology reports were compared with imaging assessment. 98 of 226 lesions were malignant and 128 of 226 lesions were benign. The area under the curve was 0.843, 0.888 and 0.917 for mammographic BIRADS score, CESM score and MPS, respectively, with p-value < 0.05. The sensitivity, specificity and accuracy rates were 91.83, 80.47 and 85.40%, respectively, when a best MPS cut-off point of 4 was used. The malignancy potential score (MPS) has higher diagnostic performance than digital mammography or CESM alone. MPS empowers the credibility of the digital mammography BIRADS score and our proposed type of enhancement in dual-energy CESM and is a diagnostic tool that increases the accuracy rate in early breast cancer diagnosis. PMID- 27452265 TI - Comparison of two radiation techniques for the breast boost in patients undergoing neoadjuvant treatment for breast cancer. AB - OBJECTIVE: After breast conservative surgery (BCS) and whole-breast radiotherapy (WBRT), the use of boost irradiation is recommended especially in patients at high risk. However, the standard technique and the definition of the boost volume have not been well defined. METHODS: We retrospectively compared an anticipated pre-operative photon boost on the tumour, administered with low-dose fractionated radiotherapy, and neoadjuvant chemotherapy with two different sequential boost techniques, administered after BCS and standard adjuvant WBRT: (1) a standard photon beam (2) and an electron beam technique on the tumour bed of the same patients. The plans were analyzed for the dosimetric coverage of the CT delineated irradiated volume. The minimal dose received by 95% of the target volume (D95), the minimal dose received by 90% of the target volume (D90) and geographic misses were evaluated. RESULTS: 15 patients were evaluated. The sequential photon and electron boost techniques resulted in inferior target volume coverage compared with the anticipated boost technique, with a median D95 of 96.3% (range 94.7-99.6%) and 0.8% (range 0-30%) and a median D90 of 99.1% (range 90.2-100%) and 54.7% (range 0-84.8%), respectively. We observed a geographic miss in 26.6% of sequential electron plans. The results of the anticipated boost technique were better: 99.4% (range 96.5-100%) and 97.1% (range 86.2-99%) for median D90 and median D95, respectively, and no geographic miss was observed. We observed a dose reduction to the heart, with left-sided breast irradiation, using the anticipated pre-operative boost technique, when analyzed for all dose-volume parameters. When compared with the sequential electron plans, the pre-operative photon technique showed a higher median ipsilateral lung Dmax. CONCLUSION: Our data show that an anticipated pre-operative photon boost results in a better coverage with respect to the standard sequential boost while also saving the organs at risk and consequently fewer side effects. ADVANCES IN KNOWLEDGE: This is the first dosimetric study that evaluated the association between an anticipated boost and neoadjuvant chemotherapy treatment. PMID- 27452267 TI - Establishment of national diagnostic reference levels for breast cancer CT protocols in radiation therapy. AB - OBJECTIVE: To establish whether CT dose variation occurs in breast cancer localization procedures between radiation therapy (RT) centres in Ireland and to propose diagnostic reference levels (DRLs) for this procedure. METHODS: All RT centres in Ireland were invited to participate in a dose audit survey, providing data on the CT dose index volume (CTDIvol), dose-length product (DLP), current time product (mAs), tube potential, scan length, slice thickness, scanning margins, use of automated exposure control (AEC) and scanner technology for 10 patients with breast cancer who were average sized. DRLs were derived for each dose descriptor by calculation of the rounded 75th percentile of the distribution of mean doses. RESULTS: Data were returned for 60 patients from 6 RT centres (50% response rate). Significant variation in mean CTDIvol and mean DLP was observed between centres (p < 0.0001). Mean scan lengths and mean mAs differed significantly between centres (p < 0.0001). Tube potential was 120 kV for all sequences across centres. AEC was employed in all but one centre. Proposed DRLs for breast localization are 26 mGy and 732 mGy cm for CTDIvol and DLP, respectively. CONCLUSION: CT dose variation occurs between centres, establishing a need for optimization. DRLs for breast cancer localization have been proposed with the potential for reduction in CT dose. ADVANCES IN KNOWLEDGE: This article provides the first reported DRL for breast cancer CT localization procedure in RT and can be used as a benchmark for comparison for other RT centres. PMID- 27452269 TI - Image quality assessment of single-shot turbo spin echo diffusion-weighted imaging with parallel imaging technique: a phantom study. AB - OBJECTIVE: This study aimed to evaluate the image quality and apparent diffusion coefficient (ADC) values of single-shot turbo spin echo (TSE) diffusion-weighted (DW) images obtained using a parallel imaging (PI) technique. METHODS: All measurements were performed on a 3.0-T whole-body MRI system and 32-channel phased-array coil. Signal-to-noise ratio (SNR) and ADC values were measured with a DW imaging (DWI) phantom comprising granulated sugar and agar. The SNRs were calculated using a subtraction method and compared among TSE-DW images at acceleration factors (AFs) of 1-4. Image blur was visually assessed on TSE-DW images of a pin phantom at AFs of 1-4. The ADC values were calculated using DW images with b = 0 and 1000 s mm(-2). The ADC values of TSE-DW images and echo planar imaging EPI-DW images were compared. RESULTS: The SNRs decreased as AFs increased, despite selecting the shortest echo time. A lower AF caused increased image blur in the phase-encoding direction. The ADC values of TSE-DWI tended to be lower than those of EPI-DWI, and AFs of 3 and 4 yielded variable ADC values on TSE-DW images. CONCLUSION: TSE-DWI with an AF of 3 or 4 yielded reduced SNRs; in addition, the image noise and artefacts associated with PI technique may have affected ADC measurements, despite improving image blur in the phase-encoding direction. ADVANCES IN KNOWLEDGE: Optimizing the imaging parameters of TSE-DWI is useful for providing good image quality and accurate ADC measurements. PMID- 27452268 TI - Evaluation of uterine ultrasound imaging in cervical radiotherapy; a comparison of autoscan and conventional probe. AB - OBJECTIVE: In cervical radiotherapy, it is essential that the uterine position is correctly determined prior to treatment delivery. The aim of this study was to evaluate an autoscan ultrasound (A-US) probe, a motorized transducer creating three-dimensional (3D) images by sweeping, by comparing it with a conventional ultrasound (C-US) probe, where manual scanning is required to acquire 3D images. METHODS: Nine healthy volunteers were scanned by seven operators, using the Clarity((r)) system (Elekta, Stockholm, Sweden). In total, 72 scans, 36 scans from the C-US and 36 scans from the A-US probes, were acquired. Two observers delineated the uterine structure, using the software-assisted segmentation in the Clarity workstation. The data of uterine volume, uterine centre of mass (COM) and maximum uterine lengths, in three orthogonal directions, were analyzed. RESULTS: In 53% of the C-US scans, the whole uterus was captured, compared with 89% using the A-US. F-test on 36 scans demonstrated statistically significant differences in interobserver COM standard deviation (SD) when comparing the C-US with the A US probe for the inferior-superior (p < 0.006), left-right (p < 0.012) and anteroposterior directions (p < 0.001). The median of the interobserver COM distance (Euclidean distance for 36 scans) was reduced from 8.5 (C-US) to 6.0 mm (A-US). An F-test on the 36 scans showed strong significant differences (p < 0.001) in the SD of the Euclidean interobserver distance when comparing the C-US with the A-US scans. The average Dice coefficient when comparing the two observers was 0.67 (C-US) and 0.75 (A-US). The predictive interval demonstrated better interobserver delineation concordance using the A-US probe. CONCLUSION: The A-US probe imaging might be a better choice of image-guided radiotherapy system for correcting for daily uterine positional changes in cervical radiotherapy. ADVANCES IN KNOWLEDGE: Using a novel A-US probe might reduce the uncertainty in interoperator variability during ultrasound scanning. PMID- 27452270 TI - Platelet-Rich Fibrin With 1.2% Rosuvastatin for Treatment of Intrabony Defects in Chronic Periodontitis: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Regenerative periodontal therapy encompasses use of various bioactive agents that are not only inflammomodulatory but also osteoclast-inhibitory or, rather, osteostimulative. Hypolipidemic statin drugs, particularly rosuvastatin (RSV), are known to be associated with alveolar bone formation and periodontal improvements. Platelet analogs such as platelet-rich fibrin (PRF), being rich sources of growth factors, have also come into widespread periodontal regenerative use. The aim of this study is to evaluate and compare efficacy of open flap debridement (OFD) with or without PRF or PRF + 1.2% RSV gel in treatment of intrabony defects (IBDs) in patients with chronic periodontitis (CP). METHODS: Ninety individuals with a total of 90 IBDs were randomly assigned to one of three treatment groups: 1) OFD alone; 2) OFD + PRF; and 3) OFD + PRF + 1.2% RSV gel placement. Measurements recorded at baseline and 9 months after surgery were: 1) plaque index (PI); 2) modified sulcus bleeding index (mSBI); 3) probing depth (PD); 4) clinical attachment level (CAL); and 5) IBD depth. RESULTS: Significant PI and mSBI reductions were observed in all three groups. PRF placement significantly enhanced improvements in periodontal parameters compared with OFD alone. Addition of 1.2% RSV gel to PRF resulted in significantly greater CAL gain and PD and IBD depth reductions over 9 months compared with other groups. CONCLUSION: OFD with RSV (1.2%) and PRF results in significantly greater periodontal benefits compared with OFD alone or with PRF. PMID- 27452271 TI - Expression profiling and functional characterization of miR-192 throughout sheep skeletal muscle development. AB - MicroRNAs (miRNAs) are evolutionarily conserved, small, non-coding RNAs that have emerged as key regulators of myogenesis. Here, we examined the miRNA expression profiles of developing sheep skeletal muscle using a deep sequencing approach. We detected 2,396 miRNAs in the sheep skeletal muscle tissues. Of these, miR-192 was found to be up-regulated in prenatal skeletal muscle, but was down-regulated postnatally. MiR-192 expression also decreased during the myogenic differentiation of sheep satellite cells (SCs). MiR-192 overexpression significantly attenuated SCs myogenic differentiation but promoted SCs proliferation, whereas miR-192 inhibition enhanced SCs differentiation but suppressed SCs proliferation. We found that miR-192 targeted retinoblastoma 1 (RB1), a known regulator of myogenesis. Furthermore, knockdown of RB1 in cultured cells significantly inhibited SCs myogenic differentiation but accelerated SCs proliferation, confirming the role of RB1 in myogenesis. Taken together, our findings enrich the ovine miRNA database, and outline the miRNA transcriptome of sheep during skeletal muscle development. Moreover, we show that miR-192 affects SCs proliferation and myogenic differentiation via down-regulation of RB1. PMID- 27452273 TI - Erratum: Newly identified motifs in Candida albicans Cdr1 protein nucleotide binding domains are pleiotropic drug resistance subfamily-specific and functionally asymmetric. PMID- 27452272 TI - Association of lymph-node antigens with lower Gag-specific central-memory and higher Env-specific effector-memory CD8(+) T-cell frequencies in a macaque AIDS model. AB - Virus-specific CD8(+) T cells exert strong suppressive pressure on human/simian immunodeficiency virus (HIV/SIV) replication. These responses have been intensively examined in peripheral blood mononuclear cells (PBMCs) but not fully analyzed in lymph nodes (LNs), where interaction between CD8(+) T cells and HIV/SIV-infected cells occurs. Here, we investigated target antigen specificity of CD8(+) T cells in LNs in a macaque AIDS model. Analysis of virus antigen specific CD8(+) T-cell responses in the inguinal LNs obtained from twenty rhesus macaques in the chronic phase of SIV infection showed an inverse correlation between viral loads and frequencies of CD8(+) T cells with CD28(+) CD95(+) central memory phenotype targeting the N-terminal half of SIV core antigen (Gag N). In contrast, analysis of LNs but not PBMCs revealed a positive correlation between viral loads and frequencies of CD8(+) T cells with CD28(-)CD95(+) effector memory phenotype targeting the N-terminal half of SIV envelope (Env-N), soluble antigen. Indeed, LNs with detectable SIV capsid p27 antigen in the germinal center exhibited significantly lower Gag-N-specific CD28(+) CD95(+) CD8(+) T-cell and higher Env-N-specific CD28(-)CD95(+) CD8(+) T-cell responses than those without detectable p27. These results imply that core and envelope antigen-specific CD8(+) T cells show different patterns of interactions with HIV/SIV-infected cells. PMID- 27452275 TI - N-dimensional measurement-device-independent quantum key distribution with N + 1 un-characterized sources: zero quantum-bit-error-rate case. AB - We study N-dimensional measurement-device-independent quantum-key-distribution protocol where one checking state is used. Only assuming that the checking state is a superposition of other N sources, we show that the protocol is secure in zero quantum-bit-error-rate case, suggesting possibility of the protocol. The method may be applied in other quantum information processing. PMID- 27452274 TI - Regulation of Tlx3 by Pax6 is required for the restricted expression of Chrnalpha3 in Cerebellar Granule Neuron progenitors during development. AB - Homeobox gene Tlx3 is known to promote glutamatergic differentiation and is expressed in post-mitotic neurons of CNS. Contrary to this here, we discovered that Tlx3 is expressed in the proliferating progenitors of the external granule layer in the cerebellum, and examined factors that regulate this expression. Using Pax6(-/-)Sey mouse model and molecular interaction studies we demonstrate Pax6 is a key activator of Tlx3 specifically in cerebellum, and induces its expression starting at embryonic day (E)15. By Postnatal day (PN)7, Tlx3 is expressed in a highly restricted manner in the cerebellar granule neurons of the posterior cerebellar lobes, where it is required for the restricted expression of nicotinic cholinergic receptor-alpha3 subunit (Chrnalpha3) and other genes involved in formation of synaptic connections and neuronal migration. These results demonstrate a novel role for Tlx3 and indicate that Pax6-Tlx3 expression and interaction is part of a region specific regulatory network in cerebellum and its deregulation during development could possibly lead to Autistic spectral disorders (ASD). PMID- 27452276 TI - Demonstration of quantum synchronization based on second-order quantum coherence of entangled photons. AB - Based on the second-order quantum interference between frequency entangled photons that are generated by parametric down conversion, a quantum strategic algorithm for synchronizing two spatially separated clocks has been recently presented. In the reference frame of a Hong-Ou-Mandel (HOM) interferometer, photon correlations are used to define simultaneous events. Once the HOM interferometer is balanced by use of an adjustable optical delay in one arm, arrival times of simulta- neously generated photons are recorded by each clock. The clock offset is determined by correlation measurement of the recorded arrival times. Utilizing this algorithm, we demonstrate a proof-of-principle experiment for synchronizing two clocks separated by 4 km fiber link. A minimum timing stability of 0.44 ps at averaging time of 16000 s is achieved with an absolute time accuracy of 73.2 ps. The timing stability is verified to be limited by the correlation measurement device and ideally can be better than 10 fs. Such results shine a light to the application of quantum clock synchronization in the real high-accuracy timing system. PMID- 27452278 TI - Comparison of Electron Imaging Modes for Dimensional Measurements in the Scanning Electron Microscope. AB - Dimensional measurements from secondary electron (SE) images were compared with those from backscattered electron (BSE) and low-loss electron (LLE) images. With the commonly used 50% threshold criterion, the lines consistently appeared larger in the SE images. As the images were acquired simultaneously by an instrument with the capability to operate detectors for both signals at the same time, the differences cannot be explained by the assumption that contamination or drift between images affected the SE, BSE, or LLE images differently. Simulations with JMONSEL, an electron microscope simulator, indicate that the nanometer-scale differences observed on this sample can be explained by the different convolution effects of a beam with finite size on signals with different symmetry (the SE signal's characteristic peak versus the BSE or LLE signal's characteristic step). This effect is too small to explain the >100 nm discrepancies that were observed in earlier work on different samples. Additional modeling indicates that those discrepancies can be explained by the much larger sidewall angles of the earlier samples, coupled with the different response of SE versus BSE/LLE profiles to such wall angles. PMID- 27452277 TI - Nutrition and mortality in the elderly over 10 years of follow-up: the Three-City study. AB - In the last 20 years, many prospective cohort studies have assessed the relationships between food consumption and mortality. Result interpretation is mainly hindered by the limited adjustment for confounders and, to a lesser extent, the small sample sizes. The aim of this study was to investigate the association between dietary habits and all-cause mortality in a multicentre prospective cohort that included non-institutionalised, community-based elderly individuals (Three-City Study). A brief FFQ was administered at baseline. Hazard ratios (HR) and 95 % CI for all-cause mortality were estimated relative to the consumption frequency of several food groups, using Cox proportional hazards models adjusted for sex, centre, socio-demographic characteristics and health status indicators. Among the 8937 participants (mean age: 74.2 years, 60.7 % women), 2016 deaths were recorded during an average follow-up of 9 years. The risk of death was significantly lower among subjects with the highest fruit and vegetable consumption (HR 0.90; 95 % CI 0.82, 0.99, P=0.03) and with regular fish consumption (HR 0.89; 95 % CI 0.81, 0.97, P=0.01). The benefit of olive oil use was found only in women (moderate olive oil use: HR 0.80; 95 % CI 0.68, 0.94, P=0.007; intensive use: HR 0.72; 95 % CI 0.60, 0.85, P=0.0002). Conversely, daily meat consumption increased the mortality risk (HR 1.12; 95 % CI, 1.01, 1.24, P=0.03). No association was found between risk of death and diet diversity and use of various fats. These findings suggest that fruits/vegetables, olive oil and regular fish consumptions have a beneficial effect on the risk of death, independently of the socio-demographic features and the number of medical conditions. PMID- 27452279 TI - Di-(2-propylheptyl) phthalate (DPHP) and its metabolites in blood of rats upon single oral administration of DPHP. AB - Di-(2-propylheptyl) phthalate (DPHP) does not act as a reproductive toxicant or endocrine disruptor in contrast to other phthalates. Considering adverse effects of phthalates to be linked to their metabolism, it was the aim of the present study to investigate in the rat the blood burden of DPHP and its metabolites as a basis for understanding the toxicological behavior of DPHP. Rats were administered single oral doses of DPHP of 0.7 and 100mg/kg body weight. Concentration-time courses of DPHP and metabolites were monitored in blood. The areas under the concentration-time curves in blood (AUCs), normalized for the dose of DPHP, showed the following order: DPHP1/3 of the root length. CONCLUSIONS: The results did not indicate any association between AP and resin composite restorations. Neither the type nor the material of the restoration was of significance for periapical status as long as the quality was adequate. PMID- 27452295 TI - Temporal summation of the nociceptive withdrawal reflex involves deactivation of posterior cingulate cortex. AB - BACKGROUND: Temporal summation of pain sensation is pivotal both in physiological and pathological nociception. In humans, it develops in parallel with temporal summation of the nociceptive withdrawal reflex (NWR) of the lower limb, an objective representation of the temporal processing of nociceptive signals into the spinal cord. METHODS: To study the contribution of cortical and subcortical structures in temporal summation of pain reflex responses, we compared the fMRI signal changes related to the temporal summation threshold (TST) of the NWR with that related to the single NWR response. We studied 17 healthy subjects using a stimulation paradigm previously determined to evoke both the TST of the NWR (SUMM) and the NWR single response (SING). RESULTS: We found a significant activation in left (contralateral) primary somatosensory cortex (SI), bilateral secondary somatosensory cortex (SII), bilateral insula, anterior cingulate cortex (ACC) and bilateral thalamus during both SUMM and SING conditions. The SUMM versus SING contrast revealed a significant deactivation in the posterior cingulate cortex (PCC) and bilateral middle occipital gyrus in SUMM when compared to SING condition. CONCLUSIONS: Our data support the hypothesis that temporal summation of nociceptive reflex responses is driven through a switch between activation and deactivation of a specific set of brain areas linked to the default mode network. This behaviour could be explained in view of the relevance of the pain processing induced by temporal summation, recognized as a more significant potential damaging condition with respect to a single, isolated, painful stimulation of comparable pain intensity. SIGNIFICANCE: The study demonstrated that TST of the NWR involves a selective deactivation of PCC. PMID- 27452296 TI - Telocytes, communicators in healthy stroma and relation to inflammation and fibrosis. PMID- 27452298 TI - Antisense Sense in Osteoclasts. AB - This commentary highlights the article by Li et al that proposes regulating Wilm's tumor-1 antisense RNA to control pathological bone resorption. PMID- 27452299 TI - Laparoscopic sleeve gastrectomy versus laparoscopic mini gastric bypass: One year outcomes. AB - PURPOSE: Sleeve gastrectomy (LSG) and mini gastric bypass (LMGB) was considered as emerging procedures but are now considered for many authors as an alternative of the Roux-Y gastric bypass because of similar percentages of weight loss and better postoperative morbidity profiles. However, studies comparing LSG and LMGB are scarce. MATERIALS AND METHODS: From January 2010 to July 2014, 262 and 161 patients underwent LSG or LMGB in two centre of bariatric surgery, respectively. At one year, rate of follow-up was 88.4%. Main outcome was % of Total Weight Loss (%TWL) at one year. Propensity score matching and multivariable analyses were used to compensate for differences in some baseline characteristics. RESULTS: After matching LSG (N = 136) and LMGB (N = 136) groups did not differ for initial BMI (kg/m(2)) (43.4 +/- 6.5 vs. 42.8 +/- 5.0; P = 0.34), % of female patients (91.9% vs. 93.4%; P = 0.64), age (years) (41.2 +/- 12.3 vs. 41.2 +/- 11.3; P = 0.99) and diabetes (15.4% vs. 19.9%; P = 0.34). At one year, %TWL, change in BMI and rate of stenosis were higher for LMGB group, respectively: 38.2 +/- 8.4 vs. 34.3 +/- 8.4 (P < 0.0001); -16.5 +/- 4.6 vs. -14.9 +/- 4.4 (P = 0.005) and 16.9% vs. 0% (P < 0.0001). In multivariate analyses (beta coefficient), LMGB was a positive independent factor of %TWL (2.8; P = 0.008). CONCLUSION: LMGB seems to have better weight loss at one year compared to LSG with higher gastric complications. Further long term studies are needed. PMID- 27452300 TI - Surgical techniques for osteoporotic vertebral collapse with delayed neurological deficits: A systematic review. AB - INTRTODUCTION: Osteoporotic vertebral collapse (OVC) with delayed neurological deficits (DND) is one severe subtype of OVC, for which surgical intervention is more complicated and difficult. Although many individual case reports and series have described the surgery for stabilization and neurological decompression of OVC with DND, no systematic review has been published. METHODS: We searched eligible studies in PubMed, SCOPUS, EMBASE and ISIWeb of Knowledge for eligible studies and conducted comprehensive analysis. RESULTS: A total of 29 publications involving 596 patients of OVC with DND were included in this review. There are 36.6%, 60.6% and 2.8% of patients receiving anterior neural decompression and reconstruction, posterior surgery which can be further divided into 6 distinct groups, and posteroanterior surgery, respectively. Among them, patients in the posteroanterior surgery had the longest time (351.0 min) for operation and the largest volume of mean blood loss (2892.0 ml). For clinical outcomes, patients in the posterior spinal shortening osteotomy with direct neural decompression group had the most significantly LKA correction effect, with mean LKA correction 21.3 degrees , while the posterior decompression and posterior column reconstruction group exhibited the lowest LKA correction loss rate (14.7%). CONCLUSION: Although the optimal treatment has not been determined for patients of OVC with DND in this study, our analysis could provide guidance for choosing an appropriate approach. Besides, effective treatment for OVC with DND requires multidisciplinary collaboration, such as geriatricians, interventional radiologists, respiratory disease experts, and spine surgeons. On light of the above analysis, we believe that individualized surgical approach should be introduced based on the clinical characteristics of each patient. PMID- 27452297 TI - Pathogenesis of Kupffer Cells in Cholestatic Liver Injury. AB - Kupffer cells are the resident macrophages in the liver. They are located in hepatic sinusoid, which allows them to remove foreign materials, pathogens, and apoptotic cells efficiently. Activated Kupffer cells secrete various mediators, including cytokines and chemokines, to initiate immune responses, inflammation, or recruitment of other liver cells. Bile duct ligation (BDL) surgery in rodents is often studied as an animal model of cholestatic liver disease, characterized by obstruction of bile flow. BDL mice show altered functional activities of Kupffer cells compared with sham-operated mice, including elevated cytokine secretion and impaired bacterial clearance. Various mediators produced by other liver cells can regulate Kupffer cell activation, which suggest that Kupffer cells orchestrate with other liver cells to relay inflammatory signals and to maintain liver homeostasis during BDL-induced liver injury. Blocking or depletion of Kupffer cells, an approach for the treatment of liver diseases, has shown controversial implications. Procedures in Kupffer cell research have limitations and may produce various results in Kupffer cell research. It is important, however, to reveal underlying mechanisms of activation and functions of Kupffer cells, followed by hepatic inflammation and fibrosis. This review summarizes present Kupffer cell studies in cholestatic liver injury. PMID- 27452301 TI - Chromosomal location of the DnaA-reactivating sequence DARS2 is important to regulate timely initiation of DNA replication in Escherichia coli. AB - In Escherichia coli, the initiator protein ATP-DnaA promotes initiation of chromosome replication in a timely manner. After initiation, DnaA-bound ATP is hydrolyzed to yield ADP-DnaA, which is inactive in initiation. DnaA-reactivating sequences (DARS1 and DARS2) on the chromosome have predominant roles in catalysis of nucleotide exchange, producing ATP-DnaA from ADP-DnaA, which is prerequisite for timely initiation. Both DARS sequences have a core region containing a cluster of three DnaA-binding sites. DARS2 is more effective in vivo than DARS1, and timely activation of DARS2 depends on binding of two nucleoid-associated proteins, IHF and Fis. DARS2 is located centrally between the chromosomal replication origin oriC and the terminus region terC. We constructed mutants in which DARS2 was translocated to several chromosomal loci, including sites proximal to oriC and to terC. Replication initiation was inhibited in cells in which DARS2 was translocated to terC-proximal sites when the cells were grown at 42 degrees C, although overall binding efficiency of IHF and Fis to the translocated DARS2 was not affected. Inhibition was largely sustained even in cells lacking MatP, a DNA-binding protein responsible for terC-specific subchromosomal structure. These results suggest that functional regulation of DARS2 is correlated with its chromosomal location under certain conditions. PMID- 27452302 TI - Time for centralizing patients with ovarian cancer: what are we waiting for? PMID- 27452304 TI - Molecular epidemiology of Vibrio cholerae O1 in northern Vietnam (2007-2009), using multilocus variable-number tandem repeat analysis. AB - Cholera is an infectious disease of major concern in Vietnam and other Asian countries. In 2009, there was a large outbreak of cholera in northern Vietnam. To investigate relationships among isolates of the causative pathogen Vibrio cholerae in this region since 2007, we carried out a multilocus variable-number tandem repeat analysis (MLVA) of 170 isolates collected between 2007 and 2009. A total of 24 MLVA types were identified using seven loci. Five clones (1-5) were identified using five loci of the large V. cholerae chromosome; clones 1 and 2 were major, and the others were minor. Clone 1 isolates were responsible for the 2009 outbreak. A shift in the predominant clone occurred between 2007 and 2009, with clone 1 likely derived from clone 2. Moreover, the former was less diverse than the latter, suggesting a single source of cholera dissemination. Epidemiological data indicated a wavelet prior to the large outbreak, suggesting that drinking water source or food chain became contaminated during dissemination. Our results reveal the utility of MLVA for analysis of V. cholerae isolates within a relatively short period and broaden our understanding of its transmission and response to cholera. PMID- 27452305 TI - [Serum concentrations of glucose, cholesterol and triglycerides in men with prolactinoma treated with cabergoline]. PMID- 27452303 TI - OPN-a induces muscle inflammation by increasing recruitment and activation of pro inflammatory macrophages. AB - NEW FINDINGS: What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full-length human OPN-a isoform is the most pro inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD-integrin-dependent manner. OPN-a upregulates expression of tenascin-C (TNC), a known Toll-like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro-inflammatory effects of OPN-a, suggesting that a potential mechanism of OPN action is by promoting TNC-TLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro inflammatory activities of human OPN isoforms (OPN-a, OPN-b and OPN-c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN-a > OPN-b > OPN-c) and dog muscle (OPN-a = OPN-c). In healthy human muscle, mechanical loading also upregulated OPN-a expression (eightfold; P < 0.01), but did not significantly upregulate OPN-c expression (twofold; P > 0.05). In vitro, OPN-a displayed the most pronounced pro-inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN-a upregulated tenascin-C (TNC), a known Toll-like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN-mediated macrophage cytokine production. In summary, OPN-a is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPN-a promotes pro inflammatory signalling in both macrophages and myoblasts, possibly through induction of TNC-TLR4 signalling. Together, our findings suggest that specific targeting of OPN-a and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance. PMID- 27452306 TI - [Empowerment of patients and physicians' role in the long-term follow-up survivors of childhood cancer]. PMID- 27452307 TI - The effects of clopidogrel and omeprazole on platelet function in normal dogs. AB - Omeprazole is used concurrently with clopidogrel to reduce gastrointestinal adverse effects. In humans, the concurrent use of these two drugs can reduce the antiplatelet efficacy of clopidogrel. Our objective was to determine the effects of omeprazole and clopidogrel on platelet function in healthy dogs. A crossover study utilized turbidimetric aggregometry (ADP and collagen) and the PFA-100(r) with the collagen/ADP cartridge to evaluate platelet function in eight healthy dogs during the administration of clopidogrel (1 mg/kg/24 h p.o.), omeprazole (1 mg/kg/24 h p.o.), and a combination of clopidogrel and omeprazole. Drug metabolite concentrations were also measured. Compared to pretreatment, on Days 3 and 5, with ADP as the agonist, there was a significant decrease in maximum amplitude on aggregometry for both clopidogrel and clopidogrel/omeprazole groups. The following revealed no significant differences between clopidogrel and clopidogrel/omeprazole groups when compared on Days 3 and 5: maximum amplitude on aggregometry with ADP or collagen agonists, and PFA-100(r) closure times. When compared to the clopidogrel group, clopidogrel metabolite concentrations in the clopidogrel/omeprazole group were significantly higher on Days 3 and 5. The concurrent administration of omeprazole and clopidogrel in healthy dogs was associated with an increase in the plasma concentration of an inactive metabolite of clopidogrel, but does not significantly alter the antiplatelet effects of clopidogrel. PMID- 27452308 TI - Neuroprotective and Anti-Inflammatory Effects of Diphenylheptanes from the Fruits of Amomum tsaoko, a Chinese Spice. AB - Two novel diphenylheptanes, 2,3- dihydro-2 - (4' - hydroxy-phenylethyl) - 6 - [(3",4" - dihydroxy-5" - methoxy) phenyl] -4 - pyrone (CG-A) and 4 - dihydro-2 - (4' - hydroxy-phenylmethyl) -6 - [(3",4" - dihydroxy-5" - methoxyphenyl) methylene]-pyran-3, 5 - dione (CG-B), were isolated from the dried fruits of Amomum tsaoko, a commercially important spice. This study was designed to investigate their protective effects against H2O2-induced nerve injury, using PC 12 cells to determine the cell cytotoxicity and cell viability. The inhibitory effect on (nitric oxide) NO production was also determined in (lipopolysaccharide) LPS-stimulated macrophage RAW 264.7 cells. The results showed that CG-A and CG-B displayed significant neuroprotective effect and exhibited anti-inflammatory activity in a dose-dependent manner. These findings suggest that CG-A and CG-B are very important nutritional ingredients responsible for the neuroprotective and anti-inflammatory health benefits of A. tsaoko. PMID- 27452310 TI - Persistence of levoatrial cardinal vein with an interatrial course. PMID- 27452311 TI - Diagnostic evaluation and treatment strategy in patients with suspected prosthetic heart valve dysfunction: The incremental value of MDCT. AB - BACKGROUND: In patients with suspected prosthetic heart valve (PHV) dysfunction, routine evaluation echocardiography and fluoroscopy may provide unsatisfactory results for identifying the cause of dysfunction. This study assessed the value of MDCT as a routine, complementary imaging modality in suspected PHV-dysfunction for diagnosing the cause of PHV dysfunction and proposing a treatment strategy. METHODS: Patients with suspected PHV dysfunction were prospectively recruited. All patients underwent routine diagnostic work-up (TTE, TEE +/- fluoroscopy) and additional MDCT imaging. An expert panel reviewed all cases and assessed the diagnosis and treatment strategy, first based on routine evaluation only, second with additional MDCT information. RESULTS: Forty-two patients were included with suspected PHV obstruction (n = 30) and PHV regurgitation (n = 12). The addition of MDCT showed incremental value to routine evaluation in 26/30 (87%) cases for detecting the specific cause of PHV obstruction and in 7/12 (58%) regurgitation cases for assessment of complications and surgical planning. The addition of MDCT resulted in treatment strategy change in 8/30 (27%) patients with suspected obstruction and 3/12 (25%) patients with regurgitation. CONCLUSION: In addition to echocardiography and fluoroscopy, MDCT may identify the cause of PHV dysfunction and alter the treatment strategy. PMID- 27452312 TI - The 100 most-cited original articles in cardiac computed tomography: A bibliometric analysis. AB - Bibliometric analysis is the application of statistical methods to analyze quantitative data about scientific publications. It can evaluate research performance, author productivity, and manuscript impact. To the best of our knowledge, no bibliometric analysis has focused on cardiac computed tomography (CT). The purpose of this paper was to compile a list of the 100 most-cited articles related to cardiac CT literature using Scopus and Web of Science (WOS). A list of the 100 most-cited articles was compiled by order of citation frequency, as well a list of the top 10 most-cited guideline and review articles and the 20 most-cited articles of the years 2014-2015. The database of 100 most cited articles was analyzed to identify characteristics of highly cited publications. For each manuscript, the number of authors, study design, size of patient cohort and departmental affiliations were cataloged. The 100 most-cited articles were published from 1990 to 2012, with the majority (53) published between 2005 and 2009. The total number of citations varied from 3354 to 196, and the number of citations per year varied from 9.5 to 129.0 with a median and mean of 30.9 and 38.7, respectively. The majority of publications had a study patients sample size of 200 patients or less. The USA and Germany were the nations with the highest number of frequently cited publications. This bibliometric analysis provides insights on the most-cited articles published on the subject of cardiac CT and calcium volume, thus helping to characterize the field and guide future research. PMID- 27452313 TI - Irisin ameliorates hepatic glucose/lipid metabolism and enhances cell survival in insulin-resistant human HepG2 cells through adenosine monophosphate-activated protein kinase signaling. AB - Irisin is a newly identified myokine that promotes the browning of white adipose tissue, enhances glucose uptake in skeletal muscle and modulates hepatic metabolism. However, the signaling pathways involved in the effects on hepatic glucose and lipid metabolism have not been resolved. This study aimed to examine the role of irisin in the regulation of hepatic glucose/lipid metabolism and cell survival, and whether adenosine monophosphate-activated protein kinase (AMPK), a master metabolic regulator in the liver, is involved in irisin's actions. Human liver-derived HepG2 cells were cultured in normal glucose-normal insulin (NGNI) or high glucose-high insulin (HGHI/insulin-resistant) condition. Hepatic glucose and lipid metabolism was evaluated by glucose output and glycogen content or triglyceride accumulation assays, respectively. Our results showed that irisin stimulated phosphorylation of AMPK and acetyl-CoA-carboxylase (ACC) via liver kinase B1 (LKB1) rather than Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) in HepG2 cells. Irisin ameliorated hepatic insulin resistance induced by HGHI condition. Irisin reduced hepatic triglyceride content and glucose output, but increased glycogen content, with those effects reversed by dorsomorphin, an AMPK inhibitor. Furthermore, irisin also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and promoted cell survival in an AMPK-dependent manner. In conclusion, our data indicate that irisin ameliorates dysregulation of hepatic glucose/lipid metabolism and cell death in insulin-resistant states via AMPK activation. These findings reveal a novel irisin-mediated protective mechanism in hepatic metabolism which provides a scientific basis for irisin as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes mellitus. PMID- 27452314 TI - Extremely robust and post-functionalizable gold nanoparticles coated with calix[4]arenes via metal-carbon bonds. AB - Gold nanoparticles stabilized with a thin layer of post-functionalizable calix[4]arenes were prepared through the reductive grafting of a calix[4]arene tetra-diazonium salt. These particles show exceptional stability towards extreme pH, F(-), NaCl, and upon drying. Post-functionalization of the calix-layer was demonstrated, opening the way to a wide range of applications. PMID- 27452315 TI - Abortion training in Canadian obstetrics and gynecology residency programs. AB - OBJECTIVE: To evaluate the current state of abortion training in Canadian Obstetrics and Gynecology residency programs. STUDY DESIGN: Surveys were distributed to all Canadian Obstetrics and Gynecology residents and program directors. Data were collected on inclusion of abortion training in the curriculum, structure of the training and expected competency of residents in various abortion procedures. RESULTS: We distributed and collected surveys between November 2014 and May 2015. In total, 301 residents and 15 program directors responded, giving response rates of 55% and 94%, respectively. Based on responses by program directors, half of the programs had "opt-in" abortion training, and half of the programs had "opt-out" abortion training. Upon completion of residency, 66% of residents expected to be competent in providing first-trimester surgical abortion in an ambulatory setting, and 35% expected to be competent in second-trimester surgical abortion. Overall, 15% of residents reported that they were not aware of or did not have access to abortion training within their program, and 69% desired more abortion training during residency. CONCLUSION: Abortion training in Canadian Obstetrics and Gynecology residency programs is inconsistent, and residents desire more training in abortion. This suggests an ongoing unmet need for training in this area. Policies mandating standardized abortion training in obstetrics and gynecology residency programs are necessary to improve delivery of family planning services to Canadian women. IMPLICATIONS: Abortion training in Canadian Obstetrics and Gynecology residency programs is inconsistent, does not meet resident demand and is unlikely to fulfill the Royal College of Physicians and Surgeons of Canada objectives of training in the specialty. PMID- 27452316 TI - Contraceptive use among women with multiple sclerosis: a systematic review. AB - BACKGROUND: Contraception is an important consideration for women with multiple sclerosis (MS); however, little is known about the possible effects of hormonal contraception on disease progression or other adverse outcomes (e.g., thrombosis, low bone mineral density). OBJECTIVE: To evaluate the evidence on the safety of contraceptive use among women with MS. SEARCH STRATEGY: We searched the PubMed database for peer-reviewed articles published in any language from database inception through July 2015. SELECTION CRITERIA: We included studies that examined health outcomes among women diagnosed with MS initiating or continuing a contraceptive method. We excluded case reports and case series but included all other study designs. RESULTS: From 111 articles, we identified four studies (from 5 articles) that met our inclusion criteria. Evidence from one randomized controlled trial, two retrospective cohort studies, and one cross-sectional study suggests that use of combined oral contraceptives (COCs) or oral contraceptives (OCs) (type not specified) among women with MS does not worsen the clinical course of disease, defined as disability level, disease severity or progression, relapse or number of new brain lesions on magnetic resonance imaging (body of evidence grading Level I, fair to Level II-3, poor). No studies were identified that examined the safety of other contraceptive methods or examined other outcomes of interest (venous thromboembolism, changes in bone mineral density) related to contraceptive use among women with MS. CONCLUSIONS: Limited evidence suggests that COC or OC use after MS onset does not worsen the clinical course of disease. PMID- 27452317 TI - The US etonogestrel implant mandatory clinical training and active monitoring programs: 6-year experience. AB - OBJECTIVE: The objective was to monitor the effectiveness of the etonogestrel implant clinical training program through a voluntary active monitoring program (AMP). STUDY DESIGN: US health care providers underwent mandatory training by the manufacturer on etonogestrel implant insertion, localization and removal. After training, health care providers could enroll in a voluntary AMP to provide outcome data to meet a postmarketing commitment of the manufacturer with the US Food and Drug Administration (FDA). Those who volunteered completed and faxed forms to the manufacturer after implant insertion and removal detailing the procedure and device-related outcomes, including insertion-, localization- or removal-associated events. Experts reviewed outcome data quarterly, which the Sponsor then reported to the FDA. RESULTS: Among 42,337 health care providers completing the training program, 4294 (10.1%) volunteered to participate in the AMP. The 26,198 forms submitted over 6.4 years included more insertion (n=20,497) forms than removal forms (n=5701). The volunteers reported 646 events on 566 (2.2%) forms related to insertion (n=197), localization (n=34), removal (n=357) and "other" (n=58). Clinically important events included noninsertion (n=4), serum etonogestrel positive but implant not found (n=1), and possible nerve (n=66) or vascular (n=5) injury. The reports did not include any insertion-, localization- or removal-associated hospitalizations. Eight (0.14%) removal reports described referral for surgical implant removal. CONCLUSION: Events related to insertion, localization or removal of the etonogestrel implant are uncommon among US providers who received mandatory training in the use of the implant. IMPLICATIONS: This report presents results from the first mandatory US contraceptive training program. Health care providers volunteered to report information about etonogestrel implant insertion, localization and removal. Although the data do not demonstrate whether a mandatory program improves outcomes, they elucidate the utility and real-life experience that clinical training programs can provide. PMID- 27452318 TI - Intravascular migration of contraceptive implants: two more cases. AB - CASES: In addition to previously published case reports, further cases of intravascular migration of contraceptive implants have been identified from an information request to two national adverse reaction spontaneous reporting systems. We report on two new cases of insertion into the venous system with subsequent embolism to a pulmonary artery. CONCLUSION: Incorporating barium sulfate into the implant has facilitated diagnosis of these very rare adverse events with the initial diagnosis of embolism to the pulmonary arterial tree made by chest X-ray. Removal of an implant from a segmental branch of a pulmonary artery is technically challenging and not without risks. Unsuccessful removal appears to be preceded by a delay in diagnosis leading to endothelialization of the implant in the pulmonary arterial wall. IMPLICATIONS: Subdermal placement of contraceptive implants over the anterior surface of the biceps rather than in the sulcus between the biceps and triceps may negate this rare but reported risk. PMID- 27452319 TI - IMAGING DIAGNOSIS-USE OF RADIOGRAPHY, COMPUTED TOMOGRAPHY, AND ENDOSCOPY IN THE DIAGNOSIS OF ESOPHAGEAL PERFORATION BY AN EXTRA-LUMINAL TRACHEAL RING PROSTHESIS IN A GOLDEN RETRIEVER. AB - A 6-year-old neutered male, Golden retriever presented with regurgitation and excitement-induced coughing. Two years prior, extra-thoracic tracheal collapse was diagnosed and extra-luminal tracheal ring prostheses were placed. Radiographs at presentation showed mineralized and undulant cervical tracheal cartilages. A dorsally broad-based soft tissue opacity bulged into the caudal cervical tracheal lumen. Esophageal dysmotility and barium accumulation were identified at this level on contrast esophography. Computed tomography showed migration of a prosthetic tracheal ring, resulting in perforation of the esophagus. Hair, foreign material, and dynamic tracheal narrowing were identified on esophagoscopy and tracheoscopy, respectively. Esophagostomy and foreign body removal were performed. PMID- 27452321 TI - Pickering emulsions stabilized by hydrophilic nanoparticles: in situ surface modification by oil. AB - We propose a novel route for the stabilization of oil-in-water Pickering emulsions using inherently hydrophilic nanoparticles. In the case of dialkyl adipate oils, in situ hydrophobisation of the particles by dissolved oil molecules in the aqueous phase enables stable emulsions to be formed. Emulsion stability is enhanced upon decreasing the chain length of the oil due to its increased solubility in the precursor aqueous phase. The oil thus acts like a surfactant in this respect in which hydrogen bonds form between the carbonyl group of the ester oil and the hydroxyl group on particle surfaces. The particles chosen include both fumed and precipitated anionic silica and cationic zirconia. Complementary experiments including relevant oil-water-solid contact angles and infra-red analysis of dried particles after contact with oil support the proposed mechanism. PMID- 27452320 TI - Excessive Reversal of Epidermal Growth Factor Receptor and Ephrin Signaling Following Tracheal Occlusion in Rabbit Model of Congenital Diaphragmatic Hernia. AB - Congenital diaphragmatic hernia (CDH) causes severe pulmonary hypoplasia from herniation of abdominal contents into the thorax. Tracheal occlusion (TO) for human CDH improves survival, but morbidity and mortality remain high, and we do not fully understand the cellular pathways and processes most severely impacted by CDH and TO. We created a left diaphragmatic hernia (DH) in rabbit fetuses with subsequent TO and collected left lung sections for NextGen mRNA sequencing. DH, TO, and DHTO fetuses had comparable body and organ growth to control except for lower lung weights in DH (p<0.05). Of 13,687 expressed genes, DHTO had 687 differentially expressed genes compared to DH, but no other group-group comparison had more than 10. Considering genes in combination, many of the genes reduced in DH were more highly expressed in DHTO than in control. Benchmarking fetal rabbit lung gene expression to published lung development data, both DH and DHTO lungs were more highly correlated with the gene expression of immature lung. DNA synthesis was upregulated in DHTO compared to DH and ribosome and protein synthesis pathways were downregulated. DH reduced total and epithelial cell proliferation by half and two-thirds respectively, and DHTO increased proliferation by 2.5 and 3.4-fold respectively. Signaling pathways downregulated by DH and upregulated in DHTO were epidermal growth factor receptor signaling, ephrin signaling, and cell migration; however, levels of ephrin and EGFR signaling in DHTO exceeded that of control. Identification and inhibition of the ligands responsible for this dysregulated signaling could improve lung development in CDH. PMID- 27452322 TI - Impact of self-rated health among elderly on visits tofamily physicians. AB - Aim To evaluate animpact of eight dimensions of self-rated health measured by the SF-36 questionnaire on visits to family physicians among people older than 65. Methods This cross-sectional study was carried out in family medicine outpatient departments of the Public Institution Primary Health Care Center of Canton Sarajevo, Bosnia and Herzegovina. The study included 200 respondents divided into two age groups:18-65 (n=100) and older than 65 (n=100). The SF-36 questionnaire for self-assessment of health status and a questionnaire for the evaluation of socio-demographic characteristics of respondents and health care utilization were used. Results In the group of respondents aged 18-65 the dimension that was related to physical functioning was assessed as best(79.1+/-25.6), while the dimension concerning the vitality was assessed as the worst (56.1+/-19.9). In the group of respondents older than 65 the dimension related to social functioning was assessed as best (65.4+/-24.9), and the dimensions related to general health was assessed as worst (47.7+/-20.4). Family physicians were visited by significantly more respondents older than 65 than those from the age group 18-65 (94% vs.74%) (p= 0.000). Scores on the scales of general health (p=0.021) and social functioning (p=0.024) in respondents older than 65 had a significant impact on visits to family physicians. Conclusion Poor self-rated general health and better social functioning are important predictors of visiting family physicians by elderly persons. PMID- 27452323 TI - Relationship between ultrasonographically determined kidney volume and progression of chronic kidney disease. AB - Aim To investigate a correlation between calculated creatinine clearance as a measure of kidney's functional abilities and ultrasonographically determined kidney volume, which represents actual size of the kidney, in fact residual renal mass in chronic kidney disease, in order to determine possibilities of ultrasound as a diagnostic method in diagnosing and follow up of chronic renal disease. Methods Prospective study included 150 patients with registered demographic and anthropometric data, and also with relevant laboratory tests of renal function. Longitudinal diameter, thickness and width of the kidney and renal volume calculated according to the Dinkel's formula were measured by ultrasound. A correlation between the measured volume of the kidneys and calculated creatinine clearance was done by the Spearman method, with statistical significance of p<0.05. Results Statistically significant correlation between the estimated creatinine clearance values and the average of the calculated values of kidney volume was found (p<0.01). Average value of the kidneys' volume showed a linear decrease with the progression of chronic kidney disease: the kidney volume in the control healthy group was 171.7 +/- 32.6 mL (95.22- 229.59 mL), and in the subjects classified in stage IV it was 74.7 +/- 24.6 mL (43.22-165.65 mL). Conclusion Calculated volume of kidney well correlated with creatinine clearance as a measure of functional ability of the kidneys and with the stage of chronic renal disease. It can be used in clinical practice for monitoring of chronic kidney disease in conjunction with other clinical and laboratory parameters. PMID- 27452324 TI - Comparison of the accuracy and correctness of mortality estimates for Intensive Care Unit patients in internal clinics of the Czech Republic using APACHE II, APACHE IV, SAPS 3 and MPMoIII models. AB - Aim To verify and compare the accuracies of mortality predictions in the Intensive Care Unit (ICU) of the Internal Clinic of Central Military Hospital in Prague, Czech Republic, using model APACHE II and the newer systems of the APACHE IV, SAPS 3 and MPMo III. Methods The data were collected retrospectively between 2011 and 2012, 1000 patients were evaluated. The assessment of the overall accuracy of the mortality predictions was performed using the standardized mortality ratio (SMR), and the calibration was assessed using the Lemeshow-Hosmer "goodness-of-fit" C statistic. Discrimination was evaluated using ROC curves based on calculations of the areas under the curve (AUCs). Results The APACHE II, SAPS 3, and MPMo III systems significantly overestimated the expected mortality, whereas the APACHE IV model led to correct estimations of the overall mortality. The discrimination capabilities of the models assessed according to the constructions of the ROC curves were evaluated as good, only the APACHE II was evaluated as satisfactory. The calibrations of all models were evaluated as unsatisfactory. Conclusion The best mortality estimation for the investigated population sample was provided by the APACHE IV system. The discrimination capabilities of all models for the studied population were satisfactory, but the calibration of all of the systems was unsatisfactory. The conclusions of our study are limited by the relatively small size of the investigated sample and the fact that this study was conducted at only a single site. PMID- 27452325 TI - Radiological evaluation of lumbosacral spine for post discectomy segmental instability. AB - Aim To establish presence of segmental instability in patients operated with standard discectomy comparing measurement of translation and rotation on postoperative functional radiographs of lumbosacral spine with reference values,and to explore difference between patients operated on one or two levels. Methods The study included 71 patients, who were operated due to herniated lumbar disc. They were divided into two groups operated on one level (group A) or two adjacent levels (group B). All patients had been imaged in a standing position with functional lateral radiography. Radiographic images were digitized and then computerized measurement of translation and rotation was made. Measurement data were compared between the groups and with reference values obtained in healthy adults. Results Standard lumbar discectomy leads to an increase in translation, however, it reached statistical significance only for L4/L5 level and a decrease of rotation, which showed statistical significance for all samples, relative to the reference values. There was no statistically significant difference in the values of translation and rotation between the groups for corresponding levels, except for the value of the rotation for L4/L5 level as adjacent, unoperated level. Comparison of translation and rotation between the operated and adjacent levels did not show a statistically significant difference. When it comes to comparing the measured and predicted translation, there was a statistically significant difference only at the L5/S1 as anunoperated level. Conclusion Standard discectomy does not lead to radiologically significant segmental instability, and two-level surgery has not caused more pronounced signs of instability comparing to onelevel surgery. PMID- 27452326 TI - Impact of timing on surgical outcome in patients with cauda equina syndrome caused by lumbar disc herniation. AB - Aim To analyze the relationship between timing of surgery and outcome in patients with cauda equina syndrome caused by lumbar disc herniation. Methods A retrospective, non-randomized clinical study included 25 consecutive patients with cauda equina syndrome (CES) caused by lumbar disc herniation. All patients were operated within 24 hours after hospitalization at the Department of Neurosurgery, Cantonal Hospital Zenica, Bosnia and Herzegovina, between January 2000 and December 2010. All patients were evaluated before surgery on the basis of complete history, neurological examination and neuroimaging evaluations using CT (computed tomography)and MRI (magnetic resonance imaging). Results Statistically significant difference between preoperative and postoperative bladder (p=0.05) and bowel (p=0.05) function was found. A significant number of patients had bladder and bowel recovery after surgery, nine (36%) and 11 (44%), respectively. Significant recovery of muscle strength was noted with complete recovery(5/5) in 12 (48%) and partial recovery in 13 (52%) patients. Complete sensory recovery was noted in 16 (64%), incomplete in four (16%), and in five (20%) patients there were no changes. Most commonly, patients with complete sensory recovery were operated within 48 hours of symptom onset. In most patients early surgery was associated with better outcome. Conclusion This research showed that early decompression correlated with better outcome. Patients with cauda equina syndrome must be cleared for surgery in optimal conditions and, if it possible within optimal timing for recovery (within 48 hours). PMID- 27452327 TI - Relation of red cell distribution width with dipper and non-dipper hypertension. AB - Aim Red cell distribution width (RDW), an index of erythrocyte size, is associated with high risk for cardiovascular disease. Nondipping hypertension (HT) is lack of nocturnal fall in blood pressure(BP). The association between RDW and non-dipping BP in normotensive and hypertensive patients was investigated. Methods A total of 170 patients were categorized into 4 groups: Normotensive Dipper (NT-D), Normotensive-Non-dipper (NTND), Hypertensive-Dipper (HT-D) and Hypertensive-Non-dipper(HT-ND). RDW and hs-CRP levels were measured. Results Hypertensive patients had higher RDW and hs-CRP levels(14.5 +/- 0.87 vs.12.7 +/- 0.66, p<0.001 for RDW; 0.99 +/- 0.52 vs.0.63 +/- 0.43, p<0.001 for hs-CRP). Besides, the RDW levels were higher in non-dippers (13.0 +/- 0.63 vs.12.4 +/- 0.55, p<0.001 for NT-ND and NT-D; 14.9 +/- 0.78 vs.14.2 +/- 0.82, p<0.001 for HT ND and HT-D) Conclusion RDW is elevated in non-dipping BP both in normotensive and hypertensive subjects, which may be related with increased inflammatory state. PMID- 27452328 TI - Effects of magnesium sulfate on airway smooth muscle contraction in rats. AB - Aim To investigate the effect of magnesium sulfate (MgSO4) at different doses on isolated tracheal smooth muscle contraction in rats induced by different mechanisms. Methods Twelve rats' tracheas were placed into organ bath. Consecutively, acetylcholine (10-6,10-5,10-4 M), histamine(10-8,10-5,10-3 M) and KCl (30,60 mM) solutions was administered for contractions. MgSO4 from 10-4 to 10 1 M concentrations were subsequently administered after each constrictive agent and relaxation degrees were recorded. Results In the acetylcholine and KCl groups, dose dependent strong contractions were observed, but not in the histamine group and that group was excluded. Significant relaxation occurred with gradually increasing doses of MgSO4. In the high dose KCl group, a slight increase in contractions after the administration of 10-4 and 10-3 M MgSO4 was recorded. Conclusion We suggest that MgSO4 is effective in relaxing airway smooth muscle contractions caused by different factors; however, it must be considered that low doses of MgSO4 may only lead to a slight increase in contractions. PMID- 27452329 TI - Secular trend of anthropometric parameters of newborns in municipalities of Tuzla Canton (1976 - 2007). AB - Aim To determine the acceleration of birth weight and birth length of newborns in the municipalities of Tuzla Canton in the last four decades. Tuzla Canton (TC) as an administrative territorial unit of the FBiH includes 13 municipalities. Methods In this retrospective study data from the Protocol Book of Gynecology and Obstetrics Clinic, University Clinical Center, from 1976 to 2007 were used. The sample of live-born infants by municipalities was divided into four sub-samples: a subsample of infants born in 1976, 1987, 1997 and 2007. During the monitored years there were 19,312 live births in Tuzla Canton (TC), but the study included 17,907 newborns of both sexes. Statistical data processing was performed using standard methods, descriptive and inference statistics. Results Ascertained results of the secular trend for birth weight showed that this parameter had positive values in seven municipalities, but in six municipalities it was negative. The highest values of increasing birth length of newborns, which were statistically significant, were found in the municipalities of Srebrenik and this increase was 0.06 cm per year. Conclusion Different values of the secular trend in the monitored TC are result of different socio-economic and ecological conditions in these municipalities, as well as of violent mass population migration that occurred as a result of the war in BiH in the period from 1992 to 1995. PMID- 27452330 TI - IGFBP-1 marker of cervical ripening and predictor of preterm birth. AB - Aim To establish a correlation between positive values of IGFBP-1(>10 mg/L, Actim Partus Test, APT) and premature cervical ripening in imminent preterm labor. Methods A prospective study was conducted in primary health care centers in Tuzla, Gynecology and Obstetrics Clinic of the University Clinical Centre in Tuzla and General Hospital Tesanj. The study included 50 women (singleton pregnancy, 28-37 week) with imminent preterm labor diagnosed by cervical biometry and modified Bishop score) (examinees) and 30 healthy pregnant women (control group). The presence of IGFBP-1 was tested in cervical secretion several times in weeks 28-37 until a positive test was shown. Results IGFBP-1 was positive in 43 (86%) examinees and in six (20%) patients from the control group (p=0.001). In 31 (62%) examinees APT was positive in weeks 28-30, and in nine (18%) in weeks 31- 33, while three (6%) examinees had positive test in 34-37 week; in the control group, three (10%) were tested positive in weeks 31-33 and three (10%) in weeks 34-37. At first testing (28-30 weeks) APT was statistically significantly more frequently positive in the examined group (p<0.05). Later, tests did not find statistically significant difference in the frequency of positivity between the control and examined group (p=0.08). Conclusion Elevated values of IGFBP -1 in cervical secretion were highly correlated with preterm labor. Screening for IGFBP could help in preventing preterm labor and its complications. PMID- 27452331 TI - A new interlayer potential for hexagonal boron nitride. AB - A new interlayer potential is developed for interlayer interactions of hexagonal boron nitride sheets, and its performance is compared with other potentials in the literature using molecular dynamics simulations. The proposed potential contains Coulombic and Lennard-Jones 6-12 terms, and is calibrated with recent experimental data including the hexagonal boron nitride interlayer distance and elastic constants. The potentials are evaluated by comparing the experimental and simulated values of interlayer distance, density, elastic constants, and thermal conductivity using non-equilibrium molecular dynamics. The proposed potential is found to be in reasonable agreement with experiments, and improves on earlier potentials in several respects. Simulated thermal conductivity values as a function of the number of layers and of temperature suggest that the proposed LJ 6-12 potential has the ability to predict some phonon behaviour during heat transport in the out-of-plane direction. PMID- 27452332 TI - Geometrical control of the interatomic coulombic decay process in quantum dots for infrared photodetectors. AB - In electron dynamics calculations the interatomic Coulombic decay (ICD) process has recently been shown to take place in two vertically-aligned quantum dots (QDs). Energy emitted during the relaxation of one electron in one QD is converted into kinetic energy of another electron ejected from a neighboring QD. As the electronic structure of QDs can be controlled by their geometries, we prove here in thorough scans of the transversal and vertical QD confinement potentials' widths that geometries are likewise control parameters for ICD. Such a comprehensive investigation has been enabled by a significant development of the calculations in terms of speed achieved among others by optimization of the grid and Coulomb interaction operator representations. As key result of this study we propose two cigar-shaped singly-charged GaAs QDs vertically aligned in the direction of their long side for a most efficient QD ICD realization useful for an infrared photodetector. (c) 2016 Wiley Periodicals, Inc. PMID- 27452333 TI - Water Touch-and-Bounce from a Soft Viscoelastic Substrate: Wetting, Dewetting, and Rebound on Bitumen. AB - Understanding the interaction between liquids and deformable solid surfaces is a fascinating fundamental problem, in which interaction and coupling of capillary and viscoelastic effects, due to solid substrate deformation, give rise to complex wetting mechanisms. Here we investigated as a model case the behavior of water drops on two smooth bitumen substrates with different rheological properties, defined as hard and soft (with complex shear moduli in the order of 10(7) and 10(5) Pa, respectively, at 1 Hz), focusing both on wetting and on dewetting behavior. By means of classical quasi-static contact angle measurements and drop impact tests, we show that the water drop behavior can significantly change from the quasi-static to the dynamic regime on soft viscoelastic surfaces, with the transition being defined by the substrate rheological properties. As a result, we also show that on the hard substrate, where the elastic response is dominant under all investigated conditions, classical quasi-static contact angle measurements provide consistent results that can be used to predict the drop dynamic wetting behavior, such as drop deposition or rebound after impact, as typically observed for nondeformable substrates. Differently, on soft surfaces, the formation of wetting ridges did not allow to define uniquely the substrate intrinsic advancing and receding contact angles. In addition, despite showing a high adhesion to the soft surface in quasi-static measurements, the drop was surprisingly able to rebound and escape from the surface after impact, as it is typically observed for hydrophobic surfaces. These results highlight that measurements of wetting properties for viscoelastic substrates need to be critically used and that wetting behavior of a liquid on viscoelastic surfaces is a function of the characteristic time scales. PMID- 27452334 TI - Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome. AB - OBJECTIVE: To use whole exome sequencing (WES) of a family trio to identify a genetic cause for polyvalvular syndrome. METHODS AND RESULTS: A male child was born with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus that were closed surgically. Subsequently, the phenotype of polyvalvular syndrome with involvement of both semilunar and both atrioventricular valves emerged. His family history was negative for congenital heart disease. Because of hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism, either Noonan syndrome- or William syndrome-spectrum disorders were suspected clinically. However, chromosomal analysis was normal and commercially available Noonan syndrome and William syndrome genetic tests were negative. Whole exome sequencing of the patient and both parents was performed. Variants were analyzed by sporadic and autosomal recessive inheritance models. A sporadic mutation, annotated as c.1491 T > A, in TAB2, resulting in a nonsense mutation, p.Y497X, in the TAB2-encoded TGF-beta activated kinase 1 (TAK1) was identified as the most likely disease-susceptibility gene. This mutation results in elimination of the terminal 197 amino acids, including the C-terminal binding motif critical for interactions with TRAF6 and TAK1. CONCLUSIONS: The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome. PMID- 27452336 TI - Patient safety and quality improvement: a 'CLER' time to move beyond peripheral participation. AB - In the United States, the Accreditation Council for Graduate Medical Education (ACGME) has instituted a new program, the Clinical Learning Environment Review (CLER), that places focus in six important areas of the resident and fellow working and learning environment. Two of these areas are patient safety and quality improvement (QI). In their early CLER reviews of institutions housing ACGME-accredited training programs, ACGME has found that despite significant progress in patient safety and QI to date much work remains, especially when it comes to meaningful engagement of medical trainees in this work. In this article, the authors argue that peripheral involvement of trainees in patient safety and QI work does not allow the experiential learning that is necessary for professional development and the ultimate ability to execute performance that meets the needs of patients in contemporary clinical practice. Rather, as leaders in patient safety and QI have advocated since early in this movement, embedded and immersed experiences are necessary for learning and success. PMID- 27452335 TI - Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRbeta activity. AB - Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11 H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293T cells co transfected with full length human LXRbeta expression vector. The 25,25-difluoro 27-norcholestenoic acid was an inverse agonist and antagonist similar to its non fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5 ene-3beta,26-diol was an agonist. Molecular dynamics simulation of the ligand receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the case of the difluoroalcohol, the fluorine atoms actively participated in the interaction with several residues in the ligand binding pocket leading to a stabilization of the active receptor conformation. PMID- 27452337 TI - Targeting the angio-proteostasis network: Combining the forces against cancer. AB - The VEGF family of pro-angiogenic factors has represented a pillar for targeted cancer therapy for more than a decade. In comparison, the field of protein homeostasis (proteostasis) focusing on the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, has just recently emerged as an attractive anti-cancer approach. Recent findings suggest that both signaling pathways are incontestably interrelated to ensure cell survival. Herein, we summarize recent findings that demonstrate how these two fundamental aspects of cancer cell survival intersect and provide genetic and pharmacological evidence of the interplay between angiogenic factors such as VEGF-A or PlGF and the individual members of the UPR such as IRE1, PERK and ATF6. We further describe how this interaction does not only affect the cancer cells, but also the surrounding microenvironmental niche that is also involved in tumor progression. Furthermore, by summarizing the recent therapeutic implications of both anti angiogenic and proteostatic approaches, we emphasize how these novel findings could be used synergistically to improve cancer therapy. PMID- 27452338 TI - MicroRNAs and psychiatric disorders: From aetiology to treatment. AB - The emergence of psychiatric disorders relies on the interaction between genetic vulnerability and environmental adversities. Several studies have demonstrated a crucial role for epigenetics (e.g. DNA methylation, post-translational histone modifications and microRNA-mediated post-transcriptional regulation) in the translation of environmental cues into adult behavioural outcome, which can prove to be harmful thus increasing the risk to develop psychopathology. Within this frame, non-coding RNAs, especially microRNAs, came to light as pivotal regulators of many biological processes occurring in the Central Nervous System, both during the neuronal development as well as in the regulation of adult function, including learning, memory and neuronal plasticity. On these basis, in recent years it has been hypothesised a central role for microRNA modulation and expression regulation in many brain disorders, including neurodegenerative disorders and mental illnesses. Indeed, the aim of the present review is to present the most recent state of the art regarding microRNA involvement in psychiatric disorders. We will first describe the mechanisms that regulate microRNA biogenesis and we will report evidences of microRNA dysregulation in peripheral body fluids, in postmortem brain tissues from patients suffering from psychopathology as well as in animal models. Last, we will discuss the potential to consider microRNAs as putative target for pharmacological intervention, using common psychotropic drugs or more specific tools, with the aim to normalize functions that are disrupted in different psychiatric conditions. PMID- 27452339 TI - The ways and means of fragment-based drug design. AB - Fragment-based drug design (FBDD) has emerged as a mainstream approach for the rapid and efficient identification of building blocks that can be used to develop high-affinity ligands against protein targets. One of the strengths of FBDD is the relative ease and low cost of the primary screen to identify fragments that bind. However, the fragments that emerge from primary screens often have low affinities, with KD values in the high MUM to mM range, and a significant challenge for FBDD is to develop the initial fragments into more potent ligands. Successful fragment elaboration often requires co-structures of the fragments bound to their target proteins, as well as a range of biophysical and biochemical assays to track potency and efficacy. These challenges have led to the development of specific chemical strategies for the elaboration of weakly-binding fragments into more potent "hits" and lead compounds. In this article we review different approaches that have been employed to meet these challenges and describe some of the strategies that have resulted in several fragment-derived compounds entering clinical trials. PMID- 27452340 TI - Influence of steroid hormones on ventricular repolarization. AB - QT interval prolongation, corrected for heart rate (QTc), either spontaneous or drug-induced, is associated with an increased risk of torsades de pointes and sudden death. Women have longer QTc than men and are at higher risk of torsades de pointes, particularly during post-partum and the follicular phase. Men with peripheral hypogonadism have longer QTc than healthy controls. The role of the main sex steroid hormones has been extensively studied with inconsistent findings. Overall, estradiol is considered to promote QTc lengthening while progesterone and testosterone shorten QTc. New findings suggest more complex regulation of QTc by sex steroid hormones involving gonadotropins (i.e. follicle stimulating hormone), the relative concentrations of sex steroid hormones (which depends on gender, i.e., progesterone/estradiol ratio in women). Aldosterone, another structurally related steroid hormone, can also prolong ventricular repolarization in both sex. Better understanding of pathophysiological hormonal processes which may lead to increased susceptibility of women (and possibly hypogonadic men) to drug-induced arrhythmia may foster preventive treatments (e.g. progesterone in women). Exogenous hormonal intake might offer new therapeutic opportunities or, alternatively, increase the risk of torsades de pointes. Some exogenous sex steroids may also have paradoxical effects on ventricular repolarization. Lastly, variations of QTc in women linked to the menstrual cycle and sex hormone fluctuations are generally ignored in regulatory thorough QT studies. Investigators and regulatory agencies promoting inclusion of women in thorough QT studies should be aware of this source of variability especially when studying drugs over several days of administration. PMID- 27452342 TI - Direct versus indirect inlay/onlay composite restorations in posterior teeth. A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the long-term clinical performance of direct versus indirect composite inlays/onlays in posterior teeth. DATA: Screening for inclusion eligibility, quality assessment of studies and data extraction was performed independently by two authors. SOURCES: The electronic databases MEDLINE, EMBASE, Cochrane Oral Health Group's Trials Register and CENTRAL were searched (14.12.2015), with no restriction to publication date or language. We included only randomised controlled trials (RCTs) and evaluated them according to Cochrane risk of bias tool. The main outcome assessed was the restoration failure, determined by several clinical parameters. STUDY SELECTION: Two studies concerning direct and indirect inlays (82 patients with 248 restorations) and one study for onlays (157 patients with 176 restorations) satisfied the inclusion criteria. Two trials, one of unclear and one of high risk of bias, could be mathematically combined. The meta-analysis indicated no statistically significant difference in the risk failure between direct and indirect inlays, after 5 years (RR: 1.54; 95% Cl: 0.42, 5.58; p=0.52) or 11 years of function (RR: 0.95; 95% Cl: 0.34, 2.63; p=0.92). Only one parameter, the marginal discoloration, slightly favored direct inlays after 11 years (RR: 0.41; 95% Cl: 0.17, 0.96; p=0.04). Only one study dealt with onlays; an overall 5-year survival of 87% (95% CI: 81-93%) was reported. CONCLUSION: The difference of the two techniques did not reach statistical significance in order to recommend one technique over the other. The scarcity of primary studies support the need for further well-designed long-term studies in order to reach firm conclusions about both techniques. CLINICAL SIGNIFICANCE: Resin composite materials, placed directly or indirectly, exhibit a promising long-term clinical performance when rehabilitation of posterior teeth is needed. Although many years in clinical practice, the selection of the best treatment protocol still remains subjective. The available studies, and their synthesis, cannot provide reliable evidence in this field. PMID- 27452341 TI - Mitochondrial compromise in 3-year old patas monkeys exposed in utero to human equivalent antiretroviral therapies. AB - Antiretroviral (ARV) drug therapy, given during pregnancy for prevention of mother-to-child transmission of human immunodeficiency virus 1 (HIV-1), induces fetal mitochondrial dysfunction in some children. However, the persistence/reversibility of that dysfunction is unclear. Here we have followed Erythrocebus patas (patas) monkey offspring for up to 3 years of age (similar in development to a 15-year old human) after exposure of the dams to human equivalent in utero ARV exposure protocols. Pregnant patas dams (3-5/exposure group) were given ARV drug combinations that included zidovudine (AZT)/lamivudine (3TC)/abacavir (ABC), or AZT/3TC/nevirapine (NVP), for the last 10 weeks (50%) of gestation. Infants kept for 1 and 3 years also received drug for the first 6 weeks of life. In offpsring at birth, 1 and 3 years of age mitochondrial morphology, examined by electron microscopy (EM), was compromised compared to the unexposed controls. Mitochondrial DNA (mtDNA), measured by hybrid capture chemiluminescence assay (HCCA) was depleted in hearts of patas exposed to AZT/3TC/NVP at all ages (P < 0.05), but not in those exposed to AZT/3TC/ABC at any age. Compared to unexposed controls, mitochondrial reserve capacity oxygen consumption rate (OCR by Seahorse) in cultured bone marrow mesenchymal fibroblasts from 3-year-old patas offspring was ~50% reduced in AZT/3TC/ABC exposed patas (P < 0.01), but not in AZT/3TC/NVP-exposed patas. Overall the data show that 3-year-old patas sustain persistent mitochondrial dysfunction as a result of perinatal ARV drug exposure. Environ. Mol. Mutagen. 57:526-534, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27452343 TI - Effects of surface properties of polymer-based restorative materials on early adhesion of Streptococcus mutans in vitro. AB - OBJECTIVE: We investigated the effects of the surface properties of polymer-based restorative materials on early adhesion of Streptococcus mutans (UA159) in vitro. METHODS: Four direct polymer-based restorative materials, including a nanoparticle restorative (FiltekTM Z350, 3M ESPE, USA), a nano hybrid universal restorative (FiltekTM Z250 XT, 3M ESPE, USA), a low shrink posterior restorative (FiltekTM P90, 3M ESPE, USA) and a polymer-based pre-reacted glass ionomer (Beautifil II, Shofu, Japan), were selected. After polishing under different conditions, surface morphology was examined using scanning electron microscopy. Surface roughness (SR), water contact angle (CAW) and surface free energy (SFE) were determined by profilometry and the sessile drop method. Early adhesion of S. mutans was investigated using confocal laser scanning microscopy. The area occupied by adherent bacteria (A%) was calculated with COMSTAT2 software. The correlations between A% and SR, CAW, and SFE were analyzed by linear regression using SPSS 20.0 software at a significance level of 0.05. RESULTS: The value of A% was strongly correlated with SR (r=0.893, P<0.01) for surface roughness (Ra) of 0.02-0.80MUm, whereas a weaker correlation was obtained between A% and SR when Ra<=0.20MUm (r=0.643, P < 0.01). On super smooth surfaces (0.02MUm<=Ra<=0.06MUm), SR did not influence early bacterial adhesion (r=0.001, P>0.05), a medium positive correlation between A% and SFE was obtained (r=0.426, P<0.01), and no correlation between A% and CAW was found (r=-0.028, P>0.05) CONCLUSIONS: Early adhesion of S. mutans on direct polymer-based restorative materials was mainly affected by SR. SFE influenced early adhesion of S. mutans on super smooth surfaces, while hydrophobicity did not. PMID- 27452344 TI - Erratum to: The Actinobacterium Corynebacterium glutamicum, an Industrial Workhorse. AB - This erratum is being published to correct the 3rd author's name of above manuscript by Lee et al. that was published in Journal of Microbiology and Biotechnology (2016, 26: 807-822). The 3rd author name(Eungsoo Kim) should appear as 'Eung-Soo Kim'. PMID- 27452345 TI - Cell-on-hydrogel platform made of agar and alginate for rapid, low-cost, multidimensional test of antimicrobial susceptibility. AB - Antimicrobial resistance (AMR) is a rapidly increasing threat to the effective treatment of infectious diseases worldwide. The two major remedies include: (1) using narrow-spectrum antibiotics based on rapid diagnosis; and (2) developing new antibiotics. A key part of both remedies is the antimicrobial susceptibility test (AST). However, the current standard ASTs that monitor colony formation are costly and time-consuming and the new strategies proposed are not yet practical to be implemented. Herein, we report a strategy to fabricate whole-hydrogel microfluidic chips using alginate-doped agar. This agar-based microfabrication makes it possible to prepare inexpensive hydrogel devices, and allows a seamless link between microfluidics and conventional agar-based cell culture. Different from common microfluidic systems, in our system the cells are cultured on top of the device, similar to normal agar plate culture; on the other hand, the microfluidic channels inside the hydrogel allow precise generation of linear gradient of drugs, thus giving a better performance than the conventional disk diffusion method. Cells in this system are not exposed to any shear flow, which allows the reliable tracking of individual cells and AST results to be obtained within 2-3 hours. Furthermore, our system could test the synergistic effect of drugs through two-dimensional gradient generation. Finally, the platform could be directly implemented to new drug discovery and other applications wherein a fast, cost-efficient method for studying the response of microorganisms upon drug administration is desirable. PMID- 27452346 TI - Molecular mechanisms and the conflict between courtship and aggression in three spined sticklebacks. AB - In nature, animals often face conflicting demands. For example, breeding males must attract a mate but at the same time be ready to defend against rivals. The molecular mechanisms by which the brain resolves behavioural trade-offs are largely unknown. In this study, we compared the brain transcriptional responses of territorial male three-spined sticklebacks to a mating opportunity with a female and to a territorial challenge by a rival male. We focused on the diencephalon and the cerebellum, two regions of the brain implicated in courtship and aggression. There was a set of genes that were differentially expressed in response to both a courtship opportunity and a territorial challenge. Closer inspection of the direction of regulation revealed that genes that were downregulated in response to a courtship opportunity were upregulated in response to a territorial challenge and vice versa. Our study reveals some of the potential molecular mechanisms underlying behavioural trade-offs between sex and aggression, along with a possible solution to the conflict via social context dependent gene regulation. PMID- 27452347 TI - Factors influencing remission in rheumatoid arthritis patients: results from Karnataka rheumatoid arthritis comorbidity (KRAC) study. AB - AIM: To study the prevalence of remission in rheumatoid arthritis (RA) patients and the influence of different factors like literacy, socioeconomic status, presence of comorbidity and treatment strategy in achieving remission. METHODS: The study involved 1990 RA patients who were recruited for the Karnataka Rheumatoid arthritis comorbidity (KRAC) study. Based on the factors evaluated, the study participants were classified as follows: age, < 30 years, 30-39 years, 40-49 years, 50-59 years and >= 60 years; educational status, illiterate/no formal education, high school or less, graduate, post-graduate and doctorate; family income (? per annum), < 50 000, 50-100 000, 100-500 000, and > 500 000; duration of illness prior (DOIP): <= 6 months, 6-24 months, 24-120 months and > 120 months. Joint counts were performed by a rheumatologist or trained joint assessor. To assess the treatment outcome, the disease activity score was calculated using the Disease activity Score of 28 joints - erythrocyte sedimentation rate (DAS 28-3 ESR). RESULTS: As per the DAS 28-3 ESR score, around 20% (n = 397) of the study subjects achieved remission. The corresponding mean +/ SD of DAS 28-3 ESR noted for remission and non-remission groups were 2.13 +/- 0.42 and 4.32 +/- 1.28. The majority of the patients were treated with double disease-modifying anti-rheumatic drugs (DMARDs) (60.7%). The likelihood of remission was found to be more in patients who reported DOIP <= 6 months. Furthermore, the chances of remission reduced with increase in patient's age and the highest remission rate was noted for 30-39 years age group (59%), followed by 40-49 years (35.4%) and 50-59 years (19.7%). CONCLUSION: The prevalence of remission noted was around 20%. Early treatment, escalating dose of DMARDs, and patient counseling are important contributing factors for attaining remission. PMID- 27452348 TI - A novel HLA-B*38 variant, B*38:15, detected in a Taiwanese individual. AB - One nucleotide substitution at residue 346 of HLA-B*38:02:01 results in a novel allele, HLA-B*38:15. PMID- 27452349 TI - Sex Differences in Pain. AB - Females greatly outnumber males as sufferers of chronic pain. Although social and psychological factors certainly play a role in the differences in prevalence and incidence, biological differences in the functioning of the immune system likely underlie these observed effects. This Review examines the current literature on biological sex differences in the functioning of the innate and adaptive immune systems as they relate to pain experience. With rodent models, we and others have observed that male mice utilize microglia in the spinal cord to mediate pain, whereas females preferentially use T cells in a similar manner. The difference can be traced to differences in cell populations, differences in suppression by hormones, and disparate cellular responses in males and females. These sex differences also translate into human cellular responses and may be the mechanism by which the disproportionate chronic pain experience is based. Recognition of the evidence underlying sex differences in pain will guide development of treatments and provide better options for patients that are tailored to their physiology. (c) 2016 Wiley Periodicals, Inc. PMID- 27452350 TI - An amphiphilic graft copolymer-based nanoparticle platform for reduction responsive anticancer and antimalarial drug delivery. AB - Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL(-1). Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (+/-)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block. PMID- 27452351 TI - Diversification of ortho-Fused Cycloocta-2,5-dien-1-one Cores and Eight- to Six Ring Conversion by sigma Bond C-C Cleavage. AB - Sequential treatment of 2-C6 H4 Br(CHO) with LiC=CR(1) (R(1) =SiMe3 , tBu), nBuLi, CuBr?SMe2 and HC=CCHClR(2) [R(2) =Ph, 4-CF3 Ph, 3-CNPh, 4-(MeO2 C)Ph] at 50 degrees C leads to formation of an intermediate carbanion (Z)-1,2-C6 H4 {CA (=O)C=CB R(1) }{CH=CH(CH(-) )R(2) } (4). Low temperatures (-50 degrees C) favour attack at CB leading to kinetic formation of 6,8-bicycles containing non classical C-carbanion enolates (5). Higher temperatures (-10 degrees C to ambient) and electron-deficient R(2) favour retro sigma-bond C-C cleavage regenerating 4, which subsequently closes on CA providing 6,6-bicyclic alkoxides (6). Computational modelling (CBS-QB3) indicated that both pathways are viable and of similar energies. Reaction of 6 with H(+) gave 1,2-dihydronaphthalen-1 ols, or under dehydrating conditions, 2-aryl-1-alkynylnaphthlenes. Enolates 5 react in situ with: H2 O, D2 O, I2 , allylbromide, S2 Me2 , CO2 and lead to the expected C-E derivatives (E=H, D, I, allyl, SMe, CO2 H) in 49-64 % yield directly from intermediate 5. The parents (E=H; R(1) =SiMe3 , tBu; R(2) =Ph) are versatile starting materials for NaBH4 and Grignard C=O additions, desilylation (when R(1) =SiMe) and oxime formation. The latter allows formation of 6,9-bicyclics via Beckmann rearrangement. The 6,8-ring iodides are suitable Suzuki precursors for Pd-catalysed C-C coupling (81-87 %), whereas the carboxylic acids readily form amides under T3P(r) conditions (71-95 %). PMID- 27452352 TI - Computer modelling of an impedance-controlled pulsing protocol for RF tumour ablation with a cooled electrode. AB - PURPOSE: To develop computer models to mimic the impedance-controlled pulsing protocol implemented in radiofrequency (RF) generators used for clinical practice of radiofrequency ablation (RFA), and to assess the appropriateness of the models by comparing the computer results with those obtained in previous experimental studies. METHODS: A 12-min RFA was modelled using a cooled electrode (17G, 3 cm tip) inserted in hepatic tissue. The short (transverse) diameter of the coagulation zone was assessed under in vivo (with blood perfusion (BP) and considering clamping) and ex vivo (at 21 degrees C) conditions. The computer results obtained by programming voltage pulses were compared with current pulses. RESULTS: The differences between voltage and current pulses were noticeable: using current instead of voltage allows larger coagulation zones to be created, due to the higher energy applied by current pulses. If voltage pulses are employed the model can accurately predict the number of roll-offs, although the waveform of the applied power is clearly not realistic. If current voltages are employed, the applied power waveform matches well with those reported experimentally, but there are significantly fewer roll-offs. Our computer results were overall into the ranges of experimental ones. CONCLUSIONS: The proposed models reproduce reasonably well the electrical-thermal performance and coagulation zone size obtained during an impedance-controlled pulsing protocol. PMID- 27452353 TI - Problems solutions. PMID- 27452354 TI - Washington medical update. PMID- 27452357 TI - Cme credit quiz. PMID- 27452356 TI - Demyelinative and degenerative diseases of the nervous system. AB - The greatest challenge to the wisdom and skill of physicians is presented by diseases for which no cure is known. The authors of this symposium, in explaining the characteristic clinical pictures of parkinsonism, the muscular dystrophies, multiple sclerosis, and dementia, have delineated the foundation of understanding of these conditions. With this knowledge practitioners can apply the authoritative measures available and at the same time give patients appropriate psychologic support. PMID- 27452358 TI - The medical bookshelf. PMID- 27452359 TI - Interstate postgraduate medical assembly. PMID- 27452361 TI - Therapeutic Index. PMID- 27452362 TI - Ciliopathies: Inpp5e links lipids, cysts and cilia. PMID- 27452363 TI - Anti-complement-factor H-associated glomerulopathies. AB - Atypical haemolytic uraemic syndrome (aHUS), an important cause of acute kidney injury, is characterized by dysregulation of the complement pathway, frequent need for dialysis, and progression to end-stage renal disease. Autoantibodies against complement factor H (FH), the main plasma regulatory protein of the alternative pathway of the complement system, account for a considerable proportion of children with aHUS. The autoantibodies are usually associated with the occurrence of a homozygous deletion in the genes encoding the FH-related proteins FHR1 and FHR3. High levels of autoantibodies, noted at the onset of disease and during relapses, induce functional deficiency of FH, whereas their decline, in response to plasma exchanges and/or immunosuppressive therapy, is associated with disease remission. Management with plasma exchange and immunosuppression is remarkably effective in inducing and maintaining remission in aHUS associated with FH autoantibodies, whereas terminal complement blockade with eculizumab is considered the most effective therapy in other forms of aHUS. Anti-FH autoantibodies are also detected in a small proportion of patients with C3 glomerulopathies, which are characterized by chronic glomerular injury mediated by activation of the alternative complement pathway and predominant C3 deposits on renal histology. PMID- 27452364 TI - Idiopathic hypercalciuria and formation of calcium renal stones. AB - The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall's plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is <400 mg per day, and treatment with potassium citrate has been used to prevent stones. Urine calcium levels >200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone disease. PMID- 27452365 TI - RNA Structural Modules Control the Rate and Pathway of RNA Folding and Assembly. AB - Structured RNAs fold through multiple pathways, but we have little understanding of the molecular features that dictate folding pathways and determine rates along a given pathway. Here, we asked whether folding of a complex RNA can be understood from its structural modules. In a two-piece version of the Tetrahymena group I ribozyme, the separated P5abc subdomain folds to local native secondary and tertiary structure in a linked transition and assembles with the ribozyme core via three tertiary contacts: a kissing loop (P14), a metal core-receptor interaction, and a tetraloop-receptor interaction, the first two of which are expected to depend on native P5abc structure from the local transition. Native gel, NMR, and chemical footprinting experiments showed that mutations that destabilize the native P5abc structure slowed assembly up to 100-fold, indicating that P5abc folds first and then assembles with the core by conformational selection. However, rate decreases beyond 100-fold were not observed because an alternative pathway becomes dominant, with nonnative P5abc binding the core and then undergoing an induced-fit rearrangement. P14 is formed in the rate-limiting step along the conformational selection pathway but after the rate-limiting step along the induced-fit pathway. Strikingly, the assembly rate along the conformational selection pathway resembles that of an isolated kissing loop similar to P14, and the rate along the induced-fit pathway resembles that of an isolated tetraloop-receptor interaction. Our results indicate substantial modularity in RNA folding and assembly and suggest that these processes can be understood in terms of underlying structural modules. PMID- 27452366 TI - Canonical DNA Repair Pathways Influence R-Loop-Driven Genome Instability. AB - DNA repair defects create cancer predisposition in humans by fostering a higher rate of mutations. While DNA repair is quite well characterized, recent studies have identified previously unrecognized relationships between DNA repair and R loop-mediated genome instability. R-loops are three-stranded nucleic acid structures in which RNA binds to genomic DNA to displace a loop of single stranded DNA. Mutations in homologous recombination, nucleotide excision repair, crosslink repair, and DNA damage checkpoints have all now been linked to formation and function of transcription-coupled R-loops. This perspective will summarize recent literature linking DNA repair to R-loop-mediated genomic instability and discuss how R-loops may contribute to mutagenesis in DNA-repair deficient cancers. PMID- 27452367 TI - Metabolic response evaluation for colorectal liver metastases and correlation to pathologic response and tumour markers. AB - BACKGROUND: Tumour metabolic response to chemotherapy is increasingly recognized as a prognostic indicator for colorectal cancer liver metastases (CRCLM). However, its clinical role and the underlying biological mechanism of its prognostic ability are unclear. This study compares metabolic to pathologic response for CRCLM, and correlates metabolic response to tumour expression of six key biomarkers. METHODS: Thirty-seven patients who had positron emission tomography imaging before and after pre-operative chemotherapy prior to liver resection for CRCLM were included. Metabolic response was assessed according to the positron emission tomography response criteria in solid tumours (PERCIST) and correlated to recurrence-free and overall survival. PERCIST was compared to tumour regression grading, computed tomography (CT) response, tumour necrosis and mucin and immunohistochemical expression of Ki-67, hypoxia inducible factor 1alpha, vascular endothelial growth factor, p53, p16 and vimentin. Area under the receiver operating characteristic curve (AUC), Kaplan-Meier survival, Spearman's correlation (rs ) and multivariate Cox regression analyses were used. RESULTS: PERCIST correlated significantly to 2-year mortality (AUC = 0.162, P < 0.01) and 2-year recurrence (AUC = 0.284, P = 0.03). Metabolically responsive tumours conferred a better overall survival (P = 0.01) and recurrence-free survival (P = 0.03). Tumour regression grading did not stratify for outcome. Metabolic response was significantly correlated to Ki-67 and p16 expression (rs = 0.559 and rs = 0.549, respectively). Multivariate analysis revealed only PERCIST to be correlated to death and recurrence. CONCLUSION: Pre-operative PERCIST assessment of CRCLM was more prognostic than pathologic and CT response assessment. Metabolic non-response correlated with tumour proliferation and loss of tumour suppression. PMID- 27452369 TI - Discovering Regulated Metabolite Families in Untargeted Metabolomics Studies. AB - The identification of metabolites by mass spectrometry constitutes a major bottleneck which considerably limits the throughput of metabolomics studies in biomedical or plant research. Here, we present a novel approach to analyze metabolomics data from untargeted, data-independent LC-MS/MS measurements. By integrated analysis of MS(1) abundances and MS/MS spectra, the identification of regulated metabolite families is achieved. This approach offers a global view on metabolic regulation in comparative metabolomics. We implemented our approach in the web application "MetFamily", which is freely available at http://msbi.ipb halle.de/MetFamily/ . MetFamily provides a dynamic link between the patterns based on MS(1)-signal intensity and the corresponding structural similarity at the MS/MS level. Structurally related metabolites are annotated as metabolite families based on a hierarchical cluster analysis of measured MS/MS spectra. Joint examination with principal component analysis of MS(1) patterns, where this annotation is preserved in the loadings, facilitates the interpretation of comparative metabolomics data at the level of metabolite families. As a proof of concept, we identified two trichome-specific metabolite families from wild-type tomato Solanum habrochaites LA1777 in a fully unsupervised manner and validated our findings based on earlier publications and with NMR. PMID- 27452370 TI - Tracking the Structural and Electronic Configurations of a Cobalt Proton Reduction Catalyst in Water. AB - X-ray transient absorption spectroscopy (X-TAS) has been used to study the light induced hydrogen evolution reaction catalyzed by a tetradentate macrocyclic cobalt complex with the formula [LCo(III)Cl2](+) (L = macrocyclic ligand), [Ru(bpy)3](2+) photosensitizer, and an equimolar mixture of sodium ascorbate/ascorbic acid electron donor in pure water. X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) analysis of a binary mixture of the octahedral Co(III) precatalyst and [Ru(bpy)3](2+) after illumination revealed in situ formation of a Co(II) intermediate with significantly distorted geometry and electron-transfer kinetics of 51 ns. On the other hand, X-TAS experiments of the complete photocatalytic system in the presence of the electron donor showed the formation of a square planar Co(I) intermediate species within a few nanoseconds, followed by its decay in the microsecond time scale. The Co(I) structural assignment is supported by calculations based on density functional theory (DFT). At longer reaction times, we observe the formation of the initial Co(III) species concomitant to the decay of Co(I), thus closing the catalytic cycle. The experimental X-ray absorption spectra of the molecular species formed along the catalytic cycle are modeled using a combination of molecular orbital DFT calculations (DFT-MO) and finite difference method (FDM). These findings allowed us to assign the full mechanistic pathway, followed by the catalyst as well as to determine the rate-limiting step of the process, which consists in the protonation of the Co(I) species. This study provides a complete kinetics scheme for the hydrogen evolution reaction by a cobalt catalyst, revealing unique information for the development of better catalysts for the reductive side of hydrogen fuel cells. PMID- 27452368 TI - Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions. AB - Claudins are tetraspan transmembrane tight-junction proteins that regulate epithelial barriers. In the distal airspaces of the lung, alveolar epithelial tight junctions are crucial to regulate airspace fluid. Chronic alcohol abuse weakens alveolar tight junctions, priming the lung for acute respiratory distress syndrome, a frequently lethal condition caused by airspace flooding. Here we demonstrate that in response to alcohol, increased claudin-5 paradoxically accompanies an increase in paracellular leak and rearrangement of alveolar tight junctions. Claudin-5 is necessary and sufficient to diminish alveolar epithelial barrier function by impairing the ability of claudin-18 to interact with a scaffold protein, zonula occludens 1 (ZO-1), demonstrating that one claudin affects the ability of another claudin to interact with the tight-junction scaffold. Critically, a claudin-5 peptide mimetic reverses the deleterious effects of alcohol on alveolar barrier function. Thus, claudin controlled claudin scaffold protein interactions are a novel target to regulate tight-junction permeability. PMID- 27452371 TI - Effect of amino acid supplementation on titer and glycosylation distribution in hybridoma cell cultures-Systems biology-based interpretation using genome-scale metabolic flux balance model and multivariate data analysis. AB - Genome-scale flux balance analysis (FBA) is a powerful systems biology tool to characterize intracellular reaction fluxes during cell cultures. FBA estimates intracellular reaction rates by optimizing an objective function, subject to the constraints of a metabolic model and media uptake/excretion rates. A dynamic extension to FBA, dynamic flux balance analysis (DFBA), can calculate intracellular reaction fluxes as they change during cell cultures. In a previous study by Read et al. (2013), a series of informed amino acid supplementation experiments were performed on twelve parallel murine hybridoma cell cultures, and this data was leveraged for further analysis (Read et al., Biotechnol Prog. 2013;29:745-753). In order to understand the effects of media changes on the model murine hybridoma cell line, a systems biology approach is applied in the current study. Dynamic flux balance analysis was performed using a genome-scale mouse metabolic model, and multivariate data analysis was used for interpretation. The calculated reaction fluxes were examined using partial least squares and partial least squares discriminant analysis. The results indicate media supplementation increases product yield because it raises nutrient levels extending the growth phase, and the increased cell density allows for greater culture performance. At the same time, the directed supplementation does not change the overall metabolism of the cells. This supports the conclusion that product quality, as measured by glycoform assays, remains unchanged because the metabolism remains in a similar state. Additionally, the DFBA shows that metabolic state varies more at the beginning of the culture but less by the middle of the growth phase, possibly due to stress on the cells during inoculation. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1163-1173, 2016. PMID- 27452372 TI - Testosterone undecanoate improves lipid profile in patients with type 1 diabetes and hypogonadotrophic hypogonadism. AB - : Testosterone deficiency (Td) has been associated with the metabolic syndrome. Few studies have evaluated this condition in type 1 diabetes (T1D). The primary aim of this study was to evaluate the effectiveness of testosterone undecanoate (TU) on insulin sensitivity, glycemic control, anthropometric parameters, blood pressure and lipid profile in patients with Td and T1D. We performed a randomized placebo-controlled multicenter study. INCLUSION CRITERIA: a) age >= 18 years; b) autoimmune diabetes; c) Td (total testosterone <10 nmol/L or calculated free testosterone <225 pmol/L and low/normal LH; d) ability to sign informed consent; e) comply with the study protocol. EXCLUSION CRITERIA: a) pituitary tumor, empty sella, hyperprolactinemia, panhypopituitarism or secondary hypogonadism; b) contraindications for treatment with testosterone undecanoate (TU); c) patients who did not agree to sign their informed consent. Six patients were randomly assigned to testosterone undecanoate (TU) treatment and 7 to placebo with the following dosing schedule: baseline, 6 weeks and 16 weeks. Blood test, anthropometric parameters, blood pressure and insulin sensitivity were determined at baseline, 6, 16 and 22 weeks. No differences were observed regarding insulin sensitivity, HbA1c or basal glucose, anthropometric parameters or blood pressure. At 22 weeks, the decrease in total cholesterol was 37.4 +/- 27.5 mg/dL in the TU group compared with an increase of 13.2 +/- 17.8 mg/dL in the placebo group (P<0.005), and LDL cholesterol concentration decreased 30.2 +/- 22.1 mg/dL, compared with an increase of 10.5 +/- 13.4 mg/dL in the placebo group (P=0.004). We conclude that treatment with TU in patients with T1D and Td improves lipid profile, with no effects on metabolic control or anthropometric parameters. PMID- 27452373 TI - Continuing efforts to standardize measured serum growth hormone values in Japan. AB - Determination of serum growth hormone (GH) levels is mandatory for diagnosis of GH deficiency and excess. In the present study, we, the Study Committee for GH and Its Related Factors, The Foundation for Growth Science, Japan measured GH values in serum samples using all the commercially available kits in Japan. Significant discrepancies in the GH values were observed among the kits in spite of using the unified recombinant human GH-based standards. To deal with the discrepancies, we established a formula using a linear structural relationship model and were able to standardize the GH values. We propose to use the formula to diagnose GH deficiency and excess in Japan. PMID- 27452374 TI - Practice Change Interventions in Long-Term Care Facilities: What Works, and Why? AB - Over the past three decades, there has been a notable increase in studies of practice change interventions in long-term care (LTC) settings. This review, based on a modified realist approach, addresses the following questions: What practice change intervention characteristics work? And, in what circumstances do they work and why? A modified realist approach was applied to identify and explain the interactions among context, mechanism, and outcome. We searched electronic databases and published literature for empirical studies of practice change interventions that (a) were conducted in LTC settings, (b) involved formal care staff members, and (c) reported a formal evaluation. Ninety-four articles met the inclusion criteria. Interventions that included only predisposing factors were least likely to be effective. Interventions that included reinforcing factors were most likely to produce sustained outcomes. We concluded that interventions aimed at practice change in LTC settings should include feasible and effective enabling and reinforcing factors. PMID- 27452376 TI - Scanning sports. PMID- 27452375 TI - Letters. PMID- 27452377 TI - A need to know. PMID- 27452378 TI - Brief reports. PMID- 27452381 TI - Specializing in Sportsmedicine. PMID- 27452382 TI - Mob Psycology. PMID- 27452383 TI - Shoulder Pain in Swimmers. AB - Even though more swimmers are seeing physicians for shoulder pain, fewer I need to be considered for surgery. PMID- 27452384 TI - Shoulder Pain in Swimmers. PMID- 27452385 TI - The Cavus Foot. AB - About one third of Dr. Subotnick's patients have high-arched feet. He describes the problems they encounter and how to treat them. PMID- 27452386 TI - Protecting Upper Extremity Injuries in Sports. AB - Athletes with upper extremity injuries can often participate in their sport if the injury is protected. These guidelines help the physician provide protection for the patient while ensuring safety to other players. PMID- 27452387 TI - Blood Lipid and ECG Responses to Carbohydrate Loading. AB - Carbohydrate loading is so popular that spaghetti is now the premarathon meal. Dr. Blair studied whether this practice has adverse effects on cardiovascular function. PMID- 27452388 TI - Physiological Characteristics of Competitive Cyclists. AB - Like other endurance athletes, competitive cyclists have exceptionally high maximal oxygen consumption values. But the author feels Vo2 max shouldn't stand alone as a predictor of success. PMID- 27452389 TI - The August Krogh Institute: A Tradition of Excellence. AB - The institute's laboratory for the theory of gymnastics maintains a worldwide reputation as a pioneer in applying muscle fiber biopsy data to sportsmedicine research. PMID- 27452391 TI - Equipment Update: PFDs Float into Fashion. AB - Personal flotation devices come in many sizes and styles now. Even though they're better looking, they won't help much unless they're worn. PMID- 27452393 TI - Association Between High Serum Total Cholesterol and Periodontitis: National Health and Nutrition Examination Survey 2011 to 2012 Study of American Adults. AB - BACKGROUND: Clinical studies have suggested that lipids increase activity of white blood cells. The objective of this study is to examine whether high serum total cholesterol (STC) is associated with periodontitis. METHODS: A total of 1,061 participants from the 2011 to 2012 National Health and Nutrition Examination Survey who underwent both periodontal examination and laboratory test for STC was included. To examine effects of high STC on periodontitis, odds ratios were calculated, adjusting for age, sex, education, income, smoking status, diabetes, body mass index, and calcium levels. RESULTS: Statistically significant associations were observed between borderline as well as high STC and periodontitis. Study participants with STC between 200 and 239 mg/dL (borderline) were 1.67 times (95% confidence interval [CI]: 1.13 to 2.47) as likely to have periodontitis as those with normal levels (<=199 mg/dL), and those with STC >=240 mg/dL (high) were 2.22 times (95% CI: 1.27 to 3.87) as likely to have periodontitis as those with normal levels. CONCLUSIONS: Positive significant association was observed between STC and periodontitis. Results of the present study provide insight into potential risk factors for periodontitis. High STC levels could be a potential risk factor for the disease; however, further studies need to be conducted to understand the actual relationship between STC levels and periodontitis and to establish causality and directional association. PMID- 27452394 TI - Effect of Curcumin on Systemic T Helper 17 Cell Response; Gingival Expressions of Interleukin-17 and Retinoic Acid Receptor-Related Orphan Receptor gammat; and Alveolar Bone Loss in Experimental Periodontitis. AB - BACKGROUND: Curcumin has anti-inflammatory and antioxidant effects and is reported to have many biologic activities. The current study examines effect of curcumin on: 1) systemic T helper 17 (Th17) cell response; 2) gingival expressions of interleukin (IL)-17 and retinoic acid receptor-related orphan receptor (ROR) gammat; and 3) alveolar bone loss (ABL) in experimental periodontitis. METHODS: Thirty-eight male albino Wistar rats were divided into four groups: 1) group 1 = periodontitis; 2) group 2 = periodontitis with curcumin treatment; 3) group 3 = periodontally healthy with curcumin treatment; and 4) group 4 = periodontally healthy. Curcumin was administered via oral gavage (30 mg/kg/d) for 15 days. After sacrifice via exsanguination, the following serum levels were determined using enzyme-linked immunosorbent assay: 1) IL-1beta; 2) IL-6; 3) IL-17A; 4) IL-23; and 5) transforming growth factor- beta. Morphometric evaluation of ABL was conducted and expression levels of IL-17 and RORgammat in gingival tissues were evaluated immunohistochemically. RESULTS: Group 2 had significantly lower ABL than group 1 (P <0.0125). Highest expression levels of IL 17 and RORgammat were observed in group 1 and were significantly higher than those in all other groups (P <0.0125). The only serum biochemical parameter significantly different among groups was level of IL-23 (P <0.05). Serum IL-23 levels were higher in groups 1 and 2 than groups 3 and 4 (P <0.0125); however, they were not significantly different for groups 1 and 2 (P >0.0125). CONCLUSION: Curcumin seems to be a promising host modulatory agent in periodontal disease pathogenesis regarding IL-17/IL-23 axis, with a decreasing effect on ABL and gingival expressions of IL-17 and RORgammat. PMID- 27452395 TI - Non-Clinical Factors Associated With Referrals to Periodontal Specialists: A Systematic Review. AB - BACKGROUND: Comprehensive understanding of the referral process and factors associated with it will assist general dentist (GD)-periodontist relationships and benefit patient care and services. Non-clinical factors (NCFs) influence clinical decision making but are rarely considered. The objective of this review is to identify NCFs found to be associated with referrals to periodontal specialists. METHODS: A systematic review of English-language literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. An electronic search was carried out using the Cumulative Index to Nursing and Allied Health Literature, Dentistry and Oral Sciences Sources, and PubMed. Search terms used included: 1) refer; 2) referral; 3) periodontal; and 4) periodontist. Potentially relevant publications were analyzed in detail using predetermined inclusion and exclusion criteria. Selected papers were assessed using the Mixed Methods Appraisal Tool, and data extracted were thematically synthesized. RESULTS: Ten studies that examined NCFs fulfilled inclusion criteria. Four NCF themes identified were practice-, GD-, patient-, and periodontist-related factors. CONCLUSIONS: Limited literature is available on NCFs associated with referrals to periodontal specialists. Within the limits of this systematic review, NCFs affecting the referral process are practice-, GD-, patient-, and periodontist-related factors. These vary among different GD populations studied. Factors that could be targeted to improve referral processes include geographic location, undergraduate training, and continuing professional development. PMID- 27452396 TI - Reduced insulin/insulin-like growth factor signaling decreases translation in Drosophila and mice. AB - Down-regulation of insulin/insulin-like growth factor signaling (IIS) can increase lifespan in C. elegans, Drosophila and mice. In C. elegans, reduced IIS results in down-regulation of translation, which itself can extend lifespan. However, the effect of reduced IIS on translation has yet to be determined in other multicellular organisms. Using two long-lived IIS models, namely Drosophila lacking three insulin-like peptides (dilp2-3,5(-/-)) and mice lacking insulin receptor substrate 1 (Irs1(-/-)), and two independent translation assays, polysome profiling and radiolabeled amino acid incorporation, we show that reduced IIS lowers translation in these organisms. In Drosophila, reduced IIS decreased polysome levels in fat body and gut, but reduced the rate of protein synthesis only in the fat body. Reduced IIS in mice decreased protein synthesis rate only in skeletal muscle, without reducing polysomes in any tissue. This lowered translation in muscle was independent of Irs1 loss in the muscle itself, but a secondary effect of Irs1 loss in the liver. In conclusion, down-regulation of translation is an evolutionarily conserved response to reduced IIS, but the tissues in which it occurs can vary between organisms. Furthermore, the mechanisms underlying lowered translation may differ in mice, possibly associated with the complexity of the regulatory processes. PMID- 27452397 TI - Prefrontal responses to Stroop tasks in subjects with post-traumatic stress disorder assessed by functional near infrared spectroscopy. AB - Studies on posttraumatic stress disorder (PTSD) showing attentional deficits have implicated abnormal activities in the frontal lobe. In this study, we utilized multichannel functional near-infrared spectroscopy (fNIRS) to investigate selective attention-related hemodynamic activity in the prefrontal cortex among 15 combat-exposed war-zone veterans with PTSD and 13 age- and gender-matched healthy controls. While performing the incongruent Stroop task, healthy controls showed significant activations in the left lateral prefrontal cortex (LPFC) compared to baseline readings. This observation is consistent with previously reported results. In comparison, subjects with PTSD failed to activate left LPFC during the same Stroop task. Our observations may implicate that subjects with PTSD experienced difficulty in overcoming Stroop interference. We also observed significant negative correlation between task reaction times and hemodynamic responses from left LPFC during the incongruent Stroop task in the PTSD group. Regarding the methodology used in this study, we have learned that an appropriate design of Stroop paradigms is important for meeting an optimal cognitive load which can lead to better brain image contrasts in response to Stroop interference between healthy versus PTSD subjects. Overall, the feasibility of fNIRS for studying and mapping neural correlates of selective attention and interference in subjects with PTSD is reported. PMID- 27452398 TI - Protective effect of epigallocatechin-3-gallate (EGCG) via Nrf2 pathway against oxalate-induced epithelial mesenchymal transition (EMT) of renal tubular cells. AB - This study evaluated effect of oxalate on epithelial mesenchymal transition (EMT) and potential anti-fibrotic property of epigallocatechin-3-gallate (EGCG). MDCK renal tubular cells were incubated with 0.5 mM sodium oxalate for 24-h with/without 1-h pretreatment with 25 MUM EGCG. Microscopic examination, immunoblotting and immunofluorescence staining revealed that oxalate-treated cells gained mesenchymal phenotypes by fibroblast-like morphological change and increasing expression of vimentin and fibronectin, while levels of epithelial markers (E-cadherin, occludin, cytokeratin and ZO-1) were decreased. EGCG pretreatment could prevent all these changes and molecular mechanisms underlying the prevention by EGCG were most likely due to reduced production of intracellular ROS through activation of Nrf2 signaling and increased catalase anti-oxidant enzyme. Knockdown of Nrf2 by small interfering RNA (siRNA) abrogated all the effects of EGCG, confirming that the EGCG protection against oxalate induced EMT was mediated via Nrf2. Taken together, our data indicate that oxalate turned on EMT of renal tubular cells that could be prevented by EGCG via Nrf2 pathway. These findings also shed light onto development of novel therapeutics or preventive strategies of renal fibrosis in the future. PMID- 27452399 TI - Whole Exome Sequencing Reveals a BSCL2 Mutation Causing Progressive Encephalopathy with Lipodystrophy (PELD) in an Iranian Pediatric Patient. AB - BACKGROUND: Progressive encephalopathy with or without lipodystrophy is a rare autosomal recessive childhood-onset seipin-associated neurodegenerative syndrome, leading to developmental regression of motor and cognitive skills. In this study, we introduce a patient with developmental regression and autism. The causative mutation was found by exome sequencing. METHODS: The proband showed a generalized hypertonia and regression of all developmental milestones. Based on the advantages of next-generation sequencing (NGS), whole exome sequencing (WES) was requested. The functional significance of variants was evaluated by NGS-specific prediction servers. Sanger sequencing was used for segregation analysis in the family. RESULTS: There was no specific sign in the clinical and paraclinical investigations of the patient to establish a conclusive clinical diagnosis. WES detected a known homozygous nonsense mutation in BSCL2 (NM_001122955.3:c. 985C>T; p.Arg329*). The variant is segregating in the pedigree with an autosomal recessive pattern. CONCLUSION: Exome sequencing is a robust method for identifying the candidate gene variants in Mendelian traits. PMID- 27452400 TI - Corrigendum: Evolved resistance to colistin and its loss due to genetic reversion in Pseudomonas aeruginosa. PMID- 27452401 TI - Comparative analysis of plastid genomes of non-photosynthetic Ericaceae and their photosynthetic relatives. AB - Although plastid genomes of flowering plants are typically highly conserved regarding their size, gene content and order, there are some exceptions. Ericaceae, a large and diverse family of flowering plants, warrants special attention within the context of plastid genome evolution because it includes both non-photosynthetic and photosynthetic species with rearranged plastomes and putative losses of "essential" genes. We characterized plastid genomes of three species of Ericaceae, non-photosynthetic Monotropa uniflora and Hypopitys monotropa and photosynthetic Pyrola rotundifolia, using high-throughput sequencing. As expected for non-photosynthetic plants, M. uniflora and H. monotropa have small plastid genomes (46 kb and 35 kb, respectively) lacking genes related to photosynthesis, whereas P. rotundifolia has a larger genome (169 kb) with a gene set similar to other photosynthetic plants. The examined genomes contain an unusually high number of repeats and translocations. Comparative analysis of the expanded set of Ericaceae plastomes suggests that the genes clpP and accD that are present in the plastid genomes of almost all plants have not been lost in this family (as was previously thought) but rather persist in these genomes in unusual forms. Also we found a new gene in P. rotundifolia that emerged as a result of duplication of rps4 gene. PMID- 27452402 TI - Phosphorylation of Cysteine String Protein Triggers a Major Conformational Switch. AB - Cysteine string protein (CSP) is a member of the DnaJ/Hsp40 chaperone family that localizes to neuronal synaptic vesicles. Impaired CSP function leads to neurodegeneration in humans and model organisms as a result of misfolding of client proteins involved in neurotransmission. Mammalian CSP is phosphorylated in vivo on Ser10, and this modulates its protein interactions and effects on neurotransmitter release. However, there are no data on the structural consequences of CSP phosphorylation to explain these functional effects. We show that Ser10 phosphorylation causes an order-to-disorder transition that disrupts CSP's extreme N-terminal alpha helix. This triggers the concomitant formation of a hairpin loop stabilized by ionic interactions between phosphoSer10 and the highly conserved J-domain residue, Lys58. These phosphorylation-induced effects result in significant changes to CSP conformation and surface charge distribution. The phospho-switch revealed here provides structural insight into how Ser10 phosphorylation modulates CSP function and also has potential implications for other DnaJ phosphoproteins. PMID- 27452403 TI - Structural Basis of Backwards Motion in Kinesin-1-Kinesin-14 Chimera: Implication for Kinesin-14 Motility. AB - Kinesin-14 is a unique minus-end-directed microtubule-based motor. A swinging motion of a class-specific N-terminal neck helix has been proposed to produce minus-end directionality. However, it is unclear how swinging of the neck helix is driven by ATP hydrolysis utilizing the highly conserved catalytic core among all kinesins. Here, using a motility assay, we show that in addition to the neck helix, the conserved five residues at the C-terminal region in kinesin-14, namely the neck mimic, are necessary to give kinesin-1 an ability to reverse its directionality toward the minus end of microtubules. Our structural analyses further demonstrate that the C-terminal neck mimic, in cooperation with conformational changes in the catalytic core during ATP binding, forms a kinesin 14 bundle with the N-terminal neck helix to swing toward the minus end of microtubules. Thus, the neck mimic plays a crucial role in coupling the chemical ATPase reaction with the mechanical cycle to produce the minus-end-directed motility of kinesin-14. PMID- 27452404 TI - Molecular Understanding of USP7 Substrate Recognition and C-Terminal Activation. AB - The deubiquitinating enzyme USP7 has a pivotal role in regulating the stability of proteins involved in fundamental cellular processes of normal biology and disease. Despite the importance of USP7, the mechanisms underlying substrate recognition and catalytic activation are poorly understood. Here we present structural, biochemical, and biophysical analyses elucidating the molecular mechanism by which the C-terminal 19 amino acids of USP7 (residues 1084-1102) enhance the ubiquitin cleavage activity of the deubiquitinase (DUB) domain. Our data demonstrate that the C-terminal peptide binds the activation cleft in the catalytic domain and stabilizes the catalytically competent conformation of USP7. Additional structures of longer fragments of USP7, as well as solution studies, provide insight into full-length USP7, the role of the UBL domains, and demonstrate that both substrate recognition and deubiquitinase activity are highly regulated by the catalytic and noncatalytic domains of USP7, a feature that could be essential for the proper function of multi-domain DUBs. PMID- 27452405 TI - High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits. AB - Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ~25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods. PMID- 27452407 TI - Low prevalence of inadequate micronutrient intake in young children in the south of Brazil: a new perspective. AB - In Brazil, children's eating patterns have been characterised by an increased consumption of ultra-processed foods that are fortified. Our aims were to (1) estimate the prevalence of inadequate micronutrient intake among children from low-income families and (2) to assess micronutrient intake from fortified foods. We carried out a cross-sectional study from a randomised field trial conducted at healthcare centres in Porto Alegre, Brazil, with 446 mother-child pairs, with the children aged 2-3 years. Dietary data were assessed using two 24-h recalls. The prevalence of inadequacy for six micronutrients was estimated using the proportion of individuals with intakes below the estimated average requirement (EAR). Micronutrient intakes from fortified foods were evaluated using EAR and upper tolerable level (UL). Healthy foods consumption was below the recommendations, except for beans, and 88.1 % of the children consumed ultra processed foods. A low prevalence of inadequate micronutrient intake was observed for Fe (1.2 %), vitamin C (4.7 %), vitamin A (5.2 %), Ca (11.4 %) and folate (15.2 %). None of the children had intakes less than the EAR for Zn. Fortified foods contributed between 11.3 and 38.3 % to micronutrient intakes, and 43.0 % of the children met the EAR for Fe, 13.9 % for vitamin C and 12.3 % for Zn using fortified foods only. In addition, 4.0 % of the children exceeded the UL for vitamin A, 3.1 % for Zn, 1.1 % for folic acid and 0.2 % for Fe. These results highlight a low prevalence of inadequate micronutrient intakes among children and suggest that such a group could be at risk of excessive micronutrient intakes provided by ultra-processed foods. PMID- 27452406 TI - DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy. AB - We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by gamma-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After gamma-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phospho-p53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA. PMID- 27452408 TI - Barriers to point-of-care ultrasound use in rural emergency departments. AB - Over the past few decades, point-of-care ultrasound (PoCUS) has come to play a major role in the practice of emergency medicine. Despite its numerous benefits, there has been a slow uptake of PoCUS use in rural emergency departments. Surveys conducted across Canada and the United States have identified a lack of equipment, training, funding, quality assurance, and an inability to maintain skills as major barriers to PoCUS use. Potential solutions include expanding residency training in ultrasound skills, extending funding for PoCUS training to rural physicians in practice, moving PoCUS training courses to rural sites, and creating telesonography training for rural physicians. With these barriers identified and solutions proposed, corrective measures must be taken so that the benefits of PoCUS are extended to patients in rural Canada where, arguably, it has the greatest potential for benefit when access to advanced imaging is not readily available. PMID- 27452409 TI - A volumetric analysis of GTVD and CTVHR as defined by the GEC ESTRO recommendations in FIGO stage IIB and IIIB cervical cancer patients treated with IGABT in a prospective multicentric trial (EMBRACE). AB - PURPOSE: To quantify the gross tumor volume at diagnosis (GTVD) and high-risk clinical target volume (CTVHR) at brachytherapy (BT) and describe subgroups of patients with different patterns of response to chemoradiotherapy (CRT) in patients with FIGO stage IIB and IIIB cervical cancer treated with image-guided adaptive brachytherapy (IGABT). Additionally, to evaluate the feasibility of IGABT achieving adequate target coverage in these groups. MATERIALS AND METHODS: Patients with FIGO stage IIB and IIIB cervical cancer enrolled in the EMBRACE study were analyzed. T2-weighted MRI scans were obtained at diagnosis and at BT. GTVD and CTVHR were defined as per the GEC ESTRO recommendations. Patients were classified taking into account that initial tumor volume and response to CRT represented by the volume of residual disease (CTVHR) and extent of residual parametrial disease are all major factors determining local dose delivery by BT, local control, and overall disease outcome. These factors were quantified applying the following criteria: (1) volume of the GTVD relative to the median volume of the GTVD; (2) the ratio (R) of CTVHR to GTVD for each patient; (3) the extent of residual parametrial disease at the time of BT. Accordingly, patients were classified into six groups (G1-G6): stage IB1-like tumors (G1), tumors with good response and any size (G2), small tumors with moderate response (G3), large tumors with moderate response (G4), tumors with poor response (G5) and those with progressive disease (G6). Tumor and treatment characteristics were then compared among the first five groups (only 3 patients were allocated to G6). RESULTS: A total of 481 patients were evaluated. The number of patients in the 6 groups were 55, 78, 123, 147, 75 and 3, respectively. The mean (SD) GTVD was 43.6 (32.8)cm3 and the mean (SD) CTVHR was 31.6 (16.1)cm3. The mean GTVD and CTVHR were 12.6cm3 and 23.7cm3 in G1 (R>1.1), 47.5cm3 and 25.3cm3 in G2 (R<0.9), 23.9 cm3 and 29.9cm3 in G3 (R 0.9-1.1), 73.4cm3 and 38.5cm3 in G4 (R 0.9-1.1), 79.4cm3 and 59.5cm3 in G5 (R>1.1), respectively. Parametrial disease extent at BT was as follows: no involvement in G1 and G2, proximal at most in G3 and G4, distal or to the pelvic wall in G5, progressive in G6. The use of interstitial needles was progressively higher among the groups (mean 0, 0, 2, 3, 6 in G1-5, P<0.001). The mean GTVBT D100 in G1-5 was 103.1Gy, 91.8Gy, 93.5Gy, 88.3Gy and 87.1Gy. The mean CTVHR D90 in G1-5 was 95.1Gy, 92.1Gy, 92.6Gy, 87.6Gy and 88.4Gy. CONCLUSIONS: In patients with FIGO stage IIB and IIIB disease, intra-FIGO stage heterogeneity and overlap between the two stages exist with respect to tumor volume, treatment response and extent of parametrial disease at BT. Taking into account GTVD, parametrial disease at BT and the ratio of CTVHR/GTVD, five major groups exist. These enable prediction of GTVBT and CTVHR dose coverage through BT. IGABT, as performed in EMBRACE, accommodates to a considerable degree for the different variants of tumor regression in these groups through adaptation of the treatment technique including the use of needles. However, major variations remain at present with regard to dose to GTVBT and to CTVHR, which are most pronounced in G4 and G5. This new classification will be validated in future in regard to clinical outcome in EMBRACE. PMID- 27452410 TI - Can reduction of uncertainties in cervix cancer brachytherapy potentially improve clinical outcome? AB - AIM: The aim of this study was to quantify the impact of different types and magnitudes of dosimetric uncertainties in cervix cancer brachytherapy (BT) on tumour control probability (TCP) and normal tissue complication probability (NTCP) curves. MATERIALS AND METHODS: A dose-response simulation study was based on systematic and random dose uncertainties and TCP/NTCP models for CTV and rectum. Large patient cohorts were simulated assuming different levels of dosimetric uncertainties. TCP and NTCP were computed, based on the planned doses, the simulated dose uncertainty, and an underlying TCP/NTCP model. Systematic uncertainties of 3-20% and random uncertainties with a 5-30% standard deviation per BT fraction were analysed. RESULTS: Systematic dose uncertainties of 5% lead to a 1% decrease/increase of TCP/NTCP, while random uncertainties of 10% had negligible impact on the dose-response curve at clinically relevant dose levels for target and OAR. Random OAR dose uncertainties of 30% resulted in an NTCP increase of 3-4% for planned doses of 70-80Gy EQD2. CONCLUSION: TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose-response curve at doses >75Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification. PMID- 27452411 TI - Which cervical and endometrial cancer patients will benefit most from intensity modulated proton therapy? AB - In this dosimetric comparison study it was shown that IMPT with robust planning reduces dose to surrounding organs in cervical and endometrial cancer treatment compared with IMRT. Especially for the para-aortic region, clinically relevant dose reductions were obtained for kidneys, spinal cord and bowel, justifying the use of proton therapy for this indication. PMID- 27452412 TI - Improving Clinical Oncology Trainees' Radiotherapy Induction. PMID- 27452413 TI - Novel approaches to preclinical research and TB vaccine development. AB - The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Low-Dose NHP Challenge Models, Novel Approaches to Animal Models for TB Vaccine R&D, Novel Antigen Delivery Strategies, and Next Generation TB Vaccines and Vaccine Concepts. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1-S30]. PMID- 27452414 TI - In response to Hyoid surgery alone for obstructive sleep apnea: A systematic review and meta-analysis. PMID- 27452415 TI - Facial mimetic, cosmetic, and functional standardized assessment of the facial artery musculomucosal (FAMM) flap. AB - OBJECTIVE: To objectively assess donor site morbidity after harvesting the facial artery musculomucosal flap. Use of the FAMM-flap in oral cavity reconstruction remains sporadic. This case series describes our newly developed standardized assessment of this flap in a floor of mouth (FOM) reconstructive setting. METHODS: Standardized postoperative assessment of the FAMM flap for donor site wound complications, functional, facial mimetic and oncologic outcomes. RESULTS: There were no wound complications. Oral competence remained intact, tongue mobility was good to excellent, average word articulation score was 98%, and mimetic function excellent in all patients. Three patients experienced ipsilateral upper lip anesthesia, and five patients were noted to have slight dysfunction of the orbicularis oris resulting in a loss of lip height at rest. CONCLUSION: The FAMM flap is a reliable option for reconstruction of ablative defects of the FOM, and should be considered a workhorse flap for oral cavity defects. Unlike the submental island flap, a complete level I dissection may be concurrently performed without compromising the vascular supply to the FAMM flap. PMID- 27452416 TI - Complex phenotypes blur conventional borders between Say-Barber-Biesecker-Young Simpson syndrome and genitopatellar syndrome. AB - Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GTPTS) are clinically similar disorders with some overlapping features. Although they are currently considered to be distinct clinical entities, both were found to be caused by de novo truncating sequence variants in the KAT6B (lysine acetyltransferase 6B) gene, strongly suggesting that they are allelic disorders. Herein, we report the clinical and genetic findings in a girl presenting with a serious multiple congenital anomaly syndrome with phenotypic features overlapping both SBBYSS and GTPTS; pointing out that the clinical distinction between these disorders is not exact and there do exist patients, in whom conventional clinical classification is problematic. Genetic analyses revealed a truncating c.4592delA (p.Asn1531Thrfs*18) variant in the last KAT6B exon. Our findings support that phenotypes associated with typical KAT6B disease-causing variants should be referred to as 'KAT6B spectrum disorders' or 'KAT6B related disorders', rather than their current SBBYSS and GTPTS classification. PMID- 27452417 TI - Effects of aging on optical quality and visual function. AB - BACKGROUND: We assessed the effects of aging on visual function and optical quality in a healthy adult population and provide reference values for different age ranges. METHODS: We conducted a prospective study with 198 healthy volunteers from 31 to 70 years of age. The visual acuity (VA) and contrast sensitivity (CS) at 3, 6, 12 and 18 cycles per degree (cpd) frequencies were assessed, together with values of optical quality and intraocular scattering obtained with a double pass system (Optical Quality Analysis System - OQAS), specifically the modulation transfer function cutoff frequency (MTFcutoff ), the Strehl ratio, the OQAS values (OV) at contrasts of 100, 20 and nine per cent and the objective scatter index (OSI). We studied the change of these variables with age and obtained standard values for optical quality and intraocular scattering parameters for four age groups: 31 to 40, 41 to 50, 51 to 60 and 61 to 70 years. RESULTS: We found significant correlations between age and all variables analysed and significant differences among the age groups considered except for CS (3 cpd) (p = 0.067). Ageing particularly affected low-contrast parameters, such as the OV nine per cent and the OSI, which decreased to 37 and 50 per cent of their original values, respectively. The OSI was found to provide high sensitivity and specificity values, when healthy and caratactous eyes were considered. The results suggest that optical deficits are compensated until 50 years of age with sensory and perceptual factors, as smaller changes were found for visual function than for objective measurements of optical quality and intraocular scattering. CONCLUSIONS: Measures of optical quality assessed by subjective psychophysical and objective techniques varied differently with age. Values obtained for each age group can be used to determine normal limits of optical quality and intraocular scattering for diagnosis of ocular conditions. PMID- 27452418 TI - Polymeric prodrug-functionalized polypropylene films for sustained release of salicylic acid. AB - Medical devices decorated with salicylic acid-based polymer chains (polymeric prodrug) that slowly release this anti-inflammatory and anti-biofilm drug at the implantation site were designed. A "grafting from" method was implemented to directly grow chains of a polymerizable derivative of salicylic acid (2 methacryloyloxy-benzoic acid, 2MBA) onto polypropylene (PP). PP was modified both at bulk and on the surface with poly(2MBA) by means of an oxidative pre irradiation method ((60)Co source), in order to obtain a grafted polymer in which salicylic acid units were linked by means of labile ester bonds. The grafting percent depended on absorbed dose, reaction time, temperature and monomer concentration. The functionalized films were analyzed regarding structure (FTIR ATR, SEM-EDX, fluorescence microscopy), temperature stability (TGA), interaction with aqueous medium (water contact angle and swelling), pH-responsive release and cytocompatibility (fibroblasts). In the obtained poly(2MBA)-grafted biomaterial, poly(2MBA) behaved as a polymeric prodrug that regulates salicylic acid release once in contact with aqueous medium, showing pH-dependent release rate. PMID- 27452419 TI - Mechanisms of imiquimod skin penetration. AB - Imiquimod (IMQ) ia an immunostimulating drug used for the treatment of neoplastic skin diseases, such as actinic keratosis (AK) and superficial basal cell carcinoma (sBCC), and as adjuvant for vaccination. Imiquimod formulation and skin delivery is highly challenging because of its very low solubility in most pharmaceutical excipients and poor penetration properties. Objectives of the work were: (1) to evaluate IMQ solubility in different solvents and pharmaceutical excipients; (2) to evaluate IMQ skin retention after the application of simple saturated solutions; (3) to evaluate the role of stratum corneum and solvent uptake on IMQ skin retention and (4) to formulate IMQ in microemulsions - prepared using previously investigated components - and compare them with the commercial formulation. The results show that IMQ solubility is not related to the solubility parameter of the solvents considered. The highest solubility was found with oleic acid (74mg/ml); in the case of PEGs, the solubility increased linearly with MW (PEG 200: 1.9mg/ml; PEG 400 7.3mg/ml, PEG 600 12.8mg/ml). Imiquimod skin retention from saturated solutions (Tween 80, oleic acid, propylene glycol, PEG 200, PEG 400, PEG 600, Transcutol, 2-pyrrolidone, DMSO) resulted relatively similar, being 1.6MUg/cm(2) in case of oleic acid (solubility 74mg/ml) and 0.18MUg/cm(2) in case of propylene glycol (solubility 0.60mg/ml). Permeation experiments on stripped skin (no stratum corneum) and isolated dermis as well as uptake experiments on isolated stratum corneum sheets demonstrated that IMQ accumulation is related to skin solvent uptake. Finally, microemulsions (MEs) prepared with the above-studied components demonstrated a very good performance. In particular, a ME composed of 10% oleic acid, 35% Transcutol, 35% Tween 80 and 20% water is able to accumulate the same amount of drug as the commercial formulation but with far more efficiency, since its concentration was 12 times lower. PMID- 27452420 TI - Stearic acid and high molecular weight PEO as matrix for the highly water soluble metoprolol tartrate in continuous twin-screw melt granulation. AB - Granules with release-sustaining properties were developed by twin screw hot melt granulation (HMG) using a combination of stearic acid (SA) and high molecular weight polyethylene oxide (PEO) as matrix for a highly water soluble model drug, metoprolol tartrate (MPT). Earlier studies demonstrated that mixing molten SA and PEO resulted in hydrogen bond formation between hydroxyl groups of fatty acid molecules and ether groups in PEO chains. These molecular interactions might be beneficial in order to elevate the sustained release effect of drugs from a SA/PEO matrix. This study aims to investigate the continuous twin screw melt granulation technique to study the impact of a SA/PEO matrix on the dissolution rate of a highly water soluble drug (MPT). Decreasing the SA/PEO ratio improved the release-sustaining properties of the matrix. The solid state of the granules was characterized using differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared (FTIR) and near infrared chemical imaging (NIR-CI) in order to understand the dissolution behavior. The results revealed a preferential interaction of the MPT molecules with stearic acid impeding the PEO to form hydrogen bonds with the stearic acid chains. However, this allowed the PEO chains to recrystallize inside the stearic acid matrix after granulation, hence, elevating the release-sustaining characteristics of the formulation. PMID- 27452421 TI - Size-exclusive effect of nanostructured lipid carriers on oral drug delivery. AB - Nanostructured lipid carriers (NLCs) are generally recognized as safe (GRAS) to form a controlled nanostructure are a new generation of lipid nanoparticles. In addition to formulation and particle surface properties, particle size had great influence for overcoming gastrointestinal (GI) barriers on the oral drug delivery of lipid based nanoparticles. In the present study, we investigated the effect of size on oral drug delivery for NLCs. The NLCs with different particle sizes (NLCs100nm, NLCs200nm and NLCs300nm) were prepared by using solvent evaporation method and the coumarin-6 (C6) or DiO/DiI was loaded in the nanoparticles as the fluorescence probe. The MTT assay indicated that both blank NLCs and C6-loaded NLCs displayed relatively low toxicity towards Caco-2 cells. Cellular uptake mechanisms of NLCs with different sizes were found to be similar and governed by active endocytosis, clathrin- and caveolae-mediated process. However, the smaller nanoparticle (NLC-100nm) showed higher uptake efficiency in Caco-2 cell (P<0.05) as well as higher permeation ability in Caco-2 cell monolayer (P<0.01), compared with NLC-200nm and NLC-300nm. The fluorescence resonance energy transfer (FRET) assay indicated that all of three NLCs could maintained the structural integrity in blood circulation after oral administration. NLC-100nm exhibited the most stability according to the most stable FRET signal. In situ rat intestinal absorption experiments and in vitro ligated rat intestinal loops model demonstrated that all NLCs could rapidly penetrate duodenum versus jejunum, ileum and colon (P<0.01). Moreover, pharmacokinetic studies showed that NLC-100nm exhibited highest Cmax and AUC compared with the other two NLCs. In conclusion, the size of 100nm might be the most suitable size for oral drug delivery of lipid based nanoparticles. PMID- 27452422 TI - Cholesteryl to improve the cellular uptake of polymersomes within HeLa cells. AB - The need to develop a greater understanding of drug delivery systems has arisen through the development of alternative biological based therapeutics. Drug delivery systems need to adapt and respond to this increasing demand for cellular transportation of highly charged species. Polymersomal drug delivery systems have displayed great potential and versatility for such a task. In this manuscript we present the synthesis, characterisation and biological evaluation of six amphiphilic random co polymers with varying amounts of cholesteryl (0-39%wt) before the subsequent formation into polymersomes. The polymersomes were then analysed for size, zeta potential, encapsulation efficiency, release kinetics and cellular uptake. Results confirmed that the polymersome containing 12%wt cholesteryl polymer displayed a ten-fold increase in cellular uptake of Fitc-CM dextran when compared to un-encapsulated drug, crossing the cellular membrane via endocytosis. The size of these vehicles ranged between 100 and 500nm, zeta potential was shown to be neutral at -0.82mV +/-0.2 with encapsulation efficiencies in the region of 60%. The ease of adaptability and preparation of such systems renders them a viable alternative to liposomal drug delivery systems. PMID- 27452423 TI - Aqueous solutions of didecyldimethylammonium chloride and octaethylene glycol monododecyl ether: Toward synergistic formulations against enveloped viruses. AB - Micellization of di-n-decyldimethylammonium chloride, [DiC10][Cl], and octaethylene glycol monododecyl ether, C12E8, mixtures have been investigated by surface tension and conductivity measurements. From these results, various physicochemical and thermodynamic key parameters (e.g. micellar mole fraction of [DiC10][Cl], interaction parameter, free energy of micellization, etc.) have been evaluated and discussed in detail. The results prove high synergistic effect between the two surfactants. Based on these results, the virucidal activity of an equimolar mixture of [DiC10][Cl] and C12E8 has been investigated. A marked synergism was observed on lipid-containing deoxyribonucleic and ribonucleic acid viruses, such as herpes virus, respiratory syncytial virus, and vaccinia viruses. In contrast, Coxsackievirus (non-enveloped virus) was not inactivated. These results support that the mechanism is based on the extraction of lipids and/or proteins from the envelope inside the mixed micelles. This extraction creates "holes" the size of which increases with concentration up to a specific value which triggers the virus inactivation. Such a mixture could be used to extend the spectrum of virucidal activity of the amphiphiles virucides commonly employed in numerous disinfectant solutions. PMID- 27452425 TI - Cell Phone Saccades: Electroencephalographic Artifact for the Twenty-first Century. PMID- 27452424 TI - An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation. AB - INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Abeta, proNGF, tPA, neuroserpin, metallo proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Abeta40 and Abeta42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Abeta correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP 3, MMP-9 activity, TNF-alpha, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Abeta42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Abeta and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia. PMID- 27452426 TI - The devil in the corner: A mixed-methods study of metaphor use by those with spinal cord injury-specific neuropathic pain. AB - OBJECTIVES: Metaphorical expressions of persistent pain play an influential role in the modulation of pain. This may be particularly distressing for those with physical disabilities such as spinal cord injury (SCI). Neuropathic pain (NP) after SCI is often described using metaphorical expressions such as burning and electricity. This study explored the use of metaphors by those with NP after SCI. DESIGN: A qualitative, semi-structured interview design was employed. METHODS: Data were analysed using content analysis (CA) and interpretative phenomenological analysis to explore prevalence of metaphor use and its meaning. Sixteen individuals aged between 23 and 82 years, with chronic NP (persisting for 3 months or longer), arising from SCI were interviewed in their homes or on hospital wards (M = 10, F = 6). Interviews lasted between 40 and 120 min. RESULTS: The results capture a range of metaphorical expressions embedded in participants' accounts. Three themes emerged: (1) pain as a personal attack, (2) the desire to be understood, and (3) conveying distress without adequate terminology. CA revealed that younger age, female gender, and outpatient status were associated with increased metaphor use. CONCLUSIONS: This study highlights the power of metaphor in eliciting understanding of NP after SCI from others, whilst demonstrating the challenge of communicating NP. Cognitive treatment that incorporates image-based techniques with acceptance and mindfulness-based therapies may encourage adaptive responses to, and interpretation of, pain. This may subsequently reduce pain-related distress and catastrophizing. Statement of contribution What is already known on this subject? Neuropathic pain is often described with metaphorical language such as burning and crushing. For those with physical limitations, metaphor use may induce or exacerbate psychological distress. However, for those with spinal cord injuries, metaphor use has received little attention. What does this study add? Metaphor use is common in those with spinal cord injury, with differences across gender and age. Core metaphors used conceptualized pain as an attacker or likened pain to heat and burning. Such language may have benefits in terms of improved understanding and increased empathy, but may be reflective of catastrophic thinking. PMID- 27452427 TI - Antifungal susceptibilities of Candida species isolated from urine culture. AB - Candida spp. are the most common opportunistic mycosis worldwide. Although Candida albicans is the most common cause of urinary tract infections, the frequency of non-albicans Candida species is increasing with common use of antifungal in the prophylaxis and treatment. This may lead to difficulties in treatment. Antifungal tests should be applied with identification of species for effective treatment. In this study, identification of Candida species isolated from urine culture and investigation of susceptibility of these strains to amphotericin B, flucytosine, fluconazole, voriconazole was aimed. In this study, 58 Candida strains isolated from urine cultures at Osmaniye State Hospital between January 2012 and April 2013 were included. Urine culture and antifungal susceptibility tests were applied. Incidence rate of Candida spp. was determined as C. albicans (56.9%), Candida glabrata (20.6%), Candida tropicalis (10.3%), Candida parapsilosis (7%), Candida krusei (3.4%), Candida kefyr (1.8%). Most of the isolates were susceptible to amphotericin B, flucytosine, fluconazole, voriconazole. Twenty three (39.7%) Candida strains were isolated from internal medical branches and Intensive Care Unit and 12 (20.6%) from the Surgical Medical Branches. C. albicans and C. glabrata species were isolated most frequently as a candiduria factor in this hospital between January 2012 and April 2013. The analysis of antifungal susceptibility profile shows no significant resistance to antifungals. PMID- 27452429 TI - Severe protein-calorie malnutrition in two brothers due to abuse by starvation. AB - OBJECTIVE: To describe the case of two siblings with severe protein-calorie malnutrition due to abuse by starvation. CASES DESCRIPTION: The two patients were simultaneously referred from the Municipal Hospital, where they were admitted to the Pediatric Gastroenterology clinic of a university hospital for diagnostic investigation of the cause of severe malnutrition and screening tests for Celiac Disease, Cystic Fibrosis and Environmental enteropathy among others. The exams were all normal, and after detailed research on the interactions of this family, we reached the conclusion that the malnutrition was due to abuse by starvation. The children spent approximately two months in the hospital, receiving a high protein and high-calorie diet, with significant nutritional recovery. COMMENTS: Abuse by starvation, although rare, should always be considered of as one of the causes of child malnutrition and pediatrician should be aware of the child's development, as well as the family interactions, to prevent more severe nutritional and emotional consequences in the future. PMID- 27452428 TI - Nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis from male urethritis in Japan. AB - Genital chlamydial infection is a principal sexually transmitted infection worldwide. Chlamydia trachomatis can cause male urethritis, acute epididymitis, cervicitis, and pelvic inflammatory disease as sexually transmitted infections. Fortunately, homotypic resistant C. trachomatis strains have not been isolated to date; however, several studies have reported the isolation of heterotypic resistant strains from patients. In this surveillance study, clinical urethral discharge specimens were collected from patients with urethritis in 51 hospitals and clinics in 2009 and 38 in 2012. Based on serial cultures, the minimum inhibitory concentration (MIC) could be determined for 19 isolates in 2009 and 39 in 2012. In 2009 and 2012, the MICs (MIC90) of ciprofloxacin, levofloxacin, tosufloxacin, sitafloxacin, doxycycline, minocycline, erythromycin, clarithromycin, and azithromycin were 2 MUg/ml and 1 MUg/ml, 0.5 MUg/ml and 0.5 MUg/ml, 0.125 MUg/ml and 0.125 MUg/ml, 0.063 MUg/ml and 0.063 MUg/ml, 0.125 MUg/ml and 0.125 MUg/ml, 0.125 MUg/ml and 0.125 MUg/ml, 0.016 MUg/ml and 0.016 MUg/ml, and 0.063 MUg/ml and 0.063 MUg/ml, respectively. In summary, this surveillance project did not identify any resistant strain against fluoroquinolone, tetracycline, or macrolide agents in Japan. PMID- 27452430 TI - Maternal breastfeeding, early introduction of non-breast milk, and excess weight in preschoolers. AB - OBJECTIVE: Investigate associations between excess weight in preschool children, breastfeeding duration and age of non-breast milk introduction. METHODS: Cross sectional study of a representative sample of 817 preschool children, aged 2 to 4 years, attending municipal day care centers in the city of Taubate. The weight and height of children were measured in the day care centers in 2009, 2010 and 2011. The body mass index z-score (BMIz) was calculated and children were classified as risk of overweight (BMIz>=1 to<2) or excess weight (BMIz>=2). Data analysis was carried out by comparison of proportions, coefficient of correlation and multivariate linear regression. RESULTS: The prevalence of risk of overweight was 18.9% and of excess weight (overweight or obesity) was 9.3%. The median duration of breastfeeding and age of introduction of non-breast milk was 6 months. The child's BMIz showed direct correlation with birth weight (r=0.154; p<0.001) and maternal Body Mass Index (BMI) (r=0.113; p=0.002). The correlation was inverse with the total duration of breastfeeding (r=-0.099; p=0.006) and age at non-breast milk introduction (r=-0.112; p=0.002). There was no correlation between the child's BMIz with birth length, duration of exclusive breastfeeding and mother's age. CONCLUSIONS: The earlier the introduction of non-breast milk, the higher the correlation with excess weight at preschool age. PMID- 27452431 TI - Human fetal membranes at term: Dead tissue or signalers of parturition? AB - Various endocrine, immune, and mechanical factors produced by feto-maternal compartments at term increase intrauterine inflammatory loads to induce labor. The role of fetal (placental) membranes (amniochorion) as providers of parturition signals has not been well investigated. Fetal membranes line the intrauterine cavity and grow with and protect the fetus. Fetal membranes exist as an entity between the mother and fetus and perform unique functions during pregnancy. Membranes undergo a telomere-dependent p38 MAPK-induced senescence and demonstrate a decline in functional and mechanical abilities at term, showing signs of aging. Fetal membrane senescence is also allied with completion of fetal maturation at term as the fetus readies for delivery, which may also indicate the end of independent life and longevity of fetal membranes as their functional role concludes. Fetal membrane senescence is accelerated at term because of oxidative stress and increased stretching. Senescent fetal membranes cells produce senescence-associated secretory phenotype (SASP-inflammation) and also release proinflammatory damage-associated molecular patterns (DAMPs), namely HMGB1 and cell-free fetal telomere fragments. In a feedback loop, SASP and DAMPs increase senescence and enhance the inflammatory load to promote labor. Membranes increase the inflammatory load to disrupt homeostatic balance to transition quiescent uterine tissues toward a labor phenotype. Therefore, along with other well described labor-promoting signals, senescent fetal membranes may also contribute to human term parturition. PMID- 27452432 TI - Carbohydrate and fatty acid perturbations in the amniotic fluid of the recipient twin of pregnancies complicated by twin-twin transfusion syndrome in relation to treatment and fetal cardiovascular risk. AB - INTRODUCTION: Twin-twin transfusion syndrome (TTTS) complicates 15% of monochorionic twin pregnancies, often being associated with recipient cardiac dysfunction. Untreated, it has a fetal mortality rate of at least 90%; although treatment by fetoscopic laser coagulation significantly improves prognosis. Measurement of recipient amniotic fluid metabolites, such as cardiac Troponin T and atrial natriuretic polypeptide, correlate with cardiac function in this fetus. The aim of this study is to describe the amniotic fluid metabolomic profile in TTTS, relate this to fetal recipient cardiac function and assess the metabolomic changes induced by fetoscopic laser coagulation. METHODS: Prospective single centre cohort study. The metabolomics profile of the amniotic fluid from the recipient sac of TTTS pregnancies was assessed using ultra high performance liquid chromatography-mass spectrometry. Profiles were compared pre- and post laser coagulation and related to fetal recipient cardiac function, as assessed using Doppler ultrasound within 4 h of treatment. RESULTS: Eleven metabolites had significant associations with recipient fetal right and left ventricular myocardial performance index pre-laser. 200 metabolites in recipient amniotic fluid demonstrated a change in relative concentrations when comparing pre- and post-laser coagulation (p < 0.005). The most prominent change is in the balance of carbohydrate and fatty acid metabolic profile contributing to fetal or placental energy metabolism. These changes were also associated with the echocardiographic measures of recipient cardiac function. DISCUSSION: Changes in carbohydrate and fatty acid metabolic profiles are noted in recipients with cardiac dysfunction, and further changes are noted after treatment. Validation and investigation may identify targets for potential pharmacological treatment. PMID- 27452433 TI - Telomere homeostasis in placentas from pregnancies with uncontrolled diabetes. AB - OBJECTIVE: Diabetes during pregnancy causes an intrauterine environment that influences lifetime sickness of the mother and the fetus. There is a correlation between diabetes and telomere shortening; however, very little is known about telomere homeostasis in the placenta. We aimed to study the telomerase complex in placentas and in cord blood leukocytes from patients with poorly controlled diabetes. METHODS: Biopsies from 16 third-trimester placentas and cord blood samples from pregnancies complicated with uncontrolled diabetes and from 16 gestational age-matched controls from uncomplicated pregnancies were examined. The expression of hTERT (human telomerase reverse transcriptase) was evaluated by immunohistochemistry and by RT-RCR. TERC gene copy number and telomere capture were evaluated by FISH. RESULTS: Telomerase expression was significantly lower in the diabetic placentas, both the protein (17.8 +/- 2.8% cellular staining vs. 37 +/- 5.32%, P = 0.012) and the mRNA levels (0.42 +/- 0.03 folds, P = 0.022). Lower expression of TERC gene copy number were shown in the diabetic placentas compared to the healthy controls (1.7 +/- 0.8% vs. 3.7 +/- 1.6%, P = 0.035). We also detected higher percentage of cells with telomere capture among the diabetic trophoblasts compared to the healthy controls (19.8 +/- 5.12% vs. 9.6 +/- 3.65%, P = 0.038). Those differences were not observed in cord blood leukocytes from the same samples. CONCLUSIONS: Uncontrolled diabetes during pregnancy disrupts telomere-telomerase homeostasis in the trophoblasts. These changes may increase the risk for metabolic diseases in adulthood among offspring of pregnancies complicated by gestational diabetes mellitus as part of intrauterine programming. These variations were not observed in cord blood leukocytes, which imply different telomere homeostasis mechanisms in fetal cord blood. PMID- 27452434 TI - The importance of selecting the right internal control gene to study the effects of antenatal glucocorticoid administration in human placenta. AB - RT-qPCR requires a suitable set of internal control genes (ICGs) for an accurate normalization. The usefulness of 7 previously published ICGs in the human placenta was analyzed according to the effects of betamethasone treatment, sex and fetal age. Raw RT-qPCR data of the ICGs were evaluated using published algorithms. The algorithms revealed that a reliable normalization was achieved using the geometrical mean of PPIA, RPL19, HMBS and SDHA. The use of a different subset ICGs out of the 7 investigated, although not statistically affected by the conditions, biased the results, as demonstrated through changes in expression of glucocorticoid receptor (NR3C1) mRNA as a target gene. PMID- 27452435 TI - Comprehensive RNA profiling of villous trophoblast and decidua basalis in pregnancies complicated by preterm birth following intra-amniotic infection. AB - INTRODUCTION: We performed RNA sequencing with the primary goal of discovering key placental villous trophoblast (VT) and decidua basalis (DB) transcripts differentially expressed in intra-amniotic infection (IAI)-induced preterm birth (PTB). METHODS: RNA was extracted from 15 paired VT and DB specimens delivered of women with: 1) spontaneous PTB in the setting of amniocentesis-proven IAI and histological chorioamnionitis (n = 5); 2) spontaneous idiopathic PTB (iPTB, n = 5); and 3) physiologic term pregnancy (n = 5). RNA sequencing was performed using the Illumina HiSeq 2500 platform, and a spectrum of computational tools was used for gene prioritization and pathway analyses. RESULTS: In the VT specimens, 128 unique long transcripts and 7 mature microRNAs differed significantly between pregnancies complicated by IAI relative to iPTB (FDR<0.1). The up-regulated transcripts included many characteristic of myeloblast-derived cells, and bioinformatic analyses revealed enrichment for multiple pathways associated with acute inflammation. In an expanded cohort including additional IAI and iPTB specimens, the expression of three proteins (cathepsin S, lysozyme, and hexokinase 3) and two microRNAs (miR-133a and miR-223) was validated using immunohistochemistry and quantitative PCR, respectively. In the DB specimens, only 11 long transcripts and no microRNAs differed significantly between IAI cases and iPTB controls (FDR<0.1). Comparison of the VT and DB specimens in each clinical scenario revealed signatures distinguishing these placental regions. DISCUSSION: IAI is associated with a transcriptional signature consistent with acute inflammation in the villous trophoblast. The present findings illuminate novel signaling pathways involved in IAI, and suggest putative therapeutic targets and potential biomarkers associated with this condition. PMID- 27452436 TI - COX-2 plays a role in angiogenic DBA(+) uNK cell subsets activation and pregnancy protection in LPS-exposed mice. AB - INTRODUCTION: Although uterine Natural Killer (uNK) cells have cytoplasmic granules rich in perforin and granzymes, these cells do not degranulate in normal pregnancy. DBA lectin(+) uNK cells produce angiogenic factors which stimulate remodeling of uterine arterioles to increase blood flow within the growing feto placental unit. We sought to investigate the importance of COX-2 on mouse pregnancy inoculated with Gram-negative bacteria Lipopolysaccharide (LPS) by treating with a selective COX-2 inhibitor (nimesulide). METHODS: We have combined histochemical, immunohistochemical, stereological, morphometric, behavioral, and litter analyses to investigate mouse pregnancy inoculated with LPS with or without pre-treatment with nimesulide 30 min before LPS injections, focusing on DBA(+) uNK cell response and viability of the pregnancy. RESULTS: LPS caused sickness behavior, an immature DBA(+) uNK influx, decreased mature DBA(+) uNK cell numbers, and triggered a new DBA(low) uNK appearance. These effects of LPS, except the sickness behavior, were prevented by nimesulide. COX-2 inhibition also prevented the down-regulation of uNK perforin and spiral arteriole alpha-actin expression stimulated by LPS. While the litter size from Nimesulide + LPS-treated mothers was significantly smaller compared to those from LPS-treated group, nimesulide alone showed no effect on the offspring. DISCUSSION: Collectively, our data indicate that COX-2 changes angiogenic DBA(+) uNK cells in order to protect mouse pregnancy after LPS injection. PMID- 27452437 TI - Epigenetic regulation of STAT5A and its role as fetal DNA epigenetic marker during placental development and dysfunction. AB - INTRODUCTION: Development of normal placenta requires regulated apoptosis of trophoblasts. However, uncontrolled apoptosis has been seen in the pregnancy related complications like hydatidiform mole and pre-eclampsia. STAT5A is a transcription factor with well-known anti-apoptotic role. Thus, we sought to study the role of STAT5A and its epigenetic regulation in placental development and pathologies and its use as fetal DNA epigenetic marker. METHODS: The present study was conducted on pregnant women who were enrolled in five groups, based on the three trimesters in normal pregnancy and two pregnancy related disorder groups: pre-eclampsia and hydatidiform mole. Placental villi samples and maternal blood were obtained from each pregnant woman and were analyzed for promoter region methylation (via methylation sensitive high resolution melting) and histone trimethylations (via chromatin immunoprecipitation) of STAT5A. RESULTS: Our data revealed higher expression of STAT5A in first trimester villi, which decreased with advancing gestation with corresponding increased DNA methylation and H3 trimethylations. Development of choriocarcinoma was associated with DNA methylation associated lower expression of STAT5A. The pattern of promoter methylation of STAT5A in cell free DNA within maternal plasma was observed to be similar to its promoter methylation in placental villi during normal pregnancy, pre-eclampsia and molar complications, which suggested its use as a novel fetal DNA epigenetic marker. DISCUSSION: Our results suggest the regulation of STAT5A via epigenetic mechanisms during normal pregnancy and the association of STAT5A epigenetic dysregulation in pregnancy related complications. Further, hypermethylated STAT5A can be utilized as novel fetal DNA epigenetic marker. PMID- 27452438 TI - Placental structural abnormalities have detrimental hemodynamic consequences in a rat model of maternal hyperglycemia. AB - INTRODUCTION: Human type 1 diabetic pregnancy is associated with placental structural and hemodynamic abnormalities. We hypothesized that in rat fetuses of hyperglycemic dams, placental and fetal blood flow velocity waveforms demonstrate compromised hemodynamics when compared to control fetuses, and these hemodynamic parameters correlate with placental structural abnormalities at near term gestation. METHODS: Streptozotocin-induced maternal hyperglycemia group comprised 10 dams with 107 fetuses and the control group 20 dams with 219 fetuses. Doppler ultrasonographic examinations were performed at gestational days 13-14, 16-17, and 19-21. After the last examination, placentas were collected for morphologic, gene expression, and cytokine analysis. RESULTS: Umbilical artery (UA), descending aorta (DAO), and ductus venosus (DV) pulsatility indices (PI) were significantly higher at each study point in maternal hyperglycemia compared to controls. Placental size, glycogen storages, venous thrombosis formation, and fluid accumulation were increased in maternal hyperglycemia. Epidermal growth factor receptor (Edgfrb), platelet derived growth factor receptor beta polypeptide (Pdgfrb), and tumor necrosis factor receptor superfamily, member 12alpha (Tnfrsf12alpha) expressions were decreased. Interleukin (IL) -2 and -4 concentrations were decreased, and IL-1beta levels were increased in maternal hyperglycemia. UA PIs correlated positively with DV PIV, DAO PI, fluid accumulation, and glycogen storages. UA PIs correlated negatively with IL-4, Edgfrb, and Pdgfrb. DISCUSSION: In maternal hyperglycemia, placental and fetal hemodynamics were compromised during the last trimester of pregnancy compared to normoglycemic pregnancies. Placental structural, metabolic, and growth related gene expression, and inflammatory marker abnormalities were associated with hemodynamic compromise. PMID- 27452439 TI - Dichotomous effects of aryl hydrocarbon receptor (AHR) activation on human fetoplacental endothelial cell function. AB - INTRODUCTION: Maternal cigarette smoking is associated with elevated fetoplacental vascular resistance and fetal growth restriction (FGR). While studies have demonstrated varying effects of nicotine on blood flow, the role of polycyclic aromatic hydrocarbons (PAHs), abundant toxins in cigarette smoke that cross the placenta, has not been elucidated. We hypothesized that exposure of human fetoplacental endothelial cells (ECs) to the PAH benzo[a]yrene (BaP) would result in up-regulation of cyclooxygenase-2 (PTGS2) and preferential production of vasoconstrictive prostanoids via activation of the aryl hydrocarbon receptor (AHR) pathway. METHODS: ECs were isolated, cultured, and treated with vehicle or BaP. ECs were subjected to real-time PCR, western blotting, enzyme immunoassays, wound scratch assays, tube formation assays, and RNA interference against AHR. Statistical analyses were performed with Student's t-test, one-way ANOVA followed by multiple comparisons testing when appropriate, or the Kruskal-Wallis H test. RESULTS: BaP induced PTGS2 expression (p < 0.05) and production of the stable metabolite of prostacyclin (p = 0.001) in fetoplacental ECs without affecting thromboxane. These effects were ablated by PTGS2 inhibition (p < 0.01) and RNA interference of AHR (p < 0.001). Surprisingly, despite the induction of prostacyclin, EC migration (p = 0.007) and tube formation (p = 0.003) were inhibited by BaP. AHR inhibition, however, rescued tube formation (p = 0.008). DISCUSSION: BaP-mediated AHR activation results in induction of PTGS2 expression and enhanced production of prostacyclin metabolite. Despite an increase in this vasodilatory and pro-angiogenic prostanoid, BaP exposure also impairs EC migration and angiogenesis through AHR. This suggests that PAH may adversely affect the fetoplacental vasculature through its regulation of angiogenesis. PMID- 27452441 TI - Punicalagin promotes human villous trophoblast differentiation. AB - Poor differentiation of trophoblasts is associated with placental dysfunction, predisposing women to multiple pregnancy disorders. Punicalagin, a prominent ellagitannin in pomegranate juice has been shown to exert anti-apoptosis and anti oxidative effects in human trophoblasts. We hypothesized that punicalagin modulates trophoblast differentiation. We found that punicalagin-treated primary trophoblast showed reduced E-cadherin, higher Syncytin 1, more beta-hCG, and increased GCM1, an upstream regulator of beta-hCG. Punicalagin exposure of villous explants enhanced the number of cytotrophoblasts expressing the proliferation marker Ki67. We conclude that punicalagin enhances trophoblast differentiation and speculate that punicalagin might be used therapeutically in pregnancies at risk for placental dysfunction. PMID- 27452440 TI - Human amnion mesenchymal cells are pro-inflammatory when activated by the Toll like receptor 2/6 ligand, macrophage-activating lipoprotein-2. AB - INTRODUCTION: Infection accounts for over 40% of preterm premature rupture of the fetal membranes (PPROM), a major cause of preterm birth. Toll-like receptors (TLR) play key roles in pathogen surveillance but their expression and function in amnion mesenchymal cells (AMC) is unclear. The aims of this study were to determine the expression of all TLR isoforms and the effect of macrophage activating lipoprotein-2 (MALP-2), derived from a common pathogen involved in PPROM, on human AMC. METHODS: AMC were isolated from normal, term amnion from repeat cesarean section. Semi-quantitative RT-PCR, immunocytochemistry, immunohistochemistry and western blotting were used to detect TLR isoform expression. Immunocytochemistry of NF-kappaB p65, pro-inflammatory cytokine secretion (ELISA), MTT assay, LDH assay, immunoblotting of cytosolic cytochrome c and cleaved caspase-3, and expression of 84 microRNAs by Qiagen miRNA PCR array were used to determine the functional effect of MALP-2 on AMC. RESULTS: TLR1-10 was detected in AMC, and protein expression of TLR2, 4, and 6 were confirmed. MALP-2 induced nuclear translocation of p65, reaching significance after 45 min (ANOVA, P < 0.05). MALP-2 did not cause apoptosis but did lead to significant secretion of IL-4, IL-6, and IL-8 (P < 0.05, 0.01, 0.001, respectively) and significant changes in miRNA-320a and miRNA-18a (P < 0.05). DISCUSSION: These results suggest that AMC elicit a pro-inflammatory response following stimulation with the known TLR2/6 ligand MALP-2. This data supports the idea that AMC express the innate immune system receptors that could help with immune surveillance during infection and contribute to inflammatory responses that lead to PPROM. PMID- 27452442 TI - Transcriptomic signatures of villous cytotrophoblast and syncytiotrophoblast in term human placenta. AB - During pregnancy, the placenta ensures multiple functions, which are directly involved in the initiation, fetal growth and outcome of gestation. The placental tissue involved in maternal-fetal exchanges and in synthesis of pregnancy hormones is the mononucleated villous cytotrophoblast (VCT) which aggregates and fuses to form and renew the syncytiotrophoblast (ST). Knowledge of the gene expression pattern specific to this endocrine and exchanges tissue of human placenta is of major importance to understand functions of this heterogeneous and complex tissue. Therefore, we undertook a global analysis of the gene expression profiles of primary cultured-VCT (n = 6) and in vitro-differentiated-ST (n = 5) in comparison with whole term placental tissue from which mononucleated VCT were isolated. A total of 880 differentially expressed genes (DEG) were observed between VCT/ST compared to whole placenta, and a total of 37 and 137 genes were significantly up and down-regulated, respectively, in VCT compared to ST. The 37 VCT-genes were involved in cellular processes (assembly, organization, and maintenance), whereas the 137 ST-genes were associated with lipid metabolism and cell morphology. In silico, all networks were linked to 3 transcriptional regulators (PPARgamma, RARalpha and NR2F1) which are known to be essential for trophoblast differentiation. A subset of six DEG was validated by RT-qPCR and four by immunohistochemistry. To conclude, recognition of these pathways is fundamental to increase our understanding of the molecular basis of human trophoblast differentiation. The present study provides for the first time a gene expression signature of the VCT and ST compared to their originated term human placental tissue. PMID- 27452443 TI - The effect of 17alpha-ethynylestradiol induced intrahepatic cholestasis of pregnancy on placental P-glycoprotein in mice: Implications in the individualized transplacental digoxin treatment for fetal heart failure. AB - INTRODUCTION: Placental P-glycoprotein (P-gp) plays a significant role in controlling transplacental digoxin transfer rate. Investigations on P-gp regulation in placenta of women with different pregnant pathological states are of great significance to individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of 17alpha ethynylestradiol induced intrahepatic cholestasis of pregnancy (ICP) on placental P-gp in mice. METHODS: ICP model in mice was induced by subcutaneous injection of 17alpha-ethynylestradiol dissolved in propylene glycol once daily from E12.5 to E16.5. Maternal plasma ALT, AST, TB, DBIL, gamma-GT, LDH, ALP and TBA concentrations were measured. HE staining was applied for observation of maternal liver cells degeneration, necrosis and intrahepatic cholestasis. Placental Abcb1a/Abcb1b/HIF-1alpha mRNA and P-gp/HIF-1alpha protein expression were determined by real-time quantitative PCR and western-blot. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay. RESULTS: The ICP group showed higher levels of maternal plasma ALT, AST, TB, DBIL, gamma-GT, LDH, ALP and TBA concentrations, reduction in fetal survival rates, lower placental and fetal weights, and typical liver cells degeneration, necrosis and intrahepatic cholestasis. The placental Abcb1a mRNA and P-gp expression of ICP group were significantly elevated, while transplacental digoxin transfer rates were significantly decreased. Both placental HIF-1alpha mRNA and protein expression was significantly elevated in the ICP group, and there was a positive correlation between Abcb1a mRNA and HIF-1alpha mRNA. CONCLUSIONS: 17alpha-ethynylestradiol induced ICP could up-regulate placental P-gp expression and reduce transplacental digoxin transfer rate in mice, which might be partly associated with higher expression of HIF-1alpha. PMID- 27452444 TI - Hemoglobin Bart hydrops fetalis: A model for studying vascular changes in placental hypoxia. AB - INTRODUCTION: Placental ischemia can be pre-placental (maternal), placental or post-placental (fetal), with corresponding changes in villous vasculature. Hydrops fetalis (HF) resulting from hemoglobin (Hb) Bart disease can serve as a model for intrauterine hypoxia, and placentas from such cases show a distinctive peripheral villous stromal myofibroblastic hypercellularity (PVSH). We hypothesized that Hb Bart disease, which results in profound fetal hypoxia, would lead to placental hypoxia on a post-placental basis. METHODS: We assessed villous vasculature using computerized morphometry, comparing placentas in 14 Hb Bart HF cases to 18 non-Hb Bart HF cases. Morphometric parameters were matched as closely as possible to those reported in the literature for comparison purposes. RESULTS: Villous vessels of Hb Bart HF showed significantly increased numbers of vessels (p = 0.001), longer vascular perimeter (p = 0.002), thickening of vascular endothelial layer (p = 0.038) and higher shape coefficient (p = 0.042) indicating a more branching pattern of vessels. In addition, placental villi of Hb Bart HF containing PVSH showed a longer vascular perimeter (p = 0.008) and narrower lumen (p = 0.002), with a higher shape coefficient (p = 0.03), in comparison to villi lacking PVSH. DISCUSSION: Contrary to expectations, the overall pattern of vascular changes in Hb Bart HF suggested multifactorial hypoxia: pre-placental, on the basis of the marked placentomegaly, compromising blood flow from uterine distention; placental, from hydropic villi causing a generalized diminished intervillous space; and post-placental from the greatly reduced capacity of Hb Bart to extract oxygen from the intervillous space. Standardized vascular morphometry will facilitate comparison between different conditions, for a better understanding of placental hypoxia. PMID- 27452445 TI - Perinatal prognosis of pregnancies complicated by placental chronic villitis or intervillositis of unknown etiology and combined lesions: About a series of 178 cases. AB - INTRODUCTION: The objective of this work was to evaluate and compare perinatal outcomes of pregnancies complicated by placental chronic intervillositis (CIUE) or villitis (CVUE) of unknown etiology and combined lesions. METHODS: Retrospective study of all cases of significant CVUE and CIUE occurring during a 12-year period in a university tertiary hospital center. Multiple pregnancies, infectious and medical termination of pregnancies (TOP) without intra-uterine growth restriction (IUGR) were excluded. RESULTS: 178 placentas were affected (78 cases of CVUE, 24 cases of CIUE and 76 cases of combined lesions involving both villitis and intervillositis) including 12 cases of recurrence. A disorder of fetal growth was found in 73% of cases and we noted 9.5% of cases of abortion. The rate of IUGR appeared to be significantly higher in case of CIUE with a fetal death risk five times higher. These complications seems to be related to more diffuse inflammatory infiltrates (p < 0.05). CVUE was associated with a significant morbidity with 42% of severe IUGR and severe alterations of umbilical artery Doppler in nearly one third of cases. Caesarean section was important (54.8%). Sixty-one percent of newborns were hospitalized and 11.4% in neonatal reanimation. In case of combined lesions, fetal outcomes appeared relatively close to those of CVUE. CVUE could recur in more severe forms or as CIUE with an increased risk for the fetus. Clinicoanatomic correlations were noted. DISCUSSION: Observation of recurrence of CVUE on CIUE or combined lesions and similar phenotypic characteristics of the infiltrates suggest that they could be two different stages of a same disease. CVUE remains a disease to be considered as serious. Association of small lesions of intervillositis does not change the prognosis. The severity of histological lesions and the initial obstetrical accident could be discriminatory to identify patients at risk of serious recurrence. Harmonized classification will be required. CONCLUSIONS: This study confirms the higher morbidity of CIUE compared to CVUE but shows the necessity of monitoring pregnancies following an episode of CVUE, which are still at risk of serious and recurrent complications. PMID- 27452446 TI - Association of structural and numerical anomalies of chromosome 22 in a patient with syndromic intellectual disability. AB - Array comparative genomic hybridization (aCGH) is now widely adopted as a first tier clinical diagnostic test for patients with developmental delay (DD)/intellectual disability (ID), autism spectrum disorders, and multiple congenital anomalies. Nevertheless, classic karyotyping still has its impact in diagnosing genetic diseases, particularly mosaic cases. We report on a 30 year old patient with syndromic intellectual disability, a 22q13.2 microdeletion and mosaic trisomy 22. The patient had the following clinical features: intrauterine growth retardation at birth, hypotonia, cryptorchidism, facial asymmetry, enophthalmus, mild prognathism, bifid uvula, hypoplastic upper limb phalanges, DD including speech delay, and ID. Whole genome aCGH showed a de novo 1 Mb interstitial heterozygous deletion in 22q13.2, confirmed by fluorescence in situ hybridization in all cells examined. Moreover, 18% cells had an extra chromosome 22 suggesting a trisomy 22 mosaicism. Almost all 22q13 deletions published so far have been terminal deletions with variable sizes (100 kb to over 9 Mb). Very few cases of interstitial 22q13.2 deletions were reported. In its mosaic form, trisomy 22 is compatible with life, and there are about 20 reports in the literature. It has a variable clinical presentation: growth restriction, dysmorphic features, cardiovascular abnormalities, hemihyperplasia, genitourinary tract anomalies and ID. Neurodevelopmental outcome ranges from normal to severe DD. The patient presents clinical features that are common to both the interstitial 22q13 deletion and the mosaic trisomy 22; characteristics related to the interstitial deletion alone and others explained solely by the mosaic trisomy. Our case points out the role of conventional cytogenetic tools in mosaic cases that could be missed by microarray technology. We therefore suggest the combination of both conventional and molecular karyotyping in the investigation of certain genetic diseases. PMID- 27452447 TI - Indications for cone beam computed tomography in children and young patients in a Turkish subpopulation. AB - BACKGROUND: Cone beam computed tomography (CBCT) imaging is widely used in children; however, it remains controversial because of the health effects of radiation. AIM: This retrospective study investigated the indications for CBCT and dentomaxillofacial pathologies in paediatric patients. MATERIALS AND METHODS: CBCT images of 329 paediatric patients (i.e., aged <18 years) were investigated retrospectively. CBCT images were obtained with five fields of view (FOV). CBCT indications were categorised as surgery and orthodontics. The effects of age, sex, and FOV were evaluated. The level of significance was P = 0.05. RESULTS: The most common orthodontic indications were malocclusion and dentomaxillofacial anomalies (38.5%), followed by the localisation of impacted teeth (33.1%). There was no relationship between sex and indications. There were significant associations between age groups and malocclusion and dentomaxillofacial anomalies, localisation of impacted teeth, and trauma. The face was the most frequently imaged region, followed by the jaws (maxilla and mandible). CONCLUSION: The most common indication for CBCT was malocclusion and dentomaxillofacial anomalies in the primary and permanent dentition age groups, whereas the localisation of impacted teeth was the most common indication in the mixed dentition age group. Generally, CBCT was indicated in orthodontics and surgery. PMID- 27452448 TI - Performance of four different agar plate methods for rectal swabs, synergy disk tests and metallo-beta-lactamase Etest for clinical isolates in detecting carbapenemase-producing Klebsiella pneumoniae. AB - The aims of the study were to compare four different agar plate methods in the identification of carbapenemase-producing Klebsiella pneumoniae (CP-Kp) from rectal samples and to assess the role of phenotypic methodologies in the identification of carbapenemase type from clinical K. pneumoniae isolates. Two chromogenic agars (Brilliance CRE and CHROMagar KPC) were compared to MacConkey agar plates with ertapenem (ERT) or imipenem (IMP) disks for the identification of CP-Kp from 912 rectal swabs. CP-Kp was detected in 329 samples by either agar methodology (299 K. pneumoniae carbapenemase positive, 27 Verona integron-encoded metallo-beta-lactamase positive and 3 K. pneumoniae carbapenemase and Verona integron-encodedmetallo-beta-lactamase positive). Sensitivity of Brilliance CRE, CHROMagar KPC and MacConkey agar plus IMP or ERT disk (inhibition zone <25 mm) was 96.8, 99.2, 67.2 and 81.8 %, while specificity was 90.9, 78.2, 98.1 and 97.9 %, respectively. Synergy meropenem-disk tests with EDTA or phenylboronic acid were used in order to detect the carbapenemase type as compared to PCR results (blaVIM, blaKPC and blaNDM) from 2515 isolates with reduced susceptibility to any of the Etest-examined carbapenems (ERT, IMP or meropenem). Metallo-beta-lactamase MP/MPI Etest was applied in 616 isolates. Sensitivity was 98.4, 90.9 and 82.2 % for phenylboronic acid synergy test, EDTA synergy test and metallo-beta-lactamase Etest, respectively, while their specificity was high (>97.5 %). Phenotypic methodologies can provide reliable results for the identification of carbapenemase production among K. pneumoniae isolates. Chromogenic agars can be applied in high-risk patients as part of surveillance and infection control programs. PMID- 27452449 TI - Improved Transplanted Stem Cell Survival in a Polymer Gel Supplemented With Tenascin C Accelerates Healing and Reduces Scarring of Murine Skin Wounds. AB - Mesenchymal stem cells (MSCs) remain of great interest in regenerative medicine because of their ability to home to sites of injury, differentiate into a variety of relevant lineages, and modulate inflammation and angiogenesis through paracrine activity. Many studies have found that despite the promise of MSC therapy, cell survival upon implant is highly limited and greatly reduces the therapeutic utility of MSCs. The matrikine tenascin C, a protein expressed often at the edges of a healing wound, contains unique EGF-like repeats that are able to bind EGFR at low affinities and induce downstream prosurvival signaling without inducing receptor internalization. In this study, we utilized tenascin C in a collagen/GAG-based polymer (TPolymer) that has been shown to be beneficial for skin wound healing, incorporating human MSCs into the polymer prior to application to mouse punch biopsy wound beds. We found that the TPolymer was able to promote MSC survival for 21 days in vivo, leading to associated improvements in wound healing such as dermal maturation and collagen content. This was most marked in a model of hypertrophic scarring, in which the scar formation was limited. This approach also reduced the inflammatory response in the wound bed, limiting CD3e+ cell invasion by approximately 50% in the early wound-healing process, while increasing the numbers of endothelial cells during the first week of wound healing as well. Ultimately, this matrikine-based approach to improving MSC survival may be of great use across a variety of cell therapies utilizing matrices as delivery vehicles for cells. PMID- 27452450 TI - Bioactive sesquiterpenoids from the flowers of Inula japonica. AB - Phytochemical investigation of the flowers of Inula japonica led to isolation of nine sesquiterpenoids, inujaponins A-I, as well as eighteen known ones. These sesquiterpenoids belong to six skeletal-types, including eudesmane, 1,10-seco eudesmane, germacrane, guaiane, 4,5-seco-guaiane, and pseudoguaiane sesquiterpenoids. Their structures were established by extensive spectroscopic analysis. The absolute configurations of inujaponin A, eupatolide, and deacetylovatifolin were determined by Cu-Kalpha X-ray crystallographic analysis. Most of the isolated compounds exhibited potent cytotoxicity against HL-60, SMMC 7721, A-549, MCF-7, and SW-480 cancer cell lines, with IC50 values ranging from 1.57 to 22.58 MUM. Some selected compounds also possessed significant inhibitory activity against LPS-induced NO production in RAW264.7 macrophages with IC50 values ranging from 1.42 to 8.99 MUM. PMID- 27452451 TI - Amides and neolignans from the aerial parts of Piper bonii. AB - Six amides, piperbonamides A-F, three neolignans piperbonins A-C, and 11 known compounds were isolated from the aerial parts of Piper bonii (Piperaceae). The structures of piperbonamides A-F and piperbonins A-C were elucidated based on the analysis of 1D and 2D NMR and MS data. Piperbonin A, (+)-trans-acuminatin, (+) cis-acuminatin, (+)-kadsurenone, and pipernonaline showed weak activity against platelet aggregation with IC50 values of 118.2, 108.5, 90.02, 107.3, and 116.3 MUM, respectively, as compared with the positive control, tirofiban, with an IC50 value of 5.24 MUM. Piperbonamides A-F were inactive against five tumor cell lines at concentrations up to 40 MUM. PMID- 27452452 TI - Triterpenoids from the leaves of Alphitonia xerocarpus Baill and their biological activity. AB - Ten previously undescribed triterpenoid saponins and a previously undescribed norlupane triterpenoid were isolated, with three known saponins, four known flavonoids, two known lupane derivatives, sitosterol and 6'-heptadecanoyl-3-O beta-d-glucopyranosylsitosterol from the leaves of Alphitonia xerocarpus (Rhamnaceae), an endemic tree of New Caledonia. The chemical structures of the purified compounds were identified by nuclear magnetic resonance and mass spectrometry. The isolated compounds were tested for their antioxidant, antityrosinase, antibacterial and cytotoxic activity. The aqueous methanol extract showed antioxidant activity (DPPH assay) due to the presence of rutin. Ceanothenic acid showed good cytotoxic activity against a KB cell line (IC50 = 2.6 MUM) and antibacterial activity against Staphylococcus aureus and Enterococcus faecalis with MIC values of 8 and 16 MUg/mL, respectively. The previously undescribed 29-hydroxyceanothenic acid exhibited moderate cytotoxic activity (IC50 = 10 MUM), good antibacterial activity against S. aureus (MIC = 4 MUg/mL) and moderate antibacterial activity against E. faecalis (MIC = 16 MUg/mL). PMID- 27452453 TI - Triple inhaled therapy for chronic obstructive pulmonary disease. AB - Combining individual drugs in a single inhaler is the most convenient way to deliver triple therapy. A long-acting muscarinic receptor antagonist (LAMA) added to an inhaled corticosteroid (ICS)/long-acting beta2-adrenoceptor agonist (LABA) fixed-dose combination (FDC) can improve efficacy of pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). New inhaled ICS/LABA/LAMA FDCs, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are in Phase III of clinical development for COPD. Triple inhaled therapy might be particularly useful in patients with severe to very severe COPD, above all in those with peripheral blood or sputum eosinophilia, asthma-COPD overlap syndrome (ACOS) or frequent exacerbators. Future prospective studies should assess efficacy and safety of triple ICS/LABA/LAMA therapy in selected COPD phenotypes. PMID- 27452454 TI - Exploiting receptor tyrosine kinase co-activation for cancer therapy. AB - Studies over the past decade have shown that many cancers have evolved receptor tyrosine kinase (RTK) co-activation as a mechanism to drive tumour progression and limit the lethal effects of therapy. This review summarises the general principles of RTK co-activation and discusses approaches to exploit this phenomenon in cancer therapy and drug discovery. Computational strategies to predict kinase co-dependencies by integrating drug screening data and kinase inhibitor selectivity profiles will also be described. We offer a perspective on the implications of RTK co-activation on tumour heterogeneity and cancer evolution and conclude by surveying emerging computational and experimental approaches that will provide insights into RTK co-activation biology and deliver new developments in effective cancer therapies. PMID- 27452455 TI - Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence. AB - Chikungunya virus (CHIKV) and related alphaviruses cause epidemics of acute and chronic musculoskeletal disease. To investigate the mechanisms underlying the failure of immune clearance of CHIKV, we studied mice infected with an attenuated CHIKV strain (181/25) and the pathogenic parental strain (AF15561), which differ by five amino acids. Whereas AF15561 infection of wild-type mice results in viral persistence in joint tissues, 181/25 is cleared. In contrast, 181/25 infection of MUMT mice lacking mature B cells results in viral persistence in joint tissues, suggesting that virus-specific antibody is required for clearance of infection. Mapping studies demonstrated that a highly conserved glycine at position 82 in the A domain of the E2 glycoprotein impedes clearance and neutralization of multiple CHIKV strains. Remarkably, murine and human antibodies targeting E2 domain B failed to neutralize pathogenic CHIKV strains efficiently. Our data suggest that pathogenic CHIKV strains evade E2 domain-B-neutralizing antibodies to establish persistence. PMID- 27452456 TI - mRNA Cap Methylation in Pluripotency and Differentiation. AB - The mRNA cap recruits factors essential for transcript processing and translation initiation. We report that regulated mRNA cap methylation is a feature of embryonic stem cell (ESC) differentiation. Expression of the mRNA cap methyltransferase activating subunit RAM is elevated in ESCs, resulting in high levels of mRNA cap methylation and expression of a cohort of pluripotency associated genes. During neural differentiation, RAM is suppressed, resulting in repression of pluripotency-associated factors and expression of a cohort of neural-associated genes. An established requirement of differentiation is increased ERK1/2 activity, which suppresses pluripotency-associated genes. During differentiation, ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency. Elevated RAM expression also increases the efficiency of fibroblast reprogramming. Thus, the mRNA cap emerges as a dynamic mark that instructs change in gene expression profiles during differentiation and reprogramming. PMID- 27452457 TI - Inflammatory Th17 Cells Express Integrin alphavbeta3 for Pathogenic Function. AB - Interleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune encephalomyelitis (EAE), and IL-23 blockade reduces the number of effector Th17 cells in the CNS. We report that pro-inflammatory Th17 cells express high integrin beta3 that is IL-23 dependent. Integrin beta3 was not upregulated on all activated T cells; rather, integrin beta3 was upregulated along with its functional partner integrin alphav on effector Th17 cells and "ex Th17" cells, and alphavbeta3(hi) RORgammat(+) cells expanded during EAE. Integrin alphavbeta3 inhibitors ameliorated clinical signs of EAE, and integrin beta3 deficiency on CD4(+) T cells alone was sufficient to block EAE induction. Furthermore, integrin-beta3-deficient Th17 cells, but not Th1 cells, were impaired in their ability to induce EAE. Integrin beta3(-/-) T cells induced smaller demyelinated lesions and showed reduced spread and accumulation within the CNS, corresponding with impaired extracellular-matrix-mediated migration. Hence, integrin beta3 is required for Th17 cell-mediated autoimmune CNS inflammation. PMID- 27452458 TI - The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells. AB - The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients. Furthermore, overexpression of R2 in non-tumorigenic cells progressively increases genome stress, promoting transformation. These cells display alterations in replication fork progression, elevated genomic uracil, and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase abolishes R2-induced genome instability. Thus, the expression level of dUTPase determines the role of high R2 in driving genome instability in cancer cells. PMID- 27452459 TI - Electrostatic Interactions between Elongated Monomers Drive Filamentation of Drosophila Shrub, a Metazoan ESCRT-III Protein. AB - The endosomal sorting complex required for transport (ESCRT) is a conserved protein complex that facilitates budding and fission of membranes. It executes a key step in many cellular events, including cytokinesis and multi-vesicular body formation. The ESCRT-III protein Shrub in flies, or its homologs in yeast (Snf7) or humans (CHMP4B), is a critical polymerizing component of ESCRT-III needed to effect membrane fission. We report the structural basis for polymerization of Shrub and define a minimal region required for filament formation. The X-ray structure of the Shrub core shows that individual monomers in the lattice interact in a staggered arrangement using complementary electrostatic surfaces. Mutations that disrupt interface salt bridges interfere with Shrub polymerization and function. Despite substantial sequence divergence and differences in packing interactions, the arrangement of Shrub subunits in the polymer resembles that of Snf7 and other family homologs, suggesting that this intermolecular packing mechanism is shared among ESCRT-III proteins. PMID- 27452460 TI - The Zinc Finger Transcription Factor Sp9 Is Required for the Development of Striatopallidal Projection Neurons. AB - Striatal medium-sized spiny neurons (MSNs), composed of striatonigral and striatopallidal neurons, are derived from the lateral ganglionic eminence (LGE). We find that the transcription factor Sp9 is expressed in LGE progenitors that generate nearly all striatal MSNs and that Sp9 expression is maintained in postmitotic striatopallidal MSNs. Sp9-null mice lose most striatopallidal MSNs because of decreased proliferation of striatopallidal MSN progenitors and increased Bax-dependent apoptosis, whereas the development of striatonigral neurons is largely unaffected. ChIP qPCR provides evidence that Ascl1 directly binds the Sp9 promoter. RNA-seq and in situ hybridization reveal that Sp9 promotes expression of Adora2a, P2ry1, Gpr6, and Grik3 in the LGE and striatum. Thus, Sp9 is crucial for the generation, differentiation, and survival of striatopallidal MSNs. PMID- 27452461 TI - Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer. AB - Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy. PMID- 27452462 TI - Endocannabinoid-Mediated Plasticity in Nucleus Accumbens Controls Vulnerability to Anxiety after Social Defeat Stress. AB - Chronic social defeat stress (CSDS) is a clinically relevant model of mood disorders. The relationship between the CSDS model and a physiologically pertinent paradigm of synaptic plasticity is not known. Here, we found that cluster analysis of the emotional behavior states of mice exposed to CSDS allowed their segregation into anxious and non-anxious groups. Endocannabinoid-mediated spike-timing dependent plasticity (STDP) in the nucleus accumbens was attenuated in non-anxious mice and abolished in anxious mice. Anxiety-like behavior in stressed animals was specifically correlated with their ability to produce STDP. Pharmacological enhancement of 2-arachidonoyl glycerol (2-AG) signaling in the nucleus accumbens normalized the anxious phenotype and STDP in anxious mice. These data reveal that endocannabinoid modulation of synaptic efficacy in response to a naturalistic activity pattern is both a molecular correlate of behavioral adaptability and a crucial factor in the adaptive response to chronic stress. PMID- 27452463 TI - Comprehensive Proteomic Analysis of Human Erythropoiesis. AB - Mass spectrometry-based proteomics now enables the absolute quantification of thousands of proteins in individual cell types. We used this technology to analyze the dynamic proteome changes occurring during human erythropoiesis. We quantified the absolute expression of 6,130 proteins during erythroid differentiation from late burst-forming units-erythroid (BFU-Es) to orthochromatic erythroblasts. A modest correlation between mRNA and protein expression was observed. We identified several proteins with unexpected expression patterns in erythroid cells, highlighting a breakpoint in the erythroid differentiation process at the basophilic stage. We also quantified the distribution of proteins between reticulocytes and pyrenocytes after enucleation. These analyses identified proteins that are actively sorted either with the reticulocyte or the pyrenocyte. Our study provides the absolute quantification of protein expression during a complex cellular differentiation process in humans, and it establishes a framework for future studies of disordered erythropoiesis. PMID- 27452464 TI - Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures. AB - Endocannabinoid signaling is considered to suppress excessive excitability of neural circuits and to protect the brain from seizures. However, the precise mechanisms of this effect are poorly understood. Here, we report that 2 arachidonoylglycerol (2-AG), one of the two major endocannabinoids, is crucial for suppressing seizures. We found that kainate-induced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase alpha, were much more severe compared with those in cannabinoid CB1 receptor knockout mice and were comparable to those in mice lacking both CB1- and CB2-receptor-mediated signaling. In the dentate gyrus, 2-AG suppressed excitatory input around the inner and middle molecular layers through CB1 and presumably CB2 receptors, respectively. This 2 AG-mediated suppression contributed to decreased granule cell excitability and the dampening of seizures. Furthermore, lack of 2-AG signaling enhanced kindling epileptogenesis and spontaneous seizures after kainate-induced status epilepticus. These results highlight critical roles of 2-AG signaling in the suppression of epileptic seizures. PMID- 27452465 TI - The Cardiomyocyte RNA-Binding Proteome: Links to Intermediary Metabolism and Heart Disease. AB - RNA functions through the dynamic formation of complexes with RNA-binding proteins (RBPs) in all clades of life. We determined the RBP repertoire of beating cardiomyocytic HL-1 cells by jointly employing two in vivo proteomic methods, mRNA interactome capture and RBDmap. Together, these yielded 1,148 RBPs, 391 of which are shared with all other available mammalian RBP repertoires, while 393 are thus far unique to cardiomyocytes. RBDmap further identified 568 regions of RNA contact within 368 RBPs. The cardiomyocyte mRNA interactome composition reflects their unique biology. Proteins with roles in cardiovascular physiology or disease, mitochondrial function, and intermediary metabolism are all highly represented. Notably, we identified 73 metabolic enzymes as RBPs. RNA-enzyme contacts frequently involve Rossmann fold domains with examples in evidence of both, mutual exclusivity of, or compatibility between RNA binding and enzymatic function. Our findings raise the prospect of previously hidden RNA-mediated regulatory interactions among cardiomyocyte gene expression, physiology, and metabolism. PMID- 27452467 TI - Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection. AB - The prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled Mycobacterium tuberculosis (Mtb). However, definitive data for this model are lacking. Among the epithelial cells of the upper airway, a specialized epithelial cell known as a microfold cell (M cell) overlies various components of mucosa-associated lymphatic tissue. Here, using multiple mouse models, we show that Mtb invades via M cells to initiate infection. Intranasal Mtb infection in mice lacking M cells either genetically or by antibody depletion resulted in reduced invasion and dissemination to draining lymph nodes. M cell depleted mice infected via aerosol also had delayed dissemination to lymph nodes and reduced mortality. Translocation of Mtb across two M cell transwell models was rapid and transcellular. Thus, M cell translocation is a vital entry mechanism that contributes to the pathogenesis of Mtb. PMID- 27452466 TI - ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. AB - Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs. PMID- 27452468 TI - Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1. AB - Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of tumor types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinical setting. We have generated a model of ADI-PEG20 resistance in mesothelioma cells. This resistance is mediated through re expression of ASS1 via demethylation of the ASS1 promoter. Through coordinated transcriptomic and metabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamine metabolites, together with a compensatory increase in the expression of polyamine biosynthetic enzymes. Upon arginine deprivation, polyamine metabolites are decreased in the ASS1-deficient cells and in plasma isolated from ASS1-deficient mesothelioma patients. We identify a synthetic lethal dependence between ASS1 deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1 negative cancers. PMID- 27452469 TI - beta-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment. AB - G-protein-coupled receptors (GPCRs) initiate a variety of signaling cascades, depending on effector coupling. beta-arrestins, which were initially characterized by their ability to "arrest" GPCR signaling by uncoupling receptor and G protein, have recently emerged as important signaling effectors for GPCRs. beta-arrestins engage signaling pathways that are distinct from those mediated by G protein. As such, arrestin-dependent signaling can play a unique role in regulating cell function, but whether neuromodulatory GPCRs utilize beta-arrestin dependent signaling to regulate neuronal excitability remains unclear. Here, we find that D3 dopamine receptors (D3R) regulate axon initial segment (AIS) excitability through beta-arrestin-dependent signaling, modifying CaV3 voltage dependence to suppress high-frequency action potential generation. This non canonical D3R signaling thereby gates AIS excitability via pathways distinct from classical GPCR signaling pathways. PMID- 27452470 TI - A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency. AB - In spinal muscular atrophy, a neurodegenerative disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein, sensory-motor synaptic dysfunction and increased excitability precede motor neuron (MN) loss. Whether central synaptic dysfunction and MN hyperexcitability are cell-autonomous events or they contribute to MN death is unknown. We addressed these issues using a stem cell-based model of the motor circuit consisting of MNs and both excitatory and inhibitory interneurons (INs) in which SMN protein levels are selectively depleted. We show that SMN deficiency induces selective MN death through cell autonomous mechanisms, while hyperexcitability is a non-cell-autonomous response of MNs to defects in pre-motor INs, leading to loss of glutamatergic synapses and reduced excitation. Findings from our in vitro model suggest that dysfunction and loss of MNs result from differential effects of SMN deficiency in distinct neurons of the motor circuit and that hyperexcitability does not trigger MN death. PMID- 27452471 TI - Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity. AB - Following skeletal muscle injury, muscle stem cells (satellite cells) are activated, proliferate, and differentiate to form myofibers. We show that mRNA decay protein AUF1 regulates satellite cell function through targeted degradation of specific mRNAs containing 3' AU-rich elements (AREs). auf1(-/-) mice undergo accelerated skeletal muscle wasting with age and impaired skeletal muscle repair following injury. Satellite cell mRNA analysis and regeneration studies demonstrate that auf1(-/-) satellite cell self-renewal is impaired due to increased stability and overexpression of ARE-mRNAs, including cell-autonomous overexpression of matrix metalloprotease MMP9. Secreted MMP9 degrades the skeletal muscle matrix, preventing satellite-cell-mediated regeneration and return to quiescence. Blocking MMP9 activity in auf1(-/-) mice restores skeletal muscle repair and maintenance of the satellite cell population. Control of ARE mRNA decay by AUF1 represents a mechanism for adult stem cell regulation and is implicated in human skeletal muscle wasting diseases. PMID- 27452472 TI - In Vivo Formation of Vacuolated Multi-phase Compartments Lacking Membranes. AB - Eukaryotic cells contain membrane-less organelles, including nucleoli and stress granules, that behave like liquid droplets. Such endogenous condensates often have internal substructure, but how this is established in the absence of membrane encapsulation remains unclear. We find that the N- and C-terminal domains of TDP43, a heterogeneous nuclear ribonucleoprotein implicated in neurodegenerative diseases, are capable of driving the formation of sub structured liquid droplets in vivo. These droplets contain dynamic internal "bubbles" of nucleoplasm, reminiscent of membrane-based multi-vesicular endosomes. A conserved sequence embedded within the intrinsically disordered region (IDR) of TDP43 promotes the formation of these multi-phase assemblies. Disease-causing point mutations in the IDR can change the propensity to form bubbles, protein dynamics within the phase, or phase-environment exchange rates. Our results show that a single IDR-containing protein can nucleate the assembly of compartmentalized liquid droplets approximating the morphological complexity of membrane-bound organelles. PMID- 27452474 TI - Capturing neon - the first experimental structure of neon trapped within a metal organic environment. AB - Despite being the fifth most abundant element in the atmosphere, neon has never been observed in an organic or metal-organic environment. This study shows the adsorption of this highly unreactive element within such an environment and reveals the first crystallographic observation of an interaction between neon and a transition metal. PMID- 27452473 TI - Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host. AB - T cells undergo profound metabolic changes to meet the increased energy demands of maintaining an antiviral response. We postulated that differences in metabolic reprogramming would shape the efficacy of CD8 T cells mounted against persistent viral infections. We found that the poorly functional PD-1(hi) T cell response against hepatitis B virus (HBV) had upregulated the glucose transporter, Glut1, an effect recapitulated by oxygen deprivation to mimic the intrahepatic environment. Glut1(hi) HBV-specific T cells were dependent on glucose supplies, unlike the more functional cytomegalovirus (CMV)-specific T cells that could utilize oxidative phosphorylation in the absence of glucose. The inability of HBV specific T cells to switch to oxidative phosphorylation was accompanied by increased mitochondrial size and lower mitochondrial potential, indicative of mitochondrial dysfunction. Interleukin (IL)-12, which recovers HBV-specific T cell effector function, increased their mitochondrial potential and reduced their dependence on glycolysis. Our findings suggest that mitochondrial defects limit the metabolic plasticity of exhausted HBV-specific T cells. PMID- 27452475 TI - Comparative analysis of cryopreservation methods in Chlamydomonas reinhardtii. AB - Chlamydomonas is a model organism used for studies of many important biological processes. Traditionally, strains have been propagated on solid agar, which requires routine passaging for long-term maintenance. Cryopreservation of Chlamydomonas is possible, yet long-term viability is highly variable. Thus, improved cryopreservation methods for Chlamydomonas are an important requirement for sustained study of genetically defined strains. Here, we tested a commercial cryopreservation kit and directly compared it's effectiveness to a methanol-based method. We also tested thaw-back procedures comparing the growth of cells in liquid culture or on solid agar media. We demonstrated that methanol was the superior cryopreservation method for Chlamydomonas compared to the commercial kit and that post-thaw culture conditions dramatically affect viability. We also demonstrated that cryopreserved cells could be successfully thawed and plated directly onto solid agar plates. Our findings have important implications for the long-term storage of Chlamydomonas that can likely be extended to other algal species. PMID- 27452476 TI - Experimental study on soluble chemical transfer to surface runoff from soil. AB - Prevention of chemical transfer from soil to surface runoff, under condition of irrigation and subsurface drainage, would improve surface water quality. In this paper, a series of laboratory experiments were conducted to assess the effects of various soil and hydraulic factors on chemical transfer from soil to surface runoff. The factors include maximum depth of ponding water on soil surface, initial volumetric water content of soil, depth of soil with low porosity, type or texture of soil and condition of drainage. In the experiments, two soils, sand and loam, mixed with different quantities of soluble KCl were filled in the sandboxes and prepared under different initial saturated conditions. Simulated rainfall induced surface runoff are operated in the soils, and various ponding water depths on soil surface are simulated. Flow rates and KCl concentration of surface runoff are measured during the experiments. The following conclusions are made from the study results: (1) KCl concentration in surface runoff water would decrease with the increase of the maximum depth of ponding water on soil surface; (2) KCl concentration in surface runoff water would increase with the increase of initial volumetric water content in the soil; (3) smaller depth of soil with less porosity or deeper depth of soil with larger porosity leads to less KCl transfer to surface runoff; (4) the soil with finer texture, such as loam, could keep more fertilizer in soil, which will result in more KCl concentration in surface runoff; and (5) good subsurface drainage condition will increase the infiltration and drainage rates during rainfall event and will decrease KCl concentration in surface runoff. Therefore, it is necessary to reuse drained fertile water effectively during rainfall, without polluting groundwater. These study results should be considered in agriculture management to reduce soluble chemical transfer from soil to surface runoff for reducing non-point sources pollution. PMID- 27452477 TI - Patient-generated Digital Images after Pediatric Ambulatory Surgery. AB - OBJECTIVE: To describe the use of digital images captured by parents or guardians and sent to clinicians for assessment of wounds after pediatric ambulatory surgery. METHODS: Subjects with digital images of post-operative wounds were identified as part of an on-going cohort study of infections after ambulatory surgery within a large pediatric healthcare system. We performed a structured review of the electronic health record (EHR) to determine how digital images were documented in the EHR and used in clinical care. RESULTS: We identified 166 patients whose parent or guardian reported sending a digital image of the wound to the clinician after surgery. A corresponding digital image was located in the EHR in only 121 of these encounters. A change in clinical management was documented in 20% of these encounters, including referral for in-person evaluation of the wound and antibiotic prescription. CONCLUSION: Clinical teams have developed ad hoc workflows to use digital images to evaluate post-operative pediatric surgical patients. Because the use of digital images to support follow up care after ambulatory surgery is likely to increase, it is important that high quality images are captured and documented appropriately in the EHR to ensure privacy, security, and a high-level of care. PMID- 27452478 TI - Analysis of iodinated contrast delivered during thermal ablation: is material trapped in the ablation zone? AB - Intra-procedural contrast-enhanced CT (CECT) has been proposed to evaluate treatment efficacy of thermal ablation. We hypothesized that contrast material delivered concurrently with thermal ablation may become trapped in the ablation zone, and set out to determine whether such an effect would impact ablation visualization. CECT images were acquired during microwave ablation in normal porcine liver with: (A) normal blood perfusion and no iodinated contrast, (B) normal perfusion and iodinated contrast infusion or (C) no blood perfusion and residual iodinated contrast. Changes in CT attenuation were analyzed from before, during and after ablation to evaluate whether contrast was trapped inside of the ablation zone. Visualization was compared between groups using post-ablation contrast-to-noise ratio (CNR). Attenuation gradients were calculated at the ablation boundary and background to quantitate ablation conspicuity. In Group A, attenuation decreased during ablation due to thermal expansion of tissue water and water vaporization. The ablation zone was difficult to visualize (CNR = 1.57 +/- 0.73, boundary gradient = 0.7 +/- 0.4 HU mm(-1)), leading to ablation diameter underestimation compared to gross pathology. Group B ablations saw attenuation increase, suggesting that iodine was trapped inside the ablation zone. However, because the normally perfused liver increased even more, Group B ablations were more visible than Group A (CNR = 2.04 +/- 0.84, boundary gradient = 6.3 +/- 1.1 HU mm(-1)) and allowed accurate estimation of the ablation zone dimensions compared to gross pathology. Substantial water vaporization led to substantial attenuation changes in Group C, though the ablation zone boundary was not highly visible (boundary gradient = 3.9 +/- 1.1 HU mm(-1)). Our results demonstrate that despite iodinated contrast being trapped in the ablation zone, ablation visibility was highest when contrast is delivered intra-procedurally. Therefore, CECT may be feasible for real-time thermal ablation monitoring. PMID- 27452479 TI - The nature of structure and bonding between transition metal and mixed Si-Ge tetramers: A 20-electron superatom system. AB - A novel superatom species with 20-electron system, Six Gey M(+) (x + y = 4; M = Nb, Ta), was properly proposed. The trigonal bipyramid structures for the studied systems were identified as the putative global minimum by means of the density functional theory calculations. The high chemical stability can be explained by the strong p-d hybridization between transition metal and mixed Si-Ge tetramers, and closed-shell valence electron configuration [1S(2) 1P(6) 2S(2) 1D(10) ]. Meanwhile, the chemical bondings between metal atom and the tetramers can be recognized by three localized two-center two-electron (2c-2e) and delocalized 3c 2e sigma-bonds. For all the doped structures studied here, it was found that the pi- and sigma-electrons satisfy the 2(N + 1)(2) counting rule, and thus these clusters possess spherically double (pi and sigma) aromaticity, which is also confirmed by the negative nucleus-independent chemical shifts values. Consequently, all the calculated results provide a further understanding for structural stabilities and electronic properties of transition metal-doped semiconductor clusters. (c) 2016 Wiley Periodicals, Inc. PMID- 27452480 TI - Self-Assembly of Oleyl Bis(2-hydroxyethyl)methyl Ammonium Bromide with Sodium Dodecyl Sulfate and Their Interactions with Zein. AB - Surface tension and aggregation behavior in an aqueous solution of the mixture of cationic surfactant oleyl bis(2-hydroxyethyl)methylammonium bromide (OHAB) and anionic surfactant sodium dodecyl sulfate (SDS) have been studied by surface tension, conductivity, turbidity, zeta potential, isothermal titration microcalorimetry (ITC), cryogenic transmission electron microscopy (Cryo-TEM), and dynamic light scattering. The mixture shows pretty low critical micellar concentration and surface tension, and successively forms globular micelles, unilamellar vesicles, multilamellar vesicles, rod-like micelles, and globular micelles again by increasing the molar fraction of OHAB from 0 to 1.00. The cooperation of hydrophobic interaction between the alkyl chains, electrostatic attraction between the headgroups as well as hydrogen bonds between the hydroxyethyl groups leads to the abundant aggregation behaviors. Furthermore, the solubilization of zein by the OHAB/SDS aggregates and their interactions were studied by ITC, total organic carbon analysis (TOC), and Cryo-TEM. Compared with pure OHAB or pure SDS solution, the amount of zein solubilized by the OHAB/SDS mixture is significantly reduced. It means that the mixtures have much stronger abilities in solubilizing zein. This result has also been proved by the observed enthalpy changes for the interaction of OHAB/SDS mixture with zein. Mixing oppositely charged OHAB and SDS reduces the net charge of mixed aggregates, and thus, the electrostatic attraction between the aggregates and zein is weakened. Meanwhile, the large size of the aggregates may increase the steric repulsion to the zein backbone. This work reveals that surfactant mixtures with larger aggregates and smaller CMCs solubilize less zein, suggesting how to construct a highly efficient and nonirritant surfactant system for practical use. PMID- 27452481 TI - Novel routes of albumin passage across the glomerular filtration barrier. AB - Albuminuria is a hallmark of kidney diseases of various aetiologies and an unambiguous symptom of the compromised integrity of the glomerular filtration barrier. Furthermore, there is increasing evidence that albuminuria per se aggravates the development and progression of chronic kidney disease. This review covers new aspects of the movement of large plasma proteins across the glomerular filtration barrier in health and disease. Specifically, this review focuses on the role of endocytosis and transcytosis of albumin by podocytes, which constitutes a new pathway of plasma proteins across the filtration barrier. Thus, we summarize what is known about the mechanisms of albumin endocytosis by podocytes and address the fate of the endocytosed albumin, which is directed to lysosomal degradation or transcellular movement with subsequent vesicular release into the urinary space. We also address the functional consequences of overt albumin endocytosis by podocytes, such as the formation of pro-inflammatory cytokines, which might eventually result in a deterioration of podocyte function. Finally, we consider the diagnostic potential of podocyte-derived albumin containing vesicles in the urine as an early marker of a compromised glomerular barrier function. In terms of new technical approaches, the review covers how our knowledge of the movement of albumin across the glomerular filtration barrier has expanded by the use of new intravital imaging techniques. PMID- 27452482 TI - Live imaging of mitochondrial dynamics in CNS dopaminergic neurons in vivo demonstrates early reversal of mitochondrial transport following MPP(+) exposure. AB - Extensive convergent evidence collectively suggests that mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD). Recently, changes in the dynamic properties of mitochondria have been increasingly implicated as a key proximate mechanism underlying neurodegeneration. However, studies have been limited by the lack of a model in which mitochondria can be imaged directly and dynamically in dopaminergic neurons of the intact vertebrate CNS. We generated transgenic zebrafish in which mitochondria of dopaminergic neurons are labeled with a fluorescent reporter, and optimized methods allowing direct intravital imaging of CNS dopaminergic axons and measurement of mitochondrial transport in vivo. The proportion of mitochondria undergoing axonal transport in dopaminergic neurons decreased overall during development between 2days post-fertilization (dpf) and 5dpf, at which point the major period of growth and synaptogenesis of the relevant axonal projections is complete. Exposure to 0.5-1.0mM MPP(+) between 4 and 5dpf did not compromise zebrafish viability or cause detectable changes in the number or morphology of dopaminergic neurons, motor function or monoaminergic neurochemistry. However, 0.5mM MPP(+) caused a 300% increase in retrograde mitochondrial transport and a 30% decrease in anterograde transport. In contrast, exposure to higher concentrations of MPP(+) caused an overall reduction in mitochondrial transport. This is the first time mitochondrial transport has been observed directly in CNS dopaminergic neurons of a living vertebrate and quantified in a PD model in vivo. Our findings are compatible with a model in which damage at presynaptic dopaminergic terminals causes an early compensatory increase in retrograde transport of compromised mitochondria for degradation in the cell body. These data are important because manipulation of early pathogenic mechanisms might be a valid therapeutic approach to PD. The novel transgenic lines and methods we developed will be useful for future studies on mitochondrial dynamics in health and disease. PMID- 27452484 TI - Changes in the prevalence, treatment, and control of hypercholesterolemia and other dyslipidemias over 10 years in Poland: the WOBASZ study. AB - INTRODUCTION Lowering exposure to dyslipidemias is one of the biggest challenges in cardiovascular disease prevention. OBJECTIVES The aim of the study was to describe the prevalence of dyslipidemias and treatment of hypercholesterolemia in Poland, and to assess changes since the period of 2003-2005. PATIENTS AND METHODS Two cross-sectional surveys of the random samples of the Polish population were performed in the years 2003-2005 (WOBASZ) and 2013-2014 (WOBASZ II). Interviews were carried out according to a standard questionnaire. Blood lipid levels were determined in a single laboratory in frozen samples using the enzymatic colorimetric method. RESULTS The analysis included 14151 participants aged 20-74 years (WOBASZ) and 5947 participants aged 20-99 years (WOBASZ II). In the 2013 2014 survey, hypercholesterolemia was found in 70.3% of men and 64.3% of women. Isolated hypertriglyceridemia was found in 5.6% of men and 2.4% of women. Isolated low levels of high-density lipoprotein cholesterol (HDL-C) were found in 5.1% of men and in 7.3% of women. The prevalence of hypercholesterolemia did not change significantly with regards to the 2003-2005 survey. An increase in the prevalence of hypertriglyceridemia was found in men (relative ratio [RR], 1.26; 95% confidence interval [CI], 1.03-1.55), and an increase in the prevalence of low HDL-C levels was observed in both sexes (men: RR, 2.26; 95% CI, 1.77-2.88; women: RR, 1.94; 95% CI, 1.61-2.33). There was an increase in the proportion of persons receiving high- or moderate-intensity statin therapy. However, 60,6% of persons with hypercholesterolemia were not aware of their condition, and only 6% were treated and achieved the treatment target. CONCLUSIONS There is an urgent need for more effective strategies for the prevention and management of dyslipidemias. PMID- 27452483 TI - Optogenetic stimulation of cortico-subthalamic projections is sufficient to ameliorate bradykinesia in 6-ohda lesioned mice. AB - Electrical deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for ameliorating the motor symptoms of Parkinson's disease (PD) including bradykinesia. The STN receives its main excitatory input from cortex; however, the contribution of cortico-subthalamic projection neurons to the effects of DBS remains unclear. To isolate the consequences of stimulating layer 5 primary motor cortex (M1) projections to the STN, we used a dual virus transfection technique to selectively express opsins in these neurons in mice made parkinsonian by unilateral nigrostriatal 6-OHDA lesioning. AAVs containing WGA-Cre constructs were injected in the STN to retrogradely place Cre in STN afferents, while AAVs containing Cre-dependent ultrafast hChR2(E123T/T159C)-EYFP opsin constructs were injected in M1 layer 5, producing specific opsin expression in M1-STN projections. Under unstimulated conditions, lesioned mice showed bradykinesia and hypokinesia (decreased movement), along with electrophysiological changes similar to those observed in PD patients. Specifically, low frequency power (theta, alpha, low beta) was increased and gamma power was decreased, while M1/STN coherence and STN phase-amplitude coupling (PAC) were increased. Optogenetic stimulation (100-130Hz) of STN afferents in these mice ameliorated bradykinesia and hypokinesia and brought the neural dynamics closer to the non-parkinsonian state by reducing theta and alpha and increasing gamma power in M1, decreasing STN PAC, and reducing theta band coherence. Histological examination of the EYFP expression revealed that, in addition to orthodromic and antidromic effects, stimulation of cortico subthalamic neurons may cause wide-spread increased glutamatergic activity due to collaterals that project to areas of the thalamus and other brain regions. PMID- 27452485 TI - Automatic detection of noisy channels in fNIRS signal based on correlation analysis. AB - BACKGROUND: fNIRS signals can be contaminated by distinct sources of noise. While most of the noise can be corrected using digital filters, optimized experimental paradigms or pre-processing methods, few approaches focus on the automatic detection of noisy channels. METHODS: In the present study, we propose a new method that detect automatically noisy fNIRS channels by combining the global correlations of the signal obtained from sliding windows (Cui et al., 2010) with correlation coefficients extracted experimental conditions defined by triggers. RESULTS: The validity of the method was evaluated on test data from 17 participants, for a total of 16 NIRS channels per subject, positioned over frontal, dorsolateral prefrontal, parietal and occipital areas. Additionally, the detection of noisy channels was tested in the context of different levels of cognitive requirement in a working memory N-back paradigm. COMPARISON WITH EXISTING METHOD(S): Bad channels detection accuracy, defined as the proportion of bad NIRS channels correctly detected among the total number of channels examined, was close to 91%. Under different cognitive conditions the area under the Receiver Operating Curve (AUC) increased from 60.5% (global correlations) to 91.2% (local correlations). CONCLUSIONS: Our results show that global correlations are insufficient for detecting potentially noisy channels when the whole data signal is included in the analysis. In contrast, adding specific local information inherent to the experimental paradigm (e.g., cognitive conditions in a block or event-related design), improved detection performance for noisy channels. Also, we show that automated fNIRS channel detection can be achieved with high accuracy at low computational cost. PMID- 27452486 TI - New mechanical thrombectomy model in the rabbit: A feasibility study. AB - BACKGROUND AND PURPOSE: Thrombolytic therapy represented the gold standard for the treatment of ischemic stroke. Its drawbacks include increased bleeding risk and low recanalization rates. Mechanical thrombectomy is a new promising therapy option. Devices used for this procedure were substantially improved during recent years. New devices require extensive preclinical invivo testing. We therefore sought to translate the commonly used pig model to a simplified and cheaper rabbit model. MATERIALS AND METHODS: We performed thromboembolisation in eight intubated and sedated adult female New Zealand white rabbits. The thrombus was created by careful rotation of autologous blood in a silicone tube and addition of barium sulfate for radiopacity. We injected the artificial thrombus via a catheter through the cannulated femoral artery. After thromboembolisation, 2D-DSA was performed to evaluate location and thrombus dimensions. COMPARISON WITH EXISITING METHOD(S): None. RESULTS: No complications or mortality were observed in our series. In seven cases (87.5%) the location of the thromboembolism was the maxillary artery and in one case (12.5%) the thrombus reached the occipital artery. The radiopaque thrombus had a length of 7.0+/-4.55mm invivo. Vessel diameters in angiographic evaluation were 2.44+/-0.21mm for the common carotid artery and 2.1+/-0.16mm for the maxillary artery. CONCLUSIONS: The novel small animal model for mechanical thrombectomy in rabbit is technically feasible and cheap. It offers comparable vessel diameters to cranial arteries and closely mimics human coagulation system. PMID- 27452487 TI - p-Value combiners for graphical modelling of EEG data in the frequency domain. AB - BACKGROUND: In the graphical modelling of brain data, we are interested in estimating connectivity between various regions of interest, and evaluating statistical significance in order to derive a network model. This process involves aggregating results across frequency ranges and several patients, in order to obtain an overall result that can serve to construct a graph. NEW METHOD: In this paper, we propose a method based on p-value combiners, which have never been used in applications to EEG data analysis. This new method is split into two aspects: frequency-wide tests and group-wide tests. The first step can be effectively adjusted to control for false detection rate. RESULTS: This two step protocol is applied to EEG data collected from distinct groups of mental health patients, in order to draw graphical models for each group and highlight structural connectivity differences. Using the method proposed, we show that it is possible to reliably achieve this while effectively controlling for false connections detection. COMPARISON WITH EXISTING METHOD(S): Conventionally, the Holm's Stepdown procedure is used for this type of problem, as it is robust to type I errors. However, it is known to be conservative and prone to false negatives. Furthermore, unlike the proposed methods, it does not directly output a decision rule on whether to accept or reject a statement. CONCLUSIONS: The proposed methodology offers significant improvements over the stepdown procedure in terms of error rate and false negative rate across the network models, as well as in term of applicability. PMID- 27452488 TI - A simplified approach for efficient isolation of functional microglial cells: Application for modeling neuroinflammatory responses in vitro. AB - Purified microglial cells in culture are frequently used to model brain inflammatory responses but obtaining large yields of these cells on a routine basis can be quite challenging. Here, we demonstrate that it is possible to achieve high-yield isolation of pure microglial (MAC-1(+) /Fcrls(+) /Ccr2(-) ) cells from postnatal brain tissue through a simple culture procedure that mainly relies on the adhesion preference of these cells to the polycation polyethyleneimine (PEI) in serum-supplemented DMEM medium. Accordingly, other synthetic or biological substrates failed to mimic PEI effects under the same culture conditions. Replacement of DMEM by DMEM/F12 nutrient mixture did not permit microglial cell isolation on PEI coating, indicating that PEI effects were context-dependent. Remarkably, the lack of culture feeding during progression of microglial cell isolation strongly improved cell yield, suggesting that nutritional deprivation was required to optimize this process. When generated in large culture flasks coated with PEI, cultures of microglial cells were easily recovered by trypsin proteolysis to produce subcultures for functional studies. These cultures responded to lipopolysaccharide (LPS, 1-10 ng/ml) treatment by secreting pro-inflammatory cytokines such as TNF-alpha, IL-6, IL-1beta and by generating nitric oxide and reactive oxygen species. Most interestingly, this response was curtailed by appropriate reference drugs. Microglial cells were also strongly responsive to the mitogenic cytokine GM-CSF, which confirms that the functional repertoire of these cells was well preserved. Because of its high yield and simplicity, we believe that the present method will prove to be especially convenient for mechanistic studies or screening assays. GLIA 2016;64:1912-1924. PMID- 27452489 TI - Moving toward 'common' use of the marmoset as a non-human primate aging model. PMID- 27452490 TI - Briefer activation time is associated with better outcomes after out-of-hospital cardiac arrest. AB - BACKGROUND: Treatment of out-of-hospital cardiac arrest (OHCA) requires prompt intervention. Better outcomes are associated with briefer time from dispatch of emergency medical services (EMS) providers to arrival on scene, application of a defibrillator or insertion of an advanced airway. We assessed whether time from receipt of a call by a telecommunicator to dispatch of EMS providers was associated with outcomes. METHODS: This was a retrospective analysis of a prospective cohort study of persons who had OHCA treated by EMS providers in Seattle, WA. Activation interval was defined as time from call pick up by telecommunicator to notification of EMS providers to respond to the call. Response interval was defined as the time from notification of EMS providers to their arrival at patient side. We determined the association between time intervals and outcomes of sustained restoration of spontaneous circulation (ROSC), survival to hospital discharge and neurologically favorable survival using multiple logistic regression. Secondary analyses assessed the relative contribution of activation versus response interval, and adjusted for post treatment patient and EMS characteristics. RESULTS: Among 2,687 patients, activation interval was mean 1.2+/-0.6min. Response interval was mean 6.1+/ 2.4min. 1,232 (45.9%) achieved ROSC; 475 (17.7%) survived to discharge; and 428 (15.9%) had favorable neurologic status at discharge. Compared to an activation interval of at least 1.5min, patients with briefer intervals were more likely to survive to discharge (adjusted odds ratio (OR) for <1min, 1.69 (95% confidence interval (CI), 1.26, 2.28); adjusted odds ratio for 1 to 1.49min, 1.54 (95% CI, 1.14, 2.08); p value=0.002). With baseline survival of 10%, the absolute increase in survival associated with a 30s decrease in activation interval was 0.7% and for a 30s decrease in response interval was 0.4%. CONCLUSIONS: Briefer activation interval was independently associated with greater survival. Further research is needed to assess whether reduction of the activation interval improves outcome after OHCA. PMID- 27452491 TI - [Outcome of Resection of Inferior Vena Cava Superior to the Renal Vein in Renal Cell Carcinoma with Vena Caval Tumor Thrombus]. AB - Surgical management with radical nephrectomy and thrombectomy has often been performed in renal cell carcinoma (RCC) with tumor thrombus infiltrating the inferior vena cava (IVC). We retrospectively reviewed the outcomes of IVC resection without venous reconstruction in patients with RCC and IVC thrombus at our institution. Eight patients with right RCC underwent radical nephrectomy and IVC resection superior to the level of the renal vein without venous reconstruction from August 2005 to February 2015. Thoracotomy, liver mobilization, and extracorporeal circulation were performed based on the IVC thrombus level. We assessed surgical outcomes, perioperative complications, and survival. At presentation, four patients had level IIIa IVC thrombus, three had level IIIb IVC thrombus, and one had level IV IVC thrombus. Perioperative imaging showed that three of the four patients who underwent neoadjuvant molecular targeting therapy achieved down-staging of the tumor thrombus level. The median operative time was 406 min, and the median estimated blood loss was 3,135 ml. With regard to IVC resectionassociated perioperative complications, one patient needed extracorporeal circulation with IVC ligation and Pringle maneuver owing to low blood pressure. Another patient underwent temporary hemodialysis for 8 days after surgery. There were no perioperative deaths, and none of the patients required permanent hemodialysis. Three patients survived the mean observation period of 25 months, including one patient with no recurrence. Three patients achieved long-term survival of more than 2 years. IVC resection without venous reconstruction may be a feasible option for patients with RCC and IVC tumor thrombus. Further study is needed to determine the most appropriate candidates for this procedure. PMID- 27452492 TI - [Efficacy and Prognostic Factors of Estracyt (r) in Patients with Castration Resistant Prostate Cancer (CRPC) : From the Data Analysis of Estracyt (r) Special Drug Use Investigation]. AB - Estracyt?R (estramustine phosphate) is a medical drug for prostate cancer with cytotoxic activity causing disruption of microtubule organization and indirect androgen production suppressing activity by its metabolite, estradiol. Based on the data obtained from the Estracyt?R Special Drug Use Investigation which surveyed the clinical efficacy and safety of Estracyt?R in patients with prostate cancer whose relapse of prostate cancer after combined androgen blockade (CAB) therapy was confirmed, we evaluated the progression-free survival, prognostic factor, decrease in prostate specific antigen (PSA) level and safety. This surveillance was conducted at 147 institutions nationwide between October, 2010 and September, 2013 and clinical efficacy was evaluated in 239 cases and safety in 329 cases. The median duration of progression-free survival, PSA progression free survival and PSA response were 169 days (95%CI, 142-190), 197 days (95%CI, 169-267) and 385 days, respectively. The decrease in PSA level was observed in 125 cases (52.3%). Rate of PSA decline >50 and >25% were 18.4 and 43.1, respectively, and rate of PSA best response (PSA decline > 50%) was 32.6%. Multivariate analysis demonstrated that long duration of prior CAB therapy, Estracyt?R - pretreatment PSA value and bone metastasis influenced progression free survival significantly. Adverse events were observed in 127 cases (38.6%). The major adverse events were anorexia which was observed in 35 cases (10.9%), gastrointestinal disorders observed in 32 cases (9.7%), abnormal laboratory test values observed in 31 cases (9.4%) and gynecomastia observed in 16 cases (4.9%). These results suggest the clinical efficacy and safety of Estracyt?R for chemotherapy-naive castration-resistant prostate cancer (CRPC), and Estracyt?R is regarded as one of the treatment options for patients with CRPC, especially for patients who had long duration of prior CAB therapy. PMID- 27452493 TI - [A Case of Synchronous Malignant Pheochromocytomas in Bilateral Adrenal Glands]. AB - We present a case of synchronous malignant pheochromocytoma in bilateral adrenal glands. A 73- year-old man presented to our hospital with bilateral adrenal masses incidentally found during abdominal ultrasonography examination for an unrelated issue. The patient had a 30-year history of hypertension and paroxysmal atrial fibrillation. Computed tomography and magnetic resonance imaging showed heterogeneous tumors in bilateral adrenal glands and an enlarged para-aortic lymph node. Hormonal examinations revealed a high value of urinary catecholamines. Metaiodobenzylguanidine (MIBG) scintigraphy showed increased uptake in bilateral adrenal glands and the lymph node. Both adrenal tumors and the node were surgically removed. Pathological examination revealed histologically distinct tissue between the two adrenal tumors. The patient received five cycles of adjuvant chemotherapy, consisting of cyclophosphamide, vincristine, and dacarbazine. The patient has been in remission for 32 months following surgical treatment. PMID- 27452494 TI - [A Case of Autosomal Dominant Polycystic Kidney Disease (ADPKD) with Metastases from Bilateral Small Renal Cell Carcinoma]. AB - The patient was a 47 year-old female who had autosomal dominant polycystic kidney disease (ADPKD) with bilateral small renal cell carcinoma (RCC). We performed bilateral partial nephrectomy and radiofrequency ablation to the residual tumor. Pathological diagnosis was clear cell carcinoma,Fuhrman grade 3. Sunitinib therapy was started nine months after the operation because multiple liver metastases occurred. Twenty-six months after the operation,she died from rapid progression of liver metastasis. PMID- 27452495 TI - [Extrarenal Retroperitoneal Angiomyolipoma Masquerading as Retroperitoneal Liposarcoma : A Report of Two Cases]. AB - We report two patients with extrarenal retroperitoneal angiomyolipoma masquerading as perinephric liposarcoma. Patient 1 : A 66-year-old man was diagnosed with a retroperitoneal tumor near the right renal hilum on an abdominal computed tomography (CT) performed before surgery for gastric cancer. A diagnosis of extrarenal retroperitoneal angiomyolipoma was made on the basis of negative uptake of fluorine- 18 2-deoxy-2-fluoro-D-glucose positron emission tomography (18F-FDG PET)/CT. However, because the tumor was found to have gradually enlarged at 18 months afterward, he underwent resection of the extrarenal fat tissue together with the right kidney. Patient 2 : A 56-year-old man underwent abdominal ultrasound during a periodic medical examination, which revealed a right retroperitoneal tumor. Because of the findings in the contrast-enhanced CT and positive uptake of 18F-FDG PET/CT, he underwent resection of the extrarenal fat tissue together with the right kidney. The pathological examination of the two tumors confirmed extrarenal angiomyolipoma. The differential diagnosis of extrarenal retroperitoneal angiomyolipoma from retroperitoneal liposarcoma is difficult even with the use of 18F-FDG PET/CT. PMID- 27452496 TI - [Multiple Recurrences in Perirenal Fatty Tissue 10 Years after Enucleation for Treatment of T1a Renal Cell Carcinoma : A Case Report]. AB - A 71-year-old man underwent simple enucleation for T1a renal cell carcinoma of the left kidney 10 years ago, and, the capsule of the tumor was injured during that surgery. The histopathological diagnosis of the tumor was papillary renal cell carcinoma type1 pT1a, G2 and the surgical margin was negative. Eight years after the surgery, computed tomography (CT) scan imaging showed a mass 13 mm in diameter which was adjacent to the left kidney. In the following year, the mass had grown to 22 mm in diameter. Thus it was suspected as local recurrence of renal cell carcinoma. Magnetic resonance imaging revealed multiple tumors in the left perirenal fatty space and positron emission tomography CT showed abnormal uptake in the same lesions with a maximal standardized uptake value of 3.2. We diagnosed multiple local recurrences of renal cell carcinoma and planned open radical nephrectomy and extirpation of perirenal fat including tumors entirely. The histopathological diagnosis of the tumor was papillary renal cell carcinomas type 1, Fuhrman grade 2>3. The patient had no recurrence or metastases 10 months after the surgery. It is possible that the tumor cells were disseminated during the first surgery due to an injury to the capsule of the tumor and resulted in multiple local recurrences. PMID- 27452497 TI - [Management of High-Risk Prostate Cancer and Left Ectopic Ureter Inserting into Seminal Vesicle with Ipsilateral Hypoplastic Kidney of a Young Patient : A Case Report]. AB - A 44-year-old male patient visited our hospital with a chief complaint of macroscopic hematuria. Prostate biopsies were performed due to prostate specific antigen (PSA) 11.6 ng/ml, and he was diagnosed with Gleason score 5+4 prostate cancer. Computed tomography showed a left hypoplastic kidney. T2- weighted magnetic resonance imaging showed the left ureter stump with ectopic insertion into the dilated left seminal vesicle. He was diagnosed with high-risk prostate cancer and left ectopic ureter inserting into the seminal vesicle with ipsilateral hypoplastic kidney. Laparoscopic left nephroureterectomy and open radical prostatectomy were performed. PMID- 27452498 TI - Customisable 3D printed microfluidics for integrated analysis and optimisation. AB - The formation of smart Lab-on-a-Chip (LOC) devices featuring integrated sensing optics is currently hindered by convoluted and expensive manufacturing procedures. In this work, a series of 3D-printed LOC devices were designed and manufactured via stereolithography (SL) in a matter of hours. The spectroscopic performance of a variety of optical fibre combinations were tested, and the optimum path length for performing Ultraviolet-visible (UV-vis) spectroscopy determined. The information gained in these trials was then used in a reaction optimisation for the formation of carvone semicarbazone. The production of high resolution surface channels (100-500 MUm) means that these devices were capable of handling a wide range of concentrations (9 MUM-38 mM), and are ideally suited to both analyte detection and process optimisation. This ability to tailor the chip design and its integrated features as a direct result of the reaction being assessed, at such a low time and cost penalty greatly increases the user's ability to optimise both their device and reaction. As a result of the information gained in this investigation, we are able to report the first instance of a 3D-printed LOC device with fully integrated, in-line monitoring capabilities via the use of embedded optical fibres capable of performing UV-vis spectroscopy directly inside micro channels. PMID- 27452499 TI - Genomics of speciation and introgression in Princess cichlid fishes from Lake Tanganyika. AB - How variation in the genome translates into biological diversity and new species originate has endured as the mystery of mysteries in evolutionary biology. African cichlid fishes are prime model systems to address speciation-related questions for their remarkable taxonomic and phenotypic diversity, and the possible role of gene flow in this process. Here, we capitalize on genome sequencing and phylogenomic analyses to address the relative impacts of incomplete lineage sorting, introgression and hybrid speciation in the Neolamprologus savoryi-complex (the 'Princess cichlids') from Lake Tanganyika. We present a time-calibrated species tree based on whole-genome sequences and provide strong evidence for incomplete lineage sorting in the early phases of diversification and multiple introgression events affecting different stages. Importantly, we find that the Neolamprologus chromosomes show centre-to-periphery biases in nucleotide diversity, sequence divergence, GC content, incomplete lineage sorting and rates of introgression, which are likely modulated by recombination density and linked selection. The detection of heterogeneous genomic landscapes has strong implications on the genomic mechanisms involved in speciation. Collinear chromosomal regions can be protected from gene flow and harbour incompatibility genes if they reside in lowly recombining regions, and coupling can evolve between nonphysically linked genomic regions (chromosome centres in particular). Simultaneously, higher recombination towards chromosome peripheries makes these more dynamic, evolvable regions where adaptation polymorphisms have a fertile ground. Hence, differences in genome architecture could explain the levels of taxonomic and phenotypic diversity seen in taxa with collinear genomes and might have contributed to the spectacular cichlid diversity observed today. PMID- 27452500 TI - Genomic, transcriptomic and proteomic analyses of Dehalobacter UNSWDHB in response to chloroform. AB - Organohalide respiring bacteria (ORB) are capable of utilising organohalides as electron acceptors for the generation of cellular energy and consequently play an important role in the turnover of natural and anthropogenically-derived organohalides. In this study, the response of a Dehalobacter sp. strain UNSWDHB to the addition of trichloromethane (TCM) after a 50 h period of its absence (suffocation) was evaluated from a transcriptomic and proteomic perspective. The up-regulation of TCM reductive dehalogenase genes (tmrABC) and their gene products (TmrABC) was confirmed at both transcriptional and proteomic levels. Other findings include the upregulation of various hydrogenases (membrane associated Ni-Fe hydrogenase complexes and soluble Fe-Fe hydrogenases), formate dehydrogenases, complex I and a pyrophosphate-energized proton pump. The elevated expression of enzymes associated with carbon metabolism, including complete Wood Ljungdahl pathway, during TCM respiration raises interesting questions on possible fates of intracellular formate and its potential role in the physiology of this bacterium. Overall, the findings presented here provide a broader view on the bioenergetics and general physiology of Dehalobacter UNSWDHB cells actively respiring with TCM. PMID- 27452501 TI - Stereo-Psychopharmacology: The Case of Citalopram and Escitalopram. PMID- 27452503 TI - Biosynthesis-driven structure-activity relationship study of premonensin derivatives. AB - The controlled derivatization of natural products is of great importance for their use in drug discovery. The ideally rapid generation of compound libraries for structure-activity relationship studies is of particular concern. We here use modified biosynthesis for the generation of such a library of reduced polyketides to interfere with the oncogenic KRas pathway. The polyketide is derivatized via side chain alteration, and variations in its redox pattern and in its backbone chain length through manipulation in the corresponding polyketide synthase. Structural and biophysical analyses revealed the nature of the interaction between the polyketides and KRas-interacting protein PDE6delta. Non-natural polyketides with low nanomolar affinity to PDE6delta were identified. PMID- 27452502 TI - Microstructural and microglial changes after repetitive mild traumatic brain injury in mice. AB - Traumatic brain injury (TBI) is a major public health issue, with recently increased awareness of the potential long-term sequelae of repetitive injury. Although TBI is common, objective diagnostic tools with sound neurobiological predictors of outcome are lacking. Indeed, such tools could help to identify those at risk for more severe outcomes after repetitive injury and improve understanding of biological underpinnings to provide important mechanistic insights. We tested the hypothesis that acute and subacute pathological injury, including the microgliosis that results from repeated mild closed head injury (rmCHI), is reflected in susceptibility-weighted magnetic resonance imaging and diffusion-tensor imaging microstructural abnormalities. Using a combination of high-resolution magnetic resonance imaging, stereology, and quantitative PCR, we studied the pathophysiology of male mice that sustained seven consecutive mild traumatic brain injuries over 9 days in acute (24 hr) and subacute (1 week) time periods. rmCHI induced focal cortical microhemorrhages and impaired axial diffusivity at 1 week postinjury. These microstructural abnormalities were associated with a significant increase in microglia. Notably, microgliosis was accompanied by a change in inflammatory microenvironment defined by robust spatiotemporal alterations in tumor necrosis factor-alpha receptor mRNA. Together these data contribute novel insight into the fundamental biological processes associated with repeated mild brain injury concomitant with subacute imaging abnormalities in a clinically relevant animal model of repeated mild TBI. These findings suggest new diagnostic techniques that can be used as biomarkers to guide the use of future protective or reparative interventions. (c) 2016 Wiley Periodicals, Inc. PMID- 27452504 TI - ATF4 regulates SREBP1c expression to control fatty acids synthesis in 3T3-L1 adipocytes differentiation. AB - Activating transcription factor 4 (ATF4), which is highly expressed in 3T3-L1 adipocytes after adipogenic induction, is essential for adipocytes differentiation. ATF4 also plays a vital role in regulating fatty acids biosynthesis, whereas the detailed mechanism of this process is still unclear. Here we demonstrated that siRNA-based ATF4 depletion in 3T3-L1 adipocytes significantly reduced the accumulation of fatty acids and triglycerides. Moreover, SREBP1c protein, which is an important transcription factor of lipogenesis, appreciably decreased while Srebp1c mRNA increased. Then we identified that ATF4 could maintain SREBP1c protein stability by directly activating the expression of USP7 which deubiquitinates SREBP1c and increases its protein content in cell. Besides, USP7 could restore the synthesis of fatty acids and triglycerides in the absence of ATF4. On the other hand, we found that ATF4 might inhibit the transcription of Srebp1c through TRB3, which is repressed by IBMX and DEX during early adipogenesis. Thus, our data indicate that ATF4 regulates SREBP1c expression to control fatty acids synthesis. PMID- 27452505 TI - Cross-Linking Treatment and Corneal Transplant in Refractory Acremonium Keratitis: Case Report. AB - OBJECTIVES: To report a case of Acremonium keratitis treated with voriconazole, corneal collagen cross-linking, and corneal transplant. MATERIALS AND METHODS: Case report. RESULTS: A 42-year-old woman who wore contact lenses daily was referred for refractory keratitis. Her main complaints were gritty sensation and pain. At slit lamp biomicroscopy, an infiltrate on the inferior paracentral cornea and an arcuate conjunctival ulceration were evident. The rest of the cornea was clear with no anterior chamber reaction. Scrapings from the corneal ulcer showed Candida parapsilosis and Acremonium species, which were sensitive to voriconazole. Despite the administration of topical, systemic, and intrastromal voriconazole for 1 month, repeat corneal scraping was positive for Acremonium, and clinical appearance and pain did not resolve. Therefore, corneal collagen cross-linking was applied. Although the pain resolved immediately after the procedure, the lesion showed no improvement. After a month of cross-linking, corneal transplant was performed for visual rehabilitation and treatment of the refractory lesion. The excised corneal button was negative for any microorganisms. CONCLUSIONS: Although corneal collagen cross-linking may be an effective treatment for Acremonium keratitis refractory to medical therapy, corneal transplant was required for visual gain and recovery. PMID- 27452507 TI - Problems+Solutions. PMID- 27452506 TI - Editor's Notes. PMID- 27452508 TI - Washington Medical Update. PMID- 27452510 TI - The Medical Bookshelf. PMID- 27452512 TI - End-stage renal failure. PMID- 27452511 TI - Editor's Mail. PMID- 27452513 TI - End-stage uremia. PMID- 27452515 TI - Primary Care Digest. PMID- 27452517 TI - PIPKIgamma and talin couple phosphoinositide and adhesion signaling to control the epithelial to mesenchymal transition. AB - Epithelial cells acquire migratory/invasive and stemness traits upon conversion to the mesenchymal phenotype. The expression of E-cadherin is a key to this transition; yet precise understanding of the pathways involved in integrating E cadherin loss to the gain of mesenchymal traits remains poorly understood. Here, we show that phosphoinositide-generating enzyme, PIPKIgamma, expression is upregulated upon epithelial-mesenchymal transition (EMT) and together with the cytoskeletal protein talin assemble into a signaling complex upon E-cadherin loss. PIPKIgamma and talin together control the adhesion and phosphoinositide signaling that regulates conversion to the mesenchymal phenotypes. PIPKIgamma and talin regulate the stability of E-cadherin transcriptional repressors, snail and slug, induced by transforming growth factor-beta1 or extracellular matrix protein. Loss of PIPKIgamma or talin or their interaction impaired EMT and the acquisition of cell motility and stemness. This demonstrates a mechanism where a phosphoinositide-generating enzyme PIPKIgamma couples with a cytoskeletal protein talin to control the acquisition of mesenchymal phenotypes. PMID- 27452518 TI - The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. AB - The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks. The Snail-repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate an lncRNA mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT. PMID- 27452519 TI - Human EHMT2/G9a activates p53 through methylation-independent mechanism. AB - p53 is a critical tumor suppressor in humans. It functions mostly as a transcriptional factor and its activity is regulated by numerous post translational modifications. Among different covalent modifications found on p53 the most controversial one is lysine methylation. We found that human G9a (hG9a) unlike its mouse orthologue (mG9a) potently stimulated p53 transcriptional activity. Both ectopic and endogenous hG9a augmented p53-dependent transcription of pro-apoptotic genes, including Bax and Puma, resulting in enhanced apoptosis and reduced colony formation. Significantly, shRNA-mediated knockdown of hG9a attenuated p53-dependent activation of Puma. On the molecular level, hG9a interacted with histone acetyltransferase, p300/CBP, resulting in increased histone acetylation at the promoter of Puma. The bioinformatics data substantiated our findings showing that positive correlation between G9a and p53 expression is associated with better survival of lung cancer patients. Collectively, this study demonstrates that depending on the cellular and organismal context, orthologous proteins may exert both overlapping and opposing functions. Furthermore, this finding has important ramifications on the use of G9a inhibitors in combination with genotoxic drugs to treat p53-positive tumors. PMID- 27452520 TI - Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer. AB - E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much higher than for wild-type keratinocytes. Moreover, E2f7/8 deficient primary keratinocytes proliferate more efficiently under stress conditions, such as low/high confluence or DNA damage. Application of in vivo stress using the DMBA/TPA skin carcinogenesis protocol revealed that combined inactivation of E2f7/8 enhanced tumorigenesis and accelerated malignant progression. Loss of atypical E2Fs resulted in increased expression of E2F target genes, including E2f1. Additional loss of E2f1 did not rescue, but worsened skin tumorigenesis. We show that loss of E2F7/8 triggers apoptosis via induction of E2F1 in response to stress, indicating that the tumor-promoting effect of E2F7/8 inactivation can be partially compensated via E2F1-dependent apoptosis. Importantly, E2F7/8 repressed a large set of E2F target genes that are highly expressed in human patients with skin cancer. Together, our studies demonstrate that atypical E2Fs act as tumor suppressors, most likely via transcriptional repression of cell cycle genes in response to stress. PMID- 27452521 TI - Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions. AB - Loss-of-function mutations in the BRCA1 and BRCA2 genes increase the risk of cancer. Owing to their function in homologous recombination repair, much research has focused on the unstable genomic phenotype of BRCA1/2 mutant cells manifest mainly as large-scale rearrangements. We used whole-genome sequencing of multiple isogenic chicken DT40 cell clones to precisely determine the consequences of BRCA1/2 loss on all types of genomic mutagenesis. Spontaneous base substitution mutation rates increased sevenfold upon the disruption of either BRCA1 or BRCA2, and the arising mutation spectra showed strong and specific correlation with a mutation signature associated with BRCA1/2 mutant tumours. To model endogenous alkylating damage, we determined the mutation spectrum caused by methyl methanesulfonate (MMS), and showed that MMS also induces more base substitution mutations in BRCA1/2-deficient cells. Spontaneously arising and MMS-induced insertion/deletion mutations and large rearrangements were also more common in BRCA1/2 mutant cells compared with the wild-type control. A difference in the short deletion phenotypes of BRCA1 and BRCA2 suggested distinct roles for the two proteins in the processing of DNA lesions, as BRCA2 mutants contained more short deletions, with a wider size distribution, which frequently showed microhomology near the breakpoints resembling repair by non-homologous end joining. An increased and prolonged gamma-H2AX signal in MMS-treated BRCA1/2 cells suggested an aberrant processing of stalled replication forks as the cause of increased mutagenesis. The high rate of base substitution mutagenesis demonstrated by our experiments is likely to significantly contribute to the oncogenic effect of the inactivation of BRCA1 or BRCA2. PMID- 27452522 TI - FOXM1 allows human keratinocytes to bypass the oncogene-induced differentiation checkpoint in response to gain of MYC or loss of p53. AB - Tumour suppressor p53 or proto-oncogene MYC is frequently altered in squamous carcinomas, but this is insufficient to drive carcinogenesis. We have shown that overactivation of MYC or loss of p53 via DNA damage triggers an anti-oncogenic differentiation-mitosis checkpoint in human epidermal keratinocytes, resulting in impaired cell division and squamous differentiation. Forkhead box M1 (FOXM1) is a transcription factor recently proposed to govern the expression of a set of mitotic genes. Deregulation of FOXM1 occurs in a wide variety of epithelial malignancies. We have ectopically expressed FOXM1 in keratinocytes of the skin after overexpression of MYC or inactivation of endogenous p53. Ectopic FOXM1 rescues the proliferative capacity of MYC- or p53-mutant cells in spite of higher genetic damage and a larger cell size typical of differentiation. As a consequence, differentiation induced by loss of p53 or MYC is converted into increased proliferation and keratinocytes displaying genomic instability are maintained within the proliferative compartment. The results demonstrate that keratinocyte oncogene-induced differentiation is caused by mitosis control and provide new insight into the mechanisms driving malignant progression in squamous cancer. PMID- 27452523 TI - Rewiring of the apoptotic TGF-beta-SMAD/NFkappaB pathway through an oncogenic function of p27 in human papillary thyroid cancer. AB - Papillary thyroid carcinoma (PTC), the most frequent thyroid cancer, is characterized by low proliferation but no apoptosis, presenting frequent lymph node metastasis. Papillary thyroid carcinoma overexpress transforming growth factor-beta (TGF-beta). In human cells, TGF-beta has two opposing actions: antitumoral through pro-apoptotic and cytostatic activities, and pro-tumoral promoting growth and metastasis. The switch converting TGF-beta from a tumor suppressor to tumor-promoter has not been identified. In the current study, we have quantified a parallel upregulation of TGF-beta and nuclear p27, a CDK2 inhibitor, in samples from PTC. We established primary cultures from follicular epithelium in human homeostatic conditions (h7H medium). TGF-beta-dependent cytostasis occurred in normal and cancer cells through p15/CDKN2B induction. However, TGF-beta induced apoptosis in normal and benign but not in carcinoma cultures. In normal thyroid cells, TGF-beta/SMAD repressed the p27/CDKN1B gene, activating CDK2-dependent SMAD3 phosphorylation to induce p50 NFkappaB-dependent BAX upregulation and apoptosis. In thyroid cancer cells, oncogene activation prevented TGF-beta/SMAD-dependent p27 repression, and CDK2/SMAD3 phosphorylation, leading to p65 NFkappaB upregulation which repressed BAX, induced cyclin D1 and promoted TGF-beta-dependent growth. In PTC samples from patients, upregulation of TGF-beta, p27, p65 and cyclin D1 mRNA were significantly correlated, while the expression of the isoform BAX-beta, exclusively transcribed in apoptotic cells, was negatively correlated. Additionally, combined ERK and p65 NFkappaB inhibitors reduced p27 expression and potentiated apoptosis in thyroid cancer cells while not affecting survival in normal thyroid cells. Our results therefore suggest that the oncoprotein p27 reorganizes the effects of TGF-beta in thyroid cancer, explaining the slow proliferation but lack of apoptosis and metastatic behavior of PTC. PMID- 27452527 TI - Intestinal malrotation with small bowel obstruction in an adult. PMID- 27452524 TI - CD84 mediates CLL-microenvironment interactions. AB - Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Signals from the CLL microenvironment promote progression of the disease and induce drug resistance. This phenomenon is largely dependent on direct contact between the malignant B cells and stromal cells. CD84 belongs to the signaling lymphocyte activation molecule family of immunoreceptors, which self-associates, forming an orthogonal homophilic dimer. We therefore hypothesized that CD84 may bridge between CLL cells and their microenvironment, promoting cell survival. Our in vitro results show that CD84 expressed on CLL cells interact with CD84 expressed on cells in their microenvironment, inducing cell survival in both sides. Blocking CD84 in vitro and in vivo disrupt the interaction of CLL cells with their microenvironment, resulting in induced cell death. Thus, our findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway. PMID- 27452526 TI - Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment. AB - Tau, an intrinsically disordered protein confined to neuronal axons, binds to and regulates microtubule dynamics. Although there have been observations of string like microtubule fascicles in the axon initial segment (AIS) and hexagonal bundles in neurite-like processes in non-neuronal cells overexpressing Tau, cell free reconstitutions have not replicated either geometry. Here we map out the energy landscape of Tau-mediated, GTP-dependent 'active' microtubule bundles at 37 degrees C, as revealed by synchrotron SAXS and TEM. Widely spaced bundles (wall-to-wall distance Dw-w~25-41 nm) with hexagonal and string-like symmetry are observed, the latter mimicking bundles found in the AIS. A second energy minimum (Dw-w~16-23 nm) is revealed under osmotic pressure. The wide spacing results from a balance between repulsive forces, due to Tau's projection domain (PD), and a stabilizing sum of transient sub-kBT cationic/anionic charge-charge attractions mediated by weakly penetrating opposing PDs. This landscape would be significantly affected by charge-altering modifications of Tau associated with neurodegeneration. PMID- 27452528 TI - Metal-Organic Frameworks Stabilize Mono(phosphine)-Metal Complexes for Broad Scope Catalytic Reactions. AB - Mono(phosphine)-M (M-PR3; M = Rh and Ir) complexes selectively prepared by postsynthetic metalation of a porous triarylphosphine-based metal-organic framework (MOF) exhibited excellent activity in the hydrosilylation of ketones and alkenes, the hydrogenation of alkenes, and the C-H borylation of arenes. The recyclable and reusable MOF catalysts significantly outperformed their homogeneous counterparts, presumably via stabilizing M-PR3 intermediates by preventing deleterious disproportionation reactions/ligand exchanges in the catalytic cycles. PMID- 27452529 TI - Elucidating modes of activation and herbicide resistance by sequence assembly and molecular modelling of the Acetolactate synthase complex in sugarcane. AB - Acetolactate synthase (ALS) catalyzes the first portion of the biosynthetic pathway leading to the generation of branched-chain amino acids. As such it is essential for plant health and is a major target for herbicides. ALS is a very poorly characterized molecule in sugarcane. The enzyme is activated and inhibited by a regulatory subunit (known as VAT1 in plants) whose mode of action is entirely unknown. Using Saccharum halepense as a template we have assembled the ALS gene of sugarcane (Saccharum hybrid) and have modelled the structure of ALS based on an Arabidopsis template (the first ALS model for a monocot). We have also assembled the ALS regulatory proteins (VAT1 and VAT2) from sugarcane and show that VAT2 is specific to true grasses. Employing a bacterial model, we have generated a structural model for VAT1, which explains why the separate domains of the proteins bind to either leucine or valine but not both. Using co-evolution studies we have determined molecular contacts by which we modelled the docking of VAT1 to ALS. In conclusion, we demonstrate how the binding of VAT1 to ALS activates ALS and show how VAT1 can also confer feedback inhibition to ALS. We validate our ALS model against biochemical data and employ this model to explain the function of a novel herbicide binding mutant in sugarcane. PMID- 27452530 TI - Optimal architecture of differentiation cascades with asymmetric and symmetric stem cell division. AB - The role of symmetric division in stem cell biology is ambiguous. It is necessary after injuries, but if symmetric divisions occur too often, the appearance of tumours is more likely. To explore the role of symmetric and asymmetric division in cell populations, we propose a mathematical model of competition of populations, in which the stem cell expansion is controlled by fully differentiated cells. We show that there is an optimal fraction of symmetric stem cell division, which maximises the long-term survival probability of the organism. Moreover, we show the optimal number of stem cells in a tissue, and we show that number has to be small enough to reduce the probability of the appearance of advantageous malignant cells, and large enough to assure that the population will not be suppressed by stochastic fluctuations. PMID- 27452577 TI - Confinement Effect in Layered Double Hydroxide Nanoreactor: Improved Optical Sensing Selectivity. AB - Confinement effect in the layered double hydroxide (LDH) nanoreactors can control the reaction rate and disperse the fluorescence guest, which are promising to be introduced in optical sensing systems. In this work, an optical sensor has been fabricated by combining the confinement effect from the LDH nanoreactors with advantageous sensing performances of graphene quantum dots (GQDs). The mechanism indicated the LDHs with two dimensional (2D) confined space provided a stable microenvironment and acted as the disperse matrix to control the distribution of intercalated GQDs. Such a confinement effect may decrease the diffusion rate of hydroxyl radicals ((*)OH), and thus (*)OH with the short lifetime (10(-9) s) is annihilated during the diffusing process into the LDH interlayer galleries. As a result, the inherently existing interference from (*)OH for detection of NO2 was eliminated. Furthermore, a rapid and portable fluorescent paper sensor coated with the as-prepared GQD-LDHs for visual detection of NO2 gas was successfully developed. Our work provides a feasible method to remarkably improve the selectivity by virtue of confinement effect. PMID- 27452578 TI - The influence of metal-ion binding on the structure and surface composition of Sonic Hedgehog: a combined classical and hybrid QM/MM MD study. AB - In this work, the influence of the metal ions present in vertebrate Sonic Hedgehog was assessed by a series of molecular mechanics molecular dynamics simulations with differing ionic compositions. The obtained data suggest that Ca(ii) binding has a very distinct influence on the composition of the protein surface surrounding the binding site by shaping several ionic interactions with negatively charged sidechains that otherwise would be pointing towards the solvent, repelling potential ligands. Furthermore, the Ca(ii) ions play an important role in the stability of the loop regions where they are coordinated. In contrast, the removal of the Zn(ii) ion results in no noticeable destabilization of its chemical surrounding, however, it is shown that the destabilizing effect of removed Ca(ii) ions is amplified if Zn(ii) is absent as well. Furthermore, a quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulation of Sonic Hedgehog with special focus on the Zn(ii) binding site has been conducted. The results indicate that QM/MM in contrast to pure MM accurately reproduces structural features also found by experimental studies and therefore is able to provide credible predictions not only of the dynamical properties of the studied system but also of protein-ligand interactions at the metal ion binding site. PMID- 27452580 TI - Letters. PMID- 27452579 TI - Regulation of the expression of corticotropin-releasing factor gene by pyroglutamylated RFamide peptide in rat hypothalamic 4B cells. AB - Pyroglutamylated RFamide peptide (QRFP), an important regulator of metabolism and energy homeostasis, has orexigenic effects. QRFP acts via a specific receptor, Gpr103. Gpr103 mRNA is expressed in the rat hypothalamic paraventricular nucleus (PVN). In the PVN, corticotropin-releasing factor (CRF), which plays a central role in regulating the stress response and is produced in response to stress, stimulates the release of adrenocorticotropic hormone from the anterior pituitary. We hypothesized that QRFP regulates CRF gene expression directly in the hypothalamus, and thus examined the direct effect of QRFP on the promoter activity and mRNA levels of CRF in hypothalamic cells. To examine these pathways, we used hypothalamic 4B cells, a homologous PVN neuronal cell line. Gpr103a and Gpr103b mRNA, and Gpr103 (a and b) proteins were expressed in the hypothalamic cells. The Gpr103 mRNA and protein levels were increased by QRFP. QRFP also stimulated CRF mRNA levels and CRF promoter activity directly in 4B cells following their transfection with the CRF promoter. The protein kinase A (PKA) and protein kinase C (PKC) pathways were involved in the QRFP-induced increases in CRF promoter activity. QRFP stimulated cAMP response element-binding protein (CREB) phosphorylation. CREB phosphorylation was inhibited by a PKC inhibitor. PKC-dependent signaling would be upstream of the CREB phosphorylation. Thus, QRFP dependent pathways are involved in the regulation of CRF gene expression in the hypothalamus. PMID- 27452582 TI - Qualifying Exams: A Continuing Dilemma. PMID- 27452583 TI - A need to know. PMID- 27452586 TI - It Pays to be a Patriarch. PMID- 27452585 TI - Brief reports. PMID- 27452587 TI - Heart Size and Sports. AB - Although Heart and Athletics fell quickly into obscurity following publication over 50 years ago, it suggests a possible solution to the enigma of overtraining. PMID- 27452588 TI - Heart Size and Sports. PMID- 27452589 TI - Physiological Profile of a Masters Runner. AB - A champion middle-distance runner laid off for 44 years, then resumed training and competition at age 70. Physiological tests support the role of genetic endowment in cardiorespiratory fitness. PMID- 27452590 TI - Groin Pain in Soccer Players. AB - When soccer became more popular, it also became more dynamic and dangerous. Since players manipulate the ball with their legs, groin injuries are common. PMID- 27452591 TI - The Thompson Test for Ruptured Achilles Tendon. AB - Active plantar flexion at the ankle does not rule out an Achilles tendon rupture. The authors review an easy way to diagnose this injury promptly. PMID- 27452593 TI - Scanning sports. PMID- 27452592 TI - Sports and Menstrual Function. AB - Until the role of exercise in amenorrhea is more fully understood, physicians should treat athletes as carefully as nonathletes. Their problems are not necessarily due to sports activities. PMID- 27452595 TI - Olympic Sportsmedicine: Shooting for the Stars. AB - An expansive plan for the 1980s starts with a training center in Colorado and ends with a nation of healthy recreationists. No one knows who will pick up the tab. PMID- 27452597 TI - Risk Factors for Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae (CP-CRE) Acquisition Among Contacts of Newly Diagnosed CP-CRE Patients. AB - OBJECTIVE Carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP CRE) are extremely drug-resistant pathogens. Screening of contacts of newly identified CP-CRE patients is an important step to limit further transmission. We aimed to determine the risk factors for CP-CRE acquisition among patients exposed to a CP-CRE index patient. METHODS A matched case-control study was performed in a tertiary care hospital in Israel. The study population was comprised of patients who underwent rectal screening for CP-CRE following close contact with a newly identified CP-CRE index patient. Cases were defined as positive tests for CP-CRE. For each case patient, 2 matched controls were randomly selected from the pool of contacts who tested negative for CP-CRE following exposure to the same index case. Bivariate and multivariate analyses were conducted using conditional logistic regression. RESULTS In total, 53 positive contacts were identified in 40 unique investigations (896 tests performed on 735 contacts) between October 6, 2008, and June 7, 2012. bla KPC was the only carbapenemase identified. In multivariate analysis, risk factors for CP-CRE acquisition among contacts were (1) contact with an index patient for >=3 days (odds ratio [OR], 9.8; 95% confidence interval [CI], 2.0-48.9), (2) mechanical ventilation (OR, 4.1; 95% CI, 1.4-11.9), and (3) carriage or infection with another multidrug-resistant organism (MDRO; OR, 2.6; 95% CI, 1.0-7.1). Among patients who received antibiotics, cephalosporins were associated with a lower risk of acquisition. CONCLUSIONS Patient characteristics (ventilation and carriage of another MDRO) as well as duration of contact are risk factors for CP-CRE acquisition among contacts. The role of cephalosporins requires further study. Infect Control Hosp Epidemiol 2016;1-7. PMID- 27452598 TI - Quantifying accessibility and use of improved sanitation: towards a comprehensive indicator of the need for sanitation interventions. AB - To prevent diseases associated with inadequate sanitation and poor hygiene, people needing latrines and behavioural interventions must be identified. We compared two indicators that could be used to identify those people. Indicator 1 of household latrine coverage was a simple Yes/No response to the question "Does your household have a latrine?" Indicator 2 was more comprehensive, combining questions about defecation behaviour with observations of latrine conditions. Using a standardized procedure and questionnaire, trained research assistants collected data from 6,599 residents of 16 rural villages in Indonesia. Indicator 1 identified 30.3% as not having a household latrine, while Indicator 2 identified 56.0% as using unimproved sanitation. Indicator 2 thus identified an additional 1,710 people who were missed by Indicator 1. Those 1,710 people were of lower socioeconomic status (p < 0.001), and a smaller percentage practiced appropriate hand-washing (p < 0.02). These results show how a good indicator of need for sanitation and hygiene interventions can combine evidences of both access and use, from self-reports and objective observation. Such an indicator can inform decisions about sanitation-related interventions and about scaling deworming programmes up or down. Further, a comprehensive and locally relevant indicator allows improved targeting to those most in need of a hygiene-behaviour intervention. PMID- 27452601 TI - ATXN2 polymorphism modulates age at onset in Machado-Joseph disease. PMID- 27452600 TI - Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson's disease. AB - Apathy is a debilitating and under-recognized condition that has a significant impact in many neurodegenerative disorders. In Parkinson's disease, it is now known to contribute to worse outcomes and a reduced quality of life for patients and carers, adding to health costs and extending disease burden. However, despite its clinical importance, there remains limited understanding of mechanisms underlying apathy. Here we investigated if insensitivity to reward might be a contributory factor and examined how this relates to severity of clinical symptoms. To do this we created novel ocular measures that indexed motivation level using pupillary and saccadic response to monetary incentives, allowing reward sensitivity to be evaluated objectively. This approach was tested in 40 patients with Parkinson's disease, 31 elderly age-matched control participants and 20 young healthy volunteers. Thirty patients were examined ON and OFF their dopaminergic medication in two counterbalanced sessions, so that the effect of dopamine on reward sensitivity could be assessed. Pupillary dilation to increasing levels of monetary reward on offer provided quantifiable metrics of motivation in healthy subjects as well as patients. Moreover, pupillary reward sensitivity declined with age. In Parkinson's disease, reduced pupillary modulation by incentives was predictive of apathy severity, and independent of motor impairment and autonomic dysfunction as assessed using overnight heart rate variability measures. Reward sensitivity was further modulated by dopaminergic state, with blunted sensitivity when patients were OFF dopaminergic drugs, both in pupillary response and saccadic peak velocity response to reward. These findings suggest that reward insensitivity may be a contributory mechanism to apathy and provide potential new clinical measures for improved diagnosis and monitoring of apathy.media 1vid110.1093/brain/aww188_video_abstractaww188_video_abstract. PMID- 27452602 TI - Amyloid-beta deposition and regional grey matter atrophy rates in dementia with Lewy bodies. AB - Alzheimer's disease pathology frequently coexists with Lewy body disease at autopsy in patients with probable dementia with Lewy bodies. More than half of patients with probable dementia with Lewy bodies have high amyloid-beta deposition as measured with 11C-Pittsburgh compound B binding on positron emission tomography. Biomarkers of amyloid-beta deposition precede neurodegeneration on magnetic resonance imaging during the progression of Alzheimer's disease, but little is known about how amyloid-beta deposition relates to longitudinal progression of atrophy in patients with probable dementia with Lewy bodies. We investigated the associations between baseline 11C Pittsburgh compound B binding on positron emission tomography and the longitudinal rates of grey matter atrophy in a cohort of clinically diagnosed patients with dementia with Lewy bodies (n = 20), who were consecutively recruited to the Mayo Clinic Alzheimer's Disease Research Centre. All patients underwent 11C-Pittsburgh compound B positron emission tomography and magnetic resonance imaging examinations at baseline. Follow-up magnetic resonance imaging was performed after a mean (standard deviation) interval of 2.5 (1.1) years. Regional grey matter loss was determined on three-dimensional T1-weighted magnetic resonance imaging with the tensor-based morphometry-symmetric normalization technique. Linear regression was performed between baseline 11C Pittsburgh compound B standard unit value ratio and longitudinal change in regional grey matter volumes from an in-house modified atlas. We identified significant associations between greater baseline 11C-Pittsburgh compound B standard unit value ratio and greater grey matter loss over time in the posterior cingulate gyrus, lateral and medial temporal lobe, and occipital lobe as well as caudate and putamen nuclei, after adjusting for age (P < 0.05). Greater baseline 11C-Pittsburgh compound B standard unit value ratio was also associated with greater ventricular expansion rates (P < 0.01) and greater worsening over time in Clinical Dementia Rating Scale, sum of boxes (P = 0.02). In conclusion, in patients with probable dementia with Lewy bodies, higher amyloid-beta deposition at baseline is predictive of faster neurodegeneration in the cortex and also in the striatum. This distribution is suggestive of possible interactions among amyloid-beta, tau and alpha-synuclein aggregates, which needs further investigation. Furthermore, higher amyloid-beta deposition at baseline predicts a faster clinical decline over time in patients with probable dementia with Lewy bodies. PMID- 27452603 TI - Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial. AB - Bile acids (BAs) are increasingly recognised as metabolic regulators, potentially improving insulin sensitivity following bariatric surgery. However, physiological relevance of such observations remains unknown. Hence, we analysed serum BA composition and associated gut-derived hormone levels following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 non-smoking men (45 55 yr) with MetS were randomised to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control arm. Before and after a 6 months intervention period clinical and laboratory parameters, body composition, serum BA profile, FGF-19, and GLP-1 concentrations were determined in fasting blood samples. 30 participants in the control and 33 participants in the treatment arm completed the study and were included in the data analysis. In participants of the treatment arm lifestyle-induced weight loss resulted in markedly improved insulin sensitivity. Serum levels of BA species and total GLP-1 decreased, while FGF-19 remained stable. Serum BA composition changed towards an increased 12alpha hydroxylated/non-12alpha-hydroxylated ratio. None of these parameters changed in participants of the control arm. Our results demonstrate that improved metabolic control by lifestyle modifications lowers serum levels of BAs and GLP-1 and changes serum BA composition towards an increased 12alpha/non-12alpha ratio (ICTRP Trial Number: U1111-1158-3672). PMID- 27452604 TI - Osteoinductive Activity of Selected Demineralized Bone Matrix Products from Donors of Different Ages. AB - BACKGROUND: Despite previous confirmation of osteoinductive potential of demineralized bone matrix (DBM) by other researchers, there is not yet any evidence of studies showing the osteoinductive activity of DBM products from South Africa tissue banks using both in vitro and animal models. This work evaluated the osteoinductivity of DBM both in vitro and in vivo. METHOD: DBM particles from six donors from the Centre for Tissue Engineering and C2C12 were cultured (5x104) in 24-well plates using DMEM/F-12 medium supplemented with 10% FBS. After 24 h medium was replaced with medium containing 1% FBS and 5 mg/ml of DBM particles. Bone morphogenetic protein-2 (BMP-2,500 pg/ml) was used as a positive control. After 48 h of incubation, cells were assayed for osteoinductive potentials. In an in vivo study, 27 Wistar rats aged six to eight weeks were divided into three groups and experimentally observed for 7, 14 and 28 days. Implants were explanted according to the duration of the experiment. RESULTS: Increase in cell growth was observed in C2C12 treated with DBM samples. BMP-2 and DBM samples were found to stimulate alkaline phosphatase activity and ELISA assay. Animal weight increase was observed during the 7, 14 and 28 days. Cartilage regeneration were also observed in the histology results. CONCLUSION: BMP-2 played a role in the differentiation of myoblast cells into osteoblasts. DBM products showed different osteoinductive capacity both in vitro and in vivo. Findings were variable and time-dependent. From our results, this study supports the effectiveness of DBM fromdonors aged between 45 to 55 years. PMID- 27452605 TI - Coping With Diverse Sex Development: Treatment Experiences and Psychosocial Support During Childhood and Adolescence and Adult Well-Being. AB - Objectives: The purpose of this exploratory, retrospective, and correlational study was to examine the relationships between childhood treatment experiences, parental care, and social support, and outcome in adults with different diverse sex development (DSD). Methods: The data of 69 participants from an exploratory questionnaire were collected in a retrospective German study. Results: The majority received medical treatment in relation to their DSD during childhood and adolescence. Seventy percent reported having had a best friend and 29% a confidant during childhood. Sixty-one percent showed clinically relevant psychological distress, and 45% reported suicidal thoughts at least at one point in their lives. Quality of parental care and having had a best friend correlated positively with adult outcome, whereas treatment experiences correlated with aspects of impaired adjustment. Conclusions: Social support and DSD-related treatment experiences appear to have an impact on adult well-being. Appropriate psychosocial care including peer-to-peer support should be made available to children with DSD and their families. PMID- 27452606 TI - A simple Gateway-assisted construction system of TALEN genes for plant genome editing. AB - TALEN is an artificial nuclease being applied for sequence-specific genome editing. For the plant genome editing, a pair of TALEN genes is expressed in the cells, and a binary plasmid for Agrobacterium-mediated transformation should be assembled. We developed a novel procedure using the Gateway-assisted plasmids, named Emerald-Gateway TALEN system. We constructed entry vectors, pPlat plasmids, for construction of a desired TALEN gene using Platinum Gate TALEN kit. We also created destination plasmid, pDual35SGw1301, which allowed two TALEN genes to both DNA strands to recruit using Gateway technology. Resultant TALEN genes were evaluated by the single-strand annealing (SSA) assay in E. coli cells. By this assay, the TALENs recognized the corresponding targets in the divided luciferase gene, and induced a specific recombination to generate an active luciferase gene. Using the TALEN genes constructed, we created a transformant potato cells in which a site-specific mutation occurred at the target site of the GBSS gene. This suggested that our system worked effectively and was applicable as a convenient tool for the plant genome editing. PMID- 27452607 TI - Comparison of multiplex real-time PCR and PCR-reverse blot hybridization assay for the direct and rapid detection of bacteria and antibiotic resistance determinants in positive culture bottles. AB - The aim of this study was to evaluate the performance of a commercially available multiplex real-time PCR assay and a PCR-reverse blot hybridization assay (PCR REBA) for the rapid detection of bacteria and identification of antibiotic resistance genes directly from blood culture bottles and to compare the results of these molecular assays with conventional culture methods. The molecular diagnostic methods were used to evaluate 593 blood culture bottles from patients with bloodstream infections. The detection positivity of multiplex real-time PCR assay for Gram-positive bacteria, Gram-negative bacteria and Candida spp. was equivalent to PCR-REBA as 99.6 %, 99.1 % and 100 %, respectively. Using conventional bacterial cultures as the gold standard, the sensitivity, specificity, positive predictive value and negative predictive value of these two molecular methods were 99.5 % [95 % confidence interval (CI), 0.980-1.000; P<0.001), 100 % (95 % CI, 0.983-1.000; P<0.001), 100 % and 99 %, respectively. However, positivity of the Real-methicillin-resistant Staphylococcusaureus multiplex real-time PCR assay targeting the mecA gene to detect methicillin resistance was lower than that of the PCR-REBA method, detecting an overall positivity of 98.4 % (n=182; 95 % CI, 0.964-1.000; P<0.009) and 99.5 % (n=184; 95 % CI, 0.985-1.000; P<0.0001), respectively. The entire two methods take about 3 h, while results from culture can take up to 48-72 h. Therefore, the use of these two molecular methods was rapid and reliable for the characterization of causative pathogens in bloodstream infections. PMID- 27452609 TI - Transplant survival: knowing the future. PMID- 27452608 TI - Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study. AB - BACKGROUND: Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of progressive injury due to fibrosis. METHODS: This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study. We prospectively collected biopsies from renal allograft recipients (n=204) with stable renal function 3 months after transplantation. We used microarray analysis to investigate gene expression in 159 of these tissue samples. We aimed to identify genes that correlated with the Chronic Allograft Damage Index (CADI) score at 12 months, but not fibrosis at the time of the biopsy. We applied a penalised regression model in combination with permutation-based approach to derive an optimal gene set to predict allograft fibrosis. The GoCAR study is registered with ClinicalTrials.gov, number NCT00611702. FINDINGS: We identified a set of 13 genes that was independently predictive for the development of fibrosis at 1 year (ie, CADI-12 >=2). The gene set had high predictive capacity (area under the curve [AUC] 0.967), which was superior to that of baseline clinical variables (AUC 0.706) and clinical and pathological variables (AUC 0.806). Furthermore routine pathological variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC 0.754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC 0.916). The 13 genes also accurately predicted early allograft loss (AUC 0.842 at 2 years and 0.844 at 3 years). We validated the predictive value of this gene set in an independent cohort from the GoCAR study (n=45, AUC 0.866) and two independent, publically available expression datasets (n=282, AUC 0.831 and n=24, AUC 0.972). INTERPRETATION: Our results suggest that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the development of irreversible damage, thus allowing therapy to be modified to prevent progression to fibrosis. FUNDING: National Institutes of Health. PMID- 27452610 TI - Risk factors for cardiopulmonary dysfunction in early-onset severe pre-eclampsia. AB - OBJECTIVE: To explore associations between patient characteristics and cardiopulmonary function among patients with early-onset severe pre-eclampsia being treated with expectant management. METHOD: The present retrospective study included patients who received expectant management for early-onset pre-eclampsia between January 1 and December 31, 2014 at Shanghai Jiao Tong University School of Medicine, China. Patients were divided into two groups based on cardiopulmonary function, a decompensatory group and a normal group. The clinical characteristics of patients in the two groups were compared by binary logistic regression analysis and using the Student t test. RESULTS: Data from 93 patients were included in the analysis. Serum creatinine levels (P=0.017), ascites (P=0.001), and increased proteinuria (P=0.015) were associated with decompensation of cardiopulmonary function during early-onset severe pre eclampsia. Hypoproteinemia was associated with significantly increased odds of ascites occurring (odds ratio 3.16; 95% confidence interval 1.34-7.44) and the mean serum albumin level was higher in patients without ascites (P<0.001). CONCLUSIONS: Renal insufficiency and ascites were associated with cardiopulmonary dysfunction. Ascites should receive greater medical attention during the expectant management of early-onset severe pre-eclampsia. PMID- 27452611 TI - Diagnosis of pre-eclampsia and assessment of severity through examination of the placenta with acoustic radiation force impulse elastography. AB - OBJECTIVE: To assess the value of placental shear wave velocity (SWV) measurement by acoustic radiation force impulse (ARFI) imaging for the diagnosis of pre eclampsia and to determine the relationship between the SWV and the severity of pre-eclampsia. METHODS: A prospective study was performed at a center in Turkey between August 2014 and March 2015. The study included consecutive pregnant women in the second or third trimester diagnosed with pre-eclampsia and healthy pregnant women without pre-eclampsia of similar ages. Patients with pre-eclampsia were divided into two groups (severe or mild disease) on the basis of revised American College of Obstetricians and Gynecologists criteria. All patients underwent ARFI, and the SWV was measured at several placental locations. RESULTS: Overall, 86 women were enrolled (42 with pre-eclampsia, 44 controls). Minimum, maximum, and mean SWV values were significantly higher in the pre-eclampsia group than in the control group (P<0.001 for all). These values were also significantly higher among patients with severe pre-eclampsia than among patients with mild pre eclampsia (P<0.001 for all). CONCLUSION: Measurement of the placental SWV with ARFI imaging is a useful additional method for the diagnosis of pre-eclampsia and for determination of the disease severity. PMID- 27452612 TI - Zinc Levels in Left Ventricular Hypertrophy. AB - Zinc is one of the most important trace elements in the body and zinc homeostasis plays a critical role in maintaining cellular structure and function. Zinc dyshomeostasis can lead to many diseases, such as cardiovascular disease. Our aim was to investigate whether there is a relationship between zinc and left ventricular hypertrophy (LVH). A total of 519 patients was enrolled and their serum zinc levels were measured in this study. We performed analyses on the relationship between zinc levels and LVH and the four LV geometry pattern patients: normal LV geometry, concentric remodeling, eccentric LVH, and concentric LVH. We performed further linear and multiple regression analyses to confirm the relationship between zinc and left ventricular mass (LVM), left ventricular mass index (LVMI), and relative wall thickness (RWT). Our data showed that zinc levels were 710.2 +/- 243.0 MUg/L in the control group and were 641.9 +/- 215.2 MUg/L in LVH patients. We observed that zinc levels were 715 +/- 243.5 MUg/L, 694.2 +/- 242.7 MUg/L, 643.7 +/- 225.0 MUg/L, and 638.7 +/- 197.0 MUg/L in normal LV geometry, concentric remodeling, eccentric LVH, and concentric LVH patients, respectively. We further found that there was a significant inverse linear relationship between zinc and LVM (p = 0.001) and LVMI (p = 0.000) but did not show a significant relationship with RWT (p = 0.561). Multiple regression analyses confirmed that the linear relationship between zinc and LVM and LVMI remained inversely significant. The present study revealed that serum zinc levels were significantly decreased in the LVH patients, especially in the eccentric LVH and concentric LVH patients. Furthermore, zinc levels were significantly inversely correlated with LVM and LVMI. PMID- 27452613 TI - Enucleation with or without adjuvant therapy versus marsupialization with or without secondary enucleation in the treatment of keratocystic odontogenic tumors: A systematic review and meta-analysis. AB - The purpose of this study was to compare the recurrence rate (RR) of keratocystic odontogenic tumors (KOTs) in patients who underwent enucleation with or without adjuvant therapy, to patients who underwent decompression with or without residual cystectomy. An extensive search of major databases through PubMed, EMBASE, and Cochrane CENTRAL was conducted to identify all relevant articles published without date and language restrictions from inception to December 2015. Relevant articles were selected based on the specific inclusion criteria. A weighted RR and odds ratio (OR) using a Mantel-Haenszel (M-H) test and random effect model with 95% confidence interval (CI) were performed. Meta-regression analysis was conducted to further identify the influence of the duration of follow-up periods on the overall OR. A total of 997 KOTs enrolled in 14 studies were included in this analysis. There was a significant advantage for the enucleation +/- adjuvant therapy group in preventing recurrence for patients with KOTs (M-H, OR, 0.514; 95% CI, 0.302-0.875; p = 0.014). The overall pooled weighted RR for enucleation +/- adjuvant therapy and decompression +/- secondary cystectomy were 18.2% and 27.1%, respectively. The meta-regression analysis showed that duration of follow-up time did not significantly influence the OR of KOT recurrence (Q = 0.506, p = 0.646). In conclusion, initial cystectomy +/- adjuvant therapy was associated with fewer recurrences than decompression +/- secondary cystectomy. PMID- 27452614 TI - Alkaline direct transesterification of different species of Stichococcus for bio oil production. AB - The cost of bio-oil refining from microalgal biomass can be significantly reduced by combining extraction and transesterification. The characterisation and optimisation of the combined steps have been carried out on strains of Stichococcus bacillaris, focusing on catalyst type and concentration, reaction time and temperature, methanol/biomass ratio, pre-mixing time and water content in the biomass. The bio-oil yield has been referenced as production of fatty acid methyl esters (FAMEs). The maximum yield (~17%) was achieved using dried biomass with alkaline catalyst at 60 degrees C and methanol/biomass weight ratio of 79:1. Alkaline catalyst conditions gave faster reaction rates and higher bio-oil yields than acid catalyst. Yield was also strongly affected by water content in the biomass. A mechanistic interpretation has been proposed to elucidate the effect of the different operating conditions. However, the structural characteristics of the Chlorophyta cell wall can be very different, leading to different bio-oil yields when the same protocol is applied. Therefore, the optimised protocol of direct transesterification for Stichococcus bacillaris strains was tested on other Stichococcus strains and several other Chlorophyta species characterised by a different cell wall structure. It was clearly demonstrated that different results for bio-oil yield were obtained within the same microalgal species and much more within different microalgal genera. PMID- 27452615 TI - The Effect of Water and Confinement on Self-Assembly of Imidazolium Based Ionic Liquids at Mica Interfaces. AB - Tuning chemical structure and molecular layering of ionic liquids (IL) at solid interfaces offers leverage to tailor performance of ILs in applications such as super-capacitors, catalysis or lubrication. Recent experimental interpretations suggest that ILs containing cations with long hydrophobic tails form well-ordered bilayers at interfaces. Here we demonstrate that interfacial bilayer formation is not an intrinsic quality of hydrophobic ILs. In contrast, bilayer formation is triggered by boundary conditions including confinement, surface charging and humidity present in the IL. Therefore, we performed force versus distance profiles using atomic force microscopy and the surface forces apparatus. Our results support models of disperse low-density bilayer formation in confined situations, at high surface charging and/or in the presence of water. Conversely, interfacial structuring of long-chain ILs in dry environments and at low surface charging is disordered and dominated by bulk structuring. Our results demonstrate that boundary conditions such as charging, confinement and doping by impurities have decisive influence on structure formation of ILs at interfaces. As such, these results have important implications for understanding the behavior of solid/IL interfaces as they significantly extend previous interpretations. PMID- 27452616 TI - Drying soil in North China drove the outbreak range expansion of meadow moth by facilitating long-distance migration. AB - Studies of the mechanism underlying the range expansion of organisms have mainly focused on environmental conditions at the edges of species' distributions, potentially ignoring other possible factors. Here, we demonstrated the outbreak range expansion of meadow moth from North China to Northeast China in the past three outbreak periods. We found that the negligible infestation in Northeast China in the 1950s could not be explained by local climatic conditions. However, the soil moisture in North China decreased distinctly from 1951 to 2011 and was significantly and positively correlated with the timing of the first adult peak on plateaus, meaning that the deterioration of habitat conditions could result in earlier peaks of adults in areas of high-elevation by stimulating the short distance dispersal of adults from the plains to the plateaus. Adults peaking earlier have a stronger tendency to emigrate due to mismatched phenology. Hence, drying soil in North China caused the frequent long-distance migration of meadow moth after the 1970s and drove the outbreak range expansion. This study suggests that, for a migratory species, the deterioration of habitat conditions in overwintering areas might also influence the distribution of this species in breeding areas at high latitudes by facilitating migration activities. PMID- 27452618 TI - Spontaneous resolution of a mediastinal mass in a woman with myasthenia gravis. PMID- 27452617 TI - Biobehavioural analysis of the vestibular system and posture control in patients with cervicogenic dizziness. A cross-sectional study. AB - BACKGROUND: Cervicogenic dizziness is a musculoskeletal disorder mainly characterised by dizziness and disequilibrium associated with neck pain. The pathophysiology is unclear and the neurophysiological basis remains to be ascertained. The aim of this study is to compare the vestibulo-ocular reflex and postural control between patients with cervicogenic dizziness and asymptomatic subjects, and to assess the association between debilitating dizziness and other psychosocial variables. MATERIALS AND METHODS: A total of 20 patients and 22 asymptomatic subjects were selected. Vestibulo-ocular reflex was assessed by performing the head impulse test. Computerised dynamic posturography was used to evaluate the postural control by means of the sensory organisation test. In addition, subjects self-reported their degree of disability due to dizziness, cervical disability, kinesiophobia, and state of anxiety and depression. RESULTS: There were no differences in the vestibulo-ocular reflex (P>.05). However, we found differences with a medium-to-large effect size (d>0.60) in variables related to proprioception and visual information integration; the former variable set was related to disability due to dizziness. Disability due to dizziness presents strong-to-moderate associations with cervical disability, kinesiophobia, and anxiety. CONCLUSION: Our data rule out changes in the vestibular system in cervicogenic dizziness, but they do point to proprioceptive impairment. According to our results, the association between dizziness-related disability and other psychosocial factors in cervicogenic dizziness is very relevant for clinical medicine and for future research projects. PMID- 27452619 TI - Analysis of the relationship between cognitive skills and unilateral sensory hearing loss. AB - OBJECTIVE: To analyse cognitive skills in patients with severe unilateral hearing loss versus those in subjects with normal hearing. METHODS: 40 adults participated: 20 patients (10 women and 10 men) with severe unilateral hearing loss and 20 healthy subjects matched to the study group. Cognitive abilities were measured with the Spanish version of the Woodcock Johnson Battery-Revised; central auditory processing was assessed with monaural psychoacoustic tests. Box plots were drawn and t tests were performed for samples with a significance of P<=.05. RESULTS: A comparison of performances on the filtered word testing and time-compressed disyllabic word tests between patients and controls revealed a statistically significant difference (P<=.05) with greater variability among responses by hearing impaired subjects. This same group also showed a better cognitive performance on the numbers reversed, visual auditory learning, analysis synthesis, concept formation, and incomplete words tests. CONCLUSIONS: Patients with hearing loss performed more poorly than controls on the filtered word and time-compressed disyllabic word tests, but more competently on memory, reasoning, and auditory processing tasks. Complementary tests, such as those assessing central auditory processes and cognitive ability tests, are important and helpful for designing habilitation/rehabilitation and therapeutic strategies intended to optimise and stimulate cognitive skills in subjects with unilateral hearing impairment. PMID- 27452620 TI - Hypopituitarism: An uncommon cause of developmental delay. PMID- 27452621 TI - Brain perfusion SPECT with 99mTc-HMPAO in the diagnosis and follow-up of patients with anti-NMDA receptor encephalitis. PMID- 27452622 TI - Aseptic meningitis and anti-beta2-glycoprotein 1 antibodies in Sweet syndrome. PMID- 27452623 TI - Comparative study of antiepileptic drug use during pregnancy over a period of 12 years in Spain. Efficacy of the newer antiepileptic drugs lamotrigine, levetiracetam, and oxcarbazepine. AB - INTRODUCTION: The prescription pattern of antiepileptic drugs (AEDs) during pregnancy is changing but to what extent this is occurring in Spain remains unknown. The efficacy of newer drugs for controlling seizures is a key issue and may have changed over the years as doctors gained familiarity with these drugs during pregnancy. To assess these 2 topics, we report the results from the Spanish EURAP register gathered over a 12-year period. MATERIAL AND METHODS: After signing informed consent forms, patients were included in the register and evaluated at onset of pregnancy, at the end of the second and third trimesters, after delivery, and one year after delivery. For the purposes of this study, we analysed AEDs, type of epilepsy, seizure frequency per trimester and throughout pregnancy, percentage of seizure-free pregnancies, and frequency of congenital malformations. We then compared data from 2 periods (June 2001-October 2007) and (January 2008-May 2015) RESULTS: We compared 304 monotherapies from the older period to 127 from the more recent one. There was a clear increase in the use of levetiracetam (LEV) with declining use of carbamazepine (CBZ), phenytoin, and phenobarbital; a slight decline in use of valproate (VPA), and a slight increase in the use of lamotrigine (LTG) and oxcarbazepine (OXC). Epilepsy types treated with CBZ and VPA remained unchanged, whereas fewer cases of generalised epilepsy were treated with LTG in the new period. This trend was not associated with significant changes in seizure frequency, but rather linked to better control over de novo seizures in the third trimester. LEV was similar to CBZ and VPA with regard to levels of seizure control, and more effective than LTG. Generalised epilepsy accounted for 64% of the cases treated with LEV. CONCLUSIONS: The prescription pattern of AEDs during pregnancy has changed in Spain, with diminishing use of CBZ, phenytoin, and phenobarbital. Changes also reflect the type of epilepsy, since there is less use of LTG for generalised epilepsy. LEV provides similar seizure control to that of the older AEDs, and it is more effective and better than LTG. PMID- 27452624 TI - Primary central nervous system lymphoma mimicking cerebellopontine angle tumour. PMID- 27452625 TI - A new mutation in a patient with Wolfram syndrome. PMID- 27452626 TI - Medulloblastoma with epithelioid features in the cerebellar vermis. AB - A 6-year-old girl was admitted with a mass lesion in the cerebellar vermis. She underwent subtotal tumor resection, and on immunohistopathology the tumor consisted of two different parts: typical medulloblastoma (MB) characteristics and atypical teratoid/rhabdoid tumor (AT/RT) features, despite positive integrase interactor 1 expression. The patient was diagnosed with MB with epithelioid features. Chemoradiation therapy was started because of tumor recurrence at the primary site and dissemination to the spinal cord, as determined on magnetic resonance imaging 2 weeks after surgery. The patient died due to tumor progression 13 months after initial diagnosis, although transient partial remission was achieved. PMID- 27452627 TI - Protein microarray applications: Autoantibody detection and posttranslational modification. AB - The discovery of DNA microarrays was a major milestone in genomics; however, it could not adequately predict the structure or dynamics of underlying protein entities, which are the ultimate effector molecules in a cell. Protein microarrays allow simultaneous study of thousands of proteins/peptides, and various advancements in array technologies have made this platform suitable for several diagnostic and functional studies. Antibody arrays enable researchers to quantify the abundance of target proteins in biological fluids and assess PTMs by using the antibodies. Protein microarrays have been used to assess protein protein interactions, protein-ligand interactions, and autoantibody profiling in various disease conditions. Here, we summarize different microarray platforms with focus on its biological and clinical applications in autoantibody profiling and PTM studies. We also enumerate the potential of tissue microarrays to validate findings from protein arrays as well as other approaches, highlighting their significance in proteomics. PMID- 27452628 TI - Intra-organ growth coordination in Drosophila is mediated by systemic ecdysone signaling. AB - Regulation of final organ size is a complex developmental process that involves the integration of systemic and organ-specific processes. Previously, we have shown that in developing Drosophila, perturbing the growth of one imaginal disc - the parts of a holometabolous larva that become the external adult organs - retards growth of other discs and delays development, resulting in tight inter organ growth coordination and the generation of a correctly proportioned adult. Whether different parts of the same imaginal disc similarly coordinate their growth to generate a functioning adult organ is, however, unclear. In this study, we use the wing imaginal disc in Drosophila to study and identify mechanisms of intra-organ growth coordination. We generate larvae in which the two compartments of the wing imaginal disc have ostensibly different growth rates (wild-type or growth-perturbed). We find that there is tightly coordinated growth between the wild-type and growth-perturbed compartments, where growth of the wild-type compartment is retarded to match that of the growth-perturbed compartment. Crucially, this coordination is disrupted by application of exogenous 20 hydroxyecdysone (20E), which accelerates growth of the wild-type compartment. We further elucidate the role of 20E signaling in growth coordination by showing that in wild-type discs, compartment-autonomous up-regulation of 20E signaling accelerates compartment growth and disrupts coordination. Interestingly, growth acceleration through exogenous application of 20E is inhibited with suppression of the Insulin/Insulin-like Growth Factor Signaling (IIS) pathway. This suggests that an active IIS pathway is necessary for ecdysone to accelerate compartment growth. Collectively, our data indicate that discs utilize systemic mechanisms, specifically ecdysone signaling, to coordinate intra-organ growth. PMID- 27452629 TI - Smads and insect hemimetabolan metamorphosis. AB - In contrast with Drosophila melanogaster, practically nothing is known about the involvement of the TGF-beta signaling pathway in the metamorphosis of hemimetabolan insects. To partially fill this gap, we have studied the role of Smad factors in the metamorphosis of the German cockroach, Blattella germanica. In D. melanogaster, Mad is the canonical R-Smad of the BMP branch of the TGF-beta signaling pathway, Smox is the canonical R-Smad of the TGF-beta/Activin branch and Medea participates in both branches. In insects, metamorphosis is regulated by the MEKRE93 pathway, which starts with juvenile hormone (JH), whose signal is transduced by Methoprene-tolerant (Met), which stimulates the expression of Kruppel homolog 1 (Kr-h1) that acts to repress E93, the metamorphosis trigger. In B. germanica, metamorphosis is determined at the beginning of the sixth (final) nymphal instar (N6), when JH production ceases, the expression of Kr-h1 declines, and the transcription of E93 begins to increase. The RNAi of Mad, Smox and Medea in N6 of B. germanica reveals that the BMP branch of the TGF-beta signaling pathway regulates adult ecdysis and wing extension, mainly through regulating the expression of bursicon, whereas the TGF-beta/Activin branch contributes to increasing E93 and decreasing Kr-h1 at the beginning of N6, crucial for triggering adult morphogenesis, as well as to regulating the imaginal molt timing. PMID- 27452630 TI - Developments in imaging methods used in hip arthroplasty: A diagnostic algorithm. AB - BACKGROUND: Several imaging modalities can be used to diagnose complications of hip prosthesis placement. Despite progress in these imaging techniques, there are, as yet, no guidelines as to their respective indications. METHODS: We formed a panel of experts in fields related to prosthesis imaging (radiology, nuclear medicine, orthopedic surgery) and conducted a review of the literature to determine the value of each modality for diagnosing complications following hip replacement. RESULTS: Few recent studies have investigated the benefits related to the use of the latest technical developments, and studies comparing different methods are extremely rare. CONCLUSIONS: We have developed a diagnostic tree based on the characteristics of each imaging technique and recommend its use. Computed topography was found to be the most versatile and cost-effective imaging solution and therefore a key tool for diagnosing the complications of hip replacement surgery. PMID- 27452631 TI - Imaging of meniscus and ligament injuries of the knee. AB - Magnetic resonance imaging has now an indisputable role for the diagnosis of meniscus and ligament injuries of the knee. Some technical advances have improved the diagnostic capabilities of magnetic resonance imaging so that diagnoses, which may change the therapeutic approach, such as a partial tear of the anterior cruciate ligament or confirmation of unstable meniscal injuries, are now made easier. This article describes the essential about magnetic resonance imaging technique and pathological results for the menisci, collateral ligaments and damage to the central pivot of the cruciate knee ligaments. PMID- 27452632 TI - Nanofibrous polycaprolactone scaffolds with adhered platelets stimulate proliferation of skin cells. AB - OBJECTIVES: Faulty wound healing is a global healthcare problem. Chronic wounds are generally characterized by a reduction in availability of growth factors. New strategies are being developed to deliver growth factors more effectively. METHODS: In this study, we introduced electrospun scaffolds composed of polycaprolactone (PCL) nanofibers functionalized with adhered platelets, as a source of numerous growth factors. Three concentrations of platelets were immobilized to nanofibrous scaffolds by simple adhesion, and their influence on adhesion, proliferation and metabolic activity of seeded cells (murine fibroblasts, keratinocytes and melanocytes) was investigated. RESULTS: The data obtained indicated that presence of platelets significantly promoted cell spreading, proliferation and metabolic activity in all the skin-associated cell types. There were no significant differences among tested concentrations of platelets, thus even the lowest concentration sufficiently promoted proliferation of the seeded cells. CONCLUSIONS: Such complex stimulation is needed for improved healing of chronic wounds. However, the nanofibrous system can be used not only as a skin cover, but also in broader applications in regenerative medicine. PMID- 27452633 TI - Pharmacokinetic effects of curcumin on docetaxel mediated by OATP1B1, OATP1B3 and CYP450s. AB - Curcumin can synergistically enhance docetaxel's in vitro and in vivo antitumor activity and has been co-administrated with docetaxel in clinical trials. The aim of our study is to investigate the effect of curcumin on the pharmacokinetics of docetaxel and explore its mechanism on OATP1B1, OATP1B3 and human liver microsomes (HLMs). In rats, curcumin increased the docetaxel area under the plasma concentration-time curve (AUC0-8h) and the terminal half-life (t1/2) to 1.86- and 1.55-fold, respectively. Moreover, curcumin decreased the clearance (CL) of docetaxel to 52.1%. Human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1 and OATP1B3 were used to observe the effects of curcumin on OATP1B1 and OATP1B3-mediated uptake of docetaxel. Curcumin exhibited potent inhibition on OATP1B1 and OATP1B3-mediated docetaxel uptake with IC50 values of 3.81 +/- 1.19 MUM and 33.70 +/- 1.22 MUM, respectively. The inhibition of curcumin on docetaxel metabolism in HLMs indicated that curcumin can modestly inhibit the metabolism of docetaxel with the IC50 value of 22.70 +/- 1.13 MUM and Ki value of 24.72 +/- 4.24 MUM. The preclinical and clinical improved docetaxel's therapeutic efficacy when co-administrated with curcumin may be due to the inhibition of curcumin on OATP1B1, OATP1B3 and HLMs activities. Close attention should be paid when combined treatment with docetaxel and curcumin carried out clinically. PMID- 27452634 TI - Patient-preference disability assessment for disabling knee osteoarthritis: Validity and responsiveness of the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire. AB - BACKGROUND: The McMaster-Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) measurement of function may be more comprehensive and add useful information about disability than traditional fixed-item questionnaires, especially about issues that really matter to the patient, for developing personalized medicine. OBJECTIVES: We aimed to assess priorities in disability and restriction in participation in patients with disabling knee osteoarthritis (OA) by the MACTAR and evaluate its validity and responsiveness. METHODS: We evaluated 127 in- and outpatients with knee OA in two tertiary care teaching hospitals between August 2010 and July 2012 by using the MACTAR, the Western Ontario and McMaster Universities Osteoarthritis Index, Lequesne scale, Fear Avoidance Beliefs Questionnaire, a life satisfaction score and pain, global assessment of disease activity and functional impairment scores on a numerical rating scale. Validity was assessed by Pearson correlation and responsiveness by the standardized response mean (SRM) and effect size (ES). RESULTS: Patients ranked 35 different activities by the MACTAR; the 3 domains of the International Classification of Functioning, Disability and Health most often identified were mobility (cited 233 times, 52.3%); community, social and civic life (cited 122 times, 27.4%); and domestic life (cited 64 times, 14.4%). The MACTAR score was best correlated with functional impairment (r=0.5). Convergent and divergent validity was as expected. In all, 108 patients completed a 6-month follow-up evaluation: 27 patients shifted their priorities at 6 months, for a decrease in SRM and ES. The SRM (0.64) and ES (0.92) for the MACTAR without shifts in priorities were the highest among the outcome measures tested; for patients considering their condition improved, the values were 0.85 and 1.17, respectively. CONCLUSIONS: For assessing priorities in disability and restriction in participation among patients with knee OA, the MACTAR has acceptable validity and responsiveness. PMID- 27452635 TI - Impact of a Cognitive Behavioral Intervention on Health-Related Quality of Life and General Heart Rate Variability in Patients Following Cardiac Surgery: An Effectiveness Study. AB - BACKGROUND: Although there is evidence supporting the efficacy of cognitive behavioral therapy (CBT) in decreasing psychologic symptoms and improving health related quality of life in patients who have undergone coronary artery bypass graft surgery, the effectiveness of these interventions in usual health care practice, and their effect on general heart rate variability (HRV), has not been tested. OBJECTIVE: This study investigated the effectiveness of CBT in improving health-related quality of life and HRV in patients with postcardiac surgery. METHODS: However, 2 months following surgery, 150 patients were assigned sequentially to a CBT group that received the intervention for 9 months or a comparison group that received usual care. Patients were assessed at baseline and after 10 months with the 36-item Short Form Health Survey. HRV was also assessed. RESULTS: In total, 43 patients in the CBT group and 46 in the usual care group completed the study. The CBT group demonstrated significant improvements in health-related quality of life and significant increases in general HRV. Significant group-by-time interaction effects were found for the several 36-item Short Form Health Survey scales and mental component summary and a time-domain HRV parameter indicating that the pattern of change in scores over time differed significantly between the 2 groups. CONCLUSION: CBT administered in a "real world" clinical setting can effectively improve health-related quality of life and the general HRV in patients who have undergone cardiac surgery. PMID- 27452636 TI - Salivary and fecal microbiota and metabolome of celiac children under gluten-free diet. AB - Celiac disease (CD) is an inflammatory autoimmune disorder resulting from the combination of genetic predisposition and gluten ingestion. A life-long gluten free diet (GFD) is the only therapeutic approach. Dysbiosis, which can precede the CD pathogenesis and/or persist when subjects are on GFD, is reviewed and discussed. Salivary microbiota and metabolome differed between healthy and celiac children treated under GFD (T-CD) for at least two years. The type of GFD (African- vs Italian-style) modified the microbiota and metabolome of Saharawi T CD children. Different studies showed bacterial dysbiosis at duodenal and/or fecal level of patients with active untreated CD (U-CD) and T-CD compared to healthy subjects. The ratio of protective anti-inflammatory bacteria such as Lactobacillus-Bifidobacterium to potentially harmful Bacteroides Enterobacteriaceae was the lowest in U-CD and T-CD children. In agreement with dysbiosis, serum, fecal and urinary metabolome from U-CD and T-CD patients showed altered levels of free amino acids and volatile organic compounds. However, consensus across studies defining specific bacteria and metabolites in U-CD or T CD patients is still lacking. Future research efforts are required to determine the relationships between CD and oral and intestinal microbiotas to improve the composition of GFD for restoring the gut dysbiosis as a preventative or therapeutic approach for CD. PMID- 27452637 TI - Influence of ruminal methane on digesta retention and digestive physiology in non lactating dairy cattle. AB - Enteric methane (CH4) production is a side-effect of herbivore digestion, but it is unknown whether CH4 itself influences digestive physiology. We investigated the effect of adding CH4 to, or reducing it in, the reticulorumen (RR) in a 4*4 Latin square experiment with rumen-fistulated, non-lactating cows, with four treatments: (i) control, (ii) insufflation of CH4 (iCH4), (iii) N via rumen fistula, (iv) reduction of CH4 via administration of bromochloromethane (BCM). DM intake (DMI), apparent total tract digestibility, digesta mean retention times (MRT), rumen motility and chewing activity, spot breath CH4 emission (CH4exhal, litre/kg DMI) as well as CH4 dissolved in rumen fluid (CH4RRf, ug/ml) were measured. Data were analysed using mixed models, including treatment (or, alternatively, CH4exhal or CH4RRf) and DMI relative to body mass0.85 (rDMI) as covariates. rDMI was the lowest on the BCM treatment. CH4exhal was highest for iCH4 and lowest for BCM treatments, whereas only BCM affected (reduced) CH4RRf. After adjusting for rDMI, CH4RRf had a negative association with MRT in the gastrointestinal tract but not in the RR, and negative associations with fibre digestibility and measures of rumination activity. Adjusting for rDMI, CH4exhal had additionally a negative association with particle MRT in the RR and a positive association with rumen motility. Thus, higher rumen levels of CH4 (CH4exhal or CH4RRf) were associated with shorter MRT and increased motility. These findings are tentatively interpreted as a feedback mechanism in the ruminant digestive tract that aims at mitigating CH4 losses by shortening MRT at higher CH4. PMID- 27452638 TI - ROOT HAIR DEFECTIVE SIX-LIKE4 (RSL4) promotes root hair elongation by transcriptionally regulating the expression of genes required for cell growth. AB - ROOT HAIR DEFECTIVE SIX-LIKE4 (RSL4) is necessary and sufficient for root hair elongation in Arabidopsis thaliana. Root hair length is determined by the duration for which RSL4 protein is present in the developing root hair. The aim of this research was to identify genes regulated by RSL4 that affect root hair growth. To identify genes regulated by RSL4, we identified genes whose expression was elevated by induction of RSL4 activity in the presence of an inhibitor of translation. Thirty-four genes were identified as putative targets of RSL transcriptional regulation, and the results suggest that the activities of SUPPRESSOR OF ACTIN (SAC1), EXOCSYT SUBUNIT 70A1 (EXO70A1), PEROXIDASE7 (PRX7) and CALCIUM-DEPENDENT PROTEIN KINASE11 (CPK11) are required for root hair elongation. These data indicate that RSL4 controls cell growth by controlling the expression of genes encoding proteins involved in cell signalling, cell wall modification and secretion. PMID- 27452639 TI - Circulating levels of endocannabinoids and oxylipins altered by dietary lipids in older women are likely associated with previously identified gene targets. AB - Postmenopausal women (PMW) report marginal n-3 PUFA intakes and are at risk of chronic diseases associated with the skeletal, muscular, neuroendocrine, and cardiovascular systems. How n-3 PUFA affect the amounts of endocannabinoids (ECs) and oxylipins (OLs) of metabolic and physiologic importance in PMW is not clear. Based on our recent findings that dietary n-3 PUFA alter gene targets of the EC system and lower pro-inflammatory OL we proceeded to characterize these actions in blood of PMW. Our aim was to determine levels of the ECs, OLs, and global metabolites (GM) in white PMW (75+/-7y), randomized in a double-masked manner, from baseline to 6mo after receiving a fish oil supplement of n-3 PUFA (720mg 20:5n3+480mg 22:6n3/d, n=20) or placebo (1.8g oleic acid/d, n=20). ECs and OLs in serum were determined by UPLC-MS/MS and GM by GC-MS and LC-MS/MS. Plasma 20:5n3 and 22:6n3 levels increased in PMW given fish oil. EC n-6 acyl-ethanolamides, arachidonate-derived diols were decreased and 20:5n3 and 22:6n3 diols, epoxides, and alcohols were increased in PMW given fish oil. GM analysis revealed that n-3 PUFA supplementation increased renal steroid hormone and proteolytic metabolite levels in PMW. Herein, we confirm that gene targets of the EC system, previously found as modifiable by n-3 PUFA result in changes in the levels of ECs and OLs in PMW. This study shows phenotypic responses (in levels) to n-3 PUFA supplementation in PMW and increases of n-3 acyl-ethanolamide and n-3-derived OL of clinical considerations in aging. PMID- 27452641 TI - Community-Based Emergency Care: A Model for Prehospital Care in Remote Canadian Communities. PMID- 27452640 TI - Isolation and characterization of Helicobacter pylori recovered from gastric biopsies under anaerobic conditions. AB - BACKGROUND AND AIM: Helicobacter pylori can survive long incubation periods under anaerobic conditions, and should be possible to isolate under anaerobic conditions. Our aim was to isolate H. pylori in anaerobic conditions, from gastric biopsies of H. pylori infected patients. METHODS: We enrolled 27 patients with bleeding (erosive) gastritis (mean age 36.3 years, 55.6% male) from Hanoi, Vietnam. H. pylori status was confirmed by qPCR. RESULTS: H. pylori were recovered under anaerobic and micro-aerobic conditions from gastric biopsies in 16 patients. Anaerobic conditions yielded significantly higher H. pylori recovery rates than micro-aerobic conditions (81.3% vs. 31.3%, P= 0.01). H. pylori isolates were characterized by PCR for specific virulence markers and the genotypes were similar to those previously described in this region of the world. CONCLUSIONS: H. pylori can be isolated under anaerobic conditions. These findings may provide new insight into the physiology of this human pathogen and help to identify the route of H. pylori transmission. PMID- 27452642 TI - Update on extracellular vesicles inside red blood cell storage units: Adjust the sails closer to the new wind. AB - Release of vesicles from cells is a universal biological system, an adaptive cellular response to endogenous or external physiological or stressful stimuli and a genius means for intercellular, inter-organ and even inter-organism communication. These secreted vesicles that are collectively designated extracellular vesicles (EVs) have increasingly attracted the interest of cell biologists due to their imaginable interactions with every piece of the known biological systems in both health and disease states. Although EVs isolation and characterization are challenges, owing to their particular physicochemical features and complex biology, recent technological innovation has offered better understanding and inevitably, driven the revision of previously established theories on them. However, a crucial question remains unsolved: the physiological relevance of EVs in vivo. Since membrane vesiculation is an integral part of red blood cell (RBC) aging and homeostatic machinery and a prominent feature of RBC storage lesion, the characterization of storage EVs and their probable clinical relevance with the therapeutic or adverse effects of transfusions are extremely important targets in the research fields of transfusion biology and medicine. The scientists involved should transfer nascent knowledge and state-of-the-art technological tools in the packed RBC unit in order to: (i) update the inventory of biochemical and biophysical features of storage EVs; (ii) gain insight into the molecular pathways/signals underlying their generation; and (iii) clarify their dependence on blood donor, storage strategies and analytical variations, in order to step forward on understanding their interactions with stored or recipient target cells. PMID- 27452643 TI - Immunomodulatory effects of exosomes produced by virus-infected cells. AB - Viruses have developed a spectrum of ways to modify cellular pathways to hijack the cell machinery for the synthesis of their nucleic acid and proteins. Similarly, they use intracellular vesicular mechanisms of trafficking for their assembly and eventual release, with a number of viruses acquiring their envelope from internal or plasma cell membranes. There is an increasing number of reports on viral exploitation of cell secretome pathways to avoid recognition and stimulation of the immune response. Extracellular vesicles (EV) containing viral particles have been shown to shield viruses after exiting the host cell, in some cases challenging the boundaries between viral groups traditionally characterised as enveloped and non-enveloped. Apart from viral particles, EV can spread the virus also carrying viral genome and can modify the target cells through their cargo of virus-coded miRNAs and proteins as well as selectively packaged cellular mRNAs, miRNAs, proteins and lipids, differing in composition and quantities from the cell of origin. PMID- 27452644 TI - Multiple small versus few large amount aspirations for bone marrow harvesting in autologous and allogeneic bone marrow transplantation. AB - For successful bone marrow transplantation it is necessary to obtain enough progenitor cells during the bone marrow (BM) harvesting procedure. Most centers are using multiple aspirations of maximum 2 ml BM (A), while other centers are using few larger amount aspirations for BM harvesting (B). There is still a discussion about possible differences in graft composition between A and B. To evaluate the feasibility in children we evaluated twenty BM harvestings that were performed in 18 donors, 7 autologous (median age 6.93y; 2.48-16.6) and 13 allogeneic donors (median age 19.75y; 6.45-50.7). A and B were performed crosswise by 2 operators starting with A (2 ml) or B (100 ml) changing to B or A, collecting identically amounts with both methods. We found no statistically significant difference between A and B for MNC, T-cells, and CFU (MNC/ml 824572 versus 725000, p = 0.728; MNC/kg 3.1 107 versus 2.9 107, p = 0.296; CD3/ml 162500 versus 300000, p = 0.310; CFU/105 MNC 1678 versus 1315, p = 0.094), but for CD34+ cells (CD34/kg 2.62 versus 2.09, p = 0.045). BM harvest by the large amount few punctures method (B) is as sufficient as the commonly used small amount frequent punctures method (A), and could be therefore used equally. PMID- 27452645 TI - Mesenchymal stromal cells as multifunctional cellular therapeutics - a potential role for extracellular vesicles. AB - Mesenchymal stromal cells (MSCs), multipotent cells present in tissues throughout the body, can reconstitute adipogenic, osteogenic and chondrogenic tissues, but are also of great interest as mediators of immune modulation and suppression. MSCs are able to improve transplant engraftment, treat graft versus host disease and suppress T cell responses and therefore have great potential as therapeutic agents. Their immune modulatory capacity is mediated through both cell-to-cell contact and cytokine secretion, but it is becoming clear that extracellular vesicles (EV) produced by MSC also possess immunomodulatory properties. These vesicles are easy to prepare and store, do not carry nuclear material and cannot form tumours, and therefore also represent a highly desirable therapeutic agent. This review outlines the formation and characterisation of extracellular vesicles, the reported function of MSC-EVs in vitro and in vivo, and addresses some of the emerging issues with nomenclature, EV therapeutic dose and tissue source. The development of GMP-grade production protocols and effective characterisation of MSC extracellular vesicles is essential to their successful use as immune modulating therapeutic agents, and this review outlines the current status of the research in this area. PMID- 27452646 TI - Listening post: A message from the World Apheresis Association Allied Health Representative 2016-2018. PMID- 27452647 TI - International Forum: Looking forward to a collaborative future: A message from Dr William Clark, World Apheresis Association President, 2016-2018. PMID- 27452648 TI - Vision and driving status of older Australians with cataract: an investigation of public hospital waiting lists. AB - BACKGROUND: Although cataract surgery can restore sight, lengthy waiting times are common in public hospitals in Australia. We investigated the driving status of older people during their surgical waiting period. METHODS: Baseline, cross sectional data from two prospective cohort studies of patients aged 50 years and older on Australian public hospital cataract surgery waiting lists were analysed. Participants underwent assessment of vision and completed the Driving Habits Questionnaire. The vision status was compared between current drivers and former drivers. RESULTS: Participants (n = 442) were on average 73 +/- 8 years of age and approximately half were women (229/442, 52 per cent). Habitual vision was 6/12(+2) on average (0.26 +/- 0.21 logMAR). There were 263 (60 per cent) current drivers, 110 (25 per cent) former drivers and 69 participants (16 per cent) who had never driven. Among the current drivers, 82/263 (31 per cent) failed visual acuity requirements for an unconditional drivers' license (6/12 acuity with one or both eyes). The former drivers had worse visual acuity than the current drivers (between group difference 0.12 +/- 0.20 logMAR, p < 0.0001) and worse contrast sensitivity (between group difference -0.14 +/- 0.22 log units, p < 0.0001). Both high contrast visual acuity and contrast sensitivity were independently associated with still driving. More than half (140/263, 53 per cent) of the drivers believed that their cataract had affected their driving and 23 current drivers (nine per cent) reported a crash in the last 12 months. CONCLUSION: We report on the level of visual impairment among older drivers waiting for cataract surgery. Approximately one-third did not meet the required visual acuity standard for driving and hence would require further ophthalmic assessment and a conditional license to continue to drive. Approximately one quarter of the surgical candidates were no longer driving and this was associated with greater visual impairment. These findings support a need for timely and appropriately prioritised access to cataract surgical services. PMID- 27452649 TI - Letter to the Editor; P. Van Damme et al. Vaccine 34 (2016) 757-761. PMID- 27452650 TI - Re: Letter to the Editor: P. van Damme et al., Vaccine 34 (2016) 757-761, as a reply to Ryser et al's letter in Vaccine. PMID- 27452651 TI - Answer to the review from Halstead and Russell "Protective and immunological behavior of chimeric yellow fever dengue vaccine" (DOI 10.1016/j.vaccine.2016.02.004). PMID- 27452652 TI - Response to Hadinegoro et al. PMID- 27452654 TI - Right-handed and left-handed G-quadruplexes have the same DNA sequence: distinct conformations induced by an organic small molecule and potassium. AB - Herein, we report two distinct G-quadruplex conformations of the same G-rich oligonucleotide, regulated by a small molecule. This is the first report in which both right- and left-handed G-quadruplex conformations have been obtained from the same sequence. We discriminated these two distinct conformations and investigated their kinetics and thermodynamics. PMID- 27452653 TI - Investigation of optimization-based reconstruction with an image-total-variation constraint in PET. AB - Interest remains in reconstruction-algorithm research and development for possible improvement of image quality in current PET imaging and for enabling innovative PET systems to enhance existing, and facilitate new, preclinical and clinical applications. Optimization-based image reconstruction has been demonstrated in recent years of potential utility for CT imaging applications. In this work, we investigate tailoring the optimization-based techniques to image reconstruction for PET systems with standard and non-standard scan configurations. Specifically, given an image-total-variation (TV) constraint, we investigated how the selection of different data divergences and associated parameters impacts the optimization-based reconstruction of PET images. The reconstruction robustness was explored also with respect to different data conditions and activity up-takes of practical relevance. A study was conducted particularly for image reconstruction from data collected by use of a PET configuration with sparsely populated detectors. Overall, the study demonstrates the robustness of the TV-constrained, optimization-based reconstruction for considerably different data conditions in PET imaging, as well as its potential to enable PET configurations with reduced numbers of detectors. Insights gained in the study may be exploited for developing algorithms for PET-image reconstruction and for enabling PET-configuration design of practical usefulness in preclinical and clinical applications. PMID- 27452655 TI - Microwave-assisted extraction of three bioactive alkaloids from Peganum harmala L. and their acaricidal activity against Psoroptes cuniculi in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Peganum harmala L. is a perennial herbaceous, glabrous plant that grows in semi-arid conditions, steppe areas and sandy soils. It is used to treat fever, diarrhoea, subcutaneous tumours, arthralgia, rheumatism, cough, amnesia and parasitic diseases in folk medicines. In this paper, we aimed to develop a simpler and faster method for the extraction of three alkaloids from Peganum harmala L. than other conventional methods by optimizing the parameters of a microwave-assisted extraction (MAE) method, and to investigate the acaricidal activities of three compounds against Psoroptes cuniculi. MATERIALS AND METHODS: After optimizing the operating parameters with the single factor experiment and a Box-Behnken design combined with a response surface methodology, a MAE method was developed for extracting the alkaloids from the seeds, and a high-performance liquid chromatography was used to quantify these compounds. An in vitro experiments were used to study the acaricidal activities. RESULTS: The optimal conditions of MAE method were as follows: liquid to-solid ratio 31.3:1mL/g, ethanol concentration 75.5%, extraction time 10.1min, temperature 80.7 degrees C, and microwave power 600W. Compared to the heat reflux extraction (HRE, 60min) and the ultrasonic-assisted extraction (UAE, 30min) methods, MAE method require the shortest time (10min) and obtain the highest yield of three compounds (61.9mg/g). Meanwhile, the LT50 values for the vasicine (1.25 and 2.5mg/mL), harmaline (1.25 and 2.5mg/mL), harmine (1.25 and 2.5mg/mL) and MAE extract (100mg/mL) against Psoroptes cuniculi were 12.188h, 9.791h, 11.994h, 10.095h, 11.293h, 9.273h and 17.322h, respectively. CONCLUSIONS: The MAE method developed exhibited the highest extraction yield within the shortest time and thus could be used to extract the active compounds from Peganum harmala L. on an industrial basis. As the active compounds of Peganum harmala L., vasicine, harmalin and harmine presented the marked acaricidal activities against Psoroptes cuniculi, and could be widely applied for the treatments of acariasis in animals. PMID- 27452656 TI - Zhikang Capsule ameliorates dextran sodium sulfate-induced colitis by inhibition of inflammation, apoptosis, oxidative stress and MyD88-dependent TLR4 signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zhikang Capsule (ZKC) is a traditional Chinese medicine (TCM) modified from classic formulas Qi-Li-San (an ancient formula dating to Qing Dynasty) and Fu-Jin-Sheng-Ji-San (written into The Golden Mirror of Medicine). ZKC contains 14 kinds of materials and has been widely used for the clinical therapy of inflammatory bowel diseases (IBD) for a long time. However, the therapeutic mechanisms of ZKC are still unclear. AIM OF THE STUDY: To determine the protective effect of ZKC on dextran sodium sulfate (DSS)-induced colitis and explore the underlying mechanisms. MATERIALS AND METHODS: C57BL/6 mice were fed with 3% DSS in drinking water for one week to induce experimental colitis. They were randomly assigned to six groups according to the treatment conditions. The histological changes of colon tissues were observed by hematoxylin and eosin (H&E) staining. The serum concentration of pro-inflammatory cytokines (TNF-alpha, IFN-gamma, IL-1beta, and IL-12) and anti-inflammatory mediators (IL-4 and IL-10) was detected by enzyme-linked immune sorbent assays (ELISAs). The production of MPO, SOD, MDA, NO, and caspase-3 was assessed by biochemical assay kits. The expression of iNOS, ICAM-1, and NF-KappaB was evaluated by immunohistochemistry staining. The levels of TLR4, MyD88, and TRAF6 were determined by western blot. RESULTS: Histologic analysis exhibited that ZKC alleviated the inflammation, loss of goblet cells, and submucosal edema induced by DSS. ZKC significantly suppressed the pro-inflammatory cytokines and promoted the anti-inflammatory mediators. The antioxidation of ZKC was indicated by increased activity of SOD and reduced production of MDA, NO, and iNOS in ZKC treated mice. Furthermore, ZKC repressed the colonic expression of caspase-3 and the activity of the MyD88-dependent TLR4 signaling pathway. CONCLUSIONS: This research demonstrated the protective effect of ZKC on DSS-induced colitis. For the first time, we identified four therapeutic mechanisms of ZKC, including effective inhibition of the inflammatory responses, significant alleviation of intestinal epithelium apoptosis, considerable prevention of oxidative stress, and selective down-regulation of the MyD88-dependent TLR4 signaling pathway. With high therapeutic effects and low toxic effects, ZKC exhibits great superiority over western medicines in IBD treatment. PMID- 27452657 TI - Contributions of Indian Council of Medical Research (ICMR) in the area of Medicinal plants/Traditional medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants belong to the oldest known health care products that have been used by human beings all over the world and are major components of the formulations used in indigenous system of medicine practiced in many countries. Besides, finding place as health supplements, nutraceuticals, cosmetics, herbal tea etc. there has been a global insurgence of interest, including India, leading to enormous research/activities in the area of medicinal plants. AIM OF THE STUDY: The article is aimed to provide the effort and initiatives of ICMR towards research on medicinal plants and its contributions on consolidation of Indian research on medicinal plants that are very relevant and important in the national context. METHODS: The various initiatives undertaken by ICMR on research on traditional medicines/medicinal plants in the past are reviewed and documented in this article. RESULTS: The multi-disciplinary, multicentric research initiatives of ICMR have resulted in validation of traditional treatment Kshaarasootra (medicated Ayurvedic thread) for anal fistula, Vijayasar (heart wood of Pterocarpus marsupium Roxb.) for diabetes mellitus, encouraging micro- and macrofilaricidal activity of Shakotak (stem bark of Streblus asper Lour.) in experimental studies an iridoid glycosides fraction isolated from root/rhizomes of Picrorhiza kurroa Royle ex Benth. (designated as Picroliv) for viral hepatitis. Other developmental and compilation of research works on Indian medicinal plants have resulted in publications of the thirteen volumes of quality standards, comprising of 449 Indian medicinal plants; three volumes of 90 phytochemical reference standards; fifteen volumes of review monographs on 4167 medicinal plant species; and one publication each on perspectives of Indian medicinal plants for management of liver disorders, lymphatic filariasis and diabetes mellitus (details available at http://www.icmr.nic.in/mpsite). CONCLUSION: The ICMR efforts assume special significance in the light of multifaceted use of medicinal plants, and the need of better drugs and remedies for various diseases. Further, the indigenous system of medicine, and the plant drugs, could promise to provide both concepts of therapy, as well as therapeutic agents in the areas, where modern system of medicines has few answers. The developement of quality standards and review monographs also help the regulators, pharmacopoeial bodies and drug industry towards generation of quality herbal drugs or traditional medicine preparations. These initiatives are also in favour of the World Health Organisation advocating herbal medicines as a valid alternative system of therapy in the form of phytomedicines or herbal drugs or herbal drug preparations or herbal medicinal products. PMID- 27452658 TI - Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, Zizyphus jujuba is used for anticonvulsant, hypnotic-sedative, anxiolytic, tranquilizer, antioxidant and anti inflammatory properties. Likewise silymarin is popularly used for its potent antioxidant and hepatoprotective effects. Stroke being a multifactorial disease with unsatisfactory treatment outcomes, necessitates development of multimodal therapeutic interventions. Thus, we evaluated the therapeutic benefits of herbal combination of Z. jujuba and silymarin in a focal cerebral ischemia model. AIM OF THE STUDY: To evaluate the neuroprotective potential of hydroalcoholic extract of Z. jujuba (HEZJ) fruit and silymarin alone and in combination in middle cerebral artery occlusion (MCAo) model of focal cerebral ischemia in rats. MATERIALS AND METHODS: Male Wistar rats were pretreated with HEZJ (100, 250 and 500mg/kg, p.o.) or silymarin (250mg/kg, p.o.) for 3 days prior to induction of MCAo. Neurological deficit score, motor impairment and cerebral infarction were assessed 24h following MCAo. HEZJ (250mg/kg) co-administered with silymarin (250mg/kg) for 3 days prior to induction of MCAo was also evaluated for above parameters and oxidative stress. Malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD) levels in the cortex, striatum and hippocampal brain regions were estimated 24h post MCAo. RESULTS: Pretreatment with HEZJ and silymarin reduced the neurological deficit score, motor impairment and cerebral infarction volume. HEZJ and silymarin pretreatment also ameliorated the oxidative stress in different brain regions, which was evident from increased SOD levels, decreased MDA and NO levels as compared to MCAo control rats. Interestingly neuroprotective efficacy was potentiated by pretreatment with HEZJ and silymarin combination. CONCLUSION: Pretreatment with HEZJ and silymarin combination was observed to have better neuroprotection mediated via amelioration of oxidative stress in the focal cerebral ischemia model. PMID- 27452659 TI - Understanding the mode-of-action of Cassia auriculata via in silico and in vivo studies towards validating it as a long term therapy for type II diabetes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cassia auriculata (CA) is used as an antidiabetic therapy in Ayurvedic and Siddha practice. This study aimed to understand the mode of-action of CA via combined cheminformatics and in vivo biological analysis. In particular, the effect of 10 polyphenolic constituents of CA in modulating insulin and immunoprotective pathways were studied. MATERIALS AND METHODS: In silico target prediction was first employed to predict the probability of the polyphenols interacting with key protein targets related to insulin signalling, based on a model trained on known bioactivity data and chemical similarity considerations. Next, CA was investigated in in vivo studies where induced type 2 diabetic rats were treated with CA for 28 days and the expression levels of genes regulating insulin signalling pathway, glucose transporters of hepatic (GLUT2) and muscular (GLUT4) tissue, insulin receptor substrate (IRS), phosphorylated insulin receptor (AKT), gluconeogenesis (G6PC and PCK-1), along with inflammatory mediators genes (NF-kappaB, IL-6, IFN-gamma and TNF-alpha) and peroxisome proliferators-activated receptor gamma (PPAR-gamma) were determined by qPCR. RESULTS: In silico analysis shows that several of the top 20 enriched targets predicted for the constituents of CA are involved in insulin signalling pathways e.g. PTPN1, PCK-alpha, AKT2, PI3K-gamma. Some of the predictions were supported by scientific literature such as the prediction of PI3K for epigallocatechin gallate. Based on the in silico and in vivo findings, we hypothesized that CA may enhance glucose uptake and glucose transporter expressions via the IRS signalling pathway. This is based on AKT2 and PI3K-gamma being listed in the top 20 enriched targets. In vivo analysis shows significant increase in the expression of IRS, AKT, GLUT2 and GLUT4. CA may also affect the PPAR-gamma signalling pathway. This is based on the CA-treated groups showing significant activation of PPAR-gamma in the liver compared to control. PPAR-gamma was predicted by the in silico target prediction with high normalisation rate although it was not in the top 20 most enriched targets. CA may also be involved in the gluconeogenesis and glycogenolysis in the liver based on the downregulation of G6PC and PCK-1 genes seen in CA-treated groups. In addition, CA-treated groups also showed decreased cholesterol, triglyceride, glucose, CRP and Hb1Ac levels, and increased insulin and C-peptide levels. These findings demonstrate the insulin secretagogue and sensitizer effect of CA. CONCLUSION: Based on both an in silico and in vivo analysis, we propose here that CA mediates glucose/lipid metabolism via the PI3K signalling pathway, and influence AKT thereby causing insulin secretion and insulin sensitivity in peripheral tissues. CA enhances glucose uptake and expression of glucose transporters in particular via the upregulation of GLUT2 and GLUT4. Thus, based on its ability to modulate immunometabolic pathways, CA appears as an attractive long term therapy for T2DM even at relatively low doses. PMID- 27452660 TI - Antiinflammatory and immunomodulatory activity of an ethanolic extract from the stem bark of Terminalia catappa L. (Combretaceae): In vitro and in vivo evidences. AB - ETHNOPHARMOCOLOGICAL RELEVANCE: Terminalia catappa Linn (Combretaceae) is a medicinal plant with anti-inflammatory, anti-diarrhoeal and antioxidant properties, frequently found in tropical regions. Considering its characteristics, it could be useful for the treatment of inflammatory bowel disease, which is associated with inflammation, oxidative stress and an immune dysfunction. Thus this study evaluates the immunomodulatory properties and the intestinal anti-inflammatory effect of an ethanolic extract of the stem bark of T. catappa (ETCB) both in vitro (in RAW 264.7 macrophages) and in vivo, in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis. MATERIALS AND METHODS: The phenolic compounds in ETCB were identified and quantified using HPLC-DAD-qTOF MS. The immunomodulatory activity ETCB was tested in vitro by determining the macrophage production of IL-1beta and nitrites. In vivo studies were performed in the TNBS model of rat colitis. ETCB was given (25, 50 and 100mg/kg/day) orally for two days prior to colitis induction and thereafter for 7 days. Response to treatment was assessed by scoring the gross appearance of the colon, and determining myeloperoxidase activity, gene expression of pro-inflammatory cytokines like TNF-alpha, IL-23 and IL-6, chemokines, inducible nitric oxide synthase and proteins crucial in the maintenance of the intestinal mucosal barrier integrity like mucins (MUC-2, MUC-3) and villin. RESULTS: ETCB was able to inhibit IL-1beta and nitrite production in vitro in RAW 264.7 macrophages. Moreover, treatment of TNBS colitic rats with ETCB resulted in a decreased colonic damage score and weight/length ratio. It also reduced the colonic neutrophil infiltration indicated by a lower myeloperoxidase activity and prevented the depletion of colonic glutathione levels in colitic rats. In addition, treatment with ETCB down-regulated the gene expression of pro inflammatory mediators (TNF-alpha, IL-23, IL-6 and CINC-1) and iNOS in colitic rats. Moreover, the gene expression of mucosal barrier proteins like MUC-2, MUC-3 and villin were up-regulated in colitic rats treated with ETCB. The dose of ETCB that produced the most significant beneficial effect was 100mg/kg. Regarding the chemical composition of ETCB, 31 phenolic compounds were identified, including ellagic acid, catalagin and gallic acid. CONCLUSION: The beneficial effect of ETCB in the TNBS induced colitis in rats could be related to its antioxidant, immunomodulatory and anti-inflammatory activities, which could be attributed to the phenolic compounds identified. PMID- 27452661 TI - Personalized support for chronic conditions. A novel approach for enhancing self management and improving lifestyle. AB - OBJECTIVE: Solutions for improving management of chronic conditions are under the attention of healthcare systems, due to the increasing prevalence caused by demographic change and better survival, and the relevant impact on healthcare expenditures. The objective of this study was to propose a comprehensive architecture of a mHealth system aimed at boosting the active and informed participation of patients in their care process, while at the same time overcoming the current technical and psychological/clinical issues highlighted by the existing literature. METHODS: After having studied the current challenges outlined in the literature, both in terms of technological and human requirements, we focused our attention on some specific psychological aspects with a view to providing patients with a comprehensive and personalized solution. Our approach has been reinforced through the results of a preliminary assessment we conducted on 22 patients with chronic conditions. The main goal of such an assessment was to provide a preliminary understanding of their needs in a real context, both in terms of self-awareness and of their predisposition toward the use of IT solutions. RESULTS: According to the specific needs and features, such as mindfulness and gamification, which were identified through the literature and the preliminary assessment, we designed a comprehensive open architecture able to provide a tailor-made solution linked to specific individuals' needs. CONCLUSION: The present study represents the preliminary step towards the development of a solution aimed at enhancing patients' actual perception and encouraging self management and self-awareness for a better lifestyle. Future work regards further identification of pathology-related needs and requirements through focus groups including all stakeholders in order to describe the architecture and functionality in greater detail. PMID- 27452662 TI - Contribution of Long Fibrils and Peptides to Surface and Foaming Behavior of Soy Protein Fibril System. AB - When soy glycinin (11S) is heated for a prolonged time at pH 2 (20 h at 85 degrees C), a mixture is formed consisting of long semiflexible 11S fibrils and small peptides. The surface and foaming properties of this mixture were investigated at different pHs, and compared to the behavior of pure fibrils and pure peptides, to determine the individual contributions of these two factions to the behavior of the mixture. The adsorption of these three systems at air-water interfaces and the resulting surface rheological properties were studied by combining drop shape analysis tensiometry, ellipsometry, and surface large amplitude oscillatory dilatational (LAOD) rheology. Lissajous plots of surface pressure versus deformation were used to analyze the surface rheological response in terms of interfacial microstructure. Our results show that the adsorption kinetics, dilatational rheological properties, and the foaming behavior of the mixture were mainly dominated by the small peptides in the fibril system. Compared to pH 2, the fibril mixture at pH 5 and 7 provides much better foam stability and appears to be a very promising protein material to make stable foams, even at low protein concentration (0.1 wt %). The presence of fibril clusters and peptide aggregates at pH 5 and 7 contributed to foam stability of the mixture. In contrast, pure fibril formed an interface with a highly pH responsive adsorption and rheological behavior, and the foamability and foam stability of the pure fibrils were very poor. PMID- 27452663 TI - Monitoring and managing microbes in aquaculture - Towards a sustainable industry. AB - Microorganisms are of great importance to aquaculture where they occur naturally, and can be added artificially, fulfilling different roles. They recycle nutrients, degrade organic matter and, occasionally, they infect and kill the fish, their larvae or the live feed. Also, some microorganisms may protect fish and larvae against disease. Hence, monitoring and manipulating the microbial communities in aquaculture environments hold great potential; both in terms of assessing and improving water quality, but also in terms of controlling the development of microbial infections. Using microbial communities to monitor water quality and to efficiently carry out ecosystem services within the aquaculture systems may only be a few years away. Initially, however, we need to thoroughly understand the microbiomes of both healthy and diseased aquaculture systems, and we need to determine how to successfully manipulate and engineer these microbiomes. Similarly, we can reduce the need to apply antibiotics in aquaculture through manipulation of the microbiome, i.e. by the use of probiotic bacteria. Recent studies have demonstrated that fish pathogenic bacteria in live feed can be controlled by probiotics and that mortality of infected fish larvae can be reduced significantly by probiotic bacteria. However, the successful management of the aquaculture microbiota is currently hampered by our lack of knowledge of relevant microbial interactions and the overall ecology of these systems. PMID- 27452665 TI - Stem Cell Delivery With Polymer Hydrogel for Treatment of Intervertebral Disc Degeneration: From 3D Culture to Design of the Delivery Device for Minimally Invasive Therapy. AB - Nucleus pulposus (NP) tissue damage can induce detrimental mechanical strain on the biomechanical performance of intervertebral discs (IVDs), causing subsequent disc degeneration. A novel, photocurable, injectable, synthetic polymer hydrogel (pHEMA-co-APMA grafted with PAA) has already demonstrated success in encapsulating and differentiating human mesenchymal stem cells (hMSCs) toward an NP phenotype during hypoxic conditions. After demonstration of promising results in our previous work, in this study we have further investigated the inclusion of mechanical stimulation and its impact on hMSC differentiation toward an NP phenotype through the characterization of matrix markers such as SOX-9, aggrecan, and collagen II. Furthermore, investigations were undertaken in order to approximate delivery parameters for an injection delivery device, which could be used to transport hMSCs suspended in hydrogel into the IVD. hMSC-laden hydrogel solutions were injected through various needle gauge sizes in order to determine its impact on postinjection cell viability and IVD tissue penetration. Interpretation of these data informed the design of a potential minimally invasive injection device, which could successfully inject hMSCs encapsulated in a UV-curable polymer into NP, prior to photo-cross-linking in situ. PMID- 27452667 TI - MALT lymphoma: A paradigm of NF-kappaB dysregulation. AB - Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) invariably arises from a background of chronic microbial infection and/or autoimmune disorder at diverse mucosal sites. The prolonged chronic infection and/or autoimmunity generate active immune and inflammatory responses that provide a setting for evolution and development of autoreactive B-cells, their expansion and eventual malignant transformation following acquisition of genetic changes. The immune responses also play a critical role in sustaining the growth and survival of the transformed cells as shown by complete regression of a high proportion of MALT lymphoma of the stomach, ocular adnexa and skin following anti-microbial treatment. B-cell receptor engagement by auto-antigen as well as T cell help including both cognate interaction and bystander help via soluble ligands such as CD40L and BAFF are thought to underpin the immunological drive in the lymphoma development through activation of the canonical and non-canonical NF kappaB pathway respectively. Similarly, the three MALT lymphoma associated chromosome translocations, namely t(1;14)(p22;q32)/BCL10-IGH, t(14;18)(q32;q21)/IGH-MALT1,and t(11;18)(q21;q21)/BIRC3 (API2)-MALT1, are also capable of activating both canonical and non-canonical NF-kappaB pathways. Furthermore, TNFAIP3 (A20) inactivation by deletion and/or mutation abolishes the auto-negative feedback to several signalling including BCR and TLR, which connect to the canonical NF-kappaB activation pathway. Thus, there is a considerable overlap in the molecular pathways dysregulated by immunological drive and somatic genetic changes, strongly arguing for their oncogenic cooperation in the development of MALT lymphoma. PMID- 27452666 TI - Promise of bitter melon (Momordica charantia) bioactives in cancer prevention and therapy. AB - Recently, there is a paradigm shift that the whole food-derived components are not 'idle bystanders' but actively participate in modulating aberrant metabolic and signaling pathways in both healthy and diseased individuals. One such whole food from Cucurbitaceae family is 'bitter melon' (Momordica charantia, also called bitter gourd, balsam apple, etc.), which has gained an enormous attention in recent years as an alternative medicine in developed countries. The increased focus on bitter melon consumption could in part be due to several recent pre clinical efficacy studies demonstrating bitter melon potential to target obesity/type II diabetes-associated metabolic aberrations as well as its pre clinical anti-cancer efficacy against various malignancies. The bioassay-guided fractionations have also classified the bitter melon chemical constituents based on their anti-diabetic or cytotoxic effects. Thus, by definition, these bitter melon constituents are at cross roads on the bioactivity parameters; they either have selective efficacy for correcting metabolic aberrations or targeting cancer cells, or have beneficial effects in both conditions. However, given the vast, though dispersed, literature reports on the bioactivity and beneficial attributes of bitter melon constituents, a comprehensive review on the bitter melon components and the overlapping beneficial attributes is lacking; our review attempts to fulfill these unmet needs. Importantly, the recent realization that there are common risk factors associated with obesity/type II diabetes-associated metabolic aberrations and cancer, this timely review focuses on the dual efficacy of bitter melon against the risk factors associated with both diseases that could potentially impact the course of malignancy to advanced stages. Furthermore, this review also addresses a significant gap in our knowledge regarding the bitter melon drug-drug interactions which can be predicted from the available reports on bitter melon effects on metabolism enzymes and drug transporters. This has important implications, given that a large proportion of individuals, taking bitter melon based supplements/phytochemical extracts/food based home-remedies, are also likely to be taking conventional therapeutic drugs at the same time. Accordingly, the comprehensively reviewed information here could be prudently translated to the clinical implications associated with any potential concerns regarding bitter melon consumption by cancer patients. PMID- 27452668 TI - Geometric analysis of pathways dynamics: Application to versatility of TGF-beta receptors. AB - We propose a new geometric approach to describe the qualitative dynamics of chemical reactions networks. By this method we identify metastable regimes, defined as low dimensional regions of the phase space close to which the dynamics is much slower compared to the rest of the phase space. These metastable regimes depend on the network topology and on the orders of magnitude of the kinetic parameters. Benchmarking of the method on a computational biology model repository suggests that the number of metastable regimes is sub-exponential in the number of variables and equations. The dynamics of the network can be described as a sequence of jumps from one metastable regime to another. We show that a geometrically computed connectivity graph restricts the set of possible jumps. We also provide finite state machine (Markov chain) models for such dynamic changes. Applied to signal transduction models, our approach unravels dynamical and functional capacities of signalling pathways, as well as parameters responsible for specificity of the pathway response. In particular, for a model of TGFbeta signalling, we find that the ratio of TGFBR2 to TGFBR1 receptors concentrations can be used to discriminate between metastable regimes. Using expression data from the NCI60 panel of human tumor cell lines, we show that aggressive and non-aggressive tumour cell lines function in different metastable regimes and can be distinguished by measuring the relative concentrations of receptors of the two types. PMID- 27452664 TI - Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use. AB - There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e., alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of > 50 endpoint-specific control compounds was identified. For further test development, an additional "test" set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the > 100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems. PMID- 27452669 TI - Investigation of serotype distribution and resistance genes profile in group B Streptococcus isolated from pregnant women: a Chinese multicenter cohort study. AB - We surveyed the group B Streptococcus (GBS) strains isolated from four teaching hospitals during 1-year period to investigate the current serotypes and antimicrobial resistance status of these strains. A total of 231 non-duplicate colonizing GBS isolates were collected from pregnant women. Antimicrobial susceptibility of these isolates was tested by the disk diffusion method. Serotype was performed by a multiplex polymerase chain reaction (PCR) method. Analysis of the resistance mechanisms was performed by PCR amplification and DNA sequencing. Seven serotypes (Ia, Ib, II, III, V, VI, and VIII) were identified, and the prevalence ranged from 0.9 to 35.9%. All isolates were susceptible to the penicillin, ceftriaxone, and vancomycin. The resistance of all the isolates to erythromycin, clindamycin, and levofloxacin was 61.5, 51.9, and 35.5%, respectively. The erythromycin resistance was mainly associated with the genes ermB and ermB-mef(A/E) (69.8%). The most predominant phenotype was cMLSB (77.5%). Five gene panels, including gyrA, parC, parE, gyrA-parC, and gyrA-parC-parE, were detected. The most predominant genotype was gyrA-parC-parE triple mutation (69.5%). The S81L in gyrA gene, S79Y mutation in parC gene, and H225Y mutation in parE gene were discovered. The isolates with serotype III, V, and Ia were the most important clone concerning the prevalence and resistance. PMID- 27452670 TI - Rapid detection of avian influenza virus H5N1 in chicken tracheal samples using an impedance aptasensor with gold nanoparticles for signal amplification. AB - Highly pathogenic avian influenza virus H5N1 is a continuous threat to public health and poultry industry. The recurrence of the H5N1 led us to develop a robust, specific, and rapid detection method for the virus. In this study, an impedance aptasensor was developed for the virus detection using specific H5N1 aptamer and a gold interdigitated microelectrode. Streptavidin was immobilized on the microelectrode surface and biotin labeled H5N1 aptamer was bound to the immobilized streptavidin. The microelectrode was blocked with the polyethylene glycol and the bound aptamer captured the virus. The impedance change caused by the captured virus was measured using an impedance analyzer. To enhance impedance signal, a nanoparticle-based amplifier was designed and implemented by forming a network-like gold nanoparticles/H5N1-aptamer/thiocyanuric acid. The detection limit of the impedance aptasensor was 0.25 HAU for the pure virus and 1 HAU for the tracheal chicken swab samples spiked with the H5N1 virus. The detection time of aptasensor without employing the amplifier was less than an hour. The amplifier increased impedance by a 57-fold for the 1 HAU samples. Only negligible impedance change was observed for non-target viruses such as H5N2, H5N3, H7N2, H1N1, and H2N2. This aptasensor provides a foundation for the development of a portable aptasensor instrument. PMID- 27452671 TI - Should Norepinephrine, Rather Than Phenylephrine, Be Considered the Primary Vasopressor in Anesthetic Practice?: Erratum. PMID- 27452672 TI - Adropin and irisin levels in relation to nutrition, body composition, and insulin resistance in patients with end-stage renal disease on chronic hemodialysis and peritoneal dialysis. AB - INTRODUCTION Newly discovered myokines, adropin, and irisin, are regulators of energy homeostasis and metabolism in humans. In end-stage renal disease (ESRD), the significance and role of irisin and adropin as metabolism regulators are still unclear. OBJECTIVES The aim of this study was to evaluate serum adropin and irisin levels and establish their relation to insulin resistance, nutritional status, and hydration status in patients on chronic hemodialysis (HD) and on peritoneal dialysis (PD). PATIENTS AND METHODS The study consisted of 71 subjects, including 48 patients (18 women, 30 men; median age, 56.5 years; range, 26-84 years) either on HD (n = 41) or PD (n = 7) and 36 healthy controls matched for age and sex. We measured the serum levels of adropin, irisin, creatinine, albumin, glucose, and insulin, as well as the plasma levels of lipids. The bioimpedance method was used to evaluate the body composition and overhydration in patients with ESRD. RESULTS Irisin levels were significantly lower in patients with ESRD compared with controls, but there were no differences in adropin levels between both study groups. Adropin levels were inversely correlated with body mass, lean tissue mass, total, intracellular, and extracellular water, and albumin concentrations in patients with ESRD. Irisin levels were positively correlated with glucose levels and homeostasis model assessment of insulin resistance. No significant correlations were observed between adropin and irisin concentrations and overhydration. CONCLUSIONS Adropin may be considered as a new marker of nutritional status in patients with ESRD. The significance and cause of low irisin levels characteristic for these patients are still unclear. Adropin and irisin should be further investigated as possible markers of cachexia and insulin resistance in patients with ESRD. PMID- 27452674 TI - Cost of alcohol: better data will be justified if it is put to better use. PMID- 27452675 TI - Proteome analysis of Pseudomonas putida F1 genes induced in soil environments. AB - Knowledge of the gene expression dynamics of a single soil bacterial strain contributes to the understanding of its behaviour, physiological state and surrounding microenvironment. Genes expressed in soil environments rather than in laboratory media are considered to particularly relevant. Here, we compared genome-wide gene expression profiles of the bacterium Pseudomonas putida F1 inoculated in three different types of nonsterile soils deduced using proteome analysis via sodium dodecyl sulfate-polyacrylamide gel electrophoresis combined with liquid chromatography-tandem mass spectrometry. Proteins commonly detected in all three samples and involved with bacterial growth and fundamental metabolism were excluded. Nine proteins were identified as specifically expressed in soil including an aldehyde dehydrogenase, a nitric oxide dioxygenase and five proteins encoded by a cluster of metabolism-associated genes. Expression factor analysis revealed that the nitric oxide dioxygenase-coding gene was induced by nitric oxide and the five clustered genes were induced under phosphate starvation. The expression of these genes can be attributed to response to soil environmental stimuli surrounding the F1 cells. These results strongly suggest that our soil metaproteome approach is useful for understanding the autecology and lifestyle of a single bacterial strain in soil environments and allows the prediction of the microenvironment surrounding the bacterial cells. PMID- 27452673 TI - Small-molecule binding sites to explore protein-protein interactions in the cancer proteome. AB - The Cancer Genome Atlas (TCGA) offers an unprecedented opportunity to identify small-molecule binding sites on proteins with overexpressed mRNA levels that correlate with poor survival. Here, we analyze RNA-seq and clinical data for 10 tumor types to identify genes that are both overexpressed and correlate with patient survival. Protein products of these genes were scanned for binding sites that possess shape and physicochemical properties that can accommodate small molecule probes or therapeutic agents (druggable). These binding sites were classified as enzyme active sites (ENZ), protein-protein interaction sites (PPI), or other sites whose function is unknown (OTH). Interestingly, the overwhelming majority of binding sites were classified as OTH. We find that ENZ, PPI, and OTH binding sites often occurred on the same structure suggesting that many of these OTH cavities can be used for allosteric modulation of enzyme activity or protein protein interactions with small molecules. We discovered several ENZ (PYCR1, QPRT, and HSPA6) and PPI (CASC5, ZBTB32, and CSAD) binding sites on proteins that have been seldom explored in cancer. We also found proteins that have been extensively studied in cancer that have not been previously explored with small molecules that harbor ENZ (PKMYT1, STEAP3, and NNMT) and PPI (HNF4A, MEF2B, and CBX2) binding sites. All binding sites were classified by the signaling pathways to which the protein that harbors them belongs using KEGG. In addition, binding sites were mapped onto structural protein-protein interaction networks to identify promising sites for drug discovery. Finally, we identify pockets that harbor missense mutations previously identified from analysis of TCGA data. The occurrence of mutations in these binding sites provides new opportunities to develop small-molecule probes to explore their function in cancer. PMID- 27452676 TI - Synthesis of alpha-sulfenyl monoketones via a metal-free oxidative cross dehydrogenative coupling (CDC) reaction. AB - alpha-Sulfenyl ketones are potential precursors which find a variety of applications in organic synthesis. Their typical synthesis requires pre functionalized starting materials and two to three step synthetic sequences. In addition, the selective pre-functionalization of unsymmetrical ketones is a challenge, which limits the synthesis of the desired sulfenylated ketones. To overcome these disadvantages, a metal-free, convenient one-step strategy for synthesizing alpha-sulfenyl ketones at ambient temperature via a cross dehydrogenative coupling (CDC) strategy has been developed with a broad substrate scope. Therefore, this CDC strategy for C-S bond formation is attractive and may find wide applications in organic synthesis. PMID- 27452677 TI - Effects of Ginkgo Biloba Extract EGb-761 on Neuropathic Pain in Mice: Involvement of Opioid System. AB - Neuropathic pain is considered as one of the most difficult types of pain to manage with conventional analgesics. EGb-761 is extracted from leaves of Ginkgo biloba and has analgesia and anti-inflammatory properties. This study aimed to examine the effect of EGb-761 on chronic constriction injury (CCI)-induced neuropathic pain behaviors, including thermal hyperalgesia and mechanical allodynia, and to explore the possible mechanisms underlying this action. To this end, CCI mice were intraperitoneally injected with EGb-761 (10, 20, 40, and 80 mg/kg), and thermal hyperalgesia, mechanical allodynia, cytokines, and mu-opioid receptor expression were measured. Results showed that EGb-761 attenuated thermal hyperalgesia and mechanical allodynia dose-dependently and the best delivery time window was from day 7 to day 14 after CCI. Additionally, EGb-761 treatment significantly decreased pro-inflammatory cytokines and enhanced mu opioid receptor (MOR) expression in the sciatic nerve. Moreover, the opioid antagonist naloxone prevented the effect of EGb-761 on thermal hyperalgesia and mechanical allodynia but did not influence the effect of EGb-761 on inflammatory cytokines. In conclusion, this study suggests that the potential of EGb-761 as a new analgesic for neuropathic pain treatment, and opioid system may be involved in the EGb-761-induced attenuation of thermal hyperalgesia and mechanical allodynia. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27452678 TI - Editorial (Thematic Issue: Targeted Anti-Cancer Drug Delivery). PMID- 27452679 TI - Update on Importance of Diet in Gout. AB - Gout is an inflammatory arthritis caused by deposition of monosodium urate crystals within synovial joints. Although it is most well-known for its arthritis, gout has an intimate relationship with many other cardiovascular and metabolic conditions. Current recommendations support aggressive medical therapy to treat gout, whereas dietary counseling has become less emphasized. This article argues for the absolute importance of dietary counseling in gout and proves why this counseling may impact the long term well-being of a patient with gout. PMID- 27452680 TI - Candidemia in Patients with Body Temperature Below 37 degrees C and Admitted to Internal Medicine Wards: Assessment of Risk Factors. AB - BACKGROUND: An increasing number of candidemia episodes has been reported in patients cared for in internal medicine wards. These usually older and frail patients may not be suspected as having candidemia because they lack fever at the onset of the episode. To identify the risk factors associated with the lack of fever at the onset of candidemia (ie, the collection of the first positive blood culture for Candida spp.) in patients cared for in internal medicine wards, we compared 2 group of patients with or without fever. METHODS: We retrospectively review data charts from 3 tertiary care, university hospitals in Italy, comparing patients with or without fever at onset of candidemia. Consecutive candidemic episodes in afebrile patients and matched febrile controls were identified during the 3-year study period. Patient baseline characteristics and several infection related variables were examined. Random forest analysis was used, given the number of predictors to be considered and the potential complexity of their relations with the onset of fever. RESULTS: We identified 147 candidemic episodes without fever at onset and 147 febrile candidemia episodes. Factors associated with the lack of fever at onset of candidemia were diabetes, Clostridium difficile infection, and a shorter delta time from internal medicine wards admission to the onset of candidemia. The only variable associated with fever was the use of intravascular devices. Quite unexpectedly, antifungal therapy was administered more frequently to patients without fever, and no differences on 30 day mortality rate were documented in the 2 study groups. CONCLUSIONS: Clinicians should be aware that an increasing number of patients with invasive candidiasis cared for in internal medicine wards may lack fever at onset, especially those with diabetes and C. difficile infection. Candidemia should be suspected in patients with afebrile systemic inflammatory response syndrome or in worsening clinical condition: blood cultures should be taken, and a timely and appropriate antifungal therapy should be considered. PMID- 27452683 TI - Dichotomous Role of Exciting the Donor or the Acceptor on Charge Generation in Organic Solar Cells. AB - In organic solar cells, photoexcitation of the donor or acceptor phase can result in different efficiencies for charge generation. We investigate this difference for four different 2-pyridyl diketopyrrolopyrrole (DPP) polymer-fullerene solar cells. By comparing the external quantum efficiency spectra of the polymer solar cells fabricated with either [60]PCBM or [70]PCBM fullerene derivatives as acceptor, the efficiency of charge generation via donor excitation and acceptor excitation can both be quantified. Surprisingly, we find that to make charge transfer efficient, the offset in energy between the HOMO levels of donor and acceptor that govern charge transfer after excitation of the acceptor must be larger by ~0.3 eV than the offset between the corresponding two LUMO levels when the donor is excited. As a consequence, the driving force required for efficient charge generation is significantly higher for excitation of the acceptor than for excitation of the donor. By comparing charge generation for a total of 16 different DPP polymers, we confirm that the minimal driving force, expressed as the photon energy loss, differs by about 0.3 eV for exciting the donor and exciting the acceptor. Marcus theory may explain the dichotomous role of exciting the donor or the acceptor on charge generation in these solar cells. PMID- 27452681 TI - Low Diagnostic Utility of Rechecking Hemoglobins Within 24 Hours in Hospitalized Patients. AB - BACKGROUND: Clinicians often repeat hemoglobin tests within a 24 hour period to detect or monitor anemia. We sought to determine the percentage of hemoglobin tests repeated within a single hospital day that were at least 1.0 g/dL lower than the first test. METHODS: We performed a retrospective cross-sectional analysis of hospitalized adults on medical or surgical services over 1 year at a single academic hospital. Using patient and laboratory data in the electronic health record, we analyzed the proportion of repeated hemoglobin test results that were at least 1 g/dL less than the initial hemoglobin value of that day, excluding days when transfusions were administered. RESULTS: A total of 88,722 hemoglobin tests were obtained from 12,877 unique patients, who contributed a total of 86,859 hospitalization days. In 12,230 (14.1%) of those days, 2 or more hemoglobin tests were obtained within a single day. In the 6969 days with 2 hemoglobin tests obtained and no transfusions given, 949 (13.5%) were >=1 g/dL lower than the initial hemoglobin value of that day, and 260 (3.7%) were >=2 g/dL lower. Repeated tests did not often reach transfusion thresholds: 482 (6.9%) of repeat hemoglobin values were <8 g/dL, and 64 (0.9%) were <7 g/dL. CONCLUSIONS: Hemoglobin tests were repeated in 14% of hospital days. For patients who had 2 hemoglobin tests obtained on the same day, 13.5% demonstrated a clinically significant drop. This information may be helpful to clinicians when considering whether repeat testing is appropriate. PMID- 27452684 TI - Idiopathic sclerosing encapsulating peritonitis: a rare cause of intestinal obstruction. PMID- 27452682 TI - Double Fixation: Bilateral Bisphosphonate-Related Hip Fractures. PMID- 27452685 TI - Dr Tom Swift Returns. PMID- 27452687 TI - Washington Medical Update. PMID- 27452686 TI - Editor's Mail. PMID- 27452688 TI - Problems + Solutions. PMID- 27452689 TI - Immune complex-mediated rheumatic diseases. PMID- 27452690 TI - The Medical Bookshelf. PMID- 27452694 TI - Primary Care Digest. PMID- 27452693 TI - Selected National Meetings. PMID- 27452698 TI - Letters. PMID- 27452699 TI - A need to know. PMID- 27452701 TI - Brief reports. PMID- 27452696 TI - Plexins function in epithelial repair in both Drosophila and zebrafish. AB - In most multicellular organisms, homeostasis is contingent upon maintaining epithelial integrity. When unanticipated insults breach epithelial barriers, dormant programmes of tissue repair are immediately activated. However, many of the mechanisms that repair damaged epithelia remain poorly characterized. Here we describe a role for Plexin A (PlexA), a protein with particularly well characterized roles in axonal pathfinding, in the healing of damaged epithelia in Drosophila. Semaphorins, which are PlexA ligands, also regulate tissue repair. We show that Drosophila PlexA has GAP activity for the Rap1 GTPase, which is known to regulate the stability of adherens junctions. Our observations suggest that the inhibition of Rap1 activity by PlexA in damaged Drosophila epithelia allows epithelial remodelling, thus facilitating wound repair. We also demonstrate a role for Plexin A1, a zebrafish orthologue of Drosophila PlexA, in epithelial repair in zebrafish tail fins. Thus, plexins function in epithelial wound healing in diverse taxa. PMID- 27452702 TI - Scanning sports. PMID- 27452703 TI - Sports Opportunities for the Disabled. PMID- 27452704 TI - Rhapsody of Dawn. PMID- 27452705 TI - Injury Patterns in Cross-Country Skiing. AB - In brief: The low injury rate and health benefits of cross-country skiing make it appropriate for people of all ages, including those with arthritis or physical handicaps. But as its popularity increases, so do injuries. Most are due to cold, trauma, and overuse. Dr. Hixson discusses causes and prevention measures in each category. An understanding of these injury and enhance of cross-country skiing. PMID- 27452706 TI - Biophysical Factors in Range-of-Motion Exercise. AB - In brief: Studies of the physical properties of connective tissue have helped determine improved techniques for therapeutic range-of-motion exercise. Laboratory studies indicate that the best way to permanently lengthen connective tissue structures without compromising their structural integrity is prolonged, low-intensity stretching at elevated tissue temperatures and cooling the tissue before releasing the tension. This article provides some practical therapeutic guidelines for physicians, trainers, and therapists who prescribe range-of-motion exercise for both rehabilitation and physical conditioning. PMID- 27452707 TI - Results of a Required Fitness Program. AB - In brief: Based on the belief that physical education majors should have above average fitness levels, 128 students were instructed to design and execute their own fitness development project to improve strength, endurance, and flexibility. Most relied on jogging, stair running, swimming, and cycling; others performed weight training, calisthenics, racket sports, and aerobic dancing. Generally, both men and women showed statistically significant increases in all the fitness tests. The authors believe that success was encouraged by the students' daily contact with instructors, the fact that their fitness improvement affected their grades, and the knowledge they gained from the course. PMID- 27452709 TI - Coming in sportsmedicine. PMID- 27452708 TI - Physiological Characteristics of Female Masters Swimmers. AB - In brief: Two female masters swimmers, ages 70 and 71, members of the 1980 All American Masters Swim Team, were compared with sedentary females of the same age and with younger female athletes. They had considerably lower percent body fat than normal sedentary women in their 70s and were well within the range for normal women who are 19 to 25 years old. Their Vo2 max values were approximately twice those for normal women in their 70s and comparable to considerably younger nonathletes. These findings show that regular physical training may delay the accumulation of excess fat that accompanies inactivity during aging and may also offset the age-related decline in aerobic power. PMID- 27452710 TI - Is Red Tape Strangling Federal Fitness Programs? AB - Fitness programs for federal employees are sensitive to political influence and have management problems that are unlike those in industry programs. PMID- 27452711 TI - Sled-Skiing: Winter Challenge for the Disabled. AB - Sled-skiing is easy to learn and allows individuals with mobility impairments to share the slopes with Alpine skiers. PMID- 27452715 TI - Differential roles of the dorsal prefrontal and posterior parietal cortices in visual search: a TMS study. AB - Although previous studies have shown that fronto-parietal attentional networks play a crucial role in bottom-up and top-down processes, the relative contribution of the frontal and parietal cortices to these processes remains elusive. Here we used transcranial magnetic stimulation (TMS) to interfere with the activity of the right dorsal prefrontal cortex (DLPFC) or the right posterior parietal cortex (PPC), immediately prior to the onset of the visual search display. Participants searched a target defined by color and orientation in "pop out" or "search" condition. Repetitive TMS was applied to either the right DLPFC or the right PPC on different days. Performance was evaluated at baseline (no TMS), during TMS, and after TMS (Post-session). RTs were prolonged when TMS was applied over the DLPFC in the search, but not in the pop-out condition, relative to the baseline session. In comparison, TMS over the PPC prolonged RTs in the pop out condition, and when the target appeared in the left visual field for the search condition. Taken together these findings provide evidence for a differential role of DLPFC and PPC in the visual search, indicating that DLPFC has a specific involvement in the "search" condition, while PPC is mainly involved in detecting "pop-out" targets. PMID- 27452717 TI - A strategy to minimize the energy offset in carrier injection from excited dyes to inorganic semiconductors for efficient dye-sensitized solar energy conversion. AB - Photoinduced carrier injection from dyes to inorganic semiconductors is a crucial process in various dye-sensitized solar energy conversions such as photovoltaics and photocatalysis. It has been reported that an energy offset larger than 0.2 0.3 eV (threshold value) is required for efficient electron injection from excited dyes to metal-oxide semiconductors such as titanium dioxide (TiO2). Because the energy offset directly causes loss in the potential of injected electrons, it is a crucial issue to minimize the energy offset for efficient solar energy conversions. However, a fundamental understanding of the energy offset, especially the threshold value, has not been obtained yet. In this paper, we report the origin of the threshold value of the energy offset, solving the long-standing questions of why such a large energy offset is necessary for the electron injection and which factors govern the threshold value, and suggest a strategy to minimize the threshold value. The threshold value is determined by the sum of two reorganization energies in one-electron reduction of semiconductors and typically-used donor-acceptor (D-A) dyes. In fact, the estimated values (0.21-0.31 eV) for several D-A dyes are in good agreement with the threshold value, supporting our conclusion. In addition, our results reveal that the threshold value is possible to be reduced by enlarging the pi-conjugated system of the acceptor moiety in dyes and enhancing its structural rigidity. Furthermore, we extend the analysis to hole injection from excited dyes to semiconductors. In this case, the threshold value is given by the sum of two reorganization energies in one-electron oxidation of semiconductors and D-A dyes. PMID- 27452716 TI - Asymmetric distribution of Spalt in Drosophila wing squamous and columnar epithelia ensures correct cell morphogenesis. AB - The Drosophila wing imaginal disc is a sac-like structure that is composed of two opposing cell layers: peripodial epithelium (PE, also known as squamous epithelia) and disc proper (DP, also known as pseudostratified columnar epithelia). The molecular mechanism of cell morphogenesis has been well studied in the DP but not in the PE. Although proper Dpp signalling activity is required for proper PE formation, the detailed regulation mechanism is poorly understood. Here, we found that the Dpp target gene sal is only expressed in DP cells, not in PE cells, although pMad is present in the PE. Increasing Dpp signalling activity cannot activate Sal in PE cells. The absence of Sal in the PE is essential for PE formation. The ectopic expression of sal in PE cells is sufficient to increase the PE cell height. Down-regulation of sal in the DP reduced DP cell height. We further demonstrated that the known PE cell height regulator Lines, which can convert PE into a DP cell fate, is mediated by sal mis-activation in PE because sal-RNAi and lines co-expression largely restores PE cell morphology. By revealing the microtubule distribution, we demonstrated that Lines- and Sal heightened PE cells are morphologically similar to the intermediate cell with cuboidal morphology. PMID- 27452718 TI - Are Vocal Alterations Caused by Smoking in Reinke's Edema in Women Entirely Reversible After Microsurgery and Smoking Cessation? AB - BACKGROUND: Reinke's edema is a benign lesion of the vocal folds that affects chronic smokers, especially women. The voice becomes hoarse and virilized, and the treatment is microsurgery. However, even after surgery and smoking cessation, many patients remain with a deep and hoarse voice. OBJECTIVES: The aim of the present study was to compare pre- and postoperative acoustic and perceptual auditory vocal analyses of women with Reinke's edema and of women in the control group, who were non-smokers. METHODS: A total of 20 women with videolaryngoscopy diagnosis of Reinke's edema who underwent laryngeal microsurgery were evaluated pre- and postoperatively (6 months) by videolaryngoscopy, acoustic voice, and perceptual-auditory analyses (General degree of dysphonia, Roughness, Breathiness, Asthenia, Strain, and Instability [GRBASI] scale), and the maximum phonation times were calculated. The pre- and postoperative parameters of the women with Reinke's edema were compared with those of the control group of women with no laryngeal lesions, smoking habit, or vocal symptoms. RESULTS: Acoustic vocal perceptual-auditory analyses and the maximum phonation time of women with Reinke's edema improved significantly in the postoperative evaluations; nevertheless, 6 months after surgery, their voices became worse than the voices of the women from the control group. CONCLUSIONS: Abnormalities caused by smoking in Reinke's edema in women are not fully reversible with surgery and smoking cessation. One explanation would be the presence of possible structural alterations in fibroblasts caused by the toxicity of cigarette components, resulting in the uncontrolled production of fibrous matrix in the lamina propria, and preventing complete vocal recovery. PMID- 27452719 TI - Monoamine transporter contributions to l-DOPA effects in hemi-parkinsonian rats. AB - l-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to abnormal involuntary movement or dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining dopamine system and the semi-homologous serotonin and norepinephrine systems. Serotonin and norepinephrine transporters (SERT and NET, respectively) have affinity for dopamine uptake especially when dopamine transporters (DAT) are scant. Monoamine reuptake inhibitors have been reported to modulate l-DOPA's anti-parkinsonian effects, but DAT, SERT, and NET's contribution to dyskinesia has not been well delineated. The current investigation sought to uncover the differential expression and function of DAT, SERT, and NET in the l-DOPA-treated hemi-parkinsonian rat. Protein analysis of striatal monoamine transporters in unilateral sham or 6-hydroxydopamine-lesioned rats treated with l-DOPA (0 or 6 mg/kg) showed lesion-induced DAT loss and l-DOPA induced gain in SERT:DAT and NET:DAT ratios in lesioned rats which positively correlated with dyskinesia expression, suggesting functional shifts among monoamine transporters in the dyskinetic state. SERT blockade with citalopram (3, 5 mg/kg) reduced LID while DAT and NET blockade with GBR-12909 (5, 10 mg/kg) and nisoxetine (5, 10 mg/kg), respectively, mildly exacerbated dyskinesia expression. Transporter inhibition did not significantly alter l-DOPA's ability to reverse motor deficit. Overall, DA and DAT loss with l-DOPA treatment appear to precipitate gain in SERT and NET function. Strong correlations with LID and direct behavioral comparisons of selective transporter blockade reveal novel implications for SERT, DAT, and NET as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients. PMID- 27452720 TI - Recombinant soluble IFN receptor (sIFNAR2) exhibits intrinsic therapeutic efficacy in a murine model of Multiple Sclerosis. AB - Endogenous interferon beta (IFNbeta) is an important cytokine involved in several chronic inflammatory diseases, such as Multiple Sclerosis (MS). In spite of the numerous therapeutic approaches available for MS patients, the administration of recombinant IFNbeta continues being one of the first line treatment to these patients. The soluble form of IFNbeta receptor (sIFNAR2) could act as critical regulator of the endogenous and the systemically administered IFNbeta, but whether it functions as an agonist or antagonist of its ligand is not completely elucidated. Morover, the possible role of sIFNAR2 in autoimmune diseases like MS is still unknown and so far overlooked. Here we evaluated the efficacy of the combined therapy of IFNbeta and our recombinant protein analogous to human sIFNAR2 as a treatment in a chronic mice model of MS (CP-EAE). We also tested the effect of the sIFNAR2 administered as a monotherapy over these EAE-animals. The results showed that our recombinant sIFNAR2 protein potentiates the immunomodulatory effects of exogenous IFNbeta in CP-EAE by increasing the reduction of the induced inflammation and the tissue damage. Furthermore, we demonstrate for the first time that sIFNAR2 shows intrinsic properties by modulating the CP-EAE progression and the neuroinflammation processes related to this disease. Another intrinsic activity showed by sIFNAR2 is the inhibition of the T cells proliferation, which increase its potential as therapeutic molecule. PMID- 27452722 TI - Rolling ball sifting algorithm for the augmented visual inspection of carotid bruit auscultation. AB - Carotid bruits are systolic sounds associated with turbulent blood flow through atherosclerotic stenosis in the neck. They are audible intermittent high frequency (above 200 Hz) sounds mixed with background noise and transmitted low frequency (below 100 Hz) heart sounds that wax and wane periodically. It is a nontrivial task to extract both bruits and heart sounds with high fidelity for further computer-aided auscultation and diagnosis. In this paper we propose a rolling ball sifting algorithm that is capable to filter signals with a sharper frequency selectivity mechanism in the time domain. By rolling two balls (one above and one below the signal) of a suitable radius, the balls are large enough to roll over bruits and yet small enough to ride on heart sound waveforms. The high-frequency bruits can then be extracted according to a tangibility criterion by using the local extrema touched by the balls. Similarly, the low-frequency heart sounds can be acquired by a larger radius. By visualizing the periodicity information of both the extracted heart sounds and bruits, the proposed visual inspection method can potentially improve carotid bruit diagnosis accuracy. PMID- 27452723 TI - Subcellular localization of phosphoprotein 8-50 in regenerating muscle. .An immuno-electron microscopic study. AB - Phosphoprotein 8-50, also termed growth-associated protein GAP43, is a membrane bound phosphoprotein expressed in neurons. It is particularly abundant during periods of axonal outgrowth in development and regeneration of the central and peripheral nervous systems. Recently the expression of phosphoprotein 8-50 in regenerating muscle fibers was reported and it was assumed that phosphoprotein 8 50, in muscles, plays a role in the determination of the growth morphology of regenerating muscle fibers. Thus, phosphoprotein 8-50 no longer can be regarded as a neuron-specific molecule. In this paper we study the subcellular localization of phosphoprotein 8-50 in regenerating human skeletal muscle fibers by electron immunohistochemistry. Phosphoprotein 8-50 immunoreactivity is randomly distributed over the nuclear and perinuclear area of regenerating muscle fibers. Previously, by light-microscopy phosphoprotein 8-50 immunoreactivity was demonstrated on the inner face of the sarcolemma in hypotrophic type 1 fibers in congenital fiber type disproportion. It is this distribution of phosphoprotein 8 50 in developmentally disordered myocytes in particular which allows an analogy to the corresponding results found for growing axons. But we did not find subsarcolemmal expression of 8-50 in regenerating muscle fibers. Probably this indicates that there is a difference in 8-50 expression between regeneration of muscle fibers and developmentally retarded/immature myofibers. The presented data suggest that phosphoprotein 8-50 is inserted only stage-dependent in the extending sarcolemma of the growing muscle fiber. Analogously to the nervous system, phosphoprotein 8-50 may serve a local function involving transmembrane signalling by means of calmodulin binding ofphosphoprotein 8-50 and/or phosphoprotein 8-50 phosphorylation and dephosphorylation. [Neural Res 1998; 20: 360-364]. PMID- 27452721 TI - Inhibition of vasopressin V1a receptors in the medioventral bed nucleus of the stria terminalis has sex- and context-specific anxiogenic effects. AB - Vasopressin V1a receptors (V1aR) are thought to contribute to the pathophysiology of psychiatric disorders such as anxiety and depression, sparking interest in V1aR as a therapeutic target. Although the global effects of V1aR have been documented, less is known about the specific neural circuits mediating these effects. Moreover, few studies have examined context-specific V1aR function in both males and females. By using the California mouse, we first studied the effects of sex and social defeat stress on V1aR binding in the forebrain. In females but not males, V1aR binding in the bed nucleus of the stria terminalis (BNST) was negatively correlated to social interaction behavior. In females stress also increased V1aR binding in the nucleus accumbens (NAc). Infusions of V1aR antagonist in to the medioventral BNST (BNSTmv) had anxiogenic effects only in animals naive to defeat. For males, inhibition of V1aR in BNSTmv had anxiogenic effects in social and nonsocial contexts, but for females, anxiogenic effects were limited to social contexts. In stressed females, inhibition of V1aR in the NAc shell had no effect on social interaction behavior, but had an anxiogenic effect in an open field test. These data suggest that V1aR in BNSTmv have anxiolytic and prosocial effects in males, and that in females, prosocial and anxiolytic effects of V1aR appear to be mediated independently by receptors in the BNSTmv and NAc shell, respectively. These findings suggest that males have more overlap in neural circuits modulating anxiety in social and nonsocial contexts than females. PMID- 27452724 TI - The effect of trapidil on the reactive astrocytic proliferation following spinal cord trauma in rats: Light and electron microscopic findings. AB - Platelet-derived growth factor (POCF) released from platelets is one ofthe mitogens in serum, which plays a major role upon the cell biology, namely enhancing cell division and controlling of the maturation, especially upon the glial cell growth and its differentiation. Trapidil, which is an anti-POCF agent, inhibits the effect of POCF, especially the proliferative effects on the glial and tumoral cells in vitro. Previous studies suggested that the astrocytic proliferation stimulated by POCF was inhibited by trapidil via the selective antagonism. Trapidil was not found to have a considerable effect on the prevention of nonpermissive astrocytes in this study. It should be theorised that trapidil, administered immediately even after the trauma, could not reach the injury site in effective measure because of secondary events such as edema and impairment of blood circulation. This suggestion should be another subject for studies concerning trapidil which is administered prior to the trauma. [Neural Res 1998; 20: 365-373]. PMID- 27452726 TI - Molecular characterization of a collection of Neisseria meningitidis isolates from Croatia, June 2009 to January 2014. AB - In the last decade, the incidence of invasive meningococcal disease (IMD) in Croatia remained stable at approximately 1 case per 100 000 inhabitants, affecting mainly children aged <=5 years. We report the molecular characterization of meningococci causing IMD occurring from June 2009 to January 2014 in Croatia. Genomic DNA from 50 clinical isolates was analysed for serogroup, multilocus sequence typing and allele type of the two outer membrane protein genes, porA and the iron-regulated fetA. Furthermore, 22 of them were characterized by using whole-genome sequencing to define the meningococcal vaccine four-component meningococcal serogroup B (4CMenB) antigen genes factor H binding protein (fHbp), Neisseria heparin-binding antigen (nhba) and Neisseria adhesin A (nadA) and the antimicrobial target resistance genes for penicillin (penicillin binding protein 2, penA), ciprofloxacin (DNA gyrase subunit A, gyrA) and rifampicin (beta-subunit of RNA polymerase, rpoB). The Etest was used to phenotypically determine the antimicrobial susceptibility of isolated meningococci. The main serogroup/clonal complex combinations were MenB cc41/44, MenC/cc11, MenW/cc174 and MenY/cc23. PorA P1.7-2, FetA F5-5 and F1-5 were the most represented through the serogroups. Meningococci with decreased susceptibility to penicillin (38.9 %) and one strain resistant to ciprofloxacin were identified. Forty-two percent of MenB showed the presence of at least one of the 4CMenB vaccine antigens (fHbp, NHBA, NadA and PorA). Our findings highlight the genetic variability of meningococci causing IMD in Croatia, especially for the serogroup B. Molecular-based characterization of meningococci is crucial to enhance IMD surveillance and to better plan national immunization programmes. PMID- 27452727 TI - Intercellular signal communication among odontoblasts and trigeminal ganglion neurons via glutamate. AB - Various stimuli to the exposed surface of dentin induce changes in the hydrodynamic force inside the dentinal tubules resulting in dentinal pain. Recent evidences indicate that mechano-sensor channels, such as the transient receptor potential channels, in odontoblasts receive these hydrodynamic forces and trigger the release of ATP to the pulpal neurons, to generate dentinal pain. A recent study, however, has shown that odontoblasts also express glutamate receptors (GluRs). This implies that cells in the dental pulp tissue have the ability to release glutamate, which acts as a functional intercellular mediator to establish inter-odontoblast and odontoblast-trigeminal ganglion (TG) neuron signal communication. To investigate the intercellular signal communication, we applied mechanical stimulation to odontoblasts and measured the intracellular free Ca2+ concentration ([Ca2+]i). During mechanical stimulation in the presence of extracellular Ca2+, we observed a transient [Ca2+]i increase not only in single stimulated odontoblasts, but also in adjacent odontoblasts. We could not observe these responses in the absence of extracellular Ca2+. [Ca2+]i increases in the neighboring odontoblasts during mechanical stimulation of single odontoblasts were inhibited by antagonists of metabotropic glutamate receptors (mGluRs) as well as glutamate-permeable anion channels. In the odontoblast-TG neuron coculture, we observed an increase in [Ca2+]i in the stimulated odontoblasts and TG neurons, in response to direct mechanical stimulation of single odontoblasts. These [Ca2+]i increases in the neighboring TG neurons were inhibited by antagonists for mGluRs. The [Ca2+]i increases in the stimulated odontoblasts were also inhibited by mGluRs antagonists. We further confirmed that the odontoblasts express group I, II, and III mGluRs. However, we could not record any currents evoked from odontoblasts near the mechanically stimulated odontoblast, with or without extracellular Mg2+, indicating that N-methyl-d-aspartic acid receptor does not contribute to inter-odontoblast signal communication. The results suggest that a mechanically stimulated odontoblast is capable of releasing glutamate into the extracellular space via glutamate-permeable anion channels. The released glutamate activates mGluRs on the odontoblasts in an autocrine/paracrine manner, forming an inter-odontoblasts communication, which drives dentin formation via odontoblast-odontoblast signal communication. Glutamate and mGluRs also mediate neurotransmission between the odontoblasts and neurons in the dental pulp to modulate sensory signal transmission for dentinal sensitivity. PMID- 27452728 TI - Immune DNA signature of T-cell infiltration in breast tumor exomes. AB - Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types. The Cancer Genome Atlas (TCGA) represents the largest collection of cancer molecular data, but lacks detailed information about the immune environment. Here, we show that exome reads mapping to the complementarity-determining-region 3 (CDR3) of mature T-cell receptor beta (TCRB) can be used as an immune DNA (iDNA) signature. Specifically, we propose a method to identify CDR3 reads in a breast tumor exome and validate it using deep TCRB sequencing. In 1,078 TCGA breast cancer exomes, the fraction of CDR3 reads was associated with TILs fraction, tumor purity, adaptive immunity gene expression signatures and improved survival in Her2+ patients. Only 2/839 TCRB clonotypes were shared between patients and none associated with a specific HLA allele or somatic driver mutations. The iDNA biomarker enriches the comprehensive dataset collected through TCGA, revealing associations with other molecular features and clinical outcomes. PMID- 27452729 TI - Fuzzy nanostructure growth on Ta/Fe by He plasma irradiation. AB - In this study, we show from helium (He) plasma irradiation to tantalum and iron surfaces that morphology changes in nanoscale occur on the both metals. In particular, from systematic irradiation experiments, it is identified that fuzzy nanostructures are grown on the both metals. The necessary conditions for the morphology changes are discussed based on the experimental results in terms of the helium migration, the physical sputtering, and the shear modulus of materials. Because oxides or oxinitrides of iron and tantalum are thought of as visible light responsive photocatalytic materials, the present work shows wide potential of usage of plasmas as a tool to tailor photocatalytic materials. PMID- 27452730 TI - Fecal Microbiota Therapy as Rescue Therapy for Life-Threatening Clostridium difficile Infection in the Critically Ill: A Small Case Series. PMID- 27452731 TI - Approach for Identifying Human Leukocyte Antigen (HLA)-DR Bound Peptides from Scarce Clinical Samples. AB - Immune-mediated diseases strongly associating with human leukocyte antigen (HLA) alleles are likely linked to specific antigens. These antigens are presented to T cells in the form of peptides bound to HLA molecules on antigen presenting cells, e.g. dendritic cells, macrophages or B cells. The identification of HLA-DR-bound peptides presents a valuable tool to investigate the human immunopeptidome. The lung is likely a key player in the activation of potentially auto-aggressive T cells prior to entering target tissues and inducing autoimmune disease. This makes the lung of exceptional interest and presents an ideal paradigm to study the human immunopeptidome and to identify antigenic peptides.Our previous investigation of HLA-DR peptide presentation in the lung required high numbers of cells (800 * 10(6) bronchoalveolar lavage (BAL) cells). Because BAL from healthy nonsmokers typically contains 10-15 * 10(6) cells, there is a need for a highly sensitive approach to study immunopeptides in the lungs of individual patients and controls.In this work, we analyzed the HLA-DR immunopeptidome in the lung by an optimized methodology to identify HLA-DR-bound peptides from low cell numbers. We used an Epstein-Barr Virus (EBV) immortalized B cell line and bronchoalveolar lavage (BAL) cells obtained from patients with sarcoidosis, an inflammatory T cell driven disease mainly occurring in the lung. Specifically, membrane complexes were isolated prior to immunoprecipitation, eluted peptides were identified by nanoLC-MS/MS and processed using the in-house developed ClusterMHCII software. With the optimized procedure we were able to identify peptides from 10 * 10(6) cells, which on average correspond to 10.9 peptides/million cells in EBV-B cells and 9.4 peptides/million cells in BAL cells. This work presents an optimized approach designed to identify HLA-DR-bound peptides from low numbers of cells, enabling the investigation of the BAL immunopeptidome from individual patients and healthy controls in order to identify disease-associated peptides. PMID- 27452732 TI - A high-content image-based method for quantitatively studying context-dependent cell population dynamics. AB - Tumor progression results from a complex interplay between cellular heterogeneity, treatment response, microenvironment and heterocellular interactions. Existing approaches to characterize this interplay suffer from an inability to distinguish between multiple cell types, often lack environmental context, and are unable to perform multiplex phenotypic profiling of cell populations. Here we present a high-throughput platform for characterizing, with single-cell resolution, the dynamic phenotypic responses (i.e. morphology changes, proliferation, apoptosis) of heterogeneous cell populations both during standard growth and in response to multiple, co-occurring selective pressures. The speed of this platform enables a thorough investigation of the impacts of diverse selective pressures including genetic alterations, therapeutic interventions, heterocellular components and microenvironmental factors. The platform has been applied to both 2D and 3D culture systems and readily distinguishes between (1) cytotoxic versus cytostatic cellular responses; and (2) changes in morphological features over time and in response to perturbation. These important features can directly influence tumor evolution and clinical outcome. Our image-based approach provides a deeper insight into the cellular dynamics and heterogeneity of tumors (or other complex systems), with reduced reagents and time, offering advantages over traditional biological assays. PMID- 27452733 TI - Incidence and Predictors of 30-Day Readmission After Robot-Assisted Radical Prostatectomy. AB - OBJECTIVE: To evaluate the incidence and predictors of 30-day readmission in prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: Overall, 1402 consecutive PCa patients treated with RARP at a single center between 2006 and 2013 were identified. Uni- and multivariate logistic regression analyses assessed predictors of 30-day readmission after surgery. RESULTS: Overall, 38 patients (2.7%) experienced hospital readmission within 30 days after discharge. The most common causes of rehospitalization were fever in 12 patients (31.6%), lymphoceles in 11 (28.9%), and urine leak in 6 (15.8%). By multivariable analyses, D'Amico risk group and occurrence of postoperative complications (odds ratio [OR], 2.89) represented independent predictors of 30-day readmission (all P <= .02). When analyzing the type of complication associated with the risk of readmission, fever (OR, 6.19; P = .01), urine leak (OR, 10.83; P < .01) and cardiocirculatory complications (OR, 18.57; P < .001) were significantly associated with 30-day readmission. CONCLUSION: Patients undergoing RARP have a relatively low risk of 30-day readmission (2.7%). The occurrence of an early postoperative complication and a higher D'Amico risk group were independent predictors of 30-day readmission. In addition, fever, urine leak, and cardiocirculatory complications are significantly associated with a higher risk of readmission. PMID- 27452734 TI - Platelet glycoproteins associated with aspirin-treatment upon platelet activation. AB - Platelet glycoproteins are known to play central roles in hemostasis and vascular integrity and have pathologic roles in vascular occlusive diseases such as myocardial infarction and stroke. Characterizing glycoproteins within and secreted by platelets can provide insight into the mechanisms that underlie vascular pathologies and the therapeutic benefits or failure of anti-platelet agents. To study the impact of aspirin, which is commonly prescribed for primary and secondary cardiovascular prevention, on the platelet glycoproteome, we evaluated washed platelets from ten donors. The platelet glycoproteome, was studied using an iTRAQ in resting and stimulated states and with and without aspirin treatment. Using solid phase extraction of glycosite-containing peptides (SPEG), we were able to identify 799 unique N-linked glycosylation sites (glycosites) in platelets, representing the largest and the most comprehensive analysis to date. We were able to identity a number of glycoproteins impacted by aspirin treatment, which we validated using global proteomics analysis of platelets and their secreted proteins. In our analyses, metallopeptidase inhibitor 1 (TIMP1) was the single most significantly affected glycoprotein by aspirin treatment. ELISA assays confirmed proteomic results and validated our strategy. Functional analysis demonstrated that TIMP1 levels were highly correlated with platelet reactivity in vitro, with a correlation coefficient of 0.5. The release of TIMP1 from platelets, which was previously unknown to be affected by aspirin treatment, may play important roles in hemostasis and/or vascular integrity. If validated, our findings may be useful for developing assays that assess platelet response to aspirin or other anti-platelet therapies. PMID- 27452735 TI - Changes in serum NGF levels after the exercise load in dogs: a pilot study. AB - Serum nerve growth factor (NGF) levels are increased by the external stress in mice, humans and horses; however, similar variations have been unclear in dogs. Since dogs are usually subjected to conditions of work, exercise and activity as important partners of humans, we measured serum NGF levels post-exercise and compared them with serum cortisol levels, as a biomarker of physical stress. Serum cortisol levels were immediately elevated post-exercise and returned to basal levels within 1 hr. On the other hand, serum NGF levels were significantly increased 1 hr post-exercise and gradually returned to basal levels. Further research is necessary; nevertheless, we have demonstrated for the first time that serum NGF levels respond to exercise stress in dogs. PMID- 27452736 TI - Effects of D-allulose on glucose metabolism after the administration of sugar or food in healthy dogs. AB - D-allulose is a C-3 epimer of D-fructose and has recently been investigated for its hypoglycemic effects. In the present study, the effects of D-allulose on glucose metabolism were evaluated in healthy dogs administrated sugar or food. The oral administrations of D-allulose decreased plasma glucose concentrations after oral glucose or maltose administration, with a diminished plasma insulin rise. The glucose suppressive effect of D-allulose was also observed after intravenous glucose administrations without increase in plasma insulin concentration. In contrast, D-allulose showed no effect on plasma glucose and insulin concentrations after feeding. The present results suggest that D-allulose administration may be beneficial in dogs with impaired glucose tolerance. Further studies investigating the therapeutic efficacy of D-allulose in diabetic dogs are required. PMID- 27452737 TI - Potential risk of AMC ceramic liner for dissociation after square seating. PMID- 27452738 TI - The Japanese Orthopedic Association Back Pain Evaluation Questionnaire: A Turkish validation study. AB - BACKGROUND: The aim of this study was to apply cross-cultural adaptation and validity assessment to the Turkish translation of the Japanese Orthopedic Association Back Pain Evaluation Questionnaire applied to patients conservatively monitored for lumbar disc hernia and narrowing of the lumbar canal. METHODS: The questionnaire was translated into Turkish based on guidelines. In respect of the comprehensibility of the obtained pre-final version of the questionnaire, a pilot test was applied to 20 healthy individuals. The patients were requested to complete the final version of the questionnaire after an orthopedic and physical therapy assistant doctor (resident) had completed the diagnosis and demographic information. To evaluate the retest reliability, the test was applied a second time, 14 days (+/-3 days) after the first application, again in the Orthopedics and Physical Therapy Outpatient Clinic. RESULTS: The study was completed with a total of 215 individuals, comprising 107 patients and 108 healthy volunteers. When Turkish version of the questionnaire scale was evaluated of the patients and healthy volunteers together, the internal consistency was determined at the levels of Cronbach's alpha excellent. The lowest correlations of all the questionnaire scale items with the scale sub-dimensions was at the level of r = 0.509, which demonstrated that there was a sufficient validity level of the Turkish translated questionnaire scale. A statistically significant direct correlation at a high level was seen between the pre and post points in all the scale sub-dimensions. CONCLUSIONS: The results of the current study showed that Turkish version of the questionnaire had sufficient reliability and validity in the evaluation of low back pain and resulting dysfunction and disability in patients with LDH and narrowing of the lumbar canal. PMID- 27452739 TI - Prevalence of radiological findings related to femoroacetabular impingement in professional baseball players in Japan. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a known patho-mechanism that causes hip pain and osteoarthritis (OA) and is considered uncommon in Japan, while secondary OA due to hip dysplasia is considered common. However, no studies have specifically targeted athletes in Japan and/or Asia. This study aimed to determine FAI prevalence using radiological findings among baseball players playing on a professional, Japanese team. METHODS: We retrospectively assessed 63 plain anteroposterior (AP) hip radiographs (126 hips from 47 [74.6%] Asian players and 16 [25.3%] non-Asian players) obtained for medical evaluations. Radiographs were used to measure lateral center-edge (LCE) angle; acetabular roof obliquity (ARO); and the presence of crossover sign (COS), posterior wall sign (PWS), coxa profunda, pistol grip deformity, herniation pits, and labral ossification. Further, the prevalence of radiographic indicators related to FAI was compared between Asian and non-Asian players. RESULTS: In the 126 hips examined, 10 hips (7.94%) were classified as having hip dysplasia (LCE angles < 20 degrees ). Of the remaining 116 hips, eight (6.9%) had LCE angles > 40 degrees , and 24 hips (20.7%) had AROs of <0 degrees , indicating acetabular over coverage. In Asian players, COS was identified in 47 hips (54.0%), positive PWS in 38 hips (43.7%), positive coxa profunda in 8 hips (9.2%), and pistol grip deformity in 37 hips (42.5%). Further, herniation pits and positive labral ossification were identified in 25 (28.7%) and 11 (12.6%) hips, respectively. A comparative review of COS prevalence (Asians vs. non-Asians) revealed that COS was significantly higher in Asian players. No differences were observed in the mean LCE angle, mean ARO, or other radiographic indicators. CONCLUSIONS: Radiological indicators related to FAI were identified in 76.6% (72/94 hips) of the Asian professional baseball players; this prevalence was considerably higher than that reported for general Asian populations. We consider that elite Asian athletes may frequently show morphological deformities related to FAI. PMID- 27452740 TI - Recurrence of acute myelogenous leukemia with granulocytic sarcoma-associated tarsal tunnel syndrome in an elderly patient. PMID- 27452741 TI - Correlation between coxa profunda and morphological parameters of acetabular coverage in a Japanese cohort: A CT study. AB - BACKGROUND: Coxa profunda is generally considered an indicator of acetabular overcoverage. However, recent studies have opposed this view. The correlation between coxa profunda and acetabular overcoverage thus remains controversial. The purpose of this study was to investigate the prevalence of coxa profunda and the association between coxa profunda and acetabular coverage based on sex in Japanese subjects using computed tomography. METHODS: We reviewed the computed tomography scans of 151 Japanese consecutive patients (302 hips) aged <50 years who underwent abdominopelvic computed tomography for symptoms unrelated to hip disease. Coxa profunda was diagnosed when the floor of the acetabular fossa touched or was medial to the ilioischial line. We measured the lateral center edge angle, acetabular roof obliquity angle, acetabular version, and anterior and posterior acetabular sector angles as parameters of acetabular coverage. RESULTS: Coxa profunda was observed in 45.7% of all subjects, and was more common in females (63.0%) than in males (29.5%). We found no significant differences in the incidence of coxa profunda among subjects with dysplasia, overcoverage, and normal coverage. Males with coxa profunda showed significantly greater lateral center edge angle, anterior acetabular sector angle, and lower acetabular roof obliquity angle, whereas anterior and posterior acetabular sector angles were greater in all subjects and females with coxa profunda. Coxa profunda showed poor sensitivity (57.7%) and specificity (56.8%) for detecting overcoverage in all subjects. CONCLUSIONS: Coxa profunda is a common radiographic feature in Japanese patients, especially in women. Coxa profunda may be less useful for diagnosing acetabular overcoverage because of its common occurrence with various hip morphologies and its poor specificity for detecting acetabular overcoverage. However, men with coxa profunda have greater acetabular coverage, so coxa profunda may contribute to acetabular coverage in men. We should take into account that coxa profunda may have different implications between the sexes. PMID- 27452742 TI - Myofibroma arising from a digital artery. PMID- 27452743 TI - Effects of two different degrees of lateral-wedge insoles on unilateral lower extremity load-bearing line in patients with medial knee osteoarthritis. AB - OBJECTIVE: The aim of this study is to assess the effect of 5 and 10 degrees lateral-wedge insoles on unilateral lower extremity load carrying line in patients with medial knee osteoarthritis using the L.A.S.A.R. posture alignment system. PATIENTS AND METHODS: Twenty subjects (10 females and 10 males, mean age 67.7 +/- 5.4 years (range: 58-78) with bilateral medial knee osteoarthritis were included in the study. The laser line projected on the person by the L.A.S.A.R. posture alignment system showed joint load carrying line. The location of the joint load carrying line in static standing with one foot on the force plate was assessed with barefoot, and 5 degrees and 10 degrees lateral-wedge insoles. Displacement of the load carrying line was measured using a ruler placed tangentially to the patella at the level of joint line. RESULTS: The load carrying lines measured with 5 degrees and 10 degrees lateral-wedge insoles were significantly laterally located compared to that without wearing insole (p < 0.001). 10 degrees lateral-wedge insole caused a significant more lateral shifting of the load carrying line than 5 degrees lateral-wedge insole (p < 0.001). CONCLUSION: Both wedge insoles was effective in moving of the unilateral lower extremity load carrying line to the lateral. Lateral wedged insoles are biomechanically effective and reduce loading of the medial compartment in patients with medial knee osteoarthritis. PMID- 27452744 TI - A giant clear cell sarcoma on right scapular: A case report. AB - Clear-cell sarcoma is a rare and malignant soft tissue tumor most commonly located at the distal end of extremities and rarely at the trunk. Data on the clinical features of the tumor is limited, complicating the analysis of prognosis and establishment of treatment protocols. In our study, we present a case diagnosed with clear-cell sarcoma in his right scapula and treated with tumor resection and chemotherapy, combination of dacarbazine, pharmorubicin and cisplatin. The patient died due to multiple organ failure eight months after operation. Early diagnosis, attentive care, and extended surgical resection combined with adjuvant therapy is of essence in treatment of clear-cell sarcoma. PMID- 27452745 TI - Optimal postoperative nutrition support for patients with gastrointestinal malignancy: A systematic review and meta-analysis. AB - OBJECTIVE: To improve clinical outcomes, parenteral nutrition, standard enteral nutrition and immuno-enhanced nutrition are widely used in the gastrointestinal tumor patients undergoing surgery, but the optimal management of postoperative nutrition support remains uncertain. METHODS: We systematically searched the PUBMED, EMBASE and CNKI to identify latent studies which the effects of standard EN compared with PN or IEN on gastrointestinal tumor patients until the end of November, 2015. The quality of included trials was assessed according to the handbook for Cochrane reviewer. Statistical analysis was carried out by RevMan5.1 software. RESULTS: 30 randomized controlled trials containing 3854 patients were contained in our meta-analysis, the results indicated that postoperative SEN could absolutely reduce the incidence of postoperative infectious (P < 0.00001) and non-infectious complications (P = 0.0003), together with its positive effect on the length of hospital stay (P < 0.00001). Additionally, enteral nutrition enhanced with immune stimulation was confirmed to be better, with a significant difference between groups in terms of total infectious (P < 0.00001) and non infectious complications (P = 0.04), and IEN could also significantly shorten the length of hospital stay (P < 0.00001). CONCLUSION: Early use of Enteral nutrition in digestive tumor patients after surgery could significantly reduce the postoperative complications and shorten the length of hospital stay, IEN should be the optimal management, while the use of parenteral nutrition should be restrict to few patients with severe intolerance to enteral nutrition. PMID- 27452746 TI - [Persistent inflammation immunosuppression catabolism syndrome: a special type of chronic critical illness]. AB - After the concept of "chronic critical illness (CCI)" was proposed, the new concept persistent inflammation immunosuppression catabolism syndrome (PICS) is present recently. Patients with PICS are manifested by fast decreasing body weight, poor nutritional status, long-term immunosuppression and repeated nosocomial infections. These patients are faced with great challenges of persistent inflammation, acquired immunosuppression and high catabolism, which finally results in repeated nosocomial infections, prolonged hospital stay and increased mortality. At present, main problems of PICS diagnosis standard include varying length of ICU stay, difference in normal C reactive protein value, poor value of nutrition indexes, absence of clinical verification. Though associated pathophysiology mechanism is not clear, PICS is preventable and magageable with certain therapy, including early comprehensive prevention and treatment focused on infection control for CCI patients to stop the progression of PICS, application of immune modulator to improve immune function and prognosis of patients, and reasonable nutritional support and treatment. Besides, through the analysis of the association between PICS and CCI, authors draw a conclusion that PICS is a new phenotype of CCI, and immune paralysis is its main feature. PMID- 27452747 TI - [Prevention and management of refeeding syndrome in patients with chronic critical illness]. AB - Nutritional support is an important means to treat the patients with chronic critical illness for commonly associated malnutrition. Refeeding syndrome is a serious complication during the process, mainly manifested as severe electrolyte with hypophosphataemia being the most common. Refeeding syndrome is not uncommon but it is often ignored. In our future clinical work, we need to recognize this chinical situation and use preventative and treatment measures. According to NICE clinical nutrition guideline, we discussed the risk factors, treatment methods and preventive measures of refeeding syndrome in patients with chronic critical illness. We argued that for patients with high risk refeeding syndrome, nutritional support treatment should be initially low calorie and slowly increased to complete requirement. Circulation capacity should be recovered, fluid balance must be closely monitored and supplement of vitamins, microelement, electrolytes should be noted. After the emergence of refeeding syndrome, we should reduce or even stop the calorie intake, give an active treatment for electrolyte disorder, provide vitamin B, and maintain the functions of multiple organs. PMID- 27452748 TI - [Maintenance of intestinal barrier function in patients with chronic critical illness]. AB - The syndrome known as chronic critical illness (CCI) is defined as that critically ill patients survive their initial acute illness but go on to experience persistent organ failures necessitating prolonged intensive care. Intestinal barrier is the physical barrier that separates the internal and external environments and prevents the invasion of pathogenic antigens. Due to its pathogenesis, many CCI patients have injured intestinal barrier. Gut is the motor organ of stress responses, and gut-associated infections may initiate multiple organ dysfunction. In this way, it is important to maintain intestinal barrier of such patients. Apart from treatment for underlying diseases, resuscitation aiming at improving tissue perfusion, appropriate nutritional support, protection of normal intestinal flora, and provision of probiotics can maintain intestinal barrier of CCI patients. The maintenance and support of barrier function requires attention. PMID- 27452749 TI - [Effect of exercise training on rehabilitation of the chronic critical illness patients]. AB - Over the past decades, the evolution of the techniques used in the intensive care has led on one side to better survival rates in ICU patients. On the other side, it has resulted in a growing number of patients who survive an acute event to chronic condition, and who then become dependent on one or more life support treatments. Such patients are called chronic critical illness(CCI) patients. Even these patients can dismiss from intensive care unit (ICU) or transfer to specialized rehabilitation care settings, the mortality of these patients is still very high. Therefore, how to promote the rehabilitation of CCI patients is one of the most important research points of epidemiology, public health and social economics. Exercise training can promote rehabilitation, improve quality of life and independent functional status in these patients, which should be used as one of the standard treatment protocols for CCI patients. PMID- 27452750 TI - [Opinions on the prevention and treatment of chronic critical illness]. AB - Chronic critical illness (CCI) is an inevitable result of overpopulation and aging, as well as the development of medicine. The number of CCI patients will constantly increase and become an unaffordable economic burden for families, societies and countries. CCI could be prevented by multiple measures. Firstly, doctors must know about the pathophysiology and etiology of the disease. When providing organ function support for CCI patient, we have to know and treat the cause of the disease as early as possible. Secondly, we need to precisely monitor the insults caused by the disease and/or improper host response to the disease, evaluate the organ reserve function, and predict the outcomes and life quality after discharging from hospital. In addition, it is necessary to strengthen the humanity training of health care workers, publicize the correct thanatopsis in the whole society that every life is "born to die", and define the core role of medicine as "to comfort always". PMID- 27452751 TI - [Rationality of N3 classification and its sub-classification in TNM classification system for advanced gastric cancer]. AB - OBJECTIVE: To investigate the rationality of N3 classification and its sub classification in the 7th UICC/AJCC TNM classification system. METHODS: Clinicopathological data of 610 patients with stage N3 advanced gastric cancer who underwent standard D2 and D2+ radical surgery at the Department of Surgical Oncology, The First Hospital of China Medical University, from January 1980 to March 2010 were analyzed retrospectively. Patients were divided into N3a and N3b groups, and clinicopathological characteristics and prognosis were compared between N3a and N3b patients. Overall survival rate was determined using the Kaplan-Meier estimator. The log-rank test was used to identify differences between the survival curves of different groups. In multivariate analysis, Cox proportional hazard model was used to identify independent factors associated with prognosis. RESULTS: Among 610 patients, 426 were men and 184 were women, 394 were N3a and 216 were N3b, with a mean age of(57+/-11) years old (range 23 to 83). A total of 19 842 lymph nodes were examined, in which 9 575 nodes were positive, with the metastatic ratio of 48.3%. The 5-year overall survival rate was 20.0%. Univariate analysis of prognostic factors suggested that tumor location (P=0.000), tumor size (P=0.003), Borrmann type (P=0.000), pathologic type (P=0.043), lymphatic vessel invasion (P=0.000), growth pattern (P=0.019), invasion depth (P=0.000), resection extent (P=0.000) and N3 sub-classification (P=0.000) were significantly associated with the prognosis of N3 patients. Further analysis showed that tumor size (P=0.028), invasion depth (P=0.000) and gastric resection extent (P=0.002) were significantly associated with the prognosis of N3a patients, while Borrmann type (P=0.034), lymphatic vessel invasion (P=0.002), invasion depth (P=0.008) and resection extent (P=0.003) were significantly associated with the prognosis of N3b patients. Multivariate analysis revealed that lymphatic vessel invasion (P=0.009), resection extent (P=0.001), invasion depth (P=0.000) and N3 sub-classification (P=0.000) were independent prognostic factors of N3 patients; resection extent (P=0.004) and invasion depth (P=0.001) were independent prognostic factors of N3a patients; lymphatic vessel invasion (P=0.006) and invasion depth (P=0.009) were independent prognostic factors of N3b patients. Comparison of 5-year survival rate revealed that there was significant difference between T2-4N3a and T2-4N3b patients (P=0.000), while there was no significant difference between T2N3a and T2N3b patients (P=0.140). On the contrary, there were significant differences between T3N3a and T3N3b patients, T4aN3a and T4aN3b patients, T4bN3a and T4bN3b patients, respectively (all P<0.05). Further comparison demonstrated that there were significant differences between T4aN3a and T4bN3a patients, T4aN3b and T4bN3b patients, respectively (P=0.000, P=0.041). Besides, there were no significant differences in 5-year survival rate between T2N3 (at present, staged as III(A), T3N3a (III(B) and T4aN3a (III(C) patients(P=0.506), and T3N3b (III(B), T4aN3b (III(C) and T4bN3a (III(C) patients(P=0.283), respectively. CONCLUSIONS: N3 sub classification should be included in the final TNM classification system. It is suggested that T2N3, T3N3a and T4aN3a may be categorized into III(A stage, T3N3b, T4aN3b and T4bN3a may be categorized into III(B stage,T4bN3b may be categorized into III(C stage or IIII( stage. PMID- 27452752 TI - [Analysis of risk factors and prognosis of esophagojejunal anastomotic leakage in gastric cancer patients after curative total gastrectomy]. AB - OBJECTIVE: To identify the risk factors of esophagojejunal anastomotic leakage (EJAL) and its impact on prognosis of gastric cancer patients after curative total gastrectomy. METHODS: Clinical and follow-up data of 1254 gastric cancer patients who underwent radical total gastrectomy at the Department of Digestive Surgery, Xijing Hospital, from January 2012 to May 2015 were retrospectively collected. Risk factors of EJAL and prognostic factors of patients were analyzed respectively. In order to reduce the influences of other prognostic factors on survival, patients with and without EJAL were selected using Gmatch methods based on the results of prognostic factor analysis. Survival of those with or without EJAL was examined before and after match respectively. RESULTS: EJAL occurred in 31 of 1 254 patients(2.5%). The leakage was diagnosed at a median of 6 (range, 4 12) days after surgery. Multivariate analysis demonstrated that preoperative low serum albumin(<35 g/L)(P=0.018), pulmonary insufficiency(P=0.006), long duration of operation(>=240 min)(P=0.001) were independent risk factors of EJAL. All the patients were followed up for 3-40(median 18) months. Multivariate analysis showed that age(>=65, P=0.000), intraoperative blood transfusion (P=0.016), EJAL (P=0.000), tumor location (distal, P=0.020; total, P=0.001), depth of invasion (T4, P=0.005) and lymph node metastasis (N2, P=0.002, N3, P=0.000) were prognostic predictors. Twenty-six patients with EJAL were successfully matched to 104 patients without EJAL in a ratio of 1/4 ratio. Patients with EJAL had a significantly worse overall 3-year survival rate than those without (44.3% vs. 66.7%, P=0.002). CONCLUSIONS: EJAL after curative total gastrectomy leads to worse survival. Patients with preoperative low serum albumin, pulmonary insufficiency and long duration of operation should be taken care of during perioperative period to prevent the occurrence of EJAL. PMID- 27452753 TI - [Efficacy and safety of the Jinling procedure in the treatment of adult Hirschsprung disease]. AB - OBJECTIVE: To investigate the safety, efficacy and long-term outcomes of Jinling procedure in the treatment of adult Hirschsprung disease. METHODS: Clinical and follow-up data of 125 patients with adult Hirschsprung disease undergoing Jinling procedure at the Department of General Surgery between January 2000 and January 2013 were summarized. All the patients were diagnosed by CT, barium enema, anorectal pressure detection and pathology examination. Abdominal symptoms, gastrointestinal quality of life index(GIQLI, the lower score, the worse quality of life), Wexner constipation score (higher score indicated worse symptom), defecography (evaluation included rectocele, mucosal prolapse, intramucosal intussusception, perineal prolapse) and other operative complications were compared before and after operation. RESULTS: Among 125 patients, 69 were male and 56 were female with median age of (41.2+/-15.5) (18 to 75) years. The follow up rates were 94.4%(118/125), 92.0%(115/125), 89.6%(112/125) and 88.0%(110/125) at postoperative months 1, 3, 6, and 12. Incidences of abdominal distension and abdominal pain were 100% and 82.4%(103/125) before operation, and were 7.3%(8/110) and 20.9%(23/110) at 12 months after surgery. Wexner score was significantly lower at postoperative months 1(8.7+/-2.9), 3 (7.2+/-2.8), 6(6.7+/ 2.2) and 12(6.3+/-1.7) than that before operation (21.4+/-7.2) (P<0.01). GIQLI score was 51.6+/-11.9 before operation, though it decreased at 1 month (47.3+/ 5.5)(P<0.05) after surgery, but increased significantly at postoperative months 3, 6, 12(68.9+/-8.0, 96.5+/-8.2, 103.2+/-8.6)(P<0.01). Abnormal rate of defecography was 70.4%(81/115), 48.2%(54/112) and 27.3%(30/110) at postoperative months 3, 6, 12, which was significantly lower than 91.2%(114/125) before operation (P<0.01). Morbidity of postoperative complication was 29.6%(37/125), including 5 cases of surgical site infection (4.0%), 2 of anastomotic bleeding (1.6%), 8 of anastomotic leakage (6.4%, one died of severe abdominal infection), 4 of urinary retention (3.2%), 3 of recurrent constipation (2.4%, without megacolon relapse), 11 of bowel obstruction (8.8%), 2 of anastomotic stricture(1.6%) and 2 of refractory staphylococcus aureus enteritis (1.6%, diagnosed by stool smear and culture, and both died finally). CONCLUSION: Jinling procedure is a safe and effective surgical procedure for adult Hirschsprung's disease. PMID- 27452754 TI - [Short-term efficacy comparison between preoperative three dimensional conformal radiotherapy and volumetric modulated arc therapy concurrently combined with chemotherapy in the treatment of locally advanced rectal carcinoma]. AB - OBJECTIVE: To compare the short-term efficacy and treatment-related adverse reaction between preoperative three dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) concurrently combined with chemotherapy in the treatment of locally advanced rectal carcinoma (LARC). METHODS: Clinical data of 334 patients with LARC undergoing preoperative 3D CRT(172 cases) or VMAT(162 cases) with concurrent Xelox chemotherapy (main protocol: capecitabine plus oxaliplatin) and surgery in Sun Yat-sen University Cancer Center from May 2007 to April 2013 were retrospectively analyzed. The total radiation dose of VMAT group was: 50 Gy/2.0 Gy per fraction *23 fractions for planning target volume 1(PTV1) and 46 Gy/1.84 Gy per fraction *25 fractions for PTV2; the total radiation dose of 3D-CRT group was: 46 Gy/2.0 Gy per fraction *23 fractions for PTV. The treatment-related adverse reaction of both groups during chemoradiotherapy was measured according to the criteria of Common Terminology Criteria for Adverse Events v3.0 (CTCAE 3.0). Rate of adverse reaction and short-term efficacy between 3D-CRT and VMAT group were compared, in terms of radiotherapy break, hematological and non-hematological toxicity, average duration of surgery and perioperative hospitalization, intraoperative blood loss, surgical procedures, R0 excision, sphincter preservation, postoperative complications, pathological complete response (pCR), and postoperative pathological staging. RESULTS: There were no significant differences in baseline clinical parameters between 3D-CRT and VMAT group (all P>0.05), except for the distance from lower tumor margin to anal verge (P=0.009). The median radiation dose for all the patients was 46 (45 to 70) Gy. There was no significant difference in the rate of radiotherapy cessation between 3D-CRT and VMAT group [1.7%(3/172) vs. 1.2%(2/162), P=1.000]. During concurrent chemotherapy, incidences of grade 2 to 3 hematological toxicities, grade 2 diarrhea, and grade 3 non-hematological toxicities were not significantly different(all P>0.05), while in grade 2 non-hematological toxicities, ratio of radiodermatitis and hand-foot syndrome was higher in VMAT group as compared to 3D CRT group [25.9%(42/162) vs. 10.5%(18/172), P=0.000; 3.7%(6/162) vs. 0, P=0.012]. There was no grade 4 adverse event in both groups. Surgical procedure, average duration of surgery, R0 excision, anus preservation, postoperative complications, pCR, and postoperative pathological staging were not significantly different(all P>0.05). As compared to 3D-CRT group, VMAT group had less intraoperative blood loss [(114.6+/-100) ml vs. (169+/-143.9) ml, P<0.001] and shorter perioperative hospitalization [16(8 to 84) d vs. 20(10 to 47) d, P<0.001]. There was no death case in two groups within 30 days after operation. CONCLUSIONS: Compared with 3D CRT technique, preoperative VMAT technique can not significantly reduce the incidence of treatment-related adverse reaction and improve the short-term efficacy in the treatment of LARC. PMID- 27452755 TI - [Analysis of transmission characteristics of digestive tracts in 1890 patients with chronic constipation]. AB - OBJECTIVE: To investigate the characteristics of gastrointestinal transit in chronic constipation patients depending on a small amount barium(SAB) gastrointestinal transit test. METHODS: Imaging data of 1890 cases with chronic constipation diagnosed with Rome III( criteria undergoing the SAB gastrointestinal transit test at Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University from January 2009 to March 2015 were retrospectively analyzed. All the patients took 20 g medical barium sulfate diluted in porridge and erect position abdominal X-ray photographs were then taken at 4, 8, 12, 24 hours after meal and once in every 24 hour sequentially. Transit characteristics of whole gut and various segments, including stomach, small intestine, right hemicolon, left hemicolon and rectum were assessed according to the predetermined criteria. RESULTS: All the 1890 patients showed good compliance with the complete test. Among these patients, 794 cases(42%) were diagnosed as normal transit and 1096 cases(58%) as gastrointestinal slow transit. Classified by the site of slow transit, 151 cases(8%) were abnormal gastric transit, 175(9%) cases were abnormal small intestinal transit, 986(52%) cases were slow right hemicolon transit, 1039 cases(55%) were slow left hemicolon transit, 139 cases(7%) were outlet obstruction. Among the 1096 patients with slow gut transit, 907 cases(83%) were multiple segments slow transit and 189 cases(17%) were single segment slow transit. Among 907 patients with multiple segmental slow transit, 668 cases(74%) were total colon slow transit, 61 cases(7%) were colonic slow transit combined with outlet obstruction, 138 cases(15%) were small intestine slow transit coincided with colon slow transit, 40 cases(4%) were total segments slow transit in the whole gut. Of 189 cases of single segment slow transit, 17 cases(9%) were unique gastric delayed empting, 37 cases(20%) were unitary small intestine transit dysfunction, 19 cases(10%) were right hemicolon transit defect, 78 cases(41%) were left hemicolon transit deterioration, 38 cases(20%) were outlet obstruction. CONCLUSIONS: The characteristics of gastrointestinal transit test in patients with chronic constipation varied from each other. Majority presents multi-segment slow transit combined with colon slow transit. SAB gastrointestinal transit test is helpful for surveying the transit characteristics of each segment of gut and worth clinical generalization and application. PMID- 27452756 TI - [Analysis of metastatic patterns after curative colorectal cancer surgery based on primary tumor location]. AB - OBJECTIVE: To evaluate metastatic patterns of colorectal cancer following curative surgery based on primary tumor location in order to provide evidence for the decision of individualized adjuvant therapy and postoperative follow-up. METHODS: Clinical and follow-up data of 904 patients who underwent curative colorectal cancer in The Affiliated Tumor Hospital of Zhengzhou University from October 2004 to October 2012 with complete follow-up data were analyzed retrospectively. A total 274 patients belonged to right-sided colon cancer group (cecum, ascending, hepatic flexure, and transverse colon), 243 belonged to left sided colon cancer group(splenic flexure, descending, and sigmoid colon), and 387 belonged to rectal cancer group. The overall rate of distal metastasis and site specific metastasis rates (liver, lung, and peritoneum) were compared among these 3 groups. RESULTS: The cohort patients had a median follow-up of 37(4-122) months, and the median follow-up duration was similar in right-sided, left-sided, and rectal cancer groups with 39(5-119), 39(6-122) and 36(5-121) months(P=0.513). During the follow-up period, 44 patients (4.9%) had local recurrence alone, 137 (15.2%) distal metastasis alone, and 30(3.3%) local recurrence combined with distal metastasis. Compared to right-sided colon cancer group, rectal and left sided cancer groups had significantly higher overall metastasis rates [23.5% (91/387), 17.3% (42/243) vs. 12.0% (33/274), P=0.000). With respect to specific regions, lung metastasis rate in rectal cancer group was 9.3%, which was significantly higher than that in left-sided(4.5%) and right-sided colon cancer group(2.6%)(P=0.001). Other sites of metastasis did not yield significant differences, including liver(P=0.130) and peritoneum(P=0.858). CONCLUSIONS: Cancer location may be used as a reference of personalized adjuvant therapy and postoperative follow-up surveillance programs. Lower threshold for adjuvant therapy in rectal and left-sided colon cancers, and more aggressive surveillance for lung metastasis by chest X-ray or CT should be considered. PMID- 27452757 TI - [Comparison of long-term survival and postoperative complications between Billroth I( and II( reconstruction in patients with distal gastric cancer]. AB - OBJECTIVE: To compare the long-term survival and postoperative complications of distal gastric cancer patients between Billroth I((BI() and Billroth II((BII() reconstruction. METHODS: Clinicopathological data of 992 patients with distal gastric cancer who underwent D2 curative gastrectomy in our department from May 2008 to April 2015 were recorded, including 207 patients of BI( reconstruction and 785 of BII( reconstruction, were retrospectively analyzed. Patients presenting a previous history of cancer, gastric resection or cytotoxic chemotherapy, and those presenting liver or intraperitoneal tumor dissemination or unresectable infiltration into contiguous organs were excluded. Patients in BI( and BII( group were selected using gmatch methods based on age (+/-10 years), gender, tumor size (+/-1 cm), differentiated degree and depth of invasion in order to reduce the selection bias of clinicopathological characteristics. The final number of patients matched was 191 respectively. RESULTS: Compared with BII( group, the BI( group had a significantly shorter operation time (181.7 min vs. 220.7 min, P=0.000) and a shorter postoperative hospitalization stay (7.6 days vs. 8.1 days, P=0.046). The postoperative complications including anastomotic leakage, wound dehiscence, wound infection, intraperitoneal hemorrhage, intestinal obstruction, duodenal stump fistula, pulmonary infection and fever had no significant difference(P>0.05). Three-year survival between two groups was comparable (82.9% vs. 78.7%, P=0.379). CONCLUSIONS: Compared with BII(, BI( reconstruction is more suitable for patients with distal gastric cancer. PMID- 27452758 TI - [Detection and analysis of the characteristic expression of microRNAs of anal fistula patients]. AB - OBJECTIVE: To detect and analyze the characteristic miRNAs profile of anal fistula and explore their possible target genes and potential clinical significance. METHODS: The anal mucosa close to the hemorrhoids were collected from three patients undergoing fistulectomy and hemorrhoidectomy (fistula group) as well as three patients receiving only hemorroidectomy(hemorrhoids group), matching with fistula group in age, gender and body weight. miRNA microarray was used to compare the expression of 1 285 human miRNAs of the anal mucosa between two groups. Cluster analysis was adopted to analyze the accumulation of the differentially expressed miRNAs(P<0.05, fold>=2.0 or <=0.5) and their target genes were predicted with 10 softwares such as DIANAmT, miRanda, miRDB, miRWalk etc. Comprehensive scoring was performed to identify genes with highest predictive score. Gene ontology (GO) concentration technique was used to analyze the target gene-associated biological process. Immunohistochemistry was used to examine protein expression of genes with the highest score. RESULTS: Among 1285 miRNAs in fistula group, 13 miRNAs were differentially expressed with those in hemorrhoid group, including 2 of up-regulation and 11 of down-regulation. Paired t test showed that in fistula group, miRNA-3609 up-regulation was 5.98 folds(P=0.0231) and miR-181a-2-3p down-regulation was 0.13 folds(P=0.0067) compared to those in hemorrhoid group, which had the greatest differential expression. Cluster analysis suggested that up-regulated miR-3609 and miR-6086 had similar change trend in both groups. Among 11 down-regulated miRNAs, miR 125bp-1-3p and miR-548q had similar expression and other 9 miRNAs had similar expression as well, including miR-1185-1-3p, miR-532-3p, miR-1233-5p, miR-769-5p, miR-149-5p, miR-99b-3p, miR-141-3p, miR-138-5p, and miR-181a-2-3p. Target gene prediction analysis of above 13 genes showed that 7 miRNAs(53.8%) were eligible to predict their potential target genes, yielding totally 104 possible target genes. The rest of 6 miRNAs(46.2%) failed to predict any target gene. The highest score in prediction of target gene was chitinase 1(ChIT1) and its corresponding differential miRNA was miR-769-5p(r=-0.94286, P=0.0167). Gene ontology analysis showed that the most associated biological process related with these 104 target genes was keratinization, immune response and signal transduction. Immunohistochemistry revealed ChiT1 expression of anal mucosa in fistula group was significantly higher compared to hemorrhoid group(P<0.01). CONCLUSIONS: There is a characteristic miRNAs profile in anal fistula patients, which may play a role in the occurrence and development of anal fistula. PMID- 27452759 TI - [Effect of tumor-associated macrophages on invasion and metastasis of gastric cancer cells]. AB - OBJECTIVE: To explore the influence of tumor-associated macrophages(TAMs) on the ability of invasion and metastasis of gastric cancer cells, and its associated mechanism. METHODS: Immunohistochemistry was used to examine the expression of TAM in 10 samples of normal gastric mucosa and 15 samples of gastric cancer tissues from sample bank of Department of Pathology, Union Hospital. Phorbol 12 myristate 13-acetate(PMA) and macrophage colony stimulating factor (M-CSF) were used to make THP-1 monocytes differentiate into TAMs. AGS gastric cancer cells were divided into two groups: experiment group was cultured with RPMI/1640 condition medium containing 50% TAM and control group was cultured with RPMI/1640 complete medium. The ability of invasion and metastasis of gastric cancer cells was measured by Transwell assays. Real-time PCR and Western blot were applied to detect the expression of MMPs and its inhibitor TIMPs before and after stimulation of TAMs. RESULTS: Immunohistochemistry results showed that CD68(+) cell number in normal gastric mucosa tissue was significantly less than that in gastric cancer tissue [(11.3+/-0.8)/HP vs. (31.6+/-1.4)/HP, P<0.000 1]. When treated with PMA and M-CSF, THP-1 cells were differentiated into type M2 TAMs with high expression of specific markers CD68, CD163, CD204 and CD206. Transwell test revealed that the number of piercing cells in the experimental group was significantly more than that in control group [(36.8+/-1.1)/HP vs. (12.8+/ 0.9)/HP, t=17.5, P=0.000). Compared to control group, the expression of MMP-2, MMP-9 mRNA in experimental group respectively increased by 1.61 and 1.87 folds(P=0.017 and P=0.009). Protein level of MMP-2, MMP-9 was up-regulated accordingly. The expression of TIMP-1 and TIMP-3 mRNA was not significantly different between two groups(P=0.120 and P=0.096). CONCLUSIONS: TAMs may promote the invasion and metastasis of gastric cancer cells through increasing expression of MMP-9 and MMP-2, which may be one of the mechanisms of gastric cancer development. PMID- 27452760 TI - [Comparative study of CT versus gross pathology in rabbit VX2 colorectal cancer model]. AB - OBJECTIVE: To establish rabbit VX2 colorectal cancer(CRC) model and to compare CT images with gross pathology in order to offer help for TNM staging in patients with CRC. METHODS: VX2 tumor pieces were implanted into colonic wall in 9 New Zealand white rabbits and rectal wall in 2 New Zealand white rabbits. Four weeks after inoculation, Ultravist(370 mg/ml) was injected through ear marginal vein with high pressure injector for stage 3 scanning of chest, abdomen and pelvis, and enhanced CT (collimation 0.5 mm mm * 320, pitch factor 0.828, bulb rotation speed 0.5 s/cycle, 120 kV, automatic ma, range 80 to 100 mAs) was performed to determine the presence of CRC or metastasis once a week for 4-6 weeks. Once inoculated CRC or metastases occurred or 6 weeks after implantation, the rabbits were sacrificed regardless of the presence or absence of CRC or metastasis on the CT images. One rabbit was used for gross anatomy observation. Others were placed in wood boxes with -80centi-degree for 24 hours, then samples of 3 mm thickness were cut using a motorized saw to make macropathology. Each cutting surface of the specimens was photographed in serial number. If certain or suspected lesions were found on the slices, such part was labeled and then placed in 10% phosphate buffered formaldehyde numbered box for subsequent pathological examination. CT image postprocessing was performed referring to the gross slice specimens and all findings were compared with the pathological reports. RESULTS: Among 11 rabbits, tumor was successfully established in 8 rabbits. Pathology showed that single lung metastasis (7 to 10 mm) was found in 2 rabbits and liver metastasis (9 mm) in 1 rabbit. Number of lymph node located around the inoculated tumor was 22 and that around mesenteric vessels was 13 with diameter of 2 to 16 mm. Among these 35 lymph nodes from 8 successful rabbits, 9 nodes were positive, including 7 around inoculated tumor and 2 around mesenteric vessels. CT identified above 8 primary inoculated tumors, 2 lung metastatic lesions and 1 liver metastatic lesion, with detection rate of 100%. For the detection of lymph node in CT, 27 nodes were identified in the pericolorectal region (17 nodes) and perimesenteric vessels (10 nodes), in which 6 were positive metastasis (ring-shaped enrichment and central low density necrosis), resulting in a detection rate of 77.1%(27/35 nodes), and positive detection rate of 66.7% (6/9 nodes), respectively. CONCLUSION: Living rabbit CT-gross pathological slice(3 mm-cut) of VX2 CRC model can be applied in image evaluation of small metastatic lesion. PMID- 27452761 TI - [Perioperative nutritional support in patients with digestive tract cancer]. AB - Tumor patients are high-risk group of malnutrition, and the characteristics of pathophysiology of digestive tract tumor can aggravate the malnutrition, so the perioperative nutritional support should be planed and implemented for these patients. However, the understanding of nutritional support is still insufficient. Reducing preoperative fasting time, reasonable preoperative nutritional support, early postoperative enteral nutrition and multiple forms in combination are the optimal strategy of the perioperative nutritional treatment and management. As the condition of cancer patients is always complicated, in the practice of clinical implementation, medical guidelines, patients condition and clinical experience of the medical practitioners should be combined to accelerate the effect of nutritional support and to improve the outcome of the patients. PMID- 27452762 TI - [Transformation of patient-derived tumor xenografts into lymphomas: characteristics, influence factors and precautions]. AB - The patient-derived tumor xenografts (PDX) model is an animal model established by directly engrafting fresh tumor tissue of patients into immunodeficiency mice after surgery or biopsy, which plays an important role in the study of tumor biology. However, the transformation of PDX into lymphoma limits the application of this model. The characters of this transformation include that epithelial tumors origin, predorminance of B-cell lymphomas, lost of architectural feature of primary tumor, absence of epithelial tumor markers, and CD45 and CD20 expression. That were characteristics of human B lymphocytes, and possible infection of Epstein-Barr virus(EBV). The biology of primary tumor, EBV infection, inflammation infiltration in primary tumors and the host immune status are the main related factors in this transformation. Therefore, selective xenograft by the detection of EBV infection and inflammation infiltration in primary tumors may be effective methods to prevent lymphomagenesis. PMID- 27452763 TI - Shared decision making in Swedish community mental health services - an evaluation of three self-reporting instruments. AB - BACKGROUND: Despite the potential impact of shared decision making on users satisfaction with care and quality in health care decisions, there is a lack of knowledge and skills regarding how to work with shared decision making among health care providers. AIM: The aim of this study was to evaluate the psychometric properties of three instruments that measure varied dimensions of shared decision making, based on self-reports by clients, in a Swedish community mental health context. METHOD: The study sample consisted of 121 clients with experience of community mental health care, and involved in a wide range of decisions regarding both social support and treatment. The questionnaires were examined for face and content validity, internal consistency, test-retest reliability and construct validity. RESULTS: The instruments displayed good face and content validity, satisfactory internal consistency and a moderate to good level of stability in test-retest reliability with fair to moderate construct correlations, in a sample of clients with serious mental illness and experience of community mental health services in Sweden. CONCLUSIONS: The questionnaires are considered to be relevant to the decision making process, user-friendly and appropriate in a Swedish community mental health care context. They functioned well in settings where non-medical decisions, regarding social and support services, are the primary focus. The use of instruments that measure various dimensions of the self-reported experience of clients, can be a key factor in developing knowledge of how best to implement shared decision making in mental health services. PMID- 27452764 TI - Olfactory Response and Feeding Preference of Liriomyza huidobrensis (Diptera: Agromyzidae) to Potato Cultivars. AB - Liriomyza huidobrensis (Blanchard) is a serious invasive pest of potato in Korea. In sessile insect herbivores like leafminer flies, host plant choice is a critical decision made by adults for offspring survival, and one that is often influenced by host plant quality. In annual host plants like potato, leafminer choice is sometimes influenced by cultivar characteristics. To determine the basis of host selection, the odor and feeding preferences of adult L. huidobrensis were examined using a five-arm olfactometer offering a choice of five different potato cultivars: 'Chubeak', 'Seohong', 'Goun', 'Dejima', and 'Sumi'. Preferences of adult leafminers varied significantly among potato cultivars. Liriomyza huidobrensis showed a preference for the Goun cultivar in both olfactory and adult feeding tests. When measured 2 wk after release onto actual plants, plant damage ratings and the number of mines were consistent with the feeding preference results. Further studies should examine the influence of cultivar characteristics on larval fitness and adult longevity to develop a resistant potato cultivar through the selection behavior of leafminers. PMID- 27452765 TI - Overcoming PCR Inhibition During DNA-Based Gut Content Analysis of Ants. AB - Generalist predators play an important role in many terrestrial systems, especially within agricultural settings, and ants (Hymenoptera: Formicidae) often constitute important linkages of these food webs, as they are abundant and influential in these ecosystems. Molecular gut content analysis provides a means of delineating food web linkages of ants based on the presence of prey DNA within their guts. Although this method can provide insight, its use on ants has been limited, potentially due to inhibition when amplifying gut content DNA. We designed a series of experiments to determine those ant organs responsible for inhibition and identified variation in inhibition among three species (Tetramorium caespitum (L.), Solenopsis invicta Buren, and Camponotus floridanus (Buckley)). No body segment, other than the gaster, caused significant inhibition. Following dissection, we determined that within the gaster, the digestive tract and crop cause significant levels of inhibition. We found significant differences in the frequency of inhibition between the three species tested, with inhibition most evident in T. caespitum The most effective method to prevent inhibition before DNA extraction was to exude crop contents and crop structures onto UV-sterilized tissue. However, if extracted samples exhibit inhibition, addition of bovine serum albumin to PCR reagents will overcome this problem. These methods will circumvent gut content inhibition within selected species of ants, thereby allowing more detailed and reliable studies of ant food webs. As little is known about the prevalence of this inhibition in other species, it is recommended that the protocols in this study are used until otherwise shown to be unnecessary. PMID- 27452766 TI - Effects of sigma factor competition are promoter initiation kinetics dependent. AB - In Escherichia coli, the expression of a sigma factor is expected to indirectly down-regulate the expression of genes recognized by another sigma factor, due to sigma factor competition for a limited pool of RNA polymerase core enzymes. Evidence suggests that the sensitivity of genes to indirect down-regulation differs widely. We studied the variability in this sensitivity in promoters primarily recognized by RNAP holoenzymes carrying sigma(70). From qPCR and live single-cell, single-RNA measurements of the transcription kinetics of several sigma(70)-dependent promoters in various conditions and from the analysis of sigma factors population-dependent models of transcription initiation, we find that, the smaller is the time-scale of the closed complex formation relative to the open complex formation, the weaker is a promoter's responsiveness to changes in sigma(38) numbers. We conclude that, in E. coli, a promoter's responsiveness to indirect regulation by sigma factor competition is determined by the sequence dependent kinetics of the rate limiting steps of transcription initiation. PMID- 27452767 TI - Effect of CPAP Withdrawal on BP in OSA: Data from Three Randomized Controlled Trials. AB - BACKGROUND: Based on meta-analyses, the BP-lowering effect of CPAP therapy in patients with OSA is reported to be approximately 2 to 3 mm Hg. This figure is derived from heterogeneous trials, which are often limited by poor CPAP adherence, and thus the treatment effect may possibly be underestimated. We analyzed morning BP data from three randomized controlled CPAP withdrawal trials, which included only patients with optimal CPAP compliance. METHODS: Within the three trials, 149 patients with OSA who were receiving CPAP were randomized to continue therapeutic CPAP (n = 65) or to withdraw CPAP (n = 84) for 2 weeks. Morning BP was measured at home before and after sleep studies in the hospital. RESULTS: CPAP withdrawal was associated with a return of OSA (apnea-hypopnea index [AHI] at a baseline of 2.8/h and at follow-up of 33.2/h). Office systolic BP (SBP) increased in the CPAP withdrawal group compared with the CPAP continuation group by +5.4 mm Hg (95% CI, 1.8-8.9 mm Hg; P = .003) and in the home SBP group by +9.0 mm Hg (95% CI, 5.7-12.3 mm Hg; P < .001). Office diastolic BP (DBP) increased by +5.0 mm Hg (95% CI, 2.7-7.3 mm Hg; P < .001), and home DBP increased by +7.8 mm Hg (95% CI, 5.6-10.4 mm Hg; P < .001). AHI, baseline home SBP, use of statin drugs, sex, and the number of antihypertensive drugs prescribed were all independently associated with SBP change in multivariate analysis, controlling for age, BMI, smoking status, diabetes, and sleepiness. CONCLUSIONS: CPAP withdrawal results in a clinically relevant increase in BP, which is considerably higher than in conventional CPAP trials; it is also underestimated when office BP is used. Greater OSA severity is associated with a higher BP rise in response to CPAP withdrawal. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01332175 and NCT01797653) URL: www.clinicaltrials.gov and ISRCTN registry (ISRCTN 93153804) URL: http://www.isrctn.com/. PMID- 27452768 TI - Estimating Ten-Year Trends in Septic Shock Incidence and Mortality in United States Academic Medical Centers Using Clinical Data. AB - BACKGROUND: Reports that septic shock incidence is rising and mortality rates declining may be confounded by improving recognition of sepsis and changing coding practices. We compared trends in septic shock incidence and mortality in academic hospitals using clinical vs claims data. METHODS: We identified all patients with concurrent blood cultures, antibiotics, and vasopressors for >= two consecutive days, and all patients with International Classification of Diseases, 9th edition (ICD-9) codes for septic shock, at 27 academic hospitals from 2005 to 2014. We compared annual incidence and mortality trends. We reviewed 967 records from three hospitals to estimate the accuracy of each method. RESULTS: Of 6.5 million adult hospitalizations, 99,312 (1.5%) were flagged by clinical criteria, 82,350 (1.3%) by ICD-9 codes, and 44,651 (0.7%) by both. Sensitivity for clinical criteria was higher than claims (74.8% vs 48.3%; P < .01), whereas positive predictive value was comparable (83% vs 89%; P = .23). Septic shock incidence, based on clinical criteria, rose from 12.8 to 18.6 cases per 1,000 hospitalizations (average, 4.9% increase/y; 95% CI, 4.0%-5.9%), while mortality declined from 54.9% to 50.7% (average, 0.6% decline/y; 95% CI, 0.4%-0.8%). In contrast, septic shock incidence, based on ICD-9 codes, increased from 6.7 to 19.3 per 1,000 hospitalizations (19.8% increase/y; 95% CI, 16.6%-20.9%), while mortality decreased from 48.3% to 39.3% (1.2% decline/y; 95% CI, 0.9%-1.6%). CONCLUSIONS: A clinical surveillance definition based on concurrent vasopressors, blood cultures, and antibiotics accurately identifies septic shock hospitalizations and suggests that the incidence of patients receiving treatment for septic shock has risen and mortality rates have fallen, but less dramatically than estimated on the basis of ICD-9 codes. PMID- 27452769 TI - OSA Is a Risk Factor for Recurrent VTE. AB - BACKGROUND: OSA is a risk factor for a first episode of pulmonary embolism (PE), although its impact on the risk of thromboembolism recurring is uncertain. Our objective was to explore the prognostic value of OSA after the discontinuation of oral anticoagulation (OAC) in patients with a first episode of PE. METHODS: In 120 consecutive patients who had stopped OAC for a first episode of PE, we performed home respiratory polygraphy and recorded sleep characteristics, classic risk factors for PE, blood pressure measurements, spirometric parameters, physical activity, and levels of D-dimer and prothrombin fragment 1+2 (F1+2). Patients were followed for 5 to 8 years, and the main end point was PE recurrence. Restarting OAC for any thromboembolic event was evaluated as a secondary end point. RESULTS: During the follow-up period, 19 patients had a PE recurrence, and 16 of them had an apnea-hypopnea index (AHI) >= 10 h-1. In a multivariate Cox regression model, an AHI >= 10 h-1 (hazard ratio [HR], 20.73; 95% CI, 1.71-251.28), mean nocturnal oxygen saturation (nSao2) (HR, 0.39; 95% CI, 0.20-0.78), time with Sao2 < 90% (CT90%) (HR, 0.90; 95% CI, 0.82-0.98), and D dimer level (HR, 1.001; 95% CI, 1.00-1.002) were identified as independent risk factors for recurrent PE. Twenty-four patients resumed OAC, and AHI >= 10 h-1 (HR, 20.66; 95% CI, 2.27-188.35), mean nSao2 (HR, 0.54; 95% CI, 0.32-0.94), and Epworth Sleepiness Scale (ESS) (HR, 0.73; 95% CI, 0.56-0.97) were retained as independent risk factors for the resumption of OAC. CONCLUSIONS: After a first episode of PE, OSA is an independent risk factor for PE recurrence or restarting OAC for a new thromboembolic event. PMID- 27452771 TI - Multiple Risk Factor Interventions for Primary Prevention of CVD in LMIC: A Cochrane Review. AB - This study sought to determine the effectiveness of multiple risk factor interventions aimed at modifying major cardiovascular risk factors for the primary prevention of cardiovascular disease in low- and middle-income countries (LMIC). We searched electronic databases for randomized controlled trials of health promotion interventions to achieve behavior change. The pooled effect indicated a reduction in systolic blood pressure (-6.72 mm Hg; 95% confidence interval [CI]: -9.82 to -3.61; I2 = 91%), diastolic blood pressure (-4.40 mm Hg; 95% CI: -6.47 to -2.34; I2 = 92%), body mass index (-0.76 kg/m2; 95% CI: -1.29 to -0.22; I2 = 80%), and waist circumference (-3.31 cm; 95% CI: -4.77 to -1.86; I2 = 55%) in favor of multiple risk factor interventions. There is some evidence that multiple risk factor interventions may lower blood pressure levels and anthropometrics in populations in LMIC settings at high risk of hypertension and diabetes. PMID- 27452770 TI - A Novel Spirometric Measure Identifies Mild COPD Unidentified by Standard Criteria. AB - BACKGROUND: In chronic obstructive pulmonary disease, both smaller and larger airways are affected. FEV1 mainly reflects large airways obstruction, while the later fraction of forced exhalation reflects reduction in terminal expiratory flow. In this study, the objective was to evaluate the relationship between spirometric ratios, including the ratio of forced expiratory volume in 3 and 6 seconds (FEV3/FEV6), and small airways measures and gas trapping at quantitative chest CT scanning, and clinical outcomes in the Genetic Epidemiology of COPD (COPDGene) cohort. METHODS: Seven thousand eight hundred fifty-three current and ex-smokers were evaluated for airflow obstruction by using recently defined linear iteratively derived equations of Hansen et al to determine lower limit of normal (LLN) equations for prebronchodilator FEV1/FVC, FEV1/FEV6, FEV3/FEV6, and FEV3/FVC. General linear and ordinal regression models were applied to the relationship between prebronchodilator spirometric and radiologic and clinical data. RESULTS: Of the 10,311 participants included in the COPDGene phase I study, participants with incomplete quantitative CT scanning or relevant spirometric data were excluded, resulting in 7,853 participants in the present study. Of 4,386 participants with FEV1/FVC greater than or equal to the LLN, 15.4% had abnormal FEV3/FEV6. Compared with normal FEV3/FEV6 and FEV1/FVC, abnormal FEV3/FEV6 was associated with significantly greater gas trapping; St. George's Respiratory Questionnaire score; modified Medical Research Council dyspnea score; and BMI, airflow obstruction, dyspnea, and exercise index and with shorter 6-min walking distance (all P < .0001) but not with CT scanning evidence of emphysema. CONCLUSIONS: Current and ex-smokers with prebronchodilator FEV3/FEV6 less than the LLN as the sole abnormality identifies a distinct population with evidence of small airways disease in quantitative CT scanning, impaired indexes of physical function and quality of life otherwise deemed normal by using the current spirometric definition. PMID- 27452772 TI - Perspectives from NHLBI Global Health Think Tank Meeting for Late Stage (T4) Translation Research. AB - Almost three-quarters (74%) of all the noncommunicable disease burden is found within low- and middle-income countries. In September 2014, the National Heart, Lung, and Blood Institute held a Global Health Think Tank meeting to obtain expert advice and recommendations for addressing compelling scientific questions for late stage (T4) research-research that studies implementation strategies for proven effective interventions-to inform and guide the National Heart, Lung, and Blood Institute's global health research and training efforts. Major themes emerged in two broad categories: 1) developing research capacity; and 2) efficiently defining compelling scientific questions within the local context. Compelling scientific questions included how to deliver inexpensive, scalable, and sustainable interventions using alternative health delivery models that leverage existing human capital, technologies and therapeutics, and entrepreneurial strategies. These broad themes provide perspectives that inform an overarching strategy needed to reduce the heart, lung, blood, and sleep disorders disease burden and global health disparities. PMID- 27452774 TI - Targeted selection of brownfields from portfolios for sustainable regeneration: User experiences from five cases testing the Timbre Brownfield Prioritization Tool. AB - Prioritizing brownfields for redevelopment in real estate portfolios can contribute to more sustainable regeneration and land management. Owners of large real estate and brownfield portfolios are challenged to allocate their limited resources to the development of the most critical or promising sites, in terms of time and cost efficiency. Authorities worried about the negative impacts of brownfields - in particular in the case of potential contamination - on the environment and society also need to prioritize their resources to those brownfields that most urgently deserve attention and intervention. Yet, numerous factors have to be considered for prioritizing actions, in particular when adhering to sustainability principles. Several multiple-criteria decision analysis (MCDA) approaches and tools have been suggested in order to support these actors in managing their brownfield portfolios. Based on lessons learned from the literature on success factors, sustainability assessment and MCDA approaches, researchers from a recent EU project have developed the web-based Timbre Brownfield Prioritization Tool (TBPT). It facilitates assessment and prioritization of a portfolio of sites on the basis of the probability of successful and sustainable regeneration or according to individually specified objectives. This paper introduces the challenges of brownfield portfolio management in general and reports about the application of the TBPT in five cases: practical test-uses by two large institutional land owners from Germany, a local and a regional administrative body from the Czech Republic, and an expert from a national environmental authority from Romania. Based on literature requirements for sustainability assessment tools and on the end-users' feedbacks from the practical tests, we discuss the TBPT's strengths and weaknesses in order to inform and give recommendations for future development of prioritization tools. PMID- 27452773 TI - Atomic resolution structure determination by the cryo-EM method MicroED. AB - The electron cryo-microscopy (cryoEM) method MicroED has been rapidly developing. In this review we highlight some of the key steps in MicroED from crystal analysis to structure determination. We compare and contrast MicroED and the latest X-ray based diffraction method the X-ray free-electron laser (XFEL). Strengths and shortcomings of both MicroED and XFEL are discussed. Finally, all current MicroED structures are tabulated with a view to the future. PMID- 27452775 TI - Comparison of adaptive neuro-fuzzy inference system (ANFIS) and Gaussian processes for machine learning (GPML) algorithms for the prediction of skin temperature in lower limb prostheses. AB - Monitoring of the interface temperature at skin level in lower-limb prosthesis is notoriously complicated. This is due to the flexible nature of the interface liners used impeding the required consistent positioning of the temperature sensors during donning and doffing. Predicting the in-socket residual limb temperature by monitoring the temperature between socket and liner rather than skin and liner could be an important step in alleviating complaints on increased temperature and perspiration in prosthetic sockets. In this work, we propose to implement an adaptive neuro fuzzy inference strategy (ANFIS) to predict the in socket residual limb temperature. ANFIS belongs to the family of fused neuro fuzzy system in which the fuzzy system is incorporated in a framework which is adaptive in nature. The proposed method is compared to our earlier work using Gaussian processes for machine learning. By comparing the predicted and actual data, results indicate that both the modeling techniques have comparable performance metrics and can be efficiently used for non-invasive temperature monitoring. PMID- 27452776 TI - Feedback control of electrical stimulation electrode arrays. AB - Electrical stimulation electrode arrays are an emerging technology that enables muscles to be artificially contracted through the activation of their associated motor neurons. A principal application of electrical stimulation is to assist human motion for orthotic or therapeutic purposes. This paper develops a framework for the design of model-based electrode array feedback controllers that balance joint angle tracking performance with the degree of disturbance and modeling mismatch that can exist in the true underlying biomechanical system. This framework is used to develop a simplified control design procedure that is suitable for application in a clinical setting. Experimental results evaluate the feasibility of the control design approach through tests on ten participants using both fabric and polycarbonate electrode arrays. PMID- 27452777 TI - Reply to 'Frontal Fibrosing Alopecia Severity Index (FFASI): a validated scoring system for assessing frontal fibrosing alopecia': reply from the authors. PMID- 27452778 TI - Psychological Correlates of Burden Among Jordanian Caregivers of Patients With Serious Mental Illness. AB - PURPOSE: To examine prediction power of personality traits, expressed emotion, and coping strategies on caregivers' burden. DESIGNS AND METHODS: Cross-sectional descriptive correlational design was used to collect data from 196 caregivers using the Self-Administered Questionnaire from Jordanian caregivers of patients with serious mental illness. FINDINGS: Jordanian caregivers had a moderate-to severe burden level (M = 47.1, SD = 11.5). Burden had a significant negative relationship with coping (r = -.15, p = .04) and significant positive relationship with personality dysfunction (r = .16, p = .021). Emotional expression, coping, and personality were found to be significant predictors of burden (F = 5.16, p = .002). PRACTICE IMPLICATIONS: Mental health professionals need to address family caregivers in their plans of care. PMID- 27452779 TI - The use of multiple imputation method for the validation of 24-h food recalls by part-time observation of dietary intake in school. AB - External validation of food recall over 24 h in schoolchildren is often restricted to eating events in schools and is based on direct observation as the reference method. The aim of this study was to estimate the dietary intake out of school, and consequently the bias in such research design based on only part-time validated food recall, using multiple imputation (MI) conditioned on the information on child age, sex, BMI, family income, parental education and the school attended. The previous-day, web-based questionnaire WebCAAFE, structured as six meals/snacks and thirty-two foods/beverage, was answered by a sample of 7 11-year-old Brazilian schoolchildren (n 602) from five public schools. Food/beverage intake recalled by children was compared with the records provided by trained observers during school meals. Sensitivity analysis was performed with artificial data emulating those recalled by children on WebCAAFE in order to evaluate the impact of both differential and non-differential bias. Estimated bias was within +/-30 % interval for 84.4 % of the thirty-two foods/beverages evaluated in WebCAAFE, and half of the latter reached statistical significance (P<0.05). Rarely (<3 %) consumed dietary items were often under-reported (fish/seafood, vegetable soup, cheese bread, French fries), whereas some of those most frequently reported (meat, bread/biscuits, fruits) showed large overestimation. Compared with the analysis restricted to fully validated data, MI reduced differential bias in sensitivity analysis but the bias still remained large in most cases. MI provided a suitable statistical framework for part-time validation design of dietary intake over six daily eating events. PMID- 27452780 TI - [Comparative immunohistochemical assessment of the effect of repetitive anesthesia with isoflurane and sevoflurane on rat liver]. AB - BACKGROUND AND OBJECTIVES: Inhalation anesthetics are used in human, as well as veterinary medical practice. In the present study we investigated the effect of isoflurane and sevoflurane on rat hepatocytes. METHODS: A total of 40 Wistar female rats were used in this study. Animals were divided in groups of 5 rats. Groups IM, SM served as control groups. Groups I1, I2, I3 were used to study isoflurane and S1, S2, S3 for sevoflurane study. They were anesthetized 3 times, for 2h long, at 2 days interval with a concentration of: 1.5% isoflurane (I1, I2, I3) and 2% sevoflurane (S1, S2, S3). The oxygen supply throughout the anesthesia was 1LO2/min. Groups IM, IS, I1, S1 were sacrificed immediately after the last anesthesia. Groups I2, S2 were sacrificed 6h after the last anesthesia, and groups I3, S3, 24h post-anesthesia. Liver samples were harvested to highlight caspase-3 in apoptotic hepatocytes. RESULTS: Following isoflurane administration, there were less than 1% cells in apoptosis highlighted in rat livers from groups IM, I1 and I2. At 24h post-anesthesia (group I3), a small number of apoptotic hepatocytes was highlighted (around 3.23% cells in apoptosis), with a strictly periacinar disposition, randomly distributed in a small number of hepatic lobules. After sevoflurane administration, less than 1% apoptotic hepatocytes were identified at all control moments throughout the study. CONCLUSIONS: The results suggest that the anesthetics do not present a considerable hepatotoxicity. The comparative assessment of the two anesthetics shows that sevoflurane is superior to isoflurane. PMID- 27452781 TI - Effect of 4-week inhalation exposure to 1-bromopropane on blood pressure in rats. AB - The pathophysiology of hypertension is complex and multifactorial, and includes exposure to various chemical substances. Several recent studies have documented the reproductive and neurological toxicities of 1-bromopropane (1-BP). Given that 1-BP increased reactive oxygen species in the brain of rats, we hypothesized that 1-BP also has cardiovascular toxicity through increased oxidative stress. To test this hypothesis, male F344 and Wistar Nagoya rats (n = 7-8 per group per test) were exposed to 0 or 1000 ppm of 1-BP via inhalation for 4 weeks (8 h per day, 7 days per week). The exposure to 1-BP increased systolic blood pressure. This effect was associated with a significant decrease in the reduced/oxidized glutathione ratio. A significant increase in nitrotyrosine levels, activation of the NADPH oxidase pathway, which was evidenced by upregulation of gp91phox, a NADPH oxidase subunit, and significant decreases in the expressions of antioxidant molecules such as Cu/Zn- and Mn-superoxide dismutase catalase, and nuclear factor erythroid 2-related factor 2, were observed in the aortas of Wistar Nagoya rats exposed to 1-BP. Our results indicate that subacute (4-week) inhalation exposure to 1-BP increases blood pressure and suggest that this cardiovascular toxic effect is due, at least in part, to increased oxidative stress mediated through activation of the NADPH oxidase pathway. Further study is needed to assess whether NADPH oxidase activation causes the increase in blood pressure in the rats exposed to 1-BP. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27452782 TI - Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study. AB - BACKGROUND: Antibiotics are used frequently in the neonatal intensive care unit. We aimed to inform antibiotic stewardship strategies in a level 3 neonatal intensive care unit by surveillance and assessment of all antibiotic use during a 14-month period, identifying scenarios where antibiotic use can be reduced, and implementing interventions while monitoring safety. METHODS: The SCOUT study is an observational study in the level 3 neonatal intensive care unit at Parkland Hospital, Dallas, TX, USA. All antibiotic use in infants admitted to the neonatal intensive care unit between March 1, 2012, and Nov 30, 2012 (9 months), was monitored and analysed. After the baseline period (Oct 3, 2011, to Nov 30, 2012), continuation of empirical antibiotic therapy for ruled-out sepsis courses beyond 48 h, pneumonia, and "culture-negative" sepsis were selected as targets for antibiotic stewardship interventions. During the intervention period (Oct 1, 2013, to June 30, 2014), empirical antibiotic therapy was set to discontinue after 48 h in the electronic medical record and the duration of therapy for pneumonia and culture-negative sepsis was limited to 5 days. Antibiotic use, defined as days of therapy per 1000 patient-days, was compared between the baseline and intervention periods. The primary outcome was the change in total antibiotic days of therapy per 1000 patient-days between the baseline and intervention periods. Safety outcomes measured were instances in which infants received 5 or more days of therapy and subsequently had antibiotic therapy reinstituted within 14 days for any indication; a composite of late-onset sepsis, necrotising enterocolitis (modified Bell stage >=2), or death in infants 32 weeks' gestation or younger; prevalence of multidrug-resistant organism colonisation; and length of hospital stay. FINDINGS: 2502 infants were admitted to the neonatal intensive care unit during the two study periods (1607 in the baseline period and 895 in the intervention period). Antibiotic use declined from 343.2 days of therapy per 1000 patient-days during the baseline period to 252.2 days of therapy per 1000 patient-days in the intervention period (p<0.0001), representing an overall decrease of 27%. No difference in safety outcomes was observed between the intervention and baseline periods. INTERPRETATION: Thorough assessment of antibiotic consumption in a neonatal intensive care unit can inform high-yield stewardship targets tailored to the individual centre. Effective interventions to reduce antibiotic use can then be designed and implemented in a collaborative manner. FUNDING: The Gerber Foundation. PMID- 27452783 TI - Reducing unnecessary antibiotic exposure in preterm neonates: an achievable goal. PMID- 27452784 TI - Imported leprosy: If you think about it, you can diagnose it. PMID- 27452785 TI - Early neonatal lamb mortality: postmortem findings. AB - An investigation of stillbirth and early neonatal lamb mortality was conducted in sheep flocks in Norway. Knowledge of actual causes of death are important to aid the interpretation of results obtained during studies assessing the risk factors for lamb mortality, and when tailoring preventive measures at the flock, ewe and individual lamb level. This paper reports on the postmortem findings in 270 liveborn lambs that died during the first 5 days after birth. The lambs were from 17 flocks in six counties. A total of 27% died within 3 h after birth, 41% within 24 h and 80% within 2 days. Most lambs (62%) were from triplet or higher order litters. In 81% of twin and larger litters, only one lamb died. The most frequently identified cause of neonatal death was infectious disease (n=97, 36%); 48% (n=47) of these died from septicaemia, 25% (n=24) from pneumonia, 22% (n=21) from gastrointestinal infections and 5% (n=5) from other infections. Escherichia coli accounted for 65% of the septicaemic cases, and were the most common causal agent obtained from all cases of infection (41%). In total, 14% of neonatal deaths resulted from infection by this bacterium. Traumatic lesions were the primary cause of death in 20% (n=53) of the lambs. A total of 46% of these died within 3 h after birth and 66% within 24 h. Severe congenital malformations were found in 10% (n=27) of the lambs, whereas starvation with no concurrent lesions was the cause of death in 6% (n=17). In 16% (n=43) of the lambs, no specific cause of death was identified, lambs from triplet and higher order litters being overrepresented among these cases. In this study, the main causes of neonatal lamb mortality were infection and traumatic lesions. Most neonatal deaths occurred shortly after birth, suggesting that events related to lambing and the immediate post-lambing period are critical for lamb survival. PMID- 27452786 TI - Driving with central field loss III: vehicle control. AB - BACKGROUND: Visual impairment associated with central field loss may make vehicle control more difficult due to the degraded view of the road. We evaluated how central field loss affects vehicle control in a driving simulator. METHODS: Nineteen participants with binocular central field loss (acuity 6/9 to 6/60) and 15 controls with normal vision drove 10 scenarios, each about eight to 12 minutes. Speed, lane offset and steering wheel reversal rate were measured on straights, left and right curves, along city (approximately 50 km/h) and rural highway (approximately 100 km/h) routes. Following distance was measured on two city straight segments. RESULTS: Subjects with central field loss had higher steering wheel reversal rates (0.55 versus 0.45 reversals per second, p = 0.015), suggesting that the steering task was more demanding for them, requiring more steering corrections; however, they did not differ in other performance measures. Nearly all maintained a safe following distance, although they were more likely than controls with normal vision to lose sight of the lead car in scenarios that required following a car. CONCLUSIONS: Most measures of vehicle control did not significantly differ between participants with central field loss and those with normal vision; however, the higher steering wheel reversal rates suggest that, in compensating for their vision impairment, drivers with central field loss had to allocate extra steering effort to maintain their lane position, which in turn could reduce attentional resources for other driving tasks. PMID- 27452787 TI - The effect of chlorination and hydrodynamic shear stress on the persistence of bacteriophages associated with drinking water biofilms. AB - AIMS: This work aimed to assess at pilot scale the effect of chlorination and water flushing on 2-month-old drinking water biofilms and, above all, on biofilm associated F-specific RNA bacteriophages MS2, GA and Qbeta. METHODS AND RESULTS: Chlorination (4 mg l(-1) ) was applied first with a hydrodynamic shear stress of 1 Pa and second with an increase in hydrodynamic shear stress to 10 Pa. Despite a rapid decrease in the number of biofilm bacteria and associated phages, infectious phages were still detected on surfaces after completion of the 150 min cleaning procedure. The resulting sequence of phage removal was: GA > Qbeta ? MS2. CONCLUSIONS: The effect of chlorine on biofilm bacteria and biofilm associated phages was limited to the upper layers of the biofilm and was not enhanced by an increase in hydrodynamic shear stress. A smaller decrease was observed for MS2 than for GA or Qbeta after completion of the cleaning procedure. SIGNIFICANCE AND IMPACT OF THE STUDY: The differences observed between the three phages suggest that the location of the viral particles in the biofilm, which is related to their surface properties, affects the efficiency of chlorine disinfection. PMID- 27452788 TI - Reply. PMID- 27452789 TI - Topological detector: measuring continuous dosimetric quantities with few-element detector array. AB - A prototype topological detector was fabricated and investigated for quality assurance of radiation producing medical devices. Unlike a typical array or flat panel detector, a topological detector, while capable of achieving a very high spatial resolution, consists of only a few elements and therefore is much simpler in construction and more cost effective. The key feature allowing this advancement is a geometry-driven design that is customized for a specific dosimetric application. In the current work, a topological detector of two elements was examined for the positioning verification of the radiation collimating devices (jaws, MLCs, and blades etc). The detector was diagonally segmented from a rectangular thin film strip (2.5 cm * 15 cm), giving two contiguous but independent detector elements. The segmented area was the central portion of the strip measuring 5 cm in length. Under irradiation, signals from each detector element were separately digitized using a commercial multichannel data acquisition system. The center and size of an x-ray field, which were uniquely determined by the collimator positions, were shown mathematically to relate to the difference and sum of the two signals. As a proof of concept, experiments were carried out using slit x-ray fields ranging from 2 mm to 20 mm in size. It was demonstrated that, the collimator positions can be accurately measured with sub-millimeter precisions. PMID- 27452790 TI - Liquid exfoliation of alkyl-ether functionalised layered metal-organic frameworks to nanosheets. AB - We report the synthesis of a 2D-layered metal-organic framework incorporating weakly interacting chains designed to aid exfoliation of the layers into nanosheets. Dispersion of the nanosheets exposes labile metal-sites which are shown to exchange solvent molecules allowing the nanosheets to act as sensors in suspension. PMID- 27452792 TI - Oxidative stress induces the decline of brain EPO expression in aging rats. AB - Brain Erythropoietin (EPO), an important neurotrophic factor and neuroprotective factor, was found to be associated with aging. Studies found EPO expression was significantly decreased in the hippocampus of aging rat compared with that of the youth. But mechanisms of the decline of the brain EPO during aging remain unclear. The present study utilized a d-galactose (d-gal)-induced aging model in which the inducement of aging was mainly oxidative injury, to explore underlying mechanisms for the decline of brain EPO in aging rats. d-gal-induced aging rats (2months) were simulated by subcutaneously injecting with d-gal at doses of 50mg.kg(-1), 150mg.kg(-1) and 250mg.kg(-1) daily for 8weeks while the control group received vehicle only. These groups were all compared with the aging rats (24months) which had received no other treatment. The cognitive impairment was assessed using Morris water maze (MWM) in the prepared models, and the amount of beta-galactosidase, the lipid peroxidation product malondialdehyde (MDA) level and the superoxide dismutase (SOD) activity in the hippocampus was examined by assay kits. The levels of EPO, EPOR, p-JAK2 and hypoxia-inducible factor-2alpha (HIF-2alpha) in the hippocampus were detected by western blot. Additionally, the correlation coefficient between EPO/EPOR expression and MDA level was analyzed. The MWM test showed that compared to control group, the escape latency was significantly extended and the times of crossing the platform was decreased at the doses of 150mg.kg(-1) and 250mg.kg(-1) (p<0.05). Also, the amount of beta galactosidase and the MDA level in the hippocampus were significantly increased but the SOD activity was significantly decreased (p<0.05, 0.01 and 0.01, respectively). Similar to aging rats, the expressions of EPO, EPOR, p-JAK2, and HIF-2alphain the brain of d-gal-treated rats were significantly decreased (p<0.05) at 150mg.kg(-1) and 250mg.kg(-1). Interestingly, negative correlations were found between EPOR (r=-0.699, p<0.01), EPO (r=-0.701, p<0.01) and the MDA level. These results indicated that aging could result in the decline of EPO in the hippocampus and oxidative stress might be the main reason for the decline of brain EPO in aging rats, involved with the decrease of HIF-2alpha stability. PMID- 27452793 TI - Deposition Kinetics of Bioinspired Phenolic Coatings on Titanium Surfaces. AB - Polyphenols can form functional coatings on a variety of different materials through auto-oxidative surface polymerization in a manner similar to polydopamine coatings. However, the mechanisms behind the coating deposition are poorly understood. We report the coating deposition kinetics of the polyphenol tannic acid (TA) and the simple phenolic compound pyrogallol (PG) on titanium surfaces. The coating deposition was followed in real time over a period of 24 h using a quartz crystal microbalance with dissipation monitoring (QCM-D). TA coatings revealed a multiphasic layer formation: the deposition of an initial rigid layer was followed by the buildup of an increasingly dissipative layer, before mass adsorption stopped after approximately 5 h of coating time. The PG deposition was biphasic, starting with the adsorption of a nonrigid viscoelastic layer which was followed by layer stiffening upon further mass adsorption. Coating evaluation by ellipsometry and AFM confirmed the deposition kinetics determined by QCM-D and revealed maximum coating thicknesses of approximately 50 and 75 nm for TA and PG, respectively. Chemical characterization of the coatings and polymerized polyphenol particles indicated the involvement of both physical and chemical interactions in the auto-oxidation reactions. PMID- 27452791 TI - An Integrative Perspective on the Role of Dopamine in Schizophrenia. AB - We propose that schizophrenia involves a combination of decreased phasic dopamine responses for relevant stimuli and increased spontaneous phasic dopamine release. Using insights from computational reinforcement-learning models and basic-science studies of the dopamine system, we show that each of these two disturbances contributes to a specific symptom domain and explains a large set of experimental findings associated with that domain. Reduced phasic responses for relevant stimuli help to explain negative symptoms and provide a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with negative symptoms: reduced learning from rewards; blunted activation of the ventral striatum, midbrain, and other limbic regions for rewards and positive prediction errors; blunted activation of the ventral striatum during reward anticipation; blunted autonomic responding for relevant stimuli; blunted neural activation for aversive outcomes and aversive prediction errors; reduced willingness to expend effort for rewards; and psychomotor slowing. Increased spontaneous phasic dopamine release helps to explain positive symptoms and provides a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with positive symptoms: aberrant learning for neutral cues (assessed with behavioral and autonomic responses), and aberrant, increased activation of the ventral striatum, midbrain, and other limbic regions for neutral cues, neutral outcomes, and neutral prediction errors. Taken together, then, these two disturbances explain many findings in schizophrenia. We review evidence supporting their co occurrence and consider their differential implications for the treatment of positive and negative symptoms. PMID- 27452795 TI - Descriptive study of dental injury incurred by junior high school and high school students during participation in school sports clubs. AB - AIM: Students often injure their teeth during participation in school-based sports clubs. This study examined the frequencies and types of dental injuries sustained at school sports clubs and compared the risk of dental injury among different sports. METHODS: Based on injury statistics from the Japan Sport Council of the junior high schools and high schools in seven prefectures during fiscal year 2006, the risk of dental injury was estimated using a rate ratio (RR) by calculating the ratio of occurrence of dental injury under various circumstances. RESULTS: The RRs of exercise-related dental injury for boys and girls in junior high school were 0.7 (P < 0.001) and 1.3 (P < 0.05), respectively, and for those in high school were 2.6 (P < 0.001) and 2.7 (P < 0.001), respectively. In junior high school, softball (RR = 7.7) for boys and handball (RR = 3.9) for girls commonly led to dental injuries. In high school, Japanese-style wrestling (RR = 18.5) and rugby (RR = 7.3) for boys and handball (RR = 6.5) for girls had high risks for dental injury. Crown fracture was the predominant dental injury among boys and girls attending both junior high school and high school. The proportion of alveolar fracture was higher in school sports clubs than outside school sports clubs among high school boys. Contact or limited contact sports had significantly higher risks for dental injuries than did noncontact sports. CONCLUSION: The results of this study suggest that teachers and administrators at schools should pay attention to the risk of dental injury among students participating in high-risk sports. PMID- 27452794 TI - Developing an Algorithm to Detect Early Childhood Obesity in Two Tertiary Pediatric Medical Centers. AB - OBJECTIVE: The objective of this study is to develop an algorithm to accurately identify children with severe early onset childhood obesity (ages 1-5.99 years) using structured and unstructured data from the electronic health record (EHR). INTRODUCTION: Childhood obesity increases risk factors for cardiovascular morbidity and vascular disease. Accurate definition of a high precision phenotype through a standardize tool is critical to the success of large-scale genomic studies and validating rare monogenic variants causing severe early onset obesity. DATA AND METHODS: Rule based and machine learning based algorithms were developed using structured and unstructured data from two EHR databases from Boston Children's Hospital (BCH) and Cincinnati Children's Hospital and Medical Center (CCHMC). Exclusion criteria including medications or comorbid diagnoses were defined. Machine learning algorithms were developed using cross-site training and testing in addition to experimenting with natural language processing features. RESULTS: Precision was emphasized for a high fidelity cohort. The rule-based algorithm performed the best overall, 0.895 (CCHMC) and 0.770 (BCH). The best feature set for machine learning employed Unified Medical Language System (UMLS) concept unique identifiers (CUIs), ICD-9 codes, and RxNorm codes. CONCLUSIONS: Detecting severe early childhood obesity is essential for the intervention potential in children at the highest long-term risk of developing comorbidities related to obesity and excluding patients with underlying pathological and non-syndromic causes of obesity assists in developing a high precision cohort for genetic study. Further such phenotyping efforts inform future practical application in health care environments utilizing clinical decision support. PMID- 27452796 TI - Discoloration of the mucosa caused by different restorative materials - a spectrophotometric in vitro study. AB - OBJECTIVES: To evaluate the discoloration of the mucosa caused by different ceramic and metal-based materials. MATERIAL AND METHODS: On six pig maxillae, trap-door flaps were prepared bilaterally. Different ceramic and metal-based specimens were placed underneath the flap. To simulate increasing mucosal thicknesses (MC), connective tissue grafts (CTGs) were harvested. Spectrophotometric measurements were performed prior to flap elevation (TBL ) and for each material under the flap alone (1 mm MC) (TMC1 ), with a 1-mm CTG (2-mm MC) (TMC2 ) and with a 2-mm CTG (3-mm MC) (TMC3 ). Tested materials were as follows: Zr1 (zirconia), Zr2 (zirconia + pink ceramic), Zr3 (zirconia), Zr4 (fluorescent zirconia), Zr5 (zirconia), Zr6 (high translucent zirconia), Zr7 (low translucent zirconia) and Zr8 (low translucent zirconia), Gol (gold alloy), Ti1 (titanium alloy), Ti2 (anodized gold-shaded titanium alloy) and Ti3 (anodized pink-shaded titanium alloy). Color differences (DeltaE) were calculated comparing the measurement of the native tissue (TBL ) and the measurements with varying mucosal thicknesses (TMC1-3 ). RESULTS: For ceramic materials, the median DeltaE values for the different time-point comparison ranged as follows: 3.80 (Zr4) - 7.47 (Zr2) (pooled); 3.15 (Zr4) - 8.13 (Zr2) (TBL -TMC1 ); 3.39 (Zr4) - 7.24 (Zr2) (TBL -TMC2 ); 4.31 (Zr8) - 6.99 (Zr2) (TBL -TMC3 ). For metal-based materials, the median DeltaE values were as follows: 4.20 (Gol) - 5.82 (Ti3) (pooled); 3.21 (Gol) - 13.56 (Ti1) (TBL -TCM1 ); 4.0 (Ti1) - 5.27 (Gol) (TBL TCM2 ); 3.11 (Ti1) - 5.11 (Gol) (TBL -TCM2 ). The comparison of the materials and the time points showed in the nonparametric linear mixed model a significant interaction effect between material and time point (P < 0.001). The side was not a significant main effect, nor as term in an interaction with the other two effects. CONCLUSIONS: Reconstructive materials result in an evident discoloration of the mucosal tissue, tending to decrease with increasing mucosal thickness. The use of fluorescent zirconia (ceramic materials) or gold alloy (metal-based materials) lead to the least discoloration. PMID- 27452797 TI - Androgen induces gonadal soma-derived factor, Gsdf, in XX gonads correlated to sex-reversal but not Dmrt1 directly, in the teleost fish, northern medaka (Oryzias sakaizumii). AB - In the inbred HNI-II strain of Oryzias sakaizumii, Dmy and Gsdf are expressed in XY gonads from Stages 35 and 36, respectively, similarly to the inbred Hd-rR strain of Oryzias latipes. However, Dmrt1 respectively becomes detectable at Stage 36 and 5 days post hatching (dph) in the two strains. In XX HNI-II embryos, 17alpha-methyltestosterone (MT) induces Gsdf mRNA from Stage 36, accompanied by complete sex-reversal in all treated individuals (MT, 10 ng/mL), while Dmrt1 mRNA was first detectable at 5 dph. In XX d-rR, MT induced Gsdf mRNA expression and sex-reversal in only some of the treated individuals. Together, these results suggest the testis differentiation cascade in XY individuals differs between the HNI-II and Hd-rR strains. In addition, it is suggested that androgen-induced XX sex-reversal proceeds via an androgen-Gsdf-Dmrt1 cascade and that Gsdf plays an important role in sex-reversal in medaka. PMID- 27452798 TI - Melatonin modulates glucocorticoid receptor mediated inhibition of antioxidant response and apoptosis in peripheral blood mononuclear cells. AB - Pineal melatonin is known for its immunomodulatory and anti-stress properties. It modulates stress condition by regulating antioxidant responses and apoptosis in the immune cells. Stress causes increased glucocorticoid level that acts through glucocorticoid receptor (GR) and is translocated into nucleus under regulation of HSP90 based chaperone machinery. Melatonin influences glucocorticoid and GR mediated stress condition in rodents, but till date there are no reports which could suggest the effect of melatonin treatment on GR mediated apoptosis and inhibition of Nrf-2/hemeoxygenase-1 (HO-1) induced antioxidant status in immunocompetent cells (peripheral blood mononuclear cells; PBMCs). Therefore, in the present study, we considered GR mediated inhibition of Nrf2 and HO-1 along with anti-apoptotic Bcl-2 expression in PBMCs. The PBMCs were treated with synthetic glucocorticoid; dexamethasone (Dex) and melatonin (Mel), to explore the effect of melatonin treatment in regulation of GR mediated apoptosis and inhibition of antioxidant status in immune cells. It was noted that melatonin treatment retained GR into cytoplasm by inhibiting the dissociation of HSP90 from GR-HSP90 complex and enhanced expression of Nrf2/HO-1 and Bcl-2 expression. This led to increased HO-1 expression and elevated Bcl-2 led to increased Bcl-2/Bax ratio that might ultimately enhanced the cellular antioxidant response and survival under glucocorticoid mediated stress condition. Our observations suggest that the declined GR nuclear translocation upon melatonin treatment might be responsible for the up-regulation of Nrf2 mediated HO-1 activity and increased Bcl-2/Bax ratio in PBMCs to maintain the immune homeostasis under stress condition. PMID- 27452799 TI - Mammary cell-activating factor regulates the hormone-independent transcription of the early lactation protein (ELP) gene in a marsupial. AB - The regulation of the tammar wallaby (Macropus eugenii) early lactation protein (ELP) gene is complex. ELP is responsive to the lactogenic hormones; insulin (I), hydrocortisone (HC) and prolactin (PRL) in mammary gland explants but could not be induced with lactogenic hormones in tammar primary mammary gland cells, nor in KIM-2 conditionally immortalised murine mammary epithelial cells. Similarly, ELP promoter constructs transiently-transfected into human embryonic kidney (HEK293T) cells constitutively expressing the prolactin receptor (PRLR) and Signal Transducer and Activator of Transcription (STAT)5A were unresponsive to prolactin, unlike the rat and mouse beta-casein (CSN2) promoter constructs. Identification of the minimal promoter required for the hormone-independent transcription of tammar ELP in HEK293Ts and comparative analysis of the proximal promoters of marsupial ELP and the orthologous eutherian colostrum trypsin inhibitor (CTI) gene suggests that mammary cell-activating factor (MAF), an E26 transformation-specific (ETS) factor, may bind to an AGGAAG motif and activate tammar ELP. PMID- 27452800 TI - Thyroid-stimulating hormone improves insulin sensitivity in skeletal muscle cells via cAMP/PKA/CREB pathway-dependent upregulation of insulin receptor substrate-1 expression. AB - Thyroid-stimulating hormone (TSH) receptor is expressed in extrathyroidal tissues such as hepatocytes, adipocytes, and skeletal muscle, which suggests a possible novel role of TSH in various metabolic processes in extrathyroidal tissues independent of thyroid hormones. We investigated whether TSH has any effects on glucose tolerance and insulin sensitivity in the skeletal muscle using diet induced obesity (DIO) mouse models and rodent skeletal muscle cells. TSH improved glucose tolerance in DIO mice and this was associated with an improvement of skeletal muscle insulin sensitivity resulting from the increased expression of insulin receptor substrate (IRS)-1 protein and mRNA therein. TSH significantly increased both basal and insulin-stimulated glucose transport in rat L6 myotubes and increased the expression of IRS-1 protein and mRNA in these cells as well. TSH also stimulated Irs1 promoter activation; this stimulation was abolished by protein kinase A (PKA) inhibition using H89 or by mutation of the cAMP-response element site located at -1155 to -875 bp of the Irs1 promoter region, supporting a novel role of TSH activated-cAMP/PKA/CREB signaling in the regulation of Irs1 expression. In conclusion, TSH improves insulin sensitivity in skeletal muscle by increasing Irs1 gene expression. This regulatory effect is mediated by a PKA-CREB dependent pathway. PMID- 27452802 TI - Radiation Exposure by Three-Dimensional Rotational Angiography (3DRA) During Trans-catheter Melody Pulmonary Valve Procedures (TMPV) in a Pediatric Cardiac Catheterization Laboratory. AB - This retrospective study aims to evaluate radiation exposure by three-dimensional rotational angiography (3DRA) during trans-catheter Melody pulmonary valve (TMPV) procedures. 3DRA has been reported to have added value in the management of complex congenital heart disease aiding in the performance of interventional procedures albeit with concerns of higher radiation exposure. We test the hypothesis that 3DRA does not cause additional radiation exposure during TMPV procedures. We analyzed all 81 TMPV procedures performed at St. Louis Children's Hospital, MO, USA, from January 1, 2011 to December 31, 2014. Dose-area product (DAP), DAP indexed to body weight (DAP/BW), fluoroscopy time (FT), and weight fluoroscopy time product of each procedure were recorded. We reviewed each procedure's images to determine whether additional interventions were performed (e.g., pulmonary artery angioplasty or treatment of conduit pseudo-aneurysm). 3DRA was used in 36 % of the procedures. 3DRA group had a higher number of additional procedures performed. The 3DRA group did not differ from the non-3DRA group in DAP, DAP/BW, and weight-fluoroscopy time product. 3DRA does not cause greater radiation exposure during TMPV procedures. PMID- 27452801 TI - A microdialysis method to measure in vivo hydrogen peroxide and superoxide in various rodent tissues. AB - Reactive oxygen species (ROS) play a critical role in cell signaling and disease pathogenesis. Despite their biological importance, assessment of ROS often involves measurement of indirect byproducts or measurement of ROS from excised tissue. Herein, we describe a microdialysis technique that utilizes the Amplex Ultrared assay to directly measure hydrogen peroxide (H2O2) and superoxide in tissue of living, anesthetized rats and mice. We demonstrate the application of this methodology in the penis, adipose tissue, skeletal muscle, kidney, and liver. We provide data demonstrating the impact of important methodological considerations such as membrane length, perfusion rate, and time-dependence upon probe insertion. In this report, we provide a complete list of equipment, troubleshooting tips, and suggestions for implementing this technique in a new system. The data herein demonstrate the feasibility of measuring both in vivo H2O2 and superoxide in the extracellular environment of various rodent tissues, providing a technique with potential application to a vast array of disease states which are subject to oxidative stress. PMID- 27452803 TI - The Use of Speckle Tracking Echocardiography for Early Detection of Myocardial Dysfunction in Patients with Duchenne Muscular Dystrophy. AB - Cardiac complications are the leading cause of death in patients with Duchenne muscular dystrophy (DMD). Two-dimensional echocardiography is the current standard for monitoring of LV systolic function in these patients, but it might not detect early systolic dysfunction. The current study examined the use of speckle tracking echocardiography (STE) to detect early signs of cardiac dysfunction in DMD patients. A retrospective review of charts and offline strain analysis of transthoracic echocardiographic studies of DMD patients at our institution from April 2014 to January 2015 were performed and compared to age matched healthy male subjects. Nineteen DMD patients (age range 12.6 +/- 3.1 years) with normal ejection fraction and shortening fraction were compared with sixteen controls. The global circumferential strain was lower in DMD patients compared with controls (-14.7 +/- 4.7 vs. -23.1 +/- 2.9 %, respectively, p value: 0.001). Circumferential strain measured at basal, mid-ventricular and apical parasternal short-axis views was lower in DMD patients compared with controls. Segmental circumferential strain was lower in DMD patients in most segments compared with controls. The global longitudinal strain was lower in DMD patients compared with controls (-13.6 +/- 5 vs. -18.8 +/- 3 %, respectively, p value: 0.001). Segmental longitudinal strain measured in various segments was lower in DMD patients compared with controls. DMD patients can have occult cardiovascular dysfunction as shown by reduction in circumferential and longitudinal strain measurements with STE despite normal standard echocardiographic parameters. The clinical significance of early detection of cardiac dysfunction in these patients warrants further studies. PMID- 27452804 TI - Behavioral and neuroimaging responses induced by mental imagery of threatening scenarios. AB - Functional neuroimaging studies have shown that actual situations of uncertain or distant threats increase the activity of forebrain regions, whereas proximal threats increase the activity of the dorsal midbrain. This experiment aimed at testing the hypothesis that brain activity elicited by imagined scenarios of threats with two different magnitudes, potential and imminent, resembles that found in response to actual threats. First, we measured subjective responses to imagined scenarios of potential and imminent threats compared with neutral and pleasant scenarios. The same scenarios were used as a paradigm in a functional magnetic resonance imaging experiment. Behavioral results show that the scenarios draw a gradient of hedonic valence and arousal dimensions. Both potential and imminent threat scenarios increased subjective anxiety; the imminent threat scenario also increased feelings of discomfort and bodily symptoms. The functional magnetic resonance imaging results revealed modulations of BOLD signal in the ventromedial prefrontal cortex by potential threat and in the periaqueductal gray matter by imminent threat. These results agree with previously reported evidence using actual threat situations, indicating that mental imagery is a reliable method for studying the functional neuroanatomy of relevant behavioral processes. PMID- 27452805 TI - Long-term caloric restriction in mice may prevent age-related learning impairment via suppression of apoptosis. AB - Caloric restriction (CR) is the most reliable intervention to extend lifespan and prevent age-related disorders in various species from yeast to rodents. However, the underlying mechanisms have not yet been clearly defined. Therefore, we aimed to identify the underlying mechanisms of long-term CR on age-related learning impairment in C57/BL mice. Thirty six-week-old male C57/BL mice were randomly divided into three groups: normal control group (NC group, n=10), high energy group (HE group, n=10), and CR group (n=10). After 10 months, the Morris water maze test was performed to monitor learning abilities. Western blotting, immunohistochemistry and real-time polymerase chain reaction were used to monitor changes in protein and mRNA levels associated with apoptosis-related proteins in the hippocampus. The average escape latency was lower in the CR group compared with the NC group, and the average time taken to first cross the platform in the CR group was significantly shorter than the HE group. Both Bcl-2 protein and mRNA expression levels in the CR group were significantly higher than those of the NC group and HE group. The expression of Bax, Caspase-3 and PARP protein in the CR group was significantly lower than the NC group. Our findings demonstrate that long-term CR may prevent age-related learning impairments via suppressing apoptosis in mice. PMID- 27452806 TI - The epidemiology and transmissibility of Zika virus in Girardot and San Andres island, Colombia, September 2015 to January 2016. AB - Transmission of Zika virus (ZIKV) was first detected in Colombia in September 2015. As of April 2016, Colombia had reported over 65,000 cases of Zika virus disease (ZVD). We analysed daily surveillance data of ZVD cases reported to the health authorities of San Andres and Girardot, Colombia, between September 2015 and January 2016. ZVD was laboratory-confirmed by reverse transcription polymerase chain reaction (RT-PCR) in the serum of acute cases within five days of symptom onset. We use daily incidence data to estimate the basic reproductive number (R0) in each population. We identified 928 and 1,936 reported ZVD cases from San Andres and Girardot, respectively. The overall attack rate for reported ZVD was 12.13 cases per 1,000 residents of San Andres and 18.43 cases per 1,000 residents of Girardot. Attack rates were significantly higher in females in both municipalities (p < 0.001). Cases occurred in all age groups with highest rates in 20 to 49 year-olds. The estimated R0 for the Zika outbreak was 1.41 (95% confidence interval (CI): 1.15-1.74) in San Andres and 4.61 (95% CI: 4.11-5.16) in Girardot. Transmission of ZIKV is ongoing in the Americas. The estimated R0 from Colombia supports the observed rapid spread. PMID- 27452807 TI - Effect of charge localization on the in vivo optical imaging properties of near infrared cyanine dye/monoclonal antibody conjugates. AB - Near-infrared (NIR) fluorophores show superior in vivo imaging properties than visible-light fluorophores because of the increased light penetration in tissue and lower autofluorescence of these wavelengths. We have recently reported that new NIR cyanine dyes containing a novel C4'-O-alkyl linker exhibit greater chemical stability and excellent optical properties relative to existing C4'-O aryl variants. In this study, we synthesized two NIR cyanine dyes with the same core structure and charge but different indolenine substituents: FNIR-Z-759 bearing a combination of two sulfonates and two quaternary ammonium cations, and FNIR-G-765 bearing a combination of two sulfonates and two guanidines, resulting in zwitterionic charge with distinct cationic moieties. In this study, we compare the in vitro and in vivo optical imaging properties of monoclonal antibody (mAb) conjugates of FNIR-Z-759 and FNIR-G-765 with panitumumab (pan) at antibody-to-dye ratios of 1 : 2 or 1 : 5. One-to-five conjugation of pan-to-FNIR-G-765 was not successful due to aggregate formation during the conjugation reaction. Conjugates of both dyes to pan (2 : 1) demonstrated similar quenching capacity, stability, and brightness in target cells in vitro. However, FNIR-Z-759 conjugates showed significantly lower accumulation in the mouse liver, resulting in higher tumor-to liver ratio. Thus, FNIR-Z-759 conjugates appear to have superior in vivo imaging characteristics compared with FNIR-G-765 conjugates, especially in the abdominal region. Moreover, from a chemistry point of view, mAb conjugation with FNIR-Z-759 has an advantage over FNIR-G-765, because it does not form aggregates at high dye to-mAb ratio. These results suggest that zwitterionic cyanine dyes are a superior class of fluorophores for conjugating with mAbs for fluorescence imaging applications due to improving target-to-background contrast in vivo. However, zwitterionic cyanine dyes should be designed carefully, as small changes to the structure can alter in vivo pharmacokinetics of mAb-dye conjugates. PMID- 27452808 TI - Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate Versus Heparin. AB - Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 MUg/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze-thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 MUg/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation. PMID- 27452809 TI - Signatures of Subacute Potentially Catastrophic Illness in the ICU: Model Development and Validation. AB - OBJECTIVES: Patients in ICUs are susceptible to subacute potentially catastrophic illnesses such as respiratory failure, sepsis, and hemorrhage that present as severe derangements of vital signs. More subtle physiologic signatures may be present before clinical deterioration, when treatment might be more effective. We performed multivariate statistical analyses of bedside physiologic monitoring data to identify such early subclinical signatures of incipient life-threatening illness. DESIGN: We report a study of model development and validation of a retrospective observational cohort using resampling (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis type 1b internal validation) and a study of model validation using separate data (type 2b internal/external validation). SETTING: University of Virginia Health System (Charlottesville), a tertiary-care, academic medical center. PATIENTS: Critically ill patients consecutively admitted between January 2009 and June 2015 to either the neonatal, surgical/trauma/burn, or medical ICUs with available physiologic monitoring data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 146 patient-years of vital sign and electrocardiography waveform time series from the bedside monitors of 9,232 ICU admissions. Calculations from 30-minute windows of the physiologic monitoring data were made every 15 minutes. Clinicians identified 1,206 episodes of respiratory failure leading to urgent unplanned intubation, sepsis, or hemorrhage leading to multi-unit transfusions from systematic individual chart reviews. Multivariate models to predict events up to 24 hours prior had internally validated C-statistics of 0.61-0.88. In adults, physiologic signatures of respiratory failure and hemorrhage were distinct from each other but externally consistent across ICUs. Sepsis, on the other hand, demonstrated less distinct and inconsistent signatures. Physiologic signatures of all neonatal illnesses were similar. CONCLUSIONS: Subacute potentially catastrophic illnesses in three diverse ICU populations have physiologic signatures that are detectable in the hours preceding clinical detection and intervention. Detection of such signatures can draw attention to patients at highest risk, potentially enabling earlier intervention and better outcomes. PMID- 27452810 TI - Percutaneous trans-abdominal external looped needle with two holes in the trocar sheath for port-site closures in difficult obese cases. AB - INTRODUCTION: Port closure is essential after successful laparoscopic surgery to prevent incisional hernia. However, good fascial closure still represents a problem, especially in obese patients and when the port wound is oblique. We report a novel technique for port-site closures in such cases. METHODS: This study involved 67 obese patients who underwent laparoscopic surgery. We used a novel technique for port-site closure that employed a looped needle passed through two holes in the port sheath. RESULTS: The method was used in 67 patients (45 laparoscopic cholecystectomies, 22 laparoscopic hernia repairs), with a mean BMI of 35.7 kg/m2 . No intraoperative incidents or port-site hernias were reported during follow-up (mean, 22 months). CONCLUSION: Our procedure is safe, easy, and effective for fascial port site closures, especially in cases of difficult obese patients and oblique port wounds. PMID- 27452811 TI - Idarucizumab for dabigatran reversal in patients with atrial fibrillation undergoing emergency surgery for acute aortic syndrome. PMID- 27452812 TI - Dietary flavonoid luteolin attenuates uropathogenic Escherichia. Coli invasion of the urinary bladder. AB - Uropathogenic Escherichia coli (UPEC), the primary uropathogen, adhere to and invade bladder epithelial cells (BECs) to establish a successful urinary tract infection (UTI). Emerging antibiotic resistance requires novel nonantibiotic strategies. Our previous study indicated that luteolin attenuated adhesive and invasive abilities as well as cytotoxicity of UPEC on T24 BECs through down regulating UPEC virulence factors. The aims of this study were to investigate the possible function of the flavonoid luteolin and the mechanisms by which luteolin functions in UPEC-induced bladder infection. Firstly, obvious reduction of UPEC invasion but not adhesion were observed in luteolin-pretreated 5637 and T24 BECs sa well as mice bladder via colony counting. The luteolin-mediated suppression of UPEC invasion was linked to elevated levels of intracellular cAMP induced by inhibiting the activity of cAMP-phosphodiesterases (cAMP-PDEs), which resulting activation of protein kinase A, thereby negatively regulating Rac1-GTPase mediated actin polymerization. Furthermore, p38 MAPK was primarily and ERK1/2 was partially involved in luteolin-mediated suppression of UPEC invasion and actin polymerization, as confirmed with chemical activators of p38 MAPK and ERK1/2. These data suggest that luteolin can protect bladder epithelial cells against UPEC invasion. Therefore, luteolin or luteolin-rich products as dietary supplement may be beneficial to control the UPEC-related bladder infections, and cAMP-PDEs may be a therapy target for UTIs treatment. (c) 2016 BioFactors, 42(6):674-685, 2016. PMID- 27452813 TI - Ligand-free Cu-catalyzed [3 + 2] cyclization for the synthesis of pyrrolo[1,2 a]quinolines with ambient air as a terminal oxidant. AB - A ligand-free Cu-catalyzed [3 + 2] cycloaddition of ethyl 2-(quinolin-2 yl)acetates, ethyl 2-(isoquinolin-1-yl)acetates, and ethyl 2-(pyridin-2 yl)acetates with (E)-chalcones for a "one-pot" synthesis of pyrrolo[1,2 a]quinolines, pyrrolo[2,1-a]isoquinolines and indolizines has been developed. The annulation products were isolated in moderate to good yields with air as the sole oxidant under mild conditions. PMID- 27452814 TI - Enterocutaneous fistula: analysis of clinical outcomes from a single Victorian tertiary referral centre. AB - BACKGROUND: Enterocutaneous fistulas (ECFs) are complex and can result in significant morbidity and mortality. The study aimed to evaluate ECF outcomes in a single tertiary hospital. METHODS: A retrospective study of all patients treated with ECF between the period of January 2009 and June 2014 was conducted. Baseline demographic data assessed included the primary aetiology of the fistula, site of the fistula and output of the fistula. Outcomes measures assessed included re-fistulation rate, return to theatre, wound complications, fistula closure rate and death over the study period. RESULTS: A total of 16 patients with ECF were recorded within the study period. Mean age of the patient cohort was 55.8 +/- 11.8 years with a female predominance (11 females, 5 males). Primary aetiology were Crohn's disease (31%), post intra-abdominal surgery not related to bowel neoplasia (50%) and post intra-abdominal surgery related to bowel neoplasia (19%). Majority of the fistulas developed from the small bowel (75%) and had low output (63%). Operative intervention was required in 81% of patients with an overall closure rate of 100%. Median operations required for successful closure was 1.15 operations. Mean duration between index operation and curative operation was 8 +/- 12.7 months. CONCLUSION: Appropriate bundle of care (perioperative care, surgical timing and surgical technique) can produce excellent results in patients with ECF. PMID- 27452815 TI - Dynamics of extinction debt across five taxonomic groups. AB - Species extinction following habitat loss is well documented. However, these extinctions do not happen immediately. The biodiversity surplus (extinction debt) declines with some delay through the process of relaxation. Estimating the time constants of relaxation, mainly the expected time to first extinction and the commonly used time for half the extinction debt to be paid off (half-life), is crucial for conservation purposes. Currently, there is no agreement on the rate of relaxation and the factors that it depends on. Here we find that half-life increases with area for all groups examined in a large meta-analysis of extinction data. A common pattern emerges if we use average number of individuals per species before habitat loss as an area index: for mammals, birds, reptiles and plants, the relationship has an exponent close to a half. We also find that the time to first determined extinction is short and increases slowly with area. PMID- 27452816 TI - beta-Glucuronidase-coupled assays of glucuronoyl esterases. AB - Glucuronoyl esterases (GEs) are microbial enzymes with potential to cleave the ester bonds between lignin alcohols and xylan-bound 4-O-methyl-d-glucuronic acid in plant cell walls. This activity renders GEs attractive research targets for biotechnological applications. One of the factors impeding the progress in GE research is the lack of suitable substrates. In this work, we report a facile preparation of methyl esters of chromogenic 4-nitrophenyl and 5-bromo-4-chloro-3 indolyl beta-D-glucuronides for qualitative and quantitative GE assay coupled with beta-glucuronidase as the auxiliary enzyme. The indolyl derivative affording a blue indigo-type product is suitable for rapid and sensitive assay of GE in commercial preparations as well as for high throughput screening of microorganisms and genomic and metagenomic libraries. PMID- 27452817 TI - Preventive Medicine-A Social and Personal Affair. PMID- 27452819 TI - For the Record. PMID- 27452818 TI - Editor's Mail. AB - The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space. PMID- 27452821 TI - The Medical Bookshelf. PMID- 27452820 TI - Primary Care Digest. PMID- 27452822 TI - Dr Tom Swifties.... PMID- 27452823 TI - Albumin vs Salt for Volume Expansion. PMID- 27452824 TI - Washington Medical Update. PMID- 27452826 TI - Pulmonary disease. PMID- 27452825 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27452827 TI - Home oxygen therapy. PMID- 27452830 TI - Selected National Meetings. PMID- 27452828 TI - Teaching the Elderly Proper Drug Use. PMID- 27452832 TI - Stability of melamine-exfoliated graphene in aqueous media: quantum-mechanical insights at the nanoscale. AB - In recent experiments, melamine (1,3,5-triazine-2,4,6-triamine) has been proposed as an effective exfoliating agent to obtain high quality graphene from graphite. After washing out the melamine in excess, small amounts (ppm) are still needed to stabilize the dispersion of graphene flakes in aqueous media. To understand the origin of this behaviour, we investigated the melamine-graphene-water system and the fundamental interactions that determine its structure and energetics. To disentangle the subtle interplay of hydrogen-bonding and dispersive forces we used state-of-the-art ab initio calculations based on density functional theory. First, we focused on the case of water molecules interacting with melamine graphene assemblies at different melamine coverages. We found that water-melamine interactions provide the driving force for washing off the melamine from graphene. Then, we addressed the interaction of single and double layers of water molecules with the graphene surface in the presence of an adsorbed melamine molecule. We found that this melamine acts as a non-covalent anchor for keeping a number of water molecules conveniently close to the graphene surface, thus helping its stabilization in aqueous media. Our analysis helps understanding how competing weak forces can lead to a stable graphene water suspension thanks to small amounts of adsorbed melamine. From our results, we derive simple indications on how the water-graphene interfacial properties can be tuned via non covalent adsorption of small functional molecules with H-bond donor/acceptor groups. These new hints can be helpful to prepare stable graphene dispersions in water and so to unlock graphene potential in aqueous environments. PMID- 27452833 TI - An endolytic mutanase from novel strain Paracoccus mutanolyticus: its application potential in dentistry. AB - Mutanase, alpha-(1->3)-glucanase, belonging to the family glucanohydrolase, catalyses mutan [alpha-(1->3)-glucan] synthesized by cariogenic streptococci and hence has potential in caries prophylaxis. A novel bacterial strain with potential to produce higher mutanase (glucanohydrolase) activity was isolated from soils contaminated with cellulosic waste. One of the isolated strains, RSP 02, was subjected to biochemical and 16S rRNA molecular analysis, and we noticed that it belongs to the genus Paracoccus. The mutanase production (800- 1200 U l 1) in this strain was growth associated and substrate induced, and the activity was comparable with the strains reported earlier. The enzyme displayed a molecular mass of 138 kDa by native PAGE studies, showed endolytic activity and produced nigerose as end product. In vitro studies revealed production of 140+/ 2.82 ug of glucose equivalents in 30 min from the biofilm formed on glass surface indicating its potentiality in dentistry. To the best of our knowledge, this is the first report on the production of mutanase by Paracoccus sp.; hence, this isolated bacterial strain is designated as Paracoccus mutanolyticus RSP-02. PMID- 27452834 TI - Determination of Exposure to the Alternaria Mycotoxin Tenuazonic Acid and Its Isomer allo-Tenuazonic Acid in a German Population by Stable Isotope Dilution HPLC-MS(3). AB - The content of the Alternaria toxin tenuazonic acid and its isomer allo tenuazonic acid was quantitated in urine of a German cohort (n = 48) using a newly developed and successfully validated solid phase extraction based stable isotope dilution HPLC-MS(3) method. Tenuazonic acid was detected in all of the samples and quantifiable in 97.9% of these samples in a range of 0.16-44.4 ng/mL (average = 6.58 ng/mL) or 0.07-63.8 ng/mg creatinine (average = 8.13 ng/mg creatinine). allo-Tenuazonic acid was for the first time detected in human urine (95.8% of the samples positive) and quantitated in 68.8% of the samples in a range of 0.11-5.72 ng/mL (average = 1.25 ng/mL) or 0.08-10.1 ng/mg creatinine (average = 1.52 ng/mg creatinine), representing 3.40-25.0% of the sum of both isomers (average = 12.4%). Food-frequency questionnaires were used to document food consumption of study participants to correlate mycotoxin exposure to nutritional habits. Although no statistically significant correlation between consumption of a specific food and urinary excretion of tenuazonic acid could be determined, a trend regarding elevated intake of cereal products and higher excretion of tenuazonic acid was evident. On the basis of these results, a provisional mean daily intake (PDI) for both tenuazonic acid and allo-tenuazonic acid was calculated, being 0.183 and 0.025 MUg/kg body weight, respectively. A combined mean PDI for both isomers amounts to 0.208 MUg/kg body weight with the highest individual PDI for one of the participants (1.582 MUg/kg body weight) slightly exceeding the threshold of toxicological concern assumed for tenuazonic acid by the European Food Safety Authority of 1.500 MUg/kg body weight. This is the first study to investigate the tenuazonic acid content in human urine of a larger sample cohort enabling the calculation of PDIs for tenuazonic acid and allo-tenuazonic acid. PMID- 27452836 TI - Isolation-induced vocalization in the infant rat depends on the nucleus accumbens. AB - Mammalian infants vocalize when socially isolated. Vocalization guides the return of the caregiver and thereby maintains an environment critical to the infant's survival. Although the role of the periaqueductal gray area (PAG) in these vocalizations is established, other aspects of the relevant neural circuitry remain under-studied. Here we report that output from the nucleus accumbens (Acb) is necessary for isolation-induced vocalizations of infant rats aged postnatal days (PND) 11-13. Local inhibition via infusion of the GABAA agonist muscimol (.8 MUg/side) of the Acb, but not the dorsolateral striatum, blocked isolation induced vocalizations, independent of whether the isolation was at room temperature, followed a brief reunion with the dam, or occurred in a cool (10 degrees C) environment. These findings highlight a possible anatomical area mediating the mammalian infant response to social separation and, more generally, to the development of social attachment. PMID- 27452838 TI - Scanning sports. PMID- 27452835 TI - Combretastatin A-4 efficiently inhibits angiogenesis and induces neuronal apoptosis in zebrafish. AB - Cis-stilbene combretastatin A-4 (CA-4) and a large group of its derivant compounds have been shown significant anti-angiogenesis activity. However the side effects even the toxicities of these chemicals were not evaluated adequately. The zebrafish model has become an important vertebrate model for evaluating drug effects. The testing of CA-4 on zebrafish is so far lacking and assessment of CA-4 on this model will provide with new insights of understanding the function of CA-4 on angiogenesis, the toxicities and side effects of CA-4. We discovered that 7-9 ng/ml CA-4 treatments resulted in developmental retardation and morphological malformation, and led to potent angiogenic defects in zebrafish embryos. Next, we demonstrated that intraperitoneal injection of 5, 10 and 20 mg/kg CA-4 obviously inhibited vessel plexus formation in regenerated pectoral fins of adult zebrafish. Interestingly, we proved that CA-4 treatment induced significant cell apoptosis in central nervous system of zebrafish embryos and adults. Furthermore, it was demonstrated that the neuronal apoptosis induced by CA-4 treatment was alleviated in p53 mutants. In addition, notch1a was up regulated in CA-4 treated embryos, and inhibition of Notch signaling by DAPT partially rescued the apoptosis in zebrafish central nervous system caused by CA 4. PMID- 27452837 TI - Anodal tDCS targeting the left temporo-parietal junction disrupts verbal reality monitoring. AB - Using transcranial direct current stimulation (tDCS) we aimed to investigate the causal role of the left temporo-parietal and prefrontal regions in source monitoring. Forty-two healthy participants received tDCS while performing a verbal reality-monitoring task (requiring discrimination between imagined and heard words) and a verbal internal source-monitoring task (requiring discrimination between imagined and said words). In 2 randomized crossover studies, 21 participants received active and sham anodal tDCS applied over the left temporo-parietal junction (TPJ) and 21 participants received active and sham cathodal tDCS applied over the left prefrontal cortex (PFC). The reference electrode was placed over the right occipital region in both experiments. Active tDCS over the left TPJ decreased reality-monitoring performance but did not modulate internal source-monitoring performance. Participants were more likely to misattribute self-generated events to externally perceived events (externalization bias). Active tDCS over the left PFC did not modulate performance of participants in both tasks. In summary, anodal tDCS applied over the left TPJ, assumed to enhance cortical excitability, can alter reality monitoring processes in healthy subjects. Such abnormal reality-monitoring performances have been reported in hallucinating patients with schizophrenia known to display hyperactivity of the left TPJ. Our results highlighted the role of the left TPJ in self/other recognition. PMID- 27452839 TI - Letters. PMID- 27452841 TI - Brief reports. PMID- 27452843 TI - A need to know. PMID- 27452845 TI - An Alternate Approach to Coaching. PMID- 27452846 TI - Gad Made the Schoolyard. PMID- 27452847 TI - The Effect of Track-and-Field Training on Cardiovascular Fitness. AB - In brief: Distance runners, sprinters, jumpers, and weightmen in track and field offer advantages for studying the effects of physical exertion on selected cardiovascular parameters because they undertake a variety of training programs. Fifty-six athletes and 40 controls were tested for percent body fat, maximal oxygen consumption, and plasma lipids before and after a seven-month training season. Sprinters had lower percent body fat and distance runners had higher vo2 max values than the other groups, but all groups had low plasma lipids. However, a season of training did not beneficially change these variables-probably because the athletes were already fit. PMID- 27452848 TI - Cross-Country Skiing: Precautions for Cardiac Patients. AB - In brief: Cross-country skiing is an attractive winter alternative to walking or jogging, but persons with coronary artery disease must be aware of its high energy costs and make appropriate adjustments. Oxygen costs can be affected by variations in efficiency, arm work, snow, cold temperatures, inclines, altitude, and skier misperceptions. The authors give safety recommendations to reduce the hazards and enable cross-country skiers to enjoy their winter sport. PMID- 27452849 TI - Eye Protection for Squash and Racquetball Players. AB - In brief: The author discusses 19 ocular injuries in squash and racquetball players who wore eye guards with an opening between the upper and lower rim. The more recently developed eye guards that protect the eye with thick plastic should prevent direct injury from rackets or balls. PMID- 27452850 TI - Women and Diving. AB - In brief: Women who want to scuba dive should be physically fit and should not be overly dependent on a male diving buddy. In his discussion on diving and menstruation, the author says that postmenopausal women can dive safely, and those who are menstruating can dive within the limits of their comfort. He stresses that pregnant women and women who are trying to become pregnant should not dive. Women who use oral contraceptives should dive conservatively, because it is not known if birth control pills increase the risk of decompression sickness. The author also discusses thermal balance problems and when to resume diving after childbirth. PMID- 27452851 TI - Injuries in Tae Kwon Do. AB - In brief: Tae Kwon Do, the martial art of Korea, is a highly disciplined sport teaching well-coordinated, rapid, forceful techniques. It is typically associated with minor injuries, particularly contusions, sprains, and strains of the lower and upper extremities. More serious injuries rarely occur, although they have been recorded. A knowledge of injuries in other sports is useful in managing those in Tae Kwon Do. More thorough education of students and instructors will reduce morbidity and rehabilitation time. PMID- 27452852 TI - Injuries to Young Athletes. PMID- 27452853 TI - Medical Care and Injury Surveillance in the High School Setting. AB - In brief: To avoid the bias of injury studies based only on coaches' perceptions, four athletic trainers served in high schools in a two-year study to identify and evaluate all injuries resulting from athletic participation. There were 1,181 injuries in 3,049 participants in 19 sports. Sprains and strains accounted for two thirds of the injuries, and the most common injury was the ankle sprain. Thirty-nine percent of injuries were evaluated by a physician, and 25 injuries required hospitalization. The athletic trainers probably increased physician visits and x-ray examinations and sensitized the schools to the need for injury prevention, recognition, treatment, and rehabilitation. PMID- 27452854 TI - Physician Skis for Fitness, Races for Reward. AB - Milton Hanson was looking forward to a five-month cross-country skiing vacation, but the challenge of ski racing induced him to enter a series of international races. PMID- 27452855 TI - Scouting the Elite, Unbreakable Football Player. AB - Some NFL football teams see physiological profiling as a means to protect and enhance their competitive and business success. Whether football players will benefit by increased performance and fewer injuries remains to be seen. PMID- 27452856 TI - Taping to Alleviate Heel Pain in Runners. PMID- 27452857 TI - Cheerleading: New Problems in a Changing Sport. AB - High school and college cheerleading is becoming more sophisticated and competitive, yet research on injuries and conditioning is virtually nonexistent. Liability problems may produce additional changes. PMID- 27452859 TI - Somatotopic Map and Inter- and Intra-Digit Distance in Brodmann Area 2 by Pressure Stimulation. AB - The somatotopic representation of the tactile stimulation on the finger in the brain is an essential part of understanding the human somatosensory system as well as rehabilitation and other clinical therapies. Many studies have used vibrotactile stimulations and reported finger somatotopic representations in the Brodmann area 3 (BA 3). On the contrary, few studies investigated finger somatotopic representation using pressure stimulations. Therefore, the present study aimed to find a comprehensive somatotopic representation (somatotopic map and inter- and intra-digit distance) within BA 2 of humans that could describe tactile stimulations on different joints across the fingers by applying pressure stimulation to three joints-the first (p1), second (p2), and third (p3) joints-of four fingers (index, middle, ring, and little finger). Significant differences were observed in the inter-digit distance between the first joints (p1) of the index and little fingers, and between the third joints (p3) of the index and little fingers. In addition, a significant difference was observed in the intra digit distance between p1 and p3 of the little finger. This study suggests that a somatotopic map and inter- and intra-digit distance could be found in BA 2 in response to pressure stimulation on finger joints. PMID- 27452861 TI - Significant up-regulation of 1-ACBP, B-ACBP and PBR genes in immune cells within the oesophageal malignant tissue and a possible link in carcinogenic angiogenesis. AB - Oesophageal cancer ranks as the sixth most common malignancy in the world, and recent evidence has shown that its incidence is increasing. ACBPs (Acyl-coA binding proteins) act as intracellular carrier-proteins for medium to long chain acyl-coA, mediating fatty acid transport to the mitochondrion for beta-oxidation. ACBPs are also believed to be putative ligands of PBR (peripheral benzodiazepine receptor), and once they bind to this receptor they facilitate mitochondrial membrane permeabilization, presumably favouring apoptosis. The main aim of the study was to establish the expression patterns of 1- Acyl-coA binding proteins (1 ACBP), B- Acyl-coA binding proteins (B-ACBP), and peripheral bezodiazepine receptor (PBR) in oesophageal cancer, and to link their roles with the disease. In situ hybridization and quantitative real-time PCR methods were performed to determine localization and the expression levels of the three genes in oesophageal cancer. All three genes illustrated substantial up-regulation within the malignant tissue sections as compared to normal oesophageal sections, all three transcripts localized specifically to mast cells, plasma cells and lymphocytes in diseased and normal tissue section. In the diseased tissue B-ACBP and 1-ACBP mRNA localized to endothelial cells of blood vessels in the submucosa. B-ACBP also localized to the nucleus of squamous epithelial cells. PBR localization was indicated in tumour islands of invasive tissue sections. Quantitative RT-PCR also indicated that the expression levels of PBR were higher as compared to the ACBP genes expression in tumours. These results show that 1 ACBP, B-ACBP and PBR play a role in the pathogenesis of oesophageal tumours and possibly in carcinogenic angiogenesis. PMID- 27452860 TI - Oral CoQ10 attenuates high salt-induced hypertension by restoring neurotransmitters and cytokines in the hypothalamic paraventricular nucleus. AB - High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1beta, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1beta, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension. PMID- 27452862 TI - The therapeutic effect of bevacizumab on plaque neovascularization in a rabbit model of atherosclerosis during contrast-enhanced ultrasonography. AB - The purpose of the study was to assess the therapeutic effect of the angiogenesis inhibitor bevacizumab on plaques of various stages in rabbit models using contrast-enhanced ultrasonography (CEUS). Abdominal aortic atherosclerosis was induced in 55 rabbits. Thirty-six randomly selected rabbits were divided into 2 groups according to the timing of the bevacizumab injection: an early-stage plaque group (Group ESP) and a later-stage plaque group (Group LSP). The remainder were considered the control group. Standard ultrasonography and CEUS imaging of the abdominal aorta were performed. The animals were euthanized after CEUS, and plaque specimens were harvested for histological staining of CD31. The control group exhibited a substantially higher enhanced intensity, a higher ratio of enhanced intensity in the plaque to that in the lumen, and an increased number of CD31-positive microvessels in the plaque sections than Groups ESP and LSP (P < 0.05 for all). A higher enhanced intensity (P = 0.044), a higher ratio of enhanced intensity in the plaque to that in the lumen (P = 0.023) and more CD31 positive microvessels in the plaque sections (P = 0.006) were found in Group LSP than in Group ESP. Bevacizumab demonstrated more advanced inhibition of neovascularization in early-stage plaques in rabbits. PMID- 27452863 TI - Activation of alpha2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint. AB - This study tested whether activation of adrenoreceptors in chondrocytes has roles in degenerative remodelling of temporomandibular joint (TMJ) and to determine associated mechanisms. Unilateral anterior crossbite (UAC) was established to induce TMJ degeneration in rats. Saline vehicle, alpha2- and beta-adrenoreceptor antagonists or agonists were injected locally into the TMJ area of UAC rats. Cartilage degeneration, subchondral bone microarchitecture and the expression of adrenoreceptors, aggrecans, matrix metalloproteinases (MMPs) and RANKL by chondrocytes were evaluated. Chondrocytes were stimulated by norepinephrine to investigate signal transduction of adrenoreceptors. Increased alpha2A adrenoreceptor expression was observed in condylar cartilage of UAC rats, together with cartilage degeneration and subchondral bone loss. Norepinephrine depresses aggrecans expression but stimulates MMP-3, MMP-13 and RANKL production by chondrocytes through ERK1/2 and PKA pathway; these effects were abolished by an alpha2A-adrenoreceptor antagonist. Furthermore, inhibition of alpha2A adrenoreceptor attenuated degenerative remodelling in the condylar cartilage and subchondral bone, as revealed by increased cartilage thickness, proteoglycans and aggrecan expression, and decreased MMP-3, MMP-13 and RANKL expressions in cartilage, increased BMD, BV/TV, and decreased Tb.Sp in subchondral bone. Conversely, activation of alpha2A-adrenoreceptor intensified aforementioned degenerative changes in UAC rats. It is concluded that activation of alpha2A adrenergic signal in chondrocytes promotes TMJ degenerative remodelling by chondrocyte-mediated pro-catabolic activities. PMID- 27452864 TI - Strain-dependent and distinctive T-cell responses to HIV antigens following immunisation of mice with differing chimpanzee adenovirus vaccine vectors. AB - In vivo vaccination studies are conventionally conducted in a single mouse strain with results, only reflecting responses to a single immunogenetic background. We decided to examine the immune response to an HIV transgene (gag, pol and nef fusion protein) in 3 strains of mice (CBA, C57BL/6 and BALB/c) to determine the spectrum of responses and in addition to determine whether the serotype of the adenoviral vector used (ChAd3 and ChAd63) impacted the outcome of response. Our results demonstrated that all three strains of mice responded to the transgene and that the magnitude of responses were different between the strains. The C57BL/6 strain showed the lowest range of responses compared to the other strains and, very few responses were seen to the same peptide pool in all three strains of mice. In CBA and BALB/c mice there were significant differences in IFNgamma production dependent on the adenoviral vector used. Our results suggest that employing a single strain of mouse may underestimate the efficacy and efficiency of vaccine products. PMID- 27452865 TI - Safety of the 2011-12, 2012-13, and 2013-14 seasonal influenza vaccines in pregnancy: Preterm delivery and specific malformations, a study from the case control arm of VAMPSS. AB - BACKGROUND: Pregnant women have higher risks of influenza complications, but vaccine coverage is incomplete. Because concern about fetal harm limits uptake, we investigated risks for preterm delivery (PTD) and specific birth defects following vaccination in the 2011-12 through 2013-14 influenza seasons. METHODS: We used data from the Slone Epidemiology Center's Birth Defects Study. For PTD, propensity score-adjusted time-varying hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for exposure anytime in pregnancy and for each trimester. For 42 specific major birth defects or birth defect categories, propensity score-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS: For PTD (1803 fullterm deliveries, 107 PTD for all seasons combined), an elevated adjusted risk was observed for only the 2nd trimester of the 2011-12 season (HR=2.60, 95% CI 1.21, 5.61) - a reduction in gestational length of <2days. For the 42 specific defects or categories of defects (2866 cases, 1411 controls for all seasons combined) most adjusted risks were close to 1.0; the highest was 2.38 for omphalocele and the lowest was 0.50 for atrioventricular canal defects. None had lower confidence bounds >1.0. For each season separately, only one elevated OR had a lower 95% CI >1.0: omphalocele in 2011-12 (OR=5.19, 95% CI 1.44, 18.7). CONCLUSIONS: Our results regarding risks for PTD and birth defects are generally reassuring. The few risks that were observed are compatible with chance, but warrant testing in other data. Given that vaccine components and manufacturing processes vary, continuing studies are needed to evaluate risks and safety of each season's vaccine and specific products. PMID- 27452866 TI - Vaccine-preventable disease-related hospitalization among immigrants and refugees to Canada: Study of linked population-based databases. AB - While immigrants tend to be healthier especially when they first arrived, this healthy immigrant effect may not apply to vaccine-preventable diseases (VPD) especially among immigrants from countries without vaccination programs. There is therefore an important information gap regarding differential health outcome and hospitalization usage by immigrant status, landing cohort, world region and immigrant category. This study focused on acute-care hospitalization, and used two recently linked population-based databases in Canada, namely, the 2006 Census linked to the Hospital Discharge Abstract (DAD), and the Immigrant Landing File linked to the DAD (ILF-DAD) to estimate crude and age-standardized VPD-related hospitalization rates (ASHR) by the above-mentioned immigrant characteristics to be compared with that for overall Canadian-born reference population. Based on the 2006 Census-DAD linked database, VPD-specific ASHR for overall immigrants was significantly higher than that for the Canadian-born population (1.6, 95% CI, 1.5, 1.6 vs 1.2, 95% CI, 1.1, 1.2, respectively). VPD-specific ASHRs by landing cohorts also increased with years in Canada (e.g. 1.4, 95% CI, 1.3, 1.5 for the 1990-2006 cohort, and 1.6, 95% CI, 1.5, 1.7 for the pre-1980 cohort). Based on the 1980-2006 ILF-DAD, the VPD-specific ASHRs were highest among Southeast and East Asians (e.g. 2.1, 95% CI, 1.9, 2.3 for East Asia). Compared with the Canadian-born, economic class immigrants overall had significantly lower ASHR (1.4, 95% CI 1.2, 1.6), but the low rate was mainly due to the dependants (spouse or children) within this class (0.8, 95% CI 0.6, 1.1). Both family and refugee categories had significantly higher ASHRs (1.3, 95% CI, 1.2, 1.5 and 1.7, 95% CI, 1.4, 2.1, respectively), especially among those refugees assisted by government (2.0, 95% CI, 1.4, 2.6). With increasing immigration, changing source countries and emerging needs for refugee settlements in Canada, these newly linked datasets help to monitor VPD-related hospitalization pattern among Canadian immigrants. PMID- 27452867 TI - Adaptive immune response to whole cell pertussis vaccine reflects vaccine quality: A possible complementation to the Pertussis Serological Potency test. AB - Whole cell Bordetella pertussis (wP) vaccines are still used in many countries to protect against the respiratory disease pertussis. The potency of whole-cell pertussis vaccine lots is determined by an intracerebral challenge test (the Kendrick test). This test is criticized due to lack of immunological relevance of the read-out after an intracerebral challenge with B. pertussis. The alternative in vivo test, which assesses specific antibody levels in serum after wP vaccination, is the Pertussis Serological Potency test (PSPT). Although the PSPT focuses on a parameter that contributes to protection, the protective immune mechanisms after wP vaccination includes more elements than specific antibody responses only. In this study, additional parameters were investigated, i.e. circulating pro-inflammatory cytokines, antibody specificity and T helper cell responses and it was evaluated whether they can be used as complementary readout parameters in the PSPT to assess wP lot quality. By deliberate manipulation of the vaccine preparation procedure, a panel of high, intermediate and low quality wP vaccines were made. The results revealed that these vaccines induced similar IL-6 and IP10 levels in serum 4h after vaccination (innate responses) and similar antibody levels directed against the entire bacterium. In contrast, the induced antibody specificity to distinct wP antigens differed after vaccination with high, intermediate and low quality wP vaccines. In addition, the magnitude of wP induced Th cell responses (Th17, Th1 and Th2) was reduced after vaccination with a wP vaccine of low quality. T cell responses and antibody specificity are therefore correlates of qualitative differences in the investigated vaccines, while the current parameter of the PSPT alone was not sensitive enough to distinguish between vaccines of different qualities. This study demonstrates that assessment of the magnitude of Th cell responses and the antigen specificity of antibodies induced by wP vaccination could form valuable complementary parameters to the PSPT. PMID- 27452868 TI - A Cell-Cell Communication-Based Screening System for Novel Microbes with Target Enzyme Activities. AB - The development of synthetic biological devices has increased rapidly in recent years and the practical benefits of such biological devices are becoming increasingly clear. Here, we further improved the design of a previously reported high-throughput genetic enzyme screening system by investigating device compatible biological components and phenol-mediated cell-cell communication, both of which increased the efficiency and practicality of the screening device without requiring the use of flow cytometry analysis. A sensor cell was designed to detect novel microbes with target enzyme activities on solid media by forming clear, circular colonies with fluorescence around the unknown microbes producing target enzymes. This mechanism of detection was enabled by the combination of pre effector phenolic substrate treatment in the presence of target enzyme-producing microbes and control of the growth and fluorescence of remote sensor cells via phenol-mediated cell-cell communication. The sensor cells were applied to screen soil bacteria with phosphatase activity using phenyl phosphate as phenolic substrates. The sensor cells facilitated successful visualization of phosphatase activity in unknown microbes, which were identified by 16S rRNA analysis. Enzyme activity assays confirmed that the proposed screening technique was able to find 23 positive clones out of 33 selected colonies. Since many natural enzymatic reactions produce phenolic compounds from phenol-derived substrates, we anticipate that the proposed technique may have broad applications in the assessment and screening of novel microbes with target enzymes of interest. This method also can provide insights into the identification of novel enzymes for which screening assays are not yet available. PMID- 27452869 TI - Upshaw-Schulman syndrome and pregnancy: successful management with plasma infusions. PMID- 27452870 TI - Accounting for Competing Events in Multivariate Analyses of Hospital-Acquired Infection Risk Factors. PMID- 27452871 TI - Protein quality as determined by the Digestible Indispensable Amino Acid Score: evaluation of factors underlying the calculation. AB - The Food and Agriculture Organization of the United Nations recently recommended the adoption of a new and improved scoring system (Digestible Indispensable Amino Acid Score [DIAAS]) to quantify dietary protein quality. The DIAAS is based on the relative digestible content of the indispensable amino acids (IAAs) and the amino acid requirement pattern. Factors involved in calculation of the DIAAS include: use of the content and profile of IAAs as the basis for quality; methods for determination of the protein and amino acid content of the protein source; accuracy of individual requirement values for IAAs; normalization of IAA requirements by the estimated average requirement for protein; and basing the DIAAS on the true ileal digestibility of each IAA in the test protein. This review outlines the rationale for including each of these factors in the calculation of the DIAAS and describes associated potential errors. PMID- 27452872 TI - Polaritonic Rabi and Josephson Oscillations. AB - The dynamics of coupled condensates is a wide-encompassing problem with relevance to superconductors, BECs in traps, superfluids, etc. Here, we provide a unified picture of this fundamental problem that includes i) detuning of the free energies, ii) different self-interaction strengths and iii) finite lifetime of the modes. At such, this is particularly relevant for the dynamics of polaritons, both for their internal dynamics between their light and matter constituents, as well as for the more conventional dynamics of two spatially separated condensates. Polaritons are short-lived, interact only through their material fraction and are easily detuned. At such, they bring several variations to their atomic counterpart. We show that the combination of these parameters results in important twists to the phenomenology of the Josephson effect, such as the behaviour of the relative phase (running or oscillating) or the occurence of self trapping. We undertake a comprehensive stability analysis of the fixed points on a normalized Bloch sphere, that allows us to provide a generalized criterion to identify the Rabi and Josephson regimes in presence of detuning and decay. PMID- 27452873 TI - Identification of common and differential mechanisms of glomerulus and tubule senescence in 24-month-old rats by quantitative LC-MS/MS. AB - Kidney aging together with related renal disease had become a major clinical problem. Understanding the mechanisms of aging was important for suspending senescence and decreasing the incidence of aging-related diseases. In the present work, 24-month-old F344 rats were used as aging rats and 3-month-old rats were used as young controls. Senescence-associated-beta-galactosidase staining results showed that the degree of senescence in renal tubules was more severe than that in glomeruli. We performed quantitative LC-MS to assess the differential protein expression profiles of senescent glomeruli and tubules. Bioinformatics analysis showed that aging, response to oxidative stress, nucleotide metabolism, amine acid metabolism, and inflammatory response were common mechanisms of glomerulus and tubule senescence. Differentially expressed proteins network mediated Golgi vesicle transport, actin filament based process, and regulation of cell death were associated with tubule senescence. More importantly, we found that the changes of four and a half LIM protein 2 (FHL2) were opposite in senescent glomeruli and tubules, and FHL2 could regulate p16 by suppressing T-box 3, which was involved in regulation of senescence in glomeruli and tubules. In conclusion, we assessed the mechanisms of senescence in aging glomeruli and tubules, and the results yielded new insight into kidney senescence. PMID- 27452874 TI - Differentiation of neurodegenerative parkinsonian syndromes by volumetric magnetic resonance imaging analysis and support vector machine classification. AB - BACKGROUND: Clinical differentiation of parkinsonian syndromes is still challenging. OBJECTIVES: A fully automated method for quantitative MRI analysis using atlas-based volumetry combined with support vector machine classification was evaluated for differentiation of parkinsonian syndromes in a multicenter study. METHODS: Atlas-based volumetry was performed on MRI data of healthy controls (n = 73) and patients with PD (204), PSP with Richardson's syndrome phenotype (106), MSA of the cerebellar type (21), and MSA of the Parkinsonian type (60), acquired on different scanners. Volumetric results were used as input for support vector machine classification of single subjects with leave-one-out cross-validation. RESULTS: The largest atrophy compared to controls was found for PSP with Richardson's syndrome phenotype patients in midbrain (-15%), midsagittal midbrain tegmentum plane (-20%), and superior cerebellar peduncles (-13%), for MSA of the cerebellar type in pons (-33%), cerebellum (-23%), and middle cerebellar peduncles (-36%), and for MSA of the parkinsonian type in the putamen (-23%). The majority of binary support vector machine classifications between the groups resulted in balanced accuracies of >80%. With MSA of the cerebellar and parkinsonian type combined in one group, support vector machine classification of PD, PSP and MSA achieved sensitivities of 79% to 87% and specificities of 87% to 96%. Extraction of weighting factors confirmed that midbrain, basal ganglia, and cerebellar peduncles had the largest relevance for classification. CONCLUSIONS: Brain volumetry combined with support vector machine classification allowed for reliable automated differentiation of parkinsonian syndromes on single-patient level even for MRI acquired on different scanners. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27452875 TI - Carrying capacity in arid rangelands during droughts: the role of temporal and spatial thresholds. AB - Assessing the carrying capacity is of primary importance in arid rangelands. This becomes even more important during droughts, when rangelands exhibit non equilibrium dynamics, and the dynamics of livestock conditions and forage resource are decoupled. Carrying capacity is usually conceived as an equilibrium concept, that is, the consumer density that can co-exist in long-term equilibrium with the resource. As one of the first, here we address the concept of carrying capacity in systems, where there is no feedback between consumer and resource in a limited period of time. To this end, we developed an individual-based model describing the basic characteristics of a rangeland during a drought. The model represents a rangeland composed by a single water point and forage distributed all around, with livestock units moving from water to forage and vice versa, for eating and drinking. For each livestock unit we implemented an energy balance and we accounted for the gut-filling effect (i.e. only a limited amount of forage can be ingested per unit time). Our results showed that there is a temporal threshold above which livestock begin to experience energy deficit and burn fat reserves. We demonstrated that such a temporal threshold increases with the number of animals and decreases with the rangeland conditions (amount of forage). The temporal threshold corresponded to the time livestock take to consume all the forage within a certain distance from water, so that the livestock can return to water for drinking without spending more energy than they gain within a day. In this study, we highlight the importance of a time threshold in the assessment of carrying capacity in non-equilibrium conditions. Considering this time threshold could explain contrasting observations about the influence of livestock number on livestock conditions. In case of private rangelands, the herd size should be chosen so that the spatial threshold equals (or exceeds) the length of the drought. PMID- 27452876 TI - Limited mechanical effects of intermuscular myofascial connections within the intact rat anterior crural compartment. AB - Skeletal muscles of the rat anterior crural compartment are mechanically connected by epimuscular myofascial connections, but the relevance for mechanical muscle function within physiological ranges of joint motion is unclear. We evaluated the net effect at the ankle joint of epimuscular myofascial connections between tibialis anterior (TA) and extensor digitorum longus (EDL) muscles in the rat (n=8) and determined which anatomical structures may mediate such epimuscular mechanical interactions. We assessed (1) effects of knee angle (i.e. changes in EDL length and position relative to TA) and interactions of knee angle with fasciotomy and proximal EDL tenotomy on TA ankle moment and (2) the effect of knee angle on TA and EDL ankle moment summation. Knee angle was varied between 60 degrees and 130 degrees . Ankle angle was kept constant (90 degrees ). TA and EDL were excited individually and simultaneously (TA&EDL). The mathematical sum of individual TA and EDL moments was compared with the moment exerted by TA&EDL to assess the extent of non-additive ankle moment summation. Magnitude of TA ankle moment was not affected by knee angle, but frontal plane moment direction was. However, dissections indicated that this was not caused by the compartmental fascia or EDL length changes. Moment summation was non-additive in magnitude (+1.1+/-1.1% mean+/-s.d.) and frontal plane direction. The latter was affected by knee angle and ranged from +0.2+/-0.3 degrees at 60 degrees to +1.1+/-0.6 degrees at 130 degrees . As the net effects found were very limited, we conclude that myofascial connections between muscles in the anterior crural compartment have limited mechanical relevance during normal movement. PMID- 27452877 TI - Artificial neural networks to predict 3D spinal posture in reaching and lifting activities; Applications in biomechanical models. AB - Spinal posture is a crucial input in biomechanical models and an essential factor in ergonomics investigations to evaluate risk of low back injury. In vivo measurement of spinal posture through the common motion capture techniques is limited to equipped laboratories and thus impractical for workplace applications. Posture prediction models are therefore considered indispensable tools. This study aims to investigate the capability of artificial neural networks (ANNs) in predicting the three-dimensional posture of the spine (S1, T12 and T1 orientations) in various activities. Two ANNs were trained and tested using measurements from spinal postures of 40 male subjects by an inertial tracking device in various static reaching and lifting (of 5kg) activities. Inputs of each ANN were position of the hand load and body height, while outputs were rotations of the three foregoing segments relative to their initial orientation in the neutral upright posture. Effect of posture prediction errors on the estimated spinal loads in symmetric reaching activities was also investigated using a biomechanical model. Results indicated that both trained ANNs could generate outputs (three-dimensional orientations of the segments) from novel sets of inputs that were not included in the training processes (root-mean-squared-error (RMSE)<11 degrees and coefficient-of-determination (R2)>0.95). A graphic user interface was designed and made available to facilitate use of the ANNs. The difference between the mean of each measured angle in a reaching task and the corresponding angle in a lifting task remained smaller than 8 degrees . Spinal loads estimated by the biomechanical model based on the predicted postures were on average different by < 12% from those estimated based on the exact measured postures (RMSE=173 and 35N for the L5-S1 compression and shear loads, respectively). PMID- 27452878 TI - Comparison of cortisol and thyroid hormones between tuberculosis-suspect and healthy elephants of Nepal. AB - We compared cortisol and thyroid hormone (T3 and T4) concentrations between tuberculosis (TB)-suspected (n=10) and healthy (n=10) elephants of Nepal. Whole blood was collected from captive elephants throughout Nepal, and TB testing was performed using the ElephantTB STAT-PAK(r) and DPP VetTB(r) serological assays that detect antibodies against Mycobacterium tuberculosis and M. bovis in elephant serum. Cortisol, T3 and T4 were quantified by competitive enzyme immunoassays, and the results showed no significant differences in hormone concentrations between TB-suspect and healthy elephants. These preliminary data suggest neither adrenal nor thyroid function is altered by TB disease status. However, more elephants, including those positively diagnosed for TB by trunk wash cultures, need to be evaluated over time to confirm results. PMID- 27452879 TI - Molecular epidemiology of pathogenic Leptospira spp. among large ruminants in the Philippines. AB - The extent of Leptospira infection in large ruminants resulting to economic problems in livestock industry in a leptospirosis-endemic country like the Philippines has not been extensively explored. Therefore, we determined the prevalence and carrier status of leptospirosis in large ruminants using molecular techniques and assessed the risk factors of acquiring leptospirosis in these animals. Water buffalo and cattle urine samples (n=831) collected from 21 farms during 2013-2015 were subjected to flaB-nested PCR to detect pathogenic Leptospira spp. Leptospiral flaB was detected in both species with a detection rate of 16.1%. Leptospiral DNA was detected only in samples from animals managed in communal farms. Sequence analysis of Leptospira flaB in large ruminants revealed the formation of three major clusters with L. borgpetersenii or L. kirschneri. One farm contained Leptospira flaB sequences from all clusters identified in this study, suggesting this farm was the main source of leptospires for other farms. This study suggested that these large ruminants are infected with various pathogenic Leptospira species causing possible major economic loss in the livestock industry as well as potential Leptospira reservoirs that can transmit infection to humans and other animals in the Philippines. PMID- 27452880 TI - Combination of carvacrol and thymol against the poultry red mite (Dermanyssus gallinae). AB - Pest management by conventional pesticides has become progressively hindered by developing pest resistance and increase in consumers demand for safe and residue free foodstuffs. This will create a considerable market opportunity for alternative products, including botanical pesticides. The present study was conducted to assess the combination of carvacrol and thymol, their repellent activity, and residual toxicity against Dermanyssus gallinae with the aim of designing a new strategy relying on natural compounds for the control of D. gallinae. Different ratios of carvacrol-thymol, 5:0, 4:1, 3:2, 2:3, 1:4, and 0:5 based on LD50 values, were tested for their toxicity on D. gallinae. For residual toxicity assay, mortality rate of mites recorded after being exposed to the surfaces 1, 3, 7, 14, 21, and 28 days post spraying by carvacrol-thymol preparation. In combination toxicity, carvacrol-thymol in 4:1 ratio showed the highest efficacy against D. gallinae. The highest repellent activity was observed in carvacrol-thymol 5:0 combination. Addition of thymol to carvacrol resulted in a decrease in repellent activity of carvacrol as was seen in carvacrol-thymol 3:2, 2:3, and 1:4 ratios (p < 0.05). Carvacrol-thymol in 4:1 ratio at 2 % concentration displayed good residual toxicity and was effective against D. gallinae till 14 days post spraying (p < 0.05). The present study showed that the combination of carvacrol-thymol particularly with a 4:1 ratio displayed improved acaricidal activity and good residual toxicity. However, combining the application of carvacrol and thymol did not show any synergistic effect on repellent activity. Overall, carvacrol-thymol can be suggested as an alternative strategy for the control of D. gallinae. PMID- 27452881 TI - Histological location of myxosporean plasmodia in fish tissue with Luna's method. AB - In the present study, a staining technique, Luna's method, has been used for detection and tissue location of myxosporean spores/plasmodia in histological sections of gills and liver. The Luna's staining was performed on the sections of the tissue fixed in Bouin's, embedded in paraffin wax. The mature plasmodia were stained in bright red color and pansporoblasts and gill tissue stained in blue. This staining helped to detect and locate even a single myxospore of less than 15 MUm in size located within the tissues of the host. PMID- 27452882 TI - Collagenase-I and stromelysin distribution in fresh human herniated intervertebral disc: A possible link to the in vivo inflammatory reactions. AB - Chondrocytes may play an Important role in the inflammatory reactions involving intervertebral discs: the role of metalloproteases (MMP.) and the imbalance between proteases and their inhibitors seems to play a crucial role in the disc degenerative process. In the present study we have analysed the production of collagenase-1 and stromelysin in different parts of herniated intervertebral discs. Ten samples of herniated lumbar discs were obtained from adult patients operated on for primary microdiscectomy because of persistent radicular symptoms and subdivided into three samples: 1. The nearest to the nerve root in close contact with it, 2. the sample obtained from the intervertebral space, and 3. the sample obtained from the vertebral plates. The DNA content of each specimen was measured in order to obtain the best estimate of the cell content as well as to normalise the content of collagenase-1 and stromelysin found in the same tissues with respect to the number of cells. In 9 out of the 7 0 cases the DNA content was significantly higher in samples obtained from the intervertebral plates than in samples obtained near the nerve root or the intervertebral space. DNA content did not show any significant difference considering disc samples contiguous to the nerve root and samples obtained from the intervertebral space. The production of collagenase-1 did not show a specific pattern, being produced in similar quantities in the three disc compartments. The production of stromelysin was significantly lower in disc samples obtained from the intervertebral plates. In conclusion the results of the present study suggest firstly that in the herniated lumbar disc the reactivity and the production of pro-inflammatory agents is independent of DNA content, i.e. the cellularity of the sample, and secondly that activated cells in the intervertebral space and in the part of the disc in contact with the nerve root, even if scarce in number, are able to synthesise a proportionally higher quantity of MMP than the high-cellular disc fragments from the intervertebral plates, potentially playing a specific role in the inflammatory reactions. [Neurol Res 1999; 21: 677-681]. PMID- 27452883 TI - Primary Care Physicians' Experiences With and Attitudes Toward Pediatric Quality Reporting. AB - OBJECTIVE: To assess primary care providers' experiences with and attitudes toward pediatric-focused quality reports and identify key associated physician/practice characteristics. METHODS: We performed a cross-sectional survey of pediatricians and family physicians providing primary care to publicly insured children in 3 states (North Carolina, Ohio, Pennsylvania). The survey included questions about receipt of pediatric quality reports, use of reports for quality improvement (QI), and beliefs about the effectiveness of reports for QI. We used multivariable analyses to assess associations between responses and physician/practice characteristics, including exposure to federally funded demonstration projects aimed at increasing quality reporting to physicians serving publicly insured children. We supplemented these analyses with a thematic investigation of data from 46 interviews with physicians, practice staff, and state demonstration staff. RESULTS: Seven hundred twenty-seven physicians responded to the survey (overall response rate: 45.2%). Most physicians were receiving quality reports related to pediatric care (79.8%; 95% confidence interval [CI], 77.2%-82.4%) and believed that quality reports can be effective in helping guide QI (70.5%; 95% CI, 67.5%-73.5%). Fewer used quality reports to guide QI efforts (32.5%; 95% CI, 29.5%-35.6%). There were no significant associations between demonstration exposure and experiences or attitudes. Interview data suggested that physicians were receptive to quality reporting, but significant barriers remain to using such reports for QI, such as limited staff time or training in QI. CONCLUSIONS: Although pediatric quality reporting is considered a promising strategy, in this study, state efforts appeared insufficient to overcome the barriers to using reports to guide practice-based QI. PMID- 27452884 TI - Recombinant human soluble thrombomodulin and short-term mortality of infection patients with DIC: a meta-analysis. AB - OBJECTIVE: Several studies have demonstrated that recombinant human soluble thrombomodulin (rhTM) has potential advantages for the treatment for patients with infection complicated by disseminated intravascular coagulation (DIC). However, whether injection of rhTM can affect the mortality of those patients in clinical treatment remains controversial. Therefore, we conducted a meta-analysis to evaluate the clinical efficacy for patients with infection complicated by DIC. METHODS: The PubMed, Web of Science, Embase, and Cochrane Library databases were searched for relevant articles that met the inclusion criteria through April 2016. Reference lists of the retrieved articles were also reviewed. The 28- or 30 day mortality and bleeding risk after using rhTM were evaluated. RESULTS: Ten observational studies and 2 randomized controlled trials (RCTs) involving 18288 patients were included in this meta-analysis. The risk ratio for the 28- or 30 day mortality was 0.81 (95% confidence interval, 0.61-1.06) in RCT studies and 0.96 (95% confidence interval, 0.92-1.01) in observational studies. There were no significant differences in the bleeding risk between the rhTM group and the control group. CONCLUSION: Based on the current studies, using rhTM for the treatment for infection patients complicated with DIC does not decrease the short term mortality of those patients. More high-quality RCT studies need to be performed to confirm this finding. PMID- 27452885 TI - Allergic reaction from fingerprint kit attributable to unlabeled gluten, probable wheat flour. PMID- 27452887 TI - Antibiotics for respiratory infections during pregnancy: prevalence and risk factors. PMID- 27452886 TI - Level of Asthma Controller Therapy Before Admission to the Hospital. AB - BACKGROUND: In asthma, choice of controller therapy and adherence to treatment can affect the risk of future severe exacerbations leading to hospitalization. OBJECTIVE: Our objective was to characterize treatment dispensation profiles before hospital admission for asthma. METHODS: Using a 1/97th random sample of the national French claims data, patients with asthma aged 6 to 40 years were identified between 2006 and 2014. Patients with subsequent asthma-related hospitalization were selected. On the basis of controller therapy dispensed in the 12 months before admission, treatment profiles were categorized into clusters, using Ward's minimum-variance hierarchical clustering method. RESULTS: Of 17,846 patients with asthma, we identified 275 patients (1.5%) with an asthma related hospitalization. Three distinct clusters were identified. The first cluster (63.6%) included patients with few dispensations of any controller medication (<1 unit). The second cluster (32.4%) consisted of patients with frequent dispensations of long-acting beta agonists (LABAs)/inhaled corticosteroids (ICS) in fixed-dose combinations. The third cluster (4%) comprised patients receiving free combinations of ICS and LABAs, with more dispensations of LABAs than of ICS. CONCLUSIONS: In France, before an asthma related hospitalization, more than 60% of patients received little controller therapy and 4% were exposed to higher dispensation of LABAs than of ICS. These results indicate that a large fraction of asthma-related hospitalizations can potentially be prevented with better pharmacotherapy. PMID- 27452888 TI - Sublingual Immunotherapy for the Polyallergic Patient. AB - Allergen immunotherapy is the only disease-modifying treatment for allergic diseases. Sublingual immunotherapy (SLIT) in liquid and tablet form has been used by clinicians in Europe for years, but has only recently gained popularity and approval in the United States. In 2014, the US Food and Drug Administration approved 3 SLIT tablets for the treatment of allergic rhinitis, with or without allergic conjunctivitis. Immunotherapy treatment strategies for the polysensitized patient vary between the United States and Europe. This variation hinges upon whether the polysensitized patient is truly polyallergic. Polysensitization is the positive response to 2 or more allergens on skin prick testing or in vitro specific-IgE testing. Polyallergy is the symptomatic clinical response to 2 or more allergens. In this review, we discuss the use of SLIT in the United States with a focus on treating the polyallergic patient with SLIT. PMID- 27452889 TI - A survey of aspirin desensitization practices among allergists and fellows in training in the United States. PMID- 27452890 TI - Contributions of knowledge products to health policy: a case study on the Public Health Status and Forecasts Report 2010. AB - BACKGROUND: The Dutch Public Health Status and Forecasts report (PHSF Report) integrates research data and identifies future trends affecting public health in the Netherlands. To investigate how PHSF contributions to health policy can be enhanced, we analysed the development process whereby the PHSF Report for 2010 was produced (PHSF-2010). METHOD: To collect data, a case study approach was used along the lines of Contribution Mapping including analysis of documents from the PHSF-2010 process and interviews with actors involved. All interviews were recorded and transcribed ad verbatim and coded using an inductive code list. RESULTS: The PHSF-2010 process included activities aimed at alignment between researchers and policy-makers, such as informal meetings. However, we identified three issues that are easily overlooked in knowledge development, but provide suggestions for enhancing contributions: awareness of divergent; continuously changing actor scenarios; vertical alignment within organizations involved and careful timing of draft products to create early adopters. CONCLUSION: To enhance the contributions made by an established public health report, such as the PHSF Report, it is insufficient to raise the awareness of potential users. The knowledge product must be geared to policy-makers' needs and must be introduced into the scenarios of actors who may be less familiar. The demand for knowledge product adaptations has to be considered. This requires continuous alignment efforts in all directions: horizontal and vertical, external and internal. The findings of this study may be useful to researchers who aim to enhance the contributions of their knowledge products to health policy. PMID- 27452892 TI - The health of UK civilians deployed to Iraq. AB - Background: Modern military operations have incorporated deployed civilians in a variety of roles (e.g. diplomats, private security staff). Many of these roles expose individuals to potentially dangerous or traumatic events. Evidence has shown that such exposures can cause psychological health problems in military personnel. It is likely that the same would be seen among civilians working in such environments. There is however limited research into the health of civilians deployed to war zones. This study compared health outcomes and related behaviours among UK regular and reserve Army personnel with UK civilian personnel deployed in direct support of the UK military in Iraq. Methods: The study sample comprised of 159 Ministry of Defence civilians, 1542 Army regulars and 408 Army reservists, all of whom served in non-combat roles. Data were gathered by questionnaires which asked about deployment experiences, lifestyle factors and health outcomes [i.e. post-traumatic stress disorder (PTSD), general health, multiple physical symptoms and alcohol use]. Results: Fewer deployed UK civilians smoked than regular Army personnel (adjusted OR 0.83 95% CI 0.70-0.98). UK civilians had better overall health and were less likely to report multiple physical symptoms compared with reservists (adjusted ORs 0.64 95% CI 0.44-0.93 and 0.60 95% CI 0.39 0.93, respectively). Conclusions: Overall, the psychological health of deployed civilians appears to be better than that of Army personnel deployed in non-combat roles. Civilians are also less likely to engage in some risky behaviours. PMID- 27452893 TI - Anxious and depressive symptoms in the French Asbestos-Related Diseases Cohort: risk factors and self-perception of risk. AB - Background: Asbestos is known to be an independent risk factor for lung and pleural cancers. However, to date, little attention has been paid to the psychological effects of asbestos exposure among exposed subjects. The objectives of this study were to estimate the prevalence of anxious and depressive symptoms among >2000 French participants of the Asbestos-Related Diseases Cohort (ARDCO), 6 years after their inclusion, to identify the risk factors associated with those anxious and depressive symptoms and to evaluate the impact of the asbestos-risk perception. Methods: The ARDCO was constituted in four regions of France between October 2003 and December 2005, by including former asbestos workers. Between 2011 and 2012, participants of the ARDCO program were invited to undergo another chest CT scan 6 years after the previous scan. Participants were asked to complete questionnaires including asbestos exposure assessment, Hospital Anxiety and Depression Scale (HADS), asbestos-risk perception and self-perception of asbestos-related diseases. Results: Among the 2225 participants, 2210 fully completed questionnaires were collected and analyzed. The prevalence of symptoms of probable anxiety and probable depression was 19.7% and 9.9%, respectively. The risk of anxious and depressive symptoms was independently associated with self perception of the intensity of asbestos exposure, asbestos-risk perception and self-perception of asbestos-related diseases. Conclusion: The results obtained in this large study confirm that previously asbestos-exposed subjects are likely to develop anxious and depressive symptoms. Finally, implications related to the prevention of anxiety and depression among asbestos-exposed workers is discussed. PMID- 27452894 TI - A national FFQ for the Netherlands (the FFQ-NL 1.0): validation of a comprehensive FFQ for adults. AB - A standardised, national, 160-item FFQ, the FFQ-NL 1.0, was recently developed for Dutch epidemiological studies. The objective was to validate the FFQ-NL 1.0 against multiple 24-h recalls (24hR) and recovery and concentration biomarkers. The FFQ-NL 1.0 was filled out by 383 participants (25-69 years) from the Nutrition Questionnaires plus study. For each participant, one to two urinary and blood samples and one to five (mean 2.7) telephone-based 24hR were available. Group-level bias, correlation coefficients, attenuation factors, de-attenuated correlation coefficients and ranking agreement were assessed. Compared with the 24hR, the FFQ-NL 1.0 estimated the intake of energy and macronutrients well. However, it underestimated intakes of SFA and trans-fatty acids and alcohol and overestimated intakes of most vitamins by >5 %. The median correlation coefficient was 0.39 for energy and macronutrients, 0.30 for micronutrients and 0.30 for food groups. The FFQ underestimated protein intake by an average of 16 % and K by 5 %, relative to their urinary recovery biomarkers. Attenuation factors were 0.44 and 0.46 for protein and K, respectively. Correlation coefficients were 0.43-0.47 between (fatty) fish intake and plasma EPA and DHA and 0.24-0.43 between fruit and vegetable intakes and plasma carotenoids. In conclusion, the overall validity of the newly developed FFQ-NL 1.0 was acceptable to good. The FFQ-NL 1.0 is well suited for future use within Dutch cohort studies among adults. PMID- 27452895 TI - Duly noted: Lessons from a two-site intervention to assess and improve the quality of clinical documentation in the electronic health record. AB - BACKGROUND: Communication errors are identified as a root cause contributing to a majority of sentinel events. The clinical note is a cornerstone of physician communication, yet there are few published interventions on teaching note writing in the electronic health record (EHR). This is a prospective, two-site, quality improvement project to assess and improve the quality of clinical documentation in the EHR using a validated assessment tool. METHODS: Internal Medicine (IM) residents at the University of Kentucky College of Medicine (UK) and Montefiore Medical Center/Albert Einstein College of Medicine (MMC) received one of two interventions during an inpatient ward month: either a lecture, or a lecture and individual feedback on progress notes. A third group of residents in each program served as control. Notes were evaluated with the Physician Documentation Quality Instrument 9 (PDQI-9). RESULTS: Due to a significant difference in baseline PDQI 9 scores at MMC, the sites were not combined. Of 75 residents at the UK site, 22 were eligible, 20 (91%) enrolled, 76 notes in total were scored. Of 156 residents at MMC, 22 were eligible, 18 (82%) enrolled, 40 notes in total were scored. Note quality did not improve as measured by the PDQI-9. CONCLUSION: This educational quality improvement project did not improve the quality of clinical documentation as measured by the PDQI-9. This project underscores the difficulty in improving note quality. Further efforts should explore more effective educational tools to improve the quality of clinical documentation in the EHR. PMID- 27452896 TI - Effects of Linearly Polarized Near-Infrared Irradiation Near the Stellate Ganglion Region on Pain and Heart Rate Variability in Patients with Neuropathic Pain. AB - Background: Neuropathic pain associated with sympathetic overactivity can be effectively relieved by light irradiating the region near stellate ganglion (SGI), applied as an alternative to a conventional sympathetic blockade. The clinical effect of SGI on heart rate variability (HRV) and its association with pain outcomes require investigation. Objective: This study attempted to identify the effects of SGI on pain outcomes and HRV indices and to determine the association between pain and HRV outcomes. Design: A prospective double-blind, randomized study. Setting: An outpatient pain medicine clinic. Subjects and Methods: A total of 44 patients were enrolled and randomized into the experimental group ( n = 22) and control group ( n = 22). The experimental group received 12 sessions (twice weekly) of standard SGI, whereas the control group received the same protocol with sham irradiation. Pain and HRV were measured before and after each irradiation session. All outcome measures used in the first and second-half treatment courses were analyzed. Results: Pain and HRV outcome measures of the experimental group significantly improved after SGI when compared with the control group in both courses. Considering time and frequency domains, the changes in HRV in the second-half treatment course exceeded those in the first-half treatment course. Pain was significantly associated with postirradiated HRV indices ( P < 0.001). Conclusions: Twelve sessions of SGI exerted time-dependent positive effects on pain and sympathovagal imbalance. HRV outcomes, including time and frequency domains, were an independent indicator of the clinical efficiency of SGI for treating pain in patients with neuropathic pain. PMID- 27452897 TI - Antimelanoma differentiation-associated protein 5 antibody level is a novel tool for monitoring disease activity in rapidly progressive interstitial lung disease with dermatomyositis. AB - BACKGROUND: Antimelanoma differentiation-associated protein (anti-MDA)5 antibodies are associated with rapidly progressive interstitial lung disease (RP ILD) in patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). OBJECTIVES: We aimed to evaluate the relevance of monitoring anti-MDA5 antibody levels for the management of RP-ILD in patients with CADM or DM. METHODS: Twelve patients with CADM (n = 10) or DM (n = 2) accompanied by RP-ILD were included. Baseline characteristics and outcomes were recorded. Serial measurements of anti-MDA5 antibody levels were measured. All patients were treated with corticosteroids, tacrolimus and intravenous cyclophosphamide. RESULTS: All patients achieved RP-ILD remission after combined immunosuppressive therapy for a mean of 6.8 months, with significant decreases noted in the mean anti-MDA5 antibody levels at remission. Six (50%) patients became anti-MDA5 antibody negative after therapy. After a mean follow-up of 31 months, RP-ILD relapse was observed in four (33%) patients in both the anti-MDA5 antibody sustained positive group and the negative conversion group. However, relapsed patients in the sustained positive group relapsed earlier than those in the negative conversion group. Thus, a decrease in anti-MDA5 antibody levels during remission was associated with longer remission. Relapses were associated with a reincrease of anti-MDA5 antibody levels in four of four (100%) patients. In contrast, none of the patients without reincrease in anti-MDA5 antibody exhibited symptoms of relapse during follow-up. Therefore, reincrease in anti MDA5 antibody levels was associated with relapse. CONCLUSIONS: The anti-MDA5 antibody level is a novel parameter for monitoring and a good predictor of RP-ILD relapse in patients with CADM or DM. PMID- 27452898 TI - Genome Analysis and Development of a Multiplex TaqMan Real-Time PCR for Specific Identification and Detection of Clavibacter michiganensis subsp. nebraskensis. AB - The reemergence of the Goss's bacterial wilt and blight disease in corn in the United States and Canada has prompted investigative research to better understand the genome organization. In this study, we generated a draft genome sequence of Clavibacter michiganensis subsp. nebraskensis strain DOAB 395 and performed genome and proteome analysis of C. michiganensis subsp. nebraskensis strains isolated in 2014 (DOAB 397 and DOAB 395) compared with the type strain, NCPPB 2581 (isolated over 40 years ago). The proteomes of strains DOAB 395 and DOAB 397 exhibited a 99.2% homology but had 92.1 and 91.8% homology, respectively, with strain NCPPB 2581. The majority (99.9%) of the protein sequences had a 99.6 to 100% homology between C. michiganensis subsp. nebraskensis strains DOAB 395 and DOAB 397, with only four protein sequences (0.1%) exhibiting a similarity <70%. In contrast, 3.0% of the protein sequences of strain DOAB 395 or DOAB 397 showed low homologies (<70%) with the type strain NCPPB 2581. The genome data were exploited for the development of a multiplex TaqMan real-time polymerase chain reaction (PCR) tool for rapid detection of C. michiganensis subsp. nebraskensis. The specificity of the assay was validated using 122 strains of Clavibacter and non-Clavibacter spp. A blind test and naturally infected leaf samples were used to confirm specificity. The sensitivity (0.1 to 1.0 pg) compared favorably with previously reported real-time PCR assays. This tool should fill the current gap for a reliable diagnostic technique. PMID- 27452899 TI - Chip Technologies for Screening Chemical and Biological Agents Against Plant Parasitic Nematodes. AB - Plant-parasitic nematodes cause substantial damage to agricultural crops worldwide. Long-term management of these pests requires novel strategies to reduce infection of host plants. Disruption of nematode chemotaxis to root systems has been proposed as a potential management approach, and novel assays are needed to test the chemotactic behavior of nematodes against a wide range of synthetic chemicals and root exudates. Two microfluidic chips were developed that measure the attraction or repulsion of nematodes to chemicals ("chemical chip") and young plant roots ("root chip"). The chip designs allowed for chemical concentration gradients to be maintained up to 24 h, the nematodes to remain physically separate from the chemical reservoirs, and for images of nematode populations to be captured using either a microscope or a flatbed scanner. In the experiments using the chemical chips, seven ionic solutions were tested on second stage juveniles (J2s) of Meloidogyne incognita and Heterodera glycines. Results were consistent with previous reports of repellency of M. incognita to a majority of the ionic solutions, including NH4NO3, KNO3, KCl, MgCl2, and CaCl2. H. glycines was found to be attracted to both NH4NO3 and KNO3, which has not been reported previously. A software program was written to aid in monitoring the location of nematodes at regular time intervals using the root chip. In experiments with the root chip, H. glycines J2s were attracted to roots of 3-day old, susceptible (cultivar Williams 82) soybean seedlings, and attraction of H. glycines to susceptible soybean was similar across the length of the root. Attraction to resistant (cultivar Jack) soybean seedlings relative to the water only control was inconsistent across runs, and H. glycines J2s were not preferentially attracted to the roots of resistant or susceptible cultivars when both were placed on opposite sides of the same root chip. The chips developed allow for direct tests of plant-parasitic nematode chemotaxis to chemicals and roots with minimal human intervention. PMID- 27452900 TI - Effect of Fungicide Applications on Monilinia fructicola Population Diversity and Transposon Movement. AB - In this study, we investigated whether fungicide-induced mutagenesis previously reported in Monilinia fructicola could accelerate genetic changes in field populations. Azoxystrobin and propiconazole were applied to nectarine trees at weekly intervals for approximately 3 months between bloom and harvest in both 2013 and 2014. Fungicides were applied at half-label rate to allow recovery of isolates and to increase chances of sublethal dose exposure. One block was left unsprayed as a control. In total, 608 single-spore isolates were obtained from blighted blossoms, cankers, and fruit to investigate phenotypic (fungicide resistance) and genotypic (simple-sequence repeat [SSR] loci and gene region) changes. In both years, populations from fungicide-treated and untreated fruit were not statistically different in haploid gene diversity (P = 0.775 for 2013 and P = 0.938 for 2014), allele number (P = 0.876 for 2013 and P = 0.406 for 2014), and effective allele number (P = 0.861 for 2013 and P = 0.814 for 2014). Isolates from blossoms and corresponding cankers of fungicide treatments revealed no changes in SSR analysis or evidence for induced Mftc1 transposon translocation. No indirect evidence for increased genetic diversity in the form of emergence of reduced sensitivity to azoxystrobin, propiconazole, iprodione, and cyprodinil was detected. High levels of population diversity in all treatments provided evidence for sexual recombination of this pathogen in the field, despite apparent absence of apothecia in the orchard. Our results indicate that fungicide-induced, genetic changes may not occur or not occur as readily in field populations as they do under continuous exposure to sublethal doses in vitro. PMID- 27452901 TI - The Semidwarfing Alleles Rht-D1b and Rht-B1b Show Marked Differences in Their Associations with Anther-Retention in Wheat Heads and with Fusarium Head Blight Susceptibility. AB - The semidwarfing alleles reduced height (Rht)-D1b and Rht-B1b are widely deployed in wheat breeding. Both alleles have similar effects on plant height but differ in their effect on Fusarium head blight (FHB) severity. A double-haploid population and a backcross population, segregating for Rht-B1a/Rht-B1b and Rht D1a/Rht-D1b, were evaluated for FHB severity, plant height, and anther retention in field trials in three consecutive years. The semidwarfing alleles reduced plant height and increased the proportion of retained anthers. Reduced plant height and a high proportion of retained anthers were associated with increased FHB severity. The Rht-D1b allele had a significantly greater impact on anther retention and FHB severity than the Rht-B1b allele. Fusarium graminearum establishes infection sites predominantly inside the floral cavity and retained anthers potentially support colonization and initial hyphal growth, leading to a higher disease level in genotypes with a higher proportion of retained anthers. This is the first report demonstrating that differences in disease severity associated with Rht-D1b and Rht-B1b can be partly explained by their different effect on the extent of anther retention. PMID- 27452902 TI - The urea carboxylase and allophanate hydrolase activities of urea amidolyase are functionally independent. AB - Urea amidolyase (UAL) is a multifunctional biotin-dependent enzyme that contributes to both bacterial and fungal pathogenicity by catalyzing the ATP dependent cleavage of urea into ammonia and CO2 . UAL is comprised of two enzymatic components: urea carboxylase (UC) and allophanate hydrolase (AH). These enzyme activities are encoded on separate but proximally related genes in prokaryotes while, in most fungi, they are encoded by a single gene that produces a fusion enzyme on a single polypeptide chain. It is unclear whether the UC and AH activities are connected through substrate channeling or other forms of direct communication. Here, we use multiple biochemical approaches to demonstrate that there is no substrate channeling or interdomain/intersubunit communication between UC and AH. Neither stable nor transient interactions can be detected between prokaryotic UC and AH and the catalytic efficiencies of UC and AH are independent of one another. Furthermore, an artificial fusion of UC and AH does not significantly alter the AH enzyme activity or catalytic efficiency. These results support the surprising functional independence of AH from UC in both the prokaryotic and fungal UAL enzymes and serve as an important reminder that the evolution of multifunctional enzymes through gene fusion events does not always correlate with enhanced catalytic function. PMID- 27452903 TI - Nosocomial bloodstream infections in neurosurgery: a 10-year analysis in a center with high antimicrobial drug-resistance prevalence. AB - BACKGROUND: Data on nosocomial bloodstream infections (NBSI) in neurosurgery is limited. This study aimed to analyze the epidemiology, microbiology, outcome, and risk factors for death in neurosurgical patients with NBSI in a multidrug resistant setting. METHODS: Neurosurgical patients with a confirmed NBSI within the period 2003-2012 were retrospectively analyzed. NBSI was diagnosed when a pathogen was isolated from a blood sample obtained after the first 48 h of hospitalization. Patients' demographic, clinical, and microbiological data were recorded and analyzed using univariate and multivariate analysis. RESULTS: A total of 236 patients with NBSI were identified and 378 isolates were recovered from blood cultures. Incidence of NBSI was 4.3 infections/1000 bed-days. Gram negative bacteria slightly predominated (54.5 %). The commonest bacteria were coagulase-negative staphylococci (CoNS, 26 %), Klebsiella pneumoniae (15.3 %), Pseudomonas aeruginosa (14.8 %), and Acinetobacter baumannii (13.2 %). Carbapenem resistance was found in 90 % of A. baumannii, in 66 % of P. aeruginosa, and in 22 % (2003-2007) to 77 % (2008-2012) of K. pneumoniae isolates (p < 0.05). Most CoNS and Staphylococcus aureus isolates (94 and 80 %, respectively) were methicillin resistant. All Gram-negative isolates were sensitive to colistin and all Gram positive isolates were sensitive to vancomycin and linezolid. Antimicrobial consumption decreased after 2007 (p < 0.05). Overall mortality was 50.4 %. In multivariate analysis, advanced age and stay in an Intermediate Care Unit (IMCU) were independent risk factors for in-hospital mortality (p < 0.05). CONCLUSIONS: Overall, high incidence of NBSI and considerable resistance of Gram-positive and particularly Gram-negative bacteria were noted in neurosurgical patients. Mortality was high with advanced age and stay in IMCU being the most important death-related factors. PMID- 27452904 TI - Waist-to-height ratio, body mass index and waist circumference for screening paediatric cardio-metabolic risk factors: a meta-analysis. AB - Waist-to-height ratio (WHtR) is superior to body mass index and waist circumference for measuring adult cardio-metabolic risk factors. However, there is no meta-analysis to evaluate its discriminatory power in children and adolescents. A meta-analysis was conducted using multiple databases, including Embase and Medline. Studies were included that utilized receiver-operating characteristics curve analysis and published area under the receiver-operating characteristics curves (AUC) for adiposity indicators with hyperglycaemia, elevated blood pressure, dyslipidemia, metabolic syndrome and other cardio metabolic outcomes. Thirty-four studies met the inclusion criteria. AUC values were extracted and pooled using a random-effects model and were weighted using the inverse variance method. The mean AUC values for each index were greater than 0.6 for most outcomes including hypertension. The values were the highest when screening for metabolic syndrome (AUC > 0.8). WHtR did not have significantly better screening power than other two indexes in most outcomes, except for elevated triglycerides when compared with body mass index and high metabolic risk score when compared with waist circumference. Although not being superior in discriminatory power, WHtR is convenient in terms of measurement and interpretation, which is advantageous in practice and allows for the quick identification of children with cardio-metabolic risk factors at an early age. PMID- 27452905 TI - Aminotroponiminates as tunable, redox-active ligands: reversible single electron transfer and reductive dimerisation. AB - Aminotroponiminates (atis) are shown to be redox-active ligands. Under strongly reducing conditions, the result of electron transfer can be controlled by the choice of the metal bound to the ati ligand. Either reversible electron transfer or a reductively induced dimerisation is observed. The latter reaction is (regio- and diastereo-) selective and chemically reversible. PMID- 27452906 TI - PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion. AB - Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells. PMID- 27452907 TI - Shikonin induces apoptosis of lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling antagonized by p300. AB - Shikonin derivatives exert powerful cytotoxic effects including induction of apoptosis. Here, we demonstrate the cytotoxic efficacy of shikonin in vivo in xenograft models, which did not affect body weight as well as its reduction of cell viability in vitro using several non-small cell lung cancer (NSCLC) cell lines. We found that inhibition of AKT by shikonin activated the forkhead box (FOX)O3a/early growth response protein (EGR)1 signaling cascade and enhanced the expression of the target gene Bim, leading to apoptosis in lung cancer cells. Overexpression of wild-type or a constitutively active mutant of FOXO3a enhanced shikonin-induced Bim expression. The NAD+-dependent histone deacetylase sirtuin (SIRT)1 amplified the pro-apoptotic effect by deacetylating FOXO3a, which induced EGR1 binding to the Bim promoter and activated Bim expression. Meanwhile, PI3K/AKT activity was enhanced, whereas that of FOXO3a was reduced and p300 was upregulated by treatment with a sublethal dose of shikonin. FOXO3a acetylation was enhanced by p300 overexpression, while shikonin-induced Bim expression was suppressed by p300 overexpression, which promoted cell survival. FOXO3a acetylation was increased by p300 overexpression and treatment with SIRT1 inhibitor, improving cell survival. In addition, shikonin-induced FOXO3a nuclear localization was blocked by AKT activation and SIRT1 inhibition, which blocked Bim expression and conferred resistance to the cytotoxic effects of shikonin. The EGR1 increase induced by shikonin was restored by pretreatment with SIRT1 inhibitor. These results suggest that shikonin induces apoptosis in some lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling, and that AKT and p300 negatively regulate this process via Bim upregulation. PMID- 27452908 TI - Adenoviral CCN gene transfers induce in vitro and in vivo endoplasmic reticulum stress and unfolded protein response. AB - The endoplasmic reticulum (ER) is primarily recognized as the site of synthesis and folding of secreted membrane-bound and certain organelle-targeted proteins. Optimum protein folding requires several factors, including ATP, Ca2+ and an oxidizing environment to allow disulphide-bond formation. ER is highly sensitive to stress that perturb cellular energy levels, the redox state or the Ca2+ concentration. Such stresses reduce the protein folding capacity of the ER, resulting in the accumulation and aggregation of unfolded proteins, a condition referred to as unfolded protein response (UPR). Matricellular proteins of the CCN (CYR61, CTGF, NOV) family play essential roles in extracellular matrix signaling and turnover. They exhibit a similar type of organization and share a closely related primary structure, including 38 conserved cysteine residues. Since CCN1/CYR61 overexpression in hepatic stellate cells (HSC) induces ER stress related apoptosis, we endeavored to investigate whether the adenovirus mediated gene transfer of other members of CCN proteins incurs ER stress in primary HSC and hepatocytes. We found Ad5-CMV-CCN2, Ad5-CMV-CCN3 and Ad5-CMV-CCN4 to induce ER stress and UPR comparable to Ad5-CMV-CCN1. UPR is a pro-survival response to reduce accumulation of unfolded proteins and restore normal ER functioning. If, however protein aggregation is persistent and the stress cannot be resolved, signaling switches from pro-survival to pro-apoptosis. The observed CCN-induced UPR is relevant in wound healing responses and essential for hepatic tissue repair following liver injury. Adenoviral gene transfer induced massive amounts of matricellular proteins proving to effectively mitigate liver fibrosis if targeted cell specific in HSC and myofibroblasts. PMID- 27452909 TI - Preoperative sarcopenia is a predictor of postoperative pulmonary complications in esophageal cancer following esophagectomy: A retrospective cohort study. AB - OBJECTIVES: The number of geriatric patients with esophageal cancer has been increasing. Geriatric syndromes such as sarcopenia might adversely affect postoperative recovery. The aim of this study was to evaluate the relationships between sarcopenia and postoperative complications, and the associations between sarcopenia and perioperative functional changes in patients with esophageal cancer following esophagectomy. MATERIALS AND METHODS: Participants comprised 104 patients who underwent esophagectomy from July 2011 to April 2015. Preoperative sarcopenia was diagnosed by the presence of low muscle mass and low physical functions according to Asian Working Group for Sarcopenia criteria. Low physical function was defined by loss of grip strength and/or slow walking speed. Postoperative pulmonary, cardiac, infectious, and surgical complications were extracted. Perioperative functional changes were calculated (value at postoperative day 30-value before surgery). For statistical analyses, both uni- and multivariate logistic regression analyses were performed. RESULTS: Twenty nine patients (27.9%) were diagnosed with sarcopenia. The incidence of postoperative pulmonary complications was significantly higher in the sarcopenia group (37.9%) than in the non-sarcopenia group (17.3%; P=0.04). There was no relationship between sarcopenia and other complications or perioperative functional changes. Multivariate analysis identified sarcopenia (odds ratio (OR), 3.13; 95% confidence interval (CI), 1.12-8.93) and high Brinkman index (OR, 3.46; 95% CI, 1.20-11.77) as independent risk factors for the development of pulmonary complications. CONCLUSION: The assessment of sarcopenia may be useful to predict the postoperative pulmonary complications following esophagectomy. On the other hand, sarcopenia does not predict cardiac, infectious, and surgical complications or perioperative function. PMID- 27452910 TI - Gastrokine 1 mRNA in human sera is not informative biomarker for gastric cancer. AB - BACKGROUND: We aimed to ascertain if Gastrokine 1 mRNA in the sera of patients with gastric cancer might be an informative biomarker for the disease. RESULTS: Analysis of GKN1 mRNA in serum samples from healthy individuals (n = 23) and from patients with diagnosis of gastric cancer (n = 16), performed by using absolute quantification based on standard curve method, did not show any significative statistical difference between the two unpaired group of individuals. CONCLUSIONS: Our preliminary results did not confirm GKN1 as a potential biomarker for gastric cancer. PMID- 27452911 TI - Influence of iodine supply on the radiation-induced DNA-fragmentation. AB - The protective effect of stable iodide against radiation on thyroid cells was investigated. One physiological effect of stable iodine is well-rooted: stable iodine leads to a reduced thyroid uptake of radioactive iodine. This work wants to focus on an intrinsic effect of stable iodine by which DNA-damage in cells is prevented. To investigate this intrinsic effect thyroid cells (FRTL-5) were externally irradiated by use of a linear accelerator (LINAC) applying energy doses of 0.01 Gy-400 Gy and by incubation with various activity concentrations of 131I (0.1-50 MBq/ml for 24 h). We added stable iodine (NaI) to the cells prior to external irradiation and investigated the effect of the concentration of stable iodine (1, 5, 15 MUg/ml). In order to clarify whether thyroid cells have a distinctive and iodine-dependent reaction to ionizing radiation, keratinocytes (HaCaT) without NIS were exposed in the same way. As indicators for the cellular reaction, the extent of DNA fragmentation was determined (Roche, Mannheim, Germany). Both cell types showed distinct ability for apoptosis as proven with camptothecin. The addition of "cold" iodine from 1 to 15 MUg/ml without irradiation ("negative control") did not change the response in both cell types. Plausibly, the radio-sensitivity of both cell types did increase markedly with increasing radiation dose but the radiation effect is diminished if iodine is added to the thyroid cells beforehand. The DNA-damage in thyroid cells after addition of cold iodine is reduced by a factor of 2-3. The skin cells did not show an significant change of radio-sensitivity depending on the presence of cold iodine. Elementary iodine possibly acts as a radical scavenger and thus markedly reduces the secondary radiation damage caused by the formation of cytotoxic radicals. This intrinsic radioprotective effect of iodine is seen only in cells with NIS. PMID- 27452912 TI - Assessment of lithogenic radioactivity in the Euganean Hills magmatic district (NE Italy). AB - The Euganean Hills of North East Italy have long been recognised as an area characterized by a higher than average natural radiation background. This is due to two main reasons: a) primary lithogenic radiation due to rhyolitic and trachytic outcrops, which are "acidic alkaline" magmatic rocks potentially enriched in uranium and thorium; b) secondary sources related to a geothermal field - widely exploited for spa tourism in the area since the Roman age - producing surface release of radon-enriched fluids. Though radioactivity levels in the Euganean district have been often investigated in the past - including recent works aimed at assessing the radiation doses from radon and/or total gamma radiation - no effort has been put so far into producing a thorough assessment linking radiation protection data to geological-structural features (lithology, faults, water, organic matter content, etc.). This work represents the first part of the interdisciplinary project "Geological and geochemical control on Radon occurrence and natural radioactivity in the Euganean Hills district (North Eastern Italy)", aimed at producing detailed results of the actual radiation levels in connection mainly with lithological parameters. A detailed sampling strategy, based on lithostratigraphy, petrology and mineralogy, has been adopted. The 151 rock samples collected were analyzed by high resolution gamma-ray spectrometry with ex situ HPGe detectors. Statistical and geostatistical analyses were performed, and outlier values of U and Th - possibly associated with anomalies in the geological formation - were identified. U, Th and K concentration maps were developed using both the entire database and then again after expunging the outliers; the two were then compared. In all maps the highest values can be associated to trachyte and rhyolite lithologies, and the lowest ones to sedimentary formations. The external dose due to natural radionuclides in the soil - the so called terrestrial gamma dose rate - has been calculated using the U, Th and K distribution measured in the bedrock samples. PMID- 27452913 TI - Radon exhalation study of manganese clay residue and usability in brick production. AB - The reuse of by-products and residue streams is an important topic due to environmental and financial aspects. Manganese clay is a residue of manganese ore processing and is generated in huge amounts. This residue may contain some radionuclides with elevated concentrations. In this study, the radon emanation features and the massic exhalation rate of the heat-treated manganese clay were determined with regard to brick production. From the manganese mud depository, 20 samples were collected and after homogenization radon exhalation characteristics were determined as a function of firing temperatures from 100 to 750 degrees C. The major naturally occurring radionuclides 40K, 226Ra and 232Th concentrations were 607 +/- 34, 52 +/- 6 and 40 +/- 5 Bq kg-1, respectively, comparable with normal clay samples. Similar to our previous studies a strong correlation was found between the internal structure and the radon emanation. The radon emanation coefficient decreased by ~96% from 0.23 at 100 degrees C to 0.01 at 750 degrees C. The massic radon exhalation rate of samples fired at 750 degrees C reduced by 3% compared to samples fired at 100 degrees C. In light of the results, reusing of manganese clay as a brick additive is possible without any constraints. PMID- 27452914 TI - Genetic and environmental influences on the association between performance-based self-esteem and exhaustion: A study of the self-worth notion of burnout. AB - In the self-worth model, burnout is considered to be a syndrome of performance based self-esteem (PBSE) and experiences of exhaustion. Studies have shown that PBSE and burnout indices such as Pines' Burnout Measure (BM) are associated. Whether these variables have overlapping etiologies has however not been studied before. Genetic and environmental components of covariation between PBSE and exhaustion measured with Pines' BM were examined in a bivariate Cholesky model using data from 14,875 monozygotic and dizygotic Swedish twins. Fifty-two per cent of the phenotypic correlation (r = 0.41) between PBSE and Pines' BM was explained by genetics and 48% by environmental factors. The findings of the present study strengthen the assumption that PBSE should be considered in the burnout process as proposed by the self-worth conception of burnout. The present results extend our understanding of the link between this contingent self-esteem construct and exhaustion and provide additional information about the underlying mechanisms in terms of genetics and environment. This finding corroborates the assumed syndrome view on burnout, while it also suggests an altered view of how the syndrome emerges and how it can be alleviated. PMID- 27452915 TI - World Brain Day 2016: celebrating brain health in an ageing population. PMID- 27452916 TI - Comparison of four risk scores for in-hospital mortality in patients undergoing heart valve surgery: A multicenter study in a Chinese population. AB - BACKGROUND AND AIM OF THE STUDY: To compare four risk scores with regard to their validity to predict in-hospital mortality after heart valve surgery in a multicenter patient population of China. MATERIALS AND METHODS: From January 2009 to December 2012, data from 12,412 consecutive patients older than 16 years who underwent heart valve surgery at four cardiac surgical centers were collected and scored according to the EuroSCORE II, Ambler risk score, NYC risk score, and STS risk score. The patients were divided into two subgroups according to the types of valve procedures, and the performance of the four risk scores for each group was assessed. Calibration was assessed by the Hosmer-Lemeshow (H-L) test. Discrimination was tested by calculating the area under the receiver operating characteristic (ROC) curve. RESULTS: Observed mortality was 2.09% overall. The EuroSCORE II, Ambler score, and NYC score overpredicted observed mortality (Hosmer-Lemeshow: P = 0.002, P < 0.0001, and P < 0.0001, respectively) and the STS score underpredicted observed mortality (Hosmer-Lemeshow: P = 0.001). The discriminative power in the entire cohort for in-hospital mortality was highest for the STS score (0.735), followed by the EuroSCORE II score (0.704), NYC score (0.693), and Ambler score (0.674). Meanwhile, the STS score and EuroSCORE II give an accurate prediction in patients undergoing single valve surgery compared with the Ambler score and NYC score. However, all four risk scores give an imprecise prediction in patients undergoing multiple valve surgery. CONCLUSIONS: Both the STS score and Euroscore II, especially the STS score, were suitable for individual operative risk in Chinese patients undergoing single valve surgery compared with the Ambler score and NYC score, however, all four risk scores were not suitable for prediction in Chinese patients undergoing multiple valve surgery. Therefore, the creation of a new model which accurately predicts outcomes in patients undergoing multiple valve surgery is possibly required in China. PMID- 27452918 TI - Light-Induced Direct Arylation in the Solid Crystalline State as a Strategy Towards pi-Expanded Imidazoles. AB - pi-Expanded imidazoles bearing the 2-iodophenyl substituent at position 2 undergo direct photoinduced intramolecular arylation in the solid, crystalline state leading to large non-planar heterocycles. An analogous reaction employing 2 bromophenyl and 2-chlorophenyl substituents is considerably slower. Such processes have never before been demonstrated to occur in crystals and have allowed the efficient synthesizes of structurally unique compounds containing either the phenanthro[9',10':4,5]imidazo[1,2-f]phenanthridine moiety or structurally related skeletons. The reaction occurs in the thin crystalline layers irradiated with UV photons in an almost quantitative manner over 48-72 h. Several previously unknown architectures have been prepared using this methodology. Furthermore, the optical properties of these pi-expanded imidazoles can be altered with the addition of heteroatoms and/or electron-donating groups. PMID- 27452917 TI - Heritability of major depressive and comorbid anxiety disorders in multi generational families at high risk for depression. AB - Family studies have shown that MDD is highly transmittable but have not studied its heritability. Twin studies show heritability of about 40% and do not include anxiety disorders. We assessed heritability of MDD and comorbid anxiety disorders in a multigenerational study of family members at high risk for MDD. In addition, we tested the hypothesis that examined clinical subtypes of MDD defined by early and late age of onset would be under relatively stronger genetic control than broadly defined DSM-IV MDD. The first generation with moderate to severe MDD was recruited from an ambulatory psychiatric treatment setting, and their descendants in the second, third, and fourth generation, were interviewed by clinicians up to six times during a 30-year period. Lifetime rates of MDD and anxiety disorders were collected for 545 participants from 65 multigenerational families. The heritability (h2 ) of MDD in this high risk sample was estimated at 67%. Anxiety and sequential comorbidity of anxiety disorders and MDD revealed h2 of 49% and 53%, respectively, and strong positive genetic correlation (rhog = 0.92, P = 7.3 * 10-7 ). Early onset MDD did not appear to be under greater genetic control than broadly defined DSM-IV MDD. Individuals who are direct descendants of subjects ascertained for moderate to severe MDD have strong genetic vulnerability to develop anxiety or MDD. Our findings support family based studies as appropriate and useful design to understand the heritability of common disorders such as MDD. (c) 2016 Wiley Periodicals, Inc. PMID- 27452919 TI - Crocetin protects ultraviolet A-induced oxidative stress and cell death in skin in vitro and in vivo. AB - Crocetin, the aglycone of crocin, is a carotenoid found in fruits of gardenia (Gardeina jasminoides Ellis) and saffron (Crocus sativus L.). We investigated the protective effects of crocetin against ultraviolet-A (UV-A)-induced skin damage and explored the underlying mechanism. Human skin-derived fibroblasts cells (NB1 RGB) were damaged by exposure to UV-A irradiation (10J/cm(2)). Crocetin protected these cells against cell death and reduced the production of reactive oxygen species induced by UV-A irradiation. Crocetin treatment also suppressed induction of caspase-3 activation by UV-A irradiation. The effects of crocetin against oxidative stress were also examined by imaging of Keap1-dependent oxidative stress detector (OKD) mice. UV-A irradiation upregulated oxidative stress in the OKD mice skin, while crocetin administration (100mg/kg, p.o.) ameliorated this oxidative stress. Crocetin administration also decreased lipid peroxidation in the skin. These findings suggest that crocetin its observed protective effects against UV-A induced skin damage by reducing reactive oxygen species production and cell apoptosis. PMID- 27452920 TI - Acute flaccid weakness with myelopathy and peripheral nerve involvement in 2 children: Recent characterization of a previously observed phenomenon. AB - BACKGROUND: Acute flaccid weakness may be the first presentation of acute transverse myelitis (ATM), an immune-mediated central nervous system disorder or may be the first presentation of anterior horn cell syndrome or peripheral nervous system disease. CASE REPORTS: We describe two previously healthy female infants who presented with acute flaccid paralysis and encephalopathy. Neuroimaging revealed central cord signal changes in both cases and surprisingly electrophysiological studies performed revealed a generalized axonal motor neuropathy as well. CONCLUSION: Clinical, radiological and neurophysiological assessment are important to aid in the diagnosis and subsequent management of children with overlapping inflammatory peripheral and central nervous system syndromes. PMID- 27452921 TI - Talar dome detection and its geometric approximation in CT: Sphere, cylinder or bi-truncated cone? AB - OBJECTIVE: The purpose of our study is to give a relatively objective definition of talar dome and its shape approximations to sphere (SPH), cylinder (CLD) and bi truncated cone (BTC). MATERIALS AND METHODS: The "talar dome" is well-defined with the improved Dijkstra's algorithm, considering the Euclidean distance and surface curvature. The geometric similarity between talar dome and ideal shapes, namely SPH, CLD and BTC, is quantified. 50 unilateral CT datasets from 50 subjects with no pathological morphometry of tali were included in the experiments and statistical analyses were carried out based on the approximation error. RESULTS: The similarity between talar dome and BTC was more prominent, with smaller mean, standard deviation, maximum and median of the approximation error (0.36+/-0.07mm, 0.32+/-0.06mm, 2.24+/-0.47mm and 0.28+/-0.06mm) compare with fitting to SPH and CLD. In addition, there were significant differences between the fitting error of each pair of models in terms of the 4 measurements (p-values<0.05). The linear regression analyses demonstrated high correlation between CLD and BTC approximations (R2=0.55 for median, R2>0.7 for others). Color maps representing fitting error indicated that fitting error mainly occurred on the marginal regions of talar dome for SPH and CLD fittings, while that of BTC was small for the whole talar dome. CONCLUSION: The successful restoration of ankle functions in displacement surgery highly depends on the comprehensive understanding of the talus. The talar dome surface could be well-defined in a computational way and compared to SPH and CLD, the talar dome reflects outstanding similarity with BTC. PMID- 27452922 TI - Adsorption, Ordering, and Local Environments of Surfactant-Encapsulated Polyoxometalate Ions Probed at the Air-Water Interface. AB - The continued development and application of surfactant-encapsulated polyoxometalates (SEPs) relies on understanding the ordering and organization of species at their interface and how these are impacted by the various local environments to which they are exposed. Here, we report on the equilibrium properties of two common SEPs adsorbed to the air-water interface and probed with surface-specific vibrational sum-frequency generation (SFG) spectroscopy. These results reveal clear shifts in vibrational band positions, the magnitude of which scales with the charge of the SEP core, which is indicative of a static field effect on the surfactant coating and the associated local chemical environment. This static field also induces ordering in surrounding water molecules that is mediated by charge screening via the surface-bound surfactants. From these SFG measurements, we are able to show that Mo132-based SEPs are more polar than Mo72V30 SEPs. Disorder in the surfactant chain packing at the highly curved SEP surfaces is attributed to large conic volumes that can be sampled without interactions with neighboring chains. Measurements of adsorption isotherms yield free energies of adsorption to the air-water interface of -46.8 +/- 0.4 and -44.8 +/- 1.2 kJ/mol for the Mo132 and Mo72V30 SEPs, respectively, indicating a strong propensity for the fluid surface. The influence of intermolecular interactions on the surface adsorption energies is discussed. PMID- 27452923 TI - ICN: a normalization method for gene expression data considering the over expression of informative genes. AB - The global increase of gene expression has been frequently established in cancer microarray studies. However, many genes may not deliver informative signals for a given experiment, due to insufficient expression or even non-expression, despite the DNA microarrays massively measuring genes in parallel. Hence the informative gene set, rather than the whole genome, should be more reasonable to represent the genome expression level. We observed that the trend of over-expression for informative genes is more obvious in human cancers, which is to some extent masked using the whole genome without any filtering. Accordingly we proposed a novel normalization method, Informative CrossNorm (ICN), which performs the cross normalization (CrossNorm) on the expression matrix merely containing the informative genes. ICN outperforms other methods with a consistently high precision, F-score, and Matthews correlation coefficient as well as an acceptable recall based on three available spiked-in datasets with ground truth. In addition, nine potential therapeutic target genes for esophageal squamous cell carcinoma (ESCC) were identified using ICN integrated with a protein-protein interaction network, which biologically demonstrates that ICN shows superior performance. Consequently, it is expected that ICN could be applied routinely in cancer microarray studies. PMID- 27452926 TI - A Place in the Sun: The Importance of Radiology in Multidisciplinary Conference. PMID- 27452925 TI - [Is FDG TEP CT practice changing in the management of sarcomas in adults?]. AB - BACKGROUND: FDG PET (PET)+/-computed tomography (CT) has increasingly been used in some areas of oncology imaging. It is sometimes performed outside recommendations, at diagnosis or monitoring of sarcomas. We assessed the value of PET-CT in routine practice in sarcomas. MATERIAL AND METHODS: All consecutive sarcoma adult patient charts presented at the multidisciplinary sarcoma meeting in a tertiary care center over a period of 10months were examined in order to analyze the performances of PET-CT when available. RESULTS: Of 232 patients, 50 (21 %) underwent a PET-CT. Sensitivity and specificity of PET-CT were 94.7 %, 57.1 %, respectively. SUV values were highly variable, including for a given histology or grade. PET-CT resulted in practice changing in 14 % of cases. When extrapulmonary metastases are suspected and for some subtypes of sarcomas, PET-CT could provide additional information because in view of its good sensitivity. CONCLUSION: Given the most frequent pulmonary tropism, first hand chest CT may be sufficient at first diagnostic work-up for the detection of pulmonary metastases. However, the relatively poor specificity suggests that further analyses should be performed to identify clinical situations where PET-CT may be of added value compared to current standards. PMID- 27452924 TI - In Vivo therapeutic potential of mesenchymal stem cell-derived extracellular vesicles with optical imaging reporter in tumor mice model. AB - Mesenchymal stem cells (MSCs) can be used as a therapeutic armor for cancer. Extracellular vesicles (EVs) from MSCs have been evaluated for anticancer effects. In vivo targeting of EVs to the tumor is an essential requirement for successful therapy. Therefore, non-invasive methods of monitoring EVs in animal models are crucial for developing EV-based cancer therapies. The present study to develop bioluminescent EVs using Renilla luciferase (Rluc)-expressing MSCs. The EVs from MSC/Rluc cells (EV-MSC/Rluc) were visualized in a murine lung cancer model. The anticancer effects of EVs on Lewis lung carcinoma (LLC) and other cancer cells were assessed. EV-MSC/Rluc were visualized in vivo in the LLC-efffuc tumor model using optical imaging. The induction of apoptosis was confirmed with Annexin-V and propidium iodide staining. EV-MSC/Rluc and EV-MSCs showed a significant cytotoxic effect against LLC-effluc cells and 4T1; however, no significant effect on CT26, B16F10, TC1 cells. Moreover, EV-MSC/Rluc inhibited LLC tumor growth in vivo. EV-MSC/Rluc-mediated LLC tumor inhibitory mechanism revealed the decreased pERK and increased cleaved caspase 3 and cleaved PARP. We successfully developed luminescent EV-MSC/Rluc that have a therapeutic effect on LLC cells in both in vitro and in vivo. This bioluminescent EV system can be used to optimize EV-based therapy. PMID- 27452927 TI - Construction of Optically Active Isotwistanes and Aminocyclitols Using Chiral Cyclohexadiene as a Common Intermediate. AB - We have developed a new method for synthesizing chiral isotwistane and homoisotwistane skeletons as well as aminocyclitols in a highly stereoselective manner. These results were achieved through the use of a common intermediate, which was derived from the ytterbium-catalyzed asymmetric Diels-Alder reaction of Danishefsky diene. PMID- 27452928 TI - Human bronchial epithelial cells injury and cytokine production induced by Tityus serrulatus scorpion venom: An in vitro study. AB - Tityus serrulatus is the scorpion specie responsible for the majority of scorpion sting accidents in Brazil. Symptoms of envenomation by Tityus serrulatus range from local pain to severe systemic reactions such as cardiac dysfunction and pulmonary edema. Thus, this study has evaluated the participation of bronchial epithelial cells in the pulmonary effects of Tityus serrulatus scorpion venom (Tsv). Human bronchial epithelial cell line BEAS-2B were utilized as a model target and were incubated with Tsv (10 or 50 MUg/mL) for 1, 3, 6 and 24 h. Effects on cellular response of venom-induce cytotoxicity were examined including cell viability, cell integrity, cell morphology, apoptosis/necrosis as well as cell activation through the release of pro-inflammatory cytokines IL-1beta, IL-6 and IL-8. Tsv caused a decrease in cell viability at 10 and 50 MUg/mL, which was confirmed by lactate dehydrogenase (LDH) measurement. Flow cytometry analyses revealed necrosis as the main cell death pathway caused by Tsv. Furthermore, Tsv induced the release of IL-1beta, IL-6 and IL-8. Altogether, these results demonstrate that Tsv induces cytotoxic effects on bronchial epithelial cells, involving necrosis and release of pro-inflammatory cytokines, suggesting that bronchial epithelial cells may play a role in the pulmonary injury caused by Tsv. PMID- 27452929 TI - Cry1Ac toxicity enhancement towards lepidopteran pest Ephestia kuehniella through its protection against excessive proteolysis. AB - Bacillus thuringiensis has been extensively used in agroecosystems for four decades due to its high specific toxicity. Strategies based on B. thuringiensis proteins combinations for the improvement of its activity present an important focus for biopesticides development. However, the widespread use of B. thuringiensis delta-endotoxins has often been challenged by a lack of understanding of the target insect physiology as well as its midgut biochemistry. In the present investigation, we have evidenced and explained the toxicity improvement of Cry1Ac delta-endotoxins against Ephestia kuehniella larvae through in vivo combination with P20 helper protein. Tracking the fate of Cry1Ac in tested midgut larvae showed considerable differences between delta-endotoxins produced in the presence of P20 and those produced in its absence which could explain the obtained larvicidal activity enhancement. The P20 presence slightly increased Cry1Ac inclusions solubility in E. kuehniella midgut conditions. However, a protection against excessive degradation of protoxin and toxin forms of Cry1Ac was strongly decreased in the case of delta-endotoxins produced in the presence of P20 as compared to those from P20 lacking control. Thus, the P20 protective effect on Cry1Ac after larvae ingestion has been proven. This finding could be helpful to further understand the roles of P20 helper protein in toxicity enhancement of B. thuringiensis toxins. PMID- 27452930 TI - Determination and characterization of destruxin production in Metarhizium anisopliae Tk6 and formulations for Aedes aegypti mosquitoes control at the field level. AB - Destruxins, cyclic hexadepsipeptide toxins, secreted by the entomopathogenic fungus, Metarhizium anisopliae through extracellular synthesis. The present study reports a new approach for the analysis of DTXs produced by the fungal strain Metarhizium anisoliae Tk6, using FRIR-HPLC-LC-MS and H(1) NMR. The results also showed that production of the major DTXs A, B, C, and E have to be determined in Czapek Dextrose (CD) liquid culture filtrate from 9 to 12 days post-inoculation. Purified DTX were further tested in bioassays to assess their effects of Aedes aegypti mosquitoes. The four major purified DTX compounds were found to cause a toxic effect on the larval developmental stages of mosquitoes with high mortality rates. However, DTX E outperformed the other three DTXs by causing the highest mortality three days after inoculation. This result gives an alternative approach of using DTXs in mosquitoes control and used as a new method for other pest management. PMID- 27452931 TI - Food-poisoning outbreak and fatality following ingestion of sea turtle meat in the rural community of Ndrondroni, Moheli Island, Comoros, December 2012. AB - On 24-December-2012 newspapers reported food-poisoning cases in Ndrondroni, Comoros. The authors conducted an investigation and a case-control study to identify the source and control the outbreak. They identified eight cases. A 6 month breastfed infant died. The results suggest consumption of Eretmochelys imbricata caused the outbreak. A bio-toxin ingested by the turtle might be the source. The local authorities informed the population on the danger of turtle meat consumption. Cooking does not destroy the toxin. PMID- 27452932 TI - Characterization of ion channels on subesophageal ganglion neurons from Chinese tarantula Ornithoctonus huwena: Exploring the myth of the spider insensitive to its venom. AB - Chinese tarantula Ornithoctonus huwena is one of the most venomous spiders distributing in the hilly areas of southern China. In this study, using whole cell patch-clamp technique we investigated electrophysiological and pharmacological properties of ion channels from tarantula subesophageal ganglion neurons. It was found that the neurons express multiple kinds of ion channels at least including voltage-gated calcium channels, TTX-sensitive sodium channels and two types of potassium channels. They exhibit pharmacological properties similar to mammalian subtypes. Spider calcium channels were sensitive to omega-conotoxin GVIA and diltiazem, two well-known inhibitors of mammalian neuronal high-voltage activated (HVA) subtypes. 4-Aminopyridine and tetraethylammonium could inhibit spider outward transient and delayed-rectifier potassium channels, respectively. Huwentoxin-I and huwentoxin-IV are two abundant toxic components in the venom of Ornithoctonus huwena. Interestingly, although in our previous work they inhibit HVA calcium channels and TTX-sensitive sodium channels from mammalian sensory neurons, respectively, they fail to affect the subtypes from spider neurons. Moreover, the crude venom has no effect on delayed-rectifier potassium channels and only slightly reduces transient outward potassium channels with an IC50 value of ~51.3 mg/L. Therefore, our findings provide important evidence for ion channels from spiders having an evolution as self-defense and prey mechanism. PMID- 27452933 TI - Papillary Lesions of Breast. AB - INTRODUCTION: Papillary breast lesions constitute a pathological heterogeneous group and are characterized by growth in the milk ducts. In this study, we aimed to present in view of literature patients who underwent lumpectomy due to breast mass and with papillary lesion in histopathological examination. MATERIAL METHOD: The pathology records and informations of 42 patients who were operated between 2006-2014 in our clinic and considered to have papillary lesion in histopathological examination were examined retrospectively. The patients were evaluated for age, gender, complaints, lesion localizations, performed surgery, histopathological type, follow-up period and the lesions occurring during follow up. FINDINGS: The excisional biopsy in the form of lumpectomy was made to 34 patients who were reported as benign papillary lesion in coreneedle biopsy performed. The lesion in 11 patients were marked preoperatively by radiology clinic. 33 patients who had benign papillary lesion in excisional biopsy were followed. Modified radical mastectomy was performed to a total of 9 patients including 1 patient with malignant papillary lesion in excisional biopsy and 8 patients with malignant papillary lesion in coreneed lebiopsy. RESULT: Histopathological diagnosis should be confirmed by performing definitely excisional biopsy in patients who detected benign papillary lesions by coreneedle biopsy and strict clinical follow-up should be made for developing malignancies in patients who detected benign papillary lesions. PMID- 27452934 TI - Laparoscopic Spleen Surgery: Baia Mare County Emergency Hospital Experience, Romania. AB - BACKGROUND: Spleen surgery is a surgery without anastomosis and without the modification of the body's physiological circuits; therefore, the difference in the size of the incision between the laparoscopic and the open approach determines the main advantages of the laparoscopic surgery: small amounts of painkillers, reduced postoperative complication rate, low duration of hospitalization and reduced intra- and postoperative blood transfusion requirements. METHODS: Data from the medical records of 4 patients who underwent laparoscopic surgery were retrospectively analyzed. They underwent surgery for idiopathic thrombocytopenic purpura, splenic cyst and abscess. RESULTS: Mean age of patients was 56 years old, postoperative hospital stay was 4 days in all cases, the surgery lasted 150 minutes on average and a single unit of blood was given after surgery. CONCLUSIONS: Laparoscopic spleen surgery is achievable and safe in the initial experience of the Baia Mare County Emergency Hospital, Romania; it enables a rapid postoperative recovery of the patients and the preservation of the spleen in diseases only partially affecting the splenic parenchyma. PMID- 27452935 TI - Laparoscopic Treatment of Intraabdominal Cystic Lymphangioma. AB - The abdominal cystic lymphangioma (CL) in adults is a rare benign tumor of the lymphatic system. METHODS: We report a retrospective study from January 2002 to Decemberr 2014 concerning 18 patients who underwent surgical removal of a CL, 9 patients with laparoscopic approach included. The localization, size, and number, diagnostic, treatment and results have been reported for patients approached laparoscopically. RESULTS: There were 8 women and 1 man with median age at diagnosis was 35,6 years (range 20-51 years). Clinically, the main symptom was an abdominal pain found in 8 patients (88.8%). Physical examination revealed an abdominal mass in 5 patients (55.5%). The CL was asymptomatic in four patients; the discovery of CL was performed preoperatively during an ultrasound for another pathology (n=3) or intraoperatively (n=1). US exam CT scan usually allow the preoperative diagnosis. The most common site was shared equally between the mesentery (n = 3; 33%) and left retroperitoneum (n = 3;33%), followed by the right retroperitoneum and the posterior cavity of the lesser omentum and great omentum, each one case. The most common procedures performed were: laparoscopic total cystectomy of a closed cyst in two patients and evacuation of larger cysts followed by total cystectomy in seven patients. No conversion, no mortalities and no morbidity was noted. Mean hospital stay was 3.4 days. No recidive after 28 months in the average after treatment. CONCLUSIONS: The laparoscopic approach is the gold standard in the treatment of intraabdominal CL.We recommend complete surgical excision to avoid recurrence. PMID- 27452936 TI - Effect of High Perioperative Oxygen Fraction on Surgical Site Infection Following Surgery for Acute Sigmoid Diverticulitis. A Prospective, Randomized, Double Blind, Controlled, Monocentric Trial. AB - Propose: The clinical role of hyperoxiato prevent postoperative surgical site infection (SSI) remains uncertain since randomized controlled trials on this topic have reported different results. One of the principal reasons for such mixed results can be that previous trials have entered a heterogeneous population of patients and set of procedures. The aim of our study was to assess the influence of hyperoxygenation on SSI usingan homogeneous study population. METHODS: We studied, in a prospective randomized study, extended on a time interval January 2009 to May 2015, 85 patients who underwent open intraperitoneal anastomosis for acute sigmoid diverticulitis. Patients were assigned randomly to an oxygen/air mixture with a faction of inspiration (FiO2) of 30% (n=43) or 80% (n=42). Administration was started after induction of anesthesia and maintained for 6 hours after surgery. RESULTS: The overall wound site infection rate was 24.7% (21 out of 85): 14 patients (32.5%) had a wound infection in the 30% FiO2 group and 7 (16.6%) in the 80% FiO2 group (p 0.05). The risk of SSI was 43% lower in the 80% FiO2 group (RR, 0.68; 95% confidence interval, 0.35-0.88) versus 30% FiO2. CONCLUSIONS: Therefore, supplemental 80% FiO2 during and 6 hours after open surgery for acute sigmoid diverticulitis, reducing post-operative SSI, should be considered part of ongoing quality improvement activities related to surgical care, accompanied by few risk to the patients and little associates cost. PMID- 27452937 TI - Clinical Profile of Patients with Postoperative Adhesive Intestinal Obstruction and its Association with Intraoperative Peritoneal Adhesion Index. AB - Adhesions following surgery represent a major unsolved problem. They occur after 50% to 100% of all surgical interventions in the abdomen and may complicate the work of the surgeon considerably. Peritoneal adhesions are pathological bands that typically form between the omentum, the small and large bowels, the abdominal wall, and other intra-abdominal organs. These bands may be a thin film of connective tissue, a thick fibrous bridge containing blood vessels and nerve tissue, or a direct adhesion between two organ surfaces. AIMS AND OBJECTIVES: 1. To study the clinical profile of patients with adhesive intestinal obstruction undergoing laparotomy. 2. To assess and analyze the intra-operative peritoneal adhesion index (PAI) in individual cases. 3. To associate the clinical profile with peritoneal adhesion index in patients of adhesive intestinal obstruction. RESULT: The study was conducted in the Department of Surgery, Himalayan Institute of Medical Sciences (HIMS), SRH University, Dehradun, India over a period of 12 months. A total of 30 patients with diagnosis of post operative adhesive intestinal obstruction were recruited in the study. It was observed that adhesions over each abdominal region contributed equal to the total PAI. In this study it was observed that the patients who had previous emergency surgery had higher incidence of adhesions, than elective surgery whereas those patients who underwent both elective and emergency surgeries, the incidence of adhesions were lowest. Analysis of variance with respect to abdominal scar resulted that the difference between groups was observed to be statistically not significant (P 0.05), so patients with all type of abdominal scars of previous surgeries has equal chance of developing adhesions. CONCLUSION: PAI is a sensitive tool for clinical and intra-operative assessment of adhesive intestinal obstruction for the quantification of the adhesions and gives a precise description of the underlying intra-abdominal condition while planning a surgical management of the disease. PMID- 27452938 TI - Chest Tube Insertion in the Delayed Esophageal Perforation Phenomenon: A Tragic or Beneficial Outcome? AB - A 53-year-old woman with foreign body esophageal perforation, was first misdiagnosed as pulmonary thromboembolism. In referral hospital her chest computed tomography was reported as giant hiatal hernia or giant pulmonary abscess. She was treated for abscess, after several days, right hemithorax tube thoracostomy was performed. After that, she developed necrotizing fasciitis on the chest wall. After a 19-day delay, we found a 5-cm mid-thoracic esophageal tearing during thoracotomy and repaired it. After 2 years follow up the patient condition is good. This report describes a unique case of mid-thoracic foreign body esophageal perforation and rupture with a delay in diagnosis with a tragic course. PMID- 27452939 TI - Laparoscopic Cholecystectomy for a Patient with a Lumboperitoneal Shunt: A Rare Case. AB - A rare factor that can complicate the perioperative course of laparoscopic cholecystectomy is previous placement of a lumboperitoneal (LP) shunt. Thus far, only two articles describing this situation have been published. Here, we report on a 41-year-old female patient with gallstone disease and a LP shunt placement in the preceding year due to idiopathic intracranial hypertension. It is a syndrome of increased intracranial pressure without any known cause that mainly affects young obese women. The patient was operated upon using standard port placement and peritoneal insufflation. The postoperative period was uneventful and the patient was discharged shortly after the procedure. Due to the increasing incidence and prevalence of obesity, the number of general surgical patients with a LP shunt will likely increase. Based on our experience and evidence in the literature, we conclude that performing a laparoscopy for a patient with a LP shunt is safe. PMID- 27452940 TI - Isolated Ileum Perforation Following Veal Attack in a Pacient with an Undiagnosed Inguinal Hernia: Case Report and Review of the Literature. AB - We present a rare case of a 74 year old man admitted by ambulance to our department following a blunt minor abdominal trauma (veal attack). He complained of pain in the left abdominal flank and in the lower abdomen. The lower abdomen was tender, moderate distended but not rigid. He also had a left inguinal uncomplicated hernia. Because he was hemodynamic stable we performed a CT - scan who revealed several pockets of free air anteriorly in the midline. One hour and a half after admission the pacient underwent exploratory laparotomy, revealing a antimesostenic perforation of the ileum about 120 cm from the ileo-cecal valve. Simple closure in one layer was performed. The inguinal hernia wasn't repaired at the time of the first surgery. The postoperative course was favorable, the pacient being discharged on the 8th postoperative day. PMID- 27452941 TI - An Unexpected Discovery. AB - Meckel's Diverticulum is the most common congenital malformation of the gastrointestinal tract with a prevalence of 2 % in the general population, being twice as common and symptomatic in males. Not seldom is the diagnosis made incidentally, upon laparotomy for other intra-abdominal conditions, namely acute appendicitis. Simple Diverticulectomy is the surgical treatment of choice. We present the case of S.M., a 38 year-old male who was admitted to the Surgery Department of the Bucharest Clinical Emergency Hospital for sudden onset of initially periumbilical pain, which later migrated and localized in the right iliac fossa (RIF) accompanied by vomiting after the onset of pain, approximately 24 hours prior to admission. Examination of the abdomen revealed localized peritoneal signs. An Alvarado score of 8 was calculated. A laparotomy for appendectomy was performed, upon which the sigmoid colon was found in the RIF, and an appendix of 10 cm in length was visualized in a subhepatic, ascendant position. At a distance of 90 cm from the ileocecal valve, a Meckel's Diverticulum with dimensions of 7/4 cm was discovered. A retrograde appendectomy was performed first, along with a simple diverticulectomy, with the use of a TA 30 mm stapler. The operative time was 90 minutes without intraoperative complications, and an uneventful postoperative recovery, culminating with discharge of the patient on the fifth postoperative day. Despite its high prevalence, Meckel's Diverticulum still represents a diagnostic challenge, especially in the adult population, notably in asymptomatic patients. Moreover, ectopic gastric or pancreatic tissue, present in 50% of the cases, leads to a vast array of differential diagnoses. Due to its numerous life-threatening complications such as bleeding, intestinal obstruction, volvulus, intussusception, diverticulitis, fistulization and perforation, accurate diagnosis and timely treatment is crucial. PMID- 27452942 TI - A Rare Cause of Bowel Obstruction: Peritoneal Metastases in Osteosarcoma at the Tibia in a Young Female Patient with Brain Metastasis. Case Report. AB - Osteosarcomas are the most frequent primary malignant bone tumors in children and adolescents. Like brain metastases in osteosarcomas, the bowel metastases are very rare. We present the case of a 23-year-old female patient, diagnosed and operated in 2008 of osteosarcoma at the tibia, for which she had sessions of neoadjuvant and adjuvant chemotherapy, but presented lungs metastases for which she underwent surgery in 2014. Then, in March 2015, she was diagnosed with an intracranial expansive process, an osteosarcoma metastasis, for which a total ablation of the tumor was performed during the early postoperatory period, being transferred to the General Surgery Clinic for abdominal pain, abdominal distention, vomiting, and lack of intestinal transit regarding faeces and intestinal gas. Both clinically and imagistically, the diagnosis was of bowel obstruction. This was the reason for performing surgery, thus discovering a bowel obstruction secondary to a metastasis of the terminal ileum and liver metastases that were confirmed as osteosarcoma metastases from an anatomopathological and immunohistochemical point of view. The bowel metastases and the osteosarcoma brain metastases are very rare entities and, their association, most often with young patients, is exceptional. However, bowel metastases must be taken into account as a possible cause of bowel obstruction in patients with osteosarcoma. PMID- 27452943 TI - Total Hip Replacement in Congenital Hip Dislocation in 14 Years Female Patient. AB - INTRODUCTION: development dysplasia of the hip is one of the common disorders in pediatric orthopaedics. This requires an early orthopaedic treatment. Neglected cases can lead to hip dislocation, which has an incidence of 1.4 / mille new borns, being bilateral in 70-80% of cases and prevalence of girls being 7 / 1-4 / 1 (girls / boys). Congenital hip dislocation requires a complex surgical and orthopaedic treatment. In most cases develop hip osteoarthritis in adulthood, requiring total hip replacement. In certain selected cases total hip replacement is required since the pediatric age. METHODS: We present the case of a 14 year old patient who was admitted to our clinic for limping with leg-length discrepancy, pain in the right groin. The disease has an insidious onset at the start of the walking age. The treatment was denied until the age of 9, when was performed open reduction of the hip, shortening osteotomy of the femur, right hip adductor tenotomy muscles. Despite treatment the disease has an poor outcome, patient was presenting at age of 14 a shortening of the right leg 7 cm, with the greater trochanter elevated, positive Trendelenburg sign, limiting of daily activities, Harris score 48. We performed transkeletal traction for one month, after that performing total hip replacement. The postoperative evolution was excellent, the patient having no pain, with a 2 cm leg-length discrepancy, starting to walk at 3 month after surgery. CONCLUSIONS: Although total hip replacement in congenital hip dislocation at pediatric age is an exceptional procedure, in some cases carefully selected it proves to be a viable alternative in the medium term. PMID- 27452944 TI - Bouveret Syndrome - An Exceptional Complication of a Very Frequent Disease. AB - The Bouveret syndrome is an exceptional complication of the gallbladder lithiasis. Hereby it is described the case of a patient with a history of gallstones complicated on the long-term outcome with gastric outlet obstruction, due to a large gallstone of the duodenum, migrated via a cholecysto-duodenal fistula. The clinical, radiological features and the patient management are described. PMID- 27452945 TI - Influencing and protective factors of suicidal ideation among older adults. AB - Suicide is a global issue, but few studies have explored the triggers and psychological feelings of suicidal ideation in older adults. A qualitative design with face-to-face semistructured interviews examined the experience of suicidal ideation in adults aged 65 years and older. A purposive sampling of 32 outpatients with suicidal ideation from a medical centre in northern Taiwan participated. Interview data identified three themes: triggers for suicidal ideation, contributing psychological changes, and factors of adaptive response. The triggers for suicidal ideation included physical discomfort, loss of respect and/or support from family, impulsive emotions due to conflicts with others, and painful memories. Psychological changes contributed to suicidal ideation: feelings of loneliness, a sense of helplessness, or lack of self-worth. Participants described adaptive responses that acted as protective factors of suicidal ideation: support from family and friends, control of emotions, establishing a support network, comfort from religion, medication, and focussing on the family. Mental health nurses and clinicians should incorporate evaluations of stressful life events and psychological changes into a screening scale for older adults to improve detection of those at risk for suicide. Teaching coping strategies could provide timely interventions to secure the safety of this older population of adults. PMID- 27452946 TI - Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription. AB - Enhancers can stimulate transcription by a number of different mechanisms which control different stages of the transcription cycle of their target genes, from recruitment of the transcription machinery to elongation by RNA polymerase. These mechanisms may not be mutually exclusive, as a single enhancer may act through different pathways by binding multiple transcription factors. Multiple enhancers may also work together to regulate transcription of a shared target gene. Most of the evidence supporting different enhancer mechanisms comes from the study of single genes, but new high-throughput experimental frameworks offer the opportunity to integrate and generalize disparate mechanisms identified at single genes. This effort is especially important if we are to fully understand how sequence variation within enhancers contributes to human disease. PMID- 27452948 TI - Pain by Association? Experimental Modulation of Human Pain Thresholds Using Classical Conditioning. AB - A classical conditioning framework is often used for clinical reasoning about pain that persists after tissue healing. However, experimental studies demonstrating classically conditioned pain in humans are lacking. The current study tested whether non-nociceptive somatosensory stimuli can come to modulate pain thresholds after being paired with painful nociceptive stimuli in healthy humans. We used a differential simultaneous conditioning paradigm in which one nonpainful vibrotactile conditioned stimulus (CS(+)) was simultaneously paired with an unconditioned painful laser stimulus, and another vibrotactile stimulus (CS(-)) was paired with a nonpainful laser stimulus. After acquisition, at-pain threshold laser stimuli were delivered simultaneously with a CS(+) or CS(-) vibrotactile stimulus. The primary outcome was the percentage of at-threshold laser stimuli that were reported as painful. The results were as expected: after conditioning, at-threshold laser trials paired with the CS(+) were reported as painful more often, as more intense, and as more unpleasant than those paired with the CS(-). This study provides new evidence that pain thresholds can be modulated via classical conditioning, even when the stimulus used to test the threshold cannot be anticipated. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain. PERSPECTIVE: This study provides new evidence that human pain thresholds can be influenced by non-nociceptive somatosensory stimuli, via a classical conditioning effect. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain. PMID- 27452947 TI - Two hAT transposon genes were transferred from Brassicaceae to broomrapes and are actively expressed in some recipients. AB - A growing body of evidence is pointing to an important role of horizontal gene transfer (HGT) in the evolution of higher plants. However, reports of HGTs of transposable elements (TEs) in plants are still scarce, and only one case is known of a class II transposon horizontally transferred between grasses. To investigate possible TE transfers in dicots, we performed transcriptome screening in the obligate root parasite Phelipanche aegyptiaca (Orobanchaceae), data-mining in the draft genome assemblies of four other Orobanchaceae, gene cloning, gene annotation in species with genomic information, and a molecular phylogenetic analysis. We discovered that the broomrape genera Phelipanche and Orobanche acquired two related nuclear genes (christened BO transposase genes), a new group of the hAT superfamily of class II transposons, from Asian Sisymbrieae or a closely related tribe of Brassicaceae, by HGT. The collinearity of the flanking genes, lack of a classic border structure, and low expression levels suggest that BO transposase genes cannot transpose in Brassicaceae, whereas they are highly expressed in P. aegyptiaca. PMID- 27452949 TI - Understanding and improving the one and three times GDP per capita cost effectiveness thresholds. AB - Researchers and policymakers have long been interested in developing simple decision rules to aid in determining whether an intervention is, or is not, cost effective. In global health, interventions that impose costs per disability adjusted life year averted less than three and one times gross domestic product per capita are often considered cost-effective and very cost-effective, respectively. This article explores the conceptual foundation and derivation of these thresholds. Its goal is to promote understanding of how these thresholds were derived and their implications, as well as to suggest options for improvement. These thresholds are intended to reflect the monetary value of the benefits to affected individuals, based on their preferences for spending on health vs spending on other goods and services. However, the current values were not rigorously derived, which means that their application may lead to inappropriate conclusions regarding which interventions should be adopted as well as misallocation of resources across health and other investments. Improving the basis for these cost-effectiveness thresholds is of particular importance in low- and middle-income countries, given the limited resources available and the significant needs of their populations. PMID- 27452950 TI - Bringing to an end mother-to-child transmission of hepatitis B: A role for quantitative hepatitis B surface antigen? PMID- 27452951 TI - Clinical Outcomes for Patients with Gleason Score 9-10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis. AB - BACKGROUND: The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons. OBJECTIVE: To compare outcomes of patients with GS 9-10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT+brachytherapy [EBRT+BT]), and RP. DESIGN, SETTING, PARTICIPANTS: Retrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT+BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT+BT patients (1.2% and 16.1%, p<0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT+BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p=0.0005) or RP (79.1% and 61.5%, p<0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts. CONCLUSIONS: Radiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9-10 CaP. PATIENT SUMMARY: While some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to be made and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patients with very aggressive cancers (defined as Gleason score 9-10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival. PMID- 27452952 TI - Reply to Lars Egevad, Hemamali Samaratunga, John R. Srigley, Brett Delahunt's Letter to the Editor re: Anthony Zietman, Joseph Smith, Eric Klein, Michael Droller, Prokar Dasgupta, James Catto. Describing the Grade of Prostate Cancer: Consistent Use of Contemporary Terminology Is Now Required. Eur Urol 2016;70:1. PMID- 27452953 TI - A 54-year-old man with 12 intracranial aneurysms and familial subarachnoid hemorrhage: case report. AB - Unruptured intracranial aneurysms occur in 1-3 % of the general population, and the risk of rupture is generally considered to be low. However, patients with multiple aneurysms and familial predisposition carry a particular risk of subarachnoid hemorrhage (SAH). A 54-year-old hypertensive man underwent screening with a head CT angiography (CTA) because of his comorbidities. CTA revealed multiple bilateral aneurysms around the circle of Willis. At first surgery, seven aneurysms were clipped (BA, ACOM, ICA *2, and MCA *3), two of which were detected intraoperatively only. During the second surgery, another three aneurysms were surgically clipped (PCOM and MCA *2), one of which was detected intraoperatively. Follow-up angiography revealed another two aneurysms. A PCOM aneurysm was treated by coil embolization and a VA aneurysm clipped surgically during a third admission. The patient made an uneventful recovery. However, 4 months after his second surgery, his daughter underwent surgical clipping of a right-sided ICA aneurysm. This case report highlights both the importance of screening of high risk patients with family history of SAH, as well as its limitations, as our patient developed two de novo aneurysms during 6-month follow-up and CTA preoperatively missed three small aneurysms. PMID- 27452955 TI - Discussion. PMID- 27452954 TI - Comparative analysis of biologic versus synthetic mesh outcomes in contaminated hernia repairs. AB - BACKGROUND: Contaminated operative fields pose significant challenges for surgeons performing ventral hernia repair. Although biologic meshes have been utilized increasingly in these fields, recent evidence suggests that synthetic meshes represent a viable option. We analyzed the outcomes of biologic and synthetic mesh utilized in patients undergoing major ventral hernia repair in clean-contaminated/contaminated fields. METHODS: We conducted a multicenter, retrospective review of patients undergoing open ventral hernia repair in clean contaminated/contaminated fields using biologic or synthetic mesh. Patient and hernia details were characterized. Primary outcomes included 90-day surgical site event, surgical site infection, and hernia recurrence. RESULTS: A total of 126 patients undergoing major ventral hernia repair in clean contaminated/contaminated fields (69 biologic and 57 synthetic meshes) were analyzed. Groups were similar in both patient and hernia characteristics. There were 13 (22.8%) surgical site events in the synthetic cohort compared to 29 (42.0%) in the biologic cohort, P = .024. Similarly, surgical site infections were less frequent in the synthetic group, with 7 (12.3%) vs 22 (31.9%), P = .01. With a mean follow-up of 20 months, there were more recurrences in the biologic group: 15 (26.3%) vs 4 (8.9%) in the synthetic group, P = .039. CONCLUSION: The choice of mesh for clean-contaminated/contaminated ventral hernia repair remains debatable. We demonstrated that using synthetic sublay mesh resulted in a significantly lower wound morbidity and more durable outcomes versus a similar cohort of biologic repairs. This is likely secondary to improved bacterial clearance and faster integration of macroporous synthetics. Overall, our findings not only support suitability of synthetic mesh in contaminated settings but also challenge the purported advantage of biologics in clean-contaminated/contaminated ventral hernia repairs. PMID- 27452956 TI - Spatially resolved time-frequency analysis of odour coding in the insect antennal lobe. AB - Antennal lobes constitute the first neurophils in the insect brain involved in coding and processing of olfactory information. With their stereotyped functional and anatomical organization, they provide an accessible model with which to investigate information processing of an external stimulus in a neural network in vivo. Here, by combining functional calcium imaging with time-frequency analysis, we have been able to monitor the oscillatory components of neural activity upon olfactory stimulation. The aim of this study is to investigate the presence of stimulus-induced oscillatory patterns in the honeybee antennal lobe, and to analyse the distribution of those patterns across the antennal lobe glomeruli. Fast two-photon calcium imaging reveals the presence of low-frequency oscillations, the intensity of which is perturbed by an incoming stimulus. Moreover, analysis of the spatial arrangement of this activity indicates that it is not homogeneous throughout the antennal lobe. On the contrary, each glomerulus displays an odorant-specific time-frequency profile, and acts as a functional unit of the oscillatory activity. The presented approach allows simultaneous recording of complex activity patterns across several nodes of the antennal lobe, providing the means to better understand the network dynamics regulating olfactory coding and leading to perception. PMID- 27452957 TI - Antifungal potential of eugenyl acetate against clinical isolates of Candida species. AB - The study evaluated the efficiency of eugenyl acetate (EA), a phytochemical in clove essential oil, against clinical isolates of Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida glabrata. Minimum inhibitory concentrations (MIC) of EA against Candida isolates were in the range between 0.1% and 0.4% (v/v). Spot assay further confirmed the susceptibility of Candida isolates to the compound upon treatment with respective 1 * MIC. Growth profile measured in time kill study evidence that the compound at 1 * MIC and 1/2 * MIC retarded the growth of Candida cells, divulging the fungicidal activity. Light microscopic observation demonstrated that upon treated with EA, rough cell morphology, cell damage, and fragmented patterns were observed in C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata. Furthermore, unusual morphological changes of the organism were observed in scanning electron microscopic study. Therefore, it is validated that the compound could cause cell damage resulting in the cell death of Candida clinical isolates. Eventually, the compound at sub-MIC (0.0125% v/v) significantly inhibited serum-induced germ tube formation by C. albicans. Eugenyl acetate inhibited biofilm forming ability of the organisms as well as reduced the adherence of Candida cells to HaCaT keratinocytes cells. In addition, upon treatment with EA, the phagocytic activity of macrophages was increased significantly against C. albicans (P < 0.05). The results demonstrated the potential of EA as a valuable phytochemical to fight against emerging Candida infections. PMID- 27452958 TI - Impact of cell culture on recombinant monoclonal antibody product heterogeneity. AB - Recombinant monoclonal antibodies are commonly expressed in mammalian cell culture and purified by several steps of filtration and chromatography. The resulting high purity bulk drug substance still contains product variants differing in properties such as charge and size. Posttranslational modifications and degradations occurring during cell culture are the major sources of heterogeneity in bulk drug substance of recombinant monoclonal antibodies. The focus of the current review is the impact of cell culture conditions on the types and levels of various modifications and degradations of recombinant monoclonal antibodies. Understanding the relationship between cell culture and product variants can help to make consistently safe and efficacious products. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1103-1112, 2016. PMID- 27452959 TI - Angioimmunoblastic T-Cell Lymphoma in a Patient with Klinefelter Syndrome. AB - BACKGROUND Although patients with Klinefelter syndrome have elevated risk and incidence rates for several solid cancers, reports on the incidence of hematological malignancies have been equivocal. CASE REPORT We report a patient diagnosed with angioimmunoblastic T-cell lymphoma in whom Klinefelter syndrome was newly detected. Moreover, we discuss the development of a variety of lymphomas in patients with Klinefelter syndrome. CONCLUSIONS This is the first case describing angioimmunoblastic T-cell lymphoma in a patient with Klinefelter syndrome who was treated with chemotherapy. PMID- 27452961 TI - Effects of dietary supplementation with freshwater microalgae on growth performance, nutrient digestibility and gut health in weaned piglets. AB - In pigs, digestive disorders associated with weaning lead to antibiotic use to maintain intestinal health. Microalgae have been studied in humans and rodents for their beneficial effects on health. The nutritional value of microalgae in animal diets has been assessed, but results were not conclusive. Dietary supplementation with microalgae as an alternative to antibiotic use was studied in two trials (72 piglets with initial BW=9.1+/-1.1 kg in trial 1 and 24 piglets with initial BW=9.1+/-0.9 kg in trial 2). All piglets were weaned at 28 days of age and then housed in individual cages. Piglets were randomly allocated to one of the four diets during 2 weeks after weaning: a standard diet with no supplementation (NC) or the standard diet supplemented with 1% Spirulina (SP), with 1% Chlorella (CV), or with 0.2% of colistin as positive control (PC). Trial 1 was performed to determine the effect of microalgae supplementation from 28 to 42 days on performance and incidence of diarrhoea. Animals received then a standard diet from 42 to 56 days of age. Trial 2 was performed from 28 to 42 days of age to assess nutrient digestibility of the experimental diets and to determine inflammatory status and intestinal morphology at 42 days of age. In trial 1, 94% of the pigs had diarrhoea in the 1st week after weaning with no beneficial effect of colistin on diarrhoea incidence, average daily feed intake (ADFI), average daily gain (ADG), and gain : feed (G : F) ratio. This suggests that the diarrhoea was due to digestive disorders that did not result from enterotoxigenic Escherichia coli infection. Supplementation with either Spirulina or Chlorella did not affect ADFI, ADG and G : F in trials 1 and 2 (P>0.10). Diarrhoea incidence was reduced in CV pigs compared with NC, SP and PC pigs (P<0.05). Total tract digestibility in pig receiving microalgae was greater for gross energy (P<0.05), and tended to be greater for dry matter, organic matter and NDF (P<0.10) compared with NC and PC pigs. Villus height at the jejunum was greater in SP and CV pigs compared with NC and PC pigs (P<0.05). This study shows a potential effect of both Spirulina and Chlorella supplementation on intestinal development and a potential of Chlorella supplementation to manage mild digestive disorders. Further investigation is necessary to determine the mechanism action of Spirulina and Chlorella on gut health and physiology. PMID- 27452962 TI - Human cartilaginous endplate degeneration is induced by calcium and the extracellular calcium-sensing receptor in the intervertebral disc. AB - The cartilaginous endplates (CEPs) are thin layers of hyaline cartilage found adjacent to intervertebral discs (IVDs). In addition to providing structural support, CEPs regulate nutrient and metabolic exchange in the disc. In IVD pathogenesis, CEP undergoes degeneration and calcification, compromising nutrient availability and disc cell metabolism. The mechanism(s) underlying the biochemical changes of CEP in disc degeneration are currently unknown. Since calcification is often observed in later stages of IVD degeneration, we hypothesised that elevations in free calcium (Ca2+) impair CEP homeostasis. Indeed, our results demonstrated that the Ca2+ content was consistently higher in human CEP tissue with grade of disc degeneration. Increasing the levels of Ca2+ resulted in decreases in the secretion and accumulation of collagens type I, II and proteoglycan in cultured human CEP cells. Ca2+ exerted its effects on CEP matrix protein synthesis through activation of the extracellular calcium-sensing receptor (CaSR); however, aggrecan content was also affected independent of CaSR activation as increases in Ca2+ directly enhanced the activity of aggrecanases. Finally, supplementing Ca2+ in our IVD organ cultures was sufficient to induce degeneration and increase the mineralisation of CEP, and decrease the diffusion of glucose into the disc. Thus, any attempt to induce anabolic repair of the disc without addressing Ca2+ may be impaired, as the increased metabolic demand of IVD cells would be compromised by decreases in the permeability of the CEP. PMID- 27452960 TI - The neurobiology of addiction: the perspective from magnetic resonance imaging present and future. AB - BACKGROUND AND AIMS: Addiction is associated with severe economic and social consequences and personal tragedies, the scientific exploration of which draws upon investigations at the molecular, cellular and systems levels with a wide variety of technologies. Magnetic resonance imaging (MRI) has been key to mapping effects observed at the microscopic and mesoscopic scales. The range of measurements from this apparatus has opened new avenues linking neurobiology to behaviour. This review considers the role of MRI in addiction research, and what future technological improvements might offer. METHODS: A hermeneutic strategy supplemented by an expansive, systematic search of PubMed, Scopus and Web of Science databases, covering from database inception to October 2015, with a conjunction of search terms relevant to addiction and MRI. Formal meta-analyses were prioritized. RESULTS: Results from methods that probe brain structure and function suggest frontostriatal circuitry disturbances within specific cognitive domains, some of which predict drug relapse and treatment response. New methods of processing imaging data are opening opportunities for understanding the role of cerebral vasculature, a global view of brain communication and the complex topology of the cortical surface and drug action. Future technological advances include increases in MRI field strength, with concomitant improvements in image quality. CONCLUSIONS: The magnetic resonance imaging literature provides a limited but convergent picture of the neurobiology of addiction as global changes to brain structure and functional disturbances to frontostriatal circuitry, accompanied by changes in anterior white matter. PMID- 27452963 TI - The crucial role of neutrophil granulocytes in bone fracture healing. AB - Delayed bone fracture healing and the formation of non-unions represent an important clinical problem, particularly in polytrauma patients who suffer from posttraumatic systemic inflammation. However, the underlying pathomechanisms remain unclear. Neutrophil granulocytes are crucial effector cells in the systemic immune response and represent the most abundant immune cell population in the early fracture haematoma. Here we investigated the role of neutrophils in a mouse model of uncomplicated fracture healing and compromised fracture healing induced by an additional thoracic trauma. Twenty four hours before injury, 50 % of the mice were systemically treated with an anti-Ly-6G-antibody to reduce neutrophil numbers. In the isolated fracture model, Ly-6G-Ab treatment significantly increased the concentration of both pro- and anti-inflammatory cytokines, including interleukin (IL)-6 and IL-10, and chemokines, for example, C X-C motif ligand 1 (CXCL1) and monocyte chemotactic protein-1 (MCP-1), in the fracture haematoma. Monocyte/macrophage recruitment was also significantly enhanced. After 21 d, bone regeneration was considerably impaired as demonstrated by significantly diminished bone content and impaired mechanical properties of the fracture callus. These results indicate that undisturbed neutrophil recruitment and function in the inflammatory phase after fracture is crucial to initiate downstream responses leading to bone regeneration. In the combined trauma model, the reduction of neutrophil numbers ameliorated pulmonary inflammation but did not provoke any significant effect on bone regeneration, suggesting that neutrophils may not play a crucial pathomechanistic role in compromised fracture healing induced by an additional thoracic trauma. PMID- 27452964 TI - Free-living monitoring of Parkinson's disease: Lessons from the field. AB - Wearable technology comprises miniaturized sensors (eg, accelerometers) worn on the body and/or paired with mobile devices (eg, smart phones) allowing continuous patient monitoring in unsupervised, habitual environments (termed free-living). Wearable technologies are revolutionizing approaches to health care as a result of their utility, accessibility, and affordability. They are positioned to transform Parkinson's disease (PD) management through the provision of individualized, comprehensive, and representative data. This is particularly relevant in PD where symptoms are often triggered by task and free-living environmental challenges that cannot be replicated with sufficient veracity elsewhere. This review concerns use of wearable technology in free-living environments for people with PD. It outlines the potential advantages of wearable technologies and evidence for these to accurately detect and measure clinically relevant features including motor symptoms, falls risk, freezing of gait, gait, functional mobility, and physical activity. Technological limitations and challenges are highlighted, and advances concerning broader aspects are discussed. Recommendations to overcome key challenges are made. To date there is no fully validated system to monitor clinical features or activities in free living environments. Robust accuracy and validity metrics for some features have been reported, and wearable technology may be used in these cases with a degree of confidence. Utility and acceptability appears reasonable, although testing has largely been informal. Key recommendations include adopting a multidisciplinary approach for standardizing definitions, protocols, and outcomes. Robust validation of developed algorithms and sensor-based metrics is required along with testing of utility. These advances are required before widespread clinical adoption of wearable technology can be realized. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27452965 TI - Synthesis of the 2-formylpyrrole spiroketal pollenopyrroside A and structural elucidation of xylapyrroside A, shensongine A and capparisine B. AB - A convergent synthesis of the 2-formyl pyrrole spiroketal pollenopyrroside A is reported. The key step involves a Maillard-type condensation of an amine derived from deoxy-d-ribose with a dihydropyranone to furnish the 2-formylpyrrole ring system. Spectroscopic and physical data of 9-epi-pollenopyrroside A are also provided, elucidating the structures of the previously isolated 2-formylpyrrole spiroketals capparisine B, shensongine A and xylapyrroside A. PMID- 27452966 TI - Diagnosis and management of adult hereditary cardio-neuromuscular disorders: A model for the multidisciplinary care of complex genetic disorders. AB - Genetic disorders that disrupt the structure and function of the cardiovascular system and the peripheral nervous system are common enough to be encountered in routine cardiovascular practice. Although often these patients are diagnosed in childhood and come to the cardiologist fully characterized, some patients with hereditary neuromuscular disease may not manifest until adulthood and will present initially to the adult cardiologist for an evaluation of an abnormal ECG, unexplained syncope, LV hypertrophy, and or a dilated cardiomyopathy of unknown cause. Cardiologists are often ill-equipped to manage these patients due to lack of training and exposure as well as the complete absence of practice guidelines to aid in the diagnosis and management of these disorders. Here, we review three key neuromuscular diseases that affect the cardiovascular system in adults (myotonic dystrophy type 1, Friedreich ataxia, and Emery-Dreifuss muscular dystrophy), with an emphasis on their clinical presentation, genetic and molecular pathogenesis, and recent important research on medical and interventional treatments. We also advocate the development of interdisciplinary cardio-neuromuscular clinics to optimize the care for these patients. PMID- 27452967 TI - Spinal Intramedullary Syphilitic Gumma: An Unusual Presentation of Neurosyphilis. AB - BACKGROUND: Spinal syphilitic gumma is an unusual presentation of neurosyphilis, with a limited number of cases reported in the literature. Owing to its extreme rarity, the diagnosis and treatment of spinal syphilitic gumma and the relevant prognosis have not been outlined. CASE DESCRIPTION: A 65-year-old woman with a history of neck, shoulder, and back pain presented with progressive sensorimotor disturbance of the extremities. Serologic tests revealed the presence of syphilis. Magnetic resonance imaging demonstrated an intramedullary nodule at the C5 level. A suspected diagnosis of spinal intramedullary tumor was made, and surgical resection of the nodule was performed. Histologic and immunohistochemical findings revealed a syphilitic gumma. We also conducted a comprehensive review of the published literature in all languages regarding spinal syphilitic gumma. The clinical and radiologic features, laboratory findings, therapeutic strategies, and follow-up data were analyzed. CONCLUSIONS: Spinal syphilitic gumma can occur in the intramedullary region, and clinicians should be aware of this extremely rare entity, as it can be easily mistaken for more common neoplasms occurring at this site. The magnetic resonance imaging appearance of this entity has some suggestive characteristics, and a confident diagnosis depends on the pathology. Surgical resection can help to relieve acute spinal cord compression, and systemic antibiotic treatment for syphilis should be emphasized for long-term control. PMID- 27452968 TI - Intraoperative Hypotension During Second Stage of Deep Brain Stimulator Placement: Same Day versus Different Day Procedures. AB - BACKGROUND: We evaluated blood pressure management associated with implantable pulse generator (IPG) procedure on same day (SD) versus different day (DD) from deep brain stimulation (DBS) placement. METHODS: A retrospective chart review of 99 records for vasopressors given during IPG using a negative binomial regression model was performed. An association between SD versus DD, cumulative vasopressor dose, and minimum and maximum mean arterial pressure (MAP) were sought. RESULTS: No significant association between SD versus DD DBS and the number of times vasopressors were given during stage II, estimated ratio of means (CI) of 1.8 (0.9-3.5); P = 0.07. Day of stage II had no association with the cumulative dose of vasopressor given during stage II, with an estimated difference in means (CI) of 2.4 (-0.4 to 5.3). The SD group had a significantly lower mean of minimum stage II MAP compared with DD, with an estimated difference in means (CI) of 10.5 (-17.4 to -3.5; P < 0.001). There was no association with maximum stage II MAP, with an estimated difference in means (CI) of -2.8 (-17.6 to 12.0; P = 0.63). CONCLUSION: No difference in intraoperative vasopressor use was found between SD versus DD IPG placement, but the SD group had a significantly lower minimum MAP. PMID- 27452969 TI - Clinicopathological, Radiological, and Genetic Analyses of Cerebellar Gangliogliomas with Long-Term Survival. AB - OBJECTIVE: Cerebellar gangliogliomas show different image findings and clinical behaviors from the supratentorial; however, their molecular basis and optimal managements remain to be elucidated. We report 3 children with cerebellar ganglioglioma and long-term survival, focusing on clinicopathological and radiological findings and genetic analyses. PATIENTS AND METHODS: We retrospectively analyzed 3 children with cerebellar ganglioglioma treated in our institute between 2000 and 2010. Immunohistochemical examinations were performed to determine the expression of KI-67, glial fibrillary acidic protein, synaptophysin, BRAFV600E and IDH-1 R132H mutated proteins. Standard Sanger sequencing was used to confirm BRAF, IDH-1/2, and Histone H3.3 mutations. Methylation-specific polymerase chain reaction was used to evaluate MGMT promoter methylation. RESULTS: In all cases, magnetic resonance imaging demonstrated an infiltrative tumor in cerebellar peduncle and hemisphere. All 3 children are alive (>12 years survival), and their residual tumors have been stable for more than 5 years after the treatments. Their tumors showed distinctive features of ganglioglioma with low Ki-67 index (2%-4%), positive for the BRAFV600E mutation, but negative for IDH1/2 mutations. The MGMT promoter methylation was observed in all of them. CONCLUSIONS: Our study showed that all 3 children achieved long-term survival with residual tumors. These tumors might indicate a benign prognosis of pediatric cerebellar gangliogliomas, regardless of the infiltrating manifestation and the presence of BRAF mutation. PMID- 27452970 TI - Basiespinal Cerebrospinal Fluid Leak as a Complication After Adenoidectomy: Case Report and Literature Review. AB - BACKGROUND: Adenoidectomy is one of the most common procedures in the field of pediatric otolaryngology. Postoperative bleeding is one of the most frequent complications (0.4%). In turn, cerebrospinal fluid fistula is a very uncommon but critical complication in this type of surgery. METHODS: We report the case of a 3 year-old patient who underwent adenoidectomy and presented a cerebrospinal fluid leak associated with pneumocephalus and meningitis. RESULTS: The solution provided was a suture in layers of the fistula tract, reinforced with basipharyngeal vascularized and rotation random flap of mucosa, and a free graft of muscle, through a transoral endoscopic approach. CONCLUSIONS: Cerebrospinal fluid leak as a complication after adenoidectomy is exceedingly rare. These pharyngospinal fistulae are determined by the anatomic features associated with intraoperative hemorrhagic complications, and it is essential that we take them into account when facing postoperative complications in the follow-up. The use of vascularized flaps based on the irrigation of the ascending pharyngeal artery with endoscopic techniques offers low-morbidity solutions, which are more efficient than traditional methods. PMID- 27452971 TI - Malignant Peripheral Nerve Sheath Tumors. PMID- 27452972 TI - Positive and negative innate immune responses in zebrafish under light emitting diodes conditions. AB - Certain light emitting diodes (LEDs) have become popular in fish farming beacause of a promoting effect on growth and reproduction. However, little information is available on innate immune responses in related tissues under LEDs conditions. The present study assessed the effects of a white fluorescent bulb (the control) and two different light-emitting diodes (LEDs: blue, LDB, peak at 450 nm; red, LDR, 630 nm) on growth and innate immune responses in the serum, liver and ovary of zebrafish for 8 weeks. LDB significantly enhanced specific growth rate (SGR), food intake (FI), and serum globulin levels. In contrast, LDR sharply inhibited SGR, FI, and the levels of albumin and globulin. Under LDB condition, there was an increase in protein levels of alkaline phophatase (AKP) and protein and activity levels of lysozyme (LZM) in the liver, and the levels of mRNA, protein, and activity of LZM in the ovary. Under LDR condition, LZM was dramatically down regulated at mRNA, protein and activity levels in the ovary, suggesting that LZM was regulated at a transcriptional level. In the liver of the LDR group, though AKP mRNA levels sharply increased, its protein and activity levels significantly declined, indicating that AKP was regulated at translational level. Furthermore, a positive correlation between transcription factor NF-kappaB RelA mRNA levels and expression levels of AKP and LZM was observed in the liver and ovary, implying a transcriptional regulation of NF-kappaB RelA. In conclusion, the present study demonstrated a positive effect of LDB and negative effect of LDR on fish growth and innate immune responses, possibly associated with modifications at transcriptional, translational, and post-translational levels, and the transcriptional regulation of the NF-kappaB signaling molecule. PMID- 27452973 TI - Genomic organization, expression and antimicrobial activity of a hepcidin from taimen (Hucho taimen, Pallas). AB - Hepcidin, an antimicrobial peptide, plays a crucial role in innate immune system of teleost fish. As a cysteine-rich peptide, hepcidin possesses a dual function including iron regulation and innate immunity. In the present study, a full length hepcidin cDNA (HtHep) was cloned and characterized by RT-PCR and RACE techniques from taimen (Hucho taimen, Pallas), which is a type of rare, precious and cold-water fish species in China. The cDNA contains an open reading frame (ORF) of 267 bp encoding 88 amino acid (aa), with 170 bp located in the 5(') untranslated region (UTR) and 151 bp in the 3' UTR. The genomic sequences analysis showed that the HtHep gene consisted of three exons and two introns (with the length 94 and 251 bp, respectively). With a predicted molecular mass of 2881.4 Da and a theoretical pI of 8.53, the deduced amino acid encodes a signal peptide of 24 aa, prodomain of 39 aa and mature peptide of 25 aa. The signal peptidase (SA-VP) and the motif RX (K/R)R of propeptide convertase suggested the cleavage site of signal and mature peptide. Eight conserved cysteine residues were also identified and formed four disulfide bonds. Pair-wise alignments showed that HtHep clustered together with two fish species of Salmonidae family (Salmo salar and Oncorhynchus mykiss) in HAMP1 branch. Quantitative RT-PCR analysis indicated that the mRNA levels of HtHep were detected in a wide range of tissues and the highest level was detected in the liver. Its expression was also detected early during embryonic stage and could be up-regulated in the liver when challenged with pathogenic bacteria (Yersinia ruckeri). The recombinant HtHep (rHtHep) had antimicrobial activity against both gram-positive (Micrococcus lysodeikticus and Staphylococcus aureus) and gram-negative bacteria (Escherichia coli). Our results suggested that HtHep might be involved in the innate immune defense against bacterial pathogens in taimen. PMID- 27452974 TI - A review of risk factors for bovine tuberculosis infection in cattle in the UK and Ireland. AB - Bovine tuberculosis (bTB) is an important disease of cattle caused by infection with Mycobacterium bovis, a pathogen that may be extremely difficult to eradicate in the presence of a true wildlife reservoir. Our objective was to identify and review relevant literature and provide a succinct summary of current knowledge of risk factors for transmission of infection of cattle. Search strings were developed to identify publications from electronic databases to February 2015. Abstracts of 4255 papers identified were reviewed by three reviewers to determine whether the entire article was likely to contain relevant information. Risk factors could be broadly grouped as follows: animal (including nutrition and genetics), herd (including bTB and testing history), environment, wildlife and social factors. Many risk factors are inter-related and study designs often do not enable differentiation between cause and consequence of infection. Despite differences in study design and location, some risk factors are consistently identified, e.g. herd size, bTB history, presence of infected wildlife, whereas the evidence for others is less consistent and coherent, e.g. nutrition, local cattle movements. We have identified knowledge gaps where further research may result in an improved understanding of bTB transmission dynamics. The application of targeted, multifactorial disease control regimens that address a range of risk factors simultaneously is likely to be a key to effective, evidence-informed control strategies. PMID- 27452975 TI - Super-resolution spectroscopic microscopy via photon localization. AB - Traditional photon localization microscopy analyses only the spatial distributions of photons emitted by individual molecules to reconstruct super resolution optical images. Unfortunately, however, the highly valuable spectroscopic information from these photons have been overlooked. Here we report a spectroscopic photon localization microscopy that is capable of capturing the inherent spectroscopic signatures of photons from individual stochastic radiation events. Spectroscopic photon localization microscopy achieved higher spatial resolution than traditional photon localization microscopy through spectral discrimination to identify the photons emitted from individual molecules. As a result, we resolved two fluorescent molecules, which were 15 nm apart, with the corresponding spatial resolution of 10 nm-a four-fold improvement over photon localization microscopy. Using spectroscopic photon localization microscopy, we further demonstrated simultaneous multi-colour super-resolution imaging of microtubules and mitochondria in COS-7 cells and showed that background autofluorescence can be identified through its distinct emission spectra. PMID- 27452977 TI - On the scaling problem and micro-macro derivation of crowd models: Comment on "Human behaviours in evacuation crowd dynamics: From modelling to "big data" toward crisis management" by Nicola Bellomo et al. PMID- 27452976 TI - Exploring lateral genetic transfer among microbial genomes using TF-IDF. AB - Many microbes can acquire genetic material from their environment and incorporate it into their genome, a process known as lateral genetic transfer (LGT). Computational approaches have been developed to detect genomic regions of lateral origin, but typically lack sensitivity, ability to distinguish donor from recipient, and scalability to very large datasets. To address these issues we have introduced an alignment-free method based on ideas from document analysis, term frequency-inverse document frequency (TF-IDF). Here we examine the performance of TF-IDF on three empirical datasets: 27 genomes of Escherichia coli and Shigella, 110 genomes of enteric bacteria, and 143 genomes across 12 bacterial and three archaeal phyla. We investigate the effect of k-mer size, gap size and delineation of groups on the inference of genomic regions of lateral origin, finding an interplay among these parameters and sequence divergence. Because TF-IDF identifies donor groups and delineates regions of lateral origin within recipient genomes, aggregating these regions by gene enables us to explore, for the first time, the mosaic nature of lateral genes including the multiplicity of biological sources, ancestry of transfer and over-writing by subsequent transfers. We carry out Gene Ontology enrichment tests to investigate which biological processes are potentially affected by LGT. PMID- 27452978 TI - Obese women experience multiple challenges with breastfeeding that are either unique or exacerbated by their obesity: discoveries from a longitudinal, qualitative study. AB - Obese women are at risk for shorter breastfeeding duration, but little is known about how obese women experience breastfeeding. The aim of this study was to understand obese women's breastfeeding experiences. We enrolled pregnant women in upstate New York, who were either obese [n = 13; body mass index (BMI) >=30 kg/m2 ] or normal weight (n = 9; BMI 18.5-24.9 kg/m2 ) before conception and intended to breastfeed. A longitudinal, qualitative study was conducted from February 2013 through August 2014 with semi-structured interviews during pregnancy and at specific times post-partum through 3 months. Interviews were audio recorded, transcribed and analyzed using content analysis. Themes that emerged in analysis were compared between obese and normal-weight women. Differences were identified and described. Prenatally, obese women expressed less confidence about breastfeeding than normal-weight women. Post-partum, obese women and their infants had more health issues that affected breastfeeding, such as low infant blood glucose. Compared with normal-weight women, they also experienced more challenges with latching and positioning their infants. Breastfeeding required more time, props and pillows, which limited where obese women could breastfeed. Obese women also experienced more difficulty finding nursing bras and required more tangible social support than normal-weight women. In conclusion, obese women experienced more challenges than women of normal weight; some challenges were similar to those of normal-weight women but were experienced to a greater degree or a longer duration. Other challenges were unique. Obese women could benefit from targeted care prenatally and during the hospital stay as well as continued support post-partum to improve breastfeeding outcomes. (c) 2016 John Wiley & Sons Ltd. PMID- 27452979 TI - The influence of NBD fluorescent probe on model membranes containing POPC and DPPC. AB - To investigate the effect of fluorescent probe on the properties of membranes, we studied model membranes composed of 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-palmitoyl 2-oleoyl-sn-glycero-3-phosphocholine (POPC) in the presence and absence of fluorescent probe. The morphology of giant unilamellar vesicles (GUVs) has been observed as a function of temperature and composition by fluorescence microscopy using NBD-DOPE or C6-NBD-PC as the probe. The phase behavior of model membranes containing no fluorescent probe was investigated by 2H-NMR spectroscopy. We found that the bright phase observed on GUVs was the fluid phase enriched in POPC and the dark phase was the gel phase enriched in DPPC. NBD-DOPE and C6-NBD-PC preferentially participated in the fluid-phase domains when GUVs were in the gel + fluid phase coexistence. Inclusion of both fluorescent probes (1 mol%) lowered the transition temperature of POPC/DPPC membranes. In addition, C6-NBD-PC exhibited a stronger effect than NBD-DOPE, which was considered to be associated with the structures of fluorescent molecules. PMID- 27452980 TI - Effects of grazing on photosynthetic features and soil respiration of rangelands in the Tianshan Mountains of Northwest China. AB - Rangelands play a critical role in the global carbon cycle. However, the eco physiological mechanisms associated with the effects of grazing on leaf photosynthesis and soil respiration remain poorly understood. To examine the impacts of grazing on leaf photosynthesis and soil respiration, we measured the photosynthetic parameters of the dominant species (Trifolium repens) and the soil respiration in grazed and ungrazed rangelands in the Tianshan Mountains of China. We found that grazing reduced the daily maximum net photosynthetic rate and soil respiration rates by 35% and 15%, respectively. The photosynthetic quantum yield, dark respiratory rate, and water use efficiency of T. repens leaves were reduced in grazed plots by 33.3%, 69.2%, and 21.5%, respectively. Our results demonstrated that grazing reduced carbon assimilation while increasing soil respiration within the rangelands in the Tianshan Mountains. PMID- 27452981 TI - Protective effect of tunica albuginea incision with tunica vaginalis flap coverage on tissue damage and oxidative stress following testicular torsion: Role of duration of ischemia. AB - OBJECTIVE: This experimental study used a rat model to investigate the effect of a tunica albuginea incision with tunica vaginalis flap coverage on tissue damage and oxidative stress caused by testicular torsion and its relationship with the duration of ischemia. MATERIALS AND METHODS: The test animals were divided into the following groups: G1, sham procedure; G2, testicular torsion for 1, 5, or 9 h followed by detorsion; G3, testicular torsion for 1, 5, or 9 h followed by detorsion using flap technique. Testicular torsion was induced by 720 degrees counterclockwise rotation of the left testis. After the period of torsion, the flap technique was employed for detorsion. The oxidative stress and testosterone levels were measured at 24 h post procedure. Further assessment was carried out by histomorphometry at 30 days post procedure. The histological parameters included the Johnsen score, diameter of the seminiferous tubules, and thickness of seminiferous tubule epithelium. RESULTS: The histological parameters in the G2 group showed a significant change in relationship with the duration of ischemia. In the G3 group, flap coverage improved the histological parameters only for the 9-hour torsion subjects. The levels of testosterone, glutathione peroxidase (GPX), and superoxide dismutase significantly decreased in all subgroups of G2 and G3, and the malondialdehyde level increased as the duration of ischemia increased. Flap coverage decreased the malondialdehyde level only in the 9-hour torsion subjects. CONCLUSIONS: Flap coverage reduced tissue damage as the duration of ischemia increased. The findings of the rat model suggested that a tunica albuginea incision with tunica vaginalis flap might have provided a protective effect in long-term ischemia. PMID- 27452982 TI - BODY MASS INDEX AND SELF-EMPLOYMENT IN SOUTH KOREA. AB - This study assesses differential labour performance by body mass index (BMI), focusing on heterogeneity across three distinct employment statuses: unemployed, self-employed and salaried. Data were drawn from the Korean Labor and Income Panel Study. The final sample included 15,180 person-year observations (9645 men and 5535 women) between 20 and 65 years of age. The findings show that (i) overweight/obese women are less likely to have salaried jobs than underweight/normal weight women, whereas overweight/obese men are more likely to be employed in both the salaried and self-employed sectors than underweight/normal men, (ii) overweight/obese women have lower wages only in permanent salaried jobs than underweight/normal weight women, whereas overweight/obese men earn higher wages only in salaried temporary jobs than underweight/normal weight women, (iii) overweight/obese women earn lower wages only in service, sales, semi-professional and blue-collar jobs in the salaried sector than underweight/normal weight women, whereas overweight/obese men have lower wages only in sales jobs in the self-employed sector than underweight/normal weight women. The statistically significant BMI penalty in labour market outcomes, which occurs only in the salaried sector for women, implies that there is an employers' distaste for workers with a high BMI status and that it is a plausible mechanism for job market penalty related to BMI status. Thus, heterogeneous job characteristics across and within salaried versus self-employed sectors need to be accounted for when assessing the impact of BMI status on labour market outcomes. PMID- 27452983 TI - Improving protein-protein interactions prediction accuracy using protein evolutionary information and relevance vector machine model. AB - Predicting protein-protein interactions (PPIs) is a challenging task and essential to construct the protein interaction networks, which is important for facilitating our understanding of the mechanisms of biological systems. Although a number of high-throughput technologies have been proposed to predict PPIs, there are unavoidable shortcomings, including high cost, time intensity, and inherently high false positive rates. For these reasons, many computational methods have been proposed for predicting PPIs. However, the problem is still far from being solved. In this article, we propose a novel computational method called RVM-BiGP that combines the relevance vector machine (RVM) model and Bi gram Probabilities (BiGP) for PPIs detection from protein sequences. The major improvement includes (1) Protein sequences are represented using the Bi-gram probabilities (BiGP) feature representation on a Position Specific Scoring Matrix (PSSM), in which the protein evolutionary information is contained; (2) For reducing the influence of noise, the Principal Component Analysis (PCA) method is used to reduce the dimension of BiGP vector; (3) The powerful and robust Relevance Vector Machine (RVM) algorithm is used for classification. Five-fold cross-validation experiments executed on yeast and Helicobacter pylori datasets, which achieved very high accuracies of 94.57 and 90.57%, respectively. Experimental results are significantly better than previous methods. To further evaluate the proposed method, we compare it with the state-of-the-art support vector machine (SVM) classifier on the yeast dataset. The experimental results demonstrate that our RVM-BiGP method is significantly better than the SVM-based method. In addition, we achieved 97.15% accuracy on imbalance yeast dataset, which is higher than that of balance yeast dataset. The promising experimental results show the efficiency and robust of the proposed method, which can be an automatic decision support tool for future proteomics research. For facilitating extensive studies for future proteomics research, we developed a freely available web server called RVM-BiGP-PPIs in Hypertext Preprocessor (PHP) for predicting PPIs. The web server including source code and the datasets are available at http://219.219.62.123:8888/BiGP/. PMID- 27452984 TI - PACSIN2 polymorphism is associated with thiopurine-induced hematological toxicity in children with acute lymphoblastic leukaemia undergoing maintenance therapy. AB - Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR). In addition to the TPMT genotype, confirmed to be a major determinant of drug related toxicities, we identified the PACSIN2 rs2413739TT genotype as being a significant risk factor for 6-MP-induced toxicity in wild-type TPMT patients. A gene-gene interaction between MTRR (rs1801394) and MTHFR (rs1801133) was detected by GMDR and proved to have an independent effect on the risk of stomatitis, as shown by LR analysis. To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy. PMID- 27452986 TI - Response. PMID- 27452985 TI - Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. AB - Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI-121772.). PMID- 27452987 TI - Comparison of Weight-Based Dose vs. Standard Dose Diltiazem in Patients with Atrial Fibrillation Presenting to the Emergency Department. AB - BACKGROUND: Despite evidence-based recommended weight-based (WB) dosing of diltiazem for the initial treatment of atrial fibrillation (AF) with rapid ventricular response (RVR), many providers utilize lower initial doses of diltiazem. OBJECTIVE: We sought to determine whether a low, standard dose of diltiazem is noninferior to WB diltiazem as an initial bolus dose in the treatment of AF with RVR. METHODS: This retrospective review included patients who presented to the emergency department (ED) of an urban, academic tertiary medical center experiencing AF with RVR from November 2010 to August 2014. Adult patients were categorized by the dose of diltiazem received; 10 mg standard dose or 0.2-0.3 mg/kg WB dose. The primary outcome of successful treatment was defined as a composite of the following parameters 15 min after the initial bolus dose: heart rate (HR) < 100 beats/min, reduction of HR >= 20%, or a conversion to normal sinus rhythm. RESULTS: Four hundred and fifty-six patients who received diltiazem were included for study evaluation (standard dose: n = 255 patients, WB: n = 201 patients). Baseline characteristics, medical history, and medication use before ED presentation were similar between the groups. Significant differences at baseline between the groups included weight and HR at presentation. The primary outcome of successful treatment was attained in 60.8% of the standard dose patients and 68.7% of the WB patients (p = 0.082). CONCLUSIONS: In patients presenting to the ED, we found that standard dose diltiazem was noninferior to WB dosing in the initial treatment of AF with RVR. PMID- 27452988 TI - Synthesis and chiral recognition of amylose derivatives bearing regioselective phenylcarbamate substituents at 2,6- and 3-positions for high-performance liquid chromatography. AB - Eighteen novel amylose derivatives bearing different phenylcarbamate substituents at 2,6- and 3-positions of a glucose ring were synthesized through the regioselective protection at 2- and 6-positions using a bulky trialkylsilyl chloride. Their chiral recognition abilities were then evaluated as the chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) after coating them on the surface of macroporous silica gel. The chiral recognition abilities of these CSPs intricately depended on the nature, position and number of the substituents on the phenyl moieties. The introduction of substituents at meta-position of aromatic moieties at 2- and 6-positions of glucose unit was more attractive than other positions to improve the chiral recognition ability of these amylose derivatives. Each CSP seems to possess its own characteristic resolving power, and those based on amylose 3-(3,5-dichlorophenylcarbamate) showed comparatively better chiral recognition than others. For some racemates, the amylose derivatives with different phenylcarbamate substituents at 2,6- and 3 positions exhibited higher enantioselectivity than the amylose tris(3,5 dimethylphenylcarbamate), which is commercially available as Chiralpak AD, one of the most powerful CSPs. The structures of the obtained amylose derivatives were also investigated by circular dichroism spectroscopy. PMID- 27452989 TI - Exploring chiral separation of 3-carboxamido-5-aryl isoxazole derivatives by supercritical fluid chromatography on amylose and cellulose tris dimethyl- and chloromethyl phenylcarbamate polysaccharide based stationary phases. AB - Four polysaccharide based chiral stationary phases were chosen, two chlorinated: LuxTM Amylose-2 (tris-5-chloro-2-methylphenylcarbamate of amylose) and LuxTM Cellulose-2 (tris-3-chloro-4-methylphenylcarbamate of cellulose) and two methylated: Chiralpak(r) AD-H (tris-3,5-dimethylphenylcarbamate of amylose) and Chiralcel(r) OD-H (tris-3,5-dimethylphenylcarbamate of cellulose) to separate four 3-carboxamido-5-aryl isoxazole derivatives by supercritical fluid chromatography. The effect of chiral stationary phase, co-solvent nature (MeOH, EtOH, 2-PrOH and ACN) and percentage (10-20%), temperature (20-45 degrees C) and chemical structure of the compounds on retention, resolution and elution order were thoroughly studied. In addition, thermodynamic parameters were determined from the linear portion of the Van't Hoff plots. For all the derivatives, the LuxTM Cellulose-2 and Chiralpak(r) AD-H provided excellent resolutions (Rs=9.78) in short run time (under 6min). The preparation of about 10mg of each of the eight enantiomers was achieved successfully on a Chiralpak(r) AD-H with various percentages of ethanol as a co-solvent. Lastly, the enantiomeric purity of each of the eight individual enantiomer generated was determined and found higher than 98%. PMID- 27452990 TI - Insights in understanding aggregate formation and dissociation in cation exchange chromatography for a structurally unstable Fc-fusion protein. AB - Cation-exchange chromatography (CEX) of a structurally unstable Fc-fusion protein exhibited multi-peak elution profile upon a salt-step elution due to protein aggregation during intra-column buffer transition where low pH and high salt coexisted. The protein exhibited a single-peak elution behavior during a pH-step elution; nevertheless, the levels of soluble aggregates (i.e. high molecular weight species, HMW) in the CEX eluate were still found up to 12-fold higher than that for the load material. The amount of the aggregates formed upon the pH-step elution was dependent on column loading with maximum HMW achieved at intermediate loading levels, supporting the hypothesis that the aggregation was the result of both the conformational changes of the bound protein and the solution concentration of the aggregation-susceptible proteins during elution. Factors such as high load pH, short protein/resin contact time, hydrophilic resin surface, and weak ionizable ligand were effective, to some extent, to reduce aggregate formation by improving the structural integrity of the bound protein. An orthogonal technique, differential scanning fluorimetry (DSF) using Sypro Orange dye confirmed that the bound protein exposed more hydrophobic area than the native molecule in free solution, especially in the pH 4-5 range. The Sypro Orange dye study of resin surface property also demonstrated that the poly[styrene-divinylbenzene]-based Poros XS with polyhydroxyl surface coating is more hydrophobic compared to the agarose-based CM Sepharose FF and SP Sepharose FF. The hydrophobic property of Poros XS contributed to stronger interactions with the partially unfolded bound protein and consequently to the higher aggregate levels seen in Poros XS eluate. This work also investigates the aggregation reversibility in CEX eluate where up to 66% of the aggregates were observed to dissociate into native monomers over a period of 120h, and links the aggregate stability to such conditions as resin surface properties and charged ligand type. Experimental data was correlated semi-quantitatively with theoretical protein charge and hydrophobicity calculations using homology modeling within the BIOVIA Discovery Studio software. Finally, an arginine sulphopropyl (Arg-SP) agarose resin immobilized with multi-functional ligands was prepared to verify the proposed hypothesis and to eliminate the aggregate formation. The findings of this work provide general insights in understanding aggregate formation and dissociation for structurally unstable proteins in the CEX step. PMID- 27452991 TI - The bridge between thin layer chromatography-mass spectrometry and high performance liquid chromatography-mass spectrometry: The realization of liquid thin layer chromatography-mass spectrometry (LTLC-MS). AB - The combination of thin layer chromatography (TLC) and mass spectrometry (MS) has been studied for decades, but for most cases MS detection is done after TLC separation is finished. Here, an online simultaneous TLC-MS analysis system, liquid thin layer chromatography-mass spectrometry (LTLC-MS), is developed which successfully synchronize TLC separation process and MS detection process like GC MS and HPLC-MS do. And there's no need to use specially designed TLC, just regular TLC plates are enough. LTLC-MS method is composed of a newly developed ambient ionization method, glow discharge-matrix assisted infrared desorption ionization (GD-MAIRDI), and forced-flow TLC (FFTLC) technique, which guarantees the MS detection process does not disturb the TLC separation process throughout the whole analysis. The whole LTLC-MS analysis only need two steps and less than 15min. Mixtures as well as the two main components of a pain relief pills have been successfully analyzed by LTLC-MS. This proof of concept study opens up new possibilities of combining TLC with MS, and will further broaden the application abilities of TLC. PMID- 27452993 TI - The Medical Bookshelf. PMID- 27452994 TI - Editor's Mail. AB - The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space. PMID- 27452992 TI - Analytical pyrolysis and stable isotope analyses reveal past environmental changes in coralloid speleothems from Easter Island (Chile). AB - This study comprises an innovative approach based on the combination of chromatography (analytical pyrolysis and pyrolysis compound-specific isotope analysis (Py-CSIA)), light stable isotopes, microscopy and mineralogy analyses to characterize the internal layering of coralloid speleothems from the Ana Heva lava tube in Easter Island (Chile). This multidisciplinary proxy showed that the speleothems consist of banded siliceous materials of low crystallinity with different mineralogical compositions and a significant contribution of organic carbon. Opal-A constitutes the outermost grey layer of the coralloids, whereas calcite and amorphous Mg hydrate silicate are the major components of the inner whitish and honey-brown layers, respectively. The differences found in the mineralogical, elemental, molecular and isotopic composition of these distinct coloured layers are related to environmental changes during speleothem development. Stable isotopes and analytical pyrolysis suggested alterations in the water regime, pointing to wetter conditions during the formation of the Ca rich layer and a possible increase in the amount of water dripping into the cave. The trend observed for delta(15)N values suggested an increase in the average temperature over time, which is consistent with the so-called climate warming during the Holocene. The pyrolysis compound-specific isotope analysis of each speleothem layer showed a similar trend with the bulk delta(13)C values pointing to the appropriateness of direct Py-CSIA in paleoenvironmental studies. The delta(13)C values for n-alkanes reinforced the occurrence of a drastic environmental change, indicating that the outermost Opal layer was developed under drier and more arid environmental conditions. PMID- 27452995 TI - Dr Tom Swifties.... PMID- 27452996 TI - Washington Medical Update. PMID- 27452997 TI - Correction. PMID- 27452998 TI - Problems + Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27452999 TI - Primary Care Digest. PMID- 27453001 TI - Solitary thyroid nodule. PMID- 27453000 TI - Endocrinology. PMID- 27453003 TI - Selected National Meetings. PMID- 27453006 TI - Distinctive Mesenchymal-Parenchymal Cell Pairings Govern B Cell Differentiation in the Bone Marrow. AB - Bone marrow niches for hematopoietic progenitor cells are not well defined despite their critical role in blood homeostasis. We previously found that cells expressing osteocalcin, a marker of mature osteolineage cells, regulate the production of thymic-seeding T lymphoid progenitors. Here, using a selective cell deletion strategy, we demonstrate that a subset of mesenchymal cells expressing osterix, a marker of bone precursors in the adult, serve to regulate the maturation of early B lymphoid precursors by promoting pro-B to pre-B cell transition through insulin-like growth factor 1 (IGF-1) production. Loss of Osx(+) cells or Osx-specific deletion of IGF-1 led to a failure of B cell maturation and the impaired adaptive immune response. These data highlight the notion that bone marrow is a composite of specialized niches formed by pairings of specific mesenchymal cells with parenchymal stem or lineage committed progenitor cells, thereby providing distinctive functional units to regulate hematopoiesis. PMID- 27453009 TI - The effect of bone marrow-derived mesenchymal stem cells on chemotherapy induced ovarian failure in albino rats. AB - OBJECTIVES: Chemotherapy targets rapidly dividing tissues in the body. It destroys the progenitor cells in gonads resulting in premature ovarian failure. Studies have suggested that bone marrow-derived stem cells can generate oocytes in chemotherapy treated female rats after transplantation. The present study aimed to assess mechanism of homing, the action of injected BM-MSCs on ovarian function after ovarian damage. EXPERIMENTAL DESIGN: Seventy two female albino rats were randomly allocated into Control and CTX group, The Experimental protocol was lasted for 12 weeks during which serum FSH and E2 were monitored twice at the end of the 2nd week (12 rats) and 8th week (6 rats). Stem cells identification and homing were evaluated by Flowcytometry and tagging of stem cells with iron oxide particles respectively. Also, histopathological examination was done to evaluate both degeneration (6 rats at 4th week) and regeneration (6 rats at 12th week) of ovarian tissue together with assessment of the levels of TNF-alpha in ovarian homogenate and IGF-I as a growth factor in ovarian tissue. PRINCIPAL OBSERVATIONS: Partial improvement of E2 and FSH levels as well as ovarian architecture. Elevation of ovarian TNF- alpha levels and of IGF-I immunohistochemical expressions in ovarian tissues of BM-MSCs injected rats were noticed following homing of BM- MSCs in the ovarian stroma in both control and chemotherapy groups. CONCLUSION: Injected BM- MSCs can home in the stroma of the injured ovaries. IGF-I and TNF- alpha may have a role in the attraction of stem cells in vivo. PMID- 27453010 TI - A need to know. PMID- 27453011 TI - New Team Members. PMID- 27453007 TI - Murine iPSC-Derived Macrophages as a Tool for Disease Modeling of Hereditary Pulmonary Alveolar Proteinosis due to Csf2rb Deficiency. AB - Induced pluripotent stem cells (iPSCs) represent an innovative source for the standardized in vitro generation of macrophages (Mphi). We here describe a robust and efficient protocol to obtain mature and functional Mphi from healthy as well as disease-specific murine iPSCs. With regard to morphology, surface phenotype, and function, our iPSC-derived Mphi (iPSC-Mphi) closely resemble their counterparts generated in vitro from bone marrow cells. Moreover, when we investigated the feasibility of our differentiation system to serve as a model for rare congenital diseases associated with Mphi malfunction, we were able to faithfully recapitulate the pathognomonic defects in GM-CSF signaling and Mphi function present in hereditary pulmonary alveolar proteinosis (herPAP). Thus, our studies may help to overcome the limitations placed on research into certain rare disease entities by the lack of an adequate supply of disease-specific primary cells, and may aid the development of novel therapeutic approaches for herPAP patients. PMID- 27453008 TI - MiR-34a Promotes Osteogenic Differentiation of Human Adipose-Derived Stem Cells via the RBP2/NOTCH1/CYCLIN D1 Coregulatory Network. AB - MiR-34a was demonstrated to be upregulated during the osteogenic differentiation of human adipose-derived stem cells (hASCs). Overexpression of miR-34a significantly increased alkaline phosphatase activity, mineralization capacity, and the expression of osteogenesis-associated genes in hASCs in vitro. Enhanced heterotopic bone formation in vivo was also observed upon overexpression of miR 34a in hASCs. Mechanistic investigations revealed that miR-34a inhibited the expression of retinoblastoma binding protein 2 (RBP2) and reduced the luciferase activity of reporter gene construct comprising putative miR-34a binding sites in the 3' UTR of RBP2. Moreover, miR-34a downregulated the expression of NOTCH1 and CYCLIN D1 and upregulated the expression of RUNX2 by targeting RBP2, NOTCH1, and CYCLIN D1. Taken together, our results suggested that miR-34a promotes the osteogenic differentiation of hASCs via the RBP2/NOTCH1/CYCLIN D1 coregulatory network, indicating that miR-34a-targeted therapy could be a valuable approach to promote bone regeneration. PMID- 27453014 TI - Brief reports. PMID- 27453012 TI - Letters. PMID- 27453016 TI - Take the Muscles and Run. PMID- 27453017 TI - Scanning sports. PMID- 27453019 TI - Exercise and Arthritis: An Encouraging Report. PMID- 27453020 TI - A Survey of Overuse Running Injuries. AB - In brief: This retrospective survey of the clinical records of 1,650 patients seen from 1978 to 1980 identified 1,819 injuries. Almost 60% of the patients were men, but women under age 30 had the greatest risk of overuse running injuries. The knee was the most commonly injured site, and patellofemoral pain syndrome was the most common injury. Most patients had moderate to severe degrees of varus alignment and subsequent overpronation. Because certain injuries were more frequent in one sex or the other, the authors say future studies should differentiate injuries by sex. PMID- 27453021 TI - Correction. PMID- 27453022 TI - Radiology in Sportsmedicine. AB - In brief: A group of radiologists and orthopedic surgeons discusses the use of x rays, CAT scans, bone scans, arthrograms, and xeroradiograms in diagnosing sports injuries. Head, spine, knee, and ankle injuries, spleen ruptures, shoulder separations, and stress fractures are covered. The panelists agree that radiologists and sports physicians should maintain good working relationships so that examinations can be tailored to each athlete using the least number of films possible. PMID- 27453023 TI - A Team Physician's Bag. AB - In brief: The author has created a sportsmedicine bag to cover life-threatening emergencies that might arise during football or hockey games. The items in it can be divided into (1) medication to handle the acute phase and a container to carry it, (2) ancillary equipment for cardiopulmonary and head/neck trauma, and (3) a communication system to call an ambulance quickly. The author also suggests carrying a backboard and universal knee splint. PMID- 27453024 TI - Deep Vein Thrombosis in Marathon Runners. AB - In brief: In these case reports of two highly trained runners, deep vein thrombosis (DVT) was initially diagnosed as an intramuscular hematoma and a Baker's cyst. Both runners responded well to anticoagulant therapy and were able to resume their training programs. Even though otherwise healthy, conditioned patients are not typical candidates, the authors urge that DVT be considered in the differential diagnosis of athletes with leg pain or swelling because of the threat of pulmonary embolism. PMID- 27453025 TI - Echocardiography and the Athlete's Heart. AB - In brief: Echocardiographic studies permit direct, accurate measurements of the ventricular wall thickness and cavity diameter. The authors review several of these studies, which show that elite athletes' left ventricles are larger than those of sedentary persons. Left ventricular wall thickness is greater in athletes excelling in sports involving static exercise, whereas those in endurance sports have larger ventricular cavities. These differences in cardiac dimensions may be the result of genetic makeup, prolonged and strenuous training, or a combination of both. Studies of short-term training showed only minor or no changes in left ventricular morphology, although significant improvements in performance and aerobic capacity were reported. PMID- 27453026 TI - Injuries in Competitive Cycling. AB - In brief: There are relatively few injuries in competitive cycling, and abrasions are the most common. In this study most injuries occurred to the left side of the cyclist, and most common causes were flat tires and colliding with other cyclists. The number of injuries decreased as the cyclist gained more experience. Preventive measures include keeping the bicycle in top mechanical condition, wearing strong, durable clothing and a helmet, and knowing how to fall. PMID- 27453027 TI - Twin Studies and Sports: Estimating the Future? AB - Twins are a scientist's dream, because studying them reveals the relative Influences of heredity and environment on many facets of human nature-including human performance. PMID- 27453028 TI - Medical Care for Athletes: What Is the Coach's Role? AB - The ability of high school coaches to provide medical care for athletic Injuries is under Increased scrutiny. Several states require that coaches be certified in emergency techniques, but most don't. PMID- 27453029 TI - Transatlantic Fitness on the Queen Elizabeth 2. AB - There is nothing quite like the mystery or excitement of a transatlantic journey, especially when the opportunities to exercise are as entertaining as the other nautical diversions. PMID- 27453030 TI - Strength Training for the Neck. PMID- 27453032 TI - Cognitive impairment in progressive supranuclear palsy-Richardson's syndrome is related to white matter damage. AB - INTRODUCTION: Beside motor symptoms, patients with progressive supranuclear palsy syndrome (PSPs) commonly present cognitive and behavioral disorders. In this study we aimed to assess the structural brain correlates of cognitive impairment in PSPs. METHODS: We enrolled 23 patients with probable PSP Richardson's syndrome and 15 matched healthy controls. Patients underwent an extensive clinical and neuropsychological evaluation. Cortical thickness measures and diffusion tensor metrics of white matter tracts were obtained. Random forest analysis was used to identify the strongest MRI predictors of cognitive impairment in PSPs at an individual patient level. RESULTS: PSPs patients were in a moderate stage of the disease showing mild cognitive deficits with prominent executive dysfunction. Relative to controls, PSPs patients had a focal, bilateral cortical thinning mainly located in the prefrontal/precentral cortex and temporal pole. PSPs patients also showed a distributed white matter damage involving the main tracts including the superior cerebellar peduncle, corpus callosum, corticospinal tract, and extramotor tracts, such as the inferior fronto-occipital, superior longitudinal and uncinate fasciculi, and cingulum, bilaterally. Regional cortical thinning measures did not relate with cognitive features, while white matter damage showed a significant impact on cognitive impairment (r values ranging from -0.80 to 0.74). CONCLUSIONS: PSPs patients show both focal cortical thinning in dorsolateral anterior regions and a distributed white matter damage involving the main motor and extramotor tracts. White matter measures are highly associated with cognitive deficits. Diffusion tensor MRI metrics are likely to be the most sensitive markers of extramotor deficits in PSPs. PMID- 27453033 TI - Shedding PEG Palisade by Temporal Photostimulation and Intracellular Reducing Milieu for Facilitated Intracellular Trafficking and DNA Release. AB - The dilemma of poly(ethylene glycol) surface modification (PEGylation) inspired us to develop an intracellularly sheddable PEG palisade for synthetic delivery systems. Here, we attempted to conjugate PEG to polyethylenimine (PEI) through tandem linkages of disulfide-bridge susceptible to cytoplasmic reduction and an azobenzene/cyclodextrin inclusion complex responsive to external photoirradiation. The subsequent investigations revealed that facile PEG detachment could be achieved in endosomes upon photoirradiation, consequently engendering exposure of membrane-disruptive PEI for facilitated endosome escape. The liberated formulation in the cytosol was further subjected to complete PEG detachment relying on disulfide cleavage in the reductive cytosol, thus accelerating dissociation of electrostatically assembled PEI/DNA polyplex to release DNA by means of polyion exchange reaction with intracellularly charged species, ultimately contributing to efficient gene expression. PMID- 27453034 TI - Electronic data collection in epidemiological research. The use of REDCap in the Pelotas birth cohorts. AB - OBJECTIVES: This paper describes the use of Research Electronic Data Capture (REDCap) to conduct one of the follow-up waves of the 2004 Pelotas birth cohort. The aim is to point out the advantages and limitations of using this electronic data capture environment to collect data and control every step of a longitudinal epidemiological research, specially in terms of time savings and data quality. METHODS: We used REDCap as the main tool to support the conduction of a birth cohort follow-up. By exploiting several REDCap features, we managed to schedule assessments, collect data, and control the study workflow. To enhance data quality, we developed specific reports and field validations to depict inconsistencies in real time. RESULTS: Using REDCap it was possible to investigate more variables without significant increases on the data collection time, when comparing to a previous birth cohort follow-up. In addition, better data quality was achieved since negligible out of range errors and no validation or missing inconsistencies were identified after applying over 7,000 interviews. CONCLUSIONS: Adopting electronic data capture solutions, such as REDCap, in epidemiological research can bring several advantages over traditional paper based data collection methods. In favor of improving their features, more research groups should migrate from paper to electronic-based epidemiological research. PMID- 27453035 TI - A novel alignment-free method for detection of lateral genetic transfer based on TF-IDF. AB - Lateral genetic transfer (LGT) plays an important role in the evolution of microbes. Existing computational methods for detecting genomic regions of putative lateral origin scale poorly to large data. Here, we propose a novel method based on TF-IDF (Term Frequency-Inverse Document Frequency) statistics to detect not only regions of lateral origin, but also their origin and direction of transfer, in sets of hierarchically structured nucleotide or protein sequences. This approach is based on the frequency distributions of k-mers in the sequences. If a set of contiguous k-mers appears sufficiently more frequently in another phyletic group than in its own, we infer that they have been transferred from the first group to the second. We performed rigorous tests of TF-IDF using simulated and empirical datasets. With the simulated data, we tested our method under different parameter settings for sequence length, substitution rate between and within groups and post-LGT, deletion rate, length of transferred region and k size, and found that we can detect LGT events with high precision and recall. Our method performs better than an established method, ALFY, which has high recall but low precision. Our method is efficient, with runtime increasing approximately linearly with sequence length. PMID- 27453036 TI - Acetate ligands determine the crystal structure of CdSe nanoplatelets - a density functional theory study. AB - Cadmium selenide (CdSe) nanoplatelets of a few atomic layers thick exhibit extremely sharp photoluminescence peaks and are synthesized in the zinc blende crystal structure, whereas the most stable bulk polymorph of CdSe is the wurtzite structure. These platelets can be synthesized very monodispersely in thickness, and are covered with acetate ligands. Here, we show by means of density functional theory (DFT) calculations that these ligands play a pivoting role in the stabilization of 2D nanosheets as a whole, including the deviating crystal structure. The relative stability as a function of slab thickness, strong effects on electronic properties, and implications for synthesis are discussed. PMID- 27453037 TI - Prevention of syncopal-type reactions after whole blood donation: a cluster randomized trial assessing hydration and muscle tension exercise. AB - BACKGROUND: The prevention of presyncopal and syncopal reactions to whole blood donation is important for both the donor's safety and their retention as blood donors. The best strategy to achieve this remains debated. STUDY DESIGN AND METHODS: A prospective cluster-randomized trial comparing three hydration modes (500 mL of an isotonic drink, 500 mL of water, just before phlebotomy, or advice to drink [control arm]) coupled or not with light muscle tensing exercises, was carried out in mobile and fixed units of two regional blood centers in southeast France between January and July 2014. The main outcome was the cumulative incidence of presyncope (feeling faint) and syncope (fainting) at the donation site or in the 48 hours after leaving the site. Secondary outcomes were the cumulative incidence of these adverse events during donation, immediately after blood donation, or within 48 hours. RESULTS: Overall, presyncope or syncope occurred in 5.5% of the 4576 donors. Compared to controls, drinking 500 mL (isotonic solution or water) significantly reduced the rate of events (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.55-0.99; p = 0.041) independently of muscle tensing exercise. Muscle tensing exercises significantly reduced syncopal type reactions during the donation (OR, 0.64; 95% CI, 0.42-0.98; p = 0.041), and an isotonic drink significantly reduced delayed off-site syncopal-type reactions (OR, 0.62; 95% CI, 0.40-0.98; p = 0.040) and tiredness after donation (OR, 0.75; 95% CI, 0.59-0.94; p = 0.014). CONCLUSIONS: Drinking 500mL of water or isotonic drink close to phlebotomy is useful in preventing presyncopal or syncopal reactions in blood donors. Isotonic drinks have the advantage of preventing delayed reactions and tiredness after whole blood donation. PMID- 27453038 TI - Tuberosity-alveolar block as a donor site for localised augmentation of the maxilla: a retrospective clinical study. AB - Bone from the maxillary tuberosity has been harvested in particulate form to use for augmentation for several years, but block grafts have not been extensively used. A considerable advantage of a particulate bone graft from the maxillary tuberosity over those from other intraoral donor sites is the relative simplicity of harvesting and minimal complications. We have retrospectively assessed the efficacy of tuberosity-alveolar block bone (posterior maxillary alveolar ridge) in the augmentation of adjacent defects in the maxilla using data from 14 patients (10 men and four women, mean (range) age 55 (38-69) years) who had had 20 bony augmentations with block bone from the alveolar tuberosity during 2014. Patients were divided into three groups according to the technique by which the bone was collected. The first group had a graft from the alveolar tuberosity covered with titanium mesh (titanium mesh group); the second group had the block bone covered by platelet rich fibrin and collagen membrane (platelet rich fibrin group), and in the third group the graft was covered only with periosteum (periosteum group). The primary width of the bone was recorded at the time of placement of the graft and changes were evaluated 4-6 months later when the implant was inserted. The changes in the width of the bone were 4.1, 3.3, and 2.5 in the platelet rich fibrin, titanium mesh, and periosteum groups, respectively. The difference in bony change among groups was not significant except between the platelet rich fibrin and and periosteum groups (p=0.005). Tuberosity-alveolar block bone graft may be a good source of bone for augmentation of deficient ridges, and more favourable results can be expected by the addition of resorbable membranes and growth factors. PMID- 27453039 TI - A fly's eye view of zinc homeostasis: Novel insights into the genetic control of zinc metabolism from Drosophila. AB - The core zinc transport machinery is well conserved between invertebrates and mammals, with the vinegar fly Drosophila melanogaster having clear homologues of all major groups of mammalian ZIP and ZNT transport genes. Functional characterization of several of the fly genes has revealed functional conservation between related fly and mammalian zinc transporters in some but not all cases, indicating that Drosophila is a useful model for examining mammalian zinc metabolism. Furthermore, Drosophila research, sometimes quite serendipitously, has provided novel insights into the function of zinc transporters and into zinc related pathologies, which are highlighted here. Finally, the future research potential of the fly in nutrient metabolism is explored, with reference to emerging experimental technologies. PMID- 27453040 TI - Biological processing of dinuclear ruthenium complexes in eukaryotic cells. AB - The biological processing - mechanism of cellular uptake, effects on the cytoplasmic and mitochondrial membranes, intracellular sites of localisation and induction of reactive oxygen species - of two dinuclear polypyridylruthenium(ii) complexes has been examined in three eukaryotic cells lines. Flow cytometry was used to determine the uptake of [{Ru(phen)2}2{MU-bb12}](4+) (Rubb12) and [Ru(phen)2(MU-bb7)Ru(tpy)Cl](3+) {Rubb7-Cl, where phen = 1,10-phenanthroline, tpy = 2,2':6',2''-terpyridine and bbn = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane} in baby hamster kidney (BHK), human embryonic kidney (HEK-293) and liver carcinoma (HepG2) cell lines. The results demonstrated that the major uptake mechanism for Rubb12 and Rubb7-Cl was active transport, although with a significant contribution from carrier-assisted diffusion for Rubb12 and passive diffusion for Rubb7-Cl. Flow cytometry coupled with Annexin V/TO-PRO-3 double staining was used to compare cell death by membrane damage or apoptosis. Rubb12 induced significant direct membrane damage, particularly with HepG2 cells, while Rubb7-Cl caused considerably less membrane damage but induced greater levels of apoptosis. Confocal microscopy, coupled with JC-1 assays, demonstrated that Rubb12 depolarises the mitochondrial membrane, whereas Rubb7-Cl had a much smaller affect. Cellular localisation experiments indicated that Rubb12 did not accumulate in the mitochondria, whereas significant mitochondrial accumulation was observed for Rubb7-Cl. The effect of Rubb12 and Rubb7-Cl on intracellular superoxide dismutase activity showed that the ruthenium complexes could induce cell death via a reactive oxygen species-mediated pathway. The results of this study demonstrate that Rubb12 predominantly kills eukaryotic cells by damaging the cytoplasmic membrane. As this dinuclear ruthenium complex has been previously shown to exhibit greater toxicity towards bacteria than eukaryotic cells, the results of the present study suggest that metal-based cationic oligomers can achieve selective toxicity against bacteria, despite exhibiting a non-specific membrane damage mechanism of action. PMID- 27453041 TI - Delayed onset paraparesis complicating epidural steroid injection with underlying spinal dural arteriovenous fistula. AB - We report a case of a 48-year-old man with chronic back pain attributed to discogenic lumbar radiculopathy who underwent a fluoroscopy-guided L2-3 interlaminar epidural steroid injection. 4 h later, he developed acute paraparesis, sensory loss below T10 level and urinary retention. MRI of the thoracic spine revealed diffuse abnormal T2/FLAIR signal and extensive vascular flow voids. A spinal dural arteriovenous fistula was confirmed on spinal angiography. Embolization of the spinal dural arteriovenous fistula resulted in significant improvement of symptoms. We review previously reported cases and current understanding of the pathophysiology of this complication. All cases had symptom onset several hours after the procedure. There seems to be a trend toward better outcomes with earlier treatment. PMID- 27453042 TI - Reference values for left ventricular systolic synchrony according to phase analysis of ECG-gated myocardial perfusion SPECT. AB - BACKGROUND: The aim of this study was to define reference values for left ventricular systolic synchrony and for the volume parameters of the left ventricle using myocardial perfusion SPECT-derived phase analysis method. METHODS: We evaluated data of 433 patients who underwent myocardial perfusion SPECT/CT during January 2012-February 2013 in Kuopio University Hospital. The final study population consisted of 52 patients (aged 42-84 years) who met the criteria: (1) no previously diagnosed cardiac disease, (2) normal ECG at rest, (3) no advanced coronary artery disease in CT and 4) normal myocardial perfusion in stress/rest myocardial perfusion SPECT/CT. The severity of mechanical dyssynchrony was assessed by phase analysis of gated myocardial SPECT at stress stage after pharmacological exercise and at rest using Quantitative Gated SPECT (QGS) software. Volume parameters of the left ventricle were also assessed. RESULTS: The phase histogram bandwidth at rest was 28.0 [63.7] degrees (median [95th percentile]). The standard deviation of phase histogram at rest was 7.8 [26.5] degrees. Entropy at the rest study was 54.0 [63.7] %. All left ventricular dyssynchrony parameters were statistically significantly higher at stress compared to rest. There were no statistically significant differences in dyssynchrony values between men and women. In volume parameters, reference values in male were expectedly higher than in female. Cardiac output did not differ significantly between genders. CONCLUSION: In subjects without signs of cardiac diseases, the left ventricular systolic function is well synchronized. Phase analysis measurement does not depend on gender, age, BMI or blood pressure, but the values of dyssynchrony parameters increase during pharmacological stress. PMID- 27453043 TI - A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy. AB - An emerging therapeutic strategy for cancer is to induce selective lethality in a tumor by exploiting interactions between its driving mutations and specific drug targets. Here we use a multi-species approach to develop a resource of synthetic lethal interactions relevant to cancer therapy. First, we screen in yeast ~169,000 potential interactions among orthologs of human tumor suppressor genes (TSG) and genes encoding drug targets across multiple genotoxic environments. Guided by the strongest signal, we evaluate thousands of TSG-drug combinations in HeLa cells, resulting in networks of conserved synthetic lethal interactions. Analysis of these networks reveals that interaction stability across environments and shared gene function increase the likelihood of observing an interaction in human cancer cells. Using these rules, we prioritize ~10(5) human TSG-drug combinations for future follow-up. We validate interactions based on cell and/or patient survival, including topoisomerases with RAD17 and checkpoint kinases with BLM. PMID- 27453044 TI - CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations. AB - Intratumor genetic heterogeneity underlies the ability of tumors to evolve and adapt to different environmental conditions. Using CRISPR/Cas9 technology and specific DNA barcodes, we devised a strategy to recapitulate and trace the emergence of subpopulations of cancer cells containing a mutation of interest. We used this approach to model different mechanisms of lung cancer cell resistance to EGFR inhibitors and to assess effects of combined drug therapies. By overcoming intrinsic limitations of current approaches, CRISPR-barcoding also enables investigation of most types of genetic modifications, including repair of oncogenic driver mutations. Finally, we used highly complex barcodes inserted at a specific genome location as a means of simultaneously tracing the fates of many thousands of genetically labeled cancer cells. CRISPR-barcoding is a straightforward and highly flexible method that should greatly facilitate the functional investigation of specific mutations, in a context that closely mimics the complexity of cancer. PMID- 27453045 TI - A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase. AB - Dynamic protein phosphorylation is a fundamental mechanism regulating biological processes in all organisms. Protein phosphatase 2A (PP2A) is the main source of phosphatase activity in the cell, but the molecular details of substrate recognition are unknown. Here, we report that a conserved surface-exposed pocket on PP2A regulatory B56 subunits binds to a consensus sequence on interacting proteins, which we term the LxxIxE motif. The composition of the motif modulates the affinity for B56, which in turn determines the phosphorylation status of associated substrates. Phosphorylation of amino acid residues within the motif increases B56 binding, allowing integration of kinase and phosphatase activity. We identify conserved LxxIxE motifs in essential proteins throughout the eukaryotic domain of life and in human viruses, suggesting that the motifs are required for basic cellular function. Our study provides a molecular description of PP2A binding specificity with broad implications for understanding signaling in eukaryotes. PMID- 27453046 TI - Comprehensive Identification of RNA-Binding Domains in Human Cells. AB - Mammalian cells harbor more than a thousand RNA-binding proteins (RBPs), with half of these employing unknown modes of RNA binding. We developed RBDmap to determine the RNA-binding sites of native RBPs on a proteome-wide scale. We identified 1,174 binding sites within 529 HeLa cell RBPs, discovering numerous RNA-binding domains (RBDs). Catalytic centers or protein-protein interaction domains are in close relationship with RNA-binding sites, invoking possible effector roles of RNA in the control of protein function. Nearly half of the RNA binding sites map to intrinsically disordered regions, uncovering unstructured domains as prevalent partners in protein-RNA interactions. RNA-binding sites represent hot spots for defined posttranslational modifications such as lysine acetylation and tyrosine phosphorylation, suggesting metabolic and signal dependent regulation of RBP function. RBDs display a high degree of evolutionary conservation and incidence of Mendelian mutations, suggestive of important functional roles. RBDmap thus yields profound insights into native protein-RNA interactions in living cells. PMID- 27453047 TI - Essential Roles for Polymerase theta-Mediated End Joining in the Repair of Chromosome Breaks. AB - DNA polymerase theta (Pol theta)-mediated end joining (TMEJ) has been implicated in the repair of chromosome breaks, but its cellular mechanism and role relative to canonical repair pathways are poorly understood. We show that it accounts for most repairs associated with microhomologies and is made efficient by coupling a microhomology search to removal of non-homologous tails and microhomology-primed synthesis across broken ends. In contrast to non-homologous end joining (NHEJ), TMEJ efficiently repairs end structures expected after aborted homology-directed repair (5' to 3' resected ends) or replication fork collapse. It typically does not compete with canonical repair pathways but, in NHEJ-deficient cells, is engaged more frequently and protects against translocation. Cell viability is also severely impaired upon combined deficiency in Pol theta and a factor that antagonizes end resection (Ku or 53BP1). TMEJ thus helps to sustain cell viability and genome stability by rescuing chromosome break repair when resection is misregulated or NHEJ is compromised. PMID- 27453049 TI - SAM - a helping hand in many places. AB - Read the original article at doi: 10.1002/1873-3468.12249. PMID- 27453050 TI - The (Re) Production of the Genetically Related Body in Law, Technology and Culture: Mitochondria Replacement Therapy. AB - Advances in medicine in the latter half of the twentieth century have dramatically altered human bodies, expanding choices around what we do with them and how they connect to other bodies. Nowhere is this more so than in the area of reproductive technologies (RTs). Reproductive medicine and the laws surrounding it in the UK have reconfigured traditional boundaries surrounding parenthood and the family. Yet culture and regulation surrounding RTs have combined to try to ensure that while traditional boundaries may be pushed, they are reconstructed in similar ways. This paper looks at the most recent RT to be permitted in the UK, mitochondria (mtDNA) replacement therapy (MRT). Despite controversial media headlines surrounding the technique, MRT is in fact an example of how science and regulation seek to expand models of traditional relatedness in a way that doesn't challenge the existing order. Yet, like other RTs, while attempts are made to ensure it doesn't push traditional boundaries too far, fissures and inconsistencies appear in law and culture, which give interesting insights into how genetics, parentage and identity are being mediated in new but familiar ways. PMID- 27453048 TI - Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4(+) T Cells. AB - Whereas phosphorylation of serine, threonine, and tyrosine is exceedingly well characterized, the role of histidine phosphorylation in mammalian signaling is largely unexplored. Here we show that phosphoglycerate mutase family 5 (PGAM5) functions as a phosphohistidine phosphatase that specifically associates with and dephosphorylates the catalytic histidine on nucleoside diphosphate kinase B (NDPK B). By dephosphorylating NDPK-B, PGAM5 negatively regulates CD4(+) T cells by inhibiting NDPK-B-mediated histidine phosphorylation and activation of the K(+) channel KCa3.1, which is required for TCR-stimulated Ca(2+) influx and cytokine production. Using recently developed monoclonal antibodies that specifically recognize phosphorylation of nitrogens at the N1 (1-pHis) or N3 (3-pHis) positions of the imidazole ring, we detect for the first time phosphoisoform specific regulation of histidine-phosphorylated proteins in vivo, and we link these modifications to TCR signaling. These results represent an important step forward in studying the role of histidine phosphorylation in mammalian biology and disease. PMID- 27453052 TI - Revisiting an old concept: the coupled oscillator model for VCD. Part 2: implications of the generalised coupled oscillator mechanism for the VCD robustness concept. AB - Using two illustrative examples it is shown that the generalised coupled oscillator (GCO) mechanism implies that the stability of the VCD sign computed for a given normal mode is not reflected by the magnitude of the ratio zeta between the rotational strength and dipole strength of the respective mode, i.e., the VCD robustness criterium proposed by Gobi and Magyarfalvi. The performed VCD GCO analysis brings further insight into the GCO mechanism and also into the VCD robustness concept. First, it shows that the GCO mechanism can be interpreted as a VCD resonance enhancement mechanism, i.e. very large VCD signals can be observed when the interacting molecular fragments are in favourable orientation. Second, it shows that the uncertainties observed in the computed VCD signs are associated to uncertainties in the relative orientation of the coupled oscillator fragments and/or to uncertainties in the predicted nuclear displacement vectors, i.e. not uncertainties in the computed magnetic dipole transition moments as was originally assumed. Since it is able to identify such situations easily, the VCD GCO analysis can be used as a VCD robustness analysis. PMID- 27453051 TI - Best practice for single-trial detection of event-related potentials: Application to brain-computer interfaces. AB - The detection of event-related potentials (ERPs) in the electroencephalogram (EEG) signal is a fundamental component in non-invasive brain-computer interface (BCI) research, and in modern cognitive neuroscience studies. Whereas the grand average response across trials provides an estimation of essential characteristics of a brain-evoked response, an estimation of the differences between trials for a particular type of stimulus can provide key insight about the brain dynamics and possible origins of the brain response. The research in ERP single-trial detection has been mainly driven by applications in biomedical engineering, with an interest from machine learning and signal processing groups that test novel methods on noisy signals. Efficient single-trial detection techniques require processing steps that include temporal filtering, spatial filtering, and classification. In this paper, we review the current state-of-the art methods for single-trial detection of event-related potentials with applications in BCI. Efficient single-trial detection techniques should embed simple yet efficient functions requiring as few hyper-parameters as possible. The focus of this paper is on methods that do not include a large number of hyper parameters and can be easily implemented with datasets containing a limited number of trials. A benchmark of different classification methods is proposed on a database recorded from sixteen healthy subjects during a rapid serial visual presentation task. The results support the conclusion that single-trial detection can be achieved with an area under the ROC curve superior to 0.9 with less than ten sensors and 20 trials corresponding to the presentation of a target. Whereas the number of sensors is not a key element for efficient single-trial detection, the number of trials must be carefully chosen for creating a robust classifier. PMID- 27453053 TI - Saliva induces expression of antimicrobial peptides and promotes intracellular killing of bacteria in keratinocytes by epidermal growth factor receptor transactivation. AB - BACKGROUND: Wounds in the oral cavity, constantly exposed to both saliva and bacteria, heal quickly without infection. Furthermore, during licking of skin wounds, saliva promotes wound healing and plays a role in keeping the wound free of infection. OBJECTIVES: To investigate whether saliva induces expression of antimicrobial peptides (AMPs) in human epidermal keratinocytes and whether saliva promotes clearance of intracellular bacteria in these cells. METHODS: Expression of AMPs was investigated in the oral mucosa and ex vivo injured skin by immunohistochemistry. Human beta-defensin-3 expression was investigated in epidermal keratinocytes after saliva stimulation, using real-time polymerase chain reaction and immunofluorescence. RESULTS: We found higher expression of AMPs in the oral mucosa than in the epidermis. Saliva accelerated the injury induced expression of AMPs in human skin ex vivo and was a potent inducer of the expression of AMPs in epidermal keratinocytes. The expression of AMPs was induced by metalloproteinase-dependent epidermal growth factor receptor (EGFR) transactivation mediated by a salivary lipid. Saliva increased the intracellular clearance of Staphylococcus aureus in keratinocytes through EGFR activation. CONCLUSIONS: These findings suggest a previously unreported role of saliva in innate immunity and demonstrate for the first time that saliva induces gene expression in epidermal keratinocytes. PMID- 27453054 TI - Cannabinoid receptor 1 (CNR1) gene variant moderates neural index of cognitive disruption during nicotine withdrawal. AB - Nicotine withdrawal-related disruption of cognitive control may contribute to the reinforcement of tobacco use. Identification of gene variants that predict this withdrawal phenotype may lead to tailored pharmacotherapy for smoking cessation. Variation on the cannabinoid receptor 1 gene (CNR1) has been related to nicotine dependence, and CNR1 antagonists may increase attention and memory functioning. We targeted CNR1 variants as moderators of a validated neural marker of nicotine withdrawal-related cognitive disruption. CNR1 polymorphisms comprising the 'TAG' haplotype (rs806379, rs1535255 and rs2023239) were tested independently, as no participants in this sample possessed this haplotype. Nicotine withdrawal-related cognitive disruption was indexed as increased resting electroencephalogram (EEG) alpha-1 power density across 17 electrodes. Seventy-three Caucasian Non-Hispanic smokers (>=15 cigarettes per day) visited the laboratory on two occasions following overnight smoking/nicotine deprivation. Either two nicotine or two placebo cigarettes were smoked prior to collecting EEG data at each session. Analyses showed that rs806379 moderated the effects of nicotine deprivation increasing slow wave EEG (P = 0.004). Smokers homozygous for the major allele exhibited greater nicotine withdrawal-related cognitive disruption. The current findings suggest potential efficacy of cannabinoid receptor antagonism as a pharmacotherapy approach for smoking cessation among individuals who exhibit greater nicotine withdrawal-related cognitive disruption. PMID- 27453056 TI - Implementation of Rule 8 of the International Code of Nomenclature of Prokaryotes for the renaming of classes. Request for an Opinion. AB - The new version of Rule 8 of the International Code of Nomenclature of Prokaryotes as approved in Istanbul in 2008 has the clear advantage of establishing a uniform way to name classes of prokaryotes, similar to the way other higher taxa are named. However, retroactive implementation of the modified Rule is problematic as it destabilizes the nomenclature and requires the replacement of a large number of names of classes that have been validly published, which would be in violation of Principle 1 of the Code. Therefore, we call upon the International Committee on Systematics of Prokaryotes and its Judicial Commission to reconsider the retroactivity of Rule 8. PMID- 27453055 TI - M1-/M2-macrophage polarization in pseudolobules consisting of adipohilin-rich hepatocytes in thioacetamide (TAA)-induced rat hepatic cirrhosis. AB - INTRODUCTION: Liver steatosis is the most frequent liver disease and may further develop into non-alcoholic steatohepatitis (NASH), liver cirrhosis, and finally hepatocellular carcinoma. Adipophilin (Adp) is localized on lipid droplet membrane in cytoplasm, and its increased expression is related to development of steatosis and NASH. The relationship between M1-/M2-macrophage polarization and Adp-rich hepatocyte-consisting pseudolobules (PLs) was investigated in thioacetamide (TAA)-induced rat cirrhosis. MATERIALS AND METHOD: F344 rats were injected twice weekly with TAA (100mg/kg bodyweight) and sacrificed at post-first injection (PFI) weeks 5, 10, 15, 20, 25 and 32. Macrophage immunophenotypes and Adp-containing hepatocytes were analyzed by single immunolabeling. Adp and M1-/M2 related factors were analyzed by real -time RT-PCR. RESULTS: PLs consisting exclusively of Adp-containing hepatocytes (Adp-positive) and PLs consisting of few Adp-containing hepatocytes (Adp-negative) were clearly distinguishable at PFI week 20 onwards. The numbers of M1-macrophages (reacting to CD68 and Iba1) and M2 macrophages (reacting to CD163, CD204 and Gal-3) were considerably greater in Adp-positive PLs. Expressions for both M1 (TNF-alpha, MCP-1, and Iba1)- and M2 (IL-4, TGF-beta1, Gal-3, and Hsp25)-related factors were markedly higher in Adp positive PLs at PFI week 25. Interestingly, MHC class II-positive macrophages/dendritic cells were increased in Adp-positive clusters/foci at the early stages at PFI weeks 5 and 10, and the level was gradually decreased thereafter. CONCLUSIONS: M1-/M2-macrophages may simultaneously participate in the pathogenesis of steatosis in TAA-induced cirrhosis through M1- and M2-related factors. MHC class II cells may be responsible for steatosis at early stages, suggesting different functions from the above M1-/M2-macropahges. PMID- 27453057 TI - Cortico-cortical evoked hemodynamic responses in human language systems using intraoperative near-infrared spectroscopy during direct cortical stimulation. AB - BACKGROUND: Understanding of cortico-cortical activity in eloquent areas intraoperatively is crucial for neurosurgical procedures. Here, we used intraoperative near-infrared spectroscopy (iNIRS) during direct cortical stimulation as a robust tool to better understand the cortico-cortical connectivity in language systems. METHODS: We applied iNIRS to 3 patients who underwent epilepsy surgery due to lesions (cavernous angioma, epidermoid cyst, and low-grade glioma) located in language areas. Using iNIRS, we measured the blood concentration changes of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR) in the lateral temporal cortex during direct cortical stimulation (50Hz) at the inferior frontal area where Broca's area was probabilistically located. RESULTS: In all patients, 50Hz stimulation elicited hemodynamic changes in the superior temporal gyrus (STG). During 0.8-4.8s after stimulation, HbO2 increased and HbR decreased in the posterior part of the STG (Wernicke's area). Similar responses were observed in the anterior part of the STG 1.3-8.0s after stimulation. Finally, these changes were disappeared in the middle temporal gyrus. CONCLUSIONS: Our results suggest that cortical stimulation of Broca's area elicits hemodynamic responses in Wernicke's area via cortico-cortical connectivity. We demonstrated cortico-cortical evoked responses in language systems using iNIRS during direct cortical stimulation. Our iNIRS data will provide useful information about cortico-cortical networks underlying human brain functions intraoperatively and will contribute to neurosurgical treatment in eloquent areas. PMID- 27453058 TI - Down-regulation of purinergic P2X7 receptor expression and intracellular calcium dysregulation in peripheral blood mononuclear cells of patients with amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with intracellular Ca(2+) dysregulation. The P2X receptor family is comprised of ligand-gated ion channels that respond to extracellular adenosine triphosphate (ATP) and increases permeability of calcium into the cell. The underlying mechanisms of purinergic signalling on peripheral blood mononuclear cells (PBMCs) in ALS remain unclear. Herein, we studied the expression of P2X4/P2X7 receptors and calcium homeostasis in blood cells of ALS patients. METHODS: We used PBMCs from 42 ALS patients and 19 controls. Purinergic receptors P2X4 (P2X4R) and P2X7 (P2X7R) were examined using western blot analysis. The effect of exogenous ATP on intracellular Ca(2+) homeostasis in monocytes was measured using fluorimetry by Fura-2 on a single-cell level. RESULTS: Western blot analysis revealed stable P2X4R expression in patients and controls. P2X7R expression was significantly reduced (p=0.012) in ALS patients. Repetitive long term ATP stimulation caused a sustained decrease in Ca(2+) levels in the ALS group as measured by the area under the curve, peak amplitude and peak height. CONCLUSION: These results confirm our hypothesis that Ca(2+) abnormalities in ALS are measurable in immune cells. These findings suggest that the reduction of P2X7 receptor expression on PBMCs leads to intracellular calcium dysregulation. Our study improves the understanding of ALS pathophysiology and proposes PBMCs as a non-invasive source to study ALS. PMID- 27453060 TI - GABAergic modulation of serotonin release in the rat subfornical organ area. AB - The present study was carried out to examine whether gamma-aminobutyric acid (GABA) receptor mechanisms are involved in the release of serotonin (5 hydroxytryptamine, 5-HT) in the subfornical organ (SFO) using intracerebral microdialysis techniques. Perfusion with the GABA receptor antagonists as well as agonists was performed in the region of the SFO through a microdialysis probe and extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in freely moving rats. Perfusion with the GABAA receptor antagonist bicuculline (10 and 50MUM), but not the GABAB receptor antagonist phaclofen (10 and 50MUM), increased dialysate 5-HT and 5-HIAA concentrations in the SFO area, suggesting that the GABAergic system may tonically inhibit the 5-HT release in the SFO area through GABAA receptors. Higher perfusion with the GABAA receptor agonist muscimol (50MUM) or the GABAB receptor agonist baclofen (250MUM) decreased extracellular levels of 5-HT and 5 HIAA in the SFO area. Nonhypotensive hypovolemia induced by subcutaneous injection of polyethylene glycol (PEG, 30%, 5ml) significantly enhanced the 5-HT and 5-HIAA concentrations in the SFO area. The enhanced 5-HT and 5-HIAA levels elicited the PEG treatment were reduced by perfusion with muscimol (10MUM), but not by baclofen (50MUM). These results show the involvement of both GABAA and GABAB receptors in the modulation of the 5-HT release in the SFO area, and imply that the GABAA receptor mechanism may be importance for the serotonergic regulatory system of body fluid balance. PMID- 27453059 TI - The CB1 antagonist, SR141716A, is protective in permanent photothrombotic cerebral ischemia. AB - Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke. We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor. Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury. The CB1 antagonist was found to be protective in this model. As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor. Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment. With the incidence of stroke predicted to rise in parallel with an ever aging population, understanding mechanisms underlying ischemia and therapeutics remains a paramount goal of research. PMID- 27453061 TI - A study of single nucleotide polymorphisms of GRIN2B in schizophrenia from Chinese Han population. AB - Schizophrenia is a severe and complex mental disorder with high heritability. There is evidence that mutations in the gene of Nmethyl-d-aspartate-type glutamate receptors (NMDAR) are associated with schizophrenia. GRIN2B encodes a subunit of NMDARs, and has been identified as a candidate gene for many psychiatric disorders, especially schizophrenia. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in GRIN2B were associated with schizophrenia. Four SNPs (rs890, rs1806191, rs219872, rs172677) were genotyped in 752 schizophrenic patients and 846 healthy controls of the Chinese Han population. Our results indicate differences in allele and genotype frequencies of rs890 between case and control. These results were assessed by adapting different genetic models (codominant, dominant, recessive, overdominant, log additive models). After controlling for confounding factors including sex and age, rs890 remained associated with schizophrenia. In addition, rs890 and rs1806191 were found to form a haplotype associated with schizophrenia. In summary, our results indicate that the GRIN2B SNP rs890 might be associated with schizophrenia in the Chinese Han population. PMID- 27453062 TI - The potential danger of empiric antimicrobial therapy for nosocomial SBP. PMID- 27453063 TI - CD8+ T cells drive autoimmune hematopoietic stem cell dysfunction and bone marrow failure. AB - Bone marrow (BM) failure syndrome encompasses a group of disorders characterized by BM stem cell dysfunction, resulting in varying degrees of hypoplasia and blood pancytopenia, and in many patients is autoimmune and inflammatory in nature. The important role of T helper 1 (Th1) polarized CD4+ T cells in driving BM failure has been clearly established in several models. However, animal model data demonstrating a functional role for CD8+ T cells in BM dysfunction is largely lacking and our objective was to test the hypothesis that CD8+ T cells play a non redundant role in driving BM failure. Clinical evidence implicates a detrimental role for CD8+ T cells in BM failure and a beneficial role for Foxp3+ regulatory T cells (Tregs) in maintaining immune tolerance in the BM. We demonstrate that IL-2 deficient mice, which have a deficit in functional Tregs, develop spontaneous BM failure. Furthermore, we demonstrate a critical role for CD8+ T cells in the development of BM failure, which is dependent on the cytokine, IFNgamma. CD8+ T cells promote hematopoietic stem cell dysfunction and depletion of myeloid lineage progenitor cells, resulting in anemia. Adoptive transfer experiments demonstrate that CD8+ T cells dramatically expedite disease progression and promote CD4+ T cell accumulation in the BM. Thus, BM dysregulation in IL-2 deficient mice is mediated by a Th1 and IFNgamma-producing CD8+ T cell (Tc1) response. PMID- 27453064 TI - Ingenol mebutate in actinic keratosis: a clinical, videodermoscopic and immunohistochemical study. AB - BACKGROUND: Actinic keratosis (AK) is a cutaneous intraepithelial neoplasm that typically develops on sun-damaged skin. The incidence of AK is increasing worldwide, and it is accepted as the most frequent pre-malignant lesion in humans. OBJECTIVES: To demonstrate that ingenol mebutate gel is effective in the treatment of actinic keratoses because of its clinical, dermoscopic, capillaroscopic, histopathological and immunohistochemical treatment outcomes. METHODS: Sixty individuals with multiple non-hypertrophic AKs were enrolled into this non-randomized, open-label, prospective, trial. Acquisition of clinical, dermoscopic and capillaroscopic images at baseline (T0), immediately after treatment on 3rd (trunk and/or extremities) or 4th (scalp and/or face) day (T1), 14 days after the end of the treatment (T2) and at 60 days (T3). A subgroup of 20 patients received a cutaneous biopsy both at baseline and at T3 for histological and immunohistochemical evaluation. RESULTS: Clinical improvement was observed in 100% of cases: total clearance in 41 patients (68.3%); partial clearance in 19 patients (32.7%). After treatment, dermoscopic improvement of all non-pigmented and pigmented AK lesions was observed. Most of the dermoscopic features disappeared with treatment. Total disappearance of specific vascular structures or significant reduction in the number and calibre of new blood vessels was capillaroscopically observed in all patients analysed (P <= 0.001). The immunohistochemical expression of p63 (P = 0.002), Ki-67 (P = 0.015) and VEGF (P = 0.016) significantly decreased. CONCLUSIONS: The clinical efficacy of ingenol mebutate on AKs is confirmed by its effect on angiogenesis, stem cell activity and cell proliferation in vivo. PMID- 27453065 TI - Tailored Combination of Low Dimensional Catalysts for Efficient Oxygen Reduction and Evolution in Li-O2 Batteries. AB - The development of efficient bifunctional catalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is a key issue pertaining high performance Li-O2 batteries. Here, we propose a heterogeneous electrocatalyst consisting of LaMnO3 nanofibers (NFs) functionalized with RuO2 nanoparticles (NPs) and non-oxidized graphene nanoflakes (GNFs). The Li-O2 cell employing the tailored catalysts delivers an excellent electrochemical performance, affording significantly reduced discharge/charge voltage gaps (1.0 V at 400 mA g(-1) ), and superior cyclability for over 320 cycles. The outstanding performance arises from (1) the networked LaMnO3 NFs providing ORR/OER sites without severe aggregation, (2) the synergistic coupling of RuO2 NPs for further improving the OER activity and the electrical conductivity on the surface of the LaMnO3 NFs, and (3) the use of GNFs providing a fast electronic pathway as well as improved ORR kinetics. PMID- 27453066 TI - Methionine restriction improves renal insulin signalling in aged kidneys. AB - Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10 month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti ageing and renoprotective genes Sirt1, FGF21, klotho, and beta-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190days compared to control-fed mice, which exhibited a pre diabetic status. Our results indicate that dietary MR may offer therapeutic potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression. PMID- 27453068 TI - Cardiac destination therapy in pediatrics - Are we there yet? PMID- 27453067 TI - Toll-like Receptor function of murine macrophages, probed by cytokine induction, is biphasic and is not impaired globally with age. AB - Aging is associated with a waning of normal immune function. This "immunosenescence" is characterized by a diverse repertoire of seemingly discreet and unbalanced immune alterations. A number of studies have suggested that aging associated alterations in innate immune responsiveness, especially responsiveness dependent on Toll-like Receptor (TLR) engagement, are causally involved. We find, however, that the magnitude and dose-dependency of responsiveness to TLR engagement (assessed with respect to cytokine production) in distinct populations of murine macrophages are not altered generally with animal age or as a consequence of immunosenescence. Responses elicited with a wide array of TLR agonists were examined by extensive functional analyses, principally on the level of the individual cell. These studies reveal an intriguing "all-or-nothing" response behavior of macrophages, independent of animal age. Although reports to the contrary have been cited widely, aging-associated immune decline cannot be attributed to widespread alterations in the extents of TLR-dependent innate immune macrophage responses. PMID- 27453069 TI - GO-FAANG meeting: a Gathering On Functional Annotation of Animal Genomes. AB - The Functional Annotation of Animal Genomes (FAANG) Consortium recently held a Gathering On FAANG (GO-FAANG) Workshop in Washington, DC on October 7-8, 2015. This consortium is a grass-roots organization formed to advance the annotation of newly assembled genomes of domesticated and non-model organisms (www.faang.org). The workshop gathered together from around the world a group of 100+ genome scientists, administrators, representatives of funding agencies and commodity groups to discuss the latest advancements of the consortium, new perspectives, next steps and implementation plans. The workshop was streamed live and recorded, and all talks, along with speaker slide presentations, are available at www.faang.org. In this report, we describe the major activities and outcomes of this meeting. We also provide updates on ongoing efforts to implement discussions and decisions taken at GO-FAANG to guide future FAANG activities. In summary, reference datasets are being established under pilot projects; plans for tissue sets, morphological classification and methods of sample collection for different tissues were organized; and core assays and data and meta-data analysis standards were established. PMID- 27453070 TI - Commentary on "Countries with high circumcision prevalence have lower prostate cancer mortality". PMID- 27453071 TI - How nerve-sparing technique has been applied to radiotherapy? PMID- 27453072 TI - Reply to Letter by Dr. Christoph Kupferschmid: Commentary on "Countries with high circumcision prevalence have lower prostate cancer mortality". PMID- 27453073 TI - Unfoldomics of prostate cancer: on the abundance and roles of intrinsically disordered proteins in prostate cancer. AB - Prostatic diseases such as prostate cancer and benign prostatic hyperplasia are highly prevalent among men. The number of studies focused on the abundance and roles of intrinsically disordered proteins in prostate cancer is rather limited. The goal of this study is to analyze the prevalence and degree of disorder in proteins that were previously associated with the prostate cancer pathogenesis and to compare these proteins to the entire human proteome. The analysis of these datasets provides means for drawing conclusions on the roles of disordered proteins in this common male disease. We also hope that the results of our analysis can potentially lead to future experimental studies of these proteins to find novel pathways associated with this disease. PMID- 27453074 TI - Here/In This Issue and There/Abstract Thinking: Mindfulness Matters. PMID- 27453075 TI - Polypharmacy in Attention-Deficit/Hyperactivity Disorder: More Than the Sum of Its Parts? PMID- 27453076 TI - Early Childhood Traumatic Events and Adolescent-Onset Illicit Drug Use: Implications for Prevention and Treatment. PMID- 27453077 TI - Maternal Stress During Pregnancy and Offspring Depression. PMID- 27453078 TI - Internalizing/Externalizing Problems: Review and Recommendations for Clinical and Research Applications. AB - OBJECTIVE: More than 75,000 articles have been published on internalizing and externalizing problems. To advance clinical and research applications of internalizing/externalizing concepts and data, our objectives were as follows: to provide an overview of recent research on internalizing/externalizing problems assessed at ages 11/2 to 18 years; to identify issues raised by methods for assessing such problems; and to develop recommendations for more precise, consistent, informative, and productive assessment of such problems. METHOD: A total of 4,870 peer-reviewed articles published from January 1, 2012 through December 31, 2014 were systematically reviewed and identified by the search terms "internalizing" or "externalizing," followed by detailed coding of 693 articles that reported use of measures meeting criteria for methodologically sound assessment of internalizing/externalizing problems. RESULTS: Many articles reported data based on measures that did not meet criteria for methodologically sound assessment of internalizing/externalizing problems. The 693 articles that used measures meeting criteria for methodological soundness and that qualified for detailed coding reported findings for 649,457 children living in 65 societies on all inhabited continents. Data were obtained from parents, teachers, children, clinicians, caregivers, and others. Samples included general population, clinical, school, at-risk, multicultural, welfare, and various ethnic/racial and socioeconomic groups. Many analytic methods were used to test associations of diverse variables with internalizing/externalizing problems. CONCLUSION: The diverse procedures used to assess internalizing/externalizing problems pose challenges for clinical and research applications. To meet the challenges, recommendations are provided for using assessment instruments supported by published standardization, reliability, validity, and normative data to advance clinical services and research. PMID- 27453079 TI - Combined Stimulant and Guanfacine Administration in Attention Deficit/Hyperactivity Disorder: A Controlled, Comparative Study. AB - OBJECTIVE: Because models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and alpha2A agonism may yield enhanced clinical and cognitive responses. This study tested the hypothesis that combined effects of a dopamine and noradrenergic agonist, d-methylphenidate extended release (DMPH) with guanfacine (GUAN), an alpha2A receptor agonist, would be clinically superior to either monotherapy and would have equal tolerability. METHOD: An 8-week, double-blind, 3-arm, comparative trial randomized 7- to 14 year-olds with DSM-IV ADHD to GUAN (1-3 mg/day), DMPH (5-20 mg/day), or a combination (COMB) with fixed-flexible dosing. Outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI I) scale. Data on adverse events and safety measures were obtained. RESULTS: A total of 207 participants were randomized and received drug. Analyses showed significant treatment group main effects for ADHD-RS-IV ADHD total (p = .0001) and inattentive symptoms (p = .0001). COMB demonstrated small but consistently greater reductions in ADHD-RS-IV Inattentive subscale scores versus monotherapies (DMPH: p = .05; f(2) = .02; and GUAN: p = .02; f(2) = .02), and was associated with a greater positive response rate by CGI-I (p = .01). No serious cardiovascular events occurred. Sedation, somnolence, lethargy, and fatigue were greater in both guanfacine groups. All treatments were well tolerated. CONCLUSION: COMB showed consistent evidence of clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and alpha2A agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability. CLINICAL TRIAL REGISTRATION INFORMATION: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); http://clinicaltrials.gov/; NCT00429273. PMID- 27453080 TI - Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Psychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on alpha2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD. METHOD: Children with ADHD (n = 182; aged 7-14 years) completed an 8-week, double blind, randomized, controlled trial with 3 arms: d methylphenidate (DMPH), guanfacine (GUAN), or combination treatment with DMPH and GUAN (COMB). A nonclinical comparison group (n = 93) had baseline testing, and a subset was retested 8 weeks later (n = 38). Analyses examined treatment effects in 4 cognitive domains (working memory, response inhibition, reaction time, and reaction time variability) constructed from 20 variables. RESULTS: The ADHD group showed impaired working memory relative to the nonclinical comparison group (effect size = -0.53 SD unit). The treatments differed in effects on working memory but not other cognitive domains. Combination treatment improved working memory more than GUAN but was not significantly better than DMPH alone. Treatment did not fully normalize the initial deficit in ADHD relative to the comparison group. CONCLUSION: Combined treatment with DMPH and GUAN yielded greater improvements in working memory than placebo or GUAN alone, but the combined treatment was not superior to DMPH alone and did not extend to other cognitive domains. Although GUAN may be a useful add-on treatment to psychostimulants, additional strategies appear to be necessary to achieve normalization of cognitive function in ADHD. CLINICAL TRIAL REGISTRATION INFORMATION: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273. PMID- 27453081 TI - Effects of d-Methylphenidate, Guanfacine, and Their Combination on Electroencephalogram Resting State Spectral Power in Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Psychostimulant medications are the gold standard of treatment for attention-deficit/hyperactivity disorder (ADHD); however, a significant minority (~30%) of individuals with ADHD fail to respond favorably. Noradrenergic agents are increasingly used as ADHD monotherapies or adjuncts for suboptimal stimulant response, yet knowledge of their cortical effects is limited. This study is the first to examine comparative effects of guanfacine (an alpha adrenergic 2A agonist), psychostimulant, and their combination on resting state cortical activity in ADHD. METHOD: The sample comprised 179 participants aged 7 to 14 years old with ADHD (113 boys, 55 girls). Participants were randomized to 1 of 3 blinded conditions: guanfacine (GUAN), d-methylphenidate (DMPH), or the combination (COMB). Electroencephalography (EEG) was performed pre-, mid-, and post-medication titration, with concomitant assessment of behavioral and cognitive functioning. RESULTS: Analyses of spectral power measures during resting EEG suggested that each medication condition displayed a distinct profile of effects on cortical activity. Significant time effects suggested that GUAN decreased global alpha band (8-12 hertz [Hz]) power, DMPH and COMB increased centro-parietal beta band (13-21 Hz) power, and COMB resulted in decreased theta band (4-7 Hz) power. Relative to other medication groups, COMB was associated with significantly lower theta band power and DMPH with higher beta band power compared with those in the GUAN group. Medication-related changes in theta power were correlated with improvements in behavioral and cognitive functioning. CONCLUSION: These data reveal distinct underlying medication-related effects on neural mechanisms. The COMB condition uniquely exhibited an EEG profile that was associated with improved behavioral and cognitive functioning. Clinical trial registration information-Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273. PMID- 27453082 TI - Randomized Clinical Trial of Parent-Focused Treatment and Family-Based Treatment for Adolescent Anorexia Nervosa. AB - OBJECTIVE: There have been few randomized clinical trials (RCTs) for adolescents with anorexia nervosa (AN). Most of these posit that involving all family members in treatment supports favorable outcomes. However, at least 2 RCTs suggest that separate parent and adolescent sessions may be just as effective as conjoint treatment. This study compared the relative efficacy of family-based treatment (FBT) and parent-focused treatment (PFT). In PFT, the therapist meets with the parents only, while a nurse monitors the patient. METHOD: Participants (N = 107) aged 12 to 18 years and meeting DSM 4(th)Edition criteria for AN or partial AN were randomized to either FBT or PFT. Participants were assessed at baseline, end of treatment (EOT), and at 6 and 12 months posttreatment. Treatments comprised 18 outpatient sessions over 6 months. The primary outcome was remission, defined as >=95% of median body mass index and Eating Disorder Examination Global Score within 1 SD of community norms. RESULTS: Remission was higher in PFT than in FBT at EOT (43% versus 22%; p = .016, odds ratio [OR] = 3.03, 95% CI = 1.23-7.46), but did not differ statistically at 6-month (PFT 39% versus FBT 22%; p = .053, OR = 2.48, CI = 0.989-6.22), or 12-month (PFT 37% versus FBT 29%; p = .444, OR = 1.39, 95% CI = 0.60-3.21) follow-up. Several treatment effect moderators of primary outcome were identified. CONCLUSION: At EOT, PFT was more efficacious than FBT in bringing about remission in adolescents with AN. However, differences in remission rates between PFT and FBT at follow-up were not statistically significant. CLINICAL TRIAL REGISTRATION INFORMATION: A Randomised Controlled Trial of Two Forms of Family-Based Treatment and the Effect on Percent Ideal Body Weight and Eating Disorders Symptoms in Adolescent Anorexia Nervosa; http://www.anzctr.org.au/; ACTRN12610000216011. PMID- 27453083 TI - Male Eating Disorder Symptom Patterns and Health Correlates From 13 to 26 Years of Age. AB - OBJECTIVE: Research on the manifestations and health correlates of eating disorder symptoms among males is lacking. This study identified patterns of appearance concerns and eating disorder behaviors from adolescence through young adulthood and their health correlates. METHOD: Participants were 7,067 males from the prospective Growing Up Today Study. Surveys from 1999 to 2007 (spanning ages 13-26 years) provided repeated measures data on muscularity and leanness concerns, eating disorder behaviors (purging, overeating, binge eating, use of muscle-building products), and health correlates (obesity, non-marijuana drug use, binge drinking, and depressive symptoms). RESULTS: Latent class analyses of observations at ages 13 to 15, 16 to 18, 19 to 22, and 23 to 26 years identified 1 large Asymptomatic class and 4 symptomatic patterns: Body Image Disturbance (high appearance concerns, low eating disorder behaviors; 1.0%-6.0% per age period); Binge Eating/Purging (binge eating and purging, use of muscle-building products, low appearance concerns; 0.1%-2.5%); Mostly Asymptomatic (low levels of muscularity concern, product use, and overeating; 3.5%-5.0%); and Muscularity Concerns (high muscularity concerns and use of products; 0.6%-1.0%). The Body Image Disturbance class was associated with high estimated prevalence of depressive symptoms. Males in the Binge Eating/Purging and Muscularity Concerns classes had high prevalence of binge drinking and drug use. Despite exhibiting modestly greater appearance concerns and eating disorder behaviors than the Asymptomatic class, being in the Mostly Asymptomatic class was prospectively associated with adverse health outcomes. CONCLUSION: Results underscore the importance of measuring concerns about leanness, muscularity, and use of muscle building products when assessing eating disorder presentations among males in research and clinical settings. PMID- 27453085 TI - Stressful Life Events During Pregnancy and Offspring Depression: Evidence From a Prospective Cohort Study. AB - OBJECTIVE: The fetal programming hypothesis posits that in utero exposure to stress can alter prenatal brain development and lifelong stress response. However, human studies linking objective prenatal stressors to offspring mental illness, especially depression, are rare. The purpose of this study was to examine the association between mothers' exposure to prenatal stressful life events (SLEs) and offspring depression. METHOD: The sample comprised 10,569 members of a prospective population-based cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers reported on the occurrence and impact of 42 prenatal SLEs. Offspring depressive symptoms were assessed using a computerized version of the Clinical Interview Schedule-Revised (CIS-R) at age 17 to 18, as well as 13 self-report statements from the Short Mood and Feelings Questionnaire (SMFQ) at 6 time points from ages 10 to 11 to 18 to 19. Latent class growth analysis (LCGA) was used to identify trajectories of depressive symptoms across adolescence. RESULTS: After adjusting for potential confounders, a 1-unit increase in maternal SLE scores (range, 0-168) during gestation was associated with increased offspring depressive symptoms (beta = 0.07, p < .01) and major depression (odds ratio [OR] = 1.03, 95% CI 1.01, 1.06) at age 17 to 18. LCGA revealed 4 trajectories of depressive symptoms. High maternal SLEs (fourth quartile) were associated with membership in the trajectory characterized by stable, high levels of depression from age 10 to 11 to 18 to 19 years (OR = 1.72, 95% CI = 1.09, 2.71). CONCLUSION: These results provide support for the fetal programming hypothesis, demonstrating that prenatal exposure to acute stress is associated with offspring depression in adolescence. Stress management may be of benefit for expectant mothers. PMID- 27453084 TI - Childhood Trauma and Illicit Drug Use in Adolescence: A Population-Based National Comorbidity Survey Replication-Adolescent Supplement Study. AB - OBJECTIVE: Although potentially traumatic events (PTEs) are established risk factors for substance use disorders among adults, little is known about associations with drug use during adolescence, an important developmental stage for drug use prevention. We examined whether childhood PTEs were associated with illicit drug use among a representative sample of US adolescents. METHOD: Data were drawn from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A), which included adolescents aged 13 to 18 years (N = 9,956). Weighted logistic regression models estimated risk ratios for lifetime use of marijuana, cocaine, nonmedical prescription drugs, other drugs, and multiple drugs. RESULTS: Exposure to any PTE before age 11 years was reported by 36% of the sample and was associated with higher risk for use of marijuana (risk ratio [RR] = 1.50), cocaine (RR = 2.78), prescription drugs (RR = 1.80), other drugs (RR = 1.90), and multiple drugs (RR = 1.74). A positive monotonic relationship was observed between number of PTEs and marijuana, other drug, and multiple drug use. Interpersonal violence was associated with all drug use outcomes. Accidents and unspecified events were associated with higher risk for marijuana, cocaine, and prescription drug use. CONCLUSION: Potentially traumatic events in childhood are associated with risk for illicit drug use among US adolescents. These findings add to the literature by illustrating a potentially modifiable health behavior that may be a target for intervention. The results also highlight that adolescents with a trauma history are a high-risk group for illicit drug use and may benefit from trauma-focused prevention efforts that specifically address traumatic memories and coping strategies for dealing with stressful life events. PMID- 27453086 TI - Changes in Mental Health, Bullying Behavior, and Service Use Among Eight-Year-Old Children Over 24 Years. AB - OBJECTIVE: The aim of this study was to examine changes in the mental health problems, bullying, and service use of 8-year-old children at 4 different time points (1989, 1999, 2005, and 2013) using population-based, time-trend data. METHOD: Information from 4 cross-sectional samples was compared over a 24-year period. The target population was Finnish-speaking children born in 1981 (n = 1,038), 1991 (n = 1,035), 1997 (n = 1,030), and 2004 (n = 1,114) and living in selected school districts in the Turku University Hospital area in southwestern Finland. The participation rates varied from 84% (2005) to 95% (1989). Information about the children's psychiatric symptoms, bullying experience, and service use was obtained from parents and teachers using Rutter questionnaires. Child depression was measured using the Children's Depression Inventory (CDI). RESULTS: Parental reports showed that emotional (p < .001) and conduct (p = .001) problems among boys and emotional (p = .002) problems among girls decreased over the 24-year period. In teacher reports, there were no significant changes in hyperactivity, emotional, and conduct problems between 1989 and 2013. Girls' self reported depression scores increased between 1989 and 2005, but leveled off in 2013. There were no significant decreases in bullying behavior between 2005 and 2013 despite the introduction of a nationwide school-based anti-bullying program in 2009. Mental health service use increased constantly during the study period: in 1989, 4.2% of boys and 0.9% of girls were in contact with services, and by 2013 this had risen to 15.1% and 6.1% (p < .001). CONCLUSION: No substantial increases in children's mental health problems were seen between 1989 and 2013. Service use increased constantly, indicating lower thresholds for seeking help. Bullying behavior is strongly related to mental health problems, and that is why school-based bullying interventions, including mental health perspectives, are needed. PMID- 27453087 TI - Gestational Exposure to Selective Serotonin Reuptake Inhibitors and Offspring Psychiatric Disorders: Need for Further Investigation. PMID- 27453088 TI - Dr. Malm et al. reply. PMID- 27453090 TI - Erratum. PMID- 27453089 TI - Leo Kanner and Hans Asperger: Setting the Historical Record Straight. PMID- 27453092 TI - How to perform ABR in young children. AB - The diagnosis of hearing loss, especially in the context of newborn hearing screening, is mostly based on auditory brainstem response (ABR). According to the official CCAM nomenclature, ABR consists of recording early auditory evoked potentials to detect thresholds, study conduction times and measure amplitudes (corresponding to codes CDQP006 when performed without general anesthesia, and CDQP014 when performed with general anesthesia). ABR must be rigorously performed and interpreted, always in combination with a complete ENT examination and behavioral audiometry as soon as possible. In order to obtain good quality recordings, ABR must be performed with the infant totally immobile, during a nap. Several protocols can be used according to the child's age in order to obtain good quality sleep. ABR contribute to a precise hearing diagnosis, allowing early management by the first months of life. PMID- 27453091 TI - DIC image reconstruction using an energy minimization framework to visualize optical path length distribution. AB - Label-free microscopy techniques have numerous advantages such as low phototoxicity, simple setup and no need for fluorophores or other contrast materials. Despite their advantages, most label-free techniques cannot visualize specific cellular compartments or the location of proteins and the image formation limits quantitative evaluation. Differential interference contrast (DIC) is a qualitative microscopy technique that shows the optical path length differences within a specimen. We propose a variational framework for DIC image reconstruction. The proposed method largely outperforms state-of-the-art methods on synthetic, artificial and real tests and turns DIC microscopy into an automated high-content imaging tool. Image sets and the source code of the examined algorithms are made publicly available. PMID- 27453093 TI - Occurrence, bioaccumulation and long-range transport of short-chain chlorinated paraffins on the Fildes Peninsula at King George Island, Antarctica. AB - As a candidate persistent organic pollutant of the Stockholm Convention, short chain chlorinated paraffins (SCCPs) have recently received particular attention. In this study, we investigated, for the first time, the concentrations of SCCPs in biota samples collected from the Fildes Peninsula at King George Island and Ardley Island, Antarctica. The concentrations of SCCPs ranged from 3.5 to 256.6ng/g (dry weight, dw), with a mean of 76.6+/-61.8ng/g dw, which was lower than those detected in mid- and low-latitude regions. The long-range transport behaviour of SCCPs was confirmed by both the detection of SCCPs in Antarctic remote areas and their special congener profiles. Short carbon chain (C10) congeners predominated in the Antarctic samples, which accounted for 56.1% of the total SCCP contamination. Such enrichment of C10 congeners indicated the high potential for the long-range transport of shorter chain congeners. In addition, SCCPs tended to be enriched in the species with high lipid contents. The biomagnification potential of SCCPs was found between Archeogastropoda (Agas) and Neogastropoda (Ngas), and the biomagnification factors of shorter chain congeners of SCCPs were higher than that of the longer chain ones. Considering that the endemic species in polar regions may be sensitive and vulnerable to the adverse effects of environmental contaminants, more attention should be paid on the bioaccumulation and toxicological risks of SCCPs in polar environments. PMID- 27453094 TI - Exposure of Norwegian toddlers to perfluoroalkyl substances (PFAS): The association with breastfeeding and maternal PFAS concentrations. AB - High exposure to perfluoroalkyl substances (PFASs) has been associated with adverse health effects in children. PFASs exposure pathways of toddlers might differ from those of infants and adults, and the investigations on determinants of PFASs exposure in early childhood are scarce. Our aims were to examine the PFAS blood concentrations in Norwegian toddlers and to assess their relationship with maternal PFAS concentrations in pregnancy and breastfeeding duration. We determined PFAS concentrations in 112 plasma samples of 3-year-old children collected at 2010-2011 and 99 maternal serum samples collected around delivery at 2007-2008. PFAS concentrations in children were regressed on duration of breastfeeding, and the effect modification by maternal prenatal PFAS concentrations was examined in 55 mother-child pairs. Six PFASs were quantifiable in >50% of both maternal and children samples. Positive and significant correlations ranging between 0.50 and 0.66 were found between maternal and child concentrations of the same PFAS congeners. Nevertheless, toddlers had higher total PFAS blood concentrations than their mothers, due to higher concentrations of PFOA, PFNA and PFHxS. Every month of breastfeeding was associated with an increase of 3.3% (95% Confidence Intervals (CI): 0.8-5.8) for PFOS, 4.7% (95%CI: 2.8-6.6) for PFOA and 6.1% (95% CI: 2.6-9.7) for PFHpS in toddlers' plasma and a dose-response association was found, after adjustment for confounders. However, PFNA and PFUnDA concentrations in children were not associated with either maternal concentrations or breastfeeding duration. Our findings suggest that transplacental transfer, prenatally, and breastfeeding, postanatally, are among the main determinants of PFOS, PFOA, PFHxS and PFHpS concentrations in toddlers, while that was not the case for PFNA and PFUnDA. Nevertheless, due to the small number of mother child-pairs in our study, our results should be interpreted with caution. PMID- 27453095 TI - [Active surveillance of adverse drug reaction in the era of big data: challenge and opportunity for control selection]. AB - Electronic healthcare databases have become an important source for active surveillance of drug safety in the era of big data. The traditional epidemiology research designs are needed to confirm the association between drug use and adverse events based on these datasets, and the selection of the comparative control is essential to each design. This article aims to explain the principle and application of each type of control selection, introduce the methods and parameters for method comparison, and describe the latest achievements in the batch processing of control selection, which would provide important methodological reference for the use of electronic healthcare databases to conduct post-marketing drug safety surveillance in China. PMID- 27453096 TI - [Analysis on the data of antibiotic prescriptions comment in China, 2014-2015]. AB - OBJECTIVE: To evaluate the rationality of antibiotic use in the outpatient and emergency departments in some class 3A hospitals in China through International Network for Rational Use of Drugs(INRUD). METHODS: The antibiotic prescriptions were collected from the outpatient and emergency departments in 78 class 3A hospitals of 25 provinces through INRUD during 2014-2015. The basic information of the antibiotic prescriptions and the prescriptions rationality were evaluated. RESULTS: A total of 447 894 prescriptions of antibiotics were analyzed. From 2014 to 2015, the qualified rate the prescriptions increased from 91.52% to 93.08%, and the antibiotic use rate was similar(11.72% and 12.04%). The major irrational prescription type was inappropriate prescription, including inappropriate indication(32.42%, 34.02%)and inappropriate usage and dosage(24.22%, 18.56%). CONCLUSIONS: Totally, the antibiotic use in the outpatient and emergency department reached the standard in China. However, the use of antibiotics didn't meet the national requirements in some area. It is necessary to promote the rational use of antibiotics. PMID- 27453097 TI - [Cross-sectional study of family drug stockpile and children medication in China]. AB - OBJECTIVE: To investigate the current situation of family medicine stockpile and children medication in China, analyze the existing problems and provide the rationalized suggestions. METHODS: The questionnaire was designed and convenient sampling survey was performed in 20 children hospitals in China. Descriptive analysis was conducted on the survey results. RESULTS: A total of 13 940 completed questionnaires were returned, 98.33% of the families had medicine stockpile, the top three types of the medicine for children were cold medicine(73.95%), oral paregoric/febrifuge(48.01%)and external used drugs for skin disease(wound)(41.10%). The medicine was bought according to physician's prescription and guide(71.18%). Drug poisoning occurred in children of 238 families(1.71%), overdose use was the first cause(44.96%). 22.33% of the parents didn't read the specification carefully before medicine use. The non-appropriate medication for children were mainly the use of adult medicine(32.70%), untimely medication(30.90%), non-rational or unneeded use of febrifuge(26.35%). CONCLUSIONS: In China, the families mainly store common medicine for their children. The parents bought medicine mainly according to physician' s prescription and paid attention to the safety and efficiency of the medicine, but non-appropriate use of medicine was still common. It is necessary to improve the rational use of medicine for children through expert counsel and guidance. PMID- 27453098 TI - [Study on polymorphisms of genes with susceptibility to drug induced liver injury in a cohort receiving anti-tuberculosis treatment]. AB - OBJECTIVE: To investigate the association between the polymorphisms of genes involving in drug metabolism and transport as well as immunological reaction and the risk of anti-tuberculosis drug-induced liver injury(ATLI)in Chinese. METHODS: This 1?4 matched case-control study was conducted by using the data from a cohort study of Anti-tuberculosis Drugs Induced Adverse Reactions in National Tuberculosis Prevention and Control Progtam of China. Genes involving in three phase of drug metabolism and transport as well as related immunological reaction were chosen and single nucleotide polymorphisms(SNPs)were genotyped by TaqMan allele discrimination technology. Lasso regression and multivariate conditional logistic regression analysis were used to select susceptible genes. RESULTS: A total of 33 genes with 75 SNPs were tested. The combined results of Lasso and regression logistic regression analysis showed that genetic polymorphism of SLCO1B1 rs4149014, HSPA1L rs2227956, STAT3 rs1053023 and IL-6 rs2066992 were significantly associated with the risk of ATLI(P<0.05). CONCLUSION: SLCO1B1, HSPA1L, STAT3 and IL-6 might be the susceptibility genes of drug induced liver injury in patients receiving anti-tuberculosis treatment. PMID- 27453099 TI - [Incidence and outcome of anti-tuberculosis drug-induced hepatotoxicity in tuberculosis inpatients]. AB - OBJECTIVE: Based on the medical records and follow-up records of hospitalized patients who received anti-tuberculosis therapy in the Third People's Hospital of Zhenjiang in Jiangsu province from 2006 to 2012, we investigated the incidence and outcome of anti-tuberculosis drug induced hepatotoxicity(ATDH)and provided evidence for the prevention of ATDH. METHODS: According to tuberculosis patients' medical information and liver function test records, ATDH patients were diagnosed according to the criteria of International Consensus Meeting and American Thoracic Society respectively, then the related factors and outcomes were analyzed. RESULTS: A total of 1 967 hospitalized tuberculosis patients were reviewed retrospectively, in which 1 403(71.3%)were men, 1 790(91.0%)were pulmonary tuberculosis patients, 1 528(77.8%)were patients receiving initiative treatment, 979(49.8%)were sputum smear-positive patients, and 1 297(65.9%)had other complicated diseases. According to the criterion of International Consensus Meeting, the incidence of ATDH was 16.5%, the median time of onset was 25 days. According to the criterion of American Thoracic Society, the incidence of ATDH was 8.3%, the median time of onset was 23 days. The incidence of ATDH was significantly higher in males and HRZE therapy group(P<0.05). Under the two liver criteria, 69.5% and 70.1% of the patients changed primary therapy respectively after ATDH occurred. 89.8% and 88.4% patients' liver function returned to normal range after changing or stopping therapy. CONCLUSION: According to two liver injury criteria, the incidences of ATDH were 16.5% and 8.3% in hospitalized tuberculosis patients respectively, and ATDH mainly occurred in the first month of anti-tuberculosis treatment. The monitoring of liver function should be strengthened in males and HRZE therapy group to reduce the incidence of ATDH. PMID- 27453100 TI - [Association between statins use and liver injury based on prescription sequence symmetry analysis]. AB - OBJECTIVE: To study the association between statins use and liver-injury through prescription sequence symmetry analysis(PSSA)and evaluate the feasibility of the method to be used in Chinese Medical Insurance Database. METHODS: The data of the patients who prescribed both statins and liver-proactive drugs in Chinese Basic Medical Insurance Database in 2013 were selected as study subjects to calculate the adjusted sequence ratio(ASR)with signal detection methods to determine the study parameters and investigate the potential association between statins use and liver-injury. RESULTS: In 5 649 individuals which met the inclusion criteria, the washout period was set as one month and interval period was set as 60 days. The overall ASR of statins was 1.471(95%CI: 1.395-1.550), the ASR of atorvastatin was 1.419(95% CI: 1.335-1.508), the ASR of simvastatin was 1.307(95%CI: 1.164 1.467). The positive signal was strong in 30 days interval period. CONCLUSIONS: PSSA indicated that there might be potential association between statins use and liver-injury, especially the uses of atorvastatin and simvastatin. This signal detection method may be a fast and effective method in drug safety evaluation and can be used in Chinese Medical Insurance Database. PMID- 27453101 TI - [Interaction between passive smoking and folic acid supplement during pregnancy on autism spectrum disorder behaviors in children aged 3 years]. AB - OBJECTIVE: To explore the interaction between passive smoking and folic acid supplement during pregnancy on children autism spectrum disorder(ASD)behaviors. METHODS: Children aged about 3 years were enrolled at kindergarten entrance in Longhua district of Shenzhen in 2014. Self-administered questionnaires were completed by their primary caregivers and the information about children' s age, gender, history of preterm birth and low birth weight, parents' education level, parents' reproductive age and family income were collected. The children ASD behaviors were assessed with Autism Behavior Checklist(ABC). According to the cut point of ABC, the children were divided into normal group with score less than 31, sub-clinical group with score ranging from 31 to 61 and suspect clinical group with score no less than 62. After controlling for potential confounders, multivariate logistic regression analysis was performed to evaluate the main effects and the interaction between passive smoking and folic acid supplement during pregnancy on children ASD behaviors. RESULTS: Maternal passive smoking during pregnancy was significantly associated with children ASD behaviors(sub clinical group: OR=1.48; suspect clinical group: OR= 2.85), and maternal folic acid supplement during pregnancy was not related to children ASD behaviors(sub clinical group: OR=1.04; suspect clinical group: OR=0.75). Stratified analysis showed that folic acid supplement during pregnancy was negatively associated with children ASD behaviors(suspect clinical group: OR=0.30)among children without mothers' passive smoking during pregnancy, and that mothers' passive smoking during pregnancy was positively associated with children ASD behaviors(sub clinical group: OR=1.52; suspect clinical group: OR=4.45)among the children whose mothers had folic acid supplement during pregnancy. Furthermore, an interaction effect on children ASD behaviors was found between passive smoking and folic acid supplement during pregnancy(suspect clinical group: OR=5.30). CONCLUSION: Passive smoking and folic acid supplement during pregnancy were related to children ASD behaviors and had an interaction on children ASD behaviors. PMID- 27453102 TI - [Analysis on drug resistance of Mycobacterium tuberculosis and influencing factors in six provinces of China]. AB - OBJECTIVE: To analyze the drug-resistance of clinical Mycobacterium tuberculosis strains isolated from the tuberculosis(TB)patients in six provinces in China and related risk factors, and provide evidences for the effective prevention and treatment of drug resistant TB. METHODS: Six provinces were selected from China. The background information of the TB patients was investigated with questionnaire survey, and the drug susceptibilities of the clinical M. tuberculosis strains to isoniazid, rifampin, ethambutol and streptomycin were tested by means of the proportional drug susceptibility test. Then the results and related risk factors were analyzed with software SPSS 20.0. RESULTS: The overall drug resistant rate and multi drug-resistant(MDR)rate were 23.42% and 13.51% respectively. The overall drug resistant rate and MDR rate in Beijing, Jilin, Hunan, Henan, Shaanxi, Xinjiang were 21.50%, 12.24%, 36.27%, 42.86%, 27.78%, 24.39% and 4.67%, 8.16%, 24.51%, 26.53%, 15.28%, 14.15%, respectively. The chi(2) analysis results showed that the differences in single drug-resistant rate, overall drug resistant rate and MDR rate in these provinces had significant differences(P=0.000). The univariate statistical analysis results showed that the retreatment for TB and TB treatment history were the risk factors associated with drug resistance(P<0.05). CONCLUSION: The drug resistance of TB was very serious in China, but the TB drug resistance varied with province. The preventive intervention should be strengthened against all the major risk factors associated with the drug resistance for the better prevention and control of TB. PMID- 27453103 TI - [Drug resistance and influencing factors in adult AIDS patients receiving antiretroviral treatment in Dehong, Yunnan province]. AB - OBJECTIVE: To investigate the incidence of drug resistance in adult AIDS patients receiving antiretroviral treatment(ART)and influencing factors in Dehong prefecture, Yunnan province during 2012-2014. METHODS: For this cohort study, all the AIDS patients aged over 15 and receiving ART in Dehong were screened for HIV drug resistance in 2012, and 3 715 patients who had received ART for more than 6 months were enrolled for 12 months and 24 months follow up. RESULTS: Among the 3 715 patients, 56.6% were males, 72.6% were aged 26-45 years and 76.0% were married. The main treatment regimen was nevirapine(NVP)+ lamivudine(3TC)+ zidovudine(AZT)(38.2%). A total of 3 556 patients(95.7%)received at least one viral load testing during the two years follow-up, among them 253(7.1%)patients had VL>=1 000 copies/ml, in which 211(83.4%)received drug resistance related gene mutation testing, the results indicated that the drug resistance developed in 52 and 39 patients in 2013 and 2014(1.43 per 100 person years and 0.88 per 100 person years)respectively. The overall HIV drug incidence was 1.13 per 100 person years. Multivariate regression analysis indicated that age <=25 years, to be infected through drug use, treatment regimen as D4T+ 3TC +NVP and baseline CD4(+) T cells <=200 cells/MUl were the risk factor of HIV drug resistance. Eleven HIV gene subtypes were detected in the 82 patients with newly developed drug resistance, CRF_BC was predominant(31.7%), followed by CRF01_AE(22.0%)and C(19.5%). Ten patients were infected with mixed subtypes of CRF_BC/B', CRF_BC/CRF_01B and CRF_BC/C. Most of the 82 patients were resistant to NRTIs and NNRTIs, the main mutation loci were M184V and K103N. CONCLUSIONS: The incidence of drug resistance in adult AIDS patients receiving ART was relatively low in Dehong. However, it is necessary to conduct the health education in young people and drug users to improve the treatment compliance and strengthen the surveillance for HIV drug resistance. PMID- 27453104 TI - [Mortality rate and influencing factors among index partners of HIV discordant couples in the context of antiretroviral therapy, Zhumadian, Henan province, 2008 2014]. AB - OBJECTIVE: To analyze the mortality rate in index partners of HIV discordant couples in the context of antiretroviral therapy and related factors in Zhumadian, Henan province. METHODS: An open and prospective cohort survey was conducted annually during 2008-2014. Information about the index partners ' demographic characteristics, CD4(+) T(CD4)cell counts, viral load, AIDS-related syndromes, date of therapy initiation, level of treatment institution, and outcome of death were collected. Life table was used to calculate survival rate, and Cox proportional hazards model was used to analyze the mortality related factors. RESULTS: Among 4 196 index partners receiving antiretroviral therapy between 2008 and 2014, 350 were fatal, with the mortality rate of 1.88 per 100 person years(95%CI: 1.86-1.90). The survival rates of these patients with the duration of follow-up from 1 to 7 years were 99.64%, 97.70%, 95.62%, 93.54%, 91.25%, 86.86% and 82.36% respectively. Factors related to the survival of the index partners of HIV discordant couples were age >= 50 years(HR=3.48, 95% CI: 2.67-4.55), junior high school or above education level(HR=0.75, 95% CI: 0.56 1.00), baseline CD4 cell counts >350 cells per MUl(HR=0.55, 95% CI: 0.42-0.72), baseline viral load >400 copies/ml(HR=1.71, 95% CI: 1.32-2.22)and initiating treatment prior to cohort entry(HR=0.65, 95% CI: 0.41-1.05). CONCLUSIONS: The mortality rate of index partners receiving antiretroviral therapy was relatively low, indicating a better effect of long-term treatment on patients' survival. It is necessary to further identify and control the key factors influencing the survival of patients receiving therapy, improve the timeliness and adherence of the treatment, keeping patients' immunity level. Meanwhile, much attention should be paid to the drug resistance due to long term treatment and treatment failure. PMID- 27453105 TI - [Prevalence of intimate partner violence in heterosexual men attending HIV voluntary counsel and test clinics and related factors in Shanghai]. AB - OBJECTIVE: To understand prevalence of intimate partner violence(IPV)in heterosexual men(HM)attending HIV voluntary counseling and testing(VCT)clinics and related factors in Shanghai. METHODS: All the HM attending two VCT clinics in Shanghai during March-August, 2015 were recruited to participate in a cross sectional survey with questionnaire interview and blood test for HIV. IPV was evaluated by using the questionnaire developed by WHO Multi-Country Study on Women' s Health and Domestic Violence against Women. RESULTS: A total of 327 participants were recruited, their average age was 29.4 years(s?6.1). Among them 60.2%(197/327)were aged 26-35, 57.8%(189/327)never married, 78.8%(260/327)had educational level of >=college degree, 49.5%(162/327)were not local residents; 72.2%(236/327)had steady female partners, 72.2%(236/327)had 2 or more female partners in the past year, 6.1%(20/327)reported being diagnosed with sexually transmitted disease(STD). 1.8%(6/327)were tested to be HIV-positive. 28.4%(93/327)had IPV behaviors against heterosexual partners. Multivariate logistic regression analysis indicated that IPV behavior against heterosexual partners was significantly associated with experience of commercial sex(aOR=2.19, 95%CI: 1.16-4.15)and witness of domestic violence in early life(aOR=3.19; 95%CI: 1.58-6.45). CONCLUSIONS: IPV prevalence was relatively high in HM attendants in VCT clinics in Shanghai and IPV intervention is needed to conduct in VCT clinics. Multivariate regression analysis showed that the factors associated with IPV behaviors included having sex with female sex workers and the witness of domestic violence between parents. Future research is needed to further explore the association between IPV and HIV infection. PMID- 27453106 TI - [Association between HIV infection and female sex workers in middle aged and old men in a city in Hubei provine, 2014]. AB - OBJECTIVE: To understand the HIV infection status in middle aged and old men and the association between HIV infection and female sex workers in a city in Hubei province and provide evidence for the targeted prevention and control of HIV infection. METHODS: Ten communities/villages were selected through stratified cluster sampling from the suburban and rural areas of the city. A total of 634 men aged >=50 years were surveyed by using self-designed questionnaire in December, 2014. RESULTS: The awareness rate of HIV/AIDS related knowledge was 13.3%(68/513). Among the men surveyed, 63.2%(371/587)thought they couldn't be infected with HIV, 9.1%(52/573)believed that extramarital sex is acceptable, and 32.4%(189/583)considered that commercial sexual behavior is just as well. Among the surveyed men reporting sexual behavior in the past 6 months, 6.6%(15/228)had sex with regular sexual partners, in which 63.6%(7/11)never used condoms, 21.8%(128/586)reported that some friends had commercial sexual behaviors. Among 601 men receiving HIV testing, 7 were HIV positive(1.2%). The HIV detection rates among the men living at 3 communities near red light district were 4.2%(5/119), 1.1%(1/95)and 0.5%(1/192)respectively; while no HIV infections were found in the men living at 2 towns far away from red light district. Seventy seven of 581 men surveyed(13.2%)reported to meet visiting female sex workers and they had higher HIV positive rate(5.2%, 4/77)than those without such experiences(0.6%, 3/504)(P=0.007). CONCLUSION: The middle aged and old men in this city had low awareness of HIV/AIDs related knowledge, and high-risk sexual behaviors existed among them. HIV positive rate was relatively high in this population, and HIV infection might be associated with sex service. PMID- 27453107 TI - [Disease burden of famale breast cancer in China]. AB - OBJECTIVE: To analyze the data on burden of female breast cancer in China. METHODS: The data from Chinese Cancer Registry Annual Report 2012, three national death cause surveys in China, Disease Surveillance Points system(DSP), China Health Statistics Yearbook, GLOBOCAN 2012, Cancer Incidence in Five Continents(CI5), WHO Mortality Database and Global Burden of Disease(GBD)2013 were used to extract the incidence, mortality and disability-adjusted life years(DALY)of female breast cancer and analyze related trends in China. RESULTS: The data from three national death cause surveys showed that the crude mortality of breast cancer doubled from year 1973-1975 to year 2004-2005, the increase was higher in urban area(127.4%)than in rural area(75.2%). WHO Mortality Database showed that average annual percentage change(AAPC)of breast cancer crude mortality increased by 3.1%(P<0.05)from 1987 to 2000, and China Health Statistics Yearbook showed that the AAPC in urban females increased by 2.7% from 2002 to 2013(P<0.05), whereas the AAPC in rural females showed no significant change(P>0.05). It was estimated by GLOBOCAN 2012 that in 2012 the age standardized incidence and age-standardized mortality of breast cancer in China was 22.1 per 100 000 and 5.4 per 100 000, respectively. The age-specific incidence began to increase obviously at age of 40 years and peaked at age 45-59 years(GLOBOCAN 2012). Chinese Cancer Registry Annual Report 2012 showed that breast cancer incidence and mortality were 2-fold and 1.5-fold higher in urban females than in rural females in 2009. It was estimated that the breast cancer case number and death number in females in China would increase to 251 600 and 75 900, respectively, more increose in age group >=65 years. Only GBD 2013 reported DALY, the DALY caused by breast cancer in China was 1 666.0 thousand in 2013, accounting for 12.7% of global DALY, and increased by 56.7% from 1990(1 062.6 thousand), the peak age-specific DALY rate was at 50 to 59 years, and national average ratio of years lived with disability(YLD)was 8.7%(ranging from 8.1% to 9.0% at provincial level). CONCLUSIONS: Burden of disease caused by female breast cancer is becoming increasingly severe in China, especially in urban areas. It is necessary to strengthen the population-based prevention and control programs and further studies may focus on DALY. PMID- 27453108 TI - [Analysis on causes of death of residents in Beijing, 1965-1974]. AB - OBJECTIVE: To fill up the absence of data on causes of death of urban residents in Beijing during 1965-1974 and provide evidence for the similar study in other areas. METHODS: All possible sources for death data during 1965-1974 were identified through expert consultations and record search. Stratified sampling was conducted to collect the death data of urban residents during this period in Beijing. The mortality rate, death cause constituent and rank of death causes were used in this descriptive analysis. RESULTS: A total of 11 668 records of deaths from 1965 to 1974 were collected from 10 local police stations in urban area of Beijing. The top 10 death causes in the urban residents were heart disease, tumor, cerebrovascular disease, accidental injury, respiratory system disease, digestive system disease, communicable disease and parasitic disease, nervous system disease, urogenital and reproductive system disease, endocrine and nutrition metabolic diseases. The deaths caused by these diseases accounted for 84.19% of the total deaths. Accidental injury accounted for 13.22% of the total deaths, which was significantly higher than that in either 1964 or 1975, two years before and after this period(P<0.01). Suicide accounted for 54.47% of the total accidental injury deaths. For men, accidental injury was the leading death cause, followed by cancer and heart disease; for women, heart disease, cancer and cerebrovascular disease were the top three death causes. CONCLUSION: The major death cause in urban residents changed from infectious diseases to chronic and non-communicable diseases during 1965-1974. A remarkable high proportion of deaths caused by accidental injury was due to the historical background during that period in Beijing, China. PMID- 27453109 TI - [Marital status and high-risk sexual behaviors among newly reported HIV infected men who have sex with men in China in 2012, one year follow up study]. AB - OBJECTIVE: To analyze the changes of marital status and high-risk sexual behaviors in newly reported HIV infected men who have sex with men(MSM)and provide evidence for the targeted behavior intervention in this population and the prevention of secondary HIV infection. METHODS: Data collected from HIV/AIDS case reporting cards and follow-up cards between December 31(st), 2012 and December 31(st), 2013 were used and newly reported HIV infected MSM were recruited, their demographic characteristics, marital status, and high-risk sexual behaviors were analyzed. RESULTS: Of 15 768 newly reported HIV infected MSM in 2012, 10 426(66.1%)were unmarried and 10 970(69.6%)had educational level of >=senior high school. Among the 15 049 HIV infected MSM receiving follow up in 2012, 14 451(96.0%)still received follow up in 2013. The number HIV infected MSM who had protected sexual behaviors increased from 9 779(67.7%)in 2012 to 13 277(91.1%)in 2013. Among the HIV infected MSM who had married, 64.1% remained their marital status in 2013. Among the HIV infected MSM, those who had educational level of >=senior high school(OR=1.540, 95% CI: 1.138-2.085), workers(OR=1.430, 95% CI: 1.131-1.808), staff(OR=1.610, 95%CI: 1.236-2.098)or farmers(OR=1.661, 95%CI: 1.214-2.271)were more likely to have protected sexual behaviors than those who had educational level of primary school or were engaged in commercial services. Those who had never married,(OR=0.563, 95% CI: 0.439 0.722), divorced(OR=0.624, 95% CI: 0.448-0.870)or remarried(OR=0.444, 95% CI: 0.288-0.687)were more likely to have high-risk sexual behaviors. CONCLUSION: Standardized follow-up seemed helpful for the newly diagnosed HIV infected MSM to have protected sexual behaviors. Highly effective intervention should be focused on MSM who have no spouses or regular sexual partners, with low educational level, or are engaged in commercial services to prevent secondary HIV transmission. PMID- 27453110 TI - [Relationship and interaction between folate and expression of methyl-CpG-binding protein 2 in cervical cancerization]. AB - OBJECTIVE: To explore the interaction between folate and the expression of methyl CpG-binding protein 2(MeCP2)in cervical cancerization. METHODS: Forty one patients diagnosed with cervical squamous cell carcinoma(SCC), 71 patients diagnosed with cervical intraepithelial neoplasm(CIN1, n=34; CIN2 +, n=37)and 61 women with normal cervix(NC)were recruited in this study. Microbiological assay was conducted to detect the levels of serum folate and RBC folate, Western blot assay and real-time PCR were performed to detect the expression levels of MeCP2 protein and mRNA, respectively. The data were analyzed by Kruskal-Wallis H test, chi(2) test, trend chi(2) test and Spearman correlation with SPSS statistical software(version 20.0), and the interaction were evaluated by using generalized multifactor dimensionality reduction(GMDR)model. RESULTS: The levels of serum folate(H=44.71, P<0.001; trend chi(2)=24.48, P<0.001)and RBC folate(H=5.28, P<0.001; trend chi(2)=3.83, P<0.05)decreased gradually along with the severity of cervical lesions. There was a positive correlation between serum folate level and RBC folate level(r=0.270, P< 0.001). The expression levels of MeCP2 protein(H=33.72, P<0.001; trend chi(2)=14.74, P<0.001)and mRNA(H=19.50, P<0.001; trend chi(2)=10.74, P<0.001)increased gradually along with the severity of cervical lesions. There were negative correlation between folate level and the expression level of MeCP2 protein(serum folate: r=-0.226, P=0.003; RBC folate: r= 0.164, P=0.004). Moreover, the results by GMDR model revealed there were interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and MeCP2 mRNA high expression in SCC and CIN2 + patients. CONCLUSION: Folate deficiency and high expression of MeCP2 gene might increase the risk of cervical cancer and its precancerous lesions through interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and mRNA high expression in the progression of cervical cancerization. PMID- 27453111 TI - [Study of auxiliary diagnostic value of viral load test for samples with indeterminate HIV antibody detection results]. AB - OBJECTIVE: To evaluate the auxiliary diagnostic value of viral load test for samples with indeterminate HIV antibody detection results. METHODS: Thirty-two samples with indeterminate HIV antibody detection results collected from MSM were used for two viral load tests in Tianjin in 2015. Follow up was conducted for this population to confirm their HIV infection status. RESULTS: Virus loads were detected in the 2 viral load tests. In the follow-up survey, the results of HIV antibody test of all the samples were positive. The results of viral load test were completely consistent with those of HIIV antibody confirmation test. CONCLUSION: The viral load test was effective in the auxiliary diagnosis of HIV infection in window phase, which can be used for the samples with indeterminate HIV antibody detection results. PMID- 27453112 TI - [Association between IKZF3 gene polymorphisms and systemic lupus erythematosus in Han ethnic group in southern China: a case-control study]. AB - OBJECTIVE: To understand the association between IKZF3 gene polymorphism and the risk of systemic lupus erythematosus(SLE)in Han ethnic group in southern China. METHODS: A case-control study was conducted among 213 SLE patients and 234 healthy controls. Venous blood samples were collected from them to measure single nucleotide polymorphism(SNP)in IKZF3 by using the method of restriction fragment length polymorphism(PCR-RFLP). Multivariate logistic analysis and generalized multifactor dimensionality reduction(GMDR)method were used under multiple genetic models(additive, dominant, recessive), to analyze the association between IKZF3 and SLE susceptibility or different clinical features and gene-gene interactions. In addition, bioinformatics analysis was also conducted. RESULTS: As for rs114509391, CA genotype might decrease the risk of SLE compared with AA genotype(OR=0.14, 95%CI: 0.03-0.56, P=0.006)and significant association was also observed under dominant model(OR=0.26, 95%CI: 0.09-0.81, P=0.02). Stratified analysis indicated that rs9635726 and rs9909593 were related to SLE onset. The study of clinical features showed that rs907091 was associated with both renal disorder(additive: OR=0.59, 95%CI: 0.35-0.98, P=0.043)and anti-SSB(dominant: OR=0.41, 95%CI: 0.18-0.96, P=0.040). rs9635726 GG and GA genotype might decrease the risk of anti-SSB compared with AA genotype(OR=0.37, 95%CI:0.16-0.88, P=0.025). In addition, bioinformatics analysis indicated that all the studied SNPs were functional. CONCLUSION: IKZF3 rs114509391, rs9635726 and rs9909593 polymorphisms might be related to SLE susceptibility in Han ethnic group in southern China and rs9909593, rs907091 might be associated with renal disorder and anti-SSB. PMID- 27453113 TI - [Correlation between high risk type human papillomavirus E6/E7 mRNA and cervical cancer]. AB - OBJECTIVE: To investigate the correlation between the positive rate of high risk human papillomavirus(HPV)mRNA E6/E7 and cervical cancer, and provide evidence for the prevention and treatment of cervical cancer. METHODS: A total of 100 cervical cancer cases and 100 healthy controls were selected in our hospital from January 2015 to December 2015. The fluorescence quantitative PCR and pathological examination on HPV E6/E7 mRNA were carried out. The correlation between HPV E6/E7 mRNA and cervical squamous epithelial lesions were analyzed. RESULTS: In case group, the positive rate of HPV E6/E7 mRNA was 76.0%(76/100). In control group, the positive rate was 13.0%(13/100). The positive rate in case group was significantly higher than that in control group, and the difference was statistically significant(chi(2)=24.522, P<0.001). The positive predictive value and negative predictive value of the two groups were compared, and the difference was not significant(P>0.05). The positive rate of HPV E6/E7 mRNA was significantly higher than high-grade squamous intraepithelial lesion(SIL)rate(26.1%), low-grade SIL rate(17.6%)and atypical squamous cell hyperplasia rate(6.7%), the difference was statistically significant(chi(2)=7.615, P= 0.001; chi(2) =9.114, P=0.001; chi(2)=18.241, P<0.001). CONCLUSIONS: The detection rate of HPV E6/E7 mRNA in cervical cancer patients was high. And with the increased severity of cervical squamous epithelial lesions, the positive rate of HPV E6/E7 mRNA increased. PMID- 27453114 TI - [Association between cured meat consumption and risk of colorectal cancer in people with different dietary habits and lifestyles]. AB - OBJECTIVE: To explore the association between the intakes of cured meat and the risk of colorectal cancer, and analyze the role of the interaction between cured meat intake and dietary habit or lifestyle for the risk of colorectal cancer. METHODS: A well-designed questionnaire were used to collect retrospective information about demography, lifestyle and dietary habit from 400 patients diagnosed with colorectal cancer and 400 controls matched by age and gender. Logistic regression analysis was conducted to examine the possible association between the intake of cured meat and the risk of colorectal cancer. Generalized multifactor dimensionality reduction(GMDR)was used to analyze the interaction between cured meat intake and other dietary habits or lifestyle factors. RESULTS: Data from conditional logistic regression analysis showed that compared with the people who had <8 times per year of cured meat intake, those had 8-23 times of cured meat intakes(OR=3.480, 95%CI: 2.022-5.991, P<0.001), 24-47 times of cured meat intakes(OR=4.526, 95%CI: 2.553-8.025, P<0.001), >=48 times of cured meat intakes(OR=5.472, 95% CI: 3.105-9.642, P<0.001)had increased risk of colorectal cancer. There was a multiplied interaction between cured meat intake and pepper intake(OR=0.379, 95% CI: 0.190-0.758, P=0.009). The synergistic effect existed between cured meat intake and pickled vegetable intake; and the antagonism existed between cured meat intake and tea-drinking habit. GMDR analysis showed that interaction among red meat intake, pickled vegetable and cured meat intake on the risk of colorectal cancer might exist(P=0.001). CONCLUSIONS: With the increase of frequency of cured meat intake, the risk of colorectal cancer increased gradually. The synergistic effect might existed between pickled vegetable intake and cured meat intake. Tea-drinking, pepper intake and cured meat intake might be antagonism in the pathogenesis of colorectal cancer. Red meat intake, pickled vegetable intake and cured meat intake might have combined effect to increase the risk of colorectal cancer. PMID- 27453116 TI - [Effect of folic acid supplementation in childbearing aged women during pregnancy on neonate birth weight in Shaanxi province]. AB - OBJECTIVE: To investigate the effect of folic acid supplementation in childbearing aged women during pregnancy on the birth weight of newborns in Shaanxi province. METHODS: A questionnaire survey was conducted among the childbearing aged women selected through multistage stratified random sampling in Shaanxi during 2010-2013, all of these childbearing aged women were in pregnancy or had definite pregnancy outcomes. The birth weight of newborns and folic acid supplementation during pregnancy were used as the dependent variables and independent variables respectively in multiple linear regression model and quantile regression model and confounding factors were controlled. RESULTS: Multiple linear regression analysis showed that the birth weight of newborns whose mothers had folic acid supplementation during pregnancy were significantly higher than those whose mothers had no folic acid supplementation during pregnancy, an average increase of 29.56 g(B=29.56, t=4.69 and P<0.01). Quantile regression analysis showed from very low to higher percentiles(q=0-0.55, q=0.65, q=0.75-0.80), the birth weights of newborns whose mothers supplemented folic acid were higher than those whose mother did not supplement folic acid, the difference was significant, but the increase varied. As the increase of the percentiles of birth weight, the body weight increase declined gradually in those whose mothers had folic acid supplementation compared with those whose mothers had no folic acid supplementation. CONCLUSION: Folic acid supplementation during pregnancy can increase the birth weight of newborns, the influence was greater in newborns with lower body weight than in newborns with higher body weight. PMID- 27453115 TI - [Association between gestational weight gain and preterm birth: a retrospective epidemiological analysis in Wuhan]. AB - OBJECTIVE: To understand the influence of gestational weight gain(GWG)on preterm birth in Wuhan. METHODS: The retrospective epidemiological study was conducted in Wuhan Medical and Health Center for Women and Children between 2012 and 2014. Women who went to this hospital for antenatal care or giving birth were selected. Information was collected by using questionnaires, health care manual and clinical records. We used restricted cubic spline and multivariate logistic regression analysis to study the relationship between GWG and preterm birth. RESULTS: A total of 11 323 pregnant women participated in the investigation with 11 020(97.32%)of them eligible for our study. The results from the restricted cubic spline indicated that after adjusting for confounding factors, a U-curve was observed for GWG and preterm births(non-linearity test P< 0.001). Multivariate logistic regression analysis also indicated that both inadequate GWG(weight gainP90)were independent risk factors for preterm birth compared with normal GWG(weight gain P10-P90)with odds ratios of 1.59(1.25-2.01)and 1.46(1.13-1.88), respectively. CONCLUSIONS: Inappropriate GWG was the risk factor for preterm birth. Weight monitoring should be strengthened for pregnant women to reduce risk of preterm birth. PMID- 27453119 TI - [Application of directed acyclic graphs in control of confounding]. AB - Observational study is a method most commonly used in the etiology study of epidemiology, but confounders, always distort the true causality between exposure and outcome when local inferencing. In order to eliminate these confounding, the determining of variables which need to be adjusted become a key issue. Directed acyclic graph(DAG)could visualize complex causality, provide a simple and intuitive way to identify the confounding, and convert it into the finding of the minimal sufficient adjustment for the control of confounding. On the one hand, directed acyclic graph can choose less variables, which increase statistical efficiency of the analysis. On the other hand, it could help avoiding variables that is not measured or with missing values. In a word, the directed acyclic graph could facilitate the reveal of the real causality effectively. PMID- 27453117 TI - [Prevalence of AIDS-related sexual behaviors and HIV infection status in young men who have sex with men in China: a Meta-analysis]. AB - OBJECTIVE: To assess the prevalence of AIDS-related sexual behaviors and HIV infection status in young men who have sex with men(YMSM)in China. METHODS: Literature retrieval was conducted to obtain the related literature indexed by CNKI, Wangfang and PubMed databases from January 2005 to February 2015. Two reviewers independently screened the literature according to the inclusion and exclusion criteria, extracted data and assessed the methodological quality. Meta analysis was performed by the R software. RESULTS: Thirty seven studies involving 32 110 YMSM were included. 75.5%(95% CI: 68.8%-81.2%)YMSM sought sexual partners through Internet and 65.5%(95%CI: 60.0%-70.6%)had more than 2 sexual partners. In the last 6 months, 89.1%(95%CI: 84.2%-92.6%)YMSM had anal intercourse and 42.0%(95%CI: 37.4%-46.6%)used condom consistently; 11.4%(95%CI: 8.4%-15.4%)had vaginal intercourse and 36.9%(95%CI: 32.4%-41.6%)used condom consistently. The pooled prevalence of HIV infection was 5.0%(95%CI: 3.9%-6.5%), sub-group analysis showed that the prevalence of HIV infection in the eastern, central and western China were 4.2%(95%CI: 2.6%-6.6%), 1.9%(95%CI: 0.8%-4.6%), 6.3%(95% CI: 4.7% 8.5%), respectively, and there were significant differences among different areas. CONCLUSION: The prevalence of AIDS-related risk sexual behaviors and incidence of HIV infection in YMSM were high in China, it is necessary to conduct AIDS intervention in this population. PMID- 27453118 TI - [Meta-analysis on effect of combined supplementation of folic acid, vitamin B12 and B6 on risk of cardio-cerebrovascular diseases in randomized control trials]. AB - OBJECTIVE: To evaluate the effect of the combined supplementation of folic acid, vitamin B12 and B6 on the risk of cardio-cerebrovascular diseases. METHODS: The literatures of randomized control trials about the relationship between the combined supplementation of folic acid, vitamin B12 and B6 and risk of cardio cerebrovascular diseases from 1980 to 2014 were retrieved, and the eligible studies were screened for a Meta-analysis. The study indicators were the incidences of cardiovascular disease events, myocardial infarction and stroke. The cffect indicators were relative risk(RR)and 95% confidence interval(CI). Jadad score was used for the quality evaluation of the trials used in the study. RESULTS: The literatures of 11 randomized control trials, involving 26 395 patients, were used in the Meta-analysis. The combined supplementation of B vitamins had no effect on the incidence of cardiovascular disease events(RR=1.00, 95% CI: 0.94-1.07)based on 8 studies. The combined supplementation of B vitamins had no effect on the incidence of myocardial infarction(RR= 1.03, 95% CI: 0.94 1.13)based on 9 studies. The combined supplementation of B vitamins could reduce the incidence of stroke by 14%(RR=0.86, 95%CI: 0.78-0.95)based on 9 studies. Compared with the control group, Taking folic acid combined with vitamin B12 and B6 could reduce the level of homocysteine by 2.53 MUmol/L(95%CI:-3.93--1.12). Subgroup analysis indicated that the follow-up time, the dosage of folic acid and vitamin B12 and B6, the history of diseases had no confounding effect on the incidence of cardio-cerebrovascular disease events. But the subgroup analysis for stroke showed that with the extension of follow-up time, the supplementation of B vitamins could reduce the risk of stroke. The effect of folic acid and B12 in small dosage seemed more significant in the prevention of stroke, while the preventive effect of B6 increased with increasing dosage. The preventive effect of combined supplementation of B vitamins was more significant for the patients with a history of cardio-cerebrovascular diseases. CONCLUSION: Taking folic acid combined with vitamin B6 and B12 might have no significant effect on the incidences of cardio-cerebrovascular disease events and myocardial infarction, but could lower the risk of stroke and the level of homocysteine. PMID- 27453120 TI - [Discussion of breast cancer screening model in China]. AB - Cancer screening has been considered as double-edged sword with both advantages and disadvantages. For decades, there have been strong interests in screening strategies for the early detection of cancers to reduce the mortality, especially breast X-ray(mammography)screening. However, several evidences also suggested that the benefit of reduction of breast-cancer mortality with mammography might become a problem due to the repeat mammography, subsequent biopsies, and overdiagnosis. And different screening strategies with different models, different intervals, and different target populations also incurred debates. After systematical analysis and discussion, we suggested to focus on high-risk population, improve the accuracy of screening technique, conduct the informed consent of participants, and explore individual screening mode in the screening of breast cancer. PMID- 27453121 TI - [Schistosomiasis must be eradicated: a review of fighting schitosomiasis in Qingpu, Shanghai]. AB - Qingpu, in western suburban of Shanghai, was one of serious schistosomiasis endemic counties in China. In 1958, in response to Chairman Mao' s call " Schistosomiasis must be eradicated", Shanghai First Medical College organized a research group to carry out schitosomiasis control in Qingpu. The prevalence of schistosomiasis was about 39% in 390 000 people and 8.4% in cattle. Oncomelania was distributed in an area of 70 million meter(2). The fighting project could be divided into two steps, the first one was from 1958 to 1974, during this period, the epidemic survey and patient treatment were conducted, and oncomelania control was carried out by using different kind of molluscides. In 1975, up to 92% of patients were cured, and 98% of oncomelania were killed. The second step was from 1975 to 1985, the main tasks were the consolidation of control achievement and surveillance. During this period oral medicines were used instead of venous injections. After the improvement of oncomelania detection method, the oncomelania clustering were found under rock duck and brick shore. In 1985, it was confirmed that schistosomiasis had been eradicated in Qingpu and other suburb areas of Shanghai. PMID- 27453122 TI - [Epidemiological studies of disability in the elderly]. AB - China has entered an aging society, the disabled elder population has been>= 10 000 000. The overall health status of the elderly is not optimistic, they have higher morbidity and disability rates. Several studies have showed that elderly disability rate varied with age, gender and living area. And it might be affected by the health factors, sociological factors, and other life behavior factors. It is very important to conduct further study of the epidemiology of disability in the elderly for the development of long-term health care policy in this population. PMID- 27453123 TI - [Progress in research of detection assay for pathogens causing community acquirerd pneumonia]. AB - Community-acquired pneumonia(CAP)is a common respiratory infectious disease. The etiologic diagnosis of CAP remains an uneasy task. Early etiologic diagnosis is critical for proper treatment and might improve the prognosis. So, it is important to identify pathogens causing CAP in early time and accurate way with sensitive and effective method. This paper summarizes the recent progress in the research of the detection assay for CAP. PMID- 27453124 TI - Phylogenetically Diverse Aerobic Anoxygenic Phototrophic Bacteria Isolated from Epilithic Biofilms in Tama River, Japan. AB - The diversity of aerobic anoxygenic phototrophic (AAP) bacteria in freshwater environments, particularly in rivers, has not been examined in as much detail as in ocean environments. In the present study, we investigated the phylogenetic and physiological diversities of AAP bacteria in biofilms that developed on submerged stones in a freshwater river using culture methods. The biofilms collected were homogenized and inoculated on solid media and incubated aerobically in the dark. Sixty-eight red-, pink-, yellow-, orange-, or brown-colored colonies were isolated, and, of these, 28 isolates contained the photosynthetic pigment, bacteriochlorophyll (BChl) a. Phylogenetic analyses based on 16S rRNA gene sequences showed that the isolates were classified into 14 groups in 8 operational taxonomic units (OTUs) and distributed in the orders Rhodospirillales, Rhodobacterales, and Sphingomonadales of Alphaproteobacteria and in Betaproteobacteria. Physiological analyses confirmed that none of the representative isolates from any of the groups grew under anaerobic phototrophic conditions. Seven isolates in 4 OTUs showed a 16S rRNA gene sequence identity of 98.0% or less with any established species, suggesting the presence of previously undescribed species of AAP bacteria. Six isolates in 2 other OTUs had the closest relatives, which have not been reported to be AAP bacteria. Physiological comparisons among the isolates revealed differences in preferences for nutrient concentrations, BChl contents, and light-harvesting proteins. These results suggest that diverse and previously unknown AAP bacteria inhabit river biofilms. PMID- 27453125 TI - Multidrug Delivery Systems Based on Human Serum Albumin for Combination Therapy with Three Anticancer Agents. AB - When administering several anticancer drugs within a single carrier, it is important to regulate their spatial distribution so as to avoid possible mutual interference and to thus enhance the drugs' selectivity and efficiency. To achieve this, we proposed to develop human serum albumin (HSA)-based multidrug delivery systems for combination anticancer therapy. We used three anticancer agents (an organic drug [5-fluorouracil, or 5FU], a metallic agent [2 benzoylpyridine thiosemicarbazide copper II, or BpT], and a gene agent [AS1411]) to treat liver cancer and confirm our hypothesis. The structure of the HSA palmitic acid (PA)-5FU-BpT complex revealed that 5FU and BpT, respectively, bind to the IB and IIA subdomains of HSA. Our MALDI-TOF-MS spectral data show that one AS1411 molecule is conjugated to Cys-34 of the HSA-5FU-BpT complex via a linker. Compared with unregulated three-drug combination therapy, the HSA-5FU-BpT-AS1411 complex enhances cytotoxicity in Bel-7402 cells approximately 7-fold in vitro; however, in normal cells it does not raise cytotoxicity levels. Importantly, our in vivo results demonstrate that the HSA-5FU-BpT-AS1411 complex is superior to the unregulated three-drug combination in enhancing targeting ability, inhibiting liver tumor growth, and causing fewer side effects. PMID- 27453127 TI - A prospective 5-year study of the frequency of arrhythmias during serial exercise testing and clinical follow-up after Melody valve implant. AB - BACKGROUND: Although percutaneous Melody valve implant has become an accepted alternative to surgical pulmonary valve replacement in patients with congenital heart disease, the benefit regarding frequency and severity of arrhythmias remains undefined. OBJECTIVE: The purpose of this study was to evaluate the impact of Melody valve implant on the type and frequency of arrhythmias during cardiopulmonary exercise testing (CPET) and subsequent clinical outcome. METHODS: As part of the phase I Melody valve clinical trial, 136 patients with congenital heart disease underwent prospective serial evaluation including CPET before implant, 6 months after implant, and annually thereafter for 5 years. Arrhythmias were defined as premature ventricular complexes (PVCs) and supraventricular or ventricular tachycardia (VT). RESULTS: Before Melody implant, PVCs occurred in 55 patients (40%) and nonsustained ventricular tachycardia (NSVT) in 1 patient during CPET. Median age at valve implantation was 19.0 years (range 7-53 years). During median follow-up of 4.9 years (range 0.8-7.3 years), there was no significant change in the proportion of patients with PVCs during CPET at any follow-up interval (40%-45%). However, postimplant, NSVT occurred in 18 patients, including 8 during CPET. Diagnoses in the patients with NSVT were tetralogy of Fallot (11), transposition (2), and post-Ross procedure (5). Improved hemodynamic status was not associated with resolution or prevention of arrhythmias. CONCLUSION: Despite improvement in hemodynamics, Melody valve implant was not associated with resolution or prevention of arrhythmias during CPET. PVCs or VT may be related to pathologic hypertrophy, fibrosis, dilation, or possible mechanical effects of the Melody device. PMID- 27453126 TI - Characterization of the epicardial substrate for catheter ablation of Brugada syndrome. AB - BACKGROUND: Catheter ablation in the right ventricular outflow tract (RVOT) may modify the electrophysiologic substrate for recurrent ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with Brugada syndrome (BrS). OBJECTIVE: The purpose of this study was to investigate the mechanism and arrhythmogenic substrate of VT/VF and to evaluate the long-term outcomes of catheter ablation in patients with BrS. METHODS: Eleven consecutive patients with BrS referred to 2 academic medical centers underwent combined epicardial endocardial electroanatomic mapping. Catheter ablation was performed in regions of localized conduction slowing. Transmural dispersion of late activation was calculated as the difference between the latest activation between epicardium and endocardium, and low-voltage areas were analyzed. RESULTS: Eleven patients met diagnostic criteria for BrS (spontaneous type 1, n = 9; Na channel provocation = 2). All patients were found to have a localized region in the anterior epicardial RVOT with conduction slowing evidenced by prolonged electrogram duration (78.79 +/- 19.87 ms vs 58.93 +/- 10.11 ms in epicardial right ventricle, and 59.87 +/- 12.61 ms in endocardial RVOT, P <.005, respectively) with variable low voltage (0.97 +/- 0.48 mV; median scar area 19.8 +/- 25.9 cm2). Epicardial ablation resulted in normalization of spontaneous type 1 Brugada ECG pattern in all patients, and 73% were free from VT/VF at 25 +/- 11 months. CONCLUSION: Prolonged electrograms localized to epicardial RVOT with variable low voltage were identified in all patients with BrS. J-point and ST-segment elevation correlated with greater transmural dispersion of late activation and was independent of total low-voltage area. Despite normalization of spontaneous type 1 pattern in all patients after ablation, recurrence was still observed, suggesting the implantable cardioverter-defibrillator as the cornerstone therapy for BrS. PMID- 27453129 TI - IMPACT OF PRENATAL MATERNAL FACTORS AND BIRTH ORDER ON THE ANTHROPOMETRIC STATUS OF NEWBORNS IN IRAN. AB - This cross-sectional study was carried out to capture possible maternal factors affecting newborns' anthropometric measurements. Data were collected from eight public health centres and referral university hospital records in Tabriz and Heriss districts, north-west Iran, for 807 mother-neonate pairs delivering live singleton births and their offspring during the two years up to August 2014. The incidence of low birth weight (LBW) was 5.1%. A close correlation was found between maternal anthropometry and birth order with neonatal anthropometric data. Birth order and maternal height and body mass index (BMI) positively affected neonates' birth size (weight, length and head circumference). The rate of LBW was significantly higher for older (>=35 years), taller (>=170 cm), underweight (BMI<18.5) and non-iron-taking women and in the first-born babies. The odds of having LBW newborns in older, taller, underweight, obese and irregular iron taking women were 3.82, 4.00, 9.07, 3.50 and 2.50 times those of mid-age group, middle-height, overweight and regular iron-taking women, respectively. First-born newborns were 5.97 times more likely to be LBW compared with second-birth neonates. The results indicate that maternal anthropometric indices, age, iron intake and birth order influence the risk of LBW in newborns. PMID- 27453128 TI - East Eurasian ancestry in the middle of Europe: genetic footprints of Steppe nomads in the genomes of Belarusian Lipka Tatars. AB - Medieval era encounters of nomadic groups of the Eurasian Steppe and largely sedentary East Europeans had a variety of demographic and cultural consequences. Amongst these outcomes was the emergence of the Lipka Tatars-a Slavic-speaking Sunni-Muslim minority residing in modern Belarus, Lithuania and Poland, whose ancestors arrived in these territories via several migration waves, mainly from the Golden Horde. Our results show that Belarusian Lipka Tatars share a substantial part of their gene pool with Europeans as indicated by their Y chromosomal, mitochondrial and autosomal DNA variation. Nevertheless, Belarusian Lipkas still retain a strong genetic signal of their nomadic ancestry, witnessed by the presence of common Y-chromosomal and mitochondrial DNA variants as well as autosomal segments identical by descent between Lipkas and East Eurasians from temperate and northern regions. Hence, we document Lipka Tatars as a unique example of former Medieval migrants into Central Europe, who became sedentary, changed language to Slavic, yet preserved their faith and retained, both uni- and bi-parentally, a clear genetic echo of a complex population interplay throughout the Eurasian Steppe Belt, extending from Central Europe to northern China. PMID- 27453130 TI - A comparison of orbitally-shaken and stirred-tank bioreactors: pH modulation and bioreactor type affect CHO cell growth and protein glycosylation. AB - Orbitally shaken bioreactors (OSRs) support the suspension cultivation of animal cells at volumetric scales up to 200 L and are a potential alternative to stirred tank bioreactors (STRs) due to their rapid and homogeneous mixing and high oxygen transfer rate. In this study, a Chinese hamster ovary cell line producing a recombinant antibody was cultivated in a 5 L OSR and a 3 L STR, both operated with or without pH control. Effects of bioreactor type and pH control on cell growth and metabolism and on recombinant protein production and glycosylation were determined. In pH-controlled bioreactors, the glucose consumption and lactate production rates were higher relative to cultures grown in bioreactors without pH control. The cell density and viability were higher in the OSRs than in the STRs, either with or without pH control. Volumetric recombinant antibody yields were not affected by the process conditions, and a glycan analysis of the antibody by mass spectrometry did not reveal major process-dependent differences in the galactosylation index. The results demonstrated that OSRs are suitable for recombinant protein production from suspension-adapted animal cells. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1174-1180, 2016. PMID- 27453131 TI - Immunomodulatory effects of individual and combined mycotoxins in the THP-1 cell line. AB - Mycotoxins commonly contaminate food and may pose a risk for disease in humans and animals. As they frequently co-occur, mixed exposures often take place. Monocyte function, including differentiation into active macrophages, is a central part of the immune response. Here we studied effects of naturally co occurring mycotoxins in grain on monocyte function, and effects of individual and combined exposure on the differentiation process from monocytes into macrophages. The THP-1 cell line was used as a model system. The mycotoxins 2-amino-14,16 dimethyloctadecan-3-ol (AOD), alternariol (AOH), enniatin B (ENNB), deoxynivalenol (DON), sterigmatocystin (ST) and zearalenone (ZEA) differently affected cell viability in THP-1 monocytes, with DON as the most potent. AOH, ZEA and DON inhibited differentiation from monocytes into macrophages. Using this differentiation model, combined exposure of AOH, ZEA and DON were mainly found to be additive. However, the combination AOH+ZEA had somewhat synergistic effect at lower concentrations. Furthermore, alterations in macrophage functionality were found, as single exposure of AOH and ZEA inhibited lipopolysaccharide (LPS) induced TNF-alpha secretion, while DON increased this response. Overall, the mycotoxins affected monocyte viability and differentiation into macrophages differently. Combined exposures affected the differentiation process mainly additively. PMID- 27453132 TI - Identification of novel reaction products of methylene-bis-phenylisocyanate ("MDI") with oxidized glutathione in aqueous solution and also during incubation of MDI with a murine hepatic S9 fraction. AB - Methylene diphenyl diisocyanate (MDI) is an important industrial chemical and asthmagenic respiratory sensitizer, however its metabolism remains unclear. In this study we used LC-MS and LC-MS/MS to identify novel reaction products of MDI with oxidized glutathione (GSSG), including an 837m/z [M+H](+) ion corresponding to GSSG bound (via one of its N-termini) to partially hydrolyzed MDI, and an 863m/z [M+H](+) ion corresponding to GSSG cross-linked by MDI (via its two gamma glutamine N-termini). Further studies with heavy isotope labeled and native reduced glutathione (GSH) identified an [M+H](+) ion corresponding to previously described mono(GSH)-MDI, and evidence for "oligomeric" GSH-MDI conjugates. This study also investigated transformational changes in MDI after incubation with an S9 fraction prepared from murine liver. LC-MS analyses of the S9 reaction products revealed the formation of [M+H](+) ions with m/z's and retention times identical to the newly described GSSG-MDI (837 and 863) conjugates and the previously described mono(GSH)-MDI conjugate. Together the data identify novel biological transformations of MDI, which could have implications for exposure related health effects, and may help target future in vivo studies of metabolism. PMID- 27453133 TI - Land cover changes and greenhouse gas emissions in two different soil covers in the Brazilian Caatinga. AB - The Caatinga biome covers an area of 844,453km(2) and has enormous endemic biodiversity, with unique characteristics that make it an exclusive Brazilian biome. It falls within the earth's tropical zone and is one of the several important ecoregions of Brazil. This biome undergoes natural lengthy periods of drought that cause losses in crop and livestock productivity, having a severe impact on the population. Due to the vulnerability of this ecosystem to climate change, livestock has emerged as the main livelihood of the rural population, being the precursor of the replacement of native vegetation by grazing areas. This study aimed to measure GHG emissions from two different soil covers: native forest (Caatinga) and pasture in the municipality of Sao Joao, Pernambuco State, in the years 2013 and 2014. GHG measurements were taken by using static chamber techniques in both soil covers. According to a previous search, so far, this is the first study measuring GHG emissions using the static chamber in the Caatinga biome. N2O emissions ranged from -1.0 to 4.2mgm(-2)d(-1) and -1.22 to 3.4mgm( 2)d(-1) in the pasture and Caatinga, respectively, and they did not significantly differ from each other. Emissions were significantly higher during dry seasons. Carbon dioxide ranged from -1.1 to 14.1 and 1.2 to 15.8gm(-2)d(-1) in the pasture and Caatinga, respectively. CO2 emissions were higher in the Caatinga in 2013, and they were significantly influenced by soil temperature, showing an inverse relation. Methane emission ranged from 6.6 to 6.8 and -6.0 to 4.8mgm(-2)d(-1) in the pasture and Caatinga, respectively, and was significantly higher only in the Caatinga in the rainy season of 2014. Soil gas fluxes seemed to be influenced by climatic and edaphic conditions as well as by soil cover in the Caatinga biome. PMID- 27453134 TI - Relative impact of emissions controls and meteorology on air pollution mitigation associated with the Asia-Pacific Economic Cooperation (APEC) conference in Beijing, China. AB - The Beijing government and its surrounding provinces implemented a series of measures to ensure haze-free skies during the 22(nd) Asia-Pacific Economic Cooperation (APEC) conference (November 10(th)-11(th), 2014). These measures included restrictions on traffic, construction, and industrial activity. Twelve hour measurements of the concentration and composition of ambient fine particulate matter (PM2.5) were performed for 5 consecutive months near the APEC conference site before (September 11(th)-November 2(nd), 2014), during (November 3(rd)-12(th), 2014) and after (November 13(th), 2014-January 31(st), 2015). The measurements are used in a positive matrix factorization model to determine the contributions from seven sources of PM2.5: secondary aerosols, traffic exhaust, industrial emission, road dust, soil dust, biomass burning and residual oil combustion. The source apportionment results are integrated with backward trajectory analysis using Weather Research and Forecast (WRF) meteorological simulations, which determine the relative influence of new regulation and meteorology upon improved air quality during the APEC conference. Data show that controls are very effective, but meteorology must be taken into account to determine the actual influence of the controls on pollution reduction. The industry source control is the most effective for reducing concentrations, followed by secondary aerosol and biomass controls, while the least effective control is for the residual oil combustion source. The largest reductions in concentrations occur when air mass transport is from the west-northwest (Ulanqab). Secondary aerosol and traffic exhaust reductions are most significant for air mass transport from the north-northwest (Xilingele League) origin, and least significant for northeast transport (Chifeng via Tangshan conditions). The largest reductions of soil dust, biomass burning, and industrial source are distinctly seen for Ulanqab conditions and least distinct for Xilingele League. PMID- 27453135 TI - Metals bioaccumulation and biomarkers responses in the Neotropical freshwater clam Anodontites trapesialis: Implications for monitoring coal mining areas. AB - As one of the most impactful industries, coal mining can promote several alterations at surrounding environment. In surface water, elevated concentrations of metals like Mn, Zn, Fe and Al are often observed. Thus, the aim of this study was to investigate the bioaccumulation and the sub-lethal effects of these metals on various organs of the Neotropical bivalve Anodontites trapesialis confined along a stream located near a coal mine, in order to assess a set of biomarkers that could be used for effectively monitoring coal mining areas. Clams were caged, for 96h, at two sites located upstream (Up1 and Up2) and two sites downstream (Dw1 and Dw2) from the mine. Metals bioaccumulation was determined in gills, mantle, digestive gland, muscle and hemolymph and the following biomarkers were measured in A. trapesialis tissues: total antioxidant capacity against peroxyl radicals, metallothionein content, lipid peroxidation (LPO), proteins carbonylation, glutathione S-transferase activity, superoxide dismutase activity and acetylcholinesterase (AChE) activity. The results showed that Al and Fe bioaccumulation in the gills and hemolymph, Al bioaccumulation in the mantle and muscle, increased LPO in the gills (Dw1 and Dw2) and mantle (Dw1), as well as reduced AChE activity in the muscle (Dw1 and Dw2) should be considered effective biomarkers for monitoring coal mining areas. A. trapesialis proved to be an efficient biological model, considering that biomarkers responses were observed in the clams after only 96h of confinement at Dw sites, accordingly this species could be a good candidate for monitoring Neotropical freshwaters. PMID- 27453136 TI - Short-term influence of coal mine reclamation using coal combustion residues on groundwater quality. AB - Two full-scale coal mine reclamation projects using coal combustion residues (CCRs) were recently carried out at highwall pit complexes near the Conesville and Cardinal coal-fired power plants owned by American Electric Power. The environment impacts of the reclamation projects were examined by regularly monitoring the leaching characteristics of the backfilling CCRs and the water quality of the uppermost aquifers underlying the sites. With over five years of field monitoring, it shows that the water quality at both demonstration sites had changed since the reclamation began. By analyzing the change of the hydrogeochemical properties, it was concluded that the water quality impact observed at the Conesville Five Points site was unlikely due to the seepage of FGD material leachates. Reclamation activities, such as logging, grading, and dewatering changed the hydrogeological conditions and resulted in the observed water quality changes. The same hydrogeological effect on water quality was also found at the Cardinal Star Ridge site during the early stage of the reclamation (approximately the first 22months). Subsequent measurements showed the water quality to be strongly influenced by the water in the reclaimed highwall pit. Despite the changes to the water quality, the impacts are insignificant and temporary. None of the constitutes showed concentration levels higher than the regulatory leaching limits set by the Ohio Department of Natural Resources' Division of Mineral Resources Management for utilizing CCRs in mined land reclamation. Compared to the local aquifers, the concentrations of eleven selected constituents remained at comparable levels throughout the study period. There are four constituents (i.e., As, Be, Sb, and Tl) that exceeded their respective MCLs after the reclamation began. These detections were found shortly (i.e., within 2years) after the reclamation began and decreased to the levels either lower than the respective detection limits or similar to the background levels. PMID- 27453137 TI - Seawater intrusion in karstic, coastal aquifers: Current challenges and future scenarios in the Taranto area (southern Italy). AB - Mediterranean areas are characterized by complex hydrogeological systems, where management of freshwater resources, mostly stored in karstic, coastal aquifers, is necessary and requires the application of numerical tools to detect and prevent deterioration of groundwater, mostly caused by overexploitation. In the Taranto area (southern Italy), the deep, karstic aquifer is the only source of freshwater and satisfies the main human activities. Preserving quantity and quality of this system through management policies is so necessary and such task can be addressed through modeling tools which take into account human impacts and the effects of climate changes. A variable-density flow model was developed with SEAWAT to depict the "current" status of the saltwater intrusion, namely the status simulated over an average hydrogeological year. Considering the goals of this analysis and the scale at which the model was built, the equivalent porous medium approach was adopted to represent the deep aquifer. The effects that different flow boundary conditions along the coast have on the transport model were assessed. Furthermore, salinity stratification occurs within a strip spreading between 4km and 7km from the coast in the deep aquifer. The model predicts a similar phenomenon for some submarine freshwater springs and modeling outcomes were positively compared with measurements found in the literature. Two scenarios were simulated to assess the effects of decreased rainfall and increased pumping on saline intrusion. Major differences in the concentration field with respect to the "current" status were found where the hydraulic conductivity of the deep aquifer is higher and such differences are higher when Dirichlet flow boundary conditions are assigned. Furthermore, the Dirichlet boundary condition along the coast for transport modeling influences the concentration field in different scenarios at shallow depths; as such, concentration values simulated under stressed conditions are lower than those simulated under undisturbed conditions. PMID- 27453138 TI - Phosphorus recovery from municipal wastewater: An integrated comparative technological, environmental and economic assessment of P recovery technologies. AB - Phosphorus (P) is an essential and limited resource. Municipal wastewater is a promising source of P via reuse and could be used to replace P derived from phosphate rocks. The agricultural use of sewage sludge is restricted by legislation or is not practiced in several European countries due to environmental risks posed by organic micropollutants and pathogens. Several technologies have been developed in recent years to recover wastewater P. However, these technologies target different P-containing flows in wastewater treatment plants (effluent, digester supernatant, sewage sludge, and sewage sludge ash), use diverse engineering approaches and differ greatly with respect to P recycling rate, potential of removing or destroying pollutants, product quality, environmental impact and cost. This work compares 19 relevant P recovery technologies by considering their relationships with existing wastewater and sludge treatment systems. A combination of different methods, such as material flow analysis, damage units, reference soil method, annuity method, integrated cost calculation and a literature study on solubility, fertilizing effects and handling of recovered materials, is used to evaluate the different technologies with respect to technical, ecological and economic aspects. With regard to the manifold origins of data an uncertainty concept considering validity of data sources is applied. This analysis revealed that recovery from flows with dissolved P produces clean and plant-available materials. These techniques may even be beneficial from economic and technical perspectives under specific circumstances. However, the recovery rates (a maximum of 25%) relative to the wastewater treatment plant influent are relatively low. The approaches that recover P from sewage sludge apply complex technologies and generally achieve effective removal of heavy metals at moderate recovery rates (~40-50% relative to the WWTP input) and comparatively high costs. Sewage sludge ash is the most promising P source, with recovery rates of 60-90% relative to the wastewater P. The costs highly depend on the purity requirements of the recycled products but can be kept comparatively low, especially if synergies with existing industrial processes are exploited. PMID- 27453139 TI - In-situ chemical oxidation: Principle and applications of peroxide and persulfate treatments in wastewater systems. AB - Hydrogen peroxide (H2O2) and persulfate are the most efficient and commonly used oxidants in in-situ chemical oxidation (ISCO) of organic contaminants. This review focuses on the principle and activation techniques used in H2O2 and persulfate based ISCO processes. It is crucial to understand the effect of activation techniques on process chemistry and free radicals behaviour in order to achieve high degradation efficiency. The chemistry of interaction of activated H2O2 and persulfate with organic contaminants is complex and many parameters influence the performance of ISCO processes, namely non-productive reactants, reaction intermediates, oxygen and pH. The poor understanding of interaction behaviour and reaction chemistry of oxidants with organic contaminants prevents the utilization of full potential of the process. Therefore, particular attention has been given to the factors affecting degradation efficiency and the performance of ISCO processes. Further, the mechanism of contaminant degradation using activated H2O2 and persulfate significantly differ from each other. The interaction of SO4(-) radical usually involves electron transfer reactions whereas HO radical involve electron-transfer and hydrogen-atom abstraction reactions. Moreover, the research gaps have been identified based on the knowledge of current research and recommendations are made for further understanding of ISCO processes. PMID- 27453140 TI - A risk assessment tool applied to the study of shale gas resources. AB - The implementation of a risk assessment tool with the capacity to evaluate the risks for health, safety and the environment (HSE) from extraction of non conventional fossil fuel resources by the hydraulic fracturing (fracking) technique can be a useful tool to boost development and progress of the technology and winning public trust and acceptance of this. At the early project stages, the lack of data related the selection of non-conventional gas deposits makes it difficult the use of existing approaches to risk assessment of fluids injected into geologic formations. The qualitative risk assessment tool developed in this work is based on the approach that shale gas exploitation risk is dependent on both the geologic site and the technological aspects. It follows from the Oldenburg's 'Screening and Ranking Framework (SRF)' developed to evaluate potential geologic carbon dioxide (CO2) storage sites. These two global characteristics: (1) characteristics centered on the natural aspects of the site and (2) characteristics centered on the technological aspects of the Project, have been evaluated through user input of Property values, which define Attributes, which define the Characteristics. In order to carry out an individual evaluation of each of the characteristics and the elements of the model, the tool has been implemented in a spreadsheet. The proposed model has been applied to a site with potential for the exploitation of shale gas in Asturias (northwestern Spain) with tree different technological options to test the approach. PMID- 27453141 TI - Free fatty acid profiling of marine sentinels by nanoLC-EI-MS for the assessment of environmental pollution effects. AB - The present work aims to elucidate the free fatty acid (FFA) profile of the mussel Mytilus galloprovincialis caged in an anthropogenically impacted area and in a reference site through an innovative and validated analytical approach for the assessment of biological alterations induced by marine pollution. The FFA pattern is involved in the regulation of different cellular pathways and differs with respect to metabolic stimuli. To this purpose, the lipid fraction of mussels coming from both sampling areas was extracted and the FFA fractions were isolated and purified by a solid phase extraction; then, nano-scale liquid chromatography coupled to electron ionization mass spectrometry (nanoLC-EI-MS) was employed for the characterization of the two samples. A total of 19 and 17 FFAs were reliably identified in the mussels coming from the reference and polluted site, respectively. Significant qualitative and quantitative differences found in saturated, monounsaturated and polyunsaturated species may be exploited as typical pollution biomarkers (e.g. alteration of the fatty acid biosynthetic system and lipotoxicity) and explain adverse and compromising effects (e.g. oxidative stress and inflammatory processes) related to environmental pollution. PMID- 27453142 TI - The mortality impacts of fine particles in France. AB - INTRODUCTION: Worldwide, air pollution has become a main environmental cause of premature mortality. This burden is largely due to fine particles. Recent cohort studies have confirmed the health risks associated with chronic exposure to PM2.5 for European and French populations. We assessed the mortality impact of PM2.5 in continental France using these new results. METHODS: Based on a meta-analysis of French and European cohorts, we computed a shrunken estimate of PM2.5-mortality relationship for the French population (RR 1.15 [1.05:1.25] for a 10MUg/m(3) increase in PM2.5). This RR was applied to PM2.5 annual concentrations estimated at a fine spatial scale, using a classical health impacts assessment method. The health benefits associated with alternative scenarios of improving air quality were computed for 36,219 French municipalities for 2007-2008. RESULTS: 9% of the total mortality in continental France is attributable to anthropogenic PM2.5. This represents >48,000 deaths per year, and 950,000years of life lost per year, more than half occurring in urban areas larger than 100,000 inhabitants. If none of the municipalities exceeded the World Health Organization guideline value for PM2.5 (10MUg/m(3)), the total mortality could be decreased by 3%, corresponding to 400,000years of life saved per year. CONCLUSION: Results were consistent with previous estimates of the long-term mortality impacts of fine particles in France. These findings show that further actions to improve air quality in France would substantially improve health. PMID- 27453144 TI - Breastfeeding duration and associated factors between 1960 and 2000. AB - OBJECTIVE: To describe a historical series on the median duration of breastfeeding in a population of mothers whose children were born from the 1960s onwards, identifying factors associated with the interruption of breastfeeding in each decade. METHODS: Data were analyzed from the Pro-Saude Study, a longitudinal epidemiological investigation started in 1999 among technical and administrative employees of a university in the state of Rio de Janeiro. Breastfeeding duration was collected in two study phases: Phase 1 (1999), and phase 4 (2011-2012). Of these, those who had at least one child and reported the duration of breastfeeding for the first child were selected (n=1539). To analyze the duration of breastfeeding, survival curves were constructed using the Kaplan-Meier method and the effect of covariates on the duration of breastfeeding was estimated by Cox regression model. RESULTS: It was found that the median duration of breastfeeding was higher in the 1990s and 2000s and lower in the 1970s, compared to the 1960s. In addition, there was an association between higher income and maternal age with breastfeeding interruption, which was focused in the 1970s. CONCLUSION: There was shorter duration of breastfeeding in the 1970s compared to the 1960s. Increased duration and prevalence of breastfeeding from the 1970s onwards coincided with the national trend and the promotion of this practice since 1980. PMID- 27453143 TI - Relationship between legacy and emerging organic pollutants in Antarctic seabirds and their foraging ecology as shown by delta13C and delta15N. AB - Foraging ecology and the marine regions exploited by Antarctic seabirds outside of breeding strongly influence their exposure to persistent organic pollutants (POPs). However, relationships between them are largely unknown, an important knowledge gap given that many species are capital breeders and POPs may be deleterious to seabirds. This study investigates the relationship between Antarctic seabird foraging ecology (measured by delta13C and delta15N) and POPs accumulated in their eggs prior to breeding. Organochlorinated pesticides, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and dechlorane plus (DP) were measured in eggs of chinstrap, Adelie, and gentoo penguins (Pygoscelis antarctica, P. adeliae, P. papua), as well as south polar skua (Catharacta maccormicki), sampled on King George Island. Total POP levels were as follows: skua (3210+/-3330ng/g lipid weight)>chinstrap (338+/ 128ng/g)>Adelie (287+/-43.3ng/g)>gentoo (252+/-49.4ng/g). Trophic position and pre-breeding foraging sites were important in explaining POP accumulation patterns across species. The most recalcitrant compounds were preferentially accumulated in skuas, occupying one trophic level above penguins. In contrast, their Antarctic endemism, coupled with influence from cold condensation of pollutants, likely contributed to penguins exhibiting higher concentrations of more volatile compounds (e.g., hexachlorobenzene, PCB-28 and -52) than skuas. Regional differences in penguin pre-breeding foraging areas did not significantly affect their POP burdens, whereas the trans-equatorial migration and foraging sites of skuas were strongly reflected in their pollutant profiles, especially for PBDEs and DPs. Overall, our results provide new insights on migratory birds as biovectors of POPs, including non-globally regulated compounds such as DP, from northern regions to Antarctica. PMID- 27453145 TI - Going international? Risk taking by cryptomarket drug vendors. AB - BACKGROUND: Since 2011, we have witnessed the rise of 'dark net' drug marketplaces known as cryptomarkets. Cryptomarkets operate on the same model as eBay as they provide a platform where authorized vendors can set up a virtual shop and place listings. Building on a growing body of literature that seeks to understand cryptomarket participants, this paper seeks to explain the decision of cryptomarket vendors to take on risk. METHODS: We collected data on Silk Road 1 (SR1), the first cryptomarket launched in 2011. We propose a multilevel model that takes into account the characteristics of listings, vendors and their environment to explain the decision of vendors to take on risk. RESULTS: Our results demonstrate that all levels in the model significantly explain the decision to take on risk. Risk taking, operationalized as a willingness to ship drugs across international borders, was associated with the weights of drug packages mailed, the vendors' reputations and numbers of listings, the country level perceived effectiveness of law enforcement according to experts, and the opportunities available to vendors as measured by the wealth and the drug expenditures of potential customers. CONCLUSIONS: Our results support some previous research findings on the factors explaining risk taking. We extend existing literature by emphasizing the relevance of the environment of drug dealers to predict risk taking. PMID- 27453146 TI - A public health approach to increased synthetic cannabinoid-related morbidity among New York City residents, 2014-2015. PMID- 27453147 TI - Alprazolam use and related harm among opioid substitution treatment clients - 12 months follow up after regulatory rescheduling. AB - BACKGROUND: Alprazolam, has been associated with disproportionate harms compared to other benzodiazepines, especially among people in opioid substitution treatment (OST). We examine the effect of the rescheduling of alprazolam in Australia, from Schedule 4 to Schedule 8 in February 2014 amongst a high-risk population of clients in OST. METHODS: OST participants who reported recent (last month) alprazolam use were recruited from three Sydney clinics. Participants (n=57) were interviewed immediately prior to rescheduling and again three months and 12 months after rescheduling. We examined self-reported patterns of drug use, drug availability, mental and physical health. A linear mixed models approach was used to analyse changes in alprazolam and other benzodiazepine use. RESULTS: Mean days of alprazolam use in the past 28 days decreased from 13.7 to 7.1 days, and mean weekly alprazolam dose decreased from 15.1mg to 6.1mg at 12 months follow-up (p=0.001). Total weekly benzodiazepine use also reduced from a mean of 222mg diazepam equivalent to 157mg (p=0.044). Other substance use did not change significantly. Reported mode of cost price of street alprazolam doubled from $5 to $10 over the 12-month period. CONCLUSION: Alprazolam rescheduling resulted in an overall reduction in alprazolam and total benzodiazepine use, without substitution with other drugs, in the short term. Unintended harms were not observed. Rescheduling appears to have been effective in reducing alprazolam use in this high-risk population. PMID- 27453148 TI - Supportive housing and surveillance. AB - Urban centres in the US, Britain and Canada have responded to identified visible 'social problems' such addiction, mental health and homelessness by providing some supportive housing for the urban poor and marginalized. While some critics have questioned what supportive housing specifically entails in terms of the built environment, what remains under explored, though a growing area of concern, is the relationship between surveillance and supportive housing for urban residents identified as having addiction and mental health problems - a gap addressed in this paper. Drawing upon qualitative ethnographic observational data we examine some of the measures of control and coercion that are encroaching into social housing primarily established for poor and marginalized people with addiction and mental health problems in the urban centre of Vancouver, Canada. We witnessed three modes of regulation and control, that vary widely, among the residencies observed: physical surveillance technologies; site-specific modes of coercion; police presence and staff surveillance, which all together impact the everyday lives of residents living in low-income and supportive housing. We argue that supportive housing has the potential to provide its intended commitment - safe and secure affordable housing. However, owing to an (over)emphasis on 'security', the supportive housing we observed were also sites of social control. PMID- 27453149 TI - Elaboration of tetra-orthogonally-substituted aromatic scaffolds towards novel EGFR-kinase inhibitors. AB - Nitration of three regioisomers of bromo-fluorobenzaldehyde proceeds regioselectively, notably with H2SO4/HNO3 at 0 degrees C. The thereby synthesized tetrasubstituted aromatics, endowed with orthogonal substituents, can be elaborated via Pd-catalysed coupling, reduction and reductive amination reactions. As a test-case, these compounds were converted into EGFR inhibitors related to Gefitinib, whose activity was rationalised by docking studies. PMID- 27453150 TI - Controllable Phase Transformation and Mid-infrared Emission from Er(3+)-Doped Hexagonal-/Cubic-NaYF4 Nanocrystals. AB - The morphology of hexagonal phase NaYF4:Er(3+) nanorods synthesized by hydrothermal method changed greatly after a continuing calcination, along with a phase transformation to cubic phase. Photoluminescence (PL) spectra indicated that mid-infrared (MIR) emission was obtained in both hexagonal and cubic phase NaYF4:Er(3+) nanocrystals for the first time. And the MIR emission of NaYF4:Er(3+) nanocrystals enhanced remarkably at higher calcination temperature. To prevent uncontrollable morphology from phase transformation, the cubic phase NaYF4:Er(3+) nanospheres with an average size of ~100 nm were prepared via a co precipitation method directly. In contrast, the results showed better morphology and size of cubic phase NaYF4:Er(3+) nanocrystals have realized when calcined at different temperatures. And PL spectra demonstrated a more intense MIR emission in the cubic phase NaYF4:Er(3+) nanocrystals with an increasing temperature. Besides, the MIR emission peak of Er(3+) ions had an obvious splitting in cubic phase NaYF4. Therefore, cubic phase NaYF4:Er(3+) nanospheres with more excellent MIR luminescent properties seems to provide a new material for nanocrystal-glass composites, which is expected to open a broad new field for the realization of MIR lasers gain medium. PMID- 27453151 TI - Corrigendum: Seven wood-inhabiting new species of the genus Trichoderma (Fungi, Ascomycota) in Viride clade. PMID- 27453152 TI - Functional Connectivity Networks in Asymptomatic and Symptomatic DYT1 Carriers. AB - BACKGROUND: DYT1 mutation is characterized by focal to generalized dystonia and incomplete penetrance. To explore the complex perturbations in the different neural networks and the mutual interactions among them, we studied symptomatic and asymptomatic DTY1 mutation carriers by resting-state functional MRI. METHODS: A total of 7 symptomatic DYT1, 10 asymptomatic DYT1, and 26 healthy controls were considered. Resting-state functional MRI (Oxford Centre for Functional MRI of the Brain) [FMRIB] Software Library) (FSL) MELODIC, dual regression, (as a toolbox of FSL, with Nets is referred to "networks") (FSLNets) (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FSLNets) was performed on 9 resting-state neural networks. RESULTS: DYT1 mutation signature (symptomatic DYT1 and asymptomatic DYT1) was characterized by increased connectivity in the dorsal attention network and in the left fronto-parietal network. Functional correlates of symptomatic DYT1 patients (symptomatic DYT1 vs healthy controls) showed increased connectivity in the sensorimotor network. DISCUSSION: This study argues that DYT1 dystonia is a network disorder, with crucial nodes in sensory-motor integration of posterior parietal structures. A better characterization of cortical networks involved in dystonia is crucial for possible neurophysiological therapeutic interventions. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27453153 TI - Single microwave-photon detector using an artificial Lambda-type three-level system. AB - Single-photon detection is a requisite technique in quantum-optics experiments in both the optical and the microwave domains. However, the energy of microwave quanta are four to five orders of magnitude less than their optical counterpart, making the efficient detection of single microwave photons extremely challenging. Here we demonstrate the detection of a single microwave photon propagating through a waveguide. The detector is implemented with an impedance-matched artificial Lambda system comprising the dressed states of a driven superconducting qubit coupled to a microwave resonator. Each signal photon deterministically induces a Raman transition in the Lambda system and excites the qubit. The subsequent dispersive readout of the qubit produces a discrete 'click'. We attain a high single-photon-detection efficiency of 0.66+/-0.06 with a low dark-count probability of 0.014+/-0.001 and a reset time of ~400 ns. This detector can be exploited for various applications in quantum sensing, quantum communication and quantum information processing. PMID- 27453155 TI - 5-MeO-DALT; a novel designer drug on the market causing acute delirium and rhabdomyolysis. PMID- 27453154 TI - Improving biofeedback for the treatment of fecal incontinence in women: implementation of a standardized multi-site manometric biofeedback protocol. AB - BACKGROUND: Standardized training and clinical protocols using biofeedback for the treatment of fecal incontinence (FI) are important for clinical care. Our primary aims were to develop, implement, and evaluate adherence to a standardized protocol for manometric biofeedback to treat FI. METHODS: In a Pelvic Floor Disorders Network (PFDN) trial, participants were enrolled from eight PFDN clinical centers across the United States. A team of clinical and equipment experts developed biofeedback software on a novel tablet computer platform for conducting standardized anorectal manometry with separate manometric biofeedback protocols for improving anorectal muscle strength, sensation, and urge resistance. The training protocol also included education on bowel function, anal sphincter exercises, and bowel diary monitoring. Study interventionists completed online training prior to attending a centralized, standardized certification course. For the certification, expert trainers assessed the ability of the interventionists to perform the protocol components for a paid volunteer who acted as a standardized patient. Postcertification, the trainers audited interventionists during trial implementation to improve protocol adherence. KEY RESULTS: Twenty-four interventionists attended the in-person training and certification, including 46% advanced practice registered nurses (11/24), 50% (12/24) physical therapists, and 4% physician assistants (1/24). Trainers performed audio audits for 88% (21/24), representing 84 audited visits. All certified interventionists met or exceeded the prespecified 80% pass rate for the audit process, with an average passing rate of 93%. CONCLUSIONS & INFERENCES: A biofeedback protocol can be successfully imparted to experienced pelvic floor health care providers from various disciplines. Our process promoted high adherence to a standard protocol and is applicable to many clinical settings. PMID- 27453156 TI - Dissociable changes in functional network topology underlie early category learning and development of automaticity. AB - Recent work has shown that multimodal association areas-including frontal, temporal, and parietal cortex-are focal points of functional network reconfiguration during human learning and performance of cognitive tasks. On the other hand, neurocomputational theories of category learning suggest that the basal ganglia and related subcortical structures are focal points of functional network reconfiguration during early learning of some categorization tasks but become less so with the development of automatic categorization performance. Using a combination of network science and multilevel regression, we explore how changes in the connectivity of small brain regions can predict behavioral changes during training in a visual categorization task. We find that initial category learning, as indexed by changes in accuracy, is predicted by increasingly efficient integrative processing in subcortical areas, with higher functional specialization, more efficient integration across modules, but a lower cost in terms of redundancy of information processing. The development of automaticity, as indexed by changes in the speed of correct responses, was predicted by lower clustering (particularly in subcortical areas), higher strength (highest in cortical areas), and higher betweenness centrality. By combining neurocomputational theories and network scientific methods, these results synthesize the dissociative roles of multimodal association areas and subcortical structures in the development of automaticity during category learning. PMID- 27453159 TI - Cerebellar output encodes a corrective saccadic command (Commentary on Sun et al.). PMID- 27453158 TI - Predicting the transition from normal aging to Alzheimer's disease: A statistical mechanistic evaluation of FDG-PET data. AB - The assessment of the degree of order of brain metabolism by means of a statistical mechanistic approach applied to FDG-PET, allowed us to characterize healthy subjects as well as patients with mild cognitive impairment and Alzheimer's Disease (AD). The intensity signals from 24 volumes of interest were submitted to principal component analysis (PCA) giving rise to a major first principal component whose eigenvalue was a reliable cumulative index of order. This index linearly decreased from 77 to 44% going from normal aging to AD patients with intermediate conditions between these values (r=0.96, p<0.001). Bootstrap analysis confirmed the statistical significance of the results. The progressive detachment of different brain regions from the first component was assessed, allowing for a purely data driven reconstruction of already known maximally affected areas. We demonstrated for the first time the reliability of a single global index of order in discriminating groups of cognitively impaired patients with different clinical outcome. The second relevant finding was the identification of clusters of regions relevant to AD pathology progressively separating from the first principal component through different stages of cognitive impairment, including patients cognitively impaired but not converted to AD. This paved the way to the quantitative assessment of the functional networking status in individual patients. PMID- 27453157 TI - Structural brain development between childhood and adulthood: Convergence across four longitudinal samples. AB - Longitudinal studies including brain measures acquired through magnetic resonance imaging (MRI) have enabled population models of human brain development, crucial for our understanding of typical development as well as neurodevelopmental disorders. Brain development in the first two decades generally involves early cortical grey matter volume (CGMV) increases followed by decreases, and monotonic increases in cerebral white matter volume (CWMV). However, inconsistencies regarding the precise developmental trajectories call into question the comparability of samples. This issue can be addressed by conducting a comprehensive study across multiple datasets from diverse populations. Here, we present replicable models for gross structural brain development between childhood and adulthood (ages 8-30years) by repeating analyses in four separate longitudinal samples (391 participants; 852 scans). In addition, we address how accounting for global measures of cranial/brain size affect these developmental trajectories. First, we found evidence for continued development of both intracranial volume (ICV) and whole brain volume (WBV) through adolescence, albeit following distinct trajectories. Second, our results indicate that CGMV is at its highest in childhood, decreasing steadily through the second decade with deceleration in the third decade, while CWMV increases until mid-to-late adolescence before decelerating. Importantly, we show that accounting for cranial/brain size affects models of regional brain development, particularly with respect to sex differences. Our results increase confidence in our knowledge of the pattern of brain changes during adolescence, reduce concerns about discrepancies across samples, and suggest some best practices for statistical control of cranial volume and brain size in future studies. PMID- 27453160 TI - Effect of early feed restriction on physiological responses, performance and ascites incidence in broiler chickens raised in normal or cold environment. AB - Intensive selection of broilers for faster growth and better feed efficiency resulted in greater susceptibility to metabolic disorders such as ascites syndrome, which is one of the major causes of mortality and economic loss in broiler industry. Whereas cool temperature is one of the primary triggers for ascites, early feed restriction (FDR) significantly alleviates its incidence and mortality. However, little is known about effects of FDR, cold environmental temperature and their interaction on physiological responses in broiler chickens. For this purpose, 320 one-day-old male broilers were divided into two treatment groups of Ad libitum (Ad) and feed restricted (FR) with eight pen replicates each. Chickens in FR group underwent feed access limitation from days 7 to 14 of age. On day 21 half of the birds (four pens) in each group exposed to the cold temperature (CT) and the other half (four pens) continued at normal temperature (NT). Average daily feed intake, average daily weight gain and feed conversion ratio (FCR) were measured at days 7, 14, 21, 28 and 42. At 39 and 46 days of age two chicks with a BW around the pen average were selected from each pen and slaughtered after collecting blood samples. Then, relative weight of internal organs and right ventricle weight per total ventricle weight (RV : TV) ratio were calculated. Compared with NT group, CT birds had higher daily feed intake and FCR (P<0.05) from day 28 to 42. Cumulative ascites mortality in CT chickens was higher (P<0.001) than NT chicks. Within the CT group, ascites mortality in FR chickens was reduced (P<0.001) to 1.25% compared with 8.75% in Ad chicks. Birds in CT group had significantly (P<0.05) thicker right ventricle and greater relative weight of heart, hematocrit and triiodothyronine concentration. However, none of these parameters were affected by FDR. Under cold stress conditions, FDR reduced activity of alanine aminotransferase and aspartate aminotransferase (P<0.05). Serum triglyceride, cholesterol, high-density lipoprotein and total protein were not influenced by either temperature or feeding regimen. In conclusion, these findings suggest that FDR reduces ascites incidence mainly by allowing better development of internal organs, which helps them to cope with the high metabolic pressure and suffer less damage. PMID- 27453161 TI - Glasgow Prognostic Score: Another Global Positioning System to Assess Patients with Lung Cancer? PMID- 27453162 TI - Chasing Therapeutic Targets in Thymic Malignancies: Finding Needles in the Haystack to Frame a Comprehensive Canvas? PMID- 27453163 TI - Staging, Tumor Profile, and Prognostic Groups in Lung Cancer or the New Tower of Babel. PMID- 27453165 TI - On the Article "Nodal Upstaging Is More Common with Thoracotomy Than with VATS during Lobectomy for Early-Stage Lung Cancer: An Analysis from the National Cancer Data Base" by Medbery et al. PMID- 27453166 TI - Location, Location, Location: The Reality of Tumor Real Estate and Nodal Upstaging. PMID- 27453167 TI - Community Interventions for Health can support clinicians in advising patients to reduce tobacco use, improve dietary intake and increase physical activity. AB - AIMS AND OBJECTIVES: To increase clinical interventions to reduce modifiable risk factors for noncommunicable disease in low- and middle-income countries. BACKGROUND: Noncommunicable disease is the leading cause of death in the world and is common in low- and middle-income countries. Risk factors for noncommunicable disease are modifiable and health professionals are in an unique position to intervene and influence them. DESIGN: Clinical interventions were used as part of the Community Interventions for Health programme, a nonrandomised, controlled study undertaken in three communities - one each in China, India and Mexico. METHODS: All clinicians in intervention and control areas of the study were invited to complete surveys. A total of 2280 completed surveys at baseline and 2501 at follow-up. Culturally appropriate interventions to reduce tobacco use, improve dietary intake and increase physical activity were delivered in the intervention areas. RESULTS: Clinicians in the intervention group felt more prepared to advise smoking cessation and improvement of diet. They were more likely to test serum cholesterol and blood pressure, but less likely to take measurements of height, hip, waist and skin-fold thickness. There were more resources available to clinicians in the intervention group and they used counselling more and complementary medicine less than those in the control group. CONCLUSIONS: Community interventions which have been shown to have a positive effect in the community and workplace also change clinical practice. RELEVANCE TO CLINICAL PRACTICE: Community interventions make clinicians, including nurses, more likely to feel prepared to offer advice and more likely to use counselling. This would be expected to reduce risk factors in patients. PMID- 27453164 TI - Consensus Report of the 2015 Weinman International Conference on Mesothelioma. AB - On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM. PMID- 27453168 TI - Antimicrobial stewardship in a Gastroenterology Department: Impact on antimicrobial consumption, antimicrobial resistance and clinical outcome. AB - BACKGROUND: A major cause of the increase in antimicrobial resistance is the inappropriate use of antimicrobials. AIMS: To evaluate the impact on antimicrobial consumption and clinical outcome of an antimicrobial stewardship program in an Italian Gastroenterology Department. METHODS: Between October 2014 and September 2015 (period B), a specialist in infectious diseases (ID) controlled all antimicrobial prescriptions and decided about the therapy in agreement with gastroenterologists. The defined daily doses of antimicrobials (DDDs), incidence of MDR-infections, mean length of stay and overall in-hospital mortality rate were compared with those of the same period in the previous 12 months (period A). RESULTS: During period B, the ID specialist performed 304 consultations: antimicrobials were continued in 44.4% of the cases, discontinued in 13.8%, not recommended in 12.1%, de-escalated 9.9%, escalated in 7.9%, and started in 4.0%. Comparing the 2 periods, we observed a decreased of antibiotics consumption (from 109.81 to 78.45 DDDs/100 patient-days, p=0.0005), antifungals (from 41.28 to 24.75 DDDs/100pd, p=0.0004), carbapenems (from 15.99 to 6.80 DDDsx100pd, p=0.0032), quinolones (from 35.79 to 17.82 DDDsx100pd, p=0.0079). No differences were observed in incidence of MDR-infections, length of hospital stay (LOS), and mortality rate. CONCLUSIONS: ASP program had a positive impact on reducing the consumption of antimicrobials, without an increase in LOS and mortality. PMID- 27453169 TI - Prevalence and characteristics of acid gastro-oesophageal reflux disease in Jackhammer oesophagus. AB - BACKGROUND: An association between acid gastro-oesophageal reflux disease (GERD) and Jackhammer oesophagus has been suggested. AIM: To assess the prevalence and characteristics of acid-GERD in Jackhammer oesophagus and the efficacy of proton pump inhibitors. METHODS: Data and outcomes of patients with Jackhammer oesophagus were assessed. Two groups were compared: (i) GERD, defined by endoscopic oesophagitis or by an increase in acid exposure time or by an acid hypersensitive oesophagus and (ii) non-GERD defined by normal oesophageal acid exposure without acid-hypersensitive oesophagus. RESULTS: Among the 1994 high resolution manometries performed, 44 Jackhammer oesophagus (2.2%) were included (sex ratio M/F: 19/25; median age: 66 [61-75] years). Nineteen patients (43.2%) had GERD, 16 (36.4%) had no GERD and 9 patients (20.4%) were undetermined. Dysphagia was the predominant symptom (37/43 (86%)). After a median follow-up of 25.3 months [9.6-31.4], dysphagia was improved in 22/36 (61.1%) patients. Dysphagia improvement as well as other symptoms improvement was not associated with GERD status or proton-pump inhibitors use. CONCLUSION: The prevalence of GERD is high among patients with Jackhammer oesophagus. The rates of symptom improvement in Jackhammer oesophagus were high regardless of the use of proton pump inhibitors treatment or of the presence of GERD. PMID- 27453170 TI - Admission profile and discharge outcomes for infants aged less than 6 months admitted to inpatient therapeutic care in 10 countries. A secondary data analysis. AB - Evidence on the management of acute malnutrition in infants aged less than 6 months (infants <6mo) is scarce. To understand outcomes using current protocols, we analysed a sample of 24 045 children aged 0-60 months from 21 datasets of inpatient therapeutic care programmes in 10 countries. We compared the proportion of admissions, the anthropometric profile at admission and the discharge outcomes between infants <6mo and children aged 6-60 months (older children). Infants <6mo accounted for 12% of admissions. The quality of anthropometric data at admission was more problematic in infants <6mo than in older children with a greater proportion of missing data (a 6.9 percentage point difference for length values, 95% CI: 6.0; 7.9, P < 0.01), anthropometric measures that could not be converted to indices (a 15.6 percentage point difference for weight-for-length z-score values, 95% CI: 14.3; 16.9, P < 0.01) and anthropometric indices that were flagged as outliers (a 2.7 percentage point difference for any anthropometric index being flagged as an outlier, 95% CI: 1.7; 3.8, P < 0.01). A high proportion of both infants <6mo and older children were discharged as recovered. Infants <6mo showed a greater risk of death during treatment (risk ratio 1.30, 95% CI: 1.09; 1.56, P < 0.01). Infants <6mo represent an important proportion of admissions to therapeutic feeding programmes, and there are crucial challenges associated with their care. Systematic compilation and analysis of routine data for infants <6mo is necessary for monitoring programme performance and should be promoted as a tool to monitor the impact of new guidelines on care. PMID- 27453171 TI - Thioridazine Sensitizes Esophageal Carcinoma Cell Lines to Radiotherapy-Induced Apoptosis In Vitro and In Vivo. AB - BACKGROUND Radiotherapy is one of the primary treatments for esophageal squamous cell carcinoma (ESCC). Identification of novel radio-sensitizing agents will improve the therapeutic outcome of radiotherapy. This study aimed to determine the radio-sensitizing effect of the antipsychotic agent thioridazine in ESCC and explored the underlying mechanisms. MATERIAL AND METHODS ECA-109 and TE-1 ESCC cells were treated with thioridazine and radiotherapy alone and in combination. Cell survival was measured by MTT assay. Cell cycle and apoptosis were monitored by flow cytometry. Western blot analysis was used to analyze the expression of phospho-PI3K, phosphor-AKT, phospho-mTOR, Caspase-3, Caspase-9, Bax, Bcl-2, Bal xl, Bak, and p53. The xenograft mouse model was used to study the in vivo anticancer effect of thioridazine and irradiation. RESULTS Combined treatment with thioridazine and irradiation significantly reduced viability of ESCC cells compared with thioridazine or irradiation treatment alone. Thioridazine and irradiation treatment induced G0/G1 phases cell cycle arrest through down regulation of CDK4 and cyclinD1. In addition, thioridazine and irradiation treatment induced apoptosis through up-regulation of cleaved capase-3 and 9, as well as an increase in the expression of Bax and Bak and a decrease in the expression of Bcl-2 and Bcl-xl. Furthermore, thioridazine and irradiation treatment inhibited the PI3K-AKT-mTOR pathway and up-regulated the expression of p53. In xenograft mice, thioridazine and irradiation reduced ESCC tumor growth. CONCLUSIONS Thioridazine sensitizes ESCC cells to radiotherapy. Thioridazine may play a role in ESCC radiation therapy as a promising radiosensitizer. PMID- 27453172 TI - Mediastinal pathology and the contributions of Dr. Juan Rosai. AB - Dr. Juan Rosai is one of the most prolific contributors to the literature on mediastinal pathology, and he has added steadily to that body of work over a 50 year period. Rosai has written several landmark articles in this topical area, including articles on thymic epithelial lesions, mediastinal neuroendocrine tumors, mediastinal lymphoma and other hematopoietic lesions, thymolipoma, thymoliposarcoma, mediastinal solitary fibrous tumor, intrathymic langerhans-cell histiocytosis, mediastinal germ cell neoplasms, and multilocular thymic cyst. This review recounts his role as one of the principal figures in the surgical pathology of mediastinal diseases. PMID- 27453173 TI - The Controlling Cancer Summit, 17-19 May 2016, London, UK. AB - The Controlling Cancer Summit, London, UK, 17-19 May 2016 The Controlling Cancer Summit is an intimate informal meeting that annually gathers international academic and clinical researchers to network and debate the current advancements and challenges of oncology research. This year, it focused not only on diagnostic/prognostic biomarkers and genetic influences in cancer but also novel and sometimes unconventional therapeutic interventions. This report will summarize the meeting highlights that contribute to our comprehension of cancer biology and new innovative ways to target this disease. PMID- 27453174 TI - Association between borderline neonatal thyroid-stimulating hormone concentrations and educational and developmental outcomes: a population-based record-linkage study. AB - BACKGROUND: Congenital hypothyroidism causes intellectual delay unless identified and effectively treated soon after birth. Newborn screening has almost eliminated intellectual disability associated with congenital hypothyroidism. However, clinical uncertainty remains about infants with thyroid-stimulating hormone (TSH) concentrations less than the newborn screening cutoffs. We assessed the association between neonatal TSH concentrations and educational and developmental outcomes. METHODS: We did a population-based record-linkage study of all liveborn infants undergoing newborn screening from 1994 to 2008 in New South Wales, Australia, with assessments of childhood development or school performance. Very low-birthweight babies (<1500 g) were excluded. Developmental and educational outcomes were obtained and these were linked to individual records by the New South Wales Centre for Health Record Linkage. The primary educational outcome was the proportion of students with National Assessment Program Literacy and Numeracy (NAPLAN) results lower than the national minimum standard in reading or numeracy measured at all ages, and the primary developmental outcome was the proportion of children who were classified as being developmentally high risk (vulnerable in two or more of the five developmental domains assessed by the Australian Early Development Census) at age 4-6 years. The proportions of infants with each outcome were calculated per percentile (0-100) of TSH concentration. Multivariable logistic regression was used to account for potential confounding by maternal and fetal variables known to affect neonatal TSH concentrations or neurodevelopmental outcomes. FINDINGS: 503 706 infants had a neonatal TSH result that linked to a developmental or educational outcome. 149 569 infants born between 2002 and 2008 were linked to an Australian Early Development Census developmental outcome and 354 137 were linked to a NAPLAN educational outcome. Median follow-up for educational outcome was 10 years (IQR 8-12) and for developmental outcome was 5 years (5-6). 5.5% (14 137 of 257 752) of infants scored less than the national minimum standard for numeracy in percentiles lower than the 75th percentile and this increased with each increase of percentile group to 11.3% (15 of 133) of infants with a TSH concentration between the 99.90th and 99.95th percentile. Infants with a neonatal TSH concentration in the 99.95th percentile or higher (above newborn screening cutoff) and likely to have diagnosed and treated congenital hypothyroidism had similar results to infants with a TSH concentration lower than the 75th percentile for both educational and developmental outcomes. Infants with a neonatal TSH concentration between the 99.5th and 99.9th percentile were more likely to have special needs (adjusted odds ratio [aOR] 1.68, 95% CI 1.23-2.30), poor numeracy performance (aOR 1.57, 1.29-1.90), and developmentally high risk (aOR 1.52, 1.20-1.93). INTERPRETATION: We found an association between neonatal TSH concentrations lower than the present newborn screening thresholds and poor educational and developmental outcomes. This association needs further investigation to assess whether assessment and treatment of these infants might improve their long-term cognitive outcomes. FUNDING: Australian National Health and Medical Research. PMID- 27453175 TI - The continuous spectrum of thyroid hormone action during early life. PMID- 27453177 TI - The Medical Bookshelf. PMID- 27453179 TI - Washington Medical Update. PMID- 27453178 TI - Editor's Mail. AB - The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space. PMID- 27453180 TI - Primary Care Digest. PMID- 27453176 TI - Systemic localization of seven major types of carbohydrates on cell membranes by dSTORM imaging. AB - Carbohydrates on the cell surface control intercellular interactions and play a vital role in various physiological processes. However, their systemic distribution patterns are poorly understood. Through the direct stochastic optical reconstruction microscopy (dSTORM) strategy, we systematically revealed that several types of representative carbohydrates are found in clustered states. Interestingly, the results from dual-color dSTORM imaging indicate that these carbohydrate clusters are prone to connect with one another and eventually form conjoined platforms where different functional glycoproteins aggregate (e.g., epidermal growth factor receptor, (EGFR) and band 3 protein). A thorough understanding of the ensemble distribution of carbohydrates on the cell surface paves the way for elucidating the structure-function relationship of cell membranes and the critical roles of carbohydrates in various physiological and pathological cell processes. PMID- 27453181 TI - Rheumatic disease. PMID- 27453182 TI - Juvenile rheumatoid arthritis. PMID- 27453185 TI - Selected National Meetings. PMID- 27453187 TI - Successful outcome using bortezomib in adult refractory IgA vasculitis: a case report. PMID- 27453189 TI - Cryopreserved hepatic progenitor cells derived from human embryonic stem cells can arrest progression of liver fibrosis in rats. AB - Hepatocytes generated from human embryonic stem cells (hESCs) are considered to be an excellent candidate for restoring the liver function deficiencies. We have earlier standardized a three-step differentiation protocol to generate functional hepatocyte-like cells (HLCs) from hESCs, which expressed the major hepatic markers. We have also found that the HLCs remain stable and functional even after extended period of in vitro culture and cryopreservation. In the present study, we have aimed to investigate the therapeutic potential of cryopreserved-thawed hESC-derived hepatic progenitor cells following transplantation in carbon tetrachloride-induced fibrotic rat livers. Significant therapeutic effects, including improved hepatic histology and normal serum biochemistry of hepatic enzymes along with increased survival rate, were observed in the cell transplanted rats. This result is an encouraging indication to develop methods for clinical application of hESC-derived hepatic lineage cells. PMID- 27453190 TI - Effects of pomegranate seed oil on oxidative stress markers, serum biochemical parameters and pathological findings in kidney and heart of streptozotocin induced diabetic rats. AB - PURPOSE: Oxidative stress due to hyperglycemia is a major cause of diabetes complications. The aim of this study was to evaluate the effects of pomegranate seed oil (PSO) on serum biochemical parameters, cardiomyopathy and nephropathy induced by diabetes mellitus. METHOD: W/A adult rats were divided into four groups (12 each): group 1, received saline (1 mL/kg), group 2, received streptozotocin (STZ, 65 mg/kg, a single dose as i.p.), groups 3 and 4, received STZ + PSO (0.4 and 0.8 mL/kg, daily by gavage, respectively). After three weeks, six rats of each group and one week later the remaining animals were anesthetized, blood samples were taken for measuring serum biochemical parameters. Sections of heart and kidneys were used for histopathological studies and the remaining tissues were homogenized for measuring malondialdehyde (MDA) and total sulfhydryl groups. RESULTS: Significant elevation of serum creatinine and urea, LDL, triglyceride, glucose levels as well as urine markers, MDA levels in tissue homogenates and a significant decrease in total thiol content and serum HDL were observed in STZ-treated group as compared with control group. PSO treatment resulted in a significant decrease in tissue MDA content, serum creatinine and urea levels as well as urine markers as compared with STZ-treated group. Lipid profile was ameliorated with PSO treatment. PSO also significantly reversed STZ-induced depletion in thiol content and histological abnormality. Effect of PSO was more specific at 28th than 21th days of study. CONCLUSION: The results showed that PSO has a protective effect against diabetes complications in rats. PMID- 27453192 TI - Erratum. PMID- 27453191 TI - Provider Use of a Novel EHR display in the Pediatric Intensive Care Unit. Large Customizable Interactive Monitor (LCIM). AB - OBJECTIVES: The purpose of this study was to explore providers' perspectives on the use of a novel technology, "Large Customizable Interactive Monitor" (LCIM), a novel application of the electronic health record system implemented in a Pediatric Intensive Care Unit. METHODS: We employed a qualitative approach to collect and analyze data from pediatric intensive care physicians, pediatric nurse practitioners, and acute care specialists. Using semi-structured interviews, we collected data from January to April, 2015. The research team analyzed the transcripts using an iterative coding method to identify common themes. RESULTS: Study results highlight contextual data on providers' use routines of the LCIM. Findings from thirty six interviews were classified into three groups: 1) providers' familiarity with the LCIM; 2) providers' use routines (i.e. when and how they use it); and 3) reasons why they use or do not use it. CONCLUSION: It is important to conduct baseline studies of the use of novel technologies. The importance of training and orientation affects the adoption and use patterns of this new technology. This study is notable for being the first to investigate a LCIM system, a next generation system implemented in the pediatric critical care setting. Our study revealed this next generation HIT might have great potential for family-centered rounds, team education during rounds, and family education/engagement in their child's health in the patient room. This study also highlights the effect of training and orientation on the adoption patterns of new technology. PMID- 27453193 TI - Erratum. PMID- 27453194 TI - Erratum. PMID- 27453196 TI - Correction: Photochemical etiology of promising ancestors of the RNA nucleobases. AB - Correction for 'Photochemical etiology of promising ancestors of the RNA nucleobases' by M. M. Brister et al., Phys. Chem. Chem. Phys., 2016, DOI: . PMID- 27453195 TI - Clade-level Spatial Modelling of HPAI H5N1 Dynamics in the Mekong Region Reveals New Patterns and Associations with Agro-Ecological Factors. AB - The highly pathogenic avian influenza (HPAI) H5N1 virus has been circulating in Asia since 2003 and diversified into several genetic lineages, or clades. Although the spatial distribution of its outbreaks was extensively studied, differences in clades were never previously taken into account. We developed models to quantify associations over time and space between different HPAI H5N1 viruses from clade 1, 2.3.4 and 2.3.2 and agro-ecological factors. We found that the distribution of clades in the Mekong region from 2004 to 2013 was strongly regionalised, defining specific epidemiological zones, or epizones. Clade 1 became entrenched in the Mekong Delta and was not supplanted by newer clades, in association with a relatively higher presence of domestic ducks. In contrast, two new clades were introduced (2.3.4 and 2.3.2) in northern Viet Nam and were associated with higher chicken density and more intensive chicken production systems. We suggest that differences in poultry production systems in these different epizones may explain these associations, along with differences in introduction pressure from neighbouring countries. The different distribution patterns found at the clade level would not be otherwise apparent through analysis treating all outbreaks equally, which requires improved linking of disease outbreak records and genetic sequence data. PMID- 27453197 TI - Hepatitis E viral loads in plasma pools for fractionation. AB - BACKGROUND: It is now recognized that blood donors may be silently infected with hepatitis E virus (HEV) and that plasma pools used in the manufacture of plasma derived medicinal products may also contain detectable virus RNA. The occurrence of HEV-infected blood and plasma donors can vary considerably depending on local epidemiology. STUDY DESIGN AND METHODS: Manufacturing plasma pools from North America, Europe, the Middle East, and Asia were examined for the presence of HEV using transcription-mediated amplification of HEV RNA; confirmatory testing was performed using real-time reverse transcription polymerase chain reaction and sequencing. RESULTS: A total of 484 pools were tested. Asian pools were most frequently positive for HEV RNA and had higher viral loads, although none exceeding 300 IU/mL, and the sequenced strains (n = 5) clustered with Genotype 4, including one significantly divergent sequence. Only HEV Genotype 3 was identified in North American (n = 5) and European (n = 5) pools. There was no evidence of HEV in any pools tested from the Middle East. CONCLUSIONS: HEV was detected in manufacturing plasma pools from three different continents; viral loads were low-consistent with large pool sizes and moderate levels of HEV viremia at the individual donation level-but are nevertheless informative for risk assessment of plasma-derived medicinal products. Where sequencing was possible, analysis confirmed the presence of viruses consistent with locally circulating genotypes in the respective regions. The absence of HEV in Middle Eastern pools is consistent with the low prevalence of HEV in this region, likely due to low pork consumption. PMID- 27453199 TI - Cholesterol-dependent thermotropic behavior and organization of neuronal membranes. AB - The composition of neuronal membranes is unique with diverse lipid composition due to evolutionary requirement. The organization and dynamics of neuronal membranes are crucial for efficient functioning of neuronal receptors. We have previously established hippocampal membranes as a convenient natural source for exploring lipid-protein interactions, and organization of neuronal receptors. Keeping in mind the pathophysiological role of neuronal cholesterol, in this work, we used differential scanning calorimetry (DSC) and small angle X-ray scattering (SAXS) to explore thermotropic phase behavior and organization (thickness) of hippocampal membranes under conditions of varying cholesterol content. Our results show that the apparent phase transition temperature of hippocampal membranes displays characteristic linear dependence on membrane cholesterol content. These results are in contrast to earlier results with binary lipid mixtures containing cholesterol where phase transition temperature was found to be not significantly dependent on cholesterol concentration. Interestingly, SAXS data showed that hippocampal membrane thickness remained more or less invariant, irrespective of cholesterol content. We believe that these results constitute one of the early reports on the thermotropic phase behavior and organizational characterization of hippocampal membranes under varying cholesterol content. These results could have implications in the functioning of neuronal receptors in healthy and diseased states. PMID- 27453200 TI - Oligomer formation of Clostridium perfringens epsilon-toxin is induced by activation of neutral sphingomyelinase. AB - BACKGROUND: Clostridium perfringens epsilon-toxin is responsible for fatal enterotoxemia in ungulates. The toxin forms a heptamer in the lipid rafts of Madin-Darby Canine Kidney (MDCK) cells, leading to cell death. Here, we showed that epsilon-toxin requires neutral sphingomyelinase (nSMase) activity during oligomerization. METHODS: We tested the role of nSMase in the oligomerization of epsilon-toxin using specific inhibitors, knockdown of nSMase, formation of ceramide, and localization of epsilon-toxin and ceramide by immunofluorescence staining. RESULTS: Epsilon-toxin induced the production of ceramide is a dose- and time-dependent manner in ACHN cells. GW4869, an inhibitor of nSMase, inhibited ceramide production induced by the toxin. GW4869 and knockdown of nSMase blocked toxin-induced cell death and oligomer formation of epsilon-toxin. Confocal microscopy images showed that the toxin induced ceramide clustering and colocalized with ceramide. CONCLUSIONS: These results demonstrated that oligomer formation of epsilon-toxin is facilitated by the production of ceramide through activation of nSMase caused by the toxin. GENERAL SIGNIFICANCE: Inhibitors of nSMase may confer protection against infection. PMID- 27453201 TI - Beta thalassemia in 31,734 cases with HBB gene mutations: Pathogenic and structural analysis of the common mutations; Iran as the crossroads of the Middle East. AB - Thalassemia is one of the most common single gene disorders worldwide. Nearly 80 to 90 million with minor beta thalassemia and 60-70 thousand affected infants are born annually worldwide. A comprehensive search on several databases including PubMed, InterScience, British Library Direct, and Science Direct was performed extracting papers about mutation detection and frequency of beta thalassemia. All papers reporting on the mutation frequency of beta thalassemia patients were selected to analyze the frequency of mutations in different regions and various ethnicities. Mutations of 31,734 individuals were identified. Twenty common mutations were selected for further analysis. Genotype-phenotype correlation, interactome, and in silico analyses of the mutations were performed using available bioinformatics tools. Secondary structure prediction was achieved for two common mutations with online tools. The mutations were also common among the countries neighboring Iran, which are responsible for 71% to 98% of mutations. Computational analyses could be used in addition to segregation and expression analysis to assess the extent of pathogenicity of the variant. The genetics of beta thalassemia in Iran is more extensively heterogeneous than in neighboring countries. Some common mutations have arisen historically from Iran and moved to other populations due to population migrations. Also, due to genetic drift, the frequencies of some mutations have increased in small populations. PMID- 27453202 TI - Neuropsychological rehabilitation of childhood brain injury: a practical guide. PMID- 27453198 TI - Screening for transmembrane association in divisome proteins using TOXGREEN, a high-throughput variant of the TOXCAT assay. AB - TOXCAT is a widely used genetic assay to study interactions of transmembrane helices within the inner membrane of the bacterium Escherichia coli. TOXCAT is based on a fusion construct that links a transmembrane domain of interest with a cytoplasmic DNA-binding domain from the Vibrio cholerae ToxR protein. Interaction driven by the transmembrane domain results in dimerization of the ToxR domain, which, in turn, activates the expression of the reporter gene chloramphenicol acetyl transferase (CAT). Quantification of CAT is used as a measure of the ability of the transmembrane domain to self-associate. Because the quantification of CAT is relatively laborious, we developed a high-throughput variant of the assay, TOXGREEN, based on the expression of super-folded GFP and detection of fluorescence directly in unprocessed cell cultures. Careful side-by-side comparison of TOXCAT and TOXGREEN demonstrates that the methods have comparable response, dynamic range, sensitivity and intrinsic variability both in LB and minimal media. The greatly enhanced workflow makes TOXGREEN much more scalable and ideal for screening, since hundreds of constructs can be rapidly assessed in 96 well plates. Even for small scale investigations, TOXGREEN significantly reduces time, labor and cost associated with the procedure. We demonstrate applicability with a large screening for self-association among the transmembrane domains of bitopic proteins of the divisome (FtsL, FtsB, FtsQ, FtsI, FtsN, ZipA and EzrA) belonging to 11 bacterial species. The analysis confirms a previously reported tendency for FtsB to self-associate, and suggests that the transmembrane domains of ZipA, EzrA and FtsN may also possibly oligomerize. PMID- 27453203 TI - BMIT facility at the Canadian Light Source: Advances in X-ray phase-sensitive imaging. AB - The BioMedical Imaging and Therapy (BMIT) facility [1,2] located at the Canadian Light Source, provides synchrotron-specific imaging and radiation therapy capabilities. There are two separate beamlines used for experiments: the bending magnet (05B1-1) and the insertion device (05ID-2) beamline. The bending magnet beamline provides access to monochromatic beam spanning a spectral range of 15 40keV, and the beam is 240mm wide in the POE-2 experimental hutch. Users can also perform experiments with polychromatic (pink) beam. The insertion device beamline was officially opened for general user program in 2015. The source for the ID beamline is a multi-pole, superconducting 4.3T wiggler. The high field gives a critical energy over 20keV. The optics hutches prepare a beam that is 220mm wide in the last experimental hutch SOE-1. The monochromatic spectral range spans 25 150+keV. Several different X-ray detectors are available for both beamlines, with resolutions ranging from 2MUm to 200MUm. BMIT provides a number of imaging techniques including standard absorption X-ray imaging, K-edge subtraction imaging (KES), in-line phase contrast imaging (also known as propagation based imaging, PBI) and Diffraction Enhanced Imaging/Analyzer Based Imaging (DEI/ABI), all in either projection or CT mode. PBI and DEI/ABI are particularly important tools for BMIT users since these techniques enable visualization of soft tissue and allow for low dose imaging. PMID- 27453204 TI - Occupational radiation exposure in vascular interventional radiology: A complete evaluation of different body regions. AB - PURPOSE: To perform a complete evaluation on radiation doses, received by primary and assistant medical staff, while performing different vascular interventional radiology procedures. MATERIALS AND METHODS: We evaluated dose received in different body regions during three categories of vascular procedures: lower limb angiography (Angiography), lower limb percutaneous transluminal angioplasty (Angioplasty) and stent graft placement for abdominal aortic aneurysm treatment (A. A. A. Treatment). We positioned the dosimeters near the eye lens, thyroid, chest, abdomen, hands, and feet of the interventional physicians. Equivalent dose was compared with annual dose limits for workers in order to determine the maximum number of procedures per year that each physician could perform. We assessed 90 procedures. RESULTS: We found the highest equivalent doses in the A. A. A. Treatment, in which 90% of the evaluations indicated at least one region receiving more than 1mSv per procedure. Angioplasty was the only procedural modality that provided statistically different doses for different professionals, which is an important aspect on regards to radiological protection strategies. In comparison with the dose limits, the most critical region in all procedures was the eye lens. CONCLUSIONS: Since each body region of the interventionist is exposed to different radiation levels, dose distribution measurements are essential for radiological protection strategies. These results indicate that dosimeters placed in abdomen instead of chest may represent more accurately the whole body doses received by the medical staff. Additional dosimeters and a stationary shield for the eye lens are strongly recommended. PMID- 27453205 TI - Brain activation difference evoked by different binocular disparities of stereograms: An fMRI study. AB - The binocular disparity of two retina images is a main cue of stereoscopic vision. However, the global dependency between brain response and binocular disparity still remains unclear. Here, we used functional Magnetic Resonance Imaging (fMRI) to identify stereopsis-related brain regions with a modified Random Dot Stereogram (RDS) and plotted the activation variation curves under different disparity size. In order to eliminate the confounding shape difference between the stereogram and the plane, commonly seen in RDS, we modified the RDS to a checkerboard version. We found that V3A, V7 and MT+/V5 in dorsal visual stream were activated in stereoscopic experiment, while little activation was found in ventral visual regions. According to the activation trends, 13 subjects were divided into three groups: 5 subjects with turning points (a shift from increased to decreased activation), 5 subjects without turning points and 3 subjects with activation unrelated to disparity. We inferred that the dorsal visual stream primarily processes spatial depth information, rather than shape information. PMID- 27453206 TI - Effects of citalopram on jaw-closing muscle activity during sleep and wakefulness in mice. AB - In this study, we investigated the effects of chronic administration of the selective serotonin reuptake inhibitor (SSRI) citalopram on sleep/wake cycles and masseter (jaw-closing) muscle electromyogram (EMG) activity over a 24-h period. From the dark to the light period, the times of wakefulness decreased, while those of non-rapid eye movement (NREM) and REM sleep increased. Citalopram did not induce major alterations in the temporal changes of sleep-wake distributions, except for leading to a decrease in the time of NREM sleep during the light period and an increase in the durations of REM sleep episodes. Moreover, citalopram did not modify mean masseter EMG activity during any of the vigilance states and did not affect the temporal changes related to the shifts between dark/light periods. However, citalopram increased the time engaged in masseter EMG activation during NREM sleep in the second and the first halves of the dark and light periods, respectively. These results suggest that chronic citalopram treatment does not affect the temporal changes of sleep-wake distributions, but has a limited facilitatory influence that fails to increase the number of epochs of high levels of masseter muscle activation. PMID- 27453207 TI - Nanoporous two-dimensional MoS2 membranes for fast saline solution purification. AB - Finding a membrane with both high permeability and high salt rejection is very important for saline solution purification. Here, we report the performance of molybdenum disulfide (MoS2) membranes with nanoscale pores for saline solution purification via all-atom molecular dynamics simulations. It was found that the nanoporous two-dimensional MoS2 membrane can impede salt ions, while allowing highly efficient permeation of water molecules. By engineering the appropriate sizes of the nanopores within two-dimensional MoS2 membranes, their water permeability can be tens of times as high as that of conventional reverse osmosis membranes, while still maintaining a high salt rejection rate. These remarkable water permeability and salt rejection properties of the nanoporous monolayer MoS2 membranes are attributed to the formation of single chain hydrogen bonds, which link the water molecules within the nanopores and those at the immediate exteriors of the nanopores, causing significant reduction in the resistance of water molecules passing through the nanopores, which are small enough for any salt ions to pass through. Therefore such nanoporous monolayer MoS2 membranes have great potential for saline solution purification. PMID- 27453208 TI - Factors influencing the quality of sunscreen application in a pilot comparative study. PMID- 27453209 TI - Perturbation of the Warburg effect increases the sensitivity of cancer cells to TRAIL-induced cell death. AB - Tumor necrosis-factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-superfamily that selectively induces apoptosis through death receptors (DRs) 4 and/ or DR5 in cancer cells, without affecting normal cells. Unfortunately, many clinical studies have shown that cancer cells acquire TRAIL resistance and thus avoid TRAIL-induced apoptosis. In the current study, we newly found that PTBP1, a splicer protein that plays an important role in energy metabolism is highly expressed in TRAIL-resistant human colon cancer DLD-1. Interestingly, silencing PTBP1 by using siRNA for PTBP1 (siR-PTBP1) resulted in a significant increase in TRAIL-sensitivity along with the switching of pyruvate kinase muscle (PKM) isoforms from PKM2 to PKM1, leading to impaired Warburg effect, because the intracellular ATP levels were significantly increased and the production of lactate decreased. Notably, siR-PTBP1 canceled the resistance by increasing the expression level of DR5 and effectively inducing the translocation of DR5 to the cell surface membrane. Also, siR-PTBP1 up-regulated the expression level of CCN1, which contributed to the enhanced sensitivity to TRAIL-induced apoptosis. These findings indicate that silencing PTBP1, thus impairing the Warburg effect positively affected TRAIL-induced apoptosis and that this splicer protein may thus serve as a possible target molecule to cancel the resistance of cancer cells to TRAIL. PMID- 27453210 TI - Genetic Counselling for Psychiatric Disorders: Accounts of Psychiatric Health Professionals in the United Kingdom. AB - Genetic counselling is not routinely offered for psychiatric disorders in the United Kingdom through NHS regional clinical genetics departments. However, recent genomic advances, confirming a genetic contribution to mental illness, are anticipated to increase demand for psychiatric genetic counselling. This is the first study of its kind to employ qualitative methods of research to explore accounts of psychiatric health professionals regarding the prospects for genetic counselling services within clinical psychiatry in the UK. Data were collected from 32 questionnaire participants, and 9 subsequent interviewees. Data analysis revealed that although participants had not encountered patients explicitly demanding psychiatric genetic counselling, psychiatric health professionals believe that such a service would be useful and desirable. Genomic advances may have significant implications for genetic counselling in clinical psychiatry even if these discoveries do not lead to genetic testing. Psychiatric health professionals describe clinical genetics as a skilled profession capable of combining complex risk communication with much needed psychosocial support. However, participants noted barriers to the implementation of psychiatric genetic counselling services including, but not limited to, the complexities of uncertainty in psychiatric diagnoses, patient engagement and ethical concerns regarding limited capacity. PMID- 27453211 TI - Revisiting the neuronal localization and trafficking of CLN3 in juvenile neuronal ceroid lipofuscinosis. AB - Juvenile neuronal ceroid lipofuscinosis, the most common neurodegenerative disease affecting children, is caused by mutations of the CLN3 gene encoding CLN3, a transmembrane protein with so far undefined function. The embryonic expression of the gene has not been studied in detail before. Moreover, the protein CLN3 was mostly localized on the subcellular level to lysosomes but the exclusiveness is still under debate. Here, we analyze the expression pattern of murine CLN3 at different developmental stages by in situ hybridizations. We observe expression maxima in the developing thalamus and cerebral cortex and outside of the central nervous system in the gastrointestinal tract and other peripheral organs. In differentiated primary neurons, the protein CLN3 shows mainly a somatodendritic localization. In primary neurons, we thoroughly revisit the subcellular localization of CLN3 and find a predominant localization in late endosomal-lysosomal compartments. Moreover, we expressed the major mutant form of CLN3 - CLN3deltaExon7/8 - in neurons and demonstrate that it is retained in the endoplasmatic reticulum. Time-lapse microscopy analysis of neurons revealed co trafficking of CLN3 with the late endosomal marker Rab7, but not with the early endosomal marker Rab5. Furthermore, a constitutive active mutant of Rab7 traps CLN3 in enlarged endosomes. Our subcellular localization study in neurons refines the localization and subcellular targeting of CLN3 to late endosomal-lysosomal compartments and provides information on the velocity of CLN3 in living neurons which has not been investigated before. PMID- 27453212 TI - Can the inferior alveolar nerve be used as a marker in frozen section for free margin control after segmental mandibulectomy in tumour ablation? AB - This study critically assessed the possibility of tumour spread along the inferior alveolar nerve (IAN) and its sensitivity as an intraoperative marker for clear bony margin control in frozen section during segmental mandibulectomy. Fifteen patients with oral squamous cell carcinoma (OSCC) involving the mandible and requiring a segmental mandibulectomy were included in this prospective trial. The ends of the IAN were analyzed using quick section analysis and the results compared with those of the definite pathological report. Nerve tissue could be identified in 25 of the 27 specimens collected. No specimen revealed tumour invasion. All histological diagnoses were finally confirmed. Three positive bony margins with microscopic carcinoma infiltrates were found, whereas corresponding nerve tissue did not confirm tumour invasion. This study supports the assumption that the pattern of tumour invasion is rarely primarily along the IAN in OSCC involving the mandible. Quick section analysis of the nerve tissue alone is therefore not a valid marker for intraoperative bony margin control. However, it can be used as an additional intraoperative diagnostic tool combined with other methods in rare cases of primary tumour spread along the IAN. A review of current knowledge regarding bony margin control published in the literature is provided. PMID- 27453213 TI - Aurantimonas endophytica sp. nov., a novel endophytic bacterium isolated from roots of Anabasis elatior (C. A. Mey.) Schischk. AB - An orange-coloured, aerobic, motile, short-rod-shaped bacterial strain, designated EGI 6500337T, was isolated from the surface-sterilized root of a halophyte, Anabasis elatior (C. A. Mey.) Schischk, collected from Urumqi, Xinjiang province, north-west China. Growth occurred at 5-35 degrees C (optimum 30 degrees C), at pH 6.0-9.0 (optimum pH 7.0) and in the presence of 0-6 % (w/v) NaCl (optimum 0-1 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain EGI 6500337T formed a distinct lineage in the cluster that comprised the genera Aurantimonas and Aureimonas in the family Aurantimonadaceae. The 16S rRNA gene sequence of strain EGI 6500337T shared highest similarity with those of Aurantimonas coralicida DSM 14790T (97.15 %) and Aurantimonas manganoxydans DSM 21871T (97.15 %). Strain EGI 6500337T contained Q-10 as the dominant isoprenoid quinone. The major cellular fatty acids were C18 : 1omega7c and C19 : 0omega8c cyclo. The polar lipid profile of strain EGI 6500337T contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine and phosphatidylethanolamine as major components, similarly to members of the genus Aurantimonas. The DNA G+C content of strain EGI 6500337T was 66.8 mol%. The level of DNA-DNA relatedness between strain EGI 6500337T and Aurantimonas coralicida DSM 14790T was 24.7+/-2.9 %. On the basis of the phylogenetic analysis, chemotaxonomic data and phenotypic characteristics, strain EGI 6500337T represents a novel species of the genus Aurantimonas, for which the name Aurantimonas endophytica sp. nov. is proposed. The type strain is EGI 6500337T (=KCTC 52296T=CPCC 100904T). PMID- 27453214 TI - Minimum length of the adaptation and collection period in digestibility trials with sheep fed ad libitum only forage or forage plus concentrate. AB - Two in vivo digestibility trials with sheep were conducted to identify the minimum period length of feeding a new diet to obtain reproducible values of nutritional variables onward and the minimum length of collection period as to obtain maximal precision for each variable. Trial 1 was conducted with ten Polwarth male sheep (34 +/- 5 kg body weight (BW)) throughout three 21-day periods, in a completely randomized two-way crossover design. The animals were divided into two groups (Group A and B, n = 5 per group) which were fed ad libitum with a sequence of the following diets throughout the periods: Group A: hay - hay plus concentrate - hay; Group B: hay plus concentrate - hay - hay plus concentrate. The concentrate was included in a proportion of 0.33 of the total diet. The intake, and the faecal and urinary excretion were measured daily throughout the experiment. For evaluating rumen fermentation variables, in Trial 2 four Santa Ines male sheep (65 +/- 5 kg BW) fitted with ruminal cannula were used. The animals were randomly divided into two groups (n = 2 per group), and the trial was conducted through four 21 days experimental period, in a three-way crossover design, using experimental diets and feeding management similar to Trial 1. The results indicated that, even though no clear or consistent steady state condition was identified for rumen fermentation or urinary excretion variables, the adaptation period for measuring OM digestibility in in vivo trials with sheep fed ad libitum where the diet shifts from one of only hay to another containing concentrate, or vice-versa, should be at least 12 days long. Moreover, although no precision improvement was obtained by increasing the collection period above 1 day for measuring OM digestibility, the minimal length of collection period should be 4 days for measuring faecal excretion variables and 7 days for measuring urinary excretion variables. PMID- 27453215 TI - Formyl-Modified Polyaniline for the Catalytic Dehydration of Fructose to 5 Hydroxymethylfurfural. AB - We report an unprecedented solid organic-base catalyst, formyl-modified polyaniline (FS-PAN), for the dehydration of fructose to 5-hydroxymethylfurfural (HMF) with a high yield of 90.4 mol %. We demonstrate that the nitrogen atoms incorporated between the phenyl rings in the backbone of the polyaniline chain contribute to the basicity of the catalyst. The grafting of electron-withdrawing formyl groups to the imine nitrogen atoms leads to a significant increase of basicity of the polymer catalyst owing to the greater localization of electrons at the amide nitrogen atom formed. A linear dependence of the yield of HMF on the grafting level of formyl groups in FS-PAN indicates that the amide acts as the active phase. A possible reaction mechanism for this organic-base-catalyzed dehydration reaction is proposed. The side-reaction of HMF rehydration is inhibited thoroughly, and the condensation of any reaction intermediates to undesirable oligomers is restrained by this base catalyst. This organic-base catalyst can be recycled completely without loss of activity. This research highlights the first application of a highly effective and stable solid base catalyst for the transformation of renewable carbohydrates into fine chemicals. PMID- 27453216 TI - Assessment of Urologists' Knowledge of Intraoperative Floppy Iris Syndrome. AB - OBJECTIVES: To assess urologists' awareness of intraoperative floppy iris syndrome. MATERIALS AND METHODS: A questionnaire composed of 21 questions was emailed to all of the Urology residency programs in the U.S. and all members of the Western section of the American Urological Association. Responses were collected and analyzed using statistical software. RESULTS: A total of 175 responses were collected from residents, fellows, and attending physicians from a wide range of geographic locations, subspecialties, and practice settings. Thirty percent of the urologists would routinely discuss intraoperative floppy iris syndrome with patients prior to start of benign prostate hyperplasia treatment. Twenty-one percent of the respondents never asked patients about ophthalmologic conditions prior to benign prostate hyperplasia treatment. If patients had concurrent visual complaints, only 37% of the respondents would routinely encourage patients to speak to an ophthalmologist and only 13% would routinely refer patients to an ophthalmologist. A comparison among the subgroups based on training status and practice settings further showed that a significantly higher percentage of residents would not ask about visual complaints or refer patients with visual complaints to an ophthalmologist compared with fellows and attending physicians (P <.01); however, there was no significant difference between urologists in academic and nonacademic settings (P >.05). CONCLUSION: Despite continuing effort to educate physicians about intraoperative floppy iris syndrome, there still exists a knowledge gap that may compromise patient care and further education is needed. PMID- 27453217 TI - Concordance of Pathologic Features Between Metastatic Sites and the Primary Tumor in Surgically Resected Metastatic Renal Cell Carcinoma. AB - OBJECTIVE: To evaluate the concordance of pathologic features in metastatic renal cell carcinoma (RCC) between the primary nephrectomy and metastasectomy specimens. METHODS: Primary nephrectomy (n = 454) and matched metastasectomy specimens (n = 680) from patients treated between 1970 and 2009 for RCC were re reviewed by 1 urologic pathologist in a blinded fashion. RCC histologic subtype, grade, coagulative necrosis, and the presence of sarcomatoid differentiation were compared between the primary and the metastatic tumor with kappa statistics. RESULTS: Concordance with the primary tumor was observed for subtype in 647 (95%, kappa = 0.71) of the metastases, for grade in 411 (60%, kappa = 0.35), necrosis in 460 (68%, kappa = 0.32), and sarcomatoid differentiation in 643 (95%, kappa = 0.60). Upgrading was observed in 100%, 63%, and 13% of patients with grades 1, 2, and 3 primary tumors, respectively (no patient had a grade 1 metastatic lesion). Metastatic tumors treated with metastasectomy within 30 days of nephrectomy (n = 145) had similar rates of concordant subtype, necrosis, and sarcomatoid differentiation to those undergoing metastasectomy beyond 30 days from nephrectomy (P >.05 for all), but had higher rates of concordant grade (71% vs 58%, P = .003). Pre-metastasectomy exposure to systemic targeted or immunotherapy was not associated with a change in concordance of histopathologic features. CONCLUSION: Among 454 surgically managed metastatic RCC patients, we observed a high degree of concordance for histologic subtype and sarcomatoid differentiation, and varying degrees of discordance for grade and coagulative tumor necrosis, between primary and metastatic tumors. Further investigation is warranted to understand the biologic and therapeutic implications of these observations. PMID- 27453218 TI - Mantle cell lymphoma involving the breast in a male patient. PMID- 27453219 TI - Clinical Outcomes among Transferred Children with Ischemic and Hemorrhagic Strokes in the Nationwide Inpatient Sample. AB - INTRODUCTION: Children with ischemic stroke (IS) and hemorrhagic stroke (HS) may require interfacility transfer for higher level of care. We compared the characteristics and clinical outcomes of transferred and nontransferred children with IS and HS. METHODS: Children aged 1-18 years admitted to hospitals in the United States from 2008 to 2011 with a primary discharge diagnosis of IS and HS were identified from the National Inpatient Sample database by ICD-9 codes. Using logistic regression, we estimated the odds ratios (OR) and 95% confidence intervals (CI) for in-hospital mortality and discharge to nursing facilities (versus discharge home) between transferred and nontransferred patients. RESULTS: Of the 2815 children with IS, 26.7% were transferred. In-hospital mortality and discharge to nursing facilities were not different between transferred and nontransferred children in univariable analysis or in multivariable analysis that adjusted for age, sex, and confounding factors. Of the 6879 children with HS, 27.1% were transferred. Transferred compared to nontransferred children had higher rates of both in-hospital mortality (8% versus 4%, P = .003) and discharge to nursing facilities (25% versus 20%, P = .03). After adjusting for age, sex, and confounding factors, in-hospital mortality (OR 1.5, 95% CI 1.1-2.4, P = .04) remained higher in transferred children, whereas discharge to nursing facilities was not different between the groups. CONCLUSION: HS but not IS was associated with worse outcomes for children transferred to another hospital compared to children who were not transferred. Additional study is needed to understand what factors may contribute to poorer outcomes among transferred children with HS. PMID- 27453220 TI - Isolation of Bartonella henselae, Bartonella koehlerae subsp. koehlerae, Bartonella koehlerae subsp. bothieri and a new subspecies of B. koehlerae from free-ranging lions (Panthera leo) from South Africa, cheetahs (Acinonyx jubatus) from Namibia and captive cheetahs from California. AB - Bartonellae are blood- and vector-borne Gram-negative bacteria, recognized as emerging pathogens. Whole-blood samples were collected from 58 free-ranging lions (Panthera leo) in South Africa and 17 cheetahs (Acinonyx jubatus) from Namibia. Blood samples were also collected from 11 cheetahs (more than once for some of them) at the San Diego Wildlife Safari Park. Bacteria were isolated from the blood of three (5%) lions, one (6%) Namibian cheetah and eight (73%) cheetahs from California. The lion Bartonella isolates were identified as B. henselae (two isolates) and B. koehlerae subsp. koehlerae. The Namibian cheetah strain was close but distinct from isolates from North American wild felids and clustered between B. henselae and B. koehlerae. It should be considered as a new subspecies of B. koehlerae. All the Californian semi-captive cheetah isolates were different from B. henselae or B. koehlerae subsp. koehlerae and from the Namibian cheetah isolate. They were also distinct from the strains isolated from Californian mountain lions (Felis concolor) and clustered with strains of B. koehlerae subsp. bothieri isolated from free-ranging bobcats (Lynx rufus) in California. Therefore, it is likely that these captive cheetahs became infected by an indigenous strain for which bobcats are the natural reservoir. PMID- 27453221 TI - How Does Patient Radiation Exposure Compare With Low-dose O-arm Versus Fluoroscopy for Pedicle Screw Placement in Idiopathic Scoliosis? AB - BACKGROUND: Intraoperative C-arm fluoroscopy and low-dose O-arm are both reasonable means to assist in screw placement for idiopathic scoliosis surgery. Both using pediatric low-dose O-arm settings and minimizing the number of radiographs during C-arm fluoroscopy guidance decrease patient radiation exposure and its deleterious biological effect that may be associated with cancer risk. We hypothesized that the radiation dose for C-arm-guided fluoroscopy is no less than low-dose O-arm scanning for placement of pedicle screws. METHODS: A multicenter matched-control cohort study of 28 patients in total was conducted. Fourteen patients who underwent O-arm-guided pedicle screw insertion for spinal fusion surgery in 1 institution were matched to another 14 patients who underwent C-arm fluoroscopy guidance in the other institution in terms of the age of surgery, body weight, and number of imaged spine levels. The total effective dose was compared. A low-dose pediatric protocol was used for all O-arm scans with an effective dose of 0.65 mSv per scan. The effective dose of C-arm fluoroscopy was determined using anthropomorphic phantoms that represented the thoracic and lumbar spine in anteroposterior and lateral views, respectively. The clinical outcome and complications of all patients were documented. RESULTS: The mean total effective dose for the O-arm group was approximately 4 times higher than that of the C-arm group (P<0.0001). The effective dose for the C-arm patients had high variability based on fluoroscopy time and did not correlate with the number of imaged spine levels or body weight. The effective dose of 1 low-dose pediatric O-arm scan approximated 85 seconds of the C-arm fluoroscopy time. All patients had satisfactory clinical outcomes without major complications that required returning to the operating room. CONCLUSIONS: Radiation exposure required for O arm scans can be higher than that required for C-arm fluoroscopy, but it depends on fluoroscopy time. Inclusion of more medical centers and surgeons will better account for the variability of C-arm dose due to distinct patient characteristics, surgeon's preference, and individual institution's protocol. LEVEL OF EVIDENCE: Level III-case-control study. PMID- 27453222 TI - Distribution and Risk Factors of Disability Attributed to Personality Disorders: A National Cross-sectional Survey in China. AB - BACKGROUND: Personality disorders can lead to some disability. However, little is known about the disability prevalence and function impairments. This study aimed to describe the disability prevalence attributed to personality disorders, its distribution, impairments of daily activities and social functions, and risk factors in China. METHODS: Using a descriptive and analytic epidemiological method, data from the Second China National Sample Survey on Disability in 2006 were analyzed. The disability prevalence attributed to personality disorders, its distribution in different people and regions, and risk factors were statistically calculated. RESULTS: Respondents included 1,909,205 adults. The disability prevalence rate attributed to personality disorders in China was 5.9/100,000. The disability rate attributed to personality disorders of males was higher than that of females (P = 0.012), while the rate of the unemployed was higher than that of the employed (P < 0.001). Furthermore, the rates of unmarried/divorced/widowed people and the illiterate population were higher than those of married and educated people (P < 0.001). Regarding the severity of disability attributable to personality disorders, mild disability accounted for a majority or 60% of the respondents. The data showed that disability mainly impaired respondents' ability to engage in daily activities, get along with people, and participate in social situations. According to the case-control study, marriage, employment, and higher education were protective factors of disability. CONCLUSIONS: The prevalence of disability attributed to personality disorders is low in China and always leads to mild disability. The distribution of disability attributed to personality disorders also varies in the Chinese population. PMID- 27453223 TI - Routine Hemostasis and Hemogram Parameters: Valuable Assessments for Coagulation Disorder and Chemotherapy in Cancer Patients. AB - BACKGROUND: The clotting system abnormalities are the common complication in cancer patients. The aim of this retrospective study was to evaluate the coagulation state, clinical features, and treatment in cancer patients by routine tests. METHODS: A total of 2328 patients with different types of cancer were classified as the positive group (n = 1419, including 53 patients with thrombosis) and the negative group (n = 909) based on D-dimer (DD) value. Of the 2328 cases, 354 were admitted for chemotherapy. Hemostasis test and complete blood count (CBC) were performed during treatment or following-up. RESULTS: This study showed that the hypercoagulable state was affected not only by clinical staging (P < 0.0001) but also by metastasis site (P < 0.0001 for bone vs. lung). Compared to negative DD group, the higher fibrinogen level, the extended activated partial thromboplastin time, and prothrombin time interacted markedly with disease clinical stage (P < 0.05) in the positive group. Between positive DD groups with and without thrombus, the significantly statistic difference in white blood cell (WBC) and DD (P < 0.05) rather than in red blood cell (RBC) and platelet count was observed. However, the higher DD level was not correlated with WBC, RBC, and platelet count in the positive DD group. Furthermore, the hypercoagulable plasma profile in cancer patients was moderated 2-3 weeks after chemotherapy (P < 0.05 for first six cycles). CONCLUSIONS: The routine hemostatic parameters and CBC are valuable to assessment for thrombosis and chemotherapy even for disease prognosis. PMID- 27453224 TI - Clinical Manifestation of Calreticulin Gene Mutations in Essential Thrombocythemia without Janus Kinase 2 and MPL Mutations: A Chinese Cohort Clinical Study. AB - BACKGROUND: Recently, calreticulin (CALR) gene mutations have been identified in patients with essential thrombocythemia (ET). A high-frequency of ET cases without Janus kinase 2 (JAK2) mutations contain CALR mutations and exhibit clinical characteristics different from those with mutant JAK2. Thus, we investigated the frequency and clinical features of Chinese patients of Han ethnicity with CALR mutations in ET. METHODS: We recruited 310 Chinese patients of Han ethnicity with ET to analyze states of CALR, JAK2V617F, and MPLW515 mutations by polymerase chain reaction and direct sequencing. We analyzed the relationship between the mutations and clinical features. RESULTS: CALR, JAK2V617F, and MPLW515 mutations were detected in 30% (n = 92), 48% (n = 149), and 1% (n = 4) of patients with ET, respectively. The mutation types of CALR involved deletion and insertion of base pairs. Most of them were Type 1 (52-bp deletion) and Type 2 (5-bp insertion, TTGTC) mutations, leading to del367fs46 and ins385fs47, respectively. The three mutations were exclusive. Clinically, patients with mutated CALR had a lower hemoglobin level, lower white blood cell (WBC) count, and higher platelet count compared to those with mutated JAK2 (P < 0.05). Furthermore, a significant difference was found in WBCs between wild-type patients (triple negative for JAK2, MPL, and CALR mutations) and patients with JAK2 mutations. Patients with CALR mutations predominantly clustered into low or intermediate groups according to the International Prognostic Score of thrombosis for ET (P < 0.05). CONCLUSIONS: CALR mutations were frequent in Chinese patients with ET, especially in those without JAK2 or MPL mutations. Compared with JAK2 mutant ET, CALR mutant ET showed a different clinical manifestation and an unfavorable prognosis. Thus, CALR is a potentially valuable diagnostic marker and therapeutic target in ET. PMID- 27453225 TI - Evaluation of Diagnostic Efficiency of Ultrasound Features on Malignant Thyroid Nodules in Chinese Patients. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of ultrasonic features in predicting the malignancy of thyroid nodules in a group of Chinese patients. METHODS: In all, 762 patients with thyroid nodules (424 malignant and 338 benign) underwent ultrasound (US) check and surgery between March 2011 and July 2014 at Peking University First Hospital were identified. Univariate and receiver operating characteristic (ROC) analyses were performed to calculate the sensitivity, specificity, negative and positive predictive values of each US feature, and the accuracy of their combinations for prediction of malignancy. RESULTS: Patients with malignant nodules were younger and without obvious risk history than those in the benign group (P < 0.001, P = 0.93). No individual US sign was fully predictive of a malignant lesion. The Youden indexes of irregular margins and hypoechogenicity were the first and second highest in all US features, which were 51.9% and 45.2%, respectively. The sensitivity of solid components (89.7%) and hypoechogenicity (89.2%) and the specificity of taller than-wide shape (98.5%) and microcalcifications (90.6%) were the first and second highest in all US features. Intranodular flow on a color Doppler examination was a weak predictor of malignancy. Under ROC analysis excepting intranodular flow, the 95% confidence interval (CI) of areas under the curves of hypoechogenicity and irregular margins with any one of the US features were overlapped that of five-feature combinations (95% CI: 0.850-0.901). CONCLUSIONS: We should be alert with taller-than-wide shape and microcalcifications. Intranodular flow was a weak predictor of malignancy. According to Youden indexes and ROC analysis, irregular margins and hypoechogenicity combined with solid component or taller-than-wide shapes or microcalcifications have a high predicative value for malignant thyroid nodules in Chinese patients. PMID- 27453226 TI - Needle Sensation and Personality Factors Influence Therapeutic Effect of Acupuncture for Treating Bell's Palsy: A Secondary Analysis of a Multicenter Randomized Controlled Trial. AB - BACKGROUND: It has not been solved what kind of needle sensation might influence outcomes of acupuncture treatment. Effects of personality factors on the therapeutic effect of acupuncture have not been investigated. This study aimed to find the effects of the traits of personality on the objective outcome when different acupuncture techniques were used in treating patients with Bell's palsy. METHODS: We performed a secondary analysis of a prospective multicenter randomized controlled trial of acupuncture for Bell's palsy. Patients were randomly assigned to the de qi and control groups, respectively. The primary outcome was facial nerve function at month 6. The intensity of each needle sensation was rated by a visual analog scale. Psychosocial factors were assessed by the pretreatment mediator questionnaire; 16 Personality Factor Questionnaire (16PF) was used for assessing personality factors and digit cancellation test for assessing attention. RESULTS: After 6 months, patients in the de qi group had better facial function (adjusted odds ratio [OR]: 4.16, 95% confidence interval [CI]: 2.23-7.78). Path analysis showed that intensity of needle sensation of fullness had direct effect on House-Brackmann (HB) score at month 6. In de qi group, the low HB score on day 1 (OR: 0.13, 95% CI: 0.03-0.45) and the low Social Boldness score (OR: 0.63, 95% CI: 0.41-0.97) in 16PF were associated with better facial function. In control group, low HB score on day 1 (OR: 0.25, 95% CI: 0.13 0.50), low Vigilance score (OR: 0.66, 95% CI: 0.50-0.88), and high Tension score (OR: 1.41, 95% CI: 1.12-1.77) in 16PF were related to better facial function. CONCLUSIONS: The needle sensation of fullness could predict better facial function and personality traits might influence outcomes of acupuncture treatment. Both of them should be considered seriously in acupuncture treatment and research. PMID- 27453227 TI - Risk Factors for Mesh Exposure after Transvaginal Mesh Surgery. AB - BACKGROUND: Mesh exposure after surgery continues to be a clinical challenge for urogynecological surgeons. The purpose of this study was to explore the risk factors for polypropylene (PP) mesh exposure after transvaginal mesh (TVM) surgery. METHODS: This study included 195 patients with advanced pelvic organ prolapse (POP), who underwent TVM from January 2004 to December 2012 at the First Affiliated Hospital of Chinese PLA General Hospital. Clinical data were evaluated including patient's demography, TVM type, concomitant procedures, operation time, blood loss, postoperative morbidity, and mesh exposure. Mesh exposure was identified through postoperative vaginal examination. Statistical analysis was performed to identify risk factors for mesh exposure. RESULTS: Two-hundred and nine transvaginal PP meshes were placed, including 194 in the anterior wall and 15 in the posterior wall. Concomitant tension-free vaginal tape was performed in 61 cases. The mean follow-up time was 35.1 +/- 23.6 months. PP mesh exposure was identified in 32 cases (16.4%), with 31 in the anterior wall and 1 in the posterior wall. Significant difference was found in operating time and concomitant procedures between exposed and nonexposed groups (F = 7.443, P = 0.007; F = 4.307, P = 0.039, respectively). Binary logistic regression revealed that the number of concomitant procedures and operation time were risk factors for mesh exposure (P = 0.001, P = 0.043). CONCLUSION: Concomitant procedures and increased operating time increase the risk for postoperative mesh exposure in patients undergoing TVM surgery for POP. PMID- 27453228 TI - Prostate-specific Antigen Density Variation Rate as a Potential Guideline Parameter for Second Prostate Cancer Detection Biopsy. AB - BACKGROUND: The diagnostic value of current prostate-specific antigen (PSA) tests is challenged by the poor detection rate of prostate cancer (PCa) in repeat prostate biopsy. In this study, we proposed a novel PSA-related parameter named PSA density variation rate (PSADVR) and designed a clinical trial to evaluate its potential diagnostic value for detecting PCa on a second prostate biopsy. METHODS: Data from 184 males who underwent second ultrasound-guided prostate biopsy 6 months after the first biopsy were included in the study. The subjects were divided into PCa and non-PCa groups according to the second biopsy pathological results. Prostate volume, PSA density (PSAD), free-total PSA ratio, and PSADVR were calculated according to corresponding formulas at the second biopsy. These parameters were compared using t-test or Mann-Whitney U-test between PCa and non-PCa groups, and receiver operating characteristic analysis were used to evaluate their predictability on PCa detection. RESULTS: PCa was detected in 24 patients on the second biopsy. Mean values of PSA, PSAD, and PSADVR were greater in the PCa group than in the non-PCa group (8.39 MUg/L vs. 7.16 MUg/L, 0.20 vs. 0.16, 14.15% vs. -1.36%, respectively). PSADVR had the largest area under the curve, with 0.667 sensitivity and 0.824 specificity when the cutoff was 10%. The PCa detection rate was significantly greater in subjects with PSADVR >10% than PSADVR <=10% (28.6% vs. 6.5%, P< 0.001). In addition, PSADVR was the only parameter in this study that showed a significant correlation with mid-to-high-risk PCa (r = 0.63, P = 0.03). CONCLUSIONS: Our results demonstrated that PSADVR improved the PCa detection rate on second biopsies, especially for mid-to-high-risk cancers requiring prompt treatment. PMID- 27453229 TI - Oculopharyngeal Weakness, Hypophrenia, Deafness, and Impaired Vision: A Novel Autosomal Dominant Myopathy with Rimmed Vacuoles. AB - BACKGROUND: Myopathies with rimmed vacuoles are a heterogeneous group of muscle disorders with progressive muscle weakness and varied clinical manifestations but similar features in muscle biopsies. Here, we describe a novel autosomal dominant myopathy with rimmed vacuoles in a large family with 11 patients of three generations affected. METHODS: A clinical study including family history, obstetric, pediatric, and development history was recorded. Clinical examinations including physical examination, electromyography (EMG), serum creatine kinase (CK), bone X-rays, and brain magnetic resonance imaging (MRI) were performed in this family. Open muscle biopsies were performed on the proband and his mother. To find the causative gene, the whole-exome sequencing was carried out. RESULTS: Disease onset was from adolescence to adulthood, but the affected patients of the third generation presented an earlier onset and more severe clinical manifestations than the older generations. Clinical features were characterized as dysarthria, dysphagia, external ophthalmoplegia, limb weakness, hypophrenia, deafness, and impaired vision. However, not every patient manifested all symptoms. Serum CK was mildly elevated and EMG indicated a myopathic pattern. Brain MRI showed cerebellum and brain stem mildly atrophy. Rimmed vacuoles and inclusion bodies were observed in muscle biopsy. The whole-exome sequencing was performed, but the causative gene has not been found. CONCLUSIONS: We reported a novel autosomal dominant myopathy with rimmed vacuoles characterized by dysarthria, dysphagia, external ophthalmoplegia, limb weakness, hypophrenia, deafness, and impaired vision, but the causative gene has not been found and needs further study. PMID- 27453230 TI - "Target" and "Sandwich" Signs in Thigh Muscles have High Diagnostic Values for Collagen VI-related Myopathies. AB - BACKGROUND: Collagen VI-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). Muscle magnetic resonance imaging (MRI) has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies. METHODS: Eleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders (disease controls). T1-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuri's scale. We assessed the sensitivity and specificity of the MRI features of collagen VI-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated. RESULTS: Eleven patients with collagen VI gene mutation-related myopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius (P = 0.033); therefore, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A "target" sign in rectus femoris (RF) was present in seven cases, and a "sandwich" sign in vastus lateralis (VL) was present in ten cases. The "target" and "sandwich" signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96.9% for the diagnosis of collagen VI-related myopathies, respectively. Fatty infiltration scores were 2.0-3.0 in seven patients with mutations in the triple-helical domain, and 1.0-1.5 in three of four patients with mutations in the N- or C-domain of the collagen VI genes. CONCLUSIONS: The "target" sign in RF and "sandwich" sign in VL are common MRI features and are useful for the diagnosis of collagen VI-related myopathies. The severity of fatty infiltration of muscles may have a relationship with the mutation location of collagen VI gene. PMID- 27453231 TI - A Novel Tectonic Keratoplasty with Femtosecond Laser Intrastromal Lenticule for Corneal Ulcer and Perforation. AB - BACKGROUND: Small incision refractive lenticule extraction (SMILE) is an effective laser procedure that treats myopia. This research was to describe a novel approach to treat corneal ulcer or perforation using the corneal lenticules obtained from SMILE and to evaluate the safety and effectiveness of tectonic keratoplasty with femtosecond laser intrastromal lenticule (TEKIL). METHODS: A total of twenty patients (22 eyes) were monitored for at least 6 months and were assessed using slit lamp microscopy, optical coherence tomography, and best corrected visual acuity (BCVA). Postoperative complications throughout the study period were recorded. RESULTS: Corneal ulcer in 14 patients (16 eyes) and corneal perforation in six patients (6 eyes) were treated with TEKIL. The patients were ten females and ten males, with a mean age of 58.5 +/- 16.3 years (range: 16-81 years). In this study, the most causes of corneal ulcer or perforation were immunologic causes (54.5%). After TEKIL procedure, global integrity was achieved in all cases. No immune rejection or perforation was detected. The mean BCVA improved from 0.17 +/- 0.20 preoperatively to 0.27 +/- 0.25 postoperatively at the final follow-up (t = 2.095, P = 0.052). The postoperative BCVA improved in 12 eyes (54.5%) and maintained in nine eyes (40.9%). Vision function successfully maintained in all eyes (100%). In three cases, corneal ulcers were treated by reoperation of TEKIL at 3 months after the initial surgery for the reason that the residual corneal thickness was <250 MUm. CONCLUSIONS: TEKIL seems to be an effective treatment for corneal ulcer and perforation in the condition of emergency and donor shortage. PMID- 27453232 TI - Ability of Mn(2+) to Permeate the Eye and Availability of Manganese-enhanced Magnetic Resonance Imaging for Visual Pathway Imaging via Topical Administration. AB - BACKGROUND: Manganese-enhanced magnetic resonance imaging (MEMRI) for visual pathway imaging via topical administration requires further research. This study investigated the permeability of the corneal epithelium and corneal toxicity after topical administration of Mn2+ to understand the applicability of MEMRI. METHODS: Forty New Zealand rabbits were divided into 0.05 mol/L, 0.10 mol/L, and 0.20 mol/L groups as well as a control group (n = 10 in each group). Each group was further subdivided into epithelium-removed and epithelium-intact subgroups (n = 5 in each subgroup). Rabbits were given 8 drops of MnCl2in 5 min intervals. The Mn2+ concentrations in the aqueous and vitreous humors were analyzed using inductively coupled plasma-mass spectrometry at different time points. MEMRI scanning was carried out to image the visual pathway after 24 h. The corneal toxicity of Mn2+ was evaluated with corneal imaging and pathology slices. RESULTS: Between the aqueous and vitreous humors, there was a 10 h lag for the peak Mn2+ concentration times. The intraocular Mn2+ concentration increased with the concentration gradients of Mn2+ and was higher in the epithelium-removed subgroup than that in the epithelium-intact subgroup. The enhancement of the visual pathway was achieved in the 0.10 mol/L and 0.20 mol/L epithelium-removed subgroups. The corresponding peak concentrations of Mn2+ were 5087 +/- 666 ng/ml, 22920 +/- 1188 ng/ml in the aqueous humor and 884 +/- 78 ng/ml, 2556 +/- 492 ng/ml in the vitreous body, respectively. Corneal injury was evident in the epithelium-removed and 0.20 mol/L epithelium-intact subgroups. CONCLUSIONS: The corneal epithelium is a barrier to Mn2+, and the iris and lens septum might be another intraocular barrier to the permeation of Mn2+. An elevated Mn2+ concentration contributes to the increased permeation of Mn2+, higher MEMRI signal, and corneal toxicity. The enhancement of the visual pathway requires an effective Mn2+ concentration in the vitreous body. PMID- 27453233 TI - Identifying a Safe Range of Stimulation Current for Intraoperative Neuromonitoring of the Recurrent Laryngeal Nerve: Results from a Canine Model. AB - BACKGROUND: Intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) has been widely applied during thyroid surgery. However, the safe range of stimulation intensity for IONM remains undetermined. METHODS: Total thyroidectomies were performed on twenty dogs, and their RLNs were stimulated with a current of 5-20 mA (step-wise in 5 mA increments) for 1 min. The evoked electromyography (EMG) of vocal muscles before and after supramaximal stimulation were recorded and compared. Acute microstructural morphological changes in the RLNs were observed immediately postoperatively under an electron microscope. RESULTS: The average stimulating threshold for RLNs stimulated with 15 mA and 20 mA showed no significant changes compared to the unstimulated RLNs (15 mA group: 0.320 +/- 0.123 mA vs. 0.315 +/- 0.097 mA, P = 0.847; 20 mA group: 0.305 +/- 0.101 mA vs. 0.300 +/- 0.103 mA, P = 0.758). Similar outcomes were shown in average evoked EMG amplitude (15 mA group: 1,026 +/- 268 MUV vs. 1,021 +/- 273 MUV, P = 0.834; 20 mA group: 1,162 +/- 275 MUV vs. 1,200 +/- 258 MUV, P = 0.148). However, obvious acute microstructural morphological changes were observed in the nerves that were stimulated with 20 mA. CONCLUSIONS: A stimulation intensity less than 15 mA might be safe for IONM of the RLN. PMID- 27453235 TI - Localization of Anterosuperior Point of Transverse-sigmoid Sinus Junction Using a Reference Coordinate System on Lateral Skull Surface. AB - BACKGROUND: During craniotomies using the transpetrosal-presigmoid approach, exposure of the sigmoid sinus remains an essential but hazardous step. In such procedures, accurate localization of the anterosuperior point of the transverse sigmoid sinus junction (ASTS) is very important for reducing surgical morbidity. This study aimed to create an accurate and practical method for identifying the ASTS. METHODS: On the lateral surfaces of 40 adult skulls (19 male skulls and 21 female skulls), a rectangular coordinate system was defined to measure the x and y coordinates of two points: the ASTS and the squamosal-parietomastoid suture junction (SP). With the coordinate system, the distribution characteristics of the ASTS were statistically analyzed and the differences between the ASTS and SP were investigated. RESULTS: For ASTS-x, significant differences were found in different sides (P = 0.020); the ASTS-x in male skulls was significantly higher on the right side (P = 0.017); there was no significant difference between the sides in female skulls. There were no significant differences in gender or interaction of gender and side for ASTS-x, and for ASTS-y, there were no significant differences in side, gender, or interaction of gender and side. For both sides combined, the mean ASTS-x was significantly higher than the mean SP-x (P = 0.003) and the mean ASTS-y was significantly higher than the mean SP-y (P = 0.011). CONCLUSIONS: This reference coordinate system may be an accurate and practical method for identifying the ASTS during presigmoid craniotomy. The SP might be difficult to find during presigmoid craniotomy and, therefore, it is not always a reliable landmark for defining the ASTS. PMID- 27453234 TI - Amyloid beta Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease. AB - BACKGROUND: Amyloid beta (Abeta) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Abeta accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model. METHODS: The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Abeta (oAbeta) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence. RESULTS: In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAbeta (1-42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation. CONCLUSIONS: oAbeta-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population. PMID- 27453236 TI - Biomechanical Study of the Fixation Strength of Anteromedial Plating for Humeral Shaft Fractures. AB - BACKGROUND: Open reduction and internal fixation with plate and screws are the gold standard for the surgical treatment of humeral shaft fractures, this study was to compare the mechanical properties of anteromedial, anterolateral, and posterior plating for humeral shaft fractures. METHODS: A distal third humeral shaft fracture model was constructed using fourth-generation sawbones (#3404, composite bone). A total of 24 sawbones with a distal third humeral shaft fracture was randomly divided into three Groups: A, B, and C (n = 8 in each group) for anteromedial, anterolateral, and posterior plating, respectively. All sawbones were subjected to horizontal torsional fatigue tests, horizontal torsional and axial compressive fatigue tests, four-point bending fatigue tests in anteroposterior (AP) and mediolateral (ML) directions and horizontal torsional destructive tests. RESULTS: In the horizontal torsional fatigue tests, the mean torsional angle amplitude in Groups A, B, and C were 6.12 degrees , 6.53 degrees , and 6.81 degrees . In horizontal torsional and axial compressive fatigue tests, the mean torsional angle amplitude in Groups A, B, and C were 5.66 degrees , 5.67 degrees , and 6.36 degrees . The mean plate displacement amplitude was 0.05 mm, 0.08 mm, and 0.10 mm. Group A was smaller than Group C (P < 0.05). In AP four point bending fatigue tests, the mean plate displacement amplitude was 0.16 mm, 0.13 mm, and 0.20 mm. Group B was smaller than Group C (P < 0.05). In ML four point bending fatigue tests, the mean plate displacement amplitude were 0.16 mm, 0.19 mm, and 0.17 mm. In horizontal torsional destructive tests, the mean torsional rigidity in Groups A, B, and C was 0.82, 0.75, and 0.76 N.m/deg. The yielding torsional angle was 24.50 degrees , 25.70 degrees , and 23.86 degrees . The mean yielding torque was 18.46, 18.05, and 16.83 N.m, respectively. CONCLUSIONS: Anteromedial plating was superior to anterolateral or posterior plating in all mechanical tests except in AP four-point bending fatigue tests compared to the anterolateral plating group. We can suggest that anteromedial plating is a clinically safe and effective way for humeral shaft fractures. PMID- 27453237 TI - Notification Rate of Tuberculosis among Migrants in China 2005-2014: A Systematic Review and Meta-analysis. AB - BACKGROUND: Migrations have been reported to be associated with the high risk of tuberculosis (TB), but there is no systematic analysis of the available data for TB among migrant in China. The aim of this study was to examine the notification rate of active and sputum smear-positive TB by a systematic review and meta analysis. METHODS: A systematic review and meta-analysis were performed to examine the notification rate of active and sputum smear-positive TB among migrants in China. Two reviewers searched the cross-sectional studies published in PubMed, EMBASE, SciFinder, and Web of Science in English and in CNKI and Wanfang databases in Chinese. Pooled estimates of notification rate of TB among migrants were calculated using a random effects model. Meta-regression analysis and subgroup analysis stratified by year, region were also performed. RESULTS: Seventy eligible studies met the inclusion criteria for the final analysis. The overall notification rate of active TB and sputum smear-positive cases among migrants were 53.12 (95% confidence interval [CI]: 47.32-59.63) and 24.53 (95% CI: 22.01-27.34) per 100,000 populations, respectively. The notification rate of active TB significantly increased from 50.95 (95% CI: 41.11-63.14) per 100,000 populations in 2005 to 84.62 (95% CI: 78.00-91.80) per 100,000 populations in 2014 while that of smear-positive TB was constant during the study time (P = 0.79). The geographic difference was identified both for active and sputum smear positive TB, with the higher notification rates mainly distributing along the eastern coastal areas. CONCLUSIONS: The pooled estimate of active TB and sputum smear-positive TB among migrants was lower than the national notification rate among general population, but the gap between our data and national notification rate among general population is narrowed down during 2005-2014. PMID- 27453239 TI - Neuroimaging Features of Pituicytomas. PMID- 27453238 TI - Hip Squeaking after Ceramic-on-ceramic Total Hip Arthroplasty. AB - OBJECTIVE: The present study aimed to review the characteristics and influencing factors of squeaking after ceramic-on-ceramic (CoC) total hip arthroplasty (THA) and to analyze the possible mechanisms of the audible noise. DATA SOURCES: The data analyzed in this review were based on articles from PubMed and Web of Science. STUDY SELECTION: The articles selected for review were original articles and reviews found based on the following search terms: "total hip arthroplasty", "ceramic-on-ceramic", "hip squeaking", and "hip noise." RESULTS: The mechanism of the squeaking remains unknown. The possible explanations included stripe wear, edge loading, a third body, fracture of the ceramic liner, and resonance of the prosthesis components. Squeaking occurrence is influenced by patient, surgical, and implant factors. CONCLUSIONS: Most studies indicated that squeaking after CoC THA was the consequence of increasing wear or impingement, caused by prosthesis design, patient characteristics, or surgical factors. However, as conflicts exist among different articles, the major reasons for the squeaking remain to be identified. PMID- 27453240 TI - Late-onset Deep Mesh Infection: A Study of Eight Cases Detected from 2666 Consecutive Patients with Abdominal Wall Hernia Repairs. PMID- 27453241 TI - Lung Cancer with Diffuse Ground-glass Shadow in Two Lungs and Respiratory Failure. PMID- 27453242 TI - Cervical Disc Arthroplasty Combined with Interbody Fusion for the Treatment of Cervical Myelopathy with Diffuse Idiopathic Skeletal Hyperostosis: A Case Report. PMID- 27453243 TI - Renal Parenchymal Malakoplakia Presenting as Acute Renal Failure in a Young Woman. PMID- 27453244 TI - Prenatal Diagnosis of Ellis-van Creveld Syndrome by Targeted Sequencing. PMID- 27453245 TI - Gram Stain and Molecular Method for the Diagnosis of Bacterial Pneumonia. PMID- 27453246 TI - Combination of Gram Stain, Sputum Culture, and Molecular Method for Diagnosis and Guiding Target Therapies of Bacterial Pneumonia. PMID- 27453247 TI - Difficult Airway Management: Correct Concepts and Algorithm are Important for Patient Safety. PMID- 27453248 TI - Author's Reply to the Letter to Editor "Difficult Airway Management: Correct Concepts and Algorithm are Important for Patient Safety". PMID- 27453249 TI - Pathogenicity of the Homoplasmic m.8701A>G Variant Requires Confirmation. PMID- 27453250 TI - A Mitochondrial DNA A8701G Mutation Partly Associated with Maternally Inherited Hypertension and Dilated Cardiomyopathy in a Chinese Pedigree. PMID- 27453251 TI - Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension. AB - INTRODUCTION AND OBJECTIVES: Recent advances in genetics have led to the discovery of new genes associated with pulmonary arterial hypertension, such as TBX4 and KCNK3. The phenotype and prognosis associated with these new genes have been scarcely described and their role in the Spanish population is unknown. The aim of this study was to characterize the genetics of a Spanish cohort of patients with idiopathic and hereditary pulmonary arterial hypertension and to describe the phenotype and prognostic factors associated with BMPR2 and the new genes (KCNK3 and TBX4). METHODS: A total of 165 adult patients were screened for BMPR2, KCNK3, and TBX4 mutations, 143 with idiopathic pulmonary arterial hypertension and 22 with hereditary pulmonary arterial hypertension. Baseline characteristics and survival were compared among the different subgroups and predictors of poor outcomes were analyzed. We also performed family screening. RESULTS: The genetic study identified a possibly associated mutation in 11.10% of the idiopathic cases (n = 16) and in 68.18% of the hereditary cases (n = 15). There were 19 mutations in BMPR2, 4 in TBX4, and 3 in KCNK3. The forms associated with TBX4 showed the highest survival rate (P < .01). Advanced functional class at diagnosis was the only factor associated with poor outcomes in the hereditary forms. In the family screening, 37.5% of relatives tested positive. CONCLUSIONS: The genetics of pulmonary arterial hypertension in the Spanish population may differ from other populations, with a lower proportion of BMPR2 causative mutations. In our cohort, TBX4-related forms of pulmonary arterial hypertension showed a more benign course and late diagnosis was the only predictor of adverse outcomes in the hereditary forms of the disease. PMID- 27453252 TI - The Role of Sex and Domestic Physical Activity on the Metabolically Healthy and Unhealthy Obesity. The HERMEX Study. PMID- 27453253 TI - Human Trefoil Factor 3 induces the transcription of its own promoter through STAT3. AB - Human trefoil factor 3 (hTFF3) is a small peptide of potential therapeutic value. The mechanisms underlying the transcriptional regulation of hTFF3 remain unclear. The purpose of this study was to identify the core functional elements for the self-induction action of hTFF3 and transcription factors. First, truncated promoters were constructed to identify the functional regions of the hTFF3 promoter. Next, point mutation, chromatin immunoprecipitation, RNA interference, and gene overexpression experiments were performed to analyze the transcriptional binding sites responsible for the self-induced transcription of hTFF3. Our results revealed the -1450 bp to -1400 bp fragment of the hTFF3 promoter was the functional region for the self-induction action of hTFF3. Bioinformatics analysis confirmed that a STAT3 binding site is present in the -1417 bp to -1409 bp region. Subsequently, site-directed mutagenesis analysis determined that this STAT3 binding site was critical for the self-induction effect of hTFF3. ChIP experiments confirmed that STAT3 binds to the hTFF3 promoter. STAT3 overexpression and knockdown experiments revealed that STAT3 enhanced the self induction effect and the expression of hTFF3. This study confirmed that hTFF3 exhibits self-induction action, and that STAT3 is the key transcription factor to maintain the function of self-induction. PMID- 27453254 TI - Photoemission Fingerprints for Structural Identification of Titanium Dioxide Surfaces. AB - The wealth of properties of titanium dioxide relies on its various polymorphs and on their mixtures coupled with a sensitivity to crystallographic orientations. It is therefore pivotal to set out methods that allow surface structural identification. We demonstrate herein the ability of photoemission spectroscopy to provide Ti LMV (V = valence) Auger templates to quantitatively analyze TiO2 polymorphs. The Ti LMV decay reflects Ti 4sp-O 2p hybridizations that are intrinsic properties of TiO2 phases and orientations. Ti LMV templates collected on rutile (110), anatase (101), and (100) single crystals allow for the quantitative analysis of mixed nanosized powders, which bridges the gap between surfaces of reference and complex materials. As a test bed, the anatase/rutile P25 is studied both as received and during the anatase-to-rutile transformation upon annealing. The agreement with X-ray diffraction measurements proves the reliability of the Auger analysis and highlights its ability to detect surface orientations. PMID- 27453255 TI - Relationship between Arterial Stiffness and Blood Pressure Drop During the Sit-to stand Test in Patients with Diabetes Mellitus. AB - AIM: Patients with orthostatic hypotension (OH) have high arterial stiffness. Patients with diabetes mellitus (DM) often have cardiac autonomic neuropathy that leads to OH; however, whether OH is an indicator of arterial stiffness progression is unclear. We aimed to investigate whether the cardio-ankle vascular index (CAVI) varies between DM patients with and without OH using the sit-to stand test (STST). METHODS: One hundred and fifty-nine patients with DM underwent CAVI assessment and blood pressure (BP) and heart rate change evaluation during the STST. OH was defined as a decline in systolic BP (SBP) and/or diastolic BP of at least 20 mmHg or 10 mmHg, respectively, in the initial and late upright positions compared with that in the sitting position. RESULTS: OH was diagnosed in 42 patients (26.4%). DM patients with OH had significantly higher CAVI (9.36+/ 1.15 versus 8.89+/-1.18, p=0.026) than those without OH. CAVI was significantly inversely correlated with systolic and diastolic BP changes (R=-0.347, p<0.001 and R=-0.314, p<0.001, respectively) in the initial upright position. Multivariate regression analysis revealed that age, SBP changes, and low frequency component in the initial upright position were independent determinants of CAVI. CONCLUSION: Patients with DM having large BP drops occurring when moving from sitting to standing have high arterial stiffness. A significant BP drop during the STST necessitates careful evaluation of advanced arterial stiffness in patient with DM. PMID- 27453257 TI - Silanediol-Catalyzed Chromenone Functionalization. AB - Promising levels of enantiocontrol are observed in the silanediol-catalyzed addition of silyl ketene acetals to benzopyrylium triflates. This rare example of enantioselective, intermolecular chromenone functionalization with carbonyl containing nucleophiles has potential applications in the synthesis of bioactive chromanones and tetrahydroxanthones. PMID- 27453256 TI - Five-Year Safety and Performance Results from the Argus II Retinal Prosthesis System Clinical Trial. AB - PURPOSE: The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end stage RP. DESIGN: Prospective, multicenter, single-arm clinical trial. Within patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II. PARTICIPANTS: Thirty participants in 10 centers in the United States and Europe. METHODS: The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES: The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. RESULTS: Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3 year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. CONCLUSIONS: The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada. PMID- 27453258 TI - Group-contribution based property estimation and uncertainty analysis for flammability-related properties. AB - This study presents new group contribution (GC) models for the prediction of Lower and Upper Flammability Limits (LFL and UFL), Flash Point (FP) and Auto Ignition Temperature (AIT) of organic chemicals applying the Marrero/Gani (MG) method. Advanced methods for parameter estimation using robust regression and outlier treatment have been applied to achieve high accuracy. Furthermore, linear error propagation based on covariance matrix of estimated parameters was performed. Therefore, every estimated property value of the flammability-related properties is reported together with its corresponding 95%-confidence interval of the prediction. Compared to existing models the developed ones have a higher accuracy, are simple to apply and provide uncertainty information on the calculated prediction. The average relative error and correlation coefficient are 11.5% and 0.99 for LFL, 15.9% and 0.91 for UFL, 2.0% and 0.99 for FP as well as 6.4% and 0.76 for AIT. Moreover, the temperature-dependence of LFL property was studied. A compound specific proportionality constant (K(LFL)) between LFL and temperature is introduced and an MG GC model to estimate K(LFL) is developed. Overall the ability to predict flammability-related properties including the corresponding uncertainty of the prediction can provide important information for a qualitative and quantitative safety-related risk assessment studies. PMID- 27453259 TI - New SPE-LC-MS/MS method for simultaneous determination of multi-class cyanobacterial and algal toxins. AB - Cyanobacterial and algal toxins comprise a large group of harmful metabolites, belonging to different chemical classes, with a variety of chemical structures, physicochemical properties and toxic activities. In this study, a fast, simple and sensitive analytical method was developed for the simultaneous determination of multi-class cyanobacterial and algal toxins in water. The target compounds were: Cylindrospermopsin, Anatoxin-a, Nodularin, 12 Microcystins ([D-Asp3]MC-RR, MC-RR, MC-YR, MC-HtyR, [D-Asp3]MC-LR, MC-LR, MC-HilR, MC-WR, MC-LA, MC-LY, MC-LW and MC-LF), Okadaic acid and Domoic acid. Analytes were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A dual Solid Phase Extraction (SPE) cartridge assembly was applied for the extraction of target compounds from water. Optimized SPE parameters included cartridge material, initial sample pH, sequence of the cartridges in the SPE assembly as well as composition and volume of the elution solvent. The method was validated, providing acceptable mean recoveries and reproducibility for most analytes. Limits of detection were at the ngL-1 level. The method was successfully applied in real lake water samples from Greece, where a wide range of Microcystins were detected for the first time, at concentrations ranging from 0.034 to 63MUgL-1. PMID- 27453260 TI - Fate and transport modeling of phthalate esters from biosolid amended soil under corn cultivation. AB - Phthalate esters (PAEs) are prevalent in the environment due to the broad range of industrial, agriculture and domestic applications. The ubiquitous use of PAEs has resulted in their potential to reach groundwater sources through application of agri-chemicals and municipal biosolids. A study was conducted to monitor the fate and transport of seven commonly detected PAEs in the environment including: dimethyl phthalate (DMP), diethyl phthalate (DEP), benzyl butyl phthalate (BBP), bis(di-ethyl hexyl) phthalate (DEHP), di-n-octyl phthalate (DnOP), dipentyl phthalate (DPP), and di-n-butyl phthalate (DnBP). Biosolids sourced from the Halifax Regional Municipality were applied at three rates on field-based lysimeter cells which were cropped to corn (Zea mays) for one growing season. In the present study, breakthrough curves (BTCs) were established for phthalates leaching from a corn-cultivated agricultural soil profile. The HYDRUS-1D model and a two-site sorption model were applied to predict transport parameters of PAEs using an inverse solution approach. Results of our research revealed that higher PAE adsorption was observed based on increasing carbon chain number. In addition, higher values of F (i.e. the fraction of type-1 sorption sites assumed to be in equilibrium with the solution phase) and lower values of D (i.e. dispersion coefficient) were observed for PAEs with large carbon chains which was validated both through the empirical dataset and the model simulations. PMID- 27453261 TI - Introduction. PMID- 27453262 TI - Parallel Quantum Circuit in a Tunnel Junction. AB - Spectral analysis of 1 and 2-states per line quantum bus are normally sufficient to determine the effective Vab(N) electronic coupling between the emitter and receiver states through the bus as a function of the number N of parallel lines. When Vab(N) is difficult to determine, an Heisenberg-Rabi time dependent quantum exchange process must be triggered through the bus to capture the secular oscillation frequency Omegaab(N) between those states. Two different linear and regimes are demonstrated for Omegaab(N) as a function of N. When the initial preparation is replaced by coupling of the quantum bus to semi-infinite electrodes, the resulting quantum transduction process is not faithfully following the Omegaab(N) variations. Because of the electronic transparency normalisation to unity and of the low pass filter character of this transduction, large Omegaab(N) cannot be captured by the tunnel junction. The broadly used concept of electrical contact between a metallic nanopad and a molecular device must be better described as a quantum transduction process. At small coupling and when N is small enough not to compensate for this small coupling, an N(2) power law is preserved for Omegaab(N) and for Vab(N). PMID- 27453263 TI - Efficacy and toxicity of plasmonic photothermal therapy (PPTT) using gold nanorods (GNRs) against mammary tumors in dogs and cats. AB - Plasmonic photothermal therapy (PPTT) was introduced as a promising treatment of cancer. This work was conducted to evaluate the cytotoxic effect of intratumoral (IT) injection of 75MUg gold nanorods (GNRs)/kg of body weight followed by direct exposure to 2 w/cm2 near infra-red laser light for 10min on ablation of mammary tumor in 10 dogs and 6 cats. Complete blood count (CBC), liver and kidney function were checked before the start of treatment and one month after injection of GNRs. Results showed that 62.5% (10/16), 25% (4/16) and 12.5% (2/16) of treated animals showed complete remission, partial remission and no response, respectively. Tumor was relapsed in 4 cases of initially responding animals (25%). Overall survival rate was extended to 315.5+/-20.5days. GNRs have no toxic effect on blood profile, liver or kidney functions. In conclusion, GNRs can be safely used for treatment of mammary tumors in dogs and cats. PMID- 27453264 TI - Lanthanum chloride enhances cisplatin-induced apoptosis in ovarian cancer cells. AB - Ovarian cancer begins in an ovary. It is the leading cause of mortality from gynecologic cancer. Cisplatin is an anti-ovarian tumor drug. However, repeated use of cisplatin causes serious resistance. Recently, Lanthanum chloride (LaCl3) was found to inhibit the proliferation and promote the apoptosis in some cancer cells. In this study, we investigated the influence of LaCl3 on cisplatin-induced apoptosis in the ovarian cell line (COC1). Cell-based assays and analysis of cellular ultra structure were used. Result showed that LaCl3 enhanced cisplatin induced apoptosis in COC1. Furthermore, the application of Cisplatin also altered the expression level of tumor related proteins, such as ERCC1, Ki67, and CDK6. Overall, we determined the inhibitory effect of LaCl3 on the COC1 growth when treated with Cisplatin, which may serve as a basis for the clinical application of LaCl3 in the treatment of ovarian cancer. PMID- 27453265 TI - Synthesis, SAR and biological evaluation of a novel series of 1-(2-chloroethyl)-1 nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl) urea: Organoselenium compounds for cancer therapy. AB - Thioredoxin reductase 1 (TrxR1) is an important potential anticancer drug target and closely related to both carcinogenesis and cancer progression. Ethaselen (BBSKE), a novel organoselenium compound inhibiting TrxR1 with selective antitumor effect, while its symmetrical structure results in poor solubility. Carmustine (BCNU), a DNA cross-link agent and also a deactivator of TrxR, is with high toxicity and low selectivity which limit its clinical application to some extents. Herein, a novel compound, 1-(2-chloroethyl)-1-nitroso-3-(2-(3 oxobenzoelenazol-2(3H)-yl)ethyl)urea(4a-1), which was designed through the combination of Ethaselen and Carmustine, showed good solubility, good tagetability, low toxicity and excellent antitumor activity by synergism. Using the structure of 4a-1 as a key active scaffold, a series of novel 1-(2 chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl)urea was designed, synthesized and evaluated to explore the structure-activity relationships (SARs) of these inhibitors and to improve their antitumor activities. Notably, 1-(2 chloroethyl)-3-(2-(6-fluoro-3-oxobenzoselenazol-2(3H)-yl)ethyl)-1-nitrosourea(4b 1) was found to exhibit more potent antitumor activities comparable to 4a-1 against all the four cancer cell lines, including Mia PaCa-2, PANC-1, RKO, LoVo. These results have highlighted compound 4b-1 as a new potential lead candidate for future development of novel potent broad-spectrum antitumor agents. In addition, a SAR model was established to conduct further structural modification. PMID- 27453266 TI - Effect of FUT3 gene silencing with miRNA on proliferation, invasion and migration abilities of human KATO-III gastric cancer cell line. AB - This study investigated the effects of FUT3 gene expression inhibition with miRNA on the proliferation, invasion and migration abilities of KATO-III cells. KATO III cells were transfected with plasmid pcDNATM6.2-GW/EmGFP-FUT3-miR(FUT3-miRNA) and negative control plasmid in mediation of liposome, respectively, using untransfected cells as blank controls. Forty-eight hours after transfection, FUT3 mRNA levels were tested by RT-PCR. Levels of sLeA proteins were assayed by Western blot. The effects of FUT3-miRNA on the proliferation, invasion and migration of KATO-III cells were determined by CCK8 testing and Transwell assays, respectively. Results indicate that the transfection of FUT3-miRNA may down regulate sLeA protein expression on the surface of KATO-III cells, and significantly inhibit cell proliferation (p<0.05). As compared to the negative and blank control groups, the number of invasion and migration cells in the FUT3 miRNA group decreased significantly (each p<0.05). Experimental results indicate that the miRNA expression vector which targets the FUT3 gene can effectively inhibit the proliferation, migration and invasion abilities of KATO-III cells. PMID- 27453267 TI - A new neurotoxicity model composed of a neurovascular unit in vitro. AB - In this study, we established a 2-D model composed ofbrain microvascular endothelial cells (BMECs) and neurons, and a new 3-D model called a neurovascular unit (NVU) that included co-culturing with BMECs, hippocampal neurons, and astrocytes. First, three different cell types (BMECs, hippocampal neurons, and astrocytes) were cultured and identified; then, positive neurotoxic chemicals were used to test cell viability. Half maximal (50%) inhibitory concentration (IC50) and intracellular calcium concentrations were calculated using primary cells in both models. The results showed that Pb2+ and AL3+ exposure significantly decreased cell viability and increased intracellular calcium concentrations. The two experimental models did not display any differences in cell viability and intracellular calcium concentrations compared to the control, but they did show declining cell viability with increasing Pb2+ and AL3+ concentrations. The permeability results suggested Pb2+ and AL3+ could change the permeability of the two models. In conclusion, the two models replicated the blood-brain barrier (BBB) more accurately than the control, so it has potential usefulness in further scientific and clinical drug research. Furthermore, NVU model could be used to screen neurotoxicity chemicals due to its NVU properties. PMID- 27453268 TI - Toxicity of Hoechst 33342: implication in side population analysis. AB - In the current study, we discovered that Hoechst 33342 (H342) could produce significant toxicity to the human neuroblastoma SK-N-SH cells at concentrations typically used to identify side population (SP) cells. At 3.75 and 5 ug/ml, H342 induced cell death and apoptosis. Flow cytometry analysis revealed cell cycle arrest at S-phase. Our findings caution against using H342 for SP analysis without considering differential susceptibility of different cells to H342. Specifically, concentration of H342 needs to be adjusted carefully to minimize toxicity for each cell line. PMID- 27453269 TI - Combined PCR and Q-RT-PCR technique for detecting chimerism in a non-human Primate vascularized osteomyocutaneous allografts model. AB - Face transplantation and other composite tissue transplantation (CTA) are permissive to transplantation tolerance. The real reason, that composite tissue containing bone achieves transplantation immune tolerance more easily than the composite tissue without the bone is not clear. The chimerism may be the main mechanism in the progress of inducing the transplantation tolerance by CTA. We currently have established a non-human Primate Vascularized Osteomyocutaneous Allografts Model. To test the chimerism which comes from donor after the transplantation, we developed a method which combined reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative PCR (qRT-PCR) technique using primers specific for Macaca fascicularis sex determination region on the Y chromosome (SRY) gene. With the method, we estimated the level of the chimerism. PMID- 27453270 TI - The role of apoptosis inducing factor in the apoptosis of retinal pigment epithelium cells induced by oxidative stress. AB - To explore the role of apoptosis inducing factor (AIF) in the apoptosis of retinal pigment epithelium (RPE) cells induced by oxidative stress. RPE cell apoptotic models were constructed by H2O2, Annexin V/PI flow cytometry and MTT assay were used to determine the changes of RPE cell apoptosis and proliferation. The production of reactive oxygen species (ROS) and mitochondrial membrane potential were observed. QRT-PCR and western blot were used to determine the expression of AIF to evaluate whether AIF-mediated non caspase pathway participated in the RPE cell apoptosis induced by H2O2. After adding melatonin, the production of ROS, RPE apoptotic rate and the changes of AIF expression were also detected. The production of ROS and apoptotic rate of RPE cells increased with the increase of H2O2 concentration and treating time. The expression of AIF increased evidently in cytoplasm, while not in mitochondria. After intervention with melatonin, the production of ROS was inhibited and the apoptotic rate decreased. However, the expression of AIF was not inhibited correspondingly. AIF may participate in but not be dominant in the process of RPE cell apoptosis induced by oxidative stress. PMID- 27453271 TI - Association between miR-499 rs3746444 and the susceptibility of hepatocellular carcinoma. AB - Considering the inconsistent association between miR-499 rs3746444 and the risk of hepatocellular carcinoma (HCC), it is critical to carry out a meta-analysis in order to produce a precise result. Therefore, a meta-analysis was performed. All of the potential eligible studies were screened based on the following databases, including PubMed, EMBASE, Medline and China National Knowledge Internet (CNKI) up to December 2015. The associations between miR-499 rs3746444and HCC susceptibility was quantified using odds ratios (ORs) with its 95% confidence intervals (CIs). Nine case-control articles were included in the analysis. A total of 2593 cases and 3259 controls were included. The pooled OR was 1.27 (95% CI: 1.10 - 1.48, P = 0.002) which suggested thatmiR-499 rs3746444 was significantly associated with an increased the risk of HCC. Subgroup analysis was performed by ethnicity, miR-499 rs3746444 was significantly associated with an increased the risk of HCC in Asians (OR = 1.31, 95% CI = 1.10-1.55; P = 0.002). However, no significant result was found in Caucasians (OR = 1.10, 95% CI = 0.84 1.44; P = 0.49). In addition, miR-499 rs3746444 was significantly associated with an increased the risk of HCC in subjects with HBV infection OR = 1.31, 95% CI = 1.09-1.58; P = 0.004). This study suggested that miR-499 rs3746444 might play an important role in the development of HCC. PMID- 27453272 TI - Investigation of biological effects of some Mannich Bases containing Bis-1,2,4- Triazole. AB - In this study, the effects of Mannich bases containing bis-1,2,4-triazole on the levels of in vivo malondialdehyde (MDA) and antioxidant vitamins (A, E, C) were examined in serum, livers and kidneys of rats. DA and vitamin (A, E, C) levels were determined by high performance liquid chromatography (HPLC). Antioxidant effect was investigated by determining the MDA levels in Saccharomyces cerevisiae cells as in vitro. Furthermore, the antitumor effects of compounds were investigated against MCF-7 human breast cancer cells. Interrelations of results among control and compound groups were evaluated using SPSS statistical software package. As a result, some of the compounds showed effective biological activity when compared to control conditions. The test compounds used in this study may be effective for utilization in the selection and design of model compounds for further studies. PMID- 27453273 TI - Baicalein induces apoptosis and reduces inflammation in LPS-stimulated keratinocytes by blocking the activation of NF-kappaB: implications for alleviating oral lichen planus. AB - ic inflammatory diseases, including OLP, involves in the activation of the nuclear factor-kappa B (NF-kappaB) signaling pathway. Baicalein (BAI) is an alcohol soluble flavonoid known for its anti-inflammatory effect. However, its effectiveness on keratinocytes in OLP remains unclear. In the present study, we examined inflammation in oral mucosa tissue from OLP patients. Hematoxylin and eosin staining showed denser subepithelial lymphocytes infiltration compared to the normal oral mucosa epithelium. TNF-alpha and IL-6 were up-regulated in oral mucosa tissue of OLP patients. We next stimulated humans keratinocytes (HaCaT cells) with lipopolysaccharide (LPS) to create an inflammatory environment like that in the OLP tissue and assessed the effect of BAI on OLP and NF-kappaB signaling pathways. Our results showed that BAI treatment inhibited the level of TNF-alpha and IL-6 induced by LPS. However, the cells apoptosis was promoted after BAI treatment. Furthermore, BAI not only inhibited LPS-induced p38 MAPK and ERK1/2 phosphorylation, but also NF-kappaB activation by reducing IkappaBalpha phosphorylation and the nuclear translocation of NFkappaB-p65 and NFkappaB-p50 from cytoplasm to nucleus in keratinocytes. Our findings suggest that BAI inhibits the production of inflammatory cytokines by negatively regulating the NF kappaB signaling pathway under LPS simulation in HaCaT cells. PMID- 27453274 TI - The frequency of C609T polymorphism in the NQO1 gene and its relation to cytogenetic abnormalities in patients with myelodysplastic syndrome. AB - The aim of the present study is to evaluate the frequency of C609T polymorphism in the NQO1 (NAD(P)H) quinon oxydoreductase) gene and its relation to cytogenetic abnormalities in patients with Myelodysplastic Syndrome (MDS). The study group consisted of 80 patients MDS with 13 of them in the pediatric age group. The frequency of the NQO1 gene polymorphism was compared with a healthy control group involving 423 individuals. Cytogenetic abnormalities were detected in 43 patients (54%). In patients with MDS the overall frequency of the C609T polymorphism was not different than controls. Also, although the frequency of the C609T polymorphism was higher in patients with secondary MDS (sMDS) (OR: 1.893, 95% CI: 0.840-4.265, p=0.238) , 5/del(5q) (OR:1.298, 95% CI: 0.331-5.086,p=0.124), +21(OR:1.817, 95% CI:0.429-7698,p=0.124) and t(8;21) (OR:3.028, 95% CI: 0.604 15.172,p=0.137) groups, the difference did not reach statistical significiance. Our results do not support the view that the C609T polymorphism has a role in the pathogenesis of MDS. Also the frequency of the C609T allele did not seem to be associated with cytogenetic abnormalities. PMID- 27453275 TI - Mesenchymal stem cell-derived exosomes: A novel potential therapeutic avenue for cardiac regeneration. AB - Coronary artery diseases (CADs) represent a significant cause of death worldwide. During recent decades the rate of cardiovascular mortality has been declined as a result of modern medicine and surgery. However, despite the fact that cardiac cells, including cardiomyocytes (CMCs), vascular smooth muscle cells (VSMC) and vascular endothelial cells (VEC), can be regenerated by cardiac adult stem cell, the regenerative capacity of these cells are limited and inadequate to functionally regenerate heart damaged tissue. Thus, growth reserve of the heart fails to restore the structural integrity of the myocardium after infarction and healing is associated with scar formation. An explanation for this is that cardiac reside stem cells are present throughout the infarction site but die rapidly by apoptosis. Furthermore, microenvironment surrounding the damage site is not promising for the cells survival and renewal. Hence, recent advances in the stem cell therapy have emerged as an attractive approach to replace the lost cells. In this context, mesenchymal stem cells (MSCs) has considered as one of the most promising candidates for regeneration of cardiac cells, lost upon injury. The regenerative capacity of MSCs has primarily been centered on the hypothesis that these cells would engraft, differentiate and replace damaged cardiac cells. However, experimental and clinical observations so far have failed to establish if this differentiated is considerably relevant to MSCs cardiac regenerative properties. Recent reports have suggested that these therapeutic properties, at least in part, are mediated by paracrine factors released from MSCs. This review provides a concise summary of current evidences supporting the paracrine hypothesis of MSCs. In particular, the scope of this review focuses on the role of MSC-derived exosome (MSC-EXs) as a therapeutic modality for the treatment of CADs, particularly ischemic myocardial dysfunctions. PMID- 27453276 TI - Therapeutic application of mesenchymal stem cell-derived exosomes: A promising cell-free therapeutic strategy in regenerative medicine. AB - Mesenchymal stem cells have emerged as promising therapeutic candidates in regenerative medicine. The mechanisms underlying mesenchymal stem cells regenerative properties were initially attributed to their engraftment in injured tissues and their subsequent transdifferentiation to repair and replace damaged cells. However, studies in animal models and patients indicated that the low number of transplanted mesenchymal stem cells localize to the target tissue and transdifferentiate to appropriate cell lineage. Instead the regenerative potential of mesenchymal stem cells has been found - at least in part - to be mediated via their paracrine actions. Recently, a secreted group of vesicles, called "exosome" has been identified as major mediator of mesenchymal stem cells therapeutic efficacy. In this review, we will summarize the current literature on administration of exosomes released by mesenchymal stem cells in regenerative medicine and suggest how they could help to improve tissue regeneration following injury. PMID- 27453277 TI - Norepinephrine and acetylcholine changes during electrically-induced atrial fibrillation episodes in canine models. AB - Atrial fibrillation (AF) is the most prevalent heart rhythm disorder, and autonomic nervous system (ANS) is important to AF. This study aims to identify whether changes in transmitters released by ANS could reflect their activities. The right atrium (RA) groups (1-40V) included RA500 and RA1000. While ANS groups received high-frequency electrical stimulation (1-8V, 20 Hz, 2 ms), including left stellate ganglion stimulation (LSGS) andleft cervical vagus trunk stimulation (LVTS). The induced rate of AF, duration and atrial effective refractory period (AERP) were measured. The blood was drawn for evaluation of norepinephrine (NE) and acetylcholine (Ach) concentrations. At 12-hours, RA tissue was dissected and compared against un-stimulated controls. While AF was induced by all groups, duration and AERP were significantly different between RA pacing groups and ANS-stimulated groups, respectively (P<0.05). Specific changes in profile of NE and Ach were associated with modality of stimulation. RA1000 tended to display most significant changes (P<0.05) compared to other groups while variables concentration levels were observed in other groups. In conclusion, electrically-induced AF initiated by various modalities of stimulation showed different changes in serum and RA tissues. Fast frequency pacing caused significant atrial electrical remodeling, including ANS activity change. PMID- 27453278 TI - Molecular detection and in vitro antioxidant activity of S-allyl-L-cysteine (SAC) extracted from Allium sativum. AB - It is well known that Allium sativum has potential applications to clinical treatment of various cancers due to its remarkable ability in eliminating free radicals and increasing metabolism. An allyl-substituted cysteine derivative - S allyl-L-cysteine (SAC) was separated and identified from Allium sativum. The extracted SAC was reacted with 1-pyrenemethanol to obtain pyrene-labelled SAC (Py SAC) to give SAC fluorescence properties. Molecular detection of Py-SAC was conducted by steady-state fluorescence spectroscopy and time-resolved fluorescence method to quantitatively measure concentrations of Py-SAC solutions. The ability of removing 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radical using Py-SAC was determined through oxygen radical absorbance capacity (ORAC). Results showed the activity of Py-SAC and Vitamin C (VC) with ORAC as index, the concentrations of Py-SAC and VC were 58.43 mg/L and 5.72 mg/L respectively to scavenge DPPH, and 8.16 mg/L and 1.67 mg/L to scavenge *OH respectively. Compared with VC, the clearance rates of Py-SAC to scavenge DPPH were much higher, Py-SAC could inhibit hydroxyl radical. The ability of removing radical showed a dose dependent relationship within the scope of the drug concentration. PMID- 27453279 TI - Frequency Evaluation of T6235C (m1) and A4889G (m2) Polymorphisms of CYP1A1 Gene in a Healthy Population from the west of Mazandaran Province, Iran. AB - CYP1A1 is an important phase I xenobiotic metabolizing enzyme involved in the metabolism of numbers of toxins, endogenous hormones and drugs. Polymorphisms in this phase I gene can alter enzyme activity and induction, also are known to be associated with cancer susceptibility related to environmental toxins and hormone exposure. The present study was aimed to determine the frequencies of commonly known functional polymorphismsof CYP1A1 gene including CYP1A1 m1 (MspI), and CYP1A1 m2 (Ile-Val) in a healthy population from the west of Mazandaran province, Iran. A total of 200 unrelated healthy subjects from Mazandaran province, residing in Tonekabon city, coming for blood donating at Tonekabon Blood Transfusion Center were enrolled. Genomic DNA was extracted from peripheral blood lymphocytes of each subject. All subjects were genotyped for CYP1A1 m1 (T>C) and m2 (A>G) by polymerase chain reaction-restriction fragment length polymorphism method. The frequencies of the TT(wt/wt), TC(wt/mt) and CC(mt/mt) genotypes were as 65.5%, 32.0% and 2.5% respectively for m1 and frequencies of the AA(wt/wt), AG(wt/mt) and GG(mt/mt) genotypes were as 84.5%, 15% and 0.5% respectively for the m2. The frequencies of T and C alleles in the population were 81.5% and 18.5% respectively and the frequencies of A and G alleles were 92% and 8% respectively. Results of the present study might be important in understanding the distribution of CYP1A1 (m1) and CYP1A1 (m2) polymorphisms in Mazandaran province of Iran. Moreover, these results may determine the susceptibilities of individuals towards environmental procarcinogens that result in several cancers. PMID- 27453280 TI - Knockdown of eIF3a ameliorates cardiac fibrosis by inhibiting the TGF-beta1/Smad3 signaling pathway. AB - Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. The eukaryotic translation initiation factor (eIF) 3a is the largest subunit of the eIF3 complex and has been involved in renal fibrosis. However, the precise role of eIF3a in myofibroblast differentiation and cardiac fibrosis remains unknown. Accordingly, in our present study, we tested the expression of eIF3a in transforming growth factor beta1 (TGF-beta1)-induced rat CFs and found that eIF3a was upregulated in TGF-beta1-induced rat CFs. Then the role and mechanism of eIF3a in cardiac fibrosis were explored. Our results found that the eIF3a expression was significantly up-regulated in TGF-beta1-induced CFs. Knockdown of eIF3a significantly inhibited TGF-beta1-induced CF proliferation, as well as suppressed the expression levels of alpha-smooth muscle actin (alpha-SMA) and SM22alpha. Mechanistically, knockdown of eIF3a attenuated TGF-beta1-induced Smad3 activation in CFs. In summary, our present study firstly demonstrated that silencing eIF3a might alleviate TGF-beta1-induced cardiac fibrogenesis in CFs by inhibiting Smad3 activation, and suggest that eIF3a may be positioned as a new and promising target for the prevention and treatment of cardiac fibrosis. PMID- 27453281 TI - Pharmacogenetics of drug metabolizing enzyme: thiopurine methyl transferase phenotypes and multidrug resistance 1 gene polymorphism in inflammatory bowel disease. AB - Inflammatory bowel disease(IBD) is progressing rapidly in developing countries such as Iran. This research is intended to compile the frequency distribution of the drug metabolizing enzyme, thiopurine methyl transferase(TPMT) and the drug transporter, Multi drug resistance(MDR1) which are involved in metabolism of many therapeutics such as thiopurines in inflammatory bowel disease(IBD). Ethnicity is an important variable influencing drug response. The aims of this research were to investigate the association of TPMT phenotypes with MDR1 genotypes. TPMT activity was measured by using a non-extraction HPLC method and genotype for the C3435T polymorphism of MDR1 gene was determined in 215 unrelated IBD patients including of 85 males and 130 females and 212 unrelated healthy individuals consisted of 96 males and 116 females as control group by PCR-RFLP in Iran's western population. TPMT phenotypes demonstrated no frequency for deficient, 2.2% for low and 97.8% for normal activity that is different with results of other studies. Interestingly there were a significant negative correlation between TPMT activities as calculated based on nmol/grHb/h and positive correlation calculated in mU/L with Hb levels in IBD patients and control subjects. Dominant and codominant MDR1 C3435T gene polymorphism increased the risk of IBD by 1.45 and 1.46 times, respectively. IBD patients with MDR1 mutant genotypes C3435T, had lower TPMT activites and Hb concentrations. Using of mU/L is more appropriate than nmol6MTG/grHb/h for expressing TPMT activity. TPMT frequency of deficient and low activity in western Iran is low. The carriers of mutant C3435T MDR1 are not good TPMT methylators. PMID- 27453282 TI - How sesquiterpenes modulate signaling cascades in cancers. AB - Data obtained from high-throughput technologies has started to shed light on the interplay between signal transduction cascades and chromatin modifications thus adding another layer of complexity to the already complex regulation of the protein network. Based on the insights gleaned from almost a decade of research, it has now been convincingly revealed that sesquiterpenes effectively modulated different intracellular signaling cascades in different cancers. In this review we summarize how sesquiterpenes mediated Wnt, Shh, Notch and TRAIL induced signaling cascades. PMID- 27453283 TI - Expression of CD44 variant isoforms, CD44v3 and CD44v6, are associated with prognosis in nasopharyngeal carcinoma. AB - OBJECTIVE: The clinical and prognostic significance of CD44 variant isoform expression in nasopharyngeal carcinoma is not well known. This study aimed to clarify whether CD44 variant isoform expression serves as a prognostic factor in nasopharyngeal carcinoma. METHODS: Forty-two nasopharyngeal carcinoma patients, who underwent concurrent chemoradiotherapy as the initial treatment, were the subjects of investigation. Expression of CD44 variant isoforms, CD44v3, CD44v4, CD44v5, CD44v6 and CD44v7, in nasopharyngeal carcinoma was assessed in relation to concurrent chemoradiotherapy resistance and disease-specific survival of the patients. RESULTS AND CONCLUSION: The patients with CD44v6 high expression showed a clinically incomplete response to concurrent chemoradiotherapy at the primary site. The disease-specific survival rate was lower in patients with high expression of CD44v3 than in those with low expression. These results suggest that analysis of CD44v6 and CD44v3 expression is useful in estimating prognosis and determining effective treatment strategies in nasopharyngeal carcinoma. PMID- 27453284 TI - Malignant forms of Mediterranean spotted fever: risk factors for fatal outcomes. PMID- 27453285 TI - Artificial neural network (ANN)-based prediction of depth filter loading capacity for filter sizing. AB - This article presents an application of artificial neural network (ANN) modelling towards prediction of depth filter loading capacity for clarification of a monoclonal antibody (mAb) product during commercial manufacturing. The effect of operating parameters on filter loading capacity was evaluated based on the analysis of change in the differential pressure (DP) as a function of time. The proposed ANN model uses inlet stream properties (feed turbidity, feed cell count, feed cell viability), flux, and time to predict the corresponding DP. The ANN contained a single output layer with ten neurons in hidden layer and employed a sigmoidal activation function. This network was trained with 174 training points, 37 validation points, and 37 test points. Further, a pressure cut-off of 1.1 bar was used for sizing the filter area required under each operating condition. The modelling results showed that there was excellent agreement between the predicted and experimental data with a regression coefficient (R2 ) of 0.98. The developed ANN model was used for performing variable depth filter sizing for different clarification lots. Monte-Carlo simulation was performed to estimate the cost savings by using different filter areas for different clarification lots rather than using the same filter area. A 10% saving in cost of goods was obtained for this operation. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1436-1443, 2016. PMID- 27453286 TI - A novel algorithm for network-based prediction of cancer recurrence. AB - To develop accurate prognostic models is one of the biggest challenges in "omics" based cancer research. Here, we propose a novel computational method for identifying dysregulated gene subnetworks as biomarkers to predict cancer recurrence. Applying our method to the DNA methylome of endometrial cancer patients, we identified a subnetwork consisting of differentially methylated (DM) genes, and non-differentially methylated genes, termed Epigenetic Connectors (EC), that are topologically important for connecting the DM genes in a protein protein interaction network. The ECs are statistically significantly enriched in well-known tumorgenesis and metastasis pathways, and include known epigenetic regulators. Importantly, combining the DMs and ECs as features using a novel random walk procedure, we constructed a support vector machine classifier that significantly improved the prediction accuracy of cancer recurrence and outperformed several alternative methods, demonstrating the effectiveness of our network-based approach. PMID- 27453288 TI - High-rate anaerobic co-digestion of kraft mill fibre sludge and activated sludge by CSTRs with sludge recirculation. AB - Kraft fibre sludge from the pulp and paper industry constitutes a new, widely available substrate for the biogas production industry, with high methane potential. In this study, anaerobic digestion of kraft fibre sludge was examined by applying continuously stirred tank reactors (CSTR) with sludge recirculation. Two lab-scale reactors (4L) were run for 800days, one on fibre sludge (R1), and the other on fibre sludge and activated sludge (R2). Additions of Mg, K and S stabilized reactor performance. Furthermore, the Ca:Mg ratio was important, and a stable process was achieved at a ratio below 16:1. Foaming was abated by short but frequent mixing. Co-digestion of fibre sludge and activated sludge resulted in more robust conditions, and high-rate operation at stable conditions was achieved at an organic loading rate of 4g volatile solids (VS)L(-1)day(-1), a hydraulic retention time of 4days and a methane production of 230+/-10NmL per g VS. PMID- 27453287 TI - Association of MIF, but not type I interferon-induced chemokines, with increased disease activity in Asian patients with systemic lupus erythematosus. AB - Ethnicity is a key factor impacting on disease severity in SLE, but molecular mechanisms of these associations are unknown. Type I IFN and MIF have each been associated with SLE pathogenesis. We investigated whether increased SLE severity in Asian patients is associated with either MIF or Type I IFN. SLE patients (n = 151) had prospective recording of disease variables. Serum MIF, and a validated composite score of three Type I IFN-inducible chemokines (IFNCK:CCL2, CXCL10, CCL19) were measured. Associations of MIF and IFNCK score with disease activity were assessed, with persistent active disease (PAD) used as a marker of high disease activity over a median 2.6 years follow up. In univariable analysis, MIF, IFNCK score and Asian ethnicity were significantly associated with PAD. Asian ethnicity was associated with higher MIF but not IFNCK score. In multivariable logistic regression analysis, MIF (OR3.62 (95% CI 1.14,11.5), p = 0.03) and Asian ethnicity (OR3.00 (95% CI 1.39,6.46), p < 0.01) but not IFNCK were significantly associated with PAD. These results potentially support an effect of MIF, but not Type I IFN, in heightened SLE disease severity in Asian SLE. The associations of MIF and Asian ethnicity with PAD are at least partly independent. PMID- 27453289 TI - Swelling of phospholipid membranes by divalent metal ions depends on the location of the ions in the bilayers. AB - The Hofmeister series illustrates how salts produce a wide range of effects in biological systems, which are not exclusively explained by ion charge. In lipid membranes, charged ions have been shown to bind to lipids and either hydrate or dehydrate lipid head groups, and also to swell the water layer in multi-lamellar systems. Typically, Hofmeister phenomena are explained by the interaction of the ions with water, as well as with biological interfaces, such as proteins or membranes. We studied the effect of the divalent cations Mg(2+), Ca(2+), Fe(2+), and Zn(2+) on oriented, stacked, phospholipid bilayers made of dimyristoylphosphatidylcholine (DMPC). Using high-resolution X-ray diffraction, we observed that the cations lead to a swelling of the water layer between the bilayers, without causing significant changes to the bilayer structure. The cations swelled the bilayers in different amounts, in the order Fe(2+) > Mg(2+) > Ca(2+) > Zn(2+). By decomposing the total bilayer electron density into different molecular groups, Zn(2+) and Ca(2+) were found to interact with the glycerol groups of the lipid molecules and cause minor swelling of the bilayers. Mg(2+) and Fe(2+) were found to position near the phosphate groups and cause a strong increase in the number of hydration water molecules. Our results present a molecular mechanism-of-action for the Hofmeister series in phospholipid membranes. PMID- 27453290 TI - Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective. AB - The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA2B2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis. PMID- 27453291 TI - Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice. AB - Cre-driver mouse lines have been extensively used as genetic tools to target and manipulate genetically defined neuronal populations by expression of Cre recombinase under selected gene promoters. This approach has greatly advanced neuroscience but interpretations are hampered by the fact that most Cre-driver lines have not been thoroughly characterized. Thus, a phenotypic characterization is of major importance to reveal potential aberrant phenotypes prior to implementation and usage to selectively inactivate or induce transgene expression. Here, we present a biochemical and behavioural assessment of the dopaminergic system in hemizygous tyrosine hydroxylase (TH)-Cre mice in comparison to wild-type (WT) controls. Our data show that TH-Cre mice display preserved dopaminergic homeostasis with unaltered levels of TH and dopamine as well as unaffected dopamine turnover in striatum. TH-Cre mice also show preserved dopamine transporter expression and function supporting sustained dopaminergic transmission. In addition, TH-Cre mice demonstrate normal responses in basic behavioural paradigms related to dopaminergic signalling including locomotor activity, reward preference and anxiolytic behaviour. Our results suggest that TH Cre mice represent a valid tool to study the dopamine system, though careful characterization must always be performed to prevent false interpretations following Cre-dependent transgene expression and manipulation of selected neuronal pathways. PMID- 27453293 TI - The factors associated with sexual recovery in male patients with acute myocardial infarction under phase II cardiac rehabilitation. AB - AIMS AND OBJECTIVES: The aim of the study was to assess the prognostic factors of short-term sexual recovery in patients with acute myocardial infarction after phase II cardiac rehabilitation for six weeks. BACKGROUND: It is often observed that patients who have suffered acute myocardial infarction and have sufficient aerobic capacity for sexual activity do not recover sexual activity. Until now, few studies have investigated factors associated with recovery of sexual activity. DESIGN: Observational study. METHODS: Among 627 male patients with acute myocardial infarction who were referred for cardiac rehabilitation from October 2010-September 2014, 72 were finally analysed. Subjects who met all the following criteria were included: (1) completed a questionnaire about sexual activity before and after phase II cardiac rehabilitation; (2) showed usual sexual activity before onset of acute myocardial infarction and (3) revealed decreased sexual activity at baseline of cardiac rehabilitation compared to preacute myocardial infarction status despite >=5 maximal metabolic equivalents. Information on sociodemographic characteristics and cardiopulmonary function obtained before cardiac rehabilitation was used for the analysis. RESULTS: (1) Twenty-five of the 72 subjects (34.7%) had improved sexual activity after six weeks of cardiac rehabilitation, but 47 (65.3%) continued the status of no recovery sexual activity after cardiac rehabilitation. (2) Age, body mass index and use of statins were significantly different between subjects who recovered and those who did not. (3) No differences in other clinical characteristics and cardiopulmonary functions were detected between the two groups. (4) Age and body mass index were significant factors associated with recovery of sexual activity. CONCLUSIONS: Age and body mass index were significant factors associated with recovery of sexual activity in acute myocardial infarction patients. Aerobic capacity at baseline of cardiac rehabilitation was not an independent factor to predict the recovery of sexual activity. RELEVANCE TO CLINICAL PRACTICE: These results should be considered when educating patients under phase II cardiac rehabilitation on their return to normal sexual activity. PMID- 27453292 TI - The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. AB - Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. PMID- 27453295 TI - How can postoperative delirium be predicted in advance? A secondary analysis comparing three methods of early assessment in elderly patients. AB - BACKGROUND: Postoperative impairment of the cerebral function can appear immediately after general anesthesia and may be predictive for a postoperative delirium. We compared three tools assessing patients on recovery room admission in order to detect early signs of postoperative brain dysfunction: the Postanesthetic Recovery Score (PARS), the Richmond Agitation-Sedation Scale (RASS) and the Nursing Delirium Screening Scale (Nu-DESC). METHODS: Inclusion criteria of this secondary analysis of the randomized SuDoCo trial were: age >=60 years, schedule for elective non-cardiac surgery with an anticipated duration of >=60 minutes, general anesthesia, ability to communicate in German language. A total of 996 patients were analyzed. Investigated scores were assessed 10 minutes after recovery room admission and analyzed in terms of association with postoperative delirium, mortality and length of stay in the recovery room. Multivariate analysis: linear or logistic regression. RESULTS: Abnormal scores in patients: RASS (values <=-2 and >=1) 36.8%, Nu-DESC (>=2 points) 54.2%, PARS (<=7 points) 20.3%. Abnormal RASS values were associated with postoperative delirium (RASS values >=1: odds ratio (OR) 3.1, 95% CI: 1.7-5.6, P<0.001; RASS values <= 2: OR=2.1, 95% CI: 1.3-3.3, P=0.001). Abnormal Nu-DESC values were also associated with postoperative delirium (OR=2.4, 95% CI: 1.5-3.9, P<0.001). Abnormal PARS values were associated with a longer recovery room stay (in minutes, OR=16.6, 95% CI: 1.7-31.4, P=0.029). CONCLUSIONS: The RASS and Nu-DESC were independent predictors for a delirium within seven postoperative days. Very early assessment of the cerebral function may help to advance detection, prevention and treatment of postoperative delirium in elderly patients. PMID- 27453294 TI - The prospect of precision therapy for renal cell carcinoma. AB - The therapeutic landscape of renal cell carcinoma (RCC) has greatly expanded in the last decade. From being a malignancy orphan of effective therapies, kidney cancer has become today a tumor with several treatment options. Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK TSC1/2-mTOR and PI3K-Akt-mTOR pathways). In this complex scenario it is important to find prognostic and predictive factors that can help in decision making in the treatment of mRCC. PMID- 27453296 TI - Timing of Pharmacologic Venous Thromboembolism Prophylaxis in Severe Traumatic Brain Injury: A Propensity-Matched Cohort Study. AB - BACKGROUND: Patients with severe traumatic brain injury (sTBI) are at high risk for developing venous thromboembolism (VTE). Nonetheless, pharmacologic VTE prophylaxis is often delayed out of concern for precipitating extension of intracranial hemorrhage (ICH). The purpose of this study was to compare the effectiveness of early vs late VTE prophylaxis in patients with sTBI, and to characterize the risk of subsequent ICH-related complication. STUDY DESIGN: Adults with isolated sTBI (head Abbreviated Injury Scale score >=3 and total Glasgow Coma Scale score <=8) who received VTE prophylaxis with low-molecular weight or unfractionated heparin were derived from the American College of Surgeons Trauma Quality Improvement Program (2012 to 2014). Patients were divided into EP (<72 hours) or LP (>=72 hours) groups. Propensity score matching was used to minimize selection bias. The primary end point was VTE (pulmonary embolism or deep vein thrombosis). Secondary outcomes were defined as late neurosurgical intervention (>=72 hours) or death. RESULTS: We identified 3,634 patients with sTBI. Early prophylaxis was given in 43% of patients. Higher head injury severity, presence of ICH, and early neurosurgery were associated with late prophylaxis. Propensity score matching yielded a well-balanced cohort of 2,468 patients. Early prophylaxis was associated with lower rates of both pulmonary embolism (odds ratio = 0.48; 95% CI, 0.25-0.91) and deep vein thrombosis (odds ratio = 0.51; 95% CI, 0.36-0.72), but no increase in risk of late neurosurgical intervention or death. CONCLUSIONS: In this observational study of patients with sTBI, early initiation of VTE prophylaxis was associated with decreased risk of pulmonary embolism and deep vein thrombosis, but no increase in risk of late neurosurgical intervention or death. Early prophylaxis may be safe and should be the goal for each patient in the context of appropriate risk stratification. PMID- 27453297 TI - Twinning in Norway Following the Oslo Massacre: Evidence of a 'Bruce Effect' in Humans. AB - Emerging theory and empirical work suggest that the 'Bruce Effect', or the increase in spontaneous abortion observed in non-human species when environments become threatening to offspring survival, may also appear in humans. We argue that, if it does, the effect would appear in the odds of twins among male and female live births. We test the hypothesis, implied by our argument, that the odds of a twin among male infants in Norway fell below, while those among females rose above, expected levels among birth cohorts in gestation in July 2011 when a deranged man murdered 77 Norwegians, including many youths. Results support the hypothesis and imply that the Bruce Effect operates in women to autonomically raise the standard of fetal fitness necessary to extend the gestation of twins. This circumstance has implications for using twins to estimate the relative contributions of genes and environment to human responses to exogenous stimuli. PMID- 27453298 TI - Injected novel legal highs associated with severe soft tissue infection: A regional hand unit's experience. PMID- 27453299 TI - The mesially impacted mandibular third molar: The incidence and consequences of distal cervical caries in the mandibular second molar. AB - AIMS: Distal Cervical Caries (DCC) of the mandibular second molar (Md2M) is primarily related to retained mesially impacted third molars (Md3M). Treatment of this condition indicates the removal of the Md3M and the restoration of the Md2M and, on occasions, the loss of the Md2M. The aim of this study was to determine the incidence, treatment outcomes for patients, and calculate costs related to Md2M DCC. METHODS: A review of 121 patients who had Md3M removed due to Md2M DCC was undertaken to determine the treatment outcomes for patients. The number of patients affected by DCC of Md2M was calculated from the incidence of DCC (15%) in a cohort of patients requiring Md3M removal (1100) and the annual number of patients undergoing third molar surgery in England. Direct costs were calculated using NHS and independent treatment tariffs and indirect costs from Office of National Statistics (ONS). RESULTS: It is estimated that 152,000 patients in England undergo third molar removal on an annual basis. Approximately 27,000 Md3M are removed annually due to DCC of the Md2M; costing L27 m to treat with additional costs of L28 m if dental implant replacement of the Md2M is included. Total cost for treating Md2M DCC: L55 m/annum. CONCLUSIONS: Treating Md2M DCC and its consequences is expensive for healthcare funders such as the NHS and for patients. Md2M DCC is avoidable if patients who are at risk have prophylactic Md3M removal. This would offer potential and substantial savings in the financial cost of treating an otherwise avoidable disease. PMID- 27453300 TI - Ten-year follow-up analysis of chronic hepatitis C patients after getting sustained virological response to pegylated interferon-alpha and ribavirin therapy. AB - There is little data on the long-term follow-up outcomes of chronic hepatitis C patients achieving sustained virological response (SVR) after treatment with peglylated interferon-alpha plus ribavirin. We prospectively investigated the overall clinical, biochemical, virological and histological outcomes in a ten year cohort study of 325 patients with chronic hepatitis C achieving SVR to pegylated interferon-alpha and ribavirin therapy. Patients underwent consistent clinical, biochemical and virological evaluation every six months, and patients with pretherapy Ishak fibrosis score >=2 were invited to accept a second liver biopsy at the last follow-up. Liver biopsy specimens were evaluated using Ishak's scoring system. At the end of follow-up, five patients developed decompensated liver cirrhosis. One patient (0.3%) with pretherapy cirrhosis was diagnosed with hepatocellular carcinoma (HCC). A total of 305 patients (94%) had normal serum ALT and AST levels during the entire period of follow-up. Twenty-seven patients (8%) had conclusive evidence of virological relapse. Among the 117 patients with paired pretherapy and long-term follow-up biopsies, 96 (82%) had a decreased fibrosis score. Ninety-nine (79%) had a decrease in combined inflammation score. Thirty-seven (32%) had normal or nearly normal livers on long-term follow-up biopsy. SVR achieved with PEG-IFN-alpha and RBV combination therapy is durable, while late virological relapse may still occur in some patients. Clinical outcomes for patients who obtain SVR are excellent, although the patients with cirrhosis are still at a low risk of hepatocellular carcinoma. PMID- 27453302 TI - (Neo)adjuvant systemic therapy for melanoma. AB - Surgery still is the cornerstone of treatment for patients with stage II and III melanoma, but despite great efforts to gain or preserve locoregional control with excision of the primary tumour, satellites, intransits, sentinel node biopsy and lymphadenectomy, surgery alone does not seem to improve survival any further. Prognosis for patients with high risk melanoma remains poor with 5-year survival rates of 40 to 80%. Only interferon-2b has been approved as adjuvant therapy since 1995, but clinical integration is low considering the high risk-benefit ratio. In recent years systemic targeted- and immunotherapy have proven to be beneficial in advanced melanoma and could be a promising strategy for (neo)adjuvant treatment of patients with resectable high risk melanomas as well. Randomised, placebo- controlled phase III trials on adjuvant systemic targeted- and immunotherapy are currently being performed using new agents like ipilimumab, pembrolizumab, nivolumab, vemurafenib and dabrafenib plus trametinib. In this article we review the literature on currently known adjuvant therapies and currently ongoing trials of (neo)adjuvant therapies in high risk melanomas. PMID- 27453303 TI - Targeted PET imaging for prostate-specific membrane antigen in prostate cancer. PMID- 27453304 TI - 62nd International Congress of Meat Science and Technology. PMID- 27453305 TI - Here, There and Everywhere: The Radiolar Eyes of Fan Worms (Annelida, Sabellidae). AB - Fan worms (Annelida: Sabellidae) possess some of the strangest eyes in nature. Their eponymous fans are composed of two sets of radiolar tentacles that project from the head up out of the worm's protective tube into the water column. Primarily used for respiration and feeding, these radioles are also often involved in photoreception. They display a surprising diversity of eyes of varying levels of sophistication, ranging from scattered single ocelli to compound eyes with up to hundreds of facets. These photoreceptors could represent a relatively recent evolutionary development to cope with a sessile, tube dwelling lifestyle, and the primary cerebral eyes (haplessly positioned within the tube most of the time) amount to little more than minute pigment cups with scant visual potential. The radiolar eyes on the other hand, appear to function as visual burglar alarms for detecting looming predators and eliciting a startle response for the worm to rapidly retreat within its fortified tube. Despite sometimes resembling arthropod compound eyes, the radiolar photoreceptors have many canonically vertebrate-like physiological characteristics. Considering the unusual and apparently recently evolved nature of the fan worm radiolar photoreceptors, these animals are an excellent case for examining the emergence of novel visual systems, the development of rudimentary visually guided behaviors, and the function of distributed sensory systems. Here, we review over 100 years of investigations into the anatomical diversity of sabellid radiolar photoreceptors and eyes in an evolutionary and functional context. We provide new information on radiolar eye structure in several species of fan worms, and we attempt to organize the various eye types and ocellar structures into meaningful hierarchies. We discuss the developmental, evolutionary, and functional significance of the radiolar eyes and highlight areas of future interest in deciphering their unique nature. PMID- 27453307 TI - Thanatopsis. PMID- 27453306 TI - Problems + Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27453308 TI - The Medical Bookshelf. PMID- 27453309 TI - Avoidance of allergens. PMID- 27453310 TI - Chronic constipation in children. PMID- 27453311 TI - Dermatology. PMID- 27453312 TI - Bacterial skin infections. PMID- 27453314 TI - Primary Care Digest. PMID- 27453313 TI - The first hour after massive pulmonary embolism. PMID- 27453316 TI - Selected National Meetings. PMID- 27453319 TI - Rhizobium altiplani sp. nov., isolated from effective nodules on Mimosa pudica growing in untypically alkaline soil in central Brazil. AB - Root nodule bacteria were isolated from nodules on Mimosa pudica L. growing in neutral-alkaline soils from the Distrito Federal in central Brazil. The 16S rRNA gene sequence analysis of 10 strains placed them into the genus Rhizobium with the closest neighbouring species (each with 99 % similarity) being Rhizobium grahamii, Rhizobium cauense, Rhizobium mesoamericanum and Rhizobium tibeticum. This high similarity, however, was not confirmed by multi-locus sequence analysis (MLSA) using three housekeeping genes (recA, glnII and rpoB), which revealed R. mesoamericanum CCGE 501T to be the closest type strain (92 % sequence similarity or less). Chemotaxonomic data, including fatty acid profiles [with majority being C19 : 0 cyclo omega8c and summed feature 8 (C18 : 1omega7c/C18 : 1omega6c)], DNA G+C content (57.6 mol%), and carbon compound utilization patterns supported the placement of the novel strains in the genus Rhizobium. Results of average nucleotide identity (ANI) differentiated the novel strains from the closest species of the genus Rhizobium, R. mesoamericanum, R. grahamii and R. tibeticum with 89.0, 88.1 and 87.8 % similarity, respectively. The symbiotic genes essential for nodulation (nodC) and nitrogen fixation (nifH) were most similar (99-100 %) to those of R. mesoamericanum, another Mimosa-nodulating species. Based on the current data, these 10 strains represent a novel species of the genus Rhizobium for which the name Rhizobium altiplani sp. nov. is proposed. The type strain is BR 10423T (=HAMBI 3664T). PMID- 27453320 TI - Age-specific genetic and antigenic variations of influenza A viruses in Hong Kong, 2013-2014. AB - Age-specific genetic and antigenic variations of influenza viruses have not been documented in tropical and subtropical regions. We implemented a systematic surveillance program in two tertiary hospitals in Hong Kong Island, to collect 112 A(H1N1)pdm09 and 254 A(H3N2) positive specimens from 2013 to 2014. Of these, 56 and 72 were identified as genetic variants of the WHO recommended vaccine composition strains, respectively. A subset of these genetic variants was selected for hemagglutination-inhibition (HI) tests, but none appeared to be antigenic variants of the vaccine composition strains. We also found that genetic and antigenicity variations were similar across sex and age groups of <=18 yrs, 18 to 65 yrs, and >=65 yrs. Our findings suggest that none of the age groups led other age groups in genetic evolution of influenza virus A strains. Future studies from different regions and longer study periods are needed to further investigate the age and sex heterogeneity of influenza viruses. PMID- 27453321 TI - Dual Effect of Rosuvastatin on Glucose Homeostasis Through Improved Insulin Sensitivity and Reduced Insulin Secretion. AB - Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets. In the beta cell Ca(2+) signaling was impaired and the density of granules at the plasma membrane was increased by rosuvastatin treatment. HFD mice developed insulin resistance and increased insulin secretion prior to administration of rosuvastatin. Treatment with rosuvastatin decreased the compensatory insulin secretion and increased glucose uptake. In conclusion, our data shows dual effects on glucose homeostasis by rosuvastatin where insulin sensitivity is improved, but beta cell function is impaired. PMID- 27453323 TI - One Size Fits All: Does the Dogma Stand in Radiation Oncology? PMID- 27453322 TI - Lactoferrin Suppresses Neutrophil Extracellular Traps Release in Inflammation. AB - Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases. PMID- 27453324 TI - Phylogeny of Wilms tumor? PMID- 27453327 TI - Design, synthesis and excellent third-order NLO properties of two new polyoxometalates constructed from Keggin polyanions bonded by a solvent molecule. AB - Two new monosubstituted Keggin structural polyoxometalates [H5PMo11O39Zn(C5H5N)].(C5H5N)5.H2O (1) and [H5PW11O39Co(C5H5N)].(C5H5N)2.(C6H8N)2.1.5CH3OH (2) have been successfully synthesized under hydrothermal conditions. Structural analysis indicates that the polyoxoanion of compound 1 is a solvent molecule-bonded zinc-monosubstituted Keggin structural cluster, [PMo11O39Zn(C5H5N)](5-), while the polyoxoanion of compound 2 is a cobalt-monosubstituted phosphotungstate polyanion bonded with one pendant pyridine molecule. Both 1 and 2 show 3D supramolecular interpenetrating structures constructed of inorganic polyanion layers and organic layers. Very interestingly, compounds 1 and 2 exhibit excellent third-order NLO properties, and the TPA cross section sigma of 1 and 2 is 2571.3 GM and 2876.3 GM, respectively. PMID- 27453325 TI - Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex. AB - The recent Zika outbreak in South America and French Polynesia was associated with an epidemic of microcephaly, a disease characterized by a reduced size of the cerebral cortex. Other members of the Flavivirus genus, including West Nile virus (WNV), can cause encephalitis but were not demonstrated to cause microcephaly. It remains unclear whether Zika virus (ZIKV) and other flaviviruses may infect different cell populations in the developing neocortex and lead to distinct developmental defects. Here, we describe an assay to infect mouse E15 embryonic brain slices with ZIKV, WNV and dengue virus serotype 4 (DENV-4). We show that this tissue is able to support viral replication of ZIKV and WNV, but not DENV-4. Cell fate analysis reveals a remarkable tropism of ZIKV infection for neural stem cells. Closely related WNV displays a very different tropism of infection, with a bias towards neurons. We further show that ZIKV infection, but not WNV infection, impairs cell cycle progression of neural stem cells. Both viruses inhibited apoptosis at early stages of infection. This work establishes a powerful comparative approach to identify ZIKV-specific alterations in the developing neocortex and reveals specific preferential infection of neural stem cells by ZIKV. PMID- 27453328 TI - NDUFA4L2 expression predicts poor prognosis in clear cell renal cell carcinoma patients. AB - BACKGROUND: NDUFA4L2 is overexpressed in VHL-deficient cell lines and neuroblastoma. The clinical significance of NDUFA4L2 in clear cell renal cell carcinoma (ccRCC) has not been well studied. Therefore, we evaluated the prognostic value of NDUFA4L2 in ccRCC patients. METHODS: In our study, NDUFA4L2 expression in 86 cases of ccRCC and adjacent normal tissues was monitored by immunohistochemistry, semi-quantitative RT-PCR, and Western blot analyses. The relationship between NDUFA4L2 expression and the clinical features of ccRCC was assessed. RESULTS: The results showed that NDUFA4L2 protein expression was found to be higher in ccRCC tissues 81.4% (70/86) than in normal tissues 26.7% (23/86) (p = 0.021). The average level of NDUFA4L2 mRNA expression was found to be 122.23 +/- 6.018 and 21.34 +/- 1.036 in ccRCC tissue and adjacent normal tissue (p < 0.001). NDUFA4L2 expression levels were correlated with some clinical features of ccRCC. Multivariate analysis showed NDUFA4L2 expression was an independent prognostic factor for ccRCC patients. CONCLUSIONS: Our study has provided the significant clinical relevance of NDUFA4L2 in ccRCC and suggested that ccRCC patients with NDUFA4L2 overexpression may be suitable as a potential therapeutic target for ccRCC patients. PMID- 27453329 TI - The 7 * 1 Fermi Surface Reconstruction in a Two-dimensional f -electron Charge Density Wave System: PrTe3. AB - The electronic structure of a charge density wave (CDW) system PrTe3 and its modulated structure in the CDW phase have been investigated by employing ARPES, XAS, Pr 4 f RPES, and first-principles band structure calculation. Pr ions are found to be nearly trivalent, supporting the CDW instability in the metallic Te sheets through partial filling. Finite Pr 4 f spectral weight is observed near the Fermi level, suggesting the non-negligible Pr 4 f contribution to the CDW formation through the Pr 4 f -Te 5p hybridization. The two-fold symmetric features in the measured Fermi surface (FS) of PrTe3 are explained by the calculated FS for the assumed 7 * 1 CDW supercell formation in Te sheets. The shadow bands and the corresponding very weak FSs are observed, which originate from both the band folding due to the 3D interaction of Te sheets with neighboring Pr-Te layers and that due to the CDW-induced FS reconstruction. The straight vertical FSs are observed along kz, demonstrating the nearly 2D character for the near-EF states. The observed linear dichroism reveals the in plane orbital character of the near-EF Te 5p states. PMID- 27453330 TI - Daily shedding dynamics of E. coli O157 in an Australian grass-fed beef herd. AB - This study aimed to describe the diurnal shedding dynamics of Escherichia coli O157 in cattle managed on pasture. The purpose was to identify the value of a single measurement for predicting the shedding status on subsequent days. Over a 14-day period, 24 beef cows with known E. coli O157 shedding status were sampled twice daily or daily (21 sampling points) and E. coli O157 was enumerated from faeces. No association between shedding status of individual animals within a 7-h period was identified (odds ratio 1.5, P = 0.08). Short-interval sampling demonstrated substantial diurnal volatility in shedding of E. coli O157 that is not evident in studies based on long-interval (>7 days) sampling. The findings contribute to and support previous findings on the question why it has been difficult to achieve progress in understanding the epidemiology of E. coli O157 infection in cattle. PMID- 27453331 TI - Calpastatin overexpression reduces oxidative stress-induced mitochondrial impairment and cell death in human neuroblastoma SH-SY5Y cells by decreasing calpain and calcineurin activation, induction of mitochondrial fission and destruction of mitochondrial fusion. AB - Calpain is an intracellular Ca(2+)-dependent protease, and the activation of calpain has been implicated in neurodegenerative diseases. Calpain activity can be regulated by calpastatin, an endogenous specific calpain inhibitor. Several lines of evidence have demonstrated a potential role of calpastatin in preventing calpain-mediated pathogenesis. Additionally, several studies have revealed that calpain activation and mitochondrial damage are involved in the cell death process; however, recent evidence has not clearly indicated a neuroprotective mechanism of calpastatin against calpain-dependent mitochondrial impairment in the process of neuronal cell death. Therefore, the purpose of this study was to investigate the potential ability of calpastatin to inhibit calpain activation and mitochondrial impairment in oxidative stress-induced neuron degeneration. Calpastatin was stably overexpressed in human neuroblastoma SH-SY5Y cells. In non calpastatin overexpressing SH-SY5Y cells, hydrogen peroxide significantly decreased cell viability, superoxide dismutase activity, mitochondrial membrane potential, ATP production and mitochondrial fusion protein (Opa1) levels in the mitochondrial fraction but increased reactive oxygen species formation, calpain and calcineurin activation, mitochondrial fission protein (Fis1 and Drp1) levels in the mitochondrial fraction and apoptotic cells. Nevertheless, these toxic effects were abolished in hydrogen peroxide-treated calpastatin-overexpressing SH SY5Y cells. The results of the present study demonstrate the potential ability of calpastatin to diminish calpain and calcineurin activation and mitochondrial impairment in neurons that are affected by oxidative damage. PMID- 27453332 TI - Acute encephalopathy of the temporal lobes leading to m.3243A>G. When MELAS is not always MELAS. AB - MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a rare genetic condition whose differential diagnosis is often posed with juvenile stroke, but more rarely even with inflammatory/infectious encephalitis, causing diagnostic challenges. Here we report the case of a young man harbouring the m.3243A>G MELAS mutation presenting an acute onset mimicking the clinical and neuroimaging features of infective encephalitis. PMID- 27453334 TI - Immediate memory and electrophysiologic effects of prefrontal cortex transcranial direct current stimulation on neurotypical individuals and individuals with chronic traumatic brain injury: a pilot study. AB - : Purpose/aim: Memory impairment post-TBI is common, frequently persistent, and functionally debilitating. The purposes of this pilot study were to assess and to compare immediate behavioral auditory working memory and electrophysiologic effects of three different, randomized, conditions of left dorsolateral prefrontal cortex (LDLPFC) transcranial direct current stimulation (tDCS) applied to four neurotypical adults and four adults with chronic traumatic brain injury (TBI). MATERIALS/METHODS: Pre- and post-anodal, cathodal, and sham tDCS auditory memory performance, auditory event-related potentials (P300 amplitude and latency) and power of alpha and theta EEG bands were measured across individuals in each group. RESULTS: Post-anodal tDCS only, the neurotypical and TBI groups both demonstrated significantly improved immediate auditory memory function. Also post-anodal tDCS, the TBI group demonstrated significantly increased P300 amplitude versus post-sham tDCS. The neurotypical group demonstrated no pre- post tDCS electrophysiologic changes across conditions. CONCLUSIONS: These findings are consistent with findings of other studies of immediate tDCS effects on other types of memory in neurotypical individuals and in individuals with Parkinson's disease, Alzheimer's disease and stroke and suggest that individuals with memory impairments second to chronic TBI may benefit from LDLPFC anodal tDCS. Pairing tDCS with traditional behavioral memory interventions may facilitate TBI rehabilitation outcomes and warrants continued investigation. PMID- 27453336 TI - Use of Text Searching for Trigger Words in Medical Records to Identify Adverse Drug Reactions within an Intensive Care Unit Discharge Summary. AB - PURPOSE: To evaluate the performance of using trigger words (e.g. clues to an adverse drug reaction) in unstructured, narrative text to detect adverse drug reactions (ADRs) and compare the use of these trigger words to a targeted chart review for ADR detection within the intensive care unit (ICU) discharge summary note. MATERIALS: A retrospective medical record review was conducted. Evaluation of ADRs occurred in two phases - targeted chart review of the ICU discharge summary notes in Phase 1 and targeted chart review using specific words and phrases as triggers for ADRs in Phase 2. RESULTS: Four hundred ADRs were documented in 223 patients for Phase 1. For Phase 2, there were 219 ADRs identified in 120 patients. 138 real or accurate ADRs were identified from Phase 1 and 47 duplicate events. 34 ADRs from Phase 2 were not identified in Phase 1. Fifteen of the ADRs were inaccurately presumed in Phase 2. Fifty-eight of 127 text triggers identified at least one ADR. Low and moderate frequency trigger words were more likely to have PPVs > 5%. CONCLUSIONS: Targeted chart review using specific words and phrases as triggers for ADRs is a reasonable approach to identify ADRs and may save time compared to other methods after further refinement leads to a more accurately performing trigger word list. PMID- 27453337 TI - WT1 is involved in the Akt-JNK pathway dependent autophagy through directly regulating Gas1 expression in human osteosarcoma cells. AB - Macroautophagy (herein termed autophagy) works as a protective mechanism in tumorigenesis and development under metabolic stress condition. Multitudes of genes have been found involved in this process during past decades. In the present study, we report that Wilm's tumor suppressor1 (WT1) is involved in autophagy in osteosarcoma (OS) cells. WT1, a transcription factor with multitude of target genes, expresses in a majority of cancer types. Though wide-ranging effect of WT1 is now well documented, the function of WT1 in tumors remains poorly defined. In this chapter, it is found that high expression of WT1 positively correlates with active autophagy in human osteosarcoma cells. And further study on cell signaling pathway illustrates that Akt/JNK pathway acts as a positive regulator of autophagy induced by WT1. Here, we present evidence that WT1 modulates Akt/JNK signaling pathway mediated autophagy by controlling the expression of growth arrest-specific 1 (Gas1). We show that WT1 is required for Gas1 transcription in osteosarcoma cells. And Gas1 is upregulated followed WT1 overexpression in a time-dependent manner. Loss of Gas1 results in a reduction of WT1-induced autophagy. PMID- 27453335 TI - Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling. AB - Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigated the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Oral administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism. PMID- 27453338 TI - Hyperbaric oxygen preconditioning protects the lung against acute pancreatitis induced injury via attenuating inflammation and oxidative stress in a nitric oxide dependent manner. AB - This study aimed to investigate the protective effects of hyperbaric oxygen preconditioning (HBO-PC) on acute pancreatitis AP associated acute lung injury (ALI) and the potential mechanisms. Rats were randomly divided into sham group, AP group, HBO-PC + AP group and HBO-PC + L-NAME group. Rats in HBO-PC + AP group received HBO-PC once daily for 3 days, and AP was introduced 24 h after last HBO PC. In HBO-PC + L-NAME group, L-NAME (40 mg/kg) was intraperitoneally injected before each HBO-PC. At 24 h after AP, the blood lipase and amylase activities were measured; the lung and pancreas were harvested for pathological examination; the bronchoalveolar lavage fluid was collected for the detection of lactate dehydrogenase (LDH) and proteins; inflammatory factors, superoxide dismutase (SOD) activity and malonaldehyde content were measured in the lung and blood; the Nrf2, SOD-1 and haem oxygenase-1 (HO-1) protein expression was measured in the lung. The lung nitric oxide (NO) and NO synthase activity increased significantly after HBO-PC. HBO-PC was able to reduce blood lipase and amylase activities, improve lung and pancreatic pathology, decrease LDH and proteins in BALF, inhibit the production of inflammatory factors, reduce malonaldehyde content and increase SOD activity in the lung and blood as well as increase protein expression of Nrf2, SOD-1 and HO-1 in the lung. However, L-NAME before HBO-PC significantly attenuated protective effects of HBO-PC. HBO-PC is able to protect the lung against AP induced injury by attenuating inflammation and oxidative stress in the lung via a NO dependent manner. PMID- 27453339 TI - Bevacizumab reduced auto-phosphorylation of VEGFR2 to protect HDM-induced asthma mice. AB - Vascular endothelial growth factor (VEFG) is a major angiogenic factor involved in both normal physiological processes, such as embryonic development and wound healing, and in diseases, like cancer. Recent studies have revealed the functions of VEGF in inflammation and immunoregulation. Asthma is a chronic inflammation of the airways characterized by airway epithelial barrier dysfunction and imbalance in T-helper (Th) 1/Th2 during immunoregulation. We hypothesized that VEGF plays an important role in asthma. Utilizing a house dust mite extract (HDM)-induced murine model of asthma, we investigated whether bevacizumab, a humanized anti VEGF monoclonal antibody, could protect the epithelial barrier in murine airways. We found that bevacizumab reduced airway hyper-responsiveness (AHR) and airway inflammation induced by HDM. In addition, HDM exposure promoted expression of VEGF, and caused AHR, disruptions of the epithelial barrier, and airway inflammation. Bevacizumab ameliorated AHR and the release of Th2 cytokines, thereby protecting the epithelial barrier. Our data suggest that bevacizumab may be a new therapeutic strategy for asthma. PMID- 27453340 TI - Down-regulation of Barx2 predicts poor survival in colorectal cancer. AB - Human BarH-like homeobox 2 (Barx2), a homeodomain factor of the Bar family, has an important role in controlling the expression of cell adhesion molecules and has been reported in an increasing array of tumor types except colorectal cancer (CRC). The purpose of the current study was to characterize the expression of Barx2 and assess the clinical significance of Barx2 in CRC. First, we analyzed the expression of Barx2 in two independent public datasets from Oncomine. Subsequently, we evaluated Barx2 mRNA and protein expression by quantitative real time PCR and western blotting, respectively. It was determined that Barx2 expression was lower in tumor tissues than in adjacent non-tumorous colorectal tissues of CRC patients, consistent with results from the public datasets. Subsequently, a tissue microarray containing 196 CRC specimens was evaluated for Barx2 expression by immunohistochemical staining. It was found that low expression of Barx2 significantly correlated with TNM stage, AJCC stage, differentiation, and relapse in patients with CRC. Patients with lower levels of Barx2 expression showed reduced disease-free survival and overall survival. Furthermore, a trend toward shorter overall survival in the patient group with Barx2-negative tumors independent of advanced AJCC stage and poor differentiation was determined by Kaplan-Meier survival analysis. Based on univariate and multivariate analyses, Barx2 expression was an independent prognostic factor for determining CRC prognosis. Taken together, low Barx2 expression was associated with the progression of CRC and could serve as a potential independent prognostic biomarker for patients with CRC. PMID- 27453341 TI - The role of nuclear factor E2-Related factor 2 and uncoupling protein 2 in glutathione metabolism: Evidence from an in vivo gene knockout study. AB - Nuclear factor E2-related factor 2 (NRF2) and uncoupling protein 2 (UCP2) are indicated to protect from oxidative stress. They also play roles in the homeostasis of glutathione. However, the detailed mechanisms are not well understood. In the present study, we found Nrf2-knockout (Nrf2-KO) mice exhibited altered glutathione homeostasis and reduced expression of various genes involved in GSH biosynthesis, regeneration, utilization and transport in the liver. Ucp2 knockout (Ucp2-KO) mice exhibited altered glutathione homeostasis in the liver, spleen and blood, as well as increased transcript of cystic fibrosis transmembrane conductance regulator in the liver, a protein capable of mediating glutathione efflux. Nrf2-Ucp2-double knockout (DKO) mice showed characteristics of both Nrf2-KO and Ucp2-KO mice. But no significant difference was observed in DKO mice when compared with Nrf2-KO or Ucp2-KO mice, except in blood glutathione levels. These data suggest that ablation of Nrf2 and Ucp2 leads to disrupted GSH balance, which could result from altered expression of genes involved in GSH metabolism. DKO may not evoke more severe oxidative stress than the single gene knockout. PMID- 27453342 TI - Transcriptional regulation of BMCC1 mediated by E2F1 in neuroblastoma cells. AB - BCH motif-containing molecule at the carboxyl terminal region 1 (BMCC1)/PRUNE2 is highly expressed in patients with favorable neuroblastoma (NB), encoding a multifunctional scaffold protein that modulates several signaling networks including RhoA and AKT pathways. Accumulating evidence suggests that BMCC1 acts as a tumor-suppressor. In this study, we addressed molecular mechanism underlying transcriptional regulation of BMCC1 in NBs. We found that transcription factor E2F1 was recruited to E2F-binding site in the promoter region of BMCC1 gene. Indeed, overexpression of E2F1 resulted in an increase in the expression level of BMCC1 in NB cell lines. On the other hand, knockdown of E2F1 in NB cells yielded down-regulation of BMCC1. Also, we showed that BMCC1 and E2F1 were simultaneously induced at G1 to S phase transition. Therefore, we conclude that E2F1 directly facilitated BMCC1 transcription. Taking together, these results suggest that BMCC1 induced by E2F1 acts as a tumor suppressor through its pro-apoptotic function, resulted in favorable prognosis of NB. PMID- 27453343 TI - Age-related posterior ciliary muscle restriction - A link between trabecular meshwork and optic nerve head pathophysiology. AB - The ciliary muscle plays a major role in controlling both accommodation and outflow facility in primates. The ciliary muscle and the choroid functionally form an elastic network that extends from the trabecular meshwork all the way to the back of the eye and ultimately attaches to the elastic fiber ring that surrounds the optic nerve and to the lamina cribrosa through which the nerve passes. The ciliary muscle governs the accommodative movement of the elastic network. With age ciliary muscle mobility is restricted by progressively inelastic posterior attachments and the posterior restriction makes the contraction progressively isometric; placing increased tension on the optic nerve region. In addition, outflow facility also declines with age and limbal corneoscleral contour bows inward. Age-related loss in muscle movement and altered limbal corneoscleral contour could both compromise the basal function of the trabecular meshwork. Further, recent studies in non-human primates show that the central vitreous moves posteriorly all the way back to the optic nerve region, suggesting a fluid current and a pressure gradient toward the optic nerve. Thus, there may be pressure and tension spikes on the optic nerve region during accommodation and these pressure and tension spikes may increase with age. This constellation of events could be relevant to glaucomatous optic neuropathy. In summary, our hypothesis is that glaucoma and presbyopia may be literally linked to each other, via the choroid, and that damage to the optic nerve may be inflicted by accommodative intraocular pressure and choroidal tension "spikes", which may increase with age. PMID- 27453344 TI - Smad-independent TGF-beta2 signaling pathways in human trabecular meshwork cells. AB - Aberrant expression and signaling of Transforming Growth Factor (TGF)-beta is strongly associated with development of elevated intraocular pressure (IOP) and primary open-angle glaucoma (POAG). In cells of the trabecular meshwork, a key component of the conventional outflow pathway, TGF-beta is well-known to promote expression of multiple ocular hypertensive mediators, including genes associated with fibrosis as well as cellular contractility. These effects are mediated by induction of canonical (Smad) as well as non-canonical (MAPK, Rho GTPase) signaling cascades. In the present review, we will highlight the non-canonical, Smad-independent signaling pathways activated by TGF-beta2 in human TM cells, as well as the genes known to be induced by non-canonical TGF-beta2 signaling. PMID- 27453347 TI - Hairy cellulose nanocrystalloids: a novel class of nanocellulose. AB - Nanomaterials have secured such a promising role in today's life that imagining the modern world without them is almost impossible. A large fraction of nanomaterials is synthesized from environmentally-dangerous elements such as heavy metals, which have posed serious side-effects to ecosystems. Despite numerous advantages of synthetic nanomaterials, issues such as renewability, sustainability, biocompatibility, and cost efficiency have drawn significant attention towards natural products such as cellulose-based nanomaterials. Within the past decade, nanocelluloses, most remarkably nanocrystalline cellulose (NCC) and nanofibrillated cellulose (NFC), have successfully been used for a wide spectrum of applications spanning from nanocomposites, packaging, and mechanical and rheological property modifications, to chemical catalysis and organic templating. Yet, there has been little effort to introduce fundamentally new polysaccharide-based nanomaterials. We have been able to develop the first kind of cellulose-based nanoparticles bearing both crystalline and amorphous regions. These nanoparticles comprise a crystalline body, similar to conventional NCC, but with polymer chains protruding from both ends; therefore, these particles are called hairy cellulose nanocrystalloids (HCNC). In this article, we touch on the philosophy of HCNC synthesis, the striking superiority over existing nanocelluloses, and applications of this novel class of nanocelluloses. We hope that the emergence of hairy cellulose nanocrystalloids extends the frontiers of sustainable, green nanotechnology. PMID- 27453345 TI - Large-scale functional brain connectivity during emotional engagement as revealed by beta-series correlation analysis. AB - It has been hypothesized that the medial prefrontal cortex (mPFC) is a hub in the network that mediates appetitive responses whereas the amygdala is thought to mediate both aversive and appetitive processing. Both structures may facilitate adaptive responses to emotional challenge by linking perception, attention, memory, and motor circuits. We provide an initial exploration of these hypotheses by recording simultaneous EEG-fMRI in eleven participants viewing affective pictures. MPFC- and amygdala-seeded functional connectivity maps were generated by applying the beta-series correlation method. The mPFC-seeded correlation map encompassed visual regions, sensorimotor areas, prefrontal cortex, and medial temporal lobe structures, exclusively for pleasant content. For the amygdala seeded correlation map, a similar set of distributed brain areas appeared in the unpleasant-neutral contrast, with the addition of structures such as the insula and thalamus. A substantially sparser network was recruited for the pleasant neutral contrast. Using the late positive potential (LPP) to index the intensity of emotional engagement, functional connectivity was found to be stronger in trials with larger LPP. These results demonstrate that mPFC-mediated functional interactions are engaged specifically during appetitive processing, whereas the amygdala is coupled to distinct sets of brain regions during both aversive and appetitive processing. The strength of these interactions varies as a function of the intensity of emotional engagement. PMID- 27453346 TI - Use of grafts in rotator cuff re-rupture. AB - INTRODUCTION AND OBJECTIVES: Rotator cuff re-ruptures appear in 38-65% of cases. In order to reduce this rate, many studies have been performed using different types of biomaterial for purely mechanical aims (re-inforce the suture) and/or biological agents (growth factor transporterts). The aim of this study is to review 22 cases treated with xenografts and analyse various current alternatives. MATERIALS AND METHODS: A descriptive and retrospective study was conducted using the variables of age, sex, laterality, time of surgery, involvement in MRI, number of anchors, and final mobility results on the Constant and the University of California Los Angeles (UCLA) validated scales. RESULTS: The study included 22 patients, with a mean age of 51.7+/-4.6 years. A mean of 2 anchors were used and 13 patients were treated with a porcine intestinal submucosa implant, 6 with equine pericardium, and 3 with porcine dermis. Final results were: 37.6+/-13 points for the Constant test, and 16.9+/-3.9 points on the UCLA scale. The follow up was 36+/-10.2 months. CONCLUSIONS: In our experience, xenografts could provide good functional results and they would be a surgical alternative to tendon transfers in cases of massive tears. Further studies should be conducted with other biomaterials. PMID- 27453348 TI - Effects of radiation on the temporal bone in patients with head and neck cancer. AB - Radiotherapy is a key component in the treatment of many head and neck cancers, and its potential to cause long-term adverse effects has become increasingly recognized. In this review, we describe the short-term and long-term sequelae of radiation-associated changes in and injury to the temporal bone and its related structures. The pathophysiology of radiation-induced injury and its clinical entities, including sensorineural hearing loss, chronic otitis media, osteoradionecrosis, and radiation-associated malignancies, are described. We also discuss radiation dose to the head and neck as it relates to these conditions. An improved understanding of radiation's effects on the temporal bone will enable physicians and researchers to continue efforts to reduce radiotherapy-related sequelae and guide clinicians in diagnosing and treating the various otologic conditions that can arise in patients with head and neck cancer who have received radiotherapy. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1428-1435, 2016. PMID- 27453349 TI - Rab proteins as regulators of lipid droplet formation and lipolysis. AB - Lipid droplets (LDs) are highly dynamic organelles that not only store neutral lipids but also are involved in multiple cellular processes. Dysregulation of lipogenesis or lipolysis greatly contributes to the pathogenesis of several human diseases, including obesity, diabetes, and fatty liver disease. Rab proteins have been found to be associated with LDs in proteomic studies and are also known to extensively regulate intracellular membrane traffic, suggesting that LDs actively communicate with other membrane compartments to maintain energy homeostasis. This review discusses recent studies that provide mechanistic insights into the regulation of LD formation and catabolism by Rab proteins in mammalian cells. PMID- 27453350 TI - P/CAF mediates PAX3-FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma. AB - Alveolar rhabdomyosarcoma (ARMS) is an aggressive paediatric cancer of skeletal muscle with poor prognosis. A PAX3-FOXO1 fusion protein acts as a driver of malignancy in ARMS by disrupting tightly coupled but mutually exclusive pathways of proliferation and differentiation. While PAX3-FOXO1 is an attractive therapeutic target, no current treatments are designed to block its oncogenic activity. The present work shows that the histone acetyltransferase P/CAF (KAT2B) is overexpressed in primary tumours from ARMS patients. Interestingly, in fusion positive ARMS cell lines, P/CAF acetylates and stabilizes PAX3-FOXO1 rather than MyoD, a master regulator of muscle differentiation. Silencing P/CAF, or pharmacological inhibition of its acetyltransferase activity, down-regulates PAX3 FOXO1 levels concomitant with reduced proliferation and tumour burden in xenograft mouse models. Our studies identify a P/CAF-PAX3-FOXO1 signalling node that promotes oncogenesis and may contribute to MyoD dysfunction in ARMS. This work exemplifies the therapeutic potential of targeting chromatin-modifying enzymes to inhibit fusion oncoproteins that are a frequent event in sarcomas. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27453351 TI - Do Vertebrate Gut Metagenomes Confer Rapid Ecological Adaptation? AB - During times of rapid environmental change, survival of most vertebrate populations depends on their phenomic plasticity. Although differential gene expression and post-transcriptional processes of the host genome receive focus as the main molecular mechanisms, growing evidence points to the gut microbiota as a key driver defining hosts' phenotypes. We propose that the plasticity of the gut microbiota might be an essential factor determining phenomic plasticity of vertebrates, and that it might play a pivotal role when vertebrates acclimate and adapt to fast environmental variation. We contemplate some key questions and suggest methodological approaches and experimental designs that can be used to evaluate whether gut microorganisms provide a boost of plasticity to vertebrates' phenomes, thereby increasing their acclimation and adaptation capacity. PMID- 27453352 TI - Pushing Past Boundaries for Trait Hypervolumes: A Response to Carmona et al. PMID- 27453353 TI - Long-term Trends in Human Extra-Pair Paternity: Increased Infidelity or Adaptive Strategy? A Reply to Harris. PMID- 27453354 TI - On the nature of defect states in tungstate nanoflake arrays as promising photoanodes in solar fuel cells. AB - An electrochemical method is presented to study the nature of the defect states in sub-stoichiometric tungsten oxide nanoflake photoanodes used in water splitting. First, stoichiometric/sub-stoichiometric tungstate nanoflake arrays were deliberately developed via annealing under different atmospheres (air, O2, and H2) in different sequences. UV-Vis diffuse reflectance spectra and Tauc analysis indicated the presence of oxygen vacancies, which was also confirmed via XRD and Raman analysis, with samples annealed in an air/O2 sequence resulting in the most stoichiometric monoclinic structures. A defect sensitivity factor was proposed to explain the nature of defects whether they are deep or shallow. Mott Schottky analysis was used to confirm the expected defect donor densities, as well as to confirm the nature of the developed oxygen vacancy defect states. The tungstate photoanodes were tested in photoelectrochemical water splitting cells and their photoconversion efficiency was demonstrated and discussed in detail. PMID- 27453355 TI - Spatial gradient of human health risk from exposure to trace elements and radioactive pollutants in soils at the Puchuncavi-Ventanas industrial complex, Chile. AB - The Punchuncavi Valley in central Chile, heavily affected by a range of anthropogenic emissions from a localized industrial complex, has been studied as a model environment for evaluating the spatial gradient of human health risk, which are mainly caused by trace elemental pollutants in soil. Soil elemental profiles in 121 samples from five selected locations representing different degrees of impact from the industrial source were used for human risk estimation. Distance to source dependent cumulative non-carcinogenic hazard indexes above 1 for children (max 4.4 - min 1.5) were found in the study area, ingestion being the most relevant risk pathway. The significance of health risk differences within the study area was confirmed by statistical analysis (ANOVA and HCA) of individual hazard index values at the five sampling locations. As was the dominant factor causing unacceptable carcinogenic risk levels for children (<10 4) at the two sampling locations which are closer to the industrial complex, whereas the risk was just in the tolerable range (10-6 - 10-4) for children and adults in the rest of the sampling locations at the study area. Furthermore, we assessed gamma ray radiation external hazard indexes and annual effective dose rate from the natural radioactivity elements (226Ra, 232Th and 40K) levels in the surface soils of the study area. The highest average values for the specific activity of 232Th (31 Bq kg-1), 40K (615 Bq kg- 1), and 226Ra (25 Bq kg-1) are lower than limit recommended by OECD, so no significant radioactive risk was detected within the study area. In addition, no significant variability of radioactive risk was observed among sampling locations. PMID- 27453356 TI - Biomarker responses of Eisenia andrei to a polymetallic gradient near a lead mining site in North Tunisia. AB - Eisenia andrei earthworms were exposed for 7 and 14 days to six samples of soil taken from around an abandoned lead (Pb) mine and characterized by different levels of metal contamination (S6-S1, this latter being the most contaminated soil). The organisms were analyzed for metal bioaccumulation and for biological parameters as biomarkers of stress (lysosomal membrane stability; lipofuscin lysosomal content; lysosomal/cytoplasmic volume ratio) and genotoxicity (Micronucleus frequency). Chemical analysis showed the loads of Pb, Cd, Zn, and Cu in the worms following exposure. Among the stress biomarkers, lysosomal membrane stability was significantly affected in the coelomocytes of the earthworms exposed already 7 days to different contaminated soils. Organisms exposed for 14 days to S1 showed in the cells of the chloragogenous tissue, a particularly relevant increase in lipofuscin, a biomarker of oxidative stress, and an increase in the lysosome/cytoplasm volume ratio, indicating stressful condition at the tissue level. Moreover, in the same conditions, a decrease in total body weight was observed. At the longer exposure time, the coelomocytes of worms exposed to S1, S2, and S3 (soils with higher metal concentrations) showed a significant increase in micronuclei (MNi) frequency. Expressions of the P21 and topoisomerase genes, which are involved in DNA repair, showed significant up regulation in the cells of worms exposed to S1, S2, S3, S4 and to a less extend S6. This may indicate that the worms were only able to successfully reduce the level of DNA damage in S4 and S5 if considering MN frequency data. The biomarker data was integrated by the Earthworm Expert System, allowing an objective interpretation of the complex biological data and clearly defining the areas in which the presence of chemicals is toxic for the edaphic organisms. PMID- 27453358 TI - Successional trajectories of bacterioplankton community over the complete cycle of a sudden phytoplankton bloom in the Xiangshan Bay, East China Sea. AB - Phytoplankton bloom has imposed ecological concerns worldwide; however, few studies have been focused on the successional trajectories of bacterioplankton community over a complete phytoplankton bloom cycle. Using 16S pyrosequencing, we investigated how the coastal bacterioplankton community compositions (BCCs) respond to a phytoplankton bloom in the Xiangshan Bay, East China Sea. The results showed that BCCs were significantly different among the pre-bloom, bloom, and after-bloom stages, with the lowest bacterial diversity at the bloom phase. The BCCs at the short-term after-bloom phase showed a rapid but incomplete recovery to the pre-bloom phase, evidenced by 69.8% similarity between pre-bloom and after-bloom communities. This recovery was parallel with the dynamics of the operational taxonomic units (OTUs) affiliated with Actinobacteria, Bacteroidetes, Cyanobacteria, Alphaproteobacteria and Gammaproteobacteria, whose abundance enriched when bloom occur, and decreased after-bloom, and vice versa. Collectively, the results showed that the BCCs were sensitive to algal-induced disturbances, but could recover to a certain extent after bloom. In addition, OTUs which enriched or decreased during this process are closely associated with this temporal pattern, thus holding the potential to evaluate and indicate the succession stage of phytoplankton bloom. PMID- 27453357 TI - Fatty acid metabolism in fish species as a biomarker for environmental monitoring. AB - Pollution by Organic Contaminants (OC) in aquatic environments is a relevant issue at the global scale. Lipids comprised of Fatty Acids (FA) play many important roles in the physiology and life history of fishes. Toxic effects of OC are partly dependent on its bioaccumulation in the lipids of aquatic organisms due its physicochemical properties. Therefore, there is an increasing interest to investigate the gene expression as well as the presence and activity of proteins involved in FA metabolism. The attention on Peroxisome Proliferation Activate Receptors (PPARs) also prevails in fish species exposed to OC and in the transport, biosynthesis and beta-oxidation of FA. Several studies have been conducted under controlled conditions to evaluate these biological aspects of fish species exposed to OC, as fibrates, endocrine disrupting compounds, perfluoroalkyl acids, flame retardants, metals and mixtures of organic compounds associated with a polluted area. However, only fibrates, which are agonists of PPARs, induce biological responses suitable to be considered as biomarkers of exposure to these pollutants. According to the documented findings on this topic, it is unlikely that these physiological aspects are suitable to be employed as biomarkers with some noticeable exceptions, which depend on experimental design. This emphasises the need to investigate the responses in fish treated with mixtures of OC and in wild fish species from polluted areas to validate or refute the suitability of these biomarkers for environmental or fish health monitoring. PMID- 27453359 TI - Infectivity, effects on helper viruses and whitefly transmission of the deltasatellites associated with sweepoviruses (genus Begomovirus, family Geminiviridae). AB - Begomoviruses (family Geminiviridae) are whitefly-transmitted viruses with single stranded DNA genomes that are frequently associated with DNA satellites. These satellites include non-coding satellites, for which the name deltasatellites has been proposed. Although the first deltasatellite was identified in the late 1990s, little is known about the effects they have on infections of their helper begomoviruses. Recently a group of deltasatellites were identified associated with sweepoviruses, a group of phylogenetically distinct begomoviruses that infect plants of the family Convolvulaceae including sweet potato. In this work, the deltasatellites associated with sweepoviruses are shown to be transreplicated and maintained in plants by the virus with which they were identified, sweet potato leaf curl virus (SPLCV). These deltasatellites were shown generally to reduce symptom severity of the virus infection by reducing virus DNA levels. Additionally they were shown to be maintained in plants, and reduce the symptoms induced by two Old World monopartite begomoviruses, tomato yellow leaf curl virus and tomato yellow leaf curl Sardinia virus. Finally one of the satellites was shown to be transmitted plant-to-plant in the presence of SPLCV by the whitefly vector of the virus, Bemisia tabaci, being the first time a deltasatellite has been shown to be insect transmitted. PMID- 27453360 TI - Multiple Ionization of Free Ubiquitin Molecular Ions in Extreme Ultraviolet Free Electron Laser Pulses. AB - The fragmentation of free tenfold protonated ubiquitin in intense 70 femtosecond pulses of 90 eV photons from the FLASH facility was investigated. Mass spectrometric investigation of the fragment cations produced after removal of many electrons revealed fragmentation predominantly into immonium ions and related ions, with yields increasing linearly with intensity. Ionization clearly triggers a localized molecular response that occurs before the excitation energy equilibrates. Consistent with this interpretation, the effect is almost unaffected by the charge state, as fragmentation of sixfold deprotonated ubiquitin leads to a very similar fragmentation pattern. Ubiquitin responds to EUV multiphoton ionization as an ensemble of small peptides. PMID- 27453361 TI - Observational studies and the difficult quest for causality: lessons from vaccine effectiveness and impact studies. AB - Although randomized placebo-controlled trials (RCT) are critical to establish efficacy of vaccines at the time of licensure, important remaining questions about vaccine effectiveness (VE)-used here to include individual-level measures and population-wide impact of vaccine programmes-can only be answered once the vaccine is in use, from observational studies. However, such studies are inherently at risk for bias. Using a causal framework and illustrating with examples, we review newer approaches to detecting and avoiding confounding and selection bias in three major classes of observational study design: cohort, case control and ecological studies. Studies of influenza VE, especially in seniors, are an excellent demonstration of the challenges of detecting and reducing such bias, and so we use influenza VE as a running example. We take a fresh look at the time-trend studies often dismissed as 'ecological'. Such designs are the only observational study design that can measure the overall effect of a vaccination programme [indirect (herd) as well as direct effects], and are in fact already an important part of the evidence base for several vaccines currently in use. Despite the great strides towards more robust observational study designs, challenges lie ahead for evaluating best practices for achieving robust unbiased results from observational studies. This is critical for evaluation of national and global vaccine programme effectiveness. PMID- 27453362 TI - Impact of Donor Type on Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia. AB - Allogeneic hematopoietic cell transplantation (alloHCT) is considered the most potent postremission antileukemic therapy in adults with acute leukemia. We analyzed 172 consecutive acute leukemia patients transplanted in complete remission after a T cell-replete alloHCT from either a matched related (MRD, n = 54), unrelated (MUD, n = 67), or haploidentical (haplo, n = 51) donor to look for patient-, disease-, and transplant-related factors associated with post transplant outcomes. Patients included 123 acute myeloid leukemia patients (first complete remission [CR], n = 94; second CR, n = 28; third CR, n = 1) and 49 acute lymphoblastic leukemia (ALL) patients (first CR, n = 39; second CR, n = 9; third CR, n = 1) with a median age of 50 years (range, 19 to 74). Median follow-up for surviving patients was 38 months. Cumulative incidence of nonrelapse mortality at 1 and 3 years was 6% and 17%, respectively. The estimated rates of 3-year overall survival, disease-free survival, and relapse incidence were 59%, 50%, and 33%, respectively. In multivariate analysis, risk factors for inferior survival included diagnosis of ALL, high risk disease risk index, and use of a female donor for a male recipient. Donor type (MRD, MUD, haplo) had no impact on any transplant outcome. Given the favorable outcomes associated with alloHCT in acute leukemia and lack of effect of donor type, a strong case can be made for transplanting acute leukemia patients in remission as soon as any donor becomes available. PMID- 27453363 TI - Skilled musicians are not subject to the McGurk effect. AB - The McGurk effect is a compelling illusion in which humans auditorily perceive mismatched audiovisual speech as a completely different syllable. In this study evidences are provided that professional musicians are not subject to this illusion, possibly because of their finer auditory or attentional abilities. 80 healthy age-matched graduate students volunteered to the study. 40 were musicians of Brescia Luca Marenzio Conservatory of Music with at least 8-13 years of musical academic studies. /la/, /da/, /ta/, /ga/, /ka/, /na/, /ba/, /pa/ phonemes were presented to participants in audiovisual congruent and incongruent conditions, or in unimodal (only visual or only auditory) conditions while engaged in syllable recognition tasks. Overall musicians showed no significant McGurk effect for any of the phonemes. Controls showed a marked McGurk effect for several phonemes (including alveolar-nasal, velar-occlusive and bilabial ones). The results indicate that the early and intensive musical training might affect the way the auditory cortex process phonetic information. PMID- 27453365 TI - A hybrid Brownian dynamics/constitutive model for yielding, aging, and rejuvenation in deforming polymeric glasses. AB - We present a hybrid model for polymeric glasses under deformation that combines a minimal model of segmental dynamics with a beads-and-springs model of a polymer, solved by Brownian dynamics (BD) simulations, whose relaxation is coupled to the segmental dynamics through the drag coefficient of the beads. This coarse-grained model allows simulations that are much faster than molecular dynamics and successfully capture the entire range of mechanical response including yielding, plastic flow, strain-hardening, and incomplete strain recovery. The beads-and springs model improves upon the dumbbell model for glassy polymers proposed by Fielding et al. (Phys. Rev. Lett., 2012, 108, 048301) by capturing the small elastic recoil seen experimentally without the use of ad hoc adjustments of parameters required in the model of Fielding et al. With appropriate choice of parameters, predictions of creep, recovery, and segmental relaxation are found to be in good agreement with poly(methylmethacrylate) (PMMA) data of Lee et al. (Science, 2009, 323, 231-234). Our model shows dramatic differences in behavior of the segmental relaxation time between extensional creep and steady extension, and between extension and shear. The non-monotonic response of the segmental relaxation time to extensional creep and the small elastic recovery after removal of stress are shown to arise from sub-chains that are trapped between folds, and that become highly oriented and stretched at strains of order unity, connecting the behavior of glassy polymers under creep to that of dilute polymer solutions under fast extensional flows. We are also able to predict the effects of polymer pre-orientation in the parallel or orthogonal direction on the subsequent response to extensional deformation. PMID- 27453364 TI - Pituitary adenylate cyclase-activating polypeptide promotes eccrine gland sweat secretion. AB - BACKGROUND: Sweat secretion is the major function of eccrine sweat glands; when this process is disturbed (paridrosis), serious skin problems can arise. To elucidate the causes of paridrosis, an improved understanding of the regulation, mechanisms and factors underlying sweat production is required. Pituitary adenylate cyclase-activating polypeptide (PACAP) exhibits pleiotropic functions that are mediated via its receptors [PACAP-specific receptor (PAC1R), vasoactive intestinal peptide (VIP) receptor type 1 (VPAC1R) and VPAC2R]. Although some studies have suggested a role for PACAP in the skin and several exocrine glands, the effects of PACAP on the process of eccrine sweat secretion have not been examined. OBJECTIVES: To investigate the effect of PACAP on eccrine sweat secretion. METHODS: Reverse transcriptase-polymerase chain reaction and immunostaining were used to determine the expression and localization of PACAP and its receptors in mouse and human eccrine sweat glands. We injected PACAP subcutaneously into the footpads of mice and used the starch-iodine test to visualize sweat-secreting glands. RESULTS: Immunostaining showed PACAP and PAC1R expression by secretory cells from mouse and human sweat glands. PACAP immunoreactivity was also localized in nerve fibres around eccrine sweat glands. PACAP significantly promoted sweat secretion at the injection site, and this could be blocked by the PAC1R-antagonist PACAP6-38. VIP, an agonist of VPAC1R and VPAC2R, failed to induce sweat secretion. CONCLUSIONS: This is the first report demonstrating that PACAP may play a crucial role in sweat secretion via its action on PAC1R located in eccrine sweat glands. The mechanisms underlying the role of PACAP in sweat secretion may provide new therapeutic options to combat sweating disorders. PMID- 27453366 TI - Salivary Pepsin Lacks Sensitivity as a Diagnostic Tool to Evaluate Extraesophageal Reflux Disease. AB - OBJECTIVES: To determine the sensitivity of salivary pepsin compared with multichannel intraluminal impedance with pH testing (pH-MII), endoscopy, and gastroesophageal reflux disease (GERD) questionnaires. STUDY DESIGN: We prospectively recruited 50 children from Boston Children's Hospital who were undergoing pH-MII to evaluate for GERD. The patients completed 24-hour pH-MII testing, completed symptom and quality of life questionnaires, and provided a saliva specimen that was analyzed using the PepTest lateral flow test. A subset of patients also underwent bronchoscopy and esophagogastroduodenoscopy. Receiver operating characteristic curve analyses were performed to determine the sensitivity of salivary pepsin compared with each reference standard. RESULTS: Twenty-one of the 50 patients (42%) were salivary pepsin-positive, with a median salivary pepsin concentration of 10 ng/mL (IQR, 10-55 ng/mL). There was no significant difference in the distributions of acid, nonacid, total reflux episodes, full column reflux, or any other reflux variable in patients who were pepsin-positive compared with those who were pepsin-negative (P > .50). There was no significant correlation between the number of reflux episodes and pepsin concentration (P > .10). There was no positive relationship between salivary pepsin positivity, any extraesophageal symptoms or quality of life scores, or inflammation on bronchoscopy or esophagogastroduodenoscopy (P > .30). CONCLUSION: Salivary pepsin measurement has a low sensitivity for predicting pathological gastroesophageal reflux in children. PMID- 27453367 TI - Pediatric Critical Care Resource Use by Children with Medical Complexity. AB - OBJECTIVES: To examine the proportionate use of critical care resources among children of differing medical complexity admitted to pediatric intensive care units (ICUs) in tertiary-care children's hospitals. STUDY DESIGN: This is a retrospective, cross-sectional study of all children (<19 years of age) admitted to a pediatric ICU between January 1, 2012, and December 31, 2013, in the Pediatric Health Information Systems database. Using the Pediatric Medical Complexity Algorithm, we assigned patients to 1 of 3 categories: no chronic disease, noncomplex chronic disease (NC-CD), or complex chronic disease (C-CD). Baseline demographics, hospital costs, and critical care resource use were stratified by these groups and summarized. RESULTS: Of 136 133 children with pediatric ICU admissions, 53.0% were categorized as having C-CD. At the individual-encounter level, ICU resource use was greatest among patients with C CD compared with children with NC-CD and no chronic disease. At the hospital level, patients with C-CD accounted for more than 75% of all examined ICU resources, including ventilation days, ICU costs, extracorporeal membrane oxygenation runs, and arterial and central venous catheters. Children with a progressive condition accounted for one-half of all ICU resources. In contrast, patients with no chronic disease and NC-CD accounted for less than one-quarter of all ICU therapies. CONCLUSION: Children with medical complexity disproportionately use the majority of ICU resources in children's hospitals. Efforts to improve quality and provide cost-effective care should focus on this population. PMID- 27453368 TI - Postoperative Amplitude-Integrated Electroencephalography Predicts Four-Year Neurodevelopmental Outcome in Children with Complex Congenital Heart Disease. AB - OBJECTIVES: To evaluate the predictive value of pre- and postoperative amplitude integrated electroencephalography (aEEG) on neurodevelopmental outcomes in children operated for congenital heart disease (CHD). STUDY DESIGN: Prospectively enrolled cohort of 60 infants with CHD who underwent cardiac surgery with cardiopulmonary bypass in the first 3 months of life. Infants with a genetic comorbidity were excluded. aEEG was assessed for 12 hours pre- and 48 hours postoperatively. Background pattern was classified by the use of standard categories, and the presence of seizures and sleep-wake cycles (SWCs) was noted. Outcome at 1 and 4 years of age was assessed with standardized developmental tests. RESULTS: Preoperatively, infants either showed continuous normal voltage (n = 56) or discontinuous normal voltage (n = 4). Postoperatively, abnormal background pattern (flat trace, burst suppression, or continuous low voltage) was detected in 7 (12%), discontinuous normal voltage in 37 (61%), and continuous normal voltage in 16 (27%) infants. Nineteen infants (32%) did not return to normal SWCs within the recording period. Seizures were detected in 4 infants preoperatively and in another 4 postoperatively. After we controlled for surgical and postoperative risk factors, abnormal postoperative background pattern and lack of return to SWCs independently predicted poorer intelligence quotient at 4 years (P = .03 and P = .04 respectively) but was not related to motor outcome. CONCLUSION: aEEG is a useful bedside tool that helps to predict outcome in infants undergoing open-heart surgery for CHD. Abnormal postoperative background pattern and lack of return to SWCs are markers for subsequent impaired cognitive development. PMID- 27453369 TI - Sleep and Lipid Profile During Transition from Childhood to Adolescence. AB - OBJECTIVES: To assess the longitudinal effects of sleep duration and quality on lipid profiles during the transition from childhood to early adolescence, over a 4-year-period. STUDY DESIGN: A cohort study of children born in 1998 examined at 8 years of age (SD, 0.3; n = 105) and 12 years of age (SD, 0.5; n = 190). Sleep duration, wake after sleep onset, sleep efficiency, and weekend catch-up sleep were measured with actigraphs for 7 (8 years of age) and 8 (12 years of age) nights. Fasting serum samples were collected at 12 years of age. Covariates included age, pubertal development, socioeconomic status, body mass index, and physical activity. RESULTS: In girls, shorter sleep duration at 8 and 12 years of age was associated with lower high-density lipoprotein-cholesterol and higher triglycerides at 12 years of age. Poorer sleep quality at 8 years of age and longer weekend catch-up sleep at 12 years of age was associated with higher triglycerides at 12 years of age. From 8 to 12 years of age, improvement in sleep quality associated with higher total cholesterol, and a decrease in sleep duration with lower lipid levels. In boys, longer sleep duration at 8 years of age, and a larger decrease in sleep duration from 8 to 12 years of age was associated with higher levels of triglycerides at 12 years of age. CONCLUSIONS: Poorer sleep during transition to early adolescence is associated with an atherogenic lipid profile in early adolescent girls, and such effects are less prominent in boys. Poor sleep may have long-term associations with health, which are not mitigated by the amount of physical activity. PMID- 27453370 TI - Voluntarily Postponing Testing Is Associated with Lower Performance on the Pediatric Board Certifying Examinations. AB - OBJECTIVE: To investigate whether postponing certification testing, either voluntarily or involuntarily, affects a candidate's performance on pediatric certifying examinations. STUDY DESIGN: Both general pediatrics (GP) and pediatric subspecialty (PS) examination candidates were included in the study. Candidates were classified into 3 groups based on time since the completion of training: no delay (<12 months), short delay (12-24 months), and long delay (>=24 months). Examination scores and pass rates in the first GP and PS certifying examinations were compared to assess between-group differences. RESULTS: Significant differences in scores and pass rates were found for GP candidates who voluntarily waited 1 year or longer to take the certifying examination. Similarly, PS candidates who opted not to take the first examination available had significantly lower scores and pass rates. However, no significant difference was found for PS candidates who had to wait to take their examination owing to the Board's offered examination schedule. CONCLUSION: Candidates who postpone taking the certifying examination are less likely to pass the examination. The longer a candidate elects to wait to take the examination, the less likely he or she is to pass. The availability of the PS examinations once every 2 years does not affect pass rates and scores, as long as PS candidates take the first available examinations after completing fellowship. PMID- 27453371 TI - Risk of Suicide Attempt among Adolescents with Conduct Disorder: A Longitudinal Follow-up Study. AB - OBJECTIVE: To assess the independent or comorbid effect of conduct and mood disorders on the risk of suicide. STUDY DESIGN: The Taiwan National Health Insurance Research Database was used to derive data for 3711 adolescents aged 12 17 years with conduct disorder and 14 844 age- and sex-matched controls between 2001 and 2009. The participants were followed up to the end of 2011, and those who attempted suicide during the follow-up period were identified. RESULTS: Adolescents with conduct disorder had a higher incidence of suicide (0.9% vs 0.1%; P <.001) and attempted suicide at a younger age (17.38 +/- 2.04 vs 20.52 +/ 1.70 years of age) than did the controls. The Cox proportional hazards regression model, after adjustment for demographic data and psychiatric comorbidities, determined that conduct disorder was an independent risk factor for subsequent suicide attempts (hazard ratio, 5.17; 95% CI, 2.29-11.70). The sensitivity after those with other psychiatric comorbidities were excluded revealed a consistent finding (hazard ratio, 10.32; 95% CI, 3.71-28.71). DISCUSSION: Adolescents with conduct disorder had an increased risk of suicide attempts over the next decade. Future studies are required to clarify the underlying pathophysiology and elucidate whether prompt intervention for conduct disorder could reduce this risk. PMID- 27453372 TI - Interhospital Variability in Perioperative Red Blood Cell Ordering Patterns in United States Pediatric Surgical Patients. AB - OBJECTIVE: To evaluate perioperative red blood cell (RBC) ordering and interhospital variability patterns in pediatric patients undergoing surgical interventions at US children's hospitals. STUDY DESIGN: This is a multicenter cross-sectional study of children aged <19 years admitted to 38 pediatric tertiary care hospitals participating in the Pediatric Health Information System in 2009-2014. Only cases performed at all represented hospitals were included in the study, to limit case mix variability. Orders for blood type and crossmatch were included when done on the day before or the day of the surgical procedure. The RBC transfusions included were those given on the day of or the day after surgery. The type and crossmatch-to-transfusion ratio (TCTR) was calculated for each surgical procedure. An adjusted model for interhospital variability was created to account for variation in patient population by age, sex, race/ethnicity, payer type, and presence/number of complex chronic conditions (CCCs) per patient. RESULTS: A total of 357 007 surgical interventions were identified across all participating hospitals. Blood type and crossmatch was performed 55 632 times, and 13 736 transfusions were provided, for a TCTR of 4:1. There was an association between increasing age and TCTR (R(2) = 0.43). Patients with multiple CCCs had lower TCTRs, with a stronger relationship (R(2) = 0.77). There was broad variability in adjusted TCTRs among hospitals (range, 2.5-25). CONCLUSIONS: The average TCTR in US children's hospitals was double that of adult surgical data, and was associated with wide interhospital variability. Age and the presence of CCCs markedly influenced this ratio. Studies to evaluate optimal preoperative RBC ordering and standardization of practices could potentially decrease unnecessary costs and wasted blood. PMID- 27453373 TI - Using the Bristol Stool Scale and Parental Report of Stool Consistency as Part of the Rome III Criteria for Functional Constipation in Infants and Toddlers. AB - OBJECTIVES: To evaluate among parents of infants and toddlers the agreement between parental report and the Bristol Stool Scale (BSS) in assessing stool consistency and the effect of both methods on determining the prevalence of functional constipation (FC) according to the Rome III criteria. STUDY DESIGN: Parents of children <=48 months of age who were seen for a well-child visit completed a questionnaire about their child's bowel habits during the previous month. Cohen kappa coefficient (kappa) was used to measure intrarater agreement between parental report of stool consistency ("hard," "normal," "soft/mucous/liquid") and the BSS (types 1-2, hard; types 3-5, normal; types 6-7, loose/liquid). The prevalence of FC was assessed based on the questionnaire according to the Rome III criteria, comparing both methods of stool consistency assessment. RESULTS: Parents of 1095 children (median age, 15 months; range, 1 48) were included. Only fair agreement existed between the 2 methods of stool consistency assessment (kappa = 0.335; P < .001). According to the Rome III criteria, using parental report the prevalence of FC was 20.5% and using the BSS the prevalence was 20.9% (P = .87). The agreement between these 2 methods for assessing the prevalence of FC was excellent (kappa = 0.95; P < .001). CONCLUSIONS: Only fair agreement exists between the BSS and parental report of stool consistency among parents of infants and toddlers. Different methods of stool consistency assessment did not result in a difference in the prevalence of FC. PMID- 27453374 TI - Mandatory Closure Versus Nonintervention for Patent Ductus Arteriosus in Very Preterm Infants. AB - OBJECTIVE: To determine whether a nonintervention approach for treating hemodynamically significant patent ductus arteriosus (PDA) is associated with decreased mortality and/or morbidity compared with a mandatory closure approach in extremely low birth weight infants. STUDY DESIGN: We reviewed the medical records of 178 infants of 23-26 weeks' gestational age with PDA, requiring ventilator treatment, and with hemodynamically significant PDA >=2 mm in size. Mandatory closure was used during period I (July 2009 to December 2011, n = 81), and nonintervention was used during period II (January 2012 to June 2014, n = 97). RESULTS: During period I, 64% of infants were first treated with indomethacin, and 82% were ultimately ligated surgically. During period II, no infant was treated with indomethacin and/or ligation. The average postnatal day of PDA closure was day 13 and day 44 during periods I and II, respectively. There was significantly more use of diuretics and fluid restriction during period II compared with period I. There was no difference in mortality or morbidities such as necrotizing enterocolitis or intraventricular hemorrhage. The incidence of bronchopulmonary dysplasia (BPD) and the propensity score adjusted OR of BPD were significantly lower during period II compared with period I. CONCLUSIONS: Despite longer PDA exposure, nonintervention was associated with significantly less BPD compared with mandatory closure. Additional study is warranted to determine the benefits and risks of non-intervention for the hemodynamically significant PDA in extremely low birth weight infants. PMID- 27453375 TI - A Preschool Obesity Treatment Clinical Trial: Reasons Primary Care Providers Declined Referrals. AB - OBJECTIVE: To examine referral by primary care providers (PCPs) of preschool children with obesity (>=95th percentile for body mass index [BMI]) to a weight management intervention when offered through a randomized clinical trial (RCT), and identify reasons for not referring children. STUDY DESIGN: In phase I, 3 experts in obesity, psychology, and nutrition completed an open card sort and classified PCPs' reasons for declining referral into groups based on similarity of reasons. Categories were then defined and labeled. In phase II, 2 independent sorters placed each decline into 1 of the categories defined in phase I. RESULTS: PCPs referred 78% of eligible children to the RCT. Compared with children declined for referral, referred children had a significantly higher weight (48.4 lb vs 46.1 lb; P < .001) and BMI percentile (97.6 vs 97.0; P < .001). Eleven categories for decline were identified in phase I. In phase II, excellent reliability was obtained between each independent sorter and the phase I categories, and also between the 2 independent sorters (kappa values, 0.72-1.0). The most common reason for declining was "family not a good fit" (23.6%), followed by "doesn't believe weight is a problem" (13.9%), "family would not be interested" (12%), and "doesn't believe measurement is accurate" (11.5%). Appropriately, exclusionary criteria of the RCT was a reason as well (11.8%). CONCLUSION: The availability of weight management for preschoolers through RCTs appeared to overcome barriers of resources, time, and credible treatment cited in previous studies. However, concerns about the family's response or interest in a weight management program remained barriers, as did PCPs' perceptions about obesity in young children. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01546727. PMID- 27453376 TI - School-Age Test Proficiency and Special Education After Congenital Heart Disease Surgery in Infancy. AB - OBJECTIVE: To evaluate test proficiency and the receipt of special education services in school-age children who had undergone surgery for congenital heart disease (CHD) at age <1 year. STUDY DESIGN: Data from Arkansas-born children who underwent surgery for CHD at Arkansas Children's Hospital at age <1 year between 1996 and 2004 were linked to state birth certificates and the Arkansas Department of Education longitudinal database containing achievement test scores in literacy and mathematics for grades 3-4 and special education codes. The primary negative outcome was not achieving grade-level proficiency on achievement tests. Logistic regression accounting for repeated measures was used to evaluate for associations between achieving proficiency and demographic data, maternal education, and clinical factors. RESULTS: A total of 362 of 458 (79%) children who underwent surgery for CHD were matched to the Arkansas Department of Education database, 285 of whom had grade 3 and/or 4 achievement tests scores. Fewer students with CHD achieved proficiency in literacy and mathematics (P < .05) compared with grade-matched state students. Higher 5-minute Apgar score, shorter duration of hospitalization, and higher maternal education predicted proficiency in literacy (P < .05). White race, no cardiopulmonary bypass, and shorter hospitalization predicted proficiency in mathematics (P < .05). Sex, gestational age, age at surgery, CHD diagnosis, and type and number of surgeries did not predict test proficiency. Compared with all public school students, more children with CHD received special education services (26.9% vs 11.6%; P < .001). CONCLUSION: Children with CHD had poorer academic achievement and were more likely to receive special education services than all state students. Results from this study support the need for neurodevelopmental evaluations as standard practice in children with CHD. PMID- 27453377 TI - Pseudoarthrosis of the Ulna in Neurofibromatosis Type I. PMID- 27453378 TI - Antenatal Exposure to Magnesium Sulfate Is Associated with Reduced Cerebellar Hemorrhage in Preterm Newborns. AB - OBJECTIVE: To determine the association of antenatal magnesium sulfate with cerebellar hemorrhage in a prospective cohort of premature newborns evaluated by magnetic resonance imaging (MRI). STUDY DESIGN: Cross-sectional analysis of baseline characteristics from a prospective cohort of preterm newborns (<33 weeks gestation) evaluated with 3T-MRI shortly after birth. Exclusion criteria were clinical evidence of a congenital syndrome, congenital infection, or clinical status too unstable for transport to MRI. Antenatal magnesium sulfate exposure was abstracted from the medical records and the indication was classified as obstetric or neuroprotection. Two pediatric neuroradiologists, blinded to the clinical history, scored axial T2-weighted and iron susceptibility MRI sequences for cerebellar hemorrhage. The association of antenatal magnesium sulfate with cerebellar hemorrhage was evaluated using multivariable logistic regression, adjusting for postmenstrual age at MRI and known predictors of cerebellar hemorrhage. RESULTS: Cerebellar hemorrhage was present in 27 of 73 newborns (37%) imaged at a mean +/- SD postmenstrual age of 32.4 +/- 2 weeks. Antenatal magnesium sulfate exposure was associated with a significantly reduced risk of cerebellar hemorrhage. Adjusting for postmenstrual age at MRI, and predictors of cerebellar hemorrhage, antenatal magnesium sulfate was independently associated in our cohort with decreased cerebellar hemorrhage (OR, 0.18; 95% CI, 0.049-0.65; P = .009). CONCLUSION: Antenatal magnesium sulfate exposure is independently associated with a decreased risk of MRI-detected cerebellar hemorrhage in premature newborns, which could explain some of the reported neuroprotective effects of magnesium sulfate. PMID- 27453380 TI - Redaction of Substance Abuse Claims in Medicare Research Files Affects Spending Outcomes for Nearly One in Five Beneficiaries with Serious Mental Illness. AB - OBJECTIVE: To assess the impact of substance abuse claims redaction on Medicare spending estimates for beneficiaries with serious mental illness. DATA SOURCES: The 2012 claims and unredacted beneficiary-level Medicare spending totals from CMS's Chronic Conditions Warehouse. STUDY DESIGN: We identified beneficiaries with claims affected by the redaction by comparing claims-based spending estimates to unredacted spending totals. Differences in characteristics of beneficiaries with and without redacted claims were examined in bivariate analyses. PRINCIPAL FINDINGS: Claims-based spending totals differed from unredacted totals for 19.7 percent of the cohort. Part A spending for those with redacted claims was underreported by 57.0 percent. Characteristics of beneficiaries with and without redacted claims differed significantly. CONCLUSIONS: Researchers who rely on Medicare claims to analyze spending outcomes for beneficiaries with serious mental illness should be aware of the potential for bias due to nonrandom redaction of substance abuse data. PMID- 27453379 TI - Development and evaluation of a real-time polymerase chain reaction assay for the rapid detection of Talaromyces marneffei MP1 gene in human plasma. AB - Penicilliosis caused by Talaromyces marneffei is a common AIDS-defining illness in South and Southeast Asia. Diagnosis is based on culture which can take up to 14 days for identification, leading to treatment delay and increased mortality. We developed a TaqMan real-time PCR assay targeting the MP1 gene encoding an abundant cell wall protein specific to T. marneffei. The assay's performance was evaluated in MP1-containing plasmids, clinical isolates, and plasma from HIV infected patients with and without penicilliosis. The assay consistently detected 10 copies of MP1-containing plasmids per reaction and 100 T. marneffei yeast cells per millilitre plasma. There were no amplification with seven other Penicillium species and six other HIV-associated fungal pathogens tested. The assay was evaluated in 70 patients with AIDS: 50 patients with culture-confirmed penicilliosis and 20 patients with opportunistic infections other than penicilliosis. The diagnostic sensitivity was 70.4% (19/27, 95% CI: 51.5-84.1%) and 52.2% (12/23, 95% CI: 33.0-70.8%) in plasma samples collected prior to and within 48 h of antifungal therapy respectively. The diagnostic specificity was 100% (20/20, 95% CI: 83.9-100%). This assay provides a useful tool for the rapid diagnosis of T. marneffei infection and has the potential to improve the management of patients with penicilliosis. PMID- 27453381 TI - Unravelling the binding mechanism and protein stability of human serum albumin while interacting with nefopam analogues: a biophysical and insilico approach. AB - In this study, molecular binding affinity was investigated for Nefopam analogues (NFs), a functionalized benzoxazocine, with human serum albumin (HSA), a major transport protein in the blood. Its binding affinity and concomitant changes in its conformation, binding site and simulations were also studied. Fluorescence data revealed that the fluorescence quenching of HSA upon binding of NFs analogues is based on a static mechanism. The three analogues of NFs binding constants (KA) are in the order of NF3 > NF2 > NF1 with values of 1.53 +/- .057 * 104, 2.16 +/- .071 * 104 and 3.6 +/- .102 * 105 M-1, respectively. Concurrently, thermodynamic parameters indicate that the binding process was spontaneous, and the complexes were stabilized mostly by hydrophobic interactions, except for NF2 has one hydrogen bond stabilizes it along with hydrophobic interactions. Circular dichroism (CD) studies revealed that there is a decrease in alpha-helix with an increase in beta-sheets and random coils signifying partial unfolding of the protein upon binding of NFs, which might be due to the formation of NFs-HSA complexes. Further, molecular docking studies showed that NF1, NF2 and NF3 bound to subdomains IIIA, IB and IIA through hydrophobic interactions. However, NF1 have additionally formed a single hydrogen bond with LYS 413. Furthermore, molecular simulations unveiled that NFs binding was in support with the structural perturbation observed in CD, which is evident from the root mean square deviation and Rg fluctuations. We hope our insights will provide ample scope for engineering new drugs based on the resemblances with NFs for enhanced efficacy with HSA. PMID- 27453382 TI - Gender in Children's Firearm Deaths: Using the Data to Guide Interventions. PMID- 27453383 TI - The Reply. PMID- 27453384 TI - Suicide Prevention by Smartphone. PMID- 27453385 TI - The Reply. PMID- 27453386 TI - Benefits of Moderate Alcohol Consumption Not Disproven. PMID- 27453387 TI - The Reply. PMID- 27453388 TI - Moderate Alcohol Consumption: From Both Sides of the Atlantic and of the Channel. PMID- 27453389 TI - Ongoing Challenges with Type 2 Myocardial Infarction. PMID- 27453390 TI - The Reply. PMID- 27453391 TI - Grapefruit with Your Statin? PMID- 27453392 TI - How to Interpret Predictors of Dilation in Bicuspid Aortic Valve and Aortic Disease. PMID- 27453393 TI - From Leptin, DEXA, and Beyond. PMID- 27453394 TI - Reclassification of Eubacterium desmolans as Butyricicoccus desmolans comb. nov., and description of Butyricicoccus faecihominis sp. nov., a butyrate-producing bacterium from human faeces. AB - A Gram-positive-staining, coccoid-shaped, non-motile, asporogenous, obligately anaerobic and butyrate-producing bacterium was recovered from a healthy human's faeces. The organism was isolated by the enrichment culture technique using yeast extract-casein hydrolysate-fatty acids broth supplemented with 0.5 % mucin. Phylogenetic analysis of 16S rRNA gene sequences demonstrated that the novel strain should be classified as a member of the Eubacterium desmolans-related cluster in the family Ruminococcaceae. Furthermore, this analysis demonstrated that the type strains of Butyricicoccus pullicaecorum (95.6 %) and Eubacterium desmolans (94.7 %) were the closest phylogenetic neighbours to strain YIT 12789T. However, DNA-DNA reassociation values with these closest strains were less than 20 %. On the basis of the phenotypic, genotypic and chemotaxonomic features, the novel coccoid-shaped bacterium should be designated as a representative of a novel species of the genus Butyricicoccus, for which the name Butyricicoccus faecihominis sp. nov. is proposed. The type strain is YIT 12789T (=JCM 31056T=DSM 100989T). It is also proposed that Eubacterium desmolans be reclassified in the genus Butyricicoccus as Butyricicoccus desmolans comb. nov. PMID- 27453395 TI - A case of central nervous system infection due to Cladophialophora bantiana. AB - BACKGROUND: Cladophialophora bantiana is a melanised mold with a pronounced tropism for the central nervous system, almost exclusively causing human brain abscesses. CASE REPORT: We describe a case of cerebral infection by this fungus in an otherwise healthy 28-year-old coal-miner. Environmental occurrence, route of entry, and incubation period of this fungus are unknown, but our case is informative in that the first symptoms occurred about eight weeks after known traumatic inoculation. Lesions were compatible with tuberculous granulomas, and the patient initially received antitubercular treatment. Melanised fungal cells were seen in a brain biopsy and abscess materials. Therapy was switched from empirical antitubercular treatment to amphotericin B (0.5mg/kg/d), but was changed to voriconazole 200mg/d, i.v. on the basis of antifungal susceptibility test results. The patient responded clinically, and gradually improved. The isolate was identified by sequencing of the Internal Transcribed Spacer domain of rDNA. CONCLUSIONS: Given the non-specific clinical manifestations of C. bantiana cerebral abscesses, clinicians and laboratory workers should suspect infections caused by C. bantiana, particularly in immunocompromised patients with a trauma history. PMID- 27453396 TI - To proceed or not to proceed: ENT surgery in paediatric patients with acute upper respiratory tract infection. AB - BACKGROUND: Upper respiratory tract infection is the most common non-preventable cause of surgery cancellation. Consequently, surgeons and anaesthesiologists involved in elective ENT surgical procedures frequently face a dilemma of whether to proceed or to postpone surgery in affected children. METHODS: A literature review was conducted and a practical assessment algorithm proposed. CONCLUSION: The risk-benefit assessment should take into consideration the impact of postponing the surgery intended to bring relief to the child and the risks of proceeding with general anaesthesia in an inflamed airway. The suggested algorithm for assessment may be a useful tool to support the decision of whether to proceed or to postpone surgery. PMID- 27453398 TI - A Renewed Call to Action: The Need for Systematic Research on Interventions for FASD. PMID- 27453397 TI - Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. AB - We conducted a genome-wide association scan (GWAS) of endometriosis using 25.5 million sequence variants detected through whole-genome sequencing (WGS) of 8,453 Icelanders and imputed into 1,840 cases and 129,016 control women, followed by testing of associated variants in Danish samples. Here we report the discovery of a new endometriosis susceptibility locus on 4q12 (rs17773813[G], OR=1.28; P=3.8 * 10(-11)), upstream of KDR encoding vascular endothelial growth factor receptor 2 (VEGFR2). The variant correlates with disease severity (P=0.0046) when moderate/severe endometriosis cases are tested against minimal/mild cases. We further report association of rs519664[T] in TTC39B on 9p22 with endometriosis (P=4.8 * 10(-10); OR=1.29). The involvement of KDR in endometriosis risk highlights the importance of the VEGF pathway in the pathogenesis of the disease. PMID- 27453399 TI - Tn Antigen Mimics Based on sp(2)-Iminosugars with Affinity for an anti-MUC1 Antibody. AB - The first examples of amino acid (Ser/Thr)-sp(2)-iminosugar glycomimetic conjugates featuring an alpha-O-linked pseudoanomeric linkage are reported. The key synthetic step involves the completely diastereoselective alpha-glycosylation of Ser/Thr due to strong stereoelectronic and conformational bias imposed by the bicyclic sp(2)-iminosugar scaffold. Mucin-related glycopeptides incorporating these motifs were recognized by the monoclonal antibody (mAb) scFv-SM3, with activities depending on both the hydroxylation pattern (Glc/Gal/GlcNAc/GalNAc) of the sp(2)-iminosugar and the peptide aglycone structure (Ser/Thr). PMID- 27453402 TI - Pulmonary Hemorrhage Resulting from Suction Catheter in Video-Assisted Thoracic Surgery. PMID- 27453401 TI - Enhanced Recovery Strategies in a Patient With Severe Pulmonary Hypertension. PMID- 27453403 TI - Synthesis of a labile sulfur-centred ligand, [S(H)C(PPh2S)2](-): structural diversity in lithium(i), zinc(ii) and nickel(ii) complexes. AB - A high-yield synthesis of [Li{S(H)C(PPh2S)2}]2 [Li2.(3)2] was developed and this reagent was used in metathesis with ZnCl2 and NiCl2 to produce homoleptic complexes 4 and 5b in 85 and 93% yields, respectively. The solid-state structure of the octahedral complex [Zn{S(H)C(PPh2S)2}2] (4) reveals notable inequivalence between the Zn-S(C) and Zn-S(P) contacts (2.274(1) A vs. 2.842(1) and 2.884(1) A, respectively). Two structural isomers of the homoleptic complex [Ni{S(H)C(PPh2S)2}2] were isolated after prolonged crystallization processes. The octahedral green Ni(ii) isomer 5a exhibits the two monoprotonated ligands bonded in a tridentate (S,S',S'') mode to the Ni(ii) centre with three distinctly different Ni-S bond lengths (2.3487(8), 2.4500(9) and 2.5953(10) A). By contrast, in the red-brown square-planar complex 5b the two ligands are S,S'-chelated to Ni(ii) (d(Ni-S) = 2.165(2) and 2.195(2) A) with one pendant PPh2S group. DFT calculations revealed that the energetic difference between singlet and triplet state octahedral and square-planar isomers of the Ni(ii) complex is essentially indistinguishable. Consistently, VT and (31)P CP/MAS NMR spectroscopic investigations indicated that a mixture of isomers exists in solution at room temperature, while the singlet state square-planar isomer 5b becomes favoured at 40 degrees C. PMID- 27453404 TI - Development of dielectrophoresis separator with an insulating porous membrane using DC-Offset AC Electric Fields. AB - Our previous studies revealed that the dielectrophoresis method is effective for separating cells having different dielectric properties. The purpose of this study was to evaluate the separation characteristics of two kinds of cells by direct current (DC) voltage offset/alternating current (AC) voltage using an insulating porous membrane dielectrophoretic separator. The separation device gives dielectrophoretic (DEP) force and electrophoretic (EP) force to dispersed particles by applying the DC-offset AC voltage. This device separates cells of different DEP properties by adopting a structure in which only the parallel plate electrodes and the insulating porous membrane are disposed in the flow path through which the cell-suspension flows. The difference in the retention ratios of electrically homogeneous 4.5 MUm or 20.0 MUm diameter standard particles was a maximum of 82 points. Furthermore, the influences of the AC voltage or offset voltage on the retention ratios of mouse hybridoma 3-2H3 cells and horse red blood cells (HRBC) were investigated. The difference in the retention ratio of the two kinds of cells was a maximum of 56 points. The separation efficiency of this device is expected to be improved by changing the device shape, number of pores, and pore placement. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1292-1300, 2016. PMID- 27453405 TI - In this August issue. PMID- 27453406 TI - Is delirium the medical emergency we know least about? PMID- 27453407 TI - Erratum. PMID- 27453409 TI - The presentation of plastic surgery visual data from 1816 to 1916: The evolution of reproducible results. AB - All scientific data should be presented with sufficient accuracy and precision so that they can be both analyzed properly and reproduced. Visual data are the foundation upon which plastic surgeons advance knowledge. We use visual data to achieve reproducible results by discerning details of procedures and differences between pre- and post-surgery images. This review highlights how the presentation of visual data evolved from 1816, when Joseph Carpue published his book on nasal reconstruction to 1916, when Captain Harold Gillies began to treat over 2000 casualties from the Battle of the Somme. It shows the frailties of human nature that led some authors such as Carl von Graefe, Joseph Pancoast and Thomas Mutter to record inaccurate methods or results that could not be reproduced, and what measures other authors such as Eduard Zeis, Johann Dieffenbach, and Gurdon Buck took to affirm the accuracy of their results. It shows how photography gradually supplanted illustration as a reference standard. Finally, it shows the efforts that some authors and originators took to authenticate and preserve their visual data in what can be considered the forerunners of clinical registries. PMID- 27453410 TI - Superiority of ultrasound-guided over conventional transbronchial needle aspiration in biopsy of lymph nodes: Have we had sufficient evidence? PMID- 27453411 TI - The role of ppGalNAc-T family in breast cancer development and progression. AB - Glycosylation of proteins is an essential process in all eukaryotes. Mucin-type O linked glycosylation is an evolutionarily conserved protein modification as a kind of glycosylation of proteins. The role of O-glycosylation was well documented in multiple cancers. While in breast cancer, the enzymes that catalyzed the initiation of O-glycosylation remained elusive. In this review, we briefly introduced the process of the initiation of O-glycosylation and summarized the roles of enzymes that catalyzed the initiation step of O glycosylation in the breast cancer carcinogenesis, development, and progression. Finally, we summarized some attempts exploring the therapy against aberrant O glycosylation. PMID- 27453412 TI - The correlation analysis of primary liver cancer with Type 2 diabetes. AB - OBJECTIVE: To explore the relationship between Type 2 diabetes and primary liver cancer. MATERIALS AND METHODS: In the period from December 2008 to December 2014, all blood sugar data of patients in our hospital was collected, and the total number is 18213. Except for repeatedly hospitalized diabetic person, newborn stress status, or venous transfusion blood glucose, gestational diabetes, etc., By retrieving the medical record information of patients in the hospital, and using telephone or letter follow-up the patients, we collected 127 people with type 1 diabetes and found no liver cancer patients; Type 2 diabetes, 10,794 cases of patient information, 59 with primary liver cancer. For data analysis, Stata11.0 ratio was used as the main analysis indicators, using Chi-square test and statistical analysis. RESULTS: About 10,794 Type 2 diabetes cases with 59 primary liver cancer, the incidence is 54.66/10,000, men liver cancer incidence (92.78/10,000) than women (27.13/10,000), with significant difference (chi2 = 26.621, P < 0.001). As the growth of the age, the possibility of liver cancer in patients with diabetes increased significantly (chi2 = 19.961, P = 0.001). The rate was highest for 50-60-year-old men, and the women at age 70, and older incidence is highest. Irrespective of men or women with diabetes as the growth of the age, the possibility of liver cancer had significantly increased (P = 0.001, P = 0.002). Hepatitis B or hepatitis C incidence was 2.94%, but diabetes incidence of hepatitis men (3.98%) and women (2.01%) did not find significant differences (chi2 = 0.3361, P = 0.562). Three hundred and seventeen cases of Type 2 diabetes with hepatitis, the incidence of primary liver cancer was 11.67%, the liver cancer incidence of diabetes patients with hepatitis men (17.78%) than women (3.97%), with significant difference (chi2 = 37.429, P < 0.001). With the growth of age, the overall risk of getting liver cancer (chi2 =15.023, P = 0.01) of diabetes and hepatitis patients is significantly increased, and with the growth of age, the risk of getting liver cancer of male patients showed significant (P < 0.05), but not the female patients. Without merge hepatitis, the morbility of primary liver cancer in 10477 cases of type2 diabetes incidence is 0.21%, the liver cancer incidence men (0.34%) than women (0.11%), with significant difference (chi2 = 6.471, P = 0.011).As the growth of age, the overall risk of getting liver cancer of diabetes patients without hepatits is significantly increased (chi2 =15.612, P = 0.008) ,and the risk of getting liver cancer of male patients showed significant (P < 0.05) as the growth of the age, but not the female patients. Diabetic persons according to the illness time can be divided into 0-5 years, 5-10 years, 10-20 years, and over 20 years of four stages, including 5-10 years and 10-20 years is liver cancer patients with diabetes incidence peak, male diabetic hepatitis in patients with liver cancer incidence than women, with significant difference (chi2 = 22.757, P < 0.001). The possibility of liver cancer in patients with diabetes increased significantly (chi2 = 15.023, P = 0.01) for longer duration of illness, but only the male patients with liver cancer incidence showed significant difference with longer duration of illness, women showed no significance. CONCLUSION: Diabetes was associated with the primary liver cancer, most likely is one of the causes of primary liver cancer. PMID- 27453413 TI - Prognostic role of s-phase kinase-associated protein 2 in breast cancer: A meta analysis. AB - OBJECTIVE: Emerging evidence has shown that the F-box protein S-phase kinase associated protein 2 (Skp2) plays an important role in the pathogenesis of breast cancer (BC). Our study aimed to evaluate the prognostic value of Skp2 in BC patients using meta-analysis based on the published studies. MATERIALS AND METHODS: Eligible studies were identified by searching the online databases such as PubMed, EMBASE, and Web of Science up to October 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between Skp2 expression and indicators of BC clinical outcomes, including overall survival (OS), disease-free survival (DFS), and BC-specific survival. RESULTS: In total, nine studies with 1820 BC patients were included for final analysis. The meta-analysis suggested that Skp2 overexpression was associated with poor OS (HR = 2.58, 95% CI: 1.83-3.63, P = 0.000) and poor DFS (HR = 2.12, 95% CI: 1.48-3.05, P = 0.000) in BC patients. CONCLUSIONS: This meta-analysis indicates that enhanced Skp2 is an independent prognostic factor for poor cancer survival. PMID- 27453414 TI - High preoperative and postoperative levels of carcinoembryonic antigen and CYFRA 21-1 indicate poor prognosis in patients with pathological Stage I nonsmall cell lung cancer. AB - BACKGROUND: Serum carcinoembryonic antigen (CEA) and the soluble fragment of cytokeratin 19 (CYFRA 21-1) are supposed to have a prognostic role in patients with nonsmall cell lung cancer (NSCLC) after surgery, but it has not been used as an adjunct to the tumor-node-metastasis (TNM) staging system to provide therapy options for patients with pathological Stage I NSCLC. This study was designed to investigate the effect of serum levels of CEA and CYFRA 21-1 before and after surgery on the prognosis of patients with Stage I NSCLC. MATERIALS AND METHODS: A retrospective review was performed regarding the medical records and follow-ups of 169 patients with Stage I NSCLC before and after surgery. The patients were divided into three groups based on levels of serum CEA and CYFRA 21-1 before and after surgery: (1) continuously normal-level groups (CEA [NN] and CYFRA 21-1 [NN] groups); (2) declined to normal-level groups (CEA [HN] and CYFRA 21-1 [HN] groups); and (3) continuously high-level groups (CEA [HH] and CYFRA 21-1 [HH] groups). Survival analysis was conducted using the Kaplan-Meier method for each group. The Chi-square or Fisher exact test was employed to compare clinical and pathologic factors at the level of P < 0.05. The prognostic factor was evaluated by the Cox proportional hazards model. RESULTS: Compared with the continuously normal-level groups, the CEA [HN] group was significantly correlated to tumor size (P = 0.011), and the CYFRA 21-1 [HN] group was significantly correlated to tumor type and pathological TNM in addition to tumor size. Five-year survivals were significantly lower (P = 0.004) in the CEA [HH] group (67.3%) and the CEA [HN] group (86.5%) than in the CEA [NN] group (85.7%) and were significantly lower (P < 0.001) in the CYFRA 21-1 [HH] group (47.2%) and the CYFRA 21-1 [HN] group (70.1%) than in the CYFRA 21-1 [NN] group (90.1%). Multivariate analysis demonstrated that tumor size (21-50 mm), CEA [HH], and CYFRA 21-1 [HH] were independent unfavorable prognostic factors for overall survival (OS), whereas tumor size (21-50 mm), CEA [HH], CYFRA 21-1 [HN], and CYFRA 21-1 [HH] were independent significant prognostic factors for progression-free survival (PFS). CONCLUSION: Patients with a persistently high serum CEA or CYFRA 21-1 before and after surgery had shortest OS and PFS. These patients had worst prognosis. Adjuvant chemotherapy was likely to improve survival for these patients. PMID- 27453415 TI - Upregulated long noncoding RNA SPRY4-IT1 contributes to increased cell viability by activating zinc finger 703 expression in esophageal squamous cell carcinoma. AB - OBJECTIVES: The function of long noncoding RNA SPRY4-IT1 in human esophageal squamous cell carcinoma (ESCC) has been showed in the former studies. The purpose of this study was to further analyze the underlined mechanisms responsible for its role in ESCC cells. MATERIALS AND METHODS: Quantitative reverse transcriptase polymerase chain reaction was firstly used to measure the expression of SPRY4-IT1 in 50 ESCC patients of different clinical stages. Loss of function approach was then applied to confirm the biological function, especially cell viabilities in cultured ESCC cells, by cell counting kit-8 and clonogenic assay. We further used western blot to reveal the activation of zinc finger 703 (ZNF703) by SPRY4-IT1. RESULTS: We validated that SPRY4-IT1 was upregulated in ESCC tissues of advanced clinical stages. In vitro function assays demonstrated that SPRY4-IT1 cause promotion of cell viability in ESCC cells. We further verified that SPRY4-IT1 could also activate the expression of ZNF703 in ESCC cells, which might contribute to the role of SPRY4-IT1 in ESCC cells. CONCLUSION: SPRY4-IT1 is a vital regulator in ESCC progression, and the SPRY4-IT1/ZNF703 axis might provide novel clues for future ESCC therapy. PMID- 27453416 TI - miR-338-3p suppresses epithelial-mesenchymal transition and metastasis in human nonsmall cell lung cancer. AB - OBJECTIVES: MicroRNAs are important modulators of the cellular epithelial mesenchymal transition (EMT) process and are associated with metastasis in human nonsmall cell lung cancer (NSCLC). In this study, we tried to investigate the role of miR-338-3p in NSCLC cells. MATERIALS AND METHODS: Real-time polymerase chain reaction was applied to quantify the expression levels of miR-338-3p, as well as EMT-associated molecules in NSCLC cells. Wound healing and transwell assays were performed to evaluate the migration and invasion capacities, respectively. Dual-luciferase reporter assay was finally performed to determine the targeting of zinc finger E-box-binding protein 2 (ZEB2) by miR-338-3p. RESULTS: We found that miR-338-3p was significantly reduced in NSCLC cell lines. Forced expression of miR-338-3p in A549 cells led to the suppression of migration/invasion capacity and inhibition of epithelial markers. In addition, we proved that miR-338-3p could directly target ZEB2. CONCLUSIONS: In general, we summarized that miR-338-3p could inhibit EMT and metastasis of human NSCLC cells, which probably via directly targeting ZEB2 expression. PMID- 27453417 TI - Receptor for activated protein kinase C 1 suppresses gastric tumor progression through nuclear factor-kB pathway. AB - OBJECTIVE: Nuclear factor-kB (NF-kB) activity is crucial for survival and proliferation of many kinds of malignancies, including gastric cancer (GC). The receptor for activated protein kinase C 1 (RACK1) is known to regulate tumor development, whereas the underlined mechanism has not been described clearly. MATERIALS AND METHODS: We analyzed expression of RACK1 in paired human GC samples by both real-time polymerase chain reaction (PCR) and western blot. Effects of RACK inhibition with small interfering RNA or its overexpression in cultured GC cell lines were evaluated in cell viabilities. NF-kB signaling was investigated using luciferase reporter assay and real-time PCR. RESULTS: RACK1 was significantly decreased in GC samples. Knockdown of RACK elevated GC cell viabilities, whereas overexpression of RACK1 suppressed tumorigenesis of GC cells. Importantly, NF-kB signaling was enhanced after RACK1 expression was inhibited, suggesting the negative regulation of the pro-oncogenic NF-kB activity by RACK1 might contribute to its tumor suppressor role in GC cells. CONCLUSION: Our results support that RACK1 suppresses gastric tumor progression through the NF-kB signaling pathway. PMID- 27453418 TI - Programmed cell death 1 expression in esophageal squamous cell carcinoma and association with clinical characteristics. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the programmed cell death 1 (PD-1) expression in esophageal squamous cell carcinoma (ESCC) and association with clinical characteristics. MATERIALS AND METHODS: From January 2009 to December 2014, 88 patients with ESCC were retrospectively included in this study. Eighty-eight cancer tissues, 35 paraneoplastic atypical hyperplasia tissues (PAHTs), and 30 relative normal esophageal tissues (RNETs) were collected and tested for expression of PD-1 by immunohistochemistry assay. The PD-1 expression and clinical characteristics of the ESCC patients were evaluated. The prognosis of the ESCC patients was compared between the PD-1 positive and negative patients. RESULTS: The PD-1 positive rate was 51.2% (45/88), 22.9% (8/35), and 6.7% (2/30) for the cancer tissue, PAHT, and RNET, respectively, with statistical difference (P < 0.05); The PD-1 expression was significantly associated with lymph node metastasis (P < 0.05) and pathology grade (P < 0.05). The median overall survival was 29.8 months and 32.1 months for the PD-1 positive and negative groups without statistical difference (hazard ratio = 1.00, 95% confidence interval = 0.58-1.71, P < 0.05). CONCLUSION: PD-1 may play a key role in the process of carcinogenesis of ESCC but not associated with prognosis and overall survival. PMID- 27453419 TI - Tashinone II A-sulfoacid-natrum elevates the pain threshold through inhibiting nuclear factor kappa B pathway in neuropathic cancer pain. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of Tashinone II A-sulfoacid-natrum on the pain threshold and potential molecular mechanism for neuropathic cancer pain. METHODS: Forty-five male Balb/c mice were divided into control group model group and experiment group with each 15. The sciatic nerve muscle plexus of experiment and model group were given injection containing S180 sarcoma cell 2 * 10 6 mL for each mouse. Mice in the experiment group were given Tashinone II A-sulfoacid-natrum 25 mg/kg once a day intraperitoneal injection. Moreover, mice in the control group were given physiological saline 25 mg/kg, once a day intraperitoneal injection. The mechanical withdraw threshold and thermal withdraw latency were recorded before S180 sarcoma cell injection and in the time point of day 3, 6, 9, 12, and 14. After 14 days treatment, the mice were treated to death and the sciatic nerve CX3CR1 and nuclear factor kappa B (NF-kB) mRNA was tested by quantitative polymerase chain reaction. RESULTS: Compared with control group, the mechanical and thermal pain threshold of experiment group was significant decreased (P < 0.05). However, compared with the model group, the mechanical, and thermal pain threshold of experiment group was significant elevated in time point of day 3, 6, 9, 12, 14 for mechanical pain threshold and day 9, 12 14 for thermal pain threshold (P < 0.05); the pain threshold for the experiment and model group was decreased in the first 9 days and then elevated gradually. Compared with control group, the CX3CR1 and NF-kB mRNA relative expression in mice sciatic nerve of experiment group was significant elevated (P < 0.05); but compared with model group, the CX3CR1 and NF-kB mRNA relative expression of experiment group was significant decreased (P < 0.05). CONCLUSION: Tashinone II A-sulfoacid-natrum can elevates the mechanical and thermal pain threshold through inhibiting the NF-kB in neuropathic cancer pain rat. PMID- 27453420 TI - MicroRNA-185 is a novel tumor suppressor by negatively modulating the Wnt/beta catenin pathway in human colorectal cancer. AB - OBJECTIVE: The deregulation of microRNA-185 (miR-185) has been showed to be associated with many cancers and act as a tumor suppressor in many types of human malignancies. We hence tried to find out its role in human colorectal cancer (CRC). MATERIALS AND METHODS: miR-185 expression was investigated by real-time quantitative polymerase chain reaction. We carried out transfections to overexpress or knockdown of miR-185 by mimics or inhibitor, respectively. Functional study like cell counting kit-8 assay was performed to evaluate the proliferation. For addressing the impact of miR-185 on Wnt/beta-catenin signaling, we further applied luciferase reporter assay and Western blotting for specific proteins in this pathway. RESULTS: miR-185 was decreased in CRC cell lines when compared with corresponding control cell line. We also proved that its overexpression in LoVo cells could remarkably suppress cell proliferation whereas knocked it down in SW480 cells has the opposite effect in vitro. Mechanically, we demonstrated that miR-185 could suppress the Wnt/beta-catenin signaling and modulate the transcription and translation level of downstream molecules of this pathway, including MYC and CCND1. CONCLUSION: Taken together, these results suggested that miR-185 exerts its tumor suppressor activities probably through a negative modulation of the Wnt/beta-catenin pathway. PMID- 27453421 TI - MicroRNA-618 modulates cell growth via targeting PI3K/Akt pathway in human thyroid carcinomas. AB - OBJECTIVE: MicroRNAs (miRNAs) were popularly investigated in many cancers. The aim of this study was to evaluate the expression, role, and mechanism of microRNA 618 (miR-618) in human thyroid cancer (TC) cells. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction was carried out to examine the expression level of miR-618 in 20 TC tissues with 15 adjacent normal tissues. Synthesized mimics medicated miR-618 overexpression model was done in TC TPC-1 cell line. The effects of cell growth were determined by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide method. In addition, PI staining followed by flow cytometry was performed to analyze cell cycle. Then, we performed Western blotting to analyze the impact of miR-618 overexpression on the classical PI3K/Akt signaling pathway. RESULTS: We confirmed previous findings that miR-618 was downregulated in TC. Functionally, we found that forced expression of miR-618 suppressed cell proliferation and led to G2/M arrest in TPC 1 cells. Mechanically, we showed that miR-618 overexpression induced a significant inhibition of PI3K/Akt signaling pathway in TPC-1 cells. Importantly, restoration of Akt reversed the growth inhibitory effects of miR-618. CONCLUSION: Taken together, our results described a growth-suppressive role of miR-618 in TC cells partially targeting the PI3K/Akt signaling pathway. PMID- 27453422 TI - Long noncoding ribonucleic acids maternally expressed gene 3 inhibits lung cancer tumor progression through downregulation of MYC. AB - OBJECTIVE: Long noncoding ribonucleic acids (RNAs) nowadays emerge as important biomarkers or potential therapeutic targets discussed in human cancers. Among them, maternally expressed gene 3 (MEG3) is known to be decreased in a variety of malignancies. MATERIALS AND METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect the expression of MEG3 in forty pairs of lung cancer (LC) tissues. Overexpression of MEG3 was carried out, and we determined its effect on cell proliferation, apoptosis, and migration evaluated by cell counting kit-8, flow cytometric, and transwell analysis. Messenger RNA and protein expression of MYC were determined by qRT-PCR and western blot, respectively. RESULTS: The expression of MEG3 was downregulated in LC tissues. Forced expression of MEG3 led to reduced abilities of cell proliferation and elevated apoptosis rate. It also slightly inhibited cell migration capacity in vitro. In addition, MYC was inhibited by MEG3 overexpression at both transcriptional and translational levels. CONCLUSION: Our findings revealed MEG3 could regulate LC progression and serve as an important target for LC treatment. PMID- 27453424 TI - Agmatine ameliorates lipopolysaccharide induced depressive-like behaviour in mice by targeting the underlying inflammatory and oxido-nitrosative mediators. AB - Experimental and clinical evidence indicates that pro-inflammatory cytokines, oxidative stress and brain-derived neurotrophic factor (BDNF) signalling mechanisms play a role in the pathophysiology of depression. Agmatine is a neurotransmitter and/or neuromodulator that has emerged as a potential agent to manage diverse central nervous system disorders. Agmatine has been shown to exert antidepressant-like effect. The present study investigated ability of agmatine to abolish the depressive-like behaviour induced by the administration of the lipopolysaccharide (LPS) in mice. Agmatine (20 and 40mg/kg) was administered daily for 7days, then the mice were challenged with saline or LPS (0.83mg/kg; i.p.) on the 7th day. After 24h of LPS administration we tested mice for depressive-like behaviour. LPS treated animals presented an increase in immobility time in the forced-swim test (FST), tail suspension test (TST) which was reversed by agmatine pre-treatment (20 and 40mg/kg). Oxidative/nitrosative stress evoked by LPS was ameliorated by both doses of agmatine in hippocampus (HC) and prefrontal cortex (PFC). Administration of LPS caused an increase in interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), whereas BDNF was down regulated in the HC. Agmatine pre-treatment at 40mg/kg ameliorated LPS-induced neuroinflammation by attenuating brain IL-1beta and TNF-alpha level. In addition, agmatine pre-treatment also up-regulated the BDNF level in the HC. The present study shows that pre-treatment of agmatine is able to abolish the behavioural responses in the FST and TST elicited by the LPS-induced model of depression that may depend on the inhibition of pro-inflammatory mediators, reduction of oxidative stress as well as activation neuroplasticity-related signalling in mice, suggesting that agmatine may constitute an monotherapy/adjuvant for the management of depression associated with inflammation. PMID- 27453423 TI - The impact of inflammation on the obesity paradox in coronary heart disease. AB - BACKGROUND: Despite the well-known adverse effects of obesity on almost all aspects of coronary heart disease, many studies of coronary heart disease cohorts have demonstrated an inverse relationship between obesity, as defined by body mass index (BMI), and subsequent prognosis: the 'obesity paradox'. The etiology of this and the potential role of inflammation in this process remain unknown. PATIENTS AND METHODS: We studied 519 patients with coronary heart disease before and after cardiac rehabilitation, dividing them into groups based on C-reactive protein ((CRP)?3 mg l-1 and CRP<3 mg l-1 after cardiac rehabilitation). BMI was calculated and body fat was measured using the skin-fold method. Lean mass index (LMI) was calculated as (1-%body fat) * BMI. The population was divided according to age- and gender-adjusted categories based on LMI and body fat and analyzed by total mortality over >3-year follow-up by National Death Index in both CRP groups. RESULTS: During >3-year follow-up, all-cause mortality was higher in the high inflammation and in the low BMI group. In proportional hazard analysis, even after adjusting for ejection fraction and peak O2 consumption, higher BMI was associated with lower mortality in the entire population (hazard ratio (HR) 0.38; confidence interval 0.15-0.97) and a trend to lower mortality in both subgroups (HR 0.45 in low CRP, P=0.24 vs HR 0.32, P=0.06 in high CRP). High body fat, however, was associated with significantly lower mortality in the high CRP group (HR 0.22; P=0.03) but not in the low CRP group (HR 0.73; P=0.64). Conversely, high LMI was associated with markedly lower mortality in the low CRP group (HR 0.04; P=0.04). CONCLUSIONS: The obesity paradox has multiple underlying etiologies. Body composition has a different role in different populations with an obesity paradox by BMI. Especially in the subpopulation with persistently high CRP levels, body fat seems protective. PMID- 27453425 TI - Individual negative symptoms and domains - Relevance for assessment, pathomechanisms and treatment. AB - The negative symptoms of schizophrenia can be divided into two domains. Avolition/apathy includes the individual symptoms of avolition, asociality and anhedonia. Diminished expression includes blunted affect and alogia. Until now, causes and treatment of negative symptoms have remained a major challenge, which is partially related to the focus on negative symptoms as a broad entity. Here, we propose that negative symptoms may become more tractable when the different domains and individual symptoms are taken into account. There is now increasing evidence that the relationship with clinical variables - in particular outcome - differs between the domains of avolition/apathy and diminished expression. Regarding models of negative symptom formation, those relevant to avolition/apathy are now converging on processes underlying goal-directed behavior and dysfunctions of the reward system. In contrast, models of the diminished expression domains are only beginning to emerge. The aim of this article is to review the specific clinical, behavioral and neural correlates of individual symptoms and domains as a better understanding of these areas may facilitate specific treatment approaches. PMID- 27453426 TI - The incidence of slow flow after rotational atherectomy of calcified coronary arteries: A randomized study of low speed versus high speed. AB - OBJECTIVES: The purpose of this randomized trial was to compare the incidence of slow flow between low-speed and high-speed rotational atherectomy (RA) of calcified coronary lesions. BACKGROUND: Preclinical studies suggest that slow flow is less frequently observed with low-speed than high-speed RA because of less platelet aggregation with low-speed RA. METHODS: This was a prospective, randomized, single center study. A total of 100 patients with calcified coronary lesions were enrolled and randomly assigned in a 1:1 ratio to low-speed (140,000 rpm) or high-speed (190,000 rpm) RA. The primary endpoint was the occurrence of slow flow following RA. Slow flow was defined as slow or absent distal runoff (Thrombolysis in Myocardial Infarction [TIMI] flow grade <= 2). RESULTS: The incidence of slow flow in the low-speed group (24%) was the same as that in the high-speed group (24%) (P = 1.00; odds ratio, 1.00; 95% confidence interval, 0.40 2.50). The frequencies of TIMI 3, TIMI 2, TIMI 1, and TIMI 0 flow grades were similar between the low-speed (TIMI 3, 76%; TIMI 2, 14%; TIMI 1, 8%; TIMI 0, 2%) and high-speed (TIMI 3, 76%; TIMI 2, 14%; TIMI 1, 10%; TIMI 0, 0%) groups (P = 0.77 for trend). The incidence of periprocedural myocardial infarction was the same between the low-speed (6%) and high-speed (6%) groups (P = 1.00). CONCLUSIONS: This randomized trial did not show a reduction in the incidence of slow flow following low-speed RA as compared with high-speed RA (UMIN ID: UMIN000015702). (c) 2016 Wiley Periodicals, Inc. PMID- 27453427 TI - Inhibition of placental 11beta-hydroxysteroid dehydrogenase type 2 by lead. AB - Lead interferes with cortisol blood concentration, increases the risk of obstetrical complications, and could alter fetal development. The placenta controls maternal cortisol transfer to the fetus by the activity of the type 2 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), which converts cortisol into inactive cortisone. This study determines the effect of lead on the expression and activity of the placental 11beta-HSD2 in human trophoblast-like BeWo cells. Cells were treated with increasing concentration (0-1000nM) of PbCl2 for 24h. 11beta-HSD2 protein expression was reduced by 45% at 1000nM of PbCl2 compared to untreated cells, while the activity was significantly reduced by PbCl2 at 10, 100 and 1000nM. This study shows the direct inhibitory action of lead on placental 11beta-HSD2 activity and suggests that this heavy metal reduces the efficiency of the placental protection against the adverse effects of high cortisol level during fetal development. PMID- 27453429 TI - Entrepreneurial Orientation Scale: Adaptation to Spanish. AB - Entrepreneurship is linked to the perception of opportunities, to orientation, to attitudes, to the fear of failure and to entrepreneurial motivations. Entrepreneurial orientation is a fundamental construct for understanding the phenomenon of entrepreneurship. What is more, it is multidimensional and has attracted considerable attention from researchers in recent years. The objective of this study was to adapt the original 12-item English scale to Spanish and to analyze its psychometric properties. The participants in the present study were 925 Spanish employees (48.2% men, 51.5% women, M age = 42.49 years, SD age = 11.25) from the Autonomous Communities of Catalonia and Castilla-Leon. After applying an ESEM (RMSEA = .06; CFI = .97 and TLI = .95) a structure was determined made up of four factors which corroborated the structure of the original scale: Autonomy (alpha = .71 and CI = .68 - .73), Innovativeness (alpha = .70 and CI = .67 - .73), Risk Taking (alpha = .72 and CI = .68 - .74) and Competitive Aggressiveness (alpha = .70 and CI = .67 - .73). The four factors displayed suitable reliability. The study also found evidences of validity in relation to a series of external correlates and various scales which refer to workaholism, irritation and burnout. The scale presented here may prove useful for satisfactorily identifying, in Spanish, the entrepreneurial orientation of the working population. PMID- 27453428 TI - Optimizing multi-dimensional high throughput screening using zebrafish. AB - The use of zebrafish for high throughput screening (HTS) for chemical bioactivity assessments is becoming routine in the fields of drug discovery and toxicology. Here we report current recommendations from our experiences in zebrafish HTS. We compared the effects of different high throughput chemical delivery methods on nominal water concentration, chemical sorption to multi-well polystyrene plates, transcription responses, and resulting whole animal responses. We demonstrate that digital dispensing consistently yields higher data quality and reproducibility compared to standard plastic tip-based liquid handling. Additionally, we illustrate the challenges in using this sensitive model for chemical assessment when test chemicals have trace impurities. Adaptation of these better practices for zebrafish HTS should increase reproducibility across laboratories. PMID- 27453430 TI - Speciation of Adsorbed Phosphate at Gold Electrodes: A Combined Surface-Enhanced Infrared Absorption Spectroscopy and DFT Study. AB - Despite the significance of phosphate buffer solutions in (bio)electrochemistry, detailed adsorption properties of phosphate anions at metal surfaces remain poorly understood. Herein, phosphate adsorption at quasi-Au(111) surfaces prepared by a chemical deposition technique has been systematically investigated over a wide range of pH by surface-enhanced infrared absorption spectroscopy in the ATR configuration (ATR-SEIRAS). Two different pH-dependent states of adsorbed phosphate are spectroscopically detected. Together with DFT calculations, the present study reveals that pKa for adsorbed phosphate species at the interface is much lower than that for phosphate species in the bulk solution; the dominant phosphate anion, H2PO4(-) at 2 < pH < 7 or HPO4(2-) at 7 < pH < 12, undergoes deprotonation upon adsorption and transforms into the adsorbed HPO4 or PO4, respectively. This study leads to a conclusion different than earlier spectroscopic studies have reached, highlighting the capability of the ATR-SEIRAS technique at electrified metal-solution interfaces. PMID- 27453431 TI - Cocaine abstinence induces emotional impairment and brain region-specific upregulation of the oxytocin receptor binding. AB - The key problem in treating cocaine addiction is the maintenance of a drug-free state as negative emotional symptoms during abstinence often trigger relapse. The mechanisms underpinning the emotional dysregulation during abstinence are currently not well-understood. There is evidence suggesting a role of the neuropeptide oxytocin in the modulation of drug addiction processes. However, its involvement during long-term abstinence from cocaine use remains unclear. In this study, we aimed to behaviourally characterize a mouse model of long-term cocaine withdrawal and assess the effect of chronic cocaine administration and long-term cocaine abstinence on the central oxytocinergic system and the hypothalamic pituitary-adrenal axis. Fourteen-day escalating-dose cocaine administration (3 * 15-30 mg/kg/day) and 14-day withdrawal increased plasma corticosterone levels and oxytocin receptor (OTR) binding in piriform cortex, lateral septum and amygdala. A specific cocaine withdrawal-induced increase in OTR binding was observed in the medial septum. These biochemical alterations occurred concomitantly with the emergence of memory impairment, contextual psychomotor sensitization and an anhedonic and anxiogenic phenotype during withdrawal. Our study established a clear relationship between cocaine abstinence and emotional impairment in a novel translationally relevant model of cocaine withdrawal and demonstrated for the first time brain region-specific neuroadaptations of the oxytocin system, which may contribute to abstinence-induced negative emotional state. PMID- 27453432 TI - Staff perceptions of best practice for information transfer about multitrauma patients on discharge from the emergency department: a focus group study. AB - AIMS AND OBJECTIVES: To understand: (1) staff perceptions of best practice for information transfer for multitrauma patients on discharge from the emergency department; (2) what information should be conveyed at transfer and (3) how information is transferred. BACKGROUND: Information transfer for multitrauma patients is an integral factor for continuity of care, safety, quality assurance and patient outcomes; however, this has not been the focus of previous studies. DESIGN: This was a qualitative study using focus group interviews. METHODS: Data were collected during focus group interviews across five clinical areas. Themes were derived from the data with consensus from three data coders. Purposive sampling was used and included staff caring for trauma patients during patient transition out of the emergency department. Participants were representatives of the emergency department, perioperative care, intensive care unit, high dependency care unit and the trauma service unit. Twenty-six registered nurses and two medical officers participated. RESULTS: Five focus group interviews were held. Themes emerged from the data including 'Variability', 'Continuity' and 'Putting the pieces together'. The first three themes were all influenced by the fourth theme of 'Values/Context'. Considered together these themes influenced staff perception of the quality of information transfer for multitrauma patients on discharge from the emergency department. CONCLUSIONS: Staff perceived best practice for information transfer to be clear, concise, relevant documentation that travelled with the patient and interactive communication at handover that adhered to agreed principles and a minimum data set specific to trauma patients. RELEVANCE TO CLINICAL PRACTICE: Clinicians involved in handover need to actively listen, avoiding 'doing' at the same time, be aware of essential questions to ask about the patient. An agreed expectation between different clinical areas needs to exist about information transfer to reduce variability. The minimum data required to provide ongoing safe care for multitrauma patients are identified. PMID- 27453433 TI - Inhibition of GSK-3 reduces prostaglandin E2 production by decreasing the expression levels of COX-2 and mPGES-1 in monocyte/macrophage lineage cells. AB - Inflammatory stimuli induce prostaglandin E2 (PGE2) synthesis by upregulating cycloxgenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1). Glycogen synthase kinase-3 (GSK-3) reportedly plays an important role in inflammatory reactions, whereas the role of this enzyme in inflammatory PGE2 production remains unclear. In the present study, therefore, we examined whether inhibition of GSK-3 can reduce inflammatory PGE2 production in vitro and in vivo. When macrophage-like cells differentiated from THP-1 were stimulated with lipopolysaccharide (LPS), PGE2 production and the expression levels of COX-2 and mPGES-1 were markedly elevated. GSK-3 inhibitors LiCl and SB216763 strongly suppressed their protein levels through inhibition of mRNA expressions. Subsequently, we examined the effect of GSK-3 inhibitors on nuclear factor kappaB (NF-kappaB) and early growth response-1 (Egr-1). The GSK-3 inhibitors had no significant effect on the NF kappaB pathway, whereas they significantly decreased the expression level of Egr 1. Pharmacological and genetic inhibitions of GSK-3 also strongly suppressed PGE2 production in cultured peritoneal macrophages and in inflammatory air pouches made under the skin of living mice. These results suggested that GSK-3 plays a key role in PGE2 production by increasing COX-2 and mPGES-1 probably through Egr 1-mediated transcription and GSK-3 inhibitors may be potential as novel anti inflammatory drugs. PMID- 27453434 TI - Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy. AB - The clinical stage anti-cancer agent PR-104 has potential utility as a cytotoxic prodrug for exogenous bacterial nitroreductases expressed from replicating vector platforms. However substrate selectivity is compromised due to metabolism by the human one- and two-electron oxidoreductases cytochrome P450 oxidoreductase (POR) and aldo-keto reductase 1C3 (AKR1C3). Using rational drug design we developed a novel mono-nitro analog of PR-104A that is essentially free of this off-target activity in vitro and in vivo. Unlike PR-104A, there was no biologically relevant cytotoxicity in cells engineered to express AKR1C3 or POR, under aerobic or anoxic conditions, respectively. We screened this inert prodrug analog, SN34507, against a type I bacterial nitroreductase library and identified E. coli NfsA as an efficient bioactivator using a DNA damage response assay and recombinant enzyme kinetics. Expression of E. coli NfsA in human colorectal cancer cells led to selective cytotoxicity to SN34507 that was associated with cell cycle arrest and generated a robust 'bystander effect' at tissue-like cell densities when only 3% of cells were NfsA positive. Anti-tumor activity of SN35539, the phosphate pre prodrug of SN34507, was established in 'mixed' tumors harboring a minority of NfsA-positive cells and demonstrated marked tumor control following heterogeneous suicide gene expression. These experiments demonstrate that off-target metabolism of PR-104 can be avoided and identify the suicide gene/prodrug partnership of E. coli NfsA/SN35539 as a promising combination for development in armed vectors. PMID- 27453437 TI - Integrating independent spatio-temporal replications to assess population trends in disease spread. AB - Glaucoma is the second leading cause of blindness in the USA. A visual field test (perimetry) is used to sample and quantitate visual field function in preselected regions in the eye. These regions can be considered a spatial field with replications across independently measured individuals. At return visits, a new set of visual field measurements is obtained producing a subject specific spatio temporal dataset. We develop a Bayesian hierarchical modeling framework to analyze these spatio-temporal datasets both for individual level spread and as aggregate population level trends. Our model extends previous research utilizing a dimension reduction matrix and individual specific latent variables. Human characteristics are incorporated into the model to help explain glaucoma progression. One beneficial product of our model is smoothed estimates for individuals. We also specify how progression rates are computed for monitoring purposes so that clinicians can track changes and predict forward in time. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27453436 TI - Methylation of a panel of genes in peripheral blood leukocytes is associated with colorectal cancer. AB - The relationship between the DNA methylation status of the CpG islands of multiple genes in blood leukocytes in CRC susceptibility and prognosis, as well as possible interactions with dietary factors on CRC risk are unclear. We carried out a case-control study including 421 CRC patients and 506 controls to examine the associations between six genes (AOX-1, RARB2, RERG, ADAMTS9, IRF4, and FOXE 1), multiple CpG site methylation (MCSM) and susceptibility to CRC. High-level MCSM (MCSM-H) was defined as methylation of greater than or equal to 2 of 5 candidate genes (except for RARB2); low-level MCSM (MCSM-L) was when 1 candidate gene was methylated; non-MCSM was when none of the candidate genes were methylated. Blood cell-derived DNA methylation status was detected using methylation-sensitive high-resolution melting analysis. The hypermethylation status of each individual gene was statistically significantly associated with CRC. MCSM status was also associated with CRC (OR = 1.54, 95% CI: 1.15-2.05, P = 0.004). We observed interactions between a high level of dietary intake of cereals, pungent food, and stewed fish with brown sauce, age (older than 60 yrs), smoking and hypermethylation on risk of CRC. MCSM in peripheral blood DNA may be an important biomarker for susceptibility to CRC. PMID- 27453435 TI - Expression, regulation, and function of drug transporters in cervicovaginal tissues of a mouse model used for microbicide testing. AB - P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4) are three efflux transporters that play key roles in the pharmacokinetics of antiretroviral drugs used in the pre-exposure prophylaxis of HIV sexual transmission. In this study, we investigated the expression, regulation, and function of these transporters in cervicovaginal tissues of a mouse model. Expression and regulation were examined using real-time RT-PCR and immunohistochemical staining, in the mouse tissues harvested at estrus and diestrus stages under natural cycling or after hormone synchronization. The three transporters were expressed at moderate to high levels compared to the liver. Transporter proteins were localized in various cell types in different tissue segments. Estrous cycle and exogenous hormone treatment affected transporter mRNA and protein expression, in a tissue- and transporter-dependent manner. Depo Provera-synchronized mice were dosed vaginally or intraperitoneally with (3)H TFV, with or without MK571 co-administration, to delineate the function of cervicovaginal Mrp4. Co-administration of MK571 significantly increased the concentration of vaginally-administered TFV in endocervix and vagina. MK571 increased the concentration of intraperitoneally-administered TFV in the cervicovaginal lavage and vagina by several fold. Overall, P-gp, Bcrp, and Mrp4 were positively expressed in mouse cervicovaginal tissues, and their expression can be regulated by the estrous cycle or by exogenous hormones. In this model, the Mrp4 transporter impacted TFV distribution in cervicovaginal tissues. PMID- 27453438 TI - Fabrication and response of alpha-hydroxybutyrate sensors for rapid assessment of cardiometabolic disease risk. AB - Early diagnosis and treatment can prevent or delay progression of early-stage type 2 diabetes and prediabetes. Unfortunately, tests such as hemoglobin A1c (HbA1c)/fasting plasma glucose (FPG) alone fail to diagnose or miscategorize up to 40% of individuals with impaired glucose tolerance (IGT) or frank diabetes based on the rarely utilized oral glucose tolerance test (OGTT). The serum metabolite alpha-hydroxybutyrate (AHB) is increasingly recognized as a reliable IGT and diabetes predictor, and can be measured using liquid chromatography tandem mass spectrometry. However, to address AHB adoption as a population screening tool, the reliable and low-cost measurement techniques are proposed. A periodate based oxidation was performed for an AHB-based buffer, and both nitroprusside and Raman tests confirmed the formation of a slow-oxidation product. Electrochemical tests of AHB-based buffers using electrodes such as Au honeycomb, thiol self-assembled monolayers coated Au, 2D material (black-P) coated FTO, (3-aminophenyl) triethoxysilane modified TiO2, were performed. Many of these electrodes exhibited a systematic response when AHB concentration was varied from ~1.0-12.0ug/ml. A colorimetric assay containing a vicinal-diol recognition moiety, additives, and a photoinitiator, exhibited a different color for AHB based buffer. Benesi-Hildebrand analysis indicated the association behavior of boronic acid and AHB. These methods have a potential to be used for rapid point-of-care measurements of AHB that could enhance population-wide diabetes and prediabetes screening strategies. PMID- 27453439 TI - A novel bismuth oxychloride-graphene hybrid nanosheets based non-enzymatic photoelectrochemical glucose sensing platform for high performances. AB - A novel non-enzymatic photoelectrochemical (PEC) glucose sensor was first constructed based on the unique two-dimensional (2D) bismuth oxychloride-graphene nanohybrid sheets (BiOCl-G NHS). We have utilized a facile hydrothermal approach for the preparation of BiOCl-G NHS. Results from cyclic voltammetric and differential pulse voltammetric measurements revealed that the BiOCl-G NHS electrode is capable of generating photocurrent for glucose when its surface is irradiated with a light source (wavelength=365nm). The photocurrents produced for the presence of glucose at the bias potential of +0.50V showed a linear dependence on glucose concentration in the range between 0.5 and 10mM and had a detection limit of 0.22mM. The PEC detection of glucose at BiOCl-G NHS was not influenced by the presence of other common interfering species. The glucose levels, as determined by the BiOCl-G NHS sensor, agreed well with those obtained by the commercial glucometers. This novel non-enzymatic PEC glucose sensor exhibited good performances, such as a wider concentration range (500uM-10mM), high sensitivity (1.878uMmM-1cm-2 (500uM-2mM) and 127.2uMmM-1cm-2 (2mM-10mM)), good selectivity, reproducibility (RSD=2.4%) and applicability to real sample (human serum). PMID- 27453440 TI - Process Optimization to Improve Immunosuppressant Drug Testing Turnaround Time. AB - OBJECTIVES: Timely reporting of immunosuppressant (ISP) drug level results is needed for transplant patient management. This study characterized the local ISP testing process, identified bottlenecks and implemented process improvements to meet turnaround time requirements. METHODS: Laboratory information time stamps, direct observation and discussion with staff were used to construct a value stream map of the ISP testing process to identify process bottlenecks. Improvements were implemented to attain the required turnaround time. RESULTS: Baseline performance of the existing ISP process (seven weeks, n = 272 samples) indicated that only 28% of samples were reported by 2:00 pm Major bottlenecks were identified to be the analytical run schedule, instrument delays, difficulty identifying ISP samples at intake, and difficulty collecting specimens. Process changes resulted in a median of 76% samples reported by 2:00 pm CONCLUSIONS: : Adjusting ISP collection and analysis processes improved the laboratory's ability to meet physician requested result reporting time of 2:00 pm. PMID- 27453441 TI - Intracranial Involvement by Plasma Cell Neoplasms. AB - OBJECTIVES: Intracranial plasma cell neoplasms (PCNs) arising from the skull, dura, or brain parenchyma are rare tumors and there is only a limited experience in the literature with these lesions. METHODS: We performed a retrospective clinicopathologic study of fourteen cases of intracranial PCN at our institution encountered over a 26-year-period. RESULTS: The fourteen patients ranged in age from 30-74 years (median 66 years) and included seven males. For eight patients, their intracranial lesions were the initial presentation of multiple myeloma (MM). Three patients had prior history of MM; their intracranial tumors showed blastic plasma cell morphology, and all three died secondary to MM. The remaining three patients did not or have not developed MM. CONCLUSIONS: PCNs rarely arise in the intracranial compartment. Intracranial PCN may be the initial presentation of MM. Anecdotally, blastic morphology appears to manifest more aggressive behavior. PMID- 27453442 TI - Deep Proteome Analysis Identifies Age-Related Processes in C. elegans. AB - Effective network analysis of protein data requires high-quality proteomic datasets. Here, we report a near doubling in coverage of the C. elegans adult proteome, identifying >11,000 proteins in total with ~9,400 proteins reproducibly detected in three biological replicates. Using quantitative mass spectrometry, we identify proteins whose abundances vary with age, revealing a concerted downregulation of proteins involved in specific metabolic pathways and upregulation of cellular stress responses with advancing age. Among these are ~30 peroxisomal proteins, including the PRX-5/PEX5 import protein. Functional experiments confirm that protein import into the peroxisome is compromised in vivo in old animals. We also studied the behavior of the set of age-variant proteins in chronologically age-matched, long-lived daf-2 insulin/IGF-1-pathway mutants. Unexpectedly, the levels of many of these age-variant proteins did not scale with extended lifespan. This indicates that, despite their youthful appearance and extended lifespans, not all aspects of aging are reset in these long-lived mutants. PMID- 27453443 TI - Switch-like Transitions Insulate Network Motifs to Modularize Biological Networks. AB - Cellular decisions are made by complex networks that are difficult to analyze. Although it is common to analyze smaller sub-networks known as network motifs, it is unclear whether this is valid, because these motifs are embedded in complex larger networks. Here, we address the general question of modularity by examining the S. cerevisiae pheromone response. We demonstrate that the feedforward motif controlling the cell-cycle inhibitor Far1 is insulated from cell-cycle dynamics by the positive feedback switch that drives reentry to the cell cycle. Before cells switch on positive feedback, the feedforward motif model predicts the behavior of the larger network. Conversely, after the switch, the feedforward motif is dismantled and has no discernable effect on the cell cycle. When insulation is broken, the feedforward motif no longer predicts network behavior. This work illustrates how, despite the interconnectivity of networks, the activity of motifs can be insulated by switches that generate well-defined cellular states. PMID- 27453444 TI - Enabling Privacy-Preserving GWASs in Heterogeneous Human Populations. AB - The proliferation of large genomic databases offers the potential to perform increasingly larger-scale genome-wide association studies (GWASs). Due to privacy concerns, however, access to these data is limited, greatly reducing their usefulness for research. Here, we introduce a computational framework for performing GWASs that adapts principles of differential privacy-a cryptographic theory that facilitates secure analysis of sensitive data-to both protect private phenotype information (e.g., disease status) and correct for population stratification. This framework enables us to produce privacy-preserving GWAS results based on EIGENSTRAT and linear mixed model (LMM)-based statistics, both of which correct for population stratification. We test our differentially private statistics, PrivSTRAT and PrivLMM, on simulated and real GWAS datasets and find they are able to protect privacy while returning meaningful results. Our framework can be used to securely query private genomic datasets to discover which specific genomic alterations may be associated with a disease, thus increasing the availability of these valuable datasets. PMID- 27453445 TI - Tradeoffs between Dense and Replicate Sampling Strategies for High-Throughput Time Series Experiments. AB - An important experimental design question for high-throughput time series studies is the number of replicates required for accurate reconstruction of the profiles. Due to budget and sample availability constraints, more replicates imply fewer time points and vice versa. We analyze the performance of dense and replicate sampling by developing a theoretical framework that focuses on a restricted yet expressive set of possible curves over a wide range of noise levels and by analyzing real expression data. For both the theoretical analysis and experimental data, we observe that, under reasonable noise levels, autocorrelations in the time series data allow dense sampling to better determine the correct levels of non-sampled points when compared to replicate sampling. A Java implementation of our framework can be used to determine the best replicate strategy given the expected noise. These results provide theoretical support to the large number of high-throughput time series experiments that do not use replicates. PMID- 27453447 TI - Accurate Reconstruction of Cell and Particle Tracks from 3D Live Imaging Data. AB - Spatial structures often constrain the 3D movement of cells or particles in vivo, yet this information is obscured when microscopy data are analyzed using standard approaches. Here, we present methods, called unwrapping and Riemannian manifold learning, for mapping particle-tracking data along unseen and irregularly curved surfaces onto appropriate 2D representations. This is conceptually similar to the problem of reconstructing accurate geography from conventional Mercator maps, but our methods do not require prior knowledge of the environments' physical structure. Unwrapping and Riemannian manifold learning accurately recover the underlying 2D geometry from 3D imaging data without the need for fiducial marks. They outperform standard x-y projections, and unlike standard dimensionality reduction techniques, they also successfully detect both bias and persistence in cell migration modes. We demonstrate these features on simulated data and zebrafish and Drosophila in vivo immune cell trajectory datasets. Software packages that implement unwrapping and Riemannian manifold learning are provided. PMID- 27453446 TI - Allele-Specific Quantification of Structural Variations in Cancer Genomes. AB - Aneuploidy and structural variations (SVs) generate cancer genomes containing a mixture of rearranged genomic segments with extensive somatic copy number alterations. However, existing methods can identify either SVs or allele-specific copy number alterations but not both simultaneously, which provides a limited view of cancer genome structure. Here, we introduce Weaver, an algorithm for the quantification and analysis of allele-specific copy numbers of SVs. Weaver uses a Markov random field to estimate joint probabilities of allele-specific copy numbers of SVs and their inter-connectivity based on paired-end whole-genome sequencing data. Weaver also predicts the timing of SVs relative to chromosome amplifications. We demonstrate the accuracy of Weaver using simulations and findings from whole-genome optical mapping. We apply Weaver to generate allele specific copy numbers of SVs for MCF-7 and HeLa cell lines and identify recurrent SV patterns in 44 TCGA ovarian cancer whole-genome sequencing datasets. Our approach provides a more complete assessment of the complex genomic architectures inherent to many cancer genomes. PMID- 27453448 TI - Childhood cognition and lifetime risk of major depressive disorder in extremely low birth weight and normal birth weight adults. AB - In general population samples, better childhood cognitive functioning is associated with decreased risk of depression in adulthood. However, this link has not been examined in extremely low birth weight survivors (ELBW, <1000 g), a group known to have poorer cognition and greater depression risk. This study assessed associations between cognition at age 8 and lifetime risk of major depressive disorder in 84 ELBW survivors and 90 normal birth weight (NBW, ?2500 g) individuals up to 29-36 years of age. The Wechsler Intelligence Scale for Children, Revised (WISC-R), Raven's Coloured Progressive Matrices and the Token Test assessed general, fluid, and verbal intelligence, respectively, at 8 years of age. Lifetime major depressive disorder was assessed using the Mini International Neuropsychiatric Interview at age 29-36 years. Associations were examined using logistic regression adjusted for childhood socioeconomic status, educational attainment, age, sex, and marital status. Neither overall intelligence quotient (IQ) [WISC-R Full-Scale IQ, odds ratios (OR)=0.87, 95% confidence interval (CI)=0.43-1.77], fluid intelligence (WISC-R Performance IQ, OR=0.98, 95% CI=0.48-2.00), nor verbal intelligence (WISC-R Verbal IQ, OR=0.81, 95% CI=0.40-1.63) predicted lifetime major depression in ELBW survivors. However, every standard deviation increase in WISC-R Full-Scale IQ (OR=0.43, 95% CI=0.20 0.92) and Performance IQ (OR=0.46, 95% CI=0.21-0.97), and each one point increase on the Token Test (OR=0.80, 95% CI=0.67-0.94) at age 8 was associated with a reduced risk of lifetime depression in NBW participants. Higher childhood IQ, better fluid intelligence, and greater verbal comprehension in childhood predicted reduced depression risk in NBW adults. Our findings suggest that ELBW survivors may be less protected by superior cognition than NBW individuals. PMID- 27453449 TI - On Bridges and Stacks. PMID- 27453450 TI - In Brief: Mitophagy: mechanisms and role in human disease. AB - Mitophagy is a selective form of macro-autophagy in which mitochondria are specifically targeted for autophagic degradation. Mitophagy plays an important role in cellular homeostasis by eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to stress. Cells execute mitophagy through several non-redundant mechanisms, including the PINK1/Parkin partnership, which modulates turnover of depolarized mitochondria, and stress induced BNIP3, NIX, and FUNDC1 molecular adaptors, which interact directly with LC3 to promote mitophagy. These pathways are deregulated in human diseases, including cancer, neurodegeneration, metabolic disorders, muscle atrophy, ageing, and inflammation, reflecting the importance of mitophagy as a cellular housekeeping function. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27453451 TI - Herbicides do not ensure for higher wheat yield, but eliminate rare plant species. AB - Weed control is generally considered to be essential for crop production and herbicides have become the main method used for weed control in developed countries. However, concerns about harmful environmental consequences have led to strong pressure on farmers to reduce the use of herbicides. As food demand is forecast to increase by 50% over the next century, an in-depth quantitative analysis of crop yields, weeds and herbicides is required to balance economic and environmental issues. This study analysed the relationship between weeds, herbicides and winter wheat yields using data from 150 winter wheat fields in western France. A Bayesian hierarchical model was built to take account of farmers' behaviour, including implicitly their perception of weeds and weed control practices, on the effectiveness of treatment. No relationship was detected between crop yields and herbicide use. Herbicides were found to be more effective at controlling rare plant species than abundant weed species. These results suggest that reducing the use of herbicides by up to 50% could maintain crop production, a result confirmed by previous studies, while encouraging weed biodiversity. Food security and biodiversity conservation may, therefore, be achieved simultaneously in intensive agriculture simply by reducing the use of herbicides. PMID- 27453453 TI - Does the Level of Evidence of Paper Presentations at the Arthroscopy Association of North America Annual Meetings From 2006-2010 Correlate With the 5-Year Publication Rate or the Impact Factor of the Publishing Journal? AB - PURPOSE: The purpose of this study was to determine the proportion of paper (podium) presentations at the 2006-2010 Arthroscopy Association of North America (AANA) annual scientific meetings that were ultimately published in a peer reviewed journal. Furthermore, we aimed to evaluate whether the level of evidence correlated with the publication rate of these presentations or the impact factor (IF) of the publishing journal. METHODS: Paper presentations from the 2006-2010 AANA annual meetings were included for evaluation. Clinical studies were graded for quality using the level of evidence by 2 independent reviewers. A comprehensive strategy was used to search the databases PubMed, Medline, and Embase for publications in scientific journals that corresponded to the presentations and were published within 5 years of the presentation date. RESULTS: Three hundred twenty-eight presentations were evaluated. Overall, 179 peer-reviewed publications corresponding to particular meeting presentations were identified, for a 5-year publication rate of 55%. There was no correlation between the publication rate and the level of evidence (P = .836), the type of study (P = .628), or the joint of focus (P = .07) of the presentations. The mean IF of journals that published Level I studies (4.8 [standard error, 2.3]) was significantly higher than the mean IF of journals that published Level II, III, or IV studies (2.58 [standard error, 0.10]) (P = .017). CONCLUSIONS: Between 2006 and 2010, presentations of the highest level of evidence at AANA meetings were subsequently published at a similar rate to presentations of lower levels of evidence, albeit in journals with higher IFs. CLINICAL RELEVANCE: This study is an important initial evaluation of the ultimate clinical impact of AANA meeting presentations. The study type, joint of focus, and level of evidence of the presentations all had no correlation with the rate at which these presentations were ultimately published. PMID- 27453452 TI - Pseudo-obstruction, stroke, and mitochondrial dysfunction: A lethal combination. AB - OBJECTIVES: The m.3243A>G MTTL1 mutation is the most common cause of mitochondrial disease; yet there is limited awareness of intestinal pseudo obstruction (IPO) in this disorder. We aimed to determine the prevalence, severity, and clinical outcome of patients with m.3243A>G-related mitochondrial disease manifesting with IPO. METHODS: In this large, observational cohort study, we assessed the clinical, molecular, and radiological characteristics of patients with genetically determined m.3243A>G-related mitochondrial disease, who presented with severe symptoms suggestive of bowel obstruction in the absence of an occluding lesion. RESULTS: Between January 2009 and June 2015, 226 patients harbouring the m.3243A>G mutation were recruited to the Medical Research Council Centre Mitochondrial Disease Patient Cohort, Newcastle. Thirty patients (13%) presented acutely with IPO. Thirteen of these patients had a preceding history of stroke-like episodes, whereas 1 presented 27 years previously with their first stroke-like episode. Eight patients developed IPO concomitantly during an acute stroke-like episode. Regression analysis suggested stroke was the strongest predictor for development of IPO, in addition to cardiomyopathy, low body mass index and high urinary mutation load. Poor clinical outcome was observed in 6 patients who underwent surgical procedures. INTERPRETATION: Our findings suggest, in this common mitochondrial disease, that IPO is an under-recognized, often misdiagnosed clinical entity. Poor clinical outcome associated with stroke and acute surgical intervention highlights the importance of the neurologist having a high index of suspicion, particularly in the acute setting, to instigate timely coordination of appropriate care and management with other specialists. Ann Neurol 2016;80:686-692. PMID- 27453454 TI - Magnetic Resonance Imaging Evidence of Postoperative Cyst Formation Does Not Appear to Affect Clinical Outcomes After Autologous Osteochondral Transplantation of the Talus. AB - PURPOSE: To identify potential cysts using magnetic resonance imaging (MRI) after autologous osteochondral transplantation (AOT) for osteochondral lesions of the talus (OLTs) as well as to determine the effect of cysts on short-term clinical outcomes. METHODS: Eighty-nine MRI scans of 37 patients who had AOT for an OLT were evaluated. Radiographic variables examined included cyst presence, cyst location, bone edema, and cartilage integrity. Patient clinical variables recorded and examined for association with the presence of a cyst included gender, age, preoperative lesion size, size and number of osteochondral graft used, symptoms reported, and pre- and postoperative Foot and Ankle Outcome Score (FAOS) and Short Form-12 (SF-12) scores measured at final follow-up. RESULTS: Twenty-four patients (64.8%) had MRI evidence of cystic change after AOT for an OLT at a mean MRI follow-up time of 15 months after surgery (range 2-54). Patients with presence of a cyst after surgery were older (mean age, 42.7 years) than those without cysts (mean age, 32.7 years) (P = .041), and among patients with a cyst, older patients more often had involvement of the subchondral plate (57.3 v 36.7 years) (P < .001). No other variables associated with cyst formation had statistical significance. Mean patient FAOS scores increased from 50 (+/-19) preoperatively to 87 (+/-8) postoperatively. Mean SF-12 scores increased from 52 (+/-18) preoperatively to 85 (+/-6) postoperatively. Patients not identified as having a cyst had lower SF-12 (P = .028) and FAOS (P = .032) preoperative scores and more improvement in SF-12 (P = .006) and FAOS (P = .016) scores than patients with cysts. CONCLUSIONS: Postoperative cyst formation on MRI was found to be a common occurrence after AOT for OLT. Although increasing age was related to increased cyst prevalence, the clinical impact of cyst formation was not found to be significant at short-term follow-up. Continued long-term longitudinal follow up of postoperative cysts is needed. LEVEL OF EVIDENCE: Level IV, prognostic case series. PMID- 27453455 TI - Mapping the Beck Depression Inventory to the EQ-5D-3L in Patients with Depressive Disorders. AB - BACKGROUND: For cost-utility analyses, data on health state utilities, as provided by the EQ-5D-3L, is needed but not always available. This study specified mapping algorithms from the Beck Depression Inventory (BDI) index to the EQ-5D-3L index adjusted for specific socio-demographic variables for patients with depressive disorders. AIMS OF THE STUDY: The objective of this study was to specify mapping algorithms from the BDI index to the preference-based EQ-5D index for patients with depressive disorders, adjusting for specific socio-demographic variables. METHODS: A sample of 1,074 consecutive patients with depressive disorders from a psychotherapeutic outpatient clinic was included in the study. Standardized clinical interviews were applied to establish reliable diagnoses. For the prediction of the EQ-5D-3L index from the BDI index and selected patient socio-demographic characteristics, ordinary least squares regression with robust standard errors was used. Model prediction properties were tested using the root mean squared error and repeated random sub-sampling cross-validation. RESULTS: The BDI index predicted the EQ-5D-3L index with a significant proportion of variance explained. The highest model goodness of fit was estimated for models with the BDI index and age as independent variables. The root mean squared error of the predicted EQ-5D-3L index in the validation samples was 0.23 for all models. DISCUSSION: The mean observed EQ-5D-3L index values and the mean predicted EQ-5D-3L index values seemed not to differ between models. However, a reduction of variability using cross-validation led to those (rather) accurate mean predicted values. One limitation of this study was the restricted generalizability. Moreover, some uncertainty was introduced in model predictive performance by usage of a dependent estimation sample for validation. IMPLICATIONS FOR FURTHER RESEARCH: The specified mapping algorithms from the BDI index to the EQ-5D-3L index for patients with depressive disorders are acceptable as approximation in cost-utility analyses. A further validation in independent samples is necessary to obtain more confidence in their performance. PMID- 27453456 TI - Does Prevention Pay? Costs and Potential Cost-savings of School Interventions Targeting Children with Mental Health Problems. AB - BACKGROUND: In Sweden, the local government is responsible for funding schools in their district. One funding initiative is for schools to provide students with mental health problems with additional support via extra teachers, personal assistants, and special education classes. There are evidence-based preventive interventions delivered in schools, which have been shown to decrease the levels of students' mental health problems. However, little is known about how much the local government currently spends on students' mental health support and if evidence-based interventions could be financially beneficial. AIMS OF THE STUDY: The aim of this study was to estimate the costs of providing additional support for students' mental health problems and the potential cost-offsets, defined as reduced school-based additional support, if two evidence-based school interventions targeting children's mental health problems were implemented in routine practice. METHODS: This study uses data on the additional support students with mental health problems received in schools. Data was collected from one school district for students aged 6 to 16 years. We modeled two Swedish school interventions, Comet for Teachers and Social and Emotional Training (SET), which both had evidence of reducing mental health problems. We used a cost-offset analysis framework, assuming both interventions were fully implemented throughout the whole school district. Based on the published studies, the expected effects and the costs of the interventions were calculated. We defined the cost-offsets as the amount of predicted averted additional support for students with ongoing mental health problems who might no longer require receiving services such as one on-one time with an extra teacher, a personal assistant, or to be placed in a special education classroom. A cost-offset analysis, from a payer's perspective (the local government responsible for school financing), was conducted comparing the costs of both interventions with the potential cost-savings due to a reduction in the prevalence of mental health problems and averted additional support required. RESULTS: The school district was comprised of 6,256 students, with 310 students receiving additional support for their mental health problems. Of these, 143 received support in their original school due to either having ADHD (n = 111), psychosocial problems (n = 26), or anxiety/depression (n = 6). The payers' total cost of additional support was 2,637,850 Euro per school year (18,447 Euro per student). The cost of running both interventions for the school district was 953,643 Euro for one year, while the potential savings for these interventions were estimated to be 627,150 Euro. The estimated effects showed that there would be a reduction of students needing additional support (25 for ADHD, eight for psychosocial problems, and one for anxiety/depression), and the payer would receive a return on their invested resources in less than two years (1.5 years) after implementation. DISCUSSION: Preventive school interventions can both improve some children's mental health problems and be financially beneficial for the payer. However, they are still limited in their scope of reducing all students' mental health statuses to below clinical cut-offs; therefore, the preventive school interventions should be used as a supplement, but not a replacement, to current practices. IMPLICATIONS FOR HEALTH POLICIES: The findings have political and societal implications, in that payers can reallocate their funds toward preventive measures targeting students' mental health problems, while reducing the costs. IMPLICATIONS FOR FUTURE RESEARCH: When evaluating public health actions, it is necessary to consider their economic impact. The resources are scarce and the decision makers need knowledge on how to allocate their resources in an efficient way. Cost-offset analysis is seen as one way for decision makers to comprehend research findings; however, such analyses tend to not include the full benefits of the interventions, and actual impacts need to be fully evaluated in routine implementation. PMID- 27453457 TI - Services Use of Children and Adolescents before Admission to Psychiatric Inpatient Care. AB - BACKGROUND: Although 20% of children and adolescents in Europe suffer from overt mental health problems, their illness-related service utilisation is often unknown. If at all, existing research has only addressed the health care sector while services requirements in mental health care go far beyond the health care system, including the social, the educational and the criminal justice system. AIMS OF STUDY: This paper aims at describing the service contact patterns of children and adolescents within and outside the health care sector before they are admitted to a child and adolescent mental health hospital. Additionally, we evaluate the private out-of-pocket payments that occur for primary carers. METHOD: A cohort of consecutive admissions to a child and adolescent hospital in Austria was prospectively analysed. We collected data on service use and out-of pocket expenses before hospital admission from primary carers through face-to face interviews using an adapted version of the European Child and Adolescent Mental Health Service Receipt Inventory (EU-CAMHSRI). Clinical data came from validated questionnaires (CBCL, YSR) and from the anamnestic documentation. RESULT: Ninety percent from a cohort of 441 patients had some contact with services or took medication before they were admitted to hospital. Most often, services in the health care outpatient setting were used. Outside of the health care system, support in school, as well as counselling services, were used most frequently, whereas the persons hardly sought support in living or employment. Roughly 32,400 per 100 patients was spent privately, yet these out-of pocket expenses were very unevenly distributed. Service use and out-of-pocket spending increased with social status and were gender-specific. The more severe external behaviour symptoms were, the more non-health care services were used. DISCUSSION: Mentally ill children and adolescents use a broad range of services across sectors before admission to hospital. Service use is associated with specific symptoms of the disease, yet not with the diagnosis. For some carers, this is linked to considerable financial burden because many of those services are only partly publicly funded or are not part of the health sector. A limitation of the study is the uncertainty of self-reports. Furthermore, we do not know whether the services used were needs-based and effective, and what the utilisation patterns of non-hospitalised children and adolescents are. IMPLICATIONS FOR HEALTH POLICIES: Mental health policy for children and adolescents in Austria needs to focus on how to organise a needs-oriented and coordinated services mix across different sectors that is equally accessible regardless of the patients' socio economic background. IMPLICATIONS FOR FUTURE RESEARCH: To support planning, further research on the factors that predict service use and on the cost effectiveness of services is required. PMID- 27453458 TI - Regional Variation in Physician Adoption of Antipsychotics: Impact on US Medicare Expenditures. AB - BACKGROUND: Regional variation in US Medicare prescription drug spending is driven by higher prescribing of costly brand-name drugs in some regions. This variation likely arises from differences in the speed of diffusion of newly approved medications. Second-generation antipsychotics were widely adopted for treatment of severe mental illness and for several off-label uses. Rapid diffusion of new psychiatric drugs likely increases drug spending but its relationship to non-drug spending is unclear. The impact of antipsychotic diffusion on drug and medical spending is of great interest to public payers like Medicare, which finance a majority of mental health spending in the US. AIMS: We examine the association between physician adoption of new antipsychotics and antipsychotic spending and non-drug medical spending among disabled and elderly Medicare enrollees. METHODS: We linked physician-level data on antipsychotic prescribing from an all-payer dataset (IMS Health's XponentTM) to patient-level data from Medicare. Our physician sample included 16,932 US. psychiatrists and primary care providers with > 10 antipsychotic prescriptions per year from 1997 2011. We constructed a measure of physician adoption of 3 antipsychotics introduced during this period (quetiapine, ziprasidone and aripiprazole) by estimating a shared frailty model of the time to first prescription for each drug. We then assigned physicians to one of 306 U.S. hospital referral regions (HRRs) and measured the average propensity to adopt per region. Using 2010 data for a random sample of 1.6 million Medicare beneficiaries, we identified 138,680 antipsychotic users. A generalized linear model with gamma distribution and log link was used to estimate the effect of region-level adoption propensity on beneficiary-level antipsychotic spending and non-drug medical spending adjusting for patient demographic and socioeconomic characteristics, health status, eligibility category, and whether the antipsychotic was for an on- vs. off-label use. RESULTS: In our sample, mean patient age was 62 years, 42% were male, and 86% had low-income. Half of antipsychotic users in Medicare had an on-label indication. The weighted average propensity to adopt the three new antipsychotics varied four-fold across HRRs. For every one standard deviation increase in the propensity to adopt there was a 5% increase in antipsychotic spending after adjusting for covariates (adjusted ratio of spending 1.05, 95% CI 1.01-1.08, p = 0.005). Physician propensity to adopt new antipsychotics was not associated with non-drug medical spending (adjusted ratio 0.96, 95% CI 0.91-1.01, p < 0.117). DISCUSSION: These findings suggest wide regional variation in physicians' propensity to adopt new antipsychotic medications. While physician adoption of new antipsychotics was positively associated with antipsychotic expenditures, it was not associated with non-drug spending. Our analysis is limited to Medicare and may not generalize to other payers. Also, claims data do not allow for the measurement of health outcomes, which would be important to evaluate when calculating the value of rapid vs. slow technology adoption. PMID- 27453459 TI - The role of macrophages in anti-inflammatory activity of antidepressant drugs. AB - Depression is a common disease influencing patients' quality of life, whose etiology involves complex interactions of environmental, genetic and immunological factors. The latter factors include proinflammatory activation of monocytes and macrophages and increased serum levels of proinflammatory cytokines, altogether formulated as the "macrophage theory of depression". Our current review summarizes the impact of the most commonly used antidepressant drugs on the immune response with special emphasis on the role of macrophages in the clinically observed effects. The anti-inflammatory action of antidepressants mainly results from their direct interaction with immune cells and from changes in the concentration and the relations of neurotransmitters sensed by these cells. The summarized data revealed that Mphis are one of the leading cell populations involved in drug-mediated immune effects that can be observed both in subjects with depression as well as in individuals not suffering from depression. Thus, currently reviewed immunomodulatory effects of the experimental use of different antidepressant drugs suggest the possibility of utilizing them in complex therapeutic strategies dedicated to various inflammatory and immune mediated diseases. It is worth noting that an excessive inflammatory reaction is also associated with the pathogenesis of various cardiovascular, metabolic and neuro-endocrine diseases. Thus, the inclusion of antidepressants in the complex therapy of these disorders may have beneficial effects through the enhancement of the mood of the patient and alleviation of chronic inflammation. On the other hand, presented data suggest that the influence of chronically used antidepressants on anti-microbial and anti-tumor immunity could also be taken into consideration. PMID- 27453460 TI - Vav3 is linked to poor prognosis of pancreatic cancers and promotes the motility and invasiveness of pancreatic cancer cells. AB - BACKGROUND/OBJECTIVES: The aim of this study was to investigate the role of the guanine nucleotide exchange factor Vav3 in the motility and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells. METHODS: Immunohistochemistry was used to determine whether high Vav3 expression in human PDAC tissues is correlated with poor prognosis. Immunocytochemistry was used to determine the association and intracellular distribution of Vav3, Rac1 and Akt in PDAC cells. Phosphoprotein array analysis was performed to determine the Vav3-associated intracellular signaling pathways. Immunocytochemistry and Matrigel invasion assays were used to examine the effects of Vav3 on the formation of cell protrusions and PDAC cell invasion. RESULTS: Expression of Vav3 in PDAC tissue was significantly correlated with overall survival. Vav3 was localized in cell protrusions of migrating PDAC cells. Knockdown of Vav3 inhibited the motility and invasiveness of PDAC cells through a decrease in cell protrusions. The levels of active Rac1 or active Akt were not associated with the concentration of Vav3 in cell protrusions. The Vav3-dependent promotion of motility and invasiveness was not modulated by Rac1 or Akt. Additionally, knockdown of Vav3 increased phosphorylated WNK1 in PDAC cells, and knockdown of WNK1 inhibited the motility and invasiveness. This study suggests that Vav3 can be a useful marker for predicting the outcome of patients with PDAC and that Vav3 can promote PDAC cell motility and invasion through association with dephosphorylation of WNK1. CONCLUSIONS: Vav3 was accumulated in cell protrusions, contributed to the formation of membrane protrusions, and thereby increased the motility and invasiveness of PDAC cells. PMID- 27453461 TI - Systematic review and meta-analysis on the prevalence of vitamin D deficiency in patients with chronic pancreatitis. AB - BACKGROUND/OBJECTIVES: Patients with chronic pancreatitis (CP) are at risk of malnutrition due to malabsorption, pain and/or alcohol consumption. This can cause vitamin D insufficiency or deficiency, which is associated with osteoporosis and increased risks of fractures. We aimed to perform a meta analysis to determine the prevalence of vitamin D insufficiency and deficiency in CP patients. Furthermore, we compared these results with healthy controls. METHODS: We performed a systematic review and meta-analysis on the literature by searching PubMed and EMBASE (January 2000-December 2015) on CP and vitamin D. Primary outcome was prevalence of vitamin D insufficiency (<75 nmoL/L) and deficiency (<50 nmoL/L) in CP patients. When available, data of CP patients were compared with healthy controls. RESULTS: Nine studies were included in our meta analysis, reporting on the prevalence of vitamin D insufficiency/deficiency in 465 patients (mean age 41 years (range 18-60), 81% male) and in 378 controls (mean age 40 years (range 18-67), 76% male). Pooled prevalence of vitamin D insufficiency and deficiency in CP patients was 83% and 65%, respectively. Calculated odds ratio (OR) of vitamin D insufficiency and deficiency between CP patients and controls was 1.34 (0.54-3.29) and 1.14 (0.70-1.85), respectively (p > 0.05). CONCLUSION: There is a high prevalence of vitamin D insufficiency and deficiency in CP patients. Nevertheless, there is no significant difference in prevalence of vitamin D insufficiency and deficiency compared to healthy controls. Further research should indicate the clinical relevance and consequences of these findings for clinical practice. PMID- 27453462 TI - Is Closed-Loop, Time-Locked Primary Motor Cortex Stimulation an Ideal Target for Improving Movements in Neurological Disorders? PMID- 27453463 TI - A novel gene OsAHL1 improves both drought avoidance and drought tolerance in rice. AB - A novel gene, OsAHL1, containing an AT-hook motif and a PPC domain was identified through genome-wide profiling and analysis of mRNAs by comparing the microarray of drought-challenged versus normally watered rice. The results indicated OsAHL1 has both drought avoidance and drought tolerance that could greatly improve drought resistance of the rice plant. Overexpression of OsAHL1 enhanced multiple stress tolerances in rice plants during both seedling and panicle development stages. Functional studies revealed that OsAHL1 regulates root development under drought condition to enhance drought avoidance, participates in oxidative stress response and also regulates the content of chlorophyll in rice leaves. OsAHL1 specifically binds to the A/T rich sequence region of promoters or introns, and hence directly regulates the expression of many stress related downstream genes. PMID- 27453464 TI - "Local recurrence" is not equal to "Local dissemination" after resection for hepatocellular carcinoma. PMID- 27453465 TI - Dissociable relations between amygdala subregional networks and psychopathy trait dimensions in conduct-disordered juvenile offenders. AB - Psychopathy is a serious psychiatric phenomenon characterized by a pathological constellation of affective (e.g., callous, unemotional), interpersonal (e.g., manipulative, egocentric), and behavioral (e.g., impulsive, irresponsible) personality traits. Though amygdala subregional defects are suggested in psychopathy, the functionality and connectivity of different amygdala subnuclei is typically disregarded in neurocircuit-level analyses of psychopathic personality. Hence, little is known of how amygdala subregional networks may contribute to psychopathy and its underlying trait assemblies in severely antisocial people. We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral (BLA) and centromedial (CMA) amygdala networks in relation to affective, interpersonal, and behavioral traits of psychopathy, in conduct-disordered juveniles with a history of serious delinquency (N = 50, mean age = 16.83 +/- 1.32). As predicted, amygdalar connectivity profiles exhibited dissociable relations with different traits of psychopathy. Interpersonal psychopathic traits not only related to increased connectivity of BLA and CMA with a corticostriatal network formation accommodating reward processing, but also predicted stronger CMA connectivity with a network of cortical midline structures supporting sociocognitive processes. In contrast, affective psychopathic traits related to diminished CMA connectivity with a frontolimbic network serving salience processing and affective responding. Finally, behavioral psychopathic traits related to heightened BLA connectivity with a frontoparietal cluster implicated in regulatory executive functioning. We suggest that these trait-specific shifts in amygdalar connectivity could be particularly relevant to the psychopathic phenotype, as they may fuel a self-centered, emotionally cold, and behaviorally disinhibited profile. Hum Brain Mapp 37:4017-4033, 2016. (c) 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID- 27453466 TI - Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes. AB - Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross-reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans. PMID- 27453468 TI - Complementary Contributions of Striatal Projection Pathways to Action Initiation and Execution. AB - The performance of an action relies on the initiation and execution of appropriate movement sequences. Two basal ganglia pathways have been classically hypothesized to regulate this process via opposing roles in movement facilitation and suppression. By using a series of state-dependent optogenetic manipulations, we dissected the contributions of each pathway and found that both the direct striatonigral pathway and the indirect striatopallidal pathway are necessary for smooth initiation and the execution of learned action sequences. Optogenetic inhibition or stimulation of each pathway before sequence initiation increased the latency for initiation: manipulations of the striatonigral pathway activity slowed action initiation, and those of the striatopallidal pathway aborted action initiation. The inhibition of each pathway after initiation also impaired ongoing execution. Furthermore, the subtle activation of striatonigral neurons sustained the performance of learned sequences, while striatopallidal manipulations aborted ongoing performance. These results suggest a supportive versus permissive model, where patterns of coordinated activity, rather than the relative amount of activity in these pathways, regulate movement initiation and execution. PMID- 27453467 TI - Multiple Origins of Virus Persistence during Natural Control of HIV Infection. AB - Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity. PMID- 27453469 TI - Human SRMAtlas: A Resource of Targeted Assays to Quantify the Complete Human Proteome. AB - The ability to reliably and reproducibly measure any protein of the human proteome in any tissue or cell type would be transformative for understanding systems-level properties as well as specific pathways in physiology and disease. Here, we describe the generation and verification of a compendium of highly specific assays that enable quantification of 99.7% of the 20,277 annotated human proteins by the widely accessible, sensitive, and robust targeted mass spectrometric method selected reaction monitoring, SRM. This human SRMAtlas provides definitive coordinates that conclusively identify the respective peptide in biological samples. We report data on 166,174 proteotypic peptides providing multiple, independent assays to quantify any human protein and numerous spliced variants, non-synonymous mutations, and post-translational modifications. The data are freely accessible as a resource at http://www.srmatlas.org/, and we demonstrate its utility by examining the network response to inhibition of cholesterol synthesis in liver cells and to docetaxel in prostate cancer lines. PMID- 27453470 TI - Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses. AB - Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and-in half the subjects-multidonor class sequences were recovered from >40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies. PMID- 27453471 TI - Perinatal Licensing of Thermogenesis by IL-33 and ST2. AB - For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the "alarmin" IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration. We find that, in absence of IL-33 or ST2, beige and brown adipocytes develop normally but fail to express an appropriately spliced form of Ucp1 mRNA, resulting in absence of UCP1 protein and impairment in uncoupled respiration and thermoregulation. Together, these data suggest that IL-33 and ST2 function as a developmental switch to license thermogenesis during the perinatal period. PAPERCLIP. PMID- 27453472 TI - Dithiol Aryl Arsenic Compounds as Potential Diagnostic and Therapeutic Radiopharmaceuticals. AB - Arsenic-72 ((72)As) and (77)As have nuclear properties useful for positron emission tomography (PET) and radiotherapy, respectively. The thiophilic nature of arsenic led to the evaluation of dithioarylarsines for potential use in radiopharmaceuticals. Several dithioarylarsines were synthesized from their arylarsonic acids and dithiols and were fully characterized by NMR, ESI-MS, and X ray crystallography. This chemistry was translated to the no-carrier-added (nca) (77)As level. Because arsenic was available at the nca nanomolar level only as [(77)As]arsenate, this required addition of an aryl group directly to the As to form the [(77)As]arylarsonic acid. The [(77)As]arsenate was reduced from (77)As (V) to (77)As (III), and a modified Bart reaction was used to incorporate the aryl ring onto the (77)As, which was followed by dithiol addition. Various modifications and optimizations resulted in 95% radiochemical yield of nca [(77)As]p-ethoxyphenyl-1,2-ethanedithiolatoarsine. PMID- 27453473 TI - Herbinix luporum sp. nov., a thermophilic cellulose-degrading bacterium isolated from a thermophilic biogas reactor. AB - Phylogenetic studies were performed on a group of novel Gram-stain-positive, anaerobic, non-sporulating rod-shaped bacteria isolated from a thermophilic biogas plant. The novel organisms were able to degrade crystalline cellulose. 16S rRNA gene sequence comparison indicated that the isolates SD1DT, SD1G, SD1I and RK1P share 100 % sequence identity, and are most closely related to Herbinix hemicellulosilytica T3/55T with which they share a 16S rRNA gene sequence similarity of 96.4 %. As a representative of the whole group of isolates, strain SD1DT was further characterized. Strain SD1DT was catalase-negative, indole negative, and produced acetate, ethanol, butyric acid and hydrogen as major end products during fermentative cellobiose utilization. Cells are rod-shaped, growing optimally at 40-65 degrees C and pH 6.5-8.5. The major cellular fatty acids (>10 %) were C19 : 0cyc 9,10 dimethyl acetal, C16 : 0 and C14 : 0. The DNA G+C content was 35.1 mol%. Due to the genetic and phenotypic differences to the most closely affiliated species, the isolates represent a novel species of the genus Herbinix within the family Lachnospiraceae, for which the name Herbinix luporum sp. nov. is proposed. The type strain is SD1DT(=DSM 100831T=CECT 8959T). PMID- 27453474 TI - Non-aneurysmal subarachnoid hemorrhage in two patients with systemic lupus erythematosus: Case reports and literature review. AB - We describe two cases of non-aneurysmal subarachnoid hemorrhage (SAH) and multifocal stenosis of the intracranial arteries. The patients' histories together with magnetic resonance angiography, vessel wall imaging and transcranial Doppler (TCD) indicated that the SAH was due to vasculitis or reversible cerebral vasoconstriction syndrome (RCVS). Differential diagnosis of vasculitis and RCVS is important because the treatment strategies are different: immunosuppressants in vasculitis and calcium channel blockers in RCVS. Vessel wall magnetic resonance imaging and TCD can be helpful in differentiating them. PMID- 27453475 TI - Retrospective analysis of factors influencing oncologic outcome in 590 patients with early-intermediate glottic cancer treated by transoral laser microsurgery. AB - BACKGROUND: The purpose of this study was to identify the factors influencing oncologic outcomes for patients with early-intermediate glottic cancer treated by transoral laser microsurgery (TLM). METHODS: This was a retrospective mono institutional study. A total of 590 patients with cTis-cT3 glottic cancer underwent TLM with curative intent. RESULTS: TLM alone was performed in 538 patients (91.2%) and TLM followed by adjuvant radiotherapy (RT) was done in 52 (8.8%). Five-year recurrence-free survival (RFS) and 10-year overall survival (OS) were 85.3% and 74.7%, respectively. The larynx-preservation ratio was 95.9%. In particular, from our data, we found that occult metastases were rare (1.2%); preventive tracheotomy was not necessary; the local recurrence rate of Tis was similar to that in the T2 and T3 group; and no major or lethal complications were observed. CONCLUSION: Age (>60 vs <=60), type of cordectomy (>=IV vs <=III), status of margins, fixed arytenoid, and pathologic T classification, were the variables associated with RFS, OS, and organ-preservation rate. (c) 2016 Wiley Periodicals, Head Neck 39: 71-81, 2017. PMID- 27453476 TI - In situ eNOS/NO up-regulation-a simple and effective therapeutic strategy for diabetic skin ulcer. AB - Decreased nitric oxide (NO) synthesis and increased NO consumption in diabetes induces the inadequate blood flow to tissues that is primarily responsible for the pathogenesis and refractoriness of diabetic skin ulcers. The present study proposed a simple and effective therapeutic strategy for diabetic skin ulcers-in situ up-regulation of endothelial nitric oxide synthase (eNOS) expression and NO synthesis by statin-loaded tissue engineering scaffold (TES). In vitro experiments on human umbilical vein endothelial cells indicated that the statin loaded TES relieved the high-glucose induced decrease in cell viability and promoted NO synthesis under high-glucose conditions. In a rat model of diabetes, the statin-loaded TES promoted eNOS expression and NO synthesis in/around the regenerated tissues. Subsequently, accelerated vascularization and elevated blood supply were observed, followed by rapid wound healing. These findings suggest that the in situ up-regulation of eNOS/NO by a statin-loaded TES may be a useful therapeutic method for intractable diabetic skin wounds. PMID- 27453477 TI - Characterization of the gamma-aminobutyric acid signaling system in the zebrafish (Danio rerio Hamilton) central nervous system by reverse transcription quantitative polymerase chain reaction. AB - In the vertebrate brain, inhibition is largely mediated by gamma-aminobutyric acid (GABA). This neurotransmitter comprises a signaling machinery of GABAA, GABAB receptors, transporters, glutamate decarboxylases (gads) and 4 aminobutyrate aminotransferase (abat), and associated proteins. Chloride is intimately related to GABAA receptor conductance, GABA uptake, and GADs activity. The response of target neurons to GABA stimuli is shaped by chloride-cation co transporters (CCCs), which strictly control Cl- gradient across plasma membranes. This research profiled the expression of forty genes involved in GABA signaling in the zebrafish (Danio rerio) brain, grouped brain regions and retinas. Primer pairs were developed for reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The mRNA levels of the zebrafish GABA system share similarities with that of mammals, and confirm previous studies in non-mammalian species. Proposed GABAA receptors are alpha1beta2gamma2, alpha1beta2delta, alpha2bbeta3gamma2, alpha2bbeta3delta, alpha4beta2gamma2, alpha4beta2delta, alpha6bbeta2gamma2 and alpha6bbeta2delta. Regional brain differences were documented. Retinal hetero- or homomeric rho-composed GABAA receptors could exist, accompanying alpha1betaygamma2, alpha1betaydelta, alpha6abetaygamma2, alpha6abetaydelta. Expression patterns of alpha6a and alpha6b were opposite, with the former being more abundant in retinas, the latter in brains. Given the stoichiometry alpha6wbetaygammaz, alpha6a- or alpha6b-containing receptors likely have different regulatory mechanisms. Different gene isoforms could originate after the rounds of genome duplication during teleost evolution. This research depicts that one isoform is generally more abundantly expressed than the other. Such observations also apply to GABAB receptors, GABA transporters, GABA-related enzymes, CCCs and GABAA receptor-associated proteins, whose presence further strengthens the proof of a GABA system in zebrafish. PMID- 27453478 TI - Targeting mTOR signaling by polyphenols: A new therapeutic target for ageing. AB - Current ageing research is aimed not only at the promotion of longevity, but also at improving health span through the discovery and development of new therapeutic strategies? by investigating molecular and cellular pathways involved in cellular senescence. Understanding the mechanism of action of polyphenolic compounds targeting mTOR (mechanistic target of rapamycin) and related pathways opens up new directions to revolutionize ways to slow down the onset and development of age-dependent degeneration. Herein, we will discuss the mechanisms by which polyphenols can delay the molecular pathogenesis of ageing via manipulation or more specifically inhibition of mTOR-signaling pathways. We will also discuss the implications of polyphenols in targeting mTOR and its related pathways on health life span extension and longevity.. PMID- 27453479 TI - Accumulated alpha-synuclein affects the progression of GM2 gangliosidoses. AB - The accumulation of alpha-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional beta-subunit on the beta hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice. Our results show that Hexb-/- ASyn-/- mice demonstrated active microglia levels and less dopaminergic neuron loss, without altering the neuronal storage of ganglioside. The autophagy and ubiquitin proteasome pathways are defective in the neurons of Hexb-/- ASyn+/+ mice. In ultrastructural physiological studies, the mitochondria structures look degenerated and dysfunctional. As a result, expression of manganese superoxide dismutase 2 are reduced, and reactive oxygen species-mediated oxidative damage in the neurons of Hexb-/- ASyn+/+ mice. Interestingly, these dysfunctions improved in Hexb-/- ASyn-/- mice. But any clinical improvement were hardly observed in Hexb-/- ASyn-/- mice. Taken together, these findings suggest that ASyn accumulation plays an important role in the pathogenesis of neuropathy in SD and other LSDs, and is therefore a target for novel therapies. PMID- 27453482 TI - Getting excited: challenges in quantum-classical studies of excitons in polymeric systems. AB - A combination of classical molecular dynamics (MM/MD) and quantum chemical calculations based on the density functional theory (DFT) was performed to describe the conformational properties of diphenylethyne (DPE), methylated-DPE and poly para phenylene ethynylene (PPE). DFT calculations were employed to improve and develop force field parameters for MM/MD simulations. Many-body Green's function theory within the GW approximation and the Bethe-Salpeter (GW BSE) equation were utilized to describe the excited states of the systems. The reliability of the excitation energies based on the MM/MD conformations was examined and compared to the excitation energies from DFT conformations. The results show an overall agreement between the optical excitations based on MM/MD conformations and DFT conformations. This allows for the calculation of excitation energies based on MM/MD conformations. PMID- 27453481 TI - Carp edema virus in Polish aquaculture - evidence of significant sequence divergence and a new lineage in common carp Cyprinus carpio (L.). AB - Fish samples initially collected by local veterinarians on the common and koi carp farms in Poland between 2013 and 2015 as part of a KHV surveillance programme, when the water temperature was between 16 and 26 degrees C, and were also tested for CEV by qPCR. A partial 478 nucleotide fragment of the 4a gene was subsequently generated from 17 qPCR-positive common carp Cyprinus carpio samples from 36 farm sites tested during the period. Sequence alignments and analysis revealed the presence of CEV in Poland both in common carp as well as in koi carp farms, and phylogenetic analysis assigned the Polish CEV sequences into three distinct genogroups. A lineage which includes the original sequences obtained from koi carp in Japan (genogroup II) included sequences from both koi carp and common carp, and the second lineage (genogroup I) contained sequences from common carp only. A third lineage (genogroup III) which was more closely related to the genogroup II also consisted of sequences from common carp only. The latter represents a lineage of CEV not previously described in the literature. PMID- 27453480 TI - Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity. AB - Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid alpha-glucosidase (GAA). Children with infantile-onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory neural dysfunction in infantile-onset Pompe. Subjects (aged 2-15years, full-time MV: n=5, partial/no MV: n=4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1 CMV-GAA to the diaphragm with continued exercise. Since AAV-mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1-CMV-GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1-CMV-GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p<0.05 to p<0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p<0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains. PMID- 27453483 TI - IFN-gamma Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection. AB - Salmonella Typhimurium (S.Tm) causes acute enteropathy resolving after 4-7 days. Strikingly, antibiotic therapy does not accelerate disease resolution. We screened for factors blocking remission using a S.Tm enterocolitis model. The antibiotic ciprofloxacin clears pathogen stool loads within 3-24 hr, while gut pathology resolves more slowly (psi50: ~48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-gamma (IFN-gamma)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-gamma production by mucosal T and NK cells retards disease resolution by maintaining signaling through the transcriptional regulator STAT1 and boosting expression of inflammatory mediators like IL-1beta, TNF, and iNOS. Additionally, sustained IFN-gamma fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIIIbeta. These findings reveal a role for IFN-gamma in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment. PMID- 27453485 TI - Oral antidiabetic drug use and associated health outcomes in cancer patients. AB - WHAT IS NEW AND OBJECTIVE: To assess oral antidiabetic drug use and associated health outcomes in American non-elderly adults with cancer METHODS: A retrospective study was conducted by analysing the Marketscan((r)) Commercial Claims and Encounters Database from 2008 to 2009. Individuals 18-64 years with concomitant diagnoses of cancer (breast, prostate, colon or lung) and type 2 diabetes, and treated with oral antidiabetic medications were included. Medication adherence was assessed using the Medication Possession Ratio (MPR); logistic regression was used to analyse factors associated with non-adherence. Adherence was compared between patients with cancer and non-cancer controls matched by propensity scores. Negative binomial regression was utilized to examine the effect of antidiabetic drug adherence on all-cause hospitalizations and emergency room visits. The impact of adherence on total medical costs was then evaluated using the generalized linear model (GLM) with the log-link function and gamma error distribution. RESULTS AND DISCUSSION: Of 1918 diabetic, cancer patients who newly initiated oral diabetic drugs, only 37.6% were adherent to oral diabetic medications; a similar proportion of adherence was found in the non-cancer control population (35.8%, P = 0.24). Younger age, living in the southern region, using combination therapy vs. monotherapy, and using retail pharmacy vs. mail order pharmacy were significantly associated with non-adherence in patients with cancer. Adherence to oral antidiabetic drugs was associated with 24% fewer all-cause hospitalizations (P = 0.02). WHAT IS NEW AND CONCLUSION: We identified high prevalence of non-adherence to oral antidiabetic medications as well as negative consequences associated with non-adherence, among patients with cancer. These findings may underscore the importance of developing relevant intervention strategies for improving diabetes management and treatment outcomes among cancer patients with diabetes. PMID- 27453484 TI - CRISPR/Cas9 Screens Reveal Requirements for Host Cell Sulfation and Fucosylation in Bacterial Type III Secretion System-Mediated Cytotoxicity. AB - Type III secretion systems (T3SSs) inject bacterial effector proteins into host cells and underlie the virulence of many gram-negative pathogens. Studies have illuminated bacterial factors required for T3SS function, but the required host processes remain largely undefined. We coupled CRISPR/Cas9 genome editing technology with the cytotoxicity of two Vibrio parahaemolyticus T3SSs (T3SS1 and T3SS2) to identify human genome disruptions conferring resistance to T3SS dependent cytotoxicity. We identity non-overlapping genes required for T3SS1- and T3SS2-mediated cytotoxicity. Genetic ablation of cell surface sulfation reduces bacterial adhesion and thereby alters the kinetics of T3SS1-mediated cytotoxicity. Cell surface fucosylation is required for T3SS2-dependent killing, and genetic inhibition of fucosylation prevents membrane insertion of the T3SS2 translocon complex. These findings reveal the importance of ubiquitous surface modifications for T3SS function, potentially explaining the broad tropism of V. parahaemolyticus, and highlight the utility of genome-wide CRISPR/Cas9 screens to discover processes underlying host-pathogen interactions. PMID- 27453486 TI - Exogenous paraoxonase-1 during oocyte maturation improves bovine embryo development in vitro. AB - Paraoxonase-1 (PON1) is an enzyme found in serum and follicular fluid that protects cell membrane and circulating lipids against oxidative damage. The aims of this study were to measure the direct effects of recombinant PON1 (rPON1) on bovine oocyte maturation at the molecular level (gene expression) and to measure the carry-over effects of PON1 on pre-implantation embryo development in vitro. COCs were submitted to IVM with the addition of 0.0, 0.02, 0.04 and 0.08 mg ml( 1) of rPON1, corresponding to an average PON1 arylesterase enzyme activity of 2.2 +/- 0.4, 15.5 +/- 1.5, 30.2 +/- 3.0 and 57.9 +/- 5.0 U ml(-1) , respectively. The results indicated that addition of rPON1 during IVM improved embryo development in a dose-dependent manner as D7 embryo development was 22.2%, 29.4%, 32.2% and 37.0% for the treatment groups, respectively (p = 0.02). In conclusion, addition of PON1 enzyme during IVM exerted dose-related positive effects on embryo development rates to blastocysts. PMID- 27453487 TI - Detrimental Effects of Zinc Oxide Nanoparticles on Amphibian Life Stages. AB - While the use of nanoparticles has dramatically increased in recent years, the ecological consequences are not well known. In particular, little research has been done to investigate the potentially detrimental effects of nanoparticles on amphibians, especially across all life-history stages of salamanders and newts (caudates). To address this dearth in knowledge, we examined the effects of zinc oxide (ZnO) nanoparticles on egg, larval, and adult Rough-skinned Newts (Taricha granulosa). Chronic toxicity was tested on eggs and larvae, and acute toxicity was tested on eggs, larvae, and adults. For eggs, chronic exposure to ZnO nanoparticles caused higher mortality at 10.0 and 100.0 mg L(-1) compared to 0.0, 0.1, and 1.0 mg L(-1) . When given an acute exposure (24 hr) to 10.0 mg L(-1) nanoparticles at a late developmental stage, larvae hatched 5 days early, at a decreased developmental stage, and smaller size compared to the control. Chronic and acute exposure of larvae increased mortality up to 75% at both 10.0 and 100.0 mg L(-1) and exhibited sublethal effects, most dramatically, severe gill degradation. These results suggest nanoparticles can have lethal and sublethal effects on all life stages of amphibians. PMID- 27453489 TI - The electronic structure of Au25 clusters: between discrete and continuous. AB - Here, an approach based on synchrotron resonant photoemission is employed to explore the transition between quantization and hybridization of the electronic structure in atomically precise ligand-stabilized nanoparticles. While the presence of ligands maintains quantization in Au25 clusters, their removal renders increased hybridization of the electronic states in the vicinity of the Fermi level. These observations are supported by DFT studies. PMID- 27453488 TI - Aldehyde dehydrogenase 2 is associated with cognitive functions in patients with Parkinson's disease. AB - Neurotransmitter degradation has been proposed to cause the accumulation of neurotoxic metabolites. The metabolism of these metabolites involves aldehyde dehydrogenase 2 (ALDH2). The Asian-specific single nucleotide polymorphism rs671 causes reduced enzyme activity. This study aims to explore whether Parkinson's disease (PD) patients with reduced ALDH2 activity owing to the rs671 polymorphism are at risk for neuropsychological impairments. A total of 139 PD patients were recruited. Each participant was assessed for medical characteristics and their ALDH2 genotype. The Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Scale and the Frontal Behavioral Inventory were used to measure neuropsychological functions. We found that the MMSE scores were significantly lower in patients with inactive ALDH2 (U = 1873.5, p = 0.02). The presence of cognitive impairments was significantly more frequent in the inactive ALDH2 group (46.0%) than in the active ALDH2 group (26.3%) (chi(2) = 5.886, p = 0.01). The inactive group showed significant deterioration in hobbies and exhibited more severe "disorganization" and "hyper-sexuality" behaviours. The additive effects of the allele on the development of cognitive impairments in PD patients may be an important finding that provides further insight into the pathogenic mechanism of cognitive dysfunction in PD. PMID- 27453490 TI - Association between Nurse Staffing and In-Hospital Bone Fractures: A Retrospective Cohort Study. AB - OBJECTIVE: To determine if sufficient nurse staffing reduced in-hospital fractures in acute care hospitals. DATA SOURCES/STUDY SETTING: The Japanese Diagnosis Procedure Combination inpatient (DPC) database from July 2010 to March 2014 linked with the Surveys for Medical Institutions. STUDY DESIGN: We conducted a retrospective cohort study to examine the association of inpatient nurse-to occupied bed ratio (NBR) with in-hospital fractures. Multivariable logistic regression with generalized estimating equations was performed, adjusting for patient characteristics and hospital characteristics. DATA COLLECTION/EXTRACTION METHODS: We identified 770,373 patients aged 50 years or older who underwent planned major surgery for some forms of cancer or cardiovascular diseases. We used ICD-10 codes and postoperative procedure codes to identify patients with in hospital fractures. Hospital characteristics were obtained from the "Survey of Medical Institutions and Hospital Report" and "Annual Report for Functions of Medical Institutions." PRINCIPAL FINDINGS: Overall, 662 (0.09 percent) in hospital fractures were identified. Logistic regression analysis showed that the proportion of in-hospital fractures in the group with the highest NBR was significantly lower than that in the group with the lowest NBR (adjusted odd ratios, 0.67; 95 percent confidence interval, 0.44-0.99; p = .048). CONCLUSIONS: Sufficient nurse staffing may be important to reduce postsurgical in-hospital fractures in acute care hospitals. PMID- 27453491 TI - [Empathy-related factors in Nursing students of the Cartagena University]. AB - OBJECTIVE: To determine empathy levels and its relationship with sociodemographic, academic and family factors in nursing students. METHOD: Cross sectional study, 196 nursing students were randomly selected at the University of Cartagena, Colombia. A questionnaire that asked about sociodemographic, family and academic factors and the Scale of Physician Empathy Jefferson-version S were applied. Shapiro-Wilk test was used to assess the normality assumption. t Student, ANOVA, Pearson test and simple linear regression were used to establish the relationship (p<0.05). RESULTS: The global empathy score was 108.6+/-14.6; statistically significant associations between global empathy with the training year (p=0.004) and grade point average (R(2)=0.058; p=0.001; r=0.240) were found. Moreover, the "perspective taking" dimension with provenance (rural/urban) (p=0.010) and family functioning (p=0.003); the "compassionate care" dimension with the training year (p=0.002) and the "putting themselves in the place of the patient" dimension with academic performance (p=0.034). CONCLUSION: The empathy levels in nursing students may vary depending on various personal and academic factors,these characteristics should be taken into account for implementing teaching strategies to promote higher empathy levels since the early training years. PMID- 27453492 TI - Commentary on: The Impact of the Minimum Legal Drinking Age on Alcohol-Related Chronic Disease Mortality. PMID- 27453493 TI - Effect of polyunsaturated fatty acids (PUFAs) on airway epithelial cells' tight junction. PMID- 27453494 TI - Molecularly targeted therapies for asthma: Current development, challenges and potential clinical translation. AB - Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs. New drug candidates with their putative targets that have shown promising results in the preclinical and/or clinical trials are summarised. Examples of these interventions include restoration of Th1/Th2 balance by the use of newly developed immunomodulators such as toll-like receptor-9 activators (CYT003-QbG10 and QAX-935). Clinical trials revealed the safety and effectiveness of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) antagonists such as OC0000459, BI-671800 and ARRY-502 in the restoration of Th1/Th2 balance. Regulation of cytokine activity by the use of newly developed biologics such as benralizumab, reslizumab, mepolizumab, lebrikizumab, tralokinumab, dupilumab and brodalumab are at the stage of clinical development. Transcription factors are potential targets for asthma therapy, for example SB010, a GATA-3 DNAzyme is at its early stage of clinical trial. Other candidates such as inhibitors of Rho kinases (Fasudil and Y 27632), phosphodiesterase inhibitors (GSK256066, CHF 6001, roflumilast, RPL 554) and proteinase of activated receptor-2 (ENMD-1068) are also discussed. Preclinical results of blockade of calcium sensing receptor by the use of calcilytics such as calcitriol abrogates cardinal signs of asthma. Nevertheless, successful translation of promising preclinical data into clinically viable interventions remains a major challenge to the development of novel anti asthmatics. PMID- 27453495 TI - When to invest in clinical guidelines for children? A practice oriented tool to facilitate decision-making. AB - RATIONALE, AIMS AND OBJECTIVES: Children are not just small adults; they need to be diagnosed and treated in the context of their rapid growth and development. However, in guideline development, children's needs and interests are still overlooked. This study aims (1) to develop a tool that could stimulate guideline developers to take children into account on a more structural basis and (2) to explore how to facilitate children's participation in the process of guideline development. METHODS: The method used was a three-phase multimethod sequential design. Professionals involved in guideline development participated in interviews (n = 12), filled in a questionnaire (n = 60) and/or participated in the focus group meeting (n = 11). RESULTS: This study results in a comprehensive understanding of the considerations that professionals take into account when deciding whether guidelines need to apply to children specifically. This resulted in a tool that assists guideline developers to make this assessment more accurately. It takes the form of a flowchart that guides users through a series of critical questions. CONCLUSIONS: The flowchart reminds guideline developers to consider children as a particular patient population when prioritizing and demarcating new guideline topics. It will help to ensure that clinical guidelines address children's unique health care needs and perspectives. Facilitating children's and parents' participation in the process of guideline development is perceived as challenging; nevertheless, it should be the next step in making paediatric guidelines more child-centred and family-centred. PMID- 27453496 TI - Truly trapped rainbow by utilizing nonreciprocal waveguides. AB - The concept of a "trapped rainbow" has generated considerable interest for optical data storage and processing. It aims to trap different frequency components of the wave packet at different positions permanently. However, all the previously proposed structures cannot truly achieve this effect, due to the difficulties in suppressing the reflection caused by strong intermodal coupling and distinguishing different frequency components simultaneously. In this article, we found a physical mechanism to achieve a truly "trapped rainbow" storage of electromagnetic wave. We utilize nonreciprocal waveguides under a tapered magnetic field to achieve this and such a trapping effect is stable even under fabrication disorders. We also observe hot spots and relatively long duration time of the trapped wave around critical positions through frequency domain and time domain simulations. The physical mechanism we found has a variety of potential applications ranging from wave harvesting and storage to nonlinearity enhancement. PMID- 27453497 TI - A consortium of non-rhizobial endophytic microbes from Typha angustifolia functions as probiotic in rice and improves nitrogen metabolism. AB - Endophytic microbes isolated from plants growing in nutrient-deficient environments often possess properties that improve nutrition of agriculturally important plants. A consortium of non-rhizobial endophytic microbes isolated from a macrophyte Typha angustifolia growing in the marginal wetlands associated with a Uranium mine was characterized for their beneficial effect on rice and the mechanisms of growth promotion were investigated. The microbes were identified and characterized for their potential plant growth promoting (PGP) properties. Effect of these microbes on nitrogen (N)-metabolism of rice was tested as Typha endophytes were predominantly (N)-fixing. Relative N-use efficiency and expression of genes involved in N-uptake and assimilation were investigated in treated plants. Evidence of horizontal gene transfer (HGT) of dinitrogen reductase gene was observed within the consortium from a Pseudomonas stutzeri strain. The consortium behaved as plant probiotic and showed substantial growth benefits to Typha, their natural host as well as to rice. Typha endophytes colonized rice endosphere significantly increasing biomass, shoot length and chlorophyll content in rice plants both under N-sufficient and N-deficient conditions. N-uptake and assimilation genes were upregulated in plants treated with the endophytes even after three weeks post infection. Our results suggested, HGT of nitrogen-fixation trait to be highly prevalent among endophytes isolated from nutrient-poor habitats of the uranium mine. A long-term nitrogen deficiency response in the treated plants was elicited by the consortium improving N-uptake, assimilation and relative N-use efficiency of rice plants. This appeared to be at least one of the main strategies of plant growth promotion. PMID- 27453498 TI - Process performance and bacterial community dynamics of partial-nitritation biofilters subjected to different concentrations of cysteine amino acid. AB - Partial-nitritation processes are used for the biological treatment of high nitrogen-low organic carbon effluents, such as anaerobic digestion reject water. The release of certain products generated during the anaerobic digestion process, such as amino acids, could potentially reduce the performance of these partial nitritation bioprocesses. To investigate this, four partial-nitritation biofilters were subjected to continuous addition of 0, 150, 300, and 500 mg L-1 cysteine amino acid in their influents. The addition of the amino acid had an impact over the performance of the partial-nitritation process and the bacterial community dynamics of the systems analyzed. Ammonium oxidation efficiency decreased with the addition of the amino acid, and a net nitrogen elimination occurred in presence of cysteine through the operation period. Bacterial community dynamics showed a decrease of Nitrosomonas species and a proliferation of putative heterotrophs with nitrification capacity, such as Pseudomonas, or denitrification capacity, such as Denitrobacter or Alicycliphilus. The addition of cysteine irreversible affected the bioreactors, which could not achieve the performance obtained before the addition of the amino acid. A mathematical predictive equation of the process performance depending on cysteine concentration added and operational time under such concentration was developed. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1254 1263, 2016. PMID- 27453499 TI - Amphiphilic brush polymers produced using the RAFT polymerisation method stabilise and reduce the cell cytotoxicity of lipid lyotropic liquid crystalline nanoparticles. AB - Self-assembled lipid lyotropic liquid crystalline nanoparticles such as hexosomes and cubosomes contain internal anisotropic and isotropic nanostructures, respectively. Despite the remarkable potential of such nanoparticles in various biomedical applications, the stabilisers used in formulating the nanoparticles are often limited to commercially available polymers such as the Pluronic block copolymers. This study explored the potential of using Reversible Addition Fragmentation chain Transfer (RAFT) technology to design amphiphilic brush-type polymers for the purpose of stabilising phytantriol and monoolein-based lipid dispersions. The synthesised brush-type polymers consisted of a hydrophobic C12 short chain and a hydrophilic poly(ethylene glycol)methyl ether acrylate (PEGA) long chain with multiple 9-unit poly(ethylene oxide) (PEO) brushes with various molecular weights. It was observed that increasing the PEO brush density and thus the length of the hydrophilic component improved the stabilisation effectiveness for phytantriol and monoolein-based cubosomes. Synchrotron small-angle X-ray scattering (SAXS) experiments confirmed that the RAFT polymer-stabilised cubosomes had an internal double-diamond cubic phase with tunable water channel sizes. These properties were dependent on the molecular weight of the polymers, which were considered in some cases to be anisotropically distributed within the cubosomes. The in vitro toxicity of the cubosomes was assessed by cell viability of two human adenocarcinoma cell lines and haemolytic activities to mouse erythrocytes. The results showed that phytantriol cubosomes stabilised by the RAFT polymers were less toxic compared to their Pluronic F127-stabilised analogues. This study provides valuable insight into designing non-linear amphiphilic polymers for the effective stabilisation and cellular toxicity improvement of self-assembled lipid lyotropic liquid crystalline nanoparticles. PMID- 27453500 TI - Pigment Cell Progenitors in Zebrafish Remain Multipotent through Metamorphosis. AB - The neural crest is a transient, multipotent embryonic cell population in vertebrates giving rise to diverse cell types in adults via intermediate progenitors. The in vivo cell-fate potential and lineage segregation of these postembryonic progenitors is poorly understood, and it is unknown if and when the progenitors become fate restricted. We investigate the fate restriction in the neural crest-derived stem cells and intermediate progenitors in zebrafish, which give rise to three distinct adult pigment cell types: melanophores, iridophores, and xanthophores. By inducing clones in sox10-expressing cells, we trace and quantitatively compare the pigment cell progenitors at four stages, from embryogenesis to metamorphosis. At all stages, a large fraction of the progenitors are multipotent. These multipotent progenitors have a high proliferation ability, which diminishes with fate restriction. We suggest that multipotency of the nerve-associated progenitors lasting into metamorphosis may have facilitated the evolution of adult-specific traits in vertebrates. PMID- 27453501 TI - Oct4 Is a Key Regulator of Vertebrate Trunk Length Diversity. AB - Vertebrates exhibit a remarkably broad variation in trunk and tail lengths. However, the evolutionary and developmental origins of this diversity remain largely unknown. Posterior Hox genes were proposed to be major players in trunk length diversification in vertebrates, but functional studies have so far failed to support this view. Here we identify the pluripotency factor Oct4 as a key regulator of trunk length in vertebrate embryos. Maintaining high Oct4 levels in axial progenitors throughout development was sufficient to extend trunk length in mouse embryos. Oct4 also shifted posterior Hox gene-expression boundaries in the extended trunks, thus providing a link between activation of these genes and the transition to tail development. Furthermore, we show that the exceptionally long trunks of snakes are likely to result from heterochronic changes in Oct4 activity during body axis extension, which may have derived from differential genomic rearrangements at the Oct4 locus during vertebrate evolution. PMID- 27453502 TI - PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/beta1-Integrin Signaling. AB - Alterations in dendritic spine numbers are linked to deficits in learning and memory. While we previously revealed that postsynaptic plasticity-related gene 1 (PRG-1) controls lysophosphatidic acid (LPA) signaling at glutamatergic synapses via presynaptic LPA receptors, we now show that PRG-1 also affects spine density and synaptic plasticity in a cell-autonomous fashion via protein phosphatase 2A (PP2A)/beta1-integrin activation. PRG-1 deficiency reduces spine numbers and beta1-integrin activation, alters long-term potentiation (LTP), and impairs spatial memory. The intracellular PRG-1 C terminus interacts in an LPA-dependent fashion with PP2A, thus modulating its phosphatase activity at the postsynaptic density. This results in recruitment of adhesome components src, paxillin, and talin to lipid rafts and ultimately in activation of beta1-integrins. Consistent with these findings, activation of PP2A with FTY720 rescues defects in spine density and LTP of PRG-1-deficient animals. These results disclose a mechanism by which bioactive lipid signaling via PRG-1 could affect synaptic plasticity and memory formation. PMID- 27453503 TI - Torsins Are Essential Regulators of Cellular Lipid Metabolism. AB - Torsins are developmentally essential AAA+ proteins, and mutation of human torsinA causes the neurological disease DYT1 dystonia. They localize in the ER membranes, but their cellular function remains unclear. We now show that dTorsin is required in Drosophila adipose tissue, where it suppresses triglyceride levels, promotes cell growth, and elevates membrane lipid content. We also see that human torsinA at the inner nuclear membrane is associated with membrane expansion and elevated cellular lipid content. Furthermore, the key lipid metabolizing enzyme, lipin, is mislocalized in dTorsin-KO cells, and dTorsin increases levels of the lipin substrate, phosphatidate, and reduces the product, diacylglycerol. Finally, genetic suppression of dLipin rescues dTorsin-KO defects, including adipose cell size, animal growth, and survival. These findings identify that torsins are essential regulators of cellular lipid metabolism and implicate disturbed lipid biology in childhood-onset DYT1 dystonia. PMID- 27453506 TI - Drainage dynamics of thin liquid foam films containing soft PNiPAM microgels: influence of the cross-linking density and concentration. AB - We investigate the drainage dynamics of thin liquid foam films containing PNiPAM microgel suspensions with two cross-linking densities (1.5 and 5 mol% BIS) and at two microgel concentrations (0.1 and 1% wt). For this purpose, we use a thin-film pressure balance apparatus that can apply a controlled and sudden hydrostatic pressure on a film, and record the subsequent film thinning as a function of time. Once the film thickness has reached a stationary value, we test the adhesion between the interfaces of the film by reducing the pressure and measuring the angle between the film and the meniscus. This angle increases on reduction of pressure for adhesive films, which resists the separation of their interfaces. Non-adhesive films separate easily, and the meniscus angle stays constant. At a low microgel concentration, the more densely cross-linked microgels (5 mol% BIS) tend to drain into more adhesive films than the more loosely cross-linked particles (1.5 mol% BIS). The adhesion results from particles that bridge the two air-water interfaces of the film and are shared between them. In these cases, the film, which is initially stabilized by a bilayer of microgel particles, rearrange to a state where the microgels bridge the interfaces. These results are discussed and compared with previous studies at a low concentration of microgels, which have shown that emulsions stabilized with densely cross-linked microgels are more adhesive and less resistant to mechanical stresses than those obtained with lower cross-linking densities. In addition, micron-scale depleted zones with no microgels are observed in the films stabilized with the 5 mol% BIS particles, which eventually lead to the rupture of the films. At 1% wt, the films drain slowly, are not adhesive and have the thickness of a bilayer of microgel; while at 0.1% wt, the films have the thickness of a monolayer of microgel, are adhesive and show bridging. From the thin liquid foam film thicknesses we extract a rough estimation of the radii of adsorbed particles in the thick films before applying the pressure. Our results are consistent with particles being adsorbed in a spread conformation for the 0.1% wt sample and in a compressed conformation for the 1% wt sample. In line with previous studies on emulsions, we conclude that a larger surface coverage may reduce rearrangements, thus preventing bridging. PMID- 27453505 TI - Superoxide induces Neutrophil Extracellular Trap Formation in a TLR-4 and NOX dependent mechanism. AB - Neutrophils constitute the early innate immune response to perceived infectious and sterile threats. Neutrophil Extracellular Traps (NETs) are a novel mechanism to counter pathogenic invasion and sequelae of ischemia including cell death and oxidative stress. Superoxide is a radical intermediate of oxygen metabolism produced by parenchymal and non-parenchymal hepatic cells, and is a hallmark of oxidative stress after liver ischemia-reperfusion (I/R). While extracellular superoxide recruits neutrophils to the liver and initiates sterile inflammatory injury, it is unknown whether superoxide induces the formation of NETs. We hypothesize that superoxide induces NET formation through a signaling cascade involving Toll-like receptor 4 (TLR-4) and neutrophil NADPH Oxidase (NOX). We treated neutrophils with extracellular superoxide and observed NET DNA release, histone H3 citrullination, and increased levels of MPO-DNA complexes occurring in a TLR-4 dependent manner. Inhibition of superoxide generation by Allopurinol and inhibition of NOX by diphenyleneiodonium prevented NET formation. When mice were subjected to warm liver I/R, we found significant NET formation associated with liver necrosis and increased serum ALT in TLR-4 WT, but not TLR-4 KO mice. To reduce circulating superoxide we pretreated mice undergoing I/R with Allopurinol and N-acetylcysteine, which resulted in decreased NETs and ameliorated liver injury. Our study demonstrates a requirement for TLR-4 and NOX in superoxide induced NETs, and suggests involvement of superoxide-induced NETs in pathophysiologic settings. PMID- 27453504 TI - An exome array study of the plasma metabolome. AB - The study of rare variants may enhance our understanding of the genetic determinants of the metabolome. Here, we analyze the association between 217 plasma metabolites and exome variants on the Illumina HumanExome Beadchip in 2,076 participants in the Framingham Heart Study, with replication in 1,528 participants of the Atherosclerosis Risk in Communities Study. We identify an association between GMPS and xanthosine using single variant analysis and associations between HAL and histidine, PAH and phenylalanine, and UPB1 and ureidopropionate using gene-based tests (P<5 * 10(-8) in meta-analysis), highlighting novel coding variants that may underlie inborn errors of metabolism. Further, we show how an examination of variants across the spectrum of allele frequency highlights independent association signals at select loci and generates a more integrated view of metabolite heritability. These studies build on prior metabolomics genome wide association studies to provide a more complete picture of the genetic architecture of the plasma metabolome. PMID- 27453507 TI - Erratum: New native South American Y chromosome lineages. PMID- 27453508 TI - Alterations in conflict monitoring are related to functional connectivity in Parkinson's disease. AB - Patients with Parkinson's disease (PD) have difficulties in executive functions including conflict monitoring. The neural mechanisms underlying these difficulties are not yet fully understood. In order to examine the neural mechanisms related to conflict monitoring in PD, we evaluated 35 patients with PD and 20 healthy older adults while they performed a word-color Stroop paradigm in the MRI. Specifically, we focused on changes between the groups in task-related functional connectivity using psycho-physiological interaction (PPI) analysis. The anterior cingulate cortex (ACC), which is a brain node previously associated with the Stroop paradigm, was selected as the seed region for this analysis. Patients with PD, as compared to healthy controls, had reduced task-related functional connectivity between the ACC and parietal regions including the precuneus and inferior parietal lobe. This was seen only in the incongruent Stroop condition. A higher level of connectivity between the ACC and precuneus was correlated with a lower error rate in the conflicting, incongruent Stroop condition in the healthy controls, but not in the patients with PD. Furthermore, the patients also had reduced functional connectivity between the ACC and the superior frontal gyrus which was present in both the incongruent and congruent task condition. The present findings shed light on brain mechanisms that are apparently associated with specific cognitive difficulties in patients with PD. Among patients with PD, impaired conflict monitoring processing within the ACC based fronto-parietal network may contribute to difficulties under increased executive demands. PMID- 27453509 TI - Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trondelag Health Study). AB - Gender is an important determinant of cardiovascular risk, and men generally develop cardiovascular disease earlier than women. Increased levels of high sensitivity cardiac troponin I (hs-TnI) have been shown to be predictive of cardiovascular death, with stronger effects in women. However, it remains unclear whether the stronger association between hs-TnI and cardiovascular death in women is based on the ability of hs-TnI to predict myocardial infarction (MI) or heart failure (HF). Accordingly, we aimed to assess the influence of gender on the association between levels of hs-TnI and incident MI and HF. hs-TnI was measured in 5,060 women and 4,054 men participating in the prospective observational Nord Trondelag Health Study using the Architect STAT High-Sensitive Troponin assay. All subjects were free from known coronary heart disease at baseline. After a median follow-up of 5,105 and 6,169 days, 292 MIs and 209 admissions for HF were registered, respectively. In our total cohort, hs-TnI was associated with the incidence of both end points, with adjusted hazard ratio per 1 SD in log hs-TnI 1.19 (95% CI 1.02 to 1.39) for MI and 1.58 (1.38 to 1.82) for HF. The corresponding values for women and men were 1.35 (1.02 to 1.78) versus 1.13 (0.93 to 1.38) for MI and 1.55 (1.26 to 1.91) versus 1.61 (1.36 to 1.90) for HF. The C index for hs-TnI was stronger for women than men for MI (p <0.001), and no such difference was observed for HF (p = 0.06). In conclusion, in the general population, the association between hs-TnI concentrations and MI is stronger in women than in men. For HF, the impact of gender on the prognostic value of hs-TnI is less pronounced. Increased levels of troponin I in women may thus reflect an adverse phenotype more prone to the development of cardiovascular disease. PMID- 27453510 TI - Relation of Birth Weight to Heart Rate in Childhood, Adolescence, and Adulthood (from the Bogalusa Heart Study). AB - Low birth weight is associated with cardiovascular disease and its risk factors in adulthood. However, information is limited regarding its impact on heart rate (HR), an established risk factor for cardiovascular disease. This study assessed the hypothesis that birth weight is associated with HR at rest at different ages. The study sample consisted of 6,282 black and white participants enrolled in the Bogalusa Heart Study, aged 4 to 52 years with a mean age of 19.4 years. HR data at rest were available in 2,344 children (4 to 11 years old), 1,622 adolescents (12 to 19 years old), and 2,316 adults (20 to 52 years old). Birth certificate records, including information on birth weight and gestational age, were obtained from the Louisiana State Office of Public Health. HR showed a significant decreasing trend with increasing age, with blacks having a lower slope than whites. In multivariable linear regression analyses, adjusted for age, race, gender, body mass index, and gestational age, the association between lower birth weight (kg) and increased HR (beats/min) was significant in adults (regression coefficient, beta = -1.21, p = 0.006) but not significant in children (beta = 0.31, p = 0.461) and adolescents (beta = -0.72, p = 0.157). The association did not differ significantly between races. The birth weight-HR association did not change markedly in the models without adjustment for body mass index. In conclusion, these results suggest that the association of prenatal growth retardation with increased cardiovascular disease risk in later life might be partly through its relation with HR at rest. PMID- 27453511 TI - Comparison of Recent Trends in Patients With and Without Major Depression and Acute ST-Elevation Myocardial Infarction. AB - Depression has been associated with adverse outcomes after acute coronary syndrome, including ST-elevation myocardial infarction (STEMI). However, trends over time in the incidence and inhospital treatment of STEMI for patients with co morbid depression in the current era are unknown. We conducted a serial, cross sectional analysis of patients with STEMI (weighted n = 3,057,998) in the National Inpatient Sample from 2003 to 2012. We examined trends in STEMI incidence and percutaneous coronary intervention (PCI) for patients with and without depression. We used multivariate logistic regression to assess observed differences and to explore trends in inhospital mortality. Depression was present in 153,180 (5%) of the sample. Patients with depression were more likely to be female (55% vs 37%), of white race (86% vs 78%), and had lower crude mortality (12.0% vs 14.2%; p <0.001 for all). Over time, STEMI incidence decreased 52% in patients without depression (p for trend <0.001) but remained stable in those with depression (p for trend 0.74). Although the use of PCI increased in all subgroups over the study duration (p for trend <0.001), depression was associated with lower adjusted odds of PCI (odds ratio 0.90, 95% confidence interval 0.89 to 0.92, p <0.001). In conclusion, in contrast to the wider population, the incidence of STEMI is not decreasing in patients with co-morbid depression. Patients with STEMI and co-morbid depression are less likely to receive revascularization therapy with PCI. These concerning differences warrant further attention. PMID- 27453512 TI - Effectiveness and Safety of the Transradial 8Fr Sheathless Approach for Revascularization of Chronic Total Occlusions. AB - The experience with the transradial approach in percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) in the United States is limited. We looked at the safety and feasibility of a home-made sheathless transradial technique (STT) with regular 8Fr catheters in CTO PCI. In March 2013, we developed an 8Fr STT for CTO PCI. We compared 119 patients who had the STT versus 122 treated with a standard transradial or transfemoral approach. The primary outcomes of interest were major vascular or bleeding site access complications. In a subgroup of patients with bilateral transradial approach, we assessed and compared radial patency 3 to 6 months after the procedure. Technical success rate of the CTO PCI was 93% in both groups. There were no major vascular or bleeding complications in the STT group. Radial hematomas were frequent but grade III occurred in 4 patients (3%) treated with the STT, not different to the incidence in the other group. The STT did not result in any increase in procedure time, contrast use, or radiation dose. Radial Doppler follow-up in 28 patients revealed 2 occlusions (7.1%) on the 8Fr shealthless side and one on the 6Fr side. In conclusion, our STT with regular 8Fr guides for CTO PCI is feasible, safe, and associated with low complication rate. We show that the hybrid CTO PCI nowadays can be performed through transradial access in the majority, with limited use of transfemoral approach. PMID- 27453513 TI - Characterization and Long-Term Prognosis of Postmyocarditic Dilated Cardiomyopathy Compared With Idiopathic Dilated Cardiomyopathy. AB - Dilated cardiomyopathy (DC) is the final common pathway of different pathogenetic processes and presents a significant prognostic heterogeneity, possibly related to its etiologic variety. The characterization and long-term prognosis of postmyocarditic dilated cardiomyopathy (PM-DC) remain unknown. This study assesses the clinical-instrumental evolution and long-term prognosis of a large cohort of patients with PM-DC. We analyzed 175 patients affected with DC consecutively enrolled from 1993 to 2008 with endomyocardial biopsy (EMB) data available. PM-DC was defined in the presence of borderline myocarditis at EMB or persistent left ventricular dysfunction 1 year after diagnosis of active myocarditis at EMB. Other patients were defined as affected by idiopathic dilated cardiomyopathy (IDC). Analysis of follow-up evaluations was performed at 24, 60, and 120 months. We found 72 PM-DC of 175 enrolled patients (41%). Compared with IDC, patients with PM-DC were more frequently females and less frequently presented a familial history of DC. No other baseline significant differences were found. During the long-term follow-up (median 154, first to third interquartile range 78 to 220 months), patients with PM-DC showed a trend toward slower disease progression. Globally, 18 patients with PM-DC (25%) versus 49 with IDC (48%) experienced death/heart transplantation (p = 0.045). The prognostic advantage for patients with PM-DC became significant beyond 40 months of follow up. At multivariable time-dependent Cox analysis, PM-DC was confirmed to have a global independent protective role (hazard ratio 0.53, 95% confidence interval 0.28 to 0.97, p = 0.04). In conclusion, PM-DC is characterized by better long term prognosis compared with IDC. An exhaustive etiologic characterization appears relevant in the prognostic assessment of DC. PMID- 27453514 TI - A Prospective Analysis of Early Discharge After Transfemoral Transcatheter Aortic Valve Implantation. AB - As transcatheter aortic valve implantation (TAVI) becomes more routinely used, the recommended duration of monitoring after uncomplicated TAVI remains indeterminate. Retrospective analysis suggests that discharge within 72 hours is safe, but prospective data are largely lacking. We therefore prospectively assess the feasibility and safety of early discharge (within 72 hours) after transfemoral TAVI using Edwards SAPIEN-XT and SAPIEN-3 prostheses. Patients undergoing elective transfemoral TAVI were assessed prospectively for early discharge home. Feasibility and safety (death or repeat hospitalization within 30 days of discharge) of early discharge were assessed. Causes for failure of early discharge were assessed by prospective data collection and multivariate analysis. Of 130 patients, 76 (59%) were discharged early. Death or repeat hospitalization within 30 days occurred only in 4 cases (5%) among patients who discharged early: repeat hospitalization within 30 days was required in 3 early-discharge patients (4%), and there was a single death at 30 days. By multivariate analysis, factors associated with delayed discharge were blood transfusion (hazard ratio 13.85, 95% CI 1.61 to 119.40, p = 0.017) and pacemaker implantation (hazard ratio 4.47, 95% CI 1.34 to 14.26, p = 0.012). In conclusion, early discharge after elective transfemoral TAVI with SAPIEN-XT/SAPIEN-3 prostheses is safe and attainable in a large proportion of patients, with no evident compromise in safety. Factors associated with failure of early discharge are postprocedural blood transfusion and permanent pacemaker implantation. PMID- 27453515 TI - Evaluation of 5 Prognostic Scores for Prediction of Stroke, Thromboembolic and Coronary Events, All-Cause Mortality, and Major Adverse Cardiac Events in Patients With Atrial Fibrillation and Coronary Stenting. AB - Management of antithrombotic therapy in patients with atrial fibrillation (AF) and coronary stenting remains challenging, and there is a need for efficient tools to predict their risk of different types of cardiovascular events and death. Several scores exist such as the CHA2DS2-VASc score, the Global Registry of Acute Coronary Events (GRACE) score, the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score, the Anatomical and Clinical Syntax II Score and the Reduction of Atherothrombosis for Continued Health score. These 5 scores were investigated in patients with AF with coronary stenting with the aim of determining which was most predictive for stroke/thromboembolic (TE) events, nonlethal coronary events, all-cause mortality, and major adverse cardiac events (MACE). Among 845 patients with AF with coronary stenting seen from 2000 to 2014, 440 (52%) were admitted for acute coronary syndrome and 405 (48%) for elective percutaneous coronary intervention. The rate of cardiovascular complication was at 14.1% per year, and nonlethal coronary events were the most frequent complications with a yearly rate of 6.5%. CHA2DS2-VASc score was the best predictor of stroke/TE events with a c-statistic of 0.604 (95% CI 0.567 to 0.639) and a best cut-off point of 5. SYNTAX score was better to predict nonlethal coronary events and MACE with c-statistics of 0.634 (95% CI 0.598 to 0.669) and 0.612 (95% CI 0.575 to 0.647), respectively, with a best cut-off point of 9. GRACE score appeared to be the best to predict all-cause mortality with a c-statistic of 0.682 (95% CI 0.646 to 0.717) and a best cut-off point of 153. In conclusions, among validated scores, none is currently robust enough to simultaneously predict stroke/TE events, nonlethal coronary events, death, and MACE in patients with AF with stents. The CHA2DS2-VASc score remained the best score to assess stroke/TE risk, as was the SYNTAX score for nonlethal coronary events and MACE, and finally, the GRACE score for all-cause mortality in this study population. PMID- 27453516 TI - Effect and Significance of Early Reablation for the Treatment of Early Recurrence of Atrial Fibrillation After Catheter Ablation. AB - There are few reports on early reablation (ER) for early recurrence of atrial fibrillation (AF) after catheter ablation. The present study evaluated the efficacy and significance of ER for early recurrence within a blanking period of 3 months after ablation of both paroxysmal and persistent AF, using a propensity matched analysis. Of 874 patients who underwent catheter ablation of AF, 389 (45%) had early recurrence. Of these, 78 patients underwent an ER procedure. A total of 132 matched patients (66 in the ER and 66 in the non-ER groups, 82 patients with paroxysmal AF) were included in the analysis. During a mean follow up of 15.4 months, the patients who underwent ER had a significantly lower recurrence rate than those who did not (29 [44%] vs 42 patients [64%], p = 0.023). The benefit of ER was especially apparent in patients with paroxysmal AF (p = 0.008) but not in those with persistent AF (p = 0.774). However, 24 patients (36%) in the non-ER group did not experience recurrence after a blanking period without any reablation procedure. The total number of reablation sessions was higher in the ER group than in the non-ER group (1.2 +/- 0.5 vs 0.4 +/- 0.6, p <0.001). Nonetheless, mean number of arrhythmia outpatient clinic visits at follow-up was significantly fewer in the ER group than in the late reablation group. In conclusion, ER for early recurrence of AF after catheter ablation might be effective for preventing recurrence during follow-up, especially for paroxysmal AF. PMID- 27453517 TI - Conventional echocardiographic assessment of the canine right heart: reference intervals and repeatability. AB - INTRODUCTION: We sought to define reference intervals for echocardiographic dimensions of the canine right heart. Secondarily, we intended to describe measurement variability of these dimensions. ANIMALS: Forty-five healthy adult pet dogs of diverse somatotype. MATERIALS AND METHODS: To obtain normative data used to define reference intervals, dogs underwent one echocardiographic examination by the same operator. Raw data were subject to logarithmic (log10) transformation and allometric relationships between body weight and echocardiographic variables were determined; reference intervals intended to include 95% of the population were defined. Six of the 45 dogs were randomly selected and subject to repeated echocardiographic examination by two operators. Measurement variability was quantified through calculation of coefficients of variation and repeatability coefficients. RESULTS: The strength of the linear relationships between log10 transformed echocardiographic variables and body weight varied; the range of coefficients of determination (R(2)) was 0.055-0.872. For most variables the scaling exponents were close to values expected based on presumed allometric relationships. Of the 190 within-day, between-day and inter operator coefficients of variation generated, 165 (87%) were less than 15%. Analysis of variance revealed the operator to be a significant source of variation for 25 of 38 measurements. CONCLUSIONS: Reference intervals for echocardiographic dimensions and indices of right heart function are proposed. Repeatability of selected linear dimensions and areas obtained from two dimensional echocardiography likely is sufficient for longitudinal clinical evaluations. PMID- 27453519 TI - Prophylactic cranial irradiation in small cell lung cancer: A single institution experience. AB - AIM: To compare patient demographics, prophylactic cranial irradiation (PCI) utilization and overall survival (OS) of patients with small cell lung cancer (SCLC) referred to a large tertiary center with those reported in large clinical trials. PATIENTS AND METHODS: A retrospective review was conducted of consecutive patients with limited stage (LS) and extensive stage (ES) SCLC diagnosed at the Princess Alexandra Hospital between January 2008 and December 2013. RESULTS: Two hundred and three patients with a mean age of 65.4 (+/-10.7) years were followed for a median duration of 7.6 months (range 0.5-76.5). At diagnosis, 129 (64%) patients had ES-SCLC, including 39 (19.2%) with cerebral metastases. Median OS in LS-SCLC patients receiving PCI was 18.8 months (0.9-69.4), compared with 8.2 months (0.1-34.4) in patients who did not receive PCI (P < 0.001). Median OS in the ES-SCLC cohort receiving PCI was 13.6 months (5.2-37.5) compared to 5.6 months (0.1-73.6) in patients who did not receive the therapy (P < 0.001). There was a significant improvement in intracranial disease-free survival of 7.1 months in patients with ES-SCLC who received PCI. Forty-two LS-SCLC patients (57%) did not receive PCI due to patient suitability. CONCLUSIONS: In our SCLC cohort, median OS following PCI in LS-SCLC and ES-SCLC is comparable to published data. PCI use at our institution was lower than utilization rates in large meta analyses, predominately due to poor chemotherapy tolerance and patient suitability. This may be more representative of patients treated in clinical practice rather than those recruited into large phase III trials. PMID- 27453520 TI - [Reform of the model of specialized pediatric diploma: Vision of the juniors]. PMID- 27453521 TI - Surgical approaches to pulmonary vein stenosis in pediatric heart transplant recipients: Opportunity for success in a difficult situation. PMID- 27453522 TI - Polymorphisms of FLII implicate gene expressions and growth traits in Chinese cattle. AB - Flightless-1 (FLII) is essential for early embryogenesis, structural organization of indirect flight muscle and can inhibit adipocyte differentiation. We therefore aimed to identify common variations in FLII gene and to investigate their effects on cattle growth traits. By DNA sequencing and forced PCR-RFLP methods, we evaluated two synonymous mutations (rs41910826 and rs444484913) and one intron mutation (rs522737248) in four Chinese domestic breeds (n = 628). Association analysis indicated that these SNPs were associated with growth traits and gene expressions (P < 0.05). At rs41910826, individuals with TT and/or CT genotypes had some better body sizes in Jiaxian, Nanyang, and Qinchuan breeds. Consistently, among adult Qinchuan cattle muscles, quantitative real-time PCR study witnessed considerable increases of mRNA level of FLII in cattle with CT genotype. For rs444484913, TT and/or TC genotypes were significantly associated with increased body traits of Qinchuan cattle while the qPCR data showed that the TT genotype was more conducive to FLII expression in fetal muscle. At rs522737248, performances of cattle with AA genotype showed compelling superior merits in all four breeds, and allele A had an increasing tendency for the mRNA expression of PPARgamma in adult adipose and FLII in fetal muscle. These findings strongly demonstrate that the three SNPs of FLII gene could be utilized as molecular markers for future assisted selection in cattle breeding program. PMID- 27453523 TI - Characterization of gelatin/chitosan scaffold blended with aloe vera and snail mucus for biomedical purpose. AB - Biologically active scaffolds used in tissue engineering and regenerative medicine have been generating promising results in skin replacement. The present study aims to test the hypothesis that the incorporation of Aloe vera and snail mucus into scaffolds based on gelatin and chitosan could improve their structure, composition and biodegradability, with a potential effect on bioactivity. Homogeneous pore diameter as well as pore walls in the composite scaffold could be seen in the SEM image. The pores in the scaffolds were interconnected and their sizes ranged from 93 to 296MUm. The addition of Aloe vera and snail mucus enlarged the mean pore size with increased porosity and caused changes in the pore architecture. The FTIR analysis has shown good affinity and interaction between the matrix and the Aloe, which may decrease water-binding sites, so this fact hindered the water absorption capacity of the material. The mechanical properties could explain the highest swelling capacity of the snail scaffold, because the high percentage of elongation could facilitate the entry of liquid in it, generating a matrix with plenty of fluid retention. The real innovation in the present work could be the use of these substances (Aloe and snail mucus) for tissue engineering. PMID- 27453524 TI - Preparation, characterization and biodistribution in quails of 99mTc-folic acid/chitosan nanostructure. AB - Chitosan (CS) of low molecular weight is prepared using gamma-irradiation method in presence of H2O2 as oxidizing agent. The chemical treatment of folic acid (FA) with low molecular weight CS is carried out to prepare FACS complex based on the reaction between NH2 group of CS and gamma-COOH group of FA. The structure and properties of FACS complex was characterized by FT-IR, 1H NMR, UV, SEM, TEM, DLS and XRD analyses. TEM and DLS results showed that FACS complex has nanostructure and the mean size of particles was unimodal with average diameters in the range of 165-252nm. Radiolabeling of FACS complex (99mTc-FACS) was done with Technetium 99m (99mTc). The optimum conditions of labeling were investigated. The labeling yield was 85% at pH=6 and 30min reaction time. The effect of time on the stability of 99mTc-FACS complex was studied and the results revealed that it is stable up to 6h after labeling. Biodistribution studies of 99mTc-FACS complex in Quail showed that it distributed to different organs mainly in blood, liver and kidney. The results revealed that the uptake of 99mTc-FACS in the sexual organs (ovary and ovarian) of female Quail was higher than that in the sexual organs (testes) of male Quail, so 99mTc-FACS could be used to differentiate between them. It also showed that FACS is consumed and more essential in female than that in male. PMID- 27453525 TI - Prenatal and early-life predictors of atopy and allergic disease in Canadian children: results of the Family Atherosclerosis Monitoring In earLY life (FAMILY) Study. AB - Prenatal and early-life environmental exposures play a key role in the development of atopy and allergic disease. The Family Atherosclerosis Monitoring In earLY life Study is a general, population-based Canadian birth cohort that prospectively evaluated prenatal and early-life traits and their association with atopy and/or allergic disease. The study population included 901 babies, 857 mothers and 530 fathers. Prenatal and postnatal risk factors were evaluated through questionnaires collected during the antenatal period and at 1 year. The end points of atopy and allergic diseases in infants were evaluated through questionnaires and skin prick testing. Key outcomes included atopy (24.5%), food allergy (17.5%), cow's milk allergy (4.8%), wheezing (18.6%) and eczema (16%). The association between infant antibiotic exposure [odds ratio (OR): 2.04, 95% confidence interval (CI): 1.45-2.88] and increased atopy was noted in the multivariate analysis, whereas prenatal maternal exposure to dogs (OR: 0.60, 95% CI: 0.42-0.84) and acetaminophen (OR: 0.68, 95% CI: 0.51-0.92) was associated with decreased atopy. This population-based birth cohort in Canada demonstrated high rates of atopy, food allergy, wheezing and eczema. Several previously reported and some novel prenatal and postnatal exposures were associated with atopy and allergic diseases at 1 year of age. PMID- 27453527 TI - The imaginative mind. AB - The astounding capacity for the human imagination to be engaged across a wide range of contexts is limitless and fundamental to our day-to-day experiences. Although processes of imagination are central to human psychological function, they rarely occupy center stage in academic discourse or empirical study within psychological and neuroscientific realms. The aim of this paper is to tackle this imbalance by drawing together the multitudinous facets of imagination within a common framework. The processes fall into one of five categories depending on whether they are characterized as involving perceptual/motor related mental imagery, intentionality or recollective processing, novel combinatorial or generative processing, exceptional phenomenology in the aesthetic response, or altered psychological states which range from commonplace to dysfunctional. These proposed categories are defined on the basis of theoretical ideas from philosophy as well as empirical evidence from neuroscience. By synthesizing the findings across these domains of imagination, this novel five-part or quinquepartite classification of the human imagination aids in systematizing, and thereby abets, our understanding of the workings and neural foundations of the human imagination. It would serve as a blueprint to direct further advances in the field of imagination while also promoting crosstalk with reference to stimulus oriented facets of information processing. A biologically and ecologically valid psychology is one that seeks to explain fundamental aspects of human nature. Given the ubiquitous nature of the imaginative operations in our daily lives, there can be little doubt that these quintessential aspects of the mind should be central to the discussion. Hum Brain Mapp 37:4197-4211, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27453526 TI - Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2gamma (iPLA2gamma) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size. AB - Calcium-independent phospholipase A2gamma (iPLA2gamma) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA2gamma in cardiac myocytes, we generated cardiac myocyte-specific iPLA2gamma knock-out (CMiPLA2gammaKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA2gammaKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA2gammaKO mice demonstrated attenuated Ca(2+)-induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA2gammaKO mice (30 min of ischemia followed by 30 min of reperfusion in vivo) dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA2gammaKO mice subjected to 30 min of ischemia followed by 24 h of reperfusion in vivo developed substantially less cardiac necrosis in the area-at-risk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca(2+) by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA2gamma, these results are consistent with salvage of myocardium after I/R by iPLA2gamma loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion. PMID- 27453528 TI - 'Nurses don't deal with these issues': nurses' role in advance care planning for lesbian, gay, bisexual and transgender patients. AB - AIMS AND OBJECTIVES: We used a question from the Healthcare Equality Index to explore nurses' knowledge and understanding of medical advance directives, medical power of attorney and other legal documents for lesbian, gay, bisexual and transgender patients. BACKGROUND: Until the landmark ruling in Obergefell vs. Hodges, lesbian, gay, bisexual and transgender individuals and same-sex couples have had limited relationship rights as only a few states recognised marriages and provided legal protections for same-sex couples. Health care providers' knowledge of and attitudes towards advance care planning plays a significant role in determining whether or not individuals successfully complete advance directives, yet advance care planning for lesbian, gay, bisexual and transgender individuals is poorly understood among both health care providers and same-sex couples. DESIGN: These data were part of a larger research study that explored the current state of lesbian, gay, bisexual and transgender-sensitive nursing practice. METHOD: Undergraduate nursing students recruited and interviewed nurse key informants (n = 268) about medical advance directives, medical power of attorney and other legal documents for lesbian, gay, bisexual and transgender patients. RESULTS: Nearly 50% of key informants indicated a lack of knowledge of advance directives, over 26% reported the difficulties nurses face regarding advance directives are the same for both lesbian, gay, bisexual and transgender and heterosexual patients, and nearly 25% indicated difficulties including having to decide who has the legal right to make decisions for the patient. CONCLUSION: The study demonstrated the need for education and training for practising nurses in advance care planning for lesbian, gay, bisexual and transgender patients and same-sex couples. RELEVANCE TO CLINICAL PRACTICE: Nurses are in a position to act as educators, advocates and decision makers for their patients. Nurse's lack of understanding of advance care planning may negatively impact the type and quality of care lesbian, gay, bisexual and transgender patients receive. PMID- 27453529 TI - How Might Democrats Try to Improve and Expand the ACA in 2017? PMID- 27453530 TI - Enhancement of recombination process using silver and graphene quantum dot embedded intermediate layer for efficient organic tandem cells. AB - High performance of organic tandem solar cell is largely dependent on transparent and conductive intermediate layer (IML). The current work reports the design and fabrication of an IML using a simple solution process. The efficiency of a homo tandem device with poly(3-hexylthiophene):phenyl-C61-butyric acid methyl ester as an active layer and poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate)/poly(ethylenimine) as an IML was initially found to be 3.40%. Further enhancement of the cell efficiency was achieved using silver nanoparticles (Ag-NPs) of different sizes and graphene quantum dot embedded IML. A maximum efficiency of 4.03% was achieved using 7 nm Ag-NPs that contribute to a better recombination process. Also, the performance of the tandem cell was solely based on the electrical improvements indicated by the current - voltage measurements, external quantum efficiency and impedance analysis. The use of Ag-NPs in the IML has been shown to lengthen the life time of electron-hole pairs in the device. This study thus paves way to develop such efficient IMLs for more efficient tandem solar cells. PMID- 27453532 TI - Transition-metal norharmane compounds as possible cytotoxic agents: New insights based on a coordination chemistry perspective. AB - New first-row transition-metal compounds with the ligand norharmane (9H Pyrido[3,4-b]indole; Hnor) are reported. The compounds have the general formula [M(LL)(Hnor)(NO3)2](MeOH)0-1 (M=Co, Ni, Cu, Zn; LL=2,2'-bipyridyl (bpy), 1,10 phenanthroline (phen)) and have been characterized by physical and analytical methods. X-ray structural analysis revealed that the compound of formula [Cu(phen)(Hnor)(NO3)2], (1) has a distorted 6-coordinated octahedrally-based geometry, with a planar-based [CuN3O] core, where Cu-L varies between 1.99 and 2.04A and two weak axial CuO contacts (2.209 and 2.644A) from two different nitrates. Based on spectroscopic similarities, the other compounds appear to have the same or very similar coordination geometries. The compounds showed clear cell growth inhibitory effects in two different cancer cell lines in vitro, with the copper and zinc complexes being the most toxic and in fact almost comparable to cisplatin. Flow-cytometry analysis confirmed induction of apoptosis in cancer cells treated with the compounds. Interestingly, co-incubation of the cells with metal complexes and CuCl2 induced an increase in the cytotoxic effects, most likely due to the conversion of the metal compounds in the corresponding, and most active, copper analogues. PMID- 27453531 TI - The inhibition of calpains ameliorates vascular restenosis through MMP2/TGF-beta1 pathway. AB - Restenosis limits the efficacy of vascular percutaneous intervention, in which vascular smooth muscle cell (VSMC) proliferation and activation of inflammation are two primary causal factors. Calpains influence VSMC proliferation and collagen synthesis. However, the roles of calpastatin and calpains in vascular restenosis remain unclear. Here, restenosis was induced by ligating the left carotid artery, and VSMCs were pretreated with platelet-derived growth factor (PDGF)-BB. Adenovirus vector carrying MMP2 sequence and specific small interfering RNA against calpain-1/2 were introduced. Finally, restenosis enhanced the expression of calpain-1/2, but reduced calpastatin content. In calpastatin transgenic mice, lumen narrowing was attenuated gradually and peaked on days 14 21. Cell proliferation and migration as well as collagen synthesis were inhibited in transgenic mice, and expression of calpain-1/2 and MMP2/transforming growth factor-beta1 (TGF-beta1). Consistently, in VSMCs pretreated with PDGF-BB, calpastatin induction and calpains inhibition suppressed the proliferation and migration of VSMCs and collagen synthesis, and reduced expression of calpain-1/2 and MMP2/TGF-beta1. Moreover, simvastatin improved restenosis indicators by suppressing the HIF-1alpha/calpains/MMP2/TGF-beta1 pathway. However, MMP2 supplementation eliminated the vascular protection of calpastatin induction and simvastatin. Collectively, calpains inhibition plays crucial roles in vascular restenosis by preventing neointimal hyperplasia at the early stage via suppression of the MMP2/TGF-beta1 pathway. PMID- 27453533 TI - Ni(II) complexes with 2,2-dipyridylamine and salicylaldehydes: Synthesis, crystal structure and interaction with calf-thymus DNA and albumins. AB - The synthesis of four cationic mixed-ligand Ni(II) complexes with 2,2' dipyridylamine (dpamH) and substituted salicylaldehydes (X-saloH) was undertaken in an effort to discover new biologically active compounds. The complexes with the general formula [Ni(dpamH)2(X-salo)]Cl, 3-6, namely [Ni(dpamH)2(5-Cl salo)]Cl, 3, [Ni(dpamH)2(5-Br-salo)]Cl, 4, [Ni(dpamH)2(5-CH3-salo)]Cl, 5, and [Ni(dpamH)2(3-OCH3-salo)]Cl.CH3OH, 6, were characterized by elemental analyses, FT-IR and UV-vis spectroscopy, magnetic and conductivity measurements. In addition, two analogous nickel-salicylaldehydato complexes in the absence of dpamH were prepared and characterized as [Ni(5-Cl-salo)2(CH3OH)2], 1 and [Ni(5-Br salo)2(CH3OH)2], 2. The structures of complexes 1-6 were determined by X-ray crystallography revealing octahedral coordination of nickel (II) and monomeric nature of the compounds. Spectroscopic (UV-vis), electrochemical (cyclic voltammetry) and physicochemical (viscosity measurements) techniques were employed in order to study the binding mode and strength of the complexes to calf thymus (CT) DNA, while competitive studies with ethidium bromide (EB), performed by fluorescence spectroscopy, revealed the ability of the complexes to displace the DNA-bound EB. The complexes bind to DNA probably via intercalation exhibiting high DNA-binding constants. For the cationic complexes 3-6, the coexistence of an electrostatic interaction with CT DNA may be also suggested. The interaction of the complexes with serum albumins was studied by fluorescence emission spectroscopy and the determined binding constants exhibit relative high values. PMID- 27453534 TI - High stability and biological activity of the copper(II) complexes of alloferon 1 analogues containing tryptophan. AB - Copper(II) complex formation processes between the alloferon 1 (Allo1) (HGVSGHGQHGVHG) analogues where the tryptophan residue is introducing in the place His residue H1W, H6W, H9W and H12W have been studied by potentiometric, UV visible, CD and EPR spectroscopic, and MS methods. For all analogues of alloferon 1 complex speciation have been obtained for a 1:1 metal-to-ligand molar ratio and 2:1 of H1W because of precipitation at higher (2:1, 3:1 and 4:1) ratios. At physiological pH7.4 and a 1:1 metal-to-ligand molar ratio the tryptophan analogues of alloferon 1 form the CuH-1L and/or CuH-2L complexes with the 4N binding mode. The introduction of tryptophan in place of histidine residues changes the distribution diagram of the complexes formed with the change of pH and their stability constants compared to the respective substituted alanine analogues of alloferon 1. The CuH-1L, CuH-2L and CuH-3L complexes of the tryptophan analogues are more stable from 1 to 5 log units in comparison to those of the alanine analogues. This stabilization of the complexes may result from cation(Cu(II))-pi and indole/imidazole ring interactions. The induction of apoptosis in vivo, in Tenebrio molitor cells by the ligands and their copper(II) complexes at pH7.4 was studied. The biological results show that copper(II) ions in vivo did not cause any apparent apoptotic features. The most active were the H12W peptide and Cu(II)-H12W complex formed at pH7.4. PMID- 27453535 TI - Probing the interaction of bisintercalating (2,2':6',2"-terpyridine)platinum(II) complexes with glutathione and rabbit plasma. AB - Platinum(II) complexes have demonstrated considerable success in the treatment of cancer, but severe toxic side effects drive the search for new complexes with increased tumour selectivity and better efficacy. A critical concept that has to be considered in the context of designing novel Pt complexes is their interactions with biomolecules other than DNA. To this end, here the interactions of 16 previously reported bisintercalating (2,2':6',2"-terpyridine)platinum(II) complexes, [{Pt(terpy)}2MU-(X)]n+ (where X is a linker) with glutathione (GSH) by means of 1H and 195Pt NMR spectroscopy were investigated. The GSH half-life (GSH t1/2) was determined following the incubation of each [{Pt(terpy)}2MU-(X)]n+ complex with GSH (8mM). It was observed that complexes 1-7, 11, 12 and 14-16 reacted more rapidly than cisplatin, whereas complexes 8-10, 13 and 17 reacted more slowly (>=200min). There was no apparent correlation between linker length and the GSH t1/2. In order to understand these interactions, two complexes: 1 (t1/2<1min) and a previously studied 17 [Pt(5,6-dimethyl-1,10 phenanthroline)(1S,2S-diaminocyclohexane)] (56MESS) (GSH t1/2=4080min) were incubated with rabbit plasma. A "metallomics" approach was used to analyse plasma for all platinum species at the 5 and the 60min time point and provided results that were congruent with the reaction of the selected Pt complexes with GSH. Our studies demonstrate that the combined application of NMR spectroscopy, cytotoxicity studies and a metallomics approach can contribute to better understand the interaction of [{Pt(terpy)}2MU-(X)]n+ complexes with biomolecules to better assess which compounds may be advanced to in vivo studies. PMID- 27453536 TI - Deterministic Integration of Out-of-Plane Sensor Arrays for Flexible Electronic Applications. AB - A design strategy for fully flexible electrode arrays with out-of-plane through polymer vias (TPVs) for monolithic 3D integration of sensor readout circuitry is presented. The TPVs are formed using copper embedded in thin polyimide structure for support. The copper interconnects offer a stable impedance frequency response from DC to 100 kHz (Z ~ 20 Omega, theta ~ 0 degrees ). PMID- 27453537 TI - Monocyte Chemoattractant Protein-1 and Large Artery Structure and Function in Young Individuals: The African-PREDICT Study. AB - To better understand hypertension development, the authors determined whether monocyte chemoattractant protein-1 (MCP-1) is associated with arterial stiffness (pulse wave velocity [PWV]) and carotid intima-media wall thickness (cIMT) in a young apparently healthy black and white population (N=403, aged 20-30 years). Carotid-femoral PWV, central systolic blood pressure, and cIMT were measured, and MCP-1, reactive oxygen species, inflammatory markers (interleukin 6, tumor necrosis factor alpha), and endothelial activation (intercellular adhesion molecule, vascular cell adhesion molecule) were determined from blood samples. Although carotid-femoral PWV and cIMT were similar between blacks and whites, black men and women showed higher central systolic blood pressure, MCP-1, and reactive oxygen species than whites (all P<.05). In addition, black women had higher brachial blood pressure and interleukin 6 (all P<.001). A consistent positive association only in black women between cIMT and MCP-1 in multiple regression analyses was found (R2=0.151, beta=0.248; P=.021). In this model, cIMT was also independently associated with vascular cell adhesion molecule (beta=0.251; P=.022). The authors found elevated central systolic blood pressure and MCP-1 in young blacks, where cIMT was independently associated with MCP-1 in black women. PMID- 27453538 TI - Validation of a Web-Based Curriculum for Resident Education in Orthopedic Surgery. AB - BACKGROUND: The Orthopedic In-Training Examination is an annual standardized examination with multiple-choice questions focused on application of orthopedic surgery core knowledge and principles. The outcome of this test can be used to both predict how residents are progressing in their orthopedic knowledge as well as assess their likelihood to pass the Orthopedic Board Examinations, that is the American Boards of Orthopedic Surgery Part 1, following completion of residency. Preparation for the examination can be difficult, as residents commonly have limited study time to review the vast amounts of available published literature. The objective of our study is to evaluate the effectiveness of the Orthopaedic In Training Examination (OITE) scores and the participants' perceived utility of the curriculum for OITE preparation. METHODS: Residents from 5 US Orthopedic residencies (4 M.D. and 1 D.O.) were included in a pilot program of the Orthobullets PASS curriculum in the academic year 2013 to 2014. Only residents enrolled in the PASS curriculum who completed both the 2013 and 2014 OITEs were included in the final analysis (n = 71). We used the OITE 2013 and 2014 rank postgraduate year (RPGY) reported scores to assess for efficacy of the PASS curriculum, as the RPGY score provides postgraduate year-of-training matched analysis to control for expected increased levels of knowledge with subsequent retesting. RESULTS: While OITE scores incrementally increased for the group as a whole (n = 71, RPGY mean improvement = +2.5%, p = 0.406), the junior resident subgroup (postgraduate year 1-2) produced a statistically significant increase in scores (n = 28, RPGY mean increase = 10.1%, p = 0.0260). Nearly 90% (38/42) of curriculum participants surveyed reported a preference to complete a similar review curriculum for future OITE preparation. The participants completing greater than 150 PASS questions (n = 57) were analyzed for OITE predictive capacity of the PASS curriculum. Pearson analysis with PASS questions percent answered correctly and 2014 OITE raw score (independent and dependent variables, respectively) suggests moderate correlation of the variables (R = 0.682, p < 0.05). CONCLUSION: We propose that the Orthobullets PASS curriculum is a useful tool for OITE preparation, especially for junior residents, with a focus on achieving competency for a broad fund of orthopedic knowledge, whereas mastery of these topics would be better suited through using complementary sources. PMID- 27453539 TI - Hidradenitis suppurativa (HS) is associated with low socioeconomic status (SES): A cross-sectional reference study. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic debilitating disease, whereby school attendance and employment can be disturbed. OBJECTIVE: We sought to determine the socioeconomic status (SES) in patients with HS relative to other dermatologic patients, and whether specific clinical HS characteristics correlate with SES. METHODS: For this multicenter cross-sectional reference study, data were collected from patients with HS and sex- and age-matched dermatologic patients in a 1:2 ratio. SES was derived from the mean household income and real estate value on a neighborhood level. RESULTS: The SES distribution among 1018 patients with HS was significantly lower than among 2039 age- and sex-matched dermatologic control patients (P < .001). In patients with HS a low SES was associated with axillary involvement (odds ratio 1.42, P = .04), high body mass index (odds ratio 1.03, P = .003), and lower age at inclusion (odds ratio 0.98, P = .001), but not with disease severity or age of disease onset. LIMITATIONS: SES was based on postal code level and causality cannot be determined. CONCLUSION: In the general population, low SES is associated with an unhealthy lifestyle such as smoking and obesity. Therefore, low SES might be a risk factor for developing HS. PMID- 27453540 TI - Vitamin D status and its predictors in New Zealand aged-care residents eligible for a government-funded universal vitamin D supplementation programme. AB - OBJECTIVE: The provision of prescribed vitamin D to all aged-care residents has been implemented in New Zealand as part of a government-led falls prevention programme. To our knowledge, there has been no evaluation of this universal programme on vitamin D status and functional and health outcomes. Thus, we aimed to determine 25-hydroxyvitamin D (25(OH)D) concentrations and their predictors in aged-care residents across the country and to investigate whether the government funded programme was associated with adequate vitamin D status. DESIGN: Cross sectional survey of sociodemographic, biochemical, anthropometric, dietary and health characteristics. Blood samples were analysed for serum 25(OH)D and other biochemical measures. Multiple regression was used to examine predictors of vitamin D status. SETTING: Sixteen residential aged-care facilities throughout New Zealand. SUBJECTS: Residents aged >=60 years with residency duration >12 weeks (n 309). RESULTS: Mean serum 25(OH)D was 89.9 (95 % CI 85.2, 94.5) nmol/l and monthly supplements (1250 ug (50 000 IU)) were taken by 75 % of all residents. Of those not taking a funded supplement, 65.3 % had serum 25(OH)D 125 nmol/l. CONCLUSIONS: Residents taking supplemental vitamin D had adequate vitamin D status; however monitoring of long-term supplementation should be considered, due to the high proportion of participants with high serum 25(OH)D levels. PMID- 27453541 TI - Captain Haddock's health issues in the adventures of Tintin. Comparison with Tintin's health issues. AB - BACKGROUND: We currently lack a comprehensive and systematic description of the challenges and health impairments (HI) faced by Captain Haddock over the course of the 15 Tintin adventures in which he appears. Their respective HIs have yet to be compared. METHODS: We evaluated the spectrum of HIs that Haddock sustains in these 15 adventures as well as their causes, consequences, and their relationship to alcohol or travel beyond Belgium. We diagnosed Haddock's HIs according to descriptive terms in the text. We then classified HIs as traumatic and non traumatic, and distinguished between intentional and unintentional events. We compared the depiction of HIs involving Haddock and Tintin. RESULTS: We found 225 events leading to 249 HIs, two hospitalisations, and three medical consultations. There was a median of 19 HIs/adventure (range 4-27/adventure) with 193 cases of trauma (77.5%) and 56 non-traumatic problems (22.5%). There were 109 cases of concussion (43% of all HI, 56% of all trauma). We encountered 12 burns including ten relating to Haddock's tobacco habit. The most common forms of non-traumatic problems were linked to alcoholism (57%), and specifically drunkenness (37%). Haddock is diagnosed with cirrhosis early in Tintin's adventures. He significantly decreases his consumption of alcohol after he meets Tintin (58.3% of HI before vs 10.7% of HI after; P<0.001; OR 5.4) but not his use of tobacco. He is also susceptible to certain travel-related illnesses such as mosquito bites, ear discomfort, exposure to exotic animals, and perhaps jet lag. Overall, Haddock presents as many HIs (249 vs 244) and trauma (190 vs 193) as Tintin, but suffers significantly more HIs/adventure than Tintin (median 19 vs 8, P=0.03), and the traumas are significantly less severe, LoCs accounting for 23% of Tintin's traumatic HIs vs 2.5% for Haddock (P<0.001; OR: 5.1). CONCLUSION: Traumatic HIs and concussion are the leading cause of HIs for Tintin and Haddock but are clearly less severe for Haddock. Haddock evolves from alcoholic sea Captain to a country gent who is less addicted to alcohol than he is to tobacco. PMID- 27453542 TI - A New Skin Tensiometer Device: Computational Analyses To Understand Biodynamic Excisional Skin Tension Lines. AB - One of the problems in planning cutaneous surgery is that human skin is anisotropic, or directionally dependent. Indeed, skin tension varies between individuals and at different body sites. Many a surgeon has tried to design different devices to measure skin tension to help plan excisional surgery, or to understand wound healing. However, many of the devices have been beset with problems due to many confounding variables - differences in technical ability, material (sutures) used and variability between different users. We describe the development of a new skin tensiometer that overcomes many historical technical issues. A new skin tension measuring device is presented here. It was designed to be less user-dependent, more reliable and usable on different bodily sites. The design and computational optimizations are discussed. Our skin tensiometer has helped understand the differences between incisional and excisional skin lines. Langer, who pioneered the concept of skin tension lines, created incisional lines that differ from lines caused by forces that need to be overcome when large wounds are closed surgically (excisional tension). The use of this innovative device has led to understanding of skin biomechanics and best excisional skin tension (BEST) lines. PMID- 27453543 TI - Electroacupuncture modulates stromal cell-derived factor-1alpha expression and mobilization of bone marrow endothelial progenitor cells in focal cerebral ischemia/reperfusion model rats. AB - Stromal cell-derived factor-1alpha(SDF-1alpha) plays a crucial role in regulating the mobilization, migration and homing of endothelial progenitor cells(EPCs). Electroacupuncture(EA), a modern version of Traditional Chinese Medicine, can improve neurological recovery and angiogenesis in cerebral ischemic area. This study aimed to investigate the effects of electroacupuncture(EA) on the mobilization and migration of bone marrow EPCs and neurological functional recovery in rats model after focal cerebral ischemia/reperfusion and the potentially involved mechanisms. Sprague-Dawley rats received filament occlusion of the right middle cerebral artery for 2h followed by reperfusion for 12h, 1d, 2d, 3d, 7d respectively. Rats were randomly divided into sham group, model group and EA group. After 2h of the reperfusion, EA was given at the "Baihui" (GV 20)/Siguan ("Hegu" (LI 4)/"Taichong" (LR 3)) acupoints in the EA group. Modified neurological severity score (mNSS) was used to assess the neurological functional recovery. EPCs number and SDF-1alpha level in bone marrow(BM) and peripheral blood(PB) were detected by using fluorescence-activated cell sorting (FACS) analysis and quantitative real time polymerase chain reaction (qRT-PCR) respectively. An mNSS test showed that EA treatment significantly improved the neurological functional outcome. EPCs number in PB and BM were obviously increased in the EA group. After cerebral ischemia, the SDF-1alpha level was decreased in BM while it was increased in PB, which implied a gradient of SDF 1alpha among BM and PB after ischemia. It suggested that the forming of SDF 1alpha concentration gradient can induce the mobilization and homing of EPCs. Eletroacupuncture as a treatment can accelerate and increase the forming of SDF 1alpha concentration gradient to further induce the mobilization of EPCs and angiogenesis in ischemic brain and improve the neurological function recovery. PMID- 27453544 TI - Spectroscopic properties and location of the Tb(3+) and Eu(3+) energy levels in Y2O2S under high hydrostatic pressure. AB - In this contribution, an extensive spectroscopic study of Y2O2S doped with Eu(3+) and Tb(3+) is presented. Steady-state luminescence and luminescence excitation spectra as well as the time-resolved spectra and luminescence kinetics were obtained at high hydrostatic pressures up to 240 kbar. It was found that pressure quenches the luminescence from the (5)D3 excited state of Tb(3+) and recovers additional luminescence related to transitions from the (5)D3 state of Eu(3+). These effects are related to the pressure-induced increases in the energies of the ground electronic manifold 4f(n) of Eu(3+) and Tb(3+) ions with respect to the band edges. Analysis of the emission and excitation spectra allowed the estimation of the energies of the ground states of all lanthanide (Ln) ions (Ln(3+) and Ln(2+)) with respect to the valence and conduction bands edges of the Y2O2S host. The bandgap energy and difference between energies of the ground states of Ln(2+) and Ln(3+) have been calculated as functions of pressure. The experimental high-pressure spectroscopy results allow the calculation of the absolute values (calculated with respect to the vacuum level) of the energies and pressure-induced shifts of the conduction and valence band edges and the ground states of Ln(3+) and Ln(2+) ions in Y2O2S. PMID- 27453546 TI - Robust HCV Genotype 3a Infectious Cell Culture System Permits Identification of Escape Variants With Resistance to Sofosbuvir. AB - BACKGROUND & AIMS: Direct-acting antivirals (DAAs) effectively eradicate chronic hepatitis C virus (HCV) infection, although HCV genotype 3a is less responsive to these drugs. We aimed to develop genotype 3a infectious cultures and study the effects of inhibitors of NS5A and NS5B and resistance to sofosbuvir-the only nucleotide analog approved for treatment of chronic HCV infection. METHODS: The developed HCV genotype 3a full-length genome (DBN3a), with a strain-DBN coding sequence, modified NS5B consensus sequence, pS52 untranslated regions, and coding mutations from a culture-efficient JFH1-based core-NS5A (DBN) recombinant, was transfected into Huh7.5 cells. The efficacy of selected DAAs was determined in dose-response assays, in which the number of HCV-infected cells was measured after incubation with different concentrations of the specific DAA. Long-term culture of infected Huh7.5 cells with increasing concentrations of sofosbuvir was used to promote selection of HCV-resistant variants. RESULTS: We engineered a DBN3a variant with 17 substitutions (DBN3acc) that had replication and propagation kinetics in Huh7.5 cells comparable with prototype J6/JFH1. The adaptive mutations also produced culture-efficient DBN-based recombinants with NS5B from HCV genotype 3a strains S52 and DH11. Compared with genotype 1a, genotype 3a was less sensitive to daclatasvir, ledipasvir, and elbasvir, but equally sensitive to ombitasvir, velpatasvir, beclabuvir, dasabuvir, MK-3682, and sofosbuvir. Exposure of Huh7.5 cells infected with DBN3a to sofosbuvir led to identification of an escape variant with substitutions in NS5B, including the resistance-associated substitution S282T. This variant showed increased infectivity of Huh7.5 cells, compared with DBN3a, and was genetically stable in cell cultures without sofosbuvir. Sofosbuvir, MK-3682, dasabuvir, or combinations of sofosbuvir and ledipasvir or sofosbuvir and velpatasvir had decreased efficacy against infection with the DBN3a sofosbuvir escape variant. CONCLUSIONS: We developed a system for highly efficient culture of HCV genotype 3a. Genotype 1a has a high genetic barrier to resistance for sofosbuvir, whereas resistance to this DAA can be induced in genotype 3a. We therefore isolated HCV genotype 3a variants with reduced sensitivity to sofosbuvir, with increased fitness and with cross-resistance to other NS5B inhibitors. These findings indicate that sofosbuvir escape variants could compromise the effectiveness of nucleotide analogs against HCV. GenBank accession numbers: KX280712-KX280716. PMID- 27453545 TI - Regulation of GABAergic synapse development by postsynaptic membrane proteins. AB - In the adult mammalian brain, GABAergic neurotransmission provides the majority of synaptic inhibition that balances glutamatergic excitatory drive and thereby controls neuronal output. It is generally accepted that synaptogenesis is initiated through highly specific protein-protein interactions mediated by membrane proteins expressed in developing presynaptic terminals and postsynaptic membranes. Accumulating studies have uncovered a number of membrane proteins that regulate different aspects of GABAergic synapse development. In this review, we summarize recent advances in understanding of GABAergic synapse development with a focus on postsynaptic membrane molecules, including receptors, synaptogenic cell adhesion molecules and immunoglobulin superfamily proteins. PMID- 27453547 TI - HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant. AB - BACKGROUND & AIMS: Chronic infection with hepatitis B virus (HBV) progresses through different phases. The first, called the immune-tolerant phase, has been associated with a lack of disease activity. We examined HBV-DNA integration, clonal hepatocyte expansion, HBV antigen expression, and HBV-specific immune responses in patients in the immune-tolerant phase to assess whether this designation is appropriate or if there is evidence of disease activity. METHODS: We studied HBV-DNA integration, clonal hepatocyte expansion, and expression of hepatitis B surface antigen and core antigen in liver tissues from 26 patients with chronic HBV infection (ages, 14-39 y); 9 patients were positive for hepatitis B e antigen (HBeAg) in the immune-tolerant phase and were matched for age with 10 HBeAg-positive patients with active disease and 7 HBeAg-negative patients with active disease. Peripheral blood samples were collected and HBV specific T cells were quantified for each group. RESULTS: Detection of HBV antigens differed among groups. However, unexpectedly high numbers of HBV-DNA integrations, randomly distributed among chromosomes, were detected in all groups. Clonal hepatocyte expansion in patients considered immune tolerant also was greater than expected, potentially in response to hepatocyte turnover mediated by HBV-specific T cells, which were detected in peripheral blood cells from patients in all phases of infection. CONCLUSIONS: We measured HBV-specific T cells, HBV-DNA integration, and clonal hepatocyte expansion in different disease phases of young patients with chronic hepatitis B, with emphasis on the so-called immune-tolerant phase. A high level of HBV-DNA integration and clonal hepatocyte expansion in patients considered immune tolerant indicated that hepatocarcinogenesis could be underway-even in patients with early stage chronic HBV infection. Our findings do not support the concepts that this phase is devoid of markers of disease progression or that an immune response has not been initiated. We propose that this early phase be called a high-replication, low inflammation stage. The timing of therapeutic interventions to minimize further genetic damage to the hepatocyte population should be reconsidered. PMID- 27453549 TI - Acute endurance exercise lowers serum fibroblast growth factor 21 levels in Japanese men. AB - OBJECTIVE: The independent effects of acute endurance exercise on FGF21 metabolism are poorly understood. Therefore, the purpose of this study was to determine whether acute endurance exercise modulates serum postprandial FGF21 levels in an age-dependent manner. DESIGN: Exercise intervention trial. PATIENTS: Twenty-eight subjects participated in the experiment, of whom 13 were excluded mainly because of a serum FGF21 level below the limit of detection. Thus, data from seven young (age: 18-22 years) and eight elderly male subjects (age: 62-69 years) were analysed. MEASUREMENTS: Participants were asked to perform a cycling exercise for 30 min at 70% maximal oxygen uptake, following carbohydrate intake. Blood samples were collected pre-exercise and 0 min, 30 min, 1 h, 3 h and 24 h after the cessation of exercise. Serum FGF21 levels were measured by an enzyme linked immunosorbent assay. RESULTS: Higher serum FGF21 was observed in the elderly subjects group throughout the experiment (P < 0.05). There was no significant increase in serum FGF21 levels after the cessation of exercise, whereas serum FGF21 levels were significantly lower 24 h after the exercise compared with those pre-exercise, 0 min, 30 min and 1 h after the cessation of exercise in both groups (P < 0.01). The response did not differ between the two groups because of no significant group * time interaction. CONCLUSIONS: Acute endurance exercise lowers serum FGF21 levels 24 h following exercise. The results suggest that acute endurance exercise modulates postprandial FGF21 metabolism regardless of age. PMID- 27453548 TI - Sestrin2 Silencing Exacerbates Cerebral Ischemia/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK/PGC-1alpha Pathway in Rats. AB - Sestrin2 (Sesn2) exerts neuroprotective properties in some neurodegenerative diseases. However, the role of Sesn2 in stroke is unclear. The AMP-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha (AMPK/PGC-1alpha) pathway plays an important role in regulating mitochondrial biogenesis, which helps prevent cerebral ischemia/reperfusion (I/R) injury. Here, we aimed to determine whether Sesn2 alleviated I/R damage by regulating mitochondrial biogenesis through the AMPK/PGC-1alpha signaling pathway. To be able to test this, Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h with Sesn2 silencing. At 24 h after reperfusion, we found that neurological deficits were exacerbated, infarct volume was enlarged, and oxidative stress and neuronal damage were greater in the Sesn2 siRNA group than in the MCAO group. To explore protective mechanisms, an AMPK activator was used. Expression levels of Sesn2, p-AMPK, PGC-1alpha, NRF-1, TFAM, SOD2, and UCP2 were significantly increased following cerebral I/R. However, upregulation of these proteins was prevented by Sesn2 small interfering RNA (siRNA). In contrast, activation of AMPK with 5'-aminoimidazole-4-carboxamide riboside weakened the effects of Sesn2 siRNA. These results suggest that Sesn2 silencing may suppress mitochondrial biogenesis, reduce mitochondrial biological activity, and finally aggravate cerebral I/R injury through inhibiting the AMPK/PGC-1alpha pathway. PMID- 27453550 TI - Sjogren's syndrome presenting with isolated sensory axonal polyneuropathy. PMID- 27453551 TI - Functional Characterisation of Eel Dopamine D2 Receptors and Involvement in the Direct Inhibition of Pituitary Gonadotrophins. AB - In various vertebrate species, dopamine (DA) exerts an inhibitory action on reproduction. In the European eel, DA plays a pivotal role in the inhibitory control of gonadotroph function and the blockade of puberty. In vivo studies have suggested that this effect is mediated by receptors pharmacologically related to the D2 family. In the European eel, two distinct D2 receptor (D2-R) paralogous genes have been identified (D2A-R and D2B-R) and both were shown to be expressed in the pituitary. We investigated the potential role of each paralogue in the control of gonadotroph function in this species. Eel recombinant D2A-R or D2B-R were expressed in HEK 293 cells, with a universal Galpha subunit, and receptor activation was followed by inositol phosphate production. Recombinant D2-Rs exhibited a comparable affinity for DA, although they had differential affinities for mammalian D2-R agonists and antagonists, supporting subtle structure/activity differences. Furthermore, using eel pituitary cell primary cultures, the expression by gonadotroph cells of both native eel D2-R paralogues was examined by in situ hybridisation of D2A-R or D2B-R transcripts, coupled with immunofluorescence of luteinising hormone (LH)beta or follicle-stimulating (FSH)beta. LH and to a lesser extent, FSH cells expressed both D2-R transcripts but with a clear predominance of D2B-R. Notably, D2B-R transcripts were detected for the majority of LH cells. Accordingly, using these cultures, we showed that DA potently inhibited basal and testosterone-stimulated LHbeta expression and less potently basal and activin-stimulated FSHbeta expression. We also tested some D2-R antagonists, aiming to select the most adequate one to be used in innovative protocols for induction of eel sexual maturation. We identified eticlopride as the most potent inhibitor of DA action on basal and stimulated LH expression in vitro. Our data suggest a differential functionalisation of the duplicated receptor genes and demonstrate that mainly D2B-R is involved in the dopaminergic inhibitory control of eel gonadotroph function. PMID- 27453552 TI - Changes in PYY and gastric emptying across the phases of the menstrual cycle and the influence of the ovarian hormones. AB - Nutrition-related studies avoid the participation of pre-menopausal women due to the potential effect of the menstrual cycle (MC) on their appetite regulation. It is generally accepted that women increase their energy intake during the luteal phase (LPh) compared to the follicular (FPh), however what happens in the menstrual phase (MPh) and how this might be regulated remains uncertain. Although some research indicates changes in the gastric emptying (GE) velocity, whether PYY is affected by the MC phase, remains unknown. The aim of this study was to assess whether eating the same breakfast in each of the three MC phases would change the GE time, the PYY response and post-prandial satiety such that they might affect subsequent food intake. Furthermore, the aim was to associate any potential differences to the fluctuations in estradiol (E2) and progesterone (P4) within a MC. Nine naturally cycling women attended to the laboratory to consume a standardised breakfast on three occasions, each of them representing one of the MC phases. Breath samples to measure GE time, plasma samples to quantify PYY levels and hunger scores were collected for a total of 4 h after which food intake was assessed by an ad-libitum buffet lunch. GE and PYY levels changed significantly across the phases of the MC (p < 0.05). GE was correlated to P4 and E2-P4 ratio (r = -0.5 and 0.4, respectively). To conclude, the appetite regulators PYY and GE time change depending upon the MC phases with GE time associated with the ovarian hormone levels which suggests the necessity of controlling the MC phase in studies looking at the appetite response. PMID- 27453553 TI - Reported appetite, taste and smell changes following Roux-en-Y gastric bypass and sleeve gastrectomy: Effect of gender, type 2 diabetes and relationship to post operative weight loss. AB - Reduced energy intake drives weight loss following Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) procedures. Post-operative changes in subjective appetite, taste, and smell and food preferences are reported and suggested to contribute to reduced energy intake. We aimed to investigate the prevalence of these changes following RYGB and SG and to evaluate their relationship with weight loss. 98 patients post-RYGB and 155 post-SG from a single bariatric centre were recruited to a cross-sectional study. Participants completed a questionnaire, previously utilised in post-operative bariatric patients, to assess the prevalence of post-operative food aversions and subjective changes in appetite, taste and smell. Anthropometric data were collected and percentage weight loss (%WL) was calculated. The relationship between food aversions, changes in appetite, taste and smell and %WL was assessed. The influence of time post-surgery, gender and type 2 diabetes (T2D) were evaluated. Following RYGB and SG the majority of patients reported food aversions (RYGB = 62%, SG = 59%), appetite changes (RYGB = 91%, SG = 91%) and taste changes (RYGB = 64%, SG = 59%). Smell changes were more common post-RYGB than post-SG (RYGB = 41%, SG = 28%, p = 0.039). No temporal effect was observed post-RYGB. In contrast, the prevalence of appetite changes decreased significantly with time following SG. Post-operative appetite changes associated with and predicted higher %WL post-SG but not post-RYGB. Taste changes associated with and predicted higher %WL following RYGB but not post-SG. There was no gender effect post-RYGB. Post-SG taste changes were less common in males (female = 65%, males = 40%, p = 0.008). T2D status in females did not influence post-operative subjective changes. However, in males with T2D, taste changes were less common post-SG than post-RYGB together with lower %WL (RYGB = 27.5 +/- 2.7, SG = 14.6 +/ 2.1, p = 0.003). Further research is warranted to define the biology underlying these differences and to individualise treatments. PMID- 27453554 TI - The impact of caffeine use across the lifespan on cognitive performance in elderly women. AB - Habitual caffeine consumption has often been associated with decreasing age related cognitive decline. However, whether habitual caffeine use preferentially spares different cognitive processes is unclear. Furthermore, whether basing habitual caffeine consumption patterns on current consumption or on a lifetime measure better represents an individual's use remains unclear. In the present study, we collected information from women, aged 56-83, about their current caffeine consumption patterns and history of use, including age they began consuming caffeine. Regression models assessed the relationship between caffeine consumption and performance on batteries designed to probe speed of processing, inhibition, memory, and executive function. While we found no direct associations between caffeine exposure and cognitive performance, we found that caffeine consumption and participant BMI interacted for inhibitory function and speed of processing performance. We discuss possible protective effects of long term caffeine use as well as the possibility of dose dependent effects. PMID- 27453556 TI - Reintervention after endovascular repair for aortic dissection: A systematic review and meta-analysis. AB - OBJECTIVES: Thoracic endovascular aortic repair has been chosen as a less invasive alternative to open surgery for the treatment of aortic dissections; however, the advantages have been challenged by the postoperative reintervention during the follow-up period. This study aimed at evaluating the incidence, reasons, and potential risk factors for reintervention. METHODS: Studies reporting reintervention after endovascular repair were identified by searching PubMed and Embase in accordance with preferred reporting items for systematic reviews and meta-analyses guidelines, and by reviewing the reference lists of retrieved articles. Sensitivity analysis and subgroup analyses were performed to determine the sources of heterogeneity. Funnel plot and Egger's test were used to determine the publication bias. RESULTS: A total of 27 studies encompassing 2403 patients with aortic dissection were identified. The pooled incidence of reintervention after endovascular repair was 15% (95% confidence interval, 12-19) during 33.7 months of follow-up. The 3 most common reasons for reintervention were endoleak (33.2%), false lumen perfusion and aortic dilation (19.8%), and new dissection (6.9%). The potential factors for reintervention were the mean age of onset and diabetes mellitus determined by performing a single meta-regression analysis (P < .001 and .044, respectively). CONCLUSIONS: Current data suggest that the incidence of reintervention after endovascular therapy is relatively high during midterm follow-up. Advanced age of onset is a risk factor and diabetes mellitus is a protective factor of reintervention after endovascular therapy. The possible mechanism that diabetes mellitus protects patients from reintervention should be explored further. PMID- 27453555 TI - Key Residues for Catalytic Function and Metal Coordination in a Carotenoid Cleavage Dioxygenase. AB - Carotenoid cleavage dioxygenases (CCDs) are non-heme iron-containing enzymes found in all domains of life that generate biologically important apocarotenoids. Prior studies have revealed a critical role for a conserved 4-His motif in forming the CCD iron center. By contrast, the roles of other active site residues in catalytic function, including maintenance of the stringent regio- and stereo selective cleavage activity, typically exhibited by these enzymes have not been thoroughly investigated. Here, we examined the functional and structural importance of active site residues in an apocarotenoid-cleaving oxygenase (ACO) from Synechocystis Most active site substitutions variably lowered maximal catalytic activity without markedly affecting the Km value for the all-trans-8' apocarotenol substrate. Native C15-C15' cleavage activity was retained in all ACO variants examined suggesting that multiple active site residues contribute to the enzyme's regioselectivity. Crystallographic analysis of a nearly inactive W149A substituted ACO revealed marked disruption of the active site structure, including loss of iron coordination by His-238 apparently from an altered conformation of the conserved second sphere Glu-150 residue. Gln- and Asp-150 substituted versions of ACO further confirmed the structural/functional requirement for a Glu side chain at this position, which is homologous to Glu-148 in RPE65, a site in which substitution to Asp has been associated with loss of enzymatic function in Leber congenital amaurosis. The novel links shown here between ACO active site structure and catalytic activity could be broadly applicable to other CCD members and provide insights into the molecular pathogenesis of vision loss associated with an RPE65 point mutation. PMID- 27453557 TI - Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery? AB - BACKGROUND: Preoperative anemia and transfusion are associated with increased morbidity and mortality in cardiac surgery patients. It is unclear which of these factors plays the leading role in poor outcomes after cardiac surgery. The goal of this study was to analyze the influence of anemias of varying severity and intraoperative transfusion on long-term survival, and to characterize their interaction in cardiac surgery patients. METHODS: This was an observational cohort study conducted at a German university hospital. All patients undergoing cardiac surgery between 2006 and 2011 were screened for eligibility; duration of follow-up was 3 years. A total of 4494 patients were suitable for analysis; data on long-term survival were available for 3131 of these patients. The main outcome measure was survival at the 3-year follow-up. Length of stay and in-hospital mortality were assessed as secondary outcomes. RESULTS: Multivariate Cox regression analyses indicated that both the severity of preoperative anemia (mild anemia: hazard ratio [HR], 1.441; 95% confidence interval [CI], 1.201-1.728; severe anemia: HR, 1.805; 95% CI, 1.336-2.440) and intraoperative transfusion (HR, 1.340; 95% CI, 1.109-1.620) were associated with decreased long-term survival. Long-term survival was worse in anemic patients who received an intraoperative transfusion compared with those who did not receive an intraoperative transfusion. CONCLUSIONS: Both preoperative anemia and transfusion are by themselves and in combination associated with decreased long-term survival. When anemic patients require transfusion, our results provide evidence that the risk of death after cardiac surgery may depend to a considerable extent on the severity of preoperative anemia. PMID- 27453558 TI - Cardiorespiratory activity of C-terminal pentapeptide of substance P in anaesthetized rats. AB - Experiments were performed in anaesthetized, spontaneously breathing rats to: (1) analyse the respiratory and cardiovascular effects of C-terminal fragment of substance P (AWL2077) as referred to those exerted by the parent undecapeptide, (2) determine the involvement of lung vagal afferents to these responses. Each peptide was injected intravenously at a dose of 0.3MUmol/kg into neurally intact or midcervically vagotomized rats. Administration of both compounds decreased tidal volume, minute ventilation, mean arterial blood pressure and heart rate, showing stimulatory (SP) and depressive (AWL2077) effects on the rate of breathing. Midcervical vagotomy reversed (post-SP) and precluded (post-AWL2077) respiratory rate responses and eliminated bradycardia evoked by both peptides. These findings indicate that the examined C-terminal pentapeptide was convergent with, but less potent than substance P in central depression of tidal volume and displayed divergence in the peripheral effect on respiratory timing. PMID- 27453559 TI - The effect of consistent practice of yogic breathing exercises on the human cardiorespiratory system. AB - The purpose of this investigation was to quantify the cardiovascular, respiratory, and cerebrovascular effects of two common yogic breathing exercises (YBE): bhastrika and chaturbhuj; and to determine the effect of their consistent practice on chemosensitivity. The first study was cross-sectional and compared experienced yogic breathers (YB) with matched controls; whereas the second was a 10-week longitudinal training study. The results support four major findings. First chaturbhuj resulted in a hypoxic stimulus in experienced YB compared to control [end-tidal oxygen tension (PETO2), YB: 77.5+/-5.7mmHg, P<0.05; control: 94.3+/-12.0mmHg]. Second, performance of chaturbhuj resulted in cyclic oscillations of mean arterial pressure (MAP), heart rate (HR), and middle cerebral artery velocity (MCAv) consistent with the phases of respiration. Third, post training, performance of bhastrika reduced PETO2 (end breath-hold: 90.8 8+/ 12.1mmHg) compared to rest (100.1+/-7.4, P<0.05); it also resulted in significantly increased MAP at end breath-hold (96.7+/-13.0mmHg) compared to rest (83.0+/-6.6mmHg, P<0.05) and significantly increased mean MCAv (end breath-hold: 87.4+/-23.0cm/s, P<0.05; rest: 55.8+/-26.3cm/s). Fourth, experienced YB had lower central chemosensitivity than controls (YB: 3.4+/-0.4; control: 4.6+/ 1.2L/min/mmHg; P<0.05). In conclusion, YBE significantly alter end-tidal gases, resulting in complex oscillations of cardiovascular and cerebrovascular variables, and if practiced consistently, may reduce chemosensitivity. PMID- 27453560 TI - Intrinsic quality of goat oocytes already found denuded at collection for in vitro embryo production. AB - Although cumulus cells are essential for efficient oocyte maturation, the establishment of protocols that support IVD of embryos obtained from denuded oocytes (DOCs) is important for optimizing the use of reproductive biotechnologies. Thus, this study aimed to establish a protocol for IVD of goat DOC using different strategies of IVM and methods of oocyte activation. Four experiments were performed. Similar developmental competence of slaughterhouse DOC was obtained, regardless of maturation media (complex, semidefined or simplified). However, the ability to reach the blastocyst stage was affected by the activation method. Denuded oocytes subjected to parthenogenetic activation had greater (P < 0.05) development capacity, compared with those undergoing IVF with average cleavage rate of 83% and 75%, blastocyst rate of 49% and 28%, and blastocysts in relation to the cleaved embryos of 59% and 38, respectively. In addition, the quality of embryos evaluated after vitrification/warming was similar between parthenogenetic activation and IVF. Finally, we demonstrated that the coculture of cumulus-oocyte complex (COC) with DOC increased the competence of DOC at a ratio of 1:1 and 1:9 (DOC:COC). We believe that presence of cumulus cells (CCs) is not essential to the meiotic maturation, if at the time of removal of the oocyte from follicular environment, they already acquired competence to development. However, when the oocytes still need to acquire competence, the presence of CC may significantly contribute in their developmental capacity acquisition during IVM. Thus, regardless of the source, these oocytes will require longer time in IVM, contrary to what happens in the absence of CC. In conclusion, although DOC had a lower developmental potential, especially after IVF, they were able to produce blastocysts and the coculture of DOC with COC increased this developmental capacity. PMID- 27453561 TI - Metastatic mineralization in blacktip reef sharks, Carcharhinus melanopterus (Quoy & Gaimard 1824). PMID- 27453563 TI - The Anhydrobiotic Potential of the Terrestrial Nematodes Plectus parietinus and Plectus velox. AB - Within the taxon Nematoda, many species possess an anhydrobiotic potential similar to other microscopic animals, such as tardigrades and rotifers. This interesting capability enables them to survive conditions even of extreme dehydration. We examined the anhydrobiotic abilities of the two widespread terrestrial nematode species, Plectus parietinus and P. velox, by subjecting adult and juvenile life stages of both species to two different desiccation regimes, one with a short time of adaption (2 hr) and the other with a long time of adaption (48 hr) prior to complete desiccation and recorded the nematodes' recovery after 24 hr of rehydration. We found adults of P. parietinus to be the superior anhydrobiotes compared to adults of P. velox at short times of adaption, whereas at a long time of adaption this pattern was reversed. Moreover, our results showed that a long time of adaption significantly increased the recovery rate, independent of species or life stage. Additionally, we found adults to have a remarkable higher anhydrobiotic potential than juveniles, presumably due to a larger amount of resources in adult nematodes or due to a different morphology (cuticle, surface area to volume ratio). Plectus parietinus as well as P. velox showed a distinct anhydrobiotic potential although there were obvious differences between those two species, probably ascribable to different species-specific anhydrobiotic mechanisms and rates of water loss. PMID- 27453562 TI - Alterations in biochemical markers due to mercury (Hg) exposure and its influence on infant's neurodevelopment. AB - This study examined the role of oxidative stress due to mercury (Hg) exposure on infant's neurodevelopmental performance. A total of 944 healthy Saudi mothers and their respective infants (aged 3-12 months) were recruited from 57 Primary Health Care Centers in Riyadh City. Total mercury (Hg) was measured in mothers and infants urine and hair samples, as well as mother's blood and breast milk. Methylmercury (MeHg) was determined in the mothers and infants' hair and mother's blood. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and porphyrins were used to assess oxidative stress. The infant's neurodevelopment was evaluated using Denver Developmental Screening Test II (DDST-II) and Parents' Evaluation of Developmental Status. The median total Hg levels in mother's urine, infant's urine, mother's hair, infant's hair, and mother's blood and breast milk were 0.995MUg/l, 0.716MUg/l, 0.118MUg/g dw, 0.101MUg/g dw, 0.635MUg/l, and 0.884MUg/l respectively. The median MeHg levels in mother's hair, infant's hair, and mother's blood were 0.132MUg/g dw, 0.091MUg/g dw, and 2.341MUg/l respectively. A significant interrelationship between mothers and infants Hg measures in various matrices was noted. This suggests that mother's exposure to different forms of Hg (total and/or MeHg) from various sources contributed significantly to the metal body burden of their respective infants. Even though Hg exposure was low, it induced high oxidative stress in mothers and infants. The influence of multiplicative interaction terms between Hg measures and oxidative stress biomarkers was tested using multiple regression analysis. Significant interactions between the urinary Hg levels in mothers and infants and oxidative stress biomarkers (8-OHdG and MDA) were noted. The MeHg levels in mother-infant hair revealed similar interaction patterns. The p-values for both were below 0.001. These observations suggest that the exposure of our infants to Hg via mothers either during pregnancy and/or neonatal life, promoted oxidative stress that might have played a role in infant neurodevelopmental delays that we reported previously. The results confirmed that the interaction between infant's MeHg in hair and 8-OHdG and MDA levels was significantly associated with a delay in DDST-II performance (beta=-0.188, p=0.028). This finding provides an insight into the potential consequences of Hg-induced oxidative stress to infant's cognitive neurodevelopment for the first time. This observation still needs future studies to be validated. Given the low MeHg levels in our population, these findings are of particular importance. PMID- 27453564 TI - Surface heterogeneity: a friend or foe of protein adsorption - insights from theoretical simulations. AB - A lack in the detailed understanding of mechanisms through which proteins adsorb or are repelled at various solid/liquid interfaces limits the capacity to rationally design and produce more sophisticated surfaces with controlled protein adsorption in both biomedical and industrial settings. To date there are three main approaches to achieve anti biofouling efficacy, namely chemically adjusting the surface hydrophobicity and introducing various degrees of surface roughness, or a combination of both. More recently, surface nanostructuring has been shown to have an effect on protein adsorption. However, the current resolution of experimental techniques makes it difficult to investigate these three phase systems at the molecular level. In this molecular dynamics study we explore in all-atom detail the adsorption process of one of the most surface active proteins, EAS hydrophobin, known for its versatile ability to self-assemble on both hydrophobic and hydrophilic surfaces forming stable monolayers that facilitate further biofilm growth. We model the adsorption of this protein on organic ligand protected silica surfaces with varying degrees of chemical heterogeneity and roughness, including fully homogenous hydrophobic and hydrophilic surfaces for comparison. We present a detailed characterisation of the functionalised surface structure and dynamics for each of these systems, and the effect the ligands have on interfacial water, the adsorption process and conformational rearrangements of the protein. Results suggest that the ligand arrangement that produces the highest hydrophilic chain mobility and the lack of significant hydrophobic patches shows the most promising anti-fouling efficacy toward hydrophobin. However, the presence on the protein surface of a flexible loop with amphipathic character (the Cys3-Cys4 loop) is seen to facilitate EAS adsorption on all surfaces by enabling the protein to match the surface pattern. PMID- 27453565 TI - Functional brain imaging of episodic memory decline in ageing. AB - The episodic long-term memory system supports remembering of events. It is considered to be the most age-sensitive system, with an average onset of decline around 60 years of age. However, there is marked interindividual variability, such that some individuals show faster than average change and others show no or very little change. This variability may be related to the risk of developing dementia, with elevated risk for individuals with accelerated episodic memory decline. Brain imaging with functional magnetic resonance imaging (MRI) of blood oxygen level-dependent (BOLD) signalling or positron emission tomography (PET) has been used to reveal the brain bases of declining episodic memory in ageing. Several studies have demonstrated a link between age-related episodic memory decline and the hippocampus during active mnemonic processing, which is further supported by studies of hippocampal functional connectivity in the resting state. The hippocampus interacts with anterior and posterior neocortical regions to support episodic memory, and alterations in hippocampus-neocortex connectivity have been shown to contribute to impaired episodic memory. Multimodal MRI studies and more recently hybrid MRI/PET studies allow consideration of various factors that can influence the association between the hippocampal BOLD signal and memory performance. These include neurovascular factors, grey and white matter structural alterations, dopaminergic neurotransmission, amyloid-Beta and glucose metabolism. Knowledge about the brain bases of episodic memory decline can guide interventions to strengthen memory in older adults, particularly in those with an elevated risk of developing dementia, with promising results for combinations of cognitive and physical stimulation. PMID- 27453566 TI - A functional comparison of cardiac troponin C from representatives of three vertebrate taxa: Linking phylogeny and protein function. AB - The Ca2+ affinity of cardiac troponin C (cTnC) from rainbow trout is significantly greater than that of cTnC from mammalian species. This high affinity is thought to enable cardiac function in trout at low physiological temperatures and is due to residues Asn2, Ile28, Gln29, and Asp30 (Gillis et al., 2005, Physiol Genomics, 22, 1-7). Interestingly, the cTnC of the African clawed frog Xenopus laevis (frog cTnC) contains Gln29 and Asp30 but the residues at positions 2 and 28 are those found in all mammalian cTnC isoforms (Asp2 and Val28). The purpose of this study was to determine the Ca2+ affinity of frog cTnC, and to determine how these three protein orthologs influence the function of complete troponin complexes. Measurements of Ca2+ affinity and the rate of Ca2+ dissociation from the cTnC isoforms and cTn complexes were made by monitoring the fluorescence of anilinonapthalenesulfote iodoacetamide (IAANS) engineered into the cTnC isoforms to report changes in protein conformation. The results demonstrate that the Ca2+ affinity of frog cTnC is greater than that of trout cTnC and human cTnC. We also found that replacing human cTnC with frog cTnC in a mammalian cTn complex increased the Ca2+ affinity of the complex by 5-fold, which is also greater than complexes containing trout cTnC. Together these results suggest that frog cTnC has the potential to increase the Ca2+ sensitivity of force generation by the mammalian heart. PMID- 27453567 TI - Extracellular synthesis of cuprous selenide nanospheres by a biological-chemical coupling reduction process in an anaerobic microbial system. AB - Biosynthesis of metal nanoparticles represents a clean, eco-friendly and sustainable "green chemistry" engineering. Lately, a number of metal selenides were successfully synthesized by biological methods. Here, cuprous selenide (Cu2 Se) nanospheres were prepared under mild conditions by a novel biological chemical coupling reduction process. The simple process takes place between EDTA Cu and Na2 SeO3 in presence of an alkaline solution containing NaBH4 and a selenite-reducing bacteria, Pantoea agglomerans. It is noteworthy that the isolated Pantoea agglomerans and Cu+ ions, where the latter are obtained from reducing Cu2+ ions by NaBH4 , play a key role, and Cu+ ions not only can promote the generation of Se2- ions as a catalyst, but also can react with Se2- ions to form Cu2 Se. XRD pattern, SEM, and TEM images indicated that Cu2 Se nanoparticles were tetragonal crystal structure and the nanospheres diameter were about 100 nm. EDX, UV-vis, and FTIR spectra show that the biosynthesized Cu2 Se nanospheres are wrapped by protein and have a better stability. This work first proposes a new biosynthesis mechanism, and has important reference value for biological preparation of metal selenide nanomaterials. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1264-1270, 2016. PMID- 27453568 TI - Two-dimensional assemblies of nematic colloids in homeotropic cells and their response to electric fields. AB - Micrometer-sized colloidal particles dispersed in nematic liquid crystals interact with each other through anisotropic interactions induced by orientational deformation of the nematic field. In the case of so-called dipole nematic colloids, their interaction is of the dipole-dipole type. Two dimensional, non-close-packed colloidal assemblies having various characteristics were fabricated using optical tweezers by exploiting the attraction between anti parallel dipole nematic colloids in homeotropically aligned nematic cells. Structures comprising polygons, squares, and tetrahedra were built using equal sized particles, and hexagonal structures were built using particles of two sizes. As the nematic field is sensitive to electric fields, the response of the fabricated assemblies toward an alternating electric field was also studied. All assemblies exhibited homogeneous reversible shrinkage, and their shrinkage rates were dependent on the structure. The maximum shrinkage rate in the linear dimension of the assemblies was over 20% at 5 Vrms for a hexagon comprising tetrahedral units. PMID- 27453569 TI - Identification and Structural Analysis of New Nrf2 Activators by Mechanism-Based Chemical Transformation of 15-Deoxy-Delta12, 14 -PGJ2. AB - Mechanism-based chemical transformation of 15-deoxy-Delta12, 14 -PGJ2 (15d-PGJ2 ) resulted in a series of new NF-E2-related factor-2 (Nrf2) activators and detailed elucidation of the function of each electrophilic binding site. In addition, HO-1 expression resulting from Nrf2 activation through enhanced dissociation of the Keap1-Nrf2 complex by the new activators was proved. PMID- 27453570 TI - Electronic communication based interventions for hazardous young drinkers: A systematic review. AB - Previous reviews have specifically looked at computer-based or Internet-based approaches. However, there has been no systematic review focused upon electronic communication based interventions for hazardous young drinkers. Out of 3298 relevant citations, 13 papers consisting of 11 studies met the inclusion criteria. Effectiveness of intervention delivery was assessed using behavioural outcomes. Eight papers delivered interventions using the Web, three implemented text messaging, one used a mobile phone app and the remaining paper used a social networking site. The ability to provide personalized electronic feedback resulted in a reduction in alcohol consumption, frequency of binge drinking, and drinking in a non-risky way. However, intervention length did not appear to have an impact on overall effectiveness. Usage of text messaging and Social Network Sites (SNS) increased accessibility and ease of engaging in an intervention that is appealing and acceptable for young adults. PMID- 27453571 TI - Response to the letter "More data along with further definitions are required" by Sahin et al. PMID- 27453572 TI - Over-treatment in metastatic breast cancer. AB - Metastatic breast cancer is an incurable disease and the main goals of treatment are prolongation of survival and preservation/improvement of quality of life. Thus the main philosophy of treatment should be to use the least toxic methods, as long as they provide sufficient disease control. In ER-positive tumours this can be in many cases achieved by endocrine therapy; in HER2-positive cancers efficacy of backbone therapy can be enhanced by an anti-HER2 agent. In patients requiring chemotherapy, consecutive single agent regimen provide disease control of a duration at least comparable to multidrug regimen, at a cost of significantly lower toxicity and are a preferred strategy in the majority of cases. Available data demonstrate, however, that aggressive chemotherapy is still overused in many metastatic breast cancer patients. The objective of this manuscript is to critically review available data on treatment choices and sequence in metastatic breast cancer across all breast cancer subtypes in relation to possible overtreatment, including therapies which are not recommended by current guidelines or not even approved. Our aim is to provide guidance on applying these data to clinical practice, but also to describe various, often non scientific factors influencing therapeutic decisions in an aim to identify areas requiring educational and possibly political actions. PMID- 27453573 TI - Rational engineering of nanoporous anodic alumina optical bandpass filters. AB - Herein, we present a rationally designed advanced nanofabrication approach aiming at producing a new type of optical bandpass filters based on nanoporous anodic alumina photonic crystals. The photonic stop band of nanoporous anodic alumina (NAA) is engineered in depth by means of a pseudo-stepwise pulse anodisation (PSPA) approach consisting of pseudo-stepwise asymmetric current density pulses. This nanofabrication method makes it possible to tune the transmission bands of NAA at specific wavelengths and bandwidths, which can be broadly modified across the UV-visible-NIR spectrum through the anodisation period (i.e. time between consecutive pulses). First, we establish the effect of the anodisation period as a means of tuning the position and width of the transmission bands of NAA across the UV-visible-NIR spectrum. To this end, a set of nanoporous anodic alumina bandpass filters (NAA-BPFs) are produced with different anodisation periods, ranging from 500 to 1200 s, and their optical properties (i.e. characteristic transmission bands and interferometric colours) are systematically assessed. Then, we demonstrate that the rational combination of stacked NAA-BPFs consisting of layers of NAA produced with different PSPA periods can be readily used to create a set of unique and highly selective optical bandpass filters with characteristic transmission bands, the position, width and number of which can be precisely engineered by this rational anodisation approach. Finally, as a proof of-concept, we demonstrate that the superposition of stacked NAA-BPFs produced with slight modifications of the anodisation period enables the fabrication of NAA-BPFs with unprecedented broad transmission bands across the UV-visible-NIR spectrum. The results obtained from our study constitute the first comprehensive rationale towards advanced NAA-BPFs with fully controllable photonic properties. These photonic crystal structures could become a promising alternative to traditional optical bandpass filters based on glass and plastic. PMID- 27453574 TI - Allowing pseudoscience into EU risk assessment processes is eroding public trust in science experts and in science as a whole: The bigger picture. PMID- 27453575 TI - Integrative Functional Genomics Implicates EPB41 Dysregulation in Hepatocellular Carcinoma Risk. AB - Genome-wide association studies (GWASs) have provided many insights into cancer genetics. However, the molecular mechanisms of many susceptibility SNPs defined by GWASs in cancer heritability and in promoting cancer risk remain elusive. New research strategies, including functional evaluations, are warranted to systematically explore truly causal genetic variants. In this study, we developed an integrative functional genomics methodology to identify cancer susceptibility SNPs in transcription factor-binding sites across the whole genome. Employing integration of functional genomic data from c-Myc cistromics, 1000 Genomes, and the TRANSFAC matrix, we successfully annotated 12 SNPs present in the c-Myc cistrome with properties consistent with modulating c-Myc binding affinity in hepatocellular carcinoma (HCC). After genotyping these 12 SNPs in 1,806 HBV related HCC case subjects and 1,708 control subjects, we identified a HCC susceptibility SNP, rs157224G>T, in Chinese populations (T allele: odds ratio = 1.64, 95% confidence interval = 1.32-2.02; p = 5.2 * 10(-6)). This polymorphism leads to HCC predisposition through modifying c-Myc-mediated transcriptional regulation of EPB41, with the risk rs157224T allele showing significantly decreased gene expression. Based on cell proliferation, wound healing, and transwell assays as well as the mouse xenograft model, we identify EPB41 as a HCC susceptibility gene in vitro and in vivo. Consistent with this notion, we note that EPB41 expression is significantly decreased in HCC tissue specimens, especially in portal vein metastasis or intrahepatic metastasis, compared to normal tissues. Our results highlight the involvement of regulatory genetic variants in HCC and provide pathogenic insights of this malignancy via a genome wide approach. PMID- 27453576 TI - BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. AB - Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes. PMID- 27453577 TI - Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy. AB - Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease. PMID- 27453578 TI - Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. AB - Cell division terminates with cytokinesis and cellular separation. Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly. PMID- 27453580 TI - An angle-supported foldable phakic intraocular lens for correction of myopia: A five-year follow-up. AB - OBJECTIVE: To evaluate the efficacy and safety of an angle-supported foldable phakic intraocular lens (pIOL) for the correction of moderate to high myopia after 5 years follow-up. METHODS: Prospective and retrospective, observational, longitudinal, non-randomised consecutive series of cases conducted on a total of 100 eyes of 67 patients with moderate to high myopia implanted with an Acrysof Cachet pIOL (Alcon Laboratories Inc.) with the aim of minimising the refractive error. The ages ranged between 18 to 60years. Uncorrected distance visual acuity (UDVA), manifest refraction, corrected distance visual acuity (CDVA), endothelial cells density, pIOL position, intraocular pressure, and complications were recorded preoperatively and during the 5 year follow-up. RESULTS: Five years after implantation, the mean manifest spherical equivalent refraction reduced significantly from -11.62+/-3.35 dioptres (D) to -0.33+/-0.85D. UDVA was 20/20 or better in 5 of 25 cases (20%), and 20/40 or better in 22 cases (88%). CDVA was 20/20 or better in 17 cases (68%), and 20/32 or better in 23 cases (92%) of eyes. The residual refractive error was within +/-0.50D of emmetropia in 12 cases (48%), and within +/-1.00D in 19 cases (76%). Mean endothelial cell loss at 5 years was 11.8% central, and 13.7% peripheral. Mean endothelium-pIOL distance was 2.11+/-0.18mm, and mean pIOL-crystalline distance was 0.88+/-0.20mm. CONCLUSIONS: This angle supported pIOL provided a favourable refractive correction and predictability, as well as acceptable safety in patients with moderate to high myopia. Although endothelial cell density decreased over 5years, the results are within the range reported in previous studies with other pIOLs. PMID- 27453579 TI - Mutations in Citron Kinase Cause Recessive Microlissencephaly with Multinucleated Neurons. AB - Primary microcephaly is a neurodevelopmental disorder that is caused by a reduction in brain size as a result of defects in the proliferation of neural progenitor cells during development. Mutations in genes encoding proteins that localize to the mitotic spindle and centrosomes have been implicated in the pathogenicity of primary microcephaly. In contrast, the contractile ring and midbody required for cytokinesis, the final stage of mitosis, have not previously been implicated by human genetics in the molecular mechanisms of this phenotype. Citron kinase (CIT) is a multi-domain protein that localizes to the cleavage furrow and midbody of mitotic cells, where it is required for the completion of cytokinesis. Rodent models of Cit deficiency highlighted the role of this gene in neurogenesis and microcephaly over a decade ago. Here, we identify recessively inherited pathogenic variants in CIT as the genetic basis of severe microcephaly and neonatal death. We present postmortem data showing that CIT is critical to building a normally sized human brain. Consistent with cytokinesis defects attributed to CIT, multinucleated neurons were observed throughout the cerebral cortex and cerebellum of an affected proband, expanding our understanding of mechanisms attributed to primary microcephaly. PMID- 27453582 TI - Why don't present-biased agents make commitments? PMID- 27453581 TI - Consistency and factorial invariance of the Davidson trauma scale in heterogeneous populations: results from the 2010 Chilean earthquake. AB - This investigation seeks to validate an application of a standardized post traumatic stress symptom self-report survey, the Davidson Trauma Scale (DTS), with a large, heterogeneous population of earthquake victims. While previous studies have focused primarily on small samples, this investigation uses a unique dataset to assess the validity of this application of the DTS while accounting for heterogeneity and sample size. We use concurrent validity and reliability analysis tests to confirm the validity of the scale. Further, confirmatory factor analysis is used to test the fit of the data's factor structure against previously established trauma models. Finally, these fit tests are repeated across different mutually exclusive vulnerability subsets of the data in order to investigate how the invariance of the scale is affected by sample heterogeneity. We find that this particular application of the scale is, on the whole, reliable and valid, showing good concurrent validity. However, evidence of variability is found across specific vulnerability subsets, indicating that a heterogeneous sample can have a measurable impact on model fit. (c) 2016 The Authors International Journal of Methods in Psychiatric Research Published by John Wiley & Sons Ltd. PMID- 27453583 TI - Estimation of regression models for the mean of repeated outcomes under nonignorable nonmonotone nonresponse. AB - We propose a new class of models for making inference about the mean of a vector of repeated outcomes when the outcome vector is incompletely observed in some study units and missingness is nonmonotone. Each model in our class is indexed by a set of unidentified selection bias functions which quantify the residual association of the outcome at each occasion t and the probability that this outcome is missing after adjusting for variables observed prior to time t and for the past nonresponse pattern. In particular, selection bias functions equal to zero encode the investigator's a priori belief that nonresponse of the next outcome does not depend on that outcome after adjusting for the observed past. We call this assumption sequential explainability. Since each model in our class is nonparametric, it fits the data perfectly well. As such, our models are ideal for conducting sensitivity analyses aimed at evaluating the impact that different degrees of departure from sequential explainability have on inference about the marginal means of interest. Although the marginal means are identified under each of our models, their estimation is not feasible in practice because it requires the auxiliary estimation of conditional expectations and probabilities given high dimensional variables. We henceforth discuss estimation of the marginal means under each model in our class assuming, additionally, that at each occasion either one of following two models holds: a parametric model for the conditional probability of nonresponse given current outcomes and past recorded data, or a parametric model for the conditional mean of the outcome on the nonrespondents given the past recorded data. We call the resulting procedure 2 T -multiply robust as it protects at each of the T time points against misspecification of one of these two working models, although not against simultaneous misspecification of both. We extend our proposed class of models and estimators to incorporate data configurations which include baseline covariates and a parametric model for the conditional mean of the vector of repeated outcomes given the baseline covariates. PMID- 27453584 TI - Using bibliometrics to demonstrate the value of library journal collections. AB - Although cited reference studies are common in the library and information science literature, they are rarely performed in non-academic institutions or in the atmospheric and oceanic sciences. In this paper, we analyze over 400,000 cited references made by authors affiliated with the National Oceanic and Atmospheric Administration between 2009 and 2013. Our results suggest that these methods can be applied to research libraries in a variety of institutions, that the results of analyses performed at one institution may not be applicable to other institutions, and that cited reference analyses should be periodically updated to reflect changes in authors' referencing behavior. PMID- 27453585 TI - 2D and 3D Ultrasonographic Evaluation of Fetal Midface Hypoplasia in Two Cases with 3-M Syndrome. AB - This paper highlights the utility of 2D and 3D ultrasonography in the prenatal diagnosis of facial dysmorphisms suggestive of very rare syndromes such as 3-M syndrome. Two pregnant women at risk for fetal skeletal dysplasias were referred to our clinic for 2D/3D ultrasound scan in the second trimester of pregnancy. Only one of the patients had a familial history of 3-M syndrome. Karyotyping and genetic testing of abortion material were performed in both cases. 2D ultrasonography revealed growth retardation of the long bones in both cases. In the case without a familial history of the syndrome, 2D and 3D ultrasonography showed an absence of nasal bones and a flat malar region suggestive of 3-M syndrome, although the difficult differential diagnosis included other dysmorphic growth disorders with prenatal onset. The karyotype was normal but the pregnancy was terminated in both cases. Postmortem examination confirmed 3-M syndrome as indicated by prenatal findings. In high-risk cases with a familial history of 3-M syndrome, prenatal diagnosis of 3-M syndrome is possible by analyzing fetal DNA. In the absence of risk, a definitive prenatal diagnosis is often not possible but may be suspected in the presence of shortened long bones, normal head size and typical flattened malar region (midface hypoplasia) shown on complementary 2D and 3D sonograms. 2D and 3D ultrasonography has been shown to offer reliable information for the prenatal study of skeletal and facial anomalies and can be useful if there is a suspicion of 3-M syndrome in a pregnancy not known to be at risk. PMID- 27453586 TI - Twin Pregnancy with One Fetus and One Complete Mole - A Case Report. AB - Twin pregnancy consisting of one fetus and one complete mole (CMCF, complete hydatidiform mole and a coexistent fetus) is an obstetric rarity with an incidence of 1/22 000 to 1/100 000 pregnancies. Associated risks include prematurity, intrauterine death, vaginal bleeding, preeclampsia, hyperthyroidism, theca lutein cysts, uterine rupture and the development of malignant neoplasia in the form of a trophoblastic tumour (GTD, persistent gestational trophoblastic disease), which is thought to be the most common complication. We report the case of a 33-year-old patient diagnosed with CMCF in the 15th week of pregnancy. After comprehensive counselling the patient chose to proceed with her pregnancy under close observation and prophylactic fetal lung maturation. We were able to extend the pregnancy to 32 weeks gestation when heavy vaginal bleeding forced a decision to deliver by caesarean section. PMID- 27453587 TI - An Inexpensive, Open-Source USB Arduino Data Acquisition Device for Chemical Instrumentation. AB - Many research and teaching labs rely on USB data acquisition devices to collect voltage signals from instrumentation. However, these devices can be cost prohibitive (especially when large numbers are needed for teaching labs) and require software to be developed for operation. In this article, we describe the development and use of an open-source USB data acquisition device (with 16-bit acquisition resolution) built using simple electronic components and an Arduino Uno that costs under $50. Additionally, open-source software written in Python is included so that data can be acquired using nearly any PC or Mac computer with a simple USB connection. Use of the device was demonstrated for a sophomore-level analytical experiment using GC and a CE-UV separation on an instrument used for research purposes. PMID- 27453588 TI - Functionalized ferrocenes: The role of the para substituent on the phenoxy pendant group. AB - Six ferrocenecarboxylates with phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl as pendant groups were synthesized and fully characterized by spectroscopic, electrochemical and X-ray diffraction methods. The anti-proliferative activity of these complexes were investigated in hormone dependent MCF-7 breast cancer and MCF-10A normal breast cell lines, to determine the role of the para substituent on the phenoxy pendant group. The 4 fluorophenyl ferrocenecarboxylate is inactive in both cell lines while 4-(1H pyrrol-1-yl)phenyl ferrocenecarboxylate is highly cytotoxic in both cell lines. 4 chlorophenyl and 4-bromophenyl ferrocenecarboxylates have moderate to good anti proliferative activity in MCF-7 and low anti-proliferative activity on normal breast cell line, MCF-10A whereas the 4-iodophenyl analog is highly toxic on normal breast cell line. The phenyl ferrocenecarboxylate has proliferative effects on MCF-7 and is inactive in MCF-10A. Docking studies between the complexes and the alpha-estrogen receptor (ERalpha) were performed to search for key interactions which may explain the anti-proliferative activity of 4 bromophenyl ferrocenecarboxylate. Docking studies suggest the anti-proliferative activity of these ferrocenecarboxylates is attributed to the cytotoxic effects of the ferrocene group and not to anti-estrogenic effects. PMID- 27453589 TI - Variance Reduction Using Nonreversible Langevin Samplers. AB - A standard approach to computing expectations with respect to a given target measure is to introduce an overdamped Langevin equation which is reversible with respect to the target distribution, and to approximate the expectation by a time averaging estimator. As has been noted in recent papers [30, 37, 61, 72], introducing an appropriately chosen nonreversible component to the dynamics is beneficial, both in terms of reducing the asymptotic variance and of speeding up convergence to the target distribution. In this paper we present a detailed study of the dependence of the asymptotic variance on the deviation from reversibility. Our theoretical findings are supported by numerical simulations. PMID- 27453590 TI - A Message from the Editor. PMID- 27453591 TI - Reducing Exposure to Secondhand Smoke: Let's Keep the Momentum Going. PMID- 27453593 TI - Public Health 3.0: Applying the 2015-2020 Dietary Guidelines for Americans. PMID- 27453594 TI - The Evolution of Public Health-Hospital Collaboration in the United States. PMID- 27453595 TI - An Approach to Achieving the Health Equity Goals of the National HIV/AIDS Strategy for the United States Among Racial/Ethnic Minority Communities. PMID- 27453596 TI - Coccidioidomycosis-Associated Deaths in California, 2000-2013. AB - The number of cases of coccidioidomycosis and associated hospitalizations increased in California during 2000-2013. During that period, a total of 1,098 death records listed coccidioidomycosis as a cause, averaging 78 deaths annually (range: 43-108). The death rate peaked in 2006 and was significantly higher among males than among females, among African American patients than among white patients, and among residents of the coccidioidomycosis-endemic region of California than among residents of the less endemic regions (p<0.001). A higher death rate was associated with increasing age and was highest (8.8 per 1 million population) among adults aged >=75 years. Of coccidioidomycosis-associated deaths, 31.9% had a contributing cause of death of severe/disseminated disease, 31.8% of unspecified -coccidioidomycosis, and 28.3% of pulmonary unspecified coccidioidomycosis, per International Classification of Diseases codes. Diabetes was a contributing cause in 19.3% of deaths, and other immunocompromising conditions were a contributing cause in 15.9% of deaths. Populations at higher risk for coccidioidomycosis--associated deaths are similar to those at higher risk for coccidioidomycosis-associated hospitalizations and infection. Awareness for coccidioidomycosis among these groups and their providers is important for proper diagnosis and care. PMID- 27453597 TI - Estimating the Impact of Raising Prices and Eliminating Discounts on Cigarette Smoking Prevalence in the United States. AB - The average retail price per pack of cigarettes is less than $6, which is substantially lower than the $10 per-pack target established in 2014 by the Surgeon General to reduce the smoking rate. We estimated the impact of three cigarette pricing scenarios on smoking prevalence among teens aged 12-17 years, young adults aged 18-25 years, and adults aged >=26 years, by state: (1) $0.94 federal tax increase on cigarettes, as proposed in the fiscal year 2017 President's budget; (2) $10 per-pack retail price, allowing discounts; and (3) $10 per-pack retail price, eliminating discounts. We conducted Monte Carlo simulations to generate point estimates of reductions in cigarette smoking prevalence by state. We found that each price scenario would substantially reduce cigarette smoking prevalence. A $10 per-pack retail price eliminating discounts could result in 637,270 fewer smokers aged 12-17 years; 4,186,954 fewer smokers aged 18-25 years; and 7,722,460 fewer smokers aged >=26 years. Raising cigarette prices and eliminating discounts could substantially reduce cigarette smoking prevalence as well as smoking-related death and disease. PMID- 27453598 TI - Performance of Risk-Based and Birth-Cohort Strategies for Identifying Hepatitis C Virus Infection Among People Entering Prison, Wisconsin, 2014. AB - OBJECTIVES: The prevalence of hepatitis C virus (HCV) infection among young adults is rising in Wisconsin. We examined the prevalence of HCV infection among male and female inmates entering two Wisconsin prisons and evaluated existing and alternate risk-based strategies for identifying HCV infection at intake. METHODS: We added HCV testing to the intake procedures for all 1,239 adults prison entrants at the Wisconsin Department of Corrections (WDOC) from November 3, 2014, to January 31, 2015. We identified risk factors associated with HCV infection during the routine intake examination and calculated the sensitivity and specificity of risk-based testing strategies for identifying HCV infection. RESULTS: The prevalence of HCV antibody among prison entrants was 12.5% (95% confidence interval [CI] 10.7, 14.4) overall and was almost two times higher at the women's facility (21.3%, 95% CI 15.4, 27.2) than at the men's facility (11.0%, 95% CI 0.0, 12.9) (p<0.001). The sensitivity and specificity of the WDOC risk-based criteria were 88% (95% CI 83, 93) and 80% (95% CI 78, 83), respectively. Adding a new criterion, the 1945-1965 birth cohort, to the risk based criteria improved the sensitivity to 92% (95% CI 88, 96) and lowered the specificity to 71% (95% CI 68, 74). Compared with entrants without these risk factors, HCV antibody prevalence was significantly higher among prison entrants who had the following risk factors: injection drug use (prevalence ratio [PR] = 9.9, 95% CI 7.4, 13.2), liver disease (PR=9.7, 95% CI 7.8, 12.0), and elevated levels of alanine transaminase (PR=3.6, 95% CI 2.7, 4.9). CONCLUSION: The WDOC risk criteria for HCV testing identified 88% of HCV infections among prison entrants. Including the 1945-1965 birth cohort as a criterion along with the other WDOC risk criteria increased the sensitivity of targeted testing to 92%. These findings may be informative to jurisdictions where universal HCV testing is not feasible because of resource limitations. PMID- 27453599 TI - Tracing Airline Travelers for a Public Health Investigation: Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection in the United States, 2014. AB - OBJECTIVE: CDC routinely conducts contact investigations involving travelers on commercial conveyances, such as aircrafts, cargo vessels, and cruise ships. METHODS: The agency used established systems of communication and partnerships with other federal agencies to quickly provide accurate traveler contact information to states and jurisdictions to alert contacts of potential exposure to two travelers with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) who had entered the United States on commercial flights in April and May 2014. RESULTS: Applying the same process used to trace and notify travelers during routine investigations, such as those for tuberculosis or measles, CDC was able to notify most travelers of their potential exposure to MERS-CoV during the first few days of each investigation. CONCLUSION: To prevent the introduction and spread of newly emerging infectious diseases, travelers need to be located and contacted quickly. PMID- 27453600 TI - Assessment of Administrative Medical Claims Data for Public Health Surveillance of Invasive Group A Streptococcal Necrotizing Fasciitis in Tennessee. AB - OBJECTIVE: Necrotizing fasciitis (NF) is a severe manifestation of invasive group A streptococcal (iGAS) infection. NF is a rapidly progressive infection of the subcutaneous tissues, including the fascia, and accurate diagnosis and prompt treatment are critical. Population-based surveillance is conducted for iGAS, including the severe manifestations of NF, by the federally funded Active Bacterial Core surveillance (ABCs) program. METHODS: We used administrative claims data from a large managed care organization in Tennessee to enhance the public health surveillance for NF iGAS. For the period 2003-2012, we identified cases of NF in Tennessee by searching the claims database for diagnostic codes indicating the diagnosis of NF. We compared these cases with cases detected in selected Tennessee counties by ABCs. RESULTS: Of 356 managed care patients with a diagnostic code indicating NF, we determined that 20 (6%) patients had been hospitalized with iGAS infection and, therefore, were likely to be true NF cases. Of these 20 patients, only 11 matched with patients identified by ABCs; nine patients had not been previously identified by ABCs. During the same time period, 54 patients with NF were ascertained by ABCs. CONCLUSION: Administrative claims data have the potential to augment disease surveillance but require a large investment in resources compared with the few NF cases identified. PMID- 27453601 TI - Continuum of Care Among People Living with Perinatally Acquired HIV Infection in New York City, 2014. AB - OBJECTIVE: The HIV care continuum outlines the steps from HIV infection to diagnosis, linkage to care, and viral suppression among people living with HIV. We examined data for steps along the HIV care continuum among people living with perinatally acquired infection in New York City using surveillance data. METHODS: This study included data for people who acquired HIV infection perinatally and lived in New York City as of December 31, 2014. We defined "in care" as having >=1 CD4 or viral load test in 2014, "in continuous care" as having >=2 CD4 or viral load tests >=3 months apart in 2014, and "virally suppressed" as having a viral load of #200 copies per milliliter in the most recent test in 2014. We estimated factors associated with viral suppression from a weighted log-binomial regression model that included sex, race/ethnicity, age, and country of birth as independent variables. RESULTS: As of December 31, 2014, an estimated 1,596 people were living with perinatally acquired HIV infection in New York City. All were diagnosed, 96% were in care, 80% were in continuous care, and 61% were virally suppressed. The multivariable analysis showed significant differences in viral suppression by race/ethnicity and age. Black patients (59%, 534/907) were the least likely of all racial/ethnic groups examined to have a suppressed viral load. By age, compared with 73% (80/109) of children aged 0-12 years who were virally suppressed, 58% (568/987) of adults aged 20-29 years and 56% (54/96) of adults aged 30-39 years were virally suppressed; the adjusted prevalence ratio was 0.80 (95% confidence interval [CI] 0.69, 0.92) for those aged 20-29 years and 0.79 (95% CI 0.63, 0.99) for those aged 30-39 years. CONCLUSION: The low level of viral suppression among people living with perinatally acquired infection found in this study warrants further exploration to identify the best management strategies to improve viral suppression in this population, especially those transitioning from pediatric to adult health care. PMID- 27453602 TI - Epidemiology of Infectious Disease-Related Death After Release from Prison, Washington State, United States, and Queensland, Australia: A Cohort Study. AB - OBJECTIVES: People in prison may be at high risk for infectious diseases and have an elevated risk of death immediately after release compared with later; their risk of death is elevated for at least a decade after release. We compared rates, characteristics, and prison-related risk factors for infectious disease-related mortality among people released from prisons in Queensland, Australia, and Washington State, United States, regions with analogous available data. METHODS: We analyzed data from retrospective cohort studies of people released from prison in Queensland (1997-2007, n=37,180) and Washington State (1999-2009, n=76,208) and linked identifiers from each cohort to its respective national death index. We estimated infectious disease-related mortality rates (deaths per person-years in community) and examined associations using Cox proportional hazard models. RESULTS: The most frequent infectious disease-related underlying cause of death after release from prison was pneumonia (43%, 23/54 deaths) in the Australian cohort and viral hepatitis (40%, 69/171 deaths) in the U.S. cohort. The infectious disease-related mortality rate was significantly higher in the U.S. cohort than in the Australian cohort (51.2 vs. 26.5 deaths per 100,000 person years; incidence rate ratio = 1.93, 95% confidence interval 1.42, 2.62). In both cohorts, increasing age was strongly associated with mortality from infectious diseases. CONCLUSION: Differences in the epidemiology of infectious disease related mortality among people released from prison may reflect differences in patterns of community health service delivery in each region. These findings highlight the importance of preventing and treating hepatitis C and other infectious diseases during the transition from prison to the community. PMID- 27453603 TI - Effects of Health Level 7 Messaging on Data Quality in New York City's Immunization Information System, 2014. AB - OBJECTIVE: We compared the quality of data reported to New York City's immunization information system, the Citywide Immunization Registry (CIR), through its real-time Health Level 7 (HL7) Web service from electronic health records (EHRs), with data submitted through other methods. METHODS: We stratified immunizations administered and reported to the CIR in 2014 for patients aged 0-18 years by reporting method: (1) sending HL7 messages from EHRs through the Web service, (2) manual data entry, and (3) upload of a non-standard flat file from EHRs. We assessed completeness of reporting by measuring the percentage of immunizations reported with lot number, manufacturer, and Vaccines for Children (VFC) program eligibility. We assessed timeliness of reporting by determining the number of days from date of administration to date entered into the CIR. RESULTS: HL7 reporting accounted for the largest percentage (46.3%) of the 3.8 million immunizations reported in 2014. Of immunizations reported using HL7, 97.9% included the lot number and 92.6% included the manufacturer, compared with 50.4% and 48.0% for manual entry, and 65.9% and 48.8% for non-standard flat file, respectively. VFC eligibility was 96.9% complete when reported by manual data entry, 95.3% complete for HL7 reporting, and 87.2% complete for non-standard flat file reporting. Of the three reporting methods, HL7 was the most timely: 77.6% of immunizations were reported by HL7 in <1 day, compared with 53.6% of immunizations reported through manual data entry and 18.1% of immunizations reported through non-standard flat file. CONCLUSION: HL7 reporting from EHRs resulted in more complete and timely data in the CIR compared with other reporting methods. Providing resources to facilitate HL7 reporting from EHRs to immunization information systems to increase data quality should be a priority for public health. PMID- 27453604 TI - Pesticide-Related Hospitalizations Among Children and Teenagers in Texas, 2004 2013. AB - OBJECTIVE: Acute exposure to pesticides is associated with nausea, headaches, rashes, eye irritation, seizures, and, in severe cases, death. We characterized pesticide-related hospitalizations in Texas among children and teenagers for 2004 2013 to characterize exposures in this population, which is less well understood than pesticide exposure among adults. METHODS: We abstracted information on pesticide-related hospitalizations from hospitalization data using pesticide related International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and E-codes. We calculated the prevalence of pesticide-related hospitalizations among children and teenagers aged #19 years for all hospitalizations, unintentional exposures, intentional exposures, pesticide classifications, and illness severity. We also calculated age- and sex specific prevalence of pesticide-related hospitalizations among children. RESULTS: The prevalence of pesticide-related hospitalizations among children and teenagers was 2.1 per 100,000 population. The prevalence of pesticide-related hospitalizations per 100,000 population was 2.7 for boys and 1.5 for girls. The age-specific prevalence per 100,000 population was 5.3 for children aged 0-4 years, 0.3 for children and teenagers aged 5-14 years, and 2.3 for teenagers aged 15-19 years. Children aged 0-4 years had the highest prevalence of unintentional exposures, whereas teenagers aged 15-19 years had the highest prevalence of intentional exposures. Commonly reported pesticide categories were organophosphates/carbamates, disinfectants, rodenticides, and other pesticides (e.g., pyrethrins, pyrethroids). Of the 158 pesticide-related hospitalizations, most were coded as having minor (n=86) or moderate (n=40) illness severity. CONCLUSION: Characterizing the prevalence of pesticide-related hospitalizations among children and teenagers leads to a better understanding of the burden of pesticide exposures, including the type of pesticides used and the severity of potential health effects. This study found differences in the frequency of pesticide-related hospitalizations by sex, age, and intent (e.g., unintentional vs. intentional). PMID- 27453605 TI - Homicide Among American Indians/Alaska Natives, 1999-2009: Implications for Public Health Interventions. AB - OBJECTIVE: We determined estimates of homicide among American Indians/Alaska Natives (AI/ANs) compared with non-Hispanic white people to characterize disparities and improve AI/AN classification in incidence and mortality reporting. METHODS: We linked 1999-2009 death certificate data with Indian Health Service (IHS) patient registration data to examine death rates from homicide among AI/AN and non-Hispanic white people. Our analysis focused primarily on residents of IHS Contract Health Service Delivery Area counties and excluded Hispanic people to avoid underestimation of incidence and mortality in AI/ANs and for consistency in our comparisons. We used age-adjusted death rates per 100,000 population and stratified our analyses by sex, age, and IHS region. RESULTS: Death rates per 100,000 population from homicide were four times higher among AI/ANs (rate = 12.1) than among white people (rate = 2.8). Homicide rates for AI/ANs were highest in the Southwest (25.6 and 6.9 for males and females, respectively) and in Alaska (17.7 and 10.3 for males and females, respectively). Disparities between AI/ANs and non-Hispanic white people were highest in the Northern Plains region among men (rate ratio [RR] = 9.8, 95% confidence interval [CI] 8.5, 11.3) and among those aged 25-44 years (RR59.0, 95% CI 7.5, 10.7) and 0 24 years (RR57.4, 95% CI 6.1, 8.9). CONCLUSION: Death rates from homicide among AI/ANs were higher than previously reported and varied by sex, age, and region. Violence prevention efforts involving a range of stakeholders are needed at the community level to address this important public health issue. PMID- 27453606 TI - The Use of E-Cigarettes Among U.S. Immigrants: The 2014 National Health Interview Survey. AB - OBJECTIVE: Although e-cigarette popularity has increased substantially in recent years in the United States, it is unclear whether e-cigarette use has extended to immigrants in the United States. We characterized differences in ever and current use of e-cigarettes among non-U.S. citizens, naturalized U.S. citizens, and U.S. natives. METHODS: We used cross-sectional data from the 2014 National Health Interview Survey to measure the prevalence of e-cigarette ever and current use by immigration status, characterized as U.S. native, naturalized U.S. citizen, and non-U.S. citizen. We used multivariate logistic regression to examine the association between e-cigarette use and immigration status adjusting for demographic characteristics, socioeconomic status, and history of tobacco use. We also stratified the use of e-cigarettes by cigarette smoking status and analyzed the impact of length of residency and country of origin on e-cigarette use among immigrants. RESULTS: Naturalized U.S. citizens and non-U.S. citizens had a similar prevalence of e-cigarette use, which was significantly lower than the prevalence among U.S. natives. After adjusting for covariates, naturalized U.S. citizens had 38% lower odds and non-U.S. citizens had 54% lower odds of ever using e-cigarettes than U.S. natives. Non-U.S. citizens were less likely than U.S. natives to currently use e-cigarettes. Among both current smokers and nonsmokers of tobacco cigarettes, non-U.S. citizens were less likely than U.S. natives to indicate current e-cigarette use. U.S. immigrants with >5 years residency were more likely than U.S. immigrants with <5 years residency to try e cigarettes. CONCLUSION: Although non-U.S. citizens are less likely than U.S. natives to currently use e-cigarettes, e-cigarette use may increase with length of residency in the United States. PMID- 27453609 TI - Alcohol and Pregnancy: CDC's Health Advice and the Legal Rights of Pregnant Women. PMID- 27453607 TI - Incidence and Risk for Mood and Anxiety Disorders in a Representative Sample of Ohio Army National Guard Members, 2008-2012. AB - OBJECTIVE: We investigated the incidence of first-onset psychiatric disorders among Ohio Army National Guard members and the sociodemographic and military factors associated with these incident disorders. We aimed to identify potential risk factors and mitigating factors for a range of psychiatric disorders in a representative military sample. METHODS: We analyzed data on a representative sample of 528 Ohio Army National Guard members who were assessed in person annually for first-onset psychiatric disorders from 2008 through 2012 using structured clinical interviews. We used a multivariable discrete-time Cox proportional hazard model to determine risk factors of first-onset anxiety or mood disorders. RESULTS: The annualized incidence rate of any first-onset psychiatric disorder was 9.8 per 100 person-years at risk. Alcohol use disorder and major depressive disorder had the highest incidence rates among the unique disorders under study (5.0 and 4.2 per 100 person-years at risk, respectively). We found an association between respondents endorsing past-year deployment and a 29% increase in the risk of incident anxiety or mood disorder, whereas the past year experience of any non-deployment traumatic event was associated with a 32% increase in risk of incident anxiety or mood disorder. CONCLUSION: Soldiers experience a substantial burden of first-onset alcohol use disorder and major depressive disorder annually; the experience of non-deployment-related traumatic events contributes substantially to increasing risk, suggesting that any effort aimed at mitigating mood and anxiety disorders in this population must consider the soldier's life experience and military experience. PMID- 27453611 TI - The Academic Health Department: Academic-Practice Partnerships Among Accredited U.S. Schools and Programs of Public Health, 2015. PMID- 27453612 TI - Characteristics and Career Intentions of MD-MPH Program Graduates: A National Cohort Study. PMID- 27453613 TI - Female disability disadvantage: a global perspective on sex differences in physical function and disability. AB - The objectives were to determine whether women always fare more poorly in terms of physical function and disability across countries that vary widely in terms of their level of development, epidemiologic context and level of gender equality. Sex differences in self-reported and objective measures of disability and physical function were compared among older adults aged 55-85 in the United States of America, Taiwan, Korea, Mexico, China, Indonesia and among the Tsimane of Bolivia using population-based studies collected between 2001 and 2011. Data were analysed using logistic and ordinary least-squares regression. Confidence intervals were examined to see whether the effect of being female differed significantly between countries. In all countries, women had consistently worse physical functioning (both self-reported and objectively measured). Women also tended to report more difficulty with activities of daily living (ADL), although differences were not always significant. In general, sex differences across measures were less pronounced in China. In Korea, women had significantly lower grip strength, but sex differences in ADL difficulty were non-significant or even reversed. Education and marital status helped explain sex differences. Overall, there was striking similarity in the magnitude and direction of sex differences across countries despite considerable differences in context, although modest variations in the effect of sex were observed. PMID- 27453614 TI - Vulnerability to Renal, Heat and Respiratory Hospitalizations During Extreme Heat Among U.S. Elderly. AB - BACKGROUND: Extreme heat (EH) is a growing concern with climate change, and protecting human health requires knowledge of vulnerability factors. We evaluated whether associations between EH (maximum temperature > 97th percentile) and hospitalization for renal, heat and respiratory diseases among people >= 65 years differed by individual and area-level characteristics. METHODS: We used Medicare billing records, airport weather data, U.S. Census data and satellite land cover imagery in 109 US cities, May-September, 1992-2006, in a time-stratified case crossover design. Interaction terms between EH and individual (> 78 years, black race, sex) and home ZIP-code (percentages of non-green space, high school education, housing built before 1940) characteristics were incorporated in a single model. Next, we pooled city-specific effect estimates or regressed them on quartiles of air conditioning prevalence (ACP) in a multivariate random effects meta-analysis. RESULTS: EH and combined renal/heat/respiratory hospitalization associations were stronger among blacks, the very old, in ZIP codes with lower educational attainment or older housing and in cities with lower ACP. For example, for EH versus non-heat days, we found a 15% (95% CI 11%-19%) increase in renal/heat/respiratory hospitalizations among individuals in ZIP codes with higher percent of older homes in contrast to a 9% (95% CI 6%-12%) increase in hospitalizations in ZIP codes with lower percent older homes. CONCLUSION: Vulnerability to EH-associated hospitalization may be influenced by age, educational attainment, housing age and ACP. PMID- 27453615 TI - Circle of Care: Extending Beyond Primary Caregivers to Examine Collaborative Caretaking in Adolescent Development. AB - In the contemporary family, which is increasingly shaped by multicultural influences, parents rarely are the sole caretakers of their children. To improve understanding of family dynamics, researchers must redefine caregiving networks to include multiple caregivers, such as extended family members. This study explored the influences of caregiving networks on youth depression by examining who youths perceived as caretakers, how many caretakers were in their networks, the youths' connectedness with adults in their network, and harmony of relationships among adults within the network. Data from an ethnically diverse, urban sample of 180 middle school youths revealed participation of multiple caregivers for all groups, but ethnic differences existed in network composition. These differences in network composition are discussed within a socio-cultural context, considering how positive relationships with specific caregivers may buffer future depression. Longitudinal analyses confirmed the importance of positive relationships with caregiving networks for youth of color when predicting future depression. PMID- 27453616 TI - Optimal designs for copula models. AB - Copula modelling has in the past decade become a standard tool in many areas of applied statistics. However, a largely neglected aspect concerns the design of related experiments. Particularly the issue of whether the estimation of copula parameters can be enhanced by optimizing experimental conditions and how robust all the parameter estimates for the model are with respect to the type of copula employed. In this paper an equivalence theorem for (bivariate) copula models is provided that allows formulation of efficient design algorithms and quick checks of whether designs are optimal or at least efficient. Some examples illustrate that in practical situations considerable gains in design efficiency can be achieved. A natural comparison between different copula models with respect to design efficiency is provided as well. PMID- 27453617 TI - On the stoichiometry and stability of americium(III) complexes with a hydrophilic SO3-Ph-BTP ligand, studied by liquid-liquid extraction. AB - 1:1 and 1:2 complexes of americium(III) with a hydrophilic anionic SO3-Ph-BTP4- ligand were detected in acidic aqueous nitrate solutions by a solvent extraction method. The determined conditional stability constants of these complexes, logbeta1 = 4.35 +/- 0.07 and logbeta2 = 7.67 +/- 0.06, related to 1 M aqueous solutions, are much lower than the literature values for the analogous curium species, determined by TRLFS in very dilute aqueous solutions. There is also no evidence for the existence of the 1:3 Am3+ complex similar to the reported curium(III) complex. A hypothesis has been formulated to explain these discrepancies. It suggests the necessity to carefully check the equilibria in each phase of solvent extraction systems containing two competing ligands lipophilic and hydrophilic. PMID- 27453618 TI - On the 209Po half-life error and its confirmation: an answer to the critique. AB - Pomme et al. published a paper claiming that the 209Po half-life is 20 % higher than the erroneous value of 102 (5) a used for 50 years. Colle and Colle published a critique saying that 'this claim cannot withstand critical scrutiny'. In this work, counterarguments are presented to the critique. The experiment has been continued and a new intermediate half-life value of 122.7 (27) a was obtained. A brief review is made of the 209Po half-life value by Colle et al. and a recommended value of 122.9 (23) a is derived from both experiments. PMID- 27453619 TI - Comparison of two spectrometric counting modes for fast analysis of selected radionuclides activity. AB - The two counting modes: a normal with a single HPGE detector and second with the additional anti-Compton shield of the annular NaI(Tl) detector have been compared for fast determination of the activity concentration of thorium 232Th in the building materials. The 232Th activity concentration was calculated by measurement of its decay products: 212Pb, 212Bi and 208Tl as well 228Ac content. Although the Compton suppression mode applied in gamma spectrometry systems in general increase sensitivity of the analysis, but in case of 583 keV the most abundant 208Tl gamma-line, the significant reduction of photon counting rate was observed. PMID- 27453620 TI - Assessing Syntactic Deficits in Chinese Broca's aphasia using the Northwestern Assessment of Verbs and Sentences-Chinese (NAVS-C). AB - BACKGROUND: English-speaking patients with Broca's aphasia and agrammatism evince difficulty with complex grammatical structures, including verbs and sentences. A few studies have found similar patterns among Chinese-speaking patients with broca's aphasia, despite structural differences between these two languages. However, no studies have explicitly examined verb properties, including the number and optionality of arguments (participant roles) selected by the verb, and only a few studies have examined sentence deficits among Chinese patients. In addition, there are no test batteries presently available to assess syntactically important properties of verbs and sentences in Chinese patients. AIMS: This study used a Chinese version of the Northwestern Assessment of Verbs and Sentences (NAVS; Thompson, 2011), originally developed for English speakers with aphasia, to examine the verb and sentence deficit patterns among Chinese speakers with aphasia. As in the original NAVS, the Chinese version (NAVS-C) assessed verbs by the number and optionality of arguments as well as sentence canonicity, in the both production and comprehension. METHODS AND PROCEDURES: Fifteen Chinese patients with Broca's aphasia and fifteen age-matched healthy normal controls participated in this study. All NAVS-C tests were administered, in which participants were asked either to produce or identify verbs and sentences coinciding with action pictures. OUTCOMES & RESULTS: Despite grammatical differences between Chinese and English, the impairment caused by structural complexity of verbs and sentences was replicated in Chinese-speaking patients using the NAVS-C. Verbs with more arguments were significantly more impaired than those with fewer arguments and verbs with optional arguments were significantly more impaired than those with obligatory arguments. One deviation from English speaking patients, however, is that the Chinese-speaking patients exhibited greater difficulty with subject relative clauses than with object relative clauses because the former, rather than the latter, involve non-canonical order in Chinese. Similar to English-speaking patients, Chinese patients exhibited more difficulty with object extracted wh-questions than with subject extracted wh questions. Suggesting that wh-movement in Logical Form may also cause processing difficulty. Moreover, Chinese-speaking patients exhibited similar performance in both production and comprehension, indicating the deficits in both modalities. CONCLUSIONS: The number and optionality of verb arguments as well as canonicity of the Agent-Theme order in sentences impacts Chinese-speaking individuals with aphasia as it does in the case of English-speaking patients. These findings indicate that the NAVS-C is a useful tool for detailing deficit patterns associated with syntactic processing in patients with aphasia cross linguistically. PMID- 27453621 TI - Correlation of Solid State and Solution Coordination Numbers with Infrared Spectroscopy in Five-, Six-, and Eight-Coordinate Transition Metal Complexes of DOTAM. AB - Three new DOTAM (1,4,7,10-tetrakis(acetamido)-1,4,7,10-tetraazacyclododecane) complexes have been synthesized and characterized by X-ray crystallography: [Co(DOTAM)]Cl2*3H2O, [Ni(DOTAM)]Cl2*4H2O, and [Cu(DOTAM)](ClO4)2*H2O. Solid state and solution IR spectroscopic features for a series of [M(DOTAM)]2+ complexes (M=Mn, Co, Cu, Ni, Ca, Zn) correlate with solid state and solution coordination numbers. [Co(DOTAM)]2+, [Ni(DOTAM)]2+, and [Zn(DOTAM)]2+ are demonstrated to be six-coordinate in both the solid state and in solution, while [Mn(DOTAM)]2+ and [Ca(DOTAM)]2+ are eight-coordinate in the solid state and remain so in solution. [Cu(DOTAM)]2+, which is five-coordinate by X-ray crystallography, is shown to increase its coordination number in solution to six-coordinate. PMID- 27453622 TI - Investigating the impact of oxygen concentration and blood flow variation on photodynamic therapy. AB - Type II photodynamic therapy (PDT) is used for cancer treatment based on the combined action of a photosensitizer, a special wavelength of light, oxygen (3O2) and generation of singlet oxygen (1O2). Intra-patient and inter-patient variability of oxygen concentration ([3O2]) before and after the treatment as well as photosensitizer concentration and hemodynamic parameters such as blood flow during PDT has been reported. Simulation of these variations is valuable, as it would be a means for the rapid assessment of treatment effect. A mathematical model has been previously developed to incorporate the diffusion equation for light transport in tissue and the macroscopic kinetic equations for simulation of [3O2], photosensitizers in ground and triplet states and concentration of the reacted singlet oxygen ([1O2]rx) during PDT. In this study, the finite-element based calculation of the macroscopic kinetic equations is done for 2-(1 Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated PDT by incorporating the information of the photosensitizer photochemical parameters as well as the tissue optical properties, photosensitizer concentration, initial oxygen concentration ([3O2]0), blood flow changes and phi that have been measured in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Then, [1O2]rx calculated by using the measured [3O2] during the PDT is compared with [1O2]rx calculated based on the simulated [3O2]; both calculations showed a reasonably good agreement. Moreover, the impacts of the blood flow changes and [3O2]0 on [1O2]rx have been investigated, which showed no pronounced effect of the blood flow changes on the long-term 1O2 generation. When [3O2]0 becomes limiting, small changes in [3O2] have large effects on [1O2]rx. PMID- 27453623 TI - National Institute of Standards and Technology measurement service of the optical properties of biomedical phantoms: Current status. AB - The National Institute of Standards and Technology (NIST) has maintained scales for reflectance and transmittance over several decades. The scales are primarily intended for regular transmittance, mirrors, and solid surface scattering diffusers. The rapidly growing area of optical medical imaging needs a scale for volume scattering of diffuse materials that are used to mimic the optical properties of tissue. Such materials are used as phantoms to evaluate and validate instruments under development intended for clinical use. To address this need, a double-integrating sphere based instrument has been installed to measure the optical properties of tissue-mimicking phantoms. The basic system and methods have been described in previous papers. An important attribute in establishing a viable calibration service is the estimation of measurement uncertainties. The use of custom models and comparisons with other established scales enabled uncertainty measurements. Here, we describe the continuation of those efforts to advance the understanding of the uncertainties through two independent measurements: the bidirectional reflectance distribution function and the bidirectional transmittance distribution function of a commercially available solid biomedical phantom. A Monte Carlo-based model is used and the resulting optical properties are compared to the values provided by the phantom manufacturer. PMID- 27453624 TI - Developing International Collaborations for Early Career Researchers in Psychology. AB - International collaboration is becoming increasingly vital as the emphasis on unmet need for mental health across cultures and nations grows. Opportunities exist for early career researchers to engage in international collaboration. However, little information is provided about such opportunities in most current psychology training models. The authors are early career researchers in psychology from U.S. and Australia who have developed a collaborative relationship over the past two years. Our goal is to increase awareness of funding opportunities to support international research and to highlight the benefits and challenges associated with international collaboration based on our experience. PMID- 27453625 TI - Longitudinal effects of a two-generation preschool programme on receptive language skill in low-income Canadian children to age 10 years. AB - We explored longitudinal effects of a two-generation preschool programme on receptive language scores in children (n = 78) at age 10 years, living with low income. Scores at four time-points, programme intake, exit, age 7, and age 10 years were measured using the Peabody picture vocabulary test (3rd ed.). Effects of culture (Aboriginal, other Canadian-born, and recent immigrant), and gender of the children were explored. Between programme intake and age 10, scores improved significantly, F(3, 75) = 21.11, p < .0005. There were significant differences among cultural groups at all time-points except age 10. Scores differed significantly for girls, but not boys, at age 10, F = 5.11, p = .01. Recent immigrant boys reached the Canadian average, while girls were two-thirds of the standard deviation below average. Early intervention programmes must include a focus on the unique circumstances of recent immigrant girls; supportive transition workers in schools are one recommendation. PMID- 27453626 TI - Locally Efficient Semiparametric Estimators for Proportional Hazards Models with Measurement Error. AB - We propose a new class of semiparametric estimators for proportional hazards models in the presence of measurement error in the covariates, where the baseline hazard function, the hazard function for the censoring time, and the distribution of the true covariates are considered as unknown infinite dimensional parameters. We estimate the model components by solving estimating equations based on the semiparametric efficient scores under a sequence of restricted models where the logarithm of the hazard functions are approximated by reduced rank regression splines. The proposed estimators are locally efficient in the sense that the estimators are semiparametrically efficient if the distribution of the error prone covariates is specified correctly, and are still consistent and asymptotically normal if the distribution is misspecified. Our simulation studies show that the proposed estimators have smaller biases and variances than competing methods. We further illustrate the new method with a real application in an HIV clinical trial. PMID- 27453627 TI - Intense piano training on self-efficacy and physiological stress in aging. AB - The aim of this study was to evaluate the effects of an intense piano training program on general self-efficacy, musical self-efficacy, and physiological stress in older adults. Self-efficacy refers to perceived beliefs regarding the performance of domain-specific tasks or activities, which contribute to psychological and physical health. A key challenge is to identify activities that promote self-efficacy in the aging population. Seventeen healthy community dwelling older adults (60-85 years) with little to no previous musical training participated in a within subjects experimental design. Measures of self-efficacy and cortisol levels were administered over three time points: an initial pre testing session, a second pre-testing following a two-week no treatment control period, and a post-testing session upon the completion of piano training. Intense piano training consisted of 30 hours of training (3 hours per day) in which high levels of achievement were required. Results of a three-way Repeated Measures ANOVA over all time points with pairwise comparisons revealed significantly (p < .05) enhanced musical self-efficacy post-training, F (2, 32) = 11.5, p < .001, d = .79. No significant changes in general self-efficacy or cortisol levels were found. These results suggest that domain-specific self-efficacy may increase as a result of short-term intense music training; however, short-term music training may not be sufficient to transfer to general self-efficacy. PMID- 27453628 TI - Introduction: Untold Legacies of the First World War in Britain. AB - The current centenary of the First World War provides an unrivalled opportunity to uncover some of the social legacies of the war. The four articles which make up this special issue each examine a different facet of the war's impact on British society to explore an as yet untold story. The subjects investigated include logistics, the history of science, the social history of medicine and resistance to war. This article introduces the four which follow, locating them in the wider historiographic debates around the interface between warfare and societies engaged in war. PMID- 27453629 TI - NEW AND EMERGING PROFESSIONALS: Does Race Moderate Social Support and Psychological Distress Among Rural Older Adults? AB - Greater social support is associated with decreased psychological distress among older adults. Researchers have found racial differences in psychological distress. Might race moderate social support and psychological distress? The authors hypothesized African American collectivistic values could increase the importance of social support. Participants were rural adults aged 60 and older (N = 100). Multiple regression analyses controlled for health, income, education, and sex. Race moderated satisfaction with social support and psychological distress. However, greater satisfaction predicted less psychological distress among Caucasians while it was not associated with African Americans' distress in this sample. Achieving satisfaction with social support may be particularly important for Caucasians receiving therapy. Interventions may also address strategies to improve physical health, emotional support, and quality of social support, which significantly predicted psychological distress for both groups. PMID- 27453630 TI - Trajectories of Drinking Urges During Individual- and Couple-based Cognitive Behavioral Treatment for Alcohol Use Disorders. AB - Individuals receiving treatment for alcohol use disorders (AUDs) often experience urges to drink, and reductions in drinking urges during cognitive-behavioral therapy (CBT) predict better treatment outcomes. However, little previous work has examined patterns of daily drinking urges during treatment. The present study examined patterns of change in daily drinking urges among participants in two randomized clinical trials of males (N = 80 with 4401 daily recordings) and females (N = 101 with 8011 daily recordings) receiving individual- or couples based CBT. Drinking urges were common during treatment, occurring on 45.1% percent of days for men and 44.8% for women. Drinking urges and alcohol use for both genders decreased substantially during the course of treatment. Both genders had increases in drinking urges as more time elapsed since attending a treatment session. For men, this increase was most pronounced at the beginning of treatment, but for women it was most pronounced near the end of treatment. Alcohol use and drinking urges were both more likely to occur on weekends. The results suggest that these times may lead to higher risk for drinking, and clients may benefit from high-risk planning that is focused on these times. PMID- 27453632 TI - Accelerating the weighted histogram analysis method by direct inversion in the iterative subspace. AB - The weighted histogram analysis method (WHAM) for free energy calculations is a valuable tool to produce free energy differences with the minimal errors. Given multiple simulations, WHAM obtains from the distribution overlaps the optimal statistical estimator of the density of states, from which the free energy differences can be computed. The WHAM equations are often solved by an iterative procedure. In this work, we use a well-known linear algebra algorithm which allows for more rapid convergence to the solution. We find that the computational complexity of the iterative solution to WHAM and the closely-related multiple Bennett acceptance ratio (MBAR) method can be improved by using the method of direct inversion in the iterative subspace. We give examples from a lattice model, a simple liquid and an aqueous protein solution. PMID- 27453631 TI - Unconstrained Enhanced Sampling for Free Energy Calculations of Biomolecules: A Review. AB - Free energy calculations are central to understanding the structure, dynamics and function of biomolecules. Yet insufficient sampling of biomolecular configurations is often regarded as one of the main sources of error. Many enhanced sampling techniques have been developed to address this issue. Notably, enhanced sampling methods based on biasing collective variables (CVs), including the widely used umbrella sampling, adaptive biasing force and metadynamics, have been discussed in a recent excellent review (Abrams and Bussi, Entropy, 2014). Here, we aim to review enhanced sampling methods that do not require predefined system-dependent CVs for biomolecular simulations and as such do not suffer from the hidden energy barrier problem as encountered in the CV-biasing methods. These methods include, but are not limited to, replica exchange/parallel tempering, self-guided molecular/Langevin dynamics, essential energy space random walk and accelerated molecular dynamics. While it is overwhelming to describe all details of each method, we provide a summary of the methods along with the applications and offer our perspectives. We conclude with challenges and prospects of the unconstrained enhanced sampling methods for accurate biomolecular free energy calculations. PMID- 27453633 TI - The Aegean in the Early 7th Millennium BC: Maritime Networks and Colonization. AB - The process of Near Eastern neolithization and its westward expansion from the core zone in the Levant and upper Mesopotamia has been broadly discussed in recent decades, and many models have been developed to describe the spread of early farming in terms of its timing, structure, geography and sociocultural impact. Until now, based on recent intensive investigations in northwestern and western Anatolia, the discussion has mainly centred on the importance of Anatolian inland routes for the westward spread of neolithization. This contribution focuses on the potential impact of east Mediterranean and Aegean maritime networks on the spread of the Neolithic lifestyle to the western edge of the Anatolian subcontinent in the earliest phases of sedentism. Employing the longue duree model and the concept of 'social memory', we will discuss the arrival of new groups via established maritime routes. The existence of maritime networks prior to the spread of farming is already indicated by the high mobility of Epipalaeolithic/Mesolithic groups exploring the Aegean and east Mediterranean seas, and reaching, for example, the Cyclades and Cyprus. Successful navigation by these early mobile groups across the open sea is attested by the distribution of Melian obsidian. The potential existence of an additional Pre-Pottery Neolithic (PPN) obsidian network that operated between Cappadocia/Cilicia and Cyprus further hints at the importance of maritime coastal trade. Since both the coastal and the high seas networks were apparently already well established in this early period, we may further assume appropriate knowledge of geographic routes, navigational technology and other aspects of successful seafaring. This Mesolithic/PPN maritime know-how package appears to have been used by later groups, in the early 7th millennium calBC, exploring the centre of the Anatolian Aegean coast, and in time establishing some of the first permanent settlements in that region. In the present paper, we link this background of newcomers to the western edge of Anatolia with new excavation results from Cukurici Hoyuk, which we have analysed in terms of subsistence strategies, materiality, technology and symbolism. Additionally, further detailed studies of nutrition and obsidian procurement shed light on the distinct maritime affinity of the early settlers in our case study, something that, in our view, can hardly be attributed to inland farming societies. We propose a maritime colonization in the 7th millennium via routes from the eastern Mediterranean to the eastern Aegean, based on previously developed sea networks. The pronounced maritime affinity of these farming and herding societies allows us to identify traces of earlier PPN concepts still embedded in the social-cultural memories of the newcomers and incorporated in a new local and regional Neolithic identity. PMID- 27453634 TI - Association of SNPs in exon 2 of the MHC B-F gene with immune traits in two distinct chicken populations: Chinese Beijing-You and White Leghorn. AB - Antibody titers raised for vaccinations against avian influenza (AI) and Newcastle disease (ND) were higher in Chinese Beijing-You (BJY) than in White Leghorn (WL) (P < 0.001), but there was no breed difference in titers for sheep red blood cells (SRBC). Genotyping by PCR-SSCP identified seven haplotypes in WL and 17 in BJY. After sequencing PCR products (35 and 85, respectively), 43 (WL) and 47 (BJY) single nucleotide polymorphisms (SNPs) were found in the 264 bp of exon 2. In WL chickens, significant associations were found with antibody responses to AI (two SNPs), ND (six SNPs), and SRBC (one SNP), while in BJY there was association with responses to ND (two SNPs) and SRBC (two SNPs), but none with AI. These results indicate that the genomic region bearing exon 2 of the major histocompatibility complex B-F gene has significant effects on antibody responses to SRBC and vaccination against AI and ND. Different SNPs affected antibody titers for each of the antigens and they differed between these very distinct breeds. PMID- 27453635 TI - Challenge clusters facing LCA in environmental decision-making-what we can learn from biofuels. AB - PURPOSE: Bioenergy is increasingly used to help meet greenhouse gas (GHG) and renewable energy targets. However, bioenergy's sustainability has been questioned, resulting in increasing use of life cycle assessment (LCA). Bioenergy systems are global and complex, and market forces can result in significant changes, relevant to LCA and policy. The goal of this paper is to illustrate the complexities associated with LCA, with particular focus on bioenergy and associated policy development, so that its use can more effectively inform policymakers. METHODS: The review is based on the results from a series of workshops focused on bioenergy life cycle assessment. Expert submissions were compiled and categorized within the first two workshops. Over 100 issues emerged. Accounting for redundancies and close similarities in the list, this reduced to around 60 challenges, many of which are deeply interrelated. Some of these issues were then explored further at a policy-facing workshop in London, UK. The authors applied a rigorous approach to categorize the challenges identified to be at the intersection of biofuels/bioenergy LCA and policy. RESULTS AND DISCUSSION: The credibility of LCA is core to its use in policy. Even LCAs that comply with ISO standards and policy and regulatory instruments leave a great deal of scope for interpretation and flexibility. Within the bioenergy sector, this has led to frustration and at times a lack of obvious direction. This paper identifies the main challenge clusters: overarching issues, application and practice and value and ethical judgments. Many of these are reflective of the transition from application of LCA to assess individual products or systems to the wider approach that is becoming more common. Uncertainty in impact assessment strongly influences planning and compliance due to challenges in assigning accountability, and communicating the inherent complexity and uncertainty within bioenergy is becoming of greater importance. CONCLUSIONS: The emergence of LCA in bioenergy governance is particularly significant because other sectors are likely to transition to similar governance models. LCA is being stretched to accommodate complex and broad policy-relevant questions, seeking to incorporate externalities that have major implications for long-term sustainability. As policy increasingly relies on LCA, the strains placed on the methodology are becoming both clearer and impedimentary. The implications for energy policy, and in particular bioenergy, are large. PMID- 27453636 TI - Aortic arch pathologies - incidence and natural history. AB - Endovascular interventions have made significant progress and are moving towards treating diseases of the aortic arch. Aortic arch pathologies incur substantial morbidity as well as short and long-term mortality but the progression is not well understood. This article reviews the current evidence on the natural history of aortic arch aneurysms and acute aortic syndromes, including penetrating ulcers, intramural hematomas, acute and chronic type B dissections. Risk factors for disease progression and mortality are also identified with special reference to vascular surgeons. PMID- 27453638 TI - Age and Death: A Defence of Gradualism. AB - According to standard comparativist views, death is bad insofar as it deprives someone of goods she would otherwise have had. In The Ethics of Killing, Jeff McMahan argues against such views and in favor of a gradualist account according to which how bad it is to die is a function of both the future goods of which the decedent is deprived and her cognitive development when she dies. Comparativists and gradualists therefore disagree about how bad it is to die at different ages. In this paper I examine two prominent criticisms of gradualism and show that both misconstrue McMahan. I develop a related criticism that seems to show that a gradualist cannot coherently relate morbidity and mortality. This criticism also fails, but has an instructive implication for how policy-makers setting priorities for health care investments should regard choices between life-saving interventions and interventions against non-fatal diseases in the very young. PMID- 27453637 TI - Distributions of oxytocin and vasopressin 1a receptors in the Taiwan vole and their role in social monogamy. AB - Social monogamy is a mating strategy rarely employed by mammalian species. Laboratory studies in socially monogamous prairie voles (Microtus ochrogaster) demonstrate that oxytocin and vasopressin act within the mesolimbic dopamine pathway to facilitate pair-bond formation. Species differences in oxytocin receptor (OTR) and vasopressin 1a receptor (V1aR) distribution in this pathway are associated with species differences in mating strategy. Here we characterize the neuroanatomical distribution of OTR and V1aR binding sites in naturally occurring populations of Taiwan voles (M. kikuchii), which purportedly display social monogamy. Live trapping was conducted at two sites in 2009-2010 and receptor autoradiography for OTR and V1aR was performed on brains from 24 animals. OTR binding in two brain regions where OTR signaling regulates pair bonding were directly compared with that of prairie voles. Our results show that like prairie voles, Taiwan voles exhibit OTR in the prefrontal cortex, insular cortex, claustrum, nucleus accumbens, caudate-putamen, dorsal lateral septal nucleus, central amygdala, and ventromedial hypothalamus. Unlike prairie voles, Taiwan voles exhibit OTR binding in the CA3 pathway of the hippocampus, as well as the indusium griseum, which has only previously been documented in tuco-tucos (Ctenomys haigi, C. sociabilis), Syrian hamsters (Mesocricetus auratus) and naked mole-rats (Heterocephalus glaber). V1aR binding was present in the ventral pallidum, lateral septum, nucleus basalis, bed nucleus of the stria terminalis, hippocampus, medial amygdala, and anterior, ventromedial and dorsomedial hypothalamus. Marked individual differences in V1aR binding were noted in the cingulate cortex and several thalamic nuclei, remarkably similar to prairie voles. While pharmacological studies are needed to determine whether oxytocin and vasopressin are involved in pair-bond formation in this species, our results lay a foundation for future investigations into the role of these neuropeptides in Taiwan vole social behavior. PMID- 27453639 TI - 'I am actually doing something to keep well. That feels really good': Experiences of exercise within hospice care. AB - Background: Patients with advanced cancer frequently experience functional impairment and reduced quality of life. Therapeutic exercise can provide benefit and be made accessible through the use of tailored programmes. Most studies examining exercise programmes for people with advanced cancer have used quantitative outcome measures and focussed on objective physical function, therefore offer a limited perspective on the experience of exercise participation. Methods: This qualitative study explored patients' experiences of an exercise programme within a palliative care setting. The interviews focussed on the perceived impact on all aspects of quality of life. Results: Nine people with advanced cancer, attending a hospice-based exercise programme, completed a one-to-one interview with a senior physiotherapist to explore the physical, emotional, and social impacts of their participation. Interviews were audiotaped, transcribed verbatim and analysed using interpretive phenomenological analysis. Patients reported an awareness of the positive physical, psychological, and social consequences of exercising. Their experiences reflected on all dimensions of quality of life, the impact of others and the sense of meaning gained through participation in exercise. Conclusion: Our findings highlight that exercise in palliative care should not be viewed solely a physical intervention, but one that has potential to enhance many aspects of patients' quality of life. PMID- 27453640 TI - Revealed aspect of metabolic osteoarthritis. AB - In current scenario there is an emerging trend to consider osteoarthritis (OA) phenotypes based on their risk factors and therefore offering potential for targeted therapies. OA prevalence with other coexistence diseases, such as systemic arterial hypertension, cardiovascular disease, diabetes, and dyslipidemia are increasing. Majority of OA associated with MetS, despite overweight of patients, the occurrence of OA in joints do not bear load suggest, the chronic inflammation status existing in patients with MetS can alter the metabolism of cartilage, regardless of excessive weight. This paper indicates that factors responsible for metabolic syndrome has clear role in cartilage degeneration and further degradation. PMID- 27453641 TI - Aneurysmal bone cyst of the lunate: Case report and literature review. AB - The aneurysmal bone cyst (ABC) is a benign osteolytic bone neoplasm. Although most ABC is asymptomatic, in some cases they produce a mass effect, impinging against soft tissues or interfering with joint function. The authors present a rare case report of a lunate ABC successfully treated by curettage and bone grafting, and review the literature of this pathology. PMID- 27453642 TI - Missed adolescent acetabular apophyseal avulsion with late hip dislocation. AB - BACKGROUND: Chronic hip dislocation associated with acetabular apophyseal avulsion in adolescence is rare. Whilst superior acetabular rim fractures have a documented theoretical risk of hip instability, we have not found a case of chronic dislocation resulting from this. METHODS: We report a case of a 12-year old healthy boy who initially sustained a missed right acetabular apophyseal avulsion after falling from a quad bike. This was missed on the initial radiograph and a subsequent radiograph following weight bearing a few days later showed a hip dislocation that was also missed. Upon diagnosis at 6 weeks, he underwent open reduction but also required acetabuloplasty to stabilise the hip. RESULTS: At 2 years follow-up, he was enjoying pain free swimming, cycling and walking. His Harris hip score was 87. CONCLUSION: This case reinforces the need for recognition that in the patient presenting with knee or thigh pain, exclusion of hip pathology is required. It also explores the pitfalls of diagnosis associated with rare patterns of injury and the need for adequate investigations such as examination under anaesthetic, arthrography and MRI. The use of acetabuloplasty is shown to be a useful strategy for the unstable hip resulting from irreparable acetabular rim fracture. PMID- 27453643 TI - The management of tibial fracture non-union using the Taylor Spatial Frame. AB - We reviewed 40 complex tibial non-unions treated with Taylor Spatial Frames. 39 healed successfully. Using the ASAMI scoring, we obtained 33 excellent, 5 good, 1 fair and 1 poor bone results. The functional results were excellent in 29 patients, good in 8, fair in two and poor in one. Mean patient satisfaction score was 95%. All but one patient would have the same treatment again. 28 of the 36 patients in work when injured, returned to work at the time of their final review. Four patients had an adverse event requiring significant intervention. Average treatment cost was approximately L26,000/patient. PMID- 27453644 TI - Double J stenting: A rewarding option in the management of emphysematous pyelonephritis. AB - CONTEXT: Emphysematous pyelonephritis (EPN) is an acute necrotizing inflammation of renal parenchyma and peri-nephric tissue characterized by gas formation. In this study, we evaluated the outcome of EPN cases by medical management with or without renal decompression. MATERIALS AND METHODS: We have observed prospectively 15 cases of EPN admitted in our institute in respect to age, sex, mode of presentation, presence of comorbidity, laboratory profile, urine analysis, and outcome after medical management and drainage procedures. RESULTS: All patients improved on medical management and drainage procedure such as JJ stenting and percutaneous nephrostomy. No mortality noted in our 15 cases of EPN. CONCLUSION: Emphysematous pyelonephritis can be managed conservatively by DJ stenting, wcich is a less morbid procedure or percutaneous nephrostomy with proper antibiotics and adequate glycemic control. PMID- 27453645 TI - Unilateral versus bilateral ultrasound-guided transversus abdominis plane blocks during ureteric shock wave lithotripsy: A prospective randomized trial. AB - BACKGROUND: Ultrasound-guided transversus abdominis plane (TAP) block has been used for intra- and post-operative analgesia during abdominal operations and for ureteric shock wave lithotripsy (SWL) as well. AIM: This study aimed at comparing ultrasound-guided unilateral versus bilateral TAP blocks as analgesic techniques for unilateral ureteric SWL. SETTINGS AND DESIGN: Prospective randomized comparative study. PATIENTS AND METHODS: Sixty patients scheduled for unilateral ureteric SWL were randomly allocated into two groups: Group (U) received unilateral TAP block in the form of 25 ml of bupivacaine 0.25% (i.e., 62.5 mg), and Group (B) received bilateral TAP blocks in the form of 25 ml of bupivacaine 0.25% (i.e., 62.5 mg) on each side. STATISTICAL ANALYSIS: This was performed using SPSS program version 19 ((IBM Corp., Armonk, NY, USA) and EP 16 program. RESULTS: The mean values of intra- and post-procedural visual analog scale at different time intervals were around (30), which was statistically insignificant between groups (P > 0.05). There were no significant differences between groups regarding cardiopulmonary stability, postanesthesia care unit time, the total amount of rescue fentanyl and patient satisfaction scores (P > 0.05). There were no significant side effects in both groups. CONCLUSION: Ultrasound-guided unilateral TAP block is as safe and effective analgesic technique as bilateral TAP blocks during unilateral ureteric SWL. It can be used as the sole analgesic technique during ureteric SWL. PMID- 27453646 TI - Evaluation of renal vascular anatomy in live renal donors: Role of multi detector computed tomography. AB - BACKGROUND: Evaluation of renal vascular variations is important in renal donors to avoid vascular complications during surgery. Venous variations, mainly resulting from the errors of the embryological development, are frequently observed. AIM: This retrospective cross-sectional study aimed to investigate the renal vascular variants with multidetector computed tomography (MDCT) angiography to provide valuable information for surgery and its correlations with surgical findings. MATERIALS AND METHODS: A total of 200 patients underwent MDCT angiography as a routine work up for live renal donors. The number, course, and drainage patterns of the renal veins were retrospectively observed from the scans. Anomalies of renal veins and inferior vena cava (IVC) were recorded and classified. Multiplanar reformations (MPRs), maximum intensity projections, and volume rendering were used for analysis. The results obtained were correlated surgically. RESULTS: In the present study, out of 200 healthy donors, the standard pattern of drainage of renal veins was observed in only 67% of donors on the right side and 92% of donors on the left side. Supernumerary renal veins in the form of dual and triple renal veins were seen on the right side in about 32.5% of donors (dual right renal veins in 30.5% cases and triple right renal veins in 2.5% cases). Variations on the left side were classified into four groups: supernumerary, retro-aortic, circumaortic, and plexiform left renal veins in 1%, 2.5%, 4%, 0.5%, cases respectively. CONCLUSIONS: Developmental variations in renal veins can be easily detected on computed tomography scan, which can go unnoticed and can pose a fatal threat during major surgeries such as donor nephrectomies in otherwise healthy donors if undiagnosed. PMID- 27453647 TI - Procalcitonin is a strong predictor of urine culture results in patients with obstructing ureteral stones: A prospective, pilot study. AB - PURPOSE: The appropriate management of infected obstructing ureteral calculi is prompt genitourinary decompression. Urine cultures are the gold standard for confirming infection but often take 24-48 h to result. Although white blood cell (WBC) count is an important diagnostic laboratory test, it is a nonspecific inflammatory marker. Similarly, urinalysis (UA) can be misleading in the setting of a contaminated sample, bladder colonization, or in cases of a completely obstructed the upper urinary tract. Procalcitonin (PCT) has shown promise in predicting the presence and degree of bacterial infections. In this proof-of concept study, we explore whether PCT is effective at predicting concomitant infections in the setting of obstructing ureteral stones. MATERIALS AND METHODS: This is a prospective, single-institution observational pilot study examining adult patients who presented to the emergency room with acute obstructing ureterolithiasis. In total, 22 patients were enrolled. At the time of presentation, data obtained were vital signs, WBC count, PCT, UA, urine, and blood cultures. Fisher-exact two-tailed t-tests and receiver operating characteristic statistics with area under the curve (AUC) calculations were used to determine the correlation between urine culture results and PCT, WBC count, nitrite-positive UA, heart rate, and fever. RESULTS: In total, 5/22 patients had bacteria-positive urine cultures. PCT (P = 0.020) and nitrite-positive UA (0.024) were the only statistically significant predictors of urine culture results. In comparing the AUC, PCT (0.812) was strongly correlated with eventual urine culture results. CONCLUSIONS: This proof-of-concept pilot study gives encouraging results, in that PCT was a good predictor of positive cultures (P = 0.02, AUC 0.812). Given, the small sample size, one cannot directly compare PCT to other markers of infection. However, PCT shows promise in this arena and warrants future investigation. PMID- 27453648 TI - Video endoscopic inguinal lymphadenectomy for radical management of inguinal nodes in patients with penile squamous cell carcinoma. AB - BACKGROUND: Inguinal lymph node involvement is an important prognostic factor in penile cancer. Inguinal lymph node dissection allows staging and treatment of inguinal nodal disease. However, it causes morbidity and is associated with complications such as lymphocele, skin loss, and infection. AIMS: To report our institutional experience with video endoscopic inguinal lymphadenectomy (VEIL) for radical management of inguinal nodes in patients with penile squamous cell carcinoma. MATERIALS AND METHODS: It is a prospective analysis of data of patients that underwent VEIL, by a single surgeon, from 2008 to 2015. 14 patients of penile carcinoma were suitable for VEIL technique were included in this study and followed. Data analyzed included mean operative time, mean lymph node yield, intraoperative complications, cutaneous complication, lymph-related complications, and surgical emphysema. RESULTS: The mean age of patients was 57.8 years (range: 45-70 years). Mean operative time for VEIL was 194.86 min (178-210 min). Mean lymph node yield was 7.68 (range: 5-11 nodes). No intraoperative complication was experienced during series. We noted no cutaneous complications, localized lymphocele were seen in total 6 units out of 22 units (27.2%). Surgical emphysema is seen in 3 limbs (13.63%). There was significantly decreased overall morbidity in our study. Follow-up of 10 out of 14 patients with median of 48 months shows no recurrence. CONCLUSIONS: In our early experience, VEIL is a safe and feasible technique in patients with penile carcinoma who require radical inguinal lymphadenectomy. It allows the removal of inguinal lymph nodes within the same limits as in conventional surgical dissection and reduces surgical morbidity substantially. PMID- 27453649 TI - Effect of urine pH on the effectiveness of shock wave lithotripsy: A pilot study. AB - AIM: Shock wave lithotripsy (SWL) is a well-established modality in the treatment of urolithiasis. Studying the effect of urine pH on SWL success is appealing as pH can be manipulated before SWL to insure a better outcome. MATERIALS AND METHODS: This is a prospective study performed at a tertiary medical center. Patients presenting to the SWL unit with a single renal stone <2 cm in size were included in this study. In addition to standard laboratory and radiologic investigations, urine pH measurement was performed on all patients before their procedure. The number of sessions performed, and the stone-free rate (SFR) were assessed. Patients were divided into two groups according to stone clearance. Group 1 was stone-free, whereas Group 2 had residual stones after three sessions of SWL. Data was also classified according to different pH ranges. Influential factors were compared among the study groups and pH ranges. RESULTS: A total of 175 patients were included in this study. The SFR was 54.3%. The mean number of sessions performed was 2.2 +/- 0.8. Group 1 included 95 patients, whereas Group 2 had eighty patients. Among all studied factors, stone size (P = 0.03) and skin to stone distance (P = 0.04) significantly affected SFR with SWL. Urine pH was not found to have a statistically significant influence on SWL outcome (P = 0.51). CONCLUSION: Urine pH was not found in this study population to influence the effectiveness of SWL. Further experimental studies are required to help investigate this notion. PMID- 27453650 TI - Monopolar versus bipolar transurethral resection of prostate for benign prostatic hyperplasia: Operative outcomes and surgeon preferences, a real-world scenario. AB - CONTEXT: Monopolar transurethral resection of prostate (M-TURP) is considered the gold standard for the management of bladder outlet obstruction due to benign prostatic hyperplasia. Its newly introduced modification, bipolar TURP (B-TURP), promises to overcome its most prominent shortcomings, namely bleeding and dilutional hyponatremia. Literature is conflicting regarding merits of B-TURP over M-TURP. AIMS: To find a difference, if any, in perioperative outcomes between M-TURP and B-TURP in a real-wold setting. SETTINGS AND DESIGN: Prospective nonrandomized study. SUBJECTS AND METHODS: Operative outcomes of patients undergoing M-TURP and B-TURP from February 2014 to October 2015 were compared. STATISTICAL ANALYSIS USED: Categorical data were compared by Fischer exact test and numerical data were compared by independent samples Mann-Whitney U test. P <0.05 was considered statistically significant. RESULTS: The mean size of prostate operated by bipolar technology was significantly greater than those operated by monopolar technology (38.12 +/- 9.59 cc vs. 66.49 +/- 22.95 cc; P < 0.001). The mean fall in postoperative serum sodium concentration was 0.99 +/- 0.76 mEq/L for the B-TURP group as compared to 3.60 +/- 2.89 mEq/L for the M-TURP group (P < 0.001). The mean drop in postoperative hemoglobin concentration (P = 0.28) was statistically insignificant, even though larger glands were operated by B-TURP. There were three instances of the transurethral resection (TUR) syndrome in the M-TURP group whereas no TUR syndrome occurred in the B-TURP group. CONCLUSIONS: In spite of various contrary viewpoints in literature, surgeons prefer to operate on larger prostates using bipolar technology. B-TURP definitely reduces the incidence of bleeding and dilutional hyponatremia, making it a contender to replace M-TURP as the new gold standard. PMID- 27453651 TI - Urolithiasis and crohn's disease. AB - OBJECTIVE: To present an updated description of the relation between Crohn's disease (CD) and Urolithiasis. PATIENTS AND METHODS: A literature search for English-language original and review articles was conducted in Medline, Embase, and Cochrane databases in the month of December 2014 for papers either published or e-published up to that date, addressing the association between CD and urolithiasis as its consequence. All articles published in English language were selected for screening based on the following search terms: "CD," "renal calculus," "IBD," and "urolithiasis." We restricted the publication dates to the last 15 years (2000-2014). RESULTS: In total, 901 patients were included in this review of which 95 were identified as having CD and urolithiasis simultaneously, for a total of 10.5%. Average age was 45.07 years old, irrespective of gender. 28.6% of patients received some kind of medical intervention without any kind of surgical technique involved, 50% of patients were submitted to a surgical treatment, and the remaining 21.4% were submitted to a combination of surgical and medical treatment. Urolithiasis and pyelonephritis incidence ranged from 4% to 23% with a risk 10-100 times greater than the risk for general population or for patients with UC, being frequent in patients with ileostomy and multiple bowel resections. We found that urolithiasis occurred in 95 patients from a total of 901 patients with CD (10.5%); 61.81% in men and 38.19% in women. Stone disease seems to present approximately 4-7 years after the diagnosis of bowel disease and CaOx seems to be the main culprit. CONCLUSIONS: CD is a chronic, granulomatous bowel disease, with urolithiasis as the most common extraintestinal manifestation (EIM), particularly frequent in patients submitted to bowel surgery. This complication needs to be recognized and addressed appropriately, especially in patients with unexplained renal dysfunction, abdominal pain, or recurrent urinary tract infection. We believe this study to be an updated valuable review as most data related to this kind of EIM refers to articles published before 2000, most of them before 1990. These patients need to be followed up with a specific prevention plan to eliminate or mitigate the risk factors for stone disease, aiming at preventing its formation and its complications, preserving renal function, reducing morbidity, and ultimately improving their quality of life. PMID- 27453652 TI - Laparoendoscopic single site surgery for extravesical repair of vesicovaginal fistula using conventional instruments: Our initial experience. AB - OBJECTIVE: Vesicovaginal fistula (VVF) is a major complication with psychosocial ramifications. In literature, few VVF cases have been managed by laparoendoscopic single site surgery (LESS) and for the 1(st) time we report VVF repair by LESS using conventional laparoscopic instruments. We present our initial experience and to assess its feasibility, safety and outcome. PATIENTS AND METHODS: From March 2012 to September 2015, LESS VVF repair was done for ten patients aged between 30 and 65 (45.6 +/- 10.15) years, who presented with supratrigonal VVF. LESS was performed by modified O'Conor technique using regular trocars with conventional instruments. Data were collected regarding feasibility, intra- or post-operative pain, analgesic requirement, complication, and recovery. RESULTS: All 10 cases were completed successfully, without conversion to a standard laparoscopic or open approach. The mean operative time was 182.5 +/- 32.25 (150 250) min. The mean blood loss was 100 mL. The respective mean visual analog score for pain on day 1, 2, and 3 was 9.2 +/- 1, 5 +/- 1, and 1.4 +/- 2.3. The analgesic requirement in the form of intravenous tramadol on days 1, 2, and 3 was 160 +/- 51.6, 80 +/- 63.2, and 30 +/- 48.3, mgs respectively. No major intra- or post-operative complications were observed. The mean hospital stay was 2.6 +/- 0.7 (2-4) days. CONCLUSION: In select patients, LESS extravesical repair of VVF using conventional laparoscopic instruments is safe, feasible with all the advantages of single port surgery at no added cost. Additional experience and comparative studies with conventional laparoscopy are warranted. PMID- 27453653 TI - Radiologic indicators prior to renal cell cancer thrombectomy: Implications for vascular reconstruction and mortality. AB - BACKGROUND: Renal cancer may invade the inferior vena cava (IVC) creating more complex surgical intervention. We investigate radiologic findings that may predict vascular reconstruction prior to surgery and future renal cancer-specific mortality. MATERIALS AND METHODS: Radiologic findings included Mayo Clinic risk factors for vascular reconstruction: Right-sided tumor, anteroposterior diameter of the IVC at the ostium of the renal vein >=24.0 mm, and radiologic identification of complete occlusion of the IVC. Additional factors included thrombus in the lumen of the hepatic veins and metastasis. Along with other demographic factors, analysis included Chi-squared analysis for vascular reconstruction and logistic regression for mortality. A Kaplan-Meier curve was created for the most significant radiologic factor. RESULTS: Thirty-seven patients underwent IVC tumor thrombectomy at two institutions from April 2007 to February 2015. We found that Mayo risk factors of 0, 1, 2, and 3 and the proportions of vascular reconstruction of 0%, 0%, 12.5%, and 13.6%, respectively (P = 0.788). Hepatic vein involvement was the most significant determinate of renal cell carcinoma-specific mortality in multivariable analysis, controlling for the size of IVC at the hepatic veins, pulmonary metastasis, and Fuhrman grade (P = 0.02, Log-rank P = 0.002). CONCLUSION: Mayo risk factors did not predict vascular reconstruction in our small cohort of Level II-Level IV IVC thrombus undergoing IVC thrombectomy. Tumor thrombus traveling into the lumen of the hepatic veins was a significant risk factor for accelerated mortality. PMID- 27453654 TI - A randomized clinical trial comparing intracorpus spongiosum block versus intraurethral lignocaine in visual internal urethrotomy for short segment anterior urethral strictures. AB - OBJECTIVES: The primary objective was to compare the effectiveness in pain relief of intracorpus spongiosum block (ICSB) versus intraurethral topical anesthesia (TA) using 2% lignocaine jelly for performing visual internal urethrotomy (VIU) for short segment anterior urethral strictures. MATERIALS AND METHODS: It was a randomized, parallel group controlled trial. Participants are adult patients with a single anterior urethral stricture up to 2 cm in length. Patients were allocated to two intervention groups with thirty patients in each group. For anesthesia of the urethra, Group 1 patients received ICSB whereas Group 2 patients received intraurethral TA using 2% lignocaine jelly before VIU. Patient discomfort was assessed with visual analog scale (VAS) during the procedure and 1 h postprocedure. The increase in pulse rate and the change in systolic blood pressure (BP) during the procedure were recorded. The procedure was considered successful if there was absence of symptoms or signs of recurrent stricture and ability to pass freely 18Fr catheter during urethral calibration at last follow up. RESULTS: From March 2014 to June 2015, sixty patients were randomized into two groups of thirty patients each. The mean (+/-standard deviation) intraoperative VAS score was 2.8 +/- 1.1 in Group 1, which was significantly less (P < 0.05) than the 5.6 +/- 1.7 score in Group 2. The mean 1 h postoperative VAS score was also significantly lower in Group 1 patients (1.0 +/- 1.0) than in Group 2 patients (3.2 +/- 1.5). The change in pulse rate was significantly greater in Group 2 (21.3 +/- 10.1 beats/min) than in Group 1 (10.6 +/- 4.6 beats/min, P < 0.05). The change in systolic BP was also significantly higher in Group 2 (16.3 +/- 8.6 mmHg) than in Group 1 (9.1 +/- 4.4 mmHg, P < 0.05). The stricture-free rate at 6-month after VIU in Group 1 and Group 2 patients were 88.5% and 89.6%, respectively. CONCLUSIONS: ICSB has better pain control with similar complication and recurrence rate than intraurethral lignocaine jelly alone in VIU. PMID- 27453655 TI - Nephrolithiasis, stone composition, meteorology, and seasons in Malta: Is there any connection? AB - CONTEXT: The effect of seasons and meteorology on the incidence of nephrolithiasis has been studied in various regions around the globe, but seldom in the Mediterranean. AIMS: This retrospective analysis aims at investigating these putative effects in the Maltese Islands, whose climate is typically Mediterranean, followed by a systematic review of the literature. MATERIALS AND METHODS: Submission rate and chemical composition of all kidney stones after spontaneous passage or surgical removal between January 2009 and December 2011 were analyzed according to seasons and corresponding meteorology. RESULTS: A total of 389 stones were analyzed. A higher stone submission rate was observed in summer compared to winter (31.6% vs. 20.8%, P = 0.0008) and in the warm period compared to the cold period (57.1% vs. 42.9%, P = 0.0001). Significant correlation was established between the monthly number of stones and mean monthly maximum temperature (r = 0.50, P = 0.002), mean monthly temperature (r = 0.49, P = 0.003) and mean monthly Humidex (r = 0.49, P = 0.007). Humidex was found to be an independent predictor for stone submission (beta = 0.49, P = 0.007). The majority of stones contained calcium (83.3%), combined with oxalate (77.6%), phosphate (14.7%), and carbonate (2.8%). Some stones (11.8%) contained a mixture of >1 negatively charged molecules. Urate (11.6%), cysteine (4.6%), and ammonium magnesium-phosphate (0.5%) constituted the rest. There was no association between chemical composition and seasons. Literature review included 25 articles. Higher ambient temperature and warm seasons were the most commonly encountered risk factors for both presentation and etiology of nephrolithiasis. CONCLUSIONS: A significant positive correlation was noted between ambient temperature and stone submission rate, which was significantly higher during the warm months in Malta. PMID- 27453656 TI - Recurrence and progression in nonmuscle invasive transitional cell carcinoma of urinary bladder treated with intravesical Bacillus Calmette-Guerin: A single center experience and analysis of prognostic factors. AB - BACKGROUND: Intravesical Bacillus Calmette-Guerin (BCG) has been the standard of care for the prevention of nonmuscle invasive bladder cancer (NMIBC) recurrence following resection. Attempts to improve on the result by combining it with other agents have largely failed. This study addresses the result of BCG therapy in our patient population and compares the result with our combination BCG and interferon therapy published earlier. MATERIALS AND METHODS: The medical records of patients diagnosed with NMIBC and treated with transurethral resection and intravesical BCG were reviewed. Univariate analysis was performed on most known prognostic factors. Results were compared to published data on the use of BCG and interferon from the same institution. RESULTS: Thirty-one patients were identified. Median age was 66 (range 33-109), 80.6% were males. Fourteen patients (45%) had <= 3 tumors and 18 (58.1%) had T1 lesions. Four patients (12.9%) had Grade 3 tumors and 25 (80.6%) had Grade 2 tumors. One patient (3.2) had concurrent carcinoma in situ and 11 (35.5%) were treated upon initial diagnosis. At 5 years, the relapse-free survival was 61.3% (95% confidence interval (CI) 44.2-78.4%), progression-free survival was 85.6% (95% CI 73.3-97.9%), and overall survival was 93% (95% CI 84.1-100%). Comparison with the BCG and interferon data showed no significant difference. CONCLUSION: The result of BCG therapy in our patient population is similar to western reported data. Efficacy of BCG alone is equal to BCG and interferon within our institution. PMID- 27453657 TI - Self-inflicted foreign bodies in lower genitourinary tract in males: Our experience and review of literature. AB - OBJECTIVES: To study retrospectively the frequency, demographic, phenomenological, and psychiatric profile in patients presented with self insertion of foreign bodies in the lower genitourinary tract in our institute. MATERIALS AND METHODS: From January 2009 to 2015, the records of patients admitted with self-insertion of foreign bodies into the lower urinary tract were analyzed retrospectively regarding demographic and phenomenological profile, the mode of presentation, diagnosis, management, complications, and possible contributing factors leading to the event. RESULTS: Out of 17,978 inpatients, ten patients (0.055%) presented with foreign body insertion in the lower genitourinary tract in last 6 years. Mean age was 28.1 +/- 13.9 (7-50) years. Objects used for insertion were varied from seeds, twigs to the electric wire. The contributing factors were lack of partner, misconception about masturbation, and underlying psychiatric illness. The presenting symptoms were pain and swelling of the penis, difficulty in voiding, and skin ulceration. The diagnosis was possible by simple observation in four patients, X-ray kidney, ureter, and bladder, and sonography of the pelvis in six patients. Five patients had endoscopic retrieval of foreign body, 2 had an open, suprapubic cystotomy, urethrotomy was needed in one patient, and forceps removal in two patients. There were no postoperative complications. Psychiatric profile was evaluated in nine patients. CONCLUSIONS: Foreign body insertion to lower urinary tract was rare. A main cause for insertion of foreign bodies was autoerotism, misconceptions regarding masturbation, and underlying psychiatric illness. In addition to suitable method of surgical removal, counseling and psychiatric evaluation are necessary to prevent recurrences or for early detection of psychiatric problems. PMID- 27453658 TI - Is hemoglobin A1c level effective in predicting the prognosis of Fournier gangrene? AB - OBJECTIVES: To evaluate the effect of immune failure and/or diabetes mellitus (DM) association on the mortality and morbidity of the Fournier's Gangrene (FG), and interrelatedly, the usability of HbA1c level in the prediction of prognosis. MATERIALS AND METHODS: The data of 38 patients with the diagnosis of FG were investigated retrospectively. The patients were divided into two groups as patients with DM (Group 1, n = 18) and non-diabetics (Group 2, n = 20). The patients in group 1 were also divided into two subgroups as patients with HbA1c value >=7 (Group 1a) and HbA1c value <7 (Group 1b). RESULTS: The mean age of all 38 male patients was 66.3 +/- 6.4 years. The initial symptoms were scrotal rash and swelling (n = 20, 52.6%), high fever (>38 degrees C) (n = 22, 57.8%), purulent discharge from genital or perineal areas (n = 13, 34.2%), skin bruises (n = 11, 28.9%) and general state disorder in five patients that were admitted from day care center (13.1%). DM, as the most often comorbid disease, was detected in 18 patients (47.3%). Six patients (15.7%) were deceased during the follow-up period. CONCLUSION: In the present study, the researchers determined that diabetic patients with HbA1c level of 7 or higher had worse prognosis, and increased mortality. PMID- 27453660 TI - Spinal arteriovenous malformation presenting with urinary retention. AB - We present a case of a young female patient presenting predominantly with recurrent episodes of urinary retention. Extensive urological workup was unremarkable. There were some subtle and long-standing neurological findings which prompted us to investigate further with a spinal magnetic resonance imaging scan. The scan demonstrated a spinal arteriovenous malformation (AVM) beginning from the L4/L5 level to the S1/S2 level. Spinal AVM can be a rare cause of urinary retention, and we would like to highlight the importance of having that in the list of our differential when other more common causes have been excluded, and the patient remains symptomatic. PMID- 27453659 TI - Myeloid sarcoma of the periprostatic tissue and prostate: Case report and review of literature. AB - Myeloid sarcoma (MS) is a rare extramedullary tumor composed of immature cells of myeloid lineage that destroy the original tissue architecture in which it is found. It is most commonly identified in patients with acute myelogenous leukemia, and less often in myelodysplastic syndromes (MDSs) and other myeloproliferative disorders. It is most commonly reported in the periosteum, bone, skin, and lymph nodes but has been reported in many other sites of the body. Herein, we describe a case of MS involving the periprostatic tissue and review of literature of MS of the prostate. Our patient was initially diagnosed with MDS and was in remission following successful treatment. Six months later, the patient was diagnosed with prostate adenocarcinoma, and MS of the periprostatic tissue was incidentally discovered in the postprostatectomy pathology specimen. An extensive review of literature from 1997 to 2014 revealed a total of eight cases of MS involving the prostate. Of the eight cases of MS of the prostate, four were primary MS (absence of a history of leukemia) and four were secondary MS. Three received local radiation to the prostate with relief of obstructive symptoms, and one of them had a repeat prostate biopsy negative for leukemic cells. Despite being a rare entity, MS should be considered as a differential diagnosis of soft tissue masses, especially in patients with a history of hematological malignancies. PMID- 27453661 TI - Primary adenocarcinoma of ureter: A rare histopathological variant. AB - Primary carcinoma of ureter is an uncommon malignancy. Of which, mostly are transitional cell carcinomas followed by squamous cell carcinomas and adenocarcinomas being the rarest histopathology encountered. We report a case of adenocarcinoma ureter in a middle-aged male along with its clinical scenario. A 62-year-old male, presented with complaints of lower urinary tract symptoms. Computerized tomography urogram showed a soft tissue lesion at the right ureterovesical junction. Cystoscopic biopsy reported villous adenoma. Diethylene triamine pentaacetic acid scan reported nonfunctioning right kidney. He underwent laparoscopic right nephroureterectomy, and histopathology reported adenocarcinoma of the right lower third of ureter, with positive distal and close radial margins. The patient received external beam radiation to the postoperative bed and lymph nodes, and he is disease-free till date. PMID- 27453662 TI - A case of Carney complex presenting as acute testicular pain. AB - We describe the case of a 7-year-old boy who presented with testicular pain but was found to have bilateral testicular lesions later confirmed as Sertoli cell tumors. Genetic testing confirmed a PRKAR1A gene mutation consistent with Carney complex, a rare genetic disorder characterized by skin lesions, myxomas, and multiple endocrine neoplasms. A review of the condition is made highlighting the association with testicular tumors, particularly of Sertoli cell origin. PMID- 27453663 TI - Operative considerations for late-presenting persistent Mullerian duct syndrome. AB - Persistent Mullerian duct syndrome (PMDS) is a condition in which a 46, XY male displays masculine external genitalia, but internally retains developed Mullerian duct structures (uterus, fallopian tubes, and upper two-thirds vagina). Thoughtful operative consideration is needed to maximize the therapeutic benefit while minimizing the risk of hypogonadism, infertility, and erectile dysfunction. We report a 53-year-old male with a pelvic mass incidentally discovered on routine ultrasound, intra-operatively discovered to be PMDS. PMDS is a rare condition that may present late in life. The primary operative consideration is performing orchiopexy for cancer surveillance or orchiectomy if orchiopexy is not possible. Additional considerations include surveillance and counseling of infertility, hypogonadism, and assessment of the potential need for involvement of psychiatry. Removal of Mullerian remnants is a subject to debate. If possible, discuss with the patient their risks and options in the preoperative setting to guide operative planning. PMID- 27453664 TI - A case report of inflammatory myofibroblastic tumor of urinary bladder. AB - An old woman was admitted due to massive visible hematuria; the hematuria was difficult to control and lasted 3 days. Cystoscopy showed a solid tumor in the urinary bladder. After performing transrectal resection, histology and immunohistochemistry showed that it was inflammatory myofibroblastic tumor. PMID- 27453665 TI - Extended partial cystectomy with augmentation cystoplasty in urachal adenocarcinoma: An oncologically favorable but underutilized alternative to radical cystectomy. AB - Partial/extended partial cystectomy (EPC) is the most common surgery done for localized urachal malignancies. However, sometimes, after EPC, patients may be left with small bladder remnant, reconstruction of which will result in very small capacity bladder with resultant severe storage voiding symptoms. We report a case of urachal adenocarcinoma, in which when a small bladder remnant was left post-EPC, instead of proceeding with radical cystectomy (RC) and neobladder (the standard alternative), bladder augmentation was done with good oncological and voiding outcome. Augmentation cystoplasty has many advantages over neobladder and we suggest it as an oncologically comparable alternative to RC with neobladder, which has been underutilized in urachal malignancies as we found on literature review. PMID- 27453666 TI - High-grade undifferentiated pleomorphic sarcoma of the pelvis: A case report and review of literature. AB - High-grade spindle cell sarcomas are rare undifferentiated pleomorphic cancers that present a treatment challenge to urological practices, especially when they present in the pelvis. We report a 46-year-old male patient who presented to our urology clinic with urinary retention after having a Foley catheter placed at an outlying facility. A voiding trial was attempted, but the patient failed this trial. This failure resulted in cystoscopy with bilateral retrograde pyelograms, which revealed a compressed bladder due to extrinsic compression. This finding had been evaluated with a computed tomography (CT) scan with and without intravenous contrast that showed a 14 cm pelvic mass with bladder displacement and compression. A fine needle aspiration was done at this outlying facility, prior to referral to our office, and it confirmed spindle cell pathology. The mass was surgically excised with the histology revealing a pelvic spindle cell sarcoma with positive surgical margins. Further, metastatic work-up with CT/positron emission tomography revealed bone and lung metastasis. The patient is currently undergoing chemotherapy and radiation. In this case study, we will review staging, management, differential diagnosis, chemotherapy, and radiation. PMID- 27453667 TI - Cutaneous metastasis: An unusual presenting feature of urologic malignancies. AB - Urological malignancies are well known for their ability to metastasize widely. The incidence of cutaneous metastasis from all urologic malignancies has been reported to be 0.73-1.3% with the primary most commonly being renal cell carcinoma followed by carcinoma bladder, adenocarcinoma prostate, and testicular germ cell tumor in decreasing order of frequency. Metastasis to the skin is unusual and has been predominantly reported as a late manifestation of the disease. We describe two patients with urologic malignancies who had cutaneous metastasis as their initial presenting feature. PMID- 27453668 TI - Plasmacytoid urothelial carcinoma of the bladder with extensive scrotal wall invasion. AB - Plasmacytoid urothelial carcinoma (PUC) is an extremely rare and aggressive variant of urothelial carcinoma. We report a case of a 62-year-old male who presented with a rapid spread of PUC to involve his entire scrotal wall after failed surgery and chemotherapy. The second course of chemotherapy was effective in providing symptom control. We believe this is the first case report of PUC causing such rapid and extensive scrotal invasion. This case highlights the important features of PUC including the pattern of tumor spread along fascial planes, the tendency for initial understaging, and the rapid recurrence after initially response to chemotherapy. PMID- 27453669 TI - Giant cystic pheochromocytoma: A silent entity. AB - Pheochromocytoma is a catecholamine secreting tumor that originate from chromaffin cells. Usually, it is solid neoplasm of the adrenal medulla, however cystic pheochromocytoma is a rare neuro-endocrine tumour that is frequently asymptomatic and often diagnosed incidentally on imaging or intra-operatively. Only a few cases of cystic pheochromocytomas have been reported in the world literature. We present a case of giant cystic pheochromocytoma in a 65 years old lady who presented with a large retroperitoneal lump, which is probably the world's third largest pheochromocytoma as per the available indexed literature. PMID- 27453670 TI - Breast metastases from a malignant peripheral nerve sheath tumor of the kidney: An unusual presentation. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare soft tissue sarcomas of ectomesenchymal origin. They are commonly seen in association with neurofibromatosis type 1 (NF-1), but can also occur without a history of NF (isolated MPNST). MPNSTs are most commonly located on the extremities (brachial and sacral plexus), head and neck, and trunk regions and are rarely reported in genitourinary organs. These tumors are aggressive, with a high recurrence rate and distant metastases. MPNST involving the kidney is extremely rare, and review of the literature using PubMed from 2001 to 2014 revealed eight cases of MPNST involving the kidney (seven, primarily involving the kidney and one metastatic MPNST of the kidney). Herein, we describe a case of breast metastases from an MPNST of the kidney without a history of NF-1. The patient was initially diagnosed with a spindle cell neoplasm of the kidney with peripheral nerve sheath differentiation. Eventually, the patient developed a right breast mass that was diagnosed as metastatic MPNST. The patient refused any kind of treatment and died 6 months later in hospice care. PMID- 27453671 TI - Small renal tumor with lymph nodal enlargement: A histopathological surprise. AB - Renal cancer with lymph nodal mass on the investigation is clinically suggestive of an advanced tumor. Small renal cancers are not commonly associated with lymph nodal metastasis. Association of renal cell carcinoma with renal tuberculosis (TB) in the same kidney is also rare. We report here a case of small renal cancer with multiple hilar and paraaortic lymph nodes who underwent radical nephrectomy, and histopathology report showed renal and lymph nodal TB too. PMID- 27453672 TI - Early metastasis to anterior abdominal wall following radical cystectomy: A rare presentation. AB - Abdominal wall metastasis from urothelial cancer is extremely rare and very few such cases have been reported in the literature. As such the treatment protocols are not so well defined. We present an interesting case of a 65-year-old male patient, known case of chronic kidney disease, who presented with a large, fungating infraumbilical mass 8 months postradical cystectomy. The mass involved full thickness anterior abdominal wall and small bowel including the ileal conduit. Wide excision of the mass along with adhered bowel loops and partial excision of the ileal conduit with right ureteric reimplant was performed. The large defect in the anterior abdominal wall was closed using a mesh (permanent with a bioresorbable coating inside) and myocutaneous thigh flap. The histopathological examination of the excised mass was consistent with secondary from the urothelial tumor. PMID- 27453673 TI - Bladder leiomyoma in male patient presenting with renal oncocytoma: Are the two conditions related? AB - A 64-year-old male patient with a large pelvic mass and a right renal mass was referred to our facility. The patient underwent a right radical nephrectomy and pelvic mass excision. A histopathological examination led to a diagnosis of renal oncocytoma and urinary bladder leiomyoma. PMID- 27453674 TI - RE: Semi-rigid ureteroscopy - Proximal versus distal ureteral stone. PMID- 27453675 TI - Zero to pi Continuously Controllable Cross Phase Modulation in Doppler Broadened N-Type Electromagnetically Induced Transparency Medium. AB - We demonstrate an observation of zero to pi continuously controllable cross-phase modulation based on N-type electromagnetically induced transparency scheme in a room-temperature 87Rb vapor. We theoretically and experimentally show that the signal field acquires a pi phase shift compared with the reference light in the presence of the phase-control field. Using the method of the optical Mach-Zehnder interferometer, we demonstrate that a zero to pi continuously controllable phase gate can be built by modulating the phase-control field. In addition, our theoretical calculation agrees well with the experimental observation, and the results presented in this work hold the potential applications for the orthogonal polarization/vector gate in the quantum information processing. PMID- 27453676 TI - Two-Volt Josephson Arbitrary Waveform Synthesizer Using Wilkinson Dividers. AB - The root-mean-square (rms) output voltage of the NIST Josephson arbitrary waveform synthesizer (JAWS) has been doubled from 1 V to a record 2 V by combining two new 1 V chips on a cryocooler. This higher voltage will improve calibrations of ac thermal voltage converters and precision voltage measurements that require state-of-the-art quantum accuracy, stability, and signal-to-noise ratio. We achieved this increase in output voltage by using four on-chip Wilkinson dividers and eight inner-outer dc blocks, which enable biasing of eight Josephson junction (JJ) arrays with high-speed inputs from only four high-speed pulse generator channels. This approach halves the number of pulse generator channels required in future JAWS systems. We also implemented on-chip superconducting interconnects between JJ arrays, which reduces systematic errors and enables a new modular chip package. Finally, we demonstrate a new technique for measuring and visualizing the operating current range that reduces the measurement time by almost two orders of magnitude and reveals the relationship between distortion in the output spectrum and output pulse sequence errors. PMID- 27453677 TI - Cognitive Attributions in Depression: Bridging the Gap between Research and Clinical Practice. AB - Individuals seeking treatment for depression often are struggling with maladaptive cognitions that impact how they view themselves and the world. Research on cognitive attributions that underlie depressed mood focuses on the phenomenon of negative cognitive style, in which depressed people tend to view undesirable occurrences in life as having internal, stable, and global causes. Based on research, clinicians have developed various techniques that seek to modify depressive attributions in order to alleviate symptoms of depression. In this article, the authors review the literature on attributions in depression, present clinically relevant interventions based on empirical support, provide case examples, and summarize future directions and recommendations for researchers and practitioners. PMID- 27453678 TI - Reducing Therapist Contact in Parenting Programs: Evaluation of Internet-Based Treatments for Child Conduct Problems. AB - This study evaluated two Internet-based versions of Parent Management Training (PMT) and the effects of greatly reducing the contact required of a mental health professional on treatment of children referred for conduct problems. We were interested whether reduced contact with a therapist influenced treatment outcome, therapeutic alliance, parent adherence to treatment prescriptions, and parent reactions to and evaluations of the treatment procedures. Sixty children and their caregivers were assigned to receive either Full Contact PMT (with the amount of weekly contact similar to traditional PMT; approximately 50 minutes of direct therapist contact each week) or Reduced Contact PMT (with most information provided through recordings; approximately 10 minutes of therapist contact each week). Children in both groups showed significant and similar reductions in antisocial behaviors specifically, internalizing and externalizing symptoms more generally, and improvements in overall adaptive functioning. Therapeutic alliance also was similar across the two treatment groups. However, parents rated Full Contact treatment as more acceptable than the reduced version. Both treatments were similar in outcomes to in-person treatment as evaluated by a nonrandomized matched sample used as a benchmark in supplementary analyses. Overall, the findings indicate that therapist contact can be reduced while positive treatment outcomes are maintained but that interventions that reduce direct time with a therapist may be viewed less positively by clients. PMID- 27453680 TI - Speech in ALS: Longitudinal Changes in Lips and Jaw Movements and Vowel Acoustics. AB - PURPOSE: The goal of this exploratory study was to investigate longitudinally the changes in facial kinematics, vowel formant frequencies, and speech intelligibility in individuals diagnosed with bulbar amyotrophic lateral sclerosis (ALS). This study was motivated by the need to understand articulatory and acoustic changes with disease progression and their subsequent effect on deterioration of speech in ALS. METHOD: Lip and jaw movements and vowel acoustics were obtained for four individuals with bulbar ALS during four consecutive recording sessions with an average interval of three months between recordings. Participants read target words embedded into sentences at a comfortable speaking rate. Maximum vertical and horizontal mouth opening and maximum jaw displacements were obtained during corner vowels. First and second formant frequencies were measured for each vowel. Speech intelligibility and speaking rate score were obtained for each session as well. RESULTS: Transient, non-vowel-specific changes in kinematics of the jaw and lips were observed. Kinematic changes often preceded changes in vowel acoustics and speech intelligibility. CONCLUSIONS: Nonlinear changes in speech kinematics should be considered in evaluation of the disease effects on jaw and lip musculature. Kinematic measures might be most suitable for early detection of changes associated with bulbar ALS. PMID- 27453681 TI - Comprehensive School Reform: Meta-Analytic Evidence of Black-White Achievement Gap Narrowing. AB - : This meta-analysis extends a previous review of the achievement effects of comprehensive school reform (CSR) programs (Borman, Hewes, Overman, & Brown, 2003). That meta-analysis observed significant effects of well endowed and well researched programs, but it did not account for race/ethnicity. This article synthesizes 34 cohort or quasi-experimental outcomes of studies that incorporated the policy-critical characteristic of race/ethnicity. FINDINGS: compared with matched traditional schools, the black-white achievement gap narrowed significantly more among students in CSR schools. In addition, the aggregate effects were large, substantially to completely eliminating the achievement gap between African American and non-Hispanic white students in elementary and middle schools. Title I policies before or after the No Child Left Behind Act of 2001 seem to have had essentially no impact on the black-white achievement gap. Curricular and testing mandates along with the threat of sanctions without concomitant resource supports seem to have failed. This study suggests that educational achievement inequities need not be America's destiny. It seems that they could be eliminated through concerted political will and ample resource commitments to evidence-based educational programs. PMID- 27453679 TI - Nonoxidative removal of organics in the activated sludge process. AB - The activated sludge process is commonly used to treat wastewater by aerobic oxidation of organic pollutants into carbon dioxide and water. However, several nonoxidative mechanisms can also contribute to removal of organics. Sorption onto activated sludge can remove a large fraction of the colloidal and particulate wastewater organics. Intracellular storage of, e.g., polyhydroxyalkanoates (PHA), triacylglycerides (TAG), or wax esters can convert wastewater organics into precursors for high-value products. Recently, several environmental, economic, and technological drivers have stimulated research on nonoxidative removal of organics for wastewater treatment. In this paper, we review these nonoxidative removal mechanisms as well as the existing and emerging process configurations that make use of them for wastewater treatment. Better utilization of nonoxidative processes in activated sludge could reduce the wasteful aerobic oxidation of organic compounds and lead to more resource-efficient wastewater treatment plants. PMID- 27453683 TI - Critical Conversations about Optimal Design Column: Thorough Error Testing a Requirement for Strong EHR Usability. PMID- 27453682 TI - A Comparative Assessment of Track Plates to Quantify Fine Scale Variations in the Relative Abundance of Norway Rats in Urban Slums. AB - Norway rats (Rattus norvegicus) living in urban environments are a critical public health and economic problem, particularly in urban slums where residents are at a higher risk for rat borne diseases, yet convenient methods to quantitatively assess population sizes are lacking. We evaluated track plates as a method to determine rat distribution and relative abundance in a complex urban slum environment by correlating the presence and intensity of rat-specific marks on track plates with findings from rat infestation surveys and trapping of rats to population exhaustion. To integrate the zero-inflated track plate data we developed a two-component mixture model with one binary and one censored continuous component. Track plate mark-intensity was highly correlated with signs of rodent infestation (all coefficients between 0.61 and 0.79 and all p-values < 0.05). Moreover, the mean level of pre-trapping rat-mark intensity on plates was significantly associated with the number of rats captured subsequently (Odds ratio1.38; 95% CI 1.19-1.61) and declined significantly following trapping (Odds ratio 0.86; 95% CI 0.78-0.95). Track plates provided robust proxy measurements of rat abundance and distribution and detected rat presence even when populations appeared 'trapped out'. Tracking plates are relatively easy and inexpensive methods that can be used to intensively sample settings such as urban slums, where traditional trapping or mark-recapture studies are impossible to implement, and therefore the results can inform and assess the impact of targeted urban rodent control campaigns. PMID- 27453684 TI - Making nursing practice visible: At the brink of fulfilling the DREAM. PMID- 27453685 TI - The gamma-ray afterglows of tidal disruption events. AB - A star wandering too close to a supermassive black hole (SMBH) will be tidally disrupted. Previous studies of such 'tidal disruption event' (TDE) mostly focus on the stellar debris that are bound to the system, because they give rise to luminous flares. On the other hand, half of the stellar debris in principle are unbound and can stream to a great distance, but so far there is no clear evidence that this 'unbound debris stream' (UDS) exists. Motivated by the fact that the circum-nuclear region around SMBHs is usually filled with dense molecular clouds (MCs), here we investigate the observational signatures resulting from the collision between an UDS and an MC, which is likely to happen hundreds of years after a TDE. We focus on gamma-ray emission (0.1-105 GeV), which comes from the encounter of shock-accelerated cosmic rays with background protons and, more importantly, is not subject to extinction. We show that because of the high proton density inside an MC, the peak gamma-ray luminosity, about 1039 erg s-1, is at least 100 times greater than that in the case without an MC (only with a smooth interstellar medium). The luminosity decays on a time-scale of decades, depending on the distance of the MC, and about a dozen of these 'TDE afterglows' could be detected within a distance of about 16 Mpc by the future Cherenkov Telescope Array. Without careful discrimination, these sources potentially could contaminate the searches for starburst galaxies, galactic nuclei containing millisecond pulsars or dark matter annihilation signals. PMID- 27453686 TI - Integrating phylogeography and species distribution models: cryptic distributional responses to past climate change in an endemic rodent from the central Chile hotspot. AB - AIM: Biodiversity losses under the species level may have been severely underestimated in future global climate change scenarios. Therefore, it is important to characterize the diversity units at this level, as well as to understand their ecological responses to climatic forcings. We have chosen an endemic rodent from a highly endangered ecogeographic area as a model to look for distributional responses below the species level: Phyllotis darwini. LOCATION: The central Chile biodiversity hotspot: This area harbours a high number of endemic species, and it is known to have experienced vegetational displacements between two mountain systems during and after the Last Glacial Maximum. METHODS: We have characterized cryptic lineages inside P. darwini in a classic phylogeographic approach; those intraspecific lineages were considered as relevant units to construct distribution models at Last Glacial Maximum and at present, as border climatic conditions. Differences in distribution between border conditions for each lineage were interpreted as distributional responses to post-glacial climate change. RESULTS: The species is composed of two major phylogroups: one of them has a broad distribution mainly across the valley but also in mountain ranges, whereas the other displays a disjunct distribution across both mountain ranges and always above 1500 m. The lineage distribution model under LGM climatic conditions suggests that both lineages were co distributed in the southern portion of P. darwini's current geographic range, mainly at the valley and at the coast. MAIN CONCLUSIONS: Present distribution of lineages in P. darwini is the consequence of a cryptic distributional response to climate change after LGM: postglacial northward colonization, with strict altitudinal segregation of both phylogroups. PMID- 27453687 TI - Light and maternal influence in the entrainment of activity circadian rhythm in infants 4-12 weeks of age. AB - The influence of light and maternal activity on early infant activity rhythm were studied in 43 healthy, maternal-infant pairs. Aims included description of infant and maternal circadian rhythm of environmental light, assessing relations among of activity and light circadian rhythm parameters, and exploring the influence of light on infant activity independent of maternal activity. Three-day light and activity records were obtained using actigraphy monitors at infant ages 4, 8, and 12 weeks. Circadian rhythm timing, amplitude, 24-hour fit, rhythm center, and regularity were determined using cosinor and nonparametric circadian rhythm analyses (NPCRA). All maternal and infant circadian parameters for light were highly correlated. When maternal activity was controlled, the partial correlations between infant activity and light rhythm timing, amplitude, 24-hour fit, and rhythm center demonstrated significant relation (r = .338 to .662) at infant age 12 weeks, suggesting entrainment. In contrast, when maternal light was controlled there was significant relation between maternal and infant activity rhythm (r = 0.470, 0.500, and 0.638 at 4, 8 and 12 weeks, respectively) suggesting the influence of maternal-infant interaction independent of photo entrainment of cycle timing over the first 12 weeks of life. Both light and maternal activity may offer avenues for shaping infant activity rhythm during early infancy. PMID- 27453688 TI - Surfactant toxicity to Artemia Franciscana and the influence of humic acid and chemical composition. AB - Surfactants can be extremely toxic to aquatic species and are introduced to the environment in a variety of ways. It is thus important to understand how other environmental constituents, in this case humic acids (HAs), may alter the toxicity of anthropogenic surfactants. Hatching and mortality assays of Artemia Franciscana were performed for three different toxic surfactants: Triton X-100 (Tx-100, non-ionic), cetylpyridinium chloride (CPC, cationic), and sodium dodecyl sulfate (SDS, anionic). Humic acids of varying composition and concentrations were added to the assays to determine the toxicity mitigating ability of the HAs. Tx-100 had a significant toxic effect on Artemia mortality rates and HAs from terrestrial sources were able to mitigate the toxicity, but an aquatic HA did not. CPC and SDS limited hatching success of the Artemia and, as HAs were added, the hatching percentages increased for all HA sources, indicating toxicity mitigation. In order to determine which functional groups within HAs were responsible for the interaction with the surfactants, the HAs were chemically modified by: (i) bleaching to reduce aromatics, (ii) Soxhlet extraction to reduce lipids, and (iii) acid hydrolysis to reduce O- and N-alkyl groups. Although most of the modified HAs had some toxicity mitigating ability for each of the surfactants, there were two notable differences: 1) the lipid-extracted HA did not reduce the toxicity of Tx-100 and 2) the bleached HA had a lower toxicity mitigating ability for CPC than the other modified HAs. PMID- 27453689 TI - Generations of interdisciplinarity in bioinformatics. AB - Bioinformatics, a specialism propelled into relevance by the Human Genome Project and the subsequent -omic turn in the life science, is an interdisciplinary field of research. Qualitative work on the disciplinary identities of bioinformaticians has revealed the tensions involved in work in this "borderland." As part of our ongoing work on the emergence of bioinformatics, between 2010 and 2011, we conducted a survey of United Kingdom-based academic bioinformaticians. Building on insights drawn from our fieldwork over the past decade, we present results from this survey relevant to a discussion of disciplinary generation and stabilization. Not only is there evidence of an attitudinal divide between the different disciplinary cultures that make up bioinformatics, but there are distinctions between the forerunners, founders and the followers; as inter/disciplines mature, they face challenges that are both inter-disciplinary and inter-generational in nature. PMID- 27453690 TI - What level of competency do experienced nurses expect from a newly graduated registered nurse? Results of an Australian modified Delphi study. AB - BACKGROUND: Individuals who have recently completed accredited courses and are eligible to register as a nurse in Australia are often referred to as not being 'work-ready' by clinically based colleagues. This project identified the level of competence that can be reasonably expected of a newly registered nurse (RN) graduating in Australia. The research was undertaken using the necessary skills identified by Crookes and Brown in 2010. METHODS: A consensus methodology using a modified Delphi technique invited experienced nurses to identify the level of competency expected by the new RN in each of the skills areas. RESULTS: More than half of respondents did not believe that new graduates could practice independently in 18 of the 30 skills areas. There were only four skills areas where more than two thirds of the respondents believed the new graduate could operate independently. CONCLUSIONS: There is a lack of clarity about the level of competency of the newly graduating registered nurse in Australia. The profession and employers need clarity regarding the areas and level of competence that can reasonably be expected of a newly graduated RN. Utilising the findings of this research will enable the skills and competencies to be integrated into eligibility to practice programmes. Further research needs to be undertaken to review the foci of nursing preparation programmes to meet the needs of novice practitioners and the health care consumer population. PMID- 27453691 TI - Oridonin inhibits pancreatic cancer cell migration and epithelial-mesenchymal transition by suppressing Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Oridonin (ORI) can inhibit proliferation and migration in various types of cancer cell lines. However, the exact mechanism remains unclear. We investigated the migration inhibitory effect of ORI on human pancreatic cancer SW1990 cells and dissected the possible molecular mechanism(s). METHODS: CCK-8 assay was used to observe the cell viability. Wound healing assay, transwell assay and spontaneous metastasis model were used to observe the migration activities. Real-time PCR, immunofluorescence, western blot analysis and immunohistochemistry methods were used to observe the expression of genes or proteins. RESULTS: ORI inhibited the migration of SW1990 cells. Real-time PCR and immuno-fluorescence analyses of epithelial-to-mesenchymal transition (EMT) markers were compared between control group and ORI group. The expression of mesenchymal molecular markers, such as vimentin, snail and slug decreased. The expression of epithelial-related marker E-cadherin increased. Wnt/beta-catenin signalling was inhibited by ORI using luciferase reporter assay. ORI can decrease the beta-catenin protein level not only in the nucleus, but also in the cytoplasm and the whole cell after the treatment with ORI and glycogen synthase kinase 3beta (GSK3beta) was increased in the ORI-treated group. CHIR could attenuate the effects of ORI in SW1990 cells. We established a mice model by injecting 1 * 10(6) SW1990 cells into nude mice intraperitoneally to test whether ORI affects tumour metastasis. Metastatic formation was inhibited by ORI (5 and 10 mg/kg) compared with the control group. Tumour sections stained with anti-E-cadherin, anti-vimentin and anti-beta-catenin antibodies revealed that ORI inhibited EMT, as well as the Wnt/beta-catenin pathway in vivo. CONCLUSIONS: ORI can inhibit pancreatic cancer cell SW1990 migration and EMT by down-regulating Wnt/beta catenin signal transduction in vitro and in vivo. Therefore, it can be potentially and effectively used in the clinical management of pancreatic cancer. PMID- 27453692 TI - A minute ostracod (Crustacea: Cytheromatidae) from the Miocene Solimoes Formation (western Amazonia, Brazil): evidence for marine incursions? AB - A huge wetland (the 'Pebas system') covered western Amazonia during the Miocene, hosting a highly diverse and endemic aquatic fauna. One of the most contentious issues concerns the existence, potential pathways and effects of marine incursions on this ecosystem. Palaeontological evidences (body fossils) are rare. The finding of a new, presumably marine ostracod species (Pellucistoma curupira sp. nov.) in the upper middle Miocene Solimoes Formation initiated a taxonomic, ecological and biogeographical review of the genus Pellucistoma. We demonstrate that this marine (sublittoral, euhaline), subtropical-tropical taxon is biogeographically confined to the Americas. The biogeographical distribution of Pellucistoma largely depends on geographical, thermal and osmotic barriers (e.g. land bridges, deep and/or cold waters, sea currents, salinity). We assume an Oligocene/early Miocene, Caribbean origin for Pellucistoma and outline the dispersal of hitherto known species up to the Holocene. Pellucistoma curupira sp. nov. is dwarfed in comparison to all other species of this genus and extremely thin-shelled. This is probably related to poorly oxygenated waters and, in particular, to strongly reduced salinity. The associated ostracod fauna (dominated by the eurypotent Cyprideis and a few, also stunted ostracods of possibly marine ancestry) supports this claim. Geochemical analyses (delta18O, delta13C) on co-occurring ostracod valves (Cyprideis spp.) yielded very light values, indicative of a freshwater setting. These observations point to a successful adaptation of P. curupira sp. nov. to freshwater conditions and therefore do not signify the presence of marine water. Pellucistoma curupira sp. nov. shows closest affinities to Caribbean species. We hypothesize that Pellucistoma reached northern South America (Llanos Basin) during marine incursions in the early Miocene. While larger animals of marine origin (e.g. fishes, dolphins, manatees) migrated actively into the Pebas wetland via fluvial connections, small biota (e.g. P. curupira sp. nov.) were phoretically freighted and developed freshwater tolerance over long timescales. http://zoobank.org/urn:lsid:zoobank.org:pub:886C6476-393D-4323-8C0E-06BB8BD02FD9. PMID- 27453693 TI - THE INTRINSIC VALUE OF HFO FEATURES AS A BIOMARKER OF EPILEPTIC ACTIVITY. AB - High frequency oscillations (HFOs) are a promising biomarker of epileptic brain tissue and activity. HFOs additionally serve as a prototypical example of challenges in the analysis of discrete events in high-temporal resolution, intracranial EEG data. Two primary challenges are 1) dimensionality reduction, and 2) assessing feasibility of classification. Dimensionality reduction assumes that the data lie on a manifold with dimension less than that of the features space. However, previous HFO analysis have assumed a linear manifold, global across time, space (i.e. recording electrode/channel), and individual patients. Instead, we assess both a) whether linear methods are appropriate and b) the consistency of the manifold across time, space, and patients. We also estimate bounds on the Bayes classification error to quantify the distinction between two classes of HFOs (those occurring during seizures and those occurring due to other processes). This analysis provides the foundation for future clinical use of HFO features and guides the analysis for other discrete events, such as individual action potentials or multi-unit activity. PMID- 27453694 TI - Sexual Assault in Bisexual and Heterosexual Women Survivors. AB - Social support is related to sexual minority status and negative psychological impact among sexual assault survivors. We compared bisexual and heterosexual survivors on how different types of social support are connected to symptoms of posttraumatic stress disorder (PTSD) and depression. A community sample of bisexual and heterosexual (N = 905) women sexual assault survivors completed three annual surveys. Heterosexual women reported greater perceived social support and fewer negative reactions to disclosure of sexual assault than bisexual women, but there were no differences in frequency of social contact. Perceived social support and frequency of social contact were related to fewer psychological symptoms of PTSD and depression for all women. Heterosexual women had fewer psychological symptoms than bisexual women. Finally, perceived social support mediated the relationship of sexual orientation with depressive symptoms but not with PTSD symptoms. These findings suggest that social support and sexual orientation may explain women's post-assault adjustment. PMID- 27453696 TI - SimNest: Social Media Nested Epidemic Simulation via Online Semi-supervised Deep Learning. AB - Infectious disease epidemics such as influenza and Ebola pose a serious threat to global public health. It is crucial to characterize the disease and the evolution of the ongoing epidemic efficiently and accurately. Computational epidemiology can model the disease progress and underlying contact network, but suffers from the lack of real-time and fine-grained surveillance data. Social media, on the other hand, provides timely and detailed disease surveillance, but is insensible to the underlying contact network and disease model. This paper proposes a novel semi-supervised deep learning framework that integrates the strengths of computational epidemiology and social media mining techniques. Specifically, this framework learns the social media users' health states and intervention actions in real time, which are regularized by the underlying disease model and contact network. Conversely, the learned knowledge from social media can be fed into computational epidemic model to improve the efficiency and accuracy of disease diffusion modeling. We propose an online optimization algorithm to substantialize the above interactive learning process iteratively to achieve a consistent stage of the integration. The extensive experimental results demonstrated that our approach can effectively characterize the spatio-temporal disease diffusion, outperforming competing methods by a substantial margin on multiple metrics. PMID- 27453695 TI - Innovations in Health Value and Functional Food Development of Quinoa (Chenopodium quinoa Willd.). AB - Quinoa (Chenopodium quinoa Willd., Amaranthaceae) is a grain-like, stress tolerant food crop that has provided subsistence, nutrition, and medicine for Andean indigenous cultures for thousands of years. Quinoa contains a high content of health-beneficial phytochemicals, including amino acids, fiber, polyunsaturated fatty acids, vitamins, minerals, saponins, phytosterols, phytoecdysteroids, phenolics, betalains, and glycine betaine. Over the past 2 decades, numerous food and nutraceutical products and processes have been developed from quinoa. Furthermore, 4 clinical studies have demonstrated that quinoa supplementation exerts significant, positive effects on metabolic, cardiovascular, and gastrointestinal health in humans. However, vast challenges and opportunities remain within the scientific, agricultural, and development sectors to optimize quinoa's role in the promotion of global human health and nutrition. PMID- 27453697 TI - A Review of Pharmacological Management of Attention-Deficit/Hyperactivity Disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common psychological diagnosis in children. This disorder impacts children and adolescents in all areas of life, including academic performance, extracurricular activities, and social interactions. ADHD can continue into adulthood where unemployment and substance abuse has been described. Although behavioral therapy is recommended for all patients with ADHD, medication management typically is initiated soon after diagnosis. Psychostimulants remain the primary medication of choice. This review focuses on the clinical use of psychostimulant medication in children and adolescents. The pharmacodynamic and pharmacokinetic differences between the newest long-acting formulations as well as commonly encountered adverse drug reactions, with suggested management strategies, will be highlighted. Non stimulant therapy with atomoxetine or alpha2-adrenergic agonists is also reviewed. These agents may be warranted for patients who cannot tolerate psychostimulant therapy or have a comorbid condition. Finally, the 8-year multimodal treatment study results are also discussed. PMID- 27453698 TI - Appropriate Use of Vancomycin in NICU Despite Free-for-All Policy. AB - OBJECTIVES: Because of increases in antimicrobial resistance, the use of vancomycin in late-onset sepsis has come under scrutiny. The primary outcome of this study was to determine if vancomycin for the treatment of late-onset sepsis in the neonatal intensive care unit (NICU) was being discontinued within 72 hours according to the existing protocol. Secondary outcomes included the appropriateness of therapeutic drug monitoring associated with vancomycin, and renal dysfunction associated with the use of vancomycin in the NICU outside of the 72-hour policy. METHODS: A retrospective chart review was completed for patients in the NICU who received vancomycin for the treatment of late-onset sepsis between the dates of January 1, 2014, and July 1, 2014. RESULTS: There were 125 vancomycin treatment courses, of which 97 were included. Appropriate use of vancomycin, per policy, occurred in a total of 87 of 97 courses (89.6%). Therapeutic drug monitoring was evaluated by the number of appropriate troughs, determined using renal function and previous trough concentrations. There was not a statistically significant difference in the number of inappropriate troughs drawn between those that were continued on vancomycin appropriately (n = 17 courses; 4 of 44 inappropriate troughs) versus inappropriately (n = 10 courses; 1 of 22 inappropriate troughs; p = 0.66), despite the large number of troughs drawn. Adverse renal outcomes were not statistically significant in patients continued inappropriately on vancomycin (p = 1.0). CONCLUSIONS: Vancomycin use in the NICU for late-onset sepsis is appropriate per the existing antibiotic policy. Therapeutic drug monitoring could be improved, and adverse renal outcomes due to inappropriate continuation of vancomycin are rare. PMID- 27453699 TI - Medications for Children: A Survey of Community Pharmacists. AB - BACKGROUND: Seamless and safe discharge of children from hospital requires successful collaboration with community pharmacists, for whom pediatrics is often a small part of their practice. OBJECTIVES: The purpose of this study was to understand community pharmacists' comfort level and confidence in providing care for children. METHODS: We conducted a self-administered online survey of community pharmacists in Ontario, Canada. Respondents rated their comfort and confidence on a scale of 1 to 7 in each of 3 scenarios: oral morphine, prednisone, and amoxicillin. We also evaluated the relationship between participants' comfort level and demographics. RESULTS: We included 622 responses (377 completed and 245 partially completed surveys). A total of 182 participants (48%) were female, 271 participants (72%) had children of their own, and they had practiced pharmacy for a median (interquartile range) of 19 (5-28) years. The percentage of respondents who were comfortable (5-7 on a 7-point scale) with filling the prescriptions as written was 64% for morphine, 58% for prednisone, and 61% for amoxicillin and was not different among the scenarios. Having children was associated with increased comfort (p = 0.02), whereas other demographic variables were not. Compared to the amoxicillin scenario, pharmacists reported being significantly more likely to choose another course of action for prednisone (p = 0.01) but not for morphine (p = 0.25). Although 428 pharmacists (70%) agreed that they maintained adequate knowledge of pediatric topics, 558 (91%) were interested in more education. CONCLUSIONS: Variability exists in the confidence and comfort levels of community pharmacists when dealing with children, and many are not comfortable with the common prescriptions in this survey. PMID- 27453700 TI - Prediction of Warfarin Dose in Pediatric Patients: An Evaluation of the Predictive Performance of Several Models. AB - OBJECTIVES: The objective of this study was to evaluate the performance of pediatric pharmacogenetic-based dose prediction models by using an independent cohort of pediatric patients from a multicenter trial. METHODS: Clinical and genetic data (CYP2C9 [cytochrome P450 2C9] and VKORC1 [vitamin K epoxide reductase]) were collected from pediatric patients aged 3 months to 17 years who were receiving warfarin as part of standard care at 3 separate clinical sites. The accuracy of 8 previously published pediatric pharmacogenetic-based dose models was evaluated in the validation cohort by comparing predicted maintenance doses to actual stable warfarin doses. The predictive ability was assessed by using the proportion of variance (R(2)), mean prediction error (MPE), and the percentage of predictions that fell within 20% of the actual maintenance dose. RESULTS: Thirty-two children reached a stable international normalized ratio and were included in the validation cohort. The pharmacogenetic-based warfarin dose models showed a proportion of variance ranging from 35% to 78% and an MPE ranging from -2.67 to 0.85 mg/day in the validation cohort. Overall, the model developed by Hamberg et al showed the best performance in the validation cohort (R(2) = 78%; MPE = 0.15 mg/day) with 38% of the predictions falling within 20% of observed doses. CONCLUSIONS: Pharmacogenetic-based algorithms provide better predictions than a fixed-dose approach, although an optimal dose algorithm has not yet been developed. PMID- 27453701 TI - Comparison of Two High-Dose Magnesium Infusion Regimens in the Treatment of Status Asthmaticus. AB - OBJECTIVES: To determine the feasibility and safety of a simplified high-dose magnesium sulfate infusion (sHDMI) for the treatment of status asthmaticus. METHODS: We retrospectively compared 2 different high-dose magnesium sulfate infusion regimens, as adjunctive treatment in status asthmatics, using data that were preciously collected. The initial high-dose, prolonged magnesium infusion (HDMI) regimen consisted of a loading dose of 75 mg/kg (weight <= 30 kg) or 50 mg/kg (weight > 30 kg) over a period of 30 to 45 minutes followed by a continuous infusion of 40 mg/kg/hr for an additional 4 hours. This was compared to the sHDMI regimen that consisted of 50 mg/kg/hr for 5 hours. No loading dose was given to the patients in the sHDMI arm. Obese patients were dosed by using ideal body weight. Physiologic parameters (i.e., heart rate, blood pressure, respiratory rate, oxygen saturation) and serum magnesium (SrMg) concentrations were monitored during administration of magnesium sulfate. RESULTS: Nineteen patients receiving the initial HDMI regimen were compared with 10 patients who received the sHDMI regimen. There was no significant difference in SrMg concentrations or physiologic parameters between the 2 dose regimens. CONCLUSIONS: The HDMI and sHDMI regimens both produced SrMg concentrations that are associated with bronchodilation. The safety profile was also similar for the 2 regimens. The unambiguity of sHDMI has the potential to reduce medication errors that are associated with calculation of the loading dose, product preparation, and ultimate administration. PMID- 27453702 TI - Tobramycin and Beta-Lactam Antibiotic Use in Cystic Fibrosis Exacerbations: A Pharmacist Approach. AB - OBJECTIVES: Survey suggests that recommended doses and dosage regimens for antipseudomonal antibiotics for the treatment of acute pulmonary exacerbations in cystic fibrosis (CF) patients are not used, and one way to address these disparities is the involvement of pharmacists who are dedicated to CF. This is the first survey specifically designed for pharmacists at Cystic Fibrosis Foundation (CFF)-accredited centers to identify how tobramycin and antipseudomonal beta-lactams are being used. The purpose of this survey is to quantify this information and to promote future study to allow for implementation of tobramycin and beta-lactam dosage and monitoring standardization. METHODS: An anonymous national cross-sectional survey of pharmacists that are affliated with CFF-accredited programs was performed using Qualtrics.com. RESULTS: The survey had a 48.5% response rate. Most pediatric pharmacists (78.6%) report using extended-interval tobramycin dosage. The most common reported starting dosage was 10 mg/kg every 24 hours; most centers aim for a maximum serum concentration (Cmax) between 20 and 40 mg/L (78.6%). A total of 26 adult pharmacists reported using extended-interval dosage (96%), using an initial dosage of 10 mg/kg/day. The most common parameters used to adjust dosage were Cmax and area under the curve (AUC; 31%); the Cmax goal was 20 to 40 mg/L (84.2%). Most respondents (79%) report using beta-lactams in combination with tobramycin. Extended-infusion and continuous-infusion beta-lactams were used more in adults than pediatric patients. CONCLUSIONS: Most CF pharmacists report using extended-interval tobramycin. With the information from this survey, the establishment of future consensus recommendations by pharmacists for optimal and consistent tobramycin and antipseudomonal beta-lactam dosage and monitoring strategies needs to be considered. PMID- 27453703 TI - Oxymetazoline Metered Dose Spray: Factors Affecting Delivery Volume. AB - OBJECTIVES: The current study compared the amount of oxymetazoline delivered by various anesthesia providers when holding the bottle in the upright and inverted position. Additionally, the amount delivered from a full bottle and a half-full bottle was also investigated. METHODS: Using an analytical balance that was calibrated to zero, we evaluated the impact the position of the bottle and the volume of oxymetazoline in the bottle had on the amount being delivered by both anesthesia staff and trainees. RESULTS: When using both filled and half-filled bottles, the amount delivered increased significantly when comparing the upright versus inverted position. With a full bottle, the amount delivered when the bottle was inverted increased almost 10-fold from 62 +/- 80 to 606 +/- 366 MUL (p < 0.0001). Similarly, even with a half-filled bottle, the amount delivered increased in the inverted positions from 41 +/- 48 to 645 +/- 393 MUL. Regardless of the scenario, we also noted significant variation from provider to provider. CONCLUSIONS: Our results demonstrate that several factors may affect the amount of oxymetazoline delivered for metered dose bottles. Given the potential for severe end-organ effects with excessive dosage, alternative means of delivery are needed for its perioperative use. PMID- 27453704 TI - Use of Continuous Infusion Hydralazine in a Pediatric Patient on Mechanical Circulatory Support. AB - Hydralazine is a direct peripheral arterial vasodilator used for acute hypertension. Usually administered as a bolus dose, continuous infusion has been described during pregnancy for preeclampsia and eclampsia and in limited reports in cardiac surgeries for afterload reduction. This case describes the use of continuous infusion hydralazine for afterload reduction in an infant receiving extracorporeal membrane oxygenation (ECMO) post-cardiac surgery. Postsurgery, the patient's mean arterial pressures (MAPs) could not be controlled despite escalating doses of vasodilatory medications including nitroprusside, nicardipine, and milrinone; hence, continuous infusion hydralazine was initiated. Although the initiation of a hydralazine infusion produced a decrease in MAP, the response was unsustainable. This case highlights an alternative method for managing systemic vascular resistance and cardiac output to allow for myocardial recovery after cardiac surgery and use of extracorporeal support. At the time of this writing, this is the first published case describing hydralazine administration via continuous infusion in pediatric patients. The use of continuous infusion hydralazine for afterload reduction provided a brief, non sustained reduction in MAP in a post-cardiac surgery infant managed on ECMO support. PMID- 27453705 TI - Metabolic Acidosis with Ophthalmic Dorzolamide in a Neonate. AB - Carbonic anhydrase inhibitors are a common cause of normal anion gap metabolic acidosis; however, development is less commonly associated with ophthalmic administration of these agents. We report a case of a premature neonate who was being treated at our institution with betaxolol, dorzolamide, and latanoprost ophthalmic products for suspected bilateral congenital glaucoma. In addition, the patient was also receiving caffeine, ursodiol, and acidified liquid human milk fortifier. The patient developed a normal anion gap metabolic acidosis, and both dorzolamide ophthalmic solution and the acidified human milk fortifier were considered potential causes. Upon discontinuation of the dorzolamide ophthalmic solution and the switching of liquid human milk fortifiers, the normal anion gap metabolic acidosis gradually resolved. As a result of the pH and acidity, the acidified liquid human milk fortifier is thought to be associated with an anion gap acidosis; therefore, dorzolamide is suspected to be the primary cause of a normal gap acidosis. This case demonstrates that systemic effects can occur with ophthalmic administration of dorzolamide in a premature neonate. Ophthalmic agents should not be overlooked as a potential cause of systemic toxicity. PMID- 27453706 TI - (Es)omeprazole and Discoloration of Regurgitated Gastric Contents in Infants: Worrying for Care-Takers and a Sign of a Reduced Bioavailability. PMID- 27453707 TI - High-Throughput Microfluidic Device for Circulating Tumor Cell Isolation from Whole Blood. AB - Circulating tumor cells (CTCs) are promising markers to determine cancer patient prognosis and track disease response to therapy. We present a multi-stage microfluidic device we have developed that utilizes inertial and Dean drag forces for isolating CTCs from whole blood. We demonstrate a 94.2% +/- 2.1% recovery of cancer cells with our device when screening whole blood spiked with MCF-7 GFP cells. PMID- 27453708 TI - Imperatorin-pharmacological meaning and analytical clues: profound investigation. AB - Imperatorin, a furanocoumarin derivative, has many documented pharmacological properties which make it a candidate for possible drug development. In this review, the activity on the central nervous system, the anticancer and antiviral properties and the influence on the cardiovascular system are described. The aim of this review is also to present an overview of the techniques used for the analysis, isolation, and separation of imperatorin from plant material from the practical perspective. PMID- 27453710 TI - Expression of Concern: Discoidin Domain Receptors: Potential Actors and Targets in Cancer. PMID- 27453711 TI - A Software App for Radiotherapy with In-situ Dose-painting using high Z nanoparticles. AB - The purpose of this work is to develop an user friendly and free-to-download application software that can be employed for modeling Radiotherapy with In-situ Dose-painting (RAID) using high-Z nanoparticles (HZNPs). The RAID APP is software program written in Matlab (Mathworks, Natick, MA, USA) based on deterministic code developed to simulate the space-time intra-tumor HZNPs biodistribution within the tumor, and the corresponding dose enhancement in response to low dose rate (LDR) brachytherapy of I-125, Pd-102, Cs-131 and kilovoltage x-rays such as 50 keV and 100 keV. Through the GUI of RAID APP, the user will be directed to different features to compute various parameters related to the dose enhancement and the biodistribution of NPs within high risk tumor sub-volumes. The software was developed as tool for research purposes with potential for subsequent development to guide dose-painting treatment planning using radiosensitizers such as gold (Au) and platinum (Pt). PMID- 27453709 TI - Evaluation of metabolomics profiles of grain from maize hybrids derived from near isogenic GM positive and negative segregant inbreds demonstrates that observed differences cannot be attributed unequivocally to the GM trait. AB - INTRODUCTION: Past studies on plant metabolomes have highlighted the influence of growing environments and varietal differences in variation of levels of metabolites yet there remains continued interest in evaluating the effect of genetic modification (GM). OBJECTIVES: Here we test the hypothesis that metabolomics differences in grain from maize hybrids derived from a series of GM (NK603, herbicide tolerance) inbreds and corresponding negative segregants can arise from residual genetic variation associated with backcrossing and that the effect of insertion of the GM trait is negligible. METHODS: Four NK603-positive and negative segregant inbred males were crossed with two different females (testers). The resultant hybrids, as well as conventional comparator hybrids, were then grown at three replicated field sites in Illinois, Minnesota, and Nebraska during the 2013 season. Metabolomics data acquisition using gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) allowed the measurement of 367 unique metabolite features in harvested grain, of which 153 were identified with small molecule standards. Multivariate analyses of these data included multi-block principal component analysis and ANOVA-simultaneous component analysis. Univariate analyses of all 153 identified metabolites was conducted based on significance testing (alpha = 0.05), effect size evaluation (assessing magnitudes of differences), and variance component analysis. RESULTS: Results demonstrated that the largest effects on metabolomic variation were associated with different growing locations and the female tester. They further demonstrated that differences observed between GM and non-GM comparators, even in stringent tests utilizing near-isogenic positive and negative segregants, can simply reflect minor genomic differences associated with conventional back crossing practices. CONCLUSION: The effect of GM on metabolomics variation was determined to be negligible and supports that there is no scientific rationale for prioritizing GM as a source of variation. PMID- 27453712 TI - Confronting Practical Problems for Initiation of On-line Hemodiafiltration Therapy. AB - Conventional hemodialysis, which is based on the diffusive transport of solutes, is the most widely used renal replacement therapy. It effectively removes small solutes such as urea and corrects fluid, electrolyte and acid-base imbalance. However, solute diffusion coefficients decreased rapidly as molecular size increased. Because of this, middle and large molecules are not removed effectively and clinical problem such as dialysis amyloidosis might occur. Online hemodiafiltration which is combined by diffusive and convective therapies can overcome such problems by removing effectively middle and large solutes. Online hemodiafiltration is safe, very effective, economically affordable, improving session tolerance and may improve the mortality superior to high flux hemodialysis. However, there might be some potential limitations for setting up online hemodiafiltaration. In this article, we review the uremic toxins associated with dialysis, definition of hemodiafiltration, indication and prescription of hemodiafiltration and the limitations of setting up hemodiafiltration. PMID- 27453713 TI - A Rare Case of Polyneuropathy and Monoclonalgammopathy with Recurrent Acute Kidney Injury. AB - POEMS syndrome is a rare paraneoplastic syndrome and there are few reports of polyneuropathy and monoclonal gammopathy associated with kidney dysfunction. Here, we report a case of POEMS syndrome with recurrent acute kidney injury (AKI). A 52-year-old man presented with bilateral aggravating paresthesia and latermotor weakness of the lower extremities accompanied by repeated elevation of serum creatinine. The patient was finally diagnosed with POEMS syndrome on the basis of fulfilling the two mandatory major criteria (polyneuropathy and monoclonal gammopathy), one other major criterion (sclerotic bone lesion), and several minor criteria. A renal biopsy was performed to clarify the cause of AKI and showed membranoproliferative glomerulonephritis-like lesions with mesangiolysis and endothelial cell injury. This case illustrates that renal manifestations, not included in the diagnostic criteria for POEMS, can be apparent before various other systemic symptoms. PMID- 27453714 TI - Hypokalemic Hypertension Leading to a Diagnosis of Autosomal Dominant Polycystic Kidney Disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. Hypertension is common and occurs before decline in renal function. However, the coexistence of hypertension and hypokalemia is rare in ADPKD patients. We report on a 32-year-old woman with secondary aldosteronism. Magnetic resonance imaging of the renal arteries revealed multiple cysts of varying sizes in both the kidneys and the liver, compatible with ADPKD. Increased reninangiotensin-aldosterone system activity was secondary to cyst expansion. After initiation of angiotensin II receptor blocker, her blood pressure was controlled without additional requirement of potassium. PMID- 27453715 TI - A Pedigree with c.179 Cytosine to Threonine Missense Mutation of SLC12A3 Gene Presenting Gitelman's Syndrome. AB - A 42-year-old man came to the hospital presenting chest discomfort and general weakness. He had come to the hospital with the same symptoms 3 months ago and 12 years prior. His laboratory test showed hypokalemia, hypomagnesemia and hypocalciuria. The arterial blood gas analysis showed hypochloremic metabolic alkalosis. He had an ultrasonography guided renal biopsy, the result was normal at light microscopy and immunofluorescence microscopy. However, a special stain for Na-Cl cotransporter was weakly expressed compared with the control. The patient and his family underwent genetic sequencing about the SLC12A3 gene. He had a homozygous mutation in the 179(th) nucleotide of Exon 1 on the SLC12A3 gene (p.Thr60Met) and his parents and sisters were diagnosed as carrier state of Gitelman's syndrome (GS). GS is an inherited tubular disorder which presents mild hypokalemia, hypomagnesemia and hypocalciuria. Since the symptoms and laboratory results are not severe, it can go unnoticed by physicians. Herein we present a family with GS, diagnosed by genetic sequencing. PMID- 27453717 TI - Effect of a micro-copolymer addition on the thermal conductivity of fly ash mortars. AB - In this study, a copolymer composed of hollow spherical particles with an average particle size of 90 um was evaluated as a lightweight aggregate in Portland cement-fly ash mortars to improve the thermal conductivity (k) of the composite. Mortars were produced for three different water/binder ratios by mass (w/b), 0.4, 0.5 and 0.6. Optimized proportions were obtained for a minimum target compressive strength of 35 kgf/cm2 (3.4 MPa) according to the requirements of Mexican standards for non-structural masonry units. Thermal conductivity was determined for dry and saturated samples through the transient plane technique with average results of 0.16 W/(m.K) and 0.31 W/(m.K), respectively. These values represent an increment of 23 % and a reduction of 33 %, respectively, in comparison to an efficient Portland cement-based commercially available thermal insulator. PMID- 27453716 TI - The ghrelin and leptin responses to short-term starvation vs a carbohydrate-free diet in men with type 2 diabetes; a controlled, cross-over design study. AB - BACKGROUND: We recently have reported the 24-hour glucose, insulin and glucagon responses to a 72-hour fast compared to a 72-hour macronutrient-sufficient, carbohydrate-free diet in men with type 2 diabetes. The 72-hour time period was used because it is the time required for the major metabolic adjustments to a lack of food to be instituted. As part of that study, ghrelin and leptin responses were monitored. METHODS: Twenty-four-hour total ghrelin and overnight fasting leptin concentrations were determined in males with type 2 diabetes when ingesting a standard, mixed meal diet (control), followed by a carbohydrate-free diet for 72 h or were starved for 72 h, using a crossover design. RESULTS: A rise in ghrelin concentration before and a decrease after meals was present when the standard diet was ingested. However, in contrast to literature reports in normal subjects, a circadian variation was not apparent. Meal related changes were absent with starvation. A carbohydrate-free diet resulted in a daylong decrease in ghrelin. It also resulted in a 19 % decrease in the overnight fasting leptin concentration. Leptin was decreased 54 % with total starvation. CONCLUSION: Ingestion of a typical mixed-meal diet results in meal-related changes in ghrelin similar to those reported in normal subjects, although the circadian rhythm was not apparent. Except for the lack of meal-related changes, starvation did not change the concentration. A carbohydrate-free, high fat diet resulted in a daylong suppression of ghrelin. The leptin concentration was decreased by both the carbohydrate-free diet and starvation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01469104. PMID- 27453718 TI - A case-case study on sinonasal cancer prevention: effect from dust reduction in woodworking and risk of mastic/solvents in shoemaking. AB - BACKGROUND AND AIMS: Sinonasal cancers (SNCs) are rare neoplasms, accounting for about 3 % of head and neck cancers, with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) as the most common subtypes. ADCs present strong associations with occupational wood dust exposure. Preventive measures have progressively reduced wood dust concentrations in workplaces but no study has evaluated the effectiveness of such interventions. Few studies indicate associations between ADC and exposure to solvents, which is common in the shoe industry, but this hypothesis still needs confirmation. METHODS: In a case-case study, we contrasted 32 ADCs against 21 Non-Adenocarcinoma Epithelial Tumors (NAETs) - all recruited from the same clinical setting (Padua's University Hospital; period 2004-2015) - using questionnaires and clinical records to collect information on potential predictors. Non-occupational factors were age, sex, smoking, allergy and chronic sinusitis. Occupational factors were intensity and frequency of wood dust exposure, protection from wood dust, type of wood (in woodworking); frequency of exposure to leather dust or mastic/solvent (in shoemaking). Odds-ratio (OR), 95 % confidence interval (95 % CI) and two-tail p values were obtained through stepwise backward logistic regression for each industry, always using as reference patients never employed in either trade and adjusting for non-occupational risk factors. RESULTS: Adjusted OR was 22.5 (95 % CI = 3.50-144; p = 0.001) and 9.37 (95 % CI = 1.29-67.6; p = 0.026), respectively, in patients with low or high degree of protection against wood dust. In the shoe industry, adjusted OR was 1 and 18.8 (95 % CI = 1.29-174; p = 0.030), respectively, in patients with low or high exposure to only mastic/solvent; and 1 and 22.5 (95 % CI = 2.07-244; p = 0.011), respectively, in patients with low or high exposure to only leather dust. DISCUSSION AND CONCLUSIONS: The questionnaire used was able to estimate with simple algorithms past exposures in wood and footwear industries. The case-case design considerably increased the validity of this small study. Results in this study were always consistent with the extant literature; this could support reliability of novel findings. In woodworking, respiratory protective equipment and local exhaust ventilation reduced the risk of occupational SNC; in footwear manufacture, where preventive interventions were seldom adopted, SNC risk was significantly greater for high exposure from mastic/solvent and leather dust. PMID- 27453719 TI - Does the Low-level occupational exposure to volatile organic compounds alter the seasonal variation of selected markers of oxidative stress? A case-control study in nail technicians. AB - BACKGROUND: In this study we tested whether the seasonal variations in levels of selected biomarkers of oxidative stress in female nail technicians occupationally exposed to low levels of volatile organic compounds (VOCs) differ significantly from those observed among healthy unexposed controls. Airborne levels of selected VOCs in nail salons were also analyzed and tested for associations with seasonal variations of the levels of biomarkers among nail technicians. METHODS: The study enrolled 145 female nail technicians and 145 healthy unexposed female controls. The airborne VOCs and levels of biomarkers were assessed by GC-MS chromatography and absorption/fluorescence spectrophotometry, respectively. RESULTS: Plasma levels of thiobarbituric acid reactive species, ceruloplasmin, the activity of glutathione peroxidase (GPx1) and the SOD1/GPx1 activity ratio presented significant differences between the so-called "hot" and "cold" seasons in the case of nail technicians as well as in unexposed controls (p < <0.0001 for all four biomarkers). The pattern of these variations among nail technicians was found to be significantly different compared to that of the control subjects (p < <0.0001). Although such differences might intuitively be attributed to occupational exposure of nail technicians to VOCs, which was found to be higher during the "cold" season compared to the "hot" one, our study provided only limited evidence in favor of the hypothesis, that the different pattern of seasonal variations of biomarkers among nail technicians might have resulted from seasonal fluctuations in their occupational exposure to VOCs. CONCLUSION: Further investigation is thus needed in order to elucidate the effect of low-level occupational exposure to VOCs on seasonal variations of biomarkers of oxidative stress. PMID- 27453720 TI - Indication of nerve growth factor binding components from herbal extracts by HerboChip: a platform for drug screening on a chip. AB - BACKGROUND: HerboChip is an array of different fractions deriving from herbal extracts. This study aimed to identify effective components from Chinese medicine (CM) that interact with nerve growth factor (NGF) as a target using HerboChip. METHODS: Fifty types of CM that are traditionally used as remedies for emotion imbalance were selected and extracted with 50 % ethanol. Biotinylated-NGF was hybridized with over 300 chips coated with different HPLC-separated fractions from CM extracts and straptavidin-Cy5 was used to identify the NGF-bound fractions. RESULTS: Over 300 chips were screened within a week, and 17 positive hits were identified. The interaction of the identified herbal extracts with NGF was confirmed in cultured PC12 cells. Co-application of NGF and herbal extract interfered with NGF-induced expression of neurofilaments, including NF68 and NF200 in cell cultures. Western blot analysis comparing the intensity of phosphorylated cAMP response element-binding protein (CREB) over total CREB showed NGF-induced CREB phosphorylation was modulated by the identified herbal extracts. Five CM herbs showed activating activities on the NGF response and nine CM herbs showed inhibiting activities. CONCLUSION: The current result supported the applicability of HerboChip for screening NGF binding components from herbal extracts. PMID- 27453721 TI - The effects of embodied rhythm and robotic interventions on the spontaneous and responsive social attention patterns of children with Autism Spectrum Disorder (ASD): A pilot randomized controlled trial. AB - We compared the effects of 8-weeks of rhythm and robotic interventions with those of a comparison, standard-of-care intervention, on the spontaneous and responsive social attention patterns of school-age children with Autism Spectrum Disorder. Attention patterns were examined within a standardized pretest/posttest measure of joint attention (JA) and a training-specific social attention measure during early, mid, and late training sessions. The rhythm and comparison groups demonstrated improvements in JA. Social attention was greater in the rhythm followed by the robot and lastly the comparison group. The robot and comparison groups spent maximum time fixating on the robot and objects, respectively. Across sessions, the robot group decreased attention to the robot and increased attention to elsewhere. Overall, rhythmic movement contexts afford sustained social monitoring in children with autism. PMID- 27453722 TI - Health policy and integrated mental health care in the SADC region: strategic clarification using the Rainbow Model. AB - BACKGROUND: Mental illness is a well-known challenge to global development, particularly in low-to-middle income countries. A key health systems response to mental illness is different models of integrated health care, especially popular in the South African Development Community (SADC) region. This complex construct is often not well-defined in health policy, hampering implementation efforts. A key development in this vein has been the Rainbow Model of integrated care, a comprehensive framework and taxonomy of integrated care based on the integrative functions of primary care. The purpose of this study was to explore the nature and strategic forms of integrated mental health care in selected SADC countries, specifically how integrated care is outlined in state-driven policies. METHODS: Health policies from five SADC countries were analysed using the Rainbow Model as framework. Electronic copies of policy documents were transferred into NVivo 10, which aided in the framework analysis on the different types of integrated mental health care promoted in the countries assessed. RESULTS: Several Rainbow Model components were emphasised. Clinical integration strategies (coordination of person-focused care) such as centrality of client needs, case management and continuity were central considerations, while others such as patient education and client satisfaction were largely lacking. Professional integration (inter professional partnerships) was mentioned in terms of agreements on interdisciplinary collaboration and performance management, while organisational integration (inter-organisational relationships) emerged under the guise of inter organisational governance, population needs and interest management. Among others, available resources, population management and stakeholder management fed into system integration strategies (horizontally and vertically integrated systems), while functional integration strategies (financial, management and information system functions) included human resource, information and resource management. Normative integration (a common frame of reference) included collective attitude, sense of urgency, and linking cultures, though aspects such as conflict management, quality features of the informal collaboration, and trust were largely lacking. CONCLUSIONS: Most countries stressed the importance of integrating mental health on primary healthcare level, though an absence of supporting strategies could prove to bar implementation. Inter-service collaboration emerged as a significant goal, though a lack of (especially) normative integration dimensions could prove to be a key omission. Despite the usefulness of the Rainbow Model, it failed to adequately frame regional governance aspects of integration, as the SADC Secretariat could play an important role in coordinating and supporting the development and strengthening of better mental health systems. PMID- 27453723 TI - Reduced pain perception in children and adolescents with ADHD is normalized by methylphenidate. AB - BACKGROUND: The present study examined pain perception in children and adolescents with ADHD and the interaction between pain perception and the administration of methylphenidate (MPH) in order to generate hypotheses for further research that will help to clarify the association between ADHD diagnosis, MPH treatment and pain perception. METHODS: We included 260 children and adolescents of the "German Health Interview and Examination Survey for Children and Adolescents" (KiGGS) and analyzed parent's assessments of children's pain distribution and pain perception, as well as the influence of MPH administration on pain perception in affected children and adolescents. RESULTS: Pain perception was associated with ADHD and MPH administration, indicating that children and adolescents suffering from ADHD without MPH treatment were reported to have lower pain perception compared to both, healthy controls (HC) and ADHD patients medicated with MPH. CONCLUSION: We suggest that reduced pain perception in children and adolescents with ADHD not medicated with MPH may lead to higher risk tolerance by misjudgments of dangerous situations, expanding the importance of MPH administration in affected children and adolescents. PMID- 27453724 TI - Advancing emotion theory with multivariate pattern classification. AB - Characterizing how activity in the central and autonomic nervous systems corresponds to distinct emotional states is one of the central goals of affective neuroscience. Despite the ease with which individuals label their own experiences, identifying specific autonomic and neural markers of emotions remains a challenge. Here we explore how multivariate pattern classification approaches offer an advantageous framework for identifying emotion specific biomarkers and for testing predictions of theoretical models of emotion. Based on initial studies using multivariate pattern classification, we suggest that central and autonomic nervous system activity can be reliably decoded into distinct emotional states. Finally, we consider future directions in applying pattern classification to understand the nature of emotion in the nervous system. PMID- 27453725 TI - Ozonation as an effective way to stabilize new kinds of fermentation media used in biotechnological production of liquid fuel additives. AB - BACKGROUND: Intermediates from processing sugar beets are considered an attractive feedstock for ethanol fermentation due to their high fermentable sugar content. In particular, medium prepared from raw sugar beet juice seems to be suitable for use in fermentation processes, but it is microbiologically unstable and requires sterilization. RESULTS: This study investigates the effect of ozone treatment on the activity of microbial cells from Bacillus subtilis, Leuconostoc mesenteroides, Geobacillus stearothermophilus, Candida vini, and Aspergillus brasiliensis in raw sugar beet juice. Raw sugar beet juice contaminated with 10(5) cfu/mL of the microbial strains was treated with gaseous ozone (ozone concentration in the oxygen stream 0.1 g O3/L O2, flow rate 6 L/h, 10-30 min, 18 20 degrees C). The number of microflora decreased to 0 cfu/mL after 30 min of ozone treatment in all studied samples. CONCLUSIONS: Medium prepared from raw sugar beet juice and sterilized by ozonation is suitable for use in fermentation processes. PMID- 27453726 TI - Transcriptome analysis reveals global regulation in response to CO2 supplementation in oleaginous microalga Coccomyxa subellipsoidea C-169. AB - BACKGROUND: Microalgae are emerging as suitable feedstock for renewable biofuel production and providing a promising way to alleviate green house gas CO2. Characterizing the metabolic pathways involved in the biosynthesis of energy-rich compounds and their global regulation upon elevated CO2 is necessary to explore the mechanism underlying rapid growth and lipid accumulation, so as to realize the full potential of these organisms as energy resources. RESULTS: In the present study, 2 and 5 % CO2 increased growth rate and lipid accumulation in autotrophically cultured green alga Coccomyxa subellipsoidea C-169. Overall biomass productivity as 222 mg L(-1) day(-1) and fatty acid content as 48.5 % dry cell weight were attained in 2 % CO2, suggesting C-169 as a great candidate for lipid production via CO2 supplementation. Transcriptomic analysis of 2 % against 0.04 % CO2-cultured C-169 unveiled the global regulation of important metabolic processes. Other than enhancing gene expression in the Calvin cycle, C-169 upregulated the expression of phosphoenolpyruvate carboxylase, pyruvate carboxylase and carbamoyl-phosphate synthetase II to enhance the anaplerotic carbon assimilation reactions upon elevated CO2. Upregulation of ferredoxin and ferredoxin-NADP(+) reductase implied that plentiful energy captured through photosynthesis was transferred through ferredoxin to sustain rapid growth and lipid accumulation. Genes involved in the glycolysis, TCA cycle and oxidative phosphorylation were predominantly upregulated presumably to provide abundant intermediates and metabolic energy for anabolism. Coordinated upregulation of nitrogen acquisition and assimilation genes, together with activation of specific carbamoyl-phosphate synthetase and ornithine pathway genes, might help C-169 to maintain carbon/nitrogen balance upon elevated CO2. Significant downregulation of fatty acid degradation genes, as well as the upregulation of fatty acid synthesis genes at the later stage might contribute to the tremendous lipid accumulation. CONCLUSION: Global and collaborative regulation was employed by C-169 to assimilate more carbon and maintain carbon/nitrogen balance upon elevated CO2, which provide abundant carbon skeleton and affluent metabolic energy to sustain rapid growth and lipid accumulation. Data here for the first time bring significant insights into the regulatory profile of metabolism and acclimation to elevated CO2 in C-169, which provide important information for future metabolic engineering in the development of sustainable microalgae-based biofuels. PMID- 27453727 TI - Steam explosion pretreatment of softwood: the effect of the explosive decompression on enzymatic digestibility. AB - BACKGROUND: Steam explosion pretreatment has been examined in many studies for enhancing the enzymatic digestibility of lignocellulosic biomass and is currently the most common pretreatment method in commercial biorefineries. The information available about the effect of the explosive decompression on the biochemical conversion is, however, very limited, and no studies prove that the latter is actually enhanced by the explosion. Hence, it is of great value to discern between the effect of the explosion on the one hand and the steaming on the other hand, to identify their particular influences on enzymatic digestibility. RESULTS: The effect of the explosive decompression in the steam explosion pretreatment of spruce wood chips on their enzymatic cellulose digestibility was studied systematically. The explosion had a high influence on digestibility, improving it by up to 90 % compared to a steam pretreatment without explosion. Two factors were identified to be essentially responsible for the effect of the explosion on enzymatic digestibility: pretreatment severity and pressure difference of the explosion. A higher pretreatment severity can soften up and weaken the lignocellulose structure more, so that the explosion can better break up the biomass and decrease its particle size, which enhances its digestibility. In particular, increasing the pressure difference of the explosion leads to more defibration, a smaller particle size and a better digestibility. Though differences were found in the micro- and nanostructure of exploded and non exploded biomass, the only influence of the explosion on digestibility was found to be the macroscopic particle size reduction. Steam explosion treatments with a high severity and a high pressure difference of the explosion lead to a comparatively high cellulose digestibility of the-typically very recalcitrant softwood biomass. CONCLUSIONS: This is the first study to show that explosion can enhance the enzymatic digestibility of lignocellulosic biomass. If the enhancing effect of the explosion is thoroughly exploited, even very recalcitrant biomass like softwood can be made enzymatically digestible. PMID- 27453728 TI - Characterization of sugarcane (Saccharum spp.) leaf senescence: implications for biofuel production. AB - BACKGROUND: Second-generation ethanol (2G-bioethanol) uses lignocellulosic feedstocks for ethanol production. Sugarcane is one among the most suitable crops for biofuel production. Its juice is extracted for sugar production, while sugarcane bagasse, straw, and senescing leaves are considered industrial waste. Senescence is the age-dependent deterioration of plant cells, ultimately leading to cell death and completion of the plant life cycle. Because senescing leaves may also be used for biofuel production, understanding the process of natural senescence, including remobilization of nutrients and its effect on cell walls can provide useful information for 2G-bioethanol production from sugarcane leaves. RESULTS: The natural senescence process in leaves of the commercial sugarcane cultivar RB867515 was investigated. Senescence was characterized by strong reduction in photosynthetic pigments content, remobilization of the nutrients N, P, K, B, Cu, Fe, and Zn, and accumulation of Ca, S, Mg, B, Mn, and Al. No significant changes in the cell-wall composition occurred, and only small changes in the expression of cell wall-related genes were observed, suggesting that cell walls are preserved during senescence. Senescence-marker genes, such as SAG12-like and XET-like genes, were also identified in sugarcane and found to be highly expressed. CONCLUSIONS: Our study on nutrient remobilization under senescence in a vigorous sugarcane cultivar can contribute to the understanding on how nutrient balance in a high-yielding crop is achieved. In general, neutral monosaccharide profile did not change significantly with leaf senescence, suggesting that senescing leaves of sugarcane can be as a feedstock for biofuel production using pretreatments established for non-senescing leaves without additional efforts. Based on our findings, the potential biotechnological applications for the improvement of sugarcane cultivars are discussed. PMID- 27453729 TI - High-level expression of thermostable cellulolytic enzymes in tobacco transplastomic plants and their use in hydrolysis of an industrially pretreated Arundo donax L. biomass. AB - BACKGROUND: Biofuels production from plant biomasses is a complex multi-step process with important economic burdens. Several biotechnological approaches have been pursued to reduce biofuels production costs. The aim of the present study was to explore the production in tobacco plastome of three genes encoding (hemi)cellulolytic enzymes from thermophilic and hyperthermophilic bacterium and Archaea, respectively, and test their application in the bioconversion of an important industrially pretreated biomass feedstock (A. donax) for production of second-generation biofuels. RESULTS: The selected enzymes, endoglucanase, endo beta-1,4-xylanase and beta-glucosidase, were expressed in tobacco plastome with a protein yield range from 2 % to more than 75 % of total soluble proteins (TSP). The accumulation of endoglucanase (up to 2 % TSP) gave altered plant phenotypes whose severity was directly linked to the enzyme yield. The most severe seedling lethal phenotype was due to the impairment of plastid development associated to the binding of endoglucanase protein to thylakoids. Endo-beta-1,4-xylanase and beta-glucosidase, produced at very high level without detrimental effects on plant development, were enriched (fourfold) by heat treatment (105.4 and 255.4 U/mg, respectively). Both plastid-derived biocatalysts retained the main features of the native or recombinantly expressed enzymes with interesting differences. Plastid-derived xylanase and beta-glucosidase resulted more thermophilic than the E. coli recombinant and native counterpart, respectively. Bioconversion experiments, carried out at 50 and 60 degrees C, demonstrated that plastid derived enzymes were able to hydrolyse an industrially pretreated giant reed biomass. In particular, the replacement of commercial enzyme with plastid-derived xylanase, at 60 degrees C, produced an increase of both xylose recovery and hydrolysis rate; whereas the replacement of both xylanase and beta-glucosidase produced glucose levels similar to those observed with the commercial cocktails, and xylose yields always higher in the whole 24-72 h range. CONCLUSIONS: The very high production level of thermophilic and hyperthermophilic enzymes, their stability and bioconversion efficiencies described in this study demonstrate that plastid transformation represents a real cost-effective production platform for cellulolytic enzymes. PMID- 27453730 TI - Preferences for Exercise as a Treatment for Depression. AB - : Depression is a leading cause of disability worldwide, but most depressed individuals do not receive treatment. There is now significant support for physical exercise as an effective alternative treatment for depression, which may be more accessible than traditional psychiatric treatments. Little is known about preferences for exercise as a depression treatment. METHOD: A total of 102 individuals (50% female, mean age = 39 (SD=13.1; range: 18-62), 83% Caucasian) with likely major depression completed an online survey of exercise for depression treatment preferences and barriers to increased exercise. Results are reported by gender due to well established gender differences in exercise preferences. RESULTS: Both genders reported a high level of interest in an exercise for depression program. On average, participants preferred an individual walking program that was coached, asked them to engage in one longer bout multiple times per week, and was provided in home. However, there was significant variability within and between genders. Lack of motivation, mood, and fatigue were reported as barriers to exercise by the majority of participants of both genders. CONCLUSION: The majority of those with depression have interest in an exercise for depression program, but symptoms of depression are seen as significant barriers. Future studies should use these results to design exercise for depression programs. The variability and gender differences in our results suggest that flexible programs may be needed. PMID- 27453731 TI - BDNF Val66Met Polymorphism as a Moderator of Exercise Enhancement of Smoking Cessation Treatment in Anxiety Vulnerable Adults. AB - BACKGROUND: Exercise interventions facilitate odds of quit success among high anxiety sensitive adults smokers. We examined the dependency of these benefits on the genetic BDNF Val66Met (rs6265) polymorphism; individuals who are Met carriers have lower BDNF responses and reduced associated benefits from exercise. Accordingly, we hypothesized that the efficacy of vigorous exercise for smoking cessation would be specific to high-anxiety sensitive Val/Val carriers. METHODS: Participants were adults (N=55) of European ancestry who had participated in a randomized controlled trial comparing a smoking cessation program augmented with exercise vs. augmented with a wellness control treatment. In this secondary analysis, growth curve models for point-prevalence abstinence (PPA) and prolonged abstinence (PA) employed for the main outcome analyses were amended to test the moderator effects of the BDNF Val66Met polymorphism. RESULTS: Consistent with prediction, the advantage of exercise over control for PPA was significantly greater among high-anxiety sensitive persons with the Val/Val genotype than for those with the Val/Met genotype. This advantage did not reach statistical significance for PA. Differences in abstinence between the exercise and control interventions among low-anxiety sensitive smokers were not dependent on the BDNF Val66Met polymorphism. CONCLUSIONS: We found that the efficacy of exercise for augmenting smoking cessation treatment is intensified among high-anxiety sensitive smokers who are Val/Val carriers. This observation is consistent with findings documenting BDNF mediation of exercise benefits and greater negative affect among smokers who are Val/Val carriers. These data encourage further evaluation of the association between the BDNF polymorphism, exercise, anxiety sensitivity, and smoking cessation. PMID- 27453732 TI - Dysfunctional gut microbiota and relative co-abundance network in infantile eczema. AB - BACKGROUND: Infantile eczema is an immunological disease that is characterized by itchy and dry skin. Recent studies have suggested that gut microbiota (GM) plays a role in the development and progression of eczema. To further evaluate this potential link, we collected feces from 19 infants with eczema and 14 infants without eczema and analyzed the molecular discrepancies between the two groups using 16S rDNA analysis. RESULTS: Bacteroidaceae and Deinococcaceae were significantly enriched in eczema infants, and Bacteroidaceae was potentially involved in autoimmune diseases by promoting the Th17 (T helper cell 17) secretion of IL-17 (interleukin-17). In the infants without eczema, the co abundance network featured three core nodes: Clostridiaceae, Veillonellaceae, and Lactobacillaceae, all of which were lacking in the infants with eczema. Furthermore, our data suggested that Enterobacteriaceae was the core of the co abundance network for the diseased subjects. CONCLUSIONS: GM is closely connected to the human immune system, and the dysbiotic GM network plays a role in eczema. This study furthered our understanding of the dynamic GM network and its correlation to the occurrence of eczema. PMID- 27453733 TI - Challenges associated with insulin therapy progression among patients with type 2 diabetes: Latin American MOSAIc study baseline data. AB - BACKGROUND: Poor glycemic control in patients with type 2 diabetes is commonly recorded worldwide; Latin America (LA) is not an exception. Barriers to intensifying insulin therapy and which barriers are most likely to negatively impact outcomes are not completely known. The objective was to identify barriers to insulin progression in individuals with type 2 diabetes mellitus (T2DM) in LA countries (Mexico, Brazil, and Argentina). METHODS: MOSAIc is a multinational, non-interventional, prospective, observational study aiming to identify the patient-, physician-, and healthcare-based factors affecting insulin intensification. Eligible patients were >=18 years, had T2DM, and were treated with insulin for >=3 months with/without oral antidiabetic drugs (OADs). Demographic, clinical, and psychosocial data were collected at baseline and regular intervals during the 24-month follow-up period. This paper however, focuses on baseline data analysis. The association between glycated hemoglobin (HbA1c) and selected covariates was assessed. RESULTS: A trend toward a higher level of HbA1c was observed in the LA versus non-LA population (8.40 +/- 2.79 versus 8.18 +/- 2.28; p <= 0.069). Significant differences were observed in clinical parameters, treatment patterns, and patient-reported outcomes in LA compared with the rest of the cohorts and between Mexico, Brazil, and Argentina. Higher number of insulin injections and lower number of OADs were used, whereas a lower level of knowledge and a higher level of diabetes-related distress were reported in LA. Covariates associated with HbA1c levels included age (-0.0129; p < 0.0001), number of OADs (0.0835; p = 0.0264), higher education level (-0.2261; p = 0.0101), healthy diet (-0.0555; p = 0.0083), self-monitoring blood glucose ( 0.0512; p = 0.0033), hurried communication style in the process of care (0.1295; p = 0.0208), number of insulin injections (0.1616; p = 0.0088), adherence ( 0.1939; p <= 0.0104), and not filling insulin prescription due to associated cost (0.2651; p = 0.0198). CONCLUSION: MOSAIc baseline data showed that insulin intensification in LA is not optimal and identified several conditions that significantly affect attaining appropriate HbA1c values. Tailored public health strategies, including education, should be developed to overcome such barriers. Trial Registration NCT01400971. PMID- 27453734 TI - A study for association and interaction analysis to metabolic syndrome and the ESR1 gene on cardiovascular autonomic neuropathy in a Chinese Han population. AB - BACKGROUND: The aim of this study was to investigate the association and interaction of metabolic syndrome (MetS) and estrogen receptor alpha 1 (ESR1) gene polymorphisms on cardiovascular autonomic neuropathy (CAN). METHODS: A large scale, population-based study was conducted to analyze the interaction of MetS and ESR1 gene polymorphisms to CAN, including a total of 1977 Chinese subjects. The most common studied single nucleotide polymorphism of ESR1 gene-rs9340799, was genotyped. Multiple logistic regression (MLR) was performed to evaluate the interaction effect of environmental variables and gene polymorphisms. Interaction on an additive scale can be calculated by using the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S). RESULTS: After controlling potential confounders, MLR showed that significant association between MetS and CAN (p < 0.001). Interestingly, we found that the participants with MetS bearing the minor allele G had an increased CAN prevalence comparing those with allele A (p = 0.045), and a positive interaction was estimated by using RETI = 0.396 (95 % CI 0.262 to 0.598), AP = 0.216 (95 % CI -0.784 to 1.216) and S = 1.906 (95 % CI 0.905 to 4.015). CONCLUSION: The present findings suggest that MetS is significantly associated with CAN and provide evidence for the hypothesis that MetS and ESR1 gene polymorphism (rs9340799) have interactive effects on CAN. ClinicalTrials gov Identifier NCT02461342. PMID- 27453735 TI - Hemoglobin A1c as screening for gestational diabetes mellitus in Nordic Caucasian women. AB - BACKGROUND: Gestational diabetes mellitus (GDM) increases the risk for preeclampsia and macrosomia. GDM is conventionally diagnosed by an oral glucose tolerance test (OGTT). Hemoglobin A1c (HbA1c) is a marker for the average glucose level the last 2-3 months. We aimed to study if HbA1c alone or in combination with patient characteristics can be used to screen for GDM and reduce the number of OGTTs, and whether it could predict preeclampsia or birth weight. METHODS: 855 women from a previous study on the effect of exercise on GDM prevalence were eligible, whereof 677 were included. GDM was diagnosed by WHO 1999 criteria (GDM WHO) and modified IADPSG criteria (GDM-IADPSG), at pregnancy weeks 18-22 and 32 36. HbA1c analyzed at pregnancy weeks 18-22 and 32-36, variables from patient history and clinical examination were considered for logistic regression models. The diagnostic accuracy was assessed by ROC curve analysis. RESULTS: Accumulated GDM prevalence was 6.7 % by WHO and 7.2 % by modified IADPSG criteria. Nearly a third could potentially have avoided an OGTT by using HbA1c to exclude GDM-IADPSG with a sensitivity of 88 % at week 18-22 and 97 % at week 32-36. Further, 16 % could have avoided an OGTT with a sensitivity of 96 % using HbA1c at week 18-22 to exclude GDM-IADPSG throughout pregnancy. HbA1c was not accurate at diagnosing GDM-IADPSG, and it was inaccurate at screening for GDM-WHO at any time point. Adding other predictors did not increase the number of potentially avoidable OGTTs significantly. HbA1c was not significantly associated with preeclampsia or birth weight. CONCLUSIONS: HbA1c could potentially reduce the number of OGTTs. PMID- 27453737 TI - Devotion for newborn children. PMID- 27453736 TI - Increased depression and metabolic risk in postmenopausal breast cancer survivors. AB - OBJECTIVE: Breast cancer survivors (BCS) are at high risk for the development of obesity, type 2 diabetes mellitus, and metabolic syndrome. There is increasing interest in the association between depression and metabolic dysfunction, which is relevant in this population as depression is often present in the chronic phase of cancer recovery. Thus, the aim of this study was to evaluate metabolic risk in BCS with and without depression compared to non-cancer controls. METHODS: African American (46 %) and Caucasian (54 %) postmenopausal BCS (N = 28; age: 60 +/- 2 years; mean +/- SEM) were matched for race, age (+/-2 years), and BMI (+/-2 kg/m(2)) to non-cancer controls (N = 28). Center for Epidemiologic Studies Depression Scale (CES-D) >16 or antidepressant medication usage was used to classify depression. Metabolic status was defined by 2-hr glucose during an OGTT and classification of metabolic syndrome. RESULTS: Compared to non-cancer controls, BCS had similar 2-hr glucose, but higher fasting glucose and total cholesterol, and were 2.5 times more likely to have metabolic syndrome (21 vs. 52 %)(P's < 0.05). Conversely, HDL-C was 16 % higher in BCS (P < 0.05). Forty three % of BCS were on antidepressants compared to 14 % in non-cancer controls, despite similar mean CES-D scores (6 +/- 1). Depressed BCS (46 %) had a higher BMI, waist circumference, fasting glucose, and more metabolic syndrome components than non depressed BCS (P's < 0.05). CONCLUSIONS: BCS have a heightened prevalence of depression that may be associated with an increased prevalence of metabolic syndrome. These results support the need to monitor weight gain, depression, and the progression of metabolic abnormalities after cancer diagnosis and treatment. Further studies into the mechanistic link between depression and metabolic disease are necessary to identify strategies that can offset their impact on obesity and associated cardiovascular risk following a breast cancer diagnosis. PMID- 27453738 TI - Credibility judgments in web page design - a brief review. AB - Today, more than ever, knowledge that interfaces appearance analysis is a crucial point in human-computer interaction field has been accepted. As nowadays virtually anyone can publish information on the web, the credibility role has grown increasingly important in relation to the web-based content. Areas like trust, credibility, and behavior, doubled by overall impression and user expectation are today in the spotlight of research compared to the last period, when other pragmatic areas such as usability and utility were considered. Credibility has been discussed as a theoretical construct in the field of communication in the past decades and revealed that people tend to evaluate the credibility of communication primarily by the communicator's expertise. Other factors involved in the content communication process are trustworthiness and dynamism as well as various other criteria but to a lower extent. In this brief review, factors like web page aesthetics, browsing experiences and user experience are considered. PMID- 27453739 TI - The association between Diabetes mellitus and Depression. AB - Depression occurrence is two to three times higher in people with diabetes mellitus, the majority of the cases remaining under-diagnosed. The purpose of this review was to show the links between depression and diabetes, point out the importance of identifying depression in diabetic patients and identify the possible ways to address both diseases. Possible common pathophysiological mechanisms as stress and inflammation were explained, while emphasis was made on screening for depression in diabetic patients. An important aspect for the diabetic specialist would be the understanding of the common origins of diabetes and depression and the awareness of this quite common comorbidity, in order to improve the outcomes of both diseases. ABBREVIATIONS: DALYS = disability adjusted life years, DSM-5 = American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, DM1 = Type 1 diabetes mellitus, DM2 = Type 2 diabetes mellitus, HPA-axis = hypothalamus - pituitary - adrenal axis, SNS = sympathetic nervous system, BDI = Beck Depression Inventory, CES-D = Centre for Epidemiologic Studies Depression Scale, HADS = Hospital Anxiety and Depression Scale, PHQ = Patient Health Questionnaire. PMID- 27453740 TI - Velamentous insertion of umbilical cord with vasa praevia: case series and literature review. AB - A velamentous umbilical cord is characterized by membranous umbilical vessels at the placental insertion site that are prone to compression and rupture, especially when they are located in the membranes covering the cervical os (vasa praevia). The velamentous insertion of the umbilical cord, with a reported incidence of 1% in singleton pregnancies and 15% in monochorionic twin gestations, has been associated with obstetric complications: fetal growth restriction, prematurity, congenital anomalies, low Apgar scores, fetal bleeding with acute fetal distress and placental retention. The pathogenesis is unknown, but the trophotropism theory is the most common and supported by the association of velamentous cord insertion and placenta praevia. The prevalence of vasa praevia is of approximately 1/ 2500 deliveries; the risk factors include the use of assisted reproductive technologies, low-lying placenta or placenta praevia, bilobed or succenturiate lobe placenta and multiple gestation. The diagnosis is rarely established before delivery and consequently the fetal mortality is extremely high. We report two cases of velamentous marginal umbilical cord insertion associated with vasa praevia (type 1 vasa praevia) and placenta praevia diagnosed during a routine mid-trimester fetal 2D ultrasound scan, color and power Doppler transvaginal ultrasound cervical assessment. The ultrasound examination revealed one umbilical vessel crossing the internal os of the cervix entering the placental margin and connecting to the subchorionic vasculature, remaining immobile when the uterus was shaken, the color Doppler imaging enhancing the identification of the vessel. The patients were admitted to the hospital in the third trimester and deliveries were planed and successfully performed at 38 weeks gestation, being confirmed by a macroscopic examination ultrasound diagnostic. PMID- 27453741 TI - Considerations on risk factors correlated to the occurrence of gastric stump cancer. AB - Gastric stump cancer (GSC) is the malignant tumor that develops in the gastric remnant after partial gastrectomy was performed both for benign and malignant lesions. This paper presents the results of the case studies from the scientific literature, which focused on GSC, and has been published in the last 10 years. The search was performed with the help of the specific tools offered by the international databases. The subject was approached because of the constant rising incidence of GSC in the past few years, now reaching values between 1% and 7%. The outcome report is consistent and similar to the period that ended approximately 25 years ago, when general surgeons dedicated a significant part of their activity to treating gastric ulcer. Statistics revealed that the main risk factors are the following: the type of reconstruction after distal gastrectomy (Billroth I or Billroth II), the presence of duodenogastric reflux, the time between gastric resections, and the moment of diagnosis of gastric stump cancer, the initial pathology for which partial gastrectomy was performed, gender, age, helicobacter pylori infection, Epstein Barr virus infection and the presence of vagotomy. All the authors have significantly contributed to the article and have been involved in the writing of the manuscript in draft and any revision stages, and have read and approved the final version. PMID- 27453742 TI - The management of external marketing communication instruments in health care services. AB - In order to become known and attract consumers, a health care organization has to develop suitable external communication campaigns. Consequently, management instruments are employed to effectively evaluate the success of a campaign. The BCG Matrix, SWOT analysis and the Gantt Diagram were used in this paper to ensure the consistency and accuracy of the external communication process at an empirical level. PMID- 27453743 TI - Esophageal disorders in mixed connective tissue diseases. AB - Extra Musculoskeletal manifestations are a distinct clinical entity that refers to a combination of clinical features, which are found in multiple rheumatic diseases. Besides the standard manifestations, other organs can be damaged such as the vascular system, skin, gastrointestinal tract, musculoskeletal system, cardiopulmonary system, hematologic system, kidneys, and the central nervous system. Among the gastrointestinal MCTD symptoms, the most frequent are the esophageal ones. Treatment of patients with MCTD must be performed by both medical and surgical multidisciplinary teams in order to provide a management suitable for the patients' needs. All authors have contributed significantly and have been involved in the writing of the manuscript in draft and any revision stages, and have read and approved its final version. PMID- 27453744 TI - Biomarkers in Rheumatoid Arthritis, what is new? AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease with autoimmune pathogenesis. It affects mainly small joints (of the hands and feet) and has many systemic manifestations. Studying biomarkers in rheumatology intensely appeared from the need to understand the mechanisms underlying some rheumatic diseases. Discovering new biomarkers with key roles in various stages of evolution, remains a subject of interest for RA. Currently, according to the EULAR 2010 criteria, the rheumatoid factor (RF) and the anti-cyclic citrullinated peptide (anti-CCP) are used for RA diagnosis. Since 2010, new biomarkers were discovered and proved useful in identifying RA in early stages. For a more rigorous management of these cases, one of the key steps in the evolution of patients with RA is to recognize and distinguish the more aggressive forms of the disease through prognostic biomarkers. "Treat to target" recommends the use of 3 composite scores to monitor the evolution of the disease: disease activity score (DAS 28), simple disease activity index (SDAI) and clinical disease activity index (CDAI), but, a new test was developed which better monitors the disease activity. The introduction of biological therapies has revolutionized the treatment of RA. Despite these advances, 20-40% of the patients are declared nonresponders to at least one of the therapies. The patient exposure to the potential side effects and high costs requires the discovery of a biomarker that could identify those who can benefit from the pretreatment of a certain therapy. ABBREVIATIONS: RA = rheumatoid arthritis, RF = rheumatoid factor, DAS 28 = disease activity score, SDAI = simple disease activity index, CDAI = clinical disease activity index, ACR = American College of Rheumatology, EULAR = European League against Rheumatism, anti-CCP = antibodies against cyclic citrullinated proteins, anti-MCV = mutated citrullinated vimentin antibodies, anti-CarP = antibodies against carbamylated proteins, MBDA = multi biomarker disease activity test, COMP = cartilage oligomeric matrix protein, ADAs = antidrug antibodies, CDA = clinical disease activity index, SDAI = simplified disease activity index, ESR = erythrocyte sedimentation rate, CRP = C reactive protein, SAA = serum amyloid A, VCAM-1 = vascular cell adhesion molecule-1, IL-6 = interleukin-6, TNF-R1 = tumor necrosis factor receptor 1, EGF = epidermal growth factor, VEGF-A = vascular endothelial growth factor A. PMID- 27453745 TI - The management of health care service quality. A physician perspective. AB - Applying marketing in health care services is presently an essential element for every manager or policy maker. In order to be successful, a health care organization has to identify an accurate measurement scale for defining service quality due to competitive pressure and cost values. The most widely employed scale in the services sector is SERVQUAL scale. In spite of being successfully adopted in fields such as brokerage and banking, experts concluded that the SERVQUAL scale should be modified depending on the specific context. Moreover, the SERVQUAL scale focused on the consumer's perspective regarding service quality. While service quality was measured with the help of SERVQUAL scale, other experts identified a structure-process-outcome design, which, they thought, would be more suitable for health care services. This approach highlights a different perspective on investigating the service quality, namely, the physician's perspective. Further, we believe that the Seven Prong Model for Improving Service Quality has been adopted in order to effectively measure the health care service in a Romanian context from a physician's perspective. PMID- 27453746 TI - Outcome of urinary bladder cancer after combined therapies. AB - RATIONALE: Urinary bladder cancer is the fourth most common cancer in men and the eighth in women, being an important public health issue. OBJECTIVE: to assess the outcome of patients with urinary bladder cancer treated in an oncologic center. METHODS: Medical files of 155 patients (132M/ 23F) with urinary bladder cancer treated between 2006 and 2012 were retrospectively analyzed. The median age at diagnosis was 65 years (range: 19-85 years). Disease free survival (DFS) for patients with complete tumor resection receiving adjuvant treatment and progression free survival (PFS) for patients with post-operative residual disease was estimated. RESULTS: Stage disease's distribution was: 50 patients (32.2%) stage II, 47 (30.3%) stage III, 58 (37.4%) stage IV. Radical cystectomy was performed in 56 patients (36.1%), while 99 patients (63.9%) underwent repeated transurethral resection of the urinary bladder tumor (TURBT). The postoperative treatment included multimodal therapy in 47 patients (30.3%) (chemotherapy and external beam radiation), external beam radiation alone in 57 patients (36.8%) and chemotherapy alone (methotrexate, vinblastine, doxorubicin, and cisplatin MVAC or gemcitabine + platinum) in 51 patients (32.9%). After a median follow-up of 31 months (range: 3-79 months), 51 patients (32.9%) presented local recurrence, 32 patients (21%) distant recurrence (metastases), 10 patients (6.4%) both local and distant recurrence, and 62 patients (40%) were free of disease. The median duration until progression was of 27 months. DISCUSSION: Despite combined therapy approaches, urinary bladder carcinoma remains an aggressive disease, with high relapse rate. Earlier diagnosis and an aggressive radical surgery with the intention to cure (cystectomy), and adjuvant multimodal treatment (radiotherapy and chemotherapy) are needed for survival improvement. PMID- 27453747 TI - Fecal transplantation - the new, inexpensive, safe, and rapidly effective approach in the treatment of gastrointestinal tract diseases. AB - Introduction. Fecal transplantation was shown to effectively reduce the reoccurrence in patients with refractory Clostridium difficile infection. New data suggest that fecal transplantation could also be efficient in other gastrointestinal diseases, for instance in inflammatory bowel disease, irritable bowel syndrome, but, there are also some data that could imply the efficacy outside the gastrointestinal tract. Fecal transplantation should be considered a unique agent, capable of treating severe diseases, with essentially no adverse reactions, presenting a cure rate of over 90%. Materials and methods. This prospective study included 33 patients, of whom 28 patients with recurrent or resistant Clostridium difficile infection, who failed to be treated with conventional therapy, which presupposed vancomycin administration and 5 patients with inflammatory bowel disease, more precisely with ulcerative colitis, refractory on biologic agents (infliximab and adalimumab). In most of the cases, fecal transplant was realized with the infusion of stool through colonoscopy. Results. Most of the patients from both groups (Clostridium difficile infection and Ulcerative Colitis) responded (31 patients) with a total relief of the symptoms, after 1 FMT for Clostridium difficile group and after more than one for the ulcerative colitis group. The so-called primary cure rate was 96.42% for Clostridium group. For ulcerative colitis, group 3 of the patients needed 3 or 4 infusions for symptom relief. One patient was categorized as non-responsive (patient with UC) and needed surgery. Due to non-fecal transplant related causes, one death was reported. Conclusions. Fecal transplant is highly effective, safe, with practically no adverse effects, inexpensive, a procedure easy to be done that could be introduced in Clostridium difficile treatment protocols. As for ulcerative colitis treatment with FMT, future randomized controlled trials are needed to prove its efficiency. PMID- 27453748 TI - Predictors of early infection in cerebral ischemic stroke. AB - BACKGROUND: Infection is the most common complication of stroke. AIM: To determine the risk factors and predictors of post-stroke infection (PSI), which developed within 7 days from the onset of acute ischemic stroke. SUBJECTS: The study included 60 ischemic stroke patients admitted in the Neurology Department of Zagazig University, Egypt, who were subdivided into: [Non Stroke Associated Infection group (nSAI); 30 patients having stroke without any criteria of infection within 7 days from the onset and Stroke Associated Infection group (SAI); 30 patients having stroke with respiratory tract infection (RTI) or urinary tract infection within 7 days], in addition to 30 healthy sex and age matching subjects as control. METHODS: All the patients had a detailed history taking, thorough clinical general and neurological examination, laboratory tests (Urine analysis & urine culture, blood sugar, lipid profile and serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-10), a chest radiography to assess RTI and brain computed tomography (CT) to exclude the hemorrhagic stroke and to confirm the ischemic stroke. RESULTS: SAI patients were found to be significantly older with higher baseline blood glucose level. Also the number of patients with tube feeding, lower conscious level, more stroke severity and more large size infarcts were significantly higher in SAI patients. There was a significant elevation in the IL-10, a significant decrease in the TNF-alpha and a significant decrease in the TNF-alpha/ IL-10 ratio, in the SAI group. The baseline serum level of IL-10 >= 14.5 pg/ ml and size of infarct area > 3.5 cm3 were found to be the independent predictors of PSI. CONCLUSION: Patients with older age, tube feeding, lower conscious level, worse baseline stroke severity, large cerebral infarcts in CT scan, and increased IL-10 serum level were more susceptible to infection. The baseline serum level of IL-10 >= 14.5 pg/ ml and the size of infarct area > 3.5 cm3 were the independent predictors of PSI. PMID- 27453749 TI - Correlations between risk factors and functional evolution in patients with spastic quadriplegia. AB - Cerebral palsy is the most common cause of developing neuro-motor disability in children, in many cases, the triggering cause remaining unknown. Quadriplegia is the most severe spastic cerebral palsy, characterized by severe mental retardation and bi-pyramidal syndrome. The purpose of this paper was to demonstrate the importance of knowing the risk factors and the psychosomatic ones, determining to what extent they influence the functional evolution in patients diagnosed with spastic quadriplegia. 23 children diagnosed with spastic quadriplegia were included in the study, being aged between 1 year and half and 12 years. Patients were assessed at baseline (T1), at one year (T2) and after two years at the end of the study (T3). Patients received a comprehensive rehabilitation program for the motor and sensory deficits throughout the study. Initially, a comprehensive evaluation (etiopathogenic, clinical and functional) that started from a thorough medical history of children (the older ones), was conducted but chose parents to identify the risk factors, and a complete physical exam. At each assessment, joint and muscle balance was conducted. To assess functionality, the gross motor function classification systems (GMFCS) and manual ability (MACS) were used. Many risk factors that were classified according to the timeline in prenatal factors, perinatal and postnatal, were identified from a thorough history. A direct correlation was noticed between the decrease of coarse functionality and manual ability, both initially and in dynamic and low APGAR scores, low gestational age, low birth weight and a higher body mass index of the mother. A direct link was observed between the gross motor function and the manual ability. A significant improvement in the MACS score was noticed in patients with a better GMFCS score. PMID- 27453750 TI - New clinical application of amniotic membrane transplant for ocular surface disease. AB - The new defined anatomical and functional complex conjunctiva-limbus-cornea is a new concept, which helps clinicians better understand and treat ocular surface pathologies. The management of the ocular surface disease has changed dramatically over the years, with spectacular improvements of techniques, and of course, results. The amniotic membrane, used as a graft or as a substrate for the cultivation of limbal corneal cells has showed encouraging results. AIM: To investigate the usefulness of amniotic membrane transplantation in ocular surface pathologies. METHOD: The study is retrospective. 28 eyes of 28 patients with ocular surface pathologies (ocular burns, recent and old, symblepharon, pterygium, corneal and conjunctival tumors, persistent epithelial defect) underwent an amniotic membrane transplantation during a 1 year period. The necrotic and the scar tissue were first excised in all the patients and the amniotic membrane was sutured with an epithelial face up. Follow up ranged from 1 to 12 months. RESULTS: Good results were obtained in all 28 eyes. The anatomy of cornea and conjunctiva was improved, with limited benefits only in old ocular burn, symblepharon and in one case of extended tumors of the cornea and conjunctiva. Out of 28 eyes, 23 (82%) also had a visual acuity improvement. CONCLUSION: The amniotic membrane may be considered a good alternative for ocular surface reconstruction especially in acute status. ABBREVIATIONS: AMT = amniotic membrane transplantation, BCVA = best corrected visual acuity, BUT = break up time. PMID- 27453751 TI - Focal adenomyosis (intramural endometriotic cyst) in a very young patient - differential diagnosis with uterine fibromatosis. AB - Introduction. Adenomyosis is a widespread disease usually affecting the late reproductive years of the women's life, which has a great impact on their fertility. The most common form is diffuse adenomyosis, while focal adenomyosis, a cystic variant, is very rare, particularly in patients younger than 30 years old. Materials and methods. We reported a rare case of a 20-year-old Caucasian woman with cystic adenomyosis who was admitted in our service with severe chronic pelvic pain, dysmenorrhea, and menorrhagia, who had received conservative surgical treatment to preserve fertility and improve her obstetrical prognosis. Results and Discussions. Although the necrobiosis of a uterine fibroid was suspected preoperatively, the extemporaneous histopathological exam revealed adenomyosis associated with fibroleiomyoma with hyaline dystrophy and multiple foci of endometriosis of cystic formation in the wall of a young woman without any risk factors. Conclusion. Although a rare lesion in young patients, cystic adenomyosis should be considered when chronic pelvic pain is exacerbated during menstruation and is associated with a uterine tumor. In young patients, the differential diagnosis should be made with uterine malformations (hematometra), necrobiosis of uterine fibroids, pelvic endometriosis. The surgical treatment should be conservative with the excision of the lesion, always taking into account fertility preservation in young patients. PMID- 27453752 TI - Evolution of radical mastectomy for breast cancer. AB - Surgical treatment of breast cancer has been marked by a constant evolution since the Halsted radical mastectomy described in the late 19th century has become the current standard Madden radical mastectomy, a breast surgery that involves the ablation of tissue with the axillary lymphatic preserving both pectoral muscles. The purpose of this paper was to present the stages that have marked the evolution of this intervention and to provide an overview of the way breast cancer has been understood and treated in the last century. PMID- 27453753 TI - The multimodal management of GH-secreting pituitary adenomas: predictive factors, strategies and outcomes. AB - Object. The aim of this study was to analyze a series of 28 patients with acromegaly who underwent a multimodal surgical, medical and radiosurgical therapy, with a special attention to the advantages, complications, and predictive factors of a successful outcome. Methods. 28 consecutive cases of GH secreting pituitary adenomas, who underwent transsphenoidal endoscopic or microscopic surgery, between 1 January 2014 and 31 December 2014 were retrospectively reviewed. Tumors were classified according to the diameter, measured on MRI, as micro- or macroadenomas, and parasellar (cavernous sinus) tumor extension was analyzed based on the Knosp grading score. The mean follow-up period was of 18.4 months. Criteria justifying the complete hormonal remission were preoperative basal serum GH < 2.5 MUg/ L, preoperative nadirGH < 1 ng/ L after OGTT and normal preoperative IGF-I levels age and sex-matched. Results. An overall complete hormonal remission rate was achieved in 64.3% of the patients. The remission rate was higher in patients with microadenomas (77.8%) than in those with macroadenomas (57.9%). A number of predictive factors, which might have interfered with the hormonal remission rate from a statistical, clinical and paraclinical point of view, were identified: tumor size (r = 0.625), preoperative GH serum levels (r = -0.517), cavernous sinus extension was quantified according to Knosp grading score (r = 0.469) and the degree of tumor subtotal resection (r = 0.598). Conclusions. Favorable hormonal and visual remission rates can be achieved after transsphenoidal resection of GH-secreting pituitary adenomas; however, the management remains challenging, the increased surgical experience being important for higher cure rates. If a biochemical hormonal cure is not achieved postoperatively, adjuvant medical or radio surgical therapy can be recommended. PMID- 27453754 TI - Metastatic clear cell renal carcinoma - an unusual response to Temsirolimus in second line therapy. AB - Renal cell carcinoma (RCC) represents 3% of all cancers, with the highest incidence occurring in the most developed countries and representing the seventh most common cancer in men and the ninth most common cancer in women. The understanding of the tumor molecular biology and the discovery of new drugs that target molecular pathways have increased the arsenal against advanced renal cell carcinoma and improved the outcomes in the patients suffering from these affections. Studying the molecular signaling that controls the tumor growth and the progression has led to the development of molecular therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, resulting in a significant improvement in the overall survival and quality of life. Sunitinib represents an inhibitor of VEGFR 1-3, c-kit, FLT-3 and PDGFR. We present the case of a patient with metastatic clear cell RCC with a treatment effect following sequential VEGF and mTOR inhibitor treatment. Under sunitinib treatment, the patient had a progression free survival (PFS) of approximately 9 months, similar to the PFS observed in clinical trials. Sunitinib was well tolerated by this patient. Temsirolimus, an mTOR inhibitor, is currently only approved for the first-line treatment of mRCC patients with poor prognosis. This study analyzes a treatment effect of second line temsirolimus in a patient with metastatic renal cell carcinoma (mRCC). PMID- 27453755 TI - Saccular cyst with atypical presentation. AB - Respiratory obstruction and stridor in infants and children are not uncommon. A rare cause of these sometimes life-threatening symptoms is the congenital saccular cyst. OBJECTIVES: We present the case of a 5-year-old girl with a cervical tumor, which appeared after a laryngeal endoscopic surgery of a saccular cyst with two relapses and a particular local evolution of its recurrence through the cricothyroid membrane. MATERIAL AND METHOD: The patient data has been reviewed over the entire follow-up period and a thorough an analysis of her investigations and surgery was performed. RESULTS: The unusual evolution of this case was marked by an atypical exteriorization - not found in the published literature. The surgical approach was external, by paramedian thyrotomy, with no further long-term recurrence. CONCLUSIONS: An accurate diagnosis of saccular cysts can be made with the help of medical history, by an endoscopic visualization of the lesion and by the CT-scan imaging of the cervical region. Sometimes, saccular cysts can extend beyond laryngeal limits, determining fluid filled tumors in the cervical region. PMID- 27453756 TI - Retrospective clinicopathological study of malignant bone tumors in children and adolescents in Romania - single center experience. AB - RATIONALE: There is few data on epidemiology or clinico-pathology of malignant bone tumors in children and adolescents in Romania. These tumors are very rare compared to other malignancies, yet they account for a major source of mortality and morbidity among patients with cancer. Bone tumors often have a similar presentation and clinical approach, but they present individual characteristics that are important for treatment and prognosis. OBJECTIVE: To describe the characteristics of primary malignant bone tumors in children and adolescents in Romania. METHODS AND RESULTS: A retrospective analysis of all malignant bone tumors registered at a large referral center, "Maria Sklodowska Curie" Emergency Hospital for Children, between 2005 and 2013 was presented. A total of 146 biopsies and surgical resection specimens were reviewed during this period, and were classified as malignant bone tumors. There were 91 boys and 55 girls in the series, with a male-female ratio of 1.65:1. The average patient age was 13.32 years (2 to 19). The most common anatomical distribution of the tumors was femur 32.19%, tibia - 25.34% and humerus - 11.64%. Histologically, we found osteosarcoma in 54.1% of all bone tumors, followed by Ewing's sarcoma - 30.82% and chondrosarcoma - 8.9%. DISCUSSION: Geographic location did not appear to represent a risk factor for any particular type of bone tumor. Our results were parallel to the findings previously reported in the general literature; the distribution and the epidemiology were similar to those in the other developed and underdeveloped countries. Malignant bone tumors in our country have a high mortality rate, because of the late diagnosis. PMID- 27453757 TI - Role of the biomarkers for the diagnosis of Creutzfeldt-Jakob disease. AB - OBJECTIVE: Sporadic Creutzfeldt-Jakob disease (CJD) is a human prion disease, rapidly progressive and fatal, characterized by spongiform encephalopathy. The characteristic triad of signs - rapidly progressive dementia, myoclonus and periodic sharp wave complexes (PSWC) on electroencephalography (EEG) - usually appear in the late stages of the disease. The clinical diagnosis of CJD ante mortem involves the exclusion of the rapidly progressive non-prionic dementias, the definitive diagnosis requiring brain tissue confirmation. Authors evaluated the methods of clinical diagnosis for sporadic CJD. METHODS: This study retrospectively reviewed the medical records of patients diagnosed with probable sporadic CJD, based on brain magnetic resonance imaging (MRI), EEG, cerebrospinal fluid (CSF) analysis and extensive laboratory work-up. RESULTS: Four patients with a mean age of 67 years were included in our study. The mean duration from diagnosis until death was of 3.2 weeks. The clinical features of the disease at onset were atypical. In the final stage of the disease, all patients presented rapidly progressive dementia and myoclonus. High levels of 14-3-3 protein and tau protein and normal levels of amyloid beta1-42 were found at CSF analysis, in all patients. PSWC on EEG were present in 3 out of 4 patients at different moments of the disease. MRI showed hyperintense lesions in brain cortex, caudate nucleus, and putamen on T2, FLAIR, and DWI. CONCLUSION: CJD may present various clinical features and, since brain biopsy is usually difficult to perform, a combination of biomarkers is useful in order to establish the diagnosis in the early phase of the disease. PMID- 27453758 TI - Complex histopathological and surgical aspects in a case of giant malignant gastric perforation. AB - We present the case of a 52-year-old male patient, hospitalized on an emergency basis in the University Emergency Hospital in Bucharest, after being diagnosed with pneumoperitoneum acute abdomen, for which emergency surgery was mandatory. A 3,5-4 cm malignant gastric perforation, ascitis and peritoneal carcinomatosis were found. The histopathological exam revealed infiltrative mucinous gastric carcinoma with epiploic metastasis. Due to the lack of available gastric material, an atypical surgical solution was performed: gastric packing with epiploic material by means of transgastric traction. The solution proved to be successful for short-term recovery. The underlying condition was not focused on, the patient being directed to the Oncology Department. Acute gastric perforation is a rare complication of gastric cancer, and the association with gastric linitis is uncommon. This specific histopathological condition made the classical surgical repair techniques unsuitable for the presented case and an atypical solution had to be performed. PMID- 27453760 TI - A Case for the Nuclear Membrane as a Mechanotransducer. AB - The cell nucleus is becoming increasingly recognized as a mechanosensitive organelle. Most research on nuclear mechanosignaling focuses on the nuclear lamina and coupled actin structures. In this commentary, we discuss the possibility that the nuclear membrane senses and transduces mechanical signals similar to the plasma membrane. We briefly summarize possible (i) pathophysiological sources of nuclear membrane tension, (ii) features that render nuclear membranes particularly suited for mechanotransduction, and (iii) molecular sensing mechanisms. PMID- 27453759 TI - Minimally invasive surgery of the anterior skull base: transorbital approaches. AB - Minimally invasive approaches are becoming increasingly popular to access the anterior skull base. With interdisciplinary cooperation, in particular endonasal endoscopic approaches have seen an impressive expansion of indications over the past decades. The more recently described transorbital approaches represent minimally invasive alternatives with a differing spectrum of access corridors. The purpose of the present paper is to discuss transorbital approaches to the anterior skull base in the light of the current literature. The transorbital approaches allow excellent exposure of areas that are difficult to reach like the anterior and posterior wall of the frontal sinus; working angles may be more favorable and the paranasal sinus system can be preserved while exposing the skull base. Because of their minimal morbidity and the cosmetically excellent results, the transorbital approaches represent an important addition to established endonasal endoscopic and open approaches to the anterior skull base. Their execution requires an interdisciplinary team approach. PMID- 27453761 TI - The detection of carbon dioxide leaks using quasi-tomographic laser absorption spectroscopy measurements in variable wind. AB - Laser absorption spectroscopy (LAS) has been used over the last several decades for the measurement of trace gasses in the atmosphere. For over a decade, LAS measurements from multiple sources and tens of retroreflectors have been combined with sparse-sample tomography methods to estimate the 2-D distribution of trace gas concentrations and underlying fluxes from point-like sources. In this work, we consider the ability of such a system to detect and estimate the position and rate of a single point leak which may arise as a failure mode for carbon dioxide storage. The leak is assumed to be at a constant rate giving rise to a plume with a concentration and distribution that depend on the wind velocity. We demonstrate the ability of our approach to detect a leak using numerical simulation and also present a preliminary measurement. PMID- 27453762 TI - Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain. AB - Vascular malformations are developmental congenital abnormalities of the vascular system which may involve any segment of the vascular tree such as capillaries, veins, arteries, or lymphatics. Arteriovenous malformations (AVMs) are congenital vascular lesions, initially described as "erectile tumors," characterized by atypical aggregation of dilated arteries and veins. They may occur in any part of the body, including the brain, heart, liver, and skin. Severe clinical manifestations occur only in the brain. There is absence of normal vascular structure at the subarteriolar level and dearth of capillary bed resulting in aberrant arteriovenous shunting. The causative factor and pathogenic mechanisms of AVMs are unknown. Importantly, no marker proteins have been identified for AVM. AVM is a high flow vascular malformation and is considered to develop because of variability in the hemodynamic forces of blood flow. Altered local hemodynamics in the blood vessels can affect cellular metabolism and may trigger epigenetic factors of the endothelial cell. The genes that are recognized to be associated with AVM might be modulated by various epigenetic factors. We propose that AVMs result from a series of changes in the DNA methylation and histone modifications in the genes connected to vascular development. Aberrant epigenetic modifications in the genome of endothelial cells may drive the artery or vein to an aberrant phenotype. This review focuses on the molecular pathways of arterial and venous development and discusses the role of hemodynamic forces in the development of AVM and possible link between hemodynamic forces and epigenetic mechanisms in the pathogenesis of AVM. PMID- 27453763 TI - Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients. AB - BACKGROUND: Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients. RESULTS: Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone. CONCLUSIONS: Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes. PMID- 27453765 TI - Variation in WIC Cash-Value Voucher Redemption among American Indian Reservation Communities in Washington State. PMID- 27453764 TI - Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma. AB - BACKGROUND: Epigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma. The role of epigenetic events mediated by microRNA (miR) is less clear. Tumor and plasma miR expression was examined in patients with primary uveal melanoma with tumor monosomy-3, a predictor of metastasis. RESULTS: miR profiling of tumors by microarray found six miRs over-expressed and 19 under-expressed in 33 tumors with monosomy-3 compared to 22 without. None of the miRs differentially expressed in tumors with and without monosomy-3 was differentially expressed in tumors with and without tumor infiltrating lymphocytes. Tumors manifesting monosomy-3 were also characterized by higher levels of TARBP2 and DDX17 and by lower levels of XPO5 and HIWI, miR biogenesis factors. miR profiling of plasma by a quantitative nuclease protection assay found elevated levels of 11 miRs and reduction in four in patients with tumor monosomy-3. Only three miRs differentially expressed in the tumor arrays were detectable in plasma. miRs implicated in uveal melanoma development were not differentially expressed. Elevated plasma levels in patients with tumor monosomy-3 of miR-92b, identified in the tumor array, and of miR-199-5p and miR-223, identified in the plasma array, were confirmed by quantitative real-time polymerase chain reaction. Levels were also higher in patients compared to normal controls. CONCLUSIONS: These results support a role for epigenetic mechanisms in the development of metastasis in patients with uveal melanoma and the analysis of miRs as biomarkers of metastatic risk. They also suggest that potentially useful blood miRs may be derived from the host response as well as the tumor. PMID- 27453766 TI - Preface to Special Topic: Selected Papers from the 2015 Annual Meeting of the AES Electrophoresis Society in Salt Lake City, Utah. PMID- 27453767 TI - A "twisted" microfluidic mixer suitable for a wide range of flow rate applications. AB - This paper proposes a new "twisted" 3D microfluidic mixer fabricated by a laser writing/microfabrication technique. Effective and efficient mixing using the twisted micromixers can be obtained by combining two general chaotic mixing mechanisms: splitting/recombining and chaotic advection. The lamination of mixer units provides the splitting and recombination mechanism when the quadrant of circles is arranged in a two-layered serial arrangement of mixing units. The overall 3D path of the microchannel introduces the advection. An experimental investigation using chemical solutions revealed that these novel 3D passive microfluidic mixers were stable and could be operated at a wide range of flow rates. This micromixer finds application in the manipulation of tiny volumes of liquids that are crucial in diagnostics. The mixing performance was evaluated by dye visualization, and using a pH test that determined the chemical reaction of the solutions. A comparison of the tornado-mixer with this twisted micromixer was made to evaluate the efficiency of mixing. The efficiency of mixing was calculated within the channel by acquiring intensities using ImageJ software. Results suggested that efficient mixing can be obtained when more than 3 units were consecutively placed. The geometry of the device, which has a length of 30 mm, enables the device to be integrated with micro total analysis systems and other lab-on-chip devices. PMID- 27453768 TI - Perceived and Actual Change in Religion/Spirituality in Cancer Survivors: Longitudinal Relationships With Distress and Perceived Growth. AB - This observational cohort study examined the relationships between actual and perceived R/S change at 12 months post cancer diagnosis with depression, anxiety, and perceived growth 6 months later. Older adult military veteran cancer survivors (n = 111) completed self-report surveys at 6, 12, and 18 months post cancer diagnosis. Perceived R/S change was assessed at 12 months postdiagnosis with "Have your religious or spiritual beliefs changed as a result of your cancer" (more R/S, less R/S, other). Actual R/S change was assessed at 6 and 12 months postdiagnosis on a single item, "I have faith in God or a Higher Power" (no, somewhat, yes). A notable minority reported perceived (18.9%) and actual (14.4%) change. Greater perceived R/S change predicted more severe symptoms of depression and anxiety and greater perceived growth at 18 months postdiagnosis; perceived growth was positively associated with anxiety. Cancer survivors who report R/S changes may benefit from spiritual and/or psychological support. PMID- 27453769 TI - Spiritual Intimacy, Marital Intimacy, and Physical/Psychological Well-Being: Spiritual Meaning as a Mediator. AB - OBJECTIVE: Intimacy is an essential part of marital relationships, spiritual relationships, and is also a factor in well-being, but there is little research simultaneously examining the links among spiritual intimacy, marital intimacy, and well-being. METHODS: Structural equation modeling was used to examine associations among the latent variables-spiritual intimacy, marital intimacy, spiritual meaning, and well-being-in a cross-sectional study of 5,720 married adults aged 29-100 years (M = 58.88, SD = 12.76, 59% female). All participants were from the Adventist Health Study-2, Biopsychosocial Religion and Health Study. RESULTS: In the original structural model, all direct associations between the three latent variables of spiritual intimacy, marital intimacy, and well being were significantly positive indicating that there was a significant relationship among spiritual intimacy, marital intimacy, and well-being. When spiritual meaning was added as a mediating variable, the direct connections of spiritual intimacy to marital intimacy and to well-being became weakly negative. However, the indirect associations of spiritual intimacy with marital intimacy and with well-being were then strongly positive through spiritual meaning. This indicates that the relationship among spiritual intimacy, marital intimacy, and well-being was primarily a result of the meaning that spiritual intimacy brought to one's marriage and well-being, and that without spiritual meaning greater spirituality could negatively influence one's marriage and well-being. CONCLUSIONS: These findings suggest the central place of spiritual meaning in understanding the relationship of spiritual intimacy to marital intimacy and to well-being. PMID- 27453770 TI - Developing a mobile application to better inform patients and enable effective consultation in implant dentistry. AB - The field of dentistry lacks satisfactory tools to help visualize planned procedures and their potential results to patients. Dentists struggle to provide an effective image in their patient's mind of the end results of the planned treatment only through verbal explanations. Thus, verbal explanations alone often cannot adequately help the patients make a treatment decision. Inadequate attempts are frequently made by dentists to sketch the procedure for the patient in an effort to depict the treatment. These attempts however require an artistic ability not all dentists have. Real case photographs are sometimes of help in explaining and illustrating treatments. However, particularly in implant cases, real case photographs are often ineffective and inadequate. The purpose of this study is to develop a mobile application with an effective user interface design to support the dentist-patient interaction by providing the patient with illustrative descriptions of the procedures and the end result. Sketching, paper prototyping, and wire framing were carried out with the actual user's participation. Hard and soft dental tissues were modeled using three dimensional (3D) modeling programs and real cases. The application enhances the presentation to the patients of potential implants and implant supported prosthetic treatments with rich 3D illustrative content. The application was evaluated in terms of perceived ease of use and perceived usefulness through an online survey. The application helps improve the information sharing behavior of dentists to enhance the patients' right to make informed decisions. The paper clearly demonstrates the relevance of interactive communication technologies for dentist-patient communication. PMID- 27453771 TI - Dry and wet approaches for genome-wide functional annotation of conventional and unconventional transcriptional activators. AB - Transcription factors (TFs) are master gene products that regulate gene expression in response to a variety of stimuli. They interact with DNA in a sequence-specific manner using a variety of DNA-binding domain (DBD) modules. This allows to properly position their second domain, called "effector domain", to directly or indirectly recruit positively or negatively acting co-regulators including chromatin modifiers, thus modulating preinitiation complex formation as well as transcription elongation. At variance with the DBDs, which are comprised of well-defined and easily recognizable DNA binding motifs, effector domains are usually much less conserved and thus considerably more difficult to predict. Also not so easy to identify are the DNA-binding sites of TFs, especially on a genome wide basis and in the case of overlapping binding regions. Another emerging issue, with many potential regulatory implications, is that of so-called "moonlighting" transcription factors, i.e., proteins with an annotated function unrelated to transcription and lacking any recognizable DBD or effector domain, that play a role in gene regulation as their second job. Starting from bioinformatic and experimental high-throughput tools for an unbiased, genome-wide identification and functional characterization of TFs (especially transcriptional activators), we describe both established (and usually well affordable) as well as newly developed platforms for DNA-binding site identification. Selected combinations of these search tools, some of which rely on next-generation sequencing approaches, allow delineating the entire repertoire of TFs and unconventional regulators encoded by the any sequenced genome. PMID- 27453773 TI - Effect of intercalator and Lewis acid-base branched peptide complex formation: boosting affinity towards HIV-1 RRE RNA. AB - High throughput screening of a 4096 compound library of boronic acid and acridine containing branched peptides revealed compounds that have dissociation constants in the low nanomolar regime for HIV-1 RRE IIB RNA. We demonstrate that branched peptide boronic acids A5, A6, and A7 inhibit the production of p24, an HIV-1 capsid protein, in a dose-dependent manner. PMID- 27453772 TI - Chimeric mitochondrial peptides from contiguous regular and swinger RNA. AB - Previous mass spectrometry analyses described human mitochondrial peptides entirely translated from swinger RNAs, RNAs where polymerization systematically exchanged nucleotides. Exchanges follow one among 23 bijective transformation rules, nine symmetric exchanges (X <-> Y, e.g. A <-> C) and fourteen asymmetric exchanges (X -> Y -> Z -> X, e.g. A -> C -> G -> A), multiplying by 24 DNA's protein coding potential. Abrupt switches from regular to swinger polymerization produce chimeric RNAs. Here, human mitochondrial proteomic analyses assuming abrupt switches between regular and swinger transcriptions, detect chimeric peptides, encoded by part regular, part swinger RNA. Contiguous regular- and swinger-encoded residues within single peptides are stronger evidence for translation of swinger RNA than previously detected, entirely swinger-encoded peptides: regular parts are positive controls matched with contiguous swinger parts, increasing confidence in results. Chimeric peptides are 200 * rarer than swinger peptides (3/100,000 versus 6/1000). Among 186 peptides with > 8 residues for each regular and swinger parts, regular parts of eleven chimeric peptides correspond to six among the thirteen recognized, mitochondrial protein-coding genes. Chimeric peptides matching partly regular proteins are rarer and less expressed than chimeric peptides matching non-coding sequences, suggesting targeted degradation of misfolded proteins. Present results strengthen hypotheses that the short mitogenome encodes far more proteins than hitherto assumed. Entirely swinger-encoded proteins could exist. PMID- 27453774 TI - One-Step Selective Hydroxylation of Benzene to Phenol with Hydrogen Peroxide Catalysed by Copper Complexes Incorporated into Mesoporous Silica-Alumina. AB - Benzene was hydroxylated with hydrogen peroxide (H2O2) in the presence of catalytic amounts of copper complexes in acetone to yield phenol at 298 K. At higher temperature, phenol was further hydroxylated with H2O2 by catalysis of copper complexes to yield p-benzoquinone. The kinetic study revealed that the rate was proportional to concentrations of benzene and H2O2, but to the square root of concentration of a copper(II) complex ([Cu(tmpa)]2+: tmpa = tris(2 pyridylmethyl)amine). The addition of a spin trapping reagent resulted in formation of a spin adduct of hydroperoxyl radical (HO2*), as observed by EPR spectroscopy, inhibiting phenol formation. HO2* produced by the reaction of [Cu(tmpa)]2+ with H2O2 acts as a chain carrier for the radical chain reactions for formation of phenol. When [Cu(tmpa)]2+ was incorporated into mesoporous silica-alumina (Al-MCM-41) by a cation exchange reaction, the selectivity to production of phenol was much enhanced by prevention of hydroxylation of phenol, which was not adsorbed to Al-MCM-41. The high durability with turnover number of 4320 for the hydroxylation of benzene to phenol with H2O2 was achieved using [Cu(tmpa)]2+ incorporated into Al-MCM-41 as an efficient and selective catalyst. PMID- 27453775 TI - Atopic dermatitis prevention in children following maternal probiotic supplementation does not appear to be mediated by breast milk TSLP or TGF-beta. AB - BACKGROUND: The Probiotics in Prevention of Allergy among Children in Trondheim (ProPACT) study, a randomised, placebo controlled trial, demonstrated that maternal supplementation with probiotic milk reduced the incidence of atopic dermatitis (AD) in infancy. The mechanisms behind this effect are incompletely understood and breast milk cytokines have been postulated as possible mediating factors. In this study we aimed to assess whether breast milk TLSP and TGF-beta are affected by a maternal probiotic supplementation regime, and their contribution to the preventive effect of this regime on AD in the offspring. METHODS: TSLP and TGF-beta isoforms (TGF-beta1, TGF-beta2 and TGF-beta3) were measured using ELISA and multiplex assays, respectively, in breast milk samples collected at 10 days and 3 months postpartum from women participating in the ProPACT trial (n = 259). The natural indirect and direct effects of maternal probiotics on AD, due to changes in breast milk cytokines, were estimated using causal mediation techniques. RESULTS: Probiotic supplementation tend to lead to high levels of breast milk TSLP at 10 days postpartum (p = 0.062), but this change did not contribute to the prevention of AD according to the mediation analysis. Probiotics had no apparent effect on TSLP at 3 months or TGF-betas at either time points. Thus, these are unlikely to be mediators of the effect of maternal probiotics on AD in offspring. CONCLUSIONS: Whilst maternal probiotic supplementation resulted in higher breast milk concentrations of TLSP at 10 days postpartum, this does not appear to be a mechanism for prevention of AD by maternal probiotics. Trial registration The original trial protocol is registered in ClinicalTrials.gov (identifier NCT00159523). PMID- 27453776 TI - Environment and Autism: Current State of the Science. AB - Research into environmental risk factors for autism has grown dramatically over the past 10 years, providing evidence that non-genetic factors acting during the prenatal period may influence the underlying neurodevelopmental processes. This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated with autism spectrum disorder (ASD), including only human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past decade, and focusing on maternal lifestyle or environmental chemicals. Consistent results have been reported for an association of higher maternal intake of certain nutrients and supplements with reduction in ASD risk, with the strongest evidence for folic acid supplements. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. A few studies suggest a link with organophosphate pesticides. More rigorous ascertainment of exposure is needed for studies of substance use; most investigations adjusting for potential confounders, but relying on self-reported use, have shown no links between maternal smoking or alcohol consumption and ASD. Little research has assessed other persistent and non-persistent organic chemical pollutants, such as are found in common household or personal care products, in association with ASD specifically. More work is needed to examine fats, vitamins, and other maternal nutrients, as well as endocrine-disrupting chemicals and pesticides, in association with ASD, given sound biological plausibility and evidence regarding other neurodevelopmental outcomes. In addition, the field could be advanced by the use of large-scale epidemiologic studies, attention to critical etiologic windows and how these vary by exposure, interactions with genetic susceptibility, and a focus on underlying mechanisms. PMID- 27453778 TI - A unique case of right cervical aortic arch with anomalous left common carotid artery and absent right common carotid artery. AB - INTRODUCTION: Cervical aortic arch is a rare anomaly where-in the ascending aorta arises normally from the left ventricle and extends in such a fashion that the aortic arch is situated high in the neck on either side. This anomaly should be suspected in any child exhibiting a pulsatile swelling in the neck. CASE COMMENTARY: An 8 year old child presented with a pulsatile swelling on the right side of the neck since birth. CT angiography revealed right sided cervical aortic arch at C4-C5 level. The left common carotid artery arose from the ascending aorta at D4 with the right external and internal carotid arteries originating separately from the cervical arch. The right and left subclavian arteries arose from the descending aorta at D1 and D4 respectively. DISCUSSION: Although most patients with cervical aortic arch are asymptomatic, some have dysphagia from oesophageal compression and respiratory distress from tracheal compression. There are many anatomical variations in cervical aortic arch as mentioned by Haughton. This case is Haughton type A because apart from the presence of right cervical aortic arch, 2 additional oddities in the form of leftward descending aorta and abnormal origin of the left common carotid artery from ascending aorta with absence of right common carotid artery are noted. CONCLUSION: Cervical aortic arch is not a very commonly encountered entity and can be quite vexing for those who are seeing such a case in OPD for the first time. Although cervical aortic arch anomalies have been reported in literature, published reports of new cases will help to increase awareness regarding this anomaly and lead to a swift and efficient diagnosis and management. PMID- 27453779 TI - Attaining pathological complete regression for breast conservation - A pilot experience in a developing country. AB - CONTEXT: Local recurrence is a formidable risk consideration in employing breast conservation for breast cancer. However pathological complete regression (PCR) from chemotherapy has been associated with improved rates of recurrence. Lower PCR rates have been reported from earlier studies and our approach seeks to obtain higher PCR rates utilizing a two pronged approach of surgery and chemotherapy. OBJECTIVE: To determine success rates in attaining pathologically complete regression for breast conservation in non-metastatic breast cancer cases in a developing country and their clinical outcome. PATIENTS AND METHODS: Patients diagnosed with early stage breast cancers had sequential anthracycline/taxane based neoadjuvant/adjuvant chemotherapy administered at three weekly intervals. Following an initial excision, re-excisions were done following three courses of doxorubicin based chemotherapy. Subsequent re excisions in cases with failed complete pathological regression were repeated following additional three doxorubicin based chemotherapy cycles or at sequel third taxane based cycle. Endpoint was pathologically complete regression as determined on permanent sections. RESULTS: Patients ages ranged between 27 and 67 years, mean age 43years, SD 10.34 years, N = 20 Initial breast tumour sizes ranged between 0.5 and 9 cm, mean 4.05 cm, SD 2.38. There were three T4, four T3 tumours, seven T2 and six T1 tumours. Clinical axillary lymphadenopathy with pathological involvement was present in 11 cases. Histological diagnosis showed 13 cases of invasive ductal carcinoma (65.0%), 2 cases of ductal carcinoma insitu (10.0%), 1 papillary carcinoma (5.0%), 3 cases of invasive lobular carcinoma (15.0%) and non-specific type 1 (5.0%). Immunohistochemistry assessment available in 15 cases was positive for estrogen and progesterone receptors in 10 cases. Two cases (10.0%) exhibited 20% positivity for human epidermal growth factor receptor. Pathological complete regression (PCR) defined as no invasive or insitu tumour residuals in the excised tumour bed, was achieved in the 18 cases assessed. (100%) This was consistent with clinical complete response obtained. It was not determined in 2 cases though clinical complete response was obtained. PCR was determined in ten cases (50.0%) at the first reexcision, second reexcision in 4 cases (20.0%) and third reexcision in 4 cases (20.0%). Mean no of re-excisions 1.67 cm, SD 0.84. Six sequential anthracycline/taxane cycles were administered in 17 cases while three cases received anthracycline based chemotherapy only. Median duration of followup from diagnosis was 48 months ranging between 8 months and 144 months. There were two demises at 48 months and 36 months follow up. CONCLUSION: Extended chemotherapy sessions alongside re-excisions were successful in achieving much enhanced rates of pathologically complete remissions at 100% in this yet early report, thus improving breast conservation rates even for T3 and T4 tumours. Our study reports higher PCR rates. PMID- 27453777 TI - Mitochondrial dysfunction in Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease, which is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases. Although the cause of PD is still unclear, the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss. Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD. Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin- or genetic factor-induced PD cellular and animal models. Moreover, PINK1 and parkin, two autosomal recessive PD gene products, have important roles in mitophagy, a cellular process to clear damaged mitochondria. PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy. In this review, we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD. PMID- 27453780 TI - Effect of in ovo folic acid injection on hepatic IGF2 expression and embryo growth of broilers. AB - BACKGROUND: Insulin-like factor 2 (IGF2) plays an important role in embryonic growth process by modulating intermediary metabolism and cell proliferation. Folic acid is involved in one carbon metabolism and contributes to DNA methylation which is related to gene expression. The purpose of this study was to explore whether folic acid could regulate IGF2 expression via epigenetic mechanism and further promote embryonic growth of new-hatched broilers. METHODS: In the present study, 360 fertile eggs were selected and randomly assigned to four treatments. On 11 embryonic day of incubation (E11), 0, 50, 100 and 150 MUg folic acid were injected into eggs respectively. After hatched, growth performance of broilers were calculated. Hepatic IGF2 expression, methylation level and chromatin structure of promoter region were analyzed. RESULTS: Results have showed that IGF2 expression was up-regulated in 150 MUg folic acid group (P < 0.05) and other two dose of folic acid did not affect gene expression (P > 0.05). Meanwhile, methylation level of IGF2 promoter were lower in 100 and 150 MUg groups, which was consistent with lower expression of DNA methyltransferase 1 (DNMT1) (P < 0.05). What's more, chromatin looseness of IGF2 promoter was higher in 150 MUg group than control group (P < 0.05). Further, birth weight (BW), liver and bursa index of new-hatched chickens in 150 MUg folic acid group were higher than the other groups (P < 0.05). There were positive correlations between hepatic IGF2 expression and BW and organs index (P < 0.05). CONCLUSION: In conclusion, our data have demonstrated that 150 MUg folic acid injection on E11 could up-regulate IGF2 expression by modulating DNA hypomethylation and improving chromatin accessibility in the gene promoter region, and ulteriorly facilitate embryonic growth and organ development of broilers. PMID- 27453781 TI - Ultrastrong and Flexible Hybrid Hydrogels based on Solution Self-Assembly of Chitin Nanofibers in Gelatin Methacryloyl (GelMA). AB - We demonstrate ultrastrong and flexible hydrogels by self-assembling chitin nanofiber in the presence of gelatin methacryloyl. We tune the mechanical properties of the hydrogel with chitin nanofiber content and show proof-of concept applications in engineering vascular tissue. PMID- 27453782 TI - Oxygen Delivering Biomaterials for Tissue Engineering. AB - Tissue engineering (TE) has provided promising strategies for regenerating tissue defects, but few TE approaches have been translated for clinical applications. One major barrier in TE is providing adequate oxygen supply to implanted tissue scaffolds, since oxygen diffusion from surrounding vasculature in vivo is limited to the periphery of the scaffolds. Moreover, oxygen is also an important signaling molecule for controlling stem cell differentiation within TE scaffolds. Various technologies have been developed to increase oxygen delivery in vivo and enhance the effectiveness of TE strategies. Such technologies include hyperbaric oxygen therapy, perfluorocarbon- and hemoglobin-based oxygen carriers, and oxygen generating, peroxide-based materials. Here, we provide an overview of the underlying mechanisms and how these technologies have been utilized for in vivo TE applications. Emerging technologies and future prospects for oxygen delivery in TE are also discussed to evaluate the progress of this field towards clinical translation. PMID- 27453783 TI - Materials design at the interface of nanoparticles and innate immunity. PMID- 27453784 TI - Pediatric chronic myeloid leukemia with inv(3)(q21q26.2) and T lymphoblastic transformation: a case report. AB - BACKGROUND: Chronic myeloid leukemia (CML) comprises ~3 % of pediatric leukemia. Although therapy with tyrosine kinase inhibitors (TKIs) is highly effective for CML, multiple factors have been identified as predictive of treatment failure. Chromosomal abnormalities involving the MECOM locus at 3q26 portend therapy resistant disease in adults, yet have never been described in pediatric patients and have not been associated with T lymphoblastic progression. CASE PRESENTATION: We present a case of an 11-year-old boy with CML possessing the unique combination of T lymphoblastic transformation and a subclone harboring inv(3)(q21q26.2) at diagnosis. This is the first reported case of pediatric CML with inv(3)(q21q26.2) and the first case of T lymphoblastic progression associated with this karyotype. The patient was treated with single agent TKI therapy with robust initial response. Marrow histology at one month showed restoration of trilineage hematopoiesis and BCR-ABL RT-PCR at three months showed a 1.4 log reduction in transcript levels. CONCLUSIONS: The karyotypic abnormality of inv(3)(q21q26.2) in CML is not restricted to adult patients. Moreover, while chromosome 3 abnormalities are markers of TKI resistance in adults, our patient showed a robust early response to single agent TKI therapy. This finding suggests pediatric CML with inv(3)(q21q26.2) may have distinct features and more favorable treatment responses than those described in adults. PMID- 27453785 TI - Recombinant human thrombomodulin inhibits neutrophil extracellular trap formation in vitro. AB - The aim of this study was to investigate the effects of recombinant human-soluble thrombomodulin (rTM) on lipopolysaccharide (LPS)-induced, platelet-dependent neutrophil extracellular trap (NET) formation (NETosis). Human peripheral blood neutrophils and platelets were co-incubated with or without LPS (0.2 MUg/ml) in the presence and absence of rTM (2 MUg/ml). NETosis was confirmed by immunostaining and confocal microscopy. In the absence of platelets, LPS did not induce NETosis in the neutrophils. NETosis, however, was induced by LPS when neutrophils were co-cultured with platelets (64 % of neutrophils). Notably, rTM was able to fully inhibit NETosis in neutrophils cultured with platelets and in the presence of LPS. rTM did not induce NETosis in this co-culture system (p < 0.01 versus LPS in the absence of rTM). These results show that rTM can suppress LPS-induced platelet-dependent NETosis in vitro. PMID- 27453786 TI - First report of Panton-Valentine leukocidin-positive methicillin-susceptible Staphylococcus aureus ST88 harbouring PhiSa2usa isolated from refractory breast abscesses in Japan. AB - A methicillin-susceptible Staphylococcus aureus with Panton-Valentine leukocidin (PVL) genes was isolated from refractory breast abscesses of 12-year-old girl in Japan, and classified into ST88, spa-t1245 and coa-IIIa. This strain harboured PVL phage PhiSa2usa, which is usually found in ST8 community-acquired methicillin resistant S. aureus clone USA300. PMID- 27453787 TI - Early mortality on continuous renal replacement therapy (CRRT): the prairie CRRT study. AB - BACKGROUND: Patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) have an increased short-term and long-term risk of mortality. In most North American intensive care units (ICUs), these patients receive continuous renal replacement therapy (CRRT). OBJECTIVE: We aim to identify clinical and demographic factors associated with mortality within 24 h of initiating CRRT. DESIGN: This paper is a prospective cohort study. SETTING: The setting involves three ICUs (12-bed surgical ICU, 10-bed medical ICU, and a 7-bed combined ICU for both medical and surgical patients) of the Regina Qu'Appelle Health Region (RQHR) Saskatchewan, Canada. PATIENTS: The patients were 106 individuals with AKI who were admitted to the ICUs and received CRRT from April 2013 to September 2014. MEASUREMENTS: Date and time of admission, transfer to, and initiation of CRRT were documented. Demographic data, use of vasoactive medications, ventilator settings, pH, urine output, and chronic disease comorbidities were measured. METHODS: The methods involved a stepwise multiple variable logistic regression model using death within 24 h of starting CRRT as the dependent variable, with significant variables derived from univariate analysis as covariates. RESULTS: Of the 2634 patients admitted to the ICUs in the study period (April 2013 to September 2014), 83.6 % (2201/2634) had no AKI. Two hundred and sixty-nine or 10.2 % of the patients had stage 3 AKI. One hundred six of the 269 patients (40%) were started on CRRT. Of those on CRRT, 66/106 died in the ICU while on CRRT. Seventeen of the 66 patients (26%) died within 24 h of initiating therapy. In univariate logistic regression models, factors associated with early mortality included fraction of inspired oxygen (per 0.1 unit) (OR 1.39, 95 % CI 1.09-1.77); epinephrine dose >10 MUg/min (OR 5.81, 95 % CI 1.86 18.16); vasopressin >0.02 MUg/min (OR 3.99, 95 % CI 1.07-14.84); and norepinephrine dose >20 MUg/min (OR 11.04, 95 % CI 2.38-51.24) which were associated with early mortality. When included in stepwise multivariate logistic regression analysis, only FiO2 (per 0.1 unit) and the dose of norepinephrine of >20 MUg/min were independently associated with early mortality. LIMITATIONS: The small sample size was a limitation of this study. CONCLUSION: Patients admitted to the ICU with AKI requiring CRRT have a high risk of early mortality. In these patients, vasopressor use and hypoxia were independently associated with adverse short-term survival. PMID- 27453788 TI - The value of neurocognitive testing for acute outcomes after mild traumatic brain injury. AB - BACKGROUND: Traditionally, neurocognitive testing is performed weeks to months after head injury and is mostly performed on patients who continue to have symptoms or difficulties. In this study, we sought to determine whether these tests, when administered acutely, could assist in predicting short-term outcomes after acute traumatic brain injury (TBI). METHODS: This is an IRB-approved prospective study of adult patients who came to the emergency department of our Level-1 trauma center with TBI. Patients were enrolled prospectively after providing written informed consent and underwent three separate neurocognitive tests: the Galveston Orientation Amnesia Test (GOAT) the Rivermead Post Concussion Survey Questionnaire (RPCSQ) and the Mini Mental Status Examination (MMSE). RESULTS: A lower GOAT score was significantly associated with hospitalization (P = 0.0212) and the development of post-concussion syndrome (P = 0.0081) at late follow-up. A higher RPCSQ score was significantly associated with hospital admission (P = 0.0098), re-admission within 30 days of discharge (P = 0.0431) and evidence of post-concussion syndrome (PCS) at early follow-up (P = 0.0004). A higher MMSE score was significantly associated with not being admitted to the hospital (P = 0.0002) and not returning to the emergency department (ED) within 72 hours of discharge (P = 0.0078). Lower MMSE was also significantly associated with bleeding or a fracture on the brain CT (P = 0.0431). CONCLUSIONS: While neurocognitive testing is not commonly performed in the ED in the setting of acute head injury, it is both feasible and appears to have value in predicting hospital admission and PCS. These data are especially important in terms of helping patients understand what to expect, thus, aiding in their recovery. PMID- 27453789 TI - Erratum to: Dry aging of beef; Review. AB - [This corrects the article DOI: 10.1186/s40781-016-0101-9.]. PMID- 27453790 TI - Body Weight Dynamics Following Intentional Weight Loss and Physical Performance: The Look AHEAD Movement and Memory Study. AB - OBJECTIVE: To explore the impact of body weight change following intentional weight loss on measures of physical performance in adults with diabetes. DESIGN AND METHODS: 450 individuals with type 2 diabetes (age: 59.0+/-6.9 years, BMI: 35.5+/-5.9 kg/m2) who participated in the Look AHEAD Movement and Memory Study and lost weight one year after being randomized to an intensive lifestyle intervention were assessed. Body weight was measured annually, and participants were categorized as continued losers/maintainers, regainers, or cyclers based on a +/-5% annual change in weight. Objective measures of physical performance were measured at the year 8/9 visit. RESULTS: Forty-four, 38 and 18% of participants were classified as regainers, cyclers, and continued losers/maintainers. In women, weight cycling and regain was associated with worse follow-up expanded physical performance battery score (1.46+/-0.07 and 1.48+/-0.07 vs. 1.63+/-0.07, both p<=0.02) and slower 20-meter walking speed (1.10+/-0.04 and 1.08+/-0.04 m/s vs. 1.17+/-0.04 m/s, both p<0.05) compared to continued or maintained weight loss. Male cyclers presented with weaker grip strength compared to regainers or continued losers/maintainers (30.12+/-2.21 kg versus 34.46+/-2.04 and 37.39+/ 2.26 kg; both p<0.01). CONCLUSIONS: Weight cycling and regain following intentional weight loss in older adults with diabetes was associated with worse physical function in women and grip strength in men. PMID- 27453791 TI - Long-term ambient particle exposures and blood DNA methylation age: findings from the VA normative aging study. AB - BACKGROUND: Ambient particles have been shown to exacerbate measures of biological aging; yet, no studies have examined their relationships with DNA methylation age (DNAm-age), an epigenome-wide DNA methylation based predictor of chronological age. OBJECTIVE: We examined the relationship of DNAm-age with fine particulate matter (PM2.5), a measure of total inhalable particle mass, and black carbon (BC), a measure of particles from vehicular traffic. METHODS: We used validated spatiotemporal models to generate 1-year PM2.5 and BC exposure levels at the addresses of 589 older men participating in the VA Normative Aging Study with 1-3 visits between 2000 and 2011 (n = 1032 observations). Blood DNAm-age was calculated using 353 CpG sites from the Illumina HumanMethylation450 BeadChip. We estimated associations of PM2.5 and BC with DNAm-age using linear mixed effects models adjusted for age, lifestyle/environmental factors, and aging-related diseases. RESULTS: After adjusting for covariates, a 1-ug/m3 increase in PM2.5 (95% CI: 0.30, 0.75, P<0.0001) was significantly associated with a 0.52-year increase in DNAm-age. Adjusted BC models showed similar patterns of association (beta = 3.02, 95% CI: 0.48, 5.57, P = 0.02). Only PM2.5 (beta = 0.54, 95% CI: 0.24, 0.84, P = 0.0004) remained significantly associated with DNAm-age in two particle models. Methylation levels from 20 of the 353 CpGs contributing to DNAm age were significantly associated with PM2.5 levels in our two-particle models. Several of these CpGs mapped to genes implicated in lung pathologies including LZTFL1, PDLIM5, and ATPAF1. CONCLUSION: Our results support an association of long-termambient particle levels with DNAm-age and suggest that DNAm-age is a biomarker of particle-related physiological processes. PMID- 27453792 TI - Modulation of therapy-induced senescence by reactive lipid aldehydes. AB - Current understanding points to unrepairable chromosomal damage as the critical determinant of accelerated senescence in cancer cells treated with radiation or chemotherapy. Nonetheless, the potent senescence inducer etoposide not only targets topoisomerase II to induce DNA damage but also produces abundant free radicals, increasing cellular reactive oxygen species (ROS). Toward examining roles for DNA damage and oxidative stress in therapy-induced senescence, we developed a quantitative flow cytometric senescence assay and screened 36 redox active agents as enhancers of an otherwise ineffective dose of radiation. While senescence failed to correlate with total ROS, the radiation enhancers, etoposide and the other effective topoisomerase inhibitors each produced high levels of lipid peroxidation. The reactive aldehyde 4-hydroxy-2-nonenal, a lipid peroxidation end product, was sufficient to induce senescence in irradiated cells. In turn, sequestering aldehydes with hydralazine blocked effects of etoposide and other senescence inducers. These results suggest that lipid peroxidation potentiates DNA damage from radiation and chemotherapy to drive therapy-induced senescence. PMID- 27453793 TI - Impact of Cosmetic Lotions on Nanoparticle Penetration through ex vivo C57BL/6 Hairless Mouse and Human Skin: A Comparison Study. AB - Understanding the interactions of nanoparticles (NPs) with skin is important from a consumer and occupational health and safety perspective, as well as for the design of effective NP-based transdermal therapeutics. Despite intense efforts to elucidate the conditions that permit NP penetration, there remains a lack of translatable results from animal models to human skin. The objectives of this study are to investigate the impact of common skin lotions on NP penetration and to quantify penetration differences of quantum dot (QD) NPs between freshly excised human and mouse skin. QDs were mixed in 7 different vehicles, including 5 commercial skin lotions. These were topically applied to skin using two exposure methods; a petri dish protocol and a Franz diffusion cell protocol. QD presence in the skin was quantified using Confocal Laser Scanning Microscopy. Results show that the commercial vehicles can significantly impact QD penetration in both mouse and human skin. Lotions that contain alpha hydroxyl acids (AHA) facilitated NP penetration. Lower QD signal was observed in skin studied using a Franz cell. Freshly excised human skin was also studied immediately after the sub-cutaneous fat removal process, then after 24 hours rest ex vivo. Resting human skin 24 hours prior to QD exposure significantly reduced epidermal presence. This study exemplifies how application vehicles, skin processing and the exposure protocol can affect QD penetration results and the conclusions that maybe drawn between skin models. PMID- 27453794 TI - Ethical Challenges of Randomized Violence Intervention Trials: Examining the SHARE intervention in Rakai, Uganda. AB - OBJECTIVE: We identify complexities encountered, including unanticipated crossover between trial arms and inadequate 'standard of care' violence services, during a cluster randomized trial (CRT) of a community-level intimate partner violence (IPV) and HIV prevention intervention in Uganda. METHODS: Concepts in public health ethics - beneficence, social value of research, fairness, standard of care, and researcher responsibilities for post-trial benefits - are used to critically reflect on lessons learned and guide discussion on practical and ethical challenges of violence intervention CRTs. RESULTS: Existing ethical guidelines provide incomplete guidance for responding to unexpected crossover in CRTs providing IPV services. We struggled to balance duty of care with upholding trial integrity, and identifying and providing appropriate standard of care. While we ultimately offered short-term IPV services to controls, we faced additional challenges related to sustaining services beyond the 'short-term' and post-trial. CONCLUSION: Studies evaluating community-level violence interventions, including those combined with HIV reduction strategies, are limited yet critical for developing evidence-based approaches for effectively preventing IPV. Although CRTs are a promising design, further guidance is needed to implement trials that avoid introducing tensions between validity of findings, researchers' responsibilities to protect participants, and equitable distribution of CRT benefits. PMID- 27453795 TI - The effects of 30 mT electromagnetic fields on hippocampus cells of rats. AB - BACKGROUND: Despite the use of electromagnetic waves in the treatment of some acute and chronic diseases, application of these waves in everyday life has created several problems for humans, especially the nerve system. In this study, the effects of 30mT electromagnetic fields (EMFs) on the hippocampus is investigated. METHODS: Twenty-four 5-month Wistar rats weighing 150-200 g were divided into two groups. The experimental group rats were under the influence of an EMF at an intensity of 3 mT for approximately 4 hours a day (from 8 AM to 12 PM) during 10 weeks. After the hippocampus was removed, thin slides were prepared for transmission electron microscope (TEM) to study the ultrastructural tissue. Cell death detection POD kits were used to determine the apoptosis rate. RESULTS: The results of the TEM showed that, in the hippocampus of the experimental group, in comparison to the control group, there was a substantial shift; even intracellular organelles such as the mitochondria were morphologically abnormal and uncertain. The number of apoptotic cells in the exposed group compared to the control group showed significant changes. CONCLUSIONS: Similar to numerous studies that have reported the effects of EMFs on nerves system, it was also confirmed in this lecture. Hence, the hippocampus which is important in regulating emotions, behavior, motivation, and memory functions, may be impaired by the negative impacts of EMFs. PMID- 27453796 TI - The outermost "dura-like membrane" of vestibular schwannoma. AB - BACKGROUND: The membranous structure of vestibular schwannoma is an important factor in its surgical treatment. Herein, we report intraoperative and microscopic findings relating to an outermost dura-like membrane in cases of vestibular schwannoma and the importance of these findings. METHODS: Intraoperative findings of 16 cases of vestibular schwannoma treated with an initial surgery were studied with an aim to determine if the cases had a dura like membrane. Then we studied microscopic findings of the dura-like membrane using hematoxylin and eosin, Masson trichrome, and immunohistochemical staining in 2 cases. RESULTS: The dura-like membrane was observed in 8 out of 16 cases. The average tumor size of the cases that had a dura-like membrane was 30 +/- 8.1 mm, and Koos grading 4 was in 7 out of 8 cases, and one was grade 3. In cases without a dura-like membrane, these values were significantly smaller, with an average tumor size of 12.8 +/- 5.2 mm, and Koos grading 4 was only in 1 of 8 cases, grade 3 was in 2 cases, and other 5 cases were grade 2. The outermost dura like membrane enveloped the vestibular schwannoma around the internal acoustic meatus and was continuous with the dura mater. Reactive angiogenesis was observed in the dura mater. Microscopic findings proved its continuity with the dura mater. In one case, the facial nerve was damaged before it was identified during subcapsular dissection. In that case, the dura-like membrane negatively affected our ability to identify the facial nerve. CONCLUSIONS: A dura-like membrane sometimes envelops vestibular schwannoma around the internal acoustic meatus. Recognition of this membranous structure is important for the surgical preservation of facial and acoustic nerves. PMID- 27453797 TI - Diagnosing early upward cerebellar herniation by computed tomography: A diagnostic boom, a savior. PMID- 27453798 TI - Examining the Influence of Ethnic/Racial Socialization on Aggressive Behaviors Among Juvenile Offenders. AB - Risk assessment instruments are commonly used within the juvenile justice system to estimate a juvenile's likelihood of reoffending or engaging in aggressive or violent behavior. Although such instruments assess a broad range of factors, the influence of culture is often excluded. The current study examines the unique effect of ethnic/racial socialization on recent aggressive behaviors above and beyond three well-established risk and protective factors: delinquency history, moral disengagement, and social support. Participants were 95 juveniles who were either on probation or in detention centers in three Midwestern counties and who completed structured surveys related to personal experiences within and outside of the juvenile justice system. The findings provided partial support for our hypotheses: Consistent with previous findings, delinquency history and moral disengagement were significant predictors of recent aggressive behavior. Furthermore, when ethnic/racial socialization was added to the model, promotion of mistrust provided additional predictive validity for aggressive behavior above and beyond the other factors assessed. Based on these findings, the inclusion of education on culture may prove to be an important supplement to established intervention tools for juvenile offenders. PMID- 27453799 TI - FIB-SEM Tomography Probes the Mesoscale Pore Space of an Individual Catalytic Cracking Particle. AB - The overall performance of a catalyst particle strongly depends on the ability of mass transport through its pore space. Characterizing the three-dimensional structure of the macro- and mesopore space of a catalyst particle and establishing a correlation with transport efficiency is an essential step toward designing highly effective catalyst particles. In this work, a generally applicable workflow is presented to characterize the transport efficiency of individual catalyst particles. The developed workflow involves a multiscale characterization approach making use of a focused ion beam-scanning electron microscope (FIB-SEM). SEM imaging is performed on cross sections of 10.000 MUm2, visualizing a set of catalyst particles, while FIB-SEM tomography visualized the pore space of a large number of 8 MUm3 cubes (subvolumes) of individual catalyst particles. Geometrical parameters (porosity, pore connectivity, and heterogeneity) of the material were used to generate large numbers of virtual 3D volumes resembling the sample's pore space characteristics, while being suitable for computationally demanding transport simulations. The transport ability, defined as the ratio of unhindered flow over hindered flow, is then determined via transport simulations through the virtual volumes. The simulation results are used as input for an upscaling routine based on an analogy with electrical networks, taking into account the spatial heterogeneity of the pore space over greater length scales. This novel approach is demonstrated for two distinct types of industrially manufactured fluid catalytic cracking (FCC) particles with zeolite Y as the active cracking component. Differences in physicochemical and catalytic properties were found to relate to differences in heterogeneities in the spatial porosity distribution. In addition to the characterization of existing FCC particles, our method of correlating pore space with transport efficiency does also allow for an up-front evaluation of the transport efficiency of new designs of FCC catalyst particles. PMID- 27453800 TI - Novel Techniques in Epilepsy Management: Venous Pacing and Capture of Electrical Activity in the Primate Cortex. AB - OBJECTIVE: Pharmacotherapy for epilepsy is limited with 30% of patients refractory to this approach of suppressing seizures. Current surgical options are invasive and carry significant morbidities including infection, bleeding, and the potential for deleterious neurocognitive effects. As a result, there is a burgeoning need for innovation to develop safer and efficacious interventions. METHODS: Four distinct catheters (2 existing: Cardima catheter, Standard EPT Blazer catheter; 2 new prototypes: balloon catheter, basket catheters) were tested in 12 baboons (21-30 kg, 100% male). For each, we assessed whether or not the catheter was able to be maneuvered safely in various locations of the cerebral venous system, provide adequate cortical tissue contact to record signals, detect these signals as normal or abnormal, successfully stimulate the cortex, and capture the cortical tissue. Locations trialed included the petrosal sinus, straight sinus, vein of Galen, and occipital vein. Pacing cycle length and pacing thresholds varied among experiments. RESULTS: Successful mapping was conducted in all 12 baboons. The pacing cycle length varied from 75 ms to 650 ms depending on location of the cortex. Pacing threshold was recorded in 4/12 (33%) of the experiments; data is not available for the remaining 8/12 experiments. The threshold values ranged from 0.3 - 20 mAmps. Capture of cortical electrical activity was observed in 11/12 (91.7 %) experiments though the number of successful capture and stimulation attempts varied among experiments. The most reliable and consistent capture occurred with the use of our novel prototyped over-the-wire balloon catheter (9/12; 75%) and basket catheter (3/3; 100%). Necropsy and histology were performed post-experimentation, and only minimal complications were noted (Table 1). CONCLUSION: New electrode design can be maneuvered safely in the venous system, provide adequate cortical tissue contact to record signals, detect these signals as normal or abnormal, successfully stimulate the cortex, and capture cortical tissue. These novel devices merit further study in chronic baboons to establish long-term efficacy of continuous seizure recording. PMID- 27453801 TI - Th17 Cells in Protection from Tumor or Promotion of Tumor Progression. AB - The roles of inflammation and inflammatory cells such as Th17 cells in the development and progression of cancer have been extensively studied. However, the results have been varied, with conflicting conclusions. Most studies have focused on changes in inflammatory phenotypes once cancers have developed and disease is progressing. Far fewer studies have looked at the immune phenotypic changes that occur during progression of premalignant lesions to cancer. The impact of inflammation and, in particular, Th17 cells on tumor biology is summarized in this review, with a focus on the differences in the outcomes of studies. Possible explanations for the contradictory conclusions are also suggested. PMID- 27453802 TI - Polygenic Risk for Externalizing Psychopathology and Executive Dysfunction in Trauma-Exposed Veterans. AB - The frequent co-occurrence of antisocial behavior and other disinhibited phenotypes reflects a highly heritable externalizing spectrum. We examined the molecular genetic basis of this spectrum by testing polygenic associations with psychopathology symptoms, impulsive traits, and cognitive functions in two samples of primarily military veterans (n =537, n =194). We also investigated whether polygenic risk for externalizing moderated the effects of trauma on these phenotypes. As hypothesized, polygenic risk positively predicted externalizing psychopathology and negatively predicted performance on inhibitory control tasks. Gene-by-environment effects were also evident, with trauma exposure predicting greater impulsivity and less working memory capacity, but only at high levels of genetic liability. As expected, polygenic risk was not associated with internalizing psychopathology or episodic memory performance. This is the first independent replication of the polygenic score as a measure of genetic predispositions for externalizing and provides preliminary evidence that executive dysfunction is a heritable vulnerability for externalizing psychopathology. PMID- 27453803 TI - Selective Mapping of Psychopathy and Externalizing to Dissociable Circuits for Inhibitory Self-Control. AB - Antisociality is commonly conceptualized as a unitary construct, but there is considerable evidence for multidimensionality. In particular, two partially dissociable symptom clusters - psychopathy and externalizing - have divergent associations to clinical and forensic outcomes and are linked to unique patterns executive dysfunction. Here, we used fMRI in a sample of incarcerated offenders to map these dimensions of antisocial behavior to brain circuits underlying two aspects of inhibitory self-control: interference suppression and response inhibition. We found that psychopathy and externalizing are characterized by unique and task-selective patterns of dysfunction. While higher levels of psychopathy predicted increased activity within a distributed fronto-parietal network for interference suppression, externalizing did not predict brain activity during attentional control. By contrast, each dimension had opposite associations to fronto-parietal activity during response inhibition. These findings provide neurobiological evidence supporting the fractionation of antisocial behavior, and identify dissociable mechanisms through which different facets predispose dysfunction and impairment. PMID- 27453804 TI - Solitary Myocardial Metastasis from Locoregionally Controlled Squamous Cell Carcinoma of the Oral Cavity. AB - We present the case of a 62-year-old male originally diagnosed with squamous cell carcinoma (SCC) of the right retromolar trigone, Stage cT2N2bM0. He was treated radically with a pharyngotomy and segmental mandibular resection, right selective neck nodal dissection, and then reconstruction with a free fibular flap. The pathologic stage was T4aN1. He then received adjuvant chemoradiation therapy with a radiation dose of 6,000 cGy in 30 fractions, along with cisplatin, 100 mg/m(2) every three weeks. Good local control was repeatedly documented for two years. He then presented with shortness of breath and new-onset atrial fibrillation (AF) with rapid ventricular response. Computed tomography/pulmonary embolus protocol (CT/PE) showed no evidence of pulmonary embolism but did show a small pericardial effusion. His AF was refractory to medical management, and he was later admitted to hospital with congestive heart failure. He was found to have a large mass arising from the free wall of the right ventricle, a biopsy of which confirmed squamous cell carcinoma consistent with his head and neck primary. The patient declined further therapy and passed away within one month of presentation. This case is unusual in that the only known site of metastatic disease seen was to the myocardium of the right ventricle, presenting as cardiac arrhythmia and congestive heart failure. Although post-mortem studies show cardiac metastases to occur in 2 to 20% of cancer patients, it is rarely seen as a sole site of relapse in clinical practice. PMID- 27453805 TI - Understanding Psychological Reactance: New Developments and Findings. AB - Since Brehm first proposed reactance theory in 1966, many studies have explored the remarkable psychological phenomenon of reactance, which Miron and Brehm reviewed in 2006. We present an overview of research that has been done since then. A variety of studies have provided interesting new insights into the theory, adding to what is known about the phenomenon of reactance and the processes activated when people are confronted with threats to their freedom. Nevertheless, many issues that have not been clarified remain to be examined. We therefore close with proposing some suggestions for future research. PMID- 27453806 TI - Salzburger State Reactance Scale (SSR Scale): Validation of a Scale Measuring State Reactance. AB - This paper describes the construction and empirical evaluation of an instrument for measuring state reactance, the Salzburger State Reactance (SSR) Scale. The results of a confirmatory factor analysis supported a hypothesized three-factor structure: experience of reactance, aggressive behavioral intentions, and negative attitudes. Correlations with divergent and convergent measures support the validity of this structure. The SSR Subscales were strongly related to the other state reactance measures. Moreover, the SSR Subscales showed modest positive correlations with trait measures of reactance. The SSR Subscales correlated only slightly or not at all with neighboring constructs (e.g., autonomy, experience of control). The only exception was fairness scales, which showed moderate correlations with the SSR Subscales. Furthermore, a retest analysis confirmed the temporal stability of the scale. Suggestions for further validation of this questionnaire are discussed. PMID- 27453807 TI - The effectiveness of specialized legal counsel and case management services for indigent offenders with mental illness. AB - BACKGROUND: In recent years, jurisdictions have recognized the strain placed on limited existing resources by criminal offenders with mental illness who frequently cycle through local jail facilities. In response, many locales have developed and implemented specialized programs to more effectively and efficiently manage these offenders, particularly the process of assigning defense attorneys to these often indigent defendants. METHODS: The current study examined the impact of an Indigent Defense Counsel (IDC) program designed to provide specially trained defense attorneys, and enhanced case management services to 257 indigent jail inmates with a qualifying, major mental health diagnosis (e.g., major depression). These offenders were compared to 117 similar offenders who did not receive these services, on both their length of stay in the jail, and their likelihood of recidivism after release to the community. RESULTS: Survival analyses revealed that program participants spent about 17 fewer days in jail; however, recidivism rates between groups, measured as return to the same county jail or as statewide re-arrest, did not differ. CONCLUSIONS: These results suggest that defendants with mental illness can potentially be managed effectively in the community, with little added risk to public safety and at potential savings in jail bed days/costs. Implications for the processing of indigent criminal defendants with mental illness are presented. PMID- 27453809 TI - Energy-efficient control of a screw-drive pipe robot with consideration of actuator's characteristics. AB - Pipe robots can perform inspection tasks to alleviate the damage caused by the pipe problems. Usually, the pipe robots carry batteries or use a power cable draining power from a vehicle that has many equipments for exploration. Nevertheless, the energy is limited for the whole inspection task and cannot keep the inspection time too long. In this paper, we use the total input energy as the cost function and a more accurate DC motor model to generate an optimal energy efficient velocity control for a screw-drive pipe robot to make use of the limited energy in field environment. We also propose a velocity selection strategy that includes the actual velocity capacity of the motor, according to the velocity ratio [Formula: see text], to keep the robot working in safe region and decrease the energy dissipation. This selection strategy considers three situations of the velocity ratio [Formula: see text] and has a wide range of application. Simulations are conducted to compare the proposed method with the sinusoidal control and loss minimization control (minimization of copper losses of the motor), and results are discussed in this paper. PMID- 27453808 TI - Cadmium and Reproductive Health in Women: A Systematic Review of the Epidemiologic Evidence. AB - An evolving body of evidence supports that cadmium, a non-essential heavy metal, may be associated with multiple adverse women's reproductive health outcomes. Our objective was to conduct a systematic review of epidemiologic studies that evaluated cadmium exposure and the following reproductive health outcomes: puberty/menarche, fertility, time to pregnancy, pregnancy loss, preeclampsia, endometriosis, uterine leiomyoma, and menopause. Twenty-two studies were identified based upon our search criteria. Available evidence was inadequate to draw meaningful conclusions for most of the reproductive outcomes studied. The strongest evidence was for a possible association between cadmium and preeclampsia, which was limited to cross-sectional studies. Some evidence, although conflicting, was also observed for fertility related outcomes. This lack of evidence underscores the need for additional research on cadmium and women's reproductive health outcomes. PMID- 27453810 TI - A Genetic Algorithm Approach to Motion Sensor Placement in Smart Environments. AB - Smart environments and ubiquitous computing technologies hold great promise for a wide range of real world applications. The medical community is particularly interested in high quality measurement of activities of daily living. With accurate computer modeling of older adults, decision support tools may be built to assist care providers. One aspect of effectively deploying these technologies is determining where the sensors should be placed in the home to effectively support these end goals. This work introduces and evaluates a set of approaches for generating sensor layouts in the home. These approaches range from the gold standard of human intuition-based placement to more advanced search algorithms, including Hill Climbing and Genetic Algorithms. The generated layouts are evaluated based on their ability to detect activities while minimizing the number of needed sensors. Sensor-rich environments can provide valuable insights about adults as they go about their lives. These sensors, once in place, provide information on daily behavior that can facilitate an aging-in-place approach to health care. PMID- 27453811 TI - Social desirability bias in reporting of holiday season healthfulness. AB - Respondents participating in survey or interview based research often tend to give answers that put themselves in a favorable light, displaying social desirability bias (SDB). Understanding the susceptibility of individuals to underreport their perceived unhealthy holiday behaviors or over report holiday behaviors they perceive as healthy has important implications for health promotion and health policy surrounding the holiday season. This study examines SDB specific to the reporting of holiday food consumption and health-related behaviors. An online survey of 620 U.S. consumers was utilized to collect data in which SDB was accounted for via indirect questioning. The online survey was conducted by Purdue University from November 17-19, 2014. Up to 64% of respondents displayed SDB for the eight holiday health statements studied. Respondents over the age of 45 and without children more frequently displayed social desirability bias. Respondents who displayed SDB with respect to acceptable health related holiday food consumption behaviors may be more susceptible to social pressures surrounding other consumption decision making. Understanding SDB in health and behavior reporting, in particular for the traditionally challenging, in terms of health outcomes, holiday season is critical for health practitioners as they seek to promote healthy behaviors. PMID- 27453813 TI - Dermatophytosis in donkeys (Equus asinus) due to Microsporum racemosum, an unusual geophilic agent. AB - Reports about ringworm in donkeys are scanty and refer to zoonotic agents such as Trichophyton mentagrophytes and Trichophyton verrucosum. Seventeen Asino Amiatina donkeys semi-extensively farmed in paddocks showed alopecic nummular, scaling areas mainly on head and neck. Microsporum racemosum cultivated from the lesions was identified by morphology and PCR. Affected animals healed spontaneously. The present record reports for the first time the occurrence of ringworm due to M. racemosum in naturally infected animals. PMID- 27453814 TI - Allergic Bronchopulmonary Aspergillosis masquerading as recurrent bacterial pneumonia. AB - Allergic Bronchopulmonary Aspergillosis (ABPA) can be diagnosed in an asthmatic with suitable radiologic and immunological features. However ABPA is likely to be misdiagnosed with bacterial pneumonia. Here we report a case of ABPA masquerading as recurrent bacterial pneumonia. Treatment with high-dose inhaled corticosteroids was effective. To our best knowledge, this is the first reported case of ABPA in Vietnam. PMID- 27453812 TI - Influence of cardiorespiratory fitness and physical activity levels on cardiometabolic risk factors during menopause transition: A MONET study. AB - To determine the influence of cardiorespiratory fitness (hereafter "fitness") and physical activity levels on cardiometabolic risk factors in premenopausal women going through the menopause transition. An ancillary study including 66 premenopausal women who participated to a 5-year observational, longitudinal study (2004 to 2009 in Ottawa) on the effects of menopause transition on body composition and cardiometabolic risk factors. Women underwent a graded exercise test on treadmill to measure peak oxygen uptake (VO2 peak) at year 1 and 5 and physical activity levels were measured using accelerometers. Cardiometabolic risk factors included: waist circumference, fasting plasma lipids, glucose and insulin levels, HOMA-IR score, c-reactive protein, apolipoprotein B (apoB) and resting systolic and diastolic blood pressure. Change in fitness was not associated with changes in cardiometabolic risk factors. The changes in total physical activity levels on the other hand showed a significant negative association with apoB levels. Three-way linear mixed model repeated measures, showed lower values of waist circumference, fasting triglycerides, insulin levels, HOMA-IR score, apoB and diastolic blood pressure in women with a fitness >= 30.0 mlO2 kg(- 1) min(- 1) compared to women with a fitness < 30.0 mlO2 kg(- 1) min(- 1) (P < 0.05). However, only fasting triglycerides was lower in women with physical activity levels >= 770.0 Kcal/day (P < 0.05). Between fitness and physical activity levels, fitness was associated with more favorable values of cardiometabolic risk factors in women followed for 5 years during the menopause transition. PMID- 27453815 TI - Chronic lymphocytic lymphoma and concomitant renal cell carcinoma (Clear Cell Type): Review of the literature. AB - In the present report, a 73 years-old male patient who developed clear cell type renal cell carcinoma (RCC) 5 years after the diagnosis of chronic lymphocytic lymphoma (CLL) and plausible explanations for this association were discussed by the authors. The incidence of CLL and RCC occurring in the same patient is higher than that expected in the general population. Various explicative hypotheses of this concurrence include treatment-related development of a second malignancy, immunomodulatory mechanisms, viral aetiology, cytokine (interleukin 6) release from a tumor, and common genetic mutations. Further investigations are warranted. PMID- 27453816 TI - A case of SRSF2 mutation in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is characterized by extremely variable clinical course indicating substantial differences in the biology of the disease. Molecular characterization provides new insights useful for treatment decision making. We report on a patient diagnosed with CLL, whose disease was characterized by episodes of rapid progression and disease stabilization, and in which a SRSF2 gene mutation was identified in the absence of other commonly known mutations of CLL. To the best of our knowledge this is the first case of SRSF2 gene mutation ever reported in CLL. PMID- 27453817 TI - Bedside functional brain imaging in critically-ill children using high-density EEG source modeling and multi-modal sensory stimulation. AB - Acute brain injury is a common cause of death and critical illness in children and young adults. Fundamental management focuses on early characterization of the extent of injury and optimizing recovery by preventing secondary damage during the days following the primary injury. Currently, bedside technology for measuring neurological function is mainly limited to using electroencephalography (EEG) for detection of seizures and encephalopathic features, and evoked potentials. We present a proof of concept study in patients with acute brain injury in the intensive care setting, featuring a bedside functional imaging set up designed to map cortical brain activation patterns by combining high density EEG recordings, multi-modal sensory stimulation (auditory, visual, and somatosensory), and EEG source modeling. Use of source-modeling allows for examination of spatiotemporal activation patterns at the cortical region level as opposed to the traditional scalp potential maps. The application of this system in both healthy and brain-injured participants is demonstrated with modality specific source-reconstructed cortical activation patterns. By combining stimulation obtained with different modalities, most of the cortical surface can be monitored for changes in functional activation without having to physically transport the subject to an imaging suite. The results in patients in an intensive care setting with anatomically well-defined brain lesions suggest a topographic association between their injuries and activation patterns. Moreover, we report the reproducible application of a protocol examining a higher-level cortical processing with an auditory oddball paradigm involving presentation of the patient's own name. This study reports the first successful application of a bedside functional brain mapping tool in the intensive care setting. This application has the potential to provide clinicians with an additional dimension of information to manage critically-ill children and adults, and potentially patients not suited for magnetic resonance imaging technologies. PMID- 27453818 TI - Successful hemispherotomy for a patient with intractable epilepsy secondary to bilateral congenital brain malformation with lateralized pyramidal tract of diffusion tensor image tractography. AB - PURPOSE: To perform an epilepsy surgery on a patient with drug resistant epilepsy secondary to bilateral brain malformation. The patient was a 2-year 9-month-old boy who had congenital bilateral multiple abnormalities. He developed a complex partial seizure at 9 months old. Based on the presurgical evaluations, he underwent a right hemispherotomy. RESULTS: Brain MRI revealed congenital bilateral polymicrogyria, right schizencephaly, and corpus callosum agenesis. The abnormality was noted to be more severe in the right hemisphere. Diffusion tensor image tractography clearly detected a left pyramidal tract. On the contrary, the right hemisphere did not show a clear pyramidal tract. An interictal EEG showed epileptiform discharges over both hemispheres with right frontotemporal area dominancy. The long-term video-EEG recorded his habitual seizures arising from the right frontal area. Right hemispherotomy led to freedom from seizures and a reduced need for anti-epilepsy drugs. CONCLUSIONS: We report a patient with bilateral MRI and EEG abnormalities with clear DTI laterality who achieved seizure freedom with epilepsy surgery. PMID- 27453819 TI - Transcriptomic and functional resources for the small hive beetle Aethina tumida, a worldwide parasite of honey bees. AB - The small hive beetle (SHB), Aethina tumida, is a major pest of managed honey bee (Apis mellifera) colonies in the United States and Australia, and an emergent threat in Europe. While strong honey bee colonies generally keep SHB populations in check, weak or stressed colonies can succumb to infestations. This parasite has spread from a sub-Saharan Africa to three continents, leading to immense management and regulatory costs. We performed a transcriptomic analysis involving deep sequencing of multiple life stages and both sexes of this species. The assembled transcriptome appears to be nearly complete, as judged by conserved insect orthologs and the ability to find plausible homologs for 11,952 proteins described from the genome of the red flour beetle. Expressed genes include each of the major metabolic, developmental and sensory groups, along with genes for proteins involved with immune defenses and insecticide resistance. We also present a total of 23,085 high-quality SNP's for the assembled contigs. We highlight potential differences between this beetle and its honey bee hosts, and suggest mechanisms of future research into the biology and control of this species. SNP resources will allow functional genetic analyses and analyses of dispersal for this invasive pest. All resources are posted as Supplemental Tables at https://data.nal.usda.gov/dataset/data-transcriptomic-and-functional-resources small-hive-beetle-aethina-tumida-worldwide, and at NCBI under Bioproject PRJNA256171. PMID- 27453820 TI - Assessment of the phenotype genotype variability and correlation in m.3243A > G mutation carriers requires prospective studies. PMID- 27453821 TI - Lipid profile of platelets and platelet-derived microparticles in ovarian cancer. AB - BACKGROUND: Ovarian cancer patients have a high risk of developing venous thrombosis. The membrane lipid bilayer of platelets and platelet-derived microparticles (PMP) provides a platform for assembly of coagulation proteins and generation of blood clots. METHODS: We compared the lipid composition of platelets and PMPs in patients with ovarian cancer to those in healthy subjects. We used shotgun lipidomics to quantify 12 classes and 177 species of lipids. RESULTS: We found a significant change in 2 classes of lipids in platelets and PMPs isolated from ovarian cancer patients: higher phosphatidylinositol and lower lyso-phosphatidylcholine. The level of 28 species of lipids was also significantly altered in the direction of an increase in the pro-coagulant and a reduction in the anticoagulant lipids. We found that cancer platelets expressed less lipid phosphate phosphatase 1 (LPP1), a key enzyme in phospholipid biosynthesis pathways, than normal platelets. The reduction in LPP1 might contribute to the changes in the lipid profile of cancer platelets. CONCLUSION: Our results support a procoagulant lipid profile of platelets in ovarian cancer patients that can play a role in the increased risk of venous thrombosis in these patients. GENERAL SIGNIFICANCE: As far as we are aware, our study is the first study on platelet lipidomics in ovarian cancer. The importance of our findings for the future studies are: 1) a similar change in lipid profile of platelets and PMP may be responsible for hypercoagulability in other cancers, and 2) plasma level of high-risk lipids for venous thrombosis may be useful biomarkers. PMID- 27453822 TI - Induction of differentiation in psoriatic keratinocytes by propylthiouracil and fructose. AB - Psoriasis is characterized by uncontrolled proliferation and poor differentiation. Sirtuin1 (SIRT1) a class III deacetylase, crucial for differentiation in normal keratinocytes, is reduced in psoriasis. Down regulated SIRT1 levels may contribute to poor differentiation in psoriasis. In addition, the levels of early differentiation factors Keratin1 (K1) and Keratin10 (K10) are depleted in psoriasis. We attempted to study a possible effect of fructose, a SIRT1 upregulator and Propylthiouracil (PTU) to augment differentiation in psoriatic keratinocytes. Keratinocytes were cultured from lesional biopsies obtained from psoriatic patients and control cells were obtained from patients undergoing abdominoplasty. Cells were treated with fructose and PTU individually. K1 and K10 transcript levels were measured to evaluate early differentiation; SIRT1 protein expression was also studied to decipher its role in the mechanism of differentiation. The K1, K10 transcript levels, SIRT1 protein and transcript levels in fructose treated psoriatic keratinocytes were improved. This suggests keratinocyte differentiation was induced by fructose through SIRT1 upregulation. Whereas PTU induced differentiation, as confirmed by improved K1, K10 transcript levels followed a non-SIRT1 mechanism. We conclude that the use of fructose and PTU may be an adjunct to the existing therapies for psoriasis. PMID- 27453823 TI - Analysis of coffee bean extracts by use of ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - The number of flavour chemicals identified in coffee has reached over 1000 [1], [2]. Coffee is one of the world's most popular beverages [3], highly studied for its health-related properties [4], [5], [6]. Studies on coffee associated with human health have focused on the negative aspects, such as the toxicity of caffeine [7], [8]. Complex chemistry happens during coffee roasting and according to the literature, a number of compounds have been detected and quantified in coffee beans samples by UPLC-Q-TOF/MS [9], [10], [11], [12]. The following method offers a simple approach for the qualitative and quantitative analysis of coffee bean extracts using a Waters Acquity G2 UPLC-Q-TOF/MS instrument adapted from the method by Kenny et al., [12]. The following modifications were made:*The method by Kenny et al. was developed on a triple quadrupole mass spectrometer, the below method was developed on a Q-TOF MS.*A combination of utilising both base peak index and mass extraction at 0.05 Da allows for a sensitive, quantitative technique amidst poor background noise and poor separation with high mass accuracy (<5 ppm).*By use of MS(E) centroid experiment, greater mass spectral information for metabolite profiling could be obtained. PMID- 27453824 TI - Quality matters in strengthening global laboratory medicine. PMID- 27453825 TI - How informed are our subjects? PMID- 27453826 TI - Reporting of adverse events for marketed drugs: Need for strengthening safety database. AB - Pharmacovigilance is an evolving discipline in the Indian context. However, there is limited regulatory guidance for adverse event reporting outside the purview of clinical trials. There are number of deficiencies in the framework for adverse event reporting from the perspective of pharma industry, health-care professional and general public due to which adverse events for marketed drugs are highly underreported. This article discusses the need to strengthen national safety database by promoting and mandating reporting of adverse events by all the stakeholders. PMID- 27453827 TI - Emerging role of bioinformatics tools and software in evolution of clinical research. AB - Clinical research is making toiling efforts for promotion and wellbeing of the health status of the people. There is a rapid increase in number and severity of diseases like cancer, hepatitis, HIV etc, resulting in high morbidity and mortality. Clinical research involves drug discovery and development whereas clinical trials are performed to establish safety and efficacy of drugs. Drug discovery is a long process starting with the target identification, validation and lead optimization. This is followed by the preclinical trials, intensive clinical trials and eventually post marketing vigilance for drug safety. Softwares and the bioinformatics tools play a great role not only in the drug discovery but also in drug development. It involves the use of informatics in the development of new knowledge pertaining to health and disease, data management during clinical trials and to use clinical data for secondary research. In addition, new technology likes molecular docking, molecular dynamics simulation, proteomics and quantitative structure activity relationship in clinical research results in faster and easier drug discovery process. During the preclinical trials, the software is used for randomization to remove bias and to plan study design. In clinical trials software like electronic data capture, Remote data capture and electronic case report form (eCRF) is used to store the data. eClinical, Oracle clinical are software used for clinical data management and for statistical analysis of the data. After the drug is marketed the safety of a drug could be monitored by drug safety software like Oracle Argus or ARISg. Therefore, softwares are used from the very early stages of drug designing, to drug development, clinical trials and during pharmacovigilance. This review describes different aspects related to application of computers and bioinformatics in drug designing, discovery and development, formulation designing and clinical research. PMID- 27453828 TI - Comparison of good clinical practice compliance and readability ease of the informed consents between observational and interventional clinical studies in the Emirates. AB - BACKGROUND: Expansion of clinical trials activity into emerging regions has raised concerns regarding participant rights and research ethics. Increasing numbers of observational studies are now conducted in developing economies, including the United Arab Emirates. MATERIALS AND METHODS: This study compares the content of information provided, Good Clinical Practice (GCP) guideline compliance, and readability of informed consent forms (ICFs) for observational compared to interventional studies. RESULTS: GCP compliance for observational studies averaged at 79.5% + 6.8%, significantly (P < 0.001) lower than 92.2 + 5.0 percent for interventional studies. Readability ease and readability-grade level were assessed with Flesch-Kincaid scales. Results indicated higher readability grade-level 12.4 + 0.4 (P < 0.001) and lower readability Flesch-Kincaid reading ease score 35.7 + 3.6 for observational studies, as compared to 10.3 + 1.6 and 47.8 + 7.4 for interventional studies. CONCLUSION: Mandatory training for investigators is essential to provide readability ease and GCP compliance for the ICFs for the local population. PMID- 27453829 TI - Assessment of adherence to the statistical components of consolidated standards of reporting trials statement for quality of reports on randomized controlled trials from five pharmacology journals. AB - BACKGROUND: The Consolidated Standards of Reporting Trials (CONSORT) statement is a device to standardize reporting and improve the quality of controlled trials. However, little attention is paid to the statistical components in the CONSORT checklist. The present study evaluates the randomized controlled trials [RCTs] published in five high impact pharmacology journals with respect to its statistical methods. METHODS: Randomized Controlled Trials [RCTs] published in the years 2013 & 2014 in five pharmacology journals with high impact factor, The Journal of Clinical Pharmacology (JCP), British Journal of Clinical Pharmacology (BJCP), European Journal of Clinical Pharmacology (EJCP), Journal of Pharmacology & Pharmacotherapeutics (JPP) and Indian Journal of Pharmacology (IJP) were assessed for adherence to the statistical components of CONSORT statement. RESULTS: Of the 174 RCTs analysed, 103 described the method of sample size calculation. Of the five journals, maximum reports in JCP (34/50) and minimum in IJP (13/31) adhered to the CONSORT checklist [item 7a-sample size calculation]. Most reports mentioned the statistical methods used for analysis of data. (171/174) as per the checklist [item 12=statistical methods used]. Analysis of variance (ANOVA) was the most commonly used test (88/174). The software used for statistical analysis was mentioned in 111 RCTs and SPSS was used more frequently (58/111). The exact p value was stated in 108 reports. Certain errors in statistical analysis were also noted (40/174). CONCLUSION: These findings show inconsistencies and non- adherence to the statistical components of the CONSORT statement especially with respect to sample size calculation. Special attention must be paid to the statistical accuracy of the reports. PMID- 27453830 TI - Assessment and classification of protocol deviations. AB - INTRODUCTION: Deviations from the approved trial protocol are common during clinical trials. They have been conventionally classified as deviations or violations, depending on their impact on the trial. METHODS: A new method has been proposed by which deviations are classified in five grades from 1 to 5. A deviation of Grade 1 has no impact on the subjects' well-being or on the quality of data. At the maximum, a deviation Grade 5 leads to the death of the subject. This method of classification was applied to deviations noted in the center over the last 3 years. RESULTS: It was observed that most deviations were of Grades 1 and 2, with fewer falling in Grades 3 and 4. There were no deviations that led to the death of the subject (Grade 5). DISCUSSION: This method of classification would help trial managers decide on the action to be taken on the occurrence of deviations, which would be based on their impact. PMID- 27453831 TI - Challenges in recruitment and retention of clinical trial subjects. AB - BACKGROUND: Successful recruitment of patients is known to be one of the most challenging aspects in conduct of randomized controlled trials. Inadequate patient retention during conduct of trial affects conclusive results. OBJECTIVE: To assess the level of challenges faced by Indian investigators in recruitment and retention of trial subjects. METHODS: We developed a survey questionnaire on challenges encountered by investigators in subject recruitment and retention which was hosted on a web portal. RESULTS: Seventy-three investigators from India participated in the survey. The frequently encountered challenges in subject recruitment were complexity of study protocol (38%), lack of awareness about clinical trials in patients (37%), and sociocultural issues related to trial participation (37%). About 63% of participants strongly agreed that creating a positive awareness about clinical trials among people through press and media, having a dedicated clinical research coordinator for trial (50.7%), and designing a recruitment strategy prior to study initiation (46.6%) would enhance recruitment. Almost 50.7% of participants agreed that interacting with medical community in vicinity of the study site and educating patients about clinical trials during routine outpatient department visits (46.6%) would enhance recruitment. Experiencing a serious adverse event, subject's fear for study procedures (47%) and side effects (44%) were thought to have a moderate effect on subject retention. CONCLUSION: Our survey has put forth factors related to negative publicity by media, lack of patient education about clinical trials; complex study designs are barriers to clinical trial recruitment in India. It is essential to devise innovative and effective strategies focusing on education of public and mass media about clinical research in India. PMID- 27453832 TI - Common pitfalls in statistical analysis: Intention-to-treat versus per-protocol analysis. AB - During the conduct of clinical trials, it is not uncommon to have protocol violations or inability to assess outcomes. This article in our series on common pitfalls in statistical analysis explains the complexities of analyzing results from such trials and highlights the importance of "intention-to-treat" analysis. PMID- 27453833 TI - Single-versus double-masking in glaucoma clinical trials. PMID- 27453834 TI - Training doctors for primary care in China: Transformation of general practice education. AB - China is known for developing a cadre of "Barefoot Doctors" to address her rural healthcare needs in past. The tradition of barefoot doctors has inspired similar developments in several other countries across world. Recently China has embarked upon an ambitious new mission to create a primary care workforce consisting of trained general practitioners having international standard skillsets. This editorial provides an insight into the current status of policy deliberations with regards to training of primary care doctors and a new surge in general practice education in China. PMID- 27453835 TI - Frequently asked questions about family medicine in India. AB - Family medicine (FM) is an independent and distinct medical specialty in the developed countries such as USA, UK, Australia, and Canada since 1960s. FM teaching is imparted at undergraduate and postgraduate levels in countries such as Nepal, Pakistan, and Sri Lanka. Family practice is the practicing vocation of the majority doctors in India. The practitioners of FM include general practitioners, family physicians, FM specialists, and medical officers in the public sector. Medical students are largely unaware about FM career as this concept is not introduced at MBBS level. Faculty and senior doctors from other disciplines are also not able to answer the queries related to FM as they themselves also have gone through the same education system for last three decades, largely unexposed to the concept of academic family medicine. This article is a compilation of frequently asked questions, and their appropriate responses, presented here to dispel myths and misinformation about FM specialty. The answers are deliberated upon by Dr. Raman Kumar the founder president of the Academy of Family Physicians of India and the chief editor of the Journal of Family Medicine and Primary Care. This article was originally published as an interview in Docplexus, a popular online network and website for medical doctors in November 2015. PMID- 27453836 TI - Vaccine epidemiology: A review. AB - This review article outlines the key concepts in vaccine epidemiology, such as basic reproductive numbers, force of infection, vaccine efficacy and effectiveness, vaccine failure, herd immunity, herd effect, epidemiological shift, disease modeling, and describes the application of this knowledge both at program levels and in the practice by family physicians, epidemiologists, and pediatricians. A case has been made for increased knowledge and understanding of vaccine epidemiology among key stakeholders including policy makers, immunization program managers, public health experts, pediatricians, family physicians, and other experts/individuals involved in immunization service delivery. It has been argued that knowledge of vaccine epidemiology which is likely to benefit the society through contributions to the informed decision-making and improving vaccination coverage in the low and middle income countries (LMICs). The article ends with suggestions for the provision of systematic training and learning platforms in vaccine epidemiology to save millions of preventable deaths and improve health outcomes through life-course. PMID- 27453837 TI - Domestic violence in the Solomon Islands. AB - The Solomon Islands has one of the highest rates of family and sexual violence (FSV) in the world with 64% of women aged 15-49 have reported physical and/or sexual abuse by a partner. The National Referral Hospital (NRH) in the capital, Honiara, is the only tertiary hospital for the country. Our 4-week medical elective at the NRH was spent reflecting on healthcare challenges including FSV, with the aim of identifying cases of FSV and assessing on the current strategies to improve care for victims. Throughout our placement, we encountered many cases of probable FSV, particularly in the Emergency Department and Obstetrics and Gynecology. These patients were often not managed effectively, largely due to time pressures and overcrowding in the hospital. However, we identified a number of strategies, which have recently been implemented in order to help FSV victims in the Solomon Islands. These include strategies within the healthcare setting, in particular, the commencement of FSV reporting within the hospital, and the production of a manual to enable healthcare worker education on the issue. Strategies within the criminal justice system are also in place. These include recent changes in legislation and the work of the volunteer police force, Royal Assist Mission to the Solomon Islands, to improve attitudes toward FSV. These approaches to tackle the problem of FSV are currently in their early stages and have largely stemmed from Western policies and ideals. This report concludes that more time is needed to accurately assess the impact of the current changes before further recommendations are made. PMID- 27453838 TI - Medical Education: The Hot Seat. AB - Medical science has eventually metamorphosed from 'Knowledge based' to 'Skill based' applied social science. So, the age-old traditional courses and curriculums in Indian medical education need a overhauling with radical modifications. With a paradigm shift, we have to take into account not only the help of scientific feedback from the teachers and students but also from all the stakeholders of health care delivery system. PMID- 27453839 TI - Statistical methods and errors in family medicine articles between 2010 and 2014 Suez Canal University, Egypt: A cross-sectional study. AB - BACKGROUND: With limited statistical knowledge of most physicians it is not uncommon to find statistical errors in research articles. OBJECTIVES: To determine the statistical methods and to assess the statistical errors in family medicine (FM) research articles that were published between 2010 and 2014. METHODS: This was a cross-sectional study. All 66 FM research articles that were published over 5 years by FM authors with affiliation to Suez Canal University were screened by the researcher between May and August 2015. Types and frequencies of statistical methods were reviewed in all 66 FM articles. All 60 articles with identified inferential statistics were examined for statistical errors and deficiencies. A comprehensive 58-item checklist based on statistical guidelines was used to evaluate the statistical quality of FM articles. RESULTS: Inferential methods were recorded in 62/66 (93.9%) of FM articles. Advanced analyses were used in 29/66 (43.9%). Contingency tables 38/66 (57.6%), regression (logistic, linear) 26/66 (39.4%), and t-test 17/66 (25.8%) were the most commonly used inferential tests. Within 60 FM articles with identified inferential statistics, no prior sample size 19/60 (31.7%), application of wrong statistical tests 17/60 (28.3%), incomplete documentation of statistics 59/60 (98.3%), reporting P value without test statistics 32/60 (53.3%), no reporting confidence interval with effect size measures 12/60 (20.0%), use of mean (standard deviation) to describe ordinal/nonnormal data 8/60 (13.3%), and errors related to interpretation were mainly for conclusions without support by the study data 5/60 (8.3%). CONCLUSION: Inferential statistics were used in the majority of FM articles. Data analysis and reporting statistics are areas for improvement in FM research articles. PMID- 27453840 TI - Choosing to become a general practitioner - What attracts and what deters? An analysis of German medical graduates' motives. AB - BACKGROUND: To be able to counter the increasing shortage of general practitioners (GPs) in many countries, it is crucial to remain up-to-date with the decisive reasons why young physicians choose or reject a career in this field. MATERIALS AND METHODS: Qualitative content analysis was performed using data from a cross-sectional survey among German medical graduates (n = 659, response rate = 64.2%). Subsequently, descriptive statistics was calculated. RESULTS: The most frequent motives to have opted for a GP career were (n = 74/81): Desire for variety and change (62.2%), interest in a long-term bio-psycho social treatment of patients (52.7%), desire for independence and self determination (44.6%), positively perceived work-life balance (27.0%), interest in contents of the field (12.2%), and reluctance to work in a hospital (12.2%). The most frequent motives to have dismissed the seriously considered idea of becoming a GP were (n = 207/578): Reluctance to establish a practice or perceived associated risks and impairments (33.8%), stronger preference for another field (19.3%), perception of workload being too heavy or an unfavorable work-life balance (15.0%), perception of too low or inadequate earning opportunities (14.0%), perception of the GP as a distributor station with limited diagnostic and therapeutic facilities (11.6%), perception of too limited specialization or limited options for further sub-specialization (10.6%), rejection of (psycho-) social aspects and demands in general practice (9.7%), and perceived monotony (9.7%). CONCLUSION: While some motives appear to be hard to influence, others reveal starting points to counter the GP shortage, in particular, with regard to working conditions, the further academic establishment, and the external presentation of the specialty. PMID- 27453841 TI - Primary health care teaching to postgraduate public health students, comparison of two models: A natural experiment. AB - BACKGROUND: Primary health care as an approach forms an integral part of any public health curricula. The knowledge regarding primary health care can be delivered to public health trainee through conventional or the modular teaching models. OBJECTIVES: We aimed to observe whether there was any difference in the summative assessment scores between two different modalities of teaching primary health care to public health trainee at School of Public Health, Post Graduate Institute of Medical Education and Research, Chandigarh, India. METHODS: The present study was a natural experiment. Students of Masters of Public Health (MPH) and MD (Community Medicine) formed two natural groups. They were taught by modular and conventional methods of teaching respectively. A total of seven MPH students and nine MD students, participated in the study. RESULTS: Overall summative assessment score among MPH students was 63.9 +/- 10.0 in comparison to 61.1 +/- 10.9 among MD students. The difference in total scores was not statistically significant. CONCLUSION: We conclude that approaching a complex topic such as primary health care requires a mix of both modular and non-modular teaching to maximize outputs. PMID- 27453843 TI - State of family medicine practice in Lebanon. AB - BACKGROUND: Many difficulties are encountered in family medicine practice and were subject to multinational studies. To date, no study was conducted in Lebanon to assess the challenges that family physicians face. This study aims to evaluate the family medicine practice in Lebanon stressing on the difficulties encountered by Lebanese family physicians. MATERIALS AND METHODS: A questionnaire was sent to all 96 family medicine physicians practicing in Lebanon. Participants answered questions about characteristics of family medicine practice, evaluation of the quality of work, identification of obstacles, and their effect on the medical practice. RESULTS: The response rate was 59%, and the average number of years of practice was 10.7 years. Physicians complain mainly of heavy load at work, too many bureaucratic tasks, demanding patients, and being undervalued by the specialists. Most physicians are able to adapt between their professional and private life. CONCLUSION: Despite all the obstacles encountered, Lebanese family physicians have a moderate satisfaction toward their practice. They remain positive and enthusiastic about their profession. Until the ministry of public health revises its current health system, the primary care profession in Lebanon will remain fragile as a profession. PMID- 27453844 TI - Physicians' professionalism at primary care facilities from patients' perspective: The importance of doctors' communication skills. AB - BACKGROUND: Professionalism is the core duty of a doctor to be responsible to the society. Doctors' professionalism depicts an internalization of values and mastery of professionals' standards as an important part in shaping the trust between doctors and patients. Professionalism consists of various attributes in which current literature focused more on the perspective of the health professionals. Doctors' professionalism may influence patients' satisfaction, and therefore, it is important to know from the patients' perspectives what was expected of medical doctors' professionalism. OBJECTIVE: This study was conducted to determine the attributes of physician professionalism from the patient's perspective. MATERIALS AND METHODS: This was a qualitative research using a phenomenology study design. In-depth interviews were conducted with 18 patients with hypertension and diabetes who had been treated for at least 1 year in primary care facilities in the city of Yogyakarta, Indonesia. The results of the interview were transcribed, encoded, and then classified into categories. RESULTS: Communication skills were considered as the top priority of medical doctors' attributes of professionalism in the perspectives of the patients. CONCLUSION: This study revealed that communication skill is the most important aspects of professionalism which greatly affected in the process of health care provided by the primary care doctors. Doctor-patient communication skills should be intensively trained during both basic and postgraduate medical education. PMID- 27453842 TI - Has the inclusion of a longitudinally integrated communication skills program improved consultation skills in medical students? A pilot study. AB - BACKGROUND: Evidence highlights a lack of communication skills in doctors leading to dysfunctional consultations. To address this deficit, a private medical college instituted curricular reforms with inclusion of a longitudinal communication skills program. A pilot study was undertaken to evaluate the effectiveness of this program by comparing the consultation skills of medical students of this college with a medical college without a communication skills program. METHODS: A 4-station Objective Structured Clinical Examination (OSCE) was conducted in the third and final year. Mann-Whitney U-test was used to compare the difference in the distribution between OSCE stations total and construct scores. RESULTS: At the end of the third year, 21 (31.34%), students of the study site (medical college 1 [college with integrated longitudinal communication skills program]) and 31 (46.26%) students from the comparison site (medical college 2 [comparable college without communication skills program]) consented. Medical college 1 achieved a significantly higher overall mean total station score of 68.0% (standard deviation [SD] =13.5) versus 57.2% (SD = 15.4) (P < 0.001). Significantly higher mean scores were achieved on three stations. At the end of the final year, 19 students (29.3%) from medical college 1 and 22 (34%) students from medical college 2 consented. The difference in overall mean total station score reduced from 9.2% to 7.1% (70.2) (SD = 13.7) versus 63.1 (SD = 15.2) (P = 0.004). The mean scores of both colleges decreased in "Patient presenting with Hepatitis C Report" station (P values 0.004 and 0.775) and in "Patient Request for Faith Healing Therapy in Diabetes Mellitus" station (P values 0.0046 and 0.036), respectively. CONCLUSION: Longitudinal communication skills in an undergraduate curriculum positively impacted consultation skills. Community-based training and faculty development are required to develop effective patient-centered consultation skills. PMID- 27453845 TI - Chest pain in general practice: Frequency, management, and results of encounter. AB - OBJECTIVE: Chest pain is a common reason for an encounter in general practice. The present investigation was set out to characterize the consultation rate of chest pain, accompanying symptoms, frequency of diagnostic and therapeutic interventions, and results of the encounter. MATERIALS AND METHODS: Cross sectional data were collected from randomly selected patients in the German Sachsische Epidemiologische Studie in der Allgemeinmedizin 2 (SESAM 2) and analyzed from the Dutch Transition Project. RESULTS: Overall, 270 patients from the SESAM 2 study consulted a general practitioner due to chest pain (3% of all consultations). Chest pain was more frequent in people aged over 45 years. The most common diagnostic interventions were physical examination, electrocardiogram at rest and analysis of blood parameters. For the majority of cases, the physicians arranged a follow-up consultation or prescribed drugs. The transition project documented 8117 patients reporting chest pain with a frequency of 44.5/1000 patient years (1.7% of all consultations). Physical examination was also the most common diagnostic intervention, and physician's advice the most relevant therapeutic one. CONCLUSION: The most common causes for chest pain were musculoskeletal problems followed by cardiovascular diseases. Ischemic heart disease, psychogenic problems, and respiratory diseases each account for about 10% of the cases. However, acutely dangerous causes are rare in general practice. PMID- 27453846 TI - The value of an ENT specialist outreach service in a Family Medicine Unit for the urban poor in India. AB - OBJECTIVES: To assess the function of an otolaryngology (ENT) specialist outreach service in a Family Medicine (FM) Unit for the urban poor attached to a Tertiary Teaching Hospital in India. MATERIALS AND METHODS: The study investigated the pattern of ENT diseases in patients who came to the FM Unit and the proportion of these patients who were referred to the ENT specialist clinic at the unit. The study also analyzed the ENT problems that were managed by the ENT specialist at the unit and the conditions, which needed referral to the Tertiary Hospital. Data was collected by chart review. SETTING: Weekly ENT specialist outreach service in an FM Unit for the urban poor in India attached to a Tertiary Teaching Hospital. RESULTS: Among the outpatients who attended the unit in 12 months, 12.89% had ENT related problems, of which 23.9% were referred to the visiting ENT specialist, 88.30% of these patients were managed in the FM Unit with basic ENT facilities. CONCLUSION: This study demonstrated that majority of the patients with ENT related problems who presented to an FM Unit could be managed by the FM specialists. Of those patients who required the expertise of a specialist in ENT, the majority could be managed in the FM Unit, with basic ENT examination and treatment facilities. Triage and management by the family physician and the visiting ENT surgeon in the FM Unit is a prudent use of resources and will improve the quality of care people receive for their ENT problems. PMID- 27453847 TI - Profile of deliberate self-harm patients presenting to Emergency Department: A retrospective study. AB - BACKGROUND: Deliberate self-harm (DSH) is a major under-recognized epidemic in the low- and middle-income countries. This is a large retrospective study form the Emergency Department (ED) of Tertiary Care Center of South India to describe the clinicodemographic features of DSH cases. MATERIALS AND METHODS: This is a retrospective study conducted at ED of Christian Medical College, Vellore, India from January 01, 2011 to December 31, 2013. All cases of DSH were included in the study. The demographic details, mode of DSH and clinical outcome were extracted from the electronic medical record. Descriptive statistics are presented. Chi square test was used to compare categorical variables. For all tests, a two-sided P <= 0.05 was considered statistically significant. RESULTS: Total of 1228 patients were admitted to ED for DSH during the study period. Male and female occurred in equal ratio. More than half of the cases occurred among age group below 30 years. Consumption of pesticides (agricultural chemicals) was the single most common mode of DSH (46%), especially among men, followed by medication overdose (29.8%). Consumption of plant poison and tablet overdose was higher among women. Overall mortality due to DSH was low (1.5%) in our study. CONCLUSION: DSH is under-recognized major public health problem in low-middle income countries like India. Most cases occur among young and productive age group and in equal frequencies among men and women. Timely and the appropriate institution of treatment can decrease the morbidity and mortality due to DSH remarkably. PMID- 27453848 TI - Household use of iodized salt in rural area. AB - BACKGROUND: Iodine deficiency is the world's single greatest cause of preventable mental retardation. In developing countries, only 69% of households are consuming iodized salt. OBJECTIVE: To assess knowledge and practices with respect to the current use of iodized salt, and to estimate its uptake at the household level. MATERIALS AND METHODS: This cross-sectional survey was conducted in six villages under Rural Health Training Center. A total number of households surveyed were 253. The data collectors obtained verbal consent from the Family, and Pretested Standardized Questionnaire was administered in every selected household. The respondents were asked questions regarding salt purchasing and consumption habits, salt storage, awareness of iodized salt, and iodine deficiency diseases. Rapid iodized salt test kit (MBI kit) was used in the survey to assess iodine content in salt used in households. RESULTS: In this study, 93.7% households were using packet salt. The most common source of information was a television (31.1%). More than half (53.8%) of the households were unaware of the benefits of iodine. About 62.5% of households were consuming adequately iodized salt. Significant association was found between the practice of storing salt in closed containers and use of packaged iodized salt (Chi-square value -37.6, P < 0.001), awareness about the benefits of iodine and type of salt used (P = 0.02) while no association was observed between the socioeconomic status and type of salt used in the household. CONCLUSIONS: Though the use of packet salt was more than 90%, adequately iodized salt was consumed only in 62.5%, and more than half of the subjects lacked the knowledge about iodine deficiency diseases. PMID- 27453849 TI - Sociodemographic characteristics of tobacco users as determinants of tobacco use screening done by healthcare providers: Global Adult Tobacco Survey India 2009 2010. AB - INTRODUCTION: World Health Organization and Indian Public Health Standards recommend provision of tobacco use screening and cessation help at primary care settings. Evidence shows that brief advice by healthcare provider helps tobacco user quit. It starts with asking the patient about his tobacco use status. The rate of tobacco use screening done by healthcare providers is very low and also depends on sociodemographic characteristics of patients along with several other factors. OBJECTIVES: This paper intends to study how sociodemographic characteristics (age, gender, residence [rural/urban], education, and occupation) of tobacco users influence the tobacco use screening done by healthcare providers. MATERIALS AND METHODS: The study was a secondary data analysis of the Global Adult Tobacco Survey India 2009-2010. There were 4958 smokers and 7255 smokeless tobacco users included in the study who visited healthcare provider in the past 12 months prior to the survey. RESULTS AND DISCUSSION: The results showed that male smokers were more likely to be screened for smoking by healthcare providers as compared to female smokers. Furthermore, tobacco users in younger age groups were less likely to be screened for tobacco use by healthcare providers as compared to tobacco users in older age groups. Urban smokeless tobacco users were more likely to be screened for tobacco use by healthcare provider as compared to rural smokeless tobacco users. CONCLUSION: Healthcare providers were being biased in tobacco use screening of their patients based on demographic characteristics of patients, i.e., their age, gender, and rural/urban residence. However, the evidence shows that it is very imperative to screen each and every patient for tobacco use habit. PMID- 27453850 TI - Perception of red eye among senior secondary students in Sagamu, Southwest Nigeria. AB - BACKGROUND: Red eye is a very common presenting complaint in clinical practice among all age groups, including adolescents. Health habits formed during adolescence is carried to adulthood and is often a consequence of their perception. This study, therefore, determined the perception of students toward the red eye. AIM: To determine the perception of red eye and its associated factors among secondary school students in Sagamu. METHODS: A cross-sectional descriptive study was carried out among 1082 senior secondary school students in Sagamu local government area, using a semi-structured self-administered questionnaire. Data were analyzed using SPSS Version 20. Relevant descriptive and inferential statistics were calculated. RESULTS: The mean age of respondents was 15.27 +/- 1.48 years. There were more females (54.8%) than males. Majority (81%) had heard of red eye, and this was mainly from neighbors; 58.4% felt they could not contact red eye from an infected person. About 35% would instill onion if they had a red eye. About 50.2% felt red eye could lead to blindness. Awareness of red eye was associated with age (P = 0.005), but not with sex and religion. Among respondents, 95.5% and 96.2% had a poor perception as well as a poor attitude toward red eye, respectively. CONCLUSION: The perception and attitude of senior secondary school students in Sagamu to red eye is poor. Appropriate eye health education and promotional services, including periodic eye examination of students, should be carried out in school health services. Early presentation to eye care centers for its treatment should be encouraged. PMID- 27453851 TI - Organizational commitment and intrinsic motivation of regular and contractual primary health care providers. AB - BACKGROUND: Motivated and committed employees deliver better health care, which results in better outcomes and higher patient satisfaction. OBJECTIVE: To assess the Organizational Commitment and Intrinsic Motivation of Primary Health Care Providers (HCPs) in New Delhi, India. MATERIALS AND METHODS: Study was conducted in 2013 on a sample of 333 HCPs who were selected using multistage stage random sampling technique. The sample includes medical officers, auxiliary nurses and midwives, and pharmacists and laboratory technicians/assistants among regular and contractual staff. Data were collected using the pretested structured questionnaire for organization commitment (OC), job satisfiers, and intrinsic job motivation. Analysis was done by using SPSS version 18 and appropriate statistical tests were applied. RESULTS: The mean score for OC for entire regular staff is 1.6 +/- 0.39 and contractual staff is 1.3 +/- 0.45 which has statistically significant difference (t = 5.57; P = 0.00). In both regular and contractual staff, none of them show high emotional attachment with the organization and does not feel part of the family in the organization. Contractual staff does not feel proud to work in a present organization for rest of their career. Intrinsic motivation is high in both regular and contractual groups but intergroup difference is significant (t = 2.38; P < 0.05). Contractual staff has more dissatisfier than regular, and the difference is significant (P < 0.01). CONCLUSION: Organizational commitment and intrinsic motivation of contractual staff are lesser than the permanent staff. Appropriate changes are required in the predictors of organizational commitment and factors responsible for satisfaction in the organization to keep the contractual human resource motivated and committed to the organization. PMID- 27453852 TI - A household survey to assess community knowledge, attitude and practices on malaria in a rural population of Northern India. AB - INTRODUCTION: An extensive search on PubMed reveals very little in terms of evidence regarding the current knowledge, attitude, and practices (KAP) of the population in general and rural population, in particular, in this part of the country. Therefore, a study was conducted with the aim to assess the communities' knowledge of malaria transmission, recognition of signs and symptoms, treatment seeking. MATERIALS AND METHODS: A stratified two-stage design was used to conduct a house-to-house survey using a semi-structured questionnaire in RS Pura block of Jammu District of Jammu and Kashmir State in North India. RESULTS: A total of 300 households were included in the study. However, data on 4 households was found to be incomplete at the time of analysis and, therefore, were excluded. Out of 296 study participants interviewed 65.5% were males, while 34.5% females. All of the study participants (100%) had heard of malaria, and the main source of their information was television/newspaper. 92.5% of the study population considered malaria to be a serious health problem, thus reflecting their attitude to the disease. Regarding practices, 71.6% of the study participants preferred going to doctors at government hospitals for malaria treatment, and 56% were willing to seek medical help in <24 h in case of a child has a febrile episode. CONCLUSIONS: Results revealed that KAP among respondents were reasonably good and key sociocultural, and related indicators need to be identified as a part of malaria elimination strategy. PMID- 27453853 TI - Risk factor distribution for cardiovascular diseases among high school boys and girls of urban Dibrugarh, Assam. AB - INTRODUCTION: Chronic noncommunicable diseases (NCDs) including cardiovascular diseases (CVDs) are the leading cause of death in the world, and their incidence is rising rapidly due to increasing rates of risk factors such as hypertension, dyslipidemia, diabetes, obesity, physical inactivity, and tobacco use. These risk factors track from childhood to adulthood, and their distribution varies among males and females; hence, there is a need to determine risk factor prevalence among adolescent age group so as to plan preventive strategies. OBJECTIVE: To determine the distribution of risk factors of CVDs amongst high school boys and girls of urban Dibrugarh, Assam. SUBJECTS AND METHODS: A cross-sectional study was conducted from October 2012 to June 2013 in the schools of urban Dibrugarh, Assam wherein data was collected from 1000 students of Class 8-10 using multistage random sampling and risk factors were assessed using WHO steps methodology. STATISTICAL ANALYSIS: Statistical analysis was done using SPSS 16 software and test of differences used were Chi-square test and t-test. RESULTS: The prevalence of ever tobacco use was 32.3% among boys and 6.6% among girls (P < 0.001) while ever alcohol use was reported by 11.9% boys and 1% girls (P < 0.001). Prevalence of overweight and hypertension was found to be higher among girls (11.7% and 24.1%) as compared to boys (6.8% and 18.1%). Prevalence of hypercholesterolemia was higher among boys while high triglycerides levels were more prevalent among girls. CONCLUSION: The study revealed a high prevalence of various risk factors among boys and girls. There is a need to reduce the risk factor prevalence of CVD among this group of the population to address the future epidemic of NCD. Different health promotional activities need to be implemented to target boys and girls as the risk factor distribution among these groups is different. PMID- 27453854 TI - Modifiable risk factors of hypertension: A hospital-based case-control study from Kerala, India. AB - INTRODUCTION: Hypertension is a major cause of cardiovascular morbidity and mortality in Kerala. Excess dietary salt, low dietary potassium, overweight and obesity, physical inactivity, excess alcohol, smoking, socioeconomic status, psychosocial stressors, and diabetes are considered as modifiable risk factors for hypertension. OBJECTIVES: To estimate and compare the distribution of modifiable risk factors among hypertensive (cases) and nonhypertensive (controls) patients and to estimate the effect relationship of risk factors. MATERIALS AND METHODS: Age- and sex-matched case-control study was conducted in a tertiary care hospital in Kerala using a pretested interviewer-administered structured questionnaire based on the WHO STEPS instrument for chronic disease risk factor surveillance. Bivariate and multiple logistic regression analyses were done. RESULTS: A total of 296 subjects were included in the study. The mean age of study sample was 50.13 years. All modifiable risk factors studied vis-upsilon-vis obesity, lack of physical activity, inadequate fruits and vegetable intake, diabetes, smoking, and alcohol use were significantly different in proportion among cases and controls. Obesity, lack of physical activity, smoking, and diabetes were found to be significant risk factors for hypertension after adjusting for other risk factors. CONCLUSION: Hypertension is strongly driven by a set of modifiable risk factors. Massive public awareness campaign targeting risk factors is essential in controlling hypertension in Kerala, especially focusing on physical exercise and control of diabetes, obesity, and on quitting smoking. PMID- 27453855 TI - Correlation study between platelet count, leukocyte count, nonhemorrhagic complications, and duration of hospital stay in dengue fever with thrombocytopenia. AB - INTRODUCTION: Dengue is one of the common diseases presenting as fever with thrombocytopenia, also causing significant morbidity and complications. OBJECTIVES: Though the correlation between platelet count, bleeding manifestations and hemorrhagic complications has been extensively studied, less is known about the correlation between platelet count and non hemorrhagic complications. This study was done to see the correlation between platelet count and non hemorrhagic complications, duration of hospital stay and additive effect of leucopenia with thrombocytopenia on complications. METHODS: Our study is prospective observational study done on 99 patients who had dengue fever with thrombocytopenia. Correlations were obtained using scatter plot and SPSS software trail version. RESULTS: Transaminitis (12.12%) was the most common complication followed by acute renal injury (2%). In our study we found that, as the platelet count decreased the complication rate increased (P = 0.0006). In our study duration of hospital increased (P is 0.00597) with decreasing platelet count when compared to other study where there was no correlation between the two. There was no correlation between thrombocytopenia with leucopenia and complications (P is 0.292), similar to other study. CONCLUSION: Platelet count can be used to predict the complication and duration of hospital stay and hence better use of resources. PMID- 27453856 TI - Validity and reliability of the developmental assessment screening scale. AB - OBJECTIVES: To develop and validate the 6-year Ages and Stages Questionnaire (ASQ) for school-age children. METHODS: Parents/caregivers of children 66-78 months were recruited from 6 countries and 15 states in the United States. Similar to other ASQ intervals, the 6-year ASQ has five developmental domains targeted for children from 66 months to 78 months of age. We assessed internal consistency reliability, test-retest reliability, the scale structure, validity (correlation coefficients), and utility of the 6-year ASQ. The 6-year ASQ screens development in five domains using 30 items. RESULTS: Coefficient alpha measuring internal consistency was 0.97. Test-retest reliability was estimated by having parents complete two ASQ's on the same child within a week interval. Correlations between scores of the two ASQ's reflected stability of scores. Test-retest reliability results were robust with an intraclass correlation coefficient of 0.94. Factor analysis results resulted in a five factors structure. The Pearson correlations coefficients between the latent variables were moderate to large and statistically significant, P < 0.0001. The 6-year ASQ screens development in five domains using 30 items. The administration time varied from 10 to 60 min with a mean of 15.17 min. General utility result shows that the 6-year ASQ can be used with satisfaction by caregivers, pediatricians, professionals, and parents. CONCLUSIONS: Preliminary data on the 6-year ASQ reflected promising results. An easy-to-administer, accurate caregiver-completed screening tool may increase the frequency of screening for school-age children. PMID- 27453857 TI - Association of quality of life of carers with quality of life and functional independence of stroke survivors. AB - BACKGROUND: Stroke has a great impact not only on patients' but also on their caregivers' lives. Carers may experience high levels of burden that can result in deterioration of their health status, social life, and well-being. Association between quality of life (QOL) of carers and that of stroke survivors in Indian setting is not much researched. AIMS AND SETTINGS: To find out QOL and mental health of caregivers of individuals with stroke visiting Physiotherapy Department of Tertiary Care Center in Western India. DESIGN AND METHODOLOGY: A cross sectional survey to find QOL and mental health of caregiver of stroke survivors, self-administered screening instrument WHO-QOL BREF, functional independence measurement (FIM) scale, and BRIEF COPE were used for data collection on adult populations. STATISTICAL ANALYSIS USED: The statistical analysis was performed by descriptive analysis and correlation. RESULT: Fifty-four stroke patients and their caregivers (all adults) were included in the study. Average FIM score was 83.75 (18.46) while median was 90 (25). FIM score of patients did not much affect QOL of caregivers. DISCUSSION: Analysis of QOL data showed that QOL of caregivers was good in all domains, but patient's QOL was good only in social relations. There was no correlation found in QOL of carers and stroke survivors. Nine percent of change in caregivers social relationship scores can be attributed to patients' sphincter scores. CONCLUSION: QOL of carers and stroke survivors may be independent. Stroke patients in the study required a moderate assistance for their functional independence which does not seem to affect the caregivers QOL significantly. PMID- 27453858 TI - The influence of escort during upper endoscopy and colonoscopy on patient satisfaction and anxiety. AB - AIM: Endoscopy, including esophagogastroduodenoscopy (EGD) and colonoscopy (CS), is a diagnostic and treatment method for various diseases. We aimed to evaluate the effects of the presence of an escort by the patient on patients' satisfaction and anxiety level before and after upper endoscopy and CS. SUBJECTS AND METHODS: Patients who referred to the Hajar Hospital for elective EGD and CS were recruited. The patients were divided into two groups: The first group underwent endoscopy/CS with an escort beside the patient and the escort was waiting in the waiting room in the second group. After interventions, patients' and their escort's levels of anxiety and satisfaction were evaluated. Anxiety level was compared before and after endoscopy. RESULTS: Of 211 patients, 106 were referred for EGD and 105 for CS. Anxiety was same in both groups before the interventions (P > 0.05), which decreased in both after the EGD or CS (P < 0.05). Anxiety reduction after CS was influenced by the presence of the escort and the level of anxiety was less in this group than other group (P < 0.05). Satisfaction of the EGD and CS in the group that had an escort by their side was more than the other (P < 0.05). Escorts had a moderate level of anxiety in both groups with a marked reduction after endoscopy and CS (P < 0.05). However, the level of anxiety before and after endoscopy was similar in both groups (P > 0.05). CONCLUSION: Having an escort at the time of endoscopy or CS appears to be an effective costless complication-free measure for increasing satisfaction and reducing anxiety in patients. PMID- 27453859 TI - Effects of a physical activity program on the quality of life among elderly people in Brazil. AB - PURPOSE: To assess the quality of life (QOL) of elderly people in the "Academia da Cidade program" (ACP), a public Brazilian Government Program encourages physical and leisure activity in Recife, Brazil. MATERIALS AND METHODS: This cross-sectional study evaluated 181 elderly people attending the "ACP" at least twice a week. Demographic, socioeconomic, and clinical data were presented according to World Health Organization QOL (WHOQOL)-BREF and WHOQOL-OLD scores. RESULTS: Univariate analysis showed that WHOQOL-BREF and WHOQOL-OLD scores were positively associated with longer duration of participation in "ACP," P < 0.030 and P < 0.003, respectively, a multivariate regression analysis showed that duration of participation in "ACP" remained associated with higher WHOQOL-BREF (P = 0.023) and WHOQOL-OLD (P = 0.038) scores. CONCLUSION: A longer duration of participation in a community-based physical activity program, "ACP," may contribute to a better QOL for the elderly in Brazil. PMID- 27453860 TI - Depressive symptoms and bone mineral density in menopause and postmenopausal women: A still increasing and neglected problem. AB - BACKGROUND: The association between depression and loss of bone mineral density (BMD) has been reported as controversial. OBJECTIVE: The objective of the current study was to investigate whether an association exists between depression and low BMD during the menopausal and postmenopausal period. MATERIALS AND METHODS: A cross-sectional descriptive study was used to generate menopause symptoms experienced by Arabian women at the Primary Health Care Centers in Qatar. A multi stage sampling design was used, and a representative sample of 1650 women aged 45 65 years were included during July 2012 and November 2013. This prospective study explored the association between bone density and major depressive disorder in women. Bone mineral densitometry measurements (BMD) (g/m(2)) were assessed at the BMD unit using a lunar prodigy DXA system (Lunar Corp., Madison, WI). Data on body mass index (BMI), clinical biochemistry variables including serum 25 hydroxyvitamin D were collected. The Beck Depression Inventory was administered for depression purposes. RESULTS: Out of 1650 women 1182 women agreed to participate in the study (71.6%). The mean age and standard deviation (SD) of the menopausal age were 48.71 +/- 2.96 with depressed and 50.20 +/- 3.22 without depressed (P < 0.001). Furthermore, the mean and SD of postmenopausal age were 58.55 +/- 3.27 with depression and 57.78 +/- 3.20 without depression (P < 0.001). There were statistically significant differences between menopausal stages with regards to a number of parity, and place of living. There were statistically significant differences between menopausal stages with regards to BMI, systolic and diastolic blood pressure, Vitamin D deficiency, calcium deficiency and shisha smoking habits. Overall, osteopenia and osteoporosis and bone loss were significantly lower in postmenopausal women than in menopausal women (P < 0.001). Similarly, T-score and Z-score were lower with depression menopause and postmenopausal women (P < 0.001). The multivariate logistic regression analyses revealed that the depression, the mean serum Vitamin D deficiency, calcium level deficiency, less physical activity, comorbidity, number of parity, systolic and diastolic blood pressure and shisha smoking habits were considered as the main risk factors associated with bone mineral loss after adjusting for age, BMI and other variables. CONCLUSION: Depression is associated with low BMD with a substantially greater BMD decrease in depressed women and cases of clinical depression. Depression should be considered as an important risk factor for osteoporosis. PMID- 27453861 TI - A study of prevalence of depression and anxiety in patients suffering from tuberculosis. AB - OBJECTIVE: The study was conducted to determine the point prevalence of depression and anxiety in patients suffering from tuberculosis. MATERIAL AND METHODS: Total of 100 consecutive cases were included who were already diagnosed with tuberculosis after applying inclusion and exclusion criteria. Tools used were General Health Questionnaire 12 (GHQ-12), Beck Depression Inventory (BDI-II) and Hamilton Anxiety Rating Scale (HARS). RESULT: Out of 100 cases, 74 cases found to be having psychiatric symptoms, in which 35 cases were suffering from depression and 39 were suffering from anxiety. CONCLUSION: Psychiatric morbidity was present in the diagnosed cases of tuberculosis. Proper psycho education, timely intervention in the form of proper diagnosis and specific treatment was required. It should also be evaluated further on a bigger target population. PMID- 27453862 TI - Correlation between the percentage of body fat and surrogate indices of obesity among adult population in rural block of Haryana. AB - INTRODUCTION: The increasing prevalence of overweight and obesity has raised concerns regarding the importance of different techniques, which are used to assess body growth composition that can be used at the level of primary health care settings with minimal knowledge. The purpose of this study was to evaluate the relationship between different surrogate indices of fatness (body mass index [BMI], waist circumference [WC], waist-to-hip ratio [WHR], waist-to-height ratio [WHtR], and body fat percentage [BF%]) with the percentage of body fat and their usefulness as a predictor of obesity among adult population. MATERIALS AND METHODS: The community-based cross-sectional study done over a period of 1-year involved 1080 adult participants from a rural area in Haryana. Anthropometry, along with BF% (using hand held analyzer) were recorded using standard procedures. RESULTS: The prevalence of overweight and obesity as per the modified criteria of BMI for the Asian Indians was found to be 15.0% and 34.6%, respectively. Positive correlation was seen among all the indices except between the WHR and body adiposity index (BAI) using Pearson's correlation analysis. Maximum correlation was seen between WHtR and WC (r = 0.923), whereas WHtR depicted maximum correlation (r = 0.810) with BF%. Receiver operating characteristic curve analysis revealed that the WHtR was the most sensitive and specific indicator for the study population to predict overweight and obesity comparable to that calculated by body fat analyser followed by BAI, BMI, and WHR. CONCLUSION: A single value of WHtR irrespective of gender and the area of residence can be used as a universal screening tool for the identification of individuals at high risk of development of metabolic complications. PMID- 27453863 TI - Warfarin-induced leukocytoclastic vasculitis and proteinuria. AB - Warfarin is typically prescribed for patients with thromboembolic diseases and atrial fibrillation. In addition to the complications of bleeding, allergic skin reaction is one of its rare adverse effects. We herein report a case of a 79 year old male patient with leukocytoclastic vasculitis and proteinuria secondary to warfarin. The warfarin was discontinued and oral prednisone therapy was initiated. The cutaneous lesions and the proteinuria resolved thereafter. PMID- 27453864 TI - Recurrent mania consequent to quinolones exposure: A case report and review of literature. AB - Antibiotics are the one of the most commonly used group, of drugs, in general medical and surgical practice. The quinolone antibiotics can lead to a range of adverse neuropsychiatric effects with most of the reports due to ciprofloxacin and ofloxacin. Here, we report an interesting and rarely described psychiatric manifestation of recurrent mania following the use of quinolone antibiotics, and briefly review the available literature. PMID- 27453865 TI - Hymenolepis diminuta infection in a young boy from rural part of Northern India. AB - Hymenolepis diminuta (H. diminuta) is primarily a parasite of rats and mice. Humans are infected by eating meal contaminated with these arthropods. This infection is not seen commonly in Indian population. We present here a case report of infection with H. diminuta in a young boy from a rural area of the North India. PMID- 27453866 TI - Split-hand/feet malformation: A rare syndrome. AB - Split-hand/split-foot malformation (SHFM) is mainly inherited as an autosomal dominant trait with incomplete penetrance and characterized by malformation of the limb involving the central rays of the autopod. It presents with a deep median cleft of the hand and/or foot, aplasia/hypoplasia of the phalanges, metacarpals, and metatarsals. Pathogenic mechanism is a failure to maintain signaling from the median apical ectodermal ridge. Without this signaling, cells of the underlying progress zone stop proliferation and differentiation which in turn results in defects of the central rays. We describe a case of SHFM in 10 year-old boy. PMID- 27453867 TI - Disseminated tuberculosis with varied paradoxical reactions. AB - Paradoxical reactions are immune-mediated exacerbations of disease triggered by tuberculosis (TB) treatment. We describe a case of varied paradoxical reactions in a 9-year-old girl who was diagnosed with mediastinal TB and tuberculous ascites. The development of paradoxical reaction was gradual with pericardial effusion occurring first followed by pleural effusion and subsequently bilateral papilledema. PMID- 27453868 TI - Massive ovarian edema: A case report presenting as a diagnostic dilemma. AB - Massive ovarian edema is a rare clinical entity, posing a significant clinical challenge as it can be easily mistaken for neoplasm. Our case was a 20-year-old young woman who presented with a self-limiting episode of abdominal pain along with large solid pelvis mass. On physical examination, she had abdominal tenderness with guarding. Ultrasound examination revealed large solid ovarian mass with moderate ascites. With the diagnosis of ovarian neoplasm, laparotomy was performed, and intraoperative frozen section excluded malignancy with differentials suggesting of fibromatosis/massive ovarian edema. The patient underwent unilateral salpingo-oophorectomy. Histopathological examination confirmed the diagnosis of massive ovarian edema. Massive ovarian edema should be suspected in women at the fertility age range with solid enlargement of the ovary so that these young patients can be treated conservatively where fertility preservation is mandatory. PMID- 27453869 TI - Colloidal silver-based nanogel as nonocclusive dressing for multiple superficial pellet wounds. AB - A good dressing is mandatory to an uncomplicated wound healing, especially when foreign particles contaminate the wound. Various forms of dressing preparations are available for use and differ in chemical composition and efficacy. Silver has been a known agent with good antimicrobial and healing properties and recent times has seen an upsurge in various silver-based dressing supplements. We describe our report of use and efficacy of a silver nanoparticle- based gel dressing in the healing of multiple superficial firearm pellet wounds. PMID- 27453870 TI - Neuroleptic malignant syndrome. AB - Neuroleptic malignant syndrome (NMS) is a life-threatening emergency that is often seen as a complication of antipsychotic agents. It is characterized by a tetrad of motor, behavioral, autonomic, and laboratory abnormalities. We report a case of a 34-year-old man with a history of newly diagnosed Type 2 diabetes mellitus, mental retardation, and behavioral abnormalities who developed NMS after starting on antipsychotic agents. He presented with high temperature, muscle rigidity, tachycardia, and elevated blood pressure. After a week of hospital treatment in the general ward of a secondary care unit, he was discharged in a hemodynamically and mentally stable state. PMID- 27453871 TI - An unusual case of adolescent type 2 diabetes mellitus: Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a complex genetic disorder, characterized by neonatal hypotonia, developmental delay, short stature, childhood obesity, hypogonadism, and characteristic facial features. Here we report a 21-year-old male who presented with uncontrolled glycemic status. He was diagnosed to have diabetes mellitus at the age of 15 with osmotic symptoms - polyuria, polydipsia, and polyphagia. In the early period, after diagnosis, his blood sugars were reasonably controlled with oral hypoglycemic agents. However, a year back, he was switched onto insulin therapy due to secondary OHA failure. On examination, his body mass index was 36 kg/m(2). He had bilateral gynecomastia, decreased biparietal diameter, almond shaped eyes with esotropia. He had hypogonadism and also had mild cognitive impairment. He did not have any proximal myopathy or other focal neurological deficits. Hormonal evaluation showed low testosterone and inappropriately normal fluorescence in situ hybridization suggestive of central hypogonadism. With fetal and neonatal hypotonia, delayed developmental milestones, hypogonadism, and early onset diabetes, he fulfilled the clinical criteria for the diagnosis of PWS. Multidisciplinary approach of clinicians together with family and social support are essential to bring out the optimal outcome for such syndromic cases. PMID- 27453872 TI - Natal and neonatal teeth: Terminologies with diverse superstitions!! PMID- 27453873 TI - Toothbrush contamination: Often neglected health hazard. PMID- 27453874 TI - Indian adolescents and human immunodeficiency virus: A pilot study from Delhi. PMID- 27453875 TI - Comment on the maternal and neonatal outcomes of gestational diabetes. PMID- 27453876 TI - Mobile health: Applications in tackling the Ebola challenge. PMID- 27453877 TI - Comment on "correlates of overweight and obesity among urban adolescents in Bihar, India". PMID- 27453878 TI - Prehospital trauma care in South India: A glance through the last 15 years. PMID- 27453879 TI - National Consultation on Family Medicine Programme 2013: Report and Recommendations. PMID- 27453880 TI - The effects of onion consumption on treatment of metabolic, histologic, and inflammatory features of nonalcoholic fatty liver disease. AB - BACKGROUND: The aim of this study was to evaluate the effects of onion powder consumption on treatment of Non-alcoholic Fatty Liver Disease (NAFLD) in an experimental model of disease. METHODS: Sprague-Dawley rats were fed high-fat (HF) diet for seven weeks to induce the NAFLD. Then, they were treated by either the same diet (HF), or high-fat diet plus 7 % onion powder (HF + onion), or chow diet (control), or chow diet plus 7 % onion powder (control + onion)ad libitum for four weeks. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin, and hepatic tumor necrosis factor-alpha (TNF-alpha) gene expression were determined. Hepatic histology was examined by Hematoxylin and Eosin stain. RESULTS: Dietary food intakes and weigh gain were significantly more in animals fed control + onion diet in comparison to the other groups. Animals fed control or control + onion diet had significantly lower plasma levels of hepatic enzymes, lipid profile, glycemic indices, and hepatic TNF-alpha gene expression as compared with HF diet fed groups; however, there was no significant difference in the histopathologic features of NAFLD among different groups. CONCLUSION: Our results indicate that onion consumption can be effective in NAFLD management when it is combined with a healthy diet. PMID- 27453881 TI - Evaluation of laparoscopic sleeve gastrectomy compared with laparoscopic Roux-en Y gastric bypass for people with morbid obesity: A systematic review and meta analysis. AB - BACKGROUND: Prevalence of obesity in the world, in both developed and developing countries, is growing rapidly. Bariatric surgery is now accepted as the treatment for morbid obesity. OBJECTIVE: This study compares laparoscopic sleeve gastrectomy's effectiveness (LSG) with the most common bariatric surgery, laparoscopic Roux-en-Y (LRYGB) gastric bypass. METHODS: A systematic review was performed using relevant search data bases, including Cochrane library, PubMed, Magi ran, Iranmedex, SID and Trip database, with no time limit. Data bases were searched until July 2014 for randomized control trials. The studied population included people aged between 18-60 years, with BMI>=35 and at least one obesity related disease, or people with BMI>=40. BMI change, as the research outcome, was investigated at least in one-year follow-up period. Cochrane criteria were used to assess quality of studies. The results were extracted from the articles. RESULTS: In total, 384 articles were obtained in the search; six RCTs were included in this study. There was no significant difference between the two laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass procedures in BMI, and both groups were similar in weight loss CI [-.1.31, 0.43], p=0.32. CONCLUSION: The two procedures of bariatric surgery are effective and reliable treatments. Performing more trial studies with greater sample size and longer follow-up period for making final decision in selecting a certain surgical procedure is essential. PMID- 27453882 TI - The effectiveness of massage therapy in the treatment of infantile colic symptoms: A randomized controlled trial. AB - BACKGROUND: Infantile colic, cry-fuss and sleep problems are transient in the initial months of life, but they contribute to maternal depression, parenting stress and family mental health problems. In this randomized clinical trial, we aimed to explore the efficacy of massage therapy compared to rocking in reducing infantile colic symptoms including duration and number of cries, sleep duration and severity of infant colic. METHODS: This was a single blind RCT study with a one-week follow-up. One hundred colicky infants aged younger than 12 weeks old were randomly assigned into massage and rocking groups. Infants in the massage group received a massage for 15-20 minutes once during a day and once at night before sleeping for a week. In the control group, mothers rocked their infants gently for 5-25 minutes when the symptoms of colic appeared. Parents recorded the details of the colic symptoms in a diary every day. A GEE approach was applied to explore the effect of the intervention. RESULTS: Efficiency of massage therapy was significantly higher than rocking. At the end of the study, the mean number of daily cries was 4.26+/-1.40 in the massage and 6.9+/-2.14 the rocking groups (p<0.01). The mean of the severity score was 1.39+/-0.19 less in the massage group (p<0.01). Moreover, the mean differences of massage and rocking groups were -0.82+/-0.20 hour (p<0.01) and 0.72+/-0.35 (p= 0.04) in the duration of cries and duration of sleep, respectively. CONCLUSION: Massaging significantly improved colic symptoms during a one-week intervention for all outcomes. In addition, significant differences were found between the intervention and control groups in favor of massaging. Therefore, massage therapy is more effective than rocking for treating infant colic symptoms. PMID- 27453883 TI - Can combination of hysterosalpingography and ultrasound replace hysteroscopy in diagnosis of uterine malformations in infertile women? AB - BACKGROUND: Mullerian anomalies are associated with infertility. Hysteroscopy as the gold standard for evaluating Mullerian anomalies is an invasive, expensive and risky procedure which requires enough experience. Transvaginal sonography (TVS) and hysterosalpingography (HSG) are less invasive procedures, but there is little known about the accuracy of these tests. The aim of this study was to evaluate the accuracy of the combination of TVS and HSG with hysteroscopy as the gold standard. METHODS: Medical records of infertile women who were undertaken all three diagnostic modalities were reviewed to analyze their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Ninety-nine infertile women were assessed with a mean+/-SD age of 29.1+/-6.47 years, mean+/-SD duration of themarriage of 8.9+/-10.28 years, and mean+/-SD duration of infertility of 5.6+/- 4.16 years. The sensitivity, specificity, PPV, and NPV of TVS were 98.55%, 30%, 76.4%, and 90%, respectively. HSG had a sensitivity of 95.6%, specificity of 60%, PPV of 84.62%, and NPV of 85.71%.When both modalities were combined, the sensitivity, specificity, PPV, and NPV were 94.2, 66.67, 86.67, and 83.33%, respectively. The diagnostic accuracy of single TVS, HSG or combined techniques was statistically similar that was equal to 77.7, 84.8 and 85.8 % respectively. CONCLUSION: The accuracy of combination of two diagnostic modalities, 2D TVS and HSG is not higher than HSG alone for assessing uterine malformation in infertile women. PMID- 27453885 TI - A case-control study on risk factors for unintentional childhood poisoning in Tehran. AB - BACKGROUND: Poisoning is a major public health problem and is one of the most frequent causes of emergency hospital admissions. The aim of this study was to identify the main risk factors for unintentional childhood poisoning in Tehran, Iran and to suggest possible causes and preventative measures. METHODS: In this case-control study (case, n=140; control, n=280), two controls were selected for every case. Controls were matched by age, sex, and date of hospital attendance. All children and their guardians were then interviewed by the same person using a standard questionnaire that covered the demographic, behavioral, and risk factors associated with accidental poisonings. RESULTS: The most common type of poisoning was related to narcotics (58.6%); and among the narcotics, methadone was the most prevalent poisoning agent (74.7%). Multivariate conditional logistic regression model revealed that addiction in the family (OR=14.6; 95% CI:6.2-34.6), previous poisoning (OR=7; 95% CI:2.4- 20.2), maternal occupation (OR=4; 95% CI:1.3- 12.3), and inaccessibility of poisoning products (OR=0.03; 95% CI:0.01- 0.12) were the main risk factors in unintentional childhood poisoning. CONCLUSION: Addiction in the family as a risk factor and inaccessibility of poisoning products as a protecting factor were recognized to have the highest correlation with the unintentional child poisoning. These two factors were considered as priorities in health education programs. PMID- 27453884 TI - A content analysis of health-related advertisements in Islamic Republic of Iran broadcasting (IRIB). AB - BACKGROUND: Media advertisements especially radio and TV are one of the most important and effective ways for health promotion and consumption of healthy productions worldwide. Ministry of Health and some other ministries in Iran agreed to control and restrict the advertising of unhealthy products and services. Therefore, adequate supervision and monitoring should be done in this field. A content analysis of Health-related Advertisements was done in Islamic Republic of Iran Broadcasting (IRIB) Methods: This study was a cross-sectional research and collecting of data was carried out in 2012. Ten selected TV and radio channels were recorded from 6 a.m. to 12 p.m. for two successive months in the special weekdays. Broadcasted advertisements data were extracted by the trained observers according to a checklist and analyzed using SPSS 18 software and described with descriptive statistics. RESULTS: The percentage of different types of advertising were including 73.9% unrelated to health, 21.9% harmless health related, 2.9% less healthy, 1.3% harmful or harmful with a probability of abuse. Non-harmful to health advertisements included 95.86% of total advertisements out of ten TV and radio channels; and the remained advertisements (4.14%) were related to the harmful, less healthy foodstuff and detrimental services and products. Also, 0.8% of the advertisements were shown during children programs. CONCLUSION: The main findings of the current study revealed that majority of the advertisements of Islamic Republic Broadcasting were unrelated to health. It seems advertising of harmful for health in IRIB was less than 5%, and the levels of these type ads were less than the other countries. Even so, the policymakers need to pass and enforce some executive and governing law for the prevention of broadcasting unhealthy advertisements to increase the society health level and prevent the diseases resulted from unhealthy products causing the considerable damages in a long time. PMID- 27453886 TI - Factors affecting nurse turnover in Iran: A qualitative study. PMID- 27453887 TI - Correlation of MRI findings and cognitive function in multiple sclerosis patients using montreal cognitive assessment test. AB - BACKGROUND: Magnetic resonance imaging (MRI) has improved the diagnosis and management of patients with multiple sclerosis (MS). Montreal Cognitive Assessment (MoCA) is a brief, sensitive test that has been recommended by National Institute of Neurological Diseases and Stroke and Canadian Stroke Network (NINDS-CSN) as a reliable tool to detect mild cognitive impairments. This study aimed to evaluate the relationship between MoCA test and its sub-items with brain abnormalities in MRI of MS patients. METHODS: Based on MRI scans of 46 MS patients, third ventricle and white matter lesions volumes were measured. Disease duration and expanded disability status scale (EDSS) were recorded in each patient. In addition, cognitive domains of the patients were evaluated by Montreal cognitive assessment (MoCA) test. We analyzed data using t-test or Mann Whitney U test, Pearson correlation coefficient, and non-parametric Spearman test. Furthermore, multiple linear regression model was applied to evaluate the association between cognitive indices and MRI characteristics. RESULTS: Among MRI indices, only severity of atrophy showed a significant difference between cognitively impaired and cognitively preserved patients. Third ventricular volume was significantly correlated with total MoCA score (p=0.003, r=-0.42), but none of the juxtacortical or periventricular lesions volume revealed significant relation with total MoCA score. However, using multivariate linear regression after adjustment for educational level and disease duration, there was a significant negative association between juxtacortical lesions volume and total MoCA score as well as naming and attention sub-items. Also, memory score was adversely associated with the third ventricular volume (p=0.03, r=0.31). CONCLUSION: Cognitive disturbances detected by MoCA, may be associated with some pathological changes including atrophy, third ventricular volume, and juxtacortical lesion. MoCA, as a brief test, is not correlated with brain lesions volume in MS patients. PMID- 27453888 TI - Vascular endothelial growth factor expression and vascular density in oral squamous cell carcinoma (OSCC): A study on clinical and histopathologic significance. AB - BACKGROUND: New blood vessels formation is a critical step in tumor progression. Vascular density affects the clinical outcome and prognosis of malignant tumors. The aim of this study was to investigate the relation between the Vascular Endothelial Growth Factor (VEGF) expression and vascular density with the clinical and histopathologic features in oral squamous cell carcinoma (OSCC). METHODS: In this retrospective study, 22 paraffin embedded block of well differentiated OSCC were examined immunohistochemically for VEGF expression. Vascular density was determined by counting the blood vessels in 6 fields with 100 (HPF) on hematoxylin-eosin stained slides. The relation between the VEGF expression and vascular density with clinical and histopathologic features were analyzed by t-test, ANOVA, and Chi-square tests. RESULTS: A significant relation between gender (P=0.06) and tumor size (p=0.05) with vascular density was obtained. The relation between VEGF expression and gender (p=0.41), age (p=0.35), lymph node involvement (p=0.38), tumor size (p=0.15) and tumor differentiation (p=0.34) was not significant. The relation between vascular density and age (p=0.55), lymph node involvement (p=0.20), and tumor differentiation (p=0.80) was not significant. CONCLUSION: Blood vessels formation relates to tumor size. Controlling the tumor size by manipulating the blood vessels formation may contribute to the inhibition of tumor progression in malignant tumors. PMID- 27453889 TI - The impact of vascular diameter ratio on hemodialysis maturation time: Evidence from data mining approaches and thermodynamics law. AB - BACKGROUND: Vascular Access (VA) is an important aspect for blood circulatory in Hemodialysis (HD). Arteriovenous Fistula (AVF) is a suitable procedure to gain VA. Maturation of the AVF is a status of AVF, which can be cannulated for HD. This study aimed to discover the parameters that effectively reduce the duration between VA and start of HD, which symbolizes the maturation time (MT). METHODS: Ninety-six patients who underwent AVF creation were selected for this study. The decision tree method was used based on CART/C4.5 algorithm, which is one of the data mining approaches for data classification. Vascular diameter ratio (VDR) coefficient was obtained (VDR=Artery/Vein diameters). RESULTS: We investigated the relationship between the VDR and MT in this study and found that MT is reversely related to VDR in elderly patients, while this relation was direct in younger patients. CONCLUSION: The analysis revealed a Spearman's correlation coefficient for Vein diameter with MT. MT decreases when diameters of vein and artery are close to one another. This study can help the surgeons to identify high- risk patients who elongate MT for HD. PMID- 27453890 TI - Determinants of maternal mortality in Eastern Mediterranean region: A panel data analysis. AB - BACKGROUND: As one of the main criteria of health outcomes, maternal mortality indicates the socioeconomic development level of countries. The present study aimed at identifying and analyzing the effective factors on maternal mortality in Eastern Mediterranean Region (EMR) of the World Health Organization (WHO). METHODS: Analytical model was developed based on the literature review. Panel data of 2004-2011 periods for 22 EMR countries was used. Required data were collected from WHO online database. Based on results of diagnostic tests for panel data model, parameters of model were estimated by fixed effects method. RESULTS: Descriptive statistics demonstrated the large disparities in social, economic, and health indicators among EMRO countries. Findings obtained from evaluating the model showed a negative, significant relationship between GDP per capita (beta=-0.869, p<0.01), health expenditure) beta=-0.525, p<0.01 (female literacy rate) beta=-1.045, <0.01 (skilled birth attendance) beta=-0.899, p<0.05) and maternal mortality rate. CONCLUSION: Improved income and economic development, increased resources allocated to the health sector, improved delivery services particularly the increased use of trained staff in the delivery, improve quality of primary care centers, mitigating the risks of marginalization and its dangers, and especially improving the level of women's education and knowledge are the key factors in policy making related to maternal health promotion. PMID- 27453891 TI - Expression of Concern: Human and Environmental Dangers Posed by Ongoing Global Tropospheric Aerosolized Particulates for Weather Modification. PMID- 27453892 TI - Retraction: Human and Environmental Dangers Posed by Ongoing Global Tropospheric Aerosolized Particulates for Weather Modification. AB - [This retracts the article on p. 139 in vol. 4, PMID: 27433467.]. PMID- 27453893 TI - WHEN IT ALL GETS TO BE TOO MUCH: ADDRESSING DIABETES DISTRESS IN AFRICAN AMERICANS. PMID- 27453894 TI - LARS Artificial Ligament Versus ABC Purely Polyester Ligament for Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Graft choice for anterior cruciate ligament (ACL) reconstruction is of critical importance. Various grafts have been used so far, with autografts long considered the optimal solution for the treatment of ACL-deficient knees. Limited data are available on the long-term survivorship of synthetic grafts. PURPOSE: To compare the functional outcome and survivorship of ACL reconstructions performed using the LARS (ligament augmentation and reconstruction system) ligament and the ABC (active biosynthetic composite) purely polyester ligament. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The results of 72 patients who underwent primary arthroscopic ACL reconstruction with the LARS ligament and 31 cases with an ABC purely polyester ligament were reviewed. The mean follow-up periods for the LARS and ABC groups were 9.5 and 5.1 years, respectively. A survivorship analysis of the 2 synthetic grafts was performed using the Kaplan-Meier method with a log-rank test (Mantel Cox, 95% CI). Lysholm, Tegner activity, Knee injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC) scores as well as laxity measurements obtained using a KT-1000 arthrometer were recorded for all intact grafts, and a Mann-Whitney U test was used for comparison reasons. RESULTS: The rupture rates for LARS and ABC grafts were 31% (95% CI, 20%-42%) and 42% (95% CI, 25%-59%), respectively. For intact grafts, the mean Lysholm score was good for both groups (90 for the LARS group and 89 for the ABC group), with the majority of patients returning to their preinjury level of activities, and the mean IKDC score was 90 for the LARS group and 86 for the ABC group. CONCLUSION: The rupture rates of both LARS and ABC grafts were both high. However, the LARS ligament provided significantly better survivorship compared with the ABC ligament at short- to midterm follow-up (95% CI). PMID- 27453895 TI - Cross-Cultural Detection of Depression from Nonverbal Behaviour. AB - Millions of people worldwide suffer from depression. Do commonalities exist in their nonverbal behavior that would enable cross-culturally viable screening and assessment of severity? We investigated the generalisability of an approach to detect depression severity cross-culturally using video-recorded clinical interviews from Australia, the USA and Germany. The material varied in type of interview, subtypes of depression and inclusion healthy control subjects, cultural background, and recording environment. The analysis focussed on temporal features of participants' eye gaze and head pose. Several approaches to training and testing within and between datasets were evaluated. The strongest results were found for training across all datasets and testing across datasets using leave-one-subject-out cross-validation. In contrast, generalisability was attenuated when training on only one or two of the three datasets and testing on subjects from the dataset(s) not used in training. These findings highlight the importance of using training data exhibiting the expected range of variability. PMID- 27453896 TI - Neural systems involved in processing novel linguistic constructions and their visual referents. AB - In language, abstract phrasal patterns provide an important source of meaning, but little is known about whether or how such constructions are used to predict upcoming visual scenes. Findings from two fMRI studies indicate that initial exposure to a novel construction allows its semantics to be used for such predictions. Specifically, greater activity in the ventral striatum, a region sensitive to prediction errors, was linked to worse overall comprehension of a novel construction. Moreover, activity in occipital cortex was attenuated when a visual event could be inferred from a learned construction, which may reflect predictive coding of the event. These effects disappeared when predictions were unlikely: that is, when phrases provided no additional information about visual events. These findings support the idea that learners create and evaluate predictions about new instances during comprehension of novel linguistic constructions. PMID- 27453898 TI - 5-Hydroxymethylcytosine (5-hmC) Specific Enrichment. AB - 5-Hydroxymethylcytosine (5-hmC) is a newly discovered DNA modification in mammalian genomes. This protocol is to be a highly efficient and selective chemical approach to label and capture 5-hmC, taking advantage of a bacteriophage enzyme that adds a glucose moiety to 5-hmC specifically, which could in turn be used for high-throughput mapping via next-generation sequencing. PMID- 27453899 TI - Isolate and Sub-fractionate Cell Membranes from Caulobacter crescentus. AB - Cell membranes from Caulobacter can be isolated and separated into inner and outer membranes according their characteristic buoyant densities on a sucrose gradient. Fractionation can be used to determine the localisation of uncharacterised proteins and to enrich protein complexes present in either of these membranes for biochemical analysis such blue-native PAGE and immunoprecipitation. PMID- 27453897 TI - The Epigenetic Mechanisms of Amphetamine. AB - Amphetamine (AMPH) is a psychostimulant and the most prescribed drug to treat attention deficit hyperactive disorder (ADHD). Although therapeutically used doses are generally well tolerated, numerous side effects are still known to occur, such as jitteriness, loss of appetite and psychosis. Moreover, AMPH is liable to be abused by users looking for increased alertness, weight loss or athletic performance. A growing body of evidence indicates that drugs of abuse, including AMPH, control gene expression through chromatin modifications. However, while numerous studies have investigated the molecular mechanisms of AMPH action, only a small number of studies have explored changes in gene expression caused by AMPH. This review examines the epigenetic changes induced by chronic and acute treatments with AMPH and includes, where relevant, data obtained with other psychostimulants such as methamphetamine and cocaine. PMID- 27453900 TI - Determination of Toxoplasma gondii Replication in Naive and Activated Macrophages. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite that causes the disease toxoplasmosis. Chronic infection is established through the formation of tissue cysts predominantly in cardiac and neurologic tissues. A defining characteristic of T. gondii is its ability to evade the host's immune defenses; specifically, T. gondii can invade and persist within host phagocytes, using them to disseminate to the brain and central nervous system where cysts are then formed. This protocol is used to evaluate the ability of Toxoplasma gondii to survive and replicate within naive and activated murine bone marrow-derived macrophages at the level of single infected cells. In the following protocol macrophages are naive or activated with IFN-gamma and LPS but different activation stimuli can be utilized as well as different host cell populations and diverse inhibitors. Parasite replication is determined by evaluating the number of parasites per vacuole over time using immunofluorescence staining for parasties and microscopic analysis. Kinetic determination of parasite number per vacuole accurately reflects parasite replication over time as vacuoles-containing parasites do not fuse with one another. Isolation of murine bone marrow-derived macrophages, preparation of conditioned L929 cells for collection of macrophage colony-stimulating factor, and staining for fluorescence microscopy included in the protocol has broad applicability. This protocol works well for pathogens like Toxoplasma gondii that reside in vacuoles that do not fuse with one another and that can be visualized by microscopy. PMID- 27453901 TI - Mouse ESC Differentiation to Nkx2.1+ Lung and Thyroid Progenitors. AB - The de novo derivation of lung progenitors from pluripotent stem cells provides the opportunity to model early lung development in vitro and allows easy access to cells for tissue engineering or basic cell biology studies. This detailed protocol allows the generation of lung and thyroid progenitors from mouse embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC) lines. When used together with a published Nkx2.1-GFP knock-in ESC line, the protocol allows tracking and purification of lung and thyroid progenitors by sorting on the GFP reporter based on the induction of the earliest known marker of lung and thyroid cell fate, Nkx2.1. After sorting, a pure population of Nkx2.1+ cells can then be replated for further expansion, differentiation, and maturation in culture in serum-free conditions. PMID- 27453902 TI - Viral Immunofluorescence with Rift Valley Fever Virus Infected MEFs in a 96 Well Plate. AB - Immunofluorescence is a method to detect viral infection in multiple types of host cells. This procedure can be adapted for both high-throughput and low throughput assays for any virus for which there are antibodies available. Time of infection and virus multiplicity of infection (MOI) vary and should be optimized for each virus and host cell type. Here we give an example of viral immunofluorescence in a 96 well plate with a Rift Valley fever virus (RVFV, strain MP12) infection in mouse embryonic fibroblasts (MEF). PMID- 27453903 TI - Immunoprecipitation of ROR1. AB - ROR1 is a receptor tyrosine kinase family member studied for its roles in development and cancer. Here we describe a protocol for immunoprecipitation of endogenous ROR1 from t(1;19) (a disease subtype categorized by its chromosome translocation) acute lymphoblastic leukemia immortalized cell lines. PMID- 27453904 TI - ROR1 Flow Cytometry. AB - ROR1 is a receptor tyrosine kinase family member studied for its roles in development and cancer. Here we describe a protocol for analysis of ROR1 surface expression in acute lymphoblastic leukemia immortalized cell lines by flow cytometry. PMID- 27453905 TI - Pancreatic Acinar Cell 3-Dimensional Culture. AB - Normal pancreatic acinar cells are difficult to maintain on traditional plastic culture surfaces due to their physical properties of housing large quantities of digestive enzymes and the formation of intercellular tight junctions and gap junctions (Apte and Wilson 2005; Rukstalis et al., 2003). However, placing primary acinar cells within a 3-dimensional matrix (3D-culture) maintains the cells for sufficient time so that they can be monitored for physiological changes to different stimuli. We have used a modified collagen 3D-culture system that has been adapted from Means et al. (2005) to model the very early events associated with pancreatic cancer development. In this model, KrasG12D-expressing pancreatic acinar cells, or wildtype acinar cells treated with EGFR-dependent growth factors (i.e., TGFalpha), convert to ductal cysts that mimic the acinar-to-ductal metaplasia (ADM) stage that precedes formation of Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Ductal Adenocarcinoma (PDAC) (Means et al., 2005; Shi et al., 2013). PMID- 27453906 TI - Longitudinal Bioluminescent Quantification of Three Dimensional Cell Growth. AB - The use of three-dimensional (3D) cell culture systems is widely accepted as representing a more physiologically relevant means to propagate mammary epithelial and breast cancer cells. However, 3D cultures systems are plagued by several experimental and technical limitations as compared to their traditional 2D counterparts. For instance, quantifying the growth of mammary epithelial or breast cancer organoids longitudinally is particularly troublesome using standard [3H]thymidine or MTT assay systems, or using computer-assisted area calculations. Likewise, the nature of the multicellular aggregates and organoids formed by breast cancer cells under 3D conditions precludes efficient recovery of the cells from 3D matrices, an event that is time consuming and leads to spurious results. The assay described here utilizes stable expression of firefly luciferase as means to quantify the longitudinal outgrowth of cells propagated within a 3D matrices. The major advantages of this technique include its high-throughput nature and ability to longitudinally track single wells over a defined period of time, thereby decreasing the costs associated with assay performance. Finally, this technique can be readily combined with drug treatments and/or genetic manipulations to assay their effects on the growth of 3D organoids. PMID- 27453907 TI - Chitinase Assay from Cultured Bone Marrow Derived Macrophages. AB - Chitinases are chitin-degrading enzymes. Chitinases play essential roles in combating chitin-containing pathogens as well as established roles in asthmatic inflammation. This assay is designed to detect chitinase activity in macrophage cell lysates. The chitin substrate is labeled with 4-methylumbelliferone. Hydrolysis of chitin releases 4-methylumbelliferone, and is measured fluorometrically to determine chitinase activity. PMID- 27453908 TI - Hypoxia Studies with Pimonidazole in vivo. AB - Therapy-induced hypoxia drives changes in the tumor microenvironment that contribute to the poor response to therapy. Hypoxia is capable of driving the expression and/or activation of specific signaling cascades (e.g., c-Met, Axl, CTGF), the recruitment of tumor promoting immune cells, and the induction of cell survival pathways including autophagy (Phan et al., 2013; Hu et al., 2012; Ye et al., 2010). We have recently shown that anti-VEGF therapy-induced hypoxia can result in changes in the extracellular matrix that contribute to the aggressiveness of tumors post therapy (Aguilera et al., 2014). Importantly, therapies that induce hypoxia do not always increase epithelial plasticity and tumor aggressiveness (Ostapoff et al., 2013; Cenik et al., 2013). We have used pimonidazole to evaluate hypoxia in tumors and herein provide a detailed protocol for this useful tool to interrogate the levels of hypoxia in vivo. The utility of the HypoxyprobeTM (pimonidazole hydrochloride) immunohistochemical analysis approach allows for the assessment of hypoxia in different tissues as well as cell types. Pimonidazole is a 2-nitroimidazole that is reductively activated specifically in hypoxic cells and forms stable adducts with thiol groups in proteins, peptides, and amino acids (Cenik et al., 2013; Arnold et al., 2010; Raleigh and Koch, 1990; Raleigh et al., 1998). Furthermore, the amount of pimonidazole that is detected is directly proportional to the level of hypoxia within tumors. PMID- 27453909 TI - Microsome Isolation from Tissue. AB - This protocol details the extraction of microsomes from frozen tissue in order to further examine the protein-protein interactions occurring within the endoplasmic reticulum. This protocol was adapted from Abisambra et al. (2013) with modifications made in order to optimize for subsequent use. PMID- 27453910 TI - Extraction and Quantification of Poly P, Poly P Analysis by Urea-PAGE. AB - Inorganic polyphosphate (poly P) molecules, linear chains containing hundreds of orthophosphate (Pi) residues linked by high-energy phosphoanhydride bonds are abundant in every cell in nature. These molecules are widely distributed among bacteria, including key pathogens, and eukaryotes, poly P is present in organelles, including nuclei, mitochondria, and vesicles. PMID- 27453911 TI - RNA-binding Protein Immunoprecipitation (RIP) to Examine AUF1 Binding to Senescence-Associated Secretory Phenotype (SASP) Factor mRNA. AB - Immunoprecipitation and subsequent isolation of nucleic acids allows for the investigation of protein:nucleic acid interactions. RNA-binding protein immunoprecipitation (RIP) is used for the analysis of protein interactions with mRNA. Combining RIP with quantitative real-time PCR (qRT-PCR) further enhances the RIP technique by allowing for the quantitative assessment of RNA-binding protein interactions with their target mRNAs, and how these interactions change in different cellular settings. Here, we describe the immunoprecipitation of the RNA-binding protein AUF1 with several different factors associated with the senescence-associated secretory phenotype (SASP) (Alspach and Stewart, 2013), specifically IL6 and IL8. This protocol was originally published in Alspach et al. (2014). PMID- 27453912 TI - Ex vivo Human Natural Killer (NK) Cell Stimulation and Intracellular IFNgamma and CD107a Cytokine Staining. AB - Natural killer (NK) cells comprise 5-20% of peripheral blood mononuclear cells (PBMC) in humans. In addition to their fundamental roles in the defense against viral infections and tumor surveillance, NK cells help shape adaptive immune responses through their production of cytokines. NK cells are traditionally identified as CD3neg, CD14neg, CD19neg lymphocytes expressing CD56. Using a combination of markers that includes CD56 and CD7 greatly increases the ability to define the phenotype and function of NK cell subsets. Two key markers of NK cell function are the production of IFNgamma and the release of cytotoxic granules measured by the expression of CD107a. Here we describe a method to assess IFNgamma and CD107a expression in NK cells following stimulation with target cells or cytokines. This method can be used to assess the general functional capacity of NK cells in peripheral blood mononuclear cells from a wide range of study participants. PMID- 27453913 TI - Metabolic Assays for Detection of Neutral Fat Stores. AB - Lipid droplets (LDs) are ubiquitous intracellular structures whose formation, growth, and maintenance are highly regulated (Wang et al., 2013; Ranall et al., 2011; Goodman, 2009). Lipid metabolism and droplet dynamics are of considerable interest to agriculture, biofuel production, viral pathology, nutrition, and cancer biology (Walther and Farese, 2009; Liu et al., 2010). Accumulation of fatty acids and neutral lipids in nonadipose tissues is cytotoxic (Kourtidis et al., 2009). BODIPY 493/503 (4,4-Difluoro-1,3,5,7,8-Pentamethyl-4-Bora-3a,4a-Diaza s-Indacene) is the standard dye to study LDs within adipocytes. BODIPY 493/503 contains a nonpolar structure that, upon binding to neutral lipid, emits a green fluorescence signal with a narrow wavelength range, making it an ideal fluorophore for multi-labeling experiments. The hydrophobic nature of the dye molecules promotes rapid entry into the nonpolar environment of LDs (Listenberge and Brown, 2007). Gocze and Freeman showed that the lipid fluorescent variability is significantly lower when using BODIPY493/503 compared to Nile Red, suggesting that it may be more specific for the LD (Gocze and Freeman, 1994). Here, we describe a BODIPY 493/503 assay for the detection of neural fat stores in cultured cells (Figure 1) (Wang et al., 2013). PMID- 27453914 TI - XTT Assay of Antifungal Activity. AB - XTT assay is a colorimetric method that uses the tetrazolium dye, 2,3-bis-(2 methoxy-4-nitro-5-sulphenyl)-(2H)-tetrazolium-5-carboxanilide (XTT) to quantify cell-mediated damage to fungi. Actively respiring fungal cells convert the water soluble XTT to a water-soluble, orange colored formazan product (Meshulam et al., 1995). Here, we describe the protocol that measures the ability of plasmacytoid dendritic cells (pDCs) to exert antifungal activity. This approach was first established with human polymorphonuclear cells (PMN) by Meshulam et al. (1995) and then adapted to pDC by Ramirez-Ortiz et al. (2011) and Loures et al. (2015). It can be modified for use with other effector cells and to test compounds for antifungal activity. PMID- 27453915 TI - Adoptive Transfer of Memory B Cells. AB - The adoptive transfer of antigen-specific B cells into mice that cannot recognize that specific antigen has two main advantages. The first is determining exactly when the B cells were transferred and exposed to antigen. The second is that all B cells that can bind that antigen are the ones that were transferred; no new antigen-specific B cells will emerge from the bone marrow. Thus all B cells that were exposed to the antigen and still alive after at least 4 weeks (8 weeks or more is ideal), are memory B cells. Splenic B cells from B1-8 mice were prepared with an EasySep Mouse B Cell Enrichment Kit according to the manufacturer's protocol. Single-cell suspensions were transferred intravenously into tail veins of recipient mice. Approximately 1 million NP+ B cells were transferred per mouse. Approximately 12-24 h after transfer, mice were immunized intra peritoneally with 50 ug of NP-CGG precipitated in alum. PMID- 27453916 TI - Capturing the Driving Role of Tumor-Host Crosstalk in a Dynamical Model of Tumor Growth. AB - In 1999, Hahnfeldt et al. proposed a mathematical model for tumor growth as dictated by reciprocal communications between tumor and its associated vasculature, introducing the idea that a tumor is supported by a dynamic, rather than a static, carrying capacity. In this original paper, the carrying capacity was equated with the variable tumor vascular support resulting from the net effect of tumor-derived angiogenesis stimulators and inhibitors. This dynamic carrying capacity model was further abstracted and developed in our recent publication to depict the more general situation where there is an interaction between the tumor and its supportive host tissue; in that case, as a function of host aging (Benzekry et al., 2014). This allowed us to predict a range of host changes that may be occurring with age that impact tumor dynamics. More generally, the basic formalism described here can be (and has been), extended to the therapeutic context using additional optimization criteria (Hahnfeldt et al., 1999). The model depends on three parameters: One for the tumor cell proliferation kinetics, one for the stimulation of the stromal support, and one for its inhibition, as well as two initial conditions. We describe here the numerical method to estimate these parameters from longitudinal tumor volume measurements. PMID- 27453917 TI - Thirty-Second Net Stressor Task in Adult Zebrafish. AB - Zebrafish have become a popular animal model for behavioral neuroscience (Gerlai, 2014). Recent studies have demonstrated that brief experimental handling prior to euthanizing animals can subsequently alter biological measures quantified post mortem (e.g. cortisol levels) (Ramsay et al., 2009; Tran et al., 2014). Here we provide a detailed protocol for a simple 30-sec net stressor task for adult zebrafish that increases whole-body cortisol levels without altering the levels of whole-brain dopamine, 3, 4-dihydroxyphenylacetic acid, serotonin, and 5 hydroxyindoleacetic acid (Tran et al., 2014). PMID- 27453918 TI - A Brief Report on the Development of The Usability of Sleep Apnea Equipment-Oral Appliance (USE-OA) Questionnaire: A Pilot Study. AB - STUDY OBJECTIVES: To develop a questionnaire for measuring human factors (usability) associated with oral appliance use and to assess the feasibility of administering the questionnaire to patients with obstructive sleep apnea in a clinic setting. METHODS: We developed the 11-item Usability of Sleep Apnea Equipment-Oral Appliance (USE-OA) Questionnaire by adapting items from a published questionnaire that had been developed to assess human factors associated with positive airway pressure device use. Then we distributed the USE OA to patients at a university dental clinic between January and July 2014. We evaluated our survey methods qualitatively, calculated the response rate, and assessed completeness and response patterns of the USE-OA. RESULTS: Our formative evaluation revealed that the questionnaire was easy to distribute and administer in a clinic setting. Our response rate was 23%. A majority of respondents gave favorable usability ratings, and a small number of respondents gave unfavorable usability ratings. CONCLUSIONS: The USE-OA questionnaire can be easily administered in a dental clinic setting. Additional studies conducted in high volume sleep oral appliance clinics are needed to assess the psychometric properties of the USE-OA and to compare the results of the USE-OA to direct observation of patients getting their oral appliance ready for use and cleaning their oral appliance. PMID- 27453919 TI - High-throughput evaluation of synthetic metabolic pathways. AB - A central challenge in the field of metabolic engineering is the efficient identification of a metabolic pathway genotype that maximizes specific productivity over a robust range of process conditions. Here we review current methods for optimizing specific productivity of metabolic pathways in living cells. New tools for library generation, computational analysis of pathway sequence-flux space, and high-throughput screening and selection techniques are discussed. PMID- 27453920 TI - Intergroup Biases: A Focus on Stereotype Content. AB - Impressions of others, including societal groups, systematically array along two dimensions, warmth (trustworthiness/friendliness) and competence. Social structures of competition and status respectively predict these usually orthogonal dimensions. Prejudiced emotions (pride, pity, contempt, and envy) target each quadrant, and distinct discriminatory behavioral tendencies result. The Stereotype Content Model (SCM) patterns generalize across time (2oth century), culture (every populated continent), level of analysis (targets from individuals to subtypes to groups to nations), and measures (from neural to self report to societal indicators). Future directions include individual differences in endorsement of these cultural stereotypes and how perceivers view combinations across the SCM space. PMID- 27453921 TI - Brain estrogen production and the encoding of recent experience. AB - The vertebrate central nervous system integrates cognition and behavior, and it also acts as both a source and target for steroid hormones like estrogens. Recent exploration of brain estrogen production in the context of learning and memory has revealed several common themes. First, across vertebrates, the enzyme that synthesizes estrogens is expressed in brain regions that are characterized by elevated neural plasticity and is also integral to the acquisition, consolidation, and retrieval of recent experiences. Second, measurement and manipulation of estrogens reveal that the period following recent sensory experience is linked to estrogenic signaling in brain circuits underlying both spatial and vocal learning. Local brain estrogen production within cognitive circuits may therefore be important for the acquisition and/or consolidation of memories, and new directions testing these ideas will be discussed. PMID- 27453922 TI - Loss of Iroquois homeobox transcription factors 3 and 5 in osteoblasts disrupts cranial mineralization. AB - Cranial malformations are a significant cause of perinatal morbidity and mortality. Iroquois homeobox transcription factors (IRX) are expressed early in bone tissue formation and facilitate patterning and mineralization of the skeleton. Mice lacking Irx5 appear grossly normal, suggesting that redundancy within the Iroquois family. However, global loss of both Irx3 and Irx5 in mice leads to significant skeletal malformations and embryonic lethality from cardiac defects. Here, we study the bone-specific functions of Irx3 and Irx5 using Osx Cre to drive osteoblast lineage-specific deletion of Irx3 in Irx5(-/-) mice. Although we found that the Osx-Cre transgene alone could also affect craniofacial mineralization, newborn Irx3 (flox/flox) /Irx5(-/-)/Osx-Cre (+) mice displayed additional mineralization defects in parietal, interparietal, and frontal bones with enlarged sutures and reduced calvarial expression of osteogenic genes. Newborn endochondral long bones were largely unaffected, but we observed marked reductions in 3-4-week old bone mineral content of Irx3 (flox/flox) /Irx5(-/ )/Osx-Cre (+) mice. Our findings indicate that IRX3 and IRX5 can work together to regulate mineralization of specific cranial bones. Our results also provide insight into the causes of the skeletal changes and mineralization defects seen in Hamamy syndrome patients carrying mutations in IRX5. PMID- 27453923 TI - Status, Power, and Intergroup Relations: The Personal Is the Societal. AB - Hierarchies in the correlated forms of power (resources) and status (prestige) are constants that organize human societies. This article reviews relevant social psychological literature and identifies several converging results concerning power and status. Whether rank is chronically possessed or temporarily embodied, higher ranks create psychological distance from others, allow agency by the higher ranked, and exact deference from the lower ranked. Beliefs that status entails competence are essentially universal. Interpersonal interactions create warmth-competence compensatory tradeoffs. Along with societal structures (enduring inequality), these tradeoffs reinforce status-competence beliefs. Race, class, and gender further illustrate these dynamics. Although status systems are resilient, they can shift, and understanding those change processes is an important direction for future research, as global demographic changes disrupt existing hierarchies. PMID- 27453924 TI - Data on the circulating levels of endothelial microparticles are elevated in patients with bicuspid aortic valve and are related to aortic dilation. AB - The data included here support the research article "Circulating endothelial microparticles are elevated in bicuspid aortic valve (BAV) disease and related to aortic dilation" (Alegret et al., 2016 [1]) where circulating levels of platelet endothelial cell adhesion molecule (PECAM(+)) endothelial microparticles (EMPs) were identified as a biological variable related to aortic dilation in patients with BAV disease. The data presented in this article are composed by four tables and one figure containing the clinical and echocardiographic characteristics of the patients (Alegret et al., 2016 [1]) included in this study, and summarize the results of multivariate linear analyses. Furthermore, is also included a figure showing a representative flow cytometry dot plots and histograms used in PECAM(+) EMPs quantification is also included. PMID- 27453925 TI - Data on the characterization and anticancer action of iron(II) polypyridyl complexes. AB - This data article contains complementary figures and results related to the research article entitled, "Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms" [1] (Chen et al., 2015). The characterization of Fe(II) complexes by ESI-MS, (1)H NMR, (13)C NMR spectroscopy, FT-IR spectra, UV-vis spectra was provided. Also,the data for the stability of Fe(II) complexes 1-5 in DMSO/Milli-Q water/ culture medium (without serum or phenol red) at 37 degrees C at different periods of time by UV-vis spectra and (1)H NMR was showed. At the same time, the anticancer efficacy, cellular distribution and ROS generation in MCF-7 cells of complexes are reported. In addition, we also show the cellular localization of complex 4, the relative fluorescence intensity of complex 1 and complex 3 pretreated with anti TfR (2 MUg/mL) in MCF-7 cells using flow cytometry. The compilation of this data provides an invaluable resource for the wider research community and the interpretation of these data could be found in the research article noted above. PMID- 27453926 TI - Performance of sentinel lymph node biopsy in high-risk endometrial cancer. AB - OBJECTIVE: To determine the rate and performance of sentinel lymph node (SLN) mapping among women with high-risk endometrial cancers. METHODS: Patients diagnosed between 2012 and 2015 with uterine cancer of grade 3 endometrioid, clear cell, serous or carcinosarcoma histology and who underwent SLN mapping prior to full pelvic lymph node dissection were included. Subjects underwent methylene blue or ICG injection for laparoscopic (N = 16) or robotic-assisted laparoscopic (N = 20) staging. Outcomes included SLN mapping rates, SLN and non SLN positive rates, false negative SLN algorithm rate, and the negative predictive value (NPV) of the SLN algorithm. Fisher's exact test was used to compare mapping and node positivity rates. RESULTS: 9/36 (25%) patients with high risk uterine cancer had at least one metastatic lymph node identified. Successful mapping occurred in 30/36 (83%) patients. SLN mapped to pelvic nodes bilaterally in 20 (56%), unilaterally in 9 (25%), and aortic nodes only in 1 (3%). Malignancy was identified in 14/95 (15%) of all sentinel nodes and 12/775 (1.5%) of all non sentinel nodes (p < 0.001). The false negative rate of SLN mapping alone was 2/26 (7.7%); the NPV was 92.3%. When the SLN algorithm was applied retrospectively the false negative rate was 0/31 (0%); the NPV was 100%. CONCLUSION: SLN mapping rates for high-risk cancers are slightly lower than in prior reports of lower risk cancers. The NPV of the SLN mapping alone is 92% and rises to 100% when the SLN algorithm is applied. Such results are acceptable and consistent with larger subsets of lower risk endometrial cancers. PMID- 27453927 TI - Nonbacterial thrombotic endocarditis: A rare manifestation of gynecologic cancer. AB - *Nonbacterial thrombotic endocarditis (NBTE) is a rare complication of cancer.*NBTE may precede the diagnosis of an occult gynecologic malignancy.*Malignancy-induced NBTE must be considered in patients with unprovoked venous thromboembolism.*The most effective treatment is anticoagulation and treatment of the underlying cancer. PMID- 27453928 TI - Reproductive justice & preventable deaths: state funding, family planning, abortion, and infant mortality, US 1980-2010. AB - INTRODUCTION: Little current research examines associations between infant mortality and US states' funding for family planning services and for abortion, despite growing efforts to restrict reproductive rights and services and documented associations between unintended pregnancy and infant mortality. MATERIAL AND METHODS: We obtained publicly available data on state-only public funding for family planning and abortion services (years available: 1980, 1987, 1994, 2001, 2006, and 2010) and corresponding annual data on US county infant death rates. We modeled the funding as both fraction of state expenditures and per capita spending (per woman, age 15-44). State-level covariates comprised: Title X and Medicaid per capita funding, fertility rate, and percent of counties with no abortion services; county-level covariates were: median family income, and percent: black infants, adults without a high school education, urban, and female labor force participation. We used Possion log-linear models for: (1) repeat cross-sectional analyses, with random state and county effects; and (2) panel analysis, with fixed state effects. RESULTS: Four findings were robust to analytic approach. First, since 2000, the rate ratio for infant death comparing states in the top funding quartile vs. no funding for abortion services ranged (in models including all covariates) between 0.94 to 0.98 (95% confidence intervals excluding 1, except for the 2001 cross-sectional analysis, whose upper bound equaled 1), yielding an average 15% reduction in risk (range: 8 to 22%). Second, a similar risk reduction for state per capita funding for family planning services occurred in 1994. Third, the excess risk associated with lower county income increased over time, and fourth, remained persistently high for counties with a high percent of black infants. CONCLUSIONS: Insofar as reducing infant mortality is a government priority, our data underscore the need, despite heightened contention, for adequate public funding for abortion services and for redressing health inequities. PMID- 27453929 TI - A blood screening test for Alzheimer's disease. AB - INTRODUCTION: This study combined data across four independent cohorts to examine the positive and negative predictive values of an Alzheimer's disease (AD) blood test if implemented in primary care. METHODS: Blood samples from 1329 subjects from multiple independent, multiethnic, community-based, and clinic-based cohorts were analyzed. A "locked-down" referent group of 1128 samples was generated with 201 samples randomly selected for validation purposes. Random forest analyses were used to create the AD blood screen. Positive (PPV) and negative (NPV) predictive values were calculated. RESULTS: In detecting AD, PPV was 0.81, and NPV was 0.95 while using the full AD blood test. When detecting mild cognitive impairment, PPV and NPV were 0.74 and 0.93, respectively. Preliminary analyses were conducted to detect any "neurodegenerative disease". The full 21-protein AD blood test yielded a PPV of 0.85 and NPV of 0.94. DISCUSSION: The present study creates the first-ever multiethnic referent sample that spans community-based and clinic-based populations for implementation of an AD blood screen. PMID- 27453930 TI - MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes. AB - INTRODUCTION: MCP-1 and eotaxin-1 are encoded on chromosome 17 and have been shown to reduce hippocampal neurogenesis in mice. We investigated whether these chemokines selectively associate with memory in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. METHODS: MCP-1 and eotaxin-1 were assayed in controls, MCI, and AD dementia patients with varying phenotypes (n = 171). A subset of 55 individuals had magnetic resonance imaging (MRI) scans available. Composite scores for cognitive variables were created, and medial temporal lobe volumes were obtained. RESULTS: An interaction was noted between MCP-1 and eotaxin-1, such that deleterious associations with memory were seen when both chemokines were elevated. These associations remained significant after adding APOE genotype and comparison (non-chromosome 17) chemokines into the model. These chemokines predicted left medial temporal lobe volume and were not related to other cognitive domains. DISCUSSION: These results suggest a potentially selective role for MCP-1 and eotaxin-1 in memory dysfunction in the context of varied MCI and AD dementia phenotypes. PMID- 27453931 TI - Update on ultrasensitive technologies to facilitate research on blood biomarkers for central nervous system disorders. AB - Most research on fluid biomarkers for central nervous system (CNS) disorders has so far been performed using cerebrospinal fluid (CSF) as the biomarker source. CSF has the advantage of being closer to the brain than serum or plasma with a relative enrichment of CNS-specific proteins that are present at very low concentrations in the blood and thus difficult to reliably quantify using standard immunochemical technologies. Recent technical breakthroughs in the field of ultrasensitive assays have started to change this. Here, we review the most established ultrasensitive quantitative technologies that are currently available to general biomarker laboratories and discuss their use in research on biomarkers for CNS disorders. PMID- 27453932 TI - Plasma clusterin levels and risk of dementia, Alzheimer's disease, and stroke. AB - INTRODUCTION: Genetic variation in the clusterin gene has been associated with Alzheimer Disease (AD), and the clusterin protein is thought to play a mechanistic role. We explored the associations of clusterin plasma levels with incident dementia, AD, and stroke. METHODS: Plasma clusterin was assessed in 1532 nondemented participants from the Framingham Study Offspring cohort between 1998 and 2001 (mean age, 69 +/- 6; 53% women). We related clusterin levels to risk of incident dementia, AD, and stroke using Cox-proportional hazards models and examined potential interactions. RESULTS: A significant interaction of plasma clusterin levels with age was observed. Clusterin was significantly associated with increased risk of dementia among elderly persons (>80 years; hazard ratio [HR], 95% confidence interval = 6.25, 1.64-23.89; P = .007) and with decreased risk of dementia (HR = 0.53, 0.32-0.88; P = .013) and stroke (HR = 0.78, 0.63 0.97; P = .029) among younger participants. DISCUSSION: The association between plasma clusterin levels and risk of dementia and stroke may be modified by age or an age-related factor. PMID- 27453933 TI - Introduction to special issue on Advances in blood-based biomarkers of Alzheimer's disease. PMID- 27453934 TI - Influence of Demographic and Health Survey Point Displacements on Point-in Polygon Analyses. AB - We use Demographic and Health Survey (DHS) data to evaluate the impact of random spatial displacements on analyses that involve assigning covariate values from ancillary areal and point feature data. We introduce a method to determine the maximum probability covariate (MPC), and compare this to the naive covariate (NC) selection method with respect to obtaining the true covariate of interest. The MPC selection method outperforms the NC selection method by increasing the probability that the correct covariate is chosen. Proposed guidelines also address how characteristics of ancillary areal and point features contribute to uncertainty in covariate assignment. PMID- 27453935 TI - Influence of Demographic and Health Survey Point Displacements on Distance-Based Analyses. AB - We evaluate the impacts of random spatial displacements on analyses that involve distance measures from displaced Demographic and Health Survey (DHS) clusters to nearest ancillary point or line features, such as health resources or roads. We use simulation and case studies to address the effects of this introduced error, and propose use of regression calibration (RC) to reduce its impact. Results suggest that RC outperforms analyses involving naive distance-based covariate assignments by reducing the bias and MSE of the main estimator in most settings. Proposed guidelines also address the effect of the spatial density of destination features on observed bias. PMID- 27453936 TI - Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Genetic Engineering: Robotic Genetic Surgery. AB - As a novel technology that utilizes the endogenous immune defense system in bacteria, CRISPR/Cas9 has transcended DNA engineering into a more pragmatic and clinically efficacious field. Using programmable sgRNA sequences and nucleases, the system effectively introduces double strand breaks in target genes within an entire organism. The applications of CRISPR range from biomedicine to drug development and epigenetic modification. Studies have demonstrated CRISPR mediated targeting of various tumorigenic genes and effector proteins known to be involved in colon carcinomas. This technology significantly expands the scope of gene manipulation and allows for an enhanced modeling of colon cancers, as well as various other malignancies. PMID- 27453937 TI - Why marine phytoplankton calcify. AB - Calcifying marine phytoplankton-coccolithophores- are some of the most successful yet enigmatic organisms in the ocean and are at risk from global change. To better understand how they will be affected, we need to know "why" coccolithophores calcify. We review coccolithophorid evolutionary history and cell biology as well as insights from recent experiments to provide a critical assessment of the costs and benefits of calcification. We conclude that calcification has high energy demands and that coccolithophores might have calcified initially to reduce grazing pressure but that additional benefits such as protection from photodamage and viral/bacterial attack further explain their high diversity and broad spectrum ecology. The cost-benefit aspect of these traits is illustrated by novel ecosystem modeling, although conclusive observations remain limited. In the future ocean, the trade-off between changing ecological and physiological costs of calcification and their benefits will ultimately decide how this important group is affected by ocean acidification and global warming. PMID- 27453938 TI - Hierarchical MoS2 tubular structures internally wired by carbon nanotubes as a highly stable anode material for lithium-ion batteries. AB - Molybdenum disulfide (MoS2), a typical two-dimensional material, is a promising anode material for lithium-ion batteries because it has three times the theoretical capacity of graphite. The main challenges associated with MoS2 anodes are the structural degradation and the low rate capability caused by the low intrinsic electric conductivity and large strain upon cycling. Here, we design hierarchical MoS2 tubular structures internally wired by carbon nanotubes (CNTs) to tackle these problems. These porous MoS2 tubular structures are constructed from building blocks of ultrathin nanosheets, which are believed to benefit the electrochemical reactions. Benefiting from the unique structural and compositional characteristics, these CNT-wired MoS2 tubular structures deliver a very high specific capacity of ~1320 mAh g(-1) at a current density of 0.1 A g( 1), exceptional rate capability, and an ultralong cycle life of up to 1000 cycles. This work may inspire new ideas for constructing high-performance electrodes for electrochemical energy storage. PMID- 27453939 TI - 3D meshes of carbon nanotubes guide functional reconnection of segregated spinal explants. AB - In modern neuroscience, significant progress in developing structural scaffolds integrated with the brain is provided by the increasing use of nanomaterials. We show that a multiwalled carbon nanotube self-standing framework, consisting of a three-dimensional (3D) mesh of interconnected, conductive, pure carbon nanotubes, can guide the formation of neural webs in vitro where the spontaneous regrowth of neurite bundles is molded into a dense random net. This morphology of the fiber regrowth shaped by the 3D structure supports the successful reconnection of segregated spinal cord segments. We further observed in vivo the adaptability of these 3D devices in a healthy physiological environment. Our study shows that 3D artificial scaffolds may drive local rewiring in vitro and hold great potential for the development of future in vivo interfaces. PMID- 27453940 TI - Acoustic tweezers via sub-time-of-flight regime surface acoustic waves. AB - Micrometer-scale acoustic waves are highly useful for refined optomechanical and acoustofluidic manipulation, where these fields are spatially localized along the transducer aperture but not along the acoustic propagation direction. In the case of acoustic tweezers, such a conventional acoustic standing wave results in particle and cell patterning across the entire width of a microfluidic channel, preventing selective trapping. We demonstrate the use of nanosecond-scale pulsed surface acoustic waves (SAWs) with a pulse period that is less than the time of flight between opposing transducers to generate localized time-averaged patterning regions while using conventional electrode structures. These nodal positions can be readily and arbitrarily positioned in two dimensions and within the patterning region itself through the imposition of pulse delays, frequency modulation, and phase shifts. This straightforward concept adds new spatial dimensions to which acoustic fields can be localized in SAW applications in a manner analogous to optical tweezers, including spatially selective acoustic tweezers and optical waveguides. PMID- 27453941 TI - Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment. AB - The lack of a robust anticancer drug screening system to monitor patients during treatment delays realization of personalized treatment. We demonstrate an efficient approach to evaluate drug response using patient-derived circulating tumor cell (CTC) cultures obtained from liquid biopsy. Custom microfabricated tapered microwells were integrated with microfluidics to allow robust formation of CTC clusters without pre-enrichment and subsequent drug screening in situ. Rapid feedback after 2 weeks promotes immediate intervention upon detection of drug resistance or tolerance. The procedure was clinically validated with blood samples (n = 73) from 55 patients with early-stage, newly diagnosed, locally advanced, or refractory metastatic breast cancer. Twenty-four of these samples were used for drug evaluation. Cluster formation potential correlated inversely with increased drug concentration and therapeutic treatment. This new and robust liquid biopsy technique can potentially evaluate patient prognosis with CTC clusters during treatment and provide a noninvasive and inexpensive assessment that can guide drug discovery development or therapeutic choices for personalized treatment. PMID- 27453943 TI - Stabilizing electrodeposition in elastic solid electrolytes containing immobilized anions. AB - Ion transport-driven instabilities in electrodeposition of metals that lead to morphological instabilities and dendrites are receiving renewed attention because mitigation strategies are needed for improving rechargeability and safety of lithium batteries. The growth rate of these morphological instabilities can be slowed by immobilizing a fraction of anions within the electrolyte to reduce the electric field at the metal electrode. We analyze the role of elastic deformation of the solid electrolyte with immobilized anions and present theory combining the roles of separator elasticity and modified transport to evaluate the factors affecting the stability of planar deposition over a wide range of current densities. We find that stable electrodeposition can be easily achieved even at relatively high current densities in electrolytes/separators with moderate polymer-like mechanical moduli, provided a small fraction of anions are immobilized in the separator. PMID- 27453942 TI - High hardness in the biocompatible intermetallic compound beta-Ti3Au. AB - The search for new hard materials is often challenging, but strongly motivated by the vast application potential such materials hold. Ti3Au exhibits high hardness values (about four times those of pure Ti and most steel alloys), reduced coefficient of friction and wear rates, and biocompatibility, all of which are optimal traits for orthopedic, dental, and prosthetic applications. In addition, the ability of this compound to adhere to ceramic parts can reduce both the weight and the cost of medical components. The fourfold increase in the hardness of Ti3Au compared to other Ti-Au alloys and compounds can be attributed to the elevated valence electron density, the reduced bond length, and the pseudogap formation. Understanding the origin of hardness in this intermetallic compound provides an avenue toward designing superior biocompatible, hard materials. PMID- 27453944 TI - Terapascal static pressure generation with ultrahigh yield strength nanodiamond. AB - Studies of materials' properties at high and ultrahigh pressures lead to discoveries of unique physical and chemical phenomena and a deeper understanding of matter. In high-pressure research, an achievable static pressure limit is imposed by the strength of available strong materials and design of high-pressure devices. Using a high-pressure and high-temperature technique, we synthesized optically transparent microballs of bulk nanocrystalline diamond, which were found to have an exceptional yield strength (~460 GPa at a confining pressure of ~70 GPa) due to the unique microstructure of bulk nanocrystalline diamond. We used the nanodiamond balls in a double-stage diamond anvil cell high-pressure device that allowed us to generate static pressures beyond 1 TPa, as demonstrated by synchrotron x-ray diffraction. Outstanding mechanical properties (strain dependent elasticity, very high hardness, and unprecedented yield strength) make the nanodiamond balls a unique device for ultrahigh static pressure generation. Structurally isotropic, homogeneous, and made of a low-Z material, they are promising in the field of x-ray optical applications. PMID- 27453945 TI - Stability of Fe,Al-bearing bridgmanite in the lower mantle and synthesis of pure Fe-bridgmanite. AB - The physical and chemical properties of Earth's mantle, as well as its dynamics and evolution, heavily depend on the phase composition of the region. On the basis of experiments in laser-heated diamond anvil cells, we demonstrate that Fe,Al-bearing bridgmanite (magnesium silicate perovskite) is stable to pressures over 120 GPa and temperatures above 3000 K. Ferric iron stabilizes Fe-rich bridgmanite such that we were able to synthesize pure iron bridgmanite at pressures between ~45 and 110 GPa. The compressibility of ferric iron-bearing bridgmanite is significantly different from any known bridgmanite, which has direct implications for the interpretation of seismic tomography data. PMID- 27453946 TI - Heterogeneity of cellular circadian clocks in intact plants and its correction under light-dark cycles. AB - Recent advances in single-cell analysis have revealed the stochasticity and nongenetic heterogeneity inherent to cellular processes. However, our knowledge of the actual cellular behaviors in a living multicellular organism is still limited. By using a single-cell bioluminescence imaging technique on duckweed, Lemna gibba, we demonstrate that, under constant conditions, cells in the intact plant work as individual circadian clocks that oscillate with their own frequencies and respond independently to external stimuli. Quantitative analysis uncovered the heterogeneity and instability of cellular clocks and partial synchronization between neighboring cells. Furthermore, we found that cellular clocks in the plant body under light-dark cycles showed a centrifugal phase pattern in which the effect of cell-to-cell heterogeneity in period lengths was almost masked. The inherent heterogeneity in the properties of cellular clocks observed under constant conditions is corrected under light-dark cycles to coordinate the daily rhythms of the plant body. These findings provide a novel perspective of spatiotemporal architectures in the plant circadian system. PMID- 27453947 TI - A low upper limit on the subsurface rise speed of solar active regions. AB - Magnetic field emerges at the surface of the Sun as sunspots and active regions. This process generates a poloidal magnetic field from a rising toroidal flux tube; it is a crucial but poorly understood aspect of the solar dynamo. The emergence of magnetic field is also important because it is a key driver of solar activity. We show that measurements of horizontal flows at the solar surface around emerging active regions, in combination with numerical simulations of solar magnetoconvection, can constrain the subsurface rise speed of emerging magnetic flux. The observed flows imply that the rise speed of the magnetic field is no larger than 150 m/s at a depth of 20 Mm, that is, well below the prediction of the (standard) thin flux tube model but in the range expected for convective velocities at this depth. We conclude that convective flows control the dynamics of rising flux tubes in the upper layers of the Sun and cannot be neglected in models of flux emergence. PMID- 27453948 TI - Protein engineering by highly parallel screening of computationally designed variants. AB - Current combinatorial selection strategies for protein engineering have been successful at generating binders against a range of targets; however, the combinatorial nature of the libraries and their vast undersampling of sequence space inherently limit these methods due to the difficulty in finely controlling protein properties of the engineered region. Meanwhile, great advances in computational protein design that can address these issues have largely been underutilized. We describe an integrated approach that computationally designs thousands of individual protein binders for high-throughput synthesis and selection to engineer high-affinity binders. We show that a computationally designed library enriches for tight-binding variants by many orders of magnitude as compared to conventional randomization strategies. We thus demonstrate the feasibility of our approach in a proof-of-concept study and successfully obtain low-nanomolar binders using in vitro and in vivo selection systems. PMID- 27453949 TI - The O2-assisted Al/CO2 electrochemical cell: A system for CO2 capture/conversion and electric power generation. AB - Economical and efficient carbon capture, utilization, and sequestration technologies are a requirement for successful implementation of global action plans to reduce carbon emissions and to mitigate climate change. These technologies are also essential for longer-term use of fossil fuels while reducing the associated carbon footprint. We demonstrate an O2-assisted Al/CO2 electrochemical cell as a new approach to sequester CO2 emissions and, at the same time, to generate substantial amounts of electrical energy. We report on the fundamental principles that guide operations of these cells using multiple intrusive electrochemical and physical analytical methods, including chronopotentiometry, cyclic voltammetry, direct analysis in real-time mass spectrometry, energy-dispersive x-ray spectroscopy, x-ray photoelectron spectroscopy, and coupled thermogravimetric analysis-Fourier transform infrared spectroscopy. On this basis, we demonstrate that an electrochemical cell that uses metallic aluminum as anode and a carbon dioxide/oxygen gas mixture as the active material in the cathode provides a path toward electrochemical generation of a valuable (C2) species and electrical energy. Specifically, we show that the cell first reduces O2 at the cathode to form superoxide intermediates. Chemical reaction of the superoxide with CO2 sequesters the CO2 in the form of aluminum oxalate, Al2(C2O4)3, as the dominant product. On the basis of an analysis of the overall CO2 footprint, which considers emissions associated with the production of the aluminum anode and the CO2 captured/abated by the Al/CO2-O2 electrochemical cell, we conclude that the proposed process offers an important strategy for net reduction of CO2 emissions. PMID- 27453950 TI - PD-1 blockade enhances the vaccination-induced immune response in glioma. AB - DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD 1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor- bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy. PMID- 27453951 TI - An extra copy of p53 suppresses development of spontaneous Kras-driven but not radiation-induced cancer. AB - The tumor suppressor p53 blocks tumor progression in multiple tumor types. Radiation-induced cancer following exposure to radiation therapy or space travel may also be regulated by p53 because p53 has been proposed to respond to DNA damage to suppress tumorigenesis. Here, we investigate the role of p53 in lung carcinogenesis and lymphomagenesis in LA-1 KrasG12D mice with wild-type p53 or an extra copy of p53 (super p53) exposed to fractionated total body irradiation with low linear energy transfer (low-LET) X-rays or high-LET iron ions and compared tumor formation in these mice with unirradiated controls. We found that an additional copy of p53 suppressed both Kras-driven lung tumor and lymphoma development in the absence of radiation. However, an additional copy of p53 did not affect lymphoma development following low- or high-LET radiation exposure and was unable to suppress radiation-induced expansion of thymocytes with mutated Kras. Moreover, radiation exposure increased lung tumor size in super p53 but not wild-type p53 mice. These results demonstrate that although p53 suppresses the development of spontaneous tumors expressing KrasG12D, in the context of exposure to ionizing radiation, an extra copy of p53 does not protect against radiation induced lymphoma and may promote KrasG12D mutant lung cancer. PMID- 27453952 TI - Diffusion Imaging of White Matter In Schizophrenia: Progress and Future Directions. AB - Diffusion tensor imaging (DTI) is a powerful tool for the in-vivo assessment of white matter microstructure. The application of DTI methodologies to the study of schizophrenia has supported and advanced the hypothesis of schizophrenia as a disorder of disrupted connectivity. In the context of impaired structural connectivity, the extended time frame of white matter development may offer unique opportunities for treatment that can capitalize on the neural flexibility that is still present in the period leading up to and after disease onset. Therefore, it is important to gain a clear understanding of white matter deficits and how they may emerge and change across the illness. However, while there is broad consistency in the findings of white matter deficits in patients with schizophrenia, there is also a great deal of variability in specific findings across studies. In this review, the aim is to move beyond summarizing case control analyses, to consider the many factors that may impact DTI measures, to explain variability of findings, and to explore future directions for the field. The topics explored include ways to parse DTI patterns associated with different disease subtypes, ways in which novel and established treatments might interact with or enhance white matter, ways of dissociating developmental change from the disease process itself, and understanding the role of emerging analytic methodologies. PMID- 27453953 TI - Elucidating neural network functional connectivity abnormalities in bipolar disorder: toward a harmonized methodological approach. AB - Bipolar disorder (BD), a mood disorder characterized by emotional lability and dysregulation, is associated with alterations in functional connectivity, particularly as assessed using functional MRI. Here, we provide an overview of the extant literature, and themes that have emerged within it. We identified published research describing functional connectivity in BD using PubMed and follow-up searches. The most consistent evidence favors abnormally heightened functional connectivity between the amygdala and the lateral regions of the ventral prefrontal cortex (PFC), both during rest or emotional processing. Altered interactions between the amygdala and more medial PFC regions have been implicated in BD, but are less consistently related to core symptoms and are sometimes associated with mood state or psychosis. Interactions between medial and lateral ventral PFC have also been reported to be altered in BD, and may mediate estimates of amygdala/vlPFC connectivity. We also describe other themes, including an emerging literature examining reward circuitry, which has highlighted abnormal functional interactions between the ventral striatum and medial prefrontal cortex, as well as the advent of examining global network abnormalities in BD. Functional connectivity studies in BD have established altered interactions between PFC and the amygdala. To address the inconsistencies in the literature, we suggest avenues for the adoption of large scale, and network-based analysis of connectivity, the integration of structural connectivity and the acknowledgement of dynamic and context-related shifts in functional connectivity as a means of clarifying the abnormal neural circuitry in the disorder. PMID- 27453954 TI - A prospective study of quality of life in breast cancer patients undergoing radiation therapy. AB - PURPOSE/OBJECTIVE: The purpose of this study was to examine the impact of radiotherapy on quality of life (QOL) of breast cancer patients during and until 1 year post radiotherapy treatment. METHODS AND MATERIALS: Thirty-nine breast cancer patients treated with breast conserving surgery were enrolled in a prospective study prior to whole breast radiotherapy (50 Gy plus a 10 Gy boost). No patient received chemotherapy. Data were collected before, at week 6 of radiotherapy, 6 weeks, and 1 year post-radiotherapy. The primary outcome variable was quality of life (QOL), measured by Medical Outcomes Study 36-Item Short Form Version 2 (SF-36) (SF-36). Risk factors potentially associated with total SF-36 scores and its physical and mental health component summary scores were also examined including age, race, marital status, smoking history, menopausal status, endocrine treatment, cancer stage, sleep abnormalities (assessed by the Pittsburgh Sleep Quality Index) and perceived stress levels (assessed by Perceived Stress Scale). Mixed effect modeling was utilized to observe QOL changes during and after radiotherapy. RESULTS: Total SF-36 scores did not change significantly during and up to 1 year after radiotherapy compared to baseline measures. Nevertheless, increased BMI and increased perceived stress were predictive of reduced total SF-36 scores over time (p=0.0064, and p<0.0001, respectively). In addition, increased BMI was predictive of reduced physical component summary scores of the SF-36 (p=0.0011), while increased perceived stress was predictive of worse mental component summary scores (p<0.0001). Other proposed potential risk factors including skin toxicity from radiotherapy were not significant. CONCLUSIONS: Radiotherapy did not worsen QOL in breast cancer patients. However, pre-radiotherapy patient characteristics including BMI and perceived stress may be used to identify women who may experience decreased physical and mental function during and up to 1 year post-radiotherapy. PMID- 27453955 TI - A Myocardial Slice Culture Model Reveals Alpha-1A-Adrenergic Receptor Signaling in the Human Heart. AB - BACKGROUND: Translation of preclinical findings could benefit from a simple, reproducible, high throughput human model to study myocardial signaling. Alpha-1A adrenergic receptors (ARs) are expressed at very low levels in the human heart, and it is unknown if they function. OBJECTIVES: To develop a high throughput human myocardial slice culture model, and to test the hypothesis that alpha-1A- ARs are functional in the human heart. METHODS: Cores of LV free wall 8 mm diameter were taken from 52 hearts (18 failing and 34 nonfailing). Slices 250 MUm thick were cut with a Krumdieck apparatus and cultured using a rotating incubation unit. RESULTS: About 60 slices were cut from each LV core, and a typical study could use 96 slices. Myocyte morphology was maintained, and diffusion into the slice center was rapid. Slice viability was stable for at least 3 days in culture by ATP and MTT assays. The beta-AR agonist isoproterenol stimulated phospholamban phosphorylation, and the alpha-1A-AR agonist A61603 stimulated ERK phosphorylation, with nanomolar EC50 values in slices from both failing and nonfailing hearts. Strips cut from the slices were used to quantify activation of contraction by isoproterenol, A61603, and phenylephrine. The slices supported transduction by adenovirus. CONCLUSIONS: We have developed a simple, high throughput LV myocardial slice culture model to study signaling in the human heart. This model can be useful for translational studies, and we show for the first time that the alpha-1A-AR is functional in signaling and contraction in the human heart. PMID- 27453956 TI - Mammary Epithelial Cell Lineage Analysis via the Lyon's Hypothesis. AB - Implants of mammary glands from a single mammary fat pad in a H253 transgenic female mouse heterozygous for a lacZ-labeled X chromosome were analyzed at various time points following transplantation into the epithelium-cleared mammary fat pads of immune-compromised mice. The results show that the lacZ-marked X chromosome, demonstrated by nuclear-associated X-gal staining, was confined to a single epithelial clone that gave rise to the cap cells of all growing terminal end buds (TEB) in the expanding mammary outgrowths and also the basal cells of the elongated ducts. The nuclei of luminal cells in these ducts were uniformly negative for lacZ expression indicating that they were derived from cellular precursors that contained a silenced lac-Z marked X chromosome. This observation confirms the earlier work of Williams and Daniel, who concluded that cap cells were the precursors of the basal (myoepithelial cells) of the subtending mammary ducts. PMID- 27453957 TI - Phase-resolved ferromagnetic resonance using heterodyne detection method. AB - This paper describes a phase-resolved ferromagnetic resonance (FMR) measurement using a heterodyne method. Spin precession is driven by microwave fields and detected by 1550 nm laser light that is modulated at a frequency slightly shifted with respected to the FMR driving frequency. The evolving phase difference between the spin precession and the modulated light produces a slowly oscillating Kerr rotation signal with a phase equal to the precession phase plus a phase due to the path length difference between the excitation microwave signal and the optical signal. We estimate the accuracy of the precession phase measurement to be 0.1 rad. This heterodyne FMR detection method eliminates the need for field modulation and allows a stronger detection signal at higher intermediate frequency where the 1/f noise floor is reduced. PMID- 27453958 TI - Optical Spintronics in Organic-Inorganic Perovskite Photovoltaics. AB - Organic-inorganic halide CH3NH3PbI3 solar cells have attracted enormous attention in recent years due to their remarkable power conversion efficiency. When inversion symmetry is broken, these materials should exhibit interesting spin dependent properties as well, owing to their strong spin-orbit coupling. In this work, we consider the spin-dependent optical response of CH3NH3PbI3. We first use density functional theory to compute the ballistic spin current generated by absorption of unpolarized light. We then consider diffusive transport of photogenerated charge and spin for a thin CH3NH3PbI3 layer with a passivated surface and an Ohmic, non-selective contact. The spin density and spin current are evaluated by solving the drift-diffusion equations for a simplified 3 dimensional Rashba model of the electronic structure of the valence and conduction bands. We provide analytic expressions for the photon flux required to induce measurable spin densities, and propose that these spin densities can provide useful information about the role of grain boundaries in the photovoltaic behavior of these materials. We also discuss the prospects for measuring the optically generated spin current with the inverse spin Hall effect. PMID- 27453959 TI - Evaluating a Clinical Decision Support Interface for End-of-Life Nurse Care. AB - Clinical Decision Support Systems (CDSS) are tools that assist healthcare personnel in the decision-making process for patient care. Although CDSSs have been successfully deployed in the clinical setting to assist physicians, few CDSS have been targeted at professional nurses, the largest group of health providers. We present our experience in designing and testing a CDSS interface embedded within a nurse care planning and documentation tool. We developed four prototypes based on different CDSS feature designs, and tested them in simulated end-of-life patient handoff sessions with a group of 40 nurse clinicians. We show how our prototypes directed nurses towards an optimal care decision that was rarely performed in unassisted practice. We also discuss the effect of CDSS layout and interface navigation in a nurse's acceptance of suggested actions. These findings provide insights into effective nursing CDSS design that are generalizable to care scenarios different than end-of-life. PMID- 27453961 TI - Taming hazardous chemistry by continuous flow technology. AB - Over the last two decades, flow technologies have become increasingly popular in the field of organic chemistry, offering solutions for engineering and/or chemical problems. Flow reactors enhance the mass and heat transfer, resulting in rapid reaction mixing, and enable a precise control over the reaction parameters, increasing the overall process selectivity, efficiency and safety. These features allow chemists to tackle unexploited challenges in their work, with the ultimate objective making chemistry more accessible for laboratory and industrial applications, avoiding the need to store and handle toxic, reactive and explosive reagents. This review covers some of the latest and most relevant developments in the field of continuous flow chemistry with the focus on hazardous reactions. PMID- 27453962 TI - Catalytic enantioselective epoxidation of nitroalkenes. AB - Nitroepoxides are potentially exploitable as synthons with vicinal electrophilic centers. Nevertheless, although advances have been made in the field, enantioselective epoxidation of nitroalkenes is still a challenging process. Herein we show a convenient procedure for the preparation of optically active nitroepoxides in high enantiomeric excess and high chemical yield. The kinetic data of the best catalyst have been examined using computational methods based on DFT calculations. Interestingly, the results demonstrate that the enantioselectivity of the epoxidation of nitroalkenes by this kind of catalyst is not only kinetically but also thermodynamically controlled. PMID- 27453960 TI - A multi-modal intervention for Activating Patients at Risk for Osteoporosis (APROPOS): Rationale, design, and uptake of online study intervention material. AB - OBJECTIVE: To develop an innovative and effective educational intervention to inform patients about the need for osteoporosis treatment and to determine factors associated with its online uptake. METHODS: Postmenopausal women with a prior fracture and not currently using osteoporosis therapy were eligible to be included in the Activating Patients at Risk for OsteoPOroSis (APROPOS). Four nominal groups with a total of 18 racially/ethnically diverse women identified osteoporosis treatment barriers. We used the Information, Motivation, Behavior Skills conceptual model to develop a direct-to-patient intervention to mitigate potentially modifiable barriers to osteoporosis therapy. The intervention included videos tailored by participants' race/ethnicity and their survey responses: ranked barriers to osteoporosis treatment, deduced barriers to treatment, readiness to behavior change, and osteoporosis treatment history. Videos consisted of "storytelling" narratives, based on osteoporosis patient experiences and portrayed by actresses of patient-identified race/ethnicity. We also delivered personalized brief phone calls followed by an interactive voice response phone messages aimed to promote uptake of the videos. RESULTS: To address the factors associated with online intervention uptake, we focused on participants assigned to the intervention arm (n = 1342). These participants were 92.9% Caucasian, with a mean (SD) age 74.9 (8.0) years and the majority (77.7%) had some college education. Preference for natural treatments was the barrier ranked #1 by most (n = 130; 27%), while concern about osteonecrosis of the jaw was the most frequently reported barrier (at any level; n = 322; 67%). Overall, 28.1% (n = 377) of participants in the intervention group accessed the videos online. After adjusting for relevant covariates, the participants who provided an email address had 6.07 (95% CI 4.53-8.14) higher adjusted odds of accessing their online videos compared to those who did not. CONCLUSION: We developed and implemented a novel tailored multi-modal intervention to improve initiation of osteoporosis therapy. An email address provided on the survey was the most important factor independently associated with accessing the intervention online. The design and uptake of this intervention may have implications for future studies in osteoporosis or other chronic diseases. PMID- 27453963 TI - Hierarchically porous Pd nanospheres: facile synthesis and their application in HCOOH electrooxidation. AB - With the help of rhodamine B base (RBB), novel Pd nanospheres were synthesized by a facile one-step approach. Owing to their hierarchically porous characteristics, these nanospheres exhibited highly catalytic activity for HCOOH electrooxidation (~1.84 times and 1.67 times higher than those of a commercial Pd/C catalyst for mass and specific activity, respectively). PMID- 27453964 TI - Author's Reply. PMID- 27453965 TI - Familial hypertriglyceridemia manifests with pancytopenia and bone marrow pseudo-Niemann-Pick cells. PMID- 27453966 TI - Signet ring plasma cell myeloma. PMID- 27453967 TI - [Not available]. PMID- 27453968 TI - Scientific literature: Information overload. PMID- 27453969 TI - CardioPulse. The use of devices to treat hypertension. PMID- 27453970 TI - CardioPulse. Catheter-based renal denervation for hypertension treatment: update 2015. PMID- 27453971 TI - CardioPulse. Noise pollution and arterial hypertension. PMID- 27453972 TI - Perils, pitfalls, and promise of direct-to-consumer genetic testing. PMID- 27453973 TI - Another facet of tuberculosis. PMID- 27453974 TI - High-level meeting between two professional societies. PMID- 27453975 TI - "About smoking: from theory to public" another initiative of the Romanian Society of Pulmonology. PMID- 27453976 TI - Isolation and Quantification of Polyamide Cyclic Oligomers in Kitchen Utensils and Their Migration into Various Food Simulants. AB - Small amounts of cyclic monomers and oligomers are present in polyamide (PA) based kitchen utensils. In this study, we isolated eight PA-based cyclic monomers and oligomers from kitchen utensils made from PA6 (a polymer of epsilon caprolactam) and PA66 (a polymer of 1,6-diaminohexane and adipic acid). Their structures were identified using high-resolution mass spectrometry and 1H- and 13C-nuclear magnetic resonance spectroscopy, and their residual levels in PA based kitchen utensils and degree of migration into food simulants were quantified by high-performance liquid chromatography/mass spectrometry using purchased PA6 monomer and isolated PA66 monomers, and isolated PA6 and PA66 oligomers as calibration standards. Their total residual levels among 23 PA-based kitchen utensils made from PA6, PA66, and copolymers of PA6 and PA66 (PA6/66) ranged from 7.8 to 20 mg/g. Using water, 20% ethanol, and olive oil as food simulants, the total migration levels of the PA monomers and oligomers ranged from 0.66 to 100 MUg/cm2 under most examined conditions. However, the total migration levels of the PA66 monomer and oligomers from PA66 and PA6/66 kitchen utensils into 20% ethanol at 95 degrees C were very high (1,700 and 2,200 MUg/cm2, respectively) due to swelling by high-temperature ethanol. PMID- 27453977 TI - Transcription Factors Efg1 and Bcr1 Regulate Biofilm Formation and Virulence during Candida albicans-Associated Denture Stomatitis. AB - Denture stomatitis (DS) is characterized by inflammation of the oral mucosa in direct contact with dentures and affects a significant number of otherwise healthy denture wearers. The disease is caused by Candida albicans, which readily colonizes and form biofilms on denture materials. While evidence for biofilms on abiotic and biotic surfaces initiating Candida infections is accumulating, a role for biofilms in DS remains unclear. Using an established model of DS in immunocompetent animals, the purpose of this study was to determine the role of biofilm formation in mucosal damage during pathogenesis using C. albicans or mutants defective in morphogenesis (efg1-/-) or biofilm formation (bcr1-/-). For in vivo analyses, rats fitted with custom dentures, consisting of fixed and removable parts, were inoculated with wild-type C. albicans, mutants or reconstituted strains and monitored weekly for fungal burden (denture and palate), body weight and tissue damage (LDH) for up to 8 weeks. C. albicans wild type and reconstituted mutants formed biofilms on dentures and palatal tissues under in vitro, ex vivo and in vivo conditions as indicated by microscopy demonstrating robust biofilm architecture and extracellular matrix (ECM). In contrast, both efg1-/- and bcr1-/- mutants exhibited poor biofilm growth with little to no ECM. In addition, quantification of fungal burden showed reduced colonization throughout the infection period on dentures and palates of rats inoculated with efg1-/-, but not bcr1-/-, compared to controls. Finally, rats inoculated with efg1-/- and bcr1-/- mutants had minimal palatal tissue damage/weight loss while those inoculated with wild-type or reconstituted mutants showed evidence of tissue damage and exhibited stunted weight gain. These data suggest that biofilm formation is associated with tissue damage during DS and that Efg1 and Bcr1, both central regulators of virulence in C. albicans, have pivotal roles in pathogenesis of DS. PMID- 27453978 TI - Body Image Perception in Acromegaly Is Not Associated with Objective Acromegalic Changes but Depends on Depressive Symptoms. AB - OBJECTIVE: Diagnosis of acromegaly is delayed up to 10 years after disease onset despite obvious external/objective changes such as bone and soft tissue deformities. We hypothesized that a lack of subjective perception of the disease state, possibly mediated by psychiatric or cognitive alterations, might contribute to the delayed initiation of a diagnostic workup. DESIGN: Cross sectional study. METHODS: We investigated perceived body image by standardized questionnaires (FKB-20: Fragebogen zum Korperbild; FBeK: Fragebogen zur Beurteilung des eigenen Korpers) in 81 acromegalic patients and contrasted them to (a) a clinical control group of 60 patients with nonfunctioning pituitary adenomas (NFPA) who lack severe facial and physical alterations and (b) healthy controls. We further evaluated body image in relation to objective acromegalic changes as judged by medical experts and psychiatric pathology, e.g. depression and cognitive impairment. RESULTS: Patients with acromegaly did not lack subjective perception of the disease state; they showed more negative body image, less vitality, more insecurity/paresthesia and more accentuation of the body compared to normal controls. NFPA patients differed from acromegalic patients only in the 'vital body dynamics' scale of the FKB-20, although they hardly exhibit any physical/bodily changes. Depression correlated with worse body image. No associations were found between body image and objective acromegalic changes as judged by medical experts, cognitive decline or treatment status. CONCLUSIONS: Negative body image in acromegalic patients is unrelated to their objective appearance and similar to those of NFPA patients without major bodily changes. Depression, but not cognitive decline or treatment status, contributes to negative body image. PMID- 27453979 TI - Expression of Concern: A Space Efficient Flexible Pivot Selection Approach to Evaluate Determinant and Inverse of a Matrix. PMID- 27453980 TI - Pharmacokinetics and pharmacodynamics of insulin glargine 300 U/mL in the treatment of diabetes and their clinical relevance. AB - INTRODUCTION: A more concentrated insulin glargine formulation, containing 300 U/mL (Gla-300) was approved in 2015 in the US and Europe for the treatment of diabetes mellitus in adults. AREAS COVERED: This drug evaluation focuses on the pharmacokinetics (PK) and pharmacodynamics (PD) of Gla-300 from studies published up to May 2016. The clinical relevance of this new formulation will be addressed. EXPERT OPINION: Gla-300 was developed to produce a flatter and more prolonged PK/PD profile compared with insulin glargine 100 U/mL (Gla-100) in order to maintain effective glycemic control and reduce the risk of hypoglycemia. Compared to Gla-100, Gla-300 achieves lower and delayed peak concentrations with a PK exposure that is more stable and evenly distributed across a 24-h dosing interval. As a consequence, Gla-300 results in a consistent glucose-lowering effect with less variability over a 24-h dosing interval, which translates to a reduction in the rate of hypoglycemia (particularly nocturnal events). PMID- 27453981 TI - Homogeneous clusters of Alzheimer's disease patient population. AB - BACKGROUND: Identification of biomarkers for the Alzheimer's disease (AD) is a challenge and a very difficult task both for medical research and data analysis. METHODS: We applied a novel clustering tool with the goal to identify subpopulations of the AD patients that are homogeneous in respect of available clinical as well as in respect of biological descriptors. RESULTS: The main result is identification of three clusters of patients with significant problems with dementia. The evaluation of properties of these clusters demonstrates that brain atrophy is the main driving force of dementia. The unexpected result is that the largest subpopulation that has very significant problems with dementia has besides mild signs of brain atrophy also large ventricular, intracerebral and whole brain volumes. Due to the fact that ventricular enlargement may be a consequence of brain injuries and that a large majority of patients in this subpopulation are males, a potential hypothesis is that such medical status is a consequence of a combination of previous traumatic events and degenerative processes. CONCLUSIONS: The results may have substantial consequences for medical research and clinical trial design. The clustering methodology used in this study may be interesting also for other medical and biological domains. PMID- 27453982 TI - Integrating unified medical language system and association mining techniques into relevance feedback for biomedical literature search. AB - BACKGROUND: Finding highly relevant articles from biomedical databases is challenging not only because it is often difficult to accurately express a user's underlying intention through keywords but also because a keyword-based query normally returns a long list of hits with many citations being unwanted by the user. This paper proposes a novel biomedical literature search system, called BiomedSearch, which supports complex queries and relevance feedback. METHODS: The system employed association mining techniques to build a k-profile representing a user's relevance feedback. More specifically, we developed a weighted interest measure and an association mining algorithm to find the strength of association between a query and each concept in the article(s) selected by the user as feedback. The top concepts were utilized to form a k-profile used for the next round search. BiomedSearch relies on Unified Medical Language System (UMLS) knowledge sources to map text files to standard biomedical concepts. It was designed to support queries with any levels of complexity. RESULTS: A prototype of BiomedSearch software was made and it was preliminarily evaluated using the Genomics data from TREC (Text Retrieval Conference) 2006 Genomics Track. Initial experiment results indicated that BiomedSearch increased the mean average precision (MAP) for a set of queries. CONCLUSIONS: With UMLS and association mining techniques, BiomedSearch can effectively utilize users' relevance feedback to improve the performance of biomedical literature search. PMID- 27453983 TI - Discovery of prostate specific antigen pattern to predict castration resistant prostate cancer of androgen deprivation therapy. AB - BACKGROUND: Prostate specific antigen (PSA) is an important biomarker to monitor the response to the treatment, but has not been fully utilized as a whole sequence. We used a longitudinal biomarker PSA to discover a new prognostic pattern that predicts castration-resistant prostate cancer (CRPC) after androgen deprivation therapy. METHODS: We transformed the longitudinal PSA into a discrete sequence, used frequent sequential pattern mining to find candidate patterns from the sequences, and selected the most predictive and informative pattern among the candidates. RESULTS: Patients were less likely to be CRPC if, after PSA values reach nadir, the PSA decreases more than 0.048 ng/ml during a month, and the decrease occurs again. This pattern significantly increased the accuracy of predicting CRPC by supplementing information provided by existing PSA patterns such as pretreatment PSA. CONCLUSIONS: This result can help clinicians to stratify men by the risk of CRPC and to determine the patient that needs intensive follow-up. PMID- 27453984 TI - Global Forum 2015 dialogue on "From evidence to policy - thinking outside the box": perspectives to improve evidence uptake and good practices in the African Region. AB - BACKGROUND: The Global Forum 2015 panel session dialogue entitled "From evidence to policy - thinking outside the box" was held on 26 August 2015 in the Philippines to debate why evidence was not fully translated into policy and practice and what could be done to increase its uptake. This paper reports the reasons and possible actions for increasing the uptake of evidence, and highlights the actions partners could take to increase the use of evidence in the African Region. DISCUSSION: The Global Forum 2015 debate attributed African Region's low uptake of evidence to the big gap in incentives and interests between research for health researchers and public health policy-makers; limited appreciation on the side of researchers that public health decisions are based on multiple and complex considerations; perception among users that research evidence is not relevant to local contexts; absence of knowledge translation platforms; sub-optimal collaboration and engagement between industry and research institutions; lack of involvement of civil society organizations; lack of engagement of communities in the research process; failure to engage the media; limited awareness and debate in national and local parliaments on the importance of investing in research and innovation; and dearth of research and innovation parks in the African Region. CONCLUSION: The actions needed in the Region to increase the uptake of evidence in policy and practice include strengthening NHRS governance; bridging the motivation gap between researchers and health policy makers; restoring trust between researchers and decision-makers; ensuring close and continuous intellectual intercourse among researchers, ministry of health policy-makers and technocrats during the life course of research projects or programmes; proactive collaboration between academia and industry; regular briefings of civil society, media, relevant parliamentary committees and development partners; development of vibrant knowledge translation platforms; development of action plans for implementing research recommendations, preferably in the context of the Sustainable Development Goals; and encouragement of competition on NHRS strengthening and research output and uptake among the countries using a barometer or scorecard to review their performance at various regional ministerial forums and taking into account the lessons learned from the MDG period. PMID- 27453985 TI - "Multistage in one touch" design with a universal labelling conjugate for high sensitive lateral flow immunoassays. AB - Immunoreagents with good results in the competitive enzyme-linked immunosorbent assay are often unable to provide the required detection limit in the traditional competitive immunochromatographic assay. The solution may be either the production of new reagents or improving the test strip. In the latter case, the assay is often performed stepwise using additional liquid reagents, but this is a significant drawback for practical use. We introduce a test strip made as a dry chemical device that still provides the two-step immunochemical interactions - formation of a complex of specific antibodies with an antigen and its detection by a conjugate of antispecies antibodies with a nano-sized label. Analysis with this test strip is similar to that with ordinary test strips and requires no additional reagents and manipulation. The use of specific antibodies and marker as two separate components allows to improve the analytical parameters. The new test significantly lowers the limit of detection, making it possible to use antibodies previously ineffective in immunochromatography. The proposed approach was tested by determining zearalenone and aflatoxin B1 mycotoxins. The visual limit of detection for aflatoxin B1 decreased to 0.6ng/mL compared to 11ng/mL with an ordinary test strip. For zearalenone, a test strip was created with visual detection limit of 6ng/mL with reagents inefficient in the traditional test strip (which is not able to detect even 9MUg/mL of zearalenone). Thus, the proposed approach allows obtaining 'dry', multi-stage, immunochromatographic test strips, providing a highly sensitive detection method. PMID- 27453986 TI - One-pot synthesis of quantum dot-labeled hydrophilic molecularly imprinted polymer nanoparticles for direct optosensing of folic acid in real, undiluted biological samples. AB - A facile and efficient one-pot approach for the synthesis of quantum dot (QD) labeled hydrophilic molecularly imprinted polymer (MIP) nanoparticles for direct optosensing of folic acid (FA) in the undiluted bovine and porcine serums is described. Hydrophilic macromolecular chain transfer agent-mediated reversible addition-fragmentation chain transfer (RAFT) precipitation polymerization was used to implement the molecular imprinting of FA in the presence of CdTe quantum dots (QDs). The resulting FA-imprinted polymer nanoparticles with surface-grafted hydrophilic poly(glyceryl monomethacrylate) brushes and QDs labeling not only showed outstanding specific molecular recognition toward FA in biological samples, but also exhibited good photostability, rapid binding kinetics, and obvious template binding-induced fluorescence quenching. These characteristics make them a useful fluorescent chemosensor for directly and selectively optosensing FA in the undiluted bovine and porcine serums, with its limit of detection being 0.025MUM and average recoveries ranging from 98% to 102%, even in the presence of several interfering compounds. This advanced fluorescent MIP chemosensor is highly promising for rapid quantification of FA in such applications as clinical diagnostics and food analysis. PMID- 27453987 TI - Synthesis and sensing integration: A novel enzymatic reaction modulated Nanoclusters Beacon (NCB) "Illumination" strategy for label-free biosensing and logic gate operation. AB - A novel fluorescent label-free "turn-on" NAD(+) and adenosine triphosphate (ATP) biosensing strategy is proposed by fully exploiting ligation triggered Nanocluster Beacon (NCB). In the presence of the target, the split NCB was brought to intact, which brought the C-rich sequence and enhancer sequence in close proximity resulting in the lightening of dark DNA/AgNCs ("On" mode). Further application was presented for logic gate operation and aptasensor construction. The feasibility was investigated by Ultraviolet-visible spectroscopy (UV-vis), Fluorescence, lifetime and High Resolution Transmission Electron Microscopy (HRTEM) etc. The strategy displayed good performance in the detection of NAD(+) and ATP, with the detection limit of 0.002nM and 0.001mM, the linear range of 10-1000nM and 0.003-0.01mM, respectively. Due to the DNA/AgNCs as fluorescence reporter, the completely label-free fluorescent strategy boasts the features of simplicity and low cost, and showing little reliance on the sensing environment. Meanwhile, the regulation by overhang G-rich sequence not relying on Forster energy transfer quenching manifests the high signal-to-background ratios (S/B ratios). This method not only provided a simple, economical and reliable fluorescent NAD(+) assay but also explored a flexible G-rich sequence regulated NCB probe for the fluorescent biosensors. Furthermore, this sensing mode was expanded to the application of a logic gate design, which exhibited a high performance for not only versatile biosensors construction but also for molecular computing application. PMID- 27453988 TI - Recent advances in metamaterial split-ring-resonator circuits as biosensors and therapeutic agents. AB - Potential applications of thin film metamaterials are diverse and their realization to offer miniaturized waveguides, antennas and shielding patterns are on anvil. These artificially engineered structures can produce astonishing electromagnetic responses because of their constituents being engineered at much smaller dimensions than the wavelength of the incident electromagnetic wave, hence behaving as artificial materials. Such micro-nano dimensions of thin film metamaterial structures can be customized for various applications due to their exclusive responses to not only electromagnetic, but also to acoustic and thermal waves that surpass the natural materials' properties. In this paper, the recent major advancements in the emerging fields of diagnostics (sensors) and therapeutics involving thin film metamaterials have been reviewed and underlined; discussing their edge over conventional counterpart techniques; concentrating on their design considerations and feasible ways of achieving them. Challenges faced in sensitivity, precision, accuracy and factors that interfere with the degree of performance of the sensors are also dealt with, herein. PMID- 27453989 TI - Nitrogen-Doped Holey Graphene Film-Based Ultrafast Electrochemical Capacitors. AB - The commercialized aluminum electrolytic capacitors (AECs) currently used for alternating current (AC) line-filtering are usually the largest components in the electronic circuits because of their low specific capacitances and bulky sizes. Herein, nitrogen-doped holey graphene (NHG) films were prepared by thermal annealing the composite films of polyvinylpyrrolidone (PVP), graphene oxide (GO), and ferric oxide (Fe2O3) nanorods followed by chemical etching with hydrochloride acid. The typical electrochemical capacitor with NHG electrodes exhibited high areal and volumetric specific capacitances of 478 MUF cm(-2) and 1.2 F cm(-3) at 120 Hz, ultrafast frequency response with a phase angle of -81.2 degrees and a resistor-capacitor time constant of 203 MUs at 120 Hz, as well as excellent cycling stability. Thus, it is promising to replace conventional AEC for AC line filtering in miniaturized electronics. PMID- 27453990 TI - Isolation, Characterization and Anticancer Potential of Cytotoxic Triterpenes from Betula utilis Bark. AB - Betula utilis, also known as Himalayan silver birch has been used as a traditional medicine for many health ailments like inflammatation, HIV, renal and bladder disorders as well as many cancers from ages. Here, we performed bio guided fractionation of Betula utilis Bark (BUB), in which it was extracted in methanol and fractionated with hexane, ethyl acetate, chloroform, n-butanol and water. All six fractions were evaluated for their in-vitro anticancer activity in nine different cancer cell lines and ethyl acetate fraction was found to be one of the most potent fractions in terms of inducing cytotoxic activity against various cancer cell lines. By utilizing column chromatography, six triterpenes namely betulin, betulinic acid, lupeol, ursolic acid (UA), oleanolic acid and beta-amyrin have been isolated from the ethyl acetate extract of BUB and structures of these compounds were unraveled by spectroscopic methods. beta amyrin and UA were isolated for the first time from Betula utilis. Isolated triterpenes were tested for in-vitro cytotoxic activity against six different cancer cell lines where UA was found to be selective for breast cancer cells over non-tumorigenic breast epithelial cells (MCF 10A). Tumor cell selective apoptotic action of UA was mainly attributed due to the activation of extrinsic apoptosis pathway via up regulation of DR4, DR5 and PARP cleavage in MCF-7 cells over non tumorigenic MCF-10A cells. Moreover, UA mediated intracellular ROS generation and mitochondrial membrane potential disruption also play a key role for its anti cancer effect. UA also inhibits breast cancer migration. Altogether, we discovered novel source of UA having potent tumor cell specific cytotoxic property, indicating its therapeutic potential against breast cancer. PMID- 27453991 TI - A novel approach for multi-SNP GWAS and its application in Alzheimer's disease. AB - BACKGROUND: Genome-wide association studies (GWAS) have effectively identified genetic factors for many diseases. Many diseases, including Alzheimer's disease (AD), have epistatic causes, requiring more sophisticated analyses to identify groups of variants which together affect phenotype. RESULTS: Based on the GWAS statistical model, we developed a multi-SNP GWAS analysis to identify pairs of variants whose common occurrence signaled the Alzheimer's disease phenotype. CONCLUSIONS: Despite not having sufficient data to demonstrate significance, our preliminary experimentation identified a high correlation between GRIA3 and HLA DRB5 (an AD gene). GRIA3 has not been previously reported in association with AD, but is known to play a role in learning and memory. PMID- 27453992 TI - Tongue and Lower Lip Movement in Semivowel /w/ Production. AB - AIMS: Previous studies have shown significant correlations between the acoustic characteristics of /w/ and speech intelligibility. To understand the articulatory pattern in /w/ production, the current study investigated the movement characteristics of the tongue and lower lip in whip productions in comparison to bib productions. METHODS: Data from 19 typical adult male participants were collected using electromagnetic articulography. A number of kinematic measures of tongue body (approximately 25 mm posterior to the tongue apex) and lower lip movements were analyzed. RESULTS: The findings suggested different movement patterns of the tongue body and lower lip in whip and bib productions. The amount of lip movement in the anterior-posterior plane exhibited by each speaker did not vary between whip and bib. However, speakers did exhibit more tongue retraction/advancement, greater overall tongue movement, and faster tongue movement speed in whip than in bib. CONCLUSION: Tongue movement in the anterior posterior plane, such as tongue retraction and advancement, was found to be crucial for the production of /w/ in typical male speakers. Thus, the articulatory kinematics of the tongue in the anterior-posterior plane and its coordination with the lips need to be further examined in speakers with dysarthria to understand the underlying kinematic characteristics that influence speech intelligibility. PMID- 27453993 TI - Unexpected Normal Colloid Osmotic Pressure in Clinical States with Low Serum Albumin. AB - BACKGROUND: In clinical states associated with systemic oxidative stress (OS) and inflammation such as chronic kidney disease (CKD), oxidative modifications of serum albumin impair its quantification, resulting in apparent hypoalbuminemia. As the maintenance of oncotic pressure/colloid osmotic pressure (COP) is a major function of albumin, this study examined the impact of albumin oxidation on COP, both in-vivo and in-vitro. METHODS: Patients with proteinuria and patients on chronic hemodialysis (HD) with systemic inflammation and OS were enrolled. Blood samples were collected from 134 subjects: 32 healthy controls (HC), proteinuric patients with high (n = 17) and low (n = 31) systemic inflammation and from 54 patients on chronic hemodialysis (HD) with the highest levels of OS and inflammation. RESULTS: In-vitro oxidized albumin showed significantly higher COP values than non-oxidized albumin at identical albumin levels. In vivo, in hypoalbuminemic HD patients with the highest OS and inflammation, COP values were also higher than expected for the low albumin levels. The contribution to COP by other prevalent plasma proteins, such as fibrinogen and immunoglobulins was negligible. We imply that the calculation of COP based on albumin levels should be revisited in face of OS and inflammation. Hence, in hypoalbuminemic proteinuric patients with systemic OS and inflammation the assumption of low COP should be verified by its measurements. PMID- 27453995 TI - Analysis of Soil Structure Turnover with Garnet Particles and X-Ray Microtomography. AB - Matter turnover in soil is tightly linked to soil structure which governs the heterogeneous distribution of habitats, reaction sites and pathways in soil. Thereby, the temporal dynamics of soil structure alteration is deemed to be important for essential ecosystem functions of soil but very little is known about it. A major reason for this knowledge gap is the lack of methods to study soil structure turnover directly at microscopic scales. Here we devise a conceptual approach and an image processing workflow to study soil structure turnover by labeling some initial state of soil structure with small garnet particles and tracking their fate with X-ray microtomography. The particles adhere to aggregate boundaries at the beginning of the experiment but gradually change their position relative to the nearest pore as structure formation progresses and pores are destructed or newly formed. A new metric based on the contact distances between particles and pores is proposed that allows for a direct quantification of soil structure turnover rates. The methodology is tested for a case study about soil compaction of a silty loam soil during stepwise increase of bulk density (rho = {1.1, 1.3, 1.5} g/cm3). We demonstrate that the analysis of mean contact distances provides genuinely new insights about changing diffusion pathways that cannot be inferred neither from conventional pore space attributes (porosity, mean pore size, pore connectivity) nor from deformation analysis with digital image correlation. This structure labeling approach to quantify soil structure turnover provides a direct analogy to stable isotope labeling for the analysis of matter turnover and can be readily combined with each other. PMID- 27453994 TI - Altered Myokine Secretion Is an Intrinsic Property of Skeletal Muscle in Type 2 Diabetes. AB - Skeletal muscle secretes factors, termed myokines. We employed differentiated human skeletal muscle cells (hSMC) cultured from Type 2 diabetic (T2D) and non diabetic (ND) subjects to investigate the impact of T2D on myokine secretion. Following 24 hours of culture concentrations of selected myokines were determined to range over 4 orders of magnitude. T2D hSMC released increased amounts of IL6, IL8, IL15, TNFa, Growth Related Oncogene (GRO)a, monocyte chemotactic protein (MCP)-1, and follistatin compared to ND myotubes. T2D and ND hSMC secreted similar levels of IL1beta and vascular endothelial growth factor (VEGF). Treatment with the inflammatory agents lipopolysaccharide (LPS) or palmitate augmented the secretion of many myokines including: GROa, IL6, IL8, IL15, and TNFa, but did not consistently alter the protein content and/or phosphorylation of IkBa, p44/42 MAPK, p38 MAPK, c-Jun N-terminal kinase (JNK) and NF-kB, nor lead to consistent changes in basal and insulin-stimulated glucose uptake or free fatty acid oxidation. Conversely, treatment with pioglitazone or oleate resulted in modest reductions in the secretion of several myokines. Our results demonstrate that altered secretion of a number of myokines is an intrinsic property of skeletal muscle in T2D, suggesting a putative role of myokines in the response of skeletal muscle to T2D. PMID- 27453996 TI - Third generation sequencing technologies applied to diagnostic microbiology: benefits and challenges in applications and data analysis. AB - INTRODUCTION: The diagnosis of infectious diseases is among the most successful areas of application of new generation sequencing technologies. The field has seen the development of numerous experimental and analytical approaches for the detection and the fine description of pathogenic and non-pathogenic microorganisms. AREAS COVERED: Without claiming to be exhaustive with respect to all applications and methods developed over the years, this review focuses on the advantages and the issues brought by the new technologies, with an eye in particular to third generation sequencing methods. Both experimental procedures and algorithmic strategies are presented, following the most relevant publications which have led to progress in our ability of detecting infectious agents. Expert commentary: The technical advance brought by third generation sequencing platforms has the potential to significantly expand the range of diagnostic tools that will be available to clinicians. Nonetheless, the implementation of these technologies in clinical practice is still far from being actionable and will temporally follow the path undertaken by second generation methods, which still require the setup of standardized pipelines in both wet and dry laboratory procedures. PMID- 27453997 TI - Pretreatment with Astragaloside IV protects human umbilical vein endothelial cells from hydrogen peroxide induced oxidative stress and cell dysfunction via inhibiting eNOS uncoupling and NADPH oxidase - ROS - NF-kappaB pathway. AB - Endothelial cell injury caused by reactive oxygen species (ROS) plays a critical role in the pathogenesis of cardiovascular disorders. Astragaloside IV (AsIV) possesses potent antioxidant properties against oxidative stress through undefined mechanism(s). We sought to investigate whether AsIV protects human umbilical vein endothelial cells (HUVECs) from hydrogen peroxide (H2O2) induced oxidative stress focusing on eNOS uncoupling and the NADPH oxidase - ROS - NF kappaB pathway. Compared with HUVECs incubated with H2O2 alone, pretreatment with AsIV significantly increased the viability of HUVECs, which was accompanied with apparent increase in nitric oxide (NO) production and decrease in intracellular superoxide anion production. Furthermore, pretreatment with AsIV increased endothelial nitric oxide synthase (eNOS) dimer/monomer ratio and its critical cofactor tetrahydrobiopterin (BH4) content, decreased Nox4 protein expression (the most abundant Nox isoform in HUVECs), inhibited translocation of NF-kappaB p65 subunit into nuclear fraction while enhanced the protein expression of IkappaB-alpha (the inhibitor of NF-kappaB p65), reduced the levels of IL-1beta, IL-6, and TNF-alpha in HUVECs medium, and decreased iNOS protein expression. These results suggest that AsIV may protect HUVECs from H2O2-induced oxidative stress via inhibiting NADPH oxidase - ROS - NF-kappaB pathway and eNOS uncoupling. PMID- 27453998 TI - Investigation and management of an outbreak of multispecies mycobacteriosis in Australian lungfish (Neoceratodus fosteri) including the use of triple antibiotic treatment. AB - Disease due to non-tuberculous mycobacteria (NTM) is common in fish. Current recommendations focus on outbreak management by depopulating entire fish stocks and disinfecting tanks. Treatment is not advocated. Treatment may be appropriate, however, where individual, valuable fish are concerned. ZSL London Zoo managed an outbreak of mycobacteriosis in a valuable group of imported F1 captive-bred Australian lungfish (Neoceratodus fosteri) by depopulation, isolation, extensive testing and daily oral antibiotic treatment. Four species of Mycobacterium (M. marinum, M. fortuitum, M. chelonae and M. peregrinum) were involved in this outbreak, each with unique antibiotic sensitivities. Triple therapy with rifampicin, doxycycline and enrofloxacin for 8 months was the most effective antibiotic combination, resulting in full disease resolution. No side effects were noted and, more than 18 months post-treatment, no recurrence had occurred. This is the first report of mycobacterial disease in lungfish and the first report of a polymycobacterial outbreak in fish involving these four species of Mycobacterium. This report demonstrates the value of extensive isolation and identification. Also, as therapies currently advised in standard texts did not reflect the antibiotic sensitivity of the NTM found in the fish reported here, we recommend that antibiotic treatment should always be based on sensitivity testing. PMID- 27453999 TI - Characterization of the Two Methylation Steps Involved in the Biosynthesis of Mycinose in Tylosin. AB - The S-adenosyl-l-methionine-dependent O-methyltransferases TylE and TylF catalyze the last two methylation reactions in the tylosin biosynthetic pathway of Streptomyces fradiae. It has long been known that the TylE-catalyzed C2'''-O methylation of the 6-deoxy-d-allose bound to demethylmacrocin or demethyllactenocin precedes the TylF-catalyzed C3'''-O-methylation of the d javose (C2'''-O-methylated 6-deoxy-d-allose) attached to macrocin or lactenocin. This study reveals the unexpected substrate promiscuity of TylE and TylF responsible for the biosynthesis of d-mycinose (C3'''-O-methylated d-javose) in tylosin through the identification of a new minor intermediate 2'''-O demethyldesmycosin (2; 3'''-methyl-demethyllactenocin), which lacks a 2'''-O methyl group on the mycinose moiety of desmycosin, along with 2'''-O demethyltylosin (1; 3'''-methyl-demethylmacrocin) that was previously detected from the S. fradiae mutant containing a mutation in the tylE gene. These results unveil the unique substrate flexibility of TylE and TylF and demonstrate their potential for the engineered biosynthesis of novel glycosylated macrolide derivatives. PMID- 27454000 TI - The Non-native Helical Intermediate State May Accumulate at Low pH in the Folding and Aggregation Landscape of the Intestinal Fatty Acid Binding Protein. AB - There has been widespread interest in studying early intermediate states and their roles in protein folding. The interest in intermediate states has been further emphasized in the recent literature because of their implications for protein aggregation. Unfortunately, direct kinetic characterization of intermediates has been difficult because of the limited time resolutions offered by the kinetic techniques and the heterogeneity of the folding and aggregation landscape. Even in equilibrium experiments, the characterization of intermediate states could be difficult because (a) their populations in equilibrium could be low and/or (b) they lack any specific biochemical or biophysical signatures for their identification. In this paper, we have used fluorescence correlation spectroscopy to study the nature of a low-pH intermediate state of the intestinal fatty acid binding protein, a small protein with predominantly beta-sheet structure. Our results have shown that the pH 3 intermediate diffuses faster than the folded protein and has strong helix forming propensity. These behaviors support Lim's hypothesis according to which even an entirely beta-sheet protein would form helical bundles at the early stage. Using dynamic light scattering and thioflavin T binding measurements, we have observed that the pH 3 intermediate is prone to aggregation. We believe that early helix formation is the result of a local effect, which originates from the interaction of the neighboring amino acids around the hydrophobic core residues. This early intermediate reorganizes subsequently, and this structural reorganization is initiated by the destabilizing interactions induced by the distant residues, unfavorable entropic costs, and steric constraints of the hydrophobic side chains. Mutational analyses show further that the increase in the hydrophobicity in the hydrophobic core region increases the population of the alpha-helical intermediate, enhancing the aggregation propensity of the protein, while an identical change, distant from the hydrophobic core, does not show any effect. This study re-emphasizes an overlap between the folding and aggregation landscape of a protein, where the fine-tuning between the local and global effects may be important for the protein to fold efficiently or to aggregate. PMID- 27454001 TI - Feasibility of Using Multiple-Locus Variable-Number Tandem-Repeat Analysis for Epidemiology Study of Vibrio parahaemolyticus Infections. AB - Vibrio parahaemolyticus causes foodborne gastroenteritis, which is often associated with the consumption of raw or undercooked shellfish. Molecular typing can provide critical information for detecting outbreaks and for source attribution. In this study, we describe the development and evaluation of an optimized multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) for the characterization of V. parahaemolyticus isolates. The discriminatory power of MLVA was compared to that of pulsed-field gel electrophoresis (PFGE) by typing 73 sporadic isolates. Epidemiologic concordance was evaluated by typing 23 isolates from five epidemiologically well-characterized outbreaks. The optimized MLVA was applied in early warning, epidemiological surveillance, and source tracking for V. parahaemolyticus infections. There was no significant difference in the discriminatory power of PFGE and MLVA with six or eight VNTR loci for the sporadic isolates. All isolates within an outbreak were indistinguishable by MLVA with six loci, except for one outbreak. Typically, the epidemiological survey could be initiated according to PFGE clusters. We applied MLVA with six loci on 22 isolates in two PFGE clusters. Isolates in one PFGE cluster were distinguished by MLVA. Although a follow-up investigation showed that both clusters had no epidemiological concordance, MLVA decreased the frequency of initiation of epidemiological surveys, thereby reducing labor costs. The ability of MLVA to trace the source of infection was evaluated by isolates from two outbreaks and shrimp samples. The isolates from one of outbreaks and a shrimp had the same MLVA type, suggesting that an epidemiological survey was initiated. Data from the epidemiological investigation subsequently indicated that contaminated shrimp from a nearby city (Dongguan) might be the source of the outbreak. In conclusion, these results indicate that the optimized MLVA may be a promising tool for early warning and epidemiological surveillance of V. parahaemolyticus infections. PMID- 27454002 TI - Emotionally negative pictures enhance gist memory. AB - In prior work on how true and false memory are influenced by emotion, valence and arousal have often been conflated. Thus, it is difficult to say which specific effects are caused by valence and which are caused by arousal. In the present research, we used a picture-memory paradigm that allowed emotional valence to be manipulated with arousal held constant. Negatively valenced pictures elevated both true and false memory, relative to positive and neutral pictures. Conjoint recognition modeling revealed that negative valence (a) reduced erroneous suppression of true memories and (b) increased the familiarity of the semantic content of both true and false memories. Overall, negative valence impaired the verbatim side of episodic memory but enhanced the gist side, and these effects persisted even after a week-long delay. (PsycINFO Database Record PMID- 27454003 TI - Sparse-SEMAC: rapid and improved SEMAC metal implant imaging using SPARSE-SENSE acceleration. AB - PURPOSE: To develop an accelerated SEMAC metal implant MRI technique (Sparse SEMAC) with reduced scan time and improved metal distortion correction. METHODS: Sparse-SEMAC jointly exploits the inherent sparsity along the additional phase encoding dimension and multicoil encoding capabilities to significantly accelerate data acquisition. A prototype pulse sequence with pseudorandom ky -kz undersampling and an inline image reconstruction was developed for integration in clinical studies. Three patients with hip implants were imaged using the proposed Sparse-SEMAC with eight-fold acceleration and compared with the standard-SEMAC technique used in clinical studies (three-fold GRAPPA acceleration). Measurements were performed with SEMAC-encoding steps (SES) = 15 for Sparse-SEMAC and SES = 9 for Standard-SEMAC using high spatial resolution Proton Density (PD) and lower resolution STIR acquisitions. Two expert musculoskeletal (MSK) radiologists performed a consensus reading to score image-quality parameters. RESULTS: Sparse SEMAC enables up to eight-fold acceleration of data acquisition that results in two-fold scan time reductions, compared with Standard-SEMAC, with improved metal artifact correction for patients with hip implants without degrading spatial resolution. CONCLUSION: The high acceleration enabled by Sparse-SEMAC would enable clinically feasible examination times with improved correction of metal distortion. Magn Reson Med 78:79-87, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27454004 TI - Arsenic Mobilization from Historically Contaminated Mining Soils in a Continuously Operated Bioreactor: Implications for Risk Assessment. AB - Concentrations of soil arsenic (As) in the vicinity of the former Zloty Stok gold mine (Lower Silesia, southwest Poland) exceed 1000 MUg g(-1) in the area, posing an inherent threat to neighboring bodies of water. This study investigated continuous As mobilization under reducing conditions for more than 3 months. In particular, the capacity of autochthonic microflora that live on natural organic matter as the sole carbon/electron source for mobilizing As was assessed. A biphasic mobilization of As was observed. In the first two months, As mobilization was mainly conferred by Mn dissolution despite the prevalence of Fe (0.1 wt % vs 5.4 for Mn and Fe, respectively) as indicated by multiple regression analysis. Thereafter, the sudden increase in aqueous As[III] (up to 2400 MUg L( 1)) was attributed to an almost quintupling of the autochthonic dissimilatory As reducing community (quantitative polymerase chain reaction). The aqueous speciation influenced by microbial activity led to a reduction of solid phase As species (X-ray absorption fine structure spectroscopy) and a change in the elemental composition of As hotspots (micro X-ray fluorescence mapping). The depletion of most natural dissolved organic matter and the fact that an extensive mobilization of As[III] occurred after two months raises concerns about the long term stability of historically As-contaminated sites. PMID- 27454005 TI - Assessing electron beam sensitivity for SrTiO3 and La0.7Sr0.3MnO3 using electron energy loss spectroscopy. AB - Thresholds for beam damage have been assessed for La0.7Sr0.3MnO3 and SrTiO3 as a function of electron probe current and exposure time at 80 and 200kV acceleration voltage. The materials were exposed to an intense electron probe by aberration corrected scanning transmission electron microscopy (STEM) with simultaneous acquisition of electron energy loss spectroscopy (EELS) data. Electron beam damage was identified by changes of the core loss fine structure after quantification by a refined and improved model based approach. At 200kV acceleration voltage, damage in SrTiO3 was identified by changes both in the EEL fine structure and by contrast changes in the STEM images. However, the changes in the STEM image contrast as introduced by minor damage can be difficult to detect under several common experimental conditions. No damage was observed in SrTiO3 at 80kV acceleration voltage, independent of probe current and exposure time. In La0.7Sr0.3MnO3, beam damage was observed at both 80 and 200kV acceleration voltages. This damage was observed by large changes in the EEL fine structure, but not by any detectable changes in the STEM images. The typical method to validate if damage has been introduced during acquisitions is to compare STEM images prior to and after spectroscopy. Quantifications in this work show that this method possibly can result in misinterpretation of beam damage as changes of material properties. PMID- 27454006 TI - Cytoskeleton Aberrations in Alkaptonuric Chondrocytes. AB - Alkaptonuria (AKU) is an ultra-rare autosomal genetic disorder caused by a defect in the activity of the enzyme homogentisate 1,2-dioxygenase (HGD) that leads to the accumulation of homogentisic acid (HGA) and its oxidized product, benzoquinone acetic acid (BQA), in the connective tissues causing a pigmentation called "ochronosis." The consequent progressive formation of ochronotic aggregates generate a severe condition of oxidative stress and inflammation in all the affected areas. Experimental evidences have also proved the presence of serum amyloid A (SAA) in several AKU tissues and it allowed classifying AKU as a secondary amyloidosis. Although AKU is a multisystemic disease, the most affected system is the osteoarticular one and articular cartilage is the most damaged tissue. In this work, we have analyzed for the first time the cytoskeleton of AKU chondrocytes by means of immunofluorescence staining. We have shown the presence of SAA within AKU chondrocytes and finally we have demonstrated the co localization of SAA with three cytoskeletal proteins: actin, vimentin, and beta tubulin. Furthermore, in order to observe the ultrastructural features of AKU chondrocytes we have performed TEM analysis, focusing on the Golgi apparatus structure and, to demonstrate that pigmented areas in AKU cartilage are correspondent to areas of oxidation, 4-HNE presence has been evaluated by means of immunofluorescence. J. Cell. Physiol. 232: 1728-1738, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27454008 TI - Fast Photochromism Involving Thermally-Activated Valence Isomerization of Phenoxyl-Imidazolyl Radical Complex Derivatives. AB - Open-shell biradicals have received considerable attention in material science because of their high two-photon absorption cross sections and broad and high absorptive features over the visible region. However, the instability of the biradical caused by the open-shell nature was one of the drawbacks; therefore, novel radical compounds which can suppress unwanted reactions by tuning the open shell features are desired to expand the versatility of the radical compounds. Here, we report a novel radical-dissociation-type photochromic compound whose photochromic reaction involves a valence isomerization from the open-shell biradical to closed-shell quinoidal forms by using a phenoxyl-imidazolyl radical complex framework. The valence isomerization from the biradical to quinoid forms effectively tunes the open-shell feature in time and drastically changes the spectral features, which were revealed by time-resolved Fourier transform infrared spectroscopy. This novel fast photochromic property not only is important for fundamental spin chemistry but also expands the versatility of the radical compounds for novel advanced photofunctional materials. PMID- 27454007 TI - Assessing ECG signal quality indices to discriminate ECGs with artefacts from pathologically different arrhythmic ECGs. AB - False and non-actionable alarms in critical care can be reduced by developing algorithms which assess the trueness of an arrhythmia alarm from a bedside monitor. Computational approaches that automatically identify artefacts in ECG signals are an important branch of physiological signal processing which tries to address this issue. Signal quality indices (SQIs) derived considering differences between artefacts which occur in ECG signals and normal QRS morphology have the potential to discriminate pathologically different arrhythmic ECG segments as artefacts. Using ECG signals from the PhysioNet/Computing in Cardiology Challenge 2015 training set, we studied previously reported ECG SQIs in the scientific literature to differentiate ECG segments with artefacts from arrhythmic ECG segments. We found that the ability of SQIs to discriminate between ECG artefacts and arrhythmic ECG varies based on arrhythmia type since the pathology of each arrhythmic ECG waveform is different. Therefore, to reduce the risk of SQIs classifying arrhythmic events as noise it is important to validate and test SQIs with databases that include arrhythmias. Arrhythmia specific SQIs may also minimize the risk of misclassifying arrhythmic events as noise. PMID- 27454010 TI - Lessons learnt from the implementation of maternal immunization programs in England. PMID- 27454009 TI - Comorbid anxiety increases cognitive control activation in Major Depressive Disorder. AB - BACKGROUND: Major Depressive Disorder (MDD) and anxiety disorders often co-occur, with poorer treatment response and long-term outcomes. However, little is known about the shared and distinct neural mechanisms of comorbid MDD and anxiety (MDD+Anx). This study examined how MDD and MDD+Anx differentially impact cognitive control. METHODS: Eighteen MDD, 29 MDD+Anx, and 54 healthy controls (HC) completed the Parametric Go/No-Go (PGNG) during fMRI, including Target, Commission, and Rejection trials. RESULTS: MDD+Anx had more activation in the anterior dorsolateral prefrontal cortex, hippocampus, and caudate during Rejections, and inferior parietal lobule during correct Targets than MDD and HC. During Rejections HC had greater activation in a number of cognitive control regions compared to MDD; in the posterior cingulate compared to MDD+Anx; and in the fusiform gyrus compared to all MDD. During Commissions HC had greater activation in the right inferior frontal gyrus than all MDD. MDD had more activation in the mid-cingulate, inferior parietal lobule, and superior temporal gyrus than MDD+Anx during Commissions. CONCLUSIONS: Despite similar performance, MDD and MDD+Anx showed distinct differences in neural mechanisms of cognitive control in relation to each other, as well as some shared differences in relation to HC. The results were consistent with our hypothesis of hypervigilance in MDD+Anx within the cognitive control network, but inconsistent with our hypothesis that there would be greater engagement of salience and emotion network regions. Comorbidity of depression and anxiety may cause increased heterogeneity in study samples, requiring further specificity in detection and measurement of intermediate phenotypes and treatment Targets. PMID- 27454012 TI - [Correlation between MALDI-TOF Vitek-MSTM system and conventional identification methods of gastrointestinal infection causing bacteria]. AB - OBJECTIVE: Rapid identification of pathogens is essential for the diagnosis of gastrointestinal infections. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry has shown to be effective and fast for the identification of microorganisms. The objective of this study was to evaluate the correlation between Vitek-MSTM and conventional methods for bacterial identification causing gastrointestinal infection. METHODS: A total of 329 gastrointestinal pathogens were identified using Vitek-MSTM (v2 SARAMIS MS -ID, bioMerieux, Marcy-I'Etoile, France) and routine diagnostic methods simultaneously. In cases of discrepancy 16SrRNA gene sequencing was performed. RESULTS: The correlation between Vitek-MSTM and diagnostic methods was 100% except for Yersinia enterocolitica (94.1%), Helicobacter pylori (10%) and Aeromonas veronii (0 %). CONCLUSIONS: Vitek-MSTM is a quick and useful method for identification of enterophatogenic bacteria. It is necessary to improve the performance of the system for the identification of H. pylori and A. veronii. PMID- 27454011 TI - The hidden effects of recalling secrets: Assimilation, contrast, and the burdens of secrecy. AB - Three high-power studies (N = 3,000 total) demonstrated that asking participants to recall an experience as a manipulation can have unintended consequences. Participants who recalled preoccupying secrets made more extreme judgments of an external environment, supporting the notion that secrecy is burdensome. This influence was found, however, only among a subset of participants (i.e., participants who successfully recalled secrets that corresponded to their condition). We introduce the concept of manipulation correspondence to understand these patterns of results. Without taking into account whether participants' recalled secrets corresponded to their manipulation, there was no main effect of the recall manipulation on hill slant judgments. Among participants whose secrets did not correspond with the manipulation, a contrast effect emerged (i.e., influences on perceptual judgments opposite to the intention of the recall prompts). Moreover, the very process of recalling a secret in response to a prompt can lead to contrast from that prompt. Exposing participants to extreme exemplar secrets can experimentally produce, or counteract, this contrast effect. Preoccupying secrets are burdensome but tests of this phenomenon must take into account whether participants are actually preoccupied with their secrets (i.e., whether their recalled secrets correspond with the experimental manipulation), or experimentally ensure that participants judge their secrets as in line with the manipulation. More broadly, the current research speaks to a fundamental principle of recall manipulations; when recalling a particular experience, correspondence with the manipulation will determine its effects, and the process of recalling an experience (and comparing it to a prompt) might change how one perceives that experience. (PsycINFO Database Record PMID- 27454013 TI - Effect of Praziquantel on the Tegument and Digestive Epithelium Ultrastructure of Brachylaima sp. Metacercariae Parasitizing the Edible Land Snail Cornu aspersum. AB - The edible land snail Cornu aspersum (Pulmonata: Stylommatophora) acts as second intermediate host in the cycle of Brachylaima sp. trematode, harboring free metacercariae in its kidney. The ingestion of undercooked infected snails by humans allows metacercariae to develop to adult stage in the intestine, causing brachylaimiasis. Praziquantel (PZQ) is the drug of choice to treat trematodiasis and it is effective against Brachylaima sp. metacercariae. The objective of this work was to assess, by transmission electron microscopy (TEM), the ultrastructural changes produced on the tegument and gastrodermis of the Brachylaima metacercariae recovered from C. aspersum treated with PZQ in comparison with untreated ones. Snails naturally infected by Brachylaima sp. metacercariae were treated by PZQ both individually and in groups. Metacercariae recovered from treated and control snails were processed for TEM. The tegument of untreated metacercariae was covered by a regular and thick glycocalyx. The syncytial epithelium contained abundant T2 secretory bodies appearing as membrane bound biconcave disk-vesicles with high electron-dense and uniform content. The T2 secretory bodies located along the external area of the syncytium were mainly arranged at right angles to the apical plasma membrane. In treated metacercariae, the content of the T2 secretory bodies appeared altered, degenerating from high to low electron density, losing its uniform appearance and forming high electron dense accumulations scattered around the periphery of the vesicle and separated by low electron-dense spaces. The presence of clusters was detectable in the central area. The characteristic arrangement of the T2 secretory bodies observed in untreated metacercariae was lost in treated ones. Vesicles near the apical area of the tegument no longer maintained their arrangement perpendicular to the apical plasma membrane. The characteristic arrangement of T2 secretory bodies and mitochondria was lost. The T2 secretory bodies were also found altered in the tegumental cell bodies, suggesting that the alterations started at the production stage. Mitochondria were severely degenerated and located in the apical area of the tegument. The digestive system displayed a strong contraction, which included the disappearance of the intracecal lumen. PMID- 27454014 TI - Dark Adaptation at High Altitude: An Unexpected Pupillary Response to Chronic Hypoxia in Andean Highlanders. AB - Healy, Katherine, Alain B. Labrique, J. Jaime Miranda, Robert H. Gilman, David Danz, Victor G. Davila-Roman, Luis Huicho, Fabiola Leon-Velarde, and William Checkley. Dark adaptation at high altitude: an unexpected pupillary response to chronic hypoxia in Andean highlanders. High Alt Med Biol. 17:208-213, 2016. Chronic mountain sickness is a maladaptive response to high altitude (>2500 m above sea level) and is characterized by excessive erythrocytosis and hypoxemia resulting from long-term hypobaric hypoxia. There is no known early predictor of chronic mountain sickness and the diagnosis is based on the presence of excessive erythrocytosis and clinical features. Impaired dark adaptation, or an inability to visually adjust from high- to low-light settings, occurs in response to mild hypoxia and may serve as an early predictor of hypoxemia and chronic mountain sickness. We aimed to evaluate the association between pupillary response assessed by dark adaptometry and daytime hypoxemia in resident Andean highlanders aged >=35 years living in Puno, Peru. Oxyhemoglobin saturation (SpO2) was recorded using a handheld pulse oximeter. Dark adaptation was quantitatively assessed as the magnitude of pupillary contraction to light stimuli of varying intensities (-2.9 to 0.1 log-cd/m2) using a portable dark adaptometer. Individual and stimulus-specific multilevel analyses were conducted using mixed-effect models to elicit the relationship between SpO2 and pupillary responsiveness. Among 93 participants, mean age was 54.9 +/- 11.0 years, 48% were male, 44% were night blind, and mean SpO2 was 89.3% +/- 3.4%. The magnitude of pupillary contraction was greater with lower SpO2 (p < 0.01), and this dose relationship remained significant in multiple variable analyses (p = 0.047). Pupillary responsiveness to light stimuli under dark-adapted conditions was exaggerated with hypoxemia and may serve as an early predictor of chronic mountain sickness. This unexpected association is potentially explained as an excessive and unregulated sympathetic response to hypoxemia at altitude. PMID- 27454015 TI - Tau and beta-Amyloid-The Malignant Duo. PMID- 27454016 TI - Mechanically Flexible Organic Crystals Achieved by Introducing Weak Interactions in Structure: Supramolecular Shape Synthons. AB - Controlling mechanical properties of ordered organic materials remains a formidable challenge, despite their great potential for high performance mechanical actuators, transistors, solar cells, photonics, and bioelectronics. Here we demonstrate a crystal engineering approach to design mechanically reconfigurable, plastically flexible single crystals (of about 10) of three unrelated types of compounds by introducing active slip planes in structures via different noninterfering supramolecular weak interactions, namely van der Waals (vdW), pi-stacking, and hydrogen bonding groups. Spherical hydrophobic groups, which assemble via shape complementarity (shape synthons), reliably form low energy slip planes, thus facilitating an impressive mechanical flexibility, which allowed molding the crystals into alphabetical characters to spell out "o r g a n i c c r y s t a l". The study, which reports the preparation of a series of exotic plastic crystals by design for the first time, demonstrates the potential of soft interactions for tuning the mechanical behavior of ordered molecular materials, including those from pi-conjugated systems. PMID- 27454017 TI - Suppression of false arrhythmia alarms in the ICU: a machine learning approach. AB - This paper presents a novel approach for false alarm suppression using machine learning tools. It proposes a multi-modal detection algorithm to find the true beats using the information from all the available waveforms. This method uses a variety of beat detection algorithms, some of which are developed by the authors. The outputs of the beat detection algorithms are combined using a machine learning approach. For the ventricular tachycardia and ventricular fibrillation alarms, separate classification models are trained to distinguish between the normal and abnormal beats. This information, along with alarm-specific criteria, is used to decide if the alarm is false. The results indicate that the presented method was effective in suppressing false alarms when it was tested on a hidden validation dataset. PMID- 27454018 TI - Letter to the Editor. PMID- 27454019 TI - Screening not staging: a retrospective study of the rate of synchronous primary malignancy in 44 T1/T2 laryngeal cancer in a tertiary head and neck unit. PMID- 27454020 TI - A Method for Promoting Assembly of Metallic and Nonmetallic Nanoparticles into Interfacial Monolayer Films. AB - Two-dimensional metal nanoparticle arrays are normally constructed at liquid-oil interfaces by modifying the surfaces of the constituent nanoparticles so that they self-assemble. Here we present a general and facile new approach for promoting such interfacial assembly without any surface modification. The method use salts that have hydrophobic ions of opposite charge to the nanoparticles, which sit in the oil layer and thus reduce the Coulombic repulsion between the particles in the organic phase, allowing the particles to sit in close proximity to each other at the interface. The advantage of this method is that because it does not require the surface of the particles to be modified it allows nonmetallic particles including TiO2 and SiO2 to be assembled into dense interfacial layers using the same procedure as is used for metallic particles. This opens up a route to a new family of nanostructured functional materials. PMID- 27454021 TI - ISPNE Special Issue Editorial 2016 Stress and the Brain: From Fertility to Senility. PMID- 27454022 TI - Temperature-dependent magnetic properties of Ni nanotubes synthesized by atomic layer deposition. AB - Highly-ordered and conformal Ni nanotube arrays were prepared by combining atomic layer deposition (ALD) in a porous alumina matrix with a subsequent thermal reduction process. In order to obtain NiO tubes, one ALD NiCp2/O3 cycle was repeated 2000 times. After the ALD process, the sample is reduced from NiO to metallic Ni under hydrogen atmosphere. Their magnetic properties such as coercivity and squareness have been determined in a vibrating sample magnetometer in the temperature range from 5-300 K for applied magnetic fields parallel and perpendicular to the nanotube axis. Ni nanotubes synthesized by ALD provide a promising opportunity for potential applications in spintronics, data storage and bio-applications. PMID- 27454023 TI - Review of Lower Extremity Traction in Current Orthopaedic Trauma. AB - Although methods of traction for temporizing and definitive treatment of orthopaedic injuries are described in dated textbooks, current literature and recommendations on the use of skin and skeletal traction in orthopaedic trauma are lacking. Elaborate traction schemas have been described, but few of them have been retained in practice and even fewer have been supported by scientific data. Several options exist for traction modalities that involve the pelvis and lower extremities, including portable traction devices and traction pins. PMID- 27454024 TI - Enchondroma of the Hand: Evaluation and Management. AB - Enchondroma is the most common primary bone tumor of the hand. This benign, cartilaginous tumor often presents as a pathologic fracture. When hand enchondroma is suspected, less common conditions, such as multiple enchondromatosis syndromes and benign and malignant lesions, should be ruled out. Surgical management with curettage is the standard of care for symptomatic lesions. However, controversy surrounds the timing of surgery for pathologic fractures and the use of surgical adjuncts and postcurettage void management. Microscopically distinguishing hand enchondroma from low-grade hand chondrosarcoma is a diagnostic challenge for pathologists, but the primary surgical treatment for both conditions is curettage because the latter has a low metastatic potential. Postoperative complications are typically joint stiffness and soft-tissue[FIGURE DASH]related deformities, whereas recurrence and malignant degeneration of solitary lesions are much less common. Most patients return to full function after surgery. PMID- 27454025 TI - Design and Implementation of the Texas Medicaid DSRIP Program. AB - Texas is one of 8 states that have received a Medicaid 1115 Transformation Waiver in which federal supplemental payments are being used to incentivize delivery system reform. Under the Texas Transformation Waiver's 5-year Delivery System Reform Incentive Payment (DSRIP) program, hospitals and other providers have established regional health care partnerships, conducted regional needs assessments, and developed and implemented projects addressing local gaps in service. The projects were selected from menus, supplied by the Texas Health and Human Services Commission and the Centers for Medicare & Medicaid Services, which defined acceptable infrastructure development and/or program innovation and redesign initiatives. Providers receive payment for planning the projects and achieving metrics and milestones related to project implementation and performance. This article describes the major features of the Texas DSRIP model and the resulting implementation and performance to date in the most populous region of the state. PMID- 27454026 TI - Caulerpa cylindracea Sonder invasion modifies trophic niche in infralittoral rocky benthic community. AB - The Mediterranean basin is one of the most invaded seas of the world. Invasive species have affected coastal benthic communities inducing structural changes. Since first reports, in the early 90s, Caulerpa cylindracea is considered one of the most important invasive event in the Mediterranean Sea where it has invaded large areas of soft bottoms, seagrass meadows and rocky shores. To assess effects of C. cylindracea in rocky ecosystems, benthic food webs have been compared between invaded and non-invaded coastal conditions through stable isotopes analyses. In addition, the convex hull area of the two types of conditions has been calculated as a proxy for the total extent of trophic diversity within each food web. Results have shown that the trophic niche width is at least 1.4 times wider in invaded conditions than in non-invaded conditions. In addition, this study gives further evidence of similar feeding analogies between the invasive herbivore fish, Siganus luridus and native herbivore fish Sparisoma cretense as both are feeding at the same isotopic level. This investigation provides with new scientific data to assess bionvasions in invaded and non-invaded conditions at assemblage level in coastal systems. PMID- 27454027 TI - Evolution of novel therapeutic options for pancreatic cancer. AB - PURPOSE OF REVIEW: Pancreatic cancer is the most devastating of all cancers with an extremely poor prognosis. In US alone, over 50 000 new cases of pancreatic cancer are reported annually, and about the same number succumb to it, making pancreatic cancer the third most common cause of cancer deaths. Most patients with pancreatic cancer present with advanced disease, which cannot be resected surgically, and for these patients chemotherapy is the only option. Even patients who undergo resection require adjuvant therapy to decrease the risk of recurrence. Since the 1950s, a variety of different agents, like antimetabolites, nucleoside analogs, and DNA intercalating compounds, have been used against pancreatic cancer, alone or in combination, with little improvement in the survival statistics. The current article reviews the evolution of chemotherapy for pancreatic cancer, and discusses some novel therapeutic options that are emerging in recent times, with special emphasis on Minnelide, a novel HSP70 inhibitor, which is currently in clinical trials. RECENT FINDINGS: Approaches towards developing therapies for pancreatic cancer have evolved tremendously over the past decade. Research has shown that apart from the inherent drug resistance, drug delivery to pancreatic cancer has also posed a major challenge. The extensive desmoplastic stroma of pancreatic cancer is believed to create inordinately high interstitial fluid pressures leading to vascular collapse and substantial barrier to perfusion of chemotherapeutics, thus creating an additional layer of protection for pancreatic cancer. Recent research thus is focused not only on understanding the biology and developing strategies to target cancer cells, but also is targeted towards the depletion of stroma in order to ensure better delivery of chemotherapeutic compounds to the tumor. SUMMARY: The current article describes the novel therapies that are constantly being evaluated to address and overcome the challenges that make pancreatic cancer a difficult disease to treat. PMID- 27454028 TI - New insights in the development of pancreatic cancer. AB - PURPOSE OF REVIEW: The review intends to describe recent studies on the development of pancreatic cancer from a genetic, molecular, and microenvironment perspective. RECENT FINDINGS: Pancreatic cancer has been discovered to have distinct molecular subtypes based on transcriptome analyses that may have implications for treatment. Recent studies are also mapping the complex molecular biology of this cancer as it relates to the core signaling abnormalities inherent to this disease. There have been discoveries of novel modes of regulation of pancreatic cancer development, including alterations in key transcription factors, epigenetic modifiers, and metabolic pathways. Studies of the tumor associated microenvironment continue to reveal its complex role in tumor development. SUMMARY: Pancreatic cancer development appears to depend on a multifaceted network of signals that are dynamic, involve multiple cell types, and are linked to spatiotemporal factors in tumor evolution. Understanding the development of pancreatic cancer in this context is key to identifying novel and effective targets for treatment. PMID- 27454030 TI - Advances in pancreatology: 2016. PMID- 27454029 TI - Radiofrequency ablation for pancreatobiliary disease. AB - PURPOSE OF REVIEW: Radiofrequency ablation (RFA) has been recognized for its potential in palliative treatment for pancreatic cancer as well as malignant biliary strictures. The purpose of this review is to describe the technology, endoscopic technique, and reported outcomes of endoscopic RFA in the management of malignant biliary strictures and unresectable pancreatic cancer. RECENT FINDINGS: Intraductal biliary RFA is safe and feasible and appears to confer a survival advantage. Pancreatic endoscopic ultrasound-guided RFA is a promising new technique and may result in either resolution of tumor or reduction in size. SUMMARY: Intraductal biliary RFA and pancreatic endoscopic ultrasound-guided RFA are important modalities in malignant biliary obstruction and unresectable pancreatic cancer. Intraductal biliary RFA should be used as an adjunct to biliary stenting. Further trials are needed to determine if RFA leads to a benefit in pancreatic cancer treatment. Two prospective trials are currently underway to determine if intraductal biliary RFA indeed confers a survival advantage in malignant obstruction. PMID- 27454031 TI - Transparent, superhydrophobic, and wear-resistant surfaces using deep reactive ion etching on PDMS substrates. AB - Surfaces that simultaneously exhibit superhydrophobicity, low contact angle hysteresis, and high transmission of visible light are of interest for many applications, such as optical devices, solar panels, and self-cleaning windows. Superhydrophobicity could also find use in medical devices where antifouling characteristics are desirable. These applications also typically require mechanical wear resistance. The fabrication of such surfaces is challenging due to the competing goals of superhydrophobicity and transmittance in terms of the required degree of surface roughness. In this study, deep reactive ion etching (DRIE) was used to create rough surfaces on PDMS substrates using a O2/CF4 plasma. Surfaces then underwent an additional treatment with either octafluorocyclobutane (C4F8) plasma or vapor deposition of perfluorooctyltrichlorosilane (PFOTCS) following surface activation with O2 plasma. The effects of surface roughness and the additional surface modifications were examined with respect to the contact angle, contact angle hysteresis, and optical transmittance. To examine wear resistance, a sliding wear experiment was performed using an atomic force microscope (AFM). PMID- 27454032 TI - The interlace of Bi2S3 nanowires with TiO2 nanorods: An effective strategy for high photoelectrochemical performance. AB - A netlike heterostructure is constructed by interlacing the Bi2S3 nanowires with well-aligned TiO2 nanorod arrays via a facile and effective solvothermal method. The winding Bi2S3 nanowires with several hundred nanometers long and 20-30nm wide are distributed in the interspace of TiO2 nanorods and cross-linked with these nanorods reducing the isolation of nanorods. The photoelectrochemical characterizations show that in addition to the high stability in air without any encapsulation, the netlike heterostructure exhibits an enhanced photoelectrochemical performance compared with TiO2 nanorods and controlled Bi2S3/TiO2 nanoparticle structure. The dual roles of Bi2S3 nanowires (1) as sensitizer for the enlargement of photoresponse range and (2) as multiple electron transport channels facilitating the fast separation of photogenerated electron-hole pairs are considered as key factors for the high energy conversion efficiency of 2.96%. This facile synthesis method offers an attractive strategy to further improve the photoelectrochemical performance of semiconductors and undoubtedly shows promising applications in solar conversion and storage devices. PMID- 27454034 TI - Reply. PMID- 27454035 TI - Correspondence. PMID- 27454033 TI - Mesencephalic representations of recent experience influence decision making. AB - Decisions are influenced by recent experience, but the neural basis for this phenomenon is not well understood. Here, we address this question in the context of action selection. We focused on activity in the pedunculopontine tegmental nucleus (PPTg), a mesencephalic region that provides input to several nuclei in the action selection network, in well-trained mice selecting actions based on sensory cues and recent trial history. We found that, at the time of action selection, the activity of many PPTg neurons reflected the action on the previous trial and its outcome, and the strength of this activity predicted the upcoming choice. Further, inactivating the PPTg predictably decreased the influence of recent experience on action selection. These findings suggest that PPTg input to downstream motor regions, where it can be integrated with other relevant information, provides a simple mechanism for incorporating recent experience into the computations underlying action selection. PMID- 27454036 TI - Impact of Cu(II) Binding on Structures and Dynamics of Abeta42 Monomer and Dimer: Molecular Dynamics Study. AB - The classical force field, which is compatible with the Amber force field 99SB, has been obtained for the interaction of Cu(II) with monomer and dimers of amyloid-beta peptides using the coordination where Cu(II) is bound to His6, His13 (or His14), and Asp1 with distorted planar geometry. The newly developed force field and molecular dynamics simulation were employed to study the impact of Cu(II) binding on structures and dynamics of Abeta42 monomer and dimers. It was shown that in the presence of Cu(II) the beta content of monomer is reduced substantially compared with the wild-type Abeta42 suggesting that, in accord with experiments, metal ions facilitate formation of amorphous aggregates rather than amyloid fibrils with cross-beta structures. In addition, one possible mechanism for amorphous assembly is that the Asp23-Lys28 salt bridge, which plays a crucial role in beta sheet formation, becomes more flexible upon copper ion binding to the Abeta N-terminus. The simulation of dimers was conducted with the Cu(II)/Abeta stoichiometric ratios of 1:1 and 1:2. For the 1:1 ratio Cu(II) delays the Abeta dimerization process as observed in a number of experiments. The mechanism underlying this phenomenon is associated with slow formation of interchain salt bridges in dimer as well as with decreased hydrophobicity of monomer upon Cu-binding. PMID- 27454037 TI - Large-area thermoelectric high-aspect-ratio nanostructures by atomic layer deposition. AB - We report on the thermoelectric properties of large-area high-aspect-ratio nanostructures. We fabricate the structures by atomic layer deposition of conformal ZnO thin films on track-etched polycarbonate substrate. The resulting structure consists of ZnO tubules which continue through the full thickness of the substrate. The electrical and thermal properties of the structures are studied both in-plane and out-of-plane. They exhibit very low out-of-plane thermal conductivity down to 0.15 W m(-1) K(-1) while the in-plane sheet resistance of the films was found to be half that of the same film on glass substrate, allowing material-independent doubling of output power of any planar thin-film thermoelectric generator. The wall thickness of the fabricated nanotubes was varied within a range of up to 100 nm. The samples show polycrystalline nature with (002) preferred crystal orientation. PMID- 27454038 TI - The relocation bump: Memories of middle adulthood are organized around residential moves. AB - The lifetime temporal distribution of older adults' autobiographical memories peaks during the transitional period of late adolescence and early adulthood, a phenomenon known as the reminiscence bump. This age-specific memory enhancement suggests that transitions may provide a more general organizing structure for autobiographical memory. To test this hypothesis, we examined how older adults' memories of events that occurred between the ages of 40 and 60 were distributed around residential relocations occurring within this same time frame. The temporal distribution of memories showed a marked relocation bump around the age of the most important residential move. Although previous research has focused on the negative effects of relocation, the current findings suggest that transitions could have a positive effect on autobiographical memory. (PsycINFO Database Record PMID- 27454039 TI - Physical intelligence does matter to cumulative technological culture. AB - Tool-based culture is not unique to humans, but cumulative technological culture is. The social intelligence hypothesis suggests that this phenomenon is fundamentally based on uniquely human sociocognitive skills (e.g., shared intentionality). An alternative hypothesis is that cumulative technological culture also crucially depends on physical intelligence, which may reflect fluid and crystallized aspects of intelligence and enables people to understand and improve the tools made by predecessors. By using a tool-making-based microsociety paradigm, we demonstrate that physical intelligence is a stronger predictor of cumulative technological performance than social intelligence. Moreover, learners' physical intelligence is critical not only in observational learning but also when learners interact verbally with teachers. Finally, we show that cumulative performance is only slightly influenced by teachers' physical and social intelligence. In sum, human technological culture needs "great engineers" to evolve regardless of the proportion of "great pedagogues." Social intelligence might play a more limited role than commonly assumed, perhaps in tool-use/making situations in which teachers and learners have to share symbolic representations. (PsycINFO Database Record PMID- 27454040 TI - The perceptual and social components of metacognition. AB - When deciding whether or not to bring an umbrella to work, your confidence will be influenced by the sky outside the window (direct evidence) as well as by, for example, whether or not people walking in the street have their own umbrella (indirect or contingent evidence). These 2 distinct aspects of decision confidence have not yet been assessed independently within the same framework. Here we study the relative contributions of stimulus-specific and social contingent information on confidence formation. Dyads of participants made visual perceptual decisions, first individually and then together by sharing their wagers in their decisions. We independently manipulated the sensory evidence and the social consensus available to participants and found that both type of evidence contributed to wagers. Consistent with previous work, the amount people were prepared to wager covaried with the strength of sensory evidence. However, social agreements and disagreement affected wagers in opposite directions and asymmetrically. These different contributions of sensory and social evidence to wager were linearly additive. Moreover, average metacognitive sensitivity-namely the association between wagers and accuracy-between interacting dyad members positively correlated with dyadic performance and dyadic benefit above average individual performance. Our results provide a general framework that accounts for how both social context and direct sensory evidence contribute to decision confidence. (PsycINFO Database Record PMID- 27454041 TI - Reducing implicit racial preferences: II. Intervention effectiveness across time. AB - Implicit preferences are malleable, but does that change last? We tested 9 interventions (8 real and 1 sham) to reduce implicit racial preferences over time. In 2 studies with a total of 6,321 participants, all 9 interventions immediately reduced implicit preferences. However, none were effective after a delay of several hours to several days. We also found that these interventions did not change explicit racial preferences and were not reliably moderated by motivations to respond without prejudice. Short-term malleability in implicit preferences does not necessarily lead to long-term change, raising new questions about the flexibility and stability of implicit preferences. (PsycINFO Database Record PMID- 27454044 TI - Decoupling a hole spin qubit from the nuclear spins. AB - A huge effort is underway to develop semiconductor nanostructures as low-noise hosts for qubits. The main source of dephasing of an electron spin qubit in a GaAs-based system is the nuclear spin bath. A hole spin may circumvent the nuclear spin noise. In principle, the nuclear spins can be switched off for a pure heavy-hole spin. In practice, it is unknown to what extent this ideal limit can be achieved. A major hindrance is that p-type devices are often far too noisy. We investigate here a single hole spin in an InGaAs quantum dot embedded in a new generation of low-noise p-type device. We measure the hole Zeeman energy in a transverse magnetic field with 10 neV resolution by dark-state spectroscopy as we create a large transverse nuclear spin polarization. The hole hyperfine interaction is highly anisotropic: the transverse coupling is <1% of the longitudinal coupling. For unpolarized, randomly fluctuating nuclei, the ideal heavy-hole limit is achieved down to nanoelectronvolt energies; equivalently dephasing times up to a microsecond. The combination of large and strong optical dipole makes the single hole spin in a GaAs-based device an attractive quantum platform. PMID- 27454045 TI - Spider silk: Dynamic mechanics. PMID- 27454042 TI - Individual differences in the executive control of attention, memory, and thought, and their associations with schizotypy. AB - A large correlational study took a latent-variable approach to the generality of executive control by testing the individual-differences structure of executive attention capabilities and assessing their prediction of schizotypy, a multidimensional construct (with negative, positive, disorganized, and paranoid factors) conveying risk for schizophrenia. Although schizophrenia is convincingly linked to executive deficits, the schizotypy literature is equivocal. Subjects completed tasks of working memory capacity (WMC), attention restraint (inhibiting prepotent responses), and attention constraint (focusing visual attention amid distractors), the latter 2 in an effort to fractionate the "inhibition" construct. We also assessed mind-wandering propensity (via in-task thought probes) and coefficient of variation in response times (RT CoV) from several tasks as more novel indices of executive attention. WMC, attention restraint, attention constraint, mind wandering, and RT CoV were correlated but separable constructs, indicating some distinctions among "attention control" abilities; WMC correlated more strongly with attentional restraint than constraint, and mind wandering correlated more strongly with attentional restraint, attentional constraint, and RT CoV than with WMC. Across structural models, no executive construct predicted negative schizotypy and only mind wandering and RT CoV consistently (but modestly) predicted positive, disorganized, and paranoid schizotypy; stalwart executive constructs in the schizophrenia literature-WMC and attention restraint-showed little to no predictive power, beyond restraint's prediction of paranoia. Either executive deficits are consequences rather than risk factors for schizophrenia, or executive failures barely precede or precipitate diagnosable schizophrenia symptoms. (PsycINFO Database Record PMID- 27454043 TI - Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model. AB - Conventional cancer therapies involve the systemic delivery of anticancer agents that neither discriminate between cancer and normal cells nor eliminate the risk of cancer recurrence. Here, we demonstrate that the combination of gene, drug and phototherapy delivered through a prophylactic hydrogel patch leads, in a colon cancer mouse model, to complete tumour remission when applied to non-resected tumours and to the absence of tumour recurrence when applied following tumour resection. The adhesive hydrogel patch enhanced the stability and provided local delivery of embedded nanoparticles. Spherical gold nanoparticles were used as a first wave of treatment to deliver siRNAs against Kras, a key oncogene driver, and rod-shaped gold nanoparticles mediated the conversion of near-infrared radiation into heat, causing the release of a chemotherapeutic as well as thermally induced cell damage. This local, triple-combination therapy can be adapted to other cancer cell types and to molecular targets associated with disease progression. PMID- 27454046 TI - Nonlinear control of high-frequency phonons in spider silk. AB - Spider dragline silk possesses superior mechanical properties compared with synthetic polymers with similar chemical structure due to its hierarchical structure comprised of partially crystalline oriented nanofibrils. To date, silk's dynamic mechanical properties have been largely unexplored. Here we report an indirect hypersonic phononic bandgap and an anomalous dispersion of the acoustic-like branch from inelastic (Brillouin) light scattering experiments under varying applied elastic strains. We show the mechanical nonlinearity of the silk structure generates a unique region of negative group velocity, that together with the global (mechanical) anisotropy provides novel symmetry conditions for gap formation. The phononic bandgap and dispersion show strong nonlinear strain-dependent behaviour. Exploiting material nonlinearity along with tailored structural anisotropy could be a new design paradigm to access new types of dynamic behaviour. PMID- 27454048 TI - Nanoparticles: Neither solid nor liquid. PMID- 27454047 TI - Thermally stable coexistence of liquid and solid phases in gallium nanoparticles. AB - Gallium (Ga), a group III metal, is of fundamental interest due to its polymorphism and unusual phase transition behaviours. New solid phases have been observed when Ga is confined at the nanoscale. Herein, we demonstrate the stable coexistence, from 180 K to 800 K, of the unexpected solid gamma-phase core and a liquid shell in substrate-supported Ga nanoparticles. We show that the support plays a fundamental role in determining Ga nanoparticle phases, with the driving forces for the nucleation of the gamma-phase being the Laplace pressure in the nanoparticles and the epitaxial relationship of this phase to the substrate. We exploit the change in the amplitude of the evolving surface plasmon resonance of Ga nanoparticle ensembles during synthesis to reveal in real time the solid core formation in the liquid Ga nanoparticle. Finally, we provide a general framework for understanding how nanoscale confinement, interfacial and surface energies, and crystalline relationships to the substrate enable and stabilize the coexistence of unexpected phases. PMID- 27454049 TI - Structural biology of glutamate receptor ion channel complexes. AB - Chemical transmission at excitatory synapses in the brain is mediated by a diverse family of glutamate receptor ion channels (iGluRs), tetrameric membrane protein assemblies of molecular weight 400-600kDa. Until recently, structural information for intact iGluRs was limited to biochemically tractable homomeric receptors trapped in different conformational states. These provided key insights into the mechanisms of iGluR activation and desensitization. Structures of heteromeric AMPA and NMDA receptors, the major iGluR families in the brain, together with long awaited cryo-EM structures of an AMPA receptor TARP complex, expand this picture and reveal surprising conformational diversity, raising many fundamental and controversial questions. PMID- 27454050 TI - Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials. AB - BACKGROUND: Choice of antihypertensive drugs is also based on the expected burden of adverse events associated with each class of agents, and we have recently identified treatment discontinuation for adverse events as a measure of treatment tolerability frequently reported in randomized controlled trials (RCTs). OBJECTIVES: To investigate whether all classes of blood pressure (BP) lowering drugs increase discontinuations for adverse events when compared with placebo and whether risk of discontinuation is similar for all classes when compared in head to-head RCTs. METHODS: RCTs of BP-lowering treatment were subdivided in groups according to class of drug compared with placebo or with other classes. Risk ratios and 95% confidence intervals of major cardiovascular events and of treatment discontinuations for adverse events were calculated (random-effects model). RESULTS: Thirty-eight placebo-controlled RCTs (147 788 patients) and 37 head-to-head RCTs (242 481 patients) provided comparative information on discontinuations for adverse events. All classes of drugs significantly increased discontinuations for adverse events over those occurring on placebo: risk ratio diuretics 2.23 (1.32-3.76), beta-blockers 2.88 (1.58-5.28), calcium antagonists 2.03 (1.17-3.56), angiotensin-converting enzyme inhibitors 2.78 (1.37-5.47), central agents 1.74 (1.24-2.45), with the single exception of angiotensin receptor blockers, which did not significantly increase adverse events over placebo [risk ratio 1.13 (0.78-1.62)]. Similarly, in head-to-head comparison RCTs with other classes, angiotensin receptor blockers were the only class associated with a significantly lower risk of adverse events [risk ratio 0.71 (0.58-0.87)] when head-to-head compared with other classes. Regression analysis also shows that incidence of discontinuations for adverse events is proportional to the number of antihypertensive and other cardiovascular drugs, which accounts for the high incidence of this outcome often found in groups randomized to placebo. CONCLUSION: Reduction of cardiovascular events by all classes of BP-lowering drugs is accompanied by increased treatment discontinuations for adverse events, except when angiotensin receptor blockers are used. Treatment discontinuations are also related to treatment often accompanying antihypertensive agents. PMID- 27454051 TI - Outcome of simple decompression of the compressed ulnar nerve at the elbow - influence of smoking, gender, and electrophysiological findings. AB - BACKGROUND: Compression of the ulnar nerve at elbow is frequently treated with simple decompression. Knowledge about factors influencing results of surgery of the nerve is limited and contradictory. The primary aim was to evaluate outcome of simple decompression of the nerve using a QuickDASH questionnaire, and to investigate any influence of smoking, gender, and preoperative electrophysiological findings. A second aim was to estimate the relation between QuickDASH score and a clinical assessment of outcome by the surgeon. METHODS: Patients who were operated on with simple decompression of the ulnar nerve, excluding reoperations, from September 2009 to February 2011 were evaluated before and at 1 year after surgery using QuickDASH. Data were collected from medical records and from a self-reported health declaration. RESULTS: There were no differences in QuickDASH scores or change in total score between smokers and non-smokers or between women and men. Nerve pathology, assessed by preoperative electrophysiology, did not affect outcome. The surgeon's assessment of outcome mirrored QuickDASH score. Among all patients, 12/33 (36%) did not have a decrease in QuickDASH score >8, which is considered as a minimal clinically important difference. CONCLUSION: Smoking, gender, and preoperative electrophysiological findings do not affect outcome of surgery. There are a high number of patients who do not benefit from simple decompression of the ulnar nerve at the elbow. Patients who are planned for surgery should be informed that there is a risk for persistent problems. A simple outcome assessment by the surgeon mirrors QuickDASH score at 1 year. PMID- 27454052 TI - Examining the Relationship Between Clinical Judgment and Nursing Actions in Prelicensure Students. AB - Faculty frequently use the Lasater Clinical Judgment Rubric (LCJR) to identify students' clinical judgment; however, it is unclear whether LCJR scores relate to appropriate nursing action. In a pilot study consisting of senior-level nursing students (N = 22), participants were scored on the LCJR and anticipated nursing actions, and results were analyzed using simple linear regression. There was a statistically significant correlation (r = 0.364) between clinical judgment and nursing action. Results suggest that total LCJR scores may be an indicator of the completion of indicated nursing action. PMID- 27454053 TI - Using Evidence-based Education to Guide Quality Improvement in a Graduate Online Nursing Program: Group Projects as an Exemplar. PMID- 27454054 TI - Virtually Nursing: Emerging Technologies in Nursing Education. AB - Augmented reality and virtual simulation technologies in nursing education are burgeoning. Preliminary evidence suggests that these innovative pedagogical approaches are effective. The aim of this article is to present 6 newly emerged products and systems that may improve nursing education. Technologies may present opportunities to improve teaching efforts, better engage students, and transform nursing education. PMID- 27454055 TI - Nurse Faculty Knowledge of and Confidence in Teaching Genetics/Genomics: Implications for Faculty Development. AB - The aims of this project were to (1) assess nurse faculty members' knowledge of and confidence in teaching genetics/genomics to nursing students and (2) identify the needs of faculty members to inform a faculty development initiative. Significant knowledge gaps were noted, and more than 50% of respondents indicated that they lacked confidence in teaching genetics/genomics. Strategies to address this problem included identifying champions of genetics/genomics education, use of an educational template, and threading genetics/genomics throughout the curriculum. PMID- 27454056 TI - Barriers to Civil Academic Work Environments: Experiences of Academic Faculty Leaders. AB - Faculty-to-faculty incivility negatively affects not only the victim of the uncivil behavior but also the nursing program as a whole. This phenomenological study explored the experiences of academic nurse administrators who have dealt with incivility among and between faculty members. An interpretative approach was used to uncover themes, and suggestions are made for managing faculty-to-faculty incivility. PMID- 27454057 TI - Scholarly Joy-Stealing: 10 Mean Games Educators Play and How to Imagine Something Different Together. PMID- 27454058 TI - Engaging Nursing Students in an Edible Pharmacological Concepts Lesson: Cookies in the Curriculum. PMID- 27454059 TI - Using Innovative Teaching Strategies to Improve Nursing Student Competence and Confidence in Providing Spiritual Care. PMID- 27454060 TI - Appreciative Advising in Nursing Education. AB - The 6-phase Appreciative Advising framework for academic advising has been incorporated into a nursing program in the southeast United States, with promising initial results. Historical perspectives of academic advising, an overview of Appreciative Advising, and implementation of the framework are presented. PMID- 27454061 TI - What Are the Facts About Autism Spectrum Disorders, Selective Serotonin Reuptake Inhibitors, and Assisted Reproductive Technology? PMID- 27454062 TI - Sensitive imaging and effective capture of Cu(2+): Towards highly efficient theranostics of Alzheimer's disease. AB - As a distinct feature of Alzheimer's disease (AD), the presence of excess metal ions in the brain is most probably one of the main causative factors for the aggregation of beta-Amyloid (Abeta) proteins. The design of nanoprobes for detection and control of ion concentrations will be of great importance in predicting the progression of AD and simultaneously providing effective treatments. Herein, we report the design and synthesis of a novel yet smart nanoprobe that can sensitively detect the Cu(2+) concentration and concurrently capture Cu(2+) both in vitro and in vivo. The designed nanoprobe (UCHQ) combines two main components: upconversion nanoparticles (UCNPs) used for the detection and upconversion luminescence (UCL) imaging of Cu(2+) upon 980 nm exposure and the chelator 8-hydroxyquinoline-2-carboxylic acid (HQC) used for chelating Cu(2+) and AD therapy. The results show that the emission intensity of UCHQ is highly dependent on the Cu(2+) concentrations due to the luminescence resonance energy transfer (LRET) from UCNPs to HQC-bonded Cu(2+). Fascinatingly, the as constructed UCHQs could be used for UCL imaging of Abeta both in cells and AD mice. Most importantly, UCHQs could not only inhibit the Abeta aggregation induced apoptosis via capturing overmuch Cu(2+) but also accelerate the nontoxic structural transformation of Abeta. PMID- 27454063 TI - Surface delivery of tunable doses of BMP-2 from an adaptable polymeric scaffold induces volumetric bone regeneration. AB - The rapid and effective bone regeneration of large non-healing defects remains challenging. Bioactive proteins, such as bone morphogenetic protein (BMP)-2, are proved their osteoinductivity, but their clinical use is currently limited to collagen as biomaterial. Being able to deliver BMP-2 from any other biomaterial would broaden its clinical use. This work presents a novel means for repairing a critical size volumetric bone femoral defect in the rat by combining a osteoinductive surface coating (2D) to a polymeric scaffold (3D hollow tube) made of commercially-available PLGA. Using a polyelectrolyte film as BMP-2 carrier, we tune the amount of BMP-2 loaded in and released from the polyelectrolyte film coating over a large extent by controlling the film crosslinking level and initial concentration of BMP-2 in solution. Using microcomputed tomography and quantitative analysis of the regenerated bone growth kinetics, we show that the amount of newly formed bone and kinetics can be modulated: an effective and fast repair was obtained in 1-2 weeks in the best conditions, including complete defect bridging, formation of vascularized and mineralized bone tissue. Histological staining and high-resolution computed tomography revealed the presence of bone regeneration inside and around the tube with spatially distinct organization for trabecular-like and cortical bones. The amount of cortical bone and its thickness increased with the BMP-2 dose. In view of the recent developments in additive manufacturing techniques, this surface-coating technology may be applied in combination with various types of polymeric or metallic scaffolds to offer new perspectives of bone regeneration in personalized medicine. PMID- 27454065 TI - Solvent Effects on Molecular Aggregation in 4-(5-Heptyl-1,3,4-thiadiazol-2 yl)benzene-1,3-diol and 4-(5-Methyl-1,3,4-thiadiazol-2-yl)benzene-1,3-diol. AB - The article presents the results of spectroscopic studies of 4-(5-methyl-1,3,4 thiadiazol-2-yl)benzene-1,3-diol (C1) and 4-(5-heptyl-1,3,4-thiadiazol-2 yl)benzene-1,3-diol (C7) in organic solvent solutions. Depending on the concentration of the compound used, three bands were observed in the fluorescence emission spectra of the compounds in DMSO solutions. A single band was observed in methanol, propan-2-ol, or ethanol. The significantly shortened fluorescence lifetimes and the different shapes of circular dichroism (CD) spectra clearly indicate association of the fluorescence effects with the aggregation processes in the analyzed compounds. The differences in the course of the CD spectra also imply an effect of the substituent group structure on the molecule aggregation interactions. Therefore, it has been postulated that the occurrence of the different spectral forms induced by changes in the compound concentration may be related to the aggregation effects of C1 and C7 molecules, which are also induced by differences in the alkyl substituent structure. PMID- 27454064 TI - In vivo biodistribution studies and ex vivo lymph node imaging using heavy metal free quantum dots. AB - Quantum dots (QDs) are attractive photoluminescence probes for biomedical imaging due to their unique photophysical properties. However, the potential toxicity of QDs has remained a major obstacle to their clinical use because they commonly incorporate the toxic heavy metal cadmium within the core of the QDs. In this work, we have evaluated a novel type of heavy metal-free/cadmium-free and biocompatible QD nanoparticles (bio CFQD((r)) nanoparticles) with a good photoluminescence quantum yield. Sentinel lymph node mapping is an increasingly important treatment option in the management of breast cancer. We have demonstrated their potential for lymph node mapping by ex vivo imaging of regional lymph nodes after subcutaneous injection in the paw of rats. Using photoluminescence imaging and chemical extraction measurements based on elemental analysis by inductively coupled plasma mass spectroscopy, the quantum dots are shown to accumulate quickly and selectively in the axillary and thoracic regional lymph nodes. In addition, lifetime imaging microscopy of the QD photoluminescence indicates minimal perturbation to their photoluminescence properties in biological systems. PMID- 27454066 TI - Optimizing Prone Cardiopulmonary Resuscitation: Identifying the Vertebral Level Correlating With the Largest Left Ventricle Cross-Sectional Area via Computed Tomography Scan. AB - BACKGROUND: Placing the patient in the prone position frequently is required for some surgical procedures. If cardiac arrest occurs and the patient cannot be safely turned supine, cardiopulmonary resuscitation (CPR) may need to be performed with the patient in the prone position. Although clear landmarks have been defined for supine CPR, the optimal hand position for CPR in the prone position has not been clearly determined. The purpose of this study was to determine anatomically the optimal hand position for CPR in the prone position. METHODS: We reviewed retrospectively the chest computed tomography images of 100 patients taken in the prone position. The vertebral body levels crossing the medial angle of the scapula, the inferior angle of the scapula, and the spinous process of the vertebral body connected to the most inferior rib were identified, and we selected the image level at which the left ventricular (LV) cross sectional area was the largest. This level was defined as the optimal compression level and correlated to surface anatomical landmarks. We calculated the ratio of the distance from the C7 spinous process to the level of the largest LV cross sectional area divided by the distance from the C7 spinous process to the spinous process of the vertebral body connected with the most inferior rib. RESULTS: The level of the largest LV cross-sectional area in the prone position was 1 vertebral segment below the inferior angle of the scapula in 45% (99% confidence interval [CI], 33-58) of patients and 0 to 2 vertebral segments below that in 95% (99% CI, 86-98) of patients. The mean (SD) ratio of the distance from the C7 spinous process to the level of the largest LV cross-sectional area divided by the distance from the C7 spinous process to T12 spinous process was 67% +/- 7% (99% CI, 65-69). CONCLUSIONS: When the patient is positioned prone, the largest LV cross-sectional area is 0 to 2 vertebral segments below the inferior angle of the scapula in at least 86% of patients. Further studies are needed to determine whether this position is optimal for chest compressions in the prone position. PMID- 27454067 TI - Unlocking the Mechanisms of Anesthesia. PMID- 27454068 TI - Analgesia and Sedation Protocol for Mechanically Ventilated Postsurgical Children Reduces Benzodiazepines and Withdrawal Symptoms-But Not in All Patients. AB - Background We demonstrated recently that the implementation of a nurse-driven analgesia and sedation protocol (pediatric analgesia and sedation protocol [pASP]) for mechanically ventilated nonpostsurgical patients reduces the total dose of benzodiazepines and the withdrawal symptoms significantly. It has not been investigated if these results can also be expected in the group of patients undergoing surgery. Objectives To evaluate the effects of the pASP in mechanically ventilated postsurgical children regarding drug dosage, duration of mechanical ventilation, length of stay, and rate of withdrawal symptoms. Methods This is a two-phase prospective observational control study. The preimplementation group was managed by the physician's order and the postimplementation group was managed with the pASP including COMFORT-B, nurse interpretation of sedation, and Sophia observation withdrawal symptoms scale scoring. Measurements and Main Results One hundred and sixteen patients were included before and one hundred and ten patients after implementation. The pASP had no effect on length of pediatric intensive care unit stay or duration of mechanical ventilation. The protocol reduced total (5.0 mg/kg [0.5-58.0] vs 4.0 mg/kg [0.0-47.0]; p = 0.021) and daily doses (4.4 mg/kg/d [1.1-33.9] vs 2.9 mg/kg/d [0.0-9.9]; p < 0.001) of benzodiazepines significantly. No difference was observed in total and daily doses of opioids (5.0 mg/kg [0.1-67.0] vs 3.0 mg/kg [0.1-71.0]; p = 0.81) and (0.7 mg/kg/d [0.0-7.0] vs. 0.8 mg/kg/d [0.0-3.7]; p = 0.35), respectively. Rate of withdrawal symptoms was significantly lower after implementation (35.3 vs 20.0%; p = 0.01), but not in patients after solid organ transplantation or oncological patients. Conclusion The nurse-driven analgesia and sedation protocol is an effective procedure to reduce the total doses of benzodiazepines and occurrence of withdrawal symptoms in postsurgical children, which are naive to opioids or benzodiazepines. PMID- 27454069 TI - Laparoscopic Repair for Perforated Peptic Ulcer in Children. AB - Introduction A perforated peptic ulcer (PPU) is a rare but major complication of gastroduodenal peptic ulcer disease. Literature is scarce on this subject in the pediatric population and most articles describe a surgical treatment by laparotomy. We aim to review all our cases of pediatric PPU treated over the past 16 years and compare these to literature to deduce potential benefits and disadvantages regarding laparoscopic treatment of PPU in children. Materials and Methods A retrospective study of all cases of PPU treated at the Lenval Hospital in Nice (France) and the Queen Fabiola University Hospital for Children in Brussels (Belgium) between 1998 and 2015 was performed. Results A total of five children were treated for PPU (2 females). The average age was 11 years (range, 3 17). All of them were surgically treated with laparoscopic simple suture of the perforation and placement of an omental patch. There were no mortalities, no conversions, and no extra-abdominal complications or wound dehiscences. Mean operating time was 78.6 minutes (range, 70-115 minutes). Mean duration of intravenous treatment was 6 days (range, 4-12 days). One reintervention was performed for abdominal infection. In one patient, an abdominal drain was left in place for 2 days. The mean time before refeeding was 3.4 days (range, 3-4 days) and mean length of stay was 12 days (range, 7-30 days). Conclusion Laparoscopic repair is safe and feasible for PPU and should be the gold standard for treatment of PPU in children. PMID- 27454070 TI - Patient-derived tumor xenograft models for melanoma drug discovery. AB - INTRODUCTION: Cutaneous metastatic melanoma (MM) is an aggressive form of skin cancer, with treatment providing cures to a minority of patients. The multiple risk factors that contribute to MM development suggest that cutaneous melanomas embody a repertoire of altered genetic events requiring studies to better understand its biology in order to develop novel therapies. AREAS COVERED: Patient-derived tumor xenograft (PDTX) mouse models are noted to be superior for novel drug discovery and tumor biology studies due to their ability to maintain tumor heterogeneity and their use as real-time individualized patient models. In this review, the authors highlight the utility of PDTX models in advancing treatment options for patients with MM by creating invaluable preclinical models that exhibit patient-relevant treatment outcomes. EXPERT OPINION: There is a strong necessity to reassess current approaches in which preclinical experiments are designed and executed in order to minimize unwarranted clinical trials. With rigorously performed preclinical studies, PDTX models have the capability to effectively confirm or deny drug effective outcomes. The ability to do this, however, will demand better aids to guide experimental design, the redefining of preclinical efficacy, and the understanding that these models should be viewed as complementary to other drug prediction and efficacy tools. PMID- 27454071 TI - Course of IL-2-inducible T-cell kinase deficiency in a family: lymphomatoid granulomatosis, lymphoma and allogeneic bone marrow transplantation in one sibling; and death in the other. PMID- 27454073 TI - Medical Care When Memory Fails. PMID- 27454072 TI - Halfway there: the past, present and future of haploidentical transplantation. AB - In recent years, the use of haploidentical donors for hematopoietic cell transplantation has expanded rapidly. Approximately 50% of patients requiring hematopoietic cell transplant lack a traditional donor. The use of HLA haploidentical-related donors is attractive due to nearly universal availability of this graft source. We summarize the current and future need for haploidentical donors and detail the rise of post-transplant cyclophosphamide as the dominant haploidentical approach. Further, we examine ongoing controversies in the field of haploidentical transplant, including conditioning regimens and graft source. Finally, we review the evidence available from preliminary comparative studies and discuss future direction of research. PMID- 27454074 TI - New molecular targets for the treatment of sarcoidosis. AB - PURPOSE OF REVIEW: Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn's disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies. RECENT FINDINGS: Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis. SUMMARY: Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease. PMID- 27454075 TI - Visual orienting in children with autism: Hyper-responsiveness to human eyes presented after a brief alerting audio-signal, but hyporesponsiveness to eyes presented without sound. AB - Autism Spectrum Disorder (ASD) has been associated with reduced orienting to social stimuli such as eyes, but the results are inconsistent. It is not known whether atypicalities in phasic alerting could play a role in putative altered social orienting in ASD. Here, we show that in unisensory (visual) trials, children with ASD are slower to orient to eyes (among distractors) than controls matched for age, sex, and nonverbal IQ. However, in another condition where a brief spatially nonpredictive sound was presented just before the visual targets, this group effect was reversed. Our results indicate that orienting to social versus nonsocial stimuli is differently modulated by phasic alerting mechanisms in young children with ASD. Autism Res 2017, 10: 246-250. (c) 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research. PMID- 27454076 TI - Mitigating Prenatal Zika Virus Infection in the Americas. AB - Background: Because of the risk for Zika virus infection in the Americas and the links between infection and microcephaly, other serious neurologic conditions, and fetal death, health ministries across the region have advised women to delay pregnancy. However, the effectiveness of this policy in reducing prenatal Zika virus infection has yet to be quantified. Objective: To evaluate the effectiveness of pregnancy-delay policies on the incidence and prevalence of prenatal Zika virus infection. Design: Vector-borne Zika virus transmission model fitted to epidemiologic data from 2015 to 2016 on Zika virus infection in Colombia. Setting: Colombia, August 2015 to July 2017. Patients: Population of Colombia, stratified by sex, age, and pregnancy status. Intervention: Recommendations to delay pregnancy by 3, 6, 9, 12, or 24 months, at different levels of adherence. Measurements: Weekly and cumulative incidence of prenatal infections and microcephaly cases. Results: With 50% adherence to recommendations to delay pregnancy by 9 to 24 months, the cumulative incidence of prenatal Zika virus infections is likely to decrease by 17% to 44%, whereas recommendations to delay pregnancy by 6 or fewer months are likely to increase prenatal infections by 2% to 7%. This paradoxical exacerbation of prenatal Zika virus exposure is due to an elevated risk for pregnancies to shift toward the peak of the outbreak. Limitation: Sexual transmission was not explicitly accounted for in the model because of limited data but was implicitly subsumed within the overall transmission rate, which was calibrated to observed incidence. Conclusion: Pregnancy delays can have a substantial effect on reducing cases of microcephaly but risks exacerbating the Zika virus outbreak if the duration is not sufficient. Duration of the delay, population adherence, and the timing of initiation of the intervention must be carefully considered. Primary Funding Source: National Institutes of Health. PMID- 27454077 TI - Developing a cognitive behavioral therapy manual for delayed sleep-wake phase disorder. AB - This article reports the development of a treatment protocol, based on cognitive behavioral therapy (CBT) principles, for delayed sleep-wake phase disorder (DSWPD). The protocol consists of psycho-education, presenting a CBT model for DSWPD, case formulation, motivational interviewing, registering sleep in a diary, strategies to improve the rhythm of sleep and wakefulness, relaxation training, cognitive restructuring, strategies to cope with daytime symptoms, constructing an individualized CBT program, and learning how to deal with relapses. Qualitative data, focusing on how the patients perceived the protocol, were collected within the realm of a trial exploring the efficacy of the protocol. These findings highlighted several advantages but also disadvantages of the therapy. It is our hope that this paper might act as a platform for further clinical work and future research efforts in patients with DSWPD. PMID- 27454078 TI - A complicated case of splenic injury after colonoscopy - a video vignette. PMID- 27454079 TI - TLR9 re-expression in cancer cells extends the S-phase and stabilizes p16(INK4a) protein expression. AB - Toll-like receptor 9 (TLR9) recognizes bacterial, viral or cell damage-associated DNA, which initiates innate immune responses. We have previously shown that TLR9 expression is downregulated in several viral induced cancers including HPV16 induced cervical neoplasia. Findings supported that downregulation of TLR9 expression is involved in loss of anti-viral innate immunity allowing an efficient viral replication. Here we investigated the role of TLR9 in altering the growth of transformed epithelial cells. Re-introducing TLR9 under the control of an exogenous promoter in cervical or head and neck cancer patient-derived cells reduced cell proliferation, colony formation and prevented independent growth of cells under soft agar. Neither TLR3, 7, nor the TLR adapter protein MyD88 expression had any effect on cell proliferation, indicating that TLR9 has a unique role in controlling cell growth. The reduction of cell growth was not due to apoptosis or necrosis, yet we observed that cells expressing TLR9 were slower in entering the S-phase of the cell cycle. Microarray-based gene expression profiling analysis highlighted a strong interferon (IFN) signature in TLR9 expressing head and neck cancer cells, with an increase in IFN-type I and IL-29 expression (IFN-type III), yet neither IFN-type I nor IL-29 production was responsible for the block in cell growth. We observed that the protein half-life of p16(INK4a) was increased in TLR9-expressing cells. Taken together, these data show for the first time that TLR9 affects the cell cycle by regulating p16(INK4a) post-translational modifications and highlights the role of TLR9 in the events that lead to carcinogenesis. PMID- 27454080 TI - Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3 FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion. AB - Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression. PMID- 27454081 TI - Determination of low-molecular-weight organic acids in non-small cell lung cancer with a new liquid chromatography-tandem mass spectrometry method. AB - As compared to other classes of metabolites, determination of organic acids is an underrepresented field in cancer research and till now there has been a lack of appropriate analytical procedure for determination of serum levels of organic acids potentially associated with cancer development. The aim of the study was to develop a new rapid liquid chromatography-tandem mass spectrometry method for the quantification of six low-molecular-weight organic acids in human serum and to apply this method in an analysis of samples collected from non-small cell lung cancer (NSCLC) patients and a matched control group. The samples were prepared by solid phase extraction (Clean-up CUQAX, UCT). Chromatography was conducted on a Synergi Hydro-RP column (Phenomenex) and a gradient run of 15min. Detection was performed using a negative multiple reaction monitoring mode. The calibration ranges were as follows: 0.24-38.42MUmol/L for 2-hydroxybutyric acid, 0.09 17.23MUmol/L for fumaric acid, 0.08-15.13MUmol/L for glutaric acid, 0.11 2.22mmol/L for lactic acid, 0.39-30.98MUmol/L for pyroglutamic acid, and 0.08 16.93MUmol/L for succinic acid. Mean relative recovery range was 85.99-114.42% and the determined intra- and inter day coefficients of variation were <=14%. Among the studied acids, pyroglutamic acid showed the best discriminating potential and enabled to identify accurately NSCLC patients and control subjects regardless of the cancer stage. Further investigations of serum organic acids may allow us to better understand the underlying mechanisms involved in NSCLC and develop novel means of its detection and treatment. The developed method may be also a valuable tool to study metabolic changes associated with other types of cancer. PMID- 27454083 TI - Quality standardization of herbal medicines using effective compounds combination as labeled constituents. AB - Selection of suitable labeled constituents is vital for the quality standardization of herbal medicines (HMs). However, discovery of labeled constituents that can account for the whole efficacy of original HMs is a challenging issue. Taking tanshinones extract (TE) as an example, a strategy to establish reasonable quality control method using effective compounds combination (ECC) as labeled constituents was proposed. The strategy consists of three core steps, including chemical profiling of TE, discovery and in vivo process research of ECC, and quality standardization based on ECC. Using this strategy, a combination of four tanshinones (tanshinones IIA, cryptotanshinone, tanshinone I and dihydrotanshinone I), which was as effective as TE in cell models and in a rat model of myocardial ischemia-reperfusion, was identified as ECC in TE. Furthermore, quality standardization of TE was established based on proposed ECC using single standard for determination of multiple components (SSDMC) method. In conclusion, the presently developed ECC-based approach not only offers new insight into the understanding of the holistic effects of HMs, but also provides efficacy-associated labeled constituents for quality control of botanicals. PMID- 27454082 TI - Development of a novel sectional multiple filtering scheme for rapid screening and classifying metabolites of ziyuglycoside II in rat liver and excreta specimen based on high-resolution mass spectrometry. AB - Ziyuglycoside II, one of the major effective ingredients of Sanguisorba officinalis L., had various pharmacological activities including anticancer, anti inflammation and anti-oxidation, etc. Better understanding of the pharmacology and toxicology of ziyuglycoside II requires the detailed elucidation of its biologic fates in vivo. Herein, the metabolic fate of ziyuglycoside II in rats was investigated based on liquid chromatography coupled with quadrupole time-of flight mass spectrometry (LC-Q-TOF/MS). To accelerate and simplify the process of metabolite identification from complicated biological matrix, the sectional multiple filtering (SMF) scheme was designed according to the relationship among the molecular weight (MW), mass defect (MD) and retention time (tR) of the metabolites. SMF-I (MW: 700-850Da, MD: 0.40-0.45Da, tR: 4.0-10.0min), SMF-II (MW: 550-700Da, MD: 0.30-0.40Da, tR: 6.0-14.0min) and SMF-III (MW: 400-550Da, MD at 0.25-0.35Da, tR at 9.5-16.0min) were built and utilized to screen phase II conjugations and phase I redox metabolites and deglycosylated derivatives, respectively. As a result, dozens of metabolites, including glucuronic conjugates, hydroxylation, oxidization, dehydration and deglycosylation products, were rapidly discovered, classified and structural identified in rat urine and feces based on SMF scheme and accurate MS(1)/MS(2) information. Obviously, the SMF technique showed superior efficiency and selectivity in ziyuglycoside II metabolite identification. More importantly, SMF would find its extensive application in, but not limited to, the metabolic study for single drug or homologous compounds in traditional Chinese medicine. PMID- 27454084 TI - Quantitative determination of sulfisoxazole and its three N-acetylated metabolites using HPLC-MS/MS, and the saturable pharmacokinetics of sulfisoxazole in mice. AB - Sulfisoxazole (SFX) is still used in combination with trimethoprim in cattle despite adverse drug reactions (e.g., urolithiasis). Recently, SFX is known to be a promising repositioned drug candidate for pulmonary hypertension and cancer. We developed a simultaneous determination method of SFX and its N-acetylated metabolites (N(1)-acetyl SFX, N1AS; N(4)-acetyl SFX, N4AS; diacetyl SFX, DAS) using HPLC-MS/MS for the first time, and examined the pharmacokinetics of SFX in mice. N1AS and DAS were converted rapidly to SFX and N4AS, respectively, in mouse plasma. The time courses of plasma SFX and N4AS concentrations were well characterised following the oral administration of SFX to mice. The absorption, metabolism, and/or excretion of SFX given at >700mg/kg may be saturable, and in contrast to humans and rats, the extent of systemic exposure of mice to N4AS was much greater than that of SFX. Interestingly, the acetyl groups at both N1- and N4-positions were degraded during the ionisation required to generate precursor ions. In additional experiments the carboxyl group of N-acetyl-5-aminosalicylic acid (NA5AS) was lost instead of the acetyl group during the ionisation, and acetaminophen (AAP) appeared. As the acetyl and carboxyl groups of some substances can be degraded during ionisation in the mass spectrometer, caution is appropriate when it is sought to simultaneously quantify similar structures containing these moieties; chromatographic separation is essential. PMID- 27454085 TI - Comparison of fresh, dried and stir-frying gingers in decoction with blood stasis syndrome in rats based on a GC-TOF/MS metabolomics approach. AB - In China, ginger (Zingiberofficinale Rosc.) and its processed products, such as dried ginger and stir-frying ginger are commonly applied in traditional Chinese medicine (TCM). The paper presents the research on the effects of fresh ginger, dried ginger and stir-frying ginger extracts in blood stasis syndrome. First, a blood stasis syndrome rats model was established and then the hemorheological and blood coagulation activities were analyzed. Third, a sensitive, simple, and valid gas chromatography combined with time-of-flight mass spectrometry (GC-TOF/MS) method was established to compare the metabolic fingerprint coupled with multivariate analysis. The total 27 metabolites (16 in serum and 11 in urine) were identified and contributed to the blood stasis progress. These metabolites mainly involve six metabolism pathways in different impact-value. The altered efficacy index and metabolites can be regulated to normal levels by fresh ginger (FG), dried ginger (DG) and stir-frying ginger (SG). FG is the most effective as shown by the efficacy index, similarity analysis and peak intensity. The result presented here shows that metabolomics equipped with efficacy index makes it possible to study the blood stasis syndrome and to compare the effect and metabolites in fresh, dried and stir-frying gingers. The metabolomics approach can be recommended to study the pharmacological effect and mechanism of herbal drugs. PMID- 27454086 TI - Analysis of physicochemical properties of ternary systems of oxaprozin with randomly methylated-beta-cyclodextrin and l-arginine aimed to improve the drug solubility. AB - The influence of l-arginine on the complexing and solubilizing power of randomly methylated-beta-cyclodextrin (RamebetaCD) towards oxaprozin, a very poorly soluble anti-inflammatory drug, was examined. The interactions between the components were investigated both in solution, by phase-solubility analysis, and in the solid state, by differential scanning calorimetry, FTIR and X-ray powder diffractometry. The morphology of the solid products was examined by Scanning Electron Microscopy. Results of phase-solubility studies indicated that addition of arginine enhanced the RamebetaCD complexing and solubilizing power of about 3.0 and 4.5 times, respectively, in comparison with the binary complex (both at pH~6.8). The effect of arginine was not simply additive, but synergistic, being the ternary system solubility higher than the sum of those of the respective drug CD and drug-arginine binary systems. Solid equimolar ternary systems were prepared by physical mixing, co-grinding, coevaporation and kneading techniques, to explore the effect of the preparation method on the physicochemical properties of the final products. The ternary co-ground product exhibited a dramatic increase in both drug dissolution efficiency and percent dissolved at 60min, whose values (83.6 and 97.1, respectively) were about 3 times higher than the sum of those given by the respective drug-CD and drug-aminoacid binary systems. Therefore, the ternary co-ground system with arginine and RamebetaCD appears as a very valuable product for the development of new more effective delivery systems of oxaprozin, with improved safety and bioavailability. PMID- 27454087 TI - LC-MS/MS assay for the quantitation of FdCyd and its metabolites FdUrd and FU in human plasma. AB - The hypomethylating agent 5-fluoro-2'-deoxycytidine (FdCyd, NSC 48006) is being evaluated clinically both via the intravenous route and via the oral route in combination with 3,4,5,6-tetrahydrouridine (THU), a potent inhibitor of FdCyd catabolism. To determine the pharmacokinetics of FdCyd and downstream metabolites, we developed and validated an LC-MS/MS assay for the quantitation of FdCyd, 5-fluoro-2'-deoxyuridine (FdUrd), and 5-fluorouracil (FU) in 0.2mL human plasma. After acetonitrile protein precipitation, the sample was split and separate chromatography was achieved for FdCyd with a Synergi Polar-RP column and for FdUrd and FU with a Shodex Asahipak NH2P-50 2D column. Gradients of 0.1% acetic acid in acetonitrile and water were used. Detection with a Quattromicro quadrupole mass spectrometer with electrospray ionization in positive-ion (FdCyd) or negative-ion (FdUrd and FU) multiple reaction monitoring (MRM) mode. The assay was linear from 5 to 3000ng/mL for all three analytes and proved to be accurate (96.7-105.5%) and precise (<8.1%CV), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring FdCyd and metabolites FdUrd and FU in plasma from a patient who was administered 120mg PO FdCyd 30min after 3000mg THU. Our LC-MS/MS assay will be an essential tool to further define the pharmacology of FdCyd in ongoing and future studies. PMID- 27454088 TI - Effect of milling conditions on solid-state amorphization of glipizide, and characterization and stability of solid forms. AB - In this study, the amorphization of glipizide was systematically investigated through high-energy ball milling at different temperatures. The results of solid state amorphization through milling indicated that glipizide underwent direct crystal-to-glass transformation at 15 and 25 degrees C and crystal-to-glass-to crystal conversion at 35 degrees C; hence, milling time and temperature had significant effects on the amorphization of glipizide, which should be effectively controlled to obtain totally amorphous glipizide. Solid forms of glipizide were detailedly characterized through analyses of X-ray powder diffraction, morphology, thermal curves, vibrational spectra, and solid-state nuclear magnetic resonance. The physical stability of solid forms was investigated under different levels of relative humidity (RH) at 25 degrees C. Forms I and III are kinetically stable and do not form any new solid-state forms at various RH levels. By contrast, Form II is kinetically unstable, undergoing direct glass-to-crystal transformation when RH levels higher than 32.8%. Therefore, stability investigation indicated that Form II should be stored under relatively dry conditions to prevent rapid crystallization. High temperatures can also induce the solid-state transformation of Form II; the conversion rate increased with increasing temperature. PMID- 27454089 TI - Determination of apomorphine freebase in sublingual tablets by proton nuclear magnetic resonance spectroscopy. AB - An apomorphine sublingual tablet formulation under development contains mixtures of apomorphine freebase (FB) and apomorphine hydrochloride salt. It is important to have a reliable analytical method to determine the ratio of the base and salt forms to ensure accuracy, reproducibility and robustness of the manufacturing processes as well as to meet the requirements of the quality target product profile. A Proton Nuclear Magnetic Resonance ((1)H NMR) spectroscopy method based on the proton shift of the amine methyl group (N-CH3) in apomorphine has been developed to determine the mole percentage of freebase to the total mole of freebase and hydrochloride salt in the drug product. The method was evaluated in terms of specificity, linearity, and variability. The presence of excipients does not interfere with the analysis. A standard calibration curve of the chemical shift as a function of the proportion of freebase forms of apomorphine was established, covering the range of 100% apomorphine freebase to 100% apomorhine hydrochloride. The correlation coefficient (r(2)), slope, and Y-intercept of the regression line are 0.998, -0.00596, and 3.191, respectively. The day-to-day variability of the (1)H shift in two instruments in the standard is less than 1% RSD. Three lots of the sublingual tablet drug product were examined and quantified by the standard. The mole percent apomorphine freebase was determined to be 73.8%, 75.2%, and 76.2%, respectively, within 100.0%+/-2.0% of the target value of 75.0%. The method is a new avenue to use the (1)H NMR technique for determination of apomorphine freebase and salt ratio in a solid drug product dosage form for release testing and in-process control. PMID- 27454090 TI - Effect of cholesterol lowering treatment on plasma markers of endothelial dysfunction in chronic kidney disease. AB - The elevated cardiovascular morbidity and mortality in chronic kidney disease (CKD) is linked with endothelial dysfunction secondary to the pro-inflammatory and pro-oxidative state typical of this pathology. In consideration of the well known pleiotropic effect of statins, we investigated the effect of cholesterol lowering treatment on endothelial dysfunction markers (MED), asymmetric dimethylarginine (ADMA), vascular cell (VCAM) and intercellular (ICAM) adhesion molecule. Plasma MED concentrations, inflammation and oxidative stress indices [Kynurenine/Tryptophan (Kyn/Trp) ratio, malondialdehyde (MDA) and allantoin/uric acid (All/UA) ratio] were measured in 30 CKD patients randomized to three cholesterol lowering regimens for 12 months (simvastatin 40mg/day, ezetimibe/simvastatin 10/20mg/day, or ezetimibe/simvastatin 10/40mg/day). Treatment significantly reduced ADMA concentrations in all patients [0.694MUmol/L (0.606-0.761) at baseline vs. 0.622MUmol/L (0.563-0.681) after treatment, p<0.001]. ADMA reduction was paralleled by a significant decrease of MDA, All/AU ratio and Kyn/Trp ratio, but not VCAM and ICAM plasma concentrations. Cholesterol lowering treatment was associated with a significant reduction in plasma ADMA concentrations in CKD patients. This might be mediated by reduced oxidative stress and inflammation. PMID- 27454091 TI - Estimation of uncertainty from method validation data: Application to a reverse phase high-performance liquid chromatography method for the determination of amino acids in gelatin using 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate reagent. AB - A detailed procedure for estimating uncertainty according to the Laboratory of Government Chemists/Valid Analytical Measurement (LGC/VAM) protocol for determination of 18 amino acids in gelatin is proposed. The expanded uncertainty was estimated using mainly the method validation data (precision and trueness). Other sources of uncertainties were contributed by components in standard preparation measurements. The method scope covered a single matrix (gelatin) under a wide range of analyte concentrations. The uncertainty of method precision, MU(P) was 0.0237-0.1128pmolMUl(-1) in which hydroxyproline and histidine represented the lowest and highest values of uncertainties, respectively. Proline and phenylalanine represented the lowest and highest uncertainties value for method recovery, MU(R) that was estimated within 0.0064 0.0995pmolMUl(-1). The uncertainties from other sources, MU(Std) were 0.0325, 0.0428 and 0.0413pmolMUl(-1) that were contributed by hydroxyproline, other amino acids and cystine, respectively. Hydroxyproline and phenylalanine represented the lowest and highest values of expanded uncertainty, U(y) that were determined at 0.0949 and 0.2473pmolMUl(-1), respectively. The data were accurately defined and fulfill the technical requirements of ISO 17025:2005. PMID- 27454092 TI - From phytoaccumulation to post-harvest use of water fern for landfill management. AB - We examined the potential of Azolla japonica as a remediating plant for leachate channels and post-accumulation use as fertilizer for landfill slope. The harvested biomass of Azolla after one month grown in leachate was 254% that of the initial biomass and the predicted annual harvestable biomass of Azolla using a growth model was 32 times that of the initial biomass. Na, Fe, Mn, Mg, and P were accumulated in Azolla at very high concentrations. Such rapid increase of biomass and high accumulation rates suggest that this plant could be an excellent remediating plant. The post-harvest use of Azolla as compost was studied for the management and use of phytoaccumulating Azolla. Metal contents of Azolla compost were below permissible limits for co-composting material. Nitrogen, organic matter, P, and Mg content of the Azolla compost improved the soil condition of the landfill and enhanced ecophysiological responses of the plants. The application of Azolla compost can improve management of sanitary landfills, including the restoration of vegetation. Considering its ease of harvesting, high accumulation rates, harvestable biomass and suitability for composting, Azolla can provide a suitable solution for sustainable management of leachate channels and landfill slopes. PMID- 27454093 TI - Bacterial toxicity assessment of drinking water treatment residue (DWTR) and lake sediment amended with DWTR. AB - Drinking water treatment residue (DWTR) seems to be very promising for controlling lake sediment pollution. Logically, acquisition of the potential toxicity of DWTR will be beneficial for its applications. In this study, the toxicity of DWTR and sediments amended with DWTR to Aliivibrio fischeri was evaluated based on the Microtox((r)) solid and leachate phase assays, in combination with flow cytometry analyses and the kinetic luminescent bacteria test. The results showed that both solid particles and aqueous/organic extracts of DWTR exhibited no toxicity to the bacterial luminescence and growth. The solid particles of DWTR even promoted bacterial luminescence, possibly because DWTR particles could act as a microbial carrier and provide nutrients for bacteria growth. Bacterial toxicity (either luminescence or growth) was observed from the solid phase and aqueous/organic extracts of sediments with or without DWTR addition. Further analysis showed that the solid phase toxicity was determined to be related mainly to the fixation of bacteria to fine particles and/or organic matter, and all of the observed inhibition resulting from aqueous/organic extracts was identified as non-significant. Moreover, DWTR addition not only had no adverse effect on the aqueous/organic extract toxicity of the sediment but also reduced the solid phase toxicity of the sediment. Overall, in practical application, the solid particles, the water-soluble substances transferred to surface water or the organic substances in DWTR had no toxicity or any delayed effect on bacteria in lakes, and DWTR can therefore be considered as a non hazardous material. PMID- 27454094 TI - Alteration of extracellular enzyme activity and microbial abundance by biochar addition: Implication for carbon sequestration in subtropical mangrove sediment. AB - Biochar has attracted more and more attention due to its essential role in adsorbing pollutants, improving soil fertility, and modifying greenhouse gas emission. However, the influences of biochar on extracellular enzyme activity and microbial abundance are still lack and debatable. Currently, there is no information about the impact of biochar on the function of mangrove ecosystems. Therefore, we explored the effects of biochar on extracellular enzyme activity and microbial abundance in subtropical mangrove sediment, and further estimated the contribution of biochar to C sequestration. In this study, sediments were amended with 0 (control), 0.5, 1.0 and 2.0% of biochar and incubated at 25 degrees C for 90 days. After incubation, enzyme activities, microbial abundance and the increased percentage of sediment organic C content were determined. Both increase (phenol oxidase and beta-glucosidase) and decrease (peroxidase, N-acetyl glucosaminidase and acid phosphatase) of enzyme activities were observed in biochar treatments, but only peroxidase activity showed statistical significance (at least p < 0.01) compared to the control. Moreover, the activities of all enzymes tested were significantly related to the content of biochar addition (at least p < 0.05). On the other hand, bacterial and fungal abundance in biochar treatments were remarkably lower than control (p < 0.001), and the significantly negative relationship (p < 0.05) between bacterial abundance and the content of biochar was found. Additionally, the increased percentage of organic C gradually increased with biochar addition rate, which provided evidence for applying biochar to mitigate climate change. Given the importance of microorganisms and enzyme activities in sediment organic matter decomposition, the increased C sequestration might be explained by the large decrease of microbial abundance and enzyme activity after biochar intervention. PMID- 27454095 TI - Ecological restoration of a copper polluted vineyard: Long-term impact of farmland abandonment on soil bio-chemical properties and microbial communities. AB - This study aimed at investigating the degree of interference of high soil copper (Cu) contamination when an old vineyard is converted into a protected area. This study was performed within an intensive agricultural system; it was organized into a two-factorial nested design to analyze the impact of management (conventional vs re-naturalized orchard) and position within each orchard (tree rows and strips). Chemical and biochemical properties along with bacterial and fungal communities, evaluated with PCR-DGGE starting from total soil DNA, were analyzed. Total Cu was localized in tree rows in the old vineyard at 1000 mg kg( 1) of soil, whereas it did not exceed 80 mg kg(-1) soil in the other treatments. Total organic carbon and all biochemical properties significantly improved in re naturalized compared to conventionally cultivated site, while no significant differences were observed between tree row and strip. Moreover, a higher extractable carbon-extractable nitrogen (Cext-to-Next) ratio in the re naturalized (19.3) site than in the conventionally managed site (10.2) indicated a shift of soil system from C-limited to N-limited, confirming a successful ecological restoration. Deep improvement of soil biochemical properties exceeded the negative impact of Cu contamination. A shift of bacterial community composition as well as increased bacterial diversity in Cu contaminated treatment indicated a bacterial response to Cu stress; to the contrary, soil fungi were less susceptible than bacteria, though an overall reduction of fungal DNA was detected. Findings suggest that ecological restoration of highly polluted agricultural soils leads to overcoming the reduction of soil functionalities linked to Cu contamination and opens interesting perspectives for mitigating Cu stress in agricultural soils with strategies based on conservative agriculture. PMID- 27454096 TI - Improving environmental performance through unit-level organizational citizenship behaviors for the environment: A capability perspective. AB - Organizational citizenship behaviors for the environment (OCBEs) are increasingly advocated as a means of complementing formal practices in improving environmental performance. Adopting a capability perspective, we propose that a firm's employee involvement capability translates into environmental performance through the manifestation of unit-level OCBEs, and that this relationship is amplified by a shared vision capability. In a cross-country and multi-industry sample of 170 firms, we find support for our hypotheses, shedding light on contextual determinants of OCBEs, and on how firms may engender a positive relationship between top-down environmental initiatives and bottom-up behaviors. PMID- 27454097 TI - An optimization model for regional air pollutants mitigation based on the economic structure adjustment and multiple measures: A case study in Urumqi city, China. AB - A model based on economic structure adjustment and pollutants mitigation was proposed and applied in Urumqi. Best-worst case analysis and scenarios analysis were performed in the model to guarantee the parameters accuracy, and to analyze the effect of changes of emission reduction styles. Results indicated that pollutant-mitigations of electric power industry, iron and steel industry, and traffic relied mainly on technological transformation measures, engineering transformation measures and structure emission reduction measures, respectively; Pollutant-mitigations of cement industry relied mainly on structure emission reduction measures and technological transformation measures; Pollutant mitigations of thermal industry relied mainly on the four mitigation measures. They also indicated that structure emission reduction was a better measure for pollutants mitigation of Urumqi. Iron and steel industry contributed greatly in SO2, NOx and PM (particulate matters) emission reduction and should be given special attention in pollutants emission reduction. In addition, the scales of iron and steel industry should be reduced with the decrease of SO2 mitigation amounts. The scales of traffic and electric power industry should be reduced with the decrease of NOx mitigation amounts, and the scales of cement industry and iron and steel industry should be reduced with the decrease of PM mitigation amounts. The study can provide references of pollutants mitigation schemes to decision-makers for regional economic and environmental development in the 12th Five-Year Plan on National Economic and Social Development of Urumqi. PMID- 27454098 TI - Indigenous ecological knowledge as the basis for adaptive environmental management: Evidence from pastoralist communities in the Horn of Africa. AB - The proliferation of woody plants has been observed on rangelands globally and has significant impacts on subsistence livestock production. However, adaptation strategies to such environmental changes remain largely unexamined. This paper investigates pastoralists' adaptations to such environmental changes in the Borana zone of southern Ethiopia by integrating pastoralists' ecological knowledge, surveys of plant species composition, and census data on livestock holdings. The results indicated that a proliferation of woody plants and corresponding decline in herbaceous species would have negative impact on forage values for cattle and sheep, whereas goats would remain relatively unaffected, and camels would benefit. While census data showed declines in household herd size from 2000 to 2014, pastoralists have been adapting to the proliferation of woody plants by doubling their goat holdings, and wealthier households are investing in camels. These changes in livestock holdings based on indigenous ecological knowledge will mitigate the negative impacts of vegetation shifts on livestock production, and facilitate adaptive environmental management in the pastoral systems. PMID- 27454099 TI - Forecasting municipal solid waste generation using prognostic tools and regression analysis. AB - For an adequate planning of waste management systems the accurate forecast of waste generation is an essential step, since various factors can affect waste trends. The application of predictive and prognosis models are useful tools, as reliable support for decision making processes. In this paper some indicators such as: number of residents, population age, urban life expectancy, total municipal solid waste were used as input variables in prognostic models in order to predict the amount of solid waste fractions. We applied Waste Prognostic Tool, regression analysis and time series analysis to forecast municipal solid waste generation and composition by considering the Iasi Romania case study. Regression equations were determined for six solid waste fractions (paper, plastic, metal, glass, biodegradable and other waste). Accuracy Measures were calculated and the results showed that S-curve trend model is the most suitable for municipal solid waste (MSW) prediction. PMID- 27454100 TI - Effects of [S,S]-ethylenediaminedisuccinic acid and nitrilotriacetic acid on the efficiency of Pb phytostabilization by Athyrium wardii (Hook.) grown in Pb contaminated soils. AB - Chelate-assisted phytoextraction with biodegradable chelants has been demonstrated as an efficient method to enhance heavy metal remediation efficiency by plants, while there is little available information on phytostabilization. A pot experiment was conducted to investigate the effects of biodegradable [S,S] ethylenediaminedisuccinic acid (EDDS) and nitrilotriacetic acid (NTA) on plant growth and Pb accumulation of Pb phytostabilizer Athyrium wardii (Hook.) grown in Pb contaminated soils and to explore the feasibility of chelate-assisted phytostabilization. Greater adverse effects on plant biomass under high EDDS treatments were observed than NTA treatments. Significant increase of shoot Pb concentrations of A. wardii was noticed with increasing NTA and EDDS dosages, while EDDS induced higher shoot Pb concentrations than NTA. Moreover, root Pb concentrations of A. wardii under NTA treatments were 1.18-1.28-time higher than EDDS treatments, and a peak value of root Pb concentrations was observed at 2 mmol kg(-1) of NTA. Shoot Pb accumulations significantly increased with increasing dosages, and EDDS treatments caused a 1.44-1.6-time increase of shoot Pb accumulation than NTA. Root Pb accumulations under NTA treatments were 1.18 1.28-time higher than EDDS treatments. Maximum root Pb accumulation (155.5 mg plant(-1)) was found at 2 mmol kg(-1) of NTA on the 14th day. Higher BCF values and lower TF values were found under NTA treatments as compared to EDDS treatments. Available Pb concentrations in soil significantly increased on the 7th day with increasing NTA and EDDS dosages, then gradually decreased on the 14th day. Soil pH slightly decreased with increasing NTA and EDDS dosages. Therefore, chelate-assisted phytostabilization could be a feasible way to enhance the efficiency of Pb phytostabilization by A. wardii. PMID- 27454101 TI - Multivariate functions for predicting the sorption of 2,4,6-trinitrotoluene (TNT) and 1,3,5-trinitro-1,3,5-tricyclohexane (RDX) among taxonomically distinct soils. AB - After nearly a century of use in numerous munition platforms, TNT and RDX contamination has turned up largely in the environment due to ammunition manufacturing or as part of releases from low-order detonations during training activities. Although the basic knowledge governing the environmental fate of TNT and RDX are known, accurate predictions of TNT and RDX persistence in soil remain elusive, particularly given the universal heterogeneity of pedomorphic soil types. In this work, we proposed a new solution for modeling the sorption and persistence of these munition constituents as multivariate mathematical functions correlating soil attribute data over a variety of taxonomically distinct soil types to contaminant behavior, instead of a single constant or parameter of a specific absolute value. To test this idea, we conducted experiments measuring the sorption of TNT and RDX on taxonomically different soil types that were extensively physical and chemically characterized. Statistical decomposition of the log-transformed, and auto-scaled soil characterization data using the dimension-reduction technique PCA (principal component analysis) revealed a strong latent structure based in the multiple pairwise correlations among the soil properties. TNT and RDX sorption partitioning coefficients (KD-TNT and KD RDX) were regressed against this latent structure using partial least squares regression (PLSR), generating a 3-factor, multivariate linear functions. Here, PLSR models predicted KD-TNT and KD-RDX values based on attributes contributing to endogenous alkaline/calcareous and soil fertility criteria, respectively, exhibited among the different soil types: We hypothesized that the latent structure arising from the strong covariance of full multivariate geochemical matrix describing taxonomically distinguished soil types may provide the means for potentially predicting complex phenomena in soils. The development of predictive multivariate models tuned to a local soil's taxonomic designation would have direct benefit to military range managers seeking to anticipate the environmental risks of training activities on impact sites. PMID- 27454102 TI - Aiding alternatives assessment with an uncertainty-tolerant hazard scoring method. AB - This research developed a single-score system to simplify and clarify decision making in chemical alternatives assessment, accounting for uncertainty. Today, assessing alternatives to hazardous constituent chemicals is a difficult task rather than comparing alternatives by a single definitive score, many independent toxicological variables must be considered at once, and data gaps are rampant. Thus, most hazard assessments are only comprehensible to toxicologists, but business leaders and politicians need simple scores to make decisions. In addition, they must balance hazard against other considerations, such as product functionality, and they must be aware of the high degrees of uncertainty in chemical hazard data. This research proposes a transparent, reproducible method to translate eighteen hazard endpoints into a simple numeric score with quantified uncertainty, alongside a similar product functionality score, to aid decisions between alternative products. The scoring method uses Clean Production Action's GreenScreen as a guide, but with a different method of score aggregation. It provides finer differentiation between scores than GreenScreen's four-point scale, and it displays uncertainty quantitatively in the final score. Displaying uncertainty also illustrates which alternatives are early in product development versus well-defined commercial products. This paper tested the proposed assessment method through a case study in the building industry, assessing alternatives to spray polyurethane foam insulation containing methylene diphenyl diisocyanate (MDI). The new hazard scoring method successfully identified trade-offs between different alternatives, showing finer resolution than GreenScreen Benchmarking. Sensitivity analysis showed that different weighting schemes in hazard scores had almost no effect on alternatives ranking, compared to uncertainty from data gaps. PMID- 27454103 TI - Therapeutic compounds for Cushing's syndrome: a patent review (2012-2016). AB - INTRODUCTION: Endogenous Cushing's syndrome (CS) is a set of disorders caused by chronic exposure to excess glucocorticoids induced by neuroendocrine tumors in pituitary, adrenals, and infrequently other sites (ectopic ACTH syndrome). Due to various comorbidities, CS patients exhibit higher risks of cardiovascular diseases and thus increased mortality. Pharmaceutical therapy is an important constituent of treatment regimen. Areas covered: Patents published since 2012 are reviewed, which claim therapeutic compounds interfering with ACTH secretion and down-stream signal transduction, inhibiting cortisol biosynthesis and antagonizing glucocorticoid receptors. Advances focus on a) new analogues with improved efficacy and PK properties or less off-target toxicity; b) existing drugs (candidates) being repurposed to treat CS; and c) novel strategies such as selective inhibition of CYP11B1. Expert opinion: New compounds against established targets need to be developed because current drugs lack selectivity leading to off-target toxicity. Selective inhibition of CYP11B1 is a novel alternative strategy and is potentially versatile in controlling all types of hypercortisolism. Selective multi-targeting enzymes in steroidogenesis network is promising due to potential synergistic effects. However, doses toward each targets are not feasible to adjust because the corresponding intrinsic potencies are rigid. Targeting PRKACA mutations is promising in treating CS caused by adrenal adenomas. PMID- 27454104 TI - Enzyme replacement therapy for Anderson-Fabry disease. AB - BACKGROUND: Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers.This is an update of a Cochrane review first published in 2010, and previously updated in 2013. OBJECTIVES: To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register (date of the most recent search: 08 July 2016). We also searched 'Clinical Trials' on The Cochrane Library, MEDLINE, Embase and LILACS (date of the most recent search: 24 September 2015). SELECTION CRITERIA: Randomized controlled trials of agalsidase alfa or beta in participants diagnosed with Anderson-Fabry disease. DATA COLLECTION AND ANALYSIS: Two authors selected relevant trials, assessed methodological quality and extracted data. MAIN RESULTS: Nine trials comparing either agalsidase alfa or beta in 351 participants fulfilled the selection criteria.Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores measured by the Brief Pain Inventory severity, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval -3.79 to -0.41; at up to five months, mean difference 1.90 (95% confidence interval -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% confidence interval -3.66 to -0.34). There was a significant difference in the Brief Pain Inventory pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% confidence interval -3.92 to -0.28) but not at other time points. Death was not an outcome in either of the trials.One of the three trials comparing agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% confidence interval -2.09 to -1.31); heart, mean difference -0.90 (95% confidence interval 1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% confidence interval -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain.Only two trials compared agalsidase alfa to agalsidase beta. One of them showed no significant difference between the groups regarding adverse events, risk ratio 0.36 (95% confidence interval 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; (95% confidence interval 0.03 to 2.57).Two trials compared different dosing schedules of agalsidase alfa. One of them involved three different doses (0.2 mg/kg every two weeks; 0.1 mg/kg weekly and; 0.2 mg/kg weekly), the other trial evaluated two further doses to the dosage schedules: 0.4 mg/kg every week and every other week. Both trials failed to show significant differences with various dosing schedules on globotriaosylceramide levels. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores.One trial comparing agalsidase alfa to agalsidase beta showed no significant difference for any adverse events such as dyspnoea and hypertension.The methodological quality of the included trials was generally unclear for the random sequence generation and allocation concealment. AUTHORS' CONCLUSIONS: Trials comparing enzyme replacement therapy to placebo show significant improvement with enzyme replacement therapy in regard to microvascular endothelial deposits of globotriaosylceramide and in pain-related quality of life. There is, however, no evidence identifying if the alfa or beta form is superior or the optimal dose or frequency of enzyme replacement therapy. With regards to safety, adverse events (i.e., rigors, fever) were more significant in the agalsidase beta as compared to placebo. The long-term influence of enzyme replacement therapy on risk of morbidity and mortality related to Anderson-Fabry disease remains to be established. This review highlights the need for continued research into the use of enzyme replacement therapy for Anderson-Fabry disease. PMID- 27454105 TI - Robotic Versus Laparoscopic Right Colectomy for Colon Cancer: Analysis of the Initial Simultaneous Learning Curve of a Surgical Fellow. AB - BACKGROUND: Robotic surgery was introduced to overcome laparoscopic drawbacks. This study aimed to compare the learning curve of robotic-assisted right colectomy (RRC) versus laparoscopic-assisted right colectomy (LRC) for colon cancer with respect to operative times and perioperative outcomes. In addition, the health-related costs associated with both procedures were analyzed and compared. METHODS: Between 2012 and 2015, 30 consecutive patients underwent RRC and 50 patients LRC for colon cancer. All procedures were performed by a surgical fellow novice in minimally invasive colorectal surgery. The operative time and the cumulative sum method were used to evaluate the learning curve of RRC versus LRC. RESULTS: The mean operative times were 200.5 minutes for RRC and 204.1 minutes for LRC (P = .408) and showed a significant decrease over consecutive procedures (P < .0001). The number of cases necessary to identify a drop in the operative time was 16 for RRC and 25 for LRC. RRC procedures were associated with significantly reduced blood loss (P = .012). Two patients (4%) in the LRC group were converted to laparotomy, whereas no conversion was required in the RRC group. Surgery-related costs were significantly more expensive for RRC, but when combined with the hospitalization-related costs, LRC and RRC did not differ (P = .632). CONCLUSIONS: Both robotic and laparoscopic operative times decrease rapidly with practice. However, RRC is associated with a faster learning curve than LRC. The simultaneous development of these two minimally invasive approaches appears to be safe and feasible with acceptable health-related costs. PMID- 27454106 TI - Methylated arginine analogues: their potential role in atherosclerosis and cognition using the poloxamer-407-induced mouse model of dyslipidemia. AB - An experimental mouse model of dyslipidemia and atherosclerosis was utilized to study the generation of methylarginines in vivo, as well as any potential behavioral changes in mice associated with the production of excess methylarginines. Following 14 weeks of poloxamer 407 treatment, mice developed atherosclerosis and the plasma concentrations of monomethylarginine and asymmetric dimethylarginine were found to be significantly greater than corresponding concentrations in control mice. This finding may have contributed to the development of aortic atherosclerotic lesions in poloxamer-treated mice by interfering with nitric oxide availability and, hence, normal function of vascular endothelium. Poloxamer-407-treated mice also showed a significant decrease in locomotor and exploratory activity, together with signs of emotional stress and anxiety relative to controls. Passive avoidance testing to assess learning and memory provided suggestive evidence that poloxamer-treated mice could potentially be characterized as having undergone a disruption in the process of forgetting about an aversive event, specifically, a foot shock, when compared with control mice. Thus, it is also suggested that the increase in both plasma monomethylarginine and asymmetric dimethylarginine in poloxamer-407 treated mice may somehow influence learning and memory, because endothelial dysfunction caused by reduced nitric oxide availability has been hypothesized to negatively influence cognitive function. PMID- 27454107 TI - Antischistosomal activity of hederacochiside C against Schistosoma japonicum harbored in experimentally infected animals. AB - The present study was undertaken to investigate whether hederacochiside C (HSC) possesses antischistosomal effects and anti-inflammatory response activities in Schistosoma japonicum-infected mice. Different concentrations of HSC were administrated to the mice infected by schistosomula or adult worm by intravenous injection twice a day for five consecutive days. The total worm burden, female worm burden, and the egg burden in liver of mice treated with 400 mg/kg HSC were fewer than those in non-treated ones. Murine immune responses following HSC treatment were investigated using enzyme-linked immunosorbent assays (ELISA). Our results indicated that 200 mg/kg HSC could reduce the expression of IgG, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4 and IL-17 in comparison to infected group, exhibiting best immunomodulatory effects. In addition, scanning electron microscopical examination revealed that male worms treated with HSC lost their normal surface architecture since its surface showed extensive swelling, erosion, and peeling in tegumental regions. Remarkable amelioration was noticed in histopathological investigations, and 200 mg/kg HSC treatment could reduce the size of granulomatous inflammatory infiltrations in the liver which was reflected in nearly normalization of liver architecture. These results suggested that HSC had potential antischistosomal activity and provided a basis for subsequent experimental. PMID- 27454108 TI - Conceptual knowledge representation: A cross-section of current research. AB - How is conceptual knowledge encoded in the brain? This special issue of Cognitive Neuropsychology takes stock of current efforts to answer this question through a variety of methods and perspectives. Across this work, three questions recur, each fundamental to knowledge representation in the mind and brain. First, what are the elements of conceptual representation? Second, to what extent are conceptual representations embodied in sensory and motor systems? Third, how are conceptual representations shaped by context, especially linguistic context? In this introductory article we provide relevant background on these themes and introduce how they are addressed by our contributing authors. PMID- 27454109 TI - A pedigree-based proxy measure of genetic predisposition of drinking and alcohol use among female sex workers in China: a cross-sectional study. AB - Scientific evidence has suggested that genetic factors accounted for more than half of the vulnerability of developing alcohol use problems. However, collecting genetic data poses a significant challenge for most population-based behavioral studies. The aim of this study was to assess the utilities of a pedigree-based proxy measure of genetic predisposition of drinking (GPD) and its effect on alcohol use behaviors as well as its interactions with personal and environmental factors. In the current study, cross-sectional data were collected from 700 female sex workers (FSW) in Guangxi, China. Participants provided information on a pedigree-based proxy measure of GPD and their alcohol use behaviors. Chi-square and independent t-test was applied for examining the bivariate associations between GPD and alcohol use behaviors; multivariate and ordinal regression models were used to examine the effect of GPD on alcohol use. This study found that women with a higher composite score of GPD tended to have a higher risk of alcohol use problem compared to their counterparts (p < .05). GPD was a significant predictor of alcohol use problems (p < .05), especially among women who had mental health issues or lack of health cares. The pedigree-based measure provided a useful proxy of GPD among participants. Both FSW's mental health and health care access interact with GPD and affect their drinking patterns. By understanding the genetic basis of alcohol use, we can develop scalable and efficacious interventions that will take into consideration the individual risk profile and environmental influences. PMID- 27454110 TI - A Historical Retrospective Analysis of the Impact of Diabetes Quality Measure Attainment on Outcomes in Medicare Advantage Members. AB - The objective of this study was to assess achievement of 4 diabetes mellitus (DM) related quality measures (QMs) and examine the relationship between QM attainment, concurrent health care costs, and DM complications over 1 year by conducting a retrospective analysis of claims data for Medicare Advantage Prescription Drug plan members with DM. Claims and member-level quality data were used to assess QM achievement, concurrent health care costs, and presence of new or worsening DM complications during the QM year. Multivariable regression models were used to examine the relationship between QM achievement and outcome measures controlling for potentially confounding baseline characteristics. QM attainment rates ranged from 54.2% for DM Treatment measure to 83.4% for Cholesterol Screening measure. Odds of new or worsening complications were greater for members who did not meet the Blood Sugar Controlled performance goal (odds ratio [OR]: 1.12, P < 0.001), DM Treatment goal (OR: 1.40, P < 0.001), or Cholesterol Screening goal (OR: 1.32, P < 0.001). Failure to attain the DM Medication Adherence goal was associated with lower odds of new or worsening complications (OR: 0.94, P < 0.001). In the regression models, all-cause health care costs were greater for members who achieved the Blood Sugar Controlled quality goal (P < 0.001), but lower for members who attained DM Treatment (P < 0.001) and low density lipoprotein Cholesterol Screening goals (P < 0.001). There was no statistically significant relationship between attaining the DM Medication Adherence measure and all-cause costs. Achievement rates for individual QMs varied across the study population and relationships between QM attainment, health care costs, and DM complications during the QM measurement year were mixed. PMID- 27454111 TI - EUROPAEM EMF Guideline 2016 for the prevention, diagnosis and treatment of EMF related health problems and illnesses. AB - Chronic diseases and illnesses associated with non-specific symptoms are on the rise. In addition to chronic stress in social and work environments, physical and chemical exposures at home, at work, and during leisure activities are causal or contributing environmental stressors that deserve attention by the general practitioner as well as by all other members of the health care community. It seems necessary now to take "new exposures" like electromagnetic fields (EMF) into account. Physicians are increasingly confronted with health problems from unidentified causes. Studies, empirical observations, and patient reports clearly indicate interactions between EMF exposure and health problems. Individual susceptibility and environmental factors are frequently neglected. New wireless technologies and applications have been introduced without any certainty about their health effects, raising new challenges for medicine and society. For instance, the issue of so-called non-thermal effects and potential long-term effects of low-dose exposure were scarcely investigated prior to the introduction of these technologies. Common electromagnetic field or EMF sources: Radio frequency radiation (RF) (3 MHz to 300 GHz) is emitted from radio and TV broadcast antennas, Wi-Fi access points, routers, and clients (e.g. smartphones, tablets), cordless and mobile phones including their base stations, and Bluetooth devices. Extremely low frequency electric (ELF EF) and magnetic fields (ELF MF) (3 Hz to 3 kHz) are emitted from electrical wiring, lamps, and appliances. Very low frequency electric (VLF EF) and magnetic fields (VLF MF) (3 kHz to 3 MHz) are emitted, due to harmonic voltage and current distortions, from electrical wiring, lamps (e.g. compact fluorescent lamps), and electronic devices. On the one hand, there is strong evidence that long-term exposure to certain EMFs is a risk factor for diseases such as certain cancers, Alzheimer's disease, and male infertility. On the other hand, the emerging electromagnetic hypersensitivity (EHS) is more and more recognized by health authorities, disability administrators and case workers, politicians, as well as courts of law. We recommend treating EHS clinically as part of the group of chronic multisystem illnesses (CMI), but still recognizing that the underlying cause remains the environment. In the beginning, EHS symptoms occur only occasionally, but over time they may increase in frequency and severity. Common EHS symptoms include headaches, concentration difficulties, sleep problems, depression, a lack of energy, fatigue, and flu-like symptoms. A comprehensive medical history, which should include all symptoms and their occurrences in spatial and temporal terms and in the context of EMF exposures, is the key to making the diagnosis. The EMF exposure is usually assessed by EMF measurements at home and at work. Certain types of EMF exposure can be assessed by asking about common EMF sources. It is very important to take the individual susceptibility into account. The primary method of treatment should mainly focus on the prevention or reduction of EMF exposure, that is, reducing or eliminating all sources of high EMF exposure at home and at the workplace. The reduction of EMF exposure should also be extended to public spaces such as schools, hospitals, public transport, and libraries to enable persons with EHS an unhindered use (accessibility measure). If a detrimental EMF exposure is reduced sufficiently, the body has a chance to recover and EHS symptoms will be reduced or even disappear. Many examples have shown that such measures can prove effective. To increase the effectiveness of the treatment, the broad range of other environmental factors that contribute to the total body burden should also be addressed. Anything that supports homeostasis will increase a person's resilience against disease and thus against the adverse effects of EMF exposure. There is increasing evidence that EMF exposure has a major impact on the oxidative and nitrosative regulation capacity in affected individuals. This concept also may explain why the level of susceptibility to EMF can change and why the range of symptoms reported in the context of EMF exposures is so large. Based on our current understanding, a treatment approach that minimizes the adverse effects of peroxynitrite - as has been increasingly used in the treatment of multisystem illnesses - works best. This EMF Guideline gives an overview of the current knowledge regarding EMF-related health risks and provides recommendations for the diagnosis, treatment and accessibility measures of EHS to improve and restore individual health outcomes as well as for the development of strategies for prevention. PMID- 27454112 TI - Comparing domain interactions within antibody Fabs with kappa and lambda light chains. AB - IgG antibodies are multi-domain proteins with complex inter-domain interactions. Human IgG heavy chains (HCs) associate with light chains (LCs) of the kappa or lambda isotype to form mature antibodies capable of binding antigen. The HC/LC interaction involves 4 domains: VH and CH1 from the HC and VL and CL from the LC. Human Fabs with kappa LCs have been well characterized for their unfolding behaviors and demonstrate a significant level of cooperativity and stabilization when all 4 domains are intact. Very little is known regarding the thermodynamic properties of human Fabs with lambda LCs. Here, we dissect the domain contributions to Fab stability for both kappa and lambda LC-containing Fabs. We find the cooperativity of unfolding between the constant domains, CH1/Clambda, and variable domains, VH/Vlambda, within lambda LC-containing Fabs is significantly weaker than that of kappa LC-containing Fabs. The data suggests there may not be an evolutionary necessity for strong variable/constant domain cooperativity within lambda LC-containing Fabs. After investigating the biophysical properties of Fabs with mismatched variable and constant domain subunits (e.g., VH/Vkappa paired with CH1/Clambda or T cell receptor Calpha/Cbeta), the major role of the constant domains for both kappa- and lambda containing Fabs may be to reduce the hydrophobic exposure at the VH/VL interface. Even though Fabs with these non-native pairings were thermodynamically less stable, they secreted well from mammalian cells as well behaved monodisperse proteins, which was in contrast to what was observed with the VH/Vkappa and VH/Vlambda scFvs that secreted as a mixture of monomer and aggregates. PMID- 27454113 TI - RefSelect: a reference sequence selection algorithm for planted (l, d) motif search. AB - BACKGROUND: The planted (l, d) motif search (PMS) is an important yet challenging problem in computational biology. Pattern-driven PMS algorithms usually use k out of t input sequences as reference sequences to generate candidate motifs, and they can find all the (l, d) motifs in the input sequences. However, most of them simply take the first k sequences in the input as reference sequences without elaborate selection processes, and thus they may exhibit sharp fluctuations in running time, especially for large alphabets. RESULTS: In this paper, we build the reference sequence selection problem and propose a method named RefSelect to quickly solve it by evaluating the number of candidate motifs for the reference sequences. RefSelect can bring a practical time improvement of the state-of-the art pattern-driven PMS algorithms. Experimental results show that RefSelect (1) makes the tested algorithms solve the PMS problem steadily in an efficient way, (2) particularly, makes them achieve a speedup of up to about 100* on the protein data, and (3) is also suitable for large data sets which contain hundreds or more sequences. CONCLUSIONS: The proposed algorithm RefSelect can be used to solve the problem that many pattern-driven PMS algorithms present execution time instability. RefSelect requires a small amount of storage space and is capable of selecting reference sequences efficiently and effectively. Also, the parallel version of RefSelect is provided for handling large data sets. PMID- 27454114 TI - Effects of a physical activity intervention on autonomic and executive functions in obese young adolescents: A randomized controlled trial. AB - OBJECTIVES: The primary goals of this study were to determine the effects of a physical activity intervention on the set-shifting aspect of executive function and to explore the potential mechanistic role of cardiac autonomic control, as assessed by heart rate variability (HRV), in the relationship between physical activity and executive function in obese young adolescents. METHOD: Obese young adolescents were randomized either to participate in a physical activity program (n = 25) or to serve as the wait-list control (n = 25) for a 3-month intervention. Outcome measures included physical fitness, obesity status, executive function, and HRV; these measures were assessed at baseline and within 1 week of the conclusion of the intervention. RESULTS: The physical activity program improved the participants' physical fitness and obesity status. The program also improved executive function-related set-shifting performance, as measured by the total number of errors, and increased the HRV indices of normalized low frequency (nLF) and normalized high frequency (nHF). A positive correlation between the nHF time changes and the total number of errors was also observed. CONCLUSION: These findings suggest that 3 months of a physical activity intervention effectively increase physical fitness and improve the set-shifting aspect of executive function in obese young adolescents. Furthermore, the physical activity-related alterations in cardiac autonomic control, particularly the parasympathetic response, may be associated with enhanced executive function. (PsycINFO Database Record PMID- 27454115 TI - Heuristics for multiobjective multiple sequence alignment. AB - BACKGROUND: Aligning multiple sequences arises in many tasks in Bioinformatics. However, the alignments produced by the current software packages are highly dependent on the parameters setting, such as the relative importance of opening gaps with respect to the increase of similarity. Choosing only one parameter setting may provide an undesirable bias in further steps of the analysis and give too simplistic interpretations. In this work, we reformulate multiple sequence alignment from a multiobjective point of view. The goal is to generate several sequence alignments that represent a trade-off between maximizing the substitution score and minimizing the number of indels/gaps in the sum-of-pairs score function. This trade-off gives to the practitioner further information about the similarity of the sequences, from which she could analyse and choose the most plausible alignment. METHODS: We introduce several heuristic approaches, based on local search procedures, that compute a set of sequence alignments, which are representative of the trade-off between the two objectives (substitution score and indels). Several algorithm design options are discussed and analysed, with particular emphasis on the influence of the starting alignment and neighborhood search definitions on the overall performance. A perturbation technique is proposed to improve the local search, which provides a wide range of high-quality alignments. RESULTS AND CONCLUSIONS: The proposed approach is tested experimentally on a wide range of instances. We performed several experiments with sequences obtained from the benchmark database BAliBASE 3.0. To evaluate the quality of the results, we calculate the hypervolume indicator of the set of score vectors returned by the algorithms. The results obtained allow us to identify reasonably good choices of parameters for our approach. Further, we compared our method in terms of correctly aligned pairs ratio and columns correctly aligned ratio with respect to reference alignments. Experimental results show that our approaches can obtain better results than TCoffee and Clustal Omega in terms of the first ratio. PMID- 27454116 TI - A systematic framework to derive N-glycan biosynthesis process and the automated construction of glycosylation networks. AB - BACKGROUND: Abnormalities in glycan biosynthesis have been conclusively related to various diseases, whereas the complexity of the glycosylation process has impeded the quantitative analysis of biochemical experimental data for the identification of glycoforms contributing to disease. To overcome this limitation, the automatic construction of glycosylation reaction networks in silico is a critical step. RESULTS: In this paper, a framework K2014 is developed to automatically construct N-glycosylation networks in MATLAB with the involvement of the 27 most-known enzyme reaction rules of 22 enzymes, as an extension of previous model KB2005. A toolbox named Glycosylation Network Analysis Toolbox (GNAT) is applied to define network properties systematically, including linkages, stereochemical specificity and reaction conditions of enzymes. Our network shows a strong ability to predict a wider range of glycans produced by the enzymes encountered in the Golgi Apparatus in human cell expression systems. CONCLUSIONS: Our results demonstrate a better understanding of the underlying glycosylation process and the potential of systems glycobiology tools for analyzing conventional biochemical or mass spectrometry-based experimental data quantitatively in a more realistic and practical way. PMID- 27454117 TI - Assessing policy dialogues and the role of context: Liberian case study before and during the Ebola outbreak. AB - BACKGROUND: In the last decade participatory approaches have gained prominence in policy-making, becoming the focus of good policy-making processes. Policy dialogue is recognised as an important aspect of policy-making among several interactive and innovative policy-making models applied in different contexts and sectors. Recently there has been emphasis on the quality of policy dialogue in terms of how it should be conducted to attain participation and inclusiveness. However, there is paucity of evidence on how the context influences policy dialogue, particularly participation of stakeholders. Liberia's context, which is characterised as post-war, highly donor dependent and in recovery from the recent catastrophic Ebola outbreak, provides an opportunity to understand the influence of context on policy dialogue. METHODS: This was an exploratory study using qualitative methods. Key informant interviews were conducted using an interview guide. A total of 16 interviews were conducted, 12 at the national level and 4 at the sub national level. Data were analysed using inductive thematic content analysis. RESULTS: The respondents felt that the dialogues were a success and involved important stakeholders; however, there were concerns about the improper methodology and facilitation used to conduct them. Opinions among the respondents about the process of generating and selecting the themes for the dialogues were extremely divergent. Both before and during the Ebola outbreak, the context was instrumental in shaping the dialogues according to the issue of focus, requirements for participation and the decisions to be made. Policy dialogues have become a platform for policy discussions and decisions in Liberia. It is a process that is well recognised and appreciated and is highly attributed to the success of the negotiations during the Ebola outbreak. CONCLUSIONS: To sustain and strengthen policy dialogues in future, there needs to be proper information sharing through diverse forums and avenues, stakeholders' empowerment and competent facilitation. These will ensure that the process is credible and legitimate. PMID- 27454118 TI - CLASH: Complementary Linkage with Anchoring and Scoring for Heterogeneous biomolecular and clinical data. AB - BACKGROUND: The study on disease-disease association has been increasingly viewed and analyzed as a network, in which the connections between diseases are configured using the source information on interactome maps of biomolecules such as genes, proteins, metabolites, etc. Although abundance in source information leads to tighter connections between diseases in the network, for a certain group of diseases, such as metabolic diseases, the connections do not occur much due to insufficient source information; a large proportion of their associated genes are still unknown. One way to circumvent the difficulties in the lack of source information is to integrate available external information by using one of up-to date integration or fusion methods. However, if one wants a disease network placing huge emphasis on the original source of data but still utilizing external sources only to complement it, integration may not be pertinent. Interpretation on the integrated network would be ambiguous: meanings conferred on edges would be vague due to fused information. METHODS: In this study, we propose a network based algorithm that complements the original network by utilizing external information while preserving the network's originality. The proposed algorithm links the disconnected node to the disease network by using complementary information from external data source through four steps: anchoring, connecting, scoring, and stopping. RESULTS: When applied to the network of metabolic diseases that is sourced from protein-protein interaction data, the proposed algorithm recovered connections by 97%, and improved the AUC performance up to 0.71 (lifted from 0.55) by using the external information outsourced from text mining results on PubMed comorbidity literatures. Experimental results also show that the proposed algorithm is robust to noisy external information. CONCLUSION: This research has novelty in which the proposed algorithm preserves the network's originality, but at the same time, complements it by utilizing external information. Furthermore it can be utilized for original association recovery and novel association discovery for disease network. PMID- 27454119 TI - Cytotoxic chemotherapy and the evolution of cellular and viral resistance to antiretroviral therapy in HIV- infected individuals with lymphoma. AB - BACKGROUND: The use of combination antiretroviral therapy (cART) and cytotoxic chemotherapy for HIV-associated lymphoma runs the risks of inducing HIV drug resistance. This study examined two possible mechanisms: altered expression of membrane drug transporter protein (MTP) and acquisition of mutations in pro-viral DNA. METHODS: Expression levels of MTP and pro-viral DNA resistance mutation analysis were performed on peripheral blood mononuclear cells (PBMC) before, during, and after chemotherapy. RESULTS: Twenty nine patients completed the three time point estimations. There were no significant variations before, during, and after chemotherapy in the expression of four MTPs: ABCB1, ABCC1, ABCC2, and SLCO3A1 (OATP3A1). Pro-viral DNA sequencing revealed that only one patient developed a new nucleos/tide reverse transcriptase inhibitor-associated mutation (184V) during the course of the study, giving a mutation rate of 0.0027 per person per year. CONCLUSIONS: In conclusion, concomitant administration of cytotoxic chemotherapy and cART does not induce expression of MTP. Furthermore, no significant changes in viral resistance were observed pre- and post chemotherapy, suggesting mutagenic cytotoxic chemotherapy seems not to induce mutations in HIV pro-viral DNA. PMID- 27454121 TI - Correction: Rapid Progressing Allele HLA-B35 Px Restricted Anti-HIV-1 CD8+ T Cells Recognize Vestigial CTL Epitopes. AB - [This corrects the article DOI: 10.1371/journal.pone.0010249.]. PMID- 27454120 TI - Pdcd4 Is Involved in the Formation of Stress Granule in Response to Oxidized Low Density Lipoprotein or High-Fat Diet. AB - Stress granules (SGs) in response to various stresses have been reported in many diseases. We previously reported the implication of programmed cell death 4 (Pdcd4) in obesity-induced stress responses, but the possible link between Pdcd4 and SGs remains lacking. In this study we showed that oxidized low-density lipoprotein (ox-LDL) or high-fat diet (HFD) induced SG formation in mouse macrophages and liver tissues, and Pdcd4 deficiency in mice remarkably reduced its formation. In response to ox-LDL, either endogenous or ectopic Pdcd4 displayed granule-like expression and co-localized with SG markers including T cell-restricted intracellular antigen-1, fragile X mental retardation-related protein 1, and eukaryotic initiation factor 4A. Ectopic expression of truncated Pdcd4 that depleted specific RNA-binding motif significantly disrupted the SG formation, suggesting the direct involvement of Pdcd4 in ox-LDL-induced SGs through its RNA-binding activity. Additionally, Pdcd4 deficiency drove AKT activation and suppression of eIF2alpha phosphorylation, thereby contributing to the resistance to ox-LDL or HFD-induced SG formation. Collectively, our data suggest that Pdcd4 as a crucial regulator in SGs induced by ox-LDL or HFD maybe a potential target for mitigating SG-associated stress responses in obesity and related diseases. PMID- 27454122 TI - Facing a Clever Predator Demands Clever Responses - Red-Backed Shrikes (Lanius collurio) vs. Eurasian Magpies (Pica pica). AB - Red-backed shrikes (Lanius collurio) behave quite differently towards two common nest predators. While the European jay (Garrulus glandarius) is commonly attacked, in the presence of the Eurasian magpie (Pica pica), shrikes stay fully passive. We tested the hypotheses that this passive response to the magpie is an alternative defense strategy. Nesting shrikes were exposed to the commonly attacked European kestrel (Falco tinnunculus) in a situation in which i) a harmless domestic pigeon, ii) a commonly attacked European jay, and iii) a non attacked black-billed magpie are (separately) presented nearby. The kestrel dummy presented together with the magpie dummy was attacked with a significantly lower intensity than when it was presented with the other intruders (pigeon, jay) or alone. This means that the presence of the magpie inhibited the shrike's defense response towards the other intruder. These results support our previous hypotheses that shrikes use an alternative defense strategy in the magpie's presence. We hypothesize that the magpie is able to associate the active defense of the shrikes with the close proximity of a nest and that shrikes try not to draw the magpie's attention to the nest. The reason why this strategy is not used against the jay remains unanswered as jays as well as magpies show very similar cognitive and foraging skills enabling them to individuate the nest presence according to active parental defense. PMID- 27454123 TI - An Improved FFR Design with a Ventilation Fan: CFD Simulation and Validation. AB - This article presents an improved Filtering Facepiece Respirator (FFR) designed to increase the comfort of wearers during low-moderate work. The improved FFR aims to lower the deadspace temperature and CO2 level by an active ventilation fan. The reversing modeling is used to build the 3D geometric model of this FFR; the Computational Fluid Dynamics (CFD) simulation is then introduced to investigate the flow field. Based on the simulation result, the ventilation fan of the improved FFR can fit the flow field well when placed in the proper blowing orientation; streamlines from this fan show a cup-shape distribution and are perfectly matched to the shape of the FFR and human face when the fan blowing inward. In the deadspace of the improved FFR, the CO2 volume fraction is controlled by the optimized flow field. In addition, an experimental prototype of the improved FFR has been tested to validate the simulation. A wireless temperature sensor is used to detect the temperature variation inside the prototype FFR, deadspace temperature is lowered by 2 K compared to the normal FFR without a fan. An infrared camera (IRC) method is used to elucidate the temperature distribution on the prototype FFR's outside surface and the wearer's face, surface temperature is lowered notably. Both inside and outside temperature results from the simulation are in agreement with experimental results. Therefore, adding an inward-blowing fan on the outer surface of an N95 FFR is a feasible approach to reducing the deadspace CO2 concentration and improve temperature comfort. PMID- 27454124 TI - Relations between Recent Past Leisure Activities with Risks of Dementia and Cognitive Functions after Stroke. AB - BACKGROUND: Leisure activity participation has been shown to lower risks of cognitive decline in non-stroke populations. However, effects of leisure activities participation upon cognitive functions and risk of dementia after stroke are unclear. The purpose of this study is to examine the effects of recent past leisure activities participation upon cognitive functions and risk of incident dementia after stroke. METHODS: Hospital-based, retrospective cohort study. 88 of 1,013 patients with stroke or TIA having no prestroke dementia were diagnosed to have incident poststroke dementia (PSD) 3-6 months after stroke. Regular participation (>=3 times per week) in intellectual, recreational, social and physical activities over the year before the index stroke was retrospectively recorded at 3-6 months after stroke. RESULTS: Logistic regression analyses showed that regular participation in intellectual (RR 0.36, 95%CI 0.20-0.63) and stretching & toning physical exercise (0.37, 0.21-0.64) was significantly associated with a reduced risk of PSD after controlling for age, education, prestroke cognitive decline, stroke subtype, prior strokes and chronic brain changes including white matter changes, old infarcts and global atrophy. Results were similar in patients with past strokes in unadjusted models. Participation in increased number of activities in general (r = 0.41, p<0.01) and in intellectual (r = 0.40, p<0.01), recreational (r = 0.24, p<0.01), strenuous aerobic (r = 0.23, p<0.01) and mind-body (r = 0.10, p<0.01) activities was associated with higher poststroke Mini-mental State Examination scores in models adjusted for prestroke cognitive decline. CONCLUSIONS: Regular participation in intellectual activities and stretching & toning exercise was associated with a significantly reduced short-term risk of PSD in patients with and without recurrent strokes. Participation in greater number of recent past leisure activities was associated with better poststroke cognitive performance. Findings of this retrospective cohort study call for studies of activity intervention for prevention of cognitive decline in individuals at elevated risk of stroke. PMID- 27454126 TI - Acridine Orange Indicates Early Oxidation of Wood Cell Walls by Fungi. AB - Colonization of wood blocks by brown and white rot fungi rapidly resulted in detectable wood oxidation, as shown by a reduced phloroglucinol response, a loss of autofluorescence, and acridine orange (AO) staining. This last approach is shown to provide a novel method for identifying wood oxidation. When lignin was mildly oxidized, the association between AO and lignin was reduced such that stained wood sections emitted less green light during fluorescence microscopy. This change was detectable after less than a week, an interval that past work has shown to be too short for significant delignification of wood. Although fungal hyphae were observed in only a few wood lumina, oxidation was widespread, appearing relatively uniform over regions several hundred micrometers from the hyphae. This observation suggests that both classes of fungi release low molecular weight mild oxidants during the first few days of colonization. PMID- 27454125 TI - Shooting Mechanisms in Nature: A Systematic Review. AB - BACKGROUND: In nature, shooting mechanisms are used for a variety of purposes, including prey capture, defense, and reproduction. This review offers insight into the working principles of shooting mechanisms in fungi, plants, and animals in the light of the specific functional demands that these mechanisms fulfill. METHODS: We systematically searched the literature using Scopus and Web of Knowledge to retrieve articles about solid projectiles that either are produced in the body of the organism or belong to the body and undergo a ballistic phase. The shooting mechanisms were categorized based on the energy management prior to and during shooting. RESULTS: Shooting mechanisms were identified with projectile masses ranging from 1.10-9 mg in spores of the fungal phyla Ascomycota and Zygomycota to approximately 10,300 mg for the ballistic tongue of the toad Bufo alvarius. The energy for shooting is generated through osmosis in fungi, plants, and animals or muscle contraction in animals. Osmosis can be induced by water condensation on the system (in fungi), or water absorption in the system (reaching critical pressures up to 15.4 atmospheres; observed in fungi, plants, and animals), or water evaporation from the system (reaching up to -197 atmospheres; observed in plants and fungi). The generated energy is stored as elastic (potential) energy in cell walls in fungi and plants and in elastic structures in animals, with two exceptions: (1) in the momentum catapult of Basidiomycota the energy is stored in a stalk (hilum) by compression of the spore and droplets and (2) in Sphagnum energy is mainly stored in compressed air. Finally, the stored energy is transformed into kinetic energy of the projectile using a catapult mechanism delivering up to 4,137 J/kg in the osmotic shooting mechanism in cnidarians and 1,269 J/kg in the muscle-powered appendage strike of the mantis shrimp Odontodactylus scyllarus. The launch accelerations range from 6.6g in the frog Rana pipiens to 5,413,000g in cnidarians, the launch velocities from 0.1 m/s in the fungal phylum Basidiomycota to 237 m/s in the mulberry Morus alba, and the launch distances from a few thousands of a millimeter in Basidiomycota to 60 m in the rainforest tree Tetraberlinia moreliana. The mass specific power outputs range from 0.28 W/kg in the water evaporation mechanism in Basidiomycota to 1.97.109 W/kg in cnidarians using water absorption as energy source. DISCUSSION AND CONCLUSIONS: The magnitude of accelerations involved in shooting is generally scale-dependent with the smaller the systems, discharging the microscale projectiles, generating the highest accelerations. The mass specific power output is also scale dependent, with smaller mechanisms being able to release the energy for shooting faster than larger mechanisms, whereas the mass-specific work delivered by the shooting mechanism is mostly independent of the scale of the shooting mechanism. Higher mass-specific work-values are observed in osmosis-powered shooting mechanisms (<= 4,137 J/kg) when compared to muscle-powered mechanisms (<= 1,269 J/kg). The achieved launch parameters acceleration, velocity, and distance, as well as the associated delivered power output and work, thus depend on the working principle and scale of the shooting mechanism. PMID- 27454127 TI - Complications with Fiberoptic Endoscopic Evaluation of Swallowing in 2,820 Examinations. AB - OBJECTIVE: To perform a retrospective evaluation of the incidence of complications and adverse events during fiberoptic endoscopic evaluation of swallowing (FEES) in 2,820 examinations. PATIENTS AND METHODS: Subjects included in- and outpatients at Pisa University Hospital referred for FEES by other physicians due to dysphagia symptoms. Neurologic diseases were the most commonly diagnosed conditions in the patients tested (48.3%). Informed consent was obtained from all subjects. RESULTS: Our study showed minor side effects (discomfort, occasional gagging and vomiting) and a few complications [three cases of anterior epistaxis (0.1%), one case of posterior epistaxis (0.04%), three cases of vasovagal syncope (0.1%) and two cases of laryngospasm (0.07%)]. These cases of laryngospasm occurred in patients with amyotrophic lateral sclerosis (ALS) and spontaneously resolved after some difficulty. CONCLUSIONS: Our study confirms the published data regarding the safety of FEES and the incidence of complications with this procedure, but also highlights that in neurologic patients with neurodegenerative diseases such as ALS, laryngospasm is more likely to occur as a severe complication. The overall risk of FEES is minimal, but it is recommended that clinicians be well trained in recognising the signs and symptoms of adverse reactions and be ready to take appropriate action if these occur. PMID- 27454128 TI - Reduction of false arrhythmia alarms using signal selection and machine learning. AB - In this paper, we propose an algorithm that classifies whether a generated cardiac arrhythmia alarm is true or false. The large number of false alarms in intensive care is a severe issue. The noise peaks caused by alarms can be high and in a noisy environment nurses can experience stress and fatigue. In addition, patient safety is compromised because reaction time of the caregivers to true alarms is reduced. The data for the algorithm development consisted of records of electrocardiogram (ECG), arterial blood pressure, and photoplethysmogram signals in which an alarm for either asystole, extreme bradycardia, extreme tachycardia, ventricular fibrillation or flutter, or ventricular tachycardia occurs. First, heart beats are extracted from every signal. Next, the algorithm selects the most reliable signal pair from the available signals by comparing how well the detected beats match between different signals based on [Formula: see text]-score and selecting the best match. From the selected signal pair, arrhythmia specific features, such as heart rate features and signal purity index are computed for the alarm classification. The classification is performed with five separate Random Forest models. In addition, information on the local noise level of the selected ECG lead is added to the classification. The algorithm was trained and evaluated with the PhysioNet/Computing in Cardiology Challenge 2015 data set. In the test set the overall true positive rates were 93 and 95% and true negative rates 80 and 83%, respectively for events with no information and events with information after the alarm. The overall challenge scores were 77.39 and 81.58. PMID- 27454130 TI - False alarms during patient monitoring in clinical intensive care units are highly related to poor quality of the monitored electrocardiogram signals. AB - Electrocardiograms (ECGs) recorded from patients in intensive care were investigated to quantify any relationship between ECG signal quality and false monitoring alarms. False alarms are a considerable problem for nursing and medical staff as they distract from clinical care, and are also a problem for patients as they disturb rest, which is important for clinical recovery. ECG and alarm data were obtained for 750 patient alarms from the PhysioNet database. The final 8 s period before the alarm was triggered was investigated. All but one ECG channel in 38 ECG recordings with out-of-range data were associated with false positive alarms (p < 0.0001). The frequency contributions for baseline (BL) instability, electromyogram (EMG) muscle noise, and high frequency (HF) noise were calculated. For all three frequency bands, the contributions associated with false positive alarms were very significantly greater than for true positive alarms (p < 0.0001). The greatest difference was for BL with a mean level for false positive alarms 4.0 times greater than for true positive alarms, followed by EMG and HF at 1.6 times and 1.4 times respectively. These results confirm that attention needs to be taken to improve ECG signal quality to reduce the frequency of clinical false alarms, and hence improve conditions for clinical staff and patients. PMID- 27454129 TI - Getting the most out of PubChem for virtual screening. AB - INTRODUCTION: With the emergence of the 'big data' era, the biomedical research community has great interest in exploiting publicly available chemical information for drug discovery. PubChem is an example of public databases that provide a large amount of chemical information free of charge. AREAS COVERED: This article provides an overview of how PubChem's data, tools, and services can be used for virtual screening and reviews recent publications that discuss important aspects of exploiting PubChem for drug discovery. EXPERT OPINION: PubChem offers comprehensive chemical information useful for drug discovery. It also provides multiple programmatic access routes, which are essential to build automated virtual screening pipelines that exploit PubChem data. In addition, PubChemRDF allows users to download PubChem data and load them into a local computing facility, facilitating data integration between PubChem and other resources. PubChem resources have been used in many studies for developing bioactivity and toxicity prediction models, discovering polypharmacologic (multi target) ligands, and identifying new macromolecule targets of compounds (for drug repurposing or off-target side effect prediction). These studies demonstrate the usefulness of PubChem as a key resource for computer-aided drug discovery and related area. PMID- 27454131 TI - Sulfidation of Nano Zerovalent Iron (nZVI) for Improved Selectivity During In Situ Chemical Reduction (ISCR). AB - The high reactivity of nano zerovalent iron (nZVI) leads to inefficient treatment due to competition with various natural reductant demand (NRD) processes, especially the reduction of water to hydrogen. Here we show that this limitation can be alleviated by sulfidation (i.e., modification by reducing sulfur compounds). nZVI synthesized on carboxylmethylcelluose (CMC-nZVI) was sulfidated with either sulfide or dithionite. The reactivity of the resulting materials was examined with three complementary assays: (i) direct measurement of hydrogen production, (ii) reduction of a colorimetric redox probe (indigo disulfonate, I2S), and (iii) dechlorination of trichloroethylene (TCE). The results indicate that sulfidation at S/Fe molar ratios of >=0.3, effectively eliminates reaction with water, but retains significant reactivity with TCE. However, sulfidation with sulfide leaves most of the nZVI as Fe(0), whereas dithionite converts a majority of the nZVI to FeS (thus consuming much of the reducing capacity originally provided by the Fe(0)). Simplified numerical models show that the reduction kinetics of I2S and TCE are mainly dependent on the initial reducing equivalents and that the TCE reduction rate is affected by the aging of FeS. Overall, the results suggest that pretreatment of nZVI with reducing sulfur compounds could result in substantial improvement in nZVI selectivity. PMID- 27454132 TI - Effect of Direction and Tension of Kinesio Taping Application on Sensorimotor Coordination. AB - The present study investigates whether different directions and tensions of Kinesio((r)) Tex tape (KT) application differently influence the precision of sensorimotor synchronization, defined as the ability to coordinate actions with predictable external events. 10 healthy participants performed sets of repetitive wrist flexion-extensions synchronized to a series of paced audio stimuli with an inter-onset interval (IOI) of 500 and 400 ms. KT was applied over the wrist and finger extensor muscles. 2 facilitatory (light and moderate tension) and one inhibitory KT applications were used in different sessions. Standard deviation of the asynchrony (SDasy) and percentage difference of SDasy were calculated and compared across KT and the no-KT control cases. Direction and tension of KT application did not differently influence the ability to coordinate rhythmic movements to an auditory stimulus. However, compared with the no-KT control case, SDasy decreased significantly in all KT cases in both 500- and 400-ms IOI. Independent of direction/tension, the effect of KT on improving sensorimotor synchronization is likely associated with variations in the nature of the neuro anatomical constraints determining the control of voluntary movement. KT is then proposed to be tested on sensorimotor disorders associated with intense repetitive exercise to check for regaining effective motor control. PMID- 27454133 TI - Influence of Apnea-induced Hypoxia on Catecholamine Release and Cardiovascular Dynamics. AB - Prolonged breath-hold causes complex compensatory mechanisms such as increase in blood pressure, redistribution of blood flow, and bradycardia. We tested whether apnea induces an elevation of catecholamine-concentrations in well-trained apneic divers.11 apneic divers performed maximal dry apnea in a horizontal position. Parameters measured during apnea included blood pressure, ECG, and central, in addition to peripheral hemoglobin oxygenation. Peripheral arterial hemoglobin oxygenation was detected by pulse oximetry, whereas peripheral (abdominal) and central (cerebral) tissue oxygenation was measured by Near Infrared Spectroscopy (NIRS). Exhaled O2 and CO2, plasma norepinephrine and epinephrine concentrations were measured before and after apnea.Averaged apnea time was 247+/-76 s. Systolic blood pressure increased from 135+/-13 to 185+/-25 mmHg. End-expiratory CO2 increased from 29+/-4 mmHg to 49+/-6 mmHg. Norepinephrine increased from 623+/ 307 to 1 826+/-984 pg ml-1 and epinephrine from 78+/-22 to 143+/-65 pg ml-1 during apnea. Heart rate reduction was inversely correlated with increased norepinephrine (correlation coefficient -0.844, p=0.001). Central (cerebral) O2 desaturation was time-delayed compared to peripheral O2 desaturation as measured by NIRSabdominal and SpO2.Increased norepinephrine caused by apnea may contribute to blood shift from peripheral tissues to the CNS and thus help to preserve cerebral tissue O2 saturation longer than that of peripheral tissue. PMID- 27454134 TI - Aerobic Fitness and Technical Efficiency at High Intensity Discriminate between Elite and Subelite Tennis Players. AB - The aim of this study was to determine whether selected physiological, performance and technical parameters derived from an on-court test are capable of discriminating between tennis players of national and international levels. 38 elite and subelite tennis players were divided into international level (INT, n=8) and national level players (NAT, n=30). They all performed a specific endurance field test, and selected physiological (maximum oxygen uptake [VO2max], and ventilatory thresholds [VT1 and VT2]), performance (test duration, final stage and hits per test) and technical (technical effectiveness [TE]) parameters were compared. INT showed greater VO2max, VO2 at VT2 (ml.kg(-1).min(-1)), test duration (s), final stage (no.), hits per test (no.) and TE (% of successful hits), as compared with NAT (p<0.05). At high exercise intensity (stages 5 and 6), the INT achieved better TE than NAT (p=0.001-0.004), and the discriminant analyses showed that these technical parameters were the most discriminating factors. These results suggest that this specific endurance field test is capable of discriminating between tennis players at national and international levels, and that the better aerobic condition of the INT is associated with better technical efficiency at higher exercise intensities. PMID- 27454135 TI - Wearing Compression Garment after Endurance Exercise Promotes Recovery of Exercise Performance. AB - The present study examined the effects of wearing a lower-body compression garment (CG) after endurance exercise on recovery of physiological function. 18 males were divided into 2 experiments, the downhill running (n=10, DHR) experiments and the level running (n=8, LR) experiments. Subjects performed 30 min of DHR (gradient: - 10%) or LR (gradient: 0%) at 70% of VO2max with either wearing a CG (CG trial) or normal garment (CON trial) for 24 h after running. Changes in jump performance (counter movement jump; CMJ, rebound jump; RJ, drop jump; DJ), subjective feelings, circumferences of leg, and blood variables (creatine kinase, myoglobin, interleukin-6, high-sensitivity C-reactive protein) were evaluated before exercise, immediately after exercise, 1, 3 and 24 h following exercise. Running economy was evaluated at 24 h following exercise. CMJ height and RJ index were significantly higher in the CG trial than in the CON trial 24 h after running (P<0.05). Although changes in muscle soreness and blood variables were significantly greater in the DHR experiment than in the LR experiment, there was no significant difference between the trials in either experiment. Wearing a CG following endurance exercise facilitated recovery of jump performance under situations with severe exercise-induced muscle damage. PMID- 27454136 TI - The Ethics of Population Health Management: Collapsing the Traditional Boundary Between Patient Care and Public Health. PMID- 27454137 TI - Reply to letter: method to evaluate the abilities of scores in predicting mortality: not only receiver operating characteristic curves. PMID- 27454138 TI - Kinetics of Proximity-Induced Intramolecular DNA Strand Displacement. AB - Proximity-induced intramolecular DNA strand displacement (PiDSD) is one of the key mechanisms involved in many DNA-mediated proximity assays and protein responsive DNA devices. However, the kinetic profile of PiDSD has never been systematically examined before. Herein, we report a systematic study to explore the kinetics of PiDSD by combining the uses of three DNA strand displacement techniques, including a binding-induced DNA strand displacement to generate PiDSD, an intermolecular DNA strand-exchange strategy to measure a set of key kinetic parameters for PiDSD, and a toehold-mediated DNA strand displacement to generate fluorescence signals for the real-time monitoring of PiDSD. By using this approach, we have successfully revealed the kinetic profiles of PiDSD, determined the enhanced local effective concentrations of DNA probes that are involved in PiDSD, and identified a number of key factors that influence the kinetics of PiDSD. Our study on PiDSD establishes knowledge and strategies that can be used to guide the design and operation of various DNA-mediated proximity assays and protein-triggered DNA devices. PMID- 27454139 TI - Long lasting attentional-context dependent visuomotor memory. AB - Using a dual-task paradigm, we recently reported that visuomotor adaptation acquired under distraction of a secondary attention-demanding discrimination task could be remembered only when a similar distraction was present. In contrast, when tested without the distracting task, performance reverted to untrained levels (Song & Bedard, 2015). Here, we demonstrated that this newfound paradoxical benefit of consistent dual-task context lasts over 1 day, such that visuomotor memory retrieval is enhanced under conditions where it is more difficult to engage in attentional selection of the motor task. Furthermore, this long-term effect was evident even when the task type or sensory modality of the secondary task differed between initial adaptation and the delayed recall on the next day. We conclude that attentional diversion by performing a dual-task forms a long-term vital context for visuomotor memory independent of external contexts without taxing capacity limited attention. (PsycINFO Database Record PMID- 27454140 TI - Inefficient search strategies in simulated hemianopia. AB - We investigated whether healthy participants can spontaneously adopt effective eye movement strategies to compensate for information loss similar to that experienced by patients with damage to visual cortex (hemianopia). Visual information in 1 hemifield was removed or degraded while participants searched for an emotional face among neutral faces or a line tilted 45 degrees to the right among lines of varying degree of tilt. A bias to direct saccades toward the sighted field was observed across all 4 experiments. The proportion of saccades directed toward the "blind" field increased with the amount of information available in that field, suggesting fixations are driven toward salient visual stimuli rather than toward locations that maximize information gain. In Experiments 1 and 2, the sighted-field bias had a minimal impact on search efficiency, because the target was difficult to find. However, the sighted-field bias persisted even when the target was visually distinct from the distractors and could easily be detected in the periphery (Experiments 3 and 4). This surprisingly inefficient search behavior suggests that eye movements are biased to salient visual stimuli even when it comes at a clear cost to search efficiency, and efficient strategies to compensate for visual deficits are not spontaneously adopted by healthy participants. (PsycINFO Database Record PMID- 27454142 TI - Enhanced Nitrite Reductase Activity and Its Correlation with Oxygen Affinity in Hemoglobin Bis-Tetramers. AB - The vasoactivity of circulating cross-linked hemoglobin is consistent with the acellular protein penetrating the endothelial lining of blood vessels where hemoglobin can bind nitric oxide, the signal for relaxation of the muscles that surround blood vessels. In an important contrast, derivatives of bis-tetramers that are produced from hemoglobin by chemical coupling do not cause vasoconstriction in animal models. Presumably, they are unable to enter the endothelia where hemoglobin tetramers bind to nitric oxide. In addition, hemoglobin bis-tetramers can produce nitric oxide in circulation through their intrinsic nitrite reductase activity. Examination of this activity for hemoglobin derived bis-tetramers that are acetylated at lysyl amino groups in their alpha subunits reveals enhanced activity (k = 2.21 M(-1) s(-1)) compared to that of nonacetylated bis-tetramers (k = 0.70 M(-1) s(-1)). Plots of nitrite reductase activities as a function of the corresponding oxygen affinities of certain allosteric-state-stabilized derivatives reveal a significant correlation, providing a basis for interpretation of the correlated functions. PMID- 27454141 TI - 12-Crown-4 Ether Disrupts the Patient Brain-Derived Amyloid-beta-Fibril Trimer: Insight from All-Atom Molecular Dynamics Simulations. AB - Recent experimental data elucidated that 12-crown-4 ether molecule can disrupt Abeta40 fibrils but the mechanism of disruption remains elusive. We have performed a series of all-atom molecular dynamics simulations to study the molecular mechanism of Abeta40 fibril disruption by 12-crown-4. In the present study we have used the Abeta40 fibril trimer as it is the smallest unit that maintains a stable U-shaped structure, and serves as the nucleus to form larger fibrils. Our study reveals that 12-crown-4 ether can enter into the hydrophobic core region and form competitive, hydrophobic interactions with key hydrophobic residues; these interactions break the intersheet hydrophobic interactions and lead to the opening of the U-shaped topology and a loss of beta-sheet structure. Furthermore, we observed periods of time when 12-crown-4 was in the hydrophobic core and periods of time when it interacted with Lys28 (chain C), a "tug of war"; the 12-crown-4 binding with Lys28 destabilizes the salt-bridge between Asp23 and Lys28. In addition to the two aforementioned binding modes, the 12-crown-4 binds with Lys16, which is known to form a salt-bridge with Glu22 in antiparallel arranged Abeta fibrils. Our results are in good agreement with experimental results and suggest that molecules that have the ability to interact with both the hydrophobic core region and positively charged residues could serve as potential inhibitors of Abeta fibrils. PMID- 27454143 TI - How to treat splenic marginal zone lymphoma (SMZL) in patients unfit for surgery or more aggressive therapies: experience in 30 cases. AB - Splenic marginal zone lymphoma (SMZL) is an indolent disease that typically affects elderly patients. Thanks to its outcome, most patients don't need any specific therapy and 'a watch and wait' policy is frequently employed. Treatment is required in symptomatic cases. Splenectomy remains one of the first line options in patients fit for surgery. The best pharmacological strategy has not yet been identified for poor surgical risk cases. Amongst different possible chemotherapeutic approaches, alkylating agents, alone or in association with Rituximab, could employ in 'frail' patients. In the present study, the role of oral cyclophosphamide (100 mg per day for 15 consecutive days, every 30 for a total of six cycles) associated with anti-CD20 monoclonal antibody has been evaluated in 30 newly diagnosed SMZL patients, not fit for splenectomy or more toxic chemotherapic regimens. Overall response rate was 87% (CR 70%; PR 17%). Median PFS was 20 months (range, 1-53), with better outcome for low-risk cases according to IIL score prognostic index. Toxicity profile resulted mild. PMID- 27454144 TI - Heterogeneous Associations of Ecological Attributes with Tick-Borne Rickettsial Pathogens in a Periurban Landscape. AB - The variations in prevalence levels of two tick-borne rickettsial pathogens, Ehrlichia chaffeensis and Ehrlichia Ewingii, in a periurban environment were evaluated along with their ecological determinants. Tick life stage and sex, month of tick collection, landscape fragmentation, and ecological covariates specific to pasture and woodland sites were considered as explanatory covariates. Questing lone star ticks (Amblyomma americanum) were collected by flagging for an hour once every week during mid-April through mid-August in years 2013 and 2014. A total of 4357 adult and nymphal ticks (woodland = 2720 and pasture = 1637) were collected and assessed for pathogen prevalence by molecular methods. Female A. americanum ticks were more infected with E. chaffeensis than males or nymphs in woodland areas [? = 6.05%; ? = 12.0%; nymphs = 2.09%] and pastures [? = 8.05%; ? = 12.03%; nymphs = 3.33%], and the prevalence was influenced by edge density in the landscape. Higher E. ewingii infection was noted among female A. americanum ticks within woodland areas [? = 1.89%; ? = 2.14%; nymphs = 1.57%], but no such difference was evident in pastures [? = 1.03%; ? = 1.33%; nymphs = 1.12%]. Prevalence of E. ewingii was influenced by edge contrast index, and the percentage of pasture perimeter that was less than 20 meters from woodland areas. This study elucidates the complexity of tick-borne pathogen ecology and points to the need for further studies on the role of reservoir hosts, particularly that played by small vertebrates, which is not fully understood in the region. PMID- 27454145 TI - Seed mediated synthesis of highly mono-dispersed gold nanoparticles in the presence of hydroquinone. AB - Gold nanoparticles (AuNPs) are being studied for several biomedical applications, including drug delivery, biomedical imaging, contrast agents and tumor targeting. The synthesis of nanoparticles with a narrow size distribution is critical for these applications. We report the synthesis of highly mono-dispersed AuNPs by a seed mediated approach, in the presence of tri-sodium citrate and hydroquinone (HQ). AuNPs with an average size of 18 nm were used for the synthesis of highly mono-dispersed nanocrystals of an average size 40 nm, 60 nm, 80 nm and ~100 nm; but the protocol is not limited to these sizes. The colloidal gold was subjected to UV-vis absorbance spectroscopy, showing a red shift in lambda max wavelength, peaks at 518.47 nm, 526.37 nm, 535.73 nm, 546.03 nm and 556.50 nm for AuNPs seed (18 nm), 40 nm, 60 nm, 80 nm and ~100 nm respectively. The analysis was consistent with dynamic light scattering and electron microscopy. Hydrodynamic diameters measured were 17.6 nm, 40.8 nm, 59.8 nm, 74.1 nm, and 91.4 nm (size by dynamic light scattering-volume %); with an average poly dispersity index value of 0.088, suggesting mono-dispersity in the size distribution, which was also confirmed by transmission electron microscopy analysis. The advantage of a seed mediated approach is a multi-step growth of nanoparticle size that enables us to control the number of nanoparticles in the suspension, for size ranging from 24.5 nm to 95.8 nm. In addition, the HQ-based synthesis of colloidal nanocrystals allowed control of the particle size and size distribution by tailoring either the number of seeds, amount of gold precursor or reducing agent (HQ) in the final reaction mixture. PMID- 27454146 TI - Benchtop Delivery of Ni(cod)2 using Paraffin Capsules. AB - A facile method that allows for Ni(cod)2 to be used on the benchtop is reported. The procedure involves the preparation of paraffin-Ni(cod)2 capsules, which are stable to air and moisture. It is demonstrated that these readily available capsules can be used to promote a range of Ni(cod)2-catalyzed transformations. These studies are expected to promote the further use of Ni(cod)2 in organic synthesis. PMID- 27454147 TI - Temperature and size-dependent Hamaker constants for metal nanoparticles. AB - Theoretical values of the Hamaker constant have been calculated for metal nanoparticles using Lifshitz theory. The theory describes the Hamaker constant in terms of the permittivity of the interacting bodies. Metal nanoparticles exhibit an internal size effect that alters the dielectric permittivity of the particle when its size falls below the mean free path of the conducting electrons. This size dependence of the permittivity leads to size-dependence of the Hamaker constant for metal nanoparticles. Additionally, the electron damping and the plasma frequency used to model the permittivity of the particle exhibit temperature-dependence, which lead to temperature dependence of the Hamaker constant. In this work, both the size and temperature dependence for gold, silver, copper, and aluminum nanoparticles is demonstrated. The results of this study might be of interest for studying the colloidal stability of nanoparticles in solution. PMID- 27454148 TI - Ti3C2 MXenes with Modified Surface for High-Performance Electromagnetic Absorption and Shielding in the X-Band. AB - Electromagnetic (EM) absorbing and shielding composites with tunable absorbing behaviors based on Ti3C2 MXenes are fabricated via HF etching and annealing treatment. Localized sandwich structure without sacrificing the original layered morphology is realized, which is responsible for the enhancement of EM absorbing capability in the X-band. The composite with 50 wt % annealed MXenes exhibits a minimum reflection loss of -48.4 dB at 11.6 GHz, because of the formation of TiO2 nanocrystals and amorphous carbon. Moreover, superior shielding effectiveness with high absorption effectiveness is achieved. The total and absorbing shielding effectiveness of Ti3C2 MXenes in a wax matrix with a thickness of only 1 mm reach values of 76.1 and 67.3 dB, while those of annealed Ti3C2 MXenes/wax composites are 32 and 24.2 dB, respectively. Considering the promising performance of Ti3C2 MXenes with the modified surface, this work is expected to open the door for the expanded applications of MXenes family in EM absorbing and shielding fields. PMID- 27454150 TI - Formyl peptide receptor modulators: a patent review and potential applications for inflammatory diseases (2012-2015). AB - INTRODUCTION: The activation of leukocytes and the subsequent immune cascade play an essential role in sterile and infectious inflammation. Dysregulation of these immune responses or excess leukocyte activation can induce tissue damage, organ dysfunction and mortality. Formyl peptide receptors (FPRs) are functionally diverse pattern recognition receptors responsible for recognizing different endogenous damage-associated molecular patterns or exogenous pathogen-associated molecular patterns. FPRs mediate leukocyte activation during inflammation. FPR1 antagonists and FPR2 agonists have demonstrated significant anti-inflammatory effects based on in vitro and in vivo studies. An increasing number of synthesized compounds targeting FPRs, especially potential FPR1 antagonists and FPR2 agonists, have been disclosed in patents. AREAS COVERED: This article summarizes the current pharmacology patents related to FPR family modulators and their therapeutic indications based on a review of patent applications disclosed between 2012 and 2015. EXPERT OPINION: In this review, FPR1 modulators comprise beta-1,3-glucan synthase inhibitors containing an FPR ligand moiety, template fixed peptidomimetics, cyclosporin H, and dipeptide derivatives. FPR2 modulators include phenylurea, bridged spiro[2.4]heptane ester, naphthalene, aminotriazole, polycyclic pyrrolidine-2,5-dione, imidazolidine-2,4-dione, (2 ureidoacetamido)alkyl, amide, oxazolyl-methylether, oxazole, thiazole, and crystalline potassium salt derivatives. These compounds have potential applications for human conditions such as inflammatory lung diseases, ischemia reperfusion injury, sepsis, inflammatory bowel disease, and wound healing. FPRs are emerging as important targets for treating leukocyte-dominant inflammation. PMID- 27454151 TI - Muscle wrapping on arbitrary meshes with the heat method. AB - Muscle paths play an important role in musculoskeletal simulations by determining a muscle's length and how its force is distributed to joints. Most previous approaches estimate the way in which muscles 'wrap' around bones and other structures with smooth analytical wrapping surfaces. In this paper, we employ Newton's method with discrete differential geometry to permit muscle wrapping over arbitrary polygonal mesh surfaces that represent underlying bones and structures. Precomputing distance fields allows us to speed up computations for the common situation where many paths cross the same wrapping surfaces. We found positive results for the accuracy, robustness, and efficiency of the method. However the method did not exhibit continuous changes in path length for dynamic simulations. Nonetheless this approach provides a valuable step toward fast muscle wrapping on arbitrary meshes. PMID- 27454152 TI - Is this my voice or yours? The role of emotion and acoustic quality in self-other voice discrimination in schizophrenia. AB - INTRODUCTION: Impairments in self-other voice discrimination have been consistently reported in schizophrenia, and associated with the severity of auditory verbal hallucinations (AVHs). This study probed the interactions between voice identity, voice acoustic quality, and semantic valence in a self-other voice discrimination task in schizophrenia patients compared with healthy subjects. The relationship between voice identity discrimination and AVH severity was also explored. METHODS: Seventeen chronic schizophrenia patients and 19 healthy controls were asked to read aloud a list of adjectives characterised by emotional or neutral content. Participants' voice was recorded in the first session. In the behavioural task, 840 spoken words differing in identity (self/non-self), acoustic quality (undistorted/distorted), and semantic valence (negative/positive/neutral) were presented. Participants indicated if the words were spoken in their own voice, another person's voice, or were unsure. RESULTS: Patients were less accurate than controls in the recognition of self-generated speech with negative content only. Impaired recognition of negative self generated speech was associated with AVH severity ("voices conversing"). CONCLUSIONS: These results suggest that abnormalities in higher order processes (evaluation of the salience of a speech stimulus) modulate impaired self-other voice discrimination in schizophrenia. Abnormal processing of negative self generated speech may play a role in the experience of AVH. PMID- 27454153 TI - How Far Does Substituents' Impact Reach? The Transmission of Electronic Substituent Effects along the Polyphenylene Chain and the Evaluation of Through Bond and Through-Space Contributions. AB - Interactions between various parts of molecules determine their reactivities and are important from the point of view of molecular recognition. Concerning substituted aromatics, the correlation between the substituents' electrical properties with those of the rest of a molecule has been widely studied. However, the distances between the interacting sites generally did not exceed a dozen A. This study deals with the long polyphenylene substituted hydrocarbons and aims to answer two questions. The first question involves how rapidly interactions between a substituent in the phenyl ring and a site on the other end of the molecule decline with increasing distance between the two sites. The second is regarding how this interaction would be changed after chopping out the benzene rings, spacing units, from inside the molecules, leaving only the first, substituted benzene ring, and the last. The interactions were gauged by the electrostatic potential at the carbon atom the most distant from the substituent, and at two points in space. It was found that the interaction between two sites on a long molecule, about 120 A apart, is almost as precisely controlled by the substituent properties as in the substituted benzene molecules. The contributions of the through-bond and through-space interactions were that the latter increased as the molecules lengthened. PMID- 27454154 TI - Glyco-seek: Ultrasensitive Detection of Protein-Specific Glycosylation by Proximity Ligation Polymerase Chain Reaction. AB - We report a non-destructive biochemical technique, termed "Glyco-seek", for analysis of O-GlcNAcylated proteins. Glyco-seek combines chemoenzymatic labeling, proximity ligation, and quantitative polymerase chain reaction to detect O GlcNAcylated proteins with ultrahigh sensitivity. Our glycan-specific assay can be paired with traditional proximity ligation assays to simultaneously determine the change in total protein levels. We show that Glyco-seek detects attomoles of glycoproteins of interest from cell lysates, with sensitivity several orders of magnitude higher than that of current techniques. We used the method to directly assay the O-GlcNAcylation status of a low-abundance transcription factor from cell lysates without need for isolation or enrichment. PMID- 27454155 TI - Estradiol Upregulates Kisspeptin Expression in the Preoptic Area of both the Male and Female Rhesus Monkey (Macaca mulatta): Implications for the Hypothalamic Control of Ovulation in Highly Evolved Primates. AB - The aim of this immunohistochemical study was to evaluate the distribution of kisspeptin neurons in the preoptic area (POA) of gonadally intact adult male and female rhesus monkeys, and to determine whether imposition of an estradiol (E2) positive feedback signal in the castrate male increased kisspeptin in the POA. Additionally, kisspeptin in the POA of the intact female was examined during an LH surge induced prematurely by E2 administered in the early follicular phase. The number of kisspeptin neurons in the POA of males and females was similar. Immunoactive kisspeptin perikarya were not observed in the POA of castrate adult males, but such neurons in these animals were present within 12 h of imposing an increment in circulating E2 concentrations that in a screening study conducted 4 6 weeks earlier had elicited an LH surge. As expected, premature induction of an LH surge by E2 early in the follicular phase was associated with upregulation of kisspeptin in the POA. These results represent the first description of immunoreactive kisspeptin cell bodies in the POA of the macaque brain and provide further support for the view that (1) kisspeptin neurons in the POA of the female monkey are a target for the positive feedback action of E2 and (2) the hypothalamic mechanism which mediates this action of E2 in primates is not subjected to perinatal programming by testicular testosterone. Moreover, our findings indicate that maintenance of the kisspeptin content in the POA of intact male monkeys requires the action of E2, presumably generated by aromatization of testicular testosterone at the hypothalamic level. PMID- 27454156 TI - Reliability and validity of the Psoriasis Itch Visual Analog Scale in psoriasis vulgaris. AB - INTRODUCTION: The single-item Psoriasis Itch VAS was developed to measure itch intensity within the last 24 hours in psoriasis vulgaris to assess treatment benefit. Its psychometric properties were explored in two trials. METHODS: Data from two randomized, parallel-group phase 3 trials with subjects suffering from psoriasis vulgaris on the body (n = 426, 463) were analyzed. Cross-sectional distributional properties and construct validity of the Psoriasis Itch VAS as well as longitudinal test-retest reliability and sensitivity to change of the Psoriasis Itch VAS were investigated. All statistical tests were two-tailed. RESULTS: Across both trials, acceptable distributional properties were observed. Convergent-validity correlations between the Psoriasis Itch VAS and other patient reported and clinician-reported outcomes provided strong endorsement for construct validity as did tests of known-groups validity. Longitudinal measurement properties, involving test-retest reliability and sensitivity to change, also offered evidence for the measurement integrity of the Psoriasis Itch VAS. DISCUSSION: Results from the assessment of validity, reliability, and sensitivity to change support the use of the Psoriasis Itch VAS to measure itch intensity in psoriasis vulgaris. Data from two trials provided evidence that the Psoriasis Itch VAS is well-defined and reliable for measuring itch in psoriasis vulgaris to assess treatment benefit (i.e. therapeutic response). PMID- 27454157 TI - O-arm with navigation versus C-arm: a review of screw placement over 3 years at a major trauma center. AB - INTRODUCTION: There is a relatively high incidence of screw misplacement during spinal instrumentation due to distortion of normal anatomy following spinal trauma. The O-arm is the next-generation spinal navigation tool that provides intraoperative 3-D imaging and navigation for spine surgeries. AIMS AND OBJECTIVES: To evaluate and compare the use of O-arm as compared to C-arm for spinal trauma in a Level I trauma center in India. MATERIALS AND METHODS: In this retrospective study over 3 years (July 2010-April 2013), All patients of spinal injury who underwent spinal instrumentation were divided into O-arm group and C arm group. Accuracy of screw placement was assessed during each surgery in both groups. RESULTS: A total of 587 patients were evaluated during the study period. There were 278 patients in O-arm group and 309 patients in C-arm group. Both groups were well matched in mean age (27.7 vs. 28.9 years), ASIA grades, and level of injury. The number of screws placed was significantly higher in the C arm group as compared to the O-arm group (2173 vs. 1720). However, the O-arm group had significantly less screw malplacement rate of 0.93% (n = 16) as compared to malplacement rate in C-arm group of 8.79% (n = 191, p < 0.05). CONCLUSION: Use of O-arm imaging system ensures accurate screw placement and dramatically decreases screw malplacement rate, thus providing better patient safety. Its use is especially beneficial in academic and teaching centers where novice surgeons can attain results equivalent to that of experts in spinal instrumentation. PMID- 27454158 TI - The use of social networking applications of smartphone and associated sexual risks in lesbian, gay, bisexual, and transgender populations: a systematic review. AB - The use of social networking applications (apps) on smartphones has the potential to impact sexual health and behaviour. This was the first systematic review to critically appraise and summarize the existing literature on the use of social networking apps on smartphones and their associated sexual health and sexual behaviour effects in lesbian, gay, bisexual and transgender populations. A systematic search was conducted in five databases (CINAHL Plus, PsycINFO, PubMed, SCOPUS and Sociological Abstracts), using controlled terms and keywords. Thirteen articles from 11 studies were included in this review. Studied outcomes included rates of unprotected sexual intercourse, the number of sexual partners, drug/alcohol use prior to/during sexual intercourse, sexually transmitted infections (STIs) testing and the prevalence of STIs. Among app users, the prevalence of unprotected sex ranged from 17.0% to 66.7%. The mean number of sexual partners ranged from 1.4 to 2.9 (last 1-month period), and from 46.2 to 79.6 (lifetime). Two studies found that the prevalence of HIV infection was 1.9% and 11.4%, respectively. The self-reported prevalence of prior diagnosis of STIs other than HIV ranged from 9.1% to 51.0%. It should be noted that the heterogeneity of the study design and outcome measures across different studies hindered the comparison of findings across different studies. Furthermore, the findings in some studies are not reliable due to methodological problems. Our results highlight the need for more research with rigorous methodology to understand the negative impacts of using these apps on sexual health and sexual behaviour. For future studies, the operational definition of outcomes, including social networking app use and unprotected anal intercourse (UAI), should be clearly outlined. The use of validated tools to measure sexual behaviour and biological measures of HIV and other STDs is preferable so that outcomes can be standardized to facilitate comparisons between studies and the pooling of data. PMID- 27454159 TI - Nod factor supply under water stress conditions modulates cytokinin biosynthesis and enhances nodule formation and N nutrition in soybean. AB - Nod factors (NF) are molecules produced by rhizobia which are involved in the N2 fixing symbiosis with legume plants, enabling the formation of specific organs called nodules. Under drought conditions, nitrogen acquisition by N2-fixation is depressed, resulting in low legume productivity. In this study, we evaluated the effects of NF supply on nitrogen acquisition and on cytokinin biosynthesis of soybean plants grown under drought. NF supply to water stressed soybeans increased the CK content of all organs. The profile of CK metabolites also shifted from t-Z to cis-Z and an accumulation of nucleotide and glucoside conjugates. The changes in CK coincided with enhanced nodule formation with sustained nodule specific activity, which ultimately increased the total nitrogen fixed by the plant. PMID- 27454160 TI - The First Case Report of Robotic Multivisceral Resection for Synchronous Liver Metastasis from Pancreatic Neuroendocrine Tumor: A Case Report and Literature Review. AB - INTRODUCTION: Surgery for liver metastases in pancreatic neuroendocrine tumor (PNET) improves overall survival rate. We present the first case report for robotic multivisceral resection of distal pancreas, spleen, and left liver for metastatic PNET. MATERIALS AND METHODS: We present a case of 52-year-old female diagnosed with PNET in the pancreatic neck metastatic to the liver, responding to somatostatin and bland embolization, who underwent surgical debulking using da Vinci robotic platform. Intraoperative Doppler ultrasound was used to define the vascular distribution and tumor extension. The parenchymal liver transection was performed with vessel sealer. The distal pancreas and the spleen were approached medial to lateral and resected in an en-bloc fashion. The left liver inflow, outflow, and splenic artery and vein were transected with vascular stapler device. RESULTS: Da Vinci robot-assisted multivisceral resection has been performed with good postoperative outcome. Operative time was 369 minutes and the estimated blood loss was 100 mL. The patient had a short hospital stay with quick recovery and good outcome at 5 months follow-up after the surgery. DISCUSSION: Liver metastases in PNETs are considered an adverse factor. Aggressive surgical management is a mainstay. The laparoscopic approach to pancreatic or hepatic surgery is difficult in inexperienced hands with steep learning curve. The recent robotic system seems to overcome many limitations. This is the first case of robotic multivisceral resection for synchronous liver metastasis from PNET. Concurrent primary tumor resection with hepatectomy offers potential curative intention. PMID- 27454162 TI - Introduction of a conceptual model for integrating the MMPI-2-RF into HCR-20V3 violence risk assessments and associations between the MMPI-2-RF and institutional violence. AB - Reflecting the need to prevent violence, structured professional judgment assessment tools have been developed specifically to assess the likelihood of future violence. These tools typically integrate data from clinical interviews and collateral records to assist in the conceptualization of violence risk, but objective psychological testing may also be useful in completing the instruments. The authors describe the advantages of using the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in this manner with the Historical Clinical Management-20 Version 3 (HCR-20V3). Accordingly, they have 2 purposes. First, they sought to identify conceptual links between the constructs measured by the tools and introduce a model to integrate MMPI-2-RF findings into an HCR-20V3 risk assessment. Second, although the authors did not have collateral HCR-20V3 ratings, they sought to examine associations between the MMPI-2-RF scales and future violence in a sample of 303 psychiatric patients (233 males, 70 females) adjudicated as not guilty by reason of insanity. The authors found that the MMPI-2-RF scales demonstrated significant, meaningful associations with a count of future violent acts at the hospital. The largest associations involved scales measuring emotional dysregulation and externalizing dysfunction. These associations were qualified by relative risk ratio analyses indicating that patients producing elevations on these scales were at 1.5 to 2.5 times greater risk of future violence than those without elevations. Overall, the findings indicated that most MMPI-2-RF scales conceptually linked to the HCR-20V3 risk factors were associated with future violence. In light of these findings, the authors discuss recommendations for integrating the MMPI-2-RF when interpreting HCR-20V3 risk factors. (PsycINFO Database Record PMID- 27454161 TI - BMI1 inhibits senescence and enhances the immunomodulatory properties of human mesenchymal stem cells via the direct suppression of MKP-1/DUSP1. AB - For the application of mesenchymal stem cells (MSCs) as clinical therapeutics, the regulation of cellular aging is important to protect hMSCs from an age associated decline in their function. In this study, we evaluated the effects of hypoxia on cellular senescence and the immunomodulatory abilities of hUCB-MSCs. Hypoxic-cultured hUCB-MSCs showed enhanced proliferation and had increased immunosuppressive effects on mitogen-induced mononuclear cell proliferation. We found that BMI1, a member of the polycomb repressive complex protein group, showed increased expression in hypoxic-cultured hUCB-MSCs, and the further knock down of BMI1 in hypoxic cells induced decreased proliferative and immunomodulatory abilities in hUCB-MSCs, along with COX-2/PGE2 down-regulation. Furthermore, the expression of phosphorylated p38 MAP kinase increased in response to the over-expression of BMI1 in normoxic conditions, suggesting that BMI1 regulates the immunomodulatory properties of hUCB-MSCs via p38 MAP kinase mediated COX-2 expression. More importantly, we identified BMI1 as a direct repressor of MAP kinase phosphatase-1 (MKP-1)/DUSP1, which suppresses p38 MAP kinase activity. In conclusion, our results demonstrate that BMI1 plays a key role in the regulation of the immunomodulatory properties of hUCB-MSCs, and we suggest that these findings might provide a strategy to enhance the functionality of hUCB-MSCs for use in therapeutic applications. PMID- 27454163 TI - Analysis of alpha-particle-induced chromosomal aberrations by chemically-induced PCC. Elaboration of dose-effect curves. AB - In a similar way to high-dose exposures to low-LET radiations, cells show difficulties reaching mitosis after high-LET radiation exposure. For this reason, techniques have been proposed that are able to analyze chromosome aberrations in interphase by prematurely condensing the chromosomes (PCC-techniques). Few dose effect curves for high-LET radiation types have been reported, and none for alpha particles. The aim of this study was to evaluate, by chemically-induced PCC, the chromosome aberrations induced by several doses of alpha-particles. Monolayers of peripheral lymphocytes were exposed to an alpha-source of Americium-241 with a mean energy entering the cells of 2.7 MeV. Lymphocytes were exposed to 10 doses, from 0-2.5 Gy, and then cultured for 48 h. Colcemid and Calyculin-A were added at 24 and 1 h before harvesting, respectively. During microscope analysis, chromosome rings and extra chromosome pieces were scored in G2/M-PCC and M cells, while dicentric chromosomes were only scored in M cells. As the dose increased, fewer cells were able to reach mitosis and the proportion of G2/M-PCC cells increased. Chromosome rings were hardly observed in M cells when compared to G2/M PCC cells. Extra fragments were more frequent than rings in both G2/M-PCC and M cells, but with lower frequencies than in G2/M-PCC cells. The distribution of dicentrics and extra fragments showed a clear overdispersion; this was not so evident for rings. The dose-effect curves obtained fitted very well to a linear model. Damaged cells after alpha-particle irradiation show more difficulties in reaching mitosis than cells exposed to gamma-rays. After alpha-particle irradiation the frequency of all the chromosome aberrations considered increased linearly with the dose, and alpha-particles clearly produced more dicentrics and extra chromosome pieces with respect to gamma-rays. After alpha-particle exposure, the existence of extra chromosome fragments in PCC cells seems to be a good candidate for use as a biomarker for dose assessment. However, the observed frequencies of different types of chromosomal aberrations could be influenced by some methodological aspects; for this reason, and in order to avoid possible methodological bias, standardization of the technique will be desirable. PMID- 27454165 TI - Policy dialogues - the "bolts and joints" of policy-making: experiences from Cabo Verde, Chad and Mali. AB - BACKGROUND: Policy processes that yield good outcomes are inherently complex, requiring interactions of stakeholders in problem identification, generation of political will and selection of practical solutions. To make policy processes rational, policy dialogues are increasingly being used as a policy-making tool. Despite their increasing use for policy-making in Africa, evidence is limited on how they have evolved and are being used on the continent or in low and middle income countries elsewhere. METHODS: This was an exploratory study using qualitative methods. It utilised data related to policy dialogues for three specific policies and strategies to understand the interplay between policy dialogue and policy-making in Cabo Verde, Chad and Mali. The specific methods used to gather data were key informant interviews and document review. Data were analysed inductively and deductively using thematic content analysis. RESULTS: Participation in the policy dialogues was inclusive, and in some instances bottom up participatory approaches were used. The respondents felt that the execution of the policy dialogues had been seamless, and the few divergent views expressed often were resolved in a unanimous manner. The policies and strategies developed were seen by all stakeholders as relating to priority issues. Other specific process factors that contributed to the success of the dialogues included the use of innovative approaches, good facilitation, availability of resources for the dialogues, good communication, and consideration of the different opinions. Among the barriers were contextual issues, delays in decision-making and conflicting coordination roles and mandates. CONCLUSIONS: Policy dialogues have proved to be an effective tool in health sector management and could be a crucial component of the governance dynamics of the sector. The policy dialogue process needs to be institutionalised for continuity and maintenance of institutional intelligence. Other essential influencing factors include building capacity for coordination and facilitation of policy dialogues, provision of sustainable financing for execution of the dialogues, use of inclusive and bottom-up approaches, and timely provision of reliable evidence. Ensuring continued participation of all the actors necessitates innovation to allow dialogue outside the formal frameworks and spaces that should feed into the formal dialogue processes. PMID- 27454164 TI - The role of interdisciplinary research team in the impact of health apps in health and computer science publications: a systematic review. AB - BACKGROUND: Several studies have estimated the potential economic and social impact of the mHealth development. Considering the latest study by Institute for Healthcare Informatics, more than 165.000 apps of health and medicine are offered including all the stores from different platforms. Thus, the global mHealth market was an estimated $10.5 billion in 2014 and is expected to grow 33.5 percent annually between 2015 and 2020s. In fact, apps of Health have become the third-fastest growing category, only after games and utilities. METHODS: This study aims to identify, study and evaluate the role of interdisciplinary research teams in the development of articles and applications in the field of mHealth. It also aims to evaluate the impact that the development of mHealth has had on the health and computer science field, through the study of publications in specific databases for each area which have been published until nowadays. RESULTS: Interdisciplinary nature is strongly connected to the scientific quality of the journal in which the work is published. This way, there are significant differences in those works that are made up by an interdisciplinary research team because of they achieve to publish in journals with higher quartiles. There are already studies that warn of methodological deficits in some studies in mHealth, low accuracy and no reproducibility. Studies of low precision and poor reproducibility, coupled with the low evidence, provide low degrees of recommendation of the interventions targeted and therefore low applicability. CONCLUSIONS: From the evidence of this study, working in interdisciplinary groups from different areas greatly enhances the quality of research work as well as the quality of the publications derived from its results. PMID- 27454166 TI - Network topology measures for identifying disease-gene association in breast cancer. AB - BACKGROUND: Massive biological datasets are generated in different locations all over the world. Analysis of these datasets is required in order to extract knowledge that might be helpful for biologists, physicians and pharmacists. Recently, analysis of biological networks has received a lot of attention, as an understanding of the network can reveal information about life at the cellular level. Biological networks can be generated that examine the interaction between proteins or the relationship amongst different genes at the expression level. Identifying information from biological networks is recognized as a significant challenge, due to the inherent complexity of the structures. Computational techniques are used to analyze such complex networks with varying success. RESULTS: In this paper, we construct a new method for predicting phenotype-gene association in breast cancer using biological network analysis. Several network topological measures have been computed and fed as features into two classification models to investigate phenotype-gene association in breast cancer. More importantly, to overcome the problem of the skewed datasets, a synthetic minority oversampling technique (SMOTE) is adapted in order to transform an imbalanced dataset to a balanced one. We have applied our method on the gene co expression network (GCN), protein-protein interaction network (PPI), and the integrated functional interaction network (FI), which combined the PPIs and gene co-expression, amongst others. We assess the quality of our proposed method using a slightly modified cross-validation. CONCLUSIONS: Our method can identify phenotype-gene association in breast cancer. Moreover, use of the integrated functional interaction network (FI) has the potential to reveal more information and hidden patterns than the other networks. The software and accompanying examples are freely available at http://faculty.kfupm.edu.sa/ics/eramadan/NetTop.zip . PMID- 27454167 TI - A method for exploring implicit concept relatedness in biomedical knowledge network. AB - BACKGROUND: Biomedical information and knowledge, structural and non-structural, stored in different repositories can be semantically connected to form a hybrid knowledge network. How to compute relatedness between concepts and discover valuable but implicit information or knowledge from it effectively and efficiently is of paramount importance for precision medicine, and a major challenge facing the biomedical research community. RESULTS: In this study, a hybrid biomedical knowledge network is constructed by linking concepts across multiple biomedical ontologies as well as non-structural biomedical knowledge sources. To discover implicit relatedness between concepts in ontologies for which potentially valuable relationships (implicit knowledge) may exist, we developed a Multi-Ontology Relatedness Model (MORM) within the knowledge network, for which a relatedness network (RN) is defined and computed across multiple ontologies using a formal inference mechanism of set-theoretic operations. Semantic constraints are designed and implemented to prune the search space of the relatedness network. CONCLUSIONS: Experiments to test examples of several biomedical applications have been carried out, and the evaluation of the results showed an encouraging potential of the proposed approach to biomedical knowledge discovery. PMID- 27454168 TI - Secure Multi-pArty Computation Grid LOgistic REgression (SMAC-GLORE). AB - BACKGROUND: In biomedical research, data sharing and information exchange are very important for improving quality of care, accelerating discovery, and promoting the meaningful secondary use of clinical data. A big concern in biomedical data sharing is the protection of patient privacy because inappropriate information leakage can put patient privacy at risk. METHODS: In this study, we deployed a grid logistic regression framework based on Secure Multi-party Computation (SMAC-GLORE). Unlike our previous work in GLORE, SMAC GLORE protects not only patient-level data, but also all the intermediary information exchanged during the model-learning phase. RESULTS: The experimental results demonstrate the feasibility of secure distributed logistic regression across multiple institutions without sharing patient-level data. CONCLUSIONS: In this study, we developed a circuit-based SMAC-GLORE framework. The proposed framework provides a practical solution for secure distributed logistic regression model learning. PMID- 27454169 TI - Cancer drug discovery: recent innovative approaches to tumor modeling. AB - INTRODUCTION: Cell culture models have been at the heart of anti-cancer drug discovery programs for over half a century. Advancements in cell culture techniques have seen the rapid evolution of more complex in vitro cell culture models investigated for use in drug discovery. Three-dimensional (3D) cell culture research has become a strong focal point, as this technique permits the recapitulation of the tumor microenvironment. Biologically relevant 3D cellular models have demonstrated significant promise in advancing cancer drug discovery, and will continue to play an increasing role in the future. AREAS COVERED: In this review, recent advances in 3D cell culture techniques and their application in tumor modeling and anti-cancer drug discovery programs are discussed. The topics include selection of cancer cells, 3D cell culture assays (associated endpoint measurements and analysis), 3D microfluidic systems and 3D bio-printing. EXPERT OPINION: Although advanced cancer cell culture models and techniques are becoming commonplace in many research groups, the use of these approaches has yet to be fully embraced in anti-cancer drug applications. Furthermore, limitations associated with analyzing information-rich biological data remain unaddressed. PMID- 27454170 TI - Regional Coherence Alterations Revealed by Resting-State fMRI in Post-Stroke Patients with Cognitive Dysfunction. AB - OBJECTIVES: Post-stroke cognitive dysfunction greatly influences patients' quality of life after stroke. However, its neurophysiological basis remains unknown. This study utilized resting-state functional magnetic resonance imaging (fMRI) to investigate the alterations in regional coherence in patients after subcortical stroke. METHODS: Resting-state fMRI measurements were acquired from 16 post-stroke patients with poor cognitive function (PSPC), 16 post-stroke patients with good cognitive function (PSGC) and 30 well-matched healthy controls (HC). Regional homogeneity (ReHo) was used to detect alterations in regional coherence. Abnormalities in regional coherence correlated with scores on neuropsychological scales. RESULTS: Compared to the HC and the PSGC, the PSPC showed remarkably decreased ReHo in the bilateral anterior cingulate cortex and the left posterior cingulate cortex/precuneus. ReHo in the bilateral anterior cingulate cortex positively correlated with the scores on the Symbol Digit Modalities Test (r = 0.399, P = 0.036) and the Complex Figure Test-delayed recall subtest (r = 0.397, P = 0.036) in all post-stroke patients. Moreover, ReHo in the left posterior cingulate cortex/precuneus positively correlated with the scores on the Forward Digit Span Test (r = 0.485, P = 0.009) in all post-stroke patients. CONCLUSIONS: Aberrant regional coherence was observed in the anterior and posterior cingulate cortices in post-stroke patients with cognitive dysfunction. ReHo could represent a promising indicator of neurobiological deficiencies in post-stroke patients. PMID- 27454171 TI - False arrhythmia alarms reduction in the intensive care unit: a multimodal approach. AB - The purpose of this study was to develop algorithms to lower the incidence of false arrhythmia alarms in the ICU using information from independent sources, namely electrocardiogram (ECG), arterial blood pressure (ABP) and photoplethysmogram (PPG). Our approach relies on robust adaptive signal processing techniques in order to extract accurate heart rate (HR) values from the different waveforms. Based on the quality of available signals, heart rate was either estimated from pulsatile waveforms using an adaptive frequency tracking algorithm or computed from ECGs using an adaptive mathematical morphology approach. Furthermore, we developed a supplementary measure based on the spectral purity of the ECGs to determine whether a ventricular tachycardia or flutter/fibrillation arrhythmia has taken place. Finally, alarm veracity was determined based on a set of decision rules on HR and spectral purity values. The proposed method was evaluated on the PhysioNet/CinC Challenge 2015 database, which is composed of 1250 life-threatening alarm recordings, each categorized into either bradycardia, tachycardia, asystole, ventricular tachycardia or ventricular flutter/fibrillation arrhythmia. This resulted in overall true positive rates of 95%/99% and overall true negative rates of 76%/80% on the real time and retrospective subsets of the test dataset, respectively. PMID- 27454173 TI - Correction: Sixteen Years of Bt Maize in the EU Hotspot: Why Has Resistance Not Evolved? AB - [This corrects the article DOI: 10.1371/journal.pone.0154200.]. PMID- 27454172 TI - False alarm reduction in critical care. AB - High false alarm rates in the ICU decrease quality of care by slowing staff response times while increasing patient delirium through noise pollution. The 2015 PhysioNet/Computing in Cardiology Challenge provides a set of 1250 multi parameter ICU data segments associated with critical arrhythmia alarms, and challenges the general research community to address the issue of false alarm suppression using all available signals. Each data segment was 5 minutes long (for real time analysis), ending at the time of the alarm. For retrospective analysis, we provided a further 30 seconds of data after the alarm was triggered. A total of 750 data segments were made available for training and 500 were held back for testing. Each alarm was reviewed by expert annotators, at least two of whom agreed that the alarm was either true or false. Challenge participants were invited to submit a complete, working algorithm to distinguish true from false alarms, and received a score based on their program's performance on the hidden test set. This score was based on the percentage of alarms correct, but with a penalty that weights the suppression of true alarms five times more heavily than acceptance of false alarms. We provided three example entries based on well known, open source signal processing algorithms, to serve as a basis for comparison and as a starting point for participants to develop their own code. A total of 38 teams submitted a total of 215 entries in this year's Challenge. This editorial reviews the background issues for this challenge, the design of the challenge itself, the key achievements, and the follow-up research generated as a result of the Challenge, published in the concurrent special issue of Physiological Measurement. Additionally we make some recommendations for future changes in the field of patient monitoring as a result of the Challenge. PMID- 27454174 TI - Cell Electrosensitization Exists Only in Certain Electroporation Buffers. AB - Electroporation-induced cell sensitization was described as the occurrence of a delayed hypersensitivity to electric pulses caused by pretreating cells with electric pulses. It was achieved by increasing the duration of the electroporation treatment at the same cumulative energy input. It could be exploited in electroporation-based treatments such as electrochemotherapy and tissue ablation with irreversible electroporation. The mechanisms responsible for cell sensitization, however, have not yet been identified. We investigated cell sensitization dynamics in five different electroporation buffers. We split a pulse train into two trains varying the delay between them and measured the propidium uptake by fluorescence microscopy. By fitting the first-order model to the experimental results, we determined the uptake due to each train (i.e. the first and the second) and the corresponding resealing constant. Cell sensitization was observed in the growth medium but not in other tested buffers. The effect of pulse repetition frequency, cell size change, cytoskeleton disruption and calcium influx do not adequately explain cell sensitization. Based on our results, we can conclude that cell sensitization is a sum of several processes and is buffer dependent. Further research is needed to determine its generality and to identify underlying mechanisms. PMID- 27454175 TI - Maternal Age of Menarche and Blood Pressure in Adolescence: Evidence from Hong Kong's "Children of 1997" Birth Cohort. AB - BACKGROUND: Age of puberty has declined substantially in developed settings and is now declining in the rest of the world with economic development. Early age of puberty is associated with non-communicable diseases in adulthood, and may be a long-term driver of population health with effects over generations. In a non Western setting, we examined the association of maternal age of menarche with blood pressure in late childhood/adolescence. METHODS: We used generalised estimating equations to estimate the adjusted association of maternal age of menarche with age-, sex- and height-adjusted blood pressure z-score from 10 to 16 years in Hong Kong's population-representative birth cohort, "Children of 1997" (n = 8327). We also assessed whether associations were mediated by body mass index (BMI) or pubertal stage. RESULTS: Earlier maternal age of menarche was associated with higher systolic blood pressure in adolescence [-0.02 z-score per year older maternal age of menarche, 95% confidence interval (CI) -0.04 to 0.003]. The association of maternal age of menarche with systolic blood pressure was mediated by adiposity and/or pubertal stage at 11 years. Maternal age of menarche was not associated with diastolic blood pressure. CONCLUSION: Earlier maternal age of puberty was associated with higher systolic blood pressure, largely mediated by adiposity, highlighting the importance of tackling childhood obesity as a public health priority in view of the secular trend of declining age of puberty. PMID- 27454176 TI - Quantitative PCR Profiling of Escherichia coli in Livestock Feces Reveals Increased Population Resilience Relative to Culturable Counts under Temperature Extremes. AB - The relationship between culturable counts (CFU) and quantitative PCR (qPCR) cell equivalent counts of Escherichia coli in dairy feces exposed to different environmental conditions and temperature extremes was investigated. Fecal samples were collected in summer and winter from dairy cowpats held under two treatments: field-exposed versus polytunnel-protected. A significant correlation in quantified E. coli was recorded between the qPCR and culture-based methods (r = 0.82). Evaluation of the persistence profiles of E. coli over time revealed no significant difference in the E. coli numbers determined as either CFU or gene copies during the summer for the field-exposed cowpats, whereas significantly higher counts were observed by qPCR for the polytunnel-protected cowpats, which were exposed to higher ambient temperatures. In winter, the qPCR returned significantly higher counts of E. coli for the field-exposed cowpats, thus representing a reversal of the findings from the summer sampling campaign. Results from this study suggest that with increasing time post-defecation and with the onset of challenging environmental conditions, such as extremes in temperature, culture-based counts begin to underestimate the true resilience of viable E. coli populations in livestock feces. This is important not only in the long term as the Earth changes in response to climate-change drivers but also in the short term during spells of extremely cold or hot weather. PMID- 27454177 TI - Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1alpha. AB - The beta3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The beta3-AR signaling highly induces the expression of transcriptional coactivator PGC-1alpha and its splice variant N-terminal (NT)-PGC-1alpha, which in turn activate the transcription program of adaptive thermogenesis by co activating a number of transcription factors. We previously reported that NT-PGC 1alpha is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1alpha-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC 1alpha. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1alpha are highly enriched in mitochondrial pathways including fatty acid transport and beta-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1alpha in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1alpha-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL PGC-1alpha-/- mouse that is deficient in full-length PGC-1alpha (FL-PGC-1alpha) but expresses a slightly shorter and functionally equivalent form of NT-PGC 1alpha (NT-PGC-1alpha254). The beta3-AR-induced increase of NT-PGC-1alpha254 in FL-PGC-1alpha-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by beta3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1alpha-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1alpha regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1alpha regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis. PMID- 27454178 TI - Establishment and Characterization of a Tumor Stem Cell-Based Glioblastoma Invasion Model. AB - AIMS: Glioblastoma is the most frequent and malignant brain tumor. Recurrence is inevitable and most likely connected to tumor invasion and presence of therapy resistant stem-like tumor cells. The aim was therefore to establish and characterize a three-dimensional in vivo-like in vitro model taking invasion and tumor stemness into account. METHODS: Glioblastoma stem cell-like containing spheroid (GSS) cultures derived from three different patients were established and characterized. The spheroids were implanted in vitro into rat brain slice cultures grown in stem cell medium and in vivo into brains of immuno-compromised mice. Invasion was followed in the slice cultures by confocal time-lapse microscopy. Using immunohistochemistry, we compared tumor cell invasion as well as expression of proliferation and stem cell markers between the models. RESULTS: We observed a pronounced invasion into brain slice cultures both by confocal time lapse microscopy and immunohistochemistry. This invasion closely resembled the invasion in vivo. The Ki-67 proliferation indexes in spheroids implanted into brain slices were lower than in free-floating spheroids. The expression of stem cell markers varied between free-floating spheroids, spheroids implanted into brain slices and tumors in vivo. CONCLUSION: The established invasion model kept in stem cell medium closely mimics tumor cell invasion into the brain in vivo preserving also to some extent the expression of stem cell markers. The model is feasible and robust and we suggest the model as an in vivo-like model with a great potential in glioma studies and drug discovery. PMID- 27454180 TI - The Rolling Fingers Test. PMID- 27454179 TI - Bioinformatics Analysis Reveals Distinct Molecular Characteristics of Hepatitis B Related Hepatocellular Carcinomas from Very Early to Advanced Barcelona Clinic Liver Cancer Stages. AB - Hepatocellular carcinoma (HCC)is the fifth most common malignancy associated with high mortality. One of the risk factors for HCC is chronic hepatitis B virus (HBV) infection. The treatment strategy for the disease is dependent on the stage of HCC, and the Barcelona clinic liver cancer (BCLC) staging system is used in most HCC cases. However, the molecular characteristics of HBV-related HCC in different BCLC stages are still unknown. Using GSE14520 microarray data from HBV related HCC cases with BCLC stages from 0 (very early stage) to C (advanced stage) in the gene expression omnibus (GEO) database, differentially expressed genes (DEGs), including common DEGs and unique DEGs in different BCLC stages, were identified. These DEGs were located on different chromosomes. The molecular functions and biology pathways of DEGs were identified by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and the interactome networks of DEGs were constructed using the NetVenn online tool. The results revealed that both common DEGs and stage-specific DEGs were associated with various molecular functions and were involved in special biological pathways. In addition, several hub genes were found in the interactome networks of DEGs. The identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of HBV-related HCC through the different BCLC stages, and might be used as staging biomarkers or molecular targets for the treatment of HCC with HBV infection. PMID- 27454181 TI - Computed Tomography Angiography Allows the Classification of the First Dorsal Metatarsal Arteries. AB - Background Conventional angiography is an invasive technique. Submillimeter computed tomography angiography (CTA) has been shown to be an effective alternative for peripheral artery branches. This study aimed to assess the use of CTA to guide the choice and design of foot donor area for finger or thumb reconstruction. Methods This was a retrospective study of 79 patients who underwent finger or thumb reconstruction between January, 2011 and March, 2014. All these patients underwent preoperative CTA to determine the exact blood supply at the donor site. Preoperative imaging and intraoperative findings at the donor site were compared. Results Among the 79 patients (158 feet), 474 artery segments (dorsalis pedis artery [DPA], first dorsal metatarsal artery [FDMA], and toe web artery [TWA]) were evaluated using CTA. Image satisfaction rates of the vessels were 100.0 +/- 0.0%, 89.2 +/- 3.2%, and 60.1 +/- 5.0% for DPA, FDMA, and TWA, respectively. Among the 158 feet, 90 were Gilbert type I (57.0%), 52 were Gilbert type II (32.9%), 13 were Gilbert type III (8.2%), and 3 were with poor visibility and could not be classified (1.9%). In all 79 patients, the CTA image of the FDMA was consistent with the intraoperative observations. All reconstructed fingers survived. Follow-up was available for 69 patients. After a 6- to 18-month follow up, the reconstructed fingers and donor area recovered well, and the reconstructed fingers had strong holding power, without pain. Conclusion CTA can produce three-dimensional images for extremity arteries, allowing the preoperative assessment of blood supply and planning of donor site. PMID- 27454182 TI - Preliminary Exploration: When Angiosome Meets Prefabricated Flaps. AB - Background The best known limitation to the use of prefabricated flaps is their limited survival area. One explanation for this is insufficient neovascularization. However, blood flow of prefabricated flaps is through their innate vascular network. This could lead one to conclude that angiosomes may impede blood perfusion. This study aims to settle this contradiction between theory and clinical practice. Methods We performed a two-stage operation of a prefabricated abdominal flap in a rat model. The rats were divided into five groups (n = 6/group). Group A: fixed pedicle at a horizontal angle; Group B: fixed pedicle at an oblique angle; Group C: fixed pedicle at a vertical angle; Group D: fixed pedicle in the same position as Group A; and Group E: axial flap. Groups A and B were prefabricated for 2 weeks and Groups C and D were prefabricated for 3 weeks. Macroscopic appearance was noted, and analysis of near infrared fluorescence imaging and capillary density was performed. Results There was no significant difference in the flaps' survival area between Groups A and B. Group D had a significantly larger survival area when compared with Group C. The boundary between two angiosomes (medioventral line) seemed to limit the indocyanine green perfusion in Groups B, C, and E, while in Groups A and D, no such limitation was seen. Capillary density was positively correlated with neovascularization time. Conclusions Angiosomes impede blood perfusion in prefabricated flaps. Cross-bound neovascular vessels nourish the flap, thus overcoming the limitation of choke vessels. PMID- 27454183 TI - Victims Seeking Help from Speech-Language Pathologists: Bullying, Preparedness, and Perceptions. AB - OBJECTIVE: Antibullying initiatives indicate that all school-based personnel should accept responsibility for changing the school climate and eliminating bullying. This study examined if victims seeking assistance for bullying contacted speech-language pathologists (SLPs), SLPs' preparation to address bullying and their current perceptions of responsibilities and interventions. METHODS: A mailed survey consisting of a questionnaire and scale on bullying intervention strategies was completed by 418 school-based SLPs. RESULTS: Sixty one (14.6%) SLPs reported that victims on their caseloads told them directly about being bullied during the last month. The majority of SLPs (84.9%) reported that bullying was a problem in schools, and 65.1% reported that they had observed students being bullied in the past month. Less than half of the SLPs (46.7%) reported feeling prepared to deal with bullying episodes. Thirty-six SLPs (7.9%) reported that they did not address bullying issues because it was outside the scope of practice or job responsibilities. CONCLUSIONS: This is the first large study to report that victims seek help from SLPs directly for assistance with bullying incidents. SLPs stated that they received some training in addressing bullying issues but did not feel prepared. SLPs thought bullying was a problem but were undecided about the best strategies for assisting the students. PMID- 27454184 TI - Contemporary insights into the management of type A aortic dissection. AB - INTRODUCTION: Acute Type A Dissection remains a surgical emergency with a relatively high operative mortality despite advances in cardiac surgical techniques and medical management over the past thirty years. AREAS COVERED: In this presentation we will discuss the issues surrounding diagnosis, triage, surgical treatment and perioperative medical management as well as long term surveillance of patients suffering from Acute Type A Dissection and present the literature that supports our management strategies. Expert commentary: The ultimate goal of surgical intervention for patients with Type A Acute Aortic Dissection is an alive patient. A more complicated operation which addresses the root and arch and potentially reduces late complications should be approached with caution since it may increase the operative mortality of the procedure itself. With the recent evolution in endovascular techniques, there is hope that later complications can be reduced without increasing the risk of the primary operation. It remains to be seen whether the improved distal aortic remodeling afforded by a combined open/endovascular approach to Acute Type A Dissection will lead to decreased need for aortic reinterventions and overall long term complications of a residual descending thoracic chronic dissection. PMID- 27454185 TI - Afi-Chip: An Equipment-Free, Low-Cost, and Universal Binding Ligand Affinity Evaluation Platform. AB - Binding affinity characterization is of great importance for aptamer screening because the dissociation constant (Kd) value is a key parameter for evaluating molecular interaction. However, conventional methods often require sophisticated equipment and time-consuming processing. Here, we present a portable device, Afi Chip, as an equipment-free, rapid, low-cost, and universal platform for evaluation of the aptamer affinity. The Afi-Chip displays a distance readout based on the reaction of an enzyme catalyzing the decomposition of H2O2 for gas generation to push the movement of ink bar. Taking advantage of translating the recognition signal to distance signal and realizing the regents mixing and quantitative readout on the chip, we successfully monitored the aptamer evolution process and characterized binding affinity of aptamers against multiple types of targets, including small molecule glucose, cancer biomarker protein EpCAM, and tumor cell SW620. We also applied the Afi-Chip for rapid characterization of the affinity between anti-HCG and HCG to demonstrate the generality for the molecular interaction study. All of the Kd values obtained are comparable to those reported in the literature or obtained by sophisticated instruments such as a flow cytometer. The Afi-Chip offers a new approach for equipment-free investigation of molecular interactions, such as aptamer identification, ligand selection monitoring, and drug screening. PMID- 27454186 TI - Advances in the 1-phenanthryl-tetrahydroisoquinoline series of PAK4 inhibitors: potent agents restrain tumor cell growth and invasion. AB - A new series of novel 1-phenanthryl-tetrahydroisoquinoline derivatives were designed, synthesized and biologically evaluated for their PAK4 inhibitory activities and anti-proliferative effects against three cancer cell lines A549, MCF-7 and HT-1080. Among them, compound 12a exhibited the most potent inhibitory activity against PAK4 with an IC50 value of 0.42 MUM. Moreover, this compound inhibited the invasion of A549 tumor cells by regulating the PAK4-LIMK1-cofilin signaling pathway in vitro, and exhibited anti-tumor activity in vivo in the A549 tumor xenograft model. To further evaluate the binding mode of 12a with PAK4, the biotinylated 12a derivative has been synthesized and it was used for immunoprecipitation assay. Intriguingly, our observations suggest that 12a interacts with both the N- and C-termini of PAK4. PMID- 27454187 TI - Effects of Grounding on Body Voltage and Current in the Presence of Electromagnetic Fields. AB - OBJECTIVES: The aim of this study was to determine if grounding in the presence of electromagnetic fields (EMFs) encountered in a normal housing environment produces harmful currents in the human body. DESIGN: This study had a test-retest design, with duration of 5-15 min per participant. PARTICIPANTS: There were 50 participants, of whom 23 were males aged 12-77 years (Mage +/- standard deviation = 50.5 +/- 19.5 years) and 27 were females aged 13-79 years (Mage +/- standard deviation = 45.9 +/- 19.0 years). INTERVENTION: Each participant was instructed to touch a lamp on a desk with his or her left hand, then to move the hand away from the lamp (first one foot away and then three feet) while his/her body voltage was measured. Each participant was then grounded and instructed to repeat the same hand movements. Current was also measured during the grounded retest. OUTCOME MEASURES: The measured parameters were alternating current (AC) body voltage and current generated from contact or proximity to a lamp and other appliances situated on top of a desk. RESULTS: AC body voltage was reduced by an average of 58-fold when participants were grounded compared with when they were not grounded. AC currents generated during grounding were several orders of magnitude lower than the accepted minimum level of perception. CONCLUSION: Normal levels of EMFs existing in houses are too low to produce harmful currents when a person is grounded. PMID- 27454188 TI - Characterization of bacteriophage pAh-1 and its protective effects on experimental infection of Aeromonas hydrophila in Zebrafish (Danio rerio). PMID- 27454189 TI - The Cardiomyopathy Mutation, R146G Troponin I, Stabilizes the Intermediate "C" State of Regulated Actin under High- and Low-Free Ca(2+) Conditions. AB - The R146G mutation of troponin I (TnI) is associated with hypertrophic cardiomyopathy in humans. Earlier data pointed to stabilization of the intermediate, C state, of actin-tropomyosin-troponin by this mutant. Because cardiac disorders appear to be linked to changes in regulated actin distributions, we determined the extent to which the R146G TnI mutant alters the distribution of states at low and high Ca(2+) concentrations. We show, from measurements of the kcat for actin-activated ATPase activity at saturating Ca(2+) concentrations, that R146G TnI reduced the population of the active, M, state to 25% of the wild-type level. Together with acrylodan-tropomyosin fluorescence measurements of the B state, it appeared that the C state was populated at ~91% of the total for the R146G TnI-containing actin filaments. The C state was also more heavily populated at low Ca(2+) concentrations. Acrylodan-tropomyosin fluorescence changes showed a large diminution in the inactive state value relative to the wild-type value without a comparable increase in the active state. Furthermore, the rate of binding of rigor S1 to pyrene-labeled actin filaments containing R146G TnI was faster than the rate of binding to wild-type filaments at low free Ca(2+) concentrations. These results indicate that the inhibitory region of TnI affects the B-C and M-C equilibria of actin-tropomyosin troponin. The observation that a mutation in the inhibitory region affects the M C equilibrium may point to a novel regulatory interaction. PMID- 27454190 TI - The associations of maternal body mass index with birthweight and placental weight. Does maternal diabetes matter? A population study of 106 191 pregnancies. AB - INTRODUCTION: The aim of this study was to study whether the associations of maternal body mass index with offspring birthweight and placental weight differ by maternal diabetes status. MATERIAL AND METHODS: We performed a population study of 106 191 singleton pregnancies by using data from the years 2009-2012 in the Medical Birth Registry of Norway. We estimated changes in birthweight and in placental weight (in grams) by maternal body mass index by linear regression analysis. RESULTS: In pregnancies of women without diabetes, birthweight increased by 14.7 g (95% confidence interval 14.1-15.2) per unit increase in maternal body mass index, and the increase in placental weight was 4.2 g (95% confidence interval 4.0-4.4). In pregnancies of women with gestational diabetes, the corresponding figures were 11.8 g (95% confidence interval 8.3-15.4) and 2.9 g (95% confidence interval 1.7-4.0). In pregnancies of women with type 1 diabetes we found no significant changes in birthweight or in placental weight by maternal body mass index. Overall, mean birthweight was 513.9 g (95% confidence interval 475.6-552.1) higher in pregnancies involving type 1 diabetes than in pregnancies of women without diabetes. Mean placental weight was 102.1 g (95% confidence interval 89.3-114.9) higher. Also, in pregnancies of women with gestational diabetes, both birthweight and placental weight were higher than in women without diabetes (168.2 g and 46.5 g, respectively). Adjustments were made for maternal body mass index and gestational age at birth. CONCLUSIONS: Birthweight and placental weight increased with increasing maternal body mass index in pregnancies of women without diabetes and in pregnancies of women with gestational diabetes, but not in pregnancies of women with type 1 diabetes. Independent of body mass index, mean birthweight and mean placental weight were highest in pregnancies of women with type 1 diabetes. PMID- 27454191 TI - Diagnosing acute appendicitis: surgery or imaging? AB - AIM: Investigation of suspected appendicitis varies widely across different countries, which creates variation in outcome for patients. Use of imaging drives much of this variation, with concerns over delay of imaging and radiation exposure of computed tomography being balanced against the risks of unnecessary surgery. METHOD: Two national, prospective snapshot audits (UK n = 3326 and Netherlands n = 1934) reported investigation, management and outcome of appendicectomy and can be compared to generate treatment recommendations. RESULTS: Preoperative imaging was conducted in 32.8% of UK patients in contrast to 99.5% of patients in the Netherlands. A large difference in the normal appendicectomy rate was observed (20.6% in the UK vs 3.2% in the Netherlands) and the connection between these two outcome differences cannot be neglected. CONCLUSION: This article discusses the role of imaging in the diagnostic work-up of patients who are suspected of acute appendicitis, comparing national snapshot studies as a model to do so. PMID- 27454193 TI - Erratum. PMID- 27454194 TI - Highly Active Carbon Supported Pd-Ag Nanofacets Catalysts for Hydrogen Production from HCOOH. AB - Hydrogen is regarded as a future sustainable and clean energy carrier. Formic acid is a safe and sustainable hydrogen storage medium with many advantages, including high hydrogen content, nontoxicity, and low cost. In this work, a series of highly active catalysts for hydrogen production from formic acid are successfully synthesized by controllably depositing Pd onto Ag nanoplates with different Ag nanofacets, such as Ag{111}, Ag{100}, and the nanofacet on hexagonal close packing Ag crystal (Ag{hcp}). Then, the Pd-Ag nanoplate catalysts are supported on Vulcan XC-72 carbon black to prevent the aggregation of the catalysts. The research reveals that the high activity is attributed to the formation of Pd-Ag alloy nanofacets, such as Pd-Ag{111}, Pd-Ag{100}, and Pd Ag{hcp}. The activity order of these Pd-decorated Ag nanofacets is Pd-Ag{hcp} > Pd-Ag{111} > Pd-Ag{100}. Particularly, the activity of Pd-Ag{hcp} is up to an extremely high value, i.e., TOF{hcp} = 19 000 +/- 1630 h(-1) at 90 degrees C (lower limit value), which is more than 800 times higher than our previous quasi spherical Pd-Ag alloy nanocatalyst. The initial activity of Pd-Ag{hcp} even reaches (3.13 +/- 0.19) * 10(6) h(-1) at 90 degrees C. This research not only presents highly active catalysts for hydrogen generation but also shows that the facet on the hcp Ag crystal can act as a potentially highly active catalyst. PMID- 27454195 TI - The effects of perceived phenotypic racial stereotypicality and social identity threat on racial minorities' attitudes about police. AB - This study examines the role of perceived phenotypic racial stereotypicality and race-based social identity threat on racial minorities' trust and cooperation with police. We hypothesize that in police interactions, racial minorities' phenotypic racial stereotypicality may increase race-based social identity threat, which will lead to distrust and decreased participation with police. Racial minorities (Blacks, Latinos, Native Americans, and multi-racials) and Whites from a representative random sample of city residents were surveyed about policing attitudes. A serial multiple mediation model confirmed that racial minorities' self-rated phenotypic racial stereotypicality indirectly affected future cooperation through social identity threat and trust. Due to the lack of negative group stereotypes in policing, the model did not hold for Whites. This study provides evidence that phenotypic stereotypicality influences racial minorities' psychological experiences interacting with police. PMID- 27454196 TI - New ways to synthesize lead sulfide nanosheets-substituted alkanes direct the growth of 2D nanostructures. AB - Two-dimensional colloidal nanosheets represent very attractive optoelectronic materials. They combine good lateral conductivity with solution-processability and geometry-tunable electronic properties. In the case of PbS nanosheets, so far synthesis has been driven by the addition of chloroalkanes as coligands. Here, we demonstrate how to synthesize two-dimensional lead sulfide nanostructures using other halogen alkanes and primary amines. Further, we show that at a reaction temperature of 170 degrees C a coligand is not even necessary and the only ligand, oleic acid, controls the anisotropic growth of the two-dimensional structures. Also, using thiourea as a sulfide source, nanosheets with lateral dimensions of over 10 MUm are possible. PMID- 27454198 TI - Why Replacing Different Oxygens of Thymine with Sulfur Causes Distinct Absorption and Intersystem Crossing. AB - Recent experiments replacing oxygen atoms by sulfur in thymine have revealed that absorption and intersystem crossing properties of these derivatives are strongly dependent on the position and number of the substitutions, affecting their potential performance for photodynamical therapy. Using multireference quantum chemical methods (CASPT2 and DFT/MRCI), we calculated absorption spectra and spin orbit coupling matrix elements for thymine (Thy), 2-thiothymine (2tThy), 4 thiothymine (4tThy), and 2,4-dithiothymine (2,4dtThy), to investigate this relation between structure and photophysics. The simulations showed that a simple 4-electrons/4-orbital minimum model can explain the main experimentally observed spectral features. Moreover, the computational estimate of intersystem crossing lifetimes in this sequence of molecules revealed that the experimental value attributed to thymine in water might be underestimated by a factor 20, most probably due to an overlap of singlet/triplet absorption signals in the transient absorption spectrum. The difference between the absorptivity of 2tThy and 2tThd was also investigated, but no conclusive explanation could be found. PMID- 27454197 TI - Effect of screw position on load transfer in lumbar pedicle screws: a non idealized finite element analysis. AB - Angled screw insertion has been advocated to enhance fixation strength during posterior spine fixation. Stresses on a pedicle screw and surrounding vertebral bone with different screw angles were studied by finite element analysis during simulated multidirectional loading. Correlations between screw-specific vertebral geometric parameters and stresses were studied. Angulations in both the sagittal and axial planes affected stresses on the cortical and cancellous bones and the screw. Pedicle screws pointing laterally (vs. straight or medially) in the axial plane during superior screw angulation may be advantageous in terms of reducing the risk of both screw loosening and screw breakage. PMID- 27454199 TI - Risk selection and heterogeneous preferences in health insurance markets with a public option. AB - Conventional wisdom suggests that if private health insurance plans compete alongside a public option, they may endanger the latter's financial stability by cream-skimming good risks. This paper argues that two factors may contribute to the extent of cream-skimming: (i) degree of horizontal differentiation between public and private options when preferences are heterogeneous; (ii) whether contract design encourages choice of private insurance before information about risk is revealed. I explore the role of these factors empirically within the unique institutional setting of the German health insurance system. Using a fuzzy regression discontinuity design to disentangle adverse selection and moral hazard, I find no compelling support for extensive cream-skimming of public option by private insurers despite their ability to fully underwrite risk. A model of demand for private insurance supports the idea that heterogeneity in non pecuniary preferences and long-term structure of private insurance contracts may be muting cream-skimming in this setting. PMID- 27454200 TI - A Rare Case of Pediatric Chronic Myelogenous Leukemia Presenting with Severe Thrombocytosis without Leukocytosis. AB - Pediatric chronic myelogenous leukemia (CML) is uncommon. We report a pediatric patient with CML presenting with a normal white blood cell count and no circulating immature myeloid cells. The patient presented with extreme thrombocytosis (platelet count range: 2,175-3,064 x 109/L) noted incidentally. No splenomegaly was found. Examination of the bone marrow aspirate (BMA) revealed normal cellularity and normal myeloid: erythroid ratio with marked megakaryocytic hyperplasia. Molecular studies on the BMA detected both the major BCR/ABL1p210 fusion transcript (9,280 copies; p210/ABL1 ratio: 38.2%) and the minor p190 transcript (below limit of quantitation). The platelet count normalized within 2 weeks after treatment with the second-generation tyrosine kinase inhibitor dasatinib. Follow-up 3 months later revealed a 1.87 log reduction in p210 transcripts compared to diagnosis and no detectable p190 transcripts. This case highlights the need to include BCR/ABL1 fusion testing to accurately diagnose pediatric patients presenting with isolated thrombocytosis. PMID- 27454201 TI - Molecular characterization and targeted quantitative profiling of the sphingolipidome in rice. AB - Recent advances in comprehensive metabolite profiling techniques, the foundation of metabolomics, is facilitating our understanding of the functions, regulation and complex networks of various metabolites in organisms. Here, we report a quantitative metabolomics technique for complex plant sphingolipids, composed of various polar head groups as well as structural isomers of hydrophobic ceramide moieties. Rice (Oryza sativa L.) was used as an experimental model of monocotyledonous plants and has been demonstrated to possess a highly complex sphingolipidome including hundreds of molecular species with a wide range of abundance. We established a high-throughput scheme for lipid preparation and mass spectrometry-based characterization of complex sphingolipid structures, which provided basic information to create a comprehensive theoretical library for targeted quantitative profiling of complex sphingolipids in rice. The established sphingolipidomic approach combined with multivariate analyses of the large dataset obtained clearly showed that different classes of rice sphingolipids, particularly including subclasses of glycosylinositol phosphoceramide with various sugar-chain head groups, are distributed with distinct quantitative profiles in various rice tissues, indicating tissue-dependent metabolism and biological functions of the lipid classes and subclasses. The sphingolipidomic analysis also highlighted that disruption of a lipid-associated gene causes a typical sphingolipidomic change in a gene-dependent manner. These results clearly support the utility of the sphingolipidomic approach in application to wide screening of sphingolipid-metabolic phenotypes as well as deeper investigation of metabolism and biological functions of complex sphingolipid species in plants. PMID- 27454202 TI - Zinc-Stabilized Chitosan-Chondroitin Sulfate Nanocomplexes for HIV-1 Infection Inhibition Application. AB - Polyelectrolyte complexes (PECs) constituted of chitosan and chondroitin sulfate (ChonS) were formed by the one-shot addition of default amounts of polyanion to an excess of polycation. Key variables of the formulation process (e.g., degree of depolymerization, charge mixing ratio, the concentration, and pH of polyelectrolyte solutions) were optimized based on the PECs sizes and polydispersities. The PECs maintained their colloidal stability at physiological salt concentration and pH thanks to the complexation of polyelectrolytes with zinc(II) ion during the nanoPECs formation process. The PECs were capable of encapsulating an antiretroviral drug tenofovir (TF) with a minimal alteration on the colloidal stability of the dispersion. Moreover, the particle interfaces could efficiently be functionalized with anti-OVA or anti-alpha4beta7 antibodies with conservation of the antibody biorecognition properties over 1 week of storage in PBS at 4 degrees C. In vitro cytotoxicity studies showed that zinc(II) stabilized chitosan-ChonS nanoPECs were noncytotoxic to human peripheral blood mononuclear cells (PBMCs), and in vitro antiviral activity test demonstrated that nanoparticles formulations led to a dose-dependent reduction of HIV-1 infection. Using nanoparticles as a drug carrier system decreases the IC50 (50% inhibitory concentration) from an aqueous TF of 4.35 MUmol.L(-1) to 1.95 MUmol.L(-1). Significantly, zinc ions in this system also exhibited a synergistic effect in the antiviral potency. These data suggest that chitosan-ChonS nanoPECs can be promising drug delivery system to improve the antiviral potency of drugs to the viral reservoirs for the treatment of HIV infection. PMID- 27454203 TI - Bioaccumulation of Toxoplasma and Cryptosporidium by the freshwater crustacean Gammarus fossarum: Involvement in biomonitoring surveys and trophic transfer. AB - The protozoa Toxoplasma gondii and Cryptosporidium parvum are public health priorities because their oocysts can persist in recreational, surface, drinking, river, and sea water sources for a long time. To evaluate the capacity of the freshwater crustacean Gammarus fossarum to accumulate T. gondii and C. parvum oocysts, gammarids were exposed to 200, 2000 or 20,000 oocysts per gammarid and per day for 21 days followed by 5 days of depuration. C. parvum DNA was detected by qPCR in G. fossarum in only one out of four pools for the highest concentration and after 14 days of exposure, and T. gondii DNA was detected after 7 days of exposure to the two highest concentrations. Our results document the capacity of G. fossarum to accumulate T. gondii in its tissues proportionally to the ambient concentration; the maximum number of oocysts was detected in gammarid tissues after exposure to 20,000 oocysts per day. Mean values of 3.26 (+/-3), 21.71 (+/-15.18), and 17.41 (+/-10.89) oocysts were detected in gammarids after 7, 14, and 21 days, respectively, and after 5 days of depuration, T. gondii oocysts were still present in gammarid tissues. These results show for the first time that a freshwater crustacean can bioaccumulate T. gondii oocysts, suggesting that G. fossarum is a potential effective bioindicator of protozoan contamination in biomonitoring studies. Moreover, due to its key position in freshwater food webs, G. fossarum could also play a role in the trophic transfer of protozoa. PMID- 27454204 TI - Effect of seed pre-soaking with 24-epibrassinolide on growth and photosynthetic parameters of Brassica juncea L. in imidacloprid soil. AB - Pesticides are widely used to protect crop plants from various insect pests. However, application of pesticides causes phytotoxicity to plants which results in their impaired growth and development. Brassinosteroids are well known to protect plants under abiotic stress conditions. The purpose of the present study was to access the ameliorative role of 24-epibrassinolide (EBR) in Brassica juncea L. under imidacloprid (IMI) toxicity. B. juncea plants were raised from seeds soaked in 0.1, 1 and 100nM of EBR, and grown in soils amended with 250, 300 and 350mgkg(-1) IMI pesticide, and observed for growth, pigments and photosynthetic parameters after 30, 60 and 90 days of seed sowing. The plants grown in soil treated with IMI exhibited a significant reduction in shoot length, number of leaves, chlorophyll contents and photosynthetic parameters like photosynthetic rate, stomatal conductance, inter-cellular CO2 and transpiration rate, when compared with their respective controls. However, pigments which act as antioxidants such as carotenoids, anthocyanins and xanthophylls were increased with IMI stress. Pre-sowing seed treatment with EBR decreased the toxic effects of IMI and increased the growth, pigment biosynthesis and photosynthetic parameters of the plants grown in IMI amended soil. Maximum increase in all the growth and photosynthetic parameters was noticed in plants raised from seeds treated with 100nM EBR and grown in IMI amended soil. PMID- 27454205 TI - In silico prediction and in vivo analysis of antiestrogenic potential of 2 isopropylthioxanthone (2-ITX) in juvenile goldfish (Carassius auratus). AB - Previous studies have shown both anti-estrogenic and anti-androgenic activities of 2-isopropylthioxanthone (2-ITX), a well known food contaminant, in in vitro assays. However, no data are available on the anti-estrogenic potentials and risks of 2-ITX in aquatic organisms. This work evaluated the potential endocrine disrupting effects of 2-ITX at the level of estrogen receptor (ER) signaling cascade using juvenile goldfish (Carassius auratus) as model. Firstly, we investigated the ligand binding efficiency of 2-ITX to the ligand binding domains (LBD) of goldfish ER subtypes using a molecular docking approach. Secondly, we assessed the effects of 2-ITX on E2-induced hepatic expression of ERalpha1, ERbeta1, ERbeta2, and vitellogenin (VTG) in vivo. Crosstalk between ER-VTG and aryl hydrocarbon receptor 2 (AhR2)-cytochrome P4501A (CYP1A) was also investigated. Fish were injected with increasing doses of 2-ITX ranging from 2 to 10ug/g BW, and results were compared to the effect of tamoxifen, a well-known ER modulator. We observed that compared to ERbeta, the interaction potentials of 2 ITX to goldfish ERalpha1 LBD was more stable in the inactive receptor conformation. The in silico docking simulation analysis also revealed that 2-ITX acted as agonist for the goldfish AhR2 LBDs suggesting the ability of this compound to activate the cross-talk between the ERalpha- and AhR-signaling pathways. In vivo experiments confirm in silico simulation predictions demonstrating that 2-ITX reduced the estrogenicity of E2 at both transcriptional and post-transcriptional levels, indicating a clear anti-estrogenic effect. Co exposure of E2 and 2-ITX also resulted in a significant decrease of CYP1A gene expression with respect to 2-ITX alone. Results from these studies collectively revealed that the antiestrogenic property of 2-ITX can be ascribed to a combination of effects on multiple signaling pathways suggesting the potential for this environmental contaminant to affect the hormonal control of reproductive processes in fish. PMID- 27454206 TI - Cerebellar volume deficits in medication-naive obsessive compulsive disorder. AB - Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naive OCD patients compared to matched healthy controls (HC). In 49 medication naive right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD. PMID- 27454207 TI - Encapsulation of curcumin in polyelectrolyte nanocapsules and their neuroprotective activity. AB - Poor water solubility and low bioavailability of lipophilic drugs can be potentially improved with the use of delivery systems. In this study, encapsulation of nanoemulsion droplets was utilized to prepare curcumin nanocarriers. Nanosize droplets containing the drug were encapsulated in polyelectrolyte shells formed by the layer-by-layer (LbL) adsorption of biocompatible polyelectrolytes: poly-L-lysine (PLL) and poly-L-glutamic acid (PGA). The size of synthesized nanocapsules was around 100 nm. Their biocompatibility and neuroprotective effects were evaluated on the SH-SY5Y human neuroblastoma cell line using cell viability/toxicity assays (MTT reduction, LDH release). Statistically significant toxic effect was clearly observed for PLL coated nanocapsules (reduction in cell viability about 20%-60%), while nanocapsules with PLL/PGA coating did not evoke any detrimental effects on SH SY5Y cells. Curcumin encapsulated in PLL/PGA showed similar neuroprotective activity against hydrogen peroxide (H2O2)-induced cell damage, as did 5 MUM curcumin pre-dissolved in DMSO (about 16% of protection). Determination of concentration of curcumin in cell lysate confirmed that curcumin in nanocapsules has cell protective effect in lower concentrations (at least 20 times) than when given alone. Intracellular mechanisms of encapsulated curcumin-mediated protection engaged the prevention of the H2O2-induced decrease in mitochondrial membrane potential (MMP) but did not attenuate Reactive Oxygen Species (ROS) formation. The obtained results indicate the utility of PLL/PGA shell nanocapsules as a promising, alternative way of curcumin delivery for neuroprotective purposes with improved efficiency and reduced toxicity. PMID- 27454208 TI - Therapeutic use of colchicine and its derivatives: a patent review. AB - INTRODUCTION: Colchicine, the major alkaloid extracted from the meadow saffron (Colchicum autumnale) is one of the most prominent natural products belonging to the class of organic compounds known as tropones. Colchicine's medicinal properties have been long-known, but it has been attracting renewed attention due to its action as an antimitotic agent. AREAS COVERED: This review presents an update and analysis of the patents claiming therapeutic activity of colchicine and its derivatives published in the last five years (2010-2015). Other patents claiming the application of colchicine in the areas of biotechnology, veterinary, and agriculture are therefore excluded from this review. EXPERT OPINION: Rapid increase in the number of publications and patent filings in recent years for the significant therapeutic potential of colchicine, for several conditions beyond gout, clearly indicates the growing interest of research on this molecule. Although the molecular structure of colchicine fulfils the four Lipinski's requisites for high oral bioavailability, the toxic side effects resulting from its fast metabolism need to be assessed. Further efforts are therefore required to explore the appropriate dosage and possible administration techniques of colchicine for practical use. PMID- 27454209 TI - Use of rotavirus vaccines in preterm babies on the neonatal unit. PMID- 27454210 TI - Value of MRI in diagnostics and evaluation of myositis. AB - PURPOSE OF REVIEW: This review aims at covering the role of muscle MRI in supporting the diagnosis of myositis, in aiding to differentiate it from other muscle disorders, and in monitoring myositis patients over time by assessing response to treatment and by discriminating between muscle inflammation and chronic damage. RECENT FINDINGS: MRI can assist in 'pattern recognition' of muscle involvement across numerous myopathies, including myositis. Novel applications of magnetic resonance such as cardiac MRI, MR elastography and blood oxigenation level-dependent magnetic resonance can shed light on different aspects of myositis and usefully complement conventional MRI in assessing patients with myositis. SUMMARY: MRI can guide therapy by determining whether muscle weakness is related to edema (active inflammation) or muscle atrophy/fat replacement (chronic damage). There is a need to better standardize the assessment of MRI findings in myositis to provide defined outcome measures for use in clinical trials. VIDEO ABSTRACT. PMID- 27454211 TI - New Material Transistor with Record-High Field-Effect Mobility among Wide-Band Gap Semiconductors. AB - At an ultrathin 5 nm, we report a new high-mobility tin oxide (SnO2) metal-oxide semiconductor field-effect transistor (MOSFET) exhibiting extremely high field effect mobility values of 279 and 255 cm(2)/V-s at 145 and 205 degrees C, respectively. These values are the highest reported mobility values among all wide-band-gap semiconductors of GaN, SiC, and metal-oxide MOSFETs, and they also exceed those of silicon devices at the aforementioned elevated temperatures. For the first time among existing semiconductor transistors, a new device physical phenomenon of a higher mobility value was measured at 45-205 degrees C than at 25 degrees C, which is due to the lower optical phonon scattering by the large SnO2 phonon energy. Moreover, the high on-current/off-current of 4 * 10(6) and the positive threshold voltage of 0.14 V at 25 degrees C are significantly better than those of a graphene transistor. This wide-band-gap SnO2 MOSFET exhibits high mobility in a 25-205 degrees C temperature range, a wide operating voltage of 1.5-20 V, and the ability to form on an amorphous substrate, rendering it an ideal candidate for multifunctional low-power integrated circuit (IC), display, and brain-mimicking three-dimensional IC applications. PMID- 27454212 TI - Meta-Analysis of Cytokine and Chemokine Genes in Schizophrenia. AB - INTRODUCTION: Immune system genes, including cytokines, are associated with schizophrenia risk. Polymorphisms in cytokine genes may also impact on blood levels of cytokines, which are altered in patients with schizophrenia. We performed a meta-analysis of case-control studies of cytokine and chemokine genes in schizophrenia that have not been considered in previous quantitative reviews. METHODS: We identified articles by systematic searches of PubMed, PsycInfo, and ISI, and the reference lists of identified studies. For each cytokine or chemokine polymorphism, we performed an allele- and genotype-wise meta-analysis, using a random effects model. RESULTS: Twenty-one independent studies met the inclusion criteria, comprising polymorphisms for the IL1B, IL2, IL4, IL6, sIL6R, MCP1, and TGFB1 genes. For IL6, the A allele (OR=0.95, 95% CI 0.91-0.99) and AA genotype (OR=0.65, 95% CI 0.50-0.85) for the rs1800795 polymorphism, and for sIL6R, the A allele (OR=0.96 95%, CI 0.92-1.00) and AA genotype (OR=0.72, 95% CI 0.55-0.94) the rs8192284 polymorphism were associated with significantly decreased schizophrenia risk. In the genotype-wise analysis for IL1B, homozygosity for either allele (AA: OR=1.91, 95% CI 1.60-2.27; and GG: OR=0.40, 95% CI 0.33-0.49) of the rs1143627 polymorphism was also significantly associated with schizophrenia risk. CONCLUSIONS: Associations between polymorphisms for the IL1B, IL6, and sIL6R genes and schizophrenia risk complement and extend previous findings regarding immune dysfunction in this disorder, including genome-wide association studies. Future studies of cytokine expression in schizophrenia should consider the effect of these polymorphisms. The finding of potential "protective" alleles may also be relevant for at-risk populations. PMID- 27454214 TI - A Guide to the Management of Clozapine-Related Tolerability and Safety Concerns. AB - Clozapine is a highly effective antipsychotic medication, which provides a range of significant benefits for patients with schizophrenia, and is the standard of care for treatment-resistant schizophrenia as well as for reducing the risk of suicidal behaviors in schizophrenia and schizoaffective disorder. However, clozapine is widely underutilized, largely because prescribing clinicians lack experience in prescribing it and managing its adverse events (AEs). Clozapine is associated with 3 uncommon but immediately dangerous AEs, agranulocytosis, myocarditis/cardiomyopathy, and seizures, as well as AEs that may become dangerous if neglected, including weight gain, metabolic syndrome and constipation, and others that are annoying or distressing such as sedation, nighttime enuresis and hypersalivation. Because of the risk of agranulocytosis, clozapine formulations are available only through restricted distribution via a patient registry, with mandatory, systematized monitoring for absolute neutrophil count using a specific algorithm. We identified articles on managing clozapine associated AEs by searching PubMed using appropriate keywords and search techniques for each topic. A review of the prevalence and clinical characteristics of clozapine-associated AEs shows that these risks can be managed efficiently and effectively. The absolute risks for both agranulocytosis and myocarditis/cardiomyopathy are low, diminish after the first 6 months, and are further reduced with appropriate monitoring. Weight gain/metabolic disorders and constipation, which develop more gradually, can be mitigated with regular monitoring and timely interventions. Sedation, hypersalivation, and enuresis are common but manageable with ameliorative measures and/or medications. PMID- 27454213 TI - Development and Feasibility Testing of a Smartphone Intervention to Improve Adherence to Antipsychotic Medications. AB - Approximately 60% of individuals with schizophrenia do not take their antipsychotic medications as prescribed, and nonadherence is associated with exacerbation of psychotic symptoms, increased hospital and emergency room use, and increased healthcare costs. Behavioral-tailoring strategies that incorporate medication taking into the daily routine and use environmental supports have shown promise as adherence-enhancing interventions. Informed by the Information Motivation-Behavioral (IMB) Skills Model and using the iterative process of user centered design, we collaborated with individuals with schizophrenia and psychiatrists to develop an interactive smartphone application and web-based clinician interface, MedActive, for improving adherence to oral antipsychotic treatment. MedActive facilitates the active involvement of individuals with schizophrenia in managing their antipsychotic medication regimen by providing automated reminders for medication administration and tailored motivational feedback to encourage adherence, and by displaying user-friendly results of daily ecological momentary assessments (EMAs) of medication adherence, positive psychotic symptoms, and medication side effects for individuals and their psychiatrists. In a 2-week open trial completed by 7 individuals with schizophrenia and their psychiatrists, MedActive was determined to be both feasible and acceptable, with patient participants responding to 80% of all scheduled EMAs and providing positive evaluations of their use of the application. Psychiatrist participants were interested in viewing the information provided on the MedActive clinician interface, but cited practical barriers to regularly accessing it and integrating into their daily practice. PMID- 27454215 TI - Catatonia and Psychosis Related to Epilepsy: A Case Report. AB - Although a variety of metabolic, toxic, psychiatric, and neurologic conditions can produce catatonic syndromes, it is less widely recognized that this state may be caused by epilepsy. We present the case of a woman with catatonic behavior, which she could not recall. She also exhibited olfactory, auditory and visual hallucinations. An EEG demonstrated diffuse abnormal electrical activity, mainly on left temporal and frontal areas. Treatment with anticonvulsant drugs yielded excellent response. PMID- 27454216 TI - Myocarditis in a patient on Clozapine: What did it? AB - We are presenting a case of 37-year-old male with schizoaffective disorder who developed myocarditis within 3 weeks of starting on clozapine for his treatment resistant psychosis. The patient also had a positive titer for Influenza A which makes it a diagnostic dilemma regarding the cause of his myocarditis. It may be possible that the myocarditis was caused by the Influenza A virus or synergistically exacerbated the clozapine's propensity to cause it. Currently, there are no studies establishing the link between the two etiologies. As clozapine can be the only option for patients resistant to treatment of their psychiatric illness and there being some evidence for successful re-challenge of clozapine, we consider that this patient could have benefitted from a trial of a re-challenge, however, was lost to follow up. PMID- 27454217 TI - Elucidation of the downfield spectrum of human brain at 7 T using multiple inversion recovery delays and echo times. AB - PURPOSE: To characterize the downfield spectrum at 5-10 ppm in the human brain at a high magnetic field of 7 T. Knowledge of relaxation parameters is of interest for spectroscopy as well as chemical exchange-dependent saturation transfer experiments. METHODS: Water-suppressed spectra were recorded as echo time and inversion time series in healthy volunteers to investigate T2 and T1 values of downfield peaks in gray matter at 7T. The spectra were fitted in a two dimensional fashion to a heuristic model of a series of Voigt lines, and the relaxation times were obtained for 12 peaks of interest. RESULTS: The mean T2 values averaged over the volunteers ranged from 24 to 158 ms, whereas the mean T1 values ranged from 0.22 to 2.40 s. Spectra of specific inversion and echo times revealed superposition of the amide peaks of N-acetylaspartate with short T2 and an inhomogeneously broadened component with longer T2 . CONCLUSIONS: T2 values were shorter than expected for most peaks, whereas T1 values had a very wide range; shorter relaxation times for some peaks suggests the presence of macromolecules. Most of the larger peaks seemed to be composed of overlapping components, because the Gaussian widths in the Voigt line shape descriptions were larger than expected based on field inhomogeneities. Magn Reson Med 78:11-19, 2016. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 27454218 TI - The Efficacy of Sustained Heat Treatment on Delayed-Onset Muscle Soreness. AB - OBJECTIVE: To assess the impact of heat applied for 8 hours immediately after or 24 hours after exercise on delayed-onset muscle soreness (DOMS) in large skeletal muscle groups measured by subjective and objective means. DESIGN: Cross-sectional repeated measure design study. SETTING: Research laboratory. SUBJECTS: Three groups of 20 subjects, age range 20 to 40 years. INTERVENTION: Squats were conducted in three 5-minute bouts to initiate DOMS; 3 minutes of rest separated the bouts. One group had heat applied immediately after exercise, and a second group had heat applied 24 hours after exercise. A third group was the control group where no heat was applied. MAIN OUTCOME MEASURES: Visual analog pain scales, muscle strength of quads, range of motion of quads, stiffness of quads (Continuous Passive Motion machine), algometer to measure quadriceps soreness, and blood myoglobin. RESULTS: The most significant outcome was a reduction in soreness in the group that had low-temperature heat wraps applied immediately after exercise (P < 0.01). There was benefit to applying heat 24 hours after exercise, but to a smaller extent. This was corroborated by myoglobin, algometer, and stiffness data. CONCLUSIONS: Low-level continuous heat wraps left for 8 hours just after heavy exercise reduced DOMS in the population tested as assessed by subjective and objective measures. CLINICAL RELEVANCE: Although cold is commonly used after heavy exercise to reduce soreness, heat applied just after exercise seems very effective in reducing soreness. Unlike cold, it increases flexibility of tissue and tissue blood flow. For joint, it is still probably better to use cold to reduce swelling. PMID- 27454219 TI - One-Year Weight Loss with a Telephone-Based Lifestyle Program. AB - OBJECTIVE: Telephone-based weight loss programs are offered as an alternative to face-to-face obesity treatments, but data on the effectiveness regarding weight loss are limited. Therefore, we evaluated a telephone-based lifestyle program in a real-world setting. METHODS: The telephone-based intervention consists of regular phone calls providing individualized lifestyle recommendations, and delivery of printed materials. Anthropometric and metabolic data are collected by general practitioners or are self-reported. RESULTS: Baseline data were available from 398 participants (61% men; weight 103.12 +/- 14.21 kg; BMI 33.38 +/- 2.83 kg/m2) and 1-year data from 258 (65%) participants. In the completers, mean weight change was -4.25 +/- 5.18 kg (p < 0.001) which corresponds to a mean percentage body weight change of -4.10 +/- 4.88%. 87 participants (34%) lost more than 5% of their initial body weight, with 29 (11%) losing more than 10% of their initial body weight. 40 participants (16%) gained weight over this period. A reduction of abdominal girth of -0.59 cm (95% CI 0.34, 0.85 cm; p < 0.001) and total cholesterol of -1.55 mg/dl (95% CI 0.04, 3.05 mg/dl; p = 0.044) per kilogram weight loss was observed. CONCLUSIONS: The telephone-based lifestyle program results in a moderate weight loss after 12 months, which may be comparable to face-to-face interventions. Telephone-based weight loss support is independent of time and location and represents a tool which is also accepted by men. PMID- 27454220 TI - Lingual tonsil: clinically applicable macroscopic anatomical classification system. AB - OBJECTIVE: To classify the adult lingual tonsil according to the macroscopic appearance. STUDY DESIGN: Prospective study. LEVEL OF EVIDENCE: Four. METHODS: Lingual tonsils were classified according to their appearance and relationship to surrounding structures. This was possible following serial views of lingual tonsils. The classification was named 'Swansea classification for lingual tonsil', representing the place of origin. The classification was then discussed with fellow clinicians. Independent professional observers graded lingual tonsil pictures. Intra-observer agreements were measured to validate the classification. RESULTS: A total of 22 professional observers went through a set of six pictures of three different grades of lingual tonsil. The pictures were then graded for validation. The intra-observer agreement was 0.81, confirming good agreement. CONCLUSION: Swansea classification for lingual tonsil is reliable and reproducible. This classification should be routinely used during ENT examination, enabling accurate documentation and providing opportunities for future research and audit of practice. PMID- 27454221 TI - Lewis Acid Catalyzed Cyclization of Propargylic Alcohols with 2-Vinylphenol. AB - An unprecedented Lewis acid catalyzed, protection-free, and high-efficiency synthesis of valuable 3,4-dihydro-2H-2,4-methanochromans via cycloaddition of propargylic alkynols with 2-vinylphenol is described. This cycloaddition protocol, which tolerates a wide variety of functional groups, provides practical, versatile, and atom-economical access to a new class of appealing bridged-ring products in satisfactory yields. Compared with the reported reaction conditions for bridged-ring skeletons synthesis, the present reaction conditions are neutral, mild, and without any additives. PMID- 27454222 TI - Nursing Process Health Care Indicators: A Scoping Review of Development Methods. AB - Identifying how nursing care directly affects patients is essential to improving care quality, reducing costs, and determining nursing's contribution to overall organizational performance. This scoping review examined methods used for developing nursing process health care indicators. Key concepts and sources of evidence were identified to lay a foundation for future development and identification of valid and reliable nursing process health care indicators. PMID- 27454223 TI - RETINAL VASCULAR DEVELOPMENT WITH 0.312 MG INTRAVITREAL BEVACIZUMAB TO TREAT SEVERE POSTERIOR RETINOPATHY OF PREMATURITY: A Longitudinal Fluorescein Angiographic Study. AB - PURPOSE: To report the outcome of intravitreal 0.312 mg bevacizumab (IVB) monotherapy in acute retinopathy of prematurity (ROP) and to describe the vascular development over time. METHODS: Seventeen prematurely born infants were treated with IVB (0.312 mg in 0.025 mL per eye) because of acute ROP in posterior Zone II or Zone I, including aggressive posterior ROP. Infants were examined by fluorescein angiography (FA) using RetCam II or III (Clarity Medical Systems Inc) before IVB (n = 21 eyes), within 6 weeks (n = 23 eyes), 8 to 13 weeks (n = 22 eyes), and up to 45 months (n = 10 eyes). RESULTS: Acute ROP regressed in 19 out of 27 analyzed eyes (70%), including 100% and 80% of posterior Zone II and Zone I eyes, respectively, but only 25% of aggressive posterior ROP eyes. Early recurrences (11%, all aggressive posterior ROP) and late reactivations (18%) were observed within 1 week and at 9 to 12 weeks, respectively. All eyes showed leakage at the junction of the vascularized zone and capillary malformation on FA before treatment. Vessel branching abnormalities and circumferential vessel formation were typical FA features after treatment. Vascular outgrowth after one IVB became complete in 87.5% of eyes for which FA was available up to at least 9 weeks after IVB. CONCLUSION: A single dose of 0.312 mg bevacizumab was efficient to induce regression of ROP in posterior Zone II and most of Zone I cases, but not in aggressive posterior ROP. FA describes vascular abnormalities, the importance of which warrants further investigation. PMID- 27454224 TI - TREAT-AND-EXTEND REGIMEN USING RANIBIZUMAB FOR POLYPOIDAL CHOROIDAL VASCULOPATHY: One-Year Results. AB - PURPOSE: To investigate the efficacy of a treat-and-extend regimen (TER) using ranibizumab to treat polypoidal choroidal vasculopathy (PCV). METHODS: We retrospectively reviewed the medical records of 29 patients with PCV, who had been treated with a TER for 1 year. The primary outcome was the proportion of eyes that did not lose >=3 best-corrected visual acuity (BCVA) lines. The number of intravitreal injections and recurrences as well as the maximum treatment interval without recurrence were analyzed. RESULTS: The mean BCVA improved from 0.64 +/- 0.42 logMAR (median, 20/80) at baseline to 0.30 +/- 0.31 logMAR (median, 20/30) at 12 months (P < 0.001). The mean central subfield macular thickness improved from 307.0 +/- 70.2 MUm to 237.5 +/- 64.4 MUm (P < 0.001). None of the subjects lost >=3 lines, and 15 (51.7%) gained >=3 lines. The mean number of injections was 7.0. The mean maximum treatment interval without recurrence was 10.0 weeks. After the loading phase, 12 eyes (41.4%) showed no recurrence. Seven eyes (24.1%) demonstrated disease activity at 12 months, and 4 (13.8%) of them were never dry during the entire 12-month follow-up duration. CONCLUSION: The TER effectively improved visual acuity in PCV while reducing the number of injections. PMID- 27454225 TI - Fogging of Non-Contact Viewing Lenses During Vitreoretinal Surgery. PMID- 27454226 TI - Loss of oxidative defense and potential blockade of satellite cell maturation in the skeletal muscle of patients with cancer but not in the healthy elderly. AB - Muscle wasting in old age or cancer may result from failed myofiber regeneration and/or accelerated atrophy. This study aimed to determine from transcriptomic analysis of human muscle the integrity of the cellular stress response system in relation to satellite cell differentiation or apoptosis in patients with cancer (weight-stable (CWS) or weight-losing (CWL)) or healthy elderly (HE) when compared with healthy middle-aged controls (HMA). 28 patients with cancer (CWS: 18 and CWL: 10), HE: 21 and HMA: 20 underwent biopsy of quadriceps muscle. The expression of transcription factors for muscle regeneration (Pax3, Pax7 and MyoD) was increased in CWS and HE compared with HMA (p<=0.001). In contrast, the expression of the late myogenic differentiation marker MyoG was reduced in CWS and CWL but increased in HE (p<=0.0001). Bax was significantly increased in CWS, CWL and HE (p<=0.0001). Expression of the oxidative defense genes SOD2, GCLM, and Nrf2 was decreased in CWS and CWL but increased in HE (p<=0.0001). There is evidence for blockade of satellite cell maturation, upregulation of apoptosis and reduced oxidative defense in the muscle of cancer patients. In the healthy elderly the potential for differentiation and oxidative defense is maintained. PMID- 27454227 TI - The role of power in health policy dialogues: lessons from African countries. AB - BACKGROUND: Policy-making is a dynamic process involving the interplay of various factors. Power and its role are some of its core components. Though power exerts a profound role in policy-making, empirical evidence suggests that health policy analysis has paid only limited attention to the role of power, particularly in policy dialogues. METHODS: This exploratory study, which used qualitative methods, had the main aim of learning about and understanding policy dialogues in five African countries and how power influences such processes. Data were collected using key informant interviews. An interview guide was developed with standardised questions and probes on the policy dialogues in each country. This paper utilises these data plus document review to understand how power was manifested during the policy dialogues. Reference is made to the Arts and Tatenhove conceptual framework on power dimensions to understand how power featured during the policy dialogues in African health contexts. Arts and Tatenhove conceptualise power in policy-making in relational, dispositional and structural layers. RESULTS: Our study found that power was applied positively during the dialogues to prioritise agendas, fast-track processes, reorganise positions, focus attention on certain items and foster involvement of the community. Power was applied negatively during the dialogues, for example when position was used to control and shape dialogues, which limited innovation, and when knowledge power was used to influence decisions and the direction of the dialogues. Transitive power was used to challenge the government to think of implementation issues often forgotten during policy-making processes. Dispositional power was the most complex form of power expressed both overtly and covertly. Structural power was manifested socially, culturally, politically, legally and economically. CONCLUSIONS: This study shows that we need to be cognisant of the role of power during policy dialogues and put mechanisms in place to manage its influence. There is need for more research to determine how to channel power influence policy-making processes positively, for example through interactive policy dialogues. PMID- 27454228 TI - Protein complexes predictions within protein interaction networks using genetic algorithms. AB - BACKGROUND: Protein-protein interaction networks are receiving increased attention due to their importance in understanding life at the cellular level. A major challenge in systems biology is to understand the modular structure of such biological networks. Although clustering techniques have been proposed for clustering protein-protein interaction networks, those techniques suffer from some drawbacks. The application of earlier clustering techniques to protein protein interaction networks in order to predict protein complexes within the networks does not yield good results due to the small-world and power-law properties of these networks. RESULTS: In this paper, we construct a new clustering algorithm for predicting protein complexes through the use of genetic algorithms. We design an objective function for exclusive clustering and overlapping clustering. We assess the quality of our proposed clustering algorithm using two gold-standard data sets. CONCLUSIONS: Our algorithm can identify protein complexes that are significantly enriched in the gold-standard data sets. Furthermore, our method surpasses three competing methods: MCL, ClusterOne, and MCODE in terms of the quality of the predicted complexes. The source code and accompanying examples are freely available at http://faculty.kfupm.edu.sa/ics/eramadan/GACluster.zip . PMID- 27454229 TI - Orthogonal Synthesis of "Easy-to-Read" Information-Containing Polymers Using Phosphoramidite and Radical Coupling Steps. AB - A new orthogonal solid-phase iterative strategy is proposed for the synthesis of sequence-coded polymers. This approach relies on the use of two successive chemoselective steps: (i) phosphoramidite coupling, and (ii) radical-radical coupling. These repeated steps can be performed using two different types of building blocks, i.e. a phosphoramidite monomer that also contains an alkyl bromide and a hydroxy-functionalized nitroxide. The phosphoramidite and the hydroxy group are reacted in step (i), thus leading to a phosphite that is oxidized in situ into a phosphate bond. The alkyl bromide is activated by copper bromide in step (ii) to afford a carbon-centered radical that is spin-trapped in situ by the nitroxide. The iterative repetition of these steps allow synthesis of uniform polymers, as evidenced by high-resolution electrospray mass spectrometry. Moreover, binary information could be easily implemented in the polymers using different types of phosphoramidite monomers in step (i). Interestingly, it was found that the formed information-containing polymers are very easy to sequence by tandem mass spectrometry due to the presence of easily cleavable alkoxyamine bonds formed in step (ii). PMID- 27454230 TI - Toddle temporal-spatial deviation index: Assessment of pediatric gait. AB - This research aims to develop a gait index for use in the pediatric clinic as well as research, that quantifies gait deviation in 18-22 month-old children: the Toddle Temporal-spatial Deviation Index (Toddle TDI). 81 preterm children (<=32 weeks) with very-low-birth-weights (<=1500g) and 42 full-term TD children aged 18 22 months, adjusted for prematurity, walked on a pressure-sensitive mat. Preterm children were administered the Bayley Scales of Infant Development-3rd Edition (BSID-III). Principle component analysis of TD children's temporal-spatial gait parameters quantified raw gait deviation from typical, normalized to an average(standard deviation) Toddle TDI score of 100(10), and calculated for all participants. The Toddle TDI was significantly lower for preterm versus TD children (86 vs. 100, p=0.003), and lower in preterm children with <85 vs. >=85 BSID-III motor composite scores (66 vs. 89, p=0.004). The Toddle TDI, which by design plateaus at typical average (BSID-III gross motor 8-12), correlated with BSID-III gross motor (r=0.60, p<0.001) and not fine motor (r=0.08, p=0.65) in preterm children with gross motor scores <=8, suggesting sensitivity to gross motor development. The Toddle TDI demonstrated sensitivity and specificity to gross motor function in very-low-birth-weight preterm children aged 18-22 months, and has been potential as an easily-administered, revealing clinical gait metric. PMID- 27454231 TI - NS5A resistance leading to failure of 24-week therapy with sofosbuvir/ledipasvir and ribavirin for the treatment of hepatitis C genotype 1a infection in a HIV-1 co-infected patient. AB - Herein we report a previously undescribed case of treatment-emergent non structural protein 5A (NS5A) resistance mutations, Q30H and Y93C, leading to a failure of 24-week course of sofosbuvir/ledipasvir+ribavirin therapy for the treatment of hepatitis C virus (HCV) genotype 1a in interferon-experienced, human immunodeficiency virus type 1 (HIV-1) co-infected patient with cirrhosis. PMID- 27454232 TI - Utility of droplet digital PCR for the quantitative detection of polyomavirus JC in clinical samples. AB - BACKGROUND: Quantitative PCR (qPCR) is the standard molecular method for detection of polyomavirus JC (JCPyV) DNA reactivation in serum and cerebrospinal fluid (CSF) in patients at risk of progressive multifocal leukoencephalopathy (PML). Recently, digital PCR has shown potential benefits over qPCR in viral diagnostics. OBJECTIVE: To evaluate the performance of droplet digital PCR (ddPCR) assay in assessing JCPyV-DNA status in clinical samples of patients at risk for PML. STUDY DESIGN: JCPyV specific ddPCR was developed with primers/probes targeting Large T and the noncoding control region used in qPCR. The ddPCR accuracy of JCPyV-DNA quantification was investigated using serial dilutions of genomic JCPyV-DNA. The ddPCR JCPyV-DNA quantification and qPCR confirmation were performed on 150 CSF and 100 serum clinical samples. RESULTS: Using genomic JCPyV-DNA, ddPCR was highly sensitive, repeatable and reproducible for both molecular targets. Using clinical samples, JCPyV-DNA was detected in 13% of CSF and in 50% of serum samples with limit of detection of 30 copies/ml. Among the 19 JCPyV-DNA-positive CSF detected using the ddPCR, 15 also tested positive with the qPCR. Among the 50 JCPyV-DNA-positive serum identified with ddPCR, 41 tested positive with qPCR. All the ddPCR-negative samples were negative when assessed using qPCR. Additionally, the mean JCPyV-DNA viral load obtained with ddPCR in all samples was not significantly different from that of qPCR. CONCLUSION: The results demonstrate that ddPCR is a highly sensitive alternative for measuring JCPyV-DNA that should be considered in clinical diagnostic testing of JCPyV-DNA in patients at risk of PML and other associated diseases. PMID- 27454233 TI - PATTERN: Pain Assessment for paTients who can't TEll using Restricted Boltzmann machiNe. AB - BACKGROUND: Accurately assessing pain for those who cannot make self-report of pain, such as minimally responsive or severely brain-injured patients, is challenging. In this paper, we attempted to address this challenge by answering the following questions: (1) if the pain has dependency structures in electronic signals and if so, (2) how to apply this pattern in predicting the state of pain. To this end, we have been investigating and comparing the performance of several machine learning techniques. METHODS: We first adopted different strategies, in which the collected original n-dimensional numerical data were converted into binary data. Pain states are represented in binary format and bound with above binary features to construct (n + 1) -dimensional data. We then modeled the joint distribution over all variables in this data using the Restricted Boltzmann Machine (RBM). RESULTS: Seventy-eight pain data items were collected. Four individuals with the number of recorded labels larger than 1000 were used in the experiment. Number of avaliable data items for the four patients varied from 22 to 28. Discriminant RBM achieved better accuracy in all four experiments. CONCLUSION: The experimental results show that RBM models the distribution of our binary pain data well. We showed that discriminant RBM can be used in a classification task, and the initial result is advantageous over other classifiers such as support vector machine (SVM) using PCA representation and the LDA discriminant method. PMID- 27454234 TI - Red blood cell alloimmunization: new findings at the bench and new recommendations for the bedside. AB - PURPOSE OF REVIEW: To summarize recent discoveries from clinical studies and animal models that contribute to understanding the alloimmune response to non-ABO blood group antigens. RECENT FINDINGS: Several studies have confirmed high rates of alloimmunization among patients requiring chronic red blood cell (RBC) transfusion. Moreover, 'triggers' for alloantibody development in the transfusion setting have been identified, with a number of investigations linking recipient inflammation to a higher likelihood of alloimmunization. Additional associations between human leukocyte antigen expression and CD4 T-cell markers in 'responder' or 'nonresponder' humans have been revealed. Recent animal studies have described novel mechanistic properties by which the alloimmune response is governed, including the critical role played by dendritic cells in transfusion-associated alloimmunization. New light has also been shed on the properties of alloantibodies developed as a result of pregnancy, as well as mechanisms through which such alloimmunization may be prevented. SUMMARY: Many of the clinical/biological factors that contribute to the RBC alloimmune response have been further elucidated. This knowledge will be applied to identify individuals most likely to mount an immune response to RBC antigens, such that appropriate resources and strategies for preventing alloimmunization (or mitigating its harmful effects) can be implemented. PMID- 27454235 TI - Drawing a dog: The role of working memory and executive function. AB - Previous research suggests that young children draw animals by adapting their scheme for the human figure. This can be considered an early form of drawing flexibility. This study investigated preschoolers' ability to draw a dog that is different from the human figure. The role of working memory capacity and executive function was examined. The participants were 123 children (36-73 months old) who were required to draw both a person and a dog. The dog figure was scored on a list of features that could render it different from the human figure. Regression analyses showed that both working memory capacity and executive function predicted development in the dog drawing; the dog drawing score correlated with working memory capacity and executive function, even partialling out age, motor coordination, and drawing ability (measured with Goodenough's Draw a-Man test). These results suggest that both working memory capacity and executive function play an important role in the early development of drawing flexibility. The implications regarding executive functions and working memory are also discussed. PMID- 27454236 TI - How we categorize objects is related to how we remember them: The shape bias as a memory bias. AB - The "shape bias" describes the phenomenon that, after a certain point in development, children and adults generalize object categories based on shape to a greater degree than other perceptual features. The focus of research on the shape bias has been to examine the types of information that learners attend to in one moment in time. The current work takes a different approach by examining whether learners' categorical biases are related to their retention of information across time. In three experiments, children's (N=72) and adults' (N=240) memory performance for features of objects was examined in relation to their categorical biases. The results of these experiments demonstrated that the number of shape matches chosen during the shape bias task significantly predicted shape memory. Moreover, children and adults with a shape bias were more likely to remember the shape of objects than the color and size of objects. Taken together, this work suggests that the development of a shape bias may engender better memory for shape information. PMID- 27454237 TI - It's a two-way street: Automatic and controlled processes in children's emotional responses to moral transgressions. AB - This study examined children's automatic, spontaneous emotional reactions to everyday moral transgressions and their relations with self-reported emotions, which are more complex and infused with controlled cognition. We presented children (N=242 4-, 8-, and 12-year-olds) with six everyday moral transgression scenarios in an experimental setting, and both their spontaneous facial emotional reactions and self-reported emotions in the role of the transgressor were recorded. We found that across age self-reported guilt was positively associated with spontaneous fear, and self-reported anger was positively related to spontaneous sadness. In addition, we found a developmental increase in spontaneous sadness and decrease in spontaneous happiness. These results support the importance of automatic and controlled processes in evoking children's emotional responses to everyday moral transgressions. We conclude by providing potential explanations for how automatic and controlled processes function in children's everyday moral experiences and how these processes may change with age. PMID- 27454238 TI - The role of physical digit representation and numerical magnitude representation in children's multiplication fact retrieval. AB - Arithmetic facts, in particular multiplication tables, are thought to be stored in long-term memory and to be interference prone. At least two representations underpinning these arithmetic facts have been suggested: a physical representation of the digits and a numerical magnitude representation. We hypothesized that both representations are possible sources of interference that could explain individual differences in multiplication fact performance and/or in strategy use. We investigated the specificity of these interferences on arithmetic fact retrieval and explored the relation between interference and performance on the different arithmetic operations and on general mathematics achievement. Participants were 79 fourth-grade children (Mage=9.6 years) who completed a products comparison and a multiplication production task with verbal strategy reports. Performances on a speeded calculation test including the four operations and on a general mathematics achievement test were also collected. Only the interference coming from physical representations was a significant predictor of the performance across multiplications. However, both the magnitude and physical representations were unique predictors of individual differences in multiplication. The frequency of the retrieval strategy across multiplication problems and across individuals was determined only by the physical representation, which therefore is suggested as being responsible for memory storage issues. Interestingly, this impact of physical representation was not observed when predicting performance on subtraction or on general mathematical achievement. In contrast, the impact of the numerical magnitude representation was more general in that it was observed across all arithmetic operations and in general mathematics achievement. PMID- 27454240 TI - Effects of aging on P300 between late young-age and early middle-age adulthood: an electroencephalogram event-related potential study. AB - The aim of this study was to identify age-related changes of P300 peak amplitude and P300 latency between closely separated nonsenile age groups (late young-aged adults and early middle-aged adults) and to investigate whether or not P300 has the potential to be used as a measure of cognitive aging even among nonsenile age groups. Twenty-eight adults (25-55 years old) completed an event-related potential oddball task. The elicitation of both P300 peak amplitude and P300 latency indicated age-related changes of P300. The results of the study showed that the P300 target peak amplitude was significantly larger in late young age compared with early middle age and that P300 target latency was also significantly delayed in early middle age compared with late young age. The results of this work contribute toward research efforts on a consensus on how aging affects event-related potential and/or P300. The main conclusions are that there exist significant age-related P300 changes even between closely separated, relatively younger, and nonsenile age groups, and that P300 has the potential to be used as a measure for cognitive aging even in nonsenile adults. PMID- 27454239 TI - Burden and risk factors for gastrointestinal symptom distress in HIV patients in the modern antiretroviral era. AB - In the modern antiretroviral (ARV) era, there is limited knowledge about the prevalence and risk factors for HIV patient-reported gastrointestinal (GI) symptoms (diarrhoea/soft stool, nausea/vomiting, bloating/painful abdomen, loss of appetite, and weight loss/wasting) and distress. We prospectively analysed data (2007-2014) on distressing GI symptoms from the Ontario HIV Treatment Network Cohort Study, which follows people attending HIV clinics. Using generalized estimating equations with a logit link, we estimated the associations of psychosocial, demographic, behavioural, and clinical factors with each GI symptoms compared to asymptomatic and non-bothersome symptoms. Among 1532 included participants, 80.4% were male, mean age was 45 years, and 64.6% reported being men who have sex with men. Most were Caucasian (56.3%), a median time since HIV diagnosis of 9.8 years (interquartile range (IQR): 4.1-16.9), and 83.1% were on ARV. More than two-thirds (68.7% (95% confidence intervals (CI): 63.1% to 69.2%)) reported one or more symptoms with a median of 1.2 (IQR: 0-1.7). The proportion remained stable over time since HIV diagnosis and ARV initiation. Risk factors varied for multivariable models. A strong association with Centre for Epidemiologic Studies Depression scale scores of >=23 was found for all symptoms. Adjusted odds ratios (95% CI) were 1.72 (1.39-2.12), 2.95 (2.33-3.72), 2.20 (1.81 2.68), 4.97 (3.99-6.19), and 2.98 (2.52-3.82) for diarrhoea, nausea/vomiting, bloating, loss of appetite, and weight loss, respectively. With the exception of bloating, odds were significantly lower for those on ARV containing integrase inhibitors and greater for patients reporting current cannabis use. GI symptoms in the modern ARV era are highly prevalent and may arise as a common pathway of distress in response to psychosocial vulnerabilities, regardless of the stage of diagnosis. These findings support the need for integrated approaches to address psychological and physical distress in HIV disease. PMID- 27454241 TI - Individual variability in verbal fluency correlates with gamma-aminobutyric acid concentration in the left inferior frontal gyrus. AB - A particular feature of the inferior frontal gyrus (IFG), which is considered a central region for language processing, is leftward functional/anatomical asymmetry. However, previous studies have not clearly shown lateralization of neurotransmitters in the cortical regions. Using proton magnetic resonance spectroscopy, we measured gamma-aminobutyric acid (GABA) concentrations in the bilateral IFG. To evaluate individual variability in linguistic performance, we further used a verbal fluency test. Although GABA+/creatine (Cr) values were not different between the left and the right IFG, we found a significant correlation between category fluency scores and GABA+/Cr values in the left IFG. No correlation was found between letter fluency scores and GABA+/Cr values. We also confirmed that the result was independent of the references used (Cr and H2O). Our results show a new physiological basis of linguistic performance as well as leftward asymmetry of the IFG. PMID- 27454242 TI - The glucagon-like peptide-1 analog exendin-4 antagonizes the effect of acyl ghrelin on the respiratory exchange ratio. AB - The present study investigated the interaction of hypothalamic arcuate nucleus (ArcN) ghrelin and glucagon-like peptide-1 (GLP-1) signaling on metabolic function. Using indirect calorimetry, we first showed that acylated ghrelin, administered into the ArcN, significantly increased the respiratory exchange ratio (RER) in male Sprague-Dawley rats, representing a shift in fuel utilization toward enhanced carbohydrate oxidation and reduced lipid utilization. In contrast, treatment with similar doses of des-acyl ghrelin failed to induce reliable changes in RER. We then examined the ability of exendin-4 (Ex4) to alter acyl ghrelin's energetic effects. Ex4 is a GLP-1 agonist and has been reported previously to suppress food intake in rodent models. Rats were treated with either systemic or direct ArcN Ex4, followed by acyl ghrelin. Our results indicated that both systemic and central injections of Ex4 alone significantly reduced RER and, importantly, Ex4 pretreatment reliably attenuated the impact of ghrelin on RER. Overall, these findings provide compelling evidence that ghrelin and GLP-1 signaling interact in the hypothalamic control of metabolic function. PMID- 27454243 TI - CeFunMO: A centrality based method for discovering functional motifs with application in biological networks. AB - Detecting functional motifs in biological networks is one of the challenging problems in systems biology. Given a multiset of colors as query and a list colored graph (an undirected graph with a set of colors assigned to each of its vertices), the problem is reduced to finding connected subgraphs, which best cover the multiset of query. To solve this NP-complete problem, we propose a new color-based centrality measure for list-colored graphs. Based on this newly defined measure of centrality, a novel polynomial time algorithm is developed to discover functional motifs in list-colored graphs, using a greedy strategy. This algorithm, called CeFunMO, has superior running time and acceptable accuracy in comparison with other well-known algorithms, such as RANGI and GraMoFoNe. PMID- 27454244 TI - Identifying epigenetically dysregulated pathways from pathway-pathway interaction networks. AB - BACKGROUND: Identification of pathways that show significant difference in activity between disease and control samples have been an interesting topic of research for over a decade. Pathways so identified serve as potential indicators of aberrations in phenotype or a disease condition. Recently, epigenetic mechanisms such as DNA methylation are known to play an important role in altering the regulatory mechanism of biological pathways. It is reasonable to think that a set of genes that show significant difference in expression and methylation interact together to form a network of pathways. Existing pathway identification methods fail to capture the complex interplay between interacting pathways. RESULTS: This paper proposes a novel framework to identify biological pathways that are dysregulated by epigenetic mechanisms. Experiments on four benchmark cancer datasets and comparison with state-of-the-art pathway identification methods reveal the effectiveness of the proposed approach. CONCLUSION: The proposed framework incorporates both topology and biological relationships of pathways. Comparison with state-of-the-art techniques reveals promising results. Epigenetic signatures identified from pathway interaction networks can help to advance Molecular Pathological Epidemiology (MPE) research efforts by predicting tumor molecular changes. PMID- 27454245 TI - Binocular vision in infancy: Responsiveness to uncrossed horizontal disparity. AB - This research explored the onset of stereopsis, the ability to perceive depth from the different views provided by the two eyes. In a longitudinal study, infants were tested weekly from 6 to 20 weeks of age. The primary goal of the study was to establish the onset and the early development of sensitivity to uncrossed horizontal disparity. The infant participants were shown dynamic random dot stereograms displaying two squares, one with uncrossed horizontal disparity (0.5 degrees ) and one with vertical disparity (0.5 degrees ). The stimuli were presented on an autostereoscopic monitor. We used two methods, the forced-choice preferential looking (FPL) method and the classical natural preference (CNP) method, to measure whether the infants preferred the uncrossed over the vertical disparity display. According to the FPL data, the mean relative preferences for horizontal over vertical disparity were significantly greater than chance probability (0.50) from 13 weeks of age onward. With the CNP method we found significant preferences for uncrossed horizontal disparity from 15 weeks onward. The FPL method was hence more sensitive than the CNP method as it indicated an earlier onset of responsiveness to stereoscopic information. PMID- 27454246 TI - Computational approaches for innovative antiepileptic drug discovery. AB - INTRODUCTION: Despite the approval of a large number of antiepileptic agents over the past 25 years, there has been no significant improvement in efficacy of treatments, with one third of patients suffering from intractable epilepsy. This scenario has prompted the search for innovative drug discovery solutions. While network pharmacology and explanations of the drug resistance phenomena have been proposed to drive the search for more efficacious therapeutic solutions, such alternative approaches have not fully taken hold within the antiepileptic drug discovery community so far. AREAS COVERED: Herein, the author discusses the impact that network pharmacology and the current hypotheses of refractory epilepsy and drug repurposing could have if integrated with anti-epileptic computer-aided discovery. EXPERT OPINION: With many complex diseases, the advancement in the understanding of disorder pathophysiology in addition to the contribution of systems biology have rapidly translated into the discovery of novel drug candidates. However, antiepileptic drug developers have fallen a little behind in this regard, with fewer examples of computer-aided antiepileptic drug design and network-based approximations appearing in scientific literature. New generation single-target agents have so far shown limited success in terms of enhanced efficacy; in contrast, multi-target agents could possibly demonstrate improved safety and efficacy. PMID- 27454248 TI - A Decade of Antiretroviral Therapy Scale-up in Mozambique: Evaluation of Outcome Trends and New Models of Service Delivery Among More Than 300,000 Patients Enrolled During 2004-2013. AB - BACKGROUND: During 2004-2013 in Mozambique, 455,600 HIV-positive adults (>=15 years old) initiated antiretroviral therapy (ART). We evaluated trends in patient characteristics and outcomes during 2004-2013, outcomes of universal treatment for pregnant women (Option B+) implemented since 2013, and effect on outcomes of distributing ART to stable patients through Community ART Support Groups (CASG) since 2010. METHODS: Data for 306,335 adults starting ART during 2004-2013 at 170 ART facilities were analyzed. Mortality and loss to follow-up (LTFU) were estimated using competing risks models. Outcome determinants were estimated using proportional hazards models, including CASG participation as a time-varying covariate. RESULTS: Compared with ART enrollees in 2004, enrollees in 2013 were more commonly female (55% vs. 73%), more commonly pregnant if female (<1% vs. 30%), and had a higher median baseline CD4 count (139 vs. 235/MUL). During 2004 2013, observed 6-month mortality declined from 7% to 2% but LTFU increased from 24% to 30%. Pregnant women starting ART with CD4 count >350/MUL and WHO stage I/II under Option B+ guidelines in 2013 had low 6-month mortality (0.1%) but high 6-month LTFU (38%). During 2010-2013, 6766 patients joined CASGs. In multivariable analysis, compared with nonparticipation in CASG, CASG participation was associated with 35% lower LTFU but similar mortality. CONCLUSIONS: Initiation of ART at earlier disease stages in later calendar years might explain observed declines in mortality. Retention interventions are needed to address trends of increasing LTFU overall and the high LTFU among Option B+ pregnant women specifically. Further expansion of CASG could help reduce LTFU. PMID- 27454249 TI - Acceptability of Oral Preexposure Prophylaxis Among Men Who Have Sex With Men in Philadelphia. PMID- 27454250 TI - Enhancing PrEP Access for Black and Latino Men Who Have Sex With Men. AB - OBJECTIVE: Implementation of HIV pre-exposure prophylaxis (PrEP) programs for populations with highest incidence is critical to reducing new infections in the United States. Black and Latino men who have sex with men (BLMSM) are disproportionately burdened by HIV. We examined differences in perceived barriers and facilitators to PrEP access for BLMSM compared with other men who have sex with men (MSM). METHOD: MSM who met the Centers for Disease Control and Prevention criteria for PrEP (n = 491) completed measures of barriers and facilitators to PrEP at the systems, provider, and individual levels. Multivariate analyses examined differences by race/ethnicity, adjusting for other sociodemographic factors. RESULTS: Compared with other MSM, BLMSM (56% of the sample) were more likely to have public insurance and to access health care via public clinics [adjusted odds ratio(aOR) 3.2, P < 0.001; aOR 2.4, P < 0.01]. BLMSM were more likely to regard having to talk to their doctor about their sex life as a barrier to PrEP (aOR 3.7, P < 0.001) and were less likely to endorse agency in medical decision making (aOR 0.58, P < 0.001). BLMSM were more likely to report PrEP stigma (aOR 2.3, P < 0.001) and concerns regarding PrEP efficacy (aOR 1.6, P < 0.05). BLMSM were more likely to consider access to free sexual health care (aOR 2.1, P < 0.01) and additional supportive services, eg, counseling (aOR 3.1, P < 0.001) or text-based support (aOR 2.9, P < 0.001) to be significant facilitators of PrEP use. CONCLUSIONS: Findings suggest specific points of multilevel intervention to increase PrEP access for BLMSM and increase representation of BLMSM along the PrEP continuum of care. PMID- 27454252 TI - 12-Lead electrocardiogram as a predictor of sudden cardiac death: from epidemiology to clinical practice. AB - Sudden cardiac death (SCD) causes a high burden of premature deaths in the population affecting subjects of all ages. The identification of subjects at high risk for SCD is of great importance as the prevention of many of these events would be possible with the treatment of underlying cardiac diseases and the use of implantable cardioverter-defibrillators (ICD). However, the current selection of patients for ICD therapy is based solely on left ventricular ejection fraction, and thus a substantial portion of patients at high risk does not qualify for the therapy. Role of the standard electrocardiogram (ECG) in SCD risk stratification has been under active research during the last decade and multiple abnormalities of depolarization and repolarization on the ECG associated with an increased risk of SCD have been identified. In this review, we describe the basic pathophysiological principles behind these changes. We also review the current knowledge of the prognostic significance of ECG predictors of SCD in the general population, and in patients with coronary heart disease (CHD), heart failure, cardiomyopathies, and in inheritable arrhythmia syndromes. Also, insights into the novel digital ECG signal processing techniques are provided. PMID- 27454251 TI - Topographies of Cortical and Subcortical Volume Loss in HIV and Aging in the cART Era. AB - OBJECTIVES: Studies of HIV-associated brain atrophy often focus on a priori brain regions of interest, which can introduce bias. A data-driven, minimally biased approach was used to analyze changes in brain volumetrics associated with HIV and their relationship to aging, viral factors, combination antiretroviral therapy (cART), and gender, and smoking. DESIGN: A cross-sectional study of 51 HIV uninfected (HIV-) and 146 HIV-infected (HIV+) participants. METHODS: Structural MRI of participants was analyzed using principal component analysis (PCA) to reduce dimensionality and determine topographies of volumetric changes. Neuropsychological (NP) assessment was examined using global and domain-specific scores. The effects of HIV disease factors (eg, viral load, CD4, etc.) on brain volumes and neuropsychological were investigated using penalized regression (LASSO). RESULTS: Two components of interest were visualized using principal component analysis. An aging effect predominated for both components. The first component, a cortically weighted topography, accounted for a majority of variance across participants (43.5% of variance) and showed independent effects of HIV and smoking. A secondary, subcortically weighted topography (4.6%) showed HIV-status accentuated age-related volume loss. In HIV+ patients, the cortical topography correlated with global neuropsychological scores and nadir CD4, whereas subcortical volume loss was associated with recent viral load. CONCLUSIONS: Cortical regions showed the most prominent volumetric changes because of aging and HIV. Within HIV+ participants, cortical volumes were associated with immune history, whereas subcortical changes correlated with current immune function. Cognitive function was primarily associated with cortical volume changes. Observed volumetric changes in chronic HIV+ patients may reflect both past infection history and current viral status. PMID- 27454254 TI - Abstracts from the 3rd International Genomic Medicine Conference (3rd IGMC 2015) : Jeddah, Kingdom of Saudi Arabia. 30 November - 3 December 2015. PMID- 27454253 TI - Approximate parameter inference in systems biology using gradient matching: a comparative evaluation. AB - BACKGROUND: A challenging problem in current systems biology is that of parameter inference in biological pathways expressed as coupled ordinary differential equations (ODEs). Conventional methods that repeatedly numerically solve the ODEs have large associated computational costs. Aimed at reducing this cost, new concepts using gradient matching have been proposed, which bypass the need for numerical integration. This paper presents a recently established adaptive gradient matching approach, using Gaussian processes (GPs), combined with a parallel tempering scheme, and conducts a comparative evaluation with current state-of-the-art methods used for parameter inference in ODEs. Among these contemporary methods is a technique based on reproducing kernel Hilbert spaces (RKHS). This has previously shown promising results for parameter estimation, but under lax experimental settings. We look at a range of scenarios to test the robustness of this method. We also change the approach of inferring the penalty parameter from AIC to cross validation to improve the stability of the method. METHODS: Methodology for the recently proposed adaptive gradient matching method using GPs, upon which we build our new method, is provided. Details of a competing method using RKHS are also described here. RESULTS: We conduct a comparative analysis for the methods described in this paper, using two benchmark ODE systems. The analyses are repeated under different experimental settings, to observe the sensitivity of the techniques. CONCLUSIONS: Our study reveals that for known noise variance, our proposed method based on GPs and parallel tempering achieves overall the best performance. When the noise variance is unknown, the RKHS method proves to be more robust. PMID- 27454255 TI - CB5C affects the glucosinolate profile in Arabidopsis thaliana. AB - Cytochrome b5 (CB5) proteins are small heme-binding proteins, that influence cytochrome P450 activity. While only one CB5 isoform is found in mammals, higher plants have several isoforms of these proteins. The roles of the many CB5 isoforms in plants remain unknown. We hypothesized that CB5 proteins support the cytochrome P450 enzymes of plant specialized metabolism and found CB5C from Arabidopsis thaliana to co-express with glucosinolate biosynthetic genes. We characterized the glucosinolate profiles of 2 T-DNA insertion mutants of CB5C, and found that long-chained aliphatic glucosinolates were reduced in one of the mutant lines - a phenotype that was exaggerated upon methyl-jasmonate treatment. These results support the hypothesis, that CB5C influences glucosinolate biosynthesis, however, the mode of action remains unknown. Furthermore, the mutants differed in their biomass response to methyl jasmonate treatment. Thereby, our results highlight the varying effects of T-DNA insertion sites, as the 2 analyzed alleles show different phenotypes. PMID- 27454256 TI - Reducing false alarms in the ICU by quantifying self-similarity of multimodal biosignals. AB - False arrhythmia alarms pose a major threat to the quality of care in today's ICU. Thus, the PhysioNet/Computing in Cardiology Challenge 2015 aimed at reducing false alarms by exploiting multimodal cardiac signals recorded by a patient monitor. False alarms for asystole, extreme bradycardia, extreme tachycardia, ventricular flutter/fibrillation as well as ventricular tachycardia were to be reduced using two electrocardiogram channels, up to two cardiac signals of mechanical origin as well as a respiratory signal. In this paper, an approach combining multimodal rhythmicity estimation and machine learning is presented. Using standard short-time autocorrelation and robust beat-to-beat interval estimation, the signal's self-similarity is analyzed. In particular, beat intervals as well as quality measures are derived which are further quantified using basic mathematical operations (min, mean, max, etc). Moreover, methods from the realm of image processing, 2D Fourier transformation combined with principal component analysis, are employed for dimensionality reduction. Several machine learning approaches are evaluated including linear discriminant analysis and random forest. Using an alarm-independent reduction strategy, an overall false alarm reduction with a score of 65.52 in terms of the real-time scoring system of the challenge is achieved on a hidden dataset. Employing an alarm-specific strategy, an overall real-time score of 78.20 at a true positive rate of 95% and a true negative rate of 78% is achieved. While the results for some categories still need improvement, false alarms for extreme tachycardia are suppressed with 100% sensitivity and specificity. PMID- 27454257 TI - Statistical learning theory for high dimensional prediction: Application to criterion-keyed scale development. AB - Statistical learning theory (SLT) is the statistical formulation of machine learning theory, a body of analytic methods common in "big data" problems. Regression-based SLT algorithms seek to maximize predictive accuracy for some outcome, given a large pool of potential predictors, without overfitting the sample. Research goals in psychology may sometimes call for high dimensional regression. One example is criterion-keyed scale construction, where a scale with maximal predictive validity must be built from a large item pool. Using this as a working example, we first introduce a core principle of SLT methods: minimization of expected prediction error (EPE). Minimizing EPE is fundamentally different than maximizing the within-sample likelihood, and hinges on building a predictive model of sufficient complexity to predict the outcome well, without undue complexity leading to overfitting. We describe how such models are built and refined via cross-validation. We then illustrate how 3 common SLT algorithms supervised principal components, regularization, and boosting-can be used to construct a criterion-keyed scale predicting all-cause mortality, using a large personality item pool within a population cohort. Each algorithm illustrates a different approach to minimizing EPE. Finally, we consider broader applications of SLT predictive algorithms, both as supportive analytic tools for conventional methods, and as primary analytic tools in discovery phase research. We conclude that despite their differences from the classic null-hypothesis testing approach or perhaps because of them-SLT methods may hold value as a statistically rigorous approach to exploratory regression. (PsycINFO Database Record PMID- 27454258 TI - Antibiotic Treatment for Febrile Urinary Tract Infection: The Clock Is Ticking. PMID- 27454259 TI - Significance of immune response to Mycobacterium tuberculosis culture filtrate protein antigens in cerebrospinal fluid of tuberculous meningitis patients: A search for diagnostic marker. AB - Mycobacterium tuberculosis (H37Ra) culture filtrate proteins (CFP) are explored as a diagnostic marker for tuberculous meningitis (TBM). Cerebrospinal fluid (CSF) samples from patients were categorized as confirmed (n = 47), suspected (n = 20), and non-TBM (n = 25) cases. Immune response by Western blot revealed TBM CSF samples are having heterogeneous response to CFP. CFP ELISA was 92% sensitive and 38.30% specific. ODs of confirmed TBM and non-TBM cases were significantly different (P < 0.0001) and also the suspected TBM and non-TBM cases (P = 0.0001). No significant difference noticed in TBM and suspected TBM (P = 0.90). Thus, CFP can be a better biomarker for the diagnosis of TBM. PMID- 27454260 TI - Racial Differences in Utilization of Life-Sustaining vs Curative Inpatient Procedures After Stroke. PMID- 27454261 TI - An Overview of Offset Analgesia and the Comparison with Conditioned Pain Modulation: A Systematic Literature Review. AB - BACKGROUND: Offset analgesia (OA) is an increasingly described phenomenon to measure endogenous pain inhibition, in which a greater decrease in pain intensity is experienced than would be predicted by the decrease in painful stimulation. The temporal filtering in this OA phenomenon differs from the spatial filtering in the commonly described conditioned pain modulation (CPM). Yet, the knowledge on the efficacy of OA in chronic pain patients is scarce, compared to CPM efficacy. OBJECTIVE: This systematic review has been conducted to provide an overview of the current knowledge regarding OA, and to compare it to CPM. STUDY DESIGN: A systematic review of research studies that investigated the application or mechanisms of OA. SETTING: The present study took place at Ghent University and the University of Antwerp. METHODS: This systematic review follows the PRISMA guidelines. The electronic databases Pubmed and Web of Science were searched in January 2015. Full text clinical reports addressing OA were included. The checklists for randomized controlled trials, case-control studies, and cohort studies provided by the Dutch Institute for Healthcare Improvement and the Dutch Cochrane Centre were used to assess methodological quality. The articles received a level of evidence A1, A2, B, C, or D, based on study design and risk of bias. These levels were used to determine the strength of conclusion (level 1 to 4). RESULTS: Seventeen articles met the inclusion criteria. Sixteen studies used quantitative sensory testing to provoke OA; however, differences in protocols are present. OA can function as a non-opioid mediated assessment tool for endogenous pain inhibition, and activates brain regions such as periaqueductal gray (PAG), dorsolateral prefontral cortex, insula, medulla, pons and cerebellum, indicating strong brain derived pain modulation. The primary somatosensory cortex is, conversely, less activated during OA. OA is decreased in neuropathic patients. Nonetheless, evidence for the influence of individual factors on OA is limited. OA and CPM seem to rely on different mechanisms. LIMITATIONS: Search strategy was taken wide, wherefore a large variety of research perspectives were included. CONCLUSIONS: This systematic review displays OA as a temporal filtering mechanisms that is more brain-derived compared to the spatial assessment method CPM. There is strong evidence for reduced OA in neuropathic patients, however, evidence regarding OA in (sub)acute and central sensitization patients, and the influence of personal factors on OA is currently scarce and needs further investigation. PMID- 27454262 TI - Particulate vs Non-Particulate Steroids for Transforaminal Epidural Steroid Injections: Systematic Review and Meta-analysis of the Current Literature. AB - BACKGROUND: The efficacy of particulate and non-particulate steroids in patients receiving epidural steroid injections remains unclear. OBJECTIVE: The purpose of this meta-analysis was to compare the efficacy of particulate and non-particulate steroids in patients receiving epidural injections for radicular pain over 3 months. STUDY DESIGN: Systematic review and meta-analysis. METHODS: We reviewed PubMed, PubMed Central, Scopus, Central Register of Clinical Trials of the Cochrane Collaboration, Google Scholar, and Directory of open access journals for trials that compared efficacy of particulate steroid with non-particulate. A meta analysis was performed on treatment related to mean change in visual analogue score (VAS) between the particulate and non-particulate steroids. Two authors independently reviewed the data for inclusion. RESULTS: Seven studies comprising 3,542 patients in the particulate group and 856 patients in the non-particulate group were included. Pooled mean maximum change of VAS was higher by 0.53 (95% CI: 0.14 to 0.92; P = 0.007; I2 = 50.2%) in the particulate group compared to the non-particulate group. The non-particulate group had a larger proportion of patients with more than 50% pain relief than the particulate group [OR 0.81 (95% CI: 0.68 to 0.97, P = 0.024). LIMITATIONS: Limited number of trials that fit the inclusion criteria and were available for analysis. CONCLUSIONS: As the use of particulate steroids seems to be associated with slightly better VAS scores only, clinicians need to weigh their clinical relevance in the light of complications and recent FDA recommendations on the use of particulate steroids. PMID- 27454263 TI - Synergistic Effect of Intravenous Ibuprofen and Hydromorphone for Postoperative Pain: Prospective Randomized Controlled Trial. AB - BACKGROUND: An intravenous form of ibuprofen has recently been approved by the Food and Drug Administration (FDA) and reports are rare on its co-administration with opioids. OBJECTIVES: We researched whether an intravenous ibuprofen hydromorphone combination is synergistic, additive, or infra-additive on postoperative pain. STUDY DESIGN: A parallel-group, 1:1:1 allocation, randomized, double-blind controlled trial. SETTING: University teaching hospital in Korea. METHODS: Ninety patients, undergoing breast surgery, were divided into one of the 3 groups (I, H, IH groups). Positive analgesic efficacy was defined as a numeric rating scale (NRS) 1.1), dose reduction index (DRI, a measure of how much the dose of each drug in a combination can be reduced), and isobologram were used to define the nature of their interaction. STATISTICS: One way ANOVA, Kruskal Wallis test, and Chi square test, significance level P < 0.05. RESULTS: The median effective doses (ED50) of ibuprofen and hydromorphone were 1,447 mg and 1.5 mg, respectively. The median ED50 of the combination was ibuprofen 71 mg and hydromorphone 0.3 mg. Ibuprofen and hydromorphone showed a strong synergy (CI 0.2, DRI 20 and 5 for ibuprofen and hydromorphone at ED50). LIMITATION: Analgesic efficacy was observed during post anesthesia care unit (PACU) period only. CONCLUSIONS: The combination of intravenous ibuprofen and hydromorphone produces a strong synergistic analgesia on postoperative pain. PMID- 27454264 TI - A Randomized Trial Comparing the Safety and Efficacy of Intravenous Ibuprofen versus Ibuprofen and Acetaminophen in Knee or Hip Arthroplasty. AB - BACKGROUND: All surgical procedures are associated with a degree of pain. The experience of uncontrolled post-operative pain can have significant implications on health care costs. Recent studies have demonstrated that intravenous (IV) ibuprofen is an effective, safe, well-tolerated analgesic when administered for both abdominal hysterectomy and orthopedic surgery. The use of ibuprofen leads to a reduction in pain severity at rest and with movement and also decreases narcotic consumption. IV acetaminophen has also been shown to be effective in alleviating pain for surgical procedures. Given the established safety and efficacy of IV ibuprofen and IV acetaminophen for perioperative pain, we were interested in determining if any potential synergies are afforded by the simultaneous administration of both medications in orthopedic surgery patients. OBJECTIVES: Compare the safety and efficacy of the perioperative administration of IV ibuprofen alone and in combination with IV acetaminophen in total knee or hip arthroplasty. STUDY DESIGN: Randomized, single center, trial. SETTING: Tertiary care center in Philadelphia, Pennsylvania, United States. METHODS: Seventy-eight patients undergoing elective knee or hip arthroplasty were randomized into 2 groups. Group 1 received 800 mg of IV ibuprofen at induction, and 800 mg of IV ibuprofen every 6 hours until discharge or for up to 5 days. Group 2 received 800 mg IV ibuprofen at induction and 1000 mg IV acetaminophen at closure, and 800 mg IV ibuprofen plus 1000 mg IV acetaminophen every 6 hours until discharge for up to 5 days. The primary endpoint was demonstrated using the visual analog scale (VAS) pain scores. Secondary endpoints included opioid requirements, quality of recovery scale (QoR), length of post-anesthesia care unit (PACU) stay, antiemetic consumption, opioid consumption, and opioid related adverse events. RESULTS: Patients in Group 2 had lower VAS scores (P < 0.002) by day 3 only. Opioid requirements and adverse events were significantly less in Group 2 which was also statistically significant. Time to discharge from the PACU for Group 1 on average was 55 minutes and 38 minutes for Group 2 (P = 0.178) which was not statistically significant although may have clinical significance. Length of hospital stay was also evaluated; however, no statistical significance was noted between the 2 groups (P = 0.138). There was no significant difference in QoR scores which were 177 (SD = 15.44) for Group 1 (n = 35) and 179.5 (SD = 16.30) for Group 2 (n = 39). LIMITATIONS: The study is a single center study with the attendant risk of convenience bias. The total number of patients is also small and may call into question the reproducibility of the results. No cost analysis was undertaken as part of this study. Further research should aim at prospectively designed multi-center double blinded randomized control trials with an analysis of the pharmacoeconomics of the use of these agents. CONCLUSION: IV ibuprofen combined with IV acetaminophen demonstrated additional benefit in terms of improved pain scores on post-operative day 3 only, fewer potential adverse events related to opioid use, and decreased use of opioids when compared to IV ibuprofen alone. PMID- 27454265 TI - The Potential Impact of Venobasillar System Morphology and Applied Technique on Epidural Cement Leakage with Percutaneous Vertebroplasty. AB - BACKGROUND: Bone cement leakage during vertebroplasty is a frequently reported complication with the potential for neural injury. OBJECTIVE: To assess risk factors for epidural cement leakage during vertebroplasty. SETTING: Neurosurgical department of a scientific research institute. STUDY DESIGN: This is a prospective cross-sectional randomized trial. METHODS: Seventy-five patients with intractable pain due to low energy vertebral compression fractures between T11 and L5 were treated with vertebroplasty at 150 vertebral levels. Preoperative computed tomography (CT) scans were utilized to characterize vertebral parameters including the type of nutrient foramina in the posterior vertebral cortex. Following vertebroplasty, distance from the needle tracts to the midline and the presence and type of any epidural cement leakage were determined. Using logistic regression analysis, significant risk factors for cement leakage were determined. RESULTS: A smaller distance between the tip of the needle and the midline and a magistral type of venobasillar system were found to be significant risk factors for epidural cement leakage (P < 0.0001). Use of a bipedicular vs. monopedicular technique did not significantly affect the rate of epidural cement leakage (P = 0.3869). LIMITATIONS: This study is limited because of the relatively small number of patients and the lack of any patients who had clinical consequences as a result of extensive epidural cement leakage. CONCLUSION: The type of venobasillar system should be taken into account when planning a vertebroplasty procedure as a magistral type of venobasillar system is associated with the increased rate of epidural cement leakage. It is important to try and achieve a large distance between the needle tip and the midline, especially when a magistral type of venobasillar system is present, to reduce the risk of epidural cement leakage. PMID- 27454266 TI - Iliocostalis Thoracis-Lumborum Myofascial Pain: Reviewing a Subgroup of a Prospective, Randomized, Blinded Trial. A Challenging Diagnosis with Clinical Implications. AB - BACKGROUND: Pain of myofascial origin is a well-recognized pathology characterized by the presence of two components: referred pain; which is often distant from its source and specific to each muscle, and the trigger point, a localized hyperirritable band present in the affected muscle and able to reproduce the referred pain when stimulated. Myofascial pain (MP) commonly coexists in patients with acute or chronic pain of other etiologies. The uniqueness of the clinical presentation of some MPs and the lack of training of most specialties represent a clinical challenge. Thus, many patients with MPS receive less than optimal management of this condition. OBJECTIVE: Pain at the anterior torso, originating at the posterior torso, can mimic common pathologies that correlate with the same anatomical area such as cardiac and intra-abdominal conditions. These clinical characteristics could be caused by MP of the iliocostalis thoracis-lumborum (ITL) muscle. However, this entity has not been well addressed in the medical literature. In this report we characterize the manifestations, diagnosis, and clinical implications of ITL MP. STUDY DESIGN: Observational assessment. SETTING: Two university-based academic emergency medicine departments (ED) in an urban setting in the United States. METHODS: A convenience sample of 43 patients who presented to the ED with pain at the anterior aspect of the torso (chest, abdomen, or pelvis) and clinical evidence of MP originated in the ITL muscle.Of a clinical trial of patients with MP, we describe a subgroup of patients with MP of the ITL which was clinically evident by the presence of a trigger point (TP) in its ability to reproduce the referred pain present at the anterior aspect of the torso. Patients received a TP injection. In this trial we intend to demonstrate that TP injections using particulate steroids mixed with a local are no more effective than saline alone to treat MP. The primary outcome was pain control (decrease in intensity of 50% or more below baseline numeric pain rating). A follow-up telephone interview was performed by third-party abstractors. RESULTS: Forty-three patients presented with pain of the anterior torso and ipsilateral back, both correlating with the level of the TP of the ITL muscle. The pain had been present from 2 days to 7 years. The most common locations of pain were the right-lower quadrant and the left side of the chest. In many of them a pattern of missed diagnosis was evident despite extensive workups and consultations. Only 17 patients were able to identify the precipitating event; the most common was coughing. Two weeks after TP injection, all patients still had satisfactory pain control. After treatment, no missed pathology or returns to the ED were reported. LIMITATIONS: This descriptive portion of the ongoing study does not affect the integrity of the trial itself but could be subject to the introduction of subject selection and selective reporting bias. Similarly, this convenience sample does not establish the incidence of this pathology and challenges the external validity to other clinical settings. CONCLUSIONS: Anterior torso pain often resulted in extensive workups before ITL myofascial pain was diagnosed. TP injections were diagnostic and therapeutic of ITL myofascial pain. PMID- 27454267 TI - Two-Year Outcome of Percutaneous Bipolar Radiofrequency Neurotomy of Sacral Nerves S2 and S3 in Spinal Cord Injured Patients with Neurogenic Detrusor Overactivity: A Randomized Controlled Feasibility Study. AB - BACKGROUND: Little research has been expended on the use of bipolar radiofrequency (RF) lesioning of sacral nerves in spinal cord injured (SCI) patients with neurogenic detrusor overactivity (NDO), and no study has been undertaken to demonstrate its long-term effect. OBJECTIVE: To investigated the effect of bipolar RF ablation of the second and third sacral nerves over 2 years in SCI patients with NDO. STUDY DESIGN: A prospective, randomized controlled feasibility study. SETTING: The outpatient clinic of a single academic medical center in Korea. METHODS: Ten SCI patients with NDO were recruited. These patients were randomly assigned to 2 groups; the intervention group (n = 5) and the control group (n = 5). Control group members received optimized conventional treatment. International Consultation on Incontinence Questionnaire (ICIQ), 3-day voiding diary, and the urinary incontinence quality of life scale (I-QOL) data were obtained at baseline and at 6, 12, and 24 months after intervention. Urodynamic study (UDS) was performed at baseline and 24 months after intervention. In the intervention group, percutaneous bipolar RF neurotomy was performed on both S2 and S3 nerves in each patient. RESULTS: Frequency of urinary incontinence and ICIQ and IQOL scores showed significant effects for time and for the group x time interaction (P < 0.05). Daily mean volume of urinary incontinence showed only a significant group effect. In UDS parameters, comparisons of values at baseline and at 24 months revealed all variables showed significant intergroup differences (P < 0.05). LIMITATION: A small number of patients was recruited. CONCLUSION: Percutaneous bipolar RF ablation of sacral nerves S2 and S3 effectively reduces urinary incontinence and improves quality of life (QoL) in SCI patients with NDO and the effects lasted over 2 years. PMID- 27454268 TI - Resorption of Massive Lumbar Disc Herniation on MRI Treated with Epidural Steroid Injection: A Retrospective Study of 28 Cases. AB - BACKGROUND: Although herniated disc fragments may resolve spontaneously, the optimal treatment option for massive lumbar disc herniation (LDH) has not been determined. OBJECTIVE: To evaluate the extent of reduction in the size of massive LDH on magnetic resonance imaging (MRI) and the pain relief effect of transforaminal epidural steroid injection (TFESI) during the study period. STUDY DESIGN: Retrospective evaluation. SETTING: Hospital and ambulatory pain clinic, Korea. METHODS: After Institutional Review Board approval, we conducted a retrospective review of 28 patients who underwent at least 2 MRIs during the period from January 2012 to December 2014. The size of the herniated mass was determined from the ratio of the anterior-posterior diameter of the spinal canal (C-value) to the maximum anterior-posterior diameter of the herniated disc (H value) on axial MRI (C-H ratio). We also analyzed visual analogue scale (VAS) scores at baseline (T0), 2 weeks after the first and second TFESI (T1, T2), and at the second follow-up MRI (T3). RESULTS: The mean C-value was 18.3 +/- 2.9 mm. The mean H-value changed from 10.4 +/- 1.9 mm to 4.5 +/- 2.7 mm, and the mean C-H ratio changed from 58 +/- 1.0% to 24 +/- 1.4% (P < 0.001). Twenty-four of 28 patients demonstrated a reduction in the size of the herniation, and the mean reduction rate of the C-H ratio was 59%. In 4 patients, the LDH had not resolved on MRI, but the symptoms had diminished to such an extent that surgery was not required. The mean VAS score had significantly decreased at T1 and showed a continued decrease at the time of the last follow-up (P < 0.001). LIMITATIONS: This is a retrospective study and only offers data for patients who chose not to undergo surgery. In addition, the timing of repeat MRI was not standardized. CONCLUSION: The majority of cases of massive LDH demonstrated resolution at variable points between 3 and 21 months. TFESI could provide effective pain relief for patients with massive LDH in the interval without severe neurologic deterioration.IRB approval: Kangdong Sacred Heart Hospital: IRB Number # 14-1-10. PMID- 27454269 TI - Effect of Epidural Steroid Injection on Bone Mineral Density in Postmenopausal Women According to Antiosteoporotic Medication Use. AB - BACKGROUND: No studies to date have compared bone mineral density (BMD) changes after epidural steroid injection (ESI) between postmenopausal patients taking antiosteoporotic medication and those who are not. OBJECTIVE: The aim of the present study was to analyze the relationship between ESI and BMD changes in postmenopausal patients according to antiosteoporotic medication use. STUDY DESIGN: Retrospective analysis. SETTING: Department of Anesthesiology and Pain Medicine at Asan Medical Center, Korea. METHODS: We retrospectively analyzed postmenopausal women who underwent ESI using dexamethasone. All women had received a diagnosis of lumbar spinal stenosis and their BMD had been measured before and after treatment. BMD was evaluated by dual-energy x-ray absorptiometry at the lumbar spine, femoral neck, femoral trochanter, and total femur, and was recorded as absolute g/cm2 and T-scores. A total of 126 patients were included in the final analysis. ESI patients were grouped as follows: group 1 (n = 74) ESI patients who took antiosteoporotic medication; group 2 (n = 52) ESI patients who did not take antiosteoporotic medication. RESULTS: In group 1, there were no significant differences between baseline and post-treatment BMD absolute values (g/cm2) in the lumbar spine, femoral neck, femoral trochanter, and total femur. In group 2, significant changes in the post-treatment BMD absolute values (g/cm2) from baseline were observed in the femoral neck (-1.48 +/- 3.84%), femoral trochanter (-2.80 +/- 7.50%), and total femur (-2.23 +/- 4.52%), but not in the lumbar spine (-2.23 +/- 4.52%). LIMITATIONS: This study contained a small sample size, no control group, and no long-term follow-up of the BMD changes after ESI. CONCLUSIONS: Our data provide new evidence indicating that ESI causes BMD changes in postmenopausal women who do not take antiosteoporotic medication. Thus, we recommend that prophylactic antiosteoporotic treatment be considered for postmenopausal women who require ESI treatment. PMID- 27454270 TI - Effectiveness of Splanchnic Nerve Neurolysis for Targeting Location of Cancer Pain: Using the Pain Drawing as an Outcome Variable. AB - The effectiveness of splanchnic nerve neurolysis (SNN) for cancer-related abdominal pain has been investigated using numeric pain intensity rating as an outcome variable. The outcome variable in this study used the grid method for obtaining a targeted pain drawing score on 60 patients with pain from pancreatic or gastro-intestinal primary cancers or metastatic disease to the abdominal region. Results demonstrate excellent inter-rater agreement (intra-class correlation [ICC] coefficient at pre-SNN = 0.97 and ICC at within one month post SNN = 0.98) for the grid method of scoring the pain drawing and demonstrate psychometric generalizability among patients with cancer-related pain. Using the Wilcoxon signed rank test and associated effect sizes, results show significant improvement in dispersion of pain following SNN. Effect sizes for the difference in pre-SNN to 2 post-SNN time points were higher for the pain drawing than for pain intensity rating. Specifically, the effect size difference from pre- to within one month post-SNN was r = 0.42 for pain drawing versus r = 0.23 for pain intensity rating. Based on a smaller subset of patients who were seen within 1 - 6 months following SNN, the effect size difference from pre-SNN was r = 0.46 for pain drawing versus r = 0.00 for pain intensity rating. Collectively, these data support the use of the pain drawing as a reliable outcome measure among patients with cancer pain for procedures such as SNN that target specific location and dispersion of pain. PMID- 27454272 TI - In errata: Novel Single Puncture Approach for Simplicity In errata: In Response to Letter to the Editor: Use of High Volumen Injectate. PMID- 27454271 TI - Stimulation of the Spinal Cord and Dorsal Nerve Roots for Chronic Groin, Pelvic, and Abdominal Pain. AB - BACKGROUND: Chronic neuropathic groin pain is a common problem. It can arise following surgery or trauma, or spontaneously as part of various pelvic pain syndromes. A number of different stimulation techniques have been reported in the literature to treat this area, but due to the complex anatomy of the region, it can be difficult to target effectively with paresthesias. OBJECTIVES: In this study we report our results treating patients with chronic neuropathic groin, pelvic, and abdominal pain, using spinal cord stimulation and dorsal nerve root stimulation. STUDY DESIGN: Open label, prospective study that includes all patients treated with a new trial stimulator system at a single center between July 1, 2011, and October 31, 2013. SETTING: Academic university neurosurgical pain center, Canada. METHODS: Thirty-two patients had trials of spinal cord stimulation and/or dorsal nerve root stimulation in the thoracic or lumbar spine. Patients were evaluated on visual analog scale pain scores, SF-36, and morphine equivalent daily dose. Data were recorded at the pre-implant visit, and 3, 6, and 12 months following permanent implant. RESULTS: The 15 patients who went on to permanent implants had, on average, significant pain reduction and improvements in quality of life at the 12 month follow-up. The majority of patients who were taking opioids at the initial assessment were able to reduce their dose with treatment. Three patients with successful trials were long-term non-responders, of whom 2 had the permanent device removed. LIMITATIONS: This study would benefit from a larger sample size that would have adequate power for comparisons between patient subgroups and stimulation techniques. CONCLUSION: Dorsal nerve root stimulation is an effective long-term treatment for neuropathic groin pain. PMID- 27454273 TI - Intrathecal Dexmedetomidine, Ketamine, and their Combination Added to Bupivacaine for Postoperative Analgesia in Major Abdominal Cancer Surgery. AB - BACKGROUND: Intrathecal ketamine has been studied extensively in animals, but rarely in humans. Intrathecal dexmedetomidine prolongs the duration of spinal anesthesia. OBJECTIVE: To investigate the efficacy and safety of intrathecal dexmedetomidine, ketamine, or both when added to bupivacaine for postoperative analgesia in major abdominal cancer surgery. DESIGN: Double-blinded, randomized, controlled trial. SETTING: Academic medical center. METHODS: Ninety patients were randomly allocated to receive either intrathecal 10 mg of hyperbaric bupivacaine 0.5% and 5 ug of dexmedetomidine (group I, n = 30), 10 mg of hyperbaric bupivacaine 0.5% and 0.1 mg/kg ketamine (group II, n = 30), or 10 mg of hyperbaric bupivacaine 0.5% and 5 ug of dexmedetomidine plus 0.1 mg/kg of ketamine (group III, n = 30). Hemodynamics, pain score, time to first request of analgesia, total PCA morphine consumption, sedation score, and adverse effects in the first 24 hours postoperatively were recorded. RESULTS: Time to first request of analgesia was longer in group II (7.42 +/- 1.43 h) and group III (13.00 +/- 7.31h) compared to group I (3.50 +/- 1.57 h). PCA morphine consumption was less in group III (6.67 +/- 2.8 mg) compared to group I (9.16 +/- 3.63 mg) and group II (8.66 +/- 3.49 mg). Group III showed lower postoperative pain scores, and a higher incidence of postoperative sedation (P < 0.03). LIMITATIONS: This study is limited by its relatively small sample size. CONCLUSION: In conclusion, the combination of intrathecal dexmedetomidine and ketamine provided superior postoperative analgesia, prolonged the time to first request of rescue analgesia, and reduced the total consumption of PCA morphine, without serious side effects compared to either drug alone. PMID- 27454274 TI - A New Look on Adding Dexamethasone as an Adjuvant to Caudal Bupivacaine; Efficacy on Postoperative Pain and Vomiting in Pediatric Patients. AB - BACKGROUND: Controlling postoperative pain and vomiting in children remains a great challenge. OBJECTIVE: Study the efficacy of adding dexamethasone to caudal bupivacaine on postoperative analgesia and vomiting. STUDY DESIGN: Prospective, randomized double blind controlled clinical trial. SETTING: Assiut University Hospital. PATIENTS: Ninety children ASA I-II, undergoing lower orthopedic surgeries. METHODS: Patients were randomly allocated into 3 equal groups. All received caudal block after induction of anesthesia with 0.5 mL/kg of 0.25% bupivacaine in addition to 5 mL intravenous (IV) normal saline in the control group, IV 0.5 mg/kg dexamethasone in IV dexamethasone group and lastly 0.1 mg/kg dexamethasone in the caudal dexamethasone group. Postoperative pain scores and rescue analgesic consumption were recorded. Blood glucose, postoperative vomiting, and other side effects were evaluated up to 24 hours after extubation. RESULTS: The time of first analgesia and the number of patients requiring rescue analgesics were significantly decreased with intravenous or caudal dexamethasone. No significant increase in postoperative blood glucose levels were observed. A significant increase in B- Endorphin level at 3 and 24 hours postoperative was found in both dexamethasone groups when compared with the preoperative baseline value. The incidence of postoperative vomiting was significantly decreased in both dexamethasone groups in comparison with the control group. No other side effects were detected. LIMITATIONS: Measurement of serum cortisol. CONCLUSION: Analgesic and antiemetic effects of dexamethasone as an adjunct to caudal block with bupivacaine (0.25%) 0.5 mL/kg is similar whether administered intravenously 0.5 mg/kg or caudally 0.1 mg/kg. PMID- 27454275 TI - Short-Term Therapeutic Efficacy of the Isobar TTL Dynamic Internal Fixation System for the Treatment of Lumbar Degenerative Disc Diseases. AB - BACKGROUND: At present, posterior interbody fusion surgery with pedicle internal fixation is the gold standard for the treatment of lumbar degenerative disc diseases. However, an increasing number of studies have shown that because fused lumbar vertebrae lose their physiological activity, the compensatory range of motion (ROM) of the adjacent levels increases. To address this issue, dynamic internal fixation systems have been developed. OBJECTIVE: Our goal was to investigate the short-term therapeutic efficacy of the Isobar TTL dynamic internal fixation system for the treatment of lumbar degenerative disc diseases and its effect on the ROM of the surgical segments. STUDY DESIGN: Retrospective Evaluation. SETTING: Tertiary hospital setting in China. METHODS: Twenty-four lumbar degenerative disc disease patients who underwent posterior lumbar decompression and single-segment Isobar TTL dynamic internal fixation at our hospital between January 2013 and July 2014 were retrospectively analyzed. The preoperative and one month, 3 month, and 12 month postoperative visual analog scale (VAS) pain scores, Japanese Orthopedic Association (JOA) scores, and Oswestry Disability Index (ODI) scores were observed and recorded to assess the clinical therapeutic effect; the lumbar ROM was measured preoperatively and at the last follow-up to evaluate the preservation of functional movement in the dynamically stabilized segment. RESULTS: All patients underwent the operation successfully without complications during hospitalization and were followed for 12 to 27 months, with an average of 18 months. The patients' preoperative and one month, 3 month, and 12 month postoperative VAS scores were 6.42 +/- 0.72, 1.71 +/ 0.86, 1.38 +/- 0.65, and 1.37 +/- 0.58, respectively, and their JOA scores were 9.54 +/- 1.89, 21.21 +/- 1.98, 22.50 +/- 1.47, and 23.46 +/- 1.32, respectively. The preoperative ODI score was 42.04 +/- 2.63; the one month, 3 month, and 12 month postoperative ODI scores were 22.79 +/- 1.61, 18.63 +/- 1.61, and 15.08 +/- 1.21, respectively. These results suggest that the VAS score at each postoperative time point was significantly lower than the preoperative score and that function was significantly improved postoperatively compared with preoperative function; all of the differences had statistical significance (P < 0.05). The patients' preoperative lumbar ROM and the ROM at 12 months post operation were 3.46 +/- 1.02 and 2.25 +/- 0.79, respectively; the difference was not statistically significant (P = 0.11). LIMITATIONS: The follow-up time is not long enough. CONCLUSIONS: The treatment of lumbar degenerative disc diseases with the Isobar TTL dynamic internal fixation system can effectively relieve pain, improve quality of life, and preserve the lumbar ROM of the stabilized segment with a satisfactory clinical therapeutic effect. PMID- 27454276 TI - Ultrasound-Guided Quadratus Femoris Muscle Injection in Patients with Lower Buttock Pain: Novel Ultrasound-Guided Approach and Clinical Effectiveness. AB - BACKGROUND: The quadratus femoris (QF) muscle is a possible source of lower buttock pain as evidenced by what is known about the pathophysiology of ischiofemoral impingement syndrome. However, there are few reports about the interventional management of the QF muscle as a pain generator. OBJECTIVE: To describe an ultrasound-guided QF muscle injection technique in patients with lower buttock pain suspected of QF muscle pathology and to report the result of treatment. STUDY DESIGN: Retrospective evaluation. SETTING: Outpatient department for interventional pain management at a university hospital. METHODS: We studied 14 patients who had deep tenderness localized to the lower buttock region at a point halfway between the lateral prominence of the greater trochanter and the ischial tuberosity corresponding to the location of the QF muscle belly. Under ultrasound guidance, 8 mL of 0.25% lidocaine was injected into the QF muscle. Pain scores were assessed prior to the first injection and 2 weeks after the last injection. Patient satisfaction was also assessed. RESULTS: When compared before and 2 weeks after last QF muscle injection, the mean pain score decreased by 49.3% (6.7 +/- 2.3 to 3.4 +/- 2.1, P < 0.001). Two weeks after the last injection, approximately 70% of patients (10 of 14 patients) expressed their satisfaction as excellent or good and the average frequency of injection was 2.5 times. There were no complications observed. LIMITATIONS: The results of this study should be considered preliminary owing to the small sample size and lack of a control group, and the retrospective characteristics of this study may have introduced a selection bias. CONCLUSIONS: Ultrasound-guided QF muscle injection with local anesthetic helps alleviate pain in patients with lower buttock pain attributed to the QF muscle, and leads to high levels of satisfaction for patients. A randomized placebo-controlled trial should be considered in the future. PMID- 27454277 TI - Post Dural Puncture Headache in Fibromyalgia after Cesarean Section: A Comparative Cohort Study. AB - BACKGROUND: Patients of chronic pain syndromes like fibromyalgia (FMS) when subjected to spinal anesthesia are theoretically more liable to post dural puncture headache (PDPH) as they have enhanced central nervous system sensitization and decreased descending inhibition. OBJECTIVE: The current study aims to verify the incidence and chronicity of PDPH in FMS patients. STUDY DESIGN: Case control study. METHODS: In a comparative control study, 70 fibromyalgia patients were scheduled for an elective cesarean delivery fibromyalgia group or Group 1. Group 2 included 70 women scheduled for elective cesarean delivery who had no history of chronic pain and is used as a control group. Both groups were compared regarding the incidence of development of PDPH in the first postoperative 48 hours and the persistence of PDPH for 7 days or more. SETTINGS: Women's Health Hospital, Assiut University, antenatal Clinic. RESULTS: The fibromyalgia group reported more PDPH (18 patients, 25.7%) as compared to the control group (10 patients, 14.3%), P < 0.01. PDPH persisted for 7 or more days in 8 patients in the fibromyalgia group (11.4%) while, it persisted in 2.86% of the control patients. PDPH continued for more than 3 months in 2 patients in the fibromyalgia group (2.86%). LIMITATIONS: Difficulty in calculating the dose of analgesics as patients with fibromyalgia may use other analgesics due to musculoskeletal pain. CONCLUSION: Dural puncture increases the incidence of PDPH in fibromyalgia patients in comparison with normal controls without increasing other postoperative side effects. PMID- 27454278 TI - Clinical Effectiveness and Prognostic Indicators of Parasagittal Interlaminar Epidural Injection. AB - BACKGROUND: Interlaminar epidural steroid injection (ESI) is a well-established intervention to improve radicular leg pain. However, few studies have demonstrated the prognostic factors for interlaminar ESI. OBJECTIVE: To investigate the clinical effectiveness and prognostic indicators of parasagittal interlaminar ESI during a 2-week follow-up. STUDY DESIGN: Prospective evaluation. SETTING: An interventional pain management practice in South Korea. METHODS: After Institutional Review Board approval, parasagittal interlaminar ESI under fluoroscopic guidance was performed in 55 patients with central spinal stenosis. The numerical rating scale (NRS) and the Oswestry Disability Index (ODI) (%) were used to evaluate clinical efficacy and prognostic indicators. To determine the prognostic indicators, treatment outcomes were classified as successful (decreased NRS >= 50%, decreased ODI >= 40%) and unsuccessful (decreased NRS < 50%, decreased ODI < 40%) results. RESULTS: Parasagittal interlaminar ESI significantly improved the NRS and ODI (%) scores after 2 weeks compared to those measured pretreatment. Paresthesia provocation (P = 0.006) was a significant prognostic factor on the NRS, whereas the Beck Depression Inventory (BDI) score (P = 0.007), paresthesia provocation (P = 0.035), and epidurography finding (P = 0.038) were significant on the ODI (%) score between patients with successful and unsuccessful outcomes. LIMITATIONS: We included the method of parasagittal interlaminar ESI only, therefore, direct comparison with other techniques was not available. CONCLUSION: Parasagittal interlaminar ESI significantly improved the NRS and ODI (%) scores. Paresthesia provocation was a prognostic indicator on the NRS and ODI (%) scores, and BDI scores and epidurography findings were prognostic indicators for the ODI (%) score. PMID- 27454279 TI - Elastoplasty: A Silicon Polymer as a New Filling Material for Kyphoplasty in Comparison to PMMA. AB - BACKGROUND: Painful vertebral compression fractures (VCF) caused by osteoporosis are a common health problem in the elderly population. If conservative treatments are unsuccessful, surgical treatments like vertebroplasty or kyphoplasty are recommended. But the use of Polymethylmethacrylat (PMMA) bone cement for augmentation surgery is associated with risks. OBJECTIVES: Evaluation of the effectiveness and safety of a newly developed silicon polymer (VK100) that can be used instead of PMMA bone cement for kyphoplasty treatments. STUDY DESIGN: A retrospective study of 30 patients comparing the outcomes of kyphoplasty treatments conducted with PMMA and VK100. SETTING: Clinic for Orthopedics and Trauma Surgery Bonn, Germany. METHODS: Thirty patients with one to 3 VCF were treated either with balloon kyphoplasty using VK100 or balloon kyphoplasty using PMMA bone cement. Data from both groups was compared by a matched pair analysis. The medial vertebral height was measured at each examination radiologically. The patients stated their pain intensity using the Visual Analogue Scale (VAS) and the patient's functional impairment was evaluated with the Oswestry-Disability Index (ODI).All data were assessed before surgery, and 3 days, 3 months, 6 months, and 12 months after surgery. Intraoperative and postoperative adverse events were documented. RESULTS: The patients' functional impairment and pain improved significantly after surgery. The course of ODI and VAS was comparable in both treatment groups, but the improvement in the VK group was significantly ongoing until the 12 month follow-up. Vertebral height improvement was significant in both groups, but the PMMA group achieved a better absolute restoration. The vertebral height stayed constant during the follow-up in the VK group and worsened significantly in the PMMA group. There was no significant difference between groups concerning the occurrence of additional fractures; and no other types of complications or surgery-related adverse events were observed in either the PMMA group or in the VK group. LIMITATIONS: The study is only a matched pair analysis of 15 patients for each procedure and the amount of injected filling material was not recorded. CONCLUSION(S): The study results demonstrate that the clinical outcome of VAS and ODI of using the silicon polymer VK100 is comparable or slightly better than using PMMA. VK 100 shows a trend to minor additional fractures during the follow-up. However, height restoration is not satisfactory in comparison to PMMA, although vertebral height stayed more or less constant in the VK group. To address the augmentation success further, it would be necessary to study a larger patient group over a longer study period and to assess additional parameters such as bone density and injected amount of filling material. PMID- 27454280 TI - Anatomical Basis for Injection around First Dorsal Compartment of the Wrist: A Fresh Cadaveric Study. AB - BACKGROUND: It is important to understand the anatomical relationship between the medial and lateral branches of superficial radial nerve (SRN) and the first dorsal compartment to prevent and minimize possible injury to these nerves during various procedures around the tip of radial styloid process (RSP). OBJECTIVE: To delineate the anatomical location of the SRN in relation to the extensor pollicis brevis (EPB) and abductor pollicis longus (APL) tendons. STUDY DESIGN: Observational study. SETTING: Academic medical center. METHODS: The width of the first dorsal compartment, distance between the EPB tendon and the closest medial branch of the SRN, and distance between the APL tendon and the closest lateral branch of the SRN were measured. The distances were measured at the RSP (the tip of the RSP) and RSP+1 (1 cm proximal to the tip of the RSP) levels. RESULTS: The median distances between the EPB tendon and the closest medial branch of the SRN at the RSP and RSP+1 were 6.0 mm (range: 1.6 - 11.0 mm) and 3.2 mm (range: -2.0- 9.4 mm), respectively. The median distances from the APL tendon to the closest lateral branch of the SRN at the RSP and RSP+1 were -2.0 mm (range: -9.0- 8.4 mm) and 1.0 mm (range: -7.2- 8.0 mm), respectively. A high percentage of overlap (up to 59%) was observed between the lateral branch of the SRN and the APL tendon. LIMITATION: This study is limited by its small sample size. CONCLUSION: Due to the anatomical proximity of the branches of the SRN and the first dorsal compartment around the RSP, physicians must be cautious during procedures near this location. It is important to approach from above the EPB, rather than from above the APL, when performing blind procedures, although ultrasound guidance is preferable. PMID- 27454281 TI - Complex Regional Pain Syndrome Caused by Lumbar Herniated Intervertebral Disc Disease. AB - Most cases of complex regional pain syndrome (CRPS) occur after some inciting injury. There are a few cases of CRPS after an operation for disc disease. CRPS from a mild herniated intervertebral disc (HIVD) without surgical intervention is even rarer than CRPS after an operation for disc disease.A 22-year-old man was transferred to a pain clinic. He had continuously complained about back and right leg pain. He presented with a skin color change in the right lower leg, intermittent resting tremor, stiffness, and swelling in the right leg. He complained of a pulling sensation and numbness in his right buttock, posterior thigh, lateral calf, and ankle. This symptom was in accordance with L4/5 radiculopathy. Magnetic resonance imaging (MRI) also showed L4/5 HIVD that was central to the bilateral subarticular protrusion.He was diagnosed as having CRPS, which fits the revised International Association for the Study of Pain (IASP) criteria. He fulfilled 4 symptom categories (allodynia, temperature asymmetry and skin color change, sweating changes, decreased range of motion and motor dysfunction) and 3 of 4 sign categories (allodynia, temperature asymmetry and skin color changes, decreased range of motion and motor dysfunction). The bone scan and thermography also revealed CRPS.For the past 2 months, we have performed intensive treatments. But, he never became pain-free and walking for 5 minutes led to persistent leg pain. We decided to perform percutaneous nucleoplasty, which can directly decompress a HIVD. On the next day, he achieved dramatic symptom relief. The visual analog scale (VAS) score improved to 3, compared to the VAS score of 9 at the first visit. The skin color change, allodynia, and tremor in the right leg disappeared, and the temperature asymmetry normalized. Motor weakness of the right leg also recovered.We report an unusual case of CRPS that was caused by L4/5 HIVD without a history of trauma or surgery. It has a clear causal relationship between HIVD and CRPS and definitively fits in the newly revised IASP criteria. In conclusion, mild HIVD can cause CRPS without any trauma. And percutaneous nucleoplasty can be considered as a treatment option. PMID- 27454282 TI - Intracerebroventricular Pain Treatment with Analgesic Mixtures including Ziconotide for Intractable Pain. AB - Intracerebroventricular (ICV) administration of opioids for control of intractable cancer pain has been used since 1982. We present here our experience of intracerebroventricular administration of pain treatments including ziconotide associated with morphine and ropivacaine for patients resistant to a conventional approach, with nociceptive, neuropathic, or mixed pain. These clinical cases were conducted with patients suffering from refractory pain, more than 6/10 on a numerical pain rating scale (NPRS) while on high-dose medical treatment and/or intolerance with significant side effects from oral medication. The baseline study visit included a physical examination and an assessment of pain intensity on a NPRS. Under general anesthesia, a neuronavigation device was used to place the catheter on the floor of the third ventricle, supported by an endoscope. Then, drugs were injected in the cerebroventricular system, through a pump (external or subcutaneous). The primary objective was to measure pain evaluation with ICV treatment after a complete withdrawal of other medications.Four patients were enrolled: 3 with intractable cancer pain and one with central neuropathic pain. The median NPRS at baseline was 9.5 [8.5; 19]. The mean NPRS after one month was 3.5 [3; 4.5]. Ziconotide was initiated at 0.48 ug/d and up to a median of 1.2 ug/d [1.0; 1.56]. The median dose of morphine and ropivacaine used initially was respectively 0.36 mg/d [0.24; 0.66] up to 0.6 mg/d [0.45; 4.63] and 1.2 mg/d [0; 2.4] up to 2.23 mg/d [1.2; 3.35]. Minor side effects were initially observed but transiently. One psychiatric agitation required discontinuation of ziconotide infusion. For intractable pain, using ziconotide by intracerebroventricular infusion seems safe and efficient, specifically for chronic neoplastic pain of cervicocephalic, thoracic, or diffuse origin and also for pain arising from a central neuropathic mechanism. PMID- 27454283 TI - Interocular Symmetry of Macular Ganglion Cell Complex Thickness in Young Chinese Subjects. AB - PURPOSE: To report interocular differences in macular ganglion cell complex (mGCC) thickness in young Chinese subjects using RTVue-100 optical coherence tomography (OCT). METHODS: This was an observational, cross-sectional study. The mGCC thickness was measured in 158young Chinese subjects using RTVue-100 OCT. The normal ranges of the interocular differences were determined as falling between the 2.5th and 97.5th percentiles. Right and left eyes were compared using a paired t test. Pearson correlation analysis was performed to assess the relationships between mGCC thickness and other potential factors. The relationships between the interocular difference in the average mGCC thickness and the potential factors were evaluated by univariate and multivariate linear regression analysis. RESULTS: The mean interocular difference in the average, superior, and inferior mGCC thickness were 0.19 +/- 2.69 MUm, 0.22 +/-3.14 MUm, and 0.25+/-3.34 MUm, respectively, which were not statistically significant. The 2.5th and 97.5th percentiles of interocular difference for mean average mGCC thickness were -4.82MUm and 4.38MUm, for superior mGCC thickness, -6.67 MUm and 7.04 MUm, and for inferior mGCC thickness, -6.75 MUm and 6.27 MUm. There was a strong correlation between the right and left eyes for all the studied parameters, including spherical equivalent (SE) and axial length (AL). Interocular difference in SE (p = 0.007) were independently correlated with the interocular difference in average mGCC thickness. CONCLUSIONS: There was no significant relative interocular difference in mGCC thickness in young Chinese subjects. Interocular difference exceeding the normal limits should be considered significantly asymmetrical, and suggestive of pathology. PMID- 27454284 TI - Consumer-Oriented Approaches to Cost Containment. PMID- 27454285 TI - Real-time selective sequencing using nanopore technology. AB - The Oxford Nanopore Technologies MinION sequencer enables the selection of specific DNA molecules for sequencing by reversing the driving voltage across individual nanopores. To directly select molecules for sequencing, we used dynamic time warping to match reads to reference sequences. We demonstrate our open-source Read Until software in real-time selective sequencing of regions within small genomes, individual amplicon enrichment and normalization of an amplicon set. PMID- 27454286 TI - An Unusual Cobalt Azide Adduct That Produces a Nitrene Species for Carbon Hydrogen Insertion Chemistry. AB - A family of Co(II) complexes supported by the bulky, dianionic bis(pyrrolyl)pyridine pincer ligand pyrr2py [pyrr2py(2-) = 3,5-(t)Bu2 bis(pyrrolyl)pyridine] are reported in this work. These compounds include 1-OEt2, 1.toluene, and 1-N3Ad (Ad = 1-adamantyl), the latter which is prepared via addition of N3Ad to 1-OEt2 [1 = (pyrr2py)Co]. While complexes 1-OEt2 and 1-N3Ad are four-coordinate systems having a Co(II) ion confined in a cis-divacant octahedral geometry, complex 1.toluene possesses a Co(II) ion in a T-shaped environment where the toluene is interstitial and intercalated between two (pyrr2py)Co molecules. Complex 1-N3Ad is notable in that the organic azide binds to the metal through gamma-N in a kappa(1) fashion. Photolysis of 1-N3Ad results in N2 extrusion and formation of C-H insertion product [(pyrrpypyrrNHAd)Co] (2). We propose complex 2 form via insertion of the nitrene (NAd) into one (t)Bu C-H bond, thus resulting in a pincer ligand having a pendant secondary amine. Complexes 1-OEt2, 1.toluene, and 1-N3Ad and C-H insertion product 2 have been structurally characterized, and in the case of 1-OEt2, we also present electrochemical data. PMID- 27454288 TI - BRCA1 loses the ring but lords over resistance. AB - Germline breast cancer 1 (BRCA1) variants are associated with a high risk of breast and ovarian cancers. Many BRCA1-mediated cancers are initially responsive to platinum-based therapy; however, resistance commonly develops. The BRCA1185delAG mutation is common in the Ashkenazi Jewish population and has been thought to result in loss of function due to the introduction of a stop codon in the 5' region of the BRCA1 transcript. Two studies in this issue of the JCI reveal that the BRCA1185delAG mutation results in the production of BRCA1 that lacks the N-terminal really interesting new gene (RING) domain. RING-less BRCA1 was shown to directly mediate chemoresistance, while maintaining some homologous recombination function. These results provide important insight into BRCA1 function and indicate that other truncated proteins could arise through similar alterations in codon usage. PMID- 27454287 TI - BRCA1185delAG tumors may acquire therapy resistance through expression of RING less BRCA1. AB - Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients. PMID- 27454289 TI - RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance. AB - Patients with cancers that harbor breast cancer 1 (BRCA1) mutations initially respond well to platinum and poly(ADP-ribose) polymerase inhibitor (PARPi) therapy; however, resistance invariably arises in these patients and is a major clinical problem. The BRCA1185delAG allele is a common inherited mutation located close to the protein translation start site that is thought to produce a shortened, nonfunctional peptide. In this study, we investigated the mechanisms that lead to PARPi and platinum resistance in the SUM1315MO2 breast cancer cell line, which harbors a hemizygous BRCA1185delAG mutation. SUM1315MO2 cells were initially sensitive to PARPi and cisplatin but readily acquired resistance. PARPi and cisplatin-resistant clones did not harbor secondary reversion mutations; rather, PARPi and platinum resistance required increased expression of a really interesting gene (RING) domain-deficient BRCA1 protein (Rdd-BRCA1). Initiation of translation occurred downstream of the frameshift mutation, probably at the BRCA1 Met-297 codon. In contrast to full-length BRCA1, Rdd-BRCA1 did not require BRCA1 associated RING domain 1 (BARD1) interaction for stability. Functionally, Rdd BRCA1 formed irradiation-induced foci and supported RAD51 foci formation. Ectopic overexpression of Rdd-BRCA1 promoted partial PARPi and cisplatin resistance. Furthermore, Rdd-BRCA1 protein expression was detected in recurrent carcinomas from patients who carried germline BRCA1185delAG mutations. Taken together, these results indicate that RING-deficient BRCA1 proteins are hypomorphic and capable of contributing to PARPi and platinum resistance when expressed at high levels. PMID- 27454290 TI - p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing. AB - Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the incidence of PTB in the p53d/d mice. Decidual senescence with heightened mTORC1 signaling is also a signature of human PTB. Here, we have identified an underlying mechanism for PTB and a potential therapeutic strategy for treating the condition. Treatment of pregnant p53d/d mice with either the antidiabetic drug metformin or the antioxidant resveratrol activated AMPK signaling and inhibited mTORC1 signaling in decidual cells. Both metformin and resveratrol protected against spontaneous and inflammation-induced PTB in p53d/d females. Using multiple approaches, we determined that p53 interacts with sestrins to coordinate an inverse relationship between AMPK and mTORC1 signaling that determines parturition timing. This signature was also observed in human decidual cells. Together, these results reveal that p53-dependent coordination of AMPK and mTORC1 signaling controls parturition timing and suggest that metformin and resveratrol have therapeutic potential to prevent PTB. PMID- 27454291 TI - E2f8 mediates tumor suppression in postnatal liver development. AB - E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development. PMID- 27454293 TI - RelA: a tale of a stitch in time. AB - Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer in which NF-kappaB pathways promote biological aggressiveness. In this issue of the JCI, Lesina et al. investigated the role of RelA, the p65 partner of p50 that together form the most common NF-kappaB complex, in the early stages of pancreatic malignant transformation and in established PDAC. By deleting Rela in the context of an oncogenic Kras-driven autochthonous model of PDAC, the authors demonstrated that RelA is a mediator of oncogene-induced senescence (OIS) and the senescence associated secretory phenotype (SASP) that attenuates acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia (PanIN) formation, and PanIN progression to PDAC. Loss of the tumor-suppressor function of RelA in the early stages of Kras-driven pancreatic neoplastic transformation was associated with decreased OIS and SASP and a protumorigenic tumor microenvironment that harbored more M2 macrophages and myeloid-derived suppressor cells. The beneficial effects of RelA were mediated by increased expression of CXCL1 and its activation of CXCR2. By contrast, in advanced stages of Kras-driven murine PDAC, loss of p53 or p16 was associated with senescence bypass, and RelA deficiency in this context attenuated cancer cell proliferation and prolonged mouse survival, indicating that RelA enhances tumor progression in established PDAC. PMID- 27454292 TI - Stem-loop binding protein is a multifaceted cellular regulator of HIV-1 replication. AB - A rare subset of HIV-1-infected individuals is able to maintain plasma viral load (VL) at low levels without antiretroviral treatment. Identifying the mechanisms underlying this atypical response to infection may lead to therapeutic advances for treating HIV-1. Here, we developed a proteomic analysis to compare peripheral blood cell proteomes in 20 HIV-1-infected individuals who maintained either high or low VL with the aim of identifying host factors that impact HIV-1 replication. We determined that the levels of multiple histone proteins were markedly decreased in cohorts of individuals with high VL. This reduction was correlated with lower levels of stem-loop binding protein (SLBP), which is known to control histone metabolism. Depletion of cellular SLBP increased promoter engagement with the chromatin structures of the host gene high mobility group protein A1 (HMGA1) and viral long terminal repeat (LTR), which led to higher levels of HIV-1 genomic integration and proviral transcription. Further, we determined that TNF-alpha regulates expression of SLBP and observed that plasma TNF-alpha levels in HIV-1 infected individuals correlated directly with VL levels and inversely with cellular SLBP levels. Our findings identify SLBP as a potentially important cellular regulator of HIV-1, thereby establishing a link between histone metabolism, inflammation, and HIV-1 infection. PMID- 27454294 TI - Pravastatin to prevent obstetrical complications in women with antiphospholipid syndrome. AB - Pregnant women with antiphospholipid syndrome (APS) are at a high risk of obstetrical complications. The current standard of care, including the use of low dose aspirin and heparin, has not been shown to prevent preeclampsia or intrauterine growth restriction (IUGR). Due to the similarities in pathophysiology among preeclampsia, IUGR, and atherosclerotic cardiovascular disease, statins have been proposed for treating and/or preventing these obstetrical complications. In this issue of the JCI, Lefkou et al. report on a small, observational trial that showed a dramatic improvement in both maternal and fetal/neonatal outcomes in women with APS given pravastatin after the onset of preeclampsia and/or IUGR compared with women in the control group. These results, along with other recent clinical studies, support further evaluation of statins for prevention of preeclampsia in a large-scale randomized clinical trial. PMID- 27454295 TI - Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. AB - BACKGROUND: Administration of conventional antithrombotic treatment (low-dose aspirin plus low-molecular weight heparin [LDA+LMWH]) for obstetric antiphospholipid syndrome (APS) does not prevent life-threatening placenta insufficiency-associated complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) in 20% of patients. Statins have been linked to improved pregnancy outcomes in mouse models of PE and APS, possibly due to their protective effects on endothelium. Here, we investigated the use of pravastatin in LDA+LMWH-refractory APS in patients at an increased risk of adverse pregnancy outcomes. METHODS: We studied 21 pregnant women with APS who developed PE and/or IUGR during treatment with LDA+LMWH. A control group of 10 patients received only LDA+LMWH. Eleven patients received pravastatin (20 mg/d) in addition to LDA+LMWH at the onset of PE and/or IUGR. Uteroplacental blood hemodynamics, progression of PE features (hypertension and proteinuria), and fetal/neonatal outcomes were evaluated. RESULTS: In the control group, all deliveries occurred preterm and only 6 of 11 neonates survived. Of the 6 surviving neonates, 3 showed abnormal development. Patients who received both pravastatin and LDA+LMWH exhibited increased placental blood flow and improvements in PE features. These beneficial effects were observed as early as 10 days after pravastatin treatment onset. Pravastatin treatment combined with LDA+LMWH was also associated with live births that occurred close to full term in all patients. CONCLUSION: The present study suggests that pravastatin may improve pregnancy outcomes in women with refractory obstetric APS when taken at the onset of PE or IUGR until the end of pregnancy. PMID- 27454296 TI - Driving an improved CAR for cancer immunotherapy. AB - The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell mediated therapy for solid tumors. PMID- 27454297 TI - Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor mediated inhibition. AB - Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies. PMID- 27454298 TI - RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras driven pancreatic carcinogenesis. AB - Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC. PMID- 27454300 TI - Correction: RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression. AB - [This corrects the article DOI: 10.1371/journal.pone.0143563.]. PMID- 27454299 TI - Hypoxia-dependent regulation of inflammatory pathways in immune cells. AB - Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-kappaB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease. PMID- 27454302 TI - [Pigmented Paravenous Retinochoroidal Atrophy]. PMID- 27454301 TI - Identification of SNP and SSR Markers in Finger Millet Using Next Generation Sequencing Technologies. AB - Finger millet is an important cereal crop in eastern Africa and southern India with excellent grain storage quality and unique ability to thrive in extreme environmental conditions. Since negligible attention has been paid to improving this crop to date, the current study used Next Generation Sequencing (NGS) technologies to develop both Simple Sequence Repeat (SSR) and Single Nucleotide Polymorphism (SNP) markers. Genomic DNA from cultivated finger millet genotypes KNE755 and KNE796 was sequenced using both Roche 454 and Illumina technologies. Non-organelle sequencing reads were assembled into 207 Mbp representing approximately 13% of the finger millet genome. We identified 10,327 SSRs and 23,285 non-homeologous SNPs and tested 101 of each for polymorphism across a diverse set of wild and cultivated finger millet germplasm. For the 49 polymorphic SSRs, the mean polymorphism information content (PIC) was 0.42, ranging from 0.16 to 0.77. We also validated 92 SNP markers, 80 of which were polymorphic with a mean PIC of 0.29 across 30 wild and 59 cultivated accessions. Seventy-six of the 80 SNPs were polymorphic across 30 wild germplasm with a mean PIC of 0.30 while only 22 of the SNP markers showed polymorphism among the 59 cultivated accessions with an average PIC value of 0.15. Genetic diversity analysis using the polymorphic SNP markers revealed two major clusters; one of wild and another of cultivated accessions. Detailed STRUCTURE analysis confirmed this grouping pattern and further revealed 2 sub-populations within wild E. coracana subsp. africana. Both STRUCTURE and genetic diversity analysis assisted with the correct identification of the new germplasm collections. These polymorphic SSR and SNP markers are a significant addition to the existing 82 published SSRs, especially with regard to the previously reported low polymorphism levels in finger millet. Our results also reveal an unexploited finger millet genetic resource that can be included in the regional breeding programs in order to efficiently optimize productivity. PMID- 27454303 TI - [Functional and Morphological Microstructural Changes in SD-OCT in Long-Term Treatment for Neovascular AMD with Ranibizumab - Monotherapy Versus Combination Therapy with PDT]. AB - Background: Intravitreal anti-VEGF therapy is the gold standard in the treatment of neovascular age-related macular degeneration (nAMD). In recent literature, the benefit of additional photodynamic therapy (PDT) has been debated. The aim of our study was to compare the functional and structural effects of long-term combination therapy with PDT plus ranibizumab with monotherapy with ranibizumab. Material and Methods: In a retrospective study, patients suffering from nAMD were followed up for at least 42 months. Patients were assigned to group A (monotherapy with ranibizumab according to pro re nata [PRN]) or group B (combination therapy with one-time PDT plus ranibizumab according to PRN). The best-corrected visual acuity (BVCA) was evaluated at the starting and end points, together with central retinal thickness (CRT), maximal retinal thickness (MRT) and the maximal diameter of the base of the subretinal plaque in spectral-domain optical coherence tomography (SD-OCT), at the first measurement and at the end point. Results: Group A consisted of 21 eyes (17 patients) and group B consisted of 12 eyes (11 patients). The average follow-up from starting to end point was 64 months and 47 months, from the first measurement of SD-OCT to the end point. Within this period, patients in group A received 19 +/- 14 intravitreal injections, and patients in group B received 22 +/- 10 intravitreal injections. BCVA at the starting point was 0.31 +/- 0.26 in group A and 0.31 +/- 0.17 in group B. At the end point, BCVA in group A was 0.29 +/- 0.25 (p = 0.405), and in group B 0.25 +/- 0.20 (p = 0.142). CRT decreased in group A by 72 +/- 178 um (p = 0.024) and group B by 28 +/- 98 (p = 0.1335). MRT decreased in group A by 25 +/- 135 um (p = 0.166) and in group B by 2 +/- 118 um (p = 0.421). The base of the subretinal plaque increased in group A by 32 +/- 1468 um (p = 0.242) and in group B by 748 +/- 1024 (p = 0.025). Conclusion: In a long-term follow-up of 5.3 years, patients with nAMD in both groups exhibited good stabilisation of visual acuity. In both groups, retinal thickness decreased and the base of the subretinal plaque increased. With respect to SD-OCT morphological criteria, patients in group A (monotherapy) responded slightly better to therapy than patients in group B (combination group). PMID- 27454304 TI - [Regional Differences in the Care of Patients with Neovascular Age-Related Macular Degeneration, Based on the Non-Interventional OCEAN Study]. AB - Background: The main cause of blindness in the elderly in Germany is neovascular age-related macular degeneration (nAMD). In the non-interventional OCEAN study, data were prospectively collected on the routine clinical care of patients treated with the drug ranibizumab. Patients: As part of an interim analysis within the ongoing study (NCT02194803), stratification was performed by the 17 regions of the German associations of panel physicians and by areas of different population density. Only data were analysed for patients for whom the first treatment with ranibizumab was documented. Results: A total of 5,606 patients were documented. The present manuscript reviews 2,658 treatment-naive patients with nAMD, documented by 324 ophthalmologists. Most patients receiving an intravitreal injection were female (60 %). The average patient was aged 77.7 +/- 8.2 years at study start. The great majority of patients had statutory health insurance (91 %). At baseline, fluorescein angiography (FLA) was performed for 72 % of patients, while optical coherence tomography (OCT) was carried out for 76 %. A combination of both was performed for 54 % of patients, varying regionally from 26 % (Saxony-Anhalt) to 100 % (Berlin). The average waiting time between the first examination and the first injection was 20.0 +/- 18.5 days. With different statistical models (ANOVA adjusted, with/without interactions), significant effects on treatment delay were found for district type (population density), federal state and type of specialist. Conclusion: No major regional differences were observed in the demographic characteristics of the patient population. The main regional disparities in the care of nAMD patients were in the application of diagnostic methods and the waiting times between the first examination and the first drug administration. The regional variations in treatment delays could clearly influence the risk of worse functional outcome. PMID- 27454305 TI - [Activities of the Section Tissue for Transplantation and Biotechnology, German Ophthalmological Society: Report 2014]. PMID- 27454306 TI - [Do We Need Libraries Any More? A Plea for the Preservation of Our Cultural Heritage in Ophthalmology]. PMID- 27454307 TI - [Epidemiology and Clinical Presentation of Sarcoidosis]. AB - Sarcoidosis is a systemic disease of unknown aetiology. Typical histology shows epithelioid cell granulomas, and typical immunopathology enhanced Th1 type immune responses in the involved organs. The disease occurs worldwide, but more frequently in northern countries than in the south. In Germany, the incidence is estimated to be 10 per 100,000, and the prevalence 44-48 per 100,000. Sarcoidosis usually affects adults under 50 years of age, but can also be seen in children, adolescents and in the elderly. Women are more frequently affected than men. Familial clusters can occur. The clinical presentation of sarcoidosis varies widely and depends on the manifestations in the individual organ. Systemic symptoms include fatigue, night sweats, weight loss, fever, arthralgia and myalgia. Organ-specific symptoms include cough and dyspnoea, with pulmonary involvement, headache and palsy in neurosarcoidosis, arrhythmias and heart failure in cardiac sarcoidosis, and manifold skin lesions with skin involvement. Relapses are rarely seen in acute sarcoidosis, whereas the chronic form tends to relapse more frequently. Lofgren's syndrome, a specific phenotype of acute sarcoidosis, is characterised by bihilar lymphadenopathy, ankle arthritis and erythema nodosum. Chronic sarcoidosis can be asymptomatic, despite radiological changes, which may be extensive. By definition, sarcoidosis has become chronic after 2 years of disease with ongoing signs of activity. The long-term prognosis is generally good, but depends on the different organ manifestations and complications. PMID- 27454308 TI - [Descemet Membrane Endothelial Keratoplasty]. AB - Descemet membrane endothelial keratoplasty (DMEK) is the gold standard for the treatment of corneal endothelial disease, first and foremost Fuchs' endothelial dystrophy. Superior visual rehabilitation as well as lower and decreasing complication rates can be obtained with DMEK than with Descemet stripping automated endothelial keratoplasty (DSAEK) - still the most commonly performed type of posterior lamellar keratoplasty. Recent advancements in the DMEK method include the establishment of a standardised and reproducible surgical "no touch" technique and the emerging role of eye banks, which are able to prepare convenient pre-cut DMEK grafts. These developments pave the way for increasing numbers of corneal surgeons to add DMEK to their armamentarium, despite the more challenging nature of this procedure. However, a review of the current literature shows that this fascinating technique still offers certain challenges, which need to be further addressed. For example, graft detachment remains the most commonly encountered complication after DMEK. A plethora of prospective-randomised studies is required to further endorse the evident superiority of DMEK over alternative types of lamellar keratoplasty and to help propagate the practice of this fascinating technique. PMID- 27454309 TI - [Chemical and Thermal Eye Burns]. AB - Background: This review gives a therapeutic approach for the early treatment of chemical and thermal burns of the ocular surface (CTOS). Method: Based on a review of international literature, the experiences of University Hospital Aachen and Halle/Saale, Eye Clinic Cologne as well as experimental data of the research institute (An-Institut) at RWTH Aachen University are considered and discussed. Results: As the risk depends on the stage of CTOS, recommendations are given for acute treatment for different stages. Pathophysiological considerations will be discussed. Special treatment options for exceptional situations and for late phase CTOS are demonstrated. Conclusion: According to the latest data, the most important clinical recommendation for the acute phase of CTOS is the application of a suitable rinsing solution. Furthermore, anti-inflammatory treatment is of central importance. For the therapy of severe CTOS, approved and advanced surgical methods need to be applied. In this way, anti-inflammatory and tissue protecting mechanisms are activated simultaneously. PMID- 27454310 TI - Prediction Models of Mortality in Acute Pancreatitis in Adults: A Systematic Review. AB - Background: Acute pancreatitis (AP) varies in severity, prompting development of systems aimed at predicting prognosis to help guide therapy. Although several prediction approaches are available, their test characteristics and clinical utility are not completely understood. Purpose: To evaluate the test characteristics (prognostic accuracy, incremental predictive value) and clinical utility (effect on patient outcomes) of severity scores for predicting mortality in AP. Data Sources: Ovid MEDLINE and EMBASE (inception to 3 May 2016). Study Selection: Longitudinal studies, in any language, that evaluated the prognostic value of at least 1 clinical severity score in AP. Data Extraction: Dual data extraction and quality assessment. Data Synthesis: Of 4039 citations screened, 94 unique studies evaluating 18 scores in 53 547 patients met the inclusion criteria. All studies provided data on prognostic accuracy, whereas 6 provided data on incremental predictive values. Most scores demonstrated low prognostic accuracy. The Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Ranson criteria were studied most extensively. The median sensitivity and specificity of APACHE II at a threshold of 7 were 100% (range, 68% to 100%) and 63% (range, 21% to 96%), respectively, and those of the Ranson criteria at a threshold of 2 were 90% (range, 0% to 100%) and 67% (range, 14% to 97%), respectively. Estimates of sensitivity were based on relatively few patients. Evidence was limited regarding the incremental predictive value of the scoring systems or their effect on patient outcomes. Limitation: Substantial clinical heterogeneity and inadequate methodological and reporting quality precluded a meta-analysis. Conclusion: The test characteristics and clinical utility of AP severity scores remain uncertain. Additional studies with improved methodological rigor are needed, and the development of new scoring systems may be justified. Primary Funding Source: Global Scholarship Programme for Research Excellence for 2014 to 2015, The Chinese University of Hong Kong. PMID- 27454311 TI - Altitudinal Patterns of Species Diversity and Phylogenetic Diversity across Temperate Mountain Forests of Northern China. AB - The spatial patterns of biodiversity and their underlying mechanisms have been an active area of research for a long time. In this study, a total of 63 samples (20m * 30m) were systematically established along elevation gradients on Mount Tai and Mount Lao, China. We explored altitudinal patterns of plant diversity in the two mountain systems. In order to understand the mechanisms driving current diversity patterns, we used phylogenetic approaches to detect the spatial patterns of phylogenetic diversity and phylogenetic structure along two elevation gradients. We found that total species richness had a monotonically decreasing pattern and tree richness had a unimodal pattern along the elevation gradients in the two study areas. However, altitudinal patterns in shrub richness and herbs richness were not consistent on the two mountains. At low elevation, anthropogenic disturbances contributed to the increase of plant diversity, especially for shrubs and herbs in understory layers, which are more sensitive to changes in microenvironment. The phylogenetic structure of plant communities exhibited an inverted hump-shaped pattern along the elevation gradient on Mount Tai, which demonstrates that environmental filtering is the main driver of plant community assembly at high and low elevations and inter-specific competition may be the main driver of plant community assembly in the middle elevations. However, the phylogenetic structure of plant communities did not display a clear pattern on Mount Lao where the climate is milder. Phylogenetic beta diversity and species beta diversity consistently increased with increasing altitudinal divergence in the two study areas. However, the altitudinal patterns of species richness did not completely mirror phylogenetic diversity patterns. Conservation areas should be selected taking into consideration the preservation of high species richness, while maximizing phylogenetic diversity to improve the potential for diversification in the future. PMID- 27454312 TI - Blocking by fixed and variable stimuli: Effects of stimulus distribution on blocking. AB - An experiment with rats compared the ability of fixed and variable duration cues to produce blocking. Rats in group B (Blocking) were trained that both fixed- (F) and variable- (V) duration cues would be followed by food delivery. In a subsequent training stage F and V continued to be reinforced, but F was accompanied by X, and V by Y. In the test phase responding to X and Y was examined. Control group O (Overshadowing) received identical treatment, except that F and V were nonreinforced in the first training stage. In group B there was evidence for blocking, but only of X, which had been conditioned in compound with the fixed-duration F; there was no evidence for blocking of Y, which had been conditioned in compound with the variable-duration V. It is suggested that this result may occur because fixed cues reach a higher, more stable asymptote of associative strength than do their variable equivalents. PMID- 27454313 TI - Association of miR-146a, miR-149, miR-196a2, and miR-499 Polymorphisms with Ossification of the Posterior Longitudinal Ligament of the Cervical Spine. AB - BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) of the spine is considered a multifactorial and polygenic disease. We aimed to investigate the association between four single nucleotide polymorphisms (SNPs) of pre-miRNAs [miR-146aC>G (rs2910164), miR-149T>C (rs2292832), miR-196a2T>C (rs11614913), and miR-499A>G (rs3746444)] and the risk of cervical OPLL in the Korean population. METHODS: The genotypic frequencies of these four SNPs were analyzed in 207 OPLL patients and 200 controls by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. FINDINGS: For four SNPs in pre-miRNAs, no significant differences were found between OPLL patients and controls. However, subgroup analysis based on OPLL subgroup (continuous: continuous type plus mixed type, segmental: segmental and localized type) showed that miR-499GG genotype was associated with an increased risk of segmental type OPLL (adjusted odds ratio = 4.314 with 95% confidence interval: 1.109-16.78). In addition, some allele combinations (C-T-T-G, G-T-T-A, and G-T-C-G of miR-146a/ 149/-196a2/-499) and combined genotypes (miR-149TC/miR-196a2TT) were associated with increased OPLL risk, whereas the G-T-T-G and G-C-C-G allele combinations were associated with decreased OPLL risk. CONCLUSION: The results indicate that GG genotype of miR-499 is associated with significantly higher risks of OPLL in the segmental OPLL group. The miR-146a/-149/-196a2/-499 allele combinations may be a genetic risk factor for cervical OPLL in the Korean population. PMID- 27454314 TI - Anticodon Modifications in the tRNA Set of LUCA and the Fundamental Regularity in the Standard Genetic Code. AB - Based on (i) an analysis of the regularities in the standard genetic code and (ii) comparative genomics of the anticodon modification machinery in the three branches of life, we derive the tRNA set and its anticodon modifications as it was present in LUCA. Previously we proposed that an early ancestor of LUCA contained a set of 23 tRNAs with unmodified anticodons that was capable of translating all 20 amino acids while reading 55 of the 61 sense codons of the standard genetic code (SGC). Here we use biochemical and genomic evidence to derive that LUCA contained a set of 44 or 45 tRNAs containing 2 or 3 modifications while reading 59 or 60 of the 61 sense codons. Subsequent tRNA modifications occurred independently in the Bacteria and Eucarya, while the Archaea have remained quite close to the tRNA set as it was present in LUCA. PMID- 27454315 TI - Alkalosis and Dialytic Clearance of Phosphate Increases Phosphatase Activity: A Hidden Consequence of Hemodialysis. AB - BACKGROUND: Extracellular pyrophosphate is a potent endogenous inhibitor of vascular calcification, which is degraded by alkaline phosphatase (ALP) and generated by hydrolysis of ATP via ectonucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1). ALP activity (as routinely measured in clinical practice) represents the maximal activity (in ideal conditions), but not the real activity (in normal or physiological conditions). For the first time, the present study investigated extracellular pyrophosphate metabolism during hemodialysis sessions (including its synthesis via eNPP1 and its degradation via ALP) in physiological conditions. METHODS AND FINDINGS: 45 patients in hemodialysis were studied. Physiological ALP activity represents only 4-6% of clinical activity. ALP activity increased post-hemodialysis by 2% under ideal conditions (87.4 +/- 3.3 IU/L vs. 89.3 +/- 3.6 IU/L) and 48% under physiological conditions (3.5 +/- 0.2 IU/L vs. 5.2 +/- 0.2 IU/L). Pyrophosphate synthesis by ATP hydrolysis remained unaltered post-hemodialysis. Post hemodialysis plasma pH (7.45 +/- 0.02) significantly increased compared with the pre-dialysis pH (7.26 +/- 0.02). The slight variation in pH (~0.2 units) induced a significant increase in ALP activity (9%). Addition of phosphate in post hemodialysis plasma significantly decreased ALP activity, although this effect was not observed with the addition of urea. Reduction in phosphate levels and increment in pH were significantly associated with an increase in physiological ALP activity post-hemodialysis. A decrease in plasma pyrophosphate levels (3.3 +/ 0.3 MUmol/L vs. 1.9 +/- 0.1 MUmol/L) and pyrophosphate/ATP ratio (1.9 +/- 0.2 vs. 1.4 +/- 0.1) post-hemodialysis was also observed. CONCLUSION: Extraction of uremic toxins, primarily phosphate and hydrogen ions, dramatically increases the ALP activity under physiological conditions. This hitherto unknown consequence of hemodialysis suggests a reinterpretation of the clinical value of this parameter. PMID- 27454316 TI - Blood Coagulation and Asthma Exacerbation in Children. AB - BACKGROUND: Recent studies have demonstrated the activation of coagulation pathways in asthmatic airways. This study aimed to determine systemic blood coagulation during asthma exacerbation compared with the stable state in children. METHODS: Pediatric patients (aged between 5 and 15 years) suffering from asthma exacerbation were enrolled. von Willebrand factor (vWF), plasminogen activator inhibitor type-1 (PAI-1), protein C, D-dimer, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), and C-reactive protein (CRP) levels were measured during asthma exacerbation and stable state. RESULTS: A total of 22 patients were enrolled. The median vWF, PAI-1, and CRP during asthma exacerbation were significantly higher than those of the stable state: 147.5% (interquartile range, IQR: 111.05-196.57) versus 94% (IQR: 69.72-109.62, p < 0.001), 41.9 ng/ml (IQR: 21.91-48.61) versus 26.17 ng/ml (IQR: 15.89-34.44, p < 0.03), and 4.46 mg/l (IQR: 2.15-16.23) versus 0.87 mg/l (IQR: 0.20-3.89, p < 0.015), respectively. However, the median protein C during asthma exacerbation was significantly lower than that of the stable state: 99.5% (IQR: 86.75-117) versus 113% (IQR: 94-115.25), p = 0.01. No significant difference was found between the levels of D-dimer, F1 + 2, and TAT during asthma exacerbation and stable state. Ultimately, D-dimer was positively correlated with asthma exacerbation score (R = 0.466, p = 0.027). A significant correlation was observed between vWF and CRP (R = 0.527, p = 0.012). CONCLUSION: Evidence was found of increased endothelial activation and increased PAI-1 during asthma exacerbation. This may emphasize the potential role of blood coagulation in asthma exacerbation. PMID- 27454317 TI - Electroporation-mediated delivery of the FER gene in the resolution of trauma related fatal pneumonia. AB - Injured patients with lung contusion (LC) are at risk of developing bacterial pneumonia (PNA) followed by sepsis and death. A recent genome-wide association study (GWAS) showed FER gene expression positively correlating with survival rates among individuals with above conditions. We sought to determine whether electroporation (EP)-mediated delivery of FER gene could indeed improve survival, in a lethal model of combined LC and PNA. C57BL/6 mice sustained unilateral LC, which preceded a 500 Klebsiella colony forming unit (CFU) inoculation by 6 h. In between these insults, human FER plasmid (pFER) was introduced into the lungs followed by eight EP pulses applied externally (10 ms at 200 V cm-1). Control groups included EP of empty vector (pcDNA3) or Na+/K+-ATPase genes (pPump) and no treatment (LC+PNA). We recorded survival, histology, lung mechanics, bronchial alveolar lavage (BAL) fluid, FER and inflammatory gene expression and bacteriology. The data show that 7-day survival was significantly improved by pFER compared with control groups. pFER increased BAL monocytes and activated antibacterial response genes (nitric oxide synthase (NOS), Fizz). pFER treatment showed decreased lung and blood Klebsiella counts reaching, in some cases, complete sterilization. In conclusion, FER gene delivery promoted survival in LC+PNA mice via recruitment of activated immune cells, improving efficiency of bacterial clearance within contused lung. PMID- 27454320 TI - An effective conjugation strategy for designing short peptide-based HIV-1 fusion inhibitors. AB - Lengthy peptides corresponding to the C-terminal heptad repeat (C-peptides) of human immunodeficiency virus type 1 (HIV-1) gp41 are potent inhibitors against virus-cell fusion. Designing short C-peptide-based HIV-1 fusion inhibitors could potentially redress the physicochemical and technical liabilities of a long peptide therapeutic. However, designing such inhibitors with high potency has been challenging. We generated a conjugated architecture by incorporating small molecule inhibitors of gp41 into the N-terminus of a panel of truncated C peptides. Among these small molecule-capped short peptides, the 26-residue peptide Indole-T26 inhibited HIV-1 Env-mediated cell-cell fusion and viral replication at low nanomolar levels, reaching the potency of the only clinically used 36-residue peptide T20 (enfuvirtide). Collectively, our work opens up a new avenue for developing short peptide-based HIV-1 fusion inhibitors, and may have broad applicability to the development of modulators of other class I fusion proteins. PMID- 27454319 TI - Optimized Fragmentation Regime for Diazirine Photo-Cross-Linked Peptides. AB - Cross-linking/mass spectrometry has evolved into a robust technology that reveals structural insights into proteins and protein complexes. We leverage a new tribrid instrument with improved fragmentation capacities in a systematic comparison to identify which fragmentation method would be best for the identification of cross-linked peptides. Specifically, we explored three fragmentation methods and two combinations: collision-induced dissociation (CID), beam-type CID (HCD), electron-transfer dissociation (ETD), ETciD, and EThcD. Trypsin-digested, SDA-cross-linked human serum albumin (HSA) served as a test sample, yielding over all methods and in triplicate analysis in total 2602 matched PSMs and 1390 linked residue pairs at 5% false discovery rate, as confirmed by the crystal structure. HCD wins in number of matched peptide spectrum-matches (958 PSMs) and identified links (446). CID is most complementary, increasing the number of identified links by 13% (58 links). HCD wins together with EThcD in cross-link site calling precision, with approximately 62% of sites having adjacent backbone cleavages that unambiguously locate the link in both peptides, without assuming any cross-linker preference for amino acids. Overall quality of spectra, as judged by sequence coverage of both peptides, is best for EThcD for the majority of peptides. Sequence coverage might be of particular importance for complex samples, for which we propose a data dependent decision tree, else HCD is the method of choice. The mass spectrometric raw data has been deposited in PRIDE (PXD003737). PMID- 27454318 TI - Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction. AB - Chronic transplant dysfunction (CTD) is the primary cause of late allograft loss in kidney transplantation. Indoleamine 2,3-dioxygenase (IDO) is involved in fetomaternal tolerance and IDO gene therapy inhibits acute rejection following kidney transplantation. The aim of this study is to investigate whether gene therapy with IDO is able to attenuate CTD. Transplantation was performed in a rat Dark-Agouti to Wistar-Furth CTD model. Donor kidneys were incubated either with an adenovirus carrying IDO gene, a control adenovirus or saline. During the first 10 days recipients received low-dose cyclosporine. Body weight, blood pressure, serum creatinine and proteinuria were measured every 2 weeks. Rats were killed after 12 weeks. IDO had a striking beneficial effect on transplant vasculopathy at week 12. It also significantly improved body weight gain; it reduced blood pressure and decreased proteinuria during the follow-up. However, it did not affect the kidney function. In addition, IDO therapy significantly decreased the number of graft-infiltrating macrophages at week 12. The messenger RNA levels of forkhead box p3 and transforming grow factor-beta were elevated in the IDO treated group at week 12. Here we show for first time a clear beneficial effect of local IDO gene therapy especially on transplant vasculopathy in a rat model of renal CTD. PMID- 27454322 TI - A Potential Solution to Make the Best Use of a Living Donor-Deceased Donor List Exchange. PMID- 27454321 TI - A Structural, Functional, and Computational Analysis of BshA, the First Enzyme in the Bacillithiol Biosynthesis Pathway. AB - Bacillithiol is a compound produced by several Gram-positive bacterial species, including the human pathogens Staphylococcus aureus and Bacillus anthracis. It is involved in maintaining cellular redox balance as well as the destruction of reactive oxygen species and harmful xenobiotic agents, including the antibiotic fosfomycin. BshA, BshB, and BshC are the enzymes involved in bacillithiol biosynthesis. BshA is a retaining glycosyltransferase responsible for the first committed step in bacillithiol production, namely the addition of N acetylglucosamine to l-malate. Retaining glycosyltransferases like BshA are proposed to utilize an SNi-like reaction mechanism in which leaving group departure and nucleophilic attack occur on the same face of the hexose. However, significant questions regarding the details of how BshA and similar enzymes accommodate their substrates and facilitate catalysis persist. Here we report X ray crystallographic structures of BshA from Bacillus subtilis 168 bound with UMP and/or GlcNAc-mal at resolutions of 2.15 and 2.02 A, respectively. These ligand bound structures, along with our functional and computational studies, provide clearer insight into how BshA and other retaining GT-B glycosyltransferases operate, corroborating the substrate-assisted, SNi-like reaction mechanism. The analyses presented herein can serve as the basis for the design of inhibitors capable of preventing bacillithiol production and, subsequently, help combat resistance to fosfomycin in various pathogenic Gram-positive microorganisms. PMID- 27454323 TI - WSSV envelope protein VP51B links structural protein complexes and may mediate virus infection. AB - White spot syndrome virus (WSSV), an enveloped double-stranded DNA virus, is the causative agent of a disease that has led to severe mortalities of cultured shrimps in Taiwan and many other countries. In the previous study, Penaeus monodon chitin-binding protein (CBP) and glucose transporter 1 (Glut1), two cell membrane proteins, were found to at least interact with other 10 WSSV envelope proteins including VP51B. These envelope proteins might form a protein complex. According to the known information, VP51B was used to identify its role in the protein complex. Western blotting of the intact viral particles and fractionation of the viral components confirmed that VP51B is one of WSSV envelope proteins. In this study, the protein-protein interaction between VP51B and other WSSV envelope proteins was identified by far-western blot experiment and VP51B was found to interact with VP24, VP31, VP32, VP39B and VP41A. Furthermore, the in vivo neutralization experiment using recombinant VP51B plus with VP39B showed the best inhibition. These data indicate that VP51B participates in the WSSV protein complex and plays an important role in WSSV infection. PMID- 27454324 TI - Ovarian and tubal cancer in Denmark: an update on incidence and survival. AB - INTRODUCTION: The Nordic countries are areas with a high-incidence of ovarian cancer; however, differences between the countries exist. MATERIAL AND METHODS: We used the Danish Cancer Registry to identify 11 264 cases of ovarian cancer and 363 cases of tubal cancer during 1993-2013. We calculated age-standardized (world standard population) incidence rates for overall and subtype-specific ovarian cancer, and for tubal cancer. We compared age-standardized incidence rates, and 1 and 5-year age-standardized relative survival rates, respectively, for ovarian and tubal cancer combined in four Nordic countries using the NORDCAN database. RESULTS: The incidence rate of ovarian cancer overall in Denmark decreased statistically significantly by approximately 2.3% per year among women aged <70 years, whereas no change was seen among women aged 70+ years. In the <70-year age group, the incidence of serous tumors was fairly steady, whereas that of other and unspecified epithelial tumors decreased significantly by 6.4% per year. The incidence of tubal cancer was quite stable. In Norway and Finland, the incidence rates of ovarian and tubal cancer combined decreased from 1993 to 2013 in women aged <70 years, whereas in Sweden the incidence rates decreased independently of age. The 1- and 5-year relative survival rates of ovarian and tubal cancer combined increased during the study period in all the Nordic countries. Denmark had the lowest survival; however, the survival rates approached those of the other countries in recent years. CONCLUSIONS: In Denmark, the positive development in ovarian cancer has continued during recent years with a lower incidence and an increased survival. PMID- 27454325 TI - Association of Sasang Constitutional Types with Incident Hypertension: A 12-Year Follow-Up Study. AB - OBJECTIVES: Sasang constitutional types (SCTs) are four distinct classifications of people based on physiologic and physical characteristics. The different types have been reported to have different disease susceptibility, but there are no studies reporting the association of SCT and hypertension (HTN) over a long-term follow-up period. This study prospectively investigated the association between SCT and incidence of HTN. DESIGN: This was a prospective study in a population based cohort study in Korea. SUBJECTS: Data from two independent population-based cohorts that are embedded within the Korean Genome and Epidemiology Study were used. A total of 2083 subjects who were free of HTN at baseline were selected for the analysis. OUTCOME MEASURES: HTN was diagnosed as systolic blood pressure (BP) >=140 mmHg and diastolic BP >=90 mmHg, use of antihypertensive medication, or diagnosis by doctor. The SCTs were classified using an integrated diagnostic method that included facial features, body shape, voice, and questionnaire responses. The association between the SCT and the incidence of HTN was investigated by Cox proportional hazard regression analysis and calculation of estimated survival functions. RESULTS: The Tae-eum (TE) type showed a significantly increased risk for HTN (hazard ratio [HR] = 1.55, 95% confidence interval [CI] 1.15-2.10; p = 0.005), even after adjusting for all possible confounders. In a stratified analysis by body mass index (BMI) conducted only in the TE type, even those in the TE type with normal BMI had a significantly higher risk for HTN (HR = 1.47, 95% CI 1.07-2.03; p = 0.016). Furthermore, survival analysis showed that the TE type had a higher rate of developing HTN than the So eum and So-yang types had, regardless of obesity status. CONCLUSIONS: These results show that the TE type is an independent risk factor for HTN. Thus, early prevention and treatment for HTN in this type are needed. PMID- 27454326 TI - The oligodendrocyte-specific antibody 'CC1' binds Quaking 7. AB - The mouse monoclonal antibody marketed as anti-adenomatous polyposis coli clone CC1, often referred to as CC1, is the antibody most commonly used to specifically label mature oligodendrocytes without labeling myelin. Previous studies have shown that despite being raised against adenomatous polyposis coli, this antibody binds another unknown antigen. We show that the CC1 antibody binds Quaking 7, an RNA-binding protein that is highly up-regulated in myelinating oligodendrocytes in the central nervous system. The monoclonal antibody anti-adenomatous polyposis coli (APC) clone CC1, is the antibody most commonly used to specifically label the cell bodies of mature oligodendrocytes. Despite being raised against APC, previous studies showed this antibody binds another unknown antigen. We show that the CC1 antibody binds Quaking (QKI) 7, an RNA-binding protein which is highly up regulated in myelinating oligodendrocytes. PMID- 27454327 TI - Informatics-Based Energy Fitting Scheme for Correlation Energy at Complete Basis Set Limit. AB - Energy fitting schemes based on informatics techniques using hierarchical basis sets with small cardinal numbers were numerically investigated to estimate correlation energies at the complete basis set limits. Numerical validations confirmed that the conventional two-point extrapolation models can be unified into a simple formula with optimal parameters obtained by the same test sets. The extrapolation model was extended to two-point fitting models by a relaxation of the relationship between the extrapolation coefficients or a change of the fitting formula. Furthermore, n-scheme fitting models were developed by the combinations of results calculated at several theory levels and basis sets to compensate for the deficiencies in the fitting model at one level of theory. Systematic assessments on the Gaussian-3X and Gaussian-2 sets revealed that the fitting models drastically reduced errors with equal or smaller computational effort. (c) 2016 Wiley Periodicals, Inc. PMID- 27454329 TI - Use of a linear stapler for the treatment of ileocolic fistula in Crohn's disease. AB - AIM: The study reports an easy technique for surgical management of some forms of ileocolic fistula in Crohn's disease. METHOD: Five patients with Crohn's disease with ileocolic fistula (2011-2014) have been managed by the application of linear stapler devices. RESULTS: Postoperative course was satisfactory in all patients. At 1 year there was no evidence of stricture or fistula formation and no patient had required reoperation. CONCLUSION: The technique is easy and effective and can be used in open and laparoscopic surgery. PMID- 27454330 TI - Occipital and occipital "plus" epilepsies: A study of involved epileptogenic networks through SEEG quantification. AB - Compared with temporal or frontal lobe epilepsies, the occipital lobe epilepsies (OLE) remain poorly characterized. In this study, we aimed at classifying the ictal networks involving OLE and investigated clinical features of the OLE network subtypes. We studied 194 seizures from 29 consecutive patients presenting with OLE and investigated by stereoelectroencephalography (SEEG). Epileptogenicity of occipital and extraoccipital regions was quantified according to the 'epileptogenicity index' (EI) method. We found that 79% of patients showed widespread epileptogenic zone organization, involving parietal or temporal regions in addition to the occipital lobe. Two main groups of epileptogenic zone organization within occipital lobe seizures were identified: a pure occipital group and an occipital "plus" group, the latter including two further subgroups, occipitotemporal and occipitoparietal. In 29% of patients, the epileptogenic zone was found to have a bilateral organization. The most epileptogenic structure was the fusiform gyrus (mean EI: 0.53). Surgery was proposed in 18/29 patients, leading to seizure freedom in 55% (Engel Class I). Results suggest that, in patient candidates for surgery, the majority of cases are characterized by complex organization of the EZ, corresponding to the occipital plus group. PMID- 27454331 TI - Development of the PedsQLTM Epilepsy Module: Focus group and cognitive interviews. AB - Youth with epilepsy have impaired health-related quality of life (HRQOL). Existing epilepsy-specific HRQOL measures are limited by not having parallel self and parent-proxy versions, having a restricted age range, not being inclusive of children with developmental disabilities, or being too lengthy for use in a clinical setting. Generic HRQOL measures do not adequately capture the idiosyncrasies of epilepsy. The purpose of the present study was to develop items and content validity for the PedsQLTM Epilepsy Module. METHODS: An iterative qualitative process of conducting focus group interviews with families of children with epilepsy, obtaining expert input, and conducting cognitive interviews and debriefing was utilized to develop empirically derived content for the instrument. Eleven health providers with expertise in pediatric epilepsy from across the country provided feedback on the conceptual model and content, including epileptologists, nurse practitioners, social workers, and psychologists. Ten pediatric patients (age 4-16years) with a diagnosis of epilepsy and 11 parents participated in focus groups. Thirteen pediatric patients (age 5-17years) and 17 parents participated in cognitive interviews. RESULTS: Focus groups, expert input, and cognitive debriefing resulted in 6 final domains including restrictions, seizure management, cognitive/executive functioning, social, sleep/fatigue, and mood/behavior. Patient self-report versions ranged from 30 to 33 items and parent proxy-report versions ranged from 26 to 33 items, with the toddler and young child versions having fewer items. CONCLUSIONS: Standardized qualitative methodology was employed to develop the items and content for the novel PedsQLTM Epilepsy Module. The PedsQLTM Epilepsy Module has the potential to enhance clinical decision-making in pediatric epilepsy by capturing and monitoring important patient-identified contributors to HRQOL. PMID- 27454332 TI - Automated non-EEG based seizure detection: Do users have a say? AB - PURPOSE: Quality of life of patients with epilepsy depends largely upon unpredictability of seizure occurrence and would improve by predicting seizures or at least by detecting seizures (after their clinical onset) and react timely. Detection systems are available and researched, but little is known about the actual need and user preferences. The first indicates the market potential; the second allows us to incorporate user requirements into the engineering process. METHODS: We questioned 20 pediatric and young adult patients, 114 caregivers, and 21 involved medical doctors and described, analyzed, and compared their experiences with systems for seizure detection, their opinions on usefulness and purpose of seizure detection, and their requirements for such a device. RESULTS: Experience with detection systems is limited, but 65% of patients and caregivers and 85% of medical doctors express the usefulness, more so during night than day. The need is higher in patients with more severe intellectual disability. The higher the seizure frequency, the higher the need, opinions in the seizure-free group being more divided. Most patients and caregivers require 100% correct detection, and on average, one false alarm per seizure (one per week for those seizure-free) is accepted. Medical doctors allow 90% correct detections and between two false alarms per week and one per month depending on seizure frequency. Detection of seizures involving heavy movement and falls is judged most important by patients and caregivers and second to most by medical doctors. The latter judge heart rate monitoring most relevant, both towards seizure detection and SUDEP (sudden unexpected death in epilepsy) prevention. CONCLUSIONS: The results, including a goal of 90% correct detections and one false alarm per seizure, should be considered in development of seizure detectors. PMID- 27454333 TI - Impact of gendered ingroup/outgroup ostracism on women's academic performances. AB - This study investigated the impact of ostracism (vs. inclusion) for women in a same-sex vs. opposite-sex group on their cognitive performances. Female participants played Cyberball with other women or men and were either included or excluded. Participants then had to engage in the performance tasks. Results showed that women's performance was decreased by ostracism in a math task (but not a verbal task) yet only in the same-sex condition. Furthermore, this result was obtained only among participants who did the numeric task first. No effect was observed in the verbal task. Two replications of the initial study were conducted using the math task. The result of the first study has been replicated one time. A meta-analysis revealed a small effect of ostracism on performance in the ingroup condition, whereas the effect seems to be non-existent in the outgroup condition. Results are discussed and future perspectives are proposed. PMID- 27454334 TI - Carbon Nanotube Thin-Film Antennas. AB - Multiwalled carbon nanotube (MWCNT) and single-walled carbon nanotube (SWCNT) dipole antennas have been successfully designed, fabricated, and tested. Antennas of varying lengths were fabricated using flexible bulk MWCNT sheet material and evaluated to confirm the validity of a full-wave antenna design equation. The ~20* improvement in electrical conductivity provided by chemically doped SWCNT thin films over MWCNT sheets presents an opportunity for the fabrication of thin film antennas, leading to potentially simplified system integration and optical transparency. The resonance characteristics of a fabricated chlorosulfonic acid doped SWCNT thin-film antenna demonstrate the feasibility of the technology and indicate that when the sheet resistance of the thin film is >40 ohm/sq no power is absorbed by the antenna and that a sheet resistance of <10 ohm/sq is needed to achieve a 10 dB return loss in the unbalanced antenna. The dependence of the return loss performance on the SWCNT sheet resistance is consistent with unbalanced metal, metal oxide, and other CNT-based thin-film antennas, and it provides a framework for which other thin-film antennas can be designed. PMID- 27454335 TI - Global Efforts in the Development of Vaccines for Tuberculosis: Requirements for Improved Vaccines Against Mycobacterium tuberculosis. AB - Currently, more than 9.0 million people develop acute pulmonary tuberculosis (TB) each year and about 1.5 million people worldwide die from this infection. Thus, developing vaccines to prevent active TB disease remains a priority. This article discusses recent progress in the development of new vaccines against TB and focusses on the main requirements for development of improved vaccines against Mycobacterium tuberculosis (M. tb). Over the last two decades, significant progress has been made in TB vaccine development, and some TB vaccine candidates have currently completed a phase III clinical trial. The potential public health benefits of these vaccines are possible, but it will need much more effort, including new global governance investment on this research. This investment would certainly be less than the annual global financial toll of TB treatment. PMID- 27454336 TI - Analysis of Intrinsic Peptide Detectability via Integrated Label-Free and SRM Based Absolute Quantitative Proteomics. AB - Quantitative mass spectrometry-based proteomics of complex biological samples remains challenging in part due to the variability and charge competition arising during electrospray ionization (ESI) of peptides and the subsequent transfer and detection of ions. These issues preclude direct quantification from signal intensity alone in the absence of a standard. A deeper understanding of the governing principles of peptide ionization and exploitation of the inherent ionization and detection parameters of individual peptides is thus of great value. Here, using the yeast proteome as a model system, we establish the concept of peptide F-factor as a measure of detectability, closely related to ionization efficiency. F-factor is calculated by normalizing peptide precursor ion intensity by absolute abundance of the parent protein. We investigated F-factor characteristics in different shotgun proteomics experiments, including across multiple ESI-based LC-MS platforms. We show that F-factors mirror previously observed physicochemical predictors as peptide detectability but demonstrate a nonlinear relationship between hydrophobicity and peptide detectability. Similarly, we use F-factors to show how peptide ion coelution adversely affects detectability and ionization. We suggest that F-factors have great utility for understanding peptide detectability and gas-phase ion chemistry in complex peptide mixtures, selection of surrogate peptides in targeted MS studies, and for calibration of peptide ion signal in label-free workflows. Data are available via ProteomeXchange with identifier PXD003472. PMID- 27454337 TI - Controllable synthesis of self-assembly Co3O4 nanoflake microspheres for electrochemical performance. AB - Tuning the ratios of ethanol to water, self-assembling microspheres composed of Co3O4 nanoflakes are synthesized by the hydrothermal method. The scanning electron microscopy (SEM) images of as-grown samples obviously show that the dispersive multilayered structures gradually change into micro/nanobelts and cubic blocks structures, and then into the desired self-assembled microspheres with increasing ratios of ethanol to water. Also, all the x-ray diffraction (XRD) patterns evidently demonstrate that all obtained Co3O4 has cubic crystal structure. The corresponding synthesis mechanism is discussed in detail. More importantly, the unique self-assembling Co3O4 nanoflake microspheres have excellent electrochemical performance with large specific capacitance, good rate capability and excellent cycling performance, evidently presenting a potential capability of Co3O4 nanoflake microspheres to act as electrode materials for supercapacitors in sustainable power sources. PMID- 27454338 TI - Family-based social determinants and child health: Cross-sectional study. AB - BACKGROUND: The aim of this study was to evaluate the association between urbanization of residential area, parent education level, employment status, overweight/obesity, physical activity, and exposure to environmental tobacco smoke (ETS), in a sample of healthy Italian school-age children (5-11 years). METHODS: A cross-sectional study was conducted on 432 children resident, respectively, in a highly urban and in a rural area (Latium Region) in 2014. Information on children and families were obtained via questionnaire. RESULTS: One-third of children were overweight or obese, 15% did not participate in any sport outside school, and more than one-third were exposed to ETS in the domestic environment. Living in a rural area (adjusted OR, 2.55; 95%CI: 1.18-5.52) and lower maternal education (adjusted OR, 2.32; 95%CI: 1.03-5.27) were significant predictors of overweight/obese status. Moreover, lower maternal education level (adjusted OR, 2.74; 95%CI: 1.40-5.33) and paternal education level (adjusted OR, 3.06; 95%CI: 1.54-6.07) were significant predictors of ETS exposure. CONCLUSIONS: It is essential to investigate the reasons underlying the higher frequency of overweight/obesity in children living in rural environments compared with those in urban areas; and preventative actions should be designed to be easily understood by those with lower education levels. PMID- 27454339 TI - Effects of Surface Conditions of Titanium Dental Implants on Bacterial Adhesion. AB - OBJECTIVE: The study is to evaluate the effect of surface roughness of titanium implants on bacterial adhesion and then to investigate the efficacy of the three cleaning treatments for bacterial removal in titanium surfaces. BACKGROUND DATA: Although surface debridement is the basic element for treatment of peri implantitis to reduce bacterial adhesion, adjunctive therapies such as antiseptics and laser debridement have been proposed to improve the nonsurgical treatment options of the peri-implant infection. METHODS: Titanium specimens were divided into five groups: No. 1200 grit sandpaper polishing (Grit), 50 MUm (SB50), 100 MUm (SB100), and 250 MUm Al2O3 sandblasting (SB250), and sandblasting, large-grit, and acid-etching (SLA). Surface roughness (Ra), contact angle, and surface morphology were examined. The subsequent adhesion of Escherichia coli on the different substrates was assayed. After 8 h of bacterial culture, three different cleaning treatments, including plastic curettage, air powder abrasive system, and Er:YAG laser debridement, were applied on the specimens. RESULTS: The Ra value changed from the lower value of 0.2 MUm for the Grit group to the significantly higher value of 2.7 MUm for the SB250 group, indicating a significant difference from the SLA group (2.0 MUm). The average contact angle of SLA (101 degrees ) was significantly higher than the other groups. No significant difference in E. coli bacterial adhesion was found among the all roughened groups, except the SB50 and SB250 groups at 12 h of culture. The use of three cleaning treatments did not induce significant surface alterations. However, the E. coli adhesion was significantly reduced in the air powder abrasive system and laser debridement in comparison with that treated with the plastic curettage. CONCLUSIONS: Laser debridement could be a useful cleaning method for peri-implantitis therapy. PMID- 27454340 TI - Azide Tripodal Dendrons from Behera's Amine and Their Clicked Dendrimers. AB - Diazo transfer reactions on Behera's amine and its next-generation analogue formed G0 and G1 azide dendrons bearing three and nine tert-butyl-protected esters, respectively. The utility of the new dendrons was demonstrated by copper catalyzed azide-alkyne cycloaddition, with 1,3,5-triethynylbenzene, forming two novel dendrimers in a convergent manner. Acid-mediated dendrimer deprotection was successful, and the resulting carboxy-terminated dendrimers were analyzed by NMR and DOSY experiments. PMID- 27454341 TI - A cancer care electronic medical record highly integrated into clinicians' workflow: users' attitudes pre-post implementation. AB - The purpose was to study users' attitudes towards an electronic medical record (EMR) closely integrated into the clinicians' cancer care workflow. The EMR, implemented in an ambulatory cancer care centre, was designed as a care pathway information system providing real-time support to the coordination of shared care processes involving all the care personnel. Mixed method pre-post study design was used. The study population consisted of all care personnel. A survey measured the quality attributes of the EMR, the clinical information it produces, the perceived usefulness of the system for supporting clinical data management tasks and the perceived impacts in terms of access and quality of care. The survey shows that users' attitudes towards the EMR (response rate of 71%) measured after the go-live were positive ranging from 3.42 to 3.95 on a 5-point scale. Besides, the content analysis of 33 pre-post interviews revealed five main themes: magnitude of the changes caused by the EMR; its innovative potential; its positive benefits; an ongoing growth in users' expectancies; and the burden associated with the time required to operate the EMR. In sum, the study shows that users can largely apply innovative uses of information technologies that automate their clinical processes. PMID- 27454342 TI - Prenatal Earthquake Exposure and Midlife Uric Acid Levels Among Chinese Adults. AB - OBJECTIVE: To test whether prenatal exposure to earthquake (as a surrogate for acute prenatal stress) could have unfavorable effects on uric acid levels later in life. METHODS: We included 536 individuals who had been prenatally exposed to the Tangshan earthquake in 1976, and 536 sex- and age-matched individuals without that exposure. Serum uric acid concentrations were measured based on fasting blood samples, which were repeatedly collected in 2006, 2008, and 2010. Mean uric acid concentrations in 2010 and the increasing rate from 2006 to 2010 were compared between the 2 groups, after adjustment for age, sex, body mass index, serum concentrations of glucose, triglycerides, C-reactive protein level, estimated glomerular filtration rate, and other potential confounders. We also used multiple logistic regression to estimate the risk of hyperuricemia (>416 MUmole/liter in men or >357 MUmole/liter in women) in 2010 by calculating the odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjustment for the previously mentioned covariates. RESULTS: Participants with prenatal exposure to the earthquake had higher concentrations of serum uric acid (adjusted means 315 MUmole/liter versus 296 MUmole/liter; P = 0.001) and a higher likelihood of having hyperuricemia (multivariate adjusted OR 1.70 [95% CI 1.09-2.66]) in 2010 relative to those without the exposure. Prenatal exposure to the earthquake was consistently significantly associated with a faster increase in uric acid concentration from 2006 to 2010 (P < 0.001). CONCLUSION: Prenatal exposure to the earthquake was associated with higher serum uric acid and higher odds of hyperuricemia in early adulthood. PMID- 27454343 TI - Regulation of SATB1 during thymocyte development by TCR signaling. AB - T lymphocyte development and differentiation is a multi-step process that begins in the thymus and completed in the periphery. Sequential development of thymocytes is dependent on T cell receptor (TCR) signaling and an array of transcription factors. In this study we show that special AT-rich binding protein 1 (SATB1), a T lineage-enriched chromatin organizer and regulator, is induced in response to TCR signaling during early thymocyte development. SATB1 expression profile coincides with T lineage commitment and upregulation of SATB1 correlates with positive selection of thymocytes. CD4 thymocytes exhibit a characteristic bimodal expression pattern that corresponds to immature and mature CD4 thymocytes. We also demonstrate that GATA3, the key transcriptional regulator of alphabeta T cells positively regulates SATB1 expression in thymocytes suggesting an important role for SATB1 during T cell development. PMID- 27454344 TI - Induction of transcription factors, miRNAs and cytokines involved in T lymphocyte differentiation in BCG-vaccinated subjects. AB - The BCG vaccine induces a Th1 phenotype, which is essential for protection against Mycobacterium tuberculosis. However, the effects of BCG vaccination over time on the T helper subpopulation and the microRNAs involved in adulthood have not been studied. In the present study, we explored the involvement of microRNAs, transcription factors and multifunctional cytokines in BCG vaccination by examining their levels both before and after vaccination of healthy adults. Peripheral blood mononuclear cells were obtained at 0, 2 and 6 months after vaccination. Cells were cultured in the presence or absence of ESAT-6 and CFP-10 or M. tuberculosis filtrate. The expression levels of miRNAs and transcription factors were evaluated using qRT-PCR. Cytokine production in supernatants and serum samples was evaluated using ELISA. Multifunctional CD4+ T cells were analyzed using multiparametric flow cytometry. We observed a decrease in the expression levels of T-BET, GATA3 and FOXP3 at 2 months and miR-146a, miR-326 and miR-155 at 6 months after receiving the vaccine. In the supernatant, the production of IL-17 was increased after 6 months, with both stimuli. In contrast, IL-10, TNF-alpha and IFN-gamma increased at 2 months. In the serum, high levels of IL-10 were found after 2 months compared to time 0 and 6 months. The production of multifunctional cells that expressed the cytokine profiles CD4+TNF alpha+IFN-gamma-IL-10-, CD4+TNF-alpha+IL-1IFN-gamma-, CD4+IL-10+IFN-gamma-TNF alpha- and CD4+IL-17+IFN-gamma- predominantly increased after 2 months with and without the stimulus. Correlation analysis revealed a negative association between FOXP3 and miR-155 (r=-0.5120, p=0.0176) and between IL-17 and miR-326 (r= 0.5832, p=0.0364). This study is the first to demonstrate roles for microRNAs, transcription factors and cytokines in the T helper differentiation lineage and to describe the possible mechanism by which their expression is modulated by the presence of the BCG vaccine in adulthood. In conclusion, our results suggest that the BCG vaccine induces a modulation in transcription factors and miRNAs with high production of multifunctional cells CD4+TNF-alpha+IL-10+IFN-gamma-. PMID- 27454345 TI - Image-guided simulation of tissue deformation using a mechanical model on a surgical application. AB - This paper presents a method for localizing the position of a liver and a tumor within the tissue during a minimally invasive liver operation. From pre-operative CT scans, the liver volume and its internal structures are segmented using image processing techniques. Based on these segmentations, a three-dimensional mechanical model is built to compute the liver volume and internal structure displacement under boundary conditions such as external forces from the surgical instrument. This can help the surgeon understand the motion of internal structures when manipulating the liver. To validate our method, an experiment on a porcine liver explant was performed to assess the difference between actual tissue motion and the mechanical model. PMID- 27454346 TI - Differences in Intestinal Hydrolytic Activities between Cynomolgus Monkeys and Humans: Evaluation of Substrate Specificities Using Recombinant Carboxylesterase 2 Isozymes. AB - Cynomolgus monkeys, used as an animal model to predict human pharmacokinetics, occasionally show different oral absorption patterns to humans due to differences in their intestinal metabolism. In this study, we investigated the differences between intestinal hydrolytic activities in cynomolgus monkeys and humans, in particular the catalyzing activities of their carboxylesterase 2 (CES2) isozymes. For this purpose we used both human and monkey microsomes and recombinant enzymes derived from a cell culture system. Monkey intestinal microsomes showed lower hydrolytic activity than human microsomes for several substrates. Interestingly, in contrast to human intestinal hydrolysis, which is not enantioselective, monkey intestine showed preferential R-form hydrolysis of propranolol derivatives. Recombinant CES2 isozymes from both species, mfCES2v3 from monkeys and human hCE2, showed similar metabolic properties to their intestinal microsomes when expressed in HEK293 cells. Recombinant hCE2 and mfCES2v3 showed similar Km values for both enantiomers of all propranolol derivatives tested. However, recombinant mfCES2v3 showed extreme R-enantioselective hydrolysis, and both hCE2 and mfCES2v3 showed lower activity for O-3-methyl-n-butyryl propranolol than for O-n-valeryl and O-2-methyl-n-butyryl propranolol. This lower hydrolytic activity was characterized by lower Vmax values. Docking simulations of the protein-ligand complex demonstrated that the enantioselectivity of mfCES2v3 for propranolol derivatives was possibly caused by the orientation of its active site being deformed by an amino acid change of Leu107 to Gln107 and the insertion of Met309, compared with hCE2. In addition, molecular dynamics simulation indicated the possibility that the interatomic distance between the catalytic triad and the substrate was elongated by a 3-positioned methyl in the propranolol derivatives. Overall, these findings will help us to understand the differences in intestinal hydrolytic activities between cynomolgus monkeys and humans. PMID- 27454347 TI - Imaging of neuronal mitochondria in situ. AB - Neuronal mitochondria are receiving a rapidly increasing level of attention. This is to a significant part due to the ability to visualize neuronal mitochondria in novel ways, especially in vivo. Such an approach allows studying neuronal mitochondria in an intact tissue context, during different developmental states and in various genetic backgrounds and disease conditions. Hence, in vivo imaging of mitochondria in the nervous system can reveal aspects of the 'mitochondrial life cycle' in neurons that hitherto have remained obscure or could only be inferred indirectly. In this survey of the current literature, we review the new insights that have emerged from studies using mitochondrial imaging in intact neural preparations ranging from worms to mice. PMID- 27454348 TI - Neonatal uterine bleeding as a biomarker for reproductive disorders during adolescence: a worldwide call for systematic registration by nurse midwife. AB - Neonatal uterine bleeding (NUB) occurs in approximately 5% of newborns and is generally considered to be of little clinical significance. However, the real clinical importance of this condition and its long-term implications remain to be determined. The reason why NUB is rare despite high circulating levels of progesterone can be attributed to a progesterone resistance present in a majority of neonates. Recent work indicates that NUB represents a significant biomarker for events that can occur later-on during adolescence. Indeed, clinical studies have shown that "neonatal menstruation" constitutes a sign of fetal distress during late pregnancy, reflecting a stage of endometrium development that may subsequently have an impact on the reproductive life of the adolescent and the young adult. Via retrograde flow, NUB can cause endometrial stem/progenitor cells to arrive into the pelvic cavity and survive there, dormant underneath the peritoneal surface, until menarche activates them. Indeed, there is both clinical and epidemiological evidence of a link between NUB and adolescent endometriosis. In addition, if progesterone resistance persists till the onset of menarche, in case of an early teen pregnancy, it can result in a disorder of deep placentation. Therefore, we propose that NUB should be carefully recorded so that prospective studies can examine its links with reproductive disorders in adolescence and beyond. PMID- 27454349 TI - Vitamin D receptor 2016: novel ligands and structural insights. AB - INTRODUCTION: Vitamin D3 activates via its hormonal form 1alpha,25 dihydroxyvitamin D3 (1alpha,25(OH)2D3), the transcription factor vitamin D receptor (VDR). VDR is expressed in most human tissues and has more than 1,000 target genes. Thus, 1alpha,25(OH)2D3 and its synthetic analogs have a broad physiological impact. The crystal structures of the VDR ligand-binding domain (LBD), and its various ligands, allows further the understanding of the receptor's molecular actions. Areas covered: We discuss the most important novel VDR ligands and the further insight derived from new structural information on VDR. Expert opinion: There is an increasing appreciation of the impact of vitamin D and its receptor VDR not only in bone biology, but also for metabolic diseases, immunological disorders, and cancer. Detailed structural analysis of the interaction of additional novel ligands with VDR highlight helices 6 and 7 of the LBD as being most critical for stabilizing the receptor for an efficient interaction with co-activator proteins, i.e. for efficient agonistic action. This permits the design of even more effective VDR agonists. In addition, chemists took more liberty in replacing major parts of the 1alpha,25(OH)2D3 molecule, such as the A- and CD-rings or the side chain, with significantly different structures, such as carboranes, and still obtained functional VDR agonists. PMID- 27454350 TI - Growth of GaN micro/nanolaser arrays by chemical vapor deposition. AB - Optically pumped ultraviolet lasing at room temperature based on GaN microwire arrays with Fabry-Perot cavities is demonstrated. GaN microwires have been grown perpendicularly on c-GaN/sapphire substrates through simple catalyst-free chemical vapor deposition. The GaN microwires are [0001] oriented single-crystal structures with hexagonal cross sections, each with a diameter of ~1 MUm and a length of ~15 MUm. A possible growth mechanism of the vertical GaN microwire arrays is proposed. Furthermore, we report room-temperature lasing in optically pumped GaN microwire arrays based on the Fabry-Perot cavity. Photoluminescence spectra exhibit lasing typically at 372 nm with an excitation threshold of 410 kW cm(-2). The result indicates that these aligned GaN microwire arrays may offer promising prospects for ultraviolet-emitting micro/nanodevices. PMID- 27454351 TI - Stabilization of Overweight and Obesity in Slovenian Adolescents and Increased Risk in Those Entering Non-Grammar Secondary Schools. AB - BACKGROUND/AIM: To estimate overweight and obesity prevalence trends in Slovenian adolescents entering secondary schools in the years 2004, 2009 and 2014 and differences in the prevalence between different types of secondary schools. METHODS: Data from 17,538 adolescents entering secondary schools (mean age +/- standard deviation 15.4 +/- 0.5 years) collected during obligatory medical examination in years 2004, 2009 and 2014 was analyzed. Overweight and obesity were defined using International Obesity Task Force criteria. RESULTS: In 2004 2009 overweight and obesity prevalence increased, especially in males and stabilized thereafter (2009-2014) in both genders. It was significantly higher (p < 0.0001) in those attending secondary vocational and technical/professional versus grammar schools (2009; 28.7 vs. 16.8% overweight females and 31.6 vs. 22.3% overweight males; 2014: 29.7 vs. 17.9% overweight females and 33.6 vs. 20.4% overweight males). CONCLUSIONS: Overweight and obesity prevalence in Slovenian adolescents entering secondary schools stabilized recently. Adolescents attending secondary vocational and technical/professional schools are at an increased risk of overweight and obesity. PMID- 27454352 TI - Detection of 2-hydroxyglutarate in brain tumors by triple-refocusing MR spectroscopy at 3T in vivo. AB - PURPOSE: To test the efficacy of triple-refocusing MR spectroscopy (MRS) for improved detection of 2-hydroxyglutarate (2HG) in brain tumors at 3T in vivo. METHODS: The triple-refocusing sequence parameters were tailored at 3T, with density-matrix simulations and phantom validation, for enhancing the 2HG 2.25-ppm signal selectivity with respect to the adjacent resonances of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA). In vivo MRS data were acquired from 15 glioma patients and analyzed with LCModel using calculated basis spectra. Metabolites were quantified with reference to water. RESULTS: A triple refocusing sequence (echo time = 137 ms) was obtained for 2HG detection. The 2HG 2.25-ppm signal was large and narrow while the Glu and Gln signals between 2.2 and 2.3 ppm were minimal. The optimized triple refocusing offered improved separation of 2HG from Glu, Gln and GABA when compared with published MRS methods. 2HG was detected in all 15 patients, the estimated 2HG concentrations ranging from 2.4 to 15.0 mM, with Cramer-Rao lower bounds of 2%-11%. The 2HG estimates did not show significant correlation with total choline. CONCLUSION: The optimized triple refocusing provides excellent 2HG signal discrimination from adjacent resonances and may confer reliable in vivo measurement of 2HG at relatively low concentrations. Magn Reson Med 78:40-48, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27454353 TI - A preliminary evaluation of synthetic cannabinoid use among adolescent cannabis users: Characteristics and treatment outcomes. AB - Little is known regarding the use of synthetic cannabinoids (SC), particularly use among adolescent substance users who may be at higher risk. The present exploratory study seeks to describe SC use and subjective effects among cannabis using adolescents as well as compare the characteristics of cannabis users who do and do not use SC. Exploratory analyses evaluated cannabis treatment outcomes among SC users and non-users. Participants enrolled in a randomized, controlled intervention for cannabis-using high school students aged 14-19 (N=252) completed questionnaires regarding their use of SC and other substances. Those who used SC in the past 60days reported subjective effects of SC, consequences, and SC use disorder symptoms. Baseline characteristics, alcohol and other drug use, and treatment outcomes of SC users were compared to participants who never tried SC. Within this sample 29% had tried SC, and 6% used SC recently. Although most reported use at a relatively low rate, 43% of recent SC users reported SC use disorder symptoms. Positive and negative subjective effects of SC were endorsed, with positive subjective effects reported more often. SC use was associated with more cannabis use, but not more alcohol or other (non-SC and non-cannabis) drug use. SC users did not differ from non-users on cannabis treatment outcomes. This exploratory study described SC use, and compared characteristics and treatment outcomes among SC users and non-users. Negative subjective effects of SC were reported as occurring less often, but SC use was associated with use disorder psychopathology. SC use was associated with more problematic cannabis use at baseline, but was not associated with use of other substances or differences in treatment outcome. PMID- 27454355 TI - Animal models for cancer cachexia. AB - PURPOSE OF REVIEW: Cancer cachexia is a frequent syndrome that affects patient quality of life, anticancer treatment effectiveness, and overall survival. The lack of anticancer cachexia therapies likely relies on the complexity of the syndrome that renders difficult to design appropriate clinical trials and, conversely, on the insufficient knowledge of the underlying pathogenetic mechanisms. The aim of this review is to collect the most relevant latest information regarding cancer cachexia with a special focus on the experimental systems adopted for modeling the disease in translational studies. RECENT FINDINGS: The scenario of preclinical models for the study of cancer cachexia is not static and is rapidly evolving in parallel with new prospective treatment options. The well established syngeneic models using rodent cancer cells injected ectopically are now used alongside new ones featuring orthotopic injection, human cancer cell or patient-derived xenograft, or spontaneous tumors in genetically engineered mice. SUMMARY: The use of more complex animal models that better resemble cancer cachexia, ideally including also the administration of chemotherapy, will expand the understanding of the underlying mechanisms and will allow a more reliable evaluation of prospective drugs for translational purposes. PMID- 27454354 TI - Get with the program: Adherence to a smartphone app for smoking cessation. AB - INTRODUCTION: Although engagement is generally predictive of positive outcomes in technology-based behavioral change interventions, engagement measures remain largely atheoretical and lack treatment-specificity. This study examines the extent to which adherence measures based on the underlying behavioral change theory of an Acceptance and Commitment Therapy (ACT) app for smoking cessation predict smoking outcomes, and user characteristics associated with adherence. METHODS: Study sample was adult daily smokers in a single arm pilot study (n=84). Using the app's log file data, we examined measures of adherence to four key components of the ACT behavior change model as predictors of smoking cessation and reduction. We also examined baseline user characteristics associated with adherence measures that predict smoking cessation. RESULTS: Fully adherent users (24%) were over four times more likely to quit smoking (OR=4.45; 95% CI=1.13, 17.45; p=0.032). Both an increase in tracking the number of urges passed (OR=1.02; 95% CI=1.00, 1.03; p=0.043) and ACT modules completed (OR=1.27; 95% CI=1.01, 1.60; p=0.042) predicted cessation. Lower baseline acceptance of cravings was associated with over four times higher odds of full adherence (OR=4.59; 95% CI=1.35, 15.54; p=0.014). CONCLUSIONS: Full adherence and use of specific ACT theory-based components of the app predicted quitting. Consistent with ACT theory, users with low acceptance were most likely to adhere to the app. Further research is needed on ways to promote app engagement. PMID- 27454356 TI - Coordination of the health policy dialogue process in Guinea: pre- and post Ebola. AB - BACKGROUND: Policy dialogue can be defined as an iterative process that involves a broad range of stakeholders discussing a particular issue with a concrete purpose in mind. Policy dialogue in health is increasingly being recognised by health stakeholders in developing countries, as an important process or mechanism for improving collaboration and harmonization in health and for developing comprehensive and evidence-based health sector strategies and plans. It is with this perspective in mind that Guinea, in 2013, started a policy dialogue process, engaging a plethora of actors to revise the country's national health policy and develop a new national health development plan (2015-2024). This study examines the coordination of the policy dialogue process in developing these key strategic governance documents of the Guinean health sector from the actors' perspective. METHODS: A qualitative case study approach was undertaken, comprising of interviews with key stakeholders who participated in the policy dialogue process. A review of the literature informed the development of a conceptual framework and the data collection survey questionnaire. The results were analysed both inductively and deductively. RESULTS: A total of 22 out of 32 individuals were interviewed. The results suggest both areas of strengths and weaknesses in the coordination of the policy dialogue process in Guinea. The aspects of good coordination observed were the iterative nature of the dialogue and the availability of neutral and well-experienced facilitators. Weak coordination was perceived through the unavailability of supporting documentation, time and financial constraints experienced during the dialogue process. The onset of the Ebola epidemic in Guinea impacted on coordination dynamics by causing a slowdown of its activities and then its virtual halt. CONCLUSIONS: The findings herein highlight the need for policy dialogue coordination structures to have the necessary administrative and institutional support to facilitate their effective functioning. The findings also point to the need for further research on the practical and operational aspects of national dialogue coordination structures to determine how to best strengthen their capacities. PMID- 27454357 TI - Evaluating the necessity of PCR duplicate removal from next-generation sequencing data and a comparison of approaches. AB - BACKGROUND: Analyzing next-generation sequencing data is difficult because datasets are large, second generation sequencing platforms have high error rates, and because each position in the target genome (exome, transcriptome, etc.) is sequenced multiple times. Given these challenges, numerous bioinformatic algorithms have been developed to analyze these data. These algorithms aim to find an appropriate balance between data loss, errors, analysis time, and memory footprint. Typical analysis pipelines require multiple steps. If one or more of these steps is unnecessary, it would significantly decrease compute time and data manipulation to remove the step. One step in many pipelines is PCR duplicate removal, where PCR duplicates arise from multiple PCR products from the same template molecule binding on the flowcell. These are often removed because there is concern they can lead to false positive variant calls. Picard (MarkDuplicates) and SAMTools (rmdup) are the two main softwares used for PCR duplicate removal. RESULTS: Approximately 92 % of the 17+ million variants called were called whether we removed duplicates with Picard or SAMTools, or left the PCR duplicates in the dataset. There were no significant differences between the unique variant sets when comparing the transition/transversion ratios (p = 1.0), percentage of novel variants (p = 0.99), average population frequencies (p = 0.99), and the percentage of protein-changing variants (p = 1.0). Results were similar for variants in the American College of Medical Genetics genes. Genotype concordance between NGS and SNP chips was above 99 % for all genotype groups (e.g., homozygous reference). CONCLUSIONS: Our results suggest that PCR duplicate removal has minimal effect on the accuracy of subsequent variant calls. PMID- 27454360 TI - Centennial Celebration: Endocrine Reviews Past Highlights for March and April. PMID- 27454359 TI - Changing of the Guard. PMID- 27454358 TI - Capturing Darwin's dream. AB - Evolutionary biologists from Darwin forward have dreamed of having data that would elucidate our understanding of evolutionary history and the diversity of life. Sequence capture is a relatively old DNA technology, but its use is growing rapidly due to advances in (i) massively parallel DNA sequencing approaches and instruments, (ii) massively parallel bait construction, (iii) methods to identify target regions and (iv) sample preparation. We give a little historical context to these developments, summarize some of the important advances reported in this special issue and point to further advances that can be made to help fulfill Darwin's dream. PMID- 27454361 TI - Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the "-Omics" Era. AB - The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603-621, 2015). PMID- 27454362 TI - TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. AB - The TSH receptor (TSHR) on the surface of thyrocytes is unique among the glycoprotein hormone receptors in comprising two subunits: an extracellular A subunit, and a largely transmembrane and cytosolic B-subunit. Unlike its ligand TSH, whose subunits are encoded by two genes, the TSHR is expressed as a single polypeptide that subsequently undergoes intramolecular cleavage into disulfide linked subunits. Cleavage is associated with removal of a C-peptide region, a mechanism similar in some respects to insulin cleavage into disulfide linked A- and B-subunits with lossofaC-peptideregion. The potential pathophysiological importance of TSHR cleavage into A-and B-subunits is that some A-subunits are shed from the cell surface. Considerable experimental evidence supports the concept that A-subunit shedding in genetically susceptible individuals is a factor contributing to the induction and/or affinity maturation of pathogenic thyroid-stimulating autoantibodies, the direct cause of Graves' disease. The noncleaving gonadotropin receptors are not associated with autoantibodies that induce a "Graves' disease of the gonads." We also review herein current information on the location of the cleavage sites, the enzyme(s) responsible for cleavage, the mechanism by which A-subunits are shed, and the effects of cleavage on receptor signaling. (Endocrine Reviews 37: 114-134, 2016). PMID- 27454363 TI - Erratum. PMID- 27454364 TI - ENDOCRINE SOCIETY LAUREATE AWARDS. PMID- 27454365 TI - ENDOCRINE SOCIETY 2014 LAUREATE AWARDS. PMID- 27454368 TI - A novel application in the study of client language: Alcohol and marijuana related statements in substance-using adolescents during a simulation task. AB - The current study explored whether laboratory-based techniques can provide a strategy for studying client language as a mechanism of behavior change. Specifically, this study examined the potential of a simulation task to elicit healthy talk, or self-motivational statements in favor of healthy behavior, related to marijuana and alcohol use. Participants (N = 84) were adolescents reporting at least 10 lifetime substance use episodes recruited from various community settings in an urban Pacific Northwest setting. Participants completed the Adolescent Simulated Intoxication Digital Elicitation (A-SIDE), a validated paradigm for assessing substance use decision making in peer contexts. Participants responded to 4 types of offers in the A-SIDE: (a) marijuana, (b) food (marijuana control), (c) alcohol, and (d) soda (alcohol control). Using a validated coding scheme adapted for the current study, client language during a structured interview assessing participants' response to the simulated offers was evaluated. Associations between percent healthy talk (PHT, calculated by dividing the number of healthy statements by the sum of all substance-related statements) and cross-sectional outcomes of interest (previous substance use, substance use expectancies, and behavioral willingness) were explored. The frequency of substance-related statements differed in response to offer type; rate of PHT did not. PHT was associated with behavioral willingness to accept the offer. However, PHT was not associated with decontextualized measures of substance use. Associations between PHT and global expectancies were limited. Simulation methods may be useful in investigating the impact of context on self-talk and to systematically explore client language as a mechanism of change. (PsycINFO Database Record PMID- 27454369 TI - The couple that smokes together: Dyadic marijuana use and relationship functioning during conflict. AB - Self-reported marijuana use has been associated with poor relationship functioning and decreased stability over time. The present study examined the behavioral interactions of couples with concordant and discordant patterns of marijuana use during conflict, using individual self-reports and observation by independent coders. Heavy drinking community couples (N = 149) participated in a conflict resolution paradigm. Interactions were recorded and coded by naive coders. Approximately 30% of the sample reported past year marijuana use. Actor Partner Interdependence Models and analysis of covariance (ANCOVA) were used to evaluate the individual and interactive effects of dyadic marijuana use on maladaptive relationship functioning. A Robust Actor * Partner Marijuana Use interaction was detected for a range of behavioral outcomes, assessed by both self-report and direct observation, including relationship satisfaction, anger experience, patterns of demand and withdrawal during conflict, constructive behaviors, and overall relationship quality. Specifically, couples in which both partners used or abstained from marijuana displayed more adaptive relationship functioning across indicators relative to couples in which only 1 partner identified as a marijuana user. This pattern was particularly strong for couples in which the female partner used marijuana and the male partner did not. Couples with discordant, rather than concordant, marijuana use displayed distinct conflict resolution behaviors that were consistent with the long-term negative relationship outcomes that have been observed in previous studies. (PsycINFO Database Record PMID- 27454370 TI - Family systems therapy for substance-using mothers and their 8- to 16-year-old children. AB - Family systems therapy has shown to be a powerful adjunct to substance use treatment for couples and for adolescent substance users (Rowe, 2012). However, studies including children (8-16 years of age) in the treatment of their substance using mothers have been overlooked and are essentially nonexistent. Addressing the quality of the mother-child relationship and communication through family systems therapy may prove to be a potent intervention focus for improving mothers' substance use outcomes and parent-child interaction. As such, the current study recruited 183 mothers who sought outpatient treatment through a local substance use treatment facility and randomly assigned them to also receive family systems therapy or Women's Health Education. Self-report and observational data were collected, and assessment interviews were completed at baseline and 3, 6, 12, and 18 months postbaseline. Findings showed that women assigned to family systems therapy showed a quicker decline in alcohol, marijuana, and cocaine use, supporting the efficacy of family therapy as an important addition to mother's substance use treatment plans. Data also revealed an association between change in observed autonomy-relatedness and substance use, though mediation was not found. To our knowledge this is the first effort to successfully document a family systems therapy for substance using mothers with minor children in their care. (PsycINFO Database Record PMID- 27454371 TI - Predictors and outcomes of drinkers' use of protective behavioral strategies. AB - While protective behavioral strategies (PBSs) have the potential to reduce alcohol-related harm, there is a lack of understanding of the factors influencing adults' use of these strategies. The present study assessed the frequency of enactment of a range of PBSs among Australian adults and identified factors associated with their use and the implications for alcohol harm minimization. A sample of 2,168 Australian drinkers (1,095 males and 1,073 females) recruited via a web panel provider completed an online survey that included items relating to quantity and frequency of alcohol consumption, beliefs about the health consequences of alcohol consumption, use of 5 specific PBSs (e.g., counting drinks and eating while drinking), and demographic characteristics. In general, use of these PBSs was negatively associated with overall alcohol consumption. However, usage rates were relatively low, especially among the heaviest drinkers. Refusing unwanted drinks and alternating between alcoholic and nonalcoholic beverages were identified as especially important strategies in the Australian context, accounting for a substantial proportion of the variance in alcohol consumption. Greater efforts to increase awareness and use of PBSs are warranted. In particular, the results suggest that information relating to the importance of refusing unwanted drinks and alternating between alcoholic and nonalcoholic beverages should be actively disseminated to the drinking public. In addition, the reliance on specified numbers of standard drinks in national drinking guidelines suggests encouraging drinkers to count their drinks should be a further focus of interventions given low reported prevalence of this behavior. (PsycINFO Database Record PMID- 27454372 TI - Ascertaining the relationships between the trajectories of specific categories of alcohol-related negative consequences and subsequent drinking behavior. AB - The first year following alcohol use disorder (AUD) treatment has been identified as a period of high risk for relapse and an important timeframe for enquiry regarding alcohol-related behavior change and its maintenance. In addition, at least among individuals with AUD, alcohol use and negative consequences have been shown to be reciprocally related. A commonly used measure of alcohol-related negative consequences is the Drinker Inventory of Consequences (DrInC). Investigations of specific categories of alcohol-related negative consequences and their trajectories, however, have been lacking. Given this background, the purpose of this study was to: follow the course of the 5 DrInC categories of alcohol-related negative consequences over the first year post-AUD treatment initiation; investigate whether these trajectories varied by gender, age, and/or treatment condition; examine the relationships between these trajectories and subsequent drinking behavior; and investigate whether these relationships varied by gender, age, and/or treatment condition, via secondary data analyses. Data from the outpatient arm of Project MATCH (n = 952) were utilized. Study results revealed that the trajectory of each DrInC category was indicative of improved alcohol-related problems across the first year posttreatment initiation. Specific DrInC categories varied as a function of gender, age, and treatment condition, and the trajectories were predictive of subsequent drinking behavior. Specifically, higher intercepts during the treatment period were associated with poorer drinking behavior 1 year later. Alternatively, steeper negative slopes were associated with improved drinking behavior. Some of these relationships were modified by gender, age, and treatment condition. It was concluded that assessing alcohol-related negative consequences during the first year posttreatment initiation period has clinical utility. (PsycINFO Database Record PMID- 27454374 TI - New Paths in Sepsis Management. PMID- 27454375 TI - Is There a Role for Balanced Solutions in Septic Patients? AB - The use of fluid bolus infusion is the cornerstone for hemodynamic resuscitation of critically ill patients. Recently, the clinical use of colloids has lost strength with the publication of several trials suggesting no benefit, and possible harm of its use.On the other hand, the so-called balanced solutions, with low chloride concentrations, have emerged as an alternative with potential physiological benefits over traditional saline solution. Normal saline carries a high amount of chloride which has been associated with an increased incidence of metabolic acidosis, renal vasoconstriction, and reduced urine output. Recent observational studies associated the use of saline with acute kidney injury, which was not observed in a single prospective randomized controlled trial.The present review summarizes available literature regarding the potential clinical and laboratorial benefits of balanced solutions in septic patients. PMID- 27454376 TI - Sepsis Through the Eyes of Proteomics: The Progress in the Last Decade. AB - Sepsis is a systemic inflammatory response caused by infection whose molecular mechanisms are still not completely understood. The early detection of sepsis remains a great challenge for clinicians because no single biomarker capable of its reliable prediction, hence, delayed diagnosis frequently undermines treatment efforts, thereby contributing to high mortality. There are several experimental approaches used to reveal the molecular mechanism of sepsis progression. Proteomics coupled with mass spectrometry made possible to identify differentially expressed proteins in clinical samples. Recent advancement in liquid chromatography-based separation methods and mass spectrometers resolution and sensitivity with absolute quantitation methods, made possible to use proteomics as a powerful tool for study of clinical samples with higher coverage proteome profiles. In recent years, number of proteomic studies have been done under sepsis and/or in response to endotoxin and showed various signaling pathways, functions, and biomarkers. This review enlightened the proteomic progress in the last decade in sepsis. PMID- 27454373 TI - Implantable Device-Related Infection. AB - Over half of the nearly two million healthcare-associated infections can be attributed to indwelling medical devices. In this review, we highlight the difficulty in diagnosing implantable device-related infection and how this leads to a likely underestimate of the prevalence. We then provide a length-scale conceptualization of device-related infection pathogenesis. Within this conceptualization we focus specifically on biofilm formation and the role of host immune and coagulation systems. Using this framework, we describe how current and developing preventative strategies target specific processes along the entire length-scale. In light of the significant time horizon for the development and translation of new preventative technologies, we also emphasize the need for parallel development of in situ treatment strategies. Specific examples of both preventative and treatment strategies and how they align with the length-scale conceptualization are described. PMID- 27454377 TI - Sepsis in Solid-Organ Transplant Patients. AB - The growing population of solid organ transplant (SOT) recipients is at a significantly increased risk for developing infections. In some patients, the infection can lead to a dysregulated systemic inflammatory response with acute organ dysfunction. SOT recipients with sepsis tend to have less fever and leukocytosis instances. Moreover, they have diminished symptoms and attenuated clinical and radiologic findings. The current management of sepsis is similar to general patients. It relies mainly on early recognition and treatment, including appropriate administration of antibiotics and resuscitation with intravenous fluids and vasoactive drugs when needed. The infusion of fluids should be closely monitored because elevated central venous pressure levels and fluid overload can be particularly harmful. There is no consensus on how to manage immunosuppressive therapies during sepsis, although dose reduction or withdrawal is suggested to improve the host immunological response. There is compelling evidence suggesting that infections are associated with reduced allograft and patient survival. However, the traditional belief that SOT patients who develop sepsis have worse outcomes than non-transplanted patients has been challenged. PMID- 27454378 TI - Negative Fluid Balance in Sepsis: When and How? AB - Fluid resuscitation plays a fundamental role in the treatment of septic shock. Administration of inappropriately large quantities of fluid may lead to volume overload, which is increasingly recognized as an independent risk factor for morbidity and mortality in critical illness. In the early treatment of sepsis, timely fluid challenges should be given to optimize organ perfusion, but continuous positive fluid balance is discouraged. In fact, achievement of a negative fluid balance during treatment of sepsis is associated with better outcomes. This review will discuss the relationship between fluid overload and unfavorable outcomes in sepsis, and how fluid overload can be prevented and managed. PMID- 27454379 TI - How Can We Estimate Sepsis Incidence and Mortality? AB - Sepsis is one of the oldest and complex syndromes in medicine that has been in debate for over two millennia. Valid and comparable data on the population burden of sepsis constitute an essential resource for guiding health policy and resource allocation. Despite current epidemiological data suggesting that the global burden of sepsis is huge, the knowledge of its incidence, prevalence, mortality, and case-fatality rates is subject to several flaws. The objective of this narrative review is to assess how sepsis incidence and mortality can be estimated, providing examples on how it has been done so far in medical literature and discussing its possible biases. Results of recent studies suggest that sepsis incidence rates are increasing consistently during the last decades. Although estimates might be biased, this probably reflects a real increase in incidence over time. Nevertheless, case fatality rates have decreased, which is a probable reflex of advances in critical care provision to this very sick population at high risk of death. This conclusion can only be drawn with a reasonable degree of certainty for high-income countries. Conversely, adequately designed studies from middle- and low-income countries are urgently needed. In these countries, sepsis incidence and case-fatality rates could be disproportionally higher due to health care provision constraints and ineffective preventive measures. PMID- 27454380 TI - Corticosteroids in Severe Sepsis and Septic Shock: A Concise Review. AB - For decades, corticosteroids are proposed as adjuvant therapies for severe infections. Despite mounting evidence from randomized controlled trials, there is still an intense debate regarding the role of systemic low-dose corticosteroids as a part of the treatment of septic shock. In the present article, we review the current literature and detail aspects on the pathophysiologic rationale, the current evidence, actual practice, and future directions on this topic. PMID- 27454381 TI - The Function of SDF-1-CXCR4 Axis in SP Cells-Mediated Protective Role for Renal Ischemia/Reperfusion Injury by SHH/GLI1-ABCG2 Pathway. AB - Renal ischemia-reperfusion (I/R) injury ranks as the primary cause of acute renal injury with severe morbidity and mortality. Side population (SP) cells have recently drawn increasing attention due to their critical role in injury repair and regeneration. Unfortunately, the underlying mechanism involved in renal I/R remains poorly elucidated. Here, pronounced increases of stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) were substantiated in I/R kidneys from C57BL/6 mice subjected to clamp the bilateral renal pedicles to mimic renal ischemia. Similar up-regulation of them was also determined in SP cells upon simulated ischemia/reperfusion (SI/R). In contrast to non-SP cells, SP cells exhibited higher viability, apoptosis resistance, chemotaxis, and paracrine actions following SI/R treatment, and these were further enhanced after SDF-1 stimulation. Interestingly, blocking CXCR4 signaling with AMD3100 notably ameliorated the above effects. Mechanism analysis corroborated that SDF-1/CXCR4 further induced the expression of ATP-binding cassette transporter ABCG2, an essential element for SP-mediated kidney regeneration after renal I/R injury. Moreover, AMD3100 pretreatment strikingly attenuated ABCG2 elevation in SP cells. Additionally, sonic hedgehog (SHH)-Gli 1 signaling was involved in SDF-1/CXCR4-mediated ABCG2 expression. When SP cells pretreated with AMD3100 were intravenously injected into I/R mice, SP cell mediated decreases in blood urea nitrogen, serum creatinine, and histological score of kidney were noticeably attenuated, indicating that blocking CXCR4 pathway mitigated the therapeutic function of SP cells in renal I/R injury. Together, this research suggests that SDF-1/CXCR4 axis might act, via Shh-Gli1 ABCG2 signaling, as a positive regulator of SP cell-based therapies for renal I/R by Shh-Gli 1-ABCG2 signaling. PMID- 27454382 TI - Induction of Heme Oxygenase-1 Attenuates the Severity of Sepsis in a Non-Surgical Preterm Mouse Model. AB - Preterm sepsis is characterized by systemic bacterial invasion and inflammatory response. Its pathogenesis is unclear due to lack of proper animal models. Heme oxygenase-1 (HO-1) can affect physiologic and pathologic conditions through its anti-inflammatory, antioxidative, and anti-apoptotic properties. Since HO-1 is developmentally regulated, it may play a role in the pathogenesis of preterm sepsis. For this study, sepsis was induced using the non-surgical "cecal slurry" (CS) model. CS was given intraperitoneally at various doses to 4-day-old newborn mice to determine dose-dependent effects. The LD40 was then given and changes in bodyweight, bacterial colonization of organs, hematology, serum biochemistry, and immunomodulatory gene expression were determined. We found a dose-dependent mortality with an LD40 of 2.0 mg/g. Significant bacterial colonization and hematological changes (leukocytopenia, thrombocytopenia, and lymphocytopenia) and increased gene expression of pro-inflammatory cytokines, pattern-recognition receptors, and other genes related to immune responses were also observed. Twenty four hours post-sepsis induction, bodyweight loss was associated with mortality and organ damage. Finally, to elucidate a protective role of HO-1, 30-MUmol heme/kg was given subcutaneously 24 h pre-sepsis induction. HO activity in livers and spleens significantly increased 64% and 50% over age-matched controls 24 h post-heme administration. Importantly, heme significantly reduced mortality from 40.9% to 6.3% (P <0.005) and gene expression of pro-inflammatory cytokines (Ccl5, Cxcl10, IL-1b, and Ifng). We conclude that the CS model can be used as a model to study preterm sepsis. Because induction of HO-1 significantly reduced mortality, we speculate that HO-1 may confer protection against sepsis in preterm infants. PMID- 27454383 TI - An Enrichment Strategy For Sepsis Clinical Trials. AB - INTRODUCTION: Selecting participants for research based on their risk is an enrichment strategy with potential for enhancing clinical trials in sepsis. Adult Septic Shock Information and Stratification (ASSIST) is a tool for estimating mortality risk that incorporates a panel of biomarkers, age, lactate, and chronic health status. We assessed the utility of ASSIST as an enrichment strategy in a clinical trial testing the efficacy of a polyclonal antitumor necrosis factor alpha fragment antibody (AZD9773) in adults with severe sepsis or septic shock. We hypothesized that the effects of AZD9773 are dependent on baseline mortality risk, as estimated by ASSIST. METHODS: This was a post hoc analysis of a recently completed trial of 300 subjects, randomized to placebo, low-dose AZD9773, or high dose AZD9773. The study's primary endpoint was number of ventilator-free days. There were 286 subjects with available plasma samples from study entry. We measured the ASSIST biomarkers and assigned each subject to low, intermediate, and high-risk strata based on their ASSIST mortality probability. To mirror the study's original statistical plan, we estimated the least squares mean ventilator free days for each study arm within risk strata. RESULTS: The effect of study arm within ASSIST-based risk strata was significant (P = 0.017). Within the low-risk group, there was an increase in ventilator-free days for both drug arms. Within the intermediate-risk group, there was an increase in ventilator-free days among those in the low-dose arm, but a decrease in the high-dose arm. Among high-risk patients, there was a decrease of ventilator-free days in both drug arms. Analogous associations were observed when modeling 28-day mortality. CONCLUSIONS: In this study, a beneficial effect of AZD9773 might have been observed if the trial selected low to intermediate-risk patients. ASSIST has the potential to serve as an enrichment tool for sepsis clinical trials. PMID- 27454384 TI - Flt3 Ligand Treatment Attenuates T Cell Dysfunction and Improves Survival in a Murine Model of Burn Wound Sepsis. AB - INTRODUCTION: Sepsis is a leading cause of death among severely burned patients. Burn injury disrupts the protective skin barrier and causes immunological dysfunction. In our previous studies, we found that burn injury and wound infection causes a significant decline in lymphocyte populations, implying adaptive immune system dysfunction. In the present study, we examined the effect of treatment with Fms-like tyrosine kinase-3 Ligand (Flt3L) on T cell phenotype and function in a model of burn wound sepsis. FLt3L is an essential cytokine required for hematopoietic progenitor cell development and expansion of both myeloid and lymphoid lineages. Flt3L has been shown to potentiate innate immune functions of dendritic cells and neutrophils during burn wound sepsis. However, the ability of Flt3L to improve T cell function during burn wound sepsis has not been previously evaluated. METHODS: Mice underwent 35% total body surface area scald burn and were treated with Flt3L (10 MUg) or vehicle daily via the intraperitoneal route starting 1 day after burn injury. On day 4 after burn injury, Pseudomonas aeruginosa was used to induce wound infection. Leukocytes in spleen and wound draining lymph nodes were characterized using flow cytometry. Bacterial clearance, organ injury, and survival were also assessed. RESULTS: Flt3L treatment prevented the decline in splenic CD4 and CD8 T cells caused by burn injury and infection. Flt3L treatment also attenuated the decline in CD28 expression on CD4 and CD8 T cells and IFNgamma production by CD8 T cells in the spleen and wound draining lymph nodes. Furthermore, Flt3L decreased the levels of programmed death ligand 1 expression on splenic dendritic cells and macrophages. Flt3 treatment improved systemic bacterial clearance, decreased liver and kidney injury, and significantly improved survival in mice with burn wound sepsis. CONCLUSION: Burn injury and associated sepsis causes significant loss of T cells and evidence of T cell dysfunction. Flt3L attenuates T cell dysfunction and improves host resistance to burn wound sepsis in mice. PMID- 27454385 TI - Dysbiosis Across Multiple Body Sites in Critically Ill Adult Surgical Patients. AB - The microbiota of critically ill patients likely undergoes dramatic changes but has not been rigorously studied with a culture-independent high-throughput approach. The aim of this study was to characterize spatial and temporal variation in the microbiota of critically ill patients. Trauma and acute surgery patients admitted to the intensive care unit (ICU) were sampled at five body sites (stool, tongue, skin, trachea, urine) every 3 to 4 days. A mean of 10.8 samples was collected from 32 patients with a mean sampling period of 8.8 days. Bacterial 16S rRNA sequences were amplified and sequenced for microbiota analyses. Results were compared to data from unhospitalized adult participants in the American Gut and Human Microbiome Projects. Relative to healthy adults, alpha diversity was decreased in ICU gut and skin samples at all time points. Diversity in tongue swabs decreased over time. Beta diversity measures indicated differences in community membership between critically ill and healthy adults at each body site. Taxonomic alterations in the ICU included depletion of important commensal bacteria such as Faecalibacterium in GI samples and Corynebacterium in skin swabs and enrichment with pathogens such as Enterococcus, Mycoplasma, and Staphylococcus. A high proportion of ICU sample sets contained pathogens present simultaneously at three body sites indicating widespread colonization. In several cases, clinically relevant airway infections were preceded by the appearance of the causative pathogen in tracheal microbiome profiles. These results demonstrate that the microbiome of critically ill patients undergoes a loss of diversity, loss of site specificity, and a shift toward dominant pathogens. These changes may provide opportunities to precisely modulate the microbiome and thereby improve patient outcomes. PMID- 27454386 TI - Are Early Antibiotics Important for Everyone? AB - Since the first edition of Surviving Sepsis Campaign Guidelines, the administration of intravenous antibiotics in the first hours of sepsis is recommend. However, in the last ten years, several studies around importance of early antibiotics in emergency room or in intensive care unit produced disparate results. Therefore, is early administration of antibiotics a life-salver? In this article, we explore studies around this theme and some questions about what does "early antibiotics" mean are addressed. PMID- 27454387 TI - The Epidemiology of Sepsis in Childhood. AB - BACKGROUND: Sepsis, or systemic inflammatory response to infection, is a major childhood disease and a common cause of death in children. Despite its importance, a global perspective on the epidemiology and mortality of pediatric sepsis across the world is still lacking. METHODS: A non-systematic review of the medical articles published in Medline from 2005 to 2015. RESULTS: Studies suggest that there has been a rise in the number of pediatric sepsis cases along the last two decades, which may relate to the increased survival of preterm and low birth weight infants and children with severe chronic conditions. Children living in low-income countries represent a vulnerable population for sepsis. Despite several initiatives to improve the diagnosis and early treatment of pediatric sepsis, the mortality resulting from pediatric sepsis remains high, ranging from 5% to 40%. Poor outcomes, however, do not seem to be related to the limitation of resources but to the delay in the recognition and early treatment of sepsis. CONCLUSIONS: Educational efforts aiming to increase the awareness on sepsis by the general public and the adherence to the treatment guidelines by healthcare providers may result in significant improvements in sepsis survival. The global attention to pediatric sepsis, however, can only be achieved with the standardization of the definitions and the use of simple and sensitive diagnostic criteria that incorporate the differences in the necessities among different settings and the availability of local resources. PMID- 27454388 TI - Mechanical Ventilation in Sepsis: A Reappraisal. AB - Sepsis is the main cause of close to 70% of all cases of acute respiratory distress syndromes (ARDS). In addition, sepsis increases susceptibility to ventilator-induced lung injury. Therefore, the development of a ventilatory strategy that can achieve adequate oxygenation without injuring the lungs is highly sought after for patients with acute infection and represents an important therapeutic window to improve patient care. Suboptimal ventilatory settings cannot only harm the lung, but may also contribute to the cascade of organ failure in sepsis due to organ crosstalk.Despite the prominent role of sepsis as a cause for lung injury, most of the studies that addressed mechanical ventilation strategies in ARDS did not specifically assess sepsis-related ARDS patients. Consequently, most of the recommendations regarding mechanical ventilation in sepsis patients are derived from ARDS trials that included multiple clinical diagnoses. While there have been important improvements in general ventilatory management that should apply to all critically ill patients, sepsis-related lung injury might still have particularities that could influence bedside management.After revisiting the interplay between sepsis and ventilation induced lung injury, this review will reappraise the evidence for the major components of the lung protective ventilation strategy, emphasizing the particularities of sepsis-related acute lung injury. PMID- 27454389 TI - Asynchronicity of Organic and Psychiatric Symptoms in a Case of Sertraline Intoxication. AB - Sertraline is a selective serotonin reuptake inhibitor used as an antidepressant and antipanic agent in children and adolescents. Sertraline is well tolerated and its safety profile in overdose is favorable. However, sertraline overdose may cause a toxic hyperserotonergic state known as serotonin syndrome (SS). Serotonin syndrome may be misdiagnosed in children because it has been reported mostly in adults. In the present case report, we describe a 16-year-old female patient who ingested 2000 mg of sertraline to attempt suicide. The patient showed symptoms and signs suggestive of SS, characterized by an asynchronicity between organic and psychiatric symptoms. In addition, the patient showed a variability of psychiatric symptoms through time. Thirteen hours after sertraline overdose, she was poorly cooperative with poverty of speech and marked emotional tension, but she was oriented in space and time and was able to remember what happened to her and to reconstruct the dynamics of the fact. Twenty-four hours after sertraline overdose, the patient developed a delusion of reference associated with intense anxiety and depressed mood. In the present case report, we discuss the pathophysiologic mechanisms of the observed clinical manifestations and propose an observation period for sertraline overdose in children and adolescents that is sufficiently long (at least 72 hours) even in the absence of unstable vital signs. PMID- 27454390 TI - Intravenous Immunoglobulin Therapy in a Patient With Anti-Myelin Oligodendrocyte Glycoprotein-Seropositive Neuromyelitis Optica. PMID- 27454391 TI - Premenstrual Dysphoric Disorder Without Comorbid Psychiatric Conditions: A Systematic Review of Therapeutic Options. AB - OBJECTIVES: Premenstrual dysphoric disorder (PMDD) is a disabling condition affecting approximately 2% to 8% of women during reproductive age. It has been recently included in the mood disorder section of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, but its treatment as a primary psychiatric illness is still debated, because of the high prevalence of other mental disturbances in PMDD patients. On the other hand, clear clinical guidelines for PMDD patients not suffering from comorbid mental conditions are not yet available. The aim of the present study was therefore to systematically review the original articles pertaining to the treatment of PMDD in adult women free of any current or previous psychiatric comorbidity. METHODS: We searched PubMed to identify published studies on PMDD, including randomized controlled trials, open-label trials, and case series or case reports involving adult women with no history of comorbid mental conditions. The search was conducted in April 2015. RESULTS: We found 55 studies fulfilling our inclusion criteria, 49 of them focused on pharmacological/chemical agents and the remaining 6 on nonpharmacological interventions. CONCLUSIONS: Based on the results of our qualitative synthesis, the best therapeutic option in the treatment of adult PMDD patients free of other mental disorders are selective serotonin reuptake inhibitor antidepressants (especially paroxetine and fluoxetine) and low doses of oral estroprogestins. Other interventions, such as light therapy, cognitive behavioral therapy, food supplements, and herbal medicines, showed promising effects, but other investigations are needed to confirm their efficacy. PMID- 27454392 TI - Nearest neighbor imputation algorithms: a critical evaluation. AB - BACKGROUND: Nearest neighbor (NN) imputation algorithms are efficient methods to fill in missing data where each missing value on some records is replaced by a value obtained from related cases in the whole set of records. Besides the capability to substitute the missing data with plausible values that are as close as possible to the true value, imputation algorithms should preserve the original data structure and avoid to distort the distribution of the imputed variable. Despite the efficiency of NN algorithms little is known about the effect of these methods on data structure. METHODS: Simulation on synthetic datasets with different patterns and degrees of missingness were conducted to evaluate the performance of NN with one single neighbor (1NN) and with k neighbors without (kNN) or with weighting (wkNN) in the context of different learning frameworks: plain set, reduced set after ReliefF filtering, bagging, random choice of attributes, bagging combined with random choice of attributes (Random-Forest-like method). RESULTS: Whatever the framework, kNN usually outperformed 1NN in terms of precision of imputation and reduced errors in inferential statistics, 1NN was however the only method capable of preserving the data structure and data were distorted even when small values of k neighbors were considered; distortion was more severe for resampling schemas. CONCLUSIONS: The use of three neighbors in conjunction with ReliefF seems to provide the best trade-off between imputation error and preservation of the data structure. The very same conclusions can be drawn when imputation experiments were conducted on the single proton emission computed tomography (SPECTF) heart dataset after introduction of missing data completely at random. PMID- 27454394 TI - Relationship Between Changes in Workplace Bullying Status and the Reporting of Personality Characteristics. AB - OBJECTIVE: To examine whether a shift in work-related bullying status, from being non-bullied to being bullied or vice versa, was associated with changes in reporting of personality characteristics. METHODS: Data on bullying and personality (neuroticism, extraversion, and sense of coherence) were collected in three waves approximately 2 years apart (N = 4947). Using a within-subjects design, personality change scores that followed altered bullying status were evaluated with one-sample t tests. Sensitivity analyses targeted depressive symptoms. RESULTS: Shifts from non-bullied to frequently bullied were associated with increased neuroticism or decreased sense of coherence manageability scores. Shifts from bullied to non-bullied were associated with decreasing neuroticism and increasing extraversion scores, or increasing sense of coherence meaningfulness and comprehensibility scores. Excluding depressive cases had minor effects. CONCLUSIONS: Bullying seems to some extent to affect personality scale scores, which thus seem sensitive to environmental and social circumstances. PMID- 27454393 TI - Copper-Catalyzed Enantioselective Addition of Styrene-Derived Nucleophiles to Imines Enabled by Ligand-Controlled Chemoselective Hydrocupration. AB - The copper-catalyzed intermolecular enantioselective addition of styrenes to imines has been achieved under mild conditions at ambient temperature. This process features the use of styrenes as latent carbanion equivalents via the intermediacy of catalytically generated benzylcopper derivatives, providing an effective means for accessing highly enantiomerically enriched amines bearing contiguous stereocenters. Mechanistic studies shed light on the origin of the preferential styrene hydrocupration in the presence of an imine with the Ph-BPE derived copper catalyst. PMID- 27454395 TI - Evaluation of a Workplace-Based Sleep Education Program. AB - INTRODUCTION: Poor sleep is common among working adults. Chronic sleep deprivation is associated with health problems. A healthy sleep educational program (using webinars and other intranet-based resources) was offered to employees of a financial services corporation. METHODS: In 2015, a total of 357 employees (50% completion rate) completed both a pre- and post-program questionnaire assessing sleep quality and workplace productivity. RESULTS: Many aspects of sleep statistically improved from T1 to T2 for program participants. These included improvements in hours of sleep, sleep quality, ease of getting asleep, feeling rested, nights of poor sleep, job performance, days of sleepiness, and others. Employees reporting any limitation in productivity also showed significant improvement. CONCLUSIONS: This workplace healthy sleep intervention was associated with significant improvements in sleep quality and quantity among program participants. PMID- 27454396 TI - Ill Health-Related Job Loss: A One-Year Follow-Up of 54,026 Employees. AB - INTRODUCTION: The diagnoses of workers being unfit to work may be a relevant health indicator. Therefore, the aim of this study was to analyze the one-year incidence of an unfit to work diagnosis. METHOD: This one-year prospective study included all workers undergoing annual work medical examination from occupational health services in Troyes, France. RESULTS: Twenty-one occupational physicians followed 54,026 employees. The all-cause incidence of being unfit to return to work was 0.772%. The two main causes of being unfit to work were musculoskeletal disorders (61%) and psychopathologies (24%). The relative risk (RR) of being unfit to work, independent of the cause, was higher when employees were aged over 50 years (RR = 2.51), and female (RR = 1.51). CONCLUSIONS: Prospective results from occupational physicians' medical records may provide significant and cost effective directions to prioritize actions and target health promotion in the workplace. PMID- 27454397 TI - Sedentary Behavior and Musculoskeletal Discomfort Are Reduced When Office Workers Trial an Activity-Based Work Environment. AB - OBJECTIVE: The aim of this study was to evaluate the effect of an activity-based work (ABW) office environment on physical activity and sedentary behavior, work ability, and musculoskeletal discomfort. METHODS: Eighty-eight office workers trialed ABW for 4 weeks. Accelerometer and self-reported outcomes were measured at baseline, end-intervention, and follow-up. Data were analyzed using linear mixed models. RESULTS: Accelerometry measured sedentary time; sedentary breaks and step count did not significantly change from baseline to end-intervention (P = 0.13, 0.09, 0.18, respectively). Self-reported sitting-time was 14% lower, with standing-time and walking 11% and 3% higher in ABW than baseline (P < 0.01 for all). Low back pain was lower in ABW than baseline (odds ratio 2.0, 95% confidence interval 1.1 to 3.7). Work ability reduced from 8.4 to 7.8 points (P < 0.01) at follow-up. CONCLUSIONS: ABW environment appears to reduce self-reported sedentary behavior and low back pain and increase standing time. PMID- 27454398 TI - Change in Psychosocial Work Factors Predicts Follow-up Employee Strain: An Examination of Australian Employees. AB - OBJECTIVE: This research undertook a time-ordered investigation of Australian employees in regards to their experiences of change in psychosocial work factors across time (decreases, increases, or no change) in the prediction of psychological, physical, attitudinal, and behavioral employee strain. METHODS: Six hundred and ten employees from 17 organizations participated in Time 1 and Time 2 psychosocial risk assessments (average time lag of 16.7 months). Multi level regressions examined the extent to which change in exposure to six demands and four resources predicted employee strain at follow-up, after controlling for baseline employee strain. RESULTS: Increases in demands and decreases in resources exacerbated employee strain, but even constant moderate demands and resources resulted in poor employee outcomes, not just constant high or low exposure, respectively. CONCLUSIONS: These findings can help employers prioritize hazards, and guide tailored psychosocial organizational interventions. PMID- 27454399 TI - High Stress and Negative Health Behaviors: A Five-Year Wellness Center Member Cohort Study. AB - OBJECTIVE: The aim of this study was to examine the association between having a high stress level and health behaviors in employees of an academic medical center. METHODS: Beginning January 1, 2009, through December 31, 2013, an annual survey was completed by 676 worksite wellness members. RESULTS: Each year, about one-sixth of members had a high stress level, high stress individuals visited the wellness center less often, and most years there was a significant relationship (P < 0.05) between stress level and poor physical health behaviors (physical activity level and confidence, strength, climbing stairs), low mental health (quality of life, support, spiritual well-being and fatigue), poor nutritional habits (habits and confidence), and lower perceived overall health. CONCLUSIONS: High stress is associated with negative health behavior, and future studies, therefore, should explore strategies to effectively engage high stress employees into comprehensive wellness programs. PMID- 27454400 TI - The Relationship Between Job Satisfaction and Productivity-Related Costs: A Longitudinal Analysis. AB - OBJECTIVES: The aim of this study was to examine the longitudinal relationship between job satisfaction and total productivity-related costs, and between job satisfaction and absenteeism and presenteeism costs separately. A secondary aim was to explore whether these relationships differed across job types. METHODS: Linear generalized estimating equation analyses were used to explore the longitudinal relationships. To explore whether the relationships differed across job types, stratified analyses were performed. RESULTS: A significant relationship was found between job satisfaction and total productivity-related costs [beta = &OV0556;-273; 95% confidence interval (95% CI): -407 to -200] and between job satisfaction and presenteeism costs (beta = &OV0556;-276; 95% CI: 367 to -235), but not between job satisfaction and absenteeism costs. These relationships differed across job types. CONCLUSIONS: Higher levels of job satisfaction were longitudinally related to lower total productivity-related costs and presenteeism costs, but not to lower absenteeism costs. These relationships seem to differ across job types. PMID- 27454401 TI - Fabrication and modelling of fractal, biomimetic, micro and nano-topographical surfaces. AB - Natural surface topographies are often self-similar with hierarchical features at the micro and nanoscale, which may be mimicked to overcome modern tissue engineering and biomaterial design limitations. Specifically, a cell's microenvironment within the human body contains highly optimised, fractal topographical cues, which directs precise cell behaviour. However, recreating biomimetic, fractal topographies in vitro is not a trivial process and a number of fabrication methods have been proposed but often fail to precisely control the spatial resolution of features at different lengths scales and hence, to provide true biomimetic properties. Here, we propose a method of accurately reproducing the self-similar, micro and nanoscale topography of a human biological tissue into a synthetic polymer through an innovative fabrication process. The biological tissue surface was characterised using atomic force microscopy (AFM) to obtain spatial data in X, Y and Z, which was converted into a grayscale 'digital photomask'. As a result of maskless grayscale optical lithography followed by modified deep reactive ion etching and replica molding, we were able to accurately reproduce the fractal topography of acellular dermal matrix (ADM) into polydimethylsiloxane (PDMS). Characterisation using AFM at three different length scales revealed that the nano and micro-topographical features, in addition to the fractal dimension, of native ADM were reproduced in PDMS. In conclusion, it has been shown that the fractal topography of biological surfaces can be mimicked in synthetic materials using the novel fabrication process outlined, which may be applied to significantly enhance medical device biocompatibility and performance. PMID- 27454402 TI - Hepatitis E: prevention and treatment. AB - PURPOSE OF REVIEW: Infection with the hepatitis E virus (HEV) is very common worldwide. The epidemiology, viral genotypes, and transmission routes differ between low-resource countries and economically developed countries. These differences have resulted in the design of diverse prevention and treatment strategies to combat HEV. RECENT FINDINGS: The population seroprevalence of HEV immunoglobulin G varies between 5 and 50%. However, the diagnosis of acute hepatitis from HEV has not been common in the United States or Western Europe. Chronic progressive HEV infections have been reported among patients who are immunocompromised. Successful treatment of patients with chronic hepatitis from HEV infection with antiviral agents, such as ribavirin or interferon-alpha, has been reported. Extrahepatic manifestations of HEV infection are common. Large epidemics of hundreds or thousands of cases continue to be reported among populations in Asia and Africa. A subunit peptide HEV vaccine has been found to be highly efficacious in a large clinical trial. However, the vaccine has not been evaluated in populations of pregnant women or other risk groups and is only available in China. SUMMARY: Although HEV infections are increasingly recognized as a global public health problem, there are few methods for prevention and treatment that are widely available. PMID- 27454403 TI - Foodborne viral infections. AB - PURPOSE OF REVIEW: The aim of the study was to provide an update on foodborne viral infections describing illness burden, the main aetiological agents (enteric viruses, hepatitis viruses and emerging and zoonotic viruses) and advances in virus detection in foods. RECENT FINDINGS: Norovirus (NoV) is the most common viral foodborne pathogen globally (125 million cases and 35 000 deaths). The role of the asymptomatic food handlers in contributing to NoV outbreaks is becoming increasingly clear, with up to one-quarter of outbreaks attributable to them. Handwashing with soap and water remains the best method for removing NoV from fingers. Risk assessment for transmission of emerging viruses through the food chain should include consideration of all means by which food could post a hazard, that is not just consumption. New technologies have demonstrated the widespread nature of viral contamination in the food chain, but this does not necessarily correlate with the risk of disease. Finally, understanding people's knowledge and behaviour is just as important as understanding virus characteristics and epidemiology when assessing risks of foodborne transmission. SUMMARY: The predominant viruses transmitted through food tend to be those for which humans are the natural hosts, so that effective control measures need to prevent exposure of foods to human faeces. PMID- 27454405 TI - Ventricular-arterial coupling assessment using gated single-photon emission computed tomography: relationship with reserve pulse pressure and repolarization abnormalities. AB - AIMS: In patients with normal myocardial perfusion, ST-segment depression and reserve pulse pressure (rPP) can identify patients at higher risk of cardiovascular events. We aimed to explore the prevalence of impaired ventricular arterial coupling (VAc) in patients with normal myocardial perfusion imaging and its relationship with ST-segment depression and rPP. METHODS AND RESULTS: The present study included consecutive patients with normal myocardial perfusion imaging by single-photon emission computed tomography and ST-segment depression. Stroke volume, end-systolic pressure, arterial elastance (Ea), ventricular elastance (Ev), and VAc (Ea/Ev) were estimated both at rest and during stress. The difference between stress and rest (DeltaVAc) was calculated. A positive DeltaVAc was considered an impaired DeltaVAc (iVAc). RESULTS: A total of 92 patients were prospectively included. iVAc was identified in 44 (59%) patients with ST-segment depression compared with 3 (16%) patients with normal repolarization (P=0.001). A higher incidence of abnormal rPP was identified in patients with ST-segment depression compared with the control group (61 vs. 16%, P=0.0001). ST-segment depression was identified as the only independent predictor of iVAc (adjusted OR 7.5; 95% CI 1.9-30.0, P=0.004). CONCLUSION: Noninvasive assessment of VAc is feasible with gated single-photon emission computed tomography and appears to be related to ST-segment depression and reserve rPP. PMID- 27454404 TI - Advances in immunotherapy for melanoma management. AB - Melanoma remains a leading cause of death among young adults. Evidence that melanoma tumor cells are highly immunogenic and a better understanding of T-cell immune checkpoints have changed the therapeutic approach to advanced melanoma. Instead of targeting the tumor directly, immunotherapy targets and activates the immune response using checkpoint inhibitors, monoclonal antibodies, vaccines, and adoptive T cell therapy. This review focuses on the immune signaling and biological mechanisms of action of recent immune-based melanoma therapies as well as their clinical benefits. PMID- 27454407 TI - Degradation of MDEA in aqueous solution in the thermally activated persulfate system. AB - The feasibility of methyldiethanolamine (MDEA) degradation in thermally activated PS system was evaluated. Effects of the PS concentration, pH, activation temperature and reaction time on MDEA degradation were investigated. Simultaneity, the thermodynamic analysis and degradation process were also performed. Several findings were made in this study including the following: the degradation rates of MDEA in thermally activated PS systems were higher than other systems. MDEA could be readily degraded at 40 degrees C with a PS concentration of 25.2 mM, the process of MDEA degradation was accelerated by higher PS dose and reaction temperature, and MDEA degradation and PS consumption followed the pseudo-first-order kinetic model. The thermodynamic analysis showed that the activation process followed an endothermic path of the positive value of [Formula: see text] and spontaneous with the negative value of [Formula: see text], high temperature was favorable to the degradation of MDEA with the apparent activation energy of 87.11 KJ/mol. Combined FT-IR with GC-MS analysis techniques, MDEA could be oxidative degraded after the C-N bond broken to small molecules of organic acids, alcohols or nitro compounds until oxidized to CO2 and H2O. In conclusion, the thermally activated PS process is a promising option for degrading MDEA effluent liquor. PMID- 27454406 TI - Subjective rating of executive functions in mild Alzheimer's disease. AB - OBJECTIVES: Subjective cognitive decline is considered to be a core feature of pre-Alzheimer's disease (AD) conditions, the vast majority of literature having focused on memory concerns. Neuropsychological studies have implicated executive dysfunction on objective performance measures in AD, but no research has evaluated whether individuals with AD have concerns about their executive functions and whether it differs from their caregiver's concerns. In the present study, we sought to evaluate self- and informant ratings of executive functioning in patients with mild AD. METHOD: Participants were 23 patients with mild AD and 32 healthy elderly controls (HC) and their informants who completed the Behavior Rating Inventory of Executive Function - Adult version. RESULTS: Patients with AD and their informants reported greater executive dysfunction than the HC group and their informants, respectively, and patients reported greater difficulty than their informants. The largest effect size for both self- and informant ratings was obtained for the Working Memory scale. CONCLUSIONS: These findings indicate that subjective cognitive concerns in mild AD extend beyond the memory domain to executive functions. That greater difficulty was endorsed by patients than their informants suggests that at least in the mild stage of AD some awareness of executive dysfunction may be maintained in some patients. Implications for clinical care are discussed. PMID- 27454408 TI - What Are the Unmet Needs and Care Experiences of Adolescents and Young Adults with Cancer? A Systematic Review. AB - PURPOSE: To assess what is currently known about unmet needs and care experiences of adolescents and young adults (AYAs) with cancer, identify gaps in the research literature, and highlight potential areas for improvement in future research. METHODS: Medline, PsycINFO, CINAHL, and EMBASE databases were searched to identify relevant studies from 1990 to July 2015. Eligible articles included self reported care experiences or unmet needs of cancer patients aged between 15 and 30 years in the period between symptom onset and 2 years post-treatment. Qualitative and quantitative designs were included. RESULTS: Forty-five articles from 39 studies (23 qualitative, 12 quantitative, and 4 mixed methods) were rated as "adequate" or "good" quality and reviewed. The majority included any cancer diagnoses and none was longitudinal. There was considerable variation in age ranges and time since diagnosis between studies. Only two studies used standardized survey tools, with both tools validated on adult populations. The most common areas assessed for care experiences and needs were information/communication and fertility. In addition, care experience studies commonly examined clinical expertise and age-appropriate settings, while unmet needs studies reported on emotional support and peer interaction. CONCLUSION: Findings highlight the need for age-appropriate information and treatment facilities, access to emotional support services, and contact with peers. Fertility information and services are a priority issue for this group. Future research would benefit from a consistent definition of the AYA age range, increased used of standardized scales validated with this population, and longitudinal designs to assess changes over time. PMID- 27454410 TI - Psychoeducation and online mood tracking for patients with bipolar disorder: A randomised controlled trial. AB - BACKGROUND: Psychoeducation is an effective adjunct to medications in bipolar disorder (BD). Brief psychoeducational approaches have been shown to improve early identification of relapse. However, the optimal method of delivery of psychoeducation remains uncertain. Here, our objective was to compare a short therapist-facilitated vs. self-directed psychoeducational intervention for BD. METHODS: BD outpatients who were receiving medication-based treatment were randomly assigned to 5 psychoeducation sessions administered by a therapist (Facilitated Integrated Mood Management; FIMM; n=60), or self-administered psychoeducation (Manualized Integrated Mood Management; MIMM; n=61). Follow-up was based on patients' weekly responses to an electronic mood monitoring programme over 12 months. RESULTS: Over follow-up, there were no group differences in weekly self-rated depression symptoms or relapse/readmission rates. However, knowledge of BD (assessed with the Oxford Bipolar Knowledge questionnaire (OBQ)) was greater in the FIMM than the MIMM group at 3 months. Greater illness knowledge at 3 months was related to a higher proportion of weeks well over 12 months. LIMITATIONS: Features of the trial may have reduced the sensitivity to our psychoeducation approach, including that BD participants had been previously engaged in self-monitoring. CONCLUSIONS: Improved OBQ score, while accelerated by a short course of therapist-administered psychoeducation (FIMM), was seen after both treatments. It was associated with better outcome assessed as weeks well. When developing and testing a new psychosocial intervention, studies should consider proximal outcomes (e.g., acquired knowledge) and their short-term impact on illness course in bipolar disorder. PMID- 27454409 TI - Investigating symptom domains of bipolar disorder for Spanish-speakers using the Bipolar Inventory of Symptoms Scale. AB - BACKGROUND: A Spanish language rating scale which assesses the range of bipolar disorder symptoms is needed. There are rating scales commonly used, however they do not address commonly expressed symptoms associated with bipolar disorder and have varied rating systems. There are also few comparisons of symptom severity between Spanish and English speaking patients, due to limitations in available rating scales. METHODS: We conducted psychometric assessment of the Spanish language Bipolar Inventory of Symptoms Scale (BISS) (N=71) for persons with bipolar disorder, which assesses 5 domains: mania, depression, irritability, anxiety and psychosis. The Spanish BISS scores were then compared to the MADRS (Montgomery Asberg Depression Rating Scale) and the YMRS (Young Mania Rating Scale) as well as to BISS scores in an English speaking sample (N=102) with bipolar disorder from the same geographic locations. RESULTS: Chronbach's alphas for the Spanish BISS ranged from 0.6 to 0.93, with the psychosis domain displaying lower reliability. Correlations with the MADRS and YMRS were good and ranged from 0.70 to 0.88. The BISS differentiated well across mood states in English and Spanish versions, with mood state differentiated well using subscales and domains. For the irritability and anxiety domains, Spanish speaking participants had higher scores than English speakers across mood states. Females showed differences in symptom profiles compared to males. LIMITATIONS: The sample sizes in the Spanish speaking manic group were small. The Spanish BISS, tested here primarily in patients of Mexican ancestry, may require revision in other Spanish language populations. CONCLUSIONS: The Spanish BISS, a Spanish language symptom rating scale for bipolar disorder, demonstrates good reliability and validity. Clinical assessment in anxiety and irritability domains is particularly relevant in a Spanish speaking sample. Consistent with prior research, females report higher depression, irritability and anxiety scores irrespective of language spoken. PMID- 27454411 TI - The development of biomarkers to reduce attrition rate in drug discovery focused on oncology and central nervous system. AB - INTRODUCTION: The task of discovery and development of novel therapeutic agents remains an expensive, uncertain, time-consuming, competitive, and inefficient enterprise. Due to a steady increase in the cost and time of drug development and the considerable amount of resources required, a predictive tool is needed for assessing the safety and efficacy of a new chemical entity. AREAS COVERED: This study is focused on the high attrition rate in discovery and development of oncology and central nervous system (CNS) medicines, because the failure rate of these medicines is higher than others. Some approaches valuable in reducing attrition rates are proposed and the judicious use of biomarkers is discussed. EXPERT OPINION: Unlike the significant progress made in identifying and characterizing novel mechanisms of disease processes and targeted therapies, the process of novel drug development is associated with an unacceptably high attrition rate. The application of clinically qualified predictive biomarkers holds great promise for further development of therapeutic targets, improved survival, and ultimately personalized medicine sets for patients. Decisions such as candidate selection, development risks, dose ranging, early proof of concept/principle, and patient stratification are based on the measurements of biologically and/or clinically validated biomarkers. PMID- 27454412 TI - Ketamine for the Prevention of Posttraumatic Stress Disorder in Burned Patients. PMID- 27454413 TI - Registry-based studies of atrial fibrillation from Sweden and Denmark, 2000-2014. AB - OBJECTIVES: We have noticed an increasing number of publications in relation to atrial fibrillation (AF) based on Swedish and Danish health care registries and therefore found it of interest to perform a systematic review of study aims, data sources, exposures, outcomes, journal impact factor, and citation statistics. MATERIALS AND METHODS: We searched PubMed from 2000 to 31 December 2014. We included publications which were entirely or partly based on administrative registries and clinical quality databases, and where AF defined the study population or constituted the study exposure or outcome. RESULTS: Our review returned 1445 studies, of which 173 met the criteria for inclusion in the reviews. We noticed an abundant diversity in study aims, data sources, exposures, and outcome. The annual number of publications increased from 1 to 50. The mean (range) and median journal impact factor in the year of publication was 6.9 (0.8 51.7) and 5.7. The total cumulated number of citations up to the end of 2014 for all 173 publications was 3721, and the mean (range) and median cumulated number of citations per publication was 22.4 (0-250) and 6.0, respectively. CONCLUSIONS: The number of registry-based studies on AF reported from Sweden and Denmark increased substantially from 2000 to 2014, had a great diversity, were well cited and have added information to the understanding of AF epidemiology. PMID- 27454414 TI - Main findings and advances in biomedical engineering and bioinformatics from IWBBIO 2015. PMID- 27454416 TI - Cognitive Behavioral Therapy for Olfactory Reference Syndrome: A Case Report. PMID- 27454415 TI - Heterotrimeric G-proteins facilitate resistance to plant pathogenic viruses in Arabidopsis thaliana (L.) Heynh. AB - Heterotrimeric G-proteins, consisting of Galpha, Gbeta and Ggamma subunits, are important signal transducers in eukaryotes. In plants, G-protein-mediated signaling contributes to defense against a range of fungal and bacterial pathogens. Here we studied response of G-protein-deficient mutants to ssRNA viruses representing 2 different families: Cucumber mosaic virus (CMV) (Bromoviridae) and Turnip mosaic virus (TuMV) (Potyviridae). We found that development of spreading necrosis on infected plants was suppressed in the Gbeta deficient mutant (agb1-2) compared to wild type and Galpha-deficient mutant (gpa1 4). In accordance, ion leakage caused by viral infection was also significantly reduced in agb1-2 compared to wild type and gpa1-4. Nevertheless, both viruses replicated better in agb1-2 plants, while gpa1-4 was similar to wild type. Analysis of pathogenesis-related genes showed that Gbeta negatively regulated salicylic acid, jasmonic acid and abscisic acid marker genes during CMV and TuMV infections. Interestingly, analysis of salicylic acid deficient transgenic plants indicated that salicylic acid did not affect resistance against these viruses and did not influence the Gbeta-mediated defense response. We conclude that heterotrimeric G-proteins play a positive role in defense against viral pathogens probably by promoting cell death. PMID- 27454417 TI - Cardiac arrhythmia classification using multi-modal signal analysis. AB - In this paper, as a contribution to the Physionet/Computing in Cardiology 2015 Challenge, we present individual algorithms to accurately classify five different life threatening arrhythmias with the goal of suppressing false alarm generation in intensive care units. Information obtained by analysing electrocardiogram, photoplethysmogram and arterial blood pressure signals was utilized to develop the classification models. Prior to classification, the signals were subject to a signal pre-processing stage for quality analysis. Classification was performed using a combination of support vector machine based machine learning approach and logical analysis techniques. The predicted result for a certain arrhythmia classification model was verified by logical analysis to aid in reduction of false alarms. Separate feature vectors were formed for predicting the presence or absence of each arrhythmia, using both spectral and time-domain information. The training and test data were obtained from the Physionet/CinC Challenge 2015 database. Classification algorithms were written for two different categories of data, namely real-time and retrospective, whose data lengths were 10 s and an additional 30 s, respectively. For the real-time test dataset, sensitivity of 94% and specificity of 82% were obtained. Similarly, for the retrospective test dataset, sensitivity of 94% and specificity of 86% were obtained. PMID- 27454419 TI - Association Between Rosacea and Parkinson Disease. PMID- 27454418 TI - In vitro and in vivo alpha-amylase and alpha-glucosidase inhibiting activities of the protein extracts from two varieties of bitter gourd (Momordica charantia L.). AB - BACKGROUND: alpha-amylase and alpha-glucosidase digest the carbohydrates and increase the postprandial glucose level in diabetic patients. Inhibiting the activity of these two enzymes can control postprandial hyperglycemia, and reduce the risk of developing diabetes. Bitter gourd or balsam pear is one of the important medicinal plants used for controlling postprandial hyperglycemia in diabetes patients. However, there is limited information available on the presence of alpha-amylase and alpha-glucosidase inhibiting compounds. In the current study, the protein extracts from the fruits of M. charantia var. charantia (MCC) and M. charantia var. muricata (MCM) were tested for alpha amylase and alpha-glucosidase inhibiting activities in vitro, and glucose lowering activity after oral administration in vivo. RESULTS: The protein extract from both MCC and MCM inhibited the activity of alpha-amylase and alpha glucosidase through competitive inhibition, which was on par with Acarbose as indicated by in vitro percentage of inhibition (66 to 69 %) and IC50 (0.26 to 0.29 mg/ml). Both the protein extracts significantly reduced peak blood glucose and area under the curve in Streptozotocin-induced diabetic rats, which were orally challenged with starch and sucrose. CONCLUSIONS: Protein extracts from the fruits of the two varieties of bitter gourd inhibited alpha-amylase and alpha glucosidase in vitro and lowered the blood glucose level in vivo on par with Acarbose when orally administrated to Streptozotocin-induced diabetic rats. Further studies on mechanism of action and methods of safe and biologically active delivery will help to develop an anti-diabetic oral protein drug from these plants. PMID- 27454420 TI - A quantitative enzyme-linked immunosorbent assay for quantification of secretory immunoglobulin A in serum. AB - Secretory immunoglobulin A (SIgA) in serum is possibly the best index of SIgA presence in mucosal secretions in digestive tract and the mirror of its immunologic barrier against many pathogenic aggressions. The measurement of salivary SigA alone may be affected by total salivary secretion and its final concentration in the gland lumen is probably not useful as an appropriate index of mucosal secretions in the digestive tract. The usefulness of the determination of SigA against various epitopes in serum from patients with various autoimmune disease has been demonstrated. The aetiology of many digestive related disorders could be triggered by an alteration of mucose SIgA barrier. The determination of Igs is important for different liver diseases and specifically the SIgA in autoimmune diseases such as rheumatoid arthritis. We developed an easy and efficient immunologic assay to quantify SIgA in serum samples. PMID- 27454421 TI - "Psychometric properties of the Posttraumatic Diagnostic Scale for DSM-5 (PDS 5)": Correction to Foa et al. (2015). AB - Reports an error in "Psychometric Properties of the Posttraumatic Diagnostic Scale for DSM-5 (PDS-5)" by Edna B. Foa, Carmen P. McLean, Yinyin Zang, Jody Zhong, Mark B. Powers, Brooke Y. Kauffman, Sheila Rauch, Katherine Porter and Kelly Knowles (Psychological Assessment, Advanced Online Publication, Dec 21, 2015, np). In the article, the third sentence of the Internal Consistency subsection of the Results section should read: Item 8, "Not being able to remember important parts of the trauma," had an item-total correlation of .34, and Item 16, "Taking more risks or doing things that might cause you or others harm" had an item-total correlation of .44; the range of item-total correlations for the remaining 18 items was .62-.82, with an average of .70." (The following abstract of the original article appeared in record 2015-57068-001.) The aim of this study was to evaluate the psychometric properties of the Posttraumatic Diagnostic Scale for DSM-5 (PDS-5), a self-report measure of posttraumatic stress disorder (PTSD) based on diagnostic criteria of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Participants were 242 urban community residents, veterans, and college undergraduates recruited from 3 study sites who had experienced a DSM-5 Criterion A traumatic experience. The PDS 5 demonstrated excellent internal consistency (alpha = .95) and test-retest reliability (r = .90) and good convergent validity with the PTSD Checklist Specific Version (r = .90) and the PTSD Symptom Scale-Interview Version for DSM-5 (PSSI-5; r = .85). The PDS-5 also showed good discriminant validity with the Beck Depression Inventory-II and the State-Trait Anxiety Inventory-Trait scale (all ZH > 3.05, ps < .01). There was 78% agreement between the PDS-5 and the PSSI-5. Receiver operating characteristic analysis yielded a cutoff score of 28 for identifying a probable PTSD diagnosis. The PDS-5 is a valid and reliable measure of DSM-5 PTSD symptomatology. PMID- 27454422 TI - Admitting the Patient With Acute Stroke to the Right House-Lessons From the Sorting Hat of Hogwarts. PMID- 27454423 TI - Acute Exercise and Motor Memory Consolidation: The Role of Exercise Intensity. AB - A single bout of high intensity aerobic exercise (~90% VO2peak) was previously demonstrated to amplify off-line gains in skill level during the consolidation phase of procedural memory. High intensity exercise is not always a viable option for many patient groups or in a rehabilitation setting where low to moderate intensities may be more suitable. The aim of this study was to investigate the role of intensity in mediating the effects of acute cardiovascular exercise on motor skill learning. We investigated the effects of different exercise intensities on the retention (performance score) of a visuomotor accuracy tracking task. Thirty six healthy male subjects were randomly assigned to one of three groups that performed either a single bout of aerobic exercise at 20 min post motor skill learning at 45% (EX45), 90% (EX90) maximal power output (Wmax) or rested (CON). Randomization was stratified to ensure that the groups were matched for relative peak oxygen consumption (ml O2/min/kg) and baseline score in the tracking task. Retention tests were carried out at 1 (R1) and 7 days (R7) post motor skill learning. At R1, changes in performance scores were greater for EX90 compared to CON (p<0.001) and EX45 (p = 0.011). The EX45 and EX90 groups demonstrated a greater change in performance score at R7 compared to the CON group (p = 0.003 and p<0.001, respectively). The change in performance score for EX90 at R7 was also greater than EX45 (p = 0.049). We suggest that exercise intensity plays an important role in modulating the effects that a single bout of cardiovascular exercise has on the consolidation phase following motor skill learning. There appears to be a dose-response relationship in favour of higher intensity exercise in order to augment off-line effects and strengthen procedural memory. PMID- 27454424 TI - Reevaluating the Need for Electrocardiograms Prior to Initiation of Treatment With Propranolol for Infantile Hemangiomas. PMID- 27454425 TI - Supramolecular Templating Approach for the Solvent-Free Synthesis of Open Framework Metal Oxalates. AB - A series of open-framework metal oxalates (metal = Zn, Co, Mn, Bi, In) were prepared under solvent-free conditions by a supramolecular templating approach. These compounds have cationic, anionic, and neutral frameworks with pore apertures ranging from small 8-membered rings (8 MRs) to extra-large 16 and 20 MRs. The zinc oxalate exhibits a proton conductivity of 2.6 * 10(-3) S cm(-1) at 60 degrees C under 98% relative humidity. PMID- 27454426 TI - Genetic Features of Chinese Patients with Gitelman Syndrome: Sixteen Novel SLC12A3 Mutations Identified in a New Cohort. AB - BACKGROUND: Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy caused by inactivating mutations in the SLC12A3 gene. Although hundreds of different mutations across the SLC12A3 gene have been reported worldwide, data from mainland China are limited. We investigated the clinical manifestations and genetic features of Chinese patients with GS. METHODS: Fifty-four unrelated Chinese patients with clinically diagnosed GS were included. Clinical manifestations and biochemical parameters were collected and analyzed. All exons and flanking regions of the SLC12A3 and CLCNKB genes were screened by direct sequencing. RESULTS: Weakness was the most commonly reported symptom in this cohort of patients with GS. In gender-based analyses, higher systolic blood pressure and urine protein excretion were observed in male patients. For genetic screening, 2 pathogenic SLC12A3 mutations were identified in 38 patients (70.4%), 1 mutation in 11 patients (20.4%) and no mutation in 5 patients (9.3%). In total, 42 distinct pathogenic mutations throughout SLC12A3 were identified; 16 were novel, including 9 missense, 1 deletion, 1 insertion, 3 splice site and 2 nonsense mutations. Eleven mutations were recurrently found in different patients. Among them, T60M and D486N were identified in 11 individuals. No CLCNKB mutations were found. CONCLUSION: Sixteen novel SLC12A3 pathogenic mutations were identified in a cohort of Chinese patients with GS. T60M and D486N were most frequent and appear to be important candidate alleles in Chinese patients with GS. PMID- 27454427 TI - Fully-Automated High-Throughput NMR System for Screening of Haploid Kernels of Maize (Corn) by Measurement of Oil Content. AB - One of the modern crop breeding techniques uses doubled haploid plants that contain an identical pair of chromosomes in order to accelerate the breeding process. Rapid haploid identification method is critical for large-scale selections of double haploids. The conventional methods based on the color of the endosperm and embryo seeds are slow, manual and prone to error. On the other hand, there exists a significant difference between diploid and haploid seeds generated by high oil inducer, which makes it possible to use oil content to identify the haploid. This paper describes a fully-automated high-throughput NMR screening system for maize haploid kernel identification. The system is comprised of a sampler unit to select a single kernel to feed for measurement of NMR and weight, and a kernel sorter to distribute the kernel according to the measurement result. Tests of the system show a consistent accuracy of 94% with an average screening time of 4 seconds per kernel. Field test result is described and the directions for future improvement are discussed. PMID- 27454428 TI - Correction: "I Can Remember Sort of Vivid People...but to Me They Were Plasticine." Delusions on the Intensive Care Unit: What Do Patients Think Is Going On? AB - [This corrects the article DOI: 10.1371/journal.pone.0153775.]. PMID- 27454429 TI - Surveillance of Levofloxacin Resistance in Helicobacter pylori Isolates in Bogota Colombia (2009-2014). AB - Increased resistance of Helicobacter pylori to clarithromycin and metronidazole has resulted in recommendation to substitute fluoroquinolones for eradication therapy. The aims of the study were to determine the prevalence and changes in primary levofloxacin resistance related to H. pylori gyrA sequences. The study utilized H. pylori strains isolated from patients undergoing gastroscopy in Bogota, Colombia from 2009 to 2014. Levofloxacin susceptibility was assessed by agar dilution. Mutations in gyrA sequences affecting the quinolone resistance determining region (QRDR) were evaluated by direct sequencing. Overall, the mean prevalence of primary levofloxacin resistance was 18.2% (80 of 439 samples). Resistance increased from 11.8% (12/102) in 2009 to 27.3% (21/77) in 2014 (p = 0.001). gyrA mutations in levofloxacin resistant strains were present in QRDR positions 87 and 91. The most common mutation was N87I (43.8%, 35/80) followed by D91N (28.8%, 23/80) and N87K (11.3%, 9/80). Levofloxacin resistance increased markedly in Colombia during the six-year study period. Primary levofloxacin resistance was most often mediated by point mutations in gyrA, with N87I being the most common QRDR mutation related to levofloxacin resistance. PMID- 27454430 TI - Predicting the Prognosis of Acute Pancreatitis. PMID- 27454433 TI - [Symptom Vertigo in a Previously Healthy Adolescent]. PMID- 27454431 TI - Tubular Overexpression of Angiopoietin-1 Attenuates Renal Fibrosis. AB - Emerging evidence has highlighted the pivotal role of microvasculature injury in the development and progression of renal fibrosis. Angiopoietin-1 (Ang-1) is a secreted vascular growth factor that binds to the endothelial-specific Tie2 receptor. Ang-1/Tie2 signaling is critical for regulating blood vessel development and modulating vascular response after injury, but is dispensable in mature, quiescent vessels. Although dysregulation of vascular endothelial growth factor (VEGF) signaling has been well studied in renal pathologies, much less is known about the role of the Ang-1/Tie2 pathway in renal interstitial fibrosis. Previous studies have shown contradicting effects of overexpressing Ang-1 systemically on renal tubulointerstitial fibrosis when different engineered forms of Ang-1 are used. Here, we investigated the impact of site-directed expression of native Ang-1 on the renal fibrogenic process and peritubular capillary network by exploiting a conditional transgenic mouse system [Pax8-rtTA/(TetO)7 Ang-1] that allows increased tubular Ang-1 production in adult mice. Using a murine unilateral ureteral obstruction (UUO) fibrosis model, we demonstrate that targeted Ang-1 overexpression attenuates myofibroblast activation and interstitial collagen I accumulation, inhibits the upregulation of transforming growth factor beta1 and subsequent phosphorylation of Smad 2/3, dampens renal inflammation, and stimulates the growth of peritubular capillaries in the obstructed kidney. Our results suggest that Ang-1 is a potential therapeutic agent for targeting microvasculature injury in renal fibrosis without compromising the physiologically normal vasculature in humans. PMID- 27454432 TI - Stability and Repeatability of the Distress Thermometer (DT) and the Edmonton Symptom Assessment System-Revised (ESAS-r) with Parents of Childhood Cancer Survivors. AB - OBJECTIVE: Parents report psychological distress in association with their child's cancer. Reliable tools are needed to screen parental distress over the cancer trajectory. This study aimed to estimate the stability and repeatability of the Distress Thermometer (DT) and the Depression and Anxiety items of the Edmonton Symptom Assessment System-revised (ESAS-r-D; -A) in parents of children diagnosed with cancer. METHODS: Fifty parents (28 mothers, median age = 44) of clinically stable survivors of childhood solid and brain tumours completed questionnaires about their own distress (DT, ESAS-r-D; -A, Brief Symptom Inventory-18: BSI-18, Patient Health Questionnaire-9: PHQ-9, Generalized Anxiety Disorder-7: GAD-7) and their children's quality of life (QoL; Peds Quality of Life: PedsQL) twice, with a month interval between the two assessments. At retest, parents also evaluated life events that occurred between the two time points. Hierarchical regressions explored moderators for the temporal stability of test measures. RESULTS: Stability estimates were ICC = .78 for the DT, .55 for the ESAS-r-D, and .47 for the ESAS-r-A. Caseness agreement between test and retest was substantial for the DT, fair for the ESAS-r-D, and slight for the ESAS r-A. Repeatability analyses indicated that the error range for the DT was more than 2 pts below/above actual measurement, whereas it was more than 3 pts for the ESAS-r-A, and 2.5 for the ESAS-r-D. Instability of the DT could be explained by changes in children's physical QoL, but not by other components of QoL or life events. No moderators of stability could be identified for the ESAS-r items. CONCLUSIONS: The DT appears to be a fairly stable measure when the respondent's condition is stable yet with a relatively wide error range. Fluctuations in distress-related constructs may affect the temporal stability of the DT. The lower stability of ESAS-r items may result from shorter time-lapse instructions resulting in a greater sensitivity to change. Findings support future research on the DT as a reliable instrument in caregivers. PMID- 27454434 TI - [False Medical Treatment Investigation in Otorhinolaryngology by the MDK in Lower Saxony and Bremen]. AB - Objective: In a retrospective study the cases of possibly false medical treatment investigated by the Health Advisory Boards (MDK) in Lower Saxony and Bremen, Germany, in the years from 2012 to 2015 were analyzed. Material and Methods: All relevant data - especially diagnoses and procedures - were recorded in accordance to a standardized data entry form and were evaluated. In addition, relevant case studies are presented. Results: Altogether 206 cases of possibly false medical treatment were recorded for the investigated period. Among them there were 24 cases (12%), in which a false medical treatment was detected. The relevant case studies showed on the one hand, that relevant false medical treatment does occur in the field of ENT-surgery and on the other hand that it is sometimes very difficult do get the right decision even on a high-skilled background. Conclusions: In the field of Otorhinolaryngology there is a constant number of cases for examination in possibly false medical treatment, although the number of detection of false medical treatment is rather lower than in other disciplines. Analysis of possible false medical treatment cases produces the chance of preventing false medical treatment in future. PMID- 27454435 TI - The Host Specificities of Baculovirus per os Infectivity Factors. AB - Baculoviruses are insect-specific pathogens with a generally narrow host ranges. Successful primary infection is initiated by the proper interaction of at least 8 conserved per os infectivity factors (PIFs) with the host's midgut cells, a process that remains largely a mystery. In this study, we investigated the host specificities of the four core components of the PIF complex, P74, PIF1, PIF2 and PIF3 by using Helicoverpa armigera nucleopolyhedrovirus (HearNPV) backbone. The four pifs of HearNPV were replaced by their counterparts from a group I Autographa californica multiple nucleopolyhedrovirus (AcMNPV) or a group II Spodoptera litura nucleopolyhedrovirus (SpltNPV). Transfection and infection assays showed that all the recombinant viruses were able to produce infectious budded viruses (BVs) and were lethal to H. armigera larvae via intrahaemocoelic injection. However, feeding experiments using very high concentration of occlusion bodies demonstrated that all the recombinant viruses completely lost oral infectivity except SpltNPV pif3 substituted pif3-null HearNPV (vHaBacDeltapif3-Sppif3-ph). Furthermore, bioassay result showed that the median lethal concentration (LC50) value of vHaBacDeltapif3-Sppif3-ph was 23-fold higher than that of the control virus vHaBacDeltapif3-Hapif3-ph, indicating that SpltNPV pif3 can only partially substitute the function of HearNPV pif3. These results suggested that most of PIFs tested have strict host specificities, which may account, at least in part, for the limited host ranges of baculoviruses. PMID- 27454436 TI - Disagreement between Skin Prick Tests and Specific IgE in Early Childhood. AB - BACKGROUND: Accurate diagnosis of allergic sensitization is essential in clinical practice and allergy research, and the choice of assessment method may have an important impact. The PASTURE study (Protection against Allergy: Study of Rural Environment) examines the influence of exposure to a dairy farm environment on the occurrence of allergy in a cohort of rural European children from birth to 10 years. The aim of our study was to analyze agreement between skin prick tests (SPTs), to aeroallergens and food allergens, and specific IgE and to evaluate the association of SPT with atopic dermatitis in the 204 French children of the PASTURE study. METHODS: SPT, atopic dermatitis assessment, and specific IgE measurements were performed at 1, 4.5, and 6 years. RESULTS: A total of 137 children attended all three visits. The agreement between SPTs and specific IgE was poor except for perennial aeroallergens at 6 years and for an IgE cutoff greater than 0.7 IU/ml (kappa = 0.69, 0.5202 - 0.8621). The prevalence of positive SPTs increased with age. Positive SPTs were transient at 1 year, whereas they were persistent between 4.5 and 6 years. Positive SPTs at 1 year were predictive of the occurrence of atopic dermatitis during follow-up. CONCLUSION: SPTs did not have good agreement with serum-specific IgE in early childhood. Both tests (SPT and specific IgE) should be used. Skin allergenic reactivity increased with age and was transient at 1 year but associated with the occurrence of atopic dermatitis. PMID- 27454437 TI - Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy. AB - Diabetes elevates matrix metalloproteinase-9 (MMP-9) in the retina and its capillary cells, and activated MMP-9 damages mitochondria, accelerating retinal capillary cell apoptosis, a phenomenon which precedes the development of retinopathy. Diabetes also favors epigenetic modifications regulating the expression of many genes. DNA methylation is maintained by methylating hydroxymethylating enzymes, and retinal DNA methyltransferase (Dnmt) is activated in diabetes. Our aim is to investigate the role of DNA methylation in MMP-9 regulation. The effect of high glucose on 5-methylcytosine (5mC) and 5 hydroxymethyl cytosine (5hmC), and binding of Dnmt1 and hydroxymethylating enzyme (Tet2) on MMP-9 promoter were quantified in retinal endothelial cells. Specific role of Tet2 in MMP-9 activation was validated using Tet2-siRNA. The results were confirmed in the retina from streptozotocin-induced diabetic mouse. Although glucose increased Dnmt1 binding at MMP-9 promoter, it decreased 5mC levels. At the same promoter site, Tet2 binding and 5hmC levels were elevated. Tet2-siRNA ameliorated increase in 5hmC and MMP-9 transcription, and protected mitochondrial damage. Diabetic mice also presented similar dynamic DNA methylation changes in the retinal MMP-9 promoter. Thus, in diabetes transcription of retinal MMP-9 is maintained, in part, by an active DNA methylation-hydroxymethylation process, and regulation of this machinery should help maintain mitochondrial homeostasis and inhibit the development/progression of diabetic retinopathy. PMID- 27454438 TI - The Primary Immune Deficiency Treatment Consortium: how can it improve definitive therapy for PID? PMID- 27454439 TI - A Parts Database with Consensus Parameter Estimation for Synthetic Circuit Design. AB - Mathematical modeling and numerical simulation are crucial to support design decisions in synthetic biology. Accurate estimation of parameter values is key, as direct experimental measurements are difficult and time-consuming. Insufficient data, incompatible measurements, and specialized models that lack universal parameters make this task challenging. Here, we have created a database (PAMDB) that integrates data from 135 publications that contain 118 circuits and 165 genetic parts of the bacterium Escherichia coli. We used a succinct, universal model formulation to describe the part behavior in each circuit. We introduce a constrained consensus inference method that was used to infer the value of the model parameters and evaluated its performance through cross validation in a benchmark of 23 circuits. We discuss these results and summarize the challenges in data integration and parameter inference. This work provides a resource and a methodology that can be used as a point of reference for synthetic circuit modeling. PMID- 27454440 TI - Putting the Cart Before the Horse: Toward the Appropriate Use of DNA Methods for Quality Assurance in the Herbal Supplement Industry. PMID- 27454441 TI - Corrigendum. PMID- 27454442 TI - Detection and quantification of ATP in human blood serum. AB - Two fluorometric sensors based on the tri-serine tri-lactone scaffold and thiourea or sulfonamide moieties serving as hydrogen bond donors allowing for anion binding are described. The sensor utilizing thiourea as a recognition moiety shows fluorescence enhancement while the sensor with sulfonamide shows quenching upon addition of phosphates. Sensor arrays composed of two sensors are able to discriminate structurally similar organic phosphates in the presence of interferents in human blood serum. The quantitative analysis of ATP in human blood serum shows high accuracy (the root mean square error of prediction, 1.65%) without requiring any sample pretreatment. PMID- 27454443 TI - Prospecting Anticancer Compounds in Actinomycetes Recovered from the Sediments of Saint Peter and Saint Paul's Archipelago, Brazil. AB - Saint Peter and Saint Paul's Archipelago is a collection of 15 islets and rocks remotely located in the equatorial Atlantic Ocean. In this particular site, the present project intended to assess the biodiversity and biotechnological potential of bacteria from the actinomycete group. This study presents the first results of this assessment. From 21 sediment samples, 268 strains were isolated and codified as BRA followed by three numbers. Of those, 94 strains were grown in liquid media and submitted to chemical extractions with AcOEt (A), BuOH (B), and MeOH (M). A total of 224 extracts were screened for their cytotoxic activity and 41 were significantly active against HCT-116 cancer cells. The obtained IC50 values ranged from 0.04 to 31.55 MUg/ml. The HR-LC/MS dereplication analysis of the active extracts showed the occurrence of several known anticancer compounds. Individual compounds, identified using HR-MS combined with analysis of the AntiMarin database, included saliniketals A and B, piericidins A and C and glucopiericidin A, staurosporine, N-methylstaurosporine, hydroxydimethyl staurosporine and N-carbamoylstaurosporine, salinisporamycin A, and rifamycins S and B. BRA-199, identified as Streptomyces sp., was submitted to bioassay-guided fractionation, leading to isolation of the bioactive piericidins A and C, glucopiericidin, and three known diketopiperazines, cyclo(l-Phe-trans-4-OH-l Pro), cyclo(l-Phe-l-Pro), and cyclo(l-Trp-l-Pro). PMID- 27454444 TI - Coinage Metal Hydrides: Synthesis, Characterization, and Reactivity. AB - Hydride complexes of copper, silver, and gold encompass a broad array of structures, and their distinctive reactivity has enabled dramatic recent advances in synthesis and catalysis. This Review summarizes the synthesis, characterization, and key stoichiometric reactions of isolable or observable coinage metal hydrides. It discusses catalytic processes in which coinage metal hydrides are known or probable intermediates, and presents mechanistic studies of selected catalytic reactions. The purpose of this Review is to convey how developments in coinage metal hydride chemistry have led to new organic transformations, and how developments in catalysis have in turn inspired the synthesis of reactive new complexes. PMID- 27454445 TI - Enhanced integration of large DNA into E. coli chromosome by CRISPR/Cas9. AB - Metabolic engineering often necessitates chromosomal integration of multiple genes but integration of large genes into Escherichia coli remains difficult. CRISPR/Cas9 is an RNA-guided system which enables site-specific induction of double strand break (DSB) and programmable genome editing. Here, we hypothesized that CRISPR/Cas9-triggered DSB could enhance homologous recombination and augment integration of large DNA into E. coli chromosome. We demonstrated that CRISPR/Cas9 system was able to trigger DSB in >98% of cells, leading to subsequent cell death, and identified that mutagenic SOS response played roles in the cell survival. By optimizing experimental conditions and combining the lambda Red proteins and linear dsDNA, CRISPR/Cas9-induced DSB enabled homologous recombination of the donor DNA and replacement of lacZ gene in the MG1655 strain at efficiencies up to 99%, and allowed high fidelity, scarless integration of 2.4, 3.9, 5.4, and 7.0 kb DNA at efficiencies approaching 91%, 92%, 71%, and 61%, respectively. The CRISPR/Cas9-assisted gene integration also functioned in different E. coli strains including BL21 (DE3) and W albeit at different efficiencies. Taken together, our methodology facilitated precise integration of dsDNA as large as 7 kb into E. coli with efficiencies exceeding 60%, thus significantly ameliorating the editing efficiency and overcoming the size limit of integration using the commonly adopted recombineering approach. Biotechnol. Bioeng. 2017;114: 172-183. (c) 2016 Wiley Periodicals, Inc. PMID- 27454447 TI - Effect of a Modest Weight Loss in Normalizing Blood Pressure in Obese Subjects on Antihypertensive Drugs. AB - OBJECTIVE: To assess the effect of a lifestyle intervention in lowering/normalizing blood pressure (BP) levels in hypertensive (controlled or not) obese patients. METHODS: In this prospective observational study, 490 obese hypertensive patients, 389 controlled (BP < 140/90 mm Hg; CH) and 101 uncontrolled (BP >= 140/90 mm Hg; UH) attended a 3-month lifestyle intervention. Before and after the intervention we assessed weight, waist circumference, fat mass, BP, metabolic and renal variables, and physical activity. A multivariate regression model was used to determine the predictors of BP changes. RESULTS: 18.9% of CH and 20.0% of UH were on >= 3 antihypertensive drugs. Weight change (average -4.9 +/- 2.7%) was independent of the antihypertensive drugs employed. Systolic BP (SBP) decreased by 23 mm Hg and diastolic BP (DBP) by 9 mm Hg, in patients with UH most of whom (89%) normalized BP levels (in 49% after a weight loss < 5%). Age, gender, whole and central obesity, concomitance of type 2 diabetes, chronic renal disease, physical activity intensification, and pharmacological therapy did not affect BP lowering. In the regression analysis with SBP change as dependent variable, weight reduction (beta = 0.523, p = 0.005) and group (UH vs. CH, beta = -19.40, p = 0.0005) remained associated with SBP reduction. When DBP change was entered as dependent variable, baseline uric acid remained associated with DBP reduction (beta = 0.824, p < 0.05). CONCLUSION: Lifestyle interventions are useful for all obese hypertensive patients in most of whom a modest weight loss is sufficient to normalize BP levels avoiding the aggressive use of multiple antihypertensive drugs. PMID- 27454448 TI - Improved harmonisation from policy dialogue? Realist perspectives from Guinea and Chad. AB - BACKGROUND: Harmonisation is a key principle of the Paris Declaration. The Universal Health Coverage (UHC) Partnership, an initiative of the European Union, the Government of Luxembourg and the World Health Organization, supported health policy dialogues between 2012 and 2015 in identified countries in the WHO African Region. The UHC Partnership has amongst its key objectives to strengthen national health policy development. In Guinea and Chad, policy dialogue focused on elaborating the national health plan and other key documents. This study is an analytical reflection inspired by realist evaluative approaches to understand whether policy dialogue led to improved harmonisation amongst health actors in Guinea and Chad, and if so, how and why. METHODS: Interviews were conducted in Guinea and Chad with key informants at the national and sub-national government levels, civil society, and development partners. A review of relevant policy documents and reports was added to data collection to construct a full picture of the policy dialogue process. Context-mechanism-outcome configurations were used as the realist framework to guide the analysis on how participants' understanding of what policy dialogue was and the way the policy dialogue process unfolded led to improved harmonisation. RESULTS: Improved harmonisation as a result of policy dialogue was perceived to be stronger in Guinea than in Chad. While in both countries the participants held a shared view of what policy dialogue was and what it could achieve, and both policy dialogue processes were considered to be well implemented (i.e., well-facilitated, evidence-based, participatory, and consisted of recurring meetings and activities), certain contextual factors in Chad tempered the view of harmonisation as having improved. These were the pre existence of dialogic policy processes that had exposed the actors to the potential that policy dialogue could have; a focus on elaborating provincial level strategies, which gave the sense that the process was more bottom-up; and the perception that there were acute resource constraints, which conditioned partners' interactions. CONCLUSIONS: Policy dialogue improves harmonisation in terms of fostering information exchange amongst partners; however, it does not appear to influence the operational procedures of the actors. This has implications for aid effectiveness. PMID- 27454449 TI - Sensorimotor control: computing the immediate future from the delayed present. AB - BACKGROUND: The predictive nature of the primate sensorimotor systems, for example the smooth pursuit system and their ability to compensate for long delays have been proven by many physiological experiments. However, few theoretical models have tried to explain these facts comprehensively. Here, we propose a sensorimotor learning and control model that can be used to (1) predict the dynamics of variable time delays and current and future sensory states from delayed sensory information; (2) learn new sensorimotor realities; and (3) control a motor system in real time. RESULTS: This paper proposed a new time delay estimation method and developed a computational model for a predictive control solution of a sensorimotor control system under time delay. Simulation experiments are used to demonstrate how the proposed model can explain a sensorimotor system's ability to compensate for delays during online learning and control. To further illustrate the benefits of the proposed time-delay estimation method and predictive control in sensorimotor systems a simulation of the horizontal Vestibulo-Ocular Reflex (hVOR) system is presented. Without the proposed time-delay estimation and prediction, the hVOR can be unstable and could be affected by high frequency oscillations. These oscillations are reminiscent of a fast correction mechanism, e.g., a saccade to compensate for the hVOR delays. Comparing results of the proposed model with those in literature, it is clear that the hVOR system with impaired time-delay estimation or impaired sensory state predictor can mimic certain outcomes of sensorimotor diseases. Even more, if the control of hVOR is augmented with the proposed time-delay estimator and the predictor for eye position relative to the head, then hVOR control system can be stabilized. CONCLUSIONS: Three claims with varying degrees of experimental support are proposed in this paper. Firstly, the brain or any sensorimotor system has time-delay estimation circuits for the various sensorimotor control systems. Secondly, the brain continuously estimates current/future sensory states from the previously sensed states. Thirdly, the brain uses predicted sensory states to perform optimal motor control. PMID- 27454450 TI - Health policy dialogue: experiences from Africa. PMID- 27454452 TI - Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation. AB - PURPOSE OF REVIEW: To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. RECENT FINDINGS: CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events. However, outcome studies of three CETP inhibitors (torcetrapib, dalcetrapib and evacetrapib) were prematurely terminated because of increased mortality or futility despite marked increases in HDL-cholesterol and decreases in LDL-cholesterol except for dalcetrapib. Patients with CETP deficiency show remarkable changes in HDL and LDL and are sometimes accompanied by atherosclerotic cardiovascular diseases. Recent prospective epidemiological studies demonstrated atheroprotective roles of CETP. CETP inhibition induces formation of small dense LDL and possibly dysfunctional HDL and downregulates hepatic scavenger receptor class B type I (SR-BI). Therefore, CETP inhibitors may interrupt LDL receptor and SR-BI-mediated cholesterol delivery back to the liver. SUMMARY: For future drug development, the opposite strategy, namely enhancers of RCT via CETP and SR-BI activation as well as the inducers of apolipoprotein A-I or HDL production might be a better approach rather than delaying HDL metabolism by inhibiting a main stream of RCT in vivo. PMID- 27454453 TI - Observing wandering-related boundary transgression in people with severe dementia. AB - OBJECTIVES: Wandering-related boundary transgression (BT) in long term care (LTC) frequently manifests as intrusion into another resident's bedroom and is associated with adverse outcomes (loss of privacy, resident-to-resident altercations, and becoming lost). This observational study is the first to empirically describe the characteristics of wandering-related BT in LTC residents with severe dementia. METHOD: Using real-time observation, seven independently ambulant residents with severe dementia and a positive history of wandering and BT were observed for a minimum of twelve 30 minute periods randomized over two non-consecutive days (n=92 observation periods). Frequency and duration of locomoting/non-locomoting phases and BT (entry into out of bounds/private space), patterns of ambulation (direct, random, pacing, and lapping), and activities observed during BT were measured during observation periods. RESULTS: Across 431 locomoting phases, 58 (13%) resulted in a BT and the bedroom of another resident was most frequently (86%) involved. BT was statistically associated with random ambulation and peak activity periods, and was observed more often in those with more frequent ambulation. Most BT events were unwitnessed by others and occurred when the participant was alone. CONCLUSIONS: Describing BT has increased understanding of when, where, and how BT occurs and provides background for future intervention research. PMID- 27454451 TI - Notch, lipids, and endothelial cells. AB - PURPOSE OF REVIEW: Notch signaling is an evolutionary conserved pathway critical for cardiovascular development and angiogenesis. More recently, the contribution of Notch signaling to the homeostasis of the adult vasculature has emerged as an important novel paradigm, but much remains to be understood. RECENT FINDINGS: Recent findings shed light on the impact of Notch in vascular and immune responses to microenvironmental signals as well as on the onset of atherosclerosis. In the past year, studies in human and mice explored the role of Notch in the maintenance of a nonactivated endothelium. Novel pieces of evidence suggest that this pathway is sensitive to environmental factors, including inflammatory mediators and diet-derived by-products. SUMMARY: An emerging theme is the ability of Notch to respond to changes in the microenvironment, including glucose and lipid metabolites. In turn, alterations in Notch enable an important link between metabolism and transcriptional changes, thus this receptor appears to function as a metabolic sensor with direct implications to gene expression. PMID- 27454454 TI - The impact of the United States Preventive Services Task Force (USPTSTF) recommendations against prostate-specific antigen (PSA) testing on PSA testing in Australia. AB - OBJECTIVE: To assess the impact of the United States Preventive Services Task Force (USPTSTF) recommendations on prostate-specific antigen (PSA) testing, prostate biopsy, and prostatectomy in Australian men based on the available Medicare data. PATIENTS AND METHODS: Events were identified using Medicare item numbers for PSA testing (66655, 66659), prostate biopsy (37219), prostatectomy (37210), and prostatectomy with lymph node dissection (37211). The occurrences of each procedure was queried per 100 000 capita for consecutive financial years over the period 2000-2015. For each item number, reports were also generated for all Australian States. For PSA testing the data was stratified into three age groups of 45-54, 55-64, and 65-74 years. For assessing the rate of prostatectomy the capita rate values for two item numbers of prostatectomy (37210) and prostatectomy with lymph node dissection (37211) were combined. RESULTS: Steady declines in per capita incidences of all five item numbers assessed were seen for the three consecutive financial years (2013-2015) since the publication of the USPTSTF recommendation statement. These declines were seen across all Australian States. When examining the rate of PSA testing for the three age brackets 45-54, 55-64, and 65-74 years, similar trends were identified. CONCLUSIONS: Since the introduction of the USPTSTF recommendation statement there has been a steady nationwide decline in per capita incidences of PSA testing, prostate biopsy, and prostatectomy based on the Australian Medicare data. Whether these declines are in the right direction toward reduction in over-diagnosis and overtreatment of clinically insignificant prostate cancer or stage migration toward more locally advanced disease due to lost opportunity in diagnosing and treating early clinically significant prostate cancer will remain to be seen. PMID- 27454455 TI - High-throughput metabarcoding of eukaryotic diversity for environmental monitoring of offshore oil-drilling activities. AB - As global exploitation of available resources increases, operations extend towards sensitive and previously protected ecosystems. It is important to monitor such areas in order to detect, understand and remediate environmental responses to stressors. The natural heterogeneity and complexity of communities means that accurate monitoring requires high resolution, both temporally and spatially, as well as more complete assessments of taxa. Increased resolution and taxonomic coverage is economically challenging using current microscopy-based monitoring practices. Alternatively, DNA sequencing-based methods have been suggested for cost-efficient monitoring, offering additional insights into ecosystem function and disturbance. Here, we applied DNA metabarcoding of eukaryotic communities in marine sediments, in areas of offshore drilling on the Norwegian continental shelf. Forty-five samples, collected from seven drilling sites in the Troll/Oseberg region, were assessed, using the small subunit ribosomal RNA gene as a taxonomic marker. In agreement with results based on classical morphology based monitoring, we were able to identify changes in sediment communities surrounding oil platforms. In addition to overall changes in community structure, we identified several potential indicator taxa, responding to pollutants associated with drilling fluids. These included the metazoan orders Macrodasyida, Macrostomida and Ceriantharia, as well as several ciliates and other protist taxa, typically not targeted by environmental monitoring programmes. Analysis of a co-occurrence network to study the distribution of taxa across samples provided a framework for better understanding the impact of anthropogenic activities on the benthic food web, generating novel, testable hypotheses of trophic interactions structuring benthic communities. PMID- 27454456 TI - Species delimitation and phylogeographic analyses in the Ectocarpus subgroup siliculosi (Ectocarpales, Phaeophyceae). AB - The genus Ectocarpus (Ectocarpales, Phaeophyceae) contains filamentous algae widely distributed in marine and estuarine habitats of temperate regions in both hemispheres. While E. siliculosus has become a model organism for genomics and genetics of the brown macroalgae, accurate species delineation, distribution patterns and diversity for the genus Ectocarpus remain problematic. In this study, we used three independent species delimitation approaches to generate a robust species hypothesis for 729 Ectocarpus specimens collected mainly along the European and Chilean coasts. These approaches comprised phylogenetic reconstructions and two bioinformatics tools developed to objectively define species boundaries (General Mixed Yule Coalescence Method and Automatic Barcode Gap Discovery). Our analyses were based on DNA sequences of two loci: the mitochondrial cytochrome oxidase subunit 1 and the nuclear internal transcribed spacer 1 of the ribosomal DNA. Our analyses showed the presence of at least 15 cryptic species and suggest the existence of incomplete lineage sorting or introgression between five of them. These results suggested the possible existence of different levels of reproductive barriers within this species complex. We also detected differences among species in their phylogeographic patterns, range and depth distributions, which may suggest different biogeographic histories (e.g., endemic species or recent introductions). PMID- 27454458 TI - P2-Na2/3Ni1/3Mn5/9Al1/9O2 Microparticles as Superior Cathode Material for Sodium Ion Batteries: Enhanced Properties and Mechanisam via Graphene Connection. AB - As a promising alternative for lithium ion batteries, room-temperature sodium ion batteries (SIBs) have become one significant research frontier of energy storage devices although there are still many difficulties to be overcome. For the moment, the studies still concentrate on the preparation of new electrode materials for SIBs to meet the applicability. Herein, one new P2 Na2/3Ni1/3Mn5/9Al1/9O2 (NMA) cathode material is successfully prepared via a simple and facile liquid-state method. The prepared NMA is layered transition metal oxide, which can keep stable crystal structure during sodiation/desodiation as demonstrated by the ex situ X-ray diffraction, and its electrochemical properties can be further enhanced by connecting the cake-like NMA microparticles with reduced graphene oxide (RGO) using a ball milling method. Electrochemical tests show that the formed RGO-connected NMA (NMA/RGO) can deliver a higher reversible capacity of up to 138 mAh g(-1) at 0.1 C and also exhibit a superior high-rate capabilities and cycling stability in comparison to pure NMA. The much improved properties should be attributed to the reduced particle size and improvement of electrical conductivity and apparent Na(+) diffusion due to RGO incorporation, which is comprehensively verified by the electrochemical technologies of galvanostatic intermittent titration technique, electrochemical impedance spectroscopy and cyclic voltammetry at various scan rate as well as ex situ X-ray diffraction studies. PMID- 27454457 TI - High-frequency pulsed low-level diode laser therapy accelerates wound healing of tooth extraction socket: An in vivo study. AB - BACKGROUND AND OBJECTIVE: This study aimed to evaluate the effects of high frequency pulsed (HiFP) low-level laser therapy (LLLT) on early wound healing of tooth extraction sockets in rats. STUDY DESIGN/MATERIALS AND METHODS: Bilateral maxillary first molars were extracted from 6-week-old Sprague-Dawley rats. Sockets on the right were treated by HiFP low-level diode laser irradiation (904 910 nm); the left sides served as unirradiated controls. LLLT (0.28 W, 30 kHz, 200-ns pulse, 0.6% duty cycle, 61.2 J/cm2 total power density) was employed immediately after extraction and every 24 hours thereafter. The maxillae including the sockets were resected 3 or 7 days after extraction. Soft-tissue healing was evaluated on days 0, 3, and 7. The bone mineral content (BMC), bone volume (BV), and bone mineral density (BMD) of the extraction sockets were evaluated by microcomputed tomography, and histomorphometric analysis was carried out on day 7. Real-time PCR analysis of osteogenic marker expression and immunohistochemical detection of proliferating cell nuclear antigen (PCNA) positive cells were performed on day 3. RESULTS: Compared with control sites, the un-epithelialized areas of the extracted sites were significantly reduced by irradiation (P = 0.04), and the BMC, BV, and BMD of laser-treated sites were significantly increased (P = 0.004, 0.006, and 0.009, respectively). On day 7, the mean height of newly formed immature woven bone was higher in laser-treated sites (P = 0.24). On day 3, laser-treated sites showed significantly higher osteocalcin mRNA expression (P = 0.04) and PCNA-positive cell numbers (P = 0.01). CONCLUSION: HiFP low-level diode laser irradiation enhanced soft- and hard-tissue healing of tooth extraction sockets. Lasers Surg. Med. 48:955-964, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27454459 TI - Molecular insight into the Grandivitin- matrix metalloproteinase 9 interactions. AB - Grandivitin (GRA), a natural coumarin, can inhibit Matrix metalloproteinase 9 (MMP9). Binding characteristics are therefore of interest for pharmacodynamics of GRA and coumarin derivatives. A combination of spectroscopic methods and molecular modeling techniques was used to characterize interaction of GRA with MMP9. Fluorescence spectroscopy showed that GRA could quench the MMP9 fluorescence spectra. Changes in the UV-Vis and FT-IR spectra were observed upon ligand binding along with a significant degree of tryptophan fluorescence quenching on complex formation. Fluorescence studies showed that GRA has an ability to quench the intrinsic fluorescence of MMP9. Molecular modeling analysis showed that GRA to be bound in the large hydrophobic cavity of MMP9. Further investigation of the binding site of GRA within the MMP9 molecule suggested that hydrophobic contacts, hydrogen bond formation and electrostatic interactions account for the binding of GRA. According molecular dynamics (MD) simulation results the ligand can interact with the protein, with affecting the secondary structure of MMP9 and with a modification of its tertiary structure. The biological significance of this work is evident because MMP9 serves as a potential target protein for anticancer agents. The binding study of GRA with MMP9 is of great importance in pharmacy, pharmacology and biochemistry. This work can provide some key data to clinical research and supply the theoretical basis for the new drug candidate designing. PMID- 27454461 TI - Clinical Spine Surgery Focus Issue: The Lumbar Spine. PMID- 27454460 TI - Root coverage procedures improve patient aesthetics. A systematic review and Bayesian network meta-analysis. AB - BACKGROUND: The aim of this study was to perform a systematic review (SR) of randomized controlled trials (RCTs) to explore if periodontal plastic surgery procedures for the treatment of single and multiple gingival recessions (Rec) may improve aesthetics at patient and professional levels. MATERIAL AND METHODS: In order to combine evidence from direct and indirect comparisons by different trials a Bayesian network meta-analysis (BNM) was planned. A literature search on PubMed, Cochrane libraries, EMBASE, and hand-searched journals until January 2016 was conducted to identify RCTs presenting aesthetic outcomes after root coverage using standardized evaluations at patient and professional level. RESULTS: A total of 16 RCTs were selected in the SR; three RTCs presenting professional aesthetic evaluation with Root coverage Aesthetic Score (RES) and three showing final self-perception using the Visual Analogue Scale (VAS Est) could be included in a BNM model. Coronally Advanced Flap plus Connective Tissue Graft (CAF + CTG) and CAF + Acellular Dermal Matrix (ADM) and Autologous Fibroblasts (AF) were associated with the best RES outcomes (best probability = 24% and 64%, respectively), while CAF + CTG and CAF + CTG + Enamel matrix Derivatives (EMD) obtained highest values of VAS Est score (best probability = 44% and 26%, respectively). CONCLUSIONS: Periodontal Plastic Surgery (PPS) techniques applying grafts underneath CAF with or without the adding of EMD are associated with improved aesthetics assessed by final patient perception and RES as professional evaluation system. PMID- 27454462 TI - Sensitivity of resonant tunneling diode photodetectors. AB - We have studied the sensitivity of AlGaAs/GaAs double barrier resonant tunneling diode photodetectors with an integrated GaInNAs absorption layer for light sensing at the telecommunication wavelength of lambda = 1.3 MUm for illumination powers from pico- to microwatts. The sensitivity decreases nonlinearly with power. An illumination power increase of seven orders of magnitude leads to a reduction of the photocurrent sensitivity from S I = 5.82 * 10(3) A W(-1) to 3.2 A W(-1). We attribute the nonlinear sensitivity-power dependence to an altered local electrostatic potential due to hole-accumulation that on the one hand tunes the tunneling current, but on the other hand affects the lifetime of photogenerated holes. In particular, the lifetime decreases exponentially with increasing hole population. The lifetime reduction results from an enhanced electrical field, a rise of the quasi-Fermi level, and an increased energy splitting within the triangular potential well. The non-constant sensitivity is a direct result of the non-constant lifetime. Based on these findings, we provide an expression that allows us to calculate the sensitivity as a function of illumination power and bias voltage, show a way to model the time-resolved photocurrent, and determine the critical power up to which the resonant tunneling diode photodetector sensitivity can be assumed constant. PMID- 27454464 TI - Understanding proenvironmental intentions and behaviors: The importance of considering both the behavior setting and the type of behavior. AB - To better understand the consistency of people's proenvironmental intentions and behaviors, we set out to examine two sets of research questions. First, do people perform (1) different types of proenvironmental behaviors consistently, and (2) the same proenvironmental behavior consistently across settings? Second, are there consistent predictors of proenvironmental behavioral intentions across behavior and setting type? Participants reported four recycling and conservation behaviors across three settings, revealing significant variability in rates of behaviors across settings. Prior behavior, attitudes toward the behavior, and importance of the behaviour consistently predicted proenvironmental intentions. However, perceived behavioral control tended to predict intentions to perform proenvironmental behavior outside the home. Future research aimed at understanding and influencing different proenvironmental behaviors should carefully consider how settings affect intentions and behavior. PMID- 27454465 TI - Surface modification of oleylamine-capped Ag-Cu nanoparticles to fabricate low temperature-sinterable Ag-Cu nanoink. AB - By treating oleylamine (OA)-capped Ag-Cu nanoparticles with tetramethylammonium hydroxide (TMAH), we obtained metal nanoparticles that are suspended in polar solvents and sinterable at low temperatures. The simple process with ultra sonication enables synthesis of monodispersed and high purity nanoparticles in an organic base, where the resulting nanoparticles are dispersible in polar solvents such as ethanol and isopropyl alcohol. To investigate the surface characteristics, we conducted Fourier-transform infrared and zeta-potential analyses. After thermal sintering at 200 degrees C, which is approximately 150 degrees C lower than the thermal decomposition temperature of OA, an electrically conductive thin film was obtained. Electrical resistivity measurements of the TMAH-treated ink demonstrate that surface modified nanoparticles have a low resistivity of 13.7 * 10(-6) Omega cm. These results confirm the prospects of using low-temperature sinterable nanoparticles as the electrode layer for flexible printed electronics without damaging other stacked polymer layers. PMID- 27454463 TI - Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus. AB - Dysmenorrhea is a common chronic pelvic pain syndrome affecting women of childbearing potential. Family studies suggest that genetic background influences the severity of dysmenorrhea, but genetic predisposition and molecular mechanisms underlying dysmenorrhea are not understood. In this study, we conduct the first genome-wide association study to identify genetic factors associated with dysmenorrhea pain severity. A cohort of females of European descent (n = 11,891) aged 18 to 45 years rated their average dysmenorrhea pain severity. We used a linear regression model adjusting for age and body mass index, identifying one genome-wide significant (P < 5 * 10) association (rs7523086, P = 4.1 * 10, effect size 0.1 [95% confidence interval, 0.074-0.126]). This single nucleotide polymorphism is colocalising with NGF, encoding nerve growth factor. The presence of one risk allele corresponds to a predicted 0.1-point increase in pain intensity on a 4-point ordinal pain scale. The putative effects on NGF function and/or expression remain unknown. However, genetic variation colocalises with active epigenetic marks in fat and ovary tissues, and expression levels in aorta tissue of a noncoding RNA flanking NGF correlate. Participants reporting extreme dysmenorrhea pain were more likely to report being positive for endometriosis, polycystic ovarian syndrome, depression, and other psychiatric disorders. Our results indicate that dysmenorrhea pain severity is partly genetically determined. NGF already has an established role in chronic pain disorders, and our findings suggest that NGF may be an important mediator for gynaecological/pelvic pain in the viscera. PMID- 27454466 TI - Advancing Clinical Proteomics via Analysis Based on Biological Complexes: A Tale of Five Paradigms. AB - Despite advances in proteomic technologies, idiosyncratic data issues, for example, incomplete coverage and inconsistency, resulting in large data holes, persist. Moreover, because of naive reliance on statistical testing and its accompanying p values, differential protein signatures identified from such proteomics data have little diagnostic power. Thus, deploying conventional analytics on proteomics data is insufficient for identifying novel drug targets or precise yet sensitive biomarkers. Complex-based analysis is a new analytical approach that has potential to resolve these issues but requires formalization. We categorize complex-based analysis into five method classes or paradigms and propose an even-handed yet comprehensive evaluation rubric based on both simulated and real data. The first four paradigms are well represented in the literature. The fifth and newest paradigm, the network-paired (NP) paradigm, represented by a method called Extremely Small SubNET (ESSNET), dominates in precision-recall and reproducibility, maintains strong performance in small sample sizes, and sensitively detects low-abundance complexes. In contrast, the commonly used over-representation analysis (ORA) and direct-group (DG) test paradigms maintain good overall precision but have severe reproducibility issues. The other two paradigms considered here are the hit-rate and rank-based network analysis paradigms; both of these have good precision-recall and reproducibility, but they do not consider low-abundance complexes. Therefore, given its strong performance, NP/ESSNET may prove to be a useful approach for improving the analytical resolution of proteomics data. Additionally, given its stability, it may also be a powerful new approach toward functional enrichment tests, much like its ORA and DG counterparts. PMID- 27454467 TI - BioWes-from design of experiment, through protocol to repository, control, standardization and back-tracking. AB - BACKGROUND: One of the main challenges in modern science is the amount of data produced by the experimental work; it is difficult to store, organize and share the scientific data and to extract the wealth of knowledge. Experimental method descriptions in scientific publications are often incomplete, which complicates experimental reproducibility. The proposed system was created in order to address these issues. It provides a solution for management of the experimental data and metadata to support the reproducibility. IMPLEMENTATION: The system is implemented as a repository for experiment descriptions and experimental data. It has three main entry points: desktop application for protocol design and data processing, web interface dedicated for protocol and data management, and web based interface for mobile devices suitable for the field experiments. The functionality of desktop client can be extended using the custom plug-ins for data extraction and data processing. The system provides several methods to support experimental reproducibility: standardized terminology support, data and metadata at a single location, standardized protocol design or protocol evolution. RESULTS AND DISCUSSION: The system was tested in the framework of international infrastructure project AQUAEXCEL with five pilot installations at different institutes. The general testing in Tissue culture certified laboratory, Institute of complex systems and IFREMER verified the usability under different research infrastructures. The specific testing focused on the data processing modules and plug-ins demonstrated the modularity of the system for the specific conditions. The BioWes system represents experimental data as black box and therefore can handle any data type so as to provide broad usability for a variety of experiments and provide the data management infrastructure to improve the reproducibility and data sharing. CONCLUSIONS: The proposed system provides the tools for standard data management operations and extends the support by the standardization possibilities, protocol evolution with visualization features and modularity based on the data processing modules and device communication plug ins. The software can be used at different organization levels: from a single researcher (to improve data organization) to research consortium through the central protocols management repository. Support from the protocol design until being shared with the standardization features helps to improve the reproducibility of research work. The platform provides support from experimental protocol design to cooperation using simple sharing. PMID- 27454469 TI - Potential of Translationally Controlled Tumor Protein-Derived Protein Transduction Domains as Antigen Carriers for Nasal Vaccine Delivery. AB - Nasal vaccination offers a promising alternative to intramuscular (i.m.) vaccination because it can induce both mucosal and systemic immunity. However, its major drawback is poor absorption of large antigens in the nasal epithelium. Protein transduction domains (PTDs), also called cell-penetrating peptides, have been proposed as vehicles for nasal delivery of therapeutic peptides and proteins. Here, we evaluated the potential of a mutant PTD derived from translationally controlled tumor protein (designated TCTP-PTD 13) as an antigen carrier for nasal vaccines. We first compared the l- and d-forms of TCTP-PTD 13 isomers (l- or d-TCTP-PTD 13) as antigen carriers. Studies in mice demonstrated that nasally administered mixtures of the model antigen ovalbumin (OVA) and d TCTP-PTD 13 induced higher plasma IgG titers and secretory IgA levels in nasal washes than nasally administered OVA alone, OVA/l-TCTP-PTD 13, or i.m.-injected OVA. Plasma IgG subclass responses (IgG1 and IgG2a) of mice nasally administered OVA/d-TCTP-PTD 13 showed that the predominant IgG subclass was IgG1, indicating a Th2-biased immune response. We also used synthetic CpG oligonucleotides (CpG) as a Th1 immune response-inducing adjuvant. Nasally administered CpG plus OVA/d-TCTP PTD 13 was superior in eliciting systemic and mucosal immune responses compared to those induced by nasally administered OVA/d-TCTP-PTD 13. Furthermore, the OVA/CpG/d-TCTP-PTD 13 combination skewed IgG1 and IgG2a profiles of humoral immune responses toward a Th1 profile. These findings suggest that TCTP-derived PTD is a suitable vehicle to efficiently carry antigens and to induce more powerful antigen-specific immune responses and a more balanced Th1/Th2 response when combined with a DNA adjuvant. PMID- 27454468 TI - Bacterial agents causing meningitis during 2013-2014 in Turkey: A multi-center hospital-based prospective surveillance study. AB - This is an observational epidemiological study to describe causes of bacterial meningitis among persons between 1 month and 18 y of age who are hospitalized with suspected bacterial meningitis in 7 Turkish regions. covering 32% of the entire population of Turkey. We present here the results from 2013 and 2014. A clinical case with meningitis was defined according to followings: any sign of meningitis including fever, vomiting, headache, and meningeal irritation in children above one year of age and fever without any documented source, impaired consciousness, prostration and seizures in those < 1 y of age. Single tube multiplex PCR assay was performed for the simultaneous identification of bacterial agents. The specific gene targets were ctrA, bex, and ply for N. meningitidis, Hib, and S. pneumoniae, respectively. PCR positive samples were recorded as laboratory-confirmed acute bacterial meningitis. A total of 665 children were hospitalized for suspected acute meningitis. The annual incidences of acute laboratory-confirmed bacterial meningitis were 0.3 cases / 100,000 population in 2013 and 0.9 cases/100,000 in 2014. Of the 94 diagnosed cases of bacterial meningitis by PCR, 85 (90.4%) were meningococcal and 9 (9.6%) were pneumococcal. Hib was not detected in any of the patients. Among meningococcal meningitis, cases of serogroup Y, A, B and W-135 were 2.4% (n = 2), 3.5% (n = 3), 32.9% (n = 28), and 42.4% (n = 36). No serogroup C was detected among meningococcal cases. Successful vaccination policies for protection from bacterial meningitis are dependent on accurate determination of the etiology of bacterial meningitis. Additionally, the epidemiology of meningococcal disease is dynamic and close monitoring of serogroup distribution is comprehensively needed to assess the benefit of adding meningococcal vaccines to the routine immunization program. PMID- 27454471 TI - Recommendation of Combination of Radial Endobronchial Ultrasound With Virtual Bronchoscopic Navigation. PMID- 27454470 TI - Creation of reference DNA barcode library and authentication of medicinal plant raw drugs used in Ayurvedic medicine. AB - BACKGROUND: Ayurveda is a system of traditional medicine that originated in ancient India, and it is still in practice. Medicinal plants are the backbone of Ayurveda, which heavily relies on the plant-derived therapeutics. While Ayurveda is becoming more popular in several countries throughout the World, lack of authenticated medicinal plant raw drugs is a growing concern. Our aim was to DNA barcode the medicinal plants that are listed in the Ayurvedic Pharmacopoeia of India (API) to create a reference DNA barcode library, and to use the same to authenticate the raw drugs that are sold in markets. METHODS: We have DNA barcoded 347 medicinal plants using rbcL marker, and curated rbcL DNA barcodes for 27 medicinal plants from public databases. These sequences were used to create Ayurvedic Pharmacopoeia of India - Reference DNA Barcode Library (API RDBL). This library was used to authenticate 100 medicinal plant raw drugs, which were in the form of powders (82) and seeds (18). RESULTS: Ayurvedic Pharmacopoeia of India - Reference DNA Barcode Library (API-RDBL) was created with high quality and authentic rbcL barcodes for 374 out of the 395 medicinal plants that are included in the API. The rbcL DNA barcode differentiated 319 species (85 %) with the pairwise divergence ranging between 0.2 and 29.9 %. PCR amplification and DNA sequencing success rate of rbcL marker was 100 % even for the poorly preserved medicinal plant raw drugs that were collected from local markets. DNA barcoding revealed that only 79 % raw drugs were authentic, and the remaining 21 % samples were adulterated. Further, adulteration was found to be much higher with powders (ca. 25 %) when compared to seeds (ca. 5 %). CONCLUSIONS: The present study demonstrated the utility of DNA barcoding in authenticating medicinal plant raw drugs, and found that approximately one fifth of the market samples were adulterated. Powdered raw drugs, which are very difficult to be identified by taxonomists as well as common people, seem to be the easy target for adulteration. Developing a quality control protocol for medicinal plant raw drugs by incorporating DNA barcoding as a component is essential to ensure safety to the consumers. PMID- 27454472 TI - Fellowship Training in Lung Transplantation. PMID- 27454473 TI - Safety and Efficacy of Radial EBUS for the Investigation of Peripheral Pulmonary Lesions in Patients With Advanced COPD. AB - BACKGROUND: Peripheral pulmonary lesion (PPL) is a common scenario in patients with chronic obstructive pulmonary disease (COPD) and represents a high risk of malignancy. Severe COPD is associated with higher complication rates following percutaneous biopsy, and routine bronchoscopy. Safety and diagnostic performance of radial endobronchial ultrasound bronchoscopy (R-EBUS) in patients with advanced COPD has not been previously assessed. METHODS: We examined a retrospective cohort of patients with advanced COPD undergoing R-EBUS for the evaluation of PPL. RESULTS: During the study period, 92 patients underwent 94 R EBUS procedures. In 50 cases, patients had severe obstructive deficit with mean forced expiratory volume in 1 second (FEV1) of 1.01+/-0.28 L, and FEV1% predicted 39.7+/-8.2. In 44 cases, patients had mild-moderate obstruction with severe diffusion impairment, with mean diffusion capacity for carbon monoxide% predicted of 41.2+/-7.9. Pneumothorax requiring intercostal catheter insertion occurred in 2 patients (2.1%). In 10 cases (10.6%; 95% confidence interval, 4.4%-16.8%) patients experienced acute respiratory failure. Diagnostic yield was 63% (59/94) and overall sensitivity for primary lung malignancy was 70% (53/76). Nine patients had a diagnosis on R-EBUS obviating lung resection. CONCLUSION: R-EBUS is safe and accurate for the investigation of PPL in patients with advanced COPD. PMID- 27454474 TI - Intrabronchial Infusion of Autologous Blood Plus Thrombin for Intractable Pneumothorax After Bronchial Occlusion Using Silicon Spigots: A Case Series of 9 Patients With Emphysema. AB - BACKGROUND: Bronchial occlusion therapy using silicon spigots is effective for intractable pneumothorax. However, sometimes the pneumothorax is refractory to bronchial occlusion because of collateral ventilation. For such difficult pneumothoraces, we attempted an intrabronchial infusion of autologous blood plus thrombin to control collateral ventilation and stop air leaks. METHODS: We performed bronchial occlusions using silicon spigots in patients with spontaneous pneumothorax secondary to emphysema and refractory to chest drainage, but which was inoperable owing to each patient's poor surgical candidacy and poor overall health condition. When bronchial occlusion proved ineffective, we undertook intrabronchial infusion of autologous blood plus thrombin, 2 to 4 days after bronchial occlusion. A catheter was inserted into the subpleural area, through a gap between the silicon spigot and the bronchial wall, using a flexible bronchoscope under fluoroscopic guidance. Autologous blood, followed by a thrombin solution, was infused using the catheter. We repeated the same infusion a total of 4 to 6 times while changing the target bronchi. All interventions were performed under local anesthesia. RESULTS: The subjects were 9 men, aged from 61 to 88 years, with smoking histories. Three patients also had interstitial pneumonia, and 6 patients had undergone pleurodesis in vain before bronchial occlusion. For 4of the 9 patients, autologous blood plus thrombin infusions successfully stopped air leaks, and in 3 patients, intrabronchial infusions and pleurodesis halted leaks altogether. CONCLUSION: Intrabronchial infusion of autologous blood plus thrombin was effective for intractable pneumothoraces that could not be clinically managed, even by bronchial occlusion using silicon spigots. PMID- 27454475 TI - Ultrasound-guided Lung Biopsy in the Hands of Respiratory Physicians: Diagnostic Yield and Complications in 215 Consecutive Patients in 3 Centers. AB - BACKGROUND: The aim of the study was to determine the diagnostic yield and prevalence of complications of ultrasound-guided transthoracic needle aspiration biopsies (US-TTNAB) performed by respiratory physicians after implementation of the procedure in an everyday clinical setting at 3 different centers. METHODS: Patients were included if they during the period from January 2012 to August 2014 had a registered US-TTNAB procedure code or if a US biopsy registration form had been filled out at either of the participating centers. Histology or cytology results were used as a reference test for diagnoses that could be made based on these results. Reference test for the remaining diagnoses was clinical follow-up. The diagnostic yield of US-TTNAB was defined as the proportion of patients in which the result of the US-TTNAB was consistent with the reference test. RESULTS: A total of 215 patients in which a primary US-TTNAB had been performed were identified. The most common biopsy sites were lungs and pleurae with a total of 164 (76.3%) patients and 31 patients (14.4%), respectively. US-TTNAB diagnostic yield was 76.9% (95% CI, 70.3%-83.4%) for malignant diagnoses and 47.6% (95% CI, 31.9%-63.4%) for nonmalignant diagnoses. The most common complications of US TTNAB were pneumothorax (2.5%; 95% CI, 0.03%-4.6%) and pain at the biopsy site (2%; 95% CI, 0.04%-3.9%). No fatalities related to US-TTNAB were observed. CONCLUSION: US-TTNAB performed by respiratory physicians is a safe procedure with a low risk of complications and the diagnostic yield to establish a malignant diagnosis is acceptable. PMID- 27454476 TI - A Curious Case of a Low-Protein Pleural Effusion. PMID- 27454477 TI - Endobronchial Valve Migration: A "Whistle Blower". PMID- 27454478 TI - Lung Abscess Causing Airway Obstruction Requiring Temporary Tracheobronchial Stenting. PMID- 27454479 TI - Endobronchial High-Grade Non-Hodgkin's Lymphoma. PMID- 27454480 TI - Endobronchial Diagnosis of a Malignant Mesothelioma. PMID- 27454481 TI - Endobrochial Ultrasound Needle Breakdown During Transbronchial Needle Aspiration. PMID- 27454482 TI - The GlnR Regulon in Streptococcus mutans Is Differentially Regulated by GlnR and PmrA. AB - GlnR-mediated repression of the GlnR regulon at acidic pH is required for optimal acid tolerance in Streptococcus mutans, the etiologic agent for dental caries. Unlike most streptococci, the GlnR regulon is also regulated by newly identified PmrA (SMUGS5_RS05810) at the transcriptional level in S. mutans GS5. Results from gel mobility shift assays confirmed that both GlnR and PmrA recognized the putative GlnR box in the promoter regions of the GlnR regulon genes. By using a chemostat culture system, we found that PmrA activated the expression of the GlnR regulon at pH 7, and that this activation was enhanced by excess glucose. Deletion of pmrA (strain DeltaPmrA) reduced the survival rate of S. mutans GS5 at pH 3 moderately, whereas the GlnR mutant (strain DeltaGlnR) exhibited an acid sensitive phenotype in the acid killing experiments. Elevated biofilm formation in both DeltaGlnR and DeltaPmrA mutant strains is likely a result of indirect regulation of the GlnR regulon since GlnR and PmrA regulate the regulon differently. Taken together, it is suggested that activation of the GlnR regulon by PmrA at pH 7 ensures adequate biosynthesis of amino acid precursor, whereas repression by GlnR at acidic pH allows greater ATP generation for acid tolerance. The tight regulation of the GlnR regulon in response to pH provides an advantage for S. mutans to better survive in its primary niche, the oral cavity. PMID- 27454483 TI - Endovascular Therapy for Large Vessel Stroke in the Elderly: Hope in the New Stroke Era. AB - BACKGROUND AND PURPOSE: Acute ischemic stroke (AIS) in the elderly encompasses approximately one-third of all AIS cases. Outcome data have been for the most part discouraging in this population. We aim to evaluate the outcomes in a large contemporary series of elderly patients treated with thrombectomy. METHODS: Retrospective analysis of a single-center endovascular database for consecutive elderly (>=80 years) patients treated for anterior circulation large vessel occlusion AIS between September 2010 and April 2015. Univariate- and multivariate analyses were performed to identify the predictors of good clinical outcome (90 day modified Ranking Scale [mRS] <=2). Receiver operating characteristic curves were used to calculate the optimal final infarct volume (FIV) threshold to predict good outcomes. RESULTS: A total of 111 patients met our inclusion criteria (mean age 84.8 +/- 4.2 years; National Institutes of Health Stroke Scale [NIHSS] score 19.1 +/- 5.6; time from last-known normal to puncture, 349.6 +/- 246.6 min; 33% male; 68% Alberta Stroke Program Early CT Score [ASPECTS] >=8). The rates of successful reperfusion (modified treatment in cerebral ischemia >=2b), symptomatic intracranial hemorrhage and 90-day mortality were 80%, 7% and 41%, respectively. The overall rate of good outcome was 29% (n = 32/111) but was 52% (n = 13/25) in patients with baseline mRS score of 0-2 who were selected based on CT perfusion and treated with stent retrievers. On multivariate analysis, only ASPECTS (OR 2.17; 95% CI 1.28-3.67.7; p = 0.004) and baseline NIHSS score (OR 0.87; 95% CI 0.77-0.97; p = 0.013) were independently associated with good outcome. A FIV <=16 ml demonstrated the greatest accuracy for identifying good outcomes (sensitivity 75.0%, specificity 82.6%). CONCLUSIONS: Our results are encouraging demonstrating nearly one-third of elderly patients achieving full independence at 90 days. Contemporary treatment paradigms employing optimized patient selection and modern thrombectomy technology may result in even better outcomes. PMID- 27454484 TI - Measurement of brain tissue oxygen saturation in term infants using a new portable near-infrared spectroscopy device. AB - BACKGROUND: A small oximeter with the probe attached to the examiner's finger has been developed. The aim of this study was to determine the feasibility of measuring regional oxygenation of the brain tissue using this device in healthy term infants immediately after birth. METHODS: We conducted a prospective observational study. Using a new near-infrared spectroscopy (NIRS) device, we measured changes in regional cerebral tissue oxygen saturation (crSO2 ) during the first 10 min of life in 32 healthy term infants after delivery. Arterial oxygen saturation (SpO2 ) was also simultaneously measured. RESULTS: Median crSO2 increased from 43% (1 min after birth) to 49% (4 min after birth); thereafter, no significant changes were observed. Median SpO2 increased constantly from min 3 to min 7, from 77% to 92% and did not change significantly after 8 min. A stable oxygen saturation signal was measured in 59% of infants (crSO2 ) and in 0% of infants (SpO2 ) at 1 min, and in 97% (crSO2 ) and in 78% (SpO2 ) at 3 min. CONCLUSIONS: During the transition after birth, crSO2 can be more easily and quickly measured in healthy newborn infants using the novel NIRS device than SpO2 . PMID- 27454485 TI - Parallel learning in an autoshaping paradigm. AB - In an autoshaping task, a single conditioned stimulus (CS; lever insertion) was repeatedly followed by the delivery of an unconditioned stimulus (US; food pellet into an adjacent food magazine) irrespective of the rats' behavior. After repeated training trials, some rats responded to the onset of the CS by approaching and pressing the lever (sign-trackers). Lesions of dorsolateral striatum almost completely eliminated responding to the lever CS while facilitating responding to the food magazine (US). Lesions of the dorsomedial striatum attenuated but did not eliminate responding to the lever CS. Lesions of the basolateral or central nucleus of the amygdala had no significant effects on sign-tracking, but combined lesions of the 2 structures impaired sign-tracking by significantly increasing latency to the first lever press without affecting the number of lever presses. Lesions of the dorsal hippocampus had no effect on any of the behavioral measures. The findings suggest that sign-tracking with a single lever insertion as the CS may consist of 2 separate behaviors learned in parallel: An amygdala-mediated conditioned orienting and approach response and a dorsal striatum-mediated instrumental response. (PsycINFO Database Record PMID- 27454486 TI - Blood-Based Biomarkers Are Associated with Disease Recurrence and Survival in Gastrointestinal Stroma Tumor Patients after Surgical Resection. AB - BACKGROUND: Inflammatory blood count biomarkers may improve recurrence risk stratification and inform long-term prognosis of cancer patients. Here, we quantify the prognostic impact of blood-based biomarkers on recurrence risk and long-term survival in a large cohort of gastrointestinal stroma tumor (GIST) patients after curative surgery. METHODS: One-hundred-forty-nine consecutive GIST patients were followed-up for a median period of 4.8 years. Local recurrence, distant metastasis, and death occurred in 9, 21, and 31 patients, respectively. Time-to-event and competing risk analysis were applied to study the association between haemoglobin (Hb) level, white blood cell count (WBC), neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) with risk of local or distant recurrence (RR), recurrence free survival (RFS), and overall survival (OS). RESULTS: A low Hb (p = 0.029), and elevations in the parameters WBC (p = 0.004), NLR (p = 0.015) and dNLR (p = 0.037) were associated with a poor OS in GIST patients in multivariate analysis. Moreover, a low Hb (p = 0.049) and an elevated WBC (p = 0.001), NLR (p = 0.007), dNLR (p = 0.043) and PLR (p = 0.024) were independently associated with decreased RFS after adjusting for Miettinen score. However, only an increase of dNLR/NLR showed a significant association to higher RR (p = 0.048). Inclusion of NLR or PLR to Miettinen risk score did not reasonably improve the clinical risk prediction of 2-year RFS. CONCLUSION: Low Hb, elevated WBC, elevated dNLR, and elevated PLR are independent prognostic factors for a worse clinical outcome in GIST patients after curative resection. PMID- 27454488 TI - Controllable growth of ultrathin BiFeO3 from finger-like nanostripes to atomically flat films. AB - BiFeO3 (BFO) ultrathin films with nominal thicknesses from 2 to 12 nm were grown with a SrRuO3 (SRO) buffer layer on TiO2-terminated (001) SrTiO3 (STO) substrates using pulsed laser deposition. The surface morphologies and domain configurations of the thin films were investigated using atomic force microscopy and piezoelectric force microscopy. Periodical one-dimensional finger-like nanostripes of BFO on the SRO covered STO substrates were observed. With increasing thickness, the BFO ultrathin films develop from the finger-like nanostripes to an atomically flat surface. The formation of the finger-like nanostructures of BFO is related to the atomic step or terrace structure of the substrate. The BFO nanostripes and the atomically flat thin films both show good ferroelectricity. The as-grown domain orientations of the BFO ultrathin films are ascribed to the chemical terminations at the surface of the SRO layer. These results indicate that the surface morphologies and the domain configurations of BFO ultrathin films can be artificially designed by using substrates with optimized terrace structures and chemical termination, and these films are potentially useful in multifunctional nanoelectronic devices. PMID- 27454487 TI - Spliceosome SNRNP200 Promotes Viral RNA Sensing and IRF3 Activation of Antiviral Response. AB - Spliceosomal SNRNP200 is a Ski2-like RNA helicase that is associated with retinitis pigmentosa 33 (RP33). Here we found that SNRNP200 promotes viral RNA sensing and IRF3 activation through the ability of its amino-terminal Sec63 domain (Sec63-1) to bind RNA and to interact with TBK1. We show that SNRNP200 relocalizes into TBK1-containing cytoplasmic structures upon infection, in contrast to the RP33-associated S1087L mutant, which is also unable to rescue antiviral response of SNRNP200 knockdown cells. This functional rescue correlates with the Sec63-1-mediated binding of viral RNA. The hindered IFN-beta production of knockdown cells was further confirmed in peripheral blood cells of RP33 patients bearing missense mutation in SNRNP200 upon infection with Sendai virus (SeV). This work identifies a novel immunoregulatory role of the spliceosomal SNRNP200 helicase as an RNA sensor and TBK1 adaptor for the activation of IRF3 mediated antiviral innate response. PMID- 27454489 TI - Discrimination of rat Brunner's gland carbohydrate antigens by site-specific monoclonal antibodies. AB - Mucus produced and secreted by gastrointestinal mucosa contains various types of mucins equipped with unique sugar chains considered to play critical roles in protecting mucous membranes; therefore, the identification and verification of mucin sugar chains is important for understanding the underlying mechanisms. In our previous work, we generated three monoclonal antibodies (mAbs), RGM22, RGM26, and RGM42, which recognize sugar chains in rat gastric mucin. Here, we immunohistochemically analyzed the rat gastrointestinal mucosa and found that the antigens recognized by RGM22 and RGM42 were expressed in the rat antrum and Brunner's glands, whereas that recognized by RGM26 was detected in the antrum, but rarely in Brunner's glands. We found that these antibodies reacted with porcine gastric mucin-derived oligosaccharides bearing a common structure: GalNAcalpha1-3(Fucalpha1-2)Galbeta1-4GlcNAcbeta1-6GalNAc-ol. Moreover, epitope analysis revealed that RGM42 and RGM22 recognized alpha-linked GalNAc and GalNAcalpha1-3Gal, respectively, on the GalNAcalpha1-3(Fucalpha1-2)Gal structure, whereas RGM26 was specific for GalNAcalpha1-3(Fucalpha1-2)Gal. These results indicate that rat Brunner's glands express specific antigens bearing GalNAcalpha1 3Gal that are recognized by RGM22 and RGM42. Thus, RGM22, RGM26, and RGM42 with their unique antigen specificities could be useful tools for investigation of oligosaccharide diversity among mucins. PMID- 27454490 TI - Structure elucidation and gene cluster characterization of the O-antigen of Escherichia coli O80. AB - Mild alkaline degradation of the lipopolysaccharide of Escherichia coli O80 afforded a polysaccharide, which was studied by sugar analysis, selective cleavage of glycosidic linkages, and (1)H and (13)C NMR spectroscopy. Solvolysis of the polysaccharide with CF3CO2H cleaved the linkages of alpha-Fuc and beta linked GlcNAc and GalNAc residues to give two disaccharides. The following structure of the hexasaccharide repeating unit of the O-polysaccharide was established: The polysaccharide repeat also contains a minor O-acetyl group but its position was not determined. The O-antigen gene cluster of E. coli O80 between the conserved galF and gnd genes was analyzed and found to be consistent with the O-polysaccharide structure established. PMID- 27454492 TI - Effect of Digital Nutrition Education Intervention on the Nutritional Knowledge Levels of Information Technology Professionals. AB - The purpose of the study was to determine the changes in knowledge of information technology (IT) professionals after receiving a nutrition education intervention for a month. The sample comprised of 40 IT professionals (29 males and 11 females). The sample was drawn from four IT companies of Hyderabad city using random sampling techniques. The data on the general information of the subjects was collected. The data regarding the commonly accessed sources of nutrition and health information by the subjects was also obtained from the study. The intervention study group received nutrition education by distribution of the developed CD-ROMs to them followed by interactive sessions. To assess the impact of nutrition education intervention, the knowledge assessment questionnaire (KAQ) was developed and administered before and after the education programme. A significant improvement in the mean nutritional knowledge scores was observed among the total study subjects from 22.30 to 40.55 after the intervention (p < 0.05). The findings support the importance of providing professionals with nutrition knowledge to promote healthy dietary behaviors.Thus, the method of e learning and development of CD-Rom is essential for teaching the educated groups on nutrition, physical activity and overall health education to improve their health, lifestyle and eating habits. PMID- 27454493 TI - New Title and New Face of Our Journal. PMID- 27454491 TI - RNA structure in splicing: An evolutionary perspective. AB - Pre-mRNA splicing is a key post-transcriptional regulation process in which introns are excised and exons are ligated together. A novel class of structured intron was recently discovered in fish. Simple expansions of complementary AC and GT dimers at opposite boundaries of an intron were found to form a bridging structure, thereby enforcing correct splice site pairing across the intron. In some fish introns, the RNA structures are strong enough to bypass the need of regulatory protein factors for splicing. Here, we discuss the prevalence and potential functions of highly structured introns. In humans, structured introns usually arise through the co-occurrence of C and G-rich repeats at intron boundaries. We explore the potentially instructive example of the HLA receptor genes. In HLA pre-mRNA, structured introns flank the exons that encode the highly polymorphic beta sheet cleft, making the processing of the transcript robust to variants that disrupt splicing factor binding. While selective forces that have shaped HLA receptor are fairly atypical, numerous other highly polymorphic genes that encode receptors contain structured introns. Finally, we discuss how the elevated mutation rate associated with the simple repeats that often compose structured intron can make structured introns themselves rapidly evolving elements. PMID- 27454494 TI - The New Smartphone Application for Wrist Rehabilitation. AB - BACKGROUND: The rehabilitation after wrist surgery is extremely important. An instructed therapy in hospital is widely practiced. However, a dependent aging society and rush life style in younger generation have precluded patients to access to the frequent formal therapy. With the advancement in telecommunication technology, we have invented an application for smartphone for home-based wrist motion rehabilitation. METHODS: Twenty participants were included in four-week wrist motion rehabilitation programme after wrist surgery. Participants were instructed to use the application by physical therapist and informed details of home-based wrist rehabilitation. The feasibility of application was evaluated by satisfaction level in various aspects and the adherence to the therapy was monitored by function provided in the application. The degrees of motion were compared at the end of prescribed programme. RESULTS: Patient satisfaction was consistently high in every aspects. Also, the adherence to the therapy was high (90.42%). Ranges of motion significantly gained in every plane of wrist motion ([Formula: see text]). CONCLUSIONS: This novel smartphone application seems to be a promising and convenient alternative for patients who need to gain wrist motion without formal rehabilitation in the hospital. Adherence to the therapy is also easily traced with this application. PMID- 27454495 TI - Endoscopic Single Approach Forearm Fasciotomy for Chronic Exertional Compartment Syndrome: Long Term Follow-up. AB - BACKGROUND: Chronic exertional compartment syndrome of the forearm is an uncommon condition, occurring in some populations such as athletes. The standard surgical treatment for professional athletes who cannot avoid trigger activity is an open forearm fasciotomy, which may require a long recovery time. The aim of this study is to present a new endoscopic single approach forearm fasciotomy technique and outcomes of at least 3 years follow up. METHODS: We performed the endoscopic single approach forearm fasciotomy in 4 forearms in 3 men with the mean age of 25 years. All of the patients were evaluated at a mean follow up of 46 months using the Visual Analog Scale (VAS) for pain and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. RESULTS: DASH improved from 21.71 to 5.39, VAS score improved too All the patients referred pain absence after the stress test performed at 20 kilos and 40 kilos. In our series no post-operative complications were observed. CONCLUSIONS: The new mini-invasive technique has proved to be safe, reliable in a long-term follow-up. The main advantage is the shortening of the recovering time, that leads to a faster return to the professional activity. PMID- 27454496 TI - Hand Injury in Rock Climbing: Literature Review. AB - With the amazing increasing in number of participants, rock climbing has become a popular sport in the last decade. A growing number of participants, with different skill level, inevitably leads to an increased number of injuries related to this practice. The kind of lesions that can be observed in rock climbers is very specific and often involves the hand. For this reason is very important for any hand surgeon that is exposed to sport injuries to know which and the most common injuries related to this sport and which are the basic principles for the treatment of those. The aim of this article is to review the literature that has been published in the last ten year in this topic. On the NCBI database 22 articles where found that where related to rock climbing lesion affecting the hand or the whole body. Differences where found according to kind of rock climbing activity that was analyzed, alpine climb leads to more serious injuries, often affecting the lower limb, while in sport and recreational rock climbing the upper limb and the hand are definitely the most affected parts. Flexor pulley lesions, followed by fractures and strains are the most common lesions affecting the hand that are related to this practice. PMID- 27454497 TI - Cast Immobilisation versus Wire Fixation in the Management of Middle-aged and Elderly Patients with Distal Radius Fractures. AB - BACKGROUND: Distal radius fractures are common and traditionally these injuries are treated non-operatively. Percutaneous wiring has been recommended as simple method to provide extra stability in distal radius fractures but their exact role is uncertain. The aim of this study was to retrospectively compare the radiographic and functional outcomes following cast immobilisation and those following wire fixation in the management of distal radius fractures and investigate which method produced better outcomes. METHODS: A retrospective parallel case series was performed between April 2011 and April 2013 of patients over 50 years treated with either cast immobilisation or wire fixation. Both intra- and extra-articular fractures were included. Radiographic measurements were made pre-operatively and at three months follow up. The QuickDASH was recorded by postal questionnaire at a mean of 2 years. RESULTS: 159 patients were included; 85 cast immobilisation group and 74 wire fixation group. Improvement in radiological parameters was seen in both groups but this was significantly better after wire fixation ([Formula: see text]). QuickDASH scores were available in 64%; no significant difference in mean scores was seen after (p = 0.147); cast immobilisation 27.1 and wire fixation 26.6. CONCLUSIONS: Cast immobilisation can produce comparable functional results to wire fixation despite worse radiological outcomes. PMID- 27454498 TI - Interobserver Agreement and Intraobserver Reproducibility of Barzullah Working Classification of Distal End Radius Fractures among Orthopaedic Residents. AB - BACKGROUND: The purpose of this study is to test the hypothesis of the new classification system of distal end radius fractures (Barzullah working classification) proposed by one of the author in a prospective cohort study, among the orthopaedic residents. METHODS: The initial post-injury radiographs of 300 patients with distal radius fractures in a tertiary centre were classified by two junior residents (JR1 and JR2) and two senior residents (SR1 and SR2) in the emergency department over a period of two years. The collected data was analysed statistically by using Cohan's kappa for measuring Intraobserver reproducibility and Fleiss kappa for measuring Interobserver agreement. RESULTS: The mean kappa value for Interobserver agreement was 0.53 (moderate agreement) at the end of one year and the mean kappa value at the end of study period was 0.64 (substantial agreement). The mean kappa value for Intraobserver reproducibility of JR1 was 0.45 (moderate agreement), JR2 was 0.39 (fair agreement), SR1 was 0.62 (substantial agreement) and SR2 was 0.67 (substantial agreement). CONCLUSIONS: Barzullah working classification of distal radius fractures presented in this study has good characteristics compared to those of already studied classification systems among orthopaedic residents. PMID- 27454499 TI - Radiologic Changes by Early Motion in Neck Fractures of the Fifth Metacarpal Treated with Antegrade Intramedullary Fixation. AB - BACKGROUND: As intramedullary (IM) fixation is one of the fixation methods used in neck fractures of the fifth metacarpal, an early motion of injured finger can be allowed. The purpose of this study is to evaluate whether immediate active motion affects the stability of antegrade IM fixation in surgical treatment of neck fractures of the fifth metacarpal bone and to assess related factors. METHODS: Thirty one patients treated by closed reduction and antegrade IM fixation were consecutively enrolled. All patients started active motion of the little finger since 7 postoperative days and only daily activities including writing, typing or washing were allowed until the union of fracture. All fractures were healed within four to eight weeks. The changes of angulation, fifth metacarpal length and tip to head distance of K-wire were compared between immediate postoperative radiographs and radiographs at eight weeks. In addition, the effects by age, gender, initial angulation and comminution of the metacarpal neck were assessed. RESULTS: The average change of angulation was 0.12 degrees , 5th metacarpal length was 1.49mm and tip to head distance of K-wire was 1.31mm. There was no significant difference in the change of angulation (p = 0.137). But, there were significant differences in the change of 5th metacarpal length and tip to head distance of K-wire ([Formula: see text]). The change of angulation was related to a comminution of the metacarpal neck and that of 5th metacarpal length was related to age and sex. CONCLUSIONS: The change of 5th metacarpal length and tip to head distance of K-wire can occur by an early mobilization in the antegrade IM fixation for neck fractures of the fifth metacarpal. However, we thought that an early active motion after surgery is important to increase the patients' satisfaction, even though careful selection of candidates is necessary. PMID- 27454500 TI - Transcutaneous Peripheral Nerve Stimulation for the Treatment of Neuropathic Pain in the Upper Limb. AB - BACKGROUND: A small number of patients develop intractable peripheral nerve pain following injury or surgery to the upper limb that is refractory to pharmacological treatment. This study reports our results of using transcutaneous peripheral nerve stimulation (TPNS), a non-invasive form of neuromodulation, to treat this difficult problem. METHODS: Seventy-two patients were treated for intractable pain in the upper limb using this technique. Electrical current was delivered transcutaneously through a handheld probe, placed on the skin overlying the affected peripheral nerve proximal to the site of pain. Pain severity was determined before and immediately after treatment by subjective patient self assessment using a visual analogue pain scale. Pre-post treatment changes in pain severity were analysed by Student's test for paired data. Outcome in respect of overall effectiveness of this treatment, was graded according to the maximum duration of pain relief achieved. RESULTS: Overall, TPNS reduced pain intensity from 8.4 (SD 1.6) before treatment to 4.2 (SD 3.5) immediately after treatment, a highly significant effect ([Formula: see text]). The treatment achieved cure in 8/72 (11%) of our patients and a useful therapeutic outcome (pain relief >= 1 day) in 27/72 (38%). The treatment failed in 37/72 (51%). CONCLUSIONS: TPNS warrants consideration as a therapy for neuropathic pain in the upper limb after drug treatment has failed and before offering surgery or spinal root stimulation. PMID- 27454501 TI - Isolated Muscle Transfer to Restore Elbow Flexion in Children with Arthrogryposis. AB - BACKGROUND: Arthrogryposis is the general term given to conditions characterized by multiple joint contractures resulting in substantial disability most frequently involving a child. Early muscle transfer reconstructive surgery reliably restores elbow flexion. In the present study, we aimed to determine which preoperative condition is best able to restore elbow flexion in patients with arthrogryposis. METHODS: We retrospectively reviewed five children (seven cases) who underwent elbow flexor reconstruction (Steindler flexorplasty, four cases; latissimus dorsi transfer, two cases; pectoralis major transfer, one case). Upper-extremity function was assessed on the basis of range of elbow extension and flexion and elbow flexor muscle power pre- and postoperatively. RESULTS: The mean postoperative active flexion and extension range of motion was 82.1 degrees (60 degrees to 100 degrees ) and -15.0 degrees (-40 degrees to 0 degrees ) respectively. Mean postoperative elbow flexor muscle power was graded as a 3.4 (2 to 4) as measured with the Medical Research Council (MRC) scale. The preoperative passive elbow flexion angle was found to correlate with postoperative muscle power (MRC) (r = 0.830, p = 0.042) and postoperative active elbow flexion angle (r = 0.902, p = 0.027). Age at operation was not found to correlate with postoperative muscle power (MRC) (r = -0.063, p = 0.878) or active elbow flexion angle (r = -0.134, p = 0.743). CONCLUSIONS: We found a positive correlation between preoperative passive elbow flexion/range of elbow motion and postoperative results including active range of motion and transferred muscle power. Diminished preoperative elbow flexion appeared to correlate with having a poor outcome. The present results suggest that choosing another muscle, such as the gracilis, may be beneficial for muscle transfer in more severe cases of arthrogryposis. PMID- 27454502 TI - Congenital Anomalies of the Extremities Occurring in Siblings. AB - BACKGROUND: When examining children with congenital anomalies of the extremities, it is not uncommon for parents to ask about the possibility of similar anomalies occurring in their next child. However, the inheritance of the disease in many congenital anomalies of the extremities has never been elucidated. METHODS: In the present study we reviewed cases of their occurrence in siblings that we encountered in our department, and we investigated their characteristics. RESULTS: The results did not reveal any disease specificity, but a tendency for bilateral cases and male cases (cases in brothers) to be more common was observed. CONCLUSIONS: In recent years there have been reports of the discovery of causative genes in some congenital anomalies, but because cases of occurrence in siblings with no familial occurrence in the past are seen, there may be a variety of causative genes in many congenital anomalies. In the present study there were many male cases (cases in brothers) and many bilateral cases, and there appears to have been a strong possibility of familial occurrence in such cases, but there were also quite a few exceptions. It is necessary to bear the possibility of heredity in mind in every case and provide the parents with an explanation. PMID- 27454503 TI - Evaluation of Factors Associated with Night Pain in Women Undergoing Carpal Tunnel Release. AB - BACKGROUND: Night pain has important diagnostic and prognostic values in patients with carpal tunnel syndrome (CTS). We aimed to determine whether night pain is associated with certain patient characteristics in female patients undergoing carpal tunnel release. METHODS: We recruited 75 women with the mean age of 54 years who were scheduled for carpal tunnel release. Diagnosis of CTS was made based on both the clinical symptoms and the results of electrophysiologic studies. Patient characteristics investigated as factors potentially associated with night pain were: age, body mass index (BMI), symptom duration, comorbidities such as diabetes mellitus (DM) and thyroid disease, electrophysiologic severity of CTS, and sleep position. We conducted a logistic regression analysis to examine the relationships between the presence of night pain and the different patients' demographic and clinical variables. RESULTS: Absence of night pain was associated with increased age (odds ratio (OR), 0.918, 95% confidence interval (CI), 0.851 to 0.99) and presence of DM (OR, 0.196; 95% CI, 0.046 to 0.835). The other variables assessed were not found to be associated with presence or absence of night pain. CONCLUSIONS: This study found that in women undergoing carpal tunnel release, older patients or those having DM are slightly less likely to have night pain. As night pain is an important prognostic factor for CTS, further studies are warranted to determine whether the absence of night pain could affect outcome assessment of CTS in the elderly or patients with DM. PMID- 27454504 TI - Intramedullary Nail Fixation for Displaced and Unstable Distal Radial Fractures in Patients Aged 65 Years or Older. AB - BACKGROUND: Distal radius fractures in elderly patients are now commonly treated with a volar locking plate, but flexor pollicis longus dysfunction caused by stripping of the muscle and tendon irritation and rupture caused by prominence of the implant have been reported. Intramedullary implants can stabilize distal radius fractures while minimally affecting the flexor and extensor tendons and muscles around the site, but osteoporosis in elderly patients might affect the radiographic and functional results of distal radius fractures treated by intramedullary implants. We investigated the radiographic and functional results of intramedullary implants for distal radius fractures in patients >=65 years of age. METHODS: We reviewed medical records of 40 patients with extra-articular or simple intra-articular fractures with the sagittal fracture line treated by an intramedullary implant. RESULTS: All fractures achieved bony union, with an average radial inclination of 24.9 degrees, volar tilt of 9.2 degrees, and ulnar variance of 0.7 mm. We encountered one case of postoperative volar displacement of the distal fragment due to the small size of the intramedullary implant. The average range of motion was 69.8 and 59.9 degrees for dorsal and palmar wrist flexion, respectively. Average percentile grip strength of the uninjured side was 97%. The average Mayo modified wrist score at final follow-up was 91.9 points, with 20 patients graded as excellent, 16 as good, and 4 as fair. CONCLUSIONS: The findings of this study indicate that intramedullary implants for dorsally displaced extra-articular or simple intraarticular distal radius fractures may offer good radiological and functional outcomes without hardware irritation in elderly patients. Distal radius fractures with an osteoporotic, large medullary canal should be stabilized by implants of an appropriate size. PMID- 27454505 TI - The Anatomical Relationship Between the Dorsal Cutaneous Branch of the Ulnar Nerve and the Ulnar Styloid Process with Variations in Forearm Position. AB - BACKGROUND: There are significant variations in the anatomy of the dorsal cutaneous branch of the ulnar nerve (DCBUN). The DCBUN is at risk for iatrogenic injury during surgeries around the ulnar side of the wrist. The purpose of this study was to demonstrate the relationship between the ulnar styloid process and the DCBUN and to confirm the DCBUN's change in location with different forearm positions. METHODS: We examined 9 fresh frozen cadaveric limbs to establish the course of this nerve. The DCBUN was dissected and traced around the ulnar border of the wrist. The distance from the tip of the ulnar styloid process to the origin of the DCBUN was measured. The distances from the ulnar styloid process to the DCBUN were measured in supination, pronation, and in a neutral position of the forearm. RESULTS: The DCBUN originated on average 4.92 cm proximal to the ulnar styloid process. In all cases, the DCBUN crossed the ulnar distal to ulnar styloid process and it moved more closely to the ulnar styloid process with a forearm position change from supination to pronation. CONCLUSIONS: We recommend making a skin incision on the ulnar side around the styloid process with the forearm in supination or neutral position was another method to avoid injury of DCBUN. PMID- 27454506 TI - Relation of Lateral Antebrachial Cutaneous Nerve to the Volar Approach to Distal Radius. AB - BACKGROUND: The anatomy of the lateral antebrachial cutaneous nerve (LABCN) in relation to volar approaches to the distal radius is not well visited. With the increasing popularity of distal radius fracture fixation with volar locking plates, it is prudent to study the innervation pattern of the LABCN to minimize the risk of nerve injury. METHODS: Ten cadaveric distal radial forearms were dissected to study the relationship between the LABCN, flexor carpi radialis (FCR), superficial branch of radial nerve (SBRN), and scaphoid tubercle (ST). RESULTS: The LABCN coursed closer to the FCR than the SBRN, with branches traversing the tendon in two specimens. The LABCN was also noted to be intimately related to the radial artery, with an average distance of the LABCN from the lateral border of FCR was 6.4mm distally and 9.6mm proximally. CONCLUSIONS: There is a sparsely innervated corridor between the radial border of the FCR and terminal branches of the LABCN that provides safe access for volar approach to the distal radius. PMID- 27454507 TI - Reliability and Validity of the Japanese Version of the Michigan Hand Outcomes Questionnaire: A Comparison with the DASH and SF-36 Questionnaires. AB - BACKGROUND: The Michigan Hand Outcomes Questionnaire (MHQ) has shown reliability, validity and responsiveness and has been used to assess surgical outcomes mainly in North America. We established a Japanese version of the MHQ and evaluated its reliability and validity compared with both the short-form 36 (SF-36) questionnaire and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire in a Japanese-speaking population. METHODS: The MHQ was cross culturally adapted to a Japanese version according to guidelines. Sixty-eight patients with hand conditions were enrolled in this study and answered the MHQ, DASH questionnaire and SF-36 questionnaire. The MHQ was completed again with an interval of one or two weeks. Reproducibility and internal consistency were statistically assessed by the test-retest method and calculating Cronbach's alpha. Spearman's rank correlation was calculated to assess associations between the MHQ and the SF-36 questionnaire as well as the DASH questionnaire. RESULTS: The intraclass correlation coefficients of MHQ subscales ranged from 0.68 to 0.93. Aesthetics subscale of the left hand showed the lowest intraclass correlation but still a good correlation. Cronbach's alpha values of the MHQ ranged from 0.81 to 0.96 for all subscales. The absolute values of Spearman's rank correlation coefficient between MHQ subscales and DASH function/symptoms scores ranged from 0.49 to 0.82. Spearman's correlation coefficients of the MHQ total score to subscales of the SF-36 questionnaire ranged from 0.42 to 0.68. The strongest correlations were found between work performance of the MHQ and rolephysical of the SF-36 questionnaire. CONCLUSIONS: The Japanese version of the MHQ has adequate instrument properties for assessing hand outcomes compared with the SF-36 questionnaire as well as the DASH questionnaire. PMID- 27454508 TI - Motion Analysis of the Trapeziometacarpal Joint Using Three-dimensional Computed Tomography. AB - BACKGROUND: Zancolli theorized that the first metacarpal bone axially rotates on the semispheroidal part of the trapezium, which is controlled by ligaments. This study used three-dimensional computed tomography (3D-CT) to describe the motion of the first metacarpal bone on the trapezium. METHODS: 3D-CT images were taken of the left hand of 30 healthy volunteers (mean age [Formula: see text] years, 15 men and 15 women). They were divided into five groups: radial abduction, retroposition, adduction, palmar abduction, and opposition. The range of motion of radial abduction and palmar abduction of the trapeziometacarpal joint was measured from the first metacarpal bone to the second metacarpal bone. The range of motion of pronation was measured following Cheema's method. The main contacts of the joint surface of trapezium and the first metacarpal bone were determined on the 3D-CT images. RESULTS: Pronation of the trapeziometacarpal joint was [Formula: see text] in radial abduction, [Formula: see text] in retroposition, [Formula: see text] in adduction, [Formula: see text] in palmar abduction, and [Formula: see text] in opposition. Radial abduction was [Formula: see text] in radial abduction, [Formula: see text] in retroposition, [Formula: see text] in adduction, [Formula: see text] in palmar abduction, and [Formula: see text] in opposition. Palmar abduction was [Formula: see text] in radial abduction, [Formula: see text] in retroposition, [Formula: see text] in adduction, [Formula: see text] in palmar abduction, and [Formula: see text] in opposition. The contact surfaces of the trapezium and the first metacarpal bone were dorsal and ulnar in radial abduction, radial and ulnar in retroposition, and volar-ulnar and volarradial in opposition, respectively, while they were both central in adduction and both radial in palmar abduction. CONCLUSIONS: The range of motion of the trapeziometacarpal joint was 44 degrees for radial abduction/adduction, 48 degrees for palmar abduction/adduction, and 57 degrees for pronation/supination. The varying contact surfaces of the trapezium and the first metacarpal bone enabled a wide range of motion. PMID- 27454509 TI - Interposition Arthroplasty Versus Hematoma and Distraction for the Treatment of Osteoarthritis of the Trapeziometacarpal Joint. AB - BACKGROUND: Various surgical techniques were reported with excellent result for the treatment of trapeziometacarpal joint arthritis. However, the best treatment option was not defined yet. METHODS: This randomized prospective study compared the result of two surgical techniques: tendon interposition arthroplasty (64 patients) and K. wire distraction (56 patients) after trapeziectomy for stage 3 or 4 osteoarthritis of the trapeziometacarpal joint. RESULTS: After a mean follow up period of 6.8 (range, 3-10) years it was possible to observe a higher rate of pain relief following trapeziectomy with K. wire suspension, but no significant differences in strength, range of motion and DASH score between the two groups. On lateral unloaded radiographs the height of the space between the base of the thumb metacarpal and the scaphoid showed a mean value of 6.5 mm for both groups; the average distance between the metacarpal base and the trapezium was not statistically significant in the two groups. Complications were observed only in patients treated with trapeziectomy and interposition arthroplasty and were represented by tendinitis of the FCR in 15% of cases. CONCLUSIONS: We demonstrate that the trapezium excision and bone space distraction technique requires a smaller incision, a shorter surgical time, an easier surgical technique, and a less painful recovery, maintaining overlapping levels of functional restore. PMID- 27454510 TI - Attritional Rupture of the Little Finger Flexor Digitorum Profundus Tendon in the Carpal Tunnel in a Patient with Acromegaly. AB - Spontaneous rupture of flexor tendons within the carpal tunnel is rare in the absence of rheumatoid arthritis. Other predisposing conditions such as gout, infection, pisotriquetrial osteoarthritis, as well as hook of hamate fracture non union, have previously been reported. However, tendon ruptures of the hand in the presence of acromegaly, as well as spontaneous ruptures within the carpal tunnel, have not been described in the literature. PMID- 27454511 TI - Osteoid Osteoma of the Radial Styloid Resembling de Quervain's Disease. AB - We describe a case of osteoid osteoma in the radial styloid of a 37-year old man mimicking de Quervain's disease. The exact diagnosis was made with CT examination and confirmed by histological evaluation of the tumour. The lesion was removed by curettage and symptoms were resolved rapidly thereafter. There was no sign of recurrence at one year follow-up. PMID- 27454512 TI - Acute Compartment Syndrome in the Forearm with Trans-Ulnar Single Incision. AB - We report a case of ulnar nerve palsy caused by diaphyseal fractures of the forearm and acute compartment syndrome. Trans-ulnar single incision with a fasciotomy of the volar and dorsal compartments was used to fix the ulna. Full recovery of the ulnar nerve was achieved six months after the surgery. In cases of acute compartment syndrome with ulnar fracture, a trans-ulnar incision with compartment release is effective for the fixation of the ulna. PMID- 27454513 TI - Osteochondroma of the Radial Tuberosity in Child. AB - Osteochondromas are common benign bone tumors. They may occur on any bone preformed in cartilage, but usually are found on the metaphysis of a long bone near the physis. In this article, we report a case of the subluxation of the radial head caused by osteochondroma on the radial tuberosity. A 9-year-old female patient presented with a hard palpable mass and pain in her posterior aspect of left elbow joint. Preoperative radiography and MRI demonstrated an expansile bone lesion arising in the left radial tuberosity of the proximal radius. Resection of the bone tumor was done without any complications. Biopsy confirmed the diagnosis of osteochondroma without malignant degeneration. A one year after surgery, the elbow had full range of motion without any discomfort and complication. PMID- 27454514 TI - Intraosseous Ganglion Cyst of Scaphoid: An Uncommon Cause of Radial Wrist Pain. AB - Intraosseous ganglion cyst is a rare bone tumor and the lesion could often be missed. The diagnosis could be delayed so proper radiologic investigation and index of suspicion is necessary .Differential diagnoses of painful cystic radiolucent carpal lesion are osteoid osteoma, osteoblastoma and intraosseous ganglion. Curettage of the scaphoid lesion and filling of void with bone graft provides good functional outcomes. The cyst contains mucoid viscous material without epithelial or synovial lining. We present a case of 30 years old male with intraosseous ganglion cyst of scaphoid which was treated with curettage and bone grafting. Rarely ganglion cyst is found in small bones of hand and should be considered as differential diagnosis of chronic radial wrist pain. PMID- 27454515 TI - Anatomic Variations of the Flexor Carpi Radialis Brevis: A Report of Five Cases. AB - The flexor carpi radialis brevis (FCRB) is a rare, anomalous musculotendinous structure of the wrist. Here, we report five cases of FCRB in a consecutive series of 123 distal radius fractures that were repaired by using volar locking plates. PMID- 27454517 TI - Concurrent Minimally Invasive Carpal Tunnel Release Techniques in Distal Radius Open Reduction Internal Fixation. AB - Carpal tunnel syndrome is a common complication associated with distal radius fractures. Open carpal tunnel release in the same setting as open reduction and internal fixation of distal radius fractures is widely accepted. In this paper, we describe the technical details of a minimally invasive carpal tunnel release in the same setting as the fixation of a distal radius fracture via the same incision. Two options of minimally invasive techniques are described: The Knifelight(r) (Stryker, Kalamazoo, Michigan, USA) instrument and the single portal carpal tunnel release system (Agee, 3M Healthcare, St Paul, Minnesota, USA). Being well known and accepted techniques of carpal tunnel release, we believe that the techniques described in this paper provide a viable alternative for carpal tunnel release in the setting of distal radius fracture fixation; with the added advantages of the original minimally invasive techniques. PMID- 27454516 TI - Lipofibromatous Hamartoma of the Median and Ulnar Nerves at the Ipsilateral Wrist. AB - Lipofibromatous hamartoma (LFH) is a rare condition of the peripheral nerves that typically affects the median nerve. To the best of our knowledge, this is the first report of LFH of both, the median and ulnar nerves, at the wrist of a 63 year-old female patient. The patient presented to our hospital with a 40-year history of pain, numbness, and dysesthesia affecting all fingers of her left hand. Atrophy of the thenar muscles and the first dorsal interosseous was observed upon physical examination. Imaging studies and a surgery revealed that the patient's median and ulnar nerves were significantly enlarged, confirming the LFH diagnosis. The patient's dysesthesia and numbness improved after Carpal tunnel and Guyon canal release, and her pinch ability improved after opponensplasty. LFH has been known to be solitary, typically affecting median nerve, but it must be noted that the tumor may affect multiple nerves like in our case. PMID- 27454518 TI - A Low-Cost iPhone-Assisted Augmented Reality Solution for the Localization of Intracranial Lesions. AB - BACKGROUND: Precise location of intracranial lesions before surgery is important, but occasionally difficult. Modern navigation systems are very helpful, but expensive. A low-cost solution that could locate brain lesions and their surface projections in augmented reality would be beneficial. We used an iPhone to partially achieve this goal, and evaluated its accuracy and feasibility in a clinical neurosurgery setting. METHODOLOGY/PRINCIPAL FINDINGS: We located brain lesions in 35 patients, and using an iPhone, we depicted the lesion's surface projection onto the skin of the head. To assess the accuracy of this method, we pasted computed tomography (CT) markers surrounding the depicted lesion boundaries on the skin onto 15 patients. CT scans were then performed with or without contrast enhancement. The deviations (D) between the CT markers and the actual lesion boundaries were measured. We found that 97.7% of the markers displayed a high accuracy level (D <= 5mm). In the remaining 20 patients, we compared our iPhone-based method with a frameless neuronavigation system. Four check points were chosen on the skin surrounding the depicted lesion boundaries, to assess the deviations between the two methods. The integrated offset was calculated according to the deviations at the four check points. We found that for the supratentorial lesions, the medial offset between these two methods was 2.90 mm and the maximum offset was 4.2 mm. CONCLUSIONS/SIGNIFICANCE: This low cost, image-based, iPhone-assisted, augmented reality solution is technically feasible, and helpful for the localization of some intracranial lesions, especially shallow supratentorial intracranial lesions of moderate size. PMID- 27454519 TI - Population Dynamics and Life History of Euphorbia rosescens, a Perennial Herb Endemic to Florida Scrub. AB - Euphorbia rosescens is a recently described plant that is narrowly endemic to the Lake Wales Ridge. Little is known of the ecology or life history of this diminutive, deeply rooted polygamodioecious perennial. We studied 13 subpopulations of this species from 2004-2012 from five habitats, sampling monthly during its growing season. Subpopulations were stable year-to-year with annual survivals > 90%, but with considerable within-year dynamics, peaking in density in April and dying back in the fall and winter. Stem densities did not vary among subpopulations, habitats, or by subpopulation gender. Annual plant dormancy was common and decreased subsequent survival. Belowground biomass averaged almost 50 times higher than aboveground biomass. Subpopulations either consisted of entirely female individuals or a mixture of male and functionally andromonoecious individuals and these subpopulation genders remained stable across years. Overall, flowering has been dominated by female plants. Plants produced modest numbers of inflorescences (cyathia), and fruit production was very low. Although most plants survived fire by resprouting, fire decreased survival and had a short-term positive effect on floral production. Lack of fecundity and recruitment are concerns for this state-endangered species, but more information is needed on its breeding system and clonality to make specific management recommendations. PMID- 27454521 TI - Low Risk of International Zika Virus Spread due to the 2016 Olympics in Brazil. PMID- 27454520 TI - Mapping Variation in Cellular and Transcriptional Response to 1,25 Dihydroxyvitamin D3 in Peripheral Blood Mononuclear Cells. AB - The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (Imax) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10-8) and rs6451692 on chromosome 5 (p = 2.55 x 10-8), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, CCL28, and the translation initiation gene, PAIP1. We also identified 8 expression quantitative trait loci at a FDR<0.10 for transcriptional response to 1,25D treatment, which include the transcriptional regulator ets variant 3-like (ETV3L) and EH-domain containing 4 (EHD4). In addition, we identified response eQTLs in vitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (FRMD6), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of Imax and the response eQTL mapping enabled identification of putative Imax-associated candidate genes such as PAIP1 and the transcriptional repressor gene ZNF649. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis. PMID- 27454522 TI - Busulfan is effective second-line therapy for older patients with Philadelphia negative myeloproliferative neoplasms intolerant of or unresponsive to hydroxyurea. AB - Hydroxyurea (Hu) is widely used as first-line cytoreductive therapy for patients with high-risk Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPN), but a small proportion of patients have refractory disease or experience adverse effects. Studies have demonstrated busulfan (Bu) to be an active first-line agent, but data on its role as second-line or later therapy are minimal. To evaluate its efficacy and safety in this context, we undertook a multicenter audit of Ph-neg MPN patients who had received Bu as therapy for Hu intolerance or failure. Of 51 patients identified, 38 (75%) achieved either complete or partial hematological response following at least one Bu cycle. Bu was generally well tolerated, with only 21/135 (15%) cycles complicated by adverse effects, predominantly cytopenia; only 6% of cycles were ceased due to treatment complications. Bu is an effective and well-tolerated agent in patients with Ph neg MPN in the setting of Hu intolerance or unresponsiveness. PMID- 27454523 TI - Tribological behavior of UHMWPE against TiAl6V4 and CoCr28Mo alloys under dry and lubricated conditions. AB - This work is focused on the study of the tribological behavior of TiAl6V4 and CoCr28Mo against UHMWPE. Wear tests were achieved on a reciprocating pin-on-disc tribometer under dry and lubricated conditions. Four bio-lubricants were retained namely: saline solution (NaCl 0.9%), sesame oil, nigella sativa oil and Hyalgan(r) which is a pharmaceutical intra-articular injection containing sodium hyaluronate active agent (20mg/2mL). The coefficient of friction and wear volume of UHMWPE were evaluated after tribological tests. It is found that, the friction and wear behaviors of CoCr28Mo/UHMWPE pair under dry and bio-lubrication were the best. Results show that the use of natural oils improved significantly the tribological behavior of CoCr28Mo/UHMWPE and TiAl6V4/UHMWPE pairs. Microscopic and chemical analyses of wear tracks on UHMWPE were carried out and wear mechanisms were proposed for each materials pair. The tribological performance of the used oils was linked to their chemical composition and to their adsorption ability on the metallic surfaces. PMID- 27454524 TI - Buried absorbable polyglactin 910 sutures do not result in stronger wounds in porcine full thickness skin incisions. AB - OBJECTIVE: To test the hypothesis that the mechanical strength of wounds closed with a combination of buried dermal absorbable sutures and superficial nonabsorbable nylon sutures will be higher than wounds closed with only superficial nonabsorbable nylon sutures. METHODS: Four Yucatan pigs were anesthetized and each received four 4.5cm full thickness incisions on their dorsal surfaces, placed 8cm apart. Half of all incisions were randomly allocated and repaired with 3-0 polyglactin 910 (Vicryl(TM)) buried dermal absorbable sutures and superficial 3-0 nylon sutures, using a simple interrupted pattern. The other half received only 3-0 nylon sutures. Two pigs were humanely euthanized at day 10, with specimen harvest for mechanical testing; the other two pigs had superficial nylon sutures removed at day 10, as per current clinical practice, and were humanely euthanized at day 42, with specimen harvest for mechanical testing. Tensile loads were applied perpendicularly to the wounds with a displacement rate of 40mm per minute. RESULTS: Wounds at day 42 were >9 times stronger than wounds at day 10 (p<0.0001). There was no difference in average wound strength at either day 10 or day 42 between wounds with and without buried dermal absorbable sutures. SIGNIFICANCE: Buried dermal absorbable sutures failed to provide additional wound support at either 10 or 42 days. This result may have immediate implications for clinicians who perform cutaneous surgery and keep superficial sutures in for at least 10 days. Future research will be directed to shorter time studies, other buried dermal absorbable suture materials, and alternatives to buried dermal absorbable sutures. PMID- 27454525 TI - On the fatigue behavior of medical Ti6Al4V roughened by grit blasting and abrasiveless waterjet peening. AB - Flat fatigue specimens of biomedical Ti6Al4V ELI alloy were surface-processed by high pressure waterjet peening (WJP) without abrasive particles using moderate to severe conditions that yield roughness values in the range of those obtained by commercial grit blasting (BL) with alumina particles. Fatigue behavior of WJP and BL specimens was characterized under cyclical uniaxial tension tests (R=0.1). The emphasis was put on a comparative analysis of the surface and subsurface induced effects and in their relevance on fatigue behavior. Within the experimental setup of this investigation it resulted that blasting with alumina particles was less harmful for fatigue resistance than abrasiveless WJP. BL specimens resulted in higher subsurface hardening and compressive residual stresses. Specimens treated with more severe WJP parameters presented much higher mass loss and lower compressive residual stresses. From the analysis performed in this work, it follows that, in addition to roughness, waviness emerges as another important topographic parameter to be taken into account to try to predict fatigue behavior. It is envisaged that optimization of WJP parameters with the aim of reducing waviness and mass loss should lead to an improvement of fatigue resistance. PMID- 27454526 TI - Post-deformation shape-recovery behavior of vitamin E-diffused, radiation crosslinked polyethylene acetabular components. AB - The in-vivo progression of creep and wear in ultra-high molecular weight polyethylene (UHMWPE) acetabular liners has been clinically evaluated by measuring radiographic penetration of femoral heads. In such clinical assessments, however, viscoelastic strain relaxation has been rarely considered after a removal of hip joint loading, potentially leading to an underestimation of the penetrated thickness. The objective of this study was to investigate shape recovery behavior of pre-compressed, radiation crosslinked and antioxidant vitamin E-diffused UHMWPE acetabular liners, and also to characterize the effects of varying their internal diameter (ID) and wall thickness (WT). We applied uniaxial compression to the UHMWPE specimens of various ID (28, 32, 36mm) and WT (4.8, 6.8, 8.9mm) for 4320min under the constant load of 3000N, and subsequently monitored the strain-relaxation behavior as a function of time after unloading. It was observed that there was a considerable shape recovery of the components after removal of the external static load. Reducing ID and WT significantly accelerated the rate of creep strain recovery, and varying WT was more sensitive to the recovery behavior than ID. Creep deformation of the tested liners recovered mostly within the first 300min after unloading. Note that approximately half of the total recovery amount proceeded just within 5min after unloading. These results suggest a remarkably high capability of shape recovery of vitamin E diffused highly crosslinked UHMWPE. In conclusion, the time-dependent shape recovering and the diameter-thickness effect on its behavior should be carefully considered when the postoperative penetration is quantified in highly crosslinked UHMWPE acetabular liners (especially on the non-weight bearing radiographs). PMID- 27454527 TI - Prevalence of mcr-1 in E. coli from Livestock and Food in Germany, 2010-2015. AB - Since the first description of a plasmid-mediated colistin resistance gene (mcr 1) in November 2015 multiple reports of mcr-1 positive isolates indicate a worldwide spread of this newly discovered resistance gene in Enterobacteriaceae. Although the occurrence of mcr-1 positive isolates of livestock, food, environment and human origin is well documented only few systematic studies on the prevalence of mcr-1 are available yet. Here, comprehensive data on the prevalence of mcr-1 in German livestock and food isolates are presented. Over 10.600 E. coli isolates from the national monitoring on zoonotic agents from the years 2010-2015 were screened for phenotypic colistin resistance (MIC value >2 mg/l). Of those, 505 resistant isolates were screened with a newly developed TaqMan-based real-time PCR for the presence of the mcr-1 gene. In total 402 isolates (79.8% of colistin resistant isolates) harboured the mcr-1 gene. The prevalence was depending on the food production chain. The highest prevalence was detected in the turkey food chain (10.7%), followed by broilers (5.6%). A low prevalence was determined in pigs, veal calves and laying hens. The mcr-1 was not detected in beef cattle, beef and dairy products in all years investigated. In conclusion, TaqMan based real-time PCR provides a fast and accurate tool for detection of mcr-1 gene. The overall detection rate of 3.8% for mcr-1 among all E. coli isolates tested is due to high prevalence of mcr-1 in poultry production chains. More epidemiological studies of other European countries are urgently needed to assess German prevalence data. PMID- 27454528 TI - Oral Decontamination of Orthodontic Patients Using Photodynamic Therapy Mediated by Blue-Light Irradiation and Curcumin Associated with Sodium Dodecyl Sulfate. AB - OBJECTIVE: The aim of this study was to investigate the effects of the antimicrobial photodynamic therapy (aPDT) using the association of curcumin with the surfactant sodium dodecyl sulfate (SDS) for oral decontamination in orthodontic patients. BACKGROUND DATA: The installation of the orthodontic appliances promotes an increase in the retentive area that is available for microbial aggregation and makes difficult the oral health promotion. However, aPDT is one possible approach that is used for the reduction of oral microbial load. MATERIALS AND METHODS: Twenty-four patients (n = 24) were randomly distributed into four groups: Light group: which was treated only with the blue light, no drug; PDT group, which was treated with curcumin and blue light; PDT + S group, which was treated with curcumin plus surfactant and irradiated with blue light; and Chlorhex group, which was treated with chlorhexidine. The photosensitizer agent was prepared by adding 0.1% of SDS to a curcumin solution of 1 g/L. Two distinct LED devices emitting blue light (450 +/- 10 nm) were used as follows: extra-oral irradiation (200 mW, 80 mW/cm(2), 36 J and 14 J/cm(2)) and intra-oral irradiation (1200 mW, 472 mW/cm(2), 216 J and 85 J/cm(2)).The collection of nonstimulated saliva (n = 3; 3 mL/collection) was performed at the following steps: (1) immediately before swishing (curcumin, chlorhexidine, or water); (2) after swishing; and (3) after performing aPDT treatments. The colony forming units (CFU) were counted visually, and the values were adjusted to CFU/mL. RESULTS: There was significant Log reduction for PDT (from 6.33 +/- 0.92 to 5.78 +/- 0.96, p < 0.05), PDT + S (from 5.44 +/- 0.94 to 3.83 +/- 0.71, p < 0.01), and Chlorhex (from 5.89 +/- 0.97 to 2.55 +/- 1.80, p < 0.01) groups. The survival rate was significantly reduced in both PDT + S and Chlorhex groups compared with all situations (p < 0.05). However, there was no significant difference between PDT + S and Chlorhex groups (p >= 0.05). CONCLUSIONS: These results indicate that when associated with the surfactant SDS, the aPDT can be used as an adjutant and a convenient agent to promote the oral decontamination in clinical practice. PMID- 27454529 TI - Incidence and localizing value of vertigo and dizziness in patients with epilepsy: Video-EEG monitoring study. AB - Vertigo and dizziness are common neurological complaints that have long been associated with epilepsy. However, studies of patients with epileptic vertigo or dizziness with concurrent EEG monitoring are scarce. We performed the present study to investigate the incidence and localizing value of vertigo and dizziness in patients with epilepsy who had confirmation of EEG changes via video-EEG monitoring. Data of aura and clinical seizure episodes of 831 consecutive patients who underwent video-EEG monitoring were analyzed retrospectively. Out of 831 patients, 40 patients (4.8%) experienced vertigo or dizziness as aura (mean age, 32.8+/-11.8years), all of whom had partial seizures. Eight had mesial temporal, 20 had lateral temporal, four had frontal, one had parietal, and seven had occipital lobe onset seizures. An intracranial EEG with cortical stimulation study was performed in seven patients, and the area of stimulation-induced vertigo or dizziness coincided with the ictal onset area in only one patient. Our study showed that vertigo or dizziness is a common aura in patients with epilepsy, and that the temporal lobe is the most frequent ictal onset area in these patients. However, it can be suggested that the symptomatogenic area in patients with epileptic vertigo and dizziness may not coincide with the ictal onset area. PMID- 27454530 TI - Highlight on DPYD gene polymorphisms and treatment by capecitabine (.). AB - BACKGROUND: Sequencing of DPYD exome was conducted in a prospective cohort of advanced breast cancer patients receiving capecitabine. METHODS: A total of 243 patients were analyzed. Digestive, neurologic and hematotoxicity over cycles 1-2 showed 10.3% G3 and 2.1% G4, including one toxic death. DPYD exome, flanking intronic regions (20 bp), 3'UTR and part of 5'UTR (500 bp) were sequenced on MiSeq Illumina (Integragen, 97% coverage, HWE checked). RESULTS: In total, 48 SNPs were identified: three in 3'UTR, 19 in coding regions (four synonymous including E412E; 15 missenses including D949V, V732I, R592W, I560S, I543V, S534N, S492L, M406I, D342G, M166V, T65M, C29R), 19 in flanking intronic regions (including *2A) and seven in 5'UTR. In total, 11 SNPs have not been previously described, including three missense variations each heterozygous in three separate patients: R696H, F100L and A26T. The patient with a toxic death carried one D949V allele. The three consensual variants *2A, D949V and I560S were carried by seven patients (heterozygous). Analysis of consensual variants showed that they were associated with G3-4 toxicity (OR = 21.0, sensitivity 16.7%) but not with G4 toxicity. Adding the variants previously associated with DPD deficiency in vitro, i.e. R592W, S492L and D342N/G, increased sensitivity on G3-4 (23.3%, OR = 21.1) and was predictive of G4 toxicity (sensitivity 40%, OR = 19.0). Of note, adding the new F100L variant further improved predictivity of genotyping on G4 toxicity (sensitivity 60%, OR = 42.8). CONCLUSIONS: Present data establish the impact of consensual variants on capecitabine toxicity and reveal the existence of a novel DPYD variant, F100L, associated with G4 toxicity. PMID- 27454531 TI - Classification of motor imagery tasks for BCI with multiresolution analysis and multiobjective feature selection. AB - BACKGROUND: Brain-computer interfacing (BCI) applications based on the classification of electroencephalographic (EEG) signals require solving high dimensional pattern classification problems with such a relatively small number of training patterns that curse of dimensionality problems usually arise. Multiresolution analysis (MRA) has useful properties for signal analysis in both temporal and spectral analysis, and has been broadly used in the BCI field. However, MRA usually increases the dimensionality of the input data. Therefore, some approaches to feature selection or feature dimensionality reduction should be considered for improving the performance of the MRA based BCI. METHODS: This paper investigates feature selection in the MRA-based frameworks for BCI. Several wrapper approaches to evolutionary multiobjective feature selection are proposed with different structures of classifiers. They are evaluated by comparing with baseline methods using sparse representation of features or without feature selection. RESULTS AND CONCLUSION: The statistical analysis, by applying the Kolmogorov-Smirnoff and Kruskal-Wallis tests to the means of the Kappa values evaluated by using the test patterns in each approach, has demonstrated some advantages of the proposed approaches. In comparison with the baseline MRA approach used in previous studies, the proposed evolutionary multiobjective feature selection approaches provide similar or even better classification performances, with significant reduction in the number of features that need to be computed. PMID- 27454532 TI - OMWare: a tool for efficient assembly of genome-wide physical maps. AB - BACKGROUND: Physical mapping of DNA with restriction enzymes allows for the characterization and assembly of much longer molecules than is feasible with sequencing. However, assemblies of physical map data are sensitive to input parameters, which describe noise inherent in the data collection process. One possible way to determine the parameter values that best describe a dataset is by trial and error. RESULTS: Here we present OMWare, a tool that efficiently generated 405 de novo map assemblies of a single datasets collected from the cotton species Gossypium raimondii. The assemblies were generated using various input parameter values, and were completed more efficiently by re-using compatible intermediate results. These assemblies were assayed for contiguity, internal consistency, and accuracy. CONCLUSIONS: Resulting assemblies had variable qualities. Although highly accurate assemblies were found, contiguity and internal consistency metrics were poor predictors of accuracy. PMID- 27454533 TI - Comparative performance of double-digest RAD sequencing across divergent arachnid lineages. AB - Next-generation sequencing technologies now allow researchers of non-model systems to perform genome-based studies without the requirement of a (often unavailable) closely related genomic reference. We evaluated the role of restriction endonuclease (RE) selection in double-digest restriction-site associated DNA sequencing (ddRADseq) by generating reduced representation genome wide data using four different RE combinations. Our expectation was that RE selections targeting longer, more complex restriction sites would recover fewer loci than RE with shorter, less complex sites. We sequenced a diverse sample of non-model arachnids, including five congeneric pairs of harvestmen (Opiliones) and four pairs of spiders (Araneae). Sample pairs consisted of either conspecifics or closely related congeneric taxa, and in total 26 sample pair analyses were tested. Sequence demultiplexing, read clustering and variant calling were performed in the pyRAD program. The 6-base pair cutter EcoRI combined with methylated site-specific 4-base pair cutter MspI produced, on average, the greatest numbers of intra-individual loci and shared loci per sample pair. As expected, the number of shared loci recovered for a sample pair covaried with the degree of genetic divergence, estimated with cytochrome oxidase I sequences, although this relationship was non-linear. Our comparative results will prove useful in guiding protocol selection for ddRADseq experiments on many arachnid taxa where reference genomes, even from closely related species, are unavailable. PMID- 27454534 TI - Chiral Dodecanuclear Palladium(II) Thio Cluster: Synthesis, Structure, and Formation Mechanism Explored by ESI-MS and DFT Calculations. AB - The chiral dodecanuclear palladium(II) thio cluster LaPd12(C3H5NO2S)3(C3H6NO2S)21 (1) was prepared by reacting l-cysteine (l-Cys) with PdCl2 and La2O3 in aqueous solution under carefully controlled conditions. Compound 1 was structurally characterized by single-crystal XRD, TGA, IR, UV-vis, (13)C NMR, and CD spectroscopy. Insight into the dimerization process of 1 was obtained by ESI-MS and DFT calculations. PMID- 27454535 TI - An Important Cause of Child and Youth Homelessness. PMID- 27454536 TI - Preliminary Evaluation of the Pathomechanisms of Dysphagia After Occipitospinal Fusion: Kinematic Analysis by Videofluoroscopic Swallowing Study. AB - STUDY DESIGN: Kinematic analysis of swallowing function using videofluoroscopic swallowing study (VFSS). OBJECTIVES: The aims of this study were to analyze swallowing process in the patients who underwent occipitospinal fusion (OSF) and elucidate the pathomechanism of dysphagia after OSF. SUMMARY OF BACKGROUND DATA: Although several hypotheses about the pathomechanisms of dysphagia after OSF were suggested, there has been little tangible evidence to support these hypotheses since these hypotheses were based on the analysis of static radiogram or CT. Considering that swallowing is a compositive motion of oropharyngeal structures, the etiology of postoperative dysphagia should be investigated through kinematic approaches. METHODS: Each four patients with or without postoperative dysphagia (group D and N, respectively) participated in this study. For VFSS, all patients were monitored to swallow 5-mL diluted barium solution by fluoroscopy, and then dynamic passing pattern of the barium solution was analyzed. Additionally, O-C2 angle (O-C2A) was measured for the assessment of craniocervical alignment. RESULTS: O-C2A in group D was -7.5 degrees, which was relatively smaller than 10.3 degrees in group N (P = 0.07). In group D, all cases presented smooth medium passing without any obstruction at the upper cervical level regardless of O-C2A, whereas the obstruction to the passage of medium was detected at the apex of mid lower cervical ocurvature, where the anterior protrusion of mid-lower cervical spine compressed directly the pharyngeal space. In group N, all cases showed smooth passing of medium through the whole process of swallowing. CONCLUSION: This study presented that postoperative dysphagia did not occur at the upper cervical level even though there was smaller angle of O-C2A and demonstrated the narrowing of the oropharyngeal space towing to direct compression by the anterior protrusion of mid-lower cervical spine was the etiology of dysphagia after OSF. Therefore, surgeon should pay attention to the alignment of mid-cervical spine as well as craniocervical junction during OSF. LEVEL OF EVIDENCE: 4. PMID- 27454537 TI - Accurate and Simple Screw Insertion Procedure With Patient-Specific Screw Guide Templates for Posterior C1-C2 Fixation. AB - STUDY DESIGN: Prospective clinical trial of the screw insertion method for posterior C1-C2 fixation utilizing the patient-specific screw guide template technique. OBJECTIVE: To evaluate the efficacy of this method for insertion of C1 lateral mass screws (LMS), C2 pedicle screws (PS), and C2 laminar screws (LS). SUMMARY OF BACKGROUND DATA: Posterior C1LMS and C2PS fixation, also known as the Goel-Harms method, can achieve immediate rigid fixation and high fusion rate, but the screw insertion carries the risk of injury to neuronal and vascular structures. Dissection of venous plexus and C2 nerve root to confirm the insertion point of the C1LMS may also cause problems. We have developed an intraoperative screw guiding method using patient-specific laminar templates. METHODS: Preoperative bone images of computed tomography (CT) were analyzed using three-dimensional (3D)/multiplanar imaging software to plan the trajectories of the screws. Plastic templates with screw guiding structures were created for each lamina using 3D design and printing technology. Three types of templates were made for precise multistep guidance, and all templates were specially designed to fit and lock on the lamina during the procedure. Surgery was performed using this patient-specific screw guide template system, and placement of the screws was postoperatively evaluated using CT. RESULTS: Twelve patients with C1-C2 instability were treated with a total of 48 screws (24 C1LMS, 20 C2PS, 4 C2LS). Intraoperatively, each template was found to exactly fit and lock on the lamina and screw insertion was completed successfully without dissection of the venous plexus and C2 nerve root. Postoperative CT showed no cortical violation by the screws, and mean deviation of the screws from the planned trajectories was 0.70 +/- 0.42 mm. CONCLUSION: The multistep, patient-specific screw guide template system is useful for intraoperative screw navigation in posterior C1-C2 fixation. This simple and economical method can improve the accuracy of screw insertion, and reduce operation time and radiation exposure of posterior C1-C2 fixation surgery. LEVEL OF EVIDENCE: 3. PMID- 27454538 TI - Novel Screw Head Design of Pedicle Screw for Reducing the Correction Loss in the Patients With Thoracolumbar Vertebral Fractures: A Biomechanical Study. AB - STUDY DESIGN: A biomechanical study. OBJECTIVE: To study the different biomechanical property among fixed-axis, monoplanar and polyaxial screws in the static and dynamic tests. SUMMARY OF BACKGROUND DATA: Correction loss is a common phenomenon in the patients with thoracolumbar vertebral fractures who underwent the posterior pedicle screw fixation. The incidence varies with the kinds of fixation instrumentation used. There is higher incidence in polyaxial pedicle screws group than in fixed-axis pedicle screws. Monoplanar pedicle screws, which are mobile in the axial plane but fixed in the sagittal plane, can be a better fixation instrumentation for thoracolumbar vertebral fractures in theory. METHODS: A total of 30 porcine spinal units (L2-L4) were used for the static and dynamic tests, which were randomized into six groups (A1, A2, A3, B1, B2, and B3). Static test was performed in A1, A2, and A3. In this test, fixed-axis, monoplanar, and polyaxial screws were performed in A1, A2, and A3, respectively. The ultimate load was noted after tested. In addition, dynamic test was performed in B1, B2, and B3, used fixed-axis, monoplanar, and polyaxial screws, respectively. Correction loss (head-shank angle shift and anterior vertebral body height shift) was obtained and analyzed in each mode. RESULTS: In static test, fixed-axis and monoplanar screws had significantly higher ultimate load than polyaxial screws (P < 0.05) and fixed-axis screws had a little higher ultimate load than monoplanar screws (P < 0.05). In dynamic test, correction loss was minimal in fixed-axis screws, medium in monoplanar screws, and maximal in polyaxial screws. However, the differences were statistically significant in all comparisons but not in the comparison of fixed-axis and monoplanar screws (P > 0.05). CONCLUSION: The findings from the current study suggest that monoplanar screws can significantly increase the stiffness in axial direction compared with polyaxial screws, and reduce the risks of correction loss. For thoracolumbar vertebral fractures, monoplanar screw is a better optional instrumentation for minimally invasive surgery. LEVEL OF EVIDENCE: N/A. PMID- 27454539 TI - Risk of Implant Loosening After Cyclic Loading of Fusionless Growth Modulation Techniques: Nitinol Staples Versus Flexible Tether. AB - STUDY DESIGN: Biomechanical evaluation using porcine spines. OBJECTIVE: Compare the fixation strength of two currently used fusionless adolescent idiopathic scoliosis correction techniques following cyclic loading using porcine spines. SUMMARY OF BACKGROUND DATA: The ability of fusionless implants to control or correct scoliosis in a growing patient requires such implants to maintain spinal fixation. Because they cross the disc, motion may weaken fixation over time. METHODS: Eight pig spines were divided into cycled segments (T10-T13) and uncycled segments (T7-T8, L2-L3). Initial range of motion (ROM) was determined in torsion, flexion-extension, and lateral bending (0.5 degrees /s to 1.75 N.m).Staple group (n = 4): 6 mm parallel staples were inserted on the right anterolateral spine across each intervertebral disc. Cycled segments received six staples (three adjacent discs) and uncycled segments received four staples (two separate discs).Tether group (n = 4): 5.35 * 35 mm right anterolateral vertebral body screws were placed into each vertebra. Cycled segments received four screws and uncycled segments received four screws. Screws in cycled segments were connected with a flexible tether tensioned to straight alignment.ROM of instrumented cycled segments was measured, and then segments were loaded to the measured ROM in flexion-extension (2000 cycles), lateral bending (1000 cycles), and axial rotation (2000 cycles). Implants were axially loaded to failure. Parametric tests compared pre- to postimplant ROM; nonparametric tests compared staple to screw pullout strength; P < 0.05 was significant. RESULTS: There were no differences in ROM before instrumentation between groups. ROM was not changed except tethers decreased left lateral bending (-6.2 degrees ). Although staple pullout was less than screw pullout for cycled and uncycled segments (P < 0.05 and P = 0.057, respectively), there was no difference in pullout strength with and without cyclic loading for either group (P = 0.4). CONCLUSION: Tethers decreased lateral bending away from the tether. Screws had almost five times greater load to failure than staples. Five thousand cycles did not result in loosening of either staple or tether screws. LEVEL OF EVIDENCE: N/A. PMID- 27454540 TI - Percutaneous Endoscopic Lumbar Discectomy for L5-S1 Disc Herniation Via an Interlaminar Approach Versus a Transforaminal Approach: A Prospective Randomized Controlled Study With 2-Year Follow Up. AB - STUDY DESIGN: A prospective, randomized controlled study of patients with L5-S1 lumbar disc herniations, operated with endoscopic discectomy through an interlaminar or transforaminal approach. OBJECTIVE: To compare the results of percutaneous endoscopic lumbar discectomy in L5-S1 disc herniation through an interlaminar or transforaminal approach. SUMMARY OF BACKGROUND DATA: The transforaminal and interlaminar techniques are both acceptable approaches for L5 S1 disc herniation. This is the first study to compare these two approaches in terms of their surgical effects and advantages. METHODS: From January 2010 to June 2010, 60 patients with L5-S1 disc herniation were randomly recruited into two groups; one group underwent percutaneous endoscopic interlaminar discectomy (PEID) and the other group underwent percutaneous endoscopic transforaminal discectomy (PETD). There were 30 patients in each group. The operation time, intraoperative radiation time, postoperative bed rest time, hospitalization time, and complications were compared between the groups. The surgical effectiveness was assessed according to the Oswestry Disability Index (ODI), Visual Analog Scale (VAS), and modified MacNab criteria. RESULTS: All the patients completed follow up with a mean of 27.6 months (range, 24-37 months). In the PEID group, the mean operation time was 65.0 +/- 14.9 minutes, and the intraoperative radiation time was 0.60 +/- 0.24 seconds. For the PETD group, the mean operation time was 86.0 +/- 15.4 minutes, and the intraoperative radiation time was 6.50 +/ 1.52 seconds. There were significant differences in operation time and radiation time between the two groups (P < 0.01) but not in the postoperative bed rest time, hospitalization time, or complication rate (P > 0.05). The postoperative ODI and VAS were obviously improved in both groups when compared with preoperation (P < 0.01). According to the MacNab criteria, the satisfactory rates were 93.3% and 90.0% in the two groups, without a significant difference (P > 0.05). CONCLUSION: PEID can escape the blockade of crista iliaca, and advantages include a faster puncture orientation, a shorter operation time, and less intraoperative radiation exposure. PETD requires higher punctuation skill and more intraoperative radiation exposure. LEVEL OF EVIDENCE: 4. PMID- 27454541 TI - Association Between Rosacea and Parkinson Disease. PMID- 27454543 TI - Medical Student Use of Electronic Health Records to Track Former Patients. PMID- 27454542 TI - Global health initiatives in Africa - governance, priorities, harmonisation and alignment. AB - BACKGROUND: The advent of global health initiatives (GHIs) has changed the landscape and architecture of health financing in low and middle income countries, particularly in Africa. Over the last decade, the African Region has realised improvements in health outcomes as a result of interventions implemented by both governments and development partners. However, alignment and harmonisation of partnerships and GHIs are still difficult in the African countries with inadequate capacity for their effective coordination. METHOD: Both published and grey literature was reviewed to understand the governance, priorities, harmonisation and alignment of GHIs in the African Region; to synthesise the knowledge and highlight the persistent challenges; and to identify gaps for future research. RESULTS: GHI governance structures are often separate from those of the countries in which they operate. Their divergent funding channels and modalities may have contributed to the failure of governments to track their resources. There is also evidence that basically, earmarking and donor conditions drive funding allocations regardless of countries' priorities. Although studies cite the lack of harmonisation of GHI priorities with national strategies, evidence shows improvements in that area over time. GHIs have used several strategies and mechanisms to involve the private sector. These have widened the pool of health service policy-makers and providers to include groups such as civil society organisations (CSOs), with both positive and negative implications. GHI strategies such as co-financing by countries as a condition for support have been positive in achieving sustainability of interventions. CONCLUSIONS: GHI approaches have not changed substantially over the years but there has been evolution in terms of donor funding and conditions. GHIs still largely operate in a vertical manner, bypassing country systems; they compete for the limited human resources; they influence country policies; and they are not always harmonised with other donors. To maximise returns on GHI support, there is need to ensure that their approaches are more comprehensive as opposed to being selective; to improve GHI country level governance and alignment with countries' changing epidemiologic profiles; and to strengthen their involvement of CSOs. PMID- 27454544 TI - Risk of colorectal adenomas, advanced adenomas and cancer in patients with colonic diverticular disease: Systematic review and meta-analysis. AB - BACKGROUND AND AIM: Diverticular disease and colorectal neoplasia are common digestive disorders worldwide. Both diseases share epidemiological trends and certain risk factors including advancing age, physical inactivity, and Western diet and lifestyle. Studies assessing the association between these diseases reported inconsistent results. Thus, we conducted a systematic review and meta analysis to determine the association between diverticular disease and colorectal adenomas, advanced adenomas and cancer. METHODS: A comprehensive search of the databases MEDLINE and EMBASE was done from inception through March 2016. Inclusion criterion was the observational studies' assessment of the association between diverticular disease and colorectal neoplasia in adult participants. Pooled OR and 95% confidence interval (CI) were calculated using a random effect. RESULTS: Data were extracted from 14 observational studies (11 cross-sectional studies, one case-control study and two cohort studies). Diverticular disease was associated with increased odds of adenomas (OR = 1.67, 95% CI 1.27-2.21, 10 studies), but not associated with advanced adenomas (OR = 1.19, 95% CI 0.88-1.62, I2 = 52%, four studies) or colorectal cancer (OR = 1.36, 95% CI 0.47-3.92, I2 = 98%, seven studies). CONCLUSIONS: Our meta-analysis demonstrated that diverticular disease was associated with colorectal adenomas. Colonoscopists should be aware of this association and carefully examine the entire large bowel in individuals with diverticulosis. PMID- 27454545 TI - A meta-analysis of maturation-related variation in adolescent boy athletes' adaptations to short-term resistance training. AB - This meta-analysis investigated the maturation-related pattern of adaptations to resistance training in boy athletes. We included studies examining the effects of 4-16-week resistance training programmes in healthy boy athletes aged 10-18 years. Pooled estimates of effect size for change in strength across all studies (n = 19) were calculated using the inverse-variance random effects model for meta analyses. Estimates were also calculated for groups based on likely biological maturity status ("before", "during" and "after" peak height velocity). Using the standardised mean difference, resistance training increased strength across all groups (effect size = 0.98, [CI: 0.70-1.27]). Strength gains were larger during (1.11 [0.67-1.54]) and after (1.01 [0.56-1.46]) peak height velocity than before (0.5 [-0.06-1.07]). Adaptations to resistance training are greater in adolescent boys during or after peak height velocity. These findings should help coaches to optimise the timing of training programmes that are designed to improve strength in boy athletes. PMID- 27454546 TI - Fundamental Role of Oxygen Stoichiometry in Controlling the Band Gap and Reactivity of Cupric Oxide Nanosheets. AB - CuO is a nonhazardous, earth-abundant material that has exciting potential for use in solar cells, photocatalysis, and other optoelectronic applications. While progress has been made on the characterization of properties and reactivity of CuO, there remains significant controversy on how to control the precise band gap by tuning conditions of synthetic methods. Here, we combine experimental and theoretical methods to address the origin of the wide distribution of reported band gaps for CuO nanosheets. We establish reaction conditions to control the band gap and reactivity via a high-temperature treatment in an oxygen-rich environment. SEM, TEM, XRD, and BET physisorption reveals little to no change in nanostructure, crystal structure, or surface area. In contrast, UV-vis spectroscopy shows a modulation in the material band gap over a range of 330 meV. A similar trend is found in H2 temperature-programmed reduction where peak H2 consumption temperature decreases with treatment. Calculations of the density of states show that increasing the oxygen to copper coverage ratio of the surface accounts for most of the observed changes in the band gap. An oxygen exchange mechanism, supported by (18)O2 temperature-programmed oxidation, is proposed to be responsible for changes in the CuO nanosheet oxygen to copper stoichiometry. The changes induced by oxygen depletion/deposition serve to explain discrepancies in the band gap of CuO, as reported in the literature, as well as dramatic differences in catalytic performance. PMID- 27454547 TI - Lurasidone Dose Escalation in Early Nonresponding Patients With Schizophrenia: A Randomized, Placebo-Controlled Study. AB - OBJECTIVE: To assess the effect of dose increase in adult patients with schizophrenia who demonstrate inadequate initial response to standard-dose lurasidone and to evaluate the efficacy of low-dose lurasidone in adult patients with schizophrenia. METHODS: In this randomized, double-blind, placebo-controlled study conducted between May 2013 and June 2014, hospitalized patients with acute schizophrenia (DSM-IV-TR criteria) were randomly assigned to double-blind treatment with lurasidone 20 mg/d (n = 101), lurasidone 80 mg/d (n = 199), or placebo (n = 112). Nonresponders to lurasidone 80 mg/d (Positive and Negative Syndrome Scale [PANSS] score decrease < 20%) at 2 weeks were re-randomized to lurasidone 80 mg/d or 160 mg/d for the remaining 4 weeks of the study. The primary outcome measure was change from baseline to week 6 in PANSS total score. RESULTS: In nonresponders to lurasidone 80 mg/d (n = 95), dose increase to 160 mg/d at week 2 significantly reduced PANSS total score at week 6 study endpoint compared with continuing 80 mg/d (-16.6 vs -8.9; P < .05 [effect size = 0.52]). While a comparable magnitude of improvement was observed in Clinical Global Impression-Severity (CGI-S) score from week 2 to week 6 endpoint for lurasidone 160 mg/d versus 80 mg/d (-1.0 vs -0.6; effect size = 0.44), the difference was not statistically significant (P = .052). Patients receiving lurasidone 20 mg/d did not demonstrate significant improvement compared with placebo at week 6 in PANSS total (-17.6 vs -14.5; P = .26) or CGI-S (-0.93 vs -0.73; P = .17) scores. Few dose-related adverse effects associated with lurasidone were observed. CONCLUSIONS: In adult patients with schizophrenia demonstrating nonresponse to 2 weeks of treatment with lurasidone 80 mg/d, dose increase to 160 mg/d resulted in significant symptom improvement compared with continuing lurasidone 80 mg/d. Lurasidone 20 mg/d was not associated with significant improvement in psychotic symptoms in adult patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01821378. PMID- 27454548 TI - Effect of Hemoconcentration on Dural Sinus Computed Tomography Density in a Pediatric Population. AB - Unenhanced brain computed tomography (CT) is inexpensive, easily available, and the first-choice imaging modality for patients presenting with various neurologic symptoms. Venous thrombosis is not rare in childhood, but diagnosis can be difficult. In some cases, only denser vessels can be used to highlight an issue. The aim of this study was to retrospectively evaluate the relationship between X ray attenuation and hemoconcentration in a pediatric population. This study enrolled 99 pediatric patients who had been referred radiology department for unenhanced brain CT. Images were retrospectively evaluated for measurement of dural sinus densities from four distinct dural sinus locations. Correlation between mean Hounsfield unit (HU) values and hemoglobin/hematocrit (Hb/Htc) levels, as well as age and gender were further analyzed. There was a strong correlation between mean HU and Hb levels (r = 0.411; standard deviation: 0.001) and also between mean HU and Htc levels (r = 0.393; p < 0.001). According to the results of this study, the mean sinus density and H:H (HU:Htc) values were 44.06 HU and 1.19, respectively, in a normal pediatric group. In conclusion, before deciding between a diagnosis of thrombosis and a determination of normal findings during an evaluation of unenhanced CT in a pediatric population, radiologists should consider complete blood count results as well as H:H ratios. PMID- 27454549 TI - Iridoid Glycosides from Tabebuia avellanedae. AB - Five novel iridoid glycosides, avellanedaesides A-E (1 - 5) were isolated from the H2 O extract of Tabebuia avellanedae. Their structures were determined on the basis of NMR and MS analysis. Isolated compounds suppressed inflammatory cytokine, tumor-necrosis factor-alpha and interleukin-1beta production in cultured human myeloma THP-1 cells co-stimulated with lipopolysaccharide (LPS). In addition, the study revealed iridoid glycosides inhibited the activity of cytochrome CYP3A4 enzyme. PMID- 27454550 TI - Real-time arrhythmia detection with supplementary ECG quality and pulse wave monitoring for the reduction of false alarms in ICUs. AB - False intensive care unit (ICU) alarms induce stress in both patients and clinical staff and decrease the quality of care, thus significantly increasing both the hospital recovery time and rehospitalization rates. In the PhysioNet/CinC Challenge 2015 for reducing false arrhythmia alarms in ICU bedside monitor data, this paper validates the application of a real-time arrhythmia detection library (ADLib, Schiller AG) for the robust detection of five types of life-threatening arrhythmia alarms. The strength of the application is to give immediate feedback on the arrhythmia event within a scan interval of 3 s-7.5 s, and to increase the noise immunity of electrocardiogram (ECG) arrhythmia analysis by fusing its decision with supplementary ECG quality interpretation and real time pulse wave monitoring (quality and hemodynamics) using arterial blood pressure or photoplethysmographic signals. We achieved the third-ranked real-time score (79.41) in the challenge (Event 1), however, the rank was not officially recognized due to the 'closed-source' entry. This study shows the optimization of the alarm decision module, using tunable parameters such as the scan interval, lead quality threshold, and pulse wave features, with a follow-up improvement of the real-time score (80.07). The performance (true positive rate, true negative rate) is reported in the blinded challenge test set for different arrhythmias: asystole (83%, 96%), extreme bradycardia (100%, 90%), extreme tachycardia (98%, 80%), ventricular tachycardia (84%, 82%), and ventricular fibrillation (78%, 84%). Another part of this study considers the validation of ADLib with four reference ECG databases (AHA, EDB, SVDB, MIT-BIH) according to the international recommendations for performance reports in ECG monitors (ANSI/AAMI EC57). The sensitivity (Se) and positive predictivity (+P) are: QRS detector QRS (Se, +P) > 99.7%, ventricular ectopic beat (VEB) classifier VEB (Se, +P) = 95%, and ventricular fibrillation detector VFIB (P + = 94.8%) > VFIB (Se = 86.4%), adjusted to the clinical setting requirements, giving preference to low false positive alarms. PMID- 27454551 TI - An Implementation-Focused Bio/Algorithmic Workflow for Synthetic Biology. AB - As synthetic biology moves away from trial and error and embraces more formal processes, workflows have emerged that cover the roadmap from conceptualization of a genetic device to its construction and measurement. This latter aspect (i.e., characterization and measurement of synthetic genetic constructs) has received relatively little attention to date, but it is crucial for their outcome. An end-to-end use case for engineering a simple synthetic device is presented, which is supported by information standards and computational methods and focuses on such characterization/measurement. This workflow captures the main stages of genetic device design and description and offers standardized tools for both population-based measurement and single-cell analysis. To this end, three separate aspects are addressed. First, the specific vector features are discussed. Although device/circuit design has been successfully automated, important structural information is usually overlooked, as in the case of plasmid vectors. The use of the Standard European Vector Architecture (SEVA) is advocated for selecting the optimal carrier of a design and its thorough description in order to unequivocally correlate digital definitions and molecular devices. A digital version of this plasmid format was developed with the Synthetic Biology Open Language (SBOL) along with a software tool that allows users to embed genetic parts in vector cargoes. This enables annotation of a mathematical model of the device's kinetic reactions formatted with the Systems Biology Markup Language (SBML). From that point onward, the experimental results and their in silico counterparts proceed alongside, with constant feedback to preserve consistency between them. A second aspect involves a framework for the calibration of fluorescence-based measurements. One of the most challenging endeavors in standardization, metrology, is tackled by reinterpreting the experimental output in light of simulation results, allowing us to turn arbitrary fluorescence units into relative measurements. Finally, integration of single cell methods into a framework for multicellular simulation and measurement is addressed, allowing standardized inspection of the interplay between the carrier chassis and the culture conditions. PMID- 27454552 TI - Perceived Transcultural Self-Efficacy of Nurses in General Hospitals in Guangzhou, China. AB - BACKGROUND: Conflicts arising from cultural diversity among patients and hospital staff in China have become intense. Hospitals have an urgent need to improve transcultural self-efficacy of nurses for providing effective transcultural nursing. OBJECTIVE: The purpose of the research was to (a) evaluate the current status of perceived transcultural self-efficacy of nurses in general hospitals in Guangzhou, China; (b) explore associations between demographic characteristics of nurses and their perceived transcultural self-efficacy; and (c) assess the reliability and validity of scores on the Chinese version of the Transcultural Self-Efficacy Tool (TSET). METHODS: A cross-sectional survey of registered nurses from three general hospitals was conducted. Quota and convenience sampling were used. Participants provided demographic information and answered questions on the TSET. RESULTS: A total of 1,156 registered nurses took part. Most nurses had a moderate level of self-efficacy on the Cognitive (87.9%), Practical (87%), and Affective (89.2%) TSET subscales. Nurses who were older; who had more years of work experience, higher professional titles, higher incomes, and a minority background; and who were officially employed (not temporary positions) had higher perceived transcultural self-efficacy. Reliability estimated using Cronbach's alpha was .99 for the total TSET score; reliability for the three subscales ranged from .97 to .98. Confirmatory factor analysis of TSET scores showed good fit with a three-factor model. CONCLUSION: The results of this study can provide insights and guidelines for hospital nursing management to facilitate design of in-service education systems to improve transcultural self-efficacy of nurses. PMID- 27454554 TI - Dynamically encircling an exceptional point for asymmetric mode switching. AB - Physical systems with loss or gain have resonant modes that decay or grow exponentially with time. Whenever two such modes coalesce both in their resonant frequency and their rate of decay or growth, an 'exceptional point' occurs, giving rise to fascinating phenomena that defy our physical intuition. Particularly intriguing behaviour is predicted to appear when an exceptional point is encircled sufficiently slowly, such as a state-flip or the accumulation of a geometric phase. The topological structure of exceptional points has been experimentally explored, but a full dynamical encircling of such a point and the associated breakdown of adiabaticity have remained out of reach of measurement. Here we demonstrate that a dynamical encircling of an exceptional point is analogous to the scattering through a two-mode waveguide with suitably designed boundaries and losses. We present experimental results from a corresponding waveguide structure that steers incoming waves around an exceptional point during the transmission process. In this way, mode transitions are induced that transform this device into a robust and asymmetric switch between different waveguide modes. This work will enable the exploration of exceptional point physics in system control and state transfer schemes at the crossroads between fundamental research and practical applications. PMID- 27454553 TI - Ventilatory threshold may be a more specific measure of aerobic capacity than peak oxygen consumption rate in persons with stroke. AB - BACKGROUND: After stroke, aerobic deconditioning can have a profound impact on daily activities. This is usually measured by the peak oxygen consumption rate achieved during exercise testing (VO2-peak). However, VO2-peak may be distorted by motor function. The oxygen uptake efficiency slope (OUES) and VO2 at the ventilatory threshold (VO2-VT) could more specifically assess aerobic capacity after stroke, but this has not been tested. OBJECTIVES: To assess the differential influence of motor function on three measures of aerobic capacity (VO2-peak, OUES, and VO2-VT) and to evaluate the inter-rater reliability of VO2 VT determination post-stroke. METHODS: Among 59 persons with chronic stroke, cross-sectional correlations with motor function (comfortable gait speed [CGS] and lower extremity Fugl-Meyer [LEFM]) were compared between the different aerobic capacity measures, after adjustment for covariates, in order to isolate any distorting effect of motor function. Reliability of VO2-VT determination between three raters was assessed with intra-class correlation (ICC). RESULTS: CGS was moderately correlated with VO2-peak (r = 0.52, p < 0.0001) and weakly correlated with OUES (r = 0.41, p = 0.002) and VO2-VT (r = 0.37, p = 0.01). LEFM was weakly correlated with VO2-peak (r = 0.26, p = 0.055) and very weakly correlated with OUES (r = 0.19, p = 0.17) and VO2-VT (r = 0.14, p = 0.31). Compared to VO2-peak, VO2-VT was significantly less correlated with CGS (r difference = -0.16, p = 0.02). Inter-rater reliability of VO2-VT determination was high (ICC: 0.93, 95% CI: 0.89-0.96). CONCLUSIONS: Motor dysfunction appears to artificially lower measured aerobic capacity. VO2-VT seemed to be less distorted than VO2-peak and had good inter-rater reliability, so it may provide more specific assessment of aerobic capacity post-stroke. PMID- 27454556 TI - Molecularly Imprinted Polymer (MIP) Film with Improved Surface Area Developed by Using Metal-Organic Framework (MOF) for Sensitive Lipocalin (NGAL) Determination. AB - Electropolymerizable functional and cross-linking monomers were used to prepare conducting molecularly imprinted polymer film with improved surface area with the help of a sacrificial metal-organic framework (MOF). Subsequent dissolution of the MOF layer resulted in a surface developed MIP film. This surface enlargement increased the analyte accessibility to imprinted molecular cavities. Application of the porous MIP film as a recognition unit of an extended-gate field effect transistor (EG-FET) chemosensor effectively enhanced analytical current signals of determination of recombinant human neutrophil gelatinase-associated lipocalin (NGAL). PMID- 27454555 TI - Topological energy transfer in an optomechanical system with exceptional points. AB - Topological operations can achieve certain goals without requiring accurate control over local operational details; for example, they have been used to control geometric phases and have been proposed as a way of controlling the state of certain systems within their degenerate subspaces. More recently, it was predicted that topological operations can be used to transfer energy between normal modes, provided that the system possesses a specific type of degeneracy known as an exceptional point. Here we demonstrate the transfer of energy between two vibrational modes of a cryogenic optomechanical device using topological operations. We show that this transfer arises from the presence of an exceptional point in the spectrum of the device. We also show that this transfer is non reciprocal. These results open up new directions in system control; they also open up the possibility of exploring other dynamical effects related to exceptional points, including the behaviour of thermal and quantum fluctuations in their vicinity. PMID- 27454557 TI - Label-free, ITO-based immunosensor for the detection of a cancer biomarker: Receptor for Activated C Kinase 1. AB - A new, quite sensitive disposable immunosensor, based on the anti-RACK1 antibody, was developed for the determination of Receptor for Activated C Kinase 1 (RACK1) for the first time. Moreover, indium tin oxide (ITO) flexible sheets were modified by using aldehyde ended silane 11-(triethoxysilyl)undecanal (TESU) self assembled monolayers (SAMs) for immobilizing the anti-RACK1 antibody via covalent bonds. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and square wave voltammetry (SWV) methods were used for characterizing the immobilization steps and for determining the RACK1 concentration. To obtain a successful immunosensor, experimental factors were optimized. This quite sensitive biosensor was able to detect concentrations as low as fg mL(-1). The detection principle was based on the change in charge transfer resistance and the Nyquist plot diameter and these changes were monitored by using electrochemical impedance spectroscopy (EIS). This impedimetric immunosensor had perfect repeatability and reproducibility. We proved that the new silane agent, TESU, performs well in biosensor applications. The feasibility of the fabricated immunosensor was tested by detecting RACK1 in artificial and real human serum samples. PMID- 27454559 TI - Dorsal root ganglion stimulation approval by the Food and Drug Administration: advice on evolving the process. PMID- 27454558 TI - Inhibition of miR-21 by 3'/5'-Serinyl-Capped 2'-O-Methyl RNA Interspersed with 2' O-(2-Amino-3-Methoxypropyl) Uridine Units. AB - miRNAs are highly conserved class of small ncRNAs whose involvement in human pathophysiologies is extensively investigated. MiR-21 is a well established oncogenic miRNA whose deregulation plays a significant role in onset and progression of cancer. The need of novel approaches to downregulate miR-21 is rapidly expanding. Potent inhibition of miR-21 is achieved by chemically modified 2'-O-methyl RNA oligonucleotide. The serinol capping at 3' and 5'ends and the interspersed 2'-O-(R-2-amino-3-methoxypropyl) uridine units enhance the nuclease resistance and efficacy of 2'-O-methyl RNA for the inhibition of miR-21. This represents a simple and novel modification for developing oligonucleotide-based therapeutics. PMID- 27454560 TI - Extreme QTL mapping of germination speed in Arabidopsis thaliana. AB - Seed germination is a key life history transition for annual plants and partly determines lifetime performance and fitness. Germination speed, the elapsed time for a nondormant seed to germinate, is a poorly understood trait important for plants' competitiveness and fitness in fluctuating environments. Germination speed varied by 30% among 18 Arabidopsis thaliana populations measured, and exhibited weak negative correlation with flowering time and seed weight, with significant genotype effect (P < 0.005). To dissect the genetic architecture of germination speed, we developed the extreme QTL (X-QTL) mapping method in A. thaliana. The method has been shown in yeast to increase QTL mapping power by integrating selective screening and bulk-segregant analysis in a very large mapping population. By pooled genotyping of top 5% of rapid germinants from ~100 000 F3 individuals, three X-QTL regions were identified on chromosomes 1, 3 and 4. All regions were confirmed as QTL regions by sequencing 192 rapid germinants from an independent F3 selection experiment. Positional overlaps were found between X-QTLs and previously identified seed, life history and fitness QTLs. Our method provides a rapid mapping platform in A. thaliana with potentially greater power. One can also relate identified X-QTLs to the A. thaliana physical map, facilitating candidate gene identification. PMID- 27454562 TI - Proceedings of the First International Conference on Stepped Wedge Trial Design : York, UK, 10 March 2016. PMID- 27454563 TI - Headhunters: the search for a science of mind, by Ben Shephard. PMID- 27454564 TI - Black Skin, White Coats: Nigerian Psychiatrists, Decolonization and the Globalization of Psychiatry, 2013, by Matthew M. Heaton. PMID- 27454565 TI - Being Mortal: Illness, Medicine, and What Matters in the End, by Atul Gawande. PMID- 27454561 TI - Viral load criteria and threshold optimization to improve HIV incidence assay characteristics. AB - OBJECTIVE: Assays for classifying HIV infections as 'recent' or 'nonrecent' for incidence surveillance fail to simultaneously achieve large mean durations of 'recent' infection (MDRIs) and low 'false-recent' rates (FRRs), particularly in virally suppressed persons. The potential for optimizing recent infection testing algorithms (RITAs), by introducing viral load criteria and tuning thresholds used to dichotomize quantitative measures, is explored. DESIGN: The Consortium for the Evaluation and Performance of HIV Incidence Assays characterized over 2000 possible RITAs constructed from seven assays (Limiting Antigen, BED, Less sensitive Vitros, Vitros Avidity, BioRad Avidity, Architect Avidity, and Geenius) applied to 2500 diverse specimens. METHODS: MDRIs were estimated using regression, and FRRs as observed 'recent' proportions, in various specimen sets. Context-specific FRRs were estimated for hypothetical scenarios. FRRs were made directly comparable by constructing RITAs with the same MDRI through the tuning of thresholds. RITA utility was summarized by the precision of incidence estimation. RESULTS: All assays produce high FRRs among treated patients and elite controllers (10-80%). Viral load testing reduces FRRs, but diminishes MDRIs. Context-specific FRRs vary substantially by scenario - BioRad Avidity and Limiting Antigen provided the lowest FRRs and highest incidence precision in scenarios considered. CONCLUSION: The introduction of a low viral load threshold provides crucial improvements in RITAs. However, it does not eliminate nonzero FRRs, and MDRIs must be consistently estimated. The tuning of thresholds is essential for comparing and optimizing the use of assays. The translation of directly measured FRRs into context-specific FRRs critically affects their magnitudes and our understanding of the utility of assays. PMID- 27454566 TI - Birth in the Age of AIDS: Women, Reproduction, and HIV/AIDS in India, by Cecilia Van Hollen. PMID- 27454567 TI - Defect assisted coupling of a MoS2/TiO2 interface and tuning of its electronic structure. AB - Although MoS2 based heterostructures have drawn increased attention, the van der Waals forces within MoS2 layers make it difficult for the layers to form strong chemical coupled interfaces with other materials. In this paper, we demonstrate the successful strong chemical attachment of MoS2 on TiO2 nanobelts after appropriate surface modifications. The etch-created dangling bonds on TiO2 surfaces facilitate the formation of a steady chemically bonded MoS2/TiO2 interface. With the aid of high resolution transmission electron microscope measurements, the in-plane structure registry of MoS2/TiO2 is unveiled at the atomic scale, which shows that MoS2[1-10] grows along the direction of TiO2[001] and MoS2[110] parallel to TiO2[100] with every six units of MoS2 superimposed on five units of TiO2. Electronically, type II band alignments are realized for all surface treatments. Moreover, the band offsets are delicately correlated to the surface states, which plays a significant role in their photocatalytic performance. PMID- 27454568 TI - Birth of NaCl Crystals: Insights from Molecular Simulations. AB - Molecular dynamics simulations are used to investigate the factors that influence the nucleation of NaCl crystals in a supersaturated aqueous solution. We describe a methodology for detecting solidlike NaCl clusters (potential nuclei) and following their evolution in time until they achieve nucleation (which is very rare) or dissolve back into solution. Through an analysis of cluster lifetimes and multiple nucleation events, we demonstrate that cluster size is not the only property that influences cluster stability and the probability of achieving nucleation. We introduce a parameter called cluster crystallinity, which is a measure of the solidlike order in a particular cluster. We show that cluster order (as measured by this parameter) has a strong influence on the lifetime and nucleation probability of clusters of equal sizes, with the lifetime and probability of nucleation increasing with increasing crystallinity. These observations remain true for clusters as small as six ions, showing that the structural factors are important even at the earliest stages of crystal birth. PMID- 27454569 TI - The effect of astaxanthin on the aging rat brain: gender-related differences in modulating inflammation. PMID- 27454570 TI - Fusion gene profile of biphenotypic sinonasal sarcoma: an analysis of 44 cases. AB - AIMS: Biphenotypic sinonasal sarcoma (SNS) is a locally aggressive tumour that occurs in the sinonasal region. PAX3-MAML3 has recently been identified as a recurrent fusion gene event in this entity; however, a subset of tumours harbour alternative PAX3 rearrangement without the involvement of MAML3. In this study we sought to characterize the molecular profile of a large series of cases, with a special emphasis on tumours with alternative fusions. METHODS AND RESULTS: Forty four examples of SNS were screened by fluorescence in-situ hybridization and reverse transcription polymerase chain reaction to better characterize its molecular profile and identify potential novel fusion genes. Twenty-four were positive for PAX3-MAML3 (55%), 15 showed rearrangements of PAX3 without MAML3 involvement (34%), one showed rearrangement of MAML3 without PAX3 involvement, and four were negative for the involvement of either gene (9%). Among 15 cases with PAX3 involvement only, three were found to harbour PAX3-FOXO1. Two of these cases arose in the nasal cavities of female patients (aged 31 and 47 years), and one showed bilateral involvement of the nasal cavities of a 35-year-old male. A fourth case involved the skull base of a 47-year-old male, and was positive for PAX3-NCOA1. Patients with fusion-negative tumours were slightly older. CONCLUSION: More than half of the SNSs in this series were positive for PAX3 MAML3. However, a subset of tumours may harbour alternative PAX3 fusion genes or show no involvement of PAX3. Except for a possible weak association between age and molecular profile, the overall morphological and immunophenotypic features of all cases seem to be similar. Because of the rarity of these tumours, the impact of the molecular profile on the clinical course of these tumours remains to be determined. PMID- 27454571 TI - Temporal variations and source apportionment of Hulis-C in PM2.5 in urban Shanghai. AB - Humic-like substances (Hulis), the hydrophobic part of water-soluble organic compounds, have been recognized to play important roles in environmental behavior of PM2.5 in atmosphere. In this study, Hulis and other components of PM2.5, collected in urban Shanghai from September 2013 to August 2014 were analyzed. The annual average concentration of Hulis carbon (Hulis-C) was (2.61+/-2.58) MUg/m(3), accounting for about 50% of water-soluble organic carbon (WSOC). The monthly average Hulis-C concentration peaked in December while the lowest was in summer, coinciding with the high and low of levoglucosan and secondary inorganic aerosol (SIA). Biomass burning and secondary formation were both important sources of Hulis-C, and their contributions showed obvious seasonality. In late autumn and winter, the strong inter-correlations among Hulis-C concentrations, NO3(-)/SO4(2-) mass ratios and nitrogen oxidation ratios (NOR) were found, suggesting the atmospheric oxidation of NOx to nitrate and related gas-phase reactions may be inter-linked with Hulis-C formation. In summer, photochemical reaction was clearly the major source of Hulis-C. The investigation by backward trajectory analysis showed that the long-range transport from the Northwest brought large amounts of PM2.5 and enhanced Hulis-C and levoglucosan level, indicating biomass burning as a significant source of Hulis-C under this type of synoptic weather conditions. In comparison, Hulis formation associated with the NOx oxidation pathway was mainly associated with the short-range transport from the neighboring cities. Marine aerosol was relatively clean and had little effects on Hulis-C. The CWT (concentration weighted trajectory) model results suggested that the Yangtze River Delta (YRD) region was an important source region of Hulis-C, while the effect of some northwestern areas was not negligible. PMID- 27454572 TI - The burden of extreme heat and heatwave on emergency ambulance dispatches: A time series study in Huainan, China. AB - BACKGROUND: Although studies have well documented increased mortality risk during extreme heat and heatwaves, few have examined their impacts on emergency ambulance dispatches under different temperature metrics. Additionally, evidence on the attributable risk of emergency ambulance dispatches due to extreme heat and heatwaves is scarce around the world. METHODS: A distributed lag nonlinear model (DLNM) was applied to quantify the impact of extreme heat and heatwaves on emergency ambulance dispatches in Huainan, China, during 2011-2013. Several local extreme heat and heatwave definitions were tested by using percentile of daily mean temperature (i.e., 95th, 97.5th and 99th) and duration (i.e.,>=2 consecutive days and >=3 consecutive days). The fraction of emergency ambulance dispatches attributable to extreme heat and heatwaves was also quantitatively estimated. RESULTS: Both extreme heat and heatwaves were significantly associated with increases in emergency ambulance dispatches, and their effects appeared to be acute. For extreme heat effects, the relative risks (RRs) of emergency ambulance dispatches at lag0 steadily increased from 95th percentile of daily mean temperature (1.03, 95% confidence interval (CI): 1.01-1.05) to 99th percentile (1.07, 95% CI: 1.05-1.10). For heatwave effects, we observed that RRs of emergency ambulance dispatches at lag0 fluctuated between 1.03 and 1.05 across different heatwave definitions. Notably, the fraction of emergency ambulance dispatches attributable to extreme heat decreased with higher percentile of daily mean temperature, dropping from 2.24% (95% CI: 1.41%-2.99%) at 95th percentile to 0.69% (95% CI: 0.45%-0.92%) at 99th percentile. Likewise, we found that heatwaves with higher intensity and (or) longer duration accounted for lower fraction of emergency ambulance dispatches, varying between 0.51%-1.52%. CONCLUSIONS: Our findings may have important implications for the development of local heat warming systems and public health interventions to lessen the impact of extreme heat events on population health. PMID- 27454573 TI - Natural attenuation of fluorene and pyrene in contaminated soils and assisted with hydroxypropyl-beta-cyclodextrin. Effect of co-contamination. AB - The objectives of this study were to investigate the mutual effect of the PAHs fluorene and pyrene on their respective biodegradation and dissipation processes in an agricultural soil, and to determine the effect of hydroxypropyl-beta cyclodextrin (HPBCD), used to increase the bioavailability of PAHs, on such processes. Fluorene dissipation was primarily due to abiotic processes, although a small contribution from biodegradation was also observed. Therefore, fluorene dissipation did not increase with HPBCD and its presence did not significantly alter the dehydrogenase activity. In contrast to fluorene, pyrene dissipation depended primarily on biotic factors, with endogenous soil microorganisms capable of degrading pyrene, with large increases in dehydrogenase activity. HPBCD increased biodegradation rate of pyrene. The co-contamination of soil with both PAHs did not affect fluorene evolution, but significantly inhibited pyrene biodegradation. The different abilities of soil bacterial consortia to catabolize these PAHs are discussed. Additionally, the possibility that the abiotic loss of fluorene through volatilization had a significant effect on the microbial community biodegradation of both fluorene and pyrene is examined. PMID- 27454574 TI - Magnetic and electrical characterization of nickel-rich NiFe thin films synthesized by atomic layer deposition and subsequent thermal reduction. AB - Nickel-rich NiFe thin films (Ni92Fe8, Ni89Fe11 and Ni83Fe17) were prepared by combining atomic layer deposition (ALD) with a subsequent thermal reduction process. In order to obtain Ni x Fe1-x O y films, one ALD supercycle was performed according to the following sequence: m NiCp2/O3, with m = 1, 2 or 3, followed by one FeCp2/O3 cycle. The supercycle was repeated n times. The thermal reduction process in hydrogen atmosphere was investigated by in situ x-ray diffraction studies as a function of temperature. The metallic nickel iron alloy thin films were investigated and characterized with respect to crystallinity, morphology, resistivity, and magnetism. As proof-of-concept magnetic properties of an array of Ni83Fe17, close to the perfect Permalloy stoichiometry, nanotubes and an isolated tube were investigated. PMID- 27454575 TI - A theoretical study of ruthenium complexes with 2,2'-biimidazole-like ligands: structural, optical and emissive properties. AB - The structural and optical properties of five ruthenium complexes, recently synthesized for their photooxidative and photophysical properties, have been studied by means of density functional theory (DFT) and time-dependent DFT (TD DFT). The structures of [Ru(bpy)2(BiimH2)](2+) (bpy = 2,2'-bipyridine; BiimH2 = 2,2'-biimidazole) 1, [Ru(bpy)2(TMBiimH2)](2+) (TM BiimH2 = 4,5,4',5'-tetramethyl 2,2'-biimidazole) 5, [Ru(bpy)2(L1H2)](2+) (L1H2 = 4,5-dimethyl-2(N,N diacetyl)(carboximidamide-1H-imidazole)) 6, [Ru(bpy)2(L2H2)](2+) (L2H2 = N(1),N(1),N(2),N(2)-tetrakis(acetyl)ethanediimidamide) 7 and [Ru(phen)2(TMBiimH2)](2+) (phen = 1,10'-phenanthroline) 8 have been fully optimized in the electronic ground state as well as in the lowest triplet T1 excited state. The theoretical absorption spectra of the five complexes that compare rather well with the experimental spectra have been analyzed on the basis of TD-DFT calculations without and with spin-orbit coupling (SOC). The deprotonated form [Ru(bpy)2(L2H)](+)7d contributes mostly to the experimental absorption spectrum of complex 7. The spectra of all molecules are characterized by the presence of low-lying metal-to-ligand charge transfer (MLCT) excited states between 500 and 400 nm, ligand-centered (LC) excited states on the biimidazole-like ligands between 350 and 300 nm and on the bpy ligands between 300 and 250 nm. The theoretical emission wavelengths deduced from the lowest triplet T1 properties calculated at 661 nm (1), 690 nm (5) and 660 nm (8) reproduce the experimental emission spectra of these molecules characterized by a maximum at 638 nm (1), 646 nm (5) and 652 nm (8). In contrast the low theoretical emission wavelengths (>1000 nm) obtained for complexes 6, 7 and 7d favorable to non-radiative decays explain the low intensity of the experimental emission spectra of these two complexes. The SOC is of little effect in this class of molecules where metal-centered (MC) excited states do not perturb the lowest part of the absorption spectra leading to negligible splitting of low-lying triplet states. PMID- 27454576 TI - Prognostic factor analysis for breast cancer using gene expression profiles. AB - BACKGROUND: The survival of patients with breast cancer is highly sporadic, from a few months to more than 15 years. In recent studies, the gene expression profiling of tumors has been used as a promising means of predicting prognosis factors. METHODS: In this study, we used gene expression datasets of tumors to identify prognostic factors in breast cancer. We conducted log-rank tests and used unsupervised clustering methods to find reciprocally expressed gene sets associated with worse survival rates. Prognosis prediction scores were determined as the ratio of gene expressions. RESULTS: As a result, four prognosis prediction gene set modules were constructed. The four prognostic gene sets predicted worse survival rates in three independent gene expression data sets. In addition, we found that cancer patient with poor prognosis, i.e., triple-negative cancer, HER2 enriched, TP53 mutated and high-graded patients had higher prognosis prediction scores than those with other types of breast cancer. CONCLUSIONS: In conclusion, based on a gene expression analysis, we suggest that our well-defined scoring method of the prediction of survival outcome may be useful for developing prognostic factors in breast cancer. PMID- 27454577 TI - Treatment approaches in motor neurone disease. AB - PURPOSE OF REVIEW: Although there is no cure for motor neurone disease (MND), the advent of multidisciplinary care and neuroprotective agents has improved treatment interventions and enhanced quality of life for MND patients and their carers. RECENT FINDINGS: Evidence-based multidisciplinary care, respiratory management and disease-modifying therapy have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the quality of life for MND patients. SUMMARY: Recent progress in the understanding of the clinical, pathophysiological and genetic heterogeneity of MND has improved the approach of clinicians to treatment. Notwithstanding improvement to care and quality of life, survival benefit has become evident with the advent of a multidisciplinary care framework, early treatment with riluzole and noninvasive ventilation. Weight maintenance remains critical, with weight loss associated with more rapid disease progression. The end-of-life phase is poorly defined and treatment is challenging, but effective symptom control through palliative care is achievable and essential. Encouragingly, current progress of clinical trials continues to close the gap towards the successful development of curative treatment in MND. PMID- 27454578 TI - Next-generation sequencing approaches for the diagnosis of skeletal muscle disorders. AB - PURPOSE OF REVIEW: The development of next-generation sequencing (NGS) technologies is transforming the practice of medical genetics and revolutionizing the approach to heterogeneous hereditary conditions, including skeletal muscle disorders. Here, we review the different NGS approaches described in the literature so far for the characterization of myopathic patients and the results obtained from the implementation of such approaches in a clinical setting. RECENT FINDINGS: The overall diagnostic rate of NGS strategies for patients affected by skeletal muscle disorders is higher than the success rate obtained using the traditional gene-by-gene approach. Moreover, many recent articles have been expanding the clinical phenotypes associated with already known disease genes. SUMMARY: NGS applications will soon be the first-tier test for skeletal muscle disorders. They will improve the diagnosis in myopathic patients, promoting their inclusion into novel therapeutic trials. At the same time, they will improve our knowledge about the molecular mechanisms causing skeletal muscle disorders, favoring the development of novel therapeutic approaches. PMID- 27454579 TI - 'Robot' Hand Illusion under Delayed Visual Feedback: Relationship between the Senses of Ownership and Agency. AB - The rubber hand illusion (RHI) is an illusion of the self-ownership of a rubber hand that is touched synchronously with one's own hand. While the RHI relates to visual and tactile integration, we can also consider a similar illusion with visual and motor integration on a fake hand. We call this a "robot hand illusion" (RoHI), which relates to both the senses of ownership and agency. Here we investigate the effect of delayed visual feedback on the RoHI. Participants viewed a virtual computer graphic hand controlled by their hand movement recorded using a data glove device. We inserted delays of various lengths between the participant's hand and the virtual hand movements (90-590 ms), and the RoHI effects for each delay condition were systematically tested using a questionnaire. The results showed that the participants felt significantly greater RoHI effects with temporal discrepancies of less than 190 ms compared with longer temporal discrepancies, both in the senses of ownership and agency. Additionally, participants felt significant, but weaker, RoHI effects with temporal discrepancies of 290-490 ms in the sense of agency, but not in the sense of ownership. The participants did not feel a RoHI with temporal discrepancies of 590 ms in either the senses of agency or ownership. Our results suggest that a time window of less than 200 ms is critical for multi-sensory integration processes constituting self-body image. PMID- 27454580 TI - Intraoperative Raman spectroscopy of soft tissue sarcomas. AB - BACKGROUND AND OBJECTIVE: Soft tissue sarcomas (STS) are a rare and heterogeneous group of malignant tumors that are often treated through surgical resection. Current intraoperative margin assessment methods are limited and highlight the need for an improved approach with respect to time and specificity. Here we investigate the potential of near-infrared Raman spectroscopy for the intraoperative differentiation of STS from surrounding normal tissue. MATERIALS AND METHODS: In vivo Raman measurements at 785 nm excitation were intraoperatively acquired from subjects undergoing STS resection using a probe based spectroscopy system. A multivariate classification algorithm was developed in order to automatically identify spectral features that can be used to differentiate STS from the surrounding normal muscle and fat. The classification algorithm was subsequently tested using leave-one-subject-out cross-validation. RESULTS: With the exclusion of well-differentiated liposarcomas, the algorithm was able to classify STS from the surrounding normal muscle and fat with a sensitivity and specificity of 89.5% and 96.4%, respectively. CONCLUSION: These results suggest that single point near-infrared Raman spectroscopy could be utilized as a rapid and non-destructive surgical guidance tool for identifying abnormal tissue margins in need of further excision. Lasers Surg. Med. 48:774 781, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27454581 TI - Clinical Pathway and Monthly Feedback Improve Adherence to Antibiotic Guideline Recommendations for Community-Acquired Pneumonia. AB - BACKGROUND: Compliance with community-acquired pneumonia (CAP) guidelines remains poor despite a substantial body of evidence indicating that guideline-concordant care improves patient outcomes. The aim of this study was to compare the relative effectiveness of a general educational and a targeted emergency department intervention on improving physicians' concordance with CAP guidelines. METHODS: Two distinct interventions were implemented over specific time periods. The first intervention was educational, focusing on the development of local CAP guidelines and their dissemination through hospital-wide educational programmes. The second intervention was a targeted one for the emergency department, where a clinical pathway for the initial management of CAP patients was introduced, followed by monthly feedback to the emergency department (ED) physicians about concordance rates with the guidelines. Data on the concordance rate to CAP guidelines was collected from a retrospective chart review. RESULTS: A total of 398 eligible patient records were reviewed to measure concordance to CAP guidelines over the study period. Concordance rates during the baseline and educational intervention periods were similar (28.1% vs. 31.2%; p > 0.05). Significantly more patients were treated in accordance with the CAP guidelines after the ED focused intervention when compared to the baseline (61.5% vs. 28.1%; p < 0.05) or educational period (61.5% vs. 31.2%; p < 0.05). CONCLUSIONS: A targeted intervention with a CAP clinical pathway and monthly feedback was a successful strategy to increase adherence to empirical antibiotic recommendations in CAP guidelines. PMID- 27454583 TI - Invasive melanoma in vivo can be distinguished from basal cell carcinoma, benign naevi and healthy skin by canine olfaction: a proof-of-principle study of differential volatile organic compound emission. AB - BACKGROUND: Volatile organic compounds (VOCs) are continuously released by the body during normal metabolic processes, but their profiles change in the presence of cancer. Robust evidence that invasive melanoma in vivo emits a characteristic VOC signature is lacking. OBJECTIVES: To conduct a canine olfactory, proof-of principle study to investigate whether VOCs from invasive melanoma are distinguishable from those of basal cell carcinoma (BCC), benign naevi and healthy skin in vivo. METHODS: After a 13-month training period, the dog's ability to discriminate melanoma was evaluated in 20 double-blind tests, each requiring selection of one melanoma sample from nine controls (three each of BCC, naevi and healthy skin; all samples new to the dog). RESULTS: The dog correctly selected the melanoma sample on nine (45%) occasions (95% confidence interval 0.23-0.68) vs. 10% expected by chance alone. A one-sided exact binomial test gave a P-value of < 0.01, supporting the hypothesis that samples were not chosen at random but that some degree of VOC signal from the melanoma samples significantly increased the probability of their detection. Use of a discrete-choice model confirmed melanoma as the most influential of the recorded medical/personal covariates in determining the dog's choice of sample. Accuracy rates based on familiar samples during training were not a reliable indicator of the dog's ability to distinguish melanoma, when confronted with new, unknown samples. CONCLUSIONS: Invasive melanoma in vivo releases odorous VOCs distinct from those of BCC, benign naevi and healthy skin, adding to the evidence that the volatile metabolome of melanoma contains diagnostically useful biomarkers. PMID- 27454584 TI - Correction: Venus Kinase Receptors Control Reproduction in the Platyhelminth Parasite Schistosoma mansoni. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004138.]. PMID- 27454585 TI - Similar Sister Chromatid Arrangement in Mono- and Holocentric Plant Chromosomes. AB - Due to the X-shape formation at somatic metaphase, the arrangement of the sister chromatids is obvious in monocentric chromosomes. In contrast, the sister chromatids of holocentric chromosomes cannot be distinguished even at mitotic metaphase. To clarify their organization, we differentially labelled the sister chromatids of holocentric Luzula and monocentric rye chromosomes by incorporating the base analogue EdU during replication. Using super-resolution structured illumination microscopy (SIM) and 3D rendering, we found that holocentric sister chromatids attach to each other at their contact surfaces similar to those of monocentrics in prometaphase. We found that sister chromatid exchanges (SCEs) are distributed homogeneously along the whole holocentric chromosomes of Luzula, and that their occurrence is increased compared to monocentric rye chromosomes. The SCE frequency of supernumerary B chromosomes, present additionally to the essential A chromosome complement of rye, does not differ from that of A chromosomes. Based on these results, models of the sister chromatid arrangement in mono- and holocentric plant chromosomes are presented. PMID- 27454586 TI - Influence of trunk muscle activity and stability in front and back holding. AB - PURPOSE: A tandem carrying style is often used in the workplace, but carrying approaches are different for two people because of the holding load in the tandem posture. To understand these carrying styles, this study aimed to investigate the patterns of muscle activity and stability of the trunk influenced by front and back holding of a heavy load. METHODS: Electromyography data of eight trunk and two hip muscles, as well as displacements of the trunk, were recorded for analysis while subjects stood statically holding a handle in the front and back of the body with and without load. RESULTS: Without load, muscle activities during front holding mirrored those during back holding. With load, greater muscle activities were observed in the dorsal muscles of the trunk and lesser activities were noted in the ventral muscles in the two holding styles. More frequencies of trunk oscillations occurred in front holding with and without load. CONCLUSIONS: The results revealed that back holding of load created more stability of the upper body, whereas front holding resulted in more instability of the trunk. PMID- 27454587 TI - Fear-relevant illusory correlations in different fears and anxiety disorders: A review of the literature. AB - Fearful individuals often overestimate the relationship between fear-relevant stimuli and aversive consequences. Such fear-relevant illusory correlations (ICs) might be involved in the maintenance of anxiety disorders. In this literature review, we found clear evidence that ICs are present and enhanced in fear of animals. We also revealed some evidence for ICs related to fear of flying, social anxiety, contamination fear, panic disorder, and post-traumatic stress disorder, but with considerably less clarity. Fear-relevant ICs seem to be best explained by both a priori expectancies and biased encoding of the experienced associations. Studies to date suggest that one important biased encoding process is the enhanced aversiveness/salience of fear-relevant outcomes. Future studies may improve insight by developing more reliable IC measures and testing the effect of encoding processes on treatment outcomes. PMID- 27454588 TI - Expression of the Theobroma cacao Bax-inhibitor-1 gene in tomato reduces infection by the hemibiotrophic pathogen Moniliophthora perniciosa. AB - Programmed cell death (PCD) plays a key role in plant responses to pathogens, determining the success of infection depending on the pathogen lifestyle and on which participant of the interaction triggers cell death. The hemibiotrophic basidiomycete Moniliophthora perniciosa is the causal agent of witches' broom disease of Theobroma cacao L. (cacao), a serious constraint for production in South America and the Caribbean. It has been hypothesized that M. perniciosa pathogenesis involves PCD, initially as a plant defence mechanism, which is diverted by the fungus to induce necrosis during the dikaryotic phase of the mycelia. Here, we evaluated whether the expression of a cacao anti-apoptotic gene would affect the incidence and severity of M. perniciosa infection using the 'Micro-Tom' (MT) tomato as a model. The cacao Bax-inhibitor-1 (TcBI-1) gene, encoding a putative basal attenuator of PCD, was constitutively expressed in MT to evaluate function. Transformants expressing TcBI-1, when treated with tunicamycin, an inducer of endoplasmic reticulum stress, showed a decrease in cell peroxidation. When the same transformants were inoculated with the necrotrophic fungal pathogens Sclerotinia sclerotiorum, Sclerotium rolfsii and Botrytis cinerea, a significant reduction in infection severity was observed, confirming TcBI-1 function. After inoculation with M. perniciosa, TcBI-1 transformant lines showed a significant reduction in disease incidence compared with MT. The overexpression of TcBI-1 appears to affect the ability of germinating spores to penetrate susceptible tissues, restoring part of the non host resistance in MT against the S-biotype of M. perniciosa. PMID- 27454589 TI - Metabolic Flux Analysis of Lipid Biosynthesis in the Yeast Yarrowia lipolytica Using 13C-Labled Glucose and Gas Chromatography-Mass Spectrometry. AB - The oleaginous yeast Yarrowia lipolytica has considerable potential for producing single cell oil, which can be converted to biodiesel, a sustainable alternative to fossil fuels. However, extensive fundamental and engineering efforts must be carried out before commercialized production become cost-effective. Therefore, in this study, metabolic flux analysis of Y. lipolytica was performed using 13C labeled glucose as a sole carbon source in nitrogen sufficient and insufficient media. The nitrogen limited medium inhibited cell growth while promoting lipid accumulation (from 8.7% of their biomass to 14.3%). Metabolic flux analysis showed that flux through the pentose phosphate pathway was not significantly regulated by nitrogen concentration, suggesting that NADPH generation is not the limiting factor for lipid accumulation in Y. lipolytica. Furthermore, metabolic flux through malic enzyme was undetectable, confirming its non-regulatory role in lipid accumulation in this yeast. Nitrogen limitation significantly increased flux through ATP:citrate lyase (ACL), implying that ACL plays a key role in providing acetyl-CoA for lipid accumulation in Y. lipolytica. PMID- 27454590 TI - Ureteroenteric Fistula Revealed by 99mTc-DTPA Renal Scan. AB - A 55-year-old woman with a history of cervical carcinoma, status post hysterectomy and radiation therapy 8 years prior, presented worsening back pain for 9 months. The patient underwent a Tc-DTPA renal scan, which showed that a vertically linear tracer distribution was seen alongside the right ureter. Ureteroenteric fistula was confirmed and repaired by surgery. PMID- 27454591 TI - 18F-FDG Uptake in Neurosarcoid Dural Plaque on PET/CT. AB - While the imaging modality of choice to diagnose neurosarcoidosis is gadolinium enhanced MRI, F-FDG PET/CT maybe used to stage the disease or target the optimal biopsy site. Few cases have described intense F-FDG uptake at the sites of active neurosarcoidosis in the midbrain and pituitary gland, cerebellar hemispheres, and temporal lobes. Here, we present a case of neurosarcoidosis whose PET/CT examination demonstrated F-FDG avidity in a dural plaque. PMID- 27454592 TI - 18F-DOPA PET/CT Physiological Distribution and Pitfalls: Experience in 215 Patients. AB - PURPOSE: F-DOPA PET/CT is potentially helpful in the management of patients with low-grade brain tumors, movement disorders, and somatic neuroendocrine tumors. We describe the whole-body physiological distribution of F-DOPA uptake. PATIENTS AND METHODS: We examined 215 patients with F-DOPA PET/CT. Among these, 161 had brain scans and 54 had whole-body scans. RESULTS: Physiological distribution was negligible in the brain, with the exception of basal ganglia, whereas greatest activity was noted in the liver, pancreas, other exocrine glands, and the urinary system. Incidental tracer uptake sites were identified in 5.5% of patients. Some of these findings were due to inflammation, whereas in most cases, uptake was seen in benign tumors of the brain or in the endocrine or exocrine glands. CONCLUSIONS: F-DOPA uptake may be seen in inflammatory tissue or benign tumors. Correlations with history, physical examination, laboratory examination, CT, MRI, and histology are necessary for optimal diagnosis. PMID- 27454593 TI - Endolymphatic Sac Tumor Showing Increased Activity on 68Ga DOTATATE PET/CT. AB - Endolymphatic sac tumors (ELSTs) are rare tumors arising from the epithelium of the endolymphatic sac and duct that can be either sporadic or associated with von Hippel-Lindau (VHL) disease. We report a case of a VHL patient with histologically proven residual ELST who underwent Ga DOTATATE PET/CT showing increased activity (SUVmax, 6.29) by the ELST. The presented case of a VHL associated ELST with increased Ga DOTATATE uptake indicates cell-surface expression of somatostatin receptors by this tumor, suggesting the potential application of somatostatin receptor imaging using Ga DOTA-conjugated peptides in the workup and management of these patients. PMID- 27454594 TI - Epididymal Cystadenomas in von Hippel-Lindau Disease Showing Increased Activity on 68Ga DOTATATE PET/CT. AB - von Hippel-Lindau (VHL) disease is a familial cancer syndrome characterized by the development of a variety of malignant and benign tumors, including epididymal cystadenomas. We report a case of a VHL patient with bilateral epididymal cystadenomas who was evaluated with Ga DOTATATE PET/CT, showing intensely increased activity (SUVmax, 21.6) associated with the epididymal cystadenomas, indicating cell-surface overexpression of somatostatin receptors. The presented case supports the usefulness of somatostatin receptor imaging using Ga DOTA conjugated peptides for detection and follow-up of VHL manifestations, as well as surveillance of asymptomatic gene carriers. PMID- 27454595 TI - Primary Pulmonary Mucinous Adenocarcinoma Was Better Visualized on Delayed FDG PET/CT Imaging. AB - A 36-year-old man underwent FDG PET/CT to evaluate a lung mass in the right middle lobe. The mass on the early PET images that were acquired 50 minutes post FDG injection had only minimally increased FDG activity with uptake ratio between the mass and mediastinal blood pool of 0.93. However, on the delayed images acquired 230 minutes post-FDG administration, this ratio increased to 3.0, which enabled better notion of the lesion. Pathological examination demonstrated a primary pulmonary mucinous adenocarcinoma. PMID- 27454596 TI - Spleen Uptake on Bone Scan After Frequent Platelet and RBC Transfusions. AB - A 21-year-old man, allogeneic hematopoietic stem cell transplantation recipient, was referred to our nuclear medicine department for a suspicion of knee osteonecrosis. Bone scan with Tc-HMDP did not show abnormal bone uptake but an intense spleen accumulation. F-FDG PET/CT performed on the same day showed no pathological spleen uptake. The patient had secondary hemochromatosis resulting from frequent transfusions in the setting of a chronic graft versus host disease with hemolysis and thrombocytopenia. The last RBC and platelet transfusions were performed 9 and 2 days before the examination, respectively. Secondary hemochromatosis and recent transfusions may explain our findings. PMID- 27454597 TI - Unilateral Suppression of Brown Fat on FDG PET/CT in Horner Syndrome. AB - A 29-year-old woman underwent resection of a left anterior mediastinal thymoma and pleurectomy. Postsurgical FDG PET/CT scan demonstrated FDG avidity in the right neck and upper thoracic fat but relatively absent FDG-avid fat in the left neck and upper thorax. Bilateral FDG-avid fat was also apparent in the lower chest and upper abdomen. After surgery, the patient demonstrated Horner syndrome, with left-sided ptosis, miosis, and facial anhidrosis. It is hypothesized that left-sided sympathetic nerves were compromised during surgery, leading to Horner syndrome and denervation of ipsilateral brown fat. The unilateral FDG avidity should not be mistaken for malignancy. PMID- 27454599 TI - Demonstration of Response to Androgen Deprivation Therapy by 68Ga-PSMA PET/CT. AB - We present pretreatment and posttreatment Ga-PSMA PET/CT images of a 68-year-old man with metastatic prostate cancer who is a responder to androgen deprivation therapy. PMID- 27454598 TI - 68Ga DOTATATE PET/CT of Non-FDG-Avid Pulmonary Metastatic Hemangiopericytoma. AB - We present the FDG and Ga DOTATATE PET/CT findings of a 68-year-old woman with pulmonary metastases 28 years after her initial diagnosis of central nervous system hemangiopericytoma. The largest of the pulmonary lesions showed prominent Ga DOTATATE uptake with comparatively minimal FDG avidity. Hemangiopericytoma is a rare mesenchymal tumor that arises from malignant pericytes, cells that form the walls of capillaries and postcapillary venules. This case demonstrates the potential of radiolabeled somatostatin analogs as a therapeutic option in the setting of widespread metastatic disease. PMID- 27454600 TI - Quality and Safety in Health Care, Part XV: Preventing Infections Associated With Health Care. AB - Infections that are associated with health care are a major problem that results in many deaths, suffering, and a great deal of extra monetary costs. Fortunately, there is much that can be done to prevent these infections. This article is a brief introduction to prevention of some of the common hospital acquired infections, such as surgical site infection, ventilator-associated pneumonia, central line-associated bloodstream infections, and catheter-associated urinary tract infections. PMID- 27454601 TI - Imaging of Hepatic Ectopic Pregnancy by 18F-FDG PET/CT. AB - Hepatic ectopic pregnancy is an uncommon form of extrauterine pregnancy. A 31 year-old woman had acute abdominal pain and distention. Laboratory examination showed significantly increased serum beta-human chorionic gonadotropin level. Both ultrasound and MRI identified a lesion located at the right lobe of the liver. FDG PET/CT was performed to determine whether the other causes of elevated beta-human chorionic gonadotropin level, which showed an oval mass with mid peripherally increased FDG activity. After surgery, pathological results confirmed a diagnosis of hepatic ectopic pregnancy. PMID- 27454602 TI - Prostate-Specific Membrane Antigen (PSMA) Avid Pancreatic Neuroendocrine Tumor. AB - Ga-PSMA PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 75-year-old man with a previous history of treated prostate cancer 3 years earlier presented with rising prostate-specific antigen (PSA) level and underwent Ga-PSMA PET/CT which demonstrated a PSMA-avid focus in the neck of the pancreas. Triple-phase abdominal CT demonstrated enhancement in the arterial phase and to a lesser extent the venous phase of a soft tissue mass in the neck of the pancreas. Cytological and histopathological examination of the soft tissue mass confirmed a low-grade pancreatic neuroendocrine tumor. PMID- 27454603 TI - Inflammatory Fibroid Polyp of the Stomach Mimics Malignancy on 18F FDG PET/CT Imaging. AB - Inflammatory fibroid polyps (IFPs) are rare non-neoplastic and proliferating submucosal lesions of the gastrointestinal tract. The classic IFP, which was first described by Vanek, consists of prominent blood vessels and is characterized by a heavy inflammatory infiltrate, which is rich in eosinophilic granulocytes. The clinical presentation depends on the size and location. Inflammatory fibroid polyps cannot be differentiated from malignancy without histological examination. We report a case of IFP in the stomach that mimicked a primary gastric malignancy showing an increased F-FDG uptake. PMID- 27454604 TI - A Review of Flood Loss Models as Basis for Harmonization and Benchmarking. AB - Risk-based approaches have been increasingly accepted and operationalized in flood risk management during recent decades. For instance, commercial flood risk models are used by the insurance industry to assess potential losses, establish the pricing of policies and determine reinsurance needs. Despite considerable progress in the development of loss estimation tools since the 1980s, loss estimates still reflect high uncertainties and disparities that often lead to questioning their quality. This requires an assessment of the validity and robustness of loss models as it affects prioritization and investment decision in flood risk management as well as regulatory requirements and business decisions in the insurance industry. Hence, more effort is needed to quantify uncertainties and undertake validations. Due to a lack of detailed and reliable flood loss data, first order validations are difficult to accomplish, so that model comparisons in terms of benchmarking are essential. It is checked if the models are informed by existing data and knowledge and if the assumptions made in the models are aligned with the existing knowledge. When this alignment is confirmed through validation or benchmarking exercises, the user gains confidence in the models. Before these benchmarking exercises are feasible, however, a cohesive survey of existing knowledge needs to be undertaken. With that aim, this work presents a review of flood loss-or flood vulnerability-relationships collected from the public domain and some professional sources. Our survey analyses 61 sources consisting of publications or software packages, of which 47 are reviewed in detail. This exercise results in probably the most complete review of flood loss models to date containing nearly a thousand vulnerability functions. These functions are highly heterogeneous and only about half of the loss models are found to be accompanied by explicit validation at the time of their proposal. This paper exemplarily presents an approach for a quantitative comparison of disparate models via the reduction to the joint input variables of all models. Harmonization of models for benchmarking and comparison requires profound insight into the model structures, mechanisms and underlying assumptions. Possibilities and challenges are discussed that exist in model harmonization and the application of the inventory in a benchmarking framework. PMID- 27454605 TI - Rate of a Click Chemistry reaction under catalysis by trace-amounts of copper as evaluated by NMR spectroscopy. PMID- 27454606 TI - Development of an Influenza A Master Virus for Generating High-Growth Reassortants for A/Anhui/1/2013(H7N9) Vaccine Production in Qualified MDCK Cells. AB - In 2013, the first case of human infection with an avian influenza A virus (H7N9) was reported in China, and the human infection with this virus has continued as of 2016. At the request of the WHO, we have successfully developed candidate reassortant vaccine virus using A/Anhui/1/2013 and the high egg-growth master virus A/PR/8/1934. Recent plans regarding influenza vaccine production include using cell-cultured systems in Japan and several other countries. However, egg based vaccine viruses are not always suitable for cell-cultured vaccine production due to potential issues with growth, protein yield and antigenic stability. Therefore, in this study, we have developed a high-growth master virus (hg-PR8) adapted to qualified NIID-MDCK cells that are competent for vaccine production. The virus hg-PR8 was obtained after 20 serial passages of A/Puerto Rico/8/1934 (PR8) in NIID-MDCK cells. The viral titer of hg-PR8 was 108.6 plaque forming units per milliliter (PFU/mL). Seven amino acid substitutions were identified in the amino acid sequences of PB2, PB1, PA, NA, M and NS of hg-PR8 compared to the sequence of the original PR8 (org-PR8) strain. The growth capacities of the reassortant viruses, which possess heterologous internal genes from hg-PR8 or org-PR8, indicated that the amino acid changes in PB2 and NS2 similarly affected growth capacity in NIID-MDCK cells. To assess the suitability of hg-PR8 as a master virus, we generated 6:2 reassortant viruses possessing the HA and NA segments from A/Anhui/1/2013 (H7N9) and the remaining segments from hg PR8. The virus titers of the reassortant strains were 107-108 PFU/mL. The antigenicity of the viruses was stable during ten passages of the viruses in NIID MDCK cells. In comparison with the egg-based reassortant vaccine viruses with identical HA and NA segments, the hg-PR8-based viruses showed 1.5- to 2-fold higher protein yields in NIID-MDCK cells. PMID- 27454607 TI - GSTM1 and GSTP1, but not GSTT1 genetic polymorphisms are associated with chronic myeloid leukemia risk and treatment response. AB - BACKGROUND: Chronic myeloid leukemia (CML) is associated to the BCR-ABL1 oncogene and can successfully be treated with tyrosine kinase inhibitors (TKIs). However, it remains still under investigation which molecular factors may influence CML risk or varying responses to TKIs. The aim of this study was to assess the role of Glutathione-S-transferases (GSTs) genetic polymorphisms in CML susceptibility and TKI clinical outcome. MATERIALS: Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.319A>G (rs1695; p.105Ile>Val) were genotyped by PCR methods in 141 CML treated patients and 141 sex- and age-matched healthy individuals. RESULTS: Individual analysis of each GST gene showed no association with CML risk. A trend toward significance (p=0.07) for a recessive model was found for GSTP1 (OR: 2.04; CI: 0.94-4.4). However, the combined analysis showed that GSTM1-null/GSTP1-GG as well as GSTT1 null/GSTP1-GG were associated with CML development (p=0.03; OR: 3.54 CI: 1.2 14.57; p=0.05; OR: 12.65; CI: 1.17-21.5). The relationship with treatment outcome showed that the presence of GSTM1 gene was significantly linked with an inferior rate of major molecular response (p=0.048) and poor event free-survival (EFS) (p=0.02). Furthermore, a group of patients with GSTP1-GG genotype were significantly associated with reduced EFS comparing to those carrying other GSTP1 genotypes (p=0.049). GSTP1-GG genotypes had short time to treatment failure in a group of patients unresponsive to TKIs comparing to other GSTP1 genotypes (p=0.03). CONCLUSIONS: This study highlights the significance of GSTM1 and GSTP1 polymorphisms on CML susceptibility and response to TKIs in the Argentinean population. PMID- 27454608 TI - The Mining Minds digital health and wellness framework. AB - BACKGROUND: The provision of health and wellness care is undergoing an enormous transformation. A key element of this revolution consists in prioritizing prevention and proactivity based on the analysis of people's conducts and the empowerment of individuals in their self-management. Digital technologies are unquestionably destined to be the main engine of this change, with an increasing number of domain-specific applications and devices commercialized every year; however, there is an apparent lack of frameworks capable of orchestrating and intelligently leveraging, all the data, information and knowledge generated through these systems. METHODS: This work presents Mining Minds, a novel framework that builds on the core ideas of the digital health and wellness paradigms to enable the provision of personalized support. Mining Minds embraces some of the most prominent digital technologies, ranging from Big Data and Cloud Computing to Wearables and Internet of Things, as well as modern concepts and methods, such as context-awareness, knowledge bases or analytics, to holistically and continuously investigate on people's lifestyles and provide a variety of smart coaching and support services. RESULTS: This paper comprehensively describes the efficient and rational combination and interoperation of these technologies and methods through Mining Minds, while meeting the essential requirements posed by a framework for personalized health and wellness support. Moreover, this work presents a realization of the key architectural components of Mining Minds, as well as various exemplary user applications and expert tools to illustrate some of the potential services supported by the proposed framework. CONCLUSIONS: Mining Minds constitutes an innovative holistic means to inspect human behavior and provide personalized health and wellness support. The principles behind this framework uncover new research ideas and may serve as a reference for similar initiatives. PMID- 27454610 TI - Erratum. PMID- 27454609 TI - Disruption of the Cdc42/Par6/aPKC or Dlg/Scrib/Lgl Polarity Complex Promotes Epithelial Proliferation via Overlapping Mechanisms. AB - The establishment and maintenance of apical-basal polarity is a defining characteristic and essential feature of functioning epithelia. Apical-basal polarity (ABP) proteins are also tumor suppressors that are targeted for disruption by oncogenic viruses and are commonly mutated in human carcinomas. Disruption of these ABP proteins is an early event in cancer development that results in increased proliferation and epithelial disorganization through means not fully characterized. Using the proliferating Drosophila melanogaster wing disc epithelium, we demonstrate that disruption of the junctional vs. basal polarity complexes results in increased epithelial proliferation via distinct downstream signaling pathways. Disruption of the basal polarity complex results in JNK-dependent proliferation, while disruption of the junctional complex primarily results in p38-dependent proliferation. Surprisingly, the Rho-Rok Myosin contractility apparatus appears to play opposite roles in the regulation of the proliferative phenotype based on which polarity complex is disrupted. In contrast, non-autonomous Tumor Necrosis Factor (TNF) signaling appears to suppress the proliferation that results from apical-basal polarity disruption, regardless of which complex is disrupted. Finally we demonstrate that disruption of the junctional polarity complex activates JNK via the Rho-Rok-Myosin contractility apparatus independent of the cortical actin regulator, Moesin. PMID- 27454611 TI - Protein-protein interaction extraction with feature selection by evaluating contribution levels of groups consisting of related features. AB - BACKGROUND: Protein-protein interaction (PPI) extraction from published scientific articles is one key issue in biological research due to its importance in grasping biological processes. Despite considerable advances of recent research in automatic PPI extraction from articles, demand remains to enhance the performance of the existing methods. RESULTS: Our feature-based method incorporates the strength of many kinds of diverse features, such as lexical and word context features derived from sentences, syntactic features derived from parse trees, and features using existing patterns to extract PPIs automatically from articles. Among these abundant features, we assemble the related features into four groups and define the contribution level (CL) for each group, which consists of related features. Our method consists of two steps. First, we divide the training set into subsets based on the structure of the sentence and the existence of significant keywords (SKs) and apply the sentence patterns given in advance to each subset. Second, we automatically perform feature selection based on the CL values of the four groups that consist of related features and the k nearest neighbor algorithm (k-NN) through three approaches: (1) focusing on the group with the best contribution level (BEST1G); (2) unoptimized combination of three groups with the best contribution levels (U3G); (3) optimized combination of two groups with the best contribution levels (O2G). CONCLUSIONS: Our method outperforms other state-of-the-art PPI extraction systems in terms of F-score on the HPRD50 corpus and achieves promising results that are comparable with these PPI extraction systems on other corpora. Further, our method always obtains the best F-score on all the corpora than when using k-NN only without exploiting the CLs of the groups of related features. PMID- 27454612 TI - Deterministic Switching in Bismuth Ferrite Nanoislands. AB - We report deterministic selection of polarization variant in bismuth BiFeO3 nanoislands via a two-step scanning probe microscopy procedure. The polarization orientation in a nanoisland is toggled to the desired variant after a reset operation by scanning a conductive atomic force probe in contact over the surface while a bias is applied. The final polarization variant is determined by the direction of the inhomogeneous in-plane trailing field associated with the moving probe tip. This work provides the framework for better control of switching in rhombohedral ferroelectrics and for a deeper understanding of exchange coupling in multiferroic nanoscale heterostructures toward the realization of magnetoelectric devices. PMID- 27454613 TI - The prophylactic effects of human IgG derived from sera containing high anti-PcrV titers against pneumonia-causing Pseudomonas aeruginosa. AB - The PcrV cap structure of the type III secretory apparatus of Pseudomonas aeruginosa is a vaccine target. Human immunoglobulin G (IgG) molecules extracted from sera containing high or low anti-PcrV titers were tested for their effects against P. aeruginosa pneumonia in a mouse model. Among 198 volunteers, we selected the top 10 high anti-PcrV titer sera and the bottom 10 low anti-PcrV titer sera and extracted the IgG fraction from each serum sample. First, we examined the effects of the IgG against virulent P. aeruginosa. A lethal dose of P. aeruginosa premixed with saline, low titer human IgG, high titer human IgG, or rabbit-derived polyclonal anti-PcrV IgG was intratracheally administered into the lungs of mice, and their survival and lung inflammation were evaluated for 24 h. The high anti-PcrV titer human IgG had a prophylactic effect. Next, the prophylactic effects of intravenous administration of extracted and pooled high or low anti-PcrV titer human IgG were examined. Here, prophylactic intravenous administration of pooled high anti-PcrV titer human IgG, which showed binding capacity to P. aeruginosa PcrV, was more effective than the administration of its low titer pooled equivalent, and the measured physiological and inflammatory parameters correlated with the anti-PcrV titer levels. This result indirectly implies that high anti-PcrV titers in blood can help to protect against virulent P. aeruginosa infections. In addition, the IgG fractions from such high titer sera have potential to be a source of specific intravenous immunoglobulin products for passive vaccination against virulent P. aeruginosa infections. PMID- 27454614 TI - Sarcopenia in patients with heart failure with preserved ejection fraction: Impact on muscle strength, exercise capacity and quality of life. AB - BACKGROUND: To describe the prevalence of sarcopenia in ambulatory patients with heart failure with preserved ejection fraction (HFpEF) and its relation to reduced exercise capacity, muscle strength, and quality of life (QoL). METHODS AND RESULTS: A total of 117 symptomatic outpatients with HFpEF were prospectively enrolled in Germany, England, and Slovenia as part of the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Appendicular skeletal muscle (ASM) mass (the sum of muscle mass in both arms and legs) was assessed by DEXA. Echocardiography, 6-minute walk testing (6-MWT), muscle strength assessment, spiroergometry and QoL evaluation using EQ-5D Questionnaire were performed. Sarcopenia was defined as ASM 2 standard deviations below the mean of a healthy reference group aged 18-40years. Patients were divided into 3 groups according to the E/e' value: <=8, 9-14, and >=15. Sarcopenia was detected in 19.7% of all patients. These patients performed worse during 6-MWT (404+/-116 vs. 307+/-145m, p=0.003) and showed lower absolute peak oxygen consumption (1579+/-474 vs. 1211+/ 442mL/min, p<0.05). Both ASM and muscle strength were lowest in patients with E/e' >15 (p<0.05). Higher values of muscle strength/ASM were associated with a better QoL (r=0.5, p<0.0005). Logistic regression showed ASM to be independently associated with reduced distance walked during the 6-MWT adjusted for NYHA, height, left atrium diameter, ferritin and forced expiratory volume in 1s (FEV1) (odds ratio 1.2, p=0.02). CONCLUSION: Sarcopenia affects a clinically relevant proportion of patients with HFpEF. Low ASM is strongly linked to reduced muscle strength, exercise capacity and QoL in these patients. PMID- 27454615 TI - Factors influencing low-density lipoprotein cholesterol target achievement in primary care - Results from DYSIS China. AB - BACKGROUND: Primary care facilities are the base for hypercholesterolemia treatment. However, data regarding the effectiveness of lipid management in primary care are lacking. METHODS AND RESULTS: To evaluate lipid management in the primary care setting in China, we compared patients' characteristics and lipid management outcomes between 6100 outpatients treated at primary care versus 19,217 patients in non-primary settings using data from the DYSlipidemia International Study-China (DYSIS-CHINA). Compared to patients treated at non primary hospitals, patients who received treatment at primary settings were younger, thinner, and were more likely to be female and to have a family history of premature CVD. Overall, 26.8% of very high-risk and 40.8% of high-risk patients achieved the LDL-C target with primary care treatment, whereas these target rates were 41.2% (p<0.001) and 58.6% (p<0.001), respectively, among patients treated at non-primary hospitals. High-dose statin therapy was underused in primary care patients compared to non-primary hospital patients (p<0.001). Logistic regression analysis showed that female gender, diabetes, and obesity were negative factors, whereas life-style modification and use of high-dose statin (40mg/d simvastatin equivalent) were favorable factors in predicting LDL-C target attainment in the primary care setting. CONCLUSION: Sedentary life style, alcohol drinking, and use of suboptimal statin dosage are key factors that unfavorably affect the LDL-C target rate among patients treated at primary care facilities in China. Sufficient training for primary care physicians regarding proper statin use and support for the combined use of a statin with ezetimibe could promote LDL-C target attainment in primary care. PMID- 27454616 TI - Epicardial catheter ablation for ventricular tachycardia on uninterrupted warfarin: A safe approach for those with a strong indication for peri-procedural anticoagulation? AB - BACKGROUND: Current guidelines for epicardial catheter ablation for ventricular tachycardia (VT) advocate that epicardial access is avoided in anticoagulated patients and should be performed prior to heparinisation. Recent studies have shown that epicardial access may be safe in heparinised patients. However, no data exist for patients on oral anticoagulants. We investigated the safety of obtaining epicardial access on uninterrupted warfarin. METHODS: A prospective registry of patients undergoing epicardial VT ablation over two years was analysed. Consecutive patients in whom epicardial access was attempted were included. All patients were heparinised prior to epicardial access with a target activated clotting time (ACT) of 300-350s. Patients who had procedures performed on uninterrupted warfarin (in addition to heparin) were compared to those not taking an oral anticoagulant. RESULTS: 46 patients were included of which 13 were taking warfarin. There was no significant difference in clinical and procedural characteristics (except INR and AF) between the two groups. Epicardial access was achieved in all patients. There were no deaths and no patients required surgery. A higher proportion of patients in the warfarin group had a drop in haemoglobin of >2g/dL compared to the no-warfarin group (38.5% versus 27.3%, p=0.74) and delayed pericardial drain removal (7.8% versus 3.03%, p=0.47). There was no difference in overall procedural complication rate. No patients required warfarin reversal or blood transfusion. CONCLUSION: Epicardial access can be achieved safely and effectively in patients' anticoagulated with warfarin and heparinised with therapeutic ACT. This may be an attractive option for patients with a high stroke risk. PMID- 27454617 TI - Synthesis of pyrimidin-4-one-1,2,3-triazole conjugates as glycogen synthase kinase-3beta inhibitors with anti-depressant activity. AB - GSK-3 specific inhibitors are promising candidates for the treatment of devastating pathologies such as diabetes, neurodegenerative diseases and cancers. We have synthesized a library of pyrimidin-4-one-1,2,3-triazole conjugates using click-chemistry approach and evaluated them as glycogen synthase kinase-3beta inhibitors. Compounds 3g, 3j, 3n and 3r were found to be most potent among the eighteen pyrimidin-4-one-1,2,3-triazole conjugates synthesized and they were further evaluated for their in vivo anti-depressant activity. Compound 3n (2-((1 (3,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-methyl-6-phenylpyrimidin 4(3H)-one) exhibited the most potent inhibitory activity against GSK-3beta with IC50 value of 82nM and was also found to exhibit significant antidepressant activity at 50mg/kg, when compared with fluoxetine, a known antidepressant drug. The molecular docking studies were performed to elucidate the binding modes of the compounds with the GSK-3beta target and two crucial interactions namely, hydrogen bond formation with Val 135 and Lys 183 residues in the active site of GSK-3beta were observed. PMID- 27454618 TI - Synthesis, beta-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs. AB - Hybrid bisindole-thiosemicarbazides analogs (1-18) were synthesized and screened for beta-glucuronidase activity. All compounds showed varied degree of beta glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC50=48.4+/-1.25MUM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional beta-glucuronidase inhibition with IC50 values ranging from 0.1 to 5.7MUM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC50 values ranging from 7.12 to 15.0MUM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC50 values 33.2+/-0.75, 21.4+/-0.30 and 28.12+/-0.25MUM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds. PMID- 27454619 TI - The synthesis of novel pyrazole-3,4-dicarboxamides bearing 5-amino-1,3,4 thiadiazole-2-sulfonamide moiety with effective inhibitory activity against the isoforms of human cytosolic carbonic anhydrase I and II. AB - A series of 1-(3-substituted-phenyl)-5-phenyl-N(3),N(4)-bis(5-sulfamoyl-1,3,4 thiadiazol-2-yl)-1H-pyrazole-3,4-dicarboxamides (4-15) were synthesized. The structures of these pyrazole-sulfonamides were confirmed by FT-IR, (1)H NMR, (13)C NMR and elemental analysis methods. Human cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozymes (hCA I and II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of newly synthesized derivatives (4-15) were investigated in vitro on esterase activities of these isozymes. The Ki values were determined as 0.119-3.999MUM for hCA I and 0.084-0.878MUM for hCA II. The results showed that the compound 6 for hCA I and the compound 11 for hCA II had the highest inhibitory effect. Beside that, the compound 8 had the lowest inhibition effect on both isozymes. PMID- 27454621 TI - A Palladium-Catalyzed Method for the Synthesis of 2-(alpha-Styryl)-2,3 dihydroquinazolin-4-ones and 3-(alpha-Styryl)-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide: Access to 2-(alpha-Styryl)quinazolin-4(3H)-ones and 3-(alpha-Styryl) 1,2,4-benzothiadiazine-1,1-dioxides. AB - An efficient synthesis of 2-(alpha-styryl)-2,3-dihydroquinazolin-4-ones and 3 (alpha-styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides has been achieved in 39-94% yield through palladium-catalyzed cyclocondensation of aryl/vinyl iodides with allenamides 13-15 and 22, respectively. Base treatment of the N tosylated products provides an easy access to 2-(alpha-styryl)quinazolin-4(3H) ones and 3-(alpha-styryl)-1,2,4-benzothiadiazine-1,1-dioxides, hitherto unknown heterocycles. The method has been tested with phenyl substituted allenamides, applied for bis-heteroannulation, and used in the preparation of analogues of the natural product Luotonin F. PMID- 27454620 TI - Synthesis of pyrimidine-2,4,6-trione derivatives: Anti-oxidant, anti-cancer, alpha-glucosidase, beta-glucuronidase inhibition and their molecular docking studies. AB - This paper describes a facile protocol, efficient, and environmentally benign for the synthesis a series of barbiturate acid substituted at C5 position 3a-o. The desired compounds subjected in vitro for different set of bioassays including against anti-oxidant (DPPH and super oxide scavenger assays), anti-cancer, alpha glucosidase and beta-glucuronidase inhibitions. Compound 3m (IC50=22.9+/-0.5MUM) found to be potent alpha-glucosidase enzyme inhibitors and showed more activity than standard acarbose (IC50=841+/-1.73MUM). Compound 3f (IC50=86.9+/-4.33MUM) found to be moderate beta-Glucuronidase enzyme inhibitors and showed activity comparatively less than the standard d-saccharic acid 1,4-lactone (IC50=45.75+/ 2.16MUM). Furthermore, in sillico investigation was carried out to investigate bonding mode of barbiturate acid derivatives. PMID- 27454623 TI - Understanding the Impact of Globalization on Food Preferences, Dietary Patterns, and Health. PMID- 27454622 TI - Neuropsychiatric characteristics of PiB-negative subcortical vascular dementia versus behavioral variant frontotemporal dementia. AB - BACKGROUND: Neuropsychiatric symptoms of subcortical vascular dementia (SVaD) are mainly associated with damage to frontal-subcortical circuits and may be similar to symptoms of behavioral variant frontotemporal dementia (bvFTD). The aim of this study was to determine whether the neuropsychiatric manifestations of the Pittsburgh compound B (PiB)-negative SVaD and bvFTD groups differ. METHODS: We compared the Caregiver-Administered Neuropsychiatry Inventory (CGA-NPI) between 48 patients with PiB(-) SVaD and 31 patients with bvFTD. A stepwise logistic regression was applied to determine the best model to predict SVaD. RESULTS: The SVaD group showed a higher frequency of depression, whereas the bvFTD group had a higher frequency of elation, aberrant motor behavior and appetite/eating disorders. Regarding NPI subscores, the bvFTD group had greater severity of elation, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders, whereas SVaD did not have significantly higher subscores in any domains. The most predictive models that tend to find suggestions of SVaD, as opposed to bvFTD, are as follows: (1) the presence of depression and the absence of appetite/eating disorders, (2) higher NPI subscores of depression and lower NPI subscores of irritability and aberrant motor behavior. CONCLUSION: Apart from apathy, SVaD differed from bvFTD in that negative symptoms were more common in SVaD than bvFTD, whereas positive symptoms were predominant in bvFTD compared to SVaD. PMID- 27454624 TI - Modulation of 22-khz postejaculatory vocalizations by conditioning to new place: Evidence for expression of a positive emotional state. AB - It has been assumed that the 22-kHz ultrasonic vocalizations (USVs) are emitted by adult rats as a result of a negative emotional state. However, emission of the 22-kHz vocalizations by male rats has been also observed following ejaculation, which has a high rewarding value as shown by a conditioned place preference test. These observations suggest that 22-kHz USVs may also occur in response to a positive emotional state. The aim of this study was to determine whether the postejaculatory 22-kHz USVs are related to conditioning processes. The 22 kHz USVs were recorded in Sprague-Dawley males in the postejaculatory refractory period during conditioning processes to a new chamber unrelated to copulation. During the first session in the clean recording chamber, males vocalized marginally and exhibited intensive rearing behavior. From the second to fourth sessions, vocalization duration increased and the number of rearing decreased. Following established conditioning process, odor cues from foreign males, but not the familiar ones, resulted in decreased duration of 22-kHz USVs and increased the number of rearing. On the other hand, in the presence of mating cues (copulatory chamber and presence of the female), males exhibited increased duration of postejaculatory 22-kHz USVs and reduced number of rearing. These results demonstrated that the conditioning to the cues, both unrelated and related to copulation, is important for evoking postejaculatory 22-kHz USVs as well as the relaxation state. Furthermore, these results confirmed the postejaculatory 22-kHz USVs' involvement in expression of the positive emotional state. (PsycINFO Database Record PMID- 27454625 TI - Pearls and Pitfalls of the Volar Locking Plating for Distal Radius Fractures. AB - Volar locking plate fixation has been widely accepted method for the treatment of unstable distal radius fractures. Although the results of volar locking plate fixation are encouraging, it may cause implant-related complications such as flexor or extensor tendon injuries. In depth understanding of anatomy of the distal radius is mandatory in order to obtain adequate fixation of the fracture fragments and to avoid these complications. This article will review the anatomic characteristics of the distal radius because selecting proper implant and positioning of the plate is closely related to the volar surface anatomy of the distal radius. The number and the length of distal locking screws are also important to provide adequate fixation strength to maintain fracture fixation. We will discuss the pros and cons of the variable-angle locking plate, which was introduced in an effort to provide surgeons with more freedom for fixation. Finally, we will discuss about correcting radial length and volar tilt by using eccentric drill holes and distal locking first technique. PMID- 27454626 TI - Surgical Technique of Corrective Osteotomy for Malunited Distal Radius Fracture Using the Computer-Simulated Patient Matched Instrument. AB - The conventional corrective osteotomy for malunited distal radius fracture that employs dorsal approach and insertion of a trapezoidal bone graft does not always lead to precise correction or result in a satisfactory surgical outcome. Corrective osteotomy using a volar locking plate has recently become an alternative technique. In addition, the use of patient-matched instrument (PMI) via computed tomography simulation has been developed and is expected to simplify surgical procedures and improve surgical precision. The use of PMI makes it possible to accurately position screw holes prior to the osteotomy and simultaneously perform the correction and place the volar locking plate once the osteotomy is completed. The bone graft does not necessarily require a precise block form, and the problem of the extensor tendon contacting the dorsal plate is avoided. Although PMI placement and soft tissue release technique require some degree of specialized skill, they comprise a very useful surgical procedure. On the other hand, because patients with osteoporosis are at risk of peri-implant fracture, tandem ulnar shortening surgery should be considered to avoid excessive lengthening of the radius. PMID- 27454627 TI - Management of Complex Distal Radius Fractures: Review of Treatment Principles and Select Surgical Techniques. AB - Most distal radius fractures are the result of low-energy mechanisms that can be successfully treated either non-operatively or with a variety of operative techniques if indicated. Complex distal radius fractures occur most commonly in high-energy injuries with extensive comminution or bone loss and associated soft tissue or vascular injuries. These high-energy fractures can present many challenges in reconstructing the distal radius. Effective restoration of the bony architecture requires a thorough knowledge of distal radius anatomy, understanding of the goals of treatment, versatility in surgical approaches, and familiarity with multiple fixation options. PMID- 27454628 TI - Management of Distal Ulnar Fracture Combined with Distal Radius Fracture. AB - The distal ulna is composed of the ulnar styloid, ulnar head, and distal ulnar metaphyseal area. Most of distal ulnar metaphyseal fractures are associated with distal radius fractures and this incidence tends to be greater in osteoporotic elderly. Consideration of the treatment of distal ulna metaphyseal fracture should be addressed after treating a distal radius fracture. If it is stable, cast immobilization is preferred, however, if it shows malalignment or instability, an operative method should be considered. More than half of distal radius fractures are combined with an ulnar styloid fracture, and considerable cases of ulnar styloid fractures result in nonunion. However, ulnar styloid nonunion usually does not cause any problems on the wrist. Recent studies of distal radius fractures treated using a volar locking plate have reported that neither the initial displacement nor the size of a concomitant ulnar styloid fracture affects clinical outcome, which suggests surgical approaches may usually not be indicated for ulnar styloid fractures. PMID- 27454629 TI - The Optimal Rehabilitation Period for Patients with Distal Radius Fractures According to the MCID in DASH Scores; A Preliminary Study. AB - BACKGROUND: The statistical concept of minimal clinically important difference (MCID) enables the interpretation of small but meaningful changes that result from an intervention. This retrospective study aimed to examine the factors that influence the achievement of MCID after a distal radius fracture. METHODS: A total of 45 patients (mean age: 54.2 +/- 16 years) were included. Of these, 27 patients started rehabilitation within 3 days of surgery (Early group), and 18 patients underwent immobilization for 2 weeks after surgery, before starting rehabilitation (Non-early group). Functional outcomes and DASH scores at 4 weeks (baseline) were compared with those measured at 8 and 12 weeks for both groups, to determine whether the MCID had been achieved. RESULTS: Our results showed that at 8 weeks after surgery in the early group, the grip strength, ulnar flexion, and baseline DASH score were significantly different between the groups that did and did not show an MCID ([Formula: see text]). There was also a significant difference in the baseline DASH score at 12 weeks after surgery ([Formula: see text]). None of these factors were significant in the non-early group. Logistic regression analysis revealed that the DASH score at 4 weeks (baseline) was an independent predictor for achieving a DASH MCID at 8 weeks postoperatively in the early group (odds ratio: 1.193). Those achieving a DASH MCID at 12 weeks postoperatively were completely separated by the baseline DASH score (>= 29 points). CONCLUSIONS: If it is assumed that the effectiveness of rehabilitation depends upon achieving the DASH MCID by promoting functional recovery, early initiation might be recommended. PMID- 27454630 TI - Endoscopic Olecranon Bursal Resection for Olecranon Bursitis: A Comparative Study for Septic and Aseptic Olecranon Bursitis. AB - BACKGROUND: Open excision of the olecranon bursa has been performed traditionally. However, surgical complications such as wound healing problems and recurrence may occur after the surgery. The purpose of this study was to report on the clinical outcomes of endoscopic olecranon bursal resection performed in both septic and aseptic olecranon bursitis. METHODS: We retrospectively reviewed 30 patients who underwent endoscopic olecranon bursal resection from June 2007 to January 2012. There were 20 males and 10 females. The ages ranged from 22 to 80 years, with an average age of 57.4 years and the average follow-up was 21.1 months (6-61.5 months). There were 15 cases in the septic group. The treatment outcome was measured according to the following; the rate of recurrence, range of motion, complications associated with surgery, VAS and QuickDASH. RESULTS: There were no complications such as postoperative infection or neurovascular injuries. In the septic group, the VAS and QuickDASH scores were significantly improved from 5.6 to 0.1 and from 28 to 1.3, respectively. In the aseptic group, the VAS and QuickDASH scores were improved from 0.6 to 0.1 and from 25.7 to 0.5, respectively. In all cases, there were no recurrences and no limitations of joint motion until the final follow-up. CONCLUSIONS: We were able to obtain excellent outcomes without recurrence by performing endoscopic olecranon bursal resection in both septic and aseptic olecranon bursitis. PMID- 27454631 TI - Salvage Procedures for Distal Radioulnar Joint Complications. AB - The distal radioulnar joint (DRUJ) allows forearm rotation and load transmission across the wrist. Post-traumatic and degenerative joint disease of DRUJ may cause pain and disability. Deficiency of the soft tissue or bony supports may result in DRUJ instability. Various techniques have been developed to address arthritis and / or instability of the DRUJ. A comprehensive review of the spectrum of surgical techniques and arthroplasty options is presented. The concepts of these procedures are discussed in detail, with a focus on special points of interest to optimise outcomes and to avoid complications. The salvage of the complications of arthroplasties is also presented in detail. PMID- 27454632 TI - Dupuytren's Contracture. The Safety and Efficacy of Collagenase Treatment. AB - BACKGROUND: Our main goal was to see if treatment with collagenase injection is safe and effective and to assess patient satisfaction with this new treatment. METHODS: We prospectively followed 77 consecutive patients, treated for contracture in 91 fingers and 142 joints that received total of 109 collagenase injections. The patients were reviewed on the first and second day and at 4 and 12 months. A contracture reduced to five degrees or less at 12 months after the last injection, was considered to be a successful outcome. RESULTS: A mean of 1.2 injections were used per patient and 0.8 injections per joint. There was a significant improvement in mean passive extension deficit. Out of the 142 joints treated, 84 (59%) met our criterion for a successful outcome; 56 (80%) out of 70 MCP joints and 28 (39%) out of 72 PIP joints. There were also significant improvements in both hand function and pain. No serious adverse events were observed. The mean patient satisfaction with the treatment at the 12-month follow up was a VAS score of 78 (0 = none; 100 = complete) and only 11% stated that they would not have consented to the treatment if they had known the outcome in advance. CONCLUSIONS: Treatment of Dupuytren's disease with collagenase injection is both safe and effective. It is now our primary treatment for Dupuytren's disease. PMID- 27454633 TI - Assessment of the Accuracy of Online Information Regarding Trigger Finger. AB - BACKGROUND: Review of the recent literature suggests substantial use of the Internet by patients seeking health care information despite questionable accuracy and readability of information presented on some websites. The purpose of our study was to assess the accuracy, quality, and readability of online information regarding trigger finger. METHODS: Three terms ("trigger finger", "stenosing tenosynovitis", and "finger locking") were used to query three Internet search engines to evaluate websites regarding information about trigger finger. Three hand surgery fellows independently assessed website accuracy and quality using standardized scoring criteria. The Fleisch-Kincaid reading grade level score was used to assess website readability. Website authorship and commercial association were also noted. RESULTS: Sixty-nine unique websites were assessed. Internet information obtained using the search term "stenosing tenosynovitis" was written at a significantly higher reading level than information found using "finger locking" or "trigger finger". Website quality and accuracy were both significantly better in websites authored by physicians compared to websites authored by non-physicians. However, website accuracy was significantly poorer in websites featuring commercial association. Additionally, websites presenting information written below the 8(th) grade reading level demonstrated poorer accuracy. CONCLUSIONS: Search term has a significant effect on the readability of online information regarding trigger finger. Despite the terminology used in searches, most websites are largely inaccurate and may not be easily understandable by the general population. This demonstrates a substantial barrier to accessing accurate health care information and may impact patient outcomes. Hand surgeons should direct patients towards websites presenting accurate information with easily readable content. PMID- 27454634 TI - Recovery of Wrist Function after Volar Locking Plate Fixation for Distal Radius Fractures. AB - BACKGROUND: The purpose of our present study was to examine the recovery of the postoperative wrist function, and to compare the range of motion among each direction ofthe wrist joint during the same time periods after surgery for distal radius fractures. METHODS: Twenty patients treated with a volar locking plate were evaluated. The active range of motion and grip strength were assessed at four weeks, six weeks, three months, six months and one year after surgery. RESULTS: The ratio of the range of motion in pronation and supination recovered significantly earlier than for any other directions within six months after surgery (p = 0.0205), however, the ratio of the range of motion among the six directions was not significantly different at one year after surgery (p = 0.0823). The recovery of the range of motion in flexion was 96.8% compared with the contralateral wrist at one year after surgery, and it was not significantly lower than that in extension, radial deviation or ulnar deviation (97.8%, 93.5%, 94.4%, respectively). The grip strength of dominant hand recovered from 50% after four weeks to 66% after six weeks, 83% after three months, 91% after six months and 106% at the examination performed after one year compared with the uninjured non-dominant hand. The grip strength of non-dominant hand recovered from 52% after four weeks to 59% after six weeks, 79% after three months, 84% after six months and 94% at the examination performed after one year compared with the uninjured dominant hand. The mean DASH score was 5.3. CONCLUSIONS: The range of motion in flexion can achieve similar improvement to that in the other directions by obtaining the appropriate postoperative parameters. The optimal postoperative radiographic parameters were thus identified to be essential for successfully obtaining a recovery of the wrist function for unstable distal radius fractures. PMID- 27454635 TI - Limited Wrist Arthrodesis for Scapholunate Advanced Collapse Wrist: Triangle Fixation for Four-Corner Fusion. AB - BACKGROUND: Limited wrist arthrodesis with scaphoid excision is a useful treatment for scapholunate advanced collapse (SLAC) of the wrist. Multiple Kirschner wires were originally used for internal fixation of the four carpal bones, however long-term cast immobilization, pin tract infection, and hardware removal are still problematic. We introduce and evaluate the clinical outcomes of an internal fixation technique; triangle fixation for four-corner fusion, using three headless screws, as an alternative to conventional multiple Kirschner wires for the treatment of SLAC wrist. METHODS: Five male patients with SLAC wrist secondary to three scaphoid nonunions and two scapholunate dissociations were treated with four-corner fusion using triangle fixation with three Double threaded Japan screws. The mean age was 59.5 years (35-79 years) and the mean follow-up period was 40 months. After surgery, short arm splints were applied for 3-4 weeks, and then range of motion exercises were initiated. RESULTS: Wrist range of motion and grip strength both improved postoperatively. At the final follow-up evaluation, bone union was completely achieved and satisfactory pain relief was observed in all patients. CONCLUSIONS: Compared with the conventional Kirschner wire technique, the present technique shortens the period of splint immobilization due to a strong compression force in a skewed position, does not require pin removal or cause pin tract infections, and provides satisfactory results. PMID- 27454636 TI - Computer Aided Assessment in Microsurgical Training. AB - BACKGROUND: Acquiring competence in microsurgical suturing is a basic requirement for any trainee aspiring to perform clinical microsurgery. New methods and simulation platform continue to evolve, but the assessment of the quality of microsurgical suturing is largely subjective. We present the concept of computer aided assessment of standardised microsurgical task, using a novel training platform. The platform comprises of a simulator (hardware) that provides the trainee standardised microsurgical tasks, which are then evaluated using a customised software. METHODS: A cohort of trainees attending a five day microsurgery training course was selected. The trainees performed three standardised exercises on the platform, on the first third and the fifth day of the course. All the exercises were subjected to computer aided assessment. RESULTS: Trainees demonstrated a learning curve over the five day period through the evaluation system, with initial increase in performance followed by a plateau. Eighty four percent of the trainees were able to achieve acceptable scores. Sixteen percent of the trainees were unable to perform a suturing of acceptable quality at the end of the training (fifth day). CONCLUSIONS: The mean scores correlated with the level of difficulty of the exercise. We conclude that computer aided assessment can provide an objective view of the quality of suturing as well as skill maintenance in for trainees. PMID- 27454637 TI - An Anechoic Space at the Carpal Tunnel Inlet is a Consistent Ultrasonographic Entity which Accommodates Tendon Displacement during Finger Flexion. AB - BACKGROUND: We consistently observed the presence of anechoic spaces on standard ultrasonographic imaging of the carpal tunnel inlet in normal subjects. These spaces change in size during finger flexion and have not been characterized in a large sample of normal individuals. Ultrasonographic quantification of these spaces may indicate the available space in the region of the carpal tunnel, which allows the normal motion of tendons and the median nerve. METHODS: Transverse ultrasonographic images of the carpal tunnel inlet from 33 asymptomatic volunteers were obtained at Position A (fingers in extension) and B (fingers in flexion). Cross-sectional area (CSA), perimeter and position of anechoic space relative to median nerve were recorded. RESULTS: Analysis showed a 75.4% prevalence rate of a single anechoic space. Two discrete patterns were observed. 89.1% had a decrease in CSA and perimeter of anechoic space from Position A to B while 10.9% exhibited an increase. Mean position of the anechoic space is ulnar (7.49 +/- 3.57 mm) and dorsal (2.18 +/- 1.28 mm) to the median nerve. CONCLUSIONS: A consistent anechoic space at the carpal tunnel inlet is seen in 75.4% of normal hands and can be quantified (cross sectional area 11.75 +/- 7.36 mm(2)). It allows for the accommodation of flexor tendons during finger flexion. PMID- 27454638 TI - Pedicled Oblique Para-Umbilical Perforator (OPUP) Flap for Upper Limb Reconstruction. AB - BACKGROUND: Groin flap has been considered the workhorse flap for hand reconstruction. However it has certain drawbacks when covering defects over elbow or proximal forearm. Pedicled oblique paraumbilical perforator (OPUP) based flaps provide a good alternative in such cases. METHODS: We performed OPUP flap in 11 cases of complex upper limb reconstructions over the past one year. We report our experience with this flap. RESULTS: All flaps survived. One patient had marginal necrosis of 1 cm in the proximal end after flap division. Three patients had donor site scar hypertrophy. CONCLUSIONS: OPUP flap is superior to groin flap for larger defects or defects around the elbow. The major disadvantage is the donor site scar which is prone to hypertrophy. PMID- 27454639 TI - The "Trigger" Thumb Locked in Extension - An Unusual Presentation of a Common Paediatric Condition. AB - BACKGROUND: We report a variant of paediatric trigger thumb which is locked in extension rather than flexion. METHODS: Eleven children with 14 trigger thumbs (three bilateral) locked in extension were reviewed retrospectively over a 12 year period. The number of flexed trigger thumbs encountered over this period was established from the operating room database. RESULTS: All children were treated with release of the A1 pulley. Nine children achieved a full range of motion at the interphalangeal joint. One child with bilateral extended trigger thumbs required bilateral dorsal capsulotomy and another child developed temporary mild triggering in flexion. CONCLUSIONS: Approximately 1% of trigger thumbs treated operatively at this institution presented as the extended variant. Trigger thumb locked in extension should be considered in a child presenting with inability to flex the thumb. PMID- 27454640 TI - Effect of Intraarticular Triamcinolone Acetonide Injection for Wrist Pain in Rheumatoid Arthritis Patients: A Statistical Investigation. AB - BACKGROUND: A significant number of patients on long-term treatment and users of biologics complain of wrist pain due to synovial proliferation and arthropathic changes. Synovectomy or joint arthroplasty is often indicated for such patients, but many refuse surgery. For these patients triamcinolone acetonide was injected into the dorsum of the wrist, and evaluated the clinical benefit and safety of the wrist joint. METHODS: We injected triamcinolone acetonide into the dorsum of the wrist. We evaluated the clinical benefit and safety of intraarticular triamcinolone acetonide by analyzing data on (1) the number of injections, (2) decrease in visual analog scale pain, (3) changes in carpal height ratio, radio carpal distance ratio, and radial rotation angle in X-ray imaging, and (4) the adverse reactions of triamcinolone acetonide injection on the subcutaneous tissue and extensor tendons. RESULTS: 1. The number of injections per patient over 3 years 8 months was 1 for 44 wrists, 2 for 21 wrists, 3 for 17 wrists, 4 for 6 wrists, 5 for 3 wrists, 6 for 3 wrists, 7 for 2 wrists, 9 for 2 wrists, 12 for 4 wrists, and 13 for 1 wrist. 2. The overall mean VAS improved from 79 mm at baseline to 11 mm post-injection. 3. In the grade I and II group, CHS, RCDR and RRA were not statistically significant. In the grade III and IV group, CHR showed a significant decrease. 4. Neither subcutaneous atrophy nor extensor tendon rupture was reported. CONCLUSIONS: More than 90% of patients of all disease grades responded to an average of 1 to 4 injections per year. PMID- 27454641 TI - A Classification for Extensor Carpi Ulnaris Groove Morphology as an Aid for Ulnar Sided Wrist Pain. AB - BACKGROUND: Distal ulna groove morphology is likely to have a significant role in extensor carpi ulnaris (ECU) tendon stability. The development of a robust anatomical classification system, would be beneficial to further research into ulnar sided wrist pain and would be of use in rationalising treatment regimes. METHODS: Cadaveric specimens as well as MRI scans of patients with non-specific wrist pain were analysed independently by 3 orthopaedic surgeons twice to test the integrity of the classification system. The following classification system was developed for the distal ulna groove; Flat = L-shaped slope, S slope = S shaped, Reverse C = C-shaped slope. Findings were then subjected to Fleiss Kappa statistical analysis to evaluate how robust the classification system was. RESULTS: From the cadaveric arm of the study, 61 patients had their distal ulna groove morphology categorised according to types C, L, and S. For the MRI arm of the study 103 MRI scans were classified. ECU grove subtype C showed 8% dislocation compared to 33% and 47% for the L subtype and S sub type respectively. CONCLUSIONS: Our classification system of ECU groove morphology will help identify different components to ulnar sided wrist problems and may help establish guidelines for treatment. This classification system has been validated for both cadaveric specimens and the MRI scans. It showed substantial agreement to almost perfect agreement in the data tested, thus proving good interand intra-observer reliability. It is a useful tool to help in further research into ulnar sided wrist pain and ECU instability, and may help develop further treatment strategies in the future. PMID- 27454642 TI - Entrapment of Extensor Pollicis Longus Tendon after Volar Plating of a Smith Type Pediatric Distal Forearm Fracture. AB - Extensor pollicis longus tendon entrapment is a rare complication of volarly displaced pediatric distal radius fractures. The few pediatric case reports have described tendon entrapment associated with conservative fracture treatment, or have been recognized at subsequent revision surgery after failure to achieve closed fracture reduction. A case of extensor pollicis longus tendon entrapment after open reduction and volar plate fixation of a pediatric distal forearm fracture is reported. This complication may also occur secondarily after open reduction and volar plating of the distal radius. PMID- 27454643 TI - Osteochondritis Dissecans of the Humeral Capitellum Associated with a Large Subchondral Bone Cyst: Two Cases Report. AB - We report two rare cases of osteochondral dissecans of the humeral capitellum, each associated with a large subchondral cyst. The procedure employed for reconstruction of the massive bone defect yielded excellent clinical and radiological outcomes in both cases, and therefore seems promising for treatment of osteochondritis dissecans. PMID- 27454644 TI - Intramuscular Hemangioma of the Pronator Quadratus Muscle of Forearm. AB - Intramuscular hemangioma is a rare type that has been reported in less than 0.8% of all hemangiomas. In particular, there are few reports of intramuscular hemangioma in the upper extremity. Authors describe the experience of complete excision of the hemangioma of the pronator quadratus muscle of the forearm with good functional recovery. PMID- 27454645 TI - Chronic Synovitis after Open Carpal Tunnel Decompression. AB - Open carpal tunnel decompression is a common procedure with potential long-term complications such as scar tenderness, pillar pain and neuroma. We present the case of a 65 year-old male with chronic lipomatous hypertrophy of the wrist and chronic flexor tenosynovitis after open carpal tunnel release for its rarity and severity of symptoms that required further surgery. PMID- 27454646 TI - Fibro-Osseous Pseudotumor of the Hand. AB - Fibro-osseous pseudotumor of digits (FOPD) is an uncommon histological diagnosis. Clinical and imaging findings may resemble high-grade sarcoma or infection. We describe a patient with progressive pain and swelling at the dorsal surface of the first web space. MRI and CT imaging revealed an intramuscular heterogenous soft tissue mass defined by a mineralized peripheral ring. Core needle biopsy diagnosed FOPD. Eight months later a matured ossified nodule that was quite smaller than the initial soft tissue mass was excised. The patient is symptom free without local recurrence at 1 year follow up. Soft tissue masses of the hand pose a challenging diagnostic and therapeutic issue. An in depth interpretation of clinical, imaging and histology findings is important to avoid erroneous diagnosis and treatment. PMID- 27454647 TI - Traumatic Thumb Radial Sagittal Band Injury Mimicking EPL Rupture. AB - We present the case of a closed traumatic disruption of the thumb radial sagittal band (RSB) that sonographically mimicked rupture of the extensor pollicis longus (EPL) tendon. This injury was treated with primary repair of the RSB and lead to a good functional outcome for the patient. This case report highlights how early recognition and treatment can lead to a good functional outcome. PMID- 27454648 TI - Novel Suture Anchor Technique with Continuous Locking Stitch for Collateral Ligament Repair. AB - Collateral ligaments are difficult to repair due to large amount of fraying in detached ligaments and attenuated stumps that may not provide enough strength after the repair. Although strong locking sutures are used to repair the ligament with proper tension, these damages can cause pull-out failure or relaxation of the repaired ligaments even from undersized load that may extend postoperative splinting or casting time. Furthermore, current suture techniques can repair varus or valgus instability of the elbow and radial or ulnar instability of the fingers, but these techniques do not offer rotatory stability of these areas. We have developed a novel suture anchor technique that has overcome this problem of current suture techniques, and this can be used to correct rotatory instability in the elbow and fingers. We used this procedure in seven cases with injury of collateral ligament in the elbow and eight cases with detached collateral ligaments of finger joint. No patient experienced rerupture or any kind of residual instability. We believe that the proposed method can produce much stronger repair and may shorten the postoperative immobilization period. PMID- 27454649 TI - Technical Tip for Proximal Release During Open Carpal Tunnel Release Using a Subcutaneous Pocket. AB - Technical steps to avoid incomplete proximal release of the carpal tunnel are described. Local anaesthesia is infiltrated as a subcutaneous bleb over the distal wrist crease and extending 2-3 cm over the forearm fascia. Tumescence of local anaesthesia into the subcutaneous plane helps create a pocket between the forearm fascia and subcutaneous tissues. Intraoperatively a subcutaneous pocket is made above the transverse carpal ligament and antebrachial fascia with blunt dissection. A retractor is placed under the pocket, which facilitates optimal visualization to allow reliable complete proximal release of compression.The authors have found that this technique is reproducible and reliable across their collective experience. PMID- 27454650 TI - Relationship between early administration of abciximab and TIMI flow in STEMI patients undergoing primary angioplasty: findings from a large regional STEMI network. AB - AIMS: The aim of this study is to assess whether in S-T Elevation Myocardial Infarction (STEMI) a relationship between early administration of abciximab and Thrombolysis In Myocardial Infarction (TIMI) flow before and after primary percutaneous coronary intervention (PCI) in 960 consecutive patients exists. METHODS: From 1 February 2001 onward, in the Province of Mantua it has been operating a 'Cardiology Network for the Acute Infarction Care' having its Hub in the Central Coronary ICU/Cath Lab of Mantua Hospital and being its Spokes centers represented by the emergency rooms and Central Coronary ICUs of the four territorial hospitals. RESULTS: T1 (time from symptoms onset to first medical contact) and T2 (time from first medical contact to angioplasty) are shorter for patients rescued by first aid units rather than for those presented in emergency rooms as well as Ta (time from symptoms onset to abciximab administration). Furthermore, the patients that received abciximab before hospital arrival had less frequently a coronary occlusion [odds ratio = 0.74, 95% confidence interval (0.57-0.96), P = 0.013]. The patients with T1 less than 4 h are 753/960 (78.4%). For this type of patients, there was a significant Ta difference between the pre PCI TIMI-flow classes (F = 4.467, df = 3, P = 0.04). Planned contrasts revealed that mean time of TIMI flow 0 (M = 104.2) is statistically different from mean time of TIMI flow 3 (M = 85.7), P = 0.013. CONCLUSION: Our results suggest that the use of abciximab, free from pharmacokinetic limits of oral P2Y12 inhibitors, should be considered in STEMI patients with early presentation before primary PCI. PMID- 27454651 TI - Growth-differentiation factor 15 as a predictor of mortality in patients with heart failure: a meta-analysis. AB - AIMS: Measurement of the biomarker growth-differentiation factor 15 (GDF-15) in patients with heart failure may help in risk stratification. We assessed the relationship between GDF-15 and mortality in patients with heart failure by conducting a meta-analysis. METHODS: PubMed, Embase, ISI Web of Science, SCOPUS, and Cochrane Library databases were searched for studies that reported data on the baseline GDF-15 levels and all-cause or cardiovascular mortality. Pooled hazard ratios for mortality were calculated and presented with 95% confidence intervals (CIs). Potential sources of heterogeneity were assessed by meta regression, subgroup, and sensitivity analyses. RESULTS: Eight studies with a total of 4126 heart failure patients were included. Pooled results showed that overexpression of GDF-15 was associated with poor survival in heart failure patients (log unit GDF-15: hazard ratio = 1.86, 95% CI = 1.37-2.52). Subgroup analyses revealed similar results. However, there was evidence of heterogeneity and publication bias. The association disappeared after correction using the trim and-fill method (log unit GDF-15: hazard ratio 1.07, 95% CI 0.80-1.42). CONCLUSION: The results of this meta-analysis indicate an association of elevated GDF-15 levels with increased risk of mortality in patients with heart failure. However, the results should be interpreted with caution due to substantial heterogeneity and publication bias among the studies included in the meta analysis. PMID- 27454652 TI - Simple method for estimating soil mass loading onto plant surface using magnetic material content as a soil indicator - Influence of soil adhesion to vegetation on radioactive cesium concentration in forage. AB - A simple technique for estimating soil mass loading on vegetation was developed using magnetic material content as an indicator of soil adhesion. Magnetic material contents in plant and soil samples were determined by a magnetic analyzer. High recovery rates of 85-97% were achieved in a recovery test in which additional soil was added to powdered plant materials [stem of forage corn (Zea mays L.), aboveground part of Italian ryegrass (Lolium multiflorum Lam.)] at addition rates of 12.3-200 g dry soil kg-1 dry plant material including soil. Samples of different Japanese cultivated soils were tested and showed a range of magnetic contents of 1.27-16.1 g kg-1 on a dry weight basis. These levels are considered adequate for determining soil contamination in plant materials. Then, we applied this method for confirming the effect of soil adhesion on radioactive cesium concentrations in plant samples obtained at the area affected by the 2011 nuclear accident in Japan. The mean soil mass loading (+/-standard deviation) on forage rye (Secale cereale L.) showing mild lodging was 0.8 +/- 0.6 g kg-1, but was 7.4 +/- 5.0 g kg-1 for plants with serious lodging. No soil loading was detected on rye plants that showed no lodging. Radioactive cesium concentrations in the rye samples increased linearly with the increase in soil mass loading caused by plant lodging, and consequently mean radioactive cesium concentration for rye plants with serious lodging was about 2.7 times higher than that with no lodging. Cesium radioactivity in forage was affected by variations in soil mass loading onto forage plants caused by changes in plant growth and differences between plant species. PMID- 27454653 TI - Transparent, self-cleaning and waterproof surfaces with tunable micro/nano dual scale structures. AB - The rational design and facile fabrication of optically transparent, superhydrophobic surfaces can advance their versatile applications, including optoelectronic devices. For the easily accessible and scalable preparation of transparent, superhydrophobic surfaces, various coating methods using a solution process have been developed. However, obtaining highly transparent, non-wetting surfaces with excellent properties is challenging due to the difficulty in controlling surface roughness. Here, we report on a novel approach to control the surface roughness by fabricating tailorable micro/nano dual-scale surface structures via solution-processed nanoparticle coating. The surface roughness was able to be controlled by micro/nano dual-scale structures that can be manipulated by varying the mixture ratio of two different sizes of Al2O3 nanoparticles. The controllable micro/nano dual-scale structures were optimized to achieve the superior surface properties in both hydrophobicity and transparency, exhibiting a high water contact angle (>160 degrees ), low sliding angle (<2 degrees ) and high transmittance (>90%). These characteristics allowed an excellent transparency and self-cleaning capability as well as a superior waterproof ability even under applied voltage. Furthermore, we demonstrated the versatile applicability of the developed surface-coating method to a wide range of substrates including glass, paper, fabrics, and even flexible plastics. PMID- 27454654 TI - Kinetic analysis for the isomerization of cellobiose to cellobiulose in subcritical aqueous ethanol. AB - The isomerization of cellobiose to cellobiulose, and other degradation reactions of cellobiose were investigated in subcritical aqueous ethanol with concentrations of ethanol ranging from 0 to 60% (w/w) and at temperatures ranging from 170 to 200 degrees C. The maximum yield of cellobiulose (ca. 40%) was obtained from the treatment of cellobiose in 60% (w/w) aqueous ethanol at 190 degrees C. Glucose and fructose were also detected as byproducts. The concentration-time integral method was employed to analyze the rate constants for the isomerization and degradation processes. The rate constant of cellobiose isomerization to cellobiulose was greater than those of the degradation reactions under all experimental conditions, and it increased significantly with treatment temperature and ethanol concentration. However, the use of higher temperatures and ethanol concentrations was restricted due to decomposition of the saccharides and the low solubility of cellobiose, respectively. The effect of initial feed concentration (0.5-5.5% w/w) was also studied. The maximum productivity of cellobiulose, 54.1 kg/(h m(3)-reactor), was accomplished at a feed concentration of 5.5% (w/w) in 20% (w/w) subcritical aqueous ethanol. PMID- 27454655 TI - Novel biologically active series of N-acetylglucosamine derivatives for the suppressive activities on GAG release. AB - (d)-Glucosamine and other nutritional supplements have emerged as safe alternative therapies for osteoarthritis, a chronic and degenerative articular joint disease. N-acetyl-(d)-glucosamine, a compound that can be modified at the N position, is considered to improve the oral bioavailability of (d)-glucosamine and has been proven to possess greater in vitro chondroprotective activity compared with the parent agent. In this study, to further utilize these properties, we focus on the modification of the N position with a benzenesulfonyl and different isoxazole formyl groups. Among these compounds, the 3-(2 chlorobenzene)-5-methyl-isoxazole formyl chloride and p-methoxybenzenesulfonyl chloride modifying structures proved to be the most active of the series and efficiently processed the chondrocytes in vitro. These novel N-position substitution compounds may represent promising leads for osteoarthritis drug development. PMID- 27454656 TI - An analytical perspective of Global health initiatives in Tanzania and Zambia. AB - BACKGROUND: A number of Global health initiatives (GHIs) have been created to support low and middle income countries. Their support has been of different forms. The African Region has benefitted immensely from GHIs and continues to register an increase in health partnerships and initiatives. However, information on the functioning and operationalisation of GHIs in the countries is limited. METHODS: This study involved two country case studies, one in Tanzania and the other one in Zambia. Data were collected using a semi-structured questionnaire. The aims were to understand and profile the GHIs supporting health development and to assess their governance and alignment with country priorities, harmonisation and alignment of their interventions and efforts, and contribution towards health systems strengthening. The respondents included senior officers from health stakeholder agencies at the national and sub-national levels. The qualitative data were analysed using thematic content analysis in MAXQDA software. RESULTS: Health systems in both Tanzania and Zambia are decentralised. They have benefitted from GHI support in fighting the common health problems of HIV/AIDS, tuberculosis, malaria and vaccine-preventable diseases. In both countries, no GHI adequately made use of the existing Sector-wide Approach (SWAp) mechanisms but they largely operate through their unique structures and committees. GHI efforts to improve general health governance have not been matched with similar efforts from the countries. Their support to health system strengthening has not been comprehensive but has involved the selection of a few areas some of which were disease-focused. On the positive side, however, in both Tanzania and Zambia improved alignment with the countries' priorities is noted in that most of the proposals submitted to the GHIs refer to the priorities, objectives and strategies in the national health development plans and, GHIs depend on the national health information systems. CONCLUSION: GHIs are important funders of health in low and middle income countries. However, there is a need for the countries to take a proactive role in improving the governance, coordination and planning of the GHIs that they benefit from. This will also maximise the return on investment for the GHIs. PMID- 27454657 TI - Allogeneic hematopoietic cell transplant for patients with end stage renal disease requiring dialysis - a single institution experience. PMID- 27454659 TI - Radial Peripapillary Capillary Network Visualized Using Wide-Field Montage Optical Coherence Tomography Angiography. AB - PURPOSE: We quantitatively analyzed the features of a radial peripapillary capillary (RPC) network visualized using wide-field montage optical coherence tomography (OCT) angiography in healthy human eyes. METHODS: Twenty eyes of 20 healthy subjects were recruited. En face 3 * 3-mm OCT angiograms of multiple locations in the posterior pole were acquired using the RTVue XR Avanti, and wide field montage images of the RPC were created. To evaluate the RPC density, the montage images were binarized and skeletonized. The correlation between the RPC density and the retinal nerve fiber layer (RNFL) thickness measured by an OCT circle scan was investigated. RESULTS: The RPC at the temporal retina was detected as far as 7.6 +/- 0.7 mm from the edge of the optic disc but not around the perifoveal area within 0.9 +/- 0.1 mm of the fovea. Capillary-free zones beside the first branches of the arterioles were significantly (P < 0.0001) narrower than those beside the second ones. The RPC densities at 0.5, 2.5, and 5 mm from the optic disc edge were 13.6 +/- 0.8, 11.9 +/- 0.9, and 10.4 +/- 0.9 mm 1. The RPC density also was correlated significantly (r = 0.64, P < 0.0001) with the RNFL thickness, with the greatest density in the inferotemporal region. CONCLUSIONS: Montage OCT angiograms can visualize expansion of the RPC network. The RPC is present in the superficial peripapillary retina in proportion to the RNFL thickness, supporting the idea that the RPC may be the vascular network primarily responsible for RNFL nourishment. PMID- 27454658 TI - In Vivo Imaging of Corneal Endothelial Dystrophy in Boston Terriers: A Spontaneous, Canine Model for Fuchs' Endothelial Corneal Dystrophy. AB - PURPOSE: Boston Terriers (BTs) have a greater prevalence of corneal endothelial dystrophy (CED), in comparison to other canine breeds. Similar to Fuchs' endothelial corneal dystrophy (FECD), this condition is characterized by endothelial cell degeneration with secondary corneal edema. This study assessed corneal morphology using in vivo confocal microscopy (IVCM) and Fourier-domain optical coherence tomography (FD-OCT) in BTs with and without CED. METHODS: The corneas of 16 BTs with CED and 15 unaffected, age-matched BTs underwent clinical evaluation and were imaged using IVCM and FD-OCT. A two-sample t-test or Mann Whitney rank sum test were used to statistically compare parameters between groups. Data are presented as mean +/- SD or median (range). RESULTS: Mean age did not significantly differ between affected and unaffected dogs at 10.0 +/- 2.0 and 10.6 +/- 2.4 years, respectively (P = 0.437). Females (69%) were overrepresented among the CED-affected dogs. In CED patients, IVCM demonstrated endothelial polymegathism and pleomorphism. Corneal endothelial density was significantly less (P < 0.001) in dogs with CED (1026 +/- 260 cells/mm2) versus age-matched controls (2297 +/- 372 cells/mm2). Fourier-domain OCT demonstrated a significant increase (P < 0.01) in central corneal and endothelium-Descemet's complex thickness in dogs with CED versus age-matched controls at 1019 (485-1550) or 536 (464-650) MUm and 32 (22-56) or 25 (15-34) MUm, respectively. CONCLUSIONS: Corneal endothelial dystrophy in BTs is a bilateral, adult-onset condition that shares many similarities with FECD. Thus, CED could serve as a spontaneous disease model to study the pathogenesis of and develop novel treatments for FECD. PMID- 27454660 TI - Structural Change Can Be Detected in Advanced-Glaucoma Eyes. AB - PURPOSE: To compare spectral-domain optical coherence tomography (SD-OCT) standard structural measures and a new three-dimensional (3D) volume optic nerve head (ONH) change detection method for detecting change over time in severely advanced-glaucoma (open-angle glaucoma [OAG]) patients. METHODS: Thirty-five eyes of 35 patients with very advanced glaucoma (defined as a visual field mean deviation < -21 dB) and 46 eyes of 30 healthy subjects to estimate aging changes were included. Circumpapillary retinal fiber layer thickness (cpRNFL), minimum rim width (MRW), and macular retinal ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured using the San Diego Automated Layer Segmentation Algorithm (SALSA). Progression was defined as structural loss faster than 95th percentile of healthy eyes. Three-dimensional volume ONH change was estimated using the Bayesian-kernel detection scheme (BKDS), which does not require extensive retinal layer segmentation. RESULTS: The number of progressing glaucoma eyes identified was highest for 3D volume BKDS (13, 37%), followed by GCPIL (11, 31%), cpRNFL (4, 11%), and MRW (2, 6%). In advanced-OAG eyes, only the mean rate of GCIPL change reached statistical significance, -0.18 MUm/y (P = 0.02); the mean rates of cpRNFL and MRW change were not statistically different from zero. In healthy eyes, the mean rates of cpRNFL, MRW, and GCIPL change were significantly different from zero. (all P < 0.001). CONCLUSIONS: Ganglion cell inner plexiform layer and 3D volume BKDS show promise for identifying change in severely advanced glaucoma. These results suggest that structural change can be detected in very advanced disease. Longer follow-up is needed to determine whether changes identified are false positives or true progression. PMID- 27454661 TI - Assessment of children with vascular ring. AB - BACKGROUND: Vascular rings may cause pressure on the trachea and/or esophagus of varying degree, resulting in symptoms. This study assessed the presentation symptoms, diagnostic methods and treatment results after surgery in children with vascular ring. METHODS: Symptomatic vascular ring patients undergoing surgery between January 2010 and August 2014 at Mehmet Akif Ersoy Cardiovascular Research and Training Hospital, Istanbul, were retrospectively assessed. The presentation symptoms, demographic characteristics, and diagnostic tests were evaluated. Operative data and postoperative follow up, complications and problems were also examined in detail. RESULTS: Twenty-one patients underwent surgery, 13 (63%) of whom were male. Median age was 12 months (range, 1 month-8 years). Among these patients, 62% (n = 13) had double aortic arch, 24% (n = 5) had right-sided aortic arch + ligamentum arteriosum, 10% (n = 2) had left-sided aortic arch + aberrant right subclavian artery, and 4% (n = 1) had pulmonary sling abnormality. Computed tomography (CT) angiography was performed in 17/21 patients. All the patients were successfully operated on. In the early postoperative period, two patients had chylothorax and one had nerve paralysis of nervus laryngeus recurrens. One patient died in the early period, and two patients had ongoing stridor on follow up. CONCLUSIONS: CT angiography is effective for the differential diagnosis and visualization of vascular ring abnormality. In such cases, full recovery can be assured with early diagnosis and surgery. PMID- 27454662 TI - Is there any analgesic benefit from preoperative vs. postoperative administration of etoricoxib in total knee arthroplasty under spinal anaesthesia?: A randomised double-blind placebo-controlled trial. AB - BACKGROUND: Optimal postoperative analgesia is a challenge for the anaesthesiologist, with the ideal combination of methods, drugs, doses and timing of administration still the subject of research. The COX-2 inhibitors are a class of NSAIDs that may provide useful perioperative analgesia but the optimal timing of administration has not been elucidated. OBJECTIVE: We hypothesised that etoricoxib given 1 h before total knee arthroplasty under spinal anaesthesia will decrease the cumulative dose of intravenous and subcutaneous morphine required to maintain pain intensity of 3 or less on a 10-point numerical rating scale (NRS) during the first postoperative 48 h compared with the same dose of etoricoxib given after surgery. DESIGN: Randomised, double-blind, placebo-controlled trial. SETTING: University hospital, between January and September, 2014. PATIENTS: Overall, 165 patients scheduled for total knee arthroplasty under spinal anaesthesia. INTERVENTIONS: The patients were randomised into one of three groups: the ETORICOX-PREOP group received etoricoxib 120 mg orally 1 h before surgery, one placebo pill at the end of surgery and a further 120 mg etoricoxib after 24 h; the ETORICOX-POSTOP group received one placebo pill 1 h before surgery and etoricoxib 120 mg at the end of surgery and after 24 h. The PLACEBO group received one placebo pill 1 h before surgery, one at end of surgery and a third after 24 h. MAIN OUTCOME MEASURES: The primary outcome measure was the cumulative dose of intravenous and subcutaneous morphine required during the first postoperative 48 h to maintain a 10-point numerical pain rating scale value of 3 or less. Secondary outcomes measures were duration of analgesia from initiation of spinal anaesthesia until the first analgesic requirement and the side-effects of the treatment. RESULTS: The quantity of morphine over the first postoperative 48 h required by the ETORICOX-PREOP group (44 +/- 16 mg) and the ETORICOX-POSTOP group (52 +/- 23 mg) were both significantly less than the PLACEBO group (71 +/- 20 mg) (P = 0.001), demonstrating a morphine-sparing effect of etoricoxib of the order of 30%; the difference between the PRE vs. POST groups was statistically significant (P = 0.02), favouring a preemptive analgesic effect. Also, there was evidence of a longer time to first analgesia compared with PLACEBO in the PREOP group (P = 0.02) but no significant difference between PREOP and POSTOP groups (P = 0.30). There was no difference in side-effects among the three study groups and there were no serious adverse effects of etoricoxib. CONCLUSION: Preemptive administration of etoricoxib 120 mg orally in patients undergoing total knee arthroplasty under spinal anaesthesia is superior to postoperative administration of the same dose in terms of its morphine-sparing effect during the first postoperative 48 h, but not in prolonging the time to first analgesia, and is associated with a similar incidence of side-effects. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT 02534610. PMID- 27454663 TI - Total intravenous anaesthesia versus single-drug pharmacological antiemetic prophylaxis in adults: A systematic review and meta-analysis. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are among the most unfavourable anaesthetic outcomes attributed to the administration of inhaled anaesthetics. Accordingly, inhaled anaesthetics are frequently substituted by propofol when patients are at risk of PONV. As, on some occasions, inhalational anaesthesia may be favourable, the relative impact of propofol anaesthesia needs to be established based on robust data. OBJECTIVE: To compare the effectiveness of a single-drug pharmacological prophylaxis with total intravenous anaesthesia (TIVA) for prevention of PONV. DESIGN: Systematic review of randomised controlled trials with meta-analyses. DATA SOURCES: All available studies until 29 April 2015 were retrieved from MEDLINE, CENTRAL and EMBASE. ELIGIBILITY CRITERIA: Randomised controlled trials on adult patients undergoing general anaesthesia with at least one group receiving propofol-based intravenous anaesthesia without further antiemetic prophylaxis, and one group receiving inhalational anaesthesia with single-drug antiemetic prophylaxis. RESULTS: Fourteen studies involving 2051 patients were included. Compared with TIVA, after inhalational anaesthesia and single-drug antiemetic prophylaxis, there was no difference in the overall risk of PONV [relative risk (RR) 1.06, 95% confidence interval (CI) 0.85; 1.32, GRADE rating moderate], nor was there any difference in the risk of postoperative vomiting (RR 1.17, 95% CI 0.78; 1.76), need for rescue medication (RR 1.16, 95% CI 0.68; 1.99) or early PONV (RR 1.06, 95% CI 0.88; 1.27). However, TIVA was associated with an increased risk of late PONV (RR 1.41, 95% CI 1.10; 1.79, P = 0.006). Six studies investigated other side-effects associated with anaesthesia and found no differences between the two groups. Finally, there was evidence of a publication bias that included smaller studies favouring TIVA. CONCLUSION: This meta-analysis confirms the results from indirect comparisons in individual studies: instead of substituting inhalational anaesthesia with propofol-based TIVA, a similar antiemetic effect can be achieved by adding single-drug pharmacological prophylaxis to the inhalational anaesthetic. STUDY REGISTRATION: This systematic review with meta-analysis was registered at PROSPERO (www.crd.york.ac.uk/PROSPERO), study number CRD42015019571. PMID- 27454664 TI - An Important Cause of Child and Youth Homelessness-Reply. PMID- 27454665 TI - A Nonparametric Pharmacokinetic Approach to Determine the Optimal Dosing Regimen for 30-Minute and 3-Hour Meropenem Infusions in Critically Ill Patients. AB - BACKGROUND: Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population. METHODS: This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem. RESULTS: A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 * (Equation is included in full-text article.), Vc = Vc0 * Weight). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat. CONCLUSIONS: This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function. PMID- 27454667 TI - Question and Answers. PMID- 27454666 TI - discomark: nuclear marker discovery from orthologous sequences using draft genome data. AB - High-throughput sequencing has laid the foundation for fast and cost-effective development of phylogenetic markers. Here we present the program discomark, which streamlines the development of nuclear DNA (nDNA) markers from whole-genome (or whole-transcriptome) sequencing data, combining local alignment, alignment trimming, reference mapping and primer design based on multiple sequence alignments to design primer pairs from input orthologous sequences. To demonstrate the suitability of discomark, we designed markers for two groups of species, one consisting of closely related species and one group of distantly related species. For the closely related members of the species complex of Cloeon dipterum s.l. (Insecta, Ephemeroptera), the program discovered a total of 78 markers. Among these, we selected eight markers for amplification and Sanger sequencing. The exon sequence alignments (2526 base pairs) were used to reconstruct a well-supported phylogeny and to infer clearly structured haplotype networks. For the distantly related species, we designed primers for the insect order Ephemeroptera, using available genomic data from four sequenced species. We developed primer pairs for 23 markers that are designed to amplify across several families. The discomark program will enhance the development of new nDNA markers by providing a streamlined, automated approach to perform genome-scale scans for phylogenetic markers. The program is written in Python, released under a public licence (GNU GPL version 2), and together with a manual and example data set available at: https://github.com/hdetering/discomark. PMID- 27454668 TI - Emerging Multifunctional Metal-Organic Framework Materials. AB - Metal-organic frameworks (MOFs), also known as coordination polymers, represent an interesting type of solid crystalline materials that can be straightforwardly self-assembled through the coordination of metal ions/clusters with organic linkers. Owing to the modular nature and mild conditions of MOF synthesis, the porosities of MOF materials can be systematically tuned by judicious selection of molecular building blocks, and a variety of functional sites/groups can be introduced into metal ions/clusters, organic linkers, or pore spaces through pre designing or post-synthetic approaches. These unique advantages enable MOFs to be used as a highly versatile and tunable platform for exploring multifunctional MOF materials. Here, the bright potential of MOF materials as emerging multifunctional materials is highlighted in some of the most important applications for gas storage and separation, optical, electric and magnetic materials, chemical sensing, catalysis, and biomedicine. PMID- 27454669 TI - Effective Pincer Cobalt Precatalysts for Lewis Acid Assisted CO2 Hydrogenation. AB - The pincer ligand MeN[CH2CH2(P(i)Pr2)]2 ((iPr)PNP) was employed to support a series of cobalt(I) complexes, which were crystallographically characterized. A cobalt monochloride species, ((iPr)PNP)CoCl, served as a precursor for the preparation of several cobalt precatalysts for CO2 hydrogenation, including a cationic dicarbonyl cobalt complex, [((iPr)PNP)Co(CO)2](+). When paired with the Lewis acid lithium triflate, [((iPr)PNP)Co(CO)2](+) affords turnover numbers near 30 000 (at 1000 psi, 45 degrees C) for CO2-to-formate hydrogenation, which is a notable increase in activity from previously reported homogeneous cobalt catalysts. Though mechanistic information regarding the function of the precatalysts remains limited, multiple experiments suggest the active species is a molecular, homogeneous [((iPr)PNP)Co] complex. PMID- 27454670 TI - Association Between Rosacea and Parkinson Disease-Reply. PMID- 27454671 TI - Introduction to the special issue: 50th anniversary of APA Division 28: The past, present, and future of psychopharmacology and substance abuse. AB - This is an introduction to the special issue "50th Anniversary of APA Division 28: The Past, Present, and Future of Psychopharmacology and Substance Abuse." Taken together, the scholarly contributions included in this special issue serve as a testament to the important work conducted by our colleagues over the past five decades. Division 28 and its members have advanced and disseminated knowledge on the behavioral effects of drugs, informed efforts to prevent and treat substance abuse, and influenced education and policy issues more generally. As past and current leaders of the division, we are excited to celebrate 50 years of Division 28 and look forward to many more successful decades for our division and its members. (PsycINFO Database Record PMID- 27454672 TI - Behavior within fortuitous environments: The entwined history of Division 28 and the fields of behavioral pharmacology and toxicology. AB - Behavioral pharmacology emerged in the early to mid-20th century as an experimental and observational science, helping to consolidate an empirically based psychological science of behavior. Behavioral psychologists came to play significant roles in toxicology, neuropharmacology, and psychopharmacology. This article traces the first 3 decades of American Psychological Association Division 28. Sources include the Division 28 Oral History Project; formal interviews conducted by the author in the early 2000s with behavioral, experimental, and clinical pharmacologists; and the archived newsletters of Division 28. (PsycINFO Database Record PMID- 27454673 TI - Human drug discrimination: A primer and methodological review. AB - Drug-discrimination procedures empirically evaluate the control that internal drug states exert over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs. Historically, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have also been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This review gives some general history and background concerning the major theoretical concepts and principles of drug-discrimination research as well as its relevance to substance-use disorders. This article also provides a procedural overview and discusses key methodological issues that must be considered when designing and conducting a human drug-discrimination study. Although drug discrimination is unequivocally one of the most sophisticated and useful behavioral assays to investigate the underlying neuropharmacology of drugs in vivo, enthusiasm for its use has steadily declined in the last decade and a half. We conclude by commenting on the current state of drug-discrimination research and suggest potential avenues for future drug-discrimination research. (PsycINFO Database Record PMID- 27454675 TI - Neurocognitive enhancement or impairment? A systematic meta-analysis of prescription stimulant effects on processing speed, decision-making, planning, and cognitive perseveration. AB - Increasing numbers of adults, particularly college students, are misusing prescription stimulants primarily for cognitive/academic enhancement, so it is critical to explore whether empirical findings support neurocognitive benefits of prescription stimulants. Previous meta-analytic studies have supported small benefits from prescription stimulants for the cognitive domains of inhibitory control and memory; however, no meta-analytic studies have examined the effects on processing speed or the potential impairment on other domains of cognition, including planning, decision-making, and cognitive perseveration. Therefore, the present study conducted a meta-analysis of the available literature examining the effects of prescription stimulants on specific measures of processing speed, planning, decision-making, and cognitive perseveration among healthy adult populations. The meta-analysis results indicated a positive influence of prescription stimulant medication on processing speed accuracy, with an overall mean effect size of g = 0.282 (95% CI [0.077, 0.488]; n = 345). Neither improvements nor impairments were revealed for planning time, planning accuracy, advantageous decision-making, or cognitive perseveration; however, findings are limited by the small number of studies examining these outcomes. Findings support that prescription stimulant medication may indeed act as a neurocognitive enhancer for accuracy measures of processing speed without impeding other areas of cognition. Considering that adults are already engaging in illegal use of prescription stimulants for academic enhancement, as well as the potential for stimulant misuse to have serious side effects, the establishment of public policies informed by interdisciplinary research surrounding this issue, whether restrictive or liberal, is of critical importance. (PsycINFO Database Record PMID- 27454677 TI - Cocaine-dependent adults and recreational cocaine users are more likely than controls to choose immediate unsafe sex over delayed safer sex. AB - Cocaine users have a higher incidence of risky sexual behavior and HIV infection than nonusers. Our aim was to measure whether safer sex discount rates-a measure of the likelihood of having immediate unprotected sex versus waiting to have safer sex-differed between controls and cocaine users of varying severity. Of the 162 individuals included in the primary data analyses, 69 met the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria for cocaine dependence, 29 were recreational cocaine users who did not meet the dependence criteria, and 64 were controls. Participants completed the Sexual Discounting Task, which measures a person's likelihood of using a condom when one is immediately available and how that likelihood decreases as a function of delay to condom availability with regard to 4 images chosen by the participants of hypothetical sexual partners differing in perceived desirability and likelihood of having a sexually transmitted infection. When a condom was immediately available, the stated likelihood of condom use sometimes differed between cocaine users and controls, which depended on the image condition. Even after controlling for rates of condom use when one is immediately available, the cocaine-dependent and recreational users groups were more sensitive to delay to condom availability than controls. Safer sex discount rates were also related to intelligence scores. The Sexual Discounting Task identifies delay as a key variable that impacts the likelihood of using a condom among these groups and suggests that HIV prevention efforts may be differentially effective based on an individual's safer sex discount rate. (PsycINFO Database Record PMID- 27454676 TI - The effects of social contact on cocaine intake under extended-access conditions in male rats. AB - Social learning theories of drug use propose that drug use is influenced by the behavior of peers. We previously reported that cocaine self-administration under limited-access conditions can be either facilitated or inhibited by social contact, depending on the behavior of a peer. The purpose of this study was to determine whether social contact influences cocaine self-administration under conditions that are more representative of problematic patterns of drug use. Male rats were assigned to either isolated or pair-housed conditions in which a social partner either had access to cocaine or did not have access to cocaine. Pair housed rats were tested in custom-built operant conditioning chambers that allowed both rats to be tested simultaneously in the same chamber. In Experiment 1, rats were tested for 14 consecutive days during daily 6-hr test sessions. In Experiment 2, different doses of cocaine were tested in 23-hr test sessions conducted every 3 days. All groups of rats escalated their cocaine intake in Experiment 1; however, pair-housed rats with a partner without access to cocaine had lower levels of intake throughout the 14 days of testing. In Experiment 2, pair-housed rats with a partner without access to cocaine had lower levels of cocaine intake than did rats with a partner with access to cocaine, and this effect was observed at all doses of cocaine tested. These data indicate that the behavior of a social partner (i.e., whether or not that partner is also self administering cocaine) influences cocaine self-administration under conditions that model problematic patterns of drug use. (PsycINFO Database Record PMID- 27454678 TI - Acute effects of cannabis on breath-holding duration. AB - Distress intolerance (an individual's perceived or actual inability to tolerate distressing psychological or physiological states) is associated with cannabis use. It is unknown whether a biobehavioral index of distress intolerance, breath holding duration, is acutely influenced (increased or decreased) by cannabis. Such information may further inform understanding of the expression of psychological or physiological distress postcannabis use. This within-subjects study examined whether smoked marijuana with 2.7%-3.0% delta-9 tetrahydrocannabinol (THC), relative to placebo, acutely changed duration of breath holding. Participants (n = 88; 65.9% male) were nontreatment-seeking frequent cannabis users who smoked placebo or active THC cigarette on two separate study days and completed a breath-holding task postsmoking. Controlling for baseline breath-holding duration and participant sex, THC produced significantly shorter breath-holding durations relative to placebo. There was a significant interaction of drug administration * frequency of cannabis use, such that THC decreased breath-holding time among less frequent but not among more frequent users. Findings indicate that cannabis may exacerbate distress intolerance (via shorter breath-holding durations). As compared to less frequent cannabis users, frequent users display tolerance to cannabis' acute effects including increased ability to tolerate respiratory distress when holding breath. Objective measures of distress intolerance are sensitive to contextual factors such as acute drug intoxication, and may inform the link between cannabis use and the expression of psychological distress. (PsycINFO Database Record PMID- 27454679 TI - Targeted Molecular Imaging of Cancer Cells Using MS2-Based (129)Xe NMR. AB - We have synthesized targeted, selective, and highly sensitive (129)Xe NMR nanoscale biosensors using a spherical MS2 viral capsid, Cryptophane A molecules, and DNA aptamers. The biosensors showed strong binding specificity toward targeted lymphoma cells (Ramos line). Hyperpolarized (129)Xe NMR signal contrast and hyper-CEST (129)Xe MRI image contrast indicated its promise as highly sensitive hyperpolarized (129)Xe NMR nanoscale biosensor for future applications in cancer detection in vivo. PMID- 27454680 TI - Colloidal Nanoantennas for Hyperspectral Chemical Mapping. AB - Tip-enhanced Raman spectroscopy enables access to chemical information with nanoscale spatial resolution and single-molecule sensitivities by utilizing optical probes that are capable of confining light to subwavelength dimensions. Because the probes themselves possess nanoscale features, they are notoriously difficult to fabricate, and more critically, can result in poor reproducibility. Here, we demonstrate high-performance, predictable, and readily tunable nanospectroscopy probes that are fabricated by self-assembly. Shaped metal nanoparticles are organized into dense layers and deposited onto scanning probe tips. When coupled to a metal surface, these probes behave like nanoantenna by supporting a strong optical resonance, producing dramatic Raman field enhancements in the range of 10(8)-10(9) with sub-50 nm spatial resolution. In contrast to other nanospectroscopy probes, our colloidal probes can be fabricated in a scalable fashion with a batch-to-batch reproducibility of ~80% and serve as an important demonstration of bottom-up engineering. PMID- 27454681 TI - Information graphs for binary predictors. AB - Binary predictors are used in a wide range of crop protection decision making applications. Such predictors provide a simple analytical apparatus for the formulation of evidence related to risk factors, for use in the process of Bayesian updating of probabilities of crop disease. For diagrammatic interpretation of diagnostic probabilities, the receiver operating characteristic is available. Here, we view binary predictors from the perspective of diagnostic information. After a brief introduction to the basic information theoretic concepts of entropy and expected mutual information, we use an example data set to provide diagrammatic interpretations of expected mutual information, relative entropy, information inaccuracy, information updating and specific information. Our information graphs also illustrate correspondences between diagnostic information and diagnostic probabilities. PMID- 27454682 TI - Human Pathogens on Plants: Designing a Multidisciplinary Strategy for Research. AB - Recent efforts to address concerns about microbial contamination of food plants and resulting foodborne illness have prompted new collaboration and interactions between the scientific communities of plant pathology and food safety. This article provides perspectives from scientists of both disciplines and presents selected research results and concepts that highlight existing and possible future synergisms for audiences of both disciplines. Plant pathology is a complex discipline that encompasses studies of the dissemination, colonization, and infection of plants by microbes such as bacteria, viruses, fungi, and oomycetes. Plant pathologists study plant diseases as well as host plant defense responses and disease management strategies with the goal of minimizing disease occurrences and impacts. Repeated outbreaks of human illness attributed to the contamination of fresh produce, nuts and seeds, and other plant-derived foods by human enteric pathogens such as Shiga toxin-producing Escherichia coli and Salmonella spp. have led some plant pathologists to broaden the application of their science in the past two decades, to address problems of human pathogens on plants (HPOPs). Food microbiology, which began with the study of microbes that spoil foods and those that are critical to produce food, now also focuses study on how foods become contaminated with pathogens and how this can be controlled or prevented. Thus, at the same time, public health researchers and food microbiologists have become more concerned about plant-microbe interactions before and after harvest. New collaborations are forming between members of the plant pathology and food safety communities, leading to enhanced research capacity and greater understanding of the issues for which research is needed. The two communities use somewhat different vocabularies and conceptual models. For example, traditional plant pathology concepts such as the disease triangle and the disease cycle can help to define cross-over issues that pertain also to HPOP research, and can suggest logical strategies for minimizing the risk of microbial contamination. Continued interactions and communication among these two disciplinary communities is essential and can be achieved by the creation of an interdisciplinary research coordination network. We hope that this article, an introduction to the multidisciplinary HPOP arena, will be useful to researchers in many related fields. PMID- 27454683 TI - Human Pathogens on Plants: Designing a Multidisciplinary Strategy for Research. AB - Recent efforts to address concerns about microbial contamination of food plants and resulting foodborne illness have prompted new collaboration and interactions between the scientific communities of plant pathology and food safety. This article provides perspectives from scientists of both disciplines and presents selected research results and concepts that highlight existing and possible future synergisms for audiences of both disciplines. Plant pathology is a complex discipline that encompasses studies of the dissemination, colonization, and infection of plants by microbes such as bacteria, viruses, fungi, and oomycetes. Plant pathologists study plant diseases as well as host plant defense responses and disease management strategies with the goal of minimizing disease occurrences and impacts. Repeated outbreaks of human illness attributed to the contamination of fresh produce, nuts and seeds, and other plant-derived foods by human enteric pathogens such as Shiga toxin-producing Escherichia coli and Salmonella spp. have led some plant pathologists to broaden the application of their science in the past two decades, to address problems of human pathogens on plants (HPOPs). Food microbiology, which began with the study of microbes that spoil foods and those that are critical to produce food, now also focuses study on how foods become contaminated with pathogens and how this can be controlled or prevented. Thus, at the same time, public health researchers and food microbiologists have become more concerned about plant-microbe interactions before and after harvest. New collaborations are forming between members of the plant pathology and food safety communities, leading to enhanced research capacity and greater understanding of the issues for which research is needed. The two communities use somewhat different vocabularies and conceptual models. For example, traditional plant pathology concepts such as the disease triangle and the disease cycle can help to define cross-over issues that pertain also to HPOP research, and can suggest logical strategies for minimizing the risk of microbial contamination. Continued interactions and communication among these two disciplinary communities is essential and can be achieved by the creation of an interdisciplinary research coordination network. We hope that this article, an introduction to the multidisciplinary HPOP arena, will be useful to researchers in many related fields. PMID- 27454685 TI - Focus on Food Safety: Human Pathogens on Plants. PMID- 27454684 TI - The Importance of Multilocus Sequence Typing: Cautionary Tales from the Bacterium Xylella fastidiosa. AB - Microbial identification methods have evolved rapidly over the last few decades. One such method is multilocus sequence typing (MLST). MLST is a powerful tool for understanding the evolutionary dynamics of pathogens and to gain insight into their genetic diversity. We illustrate the importance of accurate typing by reporting on three problems that have arisen in the study of a single bacterial species, the plant pathogen Xylella fastidiosa. Two of these were particularly serious since they concerned contamination of important research material that has had detrimental consequences for Xylella research: the contamination of DNA used in the sequencing of an X. fastidiosa genome (Ann-1) with DNA from another X. fastidiosa strain, and the unrecognized mislabeling of a strain (Temecula1) distributed from a culture collection (ATCC). We advocate the routine use of MLST to define strains maintained in culture collections and emphasize the importance of confirming the purity of DNA submitted for sequencing. We also present a third example that illustrates the value of MLST in guiding the choice of taxonomic types. Beyond these situations, there is a strong case for MLST whenever an isolate is used experimentally, especially where genotypic differences are suspected to influence the outcome. PMID- 27454702 TI - Genome-Wide Association Mapping of Rice Resistance Genes Against Magnaporthe oryzae Isolates from Four African Countries. AB - Rice blast disease is emerging as a major constraint to rice production in Africa. Although a traditional gene-tagging strategy using biparental crosses can effectively identify resistance (R) genes or quantitative trait loci (QTL) against Magnaporthe oryzae, the mapping procedure required is time consuming and requires many populations to investigate the genetics of resistance. In this report, we conducted a genome-wide association study (GWAS) to rapidly map rice genes conferring resistance against eight M. oryzae isolates from four African countries. We inoculated 162 rice cultivars, which were part of the rice diversity panel 1 (RDP1) and were previously genotyped with the 44,000 single nucleotide polymorphism (SNP) chip, with the eight isolates. The GWAS identified 31 genomic regions associated with blast resistance (RABR) in the rice genome. In addition, we used polymerase chain reaction analysis to confirm the association between the Pish gene and a major RABR on chromosome 1 that was associated with resistance to four M. oryzae isolates. Our study has demonstrated the power of GWAS for the rapid identification of rice blast R or QTL genes that are effective against African populations of M. oryzae. The identified SNP markers associated with RABR can be used in breeding for resistance against rice blast in Africa. PMID- 27454674 TI - Clinical applications of hallucinogens: A review. AB - Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value. (PsycINFO Database Record PMID- 27454703 TI - Molecular Mapping of High Resistance to Bacterial Leaf Spot in Lettuce PI 358001 1. AB - Lettuce (Lactuca sativa L.) is a diploid (2n = 18) with a genome size of 2,600 Mbp, and belongs to the family Compositae. Bacterial leaf spot (BLS), caused by Xanthomonas campestris pv. vitians, is a major disease of lettuce worldwide. Leaf lettuce PI 358001-1 has been characterized as an accession highly resistant to BLS and has white seed. In order to understand inheritance of the high resistance in this germplasm line, an F3 population consisting of 163 families was developed from the cross PI 358001-1 * 'Tall Guzmaine' (a susceptible Romaine lettuce variety with black seed). The segregation ratio of reaction to disease by seedling inoculation with X. campestris pv. vitians L7 strain in the F3 families was shown to be 32:82:48 homozygous resistant/heterozygous/homozygous susceptible, fitting to 1:2:1 (n = 162, chi2 = 3.19, P = 0.20). The segregation ratio of seed color by checking F2 plants was 122:41 black/white, fitting to 3:1 (n = 163, chi2 = 0.002, P = 0.96). The results indicated that both BLS resistance and seed color were inherited as a dominant gene mode. A genetic linkage map based on 124 randomly selected F2 plants was developed to enable molecular mapping of the BLS resistance and the seed color trait. In total, 199 markers, comprising 176 amplified fragment length polymorphisms, 16 simple-sequence repeats, 5 resistant gene candidate markers, and 2 cleaved amplified polymorphic sequences (CAPS) markers were assigned to six linkage groups. The dominant resistance gene to BLS (Xcvr) was mapped on linkage group 2 and the gene locus y for seed color was identified on linkage group 5. Due to the nature of a single gene inheritance, the high-resistance gene should be readily transferred to adapted lettuce cultivars to battle against the devastating disease of lettuce. PMID- 27454704 TI - Model Calculations Suggest that the Central Carbon in the FeMo-Cofactor of Nitrogenase Becomes Protonated in the Process of Nitrogen Fixation. AB - Nitrogen activation by nitrogenase is one of the most important enzymatic processes on earth. In spite of the determination of X-ray structures of increasingly higher resolution, the nitrogenase mechanism is still not understood. In the most recent X-ray structures it has been shown that a carbon resides in the center of the MoFe-cofactor. Its role is not known. Recent spectroscopic studies, mainly EPR, have come closest to obtaining a molecular mechanism for activating nitrogen. Two hydrides have been shown to play a key role in this context. In the present study, the mechanism for nitrogenase has been investigated by hybrid DFT using a cluster model. This approach has been shown to be very successful for predicting mechanisms for other redox-active enzymes, such as the one for photosystem II, but has so far not been used in its most recent form for nitrogenase. The mechanism obtained has large similarities to the one suggested by spectroscopy, with a reductive elimination of two hydrides just before nitrogen binding. However, a very surprising finding is that the central carbon becomes protonated and has to move out of the cavity as a methyl group before the hydrides can be formed. This has not been suggested before. PMID- 27454706 TI - Increased conditioned pain modulation in athletes. AB - The potential relationship between physical activity and endogenous pain modulatory capacity remains unclear. Therefore, the aim of the current study was to compare the pain modulatory responses of athletes and non-athletes. Conditioned pain modulation (CPM) was assessed in 15 athletes and 15 non-athletes at rest. Participation was restricted to pain-free males between 18 and 40 years of age. To measure CPM capacity, a sequential CPM testing protocol was implemented, whereby a test stimulus (pressure pain threshold [PPT]) was presented before and immediately after a conditioning stimulus (4-min cold pressor test). Pain intensity ratings were obtained at 15-s intervals throughout the cold-pressor task using a numerical rating scale. Athletes demonstrated higher baseline PPTs compared to non-athletes (P = .03). Athletes also gave lower mean (P < .001) and maximum (P < .001) pain intensity ratings in response to the conditioning stimulus. The conditioning stimulus had a stronger inhibitory effect on the test stimulus in athletes, showing enhanced CPM in athletes compared to non-athletes (P < .05). This finding of enhanced CPM in athletes helps clarify previous mixed findings. Potential implications for exercise performance and injury are discussed. PMID- 27454705 TI - Use of Antibiotics Among Patients Hospitalized for Exacerbations of Asthma. PMID- 27454707 TI - Porous Carbon-Supported Gold Nanoparticles for Oxygen Reduction Reaction: Effects of Nanoparticle Size. AB - Porous carbon-supported gold nanoparticles of varied sizes were prepared using thiolate-capped molecular Au25, Au38, and Au144 nanoclusters as precursors. The organic capping ligands were removed by pyrolysis at controlled temperatures, resulting in good dispersion of gold nanoparticles within the porous carbons, although the nanoparticle sizes were somewhat larger than those of the respective nanocluster precursors. The resulting nanocomposites displayed apparent activity in the electroreduction of oxygen in alkaline solutions, which increased with decreasing nanoparticle dimensions. Among the series of samples tested, the nanocomposite prepared with Au25 nanoclusters displayed the best activity, as manifested by the positive onset potential at +0.95 V vs RHE, remarkable sustainable stability, and high numbers of electron transfer at (3.60-3.92) at potentials from +0.50 to +0.80 V. The performance is comparable to that of commercial 20 wt % Pt/C. The results demonstrated the unique feasibility of porous carbon-supported gold nanoparticles as high-efficiency ORR catalysts. PMID- 27454708 TI - Estrogenic Activity of Hyperforin in MCF-7 Human Breast Cancer Cells Transfected with Estrogen Receptor. AB - Hyperforin, a major active compound of St. John's wort extract, affects estrogenic activity. In this study, the compound evoked estrogen response element dependent luciferase activity and cell proliferation in MCF-7 cells. Hyperforin induced cell proliferation was significantly inhibited by the estrogen receptor antagonist ICI 182,780. These results suggested that hyperforin had estrogenic and cell proliferation activities, which were stimulated via the estrogen receptor. Compared to 17beta-estradiol, hyperforin showed significantly lower estrogenic activity and cell proliferation. The mechanism underlying the estrogenic activity of hyperforin was unknown, therefore, in this study, for the first time, the expression and post-translational modification of proteins were determined and compared among control, 17beta-estradiol-treated, and hyperforin treated cells using proteomic techniques. A total of 453 proteins were identified, of which 282 proteins were significantly modulated in hyperforin treated cells compared to 17beta-estradiol-treated cells. Ingenuity pathway analysis also demonstrated that hyperforin treatment induced less cell proliferation than 17beta-estradiol by downregulating estrogen receptor 1. Protein network analysis showed that cell proliferation was regulated mainly by cyclin D1 and extracellular signal-regulated kinases. In conclusion, although, hyperforin exhibited lower estrogenic activity than 17beta-estradiol, the compound induced lower levels of cancer cell proliferation in vitro. PMID- 27454709 TI - Spatio-Temporal Variation of Terpenoids in Wild Plants of Pentalinon andrieuxii. AB - Pentalinon andrieuxii (Mull.Arg.) B.F.Hansen & Wunderlin (Apocynaceae) is a vine native to the Yucatan peninsula, where it is widely used in Mayan traditional medicine to treat, among other ailments, the wounds caused by cutaneous leishmaniasis. Among the secondary metabolites isolated from P. andrieuxii are the triterpene betulinic acid and the chemically unusual tri-norsesquiterpene urechitol A; however, to date, there is no existing knowledge about the accumulation dynamics of the ubiquitous betulinic acid or the novel urechitol A in the plant. In this article, we report on the accumulation of both secondary metabolites in wild individuals of P. andrieuxii; our results show that while the content of betulinic acid in plant leaves bears no apparent relation to plant ontogeny, the content of urechitol A in root tissue is clearly related to plant development. PMID- 27454710 TI - Life-threatening false alarm rejection in ICU: using the rule-based and multi channel information fusion method. AB - False alarm (FA) rates as high as 86% have been reported in intensive care unit monitors. High FA rates decrease quality of care by slowing staff response times while increasing patient burdens and stresses. In this study, we proposed a rule based and multi-channel information fusion method for accurately classifying the true or false alarms for five life-threatening arrhythmias: asystole (ASY), extreme bradycardia (EBR), extreme tachycardia (ETC), ventricular tachycardia (VTA) and ventricular flutter/fibrillation (VFB). The proposed method consisted of five steps: (1) signal pre-processing, (2) feature detection and validation, (3) true/false alarm determination for each channel, (4) 'real-time' true/false alarm determination and (5) 'retrospective' true/false alarm determination (if needed). Up to four signal channels, that is, two electrocardiogram signals, one arterial blood pressure and/or one photoplethysmogram signal were included in the analysis. Two events were set for the method validation: event 1 for 'real-time' and event 2 for 'retrospective' alarm classification. The results showed that 100% true positive ratio (i.e. sensitivity) on the training set were obtained for ASY, EBR, ETC and VFB types, and 94% for VTA type, accompanied by the corresponding true negative ratio (i.e. specificity) results of 93%, 81%, 78%, 85% and 50% respectively, resulting in the score values of 96.50, 90.70, 88.89, 92.31 and 64.90, as well as with a final score of 80.57 for event 1 and 79.12 for event 2. For the test set, the proposed method obtained the score of 88.73 for ASY, 77.78 for EBR, 89.92 for ETC, 67.74 for VFB and 61.04 for VTA types, with the final score of 71.68 for event 1 and 75.91 for event 2. PMID- 27454711 TI - First Cytogenetic Description of Microsternarchus bilineatus (Gymnotiformes: Hypopomidae) from Negro River (Brazilian Amazon). AB - Microsternarchus bilineatus is a neotropical electric fish species widely distributed in Amazonian ecosystems. This work reports the first karyotypic description of the species M. bilineatus, which presented 2n = 48 chromosomes, with a distinct karyotypic formula between the sexes: males with 21 metacentric (m)/submetacentric (sm) + 27 subtelocentric (st)/acrocentric (a) and fundamental number (FN) = 69 and females with 20 m/sm + 28 st/a and FN = 68. We found a probable recent sex system of XX/XY type. The nucleoli organizer regions (NORs) were multiple terminally located, and the heterochromatic blocks were mostly pericentromeric. The 18S rDNA markings confirmed NORs and their distinction between sexes, which suggested some differential role of this gene related to gender in this species. The 5S rDNA presented terminal markings on a single chromosome pair, with no distinction between sexes, and the telomeric probes have shown a uniform pattern in males and females. PMID- 27454712 TI - Zika Virus and Pregnancy: What Obstetric Health Care Providers Need to Know. PMID- 27454713 TI - Postpartum Hemorrhage and Use of Serotonin Reuptake Inhibitor Antidepressants in Pregnancy. PMID- 27454714 TI - In Reply. PMID- 27454715 TI - Association of the Duration of Active Pushing With Obstetric Outcomes. PMID- 27454716 TI - In Reply. PMID- 27454717 TI - Cervical Pessary and Vaginal Progesterone in Twin Pregnancies With a Short Cervix. PMID- 27454718 TI - Cervical Pessary and Vaginal Progesterone in Twin Pregnancies With a Short Cervix. PMID- 27454719 TI - In Reply. PMID- 27454721 TI - In Reply. PMID- 27454720 TI - Ondansetron Use in Pregnancy andOndansetron Use in Pregnancy and Birth Defects: A Systematic Review. PMID- 27454723 TI - In Reply. PMID- 27454722 TI - Editor's Note on Elective Delivery Before 39 Weeks of Gestation. PMID- 27454728 TI - Committee Opinion No. 668 Summary: Menstrual Manipulation for Adolescents With Physical and Developmental Disabilities. AB - For an adolescent with physical disabilities, intellectual disabilities, or both, and for her caregivers, menstruation can present significant challenges. If, after an evaluation, the adolescent, her family, and the obstetrician gynecologist have decided that menstrual intervention is warranted, advantages and disadvantages of hormonal methods should be reviewed and individualized to each patient's specific needs. Complete amenorrhea may be difficult to achieve, and realistic expectations should be addressed with the patient and her caregivers. The goal in menstrual manipulation should be optimal suppression, which means a reduction in the amount and total days of menstrual flow. Menstrual suppression before menarche and endometrial ablation are not recommended as treatments. Optimal gynecologic health care for adolescents with disabilities is comprehensive; maintains confidentiality; is an act of dignity and respect toward the patient; maximizes the patient's autonomy; avoids harm; and assesses and addresses the patient's knowledge of puberty, menstruation, sexuality, safety, and consent. PMID- 27454729 TI - Committee Opinion No. 669 Summary: Planned Home Birth. AB - In the United States, approximately 35,000 births (0.9%) per year occur in the home. Approximately one fourth of these births are unplanned or unattended. Although the American College of Obstetricians and Gynecologists believes that hospitals and accredited birth centers are the safest settings for birth, each woman has the right to make a medically informed decision about delivery. Importantly, women should be informed that several factors are critical to reducing perinatal mortality rates and achieving favorable home birth outcomes. These factors include the appropriate selection of candidates for home birth; the availability of a certified nurse-midwife, certified midwife or midwife whose education and licensure meet International Confederation of Midwives' Global Standards for Midwifery Education, or physician practicing obstetrics within an integrated and regulated health system; ready access to consultation; and access to safe and timely transport to nearby hospitals. The Committee on Obstetric Practice considers fetal malpresentation, multiple gestation, or prior cesarean delivery to be an absolute contraindication to planned home birth. PMID- 27454730 TI - Committee Opinion No. 670 Summary: Immediate Postpartum Long-Acting Reversible Contraception. AB - Immediate postpartum long-acting reversible contraception (LARC) has the potential to reduce unintended and short-interval pregnancy. Women should be counseled about all forms of postpartum contraception in a context that allows informed decision making. Immediate postpartum LARC should be offered as an effective option for postpartum contraception; there are few contraindications to postpartum intrauterine devices and implants. Obstetrician-gynecologists and other obstetric care providers should discuss LARC during the antepartum period and counsel all pregnant women about options for immediate postpartum initiation. Education and institutional protocols are needed to raise clinician awareness and to improve access to immediate postpartum LARC insertion. Obstetrician gynecologists and other obstetric care providers should incorporate immediate postpartum LARC into their practices, counsel women appropriately about advantages and risks, and advocate for institutional and payment policy changes to support provision. PMID- 27454731 TI - Technology Assessment No. 12 Summary: Sonohysterography. AB - The primary goal of sonohysterography is to visualize the endometrial cavity in more detail than is possible with routine transvaginal ultrasonography. Sonohysterography also can be used to assess tubal patency. The indications for sonohysterography include, but are not limited to, evaluation of the following: abnormal uterine bleeding; uterine cavity, especially with regard to uterine leiomyomata, polyps, and synechiae; abnormalities detected on transvaginal ultrasonography, including focal or diffuse endometrial or intracavitary abnormalities; congenital abnormalities of the uterus; infertility; recurrent pregnancy loss; and suboptimal visualization of the endometrium on transvaginal ultrasonography. Sonohysterography should not be performed in a woman who is pregnant or who could be pregnant. Credentialing obstetrician-gynecologists to perform or supervise diagnostic sonohysterography should be based on education, training, experience, and demonstrated competence in performing and interpreting trans-vaginal ultrasonography and sonohysterography. The obstetrician gynecologist should be skilled in the transcervical placement of catheters. The sonohysterography procedure, including benefits and risks, should be explained fully to the patient before the procedure is performed. PMID- 27454732 TI - Committee Opinion No. 668: Menstrual Manipulation for Adolescents With Physical and Developmental Disabilities. AB - For an adolescent with physical disabilities, intellectual disabilities, or both, and for her caregivers, menstruation can present significant challenges. If, after an evaluation, the adolescent, her family, and the obstetrician gynecologist have decided that menstrual intervention is warranted, advantages and disadvantages of hormonal methods should be reviewed and individualized to each patient's specific needs. Complete amenorrhea may be difficult to achieve, and realistic expectations should be addressed with the patient and her caregivers. The goal in menstrual manipulation should be optimal suppression, which means a reduction in the amount and total days of menstrual flow. Menstrual suppression before menarche and endometrial ablation are not recommended as treatments. Optimal gynecologic health care for adolescents with disabilities is comprehensive; maintains confidentiality; is an act of dignity and respect toward the patient; maximizes the patient's autonomy; avoids harm; and assesses and addresses the patient's knowledge of puberty, menstruation, sexuality, safety, and consent. PMID- 27454733 TI - Committee Opinion No. 669: Planned Home Birth. AB - In the United States, approximately 35,000 births (0.9%) per year occur in the home. Approximately one fourth of these births are unplanned or unattended. Although the American College of Obstetricians and Gynecologists believes that hospitals and accredited birth centers are the safest settings for birth, each woman has the right to make a medically informed decision about delivery. Importantly, women should be informed that several factors are critical to reducing perinatal mortality rates and achieving favorable home birth outcomes. These factors include the appropriate selection of candidates for home birth; the availability of a certified nurse-midwife, certified midwife or midwife whose education and licensure meet International Confederation of Midwives' Global Standards for Midwifery Education, or physician practicing obstetrics within an integrated and regulated health system; ready access to consultation; and access to safe and timely transport to nearby hospitals. The Committee on Obstetric Practice considers fetal malpresentation, multiple gestation, or prior cesarean delivery to be an absolute contraindication to planned home birth. PMID- 27454734 TI - Committee Opinion No. 670: Immediate Postpartum Long-Acting Reversible Contraception. AB - Immediate postpartum long-acting reversible contraception (LARC) has the potential to reduce unintended and short-interval pregnancy. Women should be counseled about all forms of postpartum contraception in a context that allows informed decision making. Immediate postpartum LARC should be offered as an effective option for postpartum contraception; there are few contraindications to postpartum intrauterine devices and implants. Obstetrician-gynecologists and other obstetric care providers should discuss LARC during the antepartum period and counsel all pregnant women about options for immediate postpartum initiation. Education and institutional protocols are needed to raise clinician awareness and to improve access to immediate postpartum LARC insertion. Obstetrician gynecologists and other obstetric care providers should incorporate immediate postpartum LARC into their practices, counsel women appropriately about advantages and risks, and advocate for institutional and payment policy changes to support provision. PMID- 27454735 TI - Technology Assessment No. 12: Sonohysterography. AB - The primary goal of sonohysterography is to visualize the endometrial cavity in more detail than is possible with routine transvaginal ultrasonography. Sonohysterography also can be used to assess tubal patency. The indications for sonohysterography include, but are not limited to, evaluation of the following: abnormal uterine bleeding; uterine cavity, especially with regard to uterine leiomyomata, polyps, and synechiae; abnormalities detected on transvaginal ultrasonography, including focal or diffuse endometrial or intracavitary abnormalities; congenital abnormalities of the uterus; infertility; recurrent pregnancy loss; and suboptimal visualization of the endometrium on transvaginal ultrasonography. Sonohysterography should not be performed in a woman who is pregnant or who could be pregnant. Credentialing obstetrician-gynecologists to perform or supervise diagnostic sonohysterography should be based on education, training, experience, and demonstrated competence in performing and interpreting trans-vaginal ultrasonography and sonohysterography. The obstetrician gynecologist should be skilled in the transcervical placement of catheters. The sonohysterography procedure, including benefits and risks, should be explained fully to the patient before the procedure is performed. PMID- 27454736 TI - Two for the Price of One: A Neuroprotective Chaperone Kit within NAD Synthase Protein NMNAT2. AB - One of the most fascinating properties of the brain is the ability to function smoothly across decades of a lifespan. Neurons are nondividing mature cells specialized in fast electrical and chemical communication at synapses. Often, neurons and synapses operate at high levels of activity through sophisticated arborizations of long axons and dendrites that nevertheless stay healthy throughout years. On the other hand, aging and activity-dependent stress strike onto the protein machineries turning proteins unfolded and prone to form pathological aggregates associated with neurodegeneration. How do neurons protect from those insults and remain healthy for their whole life? Ali and colleagues now present a molecular mechanism by which the enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) acts not only as a NAD synthase involved in axonal maintenance but as a molecular chaperone helping neurons to overcome protein unfolding and protein aggregation. PMID- 27454737 TI - Genetic improvement of tomato by targeted control of fruit softening. AB - Controlling the rate of softening to extend shelf life was a key target for researchers engineering genetically modified (GM) tomatoes in the 1990s, but only modest improvements were achieved. Hybrids grown nowadays contain 'non-ripening mutations' that slow ripening and improve shelf life, but adversely affect flavor and color. We report substantial, targeted control of tomato softening, without affecting other aspects of ripening, by silencing a gene encoding a pectate lyase. PMID- 27454738 TI - Co-ChIP enables genome-wide mapping of histone mark co-occurrence at single molecule resolution. AB - Histone modifications play an important role in chromatin organization and transcriptional regulation, but despite the large amount of genome-wide histone modification data collected in different cells and tissues, little is known about co-occurrence of modifications on the same nucleosome. Here we present a genome wide quantitative method for combinatorial indexed chromatin immunoprecipitation (co-ChIP) to characterize co-occurrence of histone modifications on nucleosomes. Using co-ChIP, we study the genome-wide co-occurrence of 14 chromatin marks (70 pairwise combinations), and find previously undescribed co-occurrence patterns, including the co-occurrence of H3K9me1 and H3K27ac in super-enhancers. Finally, we apply co-ChIP to measure the distribution of the bivalent H3K4me3-H3K27me3 domains in two distinct mouse embryonic stem cell (mESC) states and in four adult tissues. We observe dynamic changes in 5,786 regions and discover both loss and de novo gain of bivalency in key tissue-specific regulatory genes, suggesting a functional role for bivalent domains during different stages of development. These results show that co-ChIP can reveal the complex interactions between histone modifications. PMID- 27454741 TI - Porphyrins as Templates for Site-Selective Atomic Layer Deposition: Vapor Metalation and in Situ Monitoring of Island Growth. AB - Examinations of enzymatic catalysts suggest one key to efficient catalytic activity is discrete size metallo clusters. Mimicking enzymatic cluster systems is synthetically challenging because conventional solution methods are prone to aggregation or require capping of the cluster, thereby limiting its catalytic activity. We introduce site-selective atomic layer deposition (ALD) on porphyrins as an alternative approach to grow isolated metal oxide islands that are spatially separated. Surface-bound tetra-acid free base porphyrins (H2TCPP) may be metalated with Mn using conventional ALD precursor exposure to induce homogeneous hydroxide synthetic handles which acts as a nucleation point for subsequent ALD MnO island growth. Analytical fitting of in situ QCM mass uptake reveals island growth to be hemispherical with a convergence radius of 1.74 nm. This growth mode is confirmed with synchrotron grazing-incidence small-angle X ray scattering (GISAXS) measurements. Finally, we extend this approach to other ALD chemistries to demonstrate the generality of this route to discrete metallo island materials. PMID- 27454739 TI - Systematic improvement of amplicon marker gene methods for increased accuracy in microbiome studies. AB - Amplicon-based marker gene surveys form the basis of most microbiome and other microbial community studies. Such PCR-based methods have multiple steps, each of which is susceptible to error and bias. Variance in results has also arisen through the use of multiple methods of next-generation sequencing (NGS) amplicon library preparation. Here we formally characterized errors and biases by comparing different methods of amplicon-based NGS library preparation. Using mock community standards, we analyzed the amplification process to reveal insights into sources of experimental error and bias in amplicon-based microbial community and microbiome experiments. We present a method that improves on the current best practices and enables the detection of taxonomic groups that often go undetected with existing methods. PMID- 27454742 TI - Plasma amyloid beta peptides: an Alzheimer's conundrum or a more accessible Alzheimer's biomarker? PMID- 27454743 TI - Misuse of gabapentin and pregabalin: a marker for a more serious malaise? PMID- 27454740 TI - Multiplexed and scalable super-resolution imaging of three-dimensional protein localization in size-adjustable tissues. AB - The biology of multicellular organisms is coordinated across multiple size scales, from the subnanoscale of molecules to the macroscale, tissue-wide interconnectivity of cell populations. Here we introduce a method for super resolution imaging of the multiscale organization of intact tissues. The method, called magnified analysis of the proteome (MAP), linearly expands entire organs fourfold while preserving their overall architecture and three-dimensional proteome organization. MAP is based on the observation that preventing crosslinking within and between endogenous proteins during hydrogel-tissue hybridization allows for natural expansion upon protein denaturation and dissociation. The expanded tissue preserves its protein content, its fine subcellular details, and its organ-scale intercellular connectivity. We use off the-shelf antibodies for multiple rounds of immunolabeling and imaging of a tissue's magnified proteome, and our experiments demonstrate a success rate of 82% (100/122 antibodies tested). We show that specimen size can be reversibly modulated to image both inter-regional connections and fine synaptic architectures in the mouse brain. PMID- 27454744 TI - Just Scan It!-Weapon Reconstruction in Computed Tomography on Historical and Current Swiss Military Guns. AB - Cross-sectional imaging, such as computed tomography, has been increasingly implemented in both historic and recent postmortem forensic investigations. It aids in determining cause and manner of death as well as in correlating injuries to possible weapons. This study illuminates the feasibility of reconstructing guns in computed tomography and gives a distinct overview of historic and recent Swiss Army guns. PMID- 27454745 TI - Sexual Transmission of Zika Virus and Persistence in Semen, New Zealand, 2016. PMID- 27454746 TI - Conjugated assembly of colloidal zinc oxide quantum dots and multiwalled carbon nanotubes for an excellent photosensitive ultraviolet photodetector. AB - Conjugation of highly dense colloidal zinc oxide quantum dots (ZnO QDs) on multiwalled carbon nanotubes (ZnO QDs@MWCNTs) is achieved for high performance ultraviolet (UV) photodetection. Significant improvement in the photoresponse of the ZnO QDs@MWCNTs photodetector (PD) is established as compared to a pristine ZnO QDs PD. The conjugation of two constituents allows the direct transfer of photoinduced charge carriers in ZnO QDs to MWCNTs for an efficient electrical path that considerably reduces charge recombination during UV exposure. Linearity in the response current with both the UV illumination intensity as well as external bias voltage reveals the photoelastic behavior of the ZnO QDs@MWCNTs PD. Moreover, the PD displays faster response and recovery times of 1.6 s and 1.9 s, respectively, than the most conventional PDs. In addition, spectral photoresponse analysis of the PD presents visible-blind behavior. Overall, conjugation of the hybrid heterostructure presented excellent photoelastic, high performance and visible-blind UV photodetection. PMID- 27454747 TI - (17)O NMR Investigation of Water Structure and Dynamics. AB - The structure and dynamics of the bound water in barium chlorate monohydrate were studied with (17)O nuclear magnetic resonance (NMR) spectroscopy in samples that are stationary and spinning at the magic-angle in magnetic fields ranging from 14.1 to 21.1 T. (17)O NMR parameters of the water were determined, and the effects of torsional oscillations of the water molecule on the (17)O quadrupolar coupling constant (CQ) were delineated with variable temperature MAS NMR. With decreasing temperature and reduction of the librational motion, we observe an increase in the experimentally measured CQ explaining the discrepancy between experiments and predictions from density functional theory. In addition, at low temperatures and in the absence of (1)H decoupling, we observe a well-resolved (1)H-(17)O dipole splitting in the spectra, which provides information on the structure of the H2O molecule. The splitting arises because of the homogeneous nature of the coupling between the two (1)H-(17)O dipoles and the (1)H-(1)H dipole. PMID- 27454748 TI - Empowering the dementia care workforce to manage behavioral symptoms of dementia: Development and training outcomes from the VOICE Dementia Care Program. AB - Nonpharmacological approaches for managing behavioral symptoms of dementia remain widely underutilized, due in part to near-universal training needs reported by dementia caregivers in recent research. This article examines the development, core components, and initial outcomes of an evidence-informed, competency-based training program in the prevention and management of behavioral symptoms of dementia among care managers and nurses within an aging services system. The Vital Outcomes Inspired by Caregiver Engagement (VOICE) Dementia Care Training Program was developed based on identification of state-of-the-art approaches to managing behaviors through expert review of the literature and structured needs assessment. Results reveal robust improvements in knowledge, attitudes, and self efficacy among training participants, with largest effect sizes (d = 1.8) on domains of knowledge and self-efficacy to manage behaviors. Findings support the feasibility and effectiveness of training in improving the abilities and confidence of aging services providers in dementia care and, specifically, in the nonpharmacological management of dementia-related behaviors. PMID- 27454749 TI - Structural specialties, curiosities, and record-breaking features of crustacean reproduction. AB - Crustaceans are a morphologically, physiologically, and ecologically highly diverse animal group and correspondingly diverse are their reproductive characteristics. They have evolved structural specialties with respect to penis construction, sperm form, sperm storage, fertilization, and brood care. Unique in the animal kingdom are safety lines that safeguard hatching and first molting. Further curiosities are dwarf males in parasitic and sessile crustaceans and bacteria-induced feminization and gigantism of crustacean hosts. Record-breaking features are relative penis length, sperm size, clutch size, chromosome number, viability of dormant eggs, and fossil ages of penis, sperm, and brooded embryos. These examples from a single invertebrate subphylum and a single life history aspect illustrate that morphological solutions to functional requirements can be as spectacular as behavioral adaptations. They may provide valuable sources for comparative morphologists, ecologists, evolutionary biologists, and applied biologists to advance topical issues such as sperm competition, posthumous paternity, evolution of brood care, adaptation to freshwater, infectious feminization, sustainable male-based fishery, maintenance of genetic diversity under conditions of limited mating opportunity, and long-term impact of pollution on genotype and phenotype. J. Morphol. 277:1399-1422, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27454751 TI - Visualization of one-dimensional diffusion and spontaneous segregation of hydrogen in single crystals of VO2. AB - Hydrogen intercalation in solids is common, complicated, and very difficult to monitor. In a new approach to the problem, we have studied the profile of hydrogen diffusion in single-crystal nanobeams and plates of VO2, exploiting the fact that hydrogen doping in this material leads to visible darkening near room temperature connected with the metal-insulator transition at 65 degrees C. We observe hydrogen diffusion along the rutile c-axis but not perpendicular to it, making this a highly one-dimensional diffusion system. We obtain an activated diffusion coefficient, [Formula: see text] applicable in metallic phase. In addition, we observe dramatic supercooling of the hydrogen-induced metallic phase and spontaneous segregation of the hydrogen into stripes implying that the diffusion process is highly nonlinear, even in the absence of defects. Similar complications may occur in hydrogen motion in other materials but are not revealed by conventional measurement techniques. PMID- 27454750 TI - Polymer-Enhanced Stability of Inorganic Perovskite Nanocrystals and Their Application in Color Conversion LEDs. AB - Cesium lead halide (CsPbX3, X = Cl, Br, I) nanocrystals (NCs) offer exceptional optical properties for several potential applications but their implementation is hindered by a low chemical and structural stability and limited processability. In the present work, we developed a new method to efficiently coat CsPbX3 NCs, which resulted in their increased chemical and optical stability as well as processability. The method is based on the incorporation of poly(maleic anhydride alt-1-octadecene) (PMA) into the synthesis of the perovskite NCs. The presence of PMA in the ligand shell stabilizes the NCs by tightening the ligand binding, limiting in this way the NC surface interaction with the surrounding media. We further show that these NCs can be embedded in self-standing silicone/glass plates as down-conversion filters for the fabrication of monochromatic green and white light emitting diodes (LEDs) with narrow bandwidths and appealing color characteristics. PMID- 27454752 TI - A new orange emitting luciferase from the Southern-Amazon Pyrophorus angustus (Coleoptera: Elateridae) click-beetle: structure and bioluminescence color relationship, evolutional and ecological considerations. AB - Bioluminescent click-beetles display a wide variation of bioluminescence colors ranging from green to orange, including an unusual intra-specific color variation in the Jamaican Pyrophorus plagiophthalamus. Recently, we collected individuals of the Pyrophorus angustus species from the Southern Amazon forest, in Brazil, which displays an orange light emitting abdominal lantern. This species was also previously described from Central America, but displaying a bioluminescence spectrum from 536 nm (dorsal) to 578 nm (ventral). The biogeographic variation of the bioluminescence color in this species could be an adaptation to environmental reflectance and inter/intraspecific sexual competition. Here, we cloned, sequenced, characterized and performed site-direct mutagenesis of this new orange emitting luciferase. The in vitro luciferase spectrum displayed a peak at 594 nm, KM values for ATP and d-luciferin of 160 MUM and 17 MUM, respectively, and an optimum pH of approximately 8.5. Comparative multialignment and site-directed mutagenesis using different color emitting click-beetle luciferases from P. angustus, Fulgeochlizus bruchi and Pyrearinus termitilluminans luciferases cloned by our group showed an integral role of residue 247 in bioluminescence color modulation. PMID- 27454753 TI - Statins for the prevention of contrast-induced acute kidney injury. AB - PURPOSE OF REVIEW: To highlight the most recently published meta-analyses on the role of statins in the prevention of contrast-induced acute kidney injury (CI AKI) and to formulate recommendations for clinical practice. RECENT FINDINGS: Nine meta-analyses were published on this topic from January 2015 to April 2016. Significant clinical heterogeneity between studies, regarding study population, treatment protocol, concomitant preventive strategies or dosage and duration of statin therapy was observed. In addition, the definition of CI-AKI was not uniform throughout all studies, and a number of other clinically meaningful endpoints, such as length of hospital stay in patients who developed CI-AKI, as well as adverse events, were rarely analyzed. SUMMARY: Despite some promising results, it is premature to adapt the existing guidelines and implement the preprocedural use of statins in daily clinical practice. At present, low volumes of iso-osmolar or low-osmolar intravascular contrast and adequate intravascular hydration in high-risk patients remain the cornerstone for the prevention of CI AKI. There is a need for additional well designed randomized controlled trials to clarify these issues and assess the risk vs benefit of statin use for the purpose of CI-AKI prevention. PMID- 27454754 TI - Privacy preserving data anonymization of spontaneous ADE reporting system dataset. AB - BACKGROUND: To facilitate long-term safety surveillance of marketing drugs, many spontaneously reporting systems (SRSs) of ADR events have been established world wide. Since the data collected by SRSs contain sensitive personal health information that should be protected to prevent the identification of individuals, it procures the issue of privacy preserving data publishing (PPDP), that is, how to sanitize (anonymize) raw data before publishing. Although much work has been done on PPDP, very few studies have focused on protecting privacy of SRS data and none of the anonymization methods is favorable for SRS datasets, due to which contain some characteristics such as rare events, multiple individual records, and multi-valued sensitive attributes. METHODS: We propose a new privacy model called MS(k, theta (*) )-bounding for protecting published spontaneous ADE reporting data from privacy attacks. Our model has the flexibility of varying privacy thresholds, i.e., theta (*) , for different sensitive values and takes the characteristics of SRS data into consideration. We also propose an anonymization algorithm for sanitizing the raw data to meet the requirements specified through the proposed model. Our algorithm adopts a greedy based clustering strategy to group the records into clusters, conforming to an innovative anonymization metric aiming to minimize the privacy risk as well as maintain the data utility for ADR detection. Empirical study was conducted using FAERS dataset from 2004Q1 to 2011Q4. We compared our model with four prevailing methods, including k-anonymity, (X, Y)-anonymity, Multi-sensitive l-diversity, and (alpha, k)-anonymity, evaluated via two measures, Danger Ratio (DR) and Information Loss (IL), and considered three different scenarios of threshold setting for theta (*) , including uniform setting, level-wise setting and frequency-based setting. We also conducted experiments to inspect the impact of anonymized data on the strengths of discovered ADR signals. RESULTS: With all three different threshold settings for sensitive value, our method can successively prevent the disclosure of sensitive values (nearly all observed DRs are zeros) without sacrificing too much of data utility. With non-uniform threshold setting, level-wise or frequency-based, our MS(k, theta (*))-bounding exhibits the best data utility and the least privacy risk among all the models. The experiments conducted on selected ADR signals from MedWatch show that only very small difference on signal strength (PRR or ROR) were observed. The results show that our method can effectively prevent the disclosure of patient sensitive information without sacrificing data utility for ADR signal detection. CONCLUSIONS: We propose a new privacy model for protecting SRS data that possess some characteristics overlooked by contemporary models and an anonymization algorithm to sanitize SRS data in accordance with the proposed model. Empirical evaluation on the real SRS dataset, i.e., FAERS, shows that our method can effectively solve the privacy problem in SRS data without influencing the ADR signal strength. PMID- 27454755 TI - Green-light laser en bloc resection for primary non-muscle-invasive bladder tumor versus transurethral electroresection: A prospective, nonrandomized two-center trial with 36-month follow-up. AB - OBJECTIVES: To evaluate the safety and efficacy of LBO laser en bloc resection compared with transurethral electroresection (TURBT) for the treatment of primary non-muscle-invasive bladder tumors. METHODS: From September 2010 to February 2012, a prospective, nonrandomized two-center trial was performed. A total of 158 patients (83 underwent laser resection and 75 TURBT) were included in the present study. The preoperative, intraoperative, and postoperative clinical characteristics were recorded and compared in the two groups. RESULTS: There were no differences with the preoperative characteristics between the patients in the two groups. The mean operative time was 21.46 +/- 10.42 minutes for laser resection and 27.47 +/- 15.30 minutes for TURBT (P = 0.004). LBO laser group was also associated with less hemoglobin decrease compared with TURBT group (0.87 +/- 0.28 g/ml vs. 1.00 +/- 0.33 g/ml, P = 0.009). Obturator nerve reflection was absent during laser resection, whereas was observed in nine patients during TURBT (P = 0.001). Two patients in the TURBT group suffered bladder perforation. Three patients in TURBT group and one patient in LBO laser group experienced urethral stricture. The recurrence-free survival rate did not differ significantly between two groups after 36 months follow-up. CONCLUSIONS: The results of our trial have shown that LBO laser en bloc resection is feasible, safe, and effective alternative for the treatment of primary non-muscle-invasive bladder tumors. Besides, it can provide intact specimen for the pathologic diagnosis. Lasers Surg. Med. 48:859-865, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27454760 TI - Veterinary Quarterly 2015 Impact Factor increases to 1.047. PMID- 27454758 TI - Frequency and predictors of a high clinical response in patients with psoriasis on biological therapy in daily practice: results from the prospective, multicenter BioCAPTURE cohort. AB - BACKGROUND: It is important to assess which patients with psoriasis are more likely to achieve high clinical responses on biologics. OBJECTIVES: To assess the number of treatment episodes (TEs) that achieve a 100% improvement in Psoriasis Area and Severity Index (PASI 100), PASI 90 or PASI <= 5 at week 24 of biological treatment, and which baseline patient characteristics predict treatment response. METHODS: Data from patients with psoriasis treated with adalimumab, etanercept, infliximab or ustekinumab were extracted from a prospective cohort. TEs with high clinical responses were described. Uni- and multivariate regression analyses were performed with the generalized estimating equation method to elucidate which baseline patient characteristics were predictors for PASI 90 and PASI <= 5 at week 24. RESULTS: In total, 454 TEs were extracted (159 adalimumab; 193 etanercept; 19 infliximab; 83 ustekinumab) from 326 patients. At week 24, in 3%, 15% and 59% of TEs, respectively, PASI 100, PASI 90 and PASI <= 5 was reached. In TEs without a PASI 100 or PASI 90 response, PASI <= 5 was still achieved in 58% and 52%, respectively. Baseline PASI >= 10 was a strong predictor for achieving PASI 90; baseline PASI < 10 and a lower baseline body mass index (BMI) were significant predictors for PASI <= 5 at week 24. CONCLUSIONS: A limited number of patients achieved PASI 100 or PASI 90 at 24 weeks of biological treatment. Including an absolute PASI score in the assessment of psoriasis severity is important. Baseline BMI was an important, modifiable predictor for a high response. PMID- 27454757 TI - Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration. AB - Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer's disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synaptic marker protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide some beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide broad insights into synergistic behavioral and epigenetic based therapeutic approaches for treatment of cognitive disorder. PMID- 27454762 TI - Is radioembolization or sorafenib the best option for patients with hepatocellular carcinoma and portal vein invasion? PMID- 27454761 TI - Misconduct, Marginality and Editorial Practices in Management, Business and Economics Journals. AB - OBJECTIVES: The paper presents data on the two problems of misconduct and marginality in management, business and economics (MBE) journals and their practices to combat these problems. DESIGN: Data was collected in three phases. First, all publicly retracted papers in MBE journals were identified through keywords searches in 7 major databases (n = 1329 journals). Second, a focused survey was distributed to editors involved in such retractions (n = 64; response rate = 28%). Finally, a survey was administered to all active journals in the seven databases to collect data on editors' perceptions and practices related to the two problems (n = 937, response rate = 31.8%). Frequency analyses, cross tabulations, and qualitative analyses of open answers were used to examine the data. RESULTS: 184 retracted papers in MBE journals were identified in 2005-2015 (no retraction was found before 2005). From 2005-2007 to 2012-2015, the number of retractions increased by a factor ten with an all-time high in 2015. The survey to journals with reported retractions illustrates how already a few cases of suspected misconduct put a strain on the editorial workload. The survey to all active journals revealed that 42% of the respondents had started to use software to screen all submitted papers, and that a majority recognized the problem of marginality, as indicated by salami-style submissions. According to some editors, reviewers easily spot such submissions whereas others argued that authors may submit thinly sliced papers in parallel to several journals, which means that this practice is only discovered post-publication. The survey question on ways to support creative contributions stimulated a rich response of ideas regarding editorial vision, engaged boards and developmental approaches. The study uses data from three specialized fields, but its findings may be highly relevant to many journals in the social sciences. PMID- 27454763 TI - On the path to untreatable infections: colistin use in agriculture and the end of 'last resort' antibiotics. PMID- 27454764 TI - Enamel Thickness Determination by Optical Coherence Tomography: In vitro Validation. AB - Optical coherence tomography (OCT) has been introduced in dentistry as a nondestructive diagnostic imaging tool that does not utilize ionizing radiation. This study investigated the agreement between polarization-sensitive OCT (PS OCT), microcomputed tomography (MU-CT), and histology for enamel thickness measurements. Human enamel samples were prepared and evaluated with MU-CT and PS OCT and then sectioned and observed via digital transversal light microscopy. For all methods, a standard transversal section (b-scan) in each sample was selected, and the enamel thickness was measured at three predetermined positions using ImageJ analysis software. The results revealed significant high agreement between all tested methods, indicating the potential of PS-OCT as a clinical tool to effectively measure enamel thickness. PMID- 27454765 TI - What Do Ovarian Cancer Patients Expect From Treatment?: Perspectives From an Online Patient Community. AB - BACKGROUND: Advances in ovarian cancer treatment have improved outcomes. However, the gap between patients' hopes and expectations and their actual outcomes remains an understudied aspect of treatment decision making. This gap has been noted to be a predictor of poorer health-related quality of life. Incorporating patient hopes and expectations for treatment into clinical care may improve patient experiences. OBJECTIVES: The aim of this study is to describe the hopes and expectations of ovarian cancer patients at diagnosis and throughout treatment transitions. METHODS: This study sampled from an online community of patients with ovarian cancer. Thirty members completed an online qualitative survey about their diagnostic and treatment journey, including hopes and expectations around treatment. RESULTS: Initially, ovarian cancer patients hoped for a complete cure or removal of cancer. As they progressed through treatment, hopes and expectations centered on issues related to living with ovarian cancer. A subset of patients emphasized a lack of information about treatment side effects. CONCLUSIONS: The shift in expectations from survival to living with ovarian cancer may demonstrate an enhanced understanding of ovarian cancer prognosis as patients learn more about their condition. Patients underscored that a more involved discussion of side effect profiles with clinicians would enhance their treatment decision making and expectation setting process. IMPLICATIONS FOR PRACTICE: Expectation setting may be improved by contextualizing treatment in terms of the transitions ovarian cancer patients experience. Providing relevant information that aligns with patient needs, desires, and concerns at critical transitions may improve clinical care and decision making. PMID- 27454766 TI - The hydroxypyridinone iron chelator CP94 increases methyl-aminolevulinate-based photodynamic cell killing by increasing the generation of reactive oxygen species. AB - Methyl-aminolevulinate-based photodynamic therapy (MAL-PDT) is utilised clinically for the treatment of non-melanoma skin cancers and pre-cancers and the hydroxypyridinone iron chelator, CP94, has successfully been demonstrated to increase MAL-PDT efficacy in an initial clinical pilot study. However, the biochemical and photochemical processes leading to CP94-enhanced photodynamic cell death, beyond the well-documented increases in accumulation of the photosensitiser protoporphyrin IX (PpIX), have not yet been fully elucidated. This investigation demonstrated that MAL-based photodynamic cell killing of cultured human squamous carcinoma cells (A431) occurred in a predominantly necrotic manner following the generation of singlet oxygen and ROS. Augmenting MAL-based photodynamic cell killing with CP94 co-treatment resulted in increased PpIX accumulation, MitoSOX-detectable ROS generation (probably of mitochondrial origin) and necrotic cell death, but did not affect singlet oxygen generation. We also report (to our knowledge, for the first time) the detection of intracellular PpIX-generated singlet oxygen in whole cells via electron paramagnetic resonance spectroscopy in conjunction with a spin trap. PMID- 27454767 TI - Diabetes-induced oxidative stress in the vitreous humor. AB - PURPOSE: Diabetes is accompanied by fundamental rearrangements in redox homeostasis. Hyperglycemia triggers the production of reactive oxygen and nitrogen species which contributes to tissue damage in various target organs. Proliferative diabetic retinopathy (PDR) is a common manifestation of diabetic complications but information on the possible role of reactive intermediates in this condition with special regard to the involvement of the vitreous in PDR associated redox alterations is scarce. The aim of the study was to determine key parameters of redox homeostasis [advanced glycation endproducts (AGE); protein carbonyl and glutathione (GSH)] content in the vitreous in PDR patients. METHODS: The study population involved 10 diabetic patients undergoing surgery for complications of proliferative diabetic retinopathy and 8 control (non-diabetic) patients who were undergoing surgery for epiretinal membranes. Vitreal fluids were assayed for the above biochemical parameters. RESULTS: We found elevated levels of AGE in the vitreous of PDR patients (812.10 vs 491.69ng AGE/mg protein). Extent of protein carbonylation was also higher in the samples of diabetic patients (2.08 vs 0.67A/100MUg protein). The GSH content also increased in the vitreous of PDR patients as compared to the control group (4.54 vs 2.35MUmol/MUg protein), respectively. CONCLUSION: The study demonstrates that diabetes-associated redox alterations also reach the vitreous with the most prominent changes being increased protein carbonylation and increased antioxidant levels. PMID- 27454769 TI - Free Fatty Acids Differentially Downregulate Chemokines in Liver Sinusoidal Endothelial Cells: Insights into Non-Alcoholic Fatty Liver Disease. AB - Non-alcoholic fatty liver disease is a prevalent problem throughout the western world. Liver sinusoidal endothelial cells (LSEC) have been shown to play important roles in liver injury and repair, but their role in the underlying pathogenetic mechanisms of non-alcoholic fatty liver disease remains undefined. Here, we evaluated the effects of steatosis on LSEC gene expression in a murine model of non-alcoholic fatty liver disease and an immortalized LSEC line. Using microarray we identified distinct gene expression profiles following exposure to free fatty acids. Gene pathway analysis showed a number of differentially expressed genes including those involved in lipid metabolism and signaling and inflammation. Interestingly, in contrast to hepatocytes, fatty acids led to decreased expression of pro-inflammatory chemokines including CCL2 (MCP-1), CXCL10 and CXCL16 in both primary and LSEC cell lines. Chemokine downregulation translated into a significant inhibition of monocyte migration and LSECs isolated from steatotic livers demonstrated a similar shift towards an anti-inflammatory phenotype. Overall, these pathways may represent a compensatory mechanism to reverse the liver damage associated with non-alcoholic fatty liver disease. PMID- 27454768 TI - Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction. AB - Atherosclerosis, the underlying cause of ischemic heart disease and stroke, is an inflammatory disease of arteries in a hyperlipidemic milieu. Endothelial expression of cellular adhesion molecules, such as endothelial-leukocyte adhesion molecule-1 (E-selectin) and intercellular adhesion molecule-1 (ICAM-1), plays a critical role in the initiation and progression of atherosclerosis. The dietary flavonoid, quercetin, has been reported to inhibit expression of cellular adhesion molecules, but the underlying mechanisms are incompletely understood. In this study, we found that quercetin dose-dependently (5-20uM) inhibits lipopolysaccharide (LPS)-induced mRNA and protein expression of E-selectin and ICAM-1 in human aortic endothelial cells (HAEC). Incubation of HAEC with quercetin also significantly reduced LPS-induced oxidant production, but did not inhibit activation of the nuclear factor-kappaB (NF-kappaB). Furthermore, quercetin induced activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent mRNA and protein expression of the antioxidant enzymes, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase, quinone 1, and glutamate-cysteine ligase. The induction of Nrf2 and antioxidant enzymes was partly inhibited by the p38 mitogen-activated protein kinase (p38) inhibitor, SB203580. Our results suggest that quercetin suppresses LPS-induced oxidant production and adhesion molecule expression by inducing Nrf2 activation and antioxidant enzyme expression, which is partially mediated by p38; and the inhibitory effect of quercetin on adhesion molecule expression is not due to inhibition of NF-kappaB activation, but instead due to antioxidant-independent effects of HO-1. PMID- 27454770 TI - Evaluation of an Automated Analysis Tool for Prostate Cancer Prediction Using Multiparametric Magnetic Resonance Imaging. AB - OBJECTIVE: To evaluate the diagnostic performance of an automated analysis tool for the assessment of prostate cancer based on multiparametric magnetic resonance imaging (mpMRI) of the prostate. METHODS: A fully automated analysis tool was used for a retrospective analysis of mpMRI sets (T2-weighted, T1-weighted dynamic contrast-enhanced, and diffusion-weighted sequences). The software provided a malignancy prediction value for each image pixel, defined as Malignancy Attention Index (MAI) that can be depicted as a colour map overlay on the original images. The malignancy maps were compared to histopathology derived from a combination of MRI-targeted and systematic transperineal MRI/TRUS-fusion biopsies. RESULTS: In total, mpMRI data of 45 patients were evaluated. With a sensitivity of 85.7% (with 95% CI of 65.4-95.0), a specificity of 87.5% (with 95% CI of 69.0-95.7) and a diagnostic accuracy of 86.7% (with 95% CI of 73.8-93.8) for detection of prostate cancer, the automated analysis results corresponded well with the reported diagnostic accuracies by human readers based on the PI-RADS system in the current literature. CONCLUSION: The study revealed comparable diagnostic accuracies for the detection of prostate cancer of a user-independent MAI-based automated analysis tool and PI-RADS-scoring-based human reader analysis of mpMRI. Thus, the analysis tool could serve as a detection support system for less experienced readers. The results of the study also suggest the potential of MAI based analysis for advanced lesion assessments, such as cancer extent and staging prediction. PMID- 27454772 TI - Externalising moods and psychological states in a cloud based system to enhance a pet-robot and child's interaction. AB - BACKGROUND: This PATRICIA research project is about using pet robots to reduce pain and anxiety in hospitalized children. The study began 2 years ago and it is believed that the advances made in this project are significant. Patients, parents, nurses, psychologists, and engineers have adopted the Pleo robot, a baby dinosaur robotic pet, which works in different ways to assist children during hospitalization. METHODS: Focus is spent on creating a wireless communication system with the Pleo in order to help the coordinator, who conducts therapy with the child, monitor, understand, and control Pleo's behavior at any moment. This article reports how this technological function is being developed and tested. RESULTS: Wireless communication between the Pleo and an Android device is achieved. The developed Android app allows the user to obtain any state of the robot without stopping its interaction with the patient. Moreover, information is sent to a cloud, so that robot moods, states and interactions can be shared among different robots. CONCLUSIONS: Pleo attachment was successful for more than 1 month, working with children in therapy, which makes the investment capable of positive therapeutic possibilities. This technical improvement in the Pleo addresses two key issues in social robotics: needing an enhanced response to maintain the attention and engagement of the child, and using the system as a platform to collect the states of the child's progress for clinical purposes. PMID- 27454771 TI - Schistosoma mansoni Tegument (Smteg) Induces IL-10 and Modulates Experimental Airway Inflammation. AB - BACKGROUND: Previous studies have demonstrated that S. mansoni infection and inoculation of the parasite eggs and antigens are able to modulate airways inflammation induced by OVA in mice. This modulation was associated to an enhanced production of interleukin-10 and to an increased number of regulatory T cells. The S. mansoni schistosomulum is the first stage to come into contact with the host immune system and its tegument represents the host-parasite interface. The schistosomula tegument (Smteg) has never been studied in the context of modulation of inflammatory disorders, although immune evasion mechanisms take place in this phase of infection to guarantee the persistence of the parasite in the host. METHODOLOGY AND PRINCIPAL FINDINGS: The aim of this study was to evaluate the Smteg ability to modulate inflammation in an experimental airway inflammation model induced by OVA and to characterize the immune factors involved in this modulation. To achieve the objective, BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with OVA aerosol after Smteg intraperitoneal inoculation. Protein extravasation and inflammatory cells were assessed in bronchoalveolar lavage and IgE levels were measured in serum. Additionally, lungs were excised for histopathological analyses, cytokine measurement and characterization of the cell populations. Inoculation with Smteg led to a reduction in the protein levels in bronchoalveolar lavage (BAL) and eosinophils in both BAL and lung tissue. In the lung tissue there was a reduction in inflammatory cells and collagen deposition as well as in IL-5, IL-13, IL-25 and CCL11 levels. Additionally, a decrease in specific anti-OVA IgE levels was observed. The reduction observed in these inflammatory parameters was associated with increased levels of IL-10 in lung tissues. Furthermore, Smteg/asthma mice showed high percentage of CD11b+F4/80+IL-10+ and CD11c+CD11b+IL-10+ cells in lungs. CONCLUSION: Taken together, these findings demonstrate that S. mansoni schistosomula tegument can modulates experimental airway inflammation. PMID- 27454773 TI - Dismantling and chemical characterization of spent Peltier thermoelectric devices for antimony, bismuth and tellurium recovery. AB - Major uses of thermoelectricity concern refrigeration purposes, using Peltier devices, mainly composed of antimony, bismuth and tellurium. Antimony was identified as a critical raw material by EU and resources of bismuth and tellurium are not inexhaustible, so it is necessary to imagine the recycling of thermoelectric devices. That for, a complete characterization is needed, which is the aim of this work. Peltier devices were manually dismantled in three parts: the thermoelectric legs, the alumina plates on which remain the electrical contacts and the silicone paste used to connect the plates. The characterization was performed using five Peltier devices. It includes mass balances of the components, X-ray diffraction analysis of the thermoelectric legs and elemental analysis of each part of the device. It appears that alumina represents 45% of a Peltier device in weight. The electrical contacts are mainly composed of copper and tin, and the thermoelectric legs of bismuth, tellurium and antimony. Thermoelectric legs appear to be Se-doped Bi2Te3 and (Bi0,5Sb1,5)Te3 for n type and p type semiconductors, respectively. This work shows that Peltier devices can be considered as a copper ore and that thermoelectric legs contain high amounts of bismuth, tellurium and antimony compared to their traditional resources. PMID- 27454774 TI - Pharmacokinetics in Wistar Rats of 5-[(4-Carboxybutanoyl)Amino]-2-Hydroxybenzoic Acid: A Novel Synthetic Derivative of 5-Aminosalicylic Acid (5-ASA) with Possible Anti-Inflammatory Activity. AB - 5-[(4-carboxybutanoyl)amino]-2-hydroxybenzoic acid (C2) is a novel synthetic derivative of 5-aminosalicylic acid (5-ASA), which is currently being evaluated ex vivo as an anti-inflammatory agent and has shown satisfactory results. This study aimed to obtain the pharmacokinetic profiles, tissue distribution and plasma protein binding of C2 in Wistar Rats. Additionally, an HPLC method was developed and validated to quantify C2 in rat plasma. The pharmacokinetic profiles of intragastric, intravenous and intraperitoneal administration routes at singles doses of 100, 50, and 100 mg/kg, respectively, were studied in Wistar rats. The elimination half-life of intravenously administered C2 was approximately 33 min. The maximum plasma level of C2 was reached approximately 24 min after intragastric administration, with a Cmax value of 2.5 g/mL and an AUCtot value of 157 MUg min-1/mL; the oral bioavailability was approximately 13%. Following a single intragastric or oral dose (100 mg/kg), C2 was distributed and detected in all examined tissues (including the brain and colon). The results showed that C2 accumulates over time. The plasma protein binding results indicated that the unbound fraction of C2 at concentrations of 1 to 20 MUg/mL ranged from 89.8% to 92.5%, meaning that this fraction of C2 is available to cross tissues. Finally, the blood-plasma partitioning (BP ratio) of C2 in rat plasma was 0.71 and 0.6 at concentrations of 5 and 10 MUg/mL, respectively, which indicates that C2 is free in the plasmatic phase and not inside blood cells. The results of this study suggest that a fraction of the administered C2 dose is absorbed in the stomach, and the fraction that is not absorbed reaches the small intestine and colon. This distribution constitutes the main advantage of C2 compared with 5-ASA for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). PMID- 27454775 TI - A method for predicting protein complex in dynamic PPI networks. AB - BACKGROUND: Accurate determination of protein complexes has become a key task of system biology for revealing cellular organization and function. Up to now, the protein complex prediction methods are mostly focused on static protein protein interaction (PPI) networks. However, cellular systems are highly dynamic and responsive to cues from the environment. The shift from static PPI networks to dynamic PPI networks is essential to accurately predict protein complex. RESULTS: The gene expression data contains crucial dynamic information of proteins and PPIs, along with high-throughput experimental PPI data, are valuable for protein complex prediction. Firstly, we exploit gene expression data to calculate the active time point and the active probability of each protein and PPI. The dynamic active information is integrated into high-throughput PPI data to construct dynamic PPI networks. Secondly, a novel method for predicting protein complexes from the dynamic PPI networks is proposed based on core-attachment structural feature. Our method can effectively exploit not only the dynamic active information but also the topology structure information based on the dynamic PPI networks. CONCLUSIONS: We construct four dynamic PPI networks, and accurately predict many well-characterized protein complexes. The experimental results show that (i) the dynamic active information significantly improves the performance of protein complex prediction; (ii) our method can effectively make good use of both the dynamic active information and the topology structure information of dynamic PPI networks to achieve state-of-the-art protein complex prediction capabilities. PMID- 27454776 TI - Acridinium-Based Photocatalysts: A Sustainable Option in Photoredox Catalysis. AB - The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earth's crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6). PMID- 27454778 TI - Deleterious Effects of Exact Exchange Functionals on Predictions of Molecular Conductance. AB - Kohn-Sham (KS) density functional theory (DFT) describes well the atomistic structure of molecular junctions and their coupling to the semi-infinite metallic electrodes but severely overestimates conductance due to the spuriously large density of charge-carrier states of the KS system. Previous works show that inclusion of appropriate amounts of nonlocal exchange in the functional can fix the problem and provide realistic conductance estimates. Here however we discover that nonlocal exchange can also lead to deleterious effects which artificially overestimate transmittance even beyond the KS-DFT prediction. The effect is a result of exchange coupling between nonoverlapping states of diradical character. We prescribe a practical recipe for eliminating such artifacts. PMID- 27454777 TI - The management and expression of pride: Age and gender effects across adolescence. AB - Understanding of the role that positive emotions play in adolescent social development requires studying the normative development of these emotions. This research examined pride expression and management across adolescence, focusing on gender and developmental differences. Participants were 206 Caucasian youth (52.9% girls) in grades 5 (Mage = 11.10 years), 8 (Mage = 14.45), 11 (Mage = 17.26), and university (Mage = 19.61). Youth responded to two vignettes assessing reactions to pride-eliciting situations. Compared to boys, girls reported more intense pride experience and a higher likelihood of expressing pride. Increases across adolescence were found for self-efficacy in suppressing pride expression, and for expressing modesty in pride-eliciting situations. Older adolescents were less likely than younger adolescents to expect to receive a negative peer reaction when inhibiting pride. These results indicate the importance of gender specific examinations of pride across adolescent development with implications for adaptive psychosocial functioning and positive psychology. PMID- 27454779 TI - Pneumococcal vaccination coverages among low-, intermediate-, and high-risk adults in Catalonia. AB - There is scarce data about pneumococcal vaccination coverages among adults in recent years. We investigated current pneumococcal vaccination coverages in Catalonia, Spain, with a cross-sectional population-based study including 2,033,465 individuals aged 50 y or older assigned to the Catalonian Health Institute at 01/01/2015 (date of survey). A previously validated institutional research clinical Database was used to classify study subjects by their vaccination status for both 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13), to identify comorbidities and underlying conditions, and establish the risk stratum of each individual: High risk stratum: functional or anatomic asplenia, cochlear implants, CSF leaks, or immunocompromising conditions; medium risk stratum: immunocompetent persons with history of chronic cardiac or respiratory disease, liver disease, diabetes mellitus, alcoholism and/or smoking; low risk stratum: persons without high or medium risk conditions. Of the total 2,033,465 study population, an amount of 789,098 (38.8%) had received PPVS23, whereas 5031 (0.2%) had received PCV13. PPSV23 coverages increased largely with increasing age: 4.8% in 50-59 y vs 35.5% in 60-69 y vs 71.9% in 70-79 y vs 79.5% in 80 y or older; p < 0.001). PCV13 coverages also increased with age, although they were very low in all age groups. PPSV23 coverages were 59.2% in high risk stratum, 48.3% in medium risk stratum and 28.1% in low risk stratum (p < 0.001). For the PCV13, uptakes were 1.2%, 0.3% and 0.1% in high, medium and low stratum, respectively (p < 0.001). In conclusion, pneumococcal vaccination coverages in Catalonian adults are not optimal, being especially small for the PCV13 (even in high-risk subjects). PMID- 27454781 TI - Laparoscopic Pediatric Inguinal Hernia Repair Using Purse-String Suture: Technical Recommendations After 20 Years Experience. PMID- 27454780 TI - Just showing up is not enough: Homework adherence and outcome in cognitive behavioral therapy for cocaine dependence. AB - OBJECTIVE: Homework in cognitive-behavioral therapy (CBT) provides opportunities to practice skills. In prior studies, homework adherence was associated with improved outcome across a variety of disorders. Few studies have examined whether the relationship between homework adherence and outcome is maintained after treatment end or is independent of treatment attendance. METHOD: This study combined data from 4 randomized clinical trials of CBT for cocaine dependence to examine relationships among homework adherence, participant variables, and cocaine use outcomes during treatment and at follow-up. The data set included only participants who attended at least 2 CBT sessions to allow for assignment and return of homework (N = 158). RESULTS: Participants returned slightly less than half (41.1%) of assigned homework. Longitudinal random effects regression suggested a greater reduction in cocaine use during treatment and through 12 month follow-up for participants who completed half or more of assigned homework (3-way interaction), F(2, 910.69) = 4.28, p = .01. In multiple linear regression, the percentage of homework adherence was associated with greater number of cocaine-negative urine toxicology screens during treatment, even when accounting for baseline cocaine use frequency and treatment attendance; at 3 months follow up, multiple logistic regression indicated homework adherence was associated with cocaine-negative urine toxicology screen, controlling for baseline cocaine use and treatment attendance. CONCLUSIONS: These results extend findings from prior studies regarding the importance of homework adherence by demonstrating associations among homework and cocaine use outcomes during treatment and up to 12 months after, independent of treatment attendance and baseline cocaine use severity. (PsycINFO Database Record PMID- 27454782 TI - Effect of 1-methylcyclopropene on the development of black mold disease and its potential effect on alternariol and alternariol monomethyl ether biosynthesis on tomatoes infected with Alternaria alternata. AB - Ethylene is a naturally produced plant regulator involved in several plant functions, such as regulation of fruit ripening. Inhibition of ethylene perception by using 1-methylcyclopropene (1-MCP) slows down the ripening of the fruit maintaining its quality and freshness. The use of 1-MCP is a commercial strategy commonly used in the food industry to extend the postharvest life of several fruits, including tomatoes. To assess how 1-MCP affected infection by Alternaria alternata on tomatoes, three different cultivars were artificially inoculated with 5MUL of an A. alternata conidial suspension (10(5)conidia/mL). Tomatoes were treated with 0.6MUL/L of 1-MCP for 24h. Spiked but untreated tomatoes were considered controls. Then, fruit were stored 6days at 10 degrees C and one more week at 20 degrees C to simulate shelf-life. Fungal growth development and mycotoxin production (alternariol, AOH and alternariol monomethyl ether, AME) were assessed both on the first and on the second week. After the first 6days at 10 degrees C, in just one variety the black mold disease was higher in the 1-MCP treated samples. However, after two weeks of storage, in all cases, tomatoes treated with 1-MCP showed more significant fungal growth disease. Regarding mycotoxin production, no large differences were observed among different treatments, which was corroborated with gene expression analysis of pksJ, a gene related to AOH and AME biosynthesis. PMID- 27454783 TI - Putrescine biosynthesis in Lactococcus lactis is transcriptionally activated at acidic pH and counteracts acidification of the cytosol. AB - Lactococcus lactis subsp. cremoris CECT 8666 is a lactic acid bacterium that synthesizes the biogenic amine putrescine from agmatine via the agmatine deiminase (AGDI) pathway. The AGDI genes cluster includes aguR. This encodes a transmembrane protein that functions as a one-component signal transduction system, the job of which is to sense the agmatine concentration of the medium and accordingly regulate the transcription of the catabolic operon aguBDAC. The latter encodes the proteins necessary for agmatine uptake and its conversion into putrescine. This work reports the effect of extracellular pH on putrescine biosynthesis and on the genetic regulation of the AGDI pathway. Increased putrescine biosynthesis was detected at acidic pH (pH5) compared to neutral pH. Acidic pH induced the transcription of the catabolic operon via the activation of the aguBDAC promoter PaguB. However, the external pH had no significant effect on the activity of the aguR promoter PaguR, or on the transcription of the aguR gene. The transcriptional activation of the AGDI pathway was also found to require a lower agmatine concentration at pH5 than at neutral pH. Finally, the following of the AGDI pathway counteracted the acidification of the cytoplasm under acidic external conditions, suggesting it to provide protection against acid stress. PMID- 27454784 TI - Developing and optimizing bacteriophage treatment to control enterohemorrhagic Escherichia coli on fresh produce. AB - Bacteriophages are potentially useful in controlling foodborne pathogens on minimally processed products since phage application is a non-destructive treatment. The purpose of this study was to evaluate the efficacy of a newly isolated environmental bacteriophage against enterohemorrhagic Escherichia coli on fresh produce, and optimize the treatment with consideration for potential application. Seven anti E. coli O157:H7 EDL933 bacteriophages were isolated from various sources; the most promising was isolated from municipal wastewater. This isolate (designated as E. coli phage OSY-SP) was propagated with the host, in a growth medium, to a titer of 10(8) PFU/ml. Before inoculation into fresh produce, E. coli phage OSY-SP was incubated with the host bacterium, spent medium was filter-sterilized, and the resulting crude lysate was used as a source of phage inocula for preliminary experiments. For optimized testing, phage in the crude lysate was purified by ultra-centrifugation and resuspension in phosphate buffered saline. Efficacy of phage treatments was determined as a function of fresh produce type (cut green pepper or spinach leaves), treatment time (2 or 5min rinsing), and temperature of holding treated produce (4 degrees C, 25 degrees , or a combination of both temperatures). Cut green pepper was treated with UV light, to eliminate background microbiota, then spot-inoculated with E. coli O157:H7 EDL933 on cut edges, and the inoculum was allowed to dry. Because of its susceptibility to damage, baby spinach leaves were not subjected to a decontamination treatment. These leaves were inoculated with the green fluorescent protein-labeled E. coli O157:H7 B6-914 to facilitate inoculum enumeration in the presence of background microbiota. Phage suspension was applied to the inoculated fresh produce that was subsequently held for three days under variable storage conditions. The optimized phage treatment decreased the populations of pathogenic E. coli by 2.4-3.0logCFU/g on cut green pepper (5-min rinse) and 3.4-3.5logCFU/g on spinach leaves (2-min rinse), during 72h storage. The majority of this decline was caused by the antimicrobial action of the phage. These findings suggest the utility of bacteriophage to selectively control pathogens on fresh produce. PMID- 27454786 TI - Focal Liver Lesions Classification and Characterization: What Value Do DWI and ADC Have? AB - OBJECTIVE: The aim of this work was to analyze the value of diffusion-weighted imaging (DWI) in the classification/characterization of focal liver lesions (FLLs). METHODS: Retrospective study, approved by ethical board, of 100 proven FLLs (20 hemangiomas, 20 focal nodular hyperplasia, 20 dysplastic nodules, 20 hepatocellular carcinomas, and 20 metastases) was performed by 1.5-T MR. For each lesion, 2 readers, blinded of medical history, have evaluated 6 sets of images: set A (T1/T2-weighted images), set B (set A + DWI), set C (set B + apparent diffusion coefficient [ADC] map), set D (set A + dynamic and hepatobiliary phases), set E (set D + DWI), set F (set E + ADC map). RESULTS: In unenhanced images, the evaluation of the ADC improves the accuracy in classification/characterization (+9%/14%, respectively), whereas in enhanced images the accuracy was increased by DWI (+7%/12%, respectively) and ADC (+13%/19%, respectively). Diffusion-weighted imaging does not improve classification/characterization of hemangiomas, may be useful in focal nodular hyperplasia/dysplastic nodules vs metastases/hepatocellular carcinoma differentiation, and increases the classification/characterization of metastases in both unenhanced and enhanced images. CONCLUSIONS: Diffusion-weighted imaging may improve classification/characterization of FLLs at unenhanced/enhanced examinations. PMID- 27454785 TI - Effectiveness of Adaptive Statistical Iterative Reconstruction for 64-Slice Dual Energy Computed Tomography Pulmonary Angiography in Patients With a Reduced Iodine Load: Comparison With Standard Computed Tomography Pulmonary Angiography. AB - OBJECTIVE: The aim of the study was to assess the effectiveness of the adaptive statistical iterative reconstruction (ASIR) for dual-energy computed tomography pulmonary angiography (DE-CTPA) with a reduced iodine load. MATERIALS AND METHODS: One hundred forty patients referred for chest CT were randomly divided into a DE-CTPA group with a reduced iodine load or a standard CTPA group. Quantitative and qualitative image qualities of virtual monochromatic spectral (VMS) images with filtered back projection (VMS-FBP) and those with 50% ASIR (VMS ASIR) in the DE-CTPA group were compared. Image qualities of VMS-ASIR images in the DE-CTPA group and ASIR images in the standard CTPA group were also compared. RESULTS: All quantitative and qualitative indices, except attenuation value of pulmonary artery in the VMS-ASIR subgroup, were superior to those in the VMS-FBP subgroup (all P < 0.001). Noise and signal-to-noise ratio of VMS-ASIR images were superior to those of ASIR images in the standard CTPA group (P < 0.001 and P = 0.007, respectively). Regarding qualitative indices, noise was significantly lower in VMS-ASIR images of the DE-CTPA group than in ASIR images of the standard CTPA group (P = 0.001). CONCLUSIONS: The ASIR technique tends to improve the image quality of VMS imaging. Dual-energy computed tomography pulmonary angiography with ASIR can reduce contrast medium volume and produce images of comparable quality with those of standard CTPA. PMID- 27454787 TI - Pulmonary Legionellosis in Oncologic Patients: Findings on Chest CT. AB - OBJECTIVE: The purpose of this study was to report the computed tomography (CT) findings of non-pneumophila Legionella pneumonia and to compare these CT findings to those caused by Legionella pneumophila in oncologic patients. METHODS: Chest CT scans of 34 oncologic patients with culture-proven Legionella infection (16 L. pneumophila and 18 non-pneumophila Legionella) were retrospectively reviewed. Radiologic checkpoints included consolidation, ground-glass opacities, cavitation, nodules, tree-in-bud opacities, septal thickening, pleural effusions, and adenopathy, as well as the halo, reversed halo, and bulging fissure signs. RESULTS: The most common imaging feature of Legionella pneumonia was consolidation, seen in 94% of patients. Ground-glass opacities were the next most common abnormality. The halo sign was present in 26% of patients, in both immunocompetent and immunosuppressed hosts. Most features occurred with similar frequency between L. pneumophila and non-pneumophila Legionella. CONCLUSIONS: Findings in L. pneumophila pneumonia and non-pneumophila Legionella pneumonia are similar but nonspecific. Airspace consolidation is almost always present; the halo sign is not uncommon. PMID- 27454788 TI - Can Abdominal Computed Tomography Imaging Help Accurately Identify a Dedifferentiated Component in a Well-Differentiated Liposarcoma? AB - PURPOSE: To assess the ability of computed tomography (CT) to differentiate an atypical lipomatous tumor/well-differentiated liposarcoma (WDLPS) from a WDLPS with a dedifferentiated component (DDLPS) within it. MATERIALS AND METHODS: Forty nine untreated patients with abdominal atypical lipomatous tumors/well differentiated liposarcomas who had undergone contrast-enhanced CT were identified using an institutional database. Three radiologists who were blinded to the pathology findings evaluated all the images independently to determine whether a dedifferentiated component was present within the WDLPS. The CT images were evaluated for fat content (<=25% or >25%); presence of ground-glass density, enhancing and/or necrotic nodules; presence of a capsule surrounding the mass; septations; and presence and pattern of calcifications. A multivariate logistic regression model with generalized estimating equations was used to correlate imaging features with pathology findings. Kappa statistics were calculated to assess agreement between the three radiologists. RESULTS: On the basis of pathological findings, 12 patients had been diagnosed with DDLPS within a WDLPS and 37 had been diagnosed with WDLPS. The presence of an enhancing or a centrally necrotic nodule within the atypical lipomatous tumor was associated with dedifferentiated liposarcoma (P = 0.02 and P = 0.0003, respectively). The three readers showed almost perfect agreement in overall diagnosis (kappa r = 0.83; 95% confidence interval, 0.67-0.99). CONCLUSIONS: An enhancing or centrally necrotic nodule may be indicative of a dedifferentiated component in well-differentiated liposarcoma. Ground-glass density nodules may not be indicative of dedifferentiation. PMID- 27454789 TI - Risk Factors for False-Negative and False-Positive Results of Magnetic Resonance Computer-Aided Evaluation in Axillary Lymph Node Staging. AB - PURPOSE: The aims of this study were to investigate the false-negative and false positive results on magnetic resonance (MR) computer-aided evaluation (CAE) in axillary lymph node (ALN) staging and to evaluate the related factors in patients with invasive breast cancer. METHODS: From July 2011 to May 2014, 103 invasive breast cancer patients who underwent preoperative MR-CAE were included. False MR CAE results in ALN staging were compared in terms of clinicopathologic features, baseline mammography, and breast ultrasonography. Logistic regression analyses were used to evaluate independent factors related to false results. RESULTS: For MR-CAE, the false-negative and false-positive results of ALN metastasis were 6.8% and 33.3%, respectively. On multivariate analysis, spiculated tumor margin (P = 0.016) and positive lymphovascular invasion (P = 0.020) were associated with false-negative results, and circumscribed tumor margin (P = 0.017) and negative lymphovascular invasion (P = 0.036) were associated with false-positive results for ALN metastasis. CONCLUSIONS: Tumor margin and lymphovascular invasion are the key factors that affect the false MR-CAE results in ALN staging. PMID- 27454790 TI - Baseline Cartilage Thickness and Meniscus Extrusion Predict Longitudinal Cartilage Loss by Quantitative Magnetic Resonance Imaging: Data From the Osteoarthritis Initiative. AB - OBJECTIVE: This study aimed to assess how meniscus damage and baseline cartilage thickness influence the rate of cartilage loss and knee pain. METHODS: Of 4796 participants in the Osteoarthritis Initiative, 86 had baseline and 48-month follow-up quantitative magnetic resonance imaging data for medial compartment cartilage thickness. Baseline meniscus pathology was scored by a musculoskeletal radiologist using Whole-Organ Magnetic Resonance Imaging Score. Findings were correlated with 72-month Knee injury and Osteoarthritis Outcome Score. RESULTS: Univariate analysis showed cartilage change was not influenced by demographic variables. Multivariable regression revealed that initial cartilage thickness ( 1.07 mm at 48 months for every 1 mm decrease at baseline, P < 0.001) and meniscus extrusion (-0.33 mm if present at baseline, P < 0.001) were the strongest predictors of medial compartment cartilage thickness at 48 months. Knee injury and Osteoarthritis Outcome Score pain scores did not correlate with cartilage loss. CONCLUSIONS: Baseline cartilage thickness and meniscus extrusion are important and independent predictors for accelerated cartilage loss. However, the degree of cartilage loss did not correlate with midterm change in clinical outcome scores. PMID- 27454791 TI - Isolation and identification of a new saponin from Cephalaria aytachii. AB - A new hederagenin-type triterpenoid glycoside (1) named Aytachoside A, along with eight known triterpene glycosides, were isolated from the aerial parts of Cephalaria aytachii Gokturk and Sumbul (Dipsacaceae). The structures of compounds 1-9 were determined by spectroscopic (1D and 2D NMR, HRESIMS) and chemical examinations. The antimicrobial effect of compound 1 was found considerably active against Escherichia coli, Pseudomonas aeruginosa and especially Salmonella typhimurium microorganisms using the MIC method. Although compound 1 was found not to have a remarkable toxic effect at a concentration lower than 300 MUg/mL, cytotoxic activity tests demonstrated that prosapogenin 1a exhibits a significant cytotoxic activity against HeLa cell lines using the MTT assay for the first time. PMID- 27454792 TI - Porous and single-crystalline ZnO nanobelts: fabrication with annealing precursor nanobelts, and gas-sensing and optoelectronic performance. AB - Porous and single-crystalline ZnO nanobelts have been prepared through annealing precursors of ZnSe . 0.5N2H4 well-defined and smooth nanobelts, which have been synthesized via a simple hydrothermal method. The composition and morphology evolutions with the calcination temperatures have been investigated in detail for as-prepared precursor nanobelts, suggesting that they can be easily transformed into ZnO nanobelts by preserving their initial morphology via calcination in air. In contrast, the obtained ZnO nanobelts are densely porous, owing to the thermal decomposition and oxidization of the precursor nanobelts. More importantly, the achieved porous ZnO nanobelts are single-crystalline, different from previously reported ones. Motivated by the intrinsic properties of the porous structure and good electronic transporting ability of single crystals, their gas-sensing performance has been further explored. It is demonstrated that porous ZnO single crystalline nanobelts exhibit high response and repeatability toward volatile organic compounds, such as ethanol and acetone, with a short response/recovery time. Furthermore, their optoelectronic behaviors indicate that they can be promisingly employed to fabricate photoelectrochemical sensors. PMID- 27454793 TI - On the Edge. PMID- 27454802 TI - Human umbilical cord blood hematopoietic stem cell expansion by the RNA-binding protein Musashi-2. PMID- 27454794 TI - Policy dialogue to improve health outcomes in low income countries: what are the issues and way forward? AB - BACKGROUND: This paper has three objectives: to review the health development landscape in the World Health Organization African Region, to discuss the role of health policy dialogue in improving harmonisation and alignment to national health policies and strategic plans, and to provide an analytical view of the critical factors in realising a good outcome from a health policy dialogue process. DISCUSSION: Strengthening policy dialogue to support the development and implementation of robust and comprehensive national health policies and plans, as well as to improve aid effectiveness, is seen as a strategic entry point to improving health sector results. However, unbalanced power relations, the lack of contextualised and relevant evidence, the diverse interests of the actors involved, and the lack of conceptual clarity on what policy dialogue entails impact the outcomes of a policy dialogue process. The critical factors for a successful policy dialogue have been identified as adequate preparation; secured time and resources to facilitate an open, inclusive and informed discussion among the stakeholders; and stakeholders' monitoring and assessment of the dialogue's activities for continued learning. Peculiarities of low income countries pose a challenge to their policy dialogue processes, including the chaotic-policy making processes, the varied capacity of the actors and donor dependence. CONCLUSION: Policy dialogue needs to be appreciated as a complex and iterative process that spans the whole process of policy-making, implementation, review and monitoring, and subsequent policy revisions. The existence of the critical factors for a successful policy dialogue process needs to be ensured whilst paying special attention to the peculiarities of low income countries and potential power relations, and mitigating the possible negative consequences. There is need to be cognisant of the varied capacities and interests of stakeholders and the need for capacity building, and to put in place mechanisms to manage conflict of interest. The likelihood of a favourable outcome from a policy dialogue process will depend on the characteristics of the issue under consideration and whether it is contested or not, and the policy dialogue process needs to be tailored accordingly. PMID- 27454803 TI - Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders. AB - IMPORTANCE: Induction of labor is a frequently performed obstetrical intervention. It would thus be of great concern if reported associations between labor induction and offspring risk of autism spectrum disorders (ASD) reflected causal influence. OBJECTIVE: To assess the associations of labor induction with ASD, comparing differentially exposed relatives (siblings and cousins discordant for induction). DESIGN, SETTING, AND PARTICIPANTS: Follow-up of all live births in Sweden between 1992 and 2005, defined in the Medical Birth Register. The register was linked to population registers of familial relations, inpatient and outpatient visits, and education records. Diagnoses of ASD were from 2001 through 2013, and data were analyzed in the 2015-2016 year. EXPOSURES: Induction of labor. MAIN OUTCOMES AND MEASURES: Autism spectrum disorders identified by diagnoses from inpatient and outpatient records between 2001 and 2013. Hazard ratios (HRs) quantified the association between labor induction and offspring ASD. In addition to considering a wide range of measured confounders, comparison of exposure-discordant births to the same woman allowed additional control for all unmeasured factors shared by siblings. RESULTS: The full cohort included 1 362 950 births, of which 22 077 offspring (1.6%) were diagnosed with ASD by ages 8 years through 21 years. In conventional models of the full cohort, associations between labor induction and offspring ASD were attenuated but remained statistically significant after adjustment for measured potential confounders (HR, 1.19; 95% CI, 1.13-1.24). When comparison was made within siblings whose births were discordant with respect to induction, thus accounting for all environmental and genetic factors shared by siblings, labor induction was no longer associated with offspring ASD (HR, 0.99; 95% CI, 0.88-1.10). CONCLUSIONS AND RELEVANCE: In this nationwide sample of live births we observed no association between induction of labor and offspring ASD within sibling comparison. Our findings suggest that concern for ASD should not factor into the clinical decision about whether to induce labor. PMID- 27454805 TI - Utility of computed tomographic imaging of the cervical spine in trauma evaluation of ground-level fall. AB - BACKGROUND: Computed tomography (CT) of the cervical spine (C-spine) is routinely ordered for low-risk mechanisms of injury, including ground-level fall. Two commonly used clinical decision rules (CDRs) to guide C-spine imaging in trauma are the National Emergency X-Radiography Utilization Study (NEXUS) and the Canadian Cervical Spine Rule for Radiography (CCR). METHODS: Retrospective cross sectional study of 3,753 consecutive adult patients presenting to an urban Level I emergency department who received C-spine CT scans were obtained over a 6-month period. The primary outcome of interest was prevalence of C-spine fracture. Secondary outcomes included fracture stability, appropriateness of imaging by NEXUS and CCR criteria, and estimated radiation dose exposure and costs associated with C-spine imaging studies. RESULTS: Of the 760 patients meeting inclusion criteria, 7 C-spine fractures were identified (0.92% +/- 0.68%). All fractures were identified by NEXUS and CCR criteria with 100% sensitivity. Of all these imaging studies performed, only 69% met NEXUS indications for imaging (50% met CCR indications). C-spine CT scans in patients not meeting CDR indications were associated with costs of $15,500 to $22,000 by NEXUS ($14,600-$25,600 by CCR) in this single center during the 6-month study period. CONCLUSION: For ground-level fall, C-spine CT is overused. The consistent application of CDR criteria would reduce annual nationwide imaging costs in the United States by $6.8 to $9.6 million based on NEXUS ($6.4-$15.6 million based on CCR) and would reduce population radiation dose exposure by 0.8 to 1.1 million mGy based on NEXUS (0.7-1.9 million mGy based on CCR) if applied across all Level I trauma centers. Greater use of evidence-based CDRs plays an important role in facilitating emergency department patient management and reducing systemwide radiation dose exposure and imaging expenditures. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 27454808 TI - Quality assurance for multiplexed assays - how can it be achieved? AB - Multiplexed assays are now a common form of analysis in routine clinical and research laboratories. Assuring the quality of this type of complex, massively parallel testing poses challenges not encountered in the traditional single-plex assay. A range of quality assurance measures is implemented at different stages in a multiplex assay, beginning in the manufacturing process, and the ensuing analytical and data interpretation stages. This article explores quality issues and the quality assurance measures that have been devised for multiplex assays ranging from simple two-plex assays to the types of assays that involve simultaneous testing on millions of test sites on a single analytical device. PMID- 27454804 TI - The impact of skin colour on human photobiological responses. AB - Terrestrial solar ultraviolet radiation (UVR) exerts both beneficial and adverse effects on human skin. Epidemiological studies show a lower incidence of skin cancer in people with pigmented skins compared to fair skins. This is attributed to photoprotection by epidermal melanin, as is the poorer vitamin D status of those with darker skins. We summarize a wide range of photobiological responses across different skin colours including DNA damage and immunosuppression. Some studies show the generally modest photoprotective properties of melanin, but others show little or no effect. DNA photodamage initiates non-melanoma skin cancer and is reduced by a factor of about 3 in pigmented skin compared with white skin. This suggests that if such a modest reduction in DNA damage can result in the significantly lower skin cancer incidence in black skin, the use of sunscreen protection might be extremely beneficial for susceptible population. Many contradictory results may be explained by protocol differences, including differences in UVR spectra and exposure protocols. We recommend that skin type comparisons be done with solar-simulated radiation and standard erythema doses or physical doses (J/m2 ) rather than those based solely on clinical endpoints such as minimal erythema dose (MED). PMID- 27454809 TI - Self-Assembly of the Cephalopod Protein Reflectin. AB - Films from the cephalopod protein reflectin demonstrate multifaceted functionality as infrared camouflage coatings, proton transport media, and substrates for growth of neural stem cells. A detailed study of the in vitro formation, structural characteristics, and stimulus response of such films is presented. The reported observations hold implications for the design and development of advanced cephalopod-inspired functional materials. PMID- 27454810 TI - Anion Complexes with Tetrazine-Based Ligands: Formation of Strong Anion-pi Interactions in Solution and in the Solid State. AB - Ligands L1 and L2, consisting of a tetrazine ring decorated with two morpholine pendants of different lengths, show peculiar anion-binding behaviors. In several cases, even the neutral ligands, in addition to their protonated HL(+) and H2L(2+) (L = L1 and L2) forms, bind anions such as F(-), NO3(-), PF6(-), ClO4(-), and SO4(2-) to form stable complexes in water. The crystal structures of H2L1(PF6)2.2H2O, H2L1(ClO4)2.2H2O, H2L2(NO3)2, H2L2(PF6)2.H2O, and H2L2(ClO4)2.H2O show that anion-pi interactions are pivotal for the formation of these complexes, although other weak forces may contribute to their stability. Complex stability constants were determined by means of potentiometric titration in aqueous solution at 298.1 K, while dissection of the free-energy change of association (DeltaG degrees ) into its enthalpic (DeltaH degrees ) and entropic (TDeltaS degrees ) components was accomplished by means of isothermal titration calorimetry measurements. Stability constants are poorly regulated by anion ligand charge-charge attraction. Thermodynamic data show that the formation of complexes with neutral ligands, which are principally stabilized by anion-pi interactions, is enthalpically favorable (-DeltaG degrees , 11.1-17.5 kJ/mol; DeltaH degrees , -2.3 to -0.5 kJ/mol; TDeltaS degrees , 9.0-17.0 kJ/mol), while for charged ligands, enthalpy changes are mostly unfavorable. Complexation reactions are invariably promoted by large and favorable entropic contributions. The importance of desolvation phenomena manifested by such thermodynamic data was confirmed by the hydrodynamic results obtained by means of diffusion NMR spectroscopy. In the case of L2, complexation equilibria were also studied in a 80:20 (v/v) water/ethanol mixture. In this mixed solvent of lower dielectric constant than water, the stability of anion complexes decreases, relative to water. Solvation effects, mostly involving the ligand, are thought to be responsible for this peculiar behavior. PMID- 27454813 TI - Sustained-release drug delivery of antimicrobials in controlling of supragingival oral biofilms. AB - INTRODUCTION: Dental caries, a bacterial biofilm-associated disease, is a prevalent oral health problem. It is a bacterial biofilm-associated disease. Conventional means of combating this disease involves oral hygiene, mostly tooth brushing. Supplementary means of prevention and treatment is often necessary. The use of sustained-release delivery systems, locally applied to the oral cavity appears to be one of the most acceptable avenues for the delivery of antimicrobial agents. Area covered: The development and current approaches of local sustained delivery technologies applied to the oral cavity for treatment and prevention of dental caries is discussed. The use of polymeric drug delivery systems, varnishes, liposomes and nanoparticles is presented. Expert opinion: The use of local sustained-release delivery systems applied to the oral cavity has numerous clinical, pharmacological and toxicological advantages over conventional means. Various sustained-release technologies have been suggested over the course of several years. The current research on oral diseases concentrates predominantly on improving the drug delivery. With progress in pharmaceutical technology, sophisticated controlled-release platforms are being developed. The sustained release concept is innovative and there are few products available for the benefit of all populations. Harmonizing academic research with the dental industry will surely expedite the development and commercialization of more products of such pharmacological nature. PMID- 27454811 TI - Phenotypic Similarities Between Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single-Family Case-Control Study. AB - IMPORTANCE: The amyloid hypothesis posits that disrupted beta-amyloid homeostasis initiates the pathological process resulting in Alzheimer disease (AD). Autosomal dominant AD (ADAD) has an early symptomatic onset and is caused by single-gene mutations that result in overproduction of beta-amyloid 42. To the extent that sporadic late-onset AD (LOAD) also results from dysregulated beta-amyloid 42, the clinical phenotypes of ADAD and LOAD should be similar when controlling for the effects of age. OBJECTIVE: To use a family with late-onset ADAD caused by a presenilin 1 (PSEN1) gene mutation to mitigate the potential confound of age when comparing ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS: This case-control study was conducted at the Knight Alzheimer Disease Research Center at Washington University, St Louis, Missouri, and other National Institutes of Aging-funded AD centers in the United States. Ten PSEN1 A79V mutation carriers from multiple generations of a family with late-onset ADAD and 12 noncarrier family members were followed up at the Knight Alzheimer Disease Research Center (1985-2015) and 1115 individuals with neuropathologically confirmed LOAD were included from the National Alzheimer Coordinating Center database (September 2005-December 2014). Data analysis was completed in January 2016, including Knight Alzheimer Disease Research Center patient data collected up until the end of 2015. MAIN OUTCOMES AND MEASURES: Planned comparison of clinical characteristics between cohorts, including age at symptom onset, associated symptoms and signs, rates of progression, and disease duration. RESULTS: Of the PSEN1 A79V carriers in the family with late-onset ADAD, 4 were female (57%); among those with LOAD, 529 were female (47%). Seven mutation carriers (70%) developed AD dementia, while 3 were yet asymptomatic in their seventh and eighth decades of life. No differences were observed between mutation carriers and individuals with LOAD concerning age at symptom onset (mutation carriers: mean, 75 years [range, 63-77 years] vs those with LOAD: mean, 74 years [range, 60-101 years]; P = .29), presenting symptoms (memory loss in 7 of 7 mutation carriers [100%] vs 958 of 1063 individuals with LOAD [90.1%]; P >= .99) and duration (mutation carriers: mean, 9.9 years [range, 2.3-12.8 years] vs those with LOAD: 9 years [range, 1-27 years]; P = .73), and rate of progression of dementia (median annualized change in Clinical Dementia Rating-Sum of Boxes score, mutation carriers: 1.2 [range, 0.1-3.3] vs those with LOAD: 1.9 [range, -3.5 to 11.9]; P = .73). Early emergence of comorbid hallucinations and delusions were observed in 57% of individuals with ADAD (4 of 7) vs 19% of individuals with LOAD (137 of 706) (P = .03). Three of 12 noncarriers (25%) from the PSEN1 A79V family are potential phenocopies as they also developed AD dementia (median age at onset, 76.0 years). CONCLUSIONS AND RELEVANCE: In this family, the amyloidogenic PSEN1 A79V mutation recapitulates the clinical attributes of LOAD. Previously reported clinical phenotypic differences between individuals with ADAD and LOAD may reflect age- or mutation dependent effects. PMID- 27454812 TI - Modeling Electrophysiological Coupling and Fusion between Human Mesenchymal Stem Cells and Cardiomyocytes. AB - Human mesenchymal stem cell (hMSC) delivery has demonstrated promise in preclinical and clinical trials for myocardial infarction therapy; however, broad acceptance is hindered by limited understanding of hMSC-human cardiomyocyte (hCM) interactions. To better understand the electrophysiological consequences of direct heterocellular connections between hMSCs and hCMs, three original mathematical models were developed, representing an experimentally verified triad of hMSC families with distinct functional ion channel currents. The arrhythmogenic risk of such direct electrical interactions in the setting of healthy adult myocardium was predicted by coupling and fusing these hMSC models to the published ten Tusscher midcardial hCM model. Substantial variations in action potential waveform-such as decreased action potential duration (APD) and plateau height-were found when hCMs were coupled to the two hMSC models expressing functional delayed rectifier-like human ether a-go-go K+ channel 1 (hEAG1); the effects were exacerbated for fused hMSC-hCM hybrid cells. The third family of hMSCs (Type C), absent of hEAG1 activity, led to smaller single-cell action potential alterations during coupling and fusion, translating to longer tissue-level mean action potential wavelength. In a simulated 2-D monolayer of cardiac tissue, re-entry vulnerability with low (5%) hMSC insertion was approximately eight-fold lower with Type C hMSCs compared to hEAG1-functional hMSCs. A 20% decrease in APD dispersion by Type C hMSCs compared to hEAG1-active hMSCs supports the claim of reduced arrhythmogenic potential of this cell type with low hMSC insertion. However, at moderate (15%) and high (25%) hMSC insertion, the vulnerable window increased independent of hMSC type. In summary, this study provides novel electrophysiological models of hMSCs, predicts possible arrhythmogenic effects of hMSCs when directly coupled to healthy hCMs, and proposes that isolating a subset of hMSCs absent of hEAG1 activity may offer increased safety as a cell delivery cardiotherapy at low levels of hMSC-hCM coupling. PMID- 27454814 TI - An investigation into the prevalence and impact of breast pain, bra issues and breast size on female horse riders. AB - For female horse riders, breast pain, bra issues and breast size may be important concerns which have yet to be considered. This study aimed to establish the prevalence of breast pain and bra issues in female horse riders and explores the impact of breast size on breast pain and bra issues. A 6-part, 32 question online survey was completed by 1324 females who participated in horse riding activities. Descriptive and chi-squared (chi2) analyses were utilised; data for 1265 participants were included in the final analysis. Breast pain was experienced by 40% of all participants and this was significantly related to self-reported cup size (chi2 = 54.825, P < 0.001), increasing linearly. Breast pain was experienced most frequently during sitting trot and 21% of symptomatic participants reported that breast pain affected their horse riding performance. At least one bra issue was reported by 59% of participants; larger-breasted participants reported experiencing all bra issues more frequently than smaller-breasted participants (P < 0.001). These results demonstrate that educational initiatives are needed to ensure female horse riders are informed about appropriate bra fit and breast support during horse riding to increase comfort and help reduce the potential negative associations with performance. PMID- 27454815 TI - Promiscuous Histone Mis-Assembly Is Actively Prevented by Chaperones. AB - Histone proteins are essential for the organization, expression, and inheritance of genetic material for eukaryotic cells. A centromere-specific H3 histone variant, centromere protein A (CENP-A), shares about 50% amino acid sequence identity with H3. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their distinct biological functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal a high degree of similarity. In this work, we characterize the structural dynamics of CENP-A/H4 and H3/H4 dimers based on a dual-resolution approach, using both microsecond-scale explicit-solvent all-atom and coarse grained (CG) molecular dynamics (MD) simulations. Our data show that the H4 histone is significantly more rigid compared with the H3 histone and its variant CENP-A, hence, serving as a reinforcing structural element within the histone core. We report that the CENP-A/H4 dimer is significantly more dynamic than its canonical counterpart H3/H4, and our results provide a physical explanation for this flexibility. Further, we observe that the centromere-specific chaperone Holliday Junction Recognition Protein (HJURP) stabilizes the CENP-A/H4 dimer by forming a specific electrostatic interaction network. Finally, replacing CENP-A S68 with E68 disrupts the binding interface between CENP-A and HJURP in all-atom MD simulation, and consistently, in vivo experiments demonstrate that replacing CENP-A S68 with E68 disrupts CENP-A's localization to the centromere. Based on all our results, we propose that, during the CENP-A/H4 deposition process, the chaperone HJURP protects various substructures of the dimer, serving both as a folding and binding chaperone. PMID- 27454816 TI - I have my own lease-So why the service plan again? Perspectives on service planning in supportive housing. AB - OBJECTIVE: This study aimed to understand multiple stakeholder perspectives implementing a recovery-oriented approach to service planning in supportive housing programs serving people with lived experience of mental illnesses. METHOD: Multiple stakeholders (N = 57) were recruited to participate in focus groups (N = 8), including 4 with tenants, 2 with service coordinators, 1 with supervisors, and 1 with leadership. Supportive housing programs were purposively sampled from a recovery-oriented organization serving 1,500 people annually. Stakeholders' experiences with service planning and implementing a recovery oriented approach to service planning were explored. The authors conducted inductive thematic analyses combined with a conceptual matrix, which yielded themes across and within multiple stakeholder focus groups. RESULTS: Three themes emerged: (a) an institutional reminder-service planning experiences elicited negative emotions and served to remind people of experiences in institutional settings, (b) one-size-fits-all service planning-stakeholders perceived the use of quality assurance tools within the planning process as rigid to others' interests beyond their own, and (c) rules and regulations-reconciling funder requirements (e.g., completion dates) while also tailoring services to tenants' particular situations challenged providers. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Even in a recovery-oriented organization, findings suggest that service planning in supportive housing has limitations in responding to each tenant's iterative recovery process. Further, in this context where people can make their home, stakeholders questioned whether the very presence of ongoing service planning activities is problematic. However, tenant-service coordinator relationships predicated on mutual respect and esteem overcame some service planning limitations. (PsycINFO Database Record PMID- 27454817 TI - Exploring the influence of encoding format on subsequent memory. AB - Distinctive encoding is greatly influenced by gist-based processes and has been shown to suffer when highly similar items are presented in close succession. Thus, elucidating the mechanisms underlying how presentation format affects gist processing is essential in determining the factors that influence these encoding processes. The current study utilised multivariate partial least squares (PLS) analysis to identify encoding networks directly associated with retrieval performance in a blocked and intermixed presentation condition. Subsequent memory analysis for successfully encoded items indicated no significant differences between reaction time and retrieval performance and presentation format. Despite no significant behavioural differences, behaviour PLS revealed differences in brain-behaviour correlations and mean condition activity in brain regions associated with gist-based vs. distinctive encoding. Specifically, the intermixed format encouraged more distinctive encoding, showing increased activation of regions associated with strategy use and visual processing (e.g., frontal and visual cortices, respectively). Alternatively, the blocked format exhibited increased gist-based processes, accompanied by increased activity in the right inferior frontal gyrus. Together, results suggest that the sequence that information is presented during encoding affects the degree to which distinctive encoding is engaged. These findings extend our understanding of the Fuzzy Trace Theory and the role of presentation format on encoding processes. PMID- 27454818 TI - Highly Safe Ionic Liquid Electrolytes for Sodium-Ion Battery: Wide Electrochemical Window and Good Thermal Stability. AB - Novel ionic liquid (IL) electrolytes are prepared by mixing 1-ethyl-3 methylimidazolium-bis-tetrafluoroborate (EMIBF4) with different concentrations of sodium salt (NaBF4). The as-prepared IL electrolytes display wide electrochemical windows of ~4 V (1-5 V), which are consistent with the quantum chemical theoretical calculation. The IL electrolyte with 0.1 M NaBF4 shows excellent ionic conductivity, namely, 9.833 * 10(-3) S cm(-1) at 20 degrees C. In addition, nonflammability and good thermal stability are exhibited by combustion test and thermogravimetric analysis (TGA), which indicate the high safety of the IL electrolyte. PMID- 27454821 TI - Taming of the monitors: reducing false alarms in intensive care units. AB - False alarms in intensive care units represent a serious threat to patients. We propose a method for detection of five live-threatening arrhythmias. It is designed to work with multimodal data containing electrocardiograph and arterial blood pressure or photoplethysmograph signals. The presented method is based on descriptive statistics and Fourier and Hilbert transforms. It was trained using 750 records. The method was validated during the follow-up phase of the CinC/Physionet Challenge 2015 on a hidden dataset with 500 records, achieving a sensitivity of 93% (95%) and a specificity of 87% (88%) for real-time (retrospective) files. The given sensitivity and specificity resulted in score of 81.62 (84.96) for real-time (retrospective) records. The presented method is an improved version of the original algorithm awarded the first and the second prize in CinC/Physionet Challenge 2015. PMID- 27454819 TI - The mammalian dynein-dynactin complex is a strong opponent to kinesin in a tug-of war competition. AB - Kinesin and dynein motors transport intracellular cargos bidirectionally by pulling them in opposite directions along microtubules, through a process frequently described as a 'tug of war'. While kinesin produces 6 pN of force, mammalian dynein was found to be a surprisingly weak motor (0.5-1.5 pN) in vitro, suggesting that many dyneins are required to counteract the pull of a single kinesin. Mammalian dynein's association with dynactin and Bicaudal-D2 (BICD2) activates its processive motility, but it was unknown how this affects dynein's force output. Here, we show that formation of the dynein-dynactin-BICD2 (DDB) complex increases human dynein's force production to 4.3 pN. An in vitro tug-of war assay revealed that a single DDB successfully resists a single kinesin. Contrary to previous reports, the clustering of many dyneins is not required to win the tug of war. Our work reveals the key role of dynactin and a cargo adaptor protein in shifting the balance of forces between dynein and kinesin motors during intracellular transport. PMID- 27454820 TI - F-actin dismantling through a redox-driven synergy between Mical and cofilin. AB - Numerous cellular functions depend on actin filament (F-actin) disassembly. The best-characterized disassembly proteins, the ADF (actin-depolymerizing factor)/cofilins (encoded by the twinstar gene in Drosophila), sever filaments and recycle monomers to promote actin assembly. Cofilin is also a relatively weak actin disassembler, posing questions about mechanisms of cellular F-actin destabilization. Here we uncover a key link to targeted F-actin disassembly by finding that F-actin is efficiently dismantled through a post-translational mediated synergism between cofilin and the actin-oxidizing enzyme Mical. We find that Mical-mediated oxidation of actin improves cofilin binding to filaments, where their combined effect dramatically accelerates F-actin disassembly compared with either effector alone. This synergism is also necessary and sufficient for F actin disassembly in vivo, magnifying the effects of both Mical and cofilin on cellular remodelling, axon guidance and Semaphorin-Plexin repulsion. Mical and cofilin, therefore, form a redox-dependent synergistic pair that promotes F-actin instability by rapidly dismantling F-actin and generating post-translationally modified actin that has altered assembly properties. PMID- 27454822 TI - Genomic studies of multiple myeloma reveal an association between X chromosome alterations and genomic profile complexity. AB - The genomic profile of multiple myeloma (MM) has prognostic value by dividing patients into a good prognosis hyperdiploid group and a bad prognosis nonhyperdiploid group with a higher incidence of IGH translocations. This classification, however, is inadequate and many other parameters like mutations, epigenetic modifications, and genomic heterogeneity may influence the prognosis. We performed a genomic study by array-based comparative genomic hybridization on a cohort of 162 patients to evaluate the frequency of genomic gains and losses. We identified a high frequency of X chromosome alterations leading to partial Xq duplication, often associated with inactive X (Xi) deletion in female patients. This partial X duplication could be a cytogenetic marker of aneuploidy as it is correlated with a high number of chromosomal breakages. Patient with high level of chromosomal breakage had reduced survival regardless the region implicated. A higher transcriptional level was shown for genes with potential implication in cancer and located in this altered region. Among these genes, IKBKG and IRAK1 are members of the NFKB pathway which plays an important role in MM and is a target for specific treatments. (c) 2016 Wiley Periodicals, Inc. PMID- 27454823 TI - Karyoevolutionary Inferences in Enigmatic Taxon Astyanax (Teleostei: Characidae). AB - Accessing the taxonomy of fish is a basic condition for the conservation of species, and the understanding of their evolutionary relationships. Many Neotropical species of fishes of the order Characiformes are considered incertae sedis because of a lack of consistent evidence of monophyly, with the genus Astyanax among them. With a cytotaxonomic and evolutionary purpose, we compared the karyotype of two species of Astyanax: Astyanax paranae and Astyanax elachylepis. Conventional cytogenetic analyses revealed 2n = 50 chromosomes for the two species, with interspecific and interpopulation karyotype variations. Heterochromatin was primarily localized in the pericentromeric regions, and it was associated with organized regions of the nucleolus (NORs) and/or telomeric regions in some acrocentric chromosomes. The in situ localization of 18S ribosomal DNA (rDNA) and 5S probes varied among A. paranae populations. In A. elachylepis, only one chromosome pair was stained by the 18S probe and another by the 5S probe, confirming a simple NORs pattern. These results support the utility of chromosome markers in Astyanax taxonomy and reveal the conserved characteristics of the karyotype of A. elachylepis, consisting exclusively of two chromosome arms, and the occurrence of simple homologous and non-syntenic sites for 18S and 5S rDNA in this species. PMID- 27454824 TI - Ratiometric Detection of beta-Amyloid and Discrimination from Lectins by a Supramolecular AIE Glyconanoparticle. AB - While the development of AIE (aggregation-induced-emission) based fluorimetric probes for biological applications has been an active research area, probes with a ratiometric signal for biomolecular recognition have been rare. Here, a ratiometric AIE glyconanoparticle formed by the supramolecular assembly between a silole-based AIEgen and fluorescent glycoprobes for the detection of amyloid beta (Abeta) peptides and fibrils, which are a signature of neurological disorders such as the Alzheimer's disease, is shown. Complexation of glycoprobes with the AIEgen produces an intensive fluorescence emission of the former because of a Forster resonance energy transfer between the two molecules. Subsequently, the presence of Abeta dissembles the particle, producing a fluorescence emission of the AIEgen. Interestingly, the addition of lectins that selectively recognize the glycoprobes results in a different ratiometric response of the particle, thereby enabling a discrimination from Abeta detection. This research offers insight into the simple construction of multifunctional ratiometric probes based on the supramolecular hybridization of a wide variety of AIEgens with fluorescent molecular probes. PMID- 27454825 TI - Maternal Hemorrhage Quality Improvement Collaborative Lessons. AB - PURPOSE: The purpose of this study was to describe user experience with implementation of an obstetric hemorrhage toolkit and determine the degree of implementation of recommended practices that occurred during a 31-hospital quality improvement learning collaborative. STUDY DESIGN AND METHODS: This descriptive qualitative study included semistructured interviews with 22 implementation team leaders and review of transcripts from collaborative reporting calls recorded during the hemorrhage collaborative. Interviews included open-ended, closed, and ranking questions. Numeric responses were analyzed with descriptive statistics. Open-ended responses and call transcripts were analyzed thematically. RESULTS: Each of the 10 core toolkit components was ranked as currently "implemented" or "implemented and sustained" by at least 77% of interviewees. Most core elements were deemed "critical to retain." Respondents found debriefing the most difficult element of the toolkit to implement and sustain. Organizational context was the overarching theme regarding factors facilitating or constraining implementation. This included organizational structure and culture, previous experience with quality improvement, resources, and clinician engagement. Nurses were deeply involved in implementation and "physician buy-in" was a frequently mentioned facilitator when present and barrier when absent. CLINICAL IMPLICATIONS: Greater understanding of and attention to organizational context and resources, greater appreciation for nursing involvement, and increased recognition of the role of organizational leadership are needed to facilitate widespread improvement initiatives in maternity care. Implementation science approaches may be useful in achieving national goals for maternal quality improvement and safety. PMID- 27454826 TI - Association of Reference Pricing for Diagnostic Laboratory Testing With Changes in Patient Choices, Prices, and Total Spending for Diagnostic Tests. AB - IMPORTANCE: Prices for laboratory and other clinical services vary widely. Employers and insurers increasingly are adopting "reference pricing" policies to create incentives for patients to select lower-priced facilities. OBJECTIVE: To measure the association between implementation of reference pricing and patient choice of laboratory, test prices, patient out-of-pocket spending, and insurer spending. DESIGN, SETTING, AND PARTICIPANTS: We conducted an observational study of changes in laboratory pricing and selection by employees of a large national grocery firm (n = 30 415) before and after the firm implemented a reference pricing policy for laboratory services and compared the findings with changes over the same period for policy holders of a large national insurer that did not implement reference pricing (n = 181 831). The grocery firm established a maximum payment limit at the 60th percentile of the distribution of prices for each laboratory test in each region. Employees were provided with data on prices at all laboratories through a mobile digital platform. Patients selecting a laboratory that charged more than the payment limit were required to pay the full difference themselves. A total of 2.13 million claims were analyzed for 285 types of in vitro diagnostic tests between 2010 and 2013. MAIN OUTCOMES AND MEASURES: Patient choice of laboratory, price paid per test, patient out-of-pocket costs, and employer spending. RESULTS: Compared with trends in prices paid by insurance policy holders not subject to reference pricing, and after adjusting for characteristics of tests and patients, implementation of reference pricing was associated with a 31.9% reduction (95% CI, 20.6%-41.6%) in average price paid per test by the third year of the program. In these 3 years, total spending on laboratory tests declined by $2.57 million (95% CI, $1.59-$3.35 million). Out-of pocket costs by patients declined by $1.05 million (95% CI, $0.73-$1.37 million). Spending by the employer declined by $1.70 million (95% CI, $0.92-$2.48 million). CONCLUSIONS AND RELEVANCE: When combined with access to price information, reference pricing was associated with patient choice of lower-cost laboratories and reductions in prices and payments by both employer and employees. PMID- 27454827 TI - Liposomes Coated with Isolated Macrophage Membrane Can Target Lung Metastasis of Breast Cancer. AB - Cancer metastasis leads to high mortality of breast cancer and is difficult to treat because of the poor delivery efficiency of drugs. Herein, we report the wrapping of a drug-carrying liposome with an isolated macrophage membrane to improve delivery to metastatic sites. The macrophage membrane decoration increased cellular uptake of the emtansine liposome in metastatic 4T1 breast cancer cells and had inhibitory effects on cell viability. In vivo, the macrophage membrane enabled the liposome to target metastatic cells and produced a notable inhibitory effect on lung metastasis of breast cancer. Our results provide a biomimetic strategy via the biological properties of macrophages to enhance the medical performance of a nanoparticle in vivo for treating cancer metastasis. PMID- 27454828 TI - Selective Electrochemical versus Chemical Oxidation of Bulky Phenol. AB - The electrochemical oxidation of selected tert-butylated phenols 2,6-di-tert butyl-4-methylphenol (1), 2,6-di-tert-butylphenol (2), 2,4,6-tri-tert-butylphenol (3), 2-tert-butylphenol (4), and 4-tert-butylphenol (5) was studied in an aprotic environment using cyclic voltammetry, square-wave voltammetry, and UV-vis spectroscopy. All compounds exhibited irreversible oxidation of the corresponding phenol or phenolate ion. Compound 2 was selectively electrochemically oxidized, while other phenol analogues underwent mostly chemical oxidation. The electrochemical oxidation of 2 produced a highly absorbing product, 3,5,3',5' tetra-tert-butyl-4,4'-diphenoquinone, which was characterized by X-ray crystal diffraction. The electrochemical oxidation was monitored as a function of electrochemical parameters and concentration. Experimental and theoretical data indicated that the steric hindrance, phenoxyl radical stability, and hydrogen bonding influenced the outcome of the electrochemical oxidation. The absence of the substituent at the para position and the presence of the bulky substituents at ortho positions were structural and electrostatic requirements for the selective electrochemical oxidation. PMID- 27454829 TI - The Development and Early to Midterm Findings of the Multicenter Revision Anterior Cruciate Ligament Study. AB - Revision anterior cruciate ligament (ACL) reconstruction can present a series of unique challenges for the both the patient and the treating surgeon. The Multicenter ACL Revision Study (MARS) was established to identify the factors contributing to ACL graft failure and report on the outcomes following revision reconstruction. In this article we review the development and early to midterm findings of the MARS group. PMID- 27454830 TI - Advances in Understanding Contact Lens Discomfort. PMID- 27454831 TI - Contact Lens Comfort. PMID- 27454833 TI - Controlled Distribution and Clustering of Silver in Ag-DLC Nanocomposite Coatings Using a Hybrid Plasma Approach. AB - Incorporation of selected metallic elements into diamond-like carbon (DLC) has emerged as an innovative approach to add unique functional properties to DLC coatings, thus opening up a range of new potential applications in fields as diverse as sensors, tribology, and biomaterials. However, deposition by plasma techniques of metal-containing DLC coatings with well-defined structural properties and metal distribution is currently hindered by the limited understanding of their growth mechanisms. We report here a silver-incorporated diamond-like carbon coating (Ag-DLC) prepared in a hybrid plasma reactor which allowed independent control of the metal content and the carbon film structure and morphology. Morphological and chemical analyses of Ag-DLC films were performed by atomic force microscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy. The vertical distribution of silver from the surface toward the coating bulk was found to be highly inhomogeneous due to top surface segregation and clustering of silver nanoparticles. Two plasma parameters, the sputtered Ag flux and ion energy, were shown to influence the spatial distribution of silver particles. On the basis of these findings, a mechanism for Ag-DLC growth by plasma was proposed. PMID- 27454834 TI - Propofol in the treatment of refractory migraine headaches. AB - INTRODUCTION: Refractory/intractable migraine headaches are associated with chronic pain that does not respond to standard care of treatment. Propofol(2,6 diisopropylphenol) in sub-anesthetic doses has been reported to be beneficial in such patients. The present article describes the complete drug profile of propofol in the management of these super-refractory migraine headaches. AREAS COVERED: The article covers different preclinical and clinical studies available in the literature. Expert commentary: Propofol is useful as an off-label drug molecule in an emergency situation of refractory migraines where it has been found to reduce the pain intensity. The molecule with a narrow therapeutic index and high abuse potential is prescribed only when conventional drugs fail to deliver any relief. There are not adequate double-blind crossover studies that substantiate the effectiveness of propofol in the treatment of migraine headaches. Furthermore, long-term outcomes for the use of propofol in migraine headaches requires an extensive investigation. PMID- 27454835 TI - High-purity 3D nano-objects grown by focused-electron-beam induced deposition. AB - To increase the efficiency of current electronics, a specific challenge for the next generation of memory, sensing and logic devices is to find suitable strategies to move from two- to three-dimensional (3D) architectures. However, the creation of real 3D nano-objects is not trivial. Emerging non-conventional nanofabrication tools are required for this purpose. One attractive method is focused-electron-beam induced deposition (FEBID), a direct-write process of 3D nano-objects. Here, we grow 3D iron and cobalt nanopillars by FEBID using diiron nonacarbonyl Fe2(CO)9, and dicobalt octacarbonyl Co2(CO)8, respectively, as starting materials. In addition, we systematically study the composition of these nanopillars at the sub-nanometer scale by atom probe tomography, explicitly mapping the homogeneity of the radial and longitudinal composition distributions. We show a way of fabricating high-purity 3D vertical nanostructures of ~50 nm in diameter and a few micrometers in length. Our results suggest that the purity of such 3D nanoelements (above 90 at% Fe and above 95 at% Co) is directly linked to their growth regime, in which the selected deposition conditions are crucial for the final quality of the nanostructure. Moreover, we demonstrate that FEBID and the proposed characterization technique not only allow for growth and chemical analysis of single-element structures, but also offers a new way to directly study 3D core-shell architectures. This straightforward concept could establish a promising route to the design of 3D elements for future nano-electronic devices. PMID- 27454836 TI - Integrative Review on Adherence in Haitians With Diabetes. AB - In light of a marked increase in the incidence and prevalence of diabetes in the United States in recent years with associated health costs totaling $245 billion for 2012, diabetes has become a major health and fiscal concern. Haitian Americans as a cultural group have unique obstacles to effective treatment and management of diabetes. This paper analyzes recent studies relevant to these challenges in anticipation of new research pertaining to this population. Although medication compliance is generally referred to as adherence, it is a complex concept and key challenge in diabetes care. Accordingly, this paper will further define adherence by describing its relevance in effective treatment and management. It will also analyze key theoretical perspectives in diabetes care, summarize recent research, and make recommendations for effective future research on the impact of diabetes education in Haitian Americans. PMID- 27454837 TI - Datum isn't; data are. PMID- 27454840 TI - The enigma of neurogenic thoracic outlet syndrome following motor vehicle collisions. AB - BACKGROUND: The concept of neurogenic thoracic outlet syndrome (N-TOS) including upper and lower plexus syndromes secondary to soft tissue neck injury after motor vehicle collisions (MVCs) has been contentious. We considered that analysis of objective data from this group of patients could provide insight into this controversial type of N-TOS. METHODS: During the 10-year period January 2001 through December 2010 we examined patients who had received a diagnosis of N-TOS following an MVC. We graded the principal diagnosis based on the objective data from our physical examination. RESULTS: In total 263 patients received a diagnosis of N-TOS during the study period. At the highest accuracy level of diagnosis there were 56 patients with ulnar entrapment syndrome (UES), 40 with carpal tunnel syndrome (CTS) and 55 with nonorganic disease (NOD), for a total of 151 (57.4%) cases in which the diagnosis of N-TOS was brought into question. The elevated arm stress test (EAST) reproduced the symptoms of UES in 33 of the 56 patients of UES (58.9%) and reproduced the symptoms of CTS in 18 of the 40 patients with CTS (45.0%). CONCLUSION: There appears to be a high incidence of misdiagnosis of N-TOS following MVCs. The EAST is not a prime test for N-TOS. PMID- 27454839 TI - Attitudes and beliefs about the surgical safety checklist: Just another tick box? AB - BACKGROUND: Following a landmark study showing decreased morbidity and mortality after implementation of the surgical safety checklist (SSC), it has been widely adopted into perioperative policy. We explored the impact of attitudes and beliefs surrounding the SSC on its uptake in Calgary. METHODS: We used qualitative methodology to examine factors influencing SSC use. We performed semistructured interviews based on Rogers' theory of diffusion of innovation. Purposive and snowball sampling were used to identify surgeons, anesthesiologists and operating room nurses from hospitals in Calgary. Data collection and analysis were based on grounded theory. Two individuals jointly analyzed data and achieved consensus on emerging themes. RESULTS: Generated themes included 1) the SSC has brought organization to previous informal perioperative checks, 2) the SSC is most helpful when it is simple, and 3) the 3 current components of the checklist are redundant. The briefing was considered the most important aspect and the debriefing the least important. Initially the SSC was difficult to implement owing to a shift in time management and perioperative culture; however, it has now assimilated into perioperative routine. Finally, though most participants agreed that the SSC might avoid some delays and complications, only a few believe there have been observable improvements to morbidity and mortality. CONCLUSION: Although the SSC has been integrated into perioperative practice in Calgary, participants believe that previous informal checkpoints were able to circumvent most perioperative issues. Although the SSC may help with flow and equipment, participants believe it fails to show a subjective, clinically important improvement. PMID- 27454841 TI - Impact of sex on the clinicopathological characteristics and prognosis of papillary thyroid cancer. AB - SUMMARY: Papillary thyroid cancer (PTC) is the most common endocrine malignancy. Observed clinical and pathological differences between the sexes of PTC patients have been reported. There is currently no consensus regarding the impact of sex on PTC prognostication. We studied 566 PTC patients and observed that there was a higher PTC incidence in women, that PTC diagnosis was more challenging in women, and that men tended to present with larger cancers. However, once PTC is diagnosed, both sexes have a similar cancer prognosis, as evaluated using the MACIS (Metastasis, Age, Completeness of Resection, Invasion, Size) score. Our observations suggest that research efforts should be especially directed at improving the diagnostic yield of preoperative fine needle aspiration biopsy in women who present with nodular thyroid disease. PMID- 27454842 TI - Letter to the editor: response to "Surgeon unemployment: Would practice sharing be a viable solution?". PMID- 27454843 TI - Letter to the editor: response to "Surgeon unemployment: Would practice sharing be a viable solution?" - Author response. PMID- 27454844 TI - 2016 Canadian Surgery Forum Abstracts. PMID- 27454845 TI - Ecological risk assessment for Pacific salmon exposed to dimethoate in California. AB - A probabilistic risk assessment of the potential direct and indirect effects of acute dimethoate exposure to salmon populations of concern was conducted for 3 evolutionarily significant units (ESUs) of Pacific salmon in California. These ESUs were the Sacramento River winter-run chinook, the California Central Valley spring-run chinook, and the California Central Valley steelhead. Refined acute exposures were estimated using the Soil and Water Assessment Tool, a river basin scale model developed to quantify the impact of land-management practices in large, complex watersheds. Both direct effects (i.e., inhibition of brain acetylcholinesterase activity) and indirect effects (i.e., altered availability of aquatic invertebrate prey) were assessed. Risk to salmon and their aquatic invertebrate prey items was determined to be de minimis. Therefore, dimethoate is not expected to have direct or indirect adverse effects on Pacific salmon in these 3 ESUs. Environ Toxicol Chem 2017;36:532-543. (c) 2016 SETAC. PMID- 27454846 TI - S100G expression and function in fibroblasts on colitis induction. AB - Supplementation with interleukin (IL)-10, an important anti-inflammatory cytokine, has shown disappointing efficacy for inflammatory bowel diseases (IBD). IL-10 may down-regulate the expression of other anti-inflammatory mediators following colitis induction. We used a colitis model characterized by hapten protein visualization, which indicates the site of hapten-protein formation after colitis induction for histological and gene expression analyses. Under IL-10 deficiency, following colitis induction inflammatory changes were reduced, and S100G expression was elevated. S100G was expressed in fibroblasts, and S100G expression was down-regulated by IL-10. S100G suppressed the production of monocyte chemotactic protein-1 (MCP-1) through the inhibition of NF-kappaB activation. Therefore, S100G, also known as Calbindin-D9k, may be an important anti-inflammatory mediator in fibroblasts following colitis induction, and down regulation of S100G expression might be one reason for the insufficient performance of IL-10 supplementation. PMID- 27454847 TI - Shikimic acid inhibits LPS-induced cellular pro-inflammatory cytokines and attenuates mechanical hyperalgesia in mice. AB - BACKGROUND AND AIMS: Shikimic acid (SA) is present in a wide variety of plants and microorganisms used in traditional and folk medicine and also is an essential starting material for the synthesis of the antiviral drug Oseltamivir (Tamiflu(r)). Some pharmacological actions observed in SA-enriched products include antioxidant and anti-inflammatory activities. Here, we investigated the anti-inflammatory and antinociceptive actions of isolated SA. METHODS: RAW 264.7 macrophage cells were treated with bacterial LPS (1MUg/mL) and the effect of SA on the modulation of cell viability, nitric oxide (NO) production, TNF-alpha, and IL-1beta content and MAPK (ERK1/2 and p38) activation was evaluated. Besides, the anti-hyperalgesic actions of SA on in vivo model of mechanical hyperalgesia induced by carrageenan (CG), dopamine (DA), TNF-alpha and prostaglandin (PGE2) were assessed. RESULTS: In RAW 264.7 cells, SA suppressed LPS-induced decrease in cell viability and nitrite accumulation to control values and inhibited up regulation of TNF-alpha (65%) and IL-1beta (39%). These effects may be mediated at least in part by inhibition of LPS-induced ERK 1/2 (22%) and p38 (17%) phosphorylation. In mice, SA at 50, 100, and 200mg/kg decreased formalin-induced nociceptive behavior (around 50%) and inhibited the inflammatory nociception induced by TNF-alpha and PGE2 (50 to 75% each). Moreover, SA (100 and 200mg/kg) significantly attenuated the mechanical hyperalgesia induced by CG and DA (25 to 40% each). CONCLUSIONS: These results indicate that SA presents anti-inflammatory actions with potential for development of drugs to treat pro-inflammatory and painful conditions. PMID- 27454848 TI - Maternal birth trauma: why should it matter to urogynaecologists? AB - PURPOSE OF REVIEW: There is increasing awareness of the importance of intrapartum events for future pelvic floor morbidity in women. In this review, we summarize recent evidence and potential consequences for clinical practice. RECENT FINDINGS: Both epidemiological evidence and data from perinatal imaging studies have greatly improved our understanding of the link between childbirth and later morbidity. The main consequences of traumatic childbirth are pelvic organ prolapse (POP) and anal incontinence. In both instances the primary etiological pathways have been identified: levator trauma in the case of POP and anal sphincter tears in the case of anal incontinence. As most such trauma is occult, imaging is required for diagnosis. SUMMARY: Childbirth-related major maternal trauma is much more common than generally assumed, and it is the primary etiological factor in POP and anal incontinence. Both sphincter and levator trauma can now be identified on imaging. This is crucial not only for clinical care and audit, but also for research. Postnatally diagnosed trauma can serve as intermediate outcome measure in intervention trials, opening up multiple opportunities for clinical research aimed at primary and secondary prevention. PMID- 27454849 TI - Obstructive anomalies of the gynecologic tract. AB - PURPOSE OF REVIEW: This review discusses current diagnosis, management and outcomes of obstructive anomalies of the gynecologic tract. RECENT FINDINGS: In this review, we will discuss the clinical presentation of obstructive anomalies, surgical management and reproductive outcomes following surgical intervention. SUMMARY: Identification of obstructive anomalies of the gynecologic tract is crucial when evaluating patients presenting with or without menses and cyclical pain. Surgical management is often the preferred modality for treatment, although menstrual suppression is recommended in certain circumstances. PMID- 27454850 TI - Delayed puberty in the female patient. AB - PURPOSE OF REVIEW: The purpose is to review current recommendations for the evaluation and management of delayed puberty in the female patient. RECENT FINDINGS: Kisspeptin activation has emerged as an important factor for initiation of pubertal development. Causes of delayed puberty can be considered in four main categories: constitutional delay of growth and puberty, hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and transient/functional hypogonadism. The most common cause of delayed puberty is constitutional delay of growth and puberty; however, consistent differentiation from idiopathic hypogonadotropic hypogonadism remains challenging. Initial assessment with broad spectrum testing in an otherwise healthy adolescent is often of low clinical value. Treatment is aimed at the underlying cause of delayed puberty whenever possible and individualized to the patient. SUMMARY: Understanding the factors that contribute to delayed puberty and a thoughtful evaluation, structured to the patient, is important to identify the cause of delayed puberty and prevent unnecessary and often expensive investigations. Insuring appropriate pubertal progression, optimizing height and bone health, as well as preservation of psychosocial well-being are the ultimate goals of management of delayed puberty. PMID- 27454851 TI - Four steps to preserving adolescent confidentiality in an electronic health environment. AB - PURPOSE OF REVIEW: Best practices in adolescent care require the ability to provide confidential services, particularly for reproductive health care. As systems implement electronic health records and patients use health portals to access information and communicate with their healthcare team, special attention should be paid to protection of adolescent confidentiality in the electronic environment. RECENT FINDINGS: Professional organizations have issued guidance for electronic health records and portal use, but implementation has varied widely between systems, with multiple risks for breaches of confidentiality. Despite interest from patients and families, adolescent health portal use remains low. SUMMARY: Understanding the legal and electronic environments in which we care for adolescent patients allows us to educate, advocate, and implement our electronic tools in a way that respects our adolescent patients' need for confidential care, the importance of their caregivers in promoting their health, and the legal rights of both. PMID- 27454852 TI - Primary vaginal dilation for vaginal agenesis: strategies to anticipate challenges and optimize outcomes. AB - PURPOSE OF REVIEW: Primary vaginal dilation is patient controlled, safe, less painful, and much lower cost compared with operative vaginoplasty and is considered first-line treatment for vaginal agenesis for women with Mayer Rokitansky-Kuster-Hauser syndrome and androgen insensitivity syndrome. RECENT FINDINGS: This review will highlight studies that assess the optimal methods of primary vaginal dilation and clarify ideal counseling, frequency of dilation, management of side-effects, and long-term physical and psychological outcomes. SUMMARY: Providers who care for women with vaginal agenesis should be prepared to not only teach the technical skill of dilation, but also to assess readiness and troubleshoot symptoms associated with dilation. PMID- 27454853 TI - Pediatric and adolescent gynecology: improving the reproductive health of youth. PMID- 27454854 TI - High-throughput identification of the microbial biodiversity of cocoa bean fermentation by MALDI-TOF MS. AB - : Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a powerful biotyping tool increasingly used for high-throughput identification of clinical microbial isolates, however, in food fermentation research this approach is still not well established. This study examines the microbial biodiversity of cocoa bean fermentation based on the isolation of micro organisms in cocoa-producing regions, followed by MALDI-TOF MS in Switzerland. A preceding 6-week storage test to mimic lengthy transport of microbial samples from cocoa-producing regions to Switzerland was performed with strains of Lactobacillus plantarum, Acetobacter pasteurianus and Saccharomyces cerevisiae. Weekly MALDI-TOF MS analysis was able to successfully identify microbiota to the species level after storing live cultures on slant agar at mild temperatures (7 degrees C) and/or in 75% aqueous ethanol at differing temperatures (-20, 7 and 30 degrees C). The efficacy of this method was confirmed by on-site recording of the microbial biodiversity in cocoa bean fermentation in Bolivia and Brazil, with a total of 1126 randomly selected isolates. MALDI-TOF MS analyses revealed known dominant cocoa bean fermentation species with Lact. plantarum and Lactobacillus fermentum in the lactic acid bacteria taxon, Hanseniaspora opuntiae and S. cerevisiae in the yeast taxon, and Acet. pasteurianus, Acetobacter fabarum, Acetobacter ghanensis and Acetobacter senegalensis in the acetic acid bacteria taxon. SIGNIFICANCE AND IMPACT OF THE STUDY: Microbial identification with MALDI TOF MS has increased the number of samples that can be analysed in a given time, a prerequisite for high-throughput methods. This method is already widely used for the identification of clinical microbial isolates, whereas in food fermentation research, including cocoa bean fermentation, microbiota is mostly identified by time-consuming, biochemical-based phenotyping and molecular approaches. This study presents the use of MALDI-TOF MS for characterizing the microbial biodiversity of cocoa bean fermentation. The feasibility of MALDI-TOF MS identification of cocoa-specific microbiota has been shown with samples collected during on-site studies in two countries of origin, Bolivia and Brazil. PMID- 27454855 TI - A single Mediterranean meal does not impair postprandial flow-mediated dilatation in healthy men with subclinical metabolic dysregulations. AB - Cardiovascular risk factors are known to exacerbate high-saturated fatty acid meal (HSFAM)-induced endothelial dysfunction, but the influence of subclinical metabolic dysregulations and the acute impact of a single mixed Mediterranean type meal (MMM) remains unknown. Thus, this study has the objective to evaluate the metabolic and vascular effect of such meals in healthy subjects with or without subclinical fasting metabolic dysregulations. Twenty-eight healthy males without overt cardiovascular risk factors randomly ingested 1 of 2 isocaloric meals on separate days. Plasma metabolic markers, fatty acid (FA) profile, and endothelial function (flow-mediated dilatation; FMD) were assessed at baseline and 2 and 4 h after meal ingestion. Unsupervised hierarchical clustering identified 2 subgroups of participants (n = 11 and 17) differing by their baseline metabolic profiles. The MMM did not significantly alter postprandial endothelial function in all subjects, irrespective of baseline metabolic parameters. In contrast, the HSFAM induced postprandial endothelial dysfunction (Delta%FMDabsolute = -5.28 +/- 2.54, p < 0.01 vs. MMM) in a subgroup of individuals with significantly greater body mass index, fasting insulinemia, and lipid parameters (n = 11). Finally, the postprandial plasma FA profiles were differentially enriched by the HSFAM and MMM, notably with saturated FAs and omega-3 polyunsaturated FAs, respectively. Collectively, our results highlight the detrimental impact of a single HSFAM on endothelial function in healthy individuals displaying subclinical fasting metabolic dysregulations. Such individuals could benefit from MMM, demonstrated herein to be without any acute detriment to endothelial function. PMID- 27454856 TI - Short-term high-fat diet alters postprandial glucose metabolism and circulating vascular cell adhesion molecule-1 in healthy males. AB - Short-term intake of a high-fat diet aggravates postprandial glucose metabolism; however, the dose-response relationship has not been investigated. We hypothesized that short-term intake of a eucaloric low-carbohydrate/high-fat diet (LCHF) would aggravate postprandial glucose metabolism and circulating adhesion molecules in healthy males. Seven healthy young males (mean +/- SE; age: 26 +/- 1 years) consumed either a eucaloric control diet (C, approximately 25% fats), a eucaloric intermediate-carbohydrate/intermediate-fat diet (ICIF, approximately 50% fats), or an LCHF (approximately 70% fats) for 3 days. An oral meal tolerance test (MTT) was performed after the 3-day dietary intervention. The concentrations of plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 (VCAM-1) were determined at rest and during MTT. The incremental area under the curve (iAUC) of plasma glucose concentration during MTT was significantly higher in LCHF than in C (P = 0.009). The first-phase insulin secretion indexes were significantly lower in LCHF than in C (P = 0.04). Moreover, the iAUC of GLP-1 and VCAM-1 concentrations was significantly higher in LCHF than in C (P = 0.014 and P = 0.04, respectively). The metabolites from ICIF and C were not significantly different. In conclusion, short-term intake of eucaloric diet containing a high percentage of fats in healthy males excessively increased postprandial glucose and VCAM-1 concentrations and attenuated first-phase insulin release. PMID- 27454857 TI - Cancer patients with delirium in the emergency department: A frequent and distressing problem that calls for better assessment. PMID- 27454858 TI - Concussions, Traumatic Brain Injury, and the Innovative Use of Omega-3s. AB - Traumatic brain injury (TBI), with its diverse heterogeneity and prolonged secondary pathogenesis, remains a clinical challenge. Clinical studies thus far have failed to identify an effective treatment strategy when a combination of targets controlling aspects of neuroprotection, neuroinflammation, and neuroregeneration is needed. Omega-3 fatty acids (n-3FA) offer the advantage of this approach. Although further clinical trial research is needed, there is a growing body of strong preclinical evidence and clinical experience that suggests that benefits may be possible from aggressively adding substantial amounts of n 3FA to optimize the nutritional foundation of TBI, concussion, and postconcussion syndrome patients. Early and optimal doses of n-3FA, even in a prophylactic setting, have the potential to improve outcomes from this potentially devastating problem. With evidence of unsurpassed safety and tolerability, n-3FA should be considered mainstream, conventional medicine, if conventional medicine can overcome its inherent bias against nutritional, nonpharmacologic therapies. PMID- 27454859 TI - Using Multicountry Ecological and Observational Studies to Determine Dietary Risk Factors for Alzheimer's Disease. AB - Rates of Alzheimer's disease (AD) are rising worldwide. The most important risk factors seem to be linked to diet. For example, when Japan made the nutrition transition from the traditional Japanese diet to the Western diet, AD rates rose from 1% in 1985 to 7% in 2008. Foods protective against AD include fruits, vegetables, grains, low-fat dairy products, legumes, and fish, whereas risk factors include meat, sweets, and high-fat dairy products. The evidence comes from ecological and observational studies as well as investigations of the mechanisms whereby dietary factors affect risk. The mechanisms linking dietary risk factors to AD are fairly well known and include increased oxidative stress from metal ions such as copper as well as from advanced glycation end products associated with high-temperature cooking, increased homocysteine concentrations, and cholesterol and its effects on amyloid beta, insulin resistance, and obesity. Lower 25-hydroxyvitamin D concentrations also are associated with increased risk of AD. In addition to reviewing the journal literature, a new ecological study was conducted using AD prevalence from 10 countries (Brazil, Chile, Cuba, Egypt, India, Mongolia, Nigeria, Republic of Korea, Sri Lanka, and the United States) along with dietary supply data 5, 10, and 15 years before the prevalence data. Dietary supply of meat or animal products less milk 5 years before AD prevalence had the highest correlations with AD prevalence in this study. Thus, reducing meat consumption could significantly reduce the risk of AD as well as of several cancers, diabetes mellitus type 2, stroke, and, likely, chronic kidney disease. TEACHING POINTS: * Single-country ecological data can be used to find links between diet and AD because the national diet changes, such as during the nutrition transition to a Western diet. * Multicountry ecological studies can be used to find links between dietary factors and risk of AD. * Prospective observational studies are useful in linking dietary components and patterns to risk of AD. * The most important dietary link to AD appears to be meat consumption, with eggs and high-fat dairy also contributing. * Diets high in grains, fruits, vegetables, and fish are associated with reduced risk of AD, but these factors cannot counter the effects of meat, eggs, and high-fat dairy. * Higher vitamin D status is associated with reduced risk of AD. PMID- 27454860 TI - Establishing a baseline for literature mining human genetic variants and their relationships to disease cohorts. AB - BACKGROUND: The Variome corpus, a small collection of published articles about inherited colorectal cancer, includes annotations of 11 entity types and 13 relation types related to the curation of the relationship between genetic variation and disease. Due to the richness of these annotations, the corpus provides a good testbed for evaluation of biomedical literature information extraction systems. METHODS: In this paper, we focus on assessing performance on extracting the relations in the corpus, using gold standard entities as a starting point, to establish a baseline for extraction of relations important for extraction of genetic variant information from the literature. We test the application of the Public Knowledge Discovery Engine for Java (PKDE4J) system, a natural language processing system designed for information extraction of entities and relations in text, on the relation extraction task using this corpus. RESULTS: For the relations which are attested at least 100 times in the Variome corpus, we realise a performance ranging from 0.78-0.84 Precision weighted F-score, depending on the relation. We find that the PKDE4J system adapted straightforwardly to the range of relation types represented in the corpus; some extensions to the original methodology were required to adapt to the multi-relational classification context. The results are competitive with state of-the-art relation extraction performance on more heavily studied corpora, although the analysis shows that the Recall of a co-occurrence baseline outweighs the benefit of improved Precision for many relations, indicating the value of simple semantic constraints on relations. CONCLUSIONS: This work represents the first attempt to apply relation extraction methods to the Variome corpus. The results demonstrate that automated methods have good potential to structure the information expressed in the published literature related to genetic variants, connecting mutations to genes, diseases, and patient cohorts. Further development of such approaches will facilitate more efficient biocuration of genetic variant information into structured databases, leveraging the knowledge embedded in the vast publication literature. PMID- 27454861 TI - Magnetic resonance neurography in the diagnosis of neuropathies of the lumbosacral plexus: a pictorial review. AB - Magnetic resonance neurography (MRN) is an important tool to detect abnormalities of peripheral nerves. This pictorial review demonstrates the MRN features of a variety of neuropathies affecting the lumbosacral plexus (LSP) and lower extremity nerves, drawn from over 1200 MRNs from our institution and supplemented by the literature. Abnormalities can be due to spinal compression, extraspinal compression, malignancy, musculoskeletal disease, iatrogenesis, inflammation, infection, and idiopathic disorders. We discuss indications and limitations of MRN in diagnosing LSP neuropathies. As MRN becomes more widely used, physicians must become familiar with the differential diagnosis of abnormalities detectable with MRN of the LSP. PMID- 27454862 TI - Autoantibodies to post-translationally modified type I and II collagen in Charcot neuroarthropathy in subjects with type 2 diabetes mellitus. AB - AIMS: Charcot neuroarthropathy (CN) is a disabling complication, culminating in bone destruction and involving joints and articular cartilage with high inflammatory environment. Its real pathogenesis is as yet unknown. In autoinflammatory diseases, such as rheumatoid arthritis, characterized by inflammation and joint involvement, autoantibodies against oxidative post translationally modified (oxPTM) collagen type I (CI) and type II (CII) were detected. Therefore, the aim of our study was to assess the potential involvement of autoimmunity in charcot neuroarthropathy, investigating the presence of autoantibodies oxPTM-CI and oxPTM-CII, in participants with charcot neuroarthropathy. METHODS: In this case-control study, we enrolled 124 participants with type 2 diabetes mellitus (47 with charcot neuroarthropathy, 37 with diabetic peripheral neuropathy without charcot neuroarthropathy, and 40 with uncomplicated diabetes), and 32 healthy controls. The CI and CII were modified with ribose and other oxidant species, and the modifications were evaluated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Binding of sera from the participants was analyzed with enzyme-linked immunosorbent assay. RESULTS: Age, body mass index, waist and hip circumferences, and lipid profile were similar across the 4 groups, as well as glycated hemoglobin and duration of diabetes among people with diabetes. An increased binding to both native and all oxidation-modified forms of CII was found in participants with CN and diabetic neuropathy. Conversely, for CI, an aspecific increased reactivity was noted. CONCLUSIONS: Our results detected the presence of autoantibodies against oxidative post-translational modified collagen, particularly type 2 collagen, in participants with charcot neuroarthropathy and diabetic neuropathy, suggesting the possible involvement of autoimmunity. Further studies are required to understand the role of autoimmunity in the pathogenesis of charcot neuroarthropathy. PMID- 27454863 TI - Factors Controlling Methane in Arctic Lakes of Southwest Greenland. AB - We surveyed 15 lakes during the growing season of 2014 in Arctic lakes of southwest Greenland to determine which factors influence methane concentrations in these systems. Methane averaged 2.5 MUmol L-1 in lakes, but varied a great deal across the landscape with lakes on older landscapes farther from the ice sheet margin having some of the highest values of methane reported in lakes in the northern hemisphere (125 MUmol L-1). The most important factors influencing methane in Greenland lakes included ionic composition (SO4, Na, Cl) and chlorophyll a in the water column. DOC concentrations were also related to methane, but the short length of the study likely underestimated the influence and timing of DOC on methane concentrations in the region. Atmospheric methane concentrations are increasing globally, with freshwater ecosystems in northern latitudes continuing to serve as potentially large sources in the future. Much less is known about how freshwater lakes in Greenland fit in the global methane budget compared to other, more well-studied areas of the Arctic, hence our work provides essential data for a more complete view of this rapidly changing region. PMID- 27454864 TI - Component-resolved diagnostics in vernal conjunctivitis. AB - PURPOSE OF REVIEW: Conventional diagnostic tests in allergy are insufficient to clarify the cause of vernal conjunctivitis. Component-resolved diagnostic (CRD) by microarray allergen assay may be useful in detecting allergens that might be involved in the inflammatory process. RECENT FINDINGS: In a recent trial in patients suffered from eosinophilic esophagitis, after 2 years of the CRD-guided exclusion diet and specific immunotherapy, significant clinical improvement was observed, and 68% of patients were discharged (cure based on negative biopsy, no symptoms, and no medication intake). Our new objective was to evaluate IgE mediated hypersensitivity by CRD in tears and serum from patients with vernal conjunctivitis and treat patients with identified triggering allergens by specific immunotherapy. Twenty-five patients with vernal conjunctivitis were evaluated. The identified triggering allergens were n Lol p 1 (11 cases), n Cyn d 1 (eight cases), group 4 and 6 grasses (six cases) and group 5 of grasses (five cases). Prick test and pollen IgE were positive in one case. Clinical improvement was observed in 13/25 vernal conjunctivitis patients after 1-year specific immunotherapy. SUMMARY: CRD seems to be a more sensitive diagnostic tool compared with prick test and IgE detection. Specific CRD-led immunotherapy may achieve clinical improvements in vernal conjunctivitis patients. PMID- 27454865 TI - Assessment of Bone Fragility in Patients With Multiple Myeloma Using QCT-Based Finite Element Modeling. AB - Multiple myeloma (MM) is a malignant plasma cell disease associated with severe bone destruction. Surgical intervention is often required to prevent vertebral body collapse and resulting neurological complications; however, its necessity is determined by measuring lesion size or number, without considering bone biomechanics. Finite element (FE) modeling, which simulates the physiological loading, may improve the prediction of fragility. To test this, we developed a quantitative computed tomography (QCT)-based FE model of the vertebra and applied it to a dataset of MM patients with and without prevalent fracture. FE models were generated from vertebral QCT scans of the T12 (T11 if T12 was fractured) of 104 MM patients, 45 with fracture and 59 without, using a low-dose scan protocol (1.5 mm slice thickness, 4.0 to 6.5 mSv effective dose). A calibration phantom enabled the conversion of the CT Hounsfield units to FE material properties. Compressive loading of the vertebral body was simulated and the stiffness, yield load, and work to yield determined. To compare the parameters between fracture and nonfracture groups, t tests were used, and standardized odds ratios (sOR, normalized to standard deviation) and 95% confidence intervals were calculated. FE parameters were compared to mineral and structural parameters using linear regression. Patients with fracture showed lower vertebral stiffness (-15.2%; p = 0.010; sOR = 1.73; 95% CI, 1.11 to 2.70), yield force (-21.5%; p = 0.002; sOR = 2.09; 95% CI, 1.27 to 3.43), and work to yield (-27.4%; p = 0.001; sOR = 2.28; 95% CI, 1.33 to 3.92) compared to nonfracture patients. All parameters correlated significantly with vBMD (stiffness: R2 = 0.57, yield force: R2 = 0.59, work to yield: R2 = 0.50, p < 0.001), BV/TV (stiffness: R2 = 0.56, yield force: R2 = 0.58, work to yield: R2 = 0.49, p < 0.001), and Tb.Sp (stiffness: R2 = 0.51, yield force: R2 = 0.53, work to yield: R2 = 0.45, p < 0.001). FE modeling identified MM patients with compromised mechanical integrity of the vertebra. Higher sOR values were obtained for the biomechanical compared to structural or mineral measures, suggesting that FE modeling improves fragility assessment in these patients. (c) 2016 American Society for Bone and Mineral Research. PMID- 27454866 TI - Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation. AB - Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies. PMID- 27454867 TI - Chosen risk level during car-following in adverse weather conditions. AB - This study examines how precipitation, light conditions and surface conditions affect the drivers' risk perception. An indicator CRI (Chosen Risk Index) is defined, which describes the chosen risk level for drivers in a car-following situation. The dataset contains about 70 000 observations of driver behaviour and weather status on a rural road. Based on the theory of risk homeostasis and an assumption that driving behaviour in situations with daylight, dry road and no precipitation reflects drivers' target level of risk, generalised linear models (GLM) were estimated for cars and trucks separately to reveal the effect of adverse weather conditions on risk perception. The analyses show that both car and truck drivers perceive the highest risk when driving on snow covered roads. For car drivers, a snow covered road in combination with moderate rain or light snow are the factors which lowers the CRI the most. For trucks, snow cover and partially covered roads significantly lowers the CRI, while precipitation did not seem to impose any higher risk. Interaction effects were found for car drivers only. PMID- 27454868 TI - Land use and traffic collisions: A link-attribute analysis using Empirical Bayes method. AB - Road traffic collisions represent one of the major public health problems among the leading causes of deaths globally. This paper examines several approaches in detecting hazardous road locations, and discusses the spatial distribution of these locations as well as their relationships with different land uses in Hong Kong. Two most commonly used methodologies in detecting hazardous road locations are used: the hot spot and hot zone methodologies. Both methodologies are performed using raw collision count, excess collision count and Empirical Bayes (EB) estimations. The EB estimation uses land use characteristics near the road network in defining the reference groups. Finally all the approaches are compared by a test to assess their stability. The results show that for different hazardous road location detection methodologies, the best fit estimation methods on sites are different. The results confirm some land use impacts in previous studies, and suggest some further patterns on road safety. The findings are useful in understanding the complex interrelationships between land use and road safety, and in facilitating planners and policy makers to build safer cities. PMID- 27454869 TI - Reversible Tuning of Individual Carbon Nanotube Mechanical Properties via Defect Engineering. AB - The structural defects that inevitably exist in real-world carbon nanotubes (CNTs) are generally considered undesirable because they break the structural perfection and may result in drastically degraded CNT properties. On the other hand, the deliberate defect introduction can provide a possibility to tailor the tube mechanical properties. Herein, we present a fully controllable technique to handle defects by using in situ transmission electron microscopy (TEM). Young's modulus, quality factor of the resonation and tensile strength of CNTs can be controllably, reversibly, and repeatedly tuned. Parallel high-resolution visualizing of structural defects suggests that the property tuning cycles are primarily attributed to the reversible conversion of defects at the atomic scale: the defects are created in the form of vacancies and interstitials under electron irradiation, and they vanish through the recombination via current-induced annealing. For applications, such as reversible frequency-tuned CNT resonators, this defect-engineering technique is demonstrated to be uniquely precise; the frequency may be tuned with 0.1%/min accuracy, improved by 1 order of magnitude compared with the existing approaches. We believe that these results will be highly valuable in a variety of property-tunable CNT-based composites and devices. PMID- 27454870 TI - Impact of Fluorine-18 2-Fluoro-2-Deoxy-D-Glucose Uptake on Preoperative Positron Emission Tomography/Computed Tomography in the Lymph Nodes of Patients with Primary Colorectal Cancer. AB - BACKGROUND/AIMS: Although the diagnostic value of fluorine-18 2-fluoro-2-deoxy-D glucose (F-18-FDG) positron emission tomography/computed tomography (F-18-FDG PET/CT) in patients with colorectal cancer (CRC) has been reported, the association between the F-18-FDG uptake in metastatic lymph nodes (FDGLN) and clinicopathological variables has not been fully investigated. We evaluated the diagnostic value of F-18-FDG-PET/CT in detecting LN metastasis from CRC, and the relationship between F-18-FDG-PET/CT-detecting LN metastasis and prognosis. METHODS: We retrospectively analyzed the medical records of 370 patients who underwent preoperative F-18-FDG-PET/CT, followed by surgical resection for CRC between January 2007 and December 2010. We analyzed the sensitivity, specificity, and accuracy of F-18-FDG-PET/CT and CT in diagnosing metastatic LNs. Survival was analyzed in 115 patients with stage III CRC. RESULTS: The sensitivity, specificity, and accuracy for detecting metastatic LNs using F-18-FDG-PET/CT were 56.8, 90.3, and 74.2%, and those for contrast-enhanced CT were 38.4, 95.5, and 65.0%, respectively. The accuracy of F-18-FDG-PET/CT was significantly associated with tumor depth and lymphatic involvement. In the survival analysis, cancer specific survival and the disease-free survival were significantly shorter in patients with stage III CRC with FDGLN than in those without FDGLN. CONCLUSION: F 18-FDG-PET/CT had low sensitivity and high specificity for detecting metastatic LNs from CRC. FDGLN independently predicted poor prognosis in patients with stage III CRC. PMID- 27454871 TI - Alterations of Na+/K+-ATPase, cholinergic and antioxidant enzymes activity by protocatechuic acid in cadmium-induced neurotoxicity and oxidative stress in Wistar rats. AB - BACKGROUND: This study assessed the possible protective mechanisms of protocatechuic acid (PCA) against cadmium (Cd)-induced oxidative stress and neurotoxicity in rats. METHODS: Male wistar strain rats weighing between 150-160g were purchased and acclimatized for two weeks. The rats were divided into seven groups of seven each; NC group received normal saline, CAD group received 6mg/kg of Cd-solution, CAD+PSG group received Cd-solution and prostigmine (5mg/kg), CAD+PCA-10 and CAD+PCA-20 groups received Cd-solution and PCA (10mg/kg and 20mg/kg) respectively, PCA-10 and PCA-20 groups received 10mg/kg and 20mg/kg PCA each. Animals were administered normal saline, Cd and PCA daily by oral gavage for 21days. After which the animals were sacrificed, the brain excised, homogenized and centrifuged. The activities of enzymes (Na+/K+-ATPase, cholinesterases, catalase, glutathione peroxidase, superoxide dismutase) and levels of oxidative stress markers (lipid peroxidation and reduced glutathione) linked to neurodegeneration were subsequently assessed. RESULTS: Significant (p<0.05) alterations in the enzyme activities and levels of oxidative stress markers were observed in CAD group when compared to the NC group. However, the activities of the enzymes were reversed in CAD+PSG and CAD+PCA groups. CONCLUSIONS: PCA may protect against cadmium-induced neurotoxicity by altering the activities of Na+/K+-ATPase, acetylcholinesterase, butyrylcholinesterase and endogenous antioxidant enzymes. PMID- 27454872 TI - Lattice Boltzmann Method of Different BGA Orientations on I-Type Dispensing Method. AB - This paper studies the three dimensional (3D) simulation of fluid flows through the ball grid array (BGA) to replicate the real underfill encapsulation process. The effect of different solder bump arrangements of BGA on the flow front, pressure and velocity of the fluid is investigated. The flow front, pressure and velocity for different time intervals are determined and analyzed for potential problems relating to solder bump damage. The simulation results from Lattice Boltzmann Method (LBM) code will be validated with experimental findings as well as the conventional Finite Volume Method (FVM) code to ensure highly accurate simulation setup. Based on the findings, good agreement can be seen between LBM and FVM simulations as well as the experimental observations. It was shown that only LBM is capable of capturing the micro-voids formation. This study also shows an increasing trend in fluid filling time for BGA with perimeter, middle empty and full orientations. The perimeter orientation has a higher pressure fluid at the middle region of BGA surface compared to middle empty and full orientation. This research would shed new light for a highly accurate simulation of encapsulation process using LBM and help to further increase the reliability of the package produced. PMID- 27454873 TI - Structural Modifications of Fructans in Aloe barbadensis Miller (Aloe Vera) Grown under Water Stress. AB - Aloe barbadensis Miller (Aloe vera) has a Crassulaceae acid metabolism which grants the plant great tolerance to water restrictions. Carbohydrates such as acemannans and fructans are among the molecules responsible for tolerating water deficit in other plant species. Nevertheless, fructans, which are prebiotic compounds, have not been described nor studied in Aloe vera, whose leaf gel is known to possess beneficial pharmaceutical, nutritional and cosmetic properties. As Aloe vera is frequently cultivated in semi-arid conditions, like those found in northern Chile, we investigated the effect of water deficit on fructan composition and structure. For this, plants were subjected to different irrigation regimes of 100%, 75%, 50% and 25% field capacity (FC). There was a significant increase in the total sugars, soluble sugars and oligo and polyfructans in plants subjected to water deficit, compared to the control condition (100% FC) in both leaf tips and bases. The amounts of fructans were also greater in the bases compared to the leaf tips in all water treatments. Fructans also increase in degree of polymerization with increasing water deficit. Glycosidic linkage analyses by GC-MS, led to the conclusion that there are structural differences between the fructans present in the leaves of control plants with respect to plants irrigated with 50% and 25% FC. Therefore, in non stressed plants, the inulin, neo-inulin and neo-levan type of fructans predominate, while in the most stressful conditions for the plant, Aloe vera also synthesizes fructans with a more branched structure, the neofructans. To our knowledge, the synthesis and the protective role of neo-fructans under extreme water deficit has not been previously reported. PMID- 27454874 TI - Correction: Investigating Clinical Failure of Bone Grafting through a Window at the Femoral Head Neck Junction Surgery for the Treatment of Osteonecrosis of the Femoral Head. AB - [This corrects the article DOI: 10.1371/journal.pone.0156903.]. PMID- 27454875 TI - 1,2-Disubstituted Alkenes as Migratory Insertion Participants in Zn(II)-Promoted Metalloamination/Cyclization of N,N-Dimethylhydrazinoalkenes. AB - Diethylzinc-mediated metalloamination/cyclization of unsaturated N,N dimethylhydrazines has been extended to the use of 1,2-disubstituted alkenes as N Zn migratory insertion acceptors. Representative 2-arylethenes and vinylcyclopropanes readily serve as reaction participants in metalloamination/cyclization-allylation cascades. PMID- 27454876 TI - Discrete classification technique applied to TV advertisements liking recognition system based on low-cost EEG headsets. AB - BACKGROUND: In this paper a new approach is applied to the area of marketing research. The aim of this paper is to recognize how brain activity responds during the visualization of short video advertisements using discrete classification techniques. By means of low cost electroencephalography devices (EEG), the activation level of some brain regions have been studied while the ads are shown to users. We may wonder about how useful is the use of neuroscience knowledge in marketing, or what could provide neuroscience to marketing sector, or why this approach can improve the accuracy and the final user acceptance compared to other works. METHODS: By using discrete techniques over EEG frequency bands of a generated dataset, C4.5, ANN and the new recognition system based on Ameva, a discretization algorithm, is applied to obtain the score given by subjects to each TV ad. RESULTS: The proposed technique allows to reach more than 75 % of accuracy, which is an excellent result taking into account the typology of EEG sensors used in this work. Furthermore, the time consumption of the algorithm proposed is reduced up to 30 % compared to other techniques presented in this paper. CONCLUSIONS: This bring about a battery lifetime improvement on the devices where the algorithm is running, extending the experience in the ubiquitous context where the new approach has been tested. PMID- 27454877 TI - Nanobiotechnology: Net charge of trace proteins. PMID- 27454878 TI - Reading the primary structure of a protein with 0.07 nm3 resolution using a subnanometre-diameter pore. AB - The primary structure of a protein consists of a sequence of amino acids and is a key factor in determining how a protein folds and functions. However, conventional methods for sequencing proteins, such as mass spectrometry and Edman degradation, suffer from short reads and lack sensitivity, so alternative approaches are sought. Here, we show that a subnanometre-diameter pore, sputtered through a thin silicon nitride membrane, can be used to detect the primary structure of a denatured protein molecule. When a denatured protein immersed in electrolyte is driven through the pore by an electric field, measurements of a blockade in the current reveal nearly regular fluctuations, the number of which coincides with the number of residues in the protein. Furthermore, the amplitudes of the fluctuations are highly correlated with the volumes that are occluded by quadromers (four residues) in the primary structure. Each fluctuation, therefore, represents a read of a quadromer. Scrutiny of the fluctuations reveals that the subnanometre pore is sensitive enough to read the occluded volume that is related to post-translational modifications of a single residue, measuring volume differences of ~0.07 nm3, but it is not sensitive enough to discriminate between the volumes of all twenty amino acids. PMID- 27454879 TI - A nanomesh scaffold for supramolecular nanowire optoelectronic devices. AB - Supramolecular organic nanowires are ideal nanostructures for optoelectronics because they exhibit both efficient exciton generation as a result of their high absorption coefficient and remarkable light sensitivity due to the low number of grain boundaries and high surface-to-volume ratio. To harvest photocurrent directly from supramolecular nanowires it is necessary to wire them up with nanoelectrodes that possess different work functions. However, devising strategies that can connect multiple nanowires at the same time has been challenging. Here, we report a general approach to simultaneously integrate hundreds of supramolecular nanowires of N,N'-dioctyl-3,4,9,10 perylenedicarboximide (PTCDI-C8) in a hexagonal nanomesh scaffold with asymmetric nanoelectrodes. Optimized PTCDI-C8 nanowire photovoltaic devices exhibit a signal to-noise ratio approaching 107, a photoresponse time as fast as 10 ns and an external quantum efficiency >55%. This nanomesh scaffold can also be used to investigate the fundamental mechanism of photoelectrical conversion in other low dimensional semiconducting nanostructures. PMID- 27454880 TI - Supramolecular electronics: Meshing organic nanowires. PMID- 27454881 TI - Measuring protein isoelectric points by AFM-based force spectroscopy using trace amounts of sample. AB - Protein charge at various pH and isoelectric point (pI) values is important in understanding protein function. However, often only trace amounts of unknown proteins are available and pI measurements cannot be obtained using conventional methods. Here, we show a method based on the atomic force microscope (AFM) to determine pI using minute quantities of proteins. The protein of interest is immobilized on AFM colloidal probes and the adhesion force of the protein is measured against a positively and a negatively charged substrate made by layer-by layer deposition of polyelectrolytes. From the AFM force-distance curves, pI values with an estimated accuracy of +/-0.25 were obtained for bovine serum albumin, myoglobin, fibrinogen and ribonuclease A over a range of 4.7-9.8. Using this method, we show that the pI of the 'footprint' of the temporary adhesive proteins secreted by the barnacle cyprid larvae of Amphibalanus amphitrite is in the range 9.6-9.7. PMID- 27454882 TI - A formative multi-method approach to evaluating training. AB - This article describes how we used a formative multi-method evaluation approach to gather real-time information about the processes of a complex, multi-day training with 24 community coalitions in the United States. The evaluation team used seven distinct, evaluation strategies to obtain evaluation data from the first Community Health Improvement Leadership Academy (CHILA) within a three prong framework (inquiry, observation, and reflection). These methods included: comprehensive survey, rapid feedback form, learning wall, observational form, team debrief, social network analysis and critical moments reflection. The seven distinct methods allowed for both real time quality improvement during the CHILA and long term planning for the next CHILA. The methods also gave a comprehensive picture of the CHILA, which when synthesized allowed the evaluation team to assess the effectiveness of a training designed to tap into natural community strengths and accelerate health improvement. We hope that these formative evaluation methods can continue to be refined and used by others to evaluate training. PMID- 27454883 TI - Crucial requirement for standardization during the development of novel recombinant BCG vaccines: Does the corresponding substrain background matter? AB - The Bacillus Calmette-Guerin (BCG) vaccine is not a single organism, but consists of substrains that vary in genotypes and phenotypes. Actually, BCG is the common name given to a family of vaccines created in 1921 by the in vitro attenuation of a virulent Mycobacterium bovis in France. Even nearly a century of use, the BCG vaccine lingers generating confusion and debate due to its diversity and failure to protect against tuberculosis (TB). That is probably owing to the enduring lack of standardization during production, distribution and administration procedures. Since the 1940s, substantial sequence modifications among the BCG substrains have been described. To increase the level of complexity, even though that the prolific generation of recombinant BCG vaccines has been promising, the relationships between those candidates used in current clinical trials and their parental substrains are either unsatisfactorily connected or have been never fully delineated. Consequently, the use of the most protective BCG substrain as the background or platform in the development of all recombinant BCG vaccine candidates has not been standardized. In order to schematize and to clarify the subject regarding substrains commonly used to generate those novel vaccines, a sequential emergence of the parental BCG vaccine substrains and their matching recombinant ones, if any, was built. Hence, for a total of 24 BCG substrains currently in circulation worldwide, 9 have been used to sustain one or more genetic modifications, resulting in around 21 novel recombinant BCG vaccines. Although this is a remarkable success, only 2 out of the 21 recombinant BCG substrains harbor a background representative of the most immunogenic group. Systematizing the novel BCG vaccines and their parental strains may facilitate our understanding of protection provided by BCG immunizations. PMID- 27454885 TI - The timeliness of the US military response to the 2014 Ebola disaster: a critical review. AB - In the face of an unprecedented epidemic of Ebola Virus Disease, in September 2014, the US military began sending thousands of personnel to Liberia and supporting areas in Senegal in its largest deployment to the African continent in over two decades. In this review, media reports, published photographs and official statements are evaluated and summarized to identify and describe key time points in the US military response. Specific events include the initial establishment of the Monrovia Medical Unit and the buildup of forces for the expanded mission, which involved enhancement of laboratory testing capacity, construction of Ebola Treatment Units, and training of health care workers. The review concludes with a discussion and critical evaluation of the timeliness of this US military response in the context of the original expectations of the humanitarian community and government officials. PMID- 27454884 TI - Nutritional Evaluation of an EPA-DHA Oil from Transgenic Camelina sativa in Feeds for Post-Smolt Atlantic Salmon (Salmo salar L.). AB - Vegetable oils (VO) are possible substitutes for fish oil in aquafeeds but their use is limited by their lack of omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFA). However, oilseed crops can be modified to produce n-3 LC-PUFA such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, representing a potential option to fill the gap between supply and demand of these important nutrients. Camelina sativa was metabolically engineered to produce a seed oil with around 15% total n-3 LC-PUFA to potentially substitute for fish oil in salmon feeds. Post-smolt Atlantic salmon (Salmo salar) were fed for 11-weeks with one of three experimental diets containing either fish oil (FO), wild-type Camelina oil (WCO) or transgenic Camelina oil (DCO) as added lipid source to evaluate fish performance, nutrient digestibility, tissue n-3 LC-PUFA, and metabolic impact determined by liver transcriptome analysis. The DCO diet did not affect any of the performance or health parameters studied and enhanced apparent digestibility of EPA and DHA compared to the WCO diet. The level of total n-3 LC PUFA was higher in all the tissues of DCO-fed fish than in WCO-fed fish with levels in liver similar to those in fish fed FO. Endogenous LC-PUFA biosynthetic activity was observed in fish fed both the Camelina oil diets as indicated by the liver transcriptome and levels of intermediate metabolites such as docosapentaenoic acid, with data suggesting that the dietary combination of EPA and DHA inhibited desaturation and elongation activities. Expression of genes involved in phospholipid and triacylglycerol metabolism followed a similar pattern in fish fed DCO and WCO despite the difference in n-3 LC-PUFA contents. PMID- 27454886 TI - Does encoding matter? A novel view on the quantitative genetic trait prediction problem. AB - BACKGROUND: Given a set of biallelic molecular markers, such as SNPs, with genotype values encoded numerically on a collection of plant, animal or human samples, the goal of genetic trait prediction is to predict the quantitative trait values by simultaneously modeling all marker effects. Genetic trait prediction is usually represented as linear regression models which require quantitative encodings for the genotypes. There are lots of work on the prediction algorithms, but none of the existing work investigated the effects of the encodings on the genetic trait prediction problem. METHODS: In this work, we view the genetic trait prediction problem from a novel angle: a multiple regression on categorical data problem, which requires encoding the categorical data into numerical data. We further proposed two novel encoding methods and we show that they are able to generate numerical features with higher predictive power. RESULTS AND DISCUSSION: Our experiments show that our methods are superior to the other encoding methods for both single marker model and epistasis model. We showed that the quantitative genetic trait prediction problem heavily depends on the encoding of genotypes, for both single marker model and epistasis model. CONCLUSIONS: We conducted a detailed analysis on the performance of the hybrid encodings. To our knowledge, this is the first work that discusses the effects of encodings for genetic trait prediction problem. PMID- 27454888 TI - The role of mastery in the relationship between perceived ethnic discrimination and depression: The HELIUS study. AB - OBJECTIVE: This study examined the mediating and moderating role of one's sense of mastery in the relationship between perceived ethnic discrimination and depression. METHOD: Questionnaire data from participants of the Healthy Life in an Urban Setting (HELIUS) study were used, containing responses from 9,141 Surinamese, Turkish, Moroccan, and Ghanaian immigrant adults, aged 18 to 70, living in Amsterdam, the Netherlands. RESULTS: Results of path modeling indicated that perceptions of ethnic discrimination were positively related to depression symptomatology, and this relationship was moderated and partially mediated by mastery. Results remained fairly robust across sex, educational level, immigrant generation, and ethnicity. CONCLUSION: This study indicated that mastery may both serve a moderating and mediating role in the relationship between perceived ethnic discrimination and depression, suggestive of a process in which the impact of perceiving discrimination becomes increasingly more deteriorating over time. Thus, interventions focused on mastery may potentially be beneficial to improve ethnic minority mental health. (PsycINFO Database Record PMID- 27454887 TI - The influence of cultural orientation on associations between Puerto Rican adolescent mothers' parenting and toddler compliance and defiance. AB - OBJECTIVES: It is imperative that individual differences in the cultural contexts of adolescent mothers, whose parenting is often linked to poor child outcomes, be better understood, especially among Puerto Rican-origin mothers who experience high rates of poverty. Behaviors that mothers use to elicit compliance from their children are important to investigate, because children's ability to engage in regulated, compliant behavior has long-term consequences for their adjustment. This study tested whether mothers' orientation to both American and Latino cultures influenced the associations between such maternal behaviors and compliant and defiant child behaviors. METHOD: The sample included 123 young, Puerto Rican-origin mothers and their 24-month-old toddlers. Behaviors coded from a toy cleanup task measured maternal guidance and control and child compliance and defiance, and acculturation and enculturation were measured with a self report questionnaire. RESULTS: Maternal guidance predicted more child compliance, with no significant variations by cultural orientation; however, mothers who were more enculturated had children who were more compliant. As predicted, mothers' more frequent use of control was related to more child defiance for mothers reporting high levels of acculturation, and not for less acculturated mothers. CONCLUSIONS: Findings support the hypothesis that individual differences in cultural orientation influence variations in associations between certain maternal and child behaviors. (PsycINFO Database Record PMID- 27454889 TI - Is There a New Alternative for a Safer Kidney Artery Ligation in Laparoscopic Donor Nephrectomy? AB - Controlled ligation and division of the renal hilum are critical steps during laparoscopic living donor nephrectomy. Major hemorrhage from technical failure, although an infrequent occurrence, can cause significant, yet preventable, morbidity or death. Polymer-secured nontransfixion clips are used worldwide for renal pedicle control during laparoscopic nephrectomy, but their use is contraindicated for renal artery ligation during laparoscopic living donor nephrectomy. Laparoscopic staplers are reliable transfixion systems for controlling kidney pedicle. However, stapler malfunction is not negligible, reaching up to 1.7%. A new double shank (DS) titanium-secured nontransfixion clip can dodge legal concerns on polymer-secured clips, while maintaining most of their advantages, without technical failures that may be seen in laparoscopic staplers. New alternatives must be proposed and explored to reach an agreement of the urological community. The new DS-titanium-secured clips could be a step forward toward a safer surgery for kidney donors, at least equivalent to hand ties to occlude the renal artery. PMID- 27454890 TI - Transport and Catabolism of Carbohydrates by Neisseria meningitidis. AB - We identified the genes encoding the proteins for the transport of glucose and maltose in Neisseria meningitidis strain 2C4-3. A mutant deleted for NMV_1892(glcP) no longer grew on glucose and deletion of NMV_0424(malY) prevented the utilization of maltose. We also purified and characterized glucokinase and alpha-phosphoglucomutase, which catalyze early catabolic steps of the two carbohydrates. N. meningitidis catabolizes the two carbohydrates either via the Entner-Doudoroff (ED) pathway or the pentose phosphate pathway, thereby forming glyceraldehyde-3-P and either pyruvate or fructose-6-P, respectively. We purified and characterized several key enzymes of the two pathways. The genes required for the transformation of glucose into gluconate-6-P and its further catabolism via the ED pathway are organized in two adjacent operons. N. meningitidis also contains genes encoding proteins which exhibit similarity to the gluconate transporter (NMV_2230) and gluconate kinase (NMV_2231) of Enterobacteriaceae and Firmicutes. However, gluconate might not be the real substrate of NMV_2230 because N. meningitidis was not able to grow on gluconate as the sole carbon source. Surprisingly, deletion of NMV_2230 stimulated growth in minimal medium in the presence and absence of glucose and drastically slowed the clearance of N. meningitidis cells from transgenic mice after intraperitoneal challenge. PMID- 27454891 TI - Prediction of glutathionylation sites in proteins using minimal sequence information and their experimental validation. AB - S-glutathionylation of proteins plays an important role in various biological processes and is known to be protective modification during oxidative stress. Since, experimental detection of S-glutathionylation is labor intensive and time consuming, bioinformatics based approach is a viable alternative. Available methods require relatively longer sequence information, which may prevent prediction if sequence information is incomplete. Here, we present a model to predict glutathionylation sites from pentapeptide sequences. It is based upon differential association of amino acids with glutathionylated and non glutathionylated cysteines from a database of experimentally verified sequences. This data was used to calculate position dependent F-scores, which measure how a particular amino acid at a particular position may affect the likelihood of glutathionylation event. Glutathionylation-score (G-score), indicating propensity of a sequence to undergo glutathionylation, was calculated using position dependent F-scores for each amino-acid. Cut-off values were used for prediction. Our model returned an accuracy of 58% with Matthew's correlation-coefficient (MCC) value of 0.165. On an independent dataset, our model outperformed the currently available model, in spite of needing much less sequence information. Pentapeptide motifs having high abundance among glutathionylated proteins were identified. A list of potential glutathionylation hotspot sequences were obtained by assigning G-scores and subsequent Protein-BLAST analysis revealed a total of 254 putative glutathionable proteins, a number of which were already known to be glutathionylated. Our model predicted glutathionylation sites in 93.93% of experimentally verified glutathionylated proteins. Outcome of this study may assist in discovering novel glutathionylation sites and finding candidate proteins for glutathionylation. PMID- 27454892 TI - Sensitivity analyses of the theoretical equations used in point velocity probe (PVP) data interpretation. AB - Point velocity probes (PVPs) are dedicated, relatively low-cost instruments for measuring groundwater speed and direction in non-cohesive, unconsolidated porous media aquifers. They have been used to evaluate groundwater velocity in groundwater treatment zones, glacial outwash aquifers, and within streambanks to assist with the assessment of groundwater-surfaced water exchanges. Empirical evidence of acceptable levels of uncertainty for these applications has come from both laboratory and field trials. This work extends previous assessments of the method by examining the inherent uncertainties arising from the equations used to interpret PVP datasets. PVPs operate by sensing tracer movement on the probe surface, producing apparent velocities from two detectors. Sensitivity equations were developed for the estimation of groundwater speed, vinfinity, and flow direction, alpha, as a function of the apparent velocities of water on the probe surface and the alpha angle itself. The resulting estimations of measurement uncertainty, which are inherent limitations of the method, apply to idealized, homogeneous porous media, which on the local scale of a PVP measurement may be approached. This work does not address experimental sources of error that may arise from the presence of cohesive sediments that prevent collapse around the probe, the effects of centimeter-scale aquifer heterogeneities, or other complications related to borehole integrity or operator error, which could greatly exceed the inherent sources of error. However, the findings reported here have been shown to be in agreement with the previous empirical work. On this basis, properly installed and functioning PVPs should be expected to produce estimates of groundwater speed with uncertainties less than +/-15%, with the most accurate values of groundwater speed expected when horizontal flow is incident on the probe surface at about 50 degrees from the active injection port. Directions can be measured with uncertainties less than 15 degrees with the most accurate measurements occurring when the flow angles are relatively low - on the order of 20 degrees . At still lower flow angles, quantitation may suffer due to experimental limitations related to tracer delivery. However, useful qualitative assessments of alpha may still be possible under these conditions. PMID- 27454893 TI - Effects of ionic strength and fulvic acid on adsorption of Tb(III) and Eu(III) onto clay. AB - High salinity and natural organic matter are both known to facilitate migration of toxic or radioactive metals in geochemical systems, but little is known on their combined effect. We investigated complexation of Tb(III) and Eu(III) (as analogues for trivalent actinides) with fulvic acid and their adsorption onto a natural clay in the presence of NaCl, MgCl2 and CaCl2 up to very high ionic strengths. (160)Tb, (152)Eu and (14)C-labelled fulvic acid were employed as radiotracers, allowing investigations at very low concentrations according to probable conditions in far-field scenarios of nuclear waste repositories. A combined Kd approach (Linear Additive Model) was tested for suitability in predicting solid-liquid distribution of metals in the presence of organic matter based on the interactions in the constituent subsystems. In this analysis, it could be shown that high ionic strength does not further enhance the mobilizing potential of humic matter. A quantitative reproduction of the influence of fulvic acid failed for most systems under study. Assumptions and limitations of the model are discussed. PMID- 27454894 TI - Associations Between Personality Traits and Adherence to Antidepressants Assessed Through Self-Report, Electronic Monitoring, and Pharmacy Dispensing Data: A Pilot Study. AB - Treatment with antidepressants is often compromised by substantial nonadherence. To understand nonadherence, specific medication-related behaviors and beliefs have been studied, but less is known about broader and temporally stable personality "traits." Furthermore, adherence has often been assessed by a single method. Hence, we investigated associations between the Big Five personality traits and adherence assessed by self-report, electronic drug use monitoring, and dispensing data. Using the Big Five Inventory, we assessed the personality traits "openness," "conscientiousness," "extraversion," "agreeableness," and "neuroticism" of patients treated with antidepressants who were invited through community pharmacies. Self-reported adherence was assessed with the Medication Adherence Rating Scale (score >24), electronic monitoring with medication event monitoring system (MEMS) devices (therapy days missed <= 10% and < 4 consecutive days missed), and dispensing data (medication possession ratio >= 80%). One hundred four women and 33 men participated (mean age, 51; standard deviation, 14). Paroxetine was most frequently prescribed (N = 53, 38%). Logistic regression analysis revealed that of the personality traits, the third and fourth quartiles of "conscientiousness" were associated with better self-reported adherence (odds ratio, 3.63; 95% confidence interval, 1.34-9.86 and odds ratio, 2.97; 95% confidence interval, 1.09-8.08; P <= 0.05). No relationships were found between personality traits and adherence assessed through electronic drug use monitoring or dispensing data. We therefore conclude that adherence to antidepressant therapy seems to be largely unrelated to personality traits. PMID- 27454895 TI - Low-Dose Dextromethorphan-Associated Transient Manic Episode: A Case Report. PMID- 27454896 TI - A new phenylpropanoid glucoside and a chain compound from the roots of Allium tuberosum. AB - A new phenylpropanoid glucoside tuberosinine D (1) and a chain compound (Z) 11R,12S,13S-trihydroxy-9-octadecenoate (2) were isolated from the roots of Allium tuberosum. The absolute configuration of 1 was established by comparing of experimental and calculated electronic circular dichroism. The absolute configuration of 2 was determined using the modified Mosher's method for the first time. PMID- 27454897 TI - Polarity dependent strongly inhomogeneous In-incorporation in GaN nanocolumns. AB - In this work, GaN/InGaN/GaN nanocolumns (NCs) have been grown by molecular beam epitaxy. Selective area growth (SAG) and self-organized growth (SOG) were performed simultaneously in patterned and unpatterned regions of the same substrate, respectively. The resulting structures show different tip morphologies and structural properties due to the different polarity along the growth direction, namely Ga-polar with r-plane faceted tips for the SAG NCs and N-polar with c-plane top facet for the SOG ones. When growing Ga-polar GaN/InGaN NCs, no indium is incorporated at a substrate temperature of [Formula: see text] degrees C. Rather, indium incorporation takes place under the same growth conditions on the N-polar NCs. The In-incorporation is investigated by means of nano x-ray fluorescence and diffraction, high-angle annular dark-field scanning transmission electron microscopy and high-resolution transmission electron microscopy. PMID- 27454898 TI - Effect of coexisting Al(III) ions on Pb(II) sorption on biochars: Role of pH buffer and competition. AB - Biochar is being widely considered as a promising amendment agent for immobilizing heavy metals in contaminated acidic soils, where plenty of soluble Al(III) ions exist. In view of uncertain significance of the effects of coexisting Al(III) on Pb(II) sorption by biochars, this study used kenaf core biochar (KB550; high carbon, low ash) and sewage sludge biochar (SB550; low carbon, high ash) pyrolyzed at 550 degrees C to elucidate the influence of coexisting Al(III) species and biochars' mineral components on Pb(II) immobilization conducted in aqueous solution with initial pHs of 3.0-4.5. Results showed that Al(III) reduced Pb(II) sorption on KB550 primarily via pH buffering against biochar alkalinity, thus inhibiting lead carbonate formation. In contrast, the reduction on SB550 mainly resulted from direct competition for sorption sites, especially on Fe-rich phengite 2M1 and metakaolinite. Because of Pb-P precipitation and Pb-K interlayer exchange, the residual Pb(II) adsorption capacity resistant to coexisting Al(III) was 3-5 times higher on SB550 than on KB550. The Pb-K interlayer exchange was enhanced by lower pH and coexisting Al(III), while Pb-P precipitation was the dominant Pb(II) sorption mechanism on SB550 resistant to Al(III) buffering and competition at higher pH. Application of these two biochars as amendments confirmed that the mineral-rich SB550 was more suitable for Pb(II) immobilization in acidic soils with high levels of extractable Al(III). PMID- 27454899 TI - Ingredients and change processes in occupational therapy for children: a grounded theory study. AB - BACKGROUND: There is limited evidence about the effectiveness of occupational therapy interventions for participation outcomes in children with coordination difficulties. Developing theory about the interventions, i.e. their ingredients and change processes, is the first step to advance the evidence base. AIM: To develop theory about the key ingredients of occupational therapy interventions for children with coordination difficulties and the processes through which change in participation might happen. MATERIAL AND METHODS: Grounded theory methodology, as described by Kathy Charmaz, was used to develop the theory. Children and parents participated in semi-structured interviews to share their experiences of occupational therapy and processes of change. Data collection and analysis were completed concurrently using constant comparison methods. RESULTS: Five key ingredients of interventions were described: performing activities and tasks; achieving; carer support; helping and supporting the child; and labelling. Ingredients related to participation by changing children's mastery experience, increasing capability beliefs and sense of control. Parents' knowledge, skills, positive emotions, sense of empowerment and capability beliefs also related to children's participation. CONCLUSION AND SIGNIFICANCE: The results identify intervention ingredients and change pathways within occupational therapy to increase participation. It is unclear how explicitly and often therapists consider and make use of these ingredients and pathway. PMID- 27454900 TI - Factors Associated with Family Reports of Pain, Dyspnea, and Depression in the Last Year of Life. AB - BACKGROUND: Pain, dyspnea, and depression are highly troubling near the end of life. OBJECTIVE: To characterize factors associated with clinically significant pain and the presence of dyspnea and depression during the last year of life in a nationally representative sample. DESIGN: Retrospective cohort study. SETTING: Health and Retirement Study, a national sample of community-dwelling US residents aged 51 and older. PARTICIPANTS: Family respondents of 8254 decedents who died between 1998 and 2012. MEASUREMENTS: Clinically significant pain often during the last year of life; dyspnea and depression for at least one month during the last year of life. RESULTS: Life support was associated with dyspnea (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.42-2.06) and depression (OR 1.20, CI 1.04 1.39), treatment for cancer with pain (OR 1.65, CI 1.41-1.92), and oxygen for a lung condition with dyspnea (OR 14.78, CI 11.28-19.38). More diagnoses were associated with dyspnea (OR 1.24, CI 1.17-1.30) and depression (OR 1.14, CI 1.08 1.21). More activities of daily living (ADL) dependencies were associated with clinically significant pain (OR 1.06, CI 1.03-1.09), dyspnea (OR 1.06, CI 1.02 1.10), and depression (OR 1.10, CI 1.07-1.12), and more instrumental activities of daily living (IADL) dependencies with depression (OR 1.12, CI 1.08-1.18). Worse self-rated health was associated with pain (OR 0.83, CI 0.77-0.88), dyspnea (OR 0.89, CI 0.84-0.95), and depression (OR 0.83, CI 0.78-0.89). Arthritis was associated with clinically significant pain (OR 2.24, CI 1.91-2.63). CONCLUSIONS: Factors associated with common, burdensome symptoms in a national sample suggest clinical and population strategies for targeting symptom assessment and management. PMID- 27454901 TI - Simple and fast determination of perfluorinated compounds in Taihu Lake by SPE UHPLC-MS/MS. AB - A simple and fast analytical method for determination of eleven Polyfluorinated Compounds (PFCs) in source water was developed in the present work. The water sample was prepared without filtered through microfiltration membrane and 500mL of source water was enriched by the solid phase extraction (SPE). The targent compounds were analyzed by ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The optimized analytical method was validated in terms of recovery, precision and method detection limits (MDLs). The recovery values after correction with the corresponding labeled standard were between 97.3 and 113.0% for samples spiked at 5ng/L, 10ng/L and 20ng/L. All PFCs showed good linearity and the linear correlation coefficient was over 0.99. The precisions were 1.0-9.0% (n=6). As the result of the enrichment, the MDL values ranged from 0.03 to 1.9ng/L and were enough for analysis of the trace levels of PFCs in the Taihu Lake. The method was further validated in determining the source water and the results showed that PFHxS, PFHxA, PFOA and PFOS were the primary PFCs in Taihu Lake which might be different from the other researches. The method can be used for determination of PFCs in water with a stable recovery, good reproducibility, low detection limit, less solvent consumption, time saving and labor saving. To our knowledge, this is the first method that describes the effect of the filter membrane on the determination of PFCs in water which might acquire more accurate concentration of PFCs in Taihu Lake. PMID- 27454906 TI - The 4-hour standard is a meaningful quality indicator: correlation of performance with emergency department crowding. AB - BACKGROUND: The 4-h standard performance is a controversial quality indicator. Crowding in emergency departments (EDs) causes increased patient morbidity and mortality. The aim of this study was to investigate the relationship between 4-h standard performance and ED crowding as measured by occupancy. METHODS: A retrospective observational study was carried out using the computerized Emergency Department Information System. Daily occupancy was considered in three ways: as minutes per day spent at occupancy thresholds of 70, 80, 90 and 100%; as the peak occupancy of resuscitation and majors beds at any point in the day; and as a percentage of the total potential ED bed minutes used during the day. RESULTS: An inverse relationship was observed between occupancy and 4-h standard performance using each method. Performance could be sustained at 70% occupancy, but deteriorated in a linear manner at a progressively increasing rate at 80, 90 and 100% occupancy (all P<0.01). A stepwise decrease in the mean performance was observed with increasing peak occupancy (P<0.001). A similar decrease in performance was observed with increasing 24-h overall occupancy (P<0.001). CONCLUSION: This study has identified a clear and consistent correlation between ED crowding and performance against the 4-h standard. Because crowding is associated with harm, the 4-h standard is a meaningful quality metric for UK hospitals. Systematic measurement of ED crowding using occupancy may play a role in improving the quality of care delivered within the urgent care system. PMID- 27454902 TI - The metabolic and pharmacokinetic studies for HM-3 in rats based on LC-Q-TOF/MS and LC-MS/MS combing a convenient biological sample processing method. AB - In this contribution, the metabolic and pharmacokinetic characteristics for the therapeutic peptide HM-3 were investigated using LC-Q-TOF/MS and LC-MS/MS systems combing a fast biological sample processing method. According to the accurate MS(1) and MS(2) data generated by LC-Q-TOF/MS, a total of 6 metabolites in rats were detected and tentatively identified as the degradation products which formed by successive loss of amino acid from HM-3. The structures of the 2 main metabolites (M1 and M2) were confirmed by comparing the chromatographic and mass spectrographic characteristics with the corresponding synthetic standards. Then, an absolute quantitative analysis method based on LC-MS/MS system was built and fully validated with respect to linearity, sensitivity, accuracy, precision, matrix effect, stability, etc. The results indicated that HM-3, M1 and M2 were linear in peak area ratios over the concentration range of 0.5-200.0ng/mL with a correlation coefficient>0.99. The intra-day and inter-day precisions (RSD%) were less than 15%, and the accuracy was below 10% in terms of RE%. The validated method was then successfully applied to the studies of preclinical pharmacokinetics for HM-3. PMID- 27454907 TI - Perspectives on health policy dialogue: definition, perceived importance and coordination. AB - BACKGROUND: Countries in the World Health Organization African Region have witnessed an increase in global health initiatives in the recent past. Although these have provided opportunities for expanding coverage of health interventions; their poor alignment with the countries' priorities and weak coordination, are among the challenges that have affected their impact. A well-coordinated health policy dialogue provides an opportunity to address these challenges, but calls for common understanding among stakeholders of what policy dialogue entails. This paper seeks to assess stakeholders' understanding and perceived importance of health policy dialogue and of policy dialogue coordination. METHODS: This was a cross-sectional descriptive study using qualitative methods. Interviews were conducted with 90 key informants from the national and sub-national levels in Lusophone Cabo Verde, Francophone Chad, Guinea and Togo, and Anglophone Liberia using an open-ended interview guide. The interviews were transcribed verbatim, coded and then put through inductive thematic content analysis using QRS software Version 10. RESULTS: There were variations in the definition of policy dialogue that were not necessarily linked to the linguistic leaning of respondents' countries or whether the dialogue took place at the national or sub-national level. The definitions were grouped into five categories based on whether they had an outcome, operational, process, forum or platform, or interactive and evidence-sharing orientation. The stakeholders highlighted multiple benefits of policy dialogue including ensuring stakeholder participation, improving stakeholder harmonisation and alignment, supporting implementation of health policies, fostering continued institutional learning, providing a guiding framework and facilitating stakeholder analysis. CONCLUSION: Policy dialogue offers the opportunity to improve stakeholder participation in policy development and promote aid effectiveness. However, conceptual clarity is needed to ensure pursuance of common objectives. While it is clear that stakeholder involvement is an important component of policy dialogue, numbers must be manageable for meaningful dialogue. Ownership and coordination of the policy dialogue are important aspects of the process, and building the institutional capacity of the ministry of health requires a comprehensive approach as opposed to strengthening selected departments within it. Likewise, capacity for policy dialogue needs to be built at the sub-national level, alongside improving the bottom-up approach in policy processes. PMID- 27454908 TI - Do more specific plans help you lose weight? Examining the relationship between plan specificity, weight loss goals, and plan content in the context of a weight management programme. AB - OBJECTIVES: The conditions under which planning for behaviour change is most effective are not fully understood. In the context of a weight management programme, we examined the interrelationship between plan specificity, type of behaviour planned (diet vs. exercise), and weight loss goals. DESIGN: Prospective design and content analysis of plans formed by participants of a 10-week weight management programme. METHODS: Participants (n = 239) formulated two plans, for dietary and exercise behaviours, respectively. Plans were rated for specificity by examining the number of plan components. Weight loss goals were assessed by asking how much weight participants intend to lose. Weight was measured objectively each of the 10 weeks. Changes in body mass index (BMI) over time and the interactions between plan specificity and weight loss goals, for all plans and separately for diet and exercise, were estimated using linear mixed models. RESULTS: Plan specificity was unrelated to weight loss, but interacted with weight loss goals in predicting linear change in BMI (t = -2.48): More specific plans were associated with higher decreases in weight in participants with high weight loss goals. Separate interaction tests for plans formulated for diet and exercise change showed that more specific dietary plans, but not exercise plans, were associated with higher decreases in weight in participants with high weight loss goals (t = -2.21). CONCLUSIONS: Within a population that is highly motivated to lose weight, the combination of high weight loss goals and formulating detailed plans for changing dietary behaviours may be most effective in supporting weight loss. Statement of contribution What is already known on this subject? More specific plans are associated with increased performance of health related behaviours. More motivated individuals form more specific plans. The interrelationship between plan specificity, plan content and behaviour-related goals in relation intervention effectiveness has not been explored to date. What does this study add? The effectiveness of forming specific plans may depend on the strength of behaviour-related goals as well as the behaviour selected for change. More detailed plans, in particular dietary plans, were related to greater weight loss, but only for participants with higher initial weight loss goals. Detailed exercise plans were not associated with weight loss, regardless of initial weight loss goals. PMID- 27454909 TI - Subchondral bone scan uptake correlates with articular cartilage degeneration in osteoarthritic knees. AB - AIM: The aim of this study was to analyze subchondral bone scan uptake in osteoarthritic knees with reference to subchondral bone microstructure and articular cartilage histology. METHODS: This cross-sectional, laboratory study evaluated 123 human distal femoral condyle specimens of 67 patients after joint replacement surgery. All patients were preoperatively examined with bone scan of the knee joint. Specimens were evaluated for cartilage histology and micro computed tomography analysis of subchondral bone. Data between bone scan, histology and micro-computed tomography were statistically analyzed using either coefficient of correlation, Student's t-test or one-way analysis of variance with Tukey post hoc test. RESULTS: Bone scan grading and histological articular cartilage degeneration scores showed significant correlation (r = 0.812, P < 0.001). Both bone scan positive and histologically confirmed osteoarthritis samples showed increase in subchondral trabecular bone volume and thickness, reflected in micro-computed tomography. Overall, positive predictive value (%) of bone scan for osteoarthritic cartilage lesions was 91.9%, and the sensitivity and specificity were 88.3% and 60%, respectively. Histology showed that bone scan has both a high positive predictive and a low negative predictive value for detection of osteoarthritic cartilage lesions. CONCLUSION: Bone scan uptake correlated with articular cartilage degeneration in osteoarthritic knees. Bone scan may be a useful diagnostic tool that reflects pathologic changes of cartilage in osteoarthritis. PMID- 27454911 TI - Crystallographic and Computational Analysis of the Barrel Part of the PsbO Protein of Photosystem II: Carboxylate-Water Clusters as Putative Proton Transfer Relays and Structural Switches. AB - In all organisms that employ oxygenic photosynthesis, the membrane-extrinsic PsbO protein is a functionally important component of photosystem II. To study the previously proposed proton antenna function of carboxylate clusters at the protein-water interface, we combined crystallography and simulations of a truncated cyanobacterial (Thermosynechococcus elongatus) PsbO without peripheral loops. We expressed the PsbO beta-barrel heterologously and determined crystal structures at resolutions of 1.15-1.5 A at 100 K at various pH values and at 297 K and pH 6. (1) Approximately half of the 177 surface waters identified at 100 K are resolved at 297 K, suggesting significant occupancy of specific water sites at room temperature, and loss of resolvable occupancy for other sites. (2) Within a loop region specific to cyanobacterial PsbO, three residues and four waters coordinating a calcium ion are well ordered even at 297 K; the ligation differs for manganese. (3) The crystal structures show water-carboxylate clusters that could facilitate fast Grotthus-type proton transfer along the protein surface and/or store protons. (4) Two carboxylate side chains, which are part of a structural motif interrupting two beta-strands and connecting PsbO to photosystem II, are within hydrogen bonding distance at pH 6 (100 K). Simulations indicate coupling between protein structure and carboxylate protonation. The crystal structure determined at 100 K and pH 10 indicates broken hydrogen bonding between the carboxylates and local structural change. At pH 6 and 297 K, both conformations were present in the crystal, suggesting conformational dynamics in the functionally relevant pH regime. Taken together, crystallography and molecular dynamics underline a possible mechanism for pH-dependent structural switching. PMID- 27454910 TI - Unintentional Pediatric Exposures to Marijuana in Colorado, 2009-2015. AB - IMPORTANCE: As of 2015, almost half of US states allow medical marijuana, and 4 states allow recreational marijuana. To our knowledge, the effect of recreational marijuana on the pediatric population has not been evaluated. OBJECTIVE: To compare the incidence of pediatric marijuana exposures evaluated at a children's hospital and regional poison center (RPC) in Colorado before and after recreational marijuana legalization and to compare population rate trends of RPC cases for marijuana exposures with the rest of the United States. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of hospital admissions and RPC cases between January 1, 2009, and December 31, 2015, at Children's Hospital Colorado, Aurora, a tertiary care children's hospital. Participants included patients 0 to 9 years of age evaluated at the hospital's emergency department, urgent care centers, or inpatient unit and RPC cases from Colorado for single substance marijuana exposures. EXPOSURE: Marijuana. MAIN OUTCOMES AND MEASURES: Marijuana exposure visits and RPC cases, marijuana source and type, clinical effects, scenarios, disposition, and length of stay. RESULTS: Eighty-one patients were evaluated at the children's hospital, and Colorado's RPC received 163 marijuana exposure cases between January 1, 2009, and December 31, 2015, for children younger than 10 years of age. The median age of children's hospital visits was 2.4 years (IQR, 1.4-3.4); 25 were girls (40%) . The median age of RPC marijuana exposures was 2 years (IQR, 1.3-4.0), and 85 patients were girls (52%). The mean rate of marijuana-related visits to the children's hospital increased from 1.2 per 100 000 population 2 years prior to legalization to 2.3 per 100,000 population 2 years after legalization (P = .02). Known marijuana products involved in the exposure included 30 infused edibles (48%). Median length of stay was 11 hours (interquartile range [IQR], 6-19) and 26 hours (IQR, 19-38) for admitted patients. Annual RPC pediatric marijuana cases increased more than 5 fold from 2009 (9) to 2015 (47). Colorado had an average increase in RPC cases of 34% (P < .001) per year while the remainder of the United States had an increase of 19% (P < .001). For 10 exposure scenarios (9%), the product was not in a child resistant container; for an additional 40 scenarios (34%), poor child supervision or product storage was reported. Edible products were responsible for 51 exposures (52%). CONCLUSIONS AND RELEVANCE: Colorado RPC cases for pediatric marijuana increased significantly and at a higher rate than the rest of the United States. The number of children's hospital visits and RPC case rates for marijuana exposures increased between the 2 years prior to and the 2 years after legalization. Almost half of the patients seen in the children's hospital in the 2 years after legalization had exposures from recreational marijuana, suggesting that legalization did affect the incidence of exposures. PMID- 27454912 TI - Organ Transplantation in Greece. PMID- 27454914 TI - Immunoisolation of Human or Xenogeneic Insulin-Producing Cells: The Next Step for Treating Patients With Type 1 Diabetes? PMID- 27454915 TI - Liver Websites. PMID- 27454916 TI - Anthony Atala, MD: Building Organs for the Future. PMID- 27454917 TI - Josette Marie Eris April 7, 1959 to April 6, 2016 TTS Councilor and Professor. PMID- 27454918 TI - P Value: Significance Is Not All Black and White. PMID- 27454920 TI - Structural, Spectroscopic, and Photochemical Investigation of an Octahedral NO Releasing {RuNO}(7) Species. AB - [Ru(Me3[9]aneN3)(bpy)(NO)](BF4)2 ([1](BF4)2) was explored by single-crystal X-ray diffractometry, leading to the first crystal structure of an octahedral {RuNO}(7) complex. The metal resides on the center of a distorted octahedron, with dN-O and ?Ru-N-O at 1.177(3) A and 141.6(2) degrees , respectively. [1](BF4)2 can be stored indefinitely under argon. Solutions of [1](2+) show no signs of decomposition when protected from air and light. The electron paramagnetic resonance X-band spectrum at 85 K in vitrified acetonitrile (MeCN) shows signals consistent with an S = (1)/2 spin state, better described as Ru(II)NO(*) (g = [2.030, 1.993, 1.880] and A = [11.0, 30.4, 3.9]/10(-4) cm(-1)). In water, the {RuNO}(7) species reacts with O2 in a 1:4 stoichiometry. The reaction is first order in both reactants with k = (1.9 +/- 0.2) M(-1) s(-1) at 25 degrees C (DeltaH(?) = 11.5 +/- 0.3 kJ mol(-1); DeltaS(?) = -189 +/- 1 J K(-1) mol(-1)). Solutions of [1](2+) evolve NO when irradiated a 365 nm with phiNO = 0.024 and 0.090 mol einstein(-1) in H2O and MeCN, respectively. PMID- 27454919 TI - Corticosteroid-Sparing and Optimization of Mycophenolic Acid Exposure in Liver Transplant Recipients Receiving Mycophenolate Mofetil and Tacrolimus: A Randomized, Multicenter Study. AB - BACKGROUND: We conducted a randomized multicenter open-label trial in de novo liver transplant recipients to assess the feasibility and potential benefit of a corticosteroid (CS)-free regimen coupled with tacrolimus (Tac) and dose intensified mycophenolate mofetil (MMF) further adjusted individually. METHODS: Adult liver transplant recipients were randomized on the day of transplantation to a CS-free regimen with Tac and MMF starting at 3 g/d and dose adjusted from day 5 according to mycophenolic acid (MPA) exposure (arm A) or a regimen with CS maintained up to 6 months, Tac and fixed-dose MMF (2 g/d) (arm B). The primary end point was the proportion of patients who experienced treated biopsy-proven acute rejection (BPAR) during the first year posttransplant. RESULTS: One hundred eighty-seven patients were randomized, and 174 comprised the per-protocol population (87 in each arm). The primary objective of noninferiority was met: 7 patients in arm A (8%) and 8 in arm B (9%) experienced treated BPAR in the first year. Two patients in arm A (2%) and 5 in arm B (6%) lost their graft, and 12 month patient survival was similar in both arms (90.8% vs 89.8%; P = 0.86). Adverse events were comparable between arms, except for a lower incidence of de novo diabetes (19.8% vs 32.6%, P = 0.049) and a higher incidence of leukopenia less than 2000/mm (28.6% vs 9.8%; P = 0.001) and neutropenia (26.7% vs 7.9%; P < 0.001) in arm A. CONCLUSIONS: Mycophenolate mofetil at intensified and individually adjusted dose in combination with Tac in de novo liver transplant recipients allows CS discontinuation from day 1 posttransplant with good tolerance and very low rejection incidence. PMID- 27454921 TI - Regioisomeric Effects of Donor-Acceptor-Acceptor' Small-Molecule Donors on the Open Circuit Voltage of Organic Photovoltaics. AB - Donor-acceptor-acceptor' small-molecule donors are synthesized to investigate regioisomeric effects on organic photovoltaic device performance. Cross conjugation in 2-((7-(N-(2-ethylhexyl)-benzothieno[3,2-b]thieno[3,2-d]pyrrol-2 yl)benzo[c][1,2,5]thiadiazol-4-yl)methylene)malononitrile leads to an increased open-circuit voltage compared with its isomer 2-((7-(N-(2-ethylhexyl) benzothieno[3,2-b]thieno[2,3-d]pyrrol-2-yl)benzo[c][1,2,5]thiadiazol-4 yl)methylene)malononitrile. A correlation is then established between molecular conjugation length and orbital energies, and hence open-circuit voltage. PMID- 27454923 TI - Gross motor coordination in junior tennis players. AB - The purpose of this study was twofold: (1) to determine the gross motor coordination performance levels of junior tennis players and (2) to analyse the effects of age and gender. Participants were junior male (n = 50) and female (n = 51) tennis players aged 6-14. Korperkoordinationstest fur Kinder (KTK) was used to assess the gross motor coordination of the participants. Results revealed that none of the participants performed lower than normal level in motor coordination. Besides, 40.6% of the participants performed above normal level. No gender differences were found on all subtests of KTK and also on total motor quotient. Although older players performed better on each test than their younger counterparts for the raw scores, no significant age effect was observed on motor quotient scores among different age groups. PMID- 27454924 TI - Digitalized K(+) Occupancy in the Nanocavity Holds and Releases Queues of K(+) in a Channel. AB - The mechanisms of ion permeation through potassium channels have been extensively examined. Molecular dynamics (MD) simulations have demonstrated that rapidly permeating ions collide near the selectivity filter (SF) ("knock-on" mechanism), but this oversimplified mechanism is insufficient to account for the experimentally observed single-channel current amplitudes. Here, we analyzed the MD-simulated ion trajectories through a Kv1.2 potassium channel using an event oriented analysis method, and surprisingly, we found that the nanocavity (NC) governs ion permeation in a digital fashion. The NC has a maximal diameter of 10 A and stands between the intracellular bulk solution and the SF, which holds only up to one K(+) during permeation. Accordingly, the K(+) concentration in the intracellular solution is translated as a digitalized zero or one K(+) in the NC. When the ion number in the NC is zero, the multiple ions in the SF are mostly immobilized. By contrast, when the number of ions in the NC is one, the structured water in the NC mediates the ion-occupied status to the queueing ions in the SF, and the ions then initiate a collective outward motion. Accordingly, the one ion in the NC serves as a catalytic intermediate for permeation, which quantitatively accounts for the experimentally obtained conductance-concentration relationships. We conclude that the ion movements are coherent across the entire pore. PMID- 27454925 TI - Openness to (reporting) experiences that one never had: Overclaiming as an outcome of the knowledge accumulated through a proclivity for cognitive and aesthetic exploration. AB - Overclaiming-in which individuals overstate their level of familiarity with items has been proposed as a potential indicator of positive self-presentation. However, the precise nature and determinants of overclaiming are not well understood. Herein, we provide novel insights into overclaiming through 4 primary studies (comprising 6 samples) and a meta-analysis. Based on past empirical work and theoretical discussions suggesting that overclaiming may be the result of several processes-including an egoistic tendency to self-enhance, intentional impression managing behavior, and memory biases-we investigate various potential dispositional bases of this behavior. We hypothesized that overclaiming would best be predicted by a dispositional tendency to be curious and explorative (i.e., high Openness to Experience) and by a dispositional tendency to be disingenuous and self-centered (i.e., low Honesty-Humility). All studies provided support for the first hypothesis; that is, overclaiming was positively associated with Openness. However, no study supported the hypothesis that overclaiming was associated with Honesty-Humility. The third and fourth studies, where multiple mechanisms were compared simultaneously, further revealed that overclaiming can be understood as a result of knowledge accumulated through a general proclivity for cognitive and aesthetic exploration (i.e., Openness) and, to a lesser extent, time spent in formal education. (PsycINFO Database Record PMID- 27454922 TI - Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between beta-Amyloid and Tauopathy. AB - IMPORTANCE: In vivo tau imaging may become a diagnostic marker for Alzheimer disease (AD) and provides insights into the pathophysiology of AD. OBJECTIVE: To evaluate the usefulness of [18F]-AV-1451 positron emission tomography (PET) imaging to stage AD and assess the associations among beta-amyloid (Abeta), tau, and volume loss. DESIGN, SETTING, AND PARTICIPANTS: An imaging study conducted at Knight Alzheimer Disease Research Center at Washington University in St Louis, Missouri. A total of 59 participants who were cognitively normal (CN) (Clinical Dementia Rating [CDR] score, 0) or had AD dementia (CDR score, >0) were included. MAIN OUTCOMES AND MEASURES: Standardized uptake value ratio (SUVR) of [18F]-AV 1451 in the hippocampus and a priori-defined AD cortical signature regions, cerebrospinal fluid Abeta42, hippocampal volume, and AD signature cortical thickness. RESULTS: Of the 59 participants, 38 (64%) were male; mean (SD) age was 74 (6) years. The [18F]-AV-1451 SUVR in the hippocampus and AD cortical signature regions distinguished AD from CN participants (area under the receiver operating characteristic curve range [95% CI], 0.89 [0.73-1.00] to 0.98 [0.92-1.00]). An [18F]-AV-1451 SUVR cutoff value of 1.19 (sensitivity, 100%; specificity, 86%) from AD cortical signature regions best separated cerebrospinal fluid Abeta42 positive (Abeta+) AD from cerebrospinal fluid Abeta42-negative (Abeta-) CN participants. This same cutoff also divided Abeta+ CN participants into low vs high tau groups. Moreover, the presence of Abeta+ was associated with an elevated [18F]-AV-1451 SUVR in AD cortical signature regions (Abeta+ participants: mean [SD], 1.3 [0.3]; Abeta- participants: 1.1 [0.1]; F = 4.3, P = .04) but not in the hippocampus. The presence of Abeta+ alone was not related to hippocampal volume or AD signature cortical thickness. An elevated [18F]-AV-1451 SUVR was associated with volumetric loss in both the hippocampus and AD cortical signature regions. The observed [18F]-AV-1451 SUVR volumetric association was modified by Abeta status in the hippocampus but not in AD cortical signature regions. An inverse association between hippocampal [18F]-AV-1451 SUVR and volume was seen in Abeta+ participants (R2 = 0.55; P < .001) but not Abeta- (R2 = 0; P = .97) participants. CONCLUSIONS AND RELEVANCE: Use of [18F]-AV-1451 has a potential for staging of the preclinical and clinical phases of AD. beta-Amyloid interacts with hippocampal and cortical tauopathy to affect neurodegeneration. In the absence of Abeta, hippocampal tau deposition may be insufficient for the neurodegenerative process that leads to AD. PMID- 27454926 TI - The psychological structure of humility. AB - Psychological inquiry into humility has advanced considerably over the past decade, yet this literature suffers from 2 notable limitations. First, there is no clear consensus among researchers about what humility is, and conceptualizations vary considerably across studies. Second, researchers have uniformly operationalized humility as a positive, socially desirable construct, while dismissing evidence from lay opinion and theological and philosophical traditions suggesting that humility may also have a darker side. To redress these issues, we conducted the first comprehensive, bottom-up analysis of the psychological structure of humility. Here we report 5 studies (total N = 1,479) that involve: (a) cluster analysis and categorization of humility-related words, generated by both lay persons and academic experts; (b) exploratory and confirmatory factor analyses of momentary and dispositional humility experiences; and (c) experimental induction of a momentary humility experience. Across these studies, we found converging evidence that humility can take 2 distinct forms, which we labeled "appreciative" and "self-abasing" humility. Appreciative humility tends to be elicited by personal success, involve action tendencies oriented toward celebrating others, and is positively associated with dispositions such as authentic pride, guilt, and prestige-based status. In contrast, self-abasing humility tends to be elicited by personal failure, involves negative self-evaluations and action tendencies oriented toward hiding from others' evaluations, and is associated with dispositions such as shame, low self-esteem, and submissiveness. Together, these findings provide a systematic and empirically grounded understanding of humility. (PsycINFO Database Record PMID- 27454927 TI - Being observed magnifies action. AB - We test the hypothesis that people, when observed, perceive their actions as more substantial because they add the audience's perspective to their own perspective. We find that participants who were observed while eating (Study 1) or learned they were observed after eating (Study 2) recalled eating a larger portion than unobserved participants. The presence of others magnified both desirable and undesirable actions. Thus, observed (vs. unobserved) participants believed they gave both more correct and incorrect answers in a lab task (Study 3) and, moving to a field study, the larger the audience, the larger the contribution badminton players claimed toward their teams' successes as well as failures (Study 4). In contrast to actions, inactions are not magnified, because they are unobservable; indeed, observed (vs. unobserved) participants believed they solved more task problems but did not skip more problems (Study 5). Taken together, these studies show that being observed fundamentally alters the subjective magnitude of one's actions. (PsycINFO Database Record PMID- 27454928 TI - Cognitive rehabilitation after severe acquired brain injury: current evidence and future directions. AB - Severe acquired brain injury (SABI) is damage to the brain, occurring after birth from traumatic or non-traumatic causes, and often resulting in deterioration of physical, cognitive, and emotional functions. Cognitive rehabilitation (CR) is aimed to help brain-injured or otherwise cognitively impaired individuals to restore normal functioning, or to compensate for cognitive deficits. Over the last years, the development of new technologies in the field of CR has led to a growing use of computer-based cognitive tools in patients with SABI. This review aims to investigate the efficacy of CR in individuals suffering from SABI, and evaluates the role of virtual reality and other innovative technologies in improving behavioural and functional outcomes. The current evidence for CR in the treatment of SABI-related deficits does not allow conclusive results to be achieved and further research is needed to identity the patient and treatment factors that contribute to successful outcomes. PMID- 27454929 TI - Fabrication of an Efficient BiVO4-TiO2 Heterojunction Photoanode for Photoelectrochemical Water Oxidation. AB - In this work, a simple planar BiVO4/TiO2 heterojunction photoanode was prepared on a fluorine-doped tin oxide (FTO) substrate for photoelectrochemical (PEC) water oxidation. The measurements of surface photovoltage, photocurrent transient behavior, and hole-scavenger-assisted PEC performance indicate that charge separation efficiency is improved compared to that of the BiVO4/FTO photoanode. This improvement is caused by the formation of the staggered BiVO4/TiO2 heterojunction. However, the photocurrent densities of the BiVO4/TiO2/FTO photoanode are higher than those of the BiVO4/FTO one only at potentials >1.2 V vs reversible hydrogen electrode, although the two BiVO4 layers with comparable light harvesting efficiencies were prepared by the same method. The hole scavenger-assisted PEC measurements reveal that the hole injection efficiency of the BiVO4/TiO2/FTO photoanode is inferior to that of the bare BiVO4/FTO anode for oxygen evolution. It shows that the surface property of the BiVO4 layers is altered as they are deposited on different substrates. On the basis of these characterizations, the cocatalyst cobalt phosphate (Co-Pi) was further deposited on the surface of BiVO4/TiO2/FTO photoanode to improve the hole injection efficiency. Subsequently, the photocurrent density and stability of the Co Pi/BiVO4/TiO2/FTO photoanode were significantly improved compared to those of the bare BiVO4/FTO photoanode. PMID- 27454930 TI - Feasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer. AB - BACKGROUND: EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel. METHODS: HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated. RESULTS: Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04). CONCLUSIONS: The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization. TRIAL REGISTRATION: ClinicalTrials.gov NCT01537536. PMID- 27454931 TI - Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. AB - We report crystal structures of zebrafish histone deacetylase 6 (HDAC6) catalytic domains in tandem or as single domains in complex with the (R) and (S) enantiomers of trichostatin A (TSA) or with the HDAC6-specific inhibitor nexturastat A. The tandem domains formed, together with the inter-domain linker, an ellipsoid-shaped complex with pseudo-twofold symmetry. We identified important active site differences between both catalytic domains and revealed the binding mode of HDAC6 selective inhibitors. HDAC inhibition assays with (R)- and (S)-TSA showed that (R)-TSA was a broad-range inhibitor, whereas (S)-TSA had moderate selectivity for HDAC6. We identified a uniquely positioned alpha-helix and a flexible tryptophan residue in the loop joining alpha-helices H20 to H21 as critical for deacetylation of the physiologic substrate tubulin. Using single molecule measurements and biochemical assays we demonstrated that HDAC6 catalytic domain 2 deacetylated alpha-tubulin lysine 40 in the lumen of microtubules, but that its preferred substrate was unpolymerized tubulin. PMID- 27454932 TI - Photoswitchable diacylglycerols enable optical control of protein kinase C. AB - Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling. PMID- 27454933 TI - Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. AB - Histone deacetylase 6 (HDAC6) is a critical target for drug design because of its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens HDAC6 and of CD1 and CD2 from Danio rerio HDAC6. We correlated these structures with activity measurements using 13 different substrates. The catalytic activity of CD2 from both species exhibited broad substrate specificity, whereas that of CD1 was highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yielded unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with eight different inhibitors, including belinostat and panobinostat (currently used in cancer chemotherapy), the macrocyclic tetrapeptide HC toxin, and the HDAC6 specific inhibitor N-hydroxy-4-(2-((2-hydroxyethyl)(phenyl)amino)-2 oxoethyl)benzamide, revealed surprising new insight regarding changes in Zn(2+) coordination and isozyme-specific inhibition. PMID- 27454934 TI - Detection of false arrhythmia alarms with emphasis on ventricular tachycardia. AB - Our approach to detecting false arrhythmia alarms in the intensive care unit breaks down into several tasks. It involves beat detection on different signals: electrocardiogram, photoplethysmogram and arterial blood pressure. The quality of each channel has to be estimated in order to evaluate the reliability of obtained beat detections. The information about the heart rate from the different channels must be integrated in order to find a final conclusion. Some alarm types require particular detectors as is the case of ventricular fibrillation. To identify false ventricular tachycardia alarms we needed to classify heart beats as normal/ventricular. For that purpose we introduce a new feature, QRS polarity type. This feature was important in order to reduce misclassification of ventricular beats: there was an improvement in the ventricular tachycardia alarm true positive rate from 69% to 81%. However, the true negative rate was reduced from 95% to 69% and our global challenge score (real-time event) dropped from 79.02 to 74.28. Our challenge algorithm achieved the third best score in the 2015 PhysioNet/CinC challenge event 1 (real time). PMID- 27454935 TI - Comments on 'Psychological intervention targeting distress for cancer patients: a meta-analytic study investigating uptake and adherence' by Brebach and colleagues (2016). PMID- 27454936 TI - Response to Schellekens et al. PMID- 27454937 TI - Neurochemical and Behavioral Responses to Unpredictable Chronic Mild Stress Following Developmental Isolation: The Zebrafish as a Model for Major Depression. AB - Unpredictable chronic mild stress (UCMS) and developmental social isolation are often utilized in laboratory animals to mimic unpredictable life stressors and early life adversity that may contribute to the development of major depressive disorder in humans. Zebrafish (Danio rerio) have been used to examine the effects of both developmental social isolation and UCMS. However, anxiety-like behavioral responses, social behavior, and neurochemical changes induced by stressors have not been well characterized. Furthermore, the possible interaction between UCMS and developmental isolation remains unexplored. In this study, we analyzed the effect of UCMS on developmentally isolated and socially reared zebrafish. The UCMS procedure entailed delivering unpredictably varying mild stressors twice a day for 15 consecutive days. To quantify social and anxiety-like behaviors, we measured the zebrafish's behavioral and neurochemical (dopaminergic and serotonergic) responses to an animated image of conspecifics in a novel tank. Our results suggest that UCMS increased anxiety-like behavioral responses, whereas developmental isolation altered motor responses during stimulus presentation. We also found that UCMS diminished weight gain and reduced whole-brain levels of dopamine and serotonin's metabolite 5-HIAA in developmentally isolated, but not socially reared zebrafish. Our findings reinforce the utility of combining developmental isolation with UCMS in zebrafish to model depressive-like behavior in humans. PMID- 27454938 TI - High-salt diet induces outward remodelling of efferent arterioles in mice with reduced renal mass. AB - AIM: The glomerular filtration rate (GFR) falls progressively in chronic kidney disease (CKD) which is caused by a reduction in the number of functional nephrons. The dysfunctional nephron exhibits a lower glomerular capillary pressure that is induced by an unbalance between afferent and efferent arteriole. Therefore, we tested the hypothesis that oxidative stress induced by CKD differentially impairs the structure or function of efferent vs. afferent arterioles. METHODS: C57BL/6 mice received sham operations (sham) or 5/6 nephrectomy (RRM) and three months of normal- or high-salt diet or tempol. GFR was assessed from the plasma inulin clearance, arteriolar remodelling from media/lumen area ratio, myogenic responses from changes in luminal diameter with increases in perfusion pressure and passive wall compliance from the wall stress/strain relationships. RESULTS: Mice with RRM fed a high salt (vs. sham) had a lower GFR (553 +/- 25 vs. 758 +/- 36 MUL min-1 g-1 kidney, P < 0.01) and a larger efferent arteriolar diameter (9.6 +/- 0.8 vs. 7.4 +/- 0.7 MUm, P < 0.05) resulting in a lower media/lumen area ratio (1.4 +/- 0.1 vs. 2.4 +/- 0.2, P < 0.01). These alterations were corrected by tempol. The myogenic responses of efferent arterioles were about one-half that of afferent arterioles and were unaffected by RRM or salt. Passive wall compliance was reduced by high salt in both afferent and efferent arterioles. CONCLUSION: A reduction in renal mass with a high-salt diet induces oxidative stress that leads to an outward eutrophic remodelling in efferent arterioles and reduced wall compliance in both afferent and efferent arterioles. This may contribute to the lower GFR in this model of CKD. PMID- 27454939 TI - "Dissecting Gonadoblastoma" of Scully: A Morphologic Variant That Often Mimics Germinoma. AB - Dr Robert E. Scully, who recognized and defined gonadoblastoma (GB), used the term "dissecting gonadoblastoma" (DGB) to describe variants with either an infiltrative type or diffuse pattern instead of the usual small nested arrangement. These patterns have not been emphasized in the literature. To investigate the features of DGB we examined 50 GBs microscopically and performed immunohistochemistry (IHC) in some. DGB was found in 38 (76%) GBs and was represented by 3 patterns. The most frequent was solid/expansile (n=26), consisting of large coalescent nests of germ cells, often (92%) interrupted by fibrovascular septa, with usually minor numbers of sex cord cells. Less frequent were small anastomosing nests (n=24) and cord-like arrangements (n=22) of germ cells irregularly distributed in a prominent stroma and with mostly inconspicuous sex cord cells. Most DGBs (24) showed >1 pattern and demonstrated the characteristic globular deposits of basement membrane, although these were often subtle. The germ cells in all patterns varied from spermatogonium-like to seminoma-like; OCT3/4 was positive only in the latter (7/7). The sex cord cells were small with dense, oval or angulated nuclei, inconspicuous nucleoli, and positivity for inhibin (9/9, strong), FOXL2 (9/9, strong), SF1 (8/9, strong), SOX9 (9/9, weak and focal), WT1 (5/7, variable), and calretinin (3/7, variable). Granulomas were present in 84% of germinoma foci, 13% of DGB foci, and 8% of classic GB foci. Twenty two of 38 DGBs had associated germinoma; 3 also had embryonal carcinoma, yolk sac tumor, and choriocarcinoma, respectively. Follow-up of 2 cases lacking an invasive tumor showed that both patients were disease free at 13 and 4.8 years after bilateral gonadectomy. We conclude that DGB is commonly seen with classic GB and displays identical IHC features, supporting it as a morphologic variant of GB. It appears likely that cord-like DGB is the earliest phase in a GB developmental continuum that may proceed successively into anastomosing, nested (classic GB), and solid/expansile patterns. DGB often mimics germinoma because of the large size of the nests, pseudoinfiltrative pattern of some cases, and inconspicuous sex cord cells. The presence of sex cord cells (identification aided by IHC for sex cord markers), the heterogenous morphology of the germ cells, and globules of basement membrane are useful differential features. The lack of a granulomatous reaction also favors DGB over germinoma. Mistaking DGB for GB with invasive germinoma may result in more aggressive therapy than warranted. The likely relationship of DGB to the relatively recently described concept of so-called "undifferentiated gonadal tissue" is discussed herein. PMID- 27454940 TI - Fumarase-deficient Uterine Leiomyomas: An Immunohistochemical, Molecular Genetic, and Clinicopathologic Study of 86 Cases. AB - Loss-of-function germline mutations in the fumarase (FH) gene of the Krebs cycle characterize hereditary leiomyomatosis and renal cell cancer syndrome. Fumarase (FH) deficiency can be diagnosed by the loss of immunohistochemical expression. In this study, we investigated the occurrence and clinicopathologic features of FH-deficient uterine smooth muscle tumors (SMTs). A total of 1583 uterine and 157 nonuterine SMTs were examined using a polyclonal FH antibody and automated immunohistochemistry, and 86 uterine leiomyomas with an FH loss were identified. The frequencies of FH deficiency for subcohorts of uterine SMTs were 1.6% for unselected nonatypical leiomyomas, 1.8% for cellular leiomyomas, 37.3% for atypical leiomyomas, and 0% for leiomyosarcomas. One extrauterine, retroperitoneal estrogen receptor-positive leiomyoma was also FH deficient. The patient age of FH-deficient uterine leiomyomas was 20 to 52 years (median, 38 y). Grossly, these tumors were often soft and amorphous resembling a fibrothecoma. Histologically, the FH-deficient nonatypical leiomyomas lacked cellular packeting and distinct collagenous zones and showed chain-like or palisading nuclear arrangements, prominent staghorn-shaped blood vessels, oval nuclei with no or at most mild atypia, small eosinophilic nucleoli, and a low mitotic rate (0 to 1/10 HPF). The FH-deficient atypical leiomyomas had nuclear atypia often manifesting as multinucleation, prominent eosinophilic nucleoli, and mitotic activity up to 7/10 HPF, with atypical mitoses seen in 32% of cases. However, similar histologic changes were seen in some non-FH-deficient atypical leiomyomas. Loss-of-function FH-gene mutations including 5 whole-gene deletions and 3 frameshift mutations were identified in 8 of 16 FH-deficient nonatypical leiomyomas using multiplex ligation-dependent probe amplification and Sanger sequencing, respectively. Follow-up data on patients with FH-deficient atypical uterine leiomyomas revealed 19 patients alive (median follow-up 27 y) and 5 patients dead. Deaths occurred 9 to 30 years after surgery at a median age of 72 years; causes of death could not be determined. These results indicate that FH-deficient uterine leiomyomas occur with a high frequency among atypical leiomyomas and infrequently in nonatypical leiomyomas and are often histologically distinctive. They seem to have a low biological potential and lack any significant association with leiomyosarcoma. PMID- 27454941 TI - Ciliated Muconodular Papillary Tumors of the Lung Can Occur in Western Patients and Show Mutations in BRAF and AKT1. AB - Ciliated muconodular papillary tumors (CMPTs) are rare peripheral lung lesions, characterized by papillary architecture and ciliated columnar cells admixed with mucinous cells and basal cells. They often have prominent surrounding intra alveolar mucin, which can lead to diagnostic confusion with mucinous adenocarcinoma. Recognition of the ciliated component is the key to diagnosis of CMPT. The literature contains few reported cases to date, all occurring in East Asian patients. Although follow-up data are limited, CMPT seems to be an indolent tumor with very good prognosis, leading some to question whether it is a reactive or hamartomatous lesion. However, a very recent molecular study has identified BRAF (40%) and EGFR (30%) alterations in CMPT, supporting a truly neoplastic process. Here for the first time, we report 4 cases of morphologically typical CMPT in western patients, occurring in 1 man (60 y) and 3 women (71 to 83 y). Interestingly, 1 case occurred in background of pronounced small airway disease with necrotizing bronchiolitis and multiple carcinoid tumorlets. We further analyzed 1 tumor using a 50 gene next-generation sequencing oncology panel that identified 2 pathogenic mutations (BRAF V600E and AKT1 E17K). Our study is the first to describe that CMPT can occur in western (non-Asian) patients. Our data confirm BRAF V600E mutation as a probable driver in a subset of these tumors, along with AKT1 mutation, which further supports that CMPT are indolent pulmonary neoplasms. PMID- 27454942 TI - OsmoPrep-associated Gastritis: A Histopathologic Mimic of Iron Pill Gastritis and Mucosal Calcinosis. AB - We have identified 8 cases of gastritis characterized by the presence of purple to black granular deposits in the superficial mucosa associated with marked reactive epithelial changes. In each case, the patient had taken OsmoPrep, a tablet form of sodium phosphate used for bowel preparation just before upper endoscopy and had undergone concurrent colonoscopy. Endoscopic findings ranged from normal gastric mucosa to severe inflammation, congestion, and friability. No other gastrointestinal sites were noted to contain the deposits or show similar mucosal injury. On initial histologic review, the deposits raised the differential diagnosis of elemental iron and mucosal calcinosis. However, none of the patients was noted to be taking iron supplements, and none had a history of renal disease or other cause of calcium dysmetabolism. Histochemical stains revealed the deposits were negative on Perls' iron stain (8/8 cases), positive on von Kossa stain (7/8 cases), and negative on Alizarin Red stain (8/8 cases)-a histochemical profile compatible with sodium phosphate but inconsistent with mucosal calcium. A crushed OsmoPrep tablet was subjected to processing and demonstrated similar histologic features and histochemical profile. In addition, biopsies of 20 consecutive patients who did not take OsmoPrep and who underwent concurrent endoscopy and colonoscopy were reviewed, and no deposits with similar histochemical profile were identified. In summary, we have characterized a unique form of gastritis associated with OsmoPrep use. Attention to clinical history and use of a select panel of histochemical stains allow for accurate diagnosis. PMID- 27454943 TI - Predictors of Outcome in the Phenotypic Spectrum of Polymorphous Low-grade Adenocarcinoma (PLGA) and Cribriform Adenocarcinoma of Salivary Gland (CASG): A Retrospective Study of 69 Patients. AB - Polymorphous low-grade adenocarcinoma (PLGA) shows histologic diversity with fascicular and targetoid features while cribriform adenocarcinoma of salivary gland (CASG) demonstrates predominant cribriform and solid patterns with glomeruloid appearance and optical clear nuclei. The current study is designed to identify pathologic features that may predict clinical outcome in 69 PLGA/CASG. Seven patients had recurrences or distant metastasis, including 3 local recurrences, 2 nodal metastases, and 2 distant metastases. The following histologic factors predicted disease-free survival on univariate analysis: tumor size, bone invasion, lymphovascular invasion, tumor necrosis, >=10% papillary pattern, and >=30% cribriform pattern. On multivariate analysis, 10% of papillary pattern and 30% cribriform pattern were independent prognostic factors of disease free survival. Histologic classification of the 69 tumors (based on the prior reported definition of CASG) showed 21 CASGs (30%), 23 PLGAs (33%), and 22 (32%) with indeterminate features of PLGA and CASG. In addition, 3 (4%) tumors demonstrated a predominant papillary pattern (>=50%). Interestingly, not all CASGs were located in the minor salivary gland and 2 tumors were identified in the parotid. One patient died from her disease and she harbored a CASG with >30% cribriform pattern. In conclusion, tumor size, bone invasion, and lymphovascular invasion are significant parameters that can predict adverse clinical behaviors in PLGA/CASG on univariate analysis. Using the prior reported definition, an overlapping histology between PLGA and CASG was noted in over a third of the cases. Regardless of tumor subclassification, the percentage of cribriform and papillary patterns seems to be prognostically relevant and should be documented. PMID- 27454944 TI - Solitary Pulmonary Capillary Hemangioma of Adult Cases: Clinicopathologic Characteristics as an Unrecognized Entity. AB - Solitary pulmonary capillary hemangioma (SPCH) is a rare disease, first described about autopsy cases in 2000 and about surgically resected cases in 2006. To date, only 9 surgically resected cases have been published in English. Here, we report 7 original cases with surgery (median age, 54 y; 4 females, 2 never-smokers). All patients were asymptomatic, and all nodules were detected by computed tomography (CT). The median (range) size of nodule was 11 (8 to 16) mm. Six of 7 cases showed the part-solid nodule appearance and 1 showed pure ground-glass nodule appearance in CT findings. The growth speed was very slow. No abnormal uptake of fluorine-18 fluorodeoxyglucose was observed in systemic positron-emission CT in all 3 cases we examined. No patients died from SPCH. Histologically, SPCH manifested as a solitary lesion composed of densely proliferating and dilated capillaries without cytologic atypia within the alveolar septa. In addition, capillaries of SPCH spread into the vascular lumen and involved the walls of bronchioles with protrusion into the lumen. Immunohistochemically, capillaries of SPCH uniformly expressed endothelial markers, such as CD31, CD34, and Factor VIII; and alpha-smooth muscle actin positive cells were also observed. To be accurately diagnosed, especially in intraoperative frozen sections, SPCH should be conceived as an entity that presents as a solitary nodule in CT. We propose that SPCH is an unrecognized benign capillary proliferative disease. PMID- 27454946 TI - Threading through Macrocycles Enhances the Performance of Carbon Nanotubes as Polymer Fillers. AB - In this work, we study the reinforcement of polymers by mechanically interlocked derivatives of single-walled carbon nanotubes (SWNTs). We compare the mechanical properties of fibers made of polymers and of composites with pristine SWNTs, mechanically interlocked derivatives of SWNTs (MINTs), and the corresponding supramolecular models. Improvements of both Young's modulus and tensile strength of up to 200% were observed for the polystyrene-MINT samples with an optimized loading of just 0.01 wt %, while the supramolecular models with identical chemical composition and loading showed negligible or even detrimental influence. This behavior is found for three different types of SWNTs and two types of macrocycles. Molecular dynamics simulations show that the polymer adopts an elongated conformation parallel to the SWNT when interacting with MINT fillers, irrespective of the macrocycle chemical nature, whereas a more globular structure is taken upon facing with either pristine SWNTs or supramolecular models. The MINT composite architecture thus leads to a more efficient exploitation of the axial properties of the SWNTs and of the polymer chain at the interface, in agreement with experimental results. Our findings demonstrate that the mechanical bond imparts distinctive advantageous properties to SWNT derivatives as polymer fillers. PMID- 27454945 TI - Continuity of Care and Health Care Utilization in Older Adults With Dementia in Fee-for-Service Medicare. AB - IMPORTANCE: Poor continuity of care may contribute to high health care spending and adverse patient outcomes in dementia. OBJECTIVE: To examine the association between medical clinician continuity and health care utilization, testing, and spending in older adults with dementia. DESIGN, SETTING, AND PARTICIPANTS: This was a study of an observational retrospective cohort from the 2012 national sample in fee-for-service Medicare, conducted from July to December 2015, using inverse probability weighted analysis. A total of 1 416 369 continuously enrolled, community-dwelling, fee-for-service Medicare beneficiaries 65 years or older with a claims-based dementia diagnosis and at least 4 ambulatory visits in 2012 were included. EXPOSURES: Continuity of care score measured on patient visits across physicians over 12 months. A higher continuity score is assigned to visit patterns in which a larger share of the patient's total visits are with fewer clinicians. Score range from 0 to 1 was examined in low-, medium-, and high continuity tertiles. MAIN OUTCOMES AND MEASURES: Outcomes include all-cause hospitalization, ambulatory care sensitive condition hospitalization, emergency department visit, imaging, and laboratory testing (computed tomographic [CT] scan of the head, chest radiography, urinalysis, and urine culture), and health care spending (overall, hospital and skilled nursing facility, and physician). RESULTS: Beneficiaries with dementia who had lower levels of continuity of care were younger, had a higher income, and had more comorbid medical conditions. Almost 50% of patients had at least 1 hospitalization and emergency department visit during the year. Utilization was lower with increasing level of continuity. Specifically comparing the highest- vs lowest-continuity groups, annual rates per beneficiary of hospitalization (0.83 vs 0.88), emergency department visits (0.84 vs 0.99), CT scan of the head (0.71 vs 0.83), urinalysis (0.72 vs 1.09), and health care spending (total spending, $22 004 vs $24 371) were higher with lower continuity even after accounting for sociodemographic factors and comorbidity burden (P < .001 for all comparisons). The rate of ambulatory care sensitive condition hospitalization was similar across continuity groups. CONCLUSIONS AND RELEVANCE: Among older fee-for-service Medicare beneficiaries with a dementia diagnosis, lower continuity of care is associated with higher rates of hospitalization, emergency department visits, testing, and health care spending. Further research into these relationships, including potentially relevant clinical, clinician, and systems factors, can inform whether improving continuity of care in this population may benefit patients and the wider health system. PMID- 27454947 TI - Raman Line Imaging of Poly(epsilon-caprolactone)/Carbon Dioxide Solutions at High Pressures: A Combined Experimental and Computational Study for Interpreting Intermolecular Interactions and Free-Volume Effects. AB - In the present study, a Raman line-imaging setup was employed to monitor in situ the CO2 sorption at elevated pressures (from 0.62 to 7.10 MPa) in molten PCL. The method allowed the quantitative measurement of gas concentration in both the time resolved and the space-resolved modes. The combined experimental and theoretical approach allowed a molecular level characterization of the system. The dissolved CO2 was found to occupy a volume essentially coincident with its van der Waals volume and the estimated partial molar volume of the probe did not change with pressure. Lewis acid-Lewis base interactions with the PCL carbonyls was confirmed to be the main interaction mechanism. The geometry of the supramolecular complex and the preferential interaction site were controlled more by steric than electronic effects. On the basis of the indications emerging from Raman spectroscopy, an equation of state thermodynamic model for the PCL-CO2 system, based upon a compressible lattice fluid theory endowed with specific interactions, has been tailored to account for the interaction types detected spectroscopically. The predictions of the thermodynamic model in terms of molar volume of solution have been compared with available volumetric measurements while predictions for CO2 partial molar volume have been compared with the values estimated on the basis of Raman spectroscopy. PMID- 27454987 TI - Exogenous hydrogen sulfide attenuates cerebral ischemia-reperfusion injury by inhibiting autophagy in mice. AB - Hydrogen sulfide (H2S), the third gas transmitter, has been proven to be neuroprotective in cerebral ischemic injury, but whether its effect is mediated by regulating autophagy is not yet clear. The present study was undertaken to explore the underlying mechanisms of exogenous H2S on autophagy regulation in cerebral ischemia. The effects and its connection with autophagy of NaHS, a H2S donor, were observed through neurological deficits and cerebral infarct volume in middle cerebral artery occlusion (MCAO) mice; autophagy-related proteins and autophagy complex levels in the ischemic hemisphere were detected with Western blot assay. Compared with the model group, NaHS significantly decreased infarct volume and improved neurological deficits; rapamycin, an autophagy activator, abolished the effect of NaHS; NaHS decreased the expression of LC3-II and up regulated p62 expression in the ischemic cortex 24 h after ischemia. However, NaHS did not significantly influence Beclin-1 expression. H2S has a neuroprotective effect on ischemic injury in MCAO mice; this effect is associated with its influence in down-regulating autophagosome accumulation. PMID- 27454988 TI - Traumatic Cochlear Nerve Avulsion Following Otic-Capsule Sparing Temporal Bone Fracture. PMID- 27454989 TI - Advances in the understanding of cluster headache. AB - INTRODUCTION: Cluster headache is the worst primary headache form; it occurs in paroxysmal excruciatingly severe unilateral head pain attacks usually grouped in cluster periods. The familial occurrence of the disease indicates a genetic component but a gene abnormality is yet to be disclosed. Activation of trigeminal afferents and cranial parasympathetic efferents, the so-called trigemino parasympathetic reflex, can explain pain and accompanying oculo-facial autonomic phenomena. In particular, pain in cluster headache is attributed, at least in part, to the increased CGRP plasma levels released by activated trigeminal system. Posterior hypothalamus was hypothesized to be the cluster generator activating the trigemino-parasympathetic reflex. Efficacy of monoclonal antibodies against CRGP is under investigation in randomized clinical trials. Areas covered: This paper will focus on main findings contributing to consider cluster headache as a neurovascular disorder with an origin from within the brain. Expert commentary: Accumulated evidence with hypothalamic stimulation in cluster headache patients indicate that posterior hypothalamus terminates rather than triggers the attacks. More extensive studies on the genetics of cluster headache are necessary to disclose anomalies behind the increased familial risk of the disease. Results from ongoing clinical trials in cluster headache sufferers using monoclonal antibodies against CGRP will open soon a new era. PMID- 27454990 TI - On the magnetic properties of iron nanostructures fabricated via focused electron beam induced deposition and autocatalytic growth processes. AB - We employ Electron beam induced deposition (EBID) in combination with autocatalytic growth (AG) processes to fabricate magnetic nanostructures with controllable shapes and thicknesses. Following this route, different Fe deposits were prepared on silicon nitride membranes under ultra-high vacuum conditions and studied by scanning electron microscopy (SEM) and scanning transmission x-ray microspectroscopy (STXM). The originally deposited Fe nanostructures are composed of pure iron, especially when fabricated via autocatalytic growth processes. Quantitative near-edge x-ray absorption fine structure (NEXAFS) spectroscopy was employed to derive information on the thickness dependent composition. X-ray magnetic circular dichroism (XMCD) in STXM was used to derive the magnetic properties of the EBID prepared structures. STXM and XMCD analysis evinces the existence of a thin iron oxide layer at the deposit-vacuum interface, which is formed during exposure to ambient conditions. We were able to extract magnetic hysteresis loops for individual deposits from XMCD micrographs with varying external magnetic field. Within the investigated thickness range (2-16 nm), the magnetic coercivity, as evaluated from the width of the hysteresis loops, increases with deposit thickness and reaches a maximum value of ~160 Oe at around 10 nm. In summary, we present a viable technique to fabricate ferromagnetic nanostructures in a controllable way and gain detailed insight into their chemical and magnetic properties. PMID- 27454991 TI - Cryptosporidium in humans and animals-a one health approach to prophylaxis. AB - Cryptosporidium is a major cause of moderate-to-severe diarrhoea in humans worldwide, second only to rotavirus. Due to the wide host range and environmental persistence of this parasite, cryptosporidiosis can be zoonotic and associated with foodborne and waterborne outbreaks. Currently, 31 species are recognized as valid, and of these, Cryptosporidium hominis and Cryptosporidium parvum are responsible for the majority of infections in humans. The immune status of the host, both innate and adaptive immunity, has a major impact on the severity of the disease and its prognosis. Immunocompetent individuals typically experience self-limiting diarrhoea and transient gastroenteritis lasting up to 2 weeks and recover without treatment, suggesting an efficient host antiparasite immune response. Immunocompromised individuals can suffer from intractable diarrhoea, which can be fatal. Effective drug treatments and vaccines are not yet available. As a result of this, the close cooperation and interaction between veterinarians, health physicians, environmental managers and public health operators is essential to properly control this disease. This review focuses on a One Health approach to prophylaxis, including the importance of understanding transmission routes for zoonotic Cryptosporidium species, improved sanitation and better risk management, improved detection, diagnosis and treatment and the prospect of an effective anticryptosporidial vaccine. PMID- 27454992 TI - [Analysis of gross deletions of COL1A1/2 genes in Chinese families affected with osteogenesis imperfecta]. AB - OBJECTIVE: To identify deletion of large fragment in COL1A1/2 genes among patients with osteogenesis imperfecta (OI). METHODS: Genomic DNA was extracted from peripheral blood samples by a standard SDS-proteinase K-phenol/chloroform method. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect gross deletions of the COL1A1/2 genes among 46 patients affected with OI, in whom no mutation was detected in the sequences of the COL1A1/2 genes. RESULTS: Heterozygous deletions of the entire COL1A1 gene and exon 20 of the COL1A2 gene were detected in probands A and B, respectively, and no gross deletion was found in the remaining 44 samples. The MLPA result of proband A was confirmed by fluorescence quantitative PCR (Q-PCR) in his family. A further conjunction point analysis through gap-PCR and DNA sequencing revealed deletion of exons 17 to 23 in the COL1A2 gene, and a 637 bp-insertion from chromosome 5 in the proband B. CONCLUSION: Two gross deletions have been found in the genes coding for collagen type I in the Chinese OI population, and the deletion of exons 17 to 23 in the COL1A2 gene is a novel mutation. This work not only has expanded the mutation spectrum of the COL1A1/2 gene, but also provided a support for prenatal genetic diagnosis for the families. PMID- 27454993 TI - [Impact of natural selection on the polymorphism of HLA-G 3'UTR among five ethnic Chinese populations]. AB - OBJECTIVE: To assess the impact of natural selection and genetic background on the polymorphisms of HLA-G 3-untranslated regions (UTR) among five ethnic Chinese populations. METHODS: PCR and DNA sequencing were used to determine the polymorphisms among 432 individuals from the five ethnic populations. Their genetic background was determined by genotyping of 10 short tandem repeats (STRs). RESULTS: Eight variations were identified among Gelao, Mongolian and Kirgiz populations, while only 7 were found in Shui and Dai people. For all 3 southern populations (Gelao, Shui, and Dai), the observed heterozygosites (Ho) was higher than expected heterozygosities (He). But this was reversed for the 2 northern populations (Mongolian and Kirgiz). The Ho and He of the 10 neutral STRs were in random distribution. Ewens-Watterson testing based on haplotypes of the HLA-G 3'UTR has suggested that a natural selection had occurred in the region where Dai and Shui had inhabited, but not in the northern region where Mongolian and Kirgiz population inhabited. Polygenetic trees based on the HLA and STRs were also different. CONCLUSION: The HLA-G 3'UTR of Dai and Shui people who lived in southern China may have subjected to a selection pressure. Based on current knowledge, this pressure may have been driven by a pathogenic selection. PMID- 27454994 TI - [Application of chromosomal microarray analysis for a cohort of Chinese patients with spontaneous miscarriage]. AB - OBJECTIVE: To explore the relationship between spontaneous miscarriage and chromosomal aberrations identifiable with chromosomal microarray analysis (CMA). METHODS: A total of 440 product-of-conceptions were collected for the CMA testing. RESULTS: Four hundred and seventeen of 440 specimens (94.7%) were successfully detected, among which 209 (50.1%) were chromosomal abnormalities. One hundred and twenty-nine (61.7%) of the 209 specimens were numerical chromosomal abnormalities, 40 specimens (19.1%) were structural anomalies, 38 specimens (18.1%) were mosaicisms, and 2 specimens (1.0%) showed regions of homozygosity. CONCLUSION: CMA analysis of products of-conception specimens can yield a higher diagnostic rate than conventional karyotyping. The identification of the cause of spontaneous miscarriage can facilitate estimation of recurrence risks for future pregnancies. PMID- 27454995 TI - [Rapid screening of MT3243A>G mutation in mitochondrial diabetes with high resolution melting curve analysis and pyrosequencing]. AB - OBJECTIVE: To establish a rapid, accurate, noninvasive and low cost method for screening MT3243A>G mutation in mitochondrial diabetes. METHODS: Blood, saliva, and urine sediment samples were collected from 6 patients with confirmed mitochondrial diabetes and 50 healthy controls from Shanghai Children's Hospital and Shanghai Sixth People's Hospital. The heterozygosity levels of MT3243A>G mutation in above samples were detected with pyrosequencing, and the data were compared. MT3243A>G mutations were rapidly screened with high resolution melting curve analysis (HRM) in the urine sediment samples of 1070 diabetic patients from 4 communities in Shanghai. Furthermore, pyrosequencing was used to validate the suspected positive samples, and the heterozygosity levels were also quantified. RESULTS: Comparative experiments found that heterozygosity of MT3243A>G mutation was 2 to 7 times higher in urine sediment than in saliva and blood samples from the 6 patients with confirmed mitochondrial diabetes. However, the heterozygosity was slightly higher in saliva than blood samples. MT3243A>G mutation was not detected in the 50 healthy controls. Two samples with suspected MT3243A>G mutation were identified in the 1070 urine sediment samples of diabetes patients with HRM screening, which were validated by pyrosequencing. The heterozygosity of MT3243A>G mutation were 33.32% and 14.67% in the urine sediment samples, respectively. CONCLUSION: Urine sediment samples can be used for rapid screening of MT3243A>G mutation for its ease to collect, noninvasiveness and higher level of heterozygosity. HRM is suitable for rapid screening for mitochondrian mutations for its low cost, while such mutations could be detected with sensitivity and accuracy by pyrosequencing. PMID- 27454996 TI - [Application of BoBs technique for detecting common chromosome microdeletion and microduplication syndromes]. AB - OBJECTIVE: To establish a strategy for screening and diagnosing common microdeletion and microduplication syndromes among children with idiopathic mental retardation and development abnormalities. METHODS: Potential chromosomal variations among patients with unexplained mental retardation, cardiac anomalies, particular facial features, learning disabilities and other clinical characteristics were detected with bacterial artificial chromosome BACs-on-Beads (BoBs) technique and karyotyping. Positive results were verified with array-based comparative genomic hybridization (Array-CGH). RESULTS: Fifty eight of the 60 patients had a normal chromosome karyotype. Ten patients with microdeletion and microduplication syndromes were detected by BoBs, which included two positive cases identified through chromosome karyotyping. Two patients were respectively diagnosed as Smith-Magenis syndrome and Prader-Willi/Angelman syndrome by BoBs and the results were confirmed by Array-CGH. CONCLUSION: BoBs is capable of detecting chromosome microdeletion and microduplication with high specificity and throughput, which can compensate the shortcomings of conventional cytogenetic technology and will be widely applied for clinical diagnosis. PMID- 27454997 TI - [Analysis of hemophilia case information of Shandong province]. AB - OBJECTIVE: To summarize the general condition, regional distribution, prevalence and clinical characteristics of Shandong province based on hemophilia case registry information. METHODS: A retrospective study was carried out on 1979 hemophilia patients registered at Shandong Hemophilia Registration Center. RESULTS: The 1979 cases have included 1704 hemophilia A and 275 hemophilia B patients. Hemophilia A was characterized as severe in 1021 patients (59.9%), moderate in 483 patients (28.4%), and mild in 200 patients (11.7%); while hemophilia B was characterized as severe in 125 patients (45.4%), moderate in 116 patients (42.2%), and mild in 34 patients (12.4%). The median age was 23 years (ranging from 1 month to 81 years), and most were young patients. Joint deformity occurred in 963 patients, and 948 patients had a family history of hemophilia. All counties of Shandong province had patients except for Changdao county and Fushan district of Yantai city. The prevalence of Heze city and Dongying city (3.39/100 000 and 3.05/100 000, respectively) were relatively higher. CONCLUSION: The above data revealed epidemiological and clinical characteristics of Shandong Province. Patient-centered registry system allowed a more detailed and accurate patient information, and promoted the comprehensive care of hemophilia, which also suggested the necessity for the establishment and improvement of the National Hemophilia Registry System. PMID- 27454998 TI - [Screening of mutations of deafness-related genes in women of child-bearing age from Shijiazhuang area]. AB - OBJECTIVE: To screen for mutations of deafness-related genes among ethic Chinese women of child-bearing age. METHODS: In 324 women, 9 mutational sites in 4 deafness-related genes (SLC26A4, GJB3, GJB2 and mtDNA 12s rRNA) were screened using a gene chip. RESULTS: Twenty women (6.17%) have carried mutations. These included 11 (3.40%) carrying a GJB2 gene mutation, 7 (2.16%) carrying a SLC26A4 gene mutation, 1 (0.31%) simultaneously carrying GJB3 and GJB2 gene mutations, and 1 (0.31%) carrying a mtDNA 12s rRNA gene mutation. CONCLUSION: Women of child bearing age have a high rate for carrying mutations of common deafness-related genes, among which 235delC in GJB2 was most common. Prenatal screening of couples with normal hearing is an effective way to prevent birth of affected children. PMID- 27454999 TI - [Molecular pathogenesis of Waardenburg syndrome type II resulting from SOX10 gene mutation]. AB - OBJECTIVE: To explore the molecular mechanism of Waardenburg syndrome type II (WS2) resulting from SOX10 gene mutation E248fs through in vitro experiment. METHODS: 293T cells were transiently transfected with wild type (WT) SOX10 and mutant type (MT) E248fs plasmids. The regulatory effect of WT/MT SOX10 on the transcriptional activity of MITF gene and influence of E248fs on WT SOX10 function were determined with a luciferase activity assay. The DNA binding capacity of the WT/MT SOX10 with the promoter of the MITF gene was determined with a biotinylated double-stranded oligonucleotide probe containing the SOX10 binding sequence cattgtc to precipitate MITF and E248fs, respectively. The stability of SOX10 and E248fs were also analyzed. RESULTS: As a loss-of-function mutation, the E248fs mutant failed to transactivate the MITF promoter as compared with the WT SOX10 (P<0.01), which also showed a dominant-negative effect on WT SOX10. The WT SOX10 and E248fs mutant were also able to bind specifically to the cattgtc motif in the MITF promoter, whereas E248fs had degraded faster than WT SOX10. CONCLUSION: Despite the fact that the E248fs has a dominant-negative effect on SOX10, its reduced stability may down-regulate the transcription of MITF and decrease the synthesis of melanin, which may result in haploinsufficiency of SOX10 protein and cause the milder WS2 phenotype. PMID- 27455000 TI - [Research on biological and genetic characteristics of human placenta mesenchymal stem cells cultured in vitro]. AB - OBJECTIVE: To investigate the biological characteristics and genetic features of human placenta mesenchymal stem cells (hPA-MSCs) cultured in vitro in order to assess its safety for clinical use. METHODS: The shapes of the 1st, 3rd, 5th, 7th, 10th, 13th, 17th and 20th generation hPA-MSCs cultured in vitro using serum free culture medium were observed. Their cell cycle, cell surface markers, and karyotype were analyzed, and relevant genes and cytokines were measured. RESULTS: The shape of hPA-MSCs has remained as fusiform or short fusiform, and there was no significant change. About 93% of hPA-MSCs cells were in G0/G1 phase and remained stable. No obvious chromosomal translocation, loss or inversion was noted by karyotyping analysis. Cytokines expression level remained stable. Related gene expression level as a whole was on the decline, but the gene expression level of the first five generations showed very slight variations, with genetic characteristics remaining stable. CONCLUSION: The hPA-MSCs cultured in vitro with serum-free medium has retained stable in the first five generations. PMID- 27455001 TI - [Analysis of a cerebrotendinous xanthomatosis case with mental retardation as the initial symptom]. AB - OBJECTIVE: To analyze a case of cerebrotendinous xanthomatosis (CTX) with mental retardation as the initial neurological symptom. METHODS: Medical imaging, histopathological assay and genetic testing were carried out to analyze the patient. RESULTS: Neurological manifestations of the 27-year-old male patient were initiated by mental retardation and subsequently memory lapses, ataxia, spastic paraplegia and fuzzy language. Other symptoms included cataract, xanthomatosis in Achilles tendon, kidney stones and high arches. The total bile acid in serum has risen to 14.7 umol/L. There were symmetrical abnormal signals in bilateral cerebellar dentate nuclei, hypointensities on T1WI and DWI and mixed signals on T2WI. Cholesterol crystallization and cholesterol granulomatous inflammation were found upon pathological examination of the Achilles tendon. The patient was found to have carried a compound heterozygous mutation of the CTX gene, which consisted of two novel mutations including c.379C>T (p.Arg127Trp) in exon 2 and c.1174G>A (p.Glu392Lys) in exon 6 of the CYP27A1 gene. CONCLUSION: Clinicians should be alert to cerebrotendinous xanthomatosis when the patient has mental retardation caused by genetic and metabolic factors beginning at a young age, particularly accompanied with tendinous xanthomatosis and cataracts. CTX can be readily diagnosed by histopathological assay and sequencing of the CYP27A1 gene. PMID- 27455002 TI - [Analysis of DIAPH3 gene mutation in a boy with autism spectrum disorder]. AB - OBJECTIVE: To analyze the clinical manifestations and gene mutation of a 6 year old boy with autism spectrum disorders (ASD). METHODS: Peripheral blood of the boy and his parents were subjected to genetic testing. RESULTS: The patient was diagnosed with typical autism. Exome sequencing has identified mutations of four candidate genes, namely TUT1, DIAPH3, REELIN and SETD2, which were confirmed with Sanger sequencing. Analysis of family members confirmed that the missense mutations of DIAPH3 and SETD2 genes were of de novo origin. CONCLUSION: Missense mutations of DIAPH3 and SETD2 genes may have contributed to the risk of ASD. Disrupted neurogenesis associated with such mutations may have been the underlying mechanism for ASD. PMID- 27455003 TI - [Clinical and genetic study of a child with mental retardation and multiple congenital anomalies and a 16p13.11 microdeletion]. AB - OBJECTIVE: To determine the genetic cause for a boy with development delay and multiple congenital anomalies. METHODS: Routine chromosomal banding was performed to analyze the karyotype of the patient and his parents. Single nucleotide polymorphism array (SNP array) was employed to investigate cryptic chromosome aberrations, and quantitative real-time PCR (qPCR) was used to confirm the result. RESULTS: Karyotype analysis revealed no obvious anomaly for the patient and his parents. The karyotype of the patient was 46,XY. SNP array has detected an 846 kb deletion at 16p13.11, which was verified by qPCR. Clinical features of the patient included development delay, distinct facial dysmorphism and multiple congenital anomalies. CONCLUSION: A case of 16p13.11 microdeletion syndrome was identified. The deletion was probably induced by non-allelic homologous recombination (NAHR) at 16p13.11. SNP array and qPCR were helpful for the discovery of the microdeletion and have played an important role in the diagnosis and genetic counseling of the patient. PMID- 27455004 TI - [Clinical features and genetic analysis of two cases with 16p13.3 microdeletion and 19q13.4 microduplication derived from familial cryptic balanced translocation]. AB - OBJECTIVE: To determine the genetic cause for two mentally retarded patients from a family, and to correlate their genotypes with clinical phenotypes. METHODS: Routine G-banded karyotyping analysis was performed. Single nucleotide polymorphism (SNP) microarray analysis was used to detect microdeletions or microduplications. Fluorescence in situ hybridization (FISH) was used to ascertain the origin of chromosomal abnormalities. RESULTS: Both proband and his uncle showed a normal karyotype. SNP microarray analysis has identified a 1.147 Mb microdeletion at 16p13.3 (85 880-1 233 819) and a 2.948-Mb microduplication at 19q13.42-q13.43 (56 008 597-58 956 816). FISH analysis confirmed that the patient has inherited a derivative chromosome 16 from his father. The proband presented with mental retardation, reduced speech, and facial dysmorphism (hypertelorism, down-slanting palpebral fissure, low nasal bridge and wide gap between front teeth). His uncle presented with a milder phenotype with mental retardation. CONCLUSION: Both the proband and his uncle have carried a chromosome microdeletion at 16p and microduplication at 19q, which were originated from their fathers carrying a balanced t(16;19) translocation. Combined SNP microarray analysis and FISH assay are useful for the detection the copy number variations and delineation of potential structural changes, which may help with evaluation of recurrence risk for this family. PMID- 27455005 TI - [Genetic diagnosis and analysis for two cases of ring chromosome 22]. AB - OBJECTIVE: To confirm the genetic diagnosis of two patients with ring chromosome 22 syndrome and investigate the mechanism underlying the formation of r(22) and potential genetic causes for the clinical phenotypes. METHODS: Cytogenetic and molecular analyses using standard G-banding, fluorescence in situ hybridization and single nucleotide polymorphism array (SNP array) were performed. RESULTS: For case 1, the karyotype was 46,XY,r(22)(p11q13). SNP array has identified a 7.0 Mb heterozygous deletion at 22q13.2q13.33. For case 2, the karyotype was 46,XY,r(22)(p11q13)[84]/45,XY,-22[6]; SNP array has detected a heterozygous microdeletion of 1.6 Mb at 22q13.33. CONCLUSION: With combined application of genetic testing, 2 cases of r(22) syndrome were diagnosed, which has improved the understanding of the genotype-phenotype correlation of r(22). PMID- 27455006 TI - [Study of two cases of prenatally detected small supernumerary marker chromosomes]. AB - OBJECTIVE: To determine the origin of two prenatally detected small supernumerary marker chromosomes (sSMCs). METHODS: The sSMCs were analyzed with combined G banding, C-banding, fluorescence in situ hybridization (FISH), and single nucleotide polymorphisms array (SNP-array) techniques. RESULTS: In case 1, G banding analysis has identified a 47,XY,+mar karyotype. Affymetrix CytoScan 750K Array scan has suggested arr 15q11.2q12(22 770 421-26 604 587)?, while FISH analysis suggested 47,XN,+mar.ish i(15)(q12)(D15Z1+,SNRPN++,PML-). In case 2, G banding analysis has suggested 46,X,+mar/46,XY, FISH analysis showed two SRY hybridization signals, indicating 46,X,i(Y)(p10)/46,XY. CONCLUSION: Multiple techniques needed be applied for verification of the origin of sSMCs identified in prenatal diagnosis. PMID- 27455007 TI - [A case of Wolf-Hirschhorn syndrome diagnosed by single nucleotide polymorphism array]. AB - OBJECTIVE: To explore the genetic causes for a child with multiple congenital malformations and epilepsy through analysis of copy number variations, and to correlate the genotype with the phenotype. METHODS: G-banding karyotyping was performed on the child and her parents. Single nucleotide polymorphisms array (SNP-array) was used to map the exact chromosomal breakpoints in the proband. The result was validated with fluorescence in situ hybridization (FISH). RESULTS: G banding analysis suggested that the proband had a karyotype of 46,XX,del(4)(p15), while both of his parents had a normal karyotype. SNP-array has identified a hemizygous deletion of 13.3 Mb on chromosome 4p16.3p15.33, which has been implicated in Wolf-Hirschhorn syndrome. FISH assay has confirmed the de novo origin of the deletion, with the karyotype and clinical phenotype of both parents taken into consideration. CONCLUSION: A case of Wolf-Hirschhorn syndrome has been diagnosed by clinical manifestation and karyotyping analysis. Compared with conventional karyotyping analysis, SNP-array has greater resolution and accuracy, and can provide useful information for genetic counseling. PMID- 27455008 TI - [Application of single nucleotide polymorphism-array for the diagnosis of Williams-Beuren syndrome in a case]. AB - OBJECTIVE: To apply single nucleotide polymorphism array (SNP-array) for the diagnosis of Williams-Beuren syndrome (WBS) in a patient. METHODS: Chromosome G banding and SNP-array were used to analyze a girl featuring mental retardation. RESULTS: The karyotypes of the child and her parents were all normal, but SNP array showed a 1.9 Mb deletion at 7q11.23 in the patient. The same deletion was not found in her parents. CONCLUSION: The mental retardation and special facies of the girl were probably due to the 7q11.23 microdeletion. SNP-array has an important value for the diagnosis of mental retardation. PMID- 27455009 TI - [Detection and genetic counseling of F8 gene inversions for patients with severe hemophilia A]. AB - OBJECTIVE: Inversions of intron 1 (Inv1) or intron 22 (Inv22) of the coagulation factor VIII gene (F8) may be found in 40%-50% of patients with severe hemophilia A. Such inversions cannot be detected by conventional sequencing. Due to homologous recombination, family-based linkage analysis may yield false positive or false negative results. In this study, Inverse-shifting PCR (IS-PCR) was used to detect potential inversions in two families affected with hemophilia A. METHODS: Peripheral venous blood, fetal amniotic fluid and fetal chorionic cells were harvested for genome DNA extraction. IS-PCR was used to detect Inv1 or Inv22 detection or its subtypes. RESULTS: IS-PCR has accurately detected Inv22 and Inv1 in both families and verified the subtypes of Inv22. CONCLUSION: Carriers of Inv22 or Inv1 may be precisely detected with IS-PCR. The results have provided valuable information for genetic counseling and prenatal diagnosis for the affected families. PMID- 27455010 TI - [Study of a CADASIL family with migraine as the presenting symptom]. AB - OBJECTIVE: To analyze the clinical features and genetic cause for a family affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: Clinical manifestations, neuroimaging, and genetic analysis were performed. RESULTS: The main clinical features have included stroke, emotional disturbance and history of migraine without progressive memory impairment. A positive family history was confirmed. Cranial MRI has revealed multi-infarct lesions and white matter hyperintensity involving bilateral basal ganglia, subcortex and brain stem. All such features were in keeping with the diagnosis of CADASIL. A rare 2182C>T mutation in exon 14 of the NOTCH3 gene was identified in all available cases. CONCLUSION: Both clinical and molecular features suggested that the family has been affected with CADASIL. PMID- 27455011 TI - [A novel pathogenic mutation of CRYGD gene in a congenital cataract family]. AB - OBJECTIVE: To detect the disease-causing mutation in a pedigree affected with autosomal dominant congenital cataract. METHODS: Genomic DNA was extracted and purified from peripheral blood samples from members of the pedigree and 100 healthy controls. Coding regions of 18 candidate genes were screened with PCR and Sanger sequencing. Identified mutations were verified among 100 healthy individuals to exclude single nucleotide polymorphisms. RESULTS: A heterozygous nonsense mutation c.471G>A of the CRYGD gene, which resulted in p.Trp157Term, was identified in all three patients. The same mutation was not found in the two normal individuals from the family and 100 healthy controls. The nonsense mutation was predicted to be "disease causing" by Mutation t@sting program. CONCLUSION: The nonsense mutation c.471G>A of the CRYGD gene probably underlies the congenital cataract in the pedigree. PMID- 27455012 TI - [Analysis of PAX6 gene mutation in a family affected with congenital aniridia]. AB - OBJECTIVE: To identify potential mutation of the PAX6 gene in a family affected with congenital aniridia from northeastern China. METHODS: Two patients were collected from the family and underwent full ophthalmologic examinations. Genomic DNA was extracted from all family numbers and 100 healthy controls. The coding regions and flanking sequence of the PAX6 gene were amplified by PCR amplification and subjected to bidirectional DNA sequencing. RESULTS: A nonsense mutation (c.718 C>T) was identified in exon 9 in both patients but not in other unaffected families or the 100 healthy controls. However, obvious difference was noted in the phenotype between the two patients. One of the patient has presented irregular cornea, which was infrequently reported. CONCLUSION: A c.718C>T transitional mutation has been found to underlie the aniridia, which showed an autosomal dominant inheritance pattern in this northeastern Chinese family. PMID- 27455013 TI - [Analysis of PAX6 gene mutations in a Chinese family affected with congenital aniridia]. AB - OBJECTIVE: To investigate the mutation of PAX6 gene in a Chinese family affected with congenital aniridia. METHODS: Blood samples were drawn from family members, and DNA was analyzed by direct sequencing. RESULTS: A heterozygous mutation (c.151 G>A) was identified in the PAX6 gene in the proband and other patients from the family. The same mutation was not found among unaffected family members and 160 unrelated healthy controls. CONCLUSION: A novel mutation in the PAX6 gene has been identified in a Chinese family affected with aniridia. PMID- 27455014 TI - [Ael subgroup due to alpha-1,3-N-acetylgalactoseaminotransferase gene 467C>T and 804insG variants]. AB - OBJECTIVE: To explore the effect of variants of alpha-1,3-N acetylgalactosaminyltransferase of the ABO gene on A antigen expression. METHODS: Three samples were assayed by serological method. The extracted DNA was genotyped by sequence-specific primer polymerase chain reaction (SSP-PCR) and direct sequencing. To identify haploid of the ABO gene, clones for exons 6 and 7 of the ABO locus were analyzed. RESULTS: All of the three samples were identified as the Ael subgroup, among which were found to carry the Ael08 and O01 alleles, while another was confirmed to harbor the Ael08 and O04 alleles. Compared with the A101 allele, two nucleotide alterations (467C>T and 804insG) at exon 7 have resulted in amino acid substitution P156L and frameshift from position 269. CONCLUSION: 467C>T and 804insG variants of the alpha-1,3-N-acetylgalactosaminyltransferase gene probably underlie the Ael phenotype. PMID- 27455015 TI - [Association of NLRP3 gene single nucleotide polymorphisms with metabolic syndrome]. AB - OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) of NLRP3 gene with metabolic syndrome (MetS). METHODS: A total of 885 subjects including 410 MetS patients and 475 healthy controls were recruited. MetS was defined based on the National Cholesterol Education Program in Adult Treatment Panel III criteria. Two common SNPs of the NLRP3 gene, rs10754558 and rs4612666, were detected using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The frequencies of G allele and GG genotype of the NLRP3 rs10754558 in the MetS group were significantly higher than those of the control group. Logistic regression analysis showed that the GG genotype (OR=2.223, 95%CI: 1.296-6.924, P=0.00034) and G allele (OR=1.440, 95%CI: 1.189 4.063, P=0.00028) were associated with increased risk of MetS. NLRP3 rs10754558 GG genotype was associated with higher level of insulin resistance and visceral adiposity index. No association of NLRP3 rs4612666 SNPs with susceptibility to MetS was identified in this population. CONCLUSION: NLRP3 gene rs10754558 polymorphisms are associated with increased risk of MetS. The G allele and genotype GG are risk factors for MetS. PMID- 27455016 TI - [Association of vascular endothelial growth factor gene polymorphisms with ectopic pregnancy among Chinese women]. AB - OBJECTIVE: To assess the association of vascular endothelial growth factor (VEGF) gene polymorphisms with ectopic pregnancy (EP) among Chinese women. METHODS: A case-control study was carried out, which compared 192 women with a history of EP with 210 post-menopausal controls who had two pregnancies but no history of EP for the genotypes of the VEGF gene. Polymorphisms of the VEGF gene including 460C/T, -1154G/A, -2578C/A and +936C/T were determined with a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No significant difference was found in the genotypic and allelic distribution of the -460C/T and +936C/T polymorphisms between the two groups. Compared with the GG genotype, the VEGF -1154 AA+GA genotype could significantly decrease the risk of EP (OR=0.61, 95%CI: 0.42-0.87). Compared with the CC genotype, VEGF -2578 AA+CA genotype could significantly reduce the risk of EP (OR=0.66, 95%CI:0.44-0.99). Haplotype analysis suggested that the T-A-A (VEGF -460/-1154/-2578) and C-A-A haplotypes could significantly decrease the risk of EP compared with the T-G-C haplotype (P=0.020, OR=0.41, 95%CI:0.19-0.89, P=0.014, OR=0.29, 95%CI:0.11-0.82). CONCLUSION: The -1154A or -2578A alleles of the VEGF gene can significantly decrease the risk of EP among Chinese women. The VEGF -460C/T, -1154G/A and 2578C/A polymorphisms showed a linkage disequilibrium. Both T-A-A and C-A-A haplotypes can significantly decrease the risk of EP. PMID- 27455017 TI - [Association of GCKR gene polymorphisms and type 2 diabetes among ethnic Uygurs]. AB - OBJECTIVE: To assess the association of glucokinase regulator protein (GCKR) gene polymorphisms and type 2 diabetes (T2D) among ethnic Uygurs from Xinjiang, China. METHODS: One thousand and six T2D patients and 1004 healthy controls were recruited. The rs780094 genotype of the GCKR gene was determined with a Sequenom Mass ARRAY system. RESULTS: The distribution of GCKR rs780094 AA, AG and GG genotypes were not statistically different between the two groups (P>0.05). After adjusting confounding factors, an association of rs780094 with T2D was observed in an additive and dominant model (OR=1.181, 95%CI: 1.021-1.366, P=0.025; OR=1.296, 95%CI: 1.043-1.610, P=0.019). The total cholesterol level was higher in AA carriers than GG and GA carriers (P<0.05). CONCLUSION: The AA genotype of the GCKR rs780094 polymorphism may increase the risk of T2D among ethnic Uygurs from Xinjiang. PMID- 27455018 TI - [Association of PLEKHA7, COL11A1 and PCMTD1-ST18 gene polymorphisms with primary angle closure glaucoma in ethnic Han Chinese from Sichuan]. AB - OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) of PLEKHA7, COL11A1 and PCMTD1-ST18 genes and primary angle closure glaucoma (PACG) among ethnic Han Chinese from Sichuan Province. METHODS: In this study, 362 subjects with PACG and 1056 age- and sex-matched healthy controls were recruited. Genotypes of 3 reported SNPs, including PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 were determined with a SNaPshot method. RESULTS: The P values for the genotype frequencies of rs11024102, rs3753841 and rs1015213 between the patient and control groups were 0.62 (OR=1.09, 95%CI: 0.91-1.30), 0.42 (OR=1.04, 95%CI: 0.87-1.41) and 0.34 (OR=1.35, 95%CI: 0.73-2.49), respectively. And the P values for the allele frequency distributions of PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 between the two groups were 0.347, 0.698 and 0.344, respectively. CONCLUSION: No significant association of PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 with PACG was found among ethnic Han Chinese from Sichuan. PMID- 27455019 TI - [Establishment of a screening method for AZF microdeletions by capillary technology and a clinical trial]. AB - OBJECTIVE: To establish an accurate, fast and simple screening method for AZF microdeletions using capillary technology and use it for clinical testing. METHODS: For each pair of primers, the 5' end of either forward or reverse primer was labeled with a FAM, JOE or TAMRA fluorescence dyes to establish multiplex quantitative fluorescence PCR systems for the establishment of a screening method of Y chromosome AZF microdeletions by capillary technology. The detection of Y chromosome AZF microdeletion was carried out on 725 cases of non-obstructive azoospermia, oligospermia or asthenospermia. RESULTS: A screening method for Y chromosome AZF microdeletions using capillary technology was established. Thirty eight cases of AZF microdeletions were found among 725 cases of non-obstructive azoospermia, oligospermia or asthenospermia, which gave a deletion rate of 5.24%. Y chromosomal microdeletions were found in 8.62% of the azoospermia group, 6.75% of the oligozoospermic group, and 2.23% of the asthenospermia group. CONCLUSION: An accurate, fast and simple screening method of Y chromosome AZF microdeletions by capillary technology has been established, which may have an important clinical value. PMID- 27455020 TI - [Application of a modified culturing method for lymphocytes in cytogenetic research]. AB - OBJECTIVE: To establish a modified method for microculturing whole human blood for cytogenetic analysis. METHODS: A novel tube rack was designed to overcome the drawbacks of directly culturing the cells within centrifuge tubes. The fractions of human plasma, human serum and two commercial fetal bovine sera were analyzed with 15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The influence of adding 0%, 5%, 10%, 15%, 20%, 25% and 30% autologous plasma to the culture on lymphocyte transformation rate and mitotic index (MI) was examined. RESULTS: The SDS-PAGE analysis showed a significant difference between commercial fetal bovine sera, and that the components of human plasma were similar to those of fetal bovine serum. The value of MI in lymphocyte was evidently increased along with addition of autologous plasma. However, this has exerted no significant effect on the transformation rate. With the addition of 10% autologous plasma, the MI value has become much higher than the conventional method. CONCLUSION: A modified method was established by application of a novel tube inclined rack and optimization of whole blood inoculation. This method is easier and cheaper, and is suitable for application in clinical practice. PMID- 27455021 TI - [Application of CRISPR-Cas9 genome editing for constructing animal models of human diseases]. AB - The CRISPR-Cas9 system is a new targeted nuclease for genome editing, which can directly introduce modifications at the targeted genomic locus. The system utilizes a short single guide RNA (sgRNA) to direct the endonuclease Cas9 in the genome. Upon targeting, Cas9 can generate DNA double-strand breaks (DSBs). As such DSBs are repaired by non-homologous end joining (NHEJ) or homology directed repair (HDR), therefore facilitates introduction of random or specific mutations, repair of endogenous mutations, or insertion of DNA elements. The system has been successfully used to generate gene targeted cell lines including those of human, animals and plants. This article reviews recent advances made in this rapidly evolving technique for the generation of animal models for human diseases. PMID- 27455022 TI - [Pulmonary surfactant homeostasis associated genetic abnormalities and lung diseases]. AB - Pulmonary surfactant (PS) is synthesized and secreted by alveolar epithelial type II (AEII) cells, which is a complex compound formed by proteins and lipids. Surfactant participates in a range of physiological processes such as reducing the surface tension, keeping the balance of alveolar fluid, maintaining normal alveolar morphology and conducting host defense. Genetic disorders of the surfactant homeostasis genes may result in lack of surfactant or cytotoxicity, and lead to multiple lung diseases in neonates, children and adults, including neonatal respiratory distress syndrome, interstitial pneumonia, pulmonary alveolar proteinosis, and pulmonary fibrosis. This paper has provided a review for the functions and processes of pulmonary surfactant metabolism, as well as the connection between disorders of surfactant homeostasis genes and lung diseases. PMID- 27455023 TI - [Research progress on molecular genetics of male homosexuality]. AB - Sexual orientation is influenced by both environmental factors and biological factors. Family and twin studies have shown that genetic factors play an important role in the formation of male homosexuality. Genome-wide scan also revealed candidate chromosomal regions which may be associated with male homosexuality, but so far no clearly related genes have been found. This article reviews the progress of relevant studies and candidate genes which are related to male homosexuality. PMID- 27455024 TI - [Advance in research on the function of telomeric shelterin component TPP1 and its relationship with characteristics of tumors]. AB - As an important telomere binding protein, TPP1 protects the ends of telomeres and maintains the stability and integrity of its structure and function by interacting with other five essential core proteins (POT1, TRF1, TRF2, TIN2, and RAP1) to form a complex called Shelterin. Recently, researchers have discovered that TPP1 participates in protection of telomeres and regulation of telomerase activity. The relationship between TPP1 and tumorigenesis, tumor progression and treatment has also been investigated. This paper reviews the latest findings of TPP1 regarding to its structure, function and interaction with other proteins involved in tumorigenesis. PMID- 27455025 TI - [Disseminated superficial actinic porokeratosis in a pedigree]. PMID- 27455026 TI - [Co-occurrence of Parkinson disease, essential tremor and cervical dystonia in a pedigree]. PMID- 27455027 TI - Theoretical study of the interactions between the first transmembrane segment of NS2 protein and a POPC lipid bilayer. AB - Non-structural protein 2 (NS2) plays a crucial role in the hepatitis C virus (HCV) assembly. NS2 was predicted to be composed of three transmembrane (TM) segments. However, the mechanism of interactions between TM segments of NS2 and surrounding lipid environment remains unclear. Molecular dynamics simulations were applied to investigate the conformation and orientation of the first transmembrane segment (TM1) as well as the interactions of TM1 with a zwitterionic POPC lipid bilayer which identifies several key residues that stabilize the position of TM1 within the membrane. Along with the charged residues R3 and K27, the S23 and H25 were found to be the key elements in establishing the conformation of TM1 inside the membrane. The peptide forms a stable alpha-helix (the sequence 12-21) connected to N-terminal haft in POPC bilayer. The results also reveal that TM1 induces the ordering of lipid and does not destabilize the lipid bilayer system. The hydrophobic mismatch in which the segment tilts an angle along the membrane normal was observed in this system. The binding free energy profile of TM1 to the membrane was also estimated using umbrella sampling. PMID- 27455029 TI - An Overview of the Application of Wearable Technology to Nursing Practice. AB - PROBLEM: Wearable technology is here and nurses are going to be increasingly responsible for patients who use it. Most research in this area has been done in other fields and now is the time for nurses to be more involved in this promising technology to improve patient lives. METHODS: This paper synthesizes the current state of wearable technology, a brief history of nurse satisfaction with technology, current research about wearable technology, and implications for its future use in nursing. FINDINGS: Other areas in health care are already employing wearable technology to improve gait in people with Parkinson's disease, provide automatic defibrillation in cardiac patients, and monitor poststroke rehabilitation. Nurses can be on the front lines of designing and patenting new ideas to improve the lives of their patients. CONCLUSIONS: Nurses have always adopted the newest technologies such as electronic health records, electronic medication administration records, and simulation experiences in education. Wearable technology is the next step in this journey and the possible uses are endless. Involving patients in their own care is a major goal of nursing and more research is needed to connect patients and their caregivers to the benefits of wearable technology. PMID- 27455028 TI - Comparison of pulsed three-dimensional CEST acquisition schemes at 7 tesla: steady state versus pseudosteady state. AB - PURPOSE: To compare two pulsed, volumetric chemical exchange saturation transfer (CEST) acquisition schemes: steady state (SS) and pseudosteady state (PS) for the same brain coverage, spatial/spectral resolution and scan time. METHODS: Both schemes were optimized for maximum sensitivity to amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects through Bloch-McConnell simulations, and compared in terms of sensitivity to APT and NOE effects, and to transmit field inhomogeneity. Five consented healthy volunteers were scanned on a 7 Tesla Philips MR-system using the optimized protocols at three nominal B1 amplitudes: 1 MUT, 2 MUT, and 3 MUT. RESULTS: Region of interest based analysis revealed that PS is more sensitive (P < 0.05) to APT and NOE effects compared with SS at low B1 amplitudes (0.7-1.0 MUT). Also, both sequences have similar dependence on the transmit field inhomogeneity. For the optimum CEST presaturation parameters (1 MUT and 2 MUT for APT and NOE, respectively), NOE is less sensitive to the inhomogeneity effects (15% signal to noise ratio [SNR] change for a B1 dropout of 40%) compared with APT (35% SNR change for a B1 dropout of 40%). CONCLUSION: For the same brain coverage, spatial/spectral resolution and scan time, at low power levels PS is more sensitive to the slow chemical exchange-mediated processes compared with SS. Magn Reson Med 77:2280-2287, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 27455030 TI - Effects of chronic illness on daily life and barriers to self-care for older women: A mixed-methods exploration. AB - This mixed-methods study examined the subjective experience of living with chronic illness and identified barriers to self-care. Community-dwelling older women with chronic illness completed an initial (N = 138) and follow-up mailed survey 6 months later (N = 130). On average, participants reported four comorbid health conditions and the corresponding physical pain, activities curtailed or relinquished, and time and energy focused on managing health. Only 34% of participants practiced all 10 key self-care behaviors. Reported barriers to self management included pain, lack of financial resources, and worry. In the regression analysis, having more depressive symptoms was a significant predictor of challenges with self-care behaviors. PMID- 27455031 TI - High-throughput quantitative method for assessing coaggregation among oral bacterial species. AB - This paper describes a high-throughput method that relies upon a microplate reader to score coaggregation 60 min postmixing, and use of a high-speed real time imaging technology to describe the rate of coaggregation over time. The results of visual, microplate, and FlowCam(TM) aggregation scores for oral bacteria Streptococcus gordonii, Streptococcus oralis, and Actinomyces oris, whose ability to coaggregate are well characterized, are compared. Following mixing of all possible pairs, the top fraction of the supernatant was added to a microplate to quantify cell-density. Pairs were also passed through a flow cell within a FlowCam(TM) to quantify the rate of coaggregation of each pair. Results from both the microplate and FlowCam(TM) approaches correlated with corresponding visual coaggregation scores and microscopic observations. The microplate-based assay enables high-throughput screening, whereas the FlowCam(TM) -based assay validates and quantifies the extent that autoaggregation and coaggregation occur. Together these assays open the door for future in-depth studies of autoaggregation and coaggregation among large panels of test strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Coaggregation between bacterial species is integral to multi-species biofilm development. Difficulties in rapidly and reproducibly identifying and quantifying coaggregation have limited mechanistic studies. This paper demonstrates two complementary quantitative methods to screen for coaggregation. The first approach uses a microplate-based high-throughput approach and the other uses a FlowCam(TM) device. The microplate-based approach enables rapid detection of coaggregation between candidate coaggregating pairs of strains simultaneously while controlling for variation between replicates. The FlowCam(TM) approach allows for in-depth analysis of the rates of coaggregation and size of aggregates formed. PMID- 27455032 TI - Principles of endoscopic ear surgery. AB - PURPOSE OF REVIEW: The aim of this review is to study the rationale, limitations, techniques, and long-term outcomes of endoscopic ear surgery. RECENT FINDINGS: The article discusses the advantages of endoscopic ear surgery in treating cholesteatoma and how the hidden sites like facial recess, sinus tympani, and anterior epitympanum are easily accessed using the endoscope. SUMMARY: Transcanal endoscopic approach allows minimally invasive removal of cholesteatoma with results that compare well to traditional postauricular tympanomastoidectomy. PMID- 27455034 TI - It is 2016: what is the best treatment for sudden sensorineural hearing loss? PMID- 27455033 TI - Minimizing free flap donor-site morbidity. AB - PURPOSE OF REVIEW: Fasciocutaneous and osteocutaneous free flap reconstruction has significantly changed the way surgeons reconstruct defects following ablation of head and neck tumors. Over time, success rates of free flaps have approached 98%, allowing surgeons to shift their focus to minimizing morbidities associated with the donor sites. The radial forearm, anterolateral thigh, and fibula free flaps are the three most commonly used flaps in head and neck reconstruction, and therefore each of their advantages and associated morbidities are of particular interest. The present article aims to review the morbidities associated with each of the commonly used head and neck free flaps and techniques to minimize them that are described in the most recent literature. RECENT FINDINGS: New techniques such as negative-pressure wound therapy, full thickness grafts, and rotational flaps have been developed recently that minimize these morbidities. SUMMARY: The techniques described in the current review may improve long-term patient outcomes both esthetically and functionally. PMID- 27455035 TI - Delirium frequency among advanced cancer patients presenting to an emergency department: A prospective, randomized, observational study. AB - BACKGROUND: The frequency of delirium among patients with cancer presenting to the emergency department (ED) is unknown. The purpose of this study was to determine delirium frequency and recognition by ED physicians among patients with advanced cancer presenting to the ED of The University of Texas MD Anderson Cancer Center. METHODS: The study population was a random sample of English speaking patients with advanced cancer who presented to the ED and met the study criteria. All patients were assessed with the Confusion Assessment Method (CAM) to screen for delirium and with the Memorial Delirium Assessment Scale (MDAS) to measure delirium severity (mild, <=15; moderate, 16-22; and severe, >=23). ED physicians were also asked whether their patients were delirious. RESULTS: Twenty two of the 243 enrolled patients (9%) had CAM-positive delirium, and their median MDAS score was 14 (range, 9-21 [30-point scale]). The median age of the enrolled patients was 62 years (range, 19-89 years). Patients with delirium had a poorer performance status than patients without delirium (P < .001); however, the 2 groups did not differ in other characteristics. Ten of the 99 patients who were 65 years old or older (10%) had CAM-positive delirium, whereas 12 of the 144 patients younger than 65 years (8%) did (P = .6). According to the MDAS scores, delirium was mild in 18 patients (82%) and moderate in 4 patients (18%). Physicians correctly identified delirium in 13 of the CAM-positive delirious patients (59%). CONCLUSIONS: Delirium is relatively frequent and is underdiagnosed by physicians in patients with advanced cancer who are visiting the ED. Further research is needed to identify the optimal screening tool for delirium in ED. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2918-2924. (c) 2016 American Cancer Society. PMID- 27455037 TI - Dermocystidium sp. Infection in Blue Ridge Sculpin Captured in Maryland. AB - Raised pale cysts were observed on Blue Ridge Sculpin Cottus caeruleomentum during stream fish community surveys in Catoctin Mountain Park, Maryland. When examined histologically, preserved sculpin exhibited multiple cysts containing spherical endospores with a refractile central body characteristic of Dermocystidium spp. Cysts were not observed on the gills or internally. The portion of the watershed in which affected sculpin were observed contained lower than expected numbers of sculpin, raising concerns about the population effects of this infection. A nearby stream lacked sculpin even though they are common in this region, further suggesting the possibility of regional effects. This is the first report of a Dermocystidium infecting any fish species in the eastern United States. Received October 16, 2015; accepted February 14, 2016. PMID- 27455036 TI - Effects of obesity and mild hypohydration on local sweating and cutaneous vascular responses during passive heat stress in females. AB - The purpose of this study was to evaluate the effect of obesity and mild hypohydration on local sweating (LSR) and cutaneous vascular conductance (CVC) responses during passive heat stress in females. Thirteen obese (age, 24 +/- 4 years; 45.4% +/- 5.2% body fat) and 12 nonobese (age, 22 +/- 2 years; 25.1% +/- 3.9% body fat) females were passively heated (1.0 degrees C rectal temperature increase) while either euhydrated (EUHY) or mildly hypohydrated (HYPO; via fluid restriction). Chest and forearm LSR (ventilated capsule) and CVC (Laser Doppler flowmetry) onset, sensitivity, and plateau/steady state were recorded as mean body temperature increased (DeltaTb). Participants began trials EUHY (urine specific gravity, Usg = 1.009 +/- 0.006) or HYPO (Usg = 1.025 +/- 0.004; p < 0.05), and remained EUHY or HYPO. Independent of obesity, HYPO decreased sweat sensitivity at the chest (HYPO = 0.79 +/- 0.35, EUHY = 0.95 +/- 0.39 Deltamg.min( 1).cm(-2)/ degrees C DeltaTb) and forearm (HYPO = 0.82 +/- 0.39, EUHY = 1.06 +/- 0.34 Deltamg.min(-1).cm(-2)/ degrees C DeltaTb); forearm LSR plateau was also decreased (HYPO = 0.66 +/- 0.19, EUHY = 0.78 +/- 0.23 mg.min(-1).cm(-2); all p < 0.05). Overall, obese females had lower chest-sweat sensitivity (0.72 +/- 0.35 vs. 1.01 +/- 0.33 Deltamg.min(-1).cm(-2)/ degrees C DeltaTb) and plateau (0.55 +/ 0.27 vs. 0.80 +/- 0.25 mg.min(-1).cm(-2); p < 0.05). While hypohydrated, obese females had a lower chest LSR (p < 0.05) versus nonobese females midway (0.45 +/- 0.26 vs. 0.73 +/- 0.23 mg.min(-1).cm(-2)) and at the end (0.53 +/- 0.27 vs. 0.81 +/- 0.24 mg.min(-1).cm(-2)) of heating. Furthermore, HYPO (relative to the EUHY trials) led to a greater decrease in CVC sensitivity in obese (-28 +/- 27 Delta% maximal CVC/ degrees C DeltaTb) versus nonobese females (+9.2 +/- 33 Delta% maximal CVC/ degrees C DeltaTb; p < 0.05). In conclusion, mild hypohydration impairs females' sweating responses during passive heat stress, and this effect is exacerbated when obese. PMID- 27455038 TI - A gustocentric perspective to understanding primary sensory cortices. AB - Most of the general principles used to explain sensory cortical function have been inferred from experiments performed on neocortical, primary sensory areas. Attempts to apply a neocortical view to the study of the gustatory cortex (GC) have provided only a limited understanding of this area. Failures to conform GC to classical neocortical principles have been implicitly interpreted as a demonstration of GC's uniqueness. Here we propose to take the opposite perspective, dismissing GC's uniqueness and using principles extracted from its study as a lens for looking at neocortical sensory function. In this review, we describe three significant findings related to gustatory cortical function and advocate their relevance for understanding neocortical sensory areas. PMID- 27455039 TI - Adiponectin protects against incident hypertension independent of body fat distribution: observations from the Dallas Heart Study. AB - BACKGROUND: Excess adipose tissue has been implicated in the pathogenesis of insulin resistance and atherosclerosis and is a key risk factor for blood pressure (BP) elevation. However, circulating levels of adiponectin, a protein produced by adipose tissue and widely implicated in the pathogenesis of insulin resistance and atherosclerosis, are inversely proportional to adiposity. The relationship between adiponectin and incident hypertension has not been determined in the general US population. METHODS: Normotensive participants (n = 1233) enrolled in the Dallas Heart Study, a multiethnic, probability-based population sample of Dallas County adults were followed for median of 7 years. Retroperitoneal, intraperitoneal, visceral, and subcutaneous adipose tissue were measured at baseline by magnetic resonance imaging. Liver fat content was measured by 1 H-magnetic resonance spectroscopy. Relative risk regression was used to determine the association of adiponectin with incident hypertension after adjustment for age, race, sex, BMI, smoking, diabetes, baseline systolic BP, total cholesterol, and regional fat depot. RESULTS: Of the 1233 study participants (median age 40 years, 40% black, and 56% women), 391 (32%) had developed hypertension over a median follow-up of 7 years. Adiponectin levels were associated with reduced risk of incident hypertension (RR 0.81, 95% CI [0.68 0.96]) in the fully adjusted model, which included liver fat. Similar results were observed after adjustment for subcutaneous or visceral fat depots when tested individually or simultaneously in the model. CONCLUSION: Our study suggested a protective role of adiponectin against incident hypertension independent of body fat distribution. PMID- 27455040 TI - In-silico interaction-resolution pathway activity quantification and application to identifying cancer subtypes. AB - BACKGROUND: Identifying subtypes of complex diseases such as cancer is the very first step toward developing highly customized therapeutics on such diseases, as their origins significantly vary even with similar physiological characteristics. There have been many studies to recognize subtypes of various cancer based on genomic signatures, and most of them rely on approaches based on the signatures or features developed from individual genes. However, the idea of network-driven activities of biological functions has gained a lot of interests, as more evidence is found that biological systems can show highly diverse activity patterns because genes can interact differentially across specific molecular contexts. METHODS: In this study, we proposed an in-silico method to quantify pathway activities with a resolution of genetic interactions for individual samples, and developed a method to compute the discrepancy between samples based on the quantified pathway activities. RESULTS: By using the proposed discrepancy measure between sample pathway activities in clustering melanoma gene expression data, we identified two potential subtypes of melanoma with distinguished pathway activities, where the two groups of patients showed significantly different survival patterns. We also investigated selected pathways with distinguished activity patterns between the two groups, and the result suggests hypotheses on the mechanisms driving the two potential subtypes. CONCLUSIONS: By using the proposed approach of modeling pathway activities with a resolution of genetic interactions, potential novel subtypes of disease were proposed with accompanying hypotheses on subtype-specific genetic interaction information. PMID- 27455041 TI - RichMind: A Tool for Improved Inference from Large-Scale Neuroimaging Results. AB - As the use of large-scale data-driven analysis becomes increasingly common, the need for robust methods for interpreting a large number of results increases. To date, neuroimaging attempts to interpret large-scale activity or connectivity results often turn to existing neural mapping based on previous literature. In case of a large number of results, manual selection or percent of overlap with existing maps is frequently used to facilitate interpretation, often without a clear statistical justification. Such methodology holds the risk of reporting false positive results and overlooking additional results. Here, we propose using enrichment analysis for improving the interpretation of large-scale neuroimaging results. We focus on two possible cases: position group analysis, where the identified results are a set of neural positions; and connection group analysis, where the identified results are a set of neural position-pairs (i.e. neural connections). We explore different models for detecting significant overrepresentation of known functional brain annotations using simulated and real data. We implemented our methods in a tool called RichMind, which provides both statistical significance reports and brain visualization. We demonstrate the abilities of RichMind by revisiting two previous fMRI studies. In both studies RichMind automatically highlighted most of the findings that were reported in the original studies as well as several additional findings that were overlooked. Hence, RichMind is a valuable new tool for rigorous inference from neuroimaging results. PMID- 27455042 TI - New modalities of neurostimulation: high frequency and dorsal root ganglion. AB - PURPOSE OF REVIEW: Neurostimulation is a well tolerated, cost-efficient, and effective method to treat chronic pain. Although spinal cord stimulation (SCS) has been shown to help patients, newer modalities such as burst, kilohertz frequency, and dorsal root ganglion stimulation may provide greater pain relief, fewer paresthesias, and better outcomes. RECENT FINDINGS: Burst stimulation, programed as five-impulse burst at a frequency of 500 Hz, delivers more charge per second than conventional stimulation. Trials of burst stimulation have shown superior pain relief, decreased paresthesias, and patient preference compared with conventional SCS. Kilohertz-frequency SCS uses low-amplitude, high-frequency (10 kHz), and short-duration pulses. The SENZA trial showed superiority in both back and leg pain with greater pain relief as well as decreased opioid use. Dorsal root ganglion stimulation stimulates the ganglion cells allowing for precise targeting of pain regions. Multiple studies, including the ACCURATE trial, have shown superior pain relief in multiple conditions. SUMMARY: Improvements in pain control and patient satisfaction suggest that these new stimulation patterns will greatly increase the utility of neurostimulation; however, clinical trials with broader patient populations have to be done to support more extensive use of these therapies. PMID- 27455043 TI - Anaesthesia for neuroradiology: thrombectomy: 'one small step for man, one giant leap for anaesthesia'. AB - PURPOSE OF REVIEW: Endovascular management of acute thrombotic strokes is a new management technique. Anaesthesia will play a key role in the management of these patients. To date there is no established method of managing these patients from an anaesthetic perspective. RECENT FINDINGS: In 2015, five landmark studies popularized intra-arterial clot retrieval for ischaemic strokes. Since then there have been a number of small studies investigating the best anaesthetic technique, taking into account patient, technical, and clinical factors. This review summarizes these studies and discusses the different anaesthetic options, with their relative merits and pitfalls. SUMMARY: There is a paucity of robust evidence for the best anaesthetic practice in this cohort of patients. Airway protection seems to be an issue in 2.5% of cases. Timing of the procedure is vital, and any delay may be detrimental to neurological outcome. In a survey of neurointerventionalists, the main concern they expressed was the potential delay to revascularization posed by anaesthesia. Patients complain of pain during mechanical clot retrieval if awake. The overall consensus seems to be favouring conscious sedation over general anaesthesia in the acute setting. PMID- 27455044 TI - Future therapies and the expanding role for diagnostic ultrasound. PMID- 27455045 TI - Adjuvants to long-acting local anesthetics: custom-made postoperative analgesia. PMID- 27455047 TI - Light-Adaptive Supramolecular Nacre-Mimetic Nanocomposites. AB - Nature provides design paradigms for adaptive, self-healing, and synergistic high performance structural materials. Nacre's brick-and-mortar architecture is renowned for combining stiffness, toughness, strength, and lightweightness. Although elaborate approaches exist to mimic its static structure and performance, and to incorporate functionalities for the engineering world, there is a profound gap in addressing adaptable mechanical properties, particularly using remote, quick, and spatiotemporal triggers. Here, we demonstrate a generic approach to control the mechanical properties of nacre-inspired nanocomposites by designing a photothermal energy cascade using colloidal graphene as light harvesting unit and coupling it to molecularly designed, thermoreversible, supramolecular bonds in the nanoconfined soft phase of polymer/nanoclay nacre mimetics. The light intensity leads to adaptive steady-states balancing energy uptake and dissipation. It programs the mechanical properties and switches the materials from high stiffness/strength to higher toughness within seconds under spatiotemporal control. We envisage possibilities beyond mechanical materials, for example, light-controlled (re)shaping or actuation in highly reinforced nanocomposites. PMID- 27455048 TI - Branching Out: Rhodium-Catalyzed Allylation with Alkynes and Allenes. AB - We present a new and efficient strategy for the atom-economic transformation of both alkynes and allenes to allylic functionalized structures via a Rh-catalyzed isomerization/addition reaction which has been developed in our working group. Our methodology thus grants access to an important structural class valued in modern organic chemistry for both its versatility for further functionalization and the potential for asymmetric synthesis with the construction of a new stereogenic center. This new methodology, inspired by mechanistic investigations by Werner in the late 1980s and based on preliminary work by Yamamoto and Trost, offers an attractive alternative to other established methods for allylic functionalization such as allylic substitution or allylic oxidation. The main advantage of our methodology consists of the inherent atom economy in comparison to allylic oxidation or substitution, which both produce stoichiometric amounts of waste and, in case of the substitution reaction, require prefunctionalization of the starting material. Starting out with the discovery of a highly branched selective coupling reaction of carboxylic acids with terminal alkynes using a Rh(I)/DPEphos complex as the catalyst system, over the past 5 years we were able to continuously expand upon this chemistry, introducing various (pro)nucleophiles for the selective C-O, C-S, C-N, and C-C functionalization of both alkynes and the double-bond isomeric allenes by choosing the appropriate rhodium/bidentate phosphine catalyst. Thus, valuable compounds such as branched allylic ethers, sulfones, amines, or gamma,delta-unsaturated ketones were successfully synthesized in high yields and with a broad substrate scope. Beyond the branched selectivity inherent to rhodium, many of the presented methodologies display additional degrees of selectivity in regard to regio-, diastereo-, and enantioselective transformations, with one example even proceeding via a dynamic kinetic resolution. Many advances presented in this account were driven by detailed mechanistic investigations including DFT-calculations, ESI-MS and in situ IR experiments and enabled the application of our chemistry for target oriented syntheses demonstrated by several examples shown herein. In general, this research topic has matured over the past years into a viable option when synthesizing chiral compounds, from small molecules such as quercus lactones to complex target structures such as Homolargazole or Clavosolide A. This demonstrates the importance and utility of these coupling reactions, especially considering the ease with which carbon-heteroatom bonds can be built stereoselectively, with many of the product classes displaying motifs common in modern APIs. PMID- 27455046 TI - Heritability of Thoracic Spine Curvature and Genetic Correlations With Other Spine Traits: The Framingham Study. AB - Hyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T4 -T12 kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (rho^G , 0.46; 95% CI, -0.67 to -0.26), vertebral fracture (rho^G , 0.39; 95% CI, 0.18 to 0.61), vBMD (rho^G , -0.23; 95% CI, -0.41 to -0.04), and paraspinal muscle density (rho^G , -0.22; 95% CI, -0.48 to 0.03). Genetic correlations between kyphosis angle and disc height narrowing (rho^G , 0.17; 95% CI, -0.05 to 0.38) and facet joint OA (rho^G , 0.05; 95% CI, -0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age-related spine traits including trunk muscle size, vertebral fracture, and bone mineral density. (c) 2016 American Society for Bone and Mineral Research. PMID- 27455049 TI - Direct Characterization of Transcription Elongation by RNA Polymerase I. AB - RNA polymerase I (Pol I) transcribes ribosomal DNA and is responsible for more than 60% of transcription in a growing cell. Despite this fundamental role that directly impacts cell growth and proliferation, the kinetics of transcription by Pol I are poorly understood. This study provides direct characterization of S. Cerevisiae Pol I transcription elongation using tethered particle microscopy (TPM). Pol I was shown to elongate at an average rate of approximately 20 nt/s. However, the maximum speed observed was, in average, about 60 nt/s, comparable to the rate calculated based on the in vivo number of active genes, the cell division rate and the number of engaged polymerases observed in EM images. Addition of RNA endonucleases to the TPM elongation assays enhanced processivity. Together, these data suggest that additional transcription factors contribute to efficient and processive transcription elongation by RNA polymerase I in vivo. PMID- 27455050 TI - Rate and Outcomes of Pulmonary Stenosis and Functional Pulmonary Atresia in Recipient Twins with Twin-Twin Transfusion Syndrome. AB - OBJECTIVE: To evaluate the rate of pulmonary stenosis and functional pulmonary atresia (PS/PA) in recipient twins prior to fetal surgery for twin-twin transfusion syndrome (TTTS) and their pre- and postnatal outcomes. METHODS: We carried out a prospective study including 260 cases of TTTS. Echocardiography was performed before laser surgery to detect the presence of PS/PA. The outcomes of recipients with and without PS/PA were compared. The need of postnatal cardiac interventions and the survival rate at 6 months of age were also evaluated. RESULTS: PS was observed in 16/260 (6.2%) of recipient twins and PA in 12/260 (4.6%). After fetal surgery, 10/28 (35.7%) recipients died, 9/28 (32.1%) showed in utero regression, and 9/28 (32.1%) had persistence of PS/PA. Postnatally, seven recipients underwent percutaneous balloon pulmonary valvuloplasty, one required surgical valvotomy and one palliative surgery. Pregnancies with recipient twins with PS/PA had lower survival of at least one twin (67.9 vs. 83.6%, p = 0.045) and lower overall survival (57.1 vs. 72.8%, p = 0.015) at 6 months of age. CONCLUSION: PS and PA were observed in 10.8% of recipients. Among these, about one third showed persistence of pulmonary valve pathology after delivery, which stresses the need for strict follow-up. PMID- 27455051 TI - Polarly localized kinase SGN1 is required for Casparian strip integrity and positioning. AB - Casparian strips are precisely localized and aligned ring-like cell wall modifications in the root of all higher plants. They set up an extracellular diffusion barrier analogous to animal tight junctions, and are crucial for maintaining the homeostatic capacity of plant roots. Casparian strips become localized because of the formation of a highly stable plasma membrane domain, consisting of a family of small transmembrane proteins called Casparian strip membrane domain proteins (CASPs). Here we report a large-scale forward genetic screen directly visualizing endodermal barrier function, which allowed us to identify factors required for the formation and integrity of Casparian strips. We present the identification and characterization of one of the mutants, schengen1 (sgn1), a receptor-like cytoplasmic kinase that we show localizes in a strictly polar fashion to the outer plasma membrane of endodermal cells and is required for the positioning and correct formation of the centrally located CASP domain. PMID- 27455052 TI - Early Phthalates Exposure in Pregnant Women Is Associated with Alteration of Thyroid Hormones. AB - INTRODUCTION: Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy. METHOD: We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG). RESULTS: Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 MUg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (beta = -5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction. CONCLUSION: We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations. PMID- 27455054 TI - Retraction: Baicalein Reduces the Invasion of Glioma Cells via Reducing the Activity of p38 Signaling Pathway. PMID- 27455053 TI - The Effectiveness and Safety of Fluoroquinolone-Containing Regimen as a First Line Treatment for Drug-Sensitive Pulmonary Tuberculosis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Fluoroquinolone is recommended as a pivotal antituberculous agent for treating multi-drug-resistant pulmonary tuberculosis. However, its effectiveness as first-line treatment remains controversial. The present study was conducted to validate the fluoroquinolone-containing regimen for drug-sensitive pulmonary tuberculosis. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials until June 5, 2015. Randomized controlled trials (RCTs) that compared antituberculous regimens containing fluoroquinolone with the standard regimen were included. RESULTS: Eleven RCTs that included 6,334 patients were selected. Fluoroquinolone-containing regimens had a higher rate of sputum culture conversion at 2 months of treatment (M-H fixed odds ratio [OR], 1.36; 95% confidence interval [CI], 1.20-1.54). However, the outcomes were less favorable (M-H fixed OR, 0.69; 95% CI, 0.59-0.82) and the associated total adverse events were more frequent (M-H fixed OR, 1.84; 95% CI, 1.46-2.31) in the fluoroquinolone containing regimen group, without a significant heterogeneity according to treatment duration. Treatment with the fluoroquinolone-containing regimen for 4 months showed a higher relapse rate. CONCLUSIONS: Despite a higher culture conversion rate at 2 months of treatment, the fluoroquinolone-containing regimen had limitations, including less favorable outcomes and more adverse events, as the first-line therapy for drug-sensitive pulmonary tuberculosis. PMID- 27455055 TI - Mumps virus pathogenesis: Insights and knowledge gaps. AB - The recent mumps outbreaks among MMR vaccinated persons have raised questions about the biological mechanisms related to mumps symptoms and complications in the background of waning immunity. Contrary to other paramyxoviruses, the understanding of mumps virus pathogenesis is limited, and further in-depth clinical studies are required to provide answers to important research questions. PMID- 27455056 TI - Lifestyle and Self-Management by Those Who Live It: Patients Engaging Patients in a Chronic Disease Model. AB - BACKGROUND: Patients pursuing organ transplantation have complex medical needs, undergo comprehensive evaluation for possible listing, and require extensive education. However, transplant patients and their supports frequently report the need for more lifestyle and self-management strategies for living with organ transplantation. OBJECTIVES: First, to explore feasibility of a successful, patient-run transplant lifestyle educational group (Transplant Living Community), designed to complement medical care and integrated into the clinical setting; and second, to report the major themes of patients' and supports' qualitative and quantitative feedback regarding the group. METHODS: Informal programmatic review and patient satisfaction surveys. RESULTS: A total of 1862 patient satisfaction surveys were disseminated and 823 were returned (response rate, 44.2%). Patients and their supports reported positive feedback regarding the group, including appreciation that the volunteer was a transplant recipient and gratitude for the lifestyle information. Five areas were associated with the success of Transplant Living Community: 1) a "champion" dedicated to the program and its successful integration into a multidisciplinary team; 2) a health care environment receptive to integration of a patient-led group with ongoing community development; 3) a high level of visibility to physicians and staff, patients, and supports; 4) a clearly presented and manageable lifestyle plan ("Play Your ACES"(a) [Attitude, Compliance, Exercise, and Support]), and 5) a strong volunteer structure with thoughtful training with the ultimate objective of volunteers taking ownership of the program. CONCLUSION: It is feasible to integrate a sustainable patient-led lifestyle and self-management educational group into a busy tertiary care clinic for patients with complex chronic illnesses. PMID- 27455057 TI - Monoarticular Poncet Disease after Pulmonary Tuberculosis: A Rare Case Report and Review of Literature. AB - INTRODUCTION: Tuberculosis is a major health problem worldwide, more so in Asian countries and especially India. Being a communicable disease, it can affect the lives of many people. Tuberculosis has varied manifestations and can affect almost every part of the human body. Pulmonary tuberculosis is the most common form. Poncet disease (tuberculous rheumatism) is a polyarticular arthritis that occurs during acute tuberculosis infection in which no mycobacterial involvement can be found or no other known cause of polyarthritis is detected. CASE PRESENTATION: We describe an atypical presentation of active pulmonary tuberculosis with monoarticular Poncet disease of the right knee in a 24-year-old woman. DISCUSSION: The diagnosis of Poncet disease is mainly clinical with exclusion of other causes. It generally presents as an acute or subacute form; however, chronic forms have been described in the literature. PMID- 27455058 TI - Future Challenges of Robotics and Artificial Intelligence in Nursing: What Can We Learn from Monsters in Popular Culture? AB - It is highly likely that artificial intelligence (AI) will be implemented in nursing robotics in various forms, both in medical and surgical robotic instruments, but also as different types of droids and humanoids, physical reinforcements, and also animal/pet robots. Exploring and discussing AI and robotics in nursing and health care before these tools become commonplace is of great importance. We propose that monsters in popular culture might be studied with the hope of learning about situations and relationships that generate empathic capacities in their monstrous existences. The aim of the article is to introduce the theoretical framework and assumptions behind this idea. Both robots and monsters are posthuman creations. The knowledge we present here gives ideas about how nursing science can address the postmodern, technologic, and global world to come. Monsters therefore serve as an entrance to explore technologic innovations such as AI. Analyzing when and why monsters step out of character can provide important insights into the conceptualization of caring and nursing as a science, which is important for discussing these empathic protocols, as well as more general insight into human knowledge. The relationship between caring, monsters, robotics, and AI is not as farfetched as it might seem at first glance. PMID- 27455059 TI - Influence of the hole geometry on the flow distribution in ventricular catheters for hydrocephalus. AB - BACKGROUND: Hydrocephalus is a medical condition consisting of an abnormal accumulation of cerebrospinal fluid within the brain. A catheter is inserted in one of the brain ventricles and then connected to an external valve to drain the excess of cerebrospinal fluid. The main drawback of this technique is that, over time, the ventricular catheter ends up getting blocked by the cells and macromolecules present in the cerebrospinal fluid. A crucial factor influencing this obstruction is a non-uniform flow pattern through the catheter, since it facilitates adhesion of suspended particles to the walls. In this paper we focus on the effects that tilted holes as well as conical holes have on the flow distribution and shear stress. METHODS: We have carried out 3D computational simulations to study the effect of the hole geometry on the cerebrospinal fluid flow through ventricular catheters. All the simulations were done with the OpenFOAM(r) toolbox. In particular, three different groups of models were investigated by varying (i) the tilt angles of the holes, (ii) the inner and outer diameters of the holes, and (iii) the distances between the so-called hole segments. RESULTS: The replacement of cylindrical holes by conical holes was found to have a strong influence on the flow distribution and to lower slightly the shear stress. Tilted holes did not involve flow distribution changes when the hole segments are sufficiently separated, but the mean shear stress was certainly reduced. CONCLUSIONS: The authors present new results about the behavior of the fluid flow through ventricular catheters. These results complete earlier work on this topic by adding the influence of the hole geometry. The overall objective pursued by this research is to provide guidelines to improve existing commercially available ventricular catheters. PMID- 27455060 TI - A Novel Peptide from Soybean Protein Isolate Significantly Enhances Resistance of the Organism under Oxidative Stress. AB - Recent studies have indicated that protein hydrolysates have broad biological effects. In the current study we describe a novel antioxidative peptide, FDPAL, from soybean protein isolate (SPI). The aim of this study was to purify and characterize an antioxidative peptide from SPI and determine its antioxidative mechanism. LC-MS/MS was used to isolate and identify the peptide from SPI. The sequence of the peptide was determined to be Phe-Asp-Pro-Ala-Leu (FDPAL, 561 Da). FDPAL can cause significant enhancement of resistance to oxidative stress both in cells as well as simple organisms. In Caenorhabditis elegans (C. elegans), FDPAL can up-regulate the expression of certain genes associated with resistance. The antioxidant activity of this peptide can be attributed to the presence of a specific amino acid sequence. Results from our work suggest that FDPAL can facilitate potential applications of proteins carrying this sequence in the nutraceutical, bioactive material and clinical medicine areas, as well as in cosmetics and health care products. PMID- 27455061 TI - Parallel algorithms for large-scale biological sequence alignment on Xeon-Phi based clusters. AB - BACKGROUND: Computing alignments between two or more sequences are common operations frequently performed in computational molecular biology. The continuing growth of biological sequence databases establishes the need for their efficient parallel implementation on modern accelerators. RESULTS: This paper presents new approaches to high performance biological sequence database scanning with the Smith-Waterman algorithm and the first stage of progressive multiple sequence alignment based on the ClustalW heuristic on a Xeon Phi-based compute cluster. Our approach uses a three-level parallelization scheme to take full advantage of the compute power available on this type of architecture; i.e. cluster-level data parallelism, thread-level coarse-grained parallelism, and vector-level fine-grained parallelism. Furthermore, we re-organize the sequence datasets and use Xeon Phi shuffle operations to improve I/O efficiency. CONCLUSIONS: Evaluations show that our method achieves a peak overall performance up to 220 GCUPS for scanning real protein sequence databanks on a single node consisting of two Intel E5-2620 CPUs and two Intel Xeon Phi 7110P cards. It also exhibits good scalability in terms of sequence length and size, and number of compute nodes for both database scanning and multiple sequence alignment. Furthermore, the achieved performance is highly competitive in comparison to optimized Xeon Phi and GPU implementations. Our implementation is available at https://github.com/turbo0628/LSDBS-mpi . PMID- 27455062 TI - The automatic visual simulation of words: A memory reactivated mask slows down conceptual access. AB - How do we represent the meaning of words? The present study assesses whether access to conceptual knowledge requires the reenactment of the sensory components of a concept. The reenactment-that is, simulation-was tested in a word categorisation task using an innovative masking paradigm. We hypothesised that a meaningless reactivated visual mask should interfere with the simulation of the visual dimension of concrete words. This assumption was tested in a paradigm in which participants were not aware of the link between the visual mask and the words to be processed. In the first phase, participants created a tone-visual mask or tone-control stimulus association. In the test phase, they categorised words that were presented with 1 of the tones. Results showed that words were processed more slowly when they were presented with the reactivated mask. This interference effect was only correlated with and explained by the value of the visual perceptual strength of the words (i.e., our experience with the visual dimensions associated with concepts) and not with other characteristics. We interpret these findings in terms of word access, which may involve the simulation of sensory features associated with the concept, even if participants were not explicitly required to access visual properties. (PsycINFO Database Record PMID- 27455063 TI - Serum Creatinine Trajectories for Community- versus Hospital-Acquired Acute Kidney Injury. AB - BACKGROUND: Patterns of acute kidney injury (AKI) can be distinguished by the rate of changes in the serum creation concentrations during hospitalizations. We hypothesized that the timing and values of minimum and maximum serum creatinine (sCr) could be used to distinguish between transient hospital-associated AKI (THA AKI) and hospital-acquired AKI (HA-AKI). MATERIALS AND METHODS: We evaluated adults admitted to 2 regionally distinct academic medical centers. Peak sCr during the hospitalization was used to define AKI, using absolute changes and timing from the minimum sCr. sCr trajectories were derived based on the rate of change between the minimum and peak creatinine concentrations. RESULTS: Peak creatinine followed the minimum creatinine for HA-AKI, while the peak creatinine preceded the minimum creatinine for THA-AKI. There were 82,403 patients included in the analyses, and 53,882 (65%) did not have AKI during the index hospitalization. There were 2,611 inpatient deaths; HA-AKI had a 4.8-fold increased risk relative to those without AKI (p < 0.01), and transient AKI had a 1.6-fold increased risk for inpatient mortality relative to inpatients without AKI (p < 0.01). CONCLUSIONS: Patients with hospital-associated AKI are at an increased risk for inpatient mortality. Creatinine trajectories can be used to describe the rate of development as well as recovery from inpatient AKI. The 24- and 48-hour interval slopes may be early indicators of developing AKI. (c) 2016 S. Karger AG, Basel. PMID- 27455064 TI - Purification and Characterization of a Rabbit Serum Factor That Kills Listeria Species and Other Foodborne Bacterial Pathogens. AB - In an in-vitro assay, rabbit serum, but not human serum, killed Listeria monocytogenes, a foodborne pathogen. The aim of our study was to purify and partially characterize this killing factor. Listericidin was purified from rabbit serum by a single-step ion-exchange chromatography with DEAE-Sephadex A-50 and its antimicrobial activity was assessed by a microdilution method. Listericidin is a protein with a molecular weight of 9 kDa and an isoelectric point of 8.1. It kills L. monocytogenes at 4 degrees C, 25 degrees C, and 37 degrees C, and its activity is resistant to heat (boiling) and acidic conditions (pH <2). Listericidin's activity is inhibited by sodium chloride and various growth media, is sensitive to proteolytic enzymes and is enhanced by calcium chloride, and is neutralized by monoclonal antibodies to human complement C3a. However, the listericidin reacts weakly with these antibodies in an ELISA. The first 33 N terminal residues of listericidin (SVQLTEKRMDKVGQYTNKELRKXXEDGMRDNPM) have homology to various complement C3a components. Listericidin also kills other Listeria spp., Vibrio spp., Salmonella spp., Escherichia spp., Cronobacter spp., and Bacillus spp. The listericidin peptide purified in a single-step chromatography is pH and heat stable, and has a broad antimicrobial spectrum against major foodborne pathogens in addition to L. monocytogenes. PMID- 27455065 TI - Space and place for WHO health development dialogues in the African Region. AB - BACKGROUND: Majority of the countries in the World Health Organization (WHO) African Region are not on track to achieve the health-related Millennium Development Goals, yet even more ambitious Sustainable Development Goals (SDGs), including SDG 3 on heath, have been adopted. This paper highlights the challenges - amplified by the recent Ebola virus disease (EVD) outbreak in West Africa - that require WHO and other partners' dialogue in support of the countries, and debate on how WHO can leverage the existing space and place to foster health development dialogues in the Region. DISCUSSION: To realise SDG 3 on ensuring healthy lives and promoting well-being for all at all ages, the African Region needs to tackle the persistent weaknesses in its health systems, systems that address the social determinants of health and national health research systems. The performance of the third item is crucial for the development and innovation of systems, products and tools for promoting, maintaining and restoring health in an equitable manner. Under its new leadership, the WHO Regional Office for Africa is transforming itself to galvanise existing partnerships, as well as forging new ones, with a view to accelerating the provision of timely and quality support to the countries in pursuit of SDG 3. WHO in the African Region engages in dialogues with various stakeholders in the process of health development. The EVD outbreak in West Africa accentuated the necessity for optimally exploiting currently available space and place for health development discourse. There is urgent need for the WHO Regional Office for Africa to fully leverage the space and place arenas of the World Health Assembly, WHO Regional Committee for Africa, African Union, Regional economic communities, Harmonization for Health in Africa, United Nations Economic Commission for Africa, African Development Bank, professional associations, and WHO African Health Forum, when it is created, for dialogues to mobilise the required resources to give the African Region the thrust it needs to attain SDG 3. CONCLUSIONS: The pursuit of SDG 3 amidst multiple challenges related to political leadership and governance, weak health systems, sub-optimal systems for addressing the socioeconomic determinants of health, and weak national health research systems calls for optimum use of all the space and place available for regional health development dialogues to supplement Member States' efforts. PMID- 27455066 TI - Decoration Increases the Conspicuousness of Raptor Nests. AB - Avian nests are frequently concealed or camouflaged, but a number of species builds noticeable nests or use conspicuous materials for nest decoration. In most cases, nest decoration has a role in mate choice or provides thermoregulatory or antiparasitic benefits. In territorial species however, decorations may serve additional or complementary functions, such as extended phenotypic signaling of nest-site occupancy and social status to potential intruders. The latter may benefit both signaler and receiver by minimizing the risk of aggressive interactions, especially in organisms with dangerous weaponry. Support for this hypothesis was recently found in a population of black kites (Milvus migrans), a territorial raptor that decorates its nest with white artificial materials. However, the crucial assumption that nest decorations increased nest-site visibility to conspecifics was not assessed, a key aspect given that black kite nests may be well concealed within the canopy. Here, we used an unmanned aircraft system to take pictures of black kite nests, with and without an experimentally placed decoration, from different altitudes and distances simulating the perspective of a flying and approaching, prospecting intruder. The pictures were shown to human volunteers through a standardized routine to determine whether detection rates varied according the nest decoration status and distance. Decorated nests consistently showed a higher detection frequency and a lower detection-latency, compared to undecorated versions of the same nests. Our results confirm that nest decoration in this species may act as a signaling medium that enhances nest visibility for aerial receivers, even at large distances. This finding complements previous work on this communication system, which showed that nest decoration was a threat informing trespassing conspecifics on the social dominance, territory quality and fighting capabilities of the signaler. PMID- 27455067 TI - Oxygen modulation of flexible PbS/Pb Schottky junction PEC cells with improved photoelectric performance. AB - Flexible photoelectric devices are emerging as a new class of photovoltaic cells. In this study, lead (Pb) foil was used as a flexible substrate to grow in situ lead sulfide (PbS) film with good uniformity and adhesion by a solvothermal elemental direct reaction, resulting in a PbS/Pb Schottky junction formed naturally between the PbS film and underlying Pb foil. We found that the photocurrent response of the photoelectrochemical (PEC) cell was greatly improved through a facile oxygen (O2)-modulation-based post-processing technique. O2 could decompose the organic residue and oxidize the Pb at the interface between the PbS film and Pb foils. Different characterization techniques, including thermogravimetric analysis, differential scanning calorimetry, x-ray diffraction, energy-dispersive x-ray spectroscopy, x-ray photoelectron spectroscopy, the change in transient photocurrent density (J p) with time (t), dark current voltage (I-V) and absorption spectra were applied to get a full understanding of the O2 modulation effect. The oxidization treatment of the PbS film could regulate the flow of charge carriers to reduce their recombination, leading to photoresponse enhancement for the PEC cells. In particular, the process could modulate the tunneling current and interface states to optimize dark I-V characteristics. In addition, the magnitude of the barrier height can be tuned by O2 modulation, which was explained by theoretical analysis and calculation. We also demonstrated that the in situ formed PbS film has outstanding adhesion on the flexible Pb substrate. Our film synthesis method and post O2-modulation design as well as the corresponding device assembly may provide a novel perspective to the flexible PCE-cell-related research. PMID- 27455068 TI - Synthetic Renal Capsule Tailoring: A Novel Renorrhaphy Technique After Subcapsular Dissection of Renal Tumors with Severe Adherent Perirenal Fat During Laparoscopic Partial Nephrectomy. AB - BACKGROUND: Multiple factors can account for surgical complexity during laparoscopic partial nephrectomy (LPN); severe adhesion of perirenal fat (PRF) is a crucial one. Consequent renal decapsulation can deem renorrhaphy a very challenging task. We propose a novel technique (synthetic renal capsule tailoring [SYRCT]) to facilitate renorrhaphy in decapsulated kidneys and suggest early decapsulation as a safe option in cases with severe PRF. MATERIALS AND METHODS: We retrospectively analyzed perioperative results of this novel technique performed in cases with severe PRF. All cases were classified as high grade in the Mayo Adhesive Probability (MAP) score. RESULTS: A total of six cases were performed with the SYRCT technique. All patients were male with a mean age of 70 years (62-76 years) and mean body mass index of 30 kg/m2 (23.66-33.86). Of the six cases, five were T1a and 1 T1b. Mean tumor size was 2.83 cm (range 1.2-6 cm). Mean operative time was 121 minutes (range 74-150 minutes); mean warm ischemia time was 17.2 minutes (range 13-25 minutes). Mean operative bleeding was 128 mL (range 50-250 mL). Mean hospital stay was 2.3 days. There were no surgical complications greater or equal to Clavien II. CONCLUSION: Performing complete renal decapsulation with subcapsular dissection and SYRCT in cases with high MAP score and severe PRF is safe and reproducible. Using this novel technique, we were able to obtain perioperative results comparable to the ones we found in LPN with normal PRF. PMID- 27455069 TI - Scoring multiple features to predict drug disease associations using information fusion and aggregation. AB - Prediction of drug-disease associations is one of the current fields in drug repositioning that has turned into a challenging topic in pharmaceutical science. Several available computational methods use network-based and machine learning approaches to reposition old drugs for new indications. However, they often ignore features of drugs and diseases as well as the priority and importance of each feature, relation, or interactions between features and the degree of uncertainty. When predicting unknown drug-disease interactions there are diverse data sources and multiple features available that can provide more accurate and reliable results. This information can be collectively mined using data fusion methods and aggregation operators. Therefore, we can use the feature fusion method to make high-level features. We have proposed a computational method named scored mean kernel fusion (SMKF), which uses a new method to score the average aggregation operator called scored mean. To predict novel drug indications, this method systematically combines multiple features related to drugs or diseases at two levels: the drug-drug level and the drug-disease level. The purpose of this study was to investigate the effect of drug and disease features as well as data fusion to predict drug-disease interactions. The method was validated against a well-established drug-disease gold-standard dataset. When compared with the available methods, our proposed method outperformed them and competed well in performance with area under cover (AUC) of 0.91, F-measure of 84.9% and Matthews correlation coefficient of 70.31%. PMID- 27455071 TI - The effect of word sense disambiguation accuracy on literature based discovery. AB - BACKGROUND: The volume of research published in the biomedical domain has increasingly lead to researchers focussing on specific areas of interest and connections between findings being missed. Literature based discovery (LBD) attempts to address this problem by searching for previously unnoticed connections between published information (also known as "hidden knowledge"). A common approach is to identify hidden knowledge via shared linking terms. However, biomedical documents are highly ambiguous which can lead LBD systems to over generate hidden knowledge by hypothesising connections through different meanings of linking terms. Word Sense Disambiguation (WSD) aims to resolve ambiguities in text by identifying the meaning of ambiguous terms. This study explores the effect of WSD accuracy on LBD performance. METHODS: An existing LBD system is employed and four approaches to WSD of biomedical documents integrated with it. The accuracy of each WSD approach is determined by comparing its output against a standard benchmark. Evaluation of the LBD output is carried out using timeslicing approach, where hidden knowledge is generated from articles published prior to a certain cutoff date and a gold standard extracted from publications after the cutoff date. RESULTS: WSD accuracy varies depending on the approach used. The connection between the performance of the LBD and WSD systems are analysed to reveal a correlation between WSD accuracy and LBD performance. CONCLUSION: This study reveals that LBD performance is sensitive to WSD accuracy. It is therefore concluded that WSD has the potential to improve the output of LBD systems by reducing the amount of spurious hidden knowledge that is generated. It is also suggested that further improvements in WSD accuracy have the potential to improve LBD accuracy. PMID- 27455070 TI - Voices of the "99 Percent": The Role of Online Narrative to Improve Health Care. AB - CONTEXT: Communal blogs facilitate online narratives by providing opportunities for individuals to co-construct meaning and to engage in discussion about lived health experiences. OBJECTIVE: To examine the role of health as a connective narrative among individuals organizing collectively in an online community. The "We are the 99 percent" Tumblr blog emerged as a spontaneous community platform of the Occupy Wall Street movement in the US. DESIGN: Researchers conducted a qualitative content analysis of a total of 2003 blog posts. MAIN OUTCOME MEASURES: Data analysis included a process of data reduction, display, and conclusion drawing and verification. RESULTS: Bloggers discussed medical crises and the role of injury and illness in maintaining financial solvency. The difficulty of obtaining health care and the lack of accessible quality care emerged as themes. In particular, unemployment and underemployment limited access to health insurance coverage. The bloggers expressed dissatisfaction with the health care system and the impact of financial status on health. These challenges were exacerbated for marginalized populations, such as women and veterans. CONCLUSION: Findings offer implications for the value of online narrative to improve health care initiatives and to provide insight to integrated health care systems, including health care practitioners, nonprofit organizations, hospitals, and policy makers. Results suggest opportunities to address the health care gaps of marginalized populations and to develop public health policy. PMID- 27455072 TI - Does Anticoagulant Medication Alter Fracture-Healing? A Morphological and Biomechanical Evaluation of the Possible Effects of Rivaroxaban and Enoxaparin Using a Rat Closed Fracture Model. AB - Low molecular weight heparin (LMWH) is routinely used to prevent thromboembolism in orthopaedic surgery, especially in the treatment of fractures or after joint replacement. Impairment of fracture-healing due to increased bone-desorption, delayed remodelling and lower calcification caused by direct osteoclast stimulation is a well-known side effect of unfractioned heparin. However, the effect of LMWH is unclear and controversial. Recent studies strongly suggest impairment of bone-healing in-vitro and in animal models, characterized by a significant decrease in volume and quality of new-formed callus. Since October 2008, Rivaroxaban (Xarelto) is available for prophylactic use in elective knee- and hip-arthroplasty. Recently, some evidence has been found indicating an in vitro dose independent reduction of osteoblast function after Rivaroxaban treatment. In this study, the possible influence of Rivaroxaban and Enoxaparin on bone-healing in vivo was studied using a standardized, closed rodent fracture model. 70 male Wistar-rats were randomized to Rivaroxaban, Enoxaparin or control groups. After pinning the right femur, a closed, transverse fracture was produced. 21 days later, the animals were sacrificed and both femora harvested. Analysis was done by biomechanical testing (three-point bending) and micro CT. Both investigated substances showed histomorphometric alterations of the newly formed callus assessed by micro CT analysis. In detail the bone (callus) volume was enhanced (sign. for Rivaroxaban) and the density reduced. The bone mineral content was enhanced accordingly (sign. for Rivaroxaban). Trabecular thickness was reduced (sign. for Rivaroxaban). Furthermore, both drugs showed significant enlarged bone (callus) surface and degree of anisotropy. In contrast, the biomechanical properties of the treated bones were equal to controls. To summarize, the morphological alterations of the fracture-callus did not result in functionally relevant deficits. PMID- 27455073 TI - Cutaneous Respirometry as Novel Technique to Monitor Mitochondrial Function: A Feasibility Study in Healthy Volunteers. AB - BACKGROUND: The protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) is proposed as a potential clinical non-invasive tool to monitor mitochondrial function. This technique has been evaluated in several animal studies. Mitochondrial respirometry allows measurement in vivo of mitochondrial oxygen tension (mitoPO2) and mitochondrial oxygen consumption (mitoVO2) in skin. This study describes the first use of a clinical prototype in skin of humans. METHODS: The clinical prototype was tested in 30 healthy volunteers. A self-adhesive patch containing 2 mg 5-aminolevulinic acid (ALA) was applied on the skin of the anterior chest wall (sternal) for induction of mitochondrial protoporphyrin IX and was protected from light for 5 h. MitoPO2 was measured by means of oxygen dependent delayed fluorescence of protoporphyrin IX. MitoVO2 was determined by dynamic mitoPO2 measurements on the primed skin, while locally blocking oxygen supply by applying local pressure with the measurement probe. MitoPO2 was recorded before and during a 60-s period of compression of the microcirculation, at an interval of 1 Hz. Oxygen consumption (i.e. the local oxygen disappearance rate) was calculated from the decay of the mitoPO2 slope. RESULTS: Oxygen dependent delayed fluorescence measurements were successfully performed in the skin of 27 volunteers. The average value (+/- SD) of mitoPO2 was 44 +/- 17 mmHg and mean mitoVO2 values were 5.8 +/- 2.3 and 6.1 +/- 1.6 mmHg s-1 at a skin temperature of 34 degrees C and 40 degrees C, respectively. No major discomfort during measurement and no long-term dermatological abnormalities were reported in a survey performed 1 month after measurements. CONCLUSION: These results show that the clinical prototype allows measurement of mitochondrial oxygenation and oxygen consumption in humans. The development of this clinically applicable device offers opportunities for further evaluation of the technique in humans and the start of first clinical studies. PMID- 27455074 TI - Parental Decisions about Prenatal Screening and Diagnosis among Infants with Trisomy 21 in a National Cohort with High Uptake of Combined First-Trimester Screening. AB - INTRODUCTION: The aim was to investigate the parental decisions about prenatal screening and diagnosis among infants with trisomy 21 (T21) in a national cohort with high uptake of combined first-trimester screening (cFTS). MATERIAL AND METHODS: This was a nationwide population-based study including infants born in 2009-2012. Information from the cFTS, fetal karyotype results and pregnancy outcome was obtained from the Danish Fetal Medicine Database on all women with a cFTS risk assessment. Cut-off for referral for invasive testing was >=1:300. Karyotype results from pregnancies with no cFTS were obtained from the Danish Cytogenetic Central Registry. RESULTS: The uptake rate of cFTS was 91.6%, and 82.8% (8,032/9,704) of the screen-positive women opted for invasive testing. Overall, 82.2% (454/552) chose to terminate an affected pregnancy. In the 4-year period, 102 of 232,962 singletons were born alive with T21. The cFTS risk was true-positive, false-negative or not obtained in 21.6, 48.0 and 30.4%, respectively, of these pregnancies. DISCUSSION: In this large national cohort, 4.4 per 10,000 live-born infants had T21. Of 102 infants with T21 from 2009 to 2012, 52.0% were born after the women had not opted for cFTS or were true positive but declined invasive testing or termination, and 48.0% were born after a false-negative risk assessment. PMID- 27455075 TI - Pro-inflammatory cytokine single nucleotide polymorphisms in Kawasaki disease. AB - AIM: Kawasaki disease (KD) is a systemic vasculitis of children associated with cardiovascular sequelae. Proinflammatory cytokines play a major role in KD pathogenesis. However, their role is both influenced and modified by regulatory T cells. IL-1 gene cluster, IL-6 and TNF-alpha polymorphisms have shown significant associations with some vasculitides. Herein we investigated their role in KD. METHODS: Fifty-five patients with KD who were randomly selected from referrals to the main pediatric hospital were enrolled in this case-control study. Single nucleotide polymorphisms (SNPs) of the following genes were assessed in patients and 140 healthy subjects as control group: IL-1alpha at -889 (rs1800587), IL 1beta at -511 (rs16944), IL-1beta at +3962 (rs1143634), IL-1R at Pst-I 1970 (rs2234650), IL-1RN/A at Mspa-I 11100 (rs315952), TNF-alpha at -308 (rs1800629), TNF-alpha at -238, IL-6 at -174 (rs1800795) and IL-6 at +565. RESULTS: Twenty-one percent of the control group had A allele at TNF-alpha -238 while only 8% of KD patients had A allele at this position (P = 0.003, OR [95%CI] = 0.32 [0.14 0.71]). Consistently, TNF-alpha genotype GG at -238 had significant association with KD (OR [95% CI] = 4.31 [1.79-10.73]). Most controls carried the CG genotype at IL-6 -174 (n = 93 [66.9%]) while GG genotype was the most common genotype (n = 27 [49%]) among patients. Carriers of the GG haplotype at TNF-alpha (-308, -238) were significantly more prevalent among the KD group. No association was found between IL-1 gene cluster, allelic or haplotypic variants and KD. CONCLUSION: TNF alpha GG genotype at -238 and GG haplotype at positions -308 and -238 were associated with KD in an Iranian population. PMID- 27455077 TI - Pediatric Palliative Care Program versus Usual Care and Healthcare Resource Utilization in British Columbia: A Matched-Pairs Cohort Study. AB - BACKGROUND: Evidence on the impact of pediatric palliative care programs (PPCP) on resource utilization is scarce and requires broader measures to include utilization beyond the hospital setting. OBJECTIVE: This research aims to provide a Canadian comparative analysis between children in a PPCP with those under usual care, including hospice use to inpatient resource use measurement. METHODS: We conducted a retrospective matched-pairs (disease and age at death) cohort comparison of children who died in hospice versus hospital (never enrolled in a PPCP), from 2008 to 2012. Utilization was retrieved from administrative databases and chart review. The main outcomes were number of admissions and length of stay (LOS). RESULTS: Eleven pairs were found. PPCP users were more likely to have advanced directives (100% vs. 27%). After controlling for disease and age, we found no significant difference in number of admissions; however, PPCP users had an increase in admissions post-referral compared to pre-referral (median 3.08 admissions), driven by the need for critical care. We did not find a significant difference in LOS, but observed longer admissions among PPCP users pre- (1.91 days/month) and post-referral (3.66 days/month) compared to usual care. Over 60% of inpatient utilization shifted to the hospice post-referral. DISCUSSION: The terminal pediatric population referred to PPCP may systematically differ from those under usual care even before enrollment, presenting with higher inpatient utilization in critical care nearing death. A significant portion of inpatient utilization shifted to the hospice, with implications for resource reallocation and enhancements in PPCP referrals. PMID- 27455076 TI - The Orphan Nuclear Receptor ERRgamma Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor mediated induction of FGF21 gene expression is largely unknown. RESULTS: Activation of the hepatic CB1 receptor by arachidonyl-2'-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) gamma increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERRgamma decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERRgamma, but not ERRalpha and ERRbeta, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERRgamma-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERRgamma to the FGF21 gene promoter. Finally, GSK5182, an ERRgamma inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion. CONCLUSION: Based on our data, we conclude that ERRgamma plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion. PMID- 27455078 TI - The Neural Substrates Underlying the Implementation of Phonological Rule in Lexical Tone Production: An fMRI Study of the Tone 3 Sandhi Phenomenon in Mandarin Chinese. AB - This study examined the neural substrates underlying the implementation of phonological rule in lexical tone by the Tone 3 sandhi phenomenon in Mandarin Chinese. Tone 3 sandhi is traditionally described as the substitution of Tone 3 with Tone 2 when followed by another Tone 3 (33 ->23) during speech production. Tone 3 sandhi enables the examination of tone processing in the phonological level with the least involvement of segments. Using the fMRI technique, we measured brain activations corresponding to the monosyllable and disyllable sequences of the four Chinese lexical tones, while manipulating the requirement on overt oral response. The application of Tone 3 sandhi to disyllable sequence of Tone 3 was confirmed by our behavioral results. Larger brain responses to overtly produced disyllable Tone 3 (33 > 11, 22, and 44) were found in right posterior IFG by both whole-brain and ROI analyses. We suggest that the right IFG was responsible for the processing of Tone 3 sandhi. Intense temporo-frontal interaction is needed in speech production for self-monitoring. The involvement of the right IFG in tone production might result from its interaction with the right auditory cortex, which is known to specialize in pitch. Future studies using tools with better temporal resolutions are needed to illuminate the dynamic interaction between the right inferior frontal regions and the left-lateralized language network in tone languages. PMID- 27455079 TI - Comparison of patency and cost-effectiveness of self-expandable metal and plastic stents used for malignant biliary strictures: a Polish single-center study. AB - INTRODUCTION: Most patients with malignant biliary obstruction are suited only for palliation by endoscopic drainage with plastic stents (PS) or self-expandable metal stents (SEMS). OBJECTIVE: To compare the clinical outcome and costs of biliary stenting with SEMS and PS in patients with malignant biliary strictures. PATIENTS AND METHODS: A total of 114 patients with malignant jaundice who underwent 376 endoscopic retrograde biliary drainage (ERBD) were studied. RESULTS: ERBD with the placement of PS was performed in 80 patients, with one step SEMS in 20 patients and two-step SEMS in 14 patients. Significantly fewer ERBD interventions were performed in patients with one-step SEMS than PS or the two-step SEMS technique (2.0+/-1.12 vs. 3.1+/-1.7 or 5.7+/-2.1, respectively, P<0.0001). The median hospitalization duration per procedure was similar for the three groups of patients. The patients' survival time was the longest in the two step SEMS group in comparison with the one-step SEMS and PS groups (596+/-270 vs. 276+/-141 or 208+/-219 days, P<0.001). Overall median time to recurrent biliary obstruction was 89.3+/-159 days for PS and 120.6+/-101 days for SEMS (P=0.01). The total cost of hospitalization with ERBD was higher for two-step SEMS than for one-step SEMS or PS (1448+/-312, 1152+/-135 and 977+/-156&OV0556;, P<0.0001). However, the estimated annual cost of medical care for one-step SEMS was higher than that for the two-step SEMS or PS groups (4618, 4079, and 3995&OV0556;, respectively). CONCLUSION: Biliary decompression by SEMS is associated with longer patency and reduced number of auxiliary procedures; however, repeated PS insertions still remain the most cost-effective strategy. PMID- 27455081 TI - Frequency and factors associated with hepatitis C virus infection among patients with diabetes, Dammam, KSA. AB - BACKGROUND: Hepatitis C virus (HCV) infection and diabetes mellitus (DM) are main causes of morbidity and mortality worldwide. There is an increasing evidence of association between HCV and type 2 DM. Comorbidity will cause devastating health and financial burdens. Early detection may help proper management and better prognosis. OBJECTIVE: The aim of this study was to examine the frequency and risk factors of HCV among Saudi patients with diabetes. PATIENTS AND METHODS: In this cross-sectional study, 1054 Saudi patients with diabetes type 1 and type 2 were randomly selected, interviewed, and tested for HCV in Dammam Medical Complex, KSA (2011), using the HCV Rapid Test. Positive cases were later confirmed using the INNO-LIA HCV score line immunoassay. RESULTS: Seropositivity of HCV was 1.9%. Regression analysis revealed the following independent predictors: sharing articles, elevated liver enzymes, exposure to blood or blood products in occupational setting, disease duration more than 5 years, tattooing, blood transfusion, and hospitalization more than two times. CONCLUSION AND RECOMMENDATIONS: The study confirmed a positive association between HCV and DM. The frequency of HCV among patients with diabetes was 1.9%. Predictors of HCV among DM patients were sharing articles, elevated transaminases, occupational exposure to blood or its products, disease duration more than 5 years, tattooing, blood transfusion, and hospitalization more than two times. We recommend screening for HCV among DM patients with elevated serum transaminases and those having the disease for more than 5 years and education of patients with diabetes as regards their high risk for HCV and how to avoid infection. PMID- 27455080 TI - No difference in mortality between terlipressin and somatostatin treatments in cirrhotic patients with esophageal variceal bleeding and renal functional impairment. AB - OBJECTIVE: To study the differences in mortality between terlipressin and somatostatin treatments in cirrhotic patients with esophageal variceal bleeding (EVB) and renal functional impairment (RFI). METHODS: The National Health Insurance Database, part of the Taiwan National Health Insurance Program, was used to enroll cirrhotic patients who had received endoscopic variceal ligation plus somatostatin or terlipressin for EVB and who were hospitalized between 1 January 2007 and 31 December 2010. The differences in mortality between the two vasoactive agents were compared and the risk factors for 30-day mortality because of EVB were identified. RESULTS: A total of 2324 cirrhotic patients with EVB were enrolled. The 30-day mortality data showed no significant differences between the somatostatin and the terlipressin groups (P=0.232). The risk of 30-day mortality was significantly higher in male patients [hazard ratio (HR): 1.50, P=0.002] and patients with hepatic encephalopathy (HR: 1.82, P<0.001), ascites (HR: 1.32, P=0.008), bacterial infections (HR: 2.10, P<0.001), hepatocellular carcinoma (HR: 2.09, P<0.001), and RFI (HR: 3.89, P<0.001). A subgroup analysis of cirrhotic patients with RFI was carried out. The overall 30-day mortality was higher in patients treated with somatostatin than in those treated with terlipressin (52.6 vs. 42.3%), but the difference failed to reach significance (adjust HR: 1.49, 95% confidence interval: 0.94-2.37, P=0.091). CONCLUSION: RFI was the most important risk factor for 30-day mortality in EVB patients. Terlipressin and somatostatin had similar effects on 30-day mortality in cirrhotic patients with EVB and RFI. PMID- 27455082 TI - Hospital utilization pattern in a hepatogastroenterology department of a research institute hospital, from 2004 to 2013. AB - BACKGROUND: The Theodor Bilharz Research Institute (TBRI) Hospital is a research and referral center for gastroenterology and hepatology. The Hepatogastroenterology (HGE) Department in TBRI Hospital is a center for endoscopy and sonography. The department also has a hepatology ICU. As a part of hospital performance improvement, medical records that satisfy the needs and demands of the healthcare team, setting a practical framework to improve the quality of medical care in TBRI Hospital, were generated. OBJECTIVE: The aim of the study was to assess the performance of the HGE Department in TBRI Hospital during the 10-year period from 2004 to 2013. MATERIALS AND METHODS: This is a retrospective observational study. Data were sourced from the electronic database of patient records in the form of automated summary discharge forms and from annual reports from the year 2004 until the year 2013, which are available in the Medical Record Unit in TBRI Hospital. HGE Department data include utilization of outpatient and emergency services and inpatient and ICU services. Hospital admission rates and readmission rates (RARs) were also used. Other utilization indices such as ultrasonography and endoscopy and hospital bed utilization indices such as average length of hospital stay (ALOS), bed occupancy rate (BOR), bed turnover rate, and mortality rate (MR) were also included. RESULTS: Outpatient cases almost doubled from 2004 to 2013 (from 6209 to14241). Inpatient cases increased by 40.5% (from 2003 to 2829). On average, the emergency admissions and ICU admissions formed about one-fourth of total admissions. RAR decreased over the 10 years (from 14.2 to 0.6). ALOS also decreased (from 9.4 to 6.1). BOR increased from 2004 to 2012 only (from 54.3 to 86.3). Bed turnover rate ranged from 21.1 to 28.5, but in 2012 it increased to 47.7 as a result of the increased BOR that year. MR decreased from 8.9 in 2004 to 0.3 in 2013. Ultrasonography increased from 3384 to 3973. Over the 10 years, the number of endoscopies increased about two-fold (from 2677 to 5100) and endoscopic ligation increased more than 10-fold. CONCLUSION AND RECOMMENDATIONS: There is an improvement in the hospital performance indicators represented in the form of increased outpatient services, decreased RAR, decreased ALOS, decreased MR, and increased utilization of endoscopies. It is recommended to implement a strategy based on the present findings for continual improvement for competency even in the future. PMID- 27455083 TI - Coping strategies of pregnant women following unexpected ultrasound results, Alexandria, Egypt. AB - BACKGROUND: Receiving a diagnosis of a potential fetal anomaly causes severe stress to a pregnant woman. Little is known about the coping strategies used by these women, especially in Egypt. OBJECTIVE: This study explored the coping strategies used by women following unexpected findings in routine antenatal ultrasound scan in Alexandria, Egypt. PATIENTS AND METHODS: A mixed method (convergent parallel) quantitative and qualitative approach was used to target pregnant women at 20-32 weeks of gestation. The quantitative study included 93 women, whereas the qualitative one included a purposively chosen subsample of 30 women representing diverse diagnoses. A 10-item questionnaire was used in the quantitative part to assess active, avoidant, and negative coping strategies. In the qualitative part, coping was assessed by analyzing the transcripts of women's experiences. RESULTS: Although women used equal numbers of avoidant and active strategies (3.34+/-0.56 vs. 3.30+/-0.73, Z=0.273, P=0.78), the reported effectiveness of active strategies ranked higher than that of the avoidant ones (chi=54.64, P<0.001). Women with an education level up to high school or higher perceived high effectiveness of active and/or avoidant strategies compared with women with less education (chi=4.087, P<0.05). CONCLUSION AND RECOMMENDATIONS: Women concurrently used more than one coping strategy. The effectiveness of active strategies was higher than that of the avoidant ones. The educational level was the only factor associated with perceived high effectiveness of active and/or avoidant strategies. Helping future mothers acquire active coping skills through counseling sessions and support groups are recommended. PMID- 27455084 TI - Integron-mediated multidrug resistance in extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae isolated from fecal specimens in Egypt. AB - BACKGROUND: The increasing incidence of hospital-acquired infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae represent a major health problem because of few therapeutic alternatives. The fecal flora can represent a reservoir for ESBL genes. Integrons are genetic structures capable of capturing gene cassettes that usually encode antibiotic-resistance determinants. OBJECTIVES: To investigate the antimicrobial susceptibility of fecal isolates of ESBL-producing Escherichia coli and Klebsiella pneumoniae from hospitalized and nonhospitalized Egyptian patients and to determine the prevalence of class 1 and class 2 integrons together with the most common ESBL-producing genes (bla TEM, SHV, CTX-M, and OXA) among the collected isolates. MATERIALS AND METHODS: Ninety six fecal samples were collected: 48 samples from hospitalized patients admitted at Kasr Al-Ainy University Hospital, Cairo and 48 from outpatient clinics. Samples were inoculated on MacConkey agar and identified. All isolates were tested for their susceptibility to different antimicrobial agents using a standard disk diffusion method. The double-disk synergy test was applied for screening ESBL. All ESBL-producing isolates were confirmed by molecular testing to detect ESBL-encoding genes (SHV, TEM, CTX-M, and OXA). To identify the strains carrying integrons 1 and 2, the conserved regions of integron-encoded integrase gene intI1 and intI2 were amplified. RESULTS: E. coli isolates accounted for 52.1% of the isolates collected from hospitalized patients and 60.4% of those collected from outpatient clinics. Results of the double-disk synergy test were positive in all E. coli and K. pneumoniae isolates, indicating the presence of ESBL production. Isolates of both groups showed variably high degrees of resistance to ciprofloxacin and co-trimoxazole. The most predominant ESBL gene in both groups was the bla CTX-M gene (93.8%) and the least prevalent was the bla OXA gene, which was not detected in any of the study isolates. Between the other two genes, the bla TEM gene was more common than the bla SHV gene in the two study groups. Class 1 integron was more prevalent among hospitalized patients, being detected in 64.6% of isolates from this group. Class 1 integron was linked with the bla CTX-M gene (P=0.039). Class 2 integron was more prevalent in the nonhospitalized group (85.4%) compared with the hospitalized group (50%) (P<0.001). CONCLUSION AND RECOMMENDATIONS: ESBL-producing E. coli and K. pneumoniae showed a marked degree of antibiotic resistance in both hospitalized and nonhospitalized study groups. The high prevalence of class 1 and 2 integrons among isolates of both groups has a serious impact on the spread of antibiotic resistance. PMID- 27455085 TI - Disruptive physician behaviors and their impact on patient care in a health insurance hospital in Alexandria, Egypt. AB - BACKGROUND: Disruptive behavior is the use of inappropriate words, actions, or inactions by physicians that interferes with their ability to function well with others. It is a current problem in the medical profession and has become a focus of public health attention due to its destructive impact on hospital staff, institutions, and quality patient care. AIM: The aim of the present study was to evaluate the perceptions of physicians about disruptive physician behaviors, and their frequency and impact on clinical outcomes. MATERIALS AND METHODS: This cross-sectional, descriptive study was carried out in one of the hospitals of the Health Insurance Organization in Alexandria, Egypt. A self-administered questionnaire based on the American College of Physician Executives and QuantiaMD Survey on disruptive physician behavior was used to measure the physicians' perceptions. It was distributed to all physicians in all the departments (n=183). The number of returned questionnaires was 120, with a response rate of 65.6%. RESULTS: Most of the respondents (93.3%) were concerned about disruptive physician behavior, 39.2% previously had such behaviors, and 78.3% had one incident at least monthly. Most respondents (98.3%) said that disruptive physician behavior affects patient care. Physicians agreed that they needed training on how to deal with disruptive behavior. The most frequent behavior was refusal to cooperate with other providers (74.2%). Disruptive behavior was attributed to workload by 35% of the respondents. CONCLUSION AND RECOMMENDATIONS: Disruptive physician behaviors are common in healthcare settings, with the most frequent behavior being refusal to cooperate with other providers. Training of physicians on team dynamics, communication skills, conflict management, and stress management is highly recommended. PMID- 27455086 TI - Hepatitis C virus in patients on regular hemodialysis in Beni-Suef Governorate, Egypt. AB - BACKGROUND: The prevalence of HCV infection among hemodialysis patients (HD) varies from country to country and from one center to another. Despite the existence of guidelines for a comprehensive infection control program, Egypt is one of the countries with high HCV prevalence. In Egypt, the prevalence of HCV in haemadalysis patients (2015) was 50.7%. OBJECTIVES: (1) To detect the prevalence of hepatitis C virus (HCV) infection and HCV seroconversion among all hemodialysis patients in Beni-Suef governorate, and (2) To detect factors associated with HCV seroconversion. MATERIALS AND METHODS: Multicenter retrospective medical records review design was conducted in 13 hemodialysis units in Beni-Suef governorate during May - June 2015; all ESRD (End stage renal disease) patients undergoing hemodialysis were included in the sample. A predesigned questionnaire was used. RESULTS: The prevalence of the HCV at begin of dialysis was 60.9% and the rate of HCV seroconversion was 9.7%. Univariate analysis confirmed that history of blood transfusion, the non-adherence to infection control guidelines, lack of isolation strategies and history of Shistosomiasis were significant risk factors for seroconversion. Meanwhile multivariate logistic regression analysis confirmed that history of blood transfusion, and history of shistosomiasis were significantly associated with HCV seroconversion. CONCLUSION: HCV infection still remains a predominant problem among patients on maintenance HD in Beni- Suef governorate History of blood transfusion and history of shistosomiasis were significant risk factors for acquiring HCV infection in these patients. PMID- 27455087 TI - Preventive and interceptive orthodontic needs among Syrian children. AB - BACKGROUND: Preventing or intercepting a developing malocclusion in a public health program requires identifying or measuring the degree of malocclusion. The present study aimed to quantify the proportion of Syrian children in Damascus who would benefit from preventive and interceptive orthodontic treatment. MATERIALS AND METHODS: In total, 1096 children (431 boys and 665 girls) of grade 1 up to grade 3 from 16 government elementary schools in Damascus city were evaluated using the index for preventive and interceptive orthodontic need (IPION). On the basis of IPION, the overall scores of children were distributed into three groups - no treatment need, moderate treatment need, and definite treatment need. According to dental development, children were divided into two groups - IPION-6 and IPION-9. RESULTS: Of the enrolled children, 15.4% showed no treatment need, 26.7% showed moderate treatment need, and 57.9% showed definite treatment need. Comparison between male and female children indicated no significant effect on the overall treatment need distribution (P=0.439). The IPION groups had a significant effect on treatment distribution (6 vs. 9, P=0.038); the IPION-9 scores were significantly higher than the IPION-6 scores. CONCLUSION AND RECOMMENDATIONS: The prevalence of preventive and interceptive orthodontic needs is unsatisfactorily high in Syrian children, which emphasizes the importance of including preventive and interceptive orthodontic treatment in the local dental healthcare program. PMID- 27455088 TI - 'There is a dependent patient in our home': designing and disseminating a family caregiving program through YouTube. AB - BACKGROUND: Family members play a major role in providing care for older people and long-term dependent patients, especially in developing countries where there is a lack of specialized nursing homes and specialized home-visiting programs. Family members are rarely provided with sufficient information or training to provide home care for their dependent relatives. There are inadequate home caregiving educational resources directed to Arabic-speaking caregivers, either in written or in audiovisual presentations. OBJECTIVES: The aims of the present study were (i) to present the process of designing a caregiving educational program entitled 'there is a dependent patient in our home', with an intention to be culturally and linguistically appropriate for a specific Arab-speaking population, and (ii) to present the experience of disseminating the program through YouTube, to be accessible for a wide range of caregivers. MATERIALS AND METHODS: The program was a product of a process involving seven phases, starting with a review of the literature and ending with disseminating 17 short 'caregiving' videos on YouTube, the most popular video-sharing website. The program presented necessary skills, instructions, and information that enabled caregivers to provide safe and competent daily caring activities for their functionally dependent relative or older adults at home. RESULTS: The program was registered in the Jordan National Library. After 2 months of broadcasting it on YouTube, the number of views exceeded 6800. Many constructive comments were received from caregivers. Language, simplicity, and attractiveness of the program were judged as the areas of satisfaction by the viewers, whereas lack of a few topics such as verbal communication with patients and dealing with daily caregivers' burden and stressors were the main reasons of dissatisfaction. CONCLUSION: This program was an endeavor to provide the Arabic library with a home caregiving resource. Adequate advertisement of the program would encourage health providers to search for and use the currently available social media as means of delivering educational services to family caregivers. PMID- 27455089 TI - Households encountering with catastrophic health expenditures in Ferdows, Iran: Retraction. PMID- 27455090 TI - Correction: Mindfulness Enhances Episodic Memory Performance: Evidence from a Multimethod Investigation. AB - [This corrects the article DOI: 10.1371/journal.pone.0153309.]. PMID- 27455091 TI - Hydrophobic Interactions Contribute to Conformational Stabilization of Endoglycoceramidase II by Mechanism-Based Probes. AB - Small compound active site interactors receive considerable attention for their ability to positively influence the fold of glycosidases. Endoglycoceramidase II (EGCII) from Rhodococcus sp. is an endo-beta-glucosidase releasing the complete glycan from ceramide in glycosphingolipids. Cleavage of the beta-glycosidic linkage between glucose and ceramide is also catalyzed by glucocerebrosidase (GBA), the exo-beta-glucosidase deficient in Gaucher disease. We demonstrate that established beta-glucoside-configured cyclophellitol-type activity-based probes (ABPs) for GBA also are effective, mechanism-based, and irreversible inhibitors of EGCII. The stability of EGCII is markedly enhanced by formation of covalent complexes with cyclophellitol ABPs substituted with hydrophobic moieties, as evidenced by an increased melting temperature, resistance against tryptic digestion, changes in (15)N-(1)H transverse relaxation optimized spectroscopy spectra of the [(15)N]Leu-labeled enzyme, and relative hydrophobicity as determined by 8-anilino-1-naphthalenesulfonic acid fluorescence. The stabilization of EGCII conformation correlates with the shape and hydrophobicity of the substituents of the ABPs. We conclude that the amphipathic active site binders with aliphatic moieties act as a "hydrophobic zipper" on the flexible EGCII protein structure. PMID- 27455092 TI - Anti-food and anti-microbial IgG subclass antibodies in inflammatory bowel disease. AB - OBJECTIVES: Inflammatory bowel disease (IBD), particularly Crohn's disease (CD), is associated with increased microbial-specific IgG and IgA antibodies, whereas alterations of anti-food antibodies are still disputed. The knowledge about IgG subclass antibodies in IBD is limited. In this study we analysed IgG subclass antibodies specific for nutritional and commensal antigens in IBD patients and controls. METHODS: Serum IgG1, IgG2, IgG3 and IgG4 specific for wheat and milk extracts, purified ovalbumin, Escherichia coli and Bacteroides fragilis lysates and mannan from Saccharomyces cerevisiae were analysed by ELISA in patients with CD (n = 56), ulcerative colitis (UC; n = 29), acute gastroenteritis/colitis (n = 12) as well as non-inflammatory controls (n = 62). RESULTS: Anti-Saccharomyces cerevisiae antibodies (ASCA) of all IgG subclasses and anti-B. fragilis IgG1 levels were increased in CD patients compared to UC patients and controls. The discriminant validity of ASCA IgG2 and IgG4 was comparable with that of ASCA pan IgG and IgA, whereas it was inferior for ASCA IgG1/IgG3 and anti-B. fragilis IgG1. Complicated CD defined by the presence of perianal, stricturing or penetrating disease phenotypes was associated with increased ASCA IgG1/IgG3/IgG4, anti-B. fragilis IgG1 and anti-E. coli IgG1 levels. Anti-food IgG subclass levels were not different between IBD patients and controls and did not correlate with food intolerance. In contrast to anti-microbial Abs, food-specific IgG responses were predominately of the IgG4 isotype and all food-specific IgG subclass levels correlated negatively with age. CONCLUSION: Our study supports the notion that the adaptive immune recognition of food and commensal antigens are differentially regulated. PMID- 27455093 TI - Mutation-based selection and analysis of Komagataeibacter hansenii HDM1-3 for improvement in bacterial cellulose production. AB - AIMS: A low yield of bacterial cellulose (BC) always results from an excessive accumulation of organic acids. Screening and the selection of bacterial mutants with a low accumulation of organic acids is an efficient approach for improving BC production. METHODS AND RESULTS: In combination with the proton suicide method (medium containing NaBr-NaBrO3 ), diethyl sulphate chemical mutagenesis coupled with 60 Co-gamma irradiation treatment were performed for the screening and selection of desired mutant lines with a high yield of BC. Two high-yield strains, Br-3 and Co-5, as well as a low-yield strain, Br-12, were obtained. Amplified fragment length polymorphism (AFLP) was applied to explore the differences between the mutant lines and the wild type. For the Br-12 line, three specific fragments were verified, corresponding to TonB-dependent transport (TBDT), exopolysaccharides output protein (PePr) and an unknown gene. For Co-5, two specific fragments were matched, acsD and UDP-galactose-4-epimerase. In addition, metabolic analysis for the mutant lines indicated that BC production may be limited by excessive accumulation of organic acids in the fermentation. The limitation would be resolved by the cross-talk of genes involved in BC biosynthesis. CONCLUSIONS: Reduced organic acid by-products from glucose in bypasses were found to be responsible for the high-yield BC synthesis in Komagataeibacter hansenii mutant strains. SIGNIFICANCE AND IMPACT OF THE STUDY: The metabolic process was varied by mutagenesis-induced gene disruption of the metabolic products. A new idea was provided for the targeted screening and characterization of mutants in the future. PMID- 27455095 TI - Camel milk and bee honey regulate profibrotic cytokine gene transcripts in liver cirrhosis induced by carbon tetrachloride. AB - The lack of studies regarding the mechanism of the protective effects of camel milk and bee honey against hepatotoxic compounds led us to perform this study. Thirty-six male rats were divided into two main groups. The first group (n = 9) comprised control non-cirrhotic rats. The rats of the second group (n = 27) were administered carbon tetrachloride (CCl4) by intraperitoneal injection to induce liver cirrhosis. The cirrhotic rats were then divided into three equal subgroups, each comprising nine animals, as follows: (i) cirrhotic rats, (ii) cirrhotic rats treated with camel milk, and (iii) cirrhotic rats treated with camel milk and bee honey. The present findings revealed that CCl4 elevated the activities of liver enzymes, blood glucose levels, non-esterified fatty acids (NEFA) in the serum and glycogen content in the liver. On the other hand, CCl4 significantly decreased phosphorylase activity in the liver tissue and significantly increased carbohydrate intolerance and insulin resistance index (HOMA-IR). Moreover, CCl4 induced a significant increase in oxidative stress, along with increased expression of the profibrotic cytokine genes TNF-alpha and TGF-beta. However, camel milk either alone or in combination with bee honey ameliorated these toxic actions. The antioxidant properties of these protective agents and their effects of downregulating certain procirrhotic cytokine gene transcripts underlie this protection. PMID- 27455094 TI - Somatostatin Receptor Expression in GH-Secreting Pituitary Adenomas Treated with Long-Acting Somatostatin Analogues in Combination with Pegvisomant. AB - BACKGROUND: Growth hormone-secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also downregulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. AIM OF THE STUDY: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve insulin-like growth factor I (IGF I) normalization in relation to the SSTR expression. MATERIALS AND METHODS: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenoma tissues was determined using immunohistochemistry. RESULTS: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pretreatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization during postsurgical medical treatment (rho = -0.538, p = 0.024). CONCLUSION: In our specific cohort, the SSTR2 expression was lower in patients pretreated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment-naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization. PMID- 27455097 TI - Lifestyle Medicine: A New Paradigm Embedded in Osteopathic Principles. PMID- 27455096 TI - Selective Factors Associated with the Evolution of Codon Usage in Natural Populations of Arboviruses. AB - Arboviruses (arthropod borne viruses) have life cycles that include both vertebrate and invertebrate hosts with substantial differences in vector and host specificity between different viruses. Most arboviruses utilize RNA for their genetic material and are completely dependent on host tRNAs for their translation, suggesting that virus codon usage could be a target for selection. In the current study we analyzed the relative synonymous codon usage (RSCU) patterns of 26 arboviruses together with 25 vectors and hosts, including 8 vertebrates and 17 invertebrates. We used hierarchical cluster analysis (HCA) and principal component analysis (PCA) to identify trends in codon usage. HCA demonstrated that the RSCU of arboviruses reflects that of their natural hosts, but not that of dead-end hosts. Of the two major components identified by PCA, the first accounted for 62.1% of the total variance, and among the 59 codons analyzed in this study, the leucine codon CTG had the highest correlation with the first principal component, however isoleucine had the highest correlation during amino acid analysis. Nucleotide and dinucleotide composition were the variables that explained most of the total codon usage variance. The results suggest that the main factors driving the evolution of codon usage in arboviruses is based on the nucleotide and dinucleotide composition present in the host. Comparing codon usage of arboviruses and potential vector hosts can help identifying potential vectors for emerging arboviruses. PMID- 27455098 TI - Correction. PMID- 27455099 TI - Efficacy of Osteopathic Manipulative Treatment for Management of Postpartum Pain. AB - CONTEXT: Pain is one of the most common postpartum complaints by women in the United States, and the pain varies in its location. Research on intervention strategies for postpartum pain has focused primarily on the lower back, but pain management for other types of postpartum pain remains unclear. OBJECTIVE: To investigate the effects of osteopathic manipulative treatment (OMT) on postpartum pain; the location, quality, and timing of pain; and the difference in pain between vaginal and cesarean delivery. METHODS: Postpartum patients who reported having pain were recruited at St Barnabas Hospital in Bronx, New York. The short form McGill Pain Questionnaire was administered along with a screening questionnaire. Second- or third-year residents in neuromusculoskeletal medicine and osteopathic manipulative medicine examined patients and then diagnosed and managed somatic dysfunction with OMT for approximately 25 minutes. The short-form McGill Pain Questionnaire was again administered after OMT. Paired t tests and McNemar tests were used to analyze changes before and after OMT for continuous and categorical variables, respectively. Differences in visual analog scale (VAS) pain scores between patients who had vaginal vs cesarean delivery were tested using analysis of variance, and group differences in pain location were tested using a Pearson chi2 test. RESULTS: A total of 59 patients were included in the study. The mean VAS score for pain was 5.0 before OMT and 2.9 after OMT (P<.001). The VAS scores before OMT significantly differed between patients who had a vaginal delivery and those who had a cesarean delivery (P<.001), but the mean decrease in VAS score was similar in both groups. Decreases in low back pain (34 [57.6%] before and 16 [27.1%] after OMT), abdominal pain (32 [54.2%] before and 22 [37.3%] after OMT), and vaginal pain (11 [18.6%] before and 5 [8.5%] after OMT) were reported after OMT (P<.05). CONCLUSION: Preliminary results demonstrate that OMT is efficacious for postpartum pain management. The lack of a control group precludes the ability to make causal claims. Future studies are needed to solidify OMT efficacy and generalizability. PMID- 27455100 TI - Self-Reported Minimalist Running Injury Incidence and Severity: A Pilot Study. AB - INTRODUCTION: Minimalist running entails using shoes with a flexible thin sole and is popular in the United States. Existing literature disagrees over whether minimalist running shoes (MRS) improve perceived severity of injuries associated with running in traditional running shoes (TRS). Additionally, the perceived injury patterns associated with MRS are relatively unknown. OBJECTIVES: To examine whether injury incidence and severity (ie, degree of pain) by body region change after switching to MRS, and to determine if transition times affect injury incidences or severity with MRS. METHODS: Runners who were either current or previous users of MRS were recruited to complete an Internet-based survey regarding self-reported injury before switching to MRS and whether self-reported pain from that injury decreased after switching. Questions regarding whether new injuries developed in respondents after switching to MRS were also included. Analyses were calculated using t tests, Wilcoxon signed rank tests, and Fischer exact tests. RESULTS: Forty-seven runners completed the survey, and 16 respondents reported injuries before switching to MRS. Among these respondents, pain resulting from injuries of the feet (P=.03) and knees (P=.01) decreased. Eighteen respondents (38.3%) indicated they sustained new injuries after switching to MRS, but the severity of these did not differ significantly from no injury. Neither time allowed for transition to MRS nor use or disuse of a stretching routine during this period was correlated with an increase in the incidence or severity of injuries. CONCLUSION: After switching to MRS, respondents perceived an improvement in foot and knee injuries. Additionally, respondents using MRS reported an injury rate of 38.3%, compared with the approximately 64% that the literature reports among TRS users. Future studies should be expanded to determine the full extent of the differences in injury patterns between MRS and TRS. PMID- 27455101 TI - Ophthalmic Diseases in Patients With Obstructive Sleep Apnea. AB - Symptomatic obstructive sleep apnea (OSA) affects 2% of women and 4% of men, but the prevalence of asymptomatic OSA is significantly higher. Several ophthalmic conditions are associated with OSA, including floppy eyelid syndrome, glaucoma, nonarteritic anterior ischemic optic neuropathy, papilledema, keratoconus, and central serous chorioretinopathy. The purpose of this review is to provide primary care physicians with a general knowledge of the signs, symptoms, and management of the ophthalmic diseases associated with OSA. PMID- 27455102 TI - Correlation Between Scores on Weekly Quizzes and Performance on the Annual Resident In-Service Examination. AB - CONTEXT: Medical residency education relies heavily on the use of written and oral testing as a means of assessing a learner's knowledge acquisition. In the United States, osteopathic emergency medicine residents take an annual specialty based resident in-service examination (RISE) for this purpose. Their performance on the RISE helps direct educators' approach to teaching and training. OBJECTIVES: To determine the correlative strength of residents' cumulative performance on a series of weekly in-house quizzes with their performance on the RISE. METHODS: In this prospective study, emergency medicine residents took a series of 15 quizzes between August 2013 and January 2014. The quizzes were administered using slides integrated with an audience-response system. Quizzes comprised questions gathered from various question banks and commercial test review resources specific to the specialty of emergency medicine. Effort was made to select questions covering topics tested on the RISE. Scores from each of the quizzes were recorded, and these data were analyzed for correlation with residents' scores on the RISE. RESULTS: Sixteen emergency medicine residents from all 4 postgraduate years participated in the study. For various reasons (vacation, illness, away rotations), not all 16 residents participated in each quiz. The mean participation rate over all 15 quizzes was 76.7%, with a mean quiz score of 57.8%. A correlation analysis was conducted between the achieved RISE score and the mean quiz score (excluding any quizzes not taken). Graphical analysis revealed a sufficiently linear relationship between the 2 variables, with no outliers. Both variables were normally distributed, as assessed by the Shapiro-Wilks test (P>.05). A strong positive correlation was found between RISE score and mean quiz score (r[14]=0.75; P=.001), with the mean quiz score over the quizzes taken explaining about 57% of the variance in the achieved RISE score. CONCLUSIONS: The results of this study imply that performance on weekly didactic quizzes may be strongly predictive of RISE performance and as such tracking these data may provide insight to educators and learners as to the most effective direction of their educational efforts. PMID- 27455103 TI - American Osteopathic Association Guidelines for Osteopathic Manipulative Treatment (OMT) for Patients With Low Back Pain. AB - BACKGROUND: Osteopathic manipulative treatment (OMT) is a distinctive modality commonly used by osteopathic physicians to complement conventional management of musculoskeletal disorders, including those that cause low back pain (LBP). Osteopathic manipulative treatment is defined in the Glossary of Osteopathic Terminology as "The therapeutic application of manually guided forces by an osteopathic physician (U.S. Usage) to improve physiologic function and/or support homeostasis that has been altered by somatic dysfunction. OMT employs a variety of techniques" (eAppendix). Somatic dysfunction is defined as "Impaired or altered function of related components of the somatic (body framework) system: skeletal, arthrodial and myofascial structures, and their related vascular, lymphatic, and neural elements. Somatic dysfunction is treatable using osteopathic manipulative treatment." These guidelines update the AOA guidelines for osteopathic physicians to utilize OMT for patients with nonspecific acute or chronic LBP published in 2010 on the National Guideline Clearinghouse.1 METHODS: This update process commenced with literature searches that included electronic databases, personal contact with key researchers of OMT and low back pain, and Internet search engines. Early in the process, the Task Force on the Low Back Pain Clinical Practice Guidelines discovered the 2014 systematic literature review conducted by Franke et al2; this study serves as the basis for this updated guideline and further builds upon the literature used to support the previous guidelines. Findings from other eligible studies published after the search parameters of the Franke et al systematic review were also incorporated. RESULTS: The authors of the systematic review identified 307 studies. Thirty-one were evaluated and 16 were excluded. Of the 15 studies included in the review, 6 were retrieved from Germany, 5 from the United States, 2 from the United Kingdom, and 2 from Italy. Two additional studies published after the Franke et al review were also included. Osteopathic manipulative treatment significantly reduces pain and improves functional status in patients, including pregnant and postpartum women, with nonspecific acute and chronic LBP. Franke et al found that in acute and chronic nonspecific LBP, moderate-quality evidence suggested that OMT had a significant effect on pain relief (mean difference [MD], -12.91; 95% CI, -20.00 to -5.82) and functional status (standard mean difference [SMD], -0.36; 95% CI, 0.58 to -0.14). More specifically, in chronic nonspecific LBP, the evidence suggested a significant difference in favor of OMT regarding pain (MD, -14.93; 95% CI, -25.18 to -4.68) and functional status (SMD, -0.32; 95% CI, -0.58 to 0.07). When examining nonspecific LBP in pregnancy, low-quality evidence suggested a significant difference in favor of OMT for pain (MD, -23.01; 95% CI, 44.13 to -1.88) and functional status (SMD, -0.80; 95% CI, -1.36 to -0.23). Conversely for nonspecific LBP postpartum, Franke et al found that moderate quality evidence suggested a significant difference in favor of OMT for pain (MD, -41.85; 95% CI, -49.43 to -34.27) and functional status (SMD, -1.78; 95% CI, 2.21 to -1.35).2 CONCLUSION: The conclusions of Franke et al further strengthen the findings that OMT reduces LBP. In a 2005 systematic review conducted by Licciardone et al3 and the basis of the LBP guidelines published in 2010, it was determined that OMT reduces pain more than expected from placebo effects alone, and these results had the potential to last beyond the first year of treatment. Franke et al specifically stated that clinically relevant effects of OMT were found for reducing pain and improving functional status in patients with acute and chronic nonspecific LBP and for LBP in pregnant and postpartum women 3 months after treatment. Larger randomized controlled trials with robust comparison groups are needed to further validate the effects of OMT on LBP. In addition, more research is needed to understand the mechanics of OMT and its short- and long-term effects, as well as the cost-effectiveness of such treatment. PMID- 27455104 TI - Mistaken Lower Extremity Dermatitis. PMID- 27455105 TI - Rash in a Returning Traveler. PMID- 27455106 TI - Medical Noncompliance: The Most Ignored National Epidemic. PMID- 27455107 TI - A Rare Case of MALT Lymphoma Underlying Ileocecal Intussusception. AB - Intussusception is an extremely rare diagnosis in adults, with an etiologic process identified in the majority of cases. The authors describe an unusual case of mucosa-associated lymphoid tissue (MALT) lymphoma as the underlying cause of ileocecal intussusception in an elderly woman. The patient presented with complaints of abdominal pain of variable intensity that had increased in severity over the past several months. A contrast-enhanced computed tomographic scan revealed evidence of ileocecal intussusception, and a subsequent exploratory laparotomy revealed high-grade bowel obstruction. Early recognition of intussusception is critical to appropriate management and resolution. PMID- 27455108 TI - Applying GIS and Machine Learning Methods to Twitter Data for Multiscale Surveillance of Influenza. AB - Traditional methods for monitoring influenza are haphazard and lack fine-grained details regarding the spatial and temporal dynamics of outbreaks. Twitter gives researchers and public health officials an opportunity to examine the spread of influenza in real-time and at multiple geographical scales. In this paper, we introduce an improved framework for monitoring influenza outbreaks using the social media platform Twitter. Relying upon techniques from geographic information science (GIS) and data mining, Twitter messages were collected, filtered, and analyzed for the thirty most populated cities in the United States during the 2013-2014 flu season. The results of this procedure are compared with national, regional, and local flu outbreak reports, revealing a statistically significant correlation between the two data sources. The main contribution of this paper is to introduce a comprehensive data mining process that enhances previous attempts to accurately identify tweets related to influenza. Additionally, geographical information systems allow us to target, filter, and normalize Twitter messages. PMID- 27455109 TI - Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. AB - We identified mRNA encoding the ecto-enzyme Enpp6 as a marker of newly forming oligodendrocytes, and used Enpp6 in situ hybridization to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Within just 2.5 h of exposure to the complex wheel, production of Enpp6-expressing immature oligodendrocytes was accelerated in subcortical white matter; within 4 h, it was accelerated in motor cortex. Conditional deletion of myelin regulatory factor (Myrf) in oligodendrocyte precursors blocked formation of new Enpp6(+) oligodendrocytes and impaired learning within the same ~2-3 h time frame. This very early requirement for oligodendrocytes suggests a direct and active role in learning, closely linked to synaptic strengthening. Running performance of normal mice continued to improve over the following week accompanied by secondary waves of oligodendrocyte precursor proliferation and differentiation. We concluded that new oligodendrocytes contribute to both early and late stages of motor skill learning. PMID- 27455111 TI - Spontaneous bilateral renal aneurysm rupture secondary to Polyarteritis Nodosa in a patient with chronic myelomonocytic leukaemia: A case report study. AB - INTRODUCTION: Polyarteritis Nodosa (PAN) is a systemic vasculitis affecting small and medium size arteries resulting in microaneurysms formation. Bilateral renal aneurysm rupture is a rare and life threatening complication. Although uncommon, PAN has been associated with chronic myelomonocytic leukaemia (CMML). PRESENTATION OF CASE: We report a case of a 77-year-old female with a known CMML, presented to hospital with abdominal pain. Left initially and right renal microaneurym ruptures were shown in CT scan within one-week interval. Microaneurysms were treated with embolization with microcoils. A diagnosis of PAN was made and treated with successful outcome with steroids, cyclophosphamide. CONCLUSION: Spontaneous bilateral renal haemorrhage as the initial manifestation of PAN in association with CMML is a rare condition and it can be associated in delays in diagnosis and treatment. Clinicians should be aware of this possible complication in their daily clinical practice. PMID- 27455110 TI - The coding of cutaneous temperature in the spinal cord. AB - The spinal cord is the initial stage that integrates temperature information from peripheral inputs. Here we used molecular genetics and in vivo calcium imaging to investigate the coding of cutaneous temperature in the spinal cord in mice. We found that heating or cooling the skin evoked robust calcium responses in spinal neurons, and their activation threshold temperatures distributed smoothly over the entire range of stimulation temperatures. Once activated, heat-responding neurons encoded the absolute skin temperature without adaptation and received major inputs from transient receptor potential (TRP) channel V1 (TRPV1)-positive dorsal root ganglion (DRG) neurons. By contrast, cold-responding neurons rapidly adapted to ambient temperature and selectively encoded temperature changes. These neurons received TRP channel M8 (TRPM8)-positive DRG inputs as well as novel TRPV1(+) DRG inputs that were selectively activated by intense cooling. Our results provide a comprehensive examination of the temperature representation in the spinal cord and reveal fundamental differences in the coding of heat and cold. PMID- 27455113 TI - Massive and life-threatening upper gastrointestinal bleeding due to invasive hepatocellular carcinoma: A case report. AB - BACKGROUND: The mean survival is less than 6 months in hepatocellular carcinoma (HCC) patients with extrahepatic metastasis. Gastrointestinal(GI) bleeding frequency due to HCC invasion is 0.05% to 2.0%, and may be fatal. CASE PRESENTATION: We encountered a case of HCC with direct invasion to the gastrium that caused a life-threatening upper GI bleeding. Our patient was a 62 year old male who was a heavy smoker and drinker for almost 30 years. He had several upper GI bleeding episodes during the previous 6 months. Computed tomography (CT) revealed a 13cm liver tumour directly invading the gastrium. Partial hepatic resection and subtotal gastrectomy were performed. Unfortunately, the patient died at the intensive care unit postoperatively due to hepatic failure. DISCUSSION: Although the prognosis of HCC that has invaded the gastrium is very poor due to the advanced stage of the disease, surgical resection may be a favourable treatment option for patients with a massive upper GI bleeding. CONCLUSIONS: The incidence of patients with massive bleeding due to gastric invasion of HCC is low, and only a few cases have been reported in the literature. Our purpose while presenting this rare case is to increase the awareness about the issue. PMID- 27455112 TI - A belly of blood: A case report describing surgical intervention in a gastric intramural haematoma precipitated by therapeutic endoscopy in an anticoagulated patient. AB - Gastric intramural hematoma, "intramural dissection" or "false aneurysm", is a rare and dangerous condition which may be more broadly classified as a spectrum of acute gastric mucosal injury. It is postulated that disruption of the mucosa and blood vessels within the submucosal layer results in dissection of the muscularis propria from the mucosa, with eventual clot formation. While a majority of cases resolve with conservative management, we describe a successfully managed case requiring surgical intervention. Progression of the haematoma was documented both endoscopically and surgically in an elderly anticoagulated patient who suffered a complication of therapeutic endoscopic intervention. A review of the literature is presented. PMID- 27455116 TI - Treatment of Fluorosis Spots Using a Resin Infiltration Technique: 14-month Follow-up. AB - The aim of this study was to report a clinical case of moderate fluorosis spots treated with infiltration of low-viscosity resin. A commercial resin was applied to the facial surfaces on the anterior teeth in both the maxillary and mandibular arches. The white spots of fluorosis lost their whitish appearance and appeared similar to sound enamel. This technique, which might constitute an alternative to white-masking of fluorosis spots, showed optimal esthetic results. PMID- 27455114 TI - Protocolized Treatment Is Associated With Decreased Organ Dysfunction in Pediatric Severe Sepsis. AB - OBJECTIVES: To determine whether treatment with a protocolized sepsis guideline in the emergency department was associated with a lower burden of organ dysfunction by hospital day 2 compared to nonprotocolized usual care in pediatric patients with severe sepsis. DESIGN: Retrospective cohort study. SETTING: Tertiary care children's hospital from January 1, 2012, to March 31, 2014. SUBJECTS: Patients older than 56 days old and younger than 18 years old with international consensus defined severe sepsis and who required PICU admission within 24 hours of emergency department arrival were included. MEASUREMENTS AND MAIN RESULTS: The exposure was the use of a protocolized emergency department sepsis guideline. The primary outcome was complete resolution of organ dysfunction by hospital day 2. One hundred eighty nine subjects were identified during the study period. Of these, 121 (64%) were treated with the protocolized emergency department guideline and 68 were not. There were no significant differences between the groups in age, sex, race, number of comorbid conditions, emergency department triage level, or organ dysfunction on arrival to the emergency department. Patients treated with protocolized emergency department care were more likely to be free of organ dysfunction on hospital day 2 after controlling for sex, comorbid condition, indwelling central venous catheter, Pediatric Index of Mortality-2 score, and timing of antibiotics and IV fluids (adjusted odds ratio, 4.2; 95% CI, 1.7-10.4). CONCLUSIONS: Use of a protocolized emergency department sepsis guideline was independently associated with resolution of organ dysfunction by hospital day 2 compared to nonprotocolized usual care. These data indicate that morbidity outcomes in children can be improved with the use of protocolized care. PMID- 27455117 TI - Ceramic Inlays: Effect of Mechanical Cycling and Ceramic Type on Restoration dentin Bond Strength. AB - This study aimed to evaluate the bond strength between dentin and five different ceramic inlays in permanent maxillary premolars, with and without mechanical cycling. One hundred permanent maxillary premolars were prepared and divided into 10 groups (n=10) according to the ceramic system (IPS e.Max Press; IPS e.Max CAD; Vita PM9; Vita Mark II; and Vita VM7) and the mechanical cycling factor (with and without [100 N, 2 Hz, 1.2*10(6) cycles]). The inlays were adhesively cemented, and all of the specimens were cut into microbars (1*1 mm, nontrimming method), which were tested under microtensile loading. The failure mode was classified and contact angle, roughness, and microtopographic analyses were performed on each ceramic surface. The mechanical cycling had a significant effect (p=0.0087) on the bond strength between dentin and IPS e.max Press. The Vita Mark II group had the highest bond strength values under both conditions, with mechanical cycling (9.7+/-1.8 MPa) and without (8.2+/-1.9 MPa), while IPS e.Max CAD had the lowest values (2.6+/-1.6 and 2.2+/-1.4, respectively). The adhesive failure mode at the ceramic/cement interface was the most frequent. Vita Mark II showed the highest value of average roughness. IPS e.max Press and Vita Mark II ceramics presented the lowest contact angles. In conclusion, the composition and manufacturing process of ceramics seem to have an influence on the ceramic surface and resin cement bond strength. Mechanical cycling did not cause significant degradation on the dentin and ceramic bond strength under the configuration used. PMID- 27455118 TI - Delayed Light Activation Improves Color Stability of Dual-Cured Resin Cements. AB - PURPOSE: To evaluate the color change caused by post-irradiation conversion (DeltaE24h and DeltaE8 days ) and artificial aging (DeltaEAGING ) of resin cements light activated through ceramics of different opacities immediately and 6 minutes after manipulating the material. MATERIALS AND METHODS: Resin cement disks (Allcem and LuxaCore) were light activated through ceramics (without ceramic, e.max HT, LT, and MO) immediately and 6 minutes after the manipulation (n = 10). Spectrophotometry was used to evaluate DeltaE24h and DeltaE8 days after 37C-dry-dark-storage for 24 hours and 8 days, and DeltaEAGING after 60C-water storage for 24 hours. Data were analyzed with three-way ANOVA and Tukey's HSD (alpha = 0.05). RESULTS: Regarding the post-irradiation color change, significant differences were found between the cements (p < 0.0001), light activation protocols (p = 0.037), and ceramics (p < 0.001). The immediate activation (16.2 +/- 0.1) showed lower DeltaE values than the delayed activation (16.5 +/- 0.1). Ceramics influenced the DeltaE values as follows: MO (14.0 +/- 1.2) < LT (14.9 +/ 1.2) ~ HT (15.4 +/- 1.2) < control (21.2 +/- 1.2). Regarding DeltaEAGING , significant differences were found between cements (p < 0.001), light activation (p = 0.006), and ceramics (p < 0.001). The delayed activation (8.4 +/- 0.1) showed lower values than the immediate activation (8.9 +/- 0.1). Ceramic spacers influenced DeltaEAGING as follows: control (5.6 +/- 0.2) < MO (6.6 +/- 0.2) < HT (11.0 +/- 0.2) ~ LT (11.5 +/- 0.2). CONCLUSION: The delayed light activation resulted in increased color stability, while the ceramic interposition resulted in lower color stability. PMID- 27455119 TI - Unknown primary adenocarcinomas: a single-center experience. AB - This study aimed to elucidate the clinical and prognostic characteristics of a homogeneous group of patients with cancer of unknown primary (CUP). Between 1999 and 2014, CUP was diagnosed in 159 (1.3%) of 11,742 cancer patients at Trakya University Hospital (Edirne, Turkey). Ninety-seven (61%) of the 159 patients were retrospectively reviewed. Among these, 61 (62.8%) patients with adenocarcinoma were included in this study. The most frequently predicted primary tumor site was the lung (37.7%), and 59% of the patients were smokers. There was a significant relationship between smoking and the lung as a potential primary cancer site (p = 0.042). The most frequent site of metastasis was the liver (60.7%). The median number of metastases per patient was two, but patients with liver metastases had a median of five metastases. The overall median survival time was 7 months. Median survival was significantly longer in patients with a predicted primary site than in patients without the predicted site (7 vs. 6 months, respectively; p = 0.038). When the patients with predicted ovarian and peritoneal tumors were excluded from the comparison, the statistical p value was still close to significant (p = 0.07). Multivariate analysis revealed that smoking, liver metastasis, serum alkaline phosphatase >=92 U/L, and progression in response to chemotherapy were independent predictors of a poor prognosis. The present study identified several independent prognostic factors in patients with unknown primary adenocarcinomas who received chemotherapy. Smoking, the presence of liver metastasis, and response to chemotherapy were independent risk factors for both progression-free and overall survival. PMID- 27455120 TI - Is giving or receiving psychologically beneficial to older mothers in South Korea? Importance of marital status. AB - In order to understand intergenerational financial transfers and subjective well being for older mothers, this study argues that marital status is an important factor to be considered. Using the first wave of the Korean Longitudinal Study of Aging (KLoSA), this study finds that married older mothers report higher levels of life satisfaction when they provide economic support but widowed older mothers feel higher levels of life satisfaction when they receive economic support. Also, regular or irregular financial support appears to also matter in the associations between financial support and life satisfaction. These findings suggest that married and widowed older mothers have different viewpoints about the parent children relationship. PMID- 27455121 TI - Reducing false arrhythmia alarms in the ICU using multimodal signals and robust QRS detection. AB - This study developed algorithms to decrease the arrhythmia false alarms in the ICU by processing multimodal signals of photoplethysmography (PPG), arterial blood pressure (ABP), and two ECG signals. The goal was to detect the five critical arrhythmias comprising asystole (ASY), extreme bradycardia (EBR), extreme tachycardia (ETC), ventricular tachycardia (VTA), and ventricular flutter or fibrillation (VFB). The different characteristics of the arrhythmias suggested the application of individual signal processing for each alarm and the combination of the algorithms to enhance false alarm detection. Thus, different features and signal processing techniques were used for each arrhythmia type. The ECG signals were first processed to reduce the signal interference. Then, a Hilbert-transform based QRS detector algorithm was utilized to identify the QRS complexes, which were then processed to determine the instantaneous heart rate. The pulsatile signals (PPG and ABP) were processed to discover the pulse onset of beats which were then employed to measure the heart rate. The signal quality index (SQI) of the signals was implemented to verify the integrity of the heart rate information. The overall score obtained by our algorithms in the 2015 Computing in Cardiology Challenge was a score of 74.03% for retrospective and 69.92% for real-time analysis. PMID- 27455122 TI - For Diabetes Shared Savings Programs, 1 Year of Data Is Not Enough. AB - Fee-for-service payment models are moving toward pay-for-performance designs, many of which rely on shared savings for financial sustainability. Shared savings programs divide the cost savings between health care purchaser and provider based on provider performance. Often, these programs measure provider performance as the delivery of agreed-upon clinical practice guidelines that usually are represented as evidence-based medicine (EBM). Multiyear studies show a negative relationship between total cost and EBM, indicating that long-term shared savings can be substantial. This study explores expectations for the rewards in the first year of a shared savings program. It also indicates the effectiveness of using 1 year of claims to assess cost savings from evidence-based care, especially in a patient population with high turnover. This study analyzed 1956 adults with diabetes insured through Medicaid. Results of linear regression showed that the relationship between total cost of care and each element of evidence-based medical care during a 1-year period was positive (higher cost) or insignificant. The results indicate that diabetes EBM programs cannot expect to see significant cost savings if the evaluation lasts only 1 year or less. The study concludes that improvements in EBM incentive programs could come from investigating the length of time needed to realize cost savings from each element of diabetes EBM. Investigating other factors that could affect the expected amount of cost savings also would benefit these programs, especially factors derived from sources external to insurance program information such as the medical record and care management data. PMID- 27455123 TI - Prebiotic-Like Condensations of Cyanamide and Glyoxal: Revisiting Intractable Biotars. AB - We report a detailed investigation into the nature of products that are generated by the reactions of cyanamide and glyoxal, two small molecules of astrochemical and prebiotic significance, under different experimental conditions. The experimental data suggest that the formation of oligomeric structures is related in part to the formation of insoluble tholins in the presence of oxygen containing molecules. Although oligomerization proceeds well in water, product isolation turned out to be impractical. Instead, solid precipitates were obtained easily in acetone. Crude mixtures have been thoroughly scrutinized by spectroscopic methods, in particular NMR and mass spectroscopy (ESI mode), which are all consistent with the generation of a few functional groups that are embedded into regular chains of five- and six-membered rings, thereby pointing to a supramolecular organization. Three different models of cross-condensation and chain growth are suggested. These synthetic explorations provide further insights into the formation of complex organic matter in interstellar scenarios and extraterrestrial bodies that might have played a pivotal role in chemical evolution. PMID- 27455124 TI - Water in Carbon Nanotubes: The Peculiar Hydrogen Bond Network Revealed by Infrared Spectroscopy. AB - A groundbreaking discovery in nanofluidics was the observation of the tremendously enhanced water permeability of carbon nanotubes, those iconic objects of nanosciences. The origin of this phenomenon is still a subject of controversy. One of the proposed explanations involves dramatic modifications of the H-bond network of nanoconfined water with respect to that of bulk water. Infrared spectroscopy is an ideal technique to follow modifications of this network through the inter- and intramolecular bonds of water molecules. Here we report the first infrared study of water uptake at controlled vapor pressure in single walled carbon nanotubes with diameters ranging from 0.7 to 2.1 nm. It reveals a predominant contribution of loose H bonds even for fully hydrated states, irrespective of the nanotube size. Our results show that, while the dominating loosely bond signature is attributed to a one-dimensional chain structure for small diameter nanotubes, this feature also results from a water layer with "free" OH (dangling) bonds facing the nanotube wall for larger diameter nanotubes. These experimental findings provide a solid reference for further modeling of water behavior in hydrophobic nanochannels. PMID- 27455126 TI - Photosynthetic membrane-less microbial fuel cells to enhance microalgal biomass concentration. AB - The aim of this study was to quantitatively assess the net increase in microalgal biomass concentration induced by photosynthetic microbial fuel cells (PMFC). The experiment was conducted on six lab-scale PMFC constituted by an anodic chamber simulating an anaerobic digester connected to a cathodic chamber consisting of a mixed algae consortia culture. Three PMFC were operated at closed circuit (PMFC(+)) whereas three PMFC were left unconnected as control (PMFC(-)). PMFC(+) produced a higher amount of carbon dioxide as a product of the organic matter oxidation that resulted in 1.5-3 times higher biomass concentration at the cathode compartment when compared to PMFC(-). PMID- 27455125 TI - The effect of harvest time, dry matter content and mechanical pretreatments on anaerobic digestion and enzymatic hydrolysis of miscanthus. AB - Miscanthus x giganteus was harvested as both green and mature biomass and the dry matter content of the driest harvest was artificially decreased by adding water in two subsamples, giving a total of five dry matter contents. All five biomass types were mechanically pretreated by roller-milling, extrusion or grinding and accumulated methane production and enzymatically-accessible sugars were measured. Accumulated methane production was studied using sigmoid curves that allowed comparison among the treatments of the rate of the methane production and ultimate methane yield. The green biomass gave the highest methane yield and highest levels of enzymatically-accessible cellulose. The driest biomass gave the best effect from extrusion but with the highest energy consumption, whereas roller-milling was most efficient on wet biomass. The addition of water to the last harvest improved the effect of roller-milling and equalled extrusion of the samples in efficiency. PMID- 27455127 TI - Reductive Transformation of p-chloronitrobenzene in the upflow anaerobic sludge blanket reactor coupled with microbial electrolysis cell: performance and microbial community. AB - A microbial electrolysis cell (MEC) combined with an upflow anaerobic sludge blanket (UASB) reactor was operated to degrade p-chloronitrobenzenes (p-ClNB) effectively. The results indicated that p-ClNB was transformed to p-chloroaniline (p-ClAn) and then reduced via dechlorination pathways. In the MEC-UASB coupled system, p-ClNB, p-ClAn removal efficiency and dechlorination efficiency reached 99.63+/-0.37%, 40.39+/-9.26% and 32.16+/-8.12%, respectively, which was significantly improved in comparison with the control UASB system. In addition, the coupled system could maintain appropriate pH and promote anaerobic sludge granulation to exert a positive effect on reductive transformation of p-ClNB. PCR DGGE experiment and 454 pyrophosphate sequencing analysis indicated that applied voltage would significantly influence the succession of microbial community and promote oriented enrichment of the functional bacteria, which could be the underlying reasons for the improved performance. This study demonstrated that MEC UASB coupled system had a promising application prospect to remove the recalcitrant pollutants effectively. PMID- 27455128 TI - Thermal degradations of wood biofuels, coals and hydrolysis lignin from the Russian Federation: Experiments and modeling. AB - The thermal degradation of wood biofuels (spruce, pine), of coals from different fields of the Russian Federation and of hydrolysis lignin is investigated using a thermogravimetric analyzer under different heating conditions and under non oxidative or oxidative atmospheres. The samples are indeed submitted to a linear temperature ramp of 10K/min or to a temperature ramp of 200K/min up to a residence temperature between 250 and 450 degrees C where they are maintained during 4h (isothermal conditions). The values of the kinetic parameters are determined for these different samples in both thermal conditions, either using the differential isoconversional method or by means of an Extended Independent Parallel Reaction (EIPR) model. The values of the kinetic parameters obtained with this EIPR model for spruce trunk are also compared with that of its main constituents (hemicellulose, cellulose and lignin). PMID- 27455129 TI - Muscle coordination, activation and kinematics of world-class and elite breaststroke swimmers during submaximal and maximal efforts. AB - The aims of this study were to describe muscular activation patterns and kinematic variables during the complete stroke cycle (SC) and the different phases of breaststroke swimming at submaximal and maximal efforts. Surface electromyography (sEMG) was collected from eight muscles in nine elite swimmers; five females (age 20.3 +/- 5.4 years; Federation Internationale de Natation [FINA] points 815 +/- 160) and four males (27.7 +/- 7.1 years; FINA points 879 +/ 151). Underwater cameras were used for 3D kinematic analysis with automatic motion tracking. The participants swam 25 m of breaststroke at 60%, 80% and 100% effort and each SC was divided into three phases: knee extension, knee extended and knee flexion. With increasing effort, the swimmers decreased their SC distance and increased their velocity and stroke rate. A decrease during the different phases was found for duration during knee extended and knee flexion, distance during knee extended and knee angle at the beginning of knee extension with increasing effort. Velocity increased for all phases. The mean activation pattern remained similar across the different effort levels, but the muscles showed longer activation periods relative to the SC and increased integrated sEMG (except trapezius) with increasing effort. The muscle activation patterns, muscular participation and kinematics assessed in this study with elite breaststroke swimmers contribute to a better understanding of the stroke and what occurs at different effort levels. This could be used as a reference for optimising breaststroke training to improve performance. PMID- 27455130 TI - Development, Quantification, Method Validation, and Stability Study of a Novel Fucoxanthin-Fortified Milk. AB - To extend the scope of application of fucoxanthin, a marine carotenoid, whole milk (WM) and skimmed milk (SM) were fortified with fucoxanthin isolated from the microalga Phaeodactylum tricornutum to a final 8 MUg/mL milk solution concentration. Using these liquid systems, a fucoxanthin analysis method implementing extraction and HPLC-DAD was developed and validated by accuracy, precision, system suitability, and robustness tests. The current method demonstrated good linearity over the range of 0.125-100 MUg/mL fucoxanthin with R(2) = 1.0000, and all validation data supported its adequacy for use in fucoxanthin analysis from milk solution. To investigate fucoxanthin stability during milk production and distribution, fucoxanthin content was examined during storage, pasteurization, and drying processes under various conditions. Fucoxanthin in milk solutions showed better stabilizing effect in 1 month of storage period. Degradation rate constant (k) on fucoxanthin during this storage period suggested that fucoxanthin stability might be negatively correlated with decrease of temperature and increase of protein content such as casein and whey protein in milk matrix. In a comparison between SM and WM, fucoxantin in SM always showed better stability than that in WM during storage and three kinds of drying processes. This effect was also deduced to relate with protein content. In the pasteurization step, >91% of fucoxanthin was retained after three pasteurization processes even though the above trend was not found. This study demonstrated for the first time that milk products can be used as a basic food matrix for fucoxanthin application and that protein content in milk is an important factor for fucoxanthin stability. PMID- 27455131 TI - Comprehensive Insights into Charge Dynamics and Improved Photoelectric Properties of Well-Designed Solar Cells. AB - Here, Zn2SnO4 nanorods/Cu4Bi4S9 (ZTO/CBS) and ZTO nanorods/CBS-graphene nanosheets (ZTO/CBS-GNs), as well as two types of bulk heterojunction (BHJ) solar cells with high flexibility were fabricated on stainless steel meshes (SSMs). The excellent photovoltaic responses of CBS-GNs and ZTO/CBS-GNs with incorporation of GNs were determined using surface photovoltage spectroscopy (SPS). The signals of time-resolved fluorescence response (TFR) and transient surface photovoltage (TPV) can provide more detailed information for transition, separation, and transport of photoinduced carriers. Besides, the ZTO nanorods/CBS-GNs cell exhibits the superior performance and the highest efficiency is 11.2%. The multichannel separation process from the TPVs indicates that the macro photoelectric signals can be attributed to the photogenerated charges separated at the interface of CBS/GNs, rather than CBS/ZTO. The multi-interfacial recombination is the major carrier loss with electrical impedance spectroscopy (EIS) and the hole selective NiO can efficiently accelerate the charge extraction to the external circuit. The comprehensive signals of SPS, EIS, TFR, and TPV provide insights into transition, separation, recombination and shifting of carriers. Importantly, the BHJ flexible solar cells with high efficiency and facile, scalable production present a potential for application. PMID- 27455133 TI - Mutation analysis of the PARKIN, PINK1, DJ1, and SNCA genes in Turkish early onset Parkinson's patients and genotype-phenotype correlations. AB - OBJECTIVE: Variations in PARK genes (PRKN, PINK1, DJ-1, and SNCA) cause early onset Parkinson's disease (EOPD) in different populations. In the current study, we aimed to evaluate the frequencies of variations in PARK genes and the effects of these variations on the phenotypes of Turkish EOPD patients. METHODS: All coding regions and exon-intron boundaries of the PRKN, PINK1, DJ-1, and SNCA genes were screened by heteroduplex analysis followed by direct sequencing of the detected variants in 50 Turkish EOPD patients. These variants were evaluated using SIFT, PolyPhen, HSF, and LOVD web-based programs. RESULTS: The frequency of EOPD-associated variations in the PRKN gene was 34%. Among these variations, p.A82E in exon 3 and p.Q409X in exon 11 was determined to be pathogenic. We also defined previously unknown cryptic variations, including c.872-35 G>A and c.872 28T>G in exon 8 of PRKN and c.252+30 T>G and c.322+4 A>G in exons 4 and 5 of DJ1, respectively, that were associated with EOPD. Although no significant association was observed between the PARK gene mutations and clinical features (P>0.05), the alterations were related to the clinical symptoms in each patient. CONCLUSION: An increasing number of studies report that PRKN, PINK1, DJ1 and SNCA mutations are associated with early-onset Parkinson's disease; however, a limited number of studies have been conducted in Turkey. Additionally, our study is the first to evaluate the frequency of SNCA mutations in a Turkish population. The aim of this study was determine the frequency distributions of the PRKN, PINK1, DJ1, and SNCA gene mutations and to analyze the relationships between these genetic variations and the clinical phenotype of EOPD in Turkish patients. PMID- 27455134 TI - Regional hyperthermia for high-risk soft tissue sarcoma treatment: present status and next questions. AB - PURPOSE OF REVIEW: Recent developments of neo-adjuvant chemotherapy treatment strategies for high-risk soft tissue sarcoma (STS) with special emphasis on regional hyperthermia (RHT) are reviewed. RECENT FINDINGS: Attempts to improve outcomes using up-front strategies in addition to surgery have essentially focused on neo-adjuvant and adjuvant chemotherapy or preoperative radiochemotherapy. Unfortunately, the results are either confounded by retrospective analyses of nonrandomized studies with small sample size or are negative showing no substantial clinical benefit in the few randomized trials. RHT targets the region of tumor burden by heat. The pleotropic effects on malignant cells and tumor stroma to counteract tumor growth and progression have been recently summarized as hallmarks of hyperthermia. An updated analysis of a completed EORTC-ESHO Intergroup randomized phase 3 trial for the most common types of high-risk STS demonstrates a significantly improved long-term overall survival for patients receiving RHT in combination with neo-adjuvant chemotherapy added to standard surgery and postoperative radiation. SUMMARY: By comparison with other strategies, RHT combined with preoperative and postoperative chemotherapy improves overall survival and adds an important but underused standard for high-risk STS. PMID- 27455132 TI - Infant milk formulas differ regarding their allergenic activity and induction of T-cell and cytokine responses. AB - BACKGROUND: Several hydrolyzed cow's milk (CM) formulas are available for avoidance of allergic reactions in CM-allergic children and for prevention of allergy development in high-risk infants. Our aim was to compare CM formulas regarding the presence of immunoreactive CM components, IgE reactivity, allergenic activity, ability to induce T-cell proliferation, and cytokine secretion. METHODS: A blinded analysis of eight CM formulas, one nonhydrolyzed, two partially hydrolyzed (PH), four extensively hydrolyzed (EH), and one amino acid formula, using biochemical techniques and specific antibody probes was conducted. IgE reactivity and allergenic activity of the formulas were tested with sera from CM-allergic patients (n = 26) in RAST-based assays and with rat basophils transfected with the human FcepsilonRI, respectively. The induction of T-cell proliferation and the secretion of cytokines in Peripheral blood mononuclear cell (PBMC) culture from CM allergic patients and nonallergic individuals were assessed. RESULTS: Immune-reactive alpha-lactalbumin and beta lactoglobulin were found in the two PH formulas and casein components in one of the EH formulas. One PH formula and the EH formula containing casein components showed remaining IgE reactivity, whereas the other hydrolyzed formulas lacked IgE reactivity. Only two EH formulas and the amino acid formula did not induce T-cell proliferation and proinflammatory cytokine release. The remaining formulas varied regarding the induction of Th2, Th1, and proinflammatory cytokines. CONCLUSION: Our results show that certain CM formulas without allergenic and low proinflammatory properties can be identified and they may also explain different outcomes obtained in clinical studies using CM formulas. PMID- 27455135 TI - DNA damage response as a therapeutic target in gynecological cancers. AB - PURPOSE OF REVIEW: The proven activity of poly ADP ribose polymerase (PARP) inhibitors in BRCA-mutated homologous recombination deficient (HRD) ovarian cancer has led to the availability to patients with ovarian cancer of the first targeted therapy with an associated predictive biomarker. Our focus has recently turned towards expanding the clinical utility of PARP inhibitors beyond BRCA mutated ovarian cancer, and to a search for novel targets within DNA damage response (DDR). RECENT FINDINGS: Early trials in unselected patients with ovarian cancer showed responses to PARP inhibition in BRCA-wildtype ovarian cancer, and recent genomic studies have demonstrated that germline or somatic aberrations in other homologous recombination genes are present in a significant proportion of ovarian cancers. In addition, PARP inhibition may be of value in molecularly defined subsets of endometrial or cervical cancers. Novel DDR inhibitors such as ATR, ATM, WEE1 or DNA-PK inhibitors are also being tested in patients. Finally, combinatorial strategies of DDR inhibitors with antiangiogenic agents, phosphoinositide 3-kinase inhibitors or immunotherapies may further increase therapeutic efficacy. SUMMARY: In the future, patients with gynaecological malignancies may be rationally selected for PARP inhibition on the basis of comprehensive evaluation of homologous recombination genomic alterations, or HRD assays. Furthermore, novel DDR inhibitors have the potential to expand the repertoire of therapeutic options available to these patients. PMID- 27455136 TI - Current developments in the treatment of early-stage classical Hodgkin lymphoma. AB - PURPOSE OF REVIEW: After presenting the current treatment recommendations for early-stage Hodgkin lymphoma, we give an overview on recently published clinical trials in this setting. Furthermore, the potential influence of current trials on the treatment of early-stage Hodgkin lymphoma and integration of newly emerging drugs into treatment protocols will be discussed. RECENT FINDINGS: Trials attempting treatment de-escalation and omission of radiotherapy on the basis of early interim PET-scans have been disappointing so far, but results of some large trials employing this strategy are still awaited. In contrast, a more defensive strategy of starting treatment with less aggressive doxorubicine, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy and intensifying treatment in early interim PET-positive patients has shown encouraging results. New drugs such as brentuximab vedotin and immune checkpoint inhibitors have shown promising results in relapsed and refractory Hodgkin lymphoma. Clinical trials of brentuximab vedotin in early-stage Hodgkin lymphoma have been initiated. Additionally, biomarker-based treatment de-escalation might be a possible route for future improvements. SUMMARY: The challenge for future clinical research in early-stage Hodgkin lymphoma is to continue to cure the majority of patients with first-line treatment while reducing long-term toxicity. New strategies to achieve that goal are currently being developed and will further refine treatment of early-stage Hodgkin lymphoma. PMID- 27455137 TI - Patterning of Solid Films via Selective Atomic Layer Deposition Based on Silylation and UV/Ozonolysis. AB - A simple methodology was successfully demonstrated for the nanoscale patterning of silicon wafers. Thin films are grown by atomic layer deposition (ALD) and patterned by using selective surface chemistry: First, all the nucleation sites on the original oxide surface are silylated in order to render them unreactive; then, a pattern is developed by selective removal of the silylation agent using a mask and a combination of ultraviolet radiation and ozonolysis. Subsequent ALD is carried out selectively on the areas where the silylation moieties have been removed. This simple procedure affords patterning of oxide surfaces with monolayer control and a lateral resolution on the order of a few tens of nanometers or better. Other selective ALD processes have shown only limited discrimination during deposition, but our method shows absolute inhibition of film growth on the silylated areas while films as thick as 10 nm are grown on the re-exposed sectors. Our example involved the deposition of hafnium oxide films on the native silicon oxide film that forms on Si(100) wafers, but we believe that the approach is general and easily extendable to other ALD processes. PMID- 27455138 TI - Resilience during war: Better unit cohesion and reductions in avoidant coping are associated with better mental health function after combat deployment. AB - OBJECTIVE: The majority of individuals who endure traumatic events are resilient; however, we do not yet understand why some individuals are more resilient than others. We used data from a prospective longitudinal study Army National Guard and Reserve personnel to examine how unit cohesion (military-specific social support) and avoidant coping relate to resilience over the first year after return from deployment. METHOD: Soldiers (N = 767) were assessed at 4 phases: predeployment (P1), immediately postdeployment (P2), 3 months' postdeployment (P3), and 1-year postdeployment (P4). RESULTS: After controlling for predeployment avoidant coping and overall social support, higher unit cohesion was associated with a reduction in avoidant coping (from P1 to P3). This reduction in avoidant coping (from P1 to P3) mediated the relationship between unit cohesion (P2) and improvement in mental health function (from P1 to P3). CONCLUSIONS: The results are consistent with the hypothesis that higher unit cohesion may mitigate increases in avoidant coping in military personnel after a combat deployment and in turn may improve mental health function. (PsycINFO Database Record PMID- 27455139 TI - "Resilience in Palestinian adolescents living in Gaza": Correction to Aitcheson et al. (2016). AB - : Reports an error in "Resilience in Palestinian Adolescents Living in Gaza" by Rozanna J. Aitcheson, Soleman H. Abu-Bader, Mary K. Howell, Deena Khalil and Salman Elbedour (Psychological Trauma: Theory, Research, Practice, and Policy, Advanced Online Publication, May 30, 2016, np). There were grammatical errors to the Method section of the abstract and the Method subsection Participants. Corrected versions are provided. (The following abstract of the original article appeared in record 2016-26488-001.) Objective: The pathogenic impact of ongoing political conflict on children and adolescents has been well-documented in the literature. The present study, by contrast, examined the factors that support adolescent health and utilized a salutogenic model to examine prevalence of depression and anxiety and predictors of resilience in a group of adolescents attending secondary school in Gaza. METHOD: There were 335 Palestinian adolescents (n = 335) enrolled in 11th and 12th grades in secondary schools in Gaza refugee camps completed the Beck Depression Inventory, the Beck Anxiety Inventory, and self-report measures assessing coping skills, self-regulation, optimism, parenting style, family sense of coherence, national identity, ethnic identity, and other demographic variables. RESULTS: Participants with stronger national identity, stronger family sense of coherence, greater self-regulation, and more optimism reported less depressive and anxious symptoms. In a logistic regression analysis, significant predictors of resilience (minimal to no anxiety and depression, n = 135) were age, optimism, family sense of coherence, ethnic identity, self-regulation, and coping skills. CONCLUSION: These findings indicate that older age, optimism, perception of family seeing the world as comprehensible, manageable, and meaningful, stronger Arab ethnic identity, greater self-regulation and stronger coping skills promote adolescent adaptation and health. Salutogenesis frames information about how resilient youth living in high threat environments may respond to preventative community-based behavioral health interventions as well as treatment of depression, anxiety, and other psychological distress among adolescents living with ongoing violence. (PsycINFO Database Record PMID- 27455140 TI - Correlates of psychological distress among urban trauma-exposed adults: Influence of age and coping preferences. AB - OBJECTIVE: This article examines direct and moderating effects of age on coping preferences for psychological distress among a sample of trauma-exposed adults to inform treatment approaches for this population. METHOD: Using data from a community survey of trauma-exposed, urban-dwelling adults (n = 181), direct and moderating effects of coping preferences on the relationship between age and psychological distress were examined using hierarchical linear regression. RESULTS: Direct effects with distress were supported for age, gender, and coping preferences of avoidance and positive reframing. No direct effects with problem focused coping were present; however, a significant interaction resulted with the relationship between age and level of reported distress. DISCUSSION: Problem focused coping may provide a buffering effect on experiences with distress for older trauma-exposed adults. Findings highlight the benefits of directive and action-oriented approaches to care for aging adults. Implications for future intervention research and clinical considerations for treating trauma over the life course are discussed. (PsycINFO Database Record PMID- 27455141 TI - Preliminary performance data of the RHE/IL-18 assay performed on SkinEthicTM RHE for the identification of contact sensitizers. AB - OBJECTIVE: The purpose of this study was to evaluate the performances of the RHE/IL-18 assay using the SkinEthicTM RHE model for the identification of contact sensitizers. METHODS: A set of 18 substances and mixtures was tested on this epidermal model, following the RHE/IL-18 protocol. The final results of the assay were obtained following 5 interpretation schemes, to determine the optimal prediction model for this assay with this specific test system. The data were analysed with a special focus on the basal level of IL-18 release and on the performance obtained with respect to three different gold standards: LLNA, HRIPT and an integrated reference, constructed from all available results. RESULTS: No important differences were found in the performance levels depending on the three gold standards. The performances obtained with the SkinEthicTM RHE model support that this model may be considered as an alternative to different reconstructed epidermis models (EpiDERMTM , EpiCSTM and VUMC-EE) for the performance of RHE/IL 18 assays. CONCLUSION: The prediction model to be used was refined, and more substances have to be tested in order to gather enough data for this evaluation and to determine the right criteria applicable for this assay using the SkinEthicTM RHE test system. PMID- 27455142 TI - Noble metal-free hydrogen-evolving photocathodes based on small molecule organic semiconductors. AB - Organic semiconductors have great potential for producing hydrogen in a sustainable and economically-viable manner because they rely on readily available materials with highly tunable properties. We demonstrate here the relevance of heterojunctions to the construction of H2-evolving photocathodes, exclusively based on earth-abundant elements. Boron subnaphthalocyanine chloride proved a very promising acceptor in that perspective. It absorbs a part of the solar spectrum complementary to alpha-sexithiophene as a donor, thus generating large photocurrents and providing a record onset potential for light-driven H2 evolution under acidic aqueous conditions using a nanoparticulate amorphous molybdenum sulfide catalyst. PMID- 27455143 TI - Carbon Counter-Electrode-Based Quantum-Dot-Sensitized Solar Cells with Certified Efficiency Exceeding 11. AB - The mean power conversion efficiency (PCE) of quantum-dot-sensitized solar cells (QDSCs) is mainly limited by the low photovoltage and fill factor (FF), which are derived from the high redox potential of polysulfide electrolyte and the poor catalytic activity of the counter electrode (CE), respectively. Herein, we report that this problem is overcome by adopting Ti mesh supported mesoporous carbon (MC/Ti) CE. The confined area in Ti mesh substrate not only offers robust carbon film with submillimeter thickness to ensure high catalytic capacity, but also provides an efficient three-dimension electrical tunnel with better conductivity than state-of-art Cu2S/FTO CE. More importantly, the MC/Ti CE can down shift the redox potential of polysulfide electrolyte to promote high photovoltage. In all, MC/Ti CEs boost PCE of CdSe0.65Te0.35 QDSCs to a certified record of 11.16% (Jsc = 20.68 mA/cm(2), Voc = 0.798 V, FF = 0.677), an improvement of 24% related to previous record. This work thus paves a way for further improvement of performance of QDSCs. PMID- 27455144 TI - Associations between school difficulties and health-related problems and risky behaviours in early adolescence: A cross-sectional study in middle-school adolescents in France. AB - Health-related problems and risky behaviours (substance use) are frequent in adolescents, may alter their physical and mental capabilities, and may thus generate school absenteeism, low academic performance, and school dropout ideation. This study assessed their associations and the contribution of socioeconomic factors among 1559 middle-school adolescents (mean age 13.5+1.3) from north-eastern France. They completed a questionnaire including socioeconomic characteristics, health-related problems (poor physical health, psychological health, social relationships, and living environment) assessed with the World Health Organization's quality of life measure (score<25th percentile), risky behaviours, school absences during the present school year, last-trimester academic performance, and school dropout ideation. Data were analysed using logistic regression models. School absenteeism was frequent (12.6% of subjects for 8-14 days, and 6.0% for >=15 days); 8.2% of subjects had low academic performance (average school-mark <10/20) and 3.9% school dropout ideation. All school difficulties were strongly associated with all health-related problems (gender-age-school-level-adjusted odds ratios gasOR between 1.5 and 4.2), and with risky behaviours (gasOR between 1.4 and 14). Socioeconomic factors differently contributed to these associations (contribution reaching 77%). Policy makers, schools, physicians and parents should be more aware of the problems and help adolescents to reduce health-related problems and risky behaviours and to increase resilience. PMID- 27455145 TI - When somatization is not the only thing you suffer from: Examining comorbid syndromes using latent profile analysis, parenting practices and adolescent functioning. AB - Understanding somatization presents a challenge to clinicians because it is often associated with other syndromes. We addressed somatization's comorbidity with other internalizing syndromes (anxiety, depression, withdrawal) using latent profile analysis. A representative sample of 3496 Israeli middle and high-school youths reported their internalizing symptoms, perceived parenting practices, psychosocial functioning, and health behaviors. Four profiles, similar across age and gender, were identified: overall-low (65.4%), moderately-high anxiety/depression/withdrawal (24.4%), high somatization (4.8%), and overall-high (5.4%). MANOVAs and follow-up ANOVAs revealed that for the most part the overall high profile evinced the worst parenting, psychosocial functioning, and health behaviors (smoking and drinking), while the overall-low group evinced the best. For most variables the high somatization and moderately high profiles displayed midway results. However, the moderately-high profile reported higher levels of harsh parenting than the high somatization profile. The high somatization profile reported similar or higher levels of smoking, risk taking, vandalism, and rule violation than the overall-high group. High somatization, either alone or alongside anxiety, depression, and withdrawal, was associated with disruptive and risk-taking behaviors. This link might reflect problems in emotion and anger regulation and become stronger in adolescence because of dysregulation processes characterizing this period. Implications for practice are discussed. PMID- 27455146 TI - Altered serum levels of TNF-alpha, IL-6 and IL-18 in manic, depressive, mixed state of bipolar disorder patients. AB - Bipolar disorder (BD) is associated with alterations of cytokines in the immune system. The aim of this study was to assess the serum levels of TNF-alpha, IL-6 and IL-18 in manic, depressive, mixed state patients of BD. The correlations between the serum cytokines levels with the demographic characteristics and the psychiatric symptoms were also assessed. We measured serum TNF-alpha, IL-6 and IL 18 levels using an enzyme-linked immunosorbent assay (ELISA) from 59 BD patients (37 in manic state, 12 in depressive state, 10 in mixed state) and 80 healthy control subjects. The psychotic symptoms of BD were assessed using the Hamilton Depression Scale (HAMD) and the Young Mania Rating Scale (YMRS). The results showed that serum TNF-alpha and IL-6 levels in manic, depressive and mixed state BD patients were significantly higher than that in controls, while serum IL-18 level was only significantly higher in depressive patients. Serum IL-6 level was significantly positively correlated with YMRS scores in manic episode as well as in mixed episode. When gender and age were added as potentially confounding covariate terms, the differences between controls and each mood state patients were still significant. Our findings provided additional evidence that elevated TNF-alpha, IL-6 and IL-18 pathway activities may be involved in the psychopathology of BD. Due to the lack of controlling important confounding factors, such as BMI, smoking status and alcohol use, further studies are required to confirm the roles of TNF-alpha, IL-6 and IL-18. PMID- 27455147 TI - Instrumental measurements of spontaneous dyskinesia and schizotypy in subjects with auditory verbal hallucinations and healthy controls. AB - Spontaneous dyskinesia is associated with non-affective psychosis. Few studies investigated dyskinesia in individuals with subclinical psychotic experiences. We examined dyskinesia using instrumental measurements of force variability in 34 individuals with frequent auditory verbal hallucinations but without a clinical psychotic disorder and 31 matched healthy controls. Schizotypy was assessed using the Schizotypal Personality Questionnaire. We found a positive correlation between dyskinesia and schizotypy in the total group. In addition, when using a cut-off point based on the 95th percentile of force variability in the control group, we found a greater proportion of subjects with dyskinesia in the group with auditory verbal hallucinations than in the control subjects. Current findings are in agreement with the concept of psychosis as a continuous phenomenon and with movement disorders being an integral part of psychosis. PMID- 27455148 TI - Social anxiety and perception of (un)trustworthiness in smiling faces. AB - In social environments the smile can be driven by different motives and convey different emotions. This makes a smiling face ambiguous and amenable to alternative interpretations. We investigated how social anxiety is related to trustworthiness evaluation of morphed dynamic smiling faces depending on changes in the eye expression. Socially anxious and non-anxious participants judged the un/trustworthiness of people with different smiles. Social anxiety was related to reduced trustworthiness of (a) faces with a neutral mouth unfolding to a smile when the eyes were neutral at the beginning or end of the dynamic sequence, and (b) faces with a smiling mouth when happy eyes slightly changed towards neutrality, surprise, fear, sadness, disgust, or anger. In contrast, social anxiety was not related to trustworthiness judgments for non-ambiguous expressions unfolding from neutral (eyes and mouth) to happy (eyes and mouth) or from happy to neutral. Socially anxious individuals are characterized by an interpretation bias towards mistrusting any ambiguous smile due to the presence of non-happy eyes. PMID- 27455149 TI - Toward an understanding of the quality of life construct: Validity and reliability of the WHOQOL-Bref in a psychiatric sample. AB - This study tested the psychometric properties of the WHOQOL-Bref by examining its construct validity, predictive validity and reliability in a psychiatric sample. The sample consisted of 403 participants recruited from mental health care facilities. Construct validity was assessed through confirmatory factor analysis (CFA) and item-domains correlations. Predictive validity was evaluated via multiple regressions. Internal consistency was analyzed by using Cronbach's alpha. Results from CFA second-order hierarchical model and item-domain correlational analyses supported the construct validity of the WHOQOL-Bref. A 5 domain model (psychological, physical, social relationships, environment and level of independence) demonstrated good-fit and adequate internal consistency. Multiple regression analyses of the domains with overall quality of life (QOL), general health and general QOL were supportive of predictive validity. This study found support for the multidimensionality of the WHOQOL-Bref which demonstrated appropriate properties for the assessment of QOL in psychiatric inpatients and outpatients. Thus, a valuable tool to be incorporated as part of the routine clinical evaluation, monitoring and an important indicator of treatment outcome and research. Our findings suggest a conceptual distinction between the physical domain and level of independence domain in this short version of the WHOQOL, as proposed by the WHOQOL-100. PMID- 27455150 TI - Weight Loss, Satiety, and the Postprandial Gut Hormone Response After Esophagectomy: A Prospective Study. AB - OBJECTIVE: To prospectively characterize changes in body weight, satiety, and postprandial gut hormone profiles following esophagectomy. BACKGROUND: With improved oncologic outcomes in esophageal cancer, there is an increasing focus on functional status and health-related quality of life in survivorship. Early satiety and weight loss are common after esophagectomy, but the pathophysiology of these phenomena remains poorly understood. METHODS: In this prospective study, consecutive patients undergoing esophagectomy with gastric conduit reconstruction were studied preoperatively and at 10 days, 6 weeks, and 3 months postoperatively. Glucagon-like peptide 1 (GLP-1) immunoreactivity of plasma collected immediately before and at 15, 30, 60, 90, 120, 150, and 180 minutes after a standardized 400-kcal mixed meal was determined. Gastrointestinal symptom scores were computed using European Organization for Research and Treatment of Cancer questionnaires. RESULTS: Body weight loss at 6 weeks and 3 months postoperatively among 13 patients undergoing esophagectomy was 11.1 +/- 2.3% (P < 0.001) and 16.3 +/- 2.2% (P < 0.0001), respectively. Early satiety (P = 0.043), gastrointestinal pain and discomfort (P = 0.01), altered taste (P= 0.006), and diarrhea (P= 0.038) scores increased at 3 months postoperatively. Area under the curve for the satiety gut hormone GLP-1 was significantly increased from 10 days postoperatively (2.4 +/- 0.2-fold increase, P < 0.01), and GLP-1 peak increased 3.8 +/- 0.6-, 4.7 +/- 0.8-, and 4.4 +/- 0.5-fold at 10 days, 6 weeks, and 3 months postoperatively (all P < 0.0001). Three months postoperatively, GLP-1 area under the curve was associated with early satiety (P = 0.0002, R = 0.74), eating symptoms (P = 0.007, R = 0.54), and trouble enjoying meals (P = 0.0004, R = 0.73). CONCLUSIONS: After esophagectomy, patients demonstrate an exaggerated postprandial satiety gut hormone response, which may mediate postoperative changes in satiety, body weight, and gastrointestinal quality of life. PMID- 27455151 TI - Pancreatic Ductal Adenocarcinoma: A New TNM Staging System is Needed! PMID- 27455152 TI - Pancreatic Ductal Adenocarcinoma: A New TNM Staging System Is Needed! PMID- 27455153 TI - Unintentional Subterfuge. PMID- 27455154 TI - Reply to Letter: "Redesigning ACS-NSQIP Data Collection and Reports Will This Translate Into Better Outcomes?" PMID- 27455155 TI - Teres Ligament Patch Reduces Relevant Morbidity After Distal Pancreatectomy (the DISCOVER Randomized Controlled Trial). AB - OBJECTIVE: The aim of this study was to analyze the impact of teres ligament covering on pancreatic fistula rate after distal pancreatectomy (DP). BACKGROUND: Postoperative pancreatic fistula (POPF) represents the most significant complication after DP. Retrospective studies suggested a benefit of covering the resection margin by a teres ligament patch. METHODS: This prospective randomized controlled study (DISCOVER trial) included 152 patients undergoing DP, between October 2010 and July 2014. Patients were randomized to undergo closure of the pancreatic cut margin without (control, n = 76) or with teres ligament coverage (teres, n = 76). The primary endpoint was the rate of POPF, and the secondary endpoints included postoperative morbidity and mortality, length of hospital stay, and readmission rate. RESULTS: Both groups were comparable regarding epidemiology (age, sex, body mass index), operative parameters (operation time [OP] time, blood loss, method of pancreas transection, additional operative procedures), and histopathological findings. Overall inhospital mortality was 0.6% (1/152 patients). In the group of patients with teres ligament patch, the rate of reoperations (1.3% vs 13.0%; P = 0.009), and also the rate of readmission (13.1 vs 31.5%; P = 0.011) were significantly lower. Clinically relevant POPF rate (grade B/C) was 32.9% (control) versus 22.4% (teres, P = 0.20). Multivariable analysis showed teres ligament coverage to be a protective factor for clinically relevant POPF (P = 0.0146). CONCLUSIONS: Coverage of the pancreatic remnant after DP is associated with less reinterventions, reoperations, and need for readmission. Although the overall fistula rate is not reduced by the coverage procedure, it should be considered as a valid measure for complication prevention due to its clinical benefit. PMID- 27455156 TI - The ALPPS Risk Score: Avoiding Futile Use of ALPPS. AB - OBJECTIVES: To create a prediction model identifying futile outcome in ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) before stage 1 and stage 2 surgery. BACKGROUND: ALPPS is a 2-stage hepatectomy, which incorporates parenchymal transection at stage 1 enabling resection of extensive liver tumors. One of the major criticisms of ALPPS is the associated high mortality rate up to 20%. METHODS: Using the International ALPPS Registry, a risk analysis for futile outcome (defined as 90-day or in-hospital mortality) was performed. Futility was modeled using multivariate regression analysis and a futility risk score formula was computed on the basis of the relative size of logistic model regression coefficients. RESULTS: Among 528 ALPPS patients from 38 centers, a futile outcome was observed in 47 patients (9%). The pre-stage 1 model included age 67 years or older [odds ratio (OR) = 5.7], and tumor entity (OR = 3.8 for biliary tumors) as independent predictors of futility from multivariate analysis. For the pre-stage 1 model scores of 0, 1, 2, 3, 4 and 5 were associated with futile risk of 2.7%, 4.9%, 8.6%, 15%, 24%, and 37%. The pre-stage 2 model included major complications (grade >= 3b) after stage 1 (OR = 3.4), serum bilirubin (OR = 4.4), serum creatinine (OR = 5.4), and cumulative pre-stage 1 risk score (OR = 1.9). The model predicted futility risk of 5%, 10%, 20%, and 50% for patients with scores of 3.9, 4.7, 5.5, and 6.9, respectively. CONCLUSIONS: Both models have an excellent prediction to assess the individual risk of futile outcome after ALPPS surgery and can be used to avoid futile use of ALPPS. PMID- 27455157 TI - Diagnosis and Treatment of the Extraesophageal Manifestations of Gastroesophageal Reflux Disease. AB - OBJECTIVE: To review the clinical presentation, diagnosis, and treatment options available for management of extraesophageal manifestations of gastroesophageal reflux disease (GERD) and to compare the most recent technological advances to the existing guidelines. SUMMARY BACKGROUND DATA: Extraesophageal manifestations of GERD include cough, laryngopharyngeal reflux (LPR), and asthma. Recent advances in diagnostic modalities may have outpaced the existing diagnostic and therapeutic clinical guidelines. METHODS: We searched the MEDLINE, Cochrane, and Embase databases for articles pertaining to the presentation, diagnosis, and treatment of extraesophageal manifestations of reflux, specifically cough due to reflux, LPR, and asthma due to reflux. Search terms applied to 3 thematic topics: diagnosis, medical treatment, and surgical treatment. We had searched the bibliographies of included studies, yielding a total of 271 articles for full review. We graded the level of evidence and classified recommendations by size of treatment effect, according to the guidelines from the American Heart Association Task Force on Practice Guidelines. RESULTS: One hundred twenty-eight articles met criteria for analysis. Our findings show that the diagnosis of cough, LPR, or asthma due to gastroesophageal reflux is difficult, as no criterion standard test exits. Also, patients often present without heartburn or regurgitation typical of GERD. Combined multichannel intraluminal impedance, the pH (MII-pH) monitoring system, and the symptom association probability (SAP) test might distinguish extraesophageal manifestations of reflux from idiopathic chronic cough, laryngitis due to other causes, and atopic asthma. In addition, extraesophageal manifestations of reflux are most effectively diagnosed with a stepwise approach incorporating empiric treatment and antisecretory therapy, combined MII-pH monitoring, and surgical intervention in few selected cases. CONCLUSIONS: Recent studies demonstrate the potential diagnostic role of MII-pH monitoring. Surgical intervention provides resolution of extraesophageal symptoms less reliably than typical symptoms when the patient has GERD. PMID- 27455158 TI - Timing of Chemical Thromboprophylaxis and Deep Vein Thrombosis in Major Colorectal Surgery: A Randomized Clinical Trial. AB - OBJECTIVE: To identify the optimal timing of perioperative chemical thromboprophylaxis (CTP) and incidence of occult preoperative deep vein thrombosis (OP-DVT) in patients undergoing major colorectal surgery. BACKGROUND: There is limited Level 1 data regarding the optimal timing of CTP in major colorectal surgery and the incidence of OP-DVT remains unclear. Both issues influence the occurrence of venous thromboembolism (VTE) and may impact Medicare reimbursement because of penalties for hospital-acquired conditions. METHODS: Patients undergoing major colorectal surgery underwent preoperative lower extremity venous duplex (LEVD) immediately before surgery. Those without OP-DVT were randomized to preoperative or postoperative CTP with 5000 units of subcutaneous heparin. Patients underwent repeat LEVD in the recovery room and on postoperative day 2. Outcome measures included early (48-hrs) and overall (30 days) postoperative VTE, bleeding complications, and OP-DVT. RESULTS: Eighteen patients (4.2%) had OP-DVT and were excluded. The randomized group included 376 patients (51.6% female) with mean age of 52.7 +/- 17.6 years. No pulmonary embolism occurred. There was no significant difference in preoperative versus postoperative CTP with respect to early postoperative DVT [3/184 (1.6%) vs 5/192 (2.6%); P = 0.72], DVT at 30 days (1.6% vs 3.6%; P = 0.34) or bleeding complications requiring reoperation (0.5% vs 1.6%; P = 0.62). CONCLUSIONS: The risk of OP-DVT is higher than that of perioperative DVT after colorectal surgery and preoperative screening LEVD should be considered to identify and treat patients at risk for pulmonary embolism. Preoperative and postoperative CTP are equally safe in protecting against VTE. CMS should account for these factors when assigning financial disincentives for perioperative VTE. TRIAL REGISTRATION: Clinicaltrials.gov #NCT01976988. PMID- 27455159 TI - We're Still in an Update Process of the BCLC System. PMID- 27455160 TI - Local Recurrence and Breast Oncological Surgery in Young Women With Breast Cancer: The POSH Observational Cohort Study. AB - OBJECTIVE: To assess clinical and surgical factors affecting local recurrence and survival in young breast cancer patients in the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). BACKGROUND: Emerging data suggest young age is a predictor of increased local recurrence. METHODS: POSH is a prospective cohort of 3024 women of 18 to 40 years with breast cancer. Cohort characteristics were grouped by mastectomy or BCS. Endpoints were local recurrence interval (LRI), distant disease-free interval (DDFI), and overall survival (OS); described using cumulative-hazard and Kaplan-Meier plots and multivariable analyses by Flexible Parametric and Cox regression models. RESULTS: Mastectomy was performed in 1464 patients and breast-conserving surgery (BCS) in 1395. Patients undergoing mastectomy had larger tumors and higher proportions of positive family history, estrogen receptor+, progesterone receptor+, and/or human epidermal growth factor receptor 2+ tumors. Local events accounted for 15% of recurrences. LRI by surgical type varied over time with LRI similar at 18 months (1.0% vs 1.0%, P = 0.348) but higher for BCS at 5 and 10 years (5.3% vs 2.6%, P < 0.001; and 11.7% vs 4.9%, P < 0.001, respectively). Similar results were found in the adjusted model. Conversely, distant-metastases and deaths were lower for BCS but not after adjusting for prognostic factors. After mastectomy chest-wall radiotherapy was associated with improved LRI (hazard ratio, HR = 0.46, P = 0.015). Positive surgical margins, and development of local recurrence predicted for reduced DDFI (HR = 0.50, P < 0.001; and HR = 0.29, P = 0.001, respectively). CONCLUSIONS: Surgical extent appears less important for DDFI than completeness of excision or, where appropriate, chest-wall radiotherapy. Despite higher local recurrence rates for BCS, surgical type does not influence DDFI or OS after adjusting for known prognostic factors in young breast cancer patients. PMID- 27455161 TI - Early Antibiotic Treatment for Pediatric Febrile Urinary Tract Infection and Renal Scarring. AB - IMPORTANCE: Existing data regarding the association between delayed initiation of antimicrobial therapy and the development of renal scarring are inconsistent. OBJECTIVE: To determine whether delay in the initiation of antimicrobial therapy for febrile urinary tract infections (UTIs) is associated with the occurrence and severity of renal scarring. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study that combined data from 2 previously conducted longitudinal studies (the Randomized Intervention for Children With Vesicoureteral Reflux trial and the Careful Urinary Tract Infection Evaluation Study). Children younger than 6 years with a first or second UTI were followed up for 2 years. EXPOSURE: Duration of the child's fever prior to initiation of antimicrobial therapy for the index UTI. MAIN OUTCOMES AND MEASURES: New renal scarring defined as the presence of photopenia plus contour change on a late dimercaptosuccinic acid renal scan (obtained at study exit) that was not present on the baseline scan. RESULTS: Of the 482 children included in the analysis, 434 were female (90%), 375 were white (78%), and 375 had vesicoureteral reflux (78%). The median age was 11 months. A total of 35 children (7.2%) developed new renal scarring. Delay in the initiation of antimicrobial therapy was associated with renal scarring; the median (25th, 75th percentiles) duration of fever prior to initiation of antibiotic therapy in those with and without renal scarring was 72 (30, 120) and 48 (24, 72) hours, respectively (P = .003). Older age (OR, 1.03; 95% CI, 1.01-1.05), Hispanic ethnicity (OR, 5.24; 95% CI, 2.15-12.77), recurrent urinary tract infections (OR, 0.97; 95% CI, 0.27-3.45), and bladder and bowel dysfunction (OR, 6.44; 95% CI, 2.89-14.38) were also associated with new renal scarring. Delay in the initiation of antimicrobial therapy remained significantly associated with renal scarring even after adjusting for these variables. CONCLUSIONS AND RELEVANCE: Delay in treatment of febrile UTIs and permanent renal scarring are associated. In febrile children, clinicians should not delay testing for UTI. PMID- 27455162 TI - Novel 5-Hydroxy, 5-Substituted Benzenesulfonamide Pyrimidine-2,4,6-Triones Attenuate Lipopolysaccharide-Induced Acute Lung Injury via Inhibition of the Gelatinases, MMP-2 and MMP-9. AB - Preclinical Research A novel series of ten 5-hydroxy, 5-substituted benzene sulfonamide pyrimidine-2,4,6-triones were synthesized and their structures ascertained using (1) H-NMR, (13) C-NMR, mass and elemental analysis. These compounds were subsequently tested for inhibition of MMP-2 and MMP-9 where most exhibited activity with compound 5i being the most potent against MMP-2 and MMP-9 with IC50 values of 2.35 nM and 8.24 nM, respectively. Compound 5i was further analyzed in a mouse LPS-induced acute lung injury model where it had protective activity. Histochemical studies indicated that 5i improved the vascular integrity of the lung. Drug Dev Res 77 : 251-257, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27455163 TI - Sun protection for preventing basal cell and squamous cell skin cancers. AB - BACKGROUND: 'Keratinocyte cancer' is now the preferred term for the most commonly identified skin cancers basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which were previously commonly categorised as non-melanoma skin cancers (NMSC). Keratinocyte cancer (KC) represents about 95% of malignant skin tumours. Lifestyle changes have led to increased exposure to the sun, which has, in turn, led to a significant increase of new cases of KC, with a worldwide annual incidence of between 3% and 8%. The successful use of preventive measures could mean a significant reduction in the resources used by health systems, compared with the high cost of the treatment of these conditions. At present, there is no information about the quality of the evidence for the use of these sun protection strategies with an assessment of their benefits and risks. OBJECTIVES: To assess the effects of sun protection strategies (i.e. sunscreen and barrier methods) for preventing keratinocyte cancer (that is, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) of the skin) in the general population. SEARCH METHODS: We searched the following databases up to May 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registries and the bibliographies of included studies for further references to relevant trials. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) of preventive strategies for keratinocyte cancer, such as physical barriers and sunscreens, in the general population (children and adults), which may provide information about benefits and adverse events related to the use of solar protection measures. We did not include trials focused on educational strategies to prevent KC or preventive strategies in high-risk groups. Our prespecified primary outcomes were BCC or cSCC confirmed clinically or by histopathology at any follow-up and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for eligibility using Early Review Organizing Software (EROS). Similarly, two review authors independently used predesigned data collection forms to extract information from the original study reports about the participants, methods of randomisation, blinding, comparisons of interest, number of participants originally randomised by arm, follow-up losses, and outcomes, and they assessed the risk of bias. We resolved any disagreement by consulting a third author and contacted trial investigators of identified trials to obtain additional information. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one RCT (factorial design) that randomised 1621 participants.This study compared the daily application of sunscreen compared with discretionary use of sunscreen, with or without beta-carotene administration, in the general population. The study was undertaken in Australia; 55.2% of participants had fair skin, and they were monitored for 4.5 years for new cases of BCC or cSCC assessed by histopathology. We found this study to be at low risk of bias for domains such as allocation, blinding, and incomplete outcome data. However, we found multiple unclear risks related to other biases, including an unclear assessment of possible interactions between the effects of the different interventions evaluated (that is, sunscreen and beta-carotene). We found no difference in terms of the number of participants developing BCC (n = 1621; risk ratio (RR) 1.03, 95% confidence interval (CI) 0.74 to 1.43) or cSCC (n = 1621; RR 0.88, 95% CI 0.50 to 1.54) when comparing daily application of sunscreen with discretionary use, even when analyses were restricted to groups without beta-carotene supplementation. This evidence was of low quality, which means that there is some certainty that future studies may alter our confidence in this evidence.We reported adverse events in a narrative way and included skin irritation or contact allergy.We identified no studies that evaluated other sun protection measures, such as the use of sun-protective clothing, sunglasses, or hats, or seeking the shade when outdoors. AUTHORS' CONCLUSIONS: In this review, we assessed the effect of solar protection in preventing the occurrence of new cases of keratinocyte cancer. We only found one study that was suitable for inclusion. This was a study of sunscreens, so we were unable to assess any other forms of sun protection. The study addressed our prespecified primary outcomes, but not most of our secondary outcomes. We were unable to demonstrate from the available evidence whether sunscreen was effective for the prevention of basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC).Our certainty in the evidence was low because there was a lack of histopathological confirmation of BCC or cSCC in a significant percentage of cases. Amongst other sources of bias, it was not clear whether the study authors had assessed any interaction effects between the sunscreen and beta-carotene interventions. We think that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. PMID- 27455164 TI - High efficiency coronary MR angiography with nonrigid cardiac motion correction. AB - PURPOSE: To improve the coronary visualization quality of four-dimensional (4D) coronary MR angiography (MRA) through cardiac motion correction and iterative reconstruction. METHODS: A contrast-enhanced, spoiled gradient echo sequence with 3D radial trajectory and self-gating was used for 4D coronary MRA data acquisition at 3 Tesla. A whole-heart 16-phase cine series was reconstructed with respiratory motion correction. Nonrigid registration was performed between the identified quiescent phases and a reference. The motion information of all included phases was then used along with the corresponding k-space data to iteratively reconstruct the final image. Healthy volunteer studies (N = 13) were conducted to compare the proposed method with the conventional strategy, which accepts data from a single, contiguous window out of the original 16-phase data. Apparent signal-to-noise ratio (aSNR) and coronary sharpness were used as the image quality metrics. RESULTS: The proposed method significantly improved aSNR (11.89 +/- 3.76 to 13.97 +/- 5.21; P = 0.005) and scan efficiency (18.8% +/- 6.0% to 40.9% +/- 9.7%; P < 0.001), compared with the conventional strategy. Sharpness of left main (P = 0.002), proximal (P = 0.04), and middle (P = 0.02) right coronary artery, and proximal left anterior descending (P = 0.04) was also significantly improved. CONCLUSION: The proposed cardiac motion-corrected reconstruction significantly improved the achievable quality of coronary visualization from 4D coronary MRA. Magn Reson Med 76:1345-1353, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27455165 TI - Iridium/Copper Co-catalyzed Anti-Stereoselective Ring Opening of Oxabenzonorbornadienes with Grignard Reagents. AB - Cooperative catalysis has been widely considered as one of the most powerful strategies to improve synthetic efficiency. A new iridium/copper cocatalyst was developed for the ring-opening reaction of oxabenzonorbornadienes with a wide variety of Grignard reagents, which afforded the corresponding anti-2-substituted 1,2-dihydronaphthalen-1-ols in high yields (up to 99% yield) under mild conditions. The effects of catalyst loading, Lewis acid, Grignard reagent loading, and reaction temperature on the yield were investigated. To the best of our knowledge, it represents the first example of ring-opening reactions of oxabicyclic alkenes with Grignard reagent nucleophiles in a trans-stereoselective manner. PMID- 27455167 TI - Thermally Reversible Physically Cross-Linked Hybrid Network Hydrogels Formed by Thermosensitive Hairy Nanoparticles. AB - This Article reports on thermally induced reversible formation of physically cross-linked, three-dimensional network hydrogels from aqueous dispersions of thermosensitive diblock copolymer brush-grafted silica nanoparticles (hairy NPs). The hairy NPs consisted of a silica core, a water-soluble polyelectrolyte inner block of poly(2-(methacryloyloxy)ethyltrimethylammonium iodide), and a thermosensitive poly(methoxydi(ethylene glycol) methacrylate) (PDEGMMA) outer block synthesized by sequential surface-initiated atom transfer radical polymerizations and postpolymerization quaternization of tertiary amine moieties. Moderately concentrated dispersions of these hairy nanoparticles in water underwent thermally induced reversible transitions between flowing liquids to self-supporting gels upon heating. The gelation was driven by the lower critical solution temperature (LCST) transition of the PDEGMMA outer block, which upon heating self-associated into hydrophobic domains acting as physical cross-linking points for the gel network. Rheological studies showed that the sol-gel transition temperature decreased with increasing hairy NP concentration, and the gelation was achieved at concentrations as low as 3 wt %. PMID- 27455166 TI - Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. AB - IMPORTANCE: The optimal duration of antibiotic treatment for community-acquired pneumonia (CAP) has not been well established. OBJECTIVE: To validate Infectious Diseases Society of America/American Thoracic Society guidelines for duration of antibiotic treatment in hospitalized patients with CAP. DESIGN, SETTING, AND PARTICIPANTS: This study was a multicenter, noninferiority randomized clinical trial performed at 4 teaching hospitals in Spain from January 1, 2012, through August 31, 2013. A total of 312 hospitalized patients diagnosed as having CAP were studied. Data analysis was performed from January 1, 2014, through February 28, 2015. INTERVENTIONS: Patients were randomized at day 5 to an intervention or control group. Those in the intervention group were treated with antibiotics for a minimum of 5 days, and the antibiotic treatment was stopped at this point if their body temperature was 37.8 degrees C or less for 48 hours and they had no more than 1 CAP-associated sign of clinical instability. Duration of antibiotic treatment in the control group was determined by physicians. MAIN OUTCOMES AND MEASURES: Clinical success rate at days 10 and 30 since admission and CAP-related symptoms at days 5 and 10 measured with the 18-item CAP symptom questionnaire score range, 0-90; higher scores indicate more severe symptoms. RESULTS: Of the 312 patients included, 150 and 162 were randomized to the control and intervention groups, respectively. The mean (SD) age of the patients was 66.2 (17.9) years and 64.7 (18.7) years in the control and intervention groups, respectively. There were 95 men (63.3%) and 55 women (36.7%) in the control group and 101 men (62.3%) and 61 women (37.7%) in the intervention group. In the intent to-treat analysis, clinical success was 48.6% (71 of 150) in the control group and 56.3% (90 of 162) in the intervention group at day 10 (P = .18) and 88.6% (132 of 150) in the control group and 91.9% (147 of 162) in the intervention group at day 30 (P = .33). The mean (SD) CAP symptom questionnaire scores were 24.7 (11.4) vs 27.2 (12.5) at day 5 (P = .10) and 18.6 (9.0) vs 17.9 (7.6) at day 10 (P = .69). In the per-protocol analysis, clinical success was 50.4% (67 of 137) in the control group and 59.7% (86 of 146) in the intervention group at day 10 (P = .12) and 92.7% (126 of 137) in the control group and 94.4% (136 of 146) in the intervention group at day 30 (P = .54). The mean (SD) CAP symptom questionnaire scores were 24.3 (11.4) vs 26.6 (12.1) at day 5 (P = .16) and 18.1 (8.5) vs 17.6 (7.4) at day 10 (P = .81). CONCLUSIONS AND RELEVANCE: The Infectious Diseases Society of America/American Thoracic Society recommendations for duration of antibiotic treatment based on clinical stability criteria can be safely implemented in hospitalized patients with CAP. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2011-001067-51. PMID- 27455168 TI - Aerobic epoxidation catalysed by transition metal substituted polyfluorooxometalates. AB - First row transition metal substituted polyfluorooxmetalates with quasi Wells Dawson structures and a nitro terminal ligand, [NaH2M(NO2)W17F6O55](q-), were used as catalysts for the aerobic epoxidation of cyclic alkenes. The Cu(NO2) analog combined the best traits of conversion and selectivity. Some C-C bond cleavage was also observed and cis isomers reacted preferentially without stereochemical inversion indicating an oxygen atom to double bond concerted reaction. PMID- 27455169 TI - How we do it: anterior and posterior nosebleed trainer, the 3D printing epistaxis project. PMID- 27455170 TI - Catastrophic antiphospholipid syndrome after cardiac surgery. AB - We report a case of catastrophic antiphospholipid syndrome in a patient following mitral valve replacement. The pathophysiology and management of this rare condition is discussed. PMID- 27455171 TI - Pleiotropic mechanisms of action of perhexiline in heart failure. AB - INTRODUCTION: The re-purposing of the anti-anginal drug perhexiline (PHX) has resulted in symptomatic improvements in heart failure (HF) patients. The inhibition of carnitine palmitoyltransferase-1 (CPT-1) has been proposed as the primary mechanism underlying the therapeutic benefit of PHX. This hypothesis is contentious. AREAS COVERED: We reviewed the primary literature and patent landscape of PHX from its initial development in the 1960s through to its emergence as a drug beneficial for HF. We focused on its physico-chemistry, molecular targets, tissue accumulation and clinical dosing. EXPERT OPINION: Dogma that the beneficial effects of PHX are due primarily to potent myocardial CPT-1 inhibition is not supported by the literature and all available evidence point to it being extremely unlikely that the major effects of PHX occur via this mechanism. In vivo PHX is much more likely to be an inhibitor of surface membrane ion channels and also to have effects on other components of cellular metabolism and reactive oxygen species (ROS) generation across the cardiovascular system. However, the possibility that minor effects of PHX on CPT-1 underpin disproportionately large effects on myocardial function cannot be entirely excluded, especially given the massive accumulation of the drug in heart tissue. PMID- 27455172 TI - Farnesylation mediates brassinosteroid biosynthesis to regulate abscisic acid responses. AB - Protein farnesylation is a post-translational modification involving the addition of a 15-carbon farnesyl isoprenoid to the carboxy terminus of select proteins(1 3). Although the roles of this lipid modification are clear in both fungal and animal signalling, many of the mechanistic functions of farnesylation in plant signalling are still unknown. Here, we show that CYP85A2, the cytochrome P450 enzyme that performs the last step in brassinosteroid biosynthesis (conversion of castasterone to brassinolide)(4), must be farnesylated to function in Arabidopsis. Loss of either CYP85A2 or CYP85A2 farnesylation results in reduced brassinolide accumulation and increased plant responsiveness to the hormone abscisic acid (ABA) and overall drought tolerance, explaining previous observations(5). This result not only directly links farnesylation to brassinosteroid biosynthesis but also suggests new strategies to maintain crop yield under challenging climatic conditions. PMID- 27455173 TI - Promising thermoelectric properties of phosphorenes. AB - Electronic, phononic, and thermoelectric transport properties of single layer black- and blue-phosphorene structures are investigated with first-principles based ballistic electron and phonon transport calculations employing hybrid functionals. The maximum values of room temperature thermoelectric figure of merit, ZT corresponding to armchair and zigzag directions of black-phosphorene, ~0.5 and ~0.25, are calculated as rather smaller than those obtained with first principles based semiclassical Boltzmann transport theory calculations. On the other hand, the maximum value of room temperature ZT of blue-phosphorene is predicted to be substantially high and remarkable values as high as 2.5 are obtained for elevated temperatures. Besides the fact that these figures are obtained at the ballistic limit, our findings mark the strong possibility of high thermoelectric performance of blue-phosphorene in new generation thermoelectric applications. PMID- 27455174 TI - New Opportunity for in Situ Exsolution of Metallic Nanoparticles on Perovskite Parent. AB - One of the main challenges for advanced metallic nanoparticles (NPs) supported functional perovskite catalysts is the simultaneous achievement of a high population of NPs with uniform distribution as well as long-lasting high performance. These are also the essential requirements for optimal electrode catalysts used in solid oxide fuel cells and electrolysis cells (SOFCs and SOECs). Herein, we report a facile operando manufacture way that the crystal reconstruction of double perovskite under reducing atmosphere can spontaneously lead to the formation of ordered layered oxygen deficiency and yield segregation of massively and finely dispersed NPs. The real-time observation of this emergent process was performed via an environmental transmission electron microscope. Density functional theory calculations prove that the crystal reconstruction induces the loss of coordinated oxygen surrounding B-site cations, serving as the driving force for steering fast NP growth. The prepared material shows promising capability as an active and stable electrode for SOFCs in various fuels and SOECs for CO2 reduction. The conception exemplified here could conceivably be extended to fabricate a series of supported NPs perovskite catalysts with diverse functionalities. PMID- 27455175 TI - Questioning the use of an age-adjusted D-dimer threshold to exclude venous thromboembolism: analysis of individual patient data from two diagnostic studies. AB - Essentials It is unclear if raising the D-dimer level to exclude venous thrombosis in older patients is valid. We compared this 'age-adjusted' strategy with other ways of interpreting D-dimer results. A non-age adjusted increase, and using higher thresholds in younger patients, was just as accurate. Age-adjustment of D-dimer thresholds does not appear to be appropriate. Click to hear Prof. le Gal's presentation on controversies in venous thromboembolism diagnosis SUMMARY: Background Using a progressively higher D-dimer level to exclude venous thromboembolism (VTE) with increasing age has been proposed but is not well validated. Objective To determine whether it is appropriate to use a progressively higher D-dimer level to exclude VTE with increasing age. Patients/methods We analyzed clinical data and blood samples from 1649 patients with a first suspected deep vein thrombosis or pulmonary embolism. We compared the negative predictive values (NPVs) for VTE, and the proportions of patients with a negative D-dimer result, by using three D-dimer interpretation strategies: a progressively higher D-dimer threshold with increasing age (age-adjusted strategy); the same higher D-dimer threshold in all patients (mean D-dimer strategy); and a progressively higher D-dimer threshold with decreasing age (inverse age-adjusted strategy). Results The NPV with the age-adjusted strategy (99.6%; 95% confidence interval [CI] 99.0-99.9%) was not different from that with the mean D-dimer strategy (99.7%; 95% CI 99.0-99.9%) or that with the inverse age adjusted strategy (99.8%; 95% CI 99.1-99.9%). The proportion of patients with a negative result with the age-adjusted strategy (50.9%; 95% CI 48.5-53.4%) was not different from the proportion of patients with a negative result with the mean D dimer strategy (51.7%; 95% CI 49.3-54.1%) or with the inverse age-adjusted strategy (49.5%; 95% CI 47.1-51.9%). Conclusions Our analysis does not support the use of a progressively higher D-dimer level to exclude VTE with increasing age. PMID- 27455176 TI - Development of PLA films containing oregano essential oil (Origanum vulgare L. virens) intended for use in food packaging. AB - Consumers' concerns about the environment and health have led to the development of new food packaging materials avoiding petroleum-based matrices and synthetic additives. The present study has developed polylactic acid (PLA) films containing different concentrations of essential oil from Origanum vulgare L. virens (OEO). The effectiveness of this new active packaging was checked for use in ready-to eat salads. A plasticising effect was observed when OEO was incorporated in PLA films. The rest of the mechanical and physical properties of developed films did not show much change when OEO was included in the film. An antioxidant effect was recorded only for films containing the highest percentages of the active agent (5% and 10%). In addition, films exhibited in vitro antibacterial activity against Staphylococcus aureus, Yersinia enterocolitica, Listeria monocytogenes, Enterococcus faecalis and Staphylococcus carnosus. Moreover, in ready-to-eat salads, antimicrobial activity was only observed against yeast and moulds, where 5% and 10% of OEO was the most effective. PMID- 27455178 TI - IGF-1 and NT-proBNP in a black and white population: The SABPA study. AB - BACKGROUND: Black populations exhibit lower concentrations of the cardioprotective peptide, insulin-like growth factor-1 (IGF-1), and are more prone to develop hypertensive heart disease than whites. We therefore determined whether lower IGF-1 in black individuals relates to a marker of cardiac overload and systolic dysfunction, namely N-terminal prohormone B-type natriuretic peptide (NT-proBNP). MATERIALS AND METHODS: We included 160 black and 195 white nondiabetic South African men and women (aged 44.4 +/- 9.81 years) and measured ambulatory blood pressure, NT-proBNP, IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). RESULTS: Although the black group presented elevated ambulatory blood pressure accompanied by lower IGF-1 compared to the white group (all P < 0.001), we found similar NT-proBNP concentrations (P = 0.72). Furthermore, in blacks we found a link between NT-proBNP and systolic blood pressure (SBP) (R(2) = 0.37; beta = 0.28; P < 0.001), but not with IGF-1. In the white group, NT-proBNP was inversely associated with IGF-1 (R(2) = 0.39; beta = 0.22; P < 0.001) after adjusting for covariates and potential confounders. As IGF 1 is attenuated in diabetes, we added the initially excluded patients with diabetes (n = 38), and the aforementioned associations remained robust. CONCLUSION: Contrary to the white group, we found no association between NT proBNP and IGF-1 in black adults. Our findings suggest that SBP and other factors may play a greater contributory role in cardiac pathology in blacks. PMID- 27455177 TI - Intersecting epidemics of HIV, HCV, and syphilis among soon-to-be released prisoners in Kyrgyzstan: Implications for prevention and treatment. AB - BACKGROUND: Central Asia is afflicted with increasing HIV incidence, low antiretroviral therapy (ART) coverage and increasing AIDS mortality, driven primarily by people who inject drugs (PWID). Reliable data about HIV, other infectious diseases, and substance use disorders in prisoners in this region is lacking and could provide important insights into how to improve HIV prevention and treatment efforts in the region. METHODS: A randomly sampled, nationwide biobehavioural health survey was conducted in 8 prisons in Kyrgyzstan among all soon-to-be-released prisoners; women were oversampled. Consented participants underwent computer-assisted, standardized behavioural health assessment surveys and testing for HIV, HCV, HBV, and syphilis. Prevalence and means were computed, and generalized linear modelling was conducted, with all analyses using weights to account for disproportionate sampling by strata. RESULTS: Among 381 prisoners who underwent consent procedures, 368 (96.6%) were enrolled in the study. Women were significantly older than men (40.6 vs. 36.5; p=0.004). Weighted prevalence (%), with confidence interval (CI), for each infection was high: HCV (49.7%; CI: 44.8-54.6%), syphilis (19.2%; CI: 15.1-23.5%), HIV (10.3%; CI: 6.9-13.8%), and HBV (6.2%; CI: 3.6-8.9%). Among the 31 people with HIV, 46.5% were aware of being HIV-infected. Men, compared to women, were significantly more likely to have injected drugs (38.3% vs.16.0%; p=0.001). Pre-incarceration and within-prison drug injection, primarily of opioids, was 35.4% and 30.8%, respectively. Independent correlates of HIV infection included lifetime drug injection (adjusted odds ratio [AOR]=38.75; p=0.001), mean number of years injecting (AOR=0.93; p=0.018), mean number of days experiencing drug problems (AOR=1.09; p=0.025), increasing duration of imprisonment (AOR=1.08; p=0.02 for each year) and having syphilis (AOR=3.51; p=0.003), while being female (AOR=3.06; p=0.004) and being a recidivist offender (AOR=2.67; p=0.008) were independently correlated with syphilis infection. CONCLUSION: Drug injection, syphilis co-infection, and exposure to increased risk during incarceration are likely to be important contributors to HIV transmission among prisoners in Kyrgyzstan. Compared to the community, HIV is concentrated 34-fold higher in prisoners. A high proportion of undiagnosed syphilis and HIV infections presents a significant gap in the HIV care continuum. Findings highlight the critical importance of evidence-based responses within prison, including enhanced testing for HIV and sexually transmitted infections, to stem the evolving HIV epidemic in the region. PMID- 27455179 TI - Fluoroquinolone-resistance mechanisms and phylogenetic background of clinical Escherichia coli strains isolated in south-east Poland. AB - Fluorochinolones are a class of broad-spectrum antimicrobials in the treatment of several infections, including those caused by Escherichia coli. Due to the increasing resistance of bacteria to antimicrobials, an understanding of fluoroquinolone resistance is important for infection control. The aim of this study was to determine susceptibility of clinical E. coli strains to fluoroquinolones and characterize their mechanisms of quinolone resistance. Totally, 79 non-duplicate clinical E. coli isolates included in this study were mainly from skin lesion -36 (45.6%) isolates; 54 (68.4%) isolates were assigned to phylogenetic B2 group. Resistance to ciprofloxacin was found in 20 isolates. In the quinolone resistance-determining region (QRDR) region of gyrA and parC, 4 types of point mutations were detected. Mutations in parC gene were found in all strains with gyrA mutations. Predominance of double mutation in codon 83 and 87 of gyrA (90%) and in codon 80 of parC (90%) was found. Moreover, plasmid-mediated quinolone resistance (PMRQ) determinants (qnrA or qnrB and/or aac(6')-Ib-cr) were present in 5 (25%) out of 20 fluoroquinolone-resistant isolates. Resistance to fluoroquinolones in all of the tested clinical E. coli isolates correlated with point mutations in both gyrA and parC. The majority of fluoroquinolone-resistant strains belonged to D and B2 phylogenetic groups. PMID- 27455180 TI - Use of SCW4 gene primers in PCR methods for the identification of six medically important Aspergillus species. AB - Aspergillus species are the cause of invasive mold infections in immunocompromised patients: Aspergillus fumigatus, A. flavus and A. terreus account for most cases of invasive aspergillosis (IA). As certain species are associated with higher mortality and vary in their resistance to antifungal therapy, diagnosis requires increasingly rapid molecular methods that enable sensitive detection and species discrimination. We have developed PCR and Multiplex PCR assays for the detection of six medically important Aspergillus spp. species DNA in bronchoalveolar lavage (BAL) specimens from hematology and intensive care unit (ICU) patients at risk of IA, using different species and genus-specific PCR primers, selected within the SCW4 gene, encoding a cell wall glucanase of A. fumigatus, similar to mannoprotein Mp65 of Candida albicans. The genus-specific PCR primers were able to amplify only Aspergillus DNAs but not that belonging to other fungal genera tested. The species-specific PCR primers allowed differentiation of each Aspergillus species by the amplicon length produced. The methods described in this study are rapid (less than 4 h), reproducible, simple and specific and demonstrate potential application in the clinical laboratory. PMID- 27455181 TI - Diagnostic and prognostic value of molecular and serological investigation of human parvovirus B19 infection during pregnancy. AB - To define diagnostic and prognostic markers of parvovirus B19 (B19V) fetal infection, two groups were investigated: 1) pregnant women with specific symptoms or contacts with symptomatic households (n=37); 2) mothers with pathological ultrasound findings and the relevant fetus at the time of prenatal diagnosis (n=16). In the first group, diagnosis of B19V infection was achieved using IgM detection in 29/37 (78.3%) of patients, while B19V DNA was detected in 36/37 (97.3%) of infected women. In the second group, intrauterine infection was investigated by amniocentesis (n=5), cordocentesis (n=3) or both (n=5). Median B19V DNA load in amniotic fluid was 8.2x107 copies/ml and in fetal blood was 2x109 copies/ml. Maternal blood was positive for B19V DNA (median 3.8x104 copies/ml) in 14/16 (87.5%) women examined. At time of fetal US investigation, all mothers were B19V IgG positive and B19V IgM were detected in 10/16 (62.5%), while fetal B19V IgG and IgM were detected in 1/8 (12.5%) and 5/8 (62.5%), respectively. Phylogenetic analysis revealed that all B19V maternal and fetal strains belonged to genotype 1A. Diagnosis of maternal, fetal and neonatal B19V infection should be based on both IgM and DNA detection. Prognostic markers of congenital B19V infection need to be defined. PMID- 27455182 TI - A cluster of Enterovirus 71 subgenogroup C2 in a nursery school, Italy, 2014. AB - During October 2014, enterovirus (EV) RNA was detected in the stools of four children attending the same class in a nursery school, and hospitalized with mild febrile and vomiting disease in Parma, Italy. Upon sequencing, the viruses were characterized as EV71 subgenogroup C2. Phylogenetic analysis of the four EV71 C2 viruses allowed the distinction of a diverging lineage within subgenogroup C2, containing the Italian EV71 C2 strains and viruses detected in France in 2013. The identification of an outbreak of EV71 C2 in Italy extended information on the geographic diffusion and clinical relevance of these viruses in Europe. PMID- 27455183 TI - Popcorn-Derived Porous Carbon for Energy Storage and CO2 Capture. AB - Porous carbon materials have drawn tremendous attention due to its applications in energy storage, gas/water purification, catalyst support, and other important fields. However, producing high-performance carbons via a facile and efficient route is still a big challenge. Here we report the synthesis of microporous carbon materials by employing a steam-explosion method with subsequent potassium activation and carbonization of the obtained popcorn. The obtained carbon features a large specific surface area, high porosity, and doped nitrogen atoms. Using as an electrode material in supercapacitor, it displays a high specific capacitance of 245 F g(-1) at 0.5 A g(-1) and a remarkable stability of 97.8% retention after 5000 cycles at 5 A g(-1). The product also exhibits a high CO2 adsorption capacity of 4.60 mmol g(-1) under 1066 mbar and 25 degrees C. Both areal specific capacitance and specific CO2 uptake are directly proportional to the surface nitrogen content. This approach could thus enlighten the batch production of porous nitrogen-doped carbons for a wide range of energy and environmental applications. PMID- 27455184 TI - Does facial expression recognition provide a toehold for the development of emotion understanding? AB - The authors explored predictions from basic emotion theory (BET) that facial emotion expression recognition skills are insular with respect to their own development, and yet foundational to the development of emotional perspective taking skills. Participants included 417 preschool children for whom estimates of these 2 emotion understanding variables and receptive language skills were obtained at 2 time points, separated by 24 weeks. Path results for autoregressive cross-lagged structural equation models revealed support for the BET predictions for younger preschoolers (ages 36 to 48 months). In contrast, results for older preschoolers (ages 49 to 67 months) revealed bidirectional influences between receptive language and emotion understanding consistent with constructionist theories of emotion. Findings support a hybrid model in which associations between receptive language and emotion understanding skills are initially nonsignificant and become significant over time. The implications of emotion expression recognition as an early toehold for the development of more advanced emotion understanding skills are discussed. (PsycINFO Database Record PMID- 27455186 TI - The effects of Tulsa's CAP Head Start program on middle-school academic outcomes and progress. AB - This study presents evidence pertinent to current debates about the lasting impacts of early childhood educational interventions and, specifically, Head Start. A group of students who were first studied to examine the immediate impacts of the Tulsa, Oklahoma, Community Action Project (CAP) Head Start program were followed-up in middle school, primarily as 8th graders. Using ordinary least squares and logistic regressions with a rich set of controls and propensity score weighting models to account for differential selection into Head Start, we compared students who had attended the CAP Head Start program and enrolled in the Tulsa Public Schools (TPS) as kindergarteners with children who also attended TPS kindergarten but had attended neither CAP Head Start nor the TPS pre-K program as 4-year-olds. CAP Head Start produced significant positive effects on achievement test scores in math and on both grade retention and chronic absenteeism for middle-school students as a whole; positive effects for girls on grade retention and chronic absenteeism; for white students on math test scores; for Hispanic students on math test scores and chronic absenteeism, and for students eligible for free lunches on math test scores, grade retention, and chronic absenteeism. We conclude that the Tulsa CAP Head Start program produced significant and consequential effects into the middle school years. (PsycINFO Database Record PMID- 27455185 TI - Numerosity but not texture-density discrimination correlates with math ability in children. AB - Considerable recent work suggests that mathematical abilities in children correlate with the ability to estimate numerosity. Does math correlate only with numerosity estimation, or also with other similar tasks? We measured discrimination thresholds of school-age (6- to 12.5-years-old) children in 3 tasks: numerosity of patterns of relatively sparse, segregatable items (24 dots); numerosity of very dense textured patterns (250 dots); and discrimination of direction of motion. Thresholds in all tasks improved with age, but at different rates, implying the action of different mechanisms: In particular, in young children, thresholds were lower for sparse than textured patterns (the opposite of adults), suggesting earlier maturation of numerosity mechanisms. Importantly, numerosity thresholds for sparse stimuli correlated strongly with math skills, even after controlling for the influence of age, gender and nonverbal IQ. However, neither motion-direction discrimination nor numerosity discrimination of texture patterns showed a significant correlation with math abilities. These results provide further evidence that numerosity and texture-density are perceived by independent neural mechanisms, which develop at different rates; and importantly, only numerosity mechanisms are related to math. As developmental dyscalculia is characterized by a profound deficit in discriminating numerosity, it is fundamental to understand the mechanism behind the discrimination. (PsycINFO Database Record PMID- 27455187 TI - The forest, the trees, and the leaves: Differences of processing across development. AB - To act and think, children and adults are continually required to ignore irrelevant visual information to focus on task-relevant items. As real-world visual information is organized into structures, we designed a feature visual search task containing 3-level hierarchical stimuli (i.e., local shapes that constituted intermediate shapes that formed the global figure) that was presented to 112 participants aged 5, 6, 9, and 21 years old. This task allowed us to explore (a) which level is perceptively the most salient at each age (i.e., the fastest detected level) and (b) what kind of attentional processing occurs for each level across development (i.e., efficient processing: detection time does not increase with the number of stimuli on the display; less efficient processing: detection time increases linearly with the growing number of distractors). Results showed that the global level was the most salient at 5 years of age, whereas the global and intermediate levels were both salient for 9 year-olds and adults. Interestingly, at 6 years of age, the intermediate level was the most salient level. Second, all participants showed an efficient processing of both intermediate and global levels of hierarchical stimuli, and a less efficient processing of the local level, suggesting a local disadvantage rather than a global advantage in visual search. The cognitive cost for selecting the local target was higher for 5- and 6-year-old children compared to 9-year-old children and adults. These results are discussed with regards to the development of executive control. (PsycINFO Database Record PMID- 27455188 TI - Breaking the double-edged sword of effort/trying hard: Developmental equilibrium and longitudinal relations among effort, achievement, and academic self-concept. AB - Ever since the classic research of Nicholls (1976) and others, effort has been recognized as a double-edged sword: while it might enhance achievement, it undermines academic self-concept (ASC). However, there has not been a thorough evaluation of the longitudinal reciprocal effects of effort, ASC, and achievement, in the context of modern self-concept theory and statistical methodology. Nor have there been developmental equilibrium tests of whether these effects are consistent across the potentially volatile early-to-middle adolescence. Hence, focusing on mathematics, we evaluate reciprocal effects models (REMs) over the first 4 years of secondary school (grades 5-8), relating effort, achievement (test scores and school grades), ASC, and ASC * Effort interactions for a representative sample of 3,144 German students (Mage = 11.75 years at Wave 1). ASC, effort, and achievement were positively correlated at each wave, and there was a clear pattern of positive reciprocal positive effects among ASC, test scores, and school grades-each contributing to the other, after controlling for the prior effects of all others. There was an asymmetrical pattern of effects for effort that is consistent with the double-edged sword premise: prior school grades had positive effects on subsequent effort, but prior effort had nonsignificant or negative effects on subsequent grades and ASC. However, on the basis of a synergistic application of new theory and methodology, we predicted and found a significant ASC * Effort interaction, such that prior effort had more positive effects on subsequent ASC and school grades when prior ASC was high-thus providing a key to breaking the double-edged sword. (PsycINFO Database Record PMID- 27455189 TI - Children's recognition of fairness and others' welfare in a resource allocation task: Age related changes. AB - The present study investigated age-related changes regarding children's (N = 136) conceptions of fairness and others' welfare in a merit-based resource allocation paradigm. To test whether children at 3- to 5-years-old and 6- to 8-years-old took others' welfare into account when dividing resources, in addition to merit and equality concerns, children were asked to allocate, judge, and reason about allocations of necessary (needed to avoid harm) and luxury (enjoyable to have) resources to a hardworking and a lazy character. While 3- to 5-year-olds did not differentiate between distributing luxury and necessary resources, 6- to 8-year olds allocated luxury resources more meritoriously than necessary resources. Further, children based their allocations of necessary resources on concerns for others' welfare, rather than merit, even when one character was described as working harder. The findings revealed that, with age, children incorporated the concerns for others' welfare and merit into their conceptions of fairness in a resource allocation context, and prioritized these concerns differently depending on whether they were allocating luxury or necessary resources. Further, with age, children weighed multiple moral concerns including equality, merit, and others' welfare, when determining the fair allocation of resources. (PsycINFO Database Record PMID- 27455190 TI - Children rectify inequalities for disadvantaged groups. AB - Children's decisions regarding the allocation of societal resources in the context of preexisting inequalities were investigated. African American and European American children ages 5 to 6 years (n = 91) and 10 to 11 years (n = 94) judged the acceptability of a medical resource inequality on the basis of race, allocated medical supplies, evaluated different resource allocation strategies, and completed a measure of status awareness based on race. With age, children were increasingly aware of wealth status disparities between African Americans and European Americans, and judged a medical resource inequality between groups more negatively. Further, with age, children rectified the resource inequality over perpetuating it, but only when African American children were disadvantaged. With age, children also referenced rights when reasoning about their judgments concerning the disadvantaged African American group. When European American children were disadvantaged, children did not systematically allocate more resources to one group over another. The results are discussed in terms of social inequalities, disadvantaged status, moral judgments, and intergroup attitudes. (PsycINFO Database Record PMID- 27455191 TI - Fe N-Heterocyclic Carbene Complexes as Promising Photosensitizers. AB - The photophysics and photochemistry of transition metal complexes (TMCs) has long been a hot field of interdisciplinary research. Rich metal-based redox processes, together with a high variety in electronic configurations and excited-state dynamics, have rendered TMCs excellent candidates for interconversion between light, chemical, and electrical energies in intramolecular, supramolecular, and interfacial arrangements. In specific applications such as photocatalytic organic synthesis, photoelectrochemical cells, and light-driven supramolecular motors, light absorption by a TMC-based photosensitizer and subsequent excited-state energy or electron transfer constitute essential steps. In this context, TMCs based on rare and expensive metals, such as ruthenium and iridium, are frequently employed as photosensitizers, which is obviously not ideal for large-scale implementation. In the search for abundant and environmentally benign solutions, six-coordinate Fe(II) complexes (Fe(II)L6) have been widely considered as highly desirable alternatives. However, not much success has been achieved due to the extremely short-lived triplet metal-to-ligand charge transfer ((3)MLCT) excited state that is deactivated by low-lying metal-centered (MC) states on a 100 fs time scale. A fundamental strategy to design useful Fe-based photosensitizers is thus to destabilize the MC states relative to the (3)MLCT state by increasing the ligand field strength, with special focus on making eg sigma* orbitals on the Fe center energetically less accessible. Previous efforts to directly transplant successful strategies from Ru(II)L6 complexes unfortunately met with limited success in this regard, despite their close chemical kinship. In this Account, we summarize recent promising results from our and other groups in utilizing strongly sigma-donating N-heterocyclic carbene (NHC) ligands to make strong-field Fe(II)L6 complexes with significantly extended (3)MLCT lifetimes. Already some of the first homoleptic bis(tridentate) complexes incorporating (CNHC^Npyridine^CNHC)-type ligands gratifyingly resulted in extension of the (3)MLCT lifetime by more than 2 orders of magnitude compared to the parental [Fe(tpy)2](2+) (tpy = 2,2':6',2"-terpyridine) complex. Quantum chemical (QC) studies also revealed that the (3)MC instead of the (5)MC state likely dictates the deactivation of the (3)MLCT state, a behavior distinct from traditional Fe(II)L6 complexes but rather resembling Ru analogues. A heteroleptic Fe(II) NHC complex featuring mesoionic bis(1,2,3-triazol-5-ylidene) (btz) ligands also delivered a 100-fold elongation of the (3)MLCT lifetime relative to its parental [Fe(bpy)3](2+) (bpy = 2,2'-bipyridine) complex. Again, a Ru-like deactivation mechanism of the (3)MLCT state was indicated by QC studies. With a COOH functionalized homoleptic complex, a record (3)MLCT lifetime of 37 ps was recently observed on an Al2O3 nanofilm. As a proof of concept, it was further demonstrated that the significant improvement in the (3)MLCT lifetime indeed benefits efficient light harvesting with Fe(II) NHC complexes. For the first time, close-to-unity electron injection from the lowest-energy (3)MLCT state to a TiO2 nanofilm was achieved by a stable Fe(II) complex. This is in complete contrast to conventional Fe(II)L6-derived photosensitizers that could only make use of high-energy photons. These exciting results significantly broaden the understanding of the fundamental photophysics and photochemistry of d(6) Fe(II) complexes. They also open up new possibilities to develop solar energy-converting materials based on this abundant, inexpensive, and intrinsically nontoxic element. PMID- 27455192 TI - Sub-millisecond (125)Te NMR spin-lattice relaxation times and large Knight shifts in complex tellurides: Validation of a quadratic relation across the spectrum. AB - (125)Te NMR spectra and spin-lattice relaxation times, T1, have been measured for several GeTe-based materials with Te excess. The spectra show inhomogeneous broadening by several thousand ppm and a systematic variation in T1 relaxation time with resonance frequency. The quadratic dependence of the spin-lattice relaxation rate, 1/T1, on the Knight shift in the Korringa relation is found to be valid over a wide range of Knight shifts. This result confirms that T1 relaxation in GeTe-based materials is mostly dominated by hyperfine interaction between nuclei and free charge carriers. In GeTe with 2.5% excess of Te, about 15% of the material exhibits a Knight shift of >=4500ppm and a T1 of only 0.3ms, indicating a high hole concentration that could correspond to close to 50% vacancies on the Ge sublattice in this component. Our findings provide a basis for determining the charge carrier concentration and its distribution in complex thermoelectric and phase-change tellurides, which should lead to a better understanding of electronic and thermal transport properties as well as chemical bonding in these materials. PMID- 27455194 TI - Decreasing Unintended Pregnancy: Opportunities Created by the Affordable Care Act. PMID- 27455193 TI - Human papillomavirus vaccine and Pap tests on college campuses: How do historically black colleges and universities (HBCUs) measure up? AB - OBJECTIVE: The availability of cervical cancer prevention services at college health centers was compared between historically black colleges and universities (HBCUs) and non-HBCUs. METHODS: Four-year, non-primarily distant learning colleges, matching HBCUs with randomly selected non-HBCUs within the same states (N = 136) were examined. Data were collected (2014-2015 academic year) on the availability of human papillomavirus (HPV) vaccine and Pap tests at college health centers. HBCUs were compared with non-HBCUs using conditional logistic regression, and correlates of offering these services were identified. RESULTS: Many institutions did not offer HPV vaccine or Pap tests. Fewer HBCUs offered HPV vaccine (18% vs 53%) and Pap tests (50% vs 76%) compared with non-HBCUs. In multivariable analyses, HBCUs remained less likely than non-HBCUs to offer HPV vaccine (odds ratio [OR] = 0.07, 95% confidence interval [CI]: 0.02-0.26) and Pap tests (OR = 0.19, 95% CI: 0.06-0.61). CONCLUSIONS: Greater effort is needed to make cervical cancer prevention services available at colleges, especially at HBCUs. PMID- 27455195 TI - Molecular and Epidemiological Analysis of a Campylobacter jejuni Outbreak in Northern Italy in November 2013. AB - Campylobacter spp. is the most common gastrointestinal pathogen worldwide with a very low reported incidence in Italy. In November of 2013, local and national public health authorities investigated an outbreak caused by Campylobacter jejuni among children in a kindergarten in Northern Italy. A case was defined as a child who had diarrhea with a laboratory-confirmed diagnosis of C. jejuni between 11 and 30 November. Stool samples from the kindergarten kitchen staff and environmental samples from the kitchen were examined for enteric pathogens. As food leftovers were not available, the menu logbook of the refectory was reviewed to identify a possible source of the outbreak. C. jejuni strains were tested for antimicrobial susceptibility and subtyped by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). We identified 20 cases among 247 schoolchildren (attack rate = 8%), all who reported having lunch in the kindergarten. The stools from the kitchen staff as well as the environmental samples were negative for enteric pathogens. The identified outbreak strains (n = 5) were sensitive to all of the antimicrobials tested; the first four strains showed an identical PFGE profile, whereas the fifth strain showed a PFGE pattern similarity of 89%. Using MLST, all five strains were assigned to a single sequence type (ST), ST451 (clonal complex, CC21); this was the first identification of ST and the third reported outbreak of C. jejuni in Italy. Molecular typing confirmed that most of the cases belonged to a clonal cluster supporting the hypothesis of a common source; however, the source was not identified. Due to a delayed start of the investigation, it was not possible to perform any microbiological evaluation of the food consumed. PMID- 27455196 TI - COCCIDIAL INFECTION OF THE ADRENAL GLANDS OF LEATHERBACK SEA TURTLES (DERMOCHELYS CORIACEA). AB - Histologic lesions incidental to the cause of death were observed in the adrenal glands of 17 subadult and adult leatherback sea turtles ( Dermochelys coriacea ) found dead or moribund on or near shore in North America. Round bodies, 250-300 MUm in diameter composed of an outer capsule and large multinucleated cells surrounding a central mass of acellular material were distributed throughout the affected glands. Protozoal etiology was suspected based on some resemblance to coccidia; however, features diagnostic for coccidial infection were lacking in all but one case, which had a focal area of adrenalitis containing zoites. A novel eucoccidian partial 18S rRNA genetic sequence was consistently detected in adrenal glands with lesions. With the use of quantitative PCR, a specific area of the V4 region of the coccidian 18S gene was quantified in affected adrenal glands and correlated significantly with density of the histologic lesions. A second distinct, but closely related, 18S sequence was also amplified from the adrenal gland of one turtle and from a fecal sample containing unsporulated coccidian oocysts. The two 18S sequences identified from leatherback sea turtles form a clade within the family Eimeriidae. Further investigation is required to understand better the morphology of the life stages, life cycle, and potential effects of this coccidian parasite on adrenal function. PMID- 27455197 TI - A PELAGIC OUTBREAK OF AVIAN CHOLERA IN NORTH AMERICAN GULLS: SCAVENGING AS A PRIMARY MECHANISM FOR TRANSMISSION? AB - Avian cholera, caused by the bacterium Pasteurella multocida , is an endemic disease globally, often causing annual epizootics in North American wild bird populations with thousands of mortalities. From December 2006 to March 2007, an avian cholera outbreak caused mortality in marine birds off the coast of Atlantic Canada, largely centered 300-400 km off the coast of the island of Newfoundland. Scavenging gulls ( Larus spp.) were the primary species detected; however, mortality was also identified in Black-legged Kittiwakes ( Rissa tridactyla ) and one Common Raven ( Corvus corax ), a nonmarine species. The most common gross necropsy findings in the birds with confirmed avian cholera were acute fibrinous and necrotizing lesions affecting the spleen, air sacs, and pericardium, and nonspecific hepatomegaly and splenomegaly. The etiologic agent, P. multocida serotype 1, was recovered from 77 of 136 carcasses examined, and confirmed or probable avian cholera was diagnosed in 85 cases. Mortality observed in scavenging gull species was disproportionately high relative to their abundance, particularly when compared to nonscavenging species. The presence of feather shafts in the ventricular lumen of the majority of larid carcasses diagnosed with avian cholera suggests scavenging of birds that died from avian cholera as a major mode of transmission. This documentation of an outbreak of avian cholera in a North American pelagic environment affecting primarily scavenging gulls indicates that offshore marine environments may be a component of avian cholera dynamics. PMID- 27455198 TI - MONITORING RANAVIRUS-ASSOCIATED MORTALITY IN A DUTCH HEATHLAND IN THE AFTERMATH OF A RANAVIRUS DISEASE OUTBREAK. AB - The ranaviruses are an emerging group of viruses that infect amphibians, fish, and reptiles. Although ranaviruses have not been linked to extinctions, emergence in amphibian communities has resulted in population declines for some species. We present the results of ranavirus-associated mortality in a Dutch national park in the aftermath of an outbreak associated with a common midwife toad virus (CMTV) like ranavirus. We monitored five bodies of water across Dwingelderveld National Park, the Netherlands, in 2011-13. Dead and live amphibians were counted weekly July-September and every 2 wk in June and October. Dead amphibians were collected and tested for ranavirus infection. In addition, we measured biologic, chemical, and physical site characteristics to test for a correlation with ranavirus associated mortality. Ranavirus infection was widespread in our study area and we observed nearly continuous presence of dead, ranavirus-infected amphibians in the presence of asymptomatic, live amphibians throughout our study. Fatalities occurred in larval, subadult, and adult amphibians. Ranavirus infection prevalence (based on fatal cases) was significantly associated with increasing fractions of adults and subadults compared to juveniles and larvae in the population, but was unrelated to any other measured site characteristics. Our findings showed that a CMTV-like ranavirus can persist long term in an ecosystem, affecting a diversity of amphibian species and life stages for a prolonged period. This study illustrates the importance of monitoring the modes of spread for ranaviruses and their impact on amphibian populations. PMID- 27455199 TI - Effect of Trichoderma on horticultural seedlings' growth promotion depending on inoculum and substrate type. AB - AIMS: The biostimulant effect of Trichoderma spp. on horticultural crops are highly variable. Thus, practical use of Trichoderma sp. requires feasible formulated products and suitable substrates. METHODS AND RESULTS: This study evaluates the survival and the growth-promotion effect of a Trichoderma saturnisporum rice formulation compared with a nonformulated conidia suspension (seven treatments in total), on tomato, pepper and cucumber seedlings grown in two substrates: (i) rich in organic matter (OM) and (ii) mineral substrate without OM. The results showed beneficial effects on seedling growth in the OM rich substrate when T. saturnisporum rice formulation (mainly at maximum concentration) was applied, but the effects were opposite when the mineral substrate without OM was used. The effects were closely linked to the level of inoculum in the substrate, which was greater upon application of the formulated inoculum as opposed to the nonformulated one. CONCLUSIONS: The use of rice to prepare the inoculum of T. saturnisporum seems to be promising for seedling growth in the nursery when it is applied in a substrate that is rich in organic matter, but it must be considered that under certain conditions of food shortage, Trichoderma sp. could show pathogenicity to seedlings. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides evidence of the complexity inherent in the use of micro-organisms in agriculture, while also confirming that the activity of the biofertilizers based on Trichoderma depends on the type of inoculum and its concentration, as well as the properties of the medium in which the fungi develop. Further studies assessing the effectiveness or possible pathogenicity of Trichoderma in different soils under greenhouse conditions must be addressed. PMID- 27455200 TI - ISBER Regional Meeting in Bethesda, Maryland. PMID- 27455201 TI - Laparoscopy Is Safe in Infants and Neonates with Congenital Heart Disease: A National Study of 3684 Patients. AB - PURPOSE: Concerns have been raised about the use of laparoscopic surgery (LS) in infants with congenital heart disease (CHD) due to their unique physiology. Prior studies on the safety and effectiveness of laparoscopy in children with CHD are limited in scope and cohort size. MATERIALS AND METHODS: We identified children <1 year of age with CHD who underwent abdominal surgery in the 2012-2013 American College of Surgeons National Surgical Quality Improvement Project Pediatric database. Patients were stratified by surgical approach: open surgery (OS) versus LS. We then compared postoperative complications, postoperative length of stay, and 30-day mortality by using multivariable regression methods. RESULTS: In total, 3684 patients met study criteria: 2502 underwent OS while 1182 underwent LS. Infants who underwent LS were older (98 days versus 36 days), larger by weight (4.2 kg versus 3.2 kg), and more likely to require nutritional support preoperatively (74.7% versus 60.5%) (all P < .001). After multivariable adjustment, LS was associated with lower overall complication rate (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.34-0.52, P < .001) and shorter postoperative length of stay (effect size -1.8 days, 95% CI -1.8-1.2, P < .001). LS and OS demonstrated similar 30-day mortality (OR 0.71, 95% CI 0.38-1.32, P = .28). CONCLUSIONS: Laparoscopy can be performed safely in infants with CHD who need abdominal surgery. Although further studies may be useful in determining which infants with congenital cardiac disease benefit the most from use of laparoscopy, minimally invasive techniques can be applied to routine and complex abdominal procedures. PMID- 27455202 TI - The Importance of an Evidence-based Workup for Recurrent Pregnancy Loss. AB - Choosing an evidence-based workup and treatment for recurrent pregnancy loss is imperative to provide best patient care and create a culture that permits rigorous research into potential (not yet evidence-based) tests and therapeutics. As health sciences technologies become more sophisticated, more precise, and less expensive, new tools may be developed that allow better evaluation and treatment of couples with recurrent pregnancy loss. The goal must remain optimizing value and adhering to evidence-based care. PMID- 27455203 TI - Recurrent Pregnancy Loss: Generally Accepted Causes and Their Management. AB - Recurrent pregnancy loss (RPL), commonly defined as 3 consecutive losses <10 weeks gestation, affects up to 5% of couples. Well-accepted causes include uterine malformation, antiphospholipid syndrome, and parental chromosomal abnormalities; however, the majority of RPL cases are idiopathic (up to 75%). This chapter covers these accepted causes of RPL and provides diagnosis and management strategies for patients falling within the above categories. PMID- 27455207 TI - Nurse workload and inexperienced medical staff members are associated with seasonal peaks in severe adverse events in the adult medical intensive care unit: A seven-year prospective study. AB - OBJECTIVE: Our purpose was to identify potential organizational factors that contributed to life-threatening adverse events in adult intensive care unit. METHODS: A prospective, observational, dynamic cohort study was carried out from January 2006 to December 2013 in a 20-bed adult medical intensive care unit. All patients admitted to the intensive care unit and who experienced one or more selected life-threatening adverse events (mainly unexpected cardiac arrest, unplanned extubation, reintubation after planned extubation, and readmission within 48h of intensive care unit discharge) were included in the analysis. Negative binomial regression was used to model how human resources, work organization, and intensive care activity influenced the monthly rate of selected severe adverse events. Data were collected from local and national databases. RESULTS: Overall, 638 severe adverse events involving 498 patients were recorded. Adverse events increased seasonally in May, November and December (p<.001 vs other months). The proportion of inexperienced nurses and doctors' working hours could not explain these seasonal peaks of adverse events. Multivariate analysis identified bed-to-nurse ratio and the arrival of inexperienced residents or senior registrars as being independently associated with the rate of adverse events (incidence risk ratio=1.36 (95% confidence interval, 1.05-1.75), and 1.07 (95% confidence interval, 1.01-1.13), respectively; p=.01 in both cases). According to this model, a one-unit increase in the day-night shifts carried out by each nurse per month tended to reduce the rate of adverse events (incidence risk ratio=0.60 (95% confidence interval, 0.36-1.01), p=.05). Severity at intensive care unit admission did not influence the rate of adverse events (incidence risk ratio=1.02 (95% confidence interval, 1.00-1.04), p=.12). CONCLUSIONS: Results identify nurse workload and the arrival of inexperienced residents or senior registrars as risk factors for the occurrence of life threatening adverse events in the adult medical intensive care unit. Limiting fluctuations in bed-to-nurse ratio and providing inexperienced medical staff members with sufficient supervision may decrease severe adverse events in critically ill patients. PMID- 27455209 TI - Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool alpha-Amino Acids for Natural Product Synthesis. AB - Chiral pool alpha-amino acids have been used as powerful tools for the total synthesis of structurally diverse natural products. Some common naturally occurring alpha-amino acids are readily available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric synthesis can be categorized prudently as chiral sources, devices, and inducers. This review specifically examines recent advances in substrate-controlled asymmetric reactions induced by the chirality of alpha-amino acid templates in natural product synthesis research and related areas. PMID- 27455208 TI - A Comprehensive Analysis of the Impact of HIV on HCV Immune Responses and Its Association with Liver Disease Progression in a Unique Plasma Donor Cohort. AB - OBJECTIVE: Human Immunodeficiency Virus (HIV) and Hepatitis C virus (HCV) co infection is recognized as a major cause of morbidity and mortality among HIV-1 infected patients. Our understanding of the impact of HIV infection on HCV specific immune responses and liver disease outcome is limited by the heterogeneous study populations with genetically diverse infecting viruses, varying duration of infection and anti-viral treatment. METHODS: Viral-specific immune responses in a cohort of 151 HCV mono- and HIV co-infected former plasma donors infected with a narrow source of virus were studied. HCV and HIV specific T cell responses were correlated with clinical data. RESULTS: HIV-1 accelerated liver disease progression and decreased HCV specific T cell immunity. The magnitude of HCV specific T cell responses inversely correlated with lower HCV RNA load and reduced liver injury as assessed by non-invasive markers of liver fibrosis. HIV co-infection reduced the frequency of HCV specific CD4+ T cells with no detectable effect on CD8+ T cells or neutralizing antibody levels. CONCLUSION: Our study highlights the impact of HIV co-infection on HCV specific CD4+ T cell responses in a unique cohort of patients for both HCV and HIV and suggests a crucial role for these cells in controlling chronic HCV replication and liver disease progression. PMID- 27455210 TI - Application of Ultrasound in a Closed System: Optimum Condition for Antioxidants Extraction of Blackberry (Rubus fructicosus) Residues. AB - Blackberry processing generates up to 20% of residues composed mainly of peel, seeds and pulp that are abundant in flavonoids. The objective of this study was to optimize the ultrasound conditions, in a closed system, for antioxidants extraction, using the response surface methodology. Blackberry (Rubus fructicosus) residues were analyzed for total phenolics, total anthocyanins, and antioxidant activity by ABTS and DPPH. The selected independent variables were ultrasound amplitude (X1: 80%-90%) and extraction time (X2: 10-15 min), and results were compared with conventional extraction methods. The optimal conditions for antioxidants extraction were 91% amplitude for 15 min. The results for total phenolic content and anthocyanins and antioxidant activity by ABTS and DPPH were of 1201.23 mg gallic acid equivalent (GAE)/100 g dry weight basis (dw); 379.12 mg/100 g.dw; 6318.98 umol Trolox equivalent (TE)/100 g.dw and 9617.22 umol TE/100 g.dw, respectively. Compared to solvent extraction methods (water and ethanol), ultrasound achieved higher extraction of all compounds except for anthocyanins. The results obtained demonstrated that ultrasound is an alternative to improve extraction yield of antioxidants from fruit residues such as blackberry. PMID- 27455211 TI - Intra-Population Variation of Secondary Metabolites in Cistus ladanifer L. AB - In previous studies, secondary metabolites in the leaf exudate of Cistus ladanifer, specifically aglycone flavonoids and diterpenes, were demonstrated to play an ecophysiological role. They protect against ultraviolet radiation, have antiherbivore activity, and are allelopathic agents. Their synthesis in the plant was also found to vary quantitatively and qualitatively in response to various environmental factors. In view of these findings, the present work was designed to clarify whether within a single population there are differences among individuals subject to the same environmental conditions. To this end, we analyzed the leaves of 100 individuals of C. ladanifer. The results showed the existence of intrapopulational variation, since, although all the individuals had the same composition of secondary chemistry, the amounts were different. The individuals of a given population of C. ladanifer differ from each other even when growing under similar conditions. According to the ammount of flavonoids and diterpenes observed in each individual, it was possible to distinguish four different groups of individuals. Most individuals, evenly distributed within the population, had low concentrations of the studied compounds, whilst other individuals synthesized greater amounts and were randomly distributed among the former. Given the functions of flavonoids and diterpenes in this species, the quantified intra-population variation may involve greater plasticity for the species in the face of environmental changes. PMID- 27455212 TI - Novel Improved Synthesis of HSP70 Inhibitor, Pifithrin-MU. In Vitro Synergy Quantification of Pifithrin-MU Combined with Pt Drugs in Prostate and Colorectal Cancer Cells. AB - We describe a novel improved approach to the synthesis of the important and well known heat shock protein 70 inhibitor (HSP70), pifithrin-MU, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-MU and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-MU and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-MU. PMID- 27455213 TI - Stability and Degradation of Caffeoylquinic Acids under Different Storage Conditions Studied by High-Performance Liquid Chromatography with Photo Diode Array Detection and High-Performance Liquid Chromatography with Electrospray Ionization Collision-Induced Dissociation Tandem Mass Spectrometry. AB - Caffeoylquinic acids (CQAs) are main constituents in many herbal medicines with various biological and pharmacological effects. However, CQAs will degrade or isomerize when affected by temperature, pH, light, etc. In this study, high performance liquid chromatography with photodiode array detection (HPLC-PDA) and high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was utilized to study the stability and degradation of CQAs (three mono-acyl CQAs and four di-acyl CQAs) under various ordinary storage conditions (involving different temperatures, solvents, and light irradiation). The results indicated that the stability of CQAs was mainly affected by temperature and light irradiation, while solvents did not affect it in any obvious way under the conditions studied. Mono acyl CQAs were generally much more stable than di-acyl CQAs under the same conditions. Meanwhile, the chemical structures of 30 degradation products were also characterized by HPLC-MS(n), inferring that isomerization, methylation, and hydrolysis were three major degradation pathways. The result provides a meaningful clue for the storage conditions of CQAs standard substances and samples. PMID- 27455214 TI - Identification of Chemical Composition of Leaves and Flowers from Paeonia rockii by UHPLC-Q-Exactive Orbitrap HRMS. AB - The Paeonia genus, an important source of crude drugs, has been extensively used in traditional Chinese medicine (TCM) to treat cardiovascular and female-related diseases. Although many peony species have been investigated, the study of Paeonia rockii is still quite limited, especially its chemical composition. Here, an advanced ultra-high-performance liquid chromatography (UHPLC) analytical technique combined with Q-Exactive Orbitrap hybrid quadrupole-Orbitrap mass spectrometry utilizing high-resolution full MS and MS/MS scan modes was applied to screen and identify the chemical constituents of this species. As a result, a total of 46 compounds were characterized, including 11 monoterpene glycosides, five phenolic acids, six tannins and 24 flavonoids. Among them, 16 compounds were reported for the first time in Paeonia rockii. PMID- 27455215 TI - A New Method for the Isolation of Ergosterol and Peroxyergosterol as Active Compounds of Hygrophoropsis aurantiaca and in Vitro Antiproliferative Activity of Isolated Ergosterol Peroxide. AB - In the present study, ergosterol peroxide and ergosterol were isolated for the first time from fresh fruit bodies of Hygrophoropsis aurantiaca (False Chanterelle). The substances were characterized mainly by spectroscopic methods (1H-NMR, (13)C-NMR, DEPT-45, DEPT-90, DEPT-135, 2D-NMR). In our study, a new specific thin layer chromatographic method was developed for determination of ergosterol and ergosterol peroxide in H. aurantiaca extract. The method is based on the separation of n-hexane extract on silica gel (Silica Gel G) TLC plates using the optimized solvent system toluene/ethyl acetate (3:1; v/v). The main advantages of the developed method are the simplicity of operation and the low cost. The in vitro study results revealed the antiproliferative properties of ergosterol peroxide against LS180 human colon cancer cells. The described effect was attributed both to altered mitochondrial activity and decreased DNA synthesis. Additionally, in the same concentration range the investigated compound was not toxic to CCD 841 CoTr human colon epithelial cells. The present study suggests that fruit bodies of H. aurantiaca have great potential for producing substances and extracts with potential applications in medicine. PMID- 27455217 TI - Erratum: Liu, H., et al. Radical Scavenging by Acetone: A New Perspective to Understand Laccase/ABTS Inactivation and to Recover Redox Mediator. Molecules 2015, 20, 19907-19913. AB - The Molecules Editorial Office wishes to report the following erratum to this paper [1].[...]. PMID- 27455216 TI - Protective Effect of the Total Flavonoids from Rosa laevigata Michx Fruit on Renal Ischemia-Reperfusion Injury through Suppression of Oxidative Stress and Inflammation. AB - Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Our previous studies have shown that the total flavonoids (TFs) from Rosa laevigata Michx fruit has various activities, however, there were no papers reporting the role of the TFs against renal IRI. In the present work, a hypoxia/reoxygenation (H/R) model in NRK-52E cells and ischemia-reperfusion model in rats were used. The results showed that the TFs significantly attenuated cell injury and markedly decreased serum creatinine (Cr) and blood urea nitrogen (BUN) levels in rats. Further investigation revealed that the TFs markedly decreased the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) and intracellular reactive oxygen species (ROS), up-regulated the levels of silent information regulator factor 2 related enzyme 1 (Sirt1), nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1), down-regulated the levels of Kelch like ECH-associated protein-1 (Keap1) and the nuclear translocation of nuclear factor-kappaBp65 (NF kappaBp65), and decreased the mRNA levels of interleukine-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Furthermore, inhibiting Sirt1 by siRNA showed that the role of the natural product in protecting renal IRI was significantly attenuated, suggesting that the effect of the extract against renal IRI depended on Sirt1. Taken together, the TFs has significantly nephroprotective effect against IRI by affecting Sirt1/Nrf2/NF kappaB signaling pathway, which should be developed as a new therapeutic agent or food additives to treat acute kidney injury in the future. PMID- 27455218 TI - Carbon Nanotube Based Groundwater Remediation: The Case of Trichloroethylene. AB - Adsorption of chlorinated organic contaminants (COCs) on carbon nanotubes (CNTs) has been gaining ground as a remedial platform for groundwater treatment. Applications depend on our mechanistic understanding of COC adsorption on CNTs. This paper lays out the nature of competing interactions at play in hybrid, membrane, and pure CNT based systems and presents results with the perspective of existing gaps in design strategies. First, current remediation approaches to trichloroethylene (TCE), the most ubiquitous of the COCs, is presented along with examination of forces contributing to adsorption of analogous contaminants at the molecular level. Second, we present results on TCE adsorption and remediation on pure and hybrid CNT systems with a stress on the specific nature of substrate and molecular architecture that would contribute to competitive adsorption. The delineation of intermolecular interactions that contribute to efficient remediation is needed for custom, scalable field design of purification systems for a wide range of contaminants. PMID- 27455219 TI - Antiproliferative Activity and Cellular Uptake of Evodiamine and Rutaecarpine Based on 3D Tumor Models. AB - Evodiamine (EVO) and rutaecarpine (RUT) are promising anti-tumor drug candidates. The evaluation of the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids of cancer cells would better recapitulate the native situation and thus better reflect an in vivo response to the treatment. Herein, we employed the 3D culture of MCF-7 and SMMC-7721 cells based on hanging drop method and evaluated the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids, and compared the results with those obtained from 2D monolayers. The drugs' IC50 values were significantly increased from the range of 6.4-44.1 MUM in 2D monolayers to 21.8-138.0 MUM in 3D multicellular spheroids, which may be due to enhanced mass barrier and reduced drug penetration in 3D models. The fluorescence of EVO and RUT was measured via fluorescence spectroscopy and the cellular uptake of both drugs was characterized in 2D tumor models. The results showed that the cellular uptake concentrations of RUT increased with increasing drug concentrations. However, the EVO concentrations uptaken by the cells showed only a small change with increasing drug concentrations, which may be due to the different solubility of EVO and Rut in solvents. Overall, this study provided a new vision of the anti-tumor activity of EVO and RUT via 3D multicellular spheroids and cellular uptake through the fluorescence of compounds. PMID- 27455220 TI - Metabolic Responses of Bacterial Cells to Immobilization. AB - In recent years immobilized cells have commonly been used for various biotechnological applications, e.g., antibiotic production, soil bioremediation, biodegradation and biotransformation of xenobiotics in wastewater treatment plants. Although the literature data on the physiological changes and behaviour of cells in the immobilized state remain fragmentary, it is well documented that in natural settings microorganisms are mainly found in association with surfaces, which results in biofilm formation. Biofilms are characterized by genetic and physiological heterogeneity and the occurrence of altered microenvironments within the matrix. Microbial cells in communities display a variety of metabolic differences as compared to their free-living counterparts. Immobilization of bacteria can occur either as a natural phenomenon or as an artificial process. The majority of changes observed in immobilized cells result from protection provided by the supports. Knowledge about the main physiological responses occurring in immobilized cells may contribute to improving the efficiency of immobilization techniques. This paper reviews the main metabolic changes exhibited by immobilized bacterial cells, including growth rate, biodegradation capabilities, biocatalytic efficiency and plasmid stability. PMID- 27455221 TI - Qingxuan Jiangya Decoction Reverses Vascular Remodeling by Inducing Vascular Smooth Muscle Cell Apoptosis in Spontaneously Hypertensive Rats. AB - Qingxuan Jiangya Decoction (QXJYD), a traditional Chinese medicine formula prescribed by academician Ke-ji Chen, has been used in China to clinically treat hypertension for decades of years. However, the molecular mechanisms of its action remain largely unknown. In this study, we examined the therapeutic efficacy of QXJYD against elevated systolic blood pressure in the spontaneously hypertensive rat (SHR) model, and investigated the underlying molecular mechanisms. We found that oral administration of QXJYD significantly reduced the elevation of systolic blood pressure in SHR but had no effect on body weight change. Additionally, QXJYD treatment significantly decreased the media thickness and ratio of media thickness/lumen diameter in the carotid arteries of SHR. Moreover, QXJYD remarkably promoted apoptosis of vascular smooth muscle cells and reduced the expression of anti-apoptotic B-cell leukemia/lymphoma 2. Furthermore, QXJYD significantly decreased the plasma Angiotensin II level in SHR. Collectively, our findings suggest that reversing vascular remodeling via inducing VSMC apoptosis could be one of the mechanisms whereby QXJYD treats hypertension. PMID- 27455222 TI - Synthesis, Biological Evaluation and Molecular Modelling of 2'-Hydroxychalcones as Acetylcholinesterase Inhibitors. AB - A series of 2'-hydroxy- and 2'-hydroxy-4',6'-dimethoxychalcones was synthesised and evaluated as inhibitors of human acetylcholinesterase (AChE). The majority of the compounds were found to show some activity, with the most active compounds having IC50 values of 40-85 uM. Higher activities were generally observed for compounds with methoxy substituents in the A ring and halogen substituents in the B ring. Kinetic studies on the most active compounds showed that they act as mixed-type inhibitors, in agreement with the results of molecular modelling studies, which suggested that they interact with residues in the peripheral anionic site and the gorge region of AChE. PMID- 27455223 TI - Chlorophyll a Covalently Bonded to Organo-Modified Translucent Silica Xerogels: Optimizing Fluorescence and Maximum Loading. AB - Chlorophyll is a pyrrolic pigment with important optical properties, which is the reason it has been studied for many years. Recently, interest has been rising with respect to this molecule because of its outstanding physicochemical properties, particularly applicable to the design and development of luminescent materials, hybrid sensor systems, and photodynamic therapy devices for the treatment of cancer cells and bacteria. More recently, our research group has been finding evidence for the possibility of preserving these important properties of substrates containing chlorophyll covalently incorporated within solid pore matrices, such as SiO2, TiO2 or ZrO2 synthesized through the sol-gel process. In this work, we study the optical properties of silica xerogels organo modified on their surface with allyl and phenyl groups and containing different concentrations of chlorophyll bonded to the pore walls, in order to optimize the fluorescence that these macrocyclic species displays in solution. The intention of this investigation was to determine the maximum chlorophyll a concentration at which this molecule can be trapped inside the pores of a given xerogel and to ascertain if this pigment remains trapped as a monomer, a dimer, or aggregate. Allyl and phenyl groups were deposited on the surface of xerogels in view of their important effects on the stability of the molecule, as well as over the fluorescence emission of chlorophyll; however, these organic groups allow the trapping of either chlorophyll a monomers or dimers. The determination of the above parameters allows finding the most adequate systems for subsequent in vitro or in vivo studies. The characterization of the obtained xerogels was performed through spectroscopic absorption, emission and excitation spectra. These hybrid systems can be employed as mimics of natural systems; the entrapment of chlorophyll inside pore matrices indicates that it is possible to exploit some of the most physicochemical properties of trapped chlorophyll for diverse technological applications. The data herein collected suggest the possibility of applying the developed methodology to other active, captive molecules in order to synthesize new hybrid materials with optimized properties, suitable to be applied in diverse technological fields. PMID- 27455224 TI - Synthesis, Characterization, and Retinol Stabilization of Fatty Amide-beta cyclodextrin Conjugates. AB - Amphiphilic cyclodextrin (CD) has been the object of growing scientific attention because of its two recognition sites, the cavity and the apolar heart, formed by self-assembly. In the present study, mono[6-deoxy-6-(octadecanamido)]-beta-CD and mono[6-deoxy-6-(octadecenamido)]-beta-CD were successfully synthesized by reacting mono-6-amino-6-deoxy-beta-CD with N-hydroxysuccinimide esters of corresponding fatty acids in DMF. The structures were analyzed using nuclear magnetic resonance spectroscopy and mass spectrometry. The amphiphilic beta-CDs were able to form self-assembled nano-vesicles in water, and the supramolecular architectures were characterized using fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy. Using the cavity-type nano vesicles, all-trans-retinol was efficiently encapsulated; it was then stabilized against the photo-degradation. Therefore, the present fatty amide-beta-CD conjugate will be a potential molecule for carrier systems in cosmetic and pharmaceutical applications. PMID- 27455225 TI - Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. AB - Epithelial-mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. Although there are controversies surrounding the causal relationship between EMT and cancer metastasis, the role of EMT in cancer drug resistance has been increasingly recognized. Numerous EMT-related signaling pathways are involved in drug resistance in cancer cells. Cells undergoing EMT show a feature similar to cancer stem cells (CSCs), such as an increase in drug efflux pumps and anti-apoptotic effects. Therefore, targeting EMT has been considered a novel opportunity to overcome cancer drug resistance. This review describes the mechanism by which EMT contributes to drug resistance in cancer cells and summarizes new advances in research in EMT-associated drug resistance. PMID- 27455226 TI - Two New Pentacyclic Triterpene Saponins from the Leaves of Akebia trifoliata. AB - Two new pentacyclic triterpene saponins, named akebiaoside K (1) and akebiaoside N (2), were isolated from the leaves of Akebia trifoliata, together with five known triterpenoids 3-7. They were all isolated from the leaves of A. trifoliata for the first time. Their structures were established by spectral and chemical means. Triterpenes 5 and 7 were found to show moderate in vitro cytotoxicity against human tumor A549, HeLa and HepG2 cell lines, with IC50 values ranging from 0.023 to 0.038 mM. Triterpenes 5-7 were further revealed to show significant in vitro alpha-glucosidase inhibitory activity with IC50 values from 0.040 to 0.220 mM, making them more potent than the reference compound acarbose (IC50 0.409 mM). Meanwhile, no obvious inhibitory effects were observed for the isolated triterpene saponins 1-4 in both bioactivity assays. PMID- 27455227 TI - Colour Evaluation, Bioactive Compound Content, Phenolic Acid Profiles and in Vitro Biological Activity of Passerina del Frusinate White Wines: Influence of Pre-Fermentative Skin Contact Times. AB - Passerina del Frusinate is an autochthonous wine grape variety, which grows in the Lazio region that is currently being evaluated by local wine producers. In this study, colour properties (CIELab coordinates), bioactive compounds (total polyphenols and flavan-3-ols), HPLC-DAD phenolic acid profiles and in vitro biological activity of monovarietal Passerina del Frusinate white wines and the effect of different maceration times (0, 18 and 24 h) were evaluated based on these parameters. Results highlighted statistically significant differences for almost all analysed parameters due to a strong influence of the pre-fermentative skin contact time. The flavan content of macerated wines was six times higher than that of the control, while total polyphenols were 1.5 times higher. According to their phytochemical content, macerated wines showed the highest antiradical capacity tested by means of DPPH(*) and ABTS(+*) assays. Besides, prolonged maceration resulted in a reduction of CIELab coordinates as well as of the content of phenolic substances and antiradical capacity. Among the phenolic acids analysed, the most abundant were vanillic acid and caffeic acid; the latter proved to be the most susceptible to degradation as a result of prolonged maceration. Passerina del Frusinate appears as a phenol-rich white wine with a strong antioxidant potential similar to that of red wines. PMID- 27455228 TI - New Isoxazolidine-Conjugates of Quinazolinones-Synthesis, Antiviral and Cytostatic Activity. AB - A novel series of (3-diethoxyphosphoryl)isoxazolidines substituted at C5 with various quinazolinones have been synthesized by the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N3-substitued 2-vinyl-3H-quinazolin-4 ones. All isoxazolidines were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-11f/cis-11f (90:10), trans-11h and trans-11i/cis-11i (97:3) showed weak activity (EC50 = 6.84, 15.29 and 9.44 MUM) toward VZV (TK+ strain) which was only one order of magnitude lower than that of acyclovir used as a reference drug. Phosphonates trans-11b/cis-11b (90:10), trans-11c, trans-11e/cis-11e (90:10) and trans-11g appeared slightly active toward cytomegalovirus (EC50 = 27-45 MUM). Compounds containing benzyl substituents at N3 in the quinazolinone skeleton exhibited slight antiproliferative activity towards the tested immortalized cells with IC50 in the 21-102 MUM range. PMID- 27455229 TI - Immobilized Lignin Peroxidase-Like Metalloporphyrins as Reusable Catalysts in Oxidative Bleaching of Industrial Dyes. AB - Synthetic and bioinspired metalloporphyrins are a class of redox-active catalysts able to emulate several enzymes such as cytochromes P450, ligninolytic peroxidases, and peroxygenases. Their ability to perform oxidation and degradation of recalcitrant compounds, including aliphatic hydrocarbons, phenolic and non-phenolic aromatic compounds, sulfides, and nitroso-compounds, has been deeply investigated. Such a broad substrate specificity has suggested their use also in the bleaching of textile plant wastewaters. In fact, industrial dyes belong to very different chemical classes, being their effective and inexpensive oxidation an important challenge from both economic and environmental perspective. Accordingly, we review here the most widespread synthetic metalloporphyrins, and the most promising formulations for large-scale applications. In particular, we focus on the most convenient approaches for immobilization to conceive economical affordable processes. Then, the molecular routes of catalysis and the reported substrate specificity on the treatment of the most diffused textile dyes are encompassed, including the use of redox mediators and the comparison with the most common biological and enzymatic alternative, in order to depict an updated picture of a very promising field for large-scale applications. PMID- 27455230 TI - 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides with Carbonyl Dipolarophiles Yielding Oxazolidine Derivatives. AB - We provide a comprehensive account of the 1,3-dipolar cycloaddition reactions of azomethine ylides with carbonyl dipolarophiles. Many different azomethine ylides have been studied, including stabilized and non-stabilized ylides. Of the carbonyl dipolarophiles, aldehydes including formaldehyde are the most studied, although there are now examples of cycloadditions with ketones, ketenes and carboxyl systems, in particular isatoic anhydrides and phthalic anhydrides. Intramolecular cycloadditions with esters can also occur under certain circumstances. The oxazolidine cycloadducts undergo a range of reactions triggered by the ring-opening of the oxazolidine ring system. PMID- 27455231 TI - Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases. AB - Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions. PMID- 27455232 TI - Synthesis and Spectral Characterization of Benzo-[6,7][1,5]diazocino[2,1 a]isoindol-12-(14H)-one Derivatives. AB - A simple synthetic route affording 27%-85% yields of benzo[6,7][1,5]diazocino[2,1 a]isoindol-12(14H)-one ring systems from readily available 3-(2-oxo-2 phenylethyl) isobenzofuran-1(3H)-ones and 2-(aminomethyl)aniline starting materials in toluene and catalysed by p-toluene-sulfonic acid is developed. The 1H- and (13)C-NMR spectra of the final products were assigned using a variety of one and two-dimensional NMR experiments. The distinction between the two potential isomers of the final products was made on the basis of heteronuclear multiple bond connectivity (HMBC) NMR spectra. PMID- 27455233 TI - Indole Alkaloids from the Leaves of Nauclea officinalis. AB - Three new indole alkaloids, named naucleamide G (1), and nauclealomide B and C (5 and 6), were isolated from the n-BuOH-soluble fraction of an EtOH extract of the leaves of Nauclea officinalis, together with three known alkaloids, paratunamide C (2), paratunamide D (3) and paratunamide A (4). The structures with absolute configurations of the new compounds were identified on the basis of 1D and 2D NMR, HRESIMS, acid hydrolysis and quantum chemical circular dichroism (CD) calculation. According to the structures of isolated indole alkaloids, their plausible biosynthetic pathway was deduced. PMID- 27455235 TI - Protective Effect of Salicornia europaea Extracts on High Salt Intake-Induced Vascular Dysfunction and Hypertension. AB - High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE's effect on vascular function was evaluated in isolated porcine coronary arteries. SE's vascular protective effect was also evaluated in vivo using normotensive and spontaneous hypertensive rats (SHRs). SE mainly contained sodium chloride (55.6%), 5-(hydroxymethyl)furfural, p coumaric acid, and trans-ferulic acid. High sodium (160 mmol/L) induced vascular dysfunction; however, SE containing the same quantity of sodium did not cause vascular dysfunction. Among the compounds in SE, trans-ferulic acid accounts for the vascular protective effect. Normotensive rats fed a high-salt diet showed significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which decreased significantly in the SE treated groups. In SHRs, high edible salt intake significantly increased SBP, DBP, and MAP, but SE intake was associated with a significantly lower MAP. Thus, SE did not induce vascular dysfunction, and trans-ferulic acid might be at least partly responsible for the vasoprotective effect of SE. Taken together, SE could be used as an alternative to purified salt to prevent and ameliorate hypertension. PMID- 27455236 TI - High Morphologic Plasticity of Microglia/Macrophages Following Experimental Intracerebral Hemorrhage in Rats. AB - As current efforts have limited effects on the clinical outcome of intracerebral hemorrhage (ICH), the mechanisms including microglia/macrophages that involved inflammation need further investigation. Here, 0.4 units of collagenase VII were injected into the left caudate putamen (CPu) to duplicate ICH rat models. In the brains of ICH rats, microglia/macrophages, the nearest cells to the hemorrhagic center, were observed as ameboid and Prussian-blue positive. Furthermore, the ameboid microglia/macrophages were differentiation (CD) 68 and interleukin-1beta (IL-1beta) positive, and neither CD206 nor chitinase3-like 3 (Ym1) positive, suggesting their strong abilities of phagocytosis and secretion of IL-1beta. According to the distance to the hemorrhagic center, we selected four areas-I, II, III, and IV-to analyze the morphology of microglia/macrophages. The processes decreased successively from region I to region IV. Microglia/macrophages in region IV had no processes. The processes in region I were radially distributed, however, they showed obvious directivity towards the hemorrhagic center in regions II and III. Region III had the largest density of compactly arrayed microglia/macrophages. All these in vivo results present the high morphologic plasticity of microglia/macrophages and their functions in the pathogenesis of ICHs. PMID- 27455237 TI - The Effects of Aquaporin-1 in Pulmonary Edema Induced by Fat Embolism Syndrome. AB - This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). In vivo, edema was more serious in FES mice compared with the control group. The expression of AQP1 and the wet-to-dry lung weight ratio (W/D) in the FES group were significantly increased compared with the control group. At the same time, inhibition of AQP1 decreased the pathological damage resulting from pulmonary edema. Then we performed a study in vitro to investigate whether AQP1 was induced by FFA release in FES. The mRNA and protein level of AQP1 were increased by FFAs in a dose- and time-dependent manner in PMVECs. In addition, the up-regulation of AQP1 was blocked by the inhibitor of p38 kinase, implicating the p38 MAPK pathway as involved in the FFA-induced AQP1 up-regulation in PMVECs. Our results demonstrate that AQP1 may play important roles in pulmonary edema induced by FES and can be regarded as a new therapy target for treatment of pulmonary edema induced by FES. PMID- 27455234 TI - Matrix Metalloproteinases in Non-Neoplastic Disorders. AB - The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action. PMID- 27455238 TI - Aluminum Toxicity-Induced Alterations of Leaf Proteome in Two Citrus Species Differing in Aluminum Tolerance. AB - Seedlings of aluminum-tolerant 'Xuegan' (Citrus sinensis) and Al-intolerant 'sour pummelo' (Citrus grandis) were fertigated for 18 weeks with nutrient solution containing 0 and 1.2 mM AlCl3.6H2O. Al toxicity-induced inhibition of photosynthesis and the decrease of total soluble protein only occurred in C. grandis leaves, demonstrating that C. sinensis had higher Al tolerance than C. grandis. Using isobaric tags for relative and absolute quantification (iTRAQ), we obtained more Al toxicity-responsive proteins from C. sinensis than from C. grandis leaves, which might be responsible for the higher Al tolerance of C. sinensis. The following aspects might contribute to the Al tolerance of C. sinensis: (a) better maintenance of photosynthesis and energy balance via inducing photosynthesis and energy-related proteins; (b) less increased requirement for the detoxification of reactive oxygen species and other toxic compounds, such as aldehydes, and great improvement of the total ability of detoxification; and (c) upregulation of low-phosphorus-responsive proteins. Al toxicity-responsive proteins related to RNA regulation, protein metabolism, cellular transport and signal transduction might also play key roles in the higher Al tolerance of C. sinensis. We present the global picture of Al toxicity induced alterations of protein profiles in citrus leaves, and identify some new Al toxicity-responsive proteins related to various biological processes. Our results provide some novel clues about plant Al tolerance. PMID- 27455240 TI - Assessment of Dextran Antigenicity of Intravenous Iron Preparations with Enzyme Linked Immunosorbent Assay (ELISA). AB - Intravenous iron preparations are typically classified as non-dextran-based or dextran/dextran-based complexes. The carbohydrate shell for each of these preparations is unique and is key in determining the various physicochemical properties, the metabolic pathway, and the immunogenicity of the iron carbohydrate complex. As intravenous dextran can cause severe, antibody-mediated dextran-induced anaphylactic reactions (DIAR), the purpose of this study was to explore the potential of various intravenous iron preparations, non-dextran-based or dextran/dextran-based, to induce these reactions. An IgG-isotype mouse monoclonal anti-dextran antibody (5E7H3) and an enzyme-linked immunosorbent assay (ELISA) were developed to investigate the dextran antigenicity of low molecular weight iron dextran, ferumoxytol, iron isomaltoside 1000, ferric gluconate, iron sucrose and ferric carboxymaltose, as well as isomaltoside 1000, the isolated carbohydrate component of iron isomaltoside 1000. Low molecular weight iron dextran, as well as dextran-based ferumoxytol and iron isomaltoside 1000, reacted with 5E7H3, whereas ferric carboxymaltose, iron sucrose, sodium ferric gluconate, and isolated isomaltoside 1000 did not. Consistent results were obtained with reverse single radial immunodiffusion assay. The results strongly support the hypothesis that, while the carbohydrate alone (isomaltoside 1000) does not form immune complexes with anti-dextran antibodies, iron isomaltoside 1000 complex reacts with anti-dextran antibodies by forming multivalent immune complexes. Moreover, non-dextran based preparations, such as iron sucrose and ferric carboxymaltose, do not react with anti-dextran antibodies. This assay allows to assess the theoretical possibility of a substance to induce antibody-mediated DIARs. Nevertheless, as this is only one possible mechanism that may cause a hypersensitivity reaction, a broader set of assays will be required to get an understanding of the mechanisms that may lead to intravenous iron-induced hypersensitivity reactions. PMID- 27455239 TI - Developments in Methods for Measuring the Intestinal Absorption of Nanoparticle Bound Drugs. AB - With the rapid development of nanotechnology, novel drug delivery systems comprising orally administered nanoparticles (NPs) have been paid increasing attention in recent years. The bioavailability of orally administered drugs has significant influence on drug efficacy and therapeutic dosage, and it is therefore imperative that the intestinal absorption of oral NPs be investigated. This review examines the various literature on the oral absorption of polymeric NPs, and provides an overview of the intestinal absorption models that have been developed for the study of oral nanoparticles. Three major categories of models including a total of eight measurement methods are described in detail (in vitro: dialysis bag, rat gut sac, Ussing chamber, cell culture model; in situ: intestinal perfusion, intestinal loops, intestinal vascular cannulation; in vivo: the blood/urine drug concentration method), and the advantages and disadvantages of each method are contrasted and elucidated. In general, in vitro and in situ methods are relatively convenient but lack accuracy, while the in vivo method is troublesome but can provide a true reflection of drug absorption in vivo. This review summarizes the development of intestinal absorption experiments in recent years and provides a reference for the systematic study of the intestinal absorption of nanoparticle-bound drugs. PMID- 27455241 TI - Psychopathological Variables and Sleep Quality in Psoriatic Patients. AB - Psoriasis is an inflammatory disease frequently associated with psychiatric disturbances and sleep disorders. The aim of the study was to assess the prevalence of depression, interaction anxiety, audience anxiety, and sleep quality in psoriatic patients. One hundred and two psoriatic patients were enrolled and underwent the following questionnaires: Zung Self-Rating Depression Scale (SDS), Interaction Anxiousness Scale (IAS), Audience Anxiousness Scale (AAS), Pittsburgh Sleep Quality Index (PSQI). The severity of skin lesions was assessed by Psoriasis Area Severity Index (PASI). The presence of a link between clinical variables and with demographic data has been investigated. Psoriasis was linked to depression, interaction and audience anxiety, as well as to poor sleep quality; 37.5% of patients were depressed, 46.1% scored above 37 at the IAS, 47.1% scored above 33 at the AAS. Thirty-nine subjects (38.2%) presented a PSQI >= 5. An association between interaction anxiety and lower limbs psoriasis related erythema as well as between PSQI and head psoriasis-related erythema was found, particularly among male patients. Hence, psoriatic patients should be assessed from a holistic point of view, in order to identify associated disorders that could benefit from targeted treatments. PMID- 27455243 TI - The Clinical Value of High-Intensity Signals on the Coronary Atherosclerotic Plaques: Noncontrast T1-Weighted Magnetic Resonance Imaging. AB - Over the past several decades, significant progress has been made in the pathohistological assessment of vulnerable plaques and in invasive intravascular imaging techniques. However, the assessment of plaque morphology by invasive modalities is of limited value for the detection of subclinical coronary atherosclerosis and the subsequent prediction or prevention of acute cardiovascular events. Recently, magnetic resonance (MR) imaging technology has reached a sufficient level of spatial resolution, which allowed the plaque visualization of large and static arteries such as the carotids and aorta. However, coronary wall imaging by MR is still challenging due to the small size of coronary arteries, cardiac and respiratory motion, and the low contrast-to noise ratio between the coronary artery wall and the surrounding structures. Following the introduction of carotid plaque imaging with noncontrast T1-weighted imaging (T1WI), some investigators have reported that coronary artery high intensity signals on T1WI are associated with vulnerable plaque morphology and an increased risk of future cardiac events. Although there are several limitations and issues that need to be resolved, this novel MR technique for coronary plaque imaging could influence treatment strategies for atherothrombotic disease and may be useful for understanding the pathophysiological mechanisms of atherothrombotic plaque formation. PMID- 27455242 TI - Molecular Approaches to Genetically Improve the Accumulation of Health-Promoting Secondary Metabolites in Staple Crops-A Case Study: The Lipoxygenase-B1 Genes and Regulation of the Carotenoid Content in Pasta Products. AB - Secondary metabolites, also known as phytochemicals, represent a large subset of plant molecules that include compounds with health-promoting effects. Indeed, a number of epidemiological studies have shown that, when taken regularly and in adequate amounts, these molecules can have long-term beneficial effects on human health, through reduction of the incidence of degenerative diseases, such as cardiovascular diseases, obesity, diabetes, and cancer. As the dietary intake of these phytochemicals is often inadequate, various strategies are in use to improve their content in staple crops, and the end-products thereof. One of the most effective strategies is crop improvement through genetic approaches, as this is the only way to generate new cultivars in which the high accumulation of a given phytochemical is stably fixed. Efforts to genetically improve quality traits are rapidly evolving, from classical breeding to molecular-assisted approaches; these require sound understanding of the molecular bases underlying the traits, to identify the genes/alleles that control them. This can be achieved through global analysis of the metabolic pathway responsible for phytochemical accumulation, to identify the link between phytochemical content and the activities of key enzymes that regulate the metabolic pathway, and between the key enzymes and their encoding genes/alleles. Once these have been identified, they can be used as markers for selection of new improved genotypes through biotechnological approaches. This review provides an overview of the major health promoting properties shown to be associated with the dietary intake of phytochemicals, and describes how molecular approaches provide means for improving the health quality of edible crops. Finally, a case study is illustrated, of the identification in durum wheat of the Lipoxygenase-B1 genes that control the final carotenoid content in semolina-based foods, such as pasta products. PMID- 27455244 TI - Prolonged Starvation Causes Up-Regulation of AQP1 in Adipose Tissue Capillaries of AQP7 Knock-Out Mice. AB - Aquaporins (AQPs) are membrane proteins involved in the regulation of cellular transport and the balance of water and glycerol and cell volume in the white adipose tissue (WAT). In our previous study, we found the co-expression of the AQP1 water channel and AQP7 in the mouse WAT. In our present study, we aimed to find out whether prolonged starvation influences the AQP1 expression of AQP7 knock-out mice (AQP7 KO) in the WAT. To resolve this hypothesis, immunoperoxidase, immunoblot and immunogold microscopy were used. AQP1 expression was found with the use of immunohistochemistry and was confirmed by immunogold microscopy in the vessels of mouse WAT of all studied groups. Semi-quantitative immunoblot and quantitative immunogold microscopy showed a significant increase (by 2.5- to 3-fold) in the abundance of AQP1 protein expression in WAT in the 72 h starved AQP7 KO mice as compared to AQP7+/+ (p < 0.05) and AQP7-/- (p < 0.01) controls, respectively. In conclusion, the AQP1 water channel located in the vessels of WAT is up-regulated in response to prolonged starvation in the WAT of AQP7 KO mice. The present data suggest that an interaction of different AQP isoforms is required for maintaining proper water homeostasis within the mice WAT. PMID- 27455245 TI - De Novo Assembly and Characterization of the Transcriptome of Grasshopper Shirakiacris shirakii. AB - BACKGROUND: The grasshopper Shirakiacris shirakii is an important agricultural pest and feeds mainly on gramineous plants, thereby causing economic damage to a wide range of crops. However, genomic information on this species is extremely limited thus far, and transcriptome data relevant to insecticide resistance and pest control are also not available. METHODS: The transcriptome of S. shirakii was sequenced using the Illumina HiSeq platform, and we de novo assembled the transcriptome. RESULTS: Its sequencing produced a total of 105,408,878 clean reads, and the de novo assembly revealed 74,657 unigenes with an average length of 680 bp and N50 of 1057 bp. A total of 28,173 unigenes were annotated for the NCBI non-redundant protein sequences (Nr), NCBI non-redundant nucleotide sequences (Nt), a manually-annotated and reviewed protein sequence database (Swiss-Prot), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Based on the Nr annotation results, we manually identified 79 unigenes encoding cytochrome P450 monooxygenases (P450s), 36 unigenes encoding carboxylesterases (CarEs) and 36 unigenes encoding glutathione S-transferases (GSTs) in S. shirakii. Core RNAi components relevant to miroRNA, siRNA and piRNA pathways, including Pasha, Loquacious, Argonaute-1, Argonaute-2, Argonaute-3, Zucchini, Aubergine, enhanced RNAi-1 and Piwi, were expressed in S. shirakii. We also identified five unigenes that were homologous to the Sid-1 gene. In addition, the analysis of differential gene expressions revealed that a total of 19,764 unigenes were up-regulated and 4185 unigenes were down-regulated in larvae. In total, we predicted 7504 simple sequence repeats (SSRs) from 74,657 unigenes. CONCLUSIONS: The comprehensive de novo transcriptomic data of S. shirakii will offer a series of valuable molecular resources for better studying insecticide resistance, RNAi and molecular marker discovery in the transcriptome. PMID- 27455246 TI - Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease. AB - Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway. PMID- 27455247 TI - High Expression of XRCC6 Promotes Human Osteosarcoma Cell Proliferation through the beta-Catenin/Wnt Signaling Pathway and Is Associated with Poor Prognosis. AB - Increasing evidences show that XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6) was upregulated and involved in tumor growth in several tumor types. However, the correlation of XRCC6 and human osteosarcoma (OS) is still unknown. This study was conducted with the aim to reveal the expression and biological function of XRCC6 in OS and elucidate the potential mechanism. The mRNA expression level of XRCC6 was measured in osteosarcoma cells and OS samples by quantitative transcription-PCR (qRT-PCR). The expression of XRCC6 protein was measured using Western blot and immunohistochemical staining in osteosarcoma cell lines and patient samples. Cell Counting Kit 8 (CCK8), colony forming and cell cycle assays were used to test cell survival capacity. We found that XRCC6 was overexpressed in OS cells and OS samples compared with the adjacent non-tumorous samples. High expression of XRCC6 was correlated with clinical stage and tumor size in OS. Reduced expression of XRCC6 inhibits OS cell proliferation through G2/M phase arrest. Most importantly, further experiments demonstrated that XRCC6 might regulate OS growth through the beta-catenin/Wnt signaling pathway. In conclusion, these findings indicate that XRCC6 exerts tumor promoting effects for OS through beta-catenin/Wnt signaling pathway. XRCC6 may serve as a novel therapeutic target for OS patients. PMID- 27455248 TI - Non-Invasive Methods to Monitor Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer: Where Do We Stand? AB - The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment. A better understanding of these acquired resistance mechanisms is essential in clinical practice as patients could be treated with specific drugs that are active against the induced alterations. The use of free circulating tumor nucleic acids or circulating tumor cells (CTCs) enables resistance mechanisms to be characterized in a non-invasive manner and reduces the need for tumor re-biopsy. This review discusses the main resistance mechanisms to TKIs and provides a comprehensive overview of innovative strategies to evaluate known resistance mechanisms in free circulating nucleic acids or CTCs and potential future orientations for these non-invasive approaches. PMID- 27455249 TI - Neuroprotective Effect of Salvianolic Acids against Cerebral Ischemia/Reperfusion Injury. AB - This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and also evaluated the morphology of astrocyte mitochondria with transmission electron microscopy. In vivo, we determined the cerebral infarction volume and measured superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Additionally, mtCx43, p-mtCx43, AKT, and p-AKT levels were determined. In vitro, we found that I/R injury induced apoptosis, decreased cell mitochondrial membrane potential (MMP), and damaged mitochondrial morphology in astrocytes. In vivo, we found that I/R injury resulted in a large cerebral infarction, decreased SOD activity, and increased MDA expression. Additionally, I/R injury reduced both the p-mtCx43/mtCx43 and p-AKT/AKT ratios. We reported that both in vivo and in vitro, SA ameliorated the detrimental outcomes of the I/R. Interestingly, co administering an inhibitor of the PI3K/AKT pathway blunted the effects of SA. SA represents a potential treatment option for cerebral infarction by up-regulating mtCx43 through the PI3K/AKT pathway. PMID- 27455250 TI - Orofacial Manifestations and Temporomandibular Disorders of Systemic Scleroderma: An Observational Study. AB - Scleroderma is a disorder involving oral and facial tissues, with skin hardening, thin lips, deep wrinkles, xerostomia, tongue rigidity, and microstomia. The aim of this study was to investigate the prevalence of oral manifestations and temporomandibular disorders (TMD) in Systemic Sclerosis (SSc) patients compared with healthy people. Eighty patients (6 men, 74 women) fulfilling ACR/EULAR SSc Criteria were enrolled. A randomly selected group of 80 patients, matched by sex and age served as control group. The examination for TMD signs and symptoms was based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a questionnaire and clinical examination. SSc patients complained more frequently (78.8%) of oral symptoms (Xerostomia, dysgeusia, dysphagia and stomatodynia) than controls (28.7%) (chi2 = 40.23 p = 0.001). TMD symptoms (muscle pain on chewing, difficulty in mouth opening, headaches) were complained by 92.5% of SSc patients and by 76.2% of controls (chi2 = 8.012 p = 0.005). At the clinical examination, 85% of SSc patients showed restricted opening versus 20.0% of controls (chi2 = 67.77 p = 0.001), 81.2% of SSc showed reduced right lateral excursion versus 50% of controls (chi2 = 17.316 p = 0.001); 73.8% of SSc showed limited left lateral excursion versus 53.8% of controls (chi2 = 6.924 p = 0.009); and 73.8% of SSc had narrow protrusion versus 56.2% of controls (chi2 = 5.385 p = 0.02). PMID- 27455251 TI - Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission. AB - Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Nav) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, predominantly fast-spiking basket cells (BCs), powerfully inhibit granule cells (GCs) in the hippocampal dentate gyrus. Notably, BCs express abundant Nav channels and HCN channels, both of which are able to support sustained action potential generation. Using whole-cell recording in rat hippocampal slices, we investigated the net LTG effect on BC output. We showed that bath application of LTG significantly decreased the amplitude of evoked compound inhibitory postsynaptic currents (IPSCs) in GCs. In contrast, simultaneous paired recordings from BCs to GCs showed that LTG had no effect on both the amplitude and the paired-pulse ratio of the unitary IPSCs, suggesting that LTG did not affect GABA release, though it suppressed cell excitability. In line with this, LTG decreased spontaneous IPSC (sIPSC) frequency, but not miniature IPSC frequency. When re-examining the LTG effect on GABAergic transmission in the cornus ammonis region 1 (CA1) area, we found that LTG markedly inhibits both the excitability of dendrite-targeting INs in the stratum oriens and the concurrent sIPSCs recorded on their targeting pyramidal cells (PCs) without significant hyperpolarization-activated current (Ih) enhancement. In summary, LTG has no effect on augmenting Ih in GABAergic INs and does not promote GABAergic inhibitory output. The antiepileptic effect of LTG is likely through Nav channel inhibition and the suppression of global neuronal network activity. PMID- 27455252 TI - Nutritional Strategies for the Individualized Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) Based on the Nutrient-Induced Insulin Output Ratio (NIOR). AB - Nutrients play a fundamental role as regulators of the activity of enzymes involved in liver metabolism. In the general population, the action of nutrients may be affected by gene polymorphisms. Therefore, individualization of a diet for individuals with fatty liver seems to be a fundamental step in nutritional strategies. In this study, we tested the nutrient-induced insulin output ratio (NIOR), which is used to identify the correlation between the variants of genes and insulin resistance. We enrolled 171 patients, Caucasian men (n = 104) and women (n = 67), diagnosed with non-alcoholic fatty liver disease (NAFLD). From the pool of genes sensitive to nutrient content, we selected genes characterized by a strong response to the NIOR. The polymorphisms included Adrenergic receptor (b3AR), Tumor necrosis factor (TNFalpha), Apolipoprotein C (Apo C III). Uncoupling Protein type I (UCP-1), Peroxisome proliferator activated receptor gamma2 (PPAR-2) and Apolipoprotein E (APOEs). We performed three dietary interventions: a diet consistent with the results of genotyping (NIOR (+)); typical dietary recommendations for NAFLD (Cust (+)), and a diet opposite to the genotyping results (NIOR (-) and Cust (-)). We administered the diet for six months. The most beneficial changes were observed among fat-sensitive patients who were treated with the NIOR (+) diet. These changes included improvements in body mass and insulin sensitivity and normalization of blood lipids. In people sensitive to fat, the NIOR seems to be a useful tool for determining specific strategies for the treatment of NAFLD. PMID- 27455253 TI - Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion. AB - Elevated homocysteine (Hcy) levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2' deoxyguanosine (8-OHdG). Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion reperfusion (MCAO). Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive) and hardly in astrocytes (GFAP-positive). 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA). Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level. PMID- 27455254 TI - Akt Activation Correlates with Snail Expression and Potentially Determines the Recurrence of Prostate Cancer in Patients at Stage T2 after a Radical Prostatectomy. AB - Our previous work demonstrated the epithelial-mesenchymal transition factor, Snail, is a potential marker for predicting the recurrence of localized prostate cancer (PCa). Akt activation is important for Snail stabilization and transcription in PCa. The purpose of this study was to retrospectively investigate the relationship between the phosphorylated level of Akt (p-Akt) in radical prostatectomy (RP) specimens and cancer biochemical recurrence (BCR). Using a tissue microarray and immunohistochemistry, the expression of p-Akt was measured in benign and neoplastic tissues from RP specimens in 53 patients whose cancer was pathologically defined as T2 without positive margins. Herein, we observed that the p-Akt level was higher in PCa than in benign tissues and was significantly associated with the Snail level. A high p-Akt image score (>=8) was significantly correlated with a higher histological Gleason sum, Snail image score, and preoperative prostate-specific antigen (PSA) value. Moreover, the high p-Akt image score and Gleason score sum (>=7) showed similar discriminatory abilities for BCR according to a receiver-operator characteristic curve analysis and were correlated with worse recurrence-free survival according to a log-rank test (p < 0.05). To further determine whether a high p-Akt image score could predict the risk of BCR, a Cox proportional hazard model showed that only a high p-Akt image score (hazard ratio (HR): 3.12, p = 0.05) and a high Gleason score sum (>=7) (HR: 1.18, p = 0.05) but not a high preoperative PSA value (HR: 0.62, p = 0.57) were significantly associated with a higher risk of developing BCR. Our data indicate that, for localized PCa patients after an RP, p-Akt can serve as a potential prognostic marker that improves predictions of BCR-free survival. PMID- 27455256 TI - Beamforming Based Full-Duplex for Millimeter-Wave Communication. AB - In this paper, we study beamforming based full-duplex (FD) systems in millimeter wave (mmWave) communications. A joint transmission and reception (Tx/Rx) beamforming problem is formulated to maximize the achievable rate by mitigating self-interference (SI). Since the optimal solution is difficult to find due to the non-convexity of the objective function, suboptimal schemes are proposed in this paper. A low-complexity algorithm, which iteratively maximizes signal power while suppressing SI, is proposed and its convergence is proven. Moreover, two closed-form solutions, which do not require iterations, are also derived under minimum-mean-square-error (MMSE), zero-forcing (ZF), and maximum-ratio transmission (MRT) criteria. Performance evaluations show that the proposed iterative scheme converges fast (within only two iterations on average) and approaches an upper-bound performance, while the two closed-form solutions also achieve appealing performances, although there are noticeable differences from the upper bound depending on channel conditions. Interestingly, these three schemes show different robustness against the geometry of Tx/Rx antenna arrays and channel estimation errors. PMID- 27455255 TI - Comparative Analysis for the Presence of IgG Anti-Aquaporin-1 in Patients with NMO-Spectrum Disorders. AB - Detection of IgG anti-Aquaporin-4 (AQP4) in serum of patients with Neuromyelitis optica syndrome disorders (NMOSD) has improved diagnosis of these processes and differentiation from Multiple sclerosis (MS). Recent findings also claim that a subgroup of patients with NMOSD, serum negative for IgG-anti-AQP4, present antibodies anti-AQP1 instead. Explore the presence of IgG-anti-AQP1 using a previously developed cell-based assay (CBA) highly sensitive to IgG-anti-AQP4. Serum of 205 patients diagnosed as NMOSD (8), multiple sclerosis (94), optic neuritis (39), idiopathic myelitis (29), other idiopathic demyelinating disorders of the central nervous system (9), other neurological diseases (18) and healthy controls (8), were used in a CBA over fixed HEK cells transfected with hAQP1-EGFP or hM23-AQP4-EGFP, treated with Triton X-100 and untreated. ELISA was also performed. Analysis of serum with our CBA indicated absence of anti-AQP1 antibodies, whereas in cells pretreated with detergent, noisy signal made reliable detection impossible. ELISA showed positive results in few serums. The low number of NMOSD serums included in our study reduces its power to conclude the specificity of AQP1 antibodies as new biomarkers of NMOSD. Our study does not sustain detection of anti-AQP1 in serum of NMOSD patients but further experiments are expected. PMID- 27455257 TI - Modeling for IFOG Vibration Error Based on the Strain Distribution of Quadrupolar Fiber Coil. AB - Improving the performance of interferometric fiber optic gyroscope (IFOG) in harsh environment, especially in vibrational environment, is necessary for its practical applications. This paper presents a mathematical model for IFOG to theoretically compute the short-term rate errors caused by mechanical vibration. The computational procedures are mainly based on the strain distribution of quadrupolar fiber coil measured by stress analyzer. The definition of asymmetry of strain distribution (ASD) is given in the paper to evaluate the winding quality of the coil. The established model reveals that the high ASD and the variable fiber elastic modulus in large strain situation are two dominant reasons that give rise to nonreciprocity phase shift in IFOG under vibration. Furthermore, theoretical analysis and computational results indicate that vibration errors of both open-loop and closed-loop IFOG increase with the raise of vibrational amplitude, vibrational frequency and ASD. Finally, an estimation of vibration-induced IFOG errors in aircraft is done according to the proposed model. Our work is meaningful in designing IFOG coils to achieve a better anti vibration performance. PMID- 27455258 TI - Force-Sensing Silicone Retractor for Attachment to Surgical Suction Pipes. AB - This paper presents a novel force-sensing silicone retractor that can be attached to a surgical suction pipe to improve the usability of the suction and retraction functions during neurosurgery. The retractor enables simultaneous utilization of three functions: suction, retraction, and retraction-force sensing. The retractor also reduces the number of tool changes and ensures safe retraction through visualization of the magnitude of the retraction force. The proposed force sensing system is based on a force visualization mechanism through which the force is displayed in the form of motion of a colored pole. This enables surgeons to estimate the retraction force. When a fiberscope or camera is present, the retractor enables measurement of the retraction force with a resolution of 0.05 N. The retractor has advantages of being disposable, inexpensive, and easy to sterilize or disinfect. Finite element analysis and experiments demonstrate the validity of the proposed force-sensing system. PMID- 27455259 TI - A Smart Spoofing Face Detector by Display Features Analysis. AB - In this paper, a smart face liveness detector is proposed to prevent the biometric system from being "deceived" by the video or picture of a valid user that the counterfeiter took with a high definition handheld device (e.g., iPad with retina display). By analyzing the characteristics of the display platform and using an expert decision-making core, we can effectively detect whether a spoofing action comes from a fake face displayed in the high definition display by verifying the chromaticity regions in the captured face. That is, a live or spoof face can be distinguished precisely by the designed optical image sensor. To sum up, by the proposed method/system, a normal optical image sensor can be upgraded to a powerful version to detect the spoofing actions. The experimental results prove that the proposed detection system can achieve very high detection rate compared to the existing methods and thus be practical to implement directly in the authentication systems. PMID- 27455260 TI - Efficient Preamble Design Technique for Millimeter-Wave Cellular Systems with Beamforming. AB - The processing time for beam training in millimeter-wave (mmWave) cellular systems can be significantly reduced by a code division multiplexing (CDM)-based technique, where multiple beams are transmitted simultaneously with their corresponding Tx beam IDs (BIDs) in the preamble. However, mmWave cellular systems with CDM-based preambles require a large number of cell IDs (CIDs) and BIDs, and a high computational complexity for CID and BID (CBID) searches. In this paper, a new preamble design technique that can increase the number of CBIDs significantly is proposed, using a preamble sequence constructed by a combination of two Zadoff-Chu (ZC) sequences. An efficient technique for the CBID detection is also described for the proposed preamble. It is shown by simulations using a simple model of an mmWave cellular system that the proposed technique can obtain a significant reduction in the complexity of the CBID detection without a noticeable performance degradation, compared to the previous technique. PMID- 27455261 TI - Incentives for Delay-Constrained Data Query and Feedback in Mobile Opportunistic Crowdsensing. AB - In this paper, we propose effective data collection schemes that stimulate cooperation between selfish users in mobile opportunistic crowdsensing. A query issuer generates a query and requests replies within a given delay budget. When a data provider receives the query for the first time from an intermediate user, the former replies to it and authorizes the latter as the owner of the reply. Different data providers can reply to the same query. When a user that owns a reply meets the query issuer that generates the query, it requests the query issuer to pay credits. The query issuer pays credits and provides feedback to the data provider, which gives the reply. When a user that carries a feedback meets the data provider, the data provider pays credits to the user in order to adjust its claimed expertise. Queries, replies and feedbacks can be traded between mobile users. We propose an effective mechanism to define rewards for queries, replies and feedbacks. We formulate the bargain process as a two-person cooperative game, whose solution is found by using the Nash theorem. To improve the credit circulation, we design an online auction process, in which the wealthy user can buy replies and feedbacks from the starving one using credits. We have carried out extensive simulations based on real-world traces to evaluate the proposed schemes. PMID- 27455262 TI - Experimental Evaluation of Unicast and Multicast CoAP Group Communication. AB - The Internet of Things (IoT) is expanding rapidly to new domains in which embedded devices play a key role and gradually outnumber traditionally-connected devices. These devices are often constrained in their resources and are thus unable to run standard Internet protocols. The Constrained Application Protocol (CoAP) is a new alternative standard protocol that implements the same principals as the Hypertext Transfer Protocol (HTTP), but is tailored towards constrained devices. In many IoT application domains, devices need to be addressed in groups in addition to being addressable individually. Two main approaches are currently being proposed in the IoT community for CoAP-based group communication. The main difference between the two approaches lies in the underlying communication type: multicast versus unicast. In this article, we experimentally evaluate those two approaches using two wireless sensor testbeds and under different test conditions. We highlight the pros and cons of each of them and propose combining these approaches in a hybrid solution to better suit certain use case requirements. Additionally, we provide a solution for multicast-based group membership management using CoAP. PMID- 27455263 TI - Design and Development for Capacitive Humidity Sensor Applications of Lead-Free Ca,Mg,Fe,Ti-Oxides-Based Electro-Ceramics with Improved Sensing Properties via Physisorption. AB - Despite the many attractive potential uses of ceramic materials as humidity sensors, some unavoidable drawbacks, including toxicity, poor biocompatibility, long response and recovery times, low sensitivity and high hysteresis have stymied the use of these materials in advanced applications. Therefore, in present investigation, we developed a capacitive humidity sensor using lead-free Ca,Mg,Fe,Ti-Oxide (CMFTO)-based electro-ceramics with perovskite structures synthesized by solid-state step-sintering. This technique helps maintain the submicron size porous morphology of the developed lead-free CMFTO electro ceramics while providing enhanced water physisorption behaviour. In comparison with conventional capacitive humidity sensors, the presented CMFTO-based humidity sensor shows a high sensitivity of up to 3000% compared to other materials, even at lower signal frequency. The best also shows a rapid response (14.5 s) and recovery (34.27 s), and very low hysteresis (3.2%) in a 33%-95% relative humidity range which are much lower values than those of existing conventional sensors. Therefore, CMFTO nano-electro-ceramics appear to be very promising materials for fabricating high-performance capacitive humidity sensors. PMID- 27455264 TI - Enhanced Gender Recognition System Using an Improved Histogram of Oriented Gradient (HOG) Feature from Quality Assessment of Visible Light and Thermal Images of the Human Body. AB - With higher demand from users, surveillance systems are currently being designed to provide more information about the observed scene, such as the appearance of objects, types of objects, and other information extracted from detected objects. Although the recognition of gender of an observed human can be easily performed using human perception, it remains a difficult task when using computer vision system images. In this paper, we propose a new human gender recognition method that can be applied to surveillance systems based on quality assessment of human areas in visible light and thermal camera images. Our research is novel in the following two ways: First, we utilize the combination of visible light and thermal images of the human body for a recognition task based on quality assessment. We propose a quality measurement method to assess the quality of image regions so as to remove the effects of background regions in the recognition system. Second, by combining the features extracted using the histogram of oriented gradient (HOG) method and the measured qualities of image regions, we form a new image features, called the weighted HOG (wHOG), which is used for efficient gender recognition. Experimental results show that our method produces more accurate estimation results than the state-of-the-art recognition method that uses human body images. PMID- 27455265 TI - Developing Ubiquitous Sensor Network Platform Using Internet of Things: Application in Precision Agriculture. AB - The application of Information Technologies into Precision Agriculture methods has clear benefits. Precision Agriculture optimises production efficiency, increases quality, minimises environmental impact and reduces the use of resources (energy, water); however, there are different barriers that have delayed its wide development. Some of these main barriers are expensive equipment, the difficulty to operate and maintain and the standard for sensor networks are still under development. Nowadays, new technological development in embedded devices (hardware and communication protocols), the evolution of Internet technologies (Internet of Things) and ubiquitous computing (Ubiquitous Sensor Networks) allow developing less expensive systems, easier to control, install and maintain, using standard protocols with low-power consumption. This work develops and test a low-cost sensor/actuator network platform, based in Internet of Things, integrating machine-to-machine and human-machine-interface protocols. Edge computing uses this multi-protocol approach to develop control processes on Precision Agriculture scenarios. A greenhouse with hydroponic crop production was developed and tested using Ubiquitous Sensor Network monitoring and edge control on Internet of Things paradigm. The experimental results showed that the Internet technologies and Smart Object Communication Patterns can be combined to encourage development of Precision Agriculture. They demonstrated added benefits (cost, energy, smart developing, acceptance by agricultural specialists) when a project is launched. PMID- 27455266 TI - On Inertial Body Tracking in the Presence of Model Calibration Errors. AB - In inertial body tracking, the human body is commonly represented as a biomechanical model consisting of rigid segments with known lengths and connecting joints. The model state is then estimated via sensor fusion methods based on data from attached inertial measurement units (IMUs). This requires the relative poses of the IMUs w.r.t. the segments-the IMU-to-segment calibrations, subsequently called I2S calibrations-to be known. Since calibration methods based on static poses, movements and manual measurements are still the most widely used, potentially large human-induced calibration errors have to be expected. This work compares three newly developed/adapted extended Kalman filter (EKF) and optimization-based sensor fusion methods with an existing EKF-based method w.r.t. their segment orientation estimation accuracy in the presence of model calibration errors with and without using magnetometer information. While the existing EKF-based method uses a segment-centered kinematic chain biomechanical model and a constant angular acceleration motion model, the newly developed/adapted methods are all based on a free segments model, where each segment is represented with six degrees of freedom in the global frame. Moreover, these methods differ in the assumed motion model (constant angular acceleration, constant angular velocity, inertial data as control input), the state representation (segment-centered, IMU-centered) and the estimation method (EKF, sliding window optimization). In addition to the free segments representation, the optimization-based method also represents each IMU with six degrees of freedom in the global frame. In the evaluation on simulated and real data from a three segment model (an arm), the optimization-based method showed the smallest mean errors, standard deviations and maximum errors throughout all tests. It also showed the lowest dependency on magnetometer information and motion agility. Moreover, it was insensitive w.r.t. I2S position and segment length errors in the tested ranges. Errors in the I2S orientations were, however, linearly propagated into the estimated segment orientations. In the absence of magnetic disturbances, severe model calibration errors and fast motion changes, the newly developed IMU centered EKF-based method yielded comparable results with lower computational complexity. PMID- 27455267 TI - Design of a Direction-of-Arrival Estimation Method Used for an Automatic Bearing Tracking System. AB - In this paper, we introduce a sub-band direction-of-arrival (DOA) estimation method suitable for employment within an automatic bearing tracking system. Inspired by the magnitude-squared coherence (MSC), we extend the MSC to the sub band and propose the sub-band magnitude-squared coherence (SMSC) to measure the coherence between the frequency sub-bands of wideband signals. Then, we design a sub-band DOA estimation method which chooses a sub-band from the wideband signals by SMSC for the bearing tracking system. The simulations demonstrate that the sub band method has a good tradeoff between the wideband methods and narrowband methods in terms of the estimation accuracy, spatial resolution, and computational cost. The proposed method was also tested in the field environment with the bearing tracking system, which also showed a good performance. PMID- 27455268 TI - Localisation of Sensor Nodes with Hybrid Measurements in Wireless Sensor Networks. AB - Localisation in wireless networks faces challenges such as high levels of signal attenuation and unknown path-loss exponents, especially in urban environments. In response to these challenges, this paper proposes solutions to localisation problems in noisy environments. A new observation model for localisation of static nodes is developed based on hybrid measurements, namely angle of arrival and received signal strength data. An approach for localisation of sensor nodes is proposed as a weighted linear least squares algorithm. The unknown path-loss exponent associated with the received signal strength is estimated jointly with the coordinates of the sensor nodes via the generalised pattern search method. The algorithm's performance validation is conducted both theoretically and by simulation. A theoretical mean square error expression is derived, followed by the derivation of the linear Cramer-Rao bound which serves as a benchmark for the proposed location estimators. Accurate results are demonstrated with 25%-30% improvement in estimation accuracy with a weighted linear least squares algorithm as compared to linear least squares solution. PMID- 27455269 TI - A High Precision Terahertz Wave Image Reconstruction Algorithm. AB - With the development of terahertz (THz) technology, the applications of this spectrum have become increasingly wide-ranging, in areas such as non-destructive testing, security applications and medical scanning, in which one of the most important methods is imaging. Unlike remote sensing applications, THz imaging features sources of array elements that are almost always supposed to be spherical wave radiators, including single antennae. As such, well-developed methodologies such as Range-Doppler Algorithm (RDA) are not directly applicable in such near-range situations. The Back Projection Algorithm (BPA) can provide products of high precision at the the cost of a high computational burden, while the Range Migration Algorithm (RMA) sacrifices the quality of images for efficiency. The Phase-shift Migration Algorithm (PMA) is a good alternative, the features of which combine both of the classical algorithms mentioned above. In this research, it is used for mechanical scanning, and is extended to array imaging for the first time. In addition, the performances of PMA are studied in detail in contrast to BPA and RMA. It is demonstrated in our simulations and experiments described herein that the algorithm can reconstruct images with high precision. PMID- 27455270 TI - Evaluation of Deployment Challenges of Wireless Sensor Networks at Signalized Intersections. AB - With the growing demand of Intelligent Transportation Systems (ITS) for safer and more efficient transportation, research on and development of such vehicular communication systems have increased considerably in the last years. The use of wireless networks in vehicular environments has grown exponentially. However, it is highly important to analyze radio propagation prior to the deployment of a wireless sensor network in such complex scenarios. In this work, the radio wave characterization for ISM 2.4 GHz and 5 GHz Wireless Sensor Networks (WSNs) deployed taking advantage of the existence of traffic light infrastructure has been assessed. By means of an in-house developed 3D ray launching algorithm, the impact of topology as well as urban morphology of the environment has been analyzed, emulating the realistic operation in the framework of the scenario. The complexity of the scenario, which is an intersection city area with traffic lights, vehicles, people, buildings, vegetation and urban environment, makes necessary the channel characterization with accurate models before the deployment of wireless networks. A measurement campaign has been conducted emulating the interaction of the system, in the vicinity of pedestrians as well as nearby vehicles. A real time interactive application has been developed and tested in order to visualize and monitor traffic as well as pedestrian user location and behavior. Results show that the use of deterministic tools in WSN deployment can aid in providing optimal layouts in terms of coverage, capacity and energy efficiency of the network. PMID- 27455271 TI - Passive Resistor Temperature Compensation for a High-Temperature Piezoresistive Pressure Sensor. AB - The main limitation of high-temperature piezoresistive pressure sensors is the variation of output voltage with operating temperature, which seriously reduces their measurement accuracy. This paper presents a passive resistor temperature compensation technique whose parameters are calculated using differential equations. Unlike traditional experiential arithmetic, the differential equations are independent of the parameter deviation among the piezoresistors of the microelectromechanical pressure sensor and the residual stress caused by the fabrication process or a mismatch in the thermal expansion coefficients. The differential equations are solved using calibration data from uncompensated high temperature piezoresistive pressure sensors. Tests conducted on the calibrated equipment at various temperatures and pressures show that the passive resistor temperature compensation produces a remarkable effect. Additionally, a high temperature signal-conditioning circuit is used to improve the output sensitivity of the sensor, which can be reduced by the temperature compensation. Compared to traditional experiential arithmetic, the proposed passive resistor temperature compensation technique exhibits less temperature drift and is expected to be highly applicable for pressure measurements in harsh environments with large temperature variations. PMID- 27455272 TI - Vibration Sensitivity Reduction of Micromachined Tuning Fork Gyroscopes through Stiffness Match Method with Negative Electrostatic Spring Effect. AB - In this paper, a stiffness match method is proposed to reduce the vibration sensitivity of micromachined tuning fork gyroscopes. Taking advantage of the coordinate transformation method, a theoretical model is established to analyze the anti-phase vibration output caused by the stiffness mismatch due to the fabrication imperfections. The analytical solutions demonstrate that the stiffness mismatch is proportional to the output induced by the external linear vibration from the sense direction in the anti-phase mode frequency. In order to verify the proposed stiffness match method, a tuning fork gyroscope (TFG) with the stiffness match electrodes is designed and implemented using the micromachining technology and the experimental study is carried out. The experimental tests illustrate that the vibration output can be reduced by 73.8% through the stiffness match method than the structure without the stiffness match. Therefore, the proposed stiffness match method is experimentally validated to be applicable to vibration sensitivity reduction in the Micro-Electro Mechanical-Systems (MEMS) tuning fork gyroscopes without sacrificing the scale factor. PMID- 27455274 TI - A High-Gain Passive UHF-RFID Tag with Increased Read Range. AB - In this work, a passive ultra-high frequency radio-frequency identification UHF RFID tag based on a 1.25 wavelengths thin dipole antenna is presented for the first time. The length of the antenna is properly chosen in order to maximize the tag read range, while maintaining a reasonable tag size and radiation pattern. The antenna is matched to the RFID chip by means of a very simple matching network based on a shunt inductance. A tag prototype, based on the Alien Higgs-3 chip, is designed and fabricated. The overall dimensions are 400 mm * 14.6 mm, but the tag width for most of its length is delimited by the wire diameter (0.8 mm). The measured read range exhibits a maximum value of 17.5 m at the 902-928 MHz frequency band. This represents an important improvement over state-of-the art passive UHF-RFID tags. PMID- 27455273 TI - Fiber Optic Sensors for Temperature Monitoring during Thermal Treatments: An Overview. AB - During recent decades, minimally invasive thermal treatments (i.e., Radiofrequency ablation, Laser ablation, Microwave ablation, High Intensity Focused Ultrasound ablation, and Cryo-ablation) have gained widespread recognition in the field of tumor removal. These techniques induce a localized temperature increase or decrease to remove the tumor while the surrounding healthy tissue remains intact. An accurate measurement of tissue temperature may be particularly beneficial to improve treatment outcomes, because it can be used as a clear end-point to achieve complete tumor ablation and minimize recurrence. Among the several thermometric techniques used in this field, fiber optic sensors (FOSs) have several attractive features: high flexibility and small size of both sensor and cabling, allowing insertion of FOSs within deep-seated tissue; metrological characteristics, such as accuracy (better than 1 degrees C), sensitivity (e.g., 10 pm. degrees C(-1) for Fiber Bragg Gratings), and frequency response (hundreds of kHz), are adequate for this application; immunity to electromagnetic interference allows the use of FOSs during Magnetic Resonance- or Computed Tomography-guided thermal procedures. In this review the current status of the most used FOSs for temperature monitoring during thermal procedure (e.g., fiber Bragg Grating sensors; fluoroptic sensors) is presented, with emphasis placed on their working principles and metrological characteristics. The essential physics of the common ablation techniques are included to explain the advantages of using FOSs during these procedures. PMID- 27455275 TI - Reduced Graphene Oxide/Au Nanocomposite for NO2 Sensing at Low Operating Temperature. AB - A reduced grapheme oxide (rGO)/Au hybrid nanocomposite has been synthesized by hydrothermal treatment using graphite and HAuCl4 as the precursors. Characterization, including X-ray diffraction (XRD), Raman spectra, X-ray photoelecton spectroscopy (XPS) and transmission electron microscopy (TEM), indicates the formation of rGO/Au. A gas sensor fabricated with rGO/Au nanocomposite was applied for NO2 detection at 50 degrees C. Compared with pure rGO, rGO/Au nanocomposite exhibits higher sensitivity, a more rapid response recovery process and excellent reproducibility. PMID- 27455276 TI - Piezoresistive Membrane Surface Stress Sensors for Characterization of Breath Samples of Head and Neck Cancer Patients. AB - For many diseases, where a particular organ is affected, chemical by-products can be found in the patient's exhaled breath. Breath analysis is often done using gas chromatography and mass spectrometry, but interpretation of results is difficult and time-consuming. We performed characterization of patients' exhaled breath samples by an electronic nose technique based on an array of nanomechanical membrane sensors. Each membrane is coated with a different thin polymer layer. By pumping the exhaled breath into a measurement chamber, volatile organic compounds present in patients' breath diffuse into the polymer layers and deform the membranes by changes in surface stress. The bending of the membranes is measured piezoresistively and the signals are converted into voltages. The sensor deflection pattern allows one to characterize the condition of the patient. In a clinical pilot study, we investigated breath samples from head and neck cancer patients and healthy control persons. Evaluation using principal component analysis (PCA) allowed a clear distinction between the two groups. As head and neck cancer can be completely removed by surgery, the breath of cured patients was investigated after surgery again and the results were similar to those of the healthy control group, indicating that surgery was successful. PMID- 27455277 TI - Design and Field Experimentation of a Cooperative ITS Architecture Based on Distributed RSUs. AB - This paper describes a new cooperative Intelligent Transportation System architecture that aims to enable collaborative sensing services. The main goal of this architecture is to improve transportation efficiency and performance. The system, which has been proven within the participation in the ICSI (Intelligent Cooperative Sensing for Improved traffic efficiency) European project, encompasses the entire process of capture and management of available road data. For this purpose, it applies a combination of cooperative services and methods for data sensing, acquisition, processing and communication amongst road users, vehicles, infrastructures and related stakeholders. Additionally, the advantages of using the proposed system are exposed. The most important of these advantages is the use of a distributed architecture, moving the system intelligence from the control centre to the peripheral devices. The global architecture of the system is presented, as well as the software design and the interaction between its main components. Finally, functional and operational results observed through the experimentation are described. This experimentation has been carried out in two real scenarios, in Lisbon (Portugal) and Pisa (Italy). PMID- 27455278 TI - Modeling and Assessment of GPS/BDS Combined Precise Point Positioning. AB - Precise Point Positioning (PPP) technique enables stand-alone receivers to obtain cm-level positioning accuracy. Observations from multi-GNSS systems can augment users with improved positioning accuracy, reliability and availability. In this paper, we present and evaluate the GPS/BDS combined PPP models, including the traditional model and a simplified model, where the inter-system bias (ISB) is treated in different way. To evaluate the performance of combined GPS/BDS PPP, kinematic and static PPP positions are compared to the IGS daily estimates, where 1 month GPS/BDS data of 11 IGS Multi-GNSS Experiment (MGEX) stations are used. The results indicate apparent improvement of GPS/BDS combined PPP solutions in both static and kinematic cases, where much smaller standard deviations are presented in the magnitude distribution of coordinates RMS statistics. Comparisons between the traditional and simplified combined PPP models show no difference in coordinate estimations, and the inter system biases between the GPS/BDS system are assimilated into receiver clock, ambiguities and pseudo-range residuals accordingly. PMID- 27455279 TI - An Improved Otsu Threshold Segmentation Method for Underwater Simultaneous Localization and Mapping-Based Navigation. AB - The main focus of this paper is on extracting features with SOund Navigation And Ranging (SONAR) sensing for further underwater landmark-based Simultaneous Localization and Mapping (SLAM). According to the characteristics of sonar images, in this paper, an improved Otsu threshold segmentation method (TSM) has been developed for feature detection. In combination with a contour detection algorithm, the foreground objects, although presenting different feature shapes, are separated much faster and more precisely than by other segmentation methods. Tests have been made with side-scan sonar (SSS) and forward-looking sonar (FLS) images in comparison with other four TSMs, namely the traditional Otsu method, the local TSM, the iterative TSM and the maximum entropy TSM. For all the sonar images presented in this work, the computational time of the improved Otsu TSM is much lower than that of the maximum entropy TSM, which achieves the highest segmentation precision among the four above mentioned TSMs. As a result of the segmentations, the centroids of the main extracted regions have been computed to represent point landmarks which can be used for navigation, e.g., with the help of an Augmented Extended Kalman Filter (AEKF)-based SLAM algorithm. The AEKF-SLAM approach is a recursive and iterative estimation-update process, which besides a prediction and an update stage (as in classical Extended Kalman Filter (EKF)), includes an augmentation stage. During navigation, the robot localizes the centroids of different segments of features in sonar images, which are detected by our improved Otsu TSM, as point landmarks. Using them with the AEKF achieves more accurate and robust estimations of the robot pose and the landmark positions, than with those detected by the maximum entropy TSM. Together with the landmarks identified by the proposed segmentation algorithm, the AEKF-SLAM has achieved reliable detection of cycles in the map and consistent map update on loop closure, which is shown in simulated experiments. PMID- 27455280 TI - An Omnidirectional Polarization Detector Based on a Metamaterial Absorber. AB - The theory, design, simulation, fabrication, and performance of an omnidirectional polarization detector (PD) with two resonances located in the X and Ka ranges based on a metamaterial absorber (MMA) are presented in this paper. The sandwich structure of PD is composed of 0.1 MUm periodic "I" shaped patches on the metasurface, a dielectric of 200 MUm FR-4 on the interlayer, and a 0.3 MUm copper film on the substrate. PD absorptivity is first used to reflect and describe the polarization of the incident wave. The numerical results, derived from the standard full wave finite integration technology (FIT) of CST 2015, indicates that the designed PD shows polarization sensitivity at all incidence angles. The effects on absorptivity produced by the incidence angles, polarization angles, and materials are investigated. The amplitude of absorptivity change caused by polarization reaches 99.802%. A laser ablation process is adopted to prepare the designed PD on a FR-4 board coated with copper on the double plane with a thickness that was 1/93 and 1/48 of wavelength at a resonance frequency of 16.055 GHz and 30.9 GHz, respectively. The sample test results verify the designed PD excellent detectability on the polarization of the incident waves. The proposed PD, which greatly enriches the applications of metamaterials in bolometers, thermal images, stealth materials, microstructure measurements, and electromagnetic devices, is easy to mass produce and market because of its strong detectability, ultrathin thickness, effective cost, and convenient process. PMID- 27455282 TI - State Estimation for a Class of Non-Uniform Sampling Systems with Missing Measurements. AB - This paper is concerned with the state estimation problem for a class of non uniform sampling systems with missing measurements where the state is updated uniformly and the measurements are sampled randomly. A new state model is developed to depict the dynamics at the measurement sampling points within a state update period. A non-augmented state estimator dependent on the missing rate is presented by applying an innovation analysis approach. It can provide the state estimates at the state update points and at the measurement sampling points within a state update period. Compared with the augmented method, the proposed algorithm can reduce the computational burden with the increase of the number of measurement samples within a state update period. It can deal with the optimal estimation problem for single and multi-sensor systems in a unified way. To improve the reliability, a distributed suboptimal fusion estimator at the state update points is also given for multi-sensor systems by using the covariance intersection fusion algorithm. The simulation research verifies the effectiveness of the proposed algorithms. PMID- 27455281 TI - Test-Retest Reliability of an Automated Infrared-Assisted Trunk Accelerometer Based Gait Analysis System. AB - The aim of this study was to determine the test-retest reliability of an automated infrared-assisted, trunk accelerometer-based gait analysis system for measuring gait parameters of healthy subjects in a hospital. Thirty-five participants (28 of them females; age range, 23-79 years) performed a 5-m walk twice using an accelerometer-based gait analysis system with infrared assist. Measurements of spatiotemporal gait parameters (walking speed, step length, and cadence) and trunk control (gait symmetry, gait regularity, acceleration root mean square (RMS), and acceleration root mean square ratio (RMSR)) were recorded in two separate walking tests conducted 1 week apart. Relative and absolute test retest reliability was determined by calculating the intra-class correlation coefficient (ICC3,1) and smallest detectable difference (SDD), respectively. The test-retest reliability was excellent for walking speed (ICC = 0.87, 95% confidence interval = 0.74-0.93, SDD = 13.4%), step length (ICC = 0.81, 95% confidence interval = 0.63-0.91, SDD = 12.2%), cadence (ICC = 0.81, 95% confidence interval = 0.63-0.91, SDD = 10.8%), and trunk control (step and stride regularity in anterior-posterior direction, acceleration RMS and acceleration RMSR in medial-lateral direction, and acceleration RMS and stride regularity in vertical direction). An automated infrared-assisted, trunk accelerometer-based gait analysis system is a reliable tool for measuring gait parameters in the hospital environment. PMID- 27455283 TI - From Discovery to Production: Biotechnology of Marine Fungi for the Production of New Antibiotics. AB - Filamentous fungi are well known for their capability of producing antibiotic natural products. Recent studies have demonstrated the potential of antimicrobials with vast chemodiversity from marine fungi. Development of such natural products into lead compounds requires sustainable supply. Marine biotechnology can significantly contribute to the production of new antibiotics at various levels of the process chain including discovery, production, downstream processing, and lead development. However, the number of biotechnological processes described for large-scale production from marine fungi is far from the sum of the newly-discovered natural antibiotics. Methods and technologies applied in marine fungal biotechnology largely derive from analogous terrestrial processes and rarely reflect the specific demands of the marine fungi. The current developments in metabolic engineering and marine microbiology are not yet transferred into processes, but offer numerous options for improvement of production processes and establishment of new process chains. This review summarises the current state in biotechnological production of marine fungal antibiotics and points out the enormous potential of biotechnology in all stages of the discovery-to-development pipeline. At the same time, the literature survey reveals that more biotechnology transfer and method developments are needed for a sustainable and innovative production of marine fungal antibiotics. PMID- 27455284 TI - Blue-Print Autophagy: Potential for Cancer Treatment. AB - The marine environment represents a very rich source of biologically active compounds with pharmacological applications. This is due to its chemical richness, which is claiming considerable attention from the health science communities. In this review we give a general overview on the marine natural products involved in stimulation and inhibition of autophagy (a type of programmed cell death) linked to pharmacological and pathological conditions. Autophagy represents a complex multistep cellular process, wherein a double membrane vesicle (the autophagosome) captures organelles and proteins and delivers them to the lysosome. This natural and destructive mechanism allows the cells to degrade and recycle its cellular components, such as amino acids, monosaccharides, and lipids. Autophagy is an important mechanism used by cells to clear pathogenic organism and deal with stresses. Therefore, it has also been implicated in several diseases, predominantly in cancer. In fact, pharmacological stimulation or inhibition of autophagy have been proposed as approaches to develop new therapeutic treatments of cancers. In conclusion, this blue-print autophagy (so defined because it is induced and/or inhibited by marine natural products) represents a new strategy for the future of biomedicine and of biotechnology in cancer treatment. PMID- 27455285 TI - APO-9'-Fucoxanthinone Extracted from Undariopsis peteseniana Protects Oxidative Stress-Mediated Apoptosis in Cigarette Smoke-Exposed Human Airway Epithelial Cells. AB - Long-term cigarette smoking increases the risk for chronic obstructive pulmonary disease (COPD), characterized by irreversible expiratory airflow limitation. The pathogenesis of COPD involves oxidative stress and chronic inflammation. Various natural marine compounds possess both anti-oxidant and anti-inflammatory properties, but few have been tested for their efficacy in COPD models. In this study, we conducted an in vitro screening test to identify natural compounds isolated from various brown algae species that might provide protection against cigarette smoke extract (CSE)-induced cytotoxicity. Among nine selected natural compounds, apo-9'-fucoxanthinone (Apo9F) exhibited the highest protection against CSE-induced cytotoxicity in immortalized human bronchial epithelial cells (HBEC2). Furthermore, the protective effects of Apo9F were observed to be associated with a significant reduction in apoptotic cell death, DNA damage, and the levels of mitochondrial reactive oxygen species (ROS) released from CSE exposed HBEC2 cells. These results suggest that Apo9F protects against CSE induced DNA damage and apoptosis by regulating mitochondrial ROS production. PMID- 27455286 TI - The Role of Spongia sp. in the Discovery of Marine Lead Compounds. AB - A comprehensive review on the chemistry of Spongia sp. is here presented, together with the biological activity of the isolated compounds. The compounds are grouped in sesquiterpene quinones, diterpenes, C21 and other linear furanoterpenes, sesterterpenes, sterols (including secosterols), macrolides and miscellaneous compounds. Among other reports we include studies on the intraspecific diversity of a Mediterranean species, compounds isolated from associated sponge and nudibranch and compounds isolated from S. zimocca and the red seaweed Laurentia microcladia. Under biological activity a table of the reported biological activities of the various compounds and the biological screening of extracts are described. The present review covers the literature from 1971 to 2015. PMID- 27455287 TI - Preparation of Chito-Oligomers by Hydrolysis of Chitosan in the Presence of Zeolite as Adsorbent. AB - An increasing interest has recently been shown to use chitin/chitosan oligomers (chito-oligomers) in medicine and food fields because they are not only water soluble, nontoxic, and biocompatible materials, but they also exhibit numerous biological properties, including antibacterial, antifungal, and antitumor activities, as well as immuno-enhancing effects on animals. Conventional depolymerization methods of chitosan to chito-oligomers are either chemical by acid-hydrolysis under harsh conditions or by enzymatic degradation. In this work, hydrolysis of chitosan to chito-oligomers has been achieved by applying adsorption-separation technique using diluted HCl in the presence of different types of zeolite as adsorbents. The chito-oligomers were retrieved from adsorbents and characterized by differential scanning calorimetry (DSC), liquid chromatography/mass spectroscopy (LC/MS), and ninhydrin test. PMID- 27455288 TI - A Meta-Analysis of the Efficacy of Interferon Monotherapy or Combined with Different Nucleos(t)ide Analogues for Chronic Hepatitis B. AB - BACKGROUND: The aim of the present study was to compare the efficacy of interferon (IFN) with or without different nucleos(t)ide analogues (NAs). METHODS: The PubMed, Wan Fang and CNKI databases were searched to identify relevant trials up to May 2015. Meta-analysis was performed with Review Manager 5.0. The stability and reliability were evaluated by publication bias tests. RESULTS: Fifty-six studies fulfilled the criteria for the meta-analysis. Compared with IFN monotherapy, combination therapy were superior in HBV DNA undetectable rate (Risk Ratio (RR) = 1.55, 95% confidence interval (CI): 1.44-1.66, p < 0.00001), HBeAg and HBsAg loss rate (RR = 1.38, 95% CI: 1.22-1.56, p < 0.00001; RR = 1.69, 95% CI: 1.03-2.78, p = 0.04, respectively) at the end of week 48 treatment. Sub-analysis showed the RRs of virological response for entecavir (ETV), adefovir (ADV), and lamivudine (LAM) were 1.64, 1.61 and 1.52, respectively; RRs of HBeAg loss rate were 1.34, 1.71 and 1.34, respectively. However, at the end of follow-up, IFN plus NAs therapy was better than IFN monotherapy only in terms of HBV DNA undetectable rate (p = 0.0007). CONCLUSIONS: Combination therapy was better than IFN monotherapy in virological and serological responses at the end of treatment. After follow-up, only HBV DNA undetectable rate was superior for combination therapy. PMID- 27455289 TI - Infection Rates by Dengue Virus in Mosquitoes and the Influence of Temperature May Be Related to Different Endemicity Patterns in Three Colombian Cities. AB - Colombia is an endemic country for dengue fever where the four serotypes of virus dengue (DENV1-4) circulate simultaneously, and all types are responsible for dengue cases in the country. The control strategies are guided by entomological surveillance. However, heterogeneity in aedic indices is not well correlated with the incidence of the disease in cities such as Riohacha, Bello and Villavicencio. As an alternative, molecular detection of dengue virus in mosquitoes has been proposed as a useful tool for epidemiological surveillance and identification of serotypes circulating in field. We conducted a spatiotemporal fieldwork in these cities to capture adult mosquitoes to assess vector infection and explain the differences between Breteau indices and disease incidence. DENV infection in females and DENV serotype identification were evaluated and infection rates (IR) were estimated. The relationship between density, dengue cases and vector index was also estimated with logistic regression modeling and Pearson's correlation coefficient. The lack of association between aedic indices and dengue incidence is in agreement with the weak associations between the density of the mosquitoes and their infection with DENV in the three cities. However, association was evident between the IR and dengue cases in Villavicencio. Furthermore, we found important negative associations between temperature and lag time from two to six weeks in Riohacha. We conclude that density of mosquitoes is not a good predictor of dengue cases. Instead, IR and temperature might explain better such heterogeneity. PMID- 27455290 TI - Measurements of Volatile Organic Compounds in a Newly Built Daycare Center. AB - We measured temporal changes in concentrations of total volatile organic compounds (TVOCs) and individual volatile organic compounds in a newly built daycare center. The temporal changes of the TVOC concentrations were monitored with a photo ionization detector (PID), and indoor air was sampled and analyzed by Gas Chromatography/Mass Spectrometry (GC/MS) and high performance liquid chromatography (HPLC) to determine the concentrations of the constituent VOCs. The measurements were performed just after completion of the building and again 3 months after completion. The TVOC concentration exceeded 1000 ug.m(-3) for all the sampling locations just after completion of building, and decreased almost one tenth after 3 months, to below the guideline values of the TVOC in Japan at 400 ug.m(-3). The concentrations of the target VOCs of which the indoor concentrations are regulated in Japan were below the guideline values for all the cases. The air-exchange rates were determined based on the temporal changes of the TVOC concentrations, and it was found that the countermeasure to increase the air exchange rate successfully decrease the TVOC concentration level in the rooms. PMID- 27455291 TI - Perception of Air Pollution in the Jinchuan Mining Area, China: A Structural Equation Modeling Approach. AB - Studies on the perception of air pollution in China are very limited. The aim of this paper is to help to fill this gap by analyzing a cross-sectional dataset of 759 residents of the Jinchuan mining area, Gansu Province, China. The estimations suggest that perception of air pollution is two-dimensional. The first dimension is the perceived intensity of air pollution and the second is the perceived hazardousness of the pollutants. Both dimensions are influenced by environmental knowledge. Perceived intensity is furthermore influenced by socio-economic status and proximity to the pollution source; perceived hazardousness is influenced by socio-economic status, family health experience, family size and proximity to the pollution source. There are no reverse effects from perception on environmental knowledge. The main conclusion is that virtually all Jinchuan residents perceive high intensity and hazardousness of air pollution despite the fact that public information on air pollution and its health impacts is classified to a great extent. It is suggested that, to assist the residents to take appropriate preventive action, the local government should develop counseling and educational campaigns and institutionalize disclosure of air quality conditions. These programs should pay special attention to young residents who have limited knowledge of air pollution in the Jinchuan mining area. PMID- 27455292 TI - Geographic Elevation, Car Driving, and Depression among Elderly Residents in Rural Areas: The Shimane CoHRE Study. AB - Given that public transportation networks are often worse in rural areas than in urban areas, it is difficult for elderly non-drivers to access health-promoting goods, services, and resources related to mental health. Moreover, geographical location, assessed by elevation, could modify this association in a rural area. The aim of this study was to test whether the association between car driving (being a driver or not) and depression, as measured by the Zung Self-Rating Depression Scale (SDS), varied by elevation. Data were collected from a cross sectional study conducted in the town of Ohnan located in a rural area of Japan. After excluding participants with missing data (n = 26), 876 participants were analysed in this study. After adjustment for potential confounders, being a non driver had a significantly higher odds ratio of SDS (40+) among elderly people living at a low elevation (odds ratio = 2.17, 95% confidence interval = 1.28 3.71). However, similar findings were not observed among elderly people living at a high elevation. These results suggest that car driving importantly predicts depression in elderly people living at relatively low elevations in rural areas. PMID- 27455293 TI - Parent-Child Relationship of Pedometer-Assessed Physical Activity and Proxy Reported Screen Time in Czech Families with Preschoolers. AB - This study focuses on determining the relationship between parents' step count (SC) and screen time (ST) and children's SC and ST on weekdays and at weekends. The participants (278 parents aged 30-45 and their 194 children aged 4-7) were recruited from 10 randomly selected Czech kindergartens. The participants recorded SC and ST duration over a week-long monitoring (>=8 h/day) during September-October 2014 and April-May 2015. The associations between parents' SC and ST and children's SC and ST were estimated using general linear regression for weekdays and weekends. Each 2500 SC increase in mothers'/fathers' daily SC at weekdays (weekends) was associated with an extra 1143/903 (928/753) daily SC in children. Each 60 min of ST increase in mothers'/fathers' ST at weekdays (weekends) was associated with an extra 7.6/7.6 (16.8/13.0) min of child daily ST. An increase of 2500 mothers' daily SC was associated with reduction of 2.5 (7.5) min of ST in children at weekdays (weekends). This study reveals a significant relationship between parent-child SC/day, parent-child ST/day, and mothers' ST and children's SC at weekends. Weekend days seem to provide a suitable space for the promotion of joint physical activity in parents and their pre-schoolers. PMID- 27455294 TI - Microbial Contamination and Hygiene of Fresh Cow's Milk Produced by Smallholders in Western Zambia. AB - A field study was performed to assess safety of smallholder fresh cow's milk around Mongu, Western Province, Zambia. This involved observation and sampling of milk along the value chain from milking to point-of-sale and storage. Samples were collected from 86 cows, from 9 farmers, selling through two dairy cooperatives, with additional samples from informal markets. Production was very low; around one litre/day/cow and 10 L/day/herd. The milk was typically transported by bicycle in high ambient temperatures without refrigeration until reaching the point-of-sale (journey times of 30-120 min), where it was sold without pasteurisation despite milk-borne zoonoses being endemic (bovine tuberculosis (bTB) and Brucellosis). Although microbiological contamination was initially low, with geometric mean total bacterial count (TBC) of 425 cfu/mL (cfu = colony forming units) upon arrival at point-of-sale, poor hygiene led to high bacterial loads later on (geometric mean TBC > 600,000 cfu/mL after two days refrigeration), with almost all samples culture positive for Staphylococcus aureus and Escherichia coli. After milking, milk was kept for 100-223 min at temperatures favouring microbial growth (median 34 degrees C) and sold without a microbial kill step. In this situation limited variation in observed standards of milk hygiene had no significant effect on milk end-product bacterial counts. Options for refrigerated transport are limited. Pasteurisation at the cooperative should be investigated, as this would largely remove pathogenic microbes present in the milk whether resulting from cattle infection or poor hygiene during milking and transportation. As milk is also purchased directly from producers, on farm milk heating options should also be assessed. Smallholders may benefit from access to national markets by providing milk to large dairies, which have systems for ensuring safety. However, this requires significant investment and an increased and more consistent supply of milk; and many consumers, unable to afford milk sold through formal sectors, would not benefit. PMID- 27455295 TI - How Does the Severity of Injury Vary between Motorcycle and Automobile Accident Victims Who Sustain High-Grade Blunt Hepatic and/or Splenic Injuries? Results of a Retrospective Analysis. AB - BACKGROUND: High-grade blunt hepatic and/or splenic injuries (BHSI) remain a great challenge for trauma surgeons. The main aim of this study was to investigate the characteristics, mortality rates, and outcomes of high-grade BHSI in motorcyclists and car occupants hospitalized for treatment of traumatic injuries in a Level I trauma center in southern Taiwan. METHODS: High-grade BHSI are defined as grade III-VI blunt hepatic injuries and grade III-V blunt splenic injuries. This retrospective study reviewed the data of 101 motorcyclists and 32 car occupants who experienced a high-grade BHSI from 1 January 2011 to 31 December 2013. Two-sided Fisher's exact or Pearson's chi-square tests were used to compare categorical data, unpaired Student's t-test was used to analyze normally distributed continuous data, and Mann-Whitney's U test was used to compare non-normally distributed data. RESULTS: In this study, the majority (76%, 101/133) of high-grade BHSI were due to motorcycle crashes. Car occupants had a significantly higher injury severity score (ISS; 26.8 +/- 10.9 vs. 20.7 +/- 10.4, respectively, p = 0.005) and organ injured score (OIS; 3.8 +/- 1.0 vs. 3.4 +/- 0.6, respectively, p = 0.033), as well as a significantly longer hospital length of stay (LOS; 21.2 days vs. 14.6 days, respectively, p = 0.038) than did motorcyclists. Car occupants with high-grade BHSI also had worse clinical presentations than their motorcyclist counterparts, including a significantly higher incidence of hypotension, hyperpnea, tube thoracostomy, blood transfusion >4 units, LOS in intensive care unit >5 days, and complications. However, there were no differences in the percentage of angiography or laparotomy performed or mortality rate between these two groups of patients. CONCLUSIONS: This study demonstrated that car occupants with high-grade BHSI were injured more severely, had a higher incidence of worse clinical presentation, had a longer hospital LOS, and had a higher incidence of complications than motorcyclists. The results also implied that specific attention should be paid to those car occupants with high grade BHSI, whose critical condition should not be underestimated because of the concept that the patients within in a car are much safer. PMID- 27455296 TI - Contamination and Risk Assessment of Heavy Metals in Lake Bed Sediment of a Large Lake Scenic Area in China. AB - The exposure of heavy metals to lake bed sediment of scenic areas may pose risks on aquatic ecosystems and human health, however very few studies on risk assessment have been reported for scenic areas. Accordingly, this study determined concentration levels, and assessed contamination characteristics and risks, of heavy metals in lake bed sediment of National Scenic Areas Songhuahu (NSAS) in China. The concentrations of Zn, Cr, Pb, Ni, and Cu were determined in 29 bed sediment samples. Results showed that the mean values of Zn, Cr, Pb, Ni, and Cu were 92.69, 90.73, 38.29, 46.77, and 49.44 mg/kg, respectively. Pearson correlation coefficients indicated that organic matter was a major factor influencing distribution of heavy metals. The results for enrichment factors indicated that contamination rates and anthropogenic inputs of single heavy metals decreased in the order Cu > Ni > Pb > Cr > Zn; results of Nemerow integrated pollution index suggested that 72.41% of sampling sites were exposed to low to moderately integrated pollution, and 27.59% of sampling sites were exposed to strongly integrated pollution. According to results for potential ecological risk index, ecological risks of single and all the heavy metals in bed sediment from all the sampling sites were low. Human risks were assessed with hazardous quotients, and the results suggested that exposure of heavy metals to bed sediment posed no or little risk to human health, and the pathway of ingestion significantly contributed to human health risks. PMID- 27455298 TI - DNA Damage in Euonymus japonicus Leaf Cells Caused by Roadside Pollution in Beijing. AB - The inhalable particles from vehicle exhaust can cause DNA damage to exposed organisms. Research on DNA damage is primarily focused on the influence of specific pollutants on certain species or the effect of environmental pollution on human beings. To date, little research has quantitatively studied the relationship between roadside pollution and DNA damage. Based on an investigation of the roadside pollution in Beijing, Euonymus japonicus leaves of differing ages grown in heavily-polluted sections were chosen as biomonitors to detect DNA damage using the comet assay technique. The percentage of DNA in the tail and tail moment was chosen as the analysis index based on SPSS data analysis. The roadside samples showed significantly higher levels of DNA damage than non roadside samples, which increased in older leaves, and the DNA damage to Euonymus japonicus leaf cells was positively correlated with haze-aggravated roadside pollution. The correlation between damage and the Air Quality Index (AQI) are 0.921 (one-year-old leaves), 0.894 (two-year-old leaves), and 0.878 (three-year old leaves). Over time, the connection between DNA damage and AQI weakened, with the sensitivity coefficient for deltayear 1 being larger than deltayear 2 and deltayear 3. These findings support the suitability and sensitivity of the comet assay for surveying plants for an estimation of DNA damage induced by environmental genotoxic agents. This study might be applied as a preliminary quantitative method for Chinese urban air pollution damage assessment caused by environmental stress. PMID- 27455297 TI - Environmental Risk Factors in Psoriasis: The Point of View of the Nutritionist. AB - Psoriasis is a common, chronic, immune-mediated skin disease with systemic pro inflammatory activation, where both environmental and genetic factors contribute to its pathogenesis. Among the risk factors for psoriasis, evidence is accumulating that nutrition plays a major role, per se, in psoriasis pathogenesis. In particular, body weight, nutrition, and diet may exacerbate the clinical manifestations, or even trigger the disease. Understanding the epidemiological relationship between obesity and psoriasis is also important for delineating the risk profile for the obesity-related comorbidities commonly found among psoriatic patients. Moreover, obesity can affect both drug's pharmacokinetics and pharmacodynamics. Additionally, the overall beneficial effects on the obesity-associated comorbidities, clinical recommendations to reduce weight and to adopt a healthy lifestyle could improve the psoriasis severity, particularly in those patients with moderate to severe disease, thus exerting additional therapeutic effects in the conventional treatment in obese patients with psoriasis. Education regarding modifiable environmental factors is essential in the treatment of this disease and represents one of the primary interventions that can affect the prognosis of patients with psoriasis. The goal is to make psoriatic patients and health care providers aware of beneficial dietary interventions. The aim of this review is to assess the relevance of the environmental factors as modifiable risk factors in psoriasis pathogenesis, with particular regard to the involvement of obesity and nutrition in the management of psoriasis, providing also specific nutrition recommendations. PMID- 27455299 TI - Efficacy of a Low Dose of Hydrogen Peroxide (Peroxy Ag+) for Continuous Treatment of Dental Unit Water Lines: Challenge Test with Legionella pneumophila Serogroup 1 in a Simulated Dental Unit Waterline. AB - This study was designed to examine the in vitro bactericidal activity of hydrogen peroxide against Legionella. We tested hydrogen peroxide (Peroxy Ag+) at 600 ppm to evaluate Legionella survival in a simulated dental treatment water system equipped with Water Hygienization Equipment (W.H.E.) device that was artificially contaminated. When Legionella pneumophila serogroup (sg) 1 was exposed to Peroxy Ag+ for 60 min we obtained a two decimal log reduction. High antimicrobial efficacy was obtained with extended periods of exposure: four decimal log reduction at 75 min and five decimal log reduction at 15 h of exposure. Involving a simulation device (Peroxy Ag+ is flushed into the simulation dental unit waterlines (DUWL)) we obtained an average reduction of 85% of Legionella load. The product is effective in reducing the number of Legionella cells after 75 min of contact time (99.997%) in the simulator device under test conditions. The Peroxy Ag+ treatment is safe for continuous use in the dental water supply system (i.e., it is safe for patient contact), so it could be used as a preventive option, and it may be useful in long-term treatments, alone or coupled with a daily or periodic shock treatment. PMID- 27455300 TI - Exploring Global Exposure Factors Resources for Use in Consumer Exposure Assessments. AB - This publication serves as a global comprehensive resource for readers seeking exposure factor data and information relevant to consumer exposure assessment. It describes the types of information that may be found in various official surveys and online and published resources. The relevant exposure factors cover a broad range, including general exposure factor data found in published compendia and databases and resources about specific exposure factors, such as human activity patterns and housing information. Also included are resources on exposure factors related to specific types of consumer products and the associated patterns of use, such as for a type of personal care product or a type of children's toy. Further, a section on using exposure factors for designing representative exposure scenarios is included, along with a look into the future for databases and other exposure science developments relevant for consumer exposure assessment. PMID- 27455301 TI - Windmill Noise Annoyance, Visual Aesthetics, and Attitudes towards Renewable Energy Sources. AB - A small focused socio-acoustic after-study of annoyance from a windmill park was undertaken after local health officials demanded a health impact study to look into neighborhood complaints. The windmill park consists of 31 turbines and is located in the South of Norway where it affects 179 dwellings. Simple exposure effect relationships indicate stronger reactions to windmills and wind turbine noise than shown internationally, with the caveat that the sample size is small (n = 90) and responses are colored by the existing local conflict. Pulsating swishing sounds and turbine engine hum are the main causes of noise annoyance. About 60 per cent of those who participated in the survey were of the opinion that windmills degrade the landscape aesthetically, and were far from convinced that land-based windmills are desirable as a renewable energy source (hydropower is an important alternative source of renewables in Norway). Attitudes play an important role in addition to visual aesthetics in determining the acceptance of windmills and the resulting noise annoyance. To compare results from different wind turbine noise studies it seems necessary to assess the impact of important modifying factors. PMID- 27455302 TI - Socio-demographic Differences in Toxic Release Inventory Siting and Emissions in Metro Atlanta. AB - Prior research has found that low socioeconomic status (SES) populations and minorities in some areas reside in communities with disproportionate exposure to hazardous chemicals. The objectives of this study were to evaluate the relevance of socio-demographic characteristics on the presence of Toxic Release Inventory (TRI) facilities, air releases, and prevalence and resolution of air quality complaints in the 20-county Atlanta Metropolitan Statistical Area (MSA). We found that there were 4.7% more minority residents in census tracts where TRI facilities were located. The odds ratio (OR) for the presence of a TRI facility was 0.89 (p < 0.01) for each 1% increase of females with a college degree and 2.4 (p < 0.01) for households with an income of $22,000-$55,000. The estimated reduction in the amount of chemicals emitted per release associated with population of females with a college degree was 18.53 pounds (p < 0.01). Complaints took longer to resolve in census tracts with higher Hispanic populations (OR = 1.031, 95% CI: 1.010-1.054). Overall, results indicate that SES and race/ethnicity are related to TRI facility siting, releases, and complaints in the Atlanta area. These findings have not been documented previously and suggest that lower SES and non-White communities may be disproportionately exposed. PMID- 27455303 TI - A Phylogenetic Survey on the Structure of the HIV-1 Leader RNA Domain That Encodes the Splice Donor Signal. AB - RNA splicing is a critical step in the human immunodeficiency virus type 1 (HIV 1) replication cycle because it controls the expression of the complex viral proteome. The major 5' splice site (5'ss) that is positioned in the untranslated leader of the HIV-1 RNA transcript is of particular interest because it is used for the production of the more than 40 differentially spliced subgenomic mRNAs. HIV-1 splicing needs to be balanced tightly to ensure the proper levels of all viral proteins, including the Gag-Pol proteins that are translated from the unspliced RNA. We previously presented evidence that the major 5'ss is regulated by a repressive local RNA structure, the splice donor (SD) hairpin, that masks the 11 nucleotides (nts) of the 5'ss signal for recognition by U1 small nuclear RNA (snRNA) of the spliceosome machinery. A strikingly different multiple-hairpin RNA conformation was recently proposed for this part of the HIV-1 leader RNA. We therefore inspected the sequence of natural HIV-1 isolates in search for support, in the form of base pair (bp) co-variations, for the different RNA conformations. PMID- 27455304 TI - Infection Counter: Automated Quantification of in Vitro Virus Replication by Fluorescence Microscopy. AB - The ability to accurately and reliably quantify viral infection is essential to basic and translational virology research. Here, we describe a simple and robust automated method for using fluorescence microscopy to estimate the proportion of virally infected cells in a monolayer. We provide details of the automated analysis workflow along with a freely available open-source ImageJ plugin, Infection Counter, for performing image quantification. Using hepatitis C virus (HCV) as an example, we have experimentally verified our method, demonstrating that it is equivalent, if not better, than the established focus-forming assay. Finally, we used Infection Counter to assess the anti-HCV activity of SMBz-CsA, a non-immunosuppressive cyclosporine analogue. PMID- 27455306 TI - Ectromelia Virus Disease Characterization in the BALB/c Mouse: A Surrogate Model for Assessment of Smallpox Medical Countermeasures. AB - In 2007, the United States- Food and Drug Administration (FDA) issued guidance concerning animal models for testing the efficacy of medical countermeasures against variola virus (VARV), the etiologic agent for smallpox. Ectromelia virus (ECTV) is naturally-occurring and responsible for severe mortality and morbidity as a result of mousepox disease in the murine model, displaying similarities to variola infection in humans. Due to the increased need of acceptable surrogate animal models for poxvirus disease, we have characterized ECTV infection in the BALB/c mouse. Mice were inoculated intranasally with a high lethal dose (125 PFU) of ECTV, resulting in complete mortality 10 days after infection. Decreases in weight and temperature from baseline were observed eight to nine days following infection. Viral titers via quantitative polymerase chain reaction (qPCR) and plaque assay were first observed in the blood at 4.5 days post-infection and in tissue (spleen and liver) at 3.5 days post-infection. Adverse clinical signs of disease were first observed four and five days post-infection, with severe signs occurring on day 7. Pathological changes consistent with ECTV infection were first observed five days after infection. Examination of data obtained from these parameters suggests the ECTV BALB/c model is suitable for potential use in medical countermeasures (MCMs) development and efficacy testing. PMID- 27455305 TI - The Role of Phlebovirus Glycoproteins in Viral Entry, Assembly and Release. AB - Bunyaviruses are enveloped viruses with a tripartite RNA genome that can pose a serious threat to animal and human health. Members of the Phlebovirus genus of the family Bunyaviridae are transmitted by mosquitos and ticks to humans and include highly pathogenic agents like Rift Valley fever virus (RVFV) and severe fever with thrombocytopenia syndrome virus (SFTSV) as well as viruses that do not cause disease in humans, like Uukuniemi virus (UUKV). Phleboviruses and other bunyaviruses use their envelope proteins, Gn and Gc, for entry into target cells and for assembly of progeny particles in infected cells. Thus, binding of Gn and Gc to cell surface factors promotes viral attachment and uptake into cells and exposure to endosomal low pH induces Gc-driven fusion of the viral and the vesicle membranes. Moreover, Gn and Gc facilitate virion incorporation of the viral genome via their intracellular domains and Gn and Gc interactions allow the formation of a highly ordered glycoprotein lattice on the virion surface. Studies conducted in the last decade provided important insights into the configuration of phlebovirus Gn and Gc proteins in the viral membrane, the cellular factors used by phleboviruses for entry and the mechanisms employed by phlebovirus Gc proteins for membrane fusion. Here, we will review our knowledge on the glycoprotein biogenesis and the role of Gn and Gc proteins in the phlebovirus replication cycle. PMID- 27455307 TI - Inactivation of RNA Viruses by Gamma Irradiation: A Study on Mitigating Factors. AB - Effective inactivation of biosafety level 4 (BSL-4) pathogens is vital in order to study these agents safely. Gamma irradiation is a commonly used method for the inactivation of BSL-4 viruses, which among other advantages, facilitates the study of inactivated yet morphologically intact virions. The reported values for susceptibility of viruses to inactivation by gamma irradiation are sometimes inconsistent, likely due to differences in experimental protocols. We analyzed the effects of common sample attributes on the inactivation of a recombinant vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein and green fluorescent protein. Using this surrogate virus, we found that sample volume and protein content of the sample modulated viral inactivation by gamma irradiation but that air volume within the sample container and the addition of external disinfectant surrounding the sample did not. These data identify several factors which alter viral susceptibility to inactivation and highlight the usefulness of lower biosafety level surrogate viruses for such studies. Our results underscore the need to validate inactivation protocols of BSL-4 pathogens using "worst-case scenario" procedures to ensure complete sample inactivation. PMID- 27455308 TI - Local Innate Responses to TLR Ligands in the Chicken Trachea. AB - The chicken upper respiratory tract is the portal of entry for respiratory pathogens, such as avian influenza virus (AIV). The presence of microorganisms is sensed by pathogen recognition receptors (such as Toll-like receptors (TLRs)) of the innate immune defenses. Innate responses are essential for subsequent induction of potent adaptive immune responses, but little information is available about innate antiviral responses of the chicken trachea. We hypothesized that TLR ligands induce innate antiviral responses in the chicken trachea. Tracheal organ cultures (TOC) were used to investigate localized innate responses to TLR ligands. Expression of candidate genes, which play a role in antiviral responses, was quantified. To confirm the antiviral responses of stimulated TOC, chicken macrophages were treated with supernatants from stimulated TOC, prior to infection with AIV. The results demonstrated that TLR ligands induced the expression of pro-inflammatory cytokines, type I interferons and interferon stimulated genes in the chicken trachea. In conclusion, TLR ligands induce functional antiviral responses in the chicken trachea, which may act against some pathogens, such as AIV. PMID- 27455309 TI - The Whitefly Bemisia tabaci Knottin-1 Gene Is Implicated in Regulating the Quantity of Tomato Yellow Leaf Curl Virus Ingested and Transmitted by the Insect. AB - The whitefly Bemisia tabaci is a major pest to agricultural crops. It transmits begomoviruses, such as Tomato yellow leaf curl virus (TYLCV), in a circular, persistent fashion. Transcriptome analyses revealed that B. tabaci knottin genes were responsive to various stresses. Upon ingestion of tomato begomoviruses, two of the four knottin genes were upregulated, knot-1 (with the highest expression) and knot-3. In this study, we examined the involvement of B. tabaci knottin genes in relation to TYLCV circulative transmission. Knottins were silenced by feeding whiteflies with knottin dsRNA via detached tomato leaves. Large amounts of knot-1 transcripts were present in the abdomen of whiteflies, an obligatory transit site of begomoviruses in their circulative transmission pathway; knot-1 silencing significantly depleted the abdomen from knot-1 transcripts. Knot-1 silencing led to an increase in the amounts of TYLCV ingested by the insects and transmitted to tomato test plants by several orders of magnitude. This effect was not observed following knot-3 silencing. Hence, knot-1 plays a role in restricting the quantity of virions an insect may acquire and transmit. We suggest that knot-1 protects B. tabaci against deleterious effects caused by TYLCV by limiting the amount of virus associated with the whitefly vector. PMID- 27455311 TI - Walnut Phenolic Extract and Its Bioactive Compounds Suppress Colon Cancer Cell Growth by Regulating Colon Cancer Stemness. AB - Walnut has been known for its health benefits, including anti-cardiovascular disease and anti-oxidative properties. However, there is limited evidence elucidating its effects on cancer stem cells (CSCs) which represent a small subset of cancer cells that provide resistance against chemotherapy. This study aimed to evaluate the anti-CSCs potential of walnut phenolic extract (WPE) and its bioactive compounds, including (+)-catechin, chlorogenic acid, ellagic acid, and gallic acid. In the present study, CD133+CD44+ cells were isolated from HCT116 cells using fluorescence-activated cell sorting (FACS) and then treated with WPE. As a result, survival of the CD133+CD44+ HCT116 cells was inhibited and cell differentiation was induced by WPE. In addition, WPE down-regulated the CSC markers, CD133, CD44, DLK1, and Notch1, as well as the beta-catenin/p-GSK3beta signaling pathway. WPE suppressed the self-renewal capacity of CSCs. Furthermore, the WPE exhibited stronger anti-CSC effects than its individual bioactive compounds. Finally, the WPE inhibited specific CSC markers in primary colon cancer cells isolated from primary colon tumor. These results suggest that WPE can suppress colon cancer by regulating the characteristics of colon CSCs. PMID- 27455310 TI - Viral RNA Silencing Suppression: The Enigma of Bunyavirus NSs Proteins. AB - The Bunyaviridae is a family of arboviruses including both plant- and vertebrate infecting representatives. The Tospovirus genus accommodates plant-infecting bunyaviruses, which not only replicate in their plant host, but also in their insect thrips vector during persistent propagative transmission. For this reason, they are generally assumed to encounter antiviral RNA silencing in plants and insects. Here we present an overview on how tospovirus nonstructural NSs protein counteracts antiviral RNA silencing in plants and what is known so far in insects. Like tospoviruses, members of the related vertebrate-infecting bunyaviruses classified in the genera Orthobunyavirus, Hantavirus and Phlebovirus also code for a NSs protein. However, for none of them RNA silencing suppressor activity has been unambiguously demonstrated in neither vertebrate host nor arthropod vector. The second part of this review will briefly describe the role of these NSs proteins in modulation of innate immune responses in mammals and elaborate on a hypothetical scenario to explain if and how NSs proteins from vertebrate-infecting bunyaviruses affect RNA silencing. If so, why this discovery has been hampered so far. PMID- 27455312 TI - Yacon (Smallanthus sonchifolius) as a Food Supplement: Health-Promoting Benefits of Fructooligosaccharides. AB - Yacon (Smallanthus sonchifolius), a perennial plant of the family Asteraceae native to the Andean regions of South America, is an abundant source of fructooligosaccharides (FOS). This comprehensive review of the literature addressed the role of yacon supplementation in promoting health and reducing the risk of chronic diseases. According to several preclinical and clinical trials, FOS intake favors the growth of health-promoting bacteria while reducing pathogenic bacteria populations. Moreover, the endproducts of FOS fermentation by the intestinal microbiota, short chain fatty acids (SCFA), act as substrates or signaling molecules in the regulation of the immune response, glucose homeostasis and lipid metabolism. As a result, glycemic levels, body weight and colon cancer risk can be reduced. Based on these findings, most studies reviewed concluded that due to their functional properties, yacon roots may be effectively used as a dietary supplement to prevent and treat chronic diseases. PMID- 27455313 TI - Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response. AB - It has been reported that barley leaves possess beneficial properties such as antioxidant, hypolipidemic, antidepressant, and antidiabetic. Interestingly, barley sprouts contain a high content of saponarin, which showed both anti inflammatory and antioxidant activities. In this study, we evaluated the effect of barley sprouts on alcohol-induced liver injury mediated by inflammation and oxidative stress. Raw barley sprouts were extracted, and quantitative and qualitative analyses of its components were performed. The mice were fed a liquid alcohol diet with or without barley sprouts for four weeks. Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used to study the effect of barley sprouts on inflammation. Alcohol intake for four weeks caused liver injury, evidenced by an increase in serum alanine aminotransferase and aspartate aminotransferase activities and tumor necrosis factor (TNF)-alpha levels. The accumulation of lipid in the liver was also significantly induced, whereas the glutathione (GSH) level was reduced. Moreover, the inflammation-related gene expression was dramatically increased. All these alcohol-induced changes were effectively prevented by barley sprouts treatment. In particular, pretreatment with barley sprouts significantly blocked inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in LPS-stimulated RAW 264.7. This study suggests that the protective effect of barley sprouts against alcohol-induced liver injury is potentially attributable to its inhibition of the inflammatory response induced by alcohol. PMID- 27455315 TI - Hypocholesterolaemic Activity of Lupin Peptides: Investigation on the Crosstalk between Human Enterocytes and Hepatocytes Using a Co-Culture System Including Caco-2 and HepG2 Cells. AB - Literature indicates that peptic and tryptic peptides derived from the enzymatic hydrolysis of lupin protein are able to modulate cholesterol metabolism in human hepatic HepG2 cells and that part of these peptides are absorbed in a small intestine model based on differentiated human Caco-2 cells. In this paper, a co culture system, including Caco-2 and HepG2 cells, was investigated with two objectives: (a) to verify whether cholesterol metabolism in HepG2 cells was modified by the peptides absorption through Caco-2 cells; (b) to investigate how lupin peptides influence cholesterol metabolism in Caco-2 cells. The experiments showed that the absorbed peptides, not only maintained their bioactivity on HepG2 cells, but that this activity was improved by the crosstalk of the two cells systems in co-culture. In addition, lupin peptides showed a positive influence on cholesterol metabolism in Caco-2 cells, decreasing the proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion. PMID- 27455314 TI - Nutritional Deficiency in Patients with Heart Failure. AB - Heart failure (HF) is the main cause of mortality and morbidity in Western countries. Although evidence-based treatments have substantially improved outcomes, prognosis remains poor with high costs for health care systems. In patients with HF, poor dietary behaviors are associated with unsatisfactory quality of life and adverse outcome. The HF guidelines have not recommended a specific nutritional strategy. Despite the role of micronutrient deficiency, it has been extensively studied, and data about the efficacy of supplementation therapy in HF are not supported by large randomized trials and there is limited evidence regarding the outcomes. The aim of the present review is to analyze the state-of-the-art of nutritional deficiencies in HF, focusing on the physiological role and the prognostic impact of micronutrient supplementation. PMID- 27455316 TI - The Effects of Montmorency Tart Cherry Concentrate Supplementation on Recovery Following Prolonged, Intermittent Exercise. AB - This study investigated Montmorency tart cherry concentrate (MC) supplementation on markers of recovery following prolonged, intermittent sprint activity. Sixteen semi-professional, male soccer players, who had dietary restrictions imposed for the duration of the study, were divided into two equal groups and consumed either MC or placebo (PLA) supplementation for eight consecutive days (30 mL twice per day). On day 5, participants completed an adapted version of the Loughborough Intermittent Shuttle Test (LISTADAPT). Maximal voluntary isometric contraction (MVIC), 20 m Sprint, counter movement jump (CMJ), agility and muscle soreness (DOMS) were assessed at baseline, and 24, 48 and 72 h post-exercise. Measures of inflammation (IL-1-beta, IL-6, IL-8, TNF-alpha, hsCRP), muscle damage (CK) and oxidative stress (LOOH) were analysed at baseline and 1, 3, 5, 24, 48 and 72 h post-exercise. Performance indices (MVIC, CMJ and agility) recovered faster and muscle soreness (DOMS) ratings were lower in the MC group (p < 0.05). Additionally, the acute inflammatory response (IL-6) was attenuated in the MC group. There were no effects for LOOH and CK. These findings suggest MC is efficacious in accelerating recovery following prolonged, repeat sprint activity, such as soccer and rugby, and lends further evidence that polyphenol-rich foods like MC are effective in accelerating recovery following various types of strenuous exercise. PMID- 27455317 TI - Potassium Intake, Bioavailability, Hypertension, and Glucose Control. AB - Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+) ATPase pump. Approximately 90% of potassium consumed (60-100 mEq) is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN) is the leading cause of cardiovascular disease (CVD) and a major financial burden ($50.6 billion) to the US public health system, and has a significant impact on all cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics) may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health. PMID- 27455318 TI - Impact of Diabetes-Specific Nutritional Formulas versus Oatmeal on Postprandial Glucose, Insulin, GLP-1 and Postprandial Lipidemia. AB - Diabetes-specific nutritional formulas (DSNFs) are frequently used as part of medical nutrition therapy for patients with diabetes. This study aims to evaluate postprandial (PP) effects of 2 DSNFs; Glucerna (GL) and Ultra Glucose Control (UGC) versus oatmeal (OM) on glucose, insulin, glucagon-like peptide-1 (GLP-1), free fatty acids (FFA) and triglycerides (TG). After an overnight fast, 22 overweight/obese patients with type 2 diabetes were given 200 kcal of each of the three meals on three separate days in random order. Blood samples were collected at baseline and at 30, 60, 90, 120, 180 and 240 min. Glucose area under the curve (AUC0-240) after GL and UGC was lower than OM (p < 0.001 for both). Insulin positive AUC0-120 after UGC was higher than after OM (p = 0.02). GLP-1 AUC0-120 and AUC0-240 after GL and UGC was higher than after OM (p < 0.001 for both). FFA and TG levels were not different between meals. Intake of DSNFs improves PP glucose for 4 h in comparison to oatmeal of similar caloric level. This is achieved by either direct stimulation of insulin secretion or indirectly by stimulating GLP-1 secretion. The difference between their effects is probably related to their unique blends of amino acids, carbohydrates and fat. PMID- 27455319 TI - Iodine Status of New Zealand Elderly Residents in Long-Term Residential Care. AB - In response to the re-emergence of iodine deficiency in New Zealand, in 2009 the government mandated that all commercially made breads be fortified with iodized salt. There has been no evaluation of the impact of the program on iodine status of the elderly, despite this population group being vulnerable to iodine deficiency or excess. The aim of this study was to describe the iodine status of elderly New Zealanders in residential aged-care homes following the implementation of the bread fortification program. A cross-sectional survey was conducted, involving 309 residents (median age 85 years) from 16 aged-care homes throughout NZ. Information on socio-demographic, anthropometric, dietary and health characteristics were collected. Casual spot urine samples were analysed for urinary iodine concentration (UIC). Blood samples were analysed for serum thyroglobulin, thyroglobulin antibodies, and other biochemical indices. The median UIC (MUIC) of the residents was 72 MUg/L, indicating mild iodine deficiency, and 29% had a UIC < 50 MUg/L. Median thyroglobulin concentration was 18 ng/mL and 26% had elevated thyroglobulin concentration (>40 ng/mL), suggesting iodine insufficiency. Diuretic use was associated with lower MUIC (p = 0.043). Synthetic thyroxine use was associated with lower odds of having a UIC < 50 MUg/L (OR 0.32, p = 0.030)) and lower median thyroglobulin (-15.2 ng/mL, p = 0.001), compared with untreated participants. Frailty was associated with elevated thyroglobulin (p = 0.029), whereas anemia was associated with lower thyroglobulin (p = 0.016). Iodine insufficiency persists in New Zealanders residing in residential aged-care homes despite increasing iodine intake from fortified bread. Research is required to establish optimal iodine intake and status in the elderly. PMID- 27455320 TI - Emerging Evidence for the Importance of Dietary Protein Source on Glucoregulatory Markers and Type 2 Diabetes: Different Effects of Dairy, Meat, Fish, Egg, and Plant Protein Foods. AB - Observational studies provide evidence that a higher intake of protein from plant based foods and certain animal-based foods is associated with a lower risk for type 2 diabetes. However, there are few distinguishable differences between the glucoregulatory qualities of the proteins in plant-based foods, and it is likely their numerous non-protein components (e.g., fibers and phytochemicals) that drive the relationship with type 2 diabetes risk reduction. Conversely, the glucoregulatory qualities of the proteins in animal-based foods are extremely divergent, with a higher intake of certain animal-based protein foods showing negative effects, and others showing neutral or positive effects on type 2 diabetes risk. Among the various types of animal-based protein foods, a higher intake of dairy products (such as milk, yogurt, cheese and whey protein) consistently shows a beneficial relationship with glucose regulation and/or type 2 diabetes risk reduction. Intervention studies provide evidence that dairy proteins have more potent effects on insulin and incretin secretion compared to other commonly consumed animal proteins. In addition to their protein components, such as insulinogenic amino acids and bioactive peptides, dairy products also contain a food matrix rich in calcium, magnesium, potassium, trans-palmitoleic fatty acids, and low-glycemic index sugars-all of which have been shown to have beneficial effects on aspects of glucose control, insulin secretion, insulin sensitivity and/or type 2 diabetes risk. Furthermore, fermentation and fortification of dairy products with probiotics and vitamin D may improve a dairy product's glucoregulatory effects. PMID- 27455321 TI - Selection of the Optimal Herbal Compositions of Red Clover and Pomegranate According to Their Protective Effect against Climacteric Symptoms in Ovariectomized Mice. AB - This study aimed to ascertain the optimal range of red clover dry extracts (RC) and dried pomegranate concentrate powder (PCP) to induce anti-climacteric effects. Thus, the dose ranges showing protective effect of mixed formulae consisting of RC and PCP were examined in ovariectomized mice. At 28 days after bilateral ovariectomy (OVX), mixed herbal compositions (RC:PCP = 1:1, 1:2, 1:4, 1:8, 2:1, 4:1, and 8:1) were administered orally, at 120 mg/kg once daily for 84 days. We evaluated that RC and PCP mixture attenuate OVX-caused obesity, hyperlipidemia, hepatic steatosis, and osteoporosis. Compared to OVX-induced control mice, body weight and abdominal fat weight in OVX-induced mice were significantly decreased, concomitantly with increase of uterus weight by RC:PCP mixture. Additionally, significant increases in serum estradiol levels were observed in all RC:PCP-treated mice. RC:PCP mixture also showed protective effect against OVX-induced hyperlipidemia, hepatic steatosis. Total body and femur mean bone mineral density (BMD), osteocalcin, bALP contents were effectively increased by RC:PCP mixture. Taken together, RC:PCP mixture (2:1, 1:1, and 4:1) has remarkable protective effects against the changes induced by OVX. In particular, RC:PCP mixture (2:1) shows the strongest effect and may be considered as a potential protective agent against climacteric symptoms. PMID- 27455322 TI - Gender Difference on the Association between Dietary Patterns and Obesity in Chinese Middle-Aged and Elderly Populations. AB - Dietary patterns are linked to obesity, but the gender difference in the association between dietary patterns and obesity remains unclear. We explored this gender difference in a middle-aged and elderly populations in Shanghai. Residents (n = 2046; aged >=45 years; 968 men and 1078 women) who participated in the Shanghai Food Consumption Survey were studied. Factor analysis of data from four periods of 24-h dietary recalls (across 2012-2014) identified dietary patterns. Height, body weight, and waist circumference were measured to calculate the body mass index. A log binominal model examined the association between dietary patterns and obesity, stratified by gender. Four dietary patterns were identified for both genders: rice staple, wheat staple, snacks, and prudent patterns. The rice staple pattern was associated positively with abdominal obesity in men (prevalence ratio (PR) = 1.358; 95% confidence interval (CI) 1.132 1.639; p = 0.001), but was associated negatively with general obesity in women (PR = 0.745; 95% CI: 0.673-0.807; p = 0.031). Men in the highest quartile of the wheat staple pattern had significantly greater risk of central obesity (PR = 1.331; 95% CI: 1.094-1.627; p = 0.005). There may be gender differences in the association between dietary patterns and obesity in middle-aged and elderly populations in Shanghai, China. PMID- 27455324 TI - A Theoretical Study of 8-Chloro-9-Hydroxy-Aflatoxin B1, the Conversion Product of Aflatoxin B1 by Neutral Electrolyzed Water. AB - Theoretical studies of 8-chloro-9-hydroxy-aflatoxin B1 (2) were carried out by Density Functional Theory (DFT). This molecule is the reaction product of the treatment of aflatoxin B1 (1) with hypochlorous acid, from neutral electrolyzed water. Determination of the structural, electronic and spectroscopic properties of the reaction product allowed its theoretical characterization. In order to elucidate the formation process of 2, two reaction pathways were evaluated-the first one considering only ionic species (Cl+ and OH(-)) and the second one taking into account the entire hypochlorous acid molecule (HOCl). Both pathways were studied theoretically in gas and solution phases. In the first suggested pathway, the reaction involves the addition of chlorenium ion to 1 forming a non classic carbocation assisted by anchimeric effect of the nearest aromatic system, and then a nucleophilic attack to the intermediate by the hydroxide ion. In the second studied pathway, as a first step, the attack of the double bond from the furanic moiety of 1 to the hypochlorous acid is considered, accomplishing the same non-classical carbocation, and again in the second step, a nucleophilic attack by the hydroxide ion. In order to validate both reaction pathways, the atomic charges, the highest occupied molecular orbital and the lowest unoccupied molecular orbital were obtained for both substrate and product. The corresponding data imply that the C9 atom is the more suitable site of the substrate to interact with the hydroxide ion. It was demonstrated by theoretical calculations that a vicinal and anti chlorohydrin is produced in the terminal furan ring. Data of the studied compound indicate an important reduction in the cytotoxic and genotoxic potential of the target molecule, as demonstrated previously by our research group using different in vitro assays. PMID- 27455323 TI - Type II Toxin-Antitoxin Systems in the Unicellular Cyanobacterium Synechocystis sp. PCC 6803. AB - Bacterial toxin-antitoxin (TA) systems are genetic elements, which are encoded by plasmid as well as chromosomal loci. They mediate plasmid and genomic island maintenance through post-segregational killing mechanisms but may also have milder effects, acting as mobile stress response systems that help certain cells of a population in persisting adverse growth conditions. Very few cyanobacterial TA system have been characterized thus far. In this work, we focus on the cyanobacterium Synechocystis 6803, a widely used model organism. We expand the number of putative Type II TA systems from 36 to 69 plus seven stand-alone components. Forty-seven TA pairs are located on the chromosome and 22 are plasmid located. Different types of toxins are associated with various antitoxins in a mix and match principle. According to protein domains and experimental data, 81% of all toxins in Synechocystis 6803 likely exhibit RNase activity, suggesting extensive potential for toxicity-related RNA degradation and toxin-mediated transcriptome remodeling. Of particular interest is the Ssr8013-Slr8014 system encoded on plasmid pSYSG, which is part of a larger defense island or the pSYSX system Slr6056-Slr6057, which is linked to a bacterial ubiquitin-like system. Consequently, Synechocystis 6803 is one of the most prolific sources of new information about these genetic elements. PMID- 27455325 TI - Purification and Characterization of a Novel Kazal-Type Trypsin Inhibitor from the Leech of Hirudinaria manillensis. AB - Kazal-type serine proteinase inhibitors are found in a large number of living organisms and play crucial roles in various biological and physiological processes. Although some Kazal-type serine protease inhibitors have been identified in leeches, none has been reported from Hirudinaria manillensis, which is a medically important leech. In this study, a novel Kazal-type trypsin inhibitor was isolated from leech H. manillensis, purified and named as bdellin HM based on the sequence similarity with bdellin-KL and bdellin B-3. Structural analysis revealed that bdellin-HM was a 17,432.8 Da protein and comprised of 149 amino acid residues with six cysteines forming three intra-molecular disulfide bonds. Bdellin-HM showed similarity with the Kazal-type domain and may belong to the group of "non-classical" Kazal inhibitors according to its Cys(I)-Cys(II) disulfide bridge position. Bdellin-HM had no inhibitory effect on elastase, chymotrypsin, kallikrein, Factor (F) XIIa, FXIa, FXa, thrombin and plasmin, but it showed a potent ability to inhibit trypsin with an inhibition constant (Ki) of (8.12 +/- 0.18) * 10(-9) M. These results suggest that bdellin-HM from the leech of H. manillensis plays a potent and specific inhibitory role towards trypsin. PMID- 27455326 TI - Colubrid Venom Composition: An -Omics Perspective. AB - Snake venoms have been subjected to increasingly sensitive analyses for well over 100 years, but most research has been restricted to front-fanged snakes, which actually represent a relatively small proportion of extant species of advanced snakes. Because rear-fanged snakes are a diverse and distinct radiation of the advanced snakes, understanding venom composition among "colubrids" is critical to understanding the evolution of venom among snakes. Here we review the state of knowledge concerning rear-fanged snake venom composition, emphasizing those toxins for which protein or transcript sequences are available. We have also added new transcriptome-based data on venoms of three species of rear-fanged snakes. Based on this compilation, it is apparent that several components, including cysteine-rich secretory proteins (CRiSPs), C-type lectins (CTLs), CTLs like proteins and snake venom metalloproteinases (SVMPs), are broadly distributed among "colubrid" venoms, while others, notably three-finger toxins (3FTxs), appear nearly restricted to the Colubridae (sensu stricto). Some putative new toxins, such as snake venom matrix metalloproteinases, are in fact present in several colubrid venoms, while others are only transcribed, at lower levels. This work provides insights into the evolution of these toxin classes, but because only a small number of species have been explored, generalizations are still rather limited. It is likely that new venom protein families await discovery, particularly among those species with highly specialized diets. PMID- 27455327 TI - Biotechnological Trends in Spider and Scorpion Antivenom Development. AB - Spiders and scorpions are notorious for their fearful dispositions and their ability to inject venom into prey and predators, causing symptoms such as necrosis, paralysis, and excruciating pain. Information on venom composition and the toxins present in these species is growing due to an interest in using bioactive toxins from spiders and scorpions for drug discovery purposes and for solving crystal structures of membrane-embedded receptors. Additionally, the identification and isolation of a myriad of spider and scorpion toxins has allowed research within next generation antivenoms to progress at an increasingly faster pace. In this review, the current knowledge of spider and scorpion venoms is presented, followed by a discussion of all published biotechnological efforts within development of spider and scorpion antitoxins based on small molecules, antibodies and fragments thereof, and next generation immunization strategies. The increasing number of discovery and development efforts within this field may point towards an upcoming transition from serum-based antivenoms towards therapeutic solutions based on modern biotechnology. PMID- 27455329 TI - Transcriptomic Analysis of the Endangered Neritid Species Clithon retropictus: De Novo Assembly, Functional Annotation, and Marker Discovery. AB - An aquatic gastropod belonging to the family Neritidae, Clithon retropictus is listed as an endangered class II species in South Korea. The lack of information on its genomic background limits the ability to obtain functional data resources and inhibits informed conservation planning for this species. In the present study, the transcriptomic sequencing and de novo assembly of C. retropictus generated a total of 241,696,750 high-quality reads. These assembled to 282,838 unigenes with mean and N50 lengths of 736.9 and 1201 base pairs, respectively. Of these, 125,616 unigenes were subjected to annotation analysis with known proteins in Protostome DB, COG, GO, and KEGG protein databases (BLASTX; E <= 0.00001) and with known nucleotides in the Unigene database (BLASTN; E <= 0.00001). The GO analysis indicated that cellular process, cell, and catalytic activity are the predominant GO terms in the biological process, cellular component, and molecular function categories, respectively. In addition, 2093 unigenes were distributed in 107 different KEGG pathways. Furthermore, 49,280 simple sequence repeats were identified in the unigenes (>1 kilobase sequences). This is the first report on the identification of transcriptomic and microsatellite resources for C. retropictus, which opens up the possibility of exploring traits related to the adaptation and acclimatization of this species. PMID- 27455330 TI - Assessing Tumor Response to Treatment in Patients with Lung Cancer Using Dynamic Contrast-Enhanced CT. AB - The aim of this study was to provide an overview of the literature available on dynamic contrast-enhanced computed tomography (DCE-CT) as a tool to evaluate treatment response in patients with lung cancer. This systematic review was compiled according to Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Only original research articles concerning treatment response in patients with lung cancer assessed with DCE-CT were included. To assess the validity of each study we implemented Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). The initial search yielded 651 publications, and 16 articles were included in this study. The articles were divided into groups of treatment. In studies where patients were treated with systemic chemotherapy with or without anti-angiogenic drugs, four out of the seven studies found a significant decrease in permeability after treatment. Four out of five studies that measured blood flow post anti-angiogenic treatments found that blood flow was significantly decreased. DCE-CT may be a useful tool in assessing treatment response in patients with lung cancer. It seems that particularly permeability and blood flow are important perfusion values for predicting treatment outcome. However, the heterogeneity in scan protocols, scan parameters, and time between scans makes it difficult to compare the included studies. PMID- 27455331 TI - Subterranean Termite Resistance of Polystyrene-Treated Wood from Three Tropical Wood Species. AB - The objective of this work was to investigate the resistance of three Indonesian wood species to termite attack. Samples from sengon (Falcataria moluccana), mangium (Acacia mangium), and pine (Pinus merkusii) were treated with polystyrene at loading levels of 26.0%, 8.6%, and 7.7%, respectively. Treated and untreated samples were exposed to environmental conditions in the field for 3 months. Untreated specimens of sengon, mangium, and pine had resistance ratings of 3.0, 4.6, and 2.4, respectively, based on a 10-point scale from 0 (no resistance) to 10 (complete or near-complete resistance). Corresponding resistance values of 7.8, 7.2, and 8.2 were determined for specimens treated with polystyrene. Overall weight loss values of 50.3%, 23.3%, and 66.4% were found for untreated sengon, mangium, and pine samples, respectively; for treated samples, the values were 7.6%, 14.4%, and 5.1%, respectively. Based on the findings in this study, overall resistance to termite attack was higher for treated samples compared to untreated samples. PMID- 27455332 TI - Nest-Gallery Development and Caste Composition of Isolated Foraging Groups of the Drywood Termite, Incisitermes minor (Isoptera: Kalotermitidae). AB - An X-ray computed-tomographic examination of nest-gallery development from timbers naturally infested by foraging groups of Incisitermes minor colonies was conducted. This study documents the colonization process of I. minor to new timbers and how the isolated groups maintain their nest-gallery system. The results suggested that development of a nest-gallery within a suitable wood item is not random, but shows selection for softer substrate and other adaptations to the different timber environments. Stigmergic coordinations were expressed in dynamic changes of the nest-gallery system; indicated by fortification behavior in sealing and re-opening a tunnel approaching the outer edge of the timber, and accumulating fecal pellets in particular chambers located beneath the timber surface. The study also examines the caste composition of isolated groups to discover how I. minor sustains colonies with and without primary reproductives. PMID- 27455328 TI - Therapeutic Targeting of Telomerase. AB - Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches. Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a 'mild' integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis. PMID- 27455333 TI - FlpS, the FNR-Like Protein of Streptococcus suis Is an Essential, Oxygen-Sensing Activator of the Arginine Deiminase System. AB - Streptococcus (S.) suis is a zoonotic pathogen causing septicemia and meningitis in pigs and humans. During infection S. suis must metabolically adapt to extremely diverse environments of the host. CcpA and the FNR family of bacterial transcriptional regulators are important for metabolic gene regulation in various bacteria. The role of CcpA in S. suis is well defined, but the function of the FNR-like protein of S. suis, FlpS, is yet unknown. Transcriptome analyses of wild type S. suis and a flpS mutant strain suggested that FlpS is involved in the regulation of the central carbon, arginine degradation and nucleotide metabolism. However, isotopologue profiling revealed no substantial changes in the core carbon and amino acid de novo biosynthesis. FlpS was essential for the induction of the arcABC operon of the arginine degrading pathway under aerobic and anaerobic conditions. The arcABC-inducing activity of FlpS could be associated with the level of free oxygen in the culture medium. FlpS was necessary for arcABC-dependent intracellular bacterial survival but redundant in a mice infection model. Based on these results, we propose that the core function of S. suis FlpS is the oxygen-dependent activation of the arginine deiminase system. PMID- 27455334 TI - Reasoning about "Capability": Wild Robins Respond to Limb Visibility in Humans. AB - Little comparative work has focused on what nonhumans understand about what physical acts others are capable of performing, and none has yet done so in the wild, or within a competitive framework. This study shows that North Island robins visually attend to human limbs in the context of determining who to steal food from. We presented 24 wild North Island Robins (Petroica longipes) with two experimenters. Robins could choose to steal a mealworm from one of two experimenters: one whose limbs were exposed and one who underwent a range of visual obstructions in two experiments. In most conditions, robins preferred to steal food located near the experimenter whose limbs were obscured by a cloth or board rather than food located near the experimenter whose limbs were not obscured. The robins' responses indicate that human limb visibility is associated with reduced access to food. Current findings lay the groundwork for a closer look at the potential general use of causal reasoning in an inter-specific context of using limbs to perform physical acts, specifically within the context of pilfering. This study presents one of the first tests of the role of visual attendance of potential limb availability in a competitive context, and could provide an alternative hypothesis for how other species have passed tests designed to examine what individuals understand about the physical acts others are capable of performing. PMID- 27455336 TI - Stimuli-Responsive Gold Nanoparticles for Cancer Diagnosis and Therapy. AB - An emerging concept is that cancers strongly depend on both internal and external signals for growth and invasion. In this review, we will discuss pathological and physical changes in the tumor microenvironment and how these changes can be exploited to design gold nanoparticles for cancer diagnosis and therapy. These intrinsic changes include extracellular and intracellular pH, extracellular matrix enzymes, and glutathione concentration. External stimuli include the application of laser, ultrasound and X-ray. The biology behind these changes and the chemistry behind the responding mechanisms to these changes are reviewed. Examples of recent in vitro and in vivo studies are also presented, and the clinical implications of these findings are discussed. PMID- 27455335 TI - Oligodendrocyte Injury and Pathogenesis of HIV-1-Associated Neurocognitive Disorders. AB - Oligodendrocytes wrap neuronal axons to form myelin, an insulating sheath which is essential for nervous impulse conduction along axons. Axonal myelination is highly regulated by neuronal and astrocytic signals and the maintenance of myelin sheaths is a very complex process. Oligodendrocyte damage can cause axonal demyelination and neuronal injury, leading to neurological disorders. Demyelination in the cerebrum may produce cognitive impairment in a variety of neurological disorders, including human immunodeficiency virus type one (HIV-1) associated neurocognitive disorders (HAND). Although the combined antiretroviral therapy has markedly reduced the incidence of HIV-1-associated dementia, a severe form of HAND, milder forms of HAND remain prevalent even when the peripheral viral load is well controlled. HAND manifests as a subcortical dementia with damage in the brain white matter (e.g., corpus callosum), which consists of myelinated axonal fibers. How HIV-1 brain infection causes myelin injury and resultant white matter damage is an interesting area of current HIV research. In this review, we tentatively address recent progress on oligodendrocyte dysregulation and HAND pathogenesis. PMID- 27455337 TI - PCR-Independent Detection of Bacterial Species-Specific 16S rRNA at 10 fM by a Pore-Blockage Sensor. AB - A PCR-free, optics-free device is used for the detection of Escherichia coli (E. coli) 16S rRNA at 10 fM, which corresponds to ~100-1000 colony forming units/mL (CFU/mL) depending on cellular rRNA levels. The development of a rapid, sensitive, and cost-effective nucleic acid detection platform is sought for the detection of pathogenic microbes in food, water and body fluids. Since 16S rRNA sequences are species specific and are present at high copy number in viable cells, these nucleic acids offer an attractive target for microbial pathogen detection schemes. Here, target 16S rRNA of E. coli at 10 fM concentration was detected against a total RNA background using a conceptually simple approach based on electromechanical signal transduction, whereby a step change reduction in ionic current through a pore indicates blockage by an electrophoretically mobilized bead-peptide nucleic acid probe conjugate hybridized to target nucleic acid. We investigated the concentration detection limit for bacterial species specific 16S rRNA at 1 pM to 1 fM and found a limit of detection of 10 fM for our device, which is consistent with our previous finding with single-stranded DNA of similar length. In addition, no false positive responses were obtained with control RNA and no false negatives with target 16S rRNA present down to the limit of detection (LOD) of 10 fM. Thus, this detection scheme shows promise for integration into portable, low-cost systems for rapid detection of pathogenic microbes in food, water and body fluids. PMID- 27455338 TI - Exploiting Chemistry to Improve Performance of Screen-Printed, Bismuth Film Electrodes (SP-BiFE). AB - Mercury substitution is a big issue in electroanalysis, and the search for a suitable, and less toxic, replacement is still under development. Of all the proposed alternatives, bismuth films appear to be the most viable solution, although they are still suffering some drawbacks, particularly the influence of deposition conditions and linearity at low concentrations. In this paper, the most promising strategies for bismuth film deposition on screen-printed electrodes (surface modifications, polymeric film deposition, insoluble salt precursors) will be evaluated for trace metal analysis. Particular attention will be devoted to bismuth chemistry, aiming to rationalize their electroanalytic performance. PMID- 27455339 TI - Vinegar Metabolomics: An Explorative Study of Commercial Balsamic Vinegars Using Gas Chromatography-Mass Spectrometry. AB - Balsamic vinegar is a popular food condiment produced from cooked grape must by two successive fermentation (anaerobic and aerobic) processes. Although many studies have been performed to determine the composition of major metabolites, including sugars and aroma compounds, no study has been undertaken yet to characterize the comprehensive metabolite composition of balsamic vinegars. Here, we present the first metabolomics study of commercial balsamic vinegars by gas chromatography coupled to mass spectrometry (GC-MS). The combination of three GC MS methods allowed us to detect >1500 features in vinegar samples, of which 123 metabolites were accurately identified, including 25 amino acids, 26 carboxylic acids, 13 sugars and sugar alcohols, four fatty acids, one vitamin, one tripeptide and over 47 aroma compounds. Moreover, we identified for the first time in vinegar five volatile metabolites: acetin, 2-methylpyrazine, 2-acetyl-1 pyroline, 4-anisidine and 1,3-diacetoxypropane. Therefore, we demonstrated the capability of metabolomics for detecting and identifying large number of metabolites and some of them could be used to distinguish vinegar samples based on their origin and potentially quality. PMID- 27455340 TI - Clonidine Overdose in a Toddler Due to Accidental Ingestion of a Compounding Cream. AB - A 22-month-old girl without any significant medical history accidentally consumed a small amount of a therapeutic compounding cream that contained camphor, gabapentin, clonidine, ketoprofen, and lidocaine. Upon presentation to the emergency department, the child exhibited immediate onset of altered mental status with wide fluctuation in her vital signs, which included intermittent apnea requiring bag-valve mask assistance and endotracheal intubation. Serum laboratory analysis measured a clonidine level of 2.6 ng/mL and undetectable camphor, gabapentin, and ketoprofen levels. While on mechanical ventilation, the patient exhibited hypothermia, bradycardia, and hypotension; all of which responded to supportive care. After approximately 12 hours in the intensive care unit, the patient was successfully extubated and remained asymptomatic. This unique case of a patient with brief, unintentional oral exposure to a compounding cream, who demonstrated severe toxicity despite only a measured, supratherapeutic clonidine concentration, is discussed. Emergency physicians and pediatricians should be alert to the potential for exposure of pediatric patients to these medicinal compounds. Furthermore, parents must be made aware of the potential dangers of compounded medications and ensure their proper usage and storage. PMID- 27455341 TI - Capnography Use During Intubation and Cardiopulmonary Resuscitation in the Pediatric Emergency Department. AB - OBJECTIVE: Capnography is indicated as a guide to assess and monitor both endotracheal intubation and cardiopulmonary resuscitation (CPR). Our primary objective was to determine the effect of the 2010 American Heart Association (AHA) guidelines on the frequency of capnography use during critical events in children in the emergency department (ED). Our secondary objective was to examine associations between patient characteristics and capnography use among these patients. METHODS: A retrospective chart review was performed on children aged 0 to 21 years who were intubated or received CPR in 2 academic children's hospital EDs between January 2009 and December 2012. Age, sex, time of arrival, medical or traumatic cause, length of CPR, return of spontaneous circulation (ROSC), documented use of capnography and colorimetry, capnography values, and adverse events were recorded. RESULTS: Two hundred ninety-two patients were identified and analyzed. Intubation occurred in 95% of cases and CPR in 30% of cases. Capnography was documented in only 38% of intubated patients and 13% of patients requiring CPR. There was an overall decrease in capnography use after publication of the 2010 AHA recommendations (P = 0.05). Capnography use was associated with a longer duration of CPR and return of spontaneous circulation. CONCLUSIONS: Despite the 2010 AHA recommendations, a minority of critically ill children are being monitored with capnography and an unexpected decrease in documented use occurred among our sample. Further education and implementation of capnography should take place to improve the use of this monitoring device for critically ill pediatric patients in the ED. PMID- 27455342 TI - Bloodstream Infections in Patients With Intestinal Failure Presenting to a Pediatric Emergency Department With Fever and a Central Line. AB - OBJECTIVE: Previous small studies have found a high occurrence of bloodstream infections (BSIs) in patients with intestinal failure, and these rates are higher than reported rates in other pediatric populations with central lines. The primary study objective was to describe the occurrence of BSIs in patients with intestinal failure who present to the pediatric emergency department (ED) with fever. METHODS: This 5-year retrospective chart review included febrile patients with intestinal failure and central lines who presented to the Children's Hospital of Pittsburgh ED between 2006 and 2011. Each febrile episode was analyzed at the visit level. RESULTS: During the study, 72 patients with 519 febrile episodes were identified. Central blood cultures were obtained in 93% (480/519) of episodes and 69% (330/480) were positive. Of all BSIs, 38% (124/330) were polymicrobial, 32% (105/330) were a single gram-positive organism, 25% (84/330) were a single gram-negative organism, and 5% (17/330) were a single fungal organism. Of the bacterial pathogens, 48% (223/460) were gram-negative. Overall, 60% were enteric organisms. CONCLUSIONS: Pediatric patients with intestinal failure and central lines have a high occurrence of BSIs with 69% of cultures positive in this study of ED febrile episodes. In contrast to reports in other populations with central lines, BSI occurrence in patients with intestinal failure and fever is higher and larger proportions are gram-negative and enteric organisms. For these patients, we recommend central and peripheral blood cultures, empiric broad spectrum antibiotics targeting gram-negative and enteric organisms, and hospital admission. PMID- 27455343 TI - An Unusual Cause of Back Pain in a 10-Year-Old Girl. AB - A 10-year-old girl with a 2-week history of atraumatic back pain presented to the emergency department with difficulty ambulating and a history of 2 episodes of urinary incontinence in the past week. Her examination was significant for pain with movement, tenderness to palpation in the lower thoracic spine, and no neurological deficits. In this case, the child was found to have a Schmorl node at T8 in the superior aspect of the vertebral body. Schmorl nodes are protrusions of the cartilage of the intervertebral disc through the vertebral body endplate and into the adjacent that is more commonly reported in the adult population. In this child, radiographic findings were normal, with no evidence of the Schmorl node. The diagnosis was made by magnetic resonance imaging. The child's symptoms significantly resolved with ibuprofen anti-inflammatory therapy. In children with atraumatic back pain lasting greater than 2 weeks with a sudden increase in severity and associated with a neurological deficit, advanced imaging is strongly recommended. PMID- 27455344 TI - Disaster Preparedness Medical School Elective: Bridging the Gap Between Volunteer Eagerness and Readiness. AB - OBJECTIVE: Eager medical students may not be prepared for unanticipated complexities of disaster response. This study aimed to answer 2 questions: does an online disaster preparedness curriculum create a convenient method to educate medical students and motivate them to be better prepared to volunteer? METHODS: An online disaster preparedness elective was created for medical students. Four modules were created using Softchalk and hosted on the Blackboard Learning Management System. Students completed embedded pre-elective, post-lesson, and post-elective surveys. RESULTS: Fifty-five students completed the elective. When posed with the statement, "I feel prepared for an emergency at the University or the immediate area," 70% stated that they disagreed or strongly disagreed before the elective. Subsequently, only 11% claimed to disagree after the elective. At the conclusion of the elective, 13% of students had prepared a personal emergency kit and 28% had prepared a family communication plan for reunification. Students were surveyed on the statement "I would like to be involved in a community disaster response while continuing my medical training." Ninety-four percent claimed to agree or strongly agree before the elective, and 93% stated the same after elective completion. CONCLUSIONS: This disaster preparedness elective was envisioned to be a resource for students. Advantages of online availability are ease of student access and minimal demand on faculty resources. A voluntary, self paced online elective in disaster preparedness has shown to create a stronger interest in disaster participation in medical students. Student readiness to volunteer improved; however, willingness remained stagnant. PMID- 27455346 TI - Principles for RNA metabolism and alternative transcription initiation within closely spaced promoters. AB - Mammalian transcriptomes are complex and formed by extensive promoter activity. In addition, gene promoters are largely divergent and initiate transcription of reverse-oriented promoter upstream transcripts (PROMPTs). Although PROMPTs are commonly terminated early, influenced by polyadenylation sites, promoters often cluster so that the divergent activity of one might impact another. Here we found that the distance between promoters strongly correlates with the expression, stability and length of their associated PROMPTs. Adjacent promoters driving divergent mRNA transcription support PROMPT formation, but owing to polyadenylation site constraints, these transcripts tend to spread into the neighboring mRNA on the same strand. This mechanism to derive new alternative mRNA transcription start sites (TSSs) is also evident at closely spaced promoters supporting convergent mRNA transcription. We suggest that basic building blocks of divergently transcribed core promoter pairs, in combination with the wealth of TSSs in mammalian genomes, provide a framework with which evolution shapes transcriptomes. PMID- 27455345 TI - Viral vector-based influenza vaccines. AB - Antigenic drift of seasonal influenza viruses and the occasional introduction of influenza viruses of novel subtypes into the human population complicate the timely production of effective vaccines that antigenically match the virus strains that cause epidemic or pandemic outbreaks. The development of game changing vaccines that induce broadly protective immunity against a wide variety of influenza viruses is an unmet need, in which recombinant viral vectors may provide. Use of viral vectors allows the delivery of any influenza virus antigen, or derivative thereof, to the immune system, resulting in the optimal induction of virus-specific B- and T-cell responses against this antigen of choice. This systematic review discusses results obtained with vectored influenza virus vaccines and advantages and disadvantages of the currently available viral vectors. PMID- 27455347 TI - NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. AB - To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology. PMID- 27455349 TI - A thrifty variant in CREBRF strongly influences body mass index in Samoans. AB - Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 * 10(-14)), and replicated the association in 2,102 additional Samoans (P = 1.2 * 10(-9)). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 * 10(-20)). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36-1.45 kg/m(2) per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a 'thrifty' variant hypothesis as a factor in human obesity. PMID- 27455350 TI - Genomic analysis of Andamanese provides insights into ancient human migration into Asia and adaptation. AB - To shed light on the peopling of South Asia and the origins of the morphological adaptations found there, we analyzed whole-genome sequences from 10 Andamanese individuals and compared them with sequences for 60 individuals from mainland Indian populations with different ethnic histories and with publicly available data from other populations. We show that all Asian and Pacific populations share a single origin and expansion out of Africa, contradicting an earlier proposal of two independent waves of migration. We also show that populations from South and Southeast Asia harbor a small proportion of ancestry from an unknown extinct hominin, and this ancestry is absent from Europeans and East Asians. The footprints of adaptive selection in the genomes of the Andamanese show that the characteristic distinctive phenotypes of this population (including very short stature) do not reflect an ancient African origin but instead result from strong natural selection on genes related to human body size. PMID- 27455352 TI - Corrigendum to: "The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis" [J. Affect. Disord. 190 (2016) 264 271]. PMID- 27455351 TI - The relationship between childhood poverty, military service, and later life depression among men: Evidence from the Health and Retirement Study. AB - BACKGROUND: Childhood poverty has been associated with depression in adulthood, but whether this relationship extends to later life major depression (MD) or is modified by military service is unclear. METHODS: Data come from the Health and Retirement Study (HRS) 2010 wave, a longitudinal, nationally representative study of older adults. Men with data on military service and childhood poverty were included (N=6330). Childhood poverty was assessed by four indicators (i.e., parental unemployment, residential instability) experienced before age 16. Military service was categorized as veteran versus civilian, and during draft versus all-volunteer (after 1973) eras. Past year MD was defined by the Composite International Diagnostic Inventory. RESULTS: Four in ten men ever served, with 13.7% in the all-volunteer military. Approximately 12% of civilians, 8% draft era and 24% all-volunteer era veterans had MD. Childhood poverty was associated with higher odds of MD (Odds Ratio (OR): 2.38, 95% Confidence Interval (CI): 1.32 4.32) and higher odds of military service (OR: 2.58, 95% CI: 1.58-4.21). Military service was marginally associated with MD (OR: 1.28, 95% CI: 0.98-1.68) and did not moderate the association between childhood poverty and MD. LIMITATIONS: Self report data is subject to recall bias. The HRS did not assess childhood physical and emotional abuse, or military combat exposure. CONCLUSIONS: Men raised in poverty had greater odds of draft and all-volunteer military service. Early-life experiences, independent of military service, appear associated with greater odds of MD. Assessing childhood poverty in service members may identify risk for depression in later life. PMID- 27455353 TI - Attentional bias in non-problem gamblers, problem gamblers, and abstinent pathological gamblers: An experimental study. AB - BACKGROUND: Attentional biases have been recognized as factors responsible for the maintenance of gambling problems. To date, no study has ever assessed the attentional biases among problem gamblers that have discontinued gambling (e.g., abstinent gamblers in treatment). METHODS: The sample consisted of 75 participants comprising three groups: non-problem gamblers, problem gamblers, and abstinent pathological gamblers undergoing treatment. The groups were discriminated using South Oaks Gambling Screen scores, with the exception of the abstinent pathological gamblers that already had a DSM-5 diagnosis for gambling disorder. Participants carried out a modified Posner Task for the assessment of attentional bias for gambling stimuli and completed the Depression Anxiety Stress Scale and the Gambling Craving Scale. RESULTS: Abstinent pathological gamblers showed an avoidance bias in the maintenance of attention, whereas problem gamblers exhibited a facilitation in detecting gambling stimuli. No biases were detected in non-problem gamblers. The results also demonstrated that compared to the other groups, abstinent pathological gamblers showed high emotional stress and problem gamblers reported a higher level of craving. LIMITATIONS: The sample size limits the generalizability of results. CONCLUSIONS: The present study demonstrated that attentional biases affect the maintenance and the discontinuation of gambling activities, and that the subjective feeling of craving for gambling may facilitate problem gamblers' attention towards gambling stimuli. PMID- 27455354 TI - Early normalization of Quality of Life predicts later remission in depression: Findings from the CO-MED trial. AB - BACKGROUND: Although normal Quality of Life (QoL) is the outcome desired by patients, it is unclear if QoL changes early in course of antidepressant treatments are independent of depression severity, and can predict subsequent remission. METHODS: The Quality of Life Inventory was obtained repeatedly in the Combining Medications to Enhance Depression Outcomes trial. Mixed model analyses assessed QoL change. Using population-based norms, participants were grouped as very low, low, or normal QoL at week 4, and association with remission was evaluated. RESULTS: Overall baseline to week 4 QoL improved significantly (p=0.0015) even after controlling for change in depression severity and baseline variables (gender, age, education, race, ethnicity, income, employment status, anxious features, depression onset before age 18, suicidal ideations, and treatment-arm). At week 4, participants with low and normal QoL had higher unadjusted odds ratio (OR) for remission at 3 months (low QoL OR=2.36, 95% confidence interval (CI)=1.25,4.44; normal QoL OR=2.59, 95% CI=1.53,4.39) and 7 months (low QoL OR=2.07, 95% CI=1.00,4.31; normal QoL OR=3.98, 95% CI=2.06,7.69) compared to those with very low QoL. Remission rates, adjusted for baseline variables, were higher only for participants with normal QoL (3 months OR=2.83, 95% CI=1.42,5.68; 7 months OR=6.10, 95% CI=2.40,15.63). LIMITATIONS: Secondary analysis, short period of assessment for QoL change, remission instead of functional recovery as long-term outcome. CONCLUSION: Quality of life improves early, independent of depression severity. Normal QoL at week 4 is associated with 2-6 times higher remission rates. Findings support QoL beyond symptomatic change as a potential mediator of remission. PMID- 27455355 TI - Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity: Dependence on cholesterol levels. AB - BACKGROUND: Impulsivity is multidimensional: Low impulse control may result in behavioural disorders, but acting on the spur of moment may also be advantageous. Previous studies have shown negative associations between different facets of impulsivity and serotonergic function. Other investigations have found negative correlations between serum lipid levels and impulsivity. METHODS: We have investigated whether the functional polymorphism -1438A/G in the serotonin 5-HT2A receptor gene (HTR2A) is associated with impulsivity levels and whether there is any interaction with serum lipid levels. This analysis was based on data of the population-representative Estonian Children Personality Behaviour and Health Study at age 25. Impulsivity was self-reported with the Adaptive and Maladaptive Impulsivity Scale. RESULTS: Subjects with the A/A genotype of the HTR2A -1438A/G polymorphism had higher scores of Maladaptive impulsivity, but not Adaptive impulsivity. In females, high LDL and total cholesterol levels increased the genotype effect. In males, in the highest quartile of total or LDL cholesterol the genotype effect was altered, with G/G homozygotes having the highest Maladaptive impulsivity levels. LIMITATIONS: Only one cohort of the European Youth Heart Study (EYHS) was used in the current study and impulsivity measures were self-reported. CONCLUSIONS: Our results do not support the notion that low cholesterol levels universally lead to higher impulsivity, but it was found that high total and LDL cholesterol levels moderate the effect of the HTR2A gene promoter polymorphism. This suggests that future studies on impulsivity need to consider the interaction of serotonergic measures with the whole range of cholesterol levels. PMID- 27455348 TI - Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. AB - To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk. PMID- 27455356 TI - Patterns of depressive disorders across 13 years and their determinants among midlife women: SWAN mental health study. AB - BACKGROUND: Little is known about the course of depression in midlife women. This study aims to identify factors that distinguish risk factors for persistent or recurrent depression from those of a milder course across 13-years of follow-up. METHODS: 297 Black and White premenopausal women aged 42-52 were enrolled at the Study of Women's Health Across the Nation Pittsburgh site. Psychiatric interviews obtained information on lifetime psychiatric diagnoses at baseline and occurrences of depression annually. We identified four depression patterns: 91(31%) had Persistent/recurrent major depressive disorder (MDD), 27(9%) Single Episode MDD, 35(12%) Minor Depression (minD) only, 144(48%) No Depression. We compared baseline risk factors for the Persistent/recurrent MDD group with each of the other three. RESULTS: A lifetime history of major or minor depression (p values =.001-.08) and 2+ very upsetting life events in the previous year (p values=.003-.04) were more likely to be reported by women in the Persistent/recurrent group than in the other three. The Persistent/recurrent group was more likely to report a family history of depression (p=.03) than the MinD group, and to report current sleep problems (p=.002) at baseline than the Single Episode MDD group. LIMITATIONS: Small numbers of women with minD or a Single Episode MDD. Childhood maltreatment and family depression history were retrospectively reported. CONCLUSIONS: A Persistent/recurrent depression course is common during midlife. In addition to personal and family histories of depression, providers of midlife health care should recognize that current sleep problems and recent very upsetting events are strong risk factors for a pernicious depression course. PMID- 27455357 TI - Primary Sjogren's syndrome is associated with significant cognitive dysfunction. AB - AIM: Cognitive dysfunction is a neurologic manifestation in primary Sjogren syndrome (PSS). On the other hand, several antibodies are related to cognitive dysfunction. The aim of this study is to assess the cognitive dysfunction of PSS patients via detailed neurologic tests. Moreover, its associations with antibodies were also evaluated. METHOD: Twenty-eight female patients with PSS and 17 healthy controls comprised the study groups. Short-term memory, long-term memory, verbal learning, visual memory, visual spatial perception, attention, verbal frequency function, executive functions and information processing speed were evaluated with neurologic tests in both of the study groups. Furthermore, anti-N-methyl-D-aspartate (NMDA) type anti-glutamate-receptor antibody, anti ribosomal-p and antiganglioside antibodies were assessed in the study groups. RESULTS: The attention, data processing speed, verbal learning, short-term verbal memory and visuo-spatial perception performances were lower in the patients with PSS when compared to the healthy controls. The difference reached statistical significance in Paced Auditory Serial Addition Test (P < 0.01), Serial Digit Learning Test (P < 0.01), clock drawing (P = 0.03), Auditory Verbal Learning Test immediate verbal memory (P = 0.01) and Benton Judgement of Line Orientation Test (P = 0.03). Even if antiganglioside antibodies were more likely to be present in the PSS group when compared to the healthy controls, no relationship was found between its positivity and cognitive dysfunction. CONCLUSION: Results of this study suggest that cognitive dysfunction is quite prevalent in PSS patients without being associated with studied antibodies. PMID- 27455359 TI - A Parulis-Like Soft Tissue Tumor in Relation With a Dental Implant: Case Report. PMID- 27455358 TI - Nuclear Magnetic Resonance Observation of alpha-Synuclein Membrane Interaction by Monitoring the Acetylation Reactivity of Its Lysine Side Chains. AB - The interaction between alpha-synuclein (alphaS) protein and lipid membranes is key to its role in synaptic vesicle homeostasis and plays a role in initiating fibril formation, which is implicated in Parkinson's disease. The natural state of alphaS inside the cell is generally believed to be intrinsically disordered, but chemical cross-linking experiments provided evidence of a tetrameric arrangement, which was reported to be rich in alpha-helical secondary structure based on circular dichroism (CD). Cross-linking relies on chemical modification of the protein's Lys C(epsilon) amino groups, commonly by glutaraldehyde, or by disuccinimidyl glutarate (DSG), with the latter agent preferred for cellular assays. We used ultra-high-resolution homonuclear decoupled nuclear magnetic resonance experiments to probe the reactivity of the 15 alphaS Lys residues toward N-succinimidyl acetate, effectively half the DSG cross-linker, which results in acetylation of Lys. The intensities of both side chain and backbone amide signals of acetylated Lys residues provide direct information about the reactivity, showing a difference of a factor of 2.5 between the most reactive (K6) and the least reactive (K102) residue. The presence of phospholipid vesicles decreases reactivity of most Lys residues by up to an order of magnitude at high lipid:protein stoichiometries (500:1), but only weakly at low ratios. The decrease in Lys reactivity is found to be impacted by lipid composition, even for vesicles that yield similar alphaS CD signatures. Our data provide new insight into the alphaS-bilayer interaction, including the pivotal state in which the available lipid surface is limited. Protection of Lys C(epsilon) amino groups by alphaS-bilayer interaction will strongly impact quantitative interpretation of DSG cross-linking experiments. PMID- 27455360 TI - From the Editor. PMID- 27455361 TI - Palliative Care: A Partnership Across the Continuum of Care. AB - Palliative care services are becoming more prevalent in the United States as greater portions of the population are requiring end-of-life services. Furthermore, recent policy changes and service foci have promoted more continuity and encompassing care. This study evaluates characteristics that distinguish hospitals with a palliative care program from hospitals without such a program in order to better define the markets and environments that promote the creation and usage of these programs. This study demonstrates that palliative care programs are more likely in communities with favorable economic factors and higher Medicare populations. Large hospitals with high occupancy rates and a high case mix index use palliative care programs to better meet patient needs and improve hospital efficiency. Managerial, nursing, and policy implications are discussed relating to further usage and implementation of palliative care programs. PMID- 27455362 TI - Value-Based Purchasing: The Effect of Hospital Ownership and Size. AB - This research tests the effect of hospital ownership and size on value-based purchasing scores. Representative samples were randomly selected of short-term acute-care hospitals from across the nation and grouped into 3 categories of both ownership and size. The ownership categories are as follows: (1) for-profit, (2) nonprofit, and (3) government. The size categories are as follows: (1) small, 99 beds or fewer; (2) medium, 100 to 249 beds; (3) large, 250 beds or more. Value based purchasing scores for the 12 process-of-care (PC) measures and the 8 patient experience-of-care (Hospital Consumer Assessment of Healthcare Providers and System [HCAHPS]) measures were calculated and combined into their single total performance score (TPS). The results reveal that for-profit controlled hospitals outperform both nonprofit and government-controlled hospitals in PC measures, HCAHPS measures, and value-based purchasing TPSs. The results also reveal that small hospitals (<=99 beds) outperform both medium hospitals (100-249 beds) and large hospitals (>=250 beds) in PC measures, HCAHPS measures, and TPS. Results are discussed. PMID- 27455364 TI - Case in Health Care Management. PMID- 27455363 TI - Neonatal Intensive Care Unit Nurses Working in an Open Ward: Stress and Work Satisfaction. AB - There is some research on the impact of open-ward unit design on the health of babies and the stress experienced by parents and nurses in neonatal intensive care units. However, few studies have explored the factors associated with nurse stress and work satisfaction among nurses practicing in open-ward neonatal intensive care units. The purpose of this study was to examine what factors are associated with nurse stress and work satisfaction among nurses practicing in an open-ward neonatal intensive care unit. A cross-sectional correlational design was used in this study. Participants were nurses employed in a 34-bed open-ward neonatal intensive care unit in a major university-affiliated hospital in Montreal, Quebec, Canada. A total of 94 nurses were eligible, and 86 completed questionnaires (91% response rate). Descriptive statistics were computed to describe the participants' characteristics. To identify factors associated with nurse stress and work satisfaction, correlational analysis and multiple regression analyses were performed with the Nurse Stress Scale and the Global Work Satisfaction scores as the dependent variables. Different factors predict neonatal intensive care unit nurses' stress and job satisfaction, including support, family-centered care, performance obstacles, work schedule, education, and employment status. In order to provide neonatal intensive care units nurses with a supportive environment, managers can provide direct social support to nurses and influence the culture around teamwork. PMID- 27455365 TI - Management of Stress and Anxiety Among PhD Students During Thesis Writing: A Qualitative Study. AB - Today, postgraduate students experience a variety of stresses and anxiety in different situations of academic cycle. Stress and anxiety have been defined as a syndrome shown by emotional exhaustion and reduced personal goal achievement. This article addresses the causes and different strategies of coping with this phenomena by PhD students at Iranian Universities of Medical Sciences. The study was conducted by a qualitative method using conventional content analysis approach. Through purposive sampling, 16 postgraduate medical sciences PhD students were selected on the basis of theoretical sampling. Data were gathered through semistructured interviews and field observations. Six hundred fifty-four initial codes were summarized and classified into 4 main categories and 11 subcategories on the thematic coding stage dependent on conceptual similarities and differences. The obtained codes were categorized under 4 themes including "thesis as a major source of stress," "supervisor relationship," "socioeconomic problem," and "coping with stress and anxiety." It was concluded that PhD students experience stress and anxiety from a variety of sources and apply different methods of coping in effective and ineffective ways. Purposeful supervision and guidance can reduce the cause of stress and anxiety; in addition, coping strategy must be in a thoughtful approach, as recommended in this study. PMID- 27455366 TI - Spa Goers' Repeated Visits for Health and Wellness and the Influential Factors: An Exploratory Study of the UK Spa Goers. AB - Dissemination of spa services across the globe and its market saturation drive demand for differentiated communication methods. This study aims to explore the influential factors on spa goers' repeated visits and their practical applications in the health and wellness spa industry. The identified factors were used as the measurement variables to examine the relation with spa goers' repeated visits. The proposed concept was tested by a mixed method combining a self-administered questionnaire and semistructured interview with 54 survey participants and 6 interviewees. It was meaningful to use a sample of the UK spa goers from the southwest region since global spa trends stem from the EU spas, and the United Kingdom is one of the market leaders. The data were analyzed using frequency, percentage, multiple logistic regression analysis, and coding process. The survey findings demonstrated that the most significant influential factor on the repeated spa visits is a memorable experience of which showed 13.7 times higher probability than the reference up-to-date facility. The details of memorable experiences were discovered throughout the interviews that include the rediscovery of self, feeling of connectedness, recharge for positive emotions, self-reward through escapism, and experience of noncommercialized local products and attractions. Therefore, using experiential marketing methods can be effective spa service marketing. PMID- 27455367 TI - Increasing Registered Nurse Retention Using Mentors in Critical Care Services. AB - Recruiting and training 1 newly hired registered nurse can cost thousands of dollars. With a high percentage of these newly hired nurses leaving their first place of employment within their first year, the financial implications may be enormous. It is imperative that health care facilities invest in recruiting and retention programs that retain high-quality nurses. Mentorship programs in retaining and easing the transition to practice for new graduate nurses, re-entry nurses, and nurses new to a specialty area are critical in nurse retention. Discussion in this study includes the effect of implementing a mentor program into the critical care services area of a 325-bed not-for-profit community hospital in northern Indiana. Based on this study, nurses with a mentor were retained at a 25% higher rate than those not mentored. Implementation of a mentor program reduced the training cost to the facility and increased retention and morale. PMID- 27455368 TI - The Influence of Hospital Market Competition on Patient Mortality and Total Performance Score. AB - The Affordable Care Act of 2010 launch of Medicare Value-Based Purchasing has become the platform for payment reform. It is a mechanism by which buyers of health care services hold providers accountable for high-quality and cost effective care. The objective of the study was to examine the relationship between quality of hospital care and hospital competition using the quality quantity behavioral model of hospital behavior. The quality-quantity behavioral model of hospital behavior was used as the conceptual framework for this study. Data from the American Hospital Association database, the Hospital Compare database, and the Area Health Resources Files database were used. Multivariate regression analysis was used to examine the effect of hospital competition on patient mortality. Hospital market competition was significantly and negatively related to the 3 mortality rates. Consistent with the literature, hospitals located in more competitive markets had lower mortality rates for patients with acute myocardial infarction, heart failure, and pneumonia. The results suggest that hospitals may be more readily to compete on quality of care and patient outcomes. The findings are important because policies that seek to control and negatively influence a competitive hospital environment, such as Certificate of Need legislation, may negatively affect patient mortality rates. Therefore, policymakers should encourage the development of policies that facilitate a more competitive and transparent health care marketplace to potentially and significantly improve patient mortality. PMID- 27455369 TI - How Does Supervisor Support Influence Turnover Intent Among Frontline Hospital Workers? The Mediating Role of Affective Commitment. AB - Turnover among frontline hospital service workers can disrupt organizational effectiveness, reduce profitability, and limit the ability to provide high quality, patient-centered care. This concern is compounded by the increasing reliance on frontline supervisors to manage this workforce, often without necessary training and support. However, research addressing the relationship between frontline supervisor support and intent to turnover among service workers and the process by which these variables are related is limited. By surveying 270 housekeeping and dietary service workers employed at 2 US hospitals, this study examined the relationship between supervisor support and turnover intent and assessed the mediating role of affective commitment between supervisor support and intent to turnover. Turnover intentions were lower for workers who reported greater levels of supervisor support and affective commitment; both supervisor support and affective commitment were significant predictors of turnover intent when tested individually. However, when controlling for affective commitment, supervisor support no longer predicted turnover intent, indicating that affective commitment fully mediated the relationship between supervisor support and intent to turnover. Implications for further research and organizational practice are discussed. PMID- 27455371 TI - The Basic Rules of Occlusion. PMID- 27455370 TI - Molecular Structures and Coding Genes of the Water-Borne Protein Pheromones of Euplotes petzi, an Early Diverging Polar Species of Euplotes. AB - Euplotes is diversified into dozens of widely distributed species that produce structurally homologous families of water-borne protein pheromones governing self /nonself-recognition phenomena. Structures of pheromones and pheromone coding genes have so far been studied from species lying in different positions of the Euplotes phylogenetic tree. We have now cloned the coding genes and determined the NMR molecular structure of four pheromones isolated from Euplotes petzi, a polar species which is phylogenetically distant from previously studied species and forms the deepest branching clade in the tree. The E. petzi pheromone genes have significantly shorter sequences than in other congeners, lack introns, and encode products of only 32 amino acids. Likewise, the three-dimensional structure of the E. petzi pheromones is markedly simpler than the three-helix up-down-up architecture previously determined in another polar species, Euplotes nobilii, and in a temperate-water species, Euplotes raikovi. Although sharing the same up down-up architecture, it includes only two short alpha-helices that find their topological counterparts with the second and third helices of the E. raikovi and E. nobilii pheromones. The overall picture that emerges is that the evolution of Euplotes pheromones involves progressive increases in the gene sequence length and in the complexity of the three-dimensional molecular structure. PMID- 27455372 TI - Comparison of Field Measurements to Methane Emissions Models at a New Landfill. AB - Estimates of methane emissions from landfills rely primarily on models due to both technical and economic limitations. While models are easy to implement, there is uncertainty due to the use of parameters that are difficult to validate. The objective of this research was to compare modeled emissions using several greenhouse gas (GHG) emissions reporting protocols including: (1) Intergovernmental Panel on Climate Change (IPCC); (2) U.S. Environmental Protection Agency Greenhouse Gas Reporting Program (EPA GHGRP); (3) California Air Resources Board (CARB); and (4) Solid Waste Industry for Climate Solutions (SWICS), with measured emissions data collected over three calendar years from a young landfill with no gas collection system. By working with whole landfill measurements of fugitive methane emissions and methane oxidation, the collection efficiency could be set to zero, thus eliminating one source of parameter uncertainty. The models consistently overestimated annual methane emissions by a factor ranging from 4-31. Varying input parameters over reasonable ranges reduced this range to 1.3-8. Waste age at the studied landfill was less than four years and the results suggest the need for measurements at additional landfills to evaluate the accuracy of the tested models to young landfills. PMID- 27455373 TI - Meeting the Demands of the Affordable Care Act: Improving Access to Primary Care. PMID- 27455374 TI - A rapid inversion technique for the measurement of longitudinal relaxation times of brain metabolites: application to lactate in high-grade gliomas at 3 T. AB - The aim of this study was to develop a time-efficient inversion technique to measure the T1 relaxation time of the methyl group of lactate (Lac) in the presence of contaminating lipids and to measure T1 at 3 T in a cohort of primary high-grade gliomas. Three numerically optimized inversion times (TIs) were chosen to minimize the expected error in T1 estimates for a given input total scan duration (set to be 30 min). A two-cycle spectral editing scheme was used to suppress contaminating lipids. The T1 values were then estimated from least squares fitting of signal measurements versus TI. Lac T1 was estimated as 2000 +/ 280 ms. After correcting for T1 (and T2 from literature values), the mean absolute Lac concentration was estimated as 4.3 +/- 2.6 mm. The technique developed agrees with the results obtained by standard inversion recovery and can be used to provide rapid T1 estimates of other spectral components as required. Lac T1 exhibits similar variations to other major metabolites observable by MRS in high-grade gliomas. The T1 estimate provided here will be useful for future MRS studies wishing to report relaxation-corrected estimates of Lac concentration as an objective tumor biomarker. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27455375 TI - A practical algorithm to reduce false critical ECG alarms using arterial blood pressure and/or photoplethysmogram waveforms. AB - There has been a high rate of false alarms for the critical electrocardiogram (ECG) arrhythmia events in intensive care units (ICUs), from which the 'crying wolf' syndrome may be resulted and patient safety may be jeopardized. This article presents an algorithm to reduce false critical arrhythmia alarms using arterial blood pressure (ABP) and/or photoplethysmogram (PPG) waveform features. We established long duration reference alarm datasets which consist of 573 ICU waveform-alarm records (283 for development set and 290 for test set) with total length of 551 patent days. Each record has continuous recordings of ECGs, ABP and/or PPG signals and contains one or multiple critical ECG alarms. The average length of a record is 23 h. There are totally 2408 critical ECG alarms (1414 in the development set and 994 in the test set), each of which was manually annotated by experts. The algorithm extracts ABP/PPG pulse features on a beat-by beat basis. For each pulse, five event feature indicators (EFIs), which correspond to the five critical ECG alarms, are generated. At the time of a critical ECG alarm, the corresponding EFI values of those ABP/PPG pulses around the alarm time are checked for adjudicating (accept/reject) this alarm. The algorithm retains all (100%) the true alarms and significantly reduces the false alarms. Our results suggest that the algorithm is effective and practical on account of its real-time dynamic processing mechanism and computational efficiency. PMID- 27455376 TI - Fractal Surfaces of Molecular Crystals Mimicking Lotus Leaf with Phototunable Double Roughness Structures. AB - Double roughness structure, the origin of the lotus effect of natural lotus leaf, was successfully reproduced on a diarylethene microcrystalline surface. Static superwater-repellency and dynamic water-drop-bouncing were observed on the surface, in the manner of natural lotus leaves. Double roughness structure was essential for water-drop-bouncing. This ability was not observed on a single roughness microcrystalline surface showing the lotus effect of the same diarylethene derivative. The double roughness structure was reversibly controlled by alternating irradiation with UV and visible light. PMID- 27455377 TI - Improving biomedical information retrieval by linear combinations of different query expansion techniques. AB - BACKGROUND: Biomedical literature retrieval is becoming increasingly complex, and there is a fundamental need for advanced information retrieval systems. Information Retrieval (IR) programs scour unstructured materials such as text documents in large reserves of data that are usually stored on computers. IR is related to the representation, storage, and organization of information items, as well as to access. In IR one of the main problems is to determine which documents are relevant and which are not to the user's needs. Under the current regime, users cannot precisely construct queries in an accurate way to retrieve particular pieces of data from large reserves of data. Basic information retrieval systems are producing low-quality search results. In our proposed system for this paper we present a new technique to refine Information Retrieval searches to better represent the user's information need in order to enhance the performance of information retrieval by using different query expansion techniques and apply a linear combinations between them, where the combinations was linearly between two expansion results at one time. Query expansions expand the search query, for example, by finding synonyms and reweighting original terms. They provide significantly more focused, particularized search results than do basic search queries. RESULTS: The retrieval performance is measured by some variants of MAP (Mean Average Precision) and according to our experimental results, the combination of best results of query expansion is enhanced the retrieved documents and outperforms our baseline by 21.06 %, even it outperforms a previous study by 7.12 %. CONCLUSIONS: We propose several query expansion techniques and their combinations (linearly) to make user queries more cognizable to search engines and to produce higher-quality search results. PMID- 27455378 TI - Tris(hydroxymethyl)phosphine, P(CH2OH)3 - A convenient and effective new reagent for the fixation of protein samples for SEM imaging. AB - Tris(hydroxymethyl)phosphine [P(CH2OH)3, THP] is demonstrated to be an alternative fixative to glutaraldehyde for preparation of proteinaceous specimens for SEM analysis. THP is easily prepared from commercially-available [P(CH2OH)4]Cl, and unlike many other alkylphosphines, is reasonably air-stable [>7days at pH 7-8]. Experiments carried out with chicken breast muscle, cross sectioned perpendicular to the muscle fibres and imaged using SEM, indicate that THP effectively fixes the muscle structure with minimal discolouration of the sample. PMID- 27455379 TI - Crystallinity, Surface Morphology, and Photoelectrochemical Effects in Conical InP and InN Nanowires Grown on Silicon. AB - The growth conditions of two types of indium-based III-V nanowires, InP and InN, are tailored such that instead of yielding conventional wire-type morphologies, single-crystal conical structures are formed with an enlarged diameter either near the base or near the tip. By using indium droplets as a growth catalyst, combined with an excess indium supply during growth, "ice cream cone" type structures are formed with a nanowire "cone" and an indium-based "ice cream" droplet on top for both InP and InN. Surface polycrystallinity and annihilation of the catalyst tip of the conical InP nanowires are observed when the indium supply is turned off during the growth process. This growth design technique is extended to create single-crystal InN nanowires with the same morphology. Conical InN nanowires with an enlarged base are obtained through the use of an excess combined Au-In growth catalyst. Electrochemical studies of the InP nanowires on silicon demonstrate a reduction photocurrent as a proof of photovolatic behavior and provide insight as to how the observed surface polycrystallinity and the resulting interface affect these device-level properties. Additionally, a photovoltage is induced in both types of conical InN nanowires on silicon, which is not replicated in epitaxial InN thin films. PMID- 27455380 TI - Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma. AB - Galectin-9, a beta-galactoside-binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominantly Th2 biased. We hypothesized that galectin-9 can modulate systemic immunity toward Th2 polarization in patients with advanced melanoma. The presence or concentration of galectin-9 was assessed in tumors and plasma, in patients with metastatic melanoma. The immunomodulatory function of galectin-9 was determined by exposing human peripheral blood mononuclear cells to galectin-9 in vitro. Galectin-9 was expressed in 57% of tumors and was significantly (3.6-fold) increased in the plasma of patients with advanced melanoma compared with healthy controls (P<0.001). High plasma galectin-9 concentration was associated with systemic Th2 polarization and reduced 2-year survival compared with low/no galectin-9 expression. In-vitro, galectin-9 reduced proliferation of healthy peripheral blood mononuclear cells, and promoted Th1 cell apoptosis, Th2-biased cell phenotypes, and cytokine secretion. Galectin-9 also stimulated monocyte differentiation toward an M2 macrophage phenotype, as assessed by chemokine/cytokine secretion and CD206 expression, observed both in vitro as well as in patients with metastatic melanoma. Elevated galectin-9 in patient plasma correlated with Th2 systemic bias and less favorable clinical outcomes for patients with metastatic melanoma. This Th2 bias appears to be not only a feature of the known mechanisms of Th1 apoptosis by T-cell immunoglobulin and mucin domain containing-3 binding, but also mediated by myeloid cell differentiation toward an M2 phenotype, that favors tumor progression. These data support galectin-9 as a novel therapeutic target for patients with metastatic melanoma. PMID- 27455381 TI - Effects of muscle fatigue on the usability of a myoelectric human-computer interface. AB - Electromyography-based human-computer interface development is an active field of research. However, knowledge on the effects of muscle fatigue for specific devices is limited. We have developed a novel myoelectric human-computer interface in which subjects continuously navigate a cursor to targets by manipulating a single surface electromyography (sEMG) signal. Two-dimensional control is achieved through simultaneous adjustments of power in two frequency bands through a series of dynamic low-level muscle contractions. Here, we investigate the potential effects of muscle fatigue during the use of our interface. In the first session, eight subjects completed 300 cursor-to-target trials without breaks; four using a wrist muscle and four using a head muscle. The wrist subjects returned for a second session in which a static fatiguing exercise took place at regular intervals in-between cursor-to-target trials. In the first session we observed no declines in performance as a function of use, even after the long period of use. In the second session, we observed clear changes in cursor trajectories, paired with a target-specific decrease in hit rates. PMID- 27455382 TI - Ten-year trends in direct costs of asthma: a population-based study. AB - INTRODUCTION: There is little information on recent trends in the economic burden of asthma. Our objective was to estimate the excess costs of asthma and their trend in British Columbia, Canada, from 2002 to 2011. METHODS: A retrospective cohort of individuals aged 5-55 years was constructed from the provincial administrative health databases, consisting of patients with physician-diagnosed asthma and a propensity-score-matched comparison sample from the general population. Total direct medical costs were calculated as the sum of hospitalizations, outpatient visits and medication costs, adjusted to 2012 Canadian dollars ($). Excess costs were defined as the difference in costs between the asthma and comparison groups. RESULTS: A total of 341 457 individuals (mean age at entry 27.3, 54.1% female) were equally divided into the asthma and comparison groups. Excess costs in patients with asthma were $1028.0 (95% CI $982.7-$1073.4) per patient-year (PY). Medications contributed to the greatest share of excess costs ($471.7/PY), whereas hospitalization and outpatient costs were, respectively, $272.2/PY and $284.1/PY. Only $192.9/PY was attributable to asthma itself. There was a 2.9%/year increase in excess costs (P < 0.001), a combination of asthma-attributable costs declining by 0.8%/year while nonasthma excess costs increasing by 3.8%/year. The most dramatic trend was observed in asthma-related outpatient costs, which decreased by %6.6/year. CONCLUSIONS: A significant share of excess costs in asthma is not attributable to the disease itself. The pattern of costs changed significantly during the study period. The burden of comorbid conditions should be considered in developing evidence-based policies for management of patients with asthma. PMID- 27455383 TI - Modulation of Symmetry-Breaking Intramolecular Charge-Transfer Dynamics Assisted by Pendant Side Chains in pi-Linkers in Quadrupolar Diketopyrrolopyrrole Derivatives. AB - The effect of the length of pendant side chains in centrosymmetric quadrupolar molecules on dynamics of their most perplexing photophysical phenomenon, i.e., symmetry-breaking intramolecular charge transfer, has been discovered. Unexpectedly, considerable influence of length of these pendant side chains in pi linkers arose as a structural factor enabling the control of the degree of fluorescence solvatochromism. The symmetry-breaking intramolecular charge transfer dynamics has been described on quadrupolar diketopyrrolopyrrole derivatives possessing fluorene moieties as pi-linkers and diarylamino groups as electron donors. On the basis of the evolution of transient fluorescence spectra obtained by a femtosecond broadband fluorescence up-conversion spectroscopy, it was found that the relative contribution of diffusive solvation and torsional relaxation in overall spectral relaxation can be modulated by the length of pendant side chain in pi-linkers. Consequently, we demonstrated that this modulation plays a significant role in determining the photophysical properties of diketopyrrolopyrroles in a polar medium. PMID- 27455384 TI - Advances in pediatric cardiology 2016. PMID- 27455385 TI - The New Antibiotic Mantra-"Shorter Is Better". PMID- 27455386 TI - Risk and Severity of Hospital-Acquired Clostridium difficile Infection in Patients Taking Proton Pump Inhibitors. AB - STUDY OBJECTIVE: To compare the rates and severity of hospital-acquired Clostridium difficile infection (CDI) among patients taking proton pump inhibitors (PPIs) versus those not taking PPIs. DESIGN: Retrospective, single center, cohort study. SETTING: Tertiary community hospital with a teaching service. PATIENTS: A total of 41,663 patients with CDI who were hospitalized between January 2013 and May 2014; of those, 17,471 patients (41.9%) had received at least one dose of a PPI (PPI group), and 24,192 patients (58.1%) had no PPI exposure (control group). MEASUREMENTS AND MAIN RESULTS: A total of 348 patients had CDI during the study period, with 269 cases present on admission. Hospital acquired CDI was defined as CDI diagnosis occurring on or after the third calendar day of admission. After excluding those patients with CDI on admission, 65 (0.38%) of 17,302 patients later developed CDI in the hospital in the PPI group compared with only 14 (0.058%) of 24,092 patients in the control group. Of these patients, 36 patients (0.21%) in the PPI group met the definition of severe CDI compared with 8 (0.03%) in the control group. This demonstrated an unadjusted relative risk (RR) of 6.46 (95% confidence interval [CI] 3.63-11.51, p<0.0001) of developing hospital-acquired CDI and an unadjusted RR of 6.27 (95% CI 2.91-13.48, p<0.0001) of developing severe CDI while taking a PPI. When evaluating only patients who developed severe-complicated CDI, there were 22 cases in the PPI group and 2 cases in the control group, demonstrating an unadjusted RR of 15.3 (95% CI 3.6-65.13, p=0.0002) of developing severe-complicated CDI. Confounding variables were similar between groups. CONCLUSION: PPI use was associated with an increase in both the rate and severity of hospital-acquired CDI. PMID- 27455387 TI - Synthesis of CdS hollow spheres coupled with g-C3N4 as efficient visible-light driven photocatalysts. AB - CdS hollow spheres (CdS HS) coupled with graphitic carbon nitride (g-C3N4) photocatalysts are synthesized and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), ultraviolet-visible diffuse reflection spectroscopy (DRS), x-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR), and photoluminescence spectroscopy (PL). The effect of CdS content on CdS HS/g-C3N4 activity is investigated by the degradation of Rhodamine B (RhB). The sample of 20 wt% CdS content shows the best photocatalytic performance under visible-light irradiation, with the corresponding RhB degradation rate reaching 97.3%. The excellent photoactivity of CdS HS/g-C3N4 is attributed to the synergistic effect of g-C3N4 and CdS HS. A possible photocatalytic mechanism of the CdS HS/g-C3N4 composite is proposed and corroborated by PL. PMID- 27455388 TI - Dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history. AB - BACKGROUND: Hyperprolactinemia is the presence of abnormally high circulating levels of prolactin. Idopathic hyperprolactinemia is the term used when no cause of prolactin hypersecretion can be identified and it is causally related to the development of miscarriage in pregnant women, especially women who have a history of recurrent miscarriage. A possible mechanism is that high levels of prolactin affect the function of the ovaries, resulting in a luteal phase defect and miscarriage. A dopamine agonist is a compound with high efficacy in lowering prolactin levels and restoring gonadal function. OBJECTIVES: To assess the effectiveness and safety of different types of dopamine agonists in preventing future miscarriage given to women with idiopathic hyperprolactinemia and a history of recurrent miscarriage. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) in all languages examining the effect of dopamine agonists on preventing future miscarriage. Women who had idiopathic hyperprolactinemia with a history of recurrent miscarriages were eligible for inclusion in this review. Comparisons planned included: dopamine agonists alone versus placebo/no treatment; and dopamine agonists combined with other therapy versus other therapy alone. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed a single trial for inclusion, evaluated trial quality and extracted data. Data were checked for accuracy. MAIN RESULTS: One study (recruiting 48 women with idiopathic hyperprolactinemia) met our inclusion criteria; 46 women (42 pregnancies - 4/46 women did not conceive during the study period) were included in the analysis. The study compared the use of a dopamine agonist (bromocriptine, 2.5 mg to 5.0 mg/day until the end of the ninth week of gestation) versus a no-treatment control. The study was judged as being at a high risk of bias. It was not possible to carry out meta-analysis due to insufficient data.The study reported both of this review's primary outcomes of miscarriage and live birth. Results from this single study suggest that, compared to no treatment, oral bromocriptine was effective in preventing future miscarriage (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.09 to 0.87, 46 participants (low-quality evidence)) in women with idiopathic hyperprolactinemia. There was no clear difference with regard to the other primary outcome of live births (RR 1.50, 95% CI 0.93 to 2.42, 46 participants (very low-quality evidence)).There was no difference with regard to this review's secondary outcome of conception (RR 0.92, 95% CI 0.77 to 1.09, 46 participants (very low-quality evidence)) between the group of women who received dopamine (21 out of 24 women conceived) and women in the no-treatment group (21 out of 22 women conceived). The included study only reported the serum prolactin levels in pregnant women and therefore the data could not be analyzed in this review. No other secondary outcomes relevant to this review were reported; adverse effects for women (nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms) and infants (birth defects, low birthweight, and developmental disabilities) were not reported.We downgraded the quality of the evidence for risk of bias in the one trial contributing outcome data (no description of allocation concealment, lack of blinding and possible reporting bias) and for imprecision (all effect estimates were based on small sample size, miscarriage was based on few events, and the 95% CIs of live birth and conception cross the line of no effect). AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence (from a single randomized trial with a small sample size, and judged to be at high risk of bias) to evaluate the effectiveness of dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and a history of recurrent miscarriage. We assessed outcomes using GRADE methodology. Miscarriage was assessed as low quality due to risk of bias concerns in the one trial contributing data (no description of allocation concealment, lack of blinding and possible reporting bias) and to imprecision (effect estimates were based on small sample size and few events). Live births and conception were assessed as of very low quality due to the same risk of bias concerns in study design and to imprecision (with a wide 95% CI consistent with either benefit or harm), and a small sample size. There were no data relating to adverse effects of the intervention for either the mother or her baby.Futher high-quality research in this area is warranted. There is a need for well-designed, larger RCTs to confirm and extend the findings of the trial reviewed here. Many questions remain unanswered. Some important considerations for future research include, the need for well-designed RCTs with large sample sizes, and for those studies to consider important outcomes (including adverse effects for both the mother and her baby). Future studies should examine the effectiveness and safety of various dopamine agonists including bromocriptine, cabergoline and quinagolide. PMID- 27455390 TI - Determining the Impact of Ligand and Alkene Substituents on Bonding in Gold(I) Alkene Complexes Supported by N-Heterocyclic Carbenes: A Computational Study. AB - The nature of the gold(I)-alkene bond in [(NHC)Au(alkene)](+) complexes (where NHC is the N-heterocyclic carbene 1,3-bis(2,6-dimethylphenyl)imidazole-2-ylidine and its derivatives) has been studied using density functional theory. By utilization of a series of electron-withdrawing and electron-donating substituents ranging from -NO2 to -NH2, an examination of substituent effects has been undertaken with 4-substituted NHC ligands, monosubstituted ethylene derivatives, and 4-substituted styrene derivatives. Natural population, natural bond orbital (NBO), molecular orbital, and bond energy decomposition analysis (EDA) methods have been used to quantify a number of important parameters, including the charge of the coordinated alkenes and the magnitude of alkene >[(NHC)Au](+) and [(NHC)Au](+)->alkene electron donation. EDA methods have also been used to quantify the strength of the [(NHC)Au](+)-(alkene) bond and the impact of both ligand and alkene substitution on different components of the interaction, including polarization, orbital, electrostatic, and Pauli repulsive contributions. Finally, molecular orbital analysis has been used to understand the activation of the alkenes in terms of orbital composition and stabilization within the [(NHC)Au(alkene)](+) complexes relative to the free alkenes. These results provide important insight into the fundamental nature of gold(I)-alkene bonding and the impact of both ligand and alkene substitution on the electronic structure of these complexes. PMID- 27455389 TI - Diffusion tensor imaging of articular cartilage at 3T correlates with histology and biomechanics in a mechanical injury model. AB - PURPOSE: We establish a mechanical injury model for articular cartilage to assess the sensitivity of diffusion tensor imaging (DTI) in detecting cartilage damage early in time. Mechanical injury provides a more realistic model of cartilage degradation compared with commonly used enzymatic degradation. METHODS: Nine cartilage-on-bone samples were obtained from patients undergoing knee replacement. The 3 Tesla DTI (0.18 * 0.18 * 1 mm3 ) was performed before, 1 week, and 2 weeks after (zero, mild, and severe) injury, with a clinical radial spin echo DTI (RAISED) sequence used in our hospital. We performed stress-relaxation tests and used a quasilinear-viscoelastic (QLV) model to characterize cartilage mechanical properties. Serial histology sections were dyed with Safranin-O and given an OARSI grade. We then correlated the changes in DTI parameters with the changes in QLV-parameters and OARSI grades. RESULTS: After severe injury the mean diffusivity increased after 1 and 2 weeks, whereas the fractional anisotropy decreased after 2 weeks (P < 0.05). The QLV-parameters and OARSI grades of the severe injury group differed from the baseline with statistical significance. The changes in mean diffusivity across all the samples correlated with the changes in the OARSI grade (r = 0.72) and QLV-parameters (r = -0.75). CONCLUSION: DTI is sensitive in tracking early changes after mechanical injury, and its changes correlate with changes in biomechanics and histology. Magn Reson Med 78:69-78, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27455391 TI - Mesoscale Simulation of Asphaltene Aggregation. AB - Asphaltenes constitute a heavy aromatic crude oil fraction with a propensity to aggregate and precipitate out of solution during petroleum processing. Aggregation is thought to proceed according to the Yen-Mullins hierarchy, but the molecular mechanisms underlying mesoscopic assembly remain poorly understood. By combining coarse-grained molecular models parametrized using all-atom data with high-performance GPU hardware, we have performed molecular dynamics simulations of the aggregation of hundreds of asphaltenes over microsecond time scales. Our simulations reveal a hierarchical self-assembly mechanism consistent with the Yen Mullins model, but the details are sensitive and depend on asphaltene chemistry and environment. At low concentrations asphaltenes exist predominantly as dispersed monomers. Upon increasing concentration, we first observe parallel stacking into 1D rod-like nanoaggregates, followed by the formation of clusters of nanoaggregates associated by offset, T-shaped, and edge-edge stacking. Asphaltenes possessing long aliphatic side chains cannot form nanoaggregate clusters due to steric repulsions between their aliphatic coronae. At very high concentrations, we observe a porous percolating network of rod-like nanoaggregates suspended in a sea of interpenetrating aliphatic side chains with a fractal dimension of ~2. The lifetime of the rod-like aggregates is described by an exponential distribution reflecting a dynamic equilibrium between coagulation and fragmentation. PMID- 27455392 TI - Use of three-dimensional models to assist in the resection of malignant cardiac tumors. AB - The application of three-dimensional (3D) printing enables the creation of material objects from digital images by depositing layers of plastic material into 3D structures and can be used for training, education, and surgical planning. We report two patients with large complex cardiac tumors where 3D technology was utilized to analyze the tumor size, location, and extension more precisely, allowing better preoperative planning and decision making. PMID- 27455393 TI - The surgical challenge of carotid artery and Fallopian canal dehiscence in chronic ear disease: a pitfall for endoscopic approach. AB - OBJECTIVE: Endoscopic procedures are becoming common in middle ear surgery. Inflammation due to chronic ear disease can cause bony erosion of the carotid artery and Fallopian canals, making them more vulnerable during surgery. The objective of this study was to determine whether or not chronic ear disease increases dehiscence of the carotid artery and Fallopian canals. DESIGN: Comparative human temporal bone study. SETTING: Otopathology laboratory. PARTICIPANTS: We selected 78 temporal bones from 55 deceased donors with chronic otitis media or cholesteatoma and then compared those two groups with a control group of 27 temporal bones from 19 deceased donors with no middle ear disease. MAIN OUTCOME MEASURES: We analysed the middle ear, carotid artery canal and Fallopian canal, looking for signs of dehiscence of its bony coverage, using light microscopy. RESULTS: We found an increased incidence in dehiscence of the carotid artery and Fallopian canals in temporal bones with chronic middle ear disease. The size of the carotid artery canal dehiscence was larger in the middle ear-diseased groups, and its bony coverage, when present, was also thinner compared to the control group. Dehiscence of the carotid artery canal was more frequently located closer to the promontory. The incidence of Fallopian canal dehiscence was significantly higher in temporal bones from donors older than 18 years with chronic middle ear disease. CONCLUSION: The increased incidence of the carotid artery and Fallopian canal dehiscence in temporal bones with chronic middle ear disease elevates the risk of adverse events during middle ear surgery. PMID- 27455394 TI - Role of anti-domain 1- beta2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome: comment. PMID- 27455395 TI - Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex. AB - Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis. PMID- 27455397 TI - The life stage-specific pathometabolism of Legionella pneumophila. AB - The genus Legionella belongs to Gram-negative bacteria found ubiquitously in aquatic habitats, where it grows in natural biofilms and replicates intracellularly in various protozoa (amoebae, ciliates). L. pneumophila is known as the causative agent of Legionnaires' disease, since it is also able to replicate in human alveolar macrophages, finally leading to inflammation of the lung and pneumonia. To withstand the degradation by its host cells, a Legionella containing vacuole (LCV) is established for intracellular replication, and numerous effector proteins are secreted into the host cytosol using a type four B secretion system (T4BSS). During intracellular replication, Legionella has a biphasic developmental cycle that alternates between a replicative and a transmissive form. New knowledge about the host-adapted and life stage-dependent metabolism of intracellular L. pneumophila revealed a bipartite metabolic network with life stage-specific usages of amino acids (e.g. serine), carbohydrates (e.g. glucose) and glycerol as major substrates. These metabolic features are associated with the differentiation of the intracellular bacteria, and thus have an important impact on the virulence of L. pneumophila. PMID- 27455398 TI - Next-generation capillary electrophoresis-mass spectrometry approaches in metabolomics. AB - Capillary electrophoresis-mass spectrometry has shown considerable potential for profiling polar ionogenic compounds in metabolomics. Hyphenation of capillary electrophoresis to mass spectrometry is generally performed via a sheath-liquid interface. However, the electrophoretic effluent is significantly diluted in this configuration thereby limiting the utility of this method for highly sensitive metabolomics studies. Moreover, in this set-up the intrinsically low-flow property of capillary electrophoresis is not effectively utilized in combination with electrospray ionization. Here, advancements that significantly improved the performance of capillary electrophoresis-mass spectrometry are considered, with a special emphasis on the sheathless porous tip interface. Attention is also devoted to various technical aspects that still need to be addressed to make capillary electrophoresis-mass spectrometry a robust approach for probing the polar metabolome. PMID- 27455399 TI - Validating Obstetric Emergency Checklists using Simulation: A Randomized Controlled Trial. AB - Background The World Health Organization's Surgical Safety Checklist has demonstrated significant reduction in surgical morbidity. The American Congress of Obstetricians and Gynecologists District II Safe Motherhood Initiative (SMI) safety bundles include eclampsia and postpartum hemorrhage (PPH) checklists. Objective To determine whether use of the SMI checklists during simulated obstetric emergencies improved completion of critical actions and to elicit feedback to facilitate checklist revision. Study Design During this randomized controlled trial, teams were assigned to use a checklist during one of two emergencies: eclampsia and PPH. Raters scored teams on critical step completion. Feedback was elicited through structured debriefing. Results In total, 30 teams completed 60 scenarios. For eclampsia, trends toward higher completion were noted for blood pressure and airway management. For PPH, trends toward higher completion rates were noted for PPH stage assessment and fundal massage. Feedback resulted in substantial checklist revision. Participants were enthusiastic about using checklists in a clinical emergency. Conclusion Despite trends toward higher rates of completion of critical tasks, teams using checklists did not approach 100% task completion. Teams were interested in the application of checklists and provided feedback necessary to substantially revise the checklists. Intensive implementation planning and training in use of the revised checklists will result in improved patient outcomes. PMID- 27455396 TI - Discriminating self from non-self in nucleic acid sensing. AB - Innate immunity against pathogens relies on an array of immune receptors to detect molecular patterns that are characteristic of the pathogens, including receptors that are specialized in the detection of foreign nucleic acids. In vertebrates, nucleic acid sensing is the dominant antiviral defence pathway. Stimulation of nucleic acid receptors results in antiviral immune responses with the production of type I interferon (IFN), as well as the expression of IFN stimulated genes, which encode molecules such as cell-autonomous antiviral effector proteins. This Review summarizes the tremendous progress that has been made in understanding how this sophisticated immune sensory system discriminates self from non-self nucleic acids in order to reliably detect pathogenic viruses. PMID- 27455400 TI - Does Ventilatory Time Retain Its Validity in Predicting Neurodevelopmental Outcome at Two Years of Age in High-Risk Congenital Diaphragmatic Hernia Survivors? AB - Objective To evaluate if in high-risk non-extracorporeal membrane oxygenation (ECMO)-treated congenital diaphragmatic hernia (CDH) survivors, ventilatory time (VT) is correlated to and can be used as clinical marker of neurodevelopmental delay at 2 years of age. Study Design Cohort study was conducted between 2008 and 2012. Mental, motor, and language development were assessed by the Bayley Scales of Infant and Toddler Development III. The correlation between VT and neurodevelopmental outcome (NDO) was analyzed using Pearson's test. Receiver operating characteristic (ROC) analysis was performed to determine the accuracy and best cutoff value of VT to predict the risk of neurodevelopmental delay. Statistical significance was set at p < 0.05. Results A total of 49 patients form the subject of this study. VT during first admission was inversely correlated with cognitive (r = -0.4116; p = 0.0033), motor (r = -0.4241; p = 0.0024), and language development (r = -0.3564; p = 0.0119). Using ROC curve analysis, VT was a significant predictor for neurodevelopmental delay in the cognitive (area under the curve [AUC]: 0.864, sensitivity: 100; specificity: 66.67; p < 0.0001) and motor (AUC: 0.902; sensitivity: 100; specificity: 73.17; p < 0.0001) scales, but not in the language scale. The best cutoff value for both scales was 9 days. Conclusion Within a population of high-risk non-ECMO-treated CDH survivors, VT appears to retain its validity as a clinical marker of adverse NDO in cognitive and motor domains. PMID- 27455402 TI - Oil-in-Water-in-Oil Multinanoemulsions for Templating Complex Nanoparticles. AB - Complex nanoemulsions involving nanodroplets with a defined inner structure have great potential for encapsulation and templating applications. We report a method to form novel complex oil-in-water-in-oil nanoemulsions using a combination of high-energy processing with mixed nonionic surfactants that simultaneously achieve ultralow interfacial tension and frustrated curvature of the water-oil interface. The method produces multinanoemulsions possessing morphologies resembling water-swollen reverse vesicles with core-shell and multicore-shell morphologies of water in cyclohexane. A combination of macroscopic and microscopic characterization conclusively verifies and quantifies the complex morphologies, which vary systematically and reproducibly with water content for water volume fractions between 0.01 and 0.10. The complex morphologies are stable tens of hours, providing a route for their use as liquid templates for internally structured nanoparticles. As a demonstration, we test the complex nanoemulsions' ability to template complex polymer nanogels. PMID- 27455401 TI - Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants. AB - Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks' postmenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p < 0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p = 0.12) when controlling for BW and energy intake. Both BW (p = 0.02) and energy intake (p = 0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth. PMID- 27455404 TI - On the chemical stability of post-lithiated garnet Al-stabilized Li7La3Zr2O12 solid state electrolyte thin films. AB - Garnet-based Al-doped Li7La3Zr2O12 has the potential to be used as a solid state electrolyte for future lithium microbattery architectures, due to its relatively high Li(+) conductivity and stability against Li. Through this work, a model experiment is presented in which the effect of post-lithiation on phase formation and chemical stability is studied for pulsed laser deposited Al-doped Li7La3Zr2O12 thin films on MgO substrates. We report the implications of the newly suggested post-lithiation route for films with thicknesses between 90 and 380 nm. The phase changes from cubic, to a mix of cubic and tetragonal Li7La3Zr2O12, to a cubic Li7La3Zr2O12 and La2Zr2O7 containing film is accompanied by a reduction in the degree of de-wetting as the thickness increases. This study reveals that the thicker, dense, and continuous films remain predominantly in a mixed phase containing cubic Li7La3Zr2O12 and the lithium free La2Zr2O7 phase whereas the thinner, de-wetted films exhibit improved lithium incorporation resulting in the absence of the lithium free phase. For tuning the electrical conductivity and effective use of these structures in future batteries, understanding this material system is of great importance as the chemical stability of the cubic Li7La3Zr2O12 phase in the thin film system will control its effective use. We report a conductivity of 1.2 * 10(-3) S cm(-1) at 325 degrees C for a 380 nm thick solid state electrolyte film on MgO for potential operation in future all solid state battery assemblies. PMID- 27455403 TI - Primary Stroke Center Hospitalization for Elderly Patients With Stroke: Implications for Case Fatality and Travel Times. AB - IMPORTANCE: Physicians often must decide whether to treat patients with acute stroke locally or refer them to a more distant Primary Stroke Center (PSC). There is little evidence on how much the increased risk of prolonged travel time offsets benefits of a specialized PSC care. OBJECTIVES: To examine the association of case fatality with receiving care in PSCs vs other hospitals for patients with stroke and to identify whether prolonged travel time offsets the effect of PSCs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of Medicare beneficiaries with stroke admitted to a hospital between January 1, 2010, and December 31, 2013. Drive times were calculated based on zip code centroids and street-level road network data. We used an instrumental variable analysis based on the differential travel time to PSCs to control for unmeasured confounding. The setting was a 100% sample of Medicare fee-for-service claims. EXPOSURES: Admission to a PSC. MAIN OUTCOMES AND MEASURES: Seven-day and 30-day postadmission case-fatality rates. RESULTS: Among 865 184 elderly patients with stroke (mean age, 78.9 years; 55.5% female), 53.9% were treated in PSCs. We found that admission to PSCs was associated with 1.8% (95% CI, -2.1% to -1.4%) lower 7 day and 1.8% (95% CI, -2.3% to -1.4%) lower 30-day case fatality. Fifty-six patients with stroke needed to be treated in PSCs to save one life at 30 days. Receiving treatment in PSCs was associated with a 30-day survival benefit for patients traveling less than 90 minutes, but traveling at least 90 minutes offset any benefit of PSC care. CONCLUSIONS AND RELEVANCE: Hospitalization of patients with stroke in PSCs was associated with decreased 7-day and 30-day case fatality compared with noncertified hospitals. Traveling at least 90 minutes to receive care offset the 30-day survival benefit of PSC admission. PMID- 27455405 TI - Synergistic anticancer efficacy of Bendamustine Hydrochloride loaded bioactive Hydroxyapatite nanoparticles: In-vitro, ex-vivo and in-vivo evaluation. AB - The present work evaluates the synergistic anticancer efficacy of bioactive Hydroxyapatite (HA) nanoparticles (HA NPs) loaded with Bendamustine HCl. Hydroxyapatite is a material with an excellent biological compatibility, a well known fact which was also supported by the results of the Hemolytic studies and a high IC50 value observed in the MTT assay. HA NPs were prepared by the chemical precipitation method and loaded with the drug via physical adsorption. In-vitro release study was performed, which confirmed the sustained release of the drug from the drug loaded HA NPs. MTT assay, Cell Uptake and FACS studies on JURKAT E6.1 cell line and in-vivo pharmacokinetic studies in Wistar rats revealed that the drug loaded HA NPs could be easily internalized by the cells and release drug in a sustained manner. The drug loaded HA NPs showed cytotoxicity similar to the drug solution at 1/10th of the drug content, which indicates a possible synergism between the activity of the anticancer drug and calcium ions derived from the carrier. An increase in intracellular Ca(2+) ions is reported to induce apoptosis in cells. Tumor regression study in Balb/c mice Ehrlich's ascites model presented a similar synergistic efficacy. The drug solution was able to decrease the tumor volume by half, while the drug loaded HA NPs reduced the tumor size by 6 times. PMID- 27455406 TI - Fabrication and characterization of ultrathin dextran layers: Time dependent nanostructure in aqueous environments revealed by OWLS. AB - Surface coatings of the polysaccharide dextran and its derivatives are key ingredients especially in label-free biosensors for the suppression of non specific binding and for receptor immobilization. Nevertheless, the nanostructure of these ultrathin coatings and its tailoring by the variation of the preparation conditions have not been profoundly characterized and understood. In this work carboxymethylated dextran (CMD) was prepared and used for fabricating ultrathin surface coatings. A grafting method based on covalent coupling to aminosilane- and epoxysilane-functionalized surfaces was applied to obtain thin CMD layers. The carboxyl moiety of the CMD was coupled to the aminated surface by EDC-NHS reagents, while CMD coupling through epoxysilane molecules was performed without any additional reagents. The surface analysis following the grafting procedures consisted of X-ray photoelectron spectroscopy (XPS), attenuated total reflection infrared spectroscopy (ATR-IR), spectroscopic ellipsometry, atomic force microscopy (AFM) and optical waveguide lightmode spectroscopy (OWLS). The XPS and AFM measurements showed that the grafting resulted in a very thin dextran layer of a few nanometers. The OWLS method allowed devising the structure of the interfacial dextran layers by the evaluation of the optogeometrical parameters. The alteration in the nanostructure of the CMD layer with the chemical composition of the silane coverage and the pH of the grafting solution was revealed by in situ OWLS, specifically, lain down chains were found to be prevalent on the surface under neutral and basic conditions on epoxysilylated surfaces. The developed methodologies allowed to design and fabricate nanometer scale CMD layers with well-controlled surface structure, which are very difficult to characterize in aqueous environments using present instrumentations and highly hydrated surface layers. PMID- 27455407 TI - High colloidal stability of gold nanorods coated with a peptide-ethylene glycol: Analysis by cyanide-mediated etching and nanoparticle tracking analysis. AB - The stability of gold nanorods was assessed following coating with various charged or uncharged ligands, mostly peptides. Highly stable monodispersed gold nanorods were obtained by coating CTAB-stabilized gold nanorods with a pentapeptide with C-terminal ethylene glycol units (peptide-EG). UV-vis spectroscopy of these nanorods suspended in saline solutions indicated no signs of aggregation, and they were easily purified using size-exclusion chromatography. A more stringent measure of nanorod stability involved observing changes in the UV-vis absorbance of gold nanorods subjected to etching with cyanide. The lambdamax absorbance of peptide-EG coated nanorods red-shifted in etchant solution. The hypothesis that changes in the nanorod aspect ratio led to this red-shift was confirmed by TEM analysis, which showed pit formation along the transverse axis. The etching process was followed in solution using nanoparticle tracking analysis. The red-shift was shown to occur while the particles remained mono-dispersed, and so was not due to aggregation. Adding both etchant solution and peptide-EG to the nanorods was further shown to allow modulation of the Deltalambdamax red-shift and increase the etchant resistance of peptide-EG nanorods. Thus, very stable gold nanorods can be produced using the peptide-EG coating approach and their optical properties modulated with etchant. PMID- 27455408 TI - Differential susceptibility to the environment: Are developmental models compatible with the evidence from twin studies? AB - According to models of differential susceptibility, the same neurobiological and temperamental traits that determine increased sensitivity to stress and adversity also confer enhanced responsivity to the positive aspects of the environment. Differential susceptibility models have expanded to include complex developmental processes in which genetic variation interacts with exposure to early environmental factors, such as prenatal stress hormones and family conflict. In this study I employed a simulation approach to explore whether, and under what conditions, developmental models of differential susceptibility are compatible with the cumulative findings from twin studies of personality and behavior, which consistently show sizable effects of genetic and nonshared environmental factors and small to negligible effects of the shared environment. Simulation results showed that, to a first approximation, current alternative models of differential susceptibility are all equally compatible with the evidence from twin research; that sizable interaction effects involving individual differences in plasticity are plausible, but only if direct environmental effects are correspondingly weak; and that a major role of shared environmental factors is plausible in early development (consistent with the developmental mechanisms postulated in the differential susceptibility literature) but not in later development. These results support the general plausibility of differential susceptibility models and suggest some realistic constraints on their assumptions. (PsycINFO Database Record PMID- 27455409 TI - Negative affect as a moderator of the relationship between hookup motives and hookup consequences. AB - OBJECTIVE: The current study examined the extent to which negative affect moderates the relationships between distinct hookup motives and hookup consequences. PARTICIPANTS: Data were collected from 271 heavy-drinking undergraduate college students. METHODS: Students from 3 US universities completed online surveys assessing hooking up-related motives, behaviors, and consequences. RESULTS: The results showed that conformity motives to hookup and negative affect predicted hookup consequences. Furthermore, negative affect moderated the relationship between hooking up for relationship reasons and hookup consequences. Specifically, among students with high negative affect, hooking up to secure a long-term relationship was positively associated with hookup consequences whereas among students with low negative affect, securing a long term relationship was negatively associated with hookup consequences. CONCLUSIONS: These findings highlight the role that motives and negative affect play in the prediction of negative hookup consequences. Moreover, the findings from the current study have the potential to inform prevention efforts designed to reduce hookup consequences. PMID- 27455410 TI - Study of the Peripheral Nerve Fibers Myelin Structure Changes during Activation of Schwann Cell Acetylcholine Receptors. AB - In the present paper we consider a new type of mechanism by which neurotransmitter acetylcholine (ACh) regulates the properties of peripheral nerve fibers myelin. Our data show the importance of the relationship between the changes in the number of Schwann cell (SC) acetylcholine receptors (AChRs) and the axon excitation (different intervals between action potentials (APs)). Using Raman spectroscopy, an effect of activation of SC AChRs on the myelin membrane fluidity was investigated. It was found, that ACh stimulates an increase in lipid ordering degree of the myelin lipids, thus providing evidence for specific role of the "axon-SC" interactions at the axon excitation. It was proposed, that during the axon excitation, the SC membrane K+- depolarization and the Ca2+ influx led to phospholipase activation or exocytosis of intracellular membrane vesicles and myelin structure reorganization. PMID- 27455411 TI - Nitrofurazone quantification in milk at the European Union minimum required performance limit of 1 ng g(-1): circumventing the semicarbazide problem. AB - Nitrofurazone is an antibiotic with carcinogenic properties. Efforts by regulatory authorities to control nitrofurazone from agricultural foods are an important public health measure that have, to some extent, been undermined by widespread use amongst laboratories of the unreliable marker metabolite semicarbazide. This work confirms what has long been suspected, namely that powdered dairy products that are initially free of semicarbazide develop semicarbazide under storage conditions such as occur normally across commercial supply chains. The low ng g(-)(1) levels of semicarbazide formed in this way are insufficient to present any food safety hazard. That such development of a marker metabolite is demonstrated to occur by innocent means effectively invalidates the use of semicarbazide as a marker metabolite for powdered dairy products, and exacerbates the regulatory need for a more suitable analytical methodology. In milk, unlike meat, nitrofurazone is known to remain stable and thus available for analysis in the intact form, rather than necessitating any use of a metabolite or fragment. However, no previous methodology that was capable of achieving the stringent European minimum required performance limit of 1 ng g(-)(1) when using intact nitrofurazone had been described for milk. This work describes a specific methodology using LC-MS/MS for milk and milk powder; it achieves detection of intact nitrofurazone (as well as furazolidone, furaltadone and nitrofurantoin) to levels well below 1 ng g(-)(1). Laboratories will no longer need to use semicarbazide as an unreliable marker metabolite for the analysis of nitrofurazone in dairy products, paving the way for regulatory authorities to better control nitrofurazone abuse with greater confidence. PMID- 27455412 TI - Injectable and Glucose-Responsive Hydrogels Based on Boronic Acid-Glucose Complexation. AB - Injectable hydrogels have been widely used for a number of biomedical applications. Here, we report a new strategy to form an injectable and glucose responsive hydrogel using the boronic acid-glucose complexation. The ratio of boronic acid and glucose functional groups is critical for hydrogel formation. In our system, polymers with 10-60% boronic acid, with the balance being glucose modified, are favorable to form hydrogels. These hydrogels are shear-thinning and self-healing, recovering from shear-induced flow to a gel state within seconds. More importantly, these polymers displayed glucose-responsive release of an encapsulated model drug. The hydrogel reported here is an injectable and glucose responsive hydrogel constructed from the complexation of boronic acid and glucose within a single component polymeric material. PMID- 27455413 TI - Study methodology and diabetes control in patients from the non-English diabetes management project (NEDMP). AB - BACKGROUND: To describe the clinical characteristics of non-English speaking patients from the Diabetes Management Project (NEDMP), and compare their diabetes management and severity of diabetic retinopathy (DR) with the English-speaking DMP sample (EDMP). DESIGN: A prospective study was conducted on non-English speaking adults with diabetes who attended the Royal Victorian Eye and Ear Hospital. PARTICIPANTS: 136 (90.1%) non-English speaking adults were assessed, with a mean age of 72.2 years (range: 50-88 years); 74 (54.4%) were male. METHODS: Participants completed interviewer-administered questionnaires and underwent visual acuity, fundus photography, optical coherence tomography, biochemistry and anthropometric measurements. The EDMP assessed 609 patients in 2009 using a similar protocol. MAIN OUTCOME MEASURES: Type and duration of diabetes, diabetes control and diabetic retinopathy. RESULTS: A total of 127 (93.4%) and 8 (5.9%) participants reported having type 2 and type 1 diabetes, respectively, with a median (IQR) duration of 17 (14) years. The proportion of patients with poor diabetes control (HbA1c >= 7%) in the NEDMP was similar to the EDMP (64.0% and 68.2%, respectively; P = 0.411). A significantly higher proportion of patients with DR in the NEDMP were found to have poor diabetes control (HbA1c >= 7%) compared to those without DR (80.9% vs. 50.0%, P = 0.003). Almost two-thirds of NEDMP patients (74/118) had DR and 23% (27/115) had diabetic macular edema. The prevalence of DR was similar between the NEDMP and EDMP studies, ranging from 25-30% and 28-29%. CONCLUSIONS: The clinical characteristics, diabetes control, and DR severity of English and non-English speaking patients were similar. The high proportion of poor diabetes management in non-English speaking patients with DR suggests educational and behavioural interventions to improve glycaemic control are warranted. PMID- 27455415 TI - Formation of organic chloramines during chlor(am)ination and UV/chlor(am)ination of algae organic matter in drinking water. AB - Surface water are frequently subjected to problems of algal blooms and release of algae organic matter (AOM) from the algae cells, which cause many water quality issues. This study investigated the formation of organic chloramines and nitrogenous disinfection by-products (N-DBPs) during chlor(am)ination and UV/chlor(am)ination of AOM in drinking water. AOM caused higher organic chloramine formation than humic acid and fulvic acid during chlor(am)ination. The formation of organic chloramines increased first and then decreased with the increase of free chlorine dosage, but kept increasing with the increase of NH2Cl dosage. During AOM chlorination, the formation of organic chloramines kept decreasing as the reaction time went by, and the maximum organic chloramine proportion (79.1%) in total chlorine occurred at 8 h. However, during AOM chloramination, the formation of organic chloramines increased first, decreased in the following and then increased again as the reaction time went by, and the maximum organic chloramine proportion (22.1%) in total chlorine occurred at 24 h. UV irradiation pretreatment did not effectively influence organic chloramine formation during AOM chlor(am)ination, but accelerated the degradation of organic chloramines during chloramination. Besides, UV pretreatment enhanced the formation of N-DBPs during the subsequent chlor(am)ination of AOM, especially dichloroacetonitrile. PMID- 27455414 TI - Novel Targeted Therapy for Precursor B Cell Acute Lymphoblastic Leukemia: anti CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate. AB - The exponential rise in molecular and genomic data has generated a vast array of therapeutic targets. Oligonucleotide-based technologies to down regulate these molecular targets have promising therapeutic efficacy. However, there is relatively limited success in translating this into effective in vivo cancer therapeutics. The primary challenge is the lack of effective cancer cell-targeted delivery methods, particularly for a systemic disease such as leukemia. We developed a novel leukemia-targeting compound composed of a monoclonal antibody directly conjugated to an antisense oligonucleotide (ASO). Our compound uses an ASO that specifically targets the transcription factor MAX dimerization protein 3 (MXD3), which was previously identified to be critical for precursor B cell (preB) acute lymphoblastic leukemia (ALL) cell survival. The MXD3 ASO was conjugated to an anti-CD22 antibody (alphaCD22 Ab) that specifically targets most preB ALL. We demonstrated that the alphaCD22 Ab-ASO conjugate treatment showed MXD3 protein knockdown and leukemia cell apoptosis in vitro. We also demonstrated that the conjugate treatment showed cytotoxicity in normal B cells, but not in other hematopoietic cells, including hematopoietic stem cells. Furthermore, the conjugate treatment at the lowest dose tested (0.2mg/kg Ab for 6 doses - twice a week for 3 weeks) more than doubled the mouse survival time in both Reh (median survival time 20.5 vs. 42.5 days, p<0.001) and primary preB ALL (median survival time 29.3 vs. 63 days, p<0.001) xenograft models. Our conjugate that uses alphaCD22 Ab to target the novel molecule MXD3, which is highly expressed in preB ALL cells, appears to be a promising novel therapeutic approach. PMID- 27455416 TI - Genetic redundancy and persistence of plasmid-mediated trimethoprim/sulfamethoxazole resistant effluent and stream water Escherichia coli. AB - Antibiotic resistant bacteria may persist in effluent receiving surface water in the presence of low (sub-inhibitory) antibiotic concentrations if the bacteria possess multiple genes encoding resistance to the same antibiotic. This redundancy of antibiotic resistance genes may occur in plasmids harboring conjugation and mobilization (mob) and integrase (intI) genes. Plasmids extracted from 76 sulfamethoxazole-trimethoprim resistant Escherichia coli originally isolated from effluent and an effluent-receiving stream were used as DNA template to identify sulfamethoxazole (sul) and trimethoprim (dfr) resistances genes plus detect the presence of intI and mob genes using PCR. Sulfamethoxazole and trimethoprim resistance was plasmid-mediated with three sul (sul1, sul2 and sul3 genes) and four dfr genes (dfrA12, dfrA8, dfrA17, and dfrA1 gene) the most prevalently detected. Approximately half of the plasmids carried class 1 and/or 2 integron and, although unrelated, half were also transmissible. Sampling site in relationship to effluent input significantly affected the number of intI and mob but not the number of sul and dfr genes. In the presence of low (sub-inhibitory) sulfamethoxazole concentration, isolates persisted regardless of integron and mobilization gene designation, whereas in the presence of trimethoprim, the presence of both integron and mobilization genes made isolates less persistent than in the absence of both or the presence of a gene from either group individually. Regardless, isolates persisted in large concentrations throughout the experiment. Treated effluent containing antibiotic resistant bacteria may be an important source of integrase and mobilization genes into the stream environment. Sulfamethoxazole-trimethoprim resistant bacteria may have a high degree of genetic redundancy and diversity carrying resistance to each antibiotic, although the role of integrase and mobilization genes towards persistence is unclear. PMID- 27455417 TI - In Vivo Kinematics of the Tibiotalar and Subtalar Joints in Asymptomatic Subjects: A High-Speed Dual Fluoroscopy Study. AB - Measurements of joint kinematics are essential to understand the pathomechanics of ankle disease and the effects of treatment. Traditional motion capture techniques do not provide measurements of independent tibiotalar and subtalar joint motion. In this study, high-speed dual fluoroscopy images of ten asymptomatic adults were acquired during treadmill walking at 0.5 m/s and 1.0 m/s and a single-leg, balanced heel-rise. Three-dimensional (3D) CT models of each bone and dual fluoroscopy images were used to quantify in vivo kinematics for the tibiotalar and subtalar joints. Dynamic tibiotalar and subtalar mean joint angles often exhibited opposing trends during captured stance. During both speeds of walking, the tibiotalar joint had significantly greater dorsi/plantarflexion (D/P) angular ROM than the subtalar joint while the subtalar joint demonstrated greater inversion/eversion (In/Ev) and internal/external rotation (IR/ER) than the tibiotalar joint. During balanced heel-rise, only D/P and In/Ev were significantly different between the tibiotalar and subtalar joints. Translational ROM in the anterior/posterior (AP) direction was significantly greater in the subtalar than the tibiotalar joint during walking at 0.5 m/s. Overall, our results support the long-held belief that the tibiotalar joint is primarily responsible for D/P, while the subtalar joint facilitates In/Ev and IR/ER. However, the subtalar joint provided considerable D/P rotation, and the tibiotalar joint rotated about all three axes, which, along with translational motion, suggests that each joint undergoes complex, 3D motion. PMID- 27455418 TI - Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression. AB - Methylglyoxal (MG) is a highly reactive dicarbonyl compound exhibiting anti-tumor activity. The anti-tumor effects of MG have been demonstrated in some types of cancer, but its role in colon cancer and the mechanisms underlying this activity remain largely unknown. We investigated its role in human colon cancer and the underlying mechanism using human colon cancer cells and animal model. Viability, proliferation, and apoptosis were quantified in DLD-1 and SW480 colon cancer cells by using the Cell Counting Kit-8, plate colony formation assay, and flow cytometry, respectively. Cell migration and invasion were assessed by wound healing and transwell assays. Glucose consumption, lactate production, and intracellular ATP production also were assayed. The levels of c-Myc protein and mRNA were quantitated by western blot and qRT-PCR. The anti-tumor role of MG in vivo was investigated in a DLD-1 xenograft tumor model in nude mice. We demonstrated that MG inhibited viability, proliferation, migration, and invasion and induced apoptosis of DLD-1 and SW480 colon cancer cells. Treatment with MG reduced glucose consumption, lactate production, and ATP production and decreased c-Myc protein levels in these cells. Moreover, MG significantly suppressed tumor growth and c-Myc expression in vivo. Our findings suggest that MG plays an anti tumor role in colon cancer. It inhibits cancer cell growth by altering the glycolytic pathway associated with downregulation of c-Myc protein. MG has therapeutic potential in colon cancer by interrupting cancer metabolism. PMID- 27455419 TI - A Water Rehabilitation Program in Patients with Hip Osteoarthritis Before and After Total Hip Replacement. AB - BACKGROUND Pain associated with coxarthrosis, typically occurring in middle-aged and elderly patients, very commonly causes considerable limitation of motor fitness and dependence on pharmacotherapy. This article provides an assessment of a rehabilitation program with tailored water exercises in patients with osteoarthritis before and after total hip replacement. MATERIAL AND METHODS A total of 192 patients (the mean age 61.03+/-10.89) suffering from hip osteoarthritis (OA) were evaluated before and after total hip replacement (THR). The clinical study covered measurements of hip active ranges of motion (HAROM) and the forces generated by pelvis stabilizer muscles. Pain intensity was assessed according to analogue-visual scale of pain (VAS) and according to the Modified Laitinen Questionnaire. The patients were divided into 6 groups (4 treatment and 2 control). We compared 2 rehabilitation programs using kinesitherapy and low-frequency magnetic field. One of them also had specially designed exercises in the water. Statistical analysis was carried out at the significance level alpha=0.05. This was a cross-sectional study. RESULTS A positive effect of water exercises on a number of parameters was found in patients with OA both before and after total hip replacement surgery. We noted a significant reduction of pain (p<0.001), increased ranges of motion and muscle strength, and reduced use of medicines (NASAIDs) (p<0.001). A correlation was found between the degree of degenerative deforming lesions and the effects of the treatment process (p<0.01). CONCLUSIONS 1. The rehabilitation program including water exercises most significantly reduced pain in patients with OA before and after total hip replacement surgery. 2. Inclusion of water exercises in a rehabilitation program can reduce the use of medicines in patient with OA and after THR. PMID- 27455420 TI - Apoptosis in response to microbial infection induces autoreactive TH17 cells. AB - Microbial infections often precede the onset of autoimmunity. How infections trigger autoimmunity remains poorly understood. We investigated the possibility that infection might create conditions that allow the stimulatory presentation of self peptides themselves and that this might suffice to elicit autoreactive T cell responses that lead to autoimmunity. Self-reactive CD4(+) T cells are major drivers of autoimmune disease, but their activation is normally prevented through regulatory mechanisms that limit the immunostimulatory presentation of self antigens. Here we found that the apoptosis of infected host cells enabled the presentation of self antigens by major histocompatibility complex class II molecules in an inflammatory context. This was sufficient for the generation of an autoreactive TH17 subset of helper T cells, prominently associated with autoimmune disease. Once induced, the self-reactive TH17 cells promoted auto inflammation and autoantibody generation. Our findings have implications for how infections precipitate autoimmunity. PMID- 27455422 TI - The prevalence of cardiovascular disease in non-communicating hydrocephalus. AB - OBJECTIVE: Hydrocephalus (HC) caused by blockade of ventricular cerebrospinal fluid (CSF) pathways is denoted non-communicating HC. One issue not previously addressed is how the prevalence of cardiovascular disease compares between patients with non-communicating HC and the general population. METHODS: We examined whether the prevalence of cardiovascular disease (arterial hypertension, angina pectoris, cardiac infarction, and diabetes) differed between cases with non-communicating HC and a general control population, represented by participants of the North-Trondelag Health 3 Survey (The HUNT3 Survey). A second control group consisted of patients with communicating hydrocephalus (idiopathic normal pressure hydrocephalus, iNPH). RESULTS: The study included 50 cases with non-communicating HC (53.4+10.5years), and two control cohorts: 35,413 participants of the HUNT3 Survey (52.8+9.6years), and 176 iNPH patients (61.2+8.3years). All individuals were aged 35-70 years. Among the non communicating HC patients, the results showed increased prevalence for arterial hypertension (males), cardiac infarction (females), and diabetes (females), as compared with the HUNT3 control group with significant odds ratio estimates. However, the prevalence of cardiovascular disease did not significantly differ between patients with non-communicating HC or iNPH. In patients with either non communicating HC or iNPH and elevated pulsatile intracranial pressure (ICP) during overnight monitoring, the prevalence of diabetes was increased. CONCLUSION: This study showed significantly increased prevalence of cardiovascular disease in non-communicating HC, indicating an association between cardiovascular disease and the development of non-communicating HC. Further, diabetes was associated with abnormal pulsatile ICP in both non-communicating HC and iNPH patients. PMID- 27455423 TI - Influence of the T1-slope on sagittal alignment of the subaxial cervical spine after posterior atlantoaxial fusion in os odontoideum. AB - OBJECTIVES: To analyze the effect of T1-slope (T1S) on sagittal alignment of the subaxial cervical spine after posterior C1-C2 fusion. PATIENTS AND METHODS: The data of 35 consecutive patients who underwent posterior C1-C2 fusion due to atlantoaxial instability with os odontoideum were retrospectively reviewed. Radiographic parameters, including T1S, C1-C2 angle and C2-C7 angle, were measured before operation and at the final follow-up. Patients were divided into 2 groups: high T1S group and low T1S group. Differences within and between groups in radiographic parameters and the relationships among T1S, C1-C2 angle and C2-C7 angle were analyzed. RESULTS: After operation, C1-C2 angle was significantly enlarged (P<0.05) while C2-C7 angle reduced (P<0.05). However, significant change was not observed in T1S (P>0.05). Postoperative C2-C7 angle had a medium positive relation with both preoperative (r=0.563, P<0.05) and postoperative T1S (r=0.547, P<0.05). C1-C2 angle was negatively related to C2-C7 angle before operation (r= 0.590, P<0.05) but not after operation (r=-0.125, P>0.05). However, change of C1 C2 angle demonstrated a medium negative relation with change of C2-C7 angle after operation (r=-0.614, P<0.05). When the patients were divided into high and low T1S groups, there were significant difference in both preoperative and postoperative C2-C7 angles between 2 groups (all P<0.05) but not in C1-C2 angle, change of C1-C2 angle or change of C2-C7 angle (all P>0.05). After operation, C1 C2 angles became larger in both groups (all P<0.05). Meanwhile, although postoperative C2-C7 angle became smaller than preoperative one in both groups, statistical difference was only observed in high T1S group (P<0.05). CONCLUSION: T1S was a useful parameter to evaluate postoperative alignment of the subaxial cervical spine after posterior C1-C2 fusion. To avoid postoperative misalignment of the subaxial cervical spine, C1-C2 should be fixed in less lordosis, especially in patients with high preoperative T1S. PMID- 27455421 TI - Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. AB - The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type 1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease. PMID- 27455424 TI - The association between post-traumatic stress disorder and lifetime DSM-5 psychiatric disorders among veterans: Data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). AB - This study examined the prevalence, correlates and psychiatric comorbidity of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) posttraumatic stress disorder (PTSD) in a nationally representative sample of U.S. veterans using data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (n = 3119 veteran respondents). The overall prevalence of lifetime PTSD was 6.9%. Lifetime PTSD prevalence was higher among veterans who were female (13.2%), aged 18-29 years (15.3%), Native American (24.1%) or Black (11.0%), previously or never married (9.6% and 11.2, respectively), had incomes less than $70,000 (7.2%-10.1%) and had >2 traumatic events (5.2%-14.7%). After adjusting for sociodemographic characteristics, comorbidity between lifetime PTSD and other psychiatric disorders was highest for any personality disorder (adjusted odds ratio [AOR] = 11.1, 95% confidence interval [CI], 5.7, 21.5), any mood disorder (AOR = 9.7, 95% CI, 4.6, 20.4) and any anxiety disorder (AOR = 9.6, 95% CI, 5.1, 17.7), followed by nicotine, drug, and alcohol use disorders (AOR = 3.4, 95% CI, 1.8, 6.5; AOR = 3.1, 95% CI, 2.0, 5.9; 2.1, 95% CI, 1.5, 3.1, respectively). Associations remained with any mood, anxiety, and personality disorders after controlling for other psychiatric disorders (AOR = 3.7, 95% CI, 1.2, 10.9; AOR = 3.5, 95% CI, 1.6, 7.4; AOR = 4.5, 95% CI, 2.3, 8.7, respectively). Veterans who sought treatment for PTSD had more comorbid conditions, although treatment was only associated with comorbid drug use disorder (AOR = 2.4, 95% CI, 1.0, 5.7). In U.S. veterans, PTSD is highly comorbid with other psychiatric disorders. Although many veterans remain untreated, comorbidity may influence treatment seeking. PMID- 27455425 TI - Dexmedetomidine protects against learning and memory impairments caused by electroconvulsive shock in depressed rats: Involvement of the NMDA receptor subunit 2B (NR2B)-ERK signaling pathway. AB - Cognitive impairment is a common adverse effect of electroconvulsive therapy (ECT) during treatment for severe depression. Dexmedetomidine (DEX), a sedative anesthetic drug, is used to treat post-ECT agitation. However, it is not known if DEX can protect against ECT-induced cognitive impairments. To address this, we used chronic unpredictable mild stress (CUMS) to establish a model of depression for ECT treatment. Our Morris water maze and sucrose preference test results suggest that DEX alleviates ECT-induced learning and memory impairments without altering the antidepressant efficacy of ECT. To further investigate the underlying mechanisms of DEX, hippocampal expression of NR2B, p-ERK/ERK, p CREB/CREB, and BDNF were quantified by western blotting. These results show that DEX suppresses over-activation of NR2B and enhances phosphorylation of ERK1/2 in the hippocampus of ECT-treated depressed rats. Furthermore, DEX had no significant effect on ECT-induced increases in p-CREB and BDNF. Overall, our findings suggest that DEX ameliorates ECT-induced learning and memory impairments in depressed rats via the NR2B-ERK signaling cascade. Moreover, CREB/BDNF seems not appear to participate in the cognitive protective mechanisms of DEX during ECT treatment. PMID- 27455426 TI - A compact fiber-optic probe-based singlet oxygen luminescence detection system. AB - This paper presents a novel compact fiberoptic based singlet oxygen near-infrared luminescence probe coupled to an InGaAs/InP single photon avalanche diode (SPAD) detector. Patterned time gating of the single-photon detector is used to limit unwanted dark counts and eliminate the strong photosensitizer luminescence background. Singlet oxygen luminescence detection at 1270 nm is confirmed through spectral filtering and lifetime fitting for Rose Bengal in water, and Photofrin in methanol as model photosensitizers. The overall performance, measured by the signal-to-noise ratio, improves by a factor of 50 over a previous system that used a fiberoptic-coupled superconducting nanowire single-photon detector. The effect of adding light scattering to the photosensitizer is also examined as a first step towards applications in tissue in vivo. PMID- 27455427 TI - Never, Never, Never Give Up: Winston Churchill, October 29, 1941. PMID- 27455428 TI - In Vitro Biocompatibility Assessment and In Vivo Behavior of a New Osteoconductive betaTCP Bone Substitute. AB - OBJECTIVE: Beta-tricalcium phosphate (betaTCP) granules (OsproLife) exhibit a pure crystalline phase and a rough microporous surface for promoting cell adhesion and microsized intragranule porosity for improving wettability and resorption necessary for bone regeneration. OsproLife is a fully resorbable, space-maintaining, and osteoconductive synthetic material for the filling of bone defects. To asses OsproLife properties, a similar synthetic biomaterial, already on the market, has been chosen as reference: Cerasorb has the same chemical composition, but different crystal structure, surface morphology, and granule size. The aim of this study is to compare the properties of OsproLife and Cerasorb. METHODS: Chemical purity, composition and physical properties, in vitro cytotoxicity, and in vivo bone performance in a rabbit model were analyzed. betaTCP OsproLife granules (test) were compared with Cerasorb (control). Histological and MUCT analyses were performed at 6, 12, and 56 weeks after implantation. RESULTS: betaTCP OsproLife and Cerasorb granules result to be both biocompatible and characterized by the same osteoconductivity and resorption rate. CONCLUSION: betaTCP OsproLife granules are a promising bone substitute for dental and orthopedic applications. PMID- 27455429 TI - Maxillary Sinus Dimensions With Respect to the Posterior Superior Alveolar Artery Decrease With Tooth Loss. AB - BACKGROUND: The posterior superior alveolar (PSA) artery is frequently encountered in the area where the lateral osteotomy is performed during direct sinus augmentation procedures. OBJECTIVE: To investigate the correlation between patient-dependent variables and measurements related to PSA using cone beam computed tomography (CBCT) data. METHODS: Three hundred ninety-four CBCT scans were evaluated to assess the PSA artery diameter and distances to the sinus floor and to alveolar crest. Patient's age, gender, and edentulism status were recorded. RESULTS: The PSA artery tends to be wider in older patients. Distances to the sinus floor or the alveolar crest tend to be shorter in women and in partially and completely edentulous patients. Also, as those distances decrease, the mediolateral width of the sinus increases. CONCLUSION: Tooth loss leads to maxillary sinus vertical collapse with respect to the PSA artery. The position of the artery is stable; so, the mediolateral dimensions at different heights from the floor increase. PRACTICAL IMPLICATIONS: The reduced distances from the PSA to the sinus floor and the alveolar crest in edentulous patients potentially increase the risk of injury during maxillary sinus lift. Additionally, when the distance to the sinus floor decreases, the mediolateral dimensions of the sinus at different heights increase, which may complicate the technique and challenge the outcomes. PMID- 27455430 TI - Dental Implant Thread Design and the Consequences on Long-Term Marginal Bone Loss. AB - AIM: The aim of this study was to present the implant macrostructure effect on marginal bone loss using 3 dental implant thread designs with differences in thread pitch, lead, and helix angle. All implants used were sourced from the same company and had the same microstructured surface. MATERIALS AND METHODS: This is a nonrandomized, retrospective, double-blind study. Data were collected by an independent Tel Aviv University group from a general practitioner's private practice patient records. In total, 1361 implants met the inclusion criteria representing the 3 types of implants macrostructure. RESULTS: Overall survival rate was 96.3% with 50 implants failing (3.7%) out of a total of 1361 implants. Survival rates for the 3 groups were: group A 96.6%, group B 95.9%, and in group C 100%. Average bone loss for groups A, B, and C were 2.02 (+/-1.70) mm, 2.10 (+/ 1.73) mm, and 1.90 (+/-1.40) mm, respectively. Pairwise comparisons revealed that less bone loss occurred in group A compared with group B (P = 0.036). CONCLUSION: Favorable long-term bone loss results were found in implants with a larger pitch, deeper apical threads, and a narrower implant core. One-piece V-thread design implants demonstrated 100% survival rate. PMID- 27455431 TI - Classification of the Root Position of the Maxillary Central Incisors and its Clinical Significance in Immediate Implant Placement. AB - PURPOSE: The aim was to classify the relationship of the sagittal root positions of the maxillary central incisor to alveolar bone using cone beam computed tomography (CBCT). METHODS: CBCT images of 934 maxillary central incisors were retrospectively reviewed included 542 men and 392 women. The sagittal root position in the alveolar bone was classified as buccal, middle, or palatal. The sagittal buccal type was further classified into 3 subtypes: I, II, and III. RESULTS: The root position type was buccal in 95.4% of the 934 incisors, middle in 4.4%, and palatal in 0.2%. In the buccal type, 47.5%, 44.2%, and 8.3% were subtypes I, II, and III, respectively. There was no significant difference in the major and subtypes of root position between the male and female subjects (both P > 0.05). CONCLUSIONS: In Chinese adults, the predominant type of sagittal root position of the maxillary central incisor is buccal. This classification system is useful in planning the implant site for immediate placement in the maxillary esthetic zone. PMID- 27455432 TI - Cardiovascular benefits and risks across the physical activity continuum. AB - PURPOSE OF REVIEW: Habitual physical activity can reduce the risk of future cardiovascular morbidity and mortality. This review evaluates recent publications that have assessed the impact of the dose of physical (in)activity on cardiovascular outcomes. RECENT FINDINGS: Sedentary behavior, characterized by prolonged sitting, is increasingly prevalent across the globe and increases the risk for cardiovascular events in a dose-dependent fashion. Similarly, the number of individuals performing endurance exercise events has tripled over the last 2 decades, and some studies suggest that the high volumes of exercise training and competition may attenuate the health benefits of a physically active lifestyle. SUMMARY: Breaking up sitting time or replacing sitting by (light) physical activity are effective strategies to attenuate its detrimental health effects. Low doses of physical activity, preferably at a high intensity, significantly reduce the risk for cardiovascular and all-cause mortality. Larger doses of exercise yield larger health benefits. Extreme doses of exercise neither increase nor decrease the risk for adverse outcomes. Athletes demonstrate a transient cardiac dysfunction and biomarker release directly postexercise. Chronic exercise training may increase the risk for atrial fibrillation, but is also associated with a superior life expectancy compared with the general population. PMID- 27455433 TI - Risk Factors for Institutionalization After Traumatic Brain Injury Inpatient Rehabilitation. AB - OBJECTIVE: To create a profile of individuals with traumatic brain injury (TBI) who received inpatient rehabilitation and were discharged to an institutional setting using characteristics measured at rehabilitation discharge. METHODS: The Traumatic Brain Injury Model Systems National Database is a prospective, multicenter, longitudinal database for people with moderate to severe TBI. We analyzed data for participants enrolled from January 2002 to June 2012 who had lived in a private residence before TBI. This cross-sectional study used logistic regression analyses to identify sociodemographic factors, lengths of stay, and cognitive and physical functioning levels that differentiated patients discharged to institutional versus private settings. RESULTS: Older age, living alone before TBI, and lower levels of function at rehabilitation discharge (independence in locomotion, bladder management, comprehension, and social interaction) were significantly associated with higher institutionalization rates and provided the best models identifying factors associated with institutionalization. Institutionalization was also associated with decreased independence in bed-chair wheelchair transfers and increased duration of posttraumatic amnesia. CONCLUSIONS: Individuals institutionalized after inpatient rehabilitation for TBI were older, lived alone before injury, had longer posttraumatic amnesia durations, and were less independent in specific functional characteristics. Research evaluating the effect of increasing postdischarge support and improving treatment effectiveness in these functional areas is recommended. PMID- 27455434 TI - Recovery Trajectories of Executive Functioning After Pediatric TBI: A Latent Class Growth Modeling Analysis. AB - OBJECTIVE: To identify latent trajectories of executive functioning (EF) recovery overtime after childhood traumatic brain injury (TBI) and examine the predictive value of known risk factors within and across recovery trajectories using latent class growth modeling (LCGM). METHOD: A total of 206 children between the ages of 3 and 7 years with a moderate to severe TBI or orthopedic injury (OI) were included. LCGM was applied to identify longitudinal trajectories of postinjury EF as assessed by the Behavior Rating Inventory of Executive Functioning General Executive Composite (GEC). Separate models were estimated for the TBI and OI groups. RESULTS: Two TBI trajectories-normal limits (70.8%) and clinically elevated (29.2%)-and 3 OI trajectories-normal limits (20.9%), subclinical (49.0%), and clinically elevated (30.17%)-were identified. Baseline GEC was the only predictor of class membership for all models. Both TBI trajectories demonstrated an increase in GEC over time, whereas only 1 of the 3 OI classes demonstrated this pattern. Family variables were associated with GEC across trajectories. CONCLUSION: The lack of association of injury characteristics with trajectory class membership highlights the heterogeneity in recovery after pediatric TBI. Associations of EF trajectories with family factors underscore the importance of involving the family in interventions for children with traumatic injuries. PMID- 27455435 TI - Prediction of Multidimensional Fatigue After Childhood Brain Injury. AB - OBJECTIVES: To determine (1) the presence of fatigue symptoms and predictors of fatigue after childhood brain injury and examine (2) the feasibility, reliability, and validity of a multidimensional fatigue measure (PedsQL Multidimensional Fatigue Scale [MFS]) obtained from parent and child perspectives. SETTING: Emergency and intensive care units of a hospital in Melbourne, Australia. PARTICIPANTS: Thirty-five families (34 parent-proxies and 32 children) aged 8 to 18 years (mean child age = 13.29 years) with traumatic brain injury (TBI) of all severities (27 mild, 5 moderate, and 3 severe) admitted to the Royal Children's Hospital. DESIGN: Longitudinal prospective study. Fatigue data collected at 6-week follow-up (mean = 6.9 weeks). MAIN OUTCOME MEASURES: Postinjury child- and parent-rated fatigue (PedsQL MFS), mood, sleep, and pain based on questionnaire report: TBI severity (mild vs moderate/severe TBI). RESULTS: A score greater than 2 standard deviations below healthy control data indicated the presence of abnormal fatigue, rates of which were higher compared with normative data for both parent and child reports (47% and 29%). Fatigue was predicted by postinjury depression and sleep disturbance for parent, but not child ratings. Fatigue, as rated by children, was not significantly predicted by TBI severity or other symptoms. The PedsQL MFS demonstrated acceptable measurement properties in child TBI participants, evidenced by good feasibility and reliability (Cronbach alpha values >0.90). Interrater reliability between parent and child reports was poor to moderate. CONCLUSIONS: Results underscore the need to assess fatigue and associated sleep-wake disturbance and depression after child TBI from both parent and child perspectives. PMID- 27455436 TI - The Prevalence of Traumatic Brain Injury Among People With Co-Occurring Mental Health and Substance Use Disorders. AB - OBJECTIVE: To estimate the rate and severity of traumatic brain injury (TBI) among people with co-occurring mental health and substance use disorders and to compare demographic, diagnostic, and institutionalization differences between those who screen positive or negative. SETTING: Outpatient community mental health center in Washington, District of Columbia. PARTICIPANTS: A total of 295 people with co-occurring mental health and substance use disorders enrolled in a prospective study of integrated treatment of substance abuse. DESIGN: Cross sectional baseline assessment. MAIN MEASURES: The Ohio State University TBI Identification Method. Standardized measures assessed psychiatric diagnoses, symptom severity, current and lifetime substance use, and history of institutionalization. RESULTS: Eighty percent screened positive for TBI, and 25% reported at least 1 moderate or severe TBI. TBI was associated with current alcohol use and psychiatric symptom severity and with lifetime institutionalization and homelessness. It was more common among participants with posttraumatic stress disorder, borderline personality disorder, and antisocial personality disorder. Men (vs women) and participants with psychotic disorders (vs those with mood disorders) had an earlier age of first TBI with loss of consciousness. CONCLUSION: TBI is common among people with co-occurring mental health and substance use disorders. Repeated and serious TBIs are common in this population. Failure to detect TBI in people with co-occurring disorders who are seeking integrated treatment could lead to misdiagnosis and inappropriately targeted treatment and rehabilitation. PMID- 27455437 TI - Depression Anxiety Stress Scales (DASS-21): Factor Structure in Traumatic Brain Injury Rehabilitation. AB - OBJECTIVE: To confirm the construct validity of the Depression Anxiety Stress Scales-21 (DASS-21) by investigating the fit of published factor structures in a sample of adults with moderate to severe traumatic brain injury (posttraumatic amnesia > 24 hours). PARTICIPANTS: Archival data from 504 patient records at the Brain Injury Rehabilitation Unit at Liverpool Hospital, Australia. Participants were aged between 16 and 71 years and were engaged in a specialist rehabilitation program. MAIN MEASURE: The DASS-21. RESULTS: Two of the 6 models had adequate fit using structural equation modeling. The data best fit Henry and Crawford's quadripartite model, which comprised a Depression, Anxiety and Stress factor, as well as a General Distress factor. The data also adequately fit Lovibond and Lovibond's original 3-factor model, and the internal consistencies of each factor were very good (alpha = 0.82-0.90). CONCLUSION: This study confirms the structure and construct validity of the DASS-21 and provides support for its use as a screening tool in traumatic brain injury rehabilitation. PMID- 27455438 TI - Preemptive Screening Strategies to Identify Postnatal CMV Diseases on the Neonatal Unit. PMID- 27455439 TI - Incidence of Symptomatic Congenital Toxoplasmosis During Ten Years in a Brazilian Hospital. AB - BACKGROUND: Population seroprevalence and rates of mother-to-child transmission are important in determining the incidence of congenital toxoplasmosis. (CT) Mother-to-child transmission depends on the timing of acute maternal infection and treatment during pregnancy. The incidence of CT varies widely across geographic regions, ranging from 1 to 10 cases per 10,000 live births. The incidence of symptomatic disease varies from 0.15 to 0.34 cases per 10,000. METHODS: This is a review of patients treated at a pediatric CT clinic at a university hospital in the south of Brazil, from 2004 to 2014. RESULTS: The annual incidence of CT varied from 0 to 14 cases per 10,000 live births, with a mean incidence of 6 cases per 10,000 during the 10 years studied (CI 95%: 3.02 8.91). The incidence of symptomatic CT varied from 0 to 9 cases per 10,000 live births, with a mean incidence of 5 per 10,000 (CI 95%: 2.44-6.94). There were 5 (14.3%) asymptomatic cases. The main findings were retinochoroiditis (54%), intracranial calcifications (37.5%) and altered cerebrospinal fluid (37.5%). CONCLUSIONS: The incidence of CT and the rate of symptomatic cases were in accordance with the previous data from other studies in Brazil, being significantly higher than in previous North American and European studies. PMID- 27455440 TI - Decrease of Rotavirus Gastroenteritis to a Low Level Without Resurgence for Five Years After Universal RotaTeq Vaccination in Finland. AB - BACKGROUND: Universal rotavirus (RV) vaccination with RotaTeq was introduced into National Immunization Programme (NIP) of Finland in September 2009. We have previously reported the reduction of RV gastroenteritis (GE) cases in the first 2 years after RV vaccination in NIP in Finland. METHODS: In Tampere University Hospital, a 2-year survey of acute GE (AGE) in children was conducted before NIP in the years 2006 to 2008. This was followed by a similar prospective survey in years 2009 to 2011 and now extended to years 2012 to 2014. Stool samples from children examined in the hospital for AGE were analyzed by real-time polymerase chain reaction assays for RV and norovirus, and positive samples were typed by sequencing. RESULTS: The proportion of RVGE of all AGE cases decreased from 52% (421 of 809 cases) in pre-NIP years to 26% (86 of 330 cases) in post-NIP years 2009 to 2011 falling to 12% (40 of 347 cases) in 2012 and 2014. The hospitalizations for RVGE were reduced by 90% and the outpatient clinic visits also by 90% in 2012 to 2014, compared with pre-NIP year; all AGE cases were reduced by 59%. Norovirus was a major causative agent of AGE in the post-NIP period, accounting for 34% of the cases in 2009 to 2011 and 29% in 2012 to 2014. CONCLUSIONS: RV vaccination in NIP has led to a major reduction of RVGE cases seen in hospital with no resurgence in 5 years after NIP. A high coverage of RV vaccination will maintain RV activity at a low level but not eliminate wild-type RV circulation. PMID- 27455441 TI - Prevalence, Serotype Distribution and Mortality Risk Associated With Group B Streptococcus Colonization of Newborns in Rural Bangladesh. AB - BACKGROUND: Group B Streptococcus (GBS) is a predominant cause of early-onset neonatal sepsis globally; however, the impact of this organism on the health of newborns in South Asia is debated, due in part to a paucity of community-based assessments. We estimated the prevalence and serotypes of GBS colonization of the umbilical cord stump and the association of colonization with mortality in a population-based cohort of newborns in rural Sylhet District, Bangladesh. METHODS: Umbilical cord swabs were collected from 646 newborns up to 3 times within the first week after birth (ages <24 hours, ~3 days, ~6 days) and processed to identify GBS serotypes. RESULTS: GBS was isolated from 6.3% (41/646) of newborns. Sixty-one percent of the GBS colonization occurred in neonates within 24 hours of delivery. Serotypes VII (37.1%, n = 13/36) and Ia (33.3%, n = 12/36) were the most predominant colonizing GBS isolates. Other detected serotypes were Ib (11.1%, n = 4/36), II (11.1%, n = 4/36), V (5.6%, n = 2/36) and VI (2.8%, n = 1/36). Mortality risk among newborns with GBS colonization was 6.6 (95% confidence interval: 2.1-20.4) times higher than for those without GBS. CONCLUSIONS: The overall prevalence of GBS colonization was lower than in settings, where GBS is a predominant etiology of neonatal illness. In addition, the GBS serotype distribution differed from that reported in the developed part of the world. However, further studies are needed to understand the true burden of GBS-related illness. Mortality risk was substantially increased in the presence of GBS on the umbilical stump, providing support for chlorhexidine antisepsis to the cord to prevent colonization of invasive pathogens. PMID- 27455442 TI - Clinical Characteristics and Risk Factors of Dengue Shock Syndrome in Children. AB - BACKGROUND: Dengue shock syndrome (DSS) represents one of the most severe manifestations of dengue virus infection. The objective of the present study was to analyze the clinical and laboratory characteristics, risk factors and outcome of DSS in children. METHODS: Patients <15 years old admitted with DSS during the 2012 and 2013 outbreak of serotype 2 of dengue virus in Paraguay were included. Demographic, clinical and laboratory data of patients with/without DSS were analyzed. RESULTS: Of 471 children hospitalized with dengue, 354 patients (75%) presented with shock at admission or developed later. The mean age of patients with DSS was 10.2 +/- 4 years (no difference with patients without shock), without gender preference. Rash (50% vs. 56%), myalgias (45% vs. 40%), vomiting (66% vs. 68%) and bleeding manifestations (24% vs. 21.2%) were similar for 2 groups. Similarly, there was no difference in the frequency of DSS between primary versus secondary infection cases (76.2% vs. 71.6%, P = 0.3). Age group >5 years [odds ratio (OR) 1.6, 95% confidence interval (CI): 1-2.8, P < 0.05), presence of abdominal pain (OR 2.5, 95% CI: 1.3-4.9, P = 0.006), an activated partial thromboplastin time prolonged (OR 4; 95% CI: 1.6-10, P < 0.001) and low fibrinogen level (OR 2.5; 95% CI: 1-5.9, P = 0.02) were found significantly associated with DSS. About 12% of patients required intensive care unit admission, and 2 patients died (lethality 0.35%). CONCLUSIONS: This study validated most of the clinical variables present in the current WHO guidelines as markers of severe disease and add additional variables that can help to predict the risk of progression to shock. PMID- 27455443 TI - Burden of Recurrent Respiratory Tract Infections in Children: A Prospective Cohort Study. AB - BACKGROUND: The burden of recurrent respiratory infections is unclear. We identified young children with recurrent respiratory infections in order to characterize the clinical manifestations, risk factors and short-term consequences. METHODS: In this prospective cohort study, 1089 children were followed from birth to 2 years of age for respiratory infections by a daily symptom diary. Nasal swabs taken during respiratory infections were analyzed for viruses from 714 children. Nasopharyngeal swabs collected at 2 months of age were cultured for bacteria. The 10% of children with the highest number of annual respiratory illness days were defined to have recurrent respiratory tract infections. RESULTS: The 90th percentile in the number of annual respiratory illness days was 98. Children above this limit (n = 109) had a median of 9.6 acute respiratory infections per year. Rhinovirus was detected in 58% of their infections. Of the children with recurrent infections, 60% were diagnosed with at least 3 episodes of acute otitis media, 73% received at least 3 antibiotic treatments and 21% were hospitalized for an acute respiratory infection. Tympanostomy was performed for 35% and adenoidectomy for 13% of the children. Asthma was diagnosed in 12% by 24 months of age. Older siblings increased the risk of recurrent respiratory infections. Early nasopharyngeal colonization with Streptococcus pneumoniae was common in children who later developed recurrent infections. CONCLUSIONS: Children with recurrent respiratory infections frequently use health care services and antibiotics, undergo surgical procedures and are at risk for asthma in early life. Having older siblings increases the risk of recurrent infections. PMID- 27455444 TI - Epidemiology and Management of Acute, Uncomplicated Septic Arthritis and Osteomyelitis: Spanish Multicenter Study. AB - BACKGROUND: Acute osteoarticular infection (OAI) is a potentially severe disease. The aim of this study was to evaluate the etiology, clinical characteristics and therapeutic approach of OAI in children in Spain. METHODS: Medical records from children <14 years with OAI from 25 hospitals between 2008 and 2012 were reviewed. Confirmed osteomyelitis (OM) and septic arthritis (SA) required a positive bacterial isolate; otherwise, they were considered probable. Probable SA with <40,000 cells/mm in joint fluid was not included. RESULTS: A total of 641 children were evaluated. Two hundred and ninety-nine cases (46%) were OM, 232 (36%) SA, 77 (12%) osteoarthritis and 33 (5%) spondylodiscitis. Children with OM were older (63 vs. 43 months for SA; P < 0.001). Magnetic resonance imaging and bone scintigraphy had the highest yield for OM diagnosis (94%). Arthrocentesis was performed in 96% of SA. A microorganism was isolated in 246 patients (38%: 33% OM vs. 55% SA; P < 0.001): Staphylococcus aureus was the most common (63%), followed by Kingella kingae (15%) and Streptococcus pyogenes (9%). Ninety-five percent of children initially received IV antibiotics, mostly cefotaxime + cloxacillin (60%) or cloxacillin (40%). Total treatment duration was 38 (+/-31) days for OM and 28 (+/-16) days for SA (P < 0.0001). Twenty percent of children with OM (46% because of complications) and 53% with SA (95% initial arthrotomy) underwent surgery. Patients with SA were compared according to initial arthrotomy (n = 123) versus arthrocentesis (n = 109), and no clinical differences were observed, except for higher rate of hip SA in the former (50% vs. 9%; P < 0.001). Children with arthrocentesis had less sequelae [6.6% vs. 1%; P = 0.03, odds ratio = 0.58 (95% confidence interval: 0.45-0.76)], but not in the multivariate analysis. CONCLUSIONS: This is the largest pediatric cohort of OAI in Spain. S. aureus was the most common isolate, although K. kingae was recovered in a high proportion of cases. Conservative management was applied in half of the patients. There was a low rate of sequelae, even with nonsurgical approaches. PMID- 27455446 TI - Challenging the dogma that 'rest is best' after concussion (Commentary on Mychasiuk et al.). PMID- 27455445 TI - Immunogenicity and safety of different schedules of 2-dose varicella vaccination in China. AB - We evaluated the safety and immunogenicity of different time intervals for a second dose of varicella vaccine in children in Zhejiang Province, China. Participants had all received a first dose of varicella vaccine and were assigned to 4 groups according to age (2-7 years). A second dose of live attenuated varicella vaccine was administered 1 month, 1 year, 3 years, or 5 years after the first. A serology assay was conducted and fluorescent-antibody-to-membrane antigen test performed to measure the antibody titers against varicella before and approximately 30 days after the second dose. Of 1,078 participants, most tolerated the second dose well. Age at first dose did not affect the response to vaccination. Geometric mean titers (GMTs) significantly differed between group 1 and all other groups, both before and after the second vaccination. The GMT for group 1 was higher than those for the other 3 groups prior to the second vaccination (GMT = 20.52, 14.68, 12.49, 12.29, respectively, p < 0.001 for all), while the opposite was true after the second vaccination (GMT = 51.14, 83.37, 85.01, 81.83, respectively, p < 0.001 for all). There was no significant difference in seropositive rate among the 4 groups prior to the second vaccination (p = 0.093), and these rates were all 100% after the second vaccination. The vaccine was well tolerated in healthy children, regardless of the timing of the second dose. GMTs showed a particularly high boost after the second dose when the interval between doses was more than 1 year. PMID- 27455447 TI - In Vitro Evaluation of the Primary Stability of Short and Conventional Implants. AB - The objective of this study was to evaluate the primary stability of short and conventional dental implants with different platform types at different site densities in vitro. One hundred twenty implants were placed in polyurethane blocks that simulate different bone densities (bone types I and IV). The implants were divided into 10 groups, with 12 implants each according to the type of prosthetic connections (external hexagon, EH; morse taper, MT) and size of the implants (conventional: 4 * 10 mm; short: 5 * 5, 5.5 * 5, 5 * 6, and 5.5 * 6 mm). Insertion torque and resonance frequency analyses were performed to evaluate the primary stability. The Kruskal-Wallis test complemented by Dunn's test and the Mann-Whitney test were used for statistical analysis. These tests were applied at the confidence level of 95% (P < .05). The implants installed in blocks with density type IV exhibited reduced insertion torque compared with implants placed in blocks with density type I. Short implants with EH exhibited increased insertion torque compared with short implants with MT in blocks with bone density type I. In general, implants installed in blocks with density type I exhibited greater primary stability. The short implants with EH with a 5.5-mm diameter and the short implants with MT with a 5-mm diameter exhibited reduced primary stability. No differences between short and conventional implants were noted. Short implants have primary stability and insertion torque at least equivalent to conventional implants irrespective of the platform type and density of the site. PMID- 27455448 TI - Abnormal mural cell recruitment in lymphatic capillaries: a common pathological feature in chronic lymphedematous skin? AB - OBJECTIVES: This study aimed to explore the structural and functional characteristics of dermal lymphatic capillaries in patients with chronic LE, specifically focused on the mural cells that are associated with skin lymphatics. METHODS: Forty-four patients (30 primary LE and 14 secondary LE) and eight healthy controls were enrolled in this study. Genetic analysis of the FOXC2 was performed in 18 patients with primary LE. Full-thickness skin was excised and immunohistologically stained for podoplanin and alpha-SMA. The proportions of alpha-SMA+ Lv (alpha-SMA+ Lv%) were calculated. Lymphatic vascular function was assessed by indocyanine green lymphography. RESULTS: Analysis of FOXC2 revealed two mutations in two patients with LDs. Histologically, thirty-nine patients exhibited increased alpha-SMA+ mural cell coverage of lymphatic capillaries. The alpha-SMA+ Lv% values in the superficial and deep dermis in patients with primary and secondary LE were significantly higher than in the control group. Compared with imaging findings in healthy limbs, in which the collecting lymphatics were clearly visualized, lymphedematous extremities all exhibited dermal backflow. CONCLUSIONS: Abnormal recruitment of mural cells in dermal lymphatic capillaries is a common pathological event in chronic LE, and may play a role in disease evolution. PMID- 27455449 TI - Proteasome inhibitors exacerbate interleukin-8 production induced by protease activated receptor 2 in intestinal epithelial cells. AB - Protease activated receptors (PARs) and the ubiquitin-proteasome system (UPS) regulate inflammatory response in intestinal cells. We aimed to elucidate putative connections between PARs and UPS pathways in intestinal epithelial cells. Caco-2 cells were treated by agonist peptides of PARs and/or IL-1beta and/or proteasome inhibitors, bortezomib or MG132. Inflammatory response was evaluated by measuring IL-8 production. Proteasome activities were also evaluated. We showed that PAR-1 and -2 activation increased release of IL-8 compared with vehicle and independently of IL-1beta. In contrast, PAR-4 agonist peptide had no effect. Caspase-like and chymotrypsin-like proteasomal activities were increased by PAR-2 activation only in the presence of IL-1beta. Interestingly, in polarized Caco-2 cells, the release of IL-8 was predominantly upregulated in the side where PAR-2 agonist peptide was added, apical or basalolateral. In contrast, proteasome activities were only affected when PAR-2 agonist peptide was added in the apical side. Proteasome inhibitors, bortezomib and MG132, enhanced IL-8 production in both sides, apical and basolateral. In conclusion, PAR-2 activation alone did not affect proteasome but needed inflammatory stimulus IL-1beta to synergistically increase chymotrypsin-like activity in intestinal epithelial cells. However, proteasome inhibition led to exacerbate inflammatory response induced by PAR-2 activation. PMID- 27455451 TI - Descriptions and Implementations of DL_F Notation: A Natural Chemical Expression System of Atom Types for Molecular Simulations. AB - DL_F Notation is an easy-to-understand, standardized atom typesetting expression for molecular simulations for a range of organic force field (FF) schemes such as OPLSAA, PCFF, and CVFF. It is implemented within DL_FIELD, a software program that facilitates the setting up of molecular FF models for DL_POLY molecular dynamics simulation software. By making use of the Notation, a single core conversion module (the DL_F conversion Engine) implemented within DL_FIELD can be used to analyze a molecular structure and determine the types of atoms for a given FF scheme. Users only need to provide the molecular input structure in a simple xyz format and DL_FIELD can produce the necessary force field file for DL_POLY automatically. In commensurate with the development concept of DL_FIELD, which placed emphasis on robustness and user friendliness, the Engine provides a single-step solution to setup complex FF models. This allows users to switch from one of the above-mentioned FF seamlessly to another while at the same time provides a consistent atom typing that is expressed in a natural chemical sense. PMID- 27455450 TI - Inflammations mediators and circulating levels of matrix metalloproteinases: Biomarkers of diabetes in Tunisians metabolic syndrome patients. AB - AIMS: This study investigates the relationships between matrix metalloproteinases, inflammations mediators and type 2 diabetes mellitus in Tunisians metabolic syndrome (Mets) patients. METHODS: The study has included 239 MetS patients and 247 controls. Mets was defined according to the NCEP-ATPIII report. Mets patients were also divided into two categories: 29 MetS non diabetics and 210 MetS diabetics. Dysglycemia markers, matrix metalloproteinase-9 (MMP-9), Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) levels and White Blood Cells (WBC) counts were determined in patients and controls. RESULTS: In our study, the level of inflammatory markers WBC, TNF-alpha and matrix metalloproteinases (MMP-8 and MMP-9) were significantly higher in diabetic patients with MetS, as compared with non-diabetic MetS patients. Inflammation mediators and MMP-9 were significantly associated with many clinical characteristics of MetS. The use of ROC "Receiver Operating Characteristic" analysis revealed the impact of TNF alpha on diabetes patients with MetS. In fact TNF alpha was found as a sensitive parameter in these patients with a sensitivity of 85%. CONCLUSION: Inflammation, matrix metalloproteinases and dysglycemia markers are not expressed in isolation but rather concurrently and are continuously interacting with each other, in MetS and diabetics patients. These markers fit with an early stage of cardiovascular disease (CVD); and measuring them could improve the risk evaluation, an early diagnosis, and the prognosis of CVD. PMID- 27455452 TI - Teaching Medical Students to Engage Meaningfully and Judiciously With Patient Data. PMID- 27455453 TI - The role of anaerobic bacteria in the cystic fibrosis airway. AB - PURPOSE OF REVIEW: Anaerobic bacteria are not only normal commensals, but are also considered opportunistic pathogens and have been identified as persistent members of the lower airway community in people with cystic fibrosis of all ages and stages of disease. Currently, the role of anaerobic bacteria in cystic fibrosis lower airway disease is not well understood. Therefore, this review describes the recent studies relating to the potential pathophysiological role(s) of anaerobes within the cystic fibrosis lungs. RECENT FINDINGS: The most frequently identified anaerobic bacteria in the lower airways are common to both cystic fibrosis and healthy lungs. Studies have shown that in cystic fibrosis, the relative abundance of anaerobes fluctuates in the lower airways with reduced lung function and increased inflammation associated with a decreased anaerobic load. However, anaerobes found within the lower airways also produce virulence factors, may cause a host inflammatory response and interact synergistically with recognized pathogens. SUMMARY: Anaerobic bacteria are potentially members of the airway microbiota in health but could also contribute to the pathogenesis of lower airway disease in cystic fibrosis via both direct and indirect mechanisms. A personalized treatment strategy that maintains a normal microbial community may be possible in the future. PMID- 27455454 TI - Test-retest analysis of multiple 31 P magnetization exchange pathways using asymmetric adiabatic inversion. AB - PURPOSE: A 31 P-MR inversion transfer (IT) method with a short adiabatic inversion pulse is proposed and its test-retest reliability was evaluated for two spectral fitting strategies. METHODS: Assessment in a test-retest design (3 Tesla, vastus muscles, 12 healthy volunteers, 14 inversion times, 22 ms asymmetric adiabatic inversion pulse, adiabatic excitation); spectral fitting in Fitting Tool for Interrelated Arrays of Datasets (FitAID) and Java Magnetic Resonance User Interface (jMRUI); least squares solution of the Bloch-McConnell Solomon matrix formalism including all 14 measured time-points with equal weighting. RESULTS: The cohort averages of k[PCr->gamma-ATP] (phosphocreatine, PCr; adenosine triphosphate, ATP) are 0.246 +/- 0.050s-1 versus 0.254 +/- 0.050s 1 , and k[Pi->gamma-ATP] 0.086 +/- 0.033s-1 versus 0.066 +/- 0.034s-1 (average +/ standard deviation, jMRUI versus FitAID). Coefficients of variation of the differences between test and retest are lowest (9.5%) for k[PCr->gamma-ATP] fitted in FitAID, larger (15.2%) for the fit in jMRUI, and considerably larger for k[Pi->gamma-ATP] fitted in FitAID (43.4%) or jMRUI (47.9%). The beginning of the IT effect can be observed with magnetizations above 92% for noninverted lines while inversion of the ATP resonances is better than -72%. CONCLUSION: The performance of the asymmetric adiabatic pulse allows an accurate observation of IT effects even in the early phase; the least squares fit of the Bloch-McConnell Solomon matrix formalism is robust; and the type of spectral fitting can influence the results significantly. Magn Reson Med 78:33-39, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27455455 TI - Optimization of fixation methods for image analysis of the hepatopancreas in whiteleg shrimp, Penaeus vannamei (Boone). AB - Pathology in penaeid shrimps relies on histology, which is subjective, time consuming and difficult to grade in a reproducible manner. Automated image analysis is faster, objective and suitable for routine screening; however, it requires standardized protocols. The first critical step is proper fixation of the target tissue. Bell & Lightner's (A Handbook of Normal Penaeid Shrimp Histology, 1988, The World Aquaculture Society, Baton Rouge) fixation protocol, widely used for routine histology of paraffin sections, is not optimized for image analysis, and no protocol for frozen sections is described in the available literature. Therefore, the aim of this study was to optimize fixation of the hepatopancreas (HP) from whiteleg shrimp (Penaeus vannamei) for both paraffin and frozen sections using a semiquantitative scoring system. For paraffin sections, four injection volumes and three injection methods were compared, for frozen sections, four freezing methods and four fixation methods. For paraffin sections, optimal fixation was achieved by increasing threefold the fixative volume recommended by Bell and Lightner, from 10% to 30% of the shrimp body weight, combined with single injection into the HP. Optimal fixation for frozen sections was achieved by freezing the cephalothorax with liquid nitrogen, followed by fixation of the section with 60% isopropanol. These optimized methods enable the future use of image analysis and improve classical histology. PMID- 27455456 TI - Effect of Prescription Drug Coupons on Statin Utilization and Expenditures: A Retrospective Cohort Study. AB - IMPORTANCE: Drug coupons are widely used, but their effects are not well understood. OBJECTIVE: To quantify the effect of coupons on statin use and expenditures. DESIGN: Retrospective cohort analysis of IMS Health LRx LifeLink database. SETTING: U.S. retail pharmacy transactions. PARTICIPANTS: Incident statin users who initiated branded atorvastatin or rosuvastatin between June 2006 and February 2013. MAIN OUTCOMES AND MEASURES: Monthly statin utilization (pill days of therapy), switching (filling a different statin), termination (failure to refill statin for 6 mo), and out-of-pocket and total costs. RESULTS: Of 1.1 million incident atorvastatin and rosuvastatin users, 2% used a coupon for at least one statin fill. At 1 year, compared with noncoupon users, those who used a statin coupon on their first fill were dispensed an equal number of monthly pill days (23.7 vs 23.8), were less likely to switch statins (14.4% vs 16.3%), and were less likely to have terminated statin therapy (31.3% vs 39.2%). At 4 years, coupon users were more likely to have switched (45.5% vs 40.8%) and less likely to have terminated statin therapy (50.6% vs 61.1%) compared with noncoupon users. Those who used greater numbers of coupons were substantially less likely to switch and terminate statin therapies. Monthly out-of-pocket costs were lower among coupon than noncoupon users at 1 year ($9.7 vs $15.1), but total monthly costs were qualitatively similar ($115.5 vs $116.9). At 4 years, monthly out-of pocket costs among coupon users remained lower ($14.3 vs $16.6) compared with noncoupon users. Sensitivity analyses supported the main results. CONCLUSIONS: Coupons for branded statins are associated with higher utilization and lower rates of discontinuation and short-term switching to other statin products. PMID- 27455457 TI - Self-reported cochlear implant management skills: development and validation of the self-administered Cochlear Implant Management Skills (CIMS-self) survey. AB - OBJECTIVE: A self-administered device management survey was developed and validated to investigate the ability of cochlear implant recipients to self report physical handling and care for their hearing implant device(s) and to identify factors that may influence self-reported management skills. DESIGN: Survey development and validation. A prospective convenience cohort design study. SETTING: Specialist hearing implant clinic. PARTICIPANTS: Forty-nine post lingually hearing impaired, adult cochlear implant recipients, at least 12 months postoperative. MAIN OUTCOME MEASURES: Survey test-retest reliability, responsiveness, criterion validity and sensitivity and specificity compared to clinician evaluation of device management skills. Correlations between self reported management skills and participant demographic, audiometric, cognitive function, clinical outcomes and device factors. RESULTS: The self-administered Cochlear Implant Management Skills survey was developed, demonstrating high test retest reliability (ICC = 0.884, P < 0.001; CI 95%: 0.721-0.952), responsiveness to intervention (management skills training) [t(20) = -3.245, P = 0.004], criterion validity (ICC = 0.765, P < 0.001; CI 95%: 0.584-0.868) and sensitivity (0.89). No associations were found between self-reported management skills and participant factors. CONCLUSIONS: This study demonstrated that a self-report survey is an effective method for the evaluation of skills required for cochlear implant device management. PMID- 27455458 TI - Extended surface for membrane association in Zika virus NS1 structure. AB - The Zika virus, which has been implicated in an increase in neonatal microcephaly and Guillain-Barre syndrome, has spread rapidly through tropical regions of the world. The virulence protein NS1 functions in genome replication and host immune system modulation. Here, we report the crystal structure of full-length Zika virus NS1, revealing an elongated hydrophobic surface for membrane association and a polar surface that varies substantially among flaviviruses. PMID- 27455460 TI - Structural basis of Cas3 inhibition by the bacteriophage protein AcrF3. AB - Bacteriophages express proteins that inactivate the CRISPR-Cas bacterial immune system. Here we report the crystal structure of the anti-CRISPR protein AcrF3 in complex with Pseudomonas aeruginosa Cas3 (PaCas3). AcrF3 forms a homodimer that locks PaCas3 in an ADP-bound form, blocks the entrance of the DNA-binding tunnel in the helicase domain, and masks the linker region and C-terminal domain of PaCas3, thereby preventing recruitment by Cascade and inhibiting the type I-F CRISPR-Cas system. PMID- 27455459 TI - Structural basis for tRNA modification by Elp3 from Dehalococcoides mccartyi. AB - During translation elongation, decoding is based on the recognition of codons by corresponding tRNA anticodon triplets. Molecular mechanisms that regulate global protein synthesis via specific base modifications in tRNA anticodons are receiving increasing attention. The conserved eukaryotic Elongator complex specifically modifies uridines located in the wobble base position of tRNAs. Mutations in Elongator subunits are associated with certain neurodegenerative diseases and cancer. Here we present the crystal structure of D. mccartyi Elp3 (DmcElp3) at 2.15-A resolution. Our results reveal an unexpected arrangement of Elp3 lysine acetyltransferase (KAT) and radical S-adenosyl methionine (SAM) domains, which share a large interface and form a composite active site and tRNA binding pocket, with an iron-sulfur cluster located in the dimerization interface of two DmcElp3 molecules. Structure-guided mutagenesis studies of yeast Elp3 confirmed the relevance of our findings for eukaryotic Elp3s and should aid in understanding the cellular functions and pathophysiological roles of Elongator. PMID- 27455462 TI - Phylogenetic plasticity in the evolution of molluscan neural circuits. AB - Recent research on molluscan nervous systems provides a unique perspective on the evolution of neural circuits. Molluscs evolved large, encephalized nervous systems independently from other phyla. Homologous body-patterning genes were re specified in molluscs to create a plethora of body plans and nervous system organizations. Octopuses, having the largest brains of any invertebrate, independently evolved a learning circuit similar in organization and function to the mushroom body of insects and the hippocampus of mammals. In gastropods, homologous neurons have been re-specified for different functions. Even species exhibiting similar, possibly homologous behavior have fundamental differences in the connectivity of the neurons underlying that behavior. Thus, molluscan nervous systems provide clear examples of re-purposing of homologous genes and neurons for neural circuits. PMID- 27455463 TI - Choosing Our Words Wisely. PMID- 27455461 TI - Skp is a multivalent chaperone of outer-membrane proteins. AB - The trimeric chaperone Skp sequesters outer-membrane proteins (OMPs) within a hydrophobic cage, thereby preventing their aggregation during transport across the periplasm in Gram-negative bacteria. Here, we studied the interaction between Escherichia coli Skp and five OMPs of varying size. Investigations of the kinetics of OMP folding revealed that higher Skp/OMP ratios are required to prevent the folding of 16-stranded OMPs compared with their 8-stranded counterparts. Ion mobility spectrometry-mass spectrometry (IMS-MS) data, computer modeling and molecular dynamics simulations provided evidence that 10- to 16 stranded OMPs are encapsulated within an expanded Skp substrate cage. For OMPs that cannot be fully accommodated in the expanded cavity, sequestration is achieved by binding of an additional Skp trimer. The results suggest a new mechanism for Skp chaperone activity involving the coordination of multiple copies of Skp in protecting a single substrate from aggregation. PMID- 27455464 TI - Carbon- and crack-free growth of hexagonal boron nitride nanosheets and their uncommon stacking order. AB - The quality of hexagonal boron nitride nanosheets (h-BNNS) is often associated with the most visible aspects such as lateral size and thickness. Less obvious factors such as sheet stacking order could also have a dramatic impact on the properties of BNNS and therefore its applications. The stacking order can be affected by contamination, cracks, and growth temperatures. In view of the significance of chemical-vapour-decomposition (CVD) assisted growth of BNNS, this paper reports on strategies to grow carbon- and crack-free BNNS by CVD and describes the stacking order of the resultant BNNS. Pretreatment of the most commonly used precursor, ammonia borane, is necessary to remove carbon contamination caused by residual hydrocarbons. Flattening the Cu and W substrates prior to growth and slow cooling around the Cu melting point effectively facilitate the uniform growth of h-BNNS, as a result of a minimal temperature gradient across the Cu substrate. Confining the growth inside alumina boats effectively minimizes etching of the nanosheet by silica nanoparticles originating from the commonly used quartz reactor tube. h-BNNS grown on solid Cu surfaces using this method adopt AB, ABA, AC', and AC'B stacking orders, which are known to have higher energies than the most stable AA' configuration. These findings identify a pathway for the fabrication of high-quality h-BNNS via CVD and should spur studies on stacking order-dependent properties of h-BNNS. PMID- 27455465 TI - Drosophila hematopoiesis under normal conditions and in response to immune stress. AB - The emergence of hematopoietic progenitors and their differentiation into various highly specialized blood cell types constitute a finely tuned process. Unveiling the genetic cascades that control blood cell progenitor fate and understanding how they are modulated in response to environmental changes are two major challenges in the field of hematopoiesis. In the last 20 years, many studies have established important functional analogies between blood cell development in vertebrates and in the fruit fly, Drosophila melanogaster. Thereby, Drosophila has emerged as a powerful genetic model for studying mechanisms that control hematopoiesis during normal development or in pathological situations. Moreover, recent advances in Drosophila have highlighted how intricate cell communication networks and microenvironmental cues regulate blood cell homeostasis. They have also revealed the striking plasticity of Drosophila mature blood cells and the presence of different sites of hematopoiesis in the larva. This review provides an overview of Drosophila hematopoiesis during development and summarizes our current knowledge on the molecular processes controlling larval hematopoiesis, both under normal conditions and in response to an immune challenge, such as wasp parasitism. PMID- 27455466 TI - Integrating environmental and self-report data to refine cannabis prevalence estimates in a major urban area of Switzerland. AB - BACKGROUND: Cannabis consumption is a topical subject because of discussions about reviewing current regulations. In this context, having a more comprehensive approach to assess and monitor prevalence and consumption is highly relevant. The objective of this work was to refine current estimates about prevalence of cannabis use by combining self-report data and results derived from wastewater analysis. METHODS: Self-report data was retrieved from surveys conducted in Switzerland and Europe. Wastewater samples were collected at the wastewater treatment plant of Lausanne, western Switzerland, over a 15 months period. The occurrence of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH), a specific metabolite of delta-9-tetrahydrocannabinol (THC), was monitored. Bayesian hierarchical models were used to estimate consumption, prevalence and number of cannabis users in the investigated area. RESULTS: According to survey data, 12-months prevalence in western Switzerland was estimated to 6.2% of the population aged 15 or older, with an estimated daily cannabis consumption of 8.1gday(-1).1000inhab(-1) (at 11.2% purity). The integrative model comprising self-report and wastewater data substantially reduced the uncertainty in the estimates and suggested a last-year prevalence of 9.4%, with a daily cannabis consumption of 14.0gday(-1).1000inhab(-1). CONCLUSION: Although in the same order of magnitude, consumption and prevalence estimates obtained with the integrative model were 78% and 52% higher compared to self-report figures, respectively. Interestingly, these figures are similar to discrepancies observed when comparing self-reported alcohol consumption and sales or tax data. The suggested integrative model allowed to account for known sources of uncertainty and provided refined estimates of cannabis prevalence in a major urban area of Switzerland. PMID- 27455467 TI - Realising the technological promise of smartphones in addiction research and treatment: An ethical review. AB - BACKGROUND: Smartphone technologies and mHealth applications (or apps) promise unprecedented scope for data collection, treatment intervention, and relapse prevention when used in the field of substance abuse and addiction. This potential also raises new ethical challenges that researchers, clinicians, and software developers must address. AIMS: This paper aims to identify ethical issues in the current uses of smartphones in addiction research and treatment. METHODS: A search of three databases (PubMed, Web of Science and PsycInfo) identified 33 studies involving smartphones or mHealth applications for use in the research and treatment of substance abuse and addiction. A content analysis was conducted to identify how smartphones are being used in these fields and to highlight the ethical issues raised by these studies. RESULTS: Smartphones are being used to collect large amounts of sensitive information, including personal information, geo-location, physiological activity, self-reports of mood and cravings, and the consumption of illicit drugs, alcohol and nicotine. Given that detailed information is being collected about potentially illegal behaviour, we identified the following ethical considerations: protecting user privacy, maximising equity in access, ensuring informed consent, providing participants with adequate clinical resources, communicating clinically relevant results to individuals, and the urgent need to demonstrate evidence of safety and efficacy of the technologies. CONCLUSIONS: mHealth technology offers the possibility to collect large amounts of valuable personal information that may enhance research and treatment of substance abuse and addiction. To realise this potential researchers, clinicians and app-developers must address these ethical concerns to maximise the benefits and minimise risks of harm to users. PMID- 27455468 TI - Atypical presentation of ocular decompression retinopathy following trabeculectomy. PMID- 27455469 TI - Medical Improv: A Novel Approach to Teaching Communication and Professionalism Skills. PMID- 27455470 TI - Two-year experience with the commercial Gamma Knife Check software. AB - The Gamma Knife Check software is an FDA approved second check system for dose calculations in Gamma Knife radiosurgery. The purpose of this study was to evaluate the accuracy and the stability of the commercial software package as a tool for independent dose verification. The Gamma Knife Check software version 8.4 was commissioned for a Leksell Gamma Knife Perfexion and a 4C unit at the University of Pittsburgh Medical Center in May 2012. Independent dose verifications were performed using this software for 319 radiosurgery cases on the Perfexion and 283 radiosurgery cases on the 4C units. The cases on each machine were divided into groups according to their diagnoses, and an averaged absolute percent dose difference for each group was calculated. The percentage dose difference for each treatment target was obtained as the relative difference between the Gamma Knife Check dose and the dose from the tissue maximum ratio algorithm (TMR 10) from the GammaPlan software version 10 at the reference point. For treatment plans with imaging skull definition, results obtained from the Gamma Knife Check software using the measurement-based skull definition method are used for comparison. The collected dose difference data were also analyzed in terms of the distance from the treatment target to the skull, the number of treatment shots used for the target, and the gamma angles of the treatment shots. The averaged percent dose differences between the Gamma Knife Check software and the GammaPlan treatment planning system are 0.3%, 0.89%, 1.24%, 1.09%, 0.83%, 0.55%, 0.33%, and 1.49% for the trigeminal neuralgia, acoustic neuroma, arteriovenous malformation (AVM), meningioma, pituitary adenoma, glioma, functional disorders, and metastasis cases on the Perfexion unit. The corresponding averaged percent dose differences for the 4C unit are 0.33%, 1.2%, 2.78% 1.99%, 1.4%, 1.92%, 0.62%, and 1.51%, respectively. The dose difference is, in general, larger for treatment targets in the peripheral regions of the skull owing to the difference in the numerical methods used for skull shape simulation in the GammaPlan and the Gamma Knife Check software. Larger than 5% dose differences were observed on both machines for certain targets close to patient skull surface and for certain targets in the lower half of the brain on the Perfexion, especially when shots with 70 and/or 110 gamma angles are used. Out of the 1065 treatment targets studied, a 5% cutoff criterion cannot always be met for the dose differences between the studied versions of the Gamma Knife Check software and the planning system for 40 treatment targets. PMID- 27455471 TI - Fricke gel dosimeter with improved sensitivity for low-dose-level measurements. AB - Fricke solution has a wide range of applications as radiation detector and dosimetry. It is particularly appreciated in terms of relevant comparative advantages, like tissue-equivalence when prepared in aqueous media like gel matrix, continuous mapping capability, independence of dose rate and incident direction, as well as linear dose response. This work presents the development and characterization of an improved Fricke gel system, based on modified chemical compositions, making possible its application in clinical radiology due to its improved sensitivity. Properties of standard Fricke gel dosimeter for high-dose levels are used as a starting point, and suitable chemical modifications are introduced and carefully investigated in order to attain high resolution for low dose ranges, like those corresponding to radiology interventions. The developed Fricke gel radiation dosimeter system achieves the expected typical dose dependency, showing linear response in the dose range from 20 up to 4000 mGy. Systematic investigations including several chemical compositions are carried out in order to obtain an adequate dosimeter response for low-dose levels. A suitable composition from among those studied is selected as a good candidate for low-dose level radiation dosimetry consisting of a modified Fricke solution fixed to a gel matrix containing benzoic acid along with sulfuric acid, ferrous sulfate, Xylenol orange, and tridistilled water. Dosimeter samples are prepared in standard vials for in-phantom irradiation and further characterization by spectrophotometry measuring visible light transmission and absorbance before and after irradiation. Samples are irradiated using typical X-ray tubes for radiology and calibrated Farmer-type ionization chamber is used as reference to measure dose rates inside phantoms at vial locations. Once sensitive material composition is optimized, dose-response curves show significant improvement regarding overall sensitivity for low dose levels. The aim of this work consists of implementing the optimized gel dosimeter to perform direct measurements of absorbed dose in samples irradiated during microcomputed tomography scanning in order to preliminary assess dose levels for further scanning of small animals for further applications in veterinary and paleontology. As a first attempt, dose distributions were measured in water-equivalent phantoms having dimensions comparable to small animals, 100 to 1000 cm3, approximately. According to the obtained results, it is found that the proposed method shows satisfactory reliability and adequate performance for a promising gel dosimetry system. PMID- 27455472 TI - A comparative study based on image quality and clinical task performance for CT reconstruction algorithms in radiotherapy. AB - CT image reconstruction is typically evaluated based on the ability to reduce the radiation dose to as-low-as-reasonably-achievable (ALARA) while maintaining acceptable image quality. However, the determination of common image quality metrics, such as noise, contrast, and contrast-to-noise ratio, is often insufficient for describing clinical radiotherapy task performance. In this study we designed and implemented a new comparative analysis method associating image quality, radiation dose, and patient size with radiotherapy task performance, with the purpose of guiding the clinical radiotherapy usage of CT reconstruction algorithms. The iDose4 iterative reconstruction algorithm was selected as the target for comparison, wherein filtered back-projection (FBP) reconstruction was regarded as the baseline. Both phantom and patient images were analyzed. A layer adjustable anthropomorphic pelvis phantom capable of mimicking 38-58 cm lateral diameter-sized patients was imaged and reconstructed by the FBP and iDose4 algorithms with varying noise-reduction-levels, respectively. The resulting image sets were quantitatively assessed by two image quality indices, noise and contrast-to-noise ratio, and two clinical task-based indices, target CT Hounsfield number (for electron density determination) and structure contouring accuracy (for dose-volume calculations). Additionally, CT images of 34 patients reconstructed with iDose4 with six noise reduction levels were qualitatively evaluated by two radiation oncologists using a five-point scoring mechanism. For the phantom experiments, iDose4 achieved noise reduction up to 66.1% and CNR improvement up to 53.2%, compared to FBP without considering the changes of spatial resolution among images and the clinical acceptance of reconstructed images. Such improvements consistently appeared across different iDose4 noise reduction levels, exhibiting limited interlevel noise (< 5 HU) and target CT number variations (< 1 HU). The radiation dose required to achieve similar contouring accuracy decreased when using iDose4 in place of FBP, up to 32%. Contouring accuracy improvement for iDose4 images, when compared to FBP, was greater in larger patients than smaller-sized patients. Overall, the iDose4 algorithm provided superior radiation dose control while maintaining or improving task performance, when compared to FBP. The reader study on image quality improvement of patient cases shows that physicians preferred iDose4-reconstructed images on all cases compared to those from FBP algorithm with overall quality score: 1.21 vs. 3.15, p = 0.0022. However, qualitative evaluation strongly indicated that the radiation oncologists chose iDose4 noise reduction levels of 3 4 with additional consideration of task performance, instead of image quality metrics alone. Although higher iDose4 noise reduction levels improved the CNR through the further reduction of noise, there was pixelization of anatomical/tumor structures. Very-low-dose scans yielded severe photon starvation artifacts, which decreased target visualization on both FBP and iDose4 reconstructions, especially for the 58 cm phantom size. The iDose4 algorithm with a moderate noise reduction level is hence suggested for CT simulation and treatment planning. Quantitative task-based image quality metrics should be further investigated to accommodate additional clinical applications. PMID- 27455473 TI - A report from the AAPM Subcommittee on Guidelines for Competency Evaluation for Clinical Medical Physicists in Radiation Oncology. AB - The goal of this report is to provide a framework from which an institution can develop a competency and credentialing program. It is not intended to be adopted as written, but rather as a list of suggestions from which the institution develops their program. A clear distinction should be made between the initial evaluation of the competency of new staff (credentialing) and the ongoing verification of the competency of existing staff. Furthermore, whenever new technologies are imple-mented, the entire staff would be subject to the credentialing process. Competencies involve the ongoing verification of the performance of a procedure according to the established policies and procedures at a facility. This can be done by audits of work product, direct observation of performance, self-evaluation, or testing. PACS number(s): 87.10.-e, 87.90.+y PMID- 27455474 TI - Biplane interventional pediatric system with cone-beam CT: dose and image quality characterization for the default protocols. AB - The aim of this study was to assess image quality and radiation dose of a biplane angiographic system with cone-beam CT (CBCT) capability tuned for pediatric cardiac procedures. The results of this study can be used to explore dose reduction techniques. For pulsed fluoroscopy and cine modes, polymethyl methacrylate phantoms of various thicknesses and a Leeds TOR 18-FG test object were employed. Various fields of view (FOV) were selected. For CBCT, the study employed head and body dose phantoms, Catphan 504, and an anthropomorphic cardiology phantom. The study also compared two 3D rotational angiography protocols. The entrance surface air kerma per frame increases by a factor of 3-12 when comparing cine and fluoroscopy frames. The biggest difference in the signal to- noise ratio between fluoroscopy and cine modes occurs at FOV 32 cm because fluoroscopy is acquired at a 1440 * 1440 pixel matrix size and in unbinned mode, whereas cine is acquired at 720 * 720 pixels and in binned mode. The high contrast spatial resolution of cine is better than that of fluoroscopy, except for FOV 32 cm, because fluoroscopy mode with 32 cm FOV is unbinned. Acquiring CBCT series with a 16 cm head phantom using the standard dose protocol results in a threefold dose increase compared with the low-dose protocol. Although the amount of noise present in the images acquired with the low-dose protocol is much higher than that obtained with the standard mode, the images present better spatial resolution. A 1 mm diameter rod with 250 Hounsfield units can be distinguished in reconstructed images with an 8 mm slice width. Pediatric specific protocols provide lower doses while maintaining sufficient image quality. The system offers a novel 3D imaging mode. The acquisition of CBCT images results in increased doses administered to the patients, but also provides further diagnostic information contained in the volumetric images. The assessed CBCT protocols provide images that are noisy, but with very good spatial resolution. PMID- 27455475 TI - Effective method of measuring the radioactivity of [ 131I]-capsule prior to radioiodine therapy with significant reduction of the radiation exposure to the medical staff. AB - Radiation Protection in Radiology, Nuclear Medicine and Radio Oncology is of the utmost importance. Radioiodine therapy is a frequently used and effective method for the treatment of thyroid disease. Prior to each therapy the radioactivity of the [131I]-capsule must be determined to prevent misadministration. This leads to a significant radiation exposure to the staff. We describe an alternative method, allowing a considerable reduction of the radiation exposure. Two [131I]-capsules (A01 = 2818.5; A02 = 7355.0 MBq) were measured multiple times in their own delivery lead containers - that is to say, [131I]-capsules remain inside the containers during the measurements (shielded measurement) using a dose calibrator and a well-type and a thyroid uptake probe. The results of the shielded measurements were correlated linearly with the [131I]-capsules radioactivity to create calibration curves for the used devices. Additional radioactivity measurements of 50 [131I]-capsules of different radioactivities were done to validate the shielded measuring method. The personal skin dose rate (HP(0.07)) was determined using calibrated thermo luminescent dosimeters. The determination coefficients for the calibration curves were R2 > 0.9980 for all devices. The relative uncertainty of the shielded measurement was < 6.8%. At a distance of 10 cm from the unshielded capsule the HP(0.07) was 46.18 MUSv/(GBq*s), and on the surface of the lead container containing the [131I]-capsule the HP(0.07) was 2.99 and 0.27 MUSv/(GBq*s) for the two used container sizes. The calculated reduction of the effective dose by using the shielded measuring method was, depending on the used container size, 74.0% and 97.4%, compared to the measurement of the unshielded [131I]-capsule using a dose calibrator. The measured reduction of the effective radiation dose in the practice was 56.6% and 94.9 for size I and size II containers. The shielded [131I]-capsule measurement reduces the radiation exposure to the staff significantly and offers the same accuracy of the unshielded measurement in the same amount of time. In order to maintain the consistency of the measuring method, monthly tests have to be done by measuring a [131I]-capsule with known radioactivity. PMID- 27455476 TI - Effect of the normalized prescription isodose line on the magnitude of Monte Carlo vs. pencil beam target dose differences for lung stereotactic body radiotherapy. AB - In lung stereotactic body radiotherapy (SBRT) cases, the pencil beam (PB) dose calculation algorithm is known to overestimate target dose as compared to the more accurate Monte Carlo (MC) algorithm. We investigated whether changing the normalized prescription isodose line affected the magnitude of MC vs. PB target dose differences. Forty-eight patient plans and twenty virtual-tumor phantom plans were studied. For patient plans, four alternative plans prescribed to 60%, 70%, 80%, and 90% isodose lines were each created for 12 patients who previously received lung SBRT treatments. Using 6 MV dynamic conformal arcs, the plans were individually optimized to achieve similar dose coverage and conformity for all plans of the same patient, albeit at the different prescription levels. These plans, having used a PB algorithm, were all recalculated with MC to compare the target dose differences. The relative MC vs. PB target dose variations were investigated by comparing PTV D95, Dmean, and D5 loss at the four prescription levels. The MC-to-PB ratio of the plan heterogeneity index (HI) was also evaluated and compared among different isodose levels. To definitively demonstrate the cause of the isodose line dependence, a simulated phantom study was conducted using simple, spherical virtual tumors planned with uniform block margins. The tumor size and beam energy were also altered in the phantom study to investigate the interplay between these confounding factors and the isodose line effect. The magnitude of the target dose overestimation by PB was greater for higher prescription isodose levels. The MC vs. PB reduction in the target dose coverage indices, D95 and V100 of PTV, were found to monotonically increase with increasing isodose lines from 60% to 90%, resulting in more pronounced target dose coverage deficiency at higher isodose prescription levels. No isodose level dependent trend was observed for the dose errors in the target mean or high dose indices, Dmean or D5. The phantom study demonstrated that the observed isodose level dependence was caused by different beam margins used for the different isodose levels: a higher prescription line required a larger beam margin, leading to more low-density lung tissues in the field and, therefore, larger dose errors at the target periphery (when calculated with PB). The phantom study also found that the observed isodose level dependence was greater for smaller targets and for higher beam energies. We hereby characterized the effect of normalized prescription isodose line on magnitude of PTV dose coverage as calculated by MC vs. PB. When comparing reported MC dose deficiency values for different patients, the selection of prescription isodose line should be considered in addition to other factors known to affect differences in calculated doses between various algorithms. PMID- 27455477 TI - Experimental validation of a kV source model and dose computation method for CBCT imaging in an anthropomorphic phantom. AB - We present an experimental validation of a kilovoltage (kV) X-ray source characterization model in an anthropomorphic phantom to estimate patient-specific absorbed dose from kV cone-beam computed tomography (CBCT) imaging procedures and compare these doses to nominal weighted CT-dose index (CTDIw) dose estimates. We simulated the default Varian on-board imager 1.4 (OBI) default CBCT imaging protocols (i.e., standard-dose head, low-dose thorax, pelvis, and pelvis spotlight) using our previously developed and easy to implement X-ray point source model and source characterization approach. We used this characterized source model to compute absorbed dose in homogeneous and anthropomorphic phantoms using our previously validated in-house kV dose computation software (kVDoseCalc). We compared these computed absorbed doses to doses derived from ionization chamber measurements acquired at several points in a homogeneous cylindrical phantom and from thermoluminescent detectors (TLDs) placed in the anthropomorphic phantom. In the homogeneous cylindrical phantom, computed values of absorbed dose relative to the center of the phantom agreed with measured values within <=2% of local dose, except in regions of high-dose gradient where the distance to agreement (DTA) was 2 mm. The computed absorbed dose in the anthropomorphic phantom generally agreed with TLD measurements, with an average percent dose difference ranging from 2.4% +/- 6.0% to 5.7% +/- 10.3%, depending on the characterized CBCT imaging protocol. The low-dose thorax and the standard dose scans showed the best and worst agreement, respectively. Our results also broadly agree with published values, which are approximately twice as high as the nominal CTDIw would suggest. The results demonstrate that our previously developed method for modeling and characterizing a kV X-ray source could be used to accurately assess patient-specific absorbed dose from kV CBCT procedures within reasonable accuracy, and serve as further evidence that existing CTDIw assessments underestimate absorbed dose delivered to patients. PMID- 27455478 TI - An energy minimization method for the correction of cupping artifacts in cone beam CT. AB - The purpose of this study was to reduce cupping artifacts and improve quantitative accuracy of the images in cone-beam CT (CBCT). An energy minimization method (EMM) is proposed to reduce cupping artifacts in reconstructed image of the CBCT. The cupping artifacts are iteratively optimized by using efficient matrix computations, which are verified to be numerically stable by matrix analysis. Moreover, the energy in our formulation is convex in each of its variables, which brings the robustness of the proposed energy minimization algorithm. The cupping artifacts are estimated as a result of minimizing this energy. The results indicate that proposed algorithm is effective for reducing the cupping artifacts and preserving the quality of the reconstructed image. The proposed method focuses on the reconstructed image without requiring any additional physical equipment; it is easily implemented and provides cupping correction using a single scan acquisition. The experimental results demonstrate that this method can successfully reduce the magnitude of cupping artifacts. The correction algorithm reported here may improve the uniformity of the reconstructed images, thus assisting the development of perfect volume visualization and threshold-based visualization techniques for reconstructed images. PMID- 27455479 TI - A novel arc geometry setting for pelvic radiotherapy with extensive nodal involvement. AB - The aim of this study was to find optimal planning approach for large planning targets with complicated geometry requiring wide field openings. The study presents a novel approach for arc geometry design for pelvic targets with extensive nodal involvement. A total of 15 patients with anorectal carcinoma or vulvar cancer were selected retrospectively. For each patient, one seven-field IMRT plan and three VMAT plans were calculated: one with two 360 degrees arcs with no limitations for the field size (VMATw); one with two asymmetrically field size-restricted 360 degrees arcs (VMATr); and the proposed novel approach which consisted of one 360 degrees arc with the field size restricted to the central PTV, and another arc divided into two 180 degrees arcs, restricting the field sizes with the focus on the lymph nodes. The techniques were compared in terms of PTV coverage (VPTV(95%)), dose maximum (D(max)), dose conformity index (CI), homogeneity index (HI), and organs at risk doses. The proposed novel approach with one full and two half arcs tended to have better PTV coverage (VPTV(95%) = 97% +/- 2%, compared to 95% +/- 3%, 95% +/- 3%, and 97% +/- 2% in VMATw, VMATr, and 7f-IMRT, respectively) and lower maxima (D(max) = 107% +/- 1%, compared to 110% +/- 3%, 110% +/- 4%, and 110% +/- 4% in VMATw, VMATr, and 7f-IMRT, respectively); and lower or equal organs at risk doses. The superiority of the proposed technique (CI = 1.16 +/- 0.05, HI = 9 +/- 2) was more pronounced compared with the VMATw plans (CI = 1.41 +/- 0.10, paired t-test p < 0.001; HI = 12 +/- 2, p < 0.001), but the proposed technique was slightly better also in comparison with the VMATr plans (CI = 1.21 +/- 0.07, p < 0.001; HI= 11 +/- 4, p = 0.015) and 7f-IMRT plans (CI = 1.18 +/- 0.03, p = 0.016; HI = 10 +/- 2, p = 0.215). Radiotherapy treatment planning for large and complicated treatment volumes benefits not only from restricting the field size but also from careful field design that considers PTV geometry. This optimizes multileaf collimator movements, leading to better dose conformity and homogeneity. PMID- 27455480 TI - The feasibility of atlas-based automatic segmentation of MRI for H&N radiotherapy planning. AB - Atlas-based autosegmentation is an established tool for segmenting structures for CT-planned head and neck radiotherapy. MRI is being increasingly integrated into the planning process. The aim of this study is to assess the feasibility of MRI based, atlas-based autosegmentation for organs at risk (OAR) and lymph node levels, and to compare the segmentation accuracy with CT-based autosegmentation. Fourteen patients with locally advanced head and neck cancer in a prospective imaging study underwent a T1-weighted MRI and a PET-CT (with dedicated contrast enhanced CT) in an immobilization mask. Organs at risk (orbits, parotids, brainstem, and spinal cord) and the left level II lymph node region were manually delineated on the CT and MRI separately. A 'leave one out' approach was used to automatically segment structures onto the remaining images separately for CT and MRI. Contour comparison was performed using multiple positional metrics: Dice index, mean distance to conformity (MDC), sensitivity index (Se Idx), and inclusion index (Incl Idx). Automatic segmentation using MRI of orbits, parotids, brainstem, and lymph node level was acceptable with a DICE coefficient of 0.73 0.91, MDC 2.0-5.1mm, Se Idx 0.64-0.93, Incl Idx 0.76-0.93. Segmentation of the spinal cord was poor (Dice coefficient 0.37). The process of automatic segmentation was significantly better on MRI compared to CT for orbits, parotid glands, brainstem, and left lymph node level II by multiple positional metrics; spinal cord segmentation based on MRI was inferior compared with CT. Accurate atlas-based automatic segmentation of OAR and lymph node levels is feasible using T1-MRI; segmentation of the spinal cord was found to be poor. Comparison with CT based automatic segmentation suggests that the process is equally as, or more accurate, using MRI. These results support further translation of MRI-based segmentation methodology into clinicalpractice. PMID- 27455481 TI - Analysis of setup error based on CTVision for nasopharyngeal carcinoma during IGRT. AB - The aim of the present study was to investigate the role of CTVision in interfractional setup errors during intensity-modulated radiation therapy (IMRT) in 12 nasopharyngeal carcinoma (NPC) patients. The trend of setup errors as a function of time during a fractionated radiotherapy course was investigated, and the influence of reconstructive thickness on image reconstruction for setup errors was analyzed. The appropriate planning target volume (PTV) margin and planning risk volume (PRV) margin were defined to provide a reference for the design of IMRT for NPC. Based on CTVision, online CT was performed weekly for each patient. Setup errors were measured by registration between the CT reconstructed image and reference image. Mean of setup errors, estimated population systematic (Sigma), and population random (sigma) errors were calculated using SPSS (v15.0). Optimum PTV and PRV margins were calculated. In the clinical data, for the LR (left-right), SI (superior-inferior), and AP (anterior-posterior) directions, Sigma was 0.8, 0.8, and 1.0 mm, respectively, and sigma was 1.0, 1.3, and 0.8 mm, respectively. In the LR, SI, and AP directions, PTV margins were at least 2.7, 2.9, and 3.0 mm, respectively, and PRV margins were at least 1.5, 1.7, and 1.7 mm, respectively. No significant differences in setup errors were observed during the fractionated radiotherapy course (p > 0.05). However, CT image reconstruction with different thicknesses affected the accuracy of measurements for setup errors, particularly in the SI direction. The application of CTVision to correct setup errors is important and can provide reasonable margins to guarantee the coverage of PTVs and spare organs at risk. A thickness of 3 mm in the reconstructed image is appropriate for the measurement of setup errors by image registration. PMID- 27455482 TI - The step-and-shoot IMRT overshooting phenomenon: a novel method to mitigate patient overdosage. AB - The goal of this work is to evaluate the dosimetric impact of an overshooting phenomenon in step-and-shoot IMRT delivery, and to demonstrate a novel method to mitigate the issue. Five pelvis IMRT patients treated on Varian 2100C EX linacs with larger than +4.5% phantom ion chamber point-dose difference relative to planned dose were investigated. For each patient plan, 5 fractions were delivered. DynaLog files were recorded and centi-MU pulses from dose integrator board for every control point (CP) were counted using a commercial pulse counter. The counter recorded CP MU agrees with DynaLog records, both showing an ~ 0.6MU overshoot of the first segment of every beam. The 3D patient dose was recalculated from the counter records and compared to the planned dose, showing that the overshoot resulted in on average 2.05% of PTV D95 error, and 2.49%, 2.61% and 2.45% of D1cc error for rectum, bladder, and bowel, respectively. The initial plans were then modified by inserting a specially designed MLC segment to the start of every beam. The modified plans were also delivered five times. The dose from the modified delivery was calculated using counter recorded CP MU. The corresponding Dx parameters were all within 0.31% from the original plan. IMRT QA results also show a 2.2% improvement in ion chamber point-dose agreement. The results demonstrate that the proposed plan modification method effectively eliminates the overdosage from the overshooting phenomenon. PMID- 27455483 TI - Evaluation of a combined respiratory-gating system comprising the TrueBeam linear accelerator and a new real-time tumor-tracking radiotherapy system: a preliminary study. AB - A combined system comprising the TrueBeam linear accelerator and a new real-time, tumor-tracking radiotherapy system, SyncTraX, was installed in our institution. The goals of this study were to assess the capability of SyncTraX in measuring the position of a fiducial marker using color fluoroscopic images, and to evaluate the dosimetric and geometric accuracy of respiratory-gated radiotherapy using this combined system for the simple geometry. For the fundamental evaluation of respiratory-gated radiotherapy using SyncTraX, the following were performed:1) determination of dosimetric and positional characteristics of sinusoidal patterns using a motor-driven base for several gating windows; 2) measurement of time delay using an oscilloscope; 3) positional verification of sinusoidal patterns and the pattern in the case of a lung cancer patient; 4) measurement of the half-value layer (HVL in mm AL), effective kVp, and air kerma, using a solid-state detector for each fluoroscopic condition, to determine the patient dose. The dose profile in a moving phantom with gated radiotherapy having a gating window <= 4 mm was in good agreement with that under static conditions for each photon beam. The total time delay between TrueBeam and SyncTraX was < 227 ms for each photon beam. The mean of the positional tracking error was < 0.4 mm for sinusoidal patterns and for the pattern in the case of a lung cancer patient. The air-kerma rates from one fluoroscopy direction were 1.93 +/- 0.01, 2.86 +/- 0.01, 3.92 +/- 0.04, 5.28 +/- 0.03, and 6.60 +/- 0.05 mGy/min for 70, 80, 90, 100, and 110 kV X-ray beams at 80 mA, respectively. The combined system comprising TrueBeam and SyncTraX could track the motion of the fiducial marker and control radiation delivery with reasonable accuracy; therefore, this system provides significant dosimetric improvement. However, patient exposure dose from fluoroscopy was not clinically negligible. PMID- 27455484 TI - Physically constrained voxel-based penalty adaptation for ultra-fast IMRT planning. AB - Conventional treatment planning in intensity-modulated radiation therapy (IMRT) is a trial-and-error process that usually involves tedious tweaking of optimization parameters. Here, we present an algorithm that automates part of this process, in particular the adaptation of voxel-based penalties within normal tissue. Thereby, the proposed algorithm explicitly considers a priori known physical limitations of photon irradiation. The efficacy of the developed algorithm is assessed during treatment planning studies comprising 16 prostate and 5 head and neck cases. We study the eradication of hot spots in the normal tissue, effects on target coverage and target conformity, as well as selected dose volume points for organs at risk. The potential of the proposed method to generate class solutions for the two indications is investigated. Run-times of the algorithms are reported. Physically constrained voxel-based penalty adaptation is an adequate means to automatically detect and eradicate hot-spots during IMRT planning while maintaining target coverage and conformity. Negative effects on organs at risk are comparably small and restricted to lower doses. Using physically constrained voxel-based penalty adaptation, it was possible to improve the generation of class solutions for both indications. Considering the reported run-times of less than 20 s, physically constrained voxel-based penalty adaptation has the potential to reduce the clinical workload during planning and automated treatment plan generation in the long run, facilitating adaptive radiation treatments. PMID- 27455485 TI - Monte Carlo calculations and experimental measurements of the TG-43U1-recommended dosimetric parameters of 125I (Model IR-Seed2) brachytherapy source. AB - A new design of 125I (Model IR-Seed2) brachytherapy source has been manufactured recently at the Applied Radiation Research School, Nuclear Science and Technology Research Institute in Iran. The source consists of six resin beads (0.5 mm diameter) that are sealed in a cylindrical titanium capsule of 0.7 mm internal and 0.8 mm external diameters. This work aims to evaluate the dosimetric parameters of the newly designed 125I source using experimental measurements and Monte Carlo (MC) simulations. Dosimetric characteristics (dose rate constant, radial dose function, and 2D and 1D anisotropy functions) of the IR-Seed2 were determined using experimental measurements and MC simulations following the recommendations by the Task Group 43 (TG-43U1) report of the American Association of Physicists in Medicine (AAPM). MC simulations were performed using the MCNP5 code in water and Plexiglas, and experimental measurements were carried out using thermoluminescent dosimeters (TLD-GR207A) in Plexiglas phantoms. The measured dose to water in Plexiglas data were used for verification of the accuracy of the source and phantom geometry in the Monte Carlo simulations. The final MC simulated data to water in water were recommended for clinical applications. The MC calculated dose rate constant (Lambda) of the IR-Seed2 125I seed in water was found to be 0.992 +/- 0.025 cGy h-1U-1. Additionally, its radial dose function by line and point source approximations, gL(r) and gp(r), calculated for distances from 0.1 cm to 7 cm. The values of gL(r) at radial distances from 0.5 cm to 5 cm were measured in a Plexiglas phantom to be between 1.212 and 0.413. The calculated and measured of values for 2D anisotropy function, F(r, theta), were obtained for the radial distances ranging from 1.5 cm to 5 cm and angular range of 0 degrees -90 degrees in a Plexiglas phantom. Also, the 2D anisotropy function was calculated in water for the clinical application. The results of these investigations show that the uncertainty of the experimental data is within +/- 7% between the measured and simulated data in Plexiglas. Based on these results, the MC-simulated dosimetric parameters of the new 125I source model in water are presented for its clinical applications in brachytherapy treatments. PMID- 27455486 TI - Clinical implications of the overshoot effect for treatment plan delivery and patient-specific quality assurance for step-and-shoot IMRT. AB - In this work, overshoot and undershoot effects associated with step-and-shoot IMRT (SSIMRT) delivery on a Varian Clinac 21iX are investigated, and their impact on patient-specific QA point dose measurements and treatment plan delivery are evaluated. Pinnacle3 SSIMRT plans consisting of 5, 10, and 15 identical 5 * 5 cm2 MLC defined segments and MU/segment values of 5 MU, 10 MU, and 20 MU were utilized and delivered at 600/300 MU/min. Independent of the number of segments the overshoot and undershoot at 600 MU/min were approximately +/- 10%, +/- 5%, and +/- 2.5% for 5 MU/segment, 10 MU/segment, and 20 MU/segment, respectively. At 300 MU/min, each of these values is approximately halved. Interfractional variation of these effects (10 fractions), as well as dosimetric variations for intermediate segments, are reduced at the lower dose rate. QA point-dose measurements for a sample (n = 29) of head and neck SSIMRT beams were on average 2.9% (600 MU/min) and 1.7% (300 MU/min) higher than Pinnacle3 planned doses. In comparison for prostate beams (n = 46), measured point doses were 0.8% (600 MU/min) and 0.4% (300 MU/min) higher. The reduction in planned-measured point dose discrepancies at 300 MU/min can be attributed in part to the inclusion of the first segment (overshoot) in the admixture of segments that deliver measured dose. Pinnacle3 plans for 10/9 head and neck/prostate treatments were adjusted by +/- 0.5 MU to include the effects of overshoot and undershoot at 600 MU/min. Comparing original and adjusted plans for each site indicated that the original plan was preferred in 70% and 89% of head and neck and prostate cases, respectively. The disparity between planned and delivered treatment that this suggests can potentially be mitigated by treating SSIMRT at a dose rate below 600 MU/min. PMID- 27455487 TI - On flattening filter-free portal dosimetry. AB - Varian introduced (in 2010) the option of removing the flattening filter (FF) in their C-Arm linacs for intensity-modulated treatments. This mode, called flattening filter-free (FFF), offers the advantage of a greater dose rate. Varian's "Portal Dosimetry" is an electronic portal imager device (EPID)-based tool for IMRT verification. This tool lacks the capability of verifying flattening filter-free (FFF) modes due to saturation and lack of an image prediction algorithm. (Note: the latest versions of this software and EPID correct these issues.) The objective of the present study is to research the feasibility of said verifications (with the older versions of the software and EPID). By placing the EPID at a greater distance, the images can be acquired without saturation, yielding a linearity similar to the flattened mode. For the image prediction, a method was optimized based on the clinically used algorithm (analytical anisotropic algorithm (AAA)) over a homogeneous phantom. The depth inside the phantom and its electronic density were tailored. An application was developed to allow the conversion of a dose plane (in DICOM format) to Varian's custom format for Portal Dosimetry. The proposed method was used for the verification of test and clinical fields for the three qualities used in our institution for IMRT: 6X, 6FFF and 10FFF. The method developed yielded a positive verification (more than 95% of the points pass a 2%/2 mm gamma) for both the clinical and test fields. This method was also capable of "predicting" static and wedged fields. A workflow for the verification of FFF fields was developed. This method relies on the clinical algorithm used for dose calculation and is able to verify the FFF modes, as well as being useful for machine quality assurance. The procedure described does not require new hardware. This method could be used as a verification of Varian's Portal Dose Image Prediction. PMID- 27455488 TI - Treatment accuracy without rotational setup corrections in intracranial SRT. AB - The aim of this study was to evaluate the impact of actual rotational setup errors on dose distributions in intracranial stereotactic radiotherapy (SRT) with different alternatives for treatment position selection. A total of 38 SRT fractions from 18patients were retrospectively evaluated with rotational setup errors obtained from actual treatments. The planning computed tomography (CT) images were rotated according to online cone-beam CT (CBCT) images and the dose distribution was recalculated to the rotated CT images using three different patient positionings derived from: 1) an automatic 6D match neglecting rotation correction (Auto6D); 2) an automatic 3D match (Auto3D); and 3) a manual 3D match from actual treatment (Treat3D). The mean conformity index (CI) was 0.92 for the original plans and 0.91 for the Auto6D plans. The mean CI decreased significantly (p < 0.01) to 0.78 and 0.80 for the Auto3D and the Treat3D plans, respectively. The mean minimum dose of the planning target volume (PTVmin) was 91.9% of the prescribed dose for the original plans and 92.1% for the Auto6D plans, while for the Auto3D and the Treat3D plans PTVmin decreased significantly (p < 0.01) to 78.9% and 80.2%, respectively. No significant differences were seen between the Auto6D and the original treatment plans in terms of the dose parameters. However, the Auto3D and the Treat3D plans were statistically significantly inferior (p < 0.01) to the Auto6D and the original plans. In addition, a significant negative correlation (p < 0.01, |r| > 0.38) was found in the Auto3D and the Treat3D cases between the rotation error and CI, PTVmin or minimum dose of gross tumour volume. In SRT, a treatment plan of comparable quality to 6D rotation correction can be achieved by using 6D registration without a rotational correction in the selection of patient positioning. This was demonstrated for typical rotation errors seen in clinical practice. PMID- 27455489 TI - Validation of the Calypso Surface Beacon Transponder. AB - Calypso L-shaped Surface Beacon transponder has recently become available for clinical applications. We herein conduct studies to validate the Surface Beacon transponder in terms of stability, reproducibility, orientation sensitivity, cycle rate dependence, and respiratory waveform tracking accuracy. The Surface Beacon was placed on a Quasar respiratory phantom and positioned at the isocenter with its two arms aligned with the lasers. Breathing waveforms were simulated, and the motion of the transponder was tracked. Stability and drift analysis: sinusoidal waveforms (200 cycles) were produced, and the amplitudes of phases 0% (inhale) and 50% (exhale) were recorded at each breathing cycle. The mean and standard deviation (SD) of the amplitudes were calculated. Linear least-squares fitting was performed to access the possible amplitude drift over the breathing cycles. Reproducibility: similar setting to stability and drift analysis, and the phantom generated 100 cycles of the sinusoidal waveform per run. The Calypso system's was re-setup for each run. Recorded amplitude and SD of 0% and 50% phase were compared between runs to assess contribution of Calypso electromagnetic array setup variation. Beacon orientation sensitivity: the Calypso tracks sinusoidal phantom motion with a defined angular offset of the beacon to assess its effect on SD and peak-to-peak amplitude. Rate dependence: sinusoidal motion was generated at cycle rates of 1 Hz, .33 Hz, and .2 Hz. Peak-to-peak displacement and SDs were assessed. Respiratory waveform tracking accuracy: the phantom reproduced recorded breathing cycles (by volunteers and patients) were tracked by the Calypso system. Deviation in tracking position from produced waveform was used to calculate SD throughout entire breathing cycle. Stability and drift analysis: Mean amplitude +/- SD of phase 0% or 50% were 20.01 +/- 0.04 mm and -19.65 +/- 0.08 mm, respectively. No clinically significant drift was detected with drift measured as 5.1 * 10-5 mm/s at phase 0% and -6.0 * 10-5 mm/s at phase 50%. Reproducibility: The SD of the setup was 0.06 mm and 0.02 mm for phases 0% and 50%, respectively. The combined SDs, including both setup and intrarun error of all runs at phases 0% and 50%, were 0.07mm and 0.11 mm, respectively. Beacon orientation: SD ranged from 0.032mm to 0.039 mm at phase 0% and from 0.084 mm to 0.096 mm at phase 50%. The SD was found not to vary linearly with Beacon angle in the range of 0 degrees and 15 degrees . A positive systematic error was observed with amplitude 0.07 mm/degree at phase 0% and 0.05 mm/degree at phase 50%. Rate dependence: SD and displacement amplitudes did not vary significantly between 0.2 Hz and 0.33 Hz. At 1 Hz, both 0% and 50% amplitude measurements shifted up appreciably, by 0.72 mm and 0.78mm, respectively. As compared with the 0.33 Hz data, SD at phase 0% was 1.6 times higher and 5.4 times higher at phase 50%. Respiratory waveform tracking accuracy: SD of 0.233 mm with approximately normal distribution in over 134 min of tracking (201468 data points). The Surface Beacon transponder appears to be stable, accurate, and reproducible. Submillimeter resolution is achieved throughout breathing and sinusoidal waveforms. PMID- 27455490 TI - A routine quality assurance test for CT automatic exposure control systems. AB - The study purpose was to develop and validate a quality assurance test for CT automatic exposure control (AEC) systems based on a set of nested polymethylmethacrylate CTDI phantoms. The test phantom was created by offsetting the 16 cm head phantom within the 32 cm body annulus, thus creating a three part phantom. This was scanned at all acceptance, routine, and some nonroutine quality assurance visits over a period of 45 months, resulting in 115 separate AEC tests on scanners from four manufacturers. For each scan the longitudinal mA modulation pattern was generated and measurements of image noise were made in two annular regions of interest. The scanner displayed CTDIvol and DLP were also recorded. The impact of a range of AEC configurations on dose and image quality were assessed at acceptance testing. For systems that were tested more than once, the percentage of CTDIvol values exceeding 5%, 10%, and 15% deviation from baseline was 23.4%, 12.6%, and 8.1% respectively. Similarly, for the image noise data, deviations greater than 2%, 5%, and 10% from baseline were 26.5%, 5.9%, and 2%, respectively. The majority of CTDIvol and noise deviations greater than 15% and 5%, respectively, could be explained by incorrect phantom setup or protocol selection. Barring these results, CTDIvol deviations of greater than 15% from baseline were found in 0.9% of tests and noise deviations greater than 5% from baseline were found in 1% of tests. The phantom was shown to be sensitive to changes in AEC setup, including the use of 3D, longitudinal or rotational tube current modulation. This test methodology allows for continuing performance assessment of CT AEC systems, and we recommend that this test should become part of routine CT quality assurance programs. Tolerances of +/- 15% for CTDIvol and +/- 5% for image noise relative to baseline values should be used. PMID- 27455491 TI - Automated Calculation of Water-equivalent Diameter (DW) Based on AAPM Task Group 220. AB - The purpose of this study is to accurately and effectively automate the calculation of the water-equivalent diameter (DW) from 3D CT images for estimating the size-specific dose. DW is the metric that characterizes the patient size and attenuation. In this study, DW was calculated for standard CTDI phantoms and patient images. Two types of phantom were used, one representing the head with a diameter of 16 cm and the other representing the body with a diameter of 32 cm. Images of 63 patients were also taken, 32 who had undergone a CT head examination and 31 who had undergone a CT thorax examination. There are three main parts to our algorithm for automated DW calculation. The first part is to read 3D images and convert the CT data into Hounsfield units (HU). The second part is to find the contour of the phantoms or patients automatically. And the third part is to automate the calculation of DW based on the automated contouring for every slice (DW,all). The results of this study show that the automated calculation of DW and the manual calculation are in good agreement for phantoms and patients. The differences between the automated calculation of DW and the manual calculation are less than 0.5%. The results of this study also show that the estimating of DW,all using DW,n=1 (central slice along longitudinal axis) produces percentage differences of -0.92% +/- 3.37% and 6.75%+/- 1.92%, and estimating DW,all using DW,n=9 produces percentage differences of 0.23% +/- 0.16% and 0.87% +/- 0.36%, for thorax and head examinations, respectively. From this study, the percentage differences between normalized size-specific dose estimate for every slice (nSSDEall) and nSSDEn=1 are 0.74% +/- 2.82% and -4.35% +/- 1.18% for thorax and head examinations, respectively; between nSSDEall and nSSDEn=9 are 0.00% +/- 0.46% and -0.60% +/- 0.24% for thorax and head examinations, respectively. PMID- 27455492 TI - Performance evaluation of the RITG148+ set of TomoTherapy quality assurance tools using RTQA2 radiochromic film. AB - Version 6.3 of the RITG148+ software package offers eight automated analysis routines for quality assurance of the TomoTherapy platform. A performance evaluation of each routine was performed in order to compare RITG148+ results with traditionally accepted analysis techniques and verify that simulated changes in machine parameters are correctly identified by the software. Reference films were exposed according to AAPM TG-148 methodology for each routine and the RITG148+ results were compared with either alternative software analysis techniques or manual analysis techniques in order to assess baseline agreement. Changes in machine performance were simulated through translational and rotational adjustments to subsequently irradiated films, and these films were analyzed to verify that the applied changes were accurately detected by each of the RITG148+ routines. For the Hounsfield unit routine, an assessment of the "Frame Averaging" functionality and the effects of phantom roll on the routine results are presented. All RITG148+ routines reported acceptable baseline results consistent with alternative analysis techniques, with 9 of the 11 baseline test results showing agreement of 0.1mm/0.1 degrees or better. Simulated changes were correctly identified by the RITG148+ routines within approximately 0.2 mm/0.2 degrees with the exception of the Field Centervs. Jaw Setting routine, which was found to have limited accuracy in cases where field centers were not aligned for all jaw settings due to inaccurate autorotation of the film during analysis. The performance of the RITG148+ software package was found to be acceptable for introduction into our clinical environment as an automated alternative to traditional analysis techniques for routine TomoTherapy quality assurance testing. PMID- 27455493 TI - Low-dose 2.5 MV cone-beam computed tomography with thick CsI flat-panel imager. AB - Most of the treatment units, both new and old models, are equipped with a megavoltage portal imager but its use for volumetric imaging is limited. This is mainly due to the poor image quality produced by the high-energy treatment beam (> 6MV). A linac at our center is equipped with a prototype 2.5 MV imaging beam. This study evaluates the feasibility of low-dose megavoltage cone-beam imaging with the 2.5MV beam and a thick cesium iodide detector, which is a high efficiency imager. Basic imaging properties such as spatial resolution and modulation transfer function were assessed for the 2.5 MV prototype imaging system. For image quality and imaging dose, a series of megavoltage cone-beam scans were acquired for the head, thorax, and pelvis of an anthropomorphic phantom and were compared to kilovoltage cone-beam and 6X megavoltage cone-beam images. To demonstrate the advantage of MV imaging, a phantom with metallic inserts was scanned and the image quality was compared to CT and kilovoltage cone beam scans. With a lower energy beam and higher detector efficiency, the 2.5 MV imaging system generally yields better image quality than does the 6 MV imaging system with the conventional MV imager. In particular, with the anthropomorphic phantom studies, the contrast to noise of bone to tissue is generally improved in the 2.5 MV images compared to 6 MV. With an image quality sufficient for bony alignment, the imaging dose for 2.5 MV cone-beam images is 2.4-3.4 MU compared to 26 MU in 6 MV cone-beam scans for the head, thorax, and pelvis regions of the phantom. Unlike kilovoltage cone-beam, the 2.5 MV imaging system does not suffer from high-Z image artifacts. This can be very useful for treatment planning in cases where high-Z prostheses are present. PMID- 27455494 TI - Evaluation of target and cardiac position during visually monitored deep inspiration breath-hold for breast radiotherapy. AB - A low-resource visually monitored deep inspiration breath-hold (VM-DIBH) technique was successfully implemented in our clinic to reduce cardiac dose in left-sided breast radiotherapy. In this study, we retrospectively characterized the chest wall and heart positioning accuracy of VM-DIBH using cine portal images from 42 patients. Central chest wall position from field edge and in-field maximum heart distance (MHD) were manually measured on cine images and compared to the planned positions based on the digitally reconstructed radiographs (DRRs). An in-house program was designed to measure left anterior descending artery (LAD) and chest wall separation on the planning DIBH CT scan with respect to breath hold level (BHL) during simulation to determine a minimum BHL for VM-DIBH eligibility. Systematic and random setup uncertainties of 3.0 mm and 2.6 mm, respectively, were found for VM-DIBH treatment from the chest wall measurements. Intrabeam breath-hold stability was found to be good, with over 96% of delivered fields within 3 mm. Average treatment MHD was significantly larger for those patients where some of the heart was planned in the field compared to patients whose heart was completely shielded in the plan (p < 0.001). No evidence for a minimum BHL was found, suggesting that all patients who can tolerate DIBH may yield a benefit from it. PMID- 27455495 TI - Determination of MLC model parameters for Monaco using commercial diode arrays. AB - Multileaf collimators (MLCs) need to be characterized accurately in treatment planning systems to facilitate accurate intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT). The aim of this study was to examine the use of MapCHECK 2 and ArcCHECK diode arrays for optimizing MLC parameters in Monaco X-ray voxel Monte Carlo (XVMC) dose calculation algorithm. A series of radiation test beams designed to evaluate MLC model parameters were delivered to MapCHECK 2, ArcCHECK, and EBT3 Gafchromic film for comparison. Initial comparison of the calculated and ArcCHECK-measured dose distributions revealed it was unclear how to change the MLC parameters to gain agreement. This ambiguity arose due to an insufficient sampling of the test field dose distributions and unexpected discrepancies in the open parts of some test fields. Consequently, the XVMC MLC parameters were optimized based on MapCHECK 2 measurements. Gafchromic EBT3 film was used to verify the accuracy of MapCHECK 2 measured dose distributions. It was found that adjustment of the MLC parameters from their default values resulted in improved global gamma analysis pass rates for MapCHECK 2 measurements versus calculated dose. The lowest pass rate of any MLC-modulated test beam improved from 68.5% to 93.5% with 3% and 2 mm gamma criteria. Given the close agreement of the optimized model to both MapCHECK 2 and film, the optimized model was used as a benchmark to highlight the relatively large discrepancies in some of the test field dose distributions found with ArcCHECK. Comparison between the optimized model-calculated dose and ArcCHECK measured dose resulted in global gamma pass rates which ranged from 70.0%-97.9% for gamma criteria of 3% and 2 mm. The simple square fields yielded high pass rates. The lower gamma pass rates were attributed to the ArcCHECK overestimating the dose in-field for the rectangular test fields whose long axis was parallel to the long axis of the ArcCHECK. Considering ArcCHECK measurement issues and the lower gamma pass rates for the MLC-modulated test beams, it was concluded that MapCHECK 2 was a more suitable detector than ArcCHECK for the optimization process. PMID- 27455496 TI - Dosimetric accuracy of the cone-beam CT-based treatment planning of the Vero system: a phantom study. AB - We report an investigation on the accuracy of dose calculation based on the cone beam computed tomography (CBCT) images of the nonbowtie filter kV imaging system of the Vero linear accelerator. Different sets of materials and tube voltages were employed to generate the Hounsfield unit lookup tables (HLUTs) for both CBCT and fan-beam CT (FBCT) systems. The HLUTs were then implemented for the dose calculation in a treatment planning system (TPS). Dosimetric evaluation was carried out on an in-house-developed cube phantom that consists of water equivalent slabs and inhomogeneity inserts. Two independent dosimeters positioned in the cube phantom were used in this study for point-dose and two-dimensional (2D) dose distribution measurements. The differences of HLUTs from various materials and tube voltages in both CT systems resulted in differences in dose calculation accuracy. We found that the higher the tube voltage used to obtain CT images, the better the point-dose calculation and the gamma passing rate of the 2D dose distribution agree to the values determined in the TPS. Moreover, the insert materials that are not tissue-equivalent led to higher dose-calculation inaccuracy. There were negligible differences in dosimetric evaluation between the CBCT- and FBCT-based treatment planning if the HLUTs were generated using the tissue-equivalent materials. In this study, the CBCT images of the Vero system from a complex inhomogeneity phantom can be applied for the TPS dose calculation if the system is calibrated using tissue-equivalent materials scanned at high tube voltage (i.e., 120 kV). PMID- 27455497 TI - Development of a Monte Carlo model for treatment planning dose verification of the Leksell Gamma Knife Perfexion radiosurgery system. AB - Detailed Monte Carlo (MC) modeling of the Leksell Gamma Knife (GK) Perfexion (PFX) collimator system is the only accurate ab initio approach appearing in the literature. As a different approach, in this work, we present a MC model based on film measurement. By adjusting the model parameters and fine-tuning the derived fluence map for each individual source to match the manufacturer's ring output factors, we created a reasonable virtual source model for MC simulations to verify treatment planning dose for the GK PFX radiosurgery system. The MC simulation model was commissioned by simple single shots. Dose profiles and both ring and collimator output factors were compared with the treatment planning system (TPS). Good agreement was achieved for dose profiles especially for the region of plateau (< 2%), while larger difference (< 5%) came from the penumbra region. The maximum difference of the calculated output factor was within 0.7%. The model was further validated by a clinical test case. Good agreement was obtained. The DVHs for brainstem and the skull were almost identical and, for the target, the volume covered by the prescription (12.5 Gy to 50% isodose line) was 95.6% from MC calculation versus 100% from the TPS. PMID- 27455498 TI - Measurement of image rotation angle in CT for radiotherapy treatment planning. AB - The geometric accuracy of CT images is essential when they are used for planning radiation therapy. In this study, a method of quantitative testing of image rotation in CT is presented, based on the automated analysis of an image of a phantom half-filled with water. A plug-in was written for ImageJ software for automated detection of a water surface in an image and measurement of its angle relative to a horizontal line. A water phantom can be used for the evaluation of image rotation for axial mode. In helical mode the movement of the table would cause movement of the water. The difference between image rotation for axial and helical scans can be evaluated by measuring and comparing the angles of the tabletop surface for both modes. Preliminary results of measurements for three CT scanners show that image rotation does not exceed 0.5 degrees , and is less than 0.1 degrees for the dedicated CT simulator. It was observed that, for one CT scanner image, the rotation angle depended on tube rotation time. PMID- 27455499 TI - Out-of-field doses and neutron dose equivalents for electron beams from modern Varian and Elekta linear accelerators. AB - Out-of-field doses from radiotherapy can cause harmful side effects or eventually lead to secondary cancers. Scattered doses outside the applicator field, neutron source strength values, and neutron dose equivalents have not been broadly investigated for high-energy electron beams. To better understand the extent of these exposures, we measured out-of-field dose characteristics of electron applicators for high-energy electron beams on two Varian 21iXs, a Varian TrueBeam, and an Elekta Versa HD operating at various energy levels. Out-of-field dose profiles and percent depth-dose curves were measured in a Wellhofer water phantom using a Farmer ion chamber. Neutron dose was assessed using a combination of moderator buckets and gold activation foils placed on the treatment couch at various locations in the patient plane on both the Varian 21iX and Elekta Versa HD linear accelerators. Our findings showed that out-of-field electron doses were highest for the highest electron energies. These doses typically decreased with increasing distance from the field edge but showed substantial increases over some distance ranges. The Elekta linear accelerator had higher electron out-of field doses than the Varian units examined, and the Elekta dose profiles exhibited a second dose peak about 20 to 30 cm from central-axis, which was found to be higher than typical out-of-field doses from photon beams. Electron doses decreased sharply with depth before becoming nearly constant; the dose was found to decrease to a depth of approximately E(MeV)/4 in cm. With respect to neutron dosimetry, Q values and neutron dose equivalents increased with electron beam energy. Neutron contamination from electron beams was found to be much lower than that from photon beams. Even though the neutron dose equivalent for electron beams represented a small portion of neutron doses observed under photon beams, neutron doses from electron beams may need to be considered for special cases. PMID- 27455500 TI - Electrocardiogram-gated coronary CT angiography dose estimates using ImPACT. AB - The primary study objective was to assess radiation doses using a modified form of the Imaging Performance Assessment of Computed Tomography (CT) scanner (ImPACT) patient dosimetry for cardiac applications on an Aquilion ONE ViSION Edition scanner, including the Ca score, target computed tomography angiography (CTA), prospective CTA, continuous CTA/cardiac function analysis (CFA), and CTA/CFA modulation. Accordingly, we clarified the CT dose index (CTDI) to determine the relationship between heart rate (HR) and X-ray exposure. As a secondary objective, we compared radiation doses using modified ImPACT, a whole body dosimetry phantom study, and the k-factor method to verify the validity of the dose results obtained with modified ImPACT. The effective dose determined for the reference person (4.66 mSv at 60 beats per minute (bpm) and 33.43 mSv at 90bpm) were approximately 10% less than those determined for the phantom study (5.28 mSv and 36.68 mSv). The effective doses according to the k-factor (0.014 mSv*mGy-1*cm-1; 2.57 mSv and 17.10 mSv) were significantly lower than those obtained with the other two methods. In the present study, we have shown that ImPACT, when modified for cardiac applications, can assess both absorbed and effective doses. The results of our dose comparison indicate that modified ImPACT dose assessment is a promising and practical method for evaluating coronary CTA. PMID- 27455501 TI - Imaging acquisition display performance: an evaluation and discussion of performance metrics and procedures. AB - When The Joint Commission updated its Requirements for Diagnostic Imaging Services for hospitals and ambulatory care facilities on July 1, 2015, among the new requirements was an annual performance evaluation for acquisition workstation displays. The purpose of this work was to evaluate a large cohort of acquisition displays used in a clinical environment and compare the results with existing performance standards provided by the American College of Radiology (ACR) and the American Association of Physicists in Medicine (AAPM). Measurements of the minimum luminance, maximum luminance, and luminance uniformity, were performed on 42 acquisition displays across multiple imaging modalities. The mean values, standard deviations, and ranges were calculated for these metrics. Additionally, visual evaluations of contrast, spatial resolution, and distortion were performed using either the Society of Motion Pictures and Television Engineers test pattern or the TG-18-QC test pattern. Finally, an evaluation of local nonuniformities was performed using either a uniform white display or the TG-18-UN80 test pattern. Displays tested were flat panel, liquid crystal displays that ranged from less than 1 to up to 10 years of use and had been built by a wide variety of manufacturers. The mean values for Lmin and Lmax for the displays tested were 0.28 +/- 0.13 cd/m2 and 135.07 +/- 33.35 cd/m2, respectively. The mean maximum luminance deviation for both ultrasound and non-ultrasound displays was 12.61% +/ 4.85% and 14.47% +/- 5.36%, respectively. Visual evaluation of display performance varied depending on several factors including brightness and contrast settings and the test pattern used for image quality assessment. This work provides a snapshot of the performance of 42 acquisition displays across several imaging modalities in clinical use at a large medical center. Comparison with existing performance standards reveals that changes in display technology and the move from cathode ray tube displays to flat panel displays may have rendered some of the tests inappropriate for modern use. PMID- 27455502 TI - Validation of total skin electron irradiation (TSEI) technique dosimetry data by Monte Carlo simulation. AB - Total skin electron irradiation (TSEI) is a complex technique which requires many nonstandard measurements and dosimetric procedures. The purpose of this work was to validate measured dosimetry data by Monte Carlo (MC) simulations using EGSnrc based codes (BEAMnrc and DOSXYZnrc). Our MC simulations consisted of two major steps. In the first step, the incident electron beam parameters (energy spectrum, FWHM, mean angular spread) were adjusted to match the measured data (PDD and profile) at SSD = 100 cm for an open field. In the second step, these parameters were used to calculate dose distributions at the treatment distance of 400 cm. MC simulations of dose distributions from single and dual fields at the treatment distance were performed in a water phantom. Dose distribution from the full treatment with six dual fields was simulated in a CT-based anthropomorphic phantom. MC calculations were compared to the available set of measurements used in clinical practice. For one direct field, MC calculated PDDs agreed within 3%/1 mm with the measurements, and lateral profiles agreed within 3% with the measured data. For the OF, the measured and calculated results were within 2% agreement. The optimal angle of 17 degrees was confirmed for the dual field setup. Dose distribution from the full treatment with six dual fields was simulated in a CT based anthropomorphic phantom. The MC-calculated multiplication factor (B12 factor), which relates the skin dose for the whole treatment to the dose from one calibration field, for setups with and without degrader was 2.9 and 2.8, respectively. The measured B12-factor was 2.8 for both setups. The difference between calculated and measured values was within 3.5%. It was found that a degrader provides more homogeneous dose distribution. The measured X-ray contamination for the full treatment was 0.4%; this is compared to the 0.5% X-ray contamination obtained with the MC calculation. Feasibility of MC simulation in an anthropomorphic phantom for a full TSEI treatment was proved and is reported for the first time in the literature. The results of our MC calculations were found to be in general agreement with the measurements, providing a promising tool for further studies of dose distribution calculations in TSEI. PMID- 27455503 TI - A cross-sectional study of the radiation dose and image quality of X-ray equipment used in IVR. AB - There are case reports of injuries caused by the radiation from interventional radiology (IVR) X-ray systems. Therefore, the management of radiation doses in IVR is important. However, no detailed report has evaluated image quality for a large number of IVR X-ray systems. As a result, it is unclear whether the image quality of the X-ray equipment currently used in IVR procedures is optimal. We compared the entrance surface doses and image quality of multiple IVR X-ray systems. This study was conducted in 2014 at 13 medical facilities using 18 IVR X ray systems. We evaluated image quality and simultaneously measured the radiation dose. Entrance surface doses for fluoroscopy (duration, 1 min) and cineradiography (duration, 10 s) are measured using a 20-cm-thick acrylic plate and skin dose monitor. The image quality (such as spatial resolution and low contrast detectability) of both fluoroscopy and cineradiography was evaluated using a QC phantom. For fluoroscopy, the average entrance surface dose using the 20-cm-thick acrylic plate was 13.9 (range 2.1-28.2) mGy/min. For cineradiography, the average entrance surface dose was 24.6 (range 5.1-49.3) mGy/10 s. We found positive correlations between radiation doses and image quality scores, in general, especially for fluoroscopy. The differences in surface dose among the 18 IVR X-ray systems were high (max/min, 9.7-fold for cineradiography; 13.4-fold for fluoroscopy). The differences in image quality scores (spatial resolution, low contrast detectability, and dynamic range) were also very large. In general, there tended to be a correlation between radiation dose and image quality. Periodical measurements of the radiation dose and image quality of the X-ray equipment used for cineradiography and fluoroscopy in IVR are necessary. The need to minimize patient exposure requires that the dose be reduced to the minimum level that will generate an image with an acceptable degree of noise. PMID- 27455504 TI - Predicting deliverability of volumetric-modulated arc therapy (VMAT) plans using aperture complexity analysis. AB - The purpose of this study was to evaluate the ability of an aperture complexity metric for volumetric-modulated arc therapy (VMAT) plans to predict plan delivery accuracy. We developed a complexity analysis tool as a plug-in script to Varian's Eclipse treatment planning system. This script reports the modulation of plans, arcs, and individual control points for VMAT plans using a previously developed complexity metric. The calculated complexities are compared to that of 649 VMAT plans previously treated at our institution from 2013 to mid-2015. We used the VMAT quality assurance (QA) results from the 649 treated plans, plus 62 plans that failed pretreatment QA, to validate the ability of the complexity metric to predict plan deliverability. We used a receiver operating characteristic (ROC) analysis to determine an appropriate complexity threshold value above which a plan should be considered for reoptimization before it moves further through our planning workflow. The average complexity metric for the 649 treated plans analyzed with the script was 0.132 mm-1 with a standard deviation of 0.036 mm-1. We found that when using a threshold complexity value of 0.180 mm-1, the true positive rate for correctly identifying plans that failed QA was 44%, and the false-positive rate was 7%. Used clinically with this threshold, the script can identify overly modulated plans and thus prevent a significant portion of QA failures. Reducing VMAT plan complexity has a number of important clinical benefits, including improving plan deliverability and reducing treatment time. Use of the complexity metric during both the planning and QA processes can reduce the number of QA failures and improve the quality of VMAT plans used for treatment. PMID- 27455505 TI - Characterization and evaluation of 2.5 MV electronic portal imaging for accurate localization of intra- and extracranial stereotactic radiosurgery. AB - 2.5 MV electronic portal imaging, available on Varian TrueBeam machines, was characterized using various phantoms in this study. Its low-contrast detectability, spatial resolution, and contrast-to-noise ratio (CNR) were compared with those of conventional 6 MV and kV planar imaging. Scatter effect in large patient body was simulated by adding solid water slabs along the beam path. The 2.5 MV imaging mode was also evaluated using clinically acquired images from 24 patients for the sites of brain, head and neck, lung, and abdomen. With respect to 6 MV, the 2.5 MV achieved higher contrast and preserved sharpness on bony structures with only half of the imaging dose. The quality of 2.5 MV imaging was comparable to that of kV imaging when the lateral separation of patient was greater than 38 cm, while the kV image quality degraded rapidly as patient separation increased. Based on the results of patient images, 2.5 MV imaging was better for cranial and extracranial SRS than the 6 MV imaging. PMID- 27455506 TI - A novel phantom and procedure providing submillimeter accuracy in daily QA tests of accelerators used for stereotactic radiosurgery*. AB - Stereotactic radiosurgery (SRS) places great demands on spatial accuracy. Steel BBs used as markers in quality assurance (QA) phantoms are clearly visible in MV and planar kV images, but artifacts compromise cone-beam CT (CBCT) isocenter localization. The purpose of this work was to develop a QA phantom for measuring with sub-mm accuracy isocenter congruence of planar kV, MV, and CBCT imaging systems and to design a practical QA procedure that includes daily Winston-Lutz (WL) tests and does not require computer aid. The salient feature of the phantom (Universal Alignment Ball (UAB)) is a novel marker for precisely localizing isocenters of CBCT, planar kV, and MV beams. It consists of a 25.4mm diameter sphere of polymethylmetacrylate (PMMA) containing a concentric 6.35mm diameter tungsten carbide ball. The large density difference between PMMA and the polystyrene foam in which the PMMA sphere is embedded yields a sharp image of the sphere for accurate CBCT registration. The tungsten carbide ball serves in finding isocenter in planar kV and MV images and in doing WL tests. With the aid of the UAB, CBCT isocenter was located within 0.10 +/- 0.05 mm of its true positon, and MV isocenter was pinpointed in planar images to within 0.06 +/- 0.04mm. In clinical morning QA tests extending over an 18 months period the UAB consistently yielded measurements with sub-mm accuracy. The average distance between isocenter defined by orthogonal kV images and CBCT measured 0.16 +/- 0.12 mm. In WL tests the central ray of anterior beams defined by a 1.5 * 1.5 cm2 MLC field agreed with CBCT isocenter within 0.03 +/- 0.14 mm in the lateral direction and within 0.10 +/- 0.19 mm in the longitudinal direction. Lateral MV beams approached CBCT isocenter within 0.00 +/- 0.11 mm in the vertical direction and within -0.14 +/- 0.15 mm longitudinally. It took therapists about 10 min to do the tests. The novel QA phantom allows pinpointing CBCT and MV isocenter positions to better than 0.2 mm, using visual image registration. Under CBCT guidance, MLC-defined beams are deliverable with sub-mm spatial accuracy. The QA procedure is practical for daily tests by therapists. PMID- 27455507 TI - Re: Estimating and reducing dose received by cardiac devices for patients undergoing radiotherapy. PMID- 27455508 TI - Response to Re: Estimating and reducing dose received by cardiac devices for patients undergoing radiotherapy. AB - In reply to Dimitris N. Mihailidis regarding our manuscript entitled "Estimating and reducing dose received by cardiac devices for patients undergoing radiotherapy". PMID- 27455509 TI - Some musings on our labor's meaning and the legacy of our departing friends; on who, why, and how we should publish obituaries. PMID- 27455512 TI - Sex and seasonal differences in hippocampal volume and neurogenesis in brood parasitic brown-headed cowbirds (Molothrus ater). AB - Brown-headed cowbirds (Molothrus ater) are one of few species in which females show more complex space use than males. Female cowbirds search for, revisit, and parasitize host nests and, in a previous study, outperformed males on an open field spatial search task. Previous research reported a female-biased sex difference in the volume of the hippocampus, a region of the brain involved in spatial memory. Neurons produced by adult neurogenesis may be involved in the formation of new memories and replace older neurons that could cause interference in memory. We tested for sex and seasonal differences in hippocampal volume and neurogenesis of brood-parasitic brown-headed cowbirds and the closely related non brood-parasitic red-winged blackbird (Agelaius phoeniceus) to determine whether there were differences in the hippocampus that reflected space use in the wild. Females had a larger hippocampus than males in both species, but hippocampal neurogenesis, measured by doublecortin immunoreactivity (DCX+), was greater in female than in male cowbirds in the absence of any sex difference in blackbirds, supporting the hypothesis of hippocampal specialization in female cowbirds. Cowbirds of both sexes had a larger hippocampus with greater hippocampal DCX+ than blackbirds. Hippocampus volume remained stable between breeding conditions, but DCX+ was greater post-breeding, indicating that old memories may be lost through hippocampal reorganization following breeding. Our results support, in part, the hypothesis that the hippocampus of cowbirds is specialized for brood parasitism. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1275-1290, 2016. PMID- 27455510 TI - NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. AB - Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4 deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1beta and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation. PMID- 27455511 TI - A rapid pro-hemostatic approach to overcome direct oral anticoagulants. AB - Direct inhibitors of coagulation factor Xa (FXa) or thrombin are promising oral anticoagulants that are becoming widely adopted. The ability to reverse their anticoagulant effects is important when serious bleeding occurs or urgent medical procedures are needed. Here, using experimental mouse models of hemostasis, we show that a variant coagulation factor, FXa(I16L), rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXa(I16L) to reverse the anticoagulant effects of FXa inhibitor depends, at least in part, on the ability of the active site inhibitor to hinder antithrombin dependent FXa inactivation, paradoxically allowing uninhibited FXa to persist in plasma. Because of its inherent catalytic activity, FXa(I16L) is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXa(I16L) also reduces the anticoagulant associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXa(I16L) may be able to fill an important unmet clinical need for a rapid, pro hemostatic agent to reverse the effects of several new anticoagulants. PMID- 27455514 TI - Meal frequency and timing: impact on metabolic disease risk. AB - PURPOSE OF REVIEW: The purpose of this article is to provide an overview of the most recent human intervention trials that have examined the impact of meal frequency or meal timing on metabolic disease risk factors. RECENT FINDINGS: Findings from intervention studies published over the past 12 months indicate that weight loss may be more pronounced with decreased meal frequency (two meals per day) versus increased meal frequency (six meals per day) under hypocaloric conditions. However, under isocaloric conditions, no effect on body weight was noted. Plasma lipid concentrations and glucoregulatory factors (fasting glucose, insulin, and insulin sensitivity) were not affected by alterations in meal frequency. As for meal timing, delaying the lunchtime meal by 3.5 h (from 1.30 p.m. to 4.30 p.m.) has no impact on body weight, but may impair glucose tolerance in young healthy adults. SUMMARY: In sum, altering meal frequency has little impact on body weight, plasma lipids, or glucoregulatory factors, whereas eating the majority of calories later in the day may be detrimental for glycemic control. These preliminary findings, however, still require confirmation by longer term, larger scale controlled trials. PMID- 27455513 TI - Effects of levomilnacipran extended-release on motivation/energy and functioning in adults with major depressive disorder. AB - The objective of this post-hoc analysis was to investigate the relationship between motivation/energy and functional impairment in patients with major depressive disorder (MDD). Data were taken from a phase 3 trial of levomilnacipran extended-release (ER) in adults with MDD (NCT01034462; N=429) that used the 18-item Motivation and Energy Inventory (MEI) to assess motivation/energy. Two subgroups with lower and higher motivation/energy were defined using baseline MEI total scores (<=28 and >28, respectively). Change from baseline in the Sheehan Disability Scale (SDS) total score was analyzed in the intent-to-treat (ITT) population and both subgroups. Path analyses were carried out in the ITT population and a lower MEI subgroup to assess the direct and indirect effects of levomilnacipran ER on SDS total score change. In the ITT population and the lower MEI subgroup, significant differences were found between levomilnacipran ER and placebo for changes in the SDS total score (-2.6 and -3.9, both P<0.01), but not in the higher MEI subgroup. The indirect effect of levomilnacipran ER on SDS total score improvement, as mediated by MEI total score change, was 79.9% in the lower MEI subgroup and 67.2% in the ITT population. Levomilnacipran ER was previously shown to improve motivation/energy in adults with MDD. The current analysis indicates that improvements in functional impairment were considerably mediated by improvements in motivation/energy, particularly in patients with lower motivation/energy at baseline. PMID- 27455515 TI - The impact of bariatric surgery on inflammation: quenching the fire of obesity? AB - PURPOSE OF REVIEW: Numerous lines of evidence support the likelihood that inflammation drives the transition from obese/metabolically healthy to obese/type 2 diabetes (T2D). Given the temporal flexibility of inflammation in obesity associated T2D, investigators have hypothesized that a precipitous drop in diabetogenic cytokines is critical for rapid 'T2D remission' following surgery but prior to significant weight loss. We review the evidence that changes in diabetogenic cytokines play a role in outcomes of bariatric surgery, including improved glycemic control. RECENT FINDINGS: A 2016 indication for bariatric surgery to treat T2D integrates the large body of data showing rapid metabolic improvement. Parameters that account for improved glycemic control prior to significant weight loss, T2D recidivism over the long term, or failure of surgery to remit T2D in some patients are incompletely understood. SUMMARY: We review the evidence that changes in diabetogenic cytokines play a role in outcomes of bariatric surgery, including improved glycemic control. We brainstorm future research directions that may improve surgical results. PMID- 27455516 TI - Public Opinion Regarding Whether Speaking With Patients About Firearms Is Appropriate: Results of a National Survey. AB - Background: Health care providers have been encouraged to discuss firearms with patients; whether patients view these discussions as appropriate is unclear. Objective: To estimate, in a national sample, the perceived appropriateness of provider discussions about firearms. Design: Probability-based online survey conducted in April 2015. Analyses used survey weights to generate nationally representative estimates. Setting: U.S. adults. Participants: 3914 English speaking adults (55% participation rate). Measurements: Participants were asked, "In general, would you think it is never, sometimes, usually, or always appropriate for physicians and other health professionals to talk to their patients about firearms?" Results: A majority (66% [95% CI, 63% to 69%]) of participants said that it is at least sometimes appropriate for providers to talk to patients about firearms. Specifically, 23% (CI, 20% to 25%) said that provider discussions about firearms were always appropriate, 14% (CI, 11% to 16%) said that they were usually appropriate, and 30% (CI, 27% to 33%) thought they were sometimes appropriate; 34% (CI, 31% to 37%) felt that such discussions were never appropriate. Views varied by firearm ownership: 54% (CI, 52% to 57%) of gun owners said that provider discussions are at least sometimes appropriate, compared with 67% (CI, 62% to 71%) of nonowners living with an owner and 70% (CI, 66% to 74%) of nonowners not living with an owner. Firearm owners who were more likely to think that firearm discussions are at least sometimes appropriate included those with children at home (62% [CI, 57% to 67%]), those who thought that having a gun at home increases suicide risk (75% [CI, 67% to 83%), and those who thought that provider discussions of seat belts are at least sometimes appropriate (73% [CI, 70% to 75%]). Limitations: The provider discussion question did not specify clinical context. Conclusion: Two thirds of non-firearm owners and over one half of firearm owners in the United States believe that health care provider discussions about firearms are at least sometimes appropriate. The observed heterogeneity underscores the need to better understand assumptions that may underlie these views, particularly among firearm owners. Primary Funding Source: Fund for a Safer Future and Joyce Foundation. PMID- 27455517 TI - Are Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease "Separate but Equal"? PMID- 27455518 TI - EEG-fMRI Gradient Artifact Correction by Multiple Motion-Related Templates. AB - OBJECTIVES: In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), artifacts on the EEG arise from the switching of magnetic field gradients in the MR scanner. These artifacts depend on head position, and are, therefore, difficult to remove in the presence of subject motion. In this study, gradient artifacts are modeled by multiple templates extracted from externally recorded motion information. METHODS: Gradient artifact correction was performed in EEG-fMRI recordings by estimating artifactual templates modulated by slowly varying splines, as well as head position information. The EEG signal quality was then compared following two common methods: averaged artifact subtraction (AAS) and optimal basis sets (OBS). RESULTS: Artifact correction using multiple templates estimated from splines or motion time courses outperformed the existing AAS and OBS approaches, as quantified by root-mean-square power across gradient epochs. Improvements were mostly seen in posterior EEG channels, where most of the residual artifacts are seen following the AAS and OBS methods. Residual spectral power was comparable to that of EEG signals recorded without fMRI scanning. CONCLUSION: Gradient artifacts can be well modeled by multiple templates estimated from head position information, resulting in an effective artifact removal. SIGNIFICANCE: This method can facilitate EEG-fMRI of uncooperative subjects in whom motion is inevitable, for example, to investigate high-frequency EEG activity in which gradient artifacts are particularly prominent. PMID- 27455519 TI - Intensity and Compactness Enabled Saliency Estimation for Leakage Detection in Diabetic and Malarial Retinopathy. AB - Leakage in retinal angiography currently is a key feature for confirming the activities of lesions in the management of a wide range of retinal diseases, such as diabetic maculopathy and paediatric malarial retinopathy. This paper proposes a new saliency-based method for the detection of leakage in fluorescein angiography. A superpixel approach is firstly employed to divide the image into meaningful patches (or superpixels) at different levels. Two saliency cues, intensity and compactness, are then proposed for the estimation of the saliency map of each individual superpixel at each level. The saliency maps at different levels over the same cues are fused using an averaging operator. The two saliency maps over different cues are fused using a pixel-wise multiplication operator. Leaking regions are finally detected by thresholding the saliency map followed by a graph-cut segmentation. The proposed method has been validated using the only two publicly available datasets: one for malarial retinopathy and the other for diabetic retinopathy. The experimental results show that it outperforms one of the latest competitors and performs as well as a human expert for leakage detection and outperforms several state-of-the-art methods for saliency detection. PMID- 27455520 TI - Simultaneous Analysis of 2D Echo Views for Left Atrial Segmentation and Disease Detection. AB - We propose a joint information approach for automatic analysis of 2D echocardiography (echo) data. The approach combines a priori images, their segmentations and patient diagnostic information within a unified framework to determine various clinical parameters, such as cardiac chamber volumes, and cardiac disease labels. The main idea behind the approach is to employ joint Independent Component Analysis of both echo image intensity information and corresponding segmentation labels to generate models that jointly describe the image and label space of echo patients on multiple apical views, instead of independently. These models are then both used for segmentation and volume estimation of cardiac chambers such as the left atrium and for detecting pathological abnormalities such as mitral regurgitation. We validate the approach on a large cohort of echoes obtained from 6,993 studies. We report performance of the proposed approach in estimation of the left-atrium volume and detection of mitral-regurgitation severity. A correlation coefficient of 0.87 was achieved for volume estimation of the left atrium when compared to the clinical report. Moreover, we classified patients that suffer from moderate or severe mitral regurgitation with an average accuracy of 82%. PMID- 27455521 TI - Edge Preserving and Noise Reducing Reconstruction for Magnetic Particle Imaging. AB - Magnetic particle imaging (MPI) is an emerging medical imaging modality which is based on the non-linear response of magnetic nanoparticles to an applied magnetic field. It is an important feature of MPI that even fast dynamic processes can be captured for 3D volumes. The high temporal resolution in turn leads to large amounts of data which have to be handled efficiently. But as the system matrix of MPI is non-sparse, the image reconstruction gets computationally demanding. Therefore, currently only basic image reconstruction methods such as Tikhonov regularization are used. However, Tikhonov regularization is known to oversmooth edges in the reconstructed image and to have only a limited noise reducing effect. In this work, we develop an efficient edge preserving and noise reducing reconstruction method for MPI. As regularization model, we propose to use the nonnegative fused lasso model, and we devise a discretization that is adapted to the acquisition geometry of the preclinical MPI scanner considered in this work. We develop a customized solver based on a generalized forward-backward scheme which is particularly suitable for the dense and not well-structured system matrices in MPI. Already a non-optimized prototype implementation processes a 3D volume within a few seconds so that processing several frames per second seems amenable. We demonstrate the improvement in reconstruction quality over the state of-the-art method in an experimental medical setup for an in-vitro angioplasty of a stenosis. PMID- 27455522 TI - EndoNet: A Deep Architecture for Recognition Tasks on Laparoscopic Videos. AB - Surgical workflow recognition has numerous potential medical applications, such as the automatic indexing of surgical video databases and the optimization of real-time operating room scheduling, among others. As a result, surgical phase recognition has been studied in the context of several kinds of surgeries, such as cataract, neurological, and laparoscopic surgeries. In the literature, two types of features are typically used to perform this task: visual features and tool usage signals. However, the used visual features are mostly handcrafted. Furthermore, the tool usage signals are usually collected via a manual annotation process or by using additional equipment. In this paper, we propose a novel method for phase recognition that uses a convolutional neural network (CNN) to automatically learn features from cholecystectomy videos and that relies uniquely on visual information. In previous studies, it has been shown that the tool usage signals can provide valuable information in performing the phase recognition task. Thus, we present a novel CNN architecture, called EndoNet, that is designed to carry out the phase recognition and tool presence detection tasks in a multi task manner. To the best of our knowledge, this is the first work proposing to use a CNN for multiple recognition tasks on laparoscopic videos. Experimental comparisons to other methods show that EndoNet yields state-of-the-art results for both tasks. PMID- 27455523 TI - Sonochemical Synthesis, Characterization, and Photocatalytic Activity of Perovskite ZnTiO3 Nanopowders. AB - Perovskite zinc titanate (ZnTiO3) nanopowders were synthesized using the sonochemical method combined with calcinations at 500 degrees C and 900 degrees C for 2 h to improve their crystallinity. The effect of calcination temperature on their structural, optical, and photocatalytic properties has been studied. The cubic phase and the mixing phase of cubic and hexagonal were observed in sample calcined at 600 degrees C and 700 degrees C, respectively, while the spinel ZnTiO3 and rutile TiO2 phase arises in sample calcined over 700 degrees C. The valence state was investigated by the X-ray absorption near-edge spectroscopy technique, and the corresponding results indicate the existence of Zn2+ and Ti4+ in the powders. The chemical states of the samples were scrutinized by X-ray photoelectron spectroscopy. The average particle size is approximately 20-240 nm. The excellent photocatalytic performance of ZnTiO3 nanoparticle calcined at 700 degrees C gave complete degradation Rhodamine B (RhB) in 75 min under ultraviolet light exposure with the k rate of 0.033 min -1 and 55% of decolorization RhB in 210 min under visible irradiation. The sample calcined at 700 degrees C ensures a good dielectric permittivity with a value 20 and the loss tangent of about 10-2 . PMID- 27455524 TI - Reconstruction of Enhanced Ultrasound Images From Compressed Measurements Using Simultaneous Direction Method of Multipliers. AB - High-resolution ultrasound (US) image reconstruction from a reduced number of measurements is of great interest in US imaging, since it could enhance both frame rate and image resolution. Compressive deconvolution (CD), combining compressed sensing and image deconvolution, represents an interesting possibility to consider this challenging task. The model of CD includes, in addition to the compressive sampling matrix, a 2-D convolution operator carrying the information on the system point spread function. Through this model, the resolution of reconstructed US images from compressed measurements mainly depends on three aspects: the acquisition setup, i.e., the incoherence of the sampling matrix, the image regularization, i.e., the sparsity prior, and the optimization technique. In this paper, we mainly focused on the last two aspects. We proposed a novel simultaneous direction method of multipliers based optimization scheme to invert the linear model, including two regularization terms expressing the sparsity of the RF images in a given basis and the generalized Gaussian statistical assumption on tissue reflectivity functions. The performance of the method is evaluated on both simulated and in vivo data. PMID- 27455525 TI - Spread-Spectrum Beamforming and Clutter Filtering for Plane-Wave Color Doppler Imaging. AB - Plane-wave imaging is desirable for its ability to achieve high frame rates, allowing the capture of fast dynamic events and continuous Doppler data. In most implementations of plane-wave imaging, multiple low-resolution images from different plane wave tilt angles are compounded to form a single high-resolution image, thereby reducing the frame rate. Compounding improves the lateral beam profile in the high-resolution image, but it also acts as a low-pass filter in slow time that causes attenuation and aliasing of signals with high Doppler shifts. This paper introduces a spread-spectrum color Doppler imaging method that produces high-resolution images without the use of compounding, thereby eliminating the tradeoff between beam quality, maximum unaliased Doppler frequency, and frame rate. The method uses a long, random sequence of transmit angles rather than a linear sweep of plane wave directions. The random angle sequence randomizes the phase of off-focus (clutter) signals, thereby spreading the clutter power in the Doppler spectrum, while keeping the spectrum of the in focus signal intact. The ensemble of randomly tilted low-resolution frames also acts as the Doppler ensemble, so it can be much longer than a conventional linear sweep, thereby improving beam formation while also making the slow-time Doppler sampling frequency equal to the pulse repetition frequency. Experiments performed using a carotid artery phantom with constant flow demonstrate that the spread spectrum method more accurately measures the parabolic flow profile of the vessel and outperforms conventional plane-wave Doppler in both contrast resolution and estimation of high flow velocities. The spread-spectrum method is expected to be valuable for Doppler applications that require measurement of high velocities at high frame rates. PMID- 27455526 TI - Control of Redundant Kinematic Degrees of Freedom in a Closed-Loop Brain-Machine Interface. AB - Brain-machine interface (BMI) systems use signals acquired from the brain to directly control the movement of an actuator, such as a computer cursor or a robotic arm, with the goal of restoring motor function lost due to injury or disease of the nervous system. In BMIs with kinematically redundant actuators, the combination of the task goals and the system under neural control can allow for many equally optimal task solutions. The extent to which kinematically redundant degrees of freedom (DOFs) in a BMI system may be under direct neural control is unknown. To address this question, a Kalman filter was used to decode single- and multi-unit cortical neural activity of two macaque monkeys into the joint velocities of a virtual four-link kinematic chain. Subjects completed movements of the chain's endpoint to instructed target locations within a two dimensional plane. This system was kinematically redundant for an endpoint movement task, as four DOFs were used to manipulate the 2-D endpoint position. Both subjects successfully performed the task and improved with practice by producing faster endpoint velocity control signals. Kinematic redundancy allowed null movements whereby the individual links of the chain could move in a way that cancels out and does not result in endpoint movement. As the subjects became more proficient at controlling the chain, the amount of null movement also increased. Task performance suffered when the links of the kinematic chain were hidden and only the endpoint was visible. Furthermore, all four DOFs of the joint-velocity control space exhibited task-relevant modulation. The relative usage of each DOF depended on the configuration of the chain, and trials in which the less prominent DOFs were utilized also had better task performance. Overall, these results indicate that the subjects incorporated the redundant components of the control space into their control strategy. Future BMI systems with kinematic redundancy, such as exoskeletal systems or anthropomorphic robotic arms, may benefit from allowing neural control over redundant configuration dimensions as well as the end-effector. PMID- 27455527 TI - Applications of Transductive Spectral Clustering Methods in a Military Medical Concussion Database. AB - Traumatic brain injury (TBI) is one of the most common forms of neurotrauma that has affected more than 250,000 military service members over the last decade alone. While in battle, service members who experience TBI are at significant risk for the development of normal TBI symptoms, as well as risk for the development of psychological disorders such as Post-Traumatic Stress Disorder (PTSD). As such, these service members often require intense bouts of medication and therapy in order to resume full return-to-duty status. The primary aim of this study is to identify the relationship between the administration of specific medications and reductions in symptomology such as headaches, dizziness, or light headedness. Service members diagnosed with mTBI and seen at the Concussion Restoration Care Center (CRCC) in Afghanistan were analyzed according to prescribed medications and symptomology. Here, we demonstrate that in such situations with sparse labels and small feature sets, classic analytic techniques such as logistic regression, support vector machines, naive Bayes, random forest, decision trees, and k-nearest neighbor are not well suited for the prediction of outcomes. We attribute our findings to several issues inherent to this problem setting and discuss several advantages of spectral graph methods. PMID- 27455528 TI - On the Benefits of Creeping Wave Antennas in Reducing Interference Between Neighboring Wireless Body Area Networks. AB - We consider the on-body, off-body, and body-to-body channels in wireless body area networks utilizing creeping wave antennas. Experimental setups are used to gather measurements in the 2.4 GHz band with body area networks operating in an office environment. Data packets providing received signal strength indicators are used to assess the performance of the creeping wave antenna in reducing interference at a neighboring on-body access point while supporting reliable on body communications. Results demonstrate that creeping wave antennas provide reliable on-body communications while significantly reducing inter-network interference; the inter-network interference is shown to be 10 dB weaker than the on-body signal. In addition, the inter-network interference when both networks utilize creeping wave antennas is shown to be 3 dB weaker than the interference when monopole antennas are used. PMID- 27455529 TI - A Microsoft Kinect-Based Point-of-Care Gait Assessment Framework for Multiple Sclerosis Patients. AB - Gait impairment is a prevalent and important difficulty for patients with multiple sclerosis (MS), a common neurological disorder. An easy to use tool to objectively evaluate gait in MS patients in a clinical setting can assist clinicians to perform an objective assessment. The overall objective of this study is to develop a framework to quantify gait abnormalities in MS patients using the Microsoft Kinect for the Windows sensor; an inexpensive, easy to use, portable camera. Specifically, we aim to evaluate its feasibility for utilization in a clinical setting, assess its reliability, evaluate the validity of gait indices obtained, and evaluate a novel set of gait indices based on the concept of dynamic time warping. In this study, ten ambulatory MS patients, and ten age and sex-matched normal controls were studied at one session in a clinical setting with gait assessment using a Kinect camera. The expanded disability status scale (EDSS) clinical ambulation score was calculated for the MS subjects, and patients completed the Multiple Sclerosis walking scale (MSWS). Based on this study, we established the potential feasibility of using a Microsoft Kinect camera in a clinical setting. Seven out of the eight gait indices obtained using the proposed method were reliable with intraclass correlation coefficients ranging from 0.61 to 0.99. All eight MS gait indices were significantly different from those of the controls (p-values less than 0.05). Finally, seven out of the eight MS gait indices were correlated with the objective and subjective gait measures (Pearson's correlation coefficients greater than 0.40). This study shows that the Kinect camera is an easy to use tool to assess gait in MS patients in a clinical setting. PMID- 27455530 TI - Delta Features From Ambient Sensor Data are Good Predictors of Change in Functional Health. AB - Sensor systems can be deployed in the homes of older adults living alone for functional health assessments. Their information is very useful for health care specialists. The problem lies in developing person independent models while facing a large variability in behavior. We address this problem by, first, proposing a new feature extraction method for data from ambient motion sensors. The method uses functional similarities between houses and daily structure to extract meaningful features. Second, we propose a change-based approach for analyzing data, taking difference scores of both the sensor features and health metrics. To evaluate our approach, experiments on longitudinal data were conducted, where the relationship between sensor data and health measurements was modeled with linear regression and (nonlinear) regression forests. These experiments show that the change-based approach yields better results and that the resulting models can be used as a reliable metric for (functional) health. In addition, feature analysis can help health care specialists understand relevant aspects of behavior. Prediction of health metrics is possible even with simple sensors. With such sensors, it is possible to detect problems and health decline in an early stage. This will have great impact on clinical practice. PMID- 27455531 TI - Adaptive Elastic Echo State Network for Multivariate Time Series Prediction. AB - Echo state network (ESN) is a new kind of recurrent neural network with a randomly generated reservoir structure and an adaptable linear readout layer. It has been widely employed in the field of time series prediction. However, when high-dimensional reservoirs are utilized to predict multivariate time series, there may be a collinearity problem. In this paper, to overcome the collinearity problem and obtain a sparse solution, we propose a new model-adaptive elastic ESN, in which adaptive elastic net algorithm is used to calculate the unknown weights. It combines the strengths of the quadratic regularization and the adaptively weighted lasso shrinkage. Hence, the proposed model can deal with the collinearity problem and enjoy the oracle property with an unbiased estimation. We exhibit the merits of our model on two benchmark multivariate chaotic datasets and two real-world applications. Experimental results substantiate the effectiveness and characteristics of the proposed model. PMID- 27455532 TI - Weighted Optimization-Based Distributed Kalman Filter for Nonlinear Target Tracking in Collaborative Sensor Networks. AB - The identification of the nonlinearity and coupling is crucial in nonlinear target tracking problem in collaborative sensor networks. According to the adaptive Kalman filtering (KF) method, the nonlinearity and coupling can be regarded as the model noise covariance, and estimated by minimizing the innovation or residual errors of the states. However, the method requires large time window of data to achieve reliable covariance measurement, making it impractical for nonlinear systems which are rapidly changing. To deal with the problem, a weighted optimization-based distributed KF algorithm (WODKF) is proposed in this paper. The algorithm enlarges the data size of each sensor by the received measurements and state estimates from its connected sensors instead of the time window. A new cost function is set as the weighted sum of the bias and oscillation of the state to estimate the "best" estimate of the model noise covariance. The bias and oscillation of the state of each sensor are estimated by polynomial fitting a time window of state estimates and measurements of the sensor and its neighbors weighted by the measurement noise covariance. The best estimate of the model noise covariance is computed by minimizing the weighted cost function using the exhaustive method. The sensor selection method is in addition to the algorithm to decrease the computation load of the filter and increase the scalability of the sensor network. The existence, suboptimality and stability analysis of the algorithm are given. The local probability data association method is used in the proposed algorithm for the multitarget tracking case. The algorithm is demonstrated in simulations on tracking examples for a random signal, one nonlinear target, and four nonlinear targets. Results show the feasibility and superiority of WODKF against other filtering algorithms for a large class of systems. PMID- 27455533 TI - A Tribute to the Life of Dr. Barnet M. Levy. PMID- 27455534 TI - FDA warns makers of unapproved thyroid drugs. PMID- 27455535 TI - Owners report cats on diets actually display more affection. PMID- 27455536 TI - Experts offer consensus on 25 behavioral signs of pain in cats. PMID- 27455537 TI - Veterinary education expanding in Texas. PMID- 27455538 TI - Idaho veterinary teaching center closing. PMID- 27455539 TI - Further queries regarding "What Is Your Diagnosis?". PMID- 27455540 TI - Continuing to tackle the issue of veterinary debt. PMID- 27455541 TI - Evidence appraisal of Wang R, Shi N, Bai J, Zheng Y, Zhau Y. Implementation and evaluation of an interprofessional simulation-based education program for undergraduate nursing students in operating room nursing education: a randomized controlled trial. BMC Med Educ. 2015;15:115. Published online July 9, 2015. PMID- 27455542 TI - Minimizing pressure ulcer risk for surgical patients. PMID- 27455543 TI - Surgical supply waste: putting it all on the table. PMID- 27455544 TI - Creating a strategic plan for perioperative pressure ulcer prevention. PMID- 27455545 TI - DID YOU KNOW? PMID- 27455546 TI - Hot topics at the AORN Surgical Conference & Expo 2016. PMID- 27455547 TI - Tyrothricin--An underrated agent for the treatment of bacterial skin infections and superficial wounds? AB - The antimicrobial agent tyrothricin is a representative of the group of antimicrobial peptides (AMP). It is produced by Bacillus brevis and consists of tyrocidines and gramicidins. The compound mixture shows activity against bacteria, fungi and some viruses. A very interesting feature of AMPs is the fact, that even in vitro it is almost impossible to induce resistances. Therefore, this class of molecules is discussed as one group that could serve as next generation antibiotics and overcome the increasing problem of bacterial resistances. In daily practice, the application of tyrothricin containing formulations is relatively limited: It is used in sore throat medications and in agents for the healing of infected superficial and small-area wounds. However, due to the broad spectrum antimicrobial activity and the low risk of resistance development it is worth to consider further fields of application. PMID- 27455548 TI - Simultaneous determination of five triterpenoid saponins in different parts of Lonicera macranthoides by RRLC-MS/MS method. AB - A rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) method was developed and validated for the determination of five major saponins (macranthoidin B, macranthoidin A, dipsacoside B, akebiasaponin D, and dipsacoside A) in the flower bud, stem, and leaf parts of Lonicera macranthoides. Chromatographic separation was performed on a ZORBAX SB-C18 column (2.1 x 50 mm, 1.8 MUm). Acetonitrile and 0.1% aqueous formic acid were adopted as mobile phase. Detection was carried out on a triple quadrupole mass spectrometer in the negative ion mode using an electrospray source. Multiple reaction monitoring (MRM) mode was employed. The established method showed good linearity (r2 >= 0.9994) for all the analytes within the test ranges and the recoveries were 95.19 103.28%. Desirable intra-day and inter-day precision as well as repeatability were obtained with relative standard deviations (RSDs) less than 5%. The method was simple, sensitive, accurate and performed well in application to the sample determination within a short analysis time of 15 min. The saponin profiles of different parts of Lonicera macranthoides were obtained based on the quantitative data, showing that the flower bud contained much higher level of saponins than the stem and leaf by several orders of magnitude, and that the quantity ratios varied remarkable between these three part. The conclusions might provide scientific evidences for the reasonable application of Lonicera macranthoides, and the proposed RRLC-MS/MS method might be useful for the quality control of this medicinal plant. PMID- 27455549 TI - Exploratory data analysis of the dependencies between skin permeability, molecular weight and log P. AB - Molecular weight and log P remain the most frequently used physicochemical properties in models that predict skin permeability. However, several reports over the past two decades have suggested that predictions made by these models may not be sufficiently accurate. In this study, exploratory data analysis of the probabilistic dependencies between molecular weight, log P and log Kp was performed on a dataset constructed from the combination of several popular datasets. The results suggest that, in general, molecular weight and log P are poorly correlated to log Kp. However, after employing several exploratory data analysis techniques, regions within the dataset of statistically significant dependence were identified. As an example of the applicability of the information extracted from the exploratory data analyses, a multiple linear regression model was constructed, bounded by the ranges of dependence. This model gave reasonable approximations to log Kp values obtained from skin permeability studies of selected non-steroidal ant-inflammatory drugs (NSAIDs) administered from a buffer solution and a lipid-based drug delivery system. A method of testing whether a given drug falls within the regions of statistical dependence was also presented. Knowing the ranges within which molecular weight and log P are statistically related to log Kp can supplement existing methods of screening, risk analysis or early drug development decision making to add confidence to predictions made regarding skin permeability. PMID- 27455550 TI - Bile salt liposomes for enhanced lymphatic transport and oral bioavailability of paclitaxel. AB - Paclitaxel (PTX), a BCS class IV drug that is characterized by its poor solubility and is a substrate for P-glycoprotein, is one of the most widely used antineoplastic agents. However, oral administration of PTX for chemotherapy is highly challenging. The aim of this study was to develop bile-salt liposomes (BS Lips) to enhance the absorption of PTX and thus improve its therapeutic outcome. The BS-Lips were prepared by the thin-film hydration method and characterized in terms of particle size and morphology. Drug release and in vitro stability in simulated gastrointestinal fluids and in media of different pH values were evaluated, as well as in vivo performance, including antitumor activity and pharmacokinetics in rats, with the plasma concentrations determined by a HPLC method. The PTX-loaded BS-Lips were successfully prepared with a diameter of approximately 150 nm and an entrapment efficiency of greater than 90 percent. Moreover, the BS-Lips were not affected by gastrointestinal enzymes or pH alternation, as evident from the unchanged particle size and the drug retained in BS-Lips after 6 h incubation. The insertion of bile salt into the lipid layer of liposomes increased the lymphatic transport of PTX by twofold. Importantly, BS Lips increased the oral bioavailability of PTX by 2.5 and 4-fold, respectively, compared with conventional liposomes (Lips) and Taxol (free drug), thereby displaying a better inhibition of tumor growth that was similar to the group injected intravenously with Taxol. In conclusion, the BS-Lips represent promising vehicles for the oral delivery of PTX, thereby enabling an intravenous-to-oral switch for cancer chemotherapy. PMID- 27455551 TI - Mucoadhesive dexamethasone acetate-polymyxin B sulfate cationic ocular nanoemulsion--novel combinatorial formulation concept. AB - Dexamethasone acetate (DEX) and polymyxin B sulfate (polymyxin B) were formulated as a cationic nanoemulsion for the treatment of ophthalmic infections. As novel concept, the positive charge to achieve mucoadhesion was not generated by toxicologically and regulatorily problematic cationic lipids or polymers, but by using a positively charged drug in combination with positively charged preservatives. The preservative also acts as co-surfactant to stabilize the emulsion. Nanoemulsions with the lipid phase Eutanol G-Lipoid S 100 (70%:30%) containing 0.05% (w/w) DEX were produced by high pressure homogenization, followed by dissolving the hydrophilic molecules in the water phase, e.g. polymyxin B (0.1%, w/w), cetylpyridinium chloride (0.01%, w/w) and glycerol (2.6%, w/w) to yield a combination product. The particles were below 200 nm with narrow size distribution. The osmolality (374 mOsm/kg), pH (5.31) and viscosity (2.45 mPa s at 37 degrees C) were compatible to the ocular administration. The zeta potential of the optimized formulation was shifted from approx. +9 mV to -11 mV after mucin incubation. The in vitro test revealed no potential cytotoxicity. The final products were stable after 180 days of storage at 4 degrees C and room temperature. The developed product is a viable alternative to the commercial ophthalmic suspensions. Moreover, this concept of generating the positive charge by cationic drug and/or preservative addition can be transferred to other ophthalmic products. PMID- 27455552 TI - Higher gene expression of CYP1A2, 2B1 and 2D2 in the brain of female compared with male rats. AB - Cytochrome P450 (CYP) in the brain plays an essential role in the local metabolism of various compounds, including clinically used drugs, toxins, and endogenous substances. In the present study, we compared the expression profiles of mRNAs for several CYP subtypes in the brain between male and female rats. The expression of CYP1A2, CYP2B1, and CYP2D2 in females was significantly higher than that in males. On the other hand, the expression level of the other CYP subtypes examined in the male brain was similar to that in the female brain. These results strongly suggest that marked gender differences exist in the expression profiles of some CYP subtypes in rat brain. PMID- 27455553 TI - Construction of HEK293 cells stably expressing wild-type organic anion transporting polypeptide 1B1 (OATP1B1*1a) and variant OATP1B1*1b and OATP1B1*15. AB - A transgenic cell line stably expressing the human organic anion transporting polypeptide (OATP1B1) was established. Human Embryonic Kidney 293 (HEK293) cell line stably expressing OATP1B1*1a sequence was amplified through PCR with the extracted total RNA as templates from human liver, then subcloned into the plasmid pMD19-T and verified by sequencing. OATP1B1*1b/OATP1B1*15 mutant sequences were obtained by site-directed mutation PCR with pMD19-T/ OATP1B1*1a as templates. The plasmids pcDNA3.1(+)/OATP1B1*1a, *1b and *15 were constructed and transfected into HEK293 cell line using Lipofectamine 2000 transfection reagent. Several stable transfected clones were obtained after selection with G418. Using rosuvastatin as a probe substrate of OATP1B1, the intracellular rosuvastatin accumulation in HEK293 and HEK-OATP1B1*1a, *1b and *15 monoclone cells were validated by a ultra-performance liquid chromatography-tandem mass spectrometry. OATP1B1 mRNA and protein expression were detected by RT-PCR and Western blot, respectively. The results from RT-PCR, rosuvastatin uptake and Western blot assay indicated that human OATP1B1 was highly expressed in transfected cells compared with controls. The HEK-293 cell lines stably expressing human OATP1B1-wild and variant (HEK-OATP1B1, *1b and *15) are potential models to study drug transport in vitro. PMID- 27455554 TI - Effects of ganoderic acids on epileptiform discharge hippocampal neurons: insights from alterations of BDNF,TRPC3 and apoptosis. AB - Recently, Ganoderma lucidum spores (GLS) have shown anti-epileptic effects. However, there are no reports on the anti-epileptic effects of its chemical constituents ganoderic acids (GAs), and more research is needed to better understand the mechanism of GLS activity. In this work, rat primary hippocampal neurons in an in vitro model were used to assess the intervention effects of GAs on epileptiform discharge hippocampal neurons and expression of both BDNF and TRPC3, with the aid of immunofluorescence, MTT method and flow cytometry. It was found that BDNF and TRPC3 are expressed in all cells and were mainly localized in the cytoplasm. The fluorescence intensities of BDNF and TRPC3 in GAs groups were higher than those of normal control and model groups, especially at 80 MUg/ml (P < 0.05). The apoptosis rate of neurons was inversely proportional to BDNF and TRPC3 changes (P < 0.01). Therefore, BDNF and TRPC3 should be involved in the occurrence and development of epilepsy. GAs might indirectly inhibit mossy fiber sprouting and adjust the synaptic reconstructions by promoting the expression of BDNF and TRPC3. Besides, GAs could exert a protective effect on hippocampal neurons by promoting neuronal survival and the recovery of injured neurons. PMID- 27455555 TI - Knockdown of the FoxM1 enhances the sensitivity of gastric cancer cells to cisplatin by targeting Mcl-1. AB - Resistance to chemotherapy is a main obstacle for effective treatment of gastric cancer, the mechanism of which is still poorly understood. Forkhead box M1 (FoxM1) plays an important role in chemo-resistance of various tumors. This study aimed to explore whether FoxM1 mediated resistance of the gastric cancer cell line SGC7901 to the chemotherapy agent cisplatin (DDP). In the study, we detected FoxM1 and Mcl-1 expression via real time-PCR and western blot and demonstrated that FoxM1 is overexpressed in cisplatin-resistance GC cells and Mcl-1 expression is regulated by FoxM1. We examined SGC7901/DDP cell viability by MTT assay, which revealed that suppression of the FoxM1/Mcl-1 pathway impaired cell viability and thus increased sensitivity to cisplatin in gastric cancer cells. Taken together, the study implied that the FoxM1/Mcl-1 pathway may overcome cispaltin resistance of gastric cancer and provide a new therapeutic target for the treatment of gastric cancer. PMID- 27455556 TI - Risk factors for neutropenia with lenalidomide plus dexamethasone therapy for multiple myeloma. AB - Neutropenia may develop as an adverse event in patients with multiple myeloma receiving lenalidomide (LEN) plus dexamethasone (DEX) therapy. In the present study, we examined the risk factors associated with grade 3/4 neutropenia during the first cycle of LEN plus DEX therapy. We observed that hemoglobin level (<= 8.5 g/dl) was a significant risk factor for grade 3/4 neutropenia during the first cycle of therapy (odds ratio: 19.40; 95% confidence interval: 2.68-141.00; p < 0.01). thus, our findings suggest that determining the hemoglobin level could be useful in the risk management for neutropenia in patients receiving LEN plus DEX therapy. PMID- 27455557 TI - Ethnopharmacology in the work of Melville William Hilton-Simpson (1881-1938)- historical analysis and current research opportunities. AB - In the early 20th century, the British anthropologist Melville William Hilton Simpson (1881-1938) did explorations in Africa, mainly the Congo region and the Aures region in Algeria. He showed considerable interest in local medicinal practices and plants used by the natives, mainly the Algerian Berbers. He left notes, letters and publications about traditional medicine which were screened for relevant information about medicinal plant use. His reports were compared with current knowledge and recent study results. Many plants described by Hilton Simpson as therapeutically relevant could prove their efficacy in current studies which again shows that historical sources may exert some reliability. The study, however, unveiled a couple of plants reported as traditionally used, but neglected by modern science so far. These, including Marrubium supinum, Cynoglossum pictum (= C. creticum), Sonchus maritimus, and two Erodium species, are strongly recommended to be further studied. Foresightedly, this approach was already intended by Hilton-Simpson himself. PMID- 27455558 TI - [THE EXCESS OF PALMITIC FATTY ACID IN FOOD AS MAIN CAUSE OF LIPOIDOSIS OF INSULIN DEPENDENT CELLS: SKELETAL MYOCYTES, CARDIO-MYOCYTES, PERIPORTAL HEPATOCYTES, KUPFFER MACROPHAGES AND B-CELLS OF PANCREAS]. AB - In phylogenesis, becoming of biologicalfunctions and biological reactions proceeds with the purpose ofpermanent increasing of "kinetic perfection ". The main role belongs to factors ofphysical, chemical and biological kinetics, their evaluation using systemic approach technique under permanent effect of natural selection. The late-in-phylogenesis insulin, proceeded with, in development of biological function of locomotion, specialization of insulin-dependent cells: skeletal myocytes, syncytium of cardiomyocytes, subcutaneous adipocytes, periportal hepatocytes, Kupffer's macrophages and beta-cells of islets of pancreas. The insulin initiated formation of new, late in phylogenesis, large pool of fatty cells-subcutaneous adipocytes that increased kinetic parameters of biological function of locomotion. In realization of biological function of locomotion only adipocytes absorb exogenous mono unsaturated and saturated fatty acids in the form of triglycerides in composition of oleic and palmitic lipoproteins of very low density using apoE/B-100 endocytosis. The rest of insulin-dependent cells absorb fatty acids in the form of unesterified fatty acids from associates with albumin and under effect of CD36 of translocase offatty acids. The insulin in all insulin-depended cells inhibits biological reaction of lipolysis enhancing contributing into development of lipoidosis. The insulin expresses transfer offatty acids in the form of unsaturated fatty acids from adipocytes into matrix of mitochondria. The insulin supplies insulin dependent cells with substrates for acquiring energy subject to that in pool of unsaturated fatty acids in adipocytes prevails hydrophobic palmitic unsaturated fatiy acid that slowly passes into matrix through external membrane ofmitochondria; oxidases of mitochondria so slowly implement its beta-oxidation that content of exogenous palmitic unsaturatedfatty acid can't be higher than phylogenetic, physiological level - 15% of all amount offatty acids transferring to insulin-dependent cells. The insulin can't both to decrease content of exogenous palmitic fatty acid and inhibit lipolysis in visceral fatty cells of omentum. PMID- 27455559 TI - [THE SOMATIC MUTATIONS AND ABERRANT METHYLATION AS POTENTIAL GENETIC MARKERS OF URINARY BLADDER CANCER]. AB - All around the world, more than 330 thousands cases of bladder cancer are registered annually hence representing actual problem of modern oncology. Still in demand are search and characteristic of new molecular markers of bladder cancer detecting in tumor cells from urinary sediment and having high diagnostic accuracy. The studies of last decade, especially using methods of genome-wide sequencing, permitted to receive a large amount of experimental data concerning development and progression of bladder cancer The review presents systematic analysis of publications available in PubMed data base mainly of last five years. The original studies of molecular genetic disorders under bladder cancer and meta analyzes were considered This approach permitted to detected the most common local alterations of DNA under bladder cancer which can be detected using routine genetic methods indifferent clinical material and present prospective interest for development of test-systems. The molecular genetic markers of disease can be activating missense mutations in 7 and 10 exons of gene of receptor of growth factor of fibroblasts 3 (FGFR3), 9 and 20 exons of gene of Phosphatidylinositol 4,5-bi-phosphate-3-kinase (PIK3CA) and mutation in -124 and -146 nucleotides in promoter of gene of catalytic subunit telomerase (TERT). The development of test systems on the basis of aberrant methylation of CpG-islets of genes-suppressors still is seemed as a difficult task because of differences in pattern of methylation of different primary tumors at various stages of clonal evolution of bladder cancer though they can be considered as potential markers. PMID- 27455560 TI - [THE COMPARATIVE ANALYSIS OF LEVEL OF OLIGOMERIC MATRIX PROTEIN OF CARTILAGE IN BLOOD SERUM OF PATIENTS WITH DISEASES OF MUSCULO-SKELETAL SYSTEM]. AB - The osteoarthritis and rheumatoid arthritis are considered as the most prevalent diseases in the structure of diseases of musculoskeletal system. The higher social significance of these nosologies dictates necessity of searching reliable cartilage biomarkers having diagnostic validity both in discerning degenerative alterations at early stage of disease of joints and in monitoring of treatment effectiveness. The content of oligomeric matrix protein of cartilage using ELISA was evaluated in blood serum ofpatients with secondary osteoarthritis under rheumatoid arthritis (n=248). The comparison of derived results was carried out using control groups. Within the framework of study relationship was evaluated between level of oligomeric matrix protein of cartilage in patients with secondary osteoarthritis under rheumatoid arthritis with values offunctional KOOS index. The analysis of derived results established trend to increasing of level of oligomeric matrix protein of cartilage in blood serum ofpatients with secondary osteoarthritis under rheumatoid arthritis as compared with control groups. The moderate correlation interdependence between cartilage biomarker and KOOS index. PMID- 27455561 TI - [THE COMPARATIVE CHARACTERISTIC OF KAOLIN-ACTIVATED THROMBOELASTOGRAPHY IN HEALTHY NEWBORNS AND NEWBORNS WITH HEART AILMENTS]. AB - The study was carried out to diferentiate reference values for kaolin-activated thromboelastography in newborns with congenital heart disease. The study included two groups ofpatients. The first one consisted of 62 newborns with congenital heart disease and the second one consisted of 35 healthy newborns. The results of kaolin-activated thromboelastography implemented in groups are evaluated as condition of normal coagulation. The valuable diferences of homeostasis system in healthy newborns and newborns with congenital heart disease (without severe concomitant pathology) are not established. They have similar indicators of kaolin-activated thromboelastography. The derived results can be applied as standards in full-term newborns with congenital heart disease. PMID- 27455562 TI - [THE SCREENING OF DIAGNOSTIC POTENTIAL OF NATIVE PROTEIN FRACTIONS OF MYCOBACTERIUM TUBERCULOSIS USING TECHNIQUE OF IMMUNE BLOTTING]. AB - The technique of immune blotting was used to analyze surface proteins obtained from cells M Tuberculosis exposed to partialmode of delipidization. At that, there were applied serums of patients with tuberculosis of lungs; HIV agents and patients with concomitant infection tuberculosis-AIDS and also HIV-negative patients without clinical signs of disease of lungs and with chronic diseases of lungs of other etiology The fractions oflow-molecular antigens with molecular mass 6.5-30 kilodaltons became diagnostically significant. To this fraction of antigens reacted serums of all patients with tuberculosis of lungs and serums of 91% of patients with concomitant tuberculosis-AIDS infection. The antigens of protein fractions with high (70-100 kilodaltons) and interim (30-69 kilodaltons) molecular mass became diagnostically insignificant. PMID- 27455563 TI - [THE UNESTERIFIED FATTY ACIDS IN BLOOD PLASMA AND INTERCELLULAR MEDIUM: EFFECT OF INSULIN AND ALBUMIN (THE LECTURE)]. AB - The high content of palmitic saturated fatty acid, palmitic triglycerides in food, the large amount of lipoproteins of very low density of the same name in blood, obvious insufficient amount of unesterified fatty acids releasing under lipolysis in blood to meet in vivo requirements in biotransforming energy of ATP are the causes of biological malfunction of homeostasis. As a rule, for every cell in vivo everything is always to be enough. The deficiency of synthesis of ATP by reason of non-optimal substratum for acquirement of ATP by mitochondria is followed by activation also phylogenetically earlier biological function of adaptation, biological reaction of stress. Thus, surplus of palmitic unesterified fatty acid after every food intake forms in vivo biological reaction of "metabolic" stress, deficiency of energy by reason of realization by mitochondria in vivo non-optimal exogenous substratum-palmitic unesterified fatty acid, deficiency of acyl- and acetyl-KoA and prognostically formation of potentially ineffective palmitic alternative of metabolism of fatty acids. The deficiency of palmitic unesterified fatty acids in biological reaction of exotrophy after every intake of food compensates biological reaction of stress, activation of releasing of palmitic unesterified fatty acids from visceral fatty cells of gland as it physiologically occurs in biological reaction of endotrophy. At that, adrenalin increases lipolysis in visceral fatty cells of gland and physiologically late insulin can't inhibit lipolysis in phylogenetically early visceral fatty cells. Increasing of content of unesterifed fatty acids in blood plasma, as it always occurs in vivo, stops absorption of glucose by cells initiating hyperglycemia, hyperinsulinemia, and syndrome of resistance to insulin. The result of such a compensation of biological reaction of exotrophy is biological reaction of endotrophy, condition of "metabolic" stress, depletion of function of beta-cells of islets with formation of diabetes mellitus type I, deficiency in vivo of insulin synthesis. The biological role of albumin - transfer of fatty acids in intercellular medium inform of unesterifed fatty acids and prevention of formation of pool of free fatty acids effecting aphysiologically. PMID- 27455564 TI - [THE ROLE OF TRANSFORMING GROWTH FACTOR-B IN IMMUNOPATHOGENESIS OF DISEASES OF CONNECTIVE TISSUE]. AB - The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor beta (TGFbeta). The involvement of TGFbeta in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem. PMID- 27455565 TI - [THE INFECTION INDUCED BY STREPTOCOCCUS OF SEROGROUP B IN PREGNANT WOMEN, PUERPERA AND NEWBORNS]. AB - The streptococci of serogroup B (Streptococcus agalactiae) are one of major etiologic agents responsible for occurrence of severe perinatal infections in puerpera and newborns. The prevalence of streptococci of group B is analyzed in various categories of women (stage of preconception training, pregnancy, puerpera) and newborns transferred for particular reasons to second stage of raising. The data of microbiological monitoring during four years was involved. It is established that prevalence of carriage of streptococci of serogroup B in genital tracts of women of reproductive age on territory of Omsk consists 6-8% in different categories of female patients and has no tendency to decrease. In most cases, high or moderate level of dissemination, association with other opportunistic microorganisms. The perinatal infection of premature newborns with low body mass at birth with S. agalactiae results in clinical manifestation of generalized infectious process. The infection of healthy premature newborns most often does not result in severe infectious pathology. However; in the half of all cases development of local (significantly more rarely - generalized) pyoinflammatory induced by S. agalactiae as both isolated and in association with other opportunistic microorganisms. The relatively high rate of realization of potential of agent in newborns of risk group requires attention to the issues of diagnostic of carriage of streptococci group B in pregnant women, inclusion of this type of analysis into standards of observation for given category of female patients with purpose of timely sanitation, development and elaboration of standards of laboratory analysis on this agent. PMID- 27455566 TI - [THE PERSPECTIVES OF STUDYING OF POLYMORPHISM OF GENES OF GAMMA-INTERFERON UNDER CHRONIC BRUCELLOSIS]. AB - The brucellosis is an actual zoonotic disease in many countries, Russia included. The complexity of individual prognosis of disease and choice of tactics of maintenance of patients is explained by heterogeneity of clinical manifestations of brucellosis and different rate of progression of organs pathology. Despite of low mortality, this pathology quite often results in disability of patient. The frequent transition of acute process into chronic one (40-60%), probability of development of primary chronic brucellosis determines interest of researchers to issues of immunopathogenesis of this disease. The article presents review of achievements in studies of polymorphism of genes of gamma-interferon in the given area. PMID- 27455567 TI - [CHOOSING ANTIBIOTIC IN MICROBIOLOGICAL ANALYSIS OF INFECTIONS OF URINARY EXCRETION SYSTEM]. AB - The effectiveness of application of test-system "Choice of antibiotic" was evaluated as a tool for incubation of maximal amount of bacteria from pathological material under acute cystitis. The results of meta-genome analysis established that test-system permits supporting growth of practically all bacteria detected in urine, including ones relating to "uncultivated for the present". The comparison of results of standard detection of sensitivity of bacteria to antibiotics and identification of effective pharmaceutical according the results of application of test-system "Choice of antibiotic" as well was implemented It is demonstrated that test- system permits choosing antibiotic during 6-20 hours wiihout isolation of pure strain. PMID- 27455568 TI - [THE EVALUATION OF MICROBIOLOGICAL DISORDERS OF MICROFLORA OF OROPHARYNX AND INTESTINE USING MATHEMATICAL MODELING TECHNIQUE]. AB - The analysis was applied to microflora of feces and oropharinx and concentration of volatile fatty acids in saliva from patients of consultative diagnostic center of G.N. Gabrichevskii Moscow research institute of epidemiology and microbiology. The computer classification program is developed on the basis of determining degree of microbiological disorders on the basis of received data and using artificial neural networks and discriminant analysis. The analysis established decreasing of probability of false classification in case of increasing of degree of microbiological disorders of microflora of intestine and absence of such a correlation for microbiological and metabolic disorders of microflora of intestine. PMID- 27455569 TI - [THE APPLICATION OF DOT-TECHNIQUE FOR DETECTING ANTIGENS OF ADENOVIRUS IN CLINICAL SAMPLES]. AB - The article substantiates possibility of application of point enzyme-linked immunosorbent assay (dot-technique) for detecting viral antigens in samples from patients. To diagnose adenovirus infection conjugate of virus-specific monoclonal antibodies and peroxidase of horse-radish were used The chromatographic rectification of conjugate from free peroxidase permits diminishing background coloring of nitrocellulose membrane and therefore to increase sensitivity. The application of direct conjugates on the basis of virus-specific monoclonal antibodies increases specifcity of dot-technique and significantly shortens time period of analysis. As in case of application of direct conjugates on the basis of polyclonal serum, samples from patients require preliminary processing with detergent for preventing non-specific reactions. The dot-technique demonstrates good coincidence with data of polymerase chain reaction and after clinical trials it can be used in diagnostic of human viral infections. PMID- 27455570 TI - [THE MYCOBIOTA OF TUNICA MUCOSA OF MOUTH AND SURFACE OF REMOVABLE ACRYLIC LAMINAR DENTAL PROSTHESES UNDER ORTHOPEDIC REHABILITATION]. AB - The analysis was carried out to detect mycobiota of tunica mucosa of mouth and surface of dental prostheses under orthopedic rehabilitation using removable acrylic laminar dental prostheses. The inoculation of biosamples received from examined patients permitted to isolate Candida albicans. The C. albicans from tunica mucosa of mouth of patients before prosthetics inoculated in low concentration making up 0.33+/-0.23 CFU/ml in comparison with concentration of 1.92+/-0.53 CFU/ml after prosthetics. The highest content of C. albicans was marked in biosample from surface of dental prostheses in comparison with biotope of tunica mucosa of mouth of patients. The concentration of microbiota from surface of dental prostheses signicantly surpassed the same on tunica mucosa of mouth of patients prior prosthetics. In patients with removable acrylic laminar dental prostheses under orthopedic rehabilitation various spectrum of representatives of microbiota was detected From biosamples from surface of dentalprostheses of patients the most frequently were inoculated such representatives of gram-positive microbiota as S. aureus, Micrococcus spp., S.haemolyticus, and of gram-negative microbiota Klebsiella pneumonae, Pseudomonas aeruginosa. The cultural analysis of biosamples from patients with removable acrylic laminar dental prostheses detected Candida albicans on tunica mucosa of mouth before and after prosthetics as well as on surfaces of prostheses. The highest concentration of C.albicans is established in case of colonization of removable acrylic laminar dental prostheses. The received data testifies possible involvement of fungi capable of expressed potential ofpathogenicity, in development and maintenance of inflammatory process of tunica mucosa of mouth under orthopedic rehabilitation using removable acrylic laminar dental prostheses. PMID- 27455571 TI - [COMPARATIVE CEREBROPROTECTIVE EFFECT OF PREVENTIVE ADMINISTRATION OF MAGNESIUM HYDROXYBUTYRATE VERSUS MAGNESIUM SULFATE AND CAVINTON IN RATS WITH COMMON CAROTID ARTERY OCCLUSION]. AB - Dose-dependent cerebroprotective effect of magnesium hydroxybutyrate (MHB) on common carotid artery occlusion model in rats was established. Administration of 150 mg/kg MHB led to significant decrease in animal mortality (up to 9.3 times) in comparison to control (p < 0.05). This MHB dose also produced significant decrease of neurological deficit on the McGraw scale in comparison to control and magnesium sulfate (50% and 20%, respectively). The MHB treated animals also showed improved locomotor and exploratory performance in the open-field test and retained memory performance in the passive avoidance test and extrapolation escape task test. The administration of 150 mg/kg MHB produced three-fold (p < 0.05) decrease of brain edema in animals with cerebral blood flow impairment in comparison to animals treated with magnesium sulfate and cavinton. PMID- 27455572 TI - [PECULIARITIES OF THE CEREBROVASCULAR EFFECTS OF GLUTAMIC ACID]. AB - Experiments on nonlinear rats subjected to global transient cerebral ischemia revealed the ability of glutamic acid to improve cerebral circulation. Consequently, the excitatory amino acid can produce adverse (neurotoxic) and positive (anti-ischemic) effects in cerebral ischemia. The cerebrovascular effect of glutamic acid in cerebral ischemia is attenuated on the background action of the MNDA receptor blocker MK-801 (0.5 mg/kg intravenously) and eliminated by bicuculline. When glutamic acid is combined with the non-competitive MNDA receptor antagonist MK-801, neither one nor another drug shows its vasodilator effect. The results are indicative of the interaction between excitatory and inhibitory systems on the level of cerebral vessels and once again confirm our previous conclusion about the decisive role of GABA(A) receptors in brain vessels in the implementation of anti-ischemic activity of endogenous compounds (melatonin) and well-known pharmacological substances (mexidol, afobazole), and new chemical compounds based on GABA-containing lipid derivatives. PMID- 27455573 TI - [IMPROVING THE EFFICACY OF THERAPY FOR PATIENTS WITH MYOCARDIAL INFARCTION COMPLICATED BY CIRCULATORY FAILURE]. AB - The effectiveness of drug remaxol inclusion in the scheme of treatment of patients with myocardial infarction on the background of degree III - III acute cardiac insufficiency was evaluated by the analysis of clinical and laboratory data of 126 patients with newly diagnosed acute myocardial infarction including ST-segment elevation on the background of acute cardiac insufficiency. Depending on the regimen, patients were divided into two groups. The first (control) group included 60 patients who received conventional thrombolytic therapy; the second (main) group included 66 patients which, after thrombolytic therapy, received remaxol (single daily intravenous administration, 400 mL at 3 - 4 mL/min rate) with controlled central venous pressure, arterial pressure, and diuresis. The course lasted for 3 - 5 days, depending on the severity of condition. A high efficiency of the treatment regimen including remaxol was established as characterized by more rapid (in comparison to conventional therapy) stabilization of disturbed systemic hemodynamics and recovery of weakened myocardial contractility, decreased risk of cardiac arrhythmias, and relieved hyperhomocysteinemia that, in turn, reduced the risk of complications such as thrombosis and thromboembolism. PMID- 27455575 TI - [INTERACTION OF BETA-BLOCKER PROPRANOLOL WITH RENIN-ANGIOTENSIN SYSTEM INHIBITORS IN RAT KIDNEY]. AB - Propranolol injection (0.5 mg/kg, s.c.) in anesthetized rats increases diuresis 1.60 times (p < 0.05) with simultaneous 1.54- and 1.62-fold increase (p < 0.05) in sodium and potassium excretion, respectively. Preliminary inhibition of renin angiotensin system (RAS) activity using ACE inhibitor enalapril (1 mg/kg, orally, 7 days) increases the sensitivity of rat kidney to drug, increasing its diuretic effect 2.33 times, natriuresis 2.49 times, and urine potassium excretion 1.80 times (p < 0.05). After the preliminary insertion of AT1 angiotensin receptor antagonist losartan (1 mg/kg, orally, 7 days), propranolol causes 1.8-fold increase in diuresis, 2.48-fold decrease in urine sodium, and 1.71-fold decrease in kaliuresis (p < 0.05). Preliminary administration of direct renin inhibitor aliskiren (4 mg/kg, orally, 7 days) is accompanied by 2.30-fold increase in the diuretic effect of propranolol, 2.56-fold increase in natriuresis, and 2.27-fold increase in urine potassium excretion (p < 0.05). It is concluded that the renal tissue RAS is involved in the mechanism of propranolol action in the kidney, acting as modulator preventing excessive loss of water and electrolytes with urine. PMID- 27455574 TI - [NEPHROPROTECTIVE PROPERTIES OF 5-HT3 RECEPTOR BLOCKER RU-63 IN EXPERIMENTAL ACUTE RENAL FAILURE UNDER HYPERGRAVITY CONDITIONS]. AB - The effective diuretic dose of 5-HT3 receptor blocker RU-63 (1 mg/kg) was found in experiments on white rats. It is established that the diuretic and saluretic effects of compound RU-63 increase on the background of impact of the gravitational factor. Compound RU-63 (1 mg/kg, subcutaneously) administered daily under hypergravity conditions (3 g in the direction of centrifugal force toward the kidneys) in animals with model ischemic acute renal failure increased excretory function of kidneys, glomerular filtration rate, and creatininuresis (on average by 180%; p < 0.05), and decreased serum creatinine, urinary excretion of protein, lactate dehydrogenase, and g-glutamyl transferase (on average by 49%; p < 0.05) as compared to the untreated control. Under similar conditions, the diuretic hydrochlorothiazide (in a dose of 20 mg/kg, intragastric) produced a more pronounced creatininuretic action than that of RU-63 (by 358%; p < 0.05). PMID- 27455576 TI - [THE STUDY OF THE EFFECTS OF ANXYOLYTIC, ANTIOXIDANT, IMMUNOCORRECTOR AND HYPERBARIC OXYGENATION ON THE DYNAMICS OF MAIN BLOOD GAS AND ELECTROLYTE INDICES AND BEHAVIORAL RESPONSE IN EXPERIMENTAL STRESS MODEL]. AB - Experiments on the model of immobilization stress in albino mice showed that a combination of mexidol, thymogen, and hyperbaric oxygenation reduced adverse effects of diazepam on behavioral response of animals in the black-and-white chamber and elevated cross maze tests and led to optimization of the blood gas composition as manifested by increased oxygen tension, normalization of the partial pressure of carbon dioxide, and restoration of the acid-base balance and blood bicarbonate level. The proposed combined treatment can be recommended for the treatment of patients with stress-induced pathology. PMID- 27455577 TI - [EFFECT OF 4-METHYLPYRAZOLE ON IMMUNE RESPONSE, FUNCTION OF Th1 AND Th2 LYMPHOCYTES, AND CYTOKINE CONCENTRATION IN RAT BLOOD AFTER ACUTE METHANOL POISONING]. AB - It was established in experiments on noninbred albino rats that the acute intoxication with methanol (1.0 LD50) decreased cellular and humoral immune responses, Th2-lymphocyte activity (to a greater extent as compared to the function of Th1 cells), reduced the blood concentration of immunoregulatory (IFN g, IL-2, IL-4) and proinflammatory (TNF, IL-1b, IL-6) cytokines on the average by 36.5% (p < 0.05), and did not affect the content of anti-inflammatory cytokines (IL-10, IL-13). Methanol antidote 4-methylpyrazole (non-competitive inhibitor of alcohol dehydrogenase) administered upon acute intoxication with methanol at a dose of 1.0 DL50 partially reduces the intoxication-induced suppression of humoral and cellular immune response, activity of T-helper cells, and production of IL-4 and restores blood levels of TNF, IL-1b, IFN-gamma, IL-4, IL-2, IL-6 to the control values. PMID- 27455579 TI - Staffing: A Matter of Life or Death. PMID- 27455578 TI - [STEROIDAL GENINS AND GLYCOSIDES OF SPIROSTAN AND FUROSTAN SERIES AS ANTHELMINTHIC AGENTS]. AB - It was established that steroidal genins and their glycosides of the spirostan series and (especially) furostan series show anticestodal activity against Hymeiolepis nana species. Search for anthelminthic agents in the indicated series of compounds is a promising direction of research. PMID- 27455580 TI - The Discomfort of Unity: Working Together In Spite of Differences. PMID- 27455581 TI - The Mindful Nurse. PMID- 27455582 TI - The Power of Partnership and Collaboration. PMID- 27455583 TI - How to Lead in Today's Changing Healthcare Landscape. PMID- 27455584 TI - What Keeps People from Lifesaving Colon Cancer Testing? PMID- 27455585 TI - Editorial Comments. PMID- 27455586 TI - Editorial Comments. PMID- 27455587 TI - Editorial Comments. PMID- 27455588 TI - Editorial Comments. PMID- 27455589 TI - Editorial Comments. PMID- 27455590 TI - Editorial Comments. PMID- 27455591 TI - Editorial Comments. PMID- 27455592 TI - Editorial Comments. PMID- 27455593 TI - Editorial Comments. PMID- 27455594 TI - [Not Available]. PMID- 27455595 TI - How Can Nurses Unify and Not Divide the Profession? PMID- 27455596 TI - [Antibiotic resistance analysis of Enterococcus spp. and Enterobacteriaceae spp. isolated from food]. AB - The isolates from foods were screened for sensitivity to clinically significant antibiotics to assess the actual situation related to the prevalence of the antibiotic-resistant microorganisms in food. The goal of this work was to study the phenotypic characteristics of the antibiotic susceptibility of Enterobacteriaceae and Enterococcus spp. isolated from the good quality foods, and evaluation of the prevalence of tetracycline resistance in this groups of microbial contaminants. 68 strains of Enterobacteriaceae family and Enterococcus spp. isolated from poultry and livestock meat, pasteurized dairy products, acquired in the retail in the Moscow region, were studied. The disk-diffusion method (DDM) analysis showed a rather high prevalence of bacteria that are resistant and forming resistance to broad-spectrum antibiotics: in general 38% of Enterobacteriaceae strains and 40% of Enterococcus spp., isolated from meat products were resistant to tetracycline and doxycycline, and 21 and 33% - from dairy products, respectively; 26% of milk isolates and 54% of meat isolates were resistant to ampicillin. Considering that the tetracyclines is the most frequently used in animal husbandry and veterinary, the incidence and levels of tetracycline resistance were evaluated using tests with higher sensitivity to minimum inhibitory concentration (MIC), than the DDM. It was shown that among the Enterobacteriaceae strains 26% of <> isolates and 38% < isolates were highly resistant to tetracycline (MIC ranged from 8 to 120 mg/kg) and 17-40% - among Enterococcus spp. These data obtained on a small number of samples, however, correspond to the frequency of tetracycline resistant strains detected in animal products in the EU (10-50%). Two multidrug-resistant enterobacteria strains - Klebsiella pneumoniae (farmer cheese) and Escherichia coli (minced turkey) were found among the .46 strains (4.4%), and they were resistant to 8 antibiotics. PMID- 27455597 TI - [Toxicological evaluation of colloidal nano-sized silver stabilized polyvinylpyrrolidone. III. Enzymological, biochemical markers, state of antioxidant defense system]. AB - Nanosized colloidal silver (NCS) with primary nanoparticles (NPs) size in the range of 10-80 nm in aqueous suspension was administered to rats with initial weight 80+/-10 gfor the first 30 day intragastrically and for lasting 62 days with the diet consumed in doses of 0.1; 1.0 and 10 mg/kg of body weight b.w) per day based on silver (Ag). The control animals received deionized water and carrier of NPs - aqueous solution of stabilizer polyvinylpyrrolidone. Activity (Vmax) was determined in liver of microsomal mixed function monooxygenase isoforms CYP 1A1, 1A2 and 2B1 against their specific substrates, the activity of liver conjugating enzymes (glutathione-S-transferase and UDP glucuronosyltransferase) in the microsomal fraction and a cytosol, and the overall and non-sedimentable activities of lysosomal hydrolases. In blood plasma there were evaluated malonic dialdehyde, PUFA diene conjugates, in erythrocytes - the activity of antioxidant enzymes. A set of standard biochemical indicators of blood serum was also determined. The studies revealed changes in a number of molecular markers of toxic action. Among them - the increase in the activity of key enzymes I and II stages of detoxification of xenobiotics, indicating its functional overvoltage; reducing the activity of glutathione peroxidase (GP), the total arylsulfatase A and B, beta-galactosidase (in the absence of changes in their non-sedimentable activity), levels of uric acid, increased alkaline phosphatase activity. These changes occurred mainly at the dose Ag of 10 mg/kg b.w., except for the GP to which the threshold dose was 1 mg/kg b.w. No significant changes in the studied markers in a dose Ag 0,1 mg/kg b.w. were identified. Possible mechanisms of the toxic action of silver NPs are discussed. PMID- 27455598 TI - [Daily calorie and macronutrient consumption in girls of different somatotypes with different shares of body fat, muscle and bone components]. AB - 211 practically healthy girls, the students of Krasnoyarsk Medical University in the ages of 16 to 20 years, have been examined. We determined their somatotypes (euriplastic, athletic, subathletic and stenoplastic) and body composition (fat, muscle, bone component). Actual nutrition in these subjects was studied by the method. of 24-hour nutrition recall involving foodstuffs models. Energy consumption in cohorts with different somatotypes did not differ from one another and ranged from 1880 to 2115 kilocalories per day, that corresponded to normal physiological needs in women of this age with the coefficient of physical activity as 1.4 (students). Only the intake of fat (% of calories) exceeded the performance standards. As for macronutrients, the majority of indicators of nutrient intake did not differ significantly among girls with different somatotype, except for fat intake in girls with athletic and stenoplastic somatotypes (p<0.034) and carbohydrate consumption in the objects with euriplastic and subathletic somatotypes (p<0.046). The most significant of the findings is the absence of veracious differences in daily energy consumption between the cohorts with different somatotypes with statistically considerable, differences in both overall dimensions (body mass and length) and the ratios between fat, muscle and bone as somatic components. In general, macronutrient consumption did not show any differences as well. Thus, apart from the energy and macronutrient consumption, definite meaning within the process of the formation of body composition can belong to the characteristics of the changes following nutrition load on lipoid spectrum of blood serum as well 'as the peculiarities of the distribution of substrate flow among cell metabolic paths, appropriate of definite somatotypes. PMID- 27455599 TI - [The analysis of domestic and international policy of food fortification with vitamins]. AB - Fortification of food products of mass consumption with vitamins is a modern, most cost-effective, efficient and physiological way to improve the vitamin status of the population. Free or voluntary enrichment on the initiative of producers is used in the industrialized countries at low risk for inadequate population intake of micronutrients. Enrichment of products of mass consumption is almost always mandatory, legislative consolidated, while target enrichment of foods intended for different groups can be both mandatory and voluntary The criteria for the effectiveness of mandatory food fortification are an increase of certain vitamin consumption, reduce of the relative number of people with inadequate intake of certain micronutrients, improvement of micronutrient sufficiency (blood level), enhancement of biomarkers of some alimentar diseases, reduction of the frequency of congenital defects (neural tube defect). Assessment of risk/benefit ratio indicates safety of mandatory fortification of flour with B vitamins. In Russia, the regulatory framework for food fortification (enrichment levels, forms of vitamins) has been yet laborated. But initiative enrichment, held in Russia, does not give the desired result. An urgent need for legislative mandatory fortification of products consumed by the majority of the population (bread, milk) with B vitamins (the lack of which is the most frequently detected in the population of Russia) arose in a lack of knowledge of the population about the benefits of fortified foods and lack of preference in the selection of such products. PMID- 27455600 TI - The effects of organic chromium on adipose anatomical parts, using pig as experimental model. AB - The aim of this study was to evaluate the influence of chromium supplements on the quality of protein and lipids of adipose anatomical parts using pig as experimental modelfor humans. An experiment was conducted on 18 fattening castrated TOPIGS male pigs, for 4 weeks, under experimental farm conditions. The source of Cr(III) was chromium . picolinate, a food supplement used in human nutrition, 200 ug.Cr per kg diet (El) and 400 ug.Cr per kg diet (E2). The analytic.data showed an improvement of the amino acids profile in belly and in ham samples. A significant decrease of fatty acids concentrations in belly samples was noticed. In conclusion, we observed a positive effect associated with the essential amino acids deposition and decreasing of fatty acids concentrations in tissues with high content offat, thus in human nutrition, chromium is used as a nutritional supplement most recommended in impaired carbohydrate metabolism. PMID- 27455601 TI - [Influence of the concentrate of red wine polyphenols on glutamate neurotoxicity]. AB - The purpose of the work was to assess the influence of the concentrate of red table wine Saperavi on the cultivated nerve cells exposed to glutamate. The selection of Saperavi as the source of phenolic compounds was not accidental: this type of grapes in the Krasnodar region has the highest content of them - up to 4-5 g/dm3 and more. Polyphenol concentrate was prepared by pre-distillation of ethanol using vacuum, evaporation of red table wine with a rotary vaporizer, with the subsequent lyophilic drying. By the methods of voltammetry and chemiluminescence an antioxidant activity, and a quantity of antioxidants in the concentrate have been determined. By HPLC it was established that a large group of phenolic compounds with high antioxidant activity was present in the concentrate of polyphenols: procyanidins (total concentration up to 425 mg/dm3), quercetin (21.8-32.6 mg/dm3), gallic acid (124.2-164.7 mg/dm3), resveratrol (6.26 13.22 mg/dm3), catechins (1026 - 1480 mg/dm3). Effect of red wine Saperavi concentrate on glutamate cytotoxicity was studied in the neuron culture of the cerebellum of 7-9-day-old rats. It was shown that the presence of. antioxidants reduced the intensity of chemiluminescence in model systems that generate free radicals. It was established that quenching of chemiluminescence in the system <> composed 68.43%, and in the system of the yolk lipoproteins - 86.36%. The application of concentrate Saperavi significantly increased the survivability of neurons: at the doses 5, 10 and 30 mcg/ml the number of intact neurons was respectively 38.6; 41.5 and 37.1%. The dose 20 mcg/ml was the most effective - the proportion of live neurons comprised 47.4%. The obtained results can be explained by the high antioxidant activity of concentrate flavonoids, including high content of biologically active compounds - catechins, quercetin, rutin, resveratrol. Thus, the consumption of red wine in quantities that exclude harmful effects, can have a positive impact on human health and the brain in particular. PMID- 27455602 TI - [Assessment of efficiency of the personalized therapy of patients with obesity and diabetes mellitus 2 types appointed on the basis of studying rs5219 polymorphism of KCNJ11 gene]. AB - The aim of the study was to develop and evaluate the effectiveness of personalized therapy forpatients with diabetes mellitus type 2 (DM) and obesity based on the study of rs5219 polymorphism of KCNJ11gene. The study involved 120 women with DM and obesity I-II degree. Genotyping was performed in patients using allele-specific amplification with the detection in real time. Depending on the genotype of KCNJ11 gene patients with DM and obesity received different treatment and were divided into 2 groups (40 patients in each): group A (C/T genotype) received standard low-calorie diet + metformin 2000 mg/day and group B (T/T genotype) received a personalized diet + vitamin-mineral complex (VMC) + metformin 2000 mg/day. Results of the study of rs5219 polymorphism of KCNJII gene in patients with,DM and obesity have shown that 49% of them were carriers of the mutated T allele in the heterozygous form and 37% - in the homozygous variant. It has been found that reducing of calories in a diet promoted weight loss in patients with DM and obesity mainly due to lean body mass in Group A and in Group B - mainly due to the fat component. A significant decrease in blood glucose under complex therapy was observed in both groups. However, after treatment in group B blood glucose levels were significantly lower than in group A. Thus, personalized therapy of patients with DM and obesity should be based on molecular genetic studies that will allow to improve the efficiency of therapeutic measures in these diseases. PMID- 27455603 TI - [Nutritional management of kidney diseases in children]. AB - The prevalence of various kidney diseases in children remains high in recent decades. Adequate nutrition management can enhance the effectiveness of drug treatment, slow the frequency of relapses andprevent the progression of the disease. The article is devoted to modern approaches to diet therapy in various kidney diseases in children with the defeat of tubular and glomerular appa ratus. For the first time the therapeutic diets for children with various kidney diseases are presented. Particular attention is paid to diet therapy in nephrotic syndrome (steroid-responsive and steroid-refractory). Dietary approaches with modern formulas for enteral nutrition in cases of steroid therapy complications in children with renal insufficiency (in predialysis stage and on dialysis) are described. Differentiated nutritional approaches for patients with different types of crystalluria are separately presented. PMID- 27455604 TI - [Using a multicomponent functional food in IBS patients with constipation a comparative controlled study]. AB - Irritable bowel syndrome (IBS) is highly prevalent functional gastrointestinal disorder associated with decrease in quality of life and a high social cost. Diet is one of several therapeutic options in IBS treatment; therefore the development and clinical evaluation of innovative functional food for IBS patients are actual. Instant drink containing 4 g inulin, 4 mg menthol and 2 mg of pyridoxine (in daily dose) has been evaluated. 49 patients 18-68 (41.5+/-16.5) years old fulfilling the Rome III criteria for IBS-C were randomly assigned into two groups: one received standard diet plus two drinks per day for 2 weeks and control group received standard diet. Response to therapy was recorded daily using Likert scale of abdominal pain, bloating and feeling of incomplete bowel emptying, frequency of bowel movement, Bristol stool scale, and quality of life was assessed by IBSQoL questionnaire before and after the treatment. The consumption of the drink with inulin and menthol contributed to a significant positive effect on the stool parameters (from 0.91+/-0.73 to 1.12+/-0.45 bowel movements per day in stool frequency, p=0.05, from 2.68+/-1.63 to 3.43+/-1.27 index Bristol scale, p=0.05), reduced the severity of abdominal pain (from 1.78+/ 0.58 to 1.47?0.61 Likert scale points, p=0.05), bloating (from 2.22+/-0.83 to 1.53+/-0.71 points ofLikertscale,p= 0.01) and a sense of incomplete bowelemptying (from 2.22 +/- 0.88 to 1.61+/- 0.81 points of Likert scale, p=0.001), as well as increased the quality of life (from 75.3+/- 12.0 to 83.3+/-6.7%, p=0.05), but a significant part of patients (10 of 25) complained the appearance of heartburn after the start of the treatment. In conclusion, the consumption of the functional drink containing inulin, menthol and pyridoxine is associated with improve in stool parameters, abdominal pain, Bristol scale index and increase in quality of life in patients with IBS-C, but produce noticeable heartburn. Changes in functional drink composition are needed to reduce adverse effects. PMID- 27455605 TI - [New international initiatives to create systems of effective risk prediction and food safety]. AB - Ensuring food safety is one of the most important problems that is directly related to health protection of the population. The problem is particularly relevant on aglobalscale because ofincreasingnumberoffood-borne diseases andimportance of the health consequence early detection. In accordance with the position of the Codex Alimentarius Commission, food safety concept also includes quality. In this case, creation of the national, supranational and international early warning systems related to the food safety, designed with the purpose to prevent or minimize risks on different stages of the food value chain in various countries, regions and climate zones specific to national nutrition and lifestyle in different groups of population, gains particular importance. The article describes the principles and working examples of international, supranational and national food safety early warning systems. Great importance is given to the hazards of microbial origin - emergent pathogens. Example of the rapid reaction to the appearance of cases, related to the melanin presence in infant formula, are presented. Analysis of the current food safety and quality control system in Russian Federation shows that main improvements are mostly related to the development of the efficient monitoring, diagnostics and rapid alert procedures forfood safety on interregional and international levels that will allow to estimate real contamination of food with the most dangerous pathogens, chemical and biological contaminants, and the development of the electronic database and scientifically proved algorithms for food safety and quality management for targeted prevention activities against existing and emerging microbiological and other etiology risks, and public health protection. PMID- 27455606 TI - [On the need to improve the system for the prevention of falsification of food products in the Eurasian Economic Union]. AB - Adulteration of food is misleading consumers about the composition of foods in order to obtain economic benefits. Olive oil, wine and other alcoholic beverages, spices, tea, fish, honey, milk and dairy products, meat products, cereal products, beverages based on fruit juices, spices, coffee are falsified with the highest frequency. In addition, sufficient data on the frequency of adulterated food products are missing not only in Russia but also in the developed countries. This is because the purpose of the manufacturer and distributors of such products is primarily an economic advantage. Therefore, the majority of incidents of falsification of food products remained undetected since their production, generally had not led to the risk of food safety, and consumers often did not notice the reduction in quality of foodstuffs. The analysis of international data and data of the Eurasian Economic Union (EAEU) has shown that, in order to improve the quality of food products and to reduce sales of adulterated food the following steps should be done: introduce the definition of falsificated food products into legislation of the EAEU; expand the list of methods for confirming the authenticity of the food and detecting the presence of substances which are not permitted for usage in the food industry; consolidate the principle of the responsibility of all participants in the treatment of food that does not comply with the mandatory requirements at the legislative level; introduce the indicators of the quality of foodstuffs in the technical regulations of the EAEU; return to the mandatory requirements for the quality of foods given in the interstate and state standards. PMID- 27455607 TI - [Bread from the bioactivated wheat grain with the raised nutrition value]. AB - Bread from the bioactivated grain of wheat differs in high content of dietary fibers, minerals and vitamins compared to traditional types of bread, but, despite this, it has low protein and lysine content. The aim of the study was the development of bread with the raised nutritional value from the bioactivated wheat grain by use of flour from cake of wheat germ (6.5%). It has been established that the flour from wheat germ has protein biological value (77.4%) and the amino acid score according to lysine (100.3%) above 12 and 40.5%, respectively, compared with those from bioactivated wheat. During calculation of nutritive, biological and energy value of products from the bioactivated wheat grain it is revealed that the biological value of bread from wheat germ flour slightly exceeded the biological value of the bread without its addition and amounted to 70.80%, due to a high protein content and a balanced amino acid composition. The protein content in the test sample of bakery products was 19.0% higher than the control, phosphorus - 13.0%, zinc - 50.0%. PMID- 27455608 TI - [Kodentsova Vera Mitrofanovna (to the 60th anniversary of the birth)]. PMID- 27455609 TI - A Special Section on Nanodiagnostics and Nanotherapeutics. PMID- 27455610 TI - Progress in the Field of Constructing Near-Infrared Light-Responsive Drug Delivery Platforms. AB - Stimuli-responsive materials have taken replace of traditional drug carriers due to their ability to achieve controlled release of their encapsulated contents. A variety of sensitive materials, such as polymers that respond to pH, light, and magnetic fields, are widely used to construct drug carriers, and achieved good results. Specifically, near-infrared light (NIR) responsive materials are of particular interest in drug delivery, as NIR can penetrate body tissue and is minimally absorbed by the body's water and hemoglobin and is less harmful to healthy cells than UV or visible light. Thus, the near-infrared excitation drug delivery systems (NIRDDSs) have some essential advantages just like being efficient to kill tumor cells, accurate to achieve the tumor sites and less damage to human body. Also, in the process of building the carriers, we may achieve a combination of controlled release chemotherapy, photothermal therapy (PTT) or photodynamic therapy (PDT). In addition, besides utilizing as drug delivery platforms, some carriers can achieve multifunctional tumor diagnosis and treatment, such as magnetic resonance imaging, optical imaging, drug carriers and PTT. In this review, based on the mechanism of NIR, we highlight diverse near infrared light-responsive drug delivery platforms and recent advances in the development of NIRDDSs for cancer therapy primarily. PMID- 27455611 TI - Nano-Delivery Vehicles/Adjuvants for DNA Vaccination Against HIV. AB - More than 75 million people has been infected HIV and it is responsible for nearly 36 million deaths on a global scale. As one of the deadliest infectious diseases, HIV is becoming the urgent issue of the global epidemic to tackle. In order to settle this problem from the source, some effective prevention strategies should be developed to control the pandemic of HIV. Vaccines, especially DNA vaccines, could be the optimal way to control the spread of HIV due to the unparalleled superiority that DNA vaccines could generate long-term humoral and cellular immune responses which could provide protective immunity for HIV. But the naked DNA could hardly enter into cells and is easily degraded by DNases and lysosomes, so designing effective delivery system is a promising strategy. Since delivery system could be constructed to promote efficient delivery of DNA into mammalian cells, protect them from degradation, and also could be established to be a target system to arrive at certain position of expectation. The current review discusses the potential of various nano-delivery vehicles/adjuvants such as polymer, lipid, liposome, peptide and inorganic material in improving efficiency of diverse modalities available for HIV DNA vaccines. PMID- 27455612 TI - Nanodrug-Mediated Thermotherapy of Cancer Stem-Like Cells. AB - Cancer stem-like cells (CSCs) are rare subpopulations of cancer cells that are resistant to conventional chemotherapy and radiotherapy and contribute to cancer metastases and tumor recurrence. Therefore, it is of significance to develop an effective therapy to eliminate the CSCs. Cancer thermotherapy realized by depositing heat into tumor in a minimally invasive way is a promising alternative to the conventional therapies for cancer treatment. However, this method is limited by its inability to target CSCs, potentially allowing the CSCs to survive and re-initiate tumor growth. More recently, nanodrug-mediated thermotherapy has been explored to selectively eliminate CSCs and specifically deposit heat in tumor to spare healthy tissue. Here, we provide a brief overview of the targeting moieties and nanoplatforms used in developing nanodrug-mediated thermotherapy of cancer with particular emphasis on the CSCs, as well as the challenges and potential directions for future research in this emerging field. PMID- 27455613 TI - Nanomedicines for Therapy of Visceral Leishmaniasis. AB - Visceral leishmaniasis (VL) or kala-azar is a vector borne infectious disease caused by the protozoan parasites of the genus Leishmania. VL is endemic in more than 85 countries with an estimated 0.2-0.5 million people at risk, causing high morbidity and mortality across the globe. In the absence of effective vaccines, treatment solely relies on chemotherapy and can be 100% fatal within two years, if left untreated. However, the present chemotherapeutics is limited by toxicity, non-compliance, location of parasites within the lysosomal vacuoles of macrophages, impairing the accession of many potential antileishmanial drugs, prolonged and cumbersome regimen that is unaffordable by rural population with alarming increase in unresponsiveness, complications of post kala-azar dermal leishmaniasis (PKDL) and HIV co-infections. Nanotechnology offers promising approach in the treatment of VL as it reduces toxicity, improves the therapeutic index of drugs, and can selectively deliver the antileishmanial cargos to the intracellular pathogens. In addition, nanoparticles can interact with the host immune system, modulating the immune response in a way that may favor the elimination of the Leishmania parasites. In this review, we give an overview of the strategies and delivery systems employed for the antileishmanial drugs towards the riddance of deadly VL. PMID- 27455614 TI - A Review on Magnetophoretic Immunoseparation. AB - Magnetophoresis is a motion of a magnetic or magnetizable particle induced by an inhomogeneous magnetic field in a fluid. Magnetophoretic immunoseparation, using micro- or nano-sized magnetic particles often modified by monoclonal or polyclonal antibodies for specific separation of biological or chemical targets, has shown a great potential in continuous-flow separation of cells and bacteria in clinical and biomedical fields. In this paper, the basic knowledge, key design considerations and recent developments on magnetophoretic immuno-separation of biological targets were reviewed. PMID- 27455615 TI - Applications of Bacterial Magnetic Nanoparticles in Nanobiotechnology. AB - The bacterial magnetic nanoparticle (BMP) has been well researched in nanobiotechnology as a new magnetic crystal. The BMPs are extracted from magnetotactic bacteria and under precise biological control. Compared with engineered magnetic nanoparticles synthesized by chemical approaches, BMPs have the properties of large production, monodispersity, high crystallinity, and close to-bulk magnetization, which enable BMPs to be the highly promising magnetic nanoparticles for nanobiotechnology. In this paper, we review the biomedical applications of BMPs in magnetic hyperthermia, drug treatment with tumour and bioseparation. In addition, the biodistribution and toxicity are also reviewed. PMID- 27455616 TI - Development of Novel Cadmium-Free AgInS2 Semiconductor Nanoparticles. AB - AgInS2 (AIS) semiconductor nanoparticles as the novel alternatives to cadmium- or lead-containing semiconductors have attracted much attention both on the theory and application research, based on their tunable fluorescence emission wavelengths, high photostability and low toxicity of chemical composition. The bandgap of AIS nanoparticles can be adjusted from 1.54 to 2.03 eV, which makes AIS nanocrystalline suitable for applications in solar energy conversion. Moreover, the fluorescence emission wavelengths can be tuned in the near-infrared regions, and thus make it the next-generation low-toxicity materials for the applications in bioimaging. In this review, the research progress of the AIS nanoparticles is summarized, including synthetic methods, properties and the possibilities to influence their shape and crystallographic structure. Furthermore, we discuss the potential applications of this novel material in photocatalysis, solar energy conversion and biological area. PMID- 27455617 TI - Prussian Blue Modified PLA Microcapsules Containing R6G for Ultrasonic/Fluorescent Bimodal Imaging Guided Photothermal Tumor Therapy. AB - A theranostic agent has been successfully constructed for fluorescence/ultrasound dual-modal imaging guided photothermal therapy by loading the fluorescent dye R6G into polylactide microcapsules (PLA MCs) followed by deposition of Prussian blue nanoparticles (PB NPs) into the surface of PLA MCs. It was proved that the obtained microcapsules of R6G@PLA/PB MCs could serve as an efficient probe to simultaneously enhance fluorescence imaging and ultrasound imaging greatly in vivo. R6G@PLA/PB MCs exhibited significant photothermal cytotoxicity. Cancer cells could be killed efficiently through photothermal effects of R6G@PLA/PB MCs due to the strong absorption of PB NPs in the near infrared region under laser irradiation. In a word, R6G@PLA/PB MCs integrate multiple capabilities for effective tumor imaging and therapy. Such a single agent provides us a possibility to interpret accurately the obtained images, identify the size and location of the tumor, as well as guide and monitor the photothermal therapy. PMID- 27455618 TI - One-Pot Synthesis of Fe3O4@PS@P(AEMH-FITC) Magnetic Fluorescent Nanocomposites for Bimodal Imaging. AB - Magnetic fluorescent nanocomposites have attracted much attention because of their merging magnetic and fluorescent properties for biomedical application. However, the procedure of synthesis of magnetic fluorescent nanocomposites is always complicated. In addition, the properties of fluorescent component could be easily influenced by magnetic component, retaining both of the magnetic and fluorescent properties into one single nanoparticle considered to be a significant challenge. Herein, we report one-pot method to synthesize multifunctional magnetic fluorescent Fe3O4@PS@P(AEMH-FITC) nanocomposites for bimodal imaging. The asprepared Fe3O4@PS@P(AEMH-FITC) nanocomposites with well define spherical core/shell structure were stable properties. Moreover, the Fe3O4@PS@P(AEMH-FITC) nanocomposites displayed efficient fluorescent and magnetic properties, respectively. Meanwhile, the magnetic resonance imaging (MRI) and HePG2 cancer cell fluorescent images experiment results suggested that Fe3O4@PS@P(AEMH-FITC) nanocomposites could be used as MRI contrast agents and Fluorescence Imaging (FLI) agents for bioimaging application. Our investigation paves a facile avenue for synthesized magnetic fluorescent nanostructures with well biocompatibility for potential bioimaging application in MRI and FLI. PMID- 27455619 TI - Graphene Oxide and Gadolinium-Chelate Functionalized Poly(lactic acid) Nanocapsules Encapsulating Perfluorooctylbromide for Ultrasound/Magnetic Resonance Bimodal Imaging Guided Photothermal Ablation of Cancer. AB - This paper successfully fabricated a novel multifunctional theranostic agent (PFOB@PLA/GO/Gd-DTPA NCs) by loading perfluorooctylbromide (PFOB) into poly(lactic acid) (PLA) nanocapsules (NCs) followed by surface functionalization with graphene oxide (GO) and gadolinium-chelate (Gd-DTPA). It was found that the resulting nanoagent could serve as a contrast agent simultaneously to enhance ultrasound (US) and magnetic resonance imaging (MRI). Benefiting from the strong absorption in the near infrared (NIR) region, the nanocapsules could efficiently kill cancer cells under NIR laser irradiation. Thus, such a single theranostic agent with the combination of realtime US imaging and high-resolution MR imaging could achieve great therapeutic effectiveness without systemic damage to the body. In addition, the cytotoxicity assay on HUVEC cells revealed a good biocompatibility of PFOB@PLA/GO/Gd-DTPA NCs, showing that the versatile nanocapsule system may hold great potential as an effective nanoplatform for contrast enhanced imaging guided photothermal therapy. PMID- 27455620 TI - Biodegradable Poly(aminoester)-Mediated p53 Gene Delivery for Cancer Therapy. AB - Gene therapy is a promising strategy in cancer treatment. However, efficient gene translation still remains challenging. In the previous work, a hydrolytically degradable poly(aminoester) with good biocompatibility was synthesized. Herein, the poly(aminoester) was explored as a vector for gene delivery and cancer therapy. The experiments revealed that the poly(aminoester) condensed plasmid DNA into nanosized particles via electrostatic interaction. The pEGFP-N1 and pGL-3 were first used as two reporter genes to study intracellular transfection. The poly(aminoester) showed higher GFP expression (33%) than PEI 25 kDa (21%). Intracellular trafficking of Cy3-labelled pGL-3 also indicated that the poly(aminoester) showed superior DNA delivery ability to nucleus compared to PEI 25 kDa. Furthermore, the therapeutic gene (p53) was translated into the breast cancer cell line (MCF-7), and then induced cell apoptosis. These results suggested that the degradable poly(aminoester) is a promising and efficient gene delivery vector for gene therapeutic applications. PMID- 27455621 TI - Effective Removal of Tetracycline from Aqueous Solution by Organic Acid-Coated Magnetic Nanoparticles. AB - Self-assembled iron oxide nanocomposites are good magnetic nano-adsorbents that can be prepared using simple methods. Four types of organic acid-functionalised (oleic acid, undecenoic acid, caprylic acid or hexanoic acid) magnetic nanoparticles (MNPs) were synthesised through a one-pot chemisorption method for the removal of tetracycline (TC) from aqueous solution. The undecenoic acid coated MNPs (UA-MNPs) exhibited the highest adsorption efficiency and can be easily retrieved with a low-gradient magnetic separator (0.4 Tesla) at pH 5.0 aqueous solution. The TC adsorption process on the UA-MNPs followed the Langmuir isotherm and the maximum adsorption capacities increased from 86.96 mg g(-1) to 222.2 mg g(-1) with the increase in temperature from 288 K to 318 K. The kinetics of adsorption fits pseudo-second-order model perfectly with a rate constant, 5.946 g mg(-1) min(-1) at 298 K. The positive values of the enthalpy (AH) and the negative value of the free energy (AG) indicated an endothermic and spontaneous adsorption process of TC on the UA-MNPs. Moreover, the UA-MNPs possessed excellent ability to adsorb the other three major types of TC antibiotics, including chlortetracycline, oxytetracycline and doxycycline. PMID- 27455622 TI - Study on River Snail Shells Unearthed from Laoniupo Shang Dynasty Site. AB - The samples of river snail shell pieces, unearthed from Laoniupo Shang dynasty site, were observed and characterized by SEM, Raman and IR to obtain the information about their chemical component and crystal structure. The uneven surface of the cuticle was covered with nanoparticles, which formed rough surface of the shells. The surface of pearl layer was combined with nano-sized flakes and kept smooth on the whole. The insection of shell was composed of three layers: the cuticle (100-120 MUm in thickness), the prismatic layer (-130-140 MUm in thickness), and the thickest pearl layer (280-300 MUm in thickness). All layers had the component of calcium carbonate with aragonite structure and they were different in nanostructures because of different biomineralization processes. PMID- 27455623 TI - Uniform Superparamagnetic Fe3O4/CMCS Composite Nanospheres for Lysozyme Adsorption. AB - In this study, uniform superparamagnetic Fe3O4/carboxymethyl chitosan composite nanospheres with high saturation magnetization were successfully synthesized via a modified inverse emulsion crosslinking approach, using genipin as a cross linking agent. These nanospheres were then characterized, and their protein adsorption capacity was further investigated under various conditions. The implementation of a sonication treatment of a mixture containing Fe3O4 nanoparticles and carboxymethyl chitosan before the emulsion process significantly promoted the homogeneity of Fe3O4 nanoparticles in an aqueous phase system. The Fe3O4/carboxymethyl chitosan composite nanospheres were of uniform spherical structure, were approximately 230 nm in size, and possessed superparamagnetic characteristics with a mean saturation magnetization as high as 35 emu g(-1), corresponding to a magnetite content of 43%. Lysozyme was then employed as a model protein to investigate the effects of pH, incubation time and ion strength on the protein adsorption capacity of the as-synthesized composite nanospheres. The as-obtained composite nanospheres could serve as a promising candidate for fast and efficient protein adsorption. PMID- 27455624 TI - Mixed Surfactant Solutions for the Dispersion of Multiwalled Carbon Nanotubes and the Study of Their Antibacterial Activity. AB - The dispersibility of mixed surfactant-modified multiwalled carbon nanotubes (MWNTs) and their effect on antibacterial activity were examined. The ratio of 9:1 between sodium dodecyl benzene-sulfate (SDBS) and hexadecyltrimethylammonium bromide (CTAB) showed the highest dispersing power for MWNTs. The use of mixed surfactants enabled the MWNTs to form a stable dispersion at a lower total surfactant concentration than their concentrations when used alone. UV-vis spectroscopy, transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FT-IR) were used to characterize the dispersion of MWNTs in the aqueous phase. The results indicated that the surfactant molecules had been successfully adsorbed onto the surface of the MWNTs. The mixed surfactant modified MWNTs exhibited a strong antibacterial activity and concentration dependence to Staphylococcus aureus (S. aureus). Based on the considerations of the cost and environmental impact, the use of mixed surfactants (SDBS-CTAB) should be more favorable for the stable dispersion of MWNTs and the improvement of antibacterial activity than the use of a single surfactant. PMID- 27455625 TI - Enhancement of Thermal Damage to Adenocarcinoma Cells by Iron Nanoparticles Modified with MUC1 Aptamer. AB - Hyperthermia cancer treatment is an adjunctive therapy that aims at killing the tumor cells with excessive heat that is usually generated by metal contrasts exposed to alternating magnetic field. The efficacy of hyperthermia is often limited by the heat damage to normal tissue due to indiscriminate distribution of the metal contrasts within the body. Tumor-targeting metal contrasts may reduce the toxicity of hyperthermia and improve the efficacy of thermotherapy against cancer. MUC1 is a glycoprotein over expressed in most adenocarcinomas, and represents an attractive therapeutic target. In this study, a MUC1 aptamer is conjugated with iron nanoparticles to construct adenocarcinoma-targeting metal contrasts. DNA hybridization studies confirmed that the aptamers were conjugated to the iron nanoparticles. Importantly, more aptamer-modified nanoparticles attached to the MUC1-positive cancer cells compared with the unmodified nanoparticles. Moreover, aptamer-modified nanoparticles significantly enhanced the targeted hyperthermia damage to MUC1-positive cancer cells in vitro (p < 0.05). The results suggest that MUC1 aptamer-modified metal particles may have potential in development of targeted hyperthermia therapy against adenocarcinomas. PMID- 27455626 TI - Monoclinic Hydroxyapatite Nanoplates Hybrid Composite with Improved Compressive Strength, and Porosity for Bone Defect Repair: Biomimetic Synthesis and Characterization. AB - Calcium phosphate cement (CPC) has been used for bone restoration despite its intrinsic fragile property. In order to enhance the CPC mechanical properties, biopolymers were introduced as filler to prepare CPC based cements. Chitosan/tetracalcium phosphate (TTCP)/dicalcium phosphate anhydrous (DCPA) based cement for bone repair has been prepared in the study. Solidification of the prepared cement was carried out in a simulate body fluid at 37 degrees C. The introduction of chitosan improved the mechanical performance of the as-prepared CPC hybrid nanocomposite. FTIR, SEM, TEM, HRTEM, XRD, and SAED were used to characterize the CPC nanocomposite. Data simulations have been performed to assist in determining the crystalline phase/s in the CPC hybrid nanocomposite. Based on the SAED, HRTEM measurements and data simulations, a monoclinic phase of hydroxyapatite (HAP) with a plate-like structure was obtained in the CPC system, which is believed to be responsible for the observed enhancement in CPC mechanical properties. The obtained composite has a biocompatibility comparable to that of commercial sample. PMID- 27455627 TI - Microstructure and Nanomechanical Properties of Single Trabecular Bone in Different Regions of Osteonecrosis of the Femoral Head. AB - This study aimed to compare the microstructure and nanomechanical properties of single trabecular bone in different regions of osteonecrosis of the femoral head. Osteonecrotic femoral heads were taken from 20 patients undergoing total hip arthroplasties between 2011 and 2014. Following incision, resin was embedded and polished, and divided into four regions according to the type of pathologic change; i.e., subchondral bone, and necrotic, sclerotic, and healthy regions. Indents from a single trabecular bone of each region were randomly selected to undergo nanoindentation. The results are (1) The elastic modulus and degree of hardness were significantly elevated in the sclerotic region, but there were no differences in necrotic and subchondral bone regions compared with healthy regions. (2) The elastic modulus and hardness of the single trabecular bone were significantly greater in central versus edge regions (for all regions). The conclusions are (1) The mechanical properties of single bone trabeculae were not markedly altered in the necrotic region. (2) The elastic modulus and degree of hardness increased significantly between the edge and central regions, regardless of whether the bone was normal or osteonecrotic. PMID- 27455628 TI - Amperometric Glucose Biosensor Based on Effective Self-Assembly Technology for Preparation of Poly(allylamine hydrochloride)/Au Nanoparticles Multilayers. AB - Novel nanomaterials and nanotechnology for use in bioassay applications represent a rapidly advancing field. This study developed a novel method to fabricate the glucose biosensor with good gold nanoparticles (AuNPs) fixed efficiency based on effective self-assembly technology for preparation of multilayers composed of poly(allylamine hydrochloride) (PAH) and AuNPs. The electrochemical properties of the biosensor based on (AuNPs/PAH)n/AuNPs/glucose oxide (GOD) with different multilayers were systematically investigated. Among the resulting glucose biosensors, electrochemical properties of the biosensor with three times self assembly processes ((AuNPs/PAH)3/AuNPs/GOD) is best. The GOD biosensor exhibited a fast amperometric response (5 s) to glucose, a good linear current-time relation over a wide range of glucose concentrations from 0.05 to 162 mM, and a low detection limit of 0.029 mM. The GOD biosensor modified with (AuNPs/PAH)n layers will have essential significance and practical application in future owing to the simple method of fabrication and good performance. PMID- 27455629 TI - Properties and Osteogenicity of Two Calcium Sulfate Materials with Micro or Nano Morphology. AB - Calcium sulfate dihydrate (CaSO4 x 2H2O, CSD) was widely used as the artificial bone graft. In this study, two kinds of CSD materials were characterized with XRD, TG/DTA, FT-IR, and SEM. They were both composed of CSD. Spherical shape particles were observed for nano-CSD with diameters of 52-300 nm. The micro-CSD were thin sheet particles with dimensions of 5-10 MUm. At 56 days post implantation in vivo, nano-CSD had good tissue compatibility. A frequently used bioactive material DBM, which was the combination of nano-CSD (nano-CSD-DBM) and micro-CSD (micro-CSD-DBM) in a 1:1 weight ratio separately. Composite materials were implanted in intramuscular pockets in nude mouse model. New bone mineralization could be both observed in the surgery site. Collagen I was also widely distributed by immunohistochemistry assay. And new bone area of nano-CSD DBM was 28 +/- 4.6% at 4 weeks post-operation. But new bone area of micro-CSD-DBM was 16 +/- 3.7% (less than nano-CSD-DBM). Nano-CSD showed increased degradation rate with obvious anginogenicity. And nano-CSD-DBM showed more excellent bone induction property as bone substitute implant. PMID- 27455630 TI - Preparation of Polypyrrole-Protein Composite Films and the Electrochemically Controlled Release of Proteins. AB - It is fabricated that an electrically controlled release system based on the (poly-L-lactic acid)-mixed polypyrrole (PLLA-PPy) films through casting film of PPy and PLLA mixed solution on the glass plate, in which polyglutamic acid (PGlu) doped PPy nanoparticles (NPs) with -50 nm diameter are synthesized via chemical oxidation. Surface conductivity of the composite film is (3.33 +/- 2.01) x 10(-3) S/cm. Bovine serum albumin (BSA), as a model protein drug, is chemically linked onto the composite film via carbodiimide chemistry due to the good surface nano structure of PLLA-PPy film. The releases of BSA from PLLA-PPy film under constant current and constant voltage can be achieved using the two-electrode electrochemical system. 6 h accumulative releases of BSA are 276 MUg/cm2 and 176 MUg/cm2 under 3 mA and 1 V electrical stimulation, respectively, accompanied with de-doping of PGlu and separation of a part of PPy NPs from the composite film. The results of cell experiment indicate that PGlu-doped PPy NPs in the prepared composite film have good cyto-compatibility. These results suggest that PPy-PLLA composite film would be able to be applied in the construction of degradable protein-drug-loaded scaffold for nerve tissue repair. PMID- 27455631 TI - An Immuno-Magnetic Nanobead Probe Competitive Assay for Rapid Detection of Salmonella choleraesuis. AB - A competitive lateral flow assay for the rapid detection of Salmonella choleraesuis was developed. Immuno-magnetic nanobeads were produced by covalently coupling anti-Salmonella choleraesuis antibody to magnetic nanobeads. These immuno-magnetic nanobeads were used as visually detected probes in the subsequent assay. Compared with the traditional sandwich assay, which is used for detecting macro-molecules, this new method was developed based on the competitive relationship between S. choleraesuis in the inspected sample and the outer membrane protein immobilized on the T line. Thus, only one antibody was necessary in the new assay, whereas a pair of rigorously selected antibodies were required in the sandwich assay. The sensitivity of the competitive assay for S. choleraesuis was 1.2 x 10(7) cfu/mL. In addition, no cross reactions were found in the 17 common non-Salmonella bacteria strains and in the 4 Salmonella strains of other serotypes. Thus, with satisfactory sensitivity and specificity, the assay can be applied for the rapid detection of pre-enriched culture that may contain S. choleraesuis. PMID- 27455632 TI - A Magnetic Nanoparticle Based Nucleic Acid Isolation and Purification Instrument for DNA Extraction of Escherichia Coli O157: H7. AB - The objective of this study was to evaluate the performance of a nucleic acid isolation and purification instrument using Escherichia coli O157:H7 as the model. The instrument was developed with magnetic nanoparticles for efficiently capturing nucleic acids and an intelligent mechanical unit for automatically performing the whole nucleic acid extraction process. A commercial DNA extraction kit from Huier Nano Company was used as reference. Nucleic acids in 1 ml of E. coli O157: H7 at a concentration of 5 x 10(8) CFU/mL were extracted by using this instrument and the kit in parallel and then detected by an ultraviolet spectrophotometer to obtain A260 values and A260/A280 values for the determination of the extracted DNA's quantity and purity, respectively. The A260 values for the instrument and the kit were 0.78 and 0.61, respectively, and the A260/A280 values were 1.98 and 1.93. The coefficient of variations of these parallel tests ranged from 10.5% to 16.7%. The results indicated that this nucleic acid isolation and purification instrument could extract a comparable level of nucleic acid within 50 min compared to the commercial DNA extraction kit. PMID- 27455633 TI - Fabrication of a Multimodal Microbubble Platform for Magnetic Resonance, Ultrasound and Fluorescence Imaging Application. AB - Magnetic resonance (MR), ultrasound (US) and fluorescence imaging are the widely used diagnostic modalities for various experimental and clinical applications. A multimodal poly(lactic acid) microbubble (MB) integrated with the three imaging modalities was fabricated by adsorbing CdTe quantum dots (QDs) onto the surface and encapsulating superparamagnetic iron oxide (SPIO) nanoparticles into the core. The strong fluorescence of the multimodal MBs confirmed that QDs were successfully deposited onto the surface. The in vitro MRI contrasting capability of the multimodal MBs at various concentrations was evaluated by T2-weighted imaging. Furthermore, the in vitro and in vivo ultrasonography indicated that CdTe and SPIO-inclusive MBs maintained excellent ultrasound contrast property. These results implied that the nano-in-micro hybrid materials have the potential as a nanomedical platform for multimodal bioimaging. PMID- 27455634 TI - Electrodeposition of Biocomposite Film Onto ZnO Nanoparticles Modified Electrode for Closed-Loop Insulin Delivery. AB - In this study, glucose responsive bioinorganic composite (BIM) was prepared through chitosan microparticles coupling concanavalin A, enzymes and dextran insulin via specific affinity. The drug-delivery device was fabricated by electrodeposition of BIM onto the nanostructured ZnO on indium tin oxide (ITO) substrate. The release profiles of device revealed that the insulin release was in response to the glucose concentration in vitro experiment. The released insulin still remained the activity after running the whole process and the device showed the capability for glucose sensing continuously. All these results suggest that the device may be a promising system for self-regulated insulin delivery and glucose monitoring. PMID- 27455635 TI - Shape-Dependent Genotoxicity of Mesoporous Silica Nanoparticles and Cellular Mechanisms. AB - Although mesoporous silica nanoparticles (MSNs) are widely used in food products, cosmetics and nanomedicines as vector for drug delivery, data on their potential genotoxocity are limited. The aim of this study was to investigate the cytotoxic and genotoxic potentials of MSNs of different shapes, and to establish a high throughput screening method for nanoparticles. We used functional macrophage receptor with collagenous structure (MARCO)-expressing DNA repair deficient chicken DT40 cells, which are designed to internalize nanoparticles and to be deficient in several specific DNA repair pathways. In addition, we verified the validity of this assay by analyzing and characterizing the genotoxicity of sphere or rod-shaped MSNs. We demonstrated that both sphere- and rod-shaped MSNs were cytotoxic, and that this effect was greater in FEN1(-/-) and REV3(-/-) cells compared with wild-type cells. Effects of rod-shaped MSNs were more severe compared with sphere-shaped MSNs. Furthermore, MSNs induced oxidative damage and a larger number of mitotic chromosomal aberrations in repair-deficient cells compared with repair-proficient cells. Taken together, this assay system using the chimeric receptor-expressing DNA repair-deficient DT40 cells provides a sensitive method to screen for genotoxicity of MSNs. PMID- 27455636 TI - Carboxylated Nanodiamond: Aggregation Properties in Aqueous Dispersion System and Application in Living Cell Fluorescence Imaging. AB - Nanodiamond, which has a lattice defect, the energy band gap and good biocompatibility, is an ideal inorganic fluorescent imaging material for cells. However, the nanodiamond aggregation is not exactly suitable for cells' endocytosis if the size is too small or too big. Therefore, it has a profound meaning to modify the surface of nanodiamond and control the dispersion of nanodiamond aggregate. In this study, the surface of the detonated nanodiamond is modified into carboxylated nanodiamond by using the method of mixed acid oxidation. Then, the nanodiamond aggregates' dispersion in water is regulated by adjusting the pH, which is first discussed as a factor influencing the size of nanodiamond aggregation. This process further induces the corresponding change of the electrostatic force between nanoparticles, improves its applicability in the field of living cell fluorescence imaging. PMID- 27455637 TI - Synergy Between Polyvinylpyrrolidone-Coated Silver Nanoparticles and Azole Antifungal Against Drug-Resistant Candida albicans. AB - In the clinical practice, resistance of Candida albicans to antifungal agents has frequently emerged. Silver-nanoparticles (Ag-NPs) have been demonstrated to have the antifungal property. We investigated the potential for synergy between polyvinylpyrrolidone (PVP)-coated Ag-NPs and azole antifungal, such as fluconazole or voriconazole, against drug-resistant C. albicans strain CA10. When antifungal agent was examined alone, fluconazole and voriconazole did not kill drug-resistant C. albicans, and PVP-coated Ag-NPs had only the moderate killing ability. In contrast, the combinational treatment of PVP-coated Ag-NPs with fluconazole or voriconazole was effective in being against the drug-resistant C. albicans. After the combinational treatment, we detected the disruption of cell membrane integrity, the tendency of PVP-coated Ag-NPs to adhere to cell membrane, and the inhibition of budding process. Moreover, after the combinational treatment, the defects in ergosterol signaling and efflux pump functions were detected. Our results suggest that the combinational use of engineered nanomaterials (ENMs), such as PVP-coated Ag-NPs, with the conventional antifungal may be a viable strategy to combat drug-resistant fungal infection. PMID- 27455638 TI - Drug-Loaded Nanoparticles from 'Ershiwuwei Shanhu' Pill Induced Cellular Swelling of SH-SY5Y Neuroblastoma Cells. AB - Drug-loaded nanoparticles from 'Ershiwuwei Shanhu' Pill (ESP) inducing cellular swelling of the SH-SY5Y neuroblastoma cells were investigated. Electron microscope was used to observe nanoparticles existing in the freeze-dried supernatant of 'Ershiwuwei Shanhu' Pill. Drug-free nanoparticles were obtained from the solution of drug-loaded nanoparticles via dialysis. The size and zeta potential of two kinds of nanoparticles were tested by granularmetric analysis and surface charge analysis. Results showed that nanoparticles could penetrate into cellular nucleus and caused cell swelling. CCK8 analysis implied that low concentration of drug-free nanoparticles from 'Ershiwuwei Shanhu' Pill can induce cell proliferation of the SH-SY5Y neuroblastoma cells, while drug-loaded nanoparticles can reduce cell viability through NF-kappaB pathway. Drug-loaded nanoparticles existed in 'Ershiwuwei Shanhu' pill might play a vital role during pharmacotherapy, which served as nanocarriers in delivering drugs into cells. PMID- 27455640 TI - Nano LC-MS Based Proteomic Analysis as a Predicting Approach to Study Cellular Responses of Carbon Nanotubes. AB - Nano-bio interface has been paid much attention recently, though with the lack of methodology to predict the potential responses in biological systems such as cells induced by nanomaterials. In this study, we described a proteomic approach to investigate the proteome change in K562 cells exposed to oxidized single walled carbon nanotubes (o-SWCNTs). 605 proteins were identified by semi quantitative proteomic analysis (SQPA), including 29 significantly changed proteins with spectra count (SpC) ratios lager than 2 or less than 0.5. Three of them including HBA, CFL1 and LMAN2 were further validated by western blotting. The differential proteins were further classified by Ingenuity Pathways Analysis (IPA) to integrate them into a signaling network. Based on the information by this network, we predict that o-SWCNT treatment activated cell aggregation, decreased cell migration, but had no effect on cell death. And these cellular responses were further experimentally demonstrated. The protein signaling network established in this study would greatly benefit the studies on the bio applications of o-SWCNTs and their toxicity studies. Our study demonstrated that proteomics could be used as a predicting tool to study nano-bio interface at cellular level. PMID- 27455639 TI - Preparation and Biocompatibility of Gold@ Polypyrrole-Chitosan with Core-Shell Nanostructure. AB - A two-step method for preparing Au@polypyrrole-chitosan core-shell nanoparticles (Au @ PPy-CS NPs) was fabricated by in situ polymerization of pyrrole monomer on the surface of Au spheres in chitosan solution. Transmission electron microscopy (TEM) images showed the presence of core-shell structure of nanoparticles. Energy Dispersive Spectroscopy (EDS) and Fourier transform infrared (FTIR) spectroscopy were adopted to verify the shell is polypyrrole-chitosan. Ultraviolet-visible (UV vis) and X-ray diffraction (XRD) showed that Au was present in the core-shell nanoparticles. The biocompatibility of Au @ PPy-CS NPs was characterized by in vitro for hemolysis assay and cytotoxicity experiments. Results indicated the Au @ PPy-CS NPs had good blood compatibility and low cytotoxicity. The Au @ PPy-CS NPs we proposed provide a promising platform of blood circulation system for early illness diagnosis and therapy. PMID- 27455641 TI - The Preparation of Chitosan Oligosaccharide/Alginate Sodium/Gelatin Nanofibers by Spiral-Electrospinning. AB - A spiral-electrospinning was used to mass-produce gelatin nanofibers with a content of chitosan oligosaccharide (COS) and alginate sodium (AS). Multiple jets were observed to form on the edges of the helix slice-spinneret simultaneously. Important electrospinning parameters, such as concentration of COS/gelatin aqueous solution, rotational velocity of spinneret and spinning distance, were examined to investigate the electrospinnability of COS/gelatin solution and the morphology of COS/gelatin nanofiber membranes. Due to the poor miscibility between COS and AS, COS/AS/gelatin nanofiber membranes were obtained from COS/gelatin solution and AS/gelatin solution by mixing electrospinning with multi spinnerets. The novel needleless electrospinning not only avoided the possibility of nozzle-clogging, but also prepared COS/AS/gelatin nanofibers on a large scale for a wide variety of applications. PMID- 27455642 TI - The Radiation Enhancement of 15 nm Citrate-Capped Gold Nanoparticles Exposed to 70 keV/MUm Carbon Ions. AB - Radiotherapy is an important modality for tumor treatment. The central goal of radiotherapy is to deliver a therapeutic dose to the tumor as much as possible whilst sparing the surrounding normal tissues. On one hand, heavy ion radiation induces maximum damage at the end of the track (called the Bragg Peak). Hadron therapy based on heavy ions is considered superior to conventional X-rays and gamma-rays radiations for tumors sited in sensitive tissues, childhood cases and radioresistant cancers. On the other hand, radiation sensitizers enhanced the radiation effects in tumors by increasing the dose specifically to the tumor cells. Recently, the use of gold nanoparticles as potential tumor selective radio sensitizers has been proposed as a breakthrough in radiotherapy with conventional radiations. The enhanced radiation effect of heavy ions in tumor by using gold nanoparticles as radio-sensitizer may provide alternative in hadron therapy. In this study, we investigated the radiosensitizing effects of carbon ions with a linear energy transfer of 70 keV/MUm in the presence of 15 nm citrate-capped AuNPs. The existing of AuNPs resulted in 5.5-fold enhancement in hydroxyl radical production and 24.5% increment in relative biological effectiveness (RBE) values for carbon-ion-irradiated HeLa cells. The study indicated gold nanoparticles can be used as potential radio-sensitizer in carbon ions therapy. PMID- 27455643 TI - Fabrication and Protein Conjugation of Aligned Polypyrrole-Poly(L-lactic acid) Fibers Film with the Conductivity and Stability. AB - The conducting composite scaffold, including fiber-cores of aligned poly(L-lactic acid) (PLLA) and shell-layer of polypyrrole (PPy), was fabricated, and then bovine serum albumin (BSA) was conjugated on the PPy shell-layer. Aligned PLLA fibers (about 300 nm diameter) were obtained by electrospinning and rotating drum collection, and then coated by PPy nanoparticles (NPs, about 50 nm diameter) via chemical oxidation. The surface resistivity of PPy-PLLA fibers film were 0.971, 0.874 kOmega. cm at the fiber's vertical and parallel directions, respectively. The results of PPy-PLLA fibers film immersed in phosphate buffer saline for 8 d indicated that the fibers morphology and the film conductivity were not significantly changed, and the fluorescent images showed that FITC-labeled BSA (FITC-BSA) were successfully conjugated in the fibers film with carbodiimide chemistry, and the largest amount of FITC-BSA conjugated in the fibers film from 100 MUg/mL proteins solution was 31.31 MUg/cm2 due to lots of poly(glutamic acid) in surface-nanogrooves of the fibers surface. Under electrical stimulation of 100 mV, the fibers film was accompanied the release of all conjugated FITC-BSA with the detachment of some PPy NPs. These results suggested that PPy-PLLA fibers film would be potentially applied in the construction of degradable tissue engineering scaffold with protein factors, especially neurotrophic factors for nerve tissue repair. PMID- 27455644 TI - Rat Testis Damage Caused by Lead Sulfide Nanoparticles After Oral Exposure. AB - Lead sulfide nanoparticals (PbS NPs) is an important semiconductor material due to its unique physical and chemical properties, but its potential health hazard to reproductive system is not clear. In the current study, we systematically explored the reproductive toxicity of PbS NPs in rats by measuring the body weight and testicular coefficient, testing serum testosterone levels, and studying the sperm survival rate and sperm abnormality rate. Furthermore, in order to study the toxic mechanism we performed lead contents measurements in testis, and investigated the pathology in testis. Our results confirmed that PbS NPs showed high reproductive toxicity due to PbS NPs in rats' testicular tissue by the establishment of PbS NPs chronic exposure model. PMID- 27455645 TI - Preparation and Evaluation of Two Apatites with Spherical Nanocrystal Morphology. AB - Spherical nanocrystal of apatite has been proved to be beneficial for osteoblast growth. Two apatites with spherical nanocrystal morphology were prepared in this study by chemical wet method and further sintering process. SEM exhibited that both apatites had spherical nanocrystal morphology. The crystal morphology and size was approaching to each other. XRD showed the apatites separately were hydroxyapatite and tricalcium phosphate phases. The cellular biocompatibility was evaluated by osteoblasts for these two spherical nanocrstal apatites. The MTT result indicated a higher cell proliferation rate for spherical tricalcium phosphate group. The ALP activity assay also strongly favored the tricalcium phosphate group. RT-PCR results indicated that Collagen I had a higher transcription level on the spherical tricalcium phosphate group. SEM results showed robust cell growth on the materials. It was concluded that the spherical nanophase tricalcium phosphate was superior to the cellular biocompatibility of spherical nanophase hydroxyapatite and the results were helpful in the manufacture of more suitable tissue engineering scaffolds. PMID- 27455646 TI - Nerve Growth Factor-Conjugated Mesoporous Silica Nanoparticles Promote Neuron Like PC12 Cell Proliferation and Neurite Growth. AB - Therapeutic strategies to promote nerve cell growth and improve their functions or stimulate nerve fiber reconnection and ameliorate the loss of neuronal functions are in high demand. A disadvantage of current conventional methods, which includes injection of nerve growth factors (NGF) either systemically or in the affected area, is rapid clearance or degradation of NGF, thereby reducing the effective concentration of NGFs that can reach the damaged nerves to stimulate the healing process. To overcome this obstacle, a nanoparticle platform based on mesoporous silica nanoparticles (MSNs) was developed to not only prevent clearance and degradation of NGFs, but also deliver the NGF directly to nerve cells to promote nerve cell proliferation and neurite growth. We synthesized (NGF)-loaded MSN (MSN-NGF) with a diameter of 65 nm. MSN-NGF significantly promoted the differentiation of neuron-like PC12 cells and growth of neurites compared to NGF alone, as confirmed by MTS cell proliferation assay and optical microscopy analysis. This study shows that MSN-NGF could be an effective therapy to speed up nerve cell growth or recovery of function. PMID- 27455647 TI - Urchin-Like Amorphous Ni2B Alloys: Efficient Antibacterial Materials and Catalysts for Hydrous Hydrazine Decomposition to Produce H2. AB - Urchin-like amorphous Ni2B alloys were successfully prepared for the first time from a mixture of Ni(NH3)6(2+) and polyvinyl alcohol (PVA) via a solution plasma process (SPP). The as-synthesized samples were characterized by X-ray powder diffraction (XRD), inductively coupled plasma atomic emission spectrometry (ICP AES) X-ray photoelectron spectroscopy (XPS), scanning transmission electron microscopy (STEM), selected-area electron diffraction patterns (SAED) and nitrogen adsorption-desorption isotherms. In the performance test, the obtained Ni-B urchins showed great antibacterial activities, comparable with those of amikacin and kanamycin, especially towards Pseudomonas aeruginosa (P. aeruginosa). Meanwhile, the magnetic properties of Ni-B urchins are enhanced in comparison with those of conventional Ni-B. During hydrous hydrazine (N2H4) decomposition, the dehydrogenation performance of Ni-B urchins is superior to those of Raney Ni and conventional Ni-B. The enhanced catalytic performance of Ni B urchins is attributed to their high surface area of active species nickel and the enhanced intrinsic activity resulting from their unique structure. PMID- 27455648 TI - 2-Deoxy-D-Glucose Modified Magnetic Nanoparticles with Dual Functional Properties: Nanothermotherapy and Magnetic Resonance Imaging. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) with appropriate surface chemistry have attracted wild attention in medical and biological application because of their current and potential usefulness such as magnetic resonance imaging (MRI) contrast enhancement, magnetic mediated hyperthermia (MMH), immunoassay, and in drug delivery, etc. In this study, we investigated the MRI contrast agents and MMH mediators properties of the novel 2-deoxy-D-glucose (2 DG) modified SPIONs. As a non-metabolizable glucose analogue, 2-DG can block glycolysis and inhibits protein glycosylation. Moreover, SPIONs coated with 2-DG molecules can be particularly attractive to resource-hungry cancer cells, therefore to realize the targeting strategy for the SPIONs. SPIONs with amino silane as the capping agent for amino-group surface modification were synthesized by the chemical co-precipitation method with modification. Glutaraldehyde was further applied as an activation agent through which 2-DG was conjugated to the amino-coated SPIONs. Physicochemical characterizations of the 2-DG-SPIONs, such as surface morphology, surface charge and magnetic properties were investigated by Transmission Electron Microscopy (TEM), zeta-Potential and Vibrating Sample Magnetometer (VSM), etc. Magnetic inductive heating characteristics of the 2-DG SPIONs were analyzed by exposing the SPIONs suspension (magnetic fluid) under alternative magnetic field (AMF). U-251 human glioma cells with expression of glucose transport proteins type 1 and 3 (GLUT1 and GLUT 3), and L929 murine fibroblast cell as negative control, were employed to study the effect of 2-DG modification on the cell uptake for SPIONs. TEM images for ultra-thin sections as well as ICP-MS were applied to evaluate the SPIONs internalization within the cells. In vitro MRI was performed after cells were co-incubated with SPIONs and the T2 relaxation time was measured and compared. The results demonstrate that 2 DG-SPIONs were supermagnetic and in spherical shape with -10 nm diameter. Possessing ideal magnetic inductive heating characteristics, which can generate very rapid and efficient heating while upon AMF exposure, 2-DG-SPIONs can be applied as novel candidature of magnetic nanothermotherapy for cancer treatment. Modification of 2-DG can greatly promote the cell uptake of SPIONs and such cellular uptake of 2-DG-SPIONs was time dependent. Surface coating by 2-DG can remarkably enhance the MR imaging ability for the SPIONs on the cells of U251 cancer cells. In summary, our investigation provides a novel glucose analogue modified SPIONs with potential application in the targeting cancer nanothermotherapy and MR imaging. PMID- 27455649 TI - Impact of Carbon Nanomaterials on Actin Polymerization. AB - Many nanomaterials have entered people's daily lives and impact the normal process of biological entities consequently. As one kind of the important nanomaterials, carbon based nanomaterials have invoked a lot of concerns from scientific researches because of their unique physicochemical properties. In eukaryotes, actin is the most abundantly distributed protein in both cytoplasm and cell nucleus, and closely controls the cell proliferation and mobility. Recently, many investigations have found some carbon based nanomaterials can affect actin cytoskeleton remarkably, including fullerenes derivatives, carbon nanotubes, graphene and its derivatives. However, these interaction processes are complicated and the underlying mechanism is far from being understood clearly. In this review, we discussed the different mechanisms of carbon nanomaterials impact on actin polymerization into three pathways, as triggering the signaling pathways from carbon nanomaterials outside of cells, increasing the production of reactive oxygen species from carbon nanomaterials inside of cells and direct interaction from carbon nanomaterials inside of cells. As a result, the dimension and size of carbon nanomaterials play a key role in regulation of actin cytoskeleton. Furthermore, we forecasted the possible investigation strategy for meeting the challenges of the future study on this topic. We hope the findings are helpful in understanding the molecular mechanism in carbon nanomaterials regulating actin polymerization, and provide new insight in novel nanomedicine development for inhibition tumor cell migration. PMID- 27455650 TI - Perspectives on State-of-the-Art Carbon Nanotube/Polyaniline and Graphene/Polyaniline Composites for Hybrid Supercapacitor Electrodes. AB - Supercapacitors are attractive alternative energy storage sources. They offer high energy/power density with other characteristics like fast discharge/charge time, long operation stability, safety etc. In a supercapacitor, working electrode material is the principal constituent. At present there are numerous electrode materials (with properties) suitable for their use in hybrid type supercapacitors. Carbon/polyaniline (PANi) composites are one class of such electrode materials. Here, perspectives on state-of-the-art carbon/PANi composites namely carbon nanotube/polyaniline and graphene/polyaniline composites expedient as hybrid type supercapacitor electrode materials will be presented. PMID- 27455651 TI - Efficient Synthesis of Highly Photoluminescent Short Dendritic CdSeS/ZnS Quantum Dots for Biolabeling. AB - A convenient and efficient approach is reported to synthesize CdSeS with low-cost and low-toxic materials. The influence of the Se/S ratio and reaction time on the photoluminescent properties of CdSeS QDs is investigated through researching the temporal evolution of the absorption and the emission. Following, the high photoluminescent short dendritic green-emitting CdSeS/ZnS QDs are prepared using the method inspired by the successive ion layer adsorption and reaction procedure, which are composed of a CdSeS core and ZnS branches. Transmission electronic microscopy and X-ray diffraction show that the CdSeS/ZnS QDs is in a cubic zinc blende structure. The photoluminescence intensity increase significantly when the ZnS branches form as a result of the charge carriers being confined in the core. The photoluminescence quantum yield of the obtained CdSeS/ZnS core-shell QDs can be up to 90%, which is much higher than that of initial CdSeS QDs (39%). In addition, CdSeS/ZnS QDs have good photoluminescence intensity after they are transferred from organic solvent into aqueous media through ligand replacement using mercaptoacetic acid. Afterwards, the E. Coli O 157 are not only successfully conjugated with CdSeS/ZnS QDs but also present clear images under UV irradiation. PMID- 27455652 TI - Non-Specific Zn2+ Ion Sensing Using Ultrasmall Gadolinium Oxide Nanoparticle as a Magnetic Resonance Imaging Contrast Agent. AB - The gadolinium oxide (Gd2O3) nanoparticles are well-known potential candidates for a positive magnetic resonance imaging (MRI) contrast agent owing to their large longitudinal water proton relaxivity (r1) value with r2/r1 ratio close to one (r2 = transverse water proton relaxivity). In addition they may be used to sense metal ions because their r1 and r2 values can be altered in the presence of metal ions. This may allow us to study metabolic processes involving metal ions and to diagnose disease related to abnormal concentrations of metal ions in the body in a non-invasive way. In this study ultrasmall Gd2O3 nanoparticles were for the first time applied to non-specifically sense Zn2+ ions in aqueous solution. We explored this by measuring r1 and r2 values in the presence of Zn2+ ions in solution. PMID- 27455653 TI - A Proof of Concept: Detection of Avian Influenza H5 Gene by a Graphene-Enhanced Electrochemical Genosensor. AB - The highly pathogenic avian influenza (HPAI) virus subtype H5N1 has been found to be the most virulent and deadliest virus strain, with capability of interspecies transmission to human infection. Most human HPAI H5N1 cases were diagnosed late in their illnesses for medical care, resulting in severe complications that led to death. In this study, a novel graphene-enhanced electrochemical DNA biosensor had been fabricated for the detection of polymerase chain reaction (PCR) amplicon derived from the haemagglutinin (H5) gene of the HPAI. The graphene-enhanced DNA biosensor showed excellent linear correlation between PCR amplicon concentration and amperometric signal with a correlation coefficient, r2 of 0.9987. The amperometric response of the proposed biosensor was compared with conventional gel electrophoresis while the feasibility of the proposed sandwich sensing platform was verified via dot blot assay. The results obtained indicate that the electrochemical DNA biosensing assay is significantly more sensitive (P < 0.05) and time efficient. This work serves as a proof of concept in hopes for further development of the graphene enhanced electrochemical DNA biosensor into a portable, on-site screening platform for point-of-care detection of various pathogens. PMID- 27455654 TI - Cytotoxicity and Antibacterial Characteristics of Graphene-Oxide Nanosheets Toward Human Pathogens. AB - Nanomaterials show great opportunities in the development of electronics, biosensors, chemical and industrial applications. In this article, we are reporting the cytotoxicity and antibacterial characteristics of graphene-oxide (GO) nanosheets toward selected human pathogens. GO is prepared by using modified Hummers method. The prepared GO is characterized using X-ray diffraction, Raman analysis and transmission electron microscopy. Our studies confirmed the antimicrobial activity of GO against various human pathogens. The cytotoxicity effects of GO nanosheets are investigated using MTT assay which confirms that GO nanosheets are non-toxic and eco-friendly. These results ensure that GO nanosheets can be a potential antibacterial agent in the biological, health related industry development and applications. PMID- 27455655 TI - Size Selective Green Synthesis of Silver and Gold Nanoparticles: Enhanced Antibacterial Efficacy of Resveratrol Capped Silver Sol. AB - In view of potential biomedical application of the noble metal nanoparticles, we report a size controlled yet simple and green synthesis of resveratrol stabilized silver and gold nanoparticles having low polydispersity of size. Here, resveratrol plays two simultaneous roles, reducing the metal ions and providing efficient capping of the small nanoparticles. This gives rise to specific size of silver and gold nanoparticles at specific ratios of metal to resveratrol. The particles have been characterized by XRD and transmission electron microscopy. The nanoparticle sols are stable for months. The UV Visible absorption spectra of the silver sol show the plasmon peak of spherical nanoparticles, presence of which is further reflected in the TEM images. Size of the silver particles obtained is in between 11 to 21 nm depending on the ratio of resveratrol to metal ion used. Resveratrol capped silver nanoparticles exhibit high antibacterial activity against Gram negative wild type E coli BW (25113). The minimum inhibitory concentration (MIC) of nano-silver against the bacterium has been estimated to be 6.48 MUg/ml, which is significantly lower than that reported in some earlier as well as recent publications. Reaction of gold ions with resveratrol, on the other hand, produces gold nanoparticles of sizes varying from 7 to 29 nm at different ratios of resveratrol to the metal ions. Particles with higher size and aspect ratio are formed at lower concentration of the capping agent whereas particles with very small size and pseudo-spherical morphology are formed at higher capping concentration. Difference in the formation kinetics of silver and gold nanoparticles has been attributed to the different growth mechanisms in the two cases. Possible modes of anchorage of resveratrol to silver nanoparticles have been investigated using surface enhanced resonance Raman spectroscopy (SERS) which shows that the silver nanoparticles are capped by resveratrol molecule primarily through O-Ag linkages of the p-OH aromatic ring. This, in turn, demonstrates the feasibility of using these nanoparticles as SERS templates. PMID- 27455656 TI - Multilayered Short Peptide-Alginate Blends as New Materials for Potential Applications in Cartilage Tissue Regeneration. AB - Peptide based nanomaterials have been gaining increased prominence due to their ability to form permeable scaffolds that promote growth and regeneration of new tissue. In this work for the first time a short hexapeptide motif VQIVYK, derived from the Tau protein family was conjugated with an organic polyamine linker, putrescine and utilized as a template for developing new materials for cartilage tissue regeneration. Our results showed that the conjugate formed extensive nanofibrous assemblies upon self-assembly under aqueous conditions. We then employed the layer-by-layer (LBL) approach to design the scaffold by first incorporating a short segment of the dentin sialophosphoprotein motif GDASYNSDESK followed by integration with the peptide sequence GSGAGAGSGAGAGSGAGA. This sequence mimics Ala, Gly, Ser repeats seen in the spider silk protein. We then incorporated the polysaccharide alginate which served as a hydrogel. To further enhance binding interactions with chondrocytes, and promote the formation of cartilage in vitro, the bionanocomposites were then attached to the chondrocyte binding peptide sequence HDSQLEALIKFM. The thermal properties as well as biodegradability of the scaffold was examined. To confirm biocompatibility, we examined cell viability, attachment and morphology in the presence of bovine chondrocytes. The cells were found to efficiently adhere to the scaffolds which formed an intricate mesh mimicking the extracellular matrix of cartilage tissue. To evaluate if differentiation occurred in the presence of the scaffolds, we examined in vitro deposition of proteoglycans. Thus, we have developed a new family of nanoscale scaffolds that may be utilized for cartilage tissue regeneration. PMID- 27455657 TI - Size-Dependent Biodistribution of lodinated Oil Nanoemulsions Observed by Dual Modal Imaging in Rats. AB - Sizes of nanoscale contrast agents play an important role in targeting specific organs and distribution in organisms. lodinated oil nanoemulsions with uniform size distribution and containing indocyanine green (ICG) fluorescent dye (25 nm, 60 nm, 100 nm) were synthesized by stirring, combined with ultrasonic emulsification technique. Rats were intravenously injected with the iodinated oil nanoemulsions with different sizes, used as contrast agents, and investigated with enhanced computed tomography (CT) and fluorescence imaging. Through experiments, the distribution and metabolism of the contrast agents in rat's bodies were studied, and their influence on enhanced CT imaging of different organs was compared. The results demonstrated that target accumulating organs for the iodinated oil nanoemulsions were liver and spleen, with obvious dosage dependence. Large sized nanoemulsion preferred to accumulate into spleen, and liver, and the phagocytosis was getting weaker with the decrease of the nanoemulsion size. The CT imaging of the inferior vena cava was rapidly enhanced and reached the highest point after administration of the nanoemulsion. The nanoemulsion gradually gathered and metabolized in the spleen and liver, resulting in rapidly decreased CT imaging, with weak rebound, of the inferior vena cava. PMID- 27455658 TI - Selenium Nanoparticles Formed by Modulation of Carrageenan Enhance Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Fabrication of nano-sized selenium (Se) particles may help to expend the applications of Se. In this study, we focused on the preparation and characterization of Se nanoparticles (Se NPs) modulated with carrageenan (CA). Furthermore, their influence on osteoblast cell growth was investigated in vitro. Spherical Se-NPs, of 100-200 nm diameter, were prepared simply by adding kappa-, iota-, and lambda-CA, which has sulfate groups, hydroxyl groups, and carboxyl groups. CA-modulated Se NPs (CA-Se NPs) were readily suspended in liquid medium with no precipitation over long time periods. In particular, it was found through Alizarin Red S staining that the growth of osteoblast D1 cells treated with lambda-CA-Se NPs was improved significantly. These results suggest that Se NPs can be prepared simply, using CA, have good suspension stability in liquid medium, and lambda-CA-Se NPs may induce the growth of osteoblast cells. PMID- 27455659 TI - The Preparation of Magnetic Silica Nanospheres and Incorporation of CdSe/ZnS Quantum Dots-DNA Probe. AB - Silica nanospheres containing magnetic particles were prepared, and CdSe/ZnS QDs functionalized with carboxyl group were incorporated into the silica nanospheres by EDC/NHS coupling reaction. The silica nanospheres were prepared by a co precipitation of ferrous and ferric solutions followed by the sol-gel reaction of TEOS (tetraethoxysilane) and APTES (3-aminopropyltriethoxysilane) using base catalyst. The size of magnetic silica nanospheres was confirmed by Transmission electron microscope (TEM). Thiol group modified single stranded oligonucleotides were immobilized on the surface of QDs and fluorescence quenching by intercalation dye (TOTO-3) after hybridization with target oligonucleotide was observed. The fluorescence from QDs could be quenched by intercalating dye (TOTO 3) after hybridization of target DNA to probe DNA. This shows that the magnetic silica-QD-DNA probe can be used to detect specific DNA. PMID- 27455660 TI - Zinc Oxide Nanoparticles Demoted MDM2 Expression to Suppress TSLP-Induced Mast Cell Proliferation. AB - Activation of murine double minute 2 (MDM2) through thymic stromal lymphopoietin (TSLP)-induced signal transducers and activators of transcription (STAT6) phosphorylation plays a critical role in proliferation and survival of mast cells. Previously, we reported that zinc oxide nanoparticles (ZnO-NP) effectively decrease the mast cell-mediated allergic inflammatory reactions. Here, we evaluated the effect of ZnO-NP on TSLP-induced proliferation of mast cells. ZnO NP significantly reduced the number of BrdU-incorporating mast cells increased by TSLP. ZnO-NP decreased the expression of MDM2 through the blockade of STAT6 phosphorylation. TSLP increased the production and mRNA expression of interleukin 13 (a growth factor of mast cells), its increase was significantly decreased by ZnO-NP (10 MUg/mL). ZnO-NP induced the down-regulation of Bcl2 (an anti-apoptotic factor) and up-regulation of Bax (an apoptotic factor) through the stabilization of p53 protein. However, ZnO-NP has no effect on caspase-3 activation, cytochrome c release into cytosol, and apoptosis-inducing factor translocation into nucleus in TSLP-stimulated cells. The results of the present study demonstrated that ZnO NP inhibited the proliferation of mast cells through the regulation of MDM2 and p53 protein levels. These finding suggest that ZnO-NP could be improved mast cell mediated various diseases. PMID- 27455661 TI - Apoptosis Induction and Imaging of Cadmium-Telluride Quantum Dots with Wogonin in Multidrug-Resistant Leukemia K562/A02 Cell. AB - Wogonin (5,7-dihydroxy-8-methoxyflavone) is one of the active components of flavonoids isolated from Scutellariae radix and possesses antitumor effect against leukemia. Cadmium-telluride quantum dots (CdTe-QDs) are a kind of nanoparticles with great potential in functioning as an efficient drug delivery vector in biomedical research. In this study, we investigated the synergistic effect of CdTe-QDs with Wogonin on the induction of apoptosis using drug resistant human leukemia KA cells. Flow cytometry analysis, assay of morphology under electron microscope, quantitative analysis of tumor volume and micro-CT imaging demonstrated that compared with that by pure CdTe-QDs or wogonin, the apoptosis rate increased sharply when treated wirh CdTe-QDs together with wogonin on KA cells. These results proved that the nanocomposites readily overcame the barrier of drug-resistance and provoked cell apoptosis in vitro and in vivo by facilitating the interaction between wogonin and KA cells. As known to all, it is an inevitable tendency that new effective therapies will take the place of conventional chemotherapy and radiotherapy presenting significant disadvantages. According to this article, CdTe-QD combined with wogonin is a possible alternative for some cancer treatments. PMID- 27455662 TI - Fabrication of C60 Tri-Diethyl Malonate Membrane via an Electrospinning Method and Its Antibacterial Property. AB - A homogeneous C60 tri-diethyl malonate membrane was fabricated by a facile electro-spinning method. Comprehensive characterizations of its assembling structure, such as SEM, TEM, TGA, UV-vis, and FTIR, were carried out. Different fullerene derivatives show different assembling characters during the electrospining process. Notably, C60 tri-diethyl malonate with close-knite structures can form a stable structure after removing the assistant polymer of PVP. The antibacterial experiments of C60 tri-diethyl malonate membrane were performed, and the results revealed that this membrane owns excellent antibacterial activity. PMID- 27455663 TI - Out-of-Plane Magnetic Moment and Lattice Distortion in Sputtered Ge Added Fe3O4 Thin Film. AB - Fe3O4 has been known to have attractive physical properties for spintronic applications such as half-metallicity, however, its complicated magnetism has yet to be elucidated fully. We investigated the sputtered polycrystalline Fe3O4 thin film in which Ge was added for stabilization of the spinal structure. From X-ray photoelectron and Raman spectroscopies, major part of added Ge is found to be quadrivalent and considered to be incorporated in the spinel structure. Out-of plane alignment of the local moment was confirmed by conversion electron Mossbauer spectroscopy and magnetization measurements with an applied field up to 70 kOe also support it. The Pawley refinement of the X-ray diffraction profile with a series of possible space groups in the spinel structure suggests that the crystal symmetry is reduced from cubic to tetragonal or orthorhombic spinels with (100) or (010) strains up to -0.231%. The uniaxial anisotropy constants K(u) for the tetragonally distorted cases estimated from the evaluated strains and the ab initio calculation were found to be around 1.05 x 10(6) erg/cm3. We consider that the magnetic anisotropy induced by the lattice distortion contributes to the out of-plane alignment of local moments in addition to the previously reported effect by the exchange coupling across crystallographic defects of the antiphase boundaries. PMID- 27455664 TI - Gold Nanoparticles Supported on Magnesium Oxide Nanorods for Oxidation of Alcohols. AB - Gold nanoparticles supported on magnesium oxide nanorods (Au-MgO) have been synthesised by a solution based chemical reduction method. Au-MgO nanorods were found to be an efficient heterogeneous catalyst for oxidation of alcohols with hydrogen peroxide in aqueous medium at room temperature. To find out the best reaction conditions for oxidation, optimization of catalyst quantity, solvent, mole equivalence of hydrogen peroxide were carried out. The scope of the reaction was extended to several aromatic and aliphatic alcohols, product yields were quantified by gas chromatography (GC) and GC/mass spectroscopy. Heterogeneity and reusability tests were performed. The use of water as a solvent and hydrogen peroxide as co-catalyst at room temperature makes the reaction interesting from sustainable development point of view. PMID- 27455665 TI - Synthesis of Iron Nanoparticles Using Azadirachta indica Extract and Its Catalytic Activity Toward Nitrophenol Reduction. AB - A simple, hasty and eco-friendly approach for the synthesis of iron nanoparticles has been developed using the medicinally important Azadirachta indica extract, which act as both reducing and stabilizing agent. The formation and morphological properties of iron nanoparticles as a function of metallic precursor and Azadirachta indica extract concentration have been investigated. The influence of solvent over the size and texture of iron nanoparticles has also been evaluated in detail. The thermal behavior of prepared nanoparticles was identified from thermogravimetric analysis. Furthermore, the catalytic activity of prepared iron nanoparticles toward the reduction of p-nitrophenol was analyzed and the reduction process was occurred within 30 sec. The cost and time efficient biosynthesis process and excellent catalytic activity of the prepared iron nanoparticles construct this protocol attractive. PMID- 27455666 TI - Synthesis and Electrochemical Properties of Nano-VO2 (B). AB - The nano-VO2 (B) has been self-assembly synthesized by hydrothermal method using different templates, which may give them some interesting properties. The as prepared samples were characterized by X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The electrochemical properties of the samples were investigated. The results show that the hexadecyltrimethyl ammonium bromide (CTAB) (soft template) was used to obtain the VO2 (B1) nanobelts. The flake graphite (hard template) was taken to get the VO2 (B2) nanosheets. The VO2 (B1) nanobelts have higher initial capacity to compare with VO2 (B2). But the VO2 (B2) nanosheets showed better cycling performance than that of VO2 (B1) nanobelts. The nano VO2 (B2) is a promising anode material for lithium ion battery application. PMID- 27455667 TI - Influence of Morphology and Common Oxidants on the Photocatalytic Property of beta-SnWO4 Nanoparticles. AB - In this paper, we report a simple, cost effective and surfactant-free method for synthesizing different morphology of beta-SnWO4 with irregular, spherical, flake like and leaf-like structures by using sonochemical method followed by calcination. A well dispersed and highly crystalline beta-SnWO4 crystallites with various sizes have been prepared. The samples were characterized by using X-ray diffraction (XRD), scanning electron microscope (SEM), UV-vis spectroscopy, particle size and Zeta potential analyser. The SEM images reveal the successful preparation of an irregular, spherical, flake-like and leaf-like structure of beta-SnWO4. The absorption maximum of as-prepared different structures of beta SnWO4 was observed in visible region. The degradation efficiency was found to be increased in leaf-like structures compared to irregular, spherical and flake-like structures of beta-SnWO4. Further, an enhanced photocatalytic effect was observed in leaf-like beta-SnWO4 nanoparticles while the common oxidants such as peroxomonosulphate (PMS), peroxodisulphate (PDS) and hydrogen peroxide (H2O2) were added. The degradation efficiency of these oxidants was found in the order of PMS > H2O2 > PDS. Generally these oxidants act as electron scavengers. From our experimental results, it is found that maximum efficiency of 93% was achieved when PMS was added. This shows the vital role of common oxidants in photocatalytic characteristics and their future applications in waste-water treatment. PMID- 27455668 TI - Magnetically Recyclable Fe3O4@His@Cu Nanocatalyst for Degradation of Azo Dyes. AB - Fe3O4@His@Cu magnetic recyclable nanocatalyst (MRCs) was synthesized by reflux method using L-histidine as linker. The composition, structure and magnetic property of the product were characterized by X-ray powder diffraction (XRD), Scanning electron microscopy (SEM), Fourier Transform infrared spectroscopy (FT IR) and vibrating sample magnetometry (VSM). Powder XRD, FT-IR and EDAX results confirmed that the as-synthesized products has Fe3O4 with spinel structure and Cu nanoparticles with moderate crystallinity without any other impurities. The surface of the Fe3O4@His nanocomposite was covered by tiny Cu nanoparticles. We examine the catalytic activity of Fe3O4@His@Cu MRCs for the degradation of two azo dyes, methyl orange (MO) and methylene blue (MB) as well as their mixture. The reusability of the nanocatalyst was good and sustained even after 3 cycles. Therefore this innovated Fe3O4@His@Cu MRCs has a potential to be used for purification of waste water. PMID- 27455669 TI - Simultaneous Surface Modification and Chemical Reduction of Graphene Oxide Using Ethylene Diamine. AB - We report a simple and facile method of reducing and modifying graphene oxide (GO) simultaneously using ethylene diamine (ED). The ED-modified and reduced GO (denoted as E-rGO) as well as the GO reduced by hydrazine hydrate (denoted as H rGO) were characterized by Fourier transform infrared spectra (FT-IR), X-ray diffraction (XRD), Raman spectra, Thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), Transmission electron microscopy (TEM) and Scanning electron microscopy (SEM). It was found that as-prepared E-rGO exhibited good dispersibility in water and water-borne polyurethane (denoted as WPU) matrix and improve greatly the mechanical properties of WPU matrix. Moreover, E-rGO showed a high electric conductivity close to that of H-rGO after ultrasonic treatment for 12 h, which indicated that ED had the desired reducibility. The present approach could help to broaden the application field of graphene nanosheets and provide a new opportunity for developing high performance graphene/polymer-matrix composites. PMID- 27455670 TI - Enhanced Conductivity and Electrochemical Performance of Electrode Material Based on Multifunctional Dye Doped Polypyrrole. AB - Polypyrrole were prepared via in-situ chemical oxidative polymerization in the presence of multisulfonate acid dye (acid violet 19). In this work, acid violet 19 could play the role as dopant, surfactant and physical cross-linker for pyrrole polymerization, and had impact on the morphology, dispersion stability, thermal stability, electrical conductivity and electrochemical behavior of the samples. The thermal stability of the dye doped polypyrrole was enhanced than pure polypyrrole due to the strong interactions between polypyrrole and acid violet 19. The dispersion stability of the samples in water was also improved by incorporating an appropriate amount of acid violet 19. The sample with 20% of acid violet 19 showed granular morphology with the smallest diameter of -50 nm and possessed the maximum electrical conductivity of 39.09 S/cm. The as-prepared multifunctional dye doped polypyrrole samples were used to fabricate electrodes and exhibited a mass specific capacitance of 379-206 F/g in the current density range of 0.2-1.0 A/g. The results indicated that the multifunctional dye could improve the performances of polypyrrole as electrode material for supercapacitors. PMID- 27455671 TI - Combined Embedding of N/F-Doping and CaCO3 Surface Modification in the TiO2 Photoanode for Dye-Sensitized Solar Cells. AB - N/F-doping and CaCO3 surface modification was carried out in TiO2 photoelectrodes for dye-sensitized solar cells (DSSCs). The combined effect of the N/F doped TiO2 and the CaCO3 coating showed a great increase of the short-circuit current (J(sc)), and photoelectric conversion efficiency (eta) of the prepared cells; the efficiency (eta) was improved from 7.00% of a commercial TiO2 photoelectrode to 7.90% of an uncoated N/F-doped electrode, and to 9.09% of a N/F-doped and CaCO3 surface modified electrode. An enhanced photoresponse in N/F-doped TiO2 nanoparticles generate more photo-excited electrons, as supported by measured UV Vis diffuse reflectance spectra. A successive CaCO3 surface modification then forms a barrier on the surface of the N/F-doped TiO2 particles; the higher basicity of the CaCO3 modified TiO2 facilitates the dye adsorption, as supported by the direct measurement of the amount of adsorbed dye. PMID- 27455672 TI - Sub-Surface and Bulk Creep Behaviour of Polyurethane/Clay Nanocomposites. AB - A series of exfoliated and intercalated polyurethane organoclay nanocomposites were prepared by in situ polymerization of polyol/organoclay mixture, chain extender and diisocyanate. The creep behaviour of subsurface and bulk of the polyurethane coatings was investigated by nanoindentation technique and uniaxial conventional creep testing method, respectively. The results showed that the creep resistance of the nanocomposites was significantly improved by incorporation of organoclay. The enhancement of creep resistance was dependent on clay content as well as organoclay structure (exfoliation or intercalation) in the polymer matrix. With 1 wt% organoclay, the creep resistance increased by about 50% for the intercalated organoclay and 6% for the exfoliated organoclay systems, respectively, compared to the pristine polyurethane. Viscoelastic model was employed to investigate the effect of organoclay loadings on the creep performance of the polyurethane. Results showed the model was in good agreement with the experimental data. Incorporation of clay leads to an increase in elastic deformation especially in exfoliated polyurethane nanocomposites and induces a higher initial displacement at the early stage of creep. PMID- 27455673 TI - Using Gold Nanoparticles as Delivery Vehicles for Targeted Delivery of Chemotherapy Drug Fludarabine Phosphate to Treat Hematological Cancers. AB - Nanotechnology is an emerging paradigm for creating functional nanoscale materials for various biomedical applications. In this study, a new nanotechnology-based drug delivery method was developed using gold nanoparticles (GNPs) as a delivery vehicle to reduce adverse drug side effects. Fludarabine Phosphate is a commercial chemotherapy drug used in cancer treatment, and has ability to kill various cancer cells. KG-1 cell, a type of acute cancer leukemia cell, was selected as a proof-of-concept target in this study. Due to the small size of GNPs, they can help Fludarabine Phosphate enter cancer cells more efficiently and better interfere with DNA synthesis in the cancer cells. To enhance targeting ability, folic acid molecules were also covalently linked to GNPs, resulting in GNP-Fludarabine-folic acid (GNP-F/f). Compared to treatments with GNP-F or drugs on its own (Fludarabine Phosphate), the GNP-F/f achieves much improved cell-killing effects. The UV-Vis spectra results also revealed that the drugs had successfully bonded covalently to the GNPs. The higher cell-killing efficiency of GNP-F/f compared with GNP-Fludarabine (GNP-F) or drugs on their own further validates the effectiveness of both the vectors (GNPs) and folic acid in enhancing the drug delivery to the cancer cells. The MTT viability tests showed that the GNPs had no cytotoxicity. PMID- 27455674 TI - Facile Instep Synthesis of Palladium Nanoparticle/Carbon@Carbon Nanotube Composites for Electrooxidation of Xylitol. AB - The development of a facile, instep, and eco-friendly synthesis method of mono dispersed low quantity palladium nanoparticle/carbon@functionllized carbon nanotube composite (Pd@C-f-CNT)electrocatalytic material was developed for use in the electrooxidation of xylitol. The prepared nanocatalyst was analyzed by powder X-ray diffraction analysis, Raman spectroscopy, X-ray photoelectron spectroscopy, and scanning and transmission electron microscopy. The electrocatalytic studies were performed using voltammetric methods. Formation of Pd NPs was observed within 2 min. The microscopic analysis showed 5- to 10-nm-sized Pd NPs that uniformly covered the CNT. The instep-formed carbon helped to improve the electrocatalytic activity of the catalyst. Our proposed method provides new insight for the development of highly efficient metal NPs/CNT nanocatalyst for direct alcohol fuel cell applications. PMID- 27455675 TI - CdSe/ZnS Core/Shell Quantum Dots in Cooperation with Other Materials for Direct and Indirect Production of Reactive Oxygen Species. AB - In this present work, CdSe/ZnS core/shell quantum dots (QDs) were exploited in the oxidation reactions of 5-aminolevulinic acid (ALA) and glutamate (GLU) for the production of reactive oxygen species (ROS). Fast and highly efficient oxidation reactions of ALA to produce the hydroxyl radicals (HO*) and of GLU to produce the superoxide anion (O2*-) were observed in the cooperation of mercaptopropionic acid (MPA) capped-CdSe/ZnS QDs (MPA-QDs) under LED irradiation. Whereas, binding between MPA-QDs and coumarin-derived dendrimer (CdD)-captured silica particles (SiCdDs) through sol-gel GA enhanced singlet oxygen production under LED irradiation by about 80% as compared to that achieved using QDs only. Confocal fluorescent microscopic images of the size and morphology of HeLa cells confirmed the ROS production from ALA, GLU in cooperation with CdSe/ZnS QDs or QDs-coated SiCdDs under LED irradiation. PMID- 27455676 TI - Strength and Mechanical Response of NaCl Using In-Situ Transmission Electron Microscopy Compression and Nanoindentation. AB - Strength and mechanical properties of single crystal sodium chloride (NaCl) are characterized. Critical deformation variations of NaCl pillared structures and films are estimated using in-situ transmission electron microscope (TEM) compression tests and nanoindentation experiments. Young's modulus and contact stiffness of NaCl pillars with diameters of 300 to 500 nm were 10.4-23.9 GPa, and 159-230 N/m, respectively. The nanohardness and Vickers hardness of the NaCl (001) film were 282-596 and 196-260 MPa, respectively. The results could provide useful information for understanding the mechanical properties, contact and local deformation of NaCl pillars and films. PMID- 27455677 TI - Tuning the Stoichiometry of Ag2S Thin Films for Resistive Switching Applications. AB - In this work silver-rich and sulfur-rich silver sulfide (Ag2S) thin films were fabricated using a diversified set of experimental methods, namely ion beam deposition and atmosphere- and solution-based sulfurizations. The composition of the Ag2S thin films was studied using X-ray diffraction, Raman spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. We found that it strongly depends on the fabrication conditions, such as sulfurization time and temperature. These conditions, in turn, affect the electrical characteristics of the thin films, namely the resistivity and resistive switching. We were able to control the Ag2S stoichiometry and infer its dependence on the fabrication parameters for all the followed methods. PMID- 27455678 TI - Mono- and Bis-Terpyridine-Based Dimer and Metallo-Organic Polymers as Ionic Templates for Preparation of Multi-Metallic Au Nanocluster and Nanowires. AB - The preparation of multi-metallic Au nanocluster and nanowires has been achieved using terpyridine-based metallo-organic polymers as multi-ionic templates through a straightforward counterion exchange with aqueous NaAuCl4 followed by a mild reduction in-situ with sodium citrate. The mild reduction of the [TpyFeTpy]2+ x 2[AuCl4]- complex, derived from [TpyFeTpy]2+ x 2Cl- 1 (tpy = 2,2':6',2" terpyridine), led to the formation of Au nanoclusters (Au NC) with diameters ranging from 7.5-88 nm. Each Au NC alone contained multiple nanoparticles, with diameters ranging from 2.5-4.5 nm. 1,4-bis-terpyridine based metallo-oraganic polymer [-TpyFeTpy-TpyFeTpy-]n(2n+) x [Cl]2n- 2 was found to generate a multi ionic metallo-polymer with AuCl4- as the counterion, after mild reduction with sodium citrate, resulting in irregular zigzag shaped Au nanowires (Au NW). The prepared Au NW from the di-metallic complex 3 should find applications within electronic devices. Both Au NC and NW were also found to possess excellent catalytic properties. PMID- 27455679 TI - Nano-Structured Carbon Matrixes Obtained from Chitin and Chitosan by a Novel Method. AB - A series of porous carbon matrixes was prepared by phosphoric (V) acid activation of unconventional precursors chitin and chitosan: impregnation with H3PO4 at concentrations ranging from 1.34 to 5.53 mole dm(-3), followed by carbonization at 600 degrees C. The obtained carbons demonstrated well-developed porosity that declined steadily in the micropore and mesosopore ranges, depending on both the kind of the precursor and the concentration of activator. The surface area and pore volume of the carbons prepared from chitin increased upon the rising impregnation ratio. The surface area and total pore volume reached their maximum values (1257 m2g(-1) and 1.007 cm3g(-1), respectively) for the acid concentration of 3.40 mole dm(-3). The chars obtained from chitosan showed the values of the BET surface area ranging from 970 to 1484 m2g(-1). Chemical analysis indicated that the activation with phosphoric acid led to the chars of exceptionally high concentration of nitrogenated functionalities and a typical amount of oxygenated surface groups. PMID- 27455680 TI - A Low Temperature, Solution-Processed Poly(4-vinylphenol), YO(x) Nanoparticle Composite/Polysilazane Bi-Layer Gate Insulator for ZnO Thin Film Transistor. AB - Low temperature, solution-processed metal oxide thin film transistors (MEOTFTs) have been widely investigated for application in low-cost, transparent, and flexible electronics. To enlarge the application area, solution-processed gate insulators (GI) have been investigated in recent years. We investigated the effects of the organic/inorganic bi-layer GI to ZnO thin film transistors (TFTs). PVP, YO(x) nanoparticle composite, and polysilazane bi-layer showed low leakage current (-10(-8) A/cm2 in 2 MV), which are applicable in low temperature processed MEOTFTs. Polysilazane was used as an interlayer between ZnO and PVP, YO(x) nanoparticle composite as a good charge transport interface with ZnO. By applying the PVP, YO(x), nanoparticle composite/polysilazane bi-layer structure to ZnO TFTs, we successfully suppressed the off current (I(off)) to -10(-11) and fabricated good MEOTFTs in 180 degrees C. PMID- 27455681 TI - Improvement of Electrochemical Properties of Ni-Rich Cathode Material by Polypyrrole Coating. AB - In this study, we attempted a nanosized coating layer of commercial polypyrrole (PPy) on LiNi0.6Co0.1Mn0.3O2 (HNCM) cathode material to overcome the side reactions with electrolyte and a decrease in the capacity of the inert coating layer. The coating method using commercial PPy is very simple. The energy dispersive X-ray spectroscopy (EDS) analysis and transmission electron microscopy (TEM) images confirmed that PPy coating layer was well dispersed and nanosized. The alternating current (AC) impedance studies revealed that the coating of PPy significantly decreased the charge-transfer resistance of HNCM electrodes. Moreover, the 1 wt% PPy-HNCM electrode exhibited good electrochemical performance with a specific discharge capacity of 177.52 mA h g(-1) at a rate of 0.1 C in the voltage range 3.0-4.3 V, whereas the capacity of the HNCM electrode was only 167.13 mA h g(-1). PMID- 27455682 TI - Synthesis and Characterization of Thermally Stable Photocurable Polymer with Cyclohexane Moiety. AB - Photocurable polymers with high transparency and thermal stability were synthesized by reaction between a commercial epoxy resin (NC9110) containing cyclohexane moiety and various kinds of cinnamic acids such as trans-cinnamic acid (CA), 3-hydroxy-trans-cinnamic acid (HCA) and 4-methoxy-trans-cinnamic acid (MCA). The photocurable polymers were synthesized with equal equivalent weight ratio of epoxy and cinnamate group. The chemical structures of the synthesized polymers were confirmed by 1H-NMR and FT-IR spectroscopies. Optical transmittance and thermal stability of the photocured polymers were investigated using UV Visible spectroscopy and thermogravimetric analysis (TGA), respectively. It was confirmed that the polymers could form thin films with very smooth surface and could be efficiently cured by UV irradiation. It was also found that the polymer after curing showed a good thermal stability and optical transmittance. There was no significant transmittance change after heat treatment at 250 degrees C for 1 h and showed no noticeable weight loss up to 360 degrees C. PMID- 27455683 TI - Synthesis of Multi-Walled Carbon Nanotubes/TiO2 Composite and Its Photocatalytic Activity. AB - TiO2 particles coated Multi-walled carbon nanotubes (MWCNT/TiO2 composite) were prepared via a sol-gel method using Multi-walled carbon nanotubes (MWCNT) and tetrabutyl titanate as raw materials. The phase constitutes and microstructures of the prepared composite were analyzed by XRD and TEM, respectively. Their photocatalytic activities were investigated under simulated ultra-violet light and visible-light irradiation for the degradation of methyl orange (MO) and methylene blue (MB) aqueous solution, respectively. The experimental results indicated that TiO2 calcined at temperatures of 400-600 degrees C in the MWCNT/TiO2 composite was mainly composed of nanometric anatase. The composite exhibited enhanced absorption properties in the visible-light region compared to pure TiO2, which was attributed to the enhanced light electron-hole separation by adding MWCNTs. PMID- 27455684 TI - Synthesis of Highly Bright Oil-Soluble Carbon Quantum Dots by Hot-Injection Method with N and B Co-Doping. AB - Oil-soluble BN-doped carbon quantum dots (CQDs) were successfully prepared in a novel hot-injection method by using 1,2-Hexadecanediol as carbon precursor and surface passivation agent. The reaction time, temperature, and surface passivation agent were investigated by fluorescence measurements to understand the underlying evolution of CQDs. The doping of N and B were carried out by choosing suitable N and B source, evaluated by their fluorescence properties. The size, morphology and surface properties were observed by TEM, AFM and FTIR measurements. The quantum yields of CQDs were also calculated to investigate the enhanced fluorescence properties. The prepared oil-soluble BN-doped CQDs were easily dispersed into organic solvent, showing great potential to produce optical and sensing devices. PMID- 27455685 TI - Effect of Particle Size and Lattice Strain on the Debye-Waller Factors of Silicon Carbide Nanoparticles. AB - Nano Silicon Carbide (SiC) particles have been produced by ball milling process. The sample was taken 0, 10, 20, 30, 40 and 50 hours of milling. The resulting nanoparticle powders were characterized by X-ray diffraction measurements. The high-energy ball milling of SiC after 50 hours resulted in particle size of about 24 nm. The Debye temperature, mean-square amplitudes of vibration, Debye-Waller factor, particle size, and lattice strain and vacancy formation of energies of SiC nanoparticles prepared by ball mill have been obtained from X-ray integrated intensities. The integrated intensities have been measured with a Philips CWU 3710 X-ray powder diffractometer fitted with a scintillation counter using filtered CuKalpha radiation at room temperature and have been corrected for thermal diffuse scattering. The X-ray Debye temperatures obtained in the present investigation has been used to estimate the vacancy formation energies for SiC nanoparticles. PMID- 27455686 TI - Low Power Consumption Design and Fabrication of Thin Film Core for Micro Fluxgate. AB - The soft magnetic characteristic of core is a critical factor to performance of the micro fluxgate. Porous thin film core can be effectively used to decrease the value of saturation magnetic field strength (H(s)) and improve soft magnetic behavior. It is conducive to impelling the micro fluxgate toward the direction of low power consumption. In this work, negative photoresist is used to fabricate a porous core by MEMS technology. Through the processes of ultraviolet-lithography, the porous pattern transfer from the mask to the microstructure on silicon substrate. The experiment result complies with the anticipation and indicates that this MEMS technique can be applied to improve the characteristic of thin film core and decrease power consumption of fluxgate sensor. PMID- 27455687 TI - Fabrication and Experimental Analysis of Axially Oriented Nanofibers. AB - A novel design of a laboratory built axially rotating collector (ARC) having capability to align electrospun nanofibers have been described. A detailed morphological comparison of such nanofibers orientation and their geometry is done using scanning electron microscopy (SEM). For comparison various polymeric solutions were electrospun on conventional static collector as well as ARC. The average diameter of polyvinyl alcohol (PVA) nanofibers was found to be 250 nm while polycaprolactone (PCL) nanofibers were found to be within a range of 600 800 nm. Conducting nanoparticles such as graphene and multi-walled carbon nanotubes (MWNTs) mixed with polymer solutions shown to have a significant influence on the overall geometry of these nanofibers and their diameter distribution. It is evident from the SEM analysis that both graphene and MWNTs in polymer solution play a crucial role in achieving a uniform diameter of nanofibers. Lastly, the formation of the aligned nanofibers using ARC has been mathematically modeled and the electromagnetic field governing the process has been simulated. PMID- 27455688 TI - Rheological Behavior of a Novel Organic-Inorganic Hybrid: Micro/Nano-Tin Fluorophosphate Glass-Polycarbonate. AB - The rheological behavior of a novel, binary organic-inorganic hybrid consisting of an ultra-low Tg tin fluorophosphate glass (Pglass) and polycarbonate (PC) was investigated using oscillatory rheometry. It was found that the complex viscosity of the hybrid showed Pglass content dependence. Under low Pglass content (10 30%), the complex viscosity of the hybrid was lower than that of pure PC. While the complex viscosity was dramatically increased and higher than that of pure PC with the content of Pglass above 30%. This phenomenon was particularly remarkable at low frequencies. Besides, with the addition of Pglass the hybrid material exhibited shear-thinning behavior and the shear-thinning characteristics became more obvious with the enhancement of the Pglass content, indicating the presence of nonlinear chemical and physical interactions between the hybrid components. Differential scanning calorimetry (DSC) measurements revealed that increasing the content of Pglass caused a decrease of the glass transition temperature (Tg) of the hybrids, suggesting that Pglass was acting as a macromolecular plasticizer for the PC. The microstructure of the Pglass in the hybrid material was characterized by scanning electron microscopy (SEM). The results showed that the Pglass were dispersed as micro- and nano-bead in the continuous phase of PC and the Pglass appeared aggregation partly with the increase of the Pglass content. This contribution was anticipated to be a guideline for the processing of this promising new class of hybrid materials. PMID- 27455689 TI - Flexible Nonstick Replica Mold for Transfer Printing of Ag Ink. AB - We report the fabrication of flexible replica molds for transfer printing of Ag ink on a rigid glass substrate. As mold precursors, acrylic mixtures were prepared from silsesquioxane-based materials, silicone acrylate, poly(propylene glycol) diacrylate, 3,3,4,4,5,5,6,6,7,7,8,8, 9,9,10,10,10-heptadecafluorodecyl methacrylate, and photoinitiator. By using these materials, the replica molds were fabricated from a silicon master onto a flexible substrate by means of UV assisted molding process at room temperature. The wettability of Ag ink decreased with increase in the water contact angle of replica molds. On the other hand, the transfer rate of Ag ink onto adhesive-modified substrates increased with increase in the water contact angle of replica molds. Transferred patterns were found to be thermally stable on the photocurable adhesive layer, whereas Ag-ink patterns transferred on non-photocurable adhesives were distorted by thermal treatment. We believe that these characteristics of replica molds and adhesives offer a new strategy for the development of the transfer printing of solution-based ink materials. PMID- 27455690 TI - The Effect of 3-Isocyanato-1-Propene on Adhesive Properties of UV-Curing Urethane/Siloxane Acrylate Resin. AB - We synthesized the urethane/siloxane acrylate oligomer from isophorone diisocyanate (IPDI), hydroxyl alkyl terminated polydimethylsiloxane and 2 hydroxyethyl acrylate (2-HEA). UV-curable resins were formulated from the synthesized oligomer, ethylene glycol phenyl ether acrylate (PHEA), 1,6 hexanediol diacrylate (HDDA), trimethylolpropane triacrylate (TMPTA) as a reactive diluent, 3-isocyanato-1-propene as an adhesion promoter and photoinitiators. The PET film was treated with plasma in order to introduce the functional group on the PET surface and the functional group was observed through X-ray photoelectron spectroscopy (XPS) and the Fourier transform infrared (FT IR). The adhesion strength between the PET film and the UV-cured resin were increased by using the adhesion promoter. Also, the thermal stability, the modulus and surface hardness were increased, as the adhesion promoter was added. PMID- 27455691 TI - Conducting Polymer Coated Graphene Oxide Electrode for Rechargeable Lithium Sulfur Batteries. AB - Poly(diallyldimethylammonium chloride) (PDDA)/graphene oxide-sulfur composites were prepared by a chemical oxidation method. For the PDDA-GO composites, conducting polymers (PDDA) were coated on the surface of GO sheets. PDDA-GO composites could be expected to increase electrical conductivity and protect restacking of graphene sheets. And then, sulfur particles were dispersed into the PDDA-GO composites by mixing in the CS2 solvent. It is expected the PDDA-GO/S composites show the limited release of polysulfides due to the fact that it can provide high surface area, because conducting polymer can be used as spacer between graphene sheets. Electrochemical performances of prepared composites were characterized by cyclic voltammetry (CV). The PDDA-GO/S composites showed a high discharge capacity of 1102 mAh g(-1) at the first cycle and a good cycle retention of 60% after 100 cycles. PMID- 27455692 TI - The Synthesis and Properties of Solution Processable a Red Phosphorescent Iridium(III) Complex with Alkyl Group. AB - The (TMP-HT)2Ir(acac) was synthesized with 2-bromo-4-(trifluoromethyl)pyridine and 5-hexyl-2-thiopheneboronic acid pinacol ester for organic light-emitting diodes (OLEDs). This material was designed on the basis of Gaussian modeling program results. The ligands have both the electron donor and acceptor in a molecule. There are pyridyl group which decrease electron density and thiophene group which increase electron density. Therefore, it showed intramolecular charge transfer (ICT) property. For solution process, the ligand have a alkyl group which has hydrophobic property. The (TMP-HT)21r(acac) was synthesized by Suzuki coupling reaction and Nonoyama reaction. The (TMP-HT)21r(acac) emitted at approximately 600 nm. The device structures were ITO/PEDOT (500 A)/TFB (170 A)/PVK:PBD (40%): (TMPHT)21r(acac) (300 A:10%)/BH:BD5% (150 A)/L201(50 A)/Liq(200 A)/Al. Electroluminescent properties were observed with devices doped with various doping concentrations. PMID- 27455693 TI - Effect of Triplet Harvesting on the Lifetime Based on Fluorescence and Phosphorescence in Hybrid White Organic Light Emitting Diodes. AB - We investigated efficient hybrid white organic light emitting diodes (WOLEDs) apply to triplet harvesting (TH) concept based on three complementary colors by mixing containing blue fluorescent emitter with phosphorescent emitters. The TH is to transfer these triplet excitons from a fluorescence to a phosphorescence, where they can decay radiatively. We fabricated several hybrid WOLEDs, having various emitting layer structures with blue fluorescent emitter and red, green phosphorescent emitter. The WOLED exhibited maximum luminous efficiency of 9.02 cd/A, and a maximum external quantum efficiency of 4.17%. The WOLED showed a highly color-stable white emission with the Commission International de L'Eclairage chromaticity of (0.38, 0.36) at 1,000 cd/m2. PMID- 27455694 TI - Prediction of Electric Field Effects on Defect-Free Self-Assembled Nano Patterning of Block Copolymer. AB - For future semiconductor device scaling, self-assembly, directed self-assembly (DSA) of block copolymers (BCPs), is a promising method with simplified processing conditions; however, critical challenge is defect control for fine pattern. Electric field is a method for the defect control. In this paper, for electric field effects to jog defects, the electric field induced self-assembled patterns is modeled and simulated by using the Monte Carlo method of dielectric polymers, the self-consistent-field theory (SCFT), and the Navier-Stokes equation. Electric field effects are quantified by using defect degree. Defective patterns are forced to undergo a phase transition to lamellar phase under electric field. For the high electric field, the excess free energy for the defect-free state becomes small. Simulation results can help to optimize electric field and process time in terms of defect area. PMID- 27455695 TI - Performance Enhancement of 3-Mercaptopropionic Acid-Capped CdSe Quantum-Dot Sensitized Solar Cells Incorporating Single-Walled Carbon Nanotubes. AB - We fabricated a series of linker-assisted quantum-dot-sensitized solar cells based on the ex situ self-assembly of CdSe quantum dots (QDs) onto TiO2 electrode using sulfide/polysulfide (S(2-)/Sn(2-)) as an electrolyte and Au cathode. Our cell were combined with single-walled carbon nanotubes (SWNTs) by two techniques; One was mixing SWNTs with TiO2 electrode and the other was spraying SWNTs onto Au electrode. Absorption spectra were used to confirm the adsorption of QDs onto TiO2 electrode. Cell performance was measured on samples containing and not containing SWNTs. Samples mixing SWNTs with TiO2 showed higher cell efficiency, on the while sample spraying SWNTs onto Au electrode showed lower efficiency compared with pristine sample (not-containing SWNTs). Electrochemical impedance spectroscopy analysis suggested that SWNTs can act as either barriers or excellent carrier transfers according their position and mixing method. PMID- 27455696 TI - Heterogeneous Charge-Transfer Nanorods by Strained Melt-Molding Lithography. AB - Hetero-nanorods consisting of two charge-transfer (CT) complexes were fabricated by the strained melt-molding lithography. Utilizing the lowered melting temperature by the formation of eutectic mixture, various well-defined CT complex nanorods can be easily fabricated by soft-lithography-assisted melt crystallization below 100 degrees C. Hetero-nanorods were fabricated by selective doping of the secondary CT complex at defects induced by applying the uniaxial strain. PMID- 27455697 TI - Effect of Cobalt Concentration and Oxygen Vacancy on Magnetism of Co Doped ZnO Nanorods. AB - Zn(1-x)Co(x)O (x = 0-0.07) single-crystalline nanorods were prepared by a modified microemulsion route. The crystalline structure, morphology, optical, and hysteresis loop at low and room temperature of as-prepared materials were characterized by XRD, TEM, PL spectra, and magnetic measurement respectively. The nanorods are 80-250 nm in diameter and about 3 MUm in length. X-ray diffraction data, TEM images confirm that the materials synthesized in optimal conditions are ZnO:Co single crystalline solid solution without any impurities related to Co. The PL spectra show that the ferromagnetic samples exhibit strong Zn interstitials and oxygen vacancy emission indicating defects may stabilize ferromagnetic order in the obtained diluted magnetic semiconductors. Magnetic measurements show that the Zn(1-x)Co(x)O nanorods exist obvious ferromagnetic characteristics with T(c) above 300 K. M(s) and coercivities first increase and then decrease with dopant concentration increasing, reaching the highest for 3% doping level. The structural and magnetic properties of these samples support the hypothesis that the FM of DMS nanorods is due to a defect mediated mechanism instead of cobalt nanoclusters and carrier mediated. PMID- 27455698 TI - Thermo Sensitivity of Polysiloxane/Silica Nanocomposites Affected by the Structure of Polymer-Filler Interface. AB - In this work thermo sensitivity was investigated with the bound rubber theory and thermoelasticity theory of the polymer-filler interface interaction between Polymethylvinylsiloxane (PMVS) and nanofillers (fumed and precipitated silica with the primary particle size of 10 nanometres). Bound rubber (the transition phase between PMVS and silica) content was measured by sol-gel analysis and swelling experiments. Results showed that the amount of bound rubber increases steadily with the increases of filler content. But the increasing rate suddenly decreased at certain silica content (between 40 and 50 phr of precipitated silica and between 30 and 40 phr of fumed silica, respectively), which was constant with the thermoelaticity experiment results. The temperature coefficients in low strain uniaxial extension are found to present sudden changing at the same silica content. This observation shows that thermo sensitivity is closely connected with the structure of polymer-filler interface. PMID- 27455699 TI - A Novel Nanofilm Sensor Based on Poly-(Alizarin Red)/Fe3O4 Magnetic Nanoparticles Multiwalled Carbon Nanotubes Composite Material for Determination of Nitrite. AB - Fe3O4 magnetic nanoparticles were synthesized by chemical co-precipitation with sodium citrate as surfactant and were characterized by FT-IR spectrometer, X-ray diffraction and transmission electron microscopy. A novel nitrite sensor was fabricated by electropolymerization of alizarin red on the surface of glassy carbon electrode modified with Fe3O4-multiwalled carbon nanotubes composite nanofilm. Under the optimal experimental conditions, it was showed that the proposed sensor exhibited good electrocatalytic activity to the oxidation of nitrite, and the peak current increased linearly with the nitrite concentration from 9.64 x 10(-6) mol x L(-1) to 1.30 x 10(-3) mol x L(-1) (R = 0.9976) with a detection limit of 1.19 x 10(-6) mol x L(-1) (S/N = 3). This sensor showed excellent sensitivity, wide linear range, stability and repeatability for nitrite determination with potential applications. PMID- 27455700 TI - TiO2 Nanowires/Poly(Methyl Methacrylate) Based Hybrid Photodetector: Improved Light Detection. AB - Hybrid photodetector with a maximum external quantum efficiency of ~3.08% in the UV region at 370 nm, was fabricated by spin-coated poly(methyl methacrylate) (PMMA) polymer onto glancing angle deposited (GLAD) vertically aligned TiO2 nanowire (NW) arrays. The TiO2 NWs/PMMA detector shows excellent rectification and constant 1.3 times photo-responsivity in the reverse bias condition from -1 V to -10 V. The photodiode possesses a low ideality factor of 5.1 as compared to bared TiO2 NWs device of 7.1. The hybrid device produces sharp turn-on of -0.8 s and turn-off transient of -0.9 s respectively. PMID- 27455701 TI - Easy Preparation and Photoelectrochemical Properties of CdS Nanoparticle/Graphene Nanosheet Nanocomposites Using Supercritical Carbon Dioxide. AB - Graphene nanosheets (GNSs) were modified with CdS nanoparticles (NPs) using supercritical CO2 (SC CO2), which has gas-like diffusivity, low viscosity, and near-zero surface tension. The resulting CdS NP/GNS nanocomposites were characterized by field-emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, Raman spectroscopy, and photoluminescence spectroscopy. Distinct morphologies of CdS NP/GNS nanocomposites decorated on the GNS surface were obtained at different SC CO2 pressures, temperatures, and durations and in different sources. Results showed that the sources and SC CO2 significantly influenced the aggregation or assembly behavior of the CdS NP/GNS nanocomposites on the GNSs. The formation mechanism of the distinct nanohybrid structures was studied by Raman mapping. A difference was noted between the Raman spectra of pristine graphene nanosheets and CdS NP/GNS nanocomposites. This result can be ascribed to the CdS NPs anchored onto the GNS defects and to the improved quality of the GNSs under SC CO2. The photo-current densities of CdS NP/GNS nanocomposites were at least three times higher than that of the pristine CdS NPs at the same applied voltage for photoelectrochemical water splitting. The findings suggested that highly efficient graphene-supported NP photoelectrocatalysts can be fabricated by the supercritical fluid method and that graphene can serve as a favorable photoelectrocatalytic carrier, with promising potential applications in environmental and energy fields. Keywords: Graphene Nanosheets, Cadmium Sulfide, Raman Spectroscopy, Photoelectrochemical. PMID- 27455702 TI - Oxide Semiconductor-Based Flexible Organic/Inorganic Hybrid Thin-Film Transistors Fabricated on Polydimethylsiloxane Elastomer. AB - We demonstrate flexible organic/inorganic hybrid thin-film transistors (TFTs) on a polydimethysilox- ane (PDMS) elastomer substrate. The active channel and gate insulator of the hybrid TFT are composed of In-Ga-Zn-O (IGZO) and blends of poly(vinylidene fluoride-trifluoroethylene) [P(VDF- TrFE)] with poly(methyl methacrylate) (PMMA), respectively. It has been confirmed that the fabri- cated TFT display excellent characteristics: the recorded field-effect mobility, sub threshold voltage swing, and I(on)/I(off) ratio were approximately 0.35 cm2 V(-1) s(-1), 1.5 V/decade, and 10(4), respectively. These characteristics did not experience any degradation at a bending radius of 15 mm. These results correspond to the first demonstration of a hybrid-type TFT using an organic gate insulator/oxide semiconducting active channel structure fabricated on PDMS elastomer, and demonstrate the feasibility of a promising device in a flexible electronic system. PMID- 27455703 TI - Tuning the Electrical Properties of Graphene via Nitrogen Plasma-Assisted Chemical Modification. AB - The control in electrical properties of graphene is essentially required in order to realize graphenebased nanoelectronics. In this study, N-doped graphene was successfully obtained via nitrogen plasma treatment. Graphene was synthesized on copper foil using thermal chemical vapor deposition. After N2 plasma treatment, the G-band of the graphene was blueshifted and the intensity ratio of 2D- to G bands decreased with increasing the plasma power. Pyrrolic-N bonding configuration induced by N2 plasma treatment was studied by X-ray photoelectron spectroscopy. Remarkably, electrical characterization including Hall measurement and I-V characteristics of the N-doped graphene exhibit semiconducting behavior as well as the n-type doping effect. PMID- 27455704 TI - Influences of Sr-Incorporated TiO2 Layer on the Photovoltaic Properties of Dye Sensitized Solar Cells. AB - Effects of a mixed overlayer composed of TiO2 and TiSrO3 on the performance of dye-sensitized solar cells (DSSCs) were investigated. The surface of TiO2 photoelectrode formed on F-doped SnO2 (FTO) was modified by soaking it in a TiCl4:SrCl2 mixed aqueous solution with various molar ratios and then calcining to produce the TiCl4:SrCl2-treated TiO2 photoelectrode (Ti:Sr-TiO2/FTO). The highest power conversion efficiency (PCE) was obtained from DSSC with Ti:Sr(7:3) TiO2/FTO, which was prepared from the mixed solution with the molar ratio of 7:3 (TiOl4:SrCl2). An enhancement in short-circuit photocurrent (J(sc)) and open circuit voltage (V(oc)) of DSSC with Ti:Sr(7:3)-TiO2/FTO was achieved, compared to those of the reference device with Ti:Sr(10:0)-TiC2/FTO (i.e., TiO2-coated TiO2/FTO). The incorporation of the mixed overlayer on the nanoporous TiO2 photoelectorde led to an improvement in the electron collection efficiency by a prolonged electron lifetime, thereby increasing the J(sc) value. The increase in V(oc) value of the device with Ti:Sr(7:3)-TiO2/FTO was due to the suppression of the charge recombination between injected electrons and I3(-) ions. PMID- 27455705 TI - Study on Ion-Conducting Properties of Ionic Liquid Containing Carbonate Electrolytes Against Carbon Electrode. AB - The ionic performances for the mixture of ethylene carbonate (EC) and dimethylcarbonate (DMC) were investigated for supercapacitor electrolyte. The usage of ethylene carbonate (EC) and dimethylcarbonate (DMC) as organic solvent could solve some problems of acetonitrile (AN). The general aim of present paper is compare to properties of electrochemical properties based on two mixed organic electrolytes. The ionic conductivity, viscosity, and electrochemical performances of EC/DMC+0.1 M TEABF4 mixtures were determined. The ionic conductivity of the electrolytes was measured by AC impedance, and the capacitative performances of the electrolytes were evaluated by using cyclic voltammetry. PMID- 27455706 TI - Optical and Electrical Characteristics of Graphene Double Layer Formed by a Double Transfer of Graphene Single Layers. AB - We demonstrate formation of double layer graphene by means of a double transfer using two single graphene layers grown by a chemical vapor deposition method. It is observed that shiftiness and broadness in the double-resonance of Raman scattering are much weaker than those of bilayer graphene formed naturally. Transport characteristics examined from transmission line measurements and field effect transistors show the similar behavior with those of single layer graphene. It indicates that interlayer separation, in electrical view, is large enough to avoid correlation between layers for the double layer structure. It is also observed from a transistor with the double layer graphene that molecules adsorpted on two inner graphene surfaces in the double layered structure are isolated and conserved from ambient environment. PMID- 27455707 TI - Nonlinear Transport in Organic Thin Film Transistors with Soluble Small Molecule Semiconductor. AB - Nonlinear transport is intensively explained through Poole-Frenkel (PF) transport mechanism in organic thin film transistors with solution-processed small molecules, which is, 6,13-bis(triisopropylsilylethynyl) (TIPS) pentacene. We outline a detailed electrical study that identifies the source to drain field dependent mobility. Devices with diverse channel lengths enable the extensive exhibition of field dependent mobility due to thermal activation of carriers among traps. PMID- 27455708 TI - Impact of Energy Level Shift of Hole Injection Layer on the Recombination Rate in OLEDs. AB - This paper reports the numerical study on the impact of energy level variation of the hole injection layer (HIL) in the organic light emitting diodes (OLEDs). We used a thin CuPc layer for the hole injection and S-TAD (2,2',7,7'-tetrakis-(N,N- diphenylamino)-9,9-spirobifluoren) for the hole transfer layer, S-DPVBi (4,4'-bis (2,2'-diphenylvinyl) -1,1'-spirobiphenyl) for the emission layer, and Alq3 (Tris (8-hyroxyquinolinato) aluminium) for the electron transfer layer. Device B has tri-layer structure except HIL. We used three models which are four layer structures for our simulation. HIL of Device A has 5.3 eV of highest occupied molecular orbital (HOMO) level and 3.8 eV of lowest unoccupied molecular orbital (LUMO) level. Also, we varied the LUMO level and HOMO level of the thin CuPc layer, which are named as Device C and Device D, respectively. Our numerical study represented that Device D has the most amount of recombination rate due to Device D has the most carrier density in the emission layer. Device A has 4.381 x 10(25) cm(-3)s(-1) of recombination, Device B has 6.439 x 10(25) cm(-3)s(-1) of recombination and Device D has 7.499 x 10(25) cm(-3)s(-1) of recombination. Consequently, nevertheless the insertion of HIL does not always improve recombination rate and we observed the recombination rate can improve about 16% according to HOMO level of HIL. PMID- 27455709 TI - Solution Processed Organic Photovoltaic Cells Using D-A-D-A-D Type Small Molecular Donor Materials with Benzodithiophene and Diketopyrrolopyrrole Units. AB - Organic photovoltaic Cells (OPVs) have been considered to be a next-generation energy source to overcome exhaustion of resources. Currently, OPVs are developed based on two types of donor material with polymer and small molecule. Polymeric donor materials have shown better power conversion efficiency (PCE) than small molecular donor materials, since it's easy to control the morphology of photoactive film. However, the difficulty in synthetic reproducibility and purification of polymeric donor were main drawback to overcome. And then, recently small molecule donor materials have been overcome bad morphology of OPVs film by using appropriate alkyl substituents and relatively long conjugation system. In this study, we designed and synthesized D-A-D-A-D type small molecular donor materials containing alternatively linked benzodithiophene (BDT) and diketopyrrolopyrrole (DPP) units. Also, we studied on the effect of photovoltaic performance of prepared small molecular D-A-D-A-D type donor with variation of thiophene links and with/without hexyl substituent. Our small molecular donors showed HOMO energy levels from -5.26 to -5.34 eV and optical bandgaps from 1.70 to 1.87 eV by CV (cyclic voltammetry) and UV/Vis spectroscopy, respectively. Finally, 3.4% of PCE can be obtained using a mixture of BDT(DPP)2-T2 and PCBM as an active layer with a Voc of 0.78 V, a Jsc of 9.72 mA/cm2, and a fill factor of 0.44 under 100 mW/cm2 AM 1.5G simulated light. We will discuss the performance of D-A-D-A-D type small molecular donor based OPVs with variation of both terminal substituents. PMID- 27455710 TI - Striped Phase of 3-Hexylthiophene Self-Assembled Monolayers on Au(1 11) Formed by Vapor Phase Deposition. AB - The formation and surface structure of 3-hexylthiophene (HTP) self-assembled monolayers (SAMs) on Au(111) prepared by solution and ambient-pressure vapor deposition at room temperature (RT) for 24 h were examined by means of scanning tunneling microscopy (STM) and cyclic voltammetry (CV). STM imaging revealed that HTP SAMs formed by solution deposition have a disordered phase, whereas those formed by vapor deposition exhibit a striped phase with a unidirectional orientation. The distance between the rows in the striped phase was measured to be 1.3 +/- 0.1 nm, and the hexyl molecular backbones of HTP in the SAMs on Au(111) are oriented parallel to the Au(111) surface with the head-to-head orientation. From this STM observation, we suggest that the formation of this striped phase in HTP SAMs prepared by vapor deposition were mainly driven by the optimization of van der Waals interactions between the hexyl chains on the surface. CV measurements also demonstrated that HTP SAMs show a high blocking efficiency for electron transfer reactions between electrolytes and the gold electrode, suggesting the formation of SAMs on Au(111) from the vapor phase. Our results obtained here will be very useful for understanding the formation and structure of HTP SAMs on Au(111) surfaces and how they are influenced by deposition method. PMID- 27455711 TI - Synthesis, Characterization and TFT Characteristics of Diketopyrrolopyrrole Based Copolymer. AB - A novel diketopyrrolopyrrole (DPP) based low band gap polymer, poly[4,8 bis(triisopropylsilylethynyl) benzo[1,2-b:4,5-b']dithiophene-2,6-diyl-alt-[2,5-di hexyl-3,6-dithiophen-2-ylpyrrolo[3,4-c]pyrrole-1,4-dione] (PTIPSBDT-DPP) is synthesized by Stille polymerization for use in thin film transistor (TFTs). The new polymer contain extended aromatic pi-conjugated segments alternating with the DPP units and are designed to increase the free energy for charge generation to overcome current limitations in photocurrent generation. In this study we describe the synthesis, thermal stability, optical, electrochemical properties and TFT characteristics. PMID- 27455712 TI - Formation of Ordered 4-Fluorobenzenethiol Self-Assembled Monolayers on Au(111) from Vapor Phase Deposition. AB - Self-assembled monolayers (SAMs) were formed by the spontaneous adsorption of 4 fluorobenzenethiol (4-FBT) on Au(111) using both solution and ambient-pressure vapor deposition methods at room temperature. The surface structure and thermal desorption properties of 4-FBT SAMs were examined by scanning tunneling microscopy (STM) and thermal desorption spectroscopy (TDS). STM imaging showed that 4-FBT SAMs formed in solution at room temperature mainly contained disordered phase with gold adatom islands, while those formed by ambient-pressure vapor deposition had well-ordered phase, which can be described as a (2 x 2?13)R45 degrees structure. In addition, thermal desorption spectroscopy (TDS) measurements showed that strong desorption peak for parent mass fragment (m/z = 128, FC6H5SH+) for 4-FBT SAMs on Au(111) was observed at 460 K, as a result of hydrogen abstract reaction of chemisorbed thiolates during desorption. PMID- 27455713 TI - Adsorption Behavior of Ferromagnetic Carbon Nanotubes for Methyl Orange from Aqueous Solution. AB - The ferromagnetic carbon nanotubes which can be easily separated from aqueous solution were prepared and characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Batch experiments were carried out to investigate the adsorption behavior of ferromagnetic carbon nanotubes for removing methyl orange (MO). The results showed that these ferromagnetic carbon nanotubes were richer in surface function groups than the carbon nanotubes did, furthermore, both gamma-Fe2O3 and Fe with ferromagnetism were found on the surface of carbon nanotubes. The results also demonstrated that ferromagnetic carbon nanotubes possessed stronger adsorption ability for MO than carbon nanotubes did. The adsorption isotherms followed Langmuir isotherm equation and the adsorption kinetics could be well described with the pseudo second-order kinetic model. The adsorption process involved an intraparticle diffusion, while it was not the only rate-controlling step. The values of AG were negative and the value of DeltaH is -12.37 kJ/mol, proving that the adsorption of MO onto ferromagnetic carbon nanotubes was a spontaneous and exothermic process. PMID- 27455714 TI - Synthesis of a Novel Phosphorus-Containing Flame Retardant Curing Agent and Its Application in Epoxy Resins. AB - A novel phosphorus-containing compound diphenyl-(2,5-dihydroxyphenyl)-phosphine oxide defined as DPDHPPO was synthesized and used as flame retardant and curing agent for epoxy resins (EP). The chemical structure was well characterized by Fourier transform infrared (FTIR) spectroscopy, 1H, 13C and 31P nuclear magnetic resonance. The flame retardant properties, combusting performances and thermal degradation behaviors of the cured epoxy resins were investigated by limiting oxygen index (LOI), vertical burning tests (UL-94), cone calorimeter and thermogravimetric analysis (TGA) tests. The morphologies and chemical compositions of char residues for cured epoxy resins were investigated by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), respectively. The water resistant properties were evaluated by putting the samples into distilled water at 70 degrees C for 168 h. The results revealed that the EP/40 wt% DPDHPPO/60 wt% PDA thermosets successfully passed UL-94 V-0 flammability rating and the LOI value was as high as 31.9%. The cone tests results revealed that the incorporation of DPDHPPO efficiently reduced the combustion parameters of epoxy resins thermosets, such as heat release rate (HRR), total heat release (THR) and so on. The TGA results indicated that the introduction of DPDHPPO promoted epoxy resins matrix decomposed ahead of time compared with that of pure EP and led to a higher char yield and thermal stability at high temperature. The morphological structures and analysis of XPS of char residues revealed that DPDHPPO benefited to the formation of a sufficient, compact and homogeneous char layer with rich flame retardant elements on the epoxy resins materials surface during combustion. After water resistance tests, EP/40 wt% DPDHPPO/60 wt% PDA thermosets still remained excellent flame retardancy, the moisture absorption of epoxy resins thermosets decreased with the increase of DPDHPPO contents in the thermosets due to the existing of P-C bonds and the rigid aromatic hydrophobic structure. PMID- 27455715 TI - Characterization of a Ternary System Based on Hybrid Nanoparticles. AB - Hybrid nanoparticles (NPs) are emerging as an important family of multifunctional nanoscale materials. Due to its unique properties cyclodextrins (CDs) present the possibility to be employed in nanostructured devices for multiple applications. Therefore the study of hybrids NPs containing CDs, metal nanoparticles and an organic molecular guest is promising for applications in separation science, sensing, optics, catalysis and medical therapy. To investigate the hybrid nanoparticles properties in light of technological and medical science interfaces we chose tramadol hydrochloride as the model molecular guest. Using 2D 1H NMR and FTIR spectroscopies and ESI-MS we studied the topology and host-guest stoichiometry of inclusion compound between 2-hydroxypropyl-alpha-cyclodextrin and tramadol. These techniques confirmed that the inclusion compounds present 1:1 stoichiometry with the tramadol aromatic moiety inserted in the CD cavity and the amine part interacting with the CD superficial OHs. Performing capillary electrophoresis experiments, the stability constants of inclusion compounds were obtained and showed that the increase of temperature during the synthesis of these NPs can decrease their stabilities. Precipitated palladium nanoparticles were determined to have 80-200 nm of size distribution and the incorporation of tramadol was evidenced by additional 1H NMR experiments. PMID- 27455716 TI - Role of LiBF4 in Ionic Liquid Membranes for Facilitated CO2 Transport. AB - The ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM BF4)/LiBF4 electrolyte was prepared for highly selective facilitated CO2 transport membranes. When LiBF4 was incorporated into BMIM BF4, synergy effects by free Li+ ion and imidazolium cations is expected to enhance the separation performance for CO2/N2 and CO2/CH4. The free state of BF4- ions in BMIM BF4/LiBF4 solutions was investigated by FT-Raman spectroscopy. For the coordination of LiBF4 with BMIMBF4, thermal gravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS) was utilized. Electrolyte membranes consisting of BMIM BF4 and LiBF4 showed selectivities of 8.40 and 8.25 for CO2/N2 and CO2/CH4, respectively. Neat BMIM BF4 membrane showed selectivities of 5.0 and 4.8, respectively. Enhanced separation performance was attributed to increased free Li+ and abundant free imidazolium cations. PMID- 27455717 TI - Dispersion of Single Walled Carbon Nanotubes Using a Novel Type of Sonication: Focused Sonication. AB - We demonstrate the use of novel type of sonication method, focused sonication, with added advantages over bath and probe type of sonication for the dispersion of single walled carbon nanotubes (SWNT). Di-chloro benzene was used as the solvent for dispersion of SWNT. Results from focused sonication and bath sonication were compared and found that focused sonication results in better dispersion. Also Raman spectroscopy was analysed to ascertain if focused sonication causes any damage to the tubes and it was found that there was no damage to the SWNT. We believe that with the added advantages like in-situ temperature control and large sample volume processing, focused sonication would prove to be the most proficient method of sonication for dispersion of nanoparticles. PMID- 27455718 TI - Synthesis of Mesoporous Carbons from Rice Husk for Supercapacitors with High Energy Density in Ionic Liquid Electrolytes. AB - High-performance mesoporous carbons (MCs) for supercapacitors were made from rice husk by one-step microwave-assisted ZnCl2 activation. The microstructures of MCs as-made were characterized by field emission scanning electron microscopy and transmission electron microscopy. The pore structure parameters of MCs were obtained by N2 adsorption technique. The electrochemical properties of MC electrodes were studied by constant current charge-discharge, cyclic voltammetry and electrochemical impedance spectroscopy in different electrolytes. The results showed that the specific surface area of MC4 made at the ZnCl2/rice husk mass of 4:1 reached 1737 m2 g(-1). The specific capacitance and energy density of the electrodes fabricated from the mixture of MC4 and microporous carbon increased with the mass percentage of MC4, reaching 157 F g(-1) and 84 Wh kg(-1) at 0.05 A g(-1), and showed good cycle stability in 1-butyl-3-methylimidazolium hexafluorophosphate electrolyte. Compared to the often-used aqueous and organic electrolytes, MC4 capacitor exhibited extremely high energy density in ionic liquid electrolyte, remaining at 28 Wh kg(-1) at 1684 W kg(-1). This work paves a new way to produce cost-effective MCs from biomass for supercapacitors with extremely high energy density in ionic liquid electrolytes. PMID- 27455719 TI - Simultaneous Reduction of Vanadium (V) and Chromium (VI) in Wastewater by Nanosized ZnWO4 Photocatalysis. AB - Vanadium (V, V) and chromium (Cr, VI) are simultaneously photocatalytically reduced to less-toxic V(VI) and Cr(III) by mimetic solar light with ZnWO4 nanoparticles prepared by hydrothermal synthesis. The reduction efficiencies can reach 68.8% for V(V) and 97.3% for Cr(VI) in 3 h, respectively, which are comparable to those by microbial fuel cell technology carried out in over 10 days. The prepared ZnWO4 nanoparticles are characterized by XRD, SEM, EDS, TEM, and Uv-vis-DRS tests. Electrochemical calculation shows high acidity benefits the rapid reduction of V(V) and Cr(VI). In addition, the applied ZnWO4 nanoparticles can be recycled and reused for 5 repeated photocatalytic reduction runs. And after 5 runs, the recycled ZnWO4 nanoparticles can also present good photocatalytic activity with a reduction efficiency of about 60% for V(V) and 90% for Cr(VI). The new procedure on the simultaneous reduction of V(V) and Cr(VI) by photocatalysis may be promisingly applied in contaminated wastewaters, combining the remediation and possible V and Cr recovery. PMID- 27455720 TI - Colorimetric Fluorescent Nanosensor Based on Hexamethylene Diisocyanate for Fluorescent Responses and Adsorption of Heavy Metal Ions. AB - An inorganic-organic hybrid material based on magnetic Fe3O4@SiO2 nanoparticles was synthesized for fluorescent responses and removal of heavy metal ions, in which superparamagnetic Fe3O4@SiO2 nanoparticles were firstly prepared and modified with hexamethylene diisocyanate (HDI) instead of 3 isocyanatopropyltriethoxysilane (IPTES) as the organic coupling agent, and then a rhodamine derivative with spirolactam structure (Rho-en) was conjugated on the HDI functionalized Fe3O4@SiO2 nanoparticles through isocyanate groups. Both of functionalized Fe3O4@SiO2 nanoparticles based on IPTES and HDI were characterized by FT-IR and XPS, and the results indicated that HDI was a good alternative as chemical bridge for surface modification on the surface of Fe3O4@SiO2 nanoparticles. The inorganic-organic hybrid composites synthesized based HDI showed naked-eye color changes and fluorescent responses towards Zn2+, Cd2+, Mn2+, Pb2+, Hg2+ and Fe3+, which could serve as the available proofs for the qualitative analysis. Moreover, the as-obtained composites not only had excellent adsorption capability for Pb2+ and Hg2+, but also showed strong magnetic sensitivity, which could help to the removal and separation of functionalized magnetic nanocomposites after capturing the heavy metal ions. In addition, the plausible interaction mode of functionalized Fe3O4@SiO2 nanoparticles with heavy metal ions was discussed. PMID- 27455721 TI - A Novel and Simple Method for the Synthesis of beta-SiC/SiO2 Coaxial Nanocables in a Large Area: Polycarbosilane Pyrolysis. AB - In the present work, beta-SiC/SiO2 coaxial nanocables are synthesized in a large area via direct pyrolysis of polymeric precursor method, in which, polycarbosilane acts the single raw material. The morphology, chemical composition and detailed microstructure of the nanocables are characterized. The core of nanocables are single crystalline beta-SiC nanowires with diameter of 30 60 nm grown along [111] direction. The uniform coating layer is amorphous SiO2 with thickness of 15 nm. Based on the pyrolysis process of polycarbosilane, the Vapor-Liquid-Solid growth mechanism is discussed. Furthermore, field emission measurements show the turn-on field and the threshold field are 3.2 V/MUm and 6.5 V/MUm, respectively. This study shows that beta-SiC/SiO2 coaxial nanocables are promising for field emission display device and other vacuum electronic devices. PMID- 27455722 TI - Annealing Mechanism and Effect of Microwave Plasma Assisted Annealing on Properties of Sputtered Pb(Zr0.52Ti0.48)O3 Thin Films. AB - To solve some problems existing in PZT films, such as: large residual stresses, interface diffusion, and lead loss, etc., which were caused by high post annealing temperatures, and to obtain thin films with high-preferred orientation and uniform size grain and dense microstructure, different technological conditions of microwave plasma assisted post-annealing had been pilot studied. X ray diffraction was used to analyze the crystal structures of the films. Transmission electronic microscope was used to analyze the surface and the interface morphology of the films. Ferroelectric properties were showed by measuring the remnant polarization and the leakage current dependence of electric field. The results indicated that it was good for reducing lead loss and annealing temperature of PZT films by microwave plasma assisted annealing. Ferroelectric properties of the film could also be enhanced by this pilot annealing method. PMID- 27455723 TI - The Effect of UV-Ozone Treatment on the Performance of Plasmonic Organic Solar Cells. AB - Silver nanoparticles (Ag NPs) solution was spin-coated on indium-tin oxide (ITO) glass substrates prior to spin-coating poly(3,4 ethylenedioxythiophene):poly(styrene- sulfonate) ( PEDOT: PSS) for the plasmonic solar cells. The sequence of spin-coating of Ag and UV-ozone treatment resulted in different device performance. For devices in which Ag NPs solution was spin coated on ITO substrates before UV-ozone treatment, power conversion efficiency increased from 3.4% to 3.7%, while the power conversion efficiency decreased if Ag NPs solution was spin-coated after UV-ozone treatment. In both cases, the short-circuit current density increased, and the open-circuit voltage remained relatively constant. The variation of power conversion efficiency mainly depended on the changing of the fill factor, which is related to film morphology of the devices. AFM measurements of PEDOT: PSS films were taken to study the influence of film morphology on device performance. PMID- 27455724 TI - Highly Efficient Phosphorescent Light-Emitting Diodes by Using New Host Material. AB - An electron-transporting triazole (Tz) and hole transporting carbazole (Cz) moieties were introduced into the fluorene structure via a Suzuki coupling reaction. The resulting material, 9-(4'-(9-(4'-(4,5-diphenyl-4H-1,2,4-triazol-3 y)-[1,1'-biphenyl]-4-yl)-9H-fluoren-9-yl)-[1,1'-biphenyl]-4-yl)-9H-carbazole (Tz FL-Cz), was synthesized and can be used as the host layer in phosphorescent OLEDs. The synthesized material exhibits wide energy gap (3.46 eV). The absorption and emission maximum of the Tz-FL-Cz was observed at 300 nm and 389 nm, respectively. Blue phosphorescent devices using Tz-FL-Cz as host material exhibited maximum current efficiency of 3.2 cd/A and power efficiency of 1.3 lm/W, respectively. PMID- 27455725 TI - Conductivity Enhancement of PEDOT:PSS Films Through the Surface Treatment with Organic Solvent. AB - The improvement of conductivity is a key factor in application of conducting polymer to elec- tronic devices. The conductivity enhancement of PEDOT: PSS films were observed after dipping in polar organic solvents, including DMSO, ethylene glycol, glycerol and IPA. The conductivity of PEDOT: PSS films increased from 0.5 S/cm to over 800 S/cm, that is, by a factor of more than 1,600. The conductivity enhancement was dependent on the type of organic solvents and dipping time of PEDOT: PSS into solvent. The enhancement of conductivity may be caused by the phase separation between PEDOT chains and PSS counter anions. PMID- 27455726 TI - Liquid Crystal Alignment on Solution Derived Zinc Oxide Films via Ion Beam Irradiation. AB - A 75-nm-thick ZnO film was deposited by a sol-gel method on indium-tin oxide (ITO)-coated glass. This film served as a liquid crystal (LC) alignment layer. We report the fabrication and characteristics of this film after ion-beam (IB) irradiation. Uniform LC alignment was achieved at an IB incident energy above 2400 eV. The IB-treated ZnO surface was analyzed by X-ray photoelectron spectroscopy (XPS), monitoring the intensity of the Zn 2p and O 1s peaks as a function of IB-irradiation energy density. The electro-optical (EO) characteristics of a twisted nematic-liquid crystal display (TN-LCD) were comparable to rubbed polyimide. PMID- 27455727 TI - Electric Characteristics of the Carbon Nanotube Network Transistor with Directly Grown ZnO Nanoparticles. AB - We report on the electrical characteristics of field effect transistors fabricated with random networks of single-walled carbon nanotubes with surfaces modified by ZnO nanoparticles. ZnO nanoparticles are directly grown on single walled carbon nanotubes by atomic layer deposition using diethylzinc (DEZ) and water. Electrical observations show that ZnO nanoparticles act as charge transfer sources that provide electrons to the nanotube channel. The valley position in ambipolar transport of nanotube transistors is negatively shifted for 3V due to the electronic n-typed property of ZnO nanoparticles. However, the Raman resonance remains invariant despite the charge transfer effect produced by ZnO nanoparticles. PMID- 27455728 TI - Schematics and Energetics of Bucky Shuttle Memory on Graphene Nanoribbon Array. AB - Conjugated carbon nanomaterials such as fullerene-nanotube, fullerene-graphene, and nanotube-graphene hybrids have great potential for various applications. This paper presents the schematics and energetics of a nonvolatile nanomemory element based on a fullerene-nanotube-graphene hybrid. The system proposed was composed of C60 fullerene and a nanotube placed on two graphene-nanoribbons with a gap. The C60 fullerene encapsulated in the nanotube can shuttle between two graphene nanoribbons along the nanotube under the alternatively applied force fields. When the encapsulated C60 fullerene settles on the graphene-nanoribbons, the local energy minima are achieved from the attractive van der Waals potential energies. Since the C60 fullerene retains its position on the graphene-nanoribbon without external force fields, the proposed system can then operate a nonvolatile memory device. PMID- 27455729 TI - A Microfluidic Microbeads Fluorescence Assay with Quantum Dots-Bead-DNA Probe. AB - A microfluidic bead-based nucleic acid sensor for the detection of tumor causing N-Ras genes using quantum dots has been developed. Presently, quantum dots-bead DNA probe based hybridization detection methods are often called as 'bead based assays' and their success is substantially influenced by the dispensing and manipulation capability of the microfluidic technology. This study reports the detection of N-Ras cancer gene by fluorescence quenching of quantum dots immobilized on the surface of polystyrene beads. A microfluidic chip was constructed in which the quantum dots-bead-DNA probes were packed in the channel. The target DNA flowed across the beads and hybridized with immobilized probe sequences. The target DNA can be detected by the fluorescence quenching of the quantum dots due to their transfer of emission energy to intercalation dye after DNA hybridization. The mutated gene also induces fluorescence quenching but with less degree than the perfectly complementary target DNA. PMID- 27455730 TI - Hybrid Structure White Organic Light Emitting Diode for Enhanced Efficiency by Varied Doping Rate. AB - Novel materials based on Zn(HPB)2 and Ir-complexes were synthesized as blue or red emitters, respectively. White organic light emitting diodes were fabricated using the Zn(HPB)2 as a blue emitting layer, Ir-complexes as a red emitting layer and Alq3 as a green emitting layer. The obtained experimental results, were based on white OLEDs fabricated using double emission layers of Zn(HPB)2 and Alq3:Ir complexes. The doping rate of the Ir-complexes was varied at 0.4%, 0.6%, 0.8% and 1.0%. When the doping rate of the Alq3:Ir-complexes was 0.6%, a white emission was achieved. The Commission Internationale de l'Eclairage coordinates of the device's white emission were (0.316, 0.331) at an applied voltage of 10.75 V. PMID- 27455731 TI - Acetone Sensing with In2O3-Coated Nb2O5 Nanorod Sensors. AB - Nb2O5-core/In2O3-shell nanorods were synthesized by thermal oxidation of Nb foil followed by sputter deposition of In2O3. The 1D nanostructures exhibited a rod like morphology with widths and lengths ranging from 20 to 70 nm and 10 to 20 /jm, respectively. The sensing properties of Nb2O5-core/In2O3-shell nanorod sensors toward acetone gas were examined. The pristine Nb2O5 nanorods showed responses ranging from -121 to -253% to CH3COCH3 concentrations of 200-1,000 ppm. In contrast, Nb2O5-core/In2O3-shell nanorods showed responses ranging from -167 to -563% over the same concentration range. These responses are comparable or superior to other metal oxide semiconductor gas sensors in the literature. The underlying mechanism of the enhanced sensing properties of Nb2O5-core/In2O3-shell nanorods toward CH3COCH3 is also discussed. PMID- 27455732 TI - Electrospun Carbon Nanotube-Reinforced Nanofiber. AB - We fabricated multi-walled carbon nanotube (MWNT) reinforced polyurethane (PU) nanofiber (MWNT-PU) web via electrospinning. In order to optimize the electrospinning conditions, we investigated the effects of various parameters including kind of solvent, viscosity of the spinning solution, and flow rate on the spinnability and properties of nanofiber. N,N-dimethylformamide (DMF), tetrahydrofuran (THF) and their mixture with various volume ratio were used as the spinning solvent. Morphology of the nanofiber was studied using scanning electron microscope (SEM) and transmission electron microscope (TEM), confirming successful fabrication of MWNT-PU nanofiber web with uniform dispersion of MWNT in longitudinal direction of the fiber. The MWNT-PU nanofiber web exhibited two times higher tensile strength than PU nanofiber web. We also fabricated electrically conducting MWNT-PU nanofiber web by coating poly(3,4 ehtylenedioxythiophene) (PEDOT) on the surface of MWNT-PU nanofiber web for electromagnetic interference (EMI) shielding application. The electromagnetic interference shielding effectiveness (EMI SE) was quite high as 25 dB in the frequency range from 50 MHz to 10 GHz. PMID- 27455733 TI - Blue Emitters Based on Aryl End-Capped Pyrene Groups for OLEDs. AB - We have synthesized four pyrene-derived blue emitting materials using Suzuki cross coupling reactions. All OLED devices using these materials as emitting materials showed efficient blue electroluminescence (EL). Particularly, a device using 1,1'-(9,9-dimethyl-9H-fluorene-2,7-diyl)bis-pyrene (1) showed best EL properties with the luminous efficiency of 4.32 cd/A, the power efficiency of 3.98 lm/W and the external quantum efficiency of 2.48% at 500 cd/m2. PMID- 27455734 TI - Syntheses of D-A-A Type Small Molecular Donor Materials Having Various Electron Accepting Moiety for Organic Photovoltaic Application. AB - Small molecular donor, DTDCTB achieved a high power conversion efficiency (PCE) value of 6.6 +/- 0.2% in vacuum-deposited planar mixed heterojunction (PMHJ) structure. However, the same material just recorded PCE of 0.34% in solution processed small molecule based bulk heterjunction (BHJ) organic photovoltaic cells. For the improvement of organic photovoltaic cells (OPVs), In this study, we designed and synthesized several D-A-A (donor-acceptor-acceptor) type molecular electron donating materials. Ditolylaminothienyl moiety as an electron donating group connected to 1,2,5-benzothiadiazole as a conjugated electron accepting unit, simultaneously with an electron accepting terminal group such as cyano alkyl acetate and N-alkyl rhodanine. The thermal, photophysical, and electrochemical properties of prepared small molecules were investigated by DSC, UV/Vis spectroscopy and Cyclic Voltametry, respectively. As a result, 0.89% of PCE can be obtained from OPV using a mixture of DTATBTER and PCBM as an active layer with a Voc of 0.87 V, a Jsc of 3.20 mA/cm2, and a fill factor of 31.9%. PMID- 27455735 TI - Glutaraldehyde Cross-Linked Chitosan Nanofibers: Preparation, Characterization and Application in Adsorption of Cu (II). AB - Chitosan nanofibers were prepared via electrospinning and cross-linked by a treatment with glutaraldehyde (GA) in order to obtain insoluble adsorbents in aqueous acidic and basic solutions. Then, the prepared nanofiber was investigated for its adsorption of Cu (II) in aqueous solution. The effects of the viscosity, conductivity of chitosan-TFA spinning solution and the properties of the nanofibers related to the molecular weight of chitosan were studied. The scanning electron microscope (SEM) images demonstrated a smooth and inter-connected morphology comprising fibers with diameters between 70 nm and 350 nm. An amount of 72 mg/g of Cu (II) adsorption was achieved and its mechanism was elucidated. After removing the adsorbed Cu (II), the cross-linked chitosan nanofibers were regenerated and could be reused. PMID- 27455736 TI - Fabrication and Thermophysical Properties of La(2-x)Zr(2-y)O7 Nanocrystal by a Sol-Gel Method. AB - Non-Stoichiometric La2Zr2O7 (La(2-x)Zr(2-y)O7) Nanocrystal was synthesized by a simple sol-gel method. The crystalline structure, oxygen vacancy concentration, thermal expansion coefficient, as well as the fracture toughness of as-prepared materials were charactered by XRD, TG-DSC, PL spectra, dilatometer, and electronic universal testing machine respectively. The crystal structure of La2Zr2O7 is of the cubic type while lattice parameter increases with the deviatation of Zr4+ and La3+ from Stoichiometric La2Zr2O7 increasing. The average linear thermal expansion coefficient of non-stoichiometric La2Zr2O7 is obviously bigger than that of La2Zr2O7 in the temperature range between 150 degrees C and 950 degrees C. The fracture toughness of La(2-x)Zr(2-y)O7 increases with x and y increasing up to x = 0.3 and y = 0.25. PMID- 27455737 TI - Addressing of LnCaP Cell Using Magnetic Particles Assisted Impedimetric Microelectrode. AB - In this study, we provide a facile, effective technique for a simple isolation and enrichment of low metastatic prostate tumor cell LNCaP using biocompatible, magnetic particles asissted impedimetric sensing system. Hydrophobic cell membrane anchors (BAM) were generated onto magnetic particles which diameters vary from 50 nm to 5 MUm and were used to capture LNCaP cells from the suspension. Finally, magnetic particle-LNCaP complex were addressed onto the surface of the interdigitated microelectrode (IDM). Cell viability was monitored by our laboratory developed-technique Electrical Cell Substrate Impedance Sensing (ECIS). The results reavealed that 50 nm-magnetic particles showed best performance in terms of cell separation and cell viability. This technique provides a simple and efficient method for the direct addressing of LNCaP cell on the surface and enhances better understanding of cell behavior for cancer management in the near future. PMID- 27455738 TI - Fabrication and Electrochemical Characterization of Polyaniline/Titanium Oxide Nanoweb Composite Electrode for Supercapacitor Application. AB - In this study, polyaniline/titanium oxide (PANi-TiO2) nanoweb composite was fabricated through electrochemical deposition and electrospinning techniques, and the composite was further utilized as an electrode for a supercapacitor. The PANi TiO2 composite film showed three-dimensional hierarchical micro/nano architecture. The film was deposited on the current collector without the use of any binders. The morphology of the PANi-TiO2 composite film was confirmed by the use of field emission scanning electron microscopy (FE-SEM) analysis that polyaniline was grown in the form of nanorods with a diameter of 100 nm-200 nm on a TiO2 nanoweb. The chemical composition and quantitative analysis were determined by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The electrochemical properties were analyzed by cyclic voltammetry (CV), chronopotentiometry, and electrochemical impedance spectroscopy (EIS). The result of electrochemical tests indicated that TiO2-PANi electrode displayed a high specific capacitance of 306.5 Fg(-1) at the scan rate of 20 mVs(-1), with the capacitance retention ratio being 103% after 500 cycles at the scan rate of 50 mVs(-1). PMID- 27455739 TI - Synthesis and Characterization of Mimosa Pudica Leaves Shaped alpha-Iron Oxide Nanostructures for Ethanol Chemical Sensor Applications. AB - Herein, the synthesis of mimosa pudica leaves shaped a-iron oxide (alpha-Fe2O3) nanostructures is reported through simple and facile hydrothermal process. The prepared alpha-Fe2O3 nanostructures were characterized in terms of their morphological, structural, compositional and optical properties through a variety of characterization techniques such as FESEM, EDS, XRD, FTIR and Raman spectroscopy. The detailed characterizations revealed the well-crystallinity and dense growth of mimosa pudica leaf shaped alpha-Fe2O3 nanostructures. Further, the prepared nanomaterials were used as efficient electron mediator to fabricate sensitive ethanol chemical sensor. The fabricated sensor exhibited a high sensitivity of -30.37 MUAmM(-1) cm(-2) and low detection limit of -0.62 MUM. The observed linear dynamic range (LDR) was in the range from 10 MUM-0.625 MUM. PMID- 27455740 TI - Effects of Temperature and Pore Structure on High Surface Area-Activated Carbon Obtained from Peanut Shells. AB - Activated carbon was synthesized from peanut shells by treating with H3PO4 with an intention to enhance the surface area and to find its electrochemical performance in EDLC as electrode material. The powdered peanut shells were pyrolyzed at three different temperatures namely 300 degrees C, 600 degrees C and 800 degrees C respectively. The structural and surface properties of the pyrolyzed carbon materials were studied using N2 adsorption/desorption, Raman, TEM and SEM analysis. There has been remarkable increase in the surface area of the carbon pyrolyzed at 600 degrees C due to the effect of pore generations. The surface area of the 600 degrees C pyrolyzed sample was found to be 1629 m2/g. The electrochemical properties of all the samples were evaluated by cyclic voltammetry, impedance spectroscopy, and galvanostatic charge-discharge tests. The system showed excellent cycleability and a maximum specific capacitance of 291 Fg(-1) was obtained in a 0.1 M H2SO4 electrolyte solution. The effects of the various properties of the activated carbon on the EDLC performance are discussed. PMID- 27455741 TI - Effect of Varying Inert Gas and Acetylene Concentration on the Synthesis of Carbon Nanotubes. AB - The multiwalled carbon nanotubes (MWCNTs) with small diameter and high purity were achieved by chemical vapor deposition technique using silicon substrate. The introduction of specific concentration of inert gas with hydrocarbon played a key role in controlling morphology and diameter of MWCNTs. Nickel mixed ferrite nanoparticles were used as a catalyst for the growth of MWCNTs. Growth parameters like concentration of hydrocarbon source and inert gas flow, composition of catalyst particles and growth temperature were studied. In this work smaller diameter and twisted MWCNTs were formed by dilution of acetylene with argon gas. Electrical properties suggest a semimetallic behavior of synthesized MWCNTs. PMID- 27455742 TI - Sol-Gel Synthesis and Characterizations of CoMoO4 Nanoparticles: An Efficient Photocatalytic Degradation of 4-Chlorophenol. AB - Cobalt molybdate CoMoO4 nanoparticles (NPs) were successfully synthesized using cobalt nitrate, ammonium molybdate, citric acid and ethyl cellulose by a simple sol-gel method. Structural, morphological, optical and magnetic properties of the obtained powder were characterized by powder X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectra, high resolution scanning electron microscope (HR-SEM), energy dispersive X-ray (EDX), UV-Visible diffuse reflectance spectra (DRS), photoluminescence (PL) spectra and vibrating sample magnetometer (VSM). XRD results indicated that the resultant powder was pure single phase crystalline with monoclinic structure. FT-IR spectra indicate the type of bonds between metals and oxygen. HR-SEM images shows that the morphology of the powder consist with well defined nanoparticles (NPs) structure. VSM results showed antiferromagnetic behavior. Photo-catalytic activity of CoMoO4 nanoparticles (NPs) was performed. The addition of TiO2 catalyst enhanced the photo-catalytic activity of CoMoO4 nanoparticles (NPs). The catalysts CoMoO4, Ti02 and mixed oxide catalyst CoMoO4-TiO2 nano- composites (NCs) were tested for the photo catalytic degradation (PCD) of 4-chlorophenol (4-CP). It was found that the PCD efficiency of CoMoO4-TiO2 NCs was higher (97.5%) than that of pure CoMoO4 (88.0%) and TiO2 (94.0%) catalysts. PMID- 27455743 TI - Flow-Induced Assembly of Colloidal Liquid Crystalline Nanosheets Toward Unidirectional Macroscopic Structures. AB - Multiscale structures of anisotropic nanoparticles up to macroscopic scales are important in order to produce practical materials through nanotechnology. As an example of such structures, hierarchical organization of colloidal liquid crystals of niobium oxide nanosheets yields stripe textures observable by naked eyes. The stripes are generated by the growth of liquid crystalline domains (tactoids) and the alignment of the tactoids under an electric field and gravity applied in the directions orthogonal to each other. The nanosheets forming the tactoids are unidirectionally aligned along the flow induced by gravity, and the aligned tactoids are stretched to be connected each other to form the stripes. Time evolution of the stripes indicates that they are generated during the settlement of the nanosheets. The nanosheets are debundled with the settlement, and thus the stripes are gradually degenerated during the settlement. Larger tactoids cause faster nanosheet settlement and stripe degeneration. The electric field applied orthogonally to gravity has roles of pinning the nanosheets to slow down their settlement and retains the stripes for several hours. PMID- 27455744 TI - Synthesis and Characterization of Multiwalled Carbon Nanotubes/Poly(HEMA-co-MMA) by Utilizing Click Chemistry. AB - The hybrid material consisting of multi walled carbon nanotubes (MWNTs) and poly(2-hydroxyethylmethacrylate-co-methylmethacrylate) [poly(HEMA-co-MMA)] was synthesized by a combination of RAFT and Click chemistry. In the primary stage, the copolymer poly(HEMA-co-MMA) was prepared by applying RAFT technique. Alkynyl side groups were incorporated onto the poly(HEMA-co-MMA) backbone by esterification reaction. Then, MWNTs-N3 was prepared by treating MWNTs with 4 azidobutylamine. The click coupling reaction between azide-functionalized MWNTs (MWNTs-N3) and the alkyne-functionalized random copolymer ((HEMA-co-MMA)-Alkyne) with the Cu(I)-catalyzed [3+2] Huisgen cycloaddition afforded the hybrid compound. The structure and properties of poly(MMA-co-HEMA)-g-MWNTs were investigated by FT-IR, EDX and TGA measurements. The copolymer brushes were observed to be immobilized onto the functionalized MWNTs by SEM and TEM analysis. PMID- 27455745 TI - Synthesis and TFT Properties of Fluorenyl Cored Conjugated Compound for Organic Thin Film Transistors. AB - The 5,5'-(4,4'-(9,9-dioctyl-9H-fluorene-2,7-diyl)bis(4,1-phenylene))bis(2 hexylthieno[3,2-b]thiophene) FCBT (6) was synthesized by connecting the fluorenyl, thienothiophenyl and phenyl units. The compound was characterized by FT-IR, H1NMR, C13NMR and mass spectroscopy. The compound has shown good solubility and thermal stability over 417 degrees C. The compound has shown hole mobility of 4.76 x 10(-6) cm2Ns. The on-off ratio and threshold voltage were 7.5 x 10(2) and -8.26 V respectively. PMID- 27455746 TI - Physical and Optical Properties of SnO2/ZnO Film Prepared by an RF Magnetron Sputtering Method. AB - Al-, Ga-, and In-doped ZnO thin films are widely used in many technical applications, such as in solar cells and on transparent conducting oxides having high optical transmission and low resistivity values. We prepared SnO2-doped ZnO thin films on quartz substrates by using an RF magnetron sputtering method at a substrate temperature of 350 degrees C. The ratio of SnO2 to ZnO was varied from 0 to 5:5 to investigate the effects of Sn on structure and physical properties of ZnO film. The samples were synthesized at a base pressure of 1.3 x 10(-4) Pa with a working pressure of 1.3 Pa and an RF power of 40 W under Ar atmosphere. The results of X-ray diffraction data revealed that pure ZnO films exhibit a strong (002) orientation and a polycrystalline wurzite hexagonal structure. However, as increasing the SnO2 concentration, ZnO transforms to an amorphous phase. The results of the Hall-effect-measurement system revealed that the resistivity values of the films increased as increasing the doping level of SnO2. The AFM data of morphology and microstructure showed that the grain size decreased with increasing SnO2 contents while the total area of grain the boundary increased. The average value of the transmittance of the films in the visible light range was 80-95% and was shifted toward to the shorter wavelengths of the absorption edges with increasing SnO2 contents. PMID- 27455747 TI - Synthesis and Hydrogen Desorption Properties of Aluminum Hydrides. AB - Aluminum hydride (AlH3 or alane) is known to store maximum 10.1 wt.% of hydrogen at relatively low temperature (< 100 degrees C), which partially fulfills the U.S. department of energy requirements for gravimetric loading capacity. However, its detailed mechanisms of appearing of different phases, structural stability, and dynamics of hydrogen desorption are still not clear. To understand the desorption properties of hydrogen in alane, thermodynamically stable alpha-AlH3 was synthesized by employing an ethereal reaction method. The dependence of pathways on phase formation and the properties of hydrogen evolution were investigated, and the results were compared with the ones for gamma-AlH3. It was found that gamma-AlH3 requires 10 degrees C higher than that of gamma-AlH3 to form, and its decomposition rate demonstrated enhanced endothermic stabilities. For desorption, all hydrogen atoms of alane evolved under an isothermal condition at 138 degrees C in less than 1 hour, and the sample completely transformed to pure aluminum. Our results show that the total amount of desorbed hydrogen from alpha-AlH3 exceeded 9.05 wt.%, with a possibility of further increase. Easy synthesis, thermal stability, and a large amount of hydrogen desorption of alane fulfill the requirements for light-weight hydrogen storage materials once the pathway of hydrogen cycling is provided. PMID- 27455748 TI - Selective Growth of Metallic and Semiconducting Single Walled Carbon Nanotubes on Textured Silicon. AB - We fabricated the etched Si substrate having the pyramidal pattern size from 0.5 to 4.2 MUm by changing the texturing process parameters, i.e., KOH concentration, etching time, and temperature. Single walled carbon nanotubes (SWNTs) were then synthesized on the etched Si substrates with different pyramidal pattern by chemical vapor deposition. We investigated the optical and electronic properties of SWNT film grown on the etched Si substrates of different morphology by using scanning electron microscopy, Raman spectroscopy and conducting probe atomic force microscopy. We confirmed that the morphology of substrate strongly affected the selective growth of the SWNT film. Semiconducting SWNTs were formed on larger pyramidal sized Si wafer with higher ratio compared with SWNTs on smaller pyramidal sized Si. PMID- 27455749 TI - Room-Temperature Ferromagnetism in TiO2 Nanocrystals Synthesized by the Controlled Hydrolysis Procedure. AB - TiO2 nanocrystals were prepared by a controlled hydrolysis procedure at room temperature. The effect of V-doping, N-doping and V/N codoping on the lattice parameters and magnetic properties of TiO2 nanocrystals was investigated by means of X-ray diffraction, high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy and vibration sample magnetometry. Doping performed at room temperature causes the expansion of lattice parameters. Undoped and doped TiO2 nanocrystals show room-temperature ferromagnetism. A monotonic correlation between saturation magnetization and the ratio of the lattice parameter c to a (c/a) was observed. Saturation magnetization of TiO2 nanocrystals increases with the value of c/a. PMID- 27455750 TI - Synthesis of Magnetic Rattle-Type Silica with Controllable Magnetite and Tunable Size by Pre-Shell-Post-Core Method. AB - In this study, we have developed the pre-shell-post-core route to synthesize the magnetic rattle-type silica. This method has not only simplified the precursor's process and reduced the reacting time, but also ameliorated the loss of magnetite and made the magnetite content and the inner core size controllable and tunable. The magnetite contents and inner core size can be easily controlled by changing the type and concentration of alkali, reaction system and addition of water. The results show that alkali aqueous solution promotes the escape of the precursor iron ions from the inner space of rattle-type silica and results in the loss of magnetite. In this case, NaOH ethanol solution is better for the formation of magnetite than ammonia because it not only offers an appropriate alkalinity to facilitate the synthesis of. magnetic particles, but also avoids the escape of the iron ions from the mesopores of rattle-type silica. The synthesis process is very simple and efficient, and it takes no more than 2 hours to complete the total preparation and handling of the magnetic rattle-type silica. The end product Fe3O4@SiO2 nanocomposites also have good magnetic properties which will perform potential application in biomedical science. PMID- 27455751 TI - The Electrical Properties for Phenolic Isocyanate-Modified Bisphenol-Based Epoxy Resins Comprising Benzoate Group. AB - Epoxy resin has been required to have a low dielectric constant (D(k)), low dissipation factor (Df), low coefficient of thermal expansion (CTE), low water absorption, high mechanical, and high adhesion properties for various applications. A series of novel phenolic isocyanate-modified bisphenol-based epoxy resins comprising benzoate group were prepared for practical electronic packaging applications. The developed epoxy resins showed highly reduced dielectric constants (D(k)-3.00 at 1 GHz) and low dissipation values (Df-0.014 at 1 GHz) as well as enhanced thermal properties. PMID- 27455752 TI - Pd-Pt Alloy with Coral-Like Nanostructures Showing High Performance for Oxygen Electrocatalytic Reduction. AB - Three-dimensional (3D) Pd-Pt alloy with coral-like nanostructures were synthesized via bubble dynamic templated electrodeposition method at room temperature. The morphology of the as-prepared nanostructures was characterized using scanning electron microscopy (SEM), EDS, high-resolution transmission electron microscopy (HRTEM), respectively. Cyclic voltammetry method was adopted to evaluate the electrocatalytic activities of the synthesized electrodes toward oxygen reduction in KCl solution. The electrochemical results indicated that the Pd-Pt alloy with coral-like nanostructures hold the high performance for oxygen reduction. PMID- 27455753 TI - Cryogenic Tensile Strength and Fatigue Life of Carbon Nanotube Multi-Yarn. AB - Carbon nanotube (CNT) multi-yarns, consisting of 30 yarns, were tested under monotonic tensile load and fatigue at the room temperature (298 K) and two cryogenic temperatures (232 and 123 K). Tensile stiffness increased with the decrease of temperature. The average ultimate tensile strength was higher at 123 K when compared to the higher temperatures (232 and 298 K). Failure mechanism changed from a combination of classical variant and independent fiber breakage at the two higher temperatures to mostly classical variant failure mechanism at the lower temperature. The CNT-yarn's fatigue life also increased with decreasing temperature. CNT-yarns have been shown to function well at lower temperatures making them usable for applications requiring operation at cryogenic temperatures, such as in satellites and high altitude aircraft. PMID- 27455754 TI - Preparation and Gas Sensing Properties of Hollow ZnS Microspheres. AB - Hollow ZnS microspheres are synthesized by a facile hydrothermal method. Morphology and structure of the ZnS microspheres are analyzed by SEM, TEM, XRD and N2 sorption technique, Gas sensing properties of the as-prepared ZnS sensor are also systematically investigated. The results show that the ZnS microspheres have well-developed porous and hollow nanostructure. The sensor based on the ZnS microspheres exhibits ultra-fast response (1-2 s) and fast recovery time (7-34 s) towards ethanol at the optimal operating temperature of 160 degrees C. Moreover, the ZnS sensor also demonstrates high selectivity to other gases such as methanol, benzene, dichloromethane and hexane, suggesting that it is a promising candidate for ethanol sensing applications. PMID- 27455755 TI - Influence of Sol-Gel Conditions on the Growth of Thiol-Functionalized Silsesquioxanes Prepared by In Situ Water Production. AB - Thiol-functionalized oligosilsesquioxanes have been synthesized by sol-gel chemistry via the in-situ water production (ISWP) approach, exploiting the esterification reaction of chloro-acetic acid and 1-propanol. The extent of hydrolysis-condensation of 3-Mercaptopropyltrimethoxysilane (McPTMS) has been studied by FT-IR and NMR spectroscopy, gel permeation chromatography (GPC) and MALDI-TOF techniques. The esterification reaction plays a key role in ruling out the oligomer structural development. In this work, we have investigated the influence of the theoretical amount of water available for the organosilane hydrolysis, defined by the ratio of chloro-acetic acid to McPTMS in the reaction mixture, and the role of different catalysts like trifluoroacetic acid (TFA) and dibutyldilauryltin (DBTL). The behavior of the catalyst is complex since, according to its nature, it may improve the kinetics of the sol-gel reactions and the esterification reaction as well. Comparing the reactions carried out with under-stoichiometric water content, the degree of condensation of the silsesquioxanes is higher if the reaction is catalyzed by TFA than by DBTL, because TFA may improve the kinetics of both hydrolysis-condensation and esterification reactions. The use of DBTL in under-stoichiometric and stoichiometric hydrolytic conditions raises the yield in ladder-like structures. The degree of condensation generally increases increasing the hydrolysis ratio as well as the yield in cage-like structures. However, when an over-stoichiometric amount of water is provided for the sol-gel reaction, condensation degree and ratio among cages and ladder-like structures appear unaffected by the employed catalyst. PMID- 27455756 TI - Modification and Wettability Study ITO Glass Coated with ZnO Film by Electrochemical Deposition and Hydrothermal Deposition. AB - ITO glass is a substrate often utilized to construct various IT devices and sensors, favored for its excellent characteristics such as rapid electron transfer kinetics, non-toxicity, chemical stability, and high electron transmission. In this paper, film with ZnO-modified nanostructures on ITO glass was fabricated by both electrochemical deposition and hydrothermal deposition, respectively. The ZnO film as-deposited was then modified by surface modification reagent (FOTMS) to obtain a hydrophobic surface. SEM, XRD, and ZYGO were used to characterize their properties. The contact angles were then measured to characterize and compare the wettability of non-modified ITO glass and ITO glass modified by zinc oxide films. PMID- 27455757 TI - Position Effect Based on Anthracene Core for OLED Emitters. AB - Green-orange emitters based on anthracene core have been successfully synthesized by substitution with triphenylamine side group in the 9, 10 or 2, 6 positions. There are larger blue shifts in the UV-visible absorption and PL spectra of the synthesized 2,6-substituted derivative compared to the 9,10-substituted derivative. When the synthesized compounds were used as emitting layers in non doped OLED devices, a related trend was observed in their optical properties. In particular, the OLED device containing the 2,6-substituted derivative was found to exhibit excellent characteristics, with maximum EL emission at 518 nm, pure green emission with CIE coordinates of (0.334, 0.604), and external quantum efficiency of 2.83%. PMID- 27455758 TI - Correlations Between Electrolyte Concentration and Solid Electrolyte Interphase Composition in Electrodeposited Lithium. AB - This study examined the electrochemical deposition and dissolution of lithium on nickel electrodes in propylene carbonate (PC) electrolytes containing different concentrations of lithium salts, including LiN(SO2C2F5)2 or LiPF6. The electrode reactions were significantly affected by the electrolyte concentration. The cyclability of the electrodes was considerably improved by increasing the electrolyte concentration. X-ray photoelectron spectroscopy (XPS) showed that the composition of the solid electrolyte interphase (SEI) was also affected by the electrolyte concentration. The SEI formed in the 1st cycle consisted mainly of LiF in 1 and 2.15 M LiN(SO2C2F5)2/PC solutions. After the 30th cycle in the former solution, there was a large decrease in the amount of LiF and a large increase in the amount of LiOH. On the other hand, in the latter solution there was a smaller decrease and a smaller increase in the amount of LiF and LiOH, respectively, as compared to the former solution after the 30th cycle. PMID- 27455759 TI - Electrochemical Performance of Glucose/Oxygen Biofuel Cells Based on Carbon Nanostructures. AB - The electrochemical performance of glucose/oxygen biofuel cells based on carbon nanostructures was investigated in the present study. Different types of carbon nanomaterials, including multi-walled carbon nanotubes (MWCNT), functionalized MWCNT (f-MWCNT), carbon nanofibers (CNF), and functionalized CNF (f-CNF) were examined for electrode fabrications. The anode for glucose/oxygen biofuel cells were prepared by sequential coating of carbon nanomaterials, charge transfer complex (CTC), glucose oxidase (GOx) and nafion membrane. The anode was then integrated with a bilirubin oxidase-immobilized cathode for the biofuel cell test. It was found that the electrochemical performance of the enzyme electrodes was remarkably enhanced by the amalgamation of carbon nanomaterials with the CTC. The biofuel cell with anode comprising of f-CNF and the cathode with MWCNT exhibited the best electrochemical performance with a maximum power density of 210 MUW/cm2 at a cell voltage of 0.44 V for 20 mM glucose concentration, which is comparable with the best power density value reported earlier. PMID- 27455760 TI - Nanostructure Modified Microelectrode for Electrochemical Detection of Dopamine with Ascorbic Acid and Uric Acid. AB - Dopamine (DA) is one kind of neurotransmitter in central nervous system which is indicator of neural disease. For this reason, determination of DA concentration in central nervous system is very important for early diagnosis of neural disease. In this study, we designed micro electrode array and fabricated by MEMS technology. Furthermore, we fabricated 3-D conducting nanostructure on electrode surface for enhanced sensitivity and selectivity due to increased surface area. Compared with macro and normal micro electrode, the 3-D nanostructure modified micro electrode shows better electrical performance. These surface modified pin type electrode was applied to detect low concentration of DA and successfully detect various concentration of DA from 100 MUM to 1 MUM with linear relationship in the presence of ascorbic acid and uric acid. From these results, our newly designed electrode shows possibility to be applied as brain biosensor for neural disease diagnosis such as Parkinson's diseases. PMID- 27455761 TI - Preparation of Macro-Porous Tin Oxide for Sensing of Sulfur Compound. AB - Macro-porous tin oxide was prepared as an enhanced sensing material for sulfur compounds, such as hydrogen sulfide. Poly-methyl-methacrylate (PMMA) was used as a template for the formation of macro-pores. Tin chloride was used as a precursor for the synthesis of tin oxide, and was impregnated over PMMA beads using a rotary vacuum evaporator. The solid Sn/PMMA material was treated thermally for 4 h at 600 degrees C. The porous morphology of tin oxide prepared in this study was observed by scanning electron microscopy. The surface area of this material measured by the nitrogen adsorption method was approximately 56 m2/g. The crystal structure of the porous material analyzed by XRD was a typical structure of tin oxide. The response of macro-porous tin oxide as a chemical gas sensor was measured using an I-V source meter and the change in signal was observed with the repeated injection of hydrogen sulfide and air. The sensing tests for macro porous tin oxide were carried out at 200 degrees C and the fast response of macro porous sensing material was also confirmed. PMID- 27455762 TI - Copper Ferrocyanide-Functionalized Magnetic Adsorbents Using Polyethyleneimine Coated Fe3O4 Nanoparticles for the Removal of Radioactive Cesium. AB - Copper ferrocyanide-functionalized magnetic nano-adsorbents were successfully synthesized by electrostatic coating of citric acid coated Fe3O4 nanoparticles with polyethyleneimine, and immobilizing copper and ferrocyanide on the surfaces of polyethyleneimine-coated nanoparticles. Radioactive cesium (Cs) adsorption tests were conducted to investigate the effectiveness of the copper ferrocyanide functionalized magnetic nano-adsorbents toward the removal of radioactive Cs. PMID- 27455763 TI - Carboxylic Group Embedded Carbon Balls as a New Supported Catalyst for Hydrogen Economic Reactions. AB - Carboxylic group functionalized carbon balls have been successfully synthesized by using a facile synthesis method and well characterized with different characterization techniques such as XPS, MAS NMR, SEM, ICP and N2 physi-sorption analysis. The synthesized material has been effectively utilized as novel support to immobilized ruthenium catalyst for hydrogen economic reactions. PMID- 27455764 TI - Fabrication of Porous alpha-TCP/Gellan Gum Scaffold for Bone Tissue Engineering. AB - alpha-tricalcium phosphate (alpha-TCP, alpha-Ca3(PO4)2) receives great attention for bone repairing due to its biodegradability and capability of transformation to human bone's main inorganic components, hydroxyapatite (HAp). alpha-TCP porous scaffold is easily procurable by sintering of the low-temperature polymorph of TCP, beta-TCR Still, porous body of alpha-TCP is too brittle to being handled and shaped, limiting its clinical application as implant materials. To improve mechanical properties of alpha-TCP porous scaffold, the present study focused on coating of a type of polysaccharides on alpha-TCP scaffolds. Gellan gum was chosen as the polysaccharide for coating because of its biodegradability as well as the potential acting as substrate for HAp deposition during hydration of alpha TCP after exposure to body fluid. After coating of gellan gum on alpha-TCP scaffolds with porosity of 75 vol%, the compressive strength increased from 0.45 MPa to around 2.00 MPa. Among the coated scaffold, the maximum compressive strength, 3.97 MPa, was obtained on the scaffold with porosity of 63 vol%. Improvement of mechanical properties of alpha-TCP/gellan gum composites was achieved to show easy handling performance for a bone substitute for tissue repairing. The dissolving rate of the coated scaffolds was also controlled by adjusting the concentration of GG solutions. PMID- 27455765 TI - Quasicrystal as a Catalyst for the Synthesis of Carbon Nanotubes. AB - The present report describes the catalytic activity of mechanically activated nano quasicrystalline Al65Cu20Fe15 and related nano crystalline Al50Cu28Fe22 for the synthesis of carbon nanotubes (CNTs). CNTs are synthesized by catalytic decomposition of ethanol through nano quasicrystalline Al65Cu20Fe15 and related crystalline Al50Cu28Fe22 alloys as a catalyst. The synthesized multi-walled CNTs exhibits tube diameter ranging from 5 to 25 nm. The synthesized CNTs are characterized by scanning and transmission electron microscopy. It is found that Al65Cu20Fe15 nanoquasicystal shows better catalytic behaviour as compared to nano crystalline Al50Cu28Fe22 alloys for decomposition of ethanol during the synthesis of multi-walled CNTs. PMID- 27455766 TI - Preparation of Carbonaceous Hemispheres Using a Hard Templating Approach. AB - Silica spheres prepared using a Stober method were covered with 4,4'-biphenylene bridged polybissilsesquioxane to form a core-shell structure. After carbonization, and the removal of the silica, carbonaceous hemispheres were obtained. The hemispheres were formed because of the collapse and shrinkage of the hollow spheres. The obtained samples were characterized using field-emission scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, X-ray diffraction, and nitrogen sorption measurements. The carbon was amorphous. Large numbers of micropores were identified in the hemispheres. The micropores were formed because of the removal of the silica. Spheres with a rattle-type structure were also found during the formation of the hollow carbonaceous spheres. PMID- 27455767 TI - Surface Enrichment of Fluorocarbon End-Capped Polymers with Different Fluorocarbon Lengths. AB - This study investigated the surface structure of fluorocarbon end-capped l poly(lactide)s (F-PLLA) with different fluorocarbon lengths by electron spectroscopy for chemical analysis (ESCA). Fluorocarbon chains of three lengths (F(CF2)n(CH2)2, where n = 6, 8, and 10) have been synthesized as the terminal group to PLLA. Angular dependent ESCA revealed that the fluorocarbon groups are segregated at the surface. Further, the results show the surface coverage of fluorocarbon groups rapidly increases with increasing the length of fluorocarbon end groups (synergy effect). The surface composition of F-PLLAs can be controlled by changing the length of fluorocarbon. PMID- 27455768 TI - Synthesis and Property of New Propeller Shaped Emitting Materials for Organic Light-Emitting Devices. AB - New propeller type emitting compound, namely 3,6-di-anthracen-9-yl-9,10-bis-(4 anthracen-9-yi-phenyl)-phenanthrene[TAnDAP] and 3,6-bis-(10-phenyl-anthracen-9 yl)-9,10-bis-[4-(10-phenyl-anthracen-9-yl)-phenyl]-phenanthrene [TAnPDAP] were synthesized through Suzuki and McMurry reactions. We investigated their physical properties such as optical, electrochemical, and electroluminescent properties. The two compounds were used as an emitting layer in OLED devices: ITO/2-TNATA (60 nm)/NPB (15 nm)/non-doped: TAnDAP or TAnPDAP (35 nm)/Alq3 (20 nm)/LiF (1 nm)/Al (200 nm). The TAnDAP OLED device showed C.I.E. value of (0.28, 0.41) and luminance efficiency of 3.81 cd/A at 10 mA/cm2. The TAnPDAP device showed C.I.E. value of (0.20, 0.27) and high luminance efficiency of 5.40 cd/A at 10 mA/cm2. TAnPDAP was found to show better luminance efficiency and C.I.E. value than TAnDAP because it has a bulky 9-phenylanthracene. PMID- 27455769 TI - Comparative Study on Surface-Initiated ATRP and SI-ARGET ATRP of Oligo(Ethylene Glycol) Methacrylate on Gold. AB - Oligo(ethylene glycol) methacrylate (OEGMA) was polymerized from a polymerization initiator-presenting gold substrate by Activator ReGenerated by Electron Transfer Atom Transfer Radical Polymerization (ARGET ATRP) in water. Compared with the normal surface-initiated ATRP (SI-ATRP), SI-ARGET ATRP of OEGMA proceeded smoothly in the presence of air with L-ascorbic acid as a reducing agent and a CuBr2/2,2'-bipyridyl complex at the ppm level. In addition, SI-ARGET ATRP did not require the additional steps for removing a polymerization inhibitor from the OEGMA monomer and for deoxygenating the solvent. The ellipsometric measurements showed that the polymerized OEGMA (pOEGMA) films prepared by SI-ARGET ATRP were on average 10 times thicker than those prepared by normal SI-ATRP with the same monomer concentration and polymerization time. PMID- 27455770 TI - Factors Affecting the Separation Performance in Ionic Liquid/Cu Nanocomposite Membranes for Facilitated CO2 Transport. AB - Based on data reported for facilitated CO2 transport membranes, we analyzed the factors that would enhance their performance by utilizing an ionic liquid (IL)/Cu nanoparticle (NP) composite. The previously reported ILs were BMIM NO3, BMIM BF4, MOIM BF4, and HMIM NO3. Compared with neat ILs, the selectivity of the ILs/Cu increased with the enhancement of permeance. We investigated the effect of the percentage of free ions in ILs and the size of the Cu NPs on CO2 separation performance. In addition, we found that the viscosity and steric effect of ILs played an important role in enhancing separation performance. In this regard, CO2 easily dissolved in the low-viscosity ILs, and their low steric effect allowed the ILs to readily interact with the surface of the Cu NPs. PMID- 27455771 TI - Novel Long-Circulating Liposomes Consisting of PEG Modified beta-Sitosterol for Gambogic Acid Delivery. AB - Long-circulating liposome is an effective formulation in field of cancer treatment. However, high expenditure of formulation and high dose of cholesterol severely restrict its application. In this paper, we developed a method by grafting polyethylene glycol 2000 on beta-sitosterol succinic anhydride ester to obtain relatively cheap polyethylene glycol-beta-sitosterol conjugates, which were used to prepare long-circulating liposome without cholesterol. Gambogic acid which is an effective antitumor ingredient with very short half-life, was used as a model drug to prepare long-circulating liposome in this research. Meanwhile, the characteristics, pharmacokinetics and distribution of this novel long circulating liposome were also investigated in comparison with other gambogic acid formulations. Polyethylene glycol-beta-sitosterol conjugates were synthesized, different liposomal formulations were also prepared by ethanol injection method, and the obtained nanoparticles were characterized by dynamic light scattering and transmission electron microscope. The long-circulating effect, pharmacokinetics and distribution of gambogic acid in rats were also explored. 1HNMR confirmed that polyethylene glycol-beta-sitosterol conjugates were synthesized successfully. Novel long-circulating liposome was successfully prepared by ethanol injection method attaining a entrapment efficiency of 89.4%, exhibiting a homogeneous particle size of 245.2 nm and -24.3 mV zeta potential with smooth continuous surface. This novel long-circulating liposome demonstrated better long-circulating effect than ordinary long-circulating liposome. The novel long-circulating liposome as-prepared not only could reduce cost of grafting polyethylene glycol on macromolecular phospholipid, but also no cholestrol in preparation was applied, expanding the application of liposome as a formulation in the field of lowering blood lipid. Therefore, polyethylene glycol-beta sitosterol conjugates are recommended substitute for polyethylene glycol modified phospholipid to prepare long-circulating liposomes. PMID- 27455772 TI - Preparation Behavior of the Mg-Fe Hydrotalcite by Urea Method and Its Cr(VI) Sorption Property. AB - The hydrotalcite of Mg6Fe2(OH)16CO3 x 4.5H2O were synthesized using urea method by adjusting the initial pH and urea amount in the reaction solution. The results showed that the co-precipitation of Mg2+ with Fe3+ cations formed Mg-Fe LDH occurring at pH 8.48-9.35. The pH played a crucial role in the Mg-Fe LDH precipitation by controlling urea/Fe3+ molar ratio in the reaction solution at 105 degrees C. The optimized urea/Fe3+ molar ratio was 12.0, where the relative yield of the Mg-Fe LDH was 80.0% and the Mg-Fe LDH was highly crystalline with small particle sizes (1-2 MUm). The affinity of the Mg-Fe mixed oxide (Mg-Fe LDO) with Cr(VI) was studied as a function of contact time, initial pH, temperature of the solutions and calcined time of Mg-Fe LDH. The adsorption conditions were optimized using response surface methodology. The maximum adsorption capacity of 38.86 mg/g was achieved at 85 min with the conditions of initial pH 5.5, temperature 55 degrees C and calcined time 4 h. It was concluded that the Mg-Fe LDO can be used as an adsorbent to removal Cr(VI) in aqueous solutions. PMID- 27455773 TI - Comparing Fullerenes by Spectral Moments. AB - Suppose G is a graph, A(G) its adjacency matrix, and MU1(G)<=(G)MU2(G)<= ... <= MU(n)(G)are eigenvalues of A(G). The numbers S(k)(G) = Sigma(i) n = 1 MU(i)k (G), 0 <= k <= n -1 are said to be the k-th spectral moment of G and the sequence S(G) = (S0(G), S1 (G),..., S(n-1)(G)is called the spectral moments sequence of G. Suppose G1 and G2 are graphs. If there exists an integer k, 1 <= k <= n - 1, such that for each i, 0 <= i <= k - 1, S(i) (G1) = S(i)(G2) and S(k)(G1) < S(k)(G2) then we write G1 -<(s) G2. The aim of this paper is order some classes of fullerene graphs with respect to the S-order. PMID- 27455775 TI - One-Step Solvothermal Synthesis of Black TiO2 Films for Enhanced Visible Absorption. AB - An economic and facile solvothermal method was reported to prepare black TiO2 films on Ti foils that possessed the property of optical absorption in the visible region. The UV-vis spectra showed that the black TiO2 samples exhibited highly enhanced visible-light absorption from 400-600 nm. The black TiO2 films were compact and uniform, composed of nanoparticles and nanosheets. Moreover, a mixed structure of anatase and rutile was present in black TiO2 films. The electron paramagnetic resonance (EPR) spectra confirmed the presence of Ti3+ in samples, which accounted for longer wavelength optical absorption. The results showed that the TiO2 films had retained their black color upon storage in ambient atmosphere for more than one month. Therefore, it was supposed that the ethylene glycol in solvothermal reaction was the key factor for the extension of the absorption spectrum. PMID- 27455776 TI - KY(MoO4)2:Eu3+ Phosphor: Template-Free Hydrothermal Synthesis and Luminescent Properties. AB - KY(MoO4)2 microcrystals with different morphologies, including rhombic, sheet like, rectangular plate-like, and hexagon plate-like, have been successfully synthesized via a simple hydrothermal method without using any templates, surfactant, or other organic additives by varying the molar ratios of Y(NO3)3/K2MoO4 and pH values of the resultant solutions. X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), photoluminescence (PL), and photoluminescent excitation spectra (PLE) were employed to characterize the samples. Furthermore, a systematic study on the photoluminescence of Eu3+ doped KY(MoO4)2 samples has been explored by varying experimental conditions. The strongest red emission can be observed clearly at 616 nm. And by controlling the doping concentration of Eu3+ in KY(MoO4)2 solutions, it can be seen that the concentration quenching occurs at 25 at.% for Eu3+. These results suggest that the well-crystallized KY(MoO4)2:Eu3+ microcrystals synthesized in our experiment can be used as a red component for white light emitting diodes (W-LEDs). PMID- 27455774 TI - Nanomechanics of Engineered Articular Cartilage: Synergistic Influences of Transforming Growth Factor-beta3 and Oscillating Pressure. AB - Articular cartilage (AC), tissue with the lowest volumetric cellular density, is not supplied with blood and nerve tissue resulting in limited ability for self repair upon injury. Because there is no treatment capable of fully restoring damaged AC, tissue engineering is being investigated. The emphasis of this field is to engineer functional tissues in vitro in bioreactors capable of mimicking in vivo envi- ronments required for appropriate cellular growth and differentiation. In a step towards engineering AC, human adipose-derived stem cells were differentiated in a unique centrifugal bioreactor under oscillating hydrostatic pressure (OHP) and supply of transforming growth factor beta 3 (TGF-beta3) that mimic in vivo environments. Static micromass and pellet cultures were used as controls. Since withstanding and absorbing loads are among the main functions of an AC, mechanical properties of the engineered AC tissues were assayed using atomic force microscopy (AFM) under a controlled indentation depth of 100 nm. Young's moduli of elasticity were quantified by modeling AFM force-indentation data using the Hertz model of contact mechanics. We found exposure to OHP causes cartilage constructs to have 45-fold higher Young's moduli compared to static cultures. Addition of TGF-beta3 further increases Young's moduli in bioreactor samples by 1.9-fold bringing it within 70.6% of the values estimated for native cartilage. Our results imply that OHP and TGF-beta3 act synergistically to improve the mechanics of engineered tissues. PMID- 27455777 TI - [Nursing and society in transition]. PMID- 27455778 TI - [International Nursing Research Conference in Edinburgh]. PMID- 27455779 TI - [Refugees for German nursing - an assessment]. PMID- 27455780 TI - [Compression therapy in varicose ulcer]. PMID- 27455781 TI - [Contact sensitivity in patients with chronic wounds]. PMID- 27455782 TI - [Not Available]. PMID- 27455783 TI - [Dressings for treatment of foot ulcers in patients with diabetes mellitus]. PMID- 27455784 TI - [Updates for nursing on the stroke unit]. PMID- 27455785 TI - [Importance of an intensive care journal for coping with the illness]. PMID- 27455786 TI - [Reconquering one's own body]. PMID- 27455787 TI - [Employment fields for college educated nurse]. PMID- 27455788 TI - [Personally discover and apply nursing research]. PMID- 27455789 TI - [Finding access possibilities for suitable information services]. PMID- 27455790 TI - [Potential? - Yes! Using assistance sources sensibly]. PMID- 27455791 TI - [Nursing carts become intelligent]. PMID- 27455792 TI - [Analysis of trace elements in a single cell using in-air micro PIXE system]. PMID- 27455793 TI - [Trace elements maintaining the vital functions]. AB - In a healthy condition, trace elements constituting the living body are regulated and maintained their balance of each other and their range of physiological optimum concentration in order to maintain the normal vital functions. When the optimum conditions of their balance and their homeostasis, however, are broken down by deficiency or excess of certain trace element, an excess accumulation or deficiency of specified element is induced and it follows that peculiar disease is caused according to function of each specified element. Generally, the disturbance of major elements such as O, C, H, N, Ca, P will induce a nutrition lesion and electrolytic abnormality, and the disturbance of 10 trace elements such as Fe, F, Si, Zn, Sr, Rb, Br, Pb, Mn, Cu being at ppm order and 14 ultra trace elements such as Al, Cd, Sn, Ba, Hg, Se, I, Mo, Ni, B, Cr, As, Co, V being at ppb order will give rise to functional disorder of enzyme and physiological active substance in living body. PMID- 27455794 TI - [Dietary reference intakes of trace elements for Japanese and problems in clinical fields]. AB - In the dietary reference intakes, EAR(estimated average requirement), RDA(recommended dietary allowance), AL(adequate intake), DG(tentative dietary goal for preventing life style related diseases) and UL(tolerable upper intake level) of eight types of trace elements (iron: Fe, zinc: Zn, copper: Cu, manganese: Mn, iodine: I, selenium: Se, chromium: Cr, molybdenum: Mo) have been set. However, in the meals of hospitals, only iron of which has been taken into account. The content of these trace elements in the enteral nutrient released after 2000 was determined by considering the content of dietary reference intakes of trace elements for Japanese and considered so not fall into deficiency. However, enteral nutrient must be used considering the content of Zn, Cu and the Zn/Cu ratio, the selenium content, and the route of administration, in order to avoid falling into deficiency. PMID- 27455795 TI - [Supplementation of trace elements in the general medicine]. AB - Trace elements are the essential nutrients. Now, 9 elements, Fe, Zn, Cu, Se, I, Go, Cr, Mn, Mo, are recognized as essential trace elements. Serum concentration of Fe, Zn and Cu are about 100 MUg/dL, and have important physiological roles. Zinc needs special care because over 300 enzymes contain Zn, and zin deficiency cause various disorders. In advancing age serum Zn concentration decrease. Although the daily requirement of zinc is 10-15 mg in adults, it is necessary to supply much more zinc than adult, by the reason of low intake and low absorption in the elderly. In the geriatric ward of the hospital, many zinc deficient patients suffered from decubitus ulcers, dermatitis, alopecia, taste disorders etc. A 86 y.o. female with deep sacral decubitus ulcer was shown in this report. Her decubitus ulcer was completely recovered after daily administration of polaprezinc containing 34 mg Zn for 18 months, A 76 y.o. female brought about severe hypocupuremia. Serum Cu concentration decreased from 112 MUg/dL to 7 MUg/dL after 5 months daily administration of 34 mg Zn. Serum Zn concentration elevated from 47 MUg/dL to 117 MUg/dL, and Cu/Zn ratio decreased 2.38 to 0.06. After stopped zinc supplementation, serum Cu rapidly increased in a 2 month period. At the same time, serum Zn decreased quickly. It was the interesting fact that anemia improved associated with the increase of serum Cu. In the geriatric ward of the hospital, it is necessary to supply zinc in order to prevent respiratory infections such as pneumonia. PMID- 27455796 TI - [Zinc transporters and zinc signaling]. AB - One of essential trace elements zinc is recognized as an emerging player in variety of cellular functions, due to the fact that the ablation of zinc homeostasis causes various health problems. The molecular reasons, however, why zinc and its regulatory systems are required for homeostasis remain unclear yet. To address these questions, this review will discuss the basic and recent advanced studies on zinc transporters involved in health and disease status. PMID- 27455797 TI - [Maintenance of cellular and body iron homeostasis]. AB - Iron is an essential nutrient being involved in numerous biological functions including oxygen transport, ATP generation, and DNA synthesis. On the other hand, excessive iron toxic to our body because it contributes to generate free radicals, which damage biomacromolecules such as nucleic acids, proteins, and lipids. Thus, maintenance of iron homeostasis at cellular as well as body level is critical for preventing our body from both iron deficiency and iron toxicity. In this manuscript, we review the mechanism underlying maintenance of cellular and body iron homeostasis and introduce recently identified hormones that regulate iron acquisition via intestine. PMID- 27455798 TI - [Copper transport and metabolism]. AB - In this review, copper metabolism and transport in mammalian tissues are introduced and discussed. Firstly, the copper required amounts and LD50 levels are shown to explain the difficult balances of copper in the cells between necessity and toxicity. Furthermore, on the basis of literatures published, relationship between copper-binding metallothioneins and mechanisms for the absorption and excretion of copper or hereditary copper metabolic disorders metabolism abnormality symptom are explained. Finally it has been indicated that apoptosis induced by heavy metals, especially copper was initiated by production of reactive oxygen species and oxidative stress in the cells. To understand precise mechanism for copper homeostasis in mammalian cells, further investigation will be needed to clarify the copper behaviors in normal and abnormal situations. PMID- 27455799 TI - [Zinc- and tin-induced apoptotic mechanisms in immune system and cranial nerve system]. AB - This review explains the mechanisms of apoptosis related to the impacts of zinc deficiency and organotin exposure on the immune and central nervous systems. In the immune systems, both zinc deficiency and trialkyltin exposure lead to severe thymic atrophy and affect T-lymphocyte development through apoptosis of double positive stage pre-T-cells(CD4+/CD8+) in the cortex region. Their apoptosis are caused mainly through decrease in Bcl-2 expression, activation of ROS production/release, oxidative stress, mitochondrial cytochrome c release and activation of caspase cascade, with increases in glucocorticoids in zinc deficiency, without the involvement of glucocorticoid in organotin exposure In the central nervous system, both zinc deficiency and trialkyltin exposure reduce learning, memory and sensory functions through neuronal apoptosis caused by activation of ROS production/release, release of pro-apoptotic factors such as cytochrome c or apoptosis-inducing factor(AIF), with Fe excessive accumulation leading to ROS production and with depletion of hippocampus Zn (mossy fiber Zn) causing various Ca2+ channel disorder of synapse in the hippocampus, and with excessive accumulation of Ca through cAMP-dependent Ca(2+)-channel disorder by excessive PTH and cAMP excessive production in the olfactory systems such as olfactory epithelium and olfactory bulb. PMID- 27455800 TI - [Zinc and gastrointestinal disorders]. AB - Zinc, an essential trace element, affects immune responses, skin metabolism, hormone composition, and some sensory function, so that the deficiency presents various symptoms such as immunodeficiency and taste obstacle. Further, the zinc deficiency also considers as a risk of various diseases. Recent reports demonstrated that -20% of the Japanese population was marginally zinc deficiency, and over 25% of the global population is at high risk of zinc deficiency. In gastrointestinal disorders, zinc plays an important role in the healing of mucosal and epithelial damage. In fact, polaprezinc, a chelate compound of zinc and L-carnosine, has been used for the treatment of gastric ulcer and gastritis. We describe here the therapeutic effect of zinc on gastrointestinal disorders. PMID- 27455801 TI - [Function of zinc in liver disease]. AB - Zinc deficiency is highly prevalent in cirrhotic patients, and contributes to several clinical symptoms such as hepatic encephalopathy and liver fibrosis. Ammonia is detoxified in liver to urea through urea cycle, and is also detoxified in extrahepatic tissue to glutamine through glutamine synthetase. The reduced ability of ammonia detoxification in liver cirrhosis is ascribed to zinc deficiency, because a member of urea cycle, ornithine transcarbamylase is a zinc enzyme. In this condition, glutamine synthesis is enhanced, which enables the body, at least temporarily, to suppress the increase of ammonia. However, the glutamine is metabolized predominantly in enterocyte to ammomia and glutamate, indicating that a vicious cycle in glutamine synthesis and glutamine breakdown occurs in liver cirrhosis. Attention should be given to the clinical significance of zinc in liver diseases. PMID- 27455802 TI - [Zinc and type 2 diabetes]. AB - Pancreatic beta cells contain the highest amount of zinc among cells within the human body, and hence, the relationship between zinc and diabetes has been a topic of great interest. While many studies demonstrating possible involvement of zinc deficiency in diabetes have been reported, precise mechanisms how zinc regulates glucose metabolism are still far from understood. Recent studies revealed that zinc can transmit signals that are driven by a variety of zinc transporters in a tissue and cell-type specific manner and deficiency in some zinc transporters may cause human diseases. Here, we review the role of zinc in metabolism particularly focusing on the emerging role of zinc transporters in diabetes. PMID- 27455803 TI - [The role of zinc in chronic kidney disease]. AB - Renal anemia is one of the most important complication as a cause of cardiovascular event in patients with chronic kidney disease (CKD). The status of renal anemia has been ameliorated by using recombinant human erythropoietin (EPO), however, the EPO resistant anemia is sometimes seen in high stage CKD patients. Heavy metal deficiency including zinc deficiency is one of the cause of EPO resistant anemia. Recently, it is reported that zinc deficiency is seen in patients with CKD. In this article, we describe zinc deficiency in patients with CKD. The ability that zinc supplementation improves their anemia in CKD patients is also described. PMID- 27455804 TI - [The functional role of zinc in skin diseases]. AB - Abstract Acrodermatitis enteropathica(AE) is caused by inherited or acquired zinc deficiency. Cutaneous clinical manifestations observed in AE include characteristic dermatitis on acral, periorificial and anogenital areas through an unknown mechanism. Recently, we found that mice fed a zinc-deficient diet develop a severe irritant contact dermatitis that has the histological features of the skin inflammation seen in AE patients. This finding highlights the possibility that the acral, periorificial and anogenital dermatitis in AE might be caused by contact with different irritants in daily life, such as chemicals, foods, urine or feces, respectively. This review focuses on the recent advances regarding the functional role of zinc in skin and describes how zinc deficiency causes various cutaneous manifestations. PMID- 27455805 TI - [Copper metabolism and genetic disorders]. AB - Copper is one of essential trace elements. Copper deficiency lead to growth and developmental failure and/or neurological dysfunction. However, excess copper is also problems for human life. There are two disorders of inborn error of copper metabolism, Menkes disease and Wilson disease. Menkes disease is an X linked recessive disorder with copper deficiency and Wilson disease is an autosomal recessive disorder with copper accumulation. These both disorders result from the defective functioning of copper transport P-type ATPase, ATP7A of Menkes disease and ATP7B of Wilson disease. In this paper, the author describes about copper metabolism of human, and clinical feature, diagnosis and treatment of Menkes disease and Wilson disease. PMID- 27455806 TI - [Iron and liver disease]. AB - Free iron in the liver is believed to facilitate the formation of reactive oxygen species (ROS), including hydroxyl radicals (*OH), which cause oxidative damage of numerous cellular components such as lipids, proteins, and nucleic acids, and also upregulate collagen synthesis. The *OH radical is known to generate promutagenic bases such as 8-hydroxy-2-deoxyguanosine (8-OHdG). In cases with chronic hepatitis C, long-term iron reduction therapy reduced the activity of hepatitis, suppressed fibrosis, and prevented hepatocarcinogenesis. In nonalcoholic steatohepatitis (NASH) livers, hepatic iron accumulation as well as oxidative DNA damage significantly increased. Humoral factor(s) in NASH serum may upregulate DMT1 expression in small intestine. Iron reduction therapy for NASH patients has a potential to reduce disease activity as well as hepatic oxidative damage. PMID- 27455807 TI - [Iron accumulation and neurodegenerative diseases]. AB - Iron, as well as copper, is essential for a wide variety of biological processes in living organisms, however, dysregulation of iron homeostasis may lead to oxidative stress via redox cycling reactions. Therefore, cellular and systemic iron homeostasis is tightly regulated by a number of iron metabolism proteins. The brain is susceptible to iron-mediated oxidative damage because of a relatively high content of iron and high consumption of oxygen. Iron-mediated neurotoxicity is symbolically seen in neurodegeneration with brain iron accumulation (NBIA) in which iron accumulates mainly in the basal ganglia. Furthermore, iron accumulation is considered to play important roles in the pathophysiology of other, more prevalent neurodegenerative diseases such as Parkinson's disease (PD). Here, from the standpoint of iron dyshomeostasis, current understandings and therapeutic approaches in NBIA and PD are briefly discussed. PMID- 27455808 TI - [Iron function and carcinogenesis]. AB - Though iron is an essential micronutrient for humans, the excess state is acknowledged to be associated with oncogenesis. For example, iron overload in the liver of the patients with hereditary hemocromatosis highly increases the risk of hepatocellular carcinoma. Also, as to asbestos-related mesothelioma, such kinds of asbestos with a higher iron content are considered to be more carcinogenic. Iron is a useful element, which enables fundamental functions for life such as oxygen carrying and electron transport. However, in the situation where organisms are unable to have good control of it, iron turns into a dangerous element which catalyzes generation of reactive oxygen. In this review, I first outline the relationships between iron and cancer in general, then give an explanation about iron-related animal carcinogenesis models. PMID- 27455809 TI - [Link between aluminum neurotoxicity and neurodegenerative disorders]. AB - Aluminum is an old element that has been known for a long time, but some of its properties are only now being discovered. Although environmentally abundant, aluminum is not essential for life; in fact, because of its specific chemical properties, aluminum inhibits more than 200 biologically important functions and exerts various adverse effects in plants, animals, and humans. Aluminum is a widely recognized neurotoxin. It has been suggested that there is a relationship between exposure to aluminum and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and parkinsonism dementia in the Kii Peninsula and Guam, as well as Alzheimer' s disease: however, this claim remains to be verified. In this chapter, we review the detailed characteristics of aluminum neurotoxicity and the link between Alzheimer' s disease and other neurodegenerative diseases, based on recent findings on metal-metal interactions and the functions of metalloproteins in synapses. PMID- 27455810 TI - [Function and disease in manganese]. AB - Manganese is a metal that has been known named a Greek word "Magnesia" meaning magnesia nigra from Roman Empire. Manganese provide the wide range of metablic function and the multiple abnomalities from its deficiency or toxicity. In 1931, the essentiality of manganese was demonstrated with the authoritative poor growth and declined reproduction in its deficiency. Manganese deficiency has been recognized in a number of species and its signs are impaired growth, impaired reproduction, ataxia, skeletal abnormalities and disorders in lipid and carbohydrate metabolism. Manganese toxicity is also acknowledged as health hazard for animals and humans. Here manganese nutrition, metabolism and metabolic function are summarized. PMID- 27455811 TI - [Association between function of selenium and heart disease]. AB - An excessive oxidative stress is considered to be responsible for the development and progression of heart disease. Deficiency of trace elements with antioxidative activities is present in patients with heart disease. Selenium (Se) is an integral part of the enzyme glutathione peroxidase(GPx), one of the central players of the heart's antioxidant system, and it's deficiency is implicated in certain types of heart disease. Our study suggests that myocardial oxidative stress in chronic heart failure may be augmented at least in part by concomitant GPx deficiency, and that the administration of Se could rescue the exhaustion of this selenoprotein, resulting in improved left ventricular function. PMID- 27455812 TI - [Biological functions of tin and disease]. AB - Tin generates a wide variety of biological functions due to its chemical character. In this article, the modes of the biological functions of tin(especially organotin compounds) are reviewed, with special emphasis on the connection with the immune system, brain nervous system and endocrine system, on the basis of our data. To sum up this article, the biological functions of organotin compounds appear to be due to the following several processes: (1) their incorporation into the cells in vesicle form through fusion or in a similar manner to their incorporation in cationic form; (2) transport to and accumulation in the regions of the Golgi apparatus and endoplasmic reticulum (ER), but not to or in the plasma membrane or nucleus because of their hydrophobicity; (3) inhibition of intracellular phospholipid transport between organelles due to impairment of the structures and functions of the Golgi apparatus and ER; (4) inhibition of the membrane-mediated signal transduction system leading to DNA synthesis via phospholipid turnover and Ca2+ mobilization, as in cell proliferation systems; (5) disturbance of the trace element balance and the localization of certain elements; (6) disorders of membrane-mediated Ca2+ homeostasis via various channel functions including Zn modulation on the plasma and organelle membranes, and protein phosphorylation, as in the signal transduction systems of memory and olfaction; (7) necrosis or apoptosis in vivo or toxic cell death in vitro. PMID- 27455813 TI - [Biological effects of arsenic and diseases: The mechanisms involved in arsenic induced carcinogenesis]. AB - Chronic arsenic exposure is associated with many diseases, including cancers. Our study using in vivo assay in gpt-delta transgenic mice showed that arsenic particularly induces G : C to T : A transversions, a mutation type induced through oxidative-stress-induced 8-OHdG formation. Gestational arsenic exposure of C3H mice was reported to increase hepatic tumor incidence. We showed that gestational arsenic exposure increased hepatic tumors having activated oncogene Ha-ras by C to A mutation. We also showed that DNA methylation status of Fosb region is implicated in tumor augmentation by gestational arsenic exposure. We further showed that long-term arsenic exposure induces premature senescence. Recent studies reported that senescence is involved in not only tumor suppression, but also tumorgenesis. All these effects of arsenic might be involved in arsenic-induced carcinogenesis. PMID- 27455814 TI - [Trace elements deficiency in children receiving nutritional management]. AB - The trace elements is very important in growth of children, especially receiving nutritional management, including parenteral or enteral nutrition. Therefore, clinicians treating children should recognize regarding both the function and deficiency of trace elements. In this article, in nutritional management of children, the basic and recent knowledge was described regarding the function of some important trace elements, including zinc, copper, selenium, and iodine. In addition, the symptoms, diagnosis, and treatments in each trace element deficiency were also described. PMID- 27455815 TI - [Significance of zinc and sarcopenia in patients undergoing surgery]. AB - Sarcopenia is characterized by muscle mass depletion and decrease in muscle power or physical activity. We evaluated significance of sarcopenia in patients undergoing living donor liver transplantation (LDLT). Patients with low skeletal muscle mass (SMM) had significantly worse survival compared with patients with normal/high SMM (p < 0.001). Correlations of preoperative zinc with prealbumin and branched-chain amino acids were significantly positive. While, correlations of zinc with tyrosine and ammonia levels were significantly negative. The low pre transplant zinc level steeply dropped for 2/3 days after LDLT and subsequently increased back to reach the pre-transplant level around the postoperative day 5, and continued to increase until normalized during 2 weeks. Perioperative nutritional therapy including zinc supplement significantly increased survival in patients with low SMM (p = 0.009). PMID- 27455816 TI - [Zinc depletion and ER stress]. AB - Zinc is required for the proper functions of proteins and cell signaling. Because the perturbation of zinc homeostasis causes various human diseases, cells need to regulate cellular zinc homeostasis strictly. However, the mechanisms by which cells respond to zinc deficiency and restore cellular homeostasis are largely unknown. Endoplasmic reticulum(ER) stress signaling is the stress response activated by the accumulation of unfolded proteins in ER. Recently, the importance of ER stress signaling during zinc deficiency has been revealed. Here, we introduce the mechanistic insight of ER stress induction and its role in the maintenance of cell homeostasis or in the pathogenesis of various diseases during zinc deficiency. PMID- 27455817 TI - [Improvement in zinc nutrition due to zinc transporter-targeting strategy]. AB - Adequate intake of zinc from the daily diet is indispensable to maintain health. However, the dietary zinc content often fails to fulfill the recommended daily intake, leading to zinc deficiency and also increases the risk of developing chronic diseases, particularly in elderly individuals. Therefore, increased attention is required to overcome zinc deficiency and it is important to improve zinc nutrition in daily life. In the small intestine, the zinc transporter, ZIP4, functions as a component that is essential for zinc absorption. In this manuscript, we present a brief overview regarding zinc deficiency. Moreover, we review a novel strategy, called "ZIP4-targeting", which has the potential to enable efficient zinc absorption from the diet. ZIP4-targeting strategy is possibly a major step in preventing zinc deficiency and improving human health. PMID- 27455818 TI - Characteristics and Outcomes of Treatment for Non-ST-Segment Elevation Acute Coronary Syndrome: Results from a Single Center Registry. AB - BACKGROUND: Acute coronary syndrome (A CS) is a leading health burden worldwide. The Siriraj non-ST-segment elevation acute coronary syndrome (NST E-A CS) registry was established in 2012. Here, we report in-hospital outcomes and one year outcomes from patients in the registry. OBJECTIVE: To investigate and report characteristics and outcomes of treatment for NSTE-ACS at one year from a single center MATERIAL AND METHOD: All patients admitted to Siriraj Hospital with diagnosis of NSTE-ACS were enrolled. Baseline demographic information, presenting signs and symptoms, electrocardiogram, and blood chemistry were recorded. In hospital complications and outcomes of treatment were also collected and recorded. After being discharged from the hospital, patients were followed-up for one year. RESULTS: Two-hundred patients were evaluated between January 2012 and August 2013. A majority of patients (65.5%) presented with angina. Median TIMI risk score was 4. Thirty-two percent of patients had GR ACE risk score greater than 140. In-hospital mortality was 3.5% (95% CI 2.0-7.0). The most common complication was heart failure (36.5%). Three patients had CVA during admission. At one year the mortality rate was 5% (95% CI 3.0-9.0). Unplanned readmission rate was 9.5%. CONCLUSION: Most patients in the registry were high-risk ACS patients. In-hospital mortality and one-year mortality rates were 3.5% and 5%, respectively. Results from this study were comparable to results reported by previous studies from the Western world PMID- 27455819 TI - Effectiveness and Safety of Generic Formulation of Cefoperazone/Sulbactam (Bacticep(r)) in Treatment of Infections at Siriraj Hospital. AB - OBJECTIVE: To compare the effectiveness and safety of generic cefoperazone/sulbactam (Bacticep(r)) and original cefoperazone/ sulbactam (Sulperazon(r)) in treatment of infections in hospitalized patients at Siriraj Hospital. MATERIAL AND METHOD: Hospitalized patients aged 18 years and older who received cefoperazone/sulbactam for at least 48 hours were identifed from the Siriraj Hospital pharmacy database. Medical records of identified patients were reviewed and relevant information was extracted and transferred onto pre-printed case record forms. Patient data relating to demographics, clinical features of infections, antibiotic therapy, and treatment outcomes were evaluated and compared between patients who received generic and original cefoperazone/sulbactam. RESULTS: Two hundred twenty nine hospitalized patients who had infections and received original or generic cefoperazonel sulbactam were included. Baseline characteristics and clinical features of infections in both groups were comparable. Favorable outcomes (72.9% vs. 72.2%, p = 1.00) and infection-related deaths (4.7% vs. 11.1%, p = 0.16) between generic cefoperazone/sulbactam group and original cefoperazone/sulbactam group, respectively, were not significantly different. Generic cefoperazone/sulbactam favorable outcomes were found to be non-inferior to original cefoperazone/sulbactam (p = 0.04), with lower bound of one-sided 95% CI for difference in favorable outcome within the pre-specified non-inferiority margin of -10% (95% CI: 0.7% with lower bound of -9.3). No significant differences in adverse events were observed between groups. CONCLUSION: Generic cefoperazone/sulbactam (Bacticep(r)) was found to be non-inferior to original cefoperazone/sulbactam for therapy of infections in hospitalized patients at Siriraj Hospital. PMID- 27455820 TI - Intracranial Hemorrhage in Patients with Hematologic Disorders: Prevalence and Predictive Factors. AB - BACKGROUND: Intracranial hemorrhage (ICH) is an uncommon complication in patients with hematologic disorders although high fatality rates have been shown in these patients. At present, no epidemiological data regarding ICH in patients with hematologic disorders has been collected and/or reported in Thailand. OBJECTIVE: The purpose of this study was to determine the incidence of ICH in hospitalized patients with hematologic disorders and to identify predictive factors associated with ICH in these patients. MATERIAL AND METHOD: The medical records of all patients with hematologic disorders admitted to Siriraj Hospital (Bangkok, Thailand) between January 2002 and September 2011 were reviewed. Patients with ICH were identified and factors associated with ICH were investigated using a retrospective case-control design. RESULTS: Of 9,62 patients identified with hematologic disorders, ICH was diagnosed in 106 (1.1%). The ICH rate was higher in acute myeloid leukemia (AML) patients than in patients with other hematologic malignancies (4.29% vs. 0.78%; p<0. 001) and higher in aplastic anemia (AA) patients than in patients with other benign hematologic disorders (4.00% vs. 0.97%; p<0.001). Cortical hemorrhage was the main presentation in all hematologic disorders, with a single lesion in the parietal area as the most common site. The overall mortality rate was 85% with most patients succumbing within two days of onset. The independent predictors of ICH were hyperleukocytosis and a low platelet count in AML patients, and ecchymosis, upper gastrointestinal hemorrhage, hematuria, and a low platelet count in AA patients. CONCLUSION: AML and AA patients had the highest risk of ICH compared with other hematologic disorders and several predictive factors for ICH were identified. PMID- 27455821 TI - Positive Pulmonary Computed Tomography Angiography in Patients with Suspected Acute Pulmonary Embolism: Clinical Prediction Rules, Thromboembolic Risk Factors, and Implications for Appropriate Use. AB - BACKGROUND: Acute pulmonary embolism (PE) is associated with a variety of non specific clinical manifestations. Using diagnostic algorithms that are based on internationally recognized guidelines, pulmonary computed tomography angiography (CTA) serves as the gold standard diagnostic imaging tool in PE. However; inappropriate use of pulmonary CTA may lead to unnecessary radiation exposure, contrast exposure, and cost. Based on our review of the literature, there is no existing data regarding prevalence and appropriate use of pulmonary CTA in suspected acute PE in Thailand. OBJECTIVE: To assess the prevalence of positive pulmonary CTA and evaluate appropriateness of use of pulmonary CTA, according to clinical prediction rules and recent guidelines. MATERIAL AND METHOD: Three hundred consecutive patients admitted to the general medical ward at a large university-based tertiary referral center who were sent for pulmonary CTA due to suspected acute PE were included. Prevalence of positive pulmonary CTA for PE and other abnormalities were analyzed. Baseline clinical characteristics (including thromboembolic risk factors) and basic investigations (including chest X-ray, ECG, pulse oximetry, and D-dimer) were compared between patients with and without acute PE. RESULTS: Acute PE was diagnosed by pulmonary CTA in 110 (36.7%) patients. According to Wells score and revised Geneva score, patients were categorized into low, moderate, and high probability, as follows: 63, 178, and 59 patients, respectively, and 44, 246, and 10 patients, respectively. Patients with high probability according to Wells score and revised Geneva score had higher rate of positive pulmonary CTA results, as compared to low and moderate probability (59.3%, 7.9%, and 39.3%, respectively, and 60%, 19.5%, and 38.2%, respectively). Predictors of positive CTA were sign of deep vein thrombosis (DVT) (OR: 2.6, 95% CI: 1.497-4.514; p<0.001), S1Q3T3 (OR: 4.211, 95% CI: 2.242-7.908; p<0.001), and enlarged right pulmonary artery (OR: 2.439, 95% CI: 1.475-4.035; p<0.001). Using multivariate analysis, all three parameters remained independent factors. In the Wells score low probability group, 31 of 63 patients were not tested for D-dimer prior to pulmonary CTA, with only one patient in that group being diagnosed with acute PE. CONCLUSION: This was the first study to investigate prevalence of positive pulmonary CTA for acute PE in a large university-based tertiary referral hospital in Thailand Prevalence of positive test for PE by pulmonary CTA in patients with suspected acute PE was approximately 33%. Sign of DVT S1Q3T3 pattern, and enlarged right pulmonary artery were significant clinical predictors of positive pulmonary CTA. Positive pulmonary CTA result was much less likely in patients with low probability, especially in the absence of thromboembolic risk factors and positive D-dimer This study emphasized the importance and value of accurate and effective triage in reducing both patient care costs and patient radiation exposure. PMID- 27455822 TI - Revised Ghent Criteria is Comparable to Original Diagnostic Criteria for Marfan Syndrome with Increased Ability to Clinically Diagnose Related Disorders. AB - BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with major features in cardiovascular ocular and skeletal systems. Due to its genetic heterogeneity and variable expressivity, Ghent nosology was established for clinical diagnosis of MFS. In 2010, Ghent diagnostic criteria were revised to better diagnose MS and categorize its related disorders. There is no previous clinical comparison between the original and revised Ghent criteria for diagnosis of MFS in Thai patients. OBJECTIVE: To compare application and efficacy of Ghent and revised Ghent criteria in adult Thai patients with clinical suspicion of MFS. MATERIAL AND METHOD: This study was a retrospective analysis of patients with clinical suspicion of MFS who attended the Medical Genetics Clinic, Siriraj Hospital between January 2003 and December 2013. Patients were clinically examined for diagnosis of MFS using both the Ghent and revised Ghent criteria. Multidisciplinary data, including physical examination, echocardiography, slit lamp examination, and genetic testing, were analyzed. RESULTS: Clinical and genetic data of 138 (77 males and 61 females) individuals with clinical suspicion of MFS were reviewed The most common presentation was cardiovascular manifestation. Of 92 patients diagnosed as MFS by original Ghent nosology 70 of those patients (76.1%) were also diagnosed as MFS by revised Ghent criteria. Forty-eight of 138 patients (34.8%) had undergone genetic testing, with FBN1 mutations detected in 23 patients. Twenty-two patients with detectable FBN1 mutations fulfilled both the Ghent and revised Ghent criteria. Of 22 patients whose diagnoses were not fulfilled by revised Ghent nosology, most were due to inadequate systemic score (SS). The use of revised Ghent nosology also facilitated improved diagnosis of MFS-related disorders. CONCLUSION: Revised Ghent nosology has further differentiated MFS from other MFS-related disorders and has further expanded the classification of MFS-related disorders. Genetic testing of FBN1 helps physicians to more accurately diagnose patients with MFS and related disorders. PMID- 27455823 TI - Survey of Thai Physicians Regarding Recognition and Management of Inflammatory Back Pain and Spondyloarthritis. AB - OBJECTIVE: To assess recognition and management of inflammatory back pain (IBP) and spondyloarthritis (SpA) among non-rheumatologists (NRs) and rheumatologists in Thailand. MATERIAL AND METHOD: A cross-sectional survey was conducted among physicians in Thailand A questionnaire designed to evaluate knowledge regarding IBP and SpA was sent to 1,336 NRs. A different questionnaire regarding SpA management in practice was sent to 112 rheumatologists. RESULTS: Of 1,448 questionnaires distributed, 367 (25.3%) questionnaires were returned (NRs: 321 [24.0%] and included rheumatologists, 46 [41.1%]). Among NRs, 26.6%, 20.9%, and 9.4% recognized all features of IBP according to Calin, Assessment of SpondyloArthritis International Society, and Berlin criteria, respectively. In the presence of typical features of ankylosing spondylitis, 57.8% of NRs made the correct diagnosis. Regarding related clinical skills and involvement, 43.8%, 53.6%, and 37.3% of NRs lacked confidence in distinguishing IBP from mechanical back pain, performing musculoskeletal examination, and interpretation of plain radiography, respectively. Expensive biologic agents (31.2%) and advanced disease stage at diagnosis (27.1%) were the main problems reported by rheumatologists. CONCLUSION: Problems in diagnosis and management of SpA patients among NRs in Thailand included lack of knowledge and lack of associated clinical skills. Issues reported by rheumatologists centered on case management limitations. In order to improve overall quality of care for SpA patients, focused strategies should be implemented for both NRs and rheumatologists that consider the needs of patients, clinicians, and policy makers. PMID- 27455824 TI - The Cost of Asthma Treatment in Phramongkutlao Hospital: Population-Based Study in Adults. AB - BACKGROUND: Asthma is a chronic respiratory disease that affects patients' quality of life and work performance. The cost of asthma treatment is a global economic burden. The costs include the direct medical costs and the indirect costs, such as the loss of productivity, which is difficult to quantify. OBJECTIVE: Analyze the cost of asthma treatment in Thailand. MATERIAL AND METHOD: Seventy-four asthmatic patients who had exacerbation were enrolled in the present study. Self-answer questionnaires were completed by the subjects including characteristics, socioeconomic factors, and level of asthma control by asthma control test (ACT) score. We evaluated the cost of asthma treatment calculated from direct medical, direct non-medical, and indirect medical costs. RESULTS: The average total cost per month was 2,752 Thai baht (US$ 86). The direct medical, direct non-medical, and indirect medical costs were 52.39%, 20.73%, and 26.88%, respectively. The direct medical costs accounted for quick-relief medications 11.91% and control medications 36.85% of the total medical cost. Loss of productivity, loss of work caused by asthma exacerbation, was the majority cost of non-medical costs. The average cost of treatment in uncontrolled was higher than partly controlled asthmatic patients but without significant difference. Healthcare payment system and age range affected the total costs of asthma treatment. CONCLUSION: The direct non-medical costs and indirect medical costs tend to play an important role of asthma treatment. The data suggested that cost savings could be achieved by improving asthma control. PMID- 27455825 TI - Comparison of Prevalence of Nutritional Status of Thai Children in the First 2 Years of Life Using National and International Growth Charts. AB - OBJECTIVE: Identify the difference of the nutritional status of Thai children from birth to 24 months of age using the national and international growth charts. MATERIAL AND METHOD: The analytic sample was of 4,224 children from the Prospective Cohort Study of Thai Children (PCTC). Age-specific prevalence of malnutrition was estimated using the NCHS, WHO, and Thai growth charts. RESULTS: Rapid growth faltering was found in both genders during the first two years, regardless of the reference, but the Thai charts reflected better Thai children. When using the Thai and NCHS charts, a steep fluctuation was observed in infancy, although the prevalence of wasting, underweight, and overweight between the references became narrower at 24 months. Meanwhile, the WHO standards identified a higher number of stunted children and showed a linear increasing trend of overweight with age, compared to the Thai reference. CONCLUSION: Although the Thai growth charts better reflect the Thai children, in consideration of a double burden of stunting and overweight in Thailand, the WHO standards can be used to identify Thai children at risk of stunting and overweight in the first two years of life. PMID- 27455826 TI - Keratoconus in Patients with Macular Stromal Dystrophy. AB - OBJECTIVE: To show the association between keratoconus and macular dystrophy. MATERIAL AND METHOD: All patients with macular dystrophy and associated clinical findings leading to a diagnosis of keratoconus by corneal topography were retrospectively reviewed during a 10-year period. Uncorrected and best-corrected visual acuity, automated refraction, manifest refraction, corneal thickness, and corneal curvature by corneal topography were evaluated RESULTS: Three patients with macular dystrophy exhibiting decreased vision, multifocal white dense deposits, and haze surrounding the deposits in the corneal stroma were evaluated. All had a steep corneal curvature of >47 diopters and a thin cornea consistent with keratoconus. Penetrating keratoplasty was performed in one patient with severely decreased vision. Macular dystrophy was diagnosed based on an Alcian blue-stained pathological specimen. CONCLUSION: Keratoconus may develop as a result of changes associated with macular dystrophy. Therefore, patients with severely decreased vision should be evaluated for keratoconus to ensure proper management. PMID- 27455827 TI - Outcome of Urgent Penetrating Keratoplasty for Corneal Ulcer at Thammasat University Hospital. AB - OBJECTIVE: To determine the eye integrity preservation after urgent penetrating keratoplasty (PKP) for corneal ulcer at Thammasat University Hospital. MATERIAL AND METHOD: A retrospective review of patients who underwent urgent PKP between September 2005 and January 2015 was conducted. Demographic data, predisposing factors, organisms, indication for surgery, time of urgent corneal graft registry, and preservation rate of eye integrity were analyzed. RESULTS: Fifty five patients (55 eyes) registered for urgent corneal graft registry from eye bank and 22 eyes underwent urgent PKP There were 14 males (63.6%) and 8 females (36.4%). A mean age was 55.9+/-15.4 years. The most common predisposing factor was ocular trauma in 11 eyes (50.0%) and the most common indication for surgery was severe corneal ulcer in 11 eyes (50.0%). The mean time of urgent corneal graft registiy was 22.1+/-1 7.2 days (3-70 days). The present study could preserve eye integrity in post urgent PKP in 18 eyes (81.8%). Other 4 eyes (18.2%) could not preserve the eye integrity. In 33 eyes who did not underwent urgent PKP 20 eyes (60.6%) could preserve eye integrity, 10 eyes (30.3%) underwent primary evisceration and 3 eyes (9.1%) underwent primary enucleation due to extensive ocular infection. CONCLUSION: Urgent PKP of corneal ulcer could provide satisfactory in eye integrity preservation. PMID- 27455828 TI - Hypothyroidism after Hemithyroidectomy: The Incidence and Risk Factors. AB - OBJECTIVE: To evaluate the incidence of post-hemithyroidectomy hypothyroidism and identify possible risk factors that indicates whether patients require thyroid function monitoring after surgery. MATERIAL AND METHOD: A retrospective review of patients with benign non-toxic thyroid disease undergoing hemithyroidectomy between April 2004 and November 2008 in the Department of Otorhinolaryngology, Siriraj Hospital was conducted All patients were in euthyroid state preoperatively. Thyroid specimens were examined for pathological diagnosis and degree of lymphocytic infiltration in thyroid tissue, and thyroid function was evaluated again six weeks after surgery. RESULTS: One hundred patients who received hemithyroidectomy were recruited for the present study. All had normal preoperative thyroid function. Six weeks after surgery, 27% of the cases developed hypothyroidism (6% overt or symptomatic hypothyroidism and 21% subclinical hypothyroidism). The mean preoperative thyrotropin level was significantly higher in the hypothyroid group than in the euthyroid group (1.9+/ 1.2 vs. 1.1+/-0.7 micro IU/ml). Fifty-eight point three percent of patients with preoperative thyroid stimulating hormone (TSH) level more than or equal 2 micro IU/ml developed hypothyroidism in comparison to only 17.1% of those with preoperative TSH <2 micro IU/ml (odds ratio 6.8). Fifteen patients had signifcant lymphocytic infiltration (grade 2-4); nine of those (60%) had post-operative hypothyroidism. In contrary, only 18 of 85 patients (21.2%) with minimal infiltrates (grade 0-1) developed hypothyroidism (odds ratio 5.6). CONCLUSION: Twenty-seven percent of the patients in the present study developed hypothyroidism after hemithyroidectomy. Preoperative TSH more than or equal 2 micro IU/ml and significant lymphocytic infiltration in thyroid tissue or thyroiditis warrant post-operative close TSH monitoring. The awareness of such risk factors for post-operative hypothyroidism would improve patients care. PMID- 27455829 TI - Oral Candida Colonization in Thai Patients with Psoriasis. AB - OBJECTIVE: To investigate the prevalence and risk factors of oral Candida colonization in psoriatic patients at Siriraj Hospital. MATERIAL AND METHOD: Sixty patients with psoriasis, aged older than 18 years, were recruited for the study group. Sixty healthy individuals similar to the patients in the study group in terms of age and gender were recruited for the control group. Candida spp. was isolated from oral swabs and oral rinses taken from all subjects. RESULTS: During the study period, 27 (45.0%) psoriatic patients used only topical treatment and the remaining patients were on systemic treatment. Oral Candida colonization was significantly higher in patients with psoriasis (30%), as compared with healthy controls (13.3%). Candida albicans was the predominant Candida species isolated. Presence of oral candidiasis was significantly associated with systemic treatment. CONCLUSION: Oral Candida colonization is associated with psoriasis, especially in patients who receive systemic treatment. PMID- 27455830 TI - Comparison of Double RBC Collection by Blood Cell Separators. AB - BACKGROUND: The problem of red blood cell (RBC) shortage occurs because of the expanding demand for blood utilization and the dfficulties in donor recruitment and retention. Resources can be maximized by using current technology to collect two units of RBC from the same donor during a single collection session. OBJECTIVE: To evaluate the performance, collection efficiency (CE), production cost, and donor satisfactions of two commercially available blood cell separators (BCS) for double dose red cell (DDRC) collection. Donor safety, clinical effectiveness, and patient safety were studied. MATERIAL AND METHOD: Thirty-one repeated male donors from the blood bank, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University were recruited for DDRC collection by two BCSs, the AlyxTM, Fresenius Kabi, NC, USA, and the MCS(r)+, Haemonetics Corporation, Scotland. The donation intervals were at least 16 weeks. The target RBC volume was 360 mL (180 mL x 2 units). Pre- and post-donation hematologic parameters were monitored and quality tests for DDRC were performed. Donor reactions (DR) were observed and donor satisfaction questionnaires were collected after donations. Eighty-six units of RBC were transfused to 33 patients. Transfusion reactions (TR) were observed, and hematocrit (Hct) increments were determined pre-transfusion and 24 hours post-transfusion. RESULTS: The AlyxTM was faster for collecting and filtrating RBC (p<0.001) and had better CE (p<0.001). All DDRC from both BCSs met all the quality standards, required by both the American Association of Blood Banks (AABB) and the Food and Drugs Administration (FDA), which were hemoglobin (Hb) >42.5 g, Hct 50 to 70% and the residual white blood cells (WBC) <5x10(6). The AlyxTM processed less whole blood (WB) volume but provided DDRC with higher RBC yield, Hb content, and RBC volume than that of MCS(r) + (p<0. 001). However; the MCS(r)+ had one advantage over the AlyxTM whereby the DDRC collected by the MCS(r)+ were washed to reduce the risk of plasma associated TR. No serious DR from either BCS was observed. All donors had Hb >10 g/dL and Hct >30% after collection, as required by AABB. Serum ferritin reduction and iron depletion found in DDRC donors were not different from WB donors. All donors were satisfied with the DDRC collection process and would like to donate again. There was no evidence of acute or delayed TR in the patients. Hct increased significantly in 69.70% of the patients. CONCLUSION: DDRC collection can be performed safely and efficiently from both BCS. The quality of DDRC from both BCSs met the AABB and FDA standards. Donor safety, transfusion safety, and effectiveness were observed. Even though the production cost of DDRC was slightly higher than that of whole blood derived filtered RBC, DDRC was better in terms of quality, risk reduction for infectious agents, and RBC alloimmunization. Production of DDRC can also be helpful supplying special RBC such as group O, Rh D negative, and phenotyped RBC. PMID- 27455831 TI - Reversible Cerebral Vasoconstriction Syndrome: A Report on Three Cases. AB - Reversible cerebral vasoconstriction syndrome (RCVS), a recently recognized syndrome, is defined as an intermittent segmental vasospasm of cerebral arteries accompanied by thunderclap headache. The major complications of RCVS include ischemic or hemorrhagic stroke, which may cause morbidity and mortality. It is important to detect RCVS in clinical practice because misdiagnosis may lead to inappropriate treatment. In Thailand, there are only two reported cases of RCVS, which may reflect an underdiagnosis of this syndrome. To raise awareness of RCVS, we reported a case series of three RCVS cases. Two of the presented cases had interesting precipitating factors, and two cases had an unusual delayed clinical course. PMID- 27455832 TI - Vagoglossopharyngeal Neuralgia Occurred Concomitantly with Ipsilateral Hemifacial Spasm and Versive Seizure-Like Movement: A First Case Report. AB - Vagoglossopharyngeal neuralgia (VGPN) is a very rare condition. VGPN with convulsive like attack is even rarer All of the cases had their head turned to the opposite side of facial pain. Hemifacial spasm occurring concurrently with VGPN has never been reported. Herein, we present the first case of VGPN that had ipsilateral hemifacial spasm and versive seizure-like movement to the same side of facial pain. We reported a 71-year-old man presenting with multiple episodes of intermittent sharp shooting pain arising on the right middle neck, followed by hemifacial spasm on right face. Then the patient became syncope while his head and gaze turned to the same side of the painful neck. Electrocardiography showed sinus arrest. Interictal Electroencephalography was normal. This patient initially responded to pregabalin for two weeks, then the symptoms became worse. Microvascular decompression and carbamazepine resulted in the complete remission of all symptoms after six months of follow-up. We could not explain the pathophysiology of unilateral versive seizure like movement. PMID- 27455833 TI - Comprehensive DFT and TD-DFT Studies on the Photophysical Properties of 5,6 Dichloro-1,3-Bis(2-Pyridylimino)-4,7-Dihydroxyisoindole: A New Class of ESIPT Fluorophore. AB - Hanson et al. [Org. Lett., 2011] reported the absorption and emission spectrum of 5,6-dichloro-1,3-bis(2-pyridylimino)-4,7-dihydroxyisoindole but the excited-state intramolecular proton transfer (ESIPT) process was not investigated. The photo physical behaviour of 5,6-dichloro-1,3-bis(2-pyridylimino)-4,7-dihydroxyisoindole was studied using the density functional theory (DFT) and time-dependent density functional theory (TD-DFT). The functional used was B3LYP and 6-31G(d) was the basis set for all the atoms. All the ten tautomers were studied for the absorption and emission properties. It is found that the tautomer where hydroxyl groups are syn to nitrogen of isoindoline ring is most stable and thus, responsible for the ESIPT process. The computed absorption and emission values of tautomers using TD-DFT are in good agreement with those obtained experimentally. PMID- 27455834 TI - Gd-nanoparticles functionalization with specific peptides for beta-amyloid plaques targeting. AB - BACKGROUND: Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteinaceous aggregates highly organized into cross-beta structure and referred to as amyloid fibrils. Nowadays, the diagnosis of these diseases remains tedious and involves multiple examinations while an early and accurate protein typing is crucial for the patients' treatment. Routinely used neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using Pittsburgh compound B, [(11)C]PIB, provide structural information and allow to assess the amyloid burden, respectively, but cannot discriminate between different amyloid deposits. Therefore, the availability of efficient multimodal imaging nanoparticles targeting specific amyloid fibrils would provide a minimally-invasive imaging tool useful for amyloidoses typing and early diagnosis. In the present study, we have functionalized gadolinium-based MRI nanoparticles (AGuIX) with peptides highly specific for Abeta amyloid fibrils, LPFFD and KLVFF. The capacity of such nanoparticles grafted with peptide to discriminate among different amyloid proteins, was tested with Abeta(1-42) fibrils and with mutated-(V30M) transthyretin (TTR) fibrils. RESULTS: The results of surface plasmon resonance studies showed that both functionalized nanoparticles interact with Abeta(1-42) fibrils with equilibrium dissociation constant (Kd) values of 403 and 350 uM respectively, whilst they did not interact with V30M-TTR fibrils. Similar experiments, performed with PIB, displayed an interaction both with Abeta(1-42) fibrils and V30M-TTR fibrils, with Kd values of 6 and 10 uM respectively, confirming this agent as a general amyloid fibril marker. Thereafter, the ability of functionalized nanoparticle to target and bind selectively Abeta aggregates was further investigated by immunohistochemistry on AD like-neuropathology brain tissue. Pictures clearly indicated that KLVFF-grafted or LPFFD-grafted to AGuIX nanoparticle recognized and bound the Abeta amyloid plaque localized in the mouse hippocampus. CONCLUSION: These results constitute a first step for considering these functionalized nanoparticles as a valuable multimodal imaging tool to selectively discriminate and diagnose amyloidoses. PMID- 27455835 TI - Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes: a randomized double-blind placebo-controlled crossover study. AB - BACKGROUND: Patients with type 2 diabetes (T2D) and coronary artery disease (CAD) have increased risk of cardiac dysfunction. The diabetic heart is characterized by increased fatty acid oxidation and reduced glucose uptake resulting in reduced cardiac efficiency. Glucagon-like peptide-1 (GLP-1) has shown to increase myocardial glucose uptake and to improve myocardial function. We examined the effect of the GLP-1 receptor agonist, liraglutide, on the systolic function of the left ventricle (LV) in patients with T2D and stable CAD. METHODS: In this placebo-controlled crossover study, 41 subjects with T2D and stable CAD were randomized to liraglutide or placebo and underwent dobutamine stress echocardiography (DSE) and exercise tolerance test at beginning and end of each intervention. The primary endpoint was changes in LV ejection fraction. Secondary endpoints were exercise capacity and other measures of systolic function: wall motion score index (WMSI), global longitudinal strain (GLS) and strain rate (GLSR). RESULTS: Liraglutide, when compared to placebo, did not improve LV ejection fraction at rest (+0.54 %; 95 % CI 2.38-3.45), at low stress (+0.03 %; 95 % CI 3.25-3.32), at peak stress (+1.12 %; 95 % CI 3.45-5.69), or at recovery (+4.06 %; 95 % CI 0.81-8.93). No significant changes in WMSI were observed at any stress levels. GLS and GLSR at rest did not improve. The maximal exercise capacity estimated by metabolic equivalents was not affected by liraglutide. CONCLUSION: In conclusion, liraglutide did not improve the systolic function of the left ventricle during DSE or the exercise capacity in patients with T2D and stable CAD. Clinical Trial Registration http://www.clinicaltrials.gov (unique identifier: NCT01595789). PMID- 27455836 TI - Lower vitamin D status may explain racial disparities in all-cause mortality among younger commercially insured women with incident metastatic breast cancer. PMID- 27455837 TI - Assessment of dual-probe Her-2 fluorescent in situ hybridization in breast cancer by the 2013 ASCO/CAP guidelines produces more equivocal results than that by the 2007 ASCO/CAP guidelines. AB - Dual-probe fluorescence in situ hybridization (D-FISH) is a widely accepted method to determine the gene amplification status of human epidermal growth factor receptor 2 (Her-2). In 2013, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the guidelines on the Her-2 testing for invasive breast cancer (BCa). The interpretation criteria for D-FISH changed accordingly. In this study, we compared the Her-2 FISH statuses based on the 2013 and 2007 ASCO/CAP guidelines in 1931 cases of BCa with Her-2 D-FISH testing at our hospital. We analyzed the clinicopathologic features of cases with equivocal results by the 2013 ASCO/CAP guidelines. Although the guideline update significantly improved the detection rate of Her-2 amplification, it also significantly increased the rate of equivocal results, posing a dilemma for clinical management. The equivocal results had a good reproducibility. The distribution of D-FISH-equivocal cases did not correlate with Her-2 status by immunohistochemistry, suggesting that Her-2 D-FISH equivocality may not reflect Her-2 overexpression. Compared with Her-2-negative cases by D-FISH, Her-2 D-FISH-equivocal cases had higher Ki67 expression, higher histological grade, more frequent lymph node metastasis, and lower estrogen receptor alpha expression, indicating a group of BCa with worse prognosis. The clinical significance of Her-2-equivocal results by D-FISH warrants further investigation. PMID- 27455838 TI - A genome-wide perspective about the diversity and demographic history of seven Spanish goat breeds. AB - BACKGROUND: The main goal of the current work was to infer the demographic history of seven Spanish goat breeds (Malaguena, Murciano-Granadina, Florida, Palmera, Mallorquina, Bermeya and Blanca de Rasquera) based on genome-wide diversity data generated with the Illumina Goat SNP50 BeadChip (population size, N = 176). Five additional populations from Europe (Saanen and Carpathian) and Africa (Tunisian, Djallonke and Sahel) were also included in this analysis (N = 80) for comparative purposes. RESULTS: Our results show that the genetic background of Spanish goats traces back mainly to European breeds although signs of North African admixture were detected in two Andalusian breeds (Malaguena and Murciano-Granadina). In general, observed and expected heterozygosities were quite similar across the seven Spanish goat breeds under analysis irrespective of their population size and conservation status. For the Mallorquina and Blanca de Rasquera breeds, which have suffered strong population declines during the past decades, we observed increased frequencies of large-sized (ROH), a finding that is consistent with recent inbreeding. In contrast, a substantial part of the genome of the Palmera goat breed comprised short ROH, which suggests a strong and ancient founder effect. CONCLUSIONS: Admixture with African goats, genetic drift and inbreeding have had different effects across the seven Spanish goat breeds analysed in the current work. This has generated distinct patterns of genome-wide diversity that provide new clues about the demographic history of these populations. PMID- 27455840 TI - Clinical trial considerations on male contraception and collection of pregnancy information from female partner: update. AB - BACKGROUND: This is an update to our 2012 publication on clinical trial considerations on male contraception and collection of pregnancy information from female partner, after critical review of recent (draft) guidances released by the International Council for Harmonisation [ICH] the Clinical Trial Facilitation Group [CTFG] and the US Food & Drug Administration [FDA]. METHODS: Relevant aspects of the new guidance documents are discussed in the context of male contraception and pregnancy reporting from female partner in clinical trials and the approach is updated accordingly. RESULTS: Genotoxicity The concept of a threshold is introduced using acceptable daily intake/permissible daily exposure to define genotoxicity requirements, hence highly effective contraception in order to avoid conception. The duration for highly effective contraception has been extended from 74 to 90 days from the end of relevant systemic exposure. Teratogenicity Pharmacokinetic considerations to estimate safety margins have been contextualized with regard to over- and underestimation of the risk of teratogenicity transmitted by a vaginal dose. The duration of male contraception after the last dose takes into account the end of relevant systemic exposure if measured, or a default period of five half-lives after last dose for small molecules and two half-lives for immunoglobulins (mAbs). Measures to prevent exposure of the conceptus via a vaginal dose apply to reproductively competent or vasectomized men, unless measurements fail to detect the compound in seminal fluid. CONCLUSION: Critical review of new guidance documents provides a comparison across approaches and resulted in an update of our previous publication. Separate algorithms for small molecules and monoclonal antibodies are proposed to guide the recommendations for contraception for male trial participants and pregnancy reporting from female partners. No male contraception is required if the dose is below a defined threshold for genotoxic concern applicable to small molecules. For men treated with teratogenic mAbs, condom use to prevent exposure of a potentially pregnant partner is unlikely to be recommended because of the minimal female exposure anticipated following a vaginal dose. The proposed safety margins for teratogenicity may evolve with further knowledge. PMID- 27455841 TI - Transcriptomic analyses of the radiation response in head and neck squamous cell carcinoma subclones with different radiation sensitivity: time-course gene expression profiles and gene association networks. AB - BACKGROUND: Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis - not only in head and neck squamous cell carcinoma (HNSCC). The underlying molecular mechanisms are largely unknown. Therefore, systemic in-depth analyses are needed to identify key regulators of radioresistance. In the present study, subclones of the CAL-33 HNSCC cell line with different radiosensitivity were analyzed to identify signaling pathways related to the different phenotypes. METHODS: Subclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL 33 cells. Differences in radiosensitivity were confirmed in colony formation assays. Selected subclones were characterized at the genomic and transcriptomic level by SKY, array CGH, and mRNA-microarray analyses. Time-course gene expression analyses upon irradiation using a natural cubic spline regression model identified temporally differentially expressed genes. Moreover, early and late responding genes were identified. Gene association networks were reconstructed using partial correlation. The Reactome pathway database was employed to conduct pathway enrichment analyses. RESULTS: The characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells. Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling. The analysis of the most important nodes of the gene association networks revealed pathways specific to the radiation response in different phenotypes of radiosensitivity. Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. Also, the expression of endogenous retrovirus ERV3-1in response to irradiation has been observed, and the related gene association networks have been identified. CONCLUSIONS: Our study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity. The resulting networks and pathways associated with the resistant phenotype are of special interest and include the SASP. The radiation-associated expression of ERV3-1 also appears highly attractive for further studies of the molecular mechanisms underlying acquired radioresistance. The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutical intervention. PMID- 27455842 TI - Peri-articular tranexamic acid injection in total knee arthroplasty: a randomized controlled trial. AB - BACKGROUND: Intravenous tranexamic acid (IV TXA) is one of the most effective agents in use for reducing blood loss following total knee arthroplasty (TKA) but its safety regarding venous thromboembolic events (VTEs) remains in question. The direct, local application of TXA may reduce systemic toxicity whilst maintaining good or better bleeding control compared to IV TXA. The topical application of TXA via Hemovac drains has been reported previously with good results. However, there are no data on peri-articular TXA injections during TKA. METHODS: We conducted an open randomized, pilot study of peri-articular vs. IV TXA in 60 patients undergoing TKA. 30 patients received either: (i) 750 mg peri-articular TXA into the medial, lateral capsules and the quadriceps tendon prior to capsular closure and tourniquet deflation (group1), or (ii) 750 mg of IV TXA just before tourniquet deflation. Blood loss in the hemovac drain and hemoglobin (Hb) concentrations were measured at 24 and 48 h (h), and the number of blood transfusions and leg circumference measurements were recorded. RESULTS: At 48 h, the total blood loss in the hemovac drain was 445 mL in group 1 vs. 520 mL in group 2 (p = 0.081) and the corresponding declines in Hb were 1.85 g/dL vs. 1.87 g/dL (p = 0.84). 16 patients received blood transfusions: 9 vs. 7 in groups 1 and 2, respectively (p = 0.928). There were no differences in thigh and lower leg circumferences, pain scores, knee flexion at discharge date and lengths of hospital stay. There were no clinically detected venous thromboembolic events. CONCLUSION: This pilot study has shown promising results for peri-articular TXA during TKA. Additional, larger studies are needed to confirm our results and be powered to show differences in efficacy and safety of peri-articular vs. IV TXA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02829346 . Retrospectively registered: 07/11/2016. PMID- 27455843 TI - Preparation and Characterization of Microemulsions of Myricetin for Improving Its Antiproliferative and Antioxidative Activities and Oral Bioavailability. AB - To improve the bioactivity and oral bioavailability of myricetin, a microemulsion formulation was successfully developed, which consisted of Cremophor RH40 (12%), Tween 80 (6%), Transcutol HP (9%), WL 1349 (18%), and distilled water (55%). With lower content of surfactants and higher stability after dilution and storage for 6 months, the optimized myricetin microemulsion (MYR-ME) could dramatically enhance the solubility of myricetin 1225 times that in water. MYR-ME significantly increased antiproliferative activity against human cancer cell HepG2 without influence on normal cell LO2. It also notably improved the cellular antioxidative activity of myricetin. Furthermore, the oral bioavailability of myricetin was remarkably enhanced by MYR-ME in Sprague-Dawley rats after oral administration, which was 14.43-fold that with myricetin suspension. Therefore, the MYR-ME developed here could be used as a potential carrier for myricetin with substantially enhanced bioactivities and bioavailability and might promote myricetin's future utilization in functional foods and cosmetics. PMID- 27455839 TI - Mitochondria, cholesterol and cancer cell metabolism. AB - Given the role of mitochondria in oxygen consumption, metabolism and cell death regulation, alterations in mitochondrial function or dysregulation of cell death pathways contribute to the genesis and progression of cancer. Cancer cells exhibit an array of metabolic transformations induced by mutations leading to gain-of-function of oncogenes and loss-of-function of tumor suppressor genes that include increased glucose consumption, reduced mitochondrial respiration, increased reactive oxygen species generation and cell death resistance, all of which ensure cancer progression. Cholesterol metabolism is disturbed in cancer cells and supports uncontrolled cell growth. In particular, the accumulation of cholesterol in mitochondria emerges as a molecular component that orchestrates some of these metabolic alterations in cancer cells by impairing mitochondrial function. As a consequence, mitochondrial cholesterol loading in cancer cells may contribute, in part, to the Warburg effect stimulating aerobic glycolysis to meet the energetic demand of proliferating cells, while protecting cancer cells against mitochondrial apoptosis due to changes in mitochondrial membrane dynamics. Further understanding the complexity in the metabolic alterations of cancer cells, mediated largely through alterations in mitochondrial function, may pave the way to identify more efficient strategies for cancer treatment involving the use of small molecules targeting mitochondria, cholesterol homeostasis/trafficking and specific metabolic pathways. PMID- 27455844 TI - Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system. AB - Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer's disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination. PMID- 27455845 TI - Can mental health diagnoses in administrative data be used for research? A systematic review of the accuracy of routinely collected diagnoses. AB - BACKGROUND: There is increasing availability of data derived from diagnoses made routinely in mental health care, and interest in using these for research. Such data will be subject to both diagnostic (clinical) error and administrative error, and so it is necessary to evaluate its accuracy against a reference standard. Our aim was to review studies where this had been done to guide the use of other available data. METHODS: We searched PubMed and EMBASE for studies comparing routinely collected mental health diagnosis data to a reference standard. We produced diagnostic category-specific positive predictive values (PPV) and Cohen's kappa for each study. RESULTS: We found 39 eligible studies. Studies were heterogeneous in design, with a wide range of outcomes. Administrative error was small compared to diagnostic error. PPV was related to base rate of the respective condition, with overall median of 76 %. Kappa results on average showed a moderate agreement between source data and reference standard for most diagnostic categories (median kappa = 0.45-0.55); anxiety disorders and schizoaffective disorder showed poorer agreement. There was no significant benefit in accuracy for diagnoses made in inpatients. CONCLUSIONS: The current evidence partly answered our questions. There was wide variation in the quality of source data, with a risk of publication bias. For some diagnoses, especially psychotic categories, administrative data were generally predictive of true diagnosis. For others, such as anxiety disorders, the data were less satisfactory. We discuss the implications of our findings, and the need for researchers to validate routine diagnostic data. PMID- 27455847 TI - Alterations in the corticotropin-releasing hormone (CRH) neurocircuitry: Insights into post stroke functional impairments. AB - Although it is well accepted that changes in the regulation of the hypothalamic pituitary adrenal (HPA) axis may increase susceptibility to affective disorders in the general population, this link has been less examined in stroke patients. Yet, the bidirectional association between depression and cardiovascular disease is strong, and stress increases vulnerability to stroke. Corticotropin-releasing hormone (CRH) is the central stress hormone of the HPA axis pathway and acts by binding to CRH receptors (CRHR) 1 and 2, which are located in several stress related brain regions. Evidence from clinical and animal studies suggests a role for CRH in the neurobiological basis of depression and ischemic brain injury. Given its importance in the regulation of the neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation to stress, CRH is likely associated in the pathophysiology of post stroke emotional impairments. The goals of this review article are to examine the clinical and experimental data describing (1) that CRH regulates the molecular signaling brain circuit underlying anxiety- and depression-like behaviors, (2) the influence of CRH and other stress markers in the pathophysiology of post stroke emotional and cognitive impairments, and (3) context and site specific interactions of CRH and BDNF as a basis for the development of novel therapeutic targets. This review addresses how the production and release of the neuropeptide CRH within the various regions of the mesocorticolimbic system influences emotional and cognitive behaviors with a look into its role in psychiatric disorders post stroke. PMID- 27455846 TI - Study protocol of the CAREST-trial: a randomised controlled trial on the (cost-) effectiveness of a CBT-based online self-help training for fear of cancer recurrence in women with curatively treated breast cancer. AB - BACKGROUND: One of the most prevalent long-term consequences of surviving breast cancer is fear of cancer recurrence (FCR), which is associated with higher (mental) healthcare costs and lower surveillance rates. The majority of breast cancer survivors report a need for professional help in dealing with FCR. An easy accessible and cost-effective evidence-based psychological intervention for reducing FCR is lacking. In the current study an online self-help training to reduce FCR will be evaluated. In addition, the secondary aim of this study is to identify factors that predict whether women can benefit from the online self-help training or not. METHODS/DESIGN: A multi-centre, parallel-groups, randomised controlled trial will be conducted to evaluate the (cost-) effectiveness of the CAREST-trial. A sample of 454 women with curatively treated breast cancer will be recruited from 8 hospitals in the Netherlands. Participants will be randomised to the intervention or usual care group (1:1). Self-report measures will be completed at baseline, 3 (post-intervention), 9, and 24 months. Primary outcome is FCR severity; secondary outcomes are healthcare costs, health status, and psychological distress. The online tailored self-help training "Less fear after cancer" is based on cognitive behavioural therapy and consists of 2 basic modules (psycho-education; basic principles of cognitive behavioural therapy) and 4 optional modules (rumination; action; relaxation; reassurance) to choose from. Each module consists of an informative part (texts, videos, audio files) and a practical part (exercises). For every patient, the intervention will be available for three months. Personal online support by an e-mail coach is available. DISCUSSION: Online self-help training may be an easy-accessible and cost effective treatment to reduce the impact of FCR at an early stage in a large group of breast cancer survivors. A strength is the 24 months follow-up period in the health economic evaluation. The results of the study will provide information on the possible strengths and benefits of online self-help training for FCR in breast cancer survivors. TRIAL REGISTRATION: This study is registered at the Netherlands Trial Register ( NTR4119 , date registered: August 15, 2013). PMID- 27455848 TI - American Cancer Society questions study claiming increase in metastatic prostate cancer. PMID- 27455849 TI - A nurse-led protocol improves the time to first dose intravenous antibiotics in septic patients post chemotherapy. AB - PURPOSE: Neutropenic sepsis is a time-dependent emergency with early interventions shown to improve outcomes. Broad spectrum intravenous antibiotic administration is the initial therapy in patients with suspected neutropenic sepsis. Compliance with early antibiotic administration in febrile neutropenia patients is poor. Innovations have been trialled to improve the time to first dose intravenous antibiotics in patients with suspected neutropenic sepsis. Consideration of extending first dose intravenous antibiotic prescribing to trained nursing staff may improve performance in this key standard. METHODS: A retrospective analysis was performed at a specialist oncology hospital in the North West of England from January 1st 2015 to January 31st 2016. The nurses on the Medical Admissions Unit (MAU) have been given the responsibility of assessing patients presenting with fever post chemotherapy including prescribing and administering the first dose of intravenous antibiotics with the aim of improving the speed of this intervention. RESULTS: During the study period, 697 patients presented to the MAU with suspected sepsis post chemotherapy. Six hundred seventy two (96.4 %) patients received their first dose of intravenous antibiotics within 60 min of presentation to the MAU. Of this group, 323 (48.1 %) were administered antibiotics within 15 min of arrival. Of the 25 (3.6 %) patients who did not receive antibiotics within 1 h, root cause analysis revealed the reason in 23 (92 %) patients was an inability to ascertain intravenous access. CONCLUSION: Nurse led protocols are an effective, safe, and sustainable method for achieving early antibiotic administration in patients with suspected febrile neutropenia. This is a key component of ensuring improved outcomes for this cohort of patients. PMID- 27455850 TI - Breast cancer and bone metastases: a call for appropriate treatment. AB - PURPOSE: The aim of this study is to provide an overview of the potential barriers to uptake of bone-targeted agents for the prevention of skeletal-related events (SREs) in patients with breast cancer and bone metastases. METHODS: A top line literature review was conducted to identify trends in and barriers to initiating bone-targeted therapy in patients with metastatic breast cancer. RESULTS: The majority of patients with bone metastases that are secondary to breast cancer clearly benefit from treatment with a bone-targeted agent such as the RANK ligand inhibitor denosumab or the bisphosphonate zoledronic acid, because both delay the onset of SREs. Evidence suggests, however, that these agents are not being used in these patients as per European guideline recommendations. CONCLUSIONS: Adoption of a number of behavioral changes may help to overcome barriers to earlier initiation of treatment with bone-targeted agents in these patients. This includes raising awareness of the guidelines that are available for bone-targeted therapies, providing physician and patient education on the appropriate use of these agents, and highlighting to physicians the importance of early treatment and regular monitoring for adverse events. Earlier initiation of treatment should help to reduce the risk of SREs and thus lessen the burden that these debilitating skeletal complications place on patients and healthcare systems. PMID- 27455851 TI - Self-reported oral health and quality of life of postmenopausal breast cancer survivors on aromatase inhibitors and women without cancer diagnoses: a longitudinal analysis. AB - INTRODUCTION: Aromatase inhibitors (AIs) are a well-established component of adjuvant therapy in postmenopausal women with hormone receptor (HR) + early stage breast cancer (BCa). We explored in an 18-month cohort study whether subjective oral health (OH), subjective periodontal health (PH), and oral health-related quality of life (OHRQoL) of postmenopausal BCa survivors on AIs differ from those of women without cancer diagnoses, and whether saliva flow, OH, PH, and OHRQoL are related. METHODS: Data were collected from 29 postmenopausal BCa survivors on AIs and 29 postmenopausal women without cancer diagnoses. Socio-demographic information, OH, PH, and OHRQoL were collected at baseline and 6, 12, and 18 months later. Unstimulated whole saliva volume per 15 min was determined by drooling. RESULTS: The two groups did not differ in background characteristics at baseline. Women on AIs had poorer OH (p = .043), PH (p = .04), and OHRQoL (p = .017), and lower saliva flow rate (p < .001) than control respondents. BCa survivors had the poorest PH at the 18-month visit. Xerostomia was correlated with OH at baseline and with OH and PH at 18 months. However, objective saliva flow rate was not correlated with OH or OHRQoL at this visit. CONCLUSIONS: This study is the first to investigate the effects of AIs on patients' subjective OH, subjective PH, and OHRQoL. The data suggest that women treated with AIs have worse OH, PH, and OHRQoL than women without cancer diagnoses. Interprofessional care is recommended so that women on AIs receive optimal supportive oral care to assure long-term OH and positive OHRQoL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01272570 https://clinicaltrials.gov/ct2/show/NCT01272570 . PMID- 27455852 TI - How to enquire and respond to domestic violence and abuse in sexual health settings. PMID- 27455853 TI - Humoral and cellular immune responses induced by the urease-derived peptide Jaburetox in the model organism Rhodnius prolixus. AB - BACKGROUND: Although the entomotoxicity of plant ureases has been reported almost 20 years ago, their insecticidal mechanism of action is still not well understood. Jaburetox is a recombinant peptide derived from one of the isoforms of Canavalia ensiformis (Jack Bean) urease that presents biotechnological interest since it is toxic to insects of different orders. Previous studies of our group using the Chagas disease vector and model insect Rhodnius prolixus showed that the treatment with Jack Bean Urease (JBU) led to hemocyte aggregation and hemolymph darkening, among other effects. In this work, we employed cell biology and biochemical approaches to investigate whether Jaburetox would induce not only cellular but also humoral immune responses in this species. RESULTS: The findings indicated that nanomolar doses of Jaburetox triggered cation-dependent, in vitro aggregation of hemocytes of fifth-instar nymphs and adults. The use of specific eicosanoid synthesis inhibitors revealed that the cellular immune response required cyclooxygenase products since indomethacin prevented the Jaburetox-dependent aggregation whereas baicalein and esculetin (inhibitors of the lipoxygenases pathway) did not. Cultured hemocytes incubated with Jaburetox for 24 h showed cytoskeleton disorganization, chromatin condensation and were positive for activated caspase 3, an apoptosis marker, although their phagocytic activity remained unchanged. Finally, in vivo treatments by injection of Jaburetox induced both a cellular response, as observed by hemocyte aggregation, and a humoral response, as seen by the increase of spontaneous phenoloxidase activity, a key enzyme involved in melanization and defense. On the other hand, the humoral response elicited by Jaburetox injections did not lead to an increment of antibacterial or lysozyme activities. Jaburetox injections also impaired the clearance of the pathogenic bacteria Staphylococcus aureus from the hemolymph leading to increased mortality, indicating a possible immunosuppression induced by treatment with the peptide. CONCLUSIONS: In our experimental conditions and as part of its toxic action, Jaburetox activates some responses of the immune system of R. prolixus both in vivo and in vitro, although this induction does not protect the insects against posterior bacterial infections. Taken together, these findings contribute to the general knowledge of insect immunity and shed light on Jaburetox's mechanism of action. PMID- 27455855 TI - Routine endoscopic ultrasound in moderate and indeterminate risk patients of suspected choledocholithiasis to avoid unwarranted ERCP: A prospective randomized blinded study. PMID- 27455854 TI - Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (The PATH Study): study protocol for a randomized controlled trial. AB - BACKGROUND: Subcutaneous administration of Ig (SCIg) has gained popularity as an alternative route of administration but has never been rigorously examined in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS/DESIGN: The primary objective of the PATH study (Polyneuropathy and Treatment with Hizentra) is to determine the efficacy of two different doses of SCIg IgPro20 (0.2 g/kg bw or 0.4 g/kg bw) in a 24-week maintenance treatment of CIDP in comparison to placebo. The primary efficacy endpoint will be the proportion of patients who show CIDP relapse (1-point deterioration on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score) or are withdrawn within 24 weeks after randomization for any reason. IVIg-dependent adult patients with definite or probable CIDP according to the European Federation of Neurological Societies/Peripheral Nerve Society who fulfil the inclusion and exclusion criteria will be eligible. Based on sample-size calculation and relapse assumptions in the three arms, a sample size of 58 is needed per arm (overall sample size will be 350, of which 174 will be randomized). All eligible patients will progress through three study periods: an IgG dependency period (<=12 weeks) to select those who are Ig dependent; an IVIg restabilization period (10 or 13 weeks), which will be performed using the 10 % IgPro10 product; and an SC treatment period (24 weeks, followed by a 1-week completion visit after last follow-up). Patients showing IVIg restabilization will be randomized to demonstrate the efficacy of SCIg IgPro20 maintenance treatment over placebo. After completing the study, subjects are eligible to enter a long-term, open label, extension study of 1 year or return to their previous treatment. In case of CIDP relapse during the 24-week SC treatment period, IgPro10 rescue medication will be offered. Safety, tolerability, and patients' preference of Ig administration route will be examined. DISCUSSION: The PATH trial, which started in March 2012, is expected to finish at the end of 2016. The results will increase knowledge about the efficacy, safety, and tolerability of SCIg in maintenance management of CIDP patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01545076 . Registered on 1 March 2012. PMID- 27455856 TI - Racial/ethnic disparities in delayed HIV diagnosis among men who have sex with men, Florida, 2000-2014. AB - Only about 85% of men who have sex with men (MSM) with human immunodeficiency virus (HIV) have been tested for and diagnosed with HIV. Racial/ethnic disparities in HIV risk and HIV care outcomes exist within MSM. We examined racial/ethnic disparities in delayed HIV diagnosis among MSM. Males aged >=13 reported to the Florida Enhanced HIV/AIDS Reporting System 2000-2014 with a reported HIV transmission mode of MSM were analyzed. We defined delayed HIV diagnosis as an AIDS diagnosis within three months of the HIV diagnosis. Multilevel logistic regressions were used to estimate adjusted odds ratios (aOR). Of 39,301 MSM, 27% were diagnosed late. After controlling for individual factors, neighborhood socioeconomic status, and rural-urban residence, non-Latino Black MSM had higher odds of delayed diagnosis compared with non-Latino White MSM (aOR 1.15, 95% confidence interval [CI] 1.08-1.23). Foreign birth compared with US birth was a risk factor for Black MSM (aOR 1.27, 95% CI 1.12-1.44), but a protective factor for White MSM (aOR 0.77, 95% CI 0.68-0.87). Rural residence was a risk for Black MSM (aOR 1.79, 95% CI 1.36-2.35) and Latino MSM (aOR 1.87, 95% CI 1.24-2.84), but not for White MSM (aOR 1.26, 95% CI 0.99-1.60). HIV testing barriers particularly affect non-Latino Black MSM. Social and/or structural barriers to testing in rural communities may be significantly contributing to delayed HIV diagnosis among minority MSM. PMID- 27455857 TI - Implications of the diversity of class I HLA associations in psoriatic arthritis. AB - We sought to validate and extend the findings of a 282 psoriatic arthritis patient cohort from Dublin using a 219 patient cohort from Bath. The central finding of this study was that several structurally unrelated HLA alleles, including B*08:01:01, B*18:01:01, B*27:05:02, B*55:01:01 and C*06:02:01, were found to be significantly associated with particular phenotypic features of psoriatic arthritis, implying that the clinical diagnosis of psoriatic arthritis designates a genetically heterogeneous subset of individuals. Radiographic sacroiliitis was associated with either B*08:01:01, or B*27:05:02 with implications about the role of MHC molecules in an adaptive immune response. There are also implications for psoriatic arthritis diagnostic criteria since some disease features used in the criteria are under genetic control. These findings have important implications for understanding the role of MHC alleles in directing the adaptive immune response to mediate the inflammation responsible for psoriatic arthritis. PMID- 27455858 TI - F(ab')2 fragments of anti-oxidized LDL IgG attenuate vascular inflammation and atherogenesis in diabetic LDL receptor-deficient mice. AB - Considerable evidence is available supporting the atherogenic role of immune complexes (IC) formed by modified forms of LDL and their corresponding antibodies in humans and other species. In this study, we assessed the effect of IgG F(ab')2 fragments of murine anti-mouse oxLDL, which binds oxLDL forming IC that cannot interact with Fcgamma receptors, on the development of atherosclerosis in diabetic LDL receptor-deficient (LDLR-/-) mice. Immunohistochemical study showed that treatment with the F(ab')2 fragments for 8weeks significantly reduced the content of macrophages and interleukin 6 expression in atherosclerotic lesions. Furthermore, histological study showed that treatment with the same F(ab')2 fragments significantly reduced atherosclerotic lesions in diabetic LDLR-/- mice. Taken together, this study demonstrated for the first time that F(ab')2 fragments of anti-oxLDL IgG inhibited vascular inflammation and atherogenesis in diabetic LDLR-/- mice and uncovered a possible new avenue for therapy in patients at high risk to progress to cardiovascular complications. PMID- 27455859 TI - Insights on methotrexate in psoriatic disease. AB - The folic acid analogue methotrexate is used as an anti-neoplastic agent and treatment for inflammatory disorders including psoriasis, dermatomyositis, lupus erythematous, sarcoidosis, and systemic sclerosis. Despite the introduction of newer biologic agents, methotrexate remains a first-line systemic therapy for many patients with disorders of chronic inflammation. Here we briefly describe the current clinical evidence for methotrexate use in psoriatic disease, our current understanding of methotrexate's anti-inflammatory properties, and the future role of methotrexate in the treatment of immune mediated disorders. PMID- 27455860 TI - Polyketides in Aspergillus terreus: biosynthesis pathway discovery and application. AB - The knowledge of biosynthesis gene clusters, production improving methods, and bioactivity mechanisms is very important for the development of filamentous fungi metabolites. Metabolic engineering and heterologous expression methods can be applied to improve desired metabolite production, when their biosynthesis pathways have been revealed. And, stable supplement is a necessary basis of bioactivity mechanism discovery and following clinical trial. Aspergillus terreus is an outstanding producer of many bioactive agents, and a large part of them are polyketides. In this review, we took polyketides from A. terreus as examples, focusing on 13 polyketide synthase (PKS) genes in A. terreus NIH 2624 genome. The biosynthesis pathways of nine PKS genes have been reported, and their downstream metabolites are lovastatin, terreic acid, terrein, geodin, terretonin, citreoviridin, and asperfuranone, respectively. Among them, lovastatin is a well known hypolipidemic agent. Terreic acid, terrein, citreoviridin, and asperfuranone show good bioactivities, especially anticancer activities. On the other hand, geodin and terretonin are mycotoxins. So, biosynthesis gene cluster information is important for the production or elimination of them. We also predicted three possible gene clusters that contain four PKS genes by homologous gene alignment with other Aspergillus strains. We think that this is an effective way to mine secondary metabolic gene clusters. PMID- 27455861 TI - Retinal homeobox promotes cell growth, proliferation and survival of mushroom body neuroblasts in the Drosophila brain. AB - The Drosophila mushroom bodies, centers of olfactory learning and memory in the fly 'forebrain', develop from a set of neural stem cells (neuroblasts) that generate a large number of Kenyon cells (KCs) during sustained cell divisions from embryonic to late pupal stage. We show that retinal homeobox (rx), encoding for an evolutionarily conserved transcription factor, is required for proper development of the mushroom bodies. Throughout development rx is expressed in mushroom body neuroblasts (MBNBs), their ganglion mother cells (MB-GMCs) and young KCs. In the absence of rx function, MBNBs form correctly but exhibit a reduction in cell size and mitotic activity, whereas overexpression of rx increases growth of MBNBs. These data suggest that Rx is involved in the control of MBNB growth and proliferation. Rx also promotes cell cycling of MB-GMCs. Moreover, we show that Rx is important for the survival of MBNBs and Kenyon cells which undergo premature cell death in the absence of rx function. Simultaneous blocking of cell death restores the normal set of MBNBs and part of the KCs, demonstrating that both, impaired proliferation and premature cell death (of MBNBs and KCs) account for the observed defects in mushroom body development. We then show that Rx controls proliferation within the MBNB clones independently of Tailless (Tll) and Prospero (Pros), and does not regulate the expression of other key regulators of MB development, Eyeless (Ey) and Dachshund (Dac). Our data support that the role of Rx in forebrain development is conserved between vertebrates and fly. PMID- 27455863 TI - A retrospective evaluation of the etiology of unilateral vocal fold paralysis over the last 25 years. AB - Previous studies have shown that the etiology of laryngeal paralysis has changed over the last decades, with an increase in the incidence of cases attributable to thyroid surgery. The aim of this study was to evaluate longitudinal changes in the etiology of unilateral vocal fold paralysis (UVFP) in a single institution over the last 25 years. This retrospective study analyzed the etiology of UVFP between 1990 and 2015 by comparing a cohort of patients treated in 1990-1992 with a cohort treated in 2013-2015. The final analysis was based on data concerning 356 patients (38.8 % males; mean age 55.3 +/- 20.4 years): 113 in the 1990-1992 cohort, and 243 in the 2013-2015 cohort. The main cause of UVFP in the population as a whole was thyroidectomy (41.3 %), followed by an idiopathic origin (25.3 %) and thoracic surgery (12.1 %); this was confirmed in both intra-group analyses. There was a statistically significant association between etiology and the sub group periods: the prevalence of post-thyroidectomy UVFP was highly significantly lower in the 2013-2015 cohort (35.4 vs 54.0 %), and the prevalence of idiopathic cases was higher (28.4 vs 18.6 %). Etiology significantly related to gender in both cohorts (p value <=0.001). In the 2013-2015 cohort, there was also a statistically significant relationship between etiology and age classes (p value 0.017), and the left side was more frequently affected than the right (67.1 vs 32.9 %). Our findings document changes in the etiological pattern of UVFP over the last 25 years, with a considerable decrease in post-thyroidectomy UVFP, and a growing predominance of idiopathic and post-thoracic surgery UVFP. PMID- 27455862 TI - Effects of Grape Skin Extract on Age-Related Mitochondrial Dysfunction, Memory and Life Span in C57BL/6J Mice. AB - Dementia contributes substantially to the burden of disability experienced at old age, and mitochondrial dysfunction (MD) was identified as common final pathway in brain aging and Alzheimer's disease. Due to its early appearance, MD is a promising target for nutritional prevention strategies and polyphenols as potential neurohormetic inducers may be strong neuroprotective candidates. This study aimed to investigate the effects of a polyphenol-rich grape skin extract (PGE) on age-related dysfunctions of brain mitochondria, memory, life span and potential hormetic pathways in C57BL/6J mice. PGE was administered at a dose of 200 mg/kg body weight/d in a 3-week short-term, 6-month long-term and life-long study. MD in the brains of aged mice (19-22 months old) compared to young mice (3 months old) was demonstrated by lower ATP levels and by impaired mitochondrial respiratory complex activity (except for mice treated with antioxidant-depleted food pellets). Long-term PGE feeding partly enhanced brain mitochondrial respiration with only minor beneficial effect on brain ATP levels and memory of aged mice. Life-long PGE feeding led to a transient but significant shift of survival curve toward higher survival rates but without effect on the overall survival. The moderate effects of PGE were associated with elevated SIRT1 but not SIRT3 mRNA expressions in brain and liver tissue. The beneficial effects of the grape extract may have been influenced by the profile of bioavailable polyphenols and the starting point of interventions. PMID- 27455864 TI - A proposal for a level for parapharyngeal extension of parotid gland. PMID- 27455865 TI - Differences in mortality among women with breast cancer by income - a register based study in Finland. AB - AIMS: The aim was to assess all-cause and breast cancer mortality by income among women with incident breast cancer and the effect of cancer stage at diagnosis and comorbidity on the differences. METHODS: The 43,439 women (age ?30) diagnosed with breast cancer in 1998-2008 in Finland were monitored using individual-level Cancer Registry data supplemented with data from Finnish health care registers and sociodemographic data. RESULTS: Overall mortality was greater among breast cancer patients of the lowest income group than in the highest one; the hazard ratio (HR) for age and incidence year adjusted all-cause mortality was 1.9 (95% CI 1.8-2.1) and for breast cancer mortality 2.0 (95% CI 1.8-2.2). The women from the lowest income group were over-represented in the breast cancer stage 'distant' (10.1% vs. 3.5% among the highest income group). The presence of comorbidities was more common in patients with the lowest income (at least one comorbidity in 54%) than in the highest (24%). The HR adjusted with stage at presentation and comorbidities was 1.6 (95% CI 1.4-1.7) for all-cause mortality and 1.6 (95% CI 1.4-1.7) for breast cancer mortality. CONCLUSIONS: Tumour stage at diagnosis was more severe among lower income groups, and the presence of comorbidities was more common, although this only accounted for a part of the higher breast cancer mortality in these groups. More information is needed about recognition, diagnosis and treatment of breast cancer to examine whether the socioeconomic differences of breast cancer mortality are related to care. PMID- 27455866 TI - DFT Study on Enzyme Turnover Including Proton and Electron Transfers of Copper Containing Nitrite Reductase. AB - The reaction mechanism of copper-containing nitrite reductase (CuNiR) has been proposed to include two important events, an intramolecular electron transfer and a proton transfer. The two events have been suggested to be coupled, but the order of these events is currently under debate. We investigated the entire enzyme reaction mechanism of nitrite reduction at the T2 Cu site in thermophilic Geobacillus CuNiR from Geobacillus thermodenitrificans NG80-2 (GtNiR) using density functional theory calculations. We found significant conformational changes of His ligands coordinated to the T2 Cu site upon nitrite binding during the catalytic reaction. The reduction potentials and pKa values calculated for the relevant protonation and reduction states show two possible routes, A and B. Reduction of the T2 Cu site in the resting state is followed by endothermic nitrite binding in route A, while exothermic nitrite binding occurs prior to reduction of the T2 Cu site in route B. We concluded that our results support the random-sequential mechanism rather than the ordered mechanism. PMID- 27455868 TI - [Not Available]. PMID- 27455869 TI - [Terbinafine : Drug-induced lupus erythematodes and triggering of psoriatic skin lesions]. AB - Based on the technical information that oral terbinafine must be used with caution in patients with pre-existing psoriasis or lupus erythematosus, the literature was summarized. Terbinafine belongs to the drugs able to induce subcutaneous lupus erythematosus (SCLE)-with a relatively high risk. The clinical picture of terbinafine-induced SCLE may be highly variable and can also include erythema exsudativum multiforme-like or bullous lesions. Thus, differentiation of terbinafine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis may be difficult. Therefore, terbinafine should be prescribed with caution in patients who show light sensitivity, arthralgias, positive antinuclear antibodies or have a history of SLE or SCLE. Case reports include wide-spread, but mostly nonlife threatening courses, which did not require systemic therapy with steroids or antimalarials in every case. Terbinafine is also able to induce or to aggravate psoriasis. The latency period seems to be rather short (<4 weeks). Terbinafine therefore is not first choice if a systemic therapy with antimycotics is indicated in a patient with psoriasis or psoriatic diathesis. Azole derivatives according to the guidelines may be used as an alternative. PMID- 27455871 TI - Formation and Reversible Morphological Transition of Bicontinuous Nanospheres and Toroidal Micelles by the Self-Assembly of a Crystalline-b-Coil Diblock Copolymer. AB - We herein report the formation of two complex nanostructures, toroidal micelles and bicontinuous nanospheres, by the self-assembly of the single structurally simple crystalline-b-coil diblock copolymer poly[bis(trifluoroethoxy)phosphazene] b-poly(styrene), PTFEP-b-PS, in one solvent (THF) and without additives. The nature of these nanostructures in solution was confirmed by DLS and cryo-TEM experiments. The two morphologies are related by means of a new type of reversible morphological evolution, bicontinuous-to-toroidal, triggered by changes in the polymer concentration. WAXS experiments showed that the degree of crystallinity of the PTFEP chains located at the core of the toroids was higher than that in the bicontinuous nanospheres, thus indicating that the final morphology of the aggregates is mostly determined by the ordering of the PTFEP core-forming blocks. PMID- 27455870 TI - PP2A(Cdc55)'s role in reductional chromosome segregation during achiasmate meiosis in budding yeast is independent of its FEAR function. AB - PP2A(Cdc55) is a highly conserved serine-threonine protein phosphatase that is involved in diverse cellular processes. In budding yeast, meiotic cells lacking PP2A(Cdc55) activity undergo a premature exit from meiosis I which results in a failure to form bipolar spindles and divide nuclei. This defect is largely due to its role in negatively regulating the Cdc Fourteen Early Anaphase Release (FEAR) pathway. PP2A(Cdc55) prevents nucleolar release of the Cdk (Cyclin-dependent kinase)-antagonising phosphatase Cdc14 by counteracting phosphorylation of the nucleolar protein Net1 by Cdk. CDC55 was identified in a genetic screen for monopolins performed by isolating suppressors of spo11Delta spo12Delta lethality suggesting that Cdc55 might have a role in meiotic chromosome segregation. We investigated this possibility by isolating cdc55 alleles that suppress spo11Delta spo12Delta lethality and show that this suppression is independent of PP2A(Cdc55)'s FEAR function. Although the suppressor mutations in cdc55 affect reductional chromosome segregation in the absence of recombination, they have no effect on chromosome segregation during wild type meiosis. We suggest that Cdc55 is required for reductional chromosome segregation during achiasmate meiosis and this is independent of its FEAR function. PMID- 27455872 TI - Coastal evacuations by fish during extreme weather events. AB - An increase in the intensity and frequency of extreme events is predicted to occur as a result of climate change. In coastal ecosystems, hurricanes and flooding can cause dramatic changes in water quality resulting in large mortality events in estuarine fauna. Facultative migration behaviors represent a key adaptation by which animals can evacuate ecological catastrophes, but remain poorly studied in marine systems. Here we identify coastal evacuations by otherwise resident riverine striped bass in the Hudson River Estuary, New York, USA, caused by an intense period of tropical storms in autumn 2011. These storms produced record rainfall and high water discharges into the Hudson River Estuary that increased the water level and reduced the water temperature, salinity and dissolved oxygen levels. Striped bass moved out of the estuary, exhibiting novel migration behaviours, that may have been in response to the strong flow and unsuitable conditions. In the months following the storms, some fish demonstrated exploratory trips back to the estuary, which may have been to assess the conditions before returning for the remainder of the winter. Behavioural adaptions to weather events by striped bass and other coastal fishes will depend on maintenance of key population segments and unimpeded evacuation routes. PMID- 27455873 TI - Paradoxical cerebral air embolism causing large vessel occlusion treated with endovascular aspiration. AB - Cerebral air embolism is a dreaded complication of invasive medical procedures. The mainstay of therapy for patients with cerebral air embolism has been hyperbaric oxygen therapy, high flow oxygen therapy, and anticonvulsants. We present a novel therapeutic approach for treatment of cerebral air embolism causing large vessel occlusion, using endovascular aspiration. Our patient developed a cerebral air embolism following sclerotherapy for varicose veins. This caused near total occlusion of the superior division of the M2 segment of the right middle cerebral artery. Symptoms included unilateral paralysis, unintelligible speech, and hemianopia; National Institutes of Health Stroke Scale (NIHSS) on presentation was 16. The air embolism was treated using a distal aspiration technique. Angiography following aspiration showed Thrombolysis in Cerebral Infarction 2B reperfusion. Following aspiration, the patient was re examined; NIHSS at that time was 4. At 1 month follow-up, the modified Rankin Scale score was 1 and NIHSS was 1. Treatment of cerebral air embolism is discussed. PMID- 27455874 TI - Sacroplasty procedural extravasation with high viscosity bone cement: comparing the intraoperative long-axis versus short-axis techniques in osteoporotic cadavers. AB - INTRODUCTION: Percutaneous sacroplasty involves image-guided injection of bone cement for sacral insufficiency fractures to alleviate pain and facilitate mobility. Correct sacral placement of the cement and the risk of cement extravasation present procedural challenges. This study compares the occurrence, number, location, and surface area of high viscosity radiopaque bone cement extravasation via biplane fluoroscopy with Dyna CT between the fluoroscopically guided intraoperative long-axis and short-axis sacroplasty techniques in osteoporotic cadavers. METHODS: Ten osteoporotic cadavers underwent bilateral percutaneous instillation of VertaPlex HV High Viscosity Radiopaque Bone Cement. Long- and short-axis sacroplasty techniques were randomly assigned to zone 1 of the left or right sacral ala of each cadaver. Cement extravasation data were summarized by technique (long-axis vs short-axis) and time period (15-min and 3 hour post-procedure syngo DynaCT scan) in the form of point and CI estimates for the true proportions of cement extravasation. RESULTS: No procedural sacral extravasation differences were observed between the long-axis and short-axis sacroplasty techniques. There were no occurrences of intra-procedural or post procedural cement extravasation at 15 min or 3 hours in association with either the long-axis sacroplasty technique or the short-axis sacroplasty technique. CONCLUSIONS: The long- and short-axis sacroplasty techniques, using high viscosity cement with careful post-procedural positioning, result in no occurrence of cement extravasation in porous osteoporotic cadaver bone. PMID- 27455876 TI - Improving the health and safety of 911 emergency call centre agents: an evaluability assessment of a knowledge transfer strategy. AB - A knowledge transfer (KT) strategy was implemented by the IRSST, an occupational health and safety research institute established in Quebec (Canada), to improve the prevention of psychological and musculoskeletal problems among 911 emergency call centre agents. An evaluability assessment was conducted in which each aspect of the KT approach was documented systematically to determine whether the strategy had the potential to be evaluated in terms of its impact on the targeted population. A review of the literature on KT in occupational health and safety and on the evaluation of such KT programmes, along with the development of a logic model based on documentary analysis and semi-structured interviews with key stakeholders, indicated that the KT strategy was likely to have had a positive impact in the 911 emergency call centre sector. Implications for future research are discussed. PMID- 27455875 TI - Certified DNA Reference Materials to Compare HER2 Gene Amplification Measurements Using Next-Generation Sequencing Methods. AB - The National Institute of Standards and Technology (NIST) Standard Reference Materials 2373 is a set of genomic DNA samples prepared from five breast cancer cell lines with certified values for the ratio of the HER2 gene copy number to the copy numbers of reference genes determined by real-time quantitative PCR and digital PCR. Targeted-amplicon, whole-exome, and whole-genome sequencing measurements were used with the reference material to compare the performance of both the laboratory steps and the bioinformatic approaches of the different methods using a range of amplification ratios. Although good reproducibility was observed in each next-generation sequencing method, slightly different HER2 copy numbers associated with platform-specific biases were obtained. This study clearly demonstrates the value of Standard Reference Materials 2373 as reference material and as a calibrator for evaluating assay performance as well as for increasing confidence in reporting HER2 amplification for clinical applications. PMID- 27455877 TI - Metabolic pathways regulated by gamma-aminobutyric acid (GABA) contributing to heat tolerance in creeping bentgrass (Agrostis stolonifera). AB - gamma-Aminobutyric acid is a non-protein amino acid involved in various metabolic processes. The objectives of this study were to examine whether increased GABA could improve heat tolerance in cool-season creeping bentgrass through physiological analysis, and to determine major metabolic pathways regulated by GABA through metabolic profiling. Plants were pretreated with 0.5 mM GABA or water before exposed to non-stressed condition (21/19 degrees C) or heat stress (35/30 degrees C) in controlled growth chambers for 35 d. The growth and physiological analysis demonstrated that exogenous GABA application significantly improved heat tolerance of creeping bentgrass. Metabolic profiling found that exogenous application of GABA led to increases in accumulations of amino acids (glutamic acid, aspartic acid, alanine, threonine, serine, and valine), organic acids (aconitic acid, malic acid, succinic acid, oxalic acid, and threonic acid), sugars (sucrose, fructose, glucose, galactose, and maltose), and sugar alcohols (mannitol and myo-inositol). These findings suggest that GABA-induced heat tolerance in creeping bentgrass could involve the enhancement of photosynthesis and ascorbate-glutathione cycle, the maintenance of osmotic adjustment, and the increase in GABA shunt. The increased GABA shunt could be the supply of intermediates to feed the tricarboxylic acid cycle of respiration metabolism during a long-term heat stress, thereby maintaining metabolic homeostasis. PMID- 27455878 TI - Collective Influence Algorithm to find influencers via optimal percolation in massively large social media. AB - We elaborate on a linear-time implementation of Collective-Influence (CI) algorithm introduced by Morone, Makse, Nature 524, 65 (2015) to find the minimal set of influencers in networks via optimal percolation. The computational complexity of CI is O(N log N) when removing nodes one-by-one, made possible through an appropriate data structure to process CI. We introduce two Belief Propagation (BP) variants of CI that consider global optimization via message passing: CI propagation (CIP) and Collective-Immunization-Belief-Propagation algorithm (CIBP) based on optimal immunization. Both identify a slightly smaller fraction of influencers than CI and, remarkably, reproduce the exact analytical optimal percolation threshold obtained in Random Struct. Alg. 21, 397 (2002) for cubic random regular graphs, leaving little room for improvement for random graphs. However, the small augmented performance comes at the expense of increasing running time to O(N(2)), rendering BP prohibitive for modern-day big data. For instance, for big-data social networks of 200 million users (e.g., Twitter users sending 500 million tweets/day), CI finds influencers in 2.5 hours on a single CPU, while all BP algorithms (CIP, CIBP and BDP) would take more than 3,000 years to accomplish the same task. PMID- 27455879 TI - 'Protective' silence surrounding AIDS: Reasons and implications of non-disclosure among pregnant women living with HIV in Rio de Janeiro (Brazil). AB - The persistence of stigma surrounding AIDS remains a challenge in the epidemic's fourth decade. Based on qualitative research, this study analyses how pregnant women living with HIV/AIDS (PWLHA) experience and cope with AIDS stigma. A total of 29 semi-structured interviews were conducted with PWLHA focusing on socioeconomic profiles, the contexts in which they discovered HIV infection, experiences with health-care sites and ways of dealing with AIDS-related stigma. We recruited PWLHA at two prevention of mother-to-child transmission sites in Rio de Janeiro, Brazil. The PWLHA's testimony indicates that access to care and treatment has a profound effect on the deconstruction of their understanding of AIDS as a fatal disease. However, fear of AIDS stigma is still predominant. The law guarantees HIV non-disclosure, and women see it as a way to protect themselves from discrimination. We argue, however, that the silence surrounding HIV diagnosis perpetuates the psychosocial and structural mechanisms that reproduce stigma. We conclude that diverse sectors of society, including health care facilities, must be involved in confronting stigma by demystifying AIDS, improving patients' knowledge of their rights, and increasing their access to material and symbolic goods. PMID- 27455882 TI - PR2S2Clust: Patched RNA-seq read segments' structure-oriented clustering. AB - RNA-seq, the next generation sequencing platform, enables researchers to explore deep into the transcriptome of organisms, such as identifying functional non coding RNAs (ncRNAs), and quantify their expressions on tissues. The functions of ncRNAs are mostly related to their secondary structures. Thus by exploring the clustering in terms of structural profiles of the corresponding read-segments would be essential and this fuels in our motivation behind this research. In this manuscript we proposed PR2S2Clust, Patched RNA-seq Read Segments' Structure oriented Clustering, which is an analysis platform to extract features to prepare the secondary structure profiles of the RNA-seq read segments. It provides a strategy to employ the profiles to annotate the segments into ncRNA classes using several clustering strategies. The system considers seven pairwise structural distance metrics by considering short-read mappings onto each structure, which we term as the "patched structure" while clustering the segments. In this regard, we show applications of both classical and ensemble clusterings of the partitional and hierarchical variations. Extensive real-world experiments over three publicly available RNA-seq datasets and a comparative analysis over four competitive systems confirm the effectiveness and superiority of the proposed system. The source codes and dataset of PR2S2Clust are available at the http://biomecis.uta.edu/~ashis/res/PR2S2Clust-suppl/ . PMID- 27455880 TI - Immunization with an SIV-based IDLV Expressing HIV-1 Env 1086 Clade C Elicits Durable Humoral and Cellular Responses in Rhesus Macaques. AB - The design of an effective HIV-1 vaccine remains a major challenge. Several vaccine strategies based on viral vectors have been evaluated in preclinical and clinical trials, with largely disappointing results. Integrase defective lentiviral vectors (IDLV) represent a promising vaccine candidate given their ability to induce durable and protective immune responses in mice after a single immunization. Here, we evaluated the immunogenicity of a SIV-based IDLV in nonhuman primates. Six rhesus monkeys were primed intramuscularly with IDLV-Env and boosted with the same vector after 1 year. A single immunization with IDLV Env induced broad humoral and cellular immune responses that waned over time but were still detectable at 1 year postprime. The boost with IDLV-Env performed at 1 year from the prime induced a remarkable increase in both antibodies and T-cell responses. Antibody binding specificity showed a predominant cross-clade gp120 directed response. Monkeys' sera efficiently blocked anti-V2 and anti-CD4 binding site antibodies, neutralized the tier 1 MW965.26 pseudovirus and mediated antibody-dependent cellular cytotoxicity (ADCC). Durable polyfunctional Env specific T-cell responses were also elicited. Our study demonstrates that an IDLV Env-based vaccine induces functional, comprehensive, and durable immune responses in Rhesus macaques. These results support further evaluation of IDLV as a new HIV 1 vaccine delivery platform. PMID- 27455881 TI - In Situ Pluripotency Factor Expression Promotes Functional Recovery From Cerebral Ischemia. AB - Recovery from ischemic tissue injury can be promoted by cell proliferation and neovascularization. Transient expression of four pluripotency factors (Pou5f1, Sox2, Myc, and Klf4) has been used to convert cell types but never been tested as a means to promote functional recovery from ischemic injury. Here we aimed to determine whether transient in situ pluripotency factor expression can improve neurobehavioral function. Cerebral ischemia was induced by transient bilateral common carotid artery occlusion, after which the four pluripotency factors were expressed through either doxycycline administration into the lateral ventricle in transgenic mice in which the four factors are expressed in a doxycycline inducible manner. Histologic evaluation showed that this transient expression induced the proliferative generation of astrocytes and/or neural progenitors, but not neurons or glial scar, and increased neovascularization with upregulation of angiogenic factors. Furthermore, in vivo pluripotency factor expression caused neuroprotective effects such as increased numbers of mature neurons and levels of synaptic markers in the striatum. Dysplasia or tumor development was not observed. Importantly, neurobehavioral evaluations such as rotarod and ladder walking tests showed that the expression of the four factors dramatically promoted functional restoration from ischemic injury. These results provide a basis for novel therapeutic modality development for cerebral ischemia. PMID- 27455883 TI - Improving the seniors' transition from hospital to the community: a case for intensive geriatric service workers. AB - BACKGROUND: Limited continuity of care, poor communication between healthcare providers, and ineffective self-management are barriers to recovery as seniors transition back to the community following an Emergency Department (ED) visit or hospitalization. The intensive geriatric service worker (IGSW) role is a new service developed in southern Ontario, Canada to address gaps for seniors transitioning home from acute care to prevent rehospitalization and premature institutionalization through the provision of intensive support and follow-up to ensure adherence to care plans, facilitate communication with care providers, and promote self-management. This study describes the IGSW role and provides preliminary evidence of its impact on clients, caregivers and the broader health system. METHODS: This mixed methods evaluation included a chart audit of all clients served, tracking of the achievement of goals for IGSW involvement, and interviews with clients and caregivers and other key informants. RESULTS: During the study period, 632 clients were served. Rates of goal achievement ranged from 25%-87% and in cases where achieved, the extent of IGSW involvement mostly exceeded recommendations. IGSWs were credited with improving adherence with treatment recommendations, increasing awareness and use of community services, and improving self-management, which potentially reduced ED visits and hospitalizations and delayed institutionalization. CONCLUSIONS: The IGSW role has the potential to improve supports for seniors and facilitate more appropriate use of health system resources, and represents a promising mechanism for improving the integration and coordination of care across health sectors. PMID- 27455884 TI - Real-time assessment of nanoparticle-mediated antigen delivery and cell response. AB - Nanomaterials are increasingly being developed for applications in biotechnology, including the delivery of therapeutic drugs and of vaccine antigens. However, there is a lack of screening systems that can rapidly assess the dynamics of nanoparticle uptake and their consequential effects on cells. Established in vitro approaches are often carried out on a single time point, rely on time consuming bulk measurements and are based primarily on populations of cell lines. As such, these procedures provide averaged results, do not guarantee precise control over the delivery of nanoparticles to cells and cannot easily generate information about the dynamics of nanoparticle-cell interactions and/or nanoparticle-mediated compound delivery. Combining microfluidics and nanotechnology with imaging techniques, we present a microfluidic platform to monitor nanoparticle uptake and intracellular processing in real-time and at the single-cell level. As proof-of-concept application, the potential of such a system for understanding nanovaccine delivery and processing was investigated and we demonstrate controlled delivery of ovalbumin-conjugated gold nanorods to primary dendritic cells. Using time-lapse microscopy, our approach allowed monitoring of uptake and processing of nanoparticles across a range of concentrations over several hours on hundreds of single-cells. This system represents a novel application of single-cell microfluidics for nanomaterial screening, providing a general platform for studying the dynamics of cell nanomaterial interactions and representing a cost-saving and time-effective screening tool for many nanomaterial formulations and cell types. PMID- 27455885 TI - The effects of parental education on exercise behavior in childhood and youth: a study in Dutch and Finnish twins. AB - Twin studies have estimated the relative contribution of genes and the environment to variance in exercise behavior and it is known that parental education positively affects exercise levels. This study investigates the role of parental education as a potential modifier of variance in exercise behavior from age 7 to 18 years. The study is based on large datasets from the Netherlands Twin Register (NTR: N = 24 874 twins; surveys around the ages of 7, 10, 12, 14, 16 and 18 years) and two Finnish twin cohorts (FinnTwin12: N = 4399; 12, 14 and 17 years; FinnTwin16: N = 4648; 16, 17 and 18 years). Regular participation in moderate-to-vigorous exercise activities during leisure time was assessed by survey. Parental education was dichotomized ("both parents with a low education" vs "at least one parent with a high education"). The mean in exercise behavior tended to be higher and the variance tended to be lower in children of high educated parents. Evidence for gene-by-environment interaction was weak. To develop successful interventions that specifically target children of low educated parents, the mechanisms causing the mean and variance differences between the two groups should be better understood. PMID- 27455886 TI - Oral Methotrexate in split dose weekly versus oral or parenteral Methotrexate once weekly in Rheumatoid Arthritis: a short-term study. AB - OBJECTIVE: To investigate whether methotrexate (MTX) administered orally to rheumatoid arthritis (RA) patients in split doses at 2-3 days' interval, would result in equal or better efficacy, tolerability and compliance, without increasing toxicity compared to single weekly dose given orally or parenterally. MATERIALS AND METHODS: One hundred and thirty-five patients fulfilling the American College of Rheumatology (ACR) 2010 criteria for RA, on 7.5 mg of MTX weekly orally, with the Simplified Disease Activity Index (SDAI) > 11 were enrolled for a 24-week period. Patients were randomly divided into three groups and were given MTX: Group 1 7.5 mg twice or thrice weekly orally, Group 2 15 mg or 22.5 mg in a single dose weekly orally and Group 3 15 mg or 22.5 mg in a single dose weekly as an intramuscular injection. The primary outcomes were low disease activity (LDA) and mean change in SDAI at week 24, whereas secondary outcomes included remission, adverse events and compliance. RESULTS: At week 24, adherence to treatment was maximum in Group 1, 69% (P = 0.09). In intention-to treat analysis at 24 weeks, Group 1, 49%, Group 2, 36% and Group 3, 47% achieved LDA (P = 0.4). There was significant difference in mean change in SDAI at week 24 from baseline (P = 0.008) among the groups. Group 3 patients were more uncomfortable with the mode of administration of MTX (P = 0.003). There was no significant difference in adverse events. CONCLUSION: Oral split doses of MTX are better than an oral single dose and similar to parenteral MTX in terms of efficacy. PMID- 27455887 TI - Using gene networks in EvoDevo analyses. AB - An intricate web of regulatory relationships between DNA, RNA, proteins and metabolites regulates how organisms achieve form and function. Genome sequencing combined with computational methods has allowed us to look at diverse readouts and generate a comprehensive framework for how molecules generate morphological phenotypes. RNAseq has evolved and proved useful for identifying links between transcription factor activity and transcript abundance, and for the generation of transcriptomes in non-model species through de novo assembly. Gene coexpression networks, combined with differential correlation analysis, offer the most versatile gene interaction exploratory tools, using gene expression patterns to determine potential associations and modularity of gene interactions and the differential associations between networks. Networks incorporating different types of biological data can help reduce the complexity of the entirety of biological information into discrete and interpretable pieces of data that can be the starting point for hypothesis construction and testing. PMID- 27455888 TI - Outcome of a drug-eluting stent in longer below-the-knee lesions in patients with critical limb ischemia. AB - BACKGROUND: The superiority of drug eluting stents versus bare metal stents or balloon angioplasty in the treatment of patients with critical limb ischemia and infrapopliteal lesions has been established. However, only shorter lesions were evaluated. This study was designed to evaluate the immediate and long-term (up to 12 months) outcome of the Xience PrimeTM Everolimus-Eluting Coronary Stent System (Abbott Vascular) in a controlled, prospective, multi-center investigation for long lesions up to 10 cm. METHODS: All patients with critical limb ischemia and long infrapopliteal lesions between 30 and 100 mm, who met the inclusion criteria, were included in this study. The primary endpoint was primary patency at 12 months, defined as absence of restenosis (>=50% stenosis) or occlusion based on quantitative analysis of contrast angiography. RESULTS: Between August 2011 and October 2013, 60 patients were enrolled in this study with a mean lesion length of 47.40+/-25.06 mm (range 2-100 mm). The primary patency rate at 12 months was 75.4%. Freedom from target lesion revascularization was 84.9%. The amputation rate was rare (94.4% freedom from amputation). At the 12-month follow up time point, a total of 36 out of 42 (85.7%) patients improved in their Rutherford classification by at least 1 class. CONCLUSIONS: The use of everolimus eluting stents in longer infrapopliteal lesions in the treatment of critical limb ischemia is safe and effective with a comparable primary patency, freedom from target lesion revascularization and amputation free survival as in short lesions. PMID- 27455889 TI - Meat proteins had different effects on oligopeptide transporter PEPT1 in the small intestine of young rats. AB - The peptide transporter 1 (PEPT1) in the apical membrane of enterocytes is the central mechanism for regulating the absorption of di- and tripeptides. Dietary proteins may affect PEPT1 abundance and peptide absorption. The present study aimed to characterize changes in PEPT1 mRNA and PEPT1 protein levels in the duodenum and jejunum of young rats after 7-day diet intervention with casein (reference), soy, beef, pork, chicken and fish proteins and further evaluate the impact on the epithelial absorption capacity. RT-PCR and western blot analyses showed that: (1) PEPT1 protein level in duodenum was higher (p < 0.05) for soy protein group than that for casein group. However, no difference was observed in jejunal PEPT1 protein level between any two diet groups (p > 0.05). The soy protein group had lower crypt depth and higher V/C ratio in the jejunum (p < 0.05). (2) PEPT1 mRNA levels were lower (p < 0.05) in rat duodenum and jejunum in pork, chicken and fish protein groups, whose trend was contrary to the results of jejunual histological observation with lower crypt depth, greater villus height and higher V/C ratio. In conclusion, different meat proteins alter distinct PEPT1 expression level and absorption capacity as reflected by gut morphology in small intestine. PMID- 27455891 TI - Metal-Support Cooperative Catalysts for Environmentally Benign Molecular Transformations. AB - Metal-support cooperative catalysts have been developed for sustainable and environmentally benign molecular transformations. The active metal centers and supports in these catalysts could cooperatively activate substrates, resulting in high catalytic performance for liquid-phase reactions under mild conditions. These catalysts involved hydrotalcite-supported gold and silver nanoparticles with high catalytic activity for organic reactions such as aerobic oxidation, oxidative carbonylation, and chemoselective reduction of epoxides to alkenes and nitrostyrenes to aminostyrenes using alcohols and CO/H2 O as reducing reagents. This high catalytic performance was due to cooperative catalysis between the metal nanoparticles and basic sites of the hydrotalcite support. To increase the metal-support cooperative effect, core-shell nanostructured catalysts consisting of gold or silver nanoparticles in the core and ceria supports in the shell were designed. These core-shell nanocomposite catalysts were effective for the chemoselective hydrogenation of nitrostyrenes to aminostyrenes, unsaturated aldehydes to allyl alcohols, and alkynes to alkenes using H2 as a clean reductant. In addition, these solid catalysts could be recovered easily from the reaction mixture by simple filtration, and were reusable with high catalytic activity. PMID- 27455892 TI - Transplantation: Increasing the use of available deceased donor kidneys. PMID- 27455890 TI - Effects of Lead and Mercury on Sulfate-Reducing Bacterial Activity in a Biological Process for Flue Gas Desulfurization Wastewater Treatment. AB - Biological sulfate-reducing bacteria (SRB) may be effective in removing toxic lead and mercury ions (Pb(II) and Hg(II)) from wet flue gas desulfurization (FGD) wastewater through anaerobic sulfite reduction. To confirm this hypothesis, a sulfite-reducing up-flow anaerobic sludge blanket reactor was set up to treat FGD wastewater at metal loading rates of 9.2 g/m(3)-d Pb(II) and 2.6 g/m(3)-d Hg(II) for 50 days. The reactor removed 72.5 +/- 7% of sulfite and greater than 99.5% of both Hg(II) and Pb(II). Most of the removed lead and mercury were deposited in the sludge as HgS and PbS. The contribution of cell adsorption and organic binding to Pb(II) and Hg(II) removal was 20.0 +/- 0.1% and 1.8 +/- 1.0%, respectively. The different bioavailable concentration levels of lead and mercury resulted in different levels of lethal toxicity. Cell viability analysis revealed that Hg(II) was less toxic than Pb(II) to the sludge microorganisms. In the batch tests, increasing the Hg(II) feeding concentration increased sulfite reduction rates. In conclusion, a sulfite-reducing reactor can efficiently remove sulfite, Pb(II) and Hg(II) from FGD wastewater. PMID- 27455893 TI - Prostate cancer: A step to identifying men at high risk of metastatic disease. PMID- 27455895 TI - Polypyrrole/Alginate Hybrid Hydrogels: Electrically Conductive and Soft Biomaterials for Human Mesenchymal Stem Cell Culture and Potential Neural Tissue Engineering Applications. AB - Electrically conductive biomaterials that can efficiently deliver electrical signals to cells or improve electrical communication among cells have received considerable attention for potential tissue engineering applications. Conductive hydrogels are desirable particularly for neural applications, as they can provide electrical signals and soft microenvironments that can mimic native nerve tissues. In this study, conductive and soft polypyrrole/alginate (PPy/Alg) hydrogels are developed by chemically polymerizing PPy within ionically cross linked alginate hydrogel networks. The synthesized hydrogels exhibit a Young's modulus of 20-200 kPa. Electrical conductance of the PPy/Alg hydrogels could be enhanced by more than one order of magnitude compared to that of pristine alginate hydrogels. In vitro studies with human bone marrow-derived mesenchymal stem cells (hMSCs) reveal that cell adhesion and growth are promoted on the PPy/Alg hydrogels. Additionally, the PPy/Alg hydrogels support and greatly enhance the expression of neural differentiation markers (i.e., Tuj1 and MAP2) of hMSCs compared to tissue culture plate controls. Subcutaneous implantation of the hydrogels for eight weeks induces mild inflammatory reactions. These soft and conductive hydrogels will serve as a useful platform to study the effects of electrical and mechanical signals on stem cells and/or neural cells and to develop multifunctional neural tissue engineering scaffolds. PMID- 27455896 TI - Mitochondrial function, ornamentation, and immunocompetence. AB - Understanding the mechanisms that link ornamental displays and individual condition is key to understanding the evolution and function of ornaments. Immune function is an aspect of individual quality that is often associated with the expression of ornamentation, but a general explanation for why the expression of some ornaments seems to be consistently linked to immunocompetence remains elusive. We propose that condition-dependent ornaments may be linked to key aspects of immunocompetence through co-dependence on mitochondrial function. Mitochondrial involvement in immune function is rarely considered outside of the biomedical literature, but the role of mitochondria as the primary energy producers of the cell and the centres of biosynthesis, the oxidative stress response, and cellular signalling place them at the hub of a variety of immune pathways. A promising new mechanistic explanation for correlations between a wide range of ornamental traits and the properties of individual quality is that mitochondrial function may be the 'shared pathway' responsible for links between ornament production and individual condition. Herein, we first review the role of mitochondria as both signal transducers and metabolic regulators of immune function. We then describe connections between hormonal pathways and mitochondria, with implications for both immune function and the expression of ornamentation. Finally, we explore the possibility that ornament expression may link directly to mitochondrial function. Considering condition-dependent traits within the framework of mitochondrial function has the potential to unify central tenets within the study of sexual selection, eco-immunology, oxidative stress ecology, stress and reproductive hormone biology, and animal physiology. PMID- 27455894 TI - Nocturia: aetiology and treatment in adults. AB - Nocturia is an extremely common condition that has major sequelae for affected patients. Through disruption of sleep, nocturia impairs quality of life and worsens health outcomes, and is associated with a variety of morbidities including diabetes, coronary artery disease, obstructive sleep apnoea, obesity, metabolic syndrome, and depression. Unsurprisingly, several studies have also linked nocturia with reduced survival. Nocturia is not simply a consequence of lower urinary tract disease; rather, it is a multifactorial disorder that is often a manifestation of an underlying renal or systemic disease. Through the use of the frequency volume chart, clinicians can accurately quantify nocturia and determine its aetiology. Evaluation of quality of life and sleep using simple measures is essential in order to assess the impact of nocturia on a patient. Numerous treatment options for nocturia exist, but most are associated with minor benefit or lack sufficient evidence supporting their use. By systematically analysing an individual's causes of nocturia, clinicians can design appropriate treatment strategies to most effectively treat this condition. PMID- 27455898 TI - All-memristive neuromorphic computing with level-tuned neurons. AB - In the new era of cognitive computing, systems will be able to learn and interact with the environment in ways that will drastically enhance the capabilities of current processors, especially in extracting knowledge from vast amount of data obtained from many sources. Brain-inspired neuromorphic computing systems increasingly attract research interest as an alternative to the classical von Neumann processor architecture, mainly because of the coexistence of memory and processing units. In these systems, the basic components are neurons interconnected by synapses. The neurons, based on their nonlinear dynamics, generate spikes that provide the main communication mechanism. The computational tasks are distributed across the neural network, where synapses implement both the memory and the computational units, by means of learning mechanisms such as spike-timing-dependent plasticity. In this work, we present an all-memristive neuromorphic architecture comprising neurons and synapses realized by using the physical properties and state dynamics of phase-change memristors. The architecture employs a novel concept of interconnecting the neurons in the same layer, resulting in level-tuned neuronal characteristics that preferentially process input information. We demonstrate the proposed architecture in the tasks of unsupervised learning and detection of multiple temporal correlations in parallel input streams. The efficiency of the neuromorphic architecture along with the homogenous neuro-synaptic dynamics implemented with nanoscale phase change memristors represent a significant step towards the development of ultrahigh-density neuromorphic co-processors. PMID- 27455897 TI - Layer 3 Excitatory and Inhibitory Circuitry in the Prefrontal Cortex: Developmental Trajectories and Alterations in Schizophrenia. AB - Convergent evidence suggests that schizophrenia is a disorder of neurodevelopment with alterations in both early and late developmental processes hypothesized to contribute to the disease process. Abnormalities in certain clinical features of schizophrenia, such as working memory impairments, depend on distributed neural circuitry including the dorsolateral prefrontal cortex (DLPFC) and appear to arise during the protracted maturation of this circuitry across childhood and adolescence. In particular, the neural circuitry substrate for working memory in primates involves the coordinated activity of excitatory pyramidal neurons and a specific population of inhibitory gamma-aminobutyric acid neurons (i.e., parvalbumin-containing basket cells) in layer 3 of the DLPFC. Understanding the relationships between the normal development of-and the schizophrenia-associated alterations in-the DLPFC circuitry that subserves working memory could provide new insights into the nature of schizophrenia as a neurodevelopmental disorder. Consequently, we review the following in this article: 1) recent findings regarding alterations of DLPFC layer 3 circuitry in schizophrenia, 2) the developmental refinements in this circuitry that occur during the period when the working memory alterations in schizophrenia appear to arise and progress, and 3) how various adverse environmental exposures could contribute to developmental disturbances of this circuitry in individuals with schizophrenia. PMID- 27455900 TI - Ameliorating effects of 1,8-cineole on LPS-induced human umbilical vein endothelial cell injury by suppressing NF-kappaB signaling in vitro. AB - 1,8-Cineole (also known as eucalyptol) is a monoterpene that occurs naturally in many aromatic plants, 1,8-cineole has been reported to ameliorate dysfunction of endothelial cells. However, the mechanism of action of 1,8-cineole is incompletely understood. We investigated the protective effect of 1,8-cineole on lipopolysaccharide (LPS)-induced human umbilical vein endothelial cell (HUVEC) injury and the underlying mechanisms. HUVECs were preincubated with 1,8-cineole for 1.5h, then exposed to LPS for 12h. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and lactate dehydrogenase leakage assays showed 1,8 cineole reduced LPS-induced HUVEC injury significantly. Results from enzyme linked immunosorbent assays revealed that 1,8-cineole suppressed LPS-induced secretion of interleukin-6 and interleukin-8, and recovered nitric oxide to normal levels. 1,8-Cineole decreased phosphorylation of nuclear factor-kappa B (NF-kappaB) p65 and expression of inducible nitric oxide synthase, and simultaneously improved protein levels of endothelial nitric oxide synthase. Immunofluorescence confirmed 1,8-cineole moderates nuclear translocation of NF kappaB. These results suggest that 1,8-cineole ameliorates HUVEC dysfunction significantly, and that this effect at least involves NF-kappaB suppression. PMID- 27455899 TI - Attention deficit hyperactivity disorder symptoms, type of offending and recidivism in a prison population: The role of substance dependence. AB - BACKGROUND: It is unclear whether adult offenders with a history of attention deficit hyperactivity disorder (ADHD) are more likely to re-offend, and if so, in any specific offences. AIM: This study aimed to examine correlates of childhood ADHD symptoms among prisoners. METHODS: A randomly selected sample of 1179 participants from the adult sentenced population of Puerto Rico (USA) reported their history of violent and non-violent offences, age of first arrest and re offending. Participants completed retrospective measures of ADHD and a diagnostic interview for substance use disorders. RESULTS: Self-reported ADHD was associated with age of first arrest, a number of violent and non-violent offences and re offending. The association with any non-violent offending was explained statistically by substance use disorders and other psychosocial covariates. ADHD was independently associated with being under 15 years of age at first arrest and with re-offending. CONCLUSIONS: Although some associations between ADHD and offending may be accounted for by co-morbidity with substance use disorders, early onset of offending and repeated violent offending appear to be directly related to ADHD. Criminal justice policies should, therefore, incorporate ADHD screening accompanied by appropriate rehabilitation programmes when such neurodevelopmental disorder is identified. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27455901 TI - Effects of K(+) channel openers on spontaneous action potentials in detrusor smooth muscle of the guinea-pig urinary bladder. AB - The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10MUM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM). A higher concentration of NS1619 (30MUM) hyperpolarized the membrane and abolished action potential firing. NS309 (10MUM) and SKA31 (100MUM), small conductance Ca(2+)-activated K(+) (SK) channel openers, dramatically increased the duration of the after-hyperpolarization and then abolished action potential firing in an apamin (100nM)-sensitive manner. Flupirtine (10MUM), a Kv7 channel opener, inhibited action potential firing without hyperpolarizing the membrane in a manner sensitive to XE991 (10MUM), a Kv7 channel blocker. BRL37344 (10MUM), a beta3-adrenceptor agonist, or rolipram (10nM), a phosphodiesterase 4 inhibitor, also inhibited action potential firing. A higher concentration of rolipram (100nM) hyperpolarized the DSM and abolished the action potentials. IbTX (100nM) prevented the rolipram-induced blockade of action potentials but not the hyperpolarization. BK and Kv7 channels appear to predominantly contribute to the stabilization of DSM excitability. Spare SK channels could be pharmacologically activated to suppress DSM excitability. BK channels appear to be involved in the cyclic AMP-induced inhibition of action potentials but not the membrane hyperpolarization. PMID- 27455902 TI - Extracellular matrix scaffolds as a platform for kidney regeneration. AB - Chronic and end stage renal disease (ESRD) have reached pandemic levels and pose a substantial public health burden. Unfortunately, available therapies lack efficacy in preventing progression to its end stage phase. Regenerative medicine promises to restore function of diseased organs among which the kidney, through two possible approaches: firstly, the maximization of the innate ability of tissues to repair or regenerate following injury; secondly, the ex vivo bio fabrication of the organ in question. When regenerative medicine is applied to the setting of chronic or ESRD, it is intuitive that endeavors to improve renal repair, promote nephrogenesis in damaged kidneys, or the de novo engineering of transplantable kidneys, could have a major impact on the current management of this pandemic. Among the different regenerative medicine technologies currently under development, cell-on-scaffold seeding technology (CSST) - involving cells seeded throughout supporting scaffold structures made from biomaterials - is the most favorable candidate in the context of realistic clinical application. In this review, we outline and describe current investigations taking place in the field of CSST as it pertains to the restoration of kidney function. PMID- 27455903 TI - Gene based therapies for kidney regeneration. AB - In this review we provide an overview of the expanding molecular toolbox that is available for gene based therapies and how these therapies can be used for a large variety of kidney diseases. Gene based therapies range from restoring gene function in genetic kidney diseases to steering complex molecular pathways in chronic kidney disorders, and can provide a treatment or cure for diseases that otherwise may not be targeted. This approach involves the delivery of recombinant DNA sequences harboring therapeutic genes to improve cell function and thereby promote kidney regeneration. Depending on the therapy, the recombinant DNA will express a gene that directly plays a role in the function of the cell (gene addition), that regulates the expression of an endogenous gene (gene regulation), or that even changes the DNA sequence of endogenous genes (gene editing). Some interventions involve permanent changes in the genome whereas others are only temporary and leave no trace. Efficient and safe delivery are important steps for all gene based therapies and also depend on the mode of action of the therapeutic gene. Here we provide examples on how the different methods can be used to treat various diseases, which technologies are now emerging (such as gene repair through CRISPR/Cas9) and what the opportunities, perspectives, potential and the limitations of these therapies are for the treatment of kidney diseases. PMID- 27455904 TI - Larvicidal Activity of Steroidal Saponins from Dracaena arborea on Aedes albopictus. AB - INTRODUCTION: Development of new and improved mosquito control methods, that are economically sustainable and effective, is a critical requirement in the management of vector-borne epidemic diseases. Aedes albopictus is one of the main vectors of various important pathogens in the tropics, which now have the potential to also spread in temperate regions, owing to the environmental and climate changes in act. MATERIALS AND METHODS: We report about the isolation of steroidal saponins from Dracaena arborea by fractionation followed by column separation. The obtained fractions and/or pure compounds were tested by biological essays for their insecticidal activity against A. albopictus larvae. RESULTS: Various compounds were found to exert larvicidal effects. In specific, spiroconazole A demonstrated the best insecticidal activity, showing LT50 value of 57.23 hours at 25 ppm. DISCUSSION: We finally discuss about the value of this finding in the context of the present strategies of Integrated Mosquito Management. PMID- 27455905 TI - Potential Therapeutic Effects of Oleuropein Aglycone in Alzheimer's Disease. AB - Alzheimer's disease (AD) is an age-associated neurodegenerative amyloid disease and is considered a social and clinical problem the last decades, particularly in the Western countries. Amyloid diseases are characterized by the deposition of typically aggregated protein/peptides in tissues that are associated with brain degeneration and progressive cognitive impairment. The amyloid plaques and neurofibrillary tangles arise as a result of self-assembly into fibrillar material of amyloid-beta protein and hyperphosphorylated tau, respectively. Moreover, mounting evidence shows that oxidative and nitrosative stress plays a central role in the pathogenesis of neurodegenerative disorders such as AD. Oleuropein belongs to a specific group of polyphenols, the secoiridoids, which are abundant in Oleaceae. Oleuropein aglycone is abundant in extra virgin olive oil and it is generated as a product of a glucosidase released when olive fruits are crushed. This secoiridoid compound has radical-scavenging activity and antioxidative effects and it is considered a promising target to prevent amyloid toxicity as an inhibitor of the oligomer nucleation and growth. The neuroprotective and antioxidant effects of flavonoids have been found to strongly depend on their structure and functional groups. Oleuropein aglycone counteracts amyloid aggregation and toxicity affecting different pathways: amyloid precursor protein processing, amyloid-beta peptide and tau aggregation, autophagy impairment, and neuroinflammation. In the current work, available literature on oleuropein aglycone effects as antioxidant and inhibitor of amyloid deposits in AD is reviewed. Moreover, we discuss the chemistry, food sources and bioavailability of oleuropein aglycone. PMID- 27455906 TI - Acute systolic heart failure and uncontrolled hypertension: what is the missing link? AB - Pheochromocytoma is a rare tumor in adults, with an estimated annual incidence of 0.8 per 100,000 persons. Cardiomyopathy is an uncommon presentation of such a rare disease. Serious cardiovascular complications of these tumors are related to potent effects of secreted catecholamines. The mechanism of pheochromocytoma related cardiomyopathy is not well understood but it is likely due to the effect of excess catecholamines and their oxidation products which have been found to have a direct toxic effect on the myocardium. We describe below a case of a 70 year old female with uncontrolled hypertension and new onset acute systolic heart failure, who on further evaluation was noted to have pheochromocytoma-related cardiomyopathy. Pheochromocytoma should be strongly considered in the differential diagnosis of non-ischemic cardiomyopathy for a patient with elevated blood pressures relative to severity of cardiac dysfunction. PMID- 27455907 TI - Characteristics of infants exposed to maternal tuberculosis and chemoprophylaxis using 3 months of isoniazid and rifampicin. AB - BACKGROUND: Although the clinical features of infants with congenital tuberculosis (TB) are well established, the features of infants exposed to TB in utero including those who are non-infected, are not well reported. TB-exposed infants are at risk of developing TB post-delivery, and chemoprophylaxis, usually isoniazid, is therefore recommended. Isoniazid/rifampicin combined is an alternative, but little is known about its effectiveness. OBJECTIVE: To determine the clinical features of infants exposed to TB in utero and the proportion who develop TB infection and disease despite chemoprophylaxis with a 3-month course of isoniazid/rifampicin. METHODS: This was a retrospective review of TB-infected women and their infants between 2007 and 2010. Features of mothers and infants at delivery, and follow-up of infants after completion of isoniazid/rifampicin are described. RESULTS: Eighty-eight infants born to 86 TB-infected women were studied. TB diagnosis was made peri-partum in 24.4% of women, and only 46.2% of those diagnosed ante-partum were on anti-TB treatment for >2 months. Human immunodeficiency virus (HIV) was positive in 97.7% of the TB-infected women and in 74.6% the CD4 count was <200 cells/mm3. Fifty-six (63.6%) infants had a low birthweight (LBW) and 45 (51.2%) were preterm. Mycobacterial culture was positive in four (4.5%) infants (three were also smear-positive) and none was diagnosed with TB on clinical or radiological findings only. At 3-month follow-up, 17 (20.2%) defaulted, and, of 67 who returned, seven (10%) did not return for tuberculin test reading, but one of 60 (1.7%) tested positive. Five infants (7.2%) were HIV PCR-positive at 6 weeks and four of their mothers were on HAART. CONCLUSION: The majority of TB-exposed infants were born to mothers with TB/HIV co-infection, and a high proportion were pre-term and of low birthweight. Although the high attrition rate made it difficult to assess the effectiveness of chemoprophylaxis with isoniazid/rifampicin, only one of the 60 infants who completed follow-up to 3 months was found to have tuberculous infection. PMID- 27455909 TI - Identification and Expression Profile of the Gonadotropin-Releasing Hormone Receptor in Common Chinese Cuttlefish, Sepiella japonica. AB - Gonadotropin-releasing hormone (GnRH) plays a vital role in the regulation of reproduction through interaction with a specific receptor (the GnRH receptor). In this study, the GnRH receptor gene from the cuttlefish Sepiella japonica (SjGnRHR) was identified and characterized. The cloned full-length SjGnRHR cDNA was 1,468 bp long and contained a 1,029 bp open reading frame encoding 342 amino acid residues, 8 bp of 5' untranslated regions (UTR), and 431 bp of 3' UTR. The putative protein was predicted to have a molecular weight of 38.75 kDa and an isoelectric point of 9.47. In addition, this protein was identified as belonging to the rhodopsin-type (class A) G protein-coupled receptor family. The predicted amino acid sequence contained two N-linked glycosylation sites and 18 phosphorylation sites. Multiple sequence alignment, phylogenetic tree analysis, and three-dimensional structure modeling were conducted to clarify SjGnRHR bioinformatics characteristics. In vitro SjGnRHR expression was carried out using HEK293 cells and the pEGFP-N1 plasmid, to verify the transmembrane properties of this protein. The interaction between the S. japonica GnRH receptor and its ligand was clarified using internalization analysis. SjGnRHR transcriptional quantification confirmed the wide distribution of SjGnRHR in various S. japonica mature tissues. In addition, the transcriptional profile of SjGnRHR in the female brain and ovary during gonadal development was analyzed. Results indicate that GnRHR may be involved in diverse S. japonica physiological functions, especially in the control of reproduction. PMID- 27455910 TI - Primary pancreatic leiomyosarcoma with metastasis to the liver diagnosed by endoscopic ultrasound-guided fine needle aspiration and fine needle biopsy: A Case Report and Review of Literature. AB - Primary pancreatic leiomyosarcomas are rare tumors of the pancreas that are usually diagnosed after resection or by biopsy. One case in the literature has utilized endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology. We report a second case of a primary pancreatic leiomyosarcoma that yielded diagnostic material on EUS-FNA cytology. A 72-year-old female presented with 3-4 months of abdominal pain. A CT scan showed a large heterogeneous, lobulated pancreatic head and uncinate mass and multiple hypoattenuating liver lesions. An EUS-FNA was performed on one of the liver lesions with a 25-gauge needle, yielding an adequate sample with lesional cells. The initial read was a spindle cell neoplasm. A subsequent endoscopic ultrasound-guided fine needle biopsy with a 22-gauge needle was performed on the pancreatic head mass to rule out two primaries and to provide tissue for a mitotic index in the case of gastrointestinal tumor. Both the cell block of the EUS-FNA and the core biopsy were equally cellular and showed interlacing spindle cells that stained positive for SMA and negative for DOG-1, CD 117, and CD34. In addition, the core biopsy of the pancreas stained positive for Desmin. A diagnosis of a primary pancreatic leiomyosarcoma was made and the patient was started on systemic chemotherapy. Primary pancreatic leiomyosarcomas are rare pancreatic tumors that may yield diagnostic material by EUS-FNA with a 25-gauge needle. Diagn. Cytopathol. 2016;44:1070-1073. (c) 2016 Wiley Periodicals, Inc. PMID- 27455911 TI - Scattering effect of the high-index dielectric nanospheres for high performance hydrogenated amorphous silicon thin-film solar cells. AB - Dielectric nanosphere arrays are considered as promising light-trapping designs with the capability of transforming the freely propagated sunlight into guided modes. This kinds of designs are especially beneficial to the ultrathin hydrogenated amorphous silicon (a-Si:H) solar cells due to the advantages of using lossless material and easily scalable assembly. In this paper, we demonstrate numerically that the front-sided integration of high-index subwavelength titanium dioxide (TiO2) nanosphere arrays can significantly enhance the light absorption in 100 nm-thick a-Si:H thin films and thus the power conversion efficiencies (PCEs) of related solar cells. The main reason behind is firmly attributed to the strong scattering effect excited by TiO2 nanospheres in the whole waveband, which contributes to coupling the light into a-Si:H layer via two typical ways: 1) in the short-waveband, the forward scattering of TiO2 nanospheres excite the Mie resonance, which focuses the light into the surface of the a-Si:H layer and thus provides a leaky channel; 2) in the long-waveband, the transverse waveguided modes caused by powerful scattering effectively couple the light into almost the whole active layer. Moreover, the finite-element simulations demonstrate that photocurrent density (Jph) can be up to 15.01 mA/cm(2), which is 48.76% higher than that of flat system. PMID- 27455912 TI - Dietary management, husbandry, and body weights of African elephants (Loxodonta africana) during successful pregnancies at Disney's Animal Kingdom. AB - Successful pregnancy in African elephants is influenced by biological and environmental factors. For managed elephants many of these factors are set directly or indirectly by their human care takers, including nutrition and husbandry. While African elephants often struggle to conceive and produce healthy offspring under human care, Disney's Animal Kingdom (DAK) has effectively managed six gestations to fruition in three cows. Despite differences between mothers in terms of BW and growth curves during gravidity, each pregnancy successfully resulted in the birth of a healthy calf. Body weight (BW) gain during pregnancy ranged from 245 to 558 kg. Obesity in elephants is associated with increased occurrence of dystocia and mortality of the fetus and mother, hence understanding normal weight gains is an integral concept. Diet (dry matter basis) included high levels of fiber throughout pregnancies (60-70% neutral detergent fiber), vitamin E supplementation (116-214 mg/kg diet of alpha-tocopherol), as well as low levels of starch (2.5-5.1%) and crude fat (1.9-2.4%). Caretaker directed exercise during pregnancy at DAK served to prevent ventral edema, and increase muscle tone to prepare cows for parturition. Demonstrating techniques for effective care of pregnant females, as well as normal growth curves and fluctuations under ex situ conditions are necessary for future positive outcomes. Ensuring reproductive success through proper husbandry and nutrition are a key to long-term conservation of elephants. Zoo Biol. 35:574-578, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27455913 TI - Fear of flying: Relying on the absence of organic disease in functional somatic symptoms. PMID- 27455914 TI - A systematic review and meta-analysis of the percentage of revised diagnoses in functional somatic symptoms. AB - BACKGROUND: Functional somatic symptoms (FSS) are bodily complaints of unclear etiology, which are (currently) not fully explained by well-recognized somatic pathology. Doctors are often hesitant to diagnose FSS, due to the risk to miss a somatic disease. The purpose of this study is to review available literature on the percentage of patients diagnosed with FSS reported to have an underlying somatic disease that explains their symptoms previously labeled as FSS. METHODS: We performed a systematic search of Medline, Embase and PsycINFO databases and reference lists of selected articles. We included studies published between January 1980 and July 2014 without language restrictions. Studies that measured the percentage of underlying somatic diseases after a diagnostic evaluation or naturalistic follow-up period in adult patients initially diagnosed with FSS were included. As primary outcome measure the weighted percentage of revised diagnoses was calculated using meta-analyses. RESULTS: Six diagnostic evaluation studies (total N=1804 patients) and 16 follow-up studies (total N=2440 patients) were included. The percentage of revised diagnosis in patients initially diagnosed with FSS was 8.8% (95% CI 1.0 to 22.2, p=0.007) in diagnostic evaluation studies and 0.5% (95% CI 0.01 to 1.5, p=0.03) in follow-up studies. Partially or possibly related diagnoses were rarely found. No specific somatic diagnosis seemed to be missed systematically. CONCLUSIONS: The percentage of underlying somatic diseases in patients previously diagnosed with FSS is relatively small but unneglectable. PMID- 27455915 TI - Bona-fide method for the determination of short range order and transport properties in a ferro-aluminosilicate slag. AB - The thermodynamics, structural and transport properties (density, melting point, heat capacity, thermal expansion coefficient, viscosity and electrical conductivity) of a ferro-aluminosilicate slag have been studied in the solid and liquid state (1273-2273 K) using molecular dynamics. The simulations were based on a Buckingham-type potential, which was extended here, to account for the presence of Cr and Cu. The potential was optimized by fitting pair distribution function partials to values determined by Reverse Monte Carlo modelling of X-ray and neutron diffraction experiments. The resulting short range order features and ring statistics were in tight agreement with experimental data and created consensus for the accurate prediction of transport properties. Accordingly, calculations yielded rational values both for the average heat capacity, equal to 1668.58 J/(kg.K), and for the viscosity, in the range of 4.09-87.64 cP. The potential was consistent in predicting accurate values for mass density (i.e. 2961.50 kg/m(3) vs. an experimental value of 2940 kg/m(3)) and for electrical conductivity (5.3-233 S/m within a temperature range of 1273.15-2273.15 K). PMID- 27455916 TI - Measures of Mental Health for Diverse Populations. PMID- 27455917 TI - Internalized Stigma of Mental Illness Scale - Thai Version: Translation and Assessment of Psychometric Properties Among Psychiatric Outpatients in Central Thailand. AB - This paper reports the translation of the English Internalized Stigma of Mental Illness scale into Thai and assessment of its psychometric properties. After forward- and backward-translation, Thai experts completed the content validity index with item agreements of .86 to 1.00. Data were collected from 390 psychiatric clinic patients in central Thailand using systematic random sampling. Unweighted least squares factor analysis with Promax rotation identified five subscales. Cronbach's alpha for scale reliability was .88, and correlations for construct validity ranged from r=.55 to .69. These findings support the validity and reliability of the Thai version of the scale. PMID- 27455918 TI - The Psychometric Properties of PHQ-4 Depression and Anxiety Screening Scale Among College Students. AB - Depression and anxiety are some of the most common causes of morbidity, social dysfunction, and reduced academic performance in college students. The combination of improved surveillance and access to care would result in better outreach. Brief screening tools can help reach larger populations of college students efficiently. However, reliability and validity of brief screeners for anxiety and depression have not been assessed in college students. Thus, the purpose of this study was to assess in a sample of college students the psychometric properties of PHQ-4, a brief screening tool for depression and anxiety. Undergraduate students were recruited from general education classes at a Midwestern university. Students were given a questionnaire that asked them whether they had been diagnosed by a doctor or health professional with anxiety or depression. Next, they were asked to respond to the items on the PHQ-4 scale. A total of 934 students responded to the survey (response rate=72%). Majority of the participants were females (63%) and Whites (80%). The internal reliability of PHQ-4 was found to be high (alpha=0.81). Those who were diagnosed with depression or anxiety had statistically significantly higher scores on PHQ-4 (p<0.01). Corrected item total correlations for PHQ-4 were between r=0.66 and r=0.80. PHQ-4 operating characteristics were estimated and area under the curve (AUC) values were 0.835 and 0.787, respectively for anxiety and depression. The PHQ-4 is a reliable and valid tool that can serve as a mass screener for depression and anxiety in young adults. Widespread implementation of this screening tool should be explored across college campuses. PMID- 27455919 TI - Validation of the Korean Version of the Depression Coping Self-Efficacy Scale (DCSES-K). AB - Coping self-efficacy is regarded as an important indicator of the quality of life and well-being for community-dwelling patients with depression. The Depression Coping Self-Efficacy Scale (DCSES) was designed to measure self-efficacy beliefs related to the ability to perform tasks specific to coping with the symptoms of depression. The purpose of this study was to examine the psychometric properties of a Korean version of the Depression Coping Self-Efficacy Scale (DCSES-K) for community-dwelling patients with depression. A cross-sectional survey design was used. Content and semantic equivalence of the instrument using translation and back-translation of the DCSES was established. A convenience sample of 149 community-dwelling patients with depression was recruited from psychiatric outpatient clinics. The reliability alpha for the DCSES-K was .93, and the internal consistency was found to be acceptable. For convergent validity, DCSES-K score was positively correlated with the General Self-Efficacy Scale (GSES-K) score. For construct validity, significant differences in DCSES-K scores were found between a lower BDI group (mean=73.7, SD=16.54) and a higher BDI group (mean=53.74, SD=16.99) (t=7.19, p<.001). For the DCSES-K, 5 factors were extracted, accounting for 62.7% of the variance. Results of this study suggest that DCSES-K can be used as a reliable and valid measure for examining self efficacy coping with depression for Korean community-dwelling patients with depression. PMID- 27455920 TI - Assessment of Suicide Risk: Validation of the Nurses' Global Assessment of Suicide Risk Index for the Portuguese Population. AB - BACKGROUND: Mental health problems, particularly depression, are a major risk factor for suicide. Currently, there is no way to predict, with 100% accuracy, who will make a suicide attempt, but during a clinical interview, it is possible to assess the risk presented by each patient based on the investigation of risk and protective factors. The assessment of these factors helps health care professionals make decisions on the interventions to put into practice, thus contributing to reducing risk. The use of suicide risk assessment tools, properly validated for the population under consideration facilitate communication and information gathering, with clinical nurse specialists in mental health playing an important role. METHOD: Because of the shortage of suicide risk assessment tools properly validated for the Portuguese population, it was our aim to translate, adapt and validate the Nurses Global Assessment of Suicide Risk (NGASR) for the Portuguese population. In this study, a questionnaire was applied to a sample of 109 patients with depressive symptoms and risk factors for suicidal behaviors. RESULTS: The analysis of the results showed that most sample participants had a very high risk of suicide. The study of the psychometric properties of the NGASR showed moderate internal consistency and good content and criterion validity. Content validity, obtained through a panel of experts, was consensual. The NGASR index had good criterion validity, showing strong correlation with the SIQ, BDI and DASS-21 (R=0.830, p<0.05). The principal components analysis showed 6 factors, and the 15 predictive variables explained 66.92% of the total variance. CONCLUSION: These results are similar to those obtained in studies conducted in other countries and, therefore, the application of the NGASR is believed to be reliable for the Portuguese population. PMID- 27455921 TI - The Development and the Structure of the Verbal Suicide Scale (VSS) - Measuring Attitudes Toward Suicide in the Group of Patients Hospitalized in the Psychiatric Unit. AB - AIM: The assessment of suicidal risk is one of the most difficult diagnostic challenges. The aim of present article is to report the process of development and preliminary validation of the Verbal Suicide Scale. MATERIAL AND METHOD: A total of 121 psychiatric inpatients aged 19-67 anonymously completed Verbal Suicide Scale (VSS). The study took place in the Clinic of Psychiatry, Medical University of Warsaw in Mazovia Specialist Health Center in Pruszkow, Poland. RESULTS: Factor analysis validated the three factor structure. Cronbach's alpha reliability for each factor was satisfactory: 0.876 for scale 1, 0.700 for scale 2 and 0.710 for scale 3. CONCLUSIONS: VSS is a short instrument for evaluating the attitude toward suicide and can be a useful tool in mental health nursing practice. Further research and analyses are required to refine the theoretical and external reliability of the method. PMID- 27455922 TI - Self-Neglect: Development and Evaluation of a Self-Neglect (SN-37) Measurement Instrument. AB - Self-neglect (SN) is a global phenomenon, largely hidden, poorly defined, and a serious public health issue. It can be intentional or unintentional and depends on the individual's capacity. Creating a safe living environment for self neglecting adults can present complex ethical challenges. The purpose of this research was to develop and evaluate the psychometric properties of an instrument to measure professional's perceptions of self-neglect. A descriptive cross sectional design was used in this two-stage study. Stage 1 involved the generation of an item pool (90 items), face and content validity; and pilot testing of the instrument. In stage 2, the questionnaire was posted to a national sample of community health and social care professionals (n=566) across Ireland, with a 60% response (n=339). Exploratory factor analysis (EFA) was conducted using scale development guidelines to identify scales and subscales of the instrument. Construct validity was established using EFA. The result was a 37 item SN instrument, composed of five factors: environment, social networks, emotional and behavioural liability, health avoidance, and self-determinism which explained 55.6% of the total variance. Factor loadings were >=0.40 for all items on each of the five subscales. Cronbach's alpha (alpha) for four subscales ranged from 0.83 to 0.89 and one subscale was 0.69. The SN-37 can be used not only to measure SN, but also to develop interventions in practice. Further testing of the SN-37 in primary care settings with diverse populations is recommended. PMID- 27455923 TI - Comparing the Sensitivity, Specificity, and Predictive Values of the Montreal Cognitive Assessment and Mini-Mental State Examination When Screening People for Mild Cognitive Impairment and Dementia in Chinese Population. AB - BACKGROUND: The study compared the sensitivity, specificity, and diagnostic value of the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) in screening for mild cognitive impairment (MCI) and dementia. METHODS: A cross-sectional descriptive design was used, and 142 participants were screened for MCI and mild dementia by using the MoCA and MMSE. The receiver operating characteristic curves and the cutoff scores with the largest area under the curve (AUC) were determined and compared to calculate the sensitivity, specificity, and diagnostic value (positive predictive value [PPV] and negative predictive value [NPV]). RESULTS: The optimal MoCA cutoff scores for MCI and dementia were 24 and 20, respectively. According to these scores, the sensitivities were 0.88 and 0.79, the specificities were 0.74 and 0.80, the AUCs were 0.91 and 0.87, the PPVs were 0.93 and 0.74, and the NPVs were 0.74 and 0.87, respectively. The optimal cutoff MMSE scores for MCI and dementia were 27 and 24, respectively. Hence, the sensitivities were 0.88 and 0.84, the specificities were 0.70 and 0.86, the AUCs were 0.88 and 0.89, the PPVs were 0.94 and 0.80, and the NPVs were 0.81 and 0.88, respectively. CONCLUSION: In the Chinese population, the MoCA is more efficient in screening for MCI than for dementia, whereas the MMSE is more efficient in screening for dementia than for MCI. The MoCA and MMSE can be used by clinical staffs for quick and accurate cognitive impairment screening, thus facilitating early and appropriate clinical intervention and treatment. PMID- 27455924 TI - Development and Initial Testing of the Parent Beliefs about Early Childhood Social-Emotional Development Instrument. AB - BACKGROUND: No instrument exists to measure parent beliefs about early social emotional development, which is foundational for child outcomes. We developed and tested an instrument to measure parent beliefs. METHODS: Positive parenting was defined from the literature and 84 items were developed based on the theory of planned behavior (TPB). The instrument was tested with mothers (N=200) from the United States. RESULTS: Data support our initial supposition of five factors based upon the TPB, which accounted for 65.5% of the total variance. CONCLUSION: The instrument demonstrates strong initial psychometric properties and is ready for further testing. PMID- 27455925 TI - Epidemiology of inpatient gout in Australia and New Zealand: temporal trends, comorbidities and gout flare site. AB - AIM: To assess the epidemiology of inpatient gout in Australia and New Zealand during the years 2009-2014. METHODS: Using the Health Roundtable Limited (HRT) dataset, all patients with a coded ICD10 primary or secondary discharge diagnosis of gout from a HRT participating Australian or New Zealand hospital between the years 2009 and 2014 were identified. The number of inpatient gout admissions, length of stay, body site of gout flare, temporal trends and comorbidities were assessed. RESULTS: During 2009-2014, the number of gout admissions increased significantly in Australia and New Zealand. The rate of inpatient gout admissions relative to the population and total HRT admissions rose in Australia and stayed static in New Zealand. Lower limb presentations were the commonest anatomical site of gout in admitted patients. Length of stay over the course of the study decreased both in patients admitted for gout and in those in the entire HRT dataset. Patients admitted for gout have longer length of stay compared to patients admitted for other reasons. Cardiovascular disease, infection and stroke were the commonest conditions that were complicated by an episode of inpatient gout. There was no influence of month or season on the pattern of gout admissions. CONCLUSION: The number of gout admissions rose in Australia numerically and as a proportion of the total population and total admissions. Gout is an increasing problem affecting individuals and the community as a whole in Australia. PMID- 27455926 TI - Changing Patterns of Fungal Toxins in Crops: Challenges for Analysts. AB - This short review discusses the need to manage climate-driven expansion of old toxins in new geographic areas (e.g., aflatoxin or fumonisin in corn in historically cooler areas, and ergot where rainfall and cropping patterns have changed). In addition, a renewed consideration of the toxins that can occur in feed sources used in cool-season dairy areas is needed (e.g., silage and distillers dry grains with solubles). A separate issue concerns genetic changes that are occurring in the species that cause Fusarium head blight/Gibberella ear rot. Small differences in climate appear to determine the distribution of the two dominant populations (native to the new world and from Asia). The chemotype that produces deoxynivalenol via the monoacetate at the 3 position results in the accumulation of somewhat more deoxynivalenol than the native population, which involves the monoacetate at the 15 position. There are also genetic changes occurring that have resulted in populations that produce different metabolites. Similarly, an increase in the area where Aspergillus flavus can thrive and the discovery of the sexual stage of this fungus have raised the potential of genetic change accelerated by climate. To address all these issues, new methods and increased availability of reference standards, as well as training and awareness, will be required. PMID- 27455927 TI - Current Status of Mycotoxin Analysis: A Critical Review. AB - It is over 50 years since the discovery of aflatoxins focused the attention of food safety specialists on fungal toxins in the feed and food supply. Since then, analysis of this important group of natural contaminants has advanced in parallel with general developments in analytical science, and current MS methods are capable of simultaneously analyzing hundreds of compounds, including mycotoxins, pesticides, and drugs. This profusion of data may advance our understanding of human exposure, yet constitutes an interpretive challenge to toxicologists and food safety regulators. Despite these advances in analytical science, the basic problem of the extreme heterogeneity of mycotoxin contamination, although now well understood, cannot be circumvented. The real health challenges posed by mycotoxin exposure occur in the developing world, especially among small-scale and subsistence farmers. Addressing these problems requires innovative approaches in which analytical science must also play a role in providing suitable out-of laboratory analytical techniques. PMID- 27455928 TI - Multiplexed Biosensors for Mycotoxins. AB - Significant progress has been made in the development of biosensors that can be used to detect low-MW toxins produced by fungi (mycotoxins). The number of formats that have been investigated is impressive and is an indication of the importance attached to finding easy-to-use, accurate, and rapid methods for detecting these toxins in commodities and foods. This review explores the details of multiplexed biosensors based on many formats, including multiplexed immunoassays, suspension arrays, membrane-based devices (flow-through and immunochromatographic), and planar microarrays. Each assay format has its own strengths and areas that need improvement. Certain formats, such as multiplexed immunochromatographic devices, are well developed and relatively easy to use, and in some cases, commercial products are being sold. Others, such as the suspension arrays and microarrays, are laboratory-based assays that, although more complicated, are also more amenable to a larger scale of multiplexing. The diversity of such efforts and the multitude of formats under investigation suggest that multiple solutions will be found to satisfy the need for multiplexed toxin detection. PMID- 27455929 TI - The Use of Biochip Array Technology for Rapid Multimycotoxin Screening. AB - The main known groups of mycotoxins are aflatoxins, fumonisins, ochratoxins, type A trichothecenes (T-2 toxin and HT-2 toxin), type B trichothecenes (deoxynivalenol), and zearalenones. They are harmful to humans, domestic animals, and livestock. In Europe, maximum permitted limits for aflatoxin B1 are set, and guidance levels are recommended for the other mycotoxins. This study applied biochip array technology to semiquantitative multimycotoxin screening at different levels to facilitate the verification of the compliance of feed material with acceptable safety standards. This application was developed and validated based on European Commission Decision No. 2002/657/EC. After a single generic sample-preparation method, simultaneous competitive chemiluminescent immunoassays were used and applied to the Evidence Investigator analyzer. The r and within-laboratory R values showed low overall CVs (10.6 and 11.6%, respectively). Low matrix effect and, consequently, low decision limits and detection capabilities proved the high sensitivity of the technology. The overall average recovery was 104%. Samples (n = 16) investigated within the Food Analysis Performance Assessment Scheme (FAPAS) program showed excellent correlation to assigned values. FAPAS proficiency-testing feed samples (n = 10) were within the schemes' z-score +/-2 range. The authentic feed samples survey showed excellent correlation with LC-MS/MS. This application is, therefore, reliable and represents an innovative, cost-effective, and multianalytical tool for mycotoxin screening. PMID- 27455930 TI - Rapid Screening of Ergot Alkaloids in Sclerotia by MALDI-TOF Mass Spectrometry. AB - Ergot is a common disease of wheat and other cereal grains that is predominantly caused by Claviceps purpurea in the field, often affecting crop yield in addition to the environment. Infected grain can be contaminated with dark sclerotia, which contain fungal metabolites such as ergot alkaloids. The occurrence of ergot alkaloids in cereal grain is a major health concern for humans and livestock. Effective and rapid screening of these mycotoxins is crucial for producers, processors, and consumers of cereal-based food and feed grain. Established methods of ergot alkaloid screening based on LC-MS or GC-MS require laborious processes. A novel method using matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF) MS was developed to identify four ergot alkaloids. Using dihydroxybenzoic acid as the matrix, ergosine, ergocornine, ergocryptine, and ergocristine were readily detected in individual sclerotia of C. purpurea. The accuracy of the identified ergot alkaloids was further confirmed by tandem MS analysis. MALDI-TOF MS is suitable for high-throughput screening of ergot alkaloids because it permits rapid and accurate identification, simple sample preparation, and no derivatization or chromatographic separation. PMID- 27455931 TI - Application of Fourier Transform Infrared (FTIR) Spectroscopy for Rapid Detection of Fumonisin B2 in Raisins. AB - The aim of this study was to investigate the potential use of FTIR spectroscopy as a rapid screening method to detect fumonisin produced by Aspergillus niger. A. niger spore suspensions isolated from raisins were inoculated in Petri dishes prepared with sultana raisin or black raisin extracts containing agar and malt extract agar (MEA). After 9 days of incubation at 25 degrees C, fumonisin B2 (FB2) production on each agar plate was determined by subjecting the agar plugs to IR spectroscopy. The presence of amino group (at 1636-1639 cm(-1)) was especially indicative of fumonisin production in MEA and the raisin extracts containing agar. The results were confirmed by HPLC analysis of the agar sample extracts after immunoaffinity column cleanup. It was determined that A. niger produced more FB2 in sultana raisins than in MEA, with no FB2 being produced in black raisin extract agar. This study demonstrated that proper sample preparation procedure followed by FTIR analysis is a useful technique for identifying toxigenic molds and their mycotoxin production in agricultural commodities. PMID- 27455932 TI - Toward Harmonization of Performance Criteria for Mycotoxin Screening Methods: The EU Perspective. AB - Screening methods are defined as methods that are used to detect the presence of a substance or class of substances at the level of interest. These methods must have the capability of high sample throughput when being used to screen large numbers of samples for potential noncompliant results. Before using a screening method for practical applications, its fitness for the intended purpose needs to be demonstrated. This is normally achieved by conducting a validation study, comparing method performance against predefined criteria. Official guidelines recently established by the European Union for the evaluation of fitness-for purpose performance parameters of screening methods to be used for the detection of mycotoxins in foods are presented and discussed herein. Practical applications of this evaluation scheme for single- and interlaboratory validation studies, as well as relevant information on screening method performances are reviewed, with emphasis on the impact of mycotoxin contamination in real samples on the fitness for-purpose of the screening test. Lastly, validation follow-up is discussed in terms of extension of the scope of the method (increasing the range of application in terms of mycotoxin/matrix combinations), method implementation and verification, and evaluation of the method's applicability to modified mycotoxins. PMID- 27455933 TI - Determination of Phosphorus and Potassium in Commercial Inorganic Fertilizers by Inductively Coupled Plasma-Optical Emission Spectrometry: Single-Laboratory Validation, First Action 2015.18. AB - A previously validated method for the determination of both citrate-EDTA-soluble P and K and acid-soluble P and K in commercial inorganic fertilizers by inductively coupled plasma-optical emission spectrometry was submitted to the expert review panel (ERP) for fertilizers for consideration of First Action Official Method(SM) status. The ERP evaluated the single-laboratory validation results and recommended the method for First Action Official Method status and provided recommendations for achieving Final Action. Validation materials ranging from 4.4 to 52.4% P2O5 (1.7-22.7% P) and 3-62% K2O (2.5-51.1% K) were used for the validation. Recoveries from validation materials for citrate-soluble P and K ranged from 99.3 to 124.9% P and from 98.4 to 100.7% K. Recoveries from validation materials for acid-soluble "total" P and K ranged from 95.53 to 99.40% P and from 98.36 to 107.28% K. Values of r for citrate-soluble P and K, expressed as RSD, ranged from 0.28 to 1.30% for P and from 0.41 to 1.52% for K. Values of r for total P and K, expressed as RSD, ranged from 0.71 to 1.13% for P and from 0.39 to 1.18% for K. Based on the validation data, the ERP recommended the method (with alternatives for the citrate-soluble and the acid-soluble extractions) for First Action Official Method status and provided recommendations for achieving Final Action status. PMID- 27455935 TI - Standard Method Performance Requirements (SMPRs(r)). PMID- 27455934 TI - Characterization of Polymorphic Forms of Rifaximin. AB - Rifaximin is a gut-selective oral antimicrobial that has no systemic adverse effects compared with placebo. It is used for the treatment of hepatic encephalopathy, traveler's diarrhea, irritable bowel syndrome, Clostridium difficile infection, ulcerative colitis, and acute diarrhea. The crystalline form present in rifaximin, alpha, has minimal systemic absorption compared to the amorphous form. The objective of this study was to obtain polymorphic forms of rifaximin using recrystallization processes. The forms were characterized and studied by thermal analysis, X-ray powder diffraction, scanning electron microscopy, and solubility testing. Six polymorphic forms of rifaximin, designated I-VI, were obtained by the crystallization process by evaporation of the solvent. Some polymorphic forms obtained in this work may not have the same excellent tolerability as the reference medicine; therefore, studies such as these are extremely important and point to the need for greater requirements by the regulatory agencies overseeing polymorph analysis of the raw materials used in the manufacture of medicines marketed globally. These analyses are not required in the majority of official compendia. Partnerships among industries, research centers, and universities would be a viable way to consolidate research in this area and contribute to improving the quality of solid drugs. PMID- 27455936 TI - AOAC SMPR((r)) 2016.006. PMID- 27455937 TI - AOAC SMPR((r)) 2016.007. PMID- 27455938 TI - AOAC SMPR((r)) 2016.008. PMID- 27455939 TI - AOAC SMPR((r)) 2016.003. PMID- 27455940 TI - AOAC SMPR((r)) 2016.004. PMID- 27455941 TI - AOAC SMPR((r)) 2016.005. PMID- 27455942 TI - Determination of Biotin by Liquid Chromatography Coupled with Immunoaffinity Column Cleanup Extraction: Single-Laboratory Validation, First Action 2016.02. PMID- 27455943 TI - Chloride in Milk, Milk Powder, Whey Powder, Infant Formula, and Adult Nutritionals by Potentiometric Titration Method: First Action 2016.03. PMID- 27455944 TI - AOAC SMPR((r)) 2016.001. PMID- 27455946 TI - Determination of Four Arsenic Species in Fruit Juice by High-Performance Liquid Chromatography-Inductively Coupled Plasma-Mass Spectrometry: Single-Laboratory Validation, First Action 2016.04. PMID- 27455945 TI - AOAC SMPR((r)) 2016.002. PMID- 27455947 TI - Chemiresistive and Gravimetric Dual-Mode Gas Sensor toward Target Recognition and Differentiation. AB - We demonstrate a dual-mode gas sensor for simultaneous and independent acquisition of electrical and mechanical signals from the same gas adsorption event. The device integrates a graphene field-effect transistor (FET) with a piezoelectric resonator in a seamless manner by leveraging multiple structural and functional synergies. Dual signals resulting from independent physical processes, i.e., mass attachment and charge transfer can reflect intrinsic properties of gas molecules and potentially enable target recognition and quantification at the same time. Fabrication of the device is based on standard Integrated Circuit (IC) foundry processes and fully compatible with system-on-a chip (SoC) integration to achieve extremely small form factors. In addition, the ability of simultaneous measurements of mass adsorption and charge transfer guides us to a more precise understanding of the interactions between graphene and various gas molecules. Besides its practical functions, the device serves as an effective tool to quantitatively investigate the physical processes and sensing mechanisms for a large library of sensing materials and target analytes. PMID- 27455948 TI - Seasonal changes in partial, reverse diel vertical migrations of cisco Coregonus artedi. AB - The objectives of this study were to (1) document changes in partial, reverse diel vertical migrations (DVM) patterns of cisco Coregonus artedi in Ten Mile Lake, MN, U.S.A., throughout the year and (2) evaluate the mechanisms that may cause shifts in migration behaviour. Results indicated that C. artedi vertical distributions remained deep in the water column during the day and night of the spring and autumn, which was related to a low risk, low reward strategy. During summer, a partial migration occurred where a portion of the population remained deeper according to the low risk, low reward strategy, while the other portion performed a more extensive high risk, high reward reverse DVM. In winter, C. artedi did not migrate because there were only low risk, low reward conditions present at all depths. The extensive partial, reverse DVM during summer probably increased the growth potential of C. artedi, helping individuals survive in a lake with low zooplankton prey resources. PMID- 27455949 TI - Instrumental motion analysis: from the research laboratory to the rehabilitation clinic. PMID- 27455950 TI - Trunk motion analysis: a systematic review from a clinical and methodological perspective. AB - INTRODUCTION: This systematic literature review aims to check the current state of affairs of non-gait-related optoelectronic trunk movement analysis; results have been analyzed from a clinical and a methodological perspective. EVIDENCE ACQUISITION: Extensive research was performed on all papers published until December 31st, 2015, dealing with trunk movement analysis assessed by optoelectronic systems, excluding those related to gait. The research was performed on the 14th of January 2016 on three databases: Scopus, Science Direct and Pubmed. A reference search and expert consultation were also performed. EVIDENCE SYNTHESIS: Out of a total number of 8431 papers, 45 were deemed relevant: they included 1334 participants, 57.9% healthy, with age range 8-85. Few studies considered the whole trunk, and none focused on each vertebra independently: the trunk was almost always divided into three segments. Thirteen studies included 20 or more markers. Most of the papers focused mainly on the biomechanics of various movements; the lumbar area and low back pain were the most studied region and pathology respectively. CONCLUSIONS: This study has shown the relative scarcity of current literature focusing on trunk motion analysis. In clinical terms, results were sparse. The only quite well represented group of papers focused on the lumbar spine and pathologies, but the scarcity of individuals evaluated make the results questionable. The use of optoelectronic systems in the evaluation of spine movement is a growing research area. Nevertheless, no standard protocols have been developed so far. Future research is needed to define a precise protocol in terms of number and position of markers along the spine and movements and tasks to be evaluated. PMID- 27455951 TI - High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. AB - Chronic infections induce T cells showing impaired cytokine secretion and up regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment. PMID- 27455952 TI - DNA polymerase iota functions in the generation of tandem mutations during somatic hypermutation of antibody genes. AB - DNA polymerase iota (Pol iota) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol iota, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol iota, and knock in mice that express full-length Pol iota that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol iota did not change overall mutagenesis. We next examined if Pol iota affected tandem mutations generated by another error-prone polymerase, Pol zeta. The frequency of contiguous mutations was analyzed using a novel computational model to determine if they occur during a single DNA transaction or during two independent events. Analyses of 2,000 mutations from both strains indicated that Pol iota-compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol iota occasionally accesses the replication fork to generate a first mutation, and Pol zeta extends the mismatch with a second mutation. PMID- 27455954 TI - Parallelised online biomass monitoring in shake flasks enables efficient strain and carbon source dependent growth characterisation of Saccharomyces cerevisiae. AB - BACKGROUND: Baker's yeast, Saccharomyces cerevisiae, as one of the most often used workhorses in biotechnology has been developed into a huge family of application optimised strains in the last decades. Increasing numbers of strains render their characterisation highly challenging, even with the simple methods of growth-based analytics. Here we present a new sensor system for the automated, non-invasive and parallelisable monitoring of biomass in continuously shaken shake flask cultures, called CGQ ("cell growth quantifier"). The CGQ implements a dynamic approach of backscattered light measurement, allowing for efficient and accurate growth-based strain characterisation, as exemplarily demonstrated for the four most commonly used laboratory and industrial yeast strains, BY4741, W303 1A, CEN.PK2-1C and Ethanol Red. RESULTS: Growth experiments revealed distinct carbon source utilisation differences between the investigated S. cerevisiae strains. Phenomena such as diauxic shifts, morphological changes and oxygen limitations were clearly observable in the growth curves. A strictly monotonic non-linear correlation of OD600 and the CGQ's backscattered light intensities was found, with strain-to-strain as well as growth-phase related differences. The CGQ measurements showed high resolution, sensitivity and smoothness even below an OD600 of 0.2 and were furthermore characterised by low background noise and signal drift in combination with high reproducibility. CONCLUSIONS: With the CGQ, shake flask fermentations can be automatically monitored regarding biomass and growth rates with high resolution and parallelisation. This makes the CGQ a valuable tool for growth-based strain characterisation and development. The exceptionally high resolution allows for the identification of distinct metabolic differences and shifts as well as for morphologic changes. Applications that will benefit from that kind of automatized biomass monitoring include, amongst many others, the characterization of deregulated native or integrated heterologous pathways, the fast detection of co-fermentation as well as the realisation of rational and growth-data driven evolutionary engineering approaches. PMID- 27455953 TI - BCL-B (BCL2L10) is overexpressed in patients suffering from multiple myeloma (MM) and drives an MM-like disease in transgenic mice. AB - Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that Eu-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease. Indeed, with age, Eu-bcl-b transgenic mice develop the characteristic features of human MM, including bone malignant plasma cell infiltration, a monoclonal immunoglobulin peak, immunoglobulin deposit in renal tubules, and highly characteristic bone lytic lesions. In addition, the tumors are serially transplantable in irradiated wild-type mice, underlying the tumoral origin of the disease. Eu-bcl-b plasmocytes show increased expression of a panel of genes known to be dysregulated in human MM pathogenesis. Treatment of Eu-bcl-b mice with drugs currently used to treat patients such as melphalan and VELCADE efficiently kills malignant plasmocytes in vivo. Finally, we find that Bcl-B is overexpressed in plasmocytes from MM patients but neither in MGUS patients nor in healthy individuals, suggesting that Bcl-B may drive MM. These findings suggest that Bcl B could be an important factor in MM disease and pinpoint Eu-bcl-b mice as a pertinent model to validate new therapies in MM. PMID- 27455955 TI - A multicenter, randomized, open-label pilot trial assessing the efficacy and safety of etanercept 50 mg twice weekly followed by etanercept 25 mg twice weekly, the combination of etanercept 25 mg twice weekly and acitretin, and acitretin alone in patients with moderate to severe psoriasis. AB - BACKGROUND: Etanercept, a soluble tumor necrosis factor receptor, and acitretin have been shown to be effective in treating psoriasis. Acitretin is widely used in Korea. However, the combination of etanercept plus acitretin has not been evaluated among Korean patients with psoriasis. The objective of this study was to investigate the efficacy and safety of combination therapy with etanercept and acitretin in patients with moderate to severe plaque psoriasis. METHODS: Sixty patients with psoriasis were randomized to receive etanercept 50 mg twice weekly (BIW) for 12 weeks followed by etanercept 25 mg BIW for 12 weeks (ETN-ETN); etanercept 25 mg BIW plus acitretin 10 mg twice daily (BID) for 24 weeks (ETN ACT); or acitretin 10 mg BID for 24 weeks (ACT). The primary efficacy measurement was the proportion of patients achieving 75 % improvement in Psoriasis Area and Severity Index (PASI 75) at week 24. Secondary end points included 50 % improvement in PASI (PASI 50) at week 24 and clear/almost-clear by Physician Global Assessment (PGA) at each visit through week 24. RESULTS: The proportions of patients achieving PASI 75, PASI 50, and PGA clear/almost-clear at week 24 in the ETN-ETN (52.4, 71.4, and 52.4 %, respectively) and ETN-ACT groups (57.9, 84.2, and 52.6 %, respectively) were higher than in the ACT group (22.2, 44.4, and 16.7 %, respectively). The incidence of adverse events was similar across all arms. This was an open-label study with a small number of patients. CONCLUSION: In Korean patients with moderate to severe plaque psoriasis, etanercept alone or in combination with acitretin was more effective than acitretin. All treatments were well tolerated throughout the study. TRIAL REGISTRATION: This study was registered on July 7, 2009 at ClinicalTrials.gov, NCT00936065 . PMID- 27455956 TI - Computational studies of human class V alcohol dehydrogenase - the odd sibling. AB - BACKGROUND: All known attempts to isolate and characterize mammalian class V alcohol dehydrogenase (class V ADH), a member of the large ADH protein family, at the protein level have failed. This indicates that the class V ADH protein is not stable in a non-cellular environment, which is in contrast to all other human ADH enzymes. In this report we present evidence, supported with results from computational analyses performed in combination with earlier in vitro studies, why this ADH behaves in an atypical way. RESULTS: Using a combination of structural calculations and sequence analyses, we were able to identify local structural differences between human class V ADH and other human ADHs, including an elongated beta-strands and a labile alpha-helix at the subunit interface region of each chain that probably disturb it. Several amino acid residues are strictly conserved in class I-IV, but altered in class V ADH. This includes a for class V ADH unique and conserved Lys51, a position directly involved in the catalytic mechanism in other ADHs, and nine other class V ADH-specific residues. CONCLUSIONS: In this study we show that there are pronounced structural changes in class V ADH as compared to other ADH enzymes. Furthermore, there is an evolutionary pressure among the mammalian class V ADHs, which for most proteins indicate that they fulfill a physiological function. We assume that class V ADH is expressed, but unable to form active dimers in a non-cellular environment, and is an atypical mammalian ADH. This is compatible with previous experimental characterization and present structural modelling. It can be considered the odd sibling of the ADH protein family and so far seems to be a pseudoenzyme with another hitherto unknown physiological function. PMID- 27455957 TI - Factors associated with knowledge of a Good Samaritan Law among young adults who use prescription opioids non-medically. AB - BACKGROUND: To date, no studies have examined the extent of knowledge and perceptions of Good Samaritan Laws (GSLs) among young adults who engage in non medical prescription opioid (NMPO) use. We sought to determine awareness of and factors associated with knowledge of Rhode Island's Good Samaritan Law (RIGSL) among young adult NMPO users. FINDINGS: We compared the sociodemographic and overdose-related characteristics of participants who were aware and unaware of the RIGSL and determined independent correlates of knowledge of the RIGSL via modified stepwise logistic regression. Among 198 eligible participants, 15.7 % were black, 62.1 % white, and 20.7 % mixed or other race. The mean age was 24.5 (SD = 3.2) and 129 (65.2 %) were male. Fewer than half (45.5 %) were aware of the RIGSL; nonetheless, the majority (95.5 %) reported a willingness to call 911 in the event of an overdose. Knowledge of the RIGSL was associated with older age, white race, a history of incarceration, a history of injection drug use, lifetime heroin use, ever witnessing or experiencing an overdose, having heard of naloxone, knowledge of where to obtain naloxone, and experience administering naloxone (all p < 0.05). In the final explanatory regression model, lifetime injection drug use, having heard of naloxone, and knowledge of where to obtain naloxone were independently associated with awareness of the RIGSL. CONCLUSIONS: Fewer than half of NMPO users surveyed knew of the RIGSL. Targeted harm reduction education is needed to address a vulnerable population of NMPO users who have not initiated injection drug use and are unaware of naloxone. Additional research is needed to determine how the effectiveness of GSLs could be improved to prevent overdose deaths among young adults. PMID- 27455958 TI - Predictors of time to relapse in amphetamine-type substance users in the matrix treatment program in Iran: a Cox proportional hazard model application. AB - BACKGROUND: The aim of this study was to determine which predictors influence the risk of relapse among a cohort of amphetamine-type substance (ATS) users in Iran. METHODS: A Cox proportional hazards model was conducted to determine factors associated with the relapse time in the Matrix treatment program provided by the Iranian National Center of Addiction Studies (INCAS) between March 2010 and October 2011. RESULTS: Participating in more treatment sessions was associated with a lower probability of relapse. On the other hand, patients with less family support, longer dependence on ATS, and those with an experience of casual sex and a history of criminal offenses were more likely to relapse. CONCLUSION: This study broadens our understanding of factors influencing the risk of relapse in ATS use among an Iranian sample. The findings can guide practitioners during the treatment program. PMID- 27455959 TI - Circadian variations in clinical symptoms and concentrations of inflammatory cytokines, melatonin, and cortisol in polymyalgia rheumatica before and during prednisolone treatment: a controlled, observational, clinical experimental study. AB - BACKGROUND: In contrast to rheumatoid arthritis (RA), no systematic investigation of diurnal variation has been carried out in polymyalgia rheumatica (PMR). The aim of the study was to provide the often-requested documentation of the 24-h time course of clinical symptoms in PMR and relate them to concentrations during the day of melatonin, inflammatory cytokines, and cortisol. Furthermore, the effects of 14 days of prednisolone treatment were studied. METHODS: Ten glucocorticoid-naive patients newly diagnosed with PMR and seven non-PMR control subjects were studied for 24 h before treatment and during the 14th day of treatment with 20 mg/day of prednisolone. Global pain and generalized muscle stiffness were monitored by using visual analogue scales, and blood was drawn repeatedly. RESULTS: In untreated patients, pain and stiffness peaked in the early morning, showing a plateau between 04:00 and 08:00, and then declined to a nadir at 16:00 (2P < 0.05). Plasma concentrations of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-4 varied with time in both groups (2P < 0.05) and peaked between 04:00 and 08:00. Furthermore, except for IL 1beta, concentrations of these cytokines and of IL-10 were higher throughout the 24-h observation period in patients than in control subjects (2P < 0.05). Also, melatonin and cortisol were consistently higher in patients (2P < 0.05) and varied with time (2P < 0.05), peaking around 02:00 and 08:00, respectively. In patients, prednisolone abolished symptoms, normalized C-reactive protein, and reduced melatonin, IL-6, IL-8, and TNF-alpha concentrations (2P < 0.05), while IL 10 increased between 10:00 and 14:00. CONCLUSIONS: In PMR, key symptoms show diurnal variation. Furthermore, in PMR, concentrations of melatonin, several pro- and anti-inflammatory cytokines, and cortisol are increased throughout the day and show diurnal variation, as also seen in healthy subjects. The time courses and the inhibitory effects of prednisolone indicate that in PMR, as proposed for RA, melatonin stimulates cytokine production, which in turn accounts at least partly for the symptoms. Furthermore, overall, cortisol may downregulate cytokine production and symptoms. Stimulation of IL-10 secretion may participate in the anti-inflammatory effects of prednisolone. These findings support use of chronotherapy in PMR and encourage study of circadian variations in other inflammatory autoimmune diseases. PMID- 27455960 TI - The effectiveness of a nurse-led intervention with the distress thermometer for patients treated with curative intent for breast cancer: design of a randomized controlled trial. AB - BACKGROUND: Distress in patients with cancer influences their quality of life. Worldwide, screening on distress with the Distress Thermometer (DT) in patients with cancer is recommended. However, the effects of the use of the DT on the psychosocial wellbeing of the patient are unknown. A study to assess the psychosocial consequences of the systematic use of the DT and its discussion by a nurse as compared to the usual care provided to outpatients who are treated for primary breast cancer is needed. METHODS/DESIGN: The effectiveness of a nurse-led intervention with the DT will be tested in a non-blinded randomized controlled trial. Patients treated with curative intent for breast cancer will be recruited from the Radboud University Medical Center. The intervention consists of the DT together with discussion of the results with the patient by a trained oncology nurse added to the usual care. Patients will be randomly allocated (1:1) to either receive usual care or the usual care plus the intervention. Primary outcome measure is global quality of life measured with the EORTC QLQ-C30. The functional and symptom scales of the EORTC QLQ-C30 and BR23, Hospital Anxiety and Depression Scale, Impact of Event Scale, Illness Cognition Questionnaire and DT (baseline and final measurement only) will be used to measure secondary outcomes. Questionnaires are obtained in both arms at baseline, after completion of each type of cancer treatment modality and during follow up, with a three and six months' interval during the first and second year respectively. DISCUSSION: This study will be the first randomized controlled longitudinal study about the effectiveness of the DT as nurse led-intervention. In case of proven effectiveness, future implementation and standardization of use of the DT as part of routine care will be recommended. TRIAL REGISTRATION: This study is registered at clinicaltrial.gov march 17, 2010 ( NCT01091584 ). PMID- 27455961 TI - Acupuncture to improve tolerance of diagnostic esophagogastroduodenoscopy in patients without systemic sedation: results of a single-center, double-blinded, randomized controlled trial (DRKS00000164). AB - BACKGROUND: Sedation prior to esophagogastroduodenoscopy is widespread and increases patient comfort. However, it demands additional trained personnel, accounts for up to 40 % of total endoscopy costs and impedes rapid hospital discharge. Most patients lose at least one day of work. 98 % of all serious adverse events occurring during esophagogastroduodenoscopy are ascribed to sedation. Acupuncture is reported to be effective as a supportive intervention for gastrointestinal endoscopy, similar to conventional premedication. We investigated whether acupuncture during elective diagnostic esophagogastroduodenoscopy could increase the comfort of patients refusing systemic sedation. METHODS: We performed a single-center, double-blinded, placebo controlled superiority trial to compare the success rates of elective diagnostic esophagogastroduodenoscopies using real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic esophagogastroduodenoscopy who refused systemic sedation were eligible; 354 patients were randomized. The primary endpoint measure was the rate of successful esophagogastroduodenoscopies. The intervention was real or placebo acupuncture before and during esophagogastroduodenoscopy. Successful esophagogastroduodenoscopy was based on a composite score of patient satisfaction with the procedure on a Likert scale as well as quality of examination, as assessed by the examiner. RESULTS: From February 2010 to July 2012, 678 patients were screened; 354 were included in the study. Baseline characteristics of the two groups showed a similar distribution in all but one parameter: more current smokers were allocated to the placebo group. The intention-to-treat analysis included 177 randomized patients in each group. Endoscopy could successfully be performed in 130 patients (73.5 %) in the real acupuncture group and 129 patients (72.9 %) in the placebo group. Willingness to repeat the procedure under the same conditions was 86.9 % in the real acupuncture group and 87.6 % in the placebo acupuncture group. CONCLUSIONS: Esophagogastroduodenoscopy without sedation is safe and can successfully be performed in two-thirds of patients. Patients planned for elective esophagogastroduodenoscopy without sedation do not benefit from acupuncture of the Sinarteria respondens (Rs) 24 Chengjiang middle line, Pericard (Pc) 6 Neiguan bilateral, or Dickdarm (IC) 4 Hegu bilateral, according to traditional Chinese medicine meridian theory. TRIAL REGISTRATION: DRKS00000164 . Registered on 10 December 2009. PMID- 27455962 TI - Predictability of frailty index and its components on mortality in older adults in China. AB - BACKGROUND: Frailty represents an increased vulnerability to external stressors due to decreased physiological reserve and dysfunction in multiple bodily systems. The relationship between frailty and mortality has been well-documented in the literature. However, less is known about the predictive powers of frailty index and its components on mortality when they are simultaneously present. This study aimed to examine the predictive powers of frailty index and its multiple components on mortality in a nationally representative sample of older adults in China. METHODS: We used a sample of 13,731 older adults from the 2008/2009 and 2011/2012 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Frailty was measured using the cumulative deficit approach, and was constructed from 38 health variables (39 deficits). We selected 8 major sets of components: activities of daily living (ADL) (6 deficits), instrumental ADL (IADL) (8 deficits), functional limitations (5 deficits), overall cognitive functioning (1 deficit), chronic disease conditions (11 deficits), self-reported health (2 deficits), hearing and vision impairment (2 deficits), and psychological distress (1 deficit). Survival analysis was used to examine the roles of the frailty and its components in mortality. RESULTS: Results showed that almost all the components of the frailty index (except chronic diseases) were significant predictors of mortality when examined individually. Among the components, ADL and IADL disabilities remained significant when considering all the components simultaneously. When the frailty and its components were simultaneously analyzed, the frailty remained a robust predictor of mortality across the age and sex groups, while most components lost their significance except ADL, IADL, and cognitive function components in some cases. CONCLUSIONS: Frailty measured by cumulative deficits has a stronger predictive power on mortality than its all individual components. ADL and IADL disability play a greater role in mortality than other components when considering all the components of frailty. PMID- 27455963 TI - Comparison of Statistical Approaches for Dealing With Immortal Time Bias in Drug Effectiveness Studies. AB - In time-to-event analyses of observational studies of drug effectiveness, incorrect handling of the period between cohort entry and first treatment exposure during follow-up may result in immortal time bias. This bias can be eliminated by acknowledging a change in treatment exposure status with time dependent analyses, such as fitting a time-dependent Cox model. The prescription time-distribution matching (PTDM) method has been proposed as a simpler approach for controlling immortal time bias. Using simulation studies and theoretical quantification of bias, we compared the performance of the PTDM approach with that of the time-dependent Cox model in the presence of immortal time. Both assessments revealed that the PTDM approach did not adequately address immortal time bias. Based on our simulation results, another recently proposed observational data analysis technique, the sequential Cox approach, was found to be more useful than the PTDM approach (Cox: bias = -0.002, mean squared error = 0.025; PTDM: bias = -1.411, mean squared error = 2.011). We applied these approaches to investigate the association of beta-interferon treatment with delaying disability progression in a multiple sclerosis cohort in British Columbia, Canada (Long-Term Benefits and Adverse Effects of Beta-Interferon for Multiple Sclerosis (BeAMS) Study, 1995-2008). PMID- 27455964 TI - A pilot study of marking accuracy and mental workload as measures of OSCE examiner performance. AB - BACKGROUND: The Objective Structured Clinical Examination (OSCE) is now a standard assessment format and while examiner training is seen as essential to assure quality, there appear to be no widely accepted measures of examiner performance. METHODS: The objective of this study was to determine whether the routine training provided to examiners improved their accuracy and reduced their mental workload. Accuracy was defined as the difference between the rating of each examiner and that of an expert group expressed as the mean error per item. At the same time the mental workload of each examiner was measured using a previously validated secondary task methodology. RESULTS: Training was not associated with an improvement in accuracy (p = 0.547) and that there was no detectable effect on mental workload. However, accuracy was improved after exposure to the same scenario (p < 0.001) and accuracy was greater when marking an excellent compared to a borderline performance. CONCLUSIONS: This study suggests that the method of training OSCE examiners studied is not effective in improving their performance, but that average item accuracy and mental workload appear to be valid methods of assessing examiner performance. PMID- 27455966 TI - Formation of Nanostructures by Peptides. AB - BACKGROUND: Amyloid fibrils, which are implicated in several diseases, are highly ordered structures formed by aggregation of proteins. Intriguingly, several short peptides, some of which are unrelated to the disease-causing proteins, also aggregate to form amyloid fibrils in vitro. The aggregation behavior of these short peptides can be modulated so that they form nanostructures that are not in any way related to amyloid fibrils. These observations have led to extensive research aimed at getting insights into how peptides aggregate to form amyloids as well as non-amyloidogenic structures. METHODS: This review examines the aggregation behavior of peptides that form highly polymorphic structures including fibrils, nanotubes, nanospheres and hydrogels. The review also describes how short peptides composed of only two and three hydrophobic and aromatic amino acids can selfassemble to form nanotubes and nanospheres. RESULTS: Peptides with widely varying amino acid composition and lengths aggregate to form indistinguishable fibrils and nanostructures. The potential application of these aggregated structures in the design of novel biomaterials is reviewed and highlighted. CONCLUSION: It is evident that highly polymorphic aggregated structures of peptides can be obtained by varying conditions such as solvent of dissolution, temperatures, pH and even surfaces of deposition. PMID- 27455967 TI - Peptide Based Viral Detection Systems for Effective Diagnosis of Common Viral Infections in India. AB - BACKGROUND: Accurate and swift detection of viruses causing diseases in humans represent continuous challenges to diagnostic and epidemiological research. Efficient and rapid diagnosis is crucial for effective implication of disease management strategies. Multitude approaches attempted to identify individual viruses, includes serological assays and molecular methods. Detection assays based on peptides have become increasingly substantial and indispensable for its advantages over conventional methods. METHODS: We have primarily outlined the progress made in peptide based diagnostic systems for the commonly found viral infections in India - Influenza virus, Chikungunya virus, Dengue virus, Rotavirus, Japanese encephalitis virus (JEV), Epstein-Barr virus (EBV), Human Immunodeficiency virus (HIV) and Hepatitis C virus (HCV). Further, we have documented the recent advancements that could impact the upcoming developments of peptide based diagnostic assays. RESULTS: In this review we identified that very few studies in development of peptide based assays for viral infections has been reported. In a country specific scenario like India and its burdened health care system, sensitive and rapid diagnostic kits based on peptides could be considered as a better alternative to the conventional serological tests including whole antigenic proteins. CONCLUSION: The finding of this review uncovers the importance of a peptide based diagnostic system for rapid detection of viral infections. Even though, in recent times, peptide based assays have intrigued researchers, further work in this domain is entailed. PMID- 27455965 TI - Determinants of Macromolecular Specificity from Proteomics-Derived Peptide Substrate Data. AB - BACKGROUND: Recent advances in proteomics methodologies allow for high throughput profiling of proteolytic cleavage events. The resulting substrate peptide distributions provide deep insights in the underlying macromolecular recognition events, as determinants of biomolecular specificity identified by proteomics approaches may be compared to structure-based analysis of corresponding protein protein interfaces. METHOD: Here, we present an overview of experimental and computational methodologies and tools applied in the area and provide an outlook beyond the protein class of proteases. RESULTS AND CONCLUSION: We discuss here future potential, synergies and needs of the emerging overlap disciplines of proteomics and structure-based modelling. PMID- 27455968 TI - Peptide Biomarkers: Exploring the Diagnostic Aspect. AB - BACKGROUND: In the past few decades, with the upsurge of various deadly diseases, development of accurate diagnostic methods is inevitable for maintaining good health. There is an urgent requirement of specific and sensitive biomarkers in order to improve diagnosis, guide molecular targeted therapy, and predict and examine therapeutic response across a wide spectrum of disease. METHOD: We undertook a structured search of bibliographic databases for peer-reviewed research literature to evaluate the significance of peptides as valuable tools for diagnostic applications as well as the techniques used for discovery of peptide biomarkers. RESULT: On the basis of extensive literature survey, peptide biomarkers are classified according to their diagnosis approach. In addition, we summarize a few techniques used in peptide biomarker discovery such as peptidomics and peptide microarray. CONCLUSION: Small size, stability, easy and inexpensive production, capability to migrate throughout the body, fast clearance from body and low immunogenicity, as well as the remarkable quality of peptides to mirror the change in protease expression or activation associated with a pathological process, have established them as a promising biomarker. PMID- 27455969 TI - Chemical Crosslinking: Role in Protein and Peptide Science. AB - BACKGROUND: Chemical crosslinking refers to intermolecular or intramolecular joining of two or more molecules by a covalent bond. The reagents that are used for the purpose are referred to as 'crosslinking reagents' or 'crosslinkers'. Based on factors like reactivity and spacer length these are classified into different types, each having its own specific function and application. In recent times, chemical crosslinking has emerged as an efficient tool for the study of biomolecules like proteins. It finds its application in various studies including the attachment of proteins to a solid support for the study of membrane receptors, protein-protein complexes, protein-DNA complexes, and others. When coupled with techniques like mass spectroscopy, it has been used not only for the determination of three dimensional structures of proteins but also for the study of protein-protein interactions and determination of interesting sites. This combination of mass spectrometry techniques and bioinformatics, added yet another dimension to our present day understanding of protein chemistry. Thus, chemical crosslinking has multitude uses that it can be put to. METHODS: We undertook a systematic search of bibliographic databases and search engine such as Google Scholar, Scifinder, Scopus, Mendeley etc for review of research literature. We excluded research paper which only reported synthesis of crosslinker molecules and did not involve any mass spectrometry studies. RESULTS: Sixty-four papers were included in the review. The majority of references were taken from last ten years as there has been an immense progress in this area in the recent years. Eleven classical papers in this field were included which talk about basic of this methodology. Thirty-two papers discussed about various types of organic groups used for designing chemical cross-linkers and various methodologies which were used to enhance the crosslinking efficiency. These papers also highlight various strategies used to enhance detection of cross-linked proteins and various computer software used to detect cross-linking sites from mass data. Twenty-one papers showed the proof concept application of this methodology to detect protein crosslinking in-vivo and in-vitro. CONCLUSION: The findings of this review confirm the importance chemical crosslinking combined with mass spectroscopy as a low cost alternative to understand protein-protein interaction. The information generated by this methodology can help in better understating of various diseases and for the development of better drugs for them. PMID- 27455970 TI - Marine Peptides as Anticancer Agents: A Remedy to Mankind by Nature. AB - BACKGROUND: In the search of bioactive molecules, nature has always been an important source and most of the drugs in clinic are either natural products or derived from natural products. The ocean has played significant role as thousands of molecules and their metabolites with different types of biological activity such as antimicrobial, anti-inflammatory, anti-malarial, antioxidant, anti HIV and anticancer activity have been isolated from marine organisms. In particular, marine peptides have attracted much attention due to their high specificity against cancer cell lines that may be attributed to the various unusual amino acid residues and their sequences in the peptide chain. This review aims to identify the various anticancer agents isolated from the marine system and their anticancer potential. METHOD: We did literature search for the anticancer peptides isolated from the different types of microorganism found in the marine system. Total one eighty eight papers were reviewed concisely and most of the important information from these papers were extracted and kept in the present manuscript. RESULTS: This review gives details about the isolation, anticancer potential and mechanism of action of the anticancer peptides of the marine origin. Many of these molecules such as aplidine, dolastatin 10, didemnin B, kahalalide F, elisidepsin (PM02734) are in clinical trials for the treatment of various cancers. CONCLUSION: With the interdisciplinary and collaborative research and technical advancements we can search more promising and affordable anticancer drugs in future. PMID- 27455971 TI - Resistance (R) Genes: Applications and Prospects for Plant Biotechnology and Breeding. AB - The discovery of novel plant resistance (R) genes (including their homologs and analogs) opened interesting possibilities for controlling plant diseases caused by several pathogens. However, due to environmental pressure and high selection operated by pathogens, several crop plants have lost specificity, broad-spectrum or durability of resistance. On the other hand, the advances in plant genome sequencing and biotechnological approaches, combined with the increasing knowledge on Rgenes have provided new insights on their applications for plant genetic breeding, allowing the identification and implementation of novel and efficient strategies that enhance or optimize their use for efficiently controlling plant diseases. The present review focuses on main perspectives of application of R-genes and its co-players for the acquisition of resistance to pathogens in cultivated plants, with emphasis on biotechnological inferences, including transgenesis, cisgenesis, directed mutagenesis and gene editing, with examples of success and challenges to be faced. PMID- 27455972 TI - Epigenetic Signals on Plant Adaptation: a Biotic Stress Perspective. AB - For sessile organisms such as plants, regulatory mechanisms of gene expression are vital, since they remain exposed to climatic and biological threats. Thus, they have to face hazards with instantaneous reorganization of their internal environment. For this purpose, besides the use of transcription factors, the participation of chromatin as an active factor in the regulation of transcription is crucial. Chemical changes in chromatin structure affect the accessibility of the transcriptional machinery and acting in signaling, engaging/inhibiting factors that participate in the transcription processes. Mechanisms in which gene expression undergoes changes without the occurrence of DNA gene mutations in the monomers that make up DNA, are understood as epigenetic phenomena. These include (1) post-translational modifications of histones, which results in stimulation or repression of gene activity and (2) cytosine methylation in the promoter region of individual genes, both preventing access of transcriptional activators as well as signaling the recruitment of repressors. There is evidence that such modifications can pass on to subsequent generations of daughter cells and even generations of individuals. However, reports indicate that they persist only in the presence of a stressor factor (or an inductor of the above-mentioned modifications). In its absence, these modifications weaken or lose heritability, being eliminated in the next few generations. In this review, it is argued how epigenetic signals influence gene regulation, the mechanisms involved and their participation in processes of resistance to biotic stresses, controlling processes of the plant immune system. PMID- 27455973 TI - Plants Defense-related Cyclic Peptides: Diversity, Structure and Applications. AB - Plant growth is prone to several unfavorable factors that may compromise or impair development and survival, including abiotic or biotic stressors. Aiming at defending themselves, plants have developed several strategies to survive and adapt to such adversities. Cyclotides are a family of plant-derived proteins that exhibit a diverse range of biological activities including antimicrobial and insecticidal activities that actively participate in plant defense processes. Three main categories of peptides have been described: (i) Cyclotides (ii) Sunflower Trypsin Inhibitor (SFTI) and (iii) peptides MCoTI-I and II, from Momordica cochinchinensis. They comprise proteins of approximately 30 amino acids, containing a head-to-tail cyclized backbone, with three disulfide bonds configured in a cystine knot topology, therefore bearing greater peptide stability. Given their features and multifunctionality, cyclotides stand out as promising sources for the discovery of new antimicrobial agents. The present review describes cyclotide occurrence, abundance and action in plants, also their and evolution. Considerations regarding their use in the context of biomedical and agronomical sciences uses are also presented. PMID- 27455974 TI - Plant Elite Squad: First Defense Line and Resistance Genes - Identification, Diversity and Functional Roles. AB - Plants exhibit sensitive mechanisms to respond to environmental stresses, presenting some specific and non-specific reactions when attacked by pathogens, including organisms from different classes and complexity, as viroids, viruses, bacteria, fungi and nematodes. A crucial step to define the fate of the plant facing an invading pathogen is the activation of a compatible Resistance (R) gene, the focus of the present review. Different aspects regarding R-genes and their products are discussed, including pathogen recognition mechanisms, signaling and effects on induced and constitutive defense processes, splicing and post transcriptional mechanisms involved. There are still countless challenges to the complete understanding of the mechanisms involving R-genes in plants, in particular those related to the interactions with other genes of the pathogen and of the host itself, their regulation, acting mechanisms at transcriptional and post-transcriptional levels, as well as the influence of other types of stress over their regulation. A magnification of knowledge is expected when considering the novel information from the omics and systems biology. PMID- 27455975 TI - Plant Proteomics and Peptidomics in Host-Pathogen Interactions: The Weapons Used by Each Side. AB - Environmental biotic stress factors act continuously on plants, through multiple molecular interactions that eventually lead to the establishment and progress of symbiotic or pathogenic complex interactions. Proteins and peptides play noteworthy roles in such biological processes, usually being the main effectors since the initial recognizing and elicitor functions until the following transduction, gene regulation and physiological responses activities. Ranging from specific regulators to direct antimicrobial agents, plant or pathogen proteins and peptides comprise the arsenal available to each side in this biological war, resulting from the genetic coding potential inherited by each one. Post-translational research tools have widely contributed with valuable information on how the plant proteome works to achieve, maintain and adjust plant immunity in order to properly cope with the challenging pathogenic derived proteomes. These key proteins and peptides have great biotechnological potential since they represent distinctive features of each pathogen group (fungi, bacteria, viruses and other) in response to molecules of defense of host plants. PMID- 27455976 TI - Evaluation of locoregional invasiveness of small-sized non-small cell lung cancers by enhanced dual-energy computed tomography. AB - BACKGROUND: To investigate the correlation between iodine-related attenuation of dual-energy computed tomography (DE-CT) and the histopathological invasiveness of surgically resected primary non-small cell lung cancers (NSCLCs) <= 3 cm in diameter. METHODS: We selected 63 consecutive NSCLC lesions from 60 patients (32 males, 28 females; age range, 39-85 years; mean age, 68 years). After injection of iodinated contrast media, arterial phases were scanned using 140-kVp and 80 kVp tube voltages. Three-dimensional iodine-related attenuation (3D-IRA) of primary tumors at the arterial phase was computed using "lung nodule" application software. The corrected 3D-IRA normalized to the patient's body weight and contrast medium concentration was then calculated. Single-factor analysis of variance (ANOVA) was used for comparison among tumor differentiation grade groups. Univariate and multivariate logistic regression analysis was used for the correlation between locoregional invasive tumor and clinical factors. RESULTS: Resected tumors were histopathologically classified into well-differentiated (G1; n = 24), moderately-differentiated (G2; n = 28), and poorly-differentiated (G3; n = 11) groups by degree of tumor differentiation. The mean +/- standard deviation of the 3D-IRA was 56.1 +/- 22.6 HU in G1 tumours, 48.5 +/- 23.9 HU in G2 tumours, and 28.4 +/- 15.8 HU in G3 tumours; significant differences were observed between groups by ANOVA. (p = 0.005). Univariate logistic analysis showed that the 3D-IRA and corrected 3D-IRAs were significantly correlated with locoregional invasive tumors (p = 0.002 and p < 0.001, respectively). Multivariate logistic analysis revealed that only the corrected 3D-IRA was significantly correlated with tumor invasiveness (p = 0.003), while gender, clinical size, and solid/subsolid type were not (p = 0.950, p = 0.057 and p = 0.456, respectively). CONCLUSIONS: The 3D IRA of small-sized NSCLCs was significantly associated with and invasiveness. Low 3D-IRA tumors tended to have greater invasiveness than high 3D-IRA tumors. PMID- 27455977 TI - Chronic congestive heart failure - a new therapeutic choice. PMID- 27455978 TI - A 25-year-old woman with diabetes in custody. PMID- 27455979 TI - NS to pay for doctor-patient phone calls. PMID- 27455980 TI - Choosing Wisely concept has universal appeal. PMID- 27455982 TI - Regaining momentum. PMID- 27455983 TI - Premiers call for more federal funding for health care. PMID- 27455981 TI - Effectiveness of the influenza vaccine in preventing admission to hospital and death in people with type 2 diabetes. AB - BACKGROUND: The health burden caused by seasonal influenza is substantial. We sought to examine the effectiveness of influenza vaccination against admission to hospital for acute cardiovascular and respiratory conditions and all-cause death in people with type 2 diabetes. METHODS: We conducted a retrospective cohort study using primary and secondary care data from the Clinical Practice Research Datalink in England, over a 7-year period between 2003/04 and 2009/10. We enrolled 124 503 adults with type 2 diabetes. Outcome measures included admission to hospital for acute myocardial infarction (MI), stroke, heart failure or pneumonia/influenza, and death. We fitted Poisson regression models for influenza and off-season periods to estimate incidence rate ratios (IRR) for cohorts who had and had not received the vaccine. We used estimates for the summer, when influenza activity is low, to adjust for residual confounding. RESULTS: Study participants contributed to 623 591 person-years of observation during the 7-year study period. Vaccine recipients were older and had more comorbid conditions compared with nonrecipients. After we adjusted for covariates and residual confounding, vaccination was associated with significantly lower admission rates for stroke (IRR 0.70, 95% confidence interval [CI] 0.53-0.91), heart failure (IRR 0.78, 95% CI 0.65-0.92) and pneumonia or influenza (IRR 0.85, 95% CI 0.74-0.99), as well as all-cause death (IRR 0.76, 95% CI 0.65-0.83), and a nonsignificant change for acute MI (IRR 0.81, 95% CI 0.62-1.04) during the influenza seasons. INTERPRETATION: In this cohort of patients with type 2 diabetes, influenza vaccination was associated with reductions in rates of admission to hospital for specific cardiovascular events. Efforts should be focused on improvements in vaccine uptake in this important target group as part of comprehensive secondary prevention. PMID- 27455984 TI - Recurrent volvulus of cecorectal anastomosis after subtotal colectomy: technical implications of an unusual complication. PMID- 27455985 TI - Clinical utility of radiofrequency ablation following transarterial injection of miriplatin-iodized oil suspension in small hepatocellular carcinoma. AB - PURPOSE: To retrospectively evaluate the clinical utility of radiofrequency ablation (RFA) following transarterial injection of miriplatin-iodized oil suspension (MPT-RFA) for hepatocellular carcinoma treatment. MATERIALS AND METHODS: We evaluated clinical outcomes of MPT-RFA for three or fewer hepatocellular carcinomas. Twenty-one patients with 30 tumors (maximum diameter: mean 1.4 +/- 0.4 cm, range 0.7-2.2 cm) received MPT-RFA. RESULTS: Nineteen patients (90.5 %, 19/21) achieved complete ablation at the first RFA session. Two patients (9.5 %, 2/21) required a second RFA session but achieved complete ablation. Primary and secondary technical success rates were 90.5 and 100 %. There were no deaths related to the procedures performed. Grade 3 or 4 increases in the serum aspartate aminotransferase, alanine aminotransferase, and bilirubin levels were found in six patients (38.1 %, 8/21). There were no liver infarctions. During the median follow-up period of 24.1 months (mean +/- SD 24.7 +/- 6.9 months, range 13.8-38.9 months), the local tumor progression rate and overall survival rate at 2 years was 5.0 % (95 % confidence interval 0.3-20.6 %) and 86.7 % (95 % confidence interval 56.3-96.5 %), respectively. The mean hospital stay was 8.4 +/- 3.1 days (range 5-18 days). CONCLUSION: MPT-RFA is a safe therapeutic option that initially provides therapeutic results. PMID- 27455987 TI - [The Freiburg monosyllabic test put to the test]. PMID- 27455986 TI - Evaluation of bone-seeking novel radiotracer 68Ga-NO2AP-Bisphosphonate for the detection of skeletal metastases in carcinoma breast. AB - PURPOSE: The successful labelling of bisphosphonates (BP) with 68Ga using macrocyclic chelators such as the based triazacyclononane (NO2AP) is a step forward in the in-house availability of a novel bone-seeking PET radiopharmaceutical with dual advantage of PET/CT imaging and generator production. In this study, we compared the novel generator-based skeletal radiotracer 68Ga-1,4,7-triazacyclonone-1,4-diacetic acid (68Ga-NO2AP-BP) with sodium fluoride (18F-NaF) for the detection of skeletal metastases in breast cancer patients. In addition, dosimetric analysis of 68Ga-NO2AP-BP was performed in a subset of patients. METHODS: This was a prospective study of histopathologically proven cases of breast cancer patients who were referred for bone scintigraphy and underwent positron emission tomography/computed tomography (PET/CT) with 18F-NaF and 68Ga-NO2AP-BP within a week in random order. The scans of each patient were compared both qualitatively for image quality and quantitatively for number of lesions and SUVmax of lesions. Dosimetric analysis was performed in five patients. Their PET/CT scans were acquired at multiple time points and urine and blood samples were collected. Dosimetric calculations were performed using OLINDA/EXM 1.1 software. Statistical analysis was done using Stata 13 (StataCorp) software package. An agreement analysis regarding number of lesions detected with the two skeletal radiotracers was carried out. RESULTS: The image quality of 68Ga-NO2AP-BP PET/CT scans were comparable to that of 18F-NaF. There was no statistically significant difference in the SUVmax of lesions, normal bone and lesion to background ratio between the two skeletal radiotracers. There was good agreement in the number of lesions detected by both skeletal radiotracers. The mean whole body effective dose for 68Ga-NO2AP-BP was 0.00583 mSv/MBq and the effective dose equivalent was 0.0086 mSv/MBq. CONCLUSION: The excellent lesion detection agreement between 68Ga-NO2AP-BP and 18F-NaF favours the former as an alternative for skeletal scintigraphy in centres without an on site cyclotron. The favourable dosimetric results and its potential to be used as a theranostic agent makes it an important generator-based skeletal radiotracer. PMID- 27455988 TI - [Numerical flow simulation : A new method for assessing nasal breathing]. AB - The current options for objective assessment of nasal breathing are limited. The maximum they can determine is the total nasal resistance. Possibilities to analyze the endonasal airstream are lacking. In contrast, numerical flow simulation is able to provide detailed information of the flow field within the nasal cavity. Thus, it has the potential to analyze the nasal airstream of an individual patient in a comprehensive manner and only a computed tomography (CT) scan of the paranasal sinuses is required. The clinical application is still limited due to the necessary technical and personnel resources. In particular, a statistically based referential characterization of normal nasal breathing does not yet exist in order to be able to compare and classify the simulation results. PMID- 27455989 TI - Controlling tip of nasotracheal tube under video laryngoscopy. PMID- 27455990 TI - SF-1 deficiency causes lipid accumulation in Leydig cells via suppression of STAR and CYP11A1. AB - Genetic mutations of steroidogenic factor 1 (also known as Ad4BP or Nr5a1) have increasingly been reported in patients with 46,XY disorders of sex development (46,XY disorders of sex development). However, because the phenotype of 46,XY disorders of sex development with a steroidogenic factor 1 mutation is wide ranging, its precise diagnosis remains a clinical problem. We previously reported the frequent occurrence of lipid accumulation in Leydig cells among patients with 46,XY disorders of sex development with a steroidogenic factor 1 mutation, an observation also reported by other authors. To address the mechanism of lipid accumulation in this disease, we examined the effects of steroidogenic factor 1 deficiency on downstream targets of steroidogenic factor 1 in in vitro and in vivo. We found that lipid accumulation in Leydig cells was enhanced after puberty in heterozygous steroidogenic factor 1 knockout mice compared with wild-type mice, and was accompanied by a significant decrease in steroidogenic acute regulatory protein and CYP11A1 expression. In mouse Leydig cell lines, steroidogenic factor 1 knockdown induced a remarkable accumulation of neutral lipids and cholesterol with reduced androgen levels. Steroidogenic factor 1 knockdown reduced the expression of steroidogenic acute regulatory protein and CYP11A1, both of which are transcriptional targets of steroidogenic factor 1 and key molecules for steroidogenesis from cholesterol in the mitochondria. Knockdown of either steroidogenic acute regulatory protein or CYP11A1 also induced lipid accumulation, and knockdown of both had an additive effect. Our data suggested that lipid accumulation in the Leydig cells of the 46,XY disorders of sex development phenotype with a steroidogenic factor 1 mutation is due, at least in part, to the suppression of steroidogenic acute regulatory protein and CYP11A1, and a resulting increase in unmetabolized cholesterol. PMID- 27455991 TI - Etanercept (SB4): A Review in Autoimmune Inflammatory Diseases. AB - Etanercept (SB4) [Benepali((r))], a tumour necrosis factor inhibitor that is a biosimilar of reference etanercept (Enbrel((r))), is approved in the EU for use in all adult indications for which reference etanercept is approved, namely rheumatoid arthritis, axial spondyloarthritis (ankylosing spondylitis and non radiographic axial spondyloarthritis), psoriatic arthritis, and plaque psoriasis. The approval of etanercept (SB4) was based on the results of stringent comparability exercises designed to demonstrate similarity to reference etanercept in terms of quality, biological activity, efficacy, safety, and immunogenicity. In two well-designed clinical trials, etanercept (SB4) was equivalent to reference etanercept with regard to pharmacokinetic properties in healthy volunteers and in terms of efficacy in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Longer-term efficacy (up to 52 weeks) was also similar in both treatment groups. Etanercept (SB4) was generally well tolerated, with a similar safety profile to that of reference etanercept. Preliminary results of the open-label extension period (100 weeks) suggest that transitioning from reference etanercept to etanercept (SB4) was associated with sustained efficacy and no change in the adverse event profile or immunogenicity. In conclusion, etanercept (SB4) provides therapeutically equivalent alternative in adult patients with autoimmune inflammatory diseases requiring treatment with etanercept. PMID- 27455993 TI - Combining Unique Multiplex Gateway Cloning and Bimolecular Fluorescence Complementation (BiFC) for High-Throughput Screening of Protein-Protein Interactions. AB - Protein interaction networks are the basis for human metabolic and signaling systems. Interaction studies often use bimolecular fluorescence complementation (BiFC) to reveal the formation and cellular localization of protein complexes. However, large-scale studies were either far from native conditions in human cells or limited by laborious restriction/ligation cloning techniques. Here, we describe a new tool for protein interaction screening based on Gateway-compatible BiFC vectors. We made a set of four new vectors that permit fusion of candidate proteins to the N or C fragment of Venus in all fusion positions. We have validated the vectors and confirmed self-association of AHCY, AHCYL1, and galectin-3. In a high-throughput BiFC screen, we identified new AHCY interaction partners: galectin-3 and PUS7L. We also describe additional steps in protein interaction analysis, applied for AHCY-galectin-3 interaction. First, we classified the interaction in intracellular vesicles using CellCognition, machine learning free software. Then we identified the vesicles as endosomal pathway compartments, in line with known galectin-3 trafficking route. This offers a platform to rapidly identify and localize new protein interactions inside living cells, a prerequisite to validate in silico interactome data, and ultimately decode complex protein networks. PMID- 27455992 TI - Posterior and prefrontal contributions to the development posttraumatic stress disorder symptom severity: an fMRI study of symptom provocation in acute stress disorder. AB - Acute stress disorder (ASD) is predictive of the development of posttraumatic stress disorder (PTSD). In response to symptom provocation, the exposure to trauma-related pictures, ASD patients showed increased activation of the medial posterior areas of precuneus and posterior cingulate cortex as well as of superior prefrontal cortex in a previous study. The current study aimed at investigating which activated areas are predictive of the development of PTSD. Nineteen ASD patients took part in an fMRI study in which they were shown personalized trauma-related and neutral pictures within 4 weeks of the traumatic event. They were assessed for severity of PTSD 4 weeks later. Activation contrasts between trauma-related and neutral pictures were correlated with subsequent PTSD symptom severity. Greater activation in, among others, right medial precuneus, left retrosplenial cortex, precentral and right superior temporal gyrus as well as less activation in lateral, superior prefrontal and left fusiform gyrus was related to subsequently increased PTSD severity. The results are broadly in line with neural areas related to etiological models of PTSD, namely multisensory associative learning recruiting posterior regions on the one hand and failure to reappraise maladaptive cognitions, thought to involve prefrontal areas, on the other. PMID- 27455995 TI - Assessing the effective use of mosquito nets in the prevention of malaria in some parts of Mezam division, Northwest Region Cameroon. AB - BACKGROUND: In Cameroon, malaria continues to be endemic and the first major cause of morbidity and mortality among the most vulnerable groups-children under 5 years of age, pregnant women, people living with HIV/AIDS and the poor. The use of long-lasting insecticide-treated bed nets (LLINs) is one of the recommended measures to prevent malaria. The present study was aimed at accessing the acceptability and effective use of LLINs on the prevalence of malaria in PMI Nkwen, Bambui and its environs. METHODS: Hospital-based diagnosis consisted of 476 blood samples that were screened using the rapid diagnostic kits to determine the prevalence of malaria among users and non-users of LLINs. A structured questionnaire was also administered to pregnant women and children less than 5 years of age (476 hospital-based and 350 from the community) which consisted of demographic information, availability, accessibility affordability, acceptability, effective use and problems encountered with the use of LLINs. RESULTS: Result obtained showed that out of the 476 hospital-based patients, 29 tested positive for malaria giving an overall prevalence of 6.09 %. Equally, results of the questionnaire showed that 743 (89.9 %) of the respondents owned LLINs with up to 649 (87.3 %) having been given to them free-of-charge, and that 578 (77.8 %) were using their LLINs to sleep, even though 18.2 % of the respondents used their LLINs for other purposes, such as fishing, nursing seeds and footfall nets. Malaria was minimal among users of LLINs than non-users and the results were significant at P <= 0.05. Also 71.9 % of the respondents said that their nets were in good condition while 52.2 % of them said the major problem with the usage of LLINs was heat and the feeling of suffocation. CONCLUSION: These results indicate that LLINs have significantly reduced the prevalence of malaria among the studied population, and so the government should not relent its efforts in the distribution of these nets especially to the vulnerable groups in order eliminate malaria and other mosquito-borne diseases. Utilization of LLINs needs to be encouraged to match ownership, while free distribution of ITNs to vulnerable groups needs to be continuous and consistent. PMID- 27455994 TI - Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases. AB - Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment. PMID- 27455996 TI - Protoplast transformation as a potential platform for exploring gene function in Verticillium dahliae. AB - BACKGROUND: Large efforts have focused on screening for genes involved in the virulence and pathogenicity of Verticillium dahliae, a destructive fungal pathogen of numerous plant species that is difficult to control once the plant is infected. Although Agrobacterium tumefaciens-mediated transformation (ATMT) has been widely used for gene screening, a quick and easy method has been needed to facilitate transformation. RESULTS: High-quality protoplasts, with excellent regeneration efficiency (65 %) in TB3 broth (yeast extract 30 g, casamino acids 30 g and 200g sucrose in 1L H20), were generated using driselase (Sigma D-9515) and transformed with the GFP plasmid or linear GFP cassette using PEG or electroporation. PEG-mediated transformation yielded 600 transformants per microgram DNA for the linear GFP cassette and 250 for the GFP plasmid; electroporation resulted in 29 transformants per microgram DNA for the linear GFP cassette and 24 for the GFP plasmid. To determine whether short interfering RNAs (siRNAs) can be delivered to the protoplasts and used for silencing genes, we targeted the GFP gene of Vd-GFP (V. dahliae GFP strain obtained in this study) by delivering one of four different siRNAs-19-nt duplex with 2-nt 3' overhangs (siRNA-gfp1, siRNA-gfp2, siRNA-gfp3 and siRNA-gfp4)-into the Vd-GFP protoplasts using PEG-mediated transformation. Up to 100 % silencing of GFP was obtained with siRNA-gfp4; the other siRNAs were less effective (up to 10 % silencing). Verticillium transcription activator of adhesion (Vta2) gene of V. dahliae was also silenced with four siRNAs (siRNA-vta1, siRNA-vta2, siRNA-vta3 and siRNA vta4) independently and together using the same approach; siRNA-vta1 had the highest silencing efficiency as assessed by colony diameter and quantitative real time PCR (qRT-PCR) analysis. CONCLUSION: Our quick, easy transformation method can be used to investigate the function of genes involved in growth, virulence and pathogenicity of V. dahliae. PMID- 27455998 TI - Federal privacy rules offer scant protection for users of health apps and wearable devices. PMID- 27455997 TI - Unravelling population genetic structure with mitochondrial DNA in a notional panmictic coastal crab species: sample size makes the difference. AB - BACKGROUND: The extent of genetic structure of a species is determined by the amount of current gene flow and the impact of historical and demographic factors. Most marine invertebrates have planktonic larvae and consequently wide potential dispersal, so that genetic uniformity should be common. However, phylogeographic investigations reveal that panmixia is rare in the marine realm. Phylogeographic patterns commonly coincide with geographic transitions acting as barriers to gene flow. In the Mediterranean Sea and adjoining areas, the best known barriers are the Atlantic-Mediterranean transition, the Siculo-Tunisian Strait and the boundary between Aegean and Black seas. Here, we perform the so far broadest phylogeographic analysis of the crab Pachygrapsus marmoratus, common across the north-eastern Atlantic Ocean, Mediterranean and Black seas. Previous studies revealed no or weak genetic structuring at meso-geographic scale based on mtDNA, while genetic heterogeneity at local scale was recorded with microsatellites, even if without clear geographic patterns. Continuing the search for phylogeographic signal, we here enlarge the mtDNA dataset including 51 populations and covering most of the species' distribution range. RESULTS: This enlarged dataset provides new evidence of three genetically separable groups, corresponding to the Portuguese Atlantic Ocean, Mediterranean Sea plus Canary Islands, and Black Sea. Surprisingly, hierarchical AMOVA and Principal Coordinates Analysis agree that our Canary Islands population is closer to western Mediterranean populations than to mainland Portugal and Azores populations. Within the Mediterranean Sea, we record genetic homogeneity, suggesting that population connectivity is unaffected by the transition between the western and eastern Mediterranean. The Mediterranean metapopulation seems to have experienced a relatively recent expansion around 100,000 years ago. CONCLUSIONS: Our results suggest that the phylogeographic pattern of P. marmoratus is shaped by the geological history of Mediterranean and adjacent seas, restricted current gene flow among different marginal seas, and incomplete lineage sorting. However, they also caution from exclusively testing well-known biogeographic barriers, thereby neglecting other possible phylogeographic patterns. Mostly, this study provides evidence that a geographically exhaustive dataset is necessary to detect shallow phylogeographic structure within widespread marine species with larval dispersal, questioning all studies where species have been categorized as panmictic based on numerically and geographically limited datasets. PMID- 27455999 TI - Going Beyond Administrative Data: Retrospective Evaluation of an Algorithm Using the Electronic Health Record to Help Identify Bleeding Events Among Hospitalized Medical Patients on Warfarin. AB - To reliably assess quality, a standardized electronic approach is needed to identify bleeding events. The study aims were the following: (1) clinically validate an electronic health record-based algorithm for bleeding and (2) assess interrater results to determine validity and reliability. Data were analyzed before and after implementation of a pharmacist-managed warfarin protocol. Bleeding was based on >=2 of 3 criteria: (1) diagnosis indicating bleeding, (2) lab value decrease suggesting bleeding, and (3) blood product use. All suspected bleeds (234) and a sample (58) not meeting criteria were compared with clinical review. There were 234 bleeding cases identified electronically. Reviewer agreement was 78.2% (kappa = 0.565). Algorithm sensitivity was 93.9% and positive predictive value 46.2%. Algorithm identification was least accurate for those with only 2 criteria but good for those with all criteria. This study supports using multiple electronic criteria to identify bleeding events. However, cases having exactly 2 criteria may require manual review for validation. PMID- 27456000 TI - Posttraumatic growth following a first episode of psychosis: a mixed methods research protocol using a convergent design. AB - BACKGROUND: The suffering people experience following a first episode of psychosis is great, and has been well-investigated. Conversely, potential positive outcomes following a first episode of psychosis have been under investigated. One such outcome that may result from a first episode of psychosis is posttraumatic growth, or a positive aftermath following the trauma of a first psychotic episode. While posttraumatic growth has been described following other physical and mental illnesses, posttraumatic growth has received very little attention following a first episode of psychosis. To address this research gap, we will conduct a mixed methods study aimed at answering two research questions: 1) How do people experience posttraumatic growth following a first episode of psychosis? 2) What predicts, or facilitates, posttraumatic growth following a first episode of psychosis? METHODS/DESIGN: The research questions will be investigated using a mixed methods convergent design. All participants will be service-users being offered treatment for a first episode of psychosis at a specialized early intervention service for young people with psychosis, as well as their case managers.. A qualitative descriptive methodology will guide data collection through semi-structured interviews with service-users. Service-users and case managers will complete questionnaires related to posttraumatic growth and its potential predictors using quantitative methods. These predictors include the impact a first episode of psychosis on service-users' lives, the coping strategies they use; the level of social support they enjoy; and their experiences of resilience and recovery. Qualitative data will be subject to thematic analysis, quantitative data will be subject to multiple regression analyses, and results from both methods will be combined to answer the research questions in a holistic way. DISCUSSION: Findings from this study are expected to show that in addition to suffering, people with a first episode of psychosis may experience positive changes. This study will be one of few to have investigated posttraumatic growth following a first episode of psychosis, and will be the first to do so with a mixed methods approach. PMID- 27456001 TI - Increased red cell distribution width in Fanconi anemia: a novel marker of stress erythropoiesis. AB - BACKGROUND: Red cell distribution width (RDW), a classical parameter used in the differential diagnosis of anemia, has recently been recognized as a marker of chronic inflammation and high levels of oxidative stress (OS). Fanconi anemia (FA) is a genetic disorder associated to redox imbalance and dysfunctional response to OS. Clinically, it is characterized by progressive bone marrow failure, which remains the primary cause of morbidity and mortality. Macrocytosis and increased fetal hemoglobin, two indicators of bone marrow stress erythropoiesis, are generally the first hematological manifestations to appear in FA. However, the significance of RDW and its possible relation to stress erythropoiesis have never been explored in FA. In the present study we analyzed routine complete blood counts from 34 FA patients and evaluated RDW, correlating with the hematological parameters most consistently associated with the FA phenotype. RESULTS: We showed, for the first time, that RDW is significantly increased in FA. We also showed that increased RDW is correlated with thrombocytopenia, neutropenia and, most importantly, highly correlated with anemia. Analyzing sequential hemograms from 3 FA patients with different clinical outcomes, during 10 years follow-up, we confirmed a consistent association between increased RDW and decreased hemoglobin, which supports the postulated importance of RDW in the evaluation of hematological disease progression. CONCLUSIONS: This study shows, for the first time, that RDW is significantly increased in FA, and this increment is correlated with neutropenia, thrombocytopenia, and highly correlated with anemia. According to the present results, it is suggested that increased RDW can be a novel marker of stress erythropoiesis in FA. PMID- 27456002 TI - Modulation of endoglin expression in islets of langerhans by VEGF reveals a novel regulator of islet endothelial cell function. AB - BACKGROUND: Endoglin/CD105 is an auxiliary receptor for transforming growth factor-beta with established roles in vascular remodelling. It has recently been shown that heterozygous endoglin deficiency in mice decreases insulin secretion in an animal model of obesity, highlighting a potential role for endoglin in the regulation of islet function. We have previously identified two different populations of endoglin expressing cells in human and mouse islets which are: (i) endothelial cells (ECs) and (ii) islet mesenchymal stromal cells. The contribution of islet EC endoglin expression to islet development and sensitivity to VEGF is unknown and is the focus of this study. RESULTS: In vitro culture of mouse islets with VEGF164 for 48 h increased endoglin mRNA levels above untreated controls but VEGF did not modulate VEGFR2, CD31 or CD34 mRNA expression or islet viability. Removal of EC-endoglin expression in vivo reduced islet EC area but had no apparent effect on islet size or architecture. CONCLUSION: EC-specific endoglin expression in islets is sensitive to VEGF and plays partial roles in driving islet vascular development, however such regulation appears to be distinct to mechanisms required to modulate islet viability and size. PMID- 27456003 TI - Survival and prognostic factors in patients with stable and unstable spinal bone metastases from solid tumors: a retrospective analysis of 915 cases. AB - BACKGROUND: Adequate prediction of survival plays an important role in treatment decisions for patients with spinal bone metastases (SBM). Several prognostic factors are already used in daily clinical practice, but factors related to stability of SBM are still unknown. Therefore, we designed this study to identify these prognostic factors. METHODS: We retrospectively assessed 915 patients from solid tumors with commonly metastased into the bone treated at our department between January 2000 and January 2012. Lung cancer (NSCLC), breast and renal cancer listed in Table 1 are the most common solid tumors with bone metastasis in this study. Prostate carcinoma was excluded due to osteoblastic SBM with no influence for stability. We calculated overall survival (OS) and bone survival (BS; time between first diagnosis of bone metastases until death) with the Kaplan Meier method and assessed prognostic factors for BS with the log-rank test and a Cox regression model separately for patients with stable and unstable SBM. RESULTS: Median follow-up was 9.3 months. OS after 6 months, 1, 2, and 5 years was 81, 62, 42, and 25 % in patients with stable SBM and 78, 57, 38, and 22 % in patients with unstable SBM (p = 0.851). BS was 57, 38, 22, and 5 % in the group of stable SBM after 6 months, 1, 2, and 5 years. For patients with unstable SBM BS after 6 months, 1, 2, and 5 years was 59, 39, 19, and 8 % (p = 0.755). In multivariate analysis we found male gender (HR = 1.27 [95 % CI 1.01-1.60], p = 0.04), Karnofsky performance status (KPS) <80 % (HR = 1.27 [95%CI 1.04-1.55], p = 0.02) and non-small cell lung cancer (NSCLC; HR = 2.77 [95%CI 1.99-3.86], p < 0.0001) to be independent prognostic factors for shortened survival in patients with stable SBM. Independent prognostic factors for unstable SBM were age per year (HR = 1.01 [95 % CI 1.0-1.02], p = 0.025), multiple SBM (HR = 1.35 [95 % CI 1.1-1.65], p = 0.003), and NSCLC (HR = 2.0 [95 % CI 1.43-2.80], p < 0.0001). Additionally, not wearing an orthopedic corset (HR = 0.77 [95 % CI 0.62-0.96], p = 0.02) was associated with prolonged BS in patients with unstable SBM and in both groups BS was significantly longer in patients without liver metastases (stable SBM: HR = 0.72 [95 % CI 0.56-0.92], p = 0.008; unstable SBM: HR = 0.71 [95 % CI 0.54-0.92], p = 0.01). CONCLUSIONS: Survival was equal for patients with stable and unstable SBM. However, prognostic factors differed in both groups and stability should therefore be considered in treatment decision-making. PMID- 27456004 TI - A synergistic DNA logic predicts genome-wide chromatin accessibility. AB - Enhancers and promoters commonly occur in accessible chromatin characterized by depleted nucleosome contact; however, it is unclear how chromatin accessibility is governed. We show that log-additive cis-acting DNA sequence features can predict chromatin accessibility at high spatial resolution. We develop a new type of high-dimensional machine learning model, the Synergistic Chromatin Model (SCM), which when trained with DNase-seq data for a cell type is capable of predicting expected read counts of genome-wide chromatin accessibility at every base from DNA sequence alone, with the highest accuracy at hypersensitive sites shared across cell types. We confirm that a SCM accurately predicts chromatin accessibility for thousands of synthetic DNA sequences using a novel CRISPR-based method of highly efficient site-specific DNA library integration. SCMs are directly interpretable and reveal that a logic based on local, nonspecific synergistic effects, largely among pioneer TFs, is sufficient to predict a large fraction of cellular chromatin accessibility in a wide variety of cell types. PMID- 27456005 TI - Varied flushing frequency and volume to prevent peripheral intravenous catheter failure: a pilot, factorial randomised controlled trial in adult medical-surgical hospital patients. AB - BACKGROUND: Research has identified high failure rates of peripheral intravenous catheter (PIVC) and varied flushing practices. METHODS: This is a single-centre, pilot, non-masked, factorial randomised controlled trial. Participants were adults, with a PIVC of expected use >=24 hours (n = 160), admitted to general medical or surgical wards of a tertiary referral hospital in Queensland (Australia). Patients were randomly allocated to one of four flush groups using manually prepared syringes and 0.9 % sodium chloride: 10 mL or 3 mL flush, every 24 or 6 hours. The primary endpoint was PIVC failure, a composite measure of occlusion, infiltration, accidental dislodgement and phlebitis. RESULTS: PIVC average dwell was 3.1 days. PIVC failure rates per 1000 hours were not significantly different for the volume intervention (4.84 [3 mL] versus 7.44 [10 mL], p = 0.06, log-rank). PIVC failure rates per 1000 hours were also not significantly different for the frequency intervention (5.06 [24 hour] versus 7.34 [6 hour], p = 0.05, log-rank). Cox proportional hazard regression found neither the flushing nor frequency intervention, or their interaction (p = 0.21) to be significantly associated with PIVC failure. However, female gender (hazard ratio [HR] 2.2 [1.3-3.6], p < 0.01), insertion in hand/posterior wrist (HR 1.7 [1.0-2.7], p < 0.05) and the rate per day of PIVC access (combined flushes and medication pushes) (HR 1.2 [1.1-1.4], p < 0.01) significantly predicted PIVC failure. CONCLUSION: Neither increased flushing volume nor frequency significantly altered the risk of PIVC failure. Female gender, hand/posterior wrist placement and episodes of access (flushes and medication) may be more important. Larger, definitive trials are feasible and required. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12615000025538 . Registered on 19 January 2015. PMID- 27456007 TI - Occupational physicians' perceptions and experience of appraisals for revalidation. AB - BACKGROUND: Formal, structured annual appraisals are now a regulatory requirement for all doctors and must meet the standards stipulated by the General Medical Council (GMC), including connection with a designated body. AIMS: To investigate occupational physicians' opinions and experience of the first year of appraisals for revalidation. METHODS: Members of the Society of Occupational Medicine (SOM) were surveyed electronically regarding the appraisal process and its software. A quiz tested knowledge of the requirements and underlying principles and regulations of appraisal for revalidation. RESULTS: In total, 163 responses were received, with 57 free-text comments. Respondents spent a mean of 31h on the appraisal process (range 0-200h). Less than half of respondents said they had a clear understanding of the appraisal process. Most respondents (88 and 92%) reported difficulties with the appraisal process and the appraisal software. Only 22% felt the time taken for the appraisal process was proportionate to the value gained. Overall, there was support for appraisal and in particular for SOM appraisers, but only half of the respondents found it useful. The average quiz score was 11 out of 15 (74%) with only one respondent scoring full marks. About 25% of respondents were not aware that the responsible officer is obliged to act on any concerns raised. The free-text comments suggested that some physicians found the process costly and stressful. CONCLUSIONS: The findings suggest that the time requirements and process of appraisal for occupational physicians could be improved, and clearer, comprehensive and more accessible guidance should be developed. PMID- 27456006 TI - Does relationship satisfaction and financial aid from offspring influence the quality of life of older parents?: a longitudinal study based on findings from the Korean longitudinal study of aging, 2006-2012. AB - BACKGROUND: Quality of life (QoL) in old age is of major importance because the global population is aging rapidly. Offspring support, including financial and emotional support, is important in later life and directly affects the wellbeing of elderly individuals. The aim of this study was to examine the relationship between QoL in older parents and offspring support. METHODS: We used baseline data from the 2006-2012 Korean Longitudinal Study of Aging, from 3,274 individuals aged 65 years or older. We measured the individual's QoL using a visual analog scale and included both relationship satisfaction and regular economic support as variables. A generalized estimating equation (GEE) model was used to perform longitudinal regression analysis on the data. RESULTS: Regarding the QoL of older parents, those with an unsatisfying relationship with their offspring had a QoL of -21.93 (SE = 0.55; P < 0.0001) compared to those with satisfying offspring relationships. Those receiving no regular financial aid from their offspring had a QoL of -0.92 (SE = 0.38; P = 0.0171) compared to those who received such economic support. Combination effects were observed, with cases living alone - and having poor offspring relationships and no regular financial support from their offspring - showing the most drastic decrease in QoL (-23.46; SE = 1.03; P < 0.0001). CONCLUSIONS: Offspring support influences the QoL of elderly individuals, and Korean children appear to play a crucial role in the QoL of their (older) parents. Considering that the role of offspring is rapidly diminishing due to industrialization policies, initiatives are required to revitalize offspring support for elderly parents. PMID- 27456008 TI - Efficacy of cryotherapy for the treatment of cutaneous leishmaniasis: meta analyses of clinical trials. AB - BACKGROUND: Cryotherapy is a local treatment for cutaneous leishmaniasis with variable efficacy and greater safety than conventional treatment. The objective of this study is to evaluate the efficacy and safety of cryotherapy for the treatment of cutaneous leishmaniasis and to compare it with pentavalent antimonials. METHODS: A meta-analysis based on a search of nine databases with eight strategies was conducted. Inclusion and exclusion criteria were applied, the methodological quality of each article was evaluated, and the reproducibility of the study selection and information extraction from each clinical trial was assured. The per lesion and per patient efficacy was calculated, and a meta analysis of relative risks with the random effects model and the Dersimonian and Laird's, Begg, and Egger tests, along with a sensitivity analysis, were performed. A meta-regression based on the methodological quality of the trials included was also performed. RESULTS: Eight studies were included in which respective per lesion efficacies of 67.3 % and 67.7 % were reported for cryotherapy and pentavalent antimonials. In 271 patients treated with cryotherapy and in 199 with pentavalent antimonials, respective per protocol and intent to treat efficacies of 63.6 % and 54.2 % were found in the first group, and per protocol and intent to treat efficacies of 74.7 % and 68.3 % were found in the second group. The relative risk for the comparison of efficacy in the two groups was 0.73 (0.42-1.29). The results of the sensitivity analysis and the meta regression analysis of relative risks were statistically equal to the overall results. CONCLUSION: This investigation provides evidence in favor of the use of cryotherapy given that its efficacy is similar to that of pentavalent antimonials. PMID- 27456009 TI - Commentary: The Expression of CD123 Can Decrease with Basophil Activation: Implications for the Gating Strategy of the Basophil Activation Test. PMID- 27456010 TI - Publication activities of German junior researchers in academic medicine: which factors impact impact factors? AB - BACKGROUND: Previous studies have shown medical students in Germany to have little interest in research while at the same time there is a lack of physician scientists. This study's aim is to investigate factors influencing publication productivity of physicians during and after finishing their medical doctorate. METHODS: We conducted a PubMed search for physicians having received their doctoral degree at Ludwig-Maxmilians-University Munich Faculty of Medicine between 2011 and 2013 (N = 924) and identified the appropriate impact factor (IF) for each journal the participants had published in. Gender, age, final grade of the doctorate, participation in a structured doctoral study program and joint publication activities between graduate and academic supervisor were defined as factors. For analyses we used nonparametric procedures. RESULTS: Men show significantly more publications than women. Before their doctoral graduation men publish 1.98 (SD +/- 3.64) articles on average, women 1.15 (+/-2.67) (p < 0.0001, d = 0.27). After completion of the doctorate (up to 06/2015), 40 % of men still publish, while only 24.3 % of women (p < 0.0001, phi = 0.17) continue to publish. No differences were found concerning the value of IFs. Similar results were found regarding the variable 'participation in a structured doctoral study program'. Until doctoral graduation, program participants publish 2.82 (+/-5.41) articles, whereas participants doing their doctorate individually only publish 1.39 (+/ 2.87) articles (p < 0.0001, d = 0.46). These differences persist in publication activities after graduation (45.5 vs. 29.7 %, p = 0.008, phi = 0.09). A structured doctorate seems to have positive influence on IFs (4.33 +/- 2.91 vs. 3.37 +/- 2.82, p = 0.006, d = 0.34). Further significant results concern the variables 'final grade' and 'age': An early doctoral graduation and an excellent or very good grade for the doctoral thesis positively influence publication productivity. Finally, joint publication activities between the graduate and his/her academic supervisor result in significantly higher IFs (3.64 +/- 3.03 vs. 2.84 +/- 2.25, p = 0.007, d = 0.28). CONCLUSIONS: The study's results support the assumption about women's underrepresentation in science as well as the relevance of structured doctoral study programs for preparing and recruiting young academics in medicine for scientific careers. Promoting women and further development of structured doctoral study programs are highly recommended. PMID- 27456011 TI - Editorial: Molecular Imaging of Protein and Peptide. PMID- 27456012 TI - 20-Year Trends in the Management of Diverticulitis Across New York State: an Analysis of 265,724 Patients. AB - INTRODUCTION: Management of acute diverticulitis (AD) has considerably changed over time. This study evaluates practice patterns for diverticulitis across demographic populations in New York State. METHODS: Two hundred sixty-five thousand seven hundred twenty-four patients with acute diverticulitis were analyzed from 1995 to 2014 from the New York-Statewide Planning and Research Cooperative System database. The likelihood of having surgery over time was compared across patient demographic subgroups using logistic regression models to calculate estimated odds ratio with their 95 % confidence intervals. Using Chi square test and Welch's t test, categorical and continuous variables were compared. RESULTS: From 1995 to 2014, there was an increase in newly diagnosed diverticulitis patients while the proportion of those patients undergoing operative management steadily decreased (31 to 10 %, p < 0.0001). Of those receiving surgery, emergent surgeries decreased (58 to 47 %, p < 0.0001) while elective surgeries increased (42 to 53 %, p < 0.0001) with the odds of having emergency surgery decreasing by 4 % annually (OR 0.96 (0.95-0.97), p < 0.0001). With the exception of patients greater than 80 years old, these linear trends were substantiated across patient subgroups. CONCLUSIONS: Over the past 20 years in New York State, there has been an increase in diverticulitis diagnoses and hospital admissions, with a decrease in surgeries performed reflecting a shift towards conservative management and more effective antibiotic treatment. PMID- 27456013 TI - The Use of Mesh in Emergent Ventral Hernia Repair: Effects on Early Patient Morbidity and Mortality. AB - INTRODUCTION: The long-term recurrence rate of ventral hernia repair is 20-50 %, with a higher rate of recurrence in cases that do not use mesh. Previous teachings have cautioned against the use of mesh in contaminated wounds. Therefore, emergent ventral hernia repair is often performed without the use of mesh. Our aim is to determine if mesh is used in these cases and its effect on 30 day wound-related morbidity using the American College of Surgeons National Surgery Quality Improvement Program database. METHODS: All emergency ventral hernia repairs performed from 2005 to 2013 were identified. The effect of mesh on postoperative morbidity and mortality was investigated. Significance was defined as p < 0.05. RESULTS: A total of 2449 patients met inclusion criteria. The use of mesh was associated with a significantly longer operative time for all wound classes and increased risk of return to the operating room in contaminated cases. Patients who returned to the operating room did not return to the OR for mesh or hernia-related complications. CONCLUSIONS: Emergency ventral hernia repair with mesh can be safely performed without an increase in wound-related or additional 30-day patient morbidity or mortality. Additional studies are needed to determine the long-term outcomes of mesh utilization in this cohort. PMID- 27456014 TI - Importance of esophageal manometry and pH monitoring for the evaluation of otorhinolaryngologic (ENT) manifestations of GERD. A multicenter study. AB - BACKGROUND/AIMS: Patients with otorhinolaryngologic (ear, nose, and throat-ENT) symptoms attributed to gastroesophageal reflux disease (GERD) are usually treated with medication based on the findings of nasal endoscopy and laryngoscopy only. This study aims to determine sensitivity and specificity of symptoms, nasal endoscopy, and laryngoscopy for the diagnosis of GERD as compared to pH monitoring. METHODS: We studied 79 patients (mean age 53 years, 38 % males) in whom ENT symptoms were assumed to be secondary to GERD. All patients underwent a transnasal laryngoscopy by the ENT team and upper endoscopy and esophageal function tests by the surgical team. GERD was defined by a pathological pH monitoring. RESULTS: Pathologic reflux by pH monitoring was documented in 36 of the 79 patients (46 %), with a mean DeMeester score of 44. In 25 of the 36 patients (69 %), distal and proximal reflux was present. Among patients with negative pH monitoring, one patient was diagnosed with achalasia. ENT symptom sensitivity for globus, hoarseness and throat clearing was respectively 11, 58, and 33 %; specificity was respectively 77, 42, and 58 %. Positive predictive value for nasal endoscopy and laryngoscopy was 46 %. Among patients with positive pH monitoring, 13 (36 %) had a hypotensive lower esophageal sphincter (p < 0.01) and 27 (34 %) had abnormal peristalsis (p < 0.01). CONCLUSIONS: In conclusion, the results of this study showed that (a) ENT symptoms were unreliable for the diagnosis of GERD and (b) laryngoscopy had a low positive predictive value for the diagnosis of GERD. These data confirm the importance of esophageal manometry and pH monitoring in any patient with suspected ENT manifestations of GERD before starting empiric therapy with acid-reducing medications since pathologic reflux by pH monitoring was confirmed in less than half of the patients with suspected GERD. PMID- 27456015 TI - MicroRNA Expression in a Readily Accessible Common Hepatic Artery Lymph Node Predicts Time to Pancreatic Cancer Recurrence Postresection. AB - Lymph node involvement in pancreatic adenocarcinoma (PAC) predicts postresection survival, but early lymph node metastasis detection is not easily accomplished. We assessed a panel of microRNAs (miRNAs) in a common hepatic artery lymph node (station 8) that is readily accessible during pancreatoduodenectomy (PD) to determine if increased miRNA levels correlate with postresection recurrence. Station 8 lymph nodes overlying the common hepatic artery collected during PD were assayed for miRNA-10b, miRNA-30c, miRNA-21, and miRNA-155 and cytokeratin-19 (CK19), an epithelial cell marker, using quantitative PCR. Expression was correlated with disease recurrence, recurrence-free survival (RFS), and overall survival (OS). Station 8 lymph nodes from 37 patients (30 periampullary carcinomas (PCs), 2 chronic pancreatitis, 5 other cancers) exhibited increased miRNA-10b levels in 14/30 PCs, and in 10 of these 14 patients, cancer recurred during the study period (2012-2015). High miRNA-10b was also associated with shorter RFS (42.5 vs. 92.4 weeks, p < 0.05) but not OS, whereas miRNA-30c, miRNA 21, and miRNA-155 levels and CK19 mRNA levels in station 8 nodes were variable and did not correlate with RFS or OS. We conclude that elevated miRNA-10b levels in station 8 lymph nodes could be utilized to assess risk for early disease progression in patients with periampullary tumors. PMID- 27456016 TI - Prognosis of Fibrolamellar Carcinoma Compared to Non-cirrhotic Conventional Hepatocellular Carcinoma. AB - BACKGROUND: Fibrolamellar carcinoma (FLC) and conventional hepatocellular carcinoma (HCC) share the same American Joint Committee on Cancer (AJCC) staging. The worse survival with HCC is attributed to the underlying cirrhosis.The aim of this study was to compare stage-matched prognosis after resection of FLC and non cirrhotic HCC. METHODS: Outcomes after resection of 65 consecutive patients with FLC and 158 non-cirrhotic patients with HCC were compared. Patients were staged according to the 7th edition AJCC staging. RESULTS: The AJCC stage distributions for FLC and HCC demonstrated a predominance of stage IV disease in FLC and stage I in HCC (FLC stage I-23 %, II-15 %, III-15 %, IV-46 % vs. HCC stage I-42 %, II 32 %, III-20 %, IV-6 %, p < 0.001). Among stage IV FLC patients, 81 % had isolated nodal metastases, which did not affect overall survival (OS) or recurrence-free survival (RFS). In FLC, OS was significantly affected by the number of tumors and vascular invasion (p < 0.05). Recurrent disease developed in 56 (86 %) FLC patients and was treated with repeat surgical resection in 25 (45 %) patients. Vascular invasion was associated with recurrent FLC, with 3-year RFS rates of 9 % and 35 %, with and without vascular invasion (p = 0.034). With respect to RFS, the AJCC staging did not stratify FLC patients, compared to non cirrhotic HCC. CONCLUSIONS: When compared to non-cirrhotic HCC, patients with FLC are not adequately stratified by AJCC staging with respect to RFS. Our results support classifying lymph node metastases in FLC as regional disease, rather than systemic disease. Important prognostic factors in FLC are the number of tumors and vascular invasion. PMID- 27456017 TI - Efficacy and Safety of Combined Ultrasonic and Bipolar Energy Source in Laparoscopic Surgery. AB - AIM: Energy devices represent an alternative to clips and staplers for vessel sealing. Outcome data of patients undergoing laparoscopic surgery with use of a novel combined ultrasonic and bipolar energy device (TB, ThunderbeatTM) was gathered. METHODS: Consecutive patients undergoing laparoscopic surgery using TB were prospectively included between November 2011 and January 2016. Large vessels were dissected using the energy device without additional clips or staplers. The type of procedure, operative time, length of stay, complications, blood transfusions, number and type of vessels being dissected, and need for additional clips were noted. RESULTS: Six hundred eighty-three patients underwent 758 procedures with dissection of 1310 large vessels. No additional hemoclips or vascular staplers were used. There were 0.7 % (5/758) intraoperative and 2.6 % (20/758) postoperative bleeding complications. Eleven bleeding occurred at the stapler line of anastomosis, leaving 1.8 % (14/758) bleeding that were potentially related to inadequate hemostasis. Failure of large vessel dissection occurred in two cases (0.15 %, 2/1310) and device-related complications in 1.1 % (8/758). Two of 42 conversions (5.5 %) were bleeding-related. CONCLUSION: TB provides a reliable and effective hemostasis. However, ligation failure may occur. As with any kind of electrosurgery, the hot tip of the instruments bears the risk of potentially fatal thermal injuries. PMID- 27456018 TI - Hand-Assisted Laparoscopic Versus Standard Laparoscopic Colectomy: Are Outcomes and Operative Time Different? AB - BACKGROUND: HAL colectomy is a technique perceived to provide the benefits of laparoscopic surgery while improving tactile feedback and operative time. Published data are largely limited to small, single-institution studies. METHODS: The 2012-2013 National Surgical Quality Improvement Program Participant Data Use File was queried for patients undergoing elective SL or HAL colectomy. Patients underwent 1:1 propensity matching and had outcomes compared. An additional subgroup analysis was performed for patients undergoing segmental resections only. RESULTS: 13,949 patients were identified, of whom 6084 (43.6 %) underwent HAL colectomy. Patients undergoing HAL versus SL colectomy had higher rates of postoperative ileus (8.7 vs. 6.3 %, p < 0.001), wound complication (8.8 vs. 6.8 %, p = 0.006), and 30-day readmission (7.5 vs. 6.0 %, p = 0.002), without any differences in operative time (156 vs. 157 min, p = 0.713). Amongst segmental colectomies, HAL remained associated with higher rates of wound complications (8.6 vs. 6.5 %, p = 0.016), postoperative ileus (8.9 vs. 6.3 %, p < 0.001), and 30-day readmission (7.1 vs. 5.9 %, p = 0.041) with no difference in operative time between HAL and SL (145 vs. 145 min, p = 0.334). CONCLUSIONS: Use of HAL colectomy is associated with increased risk of wound complications, postoperative ileus, and readmissions. Importantly, this technique is not associated with any decrease in operative time. PMID- 27456019 TI - Technical Details of an Anterior Approach to the Superior Mesenteric Artery During Pancreaticoduodenectomy. AB - INTRODUCTION: Use of central vascular ligation during dissection around the superior mesenteric artery (SMA) in pancreaticoduodenectomy (PD) for periampullary malignancies has rarely been documented. METHODS: We developed the SMA hanging technique (SHT) to facilitate central vascular ligation during PD. Briefly, SMA dissection was initiated using the supracolic anterior approach, followed by left-sided dissection. The SMA was taped under finger guidance immediately after right-sided dissection. The ligament of Treitz was detached from the SMA during left-sided dissection, facilitating adequate lymph node dissection while preserving the nerve plexus around the SMA. Forty-seven consecutive patients who underwent PD for periampullary malignancies were divided into two groups: 23 underwent SHT and 24 underwent conventional dissection. Patients' clinical results were assessed to evaluate the feasibility and validity of SHT. RESULTS: Blood loss volume, operation duration, and the incidence of bleeding during SMA dissection were significantly lower in the SHT group than in the conventional group. The short-term and oncological results were similarly acceptable in both groups. CONCLUSIONS: SHT is a feasible and safe technique with acceptable short-term outcomes. We propose the use of this procedure to standardize en bloc dissection around the SMA. PMID- 27456020 TI - Radiocarpal Injuries: Cone Beam Computed Tomography Arthrography, Magnetic Resonance Arthrography, and Arthroscopic Correlation among 21 Patients. AB - BACKGROUND AND AIMS: Patients with acute or chronic wrist pain often undergo wrist arthroscopy for evaluation of chondral and ligamentous abnormalities. The purpose of this study was to compare findings of wrist arthroscopy with cone beam computed tomography arthrography and magnetic resonance arthrography. MATERIALS AND METHODS: Altogether, 21 patients with wrist pain underwent cone beam computed tomography arthrography, magnetic resonance arthrography, and wrist arthroscopy. Chondral surfaces of the scaphoid, lunate, and radius facing the scaphoid and lunate were evaluated. The scapholunate ligament, the lunotriquetral ligament, and the triangular fibrocartilage complex were classified as either intact or torn. Sensitivity, specificity, positive and negative predictive values, and accuracy with 95% confidence intervals were assessed. RESULTS: For chondral lesions (n = 10), cone beam computed tomography arthrograms showed slightly higher specificity than magnetic resonance arthrography. The sensitivity of cone beam computed tomography arthrography was also better for these lesions, except for those on the chondral surface of the lunate. For triangular fibrocartilage complex injuries (n = 9), cone beam computed tomography arthrography showed a better specificity and sensitivity than magnetic resonance arthrography. For ligamentous injuries (n = 6), cone beam computed tomography arthrograms were more sensitive, but less specific than magnetic resonance arthrography images. However, the number of lesions was very small and the 95% confidence intervals are overlapping. CONCLUSION: Cone beam computed tomography is an emerging imaging modality that offers several advantages over computed tomography and magnetic resonance imaging. Its usefulness particularly in ligamentous injuries should be further explored in a larger study. Cone beam computed tomography arthrography seems to offer similar sensitivity, specificity, and accuracy compared to magnetic resonance arthrography and therefore serves as a valuable option in evaluating patients with wrist pain. PMID- 27456021 TI - Freedom Constrained Liner for the Treatment and Prevention of Dislocation in Total Hip Arthroplasty. AB - BACKGROUND AND PURPOSE: Dislocation is one of the most common complications following total hip arthroplasty. The aim of our study was to assess failure rate of the Biomet Freedom constrained liner (Biomet, Warsaw, IN, USA) either in revision surgery for recurrent dislocation, or as a preventive method in high dislocation risk patients. PATIENTS AND METHODS: We assessed retrospectively 105 consecutive surgical procedures in 103 patients where a Freedom constrained liner or cup was used in Turku University Hospital over a 7-year period from 2007 to 2014. The mechanical failure rate of the device was assessed based on medical records. The average age of the patients was 73.4 years. The number of male patients was 53 (51%). Mean follow-up time was 2.5 years. The association between failure of the device and potential risk factors-age, gender, indication, and approach-was analyzed with logistic regression. Results were expressed by odd ratios and 95% confidence intervals. RESULTS: The mechanical failure rate of the Freedom device was 6 out of 105 (5.7%). None of the 11 preventive primary THAs against dislocation failed, 4 out of 52 (7.7%) preventive revision THAs against dislocation failed, and 2 out of 42 (4.8%) of the treated dislocation cases failed. Four out of six failures were dislocations due to impingement and failure of the locking mechanism. Two liners failed because of loosening. The risk factors assessed were not associated with failure of the device. INTERPRETATION: We found out that the mechanical failure rate of a Freedom constrained device was low. These results encourage us to continue using the device. PMID- 27456022 TI - A Mosaicking Approach for In Vivo Thickness Mapping of the Human Tympanic Membrane Using Low Coherence Interferometry. AB - The thickness of the human tympanic membrane (TM) is known to vary considerably across different regions of the TM. Quantitative determination of the thickness distribution and mapping of the TM is of significant importance in hearing research, particularly in mathematical modeling of middle-ear dynamics. Change in TM thickness is also associated with several middle-ear pathologies. Determination of the TM thickness distribution could therefore also enable a more comprehensive diagnosis of various otologic diseases. Despite its importance, very limited data on human TM thickness distribution, obtained almost exclusively from ex vivo samples, are available in the literature. In this study, the thickness distribution for the in vivo human TM is reported for the first time. A hand-held imaging system, which combines a low coherence interferometry (LCI) technique for single-point thickness measurement, with video-otoscopy for recording the image of the TM, was used to collect the data used in this study. Data were acquired by pointing the imaging probe over different regions of the TM, while simultaneously recording the LCI and concomitant TM surface video image data from an average of 500 locations on the TM. TM thickness distribution maps were obtained by mapping the LCI imaging sites onto an anatomically accurate wide field image of the TM, which was generated by mosaicking the sequence of multiple small field-of-view video-otoscopy images. Descriptive statistics of the thickness measurements obtained from the different regions of the TM are presented, and the general thickness distribution trends are discussed. PMID- 27456023 TI - EPIRETINAL MEMBRANE IN NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION: Anatomical Features, Visual Outcomes and Prognostic Factors. AB - PURPOSE: To evaluate clinical characteristics, assess surgical outcomes, and determine prognostic factors after vitrectomy for epiretinal membrane (ERM) associated with nonexudative age-related macular degeneration (AMD). METHODS: This study comprised 171 consecutive patients with idiopathic ERM (n = 132) or nonexudative AMD-associated ERM (AMD-ERM, n = 39) undergoing vitrectomy. Preoperative morphologic characteristics on spectral-domain optical coherence tomography images and postoperative outcomes of the two groups were compared. Factors influencing postoperative best-corrected visual acuity in the AMD-ERM group were also analyzed. RESULTS: The AMD-ERM group was more likely to have an ERM with a smooth appearance (P = 0.009), a less severe vessel traction score (P = 0.002), a thinner central foveal thickness (P = 0.016), and more photoreceptor disruption than idiopathic ERM group. Mean central foveal thickness improved from 404.92 +/- 82.08 and 369.87 +/- 68.17 MUm at baseline to 339.77 +/- 39.27 and 331.72 +/- 45.76 MUm 1 year after surgery in eyes with idiopathic ERM and AMD ERM, respectively (all P < 0.001). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.30 (20/40) +/- 0.21 and 0.32 (20/42) +/- 0.18 at baseline to 0.02 (20/21) +/- 0.09 and 0.13 (20/27) +/- 0.17 1 year after surgery in the idiopathic ERM and AMD-ERM groups, respectively (all P < 0.001). Baseline integrity of the ellipsoid zone line (P = 0.009) and preoperative best-corrected visual acuity (P = 0.024) were significantly correlated with visual outcome in the AMD-ERM group. CONCLUSION: Morphologic differences between AMD-ERM and idiopathic ERM were identified. Vitrectomy resulted in significant anatomical and visual improvements in eyes with AMD-ERM, but final visual outcome was worse in these eyes than in those with idiopathic ERM. PMID- 27456024 TI - PERIPHERAL PIGMENTED STREAKS IN EYES WITH PATHOLOGIC MYOPIA. AB - PURPOSE: To determine the incidence and the characteristics of peripheral pigmented streaks in the eyes with pathologic myopia. METHODS: The widefield fundus images of 375 eyes (203 patients) with pathologic myopia were examined. The characteristics of the pigmented streaks existing in the peripheral fundus were analyzed. The spatial relationships between the steep edge of a staphyloma and the distribution of the streaks were also determined. RESULTS: Peripheral streaks were observed in 165 of the 375 eyes (44.0%) as dark, pigmented, radially oriented lesions resembling octopus tentacles. The streaks ran from the mid periphery to the equator. Large choroidal vessels were observed in the corresponding sites, so the streaks probably existed in the layer of the large choroidal vessels or deeper. The patients with streak lesions were significantly older and had a posterior staphyloma more frequently than the eyes without the streaks. The streaks were observed mainly in the area opposite the steep edge of a staphyloma. CONCLUSION: Peripheral pigmented streaks are seen in approximately 44% of eyes with pathologic myopia. The streaks existed in the layer of large choroidal vessels or deeper, and the thinning of the choroid-retina in highly myopic eyes contributes to the visibility of such deep lesions. PMID- 27456025 TI - Diagnostic and Therapeutic Challenges. PMID- 27456027 TI - Regional Variation in the Mechanical and Microstructural Properties of the Human Anterior Cruciate Ligament. AB - BACKGROUND: The anteromedial (AM) bundle of the anterior cruciate ligament (ACL) has a higher modulus and failure stress than does the posterolateral (PL) bundle. However, it is unknown how these properties vary within each bundle. PURPOSE: To quantify mechanical and microstructural properties of samples within ACL bundles to elucidate any regional variation across the ligament. We hypothesized that there are no differences within each bundle in contrast to cross-bundle variation. STUDY DESIGN: Descriptive laboratory study. METHODS: Sixteen human ACLs were dissected into AM and PL bundles. Three samples were taken from each bundle in an ordered sequence from AM (region 1 AM bundle) to PL (region 6 PL bundle). Each sample was tested in uniaxial tension, using quantitative polarized light imaging (QPLI) to quantify collagen fiber alignment. After preconditioning, samples were subjected to a stress-relaxation (SR) test followed by quasistatic ramp-to-failure (RF). Peak and equilibrium stress values were computed from the SR test and modulus quantified in the toe- and linear-regions of the RF. QPLI values describing collagen orientation (angle of polarization [AoP]) and strength of alignment (degree of linear polarization [DoLP]) were computed for the SR test and at points corresponding to the zero, transition point, and linear region of the RF. RESULTS: Toe- and linear-region modulus values decreased from region 1 to 6. Slopes of regression lines increased for the average DoLP during RF, with significance at higher strains. The standard deviation of AoP values decreased during RF, indicating tighter distribution of orientation angles, with significant correlations at all points of the RF. During SR, stress values uniformly decreased but did not show significant linear regression by region. DoLP and AoP values changed slightly during SR and demonstrated significant linear variation by region at both peak and equilibrium points. CONCLUSION: Most microstructural and material properties evaluated in this study appear to follow a linear gradient across the ACL, rather than varying by bundle. CLINICAL RELEVANCE: This AM-to-PL variation provides a more accurate description of functional tissue anatomy and can be used to assess and guide techniques of ACL reconstruction. PMID- 27456026 TI - Neuroprotection of Ro25-6981 Against Ischemia/Reperfusion-Induced Brain Injury via Inhibition of Autophagy. AB - In this study, we investigated the neuroprotective effect of Ro25-6981 against cerebral ischemia/reperfusion injury. Ro25-6981 alone or in combination with rapamycin was intracerebroventricularly administered to rats which suffered transient forebrain ischemia inducing by 4-vessel occlusion and reperfusion. Nissl staining was used to determine the survival of CA1 pyramidal cells of the hippocampus, while immunohistochemistry was performed to measure neuron-specific enolase (NSE) expression. The expression of autophagy-related proteins, such as microtubule-associated protein l light chain 3 (LC3), Beclin 1, and sequestosome 1 (p62), was assessed by immunoblotting. Nissl staining showed that neuronal damage was reduced in the hippocampal CA1 pyramidal layer in rats that received Ro25-6981. The protective effect of Ro25-6981 was dose-dependent, with a significant effect in the middle-dose range. The expression of NSE increased after Ro25-6981 treatment. Ro25-6981 significantly decreased LC3II (which is membrane bound) and Beclin 1, and increased p62. In addition, Ro25-6981 decreased rapamycin-induced neuronal damage and excessive activation of autophagy after I/R. Taken together, the results suggest that Ro25-6981 could suppress ischemic brain injury by regulating autophagy-related proteins during ischemia/reperfusion. PMID- 27456028 TI - Revision Meniscal Allograft Transplantation in the Lateral Compartment: Disparate MRI and Clinical Outcomes During the Early Postoperative Period. AB - BACKGROUND: Little is known about clinical outcomes after revision meniscal allograft transplantation (RMAT), and there are no studies on magnetic resonance imaging (MRI) evaluations during the early remodeling period. HYPOTHESIS: The objective imaging results, as determined by MRI evaluation, would be inferior to those of published data on primary meniscal allograft transplantations (MATs), although short-term clinical improvement would be achieved after RMAT. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We retrospectively reviewed 9 consecutive patients (6 male and 3 female) who underwent RMAT from 2010 to 2014. The mean patient age was 33 years (range, 28-45 years). All patients had prior failed MATs in the lateral compartment. None of the patients had malalignment or ligament instability, and 7 patients had grade 3 or higher chondral degeneration. We assessed the RMAT with routine MRI evaluations during the remodeling period of the first postoperative year to determine graft healing and the mode of refailures, if any. We also investigated the problems specific for revision operations, as well as clinical outcomes. RESULTS: Four of the 9 RMAT patients had significant intra-articular fibrosis with or without motion limitations at the time of RMAT. MRI evaluations demonstrated that the overall early refailure rate was 33.3% (3/9) during the first year; bucket-handle displacement with no meniscocapsular healing was the mode of all failures. Insufficient meniscal healing was also found in 2 other RMATs without premature failure. After a mean follow-up of 29.2 months (range, 21-45 months) in the 6 patients with preserved RMATs, Lysholm and International Knee Documentation Committee subjective scores showed significant improvements over preoperative scores (from 53.3 +/- 6.0 to 87.7 +/- 2.9 [P = .028] and from 53.4 +/- 9.0 to 69.9 +/- 4.8 [P = .043], respectively; Wilcoxon signed rank test). CONCLUSION: The MRI findings showed that poor or insufficient meniscal healing to the host joint capsule was the major drawback of RMAT. Although more than half of our patients experienced clinical improvement after RMAT, the short-term graft survival was inferior to that of primary MATs in the literature. Our findings suggest that this challenging revision procedure requires great caution, especially with regard to the effects of poor host tissue quality on meniscal healing. Although RMAT can be an effective treatment, close observation with routine MRI evaluation is necessary during the early remodeling period to assess the status of the revised meniscal allograft. PMID- 27456029 TI - Total Cellular RNA Modulates Protein Activity. AB - RNA constitutes up to 20% of a cell's dry weight, corresponding to ~20 mg/mL. This high concentration of RNA facilitates low-affinity protein-RNA quinary interactions, which may play an important role in facilitating and regulating biological processes. In the yeast Pichia pastoris, the level of ubiquitin-RNA colocalization increases when cells are grown in the presence of dextrose and methanol instead of methanol as the sole carbon source. Total RNA isolated from cells grown in methanol increases beta-galactosidase activity relative to that seen with RNA isolated from cells grown in the presence of dextrose and methanol. Because the total cellular RNA content changes with growth medium, protein-RNA quinary interactions can alter in-cell protein biochemistry and may play an important role in cell adaptation, critical to many physiological and pathological states. PMID- 27456030 TI - Bioinformatics exploration of PAK1 (P21-activated kinase-1) revealed potential network gene elements in breast invasive carcinoma. AB - P21-activated kinase-1 (PAK1) is an enzyme associated with multiple metabolic networks and different types of cancers. Hence, there is a need to study the global network map of PAK1 to understand its role and regulatory mechanisms by means of its significant molecular interactive partners. This will help to explore its global biological functions in breast cancer. In view of this, we obtained the gene expression data-sets of PAK1 from The Cancer Genome Atlas cBioportal and GeneCards databases and found that 91 PAK1-related genes are associated with breast cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway investigations of 91 genes via Database for Annotation Visualization and Integrated Discovery bioinformatics resource revealed that, PAK1 being a major kinase is associated with several metabolic pathways and involved in phosphorylation, signal transduction, apoptosis, biosynthesis and majorly cancer-related cell signalling pathways. The PAK1 interaction network derived from STRING and Cytoscape revealed that the genes Signal-Transducer-and Activator-of-Transcription-3 (STAT3), Cyclin-D1 (CCND1), Mitogen-activated protein kinase-1 (MAPK1), Ras-Homolog-Family-Member-A (RHOA) and Catenin-beta-1 have high degrees of interaction where CCND1, MAPK1 and RHOA have direct interaction with PAK1. Finally, the global expression map of PAK1 and its related genes was derived as topological frame that helped to explore and investigate PAK1 interactions. Further, the molecular modelling studies of PAK1 with its major interacting partners RHOA and STAT3 helped to explore the key interactive residues of PAK1 structure. This information can be used to develop novel therapeutic and control strategies against breast cancer. PMID- 27456032 TI - Gelatin-thrombin hemostatic matrix in neurosurgical procedures: hemostasis effectiveness and economic value of clinical and surgical procedure-related benefits. AB - OBJECTIVES: Gelatin-thrombin hemostatic matrix (FloSeal(r)) use is associated with shorter surgical times and less blood loss, parameters that are highly valued in neurosurgical procedures. We aimed to assess the effectiveness of gelatin-thrombin in neurosurgical procedures and estimate its economic value. PATIENTS AND METHODS: In a 6-month retrospective evaluation at 2 hospitals, intraoperative and postoperative information were collected from patients undergoing neurosurgical procedures where bleeding was controlled with gelatin thrombin matrix or according to local bleeding control guidelines (control group). Study endpoints were: length of surgery, estimated blood loss, hospitalization duration, blood units utilized, intensive care unit days, postoperative complications, and time-to-recovery. Statistical methods compared endpoints between the gelatin-thrombin and control groups and resource utilization costs were estimated. RESULTS: Seventy-eight patients (38 gelatin thrombin; 40 control) were included. Gelatin-thrombin was associated with a shorter surgery duration than control 166+/-40 versus 185+/-55, p=0.0839); a lower estimated blood loss (185+/-80 versus 250+/-95ml; p=0.0017); a shorter hospital stay (10+/-3 versus 13+/-3 days; p<0.001); fewer intensive care unit days (10 days/3 patients and 20 days/4 patients); and shorter time-to-recovery (3+/-2.2 versus 4+/-2.8 weeks; p=0861). Fewer gelatin-thrombin patients experienced postoperative complications (3 minor) than the control group (5 minor; 3 major). No gelatin-thrombin patient required blood transfusion; 5 units were administered in the control group. The cost of gelatin-thrombin (?268.40/unit) was offset by the shorter surgery duration (difference of 19 minutes at ?858 per hour) and the economic value of improved the other endpoint outcomes (ie, shorter hospital stay, less blood loss/lack of need for transfusion, fewer intensive care unit days, and complications). CONCLUSION: Gelatin-thrombin hemostatic matrix use in patients undergoing neurosurgical procedures was associated with better intra- and post-operative parameters than conventional hemostasis methods, with these parameters having substantial economic benefits. PMID- 27456031 TI - How I report breast magnetic resonance imaging studies for breast cancer staging and screening. AB - Magnetic resonance imaging (MRI) of the breast is the most sensitive imaging technique for the diagnosis and local staging of primary breast cancer and yet, despite the fact that it has been in use for 20 years, there is little evidence that its widespread uncritical adoption has had a positive impact on patient related outcomes.This has been attributed previously to the low specificity that might be expected with such a sensitive modality, but with modern techniques and protocols, the specificity and positive predictive value for malignancy can exceed that of breast ultrasound and mammography. A more likely explanation is that historically, clinicians have acted on MRI findings and altered surgical plans without prior histological confirmation. Furthermore, modern adjuvant therapy for breast cancer has improved so much that it has become a very tall order to show a an improvement in outcomes such as local recurrence rates.In order to obtain clinically useful information, it is necessary to understand the strengths and weaknesses of the technique and the physiological processes reflected in breast MRI. An appropriate indication for the scan, proper patient preparation and good scan technique, with rigorous quality assurance, are all essential prerequisites for a diagnostically relevant study.The use of recognised descriptors from a standardised lexicon is helpful, since assessment can then dictate subsequent recommendations for management, as in the American College of Radiology BI-RADS (Breast Imaging Reporting and Data System) lexicon (Morris et al., ACR BI-RADS(r) Atlas, Breast Imaging Reporting and Data System, 2013). It also enables audit of the service. However, perhaps the most critical factor in the generation of a meaningful report is for the reporting radiologist to have a thorough understanding of the clinical question and of the findings that will influence management. This has never been more important than at present, when we are in the throes of a remarkable paradigm shift in the treatment of both early stage and locally advanced breast cancer. PMID- 27456033 TI - Hospitalizations from Hypertensive Diseases, Diabetes, and Arrhythmia in Relation to Low and High Temperatures: Population-Based Study. AB - Little is known about the extent to which ambient temperatures contribute to the burden of hospitalizations from hypertensive diseases, diabetes, and arrhythmia. To fill this knowledge gap, we conducted a time-series study comprising entire population of Ontario, Canada during 1996-2013. A distributed lag non-linear model was developed to estimate the cumulative effect of temperatures over a 21 day lag period. We computed the burden of hospitalizations attributable to cold and heat. Furthermore, we separated the burden into components related to mild and extreme temperatures. Compared to the temperature with minimum risk of morbidity, cold temperatures (1(st) percentile) were associated with a 37% (95% confidence interval: 5%, 78%) increase in hypertension-related hospitalizations whereas no significant association with hot temperatures (99(th) percentile) was observed. Cold and hot temperatures were also associated with a 12% (1%, 24%) and a 30% (6%, 58%) increase in diabetes-related hospitalizations, respectively. Arrhythmia was not linked to temperatures. These estimates translate into ~10% of hypertension-related hospitalizations attributable to total cold, and ~9% from mild cold. Similarly, ~11% of diabetes-related hospitalizations were due to total heat, virtually all of which were from mild heat. In conclusion, ambient temperatures, especially in moderate ranges, contribute to excess hospitalizations from hypertension and diabetes. PMID- 27456035 TI - Social cognition and social problem solving abilities in individuals with alcohol use disorder. AB - BACKGROUND: Up to now, little is known about higher order cognitive abilities like social cognition and social problem solving abilities in alcohol-dependent patients. However, impairments in these domains lead to an increased probability for relapse and are thus highly relevant in treatment contexts. METHOD: This cross-sectional study assessed distinct aspects of social cognition and social problem solving in 31 hospitalized patients with alcohol use disorder (AUD) and 30 matched healthy controls (HC). Three ecologically valid scenario-based tests were used to gauge the ability to infer the mental state of story characters in complicated interpersonal situations, the capacity to select the best problem solving strategy among other less optimal alternatives, and the ability to freely generate appropriate strategies to handle difficult interpersonal conflicts. Standardized tests were used to assess executive function, attention, trait empathy, and memory, and correlations were computed between measures of executive function, attention, trait empathy, and tests of social problem solving. RESULTS: AUD patients generated significantly fewer socially sensitive and practically effective solutions for problematic interpersonal situations than the HC group. Furthermore, patients performed significantly worse when asked to select the best alternative among a list of presented alternatives for scenarios containing sarcastic remarks and had significantly more problems to interpret sarcastic remarks in difficult interpersonal situations. CONCLUSIONS: These specific patterns of impairments should be considered in treatment programs addressing impaired social skills in individuals with AUD. PMID- 27456034 TI - Effectiveness of sarpogrelate after endovascular treatment for femoropopliteal artery disease: ESPALIER study. AB - Optimal medical therapy following endovascular therapy (EVT) for femoropopliteal (FP) lesions remains unclear. Therefore, we investigated whether sarpogrelate improves primary patency after EVT for FP lesions. This study was performed as a multicenter, randomized, open-label clinical trial. 186 patients (mean age 75 +/- 9 years, 78 % men) with Rutherford class 2-5 due to an FP lesion were randomly assigned to receive or not receive sarpogrelate in addition to aspirin. Primary endpoint was 1-year primary patency and the secondary endpoints were target lesion revascularization (TLR) and secondary patency. Primary patency was defined as a treated vessel without restenosis or repeat revascularization. Restenosis was defined as >2.5 of peak systolic velocity ratio. Patient, lesion, and procedural characteristics did not differ significantly between two groups (mean lesion length 156 +/- 94 mm, total occlusion 35 %). Stenting was performed in 133 patients (76 %). Eighty-four (94 %) could ingest sarpogrelate during follow-up period. Primary patency was 66 % in sarpogrelate group and 56 % in non sarpogrelate group, showing no significant difference between the groups (p = 0.33). The incidence of TLR did not differ in both groups (sarpogrelate 24 % vs non-sarpogrelate 32 %, p = 0.12). Secondary patency also did not differ (sarpogrelate 90 % vs non-sarpogrelate 92 %, p = 0.43). When the interaction of sarpogrelate with the primary patency was analyzed in previously established subgroups, no interactions were noted for any subset. Sarpogrelate did not improve primary patency after EVT for FP disease in this study. PMID- 27456036 TI - Anodic Ag/TiO2 nanotube array formation in NaOH/fluoride/ethylene glycol electrolyte as a photoanode for dye-sensitized solar cells. AB - Self-organized, 23 MUm-thick anodic TiO2 nanotube (TNT) arrays were formed in sodium hydroxide/fluoride/ethylene glycol (EG) electrolyte at 60 V for 60 min. The presence of sodium hydroxide (NaOH) in the fluoride/EG electrolyte accelerates the formation of the TiO2 nanotube arrays. The anodic film was then decorated with silver nanoparticles (Ag NPs) by the photodeposition process and used as a photoanode in a rear-side-illuminated dye-sensitized solar cell. The Ag NPs decorated TNT arrays, with the former having diameters of 10-30 nm formed from 0.2 M of Ag-precursor solution and exhibiting the highest photoconversion efficiency (eta) of 3.7% and a short-circuit current density of 12.2 mA cm(-2) compared to eta = 3% and short-circuit current density of 9.1 mA cm(-2) for a sample without Ag NPs. The increase in eta is thought to be due to the surface plasmon resonance and excess electrons from the nanoparticles. PMID- 27456037 TI - Simple and Flexible Model for Laser-Driven Antibody-Gold Surface Interactions: Functionalization and Sensing. AB - Interactions between biomolecules and between substrates and biomolecules is a crucial issue in physics and applications to topics such as biotechnology and organic electronics. The efficiency of bio- and mechanical sensors, of organic electronics systems, and of a number of other devices critically depends on how molecules are deposited on a surface so that these acquire specific functions. Here, we tackle this vast problem by developing a coarse grained model of biomolecules having a recognition function, such as antibodies, capable to quantitatively describe in a simple manner essential phenomena: antigen-antibody and antibody substrate interactions. The model is experimentally tested to reproduce the results of a benchmark case, such as (1) gold surface functionalization with antibodies and (2) antibody-antigen immune-recognition function. The agreement between experiments and model prediction is excellent, thus unveiling the mechanism for antibody immobilization onto metals at the nanoscale in various functionalization schemes. These results shed light on the geometrical packing properties of the deposited molecules, and may open the way to a novel coarse-grained based approach to describe other processes where molecular packing is a key issue with applications in a huge number of fields from nano- to biosciences. PMID- 27456038 TI - Probiotics production and alternative encapsulation methodologies to improve their viabilities under adverse environmental conditions. AB - Probiotic products are dietary supplements containing live microorganisms producing beneficial health effects on the host by improving intestinal balance and nutrient absorption. Among probiotic microorganisms, those classified as lactic acid bacteria are of major importance to the food and feed industries. Probiotic cells can be produced using alternative carbon and nitrogen sources, such as agroindustrial residues, at the same time contributing to reduce process costs. On the other hand, the survival of probiotic cells in formulated food products, as well as in the host gut, is an essential nutritional aspect concerning health benefits. Therefore, several cell microencapsulation techniques have been investigated as a way to improve cell viability and survival under adverse environmental conditions, such as the gastrointestinal milieu of hosts. In this review, different aspects of probiotic cells and technologies of their related products are discussed, including formulation of culture media, and aspects of cell microencapsulation techniques required to improve their survival in the host. PMID- 27456039 TI - Strategic Trimethylsilyldiazomethane Insertion into pinB-SR Followed by Selective Alkylations. AB - The insertion of the diazo derivative Me3SiCHN2 into pinB-SR sigma bonds (R = Ph, Tol, Bn) allows a direct synthesis of multisubstituted H-C(SR)(Bpin)(SiMe3) compounds. Consecutive base-assisted transformations of HC(S)(B) (Si) systems lead to deborylative alkylations, Sommelet-Hauser rearrangements, and deprotoalkylations. Intramolecular cyclizations can be selectively performed either via desilylative or deborylative manifolds by fine-tuning the base employed. PMID- 27456040 TI - Someone to count on: social support as an effect modifier of viral load suppression in a prospective cohort study. AB - Though functional social support has been shown to serve as a protective factor for HIV viral load suppression in other populations, scant research has examined this relationship among men who have sex with men (MSM) in the United States. We assessed characteristics of social support, effects of social support on HIV viral load, and moderation by social support of the relationship between psychosocial indicators of a synergistic epidemic (syndemic) and HIV viral load. We analyzed longitudinal data from HIV-positive MSM using antiretroviral therapy who were enrolled in the Multicenter AIDS Cohort Study between 2002 and 2009 (n = 712). First, we conducted reliability assessments of a one-item social support measure. Then, we conducted a series of generalized longitudinal mixed models to assess our research questions. Moderation was assessed using an interaction term. A three-level (low/medium/high) social support variable demonstrated high reliability (intraclass correlation coefficients = 0.72; 95% CI: 0.70, 0.75). Black and Hispanic MSM reported lower social support than their White counterparts (p < .0001). Recent sero-conversion was associated with higher social support (p < .05). Higher numbers of concomitant syndemic indicators (depression, polysubstance use, and condomless anal sex) were associated with lower social support (p < .0001). Medium and high social support levels were associated with greater viral load suppression and lower viral load means (p < .0001). Social support moderated the relationships between syndemic and HIV viral load (p < .05). HIV-positive MSM, particularly those of color, may benefit greatly from interventions that can successfully boost functional social support. Creating strengths-based interventions may also have particularly high impact among HIV-positive MSM with the highest psychosocial burdens. PMID- 27456041 TI - High-yield cell-free synthesis of human EGFR by IRES-mediated protein translation in a continuous exchange cell-free reaction format. AB - Cell-free protein synthesis systems derived from eukaryotic sources often provide comparatively low amounts of several MUg per ml of de novo synthesized membrane protein. In order to overcome this, we herein demonstrate the high-yield cell free synthesis of the human EGFR in a microsome-containing system derived from cultured Sf21 cells. Yields were increased more than 100-fold to more than 285 MUg/ml by combination of IRES-mediated protein translation with a continuous exchange cell-free reaction format that allowed for prolonged reaction lifetimes exceeding 24 hours. In addition, an orthogonal cell-free translation system is presented that enabled the site-directed incorporation of p-Azido-L-phenylalanine by amber suppression. Functionality of cell-free synthesized receptor molecules is demonstrated by investigation of autophosphorylation activity in the absence of ligand and interaction with the cell-free synthesized adapter molecule Grb2. PMID- 27456043 TI - Communication and quality of life outcomes from an interprofessional intensive, comprehensive, aphasia program (ICAP). AB - BACKGROUND: Intensive Comprehensive Aphasia Programs (ICAPs) have developed in response to a growing need for treatments which produce changes in language function in people with aphasia, especially in the chronic phase of recovery. ICAPs are growing in number and several papers have presented preliminary results of their use, but little data exist about their efficacy or effectiveness. OBJECTIVE: This paper explores the communication effects of an ICAP program that incorporated evidenced-based individual and group treatment in an interprofessional program. METHOD: Twenty-seven individuals with chronic aphasia were provided with 30 h of interprofessional treatment a week for a four-week period in both individual and group formats. A delayed treatment, within participant research protocol was used. Language measures were taken at two intervals pre- and two intervals post treatment. Functional, narrative, and quality of life measures were taken once pre and once post treatment. RESULTS: Significant change was observed on targeted language functions post treatment. Significant treatment effects were also observed on functional and quality of life measures as well as on all impairment-based language measures for the group. CONCLUSION: The results provide evidence of linguistic and quality of life change in individuals with chronic aphasia who were treated in an interprofessional ICAP. PMID- 27456042 TI - Potential role of D-myo-inositol-3-phosphate synthase and 14-3-3 genes in the crosstalk between Zea mays and Rhizophagus intraradices under drought stress. AB - Arbuscular mycorrhizal (AM) symbiosis is known to stimulate plant drought tolerance. However, the mechanisms underlying the synergistic responses of the symbiotic partners to drought stress are largely unknown. A split-root experiment was designed to investigate the molecular interactions between a host plant and an AM fungus (AMF) under drought stress. In the two-compartment cultivation system, an entire or only a half root system of a maize plant was inoculated with an AMF, Rhizophagus intraradices, in the presence of localized or systemic drought treatment. Plant physiological parameters including growth, water status, and phosphorus concentration, and the expression of drought tolerance-related genes in both roots and R. intraradices were recorded. Although mycorrhizal inoculation in either one or both compartments systemically decreased abscisic acid (ABA) content in the whole root system subjected to systemic or local drought stress, we observed local and/or systemic AM effects on root physiological traits and the expression of functional genes in both roots and R. intraradices. Interestingly, the simultaneous increase in the expression of plant genes encoding D-myo-inositol-3-phosphate synthase (IPS) and 14-3-3-like protein GF14 (14-3GF), which were responsible for ABA signal transduction, was found to be involved in the activation of 14-3-3 protein and aquaporins (GintAQPF1 and GintAQPF2) in R. intraradices. These findings suggest that coexpression of IPS and 14-3GF is responsible for the crosstalk between maize and R. intraradices under drought stress, and potentially induces the synergistic actions of the symbiotic partners in enhancing plant drought tolerance. PMID- 27456044 TI - [Chronic cough, pleuritic chest pain, and night sweats in a 45-year-old female smoker]. AB - A 45-year-old woman presented with chronic cough, pleuritic chest pain, and night sweat. High-resolution computed tomography revealed multiple bilateral nodular lesions in a centrilobular distribution, primarily located in the upper and mid lung zones with relative sparing of the lung bases. No lymphadenopathy or pleural effusions were detected. Histological analysis confirmed the suspected diagnosis of pulmonary Langerhans cell histiocytosis. After smoking cessation the patient recovered completely. PMID- 27456045 TI - Facilitators and Barriers to Dental Care Among Mexican Migrant Women and Their Families in North San Diego County. AB - To qualitatively examine facilitators and barriers to dental care access and quality services among Mexican migrant women and their families living in North San Diego County, California. Six focus groups were conducted, with 52 participants. Three focus groups were with community residents (average group size of 10), and three were with community health workers/leaders (called Lideres; average group size of 7). The behavioral model for vulnerable populations theoretical framework guided qualitative data analyses. Predisposing factors to dental care access varied and included immigration status, language, and dental care experiences. Barriers to accessing quality dental services included high cost, lack of insurance coverage, dissatisfaction with providers, long wait times and discrimination. Participants expressed a desire for health policy changes, including affordable coverage for immigrants and their families. This study provided insights into how dental care providers, community health centers, and policymakers can improve dental care access and services to migrant populations. PMID- 27456047 TI - Current epidemiological profile and features of traumatic spinal cord injury in Heilongjiang province, Northeast China: implications for monitoring and control. AB - STUDY DESIGN: A retrospective hospital-based study. OBJECTIVES: Traumatic spinal cord injury (TSCI) is considered to be an important public health problem worldwide. Only a few studies concerning the regional epidemiological characteristics of TSCI have been published in China. The purpose is to evaluate the epidemiological characteristics of TSCI in Heilongjiang province in northeast China. SETTING: The Second Affiliated Hospital of Harbin Medical University and the Fifth Hospital of Harbin City, Heilongjiang province. METHODS: Information of 232 patients who suffered from TSCI was gathered from their charts between January 2009 and December 2013. Information on sociodemographic variables was collected from each chart, including the patient's age, sex, occupation, injury time, causes and extent of injury. RESULTS: The average age of patients with TSCI was 45.35+/-14.35 years. The male/female ratio was 4:1. The incidence of TSCI increased gradually with age and peaked in the 46- to 60-year-old age category. The most common occupation was farm laborer (35.34%). Motor vehicle collisions, followed by falls, were found to be the leading cause of TSCI. Furthermore, the majority of TSCI patients (76.29%) suffered a cervical injury. CONCLUSION: The present study reveals that TSCI is an issue in the province, and it should not be ignored. Our results provide preliminary evidence and theoretical basis for developing an integrated control program for TSCI. PMID- 27456048 TI - Intensive inpatient treatment for bulimia nervosa: Statistical and clinical significance of symptom changes. AB - OBJECTIVE: This study examines the statistical and clinical significance of symptom changes during an intensive inpatient treatment program with a strong psychotherapeutic focus for individuals with severe bulimia nervosa. METHOD: 295 consecutively admitted bulimic patients were administered the Structured Interview for Anorexic and Bulimic Syndromes-Self-Rating (SIAB-S), the Eating Disorder Inventory-2 (EDI-2), the Brief Symptom Inventory (BSI), and the Beck Depression Inventory-II (BDI-II) at treatment intake and discharge. RESULTS: Results indicated statistically significant symptom reductions with large effect sizes regarding severity of binge eating and compensatory behavior (SIAB-S), overall eating disorder symptom severity (EDI-2), overall psychopathology (BSI), and depressive symptom severity (BDI-II) even when controlling for antidepressant medication. The majority of patients showed either reliable (EDI-2: 33.7%, BSI: 34.8%, BDI-II: 18.1%) or even clinically significant symptom changes (EDI-2: 43.2%, BSI: 33.9%, BDI-II: 56.9%). Patients with clinically significant improvement were less distressed at intake and less likely to suffer from a comorbid borderline personality disorder when compared with those who did not improve to a clinically significant extent. CONCLUSIONS: Findings indicate that intensive psychotherapeutic inpatient treatment may be effective in about 75% of severely affected bulimic patients. For the remaining non-responding patients, inpatient treatment might be improved through an even stronger focus on the reduction of comorbid borderline personality traits. PMID- 27456049 TI - An on-chip micromagnet frictionometer based on magnetically driven colloids for nano-bio interfaces. AB - A novel method based on remotely controlled magnetic forces of bio-functionalized superparamagnetic colloids using micromagnet arrays was devised to measure frictional force at the sub-picoNewton (pN) scale for bio-nano-/micro electromechanical system (bio-NEMS/MEMS) interfaces in liquid. The circumferential motion of the colloids with phase-locked angles around the periphery of the micromagnets under an in-plane rotating magnetic field was governed by a balance between tangential magnetic force and drag force, which consists of viscous and frictional forces. A model correlating the phase-locked angles of the steady colloid rotation was formulated and validated by measuring the angles under controlled magnetic forces. Hence, the frictional forces on the streptavidin/Teflon interface between the colloids and the micromagnet arrays were obtained using the magnetic forces at the phase-locked angles. The friction coefficient for the streptavidin/Teflon interface was estimated to be approximately 0.036 regardless of both vertical force in the range of a few hundred pN and velocity in the range of a few tenths of MUm s(-1). PMID- 27456058 TI - New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies. AB - The recent findings on the roles of death-associated protein 6/alpha thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs. PMID- 27456059 TI - Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes. AB - Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting. PMID- 27456060 TI - Mouse aldehyde-oxidase-4 controls diurnal rhythms, fat deposition and locomotor activity. AB - Aldehyde-oxidase-4 (AOX4) is one of the mouse aldehyde oxidase isoenzymes and its physiological function is unknown. The major source of AOX4 is the Harderian gland, where the enzyme is characterized by daily rhythmic fluctuations. Deletion of the Aox4 gene causes perturbations in the expression of the circadian-rhythms gene pathway, as indicated by transcriptomic analysis. AOX4 inactivation alters the diurnal oscillations in the expression of master clock-genes. Similar effects are observed in other organs devoid of AOX4, such as white adipose tissue, liver and hypothalamus indicating a systemic action. While perturbations of clock-genes is sex-independent in the Harderian-gland and hypothalamus, sex influences this trait in liver and white-adipose-tissue which are characterized by the presence of AOX isoforms other than AOX4. In knock-out animals, perturbations in clock gene expression are accompanied by reduced locomotor activity, resistance to diet induced obesity and to hepatic steatosis. All these effects are observed in female and male animals. Resistance to obesity is due to diminished fat accumulation resulting from increased energy dissipation, as white-adipocytes undergo trans-differentiation towards brown-adipocytes. Metabolomics and enzymatic data indicate that 5-hydroxyindolacetic acid and tryptophan are novel endogenous AOX4 substrates, potentially involved in AOX4 systemic actions. PMID- 27456061 TI - Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response. AB - Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapy-treated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation. PMID- 27456062 TI - Somatic Therapy of a Mouse SMA Model with a U7 snRNA Gene Correcting SMN2 Splicing. AB - Spinal Muscular Atrophy is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe Spinal Muscular Atrophy mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self complementary (sc) adenovirus-associated virus 9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn Spinal Muscular Atrophy mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA was expressed in the heart and liver which may additionally have contributed to the observed therapeutic efficacy. This approach provides an additional therapeutic option for Spinal Muscular Atrophy and could also be adapted to treat other diseases of the central nervous system with regulatory small RNA genes. PMID- 27456064 TI - Relation between admission plasma fibrinogen levels and mortality in Chinese patients with coronary artery disease. AB - Fibrinogen (Fib) was considered to be a potential risk factor for the prognosis of patients with coronary artery disease (CAD), but there was lack of the evidence from Chinese contemporary population. 3020 consecutive patients with CAD confirmed by coronary angiography were enrolled and were grouped into 2 categories by the optimal Fib cut-off value (3.17 g/L) for all-cause mortality prediction. The end points were all-cause mortality and cardiac mortality. Cumulative survival curves showed that the risk of all-cause mortality was significantly higher in patients with Fib >=3.17 g/L compared to those with Fib <3.17 g/L (mortality rate, 11.5% vs. 5.7%, p < 0.001); and cardiovascular mortality obtained results similar to those mentioned above (cardiac mortality rate, 5.9% vs. 3.6%, p = 0.002). Subgroup analysis showed that elevated Fib levels were predictive for the risk of all-cause mortality in the subgroups according to age, medical history, and diagnosis. COX multivariate regression analysis showed that plasma Fib levels remained independently associated with all cause mortality after adjustment for multiple cardiovascular risk factors (all cause mortality, HR 2.01, CI 1.51-2.68, p < 0.001). This study has found that Fib levels were independently associated with the mortality risk in Chinese CAD patients. PMID- 27456063 TI - Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. AB - Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (n = 21) and western blotting (n = 9). IHC was used to determine the presence of tumor infiltrating lymphocytes and antigen-presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with immune cell infiltration and event-free-survival (EFS). The 25% of primary osteosarcoma tumors that express PD-L1 were more likely to contain cells that express PD-1 than PD-L1 negative tumors (91.7% vs 47.2%, p = 0.002). Expression of PD-L1 was significantly associated with the presence of T cells, dendritic cells, and natural killer cells. Although all immune cell types examined were present in osteosarcoma samples, only infiltration by dendritic cells (28.3% vs. 83.9%, p = 0.001) and macrophages (45.5% vs. 84.4%, p = 0.031) were associated with worse five-year-EFS. PD-L1 expression was significantly associated with poorer five year-EFS (25.0%. vs. 69.4%, p = 0.014). Further studies in osteosarcoma are needed to determine if targeting the PD-L1:PD-1 axis improves survival. PMID- 27456065 TI - Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor beta/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation. AB - Disruption of the TGF-beta pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-beta signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-beta pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-beta pathway member expression levels and beta catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-beta member expression with lower beta catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-beta pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and beta-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling. PMID- 27456067 TI - Determination of the unbound fraction of R- and S-methadone in human brain. PMID- 27456066 TI - Unmet Needs in LDL-C Lowering: When Statins Won't Do! AB - The use of low-density lipoprotein cholesterol (LDL-C)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statin therapy, one of the cornerstones for the prevention and treatment of cardiovascular disease (CVD), has been demonstrated to be effective in lowering LDL-C levels and in reducing the risk for CVD and is generally well-tolerated. However, compliance with statins remains suboptimal. One of the main reasons is limitations by adverse events, notably myopathies, which can lead to non-compliance with the prescribed statin regimen. Reducing the burden of elevated LDL-C levels is critical in patients with CVD as well as in patients with very high baseline levels of LDL-C (e.g. patients with familial hypercholesterolaemia), as statin therapy is insufficient for optimally reducing LDL-C below target values. In this review, we discuss alternative treatment options after maximally tolerated doses of statin therapy, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors. Difficult-to-treat patients may benefit from combination therapy with ezetimibe or a PCSK9 inhibitor (evolocumab or alirocumab, which are now available). Updates of treatment guidelines are needed to guide the management of patients who will best benefit from these new treatments. PMID- 27456068 TI - Clinical outcomes of Ghanaian Buruli ulcer patients who defaulted from antimicrobial therapy. AB - OBJECTIVES: Buruli ulcer (BU) is a tropical skin disease caused by infection with Mycobacterium ulcerans, which is currently treated with 8 weeks of streptomycin and rifampicin. The evidence to treat BU for a duration of 8 weeks is limited; a recent retrospective study from Australia suggested that a shorter course of antimicrobial therapy might be equally effective. We studied the outcomes of BU in a cohort of Ghanaian patients who defaulted from treatment and as such received less than 8 weeks of antimicrobial therapy. METHODS: A number of days of antimicrobial therapy and patient and lesion characteristics were recorded from charts from a cohort of BU patients treated at Nkawie-Toase hospital between 2008 and 2012. Patients who defaulted from treatment were retrieved, and lesion characteristics and functional limitations were recorded. RESULTS: About 54% of patients defaulted from therapy or wound care. Forty-seven defaulters with follow up completed had received <56 days of antibiotics. 84% of these patients healed after 32 days or less of antibiotics. There appeared to be an increased rate of healing in smaller lesions; 94% of WHO category I lesions had healed after 32 days or less of antibiotics. CONCLUSION: Although numbers were small, and a potential for bias exists, our findings suggest that a reduction in the duration of antimicrobial therapy in BU in small, early lesions is feasible. These findings can serve as a basis for future well-designed studies. PMID- 27456069 TI - Declining incidence of intracerebral hemorrhage over two decades in a population based study. AB - BACKGROUND AND PURPOSE: The incidence and case-fatality rate (CFR) of primary intracerebral hemorrhage (PICH) over two decades were assessed in a prospective population-based study. METHODS: Cases of incident first-ever PICH were recorded over a 2-year period (2011-2012) from multiple sources in the district of L'Aquila, central Italy. Included patients were followed up to 1 year after the event to ascertain CFRs. Current data were compared with those previously collected from 1994 through 1998. RESULTS: In all, 115 patients (52 men; 45.2%) with a first-ever PICH were included. Mean age +/- SD was 77.4 +/- 11.8 years. The hemorrhage was lobar in 43 (37.4%) patients, deep in 56 (48.7%), in the posterior fossa in 11 (9.6%) and intraventricular or multiple localized in five (4.3%). Crude annual incidence rate was 19.3 per 100 000 and 14.8 per 100 000 when standardized to the 2011 European population, indicating a 48% reduction comparing data of 2011-2012 to those of 1994-1998 (incidence rate ratio 0.52; 95% confidence interval 0.43-0.64; P < 0.001). In 2011-2012, the 7-day CFR was 27.8%, the 30-day CFR was 42.6% and the 1-year CFR was 52.2%; the 1-year standardized mortality ratio was 0.81 (95% confidence interval 0.63-1.04) compared with 1994 1998. CONCLUSIONS: The annual incidence rate of PICH was lower than that found two decades before and close to the rates recently found in other western countries. Data also indicated a non-significant trend towards a decrease in mortality, which nonetheless remained high, pointing to the need for more appropriate treatments in order to reduce PICH severity and mortality. PMID- 27456070 TI - PPARgamma agonist rosiglitazone inhibits migration and invasion by downregulating Cyr61 in rheumatoid arthritis fibroblast-like synoviocytes. AB - AIM: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have anti-inflammatory properties that reduce inflammatory cytokine production in rheumatoid arthritis (RA). Cysteine-rich angiogenic inducer 61 (Cyr61) is associated with diseases related to chronic inflammation. The aim of this study was to investigate the mechanisms underlying the effects of PPARgamma agonists on tumor necrosis factor (TNF)-alpha-induced fibroblast-like synoviocyte (FLS) invasion and migration, as well as Cyr61 production, in RA-FLS. METHODS: FLS were cultured with TNF-alpha and Cyr61 in the presence or absence of PPARgamma agonists. Matrix metalloproteinase and Cyr61 expression levels in RA-FLS and culture supernatants were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. The migration and invasion phenotypes of RA-FLS were determined by wound healing and Boyden chamber assays. RESULTS: Cyr61 protein was expressed in RA-FLS, and its intracellular expression and secretion levels were increased by TNF-alpha. Moreover, Cyr61 directly promoted RA-FLS migration and invasion. Rosiglitazone (RSG) significantly decreased TNF-alpha induced Cyr61 expression. RSG decreased TNF-alpha-induced nuclear factor (NF) kappaB activation and inhibitor of kappaBalpha degradation. Furthermore, RSG inhibited TNF-alpha-induced RA-FLS migration and invasion and decreased Cyr61 treatment-induced RA-FLS invasion. Finally, blocking Cyr61 significantly attenuated TNF-alpha-induced migration. CONCLUSIONS: Our results demonstrate for the first time that PPARgamma agonists may have beneficial effects on the migration and invasion of RA-FLS via the downregulation of Cyr61. Therefore, PPARgamma agonists could be potential treatment targets for RA. PMID- 27456071 TI - Arabidopsis thaliana root colonization by the nematophagous fungus Pochonia chlamydosporia is modulated by jasmonate signaling and leads to accelerated flowering and improved yield. AB - Pochonia chlamydosporia has been intensively studied in nematode control of different crops. We have investigated the interaction between P. chlamydosporia and the model system Arabidopsis thaliana under laboratory conditions in the absence of nematodes. This study demonstrates that P. chlamydosporia colonizes A. thaliana. Root colonization monitored with green fluorescent protein-tagged P. chlamydosporia and quantitative PCR (qPCR) quantitation methods revealed root cell invasion. Fungal inoculation reduced flowering time and stimulated plant growth, as determined by total FW increase, faster development of inflorescences and siliques, and a higher yield in terms of seed production per plant. Precocious flowering was associated with significant expression changes in key flowering-time genes. In addition, we also provided molecular and genetic evidence that point towards jasmonate signaling as an important factor to modulate progression of plant colonization by the fungus. Our results indicate that P. chlamydosporia provides benefits to the plant in addition to its nematophagous activity. This report highlights the potential of P. chlamydosporia to improve yield in economically important crops. PMID- 27456072 TI - Xenotransplantation literature update, May-June 2016. PMID- 27456073 TI - A three phase hollow fiber liquid-phase microextraction for quantification of lamotrigine in plasma of epileptic patients by capillary electrophoresis. AB - A three phase hollow fiber liquid-phase microextraction technique combined with capillary electrophoresis was developed to quantify lamotrigine (LTG) in plasma samples. The analyte was extracted from 4.0 mL of a basic donor phase (composed of 0.5 mL of plasma and 3.5 mL of sodium phosphate solution pH 9.0) through a supported liquid membrane composed of 1-octanol immobilized in the pores of the hollow fiber, and to an acidic acceptor phase (hydrochloric acid solution pH 4.0) placed in the lumen of the fiber. The extraction was carried out for 30 min at 500 rpm. The eletrophoretic analysis was carried out in 130 mmol/L MES buffer, pH 5.0 with a constant voltage of +15 kV and 20 degrees C. Sample injections were performed for 10 s, at a pressure of 0.5 psi. The detection was performed at 214 nm for both LTG and the internal standard lidocaine. Under the optimized conditions, the method showed a limit of quantification of 1.0 MUg/mL and was linear over the plasmatic concentration range of 1.0-20.0 MUg/mL. Finally, the validated method was applied for the quantification of LTG in plasma samples of epileptic patients. PMID- 27456074 TI - PNP-Pincer-Type Phosphaalkene Complexes of Late Transition Metals. AB - This account summarizes our recent studies on PNP-pincer-type phosphaalkene complexes. Phosphaalkenes with a P=C bond possess an extremely low-lying pi* orbital and have a marked tendency to engage in strong pi back-bonding with transition metals. This particular ligand property provides PNP-pincer complexes with unique structures and reactivities. 2,6-Bis(phosphaethenyl)pyridine leads to the isolation of coordinatively unsaturated complexes of Fe(I) and Cu(I); the former adopts a trigonal monopyramidal configuration, whereas the latter has a strong affinity for PF6- and SbF6- as non-coordinating anions. Unsymmetrical PNP pincer-type phosphaalkene complexes of Ir(I) bearing a dearomatized pyridine unit instantly cleave the N-H bond of NH3 and the C-H bond of MeCN at room temperature. The dearomatized iridium complexes catalyze the dehydrative coupling of amines with alcohols to afford N-alkylated amines and imines in high yields. PMID- 27456075 TI - Vascular Stains: Proposal for a Clinical Classification to Improve Diagnosis and Management. AB - Vascular stains are a common reason for consultation in pediatric dermatology clinics. Although vascular stains include all vascular malformations, the term is most often used to refer to capillary malformations, but capillary malformations include a wide range of vascular stains with different clinical features, prognoses, and associated findings. The discovery of several mutations in various capillary malformations and associated syndromes has reinforced these differences, but clinical recognition of these different types of capillary vascular stains is sometimes difficult, and the multitude of classifications and confusing nomenclature often hamper the correct diagnosis and management. From our own experience and a review of the most relevant literature on this topic, we propose categorizing patients with capillary vascular stains into seven major clinical patterns: nevus simplex, port-wine stain, reticulated capillary malformation, geographic capillary malformation, capillary malformation arteriovenous malformation (CM-AVM), cutis marmorata telangiectatica congenita, and telangiectasia. We also discuss the differential diagnosis of vascular stains as well as other conditions that can closely resemble capillary malformations and thus may potentially be misdiagnosed. PMID- 27456076 TI - Ultrasound guided FNA of thyroid performed by cytopathologists enhances Bethesda diagnostic value. AB - BACKGROUND: Ultrasound (US) guided fine needle aspiration (FNA) biopsy of thyroid are examined and reported by cytopathologists based usually on The Bethesda System for Reporting Thyroid Cytopathology (BTC) regardless of the procedure's performers. This study is designed to determine whether there is any performer dependent difference. METHODS: Six hundred and fifty-one thyroid US-FNAs in correlation with surgical follow-up (SFU) were studied. The statistical analysis was performed using the surgical pathology diagnosis as the gold standard. RESULTS: Among the 283 cases performed by cytopathologists, there were 8 (2.8%) nondiagnostic (BTC I), 197 (69.6%) benign (BTC II), 31 (11%) atypical (BTC III), 14 (5%) suspicious for follicular neoplasm (BTC IV), 12 (4.2%) suspicious for malignancy (BTC V), and 21 (7.4%) positive for malignancy (BTC VI), and there were 55 (19.4%) cases with SFU. The 368 cases performed by others showed 76 (21%) BTC I, 238 (65%) BTC II, 26 (7%) BTC III, 10 (3%) BTC IV, 9 (2.5%) BTC V 5, and 9 (2.5%) BTC VI, and there were 26 (7%) cases with SFU. The cytopathologist group achieved better sensitivity (91.3 vs.78%); slightly better specificity (83.3 vs. 82%); better positive predictive value (87.5 vs. 70%); similar negative predictive value (88.2 vs. 88%); and better overall accuracy (87.8 vs. 81%) compared with the non-cytopathologist group. Overall the difference for all statistical values is significant different (P = 0.041). CONCLUSION: US-FNA performed by cytopathologists showed a lower unsatisfactory rate and significantly better overall statistical values. Cytopathologists may play an important role in thyroid patient care. Diagn. Cytopathol. 2016;44:787-791. (c) 2016 Wiley Periodicals, Inc. PMID- 27456077 TI - Cell-Free HA-MA/PLGA Scaffolds with Radially Oriented Pores for In Situ Inductive Regeneration of Full Thickness Cartilage Defects. AB - A bioactive scaffold with desired microstructure is of great importance to induce infiltration of somatic and stem cells, and thereby to achieve the in situ inductive tissue regeneration. In this study, a scaffold with oriented pores in the radial direction is prepared by using methacrylated hyaluronic acid (HA-MA) via controlled directional cooling of a HA-MA solution, and followed with photo crosslinking to stabilize the structure. Poly(lactide-co-glycolide) (PLGA) is further infiltrated to enhance the mechanical strength, resulting in a compressive modulus of 120 kPa. In vitro culture of bone marrow stem cells (BMSCs) reveals spontaneous cell aggregation inside this type of scaffold with a spherical morphology. In vivo transplantation of the cell-free scaffold in rabbit knees for 12 w regenerates simultaneously both cartilage and subchondral bone with a Wakitani score of 2.8. Moreover, the expression of inflammatory factor interleukin-1beta (IL-1beta) is down regulated, although tumor necrosis factor alpha (TNF-alpha) is remarkably up regulated. With the anti-inflammatory, bioactive properties and good restoration of full thickness cartilage defect in vivo, the oriented macroporous HA-MA/PLGA hybrid scaffold has a great potential for the practical application in the in situ cartilage regeneration. PMID- 27456079 TI - Geographical thinking in nursing inquiry, part two: performance, possibility, and non-representational theory. AB - Part one in this two paper series reviewed the nature of geographical thinking in nursing research thus far. The current paper builds on it by looking forwards and providing a particular vision for future research. It argues that it is time to once again look to the parent discipline of human geography for inspiration, specifically to its turn towards non-representational theory, involving an emphasis on life that onflows prior to meaning, significance, and full cognition; on life's 'taking-place'. The paper introduces this way of viewing and animating the world. Some potential connections to nursing research and practice are suggested, as are some specific avenues for future inquiry. Explained is how, through non-representational theory, nursing might be re-imagined as something that reveals space-time. PMID- 27456078 TI - Composition and genetics of malaria vector populations in the Central African Republic. AB - BACKGROUND: In many African countries malaria has declined sharply due to a synergy of actions marked by the introduction of vector control strategies, but the disease remains a leading cause of morbidity and mortality in Central African Republic (CAR). An entomological study was initiated with the aim to characterize the malaria vectors in Bangui, the capital of CAR, and determine their vector competence. METHODS: A cross-sectional entomological study was conducted in 15 sites of the district of Bangui, the capital of CAR, in September-October 2013 and a second collection was done in four of those sites between November and December 2013. Mosquitoes were collected by human landing catch (HLC) indoors and outdoors and by pyrethrum spray catch of indoor-resting mosquitoes. Mosquitoes were analysed for species and multiple other attributes, including the presence of Plasmodium falciparum circumsporozoite protein or DNA, blood meal source, 2La inversion karyotype, and the L1014F kdr insecticide resistance mutation. RESULTS: Overall, 1292 anophelines were analysed, revealing a predominance of Anopheles gambiae and Anopheles funestus, with a small fraction of Anopheles coluzzii. Molecular typing of the An. gambiae complex species showed that An. gambiae was predominant (95.7 %) as compared to An. coluzzii (2.1 %), and Anopheles arabiensis was not present. In some areas the involvement of secondary vectors, such as Anopheles coustani, expands the risk of infection. By HLC sampling, An. funestus displayed a stronger endophilic preference than mosquitoes from the An. gambiae sister taxa, with a mean indoor-capture rate of 54.3 % and 67.58 % for An. gambiae sister taxa and An. funestus, respectively. Human biting rates were measured overall for each of the species with 28 or 29 bites/person/night, respectively. Both vectors displayed a strong human feeding preference as determined by blood meal source, which was not different between the different sampling sites. An. coustani appears to be highly exophilic, with 92 % of HLC samples captured outdoors. The mean CSP rate in head-thorax sections of all Anopheles was 5.09 %, and was higher in An. gambiae s.l. (7.4 %) than in An. funestus (3.3 %). CSP-positive An. coustani were also detected in outdoor HLC samples. In the mosquitoes of the An. gambiae sister taxa the kdr-w mutant allele was nearly fixed, with 92.3 % resistant homozygotes, and no susceptible homozygotes detected. CONCLUSIONS: This study collected data on anopheline populations in CAR, behaviour of vectors and transmission levels. Further studies should investigate the biting behaviour and susceptibility status of the anophelines to different insecticides to allow the establishment of appropriate vector control based on practical entomological knowledge. PMID- 27456080 TI - Predicting prolonged dose titration in patients starting warfarin. AB - PURPOSE: Patients initiating warfarin therapy generally experience a dose titration period of weeks to months, during which time they are at higher risk of both thromboembolic and bleeding events. Accurate prediction of prolonged dose titration could help clinicians determine which patients might be better treated by alternative anticoagulants that, while more costly, do not require dose titration. METHODS: A prediction model was derived in a prospective cohort of patients starting warfarin (n = 390), using Cox regression, and validated in an external cohort (n = 663) from a later time period. Prolonged dose titration was defined as a dose-titration period >12 weeks. Predictor variables were selected using a modified best subsets algorithm, using leave-one-out cross-validation to reduce overfitting. RESULTS: The final model had five variables: warfarin indication, insurance status, number of doctor's visits in the previous year, smoking status, and heart failure. The area under the ROC curve (AUC) in the derivation cohort was 0.66 (95%CI 0.60, 0.74) using leave-one-out cross validation, but only 0.59 (95%CI 0.54, 0.64) in the external validation cohort, and varied across clinics. Including genetic factors in the model did not improve the area under the ROC curve (0.59; 95%CI 0.54, 0.65). Relative utility curves indicated that the model was unlikely to provide a clinically meaningful benefit compared with no prediction. CONCLUSIONS: Our results suggest that prolonged dose titration cannot be accurately predicted in warfarin patients using traditional clinical, social, and genetic predictors, and that accurate prediction will need to accommodate heterogeneities across clinical sites and over time. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27456081 TI - Low socioeconomic status and suicidal ideation among elderly individuals. AB - BACKGROUND: Suicide rates are high among elderly individuals experiencing socioeconomic insecurity. Socioeconomic security is of critical importance for elderly individuals and directly affects mental health, including suicidal behavior. Thus, we investigated the relationship between socioeconomic status and suicidal ideation in elderly individuals. METHOD: We conducted a cross-sectional study using data on 58,590 individuals 65 years of age or older from the Korean Community Health Survey 2013. Logistic regression analysis was used to identify relationships between socioeconomic factors (food insecurity, household income, and living arrangement) and suicidal ideation in the elderly population. RESULTS: The study included 58,590 participants (24,246 males and 34,344 females). Of those, 2,847 males and 6,418 females experienced suicidal ideation. Participants with food insecure were more likely to experience suicidal ideation than were those who were food secure (males: OR = 1.60; 95% CI, 1.34-1.90; females: OR = 1.54; 95% CI, 1.38-1.72). We found a similar pattern among participants with a low household income and those living alone. Additionally, male and female subjects who were food insecure and living alone or food insecure and had a low household income showed a marked increase in suicidal ideation. CONCLUSION: Our findings suggest that low socioeconomic status is associated with an increased risk of suicidal ideation among the elderly. Furthermore, intervention programs that address the prevalence of elderly suicide, particularly among those who are socioeconomically disadvantaged, are needed. PMID- 27456082 TI - Development and validation of a Diabetes Risk Score for screening undiagnosed diabetes in Sri Lanka (SLDRISK). AB - BACKGROUND: Screening for undiagnosed diabetes is not widely undertaken due to the high costs and invasiveness of blood sampling. Simple non-invasive tools to identify high risk individuals can facilitate screening. The main objectives of this study are to develop and validate a risk score for screening undiagnosed diabetes among Sri Lankan adults and to compare its performance with the Cambridge Risk Score (CRS), the Indian Diabetes Risk Score (IDRS) and three other Asian risk scores. METHODS: Data were available from a representative sample of 4276 adults without diagnosed diabetes. In a jack-knife approach two thirds of the sample was used for the development of the risk score and the remainder for the validation. Age, waist circumference, BMI, hypertension, balanitis or vulvitis, family history of diabetes, gestational diabetes, physical activity and osmotic symptoms were significantly associated with undiagnosed diabetes (age most to osmotic symptoms least). Individual scores were generated for these factors using the beta coefficient values obtained in multiple logistic regression. A cut-off value of sum = 31 was determined by ROC curve analysis. RESULTS: The area under the ROC curve of the risk score for prevalent diabetes was 0.78 (CI 0.73-0.82). In the sample 36.3 % were above the cut-off of 31. A risk score above 31 gave a sensitivity, specificity, positive predictive value and negative predictive value of 77.9, 65.6, 9.4 and 98.3 % respectively. For Sri Lankans the AUC for the CRS and IDRS were 0.72 and 0.66 repectively. CONCLUSIONS: This simple non-invasive screening tool can identify 80 % of undiagnosed diabetes by selecting 40 % of Sri Lankan adults for confirmatory blood investigations. PMID- 27456083 TI - Fusion Imaging to Support Endovascular Aneurysm Repair Using 3D-3D Registration. AB - PURPOSE: To evaluate the feasibility and accuracy of fusion imaging (FI) during endovascular aneurysm repair (EVAR). METHODS: FI was performed in 101 consecutive EVAR patients (median age 72 years; 93 men) using automatic registration of the preoperative computed tomography angiography (CTA) with an intraoperative noncontrast cone beam CT (nCBCT; 3D-3D registration). Operative landmarks defined on the CTA were then overlaid in 3 dimensions on fluoroscopy images. Accuracy was measured as the deviation of the position of the lowest renal artery between the FI and angiography. Factors potentially influencing accuracy (alpha angle, beta angle, anesthesia, tortuosity index, neck calcification, neck length, CTA slice thickness, and conventional or sac sealing stent-graft) were analyzed in a multivariate linear regression model. RESULTS: Median procedure time for nCBCT was 3 minutes (range 2-20), with 4 minutes (range 0.4-15) for registration. An automatic registration tool was used successfully in 90 (89%) patients. Median craniocaudal deviation of the FI was 3 mm (range 0-15). Full accuracy (<1-mm deviation) was seen in 23 (23%) patients, 1- to 3-mm deviation in 23 (23%), 4- to 5-mm deviation in 22 (22%), and >5-mm deviation in 33 (33%). Caudal deviation potentially resulting in renal coverage was seen in 9 (9%). Lateral plus craniocaudal deviation was a median 5.8 mm (range 0-22). The position of the lowest renal artery compared to the FI was left and cranial in 62 (61%). Aneurysm morphology (beta angle, p=0.04), CTA slice thickness (p=0.02), and the use of 2 stiff guidewires in endovascular aneurysm sealing (p=0.01) influenced the overlay accuracy. CONCLUSION: Fusion imaging can be integrated into a daily workflow adding little to the procedure time. Craniocaudal accuracy (<5 mm) was achieved in 68% of cases, allowing optimal C-arm and angiographic catheter positioning or cannulation of target vessels in most patients. However, the accuracy of FI does not allow a noncontrast EVAR procedure without confirmation of FI overlay by a minimal contrast injection or vessel cannulation. PMID- 27456085 TI - Internet-based modular program BADI for adjustment disorder: protocol of a randomized controlled trial. AB - BACKGROUND: Adjustment disorder is one of the most common mental health diagnoses. Still it receives relatively little attention from researchers trying to establish best interventions to treat it. With high prevalence of stressful life events, which might be leading to adjustment disorder, and limited resources of mental health service providers, online interventions could be a very practical way of helping people who have these disorders or are in the risk to develop them. The proposed study protocol is aimed to describe a randomized controlled trial of an internet-based modular intervention for adjustment disorder as it is defined in a proposal for the ICD-11. METHODS/DESIGN: This study is a two-armed Randomized Controlled Trial (RCT) to examine the effectiveness of a web-based intervention BADI (Brief Adjustment Disorder Intervention) for adjustment disorder symptoms. BADI has four modules: Relaxation, Time management, Mindfulness and Strengthening relationships. It is based on stress and coping research and integrates evidence-based treatment approaches such as Cognitive Behavioural therapy (CBT), mindfulness and body-mind practices, as well as exercises for enhancing social support. Primary outcome of the study are symptoms of adjustment disorder and well-being. Engagement into the program and motivation for change is a secondary outcome. All participants after completing the baseline assessment are randomly assigned to one of the two groups: either to the one in which participant will instantly gain access to the BADI intervention or a group in which participants will be given access to the BADI program after waiting one month. Participants of BADI can choose exercises of the program flexibly. There is no particular order in which the exercises should be completed. DISCUSSION: Study will provide new insights of modular internet-based interventions efficacy for adjustment disorders. The study will also provide information about the role of motivation and expectancies on engagement in modular internet-based interventions. In case this RCT supports effectiveness of fully automated version of BADI, it could be used very broadly. It could become a cost-effective and accessible intervention for adjustment disorder. TRIAL REGISTRATION: The study was retrospectively registered with the Australian and New Zealand Clinical Trials Registry with the registration number ACTRN12616000883415 . Registered 5 July, 2016. PMID- 27456084 TI - miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1). AB - BACKGROUND: Loss-of-function mutations in PINK1 and PARKIN are the most common causes of autosomal recessive Parkinson's disease (PD). PINK1 is a mitochondrial serine/threonine kinase that plays a critical role in mitophagy, a selective autophagic clearance of damaged mitochondria. Accumulating evidence suggests mitochondrial dysfunction is one of central mechanisms underlying PD pathogenesis. Therefore, identifying regulatory mechanisms of PINK1 expression may provide novel therapeutic opportunities for PD. Although post-translational stabilization of PINK1 upon mitochondrial damage has been extensively studied, little is known about the regulation mechanism of PINK1 at the transcriptional or translational levels. RESULTS: Here, we demonstrated that microRNA-27a (miR-27a) and miR-27b suppress PINK1 expression at the translational level through directly binding to the 3'-untranslated region (3'UTR) of its mRNA. Importantly, our data demonstrated that translation of PINK1 is critical for its accumulation upon mitochondrial damage. The accumulation of PINK1 upon mitochondrial damage was strongly regulated by expression levels of miR-27a and miR-27b. miR-27a and miR 27b prevent mitophagic influx by suppressing PINK1 expression, as evidenced by the decrease of ubiquitin phosphorylation, Parkin translocation, and LC3-II accumulation in damaged mitochondria. Consequently, miR-27a and miR-27b inhibit lysosomal degradation of the damaged mitochondria, as shown by the decrease of the delivery of damaged mitochondria to lysosome and the degradation of cytochrome c oxidase 2 (COX2), a mitochondrial marker. Furthermore, our data demonstrated that the expression of miR-27a and miR-27b is significantly induced under chronic mitophagic flux, suggesting a negative feedback regulation between PINK1-mediated mitophagy and miR-27a and miR-27b. CONCLUSIONS: We demonstrated that miR-27a and miR-27b regulate PINK1 expression and autophagic clearance of damaged mitochondria. Our data further support a novel negative regulatory mechanism of PINK1-mediated mitophagy by miR-27a and miR-27b. Therefore, our results considerably advance our understanding of PINK1 expression and mitophagy regulation and suggest that miR-27a and miR-27b may represent potential therapeutic targets for PD. PMID- 27456086 TI - Minimal Margin Extracapsular Dissection: A Viable Alternative Technique for Benign Parotid Lesions? AB - OBJECTIVE: Extracapsular dissection (ECD) has become an accepted, less invasive alternative for the removal of select benign parotid lesions that may reduce complications. Minimal margin extracapsular dissection (MECD) with dissection on or closer to the tumor capsule may be a reasonable alternative to ECD. The objective of this study is to review the complications and safety of the MECD technique at a single institution. SUBJECTS AND METHODS: Medical records for patients who underwent MECD for suspected benign parotid lesions were reviewed. Outcome measurements included intraoperative findings, complications, and recurrences. RESULTS: Forty patients underwent a MECD for suspected benign parotid lesions. The average tumor size was 2.2 cm. Frozen section revealed low intermediate grade mucoepidermoid carcinoma in 2 (5%) cases, requiring completion of a superficial parotidectomy at the same setting. There was 1 case of temporary facial nerve weakness and no cases of Frey syndrome. No tumor recurrences were observed within the follow-up period (average 3.5 years.) CONCLUSION: In the hands of an experienced surgeon, MECD may be a viable alternative to formal superficial parotidectomy. This study reports low rates of nerve weakness and Frey syndrome. Long-term follow-up is necessary to determine the ultimate risk of recurrence. PMID- 27456087 TI - Margaret McCartney: Clean eating and the cult of healthism. PMID- 27456088 TI - Exposure to a putative alarm cue reduces downstream drift in larval sea lamprey Petromyzon marinus in the laboratory. AB - An experimental mesocosm study suggested larval sea lamprey Petromyzon marinus detect and respond to an alarm cue released by dead adult conspecifics. Larvae exhibited a reduced tendency to move downstream when exposed to the cue and were less likely to move under continuous v. pulsed exposure. These findings support the hypothesis that short-term exposure to the alarm cue would probably result in retraction into the burrow, consistent with the blind, cryptic lifestyle of the larval P. marinus. PMID- 27456089 TI - Arthritis in childhood human immunodeficiency virus infection predominantly associated with human leukocyte antigen B27. AB - AIM: Children with human immunodeficiency virus (HIV) infection usually present with recurrent and unusual infections. Although reported among adults, arthritis as a predominant presentation in children with HIV is rare. Reactive arthritis is considered to be the most common musculoskeletal manifestation in adults with HIV infection. However, in children, septic or HIV-related arthritis has been described. We report four children having arthritis with HIV disease and their long-term outcome; out of which three had human leukocyte antigen (HLA)-B27 related arthritis. It is important to be aware of arthritic presentation of HIV disease in children to prevent delay in diagnosis and initiation of appropriate therapy. METHODS: Clinical profile of children with HIV infection who presented with arthritis and registered at the Pediatric Immunodeficiency Clinic at PGIMER, Chandigarh were reviewed and analyzed. RESULTS: A total of 796 children with HIV infection are registered in the Pediatric Immunodeficiency Clinic since January 1994. Among these, four children had arthritis, and it was the presenting manifestation in two of them. HLA-B27 related arthritis was noted in three children, while one had HIV-associated arthritis. None of the children had septic arthritis. Arthritis resolved on treatment with antiretroviral therapy (ART) in two children, while others responded to anti-inflammatory agents and the joint symptoms remained quiescent on follow-up with a total follow-up period of 21.5 patient years. CONCLUSIONS: Clinicians must be aware of the arthritic presentation of childhood HIV infection. High degree of suspicion must be entertained to screen for HIV infection in children with arthritis, especially in those with reactive arthritis. PMID- 27456090 TI - Examination of patient flow in a rural health center in Malawi. AB - BACKGROUND: Malawi, like many low-income countries, is facing a severe health worker shortage. A potential stop-gap solution to this crisis is improving the efficiency of health center operations. Given the lack of research on center efficiency in rural health centers in Malawi, we conducted a study to identify deficiencies in center organization and barriers to patient flow. METHODS: We performed a time-motion survey at a rural health center in Ntaja, Malawi over a period of 1 week. We used a standardized questionnaire to collect information on the amount of time a patient spent with each health worker, the number of center staff that attended to each patient, and the total time spent at the center. Additionally, at the end of the visit, we conducted an exit survey to collect demographic information and data on perception of quality of care with the center visit for all patients. RESULTS: A total of 1018 patients were seen over the five day study. The average total time spent at the center by the patients was 123 min (2-366 min). Adults had an average total time spent at the center of 111 min (2 366 min) and children 134 min (7-365 min). Patient waiting time (PWT) was higher in the early morning hours ranging from 157 min (between 06:00 and 08:00) to 53 min (between 14:00 and 16:00). Health worker contact time (HCT) was higher for adults (2.3 min) than children (1.7 min). Shorter wait times were associated with higher perceptions of quality of service. CONCLUSION: Despite shortages in health workers and funds, opportunities are available to increase efficiency in rural health centers. By removing bottlenecks to increase the productivity of health workers, centers in low-income countries can treat more patients and improve service quality. PMID- 27456091 TI - A cohort analysis of men with a family history of BRCA1/2 and Lynch mutations for prostate cancer. AB - BACKGROUND: Prostate cancer (PC) is a major health concern for men worldwide, with an estimated lifetime risk of ~14 %. A recent comprehensive analysis of mutational processes revealed ageing and mismatch repair as the only altered processes in PC. We wish to test if a cohort of men with inherited risk of mismatch repair defect through BRCA1/2 or Lynch Syndrome mutations represents a target population for prostate cancer testing. METHODS: Fifty-eight men (aged 40 69 years) from families with a history of BRCA1/2 or HNPCC/Lynch mutations were invited to take part. Men with PSA >3.0 ng/ml were recommended to have transrectal ultrasound-guided prostatic biopsies. RESULTS: Overall 1 of 7 (14 %) and 1 of 20 (5 %) men with BRCA1/2 mutations were positive for a diagnosis of prostate cancer. In men with Lynch syndrome, 1 of 4 (25 %) was diagnosed to have prostate cancer. The index case with Lynch syndrome harbours a heterozygous mutation in the mismatch repair MSH6 gene. Near to complete loss of MSH6 immunoreactivity in the prostate tumour supports silencing of the remaining MSH6 allele during prostate carcinogenesis. CONCLUSION: The finding of near-to complete loss of MSH6 expression in affected men with a family history of Lynch Syndrome supports its mechanistic involvement during prostate carcinogenesis. This work therefore contributes to the argument that, in certain male populations, Lynch Syndrome mutations are biologically implicated in men with prostate cancer. PMID- 27456092 TI - Quality of life among elderly patients undergoing transcatheter or surgical aortic valve replacement- a model-based longitudinal data analysis. AB - BACKGROUND: Quality of life (QoL) measurements reported in observational studies are often biased, since patients who failed to improve are more likely to be unable to respond due to death or impairment. In order to observe the development of QoL in patients close to death, we analyzed a set of monthly QoL measurements for a cohort of elderly patients treated for aortic valve stenosis (AS) with special consideration of the effect of distance to death. METHODS: QoL in 169 elderly patients (age >= 75 years), treated either with transcatheter aortic valve replacement (TAVR; n = 92), surgical aortic-valve replacement (n = 70), or drug-based therapy (n = 7), was evaluated using the standardized EQ-5D questionnaire. Over a two-year period, patients were consulted using monthly telephone interviews or outpatient visits, leading to a total of 2463 time points at which QoL values, New York Heart Association (NYHA) Functional Classification and their status of assistance were assessed. Furthermore, post-procedural clinical events and complications were monitored. Linear and ordered logistic regression analyses with random intercept were carried out, taking into account overall trends and distance to death. RESULTS: QoL measures decreased slightly over time, were temporarily impaired at month 1 after the initial episode of hospitalization and decreased substantially at the end of life with a measurable effect starting at the sixth from last follow-up (month) before death. Many clinical complications (bleeding complications, stroke, acute kidney injury) showed an impairment of QoL measurements, but the inclusion of lagged variables demonstrated medium term (three months) QoL impairments for access site bleeding only. All other complications are associated with event-related impairments that decreased dramatically at the second and third follow-up interviews (month) after event. CONCLUSIONS: Distance to death shows clear effects on QoL and should be taken into account when analyzing QoL measures in the elderly patients treated for aortic valve stenosis. TRIAL REGISTRATION: German Clinical Trial Register Nr. DRKS00000797. PMID- 27456093 TI - Faecal carriage of antibiotic resistant Escherichia coli in asymptomatic children and associations with primary care antibiotic prescribing: a systematic review and meta-analysis. AB - BACKGROUND: The faecal reservoir provides optimal conditions for the transmission of resistance genes within and between bacterial species. As key transmitters of infection within communities, children are likely important contributors to endemic community resistance. We sought to determine the prevalence of antibiotic resistant faecal Escherichia coli from asymptomatic children aged between 0 and 17 years worldwide, and investigate the impact of routinely prescribed primary care antibiotics to that resistance. METHODS: A systematic search of Medline, Embase, Cochrane and Web of Knowledge databases from 1940 to 2015. Pooled resistance prevalence for common primary care antibiotics, stratified by study country OECD status. Random-effects meta-analysis to explore the association between antibiotic exposure and resistance. RESULTS: Thirty-four studies were included. In OECD countries, the pooled resistance prevalence to tetracycline was 37.7 % (95 % CI: 25.9-49.7 %); ampicillin 37.6 % (24.9-54.3 %); and trimethoprim 28.6 % (2.2-71.0 %). Resistance in non-OECD countries was uniformly higher: tetracycline 80.0 % (59.7-95.3 %); ampicillin 67.2 % (45.8-84.9 %); and trimethoprim 81.3 % (40.4-100 %). We found evidence of an association between primary care prescribed antibiotics and resistance lasting for up to 3 months post-prescribing (pooled OR: 1.65, 1.36-2.0). CONCLUSIONS: Resistance to many primary care prescribed antibiotics is common among faecal E. coli carried by asymptomatic children, with higher resistance rates in non-OECD countries. Despite tetracycline being contra-indicated in children, tetracycline resistance rates were high suggesting children could be important recipients and transmitters of resistant bacteria, or that use of other antibiotics is leading to tetracycline resistance via inter-bacteria resistance transmission. PMID- 27456095 TI - Measuring agreement between healthcare survey instruments using mutual information. AB - BACKGROUND: Healthcare researchers often use multiple healthcare survey instruments to examine a particular patient symptom. The use of multiple instruments can pose some interesting research questions, such as whether the outcomes produced by the different instruments are in agreement. We tackle this problem using information theory, focusing on mutual information to compare outcomes from multiple healthcare survey instruments. METHODS: We review existing methods of measuring agreement/disagreement between the instruments and suggest a procedure that utilizes mutual information to quantitatively measure the amount of information shared by outcomes from multiple healthcare survey instruments. We also include worked examples to explain the approach. RESULTS: As a case study, we employ the suggested procedure to analyze multiple healthcare survey instruments used for detecting delirium superimposed on dementia (DSD) in community-dwelling older adults. In addition, several examples are used to assess the mutual information technique in comparison with other measures, such as odds ratio and Cohen's kappa. CONCLUSIONS: Analysis of mutual information can be useful in explaining agreement/disagreement between multiple instruments. The suggested approach provides new insights into and potential improvements for the application of healthcare survey instruments. PMID- 27456094 TI - The Sources of Strength Australia Project: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: The school system has been identified as an ideal setting for the implementation of prevention and early intervention programs for suicide. However, in Australia, suicide-prevention programs that are routinely delivered in the schools are lacking. Internationally, evidence exists for the effectiveness of peer-led interventions that take a social connectedness approach to improve help-seeking for suicide. The aim of the current trial is to test the effectiveness of the Sources of Strength program to promote help-seeking for suicide in adolescents in Australian high schools. METHODS/DESIGN: This study is a two-arm, cluster-randomised, controlled trial that will compare the evidence based Sources of Strength program to a wait-list control condition. Sixteen Australian high schools will be recruited to the trial, with all adolescents in years 7 to 10 (12-16 years of age) invited to participate. Peer leaders from intervention-condition schools will receive training in the Sources of Strength program and will integrate positive messages, across 3 months, with the support of adult advisors. Activities may take the form of class presentations, posters, videos, and messages on social media sites and will aim to change help-seeking norms, strengthen youth-adult connections, and promote positive coping. The primary outcome measure for the study is help-seeking intentions, whereas secondary outcomes include help-seeking behaviour, help-seeking attitudes and norms, referral of distressed peers, availability of adult help, positive coping, and suicidal behaviour. Data will be collected pre-intervention, post intervention (after the initial 3 months of messaging), and at the end of the first (6-month follow-up) and the second year after implementation (18-month follow-up). Primary analyses will compare changes in help-seeking intentions for the intervention condition relative to the wait-list control condition using mixed-effect repeated-measures analyses to account for clustering within schools. DISCUSSION: If proven effective, this universal social connectedness program for suicide could be more widely delivered in Australian high schools, providing a valuable new resource. The Sources of Strength program has the potential to significantly contribute to the mental health of young people in Australia by improving help-seeking for suicide. The findings from this research will also contribute to the evidence-base for peer-leadership programs internationally. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000048482 . Registered on 19 January 2016. PMID- 27456102 TI - Impact of Chronic Kidney Disease on Risk for Vascular Events. AB - BACKGROUND: Chronic kidney disease (CKD) accounts for a significant proportion of the morbidity and mortality in the United States. CKD is defined as glomerular filtration rate (GFR) <60ml/min/1.73m2 or clear evidence of renal damage from biopsy. All-cause cardiovascular risk increases with decreasing GFR. Clinically, detection of CKD is through changes in creatinine clearance which estimates GFR, an indicator of kidney function. We reviewed conventional and nonconventional cardiovascular risk factors associated with CKD. Clinically, we reviewed the status of statins as a treatment option for CKD-induced dyslipidemia. OBJECTIVE: CKD has dramatic consequences on cardiovascular risk profile due to a complex pathophysiologic response to declining kidney function. In this review, we explored new, more accurate methods of detecting decreasing kidney function, discerned risk factors for the development of cardiovascular events, and examined the controversial use of statins for renoprotection. RESULTS: Detection of declining renal function by monitoring creatinine has been the clinical gold standard, but it substantially fluctuates with muscle mass, sex, and ethnicity. Newer methods using cystatin C have been at the forefront as the next substance that will be used for detection of CKD. Traditional and non-traditional risk factors contribute to the cardiovascular risk profile of patients with declining renal function. Statins, along with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)s, have been used for renoprotection, but evidence shows only modest benefits in non-dialysis patients. CONCLUSION: Cardio-renal interaction involves multiple risk factors that contribute significantly to the CKD-induced development of accelerated atherosclerosis, an inflammatory state that causes cardiovascular events. PMID- 27456103 TI - Increased Exercise Favorably Modifies Coronary Artery Disease and Peripheral Arterial Disease Outcomes. AB - Exercise therapy, especially when supervised on-site in a clinical facility or directed off-site for a home-based program, is an essential component of the management of coronary artery disease (CAD) and peripheral arterial disease (PAD). In the case of both atherosclerotic diseases, it can decrease adverse cardiovascular (CV) events. There has been a recent push toward invasive management of both CAD and PAD but accumulating clinical experience has shown the limitation of invasive management and emphasized the importance of medications, CV risk reduction, conditioning, and exercise, especially when supervised. Exercise results in increased peak oxygen consumption (V02), improvement of wellestablished CV risk factors such as plasma lipids, and an improvement in indicators of inflammation and of various metabolic factors. Fortunately, there is generally good third-party coverage of medications and vascular interventions but unfortunately, poor insurance coverage for supervised or directed exercise programs for which significant patient benefit has been established. PMID- 27456104 TI - The Mediterranean and other Dietary Patterns in Secondary Cardiovascular Disease Prevention: A Review. AB - Cardiovascular Disease (CVD) remains the leading cause of death and disability worldwide, with increased hospital discharge rates, causing a serious public health issue and an economic burden. Recent demographic transitions, including ageing of the population, low fertility, urbanization and shift towards unhealthy behaviours have resulted in an increase in the prevalence of cardiometabolic disorders (i.e. hypertension, obesity, diabetes). According to the reports of international organisations, a substantial number of heart attacks could have been prevented through lifestyle modifications (i.e. diet, physical activity, smoking cessation). Regarding secondary prevention, it is well documented that effective cardiovascular rehabilitation requires a multidisciplinary approach, including medical treatment, as well as lifestyle changes. Diet has been recognised as one of the most important modifiable and preventable factors, being undoubtedly beneficial in primary prevention, as well as among cardiac patients. However, studies among CVD patients are scarce, and with inconclusive results. The most studied dietary pattern is the Mediterranean-type diet, with several observational studies and clinical trials demonstrating its protective role against recurrent cardiac events, whereas evidence regarding other well-known models, including Western-type, Vegetarian, Asian-type and Dietary Approaches to Stop Hypertension (DASH) diet, are more limited. The aim of this review was to present an overview of the most prevalent dietary patterns and their role in the secondary CVD prevention and management. PMID- 27456105 TI - Interrelationships with Metabolic Syndrome, Obesity and Cardiovascular Risk. AB - Cardiovascular (CV) disease is the most common cause of morbidity and mortality worldwide, particularly in the presence of the metabolic syndrome (MetS). Classifications and treatment of the MetS have recently been redefined. While the majority of the cardiac components such as hypertension, diabetes mellitus (DM) and dyslipidemia (DLD) are objectively measurable elements, a few disparities among the definitions have to be considered that can variably modify diagnosis, treatment and prevention. Non-cardiac factors such as liver disease (including, but not limited to, alcoholic and non-alcoholic steatosis/hepatitis), renal disease, severe obesity, polycystic ovarian syndrome and obstructive sleep apnea (OSA), may have independent or synergistic relationship with complementary cardiac MetS elements, and these additional risk factors may have an incremental adverse impact on CV outcome. The combination of all these factors potentiates the adverse significance on CV events. MetS not only increases morbidity and mortality but also has economic ramifications for the healthcare system. Prevention of CV disease includes primary and secondary aspects. Besides overall advances to provide optimal care for hypertension, diabetes, and dyslipidemia, early-targeted inventions to diagnose, treat and prevent OSA, and severe obesity, are needed. PMID- 27456106 TI - Use of Chronic Disease Registries to Optimize Cardiovascular Health. AB - Cardiovascular disease remains a significant cause of mortality and morbidity despite relentless ongoing research all over the world. The different cardiovascular societies and research organizations are in a constant effort to improve overall cardiovascular (CV) outcome by conducting trials and establishment of guidelines. The ever growing health care costs have enforced governmental agencies to develop quality performance measures which are addressed towards increasing quality, safety, efficiency of patient care and to curtail the cost of health care. Clinical registries are observational databases which provide detailed information about patient population, a specific disease or a clinical condition, therapy or procedure. These can be utilized in estimating appropriateness of health care delivery and providing feedback to providers and health care organizations for gauging their performance at regional and national level. The introduction of electronic health records (EHR) has immensely helped the workflow and maintenance of clinical registries with their integrated software. PMID- 27456107 TI - Cardiovascular Risk Factors: Does Sex Matter? AB - Coronary heart disease (CHD) is the leading cause of death for women worldwide, most of which is believed to be preventable. Numerous risk factors for CHD are well described, and understanding these risk factors is the first step to reducing the burden of CHD. There are clear differences in risk factors between women and men. The incidence of myocardial infarction is much lower among women under the age of 50 years compared with men, but after menopause, the incidence in women dramatically increases to approach that of men. For this reason, estrogen is postulated to be cardioprotective but results of recent randomized clinical trials challenge this hypothesis. The significance of cardiovascular risk factors appears to vary between women and men, the reasons for which remain elusive but could include the interaction of these risk factors with hormones. Confounding this observation is that most early studies of cardiovascular risk factors enrolled primarily men. This review will focus solely on the differences in cardiovascular risk factors in women and men including the current role of hormone therapy in CHD prevention, sex differences in established CHD risk factors and emerging risk factors for CHD in women. PMID- 27456108 TI - Abnormal Peri-Organ or Intra-organ Fat (APIFat) Deposition: An Underestimated Predictor of Vascular Risk? AB - Adipose tissue, a major endocrine organ, consists of brown and white adipocytes. Brown fat may play a beneficial role in cardiometabolic disorders. Brown adipose tissue can also improve glucose and lipid metabolism. In contrast, the expansion of white adipose tissue has been related to obesity, type 2 diabetes mellitus and cardiovascular disease (CVD). Both the quantity and the quality of the white adipose tissue as well as its distribution may affect CVD risk. In this context, the link between adiposity and CVD risk is greater for visceral than subcutaneous fat. Apart from these fat depots, there are other adipose tissues that are either systemically (i.e. in the liver, muscle or neck) or mainly locally acting (i.e. pericardial/epicardial, perivascular and perirenal). These fat depots can affect the nearby anatomic organs via lipid accumulation and cytokine secretion. In the present narrative review, the associations of excessive peri-organ adipose tissue, namely intrahepatic, epicardial/ pericardial, perivascular, intramuscular, peripancreatic and perirenal fat, with cardiometabolic and CVD risk factors are discussed. The effects of drugs that target vascular risk and/or different fat depots are also considered. PMID- 27456109 TI - Efficacy and Safety Assessment of Hypertension Management with Coveram (Perindopril/Amlodipine Fixed Combination) in Patients with Previous Angiotensin Receptor Blocker (ARB) Treatment: Arabian Gulf STRONG Study. AB - OBJECTIVE: We evaluated the safety and efficacy of hypertension management with Coveram (perindopril/amlodipine combination) in patients with uncontrolled blood pressure (BP). All patients were on previous angiotensin receptor blocker (ARB) treatment. METHODS: This was a 3 country, multi-centre (7 cities), open-label, observational study in the Arabian Gulf. Patients (>=18 years) were recruited between October 2012 and November 2013 and followed-up for 3 months after enrolment. Outcomes included changes in BP from baseline and BP goal attainment rates as per Joint National Committee- 8 (<140/90 mmHg for diabetics and those <60 years of age and <150/90 mmHg for those >=60 years of age without diabetes). Medication tolerance was also assessed from both patient and physician perspectives. RESULTS: Hypertensive patients (n=760; mean age: 51+/-10 years; 67% were males) were included. A total of 178 patients (23%) were lost to follow-up. The perindopril/amlodipine combination was associated with an overall reduction in systolic BP (SBP) (31 mmHg; p<0.001) and diastolic BP (DBP) (18 mmHg; p<0.001) from baseline. An overall BP control rate was achieved in 87% (n=507) of the participants. There were significant incremental BP reductions with dose up titration, especially SBP (p<0.001). Those with high SBP (>180 mmHg) at baseline were associated with a mean reduction of 59 mmHg (p<0.001). The perindopril/amlodipine combination had excellent tolerance levels over the study period from both patient and physician perspectives (at 99% and 98%, respectively; p<0.001). CONCLUSIONS: The perindopril/amlodipine combination is an effective and well tolerated anti-hypertensive option in patients on previous ARB treatment. PMID- 27456111 TI - Temperamental Characteristics of Withdrawn Behavior Problems in Children. AB - Withdrawn/depressed behavior (WD) as defined by the Child Behavior Checklist (CBCL) relates to various outcomes in developmental psychopathology such as depression, pervasive developmental disorders, and suicide. We sought to examine the temperamental characteristics of children who concurrently endorse symptoms of WD. Junior Temperament and Characteristic Inventory (JTCI) and CBCL data were collected from 397 children's parents in a family study in the northeastern United States. Linear mixed models were used to test the relations between WD and temperament dimensions (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence) on the JTCI, while controlling for age, sex, item overlap, and co occurring aggression and attention problems. When controlling for definitional artifact and CBCL aggressive behavior and attention scores, high harm avoidance and low reward dependence were both significant predictors of childhood withdrawn behavior. This study marks the first characterization of a temperamental profile associated with WD in children and adolescents. PMID- 27456112 TI - Working Memory in Deaf Children Is Explained by the Developmental Ease of Language Understanding (D-ELU) Model. PMID- 27456113 TI - Physical Health Consequences of Interpersonal Trauma: A Systematic Review of the Role of Psychological Variables. AB - Interpersonal forms of trauma are among the most commonly reported traumas. These types of traumas are more damaging to well-being than noninterpersonal forms. They have also been strongly associated with somatic symptoms and more general physical health problems. Nevertheless, the results of trauma studies are mixed and suggest that pathways may vary according to the stressors, mediators, and health outcomes investigated. This article presents a systematic qualitative review of published studies that have investigated interpersonal trauma, its association with physical health, and the potential role of intervening psychological variables. A systematic search was made of four psychology and health electronic databases. Of the 863 studies reviewed, 50 were preselected, 11 of which met the inclusion and methodological quality criteria. All but one study had a cross-sectional design. The findings showed that childhood trauma exposure was the most common category of interpersonal trauma addressed in the reviewed studies and that the physical health variables investigated were diverse. The psychological variables most frequently investigated in the studies were posttraumatic stress disorder, depression, dissociation, and substance abuse. Overall, the results suggest that interpersonal trauma exposure is associated with poorer physical health; however, the role of intervening psychological variables remains unclear. The limitations of the reviewed literature are discussed, and methodological recommendations are made for future research. PMID- 27456114 TI - Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more? AB - Amongst 1.5 million fatal mycoses of humans occurring annually [1], the vast majority involve the human lung as the primary site of pathogenesis, and are derived from organisms which occupy environmental niches. On entry into the respiratory system pathogenic fungi must draw upon metabolic versatility for survival and proliferation as the mammalian lung is a nutritionally limiting environment. The nutritional stresses encountered have exposed vulnerabilities which have long been viewed as potential antifungal targets, since humans lack several of the metabolic pathways which fungi rely upon for pathogenic growth. However the ability of saprophytic fungi to proteolytically liberate amino acids from exogenous protein sources, and the differential availabilities of amino acids in diverse host niches have undermined confidence in amino acid metabolism as a target for selectively toxic antifungal therapies. Recent studies have reopened this debate by revealing a number of anabolic amino acid pathways in pathogenic fungi as being essential for viability per se. This review examines new knowledge on fungal amino acid metabolism in fungal pathogens of the human lung with a view to highlighting important new advances and gaps in understanding. PMID- 27456115 TI - Three toxins, two receptors, one mechanism: Mode of action of Cry1A toxins from Bacillus thuringiensis in Heliothis virescens. AB - Insecticidal crystal (Cry) proteins from Bacillus thuringiensis (Bt) are highly active against Lepidoptera. However, field-evolved resistance to Bt toxins is on the rise. The 12-cadherin domain protein HevCaLP and the ABC transporter HevABCC2 are both genetically linked to Cry toxin resistance in Heliothis virescens. We investigated their interaction using stably expressing non-lytic clonal Sf9 cell lines expressing either protein or both together. Untransfected Sf9 cells are innately sensitive to Cry1Ca toxin, but not to Cry1A toxins; and quantitative PCR revealed negligible expression of genes involved in Cry1A toxicity such as cadherin, ABCC2, alkaline phosphatase (ALP) and aminopeptidase N (APN). Cry1Aa, Cry1Ab or Cry1Ac caused swelling of Sf9 cells expressing HevABCC2, and caused faster swelling, lysis and up to 86% mortality in cells expressing both proteins. No such effect was observed in control Sf9 cells or in cells expressing only HevCaLP. The results of a mixing experiment demonstrated that both proteins need to be expressed within the same cell for high cytotoxicity, and suggest a novel role for HevCaLP. Binding assays showed that the toxin-receptor interaction is specific. Our findings confirm that HevABCC2 is the central target in Cry1A toxin mode of action, and that HevCaLP plays a supporting role in increasing Cry1A toxicity. PMID- 27456116 TI - Molecular cloning and characterization of ech46 endochitinase from Trichoderma harzianum. AB - In the present study, endochitinase of T. harzianum isolate-ThHP3 induced against mycelium of F. oxysporum was cloned, sequenced and characterized. The complete nucleotide sequence contained an ORF of 1293bp corresponding to 430 amino acids with 46kDa molecular weight and theoretical pI 5.59. The precursor protein contained 22 amino acids long signal peptide at N terminus. The domain architecture of endochitinase showed low complexity regions, presence of 1W9P domain specific to cyclopentapeptide and lack of carbohydrate binding modules. The ligand binding site of ech46 endochitinase was constituted by 10 amino acids. The cDNA encoding ech46 endochitinase was ligated into pET28a vector and transformed to E. coli BL21. The predicted molecular weight of recombinant endochitinase without signal peptide was 49.4kDa with a theoretical pI 6.67. SDS PAGE analysis of purified 6xHis tagged protein showed a single band of 49kDa. The refolded enzyme was active under acidic conditions with a temperature and pH optima of 50 degrees C and 4. Km and Vmax for recombinant endochitinase using 4 pNP-(GlcNAc)3 were 315.2+/-0.36MUM and 0.140+/-0.08MUMmin-1, respectively and the calculated kcat was 6.44min-1. The RT-qPCR revealed induction of ech46 by phytopathogenic fungi. PMID- 27456117 TI - Energetic and conformational features linked to the monomeric and dimeric states of bovine BLG. AB - Bovine beta-lactoglobulin (BLG) belong to the lipocalin family. This is a group of proteins involved in the binding and transporting of hydrophobic molecules. Experimental and theoretical reports have stated its complex structural behavior in solution, with coupled effects between homodimerization and ligand recognition. Nonetheless, structural evidence at the atomic level about the cause of this coupled effect has not been reported to date. To address this issue microsecond molecular dynamics (MD) simulations were combined with the molecular mechanics generalized Born surface area (MM/GBSA) approach, clustering analysis and principal component analysis (PCA), to explore the conformational complexity of BLG protein-protein self-association and palmitic acid (PLM) or dodecyl sulfate (SDS) ligand recognition in the monomeric and dimeric state. MD simulations, coupled to the MM/GBSA method, revealed that dimerization exerts contrasting effects on the ligand-binding capacity of BLG. Protein dimerization decreases PLM affinity, promoting dimer association. For SDS the dimeric state increases affinity, enhancing dimer dissociation. MD simulations based on PCA revealed that while few differences in the conformational subspace are observed between the free and bound monomer and dimer coupling for PLM, substantial changes are observed between the free and bound monomer and dimer coupling for SDS. PMID- 27456118 TI - Affinity of miriplatin to human serum albumin and its effect on protein structure and stability. AB - In this report, circular dichroism (CD) along with steady-state fluorescence spectroscopy and molecular modeling investigations were carried out to better understand the interaction of miriplatin with human serum albumin (HSA). The presence of miriplatin in solution is found to destabilize the native structure of HSA: The tertiary structure of HSA was changed and the microenvironment of Trp residue became more hydrophobic; the binding affinity of HSA with miriplatin indicating by 8-Anilino-1-naphthalenesulfonic acid (ANS) fluorescence study was 1.74*106L/mol; miriplatin induced the denaturation and unfolding of HSA and disrupted the polar contacts and decreasing the reversibility of the unfolding process of protein. In addition, molecular modeling studies indicated miriplatin bound to domain II of HSA by hydrophobic force, hydrogen bonds, and electrostatic force interactions. HSA retained most of its esterase activity even after its binding with miriplatin. These results provide valuable insight into the binding mechanism between miriplatin and a plasma protein that is known to play an important role in the drug delivery of medicinal drugs to target organs. PMID- 27456119 TI - Molecular aspects of the interaction of spermidine and alpha-chymotrypsin. AB - Polyamines such as spermidine are essential for survival. The purpose of the present study was to investigate how spermidine could influence the conformation, thermal stability and the activity of alpha-chymotrypsin. The influence of spermidine on the structure and stability of alpha-Chymotrypsin (alpha-Chy) explored using different spectroscopy method and molecular docking simulations. The stability and activity of alpha-Chy were increased in the presence of spermidine. Increasing of the alpha-Chy absorption in the presence of spermidine was as a result of the formation of a spermidine - alpha-Chy complex. The results of fluorescence spectroscopic measurements suggested that spermidine has a vigorous ability to quench the intrinsic fluorescence of alpha-Chy through the dynamic quenching procedure. Near and Far-UV CD studies also confirmed the transfer of aromatic residues to a more flexible environment. The absorption increasing of alpha-Chy in the presence of spermidine was as a result of the formation of spermidine - alpha-Chy complex. Molecular docking results also revealed the presence of one binding site with a negative value for the Gibbs free energy of the binding of spermidine to alpha-Chy. Further, the docking study revealed that van der Waals interactions and hydrogen bonds play a main role in stabilizing the complex. PMID- 27456120 TI - Microencapsulation of norfloxacin in chitosan/chitosan oligosaccharides and its application in shrimp culture. AB - Norfloxacin chitosan/chitosan oligosaccharide microcapsules (NCCM) were prepared by emulsion-chemical crosslinking method. The characteristics of obtained microcapsules were evaluated by scanning electron microscopy, Fourier transform infrared spectroscopy and release experiments. Cumulative release profile of norfloxacin from the chitosan microcapsules in natural seawater was measured and the controlled release of drugs was at a uniform rate in 48h. The chitosan microcapsules were applied onto the antibacterial study of the shrimp culture in natural seawater. It is observed that the seawater in the NCCM added groups was relatively clear and the biomass of Vibrio increased slowly in contrast to the control and norfloxacin groups. The inhibition rate of Vibrio in norfloxacin groups obvioursly decreased after the 5th day, whereas, it remained high and stable during experiment period in NCCM groups. The results showed that the chitosan microcapsules as release materials have excellent antibacterial effects on Vibrio in the farming of Penaeus vannamei Boone. The controlled release could obviously reduce dosage of antibiotics and delivery times, and effectively improve the utilization rate of norfloxacin drugs for shrimps. PMID- 27456121 TI - The changes of secondary structures and properties of lysozyme along with the egg storage. AB - The changes of lysozyme structure during egg storage were investigated by Fluorescence spectroscopy, Circular Dichroism spectroscopy and Fourier Transform Raman spectroscopy, and the relationships between lysozyme properties (enzyme activity, emulsibility and foamability) and secondary structure were also discussed. During the storage, the percentages of alpha-helix and beta-turn declined, conversely the beta-sheet and random coil increased, the polarity of microenvironment around tryptophan residue gradually decreased. The results suggested that the conformation of lysozyme became more flexible during egg storage. Lysozyme activity was decreased but ESI and FA of lysozyme rose up with the storage duration. Correlation analysis revealed that second structure of lysozyme significantly affected lysozyme properties during egg storage. These findings would certainly be useful for further study of food storage and production. PMID- 27456122 TI - Quantification of anti-aggregation activity of chaperones. AB - Anti-aggregation potential of the cell is determined by chaperones of a proteinaceous nature (mainly by small heat shock proteins) and low-molecular weight chemical chaperones. To characterize the anti-aggregation activity of chaperones in vitro, appropriate test systems based, for example, on thermal or dithiothreitol-induced aggregation of model proteins can be used. Aggregation assays usually follow increment in the light scattering intensity or apparent optical absorbance. The initial parts of the dependences of the light scattering intensity (I) on time (t) can be described by quadratic equation: I=[KLS(t-t0)]2, where KLS is a parameter characterizing the initial rate of aggregation and t0 is the duration of lag phase. Based on the dependence of KLS on the initial concentration of the protein [P]0, the power coefficient a in the equation KLS=const [P]0a is determined. The (KLS/KLS,0)1/a versus chaperone concentration plot is used for analysis of the protective action of chaperones. The anti aggregation activity of protein chaperones is expressed as an adsorption capacity of the chaperone with respect to target protein. The anti-aggregation activity of chemical chaperones is expressed as a semi-saturation concentration of the chaperone, i.e., the concentration of chaperone at which (KLS/KLS,0)1/a=0.5. PMID- 27456123 TI - Ionic surfactants-Glossoscolex paulistus hemoglobin interactions: Characterization of species in the solution. AB - Glossoscolex paulistus hemoglobin (HbGp) is an oligomeric multisubunit protein with molecular mass of 3600kDa. In the current study, the interaction of sodium dodecyl sulfate (SDS) and cetyl trimethylammonium chloride (CTAC) surfactants with the monomer d and the whole oxy-HbGp, at pH 7.0, was investigated. For pure monomer d solution, SDS promotes the dimerization of subunit d, and the monomeric and dimeric forms have sedimentation coefficient values, s20,w, around 2.1-2.4 S and 2.9-3.2 S, respectively. Analytical ultracentrifugation (AUC) and isothermal titration calorimetry (ITC) data suggest that up to 26 DS- anions are bound to the monomer. In the presence of CTAC, only the monomeric form is observed in solution for subunit d. For the oxy-HbGp, SDS induces the dissociation into smaller subunits, such as, monomer d, trimer abc, and tetramer abcd, and unfolding without promoting the protein aggregation. On the other hand, lower CTAC concentration promotes protein aggregation, mainly of trimer, while higher concentration induces the unfolding of dissociated species. Our study provides strong evidence that surfactant effects upon the HbGp-subunits are different, and depend on the surfactant: protein concentration ratio and the charges of surfactant headgroups. PMID- 27456124 TI - Synthesis of papain nanoparticles by electron beam irradiation - A pathway for controlled enzyme crosslinking. AB - Crosslinked enzyme aggregates comprise more stable and highly concentrated enzymatic preparations of current biotechnological and biomedical relevance. This work reports the development of crosslinked nanosized papain aggregates using electron beam irradiation as an alternative route for controlled enzyme crosslinking. The nanoparticles were synthesized in phosphate buffer using various ethanol concentrations and electron beam irradiation doses. Particle size increase was monitored using dynamic light scattering. The crosslinking formation by means of bityrosine linkages were measured by fluorescence spectra and the enzymatic activity was monitored using Na-Benzoyl-dl-arginine p-nitroanilide hydrochloride as a substrate. The process led to crosslinked papain nanoparticles with controlled sizes ranging from 6 to 11nm depending upon the dose and ethanol concentration. The irradiation atmosphere played an important role in the final bioactivity of the nanoparticles, whereas argon and nitrous oxide saturated systems were more effective than at atmospheric conditions in terms of preserving papain enzymatic activity. Highlighted advantages of the technique include the lack of monomers and crosslinking agents, quick processing with reduced bioactivity changes, and the possibility to be performed inside the final package simultaneously with sterilization. PMID- 27456125 TI - Microwave-assisted extraction of polysaccharides from Cyphomandra betacea and its biological activities. AB - Response Surface Methodology (RSM) was used to optimize the parameters for microwave-assisted extraction of polysaccharides from Cyphomandra betacea. The results showed a good fit with a second-order polynomial equation that was statistically acceptable at P<0.05. Optimal conditions for the extraction of polysaccharides were: extraction time, 2h; microwave power, 400W; extraction temperature, 60 degrees C; and ratio of raw material to water 1:40 (g/mL). Under the optimized conditions, the yield of polysaccharides was found to be relatively high (about 36.52%). The in vitro biological activities of antioxidant and antitumor were evaluated. The IC50 value of polysaccharides was found to be 3mg/mL. The percentage of Cell viability was determined by MTT assay. Our results showed that polysaccharides inhibited proliferation of MCF-7 (Breast carcinoma), A549 (Human lung carcinoma) and HepG2 (Liver carcinoma) with an IC50 of 0.23mg/mL, 0.17mg/mL and 0.62mg/mL respectively after 48h incubation. Polysaccharides were shown to promote apoptosis as seen in the nuclear morphological examination study using acridine orange (AO) and ethidium bromide (EB) staining. This is the first report on the effects of polysaccharides extracted from Cyphomandra betacea which exhibited stronger antioxidant and antitumor activities. PMID- 27456126 TI - The effect of silver nanoparticles and silver ions on mammalian and plant cells in vitro. AB - Silver nanoparticles (AgNPs) are the most frequently applied nanomaterials. In our experiments, we tested AgNPs (size 27 nm) manufactured by the Tollens process. Physico-chemical methods (TEM, DLS, AFM and spectrophotometry) were used for characterization and imaging of AgNPs. The effects of AgNPs and Ag(+) were studied in two experimental models (plant and mammalian cells). Human keratinocytes (SVK14) and mouse fibroblasts (NIH3T3) cell lines were selected to evaluate the cytotoxicity and genotoxicity effect on mammalian cells. Higher sensitivity to AgNPs and Ag(+) was observed in NIH3T3 than in SVK14 cells. AgNPs accumulated in the nucleus of NIH3T3 cells, caused DNA damage and increased the number of apoptotic and necrotic cells. Three genotypes of Solanum spp. (S. lycopersicum cv. Amateur, S. chmielewskii, S. habrochaites) were selected to test the toxicity of AgNPs and Ag(+) on the plant cells. The highest values of peroxidase activity and lipid peroxidation were recorded after the treatment of S. habrochaites genotype with AgNPs. Increased ROS levels were likely the reason for observed damaged membranes in S. habrochaites. We found that the cytotoxic and genotoxic effects of AgNPs depend not only on the characteristics of nanoparticles, but also on the type of cells that are treated with AgNPs. PMID- 27456127 TI - Effects of chronic deoxynivalenol exposure on p53 heterozygous and p53 homozygous mice. AB - Deoxynivalenol (DON) is a secondary metabolite associated with Fusarium species pathogenic to important food crops. A two-year feeding study reported that DON was non-carcinogenic in B6C3F1 mice. The present study was conducted to further characterize the chronic effects of DON by exposing cancer-prone transgenic p53 heterozygous (p53+/-) male mice and p53 homozygous (p53+/+) male mice to 0, 1, 5, or 10 mg DON/kg in diet for 26 weeks. Gross and microscopic organ-specific neoplastic and non-neoplastic changes and expression profiles of key hepatic and renal genes were assessed. Few toxicologic differences between p53+/+ and p53+/- mice were observed, and no tumours were observed due to DON. The results indicated that DON was non-carcinogenic and that reduced expression of the p53 gene did not play a key role in responses to DON toxicity. The lack of inflammatory and proliferative lesions in mice may be attributed to the anorectic effects of DON, which resulted in dose-dependent reductions in body weight in p53+/+ and p53+/- mice. Hepatic and renal gene expression analyses confirmed that chronic exposure to DON was noninflammatory. The effects of 26-week DON exposure on p53+/+ and p53+/-mice were consistent with those previously seen in B6C3F1 mice exposed to DON for two years. PMID- 27456129 TI - Tumor Necrosis Factor and Its Receptors Are Crucial to Control Mycobacterium bovis Bacillus Calmette-Guerin Pleural Infection in a Murine Model. AB - Tumor necrosis factor (TNF) is crucial to control Mycobacterium tuberculosis infection, which remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may cause reactivation of latent infection, resulting in overt pulmonary, pleural, and extrapulmonary tuberculosis. Herein, we investigate the roles of TNF and TNF receptors in the control of Mycobacterium bovis bacillus Calmette-Guerin (BCG) pleural infection in a murine model. As controls, wild-type mice and those with a defective CCR5, a receptor that is crucial for control of viral infection but not for tuberculosis, were used. BCG-induced pleural infection was uncontrolled and progressive in absence of TNF or TNF receptor 1 (TNFR1)/TNFR2 (TNFR1R2) with increased inflammatory cell recruitment and bacterial load in the pleural cavity, and heightened levels of pleural and serum proinflammatory cytokines and chemokines, compared to wild-type control mice. The visceral pleura was thickened with chronic inflammation, which was prominent in TNF(-/-) and TNFR1R2(-/-) mice. The parietal pleural of TNF(-/-) and TNFR1R2(-/-) mice exhibited abundant inflammatory nodules containing mycobacteria, and these mice developed nonresolving inflammation and succumbed from disseminated BCG infection. By contrast, CCR5(-/-) mice survived and controlled pleural BCG infection as wild type control mice. In conclusion, BCG-induced pleurisy was uncontrolled in the absence of TNF or TNF receptors with exacerbated inflammatory response, impaired bacterial clearance, and defective mesothelium repair, suggesting a critical role of TNF to control mycobacterial pleurisy. PMID- 27456128 TI - Increased Pyruvate Dehydrogenase Kinase 4 Expression in Lung Pericytes Is Associated with Reduced Endothelial-Pericyte Interactions and Small Vessel Loss in Pulmonary Arterial Hypertension. AB - Reduced endothelial-pericyte interactions are linked to progressive small vessel loss in pulmonary arterial hypertension (PAH), but the molecular mechanisms underlying this disease remain poorly understood. To identify relevant gene candidates associated with aberrant pericyte behavior, we performed a transcriptome analysis of patient-derived donor control and PAH lung pericytes followed by functional genomics analysis. Compared with donor control cells, PAH pericytes had significant enrichment of genes involved in various metabolic processes, the top hit being PDK4, a gene coding for an enzyme that suppresses mitochondrial activity in favor of glycolysis. Given reports that link reduced mitochondrial activity with increased PAH cell proliferation, we hypothesized that increased PDK4 is associated with PAH pericyte hyperproliferation and reduced endothelial-pericyte interactions. We found that PDK4 gene and protein expression was significantly elevated in PAH pericytes and correlated with reduced mitochondrial metabolism, higher rates of glycolysis, and hyperproliferation. Importantly, reducing PDK4 levels restored mitochondrial metabolism, reduced cell proliferation, and improved endothelial-pericyte interactions. To our knowledge, this is the first study that documents significant differences in gene expression between human donor control and PAH lung pericytes and the link between mitochondrial dysfunction and aberrant endothelial-pericyte interactions in PAH. Comprehensive characterization of these candidate genes could provide novel therapeutic targets to improve endothelial pericyte interactions and prevent small vessel loss in PAH. PMID- 27456130 TI - Hodgkin Lymphoma Cells Have a Specific Long Noncoding RNA Expression Pattern. AB - This commentary highlights the article by Tayari et al that suggests studying clinical implications of long noncoding RNAs as possible diagnostic and predictive biomarkers of Hodgkin lymphoma. PMID- 27456131 TI - Biophysical Tools for Cellular and Subcellular Mechanical Actuation of Cell Signaling. AB - The ability to spatially control cell signaling can help resolve fundamental biological questions. Optogenetic and chemical dimerization techniques along with fluorescent biosensors to report cell signaling activities have enabled researchers to both visualize and perturb biochemistry in living cells. A number of approaches based on mechanical actuation using force-field gradients have emerged as complementary technologies to manipulate cell signaling in real time. This review covers several technologies, including optical, magnetic, and acoustic control of cell signaling and behavior and highlights some studies that have led to novel insights. I will also discuss some future direction on repurposing mechanosensitive channel for mechanical actuation of spatial cell signaling. PMID- 27456132 TI - Influence of quaternization of ammonium on antibacterial activity and cytocompatibility of thin copolymer layers on titanium. AB - Antimicrobial coatings are able to improve the osseointegration of dental implants. Copolymers are promising materials for such applications due to their combined properties of two different monomers. To investigate the influence of different monomer mixtures, we have been synthesized copolymers of dimethyl (methacryloxyethyl) phosphonate (DMMEP) and dipicolyl aminoethyl methacrylate in different compositions and have them characterized to obtain the r-parameters. Some of the copolymers with different compositions have also been alkylated with 1-bromohexane, resulting in quaternized ammonium groups. The copolymers have been deposited onto titanium surfaces resulting in ultrathin, covalently bound layers. These layers have been characterized by water contact angle measurements and ellipsometry. The influence of quaternary ammonium groups on antibacterial properties and cytocompatibility was studied: Activity against bacteria was tested with a gram positive Staphylococcus aureus strain. Cytocompatibility was tested with a modified LDH assay after 24 and 72 h to investigate adhesion and proliferation of human fibroblast cells on modified surfaces. The copolymer with the highest content of DMMEP showed a good reduction of S. aureus and in the alkylated version a very good reduction of about 95%. On the other hand, poor cytocompatibility is observed. However, our results show that this trend cannot be generalized for this copolymer system. PMID- 27456133 TI - The effect of K(+) on caspase activity of corneal epithelial cells exposed to UVB. AB - Exposure of human corneal limbal epithelial (HCLE) cells to UVB triggers rapid loss of K(+) and apoptosis via activation of caspases -9, -8 and -3. It has been shown that preventing loss of intracellular K(+) can inhibit apoptosis. The goal of this study was to investigate the effect of K(+) on the UVB-induced caspase activity. HCLE cells were exposed to 150 mJ/cm(2) UVB, followed by measurement of caspase activity in cell lysates. Caspase activity was measured in the presence and absence of 100 mM K(+) in the reaction buffer. UVB-induced activity of caspases -9, -8 and -3 all decreased in the presence of 100 mM K(+). These results suggest that a role of high [K(+)] in the cell is to inhibit caspase activity. Therefore, when cells lose K(+) in response to UVB, caspases are activated and cells go into apoptosis. This supports our hypothesis that K(+) inhibits caspase activity. PMID- 27456134 TI - Investigation of a novel implantable suprachoroidal pressure transducer for telemetric intraocular pressure monitoring. AB - Intraocular Pressure (IOP) is an important and modifiable risk factor for glaucoma progression. IOP fluctuations and spikes often remain undetected despite clinical routine examinations. Therefore telemetric IOP measurement systems with continuous IOP monitoring can provide major advantages in glaucoma surveillance. To the best of our knowledge, this is the first study to investigate implantable telemetric suprachoroidal IOP sensors. Six novel telemetric pressure transducers were implanted in the suprachoroidal space of 6 eyes from 6 New Zealand White rabbits. Functionality of each microsensor was verified 1, 4, 8, 12 and 30 weeks after implantation. After cannulation of the anterior chamber different intracameral pressure levels were generated using a height adjustable water column. Telemetric assessed IOP and intracameral pressure were analysed using scatter plots and Bland-Altman analysis (95% CI). Mean bias (limits of agreement) 1, 4, 8, 12 and 30 weeks after implantation was 0.14 mmHg (-2.04 to 2.31 mmHg), 0.01 mmHg (-2.83 to 2.86 mmHg), 0.62 mmHg (-2.08 to 3.32 mmHg), 0.47 mmHg (-3.04 to 3.98 mmHg) and 0.33 mmHg (-2.75 to 3.42 mmHg) respectively. Ophthalmological examinations showed no signs of conjunctival, scleral, choroidal or retinal lesions. Histological analyses revealed a small band of fibrosis next to the implantation site but showed no signs of inflammation, necrosis or other pathologies. Implantable telemetric suprachoroidal pressure sensors provided promising concordance between telemetric and intracameral IOP values. Clinical and histological examinations revealed good biocompatibility 30 weeks after implantation. A major advantage of the suprachoroidal approach is that the anterior chamber stays unaffected during implantation. Therefore the procedure can be performed regardless of the lens status and any anterior chamber pathologies. PMID- 27456135 TI - The effect of growth factor supplementation on corneal stromal cell phenotype in vitro using a serum-free media. AB - In order to expand cells quickly and in high numbers for corneal tissue engineering applications corneal stromal cells, or keratocytes, are often cultured in the presence of serum. However, keratocytes become fibroblastic when exposed to serum leading to a downregulation of corneal stromal specific markers. The purpose of this current study was to determine if corneal stromal cells, made fibroblastic by serum, could display native quiescent keratocyte characteristics when cultured under serum-free conditions supplemented by different growth factors. Markers specific to a native keratocyte phenotype such as keratocan and aldehyde dehydrogenase 3A1 (ALDH3A1) and those specific to a fibrotic phenotype such as alpha-smooth muscle actin (alphaSMA) and collagen type III were examined. Cells were cultured in monolayer, self-assembled pellets or collagen hydrogels. Growth factors known to modulate keratocyte phenotype were chosen to supplement the serum free media, specifically insulin-like growth factor 1 (IGF-1) and transforming growth factor beta 1 and 3 (Tbeta1 and Tbeta3). The effects of serum free media, growth factors and culture system on cell proliferation and morphology and extracellular matrix (ECM) synthesis were evaluated. The expression of keratocyte markers was evaluated by real-time PCR, immunofluorescent staining and western blotting. In addition, cell migration was tested using scratch assays. When serum was removed from the cells they displayed a reduction in proliferation and ECM synthesis (not significant), in addition to a significant decrease in migratory capacity (p < 0.05). Serum-free media promoted increased expression of keratocan (130.68 +/- 47.44-fold increase; p < 0.05) and collagen type I (15.58 +/- 9.49-fold increase; p < 0.05). However, there was no significant change in ALDH3A1 and alphaSMA expression, while collagen type III expression was significantly increased (44.66 +/- 25.61-fold increase; p < 0.05). In addition, cells retained an elongated fibroblastic morphology. In monolayer, the addition of Tbeta1 and Tbeta3 to serum free media resulted in reduced expression of keratocan, ALDH3A1 and collagen type I and III, increased expression of alphaSMA (p < 0.05) and an increase in cell proliferation and ECM synthesis. Pellet cultured cells demonstrated a significant increase in ALDH3A1 and collagen type I over 14 days relative to day 5 (p < 0.05), however the expression of fibrotic markers was also enhanced. Cells in collagen hydrogels did not increase expression of keratocyte markers in serum free conditions and underwent contraction in Tbeta1 and Tbeta3 supplemented media. These results demonstrate that corneal fibroblasts only partially express the phenotypic characteristics of keratocytes when cultured in serum-free medium. While growth factors did not significantly enhance this phenotype, it appears that pellet or self-assembled culture could be more beneficial to promoting a keratocyte phenotype. PMID- 27456136 TI - Anchorage failure of young trees in sandy soils is prevented by a rigid central part of the root system with various designs. AB - BACKGROUND AND AIMS: Storms can cause huge damage to European forests. Even pole stage trees with 80-cm rooting depth can topple. Therefore, good anchorage is needed for trees to survive and grow up from an early age. We hypothesized that root architecture is a predominant factor determining anchorage failure caused by strong winds. METHODS: We sampled 48 seeded or planted Pinus pinaster trees of similar aerial size from four stands damaged by a major storm 3 years before. The trees were gathered into three classes: undamaged, leaning and heavily toppled. After uprooting and 3D digitizing of their full root architectures, we computed the mechanical characteristics of the main components of the root system from our morphological measurements. KEY RESULTS: Variability in root architecture was quite large. A large main taproot, either short and thick or long and thin, and guyed by a large volume of deep roots, was the major component that prevented stem leaning. Greater shallow root flexural stiffness mainly at the end of the zone of rapid taper on the windward side also prevented leaning. Toppling in less than 90-cm-deep soil was avoided in trees with a stocky taproots or with a very big leeward shallow root. Toppled trees also had a lower relative root biomass - stump excluded - than straight trees. CONCLUSIONS: It was mainly the flexural stiffness of the central part of the root system that secured anchorage, preventing a weak displacement of the stump. The distal part of the longest taproot and attached deep roots may be the only parts of the root system contributing to anchorage through their maximum tensile load. Several designs provided good anchorage, depending partly on available soil depth. Pole-stage trees are in-between the juvenile phase when they fail by toppling and the mature phase when they fail by uprooting. PMID- 27456137 TI - Preparation of Three-Dimensional Chitosan-Graphene Oxide Aerogel for Residue Oil Removal. AB - Graphene oxide has been used as an adsorbent in wastewater treatment. However, the hydrophily and dispersibility in aqueous solution limit its practical application in environmental protection. In this paper, a novel, environmentally friendly adsorbent, chitosan and chitosan-graphene oxide aerogels with a diverse shape, large specific surface area, and unique porous structure were prepared by a freeze-drying method. The structure of the adsorbents was investigated using scanning electron microscopy, Fourier transform-infrared spectroscopy, and X-ray diffraction (XRD); the specific surface area and swelling capability were also characterized. In addition, removal of diesel oil from seawater by chitosan aerogel (CSAG) and chitosan-graphene oxide aerogel (AGGO-1 and AGGO-2) was studied and batch adsorption experiments were carried out as a function of different adsorbent dosages (0-6 g), contact time (0-120 minutes), pH (3-9), and initial concentrations of oil residue (3-30 g/L) to determine the optimum condition for the adsorption of residue oil from seawater. The results showed that the chitosan-graphene oxide aerogels were more effective to remove diesel oil from seawater compared with pure chitosan aerogel. A removal efficiency >= 95% of the chitosan-graphene oxide aerogels could be achieved easily at the initial concentrations of 20 g/L, which indicated that the chitosan-graphene oxide aerogels can be used to treat the industrial oil leakage or effluent in the natural water. PMID- 27456138 TI - Decolorization of Methylene Blue by Persulfate Activated with FeO Magnetic Particles. AB - In this study, the degradation of methylene blue (MB) was conducted to evaluate the feasibility of using persulfate oxidation activated with iron oxide (FeO) magnetic particles. The results demonstrated that the decolorization rate of MB increased with increasing FeO concentration, exhibiting maximum efficiency at pH0 3.0. The kinetics of MB was studied in the binary FeO catalyst and persulfate oxidation system. The surface properties of FeO before and after reaction was analyzed using cyclic voltammogram (CV), three-dimensional excitation-emission fluorescence matrix (EEFM) spectroscopy, zeta potential, particle size distribution measurements, X-ray diffraction (XRD) and environmental scanning electron microscopy-energy dispersive X-ray spectrometry (ESEM-EDS). The CV data indicated that a reversible redox reaction holds the key to explaining the significant activity of the catalyst. EEFM was used to evaluate the catalyst yield of FeO by fluorescence intensity plots with excitation/emission at 220/300 nm and 260/300 nm. The XRD and ESEM-EDS results confirmed the presence of FeO in the catalyst. PMID- 27456139 TI - Photocatalytic Degradation of NOM for Power Plant Feedwater using Coating and Suspension of TiO2. AB - This study investigated the effectiveness of coating and suspension of Degussa P25 TiO2 photocatalyst to remove natural organic matter (NOM) from surface water for use as power plant feedwater. The catalyst yield, transmittance intensity and X-ray pattern as a function of the number of coatings were characterized. In addition, P25 coating photocatalytic activity was studied. The photocatalytic activity also of P25 suspension with different catalyst concentrations and the reusing of the catalyst without and with regeneration was investigated. Results obtained show that the P25 coatings were transparent with good adhesion to the glass substrate. P25 suspension was found to be more effective in the NOM photodegradation and gave a higher rate constant compared to P25 coating. The maximum rate constants were 0.028 and 0.015 min(-1) at 0.7 g/L P25 suspension and 4 coatings, respectively. After four runs without regeneration and three runs with regeneration of P25 reusing, the photoactivity to remove NOM was still significant. PMID- 27456140 TI - Reductive Removal of Selenate in Water Using Stabilized Zero-Valent Iron Nanoparticles. AB - Polysaccharide-stabilized zero-valent iron (ZVI) nanoparticles were synthesized using sodium carboxymethyl cellulose (CMC) or starch as stabilizer, and tested for reductive removal of selenate in water. Batch kinetic tests showed that the stabilized ZVI nanoparticles offer much faster selenate removal than bare ZVI particles at both pH 6.0 and pH 8.4. X-ray photoelectron spectroscopy (XPS) analyses confirmed Se(VI) was transformed to Se(IV) and Se(0), which are removed along with the nanoparticles. Neutral pH (~7) was found to be most favorable for the reductive removal. Decreasing pH to 5.0 or increasing it to 8.0 reduced the removal rate of CMC-stabilized ZVI by a factor of 4.6 or 1.3, respectively, based on the observed first-order-rate constant. Dissolved organic matter (DOM) at 5 mg/L as total organic carbon (TOC) had modest inhibitive effect, but DOM at 25 mg/L TOC decreased selenate removal by 25%. The stabilized nanoparticles hold the potential to facilitate in situ remediation of selenate-contaminated soil and groundwater. PMID- 27456141 TI - Wastewater GHG Accounting Protocols as Compared to the State of GHG Science. AB - Greenhouse gas (GHG) accounting protocols have addressed emissions from wastewater conveyance and treatment using a variety of simplifying methodologies. While these methodologies vary to some degree by protocol, within each protocol they provide consistent tools for organizational entities of varying size and scope to report and verify GHG emissions. Much of the science supporting these methodologies is either limited or the protocols have failed to keep abreast of developing GHG research. This state-of-the-art review summarizes the sources of direct GHG emissions (both those covered and not covered in current protocols) from wastewater handling; provides a review of the wastewater-related methodologies in a select group of popular protocols; and discusses where research has out-paced protocol methodologies and other areas where the supporting science is relatively weak and warrants further exploration. PMID- 27456142 TI - Ammonia Nitrogen Transformations in a Reactor with Aggregate made of Sewage Sludge Combustion Fly Ash. AB - The influence of light weight aggregate made of fly ash from sewage sludge thermal treatment (FASSTT LWA) on ammonia nitrogen metabolism, and on quantitative and qualitative changes of microorganisms colonizing the filling, was investigated. Two reactors were used in the experiment. The first was filled with gravel, the other with FASSTT LWA. The reactors were operated with a wastewater hydraulic loading rate of 5 mm(3) mm(-2) d(-1). During the eleven-week experiment, high efficiency of ammonia removal was observed. The lower concentrations of nitrites and nitrates in the effluent indicate that ammonia nitrogen removal resulted not just from nitrification. Nitrate concentration increase was reflected in a decrease in nitrogen removal efficiency. One possible explanation for this phenomenon is that in the period when ammonia nitrogen and nitrites were present in the reactor's FASSTT LWA filling, facilitating conditions occurred for the deammonification process. PMID- 27456143 TI - Seawater Intrusion Impacts on the Water Quality of the Groundwater on theNorthwest Coast of Oman. AB - The groundwater aquifer in the coastal region of the northwest of Oman has been used extensively since the early 1980s for agricultural, industrial and municipal purposes. The over pumping of this reservoir has led to the intrusion of seawater and therefore to the deterioration of the groundwater quality. In this study, an investigation was carried out in the southern part of this region to identify the quality of groundwater, to understand the main sources of groundwater mineralisation, and to check the suitability of groundwater for drinking and irrigation. The spatial distributions and temporal variations of groundwater level and electrical conductivity were studied for the period from 1982 to 2005 using data collected from 225 wells. In addition, groundwater samples were collected recently in 2012 from eight wells and analysed for pH, EC, and major ions to understand the sources of dissolved ions and assess the chemical quality of the groundwater. The study area was divided into two strips parallel to the coastline, A and B, located in the discharge and recharge parts of the aquifer, respectively. Results showed a significant increase in the degree of water mineralisation in the direction of south to north following the regional flow direction. Results showed also that the groundwater in the last area could be used for irrigation with little danger of exchangeable sodium while this aquifer is unsuitable for irrigation in the discharge area because it presents a very high salinity hazard. PMID- 27456144 TI - Adsorption of Heavy Metal Ions from Aqueous Solutions by Bentonite Nanocomposites. AB - A series of bentonite nanocomposites have been synthesized by modifying bentonite with hexadecyltrimethylammonium bromide (CTMAB) and the common complexing agents, complexone (ethylene diamine tetraacetic acid, EDTA) or mercaptocomplexant (2 Mercaptobenzothiazole, MBT). These adsorbents are used to remove heavy metal ions (Cu(2+), Zn(2+), Mn(2+),Co(2+)). The Bent-CTMAB-MBT adsorbed metal ions are higher than Bent-CTMAB-EDTA under the same ion concentration in AAS. Compared with the single ion system, the adsorption of the mixed ion system of Cu(2+), Zn(2+), Mn(2+), Co(2+) had decreased differently. In the mixed system, the adsorption of Mn(2+) is significantly lower, but the adsorption of Cu(2+) was highest. The adsorption sequence of these four metal ions was Cu(2+) > Zn(2+) > Co(2+) > Mn(2+), and the selective adsorption was closely related to the hydration energy of heavy metal ions. We could remove more metal ions in different stages with the adsorption sequence. PMID- 27456145 TI - Spatial Variability of Anaerobic Processes and Wastewater pH in Force Mains. AB - The present study focuses on anaerobic organic matter transformation processes in force mains for the purpose of improving existing sewer process models. Wastewater samples were obtained at 100 m intervals from a 1 km long pilot scale force main and measured for several wastewater parameters. Transformation rates for selected parameters were calculated and their spatial variability analyzed. In terms of electron transfer, fermentation was the most significant process, resulting in a net volatile fatty acid formation of 0.83 mmol/L. Sulfate reduction resulted in a production of 0.73 mmol/L of inorganic sulfide. Methanogenesis was negligable in all experiments despite an anaerobic residence time of more than 30 hours. As a result of the anaerobic processes, the wastewater pH decreased by approximately one pH unit, resulting in a corresponding increase in the fraction of molecular hydrogen sulfide. A significant spatial variablilty was observed for the average transformation rates of all parameters. PMID- 27456146 TI - Land Use and Hydrogeological Characteristics Influence Groundwater Invertebrate Communities. AB - We examine the influence of land use and hydrogeological characteristics on the abundance, composition and structure of groundwater invertebrate communities in a loessic aquifer from Argentina. Seven wells, selected according to surrounding land use and hydrogeological characteristics, were sampled twice. Groundwater was characterized as sodium bicarbonate, bicarbonate sulfate or sulfate type. NO3(-) was detected in all samples. Land use in the area surrounding the well, unsaturated zone thickness and geochemical characteristics of groundwater influenced the abundance, composition and community structure of groundwater invertebrates. Copepoda, Oligochaeta, Cladocera, Ostracoda and Amphipoda were highly influenced by land use, particularly by point pollution sources that produced higher abundance and changes in taxonomic composition. The lowest invertebrate abundance was observed at the wells situated in areas with the thickest unsaturated zone. Groundwater salinity and geochemical type influenced the presence of certain species, particularly Stygonitocrella sp. PMID- 27456147 TI - Bacterial colonization is decreased after tunneling femoral perineural catheters. AB - BACKGROUND: Infection of perineural catheter is rare, although bacterial colonization is frequent. An observational study reported that subcutaneous tunneling perineural catheter could decrease its colonization rate. We performed a comparative study to assess the incidence of catheter related bacterial colonization of tunnelized femoral perineural catheters. METHODS: This bicentric, randomized, single-blind, controlled and intention-to-treat study was conducted from December 2009 to December 2011. The catheter was secured with adhesive strips in the control group and was tunneled subcutaneously in the tunnelization group. Primary endpoint was catheter colonization rate assessed by by Brun Buisson quantitative culture. Secondary endpoints included catheter-related infection, inadvertent catheter dislodgement rate, incidence of technical problems with subcutaneous tunneling and, risk factors for catheter-related colonization. RESULTS: Of the total 338 patients included, 2 patients were later excluded and 78 were lost to follow-up for primary endpoint. Inadvertent removal of femoral catheter accounted for 33 of these 78 patients (10 for the tunnelization group versus 23 for the control group, P=0.02). There was a lower colonization rate in the patient group with tunnelization compared to the control group without tunnelization (6% versus 13.5%, respectively; OR=2.4; 95% CI: 1.1 5.3; P=0.02). No infection was observed. Coagulase-negative staphylococci is present in 61%. The absence of tunnelization is the only risk factor of colonization. For 7 patients, accidental perforation of perineural catheter during procedure was observed. CONCLUSIONS: Tunneled subcutaneous perineural catheter decreased the incidence of colonization. Moreover, tunnelization is an effective technique for securing the perineural catheter. PMID- 27456148 TI - Abdominal and pelvic pain: an uncommon sign in lumbar facet joint syndrome. PMID- 27456149 TI - Besta Airway Algorithm in morbidly obese patients: expertise and safety. PMID- 27456150 TI - High Thoracic Contusion Model for the Investigation of Cardiovascular Function after Spinal Cord Injury. AB - Cardiovascular disease is the leading cause of death for individuals with spinal cord injury (SCI). Because of a lack of a standardized and accessible animal model for cardiovascular disease after SCI, few laboratories have conducted pre clinical trials aimed at reinstating descending cardiovascular control. Here, we utilized common contusion methodology applied to the midline of the upper thoracic cord of adult Wistar rats accompanied with telemetric blood pressure monitoring and FluoroGold retrograde neuronal tracing, as well as lesion site and lumbrosacral afferent immunohistochemistry. We demonstrate widespread cardiovascular (i.e., impaired resting hemodynamics, autonomic dysreflexia) and hindlimb dysfunction at 1 month post-injury. Further, we provide a description of the neuroanatomical changes that accompany cardiovascular abnormalities. Specifically, we describe 1) the injury site including white matter sparing as well as lesion volume, and their correlations to cardiovascular as well as motor outcomes; 2) the severity of injury-dependent changes in sympathoexcitatory medullary neuron spinal connectivity, as measured using FluoroGold tracing; and 3) the extent of aberrant afferent plasticity within the lumbosacral region of the spinal cord, which has been linked to the development of autonomic dysreflexia. We believe that this model, which utilizes equipment common to numerous SCI laboratories, can serve as a research standard for studies specifically aimed at investigating autonomic neuroprotective and regenerative strategies following SCI. PMID- 27456151 TI - Dietary habits, food taboos, and perceptions towards weight gain during pregnancy in Arsi, rural central Ethiopia: a qualitative cross-sectional study. AB - BACKGROUND: The nutritional status of women before and during pregnancy can be determined by maternal knowledge, attitudes, and perceptions towards certain foods. The present study aimed to explore maternal dietary habits, food taboos, and cultural beliefs that can affect nutrition during pregnancy in rural Arsi, central Ethiopia. METHODS: A qualitative, cross-sectional study, involving 38 key informant in-depth interviews and eight focus group discussions, was conducted among purposefully selected pregnant women and their husbands, elderly people, community leaders, health workers, and agriculture office experts. Participants were selected purposefully from all the major agro-ecologic areas of the study site. Data was analyzed manually using the thematic framework analyses method. RESULTS: The pregnant women reported that they did not change the amount and type of foods consumed to take into account their increased nutritional need during pregnancy. The consumption of meat, fish, fruits, and some vegetables during pregnancy remained as low as the pre-pregnancy state, irrespective of the women's income and educational status. Although not practiced by all, a number of taboos related to the intake of certain food items and misconceptions that can adversely affect nutritional status during pregnancy were identified. The most common taboos were related to the consumption of green leafy vegetables, yogurt, cheese, sugar cane, and green pepper. However, the frequency and extent of the practice varied by maternal age, family composition, and literacy level. Older mothers, from rural villages, and those with no formal education were more likely to practice the taboos than younger and educated ones. Almost all of the participants disfavored weight gain during pregnancy in fear of obstetric complications associated with the delivery of a bigger infant. CONCLUSIONS: Misconceptions about weight gain during pregnancy and food taboos were widespread, particularly among older and illiterate rural communities. Thus, future nutrition programs should promote diversification of both the agricultural production and consumption. PMID- 27456152 TI - Externally limited defect generation in multiwalled carbon nanotubes upon thermal annealing, and possible mechanism. AB - Structural defects in multiwalled carbon nanotubes (MWCNTs) are found to increase upon moderate thermal annealing below 1400 K in an argon atmosphere. The defects are estimated using the ID/IG ratio in Raman spectroscopy of MWCNTs and confirmed by a direct observation using high-resolution transmission electron microscopy (HRTEM). HRTEM shows that the structural defects are created due to large damage to the outer walls of the nanotubes, while inner walls do not sustain any damage. The generation of defects on MWCNTs is attibuted to mechanical abrasion between the MWCNTs in contact, augmented by the momentum transfer from the flow of hot gas. A possible mechanism is proposed and experimentally validated by means of modulating the chemical environment of annealing from argon to hydrogen. PMID- 27456154 TI - Reassuring results on birth outcomes in children fathered by men treated with azathioprine/6-mercaptopurine within 3 months before conception: a nationwide cohort study. AB - OBJECTIVE: Information on the safety of paternal use of azathioprine (AZA) and 6 mercaptopurine (6-MP) prior to conception is limited. Based on nationwide data from the Danish health registries, we examined the association between paternal use of AZA/6-MP within 3 months before conception and adverse birth outcomes. DESIGN: This nationwide cohort study is based on data from all singletons born in Denmark from 1 January 1997 through 2013. Children fathered by men who used AZA/6 MP within 3 months before conception constituted the exposed cohort (N=699), and children fathered by men who did not use AZA/6-MP 3 months prior to conception constituted the unexposed cohort (N=1 012 624). The outcomes were congenital abnormalities (CAs), preterm birth and small for gestational age (SGA). We adjusted for multiple covariates and performed a restricted analysis of men with IBD. RESULTS: There were no significantly increased risks of CAs, preterm birth or SGA in exposed versus unexposed cohorts of children. The adjusted ORs were 0.82 (95% CI 0.53 to 1.28) for CAs, 1.17 (95% CI 0.72 to 1.92) for preterm birth and 1.38 (95% CI 0.76 to 2.51) for SGA. Restricting our analysis to fathers with IBD showed similar results with no significantly increased risk of adverse birth outcomes. CONCLUSIONS: This nationwide study is the largest to date, examining the effect of preconceptual paternal use of AZA/6-MP on birth outcomes in live born singletons. The results of no significantly increased risks of adverse birth outcomes are reassuring and support the continuation of paternal AZA/6-MP treatment during conception. PMID- 27456155 TI - Cognitive function and pre-retirement psychosocial work characteristics. PMID- 27456153 TI - Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture. AB - OBJECTIVE: Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full. DESIGN: Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells. RESULTS: Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds. CONCLUSIONS: Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT01577511. PMID- 27456156 TI - Mortality and cancer incidence in a cohort of male paid Australian firefighters. AB - OBJECTIVES: To investigate mortality and cancer incidence of paid male Australian firefighters and of subgroups of firefighters by era of first employment, duration of employment and number and type of incidents attended. METHODS: Participating fire agencies supplied records of individual firefighters including their job histories and incidents attended. The cohort was linked to the Australian National Death Index and Australian Cancer Database. SMRs and SIRs were calculated. Firefighters were grouped into tertiles by duration of employment and by number of incidents attended and relative mortality ratios and relative incidence ratios calculated. Analyses were carried out separately for full-time and part-time male firefighters. RESULTS: Compared to the Australian population, there were significant increases in overall risk of cancer, for all paid firefighters SIR 1.09 (95% CI 1.03 to 1.14), in prostate cancer, full-time firefighters 1.23 (95% CI 1.10 to 1.37), part-time 1.51 (1.28 to 1.77), and melanoma full-time 1.45 (95% CI 1.26 to 1.66), part-time firefighters 1.43 (95% CI 1.15 to 1.76). Kidney cancer was associated with longer service in internal analyses for paid firefighters. Prostate cancer was associated with longer service and increased attendance at fires, particularly structural fires for full time firefighters.The overall risk of mortality was significantly decreased and almost all major causes of death were significantly reduced for paid firefighters. CONCLUSIONS: Male paid firefighters have an increased risk of cancer. They have reduced mortality compared with the general population, which is likely to be a result of a strong healthy worker effect and likely lower smoking rates among firefighters compared with the Australian population. PMID- 27456157 TI - Comparing plasma, serum and whole blood indium concentrations from workers at an indium-tin oxide (ITO) production facility. AB - OBJECTIVE: Occupational exposure to indium compounds including indium-tin oxide (ITO) can result in potentially fatal indium lung disease. We compared plasma, serum and whole blood indium concentrations (InP, InS and InB) from workers at a single ITO production facility to assess the comparability of these matrices used for biological monitoring of indium exposure. METHOD: InP, InS and InB were measured using inductively coupled mass spectrometry from consenting workers at an ITO production facility with specimen collection occurring during June-July 2014. Matched pairs from workers were assessed to determine the matrix relationships using the Pearson correlation, paired t-tests, per cent difference, linear regression and kappa statistics. RESULTS: Indium matrices were collected from 80 workers. Mean (SD) InP, InS and InB were 3.48 (3.84), 3.90 (4.15) and 4.66 (5.32) mcg/L, respectively. The InS-InP difference was 14%; InS was higher in all but two workers. InP and InS were highly correlated (r=>0.99). The InB-InS difference was 19%; InB was higher in 85% of workers. The InB-InP difference was 34%; InB was higher in 66% of workers. InB was highly correlated with both InP and InS (r=0.97 and 0.96, respectively). kappa Statistics were 0.84, 0.83 and 0.82 for InP, InS and InB, respectively, for individuals with each matrix >=1 mcg/L (p<0.01). CONCLUSIONS: While all matrices were highly correlated, we encourage the use of InP and InS to reliably compare studies across different populations using different matrices. The higher per cent difference and increased variability of InB may limit its utility in comparisons with InP and InS in different populations. PMID- 27456158 TI - [Ebola in Guinea: experience of stigma among health professional survivors]. AB - This article aims to describe the various forms of stigma faced by Ebola health professional survivors. A study based on in-depth interviews with 20 survivors was conducted in Conakry as part of PostEboGui multidisciplinary cohort research Program (Life after Ebola) in July-August 2015. Participants were health professionals, male and female, mostly with precarious positions in the health system. The results show that stigmatization is mainly expressed through avoidance, rejection, or being refused to be reinstated in the position at work and non-acceptance of the disease by third parties. This stigmatization appears to be rooted in fear of contagion and in diverging conceptions of the disease aetiology that may engender conflict. Being health workers did not protect them against stigma and some of them faced rejection in their own health care facility. This stigmatization was not based on moral grounds, contrary to the one experienced by people living with HIV, and attitudes of solidarity were encountered in family and confessional networks. Responders found support within an association of survivors (Association des personnes gueries et affectees d'Ebola en Guinee, APEGUAEG) that was created in early 2015. Stigmatization was temporary and disappeared for most responders owing to strategies implemented by survivors and because the fear of contagion had vanished: interviews were conducted when the notion of persistence of Ebola virus in the semen was not spread in the population. This research study shows that stigma is perpetuated among health agents, towards workers who were exposed by their professional role. This observation should be considered for specific measures towards behavioural change. Finally, the very notion of "stigmatization", widely used by public health institutions, is challenged by the diversity of individual experiences that are particular to Ebola virus disease regarding their expression and evolution. Studies on stigma related to Ebola should be held in other populations and contexts for comparison. PMID- 27456159 TI - [Epidemiological aspects of Ebola virus disease in Guinea (december 2013-april 2016)]. AB - Ebola Zaire species variant Makona between its emergence in December 2013 and April 2016, resulted in an epidemic of Guinea importance and unprecedented gravity with 3814 reported cases of which 3358 were confirmed (88.0%) and 2544 were died (66.7%). The epidemic has evolved in phases: a silent phase without identification of all fatal cases until February 2014; a first outbreak from March 2014, when the alarm is raised and the virus detected, which lasted until July 2014; a second increase, which was the most intense, from August 2014 to January 2015 focused primarily on the forest Guinea; and a final increase from February 2015 centered on lower Guinea and the capital Conakry. Adapting strategies in 2015 (initiative "Zero Ebola in 60 days" active case search and suspicious deaths and awareness of active prefectures, microbanding the last affected communities and raking around these localities) and ring vaccination of contacts around confirmed cases has allowed to gradually control the main outbreak in October 2015. But a survivor was originally resurgence in forest areas between March and April 2016 with 10 cases including 8 deaths. The epidemic has particularly affected the forest Guinea region (44% and 48% of Guinean cases and deaths), elderly women (>= 50 years), and health professionals (211 cases including 115 deaths); however, almost one-third of the patients (32.6%) was not provided supportive care in the Ebola centers. The epidemic is currently marked by the resurgence of small foci, from excreting subjects cured of the virus who have been controlled so far successfully. The survivors are the subject of special attention. It is necessary to learn lessons from the response to better prepare for the future, to improve knowledge about the natural history of the Ebola virus disease, and to rethink communication in this regard with the public and its leaders. PMID- 27456160 TI - Study of the impact of cranberry extract on the virulence factors and biofilm formation by Enterococcus faecalis strains isolated from urinary tract infections. AB - Drinking of cranberry fruit juice and application of commercial preparations containing the cranberry extracts are recommended in the prevention and treatment of urinary tract infections (UTIs), especially in women with recurrent UTIs. Many studies focus on the activity of cranberries against uropathogenic Escherichia coli (E. coli) strains. However, the knowledge of the cranberry effect on Gram positive Enterococcus faecalis (E. faecalis) is limited. Therefore, the aim of our study was to establish the activity of commercial concentrated cranberry extract on the growth, virulence factors and biofilm formation of E. faecalis strains isolated from urine. Minimal inhibitory concentrations (MICs) of cranberry extract were determined by the broth microdilution method. Disc diffusion method was used to determine antimicrobial susceptibility. The impact of cranberry extract on bacterial survival, hydrophobicity, synthesis of lipase, lecithinase, DNase, hemolysin, gelatinase and biofilm mass was determined. Results show that cranberry extract inhibits the growth, enzymatic activities of bacteria and limits biofilm formation. The antibacterial activities of the studied cranberry extract confirm that it could be successfully used in prevention of UTIs caused by E. faecalis. PMID- 27456161 TI - Chemiresistive Electronic Nose toward Detection of Biomarkers in Exhaled Breath. AB - Detection of gas-phase chemicals finds a wide variety of applications, including food and beverages, fragrances, environmental monitoring, chemical and biochemical processing, medical diagnostics, and transportation. One approach for these tasks is to use arrays of highly sensitive and selective sensors as an electronic nose. Here, we present a high performance chemiresistive electronic nose (CEN) based on an array of metal oxide thin films, metal-catalyzed thin films, and nanostructured thin films. The gas sensing properties of the CEN show enhanced sensitive detection of H2S, NH3, and NO in an 80% relative humidity (RH) atmosphere similar to the composition of exhaled breath. The detection limits of the sensor elements we fabricated are in the following ranges: 534 ppt to 2.87 ppb for H2S, 4.45 to 42.29 ppb for NH3, and 206 ppt to 2.06 ppb for NO. The enhanced sensitivity is attributed to the spillover effect by Au nanoparticles and the high porosity of villi-like nanostructures, providing a large surface-to volume ratio. The remarkable selectivity based on the collection of sensor responses manifests itself in the principal component analysis (PCA). The excellent sensing performance indicates that the CEN can detect the biomarkers of H2S, NH3, and NO in exhaled breath and even distinguish them clearly in the PCA. Our results show high potential of the CEN as an inexpensive and noninvasive diagnostic tool for halitosis, kidney disorder, and asthma. PMID- 27456162 TI - Magnetic nanomaterials and sensors for biological detection. AB - It is becoming progressively more understandable that sensitivity and versatility of magnetic biosensors provides unique platform for high performance diagnostics in clinical settings. Confluence of information suggested that magnetic biosensors required well-tailored magnetic particles as probes for detection that generate large and specific biological signal with minimum possible nonspecific binding. However, there are visible knowledge gaps in our understanding of the strategies to overcome existing challenges related to even smaller size of intracellular targets and lower signal-to-noise ratio than that in whole-cell studies, therefore tool designing and development for intracellular measurement and manipulation is problematic. In this review we describe magnetic nanoparticles, synthesis and sensing principles of magnetic nanoparticles as well as surface functionalization and modification and finally magnetic nanoparticles for medical diagnostics. This review gathers important and up-to-date information and may help to develop the method of obtaining magnetic materials especially for medical application. PMID- 27456163 TI - Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity. AB - Benzophenone-uracil (BPU) scaffold-derived candidate compounds are efficient non nucleoside reverse transcriptase inhibitors (NNRTI) with extremely low solubility in water. We proposed to use hydrophobic core (methoxypolyethylene glycol polylysine) graft copolymer (HC-PGC) technology for stabilizing nanoparticle based formulations of BPU NNRTI in water. Co-lyophilization of NNRTI/HC-PGC mixtures resulted in dry powders that could be easily reconstituted with the formation of 150-250 nm stable nanoparticles (NP). The NP and HC-PGC were non toxic in experiments with TZM-bl reporter cells. Nanoparticles containing selected efficient candidate Z107 NNRTI preserved the ability to inhibit HIV-1 reverse transcriptase polymerase activities with no appreciable change of EC50. The formulation with HC-PGC bearing residues of oleic acid resulted in nanoparticles that were nearly identical in anti-HIV-1 potency when compared to Z107 solutions in DMSO (EC50=7.5+/-3.8 vs. 8.2+/-5.1 nM). Therefore, hydrophobic core macromolecular stabilizers form nanoparticles with insoluble NNRTI while preserving the antiviral activity of the drug cargo. PMID- 27456164 TI - Micropatterning of the Ferroelectric Phase in a Poly(vinylidene difluoride) Film by Plasmonic Heating with Gold Nanocages. AB - Polymer thin films with patterned ferroelectric domains are attractive for a broad range of applications, including the fabrication of tactile sensors, infrared detectors, and non-volatile memories. Herein, we report the use of gold nanocages (AuNCs) as plasmonic nanostructures to induce a ferroelectric paraelectric phase transition in a poly(vinylidene fluoride) (PVDF) thin film by leveraging its photothermal effect. This technique allows us to generate patterned domains of ferroelectric PVDF within just a few seconds. The incorporation of AuNCs significantly enhances the pyroelectric response of the ferroelectric film under near-infrared irradiation. We also demonstrate the use of such patterned ferroelectric films for near-infrared sensing/imaging. PMID- 27456165 TI - Burnout and occupational participation among dentists with teaching responsibilities in universities. AB - The aim of this study was to investigate the levels of burnout and explore the relationships between burnout and occupational participation among dentists with teaching responsibilities. Canadian Occupational Performance Measure (COPM) was used to evaluate occupational participation with questions on demographic information among 155 dentists with teaching responsibilities. Age, gender, years of experience, academic position were the factors affecting level of burnout and occupational participation. Occupational performance score was negatively correlated with emotional exhausment (r = -.731) and depersonalization (r = .693) while positively correlated with personal accomplishment (r = .611). Occupational satisfaction scores were negatively correlated with emotional exhausment (r = -.631) and depersonalization (r = -.625) while positively correlated with personal accomplishment (r = .614). Occupational participation level can effect burnout among dentists with teaching responsibilities. Further studies with a larger sample are needed to investigate these preliminary results deeply. PMID- 27456166 TI - Photoswitchable Spiropyran Dyads for Biological Imaging. AB - The synthesis of a small-molecule dyad consisting of a far-red-emitting silicon rhodamine dye that is covalently linked to a photochromic spironaphthothiopyran unit, which serves as a photoswitchable quencher, is reported. This system can be switched reversibly between the fluorescent and nonfluorescent states using visible light at wavelengths of 405 and 630 nm, respectively, and it works effectively in aqueous solution. Live-cell imaging demonstrates that this dyad has several desirable features, including excellent membrane permeability, fast and reversible modulation of fluorescence by visible light, and good contrast between the bright and dark states. PMID- 27456167 TI - Exploring metal detoxification and accumulation potential during vermicomposting of Tea factory coal ash: sequential extraction and fluorescence probe analysis. AB - Metal contamination from coal ashes (CAs) is widely recognized as a significant environmental concern. To learn more about metal detoxification and accumulation potential of earthworm species, metal-rich tea factory coal ashes (TFCA) were fed to Eisenia fetida and Lampito mauritii by employing a fluorescent tag detection method. Fascinatingly, on feeding fluorescence probed Zn and Cd along with cow dung to Eisenia fetida, the detection of the gut-proteins with a molecular mass higher than 100 kDa was a distinct evidence of metal binding. Significant increases were observed in the content of humified organic C [humic acid (HAC) and fulvic acid C (FAC)] and degree of humification during vermicomposting. Concurrently, considerably large amount of toxic metals (Cr, Cd, Pb, and Zn) was transformed from exchangeable to recalcitrant (organic matter and mineral bound) fractions. Moreover, total metal concentrations were reduced with high removal efficiency upon vermicomposting. PMID- 27456168 TI - Four-corner fusion of the wrist: clinical and radiographic outcome of 31 patients. AB - BACKGROUND: Four-corner fusion is a rational surgical option for the management of degenerative conditions of the wrist. Most related studies have compared four corner fusion with scaphoid excision or proximal row carpectomy, with a variety of reported results. To enhance the literature, we performed this study to evaluate a series of patients with degenerative conditions of the wrist treated with four-corner fusion using 3 surgical techniques and to discuss the clinical and radiographic outcome of the patients. MATERIALS AND METHODS: We retrospectively studied 31 patients (24 men, 7 women; mean age, 43 years; 9 heavy manual laborers) who underwent four-corner fusion of their wrists for degenerative conditions from 2005 to 2015. Internal fixation was done using multiple Kirschner wires (14 patients), headless compressive screws (8 patients), or a circular plate (9 patients). Mean follow-up was 4 years (1-11 years). We evaluated the clinical outcome with the Patient-Rated Wrist Evaluation (PRWE) score and fusion with radiographs. RESULTS: All patients experienced improvement of their pain, function, range of motion and grip strength (p < 0.05). Twenty three patients (74 %) reported no pain, and eight patients reported mild, occasional pain. Twenty-one patients (68 %) were able to do usual and specific activities. Mean wrist motion improved to 70 % and mean grip strength improved to 85 % of opposite wrist. Two heavy manual labor patients requested a job modification because of wrist impairment. Radiographs of the wrist showed fusion of all fused joints in 28 (90.3 %) patients and partial fusion in three patients (9.7 %). No patient with partial fusion required a reoperation for symptomatic nonunion until the period of this study. Three patients experienced complications (10 %). Two patients treated with a circular plate experienced complex regional pain syndrome and painful implant impingement; another patient treated with Kirschner wires and headless compression screws experienced radiolunate arthritis from impingement of the lunate screw to the radius. CONCLUSIONS: Four-corner fusion is a reliable limited wrist fusion technique that provides pain relief, grip strength and satisfactory range of motion in patients with degenerative conditions of the wrist. Partial union is more common with Kirschner wire fixation and complications are more common with circular plate fixation. PMID- 27456170 TI - Interfacial charge-transfer transitions and reorganization energies in sulfur bridged TiO2-x-benzenedithiol complexes (x: o, m, p). AB - Surface complexes formed between TiO2 nanoparticles and enediol compounds such as 1,2-benzenediol (o-BDO) via Ti-O-C linkages show absorption of visible light due to interfacial charge-transfer (ICT) transitions. The ICT transitions take place from the pi-conjugated systems to TiO2. Recently, we reported a surface complex formed between TiO2 and 1,2-benzenedithiol (o-BDT) via Ti-S-C linkages. This sulfur-bridged complex shows ICT transitions from the sulfur bridging atoms to TiO2. Interestingly, it was demonstrated that the ICT transitions in the sulfur bridged TiO2-o-BDT complex induce photoelectric conversion more efficiently than those in the oxygen-bridged TiO2-o-BDO complex. This result suggests that carrier recombination is suppressed with the sulfur bridging atoms. In this paper, we examine ICT transitions and reorganization energies in the sulfur-bridged TiO2-x BDT complexes (x: o, m, p) and compare them with those in the oxygen-bridged TiO2 x-BDO complexes. The estimated reorganization energies for the sulfur-bridged TiO2-x-BDT complexes (x: o, m, p) are much smaller than those for the oxygen bridged TiO2-x-BDO ones. Based on the Marcus theory, the small reorganization energy calculated for the TiO2-o-BDT complex, which is less than half of that for the TiO2-o-BDO complex, increases the activation energy of carrier recombination. The small reorganization energy is attributed to the characteristic distribution of the highest occupied molecular orbital (HOMO) on the sulfur-bridging atoms in the TiO2-o-BDT complex, which inhibits structural changes in the benzene ring in the ICT excited state. Our work reveals the important role of the sulfur bridging atoms in the suppression of carrier recombination. PMID- 27456169 TI - Surgical and nonsurgical treatments for lumbar spinal stenosis. AB - Lumbar spinal stenosis (LSS) is the most common indication for spinal surgery in older adults; however, the efficacy of surgery for LSS as compared to nonsurgical treatments remains unclear. Here, we reviewed numerous studies, including randomized control trails (RCTs), to compare nonsurgical and surgical treatments for LSS. The nonsurgical management of LSS includes medication, epidural injections, physiotherapy, lifestyle modification, and multidisciplinary rehabilitative approaches. Patients with LSS who do not improve after nonsurgical treatments are typically treated surgically using decompressive surgery, which has the strongest evidence base. Although decompressive surgical treatment is associated with modestly successful outcomes, it remains unclear whether decompression combined with fusion surgery results in clinical outcomes that are superior to those following decompression surgery alone. Future RCTs assessing the effectiveness of specific treatments based on high-quality scientific evidence are expected to aid clinical decision-making and improve treatment outcomes for LSS. PMID- 27456171 TI - Smooth and solid WS2 submicrospheres grown by a new laser fragmentation and reshaping process with enhanced tribological properties. AB - Smooth and solid WS2 submicrospheres were prepared by a laser irradiation induced fragmentation and morphological reshaping process using bulk-slice WS2 particles as targets in solution. Such submicrospheres as additives in paraffin liquid show remarkably enhanced friction reduction and anti-wear properties in comparison with raw WS2 slices. PMID- 27456173 TI - The role of Vitamin B12 in the critically ill--a review. AB - Vitamin B12 is an essential micronutrient, as humans have no capacity to produce the vitamin and it needs to be ingested from animal proteins. The ingested Vitamin B12 undergoes a complex process of absorption and assimilation. Vitamin B12 is essential for cellular function. Deficiency affects 15% of patients older than 65 and results in haematological and neurological disorders. Low levels of Vitamin B12 may also be an independent risk factor for coronary artery disease. High levels of Vitamin B12 are associated with inflammation and represent a poor outlook for critically ill patients. Treatment of Vitamin B12 deficiency is simple, but may be lifelong. PMID- 27456172 TI - Dengue virus infection induces interferon-lambda1 to facilitate cell migration. AB - A marked increase in the rate of dengue virus (DENV) infection has resulted in more than 212 deaths in Taiwan since the beginning of 2015, mostly from fatal outcomes such as dengue hemorrhagic fever and dengue shock syndrome. The pathogenic mechanisms of these fatal manifestations are poorly understood. Cytokines induce an overwhelming immune reaction and thus have crucial roles. Interferon-lambda (IFN-lambda), a newly identified IFN subtype, has antiviral effects, but its immunologic effects in DENV infection have not been investigated. In the present study, we show that DENV infection preferentially induced production of IFN-lambda1 in human dendritic cells (DCs) and human lung epithelial cells. Virus nonstructural 1 (NS1) glycoprotein was responsible for the effect. DENV-induced production of IFN-lambda1 was dependent on signaling pathways involving toll-like receptor (TLR)-3, interferon regulation factor (IRF) 3, and nuclear factor-kappaB (NF-kappaB). Blocking interaction between IFN lambda1 and its receptor IFN-lambdaR1 through siRNA interference reduced DENV induced DC migration towards the chemoattractants CCL19 and CCL21, by inhibiting CCR7 expression. Furthermore, IFN-lambda1 itself induced CCR7 expression and DC migration. Our study presents the first evidence of the mechanisms and effects of IFN-lambda1 induction in DENV-infected DCs and highlights the role of this cytokine in the immunopathogenesis of DENV infection. PMID- 27456174 TI - Factors predicting successful discontinuation of continuous renal replacement therapy. AB - This multicentre, retrospective observational study was conducted from January 2010 to December 2010 to determine the optimal time for discontinuing continuous renal replacement therapy (CRRT) by evaluating factors predictive of successful discontinuation in patients with acute kidney injury. Analysis was performed for patients after CRRT was discontinued because of renal function recovery. Patients were divided into two groups according to the success or failure of CRRT discontinuation. In multivariate logistic regression analysis, urine output at discontinuation, creatinine level and CRRT duration were found to be significant variables (area under the receiver operating characteristic curve for urine output, 0.814). In conclusion, we found that higher urine output, lower creatinine and shorter CRRT duration were significant factors to predict successful discontinuation of CRRT. PMID- 27456175 TI - Care-related pain in critically ill mechanically ventilated patients. AB - Despite advances in pain management, critically ill patients continue to have unacceptably high rates of uncontrolled pain. Using the Behavioural Pain Scale and physiological indicators of pain, this study examines pain levels in mechanically ventilated patients prior to and during routine nursing procedures. A prospective descriptive design was used to assess and describe care-related pain associated with nociceptive procedures (repositioning, endotracheal suctioning, and vascular punctures) and non-nociceptive procedures (mouth care, eye care and dressing change). A sample of 247 mechanically ventilated Jordanian patients was recruited from intensive care units in a military hospital. The overall mean procedural pain score of 6.34 (standard deviation [SD] 2.36) was significantly higher than the mean preprocedural pain score of 3.43 (SD 0.67, t[246]=20.82, P<0.001). The highest mean procedural pain scores were observed during repositioning (9.25, SD 1.29). Few patients received analgesics and/or sedatives in the hour prior to the procedures. The mean Ramsay Scale score was 2.49 (SD 0.95), indicating that patients were either anxious or responsive to command only. The mean physiological indicators of pain increased during repositioning and endotracheal suctioning and decreased during the rest of the procedures. Mechanically ventilated patients experience pain prior to and during routine nursing procedures. Harmless and comfort procedures are actually painful. When caring for nonverbal critically ill patients, clinicians need to consider care-related pain associated with their interventions. Relying on changes in vital signs as a primary indicator of pain can be misleading. PMID- 27456176 TI - Left ventricular diastolic dysfunction--an independent risk factor for weaning failure from mechanical ventilation. AB - The objective of this study was to investigate the contribution of left ventricular (LV) diastolic dysfunction to weaning failure, along with the levels of the currently used cardiac biomarkers. Forty-two mechanically ventilated patients, who fulfilled criteria for weaning from mechanical ventilation (MV), underwent a two-hour spontaneous breathing trial (SBT). Transthoracic echocardiography (TTE) was performed before the start of the SBT. The grade of LV diastolic dysfunction was assessed by pulsed-wave Doppler and tissue Doppler imaging at the level of the mitral valve. Haemodynamic and respiratory parameters were recorded. Blood levels of B-type natriuretic peptide (BNP), troponin I, creatine kinase-MB, and myoglobin were measured on MV and at the end of the SBT. Weaning success was defined as the patient's ability to tolerate spontaneous breathing for more than 48 hours. Fifteen patients failed to wean. LV diastolic dysfunction was significantly associated with weaning failure (P<0.001). The grade of diastolic dysfunction was significantly correlated with BNP levels both on MV and at the end of the SBT (P<0.001, r=0.703 and P<0.001, r=0.709, respectively). BNP levels on MV were lower in patients who successfully weaned compared to those who did not (361+/-523 ng/l versus 643+/-382 ng/l respectively, P=0.008). The presence of diastolic dysfunction was independently associated with weaning failure (odds ratio [OR] 11.23, confidence interval [CI] 1.16-109.1, P=0.037) followed by respiratory frequency/tidal volume (OR 1.05, CI 1.00-1.10, P=0.048). Therefore, assessment of LV diastolic function before the start of weaning could be useful to identify patients at risk of weaning failure. PMID- 27456177 TI - Systemic anticoagulation related to heparin locking of non-tunnelled venous dialysis catheters in intensive care patients. AB - Heparin locking of venous dialysis catheters is routinely performed in intensive care to maintain catheter patency when the catheters are not being used. Leakage of heparin into the circulation can potentially cause systemic anticoagulation and may present a risk to intensive care patients. To assess the effect of 5000 units per millilitre heparin locking of non-tunnelled dialysis catheters on systemic anticoagulation, we performed a prospective observational study of ten intensive care patients receiving heparin locking of dialysis catheters in an adult tertiary intensive care unit between July and September 2015. Activated partial thromboplastin time (APTT) was measured prior to, and three minutes after, heparin locking of catheter lumens with the manufacturer's recommended locking volume to assess the effect on systemic anticoagulation. Heparin locking of venous dialysis catheters resulted in a significant rise in APTT (P=0.002). The median rise was by 56 seconds (interquartile range 30-166.5). Following heparin locking, 80% of patients had APTT values within or above the range associated with therapeutic anticoagulation. Heparin locking of non-tunnelled venous dialysis catheters can cause systemic anticoagulation in intensive care patients and therefore poses a potential risk to patient safety. PMID- 27456178 TI - Organ donation after circulatory death in a university teaching hospital. AB - Although organ transplantation is well established for end-stage organ failure, many patients die on waiting lists due to insufficient donor numbers. Recently, there has been renewed interest in donation after circulatory death (DCD). In a retrospective observational study we reviewed the screening of patients considered for DCD between March 2007 and December 2012 in our hospital. Overall, 148 patients were screened, 17 of whom were transferred from other hospitals. Ninety-three patients were excluded (53 immediately and 40 after review by donation staff). The 55 DCD patients were younger than those excluded (P=0.007) and they died from hypoxic brain injury (43.6%), intraparenchymal haemorrhage (21.8%) and subarachnoid haemorrhage (14.5%). Antemortem heparin administration and bronchoscopy occurred in 50/53 (94.3%) and 22/55 (40%) of cases, respectively. Forty-eight patients died within 90 minutes and proceeded to donation surgery. Associations with not dying in 90 minutes included spontaneous ventilation mode (P=0.022), absence of noradrenaline infusion (P=0.051) and higher PaO2:FiO2 ratio (P=0.052). The number of brain dead donors did not decrease over the study period. The time interval between admission and death was longer for DCD than for the 45 brain dead donors (5 [3-11] versus 2 [2-3] days; P<0.001), and 95 additional patients received organ transplants due to DCD. Introducing a DCD program can increase potential organ donors without reducing brain dead donors. Antemortem investigations appear to be acceptable to relatives when included in the consent process. PMID- 27456179 TI - Comparison of PulsioFlex(r) uncalibrated pulse contour method and a modified Fick principle with transpulmonary thermodilution measurements in critically ill patients. AB - Monitoring of cardiac index (CI) by uncalibrated pulse contour (PC) methods has been shown to be inaccurate in critically ill patients. We tested accuracy and trending of a new pulse contour method and a modified Fick method using central venous oxygen saturation. We studied 21 critically ill and mechanically ventilated patients (age 20-86 years) monitored by PC (PulsioFlex(r)) and transpulmonary thermodilution (TPTD, PiCCO2(r)) as reference. At baseline, reference and PC-derived CI (CIPC) were recorded and CI obtained by Fick's method (FM, CIFICK). After four hours, measurements were performed analogously for trending analysis. CI are given in l/min/m2 as mean+/-standard deviation. At baseline CITPTD was 3.7+/-0.7, CIPC 3.8+/-0.7 and CIFICK 5.2+/-1.8. After 4 hours, CITPTD was 3.5+/-0.6, CIPC 3.8+/-1.2 and CIFICK 4.8+/-1.7. Mean bias for PC at baseline was -0.1 (limits of agreement [LOA] -1.4 to 1.2) and -0.4 (LOA 2.6 to 1.9) after four hours. Percentage errors (PE) were 34% and 60% respectively. FM revealed a bias of -1.5 (LOA -4.8 to 1.8, PE 74%) at baseline and -1.5 (LOA -4.5 to 1.4, PE 68%) at four hours. With an exclusion window of 10% of mean cardiac index, trending analysis by polar plots showed an angular bias of 5 degrees (radial LOA+/-57 degrees ) for PC and 16 degrees (radial LOA+/-51 degrees ) for FM. Although PC values at baseline were marginally acceptable, both methods fail to yield clinically acceptable absolute values. Likewise, trending ability is not adequate for both methods to be used in critically ill patients. PMID- 27456180 TI - Survey of anaesthetists' practice of sedation for gastrointestinal endoscopy. AB - We conducted a survey of Australian specialist anaesthetists about their practice of sedation for elective and emergency gastroscopy, endoscopic retrograde cholangiopancreatography (ERCP), and colonoscopy. A 24-item survey was emailed to 1,000 anaesthetists in August 2015. Responses were received from 409 anaesthetists (response rate=41%) with responses from 395 anaesthetists analysed. Pulse oximetry and oxygen administration were routine for all procedures for all respondents. Blood pressure was routinely measured by most respondents during gastroscopy (elective=88%; emergency=97%), ERCP (elective=99%; emergency=99%) and colonoscopy (elective=91%; emergency=98%). The airway was routinely managed with jaw lift or oral or nasal airway by 99%, 76% and 97% of respondents during gastroscopy, ERCP and colonoscopy, whereas in emergency procedures endotracheal intubation was routine in 49%, 64% and 17% of procedures. Propofol was routinely administered by 99% of respondents for gastroscopy and 100% of respondents for ERCP and colonoscopy. A maximum depth of sedation in which patients were unresponsive to painful stimulation was targeted by the majority of respondents for all procedures except for elective gastroscopy. These results may be used to facilitate comparison of practice in Australia and overseas, and give an indication of compliance by Australian anaesthetists with the relevant Australian and New Zealand College of Anaesthetists guideline. PMID- 27456181 TI - Successful introduction of a daily checklist to enhance compliance with accepted standards of care in the medical intensive care unit. AB - We introduced a simple checklist to act as an aid to memory for our junior medical staff to ensure that every patient in the intensive care unit (ICU) received every appropriate element of a bundle of care every day. The checklist was developed in consultation with our junior doctors and was designed to be completed every morning for every patient by the junior doctor reviewing the patient. The completed checklist was then checked again by the attending intensivist on the main daily ward round to ensure all the appropriate elements of the checklist had been applied to the patient. It was also noted each day which of the elements of the checklist had been forgotten and was therefore prompted to be completed by use of the checklist. Of the 75 patients surveyed there were 99 occasions, in 48 patients, when the checklist detected a forgotten element of the bundle of care (i.e. in 64% of patients). There was a decrease in the incidence of missed elements of the bundle of care the longer the patient stayed in the ICU. Types of missed elements varied with the duration of the ICU stay. We found that the introduction of a simple checklist, developed in collaboration with the junior medical staff who would be using the checklist every day in the ICU, resulted in the detection and correction of missed elements of a bundle of care we had previously introduced in the ICU. PMID- 27456182 TI - Feasibility and acceptability of remotely monitored pedometer-guided physical activity. AB - Nearly 70% of the Australian adult population are either sedentary, or have low levels of physical activity. There has been interest in addressing this problem by the 'mHealth', or mobile Health, arena, which is concerned with the confluence of mobile technology and health promotion. The newer generation of activity pedometers has the ability to automatically upload information, to enable aggregation and meta-data analysis of individual patient data. We conducted a ten week pilot trial of the Fitbit Zip(r) pedometer using a validated tool in ten volunteers, finding it highly acceptable to both participants and investigators. Data synching was ranked as 'very easy' or 'easy' by all participants, and investigators could successfully monitor activity levels remotely. Median (interquartile range) daily step counts of participants over the ten-week trial ranged from 5471 (4591-7026) to 18779 (15031-21505) steps. Sedentary time over the study period ranged from 1.4% to 33.3% of study days. Percentage of days reaching the target activity level of >10,000 steps/day varied markedly between participants from 4.5% to 95.7%. This study demonstrates the feasibility and acceptability of a remotely monitored pedometer-guided physical activity intervention. This technology may be useful to encourage increased exercise as a form of 'prehabilitation' of adequately screened at-risk surgical or obstetric patients. PMID- 27456183 TI - Evaluation of hospital-wide computerised decision support in an intensive care unit: an observational study. AB - We conducted an observational study with interviews in a 12-bed general/neurological intensive care unit (ICU) at a teaching hospital in Sydney, Australia, to determine whether hospital-wide computerised decision support (CDS) embedded in an electronic prescribing system is used and perceived as useful by doctors in an ICU setting. Twenty doctors were shadowed by the observer while on ward rounds (33.6 hours) and non-ward rounds (28 hours) in the ICU. These doctors were also interviewed to explore views of CDS. We found that computerised alerts were triggered frequently in the ICU (n=166, in 59% of orders), less than half of the alerts were read by doctors and only four alerts resulted in a medication order being changed. Pre-written orders were utilised frequently, however reference material was rarely accessed. Interviews with doctors revealed a willingness to use CDS features; however the primary barrier to use was lack of customisation for the ICU setting. Doctors working in the ICU triggered a high number of alerts when prescribing, 40% more alerts than doctors working on general wards of the same hospital. Certain procedures in place in the ICU (e.g. daily microbiology ward rounds) made many alerts redundant in this setting. Lack of customisation for the ICU led to dissatisfaction with CDS and infrequent use of some CDS features. PMID- 27456184 TI - A site check prior to regional anaesthesia to prevent wrong-sided blocks. AB - This paper describes the implementation of the 'Stop Before You Block' (SB4YB) initiative in an Australian teaching hospital. This process, which began in the UK in 2010, is a pre-procedure pause to confirm the correct side of a regional anaesthetic block. A change in practice was implemented with the formal roll out of a SB4YB educational program. Use of the initiative was then audited over a subsequent three-month period. It was hoped that after implementing the initiative, at least 80% of blocks would have a site check performed. However, despite apparent support for the initiative, uptake was less than expected with only about 57% of blocks having a site check performed. A site check was less frequent if the block was done as an emergency procedure, outside of an operating theatre or by a locum or visiting anaesthetist. Our conclusion from the audit was that education is insufficient to promote a change in this practice. We propose that Stop Before You Block or a block time-out should be performed prior to all unilateral nerve blocks. Success of this initiative requires education, and both cultural and systems changes to occur. We propose that a formal block time-out should become part of the surgical safety checklist and this activity should be endorsed and promoted by anaesthetic professional bodies. PMID- 27456186 TI - Quality of recovery from sedation for endoscopy. PMID- 27456185 TI - Optimising subclavian vein ultrasound imaging for central venous access. PMID- 27456187 TI - Prolonged fasting and no intraoperative glucose? PMID- 27456188 TI - Thromboelastometry and thromboelastography failed to detect hypercoagulability in thrombotic microangiopathy. PMID- 27456189 TI - Rocuronium-induced anaphylaxis not improved by low dose sugammadex: a case report. PMID- 27456190 TI - Using oxygen to improve the local anaesthetic atomisation capabilities of the LMA MADgicTM malleable stylet during awake fibreoptic intubation: a simple and effective technique. PMID- 27456191 TI - Immersion and distancing during assimilation of problematic experiences in a good outcome case of emotion-focused therapy. AB - OBJECTIVE: Some studies have suggested that a decrease in immersion (egocentric perspective on personal experiences) and an increase in distancing (observer perspective on personal experiences) are associated with the resolution of clinical problems and positive outcome in psychotherapy for depression. To help clarify how this change in perspectives relates to clinical change, the present study compared changes in immersion and distancing across therapy with progress in one client's assimilation of her problematic experiences. METHOD: We analyzed all passages referring to the central problematic experience in a good-outcome case of emotion-focused therapy for depression using the Measure of Immersion and Distancing Speech and the Assimilation of Problematic Experiences Scale. RESULTS: Results showed that immersion and distancing were associated with different stages of assimilation. Immersion was associated with stages of emerging awareness and clarification of the problem and in the application of new understandings to daily life. Distancing was associated with problem-solving and attaining insight. CONCLUSION: The decrease of immersion and increase of distancing associated with therapeutic improvement should not be taken as a recommendation to avoid immersion and encourage distancing. Immersion and distancing may work as coordinated aspects of the processes of psychotherapeutic change. PMID- 27456192 TI - Microstructural transitions in resistive random access memory composed of molybdenum oxide with copper during switching cycles. AB - The switching operation of a Cu/MoOx/TiN resistive random access memory (ReRAM) device was investigated using in situ transmission electron microscopy (TEM), where the TiN surface was slightly oxidized (ox-TiN). The relationship between the switching properties and the dynamics of the ReRAM microstructure was confirmed experimentally. The growth and/or shrinkage of the conductive filament (CF) can be classified into two set modes and two reset modes. These switching modes depend on the device's switching history, factors such as the amount of Cu inclusions in the MoOx layer and the CF geometry. High currents are needed to produce an observable change in the CF. However, sharp and stable switching behaviour can be achieved without requiring such a major change. The local region around the CF is thought to contribute to the ReRAM switching process. PMID- 27456193 TI - [Utilization of outpatient psychotherapeutic treatment : A secondary data analysis]. AB - BACKGROUND: In spite of a well-developed and complex mental healthcare system in Germany, problems remain in the capacity of psychotherapeutic care with an undersupply and long waiting times for provision of outpatient psychotherapeutic care. OBJECTIVES: The analyses address the current level of psychotherapeutic care and the role of individual medical specialties in outpatient psychotherapeutic care in Germany. MATERIAL AND METHODS: The analyses are based on secondary data from three statutory health insurance companies and the German pension funds for the years 2005-2007. Anonymized treatment data from 3.3 million insured persons with a diagnosis of a mental disorder (ICD-10 groups F0-F5) were analyzed. RESULTS: In outpatient treatment 9,670,588 psychotherapeutic accounting codes were analyzed of which 33 % were psychiatric, psychosomatic or psychotherapeutic consultations that are not covered by the scope of psychotherapy according to the standard regulations (psychotherapy guidelines). The most frequently used psychotherapeutic services were verbal interventions (accounting codes 35.100 and 31.110) and psychiatric consultations (accounting codes 14.220, 21.220 and 21.221), independent of the mental disorder. Of the patients 5.9 % received directive psychotherapy. The provider-specific analysis showed a great variation in the kind of accounting codes, which were brought into account by the different providers. CONCLUSION: With regard to the reform efforts in psychotherapeutic care, longitudinal trends in the utilization and quality of psychotherapeutic care in the individual fields of treatment should be analyzed in follow-up studies. PMID- 27456194 TI - [Robert Schumann in the psychiatric hospital in Endenich near Bonn]. AB - BACKGROUND: The composer Robert Schumann (1810-1856) spent the last two-and-a half years of his life in the private psychiatric hospital in Endenich. His medical records emerged in 1991 and were published by Appel in 2006. METHODS: Daily entries by the physicians were analyzed concerning psychopathology and organic signs as well as the illness-related correspondence of the people closest to Schumann. RESULTS: The numerous entries reveal the treatment typical at that time for what was at first considered to be "melancholy with delusions": shielding from stimuli, physical procedures, and a dietary regimen. The feared, actual diagnosis, a "general (incomplete) paralysis," becomes a certainty in the course of the paranoid-hallucinatory symptoms with cerebro-organic characteristics and agitated states, differences in pupil size, and increasing speech disturbances. CONCLUSION: In the medicine of the time, syphilis is just emerging as the suspected cause, and the term "progressive paralysis" is coined as typical for the course. Proof of Treponema pallidum infection was not available until 1905. Nevertheless, the clinical signs strongly refer to the course of neurosyphilis. People close to Robert, in particular his wife Clara and the circle of friends around Brahms and Joachim, cared intensively for him and suffered under the therapeutic isolation. The medical records and disease-related letters contradict the theory that Schumann was disposed of by being put into the psychiatric hospital; they show the concern of all during the unfavorable illness course. PMID- 27456195 TI - [Mental disorders in pregnancy and postpartum : Prevalence, course, and clinical diagnostics]. AB - The peripartum period represents a critical phase for the onset and course of mental disorders. During this phase, mental disorders occur as first onset or, more often, as recurrent or ongoing chronic conditions with onset and further course of illness in- or outside the peripartal period. No clear risk increase exists for the more prevalent mental disorders such as depressive and anxiety disorders during this period, whereas there is an increased risk for bipolar disorder. Peripartal mental disorders may impact fetal and child development through different mechanisms. The International Statistical Classification of Diseases and Related Health Problems (ICD-10) does not sufficiently take into account particularities of peripartal disorders with possible prognostic relevance. The present article gives an overview on prevalence, course, and clinical diagnostics and presents a proposal for consistent categorization of peripartal mental disorders. PMID- 27456196 TI - [Development and validation of the Subclinical Stress Symptom Questionnaire SSQ 25]. AB - BACKGROUND: Stress symptoms are widespread in the general population and often occur in the early course of mental disorders. However, no validated instrument was available for the study of subclinical stress symptoms and their relevance in the study of psychopathological trajectories. In order to advance and systematize the study of the etiology and pathogenesis of diseases in subclinical populations, the Subclinical Stress Symptom Questionnaire (SSQ-25) was developed in the present study. METHODS: In the course of three online studies, a total of 1174 subjects were recruited. The first study included item selection and the development of the questionnaire based on the analysis of item parameters, reliability, and exploratory factor analysis. To validate the factor structure, confirmatory factor analysis was used. Validation analyses were applied to distinguish the SSQ-25 from three clinical measures: Beck's Anxiety and Depression Inventory (BAI and BDI), and the Posttraumatic Stress Diagnostic Scale (PDS). In the third study the subclinical property of the instrument was investigated. RESULTS: Exploratory and confirmatory factor analyses revealed and confirmed a two-factor model (psychological and physiological stress symptoms). Cronbach's alpha was 0.95. The subclinical property of the SSQ-25 was confirmed by means of item information functions, scatter plots, residuals, and Koenker Bassett tests as opposed to established clinical measures. DISCUSSION: The SSQ-25 is a comprehensive, reliable, and valid instrument that allows a valid assessment and differentiation of subclinical stress symptoms. PMID- 27456199 TI - Visualization of heterogeneity and regional grading of gliomas by multiple features using magnetic resonance-based clustered images. AB - Preoperative glioma grading is important for therapeutic strategies and influences prognosis. Intratumoral heterogeneity can cause an underestimation of grading because of the sampling error in biopsies. We developed a voxel-based unsupervised clustering method with multiple magnetic resonance imaging (MRI) derived features using a self-organizing map followed by K-means. This method produced novel magnetic resonance-based clustered images (MRcIs) that enabled the visualization of glioma grades in 36 patients. The 12-class MRcIs revealed the highest classification performance for the prediction of glioma grading (area under the receiver operating characteristic curve = 0.928; 95% confidential interval = 0.920-0.936). Furthermore, we also created 12-class MRcIs in four new patients using the previous data from the 36 patients as training data and obtained tissue sections of the classes 11 and 12, which were significantly higher in high-grade gliomas (HGGs), and those of classes 4, 5 and 9, which were not significantly different between HGGs and low-grade gliomas (LGGs), according to a MRcI-based navigational system. The tissues of classes 11 and 12 showed features of malignant glioma, whereas those of classes 4, 5 and 9 showed LGGs without anaplastic features. These results suggest that the proposed voxel-based clustering method provides new insights into preoperative regional glioma grading. PMID- 27456198 TI - IL-10 Promotes Neurite Outgrowth and Synapse Formation in Cultured Cortical Neurons after the Oxygen-Glucose Deprivation via JAK1/STAT3 Pathway. AB - As a classic immunoregulatory and anti-inflammatory cytokine, interleukin-10 (IL 10) provides neuroprotection in cerebral ischemia in vivo or oxygen-glucose deprivation (OGD)-induced injury in vitro. However, it remains blurred whether IL 10 promotes neurite outgrowth and synapse formation in cultured primary cortical neurons after OGD injury. In order to evaluate its effect on neuronal apoptosis, neurite outgrowth and synapse formation, we administered IL-10 or IL-10 neutralizing antibody (IL-10NA) to cultured rat primary cortical neurons after OGD injury. We found that IL-10 treatment activated the Janus kinase 1 (JAK1)/signal transducers and activators of transcription 3 (STAT3) signaling pathway. Moreover, IL-10 attenuated OGD-induced neuronal apoptosis by down regulating the Bax expression and up-regulating the Bcl-2 expression, facilitated neurite outgrowth by increasing the expression of Netrin-1, and promoted synapse formation in cultured primary cortical neurons after OGD injury. These effects were partly abolished by JAK1 inhibitor GLPG0634. Contrarily, IL-10NA produced opposite effects on the cultured cortical neurons after OGD injury. Taken together, our findings suggest that IL-10 not only attenuates neuronal apoptosis, but also promotes neurite outgrowth and synapse formation via the JAK1/STAT3 signaling pathway in cultured primary cortical neurons after OGD injury. PMID- 27456200 TI - Chemical control over the energy-level alignment in a two-terminal junction. AB - The energy-level alignment of molecular transistors can be controlled by external gating to move molecular orbitals with respect to the Fermi levels of the source and drain electrodes. Two-terminal molecular tunnelling junctions, however, lack a gate electrode and suffer from Fermi-level pinning, making it difficult to control the energy-level alignment of the system. Here we report an enhancement of 2 orders of magnitude of the tunnelling current in a two-terminal junction via chemical molecular orbital control, changing chemically the molecular component between a stable radical and its non-radical form without altering the supramolecular structure of the junction. Our findings demonstrate that the energy-level alignment in self-assembled monolayer-based junctions can be regulated by purely chemical modifications, which seems an attractive alternative to control the electrical properties of two-terminal junctions. PMID- 27456201 TI - Multi-Scale Correlative Tomography of a Li-Ion Battery Composite Cathode. AB - Focused ion beam/scanning electron microscopy tomography (FIB/SEMt) and synchrotron X-ray tomography (Xt) are used to investigate the same lithium manganese oxide composite cathode at the same specific spot. This correlative approach allows the investigation of three central issues in the tomographic analysis of composite battery electrodes: (i) Validation of state-of-the-art binary active material (AM) segmentation: Although threshold segmentation by standard algorithms leads to very good segmentation results, limited Xt resolution results in an AM underestimation of 6 vol% and severe overestimation of AM connectivity. (ii) Carbon binder domain (CBD) segmentation in Xt data: While threshold segmentation cannot be applied for this purpose, a suitable classification method is introduced. Based on correlative tomography, it allows for reliable ternary segmentation of Xt data into the pore space, CBD, and AM. (iii) Pore space analysis in the micrometer regime: This segmentation technique is applied to an Xt reconstruction with several hundred microns edge length, thus validating the segmentation of pores within the micrometer regime for the first time. The analyzed cathode volume exhibits a bimodal pore size distribution in the ranges between 0-1 MUm and 1-12 MUm. These ranges can be attributed to different pore formation mechanisms. PMID- 27456202 TI - Localized recovery of complex networks against failure. AB - Resilience of complex networks to failure has been an important issue in network research for decades, and recent studies have begun to focus on the inverse recovery of network functionality through strategically healing missing nodes or edges. However, the effect of network recovery is far from fully understood, and a general theory is still missing. Here we propose and study a general model of localized recovery, where a group of neighboring nodes are restored in an invasive way from a seed node. We develop a theoretical framework to compare the effect of random recovery (RR) and localized recovery (LR) in complex networks including Erdos-Renyi networks, random regular networks, and scale-free networks. We find detailed phase diagrams for the subnetwork of occupied nodes and the "complement network" of failed nodes under RR and LR. By identifying the two competitive forces behind LR, we present an analytical and numerical approach to guide us in choosing the appropriate recovery strategy and provide estimation on its effect by using the degree distribution of the original network as the only input. Our work therefore provides insight for quantitatively understanding recovery process and its implications in infrastructure protection in various complex systems. PMID- 27456203 TI - Tolerance, loss of tolerance and regaining tolerance to self by immune-mediated events. AB - Autoimmunity has both beneficial and harmful aspects. Beneficial aspects include: (1) removal of released intracytoplasmic antigens (ags) (cells at the end of their life span or damaged by outside agents) by specific nonpathogenic IgM autoantibodies and mononuclear cells and (2) recognition and elimination of cancerous cells. In contrast, harmful aspects include: (1) mounting a pathogenic autoimmune response against a tissue-derived ag, a 'modified self,' resulting in autoimmune disease and (2) inability to recognize and eliminate a cancerous clone. The immune system continuously faces internal and external influences; however, even when it is compromised or overwhelmed, it will still endeavor to regain and maintain tolerance to self. To promote this, we developed a 'modified vaccination technique' (MVT) (described as the third vaccination method after active and passive immunizations). It has two components: purified exogenous/endogenous ag (i.e., target ag) and a high-titer-specific antibody (ab) against the target ag made into an immune complex (IC) with predetermined immune inducing components. The MVT works by ab information transfer (production of same class of immunoglobulin with the same specificity against the target ag that is present in the vaccine), thereby re-establishing tolerance to self (caused by exogenous/endogenous ags) following repeated administration of appropriate ICs. This vaccination technique can be used both prophylactically and therapeutically, and it mimics the immune system's natural abilities to respond to corrective information specifically, rapidly, safely and with minimal side effects and makes this approach a novel solution for many disorders that are difficult or impossible to cure or manage. PMID- 27456204 TI - The burden of the variability introduced by the HEp-2 assay kit and the CAD system in ANA indirect immunofluorescence test. AB - According to the recent recommendations of the American College of Rheumatology, ANA Task Force, IIF technique should be considered the gold standard in antinuclear antibodies (ANAs) testing. To overcome the lack of standardization, biomedical industries have developed several computer-aided diagnosis (CAD) systems. Two hundred and sixty-one consecutive samples with suspected autoimmune diseases were tested for ANA by means of IIF on routinely HEp-2 assay kit (Euroimmun AG). Assignment of result was made if consensus for positive/negative was reached by at least 2 out of 3 expert physicians. ANA-IIF was also carried out using 3 CAD systems: Zenit G-Sight (n = 84), Helios (n = 85) and NOVA View (n = 92); human evaluation was repeated on the same substrate of each CAD system (Immco, Aesku and Inova HEp-2 cells, respectively). To anonymize the results, we randomly named these three systems as A, B and C. We ran a statistical analysis computing several measures of agreement between the ratings, and we also improved the evaluation by using the Wilcoxon's test for nonparametric data. Agreement between the human readings on routinely HEp-2 assay kit and human readings on CAD HEp-2 assay was substantial for A (k = 0.82) and B (k = 0.72), and almost perfect for C (k = 0.89). Such readings were statistically different only in case A. Comparing experts' readings with the readings of CAD systems, when the samples were prepared using CAD HEp-2 assay kits, we found almost perfect agreement for B and C (k = 0.86; k = 0.82) and substantial agreement for A (k = 0.73). Again, human and CAD readings were statistically different only in A. When we compared the readings of medical experts on routinely HEp-2 assay kit with the output of the CAD systems that worked using their own slides, we found substantial agreement for all the systems (A: k = 0.62; B: k = 0.65; C: k = 0.71). Such readings were not statistically different. The change of the assay kit and/or the introduction of a CAD system affect the laboratory reporting, with an evident impact on the autoimmune laboratory workflow. The CAD systems may represent one of the most important novel elements of harmonization in the autoimmunity field, reducing intra- and inter-laboratory variability in a new vision of the diagnostic autoimmune platform. PMID- 27456205 TI - Emergency medical triage decisions are swayed by computer-manipulated cues of physical dominance in caller's voice. AB - In humans as well as other animals, displays of body strength such as power postures or deep masculine voices are associated with prevalence in conflicts of interest and facilitated access to resources. We conduct here an ecological and highly critical test of this hypothesis in a domain that, on first thought, would appear to be shielded from such influences: access to emergency medical care. Using acoustic manipulations of vocal masculinity, we systematically varied the perceived level of physical dominance of mock patients calling a medical call center simulator. Callers whose voice were perceived as indicative of physical dominance (i.e. those with low fundamental and formant frequency voices) obtained a higher grade of response, a higher evaluation of medical emergency and longer attention from physicians than callers with strictly identical medical needs whose voice signaled lower physical dominance. Strikingly, while the effect was important for physician participants, it was virtually non-existent when calls were processed by non-medically-trained phone operators. This finding demonstrates an unprecedented degree of vulnerability of telephone-based medical decisions to extra-medical factors carried by vocal cues, and shows that it may not simply be assumed that more medical training will shield decisions from such influences. PMID- 27456206 TI - ASTRAL, DRAGON and SEDAN scores predict stroke outcome more accurately than physicians. AB - BACKGROUND AND PURPOSE: ASTRAL, SEDAN and DRAGON scores are three well-validated scores for stroke outcome prediction. Whether these scores predict stroke outcome more accurately compared with physicians interested in stroke was investigated. METHODS: Physicians interested in stroke were invited to an online anonymous survey to provide outcome estimates in randomly allocated structured scenarios of recent real-life stroke patients. Their estimates were compared to scores' predictions in the same scenarios. An estimate was considered accurate if it was within 95% confidence intervals of actual outcome. RESULTS: In all, 244 participants from 32 different countries responded assessing 720 real scenarios and 2636 outcomes. The majority of physicians' estimates were inaccurate (1422/2636, 53.9%). 400 (56.8%) of physicians' estimates about the percentage probability of 3-month modified Rankin score (mRS) > 2 were accurate compared with 609 (86.5%) of ASTRAL score estimates (P < 0.0001). 394 (61.2%) of physicians' estimates about the percentage probability of post-thrombolysis symptomatic intracranial haemorrhage were accurate compared with 583 (90.5%) of SEDAN score estimates (P < 0.0001). 160 (24.8%) of physicians' estimates about post-thrombolysis 3-month percentage probability of mRS 0-2 were accurate compared with 240 (37.3%) DRAGON score estimates (P < 0.0001). 260 (40.4%) of physicians' estimates about the percentage probability of post-thrombolysis mRS 5 6 were accurate compared with 518 (80.4%) DRAGON score estimates (P < 0.0001). CONCLUSIONS: ASTRAL, DRAGON and SEDAN scores predict outcome of acute ischaemic stroke patients with higher accuracy compared to physicians interested in stroke. PMID- 27456207 TI - A review of patient safety incidents reported as 'severe' or 'death' from critical care units in England and Wales between 2004 and 2014. AB - We analysed 1743 patient safety incidents reported between 2004 and 2014 from critical care units in England and Wales where the harm had been classified as 'severe' (1346, 77%) or 'death' (397, 23%). We classified 593 (34%) of these incidents as resulting in temporary harm, and 782 (45%) as more than temporary harm, of which 389 (22%) may have contributed to the patient's death. We found no described harm in 368 (21%) incidents. We classified 1555 (89%) of the incidents as being avoidable or potentially avoidable. There were changes over time for some incident types (pressure sores: 10 incidents in 2007, 64 in 2012; infections: 60 incidents in 2007, 10 in 2012) and some changes in response to national guidance. We made a comparison with a dataset of all incidents reported from units in North-West England, and this confirmed that the search strategy identified more severe incidents, but did not identify all incidents that contributed to mortality. PMID- 27456208 TI - Autologous platelet rich plasma in the management of non-healing vasculitic ulcers. AB - AIM: To determine the role and efficacy of platelet rich plasma (PRP) in the healing of recalcitrant vasculitic ulcers and to study the rapidity of ulcer healing with respect to platelet concentration in the prepared PRP. METHODS: This is a pilot study which included 20 patients with biopsy-proven vasculitic ulcers after excluding human immunodeficiency virus, uncontrolled diabetes mellitus, hypertension, obesity, active smoking and platelet abnormalities in peripheral smear. PRP was prepared from whole blood by centrifugation and activated using 10% calcium chloride. Activated PRP was applied over the ulcer by spraying using a syringe. Weekly dressing was done until the ulcer healed and healing was monitored using the Leg Ulcer Measurement Tool (LUMT). RESULTS: The total number of patients were 20 (male four; female 16). The mean age was 34.5 +/- 15.36 years (2.0 SD). Mean duration of illness was 8.6 +/- 2.9 months(2.0 SD). Ulcers were located in the lower third of the leg (n = 13), ankle (n = 4) and foot (n = 3) in the descending order of frequency. On average, epithelization of the wound occurred at 4.4 weeks. Faster healing was seen in mixed connective tissue disease (average 3.5 weeks) and delayed healing in systemic lupus erythematosus (average 4.7 weeks). Average platelet count obtained in the PRP was 5.52 lakhs/mm3 to 18.6 lakhs/mm3 with an increase in platelet count of 3.4- to 6-fold, respectively. Duration of healing corresponded with the platelet concentration in the prepared PRP. All the 20 patients showed complete healing within 6 weeks. CONCLUSION: PRP is a safe, effective, outpatient procedure for the treatment of chronic recalcitrant vasculitic ulcers which improves the quality of life of patients and reduces their financial burden. PMID- 27456209 TI - The Role of the Mental Health Worker in a Housing and Accommodation Support Initiative for Indigenous Australians. AB - PURPOSE: To explore the experiences of mental health workers and perceptions of their role and the scope of their work. DESIGN AND METHODS: Qualitative design. Twenty interviews were conducted with mental health workers. Interviews were analyzed using thematic analysis. FINDINGS: Three overarching themes were identified. In this paper the overarching theme of "dimensions of my role" is discussed. Subthemes were (a) information and education, (b) person-centered care, and (c) networking and partnerships. PRACTICE IMPLICATIONS: Professional development, networking, and partnerships underpin the provision of coordinated services and ultimately person-centered care. Enhancing staff capacity building may also enable sustainability of appropriate quality services. PMID- 27456210 TI - Item Reduction, Scoring, and First Validation of the ACCEPTance by the Patients of their Treatment (ACCEPT(c)) Questionnaire. AB - OBJECTIVES: The objectives of this study were to finalize, develop the scoring, and explore the psychometric properties of the ACCEPTance by the Patients of their Treatment (ACCEPT(c)) questionnaire, as well as to provide the first elements for its interpretation and guidance for its future use. METHODS: ACCEPT(c) was finalized according to reference methods including testing in a pilot study, i.e., a multi-center, observational, longitudinal study conducted in France, in collaboration with a network of pharmacists. Principal component analysis using Varimax rotation was performed. The loadings of items on components in the principal component analysis were used to inform item selection. Validity of the measurement model of ACCEPT(c) was confirmed using Multi-trait/Multi-item Analysis based on item-scale Spearman correlations. Internal consistency reliability of the questionnaire was assessed by determining the Cronbach's alpha coefficient. Linear and logistic regressions were used to identify predictors of general acceptance, and to study predictors of persistence. RESULTS: A total of 189 patients were included. The final version of ACCEPT(c) is composed of 25 items, distributed in seven dimensions providing a comprehensive appraisal of acceptance of long-term medication, with six scores measuring acceptance of treatment specific attributes and one score measuring general treatment acceptance. The measurement properties of ACCEPT(c) were overall fairly satisfactory. Regressions showed that Acceptance/Effectiveness is a predictor of general acceptance. However, no predictor of persistence could be identified. CONCLUSION: The self-administered ACCEPT(c) questionnaire is a valid and reliable instrument for the assessment of patients' acceptance of long-term medication. Disease-specific and large prospective studies are needed to assess the ability of ACCEPT PMID- 27456211 TI - Extensive and severe CNS demyelination associated with golimumab therapy. PMID- 27456212 TI - Recent progress of sample stacking in capillary electrophoresis (2014-2016). AB - The term "sample stacking" comprises a relatively broad spectrum of techniques that already form an almost inherent part of the methodology of CZE. Their principles are different but the effect is the same: concentration of a diluted analyte into a narrow zone and considerable increase of the method sensitivity. This review brings a survey of papers on electrophoretic sample stacking published approximately since the second quarter of 2014 till the first quarter of 2016. It is organized according to the principles of the stacking methods and includes chapters aimed at the concentration adjustment principle (Kohlrausch stacking), techniques based on pH changes, micellar methods, and other stacking techniques. Not reviewed are papers on transient ITP that are covered by another review in this issue. PMID- 27456213 TI - Fine needle aspiration cytology of cylindroma of scalp: A case report. AB - Cylindromas are uncommon benign adnexal tumor. Multiple cylindromas are commonly genetically inherited and also known as "turban tumor." Cytology of dermal cylindroma is rarely discussed in previous literature. We have diagnosed a case of dermal cylindroma of scalp in an elderly female patient by fine needle aspiration cytology of the lesion and further confirmation was done by histopathology. Cytology consists of many clusters of small round to oval basaloid cells surrounded and attached with magenta coloured acellular hyaline material. The cells have very scanty cytoplasm and dark, round to oval hyperchromatic nuclei without any nuclear membrane irregularity. Histopathology revealed nests of tumor cells separated by dense pink, PAS positive basement membrane material with a jigsaw puzzle appearance. Cytology of cylindroma should be differentiated from adenoid cystic carcinoma and other benign adnexal tumor like spiradenoma. We have discussed the case of cylindroma of scalp diagnosed by cytology and confirmed by histopathology. Diagn. Cytopathol. 2016;44:1082-1084. (c) 2016 Wiley Periodicals, Inc. PMID- 27456214 TI - Second-Order Nonlinear Optical Dendrimers and Dendronized Hyperbranched Polymers. AB - Second-order nonlinear optical (NLO) dendrimers with a special topological structure were regarded as the most promising candidates for practical applications in the field of optoelectronic materials. Dendronized hyperbranched polymers (DHPs), a new type of polymers with dendritic structures, proposed and named by us recently, demonstrated interesting properties and some advantages over other polymers. Some of our work concerning these two types of polymers are presented herein, especially focusing on the design idea and structure-property relationship. To enhance their comprehensive NLO performance, dendrimers were designed and synthesized by adjusting their isolation mode, increasing the number of the dendritic generation, modifying their topological structure, introducing isolation chromophores, and utilizing the Ar-ArF self-assembly effect. To make full use of the advantages of both the structural integrity of dendrimers and the convenient one-pot synthesis of hyperbranched polymers, DHPs were explored by utilizing low-generation dendrons as big monomers to construct hyperbranched polymers. These selected works could provide valuable information to deeply understand the relationship between the structure and properties of functional polymers with dendritic structures, but not only limited to the NLO ones, and might contribute much to the further development of functional polymers with rational design. PMID- 27456215 TI - Biocompatibility of a Self-Assembled Crosslinkable Hyaluronic Acid Nanogel. AB - Hyaluronic acid nanogel (HyA-AT) is a redox sensitive crosslinkable nanogel, obtained through the conjugation of a thiolated hydrophobic molecule to the hyaluronic acid chain. Engineered nanogel was studied for its biocompatibility, including immunocompatibility and hemocompatability. The nanogel did not compromise the metabolic activity or cellular membrane integrity of 3T3, microvascular endothelial cells, and RAW 264.7 cell lines, as determined by the 3 [4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase release assays. Also, we didn't observe any apoptotic effect on these cell lines through the Annexin V-FITC test. Furthermore, the nanogel cell internalization was analyzed using murine bone marrow derived macrophages, and the in vivo and ex vivo biodistribution of the Cy5.5 labeled nanogel was monitored using a non-invasive near-infrared fluorescence imaging system. The HyA AT nanogel exhibits fairly a long half-live in the blood stream, thus showing potential for drug delivery applications. PMID- 27456216 TI - Aristotle for nursing. AB - : This article aims: (1) to introduce the wider philosophy of Aristotle to nurses and healthcare practitioners; (2) to show that Aristotle's philosophical system is an interdependent whole; and (3) to defend its plausibility and usefulness despite its ancient and alien origins. Aristotle's system can be set out as a hierarchy, with metaphysics at the top and methodology running throughout. Beneath metaphysics are the sciences, with theoretical, practical and productive (or craft) sciences in hierarchical order. This hierarchy does not imply that, say, metaphysics is superior to biology or nursing, but rather that metaphysics can be understood without reference to the other two but, as we shall see, not vice versa. Two themes run through Aristotelian philosophy. The first is Aristotle's method of inquiry, central to which is that our starting point is not pure empirical data, but rather current puzzles; complementing this method is a realist philosophy. The second theme is teleology, the understanding of action in the world in terms of ends, as when we say a plant grows roots to reach water and nutrients. IMPLICATIONS FOR NURSING: Good health is the good functioning of the material aspect of humans; flourishing is good functioning of humans per se. The goals of nursing, which are based on health, are subsumed by the overall human goal of flourishing, and this helps us to understand and set boundaries to health care. Two examples illustrate this. The first is that mental illness is strongly within the purview of nursing and health care whereas bad decisions, such as smoking, are only marginally so. The second is ethics, where it is argued that the attempt to describe ethical decision-making as in addition to and separate from the decisions made within nursing and health care itself cannot be sustained. PMID- 27456217 TI - Time domain parameters of heart rate variability in children born as small-for gestational age. AB - According to metabolic programming theory, small-for-gestational age patients are at high risk of cardiovascular diseases also because of the possible malfunction of the autonomic nervous system. Autonomic disorders can be assessed by heart rate variability. The aims of this study were to compare time domain parameters of heart rate variability in children born as small-for-gestational age and appropriate-for-gestational age and to assess the correlation of the postnatal and current somatic parameters with the time domain parameters. The small-for gestational age group consisted of 68 children aged 5-10 years who were born with birth weight below the 10th percentile. The appropriate-for-gestational age group consisted of 30 healthy peers, matched in terms of gender and age. On the basis of Holter monitoring, slightly higher average heart rate was observed in the small-for-gestational age group than in the appropriate-for-gestational age group. It was found that all the time domain parameters (SDNN, SDNNi, SDANNi, rMSSD, pNN50) were lower in the small-for-gestational age group than in the appropriate-for-gestational age group. In the small-for-gestational age group, girls had lower heart rate and some of the heart rate variability parameters (SDNN, SDNNi, SDANNi) in comparison with boys. Children born as small-for gestational age have impaired function of the autonomic nervous system. Moreover, in the small-for-gestational age group, autonomic balance moved towards the sympathetic component, which was evidenced by higher heart rate. Children with faster heart rate and lower heart rate variability parameters may be at risk of cardiovascular disease. PMID- 27456218 TI - Is a reproduction number of one a threshold for Plasmodium falciparum malaria elimination? AB - BACKGROUND: The basic reproduction number (R 0) is an important summary of the dynamics of an infectious disease. It is a threshold parameter: an infection can only invade a population if R 0 is greater than 1. However, a number of studies using simple models have suggested that for malaria, it is in theory possible for infection to persist indefinitely even if an intervention has reduced R 0 below 1. Such behaviour is known as a bistable equilibrium. Using two published mathematical models which have both been fitted to detailed, age-stratified data on multiple outcomes, the article investigates whether these more complex models behave in such a way, and hence whether a bistable equilibrium might be a real feature of Plasmodium falciparum malaria in Africa. RESULTS: With the best fitting parameter values, neither model has a bistable state, because immunity reduces onwards infectiousness. The results imply that there is a threshold such that if interventions can reduce transmission so that R 0 is below 1 for long enough, then malaria will be locally eliminated. CONCLUSIONS: This means that calculations of the reduction in R 0 that interventions can achieve (the effect size) have a useful and straightforward interpretation, whereas if the theoretical possibility of a bistable equilibrium were the real behaviour, then such effect size calculations would not have a clear interpretation. PMID- 27456219 TI - Coefficient of restitution mediated by a diamagnetic interaction. AB - We study how a magnetic bead bounces onto a horizontal diamagnetic conducting plane. The bead, falling down by gravity from a certain height, produces an Eddy current that creates a repelling force. For low velocities the bead is trapped by the surface, for intermediate ones it escapes. In such a case the induced current changes its sign, and so does the force. The balance between diamagnetic and viscoelastic interactions determines the bouncing dynamics. We find experimentally the restitution coefficient as a function of the impact speed of the bead and develop, taking into account simple energetic considerations, a model able to reproduce our findings. PMID- 27456220 TI - Loss of malic enzymes leads to metabolic imbalance and altered levels of trehalose and putrescine in the bacterium Sinorhizobium meliloti. AB - BACKGROUND: Malic enzymes decarboxylate the tricarboxylic acid (TCA) cycle intermediate malate to the glycolytic end-product pyruvate and are well positioned to regulate metabolic flux in central carbon metabolism. Despite the wide distribution of these enzymes, their biological roles are unclear in part because the reaction catalyzed by these enzymes can be by-passed by other pathways. The N2-fixing alfalfa symbiont Sinorhizobium meliloti contains both a NAD(P)-malic enzyme (DME) and a separate NADP-malic enzyme (TME) and to help understand the role of these enzymes, we investigated growth, metabolomic, and transcriptional consequences resulting from loss of these enzymes in free-living cells. RESULTS: Loss of DME, TME, or both enzymes had no effect on growth with the glycolytic substrate, glucose. In contrast, the dme mutants, but not tme, grew slowly on the gluconeogenic substrate succinate and this slow growth was further reduced upon the addition of glucose. The dme mutant strains incubated with succinate accumulated trehalose and hexose sugar phosphates, secreted malate, and relative to wild-type, these cells had moderately increased transcription of genes involved in gluconeogenesis and pathways that divert metabolites away from the TCA cycle. While tme mutant cells grew at the same rate as wild-type on succinate, they accumulated the compatible solute putrescine. CONCLUSIONS: NAD(P)-malic enzyme (DME) of S. meliloti is required for efficient metabolism of succinate via the TCA cycle. In dme mutants utilizing succinate, malate accumulates and is excreted and these cells appear to increase metabolite flow via gluconeogenesis with a resulting increase in the levels of hexose-6 phosphates and trehalose. For cells utilizing succinate, TME activity alone appeared to be insufficient to produce the levels of pyruvate required for efficient TCA cycle metabolism. Putrescine was found to accumulate in tme cells growing with succinate, and whether this is related to altered levels of NADPH requires further investigation. PMID- 27456221 TI - Effectiveness of Short-Term Dynamic Group Psychotherapy in Primary Care for Patients with Depressive Symptoms. AB - : An open prospective controlled study was designed to compare the efficacy of short-term dynamic group psychotherapy with the standard treatment in patients with depressive symptoms attended in the primary care setting. A total of 115 patients with depressive symptoms were assigned to receive psychotherapy (75 min) over 9 months (37 to 39 sessions) (n = 70) or the standard care (n = 45). Outcome measures were the differences between baseline and post-treatment in the 17-item Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HAM-A) and the Short-Form Health Survey (SF-12) questionnaire in the two study groups. At the end of dynamic group psychotherapy, statistically significant improvements in the mean scores of all questionnaires were observed, whereas in control patients, significant improvements were only observed in the HDRS-17 scale and in the Mental Component Summary score of the SF-12. The mean changes after treatment were also higher in the psychotherapy group than in controls in all outcome measures, with statistically significant differences in the mean differences in favour of the psychotherapy group. In summary, implementation of short-term dynamic group psychotherapy run by experienced psychotherapists for patients with depressive symptoms attended in routine primary care centres is feasible and effective. (c) 2016 The Authors. Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd. KEY PRACTITIONER MESSAGE: Short-term dynamic group psychotherapy was delivered as a non-pharmacological intervention to improve depressive symptoms. Statistically significant differences as compared with a control group were observed in 17-item Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HAM-A) and the Short-Form Health Survey (SF-12) questionnaire. Implementation of short-term dynamic group psychotherapy run by experienced psychotherapists for patients with depressive symptoms attended in routine primary care centres is feasible and effective. PMID- 27456222 TI - Ca(2+) in the dorsal raphe nucleus promotes wakefulness via endogenous sleep-wake regulating pathway in the rats. AB - Serotonergic neurons in the dorsal raphe nucleus (DRN) are involved in the control of sleep-wake states. Our previous studies have indicated that calcium (Ca(2+)) modulation in the DRN plays an important role in rapid-eye-movement sleep (REMS) and non-REMS (NREMS) regulation during pentobarbital hypnosis. The present study investigated the effects of Ca(2+) in the DRN on sleep-wake regulation and the related neuronal mechanism in freely moving rats. Our results showed that microinjection of CaCl2 (25 or 50 nmol) in the DRN promoted wakefulness and suppressed NREMS including slow wave sleep and REMS in freely moving rats. Application of CaCl2 (25 or 50 nmol) in the DRN significantly increased serotonin in the DRN and hypothalamus, and noradrenaline in the locus coeruleus and hypothalamus. Immunohistochemistry study indicated that application of CaCl2 (25 or 50 nmol) in the DRN significantly increased c-Fos expression ratio in wake-promoting neurons including serotonergic neurons in the DRN, noradrenergic neurons in the locus coeruleus, and orxinergic neurons in the perifornical nucleus, but decreased c-Fos expression ratio of GABAergic sleep promoting neurons in the ventrolateral preoptic nucleus. These results suggest that Ca(2+) in the DRN exert arousal effects via up-regulating serotonergic functions in the endogenous sleep-wake regulating pathways. PMID- 27456223 TI - Time-constrained mother and expanding market: emerging model of under-nutrition in India. AB - BACKGROUND: Persistent high levels of under-nutrition in India despite economic growth continue to challenge political leadership and policy makers at the highest level. The present inductive enquiry was conducted to map the perceptions of mothers and other key stakeholders, to identify emerging drivers of childhood under-nutrition. METHODS: We conducted a multi-centric qualitative investigation in six empowered action group states of India. The study sample included 509 in depth interviews with mothers of undernourished and normal nourished children, policy makers, district level managers, implementer and facilitators. Sixty six focus group discussions and 72 non-formal interactions were conducted in two rounds with primary caretakers of undernourished children, Anganwadi Workers and Auxiliary Nurse Midwives. RESULTS: Based on the perceptions of the mothers and other key stakeholders, a model evolved inductively showing core themes as drivers of under-nutrition. The most forceful emerging themes were: multitasking, time constrained mother with dwindling family support; fragile food security or seasonal food paucity; child targeted market with wide availability and consumption of ready-to-eat market food items; rising non-food expenditure, in the context of rising food prices; inadequate and inappropriate feeding; delayed recognition of under-nutrition and delayed care seeking; and inadequate responsiveness of health care system and Integrated Child Development Services (ICDS). The study emphasized that the persistence of child malnutrition in India is also tied closely to the high workload and consequent time constraint of mothers who are increasingly pursuing income generating activities and enrolled in paid labour force, without robust institutional support for childcare. CONCLUSION: The emerging framework needs to be further tested through mixed and multiple method research approaches to quantify the contribution of time limitation of the mother on the current burden of child under-nutrition. PMID- 27456224 TI - Self-assembly Controls Self-cleavage of HHR from ASBVd (-): a Combined SANS and Modeling Study. AB - In the Avocado Sunblotch Viroid (ASBVd: 249-nt) from the Avsunviroidae family, a symmetric rolling-circle replication operates through an autocatalytic mechanism mediated by hammerhead ribozymes (HHR) embedded in both polarity strands. The concatenated multimeric ASBVd (+) and ASBVd (-) RNAs thus generated are processed by cleavage to unit-length where ASBVd (-) self-cleaves with more efficiency. Absolute scale small angle neutron scattering (SANS) revealed a temperature dependent dimer association in both ASBVd (-) and its derived 79-nt HHR (-). A joint thermodynamic analysis of SANS and catalytic data indicates the rate determining step corresponds to the dimer/monomer transition. 2D and 3D models of monomeric and dimeric HHR (-) suggest that the inter-molecular contacts stabilizing the dimer (between HI and HII domains) compete with the intra molecular ones stabilizing the active conformation of the full-length HHR required for an efficient self-cleavage. Similar competing intra- and inter molecular contacts are proposed in ASBVd (-) though with a remoter region from an extension of the HI domain. PMID- 27456225 TI - Quantifying the influence of small omnivorous fishes on seagrass epiphyte load. AB - The influence of two cryptic, seagrass-inhabiting omnivorous fishes, the fan bellied leatherjacket Monacanthus chinensis and the variable sabretoothed blenny Petroscirtes variabilis, on seagrass epiphyte biomass are described. Overall, M. chinensis significantly reduced epiphyte biomass by 35.1% after 18 h in experimental aquaria, whilst P. variabilis showed a non-significant 15.7% reduction. It is concluded that some cryptic omnivorous species play an important role in epiphyte removal in seagrass beds. PMID- 27456226 TI - International Prostate Symptom Score Should Be Considered a Complement Rather Than a Substitute to Generic Preference-Based Measures for Measuring Lower Urinary Tract Symptoms Within Economic Evaluation. AB - OBJECTIVE: To determine the suitability of using the International Prostate Symptom Score (IPSS), a condition-specific instrument, within economic evaluation of lower urinary tract symptom (LUTS) interventions. METHODS: Data were obtained from a cohort of 2236 community-dwelling Australian men. Using correlations and a modified Bland-Altman plot, we investigated the convergent validity of the IPSS with two generic quality of life (GQol) instruments: the Assessment of Quality of Life 4 Dimensions (AQoL-4D) and the Short-Form 36 (SF-36). Discriminant validity was investigated using Wilcoxon-Mann-Whitney and Kruskal-Wallis tests, comparing instrument scores and utilities between subgroups varying in age, marital status, history of illness, smoking status and self-assessed general health. RESULTS: Discriminant validity was confirmed for all instruments by finding statistically significant differences in summary scores and utilities between nearly all subgroups. Convergent validity between the summary scores/utilities of the IPSS and the GQoL instruments was weak (absolute correlation value range, 0.11-0.23) but differed considerably between dimensions of the instruments (absolute correlation value range, 0.01-0.24). Weak to moderate correlation between the GQoL instruments was seen (absolute correlation value range, 0.01-0.49). CONCLUSION: Our findings suggest that the IPSS has comparable discriminant validity to the GQoL instruments and therefore useful for assessing subgroup differences related to urinary symptoms. The weak convergence between the IPSS and the GQoL instruments however suggests that, within economic evaluation, the IPSS should be viewed as a complement rather than a substitute to the GQoL instruments because it captures different quality of life constructs. PMID- 27456227 TI - Mental Health and Its Associated Factors Among North Korean Defectors Living in South Korea. AB - This study aimed to compare current mental health status between North Korean defectors and South Korean natives. The proportions of depression/anxiety and the experience of suicidal ideation from 593 North Korean defectors were compared with South Koreans (n = 2372). Logistic regression analyses were conducted to determine the associated variables. As a result, the rates of depression/anxiety and suicidal ideation were significantly higher among North Korean defectors. North Koreans also had more than twice the number of escape attempts associated with high rates of depression/anxiety, and being female and single, longer durations of stay abroad, more than twice the number of escape attempts, and longer durations after entrance to South Korea were related to high rates of suicidal ideation. From these results, additional efforts are needed to identify the North Korean defectors who are at high risk for poor mental health and to provide appropriate medical services and social support. PMID- 27456228 TI - Development and characterization of microsatellite markers in the African forest elephant (Loxodonta cyclotis). AB - BACKGROUND: African elephants comprise two species, the savanna elephant (Loxodonta africana) and the forest elephant (L. cyclotis), which are distinct morphologically and genetically. Forest elephants are seriously threatened by poaching for meat and ivory, and by habitat destruction. However, microsatellite markers have thus far been developed only in African savanna elephants and Asian elephants, Elephas maximus. The application of microsatellite markers across deeply divergent lineages may produce irregular patterns such as large indels or null alleles. Thus we developed novel microsatellite markers using DNA from two African forest elephants. FINDINGS: One hundred microsatellite loci were identified in next generation shotgun sequences from two African forest elephants, of which 53 were considered suitable for testing. Twenty-three microsatellite markers successfully amplified elephant DNA without amplifying human DNA; these were further characterized in 15 individuals from Lope National Park, Gabon. Three of the markers were monomorphic and four of them carried only two alleles. The remaining sixteen polymorphic loci carried from 3 to 8 alleles, with observed heterozygosity ranging from 0.27 to 0.87, expected heterozygosity from 0.40 to 0.86, and the Shannon diversity index from 0.73 to 1.86. Linkage disequilibrium was not detected between loci, and no locus deviated from Hardy Weinberg equilibrium. CONCLUSIONS: The markers developed in this study will be useful for genetic analyses of the African forest elephant and contribute to their conservation and management. PMID- 27456230 TI - Erratum: Divergent activity of the gonadotropin-releasing hormone receptor gene promoter among genetic lines of pigs is partially conferred by nuclear factor (NF)-kB, specificity protein (SP)1-like and GATA-4 binding sites. PMID- 27456229 TI - Predictive value of vrk 1 and 2 for rectal adenocarcinoma response to neoadjuvant chemoradiation therapy: a retrospective observational cohort study. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) followed by surgical resection is the standard therapy for locally advanced rectal cancer. However, tumor response following NACRT varies, ranging from pathologic complete response to disease progression. We evaluated the kinases VRK1 and VRK2, which are known to play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis, and as such are potential predictors of tumor response and may aid in identifying patients who could benefit from NACRT. METHODS: Sixty-seven pretreatment biopsies were examined for VRK1 and VRK2 expression using tissue microarrays. VRK1 and VRK2 Histoscores were combined by linear addition, resulting in a new variable designated as "composite score", and the statistical significance of this variable was assessed by univariate and multivariate logistic regression. The Hosmer-Lemeshow goodness-of-fit test and area under the ROC curve (AUC) analysis were carried out to evaluate calibration and discrimination, respectively. A nomogram was also developed. RESULTS: Univariate logistic regression showed that tumor size as well as composite score were statistically significant. Both variables remained significant in the multivariate analysis, obtaining an OR for tumor size of 0.65 (95 % CI, 0.45 0.94; p = 0.021) and composite score of 1.24 (95 % CI, 1.07-1.48; p = 0.005). Hosmer-Lemeshow test showed an adequate model calibration (p = 0.630) and good discrimination was also achieved, AUC 0.79 (95 % CI, 0.68-0.90). CONCLUSIONS: This study provides novel data on the role of VRK1 and VRK2 in predicting tumor response to NACRT, and we propose a model with high predictive ability which could have a substantial impact on clinical management of locally advanced rectal cancer. PMID- 27456231 TI - Convergence of a diabetes mellitus, protein energy malnutrition, and TB epidemic: the neglected elderly population. AB - BACKGROUND: On a global scale, nearly two billion persons are infected with Mycobacterium tuberculosis. From this vast reservoir of latent tuberculosis (TB) infection, a substantial number will develop active TB during their lifetime, with some being able to transmit TB or Multi-drug- resistant (MDR) TB to others. There is clinical evidence pointing to a higher prevalence of infectious diseases including TB among individuals with Diabetes Mellitus (DM). Furthermore, ageing and diabetes mellitus may further aggravate protein-energy malnutrition (PEM), which in turn impairs T-lymphocyte mediated immunologic defenses, thereby increasing the risk of developing active TB and compromising TB treatment. This article aims to a) highlight synergistic mechanisms associated with immunosenescence, DM and PEM in relation to the development of active TB and b) identify nutritional, clinical and epidemiological research gaps. METHODS: To explore the synergistic relationship between ageing, DM, tuberculosis and PEM, a comprehensive review was undertaken. The MEDLINE and the Google Scholar databases were searched for articles published from 1990 to March 2015, using different MESH keywords in various combinations. RESULTS: Ageing and DM act synergistically to reduce levels of interferon gamma (IFN- gamma), thereby increasing susceptibility to TB, for which cell mediated immunity (CMI) plays an instrumental role. These processes can set in motion a vicious nutritional cycle which can predispose to PEM, further impairing the CMI and consequently limiting host defenses. This ultimately transforms the latent TB infection into active disease. A clinical diagnostic algorithm and clinical guidelines need to be established for this population. CONCLUSION: Given the increase in ageing population with DM and PEM, especially in resource-poor settings, these synergistic tripartite interactions must be examined if a burgeoning TB epidemic is to be averted. Implementation of a comprehensive, all-encompassing approach to curb transmission is clearly indicated. To this end, clinical, nutritional and epidemiological research gaps must be addressed without a delay. PMID- 27456234 TI - Tale of a Tape. PMID- 27456232 TI - Vitamin D intervention in preschoolers with viral-induced asthma (DIVA): a pilot randomised controlled trial. AB - BACKGROUND: Trials in school-aged children suggest vitamin D supplementation reduces asthma exacerbations. Primary aim: to examine whether vitamin D3 (100,000 IU) rapidly raises serum 25-hydroxyvitamin D (25OHD) >=75 nmol/L in asthmatic preschoolers. METHODS: In a double-blind, randomised, placebo-controlled trial, preschool-aged children with asthma received 100,000 IU vitamin D3 (intervention) or placebo (control), followed by 400 IU vitamin D3 daily for 6 months. Serum 25OHD was measured at baseline, 10 days, 3 and 6 months. Outcomes included the group difference in 25OHD change from baseline at 3 months (Delta25OHD); the proportion of children with 25OHD >=75 nmol/L at 3 months; the pattern in serum vitamin D over 6 months; the proportion of children with hypercalciuria at any time point (safety); and group rates for oral corticosteroids. Continuous outcomes were analysed using generalised linear mixed models and group rate ratios of events per child were assessed using a Poisson distribution model. RESULTS: Twenty-two children were randomised (intervention:11; control:11) during winter. At 3 months, the group difference in Delta25OHD (7.2 nmol/L; 95 % CI: 13.7, 28.1) was not significant; yet, 100 % versus 54.5 % (intervention versus control) had serum 25OHD >=75 nmol/L. There was a significant group difference in Delta25OHD at 10 days (110.3 nmol/L; 95 % CI: 64.0, 156.6). One child in each group had transient hypercalciuria at 10 days. Group oral corticosteroids rates were 0.82 and 1.18/child, intervention versus control (rate ratio = 0.68; 95 % CI: 0.30, 1.62; non-significant). CONCLUSIONS: Following 100,000 IU vitamin D3, all children reached serum 25OHD >=75 nmol/L, compared with half who received placebo. Daily supplementation, sun exposure and insufficient power may explain the absence of a significant 3-month group difference in Delta25OHD. No clinically important alterations in bone metabolism biomarkers occurred. Group oral corticosteroid rates will inform sample size calculations for the larger trial. ( NCT01999907 , 25 November 2013). PMID- 27456233 TI - Pathways to potentially preventable hospitalizations for diabetes and heart failure: a qualitative analysis of patient perspectives. AB - BACKGROUND: Potentially preventable hospitalizations (PPH) for heart failure (HF) and diabetes mellitus (DM) cost the United States over $14 billion annually. Studies about PPH typically lack patient perspectives, especially across diverse racial/ethnic groups with known PPH health disparities. METHODS: English-speaking individuals with a HF or DM-related PPH (n = 90) at the largest hospital in Hawai'i completed an in-person interview, including open-ended questions on precipitating factors to their PPH. Using the framework approach, two independent coders identified patient-reported factors and pathways to their PPH. RESULTS: Seventy-two percent of respondents were under 65 years, 30 % were female, 90 % had health insurance, and 66 % had previously been hospitalized for the same problem. Patients' stories identified immediate, precipitating, and underlying reasons for the admission. Underlying background factors were critical to understanding why patients had the acute problems necessitating their hospitalizations. Six, non-exclusive, underlying factors included: extreme social vulnerability (e.g., homeless, poverty, no social support, reported by 54 % of respondents); health system interaction issues (e.g., poor communication with providers, 44 %); limited health-related knowledge (42 %); behavioral health issues (e.g., substance abuse, mental illness, 36 %); denial of illness (27 %); and practical problems (e.g., too busy, 6 %). From these findings, we developed a model to understand an individual's pathways to a PPH through immediate, precipitating, and underlying factors, which could help identify potential intervention foci. We demonstrate the model's utility using five examples. CONCLUSIONS: In a young, predominately insured population, factors well outside the traditional purview of the hospital, or even clinical medicine, critically influenced many PPH. Patient perspectives were vital to understanding this issue. Innovative partnerships and policies should address these issues, including linkages to social services and behavioral health. PMID- 27456235 TI - Empathy as a Diagnostic Tool in a 33-Year-Old Man with Eye Pain and Vision Loss: Exercises in Clinical Reasoning. PMID- 27456236 TI - Pain Medication & Regulation: It Is Personal. PMID- 27456237 TI - Capsule Commentary on Uittenbroek et al., Integrated Care for Older Adults Improves Perceived Quality of Care: Results of a Randomized Controlled Trial of Embrace. PMID- 27456238 TI - Effect of patient age awareness on diagnostic agreement of chronic or aggressive periodontitis between clinicians; a pilot study. AB - BACKGROUND: The aim of this pilot study was to test whether diagnostic agreement of aggressive and chronic periodontitis amongst Board Certified Periodontists, is influenced by knowledge of a patient's age. In 1999 at the International World Workshop age was removed as a diagnostic criteria for aggressive periodontitis. The impact of this change on the diagnostic reliability amongst clinicians has not yet been assessed. METHODS: Nine periodontal case reports were twice presented to sixteen board certified periodontists, once with age withheld and again with patient age provided. Participants were instructed to choose a diagnosis of Chronic Periodontitis or Aggressive Periodontitis. Diagnostic agreement was calculated using the Fleiss Kappa test. RESULTS: Including the patients' age in case report information increased diagnostic agreement (the kappa statistic) from 0.49 (moderate agreement) to 0.61 (substantial agreement). CONCLUSION: These results suggest that knowledge of a patients' age influenced clinical diagnosis, when distinguishing between aggressive periodontitis and chronic periodontitis, which may in turn impact treatment decision-making. PMID- 27456239 TI - Variations in nitrate isotope composition of wastewater effluents by treatment type in Hong Kong. AB - Stable isotopes (delta(15)N, delta(18)O) can serve as tracers for sources of nitrogen in the receiving environment. Hong Kong discharges ~3*10(6)m(3)d(-1) of treated wastewater into the ocean from 68 facilities implementing preliminary to tertiary treatment. We sampled treated sewage from 18 plants across 5 treatment types and examined receiving seawater from northeast Hong Kong. We analyzed nitrate and nitrite (NO3(-)+NO2(-), hereafter NOx) ammonium (NH4(+)), phosphate (PO4(+)) concentrations and delta(15)NNOx, delta(18)ONOx. Sewage effluents contained high mean nutrient concentrations (NO3(-)=260MUmolL(-1), NH4(+)=1400MUmolL(-1), PO4(+)=50MUmolL(-1)) with some indication of nitrogen removal in advanced treatment types. Mean delta(15)NNOx of sewage effluents from all plants and treatment types (120/00) was higher than natural sources and varied spatially and seasonally. There was no overall effect of sewage treatment type on delta(15)NNOx. A mass balance model indicated that sewage (>68%) remains a dominant source of nitrate pollution in seawater in Tolo Harbor. PMID- 27456240 TI - Psychological side effects of immune therapies: symptoms and pathomechanism. AB - Immunotherapies revolutionised the treatment of several disorders but show specific side-effect profiles which frequently involve psychological symptoms. Long term interferon-alpha (IFN-alpha) therapy can cause wide-ranging psychiatric side-effects from fatigue, insomnia, anxiety to full-blown depression. This treatment-emergent depression shares several symptoms with major depressive disorder (MDD) with a predominance of somatic/neurovegetative symptoms, and can be treated with antidepressants. However, this experience directed research to inflammatory mechanisms in MDD. MDD has been confirmed as a heterogeneous disorder with a subgroup of patients suffering from low-grade chronic inflammation and frequently resistant to traditional antidepressant treatment. Thus future research should develop strategies to identify those MDD patients who could benefit from drugs acting through inflammatory pathways. PMID- 27456241 TI - Helios Should Not Be Cited as a Marker of Human Thymus-Derived Tregs. Commentary: Helios(+) and Helios(-) Cells Coexist within the Natural FOXP3(+) T Regulatory Cell Subset in Humans. PMID- 27456242 TI - Evaluation of Ceiba pentandra (L.) Gaertner bark extracts for in vitro cytotoxicity on cancer cells and in vivo antitumor activity in solid and liquid tumor models. AB - The stem bark of Ceiba pentandra (L.) Gaertner is claimed to be useful in the treatment of tumors in the southern part of India. This plant possesses a number of sesquiterpenoids and isoflavones which are known for their anticancer properties. The present study was designed to scientifically evaluate the cytotoxic potential of bark extracts in in vitro on Ehrlich ascites carcinoma (EAC), MCF-7 and B16F10 cells and in vivo in EAC (Liquid tumor) model and Dalton's lymphoma ascites (DLA or solid tumor) model. The bark was powdered and extracted successively with solvents viz., petroleum ether (PE), benzene, chloroform, acetone (AC), and ethyl alcohol in the sequential order of polarity. Cytotoxicity of dried extracts was screened on EAC cells by trypan blue assay. Three potent extracts namely petroleum ether, acetone, and ethanol were screened for their cytotoxicity on MCF-7 and B16F10 cells by MTT assay and nucleomorphological alteration by propidium iodide staining. Safe doses of these extracts were evaluated by acute toxicity study in mice. Extracts were found to be safe up to 300 mg/kg in acute toxicity study. Dosage of 1/10th and 1/20th of safe dose i.e., 15 and 30 mg/kg were selected for in vivo study. In the EAC model, both doses of the extracts showed a significant (P < 0.05) improvement in mean survival time and a maximum decline in tumor induced increase in body weight (an indirect measure of tumor weight) by the PE and AC treatment at 15 mg/kg compared to control. In the DLA-model, all extracts at both tested dose levels showed >50 % reduction in tumor weight and a significant reduction (P < 0.05) in tumor volume on the 30th day compared to control. It can be concluded that these extracts possess cytotoxic and antitumor activity. PMID- 27456243 TI - The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings. AB - Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients. PMID- 27456244 TI - Angiotensin (1-7) and Alamandine: Similarities and differences. AB - A primary peptide of the renin angiotensin system (RAS), Angiotensin (Ang) II, is a vasoconstrictor and promotor of atherosclerosis. To counter this, the RAS also consists of peptides and receptors which increase nitric oxide release from the endothelium and decrease nicotinamide adenine dinucleotide phosphate oxidase related superoxide production. Two peptides, Ang (1-7) and alamandine are vasodilators, by activating the nitric oxide pathway via different receptors in the endothelium. Thus, herein we focus on the similarities and differences between alamandine and Ang (1-7) and the counterbalancing hypothesis on Ang II during endothelial dysfunction and atherosclerosis. PMID- 27456247 TI - Invited Commentary: Meeting Our Obligation to Equal Surgical Care for All. PMID- 27456246 TI - The C-terminal extension of human telomerase reverse transcriptase is necessary for high affinity binding to telomeric DNA. AB - The ribonucleoprotein enzyme telomerase maintains telomeres and is essential for cellular immortality in most cancers. Insight into the telomerase mechanism can be gained from short telomere syndromes, in which mutation of telomerase components manifests in telomere dysfunction. We carried out detailed kinetic analyses and molecular modelling of a disease-associated mutant in the C-terminal extension of the reverse transcriptase subunit of human telomerase. The kinetic analyses revealed that the mutation substantially impacts the affinity of telomerase for telomeric DNA, but the magnitude of this impact varies for primers with different 3' ends. Molecular dynamics simulations corroborate this finding, revealing that the mutation results in greater movement of a nearby loop, impacting the DNA-RNA helix differentially with different DNA primers. Thus, the data indicate that this region is the location of one of the enzyme conformational changes responsible for the long-standing observation that off rates of telomerase vary with telomeric 3' end sequence. Our data provide a molecular basis for a disease-associated telomerase mutation, and the first direct evidence for a role of the C-terminal extension in DNA binding affinity, a function analogous to the "thumb" domain of retroviral reverse transcriptases. PMID- 27456248 TI - Multimodalities Are Useful for Secondary Treatment of Local Bleeding During Hepatic Resection. PMID- 27456249 TI - Sex-Specific Aspects of Bariatric Surgery in Iran Are Far from Understood. PMID- 27456245 TI - Sex- and structure-specific differences in antioxidant responses to methylmercury during early development. AB - Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxin, particularly hazardous to developing and young individuals. MeHg neurotoxicity during early development has been shown to be sex-dependent via disturbances in redox homeostasis, a key event mediating MeHg neurotoxicity. Therefore, we investigated if MeHg-induced changes in key systems of antioxidant defense are sex-dependent. C57BL/6J mice were exposed to MeHg during the gestational and lactational periods, modeling human prenatal and neonatal exposure routes. Dams were exposed to 5ppm MeHg via drinking water from early gestational period until postnatal day 21 (PND21). On PND21 a pair of siblings (a female and a male) from multiple (5-6) litters were euthanized and tissue samples were taken for analysis. Cytoplasmic and nuclear extracts were isolated from fresh cerebrum and cerebellum and used to determine thioredoxin (Trx) and glutathione (GSH) levels, as well as thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities. The remaining tissue was used for mRNA analysis. MeHg-induced antioxidant response was not uniform for all the analyzed antioxidant molecules, and sexual dimorphism in response to MeHg treatment was evident for TrxR, Trx and GPx. The pattern of response, namely a decrease in males and an increase in females, may impart differential and sex-specific susceptibility to MeHg. GSH levels were unchanged in MeHg treated animals and irrespective of sex. Trx was reduced only in nuclear extracts from male cerebella, exemplifying a structure specific response. Results from the gene expression analysis suggest posttranscriptional mechanism of sex-specific regulation of the antioxidant response upon MeHg treatment. The study demonstrates for the first time sex-and structure-specific changes in the response of the thioredoxin system to MeHg neurotoxicity and suggests that these differences in antioxidant responses might impart differential susceptibility to developmental MeHg exposure. PMID- 27456250 TI - Evaluating the Outcomes of Operative vs Nonoperative Management of Pediatric Blunt Pancreatic Trauma. PMID- 27456251 TI - A Subset of Patients with Blunt Pancreatic Injury Can Be Managed Nonoperatively with Acceptable Outcomes: In reply to Linnaus and Notrica. PMID- 27456252 TI - Routine or Selective Opioid Antagonist for Enhanced Bowel Recovery after Surgery. PMID- 27456253 TI - Alvimopan Use, Outcomes, and Costs: In reply to Fujita. PMID- 27456254 TI - The Dead End of Current Research on Burnout Prevalence. PMID- 27456255 TI - On Surgeon Burnout: In reply to Bianchi and colleagues. PMID- 27456257 TI - Correction. PMID- 27456258 TI - Correction. PMID- 27456259 TI - [Guidelines for stage I to III melanoma]. PMID- 27456260 TI - [Detection and evaluation of malnutrition in oncology: What tools, what type of cancer and for what purposes?]. AB - Malnutrition is frequently observed in oncology. The consequences on patient survival, chemotherapy toxicities and quality of life need to be identified and treated appropriately. A set of tools are available that enable clinicians to diagnose and detect malnutrition. Each tool must consider three items: the patient's current nutritional status, reduced food intake and the characteristics of the underlying disease. The parameters and thresholds used to detect malnutrition differ according to the objective pursued. It can be economic, increasing the reimbursement of hospital stays, it can help define prognostic risk groups or its purpose can be to initiate nutritional treatment. Recent data support the assessment of parameters such as inflammatory markers, decreased muscle mass (i.e. sarcopenia) whose diagnosis is associated with a worse outcome and the quantification of food intake with simplified methods. The benefit for the patient of detecting malnutrition will be the initiation of a nutritional treatment when its efficacy has been demonstrated. A case in point is the nutritional support provided to malnourished patients before surgery with benefits in terms of mortality and morbidity and in certain head and neck cancer situations where nutritional support is systematically implemented. It is probably relevant to detect and initiate treatment early in order to promote muscle anabolism. PMID- 27456261 TI - Targeted multiple biomarker approach in predicting cardiovascular events in patients with diabetes. AB - OBJECTIVE: We hypothesised that biomarkers representing different pathophysiological pathways of atherosclerosis namely growth differentiation factor 15 (GDF-15), N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TnT) could enhance cardiovascular risk prediction in patients with type 2 diabetes mellitus. METHODS: This is a prospective study in 746 patients with type 2 diabetes mellitus, who were followed up for 60 months. The primary endpoint was defined as unplanned hospitalisation for cardiovascular disease or death. The prognostic performance of the biomarkers of interest (GDF-15 in comparison with NT-proBNP and hs-TnT) was evaluated in univariate as well as in stepwise Cox regression models. HRs are presented per standard unit increase. RESULTS: The primary endpoint was registered in 171 patients (22.9%). In univariate Cox regression models, GDF-15 as well as hs-TnT provided significant prognostic information. Even after adjusting for established cardiovascular risk factors, GDF-15, hs-TnT and NT-proBNP remained strong independent predictors of the endpoint (logGDF-15: HR 1.37, p<0.01, CI 1.12 to 1.68; loghs-TnT: HR 1.43, p<0.01, CI 1.13 to 1.1.82; logNT-proBNP: HR 1.45, p<0.01, CI 1.26 to 1.66). The number of elevated markers showed a strong complementarity to predict future long-term risk. Adding hs-TnT and GDF-15 to a zero model already including NT-proBNP led to a net reclassification improvement (NRI) of 33.6% (CI 16.0% to 50.8%, NRI for patients with event: 11.1% CI -4.7% to 26.6%, for patients without event: 22.5% CI 13.6% to 30.5%). CONCLUSIONS: GDF-15 and hs-TnT are strong independent cardiovascular biomarkers augmenting the predictive value of NT-proBNP in patients with diabetes. PMID- 27456262 TI - Acute Toxicity Associated with Use of 5F-Derivations of Synthetic Cannabinoid Receptor Agonists with Analytical Confirmation. AB - INTRODUCTION: Synthetic Cannabinoid Receptor Agonists (SCRAs) are the largest group of new psychoactive substances reported to the European Warning System and the United Nations Office on Drugs and Crime to date. The heterogeneous nature and speed of diversification of these compounds make it challenging to accurately characterise and predict harms of these compounds in pre-clinical studies, ahead of their appearance. CASE REPORT: We report the case of a 19-year-old female who purchased three products from a headshop: two new psychoactive substances (sachets of "cannabis tea" and "mushroom tea") as well as two LSD blotters. After the "cannabis tea" was smoked and the two LSD blotters and "mushroom tea" were ingested, the patient became tachycardic (HR 128), developed seizures, agitation, visual hallucinations as well as suspected serotonergic toxicity (sustained ankle clonus 20-30 beats) 1-2 hours after use. She was treated with 1 mg of intravenous midazolam. Symptoms/signs resolved within 13 hours. No further supportive care was required. Plasma, blood, and urine samples confirmed the presence of two SCRAs: 5FAKB-48 and 5F-PB-22. The patient also reported therapeutic use of both fluoxetine and citalopram for depression. DISCUSSION: To the best of our knowledge, this is the first case report of non-fatal intoxication with 5F-AKB-48 with analytical confirmation and exposure times. It also highlights the difficulties in understanding the pattern of toxicity of certain SCRAs in the context of psychotropic medications/co-morbid mental illness. PMID- 27456264 TI - Articles You May Have Missed. PMID- 27456263 TI - Single Versus Multiple Hyperbaric Sessions for Carbon Monoxide Poisoning in a Murine Model. AB - Hyperbaric oxygen (HBO) has been advocated for treatment of acute carbon monoxide (CO) poisoning. There exists considerable debate as to whether HBO prevents delayed neurologic sequelae (DNS) due to CO poisoning. Additionally, existing data in the literature supporting HBO efficacy do not identify an optimal number of HBO treatments. We sought to determine in a mouse model whether there is a difference between one versus multiple HBO sessions for the prevention of DNS. Fifty mice were randomized into five groups of ten mice each: (1) control, receiving no CO exposure or treatment; (2) CO poisoned, receiving no treatment (CO group); (3) CO poisoned, receiving normobaric oxygen for 58 min following the end of exposure (CO + NBO group); (4) CO poisoned, followed by one session of HBO(CO + HBO1); and (5) CO poisoned, followed by three HBO treatment sessions, one every 6 h (CO + HBO3). Prior to poisoning, all animals were trained in step down latency (SDL) and step-up latency (SUL) tasks. One week after exposure and treatment, all five groups were retested to evaluate the retention of this training. There was no difference detected among groups in SDL (p = 0.67 among all groups) when evaluated using a Kruskal-Wallis test. There was a significant difference among groups in SUL (p = 0.027 among all groups) when evaluated using a Kruskal-Wallis test. When individual groups were compared using a Wilcoxon signed-rank test with Bonferroni correction, there were no statistically significant differences in either SDL or SUL. There was no difference between groups treated with either one or three HBO sessions. One possibility to explain this might be that HBO sessions administered some time after a CO exposure may enhance the lipid peroxidation cascade and worsen neurologic outcomes; alternatively, HBO may simply impart no benefit when compared to NBO. PMID- 27456265 TI - Loose-fitting radial head prosthesis replacement for treatment of comminuted fracture of the radial head. AB - BACKGROUND: We investigated the curative effects of using loose-fitting radial head prosthesis replacement to treat unstable comminuted fracture of radial head. METHODS: From January 2010 to August 2012, radial head prosthesis replacement was used to treat eight cases of Mason's type III or IV radial head fractures. Three cases were in left side and 5 cases were in right side. Using the Mason criteria, 6 cases were classified as type III and 2 cases as type IV. All patients had fresh fractures. Operations were scheduled after swelling was subsided and we monitored all cases for 12 to 20 months. RESULTS: According to the Mayo evaluation criteria, we had excellent results in 5 cases, and good results in 3 cases. No infection, no heterotopic ossification, and no nerve injuries were observed in these cases. No symptoms of nerve injury were detected. Flexion and extension of elbow joint was from 20 degrees to 100 degrees (average=70.6 degrees ). Forearm pronation was from 0 degrees to 70 degrees (average=53.8 degrees ); supination was from 0 to 60 degrees (average=35 degrees ). CONCLUSIONS: We concluded that treatment of comminuted radial head fractures with loose-fitting radial head prosthesis replacement produced satisfactory results. PMID- 27456266 TI - A single mutation Gln142Lys doubles the catalytic activity of VPR, a cold adapted subtilisin-like serine proteinase. AB - Structural comparisons of the cold adapted subtilase VPR and its thermophilic homologue, aqualysin I (AQUI) indicated the presence of additional salt bridges in the latter. Few of those appear to contribute significantly to thermal stability of AQUI. This includes a putative salt bridge between residues Lys142 and Glu172 as its deletion did not have any significant effect on its stability or activity (Jonsdottir et al. (2014)). Insertion of this putative salt bridge into the structure of VPR, in a double mutant (VPRDeltaC_Q142K/S172E), however was detrimental to the stability of the enzyme. Incorporation of either the Q142K or S172E mutations into VPR, were found to significantly affect the catalytic properties of the enzyme. The single mutation Q142K was highly effective, as it increased the kcat and kcat/Km more than twofold. When the Q142K mutation was inserted into a thermostabilized, but a low activity mutant of VPR (VPRDeltaC_N3P/I5P), the activity increased about tenfold in terms of kcat and kcat/Km, while retaining the stability of the mutant. Molecular dynamics simulations of the single mutants were carried out to provide structural rationale for these experimental observations. Based on root mean square fluctuation (RMSF) profiles, the two mutants were more flexible in certain regions of the structure and the Q142K mutant had the highest overall flexibility of the three enzymes. The results suggest that weakening of specific H-bonds resulting from the mutations may be propagated over some distance giving rise to higher flexibility in the active site regions of the enzyme, causing higher catalytic activity in the mutants. PMID- 27456267 TI - A decrease of ripples precedes seizure onset in mesial temporal lobe epilepsy. AB - High-frequency oscillations (HFOs) are promising biomarkers for epileptic foci; however, their characteristic changes during the preictal period remain unclear. Here, the preictal HFOs were recorded and detected by an automated HFOs detection method in the mouse pilocarpine model as well as in patients with mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy. A total of sixteen low-voltage fast (LVF) and fifty-three hypersynchronous-onset (HYP) seizures were recorded in ten mice. The rate of ripples (80-250Hz) decreased during 1min before the onset of LVF and HYP seizures, which was primarily due to the reduction of type II (independent of epileptiform discharges) rather than type I ripples (superimposed on epileptiform activities). The ripple rate decreased until 30s before HYP seizure, whereas it increased with a peak at 40s during the 1min preictal period of LVF seizures. Furthermore, the "ripple reduction" phenomenon was also observed in all twelve seizures from nine patients with mTLE but not in neocortical epilepsy. These results indicate that ripples may potentially be helpful for understanding the mechanisms of ictogenesis in mTLE, and the different modes of ripple changes during the minute before LVF and HYP seizures might also be beneficial for the diagnosis of seizure types. PMID- 27456268 TI - Accessory respiratory muscles enhance ventilation in ALS model mice and are activated by excitatory V2a neurons. AB - Inspiratory accessory respiratory muscles (ARMs) enhance ventilation when demands are high, such as during exercise and/or pathological conditions. Despite progressive degeneration of phrenic motor neurons innervating the diaphragm, amyotrophic lateral sclerosis (ALS) patients and rodent models are able to maintain ventilation at early stages of disease. In order to assess the contribution of ARMs to respiratory compensation in ALS, we examined the activity of ARMs and ventilation throughout disease progression in SOD1G93A ALS model mice at rest using a combination of electromyography and unrestrained whole body plethysmography. Increased ARM activity, accompanied by increased ventilation, is observed beginning at the onset of symptoms. However, ARM recruitment fails to occur at rest at late stages of disease, even though the same ARMs are used for other behaviors. Using a chemogenetic approach, we demonstrate that a glutamatergic class of neurons in the brainstem and spinal cord, the V2a class, is sufficient to drive increased ARM activity at rest in healthy mice. Additionally, we reveal pathology in the medial reticular formation of the brainstem of SOD1G93A mice using immunohistochemistry and confocal imaging. Both spinal and brainstem V2a neurons degenerate in ALS model mice, accompanied by regional activation of astrocytes and microglia. These results establish inspiratory ARM recruitment as one of the compensatory mechanisms that maintains breathing at early stages of disease and indicate that V2a neuron degeneration may contribute to ARM failure at late stages of disease. PMID- 27456269 TI - Transient loss of consciousness during hypercapnia and hypoxia: Involvement of pathways associated with general anesthesia. AB - Transient loss of consciousness (TLOC), frequently triggered by perturbation in essential physiological parameters such as pCO2 or O2, is considered a passive consequence of generalized degradation in high-level cerebral functioning. However, the fact that it is almost always accompanied by atonia and loss of spinal nocifensive reflexes suggests that it might actually be part of a "syndrome" mediated by neural circuitry, and ultimately be adaptive. Widespread suppression by molecules distributed in the vasculature is also the classical explanation of general anesthesia. Recent data, however, suggest that anesthesia is due, rather, to drug action at a specific brainstem locus, the mesopontine tegmental anesthesia area (MPTA), with the spectrum of anesthetic effects resulting from secondary recruitment of specific axonal pathways. If so, might the MPTA also be involved in TLOC induced by hypercapnia and hypoxia? We exposed rats to gas mixtures that provoke hypercapnia and hypoxia and asked whether cell selective lesions of the MPTA affect TLOC. Entry into TLOC, monitored as time to loss of the righting reflex (LORR) was unaffected. However, resumption of the righting reflex (RORR), and of response to pinch stimuli (ROPR), was significantly delayed. The extent of both effects correlated with the extent of damage in the MPTA, but was unrelated to damage that extended beyond the borders of the MPTA. The results implicate neurons in a specific common-core region of the MPTA in TLOC induced by both forms of asphyxia. This is the same area responsible for general anesthesia induced by GABAergic anesthetic agents. This implies the involvement of a common set of brain nuclei and dedicated axonal pathways, rather than nonspecific global suppression, in the mechanism mediating all three instances of TLOC. PMID- 27456271 TI - Neuroprosthetics and the science of patient input. AB - Safe and effective neuroprosthetic systems are of great interest to both DARPA and CDRH, due to their innovative nature and their potential to aid severely disabled populations. By expanding what is possible in human-device interaction, these devices introduce new potential benefits and risks. Therefore patient input, which is increasingly important in weighing benefits and risks, is particularly relevant for this class of devices. FDA has been a significant contributor to an ongoing stakeholder conversation about the inclusion of the patient voice, working collaboratively to create a new framework for a patient centered approach to medical device development. This framework is evolving through open dialogue with researcher and patient communities, investment in the science of patient input, and policymaking that is responsive to patient-centered data throughout the total product life cycle. In this commentary, we will discuss recent developments in patient-centered benefit-risk assessment and their relevance to the development of neural prosthetic systems. PMID- 27456272 TI - Stem cell labeling with iron oxide nanoparticles: impact of 3D culture on cell labeling maintenance. AB - AIM: We aimed to analyze the suitability of nanoparticles (M4E) for safe human mesenchymal stem cell (hMSC) labeling and determined cell labeling maintenance in 2D and 3D culture. MATERIALS & METHODS: We investigated cell-particle interaction and the particles' impact on cell viability, growth and proliferation. We analyzed cell labeling maintenance in 2D and 3D culture invasively and noninvasively. RESULTS: M4E do not affect cell viability, growth and proliferation and do not cause chromosomal aberrations. Cell labeling maintenance is up to five-times higher in 3D conditions compared with 2D culture. CONCLUSION: M4E allow safe hMSC labeling and noninvasive identification. Our hMSC-loaded, 3D tissue-engineered construct could serve as a graft for regenerative therapies, in which M4E-labeled hMSCs can migrate to their target. PMID- 27456273 TI - Morphological and molecular analyses of a new species of Saccocoelioides Szidat, 1954 (Haploporidae Nicoll, 1914) in the fat sleeper Dormitator maculatus (Bloch) (Perciformes: Eleotridae) from the Gulf of Mexico. AB - Saccocoelioides olmecae n. sp. is described from specimens recovered from the intestine of the fat sleeper Dormitator maculatus (Bloch) (Perciformes: Eleotridae) collected in six localities along the coast of the Gulf of Mexico. The new species is mainly distinguished from the other three described species of Saccocoelioides Szidat, 1954 from North and Middle America (i.e. S. sogandaresi Lumsden, 1963, S. chauhani Lamothe-Argumedo, 1974 and S. lamothei Aguirre-Macedo & Violante-Gonzalez, 2008) by having an elongated body, a sac-like caecum, a uterus that extends to the first third of body and by having vitelline follicles longitudinally elongated reaching the posterior end of the body. Sequences of the large subunit (LSU) of the ribosomal DNA, including the domain D1-D3, and the internal transcribed spacer 2 (ITS2) were used independently and concatenated to corroborate the morphological distinction among S. olmecae n. sp., S. chauhani and S. lamothei from freshwater and brackish-water fish from Middle America. The genetic divergence estimated among the three species of Saccocoelioides was very low: 1% for LSU and from 1 to 4% for ITS2. Maximum likelihood and Bayesian inference analyses for each dataset and both datasets combined revealed that S. olmecae n. sp. represents an independent clade with moderate bootstrap support and posterior probabilities. This is the third species of Saccocoelioides described in Mexico, and the 17th species from the Americas. PMID- 27456274 TI - Minimally Invasive Hernia Repair in Robot-Assisted Radical Prostatectomy. AB - Inguinal hernia is a recognized complication of radical prostatectomy. Previous hernia repair, wound infection, midline incision, low BMI, and preexisting or subclinical hernia contribute to the risk of inguinal hernia following radical prostatectomy. Concomitant hernia repair at the time of pelvic surgery has risks and benefits. Repair during surgery prevents future hernia-related complications and saves the need for an additional procedure. However, hernia repair at the time of radical prostatectomy includes the risk of mesh infection, post-operative pain, adhesions, lack of experience, and overall minimal risk with watchful waiting. The robotic transperitoneal approach is the most commonly used technique for concomitant inguinal hernia repair with a modest addition to operative time and minimal postoperative complications. Recurrence rates following concomitant hernia repair during pelvic surgery are low. PMID- 27456270 TI - Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control? AB - For most individuals, the respiratory control system produces a remarkably stable and coordinated motor output-recognizable as a breath-from birth until death. Very little is understood regarding the processes by which the respiratory control system maintains network stability in the presence of changing physiological demands and network properties that occur throughout life. An emerging principle of neuroscience is that neural activity is sensed and adjusted locally to assure that neurons continue to operate in an optimal range, yet to date, it is unknown whether such homeostatic plasticity is a feature of the neurons controlling breathing. Here, we review the evidence that local mechanisms sense and respond to perturbations in respiratory neural activity, with a focus on plasticity in respiratory motor neurons. We discuss whether these forms of plasticity represent homeostatic plasticity in respiratory control. We present new analyses demonstrating that reductions in synaptic inputs to phrenic motor neurons elicit a compensatory enhancement of phrenic inspiratory motor output, a form of plasticity termed inactivity-induced phrenic motor facilitation (iPMF), that is proportional to the magnitude of activity deprivation. Although the physiological role of iPMF is not understood, we hypothesize that it has an important role in protecting the drive to breathe during conditions of prolonged or intermittent reductions in respiratory neural activity, such as following spinal cord injury or during central sleep apnea. PMID- 27456276 TI - High-Fat Diet-Induced Obesity Enhances Allograft Rejection: Erratum. PMID- 27456275 TI - Continuous-Flow Synthesis of Biaryls by Negishi Cross-Coupling of Fluoro- and Trifluoromethyl-Substituted (Hetero)arenes. AB - A continuous-flow method for the regioselective arylation of fluoroarenes and fluoropyridines has been developed. The telescoped procedure reported here consists of a three-step metalation, zincation, and Negishi cross-coupling sequence, providing efficient access to a variety of functionalized 2 fluorobiaryl products. Precise temperature control of the metalation step, made possible by continuous-flow technology, allowed for the efficient preparation of the arylated products in high yields and short residence times. Additionally, several examples of the regioselective arylation of benzotrifluoride derivatives are also provided. PMID- 27456277 TI - A novel three-dimensional print of liver vessels and tumors in hepatectomy. AB - Creating a three-dimensional (3D)-printed liver model is costly, and the visibility of the inner structures is slightly hindered. We developed a novel structure that simultaneously solves both of these problems. The outer frames were set up along the liver surface. Our structure did not use the transparent loading material because this material increases the printing cost. Therefore, we were able to directly observe the inside of the structure. We performed hepatectomy using this novel 3D-printed liver model. Using this model, we were able to clearly simulate the resection line and safely perform the surgery. Our process was more cost effective, had a shorter production time, and improved the visibility than other processes. We developed a novel 3D-printed liver for hepatectomy, which made the procedure easier, reduced the production cost, and improved the visibility; this approach may be useful for future surgeries. PMID- 27456278 TI - Synthesis, characterization and multifunctional properties of plasmonic Ag-TiO2 nanocomposites. AB - We report on the synthesis of multifunctional Ag-TiO2 nanocomposites and their optical, physio-chemical, surface enhanced Raman scattering (SERS) and antibacterial properties. A series of Ag-TiO2 nanocomposites were synthesized by sol-gel technique and characterized by x-ray diffraction, scanning and transmission electron microscopy, energy-dispersed x-ray analysis, photoluminescence, UV-vis, x-ray photoelectron and Raman spectroscopy and Brunauer-Emmett-Teller method. The Ag nanoparticles (NPs) (7-20 nm) were found to be uniformly distributed around and strongly attached to TiO2 NPs. The novel optical responses of the nanocomposites are due to the strong electric field from the localized surface plasmon (LSP) excitation of the Ag NPs and decreased recombination of photo-induced electrons and holes at Ag-TiO2 interface providing potential materials for photocatalysis. The nanocomposites show enhancement in the SERS signals of methyl orange (MO) molecules with increasing Ag content attributed to the long-range electromagnetic enhancement from the excited LSP of the Ag NPs. To further understand the SERS activity, molecular mechanics and molecular dynamics simulations were used to study the geometries and SERS enhancement of MO adsorbed onto Ag-TiO2 respectively. Simulation results indicate that number of ligands (MO) that adsorb onto the Ag NPs as well as binding energy per ligand increases with increasing NP density and molecule-to-surface orientation is mainly flat resulting in strong bond strength between MO and Ag NP surface and enhanced SERS signals. The antimicrobial activity of the Ag-TiO2 nanocomposites was tested against the bacterium Staphylococcus aureus and enhanced antibacterial effect was observed with increasing Ag content explained by contact killing action mechanism. These results foresee promising applications of the plasmonic metal-semiconductor based nano-biocomposites for both chemical and biological samples. PMID- 27456279 TI - Genetic relationship between the Echinococcus granulosus sensu stricto cysts located in lung and liver of hosts. AB - G1 genotype of Echinococcus granulosus sensu stricto is the major cause of hydatidosis in Northern Africa, Tunisia included. The genetic relationship between lung and liver localization were studied in ovine, bovine and human hydatid cysts in Tunisia. Allozyme variation and single strand conformation polymorphism were used for genetic differentiation. The first cause of genetic differentiation was the host species and the second was the localization (lung or liver). The reticulated genetic relationship between the liver or the lung human isolates and isolates from bovine lung, is indicative of recombination (sexual reproduction) or lateral genetic transfer. The idea of two specialized populations (one for the lung one for the liver) that are more or less successful according to host susceptibility is thus proposed. PMID- 27456280 TI - Multilocus sequence typing of Candida tropicalis shows clonal cluster enrichment in azole-resistant isolates from patients in Shanghai, China. AB - To explore the putative correlation between the multilocus sequence types (MLST) and antifungal susceptibility of clinical Candida tropicalis isolates in Mainland China. Eighty-two clinical C. tropicalis isolates were collected from sixty-nine patients at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, from July 2012 to February 2015, and antifungal susceptibility tests were performed. Genetic profiles of those 82 isolates (30 azole-resistant and 52 azole-susceptible) were characterised by multilocus sequence typing. Phylogenetic analysis of the data was conducted with the clustering method, using UPGMA (unweighted pair group method with arithmetic averages) and the minimal spanning tree algorithm. MLST clonal clusters were analysed using the eBURST V3 package. Of the six gene fragments identified in multilocus sequence typing, SAPT4 presented the highest typing efficiency, whereas SAPT2 was the least efficient. Of the 44 diploid sequence types (DSTs) differentiated, 32 DSTs and 12 genotypes were identified as new to the C. tropicalis DST database. Twenty (45.45%) of the 44 DSTs were assigned to seven major groups based on eBURST analysis. Of these, Group 6, which contained DST 376, DST 505, DST 506 and DST 507, accounted for 76.7% of the 30 azole-resistant isolates. However, the genetic relationships among the azole-susceptible isolates were relatively decentralised. This MLST analysis of the putative correlation between the MLST types and antifungal susceptibility of clinical C. tropicalis isolates in Mainland China shows that DSTs 376, 505, 506 and 507 are closely related azole-resistant C. tropicalis clones. PMID- 27456281 TI - Adenine Glycosylase MutY of Corynebacterium pseudotuberculosis presents the antimutator phenotype and evidences of glycosylase/AP lyase activity in vitro. AB - Corynebacterium pseudotuberculosis is the etiological agent of caseous lymphadenitis, a disease that predominantly affects small ruminants, causing significant economic losses worldwide. As a facultative intracellular pathogen, this bacterium is exposed to an environment rich in reactive oxygen species (ROS) within macrophages. To ensure its genetic stability, C. pseudotuberculosis relies on efficient DNA repair pathways for excision of oxidative damage such as 8 oxoguanine, a highly mutagenic lesion. MutY is an adenine glycosylase involved in adenine excision from 8-oxoG:A mismatches avoiding genome mutation incorporation. The purpose of this study was to characterize MutY protein from C. pseudotuberculosis and determine its involvement with DNA repair. In vivo functional complementation assay employing mutY gene deficient Escherichia coli transformed with CpmutY showed a 13.5-fold reduction in the rate of spontaneous mutation, compared to cells transformed with empty vector. Also, under oxidative stress conditions, CpMutY protein favored the growth of mutY deficient E. coli, relative to the same strain in the absence of CpMutY. To demonstrate the involvement of this enzyme in recognition and excision of 8-oxoguanine lesion, an in vitro assay was performed. CpMutY protein was capable of recognizing and excising 8-oxoG:A but not 8-oxoG:C presenting evidences of glycosylase/AP lyase activity in vitro. In silico structural characterization revealed the presence of preserved motifs related to the MutY activity on DNA repair, such as catalytic residues involved in glycosylase/AP lyase activity and structural DNA-binding elements, such as the HhH motif and the [4Fe-4S] cluster. The three-dimensional structure of CpMutY, generated by comparative modeling, exhibits a catalytic domain very similar to that of E. coli MutY. Taken together, these results indicate that the CpmutY encodes a functional protein homologous to MutY from E. coli and is involved in the prevention of mutations and the repair of oxidative DNA lesions. PMID- 27456283 TI - Structural, magnetic and electronic properties of Fe1+xGa2-xO4 nanoparticles synthesized by the combustion method. AB - The combustion method was used to prepare a precursor powder of an iron-gallium oxide compound which was further heat-treated in order to obtain a set of Fe1+xGa2-xO4 nanoparticles. All samples have a cubic spinel-type structure (space group Fd3[combining macron]m) and the particle size varies from 1.8 to 28.0 nm depending on the treatment conditions. From the comparative analysis by XRD, EDS, and Raman and Mossbauer spectroscopy the creation of a new spinel phase gamma FeGaO3, which was mainly located on the particle surface, was established. As a result, the composition consists of a FeGa2O4 core covered by a FeGaO3 shell. The relative content of FeGa2O4/FeGaO3 compounds in the composites can be varied by heat treatment. The maximum in the ZFC magnetization curves appeared in all samples at about 20-30 K corresponding to the spin-freezing temperature Tsg, which is much higher than in the bulk compound with a pure inverse spinel structure (Ga)[FeGa]O4. The values of effective Curie temperature ThetaC for the Fe1+xGa2-xO4 nanoparticles are rather high and positive, indicating a ferromagnetic interaction between iron ions. The high values of the magnetic frustration parameter f = ThetaC/Tsg (up to 7) indicate a high degree of magnetic frustration. The low temperature Mossbauer data reveal the magnetic ordering of Fe ions in all samples with the magnetic transition at about 20-26 K depending on the particle size. The specific features of the Mossbauer parameters indicate the properties of non-homogeneous magnetic systems with frustrated interactions specific to spin-glasses. The magnetic system behaves as a spin-glass below Tsg and it is superparamagnetic above Tsg. Such a system is called a "super-spin glass". The anisotropy energy Eanis strongly depends on the content of Fe(2+) and Fe(3+) ions which contribute to the magnetocrystalline Ecryst and exchange Eex anisotropies, respectively. The anisotropy energy can be tuned by variation of the content of the (FeGaO3)-(FeGa2O4) phases in these complex composites. PMID- 27456284 TI - Photoinduced "Double Click" Cascade Offers Access to Complex Polyheterocycles from Readily Available Isatin-Based Photoprecursors. AB - The cascade photoassisted synthetic strategy for accessing complex N,O polyheterocycles of unprecedented molecular architecture is developed. It is based on intramolecular cycloadditions of aza-o-xylylenes formed in situ via excited-state intramolecular proton transfer (ESIPT) of o-acylanilides. The photoprecursors are synthesized via a two-step one-pot method from readily available starting materials. The photochemical cascade (one experimentally simple step) results in the formation of four new heterocyclic rings with high control of diastereoselectivity. PMID- 27456282 TI - ABCG2 regulates self-renewal and stem cell marker expression but not tumorigenicity or radiation resistance of glioma cells. AB - Glioma cells with stem cell traits are thought to be responsible for tumor maintenance and therapeutic failure. Such cells can be enriched based on their inherent drug efflux capability mediated by the ABC transporter ABCG2 using the side population assay, and their characteristics include increased self-renewal, high stem cell marker expression and high tumorigenic capacity in vivo. Here, we show that ABCG2 can actively drive expression of stem cell markers and self renewal in glioma cells. Stem cell markers and self-renewal was enriched in cells with high ABCG2 activity, and could be specifically inhibited by pharmacological and genetic ABCG2 inhibition. Importantly, despite regulating these key characteristics of stem-like tumor cells, ABCG2 activity did not affect radiation resistance or tumorigenicity in vivo. ABCG2 effects were Notch-independent and mediated by diverse mechanisms including the transcription factor Mef. Our data demonstrate that characteristics of tumor stem cells are separable, and highlight ABCG2 as a potential driver of glioma stemness. PMID- 27456285 TI - The introduction of expired air resuscitation into Surf Life Saving Australia. AB - Surf Life Saving Australia, which began in the early 1900s, initially adopted the indirect resuscitation methods used by the Royal Life Saving Society. As new indirect methods became available, both organisations adapted their resuscitation techniques and followed international developments closely. In the 1950s, accumulating evidence suggested that direct methods of resuscitation, such as mouth-to-mouth ventilation, might be more efficacious. Subsequently a number of investigations were carried out in Sydney at the Royal Prince Alfred Hospital on anaesthetised and paralysed patients. These experiments were recorded for an ABC documentary and reported at the International Convention on Life Saving Techniques held in Sydney in March 1960. Following the convention, Queensland Surf Life Saving conducted training sessions in cooperation with anaesthetists Roger Bennett and Tess Brophy (later Cramond), at St Andrew's Hospital in Brisbane. Two volunteers were anaesthetised and paralysed on two separate weekends to allow over one hundred people to gain experience in expired-air and bag-mask ventilation. One of the volunteers in these training exercises kindly provided much of the material that led to this paper, providing a first hand account of the experiments and an invaluable insight into the cooperation between anaesthetists and volunteer rescue associations. PMID- 27456286 TI - A personal history of the MASTER Trial and its link to the clinical trials network of the Australian and New Zealand College of Anaesthetists. AB - The aim of this paper is to link the history of the Multicentre Australian Study of Epidural Anaesthesia in high risk surgery, the MASTER Trial, the first National Health and Medical Research Council (NHMRC) funded multicentre randomised clinical trial in Australia led by anaesthetist researchers, and the decision of The Australian and New Zealand College of Anaesthetists (ANZCA) to establish a clinical trials network, in 2003, to the success of contemporary researchers in Australia and New Zealand in anaesthesia and perioperative medicine. PMID- 27456287 TI - Anaesthesia on the Western Front-perspectives a century later. AB - This year, 2016, marks the centenary of some of the worst battles of World War I. It is timely to reflect on the experiences of those who lived through those events, and the significant effects on the development of anaesthesia that occurred as a result. War has been a catalyst that has accelerated the development of medicine and surgery throughout history. The challenges of the Western Front, with its massive numbers of injured, saw progress in the understanding and management of trauma and shock, and significant improvement in the provision of anaesthesia and the training of anaesthesia providers. The result was increased anaesthetic safety for the civilian population after the war and further development of anaesthesia and resuscitation as a specialised area of medicine. PMID- 27456288 TI - Gas: the greatest terror of the Great War. AB - The Great War began just over a century ago and this monumental event changed the world forever. 1915 saw the emergence of gas warfare-the first weapon of mass terror. It is relevant to anaesthetists to reflect on these gases for a number of reasons. Firstly and most importantly we should acknowledge and be aware of the suffering and sacrifice of those soldiers who were injured or killed so that we could enjoy the freedoms we have today. Secondly, it is interesting to consider the overlap between poison gases and anaesthetic gases and vapors, for example that phosgene can be formed by the interaction of chloroform and sunlight. Thirdly the shadow of gas warfare is very long and covers us still. The very agents used in the Great War are still causing death and injury through deployment in conflict areas such as Iraq and Syria. Industrial accidents, train derailments and dumped or buried gas shells are other sources of poison gas hazards. In this age of terrorism, anaesthetists, as front-line resuscitation specialists, may be directly involved in the management of gas casualties or become victims ourselves. PMID- 27456289 TI - Advances in the diagnosis of shock, its assessment and resuscitation during the Great War. AB - The Great War of 1914-1918 ushered in a new era of technology on the battlefield resulting in casualties on an unprecedented scale. There had been progress in many related areas of medicine before the outbreak of hostilities but these had not been applied or fully developed in clinical practice. This is particularly true for the management of haemorrhagic shock and resuscitation. This article discusses the history and development of medical treatment of shock and trauma patients during the conflict. PMID- 27456290 TI - The etymology and use of the word 'anaesthesia' Oliver Wendell Holmes' letter to W. T. G. Morton. AB - Two published versions of a letter in which Oliver Wendell Holmes, MD, recommended the name anaesthesia were identified from publications supportive of the claims of W. T. G. Morton. The earliest known publication of Holmes' letter is in a pamphlet published by Edward Warren in May-June 1847. Another version of the letter was published 12 years later in Nathan P. Rice's biography of Morton. Holmes' letter to Morton was probably lost when a substantial part of a collection of Morton's papers was damaged during storage. There are no reported copies of Holmes's letter. The currently available information does not provide any assistance in determining the correct form of Holmes's letter. PMID- 27456291 TI - Discovery of the journal written by Dr William Russ Pugh on his voyage from England to Van Diemen's Land in 1835. PMID- 27456292 TI - History Supplement 2015-Cover Note, The Longfellow portrait and ether anaesthesia. PMID- 27456293 TI - Reply. PMID- 27456294 TI - Utilizing Energy Transfer in Binary and Ternary Bulk Heterojunction Organic Solar Cells. AB - Energy transfer has been identified as an important process in ternary organic solar cells. Here, we develop kinetic Monte Carlo (KMC) models to assess the impact of energy transfer in ternary and binary bulk heterojunction systems. We used fluorescence and absorption spectroscopy to determine the energy disorder and Forster radii for poly(3-hexylthiophene-2,5-diyl), [6,6]-phenyl-C61-butyric acid methyl ester, 4-bis[4-(N,N-diisobutylamino)-2,6-dihydroxyphenyl]squaraine (DIBSq), and poly(2,5-thiophene-alt-4,9-bis(2-hexyldecyl)-4,9-dihydrodithieno[3,2 c:3',2'-h][1,5]naphthyridine-5,10-dione). Heterogeneous energy transfer is found to be crucial in the exciton dissociation process of both binary and ternary organic semiconductor systems. Circumstances favoring energy transfer across interfaces allow relaxation of the electronic energy level requirements, meaning that a cascade structure is not required for efficient ternary organic solar cells. We explain how energy transfer can be exploited to eliminate additional energy losses in ternary bulk heterojunction solar cells, thus increasing their open-circuit voltage without loss in short-circuit current. In particular, we show that it is important that the DIBSq is located at the electron donor acceptor interface; otherwise charge carriers will be trapped in the DIBSq domain or excitons in the DIBSq domains will not be able to dissociate efficiently at an interface. KMC modeling shows that only small amounts of DIBSq (<5% by weight) are needed to achieve substantial performance improvements due to long-range energy transfer. PMID- 27456297 TI - Best practice guidelines in the psychosocial management of HPV-related head and neck cancer: recommendations from the European Head and Neck Cancer Society's Make Sense Campaign. AB - Over the past three decades, oral human papillomavirus (HPV) has been associated with an increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) in several countries. Specialist oncologists in head and neck cancer are observing a wider range of demographics, sexual behaviours, and survival outcomes with their patients. Additionally, there are fewer smokers, consumers of alcohol, or people of lower socioeconomic status than in previous decades. In order to support patients, the European Head and Neck Society's Make Sense Campaign aims to promote best practice in the management of head and neck cancer through the delivery of counselling, psychological assessment, support with the patient experience following HPV-related cancer diagnosis, sexual impact (in terms of communication, behaviour and prevention), facilitating access to educational resources about HPV in head and neck squamous cell carcinoma and OPSCC, and early referral if necessary. New concerns about psychosocial distress and unmet psychosocial needs following diagnosis, therefore, exist throughout the disease and treatment periods. Oncologists treating patients with HPV-related head and neck cancer must integrate new parameters focused on infection risk transmission and sexual topics. The development and dissemination of best practice guidelines through The European Head and Neck Cancer Society Make Sense Campaign will help healthcare professionals to be more confident and resourceful in supporting patients with HPV-related head and neck cancer. PMID- 27456298 TI - Saving the best treatment for last? PMID- 27456296 TI - Chemotherapy remains an essential element of personalized care for persons with lung cancers. AB - Molecularly targeted and immunotherapies have improved the care of patients with lung cancers. These successes have rallied calls to replace or avoid chemotherapy. Yet, even in this era of precision medicine and exciting advances, cytotoxic chemotherapies remain an essential component of lung cancer treatment. In the setting of locoregional disease, chemotherapy is the only systemic therapy thus far proven to enhance curability when combined with surgery or radiation. In the metastatic setting, chemotherapy can improve the length and quality of life in many patients. Chemotherapy remains the mainstay of care for individuals whose cancers with oncogenic drivers have acquired resistance to targeted agents. Chemotherapy also has the potential to modulate the immune system to enhance the effectiveness of immune checkpoint inhibitors. In this context, chemotherapy should be framed as a critical component of the armamentarium available for optimizing cancer care rather than an unfortunate anachronism. We examine the role of chemotherapy with precision medicine in the current care of patients with lung cancers, as well as opportunities for future integration in combinations with targeted agents, angiogenesis inhibitors, immunotherapies, and antibody drug conjugates. PMID- 27456300 TI - The effect of smoking on ACL reconstruction: a systematic review. AB - OBJECTIVE: Anterior cruciate ligament reconstruction (ACLR) depends on proper healing of the graft or bone plug at the cellular level. The effect of cigarette smoke on ACLR was not commonly reported until recently. The primary purpose of this review was to determine if smoking has a negative effect on subjective or objective outcome scores after ACLR. The secondary purpose was to identify any increased risk of complications, infection, ACL re-tear, or revision procedures. METHODS: A systematic literature review of the MEDLINE, SCOPUS and PubMed databases was performed to identify all studies that compared outcomes of ACLR surgery between smokers and nonsmokers. The frequency-weighted mean was calculated for outcome measures that were similar across several studies. RESULTS: Seventeen studies were identified that met inclusion criteria for patients undergoing ACLR (mean age, 26.8 years) with a mean follow-up of 37 months. Smokers had significantly worse subjective outcome measures and worse side-to-side difference in anterior translation compared to non-smokers (2.68 mm vs 1.89 mm, respectively). In 2 studies, smokers were found to have a significantly higher risk of developing an infection and VTE (venous thromboembolism) post-operatively. The evidence for the effect of smoking on risk for subsequent re-tear is mixed. No study reported a higher rate of development of radiographic knee osteoarthritis among smokers compared to nonsmokers. CONCLUSIONS: Cigarette smoke is associated with significantly worse clinical outcome scores, an increase in anterior translation, and increased complication rates after ACL reconstruction. These findings may help orthopaedic surgeons better inform their patients about the potential negative effects of smoking on the outcomes of ACL reconstruction. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 27456299 TI - A randomized trial on chlorhexidine dressings for the prevention of catheter related bloodstream infections in neutropenic patients. AB - BACKGROUND: Central venous catheter (CVC)-related bloodstream infections (CRBSI) are a frequent cause of morbidity and mortality in patients with chemotherapy induced neutropenia. Chlorhexidine containing catheter securement dressings may prevent CRBSI. PATIENTS AND METHODS: A multicenter randomized, controlled trial was conducted at 10 German hematology departments. We compared chlorhexidine containing dressings with non-chlorhexidine control dressings in neutropenic patients. The primary end point was the incidence of definite CRBSI within the first 14 days (dCRBSI14) of CVC placement. Secondary end points included combined incidence of definite or probable CRBSI within 14 days (dpCRBSI14), overall (dpCRBSI), incidence of unscheduled dressing changes and adverse events. RESULTS: From February 2012 to September 2014, 613 assessable patients were included in the study. The incidence of dCRBSI14 was 2.6% (8/307) in the chlorhexidine and 3.9% (12/306) in the control group (P = 0.375). Both dpCRBSI14 and dpCRBSI were significantly less frequent in the study group with dpCRBSI14 in 6.5% (20/307) of the chlorhexidine group when compared with 11% (34/306) in the control group (P = 0.047), and dpCRBSI in 10.4% (32/307) versus 17% (52/306), respectively (P = 0.019). The frequency of dressing intolerance with cutaneous and soft tissue abnormalities at the contact area was similar in both groups (12.4% and 11.8%; P = 0.901). CONCLUSIONS: Although the trial failed its primary end point, the application of chlorhexidine containing catheter securement dressings reduces the incidence of definite or probable CRBSI in neutropenic patients. CLINICAL TRIALS NUMBER: NCT01544686 (Clinicaltrials.gov). PMID- 27456301 TI - Construction of a tunable multi-enzyme-coordinate expression system for biosynthesis of chiral drug intermediates. AB - Systems that can regulate and coordinate the expression of multiple enzymes for metabolic regulation and synthesis of important drug intermediates are poorly explored. In this work, a strategy for constructing a tunable multi-enzyme coordinate expression system for biosynthesis of chiral drug intermediates was developed and evaluated by connecting protein-protein expressions, regulating the strength of ribosome binding sites (RBS) and detecting the system capacity for producing chiral amino acid. Results demonstrated that the dual-enzyme system had good enantioselectivity, low cost, high stability, high conversion rate and approximately 100% substrate conversion. This study has paved a new way of exploring metabolic mechanism of functional genes and engineering whole cell catalysts for synthesis of chiral alpha-hydroxy acids or chiral amino acids. PMID- 27456302 TI - Aberrant DNA methylation reprogramming in bovine SCNT preimplantation embryos. AB - DNA methylation reprogramming plays important roles in mammalian embryogenesis. Mammalian somatic cell nuclear transfer (SCNT) embryos with reprogramming defects fail to develop. Thus, we compared DNA methylation reprogramming in preimplantation embryos from bovine SCNT and in vitro fertilization (IVF) and analyzed the influence of vitamin C (VC) on the reprogramming of DNA methylation. The results showed that global DNA methylation followed a typical pattern of demethylation and remethylation in IVF preimplantation embryos; however, the global genome remained hypermethylated in SCNT preimplantation embryos. Compared with the IVF group, locus DNA methylation reprogramming showed three patterns in the SCNT group. First, some pluripotency genes (POU5F1 and NANOG) and repeated elements (satellite I and alpha-satellite) showed insufficient demethylation and hypermethylation in the SCNT group. Second, a differentially methylated region (DMR) of an imprint control region (ICR) in H19 exhibited excessive demethylation and hypomethylation. Third, some pluripotency genes (CDX2 and SOX2) were hypomethylated in both the IVF and SCNT groups. Additionally, VC improved the DNA methylation reprogramming of satellite I, alpha-satellite and H19 but not that of POU5F1 and NANOG in SCNT preimplantation embryos. These results indicate that DNA methylation reprogramming was aberrant and that VC influenced DNA methylation reprogramming in SCNT embryos in a locus-specific manner. PMID- 27456303 TI - Non-equilibrium processing leads to record high thermoelectric figure of merit in PbTe-SrTe. AB - The broad-based implementation of thermoelectric materials in converting heat to electricity hinges on the achievement of high conversion efficiency. Here we demonstrate a thermoelectric figure of merit ZT of 2.5 at 923 K by the cumulative integration of several performance-enhancing concepts in a single material system. Using non-equilibrium processing we show that hole-doped samples of PbTe can be heavily alloyed with SrTe well beyond its thermodynamic solubility limit of <1 mol%. The much higher levels of Sr alloyed into the PbTe matrix widen the bandgap and create convergence of the two valence bands of PbTe, greatly boosting the power factors with maximal values over 30 MUW cm(-1) K(-2). Exceeding the 5 mol% solubility limit leads to endotaxial SrTe nanostructures which produce extremely low lattice thermal conductivity of 0.5 W m(-1) K(-1) but preserve high hole mobilities because of the matrix/precipitate valence band alignment. The best composition is hole-doped PbTe-8%SrTe. PMID- 27456304 TI - Early Menarche and Gestational Diabetes Mellitus at First Live Birth. AB - OBJECTIVES: To examine the association between early menarche and gestational diabetes mellitus (GDM). METHODS: Data from the National Health and Nutrition Examination Survey 2007-2012 were used to investigate the association between age at menarche and the risk of GDM at first birth among 5914 women. A growth mixture model was used to detect distinctive menarche onset patterns based on self reported age at menarche. Logistic regression models were then used to examine the associations between menarche initiation patterns and GDM after adjusting for sociodemographic factors, family history of diabetes mellitus, lifetime greatest Body Mass Index, smoking status, and physical activity level. RESULTS: Among the 5914 first-time mothers, 3.4 % had self-reported GDM. We detected three groups with heterogeneous menarche onset patterns, the Early, Normal, and Late Menarche Groups. The regression model shows that compared to the Normal Menarche Group, the Early Menarche Group had 1.75 (95 % CI 1.10, 2.79) times the odds of having GDM. No statistically significant difference was observed between the Normal and the Late Menarche Group. CONCLUSION: This study suggests that early menarche may be a risk factor of GDM. Future studies are warranted to examine and confirm this finding. PMID- 27456305 TI - Birth Size, Stunting and Recovery from Stunting in Andhra Pradesh, India: Evidence from the Young Lives Study. AB - Objectives Few Indian studies have examined the relationship between birth size and stunting in children. Studies on recovery from stunting in India are even fewer. This study, thus, investigates the relationship between birth size and stunting in Andhra Pradesh, India. This study further examines the factors associated with recovery from stunting using a longitudinal data. Methods We used data from the three waves of Young Lives Study (YLS) conducted in Andhra Pradesh in the years 2002, 2006-2007, and 2009 respectively. We used data from 1965 children in wave 1 to examine the association between birth size and stunting. For examining the factors associated with recovery from stunting between 1 and 5 years of age, and between 5 and 8 years, we use data from 582 and 670 children who were stunted at age 1 and age 5 respectively. We use multivariable logistic regression models to fulfil the objectives of the paper. Results The children who were of average- or large- size at birth were significantly less likely to be stunted than children who were of small size at birth (OR 0.61 and 0.47 respectively). Children of average/tall mothers were 0.41 times less likely to be stunted than children of shorter mothers. Severely stunted children were less likely than other stunted children to recover from stunting between 1 and 5 years of age, and between 5 and 8 years. Mother's height was statistically associated with recovery. Change in wealth status of the household was statistically associated with recovery between 1 and 5 years of age. In comparison, child immunization was associated with recovery between 5 and 8 years. Conclusions for Practice This study contributes to the understanding of the impact of birth size on childhood stunting, and to the extent of recovery from stunting in India. Further follow-up is necessary to demonstrate the impact during adolescence and adulthood. PMID- 27456306 TI - Pregnancy Outcomes Among Women with Homozygous Hemoglobin E Disease: A Retrospective Cohort Study. AB - Background Homozygous hemoglobin E (HbE) disease is common, especially in Southeast Asia where the prevalence may be as high as nearly 1 % of pregnancies and it is usually associated with mild anemia. Nevertheless, the effects of the disease on pregnancy outcomes have never been explored. Objective To compare the obstetric adverse outcomes between singleton pregnancies complicated with HbE disease and normal controls. Patients and Methods A retrospective cohort study was undertaken by assessment of the database of maternal-fetal medicine units, Chiang Mai University, Thailand, from January 2000 to December 2014 to search for the records of pregnant women complicated by the disease. The records of low risk pregnancies were randomly selected as a control group with a ratio of 10:1. Pregnancies with underlying medical diseases or fetal abnormalities as well as those with no complete data were excluded. Result During the study period, 78 women with homozygous HbE disease (study group) and 780 normal controls were recruited. Most baseline characteristics of the two groups were similar. The mean birth weight was significantly lower in the study group (2683 +/- 627 vs 2925 +/- 623 g, P = 0.001).The prevalence of fetal growth restriction was also significantly higher in the study group (13.2 vs 6.7 %, P = 0.040, relative risk 1.96; 95 % CI 1.04-3.69), whereas the rates of other outcomes such as preterm birth were comparable. Conclusion for Practice Homozygous HbE disease does not increase risk of common adverse pregnancy outcomes, but it significantly increases risk of fetal growth restriction, resulting in significantly lower mean birth weight. PMID- 27456307 TI - Dietary Patterns During Pregnancy are Associated with Gestational Weight Gain. AB - Objective The role of diet during pregnancy on gestational weight gain is unclear. This study aimed to evaluate the hypothesis that dietary patterns during pregnancy are differentially associated with the adequacy of gestational weight gain at different stages of pregnancy. Methods A total of 391 pregnant women in National Health and Nutrition Examination Survey (NHANES) 2003-2006 were included. Dietary intake was obtained using a National Cancer Institute's food frequency questionnaire. Results Three dietary patterns were identified by factor analysis with 36 food groups among pregnant women, and they were named according to food group factor loadings: 'mixed', 'healthy', and 'western'. The 'mixed' pattern characterized by a high intake of meat, dairy products, fruits, vegetables, potatoes, nuts and seeds and sweets. After adjusting for maternal sociodemographic variables and physical activity level, women in the highest tertile of 'mixed' pattern score had significantly greater odds of being in the inadequate gestational weight gain compared to those in the lowest tertile (adjusted odds ratio (AOR) 4.72; 95 % CI 1.07-20.94). Women in the mid tertile of the 'mixed' pattern had significantly lower odds of being in the excessive gestational weight gain compared to those in the lowest tertile (AOR 0.39; 95 % CI 0.15-0.99). Conclusion These results suggest that a diet high in meat, dairy products, fruits, vegetables, potatoes, and nuts and seeds during pregnancy might be associated with reducing excessive gestational weight gain. PMID- 27456308 TI - Infant Mortality, Cause of Death, and Vital Records Reporting in Ohio, United States. AB - Introduction Infant mortality rate is a sensitive metric for population health and well-being. Challenges in achieving accurate reporting of these data can lead to inaccurate targeting of public health interventions. We analyzed a cohort from a pediatric tertiary care referral medical center to evaluate concordance between autopsy cause of death (COD) and death certificate documentation for infants <1 year of age. We predicted that infant COD as documented through vital records would not correspond to that as determined by autopsy. Methods We conducted a retrospective review comparing causes of infant death reported through Ohio Department of Health documents to those on Cincinnati Children's Hospital Medical Center autopsy reports over an 8-year period from January 1, 2006 through December 31, 2013. Results We analyzed 276 total cases of which 167 (61.5 %) represented infants born preterm. Autopsy reports identified 55 % of cases had a congenital anomaly. Additionally, 34 % of all cases had primary or contributing COD related to infection and 14.5 % of all cases indicated chorioamnionitis. We identified 156 (56.5 %) death certificates discordant with autopsy COD of which 52 (33.3 %) involved infection and 24 (15.4 %) involved congenital anomalies. Discussion There are opportunities to improve COD reporting through training for providers, and improvement of established state certification systems. Future strategies to reduce infant mortality will be better informed through enhancements in vital records COD reporting. PMID- 27456309 TI - Associations Between Maternal-Foetal Attachment and Infant Developmental Outcomes: A Systematic Review. AB - Objectives Infant developmental outcomes may be influenced by a range of prenatal maternal characteristics. While there is some evidence to suggest that maternal foetal attachment may be associated with infant developmental outcomes, there is a need to systematically review this evidence to guide future research and clinical practice. Methods Five electronic databases were systematically scanned. Key journals and reference lists were hand-searched. Papers were included if: (1) pregnant women were assessed for maternal-foetal attachment; (2) the infants were later assessed, under 2 years old, for any developmental outcome (e.g., social emotional, cognition, motor, language, adaptive behaviour); and (3) they were published in English. Two independent reviewers used the STROBE checklist to appraise the quality of each paper. Results Of the 968 papers identified, eight were included in the review, and four of these were of low quality (<60 %) based on the STROBE. The developmental domains that were examined included: infant temperament (n = 5), adaptive behaviour (e.g., colic, sleep) (n = 2), and milestone attainment (n = 1). There is some evidence to suggest that lower maternal-foetal attachment is related to suboptimal developmental outcomes. However, these results should be interpreted with caution due to the limited and low quality studies available. Conclusions Although maternal-foetal attachment may be associated with infant developmental outcomes, future research is required which: (1) considers a range of developmental outcomes, (2) has increased scientific rigour, (3) assesses mother-infant dyads at different prenatal and postnatal time points, and (4) examines different target populations. PMID- 27456310 TI - Diagnosing Postpartum Hemorrhage: A New Way to Assess Blood Loss in a Low Resource Setting. AB - Introduction Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. The largest barriers to treating PPH are symptom recognition and timely diagnosis. The SAPHE (Signaling a Postpartum Hemorrhage Emergency) Mat was constructed so that each square on the Mat absorbs up to 50 mL of blood. The objective of this study was to evaluate the correlation of visually estimated blood loss (EBL) using the SAPHE Mat with actual blood loss. Methods Thirty-six patients gave birth via vaginal delivery using the SAPHE Mat. Visual estimation of blood loss using the SAPHE Mat was calculated by multiplying the number of blood- saturated squares or partial squares by 50 mL. The visual EBL was compared with the actual blood loss calculated based on Mat weight before and after use (volume blood loss). Results Visual blood loss estimations were within 100 mL of the volume blood loss 69 % of the time and within 200 mL 97 % of the time. The mean difference between the visual EBL and volume blood loss (Mat weight change) was 80.91 mL. The Pearson correlation coefficient for visual EBL and volume blood loss was positive at 0.96 (p < 0.001). Discussion The SAPHE Mat is able to provide a visual estimate of blood loss that is highly correlated with the actual blood loss on the mat. Future studies will assess the ability to deploy the SAPHE Mat in low-resource settings as a potential guide for estimating blood loss to assist in improved management of PPH. PMID- 27456311 TI - Patterns of Internet Use by Pregnant Women, and Reliability of Pregnancy-Related Searches. AB - Objective To assess patterns of e-health use in pregnancy in an underserved racially diverse inner-city population, and to assess the accuracy of pregnancy related information obtained from the Internet. Methods A cross sectional study of 503 pregnant/postpartum women belonging to an underserved racially diverse inner-city population who completed a survey regarding e-health use. To assess accuracy, four independent expert-reviewers rated the first 10 webpages on Google searches for each of five questions based upon those in ACOG bulletins. Results 70.8 % of pregnant/postpartum women belonging to an underserved racially diverse inner-city population were e-health users. E-health users were younger (mean age 29.4 vs. 31.2, P = 0.009), more likely to be nulliparous (50.3 vs. 21.3 %, P < 0.001), have English as their primary language (62.3 vs. 49.1 %, P = 0.014) and have a college/graduate education (78 vs. 26.6 %, P < 0.001). While 60 % of these women said e-health influenced decision making, only 71.3 % of them discussed their searches with their provider. Expert reviewers determined that the online information was fairly accurate (mean score: +1.48 to +4.33 on a scale of -5 to +5) but not uniformly accurate, and there was at least one webpage with inaccurate information for every question. Conclusions for practice Pregnant women frequently use e-health resources but do not routinely share their findings with their providers. Most, but not all, information obtained is accurate. Therefore it is important for providers to discuss their patients' use, and help to guide them to reliable information. PMID- 27456312 TI - Brain tumor imaging of rat fresh tissue using terahertz spectroscopy. AB - Tumor imaging by terahertz spectroscopy of fresh tissue without dye is demonstrated using samples from a rat glioma model. The complex refractive index spectrum obtained by a reflection terahertz time-domain spectroscopy system can discriminate between normal and tumor tissues. Both the refractive index and absorption coefficient of tumor tissues are higher than those of normal tissues and can be attributed to the higher cell density and water content of the tumor region. The results of this study indicate that terahertz technology is useful for detecting brain tumor tissue. PMID- 27456314 TI - Electroretinographic effects of retinal dragging and retinal folds in eyes with familial exudative vitreoretinopathy. AB - We evaluated the retinal function of retinal dragging (Rdrag) and radial retinal folds (Rfolds) in eyes with familial exudative vitreoretinopathy (FEVR) using full-field electroretinography (ERG). Seventeen eyes of nine patients with FEVR who had Rdrag or Rfolds were retrospectively studied. Eyes were classified into four groups according to the severity of the retinal alterations: Group 1, without Rdrag or Rfolds (5 eyes); Group 2, with Rdrag (4 eyes); Group 3, with Rfolds (6 eyes); and Group 4, with Rfolds in which all major retinal vessels were involved (2 eyes). The amplitudes of all ERG components and the implicit times of the photopic a- and b-waves and 30-Hz flicker responses were decreased or prolonged as the severity of the retinal alterations increased (P < 0.01). The photopic negative response was most severely affected and nearly undetectable in all eyes in Groups 3 and 4, although the other ERG components were detectable in all eyes in Group 3 and one eye in Group 4. These results suggest the decrease of retinal functions was correlated with the degree of severity of Rdrag and Rfolds in eyes with FEVR. In addition, the function of the retinal ganglion cells appears to be more severely affected compared with the others. PMID- 27456315 TI - Intellectual Disabilities and Decision Making at End of Life: A Literature Review. AB - BACKGROUND: Individuals with an intellectual disability are vulnerable to having end-of-life decisions made for them merely due to the presence of a disability. As a result, decisions made by others may not reflect the exact wishes of the individual. METHODS: This review examines literature on individuals with an intellectual disability in making end-of-life decisions from the years 2000 to 2014. A total of 38 articles were found with 12 articles having a direct focus on end-of-life decision making. RESULTS: The emerging themes include the following: (i) assumption of lack of capacity, (ii) inconsistency in evaluating capacity and communication challenges and (iii) third party decisions. CONCLUSIONS: Earlier discussions about end-of-life planning before the diagnosis of a life-limiting illness would be beneficial. Lacking is a consistent approach to determining capacity for individuals with an intellectual disability. The findings from this review provide a foundation for a decision tree in end-of-life decision making for individuals with an intellectual disability. PMID- 27456313 TI - Functions of the Alzheimer's Disease Protease BACE1 at the Synapse in the Central Nervous System. AB - Inhibition of the protease beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a promising treatment strategy for Alzheimer's disease, and a number of BACE inhibitors are currently progressing through clinical trials. The strategy aims to decrease production of amyloid-beta (Abeta) peptide from the amyloid precursor protein (APP), thus reducing or preventing Abeta toxicity. Over the last decade, it has become clear that BACE1 proteolytically cleaves a number of substrates in addition to APP. These substrates are not known to be involved in the pathogenesis of Alzheimer's disease but have other roles in the developing and/or mature central nervous system. Consequently, BACE inhibition and knockout in mice results in synaptic and other neuronal dysfunctions and the key substrates responsible for these deficits are still being elucidated. Of the BACE1 substrates that have been validated to date, a number may contribute to the synaptic deficits seen with BACE blockade, including neuregulin 1, close homologue of L1 and seizure-related gene 6. It is important to understand the impact that BACE blockade may have on these substrates and other proteins detected in substrate screens and, if necessary, develop substrate-selective BACE inhibitors. PMID- 27456317 TI - High-affinity host-guest chemistry of large-ring cyclodextrins. AB - The host-guest chemistry of large-ring cyclodextrins (LRCDs) has been largely unexplored due to the lack of suitable guest molecules that bind with significant affinities to enable potential applications. Herein, we report their complexation with dodecaborate anions (B12X12(2-)), a novel class of guest molecules. The binding constants of the inorganic guests (10(4)-10(6) M(-1)) allow their classification as the first tight binders for LRCDs. PMID- 27456318 TI - Cornual wedge resection for interstitial pregnancy and postoperative outcome. AB - INTRODUCTION: Traditionally, interstitial pregnancies were treated with cornual resection or hysterectomy via laparotomy. However, increasingly, interstitial pregnancies are treated with laparoscopic cornuotomy, ie, removal of ectopic pregnancy tissue with preservation of uterine architecture. Although this technique may increase the incidence of persistent and recurrent interstitial pregnancy, it can potentially maintain patient fertility and decrease their risk for future uterine rupture. In a case series of patients with interstitial pregnancies treated with cornual wedge resection, we examined fertility outcomes, rates of subsequent uterine rupture, and rates of persistent or recurrent interstitial pregnancy. MATERIALS AND METHODS: We conducted a retrospective medical record review of cases (n = 29) of cornual wedge resection for interstitial pregnancy, performed between 1992 and 2013 at one hospital. RESULTS: Of the 29 cases, two later presented with uterine rupture; one, who also had a prior wedge resection, was found with scar dehiscence during a subsequent caesarean section. The incidence of subsequent uterine rupture and dehiscence was 30%. There were no cases of persistent ectopic pregnancy or recurrent interstitial pregnancy. Most (71.4%) patients who were trying to conceive achieved subsequent pregnancy. DISCUSSION: There is debate regarding the recommended surgical technique to treat interstitial pregnancies; cornual resection and cornuotomy are both important considerations. Choice of the technique employed continues to require careful consideration. PMID- 27456319 TI - A Model for Rounding With Patients in a Psychiatric Hospital. AB - BACKGROUND: Hourly rounding is an organized practice where nurses perform regular checks on individual patients at fixed intervals in order to elicit any information that will improve the patient's care and well-being. Weaknesses in the existing literature on rounding include a lack of focus on the nurse-patient interaction, the absence of a guiding theoretical framework, and, lastly, marginal implementation of rounding within the psychiatric setting. PURPOSE: The intent of this paper is to address these weaknesses by describing and proposing a rounding tool, based upon the acronym ICARE, to be used in the inpatient psychiatric setting. Roach's Theory on Caring will be the theoretical underpinnings for the basis of this rounding initiative. PRACTICE IMPLICATIONS: It is the belief that the hourly rounding initiative will improve satisfaction and the overall quality of care for the psychiatric patient. PMID- 27456316 TI - Glycerol Monolaurate (GML) inhibits human T cell signaling and function by disrupting lipid dynamics. AB - Glycerol Monolaurate (GML) is a naturally occurring fatty acid widely utilized in food, cosmetics, and homeopathic supplements. GML is a potent antimicrobial agent that targets a range of bacteria, fungi, and enveloped viruses but select findings suggest that GML also has immunomodulatory functions. In this study, we have mechanistically examined if GML affects the signaling and functional output of human primary T cells. We found that GML potently altered order and disorder dynamics in the plasma membrane that resulted in reduced formation of LAT, PLC gamma, and AKT microclusters. Altered membrane events induced selective inhibition of TCR-induced phosphorylation of regulatory P85 subunit of PI3K and AKT as well as abrogated calcium influx. Ultimately, GML treatment potently reduced TCR-induced production of IL-2, IFN-gamma, TNF-alpha, and IL-10. Our data reveal that the widely used anti-microbial agent GML also alters the lipid dynamics of human T cells, leading to their defective signaling and function. PMID- 27456320 TI - Leprae reaction resembling rheumatologic disease as presenting feature of leprosy. AB - Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae with predominant involvement of skin and nerves. We present a 70-year-old man with leprosy whose initial presentation resembled rheumatologic disease, due to leprae reaction. He presented with an 8-week history of worsening neuropathic pain in the right forearm, associated with necrotic skin lesions on his fingers that had ulcerated. Physical examination revealed two tender necrotic ulcers at the tip of the right middle finger and the dorsal aspect of the left middle finger. The patient had right wrist tenosynovitis and right elbow bursitis. Apart from raised inflammatory markers, the investigations for infection, connective tissue disease, vasculitis, thromboembolic disease and malignancy were negative. During the fourth week of hospitalization, we noticed a 2-cm hypoesthetic indurated plaque on the right inner arm. Further examination revealed thickened bilateral ulnar, radial and popliteal nerves. A slit skin smear was negative. Two skin biopsies and a biopsy of the olecranon bursa revealed granulomatous inflammation. He was diagnosed with paucibacillary leprosy with neuritis. He responded well to multidrug therapy and prednisolone; his symptoms resolved over a few weeks. This case illustrates the challenges in diagnosing a case of leprosy with atypical presentation in a non-endemic country. PMID- 27456321 TI - Better cognition in migraine? PMID- 27456322 TI - On Magnetic Resonance Imaging of Intervertebral Disc Aging. PMID- 27456323 TI - Potential of plant polyphenols to combat oxidative stress and inflammatory processes in farm animals. AB - Polyphenols are secondary plant metabolites which have been shown to exert antioxidative and antiinflamma tory effects in cell culture, rodent and human studies. Based on the fact that conditions of oxidative stress and inflammation are highly relevant in farm animals, polyphenols are considered as promising feed additives in the nutrition of farm animals. However, in contrast to many studies existing with model animals and humans, potential antioxidative and antiinflammatory effects of polyphenols have been less investigated in farm animals so far. This review aims to give an overview about potential antioxidative and antiinflammatory effects in farm animals. The first part of the review highlights the occurrence and the consequences of oxidative stress and inflammation on animal health and performance. The second part of the review deals with bioavailability and metabolism of polyphenols in farm animals. The third and main part of the review presents an overview of the findings from studies which investigated the effects of polyphenols of various plant sources in pigs, poultry and cattle, with particular consideration of effects on the antioxidant system and inflammation. PMID- 27456324 TI - Impact of physical function impairment and multimorbidity on mortality among community-living older persons with sarcopaenia: results from the ilSIRENTE prospective cohort study. AB - OBJECTIVE: Sarcopaenia and physical function impairment may have a greater effect on survival than other clinical characteristics, including multimorbidity. In this study, we evaluated the impact of sarcopaenia on all-cause mortality and the interaction among muscle loss, physical function impairment and multimorbidity on mortality risk over 10 years in older community-dwellers. DESIGN: Prospective cohort study. SETTING: Population-based study. PARTICIPANTS: All persons aged 80+ years living in the community in the Sirente geographic area (L'Aquila, Italy) (n=364). Participants were categorised in the sarcopaenic or non-sarcopaenic group based on the European Working Group on Sarcopenia in Older People criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) All-cause mortality over 10 years according to the presence of sarcopaenia and (2) impact of physical function impairment, assessed using the Short Physical Performance Battery (SPPB), and multimorbidity on 10-year mortality risk in persons with sarcopaenia. RESULTS: Sarcopaenia was identified in 103 participants (29.1%). A total of 253 deaths were recorded over 10 years: 90 among sarcopaenic participants (87.4%) and 162 among non-sarcopaenic persons (65.1%; p<0.001). Participants with sarcopaenia had a higher risk of death than those without sarcopaenia (HR=2.15; 95% CI 1.02 to 4.54). When examining the effect of sarcopaenia and physical function impairment on mortality, participants with low physical performance levels showed greater mortality. Conversely, the mortality risk was unaffected by multimorbidity. CONCLUSIONS: Our findings show that physical function impairment, but not multimorbidity, is predictive of mortality in older community-dwellers with sarcopaenia. Hence, in sarcopaenic older persons, interventions against functional decline may be more effective at preventing or postponing negative health outcomes than those targeting multimorbidity. PMID- 27456325 TI - An investigation of routes to cancer diagnosis in 10 international jurisdictions, as part of the International Cancer Benchmarking Partnership: survey development and implementation. AB - OBJECTIVES: This paper describes the methods used in the International Cancer Benchmarking Partnership Module 4 Survey (ICBPM4) which examines time intervals and routes to cancer diagnosis in 10 jurisdictions. We present the study design with defining and measuring time intervals, identifying patients with cancer, questionnaire development, data management and analyses. DESIGN AND SETTING: Recruitment of participants to the ICBPM4 survey is based on cancer registries in each jurisdiction. Questionnaires draw on previous instruments and have been through a process of cognitive testing and piloting in three jurisdictions followed by standardised translation and adaptation. Data analysis focuses on comparing differences in time intervals and routes to diagnosis in the jurisdictions. PARTICIPANTS: Our target is 200 patients with symptomatic breast, lung, colorectal and ovarian cancer in each jurisdiction. Patients are approached directly or via their primary care physician (PCP). Patients' PCPs and cancer treatment specialists (CTSs) are surveyed, and 'data rules' are applied to combine and reconcile conflicting information. Where CTS information is unavailable, audit information is sought from treatment records and databases. MAIN OUTCOMES: Reliability testing of the patient questionnaire showed that agreement was complete (kappa=1) in four items and substantial (kappa=0.8, 95% CI 0.333 to 1) in one item. The identification of eligible patients is sufficient to meet the targets for breast, lung and colorectal cancer. Initial patient and PCP survey response rates from the UK and Sweden are comparable with similar published surveys. Data collection was completed in early 2016 for all cancer types. CONCLUSION: An international questionnaire-based survey of patients with cancer, PCPs and CTSs has been developed and launched in 10 jurisdictions. ICBPM4 will help to further understand international differences in cancer survival by comparing time intervals and routes to cancer diagnosis. PMID- 27456326 TI - Prevalence of overweight and obesity and some associated factors among adult residents of northeast China: a cross-sectional study. AB - OBJECTIVES: This study aims to estimate the prevalence of overweight and obesity and determine potential influencing factors among adults in northeast China. METHODS: A cross-sectional survey was conducted in Jilin Province, northeast China, in 2012. A total of 9873 men and 10 966 women aged 18-79 years from the general population were included using a multistage stratified random cluster sampling design. Data were obtained from face-to-face interview and physical examination. After being weighted according to a complex sampling scheme, the sample was used to estimate the prevalence of overweight (body mass index (BMI) 24-27.9 kg/m(2)) and obesity (BMI >28 kg/m(2)) in Jilin Province, and analyse influencing factors through corresponding statistical methods based on complex sampling design behaviours. RESULTS: The overall prevalence of overweight was 32.3% (male 34.3%; female 30.2%), and the prevalence of obesity was 14.6% (male 16.3%; female 12.8%) in Jilin Province. The prevalence of both overweight and obesity were higher in men than women (p<0.001). Influencing factors included sex, age, marriage status, occupation, smoking, drinking, diet and hours of sleep (p<0.05). CONCLUSIONS: This study estimated that the prevalence of overweight and obesity among adult residents of Jilin Province, northeast China, were high. The results of this study will be submitted to the Health Department of Jilin Province and other relevant departments as a reference, which should inform policy makers in developing education and publicity to prevent and control the occurrence of overweight and obesity. PMID- 27456327 TI - Effectiveness and safety of treatments used for the management of patent ductus arteriosus (PDA) in preterm infants: a protocol for a systematic review and network meta-analysis. AB - INTRODUCTION: Management of patent ductus arteriosus (PDA) in preterm infants is one of the most controversial topics in neonatal medicine. The availability of different pharmacotherapeutic options often poses a practical challenge to the practising neonatologist as to which one to choose as a therapeutic option. Our objectives are to determine the relative merits of the available pharmacotherapeutic options for the management of PDA. METHODS AND ANALYSIS: We will conduct a systematic review of all randomised controlled trials evaluating the use of intravenous or oral: indomethacin, ibuprofen and acetaminophen for the treatment of PDA in preterm infants. The primary outcome is failure of closure of the PDA. Secondary outcomes are neonatal mortality, need for surgical closure, duration of ventilator support, chronic lung disease, intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleeding, time to full enteral feeds and oliguria. We will search Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias (ROB) and the confidence in the estimate (with Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach). Subgroup analysis according to gestational age, birth weight, different doses of interventions, time of administration of the first dose of the intervention, and echocardiographic definition of haemodynamically significant PDA and ROB are planned. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, if adequate data are available. ETHICS AND DISSEMINATION: The results will help to reduce the uncertainty about the safety and effectiveness of the interventions, will identify knowledge gaps or will encourage further research for other therapeutic options. Therefore, its results will be disseminated through peer-reviewed publications and conference presentations. On the basis of the nature of its design, no ethics approval is necessary for this study. TRIAL REGISTRATION NUMBER: CRD42015015797. PMID- 27456329 TI - Catastrophic health expenditure according to employment status in South Korea: a population-based panel study. AB - OBJECTIVES: Catastrophic health expenditure (CHE) means that the medical spending of a household exceeds a certain level of capacity to pay. Previous studies of CHE have focused on benefits supported by the public sector or high medical cost incurred by treating diseases in South Korea. This study examines variance of CHE in these households according to changes in employment status. We also determine whether a relationship exists according to income level. DESIGN: A longitudinal study. SETTING: We used the Korean Welfare Panel Study (KOWEPS) conducted by the Korea Institute. PARTICIPANTS: The data came from 5335 households during 2009 2012. OUTCOME MEASURE: CHE, defined as health expenditures that were 40% greater than the ability of the household to pay. RESULTS: Households with people who experienced changes in job status from employed to unemployed (OR 2.79, 95% CI 2.06 to 3.78) or were unemployed with no status change (OR 1.57, 95% CI 1.28 to 1.92) were more likely to incur CHE than those containing people who were consistently employed. In addition, low-income families with members who had either lost a job (OR 3.52, 95% CI 2.44 to 5.10) or were already unemployed (OR 1.67, 95% CI 1.29 to 2.16) were more likely to incur CHE than those with family members with a consistent job. CONCLUSIONS: Given the insecure employment status of people with low income, they are more likely to face barriers in obtaining needed health services. Meeting their healthcare needs is an important consideration. PMID- 27456328 TI - Pilot study to test the feasibility of a trial design and complex intervention on PRIoritising MUltimedication in Multimorbidity in general practices (PRIMUMpilot). AB - OBJECTIVE: To improve medication appropriateness and adherence in elderly patients with multimorbidity, we developed a complex intervention involving general practitioners (GPs) and their healthcare assistants (HCA). In accordance with the Medical Research Council guidance on developing and evaluating complex interventions, we prepared for the main study by testing the feasibility of the intervention and study design in a cluster randomised pilot study. SETTING: 20 general practices in Hesse, Germany. PARTICIPANTS: 100 cognitively intact patients >=65 years with >=3 chronic conditions, >=5 chronic prescriptions and capable of participating in telephone interviews; 94 patients completed the study. INTERVENTION: The HCA conducted a checklist-based interview with patients on medication-related problems and reconciled their medications. Assisted by a computerised decision-support system (CDSS), the GPs discussed medication intake with patients and adjusted their medication regimens. The control group continued with usual care. OUTCOME MEASURES: Feasibility of the intervention and required time were assessed for GPs, HCAs and patients using mixed methods (questionnaires, interviews and case vignettes after completion of the study). The feasibility of the study was assessed concerning success of achieving recruitment targets, balancing cluster sizes and minimising drop-out rates. Exploratory outcomes included the medication appropriateness index (MAI), quality of life, functional status and adherence-related measures. MAI was evaluated blinded to group assignment, and intra-rater/inter-rater reliability was assessed for a subsample of prescriptions. RESULTS: 10 practices were randomised and analysed per group. GPs/HCAs were satisfied with the interventions despite the time required (35/45 min/patient). In case vignettes, GPs/HCAs needed help using the CDSS. The study made no patients feel uneasy. Intra-rater/inter-rater reliability for MAI was excellent. Inclusion criteria were challenging and potentially inadequate, and should therefore be adjusted. Outcome measures on pain, functionality and self-reported adherence were unfeasible due to frequent missing values, an incorrect manual or potentially invalid results. CONCLUSIONS: Intervention and trial design were feasible. The pilot study revealed important limitations that influenced the design and conduct of the main study, thus highlighting the value of piloting complex interventions. TRIAL REGISTRATION NUMBER: ISRCTN99691973; Results. PMID- 27456330 TI - Referrals to integrative medicine in a tertiary hospital: findings from electronic health record data and qualitative interviews. AB - OBJECTIVE: To examine patterns of, and decision-making processes, informing referrals for inpatient access to integrative medicine (IM) services at a large, acute care hospital. DESIGN: Retrospective electronic health record review and structured qualitative interviews. SETTING: A 630-bed tertiary care hospital with an IM service available to inpatients. PARTICIPANTS: IM referrals of all inpatients aged >=18 years between July 2012 and December 2014 were identified using the hospital's electronic health record. Fifteen physicians, 15 nurses and 7 administrators were interviewed to better understand roles and perspectives in referring patients for IM services. RESULTS: In the study hospital, primary sources of referrals for IM services were the orthopaedic and neuroscience/spine service lines. While the largest absolute number of IM referrals was made for patients with lengths of stay of 3 days or fewer, a disproportionate number of total IM referrals was made for patients with long lengths of stay (>=10 days), compared with a smaller percentage of patients in the hospital with lengths of stay >=10 days. Physicians and nurses were more likely to refer patients who displayed strong symptoms (eg, pain and anxiety) and/or did not respond to conventional therapies. IM referrals were predominantly nurse-initiated. A built in delay in the time from referral initiation to service delivery discouraged referrals of some patients. CONCLUSIONS: Conventional providers refer patients for IM services when these services are available in a tertiary hospital. Referral patterns are influenced by patient characteristics, operational features and provider perspectives. Nurses play a key role in the referral process. Overcoming cultural and knowledge differences between conventional and IM providers is likely to be a continuing challenge to providing IM in inpatient settings. PMID- 27456331 TI - Description of an incidence-based model for Assessing comorbidity patterns in disease natural history. AB - BACKGROUND: Patients with a chronic disease often suffer from other diseases called comorbidities, which can be important factors in the assessment of risks associated with the disease and its management. However, comorbidities can pose important methodological issues because factors such as time, age, duration and the disease can influence their impact on the risk of interest. METHODS: To identify comorbidities of a chronic disease, it is common practice to construct 2 separate cohorts of patients-a set with the disease and another as a random sample of patients free of the disease-and compare the event rates for each candidate's comorbidity over a specific period between the 2, while accounting for factors which may confound the results. We describe an incidence-based alternative approach that exploits the longitudinal properties of observational databases to track incident event rates along the natural history of the chronic disease. We illustrate it in a retrospective cohort of patients with chronic obstructive pulmonary disease (COPD) aged 50 and above-each patient with COPD was matched with another without COPD on certain confounding factors. RESULTS: We obtained 24 079 matched pairs. We found that chronic conditions such as lung cancer, asthma, fracture and osteoporosis were more common in patients with COPD. We also found evidence of time-varying associations. CONCLUSIONS: Our findings in COPD suggest that time is an important factor and comorbidity studies which are based on information in a single fixed period (such as first year postdiagnosis of COPD) are more likely to report spurious associations. PMID- 27456333 TI - Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation. AB - Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily, which has been implicated in the pathophysiology of the nervous system. Recently, several studies have suggested that BDNF and/or its receptor, tropomyosin related kinase B (TrkB), are involved in tumor growth and metastasis in several cancers, including prostate cancer, neuroblastoma, pancreatic ductal carcinoma, hepatocellular carcinoma, and lung cancer. Despite the increasing emphasis on BDNF/TrkB signaling in human tumors, how it participates in primary tumors has not yet been determined. Additionally, little is known about the molecular mechanisms that elicit signaling downstream of TrkB in the progression of non-small-cell lung cancer (NSCLC). In this study, we report the significant expression of BDNF in NSCLC samples and show that BDNF stimulation increases the synthesis of BDNF itself through activation of STAT3 in lung cancer cells. The release of BDNF can in turn activate TrkB signaling. The activation of both TrkB and STAT3 contribute to downstream signaling and promote human non-small-cell lung cancer proliferation. PMID- 27456332 TI - Ultrastructural demonstration of Cx43 gap junctions in induced pluripotent stem cells from human cord blood. AB - Gap junction proteins are essential for direct intercellular communication but also influence cellular differentiation and migration. The expression of various connexin gap junction proteins has been demonstrated in embryonic stem cells, with Cx43 being the most intensely studied. As Cx43 is the most prominent gap junction protein in the heart, cardiomyocyte-differentiated stem cells have been studied intensely. To date, however, little is known about the expression and the subcellular distribution of Cx43 in undifferentiated stem cells or about the structural arrangement of channels. We, therefore, here investigate expression of Cx43 in undifferentiated human cord-blood-derived induced pluripotent stem cells (hCBiPS2). For this purpose, we carried out quantitative real-time PCR and immunohistochemistry. For analysis of Cx43 ultrastructure and protein assembly, we performed freeze-fracture replica immunogold labeling (FRIL). Cx43 expression was detected at mRNA and protein level in hCBIPS2 cells. For the first time, ultrastructural data are presented on gap junction morphology in induced pluripotent stem (iPS) cells from cord blood: Our FRIL and electron microscopical analysis revealed the occurrence of gap junction plaques in undifferentiated iPS cells. In addition, these gap junctions were shown to contain the gap junction protein Cx43. PMID- 27456334 TI - Impact of Massachusetts Health Reform on Enrollment Length and Health Care Utilization in the Unsubsidized Individual Market. AB - OBJECTIVE: To evaluate the impact of the 2006 Massachusetts health reform, the model for the Affordable Care Act, on short-term enrollment and utilization in the unsubsidized individual health insurance market. DATA SOURCE: Seven years of administrative and claims data from Harvard Pilgrim Health Care. RESEARCH DESIGN: We employed pre-post survival analysis and an interrupted time series design to examine changes in enrollment length, utilization patterns, and use of elective procedures (discretionary inpatient surgeries and infertility treatment) among nonelderly adult enrollees before (n = 6,912) and after (n = 29,207) the MA reform. PRINCIPAL FINDINGS: The probability of short-term enrollment dropped immediately after the reform. Rates of inpatient encounters (HR = 0.83, 95 percent CI: 0.74, 0.93), emergency department encounters (HR = 0.85, 95 percent CI: 0.80, 0.91), and discretionary inpatient surgeries (HR = 0.66 95 percent CI: 0.45, 0.97) were lower in the postreform period, whereas the rate of ambulatory visits was somewhat higher (HR = 1.04, 95 percent CI: 1.00, 1.07). The rate of infertility treatment was higher after the reform (HR = 1.61, 95 percent CI: 1.33, 1.97), driven by women in individual (vs. family) plans. The reform was not associated with increased utilization among short-term enrollees. CONCLUSIONS: MA health reform was associated with a decrease in short-term enrollment and changes in utilization patterns indicative of reduced adverse selection in the unsubsidized individual market. Adverse selection may be a problem for specific, high-cost treatments. PMID- 27456335 TI - Danzhi Qing'e (DZQE) activates AMPK pathway and regulates lipid metabolism in a rat model of perimenopausal hyperlipidaemia. AB - What is the central question of this study? Does Danzhi Qing'e (DZQE) regulate lipid metabolism and improve ovarian function in a rat model of perimenopausal hyperlipidaemia, and could this effect be mediated through the AMPK pathway? What is the main finding and its importance? We revealed that DZQE is a pharmacotherapy that could activate the AMPK pathway to improve ovarian function and lipid metabolism during perimenopause complicated with hyperlipidaemia syndrome in an animal model. Thus, this study provides a novel therapeutic option for treating perimenopausal syndrome and highlights the therapeutic potential of DZQE in perimenopausal rats. Menopause is an important event in a woman's life. During perimenopause, accompanied by development of osteoporosis and dyslipidaemia, ovarian function gradually declines. Dyslipidaemia is a risk factor for cardiovascular disorders, cerebrovascular disease and breast cancer in postmenopausal women. All of these contribute to impairment of liver function, particularly fatty liver disease, because liver dysfunction is associated with ovarian dysfunction and hyperlipidaemia. The aim of this study was to define a therapeutic approach to improve ovarian function and attenuate lipid accumulation in order to prevent perimenopause-induced ovarian dysfunction and hyperlipidaemia. Four-week-old female Wistar rats were injected i.p. with 4 vinylcyclohexene diepoxide (4-VCD) and fed with a high-fat diet (HFD) to serve as a model of perimenopause complicated with hyperlipidaemia. The 4-VCD induces perimenopause, while the HFD causes hyperlipidaemia. Five days after administration of 4-VCD, the 4-VCD + HFD-treated rats were assessed daily for oestrous cycle stage by vaginal cytology. Rats were then assigned into groups, in which 2.5, 5.0 or 10.0 g kg-1 Danzhi Qing'e (DZQE) or estradiol valerate was administered intragastrically for 8 weeks. Expression levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), oestrogen and testosterone measured by enzyme-linked immunosorbent assay served as biomarkers for perimenopause and ovarian dysfunction. The expression levels of AMPK and acetyl CoA carboxylase in the liver were determined with Western blotting, and aspartate aminotransferase and alanine aminotransferase were analysed using an automated biochemical analyser to examine liver function. The DZQE improved ovarian function by upregulating oestrogen and testosterone concentrations in serum and downregulating FSH and LH serum concentrations. Moreover, DZQE reduced serum concentrations of triglyceride, total cholesterol and low-density lipoprotein in a dose-dependent manner to regulate lipid levels during perimenopause. Furthermore, DZQE increased AMPK at both the transcriptional and translational levels and decreased the expression of SREBP-1c gene as well as its downstream target gene, fatty acid synthase. Danzhi Qing'e improved dyslipidaemia during menopause and also had an effect on liver function. Danzhi Qing'e is an effective Chinese herbal compound, which improves ovarian function and lipid metabolism in perimenopause complicated with hyperlipidaemia at least in part through the AMPK pathway. PMID- 27456336 TI - Prevalence of G6PD deficiency and Plasmodium falciparum parasites in asymptomatic school children living in southern Ghana. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder that results in impaired enzyme activity. Although G6PD deficiency is globally distributed it is more prevalent in malaria-endemic countries. Several mutations have been identified in the G6PD gene, which alter enzyme activity. The G6PD genotype predominantly found in sub-Saharan Africa is the G6PDB (G6PD376A) with (G6PD376G) and G6PDA- (G6PD376G/202A, G6PD376G/542T, G6PD376G/680T and G6PD376G/968C) occurring at lower frequencies. AIM: The aim of this study was to identify the prevalence of G6PD deficiency and asymptomatic Plasmodium falciparum carriage in children living in southern Ghana and determine whether G6PD deficiency influences asymptomatic carriage of P. falciparum parasites. METHODS: Blood samples were obtained once a month from 170 healthy Ghanaian school children aged between 5 and 12 years from Basic schools in two communities Obom and Abura with similar rainfall patterns and malaria peak seasons. G6PD enzyme activity was assessed using the qualitative G6PD RDT kit (AccessBIO). G6PD genotyping and asymptomatic parasite carriage was determined by PCR followed by restriction fragment length polymorphism (RFLP) of DNA extracted from dried blood spots. RESULTS: The only sub-Saharan G6PD A- allele detected was the A376G/G202A found in 12.4 % (21/170), of the children and distributed as 4.1 % (7/170) A-, 1.8 % (3/170) A-/A- homozygous deficient males and females and 6.5 % (11/170) A/A- and B/A- heterozygous deficient females. Phenotypically, 10.6 % (15/142) of the children were G6PD deficient. The asymptomatic carriage of P. falciparum by PCR was 50, 29.4, 38.2 and 38.8 % over the months of February through May 2015, respectively, and 28.8, 22.4, 25.9 and 5.9 % by microscopy during the same periods. CONCLUSIONS: G6PD deficiency was significantly associated with a lowered risk of PCR-estimated asymptomatic P. falciparum carriage in children during the off peak malaria season in Southern Ghana. PMID- 27456337 TI - How important is severity for the evaluation of health services: new evidence using the relative social willingness to pay instrument. AB - The 'severity hypothesis' is that a health service which increases a patient's utility by a fixed amount will be valued more highly when the initial health state is more severe. Supporting studies have employed a limited range of analytical techniques and the objective of the present paper is to test the hypothesis using a new methodology, the Relative Social Willingness to Pay. Three subsidiary hypotheses are: (1) that the importance of the 'severity effect' varies with the type of medical problem; (2) that the relationship between value and utility varies with the severity of the initial health state; and (3) that there is a threshold beyond which severity effects are insignificant. For each of seven different health problems respondents to a web-based survey were asked to allocate a budget to five services which would, cumulatively, move a person from near death to full health. The time trade-off utilities of health states before and after the service were estimated. The social valuation of the service measured by the budget allocation was regressed upon the corresponding increase in utility and severity as measured by the pre-service health state utility. Results confirm the severity hypothesis and support the subsidiary hypotheses. However, the effects identified are quantitatively significant only for the most severe health states. This implies a relatively limited redistribution of resources from those with less severe to those with more severe health problems. PMID- 27456338 TI - 3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of L-DOPA. AB - BACKGROUND: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes. RESULTS: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-L-DOPA treatment (25 uM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 uM L-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 uM), and was enhanced by concomitant treatment with entacapone (0.3 uM). The uptake of L-DOPA into and the release of glutathione from striatal astrocytes after L-DOPA treatment (100 uM) were inhibited by simultaneous exposure to 3-OMD (100 uM). CONCLUSIONS: These data suggest that L-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with L-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance L-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of L-DOPA on dopaminergic neurons. PMID- 27456340 TI - The effect of DNA extraction methodology on gut microbiota research applications. AB - BACKGROUND: The effect that traditional and modern DNA extraction methods have on applications to study the role of gut microbiota in health and disease is a topic of current interest. Genomic DNA was extracted from three faecal samples and one probiotic capsule using three popular methods; chaotropic (CHAO) method, phenol/chloroform (PHEC) extraction, proprietary kit (QIAG). The performance of each of these methods on DNA yield and quality, microbiota composition using quantitative PCR, deep sequencing of the 16S rRNA gene, and sequencing analysis pipeline was evaluated. RESULTS: The CHAO yielded the highest and the QIAG kit the lowest amount of double-stranded DNA, but the purity of isolated nucleic acids was better for the latter method. The CHAO method yielded a higher concentration of bacterial taxa per mass (g) of faeces. Sequencing coverage was higher in CHAO method but a higher proportion of the initial sequencing reads were retained for assignments to operational taxonomic unit (OTU) in the QIAG kit compared to the other methods. The QIAG kit appeared to have longer trimmed reads and shorter regions of worse quality than the other two methods. A distinct separation of alpha-diversity indices between different DNA extraction methods was not observed. When compositional dissimilarities between samples were explored, a strong separation was observed according to sample type. The effect of the extraction method was either marginal (Bray-Curtis distance) or none (unweighted Unifrac distance). Taxon membership and abundance in each sample was independent of the DNA extraction method used. CONCLUSIONS: We have benchmarked several DNA extraction methods commonly used in gut microbiota research and their differences depended on the downstream applications intended for use. Caution should be paid when the intention is to pool and analyse samples or data from studies which have used different DNA extraction methods. PMID- 27456339 TI - The effectiveness of non-pyrethroid insecticide-treated durable wall lining to control malaria in rural Tanzania: study protocol for a two-armed cluster randomized trial. AB - BACKGROUND: Despite considerable reductions in malaria achieved by scaling-up long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), maintaining sustained community protection remains operationally challenging. Increasing insecticide resistance also threatens to jeopardize the future of both strategies. Non-pyrethroid insecticide-treated wall lining (ITWL) may represent an alternate or complementary control method and a potential tool to manage insecticide resistance. To date no study has demonstrated whether ITWL can reduce malaria transmission nor provide additional protection beyond the current best practice of universal coverage (UC) of LLINs and prompt case management. METHODS/DESIGN: A two-arm cluster randomized controlled trial will be conducted in rural Tanzania to assess whether non-pyrethroid ITWL and UC of LLINs provide added protection against malaria infection in children, compared to UC of LLINs alone. Stratified randomization based on malaria prevalence will be used to select 22 village clusters per arm. All 44 clusters will receive LLINs and half will also have ITWL installed on interior house walls. Study children, aged 6 months to 11 years old, will be enrolled from each cluster and followed monthly to estimate cumulative incidence of malaria parasitaemia (primary endpoint), time to first malaria episode and prevalence of anaemia before and after intervention. Entomological inoculation rate will be estimated using indoor CDC light traps and outdoor tent traps followed by detection of Anopheles gambiae species, sporozoite infection, insecticide resistance and blood meal source. ITWL bioefficacy and durability will be monitored using WHO cone bioassays and household surveys, respectively. Social and cultural factors influencing community and household ITWL acceptability will be explored through focus-group discussions and in-depth interviews. Cost-effectiveness, compared between study arms, will be estimated per malaria case averted. DISCUSSION: This protocol describes the large-scale evaluation of a novel vector control product, designed to overcome some of the known limitations of existing methods. If ITWL is proven to be effective and durable under field conditions, it may warrant consideration for programmatic implementation, particularly in areas with long transmission seasons and where pyrethroid-resistant vectors predominate. Trial findings will provide crucial information for policy makers in Tanzania and other malaria-endemic countries to guide resource allocations for future control efforts. TRIAL REGISTRATION: NCT02533336 registered on 13 July 2014. PMID- 27456341 TI - Hyperthermia induced HIF-1a expression of lung cancer through AKT and ERK signaling pathways. AB - BACKGROUND: Hyperthermia is a promising treatment for human lung cancer, but recurrence of the primary lesion is common, as the residual tumor becomes adapted to heat treatment and growth is induced by hypoxia-triggered HIF-1a expression. Here, we explored the effects of hyperthermia on HIF-1a expression, proliferation, and lung cancer angiogenesis. METHODS: Human NSCLC NCI-H1650 and SCLC NCI-H446 cell lines were used to examine cell viability, apoptosis, and HIF 1a expression level under a gradient of thermal conditions (37, 42 and 47 degrees C for 40 min). The 47 degrees C heat-adapted NCI-H1650 and NCI-H446 sublines (also called NCI-H1650-b and NCI-H446-b cells) had enhanced viability and HIF-1a expression levels compared to the parental and 42 degrees C heat adapted cells and were thus used for subsequent research. Concentration gradients of wortmannin and PD98095 were used to inhibit AKT and ERK expression, respectively in the NSCLC NCI-H1650-b and SCLC NCI-H446-b cell lines, and cell growth curves were drawn. Western blots were used to detect the expression of HIF 1a, extracellular signal-regulated kinase (ERK), protein kinase B (AKT), phospho ERK, and phospho-AKT. We established a subcutaneous transplantation tumor model with wortmannin and PD98095 intervention. Immunohistochemistry was used to detect the expression of HIF-1a and the vascular specific marker CD34, and tumor growth curves were drawn. RESULTS: Following hyperthermia treatment, HIF-1a expression in 47 degrees C heat-adapted NSCLC and SCLC cell lines was regulated by the AKT pathway. However, HIF-1a expression was also regulated by the ERK pathway in NSCLCs, while SCLCs did not exhibit changes in ERK. These biological behaviors are governed by signaling pathway protein phosphorylation. Furthermore, inhibiting the AKT pathway can suppress the proliferation and angiogenesis potential of both 47 degrees C heat-adapted NSCLCs and SCLCs, but inhibiting the ERK pathway only affects SCLCs. CONCLUSION: Our study suggests that following hyperthermia, the proliferation and angiogenesis potential of residual NSCLCs and SCLCs is induced by HIF-1a. However, HIF-1a expression in NSCLCs is regulated by both the AKT and ERK signaling pathway, but HIF-1a expression in SCLCs is regulated only by the AKT signaling pathway. This study sheds light on the molecular regulatory mechanisms of lung cancer recurrence following hyperthermia treatment. PMID- 27456342 TI - Motivating smokers at outdoor public smoking hotspots to have a quit attempt with a nicotine replacement therapy sample: study protocol for a randomized controlled trial. AB - BACKGROUND: About half of the daily smokers in Hong Kong have never tried and have no intention to quit smoking. More than one-third (37.9 %) of daily smokers have attempted to quit but failed. Nicotine replacement therapy (NRT) is a safe and effective pharmacotherapy to increase abstinence by reducing withdrawal symptoms during the early stage of smoking abstinence. However, the prevalence of NRT use in Hong Kong is lower than in most developed countries. The proposed study aims to assess the effectiveness of providing free NRT samples to smokers on increasing quit attempts and the quit rate. METHODS: Trained university undergraduate students as ambassadors will invite smokers at outdoor public smoking hotspots to participate in the randomized controlled trial, in which eligible smokers will be randomized to receive a 1-week free NRT sample and medication counselling (intervention) or advice to purchase NRT on their own (control). The primary outcome is self-reported quit attempts (no smoking for at least 24 hours) in the past 30 days at 1-month and 3-month telephone follow-up. DISCUSSION: The findings will inform the effectiveness of delivering free NRT samples at outdoor public smoking hotspots to increase quit attempts and abstinence. The study will also provide information on smokers' adherence to the NRT sample, side effects and safety issues related to the usage. This will improve the design of a large trial to test the effect of the NRT sample. TRIAL REGISTRATION: ClinicalTrials.gov NCT02491086 . Registered on 7 July 2015. PMID- 27456343 TI - My 60 years of traditional Chinese and Western medicine integration. PMID- 27456344 TI - Implementing the first regional hospice palliative care program in Ontario: the Champlain region as a case study. AB - BACKGROUND: Regionalization promotes planning and coordination of services across settings and providers to meet population needs. Despite the potential advantages of regionalization, no regional hospice palliative care program existed in Ontario, Canada, as of 2010. This paper describes the process and early results of the development of the first regional hospice palliative care program in Ontario. The various activities and processes undertaken and the formal agreements, policies and documents are described. METHODS: A participative approach, started in April 2009, was used. It brought together over 26 health service providers, including residential hospices, a palliative care unit, community and hospital specialist consultation teams, hospitals, community health and social service agencies (including nursing), individual health professionals, volunteers, patients and families. An extensive stakeholder and community vetting process was undertaken that included work groups (to explore key areas such as home care, the hospital sector, hospice and palliative care unit beds, provision of care in rural settings, e-health and education), a steering committee and input from over 320 individuals via e-mail and town-halls. A Transitional Leadership Group was elected to steer the implementation of the Regional Program over the summer of 2010. This group established the by-laws and details regarding the governance structure of the Regional Program, including its role, responsibilities, reporting structures and initial performance indicators that the Local Health Integration Network (LHIN) approved. RESULTS: The Regional Program was formally established in November 2010 with a competency-based Board of 14 elected members to oversee the program. Early work involved establishing standards and performance indicators for the different sectors and settings in the region, and identifying key clinical needs such as the establishment of more residential hospice capacity in Ottawa and a rural framework to ensure access for citizens in rural and remote regions. Challenges encountered are explored as are the process enablers and facilitators. The paper views the development and implementation process from the perspectives of several frameworks and models related to change management. CONCLUSIONS: Following on several initial achievements, the long term success of the Regional Program will depend on consolidating the early gains and demonstrating changes based on key measurable outcomes. PMID- 27456345 TI - The combined expression of Semaphorin4D and PlexinB1 predicts disease recurrence in colorectal cancer. AB - BACKGROUND: Binding to Sema4D and PlexinB1 induce angiogenesis and invasive growth in colorectal cancer (CRC). The expression of Semaphorin4D (Sema4D) and PlexinB1 has been shown to be related to the prognosis of patients with various malignancies. However, the correlation between the expression of Sema4D and PlexinB1 and the relapse-free survival in patients with colorectal cancer remains controversial. METHODS: The study population included patients who underwent surgery for colorectal cancer (n = 226). The expression of Sema4D and PlexinB1 were analyzed by immunohistochemistry in tissue of stage I, II, and III colon cancers. RESULTS: The immunohistochemical staining of colorectal cancer tissue specimens revealed that 95 (42 %) and 105 (46.4 %) of the specimens were positive for Sema4D and PlexinB1. The expression of Sema4D and PlexinB1 respectively were both found to be significantly related to stage, depth of tumor invasion, lymph node metastasis, lymphatic invasion, and venous invasion, respectively. Sixty three patients (27.9 %) expressed both Sema4D and PlexinB1. The positive expression of both Sema4D and PlexinB1 was found to be an independent risk factor for a worse survival (HR 1.079, CI 1.013-2.868; P = 0.044). CONCLUSION: The combination of Sema4D and PlexinB1 protein detected by immunohistochemistry was therefore useful for predicting disease recurrence in CRC patients. PMID- 27456346 TI - Chromosomal characterization in two species of an Astyanax bimaculatus complex (Characidae, Characiformes) using different techniques of chromosome banding. AB - Astyanax has been the subject of extensive cytogenetic studies due to its wide karyotypic diversity. This genus comprises species complexes, namely groups of fish of difficult morphological differentiation, such as the bimaculatus complex, which includes the characids with a rounded humeral spot. Thence, the present study proposed to accomplish a cytogenetic characterization of two species of this complex: A. asuncionensis and A. altiparanae, aiming to find chromosomal markers that differentiate these species, as well as achieve a better understanding of the karyotype evolution in the genus. For this we used different techniques of chromosome banding as C-banding, impregnation by silver nitrate, fluorochrome staining and FISH with 18S rDNA probe. This is the first cytogenetic study in A. asuncionensis, from Miranda river, which presented 2n = 50 and 18 m + 22sm + 6st + 4a (FN = 96) and single NORs. The populations of A. altiparanae also presented 2n = 50, but with different karyotypic formulae: the population of the Quexada river presented 16 m + 24sm + 4st + 6a (FN = 94) and the Esperanca stream and Jacutinga river showed 16 m + 20sm + 4st + 10a (FN = 90). All analyzed populations showed an interindividual variation in the number and location of the nucleolar organizer regions (NORs). Single and multiple NORs were detected either by impregnation with silver nitrate or by FISH with 18S rDNA probe. After C banding, the two species differed in relation to the composition and heterochromatin distribution. The meiotic cells of A. altiparanae male individuals were also analyzed, showing that, despite the high karyotype variability, chromosome pairing occurs normally. The data show that A. altiparanae and A. asuncionensis share some characteristics with other species of the bimaculatus complex, suggesting a close phylogenetic relationship among those species. However, some features can be used as differentiation chromosomal markers in altiparanae/asuncionensis morphotypes, which could result from a natural speciation process. PMID- 27456347 TI - Soft drinks and sweetened beverages and the risk of cardiovascular disease and mortality: a systematic review and meta-analysis. AB - BACKGROUND: Soft drink consumption is associated with adverse health behaviours that predispose to adverse cardiovascular risk factor profiles; however, it is unclear whether their intake independently leads to an increased risk of cardiovascular events and mortality. We conducted a systematic review and meta analysis to evaluate this. METHODS: Medline and EMBASE were searched in July 2015 for studies that considered soft drink intake and risk of mortality, myocardial infarction (MI) or stroke. Pooled risk ratios (RRs) for adverse outcomes were calculated using inverse variance with a random effects model, and heterogeneity was assessed using the I2 statistic. RESULTS: A total of seven prospective cohort studies with 308,420 participants (age range 34-75 years) were included in the review. The pooled results suggest a greater risk of stroke (RR 1.13, 95% CI 1.02 1.24), and MI (RR 1.22, 95% CI 1.14-1.30), but not vascular events with incremental increase in sugar-sweetened beverage (SSB) consumption. With incremental increase in artificially sweetened beverage (ASB) consumption, there was a greater risk of stroke (RR 1.08, 95% CI 1.03-1.14), but not vascular events or MI. In the evaluation of high vs. low SSB, there was a greater risk of MI (RR 1.19, 95% CI 1.09-1.31) but not stroke, vascular events or mortality. For ASB, there was a significantly greater risk of stroke (RR 1.14, 95% CI 1.04-1.26) and vascular events (RR 1.44, 95% CI 1.02-2.03) but not MI or mortality. CONCLUSIONS: Our results suggest an association between consumption of sugar-sweetened and ASBs and cardiovascular risk, although consumption may be a surrogate for adverse health behaviours. PMID- 27456348 TI - Metastatic thyroid carcinoma presenting as malignant pleural effusion: A cytologic review of 5 cases. AB - Malignant pleural effusion can be a manifestation of many malignancies. Involvement of pleural fluid by metatstatic thyroid carcinoma, though reported, is relatively rare. We present 5 cases of metastatic thyroid carcinoma involving the pleural fluid. The diagnosis of thyroid carcinoma in pleural fluid can be particularly challenging as thyroid transcription factor -1 (TTF-1) which is a marker for carcinoma of thyroid origin is also positive in lung adenocarcinomas (which are more frequently associated with pleural effusions) and thyroglobulin (TG) can often be negative in poorly differentiated/analplastic thyroid carcinomas. In our experience, PAX8 is a particularly useful marker in making the distinction. The diagnosis of metastatic thyroid carcinoma in pleural fluid can be challenging and knowledge of the clinical context and supporting immunohistochemical stains is essential for making the right diagnosis. Diagn. Cytopathol. 2016;44:1085-1089. (c) 2016 Wiley Periodicals, Inc. PMID- 27456349 TI - Developing community-driven quality improvement initiatives to enhance chronic disease care in Indigenous communities in Canada: the FORGE AHEAD program protocol. AB - BACKGROUND: Given the dramatic rise and impact of chronic diseases and gaps in care in Indigenous peoples in Canada, a shift from the dominant episodic and responsive healthcare model most common in First Nations communities to one that places emphasis on proactive prevention and chronic disease management is urgently needed. METHODS: The Transformation of Indigenous Primary Healthcare Delivery (FORGE AHEAD) Program partners with 11 First Nations communities across six provinces in Canada to develop and evaluate community-driven quality improvement (QI) initiatives to enhance chronic disease care. FORGE AHEAD is a 5 year research program (2013-2017) that utilizes a pre-post mixed-methods observational design rooted in participatory research principles to work with communities in developing culturally relevant innovations and improved access to available services. This intensive program incorporates a series of 10 inter related and progressive program activities designed to foster community-driven initiatives with type 2 diabetes mellitus as the action disease. Preparatory activities include a national community profile survey, best practice and policy literature review, and readiness tool development. Community-level intervention activities include community and clinical readiness consultations, development of a diabetes registry and surveillance system, and QI activities. With a focus on capacity building, all community-level activities are driven by trained community members who champion QI initiatives in their community. Program wrap-up activities include readiness tool validation, cost-analysis and process evaluation. In collaboration with Health Canada and the Aboriginal Diabetes Initiative, scale-up toolkits will be developed in order to build on lessons learned, tools and methods, and to fuel sustainability and spread of successful innovations. DISCUSSION: The outcomes of this research program, its related cost and the subsequent policy recommendations, will have the potential to significantly affect future policy decisions pertaining to chronic disease care in First Nations communities in Canada. TRIAL REGISTRATION: Current ClinicalTrial.gov protocol ID NCT02234973 . Date of Registration: July 30, 2014. PMID- 27456351 TI - Neuropsychiatric manifestations of Parkinson's disease. AB - OBJECTIVE: This clinical update review focuses on the classification and description of common neuropsychiatric manifestations in Parkinson's disease (PD). METHOD: We conducted a systematic search of the literature using Pubmed and selected the most recent and relevant papers for this review. RESULTS: Neuropsychiatric manifestations in PD are are very frequent and may arise from an abnormal psychopathological response to the disease, neurobiological changes related to the disease itself, complications of treatments or a combination of all of these. CONCLUSIONS: Neuropsychiatric symptoms may precede the motor clinical presentation of PD. Early recognition is essential. PMID- 27456350 TI - Differential impact of smoking on mortality and kidney transplantation among adult Men and Women undergoing dialysis. AB - BACKGROUND: The extent to which smoking contributes to adverse outcomes among men and women of all ages undergoing dialysis is uncertain. The objective of this study was to determine the differential impact of smoking on risks of mortality and kidney transplantation by age and by sex at dialysis initiation. METHODS: We conducted a population-based cohort of incident U.S dialysis patients (n = 1, 220, 000) from 1995-2010. Age- and sex-specific mortality and kidney transplantation rates were determined for patients with and without a history of cardiovascular disease. Multivariable Cox regression evaluated relative hazard ratios (HR) for death and kidney transplantation at 2 years stratified by atherosclerotic condition, smoking status and age. Analyses were adjusted for demographic characteristics, non-cardiovascular conditions, laboratory variables, socioeconomic and lifestyle factors. RESULTS: The average age was 62.8 (+/-15) years old, 54 % were male, and the majority was white. During 2-year follow-up, 40.5 % died and 5.7 % were transplanted. Age- and sex-specific mortality rates were significantly higher while transplantation rates were significantly lower for smokers with atherosclerotic conditions than non-smokers (P < 0.01). The adjusted mortality hazards were significantly higher for smokers with pre existing coronary disease (HR 1.15, 95 % CI (1.11-1.18), stroke (HR 1.21, 1.16 1.27) and peripheral vascular disease (HR = 1.21, 1.17-1.25) compared to non smokers without these conditions (HR 1.00, referent group). The magnitude of effect was greatest for younger patients than older patients. Contrastingly, the adjusted risks of kidney transplantation were significantly lower for smokers with coronary disease: (HR 0.60, 0.52-0.69), stroke; (HR 0.47, 0.37-0.60), and peripheral arterial disease (HR 0.55, 0.46-0.66) respectively compared to non smokers without these conditions. CONCLUSIONS: We provide compelling evidence that smoking is associated with adverse clinical outcomes and reduced lifespans among dialysis patients of all ages and sexes. The adverse impact is greatest for younger men and women. PMID- 27456353 TI - Diffusion NMR. PMID- 27456352 TI - Implementing guidelines in nursing homes: a systematic review. AB - BACKGROUND: Research on guideline implementation strategies has mostly been conducted in settings which differ significantly from a nursing home setting and its transferability to the nursing home setting is therefore limited. The objective of this study was to systematically review the effects of interventions to improve the implementation of guidelines in nursing homes. METHODS: A systematic literature search was conducted in the Cochrane Library, CINAHL, Embase, MEDLINE, DARE, HTA, CENTRAL, SveMed + and ISI Web of Science from their inception until August 2015. Reference screening and a citation search were performed. Studies were eligible if they evaluated any type of guideline implementation strategy in a nursing home setting. Eligible study designs were systematic reviews, randomised controlled trials, non-randomised controlled trials, controlled before-after studies and interrupted-time-series studies. The EPOC risk of bias tool was used to evaluate the risk of bias in the included studies. The overall quality of the evidence was rated using GRADE. RESULTS: Five cluster-randomised controlled trials met the inclusion criteria, evaluating a total of six different multifaceted implementation strategies. One study reported a small statistically significant effect on professional practice, and two studies demonstrated small to moderate statistically significant effects on patient outcome. The overall quality of the evidence for all comparisons was low or very low using GRADE. CONCLUSIONS: Little is known about how to improve the implementation of guidelines in nursing homes, and the evidence to support or discourage particular interventions is inconclusive. More implementation research is needed to ensure high quality of care in nursing homes. PROTOCOL REGISTRATION: PROSPERO 2014: CRD42014007664. PMID- 27456354 TI - Reconciling concepts of space and person-centred care of the older person with cognitive impairment in the acute care setting. AB - Although a large body of literature exists propounding the importance of space in aged care and care of the older person with dementia, there is, however, only limited exploration of the 'acute care space' as a particular type of space with archetypal constraints that maybe unfavourable to older people with cognitive impairment and nurses wanting to provide care that is person-centred. In this article, we explore concepts of space and examine the implications of these for the delivery of care to older people who are cognitively impaired. Our exploration is grounded in theorisations of space offered by key geographers and phenomenologists, but also draws on how space has been constructed within the nursing literature that refers specifically to acute care. We argue that space, once created, can be created and that nursing has a significant role to play in the process of its recreation in the pursuit of care that is person-centred. We conclude by introducing an alternative logic of space aimed at promoting the creation of more salutogenic spaces that invokes a sense of sanctuary, safeness, and inclusion, all of which are essential if the care provided to the older person with cognitive impairment is apposite to their needs. The concept of 'person-centred space' helps to crystallize the relationship between space and person-centred care and implies more intentional manipulation of space that is more conducive to caring and healing. Significantly, it marks a return to Nightingale's wisdom, that is, to put the person in the best possible conditions for nature to act upon them. PMID- 27456355 TI - Bottle milk feeding and its association with food group consumption, growth and socio-demographic characteristics in Chinese young children. AB - It is recommended that infants from the age of 12 months should be weaned from bottles. However, an overwhelming proportion of young children were still using bottle after the recommended age of bottle-weaning. This cross-sectional study examined the association between utensils for milk drinking and food group consumption, growth and socio-demographic characteristics among young children. Data from the Survey of Infant and Young Child Feeding in Hong Kong were analyzed for 649 children aged 18-48 months old. Dietary outcomes were obtained via 3-day dietary records, while utensils for milk drinking and socio-demographic characteristics were collected from a self-developed questionnaire. Length/height and weight of the children were measured by the nurses. Results showed that daily consumption of formula milk was significantly greater among bottle users or bottle plus cup users than non-bottle users (p < 0.05). Exclusive bottle users had significantly lower intakes of meat and meat alternatives than bottle plus cup users for the 18 to 24-month group (p = 0.001) and lower intakes of fruits than non-bottle users in the 48-month group (p = 0.015). BMI z-score was significantly higher for exclusive bottle users than non-bottle users, even after adjusting for socio-economic factors and child's age (p = 0.006). The results showed that the milk drinking utensil was associated with the amount of formula milk and food group consumption as well as BMI z-score. There is a need to actively discourage prolonged bottle use in order to help young children develop good dietary habits. (c) 2016 John Wiley & Sons Ltd. PMID- 27456356 TI - Downregulation of HMGB1 by miR-34a is sufficient to suppress proliferation, migration and invasion of human cervical and colorectal cancer cells. AB - High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein known to be highly expressed in human cervical (CaCx) and colorectal (CRC) cancers, and sustained high levels of HMGB1 contribute to tumourigenesis and metastasis. HMGB1 targeted cancer therapy is of recent interest, and there are not many studies on miRNA-mediated HMGB1 regulation in these cancers. Since miRNA-based therapeutics for cancer is gaining importance in recent years, it was of interest to predict miRNAs targeting HMGB1. Based on the identification of a potential miR-34a response element in HMGB1-3' untranslated region (3'UTR) and an inverse correlation between HMGB1 and miR-34a expression levels in CaCx and CRC tissues, from a subset of the local population as well as a large sampling from TCGA database, experiments were performed to validate HMGB1 as a direct target of miR 34a in CaCx and CRC cells. Ectopic expression of miR-34a decreased the wild-type HMGB1-3'UTR luciferase activity but not that of its mutant in 3'UTR luciferase assays. While forced expression of miR-34a in CaCx and CRC cells inhibited HMGB1 mRNA and protein levels, proliferation, migration and invasion, inhibition of endogenous miR-34a enhanced these tumourigenic properties. siRNA-mediated HMGB1 suppression imitated miR-34a expression in reducing proliferation and metastasis related events. Combined with the disparity in expression of miR-34a and HMGB1 in clinical specimens, the current findings would help in not only understanding the complexity of miRNA-target regulatory mechanisms but also in designing novel therapeutic interventions in CaCx and CRC. PMID- 27456357 TI - Knockdown of USP39 induces cell cycle arrest and apoptosis in melanoma. AB - The spliceosome machinery composed of multimeric protein complexes guides precursor messenger RNAs (mRNAs) (pre-mRNAs) splicing in eukaryotic cells. Spliceosome components have been shown to be downregulated in cancer and could be a promising molecular target for anticancer therapy. The ubiquitin-specific protease 39 (USP39) is essential for pre-mRNA splicing, and upregulated USP39 expression is noted in a variety of cancers. However, the role of USP39 in the development and progression of melanoma remains unclear. In the present study, USP39 expression was found to be increased in melanoma tissues compared with that in nevus tissues. USP39 silencing via lentivirus-mediated short hairpin RNA (shRNA) significantly suppressed melanoma cell proliferation, induced G0/G1 cell cycle phase arrest, and increased apoptosis in vitro. Moreover, USP39 knockdown suppressed melanoma tumor growth in a xenograft model. In addition, USP39 silencing was associated with the increased expressions of p21, p27, and Bax. Furthermore, the inhibition of USP39 expression decreased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, indicating that ERK signaling pathways might be involved in the regulation of melanoma cell proliferation by USP39. Our findings suggest that USP39 may play crucial roles in the development and pathogenesis of melanoma, and it may serve as a potential therapeutic target for melanoma. PMID- 27456358 TI - Curcumin inhibits cell growth and induces cell apoptosis through upregulation of miR-33b in gastric cancer. AB - In this work, the in vitro experiments about biological mechanisms of curcumin were conducted using the gastric cancer cell lines SGC-7901 and BGC-823. After 24 h exposure to curcumin at the concentrations of 5, 10, 15, 20, and 40 MUmol/L, two cells showed the decreased proliferation and increased apoptosis abilities. Real-time PCR, Cell Counting Kit-8 (CCK-8) assay, western blotting, and cell apoptosis assay were used to further study the underlying mechanisms of curcumin. The first stage of our studies showed that curcumin affected the expression of miR-33b, which, in turn, affected the expression of the X-linked inhibitor of apoptosis protein (XIAP) messenger RNA (mRNA). Next, curcumin was also identified to regulate the proliferation and apoptosis of SGC-7901 and BGC-823 cells. Further bioinformatics analysis and luciferase reporter assays proved that XIAP was one of the target genes of miR-33b. In the next stage, SGC-7901 and BGC-823 cells were treated with 20 MUL curcumin, miR-33b mimics, and small interfering RNA (siRNA) of XIAP, respectively. The results showed that curcumin had similar effects on cell growth and apoptosis as the upregulation of miR-33b and the upregulation of the siRNA of XIAP. The results that followed from the restore experiments showed that curcumin affected cell growth and apoptosis presumably by upregulating the XIAP targeting in gastric cancer. Collectively, our results indicate that curcumin-miR-33b-XIAP coupling might be an important mechanism by which curcumin induces the apoptosis of SGC-7901 and BGC-823 cells. PMID- 27456359 TI - Gene/protein expression of CAPN1/2-CAST system members is associated with ERK1/2 kinases activity as well as progression and clinical outcome in human laryngeal cancer. AB - Recent evidence indicates the involvement of calpains (CAPNs), a family of cysteine proteases, in cancer development and progression, as well as the insufficient response to cancer therapies. The contribution of CAPNs and regulatory calpastatin (CAST) and ERK1/2 kinases to aggressiveness, disease course, and outcome in laryngeal cancer remains elusive. This study was aimed to evaluate the CAPN1/2-CAST-ERK1/2 enzyme system mRNA/protein level and to investigate whether they can promote the dynamic of tumor growth and prognosis. The mRNA expression of marker genes was determined in 106 laryngeal cancer (SCLC) cases and 73 non-cancerous adjacent mucosa (NCLM) controls using quantitative real-time PCR. The level of corresponding proteins was analyzed by Western Blot. SLUG expression, as indicator of pathological advancement was determined using IHC staining. Significant increases of CAPN1/2-CAST-ERK1/2 levels of mRNA/protein were noted in SCLC compared to NCLM (p < 0.05). As a result, a higher level of CAPN1 and ERK1 genes was related to larger tumor size, more aggressive and deeper growth according to TFG scale and SLUG level (p < 0.05). There were also relationships of CAPN1/2 and ERK1 with incidences of local/nodal recurrences (p < 0.05). An inverse association for CAPN1/2, CAST, and ERK1/2 transcripts was determined with regard to overall survival (p < 0.05). In addition, a higher CAPN1 and phospho-ERK1 protein level was related to higher grade and stage (p < 0.05) and was found to promote worse prognosis. This is the first study to show that activity of CAPN1/2- CAST-ERK1/2 axis may be an indicator of tumor phenotype and unfavorable outcome in SCLC. PMID- 27456360 TI - MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen related receptor alpha. AB - Metastasis has become the main challenge for treatment of estrogen receptor alpha (ERalpha) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERRalpha), a nuclear receptor overexpressed in ERalpha negative breast cancer. Targeted inhibition of ERRalpha by si-RNA increased miR-497 expression while overexpression of ERRalpha inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERRalpha by binding to the 3'UTR region of ERRalpha. Luciferase assay and ChIP assay confirmed that ERalpha directly regulated the transcription of miR-497, suggesting that loss of ERalpha lowered miR-497 level in ERalpha negative breast cancer. Further, overexpression of miR-497 not only inhibited ERRalpha expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ERalpha negative breast cancer. Taken together, our findings suggested that, in ERalpha negative breast cancer, the low level of ERalpha reduced miR-497 expression, which promoted ERRalpha expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity. PMID- 27456361 TI - High expression of BAG3 predicts a poor prognosis in human medulloblastoma. AB - Bcl2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock protein (Hsp) 70, regulates various physiological and pathological processes. However, its role in human medulloblastoma has not been clarified. First of all, the expression of BAG3 was examined in formalin-fixed, paraffin-embedded specimens by immunohistochemical staining. And then, the prognostic role of BAG3 was analyzed in 51 medulloblastoma samples. Finally, the roles of BAG3 in the proliferation, migration, and invasion of Daoy medulloblastoma cell were investigated using a specific short hairpin RNA (shRNA). The expression of BAG3 in medulloblastoma tissues was higher than nontumorous samples. Furthermore, BAG3 overexpression significantly correlated with poor prognosis of patients with medulloblastoma. The overall survival and tumor-free survival in patients with BAG3 low expression were higher than high expression. Univariate and multivariate analysis showed that BAG3 overexpression was an independent prognostic marker for medulloblastoma. After the BAG3 knockdown, the Daoy cells exhibited decreased the ability to proliferate and form neurosphere. The preliminary mechanism study showed that overexpression of BAG3 might facilitate the cell cycle transition from G1 to S phase by modulating the cyclin-dependent kinase 2 (CDK2) and cyclin E expression. Additionally, we found that BAG3 might enhance the medulloblastoma cell migratory and invasive ability. In summary, BAG3 overexpression may regulate the survival and invasive properties of medulloblastoma and may serve as a potential therapy target for medulloblastoma. PMID- 27456362 TI - Depletion of UBA protein 2-like protein inhibits growth and induces apoptosis of human colorectal carcinoma cells. AB - Ubiquitin-proteasome system regulates cell proliferation, apoptosis, angiogenesis, and motility, which are processes with particular importance for carcinogenesis. UBA protein 2-like protein (UBAP2L) was found to be associated with proteasome; however, its biological function is largely unknown. In this study, the mRNA levels of UBAP2L in human normal and colorectal carcinoma tissues were analyzed using the datasets from the publicly available Oncomine database ( www.oncomine.org ) and found UBAP2L was overexpressed in colorectal carcinoma tissues. Furthermore, we elucidated the role of UBAP2L in human colorectal cancer via an RNA interference lentivirus system in three colorectal carcinoma cell lines HCT116, SW1116, and RKO. Knockdown of UBAP2L led to suppressed cell proliferation and impaired colony formation. UBAP2L depletion in HCT116 and RKO cells also induced cell cycle arrest as well as apoptosis. Moreover, the phosphorylation of PRAS40, Bad, and the cleavage of PARP were remarkably increased after UBAP2L knockdown by Intracellular signaling array and also the activation of P38 was obviously decreased and the cleavage of Caspase 3 and Bax were increased after UBAP2L silencing by western blot assay, indicated that UBAP2L might be involved in the cell growth by the regulation of apoptosis related proteins. Our findings indicated that UBAP2L may be essential for colorectal carcinoma growth and survival. Lentivirus-mediated small interfering RNA against UBAP2L might serve as a potential therapeutic approach for the treatment of colorectal cancer. PMID- 27456363 TI - Reprogramming bladder cancer cells for studying cancer initiation and progression. AB - The induced pluripotent stem cell (iPSC) technology is the forced expression of specific transcription factors in somatic cells resulting in transformation into self-renewing, pluripotent cells which possess the ability to differentiate into any type of cells in the human body. While malignant cells could also be reprogrammed into iPSC-like cells with lower efficiency due to the genetic and epigenetic barriers in cancer cells, only a limited number of cancer cell types could be successfully reprogrammed until today. In the present study, we aimed at reprogramming two bladder cancer cell lines HTB-9 and T24 using a non-integrating Sendai virus (SeV) system. We have generated six sub-clones using distinct combinations of four factors-OCT4, SOX2, KLF4 and c-MYC-in two bladder cancer cell lines. Only a single sub-clone, T24 transduced with 4Fs, gave rise to iPSC like cells. Bladder cancer cell-derived T24 4F cells represent unique features of pluripotent cells such as epithelial-like morphology, colony-forming ability, expression of pluripotency-associated markers and bearing the ability to differentiate in vitro. This is the first study focusing on the reprogramming susceptibility of two different bladder cancer cell lines to nuclear reprogramming. Further molecular characterisation of T24 4F cells could provide a better insight for biomarker research in bladder carcinogenesis and could offer a valuable tool for the development of novel therapeutic approaches in bladder carcinoma. PMID- 27456364 TI - Substrate recognition of N,N'-diacetylchitobiose deacetylase from Pyrococcus horikoshii. AB - Enzymes of carbohydrate esterase (CE) family 14 catalyze hydrolysis of N-acetyl groups at the non-reducing end of the N-acetylglucosamine (GlcNAc) residue of chitooligosaccharides or related compounds. N,N'-diacetylchitobiose deacetylase (Dac) belongs to the CE-14 family and plays a role in the chitinolytic pathway in archaea by deacetylating N,N'-diacetylchitobiose (GlcNAc2), which is the end product of chitinase. In this study, we revealed the structural basis of reaction specificity in CE-14 deacetylases by solving a crystal structure of Dac from Pyrococcus horikoshii (Ph-Dac) in complex with a novel reaction intermediate analog. We developed 2-deoxy-2-methylphosphoramido-d-glucose (MPG) as the analog of the tetrahedral oxyanion intermediate of the monosaccharide substrate GlcNAc. The crystal structure of Ph-Dac in complex with MPG demonstrated that Arg92, Asp115, and His152 side chains interact with hydroxyl groups of the glucose moiety of the non-reducing-end GlcNAc residue. The amino acid residues responsible for recognition of the MPG glucose moiety are spatially conserved in other CE-14 deacetylases. Molecular dynamics simulation of the structure of the Ph-Dac-GlcNAc2 complex indicated that the reducing GlcNAc residue is placed in a large intermolecular cleft and is not involved with specific interactions with the enzyme. This observation was consistent with results indicating that Ph-Dac displayed similar kinetic parameters for both GlcNAc and GlcNAc2. This study provides the structural basis of reaction-site specificity of Dac and related CE 14 enzymes. PMID- 27456366 TI - Reconstitutions of mitochondrial inner membrane remodeling. AB - Biological membranes exhibit function-related shapes, leading to a plethora of complex and beautiful cell and cell organellar morphologies. Most if not all of these structures have evolved for a particular physiological reason. The shapes of these structures are formed by physical forces that operate on membranes. To create particular shaped cells and cell organelles, membranes must undergo deformations which are determined by the structure and elasticity of the membrane and this process is most probable driven by proteins, lipids and/or interplay of both Zimmerberg and Kozlov (2006). Therefore, an important question of current cell biology in conjunction with physics and mathematics is to elucidate the functional cause for these different membrane morphologies as well as how they are formed. One of the most peculiar membrane shapes is observed in mitochondria. These organelles are surrounded by two membranes and especially the convoluted inner membrane displays a complex ultra-structure. A molecular understanding of how this membrane is shaped is missing to a large extent. Unlike membrane remodeling in classical curvature-dependent processes like clathrin-mediated endocytosis, mitochondria are most likely shaped by integral membrane proteins. Following, we will review the current knowledge of inner mitochondrial membrane architecture and discuss recent findings and advances in understanding the factors that shape this membrane. We will address pending questions especially with regard to the experimentally challenging nature of investigating membrane bending by hydrophobic integral membrane proteins. PMID- 27456365 TI - Nonclassical crystallization in vivo et in vitro (I): Process-structure-property relationships of nanogranular biominerals. AB - A distinct nanogranular fine structure is shared by a wealth of biominerals from several species, classes and taxa. This nanoscopic organization affects the properties and behavior of the biogenic ceramic material and confers on them attributes that are essential to their function. We present a set of structure relationship properties that are rooted in the nanogranular organization and we propose that they rest on a common pathway of formation, a colloid-driven and hence nonclassical mode of crystallization. With this common modus operandi, we reveal the most fundamental and wide spread process-structure-property relationship in biominerals. With the recent increase in our understanding of nonclassical crystallization in vitro and in vivo, this significant process structure-property relationship will serve as a source for new design approaches of bio-inspired materials. PMID- 27456367 TI - Late outcomes in children with Shone's complex: a single-centre, 20-year experience. AB - OBJECTIVE: Shone's syndrome is a complex consisting of mitral valve stenosis in addition to left ventricle outflow obstruction. There are a few studies evaluating the long-term outcomes in this population. We sought to determine the long-term outcomes in our paediatric population with Shone's syndrome and the factors associated with left heart growth. METHODS: All patients diagnosed with Shone's syndrome with biventricular circulation treated between 1978 and 2010 were reviewed. Baseline echocardiograms and data from catheterisations were also reviewed. Number of interventions (surgical+transcatheter), incidence of mitral valve replacement, and incidence of heart transplantation were tracked. Survival of the population and left heart structural growth were also reviewed. RESULTS: A total of 121 patients with Shone's syndrome presented at a median age of 28 days (0-17.3 years) and were followed-up for 7.2 years (0.01-35.5 years). These patients underwent 258 interventions during the study period, and the presence of coarctation was associated with repeat left heart interventions. The 10-year, transplant-free survival was 86%. Presence of pulmonary hypertension was associated with mortality. Left heart structural growth was seen for mitral and aortic valve annuli and left ventricular end-diastolic dimension over time. CONCLUSIONS: Shone's syndrome patients undergo a number of left heart interventions. Coarctation of the aorta is associated with an increased likelihood for repeat interventions. Survival appears to be more favourable than expected. Significant left heart growth will occur in the population. Pulmonary hypertension is associated with an increased risk of mortality. PMID- 27456369 TI - Resourcing: An approach used by foreign-born parents struggling on in childhood cancer care. AB - PURPOSE: To gain knowledge about foreign-born parents' experiences of dealing with their child's illness and treatment in the context of pediatric cancer care. METHOD: Data from 11 individual interviews with foreign-born parents were analyzed using qualitative inductive constant comparative analysis. RESULTS: To struggle on in childhood cancer care, foreign-born parents engaged in resourcing using various strategies including: information-monitoring, staying strong, support-seeking and concern-focusing. Parents experienced obstacles to information-monitoring and support-seeking related to their foreign background. CONCLUSIONS: The results provide a framework for understanding how foreign-born parents try to deal with childhood cancer care and can be used by health care staff to support their resourcing. Even though preconditions might differ, the strategies presented might also be used by native-born parents however further studied are needed. PMID- 27456368 TI - Hydrogen sulfide mediates the protection of dietary restriction against renal senescence in aged F344 rats. AB - Renal aging is always accompanied by increased oxidative stress. Hydrogen sulfide (H2S) can be up-regulated by 50% dietary restriction (DR) for 7-day and can block mitochondrial oxidative stress. H2S production exerts a critical role in yeast, worm, and fruit fly models of DR-mediated longevity. In this study, we found that renal aging could be attenuated by 30% DR for 6-month (DR-6M) and life-long (DR LL), but not for 6-week (DR-6W). The expressions of cystathionine-gamma-lyase (CGL) and cystathionine-beta- synthase (CBS) were improved by DR-6M and DR-LL. Endogenous H2S production shared the same trend with CBS and CGL, while glutathione (GSH) didn't. When comparing efficiencies of DR for different durations, more evident production of H2S was found in DR-6M and DR-LL than in DR 6W. Finally the level of oxidative stress was improved by DR-6M and DR-LL rather than by DR-6W. It concluded that aged rats had the ability to produce enough H2S on 30% DR interventions protecting against renal aging, and the effect of DR for long-term were more significant than that of DR for short-term. PMID- 27456370 TI - Clinical and neurophysiological evaluation of persistent sensory disturbances in breast cancer women after mastectomy with or without radiotherapy. AB - PURPOSE: Breast cancer surgery or radiotherapy (RT) are potential causes of persistent pain syndrome. It remains to be clarified whether numbness or pain reported by patients after mastectomy and RT are conditioned by changes in nerve transmission. The aim of this study was to examine the potential relationship between subjective sensory complications and neurophysiological examinations in breast cancer survivors with post-mastectomy pain syndrome. METHODS: Sixty breast cancer survivors (30 patients only after mastectomy - group A; and 30 after mastectomy with RT - group B) complaining of pain and sensory disturbances in the brachial plexus area and 20 healthy women (group C) were studied with regard to sensory perception and pain intensity using the Visual Analogue Scale and electroneurography (ENG). RESULTS: There was a statistically significant decrease in the amplitudes in SCV recordings following stimulation of the ulnar (p = 0.04) and lateral cutaneous antebrachii nerves (p = 0.02) in group B in comparison to group C. Additionally, a significant decrease in the amplitude and conduction velocity parameters was detected in the sensory fibers of the median and medial cutaneous antebrachii nerves in group A (p = 0.00 and p = 0.02, respectively) in comparison to group C. CONCLUSIONS: The results of this pilot study suggest persistent post-mastectomy pain syndrome sometimes appears as a result of nerve injury in course of breast cancer surgery and RT. Therefore studies in nerve conduction may be added to the comprehensive patient assessment used in planning breast cancer patients' rehabilitation after oncological treatment has finished. PMID- 27456371 TI - From an illusion of certainty into a reality of uncertainty: A longitudinal qualitative study of how people affected by laryngeal cancer use information over time. AB - PURPOSE: Patients diagnosed with laryngeal cancer and their families face unique challenges. Providing information is an essential component of care. However little is known about the way in which they use information. This study aims to explore the different types of information used by laryngeal cancer patients and their carers from diagnosis into the follow up phase. METHOD: The study adopted an interpretive longitudinal design using qualitative interviews at two specific time points. Twenty laryngeal cancer patients and 17 carers were interviewed. Data were analysed using Framework Analysis. RESULT: Two main categories of information: professional and experiential, were found to be used, drawn from a range of sources. The information received at diagnosis appeared to contribute to an 'illusion of certainty' that life would return to normal at the end of treatment. However, as patients progressed into follow-up, many were propelled into a 'reality of uncertainty' due to the "disconnect" between the expectations both patient and carer developed from information received over the cancer trajectory. CONCLUSION: The findings from this longitudinal study suggest that people affected by laryngeal cancer use two broad categories of information derived from a range of different sources and influenced by their own experiences. Health professionals need to situate information in the context of the individual's understanding and prior knowledge of health and illness to help generate more realistic expectations of treatment outcomes. The level of uncertainty experienced by both patients and their carers after treatment suggests a clear need for continued supportive care. PMID- 27456372 TI - Causes of inadequate intake of nutrients during the treatment of children with chemotherapy. AB - PURPOSE: The purpose of the research was to explore nurses' perceptions of different causes of inadequate food intake in children treated with chemotherapy and to determine how often nurses identify these causes. METHOD: Qualitative and quantitative approaches were used. Qualitative data were first gathered using semistructured interviews in a sample of six nurses and analysed by conventional content analysis. Based on the results of qualitative data and literature analysis, a 28-item questionnaire was developed and evaluated for its face validity in a sample of fifteen nurses. Questionnaires were then administered to twenty-seven nurses working at one pediatric oncology ward. Quantitative data were analysed using descriptive statistic. RESULTS: The major themes that emerge from the content analysis, describing nurses' perceptions of causes of inadequate food intake in children undergoing chemotherapy, were as follows: physiological causes of eating problems, psychological causes of eating problems, change in food selection, hospital food and individual counselling. 13 causes of inadequate food intake were identified from the questionnaire data. Pain due to mucositis was the most commonly identified cause of inadequate food intake in children, followed by nausea and vomiting, altered taste, loss of appetite and an altered smell. Psychological causes of eating problems are rarely identified. CONCLUSION: Nurses identify most of the physiological and psychological causes of inadequate food intake in children treated with chemotherapy. The early identification and management by nurses of inadequate food intakes should be part of the curriculum for nurse education as well as part of treatment planning in clinical environment. PMID- 27456373 TI - Childhood cancer: Impact on parents' marital dynamics. AB - PURPOSE: To explore and analyze how marital relationships are affected by the crisis generated by the diagnosis and intensive regimens required in the treatment of children with cancer. METHOD: A descriptive study with a qualitative data analysis was conducted. In-depth individual interviews were carried out with 18 married biological parents of children with cancer. Data was analyzed using an inductive content analysis. RESULTS: The following themes represented the couples' experiences: (1) Abrupt changes after the child's diagnosis resulting in marital strain and need to focus on the present; (2) United but distant; (3) Exchanging roles; (4) Being parents all the time; (5) Focusing on the positive side of the experience; (6) Rescuing the marital relationship. The marital relationship of parents with a child/adolescent who has cancer may undergo either positive or negative changes, with intimacy and sexuality being negatively affected by the disease. Although the relationship may be more fragile after the illness, increased mutual commitment was observed in some couples. CONCLUSIONS: Results indicate that health professionals should include parents as an important focus of their care. The establishment of solid bonds to enhance couples' communication is recommended as a way to provide anticipatory guidance to address the identified changes in marital relationships. The opportunities for dialog and partnership help couples to target their needs and recognize their strengths in order to mitigate the impact of a child's illness. PMID- 27456374 TI - Experiences with a low-iodine diet: A qualitative study of patients with thyroid cancer receiving radioactive iodine therapy. AB - PURPOSE: This study aimed to describe hormone interruption experiences related to not only physical problems, but also psychological, social, and spiritual problems, in patients who had undergone total thyroidectomy. METHODS: In-depth interviews were performed with five participants, four women and one man, aged between 28 and 58. The participants were subjected to high-dose radiation of 100 150 mCi and had experienced abrupt hormonal interruptions after undergoing total thyroidectomy. The analysis was conducted using Giorgi's descriptive phenomenological method. RESULTS: Five essential components emerged as the interviews were dissected: dietary disruption due to discomfort, distress from overall bodily congestion, feelings of isolation as normalcy is lost from their daily routine, spending daily life with unfamiliar functional declines due to the LID, a lethargic state due to the lack of a place to which patients could retreat from the stress of hormone absence. CONCLUSIONS: The participants showed insecurity and depression due to an unbalanced diet, limited activities, and an abnormal lifestyle induced by the treatment. This treatment-related information can help healthcare providers readily understand and alleviate symptoms of thyroid cancer patients treated with RAI therapy. PMID- 27456375 TI - Managing relapsed myeloma: The views of patients, nurses and doctors. AB - PURPOSE: The study aim was to explore whether there were differing opinions on the current management of relapsed myeloma between patients and health care professionals, a topic which has never been explored previously in the literature. METHODS: This qualitative study was undertaken at a regional specialist haematology centre in Ireland. Individual interviews were undertaken with multiple myeloma patients with relapsed disease (n = 8). Three focus groups were also undertaken with haematology nurse specialists, haematology doctors and staff nurses working in a haematology day unit (n = 17). The analysis of interview data was guided by thematic analysis. RESULTS: Two central themes were interpreted from the interview data: 'shared decision making with the expert patient' and 'an unpredictable disease journey'. Patients felt well informed regarding their illness but faced difficult decisions at times. Nurses and doctors stressed the importance of the early introduction of palliative care but acknowledged difficulties due to myeloma being unpredictable. CONCLUSION: Managing relapsed myeloma was fraught with complex issues. Patients developed alternative ways of coping with their disease including adopting the role of the 'expert patient', continuing to battle their disease and living with a chronic illness. Health care professionals struggle to manage the realities of a disease where the prognosis is improving. Uncertainty around patients' care and difficulties such as when 'enough is enough', continue to cause challenges. The transition to a chronic disease offers hope to patients and an opportunity for health care professionals to implement holistic care plans encouraging patients to be self proactive. PMID- 27456376 TI - Patients' and clinicians' experiences of holistic needs assessment using a cancer distress thermometer and problem list: A qualitative study. AB - PURPOSE: Psychosocial needs assessment is recommended for patients undergoing cancer treatment, but trials of effectiveness of assessment tools provide mixed results. This qualitative study aimed to understand how such tools are experienced by patients and clinicians in order to optimise use in the future. METHODS: Qualitative interviews were used in a mixed-methods sequential design following a randomised controlled trial of needs assessment using the Distress Thermometer and Problem List (DT&PL), and explored patients' and clinicians' evaluations of the needs assessment process. RESULTS: Benefits of needs assessment using the DT&PL included the potential to detect hidden distress, allow opportunity for distress to be discussed, and to deliver outcomes to address problems. However, effectiveness and patient willingness to report all forms of distress could be hindered by: clinicians feeling ill-equipped to deal with 'non-physical' distress and patients questioning their appropriateness to do so; time constraints; insufficient support services and referral guidelines; inappropriate timing; and lack of follow-up. CONCLUSIONS: The benefits of a holistic needs assessment cannot be realised without matching time and frequency of administration to the dynamic nature of distress during cancer, and making changes to the context of delivery - for instance, providing protected time, increasing referral options and clinician training. Significant investment is needed to optimise potential benefits for patients. PMID- 27456377 TI - Evaluating the cancer related fatigue by children, mothers, and nurses in Turkish pediatric oncology patients. AB - PURPOSE: The aims of this study were to evaluate cancer related fatigue by children', mothers', and nurses' perspectives in recently diagnosed pediatric oncology patients, to evaluate levels of agreement between the fatigue scales, and to evaluate the relationships between fatigue and sample characteristics. METHOD: The sample of this cohort, descriptive, correlational study consisted of 26 recently cancer diagnosed children between the ages of 7 and 12, receiving inpatient treatment in pediatric oncology/hematology units, their mothers and their nurses. The data about children's fatigue were collected using the Child Fatigue Scale-24 h, Parent Fatigue Scale-24 h and Staff Fatigue Scale-24 h, for two consecutive days in the second and third weeks of the patient's first chemotherapy treatment cycle. RESULTS: The mean scores of the Child Fatigue Scale 24 h showed the children's fatigue to be at a moderate level, a statistically significant difference was found between the CFS-24 h and PFS-24 h mean scores in the first and second measurement (p < 0.05). The Intraclass correlation showed a good agreement between scales and repeated measurements for these scales. CONCLUSION: Fatigue in recently diagnosed cancer patients is an important symptom which is of particular concern to the children, their parents and nurses. The study showed that these three scales can be used alone an also used simultaneously, and also proved that these scales are reliable for repeated measurements. PMID- 27456378 TI - Exploring patient support by breast care nurses and geographical residence as moderators of the unmet needs and self-efficacy of Australian women with breast cancer: Results from a cross-sectional, nationwide survey. AB - PURPOSE: This study investigated whether use of services of a breast care nurse (BCN) at any time during treatment for breast cancer led to reduced unmet needs and increased self-efficacy among women with breast cancer. A secondary aim was to analyse comparisons between urban and rural and remote dwellers. METHOD: Participants were Australian women who completed treatment for breast cancer at least 6 months before the survey date, recruited through two national databases of women diagnosed with breast cancer. The cross-sectional online survey consisted of two well validated measures, the SCNS-SF34 and the CASE-Cancer Scale. Statistical data were analysed using SPSS, with chi-square used to measure statistical significance. RESULTS: A total of 902 participants responded to the survey. Unmet needs in the psychological domain were most prominent. Respondents who used the services of a BCN were significantly less likely to report unmet needs regarding tiredness, anxiety; future outlook; feelings about death and dying; patient care and support from medical staff; and provision of health systems and information. Scores of self-efficacy showed women using the services of a BCN had significantly higher self-efficacy when seeking and obtaining information (rho <= 0.001) and understanding and participating in care (rho = 0.032). Urban dwellers were more likely to have choice of health care service, but overall neither unmet needs nor perceived self-efficacy varied statistically significantly by remoteness. CONCLUSIONS: Women with breast cancer experience a range of unmet needs; however those using BCN services demonstrated positive outcomes in terms of decreased unmet needs and increased self-efficacy. PMID- 27456379 TI - A randomized controlled trial of qigong on fatigue and sleep quality for non Hodgkin's lymphoma patients undergoing chemotherapy. AB - PURPOSE: This study aimed to evaluate the effects of Chan-Chuang qigong exercise in non-Hodgkin's lymphoma patients who were undergoing chemotherapy on fatigue intensity and sleep quality. METHODS: The study was a single-centre, controlled randomized study. One hundred and eight subjects were randomly assigned to the qigong group (n = 54) or control group (n = 54). The qigong group received Chan Chuang qigong exercise 20-min twice daily for 21 days in the course of the chemotherapy treatment, whereas the control group without special exercise intervention. Outcome measures included fatigue and sleep quality. RESULTS: After the three-week intervention, participants who were in the qigong group had lower fatigue intensity scores than those in the control group. The results of generalized estimating equations (GEE) analyses showed a significant group-by time interaction effect in average fatigue, worse fatigue, and overall sleep quality (p < 0.001). The average fatigue, worse fatigue, and overall sleep quality significantly decreased over time in the qigong group. CONCLUSIONS: Chan Chuang qigong exercise could be regarded as an adjunct measure in clinical practice. This study cannot completely discount the possible influence of placebo effects, and more objective clinical outcome measures are needed to produce our findings with long-term follow-up in a randomized controlled study. PMID- 27456380 TI - Application and evaluation of Benefit Finding Scale (BFS) in early-stage cancer patients from China. AB - PURPOSE: To adapt the Benefit Finding Scale (BFS) from English to a Chinese version after considering cross-cultural influences, to validate the tool for assessing benefit in Chinese-speaking patients with early-stage cancer, and to analyze the relationships between BF and sociodemographic and disease-related variables. METHODS: In part I of the study, the Chinese BFS was adapted from the English version by developing guidelines after due consideration for cross cultural influences. The translation validity index was used for assessing the quality of translation, and further refining was carried out by administering the scale on early-stage cancer patients (N1 = 200, N2 = 351) in part II and III. The Chinese version of the BFS was analyzed for reliability, dimensionality and construct validity. Relationships between BF and sociodemographic and disease related variables were analyzed by ANOVA and regression models. RESULTS: The Chinese BFS was received favorably by patients during the preliminary testing. Cronbach's alpha and interclass correlation coefficients exceeded 0.7, and factor analysis yielded six factors. Convergent validity, discriminant validity and concurrent validity results indicated a satisfactory psychometric value. Sociodemographic and disease-related predictors of BF were observed. CONCLUSION: The Chinese BFS demonstrated good patient acceptability and exhibited strong psychometric properties among Chinese patients with early-stage cancer. There were differences between Chinese cancer patients' benefit finding and patients with cancer in foreign countries, domestic cancer patients revealed high score in social relationship and family relationship dimension. Educational level, monthly individual income, treatment and physical exercise were the predictors of Chinese cancer patients' benefit finding. PMID- 27456381 TI - Feasibility of a mobile and web-based intervention to support self-management in outpatients with cancer pain. AB - PURPOSE: Cancer pain is a prevalent and distressing symptom. To enhance self management in outpatients, a multi-component intervention was developed, integrating patient self-management and professional care through healthcare technology. This article describes feasibility of the intervention in everyday practice. METHOD: Patients with moderate to severe cancer pain (n = 11) and registered nurses specialized in pain and palliative care (n = 3) participated in a four-week study. The intervention involved daily monitoring, graphical feedback, education, and advice by means of a mobile application for patients and a web application for nurses. Learnability, usability and desirability were measured in patients with a 20-item questionnaire (1-5 scale), higher scores indicating better feasibility. Patients' adherence was based on completion rates from server logs. Single semi-structured interviews with patients and a focus group interview with nurses provided insight into experiences. RESULTS: Questionnaire findings confirmed learnability (4.8), usability (4.8) and desirability (4.6) of the application for patients. Average completion rates were 76.8% for pain monitoring, 50.4% for medication monitoring and 100% for education sessions. Interviews revealed that patients were pleased with the simplicity of the mobile application and appreciated different components. Nurses agreed upon the added value and were mostly positive about the possibilities of the web application. Patients and nurses provided ideas for improvements relating to the content and technical performance of the intervention. CONCLUSIONS: Study results demonstrate feasibility of the intervention in everyday practice. Provided that content-related and technical adjustments are made, the intervention enables patients with cancer pain to practice self-management and nurses to remotely support these patients. PMID- 27456382 TI - Experiences and coping strategies of oncology patients undergoing oral chemotherapy: First steps of a grounded theory study. AB - PURPOSE: Chemotherapies are increasingly available for oral application. Previous studies have focussed on differences between orally and intravenously administered chemotherapies, mostly following quantitative designs surveying patients' preferences and adherence. The lived experience of patients undergoing oral chemotherapy has been rarely explored. Therefore, this study investigates how patients experience oral chemotherapy. METHOD: We conducted open interviews with six patients and two spouses. Recruitment took place in the outpatient clinic of an urban Swiss hospital. Data collection and analysis followed the principles of Straussian grounded theory. RESULTS: The participants reported physical and emotional reluctance towards oral chemotherapy as well as toxic side effects. Feeling responsible emerged as a core phenomenon. All participants intended to adhere to the therapy although this was challenging because of the complex medication regimen. Belief in the effectiveness of the therapy was a strengthening factor. CONCLUSIONS: All participants reported to be highly adherent to oral chemotherapy. Although they experienced some toxic side effects, they did not react. Monitoring toxicities and support in everyday life should be a core feature of care. PMID- 27456383 TI - Age differences in fatigue, decrements in energy, and sleep disturbance in oncology patients receiving chemotherapy. AB - OBJECTIVE: The number of older adults with cancer is increasing. Given the limited amount of research and the inconsistent findings regarding age differences in common physical symptoms associated with cancer and its treatments, the purposes of this study, in a sample of oncology outpatients receiving chemotherapy (CTX), were to evaluate for age differences in demographic and clinical characteristics, as well as in occurrence rates of and severity ratings for fatigue, decrements in energy, and sleep disturbance. In addition, using regression analysis techniques, within and across age groups, demographic and clinical characteristics associated with the severity of each symptom were evaluated. METHODS: Patients (n = 1343) were dichotomized into younger (<65 years) and older (>=65 years) age groups. Patients completed self-report questionnaires prior to their next dose of CTX. RESULTS: Overall, our findings suggest that compared to younger patients, older adults experience a lower or similar level of fatigue, decrements in energy, and sleep disturbance. However, it should be noted that both age groups experienced high occurrence rates and moderate to severe levels of all three symptoms. CONCLUSIONS: Clinicians need to assess all oncology patients receiving CTX for these three symptoms. Future research needs to determine the biopsychosocial reasons that underlie these age related differences in fatigue, decrements in energy, and sleep disturbance. PMID- 27456385 TI - Development of Celiac Disease Therapeutics: Report of the Third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics Workshop. PMID- 27456384 TI - High Efficacy of ABT-493 and ABT-530 Treatment in Patients With HCV Genotype 1 or 3 Infection and Compensated Cirrhosis. AB - BACKGROUND & AIMS: The combination of ABT-493 (NS3/4A protease inhibitor) plus ABT-530 (NS5A inhibitor) has shown high rates of sustained virologic response at post-treatment week 12 (SVR12) in noncirrhotic patients infected with hepatitis C virus (HCV) genotypes (GTs) 1-6. We describe 2 open-label phase 2 studies investigating the efficacy and safety of ABT-493 plus ABT-530 with or without ribavirin (RBV) in GT1- or GT3-infected patients with compensated cirrhosis. METHODS: Patients with GT1 infection received 200 mg ABT-493 plus 120 mg ABT-530 for 12 weeks. Patients with GT3 infection were randomized 1:1 to receive 300 mg ABT-493 plus 120 mg ABT-530 with or without once-daily 800 mg RBV for 12 weeks; treatment-experienced patients who were not treated with RBV received 16 weeks of therapy. Efficacy was measured by SVR12, defined as an HCV-RNA level less than 25 IU/mL. Adverse events and laboratory parameters were evaluated throughout the study. RESULTS: Twenty-seven patients with GT1 infection and 55 patients with GT3 infection were enrolled. The majority were treatment-naive (84%) and male (65%). In patients with GT1 infection, SVR12 was achieved by 96% (26 of 27; 95% confidence interval [CI], 82-99) of patients, with 1 relapse. Among GT3-infected patients, SVR12 was achieved in 96% (27 of 28; 95% CI, 82-99) of patients in the RBV-free arm (1 relapse), and in 100% (27 of 27; 95% CI, 88-100) in the RBV containing arm. The most common adverse events were headache, fatigue, and nausea. Laboratory abnormalities were rare; no patient discontinued treatment. CONCLUSIONS: In cirrhotic HCV GT1- or GT3-infected patients, ABT-493 plus ABT-530 with or without RBV achieved SVR12 rates of 96%-100% and was well tolerated. ClinicalTrials.gov identifiers NCT02243280 and NCT02243293. PMID- 27456386 TI - Trends in Liver Transplantation Multiple Listing Practices Associated With Disparities in Donor Availability: An Endless Pursuit to Implement the Final Rule. PMID- 27456387 TI - Hepatitis B Vaccination: Putting Hepatologists Out of Business? PMID- 27456388 TI - Effect of Registries and Cohort Studies on HCV Treatment. PMID- 27456389 TI - Acinar Ductal Metaplasia: Yap Fills a Gap. PMID- 27456391 TI - Addition of PLA2 to CRP enhances sepsis diagnosis. PMID- 27456392 TI - Activation of the AMPK/Sirt1 pathway by a leucine-metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans. AB - BACKGROUND: We have previously shown leucine (Leu) to activate Sirt1 by lowering its KM for NAD+, thereby amplifying the effects of other sirtuin activators and improving insulin sensitivity. Metformin (Met) converges on this pathway both indirectly (via AMPK) and by direct activation of Sirt1, and we recently found Leu to synergize with Met to improve insulin sensitivity and glycemic control while achieving ~80% dose-reduction in diet-induced obese mice. Accordingly, we sought here to define the mechanism of this interaction. METHODS: Muscle cells C2C12 and liver cells HepG2 were used to test the effect of Met-Leu on Sirt1 activation. Caenorhabditis elegans was used for glucose utilization and life span studies. RESULTS: Leu (0.5mmol/L)+Met (50-100MUmol/L) synergistically activated Sirt1 (p<0.001) at low (<=100MUmol/L) NAD+ levels while Met exerted no independent effect. This was associated with an increase in AMPK and ACC, phosphorylation, and increased fatty acid oxidation, which was prevented by AMPK or Sirt inhibition or silencing. Met-Leu also increased P-IRS1/IRS1 and P-AKT/AKT and in insulin-independent glucose disposal in myotubes (~50%, p<0.002) evident within 30 min as well as a 60% reduction in insulin EC50. In addition, in HepG2 liver cells nuclear CREB regulated transcription coactivator 2 (CRTC2) protein expression and phosphorylation of glycogen synthase was decreased, while glycogen synthase kinase phosphorylation was increased indicating decreased gluconeogenesis and glycogen synthesis. We utilized C. elegans to assess the metabolic consequences of this interaction. Exposure to high glucose impaired glucose utilization and shortened life span by ~25%, while addition of Leu+Met to high glucose worms increased median and maximal life span by 29 and 15%, respectively (p=0.023), restored normal glucose utilization and increased fat oxidation ~two-fold (p<0.005), while metformin exerted no independent effect at any concentration (0.1-0.5mmol/L). CONCLUSION: Thus, Leu and Met synergize to enable Sirt1 activation at low NAD+ concentrations (typical of energy replete states). Sirt1 and AMPK activations are required for Met-Leu's full action, which result in improvements in energy metabolism and insulin sensitivity. PMID- 27456393 TI - Developing a Compassionate Internal Supervisor: Compassion-Focused Therapy for Trainee Therapists. AB - : The concept of an 'internal supervisor' has been used in psychotherapy to describe the way in which the supervisory relationship is internalized and utilized by the supervisee. This research explores the possibility, and potential benefit, of training therapists to develop a 'compassionate internal supervisor'. A training programme was developed for trainee cognitive-behavioural therapists using adapted versions of compassion-focused therapy interventions. The training focused on guided imagery exercises and reflective practices undertaken for a 4 week period. Seven trainee cognitive-behavioural therapists were interviewed, utilizing a semi-structured format, regarding their experience of the training programme. The resulting transcriptions were analysed using Interpretative Phenomenological Analysis (IPA). The analysis identified six super-ordinate themes: (1) the varied nature of the supervisor image, (2) blocks and their overcoming, (3) increased compassion and regulation of emotion, (4) impact on cognitive processes, (5) internalization and integration, and (6) professional and personal benefit. The themes describe the varied ways in which participants created and experienced their compassionate supervisor imagery. Working with the personal blocks encountered in the process provided participants with a deeper understanding of the nature of compassion and its potential to support them in their training, practice and personal lives. The process and impact of 'internalizing' a compassionate supervisory relationship is described by participants and then discussed for potential implications for psychotherapy training and self-practice. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Compassion-focused therapy, and related compassionate-mind imagery exercises, can be adapted specifically to develop compassion in trainee psychotherapists. Creating, and engaging with, an 'ideal compassionate supervisor' in an imaginal form can support psychotherapy trainees in their clinical practice and development, their supervision and their personal lives. The cultivation of therapist self-compassion can reduce unhelpful cognitive processes such as worry, rumination and self-criticism whilst increasing self reflection, attentional flexibility and approach behaviour. Identifying, and working with, blocks to compassion is important when cultivating clinician self compassion Therapist self-practice of compassion-focused exercises can provide important insights into the nature of compassion and its cultivation in clients. PMID- 27456394 TI - Frequency and survival pattern of in-hospital cardiac arrests: The impacts of etiology and timing. AB - OBJECTIVE: Define the frequency and survival pattern of cardiac arrests in relation to the hospital day of event and etiology of arrest. SUBJECT AND METHODS: Retrospective cohort study of adult in-hospital cardiac arrests between July 1, 2005, and June 30, 2013, that were classified by etiology of deterioration. Arrests were divided based on hospital day (HD) of event (HD1, HD2 7, HD>7 days), and analysis of frequency was performed. The primary outcome of survival to discharge and secondary outcomes of return of spontaneous circulation (ROSC) and favorable neurological outcomes were compared using multivariable logistic regression analysis. RESULTS: A total of 627 cases were included, 193 (30.8%) cases in group HD1, 206 (32.9%) in HD2-7, and 228 (36.4%) in HD>7. Etiology of arrest demonstrated variability across the groups (p<0.001). Arrests due to ventilation issues increased in frequency with longer hospitalization (p<0.001) while arrests due to dysrhythmia had the opposite trend (p=0.014). Rates of survival to discharge (p=0.038) and favorable neurological outcomes (p=0.002) were lower with increasing hospital days while ROSC was not different among the groups (p=0.183). Survival was highest for HD1 (HD1: 38.9% [95% CI, 32.0-45.7%], p=0.002 vs HD2-7: 34.0% [95% CI, 27.5-40.4%], p<0.001 vs HD>7: 27.2% [95% CI, 21.4-33.0%], p<0.001). CONCLUSIONS: The etiology of cardiac arrests varies in frequency as length of hospitalization increases. Survival rates and favorable neurological outcomes are lower for in-hospital arrests occurring later in the hospitalization, even when adjusted for age, sex, and location of event. Understanding these issues may help with focusing therapies and accurate prognostication. PMID- 27456395 TI - Associations among gender, marital status, and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study. AB - AIM: To analyse the association between gender and outcomes of in-hospital cardiac arrest (IHCA) and the influences of age and marital status on the gender based difference in clinical outcome. METHODS: This retrospective observational study conducted in a single medical centre evaluated patients who had experienced IHCA from 2006 to 2014. Multivariate logistic regression analysis was used to study associations between independent variables and outcomes. Patients 18-49 years old were considered of reproductive age. The presence or absence of a legitimate spouse was retrieved from the family pedigree presented in the medical records. Reproductive age and marital status were each analysed as an interaction term with gender. RESULTS: A total of 1524 patients, of which 598 were women (39.2%), were included in this study. There were 269 patients (17.7%) of reproductive age and 490 patients (32.2%) without a living spouse. Only 215 patients (14.1%) survived to hospital discharge. Among these, 110 patients (7.2%) demonstrated a favourable neurological status. Our analysis indicated that being female was inversely associated with a favourable neurological outcome (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.29-0.87; p=0.02). Being female without a living spouse was inversely associated with a favourable neurological outcome (OR, 0.43; 95% CI, 0.17-0.96; p=0.05). Neither female nor female associated interaction terms were significantly associated with survival to hospital discharge. CONCLUSION: Female patients with IHCA had worse neurological outcomes than their male counterparts, especially for women without a living spouse. However, survival outcome did not differ between genders. PMID- 27456397 TI - High-Intensity Exercise is Associated with Fewer Symptoms of Hyperarousal. PMID- 27456398 TI - Prognostic significance of tumor-associated macrophages density in gastric cancer: a systemic review and meta-analysis. AB - INTRODUCTION: Tumor-associated macrophages (TAM) play a dual role in the development of gastric cancer (GC). This study aims to analyze the prognostic value of TAM density in GC patients. EVIDENCE ACQUISITION: We conducted a meta analysis of 11 studies (N.=1043) to investigate the correlation between TAM density and the overall survival (OS) or disease free survival (DFS) of GC patients. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by the STATA statistical software. EVIDENCE SYNTHESIS: The HR of OS of GC patients with high-density TAM is 1.56 (95% CI: 0.90~2.22, P<0.001) as compared with those with low-density TAM, and that of DFS is 1.10 (95% CI: 0.16~2.03, P=0.022), indicating that TAM density does not significantly predict the poor survival of GC. A subgroup analysis by ethnicity also revealed no significance effect between TAM density and a worse OS among both Asians and Caucasians (Asians: HR=1.47, 95% CI: 0.76~2.18, P<0.001; Caucasians: HR=2.23, 95% CI: 0.62~3.84, P=0.007, respectively). CONCLUSIONS: Our findings provide empirical evidence that TAM density is not an independent predictor for the survival of GC patients. PMID- 27456396 TI - New polymer of lactic-co-glycolic acid-modified polyethylenimine for nucleic acid delivery. AB - AIM: To develop an improved delivery system for nucleic acids. MATERIALS & METHODS: We designed, synthesized and characterized a new polymer of lactic-co glycolic acid-modified polyethylenimine (LGA-PEI). Functions of LGA-PEI polymer were determined. RESULTS: The new LGA-PEI polymer spontaneously formed nanoparticles (NPs) with DNA or RNA, and showed higher DNA or RNA loading efficiency, higher or comparable transfection efficacy, and lower cytotoxicity in several cell types including PANC-1, Jurkat and HEK293 cells, when compared with lipofectamine 2000, branched or linear PEI (25 kDa). In nude mouse models, LGA PEI showed higher delivery efficiency of plasmid DNA or miRNA mimic into pancreatic and ovarian xenograft tumors. LGA-PEI/DNA NPs showed much lower toxicity than control PEI NPs in mouse models. CONCLUSION: The new LGA-PEI polymer is a safer and more effective system to deliver DNA or RNA than PEI. PMID- 27456400 TI - Editorial Comment. PMID- 27456401 TI - Molecular Diagnosis of the Philadelphia Chromosome in Acute Lymphoblastic Leukemia. AB - The Philadelphia (Ph(1)) chromosome was the first specific chromosomal abnormality to be consistently associated with a particular neoplasm, in this case chronic myelogenous leukemia (CML,)(1). Formed by a reciprocal translocation between chromosomes 9 and 22(2), the 22q-, or Ph(1) chromosome is found in the malignant cells of more than 90% of patients with CML(3). The presence of the molecular equivalent of a Ph(1) chromosome is such a consistent finding in CML that it IS now the basis of a diagnostic test in routine clinical use. PMID- 27456399 TI - Response to docetaxel and cisplatin induction chemotherapy of locally advanced head and neck squamous cell carcinoma: a multicenter, non-comparative, open-label interventional pilot study. AB - BACKGROUND: Docetaxel, cisplatin plus 5-fluorouracil is an efficacious induction regimen but is more toxic than cisplatin plus 5-fluorouracil. This study aimed to determine whether docetaxel and cisplatin without 5-fluorouracil maintains efficacy while decreasing toxicity. METHODS: A multicenter non-comparative pilot study of locally advanced squamous cell carcinoma of the head and neck was performed. Patients received primary therapy comprising three cycles of 75 mg/m2 docetaxel and 75 mg/m2 cisplatin followed by concurrent chemoradiotherapy. The primary endpoint was the response rate to the docetaxel and cisplatin induction regimen. RESULTS: A total of 26 patients were enrolled: of these, 23 (88.5 per cent) received all three docetaxel and cisplatin cycles. Common grade 3-4 adverse events were febrile neutropenia (19.2 per cent of patients), diarrhoea (19.2 per cent) and non-neutropenic infection (15.4 per cent). The overall response rate to docetaxel and cisplatin induction chemotherapy was 65.4 per cent. A total of 23 patients (88.5 per cent) subsequently received chemoradiotherapy with a median radiotherapy dose of 70 Gy. The response rate to chemoradiotherapy was 73 per cent. At a median follow up of 44 months, the 3-year progression-free survival and overall survival rates were 62 per cent and 69 per cent, respectively. CONCLUSION: Docetaxel and cisplatin induction chemotherapy is a feasible induction regimen with comparable efficacy to docetaxel, cisplatin and 5 fluorouracil induction chemotherapy. PMID- 27456402 TI - CD10-(CALLA)-Positive Lymphocytes in Myeloma: Evidence that they are a Malignant Precursor Population and are of Germinal Centre Origin. AB - CD10 antigen has been repeatedly detected on putative lymphoid precursor populations in both the bone marrow and circulation of multiple myeloma patients, as well as on the plasma cells in some cases of myeloma. The presence of these CD10-positive cells has raised questions regarding the ontogeny of the proliferating precursor cell in myeloma. The majority opinion has implicated a CD10-positive haemopoietic progenitor cell. However, the CD10 antigen has been detected on some mature B cells, i.e. germinal centre B cells. In this paper we postulate that the proliferating precursor cell in myeloma arises from the germinal centre. The germinal centre is the site of affinity maturation of antibody responses via somatic mutation and of isotype switching. Thus the siting of the clonogenic cell in myeloma in the germinal centre explains the overwhelming predominance of IgG and IgA myelomas, the phenomenon of point mutation which occurs in myeloma proteins in the presence of stable immunoglobulin gene rearrangements and the impaired primary immune response in myeloma. It is also consistent with the requirement for antigenic exposure in the development of myelomatosis. PMID- 27456403 TI - DNA Genotypic Conservation During Phenotypic Switch from T-cell Acute Lymphoblastic Leukaemia to Acute Myeloblastic Leukaemia. AB - This communication reports a case of T-cell acute lymphoblastic leukaemia (T-ALL) which, after treatment and remission induction, relapsed 17 months after apparent disease-free remission as acute myeloblastic leukaemia (AML). Extensive immunophenotypic, analysis an initial presentation revealed a typical T-ALL phenotype (HLA-Dr(-), TdT(+), CD2(+), CD3(+), CD4(-), CD5(+), CD7(+), CD8(-), CD19(-), CD13/33(-)) that was unusual in that the majority of blasts expressed membrane TCR gammadelta chains but not TCR alphabeta chains. Similarly, the morphological (Auer rods +), cytochemical (MPO(+) and SBB(+)) and phenotypic characteristics at relapse were unequivocably consistent with a diagnosis of AML. In contrast to previous case studies of "phenotypic switch" or "metachronous bilineal leukaernia", Southern blot analysiis of TCR and Ig gene rearrangements at presentation and relapse were able, because of an unusual genotypic pattern (TCR beta +, TCR gamma +, TCR delta + and JH), to confirm the common clonal origin of the two leukaemias. It is suggested that the transition from T-ALL to AML may not be a "random" phenomenon but may rather reflect subclonal domination by mycloid blasts with relative drug resistance (i.e. synchronous bilineal differentiation with an undetectable myeloid component), or therapy-induced alterations in the balance of (myelosuppressive) factors. PMID- 27456404 TI - The Surface Phenotype of Lymphatic Leukemia, Cells: An Immunoscanning Electron Microscopy Study. AB - Bone-marrow cells from 11 cases of T- and 18 cases of B-lymphatic leukemia, at different maturation stages, were examined by scanning electron microscope (SEMI. All cases were extensively studied for the expression of surface markers by immunofluorescence. In addition six cases of T- and 10 cases of B-cell leukemia were labeled with a panel of monoclon;tl antibodies (including CD3, CD5, CD7, CD10, CD4, CD8, CD19, CD20 and CD22) and, after incubation with a colloidal gold conjugate, observed with SEM in the back-scattered electron imaging mode. Early stages of leukemic lymphoid B- and T-cell differentiation are characterized by prevalently smooth cell surfaces. Short stub-like microvilli constantly appear on more mature T cells, while complex surface features like small ruffles and pleomorphic microvilli are present in well-differentiated B-cell proliferations. Surface microvilli can be interpreted als structural features of lymphoid cells, progressively expressed with maturation and differentiation of leukemic as well as normal cells. PMID- 27456405 TI - Constitutive Expression of Multiple Cellular Oncogenes in Acute Myeloid Leukemia Cells. AB - Cellular oncogenes are frequently activated or deregulated in human malignant tumors. We have analyzed the expression of cellular oncogenes in human leukemia by Northern blot experiments in a case of acute myeloid leukemia (AML). In this case the cellular oncogenes N-myc, c-myb, c-fes and c-met were expressed at high levels. This is in contrast to normal peripheral blood mononuclear cells (PBMC) or chronic lymphocytic leukemia (CLL) cells, where these genes could not be detected. c-src2-specific RNA was not seen in either AML or PBMC cells but readily appeared in CLL cells. This appears to represent further evidence that in leukemic cells multiple cellular oncogenes might be activated. PMID- 27456406 TI - Interferon Alfa-2b Antibodies and Clinical Resistance in a Patient with Hairy Cell Leukemia. AB - A patient with hairy cell leukemia is described who, during the course of treatment of his disease with interferon alphab, developed antibodies to the drug. Coincident with antibody development, clinical resistance to the effect of alfa interferon was noted Despite an increasing dose of interferon, no signs of disease response were noted and the patient required a change in therapy to deoxycoformycin. Although similar findings have been described in patients treated with interferon alfa-2a, this is the first report of clinical resistance associated with neutralizing antibody formation in a hairy cell leukemia patient treated with interferon alfa-2b. PMID- 27456407 TI - Adult T-cell Leukemia in a Chilean Resident in Spain: Long-Lasting Remission after 2-Deoxycoformycin Treatment. AB - We report a patient born in a non-endemic area for human T-lymphotropic virus type I (HTLV-I) infection, in whom an adult T-cell leukemia (ATL) was diagnosed. After the development of acute symptomatic hypercalcemia, treatment with 2 deoxycoformycin was administered. Only mild side-effects were observed, and after treatment a long-lasting complete remission was achieved. The epidemiology of HTLV-I infection and the treatment of ATL are discussed. PMID- 27456408 TI - Acquired von Willebrand Disease in Patients with Chronic Myeloproliferative Disorders. AB - In chronic myeloproliferative disorders(CMPD), thrombohaemorrhagic complications are relatively common, in association with thromocytosis. We studied the multimeric composition of plasma von Willebrand factor(vWf) in CMPD and investigated the possibilities of in vivo or in vitro proteolysis. The relative amount of large multimers in patients with CMPD was significantly decreased in relation to the increment of platelet count compared with normal subjects. This correlated negatively with platelet count(r = -0.625, p < 0.001) but positively for the ristocetin cofactor/von Willebrand factor antigen ratio (r =: 0.392, p < 0.005). All of the patients with primary myelofibrosis who had normal or subnormal platelet counts showed an almost normal multimeric pattern. The vWf abnormalities normalized with decreasing platelet counts after starting chemotherapy or when blast crisis occurred with decreased platelet counts. These vWf abnormalities may have been caused by in vivo proteolysis, because they were not corrected even when blood was obtained in the presence of protease inhibitors. The relative amount of large multimers of vWf did not correlate with plasma concentration of plasmin or elastase which were measured as cc2 plasmin inhibitor-plasmin complex and a, proteinase inhibitor-elastase complex, respectively. So neither plasmin nor elastase appear to be the enzymes responsible for in vivo proteolysis. PMID- 27456409 TI - The Value of Immunocytochemistry in Differentiating High-Grade: Lymphoma from Other Anaplastic Tumours: A study of anaplastic tumours from 1940 to 1960. AB - Immunocytochemistry is now established in many histology laboratories for diagnostic purposes and is routinely used in ascribing an origin to poorly differentiated tumours. This raises the question of whether traditional morphological skills are being abandoned in favour of new technology and, if so, whether that is justified. Twenty-three lymph node biopsies diagnosed as anaplastic carcinoma, reticulosarcoma or unclassifiable tumour between 1940 and 1960 (when immunocytochemistry was not available) were retrieved from the archives of the Radcliffe Infirmary. Paraffin sections were stained with a panel of monoclonal antibodies previously shown to be useful in the identification of tumours of uncertain origin. Of the 15 cases given a definite morphological diagnosis six (40%) were shown to be incorrect on the basis of immunostaining. In the eight remaining cases in which no diagnosis was recorded immunostaining provided a clear diagnosis in seven instances. These results are similar to those recorded on contemporary cases and demonstrate the value of immunocytochemical staining, as an adjunct to traditional morphological examination. In addition, it is clear that currently available monoclonal antibodies are suitable for use on routinely processed material more than 30 years old. PMID- 27456410 TI - Fine-Needle Aspiration Cytology and Immunocytochemistry of Abdominal Non Hodgkin's Lymphomas. AB - The cytomorphology and immunologic characteristics of cells obtained by fine needle aspiration biopsy of 34 consecutive patients with abdominal lymphomas were analyzed. Nineteen patients had no previous diagnosis, while 15 had previously known or suspected lymphomas. On cytology 21 high-grade and 13 low-intermediate grade lymphomas were diagnosed. Immunologic characterization of aspirated cells identified one T-cell and 33 B-cell neoplasms. A monoclonal light chain expression was detected in 27 of the B-cell lymphomas. The results were in good agreement with those from histologic (n = 19) and immunohistochemical (n = 5) evaluations. The value and accuracy of fine-needle aspiration cytology in conjunction with immunocytochemistry are detailed. PMID- 27456411 TI - High-Dose Chemotherapy with Bone-Marrow Rescue for Treatment of Relapsed and Refractory Hodgkin's Disease. AB - Eleven patients with Hodgkin's disease relapsed from or refractory to conventional-dose chemotherapeutic regimens including MOPP and ABVD were treated by means of high-dose chemotherapy (either single agent melphalan or high-dose cyclophosphamide. VP 16 and BCNU) with bone-marrow rescue (autologous 9, allogeneic 2). Of the 11 patients treated, there were five complete and three partial remissions, with one toxic death. High-dose chemotherapy has the potential for achieving a substantial remission rate in Hodgkin's disease even after failure of conventional-dose chemotherapy. PMID- 27456413 TI - ORCHEM Prize: T. Magauer and O. Garcia Mancheno / Emil Fischer Medal: D. Trauner / Gmelin-Beilstein Memorial Medal: J. P. Richmond. PMID- 27456412 TI - Computational comparison of aortic root stresses in presence of stentless and stented aortic valve bio-prostheses. AB - We provide a computational comparison of the performance of stentless and stented aortic prostheses, in terms of aortic root displacements and internal stresses. To this aim, we consider three real patients; for each of them, we draw the two prostheses configurations, which are characterized by different mechanical properties and we also consider the native configuration. For each of these scenarios, we solve the fluid-structure interaction problem arising between blood and aortic root, through Finite Elements. In particular, the Arbitrary Lagrangian Eulerian formulation is used for the numerical solution of the fluid-dynamic equations and a hyperelastic material model is adopted to predict the mechanical response of the aortic wall and the two prostheses. The computational results are analyzed in terms of aortic flow, internal wall stresses and aortic wall/prosthesis displacements; a quantitative comparison of the mechanical behavior of the three scenarios is reported. The numerical results highlight a good agreement between stentless and native displacements and internal wall stresses, whereas higher/non-physiological stresses are found for the stented case. PMID- 27456414 TI - Electronic Referrals: Not Just More Efficient but Safer, Too. PMID- 27456415 TI - Minding the Gaps: Assessing Communication Outcomes of Electronic Preconsultation Exchange. AB - BACKGROUND: Effective communication between referring and specialty providers is key to optimizing patient safety. Communication was assessed in an electronic referral system by review of referrals to a public urban health care system's gastroenterology clinic that were not scheduled for appointments. METHODS: All electronic referrals to a publicly funded, urban health care system's adult gastroenterology clinic from November 1, 2009, to November 30, 2010, were reviewed that did not result in scheduling of appointments. An assessment was made of whether in-person visits were unnecessary by preconsultation exchange or whether the referrals remained unscheduled for other reasons. For the latter group, reasons why the referrals remained unscheduled were examined, and medical records were reviewed for actual patient harm when sufficient information was present in the chart or for potential harm when no further information about the referral complaint was available. RESULTS: Eighty-six (32%) of 266 not-scheduled referrals were resolved via preconsultation exchange. For another 96 (36%), patients were not ultimately considered to require appointments or were scheduled via other routes. Nine patients received unplanned care while awaiting scheduling decisions, 5 of whom had harm that was related to referral complaints, although scheduling of appointments may not have avoided this harm. Of 75 patients for whom further information was not available about the referral complaints, most were not seen back in primary care, and 55 (73%) had potential for major harm. CONCLUSION: Few adverse outcomes in electronic referrals not scheduled for in person gastroenterology visits were found, and none were clearly due to communication lapses in the referral process. Contributors to the potential for harm in referrals that were unintentionally left unscheduled included discontinuity of care and lack of patient or provider follow-up. PMID- 27456416 TI - SafeCare: An Innovative Approach for Improving Quality Through Standards, Benchmarking, and Improvement in Low- and Middle- Income Countries. AB - BACKGROUND: In low- and middle-income countries (LMICs), patients often have limited access to high-quality care because of a shortage of facilities and human resources, inefficiency of resource allocation, and limited health insurance. SafeCare was developed to provide innovative health care standards; surveyor training; a grading system for quality of care; a quality improvement process that is broken down into achievable, measurable steps to facilitate incremental improvement; and a private sector-supported health financing model. METHODS: Three organizations-PharmAccess Foundation, Joint Commission International, and the Council for Health Service Accreditation of Southern Africa-launched SafeCare in 2011 as a formal partnership. Five SafeCare levels of improvement are allocated on the basis of an algorithm that incorporates both the overall score and weighted criteria, so that certain high-risk criteria need to be in place before a facility can move to the next SafeCare certification level. A customized quality improvement plan based on the SafeCare assessment results lists the specific, measurable activities that should be undertaken to address gaps in quality found during the initial assessment and to meet the nextlevel SafeCare certificate. RESULTS: The standards have been implemented in more than 800 primary and secondary facilities by qualified local surveyors, in partnership with various local public and private partner organizations, in six sub-Saharan African countries (Ghana, Kenya, Nigeria, Namibia, Tanzania, and Zambia). CONCLUSION: Expanding access to care and improving health care quality in LMICs will require a coordinated effort between institutions and other stakeholders. SafeCare's standards and assessment methodology can help build trust between stakeholders and lay the foundation for country-led quality monitoring systems. PMID- 27456417 TI - How Does Disease-Specific Care Certification Affect Quality and How Can We Measure It? PMID- 27456418 TI - Hospital Disease-Specific Care Certification Programs and Quality of Care: A Narrative Review. AB - BACKGROUND: Disease-specific care certification (DSCC) programs have been developed to improve the quality and performance of programs or services that may be based within or associated with a hospital or other health care organization. A comprehensive summary of evidence for DSCC programs and their reported effect on the quality of care was prepared in a narrative review, the first of its kind on this topic. METHODS: A systematic search was performed to identify articles that reported about DSCC. Any article that reported DSCC and certifications, published between 2003 and August 2015 (with an update in March 2016), and conducted in the United States was included. Databases searched included PubMed, MEDLINE, and CINAHL. RESULTS: The articles were reviewed in terms of four topics: early development of DSCC, the journey toward DSCC, the relationship between DSCC and organizing process of care, and the relationship between DSCC and outcomes of care. Fifteen articles noted a positive relationship between DSCC programs and quality of care, only 6 of which reported empirical data. Therefore, a systematic review and meta-analysis were not warranted. Only 3 articles involved use of sophisticated statistical modeling with adequate control variables to investigate the effect of DSCC, which makes it difficult to conclude that the change in hospitals' or patients' outcomes were related to the certification. CONCLUSIONS: The majority (13) of the articles focused on Joint Commission DSCC, with the remaining assessing Society of Cardiovascular Patient Care "accreditation" (certification). Only two studies, each study using a cross-sectional design, that empirically examined the relationship between DSCC and outcomes of care mortality of care and readmission. More research studies are needed to evaluate the effectiveness of DSCC programs in improving outcomes of care, particularly patient-centered outcome measures, such as patient satisfaction and self-care. PMID- 27456419 TI - Implementing Delivery Room Checklists and Communication Standards in a Multi Neonatal ICU Quality Improvement Collaborative. AB - BACKGROUND: The 2015 American Academy of Pediatrics Neonatal Resuscitation Program (NRP) and International Liaison Committee on Resuscitation (ILCOR) resuscitation guidelines state, "It is still suggested that briefing and debriefing techniques be used whenever possible for neonatal resuscitation." Effective communication and reliable delivery of evidence-based best practices are critical aspects of the 2015 NRP guidelines. To promote optimal communication and best practice-focused checklists use during active neonatal resuscitation, the Readiness Bundle (RB) was integrated within the larger change package deployed in the California Perinatal Quality Care Collaborative's (CPQCC) 12 month Delivery Room Management Quality Improvement Collaborative. METHODS: The RB consisted of (1) a checklist for high-risk neonatal resuscitations and (2) briefings and debriefings to improve teamwork and communication in the delivery room (DR). Implementation of the RB was encouraged, compliance with the RB was tracked monthly up through 6 months after the completion of the collaborative, and satisfaction with the RB was evaluated. RESULTS: Twenty-four neonatal intensive care units (NICUs) participated in the CPQCCDR collaborative. Before the initiation of the collaborative, the elements of the RB were complied with in 0 of 740 reported deliveries (0%). During the 12-month collaborative, compliance with the RB improved to a median of 71%, which was surpassed in the 6-month period after the collaborative ended (80%). One-hundred percent of responding NICUs would recommend the RB to other NICUs working on improving DR management. CONCLUSIONS: The RB was rapidly adopted, with compliance sustained for 6 months after completion of the collaborative. Inclusion of the RB in the next generation of the NRP guidelines is encouraged. PMID- 27456420 TI - Patient Safety Culture and the Second Victim Phenomenon: Connecting Culture to Staff Distress in Nurses. AB - BACKGROUND: Second victim experiences can affect the wellbeing of health care providers and compromise patient safety. Many factors associated with improved coping after patient safety event involvement are also components of a strong patient safety culture, so that supportive patient safety cultures may reduce second victim-related trauma. A cross-sectional survey study was conducted to assess the influence of patient safety culture on second victim-related distress. METHODS: The Agency for Healthcare Research and Quality (AHRQ) Hospital Survey on Patient Safety Culture (HSOPSC) and the Second Victim Experience and Support Tool (SVEST), which was developed to assess organizational support and personal and professional distress after involvement in a patient safety event, were administered to nurses involved in direct patient care. RESULTS: Of 358 nurses at a specialized pediatric hospital, 169 (47.2%) completed both surveys. Hierarchical linear regres sion demonstrated that the patient safety culture survey dimension nonpunitive response to error was significantly associated with reductions in the second victim survey dimensions psychological, physical, and professional distress (p < 0.001). As a mediator, organizational support fully explained the nonpunitive response to error-physical distress and nonpunitive response to error-professional distress relationships and partially explained the nonpunitive response to error-psychological distress relationship. CONCLUSIONS: The results suggest that punitive safety cultures may contribute to self-reported perceptions of second victim-related psychological, physical, and professional distress, which could reflect a lack of organizational support. Reducing punitive response to error and encouraging supportive coworker, supervisor, and institutional interactions may be useful strategies to manage the severity of second victim experiences. PMID- 27456422 TI - Relationship between sensory attributes and volatile compounds of polish dry cured loin. AB - OBJECTIVE: The aim of this work was to determine the relationship between objective sensory descriptors and volatile flavour compound composition of Polish traditional dry-cured loin. METHODS: The volatile compounds were investigated by using solid phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS). For sensory assessment, the quantitative descriptive analysis (QDA) method was used. RESULTS: A total of 50 volatile compounds were found and assigned to 17 chemical families. Most of the detected volatile compounds derived from smoking, lipid oxidative reactions and seasoning (46.8%, 21.7%, and 18.9%, respectively). The dominant compounds were: aromatic hydrocarbon (toluene); alkanes (hexane, heptane, and 2,2,4-trimethylpentane); aldehyde (hexanal); alcohol (2-furanmethanol); ketone (3-hydroxy-2-butanone); phenol (guaiacol); and terpenes (eucalyptol, cymene, gamma-terpinen, and limonene). Correlation analysis showed that some compounds derived from smoking were positively correlated with the intensity of cured meat odour and flavour and negatively with the intensity of dried meat odour and flavour, while terpenes were strongly correlated with odour and flavour of added spices. CONCLUSION: The analysed dry-cured loins were characterized by specific and unique sensory profile. Odour and flavour of studied loins was mainly determined by volatile compounds originating from smoking, seasoning and lipid oxidation. Obtained results suggest that smoking process is a crucial stage during Polish traditional dry-cured loins production. PMID- 27456423 TI - Influence of methionine supplementation of growing diets enriched with lysine on feedlot performance and characteristics of digestion in Holstein steer calves. AB - OBJECTIVE: Two trials were conducted in order to examine the effects of level of supplemental methionine on productive performance, dietary energetic, plasma amino acid concentration, and digestive function. METHODS: Dietary treatments consisted of a steam-flaked corn-based diet containing urea as the only source of supplemental nitrogen supplemented with no supplemental amino acid (control), or control plus 1.01% lysine and 0.032%, 0.064%, 0.096%, or 0.128% methionine. In Trial 1, 150 Holstein steer calves (127+/-4.9 kg) were utilized to evaluate the influence of treatments on growth-performance, dietary energetic, plasma amino acid concentration during the first 112 days of growing period. During the initial 56-d period calves received the 5 experimental diets. During the subsequent 56-d period all calves were fed the control diet. RESULTS: During the initial 56-d period, methionine supplementation increased (linear effect, p<0.01) plasma methionine. In the presence of supplemental lysine, increases on level of methionine in diet did not affect average daily gain. However, increased gain efficiency (quadratic effect, p = 0.03) and estimated dietary net energy (NE; linear effect, p = 0.05). Estimated metabolizable methionine supply was closely associated (R2 = 0.95) with efficiency NE utilization for maintenance and gain. During the subsequent 56-d period, when all calves received the control diet (no amino acid supplementation), plasma amino acid concentrations and growth performance was not different among groups. However, the effects of methionine supplementation during the initial 56-period carried over, so that following a 56 d withdrawal of supplementation, the overall 112-d effects on gain efficiency (quadratic effect, p = 0.05) dietary NE (linear effect, p<=0.05) remained appreciable. In Trial 2, 5 cannulated Holstein steers were used to evaluate treatment effects on characteristics of digestion and amino acid supply to the small intestine. There were no treatment effects on flow of dietary and microbial N to the small intestine. Postruminal N digestion increased (p = 0.04) with increasing level of supplemental methionine. Methionine supplementation linearly increased (p<0.01) duodenal flow of methionine. Likewise, lysine supplementation increased an average of 4.6% (p = 0.04) duodenal flow of lysine. In steers that received non-supplemented diet, observed intestinal amino acid supply were in good agreement with expected. CONCLUSION: We conclude that addition of rumen protected methionine and lysine to diets may enhance gain efficiency and dietary energetics of growing Holstein calves. Observed amino acid supply to the small intestine were in good agreement with expected, supportive of NRC (2000, Level 1). PMID- 27456424 TI - Effects of purified lignin on in vitro rumen metabolism and growth performance of feedlot cattle. AB - OBJECTIVE: The objectives were to assess the effects of purified lignin from wheat straw (sodium hydroxide dehydrated lignin; SHDL) on in vitro ruminal fermentation and on the growth performance of feedlot cattle. METHODS: In vitro experiments were conducted by incubating a timothy-alfalfa (50:50) forage mixture (48 h) and barley grain (24 h) with 0, 0.25, 0.5, 1.0, and 2.0 mg/mL of rumen fluid (equivalent to 0, 2, 4, 8, and 16 g SHDL/kg diet). Productions of CH4 and total gas, volatile fatty acids, ammonia, dry matter (DM) disappearance (DMD) and digestion of neutral detergent fiber (NDF) or starch were measured. Sixty Hereford-Angus cross weaned steer calves were individually fed a typical barley silage-barley grain based total mixed ration and supplemented with SHDL at 0, 4, 8, and 16 g/kg DM for 70 (growing), 28 (transition), and 121 d (finishing) period. Cattle were slaughtered at the end of the experiment and carcass traits were assessed. RESULTS: With forage, SHDL linearly (p<0.001) reduced 48-h in vitro DMD from 54.9% to 39.2%, NDF disappearance from 34.1% to 18.6% and the acetate: propionate ratio from 2.56 to 2.41, but linearly (p<0.001) increased CH4 production from 9.5 to 12.4 mL/100 mg DMD. With barley grain, SHDL linearly increased (p<0.001) 24-h DMD from74.6% to 84.5%, but linearly (p<0.001) reduced CH4 production from 5.6 to 4.2 mL/100 mg DMD and NH3 accumulation from 9.15 to 4.49 MUmol/mL. Supplementation of SHDL did not affect growth, but tended (p = 0.10) to linearly reduce feed intake, and quadratically increased (p = 0.059) feed efficiency during the finishing period. Addition of SHDL also tended (p = 0.098) to linearly increase the saleable meat yield of the carcass from 52.5% to 55.7%. CONCLUSION: Purified lignin used as feed additive has potential to improve feed efficiency for finishing feedlot cattle and carcass quality. PMID- 27456425 TI - In vitro Solubility of Copper(II) Sulfate and Dicopper Chloride Trihydroxide for Pigs. AB - This study was conducted to determine the solubility of copper (Cu) in two sources of copper(II) sulfate (CuSO4) including monohydrate and pentahydrate and three sources of dicopper chloride trihydroxide (dCCTH) including alpha-form (dCCTH-alpha), beta-form (dCCTH-beta), and a mixture of alpha- and beta-form (dCCTH-alphabeta) at different pH and a 3-step in vitro digestion assay for pigs. In Exp. 1, Cu sources were incubated in water-based buffers at pH 2.0, 3.0, 4.8, and 6.8 for 4 h using a shaking incubator at 39 degrees C. The CuSO4 sources were completely dissolved within 15 min except at pH 6.8. The solubility of Cu in dCCTH-alpha was greater (p<0.05) than dCCTH-beta but was not different from dCCTH alphabeta during 3-h incubation at pH 2.0 and during 2-h incubation at pH 3.0. At pH 4.8, there were no significant differences in solubility of Cu in dCCTH sources. Copper in dCCTH sources were non-soluble at pH 6.8. In Exp. 2, the solubility of Cu was determined during the 3-step in vitro digestion assay for pigs. All sources of Cu were completely dissolved in step 1 which simulated digestion in the stomach. In Exp. 3, the solubility of Cu in experimental diets including a control diet and diets containing 250 mg/kg of additional Cu from five Cu sources was determined during the in vitro digestion assay. The solubility of Cu in diets containing additional Cu sources were greater (p<0.05) than the control diet in step 1. In conclusion, the solubility of Cu was influenced by pH of digesta but was not different among sources based on the in vitro digestion assay. PMID- 27456426 TI - The comparative analysis of complete genome sequences from two South African betabaculoviruses: Phthorimaea operculella granulovirus and Plutella xylostella granulovirus. AB - The complete genomes of two novel South African betabaculovirus isolates, namely Phthorimaea operculella granulovirus (PhopGV-SA) and Plutella xylostella granulovirus (PlxyGV-SA), were sequenced and compared to the respective reference isolates PhopGV-1346 and PlxyGV-K1. For both isolates, the genome size and guanine-cytosine (GC) content were similar to those of the respective reference genomes. However, numerous-single nucleotide polymorphisms (SNPs) and several insertions/deletions were observed, revealing the novelty of the isolates. Focus was placed on analysing the observed insertion/deletion events by conducting amino acid sequence alignments for all ORFs of each isolate against all respective ORFs in the corresponding reference isolate. Certain ORFs in each granulovirus genome contained significant insertion/deletion events. In addition, the PlxyGV-SA genome had single-nucleotide insertions/deletions in ORFs 38 and 49 that resulted in the extension and complete overlap of these two ORFs with the neighbouring ORFs 39 and 48, respectively. These novel isolates have significant potential for development and application as biopesticides in South Africa, and the genetic variations observed may have important implications for the biological activity and management of host resistance in the field. PMID- 27456427 TI - A novel member of the Tombusviridae from a wild legume, Gompholobium preissii. AB - As part of an investigation into viruses of wild plants in Australia, a contiguous sequence of 3935 nucleotides was obtained after shotgun sequencing of RNA isolated from an asymptomatic wild legume, Gompholobium preissii. Phylogenetic analysis of the sequence revealed that it most closely resembled that of Trailing lespedeza virus 1 (TLV1), a virus isolated from a wild legume in America. The proposed virus, named Gompholobium virus A, and TLV1 are genetically closest to viruses in the genera Alphacarmovirus and Pelarspovirus, family Tombusviridae, but they share features distinguishing them from both groups. PMID- 27456428 TI - Redox regulation of mitochondrial proteins and proteomes by cysteine thiol switches. AB - Mitochondria are hotspots of cellular redox biochemistry. Respiration as a defining mitochondrial function is made up of a series of electron transfers that are ultimately coupled to maintaining the proton motive force, ATP production and cellular energy supply. The individual reaction steps involved require tight control and flexible regulation to maintain energy and redox balance in the cell under fluctuating demands. Redox regulation by thiol switching has been a long standing candidate mechanism to support rapid adjustment of mitochondrial protein function at the posttranslational level. Here we review recent advances in our understanding of cysteine thiol switches in the mitochondrial proteome with a focus on their operation in vivo. We assess the conceptual basis for thiol switching in mitochondria and discuss to what extent insights gained from in vitro studies may be valid in vivo, considering thermodynamic, kinetic and structural constraints. We compare functional proteomic approaches that have been used to assess mitochondrial protein thiol switches, including thioredoxin trapping, redox difference gel electrophoresis (redoxDIGE), isotope-coded affinity tag (OxICAT) and iodoacetyl tandem mass tag (iodoTMT) labelling strategies. We discuss conditions that may favour active thiol switching in mitochondrial proteomes in vivo, and appraise recent advances in dissecting their impact using combinations of in vivo redox sensing and quantitative redox proteomics. Finally we focus on four central facets of mitochondrial biology, aging, carbon metabolism, energy coupling and electron transport, exemplifying the current emergence of a mechanistic understanding of mitochondrial regulation by thiol switching in living plants and animals. PMID- 27456429 TI - Mitochondrial dysfunction and diabetic retinopathy. AB - Mitochondrial dysfunction may predispose to the development of diabetes mellitus with the accompanying risk for developing diabetic retinopathy or may contribute directly to the diabetic metabolic dysregulation and thereby increase the risk of diabetic late complications including retinopathy. Diabetes mellitus in mitochondrial disease can lead to the development of vision threatening retinopathy, but visual acuity is often reduced secondary to neurological deficits resulting from the mitochondrial dysfunction. The relation between mitochondrial disease and diabetic retinopathy can be influenced by epigenetics where factors in the environment modify the expression of regulatory proteins coding for the elimination of reactive oxygen species. PMID- 27456430 TI - Micro/nano-particle decorated metal wire for cutting soft matter. AB - To cut soft materials such as biological tissues with minimal damage and reduced positional error is highly desired in medical surgery and biomechanics. After years of natural selection and evolution, mosquitoes have acquired the ability to insert their proboscises into human skin with astonishingly tiny forces. This can be associated with the unique structure of their proboscises, with micro/nano sawteeth, and the distinctive insertion manner: high frequency reciprocating saw cutting. Inspired by these, this communication describes the successful implantation of metal oxide particles onto molybdenum wire surfaces through a sol calcination process, to form a biomimetic sawblade with a high density of micro/nano saw teeth, where the acidification is essential in terms of generating active anchoring sites on the wire. When used as a sawblade in conjunction with reciprocating action to cut the viscoelastic gel, both the cut-in force and cut in displacement could be decreased substantially. The cutting speed and frequency of reciprocating action are important operating parameters influencing cut-in force. PMID- 27456432 TI - pi-pi stacking between polyaromatic hydrocarbon sheets beyond dispersion interactions. AB - High level ab initio calculations ranging from coupled cluster methods including explicitly correlated approaches to standard second order Moller-Plesset theory using spin scaling (SOS-MP2) have been performed on sandwich and slipped parallel dimer structures of a series of quasi one-dimensional acenes and on two dimensional sheets containing the pyrene to coronene series encircled with two layers of benzene rings. Sandwich (graphitic AA type) and slipped parallel (AB type) structures were considered and, within the given symmetry restrictions, full geometry optimizations were performed. Basis set superposition effects have been considered. The computed geometries show a significant biconcave deviation of the two-dimensional sheets from planarity with the central intersheet CC distances considerably smaller that van der Waals distances. The computed intersheet binding energy per carbon atom extrapolated for N -> infinity of -74.3 meV (1.713 kcal mol(-1)) per atom agrees quite well with an experimental defoliation energy of -52 meV (1.199 kcal mol(-1)) per atom (-67 meV (1.545 kcal mol(-1)) per carbon atom without corrections for H binding contributions) for polyaromatic hydrocarbons (PAHs) from graphite. A limited investigation of density functional theory (DFT) calculations using empirical dispersion contributions has been performed also showing a significant underbinding character of the D3 method. For most of the DFT variants investigated the graphene sheet models retain a quasi-planar structure in strong contrast to the aforementioned SOS-MP2 results. PMID- 27456431 TI - The effects of genomic polymorphisms in one-carbon metabolism pathways on survival of gastric cancer patients received fluorouracil-based adjuvant therapy. AB - 5-fluorouracil (5-FU) is widely used to treat patients with gastric cancer (GC). However, the response rate is quite heterogeneous. The single nucleotide polymorphisms (SNPs) and their interactions of genes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR), and Thymidylate synthase (TS), significantly affect 5-FU metabolism. In this study, 650 stage II-III patients were recruited from 1998 to 2006. Among them, 251 received 5-FU treatment and other 399 patients were untreated. The Cox regression analysis, log rank tests and Kaplan-Meier plots were adopted. In the chemotherapy cohort, MTRR 66 GA + GG genotypes decreased death risk, however, the protect effect of MTRR 66 GA + GG disappeared when GC patients simultaneously had MTHFR 677TT + TC or MTR 2756GG + GA genotypes. TS 5'-UTR 2R3R + 3R3R genotypes also prolonged overall survival of patients treated with 5-FU. And this favorable prognosis obviously enhanced when GC patients simultaneously had TS 3'-UTR DD + DI and TS 5'-UTR 2R3R + 3R3R genotypes. Our findings showed that the polymorphisms of MTRR 66 A > G and TS 5'-UTR 3R > 2R may be potential prognostic factors for GC patients receiving 5 FU. PMID- 27456433 TI - Association of platelet-to-lymphocyte ratio with silent brain infarcts in patients with paroxysmal atrial fibrillation. AB - OBJECTIVES: In this study, we aimed to evaluate whether the inflammation as measured by increased platelet to lymphocyte ratio (PLR) predispose to silent infarcts in patients with paroxysmal atrial fibrillation (PAF). METHODS: The present study investigated a total of 48 new diagnosed patients with PAF who had no signs of stroke. PLR, which was calculated as the ratio of the platelet count to the lymphocyte count, C-reactive protein and erythrocyte sedimentation rate were measured due to evaluate inflammatory state. Magnetic resonance imaging (MRI) was performed to evaluate the presence of silent brain infarcts (SBIs) in patients. We calculated CHA2DS2-VASc scores for stratifying the stroke risk of patients. RESULTS: Among our study population, the mean age was 56.40 +/- 8.99; 36 patients were female. The leading vascular risk factor was hypertension (45.8%). SBI was determined in 16 patients (33.3%) on MRI. It was found that a higher PLR is significantly associated with the presence of SBIs in patients with PAF (P = .001). High PLR group showed silent lesions predominantly multiple, greater than 5 mm, bilateral and in the subcortical region; though no statistically significant differences were found in each lesion areas (P = .214; P = .509; P = .746; P = .059, respectively). Of 16 patients who showed SBI, 1 (6.3%) patient had CHA2DS2-Vasc scores of 0; 7 (43.8%) patients had CHA2DS2-Vasc scores of 1; 6 (37.5%) patients had CHA2DS2 -Vasc scores of 2 and 2 (12.5%) patients had CHA2DS2-Vasc scores of 3. We did not find any significant relationship between CHA2DS2-Vasc scores and presence of SBI in the study patients (P = .850). DISCUSSION: High PLR might be a factor to induce inflammatory process on SBIs even with low CHA2DS2-VASc scores. PMID- 27456434 TI - Infrared and Electronic Spectroscopy of the Jet-Cooled 5-Methyl-2-furanylmethyl Radical Derived from the Biofuel 2,5-Dimethylfuran. AB - The electronic and infrared spectra of the 5-methyl-2-furanylmethyl (MFM) radical have been characterized under jet-cooled conditions in the gas phase. This resonance-stabilized radical is formed by H atom loss from one of the methyl groups of 2,5-dimethylfuran (DMF), a promising second-generation biofuel. As a resonance-stabilized radical, it plays an important role in the flame chemistry of DMF. The D0-D1 transition was studied using two-color resonant two-photon ionization (2C-R2PI) spectroscopy. The electronic origin is in the middle of the visible spectrum (21934 cm(-1) = 455.9 nm) and is accompanied by Franck-Condon activity involving the hindered methyl rotor. The frequencies and intensities are fit to a one-dimensional methyl rotor potential, using the calculated form of the ground state potential. The methyl rotor reports sensitively on the local electronic environment and how it changes with electronic excitation, shifting from a preferred ground state orientation with one CH in-plane and anti to the furan oxygen, to an orientation in the excited state in which one CH group is axial to the plane of the furan ring. Ground and excited state alkyl CH stretch infrared spectra are recorded using resonant ion-dip infrared (RIDIR) spectroscopy, offering a complementary view of the methyl group and its response to electronic excitation. Dramatic changes in the CH stretch transitions with electronic state reflect the changing preference for the methyl group orientation. PMID- 27456435 TI - Palladium-Catalyzed Synthesis of Alkynes via a Tandem Decarboxylation/Elimination of (E)-Enol Triflates. AB - A mild catalytic synthesis of alkynes via a tandem Pd-catalyzed decarboxylation/elimination of enol triflates is described. Key attributes of the method include readily available starting materials, broad functional group tolerance, and the ability to access terminal, internal, and halogenated alkynes. The preliminary scope of the reaction is demonstrated on 25 different examples with yields ranging from 63% to 96%. PMID- 27456436 TI - Review of the Australian Code for the Responsible Conduct of Research (2007). PMID- 27456438 TI - Global lessons for Australian general practice. PMID- 27456439 TI - No strong evidence bicycle helmet legislation deters cycling. PMID- 27456440 TI - Prioritising general practice research. PMID- 27456441 TI - Stroke in a young man with untreated HIV infection and neurosyphilis. PMID- 27456442 TI - Detecting ascites. PMID- 27456444 TI - hospital. PMID- 27456443 TI - Edgeworth David McIntyre, AM, MB BS, FRCSEd, FRCS, FRACS. PMID- 27456445 TI - Relieving the pressure: new Australian hypertension guideline. PMID- 27456446 TI - Rising costs of hip fractures. PMID- 27456447 TI - Presentations to general practice before a cancer diagnosis in Victoria: a cross sectional survey. AB - OBJECTIVE: To assess variations in the number of general practitioner visits preceding a cancer diagnosis, and in the length of the interval between the patient first suspecting a problem and their seeing a hospital specialist. DESIGN, SETTING AND PARTICIPANTS: Analysis of data provided to the Cancer Patient Experience Survey (CPES; survey response rate, 37.7%) by 1552 patients with one of 19 cancer types and treated in one of five Victorian Comprehensive Cancer Centre hospitals, 1 October 2012 - 30 April 2013. MAIN OUTCOME MEASURES: The primary outcome was the proportion of patients who had had three or more GP consultations about cancer-related health problems before being referred to hospital. The secondary outcome was the interval between the patient first suspecting a problem and their seeing a hospital specialist. RESULTS: 34% of the patients included in the final analyses (426 of 1248) had visited a GP at least three times before referral to a hospital doctor. The odds ratios (reference: rectal cancer; adjusted for age, sex, language spoken at home, and socio-economic disadvantage index score) varied according to cancer type, being highest for pancreatic cancer (3.2; 95% CI, 1.02-9.9), thyroid cancer (2.5; 95% CI, 0.9-6.6), vulval cancer (2.5; 95% CI, 0.7-8.7) and multiple myeloma (2.4; 95% CI, 1.1-5.5), and lowest for patients with breast cancer (0.4; 95% CI, 0.2-0.8), cervical cancer (0.5; 95% CI, 0.1-2.1), endometrial cancer (0.5; 95% CI, 0.2-1.4) or melanoma (0.7; 95% CI, 0.3-1.5). Cancer type also affected the duration of the interval from symptom onset to seeing a hospital doctor; it took at least 3 months for more than one-third of patients with prostate or colon cancer to see a hospital doctor. CONCLUSION: Certain cancer types were more frequently associated with multiple GP visits, suggesting they are more challenging to recognise early. In Victoria, longer intervals from the first symptoms to seeing a hospital doctor for colon or prostate cancer may reflect poorer community symptom awareness, later GP referral, or limited access to gastroenterology and urology services. PMID- 27456448 TI - HIP4Hips (High Intensity Physiotherapy for Hip fractures in the acute hospital setting): a randomised controlled trial. AB - OBJECTIVES: To investigate the effects of intensive acute hospital physiotherapy for patients with isolated hip fractures. DESIGN, SETTING: Single-institution, prospective, randomised trial at a level 1 trauma centre in Melbourne, March 2014 - January 2015. PARTICIPANTS: 92 patients aged 65 years or more with isolated hip fractures. Patients were excluded if the fracture was subtrochanteric or pathological, or if post-operative orders required the patient to be non-weight bearing on the operated leg. INTERVENTIONS: Randomisation to usual care physiotherapy (daily; control group) or intensive physiotherapy (three times daily; intervention group). MAIN OUTCOME MEASURES: Outcomes were assessed at post operative Day 5, at discharge, and at 6 months. The primary outcome was the modified Iowa Level of Assistance (mILOA) score, with other outcome measures including Timed Up and Go test performance and hospital length of stay (LOS). RESULTS: After controlling for sex, anaesthetic type and home setting, the between-group difference in Day 5 mILOA score favoured the intervention group (mean difference v control group, -2.7 points; P = 0.04). Hospital LOS was also shorter for the intervention group (median, 24.4 days v 35.0 days; P = 0.01). A Cox proportional hazard model that controlled for potential confounders indicated that the probability of discharge was greater for intervention group patients at all time points following surgery (P < 0.001). Re-admission and complication rates and 6-month outcomes for the two groups were not significantly different. CONCLUSIONS: Intensive acute hospital physiotherapy is safe and reduces hospital LOS after an isolated hip fracture. This has the potential to improve bed flow, given the large numbers of inpatient beds occupied by this patient population. TRIAL REGISTRATION: Clinical Trials Registry #NCT02088437. PMID- 27456449 TI - Estimating non-billable time in Australian general practice. AB - OBJECTIVES: To quantify the time that general practitioners spend on patient care that is not claimable from Medicare (non-billable) and the monetary value of this work were it claimable, and to identify variables independently associated with non-billable time. DESIGN: Prospective, cross-sectional survey, April 2012 - March 2014. SETTING: Australian general practice; a substudy of the national Bettering the Evaluation and Care of Health (BEACH) program. PARTICIPANTS: 1935 randomly sampled GPs (77.4% participation rate) from across Australia provided filled questionnaires on 66 458 patient encounters. MAIN OUTCOME MEASURES: Non billable time spent on patient care since patient's previous consultation; duration of and reasons for non-billable time; estimate of its monetary value were it claimable from Medicare; variables associated with non-billable time. RESULTS: 69.5% of GPs reported non-billable care outside patient visits; 8019 patient encounters (12.1%) were associated with an occasion of non-billable time. Mean time spent per occasion was 10.1 min (range, 1-240 min). Reasons for non billable time included arranging tests and referrals, consulting specialists or allied health professionals, medication renewals, and advice and education, and encompassed all International Classification of Primary Care Version 2 chapters. The notional average annual value per GP of this work was $10 525.95 (level A rebate) to $23 008.05 (level B). Non-billable time was independently associated with female GPs, younger GPs (under 55 years), female patients, patients aged 65 years or more, and one or more chronic problems being managed at the recorded encounter. CONCLUSION: Most GPs spend a significant amount of unpaid time on patient care between consultations, an inherent problem of the fee-for-service system. This work should inform discussions of future funding models. PMID- 27456450 TI - Guideline for the diagnosis and management of hypertension in adults - 2016. AB - The National Heart Foundation of Australia has updated the Guide to management of hypertension 2008: assessing and managing raised blood pressure in adults (updated December 2010). Main recommendations For patients at low absolute cardiovascular disease risk with persistent blood pressure (BP) >= 160/100 mmHg, start antihypertensive therapy. The decision to treat at lower BP levels should consider absolute cardiovascular disease risk and/or evidence of end-organ damage, together with accurate BP assessment. For patients at moderate absolute cardiovascular disease risk with persistent systolic BP >= 140 mmHg and/or diastolic BP >= 90 mmHg, start antihypertensive therapy. Treat patients with uncomplicated hypertension to a target BP of < 140/90 mmHg or lower if tolerated. Changes in management as a result of the guideline Ambulatory and/or home BP monitoring should be offered if clinic BP is >= 140/90 mmHg, as out-of-clinic BP is a stronger predictor of outcome. In selected high cardiovascular risk populations, aiming for a target of < 120 mmHg systolic can improve cardiovascular outcomes. If targeting < 120 mmHg, close follow-up is recommended to identify treatment-related adverse effects including hypotension, syncope, electrolyte abnormalities and acute kidney injury. Why the changes have been made A 2015 meta-analysis of patients with uncomplicated mild hypertension (systolic BP range, 140-169 mmHg) demonstrated that BP-lowering therapy is beneficial (reduced stroke, cardiovascular death and all-cause mortality). A 2015 trial comparing lower with higher blood pressure targets in selected high cardiovascular risk populations found improved cardiovascular outcomes and reduced mortality, with an increase in some treatment-related adverse events. PMID- 27456451 TI - Appropriate use of serum troponin testing in general practice: a narrative review. AB - The troponin assay was designed to assist in diagnosis and improve risk stratification for people presenting to the emergency setting with symptoms suggestive of an acute coronary syndrome. Newly developed high sensitivity assays provide reliable detection of very low concentrations of troponin and offer earlier risk stratification of patients with possible acute coronary syndrome. Cardiac troponin testing in general practice should be limited to patients presenting with ischaemic symptoms that occurred more than 24 hours previously. If these patients have no high risk clinical features and a normal electrocardiogram (ECG), they may be assessed with a single troponin assay but should be referred urgently to hospital if the result is elevated. In patients presenting with symptoms of possible acute coronary syndrome within the preceding 24 hours, or if they otherwise have symptoms consistent with unstable angina, high risk clinical features or ECG abnormalities, a serum troponin test should not be ordered and patients should be referred immediately to an emergency department. When a single troponin assay is appropriate, the test should be labelled as urgent and systems must be in place to ensure the result is conveyed immediately to the medical practitioner, as it has prognostic implications and may require an urgent action plan. PMID- 27456452 TI - Are general practice characteristics predictors of good glycaemic control in patients with diabetes? A cross-sectional study. PMID- 27456453 TI - Are general practice characteristics predictors of good glycaemic control in patients with diabetes? A cross-sectional study. PMID- 27456454 TI - A Solution-Processed Heteropoly Acid Containing MoO3 Units as a Hole-Injection Material for Highly Stable Organic Light-Emitting Devices. AB - We report hole-injection layers (HILs) comprising a heteropoly acid containing MoO3 units, phosphomolybdic acid (PMA), in organic light-emitting devices (OLEDs). PMA possesses outstanding properties, such as high solubility in organic solvents, very low surface roughness in the film state, high transparency in the visible region, and an appropriate work function (WF), that make it suitable for HILs. We also found that these properties were dependent on the postbaking atmosphere and temperature after film formation. When the PMA film was baked in N2, the Mo in the PMA was reduced to Mo(V), whereas baking in air had no influence on the Mo valence state. Consequently, different baking atmospheres yielded different WF values. OLEDs with PMA HILs were fabricated and evaluated. OLEDs with PMA baked under appropriate conditions exhibited comparably low driving voltages and higher driving stability compared with OLEDs employing conventional hole-injection materials (HIMs), poly(3,4 ethylenedioxythiophene):poly(4-styrenesulfonate), and evaporated MoO3, which clearly shows the high suitability of PMA HILs for OLEDs. PMA is also a commercially available and very cheap material, leading to the widespread use of PMA as a standard HIM. PMID- 27456455 TI - Obesity and neurocognitive recovery after sports-related concussion in athletes: a matched cohort study. AB - OBJECTIVES: Sports-related concussions (SRCs) are a significant public health concern in athletes. Data exist suggesting a link between obesity and decreased neurocognitive function, yet the effect of body mass index (BMI) on neurocognitive function and recovery after a SRC is unknown. The goal of our study was to discern the effect of BMI on recovery after SRC. METHODS: This study was a retrospective observational cohort study. Between 2013 and 2014, 7,606 athletes between the ages of 13-20 years valid baseline neurocognitive testing performed at multiple regional concussion centers sustained a concussion. Out of these athletes, 711 normal weight athletes and 711 obese athletes were matched by age, gender, number of previous concussions, and sport. The proportions of athletes returning to baseline within two weeks between the groups were defined by using 80% confidence reliable change index (RCI) criteria and were compared using Fisher's Exact Test. Kaplan-Meier survival curve analysis with log-rank test was used to compare the median time to neurocognitive recovery between groups. RESULTS: Fewer obese athletes returned to baseline within 2 weeks on measures of verbal memory, visual motor speed, reaction time, postconcussion symptom scale (PCSS), and overall recovery compared to normal weight athletes. Obese athletes also had greater median time of return to baseline with respect to reaction time, PCSS, and overall recovery. CONCLUSION: Using RCI methodology, there exists an association between obesity and increased time to return to neurocognitive and symptom baseline after SRC in athletes, specifically reaction time, symptom scores, and overall recovery. PMID- 27456458 TI - Impact of Pluronic F-68 vs Tween 80 on Fabrication and Evaluation of Acyclovir SLNs for Skin Delivery. AB - INTRODUCTION: The solid lipid nanoparticles (SLNs) of Acyclovir (ACV) were fabricated with Soya lecithin and Fractionated Coconut oil (medium chain glyceride) as a first time combination. METHODS: The research was focused on developing ACV-SLN by using high pressure hot-homogenization technique. The ingredients were used in different concentrations and ratios to identify the best formulation design. The tween 80 and Pluronic F-68 were used in various concentrations in formulation design to assess the impact on the fabrication and evaluation of SLNs. The impact of nanotechnology gain to play a vital role in the topical pharmaceutical products and the related patents will play a significant role in related industries. RESULTS: The SLNs were subjected to various characterization techniques such as XRD, FTIR, Master sizer analysis and zeta potential. The mean particle size was determined by master sizer and zeta sizer. Transmission electron microscopy (TEM) was used as a tool to analyze the morphology and other features. The zeta potential and drug entrapment efficiency (EE%) were also determined for the prepared ACV-SLNs. The efficiency of drug release from prepared formulations was studied by using in vitro study with the utilization of dialysis membrane technique. SLN dispersions exhibited the average size in nano range. CONCLUSION: SLNs with small particle size found to have predetermined encapsulation efficiency, and relatively high loading capacity and predetermined in vitro drug release profile. PMID- 27456456 TI - Plasminogen Activator Inhibitor-1 in depression: Results from Animal and Clinical Studies. AB - Evidence suggests that plasminogen activator inhibitor-1 (PAI-1) is a stress related factor, and serum PAI-1 levels are increased in patients with major depressive disorders (MDD). Herein, we analysed PAI-1 protein levels in the brain, cerebrospinal fluid (CSF) and serum of rodents exposed to chronic unpredictable mild stress or treated with escitalopram. In addition, we examined PAI-1 concentrations in serum obtained from 17 drug-free depressed patients before and after escitalopram treatment. We found that PAI-1 expression was increased in area 1 of the cingulate cortex and prelimbic cortex of the medial prefrontal cortex as well as in the hippocampal cornu ammonis 3 and dentate gyrus in stressed rats. A downregulation of PAI-1 following chronic escitalopram treatment was also found. PAI-1 levels were higher in the CSF and serum in stressed rats than in controls, although the difference did not reach statistical significance in the serum. Escitalopram treatment significantly decreased PAI-1 levels in the serum, but not in the CSF. MDD patients had significantly greater serum PAI-1 concentrations than controls. Our results suggest that PAI-1 is implicated in the pathophysiology of depression. PMID- 27456457 TI - Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer. AB - Current targeted therapies using small kinase inhibitors and antibodies have limited efficacy in treating prostate cancer (PCa), a leading cause of cancer death in American men. We have developed a novel strategy by engineering an RNA based aptamer-siRNA chimera, in which a bivalent aptamer specifically binds prostate-specific membrane antigen (PSMA) via an antibody-like structure to promote siRNA internalization in PCa cells, and two siRNAs specific to EGFR and survivin are fused between two aptamers. The chimera is able to inhibit EGFR and survivin simultaneously and induce apoptosis effectively in vitro and in vivo. In the C4-2 PCa xenograft model, the treatment with the chimera significantly suppresses tumor growth and angiogenesis. The inhibition of angiogenesis is mediated by an EGFR-HIF1alpha-VEGF-dependent mechanism. Our results support that the bivalent aptamer-driven delivery of two siRNAs could be a new combination therapeutic strategy to effectively inhibit multiple and conventionally "undruggable" targets. PMID- 27456460 TI - Examining Perceptions and Attitudes. AB - The purpose of this article is to compare and discuss the use of Likert-type scales and Q-methodology to examine perceptions and attitudes in nursing research. This article provides a brief review of each approach, and how they have been used to advance our knowledge in health-related perceptions and attitudes. Although Likert-type scales are economical, efficient, and easy to analyze, the results can be difficult to interpret or translate into meaningful practice. In contrast, Q-methodology yields holistic and in-depth information on what the prevailing perceptions and attitudes are, but its conduct is logistically challenging and the results' generalizability can be limited. The appropriate uses of either or both approaches to answer different research questions will be discussed. Nurse scientists are called upon to continue our exploration, utilization, and expansion of unique methodologies that directly speak to a meaningful examination of these important constructs in nursing research. PMID- 27456459 TI - Resting-state functional MR imaging shed insights into the brain of diabetes. AB - Diabetes mellitus is a common metabolic disease which is associated with increasing risk for multiple cognitive declines. Alterations in brain functional connectivity are believed to be the mechanisms underlying the cognitive function impairments. During the past decade, resting-state functional magnetic resonance imaging (rs-fMRI) has been developed as a major tool to study brain functional connectivity in vivo. This paper briefly reviews the diabetes-associated cognitive impairment, analysis algorithms and clinical applications of rs-fMRI. We also provide future perspectives of rs-fMRI in diabetes. PMID- 27456461 TI - Self-Efficacy and Blood Pressure Self-Care Behaviors in Patients on Chronic Hemodialysis. AB - This study examined the effects of an educative, self-regulation intervention on blood pressure self-efficacy, self-care outcomes, and blood pressure control in adults receiving hemodialysis. Simple randomization was done at the hemodialysis unit level. One hundred eighteen participants were randomized to usual care ( n = 59) or intervention group ( n = 59). The intervention group received blood pressure education sessions and 12 weeks of individual counseling on self regulation of blood pressure, fluid, and salt intake. There was no significant increase in self-efficacy scores within ( F = .55, p = .46) or between groups at 12 weeks ( F = 2.76, p = .10). Although the intervention was not successful, results from the total sample ( N = 118) revealed that self-efficacy was significantly related to a number of self-care outcomes including decreased salt intake, lower interdialytic weight gain, increased adherence to blood pressure medications, and fewer missed hemodialysis appointments. Increased blood pressure self-efficacy was also associated with lower diastolic blood pressure. PMID- 27456462 TI - Clinical features and treatment outcome of Epstein-Barr virus-positive nodal T cell lymphoma. AB - The classification of mature NK-/T-cell lymphoma mainly originating from the T cell lineage with predominantly nodal involvement and Epstein-Barr virus (EBV) positivity in a majority of tumor cells is unresolved. We analyzed the clinical features and treatment outcomes of such patients. Five patients with EBV-positive nodal T-cell lymphoma were surveyed during follow-up period. The median age was 53 years (range 33-88 years), and all patients showed nodal involvement. The patients mostly presented advanced clinical features, such as stage III or IV disease, elevated lactate dehydrogenase, and hemophagocytosis. Four patients received cyclophosphamide-containing chemotherapy at the time of diagnosis. However, three patients (75 %) showed disease progression during the early cycles of initial treatment. The median overall survival was 1.5 months (95 % CI 0.0-3.4 months). Patients with EBV-positive nodal T-cell lymphoma mainly show lymph node involvement, but also show aggressive clinical features and poor treatment outcomes, such as aggressive NK-cell leukemia. Therefore, we should consider EBV positive nodal T-cell lymphoma to be a unique disease entity distinct from peripheral T-cell lymphoma not otherwise specified. PMID- 27456463 TI - Co-occurrence of hyperleukocytosis and elevated fibrin-fibrinogen degradation product levels is a risk factor for early intracranial hemorrhage in patients with de novo acute leukemia. AB - Early intracranial hemorrhage (eICH) is a potentially fatal complication of acute leukemia. We analyzed risk factors for eICH in patients with de novo acute leukemia. Ninety-one de novo acute leukemia patients at our institution between September 2003 and June 2014 were included. Of the 91 patients, eight (8.8 %) and 83 were included in the eICH and non-eICH groups, respectively. Univariate analysis demonstrated that white blood cell (WBC) count (P = 0.018), fibrin fibrinogen degradation product (FDP) level (P = 0.0075), co-occurrence of WBC >=50,000/ul and FDP level >40 ug/ml (P < 0.001), and fever (P = 0.248) were all significant predictors of eICH at the 0.25 level. In a subsequent multivariate analysis involving these parameters, only the combination of hyperleukocytosis and elevated FDP levels was found to be significant at the 0.05 level. A significant difference in the duration of the overall survival (OS) period was detected between patients that did and did not exhibit the combination of hyperleukocytosis and elevated FDP levels (P < 0.001). Co-occurrence of hyperleukocytosis and elevated FDP levels is a significant risk factor for eICH in patients with de novo acute leukemia and has a significant adverse affect on OS. PMID- 27456464 TI - Therapeutic effect of Colla corii asini on improving anemia and hemoglobin compositions in pregnant women with thalassemia. AB - Currently there is no consensus on treating anemia in pregnant thalassemia patients. In China, Colla corii asini (CCA) has been widely used for treating anemia for more than 2000 years. However, its clinical application in the thalassemia population is limited by a lack of quantitative evidence. The present study aims to investigate the therapeutic effect of CCA in increasing hemoglobin (Hb) concentration and improving abnormal hemoglobin compositions in pregnant patients with beta-thalassemia. Seventy-two pregnant patients who met inclusion criteria were randomly assigned to either the treatment group or control group. Patients in the treatment group were given 15 g of CCA, while the control group were observed and followed up without any treatment. Levels of Hb, serum iron (SI), serum ferritin (SF) and three types of Hb components [adult hemoglobin (HbA), fetal hemoglobin (HbF), minor adult hemoglobin (HbA2)] were measured before and after treatment. Treatment with CCA led to a significant increase of Hb. The major Hb component induced by CCA was HbA, while levels of both HbA2 and HbF dropped after treatment. CCA treatment significantly increased SI, while SF remained unaffected. Our data suggest that CCA can improve anemia and optimize Hb components in pregnant patients with thalassemia without affecting iron reserves. PMID- 27456465 TI - Down Syndrome and Fragile X Syndrome in a Colombian Woman: Case Report. AB - BACKGROUND: Down syndrome (DS) and Fragile X syndrome (FXS) are the major genetic causes of intellectual disabilities. Here, we present a case of a 32-year-old woman with the diagnosis of both FXS and DS. She is the daughter of a 47-year-old pre-mutation woman who also has three sons with FXS. METHODS: Cytogenetic testing detected the presence of a complete trisomy 21. A combination of PCR and Southern blot analysis was utilized to document the presence of the FMR1 full mutation. RESULTS: The patient has physical characteristics and behavioural disturbances typical of both FXS and DS, which were confirmed by molecular testing. Her treatment plan included a trial of sertraline because of the severity of her shyness and lack of language. She had an excellent response to sertraline with improvement in shyness and social interactions, particularly with family members. CONCLUSIONS: In this study, we report the case of a woman with both FXS and DS, which is the fifth case of FXS and DS in the world's literature. The patient is from Ricaurte, a small town in Colombia, South America, where there is the world's highest prevalence for FXS. PMID- 27456466 TI - Unsharpness of generalized measurement and its effects in entropic uncertainty relations. AB - Under the scenario of generalized measurements, it can be questioned how much of quantum uncertainty can be attributed to measuring device, independent of the uncertainty in the measured system. On the course to answer the question, we suggest a new class of entropic uncertainty relation that differentiates quantum uncertainty from device imperfection due to the unsharpness of measurement. In order to quantify the unsharpness, we suggest and analyze the quantity that characterizes the uncertainty in the measuring device, based on Shannon entropy. Using the quantity, we obtain a new lower bound of entropic uncertainty with unsharpness and it has been shown that the relation can also be obtained under the scenario that sharp observables are affected by the white noise and amplitude damping. PMID- 27456467 TI - Temperature-controlled redox-neutral ruthenium(ii)-catalyzed regioselective allylation of benzamides with allylic acetates. AB - Substituted aromatic amides reacted efficiently with allylic acetates in the presence of a cationic ruthenium complex in ClCH2CH2Cl at room temperature providing ortho allylated benzamides in a highly regioselective manner without any oxidant and base. The whole catalytic reaction occurred in a Ru(ii) oxidation state and thus the oxidation step is avoided. By tuning the reaction temperature, ortho allyl and vinyl benzamides were prepared exclusively. Later, ortho allyl and vinylated benzamides were converted into biologically useful six- and five membered benzolactones in the presence of HCl. PMID- 27456468 TI - MoS2-clad microfibre laser delivering conventional, dispersion-managed and dissipative solitons. AB - Molybdenum disulfide (MoS2), whose monolayer possesses a direct band gap, displays promising applications in optoelectronics, photonics, and lasers. Recent researches have demonstrated that MoS2 has not only a significant broadband saturable absorption performance, but also a higher optical nonlinear response than graphene. However, MoS2 shows much lower optical damage threshold owing to the poorer thermal conductivity and mechanical property. Here, we exploit a MoS2 clad microfibre (MCM) as the saturable absorber (SA) for the generation of ultrashort pulses under different dispersion conditions. The improved evanescent field interaction scheme can overcome the laser-induced thermal damage, as well as take full advantage of the strong nonlinear effect of MoS2. With the MCM SA, conventional, dispersion-managed, and dissipative solitons are generated around 1600 nm in Er-doped fibre lasers with anomalous, near-zero, and normal cavity dispersions, respectively. Our work paves the way for applications of 2D layered materials in photonics, especially in laser sources. PMID- 27456470 TI - Editorial. PMID- 27456469 TI - Full transcription of the chloroplast genome in photosynthetic eukaryotes. AB - Prokaryotes possess a simple genome transcription system that is different from that of eukaryotes. In chloroplasts (plastids), it is believed that the prokaryotic gene transcription features govern genome transcription. However, the polycistronic operon transcription model cannot account for all the chloroplast genome (plastome) transcription products at whole-genome level, especially regarding various RNA isoforms. By systematically analyzing transcriptomes of plastids of algae and higher plants, and cyanobacteria, we find that the entire plastome is transcribed in photosynthetic green plants, and that this pattern originated from prokaryotic cyanobacteria - ancestor of the chloroplast genomes that diverged about 1 billion years ago. We propose a multiple arrangement transcription model that multiple transcription initiations and terminations combine haphazardly to accomplish the genome transcription followed by subsequent RNA processing events, which explains the full chloroplast genome transcription phenomenon and numerous functional and/or aberrant pre-RNAs. Our findings indicate a complex prokaryotic genome regulation when processing primary transcripts. PMID- 27456472 TI - Passive anterior tibial translation in women with and without joint hypermobility: an exploratory study. AB - AIM: Generalized joint hypermobility (GJH) is a frequent entity, which is still not fully understood. Symptoms associated with GJH are musculoskeletal disorders, decreased balance, impaired proprioception and chronic pain. The purpose of this study was to compare the passive anterior tibial translation (TT) in terms of distance and corresponding force between normomobile (NM) and hypermobile (HM) as well as between NM, symptomatic (HM-s) and asymptomatic (HM-as) hypermobile women. METHODS: A total of 195 women, 67 NM and 128 HM, whereof 56 were further classified as HM-s and 47 as HM-as, participated in this study. Passive TT was measured using an adapted Rolimeter. A manual traction force was applied and the distance of the translation measured. For the analysis, maximal translation (TTmax) and the respective force as well as the distance at 40N (TTF40) and 80N (TTF80) traction force were determined. The NM and HM groups were compared using independent samples t-tests, whereas the NM, HM-s and HM-as groups were compared using one-way analyses of variance with Tukey post hoc tests (significance level P <= 0.05). RESULTS: Comparisons revealed higher values for the variables TTmax, TTF40 and TTF80 in the HM compared to the NM group. In addition, TTmax and TTF80 were found to be higher in the HM-s compared to the NM group. CONCLUSIONS: HM women showed significantly higher TT distances, which were even more accentuated in those having symptoms. The findings point toward less passive stability of the knee joint and thus maybe a need of higher muscle activation in order to stabilize the joint. PMID- 27456471 TI - A genetic cell context-dependent role for ZEB1 in lung cancer. AB - The Zinc-finger E-box-binding Homeobox-1 (ZEB1) is a transcription factor that promotes epithelial-mesenchymal transition (EMT) and acts as an oncogene in KRAS mutated lung cancer models. Here we report that ZEB1 exerts the opposite effect in EGFR-mutated lung cancer cells, where it suppresses growth by increasing microRNA-200 targets to antagonize ERBB3, a driver of mutant EGFR-dependent cell growth. Among these targets, NOTCH1 represses ERBB3 promoter activity and the expression of ERBB3. Furthermore, we find that EGFR inhibitor treatment, which inhibits the growth of EGFR-mutated cells, induces ZEB1. Despite its growth inhibiting effect, EGFR inhibitor-induced ZEB1 strongly promotes EMT-dependent resistance to EGFR inhibitors partially through NOTCH1, suggesting a multifunctional role for NOTCH1 in EGFR-mutated cells. These results support a previously unrecognized genetic cell context-dependent role for ZEB1 and suggest that NOTCH1 may be a useful target for treating resistance to EGFR inhibitors, especially EMT-driven resistance. PMID- 27456473 TI - Haemarthrosis model in mice: BSS - Bleeding Severity Score assessment system. AB - INTRODUCTION: The prophylactic administration of clotting factor concentrate is currently the most effective strategy for the prevention of joint bleeding. As new agents with different mechanisms of action and administration schedules are developed, it will be important to study them in relevant preclinical models. AIM: The aim of this study was the standardization of a mouse haemarthrosis model in a haemophilia mouse and the development and validation of a comprehensive bleeding assessment system, the Bleeding Severity Score (BSS). METHODS AND RESULTS: Four outcome measurements were assessed, two of which, the extra articular bleeding score and intra-articular bleeding score, were determined to be the most reliable and were summarized into a BSS which was validated using a mouse haemarthrosis variability model. CONCLUSION: Using this model, the haemostatic effect of prospective drugs can be assessed in a clinically relevant joint bleeding model and will significantly increase the value of preclinical studies. PMID- 27456475 TI - Wide-Band Spatially Tunable Photonic Bandgap in Visible Spectral Range and Laser based on a Polymer Stabilized Blue Phase. AB - This work successfully develops a largely-gradient-pitched polymer-stabilized blue phase (PSBP) photonic bandgap (PBG) device with a wide-band spatial tunability in nearly entire visible region within a wide blue phase (BP) temperature range including room temperature. The device is fabricated based on the reverse diffusion of two injected BP-monomer mixtures with a low and a high chiral concentrations and afterwards through UV-curing. This gradient-pitched PSBP can show a rainbow-like reflection appearance in which the peak wavelength of the PBG can be spatially tuned from the blue to the red regions at room temperature. The total tuning spectral range for the cell is as broad as 165 nm and covers almost the entire visible region. Based on the gradient-pitched PSBP, a spatially tunable laser is also demonstrated in this work. The temperature sensitivity of the lasing wavelength for the laser is negatively linear and approximately -0.26 nm/ degrees C. The two devices have a great potential for use in applications of photonic devices and displays because of their multiple advantages, such as wide-band tunability, wide operated temperature range, high stability and reliability, no issue of hysteresis, no need of external controlling sources, and not slow tuning speed (mechanically). PMID- 27456474 TI - Subcutaneous phaeohyphomycosis caused by Exophiala spinifera in a European patient with lymphoma: a rare occurrence case report and literature review. AB - Exophiala spinifera is a dematiaceous fungus responsible for rare skin infections presenting as phaeohyphomycosis or chromoblastomycosis which has been primarily reported in tropical and subtropical areas (Asia, South and North America). We report the first case of E. spinifera phaeohyphomycosis in a European patient. The phaeohyphomycosis was limited to the skin, involving the finger of an immunocompromised patient presenting with a large B-cell lymphoma treated by R mini-CHOP regimen. Remission was initially achieved by surgical excision; however, a local subcutaneous relapse required treatment with itraconazole. We performed a literature review of the 32 previously published cases of E. spinifera phaeohyphomycosis highlighting its clinical phenotype: disseminated infection with extracutaneous involvement and poor prognosis were reported in young patients, of whom some were recently associated with CARD9 mutations, whereas cases in older immunocompromised patients were limited to the skin and showed better prognosis. There is currently no standard treatment for E. spinifera phaeohyphomycosis; however, itraconazole, alone or in combination, allowed partial or complete response in 16 out of 20 cases. PMID- 27456476 TI - Neutrophil elastase and matrix metalloproteinase 12 in cystic fibrosis lung disease. AB - Chronic lung disease remains the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Recent studies in young children with CF diagnosed by newborn screening identified neutrophil elastase (NE), a major product released from neutrophils in inflamed airways, as a key risk factor for the onset and early progression of CF lung disease. However, the understanding of how NE and potentially other proteases contribute to the complex in vivo pathogenesis of CF lung disease remains limited. In this review, we summarize recent progress in this area based on studies in betaENaC-overexpressing (betaENaC-Tg) mice featuring CF-like lung disease and novel protease-specific Forster resonance energy transfer (FRET) sensors for localization and quantification of protease activity in the lung. These studies demonstrated that NE is implicated in several key features of CF lung disease such as neutrophilic airway inflammation, mucus hypersecretion, and structural lung damage in vivo. Furthermore, these studies identified macrophage elastase (matrix metalloproteinase 12 (MMP12)) as an additional protease contributing to early lung damage in betaENaC-Tg mice. Collectively, these results suggest that NE and MMP12 released from activated neutrophils and macrophages in mucus-obstructed airways play important pathogenetic roles and may serve as potential therapeutic targets to prevent and/or delay irreversible structural lung damage in patients with CF. PMID- 27456478 TI - Maximal workload but not peak oxygen uptake is decreased during immersed incremental exercise at cooler temperatures. AB - PURPOSE: This study investigated the effects of water temperature on cardiorespiratory responses and exercise performance during immersed incremental cycle exercise until exhaustion. METHODS: Ten healthy young men performed incremental cycle exercise on a water cycle ergometer at water temperatures (T w) of 18, 26 and 34 degrees C. Workload was initially set at 60 W and was increased by 20 W every 2 min for the first four levels and then by 10 W every minute until the subject could no longer continue. RESULTS: During submaximal exercise (60-120 W), [Formula: see text] was greater at T w = 18 degrees C than at 26 or 34 degrees C. Maximal workload was lower at T w = 18 degrees C than at 26 or 34 degrees C [T w = 18 degrees C: 138 +/- 16 (SD) W, T w = 26 degrees C: 157 +/- 16 W, T w = 34 degrees C: 156 +/- 18 W], whereas [Formula: see text]O2peak did not differ among the three temperatures [T w = 18 degrees C: 3156 +/- 364 (SD) ml min(-1), T w = 26 degrees C: 3270 +/- 344 ml min(-1), T w = 34 degrees C: 3281 +/- 268 ml min(-1)]. Minute ventilation ([Formula: see text]) and tidal volume (V T) during submaximal exercise were higher at T w = 18 degrees C than at 26 or 34 degrees C, while respiratory frequency (f R) did not differ with respect to T w. CONCLUSION: Peak workload during immersed incremental cycle exercise is lower in cold water (18 degrees C) due to the higher [Formula: see text] during submaximal exercise, while the greater [Formula: see text] in cold water was due to a larger V T. PMID- 27456477 TI - Fatigue associated with prolonged graded running. AB - Scientific experiments on running mainly consider level running. However, the magnitude and etiology of fatigue depend on the exercise under consideration, particularly the predominant type of contraction, which differs between level, uphill, and downhill running. The purpose of this review is to comprehensively summarize the neurophysiological and biomechanical changes due to fatigue in graded running. When comparing prolonged hilly running (i.e., a combination of uphill and downhill running) to level running, it is found that (1) the general shape of the neuromuscular fatigue-exercise duration curve as well as the etiology of fatigue in knee extensor and plantar flexor muscles are similar and (2) the biomechanical consequences are also relatively comparable, suggesting that duration rather than elevation changes affects neuromuscular function and running patterns. However, 'pure' uphill or downhill running has several fatigue related intrinsic features compared with the level running. Downhill running induces severe lower limb tissue damage, indirectly evidenced by massive increases in plasma creatine kinase/myoglobin concentration or inflammatory markers. In addition, low-frequency fatigue (i.e., excitation-contraction coupling failure) is systematically observed after downhill running, although it has also been found in high-intensity uphill running for different reasons. Indeed, low-frequency fatigue in downhill running is attributed to mechanical stress at the interface sarcoplasmic reticulum/T-tubule, while the inorganic phosphate accumulation probably plays a central role in intense uphill running. Other fatigue-related specificities of graded running such as strategies to minimize the deleterious effects of downhill running on muscle function, the difference of energy cost versus heat storage or muscle activity changes in downhill, level, and uphill running are also discussed. PMID- 27456480 TI - Validation of the Turkish Cervical Cancer and Human Papilloma Virus Awareness Questionnaire. AB - AIM: The aim of this study was to determine the validity and reliability of the 'Cervical Cancer and Human Papilloma Virus Awareness Questionnaire' among fertility age women by adapting the scale into Turkish. BACKGROUND: Cervical cancer is the fourth most commonly form seen among women. Death from cervical cancer ranks third among causes and is one of the most preventable forms of cancer. METHODS: This cross-sectional study included 360 women from three family health centres between January 5 and June 25, 2014. RESULTS: Internal consistency showed that the Kuder-Richardson 21 reliability coefficient in the first part was 0.60, Cronbach's alpha reliability coefficient was 0.61 in the second part. The Kaiser-Meyer-Olkin value of the items on the scale was 0.712. The Barlett test was significant. The confirmatory factor analysis indicated that the model matched the data adequately. CONCLUSION: This study shows that the Turkish version of the instrument is a valid and reliable tool to evaluate knowledge, perceptions and preventive behaviours of women regarding human papilloma virus and cervical cancer. IMPLICATIONS FOR NURSING AND POLICY MAKERS: Nurses who work in the clinical and primary care settings need to screen, detect and refer women who may be at risk from cervical cancer. PMID- 27456481 TI - Identification of Stage-Specific Surface Markers in Early B Cell Development Provides Novel Tools for Identification of Progenitor Populations. AB - Whereas the characterization of B lymphoid progenitors has been facilitated by the identification of lineage- and stage-specific surface markers, the continued identification of differentially expressed proteins increases our capacity to explore normal and malignant B cell development. To identify novel surface markers with stage-specific expression patterns, we explored the reactivity of CD19(+) B cell progenitor cells to Abs targeted to 176 surface proteins. Markers with stage-specific expression were identified using a transgenic reporter gene system subdividing the B cell progenitors into four surface IgM(-) stages. This approach affirmed the utility of known stage-specific markers, as well as identifying additional proteins that selectively marked defined stages of B cell development. Among the stage-specific markers were the cell adhesion proteins CD49E, CD11A, and CD54 that are highly expressed selectively on the most immature progenitors. This work identifies a set of novel stage-specific surface markers that can be used as a complement to the classical staining protocols to explore B lymphocyte development. PMID- 27456482 TI - Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation. AB - Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6 independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration-approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation. PMID- 27456483 TI - Mucosal Inducible NO Synthase-Producing IgA+ Plasma Cells in Helicobacter pylori Infected Patients. AB - The mucosal immune system is relevant for homeostasis, immunity, and also pathological conditions in the gastrointestinal tract. Inducible NO synthase (iNOS)-dependent production of NO is one of the factors linked to both antimicrobial immunity and pathological conditions. Upregulation of iNOS has been observed in human Helicobacter pylori infection, but the cellular sources of iNOS are ill defined. Key differences in regulation of iNOS expression impair the translation from mouse models to human medicine. To characterize mucosal iNOS producing leukocytes, biopsy specimens from H. pylori-infected patients, controls, and participants of a vaccination trial were analyzed by immunohistochemistry, along with flow cytometric analyses of lymphocytes for iNOS expression and activity. We newly identified mucosal IgA-producing plasma cells (PCs) as one major iNOS(+) cell population in H. pylori-infected patients and confirmed intracellular NO production. Because we did not detect iNOS(+) PCs in three distinct infectious diseases, this is not a general feature of mucosal PCs under conditions of infection. Furthermore, numbers of mucosal iNOS(+) PCs were elevated in individuals who had cleared experimental H. pylori infection compared with those who had not. Thus, IgA(+) PCs expressing iNOS are described for the first time, to our knowledge, in humans. iNOS(+) PCs are induced in the course of human H. pylori infection, and their abundance seems to correlate with the clinical course of the infection. PMID- 27456484 TI - Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia. AB - IL-22-IL-22R signaling plays a crucial role in regulating host defenses against extracellular pathogens, particularly in the intestine, through the induction of antimicrobial peptides and chemotactic genes. However, the role of IL-22-IL-22R is understudied in Streptococcus pneumoniae lung infection, a prevalent pathogen of pneumonia. This paper presents the findings of IL-22 signaling during a murine model of pneumococcal pneumonia and improvement of bacterial burden upon IL-22 administration. IL-22 was rapidly induced in the lung during pneumococcal infection in wild-type mice, and Il22(-/-) mice had higher pneumococcal burdens compared with controls. Additionally, mice with hepatic-specific deletion of Il22ra1 also had higher bacterial burdens in lungs compared with littermate controls after intrapulmonary pneumococcal infection, suggesting that IL-22 signaling in the liver is important to control pneumococcal pneumonia. Thus, we hypothesized that enhancement of IL-22 signaling would control pneumococcal burden in lung tissues in an experimental pneumonia model. Administration of rIL 22 systemically to infected wild-type mice decreased bacterial burden in lung and liver at 24 h postinfection. Our in vitro studies also showed that mice treated with IL-22 had increased C3 expression in the liver compared with the isotype control group. Furthermore, serum from mice treated with IL-22 had improved opsonic capacity by increasing C3 binding on S. pneumoniae Taken together, endogenous IL-22 and hepatic IL-22R signaling play critical roles in controlling pneumococcal lung burden, and systemic IL-22 decreases bacterial burden in the lungs and peripheral organs by potentiating C3 opsonization on bacterial surfaces, through the increase of hepatic C3 expression. PMID- 27456486 TI - Pyk2 Controls Integrin-Dependent CTL Migration through Regulation of De-Adhesion. AB - Protein tyrosine kinase 2 (Pyk2) is required for T cell adhesion to ICAM-1; however, the mechanism by which it regulates adhesion remains unexplored. Pyk2 function in murine CTL clones and activated ex vivo CD8(+) T cells was disrupted by pharmacological inhibition, knockdown of expression with small interfering RNA, or expression of the dominant-negative C-terminal domain. We found that Pyk2 is not absolutely required for adhesion of CTL to ICAM-1, but rather delays the initial adhesion. Disruption of Pyk2 function caused cells to display an unusual elongated appearance after 1 h on ICAM-1, consistent with abnormally strong adhesion. Furthermore, the random mobility of CTL on ICAM-1 was severely compromised using all three methods of disrupting Pyk2 function. Live-cell imaging studies revealed that the decreased migration is the result of a defect in the detachment from ICAM-1 at the trailing edge when Pyk2 function is inhibited. Examination of Pyk2 tyrosine phosphorylation in normal polarized cells demonstrated that Pyk2 phosphorylated at Y579 and Y580 preferentially localizes to the leading edge, whereas Y881-phosphorylated Pyk2 is enriched at the trailing edge, suggesting that the tyrosine phosphorylation of Pyk2 is spatially regulated in migrating CTL. Additionally, inhibition of Pyk2 caused cells to form multiple LFA-1-rich tails at the trailing edge, most likely resulting from a defect in LFA 1 release required for forward movement. Our results show that Pyk2 contributes to CTL migration by regulating detachment of CTL at the trailing edge, which could explain why Pyk2 is important for chemotactic and migratory responses. PMID- 27456485 TI - Targeting T Cell Bioenergetics by Modulating P-Glycoprotein Selectively Depletes Alloreactive T Cells To Prevent Graft-versus-Host Disease. AB - T lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. In hematopoietic stem cell transplantation, acute graft-versus-host-disease (GVHD) is caused by an attack on the recipient's tissues from donor allogeneic T cells. Selectively depleting GVHD-causing cells prior to transplant may prevent GVHD. In this study, we evaluated 24 chalcogenorhodamine photosensitizers for their ability to selectively deplete reactive T lymphocytes and identified the photosensitizer 2-Se-Cl, which accumulates in stimulated T cells in proportion to oxidative phosphorylation. The photosensitizer is also a potent stimulator of P-glycoprotein (P-gp). Enhanced P gp activity promotes the efficient removal of photosensitizer not sequestered in mitochondria and protects resting lymphocytes that are essential for antipathogen and antitumor responses. To evaluate the selective depletion of alloimmune responses, donor C57BL/6 splenocytes were cocultured for 5 d with irradiated BALB/c splenocytes and then photodepleted (PD). PD-treated splenocytes were infused into lethally irradiated BALB/c (same-party) or C3H/HeJ (third-party) mice. Same-party mice that received PD-treated splenocytes at the time of transplant lived 100 d without evidence of GVHD. In contrast, all mice that received untreated primed splenocytes and third-party mice that received PD treated splenocytes died of lethal GVHD. To evaluate the preservation of antiviral immune responses, acute lymphocytic choriomeningitis virus infection was used. After photodepletion, expansion of Ag-specific naive CD8(+) T cells and viral clearance remained fully intact. The high selectivity of this novel photosensitizer may have broad applications and provide alternative treatment options for patients with T lymphocyte-mediated diseases. PMID- 27456487 TI - FcgammaRIIB-Independent Mechanisms Controlling Membrane Localization of the Inhibitory Phosphatase SHIP in Human B Cells. AB - SHIP is an important regulator of immune cell signaling that functions to dephosphorylate the phosphoinositide phosphatidylinositol 3,4,5-trisphosphate at the plasma membrane and mediate protein-protein interactions. One established paradigm for SHIP activation involves its recruitment to the phospho-ITIM motif of the inhibitory receptor FcgammaRIIB. Although SHIP is essential for the inhibitory function of FcgammaRIIB, it also has critical modulating functions in signaling initiated from activating immunoreceptors such as B cell Ag receptor. In this study, we found that SHIP is indistinguishably recruited to the plasma membrane after BCR stimulation with or without FcgammaRIIB coligation in human cell lines and primary cells. Interestingly, fluorescence recovery after photobleaching analysis reveals differential mobility of SHIP-enhanced GFP depending on the mode of stimulation, suggesting that although BCR and FcgammaRIIB can both recruit SHIP, this occurs via distinct molecular complexes. Mutagenesis of a SHIP-enhanced GFP fusion protein reveals that the SHIP-Src homology 2 domain is essential in both cases whereas the C terminus is required for recruitment via BCR stimulation, but is less important with FcgammaRIIB coligation. Experiments with pharmacological inhibitors reveal that Syk activity is required for optimal stimulation-induced membrane localization of SHIP, whereas neither PI3K or Src kinase activity is essential. BCR-induced association of SHIP with binding partner Shc1 is dependent on Syk, as is tyrosine phosphorylation of both partners. Our results indicate that FcgammaRIIB is not uniquely able to promote membrane recruitment of SHIP, but rather modulates its function via formation of distinct signaling complexes. Membrane recruitment of SHIP via Syk-dependent mechanisms may be an important factor modulating immunoreceptor signaling. PMID- 27456488 TI - Rural and urban disparities in health-seeking for fever in Myanmar: findings from a probability-based household survey. AB - BACKGROUND: The World Health Organization (WHO) recognizes Myanmar as having the highest burden of malaria in the Greater Mekong Sub-region (GMS). Early diagnosis and proper treatment are critical in containing malaria. The objective of this study was to assess determinants of seeking treatment for fever from trained providers across rural and urban areas in Eastern Myanmar. METHODS: A cross sectional survey was conducted during the high malaria seasons in the eastern part Myanmar between August and September 2014. Multi-staged cluster sampling was used to sample households. A series of questions related to treatment-seeking for fever were asked. Bivariate and multivariate logistic regressions were conducted to identify independent correlates of seeking treatment for fever from trained providers. RESULTS: The analysis was restricted to 637 participants who reported either themselves or their family members having had fever 2 weeks prior to the interview. In the multivariate analysis, rural residents were less likely to have sought treatment from trained providers (AOR = 0.60, 95 % CI 0.42-0.88; p = 0.01) while residents who had fever patients between the ages of 5 and 14 years (AOR = 1.60, 95 % CI 0.90-2.53; p = 0.05); and those who knew that sleeping under bed nets can prevent malaria (AOR = 2.08, 95 % CI 1.00-4.30; p = 0.05); were borderline more likely to have sought treatment. CONCLUSION: This study suggests that rural populations need improved access to trained providers. Additionally, future programmes should focus on increasing knowledge around malaria prevention and treatment. PMID- 27456489 TI - Characterization of the in vivo wall shear stress environment of human fetus umbilical arteries and veins. AB - The endothelial cells of the umbilical vessels are frequently used in mechanobiology experiments. They are known to respond to wall shear stress (WSS) of blood flow, which influences vascular growth and remodeling. The in vivo environment of umbilical vascular WSS, however, is not well characterized. In this study, we performed detailed characterization of the umbilical vascular WSS environments using clinical ultrasound scans combined with computational simulations. Doppler ultrasound scans of 28 normal human fetuses from 32nd to 33rd gestational weeks were investigated. Vascular cross-sectional areas were quantified through 3D reconstruction of the vascular geometry from 3D B-mode ultrasound images, and flow velocities were quantified through pulse wave Doppler. WSS in umbilical vein was computed with Poiseuille's equation, whereas WSS in umbilical artery was obtained via computational fluid dynamics simulations of the helical arterial geometry. Results showed that blood flow velocity for umbilical artery and vein did not correlate with vascular sizes, suggesting that velocity had a very weak trend with or remained constant over vascular sizes. Average WSS for umbilical arteries and vein was 2.81 and 0.52 Pa, respectively. Umbilical vein WSS showed a significant negative correlation with the vessel diameter, but umbilical artery did not show any correlation. We hypothesize that this may be due to differential regulation of vascular sizes based on WSS sensing. Due to the helical geometry of umbilical arteries, bending of the umbilical cord did not significantly alter the vascular resistance or WSS, unlike that in the umbilical veins. We hypothesize that the helical shape of umbilical arteries may be an adaptation feature to render a higher constancy of WSS and flow in the arteries despite umbilical cord bending. PMID- 27456491 TI - Impact of neighborhood resources on cardiovascular disease: a nationwide six-year follow-up. AB - BACKGROUND: Living in a socially deprived neighborhood is associated with lifestyle risk factors, e.g., smoking, physical inactivity and unhealthy diet, as well as an increased risk of cardiovascular disease, i.e., coronary heart disease and stroke. The aim was to study whether the odds of cardiovascular disease vary with the neighbourhood availability of potentially health-damaging and health promoting resources. METHODS: A nationwide sample of 2 040 826 men and 2 153 426 women aged 35-80 years were followed for six years for first hospitalization of coronary heart disease or stroke. Neighborhood availability of health-damaging resources (i.e., fast-food restaurants and bars/pubs) and health-promoting resources (i.e., health care facilities and physical activity facilities) were determined by use of geographic information systems (GIS). RESULTS: We found small or modestly increased odds ratios (ORs) for both coronary heart disease and stroke, related to the availability of both health-damaging and health-promoting resources. For example, in women, the unadjusted OR (95 % confidence interval) for stroke in relation to availability of fast-food restaurants was 1.18 (1.15 1.21). Similar patterns were observed in men, with an OR = 1.08 (1.05-1.10). However, the associations became weaker or disappeared after adjustment for neighborhood-level deprivation and individual-level age and income. CONCLUSIONS: This six year follow-up study shows that neighborhood availability of potentially health-damaging as well as health-promoting resources may make a small contribution to the risk of coronary heart disease and stroke. However, most of these associations were attenuated or disappeared after adjustment for neighborhood-level deprivation and individual-level age and income. Future studies are needed to further examine factors in the causal pathway between neighborhood deprivation and cardiovascular disease. PMID- 27456490 TI - Diaphragm assessment by two dimensional speckle tracking imaging in normal subjects. AB - BACKGROUND: Conventionally, ultrasonographic assessment of diaphragm contractility has involved measuring respiratory changes in diaphragm thickness (thickening fraction) using B-mode or caudal displacement with M-mode. Two dimensional speckle-tracking has been increasingly used to assess muscle deformation ('strain') in echocardiography. We sought to determine in a pilot study if this technology could be utilized to analyze diaphragmatic contraction. METHODS: Fifty healthy adult volunteers with normal exercise capacity underwent ultrasound imaging. A linear array transducer was used for the assessment of diaphragm thickness, thickening fraction (TF), and strain in the right anterior axillary line at approximately the ninth intercostal space. A phased array transducer was applied subcostally for the assessment of diaphragm displacement on the right mid-clavicular line. Diaphragmatic images were recorded from the end of expiration through the end of inspiration at 60 % maximal inspiratory capacity. Diaphragm strain was analyzed off-line by speckle tracking imaging. Blinded inter- and intra-rater variability was tested in 10 cases. RESULTS: Mean right diaphragm thickness at end-expiration (+/-SD: standard deviation) was 0.24 cm (+/-0.1), with TF of 45.1 % (+/-12) at 60 % peak inspiratory effort. Mean right diaphragm caudal displacement was 4.9 cm (+/-1). Mean right diaphragm strain was -40.3 % (+/-9). A moderate correlation was seen between longitudinal strain and TF (R(2) 0.44, p < 0.0001). A weak correlation was seen between strain and caudal displacement (R(2) 0.14, p < 0.01), and an even weaker correlation was seen between caudal displacement and TF (R(2) 0.1, p = 0.04). Age, gender, and body mass index were not significantly associated with right diaphragm strain or TF. Although inter- and intra-rater variability was overall good for TF, caudal displacement, and strain (inter-rater R(2); 0.8, 0.9, and 0.7, respectively [p < 0.01], intra-rater R(2); 0.9, 0.7, and 0.9, respectively [p < 0.01]), strain values did have a slightly lower inter-rater repeatability. CONCLUSIONS: Diaphragmatic strain estimated by speckle tracking imaging was associated with conventional ultrasound measures of diaphragmatic function (TF and caudal displacement). Further clinical studies are warranted to investigate its clinical utility. PMID- 27456492 TI - Complete regression of primary cutaneous malignant melanoma associated with distant lymph node metastasis: a teaching case mimicking blue nevus. AB - BACKGROUND: Malignant melanoma (MM) tends to be spontaneously regressed, however, complete regression of primary cutaneous MM is an extremely rare phenomenon. Our aim is to be aware that pathologists and/or dermatologists can readily misinterpret it as the other benign or malignant lesions. CASE PRESENTATION: A gradually growing and verrucous hypopigmented macule had been noticed in the right sole of a 65-year-old Japanese male since 2 years before, and it turned to be a solitary bluish to black patch with surrounding depigmentation and was recently decreased in size. In parallel, the patient had a rapidly growing black pigmented mass lesion at the right inguen. The cutaneous specimen from the sole showed an aggregation of many melanophages predominantly in the middle to deep layer of dermis, associated with surrounding fibrosis, reactive vascular proliferation and CD8-positive T-lymphocytic infiltrate, covered by attenuated epidermis with absence of rete ridge. However, no remnant MM cells were completely seen in the step-serial sections. We first interpreted it as blue nevus. By contrast, the inguinal mass revealed a diffuse proliferation of highly atypical mono- to multi-nucleated large cells having abundant eosinophilic cytoplasm in the enlarged lymph node tissue. Immunohistochemical findings demonstrated that these atypical cells were specifically positive for HMB45 and Melan A. Therefore, we finally made a diagnosis of complete regression of primary cutaneous MM associated with distant lymph node metastasis of MM. CONCLUSION: Careful, not only general/cutaneous but histopathological, examinations should be necessary and adjunctive aids for reaching the correct diagnosis of complete regression of cutaneous MM. PMID- 27456493 TI - Urgent EMS managed out-of-hospital delivery dispatches in Helsinki. AB - BACKGROUND: The aim of this study was to examine Helsinki Emergency Medical Services (EMS) and hospital records to determine the incidence and possible complications of out-of-hospital deliveries managed by EMS in Helsinki. METHODS: We retrospectively analysed all urgent ambulance dispatches relating to childbirth in Helsinki from January 1, 2010 to December 31, 2014 with further analysis of hospital records for the out-of-hospital deliveries. Patients were divided in to two groups: those who delivered before reaching hospital and those who did not deliver before reaching hospital and differences between groups were analysed. Deliveries with gestational age of at least 22 + 0 weeks were considered as births in statistical analysis as this is the current national practice. RESULTS: There were 799 urgent dispatches during the study period. In 102 (12.8 %) of these delivery took place before reaching the hospital. The incidence of EMS managed out-of-hospital delivery was found to be 3.0/1000 births. The annual number of out-of-hospital deliveries attended by EMS increased from 15 in 2010 to 28 in 2014. No stillbirths were reported. Neither maternal or perinatal deaths nor major maternal complications were noted in the study population. DISCUSSION: Out-of-hospital deliveries represent a small minority of EMS calls and remain a challenge to maintaining professional capabilities. Small sample size might have limited the ability of the study to pick up rare complications. CONCLUSIONS: The amount of out-of-hospital deliveries in Helsinki increased during the five-year study period. There were no maternal or perinatal mortality or major complications resulting in long-term sequelae associated with the EMS-managed out-of-hospital births. PMID- 27456494 TI - Effect of prebiotic intake on gut microbiota, intestinal permeability and glycemic control in children with type 1 diabetes: study protocol for a randomized controlled trial. AB - BACKGROUND: The gut microbiome is increasingly recognized as a contributor to disease states. Patients with type 1 diabetes (DM1) have distinct gut microbiota in comparison to non-diabetic individuals, and it has been linked to changes in intestinal permeability, inflammation and insulin resistance. Prebiotics are non digestible carbohydrates that alter gut microbiota and could potentially improve glycemic control in children with DM1. This pilot study aims to determine the feasibility of a 12-week dietary intervention with prebiotics in children with DM1. METHODS/DESIGN: This pilot study is a single-centre, randomized, double blind, placebo-controlled trial in children aged 8 to 17 years with DM1 for at least one year. Participants will be randomized to receive either placebo (maltodextrin 3.3 g orally/day) or prebiotics (oligofructose-enriched inulin 8 g orally/day; Synergy1, Beneo, Mannheim, Germany). Measures to be assessed at baseline, 3 months and 6 months include: anthropometric measures, insulin doses/regimens, frequency of diabetic ketoacidosis, frequency of severe hypoglycemia, average number of episodes of hypoglycemia per week, serum C peptide, HbA1c, serum inflammatory markers (IL-6, IFN-gamma, TNF-alpha, and IL 10), GLP-1 and GLP-2, intestinal permeability using urine assessment after ingestion of lactulose, mannitol and 3-O-methylglucose, and stool sample collection for gut microbiota profiling. DISCUSSION: This is a novel pilot study designed to test feasibility for a fully powered study. We hypothesize that consumption of prebiotics will alter gut microbiota and intestinal permeability, leading to improved glycemic control. Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for DM1 that may improve glycemic control by changes in gut microbiota, gut permeability and inflammation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02442544 . Registered on 10 March 2015. PMID- 27456495 TI - The 'problematisation' of palliative care in hospital: an exploratory review of international palliative care policy in five countries. AB - BACKGROUND: Government policy is a fundamental component of initiating change to improve the provision of palliative care at a national level. The World Health Organisation's recognition of palliative care as a basic human right has seen many countries worldwide develop national policy in palliative and end of life care. There is increasing debate about what form comprehensive palliative care services should take, particularly in relation to the balance between acute and community based services. It is therefore timely to review how national policy positions the current and future role of the acute hospital in palliative care provision. The aim of this exploratory review is to identify the role envisaged for the acute hospital in palliative and end of life care provision in five countries with an 'advanced' level of integration. METHOD: Countries were identified using the Global Atlas of Palliative Care. Policies were accessed through internet searching of government websites between October and December 2014. Using a process of thematic analysis key themes related to palliative care in hospital were identified. RESULTS: Policies from Switzerland, England, Singapore, Australia and Ireland were analysed for recurring themes. Three themes were identified: preferences for place of care and place of death outside the hospital setting, unnecessary or avoidable hospital admissions, and quality of care in hospital. No policy focused upon exploring how palliative care could be improved in the hospital setting or indeed what role the hospital may have in the provision of palliative care. CONCLUSIONS: Palliative care policy in five countries with 'advanced' levels of palliative care integration focuses on solving the 'problems' associated with hospital as a place of palliative care and death. No positive role for hospitals in palliative care provision is envisaged. Given the rapidly increasing population of people requiring palliative care, and emerging evidence that patients themselves report benefits of hospital admissions, this area requires further investigation. In particular, a co-design approach to policy development is needed to ensure that services match the needs and wants of patients and families. PMID- 27456496 TI - Natural History of Pneumoperitoneum After Laparotomy: Findings on Multidetector Row Computed Tomography. AB - BACKGROUND: Postoperative pneumoperitoneum after abdominal surgery represents a diagnostic challenge. This study was designed to analyze the appearance of pneumoperitoneum on computed tomography after uncomplicated abdominal surgery through laparotomy. METHODS: The database of the department of digestive surgery was retrospectively queried to identify all patients who underwent abdominal surgery through laparotomy during a 13-month period. This initial search retrieved a total of 384 consecutive patients. Criteria for inclusion in this study were: (a) the operation was performed in our institution, (b) the patient had computed tomography examination postoperatively, and (c) the patient had no postoperative grade >=3 complication. RESULTS: Postoperative pneumoperitoneum was visible in 38/80 patients (47.5 %), with a mean volume of 15 +/- 22.8 (SD) cm3 and multiple locations in 32/38 patients (84 %). Postoperative pneumoperitoneum was observed in 22/26 patients (85 %) until day 5 postoperative, 14/34 patients (41 %) between day 6 and day 15 postoperative, and in 2/21 patients (9.5 %) after day 15 postoperative. Its volume decreased when the time interval between surgery and computed tomography increased. Results of multivariate analysis showed that the time interval between surgery and computed tomography was the single independent variable that was associated with the presence of postoperative pneumoperitoneum. CONCLUSIONS: Postoperative pneumoperitoneum is a frequent finding on computed tomography in the early period following abdominal surgery and commonly with multiple locations. Although commonly observed before day 5 postoperative, its presence must be considered as an alarming finding after day 7 postoperative, if present in a single location with a volume >20 cm3. PMID- 27456497 TI - Missed Opportunities for Loco-Regional Treatment of Elderly Women with Breast Cancer. AB - BACKGROUND: Factors associated with surgery, adjuvant radiotherapy, and chemotherapy and whether there were missed opportunities for treatment in elderly patients were determined in an Asian setting. METHODS: All 5616 patients, diagnosed with breast cancer in University Malaya Medical Centre from 1999 to 2013 were included. In 945 elderly patients (aged 65 years and above), multivariable logistic regression was performed to identify factors associated with treatment, following adjustment for age, ethnicity, tumor, and other treatment characteristics. The impact of lack of treatment on survival of the elderly was assessed while accounting for comorbidities. RESULTS: One in five elderly patients had comorbidities. Compared to younger patients, the elderly had more favorable tumor characteristics, and received less loco-regional treatment and chemotherapy. Within stage I-IIIa elderly breast cancer patients, 10 % did not receive any surgery. These patients were older, more likely to be Malays, have comorbidities, and bigger tumors. In elderlies with indications for adjuvant radiotherapy, no irradiation (30 %) was associated with increasing age, comorbidity, and the absence of systemic therapy. Hormone therapy was optimal, but only 35 % of elderly women with ER negative tumors received chemotherapy. Compared to elderly women who received adequate treatment, those not receiving surgery (adjusted hazard ratio: 2.30, 95 %CI: 1.10-4.79), or radiotherapy (adjusted hazard ratio: 1.56, 95 %CI: 1.10-2.19), were associated with higher mortality. Less than 25 % of the survival discrepancy between elderly women receiving loco-regional treatment and no treatment were attributed to excess comorbidities in untreated patients. CONCLUSION: While the presence of comorbidities significantly influenced loco-regional treatment decisions in the elderly, it was only able to explain the lower survival rates in untreated patients up to a certain extent, suggesting missed opportunities for treatment. PMID- 27456498 TI - Scoring Systems Used to Predict Bladder Dysfunction After Laparoscopic Rectal Cancer Surgery. AB - BACKGROUND: Postoperative bladder dysfunction often occurs after rectal cancer surgery, necessitating long-term urinary catheter drainage. The aim of this study was to evaluate the feasibility of early catheter removal and to propose scoring systems that may predict urinary dysfunction after laparoscopic rectal cancer surgery. METHODS: A total of 110 patients who underwent elective laparoscopic rectal cancer surgery were included in this prospective observational study. The urinary catheter was removed on the first postoperative day. RESULTS: The overall incidence of bladder dysfunction was 29.1 % (32/110). The incidence of bladder dysfunction was significantly higher in patients with an age of 65 years or older, male gender, and anastomosis levels from the anal verge of 6 cm or below (P = 0.03, 0.002, and 0.03, respectively). By setting a cut-off of two of the risk factors, this simple scoring system can predict postoperative bladder dysfunction with sensitivity of 96.9 %, specificity of 50.0 %, and accuracy of 63.6 %. A scoring system based on regression coefficients was also conducted according to the following formula: bladder dysfunction predicting score = 18 (1 for male or 0 for female) +0.5 (age, years) -2 (anastomosis level, cm). With this method, a cut-off value of 35+ points predicts postoperative bladder dysfunction with a sensitivity of 81.3 %, specificity of 71.8 %, and accuracy of 74.5 %. CONCLUSIONS: Bladder dysfunction after laparoscopic rectal cancer surgery following early catheter removal occurred in 29.1 % of patients. Two scoring systems using three risk factors (age, male gender, and anastomosis level) may predict postoperative bladder dysfunction. PMID- 27456499 TI - Risk Factors for Predicting Occult Lymph Node Metastasis in Patients with Clinical Stage I Non-small Cell Lung Cancer Staged by Integrated Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - BACKGROUND: Lymph nodes in patients with non-small cell lung cancer (NSCLC) are often staged using integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). However, this modality has limited ability to detect micrometastases. We aimed to define risk factors for occult lymph node metastasis in patients with clinical stage I NSCLC diagnosed by preoperative integrated FDG-PET/CT. METHODS: We retrospectively reviewed the records of 246 patients diagnosed with clinical stage I NSCLC based on integrated FDG-PET/CT between April 2007 and May 2015. All patients were treated by complete surgical resection. The prevalence of occult lymph node metastasis in patients with clinical stage I NSCLC was analysed according to clinicopathological factors. Risk factors for occult lymph node metastasis were defined using univariate and multivariate analyses. RESULTS: Occult lymph node metastasis was detected in 31 patients (12.6 %). Univariate analysis revealed CEA (P = 0.04), SUVmax of the primary tumour (P = 0.031), adenocarcinoma (P = 0.023), tumour size (P = 0.002) and pleural invasion (P = 0.046) as significant predictors of occult lymph node metastasis. Multivariate analysis selected SUVmax of the primary tumour (P = 0.049), adenocarcinoma (P = 0.003) and tumour size (P = 0.019) as independent predictors of occult lymph node metastasis. CONCLUSIONS: The SUVmax of the primary tumour, adenocarcinoma and tumour size were risk factors for occult lymph node metastasis in patients with NSCLC diagnosed as clinical stage I by preoperative integrated FDG-PET/CT. These findings would be helpful in selecting candidates for mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration. PMID- 27456501 TI - Synthesis and Characterization of Tin(IV) Oxide Obtained by Chemical Vapor Deposition Method. AB - The effect of precursors on the characteristics of tin oxide obtained by chemical vapor deposition (CVD) method was investigated. The synthesis of nanosized tin(IV) oxide was carried out with the use of two different precursors: tin(II) oxalate obtained using tin chloride(II) and oxalic acid; tin(II) oxalate obtained using tin chloride(II); and ammonium oxalate. The synthesized tin(IV) oxide samples were studied by electron microscopy, X-ray diffraction and optical spectra. The lattice parameters of tin(IV) oxide samples were defined, the bandgap of samples were calculated. PMID- 27456500 TI - Overview of Probe-based Storage Technologies. AB - The current world is in the age of big data where the total amount of global digital data is growing up at an incredible rate. This indeed necessitates a drastic enhancement on the capacity of conventional data storage devices that are, however, suffering from their respective physical drawbacks. Under this circumstance, it is essential to aggressively explore and develop alternative promising mass storage devices, leading to the presence of probe-based storage devices. In this paper, the physical principles and the current status of several different probe storage devices, including thermo-mechanical probe memory, magnetic probe memory, ferroelectric probe memory, and phase-change probe memory, are reviewed in details, as well as their respective merits and weakness. This paper provides an overview of the emerging probe memories potentially for next generation storage device so as to motivate the exploration of more innovative technologies to push forward the development of the probe storage devices. PMID- 27456502 TI - Characterization of Bimetallic Fe-Ru Oxide Nanoparticles Prepared by Liquid-Phase Plasma Method. AB - The bimetallic Fe-Ru oxide nanoparticles were synthesized in the liquid-phase plasma (LPP) method which employed iron chloride and ruthenium chloride as precursors. The active species (OH., Halpha, Hbeta, and O(I)) and the iron and ruthenium ions were observed in the plasma field created by the LPP process. The spherical-shaped bimetallic Fe-Ru oxide nanoparticles were synthesized by the LPP reaction, and the size of the particles was growing along with the progression of the LPP reaction. The synthesized bimetallic Fe-Ru oxide nanoparticles were comprised of Fe2O3, Fe3O4, RuO, and RuO2. Ruthenium had a higher reduction potential than iron and resulted in higher ruthenium composition in the synthesized bimetallic nanoparticles. The control of the molar ratio of the precursors in the reactant solution was found to be employed as a means to control the composition of the elements in bimetallic nanoparticles. PMID- 27456503 TI - Real-time HER2 status detected on circulating tumor cells predicts different outcomes of anti-HER2 therapy in histologically HER2-positive metastatic breast cancer patients. AB - BACKGROUND: This study was initiated to investigate the difference in HER2 status between tumor tissue and circulating tumor cells (CTCs), as well as the predictive value of CTC HER2 status for predicting the outcomes of anti-HER2 therapy in histologically HER2-positive metastatic breast cancer (MBC) patients. METHODS: HER2 expression on CTCs was detected using a CellSearch system within 7 days before a new line of anti-HER2 therapy was begun. According to the criterion proposed in our previous report, patients were defined as CTC HER2-positive or negative. After close follow-up, the correlation between CTC HER2 status and the outcome of the treatment was evaluated by statistical analysis. RESULTS: CTCs were detected in 57.4 % (58/101) of the patients. Notably, 62.1 % (36/58) of these patients had an inconsistent HER2 status between their tissue and CTCs. The discordant rate may correlate with the time interval between histological and CTC HER2 testing and is more likely to occur in the subgroup of patients with an interval of > 1 year than in those with an interval < 1 year (70.7 % vs. 41.2 %, P = 0.043). For PFS, positive HER2 status on CTCs was shown to be a valuable predictor, both in univariate (HR = 0.321, 95%CI, 0.156-0.62, P = 0.0011) and multivariate (HR = 0.383, 95%CI, 0.166-0.831, P = 0.019) Cox regression analysis. Meanwhile, Kaplan-Meier survival curves revealed that the median PFS of CTC HER2 positive patients was significantly longer than CTC HER2-negative ones (8.5 vs. 3.5 months, P < 0.001). CONCLUSIONS: HER2 status on CTCs was different from that of tumor tissues and predicted a different outcome of the patients' anti-HER2 therapy. This difference may be correlated with the time interval between tissue and CTC HER2 testing, indicating the necessity of real-time HER2 analysis for histologically HER2-positive MBC patients. PMID- 27456504 TI - Effectiveness and Safety of Pleurodesis for Hepatic Hydrothorax: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Hepatic hydrothorax (HH) is a serious complication of end-stage liver diseases, which is associated with poor survival. There is no consensus regarding the treatment of HH. AIM: To evaluate the effectiveness and safety of pleurodesis for HH in a systematic review with meta-analysis. METHODS: All relevant papers were searched on the EMBASE and PubMed databases. As for the data from the eligible case reports, the continuous data were expressed as the median (range) and the categorical data were expressed as the frequency (percentage). As for the data from the eligible case series, the rates of complete response and complications were pooled. The proportions with 95 % confidence intervals (CIs) were calculated by using random-effect model. RESULTS: Twenty case reports including 26 patients and 13 case series including 180 patients were eligible. As for the case reports, the median age was 55 years (range 7-78) and 15 patients were male. The prevalence of ascites was 76 % (19/25). Seventeen (65.38 %) patients responded favorably to pleurodesis. As for the case series, the mean age was 51.5-63.0 years and 83 patients were male. The pooled prevalence of ascites was 90 % (95 % CI 81-97 %) in 7 studies including 71 patients. The complete response rate after pleurodesis was reported in all studies, and the pooled rate was 72 % (95 % CI 65-79 %). Complications related to pleurodesis were reported in 6 studies including 63 patients, and the pooled rate was 82 % (95 % CI 66-94 %). CONCLUSION: Pleurodesis may be a promising treatment for HH, but carries a high rate of complications. PMID- 27456505 TI - Erratum to: Comparison of hemostatic dressings for superficial wounds using a new spectrophotometric coagulation assay. PMID- 27456506 TI - Is HRQOL in dialysis associated with patient survival or graft function after kidney transplantation? AB - BACKGROUND: Health related quality of life (HRQOL) is patient-reported, and an important treatment outcome for patients undergoing renal replacement therapy. Whether HRQOL in dialysis can affect mortality or graft survival after renal transplantation (RTX) is not determined. The aims of the present study were to investigate whether pretransplant HRQOL is associated with post-RTX patient survival or graft function, and to assess whether improvement in HRQOL from dialysis to RTX is associated with patient survival. METHODS: In a longitudinal prospective study, HRQOL was measured in 142 prevalent dialysis patients (67 % males, mean age 51 +/- 15.5 years) who subsequent underwent renal transplantation. HRQOL could be repeated in 110 transplant patients 41 (IQR 34 51) months after RTX using the self-administered Kidney Disease and Quality of Life Short Form (KDQOL-SF) measure. Kaplan-Meier plots were utilized for survival analyses, and linear regression models were used to address HRQOL and effect on graft function. RESULTS: Follow-up time was 102 (IQR 97-108) months after RTX. Survival after RTX was higher in patients who perceived good physical function (PF) in dialysis compared to patients with poorer PF (p = 0.019). Low scores in the domain mental health measured in dialysis was associated with accelerated decline in graft function (p = 0.048). Improvements in the kidney-specific domains "symptoms" and "effect of kidney disease" in the trajectory from dialysis to RTX were associated with a survival benefit (p = 0.007 and p = 0.02, respectively). CONCLUSION: HRQOL measured in dialysis patients was associated with survival and graft function after RTX. These findings may be useful in clinical pretransplant evaluations. Improvements in some of the kidney-specific HRQOL domains from dialysis to RTX were associated with lower mortality. Prospective and interventional studies are warranted. PMID- 27456508 TI - Nonmedical Prescription Opioid and Heroin Use Among Adolescents Who Engage in Sports and Exercise. AB - OBJECTIVES: Previous research has found that adolescent athletes may be at increased risk of nonmedical prescription opioid use (NPOU) due to injuries. Although adolescent athletes are at an increased risk of engaging in NPOU, it has yet to be determined if they are also at greater risk for heroin use. The major purpose of this study was to examine both the trends in prevalence rates and patterns of initiation in lifetime NPOU and lifetime heroin use among adolescents who engage in sports and exercise. METHODS: Eighteen cross-sections of eighth and 10th graders were used from the Monitoring the Future study. The sample consisted of 191 682 respondents who answered questions on past-year participation in sports and exercise, lifetime NPOU, lifetime heroin use, age of NPOU onset, and age of heroin onset. RESULTS: The trends in NPOU and lifetime heroin use among adolescents who engage in sports and exercise has declined between 1997 and 2014. Logistic regression analyses found that adolescents who engage in sports and exercise had lower odds of reporting lifetime NPOU and heroin use compared with adolescents who did not engage in these activities during the past year. Analyses among lifetime heroin users found that adolescents who engage in sports and exercise had lower odds of initiating NPOU before heroin when compared with their peers who did not engage in these activities in the past year. CONCLUSIONS: Daily participation in sports and exercise may serve as a protective factor with respect to NPOU and heroin use. PMID- 27456510 TI - Informed Consent in Decision-Making in Pediatric Practice. AB - Informed consent should be seen as an essential part of health care practice; parental permission and childhood assent is an active process that engages patients, both adults and children, in their health care. Pediatric practice is unique in that developmental maturation allows, over time, for increasing inclusion of the child's and adolescent's opinion in medical decision-making in clinical practice and research. This technical report, which accompanies the policy statement "Informed Consent in Decision-Making in Pediatric Practice" was written to provide a broader background on the nature of informed consent, surrogate decision-making in pediatric practice, information on child and adolescent decision-making, and special issues in adolescent informed consent, assent, and refusal. It is anticipated that this information will help provide support for the recommendations included in the policy statement. PMID- 27456511 TI - Oxygen Targeting in Extremely Low Birth Weight Infants. AB - The use of supplemental oxygen plays a vital role in the care of the critically ill preterm infant, but the unrestricted use of oxygen can lead to unintended harms, such as chronic lung disease and retinopathy of prematurity. An overly restricted use of supplemental oxygen may have adverse effects as well. Ideally, continuous monitoring of tissue and cellular oxygen delivery would allow clinicians to better titrate the use of supplemental oxygen, but such monitoring is not currently feasible in the clinical setting. The introduction of pulse oximetry has greatly aided the clinician by providing a relatively easy and continuous estimate of arterial oxygen saturation, but pulse oximetry has several practical, technical, and physiologic limitations. Recent randomized clinical trials comparing different pulse oximetry targets have been conducted to better inform the practice of supplemental oxygen use. This clinical report discusses the benefits and limitations of pulse oximetry for assessing oxygenation, summarizes randomized clinical trials of oxygen saturation targeting, and addresses implications for practice. PMID- 27456512 TI - Recommended Amount of Sleep for Pediatric Populations. PMID- 27456509 TI - Management of Pediatric Trauma. AB - Injury is still the number 1 killer of children ages 1 to 18 years in the United States (http://www.cdc.gov/nchs/fastats/children.htm). Children who sustain injuries with resulting disabilities incur significant costs not only for their health care but also for productivity lost to the economy. The families of children who survive childhood injury with disability face years of emotional and financial hardship, along with a significant societal burden. The entire process of managing childhood injury is enormously complex and varies by region. Only the comprehensive cooperation of a broadly diverse trauma team will have a significant effect on improving the care of injured children. PMID- 27456514 TI - Informed Consent in Decision-Making in Pediatric Practice. AB - Informed consent should be seen as an essential part of health care practice; parental permission and childhood assent is an active process that engages patients, both adults and children, in health care. Pediatric practice is unique in that developmental maturation allows, over time, for increasing inclusion of the child's and adolescent's opinion in medical decision-making in clinical practice and research. PMID- 27456513 TI - Developmental Outcomes of Late Preterm Infants From Infancy to Kindergarten. AB - OBJECTIVE: To compare developmental outcomes of late preterm infants (34-36 weeks' gestation) with infants born at early term (37-38 weeks' gestation) and term (39-41 weeks' gestation), from infancy through kindergarten. METHODS: Sample included 1000 late preterm, 1800 early term, and 3200 term infants ascertained from the Early Childhood Longitudinal Study, Birth Cohort. Direct assessments of development were performed at 9 and 24 months by using the Bayley Short Form Research Edition T-scores and at preschool and kindergarten using the Early Childhood Longitudinal Study, Birth Cohort reading and mathematics theta scores. Maternal and infant characteristics were obtained from birth certificate data and parent questionnaires. After controlling for covariates, we compared mean developmental outcomes between late preterm and full-term groups in serial cross sectional analyses at each timepoint using multilinear regression, with pairwise comparisons testing for group differences by gestational age categories. RESULTS: With covariates controlled at all timepoints, at 9 months late preterm infants demonstrated less optimal developmental outcomes (T = 47.31) compared with infants born early term (T = 49.12) and term (T = 50.09) (P < .0001). This association was not seen at 24 months, (P = .66) but reemerged at preschool. Late preterm infants demonstrated less optimal scores in preschool reading (P = .0006), preschool mathematics (P = .0014), and kindergarten reading (P = .0007) compared with infants born at term gestation. CONCLUSIONS: Although late preterm infants demonstrate comparable developmental outcomes to full-term infants (early term and full-term gestation) at 24 months, they demonstrate less optimal reading outcomes at preschool and kindergarten timepoints. Ongoing developmental surveillance for late preterm infants is warranted into preschool and kindergarten. PMID- 27456515 TI - Collaboration in Practice: Implementing Team-Based Care. PMID- 27456516 TI - Are HIV and reproductive health services adapted to the needs of female sex workers? Results of a policy and situational analysis in Tete, Mozambique. AB - BACKGROUND: In the context of an implementation research project aiming at improving use of HIV and sexual and reproductive health (SRH) services for female sex workers (FSWs), a broad situational analysis was conducted in Tete, Mozambique, assessing if services are adapted to the needs of FSWs. METHODS: Methods comprised (1) a policy analysis including a review of national guidelines and interviews with policy makers, and (2) health facility assessments at 6 public and 1 private health facilities, and 1 clinic specifically targeting FSWs, consisting of an audit checklist, interviews with 18 HIV/SRH care providers and interviews of 99 HIV/SRH care users. RESULTS: There exist national guidelines for most HIV/SRH care services, but none provides guidance for care adapted to the needs of high-risk women such as FSWs. The Ministry of Health recently initiated the process of establishing guidelines for attendance of key populations, including FSWs, at public health facilities. Policy makers have different views on the best approach for providing services to FSWs-integrated in the general health services or through parallel services for key populations-and there exists no national strategy. The most important provider of HIV/SRH services in the study area is the government. Most basic services are widely available, with the exception of certain family planning methods, cervical cancer screening, services for victims of sexual and gender-based violence, and termination of pregnancy (TOP). The public facilities face serious limitations in term of space, staff, equipment, regular supplies and adequate provider practices. A stand-alone clinic targeting key populations offers a limited range of services to the FSW population in part of the area. Private clinics offer only a few services, at commercial prices. CONCLUSION: There is a need to improve the availability of quality HIV/SRH services in general and to FSWs specifically, and to develop guidelines for care adapted to the needs of FSWs. Access for FSWs can be improved by either expanding the range of services and the coverage of the targeted clinic and/or by improving access to adapted care at the public health services and ensure a minimum standard of quality. PMID- 27456517 TI - Relations of Arterial Stiffness and Brachial Flow-Mediated Dilation With New Onset Atrial Fibrillation: The Framingham Heart Study. AB - The relations of measures of arterial stiffness, pulsatile hemodynamic load, and endothelial dysfunction to atrial fibrillation (AF) remain poorly understood. To better understand the pathophysiology of AF, we examined associations between noninvasive measures of vascular function and new-onset AF. The study sample included participants aged >=45 years from the Framingham Heart Study offspring and third-generation cohorts. Using Cox proportional hazards regression models, we examined relations between incident AF and tonometry measures of arterial stiffness (carotid-femoral pulse wave velocity), wave reflection (augmentation index), pressure pulsatility (central pulse pressure), endothelial function (flow mediated dilation), resting brachial arterial diameter, and hyperemic flow. AF developed in 407/5797 participants in the tonometry sample and 270/3921 participants in the endothelial function sample during follow-up (median 7.1 years, maximum 10 years). Higher augmentation index (hazard ratio, 1.16; 95% confidence interval, 1.02-1.32; P=0.02), baseline brachial artery diameter (hazard ratio, 1.20; 95% confidence interval, 1.01-1.43; P=0.04), and lower flow mediated dilation (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99; P=0.04) were associated with increased risk of incident AF. Central pulse pressure, when adjusted for age, sex, and hypertension (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P=0.02) was associated with incident AF. Higher pulsatile load assessed by central pulse pressure and greater apparent wave reflection measured by augmentation index were associated with increased risk of incident AF. Vascular endothelial dysfunction may precede development of AF. These measures may be additional risk factors or markers of subclinical cardiovascular disease associated with increased risk of incident AF. PMID- 27456518 TI - More Versus Less Intensive Blood Pressure-Lowering Strategy: Cumulative Evidence and Trial Sequential Analysis. AB - Several randomized trials compared a more versus less intensive blood pressure lowering strategy on the risk of major cardiovascular events and death. Cumulative meta-analyses and trial sequential analyses can establish whether and when firm evidence favoring a specific intervention has been reached from accrued literature. Therefore, we conducted a cumulative trial sequential analysis of 18 trials that randomly allocated 53 405 patients to a more or less intensive blood pressure-lowering strategy. We sought to ascertain the extent to which trial evidence added to previously accrued data. Outcome measures were stroke, myocardial infarction, heart failure, cardiovascular death, and all-cause death. Achieved blood pressure was 7.6/4.5 mm Hg lower with the more intensive than the less intensive blood pressure-lowering strategy. For stroke and myocardial infarction, the cumulative Z curve crossed the efficacy monitoring boundary solely after the SPRINT (Systolic Blood Pressure Intervention Trial) study, thereby providing firm evidence of superiority of a more intensive over a less intensive blood pressure-lowering strategy. For cardiovascular death and heart failure, the cumulative Z curve crossed the conventional significance boundary, but not the sequential monitoring boundary, after SPRINT. For all-cause death, the SPRINT trial pushed the cumulative Z curve away from the futility area, without reaching the conventional significance boundary. We conclude that evidence accrued to date strongly supports the superiority of a more intensive versus a less intensive blood pressure-lowering strategy for prevention of stroke and myocardial infarction. Cardiovascular death and heart failure are likely to be reduced by a more intensive blood pressure-lowering strategy, but evidence is not yet conclusive. PMID- 27456519 TI - Accumulating Evidence of Benefits From Intensive Blood Pressure Lowering: Are We There Yet? PMID- 27456520 TI - On Endogenous Angiotensin II Antagonism in Hypertension: The Role of Dipeptidyl Peptidase III. PMID- 27456521 TI - Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension. AB - Dipeptidyl peptidase III (DPP III) cleaves dipeptide residues from the N terminus of polypeptides ranging from 3 to 10 amino acids in length and is implicated in pathophysiological processes through the breakdown of certain oligopeptides or their fragments. In this study, we newly identified the biochemical properties of DPP III for angiotensin II (Ang II), which consists of 8 amino acids. DPP III quickly and effectively digested Ang II with Km = 3.7*10(-6) mol/L. In the in vivo experiments, DPP III remarkably reduced blood pressure in Ang II-infused hypertensive mice without alteration of heart rate. DPP III did not affect hemodynamics in noradrenalin-induced hypertensive mice or normotensive mice, suggesting specificity for Ang II. When DPP III was intravenously injected every other day for 4 weeks after Ang II osmotic minipump implantation in mice, Ang II induced cardiac fibrosis and hypertrophy were significantly attenuated. This DPP III effect was at least similar to that caused by an angiotensin receptor blocker candesartan. Furthermore, administration of DPP III dramatically reduced the increase in urine albumin excretion and kidney injury and inflammation markers caused by Ang II infusion. Both DPP III and candesartan administration showed slight additive inhibition in the albumin excretion. These results reveal a novel potential use of DPP III in the treatment of hypertension and its protective effects on hypertension-sensitive organs, such as the heart and kidneys. PMID- 27456522 TI - Association of Maternal Antiangiogenic Profile at Birth With Early Postnatal Loss of Microvascular Density in Offspring of Hypertensive Pregnancies. AB - Offspring of hypertensive pregnancies are more likely to have microvascular rarefaction and increased blood pressure in later life. We tested the hypothesis that maternal angiogenic profile during a hypertensive pregnancy is associated with fetal vasculogenic capacity and abnormal postnatal microvascular remodeling. Infants (n=255) born after either hypertensive or normotensive pregnancies were recruited for quantification of postnatal dermal microvascular structure at birth and 3 months of age. Vasculogenic cell potential was assessed in umbilical vein endothelial cells from 55 offspring based on in vitro microvessel tube formation and proliferation assays. Maternal angiogenic profile (soluble fms-like tyrosine kinase-1, soluble endoglin, vascular endothelial growth factor, and placental growth factor) was measured from postpartum plasma samples to characterize severity of pregnancy disorder. At birth, offspring born after hypertensive pregnancy had similar microvessel density to those born after a normotensive pregnancy, but during the first 3 postnatal months, they had an almost 2-fold greater reduction in total vessel density (-17.7+/-16.4% versus -9.9+/-18.7%; P=0.002). This postnatal loss varied according to the vasculogenic capacity of the endothelial cells of the infant at birth (r=0.49; P=0.02). The degree of reduction in both in vitro and postnatal in vivo vascular development was proportional to levels of antiangiogenic factors in the maternal circulation. In conclusion, our data indicate that offspring born to hypertensive pregnancies have reduced vasculogenic capacity at birth that predicts microvessel density loss over the first 3 postnatal months. Degree of postnatal microvessel reduction is proportional to levels of antiangiogenic factors in the maternal circulation at birth. PMID- 27456523 TI - Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease-Induced Enlargement of Myocardial Infarct Size. AB - Chronic kidney disease (CKD) is known to increase myocardial infarct size after ischemia/reperfusion. However, a strategy to prevent the CKD-induced myocardial susceptibility to ischemia/reperfusion injury has not been developed. Here, we examined whether epoetin beta pegol, a continuous erythropoietin receptor activator (CERA), normalizes myocardial susceptibility to ischemia/reperfusion injury by its effects on protective signaling and metabolomes in CKD. CKD was induced by 5/6 nephrectomy in rats (subtotal nephrectomy, SNx), whereas sham operated rats served controls (Sham). Infarct size as percentage of area at risk after 20-minutes coronary occlusion/2-hour reperfusion was larger in SNx than in Sham: 60.0+/-4.0% versus 43.9+/-2.2%. Administration of CERA (0.6 MUg/kg SC every 7 days) for 4 weeks reduced infarct size in SNx (infarct size as percentage of area at risk=36.9+/-3.9%), although a protective effect was not detected for the acute injection of CERA. Immunoblot analyses revealed that myocardial phospho-Akt Ser473 levels under baseline conditions and on reperfusion were lower in SNx than in Sham, and CERA restored the Akt phosphorylation on reperfusion. Metabolomic analyses showed that glucose 6-phosphate and glucose 1-phosphate were reduced and malate:aspartate ratio was 1.6-fold higher in SNx than in Sham, suggesting disturbed flux of malate-aspartate shuttle by CKD. The CERA improved the malate:aspartate ratio in SNx to the control level. In H9c2 cells, mitochondrial Akt phosphorylation by insulin-like growth factor-1 was attenuated by malate aspartate shuttle inhibition. In conclusion, the results suggest that a CERA prevents CKD-induced susceptibility of the myocardium to ischemia/reperfusion injury by restoration of Akt-mediated signaling possibly via normalized malate aspartate shuttle flux. PMID- 27456524 TI - Arterial Stiffness Predicts Incident Atrial Fibrillation in the Framingham Heart Study: A Mechanistic Contribution in People With High Blood Pressure or History of Hypertension. PMID- 27456525 TI - Endogenous Ouabain: Recent Advances and Controversies. PMID- 27456526 TI - Association of Parental Hypertension With Arterial Stiffness in Nonhypertensive Offspring: The Framingham Heart Study. AB - High arterial stiffness seems to be causally involved in the pathogenesis of hypertension. We tested the hypothesis that offspring of parents with hypertension may display higher arterial stiffness before clinically manifest hypertension, given that hypertension is a heritable condition. We compared arterial tonometry measures in a sample of 1564 nonhypertensive Framingham Heart Study third-generation cohort participants (mean age: 38 years; 55% women) whose parents were enrolled in the Framingham Offspring Study. A total of 468, 715, and 381 participants had 0 (referent), 1, and 2 parents with hypertension. Parental hypertension was associated with greater offspring mean arterial pressure (multivariable-adjusted estimate=2.9 mm Hg; 95% confidence interval, 1.9-3.9, and 4.2 mm Hg; 95% confidence interval, 2.9-5.5, for 1 and 2 parents with hypertension, respectively; P<0.001 for both) and with greater forward pressure wave amplitude (1.6 mm Hg; 95% confidence interval, 0.6-2.7, and 1.9 mm Hg; 95% confidence interval, 0.6-3.2, for 1 and 2 parents with hypertension, respectively; P=0.003 for both). Carotid-femoral pulse wave velocity and augmentation index displayed similar dose-dependent relations with parental hypertension in sex-, age-, and height-adjusted models, but associations were attenuated on further adjustment. Offspring with at least 1 parent in the upper quartile of augmentation index and carotid-femoral pulse wave velocity had significantly higher values themselves (P<=0.02). In conclusion, in this community-based sample of young, nonhypertensive adults, we observed greater arterial stiffness in offspring of parents with hypertension. These observations are consistent with higher vascular stiffness at an early stage in the pathogenesis of hypertension. PMID- 27456527 TI - Efficacy and safety of dapoxetine in treatment of premature ejaculation: an evidence-based review. AB - BACKGROUND: Premature ejaculation (PE) is a major issue in male sexual health, with a global prevalence estimated to be between 20% and 40%, making it the most common sexual dysfunction in men. PE causes distress and reduced quality of life for patients and has a negative impact on interpersonal relationships. Historically, it has been treated with cognitive therapy, behavioural methods and off-label use of selective serotonin reuptake inhibitors (SSRIs) usually used to treat depression and other psychological disorders. Dapoxetine is the only SSRI specifically designed to treat PE. MECHANISM OF ACTION: Dapoxetine hydrochloride is a potent inhibitor of serotonin reuptake transporters. Dapoxetine is suited for 'on-demand' treatment of PE because of its rapid absorption and short initial half-life. EFFICACY: Evidence from published studies showed that dapoxetine 30 mg or 60 mg taken 'on-demand' results in a significant increase in intravaginal ejaculatory latency time (IELT) when compared with placebo. Most patient-reported outcomes are clearly improved relative to placebo following dapoxetine therapy, indicating greater control over ejaculation, more satisfaction with intercourse, less ejaculation-related distress and significantly reduced interpersonal difficulties. SAFETY: The most common adverse events with dapoxetine are nausea, dizziness, somnolence, headache, diarrhoea and insomnia. Usually they do not lead to drug discontinuation. CONCLUSION: Dapoxetine is the only effective and safe available on-label oral treatment for PE, and its use can result in better quality of life for the patient and their sexual partner. PMID- 27456528 TI - Lipodystrophy in Insulin-Treated Subjects and Other Injection-Site Skin Reactions: Are We Sure Everything is Clear? AB - Physicians and patients have long been aware of skin lesions at the sites of insulin injections, referred to as lipodystrophy that can present as lipoatrophy (LA) or lipohypertrophy (LH). However, the reported prevalence of these different skin lesions varies widely, emphasizing the need for a correct identification method. In this short review we discuss LA and LH and also take into account other skin lesions, such as bruising, as well as different needle injuries, including those associated with the subcutaneous injection of pegvisomant (a drug aimed at counteracting the high levels of growth hormone associated with acromegaly), long-acting exenatide (a glucagon-like peptide-1 receptor agonist), and anti-tumor necrosis factor-alpha biologic agents (used against Crohn's disease). In these latter cases specific studies are warranted to understand the pathophysiological background and possible prevention. However, the most common lesion is still insulin injection site-related LD, so a strong effort has to be made to avoid the confusion generated by previously misleading classifications which were barely able to reliably distinguish between LA and LH. PMID- 27456529 TI - ["Barking" micturition noise as sign of acute hip-TEP-late infection]. AB - This article presents the case of a patient with an acute late infection of the hip prosthesis. At first, complaints in the hip region were in the foreground. Shortly after the revision operation the patient noticed a barking noise during micturition, as sign of a pneumaturia. The following diagnostics showed a perforated sigmoid diverticulitis with a sigmoid-urinary bladder-fistula. PMID- 27456531 TI - Cyberbullying Perpetration by Arab Youth: The Direct and Interactive Role of Individual, Family, and Neighborhood Characteristics. AB - This study adopts a social-ecological/contextual perspective to explore Arab youth involvement in cyberbullying perpetration. We explored the association between individual (age, gender, and impulsivity), family (socioeconomic status and parental monitoring), and community (experiencing neighborhood violence) characteristics and cyberbullying perpetration. A moderation model exploring individual, family, and context interactions was tested. A sample of 3,178 Arab students in Grades 7 to 11 completed a structured, anonymous self-report questionnaire. The findings suggest that almost 14% of the participants have cyberbullied others during the last month. Adolescent boys with high impulsivity, low parental monitoring, and who experience a high level of violence in their neighborhood are at especially high risk of cyberbullying perpetration. Parental monitoring moderated the effects of impulsivity and experiencing neighborhood violence on adolescents' involvement in perpetrating cyberbullying. Furthermore, the results show that impulsive adolescents who experience high levels of neighborhood violence are at higher risk of cyberbullying perpetration than low impulsive children who experience the same levels of neighborhood violence. The results highlight the central role parenting plays in protecting their children from involvement in cyberbullying perpetration by buffering the effects of personal and situational risk factors. PMID- 27456530 TI - [Return to sport after surgical treatment of a posterior cruciate ligament injury : A retrospective study of 60 patients]. AB - BACKGROUND: Injuries of the posterior cruciate ligament (PCL) lead to an initial reduction of sporting activity. However, in previous studies, return to sport after operative treatment of PCL injuries has been analysed insufficiently. The aim of this study was (1) to determine the rate of return to sport in physically active patients, (2) to analyse possible changes in sporting activities and (3) to examine the influence of the severity of the initial injury. PATIENTS AND METHODS: Within a retrospective clinical and radiological follow-up at least 24 months after surgery (80.3 +/- 28.2 months), 60 patients (44.8 +/- 12.1 years) with surgically treated isolated or combined PCL injuries were included in the study. Pre-accidental and post-operative sporting activities were queried and compared in a standardised questionnaire. Possible differences with respect to the initial injury severity (Cooper classification) were examined. RESULTS: The return-to-sport rate of the physically active patients was 87.0 %. 17.6 % of patients with a combined PCL injury and 4.8 % of patients with isolated PCL injury were not able to return to sport. Significant reductions in the frequency of exercise (p = 0.0087), the duration of exercise (p = 0.0003) and the amount of regularly performed sports (p < 0.0001) were found. A change from high-impact sports to low-impact sports was noted. CONCLUSION: Patients with operatively treated PCL injuries can return to sport. However, for competitive athletes an injury to the PCL can lead to the end of their career. A reduction of sporting activities and a change from high-impact sports to low-impact sports can be expected. A persisting inability to return to sporting activities in patients with isolated PCL injuries cannot be assumed. PMID- 27456532 TI - Exploring Empathy and Callous-Unemotional Traits as Predictors of Animal Abuse Perpetrated by Children Exposed to Intimate Partner Violence. AB - We explored the relation between empathy, callous-unemotional (CU) traits, and animal abuse in a sample of 290 seven- to twelve-year-old children whose mothers were exposed to intimate partner violence (IPV). The sample comprises mostly Latino and White participants, and 55% of the children's mothers were born outside the United States (primarily Mexico). To our knowledge, among studies examining child-perpetrated animal abuse, this study is the first to examine empathy levels and one of only a few to examine CU traits. When comparing Griffith Empathy Measure (empathy) and Inventory of Callous-Unemotional Traits (callous-unemotional [CU] traits) scores with those from studies of White schoolchildren, our sample scored lower on affective empathy, higher on cognitive empathy, and lower for overall CU scores as well as Callous and Unemotional subscales. Of 290 children, 47 (16.2%) harmed an animal at least once according to either mother or child report. There were no significant sex or age differences between Abuse and No Abuse groups. The Abuse group scored significantly higher on affective empathy, CU, and Callousness/Unemotional subscales, and significantly lower on cognitive empathy. However, in regression analyses that controlled for income, only lower cognitive empathy and higher CU significantly predicted having abused an animal. In summary, low cognitive empathy (but not affective empathy) and CU traits may serve as reliable predictors of child animal abuse. However, replication of these results is necessary. A larger sample with a high percentage of Latino children whose mothers were exposed to IPV, along with a non-exposed comparison group, would be ideal. PMID- 27456533 TI - A Preliminary Test of the Interpersonal-Psychological Theory of Suicide in Women Seeking Shelter From Intimate Partner Violence. AB - Women seeking shelter from intimate partner violence (IPV) are at greater risk of suicide ideation and attempts compared with women in the general population. A theoretically grounded understanding of suicide risk in shelter-seeking women is critical to improve assessment and management of suicide risk in this population. The interpersonal-psychological theory of suicide (IPTS) proposes that suicide ideation results from hopelessness about thwarted belongingness and perceived burdensomeness. However, suicide ideation does not progress to death by suicide unless one has acquired the capability for suicide (i.e., pain tolerance and fearlessness about death) via repeated exposure to painful and fearsome events. The present study provides a preliminary test of the IPTS in a sample of 134 women seeking shelter from IPV. First, we examined factors theoretically related to suicide ideation, demonstrating that only at high levels of hopelessness was perceived burdensomeness associated with suicide ideation. The study also examined factors theoretically related to the acquired capability for suicide (ACS), indicating that physical partner violence perpetration was associated with ACS. These findings suggest that perceived burdensomeness, particularly in the context of increased hopelessness, is important in the assessment and treatment of suicide ideation. Furthermore, violence perpetration may indicate greater risk of the capability to die by suicide among women seeking shelter from IPV. PMID- 27456535 TI - Religiosity,Conservatism, and Acceptability of Anti-Female Spousal Violence in Egypt. AB - Physical violence directed at women is a significant social and public health problem globally. Initial studies tended to concentrate on developed countries, often relying on clinical or shelter samples to assess incidence and prevalence. Although prevalence is critical, reducing or eliminating some problems also requires comprehension of cultural norms and expectations. In the present study, we use a population-based survey to understand factors contributing to attitudes in support of physical violence against married women. More specifically, the aim of the study was to investigate the impact of religiosity and social conservatism on acceptability of physical spousal violence in the Arab Republic of Egypt. Data utilized were derived from Wave 6 of the World Values Survey conducted in 2013. Bivariate and multivariate regression models were fitted to the data. It was found that religiosity was significantly associated with physical spousal violence ( b = -123, t = -4.480). Individuals who attended more often were less apt to accept physical spousal violence. Social conservatism was strongly tied to approval of physical violence ( b = .368, t = -4.115). It was concluded that culturally biased and patriarchal attitudes that devalue women in Egypt, instead of religion, may be the underlying reason for spousal abuse. It was also concluded that improving higher education for both men and women would reduce physical spousal violence. PMID- 27456534 TI - Gendered Perceptions of Drugs, Aggression, and Violence. AB - Drug use has been linked empirically with aggression and violence among youth in national and State of Hawai'i samples. In addition, aggression and violence appear to be gendered experiences perceived differently by girls and boys. This article explores the intersection of drug offers/drug refusals with aggression and violence with specific attention paid to gendered perceptions of drug use situations as a context for aggression and violence. A qualitative study, in which 14 sex-specific focus group discussions were held, focused on rural Native Hawaiian middle school students ( N = 64). Students were asked to discuss drug refusal strategies in a variety of drug offer contexts. Feminist theories and approaches were used to examine the role of aggression and violence in drug refusal as perceived by Native Hawaiian girls as compared with boys. Girls and boys differed in their perceptions of aggression and violence in drug offer situations, initially as evidenced by the extent to which the girl groups focused on the intersection of drugs and violence. Furthermore, qualitative analyses reflected gender norms and stereotypes about aggression and violence perpetration, and girls' apparently unique concerns about sexual violence victimization. Implications are discussed in terms of prevention research and practice, specifically in terms of school-based prevention curricula. PMID- 27456536 TI - Oxidative stress induces transient O-GlcNAc elevation and tau dephosphorylation in SH-SY5Y cells. AB - O-linked beta-N-acetlyglucosamine or O-GlcNAc modification is a dynamic post translational modification occurring on the Ser/Thr residues of many intracellular proteins. The chronic imbalance between phosphorylation and O GlcNAc on tau protein is considered as one of the main hallmarks of Alzheimer's disease. In recent years, many studies also showed that O-GlcNAc levels can elevate upon acute stress and suggested that this might facilitate cell survival. However, many consider chronic stress, including oxidative damage as a major risk factor in the development of the disease. In this study, using the neuronal cell line SH-SY5Y we investigated the dynamic nature of O-GlcNAc after treatment with 0.5 mM H2 O2 for 30 min. to induce oxidative stress. We found that overall O GlcNAc quickly increased and reached peak level at around 2 hrs post-stress, then returned to baseline levels after about 24 hrs. Interestingly, we also found that tau protein phosphorylation at site S262 showed parallel, whereas at S199 and PHF1 sites showed inverse dynamic to O-Glycosylation. In conclusion, our results show that temporary elevation in O-GlcNAc modification after H2 O2 -induced oxidative stress is detectable in cells of neuronal origin. Furthermore, oxidative stress changes the dynamic balance between O-GlcNAc and phosphorylation on tau proteins. PMID- 27456537 TI - Moral competence and brain connectivity: A resting-state fMRI study. AB - Moral competence (MC) refers to the ability to apply certain moral orientations in a consistent and differentiated manner when judging moral issues. People greatly differ in terms of MC, however, little is known about how these differences are implemented in the brain. To investigate this question, we used functional magnetic resonance imaging and examined resting-state functional connectivity (RSFC) in n=31 individuals with MC scores in the highest 15% of the population and n=33 individuals with MC scores in the lowest 15%, selected from a large sample of 730 Master of Business Administration (MBA) students. Compared to individuals with lower MC, individuals with higher MC showed greater amygdala ventromedial prefrontal connectivity, which may reflect better ability to cope with emotional conflicts elicited by moral dilemmas. Moreover, individuals with higher MC showed less inter-network connectivity between the amygdalar and fronto parietal networks, suggesting a more independent operation of these networks. Our findings provide novel insights into how individual differences in moral judgment are associated with RSFC in brain circuits related to emotion processing and cognitive control. PMID- 27456538 TI - Sheet Probability Index (SPI): Characterizing the geometrical organization of the white matter with diffusion MRI. AB - The question whether our brain pathways adhere to a geometric grid structure has been a popular topic of debate in the diffusion imaging and neuroscience societies. Wedeen et al. (2012a, b) proposed that the brain's white matter is organized like parallel sheets of interwoven pathways. Catani et al. (2012) concluded that this grid pattern is most likely an artifact, resulting from methodological biases that cause the tractography pathways to cross in orthogonal angles. To date, ambiguities in the mathematical conditions for a sheet structure to exist (e.g. its relation to orthogonal angles) combined with the lack of extensive quantitative evidence have prevented wide acceptance of the hypothesis. In this work, we formalize the relevant terminology and recapitulate the condition for a sheet structure to exist. Note that this condition is not related to the presence or absence of orthogonal crossing fibers, and that sheet structure is defined formally as a surface formed by two sets of interwoven pathways intersecting at arbitrary angles within the surface. To quantify the existence of sheet structure, we present a novel framework to compute the sheet probability index (SPI), which reflects the presence of sheet structure in discrete orientation data (e.g. fiber peaks derived from diffusion MRI). With simulation experiments we investigate the effect of spatial resolution, curvature of the fiber pathways, and measurement noise on the ability to detect sheet structure. In real diffusion MRI data experiments we can identify various regions where the data supports sheet structure (high SPI values), but also areas where the data does not support sheet structure (low SPI values) or where no reliable conclusion can be drawn. Several areas with high SPI values were found to be consistent across subjects, across multiple data sets obtained with different scanners, resolutions, and degrees of diffusion weighting, and across various modeling techniques. Under the strong assumption that the diffusion MRI peaks reflect true axons, our results would therefore indicate that pathways do not form sheet structures at every crossing fiber region but instead at well-defined locations in the brain. With this framework, sheet structure location, extent, and orientation could potentially serve as new structural features of brain tissue. The proposed method can be extended to quantify sheet structure in directional data obtained with techniques other than diffusion MRI, which is essential for further validation. PMID- 27456540 TI - Developing the concept of sustainability in nursing. AB - Sustainability, and the related concept of climate change, is an emerging domain within nursing and nurse education. Climate change has been posited as a serious global health threat requiring action by health professionals and action at international level. Anaker & Elf undertook a concept analysis of sustainability in nursing based on Walker and Avant's framework. Their main conclusions seem to be that while defining attributes and cases can be established, there is not enough research into sustainability in the nursing literature. This paper seeks to develop their argument to argue that sustainability in nursing can be better understood by accessing non-nursing and grey literature and, for example, the literature in the developing web-based 'paraversity'. Without this understanding, and application in nursing scholarship, nurses will have a rather narrow understanding of sustainability and its suggested links with social and health inequalities and the dynamics underpinning unsustainable neoliberalist political economy. This understanding is based on the social and political determinants of health approach and the emerging domain of planetary health. However, this is a major challenge as it requires a critical reflection on what counts as nursing knowledge, a reflection which might reject sustainability and political economy as irrelevant to much of nursing practice. PMID- 27456539 TI - Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma. AB - Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy are limited. Topotecan is an approved second-line chemotherapy for small cell lung cancer (SCLC). NEC is often considered to show a biological behavior similar to SCLC. The aim of this study was to analyze the efficacy of topotecan in pretreated metastatic NEC patients. We performed a retrospective analysis of all patients treated with topotecan for metastatic NEC who presented at our center between January 2005 and December 2014 (n = 30). All 30 patients had received at least a platinum and etoposide containing regimen as prior chemotherapy. Median proliferation rate (Ki67) was 80%. As best response to topotecan five patients showed a stable disease, two patients a partial remission, resulting in a disease control rate of 23%. Of the remaining 23 patients, 14 (47%) showed a progressive disease, nine (30%) died before radiologic response could be evaluated. Median progression-free (PFS) and overall survival (OS) after start of topotecan was 2.1 and 4.1 months, respectively. In the subgroup analysis, patients with unknown primary (vs. those with a known primary) showed a significantly prolonged PFS of 3.5 months (vs. 1.9, P = 0.0107) and OS of 6.7 months (vs. 2.6 months, P = 0.0168). Grade 3/4 hematotoxicity was observed in 60% of patients. Topotecan shows only moderate antitumor activity in metastatic NEC. Disease control rate is lower than reported for SCLC. However, antitumor activity of topotecan seems higher in patients with unknown primary. PMID- 27456541 TI - Neonatal seizures are associated with redistribution and loss of GABAA alpha subunits in the hypoxic-ischaemic pig. AB - Seizures are a common manifestation of hypoxic-ischaemic brain injury in the neonate. In status epilepticus models alterations to GABAA R subunit expression have been suggested to contribute to (i) abnormal development of the GABAergic system, (ii) why seizures become self-sustaining and (iii) the development of pharmacoresistance. Detailed investigation of GABAA R subunit protein expression after neonatal hypoxia-ischaemia (HI) is currently insufficient. Using our pig model of HI and subsequent spontaneous neonatal seizures, we investigated changes in protein expression of the three predominant alpha-subunits of the GABAA R; alpha1 , alpha2 and alpha3 . Anaesthetized, ventilated newborn pigs (< 24 h old) were subjected to 30 min HI and subsequently recovered to 24 or 72 h. Amplitude integrated electroencephalography was used to monitor brain activity and identify seizure activity. Brain tissue was collected post-mortem and GABAA R alpha subunit protein expression was analysed using western blot and immunohistochemistry. GABAA R alpha1 and alpha3 protein expression was significantly reduced in animals that developed seizures after HI; HI animals that did not develop seizures did not exhibit the same reductions. Immunohistochemistry revealed decreased alpha1 and alpha3 expression, and alpha1 redistribution from the cell membrane to the cytosol, in the hippocampus of seizure animals. Multivariate analyses, controlling for HI severity and neuronal injury, revealed that seizures were independently associated with significant GABAA R alpha3 reduction. This is the first study to show loss and redistribution of GABAA R alpha-subunits in a neonatal brain experiencing seizures. Our findings are similar to those reported in models of SE and in chronic epilepsy. PMID- 27456542 TI - Treating Depression and Anxiety with Digital Cognitive Behavioural Therapy for Insomnia: A Real World NHS Evaluation Using Standardized Outcome Measures. AB - BACKGROUND: Evidence suggests that insomnia may be an important therapeutic target to improve mental health. AIMS: Evaluating changes in symptoms of depression and anxiety after supported digital cognitive behavioural therapy (dCBT) for insomnia delivered via a community-based provider (Self Help Manchester) of the Improving Access to Psychological Therapies (IAPT) service. METHOD: Supported dCBT for insomnia was delivered to 98 clients (mean age 44.9 years, SD 15.2, 66% female) of Self Help Manchester. All clients received six support calls from an eTherapy coordinator to support the self-help dCBT. During these calls levels of depression (Patient Health Questionnaire, PHQ-9) and anxiety (Generalized Anxiety Disorder, GAD-7) were determined. RESULTS: Depression (M difference-5.7, t(70) = 12.5, p < .001) and anxiety [Generalized Anxiety Disorder-7 (GAD-7), M difference-4.1, t(70) = 8.0, p < .001] were reduced following supported dCBT for insomnia. This translated into an IAPT recovery rate of 68% for depression and anxiety. CONCLUSIONS: These results suggest that dCBT for insomnia alleviates depression and anxiety in clients presenting with mental health complaints in routine healthcare. PMID- 27456543 TI - Response to own name in children: ERP study of auditory social information processing. AB - Auditory processing is an important component of cognitive development, and names are among the most frequently occurring receptive language stimuli. Although own name processing has been examined in infants and adults, surprisingly little data exist on responses to own name in children. The present ERP study examined spoken name processing in 32 children (M=7.85years) using a passive listening paradigm. Our results demonstrated that children differentiate own and close other's names from unknown names, as reflected by the enhanced parietal P300 response. The responses to own and close other names did not differ between each other. Repeated presentations of an unknown name did not result in the same familiarity as the known names. These results suggest that auditory ERPs to known/unknown names are a feasible means to evaluate complex auditory processing without the need for overt behavioral responses. PMID- 27456544 TI - The use of coffee, chewing-gum and gastrograffin in the management of postoperative ileus: A review of current evidence. AB - Postoperative ileus is one of the main complications in the postoperative period. New measures appeared with the introduction of "fast-track surgery" to accelerate recovery: coffee, chewing gum and gastrograffin. We performed a summary of current evidence, reviewing articles from MEDLINE, Cochrane Database of Systematic Reviews, ISI Web of Science, and SCOPUS databases. Employed search terms were "postoperative ileus" AND ("definition" OR "epidemiology" OR "risk factors" OR "Management"). We selected 44 articles: 9 systematic reviews 11 narrative reviews, 13 randomized clinical trials, 6 observational studies, and the remaining 5 scientific letters, assumptions, etc. There is little literature about this topic, studies are heterogeneous, with disparity in the results. In addition, they only focus on colorectal and gynecological surgery. New high quality studies are needed, preferably randomized clinical trials, in order to clarify the usefulness of these measures. PMID- 27456545 TI - Two-stage laparoscopic curative resection for synchronous multiple colorectal cancers: A case report. AB - A 75-year-old man tested positive for occult blood in the stool. A subsequent examination indicated concurrent locally advanced cancer (cT3) at the hepatic flexure and lower rectum cancer in the external anal sphincter. Because of the locally advanced rectal cancer (cT4), preoperative chemoradiotherapy was administered. First, laparoscopic right hemicolectomy and colostomy were performed at the sigmoid colon. Chemoradiotherapy for rectal cancer was initiated on day 18 after the surgeries. Seven weeks after chemoradiotherapy had been completed, laparoscopic abdominoperineal resection and right lateral pelvic lymph node dissection were performed. This case demonstrated that a second radical surgery for rectal cancer could be performed safely and laparoscopically after laparoscopic colectomy and colostomy. PMID- 27456546 TI - Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome. AB - WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function. PMID- 27456547 TI - Polycystic ovary syndrome in type 2 diabetes: does it predict a more severe phenotype? AB - OBJECTIVE: To examine the prevalence of a history of polycystic ovary syndrome (PCOS) in women with type 2 diabetes (DM2) and to compare metabolic and reproductive outcomes between women with and without PCOS. DESIGN: Cross sectional study. SETTING: Tertiary hospital. PATIENT(S): Female inpatients age 18 75 years with DM2. INTERVENTION(S): A face-to-face questionnaire was administered. MAIN OUTCOME MEASURE(S): Age at diagnosis of diabetes, history of gestational diabetes, family history of diabetes, and reproductive history, fertility history, number of miscarriages, and morbidity in pregnancy. RESULT(S): One hundred seventy-one inpatients with DM2 participated. The prevalence of a history of PCOS was 37%. Women with PCOS had an earlier mean age of diagnosis of DM2 (44.2 vs. 48.8 years), higher recalled peak body mass index (BMI; 43.1 kg/m2 vs. 36.8 kg/m2), higher rate of gestational diabetes (28% vs. 18%), and higher rate of hypertension in pregnancy (40% vs. 22%). Women with PCOS were less likely to have a family history of DM2 than those without PCOS (45% vs. 67%). CONCLUSION(S): A history of PCOS in women with DM2 is associated with earlier onset of DM2, higher BMI, and a more severe phenotype. Since PCOS subjects were less likely to have a family history of DM2, lack of a family history of DM2 in women with PCOS is not reassuring for DM2 risk. We recommend identifying PCOS in early life and intervening to reduce the risk of diabetes and its comorbidities and suboptimal reproductive outcomes. PMID- 27456548 TI - A sperm aspiration technique in the armamentarium of options to help in extreme testicular trauma-a war experience. PMID- 27456549 TI - Altered expression of the tachykinins substance P/neurokinin A/hemokinin-1 and their preferred neurokinin 1/neurokinin 2 receptors in uterine leiomyomata. AB - OBJECTIVE: To study the expression levels of tachykinins and tachykinin receptors in uterine leiomyomas and matched myometrium. DESIGN: Laboratory study. SETTING: University research laboratories and academic hospital. PATIENT(S): Women undergoing hysterectomy for symptomatic leiomyomas. INTERVENTION(S): Quantitative polymerase chain reaction, immunohistochemistry and Western blot. MAIN OUTCOME MEASURE(S): Expression and tissue immunostaining of substance P, neurokinin A, hemokinin-1, neurokinin 1 receptor full-length (NK1R-Fl) and truncated (NK1R-Tr) isoforms, and neurokinin 2 receptor (NK2R) in paired samples of leiomyoma and adjacent normal myometrium. RESULT(S): TAC1 messenger RNA (mRNA) was significantly up-regulated in leiomyomas, whereas intense immunoreaction for the three peptides was particularly abundant in connective tissue cells. Differential regulation of TACR1 mRNA was observed, and at the protein level there was a significant increased expression of NK1R short isoform (NK1R-Tr). TACR2 mRNA was significantly up-regulated in leiomyomas, although levels of NK2R protein were similar in normal and tumor cells. CONCLUSION(S): These and our previous data demonstrate that the whole tachykinin system is differentially regulated in leiomyomas. The increased expression of NK1R-Tr might stimulate leiomyoma growth in a similar way to that observed in other steroid-dependent tumors. PMID- 27456550 TI - Functional Short-Bite Ligands: Synthesis, Coordination Chemistry, and Applications of N-Functionalized Bis(diaryl/dialkylphosphino)amine-type Ligands. AB - The aim of this review is to highlight how the diversity generated by N substitution in the well-known short-bite ligand bis(diphenylphosphino)amine (DPPA) allows a fine-tuning of the ligand properties and offers a considerable scope for tailoring the properties and applications of their corresponding metal complexes. The various N-substituents include nitrogen-, oxygen-, phosphorus-, sulfur-, halogen-, and silicon-based functionalities and directly N-bound metals. Multiple DPPA-type ligands linked through an organic spacer and N-functionalized DRPA-type ligands, in which the PPh2 substituents are replaced by PR2 (R = alkyl, benzyl) groups, are also discussed. Owing to the considerable diversity of N functionalized DPPA-type ligands available, the applications of their mono- and polynuclear metal complexes are very diverse and range from homogeneous catalysis with well-defined or in situ generated (pre)catalysts to heterogeneous catalysis and materials science. In particular, sustained interest for DPPA-type ligands has been motivated, at least in part, by their ability to promote selective ethylene tri- or tetramerization in combination with chromium. Ligands and metal complexes where the N-substituent is a pure hydrocarbon group (as opposed to N functionalization) are outside the scope of this review. However, when possible, a comparison between the catalytic performances of N-functionalized systems with those of their N-substituted analogs will be provided. PMID- 27456551 TI - Removal kinetics for gaseous NO and SO2 by an aqueous NaClO2 solution mist in a wet electrostatic precipitator. AB - Removal kinetics for NO and SO2 by NaClO2 solution mist were investigated in a wet electrostatic precipitator. By varying the molar concentrations of NO, SO2, and NaClO2, the removal rates of NO and SO2 confirmed to range from 34.8 to 72.9 mmol/m3 s and 36.6 to 84.7 mmol/m3 s, respectively, at a fixed gas residence time of 0.25 s. The rate coefficients of NO and SO2 were calculated to be 0.679 (mmol/m3)-0.33 s-1 and 1.401 (mmol/m3)-0.1 s-1 based on the rates of the individual removal of NO and SO2. Simultaneous removal of NO and SO2 investigated after the evaluation of removal rates for their individual treatment was performed. At a short gas residence time, SO2 gas removed more quickly by a mist of NaClO2 solution than NO gas in simultaneous removal experiments. This is because SO2 gas, which has a relatively high solubility in solution, was absorbed more rapidly at the gas-liquid interface than NO gas. NO and SO2 gases were absorbed as nitrite [Formula: see text] and sulfite [Formula: see text] ions, respectively, by the NaClO2 solution mist at the gas-liquid interface. Then, [Formula: see text] and [Formula: see text] were oxidized to nitrate [Formula: see text] and sulfate [Formula: see text], respectively, by reactions with [Formula: see text], ClO2, HClO, and ClO in the liquid phase. PMID- 27456553 TI - Erratum. PMID- 27456552 TI - Infection of laboratory colonies of Anopheles mosquitoes with Plasmodium vivax from cryopreserved clinical isolates. AB - Plasmodium vivax is the most geographically widespread malaria parasite. Unique features of transmission biology complicate P. vivax control. Interventions targeting transmission are required for malaria eradication. In the absence of an in vitro culture, transmission studies rely on live isolates from non-human primates or endemic regions. Here, we demonstrate P. vivax gametocytes from both India and Brazil are stable during cryopreservation. Importantly, cryopreserved gametocytes from Brazil were capable of infecting three anopheline mosquito species in feedings done in the United States. These findings create new opportunities for transmission studies in diverse locales. PMID- 27456554 TI - Pharmacology of heart failure: From basic science to novel therapies. AB - Chronic heart failure is one of the leading causes for hospitalization in the United States and Europe, and is accompanied by high mortality. Current pharmacological therapy of chronic heart failure with reduced ejection fraction is largely based on compounds that inhibit the detrimental action of the adrenergic and the renin-angiotensin-aldosterone systems on the heart. More than one decade after spironolactone, two novel therapeutic principles have been added to the very recently released guidelines on heart failure therapy: the HCN channel inhibitor ivabradine and the combined angiotensin and neprilysin inhibitor valsartan/sacubitril. New compounds that are in phase II or III clinical evaluation include novel non-steroidal mineralocorticoid receptor antagonists, guanylate cyclase activators or myosine activators. A variety of novel candidate targets have been identified and the availability of gene transfer has just begun to accelerate translation from basic science to clinical application. This review provides an overview of current pharmacology and pharmacotherapy in chronic heart failure at three stages: the updated clinical guidelines of the American Heart Association and the European Society of Cardiology, new drugs which are in clinical development, and finally innovative drug targets and their mechanisms in heart failure which are emerging from preclinical studies will be discussed. PMID- 27456555 TI - Triterpenoids from the branch and leaf of Abies fargesii. AB - Eighteen triterpenoids, abifarines A-R, including fourteen previously unknown and four artifacts, together with six known ones, were isolated from the branch and leaf of Abies fargesii. Their structures were elucidated by spectroscopic data analysis. The relative configurations of abifarines A and F were further confirmed by single-crystal X-ray diffraction analysis with Mo Kalpha irradiation. All compounds were evaluated for their in vitro cytotoxicity against the mouse cancer B16 cell line, and human cancer HepG2 and MCF7 cell lines. (24R) cycloartane-3beta,24,25-triol and (24R)-cycloartane-3beta,24,25,28-tetrol showed moderate anti-proliferative effect for B16 and HepG2 cell lines with IC50 values of 32.9, 19.5 MUM and 26.4, 21.5 MUM, respectively. PMID- 27456557 TI - [Clinical and anatomical features of congenital microphthalmia and anophthalmia in children and conservative methods of rehabilitation]. AB - AIM: To develop a comprehensive classification system of distinctive clinical and anatomical features of congenital microphthalmia and anophthalmia in children and to specify indications, contraindications, and optimal timing of the primary and subsequent prosthetic treatment. MATERIAL AND METHODS: A total of 70 patients with congenital micro- or anophthalmia aged from 1 month to 12 years were examined. Besides the routine ophthalmic examination, all patients underwent eye and orbit ultrasound (axial length measurement and B-scan), computed tomography of the orbits and skull, and immunological tests for infectious diseases (enzyme linked immunosorbent assays). RESULTS: Basing on the examination RESULTS: we have determined the common types of congenital micro- and anophthalmia in children. We have also developed a stepwise prosthetic treatment aimed at better cosmetic rehabilitation. Indications and contraindications for the use of ocular prostheses in children with congenital micro- and anophthalmia have been identified. CONCLUSION: The proposed method of stepwise prosthetics is the principal option for conservative rehabilitation of children with congenital micro- or anophthalmia. PMID- 27456556 TI - Efficacy and pharmacokinetics of a modified acid-labile docetaxel-PRINT((r)) nanoparticle formulation against non-small-cell lung cancer brain metastases. AB - AIM: Particle Replication in Nonwetting Templates (PRINT((r))) PLGA nanoparticles of docetaxel and acid-labile C2-dimethyl-Si-Docetaxel were evaluated with small molecule docetaxel as treatments for non-small-cell lung cancer brain metastases. MATERIALS & METHODS: Pharmacokinetics, survival, tumor growth and mice weight change were efficacy measures against intracranial A549 tumors in nude mice. Treatments were administered by intravenous injection. RESULTS: Intracranial tumor concentrations of PRINT-docetaxel and PRINT-C2-docetaxel were 13- and sevenfold greater, respectively, than SM-docetaxel. C2-docetaxel conversion to docetaxel was threefold higher in intracranial tumor as compared with nontumor tissues. PRINT-C2-docetaxel increased median survival by 35% with less toxicity as compared with other treatments. CONCLUSION: The decreased toxicity of the PRINT-C2-docetaxel improved treatment efficacy against non-small-cell lung cancer brain metastasis. PMID- 27456558 TI - [Quantitative evaluation of uveoscleral outflow for optimization of glaucoma treatment]. AB - The leading role in glaucoma treatment is now played by prostaglandin analogues (PGAs), whose point of application is the uveoscleral outflow of aqueous humor. Quantitative evaluation of the latter is, however, a problem yet unsolved. AIM: To assess the clinical applicability of a new method for quantitative evaluation of the uveoscleral outflow in human eyes, which is meant to help with optimization of glaucoma therapy. MATERIAL AND METHODS: Patients with early (n=33) and advanced (n=30) primary open-angle glaucoma (POAG) were enrolled. Besides the routine ophthalmic examination, all patients had their uveoscleral outflow quantified with our method. Basing on these findings, we have analyzed the effect of different hypotensive eye drops, namely, betaxolol 0.5% (selective beta-1-blocker), brinzolamid 1% (carbonic anhydrase inhibitor), travoprost 0.004% (prostaglandin analogue) and travoprost 0.004%/timolol 0.5% fixed combination (TTFC; prostaglandin analogue plus non-selective beta-blocker). RESULTS: In early POAG, the uveoscleral outflow facility (Cfu) without treatment was 0.06+/-0.06, after betaxolol 0.5% as well as brinzolamid 1% use - 0.05+/-0.03, while after travoprost 0.004% and FCTT use - 0.10+/-0.06 and 0.08+/-0.05 correspondingly. In advanced POAG, Cfu was 0.04+/-0.03 without treatment, 0.06+/-0.04 - after betaxolol 0.5% or brinzolamid 1% use, 0.1+/-0.05 - after travoprost 0.004% use, and 0.1+/-0.04 - after FCTT use. CONCLUSION: Quantitative evaluation of the uveoscleral outflow with the new method that has not only been justified, but also clinically tested, provides an opportunity to optimize POAG treatment. PMID- 27456559 TI - [Treatment choice in dacryostenosis based on single-photon emission computed tomography and X-ray computed tomography findings]. AB - AIM: To develop surgical indications in dacryostenosis within the vertical portion of lacrimal pathways that would consider findings of single-photon emission computed tomography (SPECT) combined with X-ray computed tomography (CT). MATERIAL AND METHODS: A total of 96 patients with isolated vertical-portion dacryostenosis (127 cases) were enrolled. The examination included collecting Munk's scores for epiphora, optical coherence tomography of the lower tear meniscus, lacrimal scintigraphy, and SPECT/CT. Group 1 (40 cases) was composed of patients with lacrimal obstruction on CT, group 2 (87 cases) - of those whose lacrimal pathways proved passable. There were also 3 patients (4 cases) from group 1, whose lacrimal pathways, despite being blocked on CT, were still passable on SPECT. Surgeries performed in group 1 were endoscopic endonasal dacryocystorhinostomy (DCR) (36 cases) and pathways recanalization with bicanalicular intubation and balloon dacryoplasty (DCP) (4 cases). In group 2, all patients (87 cases) underwent recanalization with bicanalicular intubation (supplemented with balloon DCP in 32 cases). Surgical results were evaluated 8-12 months after the treatment. In group 2, particular attention was paid to the concordance in locations of dacryostenosis provided by CT and SPECT scans. RESULTS: Favorable outcomes of endoscopic endonasal DCR were obtained in as many as 32 cases from group 1 (88.9%), while in 4 cases (12.1%) the condition relapsed. Of those patients whose stenosis was not complete on SPECT, 3 cases (75.0%) improved, 1 (25.0%) - relapsed. In group 2, favorable outcomes were obtained in 65 cases (74.7%), relapses were 22 (25.3%). A high concordance in stenosis locations by CT and SPECT was noted in 60 cases of those who improved (92.3%) and 3 cases of those who relapsed (13.6%). CONCLUSION: The value of information provided by SPECT/CT has proved high in patients with nasolacrimal duct stenosis or obstruction. A combined scan allows to establish causal relationships between anatomical changes and functional failure of lacrimal pathways and to make an optimal treatment choice. PMID- 27456560 TI - [Nevi of conjunctiva as a risk factor of melanoma]. AB - Conjunctival nevi are the most common tumors of this location. They are usually unilateral, although bilateral cases may also be met. As to clinical presentation, all nevi are divided into: stationary or progressive nevi, blue nevi, and primary acquired melanosis. Color changes are acceptable, if they occur during pregnancy or puberty. However, if postpubertal, such changes should be considered alarming, as to possible malignization. Histopathologically, nevi are composed of melanocyte clusters in the skin stroma next to the basal layer of the epidermis. AIM: To analyze the significance of timely removal of conjunctival nevi for melanoma prevention. MATERIAL AND METHODS: A total of 52 patients were examined during 2009-2013. Of them, 48 patients had nevi of the conjunctiva and/or lacrimal caruncle, 1 patient was diagnosed with caruncular melanoma and 3 other - with conjunctival melanoma. RESULTS: Patients with stationary nevi are still being followed up. Of those who were surgically treated, none developed recurrence. Taking into account high metastatic activity of melanomas and that discovering metastases does not always happen together with diagnosing the primary lesion (often, years after treatment), the follow-up of melanoma patients must be lifelong. CONCLUSION: Timely removal of progressive conjunctival nevi is able to prevent malignancy, of which the outcome may be very unfavorable. PMID- 27456561 TI - [Patterns of ocular neurovascular reactions]. AB - AIM: To examine factors and determinants of ocular neurovascular reactions (NVR). MATERIAL AND METHODS: The study included 120 healthy participants of both sexes aged 20.9+/-0.6 years, who underwent a standard ophthalmic examination. Ocular microcirculation was recorded using laser Doppler flowmetry. Autonomic homeostasis and the intensity of slow-wave oscillations of hemodynamics were of interest. Autoregulation of cerebral blood flow was assessed by transcranial color-coded duplex scanning. RESULTS: The dynamics of perfusion control mechanisms (myogenic and neurogenic) have been studied in the young healthy population of Krasnoyarsk. The role of the autonomic nervous system in initiating a particular type of ocular NVR has been identified. The authors have also determined the significance of the nitric oxide production intensity in different types of NVR. CONCLUSION: The type of ocular NVR is determined by parameters of cerebral hemodynamics. Normotonic NVR is associated with effective autoregulation of cerebral blood flow, while hyper- and hypotonic types of reactions - with autoregulatory failure. PMID- 27456562 TI - [Hypothalamic regulation of retinal function]. AB - Studying compensatory capacity of the brain is a pressing issue. To resolve it, diversified experiments should be conducted providing an idea of the underlying mechanisms and possibilities of functional restoration. AIM: To determine the effect of unilateral electrocoagulation of supraoptic (SO) and suprachiasmatic (SCH) hypothalamic nuclei on the appearance of the electroretinogram (ERG). MATERIAL AND METHODS: We conducted chronic experiments on awake rabbits with a total duration of 30 days. RESULTS: The study revealed considerable changes in the total ERG amplitude (reduction) as well as the amplitudes of a- and b-waves. Thus, for the first 15-30 minutes after coagulation the b-wave showed an increase, while the a-wave appeared completely suppressed. Longer postcoagulation periods were associated with gradual, though incomplete, amplitude regain of the latter. CONCLUSION: The obtained data suggest that the process of ERG recovery involves compensatory mechanisms of the SO and SCH nuclei that enable partial recovery of the neurotransmitter activity of the retina. PMID- 27456563 TI - [Riboflavin photoprotection with cross-linking effect in photorefractive ablation of the cornea]. AB - Photorefractive ablation is inevitably accompanied by oxidative stress of the cornea and weakening of its biomechanical and photoprotective properties. AIM: To validate the expediency of riboflavin use in photorefractive ablation for photoprotection of the cornea and cross-linking. MATERIAL AND METHODS: The effects of riboflavin use in photorefractive ablation was first studied in a series of in vitro and in vivo experiments performed on 56 eyes of 28 rabbits, and then on 232 eyes of 142 patients with different degrees of myopia. Biomechanical testing of corneal samples was performed with Zwick/RoellVZ 2.5/TN1S tensile-testing machine. Transepithelial photorefractive keratectomy (TransPRK) and femtosecond laser-assisted in situ keratomileusis (Femto-LASIK) were performed on Wavelight-Allegretto200, MEL-80, and WaveLight-EX500 excimer laser systems and also VisuMax and WaveLight-FS200 femtosecond lasers. For preliminary examinations, an appropriate set of diagnostic tools was used. RESULTS: In vivo experiments have proved that, in the absence of conservative therapy, riboflavin is able to produce both photoprotective and cross-linking effects to the cornea. Corneal syndrome was thus reduced and re-epithelialization after TransPRK accelerated. Biomechanical testing of corneal samples revealed an increase in tolerated load from 12.9+/-1.4 N to 18.3+/-1.2 N (p=0.0002) and tensile strength from 8.6+/-1.7 MPa to 12.4+/-1.7 MPa (p=0.007). Clinical studies conducted in a group of patients with mild to moderate myopia have also confirmed the photoprotective effect of riboflavin at months 1-12 after TransPRK. There were no significant differences in uncorrected visual acuity (ranged from 0.80+/ 0.16 to 0.85+/-0.15) and corrected visual acuity at baseline (0.83+/-0.14). Evaluation of the optical and refractive effect achieved after Femto-LASIK with riboflavin photoprotection in the fellow eye has shown that this technique is not inferior to the traditional one as to its refractive accuracy, but provides better maintenance of biomechanical and photoprotective properties of the cornea. CONCLUSION: Photorefractive ablation of the cornea with preliminary saturation of the stroma with riboflavin solution ensures its photoprotection and provides an additional cross-linking effect. PMID- 27456564 TI - [Relationship between structural and functional changes in retina in Stargardt disease]. AB - AIM: To assess the relationship between structural abnormalities of the junction of the internal and external segments of photoreceptors (IS/OS junction) and functional changes. MATERIAL AND METHODS: The study enrolled 45 patients (90 eyes) with Stargardt disease, of them 22 women and 23 men. Ophthalmic examination included color vision test, static perimetry with a 60 degrees field of view, electrophysiological studies, namely, ganzfeld and multifocal electroretinography (gERG and mfERG), autofluorescence, and optical coherence tomography (OCT). RESULTS: For analysis, the patients were divided into 3 groups depending on whether or not the structure of the IS/OS junction was damaged at OCT. A strong correlation has been found between the level of IS/OS damage and the MD index. There were no differences in foveal, perifoveal, or parafoveal retinal thicknesses. Retinal volumes within the 1-, 3- and 6-mm ring-shaped zones were also similar. All three groups showed a reduction in amplitudes of the major gERG waves and mfERG changes of different severity. The most frequent defect seen in all groups and the ring-shaped zones was a reduction in the amplitude and density of retinal biopotential (P1MUv and P1 nv/deg2). CONCLUSION: A direct correlation exists between the extent and severity of structural changes in the IS/OS junction at OCT, visual functions assessed with perimetry, and disturbance of electrogenesis detected by mfERG and gERG. PMID- 27456566 TI - Building a Knowledge to Action Program in Stroke Rehabilitation. AB - The knowledge to action (KTA) process proposed by Graham et al (2006) is a framework to facilitate the development and application of research evidence into clinical practice. The KTA process consists of the knowledge creation cycle and the action cycle. The Evidence Based Review of Stroke Rehabilitation is a foundational part of the knowledge creation cycle and has helped guide the development of best practice recommendations in stroke. The Rehabilitation Knowledge to Action Project is an audit-feedback process for the clinical implementation of best practice guidelines, which follows the action cycle. The objective of this review was to: (1) contextualize the Evidence Based Review of Stroke Rehabilitation and Rehabilitation Knowledge to Action Project within the KTA model and (2) show how this process led to improved evidence-based practice in stroke rehabilitation. Through this process, a single centre was able to change clinical practice and promote a culture that supports the use of evidence based practices in stroke rehabilitation. PMID- 27456565 TI - [Reasons for intraocular pressure to resist hypotensive therapy in glaucoma patients]. AB - AIM: To study the reasons of intraocular pressure (IOP) resistance to therapy in patients with glaucoma. MATERIAL AND METHODS: During the period 2011-2013 we examined 72 primary glaucoma patients (stage I-III), 44 women and 28 men, aged 49 87 years (65.2+/-2.5 years on average) referred by local ophthalmologists due to poor response to hypotensive therapy. RESULTS: We suggest that glaucoma should be regarded as resistant if, despite combination therapy with three antihypertensive drugs at optimal doses, IOP stays above the target. In the present study, the treatment was found suboptimal in 19.4% of cases. About 45% of all patients (33 patients) demonstrated poor compliance to the prescribed treatment. Resistant glaucoma, as we have defined it, was diagnosed in 33% of cases (pigmentary glaucoma, pseudoexfoliation glaucoma, secondary unrecognized glaucoma, etc.). This group also included patients, in whom b-blockers were initially effective, but then seemed to lose their power. CONCLUSION: 1. The reasons for intraocular pressure to resist hypotensive therapy are often associated with medical inertia (inaccurate diagnosis, inadequate treatment, etc.) and lack of patient compliance. 2. Resistant glaucoma in its true sense accounts for about 35% of cases of IOP being above the target despite conservative treatment. 3. It is advisable that at the time of first presentation, any patient who fails to reach the target IOP is treated as an "uncontrolled glaucoma" case, until the reasons for his/her resistance are clear. PMID- 27456567 TI - Use of Lymphoid Progenitor Cell Assays for a More Detailed Analysis of the Cytogenetic Changes Occurring During Clonal Evolution in Acute Lymphoblastic Leukemia. AB - Karyotypic and immunophenotypic changes during clonal evolution were studied in 5 B-lineage and 5 T-lineage acute lymphoblastic leukemia (ALL) patients using leukemic progenitor cell assays in combination with cytogenetic and immunophenotypic analyses. Cytogenetic studies demonstrated a clonal chromosomal abnormality in 9 of 10 cases analyzed. The use of leukemic progenitor cell assay system revealed a distinct cytogenetic pattern of clonal evolution in 4 of the 7 patients who experienced leukemic relapses. It also made possible the identification of an abnormal clone in 2 patients in whom no analyzable metaphases were found in fresh marrow blasts. The evidence uniquely indicates that, in ALL 1) leukemic progenitor cell assays combined with fresh marrow cytogenetic and immunophenotypic analyses help clarify the sequence of cytogenetic and immunophenotypic changes during clonal evolution, 2:) cytogenetic changes may occur independent of immunophenotypic changes during clonal evolution, 3) immunologically distinct subclones may exist in a cytogenetically uniform blast population, and 4) normal diploid cells in leukemic bone marrow samples may occasionally represent clonal populations of cytogenetically "normal" leukemic blasts with submicroscopic genetic alterations. To our knowledge, this study represents the first application of leukemic progenitor cell assays in the cytogenetic analyses of ALL blasts. The described methodology can be used for further elucidation of clonal evolution in ALL as well as for more detailed analyses of individual leukemic clones derived from ALL patients. PMID- 27456568 TI - Ambiguous Phenotypes In Acute Leukemia. AB - Several excellent reviews have been written on the phenomenon of ambiguous leukemic phenotypes, discussing their problematic interpretation and potential clinical significance.(1-5) The literature on this subject has introduced, supported or dismissed terms such as biphenotypia, mixed lineage and hybrid leukemias, lineage promiscuity and infidelity, all of which classify leukemic phenotypes outside the norm or not readily classifiable according to established systems. Controversial hypotheses have been formulated regarding the mechanisms leading to the coexpression of antigens from more than one cell lineage by single leukemic blast cells. One concept proposed a relationship between heterogenous leukemic phenotypes and normal, transient, primitive stages of hemopoietic differentiation. An alternative view suggested that acquired changes of a cell's genetic machinery could result in a deviation from its normal differentiation commitment. PMID- 27456569 TI - Use of Monoclonal Antibodies for the Diagnosis of T-cell Malignancies: Applications and Limitations. AB - Biopsy samples from 136 peripheral T-cell lymphomas have been examined and compared with benign inflammatory T-cell infiltrates in an attempt to establish whether immunohistological methods may help to improve the distinction between these conditions. The results confirm and extend previous reports and indicate that the aberrant T-cell phenotypes constitute the single most reliable criterion for the distinction between benign and malignant T-cell infiltrates. These phenotypes are expressed frequently in T-cell malignancies in. lymphoid organs and are also seen in a substantial number of biopsy samples from advanced cutaneous T-cell lymphomas (CTCL). In contrast, early CTCL do not express aberrant T-cell phenotypes and are indistinguishable from benign cutaneous conditions in terms of their immunophenotypic properties. It is concluded that immunophenotypic techniques form a valuable supplement to routine histological methods for the diagnosis of T-cell lymphomas in lymphoid organs. The methods may also help to improve the diagnosis of advanced CTCL, but are of no or only limited help for the recognition of the early stages. PMID- 27456570 TI - Central Nervous System (CNS) Involvement in Acute Nonlymphocytic Leukemia (ANLL). AB - The incidence of central nervous system (CNS) involvement and effects of therapy were reviewed in 42 consecutive pediatric patients with acute nonlymphocytic leukemia (ANLL). The morphology of ileukemic cells was considered M1 in 13, M2 in 7, M3 in 5, M4 in 8, and M5 in 9. Two patients with M5 morphology presented with CNS disease at diagnosis. Systemic Ara-C treatment was included as a mainstay of remission induction and maintenance program for all patients. With the exception of the M5 group, none of the patients received direct CNS prophylactic therapy. There was a 0% incidence of CNS relapse: in this group of patients. Median duration of remission for all patients (excluding the M5 group) was 33 months. This experience may indicate that systemic treatment with Ara-C may provide some degree of CNS prophylaxis in ANLIL. PMID- 27456571 TI - Simultaneous Phenotypic and Genotypic Studies of Individual Mitotic Cells-Methods and Practical Applications. AB - Recently established techniques for simultaneous immunological and cytogenetic characterization of mitotic cell populations have opened further possibilities for the classification of certain cells in haematological neoplasias. These techniques have been termed MAC (morphology-antibody- chromosomes). Several staining procedures e.g. immunogold, immunofluorescence or immunoenzymatic techniques for simultaneous and/or consecutive cytogenetic analyses have been established and were applied for certain investigations. The advantages and disadvantages of these methods are discussed, as well as th: results which have been published until now, and future aspects of these techniques. PMID- 27456572 TI - Malignant Lymphoma of the Thyroid. AB - Thyroid lymphoma is a relatively rare disease, but has attracted the attention of many investigators because of its putative relationship with chronic lymphocytic thyroiditis (CLTH). The definite diagnosis of thyroid lymphoma, especially the histologic distinction from small cell carcinoma or CLTH, has been problematical and even regarded as impossible during the past decades. Recent progress in immunological methods including moltxular biology have resolve'd many of the diagnostic problems in this field, thereby providing a scientific basis for approaching these diseases. In this review, we have summarized the results of our recent study on thyroid lymphoma reviewing the pertinent literature. Briefly, we have discussed the important role of CETH in the etiology of thyroid lymphoma; the histologic classification of thyroid lymphoma, with special emphasis on the rellatively high incidence of intermediate lymphocytic lymphoma; the B-cell nature of proliferating cells in thyroid lymphoma; the prognostic significance of the histologic classification Working Formulation and other clinical factors; local immunologic conditions in the thyroid affected by lymphoma compared with those encountered in CLTH alone and the positive role of aspiration cytology in the early detection of thyroid lymphoma. PMID- 27456573 TI - Yorkshire Case Control Study of Leukaemias and Lymphomas Parallel Multivariate Analyses of Seven Disease Categories. AB - Between 1980 and 1986 a case control study of leukaemias aid lymphomas in Yorkshire conducted face to face interviews on 1362 cases and 2442 age and sex matched hospital controls. Case diagnoses were histopathologically confirmed and grouped into non-Hodgkin's lymphomma (NHL), Hodgkin's Disease (HD), malignant lymphocytic lymphoma (MLL.), chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL). Multivariate analyses were completed on each separate disease to evaluate risk factors relating to past medical history, occupation, environmental exposures and social contact variables. The results show a significant association (with OR adjusted for other risk factors) between a family history of leukaemia/lymphoma and HD (OR = 4.29), NHL (OR = 1.98) and AML (OR = 6.36). For HD other cancers in the family also conveyed a significant risk (OR = 1.61). Use of heart drugs l(and heart disease) was linked to the chronic leukaemias (CML, CLL). A previous cancer and NHL, CLL and AML were associated even after adjustment for radiotherapy. A complex set of risk factors including prior skin lesions and steroid use showed significant links with HD, NHL and CLL., Increasing risk of NHL was linked to small family size. A significant excess of NHL cases reported exposure to glues and similarly ALL cases with agricultural chemical exposure. There present data provide both confirmatory and novel results. Overall they concur with the hypothesis of a multifactoral aetiology encompassing both genetic and immunological components. PMID- 27456574 TI - Mitoxantrone, Etoposide and Prednisolone-a Novel Combination in The Treatment of Relapsed and Refractory Lymphoma. AB - A new combination chemotherapy comprising mitoxantrone 10 mg/m(2) iv on day 1, etoposide 100 mg/m(2) iv/po days 1 to 3 and prednisolone 25 mg/m(2) days 1 to 10 was assessed in the treatment of 18 patients with relapsed or refractory Hodgkin's disease or non-Hodgkin's lymphoma. An overall response rate of 74% was achieved. Complete remission occurred in 41% and partial remission in a further 33% of patients. Toxic effects were limited and the regime suitable for out patient administration. Treatment delays were few and due principally to mild haematological toxicity. PMID- 27456575 TI - Acute Promyelocytic Leukaemia. Relationship of Cytochemical Pattern with Clinical, Morphologic and Immunological Characteristics, and Outcome. AB - In a series of 61 acute promyelocytic leukemia (APL) cases multiple clinical and biological characteristics were studied in order to assess their prognostic significance and to evaluate the relationship of cytochemical pattern with clinical, morphologic, and immunological characteristics and outcome. Alpha naphthyl acetate esterase (ANAE) activi1:y was expressed in 23 out of 41 cases (56%). Sodium fluoride-sensitive naphthol AS-D acetate esterase was evident in only one out of 22 cases (5 %). ANAE reactivity was more frequently found in typical hypergranular APL (P = 0.003) and was associated with a shorter interval symptoms-diagnosis (P = 0.04). The expression of HLA-DK, CD33, CD13 and CD11b did not show any correlation with ANAE reactivity. Complete remission (CR) was achieved in 64 % of treated patients. The actuarial median remission duration was 22 +/- 3 months. CR rate was significantly related to the presence of fever, age, absolute reticulocyte count, and albumin level, while the remission duration was associated with absolute reticulocyte, leucocyte and granulocyte counts, and albumin level. In our study ANAE activity did not reflect any important clinical and biological features of APL, apart from its obvious correlation with morphological subtype. In addition ANAE activity did not correlate with early response to therapy nor related with long-term prognosis. PMID- 27456576 TI - Thrombopoiesis and Structural Rearrangements of the Long Arm of Chromosome 3. Review arid Analysis of Data on 64 Published Patients. AB - During the least 10 years a growing number of case reports arid small patient series have demonstrated an association between certain structural changes of the q arm of chromosom'e no. 3 (insertion, inversion, translocation (3; 3) or translocation with other chromosomes) and signs of increased platelet production and morphologic megakaryocyte abnormalitieis. Analysis of published data on 64 such patients now demonstrate that rearrangements between the two chromosomes 3 are associated with significantly higher platelet counts and higher frequencies of megakaryocytes in the marrow than are translocations between no. 3 and other chromosomes. Further, the megakaryocyte hyperplasia is due primarily to abnormally small megakaryocytes, often with hypolobulated nuclei. These quantitative,and qualitative changes of thrombopoiesis are associated with coincident breaks in 3q21 an8d 3q26 and juxtaposition of these bands so that the band sequence 3q21::q26 is formed. Apparently, this band sequence specifically stimulates and changes thrombopoiesis. PMID- 27456577 TI - Immunoglobulin DNA Analysis as a Marker of Clonality in the Follow-up of Patients with Hairy Cell Leukemia Treated with Alpha-Interferon. AB - In fourteen patients with hairy cell leukemia (HCL) the configuration of the immunoglobulin (Ig) heavy chain genes was used as a marker of clonality, to monitor the response of the neoplastic population to treatment with alpha interferon (a-IFN). In agreement with the morphological, hematological and immunological data, twelve of them showed, after a variable length of therapy, a complete disappearance of rearranged bands in peripheral blood cells. In one patient, who was treated less intensively, the molecularly-defined neoplastic population was still present on two consecutive determinations, whilst in the last patient persistence of disease was repeatedly documented despite prolonged A IFN treatment. Three further cases were analyzed sequentially: in two, no rearranged bands could be found at repeated determinations; the third, who was in complete remission whilst on 3 * 10(6) U of alpha-IFN every other day, showed recurrence of disease nine months later when on a maintenance protocol with 3 * 10(6) U/weekly. Nine bone marrow specimens were also analyzed following treatment with alpha-IFN. In four a monoclonally rearranged band could still be detected, while in another four, reversal of fibrosis and hemopoietic recovery wits coupled with the absence of a molecularly recognizable neoplastic clone. In the last (case, persistence of disease paralleled the findings in the peripheral blood cells. These data indicate that alpha-IFPJ is capable of producing a specific cytolytic effect on the leukemic population in HCL, which in some cases may lead to complete clonal remissions. Analysis at the DNA level may represent a valuable tool towards monitoring the clinical course of HCL patients and for optimal individual therapeutic scheduling. PMID- 27456578 TI - Immunophenotypic Dissection of Normal Peripheral Blood NK Associated (NKa) Subpopulations by Flow Cytometry: Morphological Features and Relationships Between Membrane NKa (CD11b, CD 16, CD56 and CD57) arid T-cell (CD2, CD3, TCR, CD5, CD7, CD8 and CD38) Associated Determinant Expression. AB - Using single and multiple colour flow cytometry (FACSCAN), this study has examined the expression of NK-associated (NKa) CD11b, CD16, CD56 and CD57 membrane antigens by normal lymphocyte subpopulations. In addition to determining the normal proportions and absolute numbers of NKa(+) cells, this investigation also related the expression of these four NKa markers to the presence of; (a) morphologically-defined large granular lymphocytes, (LGL); and (b) membrane CD2, CD3, CD8 and TCR chain expression. This was achieved by preparing highly enriched normal blood CD4-CD8(+)/CD4 CD8(+) and CD4(-)CD8(-) lymphocyte fractions (n = 6) by immunomagnetic depletion of CD4(+)/CD14(+)/CD19(+) or CD4(+)/CD8(+)/CD14(+)/CD19(+) components respectively. Morphological assessment of these fractions showed that the sequential depletion procedures resulted in the enrichment of LGL, from a mean of 9% for the "whole" lymphocyte (pre depletion) fraction, to 35% following removal of CD4(+), CD14(+) and CD19(+) cells and to 80%) following the additional removal of CD8(+) cells. FACS analysis revealed the presence of three CD8 subgroups (CD8(-), CD8(dim+) and CD8(+)), defined by differences in membrane staining intensity, and subsequent three colour (CD2/CD3/CD8) studies indicated that the main composite CD2/CD3 phenotypes for these CD8 groups were (relative frequencies in parenthesis); (a) CD8(+), CD2(+)CD3(+) (94%); (b) CD8(dim+), CD2(+) CD3(+) (31%) and CD2(+)CD3(-) (52%); and (c) CDS(-), CD2(+)CD3(+) (20%), CD2(+)CD3(-) (58%) and CD2(-)CD3(-) (22%). Analysis of paired NKa marker expression (CD11b and CD56; CD11b and CD57; CD16 and CD57), when correlated with CD3 and CD8, showed that (a) the predominant NKa phenotype of CD3(+)CD4(-)CD8(+) cells was CD11b(-)CD16(-)CD56(-)CD57(-); (b) CD3(+)CD4(-)CD8(dim+) and CD3(+)CD4(-)CD8(-) subpopulations showed CD11b(-)CD16( )CD56(-)CD57(+/-) and CD11b(+/-)CD16(-)CD56(-)CD57(-) composite phenotypes respectively (where - and +/- denote <20% and 21-60%0 NKa(+) positive cells); and (c) the highest proportions of NKa(+) cells were associated with CD3- subpopulations, with composite phenotypes for CD3-CD4-CD8(dim+) and CD3(-)CD4( )CD8(-) components being CD11b(-)CD16(+/-)CD56(+)CD57(+/-) and CD11b(+)CDl6(+)CD56(+)CD57(+/-) (where + denotes >60% NKa(+) cells). Expression of NKa determinants by normal CD4(-) lymphoid subpopulations was thus shown to increase in the order CD3(+)CD8(+) > CD3(+) CD8(dim+) or CD3(+)CD8(-) > CD3( )CD8(dim+) > CD3(-)CD8(-). Studies of TCR chain expression by NKa(+) (CD16/CD56) and NKa(-) subgroups of the CD4(-)CD8(-) fraction additionally showed that the presence of membrane TCRalphadelta (mean 18%) or TCRgammadelta (mean 35%) chains were primarily associated with the NKa(-) component and that virtually all (93%) NKa(+) cells were TCRalphabeta-TCRgammadelta. Examination of CD4(-)CD8(-)NKa(+) cells for the expression of other T-cell associated markers (CD5, CD7 and CD38) also indicated that this NKa(+) LGL-rich fraction could be further subdivided into CD2(+)CD3-CD5(-)CD7(+)CD38(+) and CD2-CD3(-)CD5(-)-CD7(+)CD38(+) subpopulations. PMID- 27456579 TI - Effect of the Choice of Primary Chemotherapy on the Cumulative Length of Stay in Hospital for Multiple Myeloma. AB - The actual use of hospital beds for patients with multiple myeloma was calculated from a randomised trial of primary treatment with either melphalan and prednisone (MP, 66 patients) or intensive combination chemotherapy with vincristine, cyclophosphamide, lomustine, melphalan and methylprednisolone (MOCCA, 64 patients). The survival of the patients was similar in both arms, and the samples, 20 and 32 patients, respectively, were well representative for the whole arms. The average numbers of hospital days were similar fur both arms. For the first year MP 33.2 (SD 27.6) vs. MOCCA 32.1 (SD 19.0), and during the first to 4th years 78.5 (SD 45.9) vs. 67.8 (SD 34.1). For the year of death it was 50.4 (SD 33.1) vii. 36.3 (SD 27.0), respectivelly. Thus the choice of primary chemotherapy whether conventional or more aggressive had no influence on the actual number of in-patient hospital days concerned. When the combination chemotherapy schedule is well tolerated it can be administered just as well on an ambulatory basis or by using it with very short admissions. It seems that the need for inpatient care for patients with multiple myeloma is mostly related to the complications of the disease itself and to intercurrent disorders including infections. PMID- 27456580 TI - Two Additional Acute Nonlymphocytic Leukemia Patients with a Sole Chromosome Abnormality of Trisomy 4. AB - We report two cases of acute nonlymphocytic leukemia (ANLL) in which the circulating leukemic cells showed trisomy of chromosome 4 as the sole cytogenetic abnormality. Trisomy 4 is rarely found in hematopoietic neoplasia and until now the few reported patients had ANLL or myelodysplastic syndrome (MDS). In these two ANLL patients with trisomy 4 (FAB-M2 and M4), we were unable to obtain information on exposure to mutagenic/carcinogenic agents. Furthermore, both of them did not manifest underlying dysplastic changes in the bone marrow and also had cells with a normal karyotype. In addition the presence of cells with trisomy 4 without associated marrow dysplasia indicates that this karyotypic change may also occur in some ANLL patients without preexisting MDS. PMID- 27456581 TI - Congenital Acute Megakaryoblastic Leukaemia in Down's Syndrome. AB - The case of a newborn with Down's syndrome and congenital leukaemia is reported. The malignant white blood cells displayed the CD41 antigen (glycoprotein Ilb/IIIa) identified by monoclonal antibodies HP1-ld and FMC24 and the CD9/p24 antigen identified by monoclonal antibody FMC27. The number of cells in S-phase was 14%, as assessed by the incorporation of 5-bromo 2-deoxyuridine. No other chromosomal abnormalities were identified in addition to 47 XY + 21. The patient died 15 days after the diagnosis, due to Pneumocystis Carinii pneumonia. Post mortem examination showed heavy leukaemic infiltration and cardiac abnormalities including inter-atrial septal defect and a patent Ductus arteriosus. This patient appears to be the first identified case of congenital leukaemia with megakaryocytic differentiation, although previous instances of transient abnormal myelopoiesis with megakaryocytic differentiation have been recorded in Down's syndrome. PMID- 27456583 TI - HSP70 is associated with the severity of inflammation in chronic rhinosinusitis. AB - BACKGROUND: Nasal secretions include cytokines and inflammatory mediators that are involved in the pathogenesis of upper airway inflammation. OBJECTIVE: We tried to find unknown biomolecules that are involved in the pathogenesis of chronic rhinosinusitis (CRS). METHODS: We collected nasal mucosal secretions from patients who were diagnosed as having CRS and who underwent endoscopic sinus surgery. A total of 63 patients who underwent nasal secretion collection were reviewed. Enzyme-linked immunosorbent assay was performed by using nasal lavage samples to evaluate which biomolecules were associated with the severity of inflammation based on the Lund-Mackay score. By using human nasal epithelial cells, we performed Western blot, real-time polymerase chain reaction, and enzyme linked immunosorbent assay to evaluate the secretory mechanism of heat shock protein (HSP) 70. RESULTS: We found that the level of interleukin 8 and HSP70 were significantly associated with the Lund-Mackay score and interleukin 17C, C-X C motif chemokine 10, and HSP27 were not significantly associated. HSP70 was also significantly associated with the surgical outcome of the enrolled patients. Furthermore, we found that exposure to hypoxia and treatment of lipoteichoic acid induced the secretion of HSP70 but that lipopolysaccharide did not induce the secretion of HSP70 in human nasal epithelial cells. CONCLUSION: Our findings indicated that HSP70 might play a role in the pathogenesis of CRS and the possibility of HSP70 as a biomolecule that represents the severity of CRS. PMID- 27456584 TI - Increased expression of the aryl hydrocarbon receptor in allergic nasal mucosa, contributing to chemokine secretion in nasal epithelium. AB - BACKGROUND: Pollutants produced by industrial and traffic-related activities have been linked to allergic responses. These noxious agents induce their effects through the aryl hydrocarbon receptor (AhR). OBJECTIVE: We analyzed the expression and distribution pattern of AhR in normal and allergic nasal mucosa, and cytokine-driven regulation of its expression. The production levels of chemokine in cultured nasal epithelial cells were evaluated after stimulation with AhR ligand. METHODS: The expression levels and distribution pattern of AhR in normal, mild, and moderate-severe persistent allergic nasal mucosa were assessed by using real-time polymerase chain reaction, Western blot, and immunohistochemistry. The expression levels of AhR were determined in cultured nasal epithelial cells treated with T-helper 2 cytokines. In cultured epithelial cells stimulated with 2-(10H-indole-30-carbonyl)-thiazole-4-carboxylic acid methyl ester, the expression levels of granulocyte macrophage colony-stimulating factor, thymus and activation regulated chemokine, macrophage inflammatory protein 1 alpha, monocyte chemotactic protein 1, regulated on activation normal T cell expressed and secreted, eotaxin, and interleukin 8 were measured with real time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Expression of AhR was observed in normal and allergic nasal mucosa where it is distributed in the epithelial layer, submucosal glands, endothelial cells, and inflammatory cells. Its expression levels are increased in allergic nasal mucosa and upregulated after stimulation with T-helper 2 cytokines. The stimulation with 2-(10H-indole-30-carbonyl)-thiazole-4-carboxylic acid methyl ester resulted in increased production of chemokines in cultured epithelial cells. CONCLUSION: Analysis of the study results indicated that increased expression levels of AhR may play a role in the pathogenesis of allergic rhinitis, which contributes to chemokine production in nasal mucosa. PMID- 27456582 TI - Hostility and quality of life among Hispanics/Latinos in the HCHS/SOL Sociocultural Ancillary Study. AB - OBJECTIVE: The purpose of this study was to determine if hostility is associated with physical and mental health-related quality of life (QoL) in US. Hispanics/Latinos after accounting for depression and anxiety. METHODS: Analyses included 5313 adults (62% women, 18-75 years) who completed the ancillary sociocultural assessment of the Hispanic Community Health Study/Study of Latinos. Participants completed the Center for Epidemiological Studies Depression Scale, Spielberger Trait Anxiety Scale, Spielberger Trait Anger Scale, Cook-Medley Hostility cynicism subscale and Short Form Health Survey. In a structural regression model, associations of hostility with mental and physical QoL were examined. RESULTS: In a model adjusting for age, sex, disease burden, income, education and years in the US., hostility was related to worse mental QoL, and was marginally associated with worse physical QoL. However, when adjusting for the influence of depression and anxiety, greater hostility was associated with better mental QoL, and was not associated with physical QoL. CONCLUSIONS: Results indicate observed associations between hostility and QoL are confounded by symptoms of anxiety and depression, and suggest hostility is independently associated with better mental QoL in this population. Findings also highlight the importance of differentiating shared and unique associations of specific emotions with health outcomes. PMID- 27456585 TI - Programmed vaccination may increase the prevalence of asthma and allergic diseases. AB - BACKGROUND: The prevalence of asthma and allergic diseases has risen in recent decades. The etiology of asthma and allergic diseases has not been entirely elucidated. OBJECTIVE: In this study, we investigated the possibility that programmed vaccination in China may have a potential role in asthma and allergic diseases. METHODS: In this animal model, newborn BALB/c mice were randomly divided into three groups: vaccine plus ovalbumin (OVA), OVA, and control. The mice of vaccine plus OVA only group were inoculated with vaccines by following the National Vaccines Inoculation Program in China. Mice of vaccine plus OVA and OVA only groups were sensitized and challenged with OVA. Airway hyperresponsiveness was assessed by lung function and serum interleukin (IL) 4 and interferon (IFN) gamma were measured. RESULTS: The results of lung function showed that mice of the vaccine plus OVA group exhibited an increase in enhanced pause (Penh) compared with that in the OVA group at methacholine concentrations of 6.25 and 12.5 mg/mL (p < 0.05). Serum IL-4 in the vaccine plus OVA group was higher than that in the OVA group (p < 0.01). The serum IFN-gamma level in the OVA group was lower than that in the control group (p < 0.01), and also lower than that in the vaccine plus OVA group (p < 0.05). The ratio of IFN-gamma to IL 4 both in the OVA and vaccine plus OVA group was lower than that in the control group (p < 0.01). CONCLUSIONS: Results of our study indicated that programmed vaccination in China may have a potential role in the prevalence of asthma and allergic diseases by inducing T-helper 2 cytokine expression and may be responsible for the increasing prevalence of asthma and allergic diseases in China. PMID- 27456586 TI - Managing anaphylaxis in the office setting. AB - BACKGROUND: Although the definition of anaphylaxis for clinical use may vary by professional health care organizations and individuals, the definition consistently includes the concepts of a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life-threatening or even fatal. METHODS: In this review, we presented the important topics in the treatment of anaphylaxis in the office setting. This review will discuss triggers and risk factors, clinical diagnosis, and management of anaphylaxis in the office setting. RESULTS: Anaphylaxis in the office setting is a medical emergency. It, therefore, is important to prepare for it, to have a posted, written anaphylaxis emergency protocol, and to rehearse the plan regularly. In this review, we presented the important steps in managing anaphylaxis in the office. Treatment of anaphylaxis should start with epinephrine administered intramuscularly at the first sign of anaphylaxis. Oxygen and intravenous fluids may be needed for moderate-to-severe anaphylaxis or anaphylaxis that is quickly developing or if the patient is unresponsive to the first injection of epinephrine. Antihistamine therapy is considered adjunctive to epinephrine, which mainly relieves itching and urticaria. Corticosteroids, with an onset of action of 4-6 hours, have no immediate effect on anaphylaxis. CONCLUSION: To prevent near-fatal and fatal reactions from anaphylaxis, the patient, the family, and the physician must remember to follow the necessary steps when treating anaphylaxis. In anaphylaxis, there is no absolute contraindication for epinephrine. PMID- 27456587 TI - New allergen sensitization might be associated with increased body mass index in children. AB - BACKGROUND: Results of previous studies have shown a relationship between obesity and allergic diseases. However, concrete evidence about the association between obesity and allergies has been lacking. OBJECTIVE: The present study aimed to evaluate the potential association between body mass index (BMI) and the change in sensitization on skin-prick tests in children over a 2-year follow-up period. METHODS: Children in first and second grade from six elementary schools were recruited in 2010. The same participants, now in third and fourth grade, were recruited again in 2012. The enrolled children underwent skin-prick tests and physical examinations in 2010 and again in 2012. RESULTS: Four hundred fourteen children (boys to girls, 208 to 206) were included. Among 414 participants, 73 children showed new sensitization and 24 children showed negative conversion of allergic sensitization after 2 years. One hundred sixty-one children showed positive results on both tests, and 156 children showed negative results on both tests. The mean (standard deviation) change in BMI (1.09 +/- 1.81 kg/m(2)) over a 2-year follow-up in newly sensitized children was significantly greater than that of other groups (p = 0.008). CONCLUSION: Children who became newly sensitized to allergens tended to exhibit significant increases in BMI. Therefore, further evaluation of the relationship between obesity and allergy is needed. PMID- 27456588 TI - Wogonin inhibits transforming growth factor beta1-induced extracellular matrix production via the p38/activator protein 1 signaling pathway in nasal polyp derived fibroblasts. AB - BACKGROUND: Wogonin has been shown to have antifibrotic and anti-inflammatory effects in the lower airway. The purpose of this study was to evaluate the effects of wogonin on transforming growth factor (TGF) beta1-induced myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction, and to determine the molecular mechanisms of wogonin in nasal polyp-derived fibroblasts (NPDF). METHODS: NPDFs were isolated from nasal polyps from eight patients. TGF-beta1-induced NPDFs were treated with wogonin. Cytotoxicity was evaluated by using a 3-(4,5- dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay. Fibroblast migration was evaluated with transwell and scratch migration assays. The expression levels of alpha-smooth muscle actin, fibronectin, phosphorylated-p38, and c-Fos were determined by Western blot and/or reverse transcription-polymerase chain reaction. The total collagen amount was analyzed with the Sircol collagen assay, and contractile activity was measured by a collagen gel contraction assay. RESULTS: Wogonin (0-60 MUM) had no significant cytotoxic effects on TGF-beta1-induced NPDFs. Migration of NPDFs was significantly inhibited by wogonin treatment. The expression levels of alpha smooth muscle actin and fibronectin were significantly reduced in wogonin-treated NPDFs. Collagen production and contraction were also significantly decreased by wogonin treatment. Wogonin markedly inhibited activation of the p38/activator protein 1 pathway in TGF-beta1-induced NPDFs. CONCLUSION: These results indicated that wogonin may inhibit TGF-beta1-induced myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction through the p38/activator protein-1 pathway in NPDFs. PMID- 27456589 TI - Temporal differences in improvement of nasal obstruction between primary and revision septoplasty. AB - BACKGROUND: Septoplasty is one of most frequently performed surgeries in otorhinolaryngologic clinics to improve nasal obstruction by correcting nasal septal deformities. Many patients require revision surgery for persistent nasal obstruction. However, the outcomes and sources of revision septoplasty are unclear. OBJECTIVE: We investigated the discrepancy between patient's subjective and objective improvements after septoplasty by comparing primary and revision procedures. METHODS: Patients who underwent septoplasty from January 2012 to December 2014 were enrolled. All the subjects were questioned regarding subjective nasal symptoms before surgery and 1 month and every 3 months after surgery, with responses rated on a 7-point Likert scale. Nasal endoscopic evaluation and acoustic rhinometry were also performed with the same schedule. RESULTS: One hundred seventy-nine patients were analyzed. Subjective nasal obstruction scores of both the primary (n = 161) and revision (n = 18) groups were significantly improved at 1 month after surgery and showed no difference between the two groups. However, this improvement was sustained to the last follow-up only in the primary group. The symptom improvement rate of the primary group (85.5% [n = 109]) was significantly higher than that of the revision group (58.8% [n = 10]) at the last follow-up. There was no difference in the degree of improvement in objective findings between the two groups, including the difference and the ratio of the minimal cross-sectional area between the wider and narrower sides, and in endoscopic findings, even at the last follow-up. CONCLUSION: Compared with primary septoplasty, the long-term efficacy of revision septoplasty may not be clear, and there are discrepancies between the subjective and objective outcomes. PMID- 27456591 TI - Changing landscapes stimulate new directions for the AJRA. PMID- 27456590 TI - Respiratory epithelial adenomatoid hamartomas: An increasingly common diagnosis in the setting of nasal polyps. AB - BACKGROUND: Respiratory epithelial adenomatoid hamartomas (REAH) are benign nose neoplasms found in the nasal cavity and sinuses. Symptoms include anosmia, nasal obstruction, facial pressure, and rhinorrhea. Although previously thought to be rare, these tumors are being increasingly recognized on pathology in patients undergoing endoscopic sinus surgery. However, REAH is difficult to diagnose before surgery because it may mimic other entities, such as nasal polyps or inverted papilloma, and is often found incidentally only after surgery. OBJECTIVE: The aims of this study were to (1) add an additional case series of REAH to the literature, (2) report unique imaging findings on computed tomography and magnetic resonance imaging, and (3) pool and summarize all available data from existing publications. METHODS: Retrospective chart review from years 2004 to 2015 and a literature review RESULTS: Twenty-three cases were found in our case series, which included 12 men (52%) and 11 women (48%), with a mean age of 59 years. No cases were found before 2007. Lund-Mackay scores were comparable with those found in chronic rhinosinusitis without nasal polyposis. Imaging consistently demonstrated a discoid-shaped mass at the olfactory cleft. Fifty previous publications were found (4 prospective, 11 retrospective studies, 9 case series, 26 cases reports), which included 660 patients diagnosed with REAH. Pooled data revealed a mean age of 54 years (range, 9-86 years) and a male to female ratio of 3:2. CONCLUSION: The results of our study further refined the average age at which REAH diagnosis occurs as 54 years old, although it may occur at any age. There is a clear male-to-female predominance (3:2). In addition, olfactory cleft widening and discoid soft tissue at the olfactory cleft are hallmark radiographic findings. The vast majority of published cases occurred during the past 4 years, which indicated increased recognition of REAH. PMID- 27456592 TI - Complications of sinusitis. AB - BACKGROUND: Sinusitis is a common disorder associated with significant patient symptomatology that adversely affects quality of life. Sinusitis can cause further morbidity and mortality through its impact on comorbid disorders, progression of inflammation, and extension of infection. OBJECTIVE: This review highlights common complications of acute bacterial rhinosinusitis (ABRS) and chronic rhinosinusitis (CRS). RESULTS: ABRS is complicated by orbital infections, such as pre- or postseptal cellulitis, and by intracranial infections, including abscesses of the epidural and subdural spaces. CRS can contribute to asthma, sleep disordered breathing, and smell disorders. CRS can be complicated by development of allergic fungal rhinosinusitis or deformity of surrounding bony structures. Fungal complications contribute to morbidity and mortality. CONCLUSION: Complications of ABRS, although relatively rare, can cause significant morbidity and mortality, and must be promptly recognized. CRS commonly complicates or drives comorbid diseases, which adversely impacts quality of life. Treatment of these complications often requires coordinated multidisciplinary care. PMID- 27456593 TI - Intact soluble P-glycoprotein is secreted by sinonasal epithelial cells. AB - BACKGROUND: P-glycoprotein (P-gp) is a 170 kDa transmembrane efflux pump, which is upregulated in chronic rhinosinusitis. Studies of leukemia demonstrated that P gp may also be secreted in an intact soluble form. The purpose of this study was to explore whether sinonasal epithelial cells were capable of secreting soluble P gp and whether P-gp has any functional role. METHODS: Soluble and cytoplasmic P gp were quantified in vehicle and lipopolysaccharide exposed cultures by enzyme linked immunosorbent assay. The molecular weight of the soluble P-gp was determined by Western blot. Naive cultures were exposed to recombinant human P-gp at 0-2000 ng/mL. The degree of membranous interpolation was determined by quantitative fluorescent immunocytochemistry and function was determined by a calcein acetoxymethyl ester assay. RESULTS: Soluble P-gp was secreted intact at 170 kDa. Mean (standard deviation) secretion was detected within vehicle wells at 55.43 +/- 26.26 ng/mL, which significantly increased to 333.27 +/- 305.98 ng/mL (p < 0.001) after lipopolysaccharide stimulation. Soluble P-gp strongly and significantly correlated with cytoplasmic P-gp (r = 0.57, p = 0.000001). Exposure to 2000 ng/mL of recombinant P-gp significantly increased corrected total cell fluorescence (1.34 +/- 1.85) relative to vehicle control 0.29 +/- 0.26 (p = 0.01) and significantly reduced calcein acetoxymethyl ester fluorescence (82.03 +/- 43.69) relative to 100 ng/mL recombinant P-gp exposed cells (123.11 +/- 42.16, p = 0.001). CONCLUSION: Cultured sinonasal epithelial cells were able to both secrete intact P-gp and could functionally interpolate soluble P-gp into their cell membrane. These in vitro findings indicated that soluble P-gp may be present in nasal mucus as a biomarker and could participate in the maintenance of P-gp overexpression in chronic rhinosinusitis and associated inflammation. PMID- 27456594 TI - Burden of illness: A systematic review of depression in chronic rhinosinusitis. AB - BACKGROUND: Depression has been reported in patients with chronic rhinosinusitis (CRS), but its prevalence varies across studies, and uncertainty remains regarding the association with baseline disease severity and treatment outcomes. OBJECTIVE: To systematically assess the prevalence of depression in CRS and to review its relationship to baseline disease severity and outcomes after treatment. METHODS: A systematic review of the prevalence of possible depression was performed by using the available methods to diagnose depression, and the results were pooled. Studies that examined the relationship of depression on baseline disease severity and treatment outcomes were organized and reported individually. RESULTS: Thirteen studies met inclusion criteria for prevalence analysis. The prevalence of possible or likely depression in patients with CRS ranged from 11.0 to 40.0%, depending on the method of diagnosis and sensitivity of various depression instruments. Positive depression screening was consistently associated with worse CRS-specific quality of life (QOL), medication usage, and health care utilization, but there were no reliable CRS-specific factors to predict the presence of depression. Patients with possible depression who underwent medical or surgical treatment for CRS tended to have improvements in CRS-specific QOL but did not achieve the same degree of QOL as patients who were not depressed. Depression-specific QOL seemed to improve after treatment for CRS. CONCLUSION: Positive depression screening was common in patients with CRS and had a negative association on the entire spectrum of QOL, health care utilization, and productivity. CRS-specific treatments were still beneficial in patients who seemed to be depressed and improved both depression-specific and CRS-specific QOL. PMID- 27456595 TI - Association of oral flora with orbital complications of acute sinusitis. AB - BACKGROUND: Acute and chronic sinusitis in children and adults can spread to the orbit. Oral flora has been seen in orbital infections, but the extent of synergy between pathogens in such infections remains unknown. METHODS: A retrospective case series of patients with complicated sinusitis that involved the orbit from acute sinusitis who were admitted to a tertiary care hospital from January 2000 to December 2014 and who had surgical cultures obtained. Patients were identified by the International Classification of Diseases, Ninth Revision code for periorbital cellulitis, subperiosteal abscess, or orbital abscess. RESULTS: Sixteen patients underwent surgical drainage via external drainage or endoscopic sinus surgery of an orbital infection associated with sinusitis and had cultures obtained. Nine patients (56%) grew organisms that exist in oral flora, whereas seven patients (44%) grew common respiratory pathogens. The most common organisms recovered were viridans group streptococcus (VGS) (50%), Staphylococcus aureus (31%), Eikenella corrodens (25%), and Prevotella species (19%). Oral flora anaerobes were cultured alongside a VGS species in seven of eight patients (88%) as opposed to the respiratory pathogens, which were less frequently associated with concomitant VGS infection (29%) (p = 0.04). CONCLUSION: There are two main sources for infectious orbital complications from acute sinusitis: respiratory pathogens and oral flora. The high prevalence of concurrent anaerobic oral flora and VGS infection supports a suspected synergy between VGS and other oral organisms. PMID- 27456597 TI - A clinical trial of a microcrystalline cellulose topical nasal spray on the acute response to allergen challenge. AB - BACKGROUND: Allergic rhinitis is a common disorder that leads to a negative impact on quality of life. Multiple options are available for treatment of the symptoms, but preventing the reaction should be an effective strategy. OBJECTIVE: We tested a nasal spray that contained microcrystalline cellulose designed to limit airborne allergens from penetrating the nasal mucosa (nasal blocker) and, therefore, prevent the initiation of the allergic reaction. METHODS: We performed a randomized, double-blind, placebo-controlled, two-way crossover clinical trial with 20 subjects who had a history of seasonal grass and/or ragweed allergy symptoms. Each subject underwent two separate nasal challenges with antigen (provocations) after application of the investigational product or placebo to both nostrils. The allergen was delivered into one nostril at a time and was administered at 2-hour intervals (identified as challenge 1 and challenge 2). We assessed peak nasal inspiratory flow and total nasal symptoms as well as the number of sneezes recorded at both 15-minute and 1-hour intervals after challenge 1 and, later, challenge 2. After a washout period, the subjects returned to undergo the alternate therapy. RESULTS: There was a significant overall decrease in peak nasal inspiratory flow after both treatments (investigational product, p = 0.005; placebo, p = 0.001), but, when the average of the change from baseline in peak nasal inspiratory flow was compared with the baseline, the results showed no significant differences between the groups (p = 0.31). Similar results were obtained for total nasal symptoms. CONCLUSION: The investigational product did not prove to be significantly better than placebo in treating seasonal allergic rhinitis symptoms. PMID- 27456596 TI - In vitro effects of anthocyanidins on sinonasal epithelial nitric oxide production and bacterial physiology. AB - BACKGROUND: T2R bitter taste receptors play a crucial role in sinonasal innate immunity by upregulating mucociliary clearance and nitric oxide (NO) production in response to bitter gram-negative quorum-sensing molecules in the airway surface liquid. Previous studies showed that phytochemical flavonoid metabolites, known as anthocyanidins, taste bitter and have antibacterial effects. Our objectives were to examine the effects of anthocyanidins on NO production by human sinonasal epithelial cells and ciliary beat frequency, and their impact on common sinonasal pathogens Pseudomonas aeruginosa and Staphylococcus aureus. METHODS: Ciliary beat frequency and NO production were measured by using digital imaging of differentiated air-liquid interface cultures prepared from primary human cells isolated from residual surgical material. Plate-based assays were used to determine the effects of anthocyanidins on bacterial swimming and swarming motility. Biofilm formation and planktonic growth were also assessed. RESULTS: Anthocyanidin compounds triggered epithelial cells to produce NO but not through T2R receptors. However, anthocyanidins did not impact ciliary beat frequency. Furthermore, they did not reduce biofilm formation or planktonic growth of P. aeruginosa. In S. aureus, they did not reduce planktonic growth, and only one compound had minimal antibiofilm effects. The anthocyanidin delphinidin and anthocyanin keracyanin were found to promote bacterial swimming, whereas anthocyanidin cyanidin and flavonoid myricetin did not. No compounds that were tested inhibited bacterial swarming. CONCLUSION: Results of this study indicated that, although anthocyanidins may elicited an innate immune NO response from human cells, they do not cause an increase in ciliary beating and they may also cause a pathogenicity-enhancing effect in P. aeruginosa. Additional studies are necessary to understand how this would affect the use of anthocyanidins as therapeutics. This study emphasized the usefulness of in vitro screening of candidate compounds against multiple parameters of both epithelial and bacterial physiologies to prioritize candidates for in vivo therapeutic testing. PMID- 27456598 TI - Three-dimensional printing of large nasal septal perforations for optimal prosthetic closure. AB - BACKGROUND: Since 1972, patients with large nasal perforations, who were symptomatic, and who were not candidates for surgery, had the option of custom prosthetic closure at Mayo Clinic. Although septal prostheses have helped many patients, 27% of pre-1982 patients chose not to keep the prosthesis in place. Two dimensional computed tomography (CT) sizing resulted in more of the patients choosing to retain the prosthesis. The introduction of three-dimensional (3-D) printing to the sizing process offered the potential of further improved retention by refinement in prosthesis fit. OBJECTIVE: To describe the fabrication of nasal septal prostheses by using 3-D printing for sizing and to compare the retention rate of 3-D-sized prostheses with those that used previous sizing methods. METHODS: Twenty-one consecutive patients who had placement of septal prostheses sized by using 3-D printed templates were studied. CT image data were used to print 3-D templates of the exact shape of the patient's septal perforation, and medical-grade silastic prostheses were fabricated to fit. In four cases, the 3-D printed template allowed preoperative surgical simulation. Metrics collected included prosthesis retention; symptoms, including intranasal crusting and epistaxis; and previous prosthetic closure failures. RESULTS: Twenty of the twenty-one patients had improvement in symptoms. The mean diameter of the perforations was 2.4 cm; the mean closure time by the end of the study period was 2.2 years. All but two patients chose to keep their prosthesis in place, for a retention rate of 90%. Seven patients with successful closure had failed previously with prior prosthesis sized without the current 3-D printing methodology. This 90% retention rate exceeded the previous rates before the introduction of 3-D sizing. CONCLUSION: Sizing done by 3-D printing for prosthetic closure of nasal septal perforations resulted in a higher retention rate in helping patients with these most-challenging nasal septal perforations. PMID- 27456599 TI - Cerebrospinal fluid rhinorrhea secondary to idiopathic intracranial hypertension: Long-term outcomes of endoscopic repairs. AB - BACKGROUND: Endoscopic endonasal repair of cerebrospinal fluid (CSF) rhinorrhea secondary to idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri or benign intracranial hypertension, has varying success rates, from 25-87%, with minimal morbidity. However, often these series have a relatively short-term follow-up. Given the pathophysiology of IIH, long-term follow-up is necessary to identify true CSF leak recurrence rates. Our investigation aimed to evaluate long-term outcomes in endoscopically repaired CSF leaks. METHODS: A retrospective chart review of all the patients with CSF rhinorrhea due to IIH who met inclusion criteria between 1996 and 2009. Outcome measures included the following: demographics, intracranial pressure, location of skull base defect, presence of encephalocele and/or meningoencephalocele, surgical repair technique, treatment with acetazolamide, whether a ventriculoperitoneal shunt was inserted, location of recurrence, history of meningitis or previous sinus surgery, and duration of follow-up. RESULTS: Thirty two patients with a total of 44 skull base defects were reviewed over a mean follow-up of 10.2 years. The mean body mass index and intracranial pressure were 36.8 kg/m(2) and 27.7 cm H2O, respectively. Seven patients (18%) required revision surgery at the same site or a distant site. We found no statistical significance that identified the recurrence risk in the outcome measurements most likely due to our small failure rate. However, early recurrences were noted to recur at the same repair site, whereas late recurrences were noted to recur at a distant site along the skull base. CONCLUSION: IIH is an increasingly recognized entity treated by otorhinolaryngologists. We present the first long-term IIH CSF leak repair series. Long-term follow-up is necessary because delayed CSF leaks occur in this population. PMID- 27456600 TI - Considerations in the management of giant frontal mucoceles with significant intracranial extension: A systematic review. AB - BACKGROUND: Giant frontal mucoceles, characterized by significant intracranial and/or intraorbital extension, can present with significant neurologic symptoms. Although typical mucoceles are managed endoscopically, giant mucoceles are often treated with an open or combined approach due to various concerns, including frontal lobe displacement, size, and rapid decompression of the intracranial component. The impact of significant intracranial extension on outcomes is not well described. OBJECTIVE: This review studied key neurologic considerations in the management of giant frontal sinus mucoceles and analyzed outcomes of different management strategies. METHODS: Systematic literature review by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Thirty-two articles, which represented 85 cases, met inclusion criteria. Neurologic symptoms on presentation ranged from headache (24.7%) and vision loss (12.9%) to extremity weakness (1.2%), frontal lobe syndrome (2.4%), and seizures (4.7%). Twenty-eight patients were treated endoscopically (34.1%), and 54 (65.9%) were treated with an external approach. Twenty-five of the open procedures included a craniotomy. Indications for the open approach included subdural empyema, enucleation, or large anterior table defects. Perioperative antibiotics were not consistently used. No perioperative seizures were reported with any approach. There were six cerebrospinal fluid leaks, all in the patients who underwent open procedures. The overall recurrence rate was 3.5%, with no recurrences reported in patients treated with an open approach. Follow-up ranged from 1 week to 8 years. CONCLUSIONS: Giant frontal mucoceles often present with various neurologic symptoms. Both open and endoscopic techniques offer excellent results. Endoscopic management is effective and preferred, except in special circumstances. An interdisciplinary team approach should be used to optimize surgical planning. PMID- 27456601 TI - A comparison of radiographic evidence of frontal sinusitis in middle-turbinate sacrificing versus middle-turbinate sparing approaches to the sella. AB - BACKGROUND: Initial descriptions of endoscopic approaches to the sella and pituitary involved resecting the middle turbinate (MT) to help improve access and visualization. Modifications of these procedures to preserve the MT have since been described, one rationale being to reduce the incidence of frontal sinusitis. The objective of this study was to establish the incidence of postoperative frontal sinusitis in MT sparing (MTsp) and MT sacrificing (MTsc) approaches to the sella. OBJECTIVE: A retrospective cohort study that compared radiographic evidence of frontal rhinosinusitis or frontal recess obstruction after skull base surgery in patients who underwent MTsc and MTsp endonasal approaches to the sella. METHODS: Consecutive retrospective review of pre- and postoperative magnetic resonance imaging from two institutions in geographic proximity but with different approaches to the sella. Mucosal thickening in the frontal sinus was measured and graded by a radiologist blinded to patient cohorts. RESULTS: Seventy five patients, based on sample size calculations, were included at each site. Baseline demographics and indications for surgery were not significantly different between the groups. No difference was seen between the groups in the overall grade of radiographic frontal sinusitis seen on postoperative imaging. A total of 8 patients (10%) in the MTsc group had measured mucosal thickening, which was increased from their preoperative scan versus 15 in the MTsp group (20%) (p = 0.10). New mucosal thickening of >1 mm was found in three patients in the MTsc group and eight patients in the MTsp group (p = 0.21); the only patient with postoperative complete frontal sinus opacification was in the MTsp group. CONCLUSIONS: The choice of MTsc versus MTsp in endonasal endoscopic approach to the sella does not seem to make a difference in the incidence of postoperative radiographic frontal sinusitis. PMID- 27456602 TI - Comparison of the aesthetic results of two common incisions in external rhinoplasty: A randomized trial. AB - OBJECTIVE: To compare the scar outcomes of two common incisions (inverted V and stair step) by using a validated scar-outcome instrument via a randomized clinical trial. METHODS: Fifty-eight consecutive cases of external rhinoplasty were randomly divided into two groups according to the type of incision. These patients were followed-up for 1 year, and the columellar scar was analyzed by using the Stony Brook Scar Evaluation Scale (SBSES) and visual analog scale (VAS) scores by an independent reviewer. RESULTS: Of 58 patients, 28 received the inverted V and the rest received the stair-step incision. Thirty-four participants (58.6%) were women. The mean (standard deviation) age of the participants was 26.2 +/- 6.6 years. After 1 month, the scar outcome was significantly better in patients with the stair-step incision (p = 0.001) by using the SBSES, but the same was not true after 1 year (p = 0.425). However, when the VAS instead of the SBSES was used to evaluate the scar, the inverted V received a better score after 12 months in this series (p = 0.005). CONCLUSION: Despite the better aesthetic outcome of the stair-step incision in the first month after the surgery, there was no significant difference between the two incisions after 1 year. However, in this series, when the VAS instead of the SBSES was used to evaluate the scar, the inverted V received a better score after 12 months. PMID- 27456603 TI - Otolaryngology. PMID- 27456604 TI - Gastro-splenic fistula as a complication of chemotherapy for large B cell lymphoma. AB - AIM: Gastro-splenic fistula is a rare entity in which malignant tumors are the primary cause, followed by perforated peptic ulcers and Crohn's disease. CASE REPORT: A 66 years old patient undergoing chemotherapy for gastric large cells B lymphoma presented fever, fatigue and worsening of general conditions. A CT scan showed the presence of an abdominal abscess resulting from a pathological communication between stomach and spleen. RESULTS: En - bloc splenectomy and gastric wedge resection was performed; gastric wall was sutured with a linear stapler. Postoperative stay was uneventful; alimentation was restarted 5 days after the surgical procedure, and the patient was discharged 2 days later CONCLUSION: We have described an unusual case of gastric fistula complicating chemotherapy early diagnosed and successfully treated. KEY WORDS: Chemothera Gastrosplenic fistula, Lymphoma, Surgery. PMID- 27456606 TI - The methylsulfinyl radical CH3SO examined. AB - Methylsulfinyl radical, a key intermediate in marine atmospheric chemistry, plays a central role in the oxidation of dimethyl sulfide. CH3SO has been extensively studied here with ab initio quantum mechanical methods, with methods as complete as CCSDT(Q) in conjunction with basis sets as large as cc-pV(5+d)Z. In this research, we report high-level computations for the ground and first excited electronic states of the methylsulfinyl radical. The structures of the X[combining tilde] (2)A'' and A (2)A' states are quite different with S-O distances of 1.499 and 1.652 A, respectively. The X[combining tilde] to A adiabatic energy difference is predicted to be 45.1 kcal mol(-1), compared to 21.1 kcal mol(-1) for the analogous well-characterized methylperoxy radical CH3OO. The CH3SO barrier to internal rotation is 0.92 kcal mol(-1). The unknown X[combining tilde] (2)A'' torsional vibrational frequency tau is predicted to be 142 cm(-1) (harmonic) and 128 cm(-1) (anharmonic). Our predictions of the A (2)A' excited state vibrational frequencies are the first to be reported. PMID- 27456605 TI - Genetic architecture dissection by genome-wide association analysis reveals avian eggshell ultrastructure traits. AB - The ultrastructure of an eggshell is considered the major determinant of eggshell quality, which has biological and economic significance for the avian and poultry industries. However, the interrelationships and genome-wide architecture of eggshell ultrastructure remain to be elucidated. Herein, we measured eggshell thickness (EST), effective layer thickness (ET), mammillary layer thickness (MT), and mammillary density (MD) and conducted genome-wide association studies in 927 F2 hens. The SNP-based heritabilities of eggshell ultrastructure traits were estimated to be 0.39, 0.36, 0.17 and 0.19 for EST, ET, MT and MD, respectively, and a total of 719, 784, 1 and 10 genome-wide significant SNPs were associated with EST, ET, MT and MD, respectively. ABCC9, ITPR2, KCNJ8 and WNK1, which are involved in ion transport, were suggested to be the key genes regulating EST and ET. ITM2C and KNDC1 likely affect MT and MD, respectively. Additionally, there were linear relationships between the chromosome lengths and the variance explained per chromosome for EST (R(2) = 0.57) and ET (R(2) = 0.67). In conclusion, the interrelationships and genetic architecture of eggshell ultrastructure traits revealed in this study are valuable for our understanding of the avian eggshell and contribute to research on a variety of other calcified shells. PMID- 27456607 TI - A family study of DRD3 rs6280, SLC1A2 rs3794087 and MAPT rs1052553 variants in essential tremor. AB - BACKGROUND/OBJECTIVE: Despite many data suggesting a role of genetic factors in the risk for essential tremor (ET), the responsible genes have not been identified. We analyzed in ET Spanish families three single nucleotide polymorphisms (SNPs): DRD3 rs6280, SLC1A2 rs3794087, and MAPT rs1052553) previously related to an increased risk for developing the disease. METHODS: We recruited 45 subjects with ET and 13 subjects without tremor belonging to 11 families who were evaluated because of familial tremor. Diagnosis of probable or definite ET was done according to TRIG criteria. Genotyping of the 3 SNPs was done using TaqMan-based qPCR assays. Data were compared with those of healthy controls of our laboratory. Family-based association testing for disease traits was performed as well. RESULTS: rs6280 and rs3794087 genotype and allelic frequencies did not differ significantly between subjects with ET and healthy controls. However, rs1052553AA genotype and the allele rs1052553A allele were significantly more frequent among ET patients. rs1052553A allele was non significantly overrepresented in ET patients compared with controls when considering only the more severely affected member of each ET family. Family based association test for disease traits showed lack of association between ET and the three SNPs studied. CONCLUSIONS: Our results showed a lack of association between rs6280 and rs3794087 with the risk for ET, though a marginal increased risk for ET was observed among the rs1052553A allele carriers, which was not confirmed with a family-based association study. PMID- 27456608 TI - Borrmann Type 4 Advanced Gastric Cancer: Focus on the Development of Scirrhous Gastric Cancer. AB - Early diagnosis of Borrmann type 4 advanced gastric cancer (AGC) is very important for improving the prognosis of AGC patients. Because there is no definite mass in most cases of Borrmann type 4 AGC, its accurate diagnosis via endoscopy requires an understanding of its pathogenesis and developmental process. Moreover, many people confuse linitis plastica (LP) type gastric cancer (GC), scirrhous GC, and Borrmann type 4 AGC. To distinguish each of these cancers, knowledge of their endoscopic and pathological differences is necessary, especially for LP type GCs in the developmental stage. In conclusion, diagnosis of pre-stage or latent LP type GC before progression to typical LP type GC requires the detection of IIc-like lesions in the fundic gland area. It is also crucial to identify any abnormalities such as sclerosis of the gastric wall and hypertrophy of the mucosal folds during endoscopy. PMID- 27456609 TI - How to Interpret the Pathological Report before and after Endoscopic Submucosal Dissection of Early Gastric Cancer. AB - Possible lymph node metastasis (LNM) and residual cancer are major concerns in endoscopic submucosal dissection (ESD) for early gastric cancer. To reduce the risk of LNM and cancer recurrence, the proper indications for ESD should be considered. Histology, size, depth of invasion, and presence of ulceration should be thoroughly evaluated before proceeding with ESD. However, with incomplete information, discrepancies often arise between the pathological diagnosis based on the forceps biopsy and that based on the totally resected specimen. In addition, the presence of lymphovascular involvement and histological homogeneity can be clarified only after ESD. If the pathological diagnosis changes after ESD, we should reevaluate the curativeness and reformulate the goal of treatment. Additional surgery is a reasonable strategy for non-curative ESD, but a patient's other health conditions should also be considered. It is simple to read pathological reports before and after ESD, but it can be a complicated art to interpret the report and formulate an optimal approach. In this review, various considerations regarding the pathological diagnosis will be discussed. PMID- 27456612 TI - Visible-Light Photoredox Catalyzed Three-Component Cyclization of 2H-Azirines, Alkynyl Bromides, and Molecular Oxygen to Oxazole Skeleton. AB - A novel three-component cyclization of 2H-azirines, alkynyl bromides, and molecular oxygen under visible-light photoredox catalysis at room temperature has been developed, which provides a direct approach to a wide range of substituted oxazoles in moderate to good yields. PMID- 27456610 TI - Theoretical exploration of the mechanism of formylmethanofuran dehydrogenase: the first reductive step in CO2 fixation by methanogens. AB - A theoretical exploration of the possible active site models of methanofuran dehydrogenase reveals that the free energy of the reduction of the carbamate group is substantially negative and is driven by the electron withdrawing amide group next to the carbonyl carbon. Comparison of the computed transition state energies with the experimental energy barrier indicates that the active site is likely to have an axial oxo and equatorial hydrosulfide ligand, the substrate is likely to be protonated and a second-sphere hydrogen-bonding interaction with the axial ligand can, substantially, lower the barrier of this reaction which involves reduction of the carbonyl center of the a carbamate to form an N-formyl group via a hydride shift from a Mo(IV) center. PMID- 27456611 TI - Perception of the plant hormone ethylene: known-knowns and known-unknowns. AB - The gaseous phytohormone ethylene is implicated in virtually all phases of plant growth and development and thus has a major impact on crop production. This agronomic impact makes understanding ethylene signaling the Philosopher's Stone of the plant biotechnology world in applications including post-harvest transport of foodstuffs, consistency of foodstuff maturity pre-harvest, decorative flower freshness and longevity, and biomass production for biofuel applications. Ethylene is biosynthesized by plants in response to environmental factors and plant life-cycle events, and triggers a signaling cascade that modulates over 1000 genes. The key components in the perception of ethylene are a family of copper dependent receptors, the bioinorganic chemistry of which has been largely ignored by the chemical community. Since identification of these receptors two decades ago, there has been tremendous growth in knowledge in the biological community on the signal transduction pathways and mechanisms of ethylene signaling. In this review, we highlight these advances and key chemical voids in knowledge that are overdue for exploration, and which are required to ultimately regulate and control ethylene signaling. PMID- 27456613 TI - Biomimetic Porous PLGA Scaffolds Incorporating Decellularized Extracellular Matrix for Kidney Tissue Regeneration. AB - Chronic kidney disease is now recognized as a major health problem, but current therapies including dialysis and renal replacement have many limitations. Consequently, biodegradable scaffolds to help repairing injured tissue are emerging as a promising approach in the field of kidney tissue engineering. Poly(lactic-co-glycolic acid) (PLGA) is a useful biomedical material, but its insufficient biocompatibility caused a reduction in cell behavior and function. In this work, we developed the kidney-derived extracellular matrix (ECM) incorporated PLGA scaffolds as a cell supporting material for kidney tissue regeneration. Biomimetic PLGA scaffolds (PLGA/ECM) with different ECM concentrations were prepared by an ice particle leaching method, and their physicochemical and mechanical properties were characterized through various analyses. The proliferation of renal cortical epithelial cells on the PLGA/ECM scaffolds increased with an increase in ECM concentrations (0.2, 1, 5, and 10%) in scaffolds. The PLGA scaffold containing 10% of ECM has been shown to be an effective matrix for the repair and reconstitution of glomerulus and blood vessels in partially nephrectomized mice in vivo, compared with only PLGA control. These results suggest that not only can the tissue-engineering techniques be an effective alternative method for treatment of kidney diseases, but also the ECM incorporated PLGA scaffolds could be promising materials for biomedical applications including tissue engineered scaffolds and biodegradable implants. PMID- 27456615 TI - Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes. PMID- 27456616 TI - Untangling the Knot in Diabetic Nephropathy: The Unanticipated Role of Glycocalyx in the Antiproteinuric Effect of Endothelin Receptor Antagonists. PMID- 27456617 TI - Endothelium-Derived Hyperpolarizing Factors: A Potential Therapeutic Target for Vascular Dysfunction in Obesity and Insulin Resistance. PMID- 27456618 TI - Defective Invariant Natural Killer T-Cell Suppression in Patients With Type 1 Diabetes. PMID- 27456619 TI - DPP-4 Inhibition and the Known Unknown. PMID- 27456620 TI - Uncovering a Mineralocorticoid Receptor-Dependent Adipose-Vascular Axis: Implications for Vascular Dysfunction in Obesity? PMID- 27456621 TI - The Immune Pathogenesis of Type 1 Diabetes: Not Only Thinking Outside the Cell but Also Outside the Islet and Out of the Box. PMID- 27456622 TI - Expression of Concern. Transcription Factor 7-Like 2 Regulates beta-Cell Survival and Function in Human Pancreatic Islets. Diabetes 2008;57:645-653. DOI: 10.2337/db07-0847; and erratum. Diabetes 2014;63:3974. DOI: 10.2337/db14-er11. PMID- 27456623 TI - Expression of Concern. Low Concentration of Interleukin-1beta Induces FLICE Inhibitory Protein-Mediated beta-Cell Proliferation in Human Pancreatic Islets. Diabetes 2006;55:2713-2722; DOI: 10.2337/db05-1430. PMID- 27456624 TI - Statement of Retraction. Hepatic Glucagon Action Is Essential for Exercise Induced Reversal of Mouse Fatty Liver. Diabetes 2011;60:2720-2729. DOI: 10.2337/db11-0455. PMID- 27456626 TI - Comment on Alarcon et al. Pancreatic beta-Cell Adaptive Plasticity in Obesity Increases Insulin Production but Adversely Affects Secretory Function. Diabetes 2016;65:438-450. PMID- 27456627 TI - Coming in sportsmedicine. PMID- 27456628 TI - Scanning sports. PMID- 27456629 TI - A Singular Approach to Ethics. PMID- 27456630 TI - Brief reports. PMID- 27456634 TI - noteworthy. PMID- 27456633 TI - Drug Testing and Moral Responsibility. PMID- 27456636 TI - Back to the Bike. PMID- 27456635 TI - Sportsmedicine forum. PMID- 27456637 TI - Comparative Training Responses to Rope Skipping and Jogging. AB - In brief: It has been suggested that ten minutes of rope skipping is equal to 30 minutes of jogging for improved cardiovascular efficiency. This study compared physiological adaptations to six-week programs of jogging and rope skipping. Twenty-six sedentary volunteers (17 women and nine men) aged 18 to 35 years were assigned to a jogging, rope-skipping, or control group. Training frequency was five times per week; each session was 30 minutes for the jogging group and ten minutes for the rope-skipping groups. Significant differences (p <.05) in o2 max were observed in each group. o2 max increased 5.1 ml. kg(-1). min(-1) for the jogging group (13%) and 2.8 ml. kg(-1). min(-1) for the rope-skipping group (7%). The rope-skipping group had higher injury and drop-out rates. It was concluded that ten minutes of rope skipping does not elicit a training response comparable to 30 minutes of jogging. PMID- 27456638 TI - Cocaine and Cardiovascular Events. AB - In brief: The recent deaths of two prominent athletes indicated cocaine's ability to precipitate serious cardiovascular events. This case report and brief literature review provide further evidence of the drug's potential cardiovascular effects. The authors report the case of a 21-year-old man who suffered a myocardial infarction (Ml) after using cocaine and amphetamines. Coronary spasm resulting from the drug abuse was the probable mechanism. Since 1982, at least 14 other persons have suffered MI after cocaine use. Because of the widespread abuse of cocaine, it should be considered a possible factor when cardiovascular events occur in otherwise healthy persons. PMID- 27456639 TI - An Inflammatory Fibroma of the Gingiva Secondary to a Poorly Fitting Athletic Mouth Protector. AB - In brief: Improved materials and fabrication techniques have enhanced the quality of athletic mouth guards, which are available in three types: custom-made, mouth formed, and stock (ready-made). In addition, increased participation by dental schools and societies has resulted in greater availability of mouth protectors. However, problems still exist. This case report involves an athlete who sustained a lesion (most commonly known as an inflammatory fibroma) from wearing an ill fitting mouth-formed protector. PMID- 27456640 TI - Nutrition Behaviors of University Majorettes. AB - In brief: The eating behaviors of a group of university majorettes and the effects of nutrition counseling on the majorettes were examined. At the start of the football season, 11 varsity majorettes received nutrition counseling and were interviewed to obtain 24-hour diet reports and information about their eating behaviors and weight-control practices. The interviews were repeated eight weeks later. The women all had distorted body images. Despite the counseling, the subjects ate poorly and used other unsound weight-loss practices in an effort to meet arbitrary target weights set by a faculty advisor. The health implications of these practices are discussed and remedial actions are suggested. PMID- 27456641 TI - Nutrition Assessment of College Wrestlers. AB - In brief: The authors used diet recall, a food record, a written test, interviews, questionnaires, and anthropometry to examine the nutrition and weight control practices and knowledge of 42 wrestlers from two college teams. Data were collected before, during, and after the wrestling season. During the season, many of the wrestlers did not meet two thirds of the recommended dietary allowance for calories, protein, vitamins C, A, B6, and thiamine, iron, zinc, and magnesium, though their diets were more adequate before and after the season. The wrestlers, who lacked a good understanding of nutrition, relied primarily on food restriction and dehydration to lose weight; some also used vomiting, laxatives, and diuretics. PMID- 27456642 TI - Organizing Sports Medicine Coverage at the Canada Summer Games. AB - In brief: This article documents the experience with medical coverage for the 1985 Canada Summer Games to help determine the demands of caring for athletes at this level of competition. A total of 599 medical and physiotherapy treatments were given to the 339 members of the British Columbian team (including 20 mission staff) during the two weeks of the games. Most treatments were carried out in the clinic by physiotherapists, suggesting that athletes were seen more frequently for chronic musculoskeletal complaints than for acute medical emergencies. However, physicians responsible for on-site care must be equipped to treat conditions ranging from corneal abrasions to acute head or neck injuries. PMID- 27456643 TI - Stimulants and Athletic Performance (Part 1 of 2): Amphetamines and Caffeine. AB - In brief: Some athletes use amphetamines and caffeine to fight fatigue, but the effects of these substances on athletic performance are unclear. Both can be harmful. Amphetamines affect the central nervous system (CNS) and can cause tremulousness, anxiety, insomnia, and fever. Caffeine can increase free fatty acid utilization, mask fatigue through CNS stimulation, and increase the force of skeletal muscle contraction. The International Olympic Committee has banned the use of amphetamines altogether, and has banned caffeine when its values are greater than 15 MU g. ml(-1) in a urine test. PMID- 27456644 TI - Sickle Cell Trait, Exercise, and Altitude. AB - In brief: Sickle cell trait is generally benign and does not shorten life, but it may confer some risk with extremes of exercise or altitude. For example, the risk of splenic infarction at mountain altitudes is small but real, and exists for whites as well as for blacks. In contrast, the risk of exercise-related death may not be increased for persons with sickle cell trait; there is still no cogent evidence that the trait predisposes to exertional rhabdomyolysis or death. It is important to realize that sickle cell trait is no barrier to outstanding athletic performance, and that athletes with the trait should take the same precautions as any other athletes-no more, no less. PMID- 27456645 TI - Lack of Influence of the Menstrual Cycle on Blood Lactate. AB - In brief: Some female athletes report that i their performance varies between phases of the menstrual cycle, and some may use oral contraceptives to modify their cycles. To determine if energy metabolism varies across the cycle, the author examined the response of blood lactate to 60 minutes of moderate intensity, steady-state exercise during the beginning (early follicular phase) and near the end (midluteal phase) of the menstrual cycle. Lactate increased during exercise in both phases, but it did not differ significantly between phases. The author concluded that the menstrual cycle exerts no effect on blood lactate concentration during moderate-intensity, steady-state exercise. PMID- 27456646 TI - Anabolic Steroids: An Australian Sports Physician Goes Public. AB - One well-known Australian sports medicine physician openly admits prescribing anabolic steroids for adult athletes who demand them. His maverick stand has caused a stir in the sports medicine hierarchy. PMID- 27456648 TI - The US Navy Seal Team: Total Commitment to Total Fitness. AB - The special warfare elite of the US Navy may well be some of the finest natural athletes around-and some of the most interesting sports medicine cases as well. PMID- 27456647 TI - Do Anabolic Steroids Pose an Ethical Dilemma for US Physicians? AB - Should physicians prescribe anabolic steroids to athletes who hope to enhance their performance, and/or should they monitor those athletes? Most physicians who are willing to talk say no to the former and maybe to the latter. PMID- 27456649 TI - Luge Participation is Hard on the Head. AB - Olympic luge athletes frequently have postrace headaches, but the cause and cure are not well understood. PMID- 27456650 TI - Sports Medicine Groups 1986. AB - Last year THE PHYSICIAN AND SPORTSMEDICINE published a list Of professional organizations that represented the growing diversity in the field of sports medicine. The list has been updated, and we've added a list of resource groups and committees that generate sports medicine information. While THE PHYSICIAN AND SPORTSMEDICINE does not endorse any of the groups listed, we do encourage you to contact ones that interest you. Organizations are arranged alphabetically within the two lists. When appropriate, we have given the name of an administrative head along with the chief elected officer. Ali correspondance should be addressed to the organization. Organizations with an emphasis in sports medicine that wish to be added to these lists Should contact THE PHYSICIAN AND SPORTSMEDICINE, Organizations Project, 4530 W 77th St, Minneapolis 55435. PMID- 27456651 TI - Calorie Supplements for Athletes. PMID- 27456652 TI - Coed Football: Hazards, Implications, and Alternatives. AB - Should teenage girls be allowed to play football with boys? The author examines data on male-female differences in size, speed, and strength. He concludes that the sport is too dangerous for most girls-and a good many boys as well-and proposes a preparticipation screening program with equal requirements for aspiring players of both sexes. PMID- 27456653 TI - Abstracts at a glance. PMID- 27456654 TI - What Is Cellulite? PMID- 27456656 TI - Hypoxia induced the differentiation of Tbx18-positive epicardial cells to CoSMCs. AB - Understanding the origin and differentiation mechanism of coronary vascular smooth muscle cells (CoSMCs) is very important to cardiovascular biology. The early cardiovascular system is formed in a hypoxic microenvironment, and Tbx18 positive epicardial cells are a source of CoSMCs. However, the effects of hypoxia on the differentiation of Tbx18-positive epicardial cells to CoSMCs and the primary regulatory mechanism are insufficiently understood. Using Tbx18:Cre/R26R(EYFP/LacZ) fate-tracing mice, we cultured highly purified Tbx18 positive epicardial cells. We further showed that hypoxia induced Tbx18-positive epicardial cells to differentiate into CoSMCs and promoted the epithelial mesenchymal transition (EMT) process of the cells in vitro. The induction of differentiation was primarily achieved via the hypoxia inducible factor-1alpha (HIF-1alpha)-mediated effects exerted on Snail. Using a cell migration assay, we showed that hypoxia enhanced the motility of Tbx18-positive epicardial cells. By constructing a hypoxic model of the embryonic epicardium in vivo, we showed that hypoxia led to premature in situ differentiation of Tbx18-positive epicardial cells to CoSMCs. Furthermore, hypoxia was sufficient to induce Snail expression in Tbx18-positive epicardial cells in vivo. Our study suggests that hypoxia intervention was sufficient to induce the differentiation of Tbx18-positive epicardial cells to CoSMCs. Furthermore, this differentiation was achieved primarily via HIF-1alpha-mediated regulation of Snail. PMID- 27456658 TI - Community Involvement of Young Adults with Intellectual Disabilities: Their Experiences and Perspectives on Inclusion. AB - BACKGROUND: Inclusion in the community is essential to enhancing a person's quality of life. Although people with intellectual disabilities have a desire to be more involved in activities, they experience barriers that limit their inclusion. METHODS: The purpose of this study was to describe the community involvement of young adults with intellectual disability. I interviewed fourteen young adults with intellectual disability to explore their involvement in work, recreation and leisure activities. FINDINGS: Four themes emerged from the data: vocational endeavours, leisure pursuits, social inclusion and supports. The contexts of their experiences either facilitated or hindered their community involvement. CONCLUSIONS: The community involvement of young adults with intellectual disability varies depending on the opportunities and supports available to them. Their inclusion in the community may be enhanced by additional transportation options, continuing education in vocational and social skills, personalized guidance from group members and environments that are welcoming to people with disabilities. PMID- 27456657 TI - Changing Polygenic Penetrance on Phenotypes in the 20(th) Century Among Adults in the US Population. AB - This study evaluates changes in genetic penetrance-defined as the association between an additive polygenic score and its associated phenotype-across birth cohorts. Situating our analysis within recent historical trends in the U.S., we show that, while height and BMI show increasing genotypic penetrance over the course of 20(th) Century, education and heart disease show declining genotypic effects. Meanwhile, we find genotypic penetrance to be historically stable with respect to depression. Our findings help inform our understanding of how the genetic and environmental landscape of American society has changed over the past century, and have implications for research which models gene-environment (GxE) interactions, as well as polygenic score calculations in consortia studies that include multiple birth cohorts. PMID- 27456659 TI - Hyper-branched anion exchange membranes with high conductivity and chemical stability. AB - In the manuscript, we report the design and preparation of hyper-branched polymer electrolytes intended for alkaline anion exchange membrane fuel cells. The resulting membrane exhibits high conductivity, lower water swelling and shows prolonged chemical stability under alkaline conditions. PMID- 27456661 TI - Correction: Self-assembly of a space-tessellating structure in the binary system of hard tetrahedra and octahedra. AB - Correction for 'Self-assembly of a space-tessellating structure in the binary system of hard tetrahedra and octahedra' by A. T. Cadotte et al., Soft Matter, 2016, DOI: . PMID- 27456660 TI - A mechanistic stochastic framework for regulating bacterial cell division. AB - How exponentially growing cells maintain size homeostasis is an important fundamental problem. Recent single-cell studies in prokaryotes have uncovered the adder principle, where cells add a fixed size (volume) from birth to division, irrespective of their size at birth. To mechanistically explain the adder principle, we consider a timekeeper protein that begins to get stochastically expressed after cell birth at a rate proportional to the volume. Cell-division time is formulated as the first-passage time for protein copy numbers to hit a fixed threshold. Consistent with data, the model predicts that the noise in division timing increases with size at birth. Intriguingly, our results show that the distribution of the volume added between successive cell-division events is independent of the newborn cell size. This was dramatically seen in experimental studies, where histograms of the added volume corresponding to different newborn sizes collapsed on top of each other. The model provides further insights consistent with experimental observations: the distribution of the added volume when scaled by its mean becomes invariant of the growth rate. In summary, our simple yet elegant model explains key experimental findings and suggests a mechanism for regulating both the mean and fluctuations in cell-division timing for controlling size. PMID- 27456662 TI - Triple Negative Breast Cancer: A Tale of Two Decades. AB - Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% of breast cancer cases worldwide. TNBC is associated with poor prognosis and lack of sustained response to conventional chemotherapeutic agents. Tumoral heterogeneity and the presence of several subtypes of TNBC such as Basal like (BL)-1, BL-2, immune-modulatory, luminal androgen receptor, mesenchymal, and mesenchymal/stem like subtype and claudin low subtype, may explain some of the difficulties faced in managing this challenging disease subgroups. Although no approved targeted therapy is available for TNBCs, molecular-profiling efforts have revealed promising molecular targets such as the vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), polyadenosine ribose polymerase inhibitors (PARPi) and DNA repair pathway, androgen pathway, and NOTCH pathway. TNBC is subject to intense research activities aiming at dissecting potential pathways, identifying potential molecular signatures and biomarkers in order to properly develop new targeted biologic modifiers. Despite this, there is a lack of approved predictive and prognostic biomarkers, and keeping in view the complexity of TNBC biology, research should be targeted towards identifying multi-factorial signatures rather than single markers. This review aims to summarize the current evidence, ongoing research and discuss future strategies for the treatment of patients with TNBC. In addition we have reviewed the recent advances in detecting predictive and prognostic biomarkers and identifying surrogate markers for early identification of potential responders to the new therapies. PMID- 27456663 TI - Hybrid Benzoxazole-Coumarin Compounds Induce Death Receptor-Mediated Switchable Apoptotic and Necroptotic Cell Death on HN-5 Head and Neck Cancer Cell Line. AB - BACKGROUND: Efficacy of multimodality approaches for the treatment of squamous cell cancer of the head and neck has remained unsatisfactory and further advances are critically required. Targeted cell death induction is a novel therapeutic approach that may help to improve clinical management of Head and Neck cancer patients. OBJECTIVE: The potency of novel hybrid benzoxazole-coumarins on the induction of apoptotic and/or necroptotic cell death were evaluated in a Head and Neck carcinoma cell line, HN-5, and a human skin cell line, AGO1522. METHODS: Quantitative toxicity of the synthesized compounds were elucidated by MTT assay, the specific activity of caspase-3 and -9 were measured by the colorimetric method and zVAD was used to block apoptosis. Expression of cell death related genes were studied using quantitative PCR. RESULTS: All three compounds were revealed IC50 value around 51.96+/-7.15 microM in HN-5 cells which were significantly lower than observed IC50 for AGO1522, 121.93+/-3.66 microM (p=0.001). Significant increase expression of FAS, FASL and TRIAL were observed in the treated cells with or without pretreatment with zVAD. In the absence of pretreatment, treatment lead to the induction of apoptosis with a significant increase in caspase-3 gene expression and caspase-3 activity without a significant increase in expression or activity of caspase-9 and other components of the intrinsic apoptotic pathway. However, in the zVAD pretreated cells, necroptotic cell death with a significant increase in expression of RIP1, RIP3, and MLKL genes was observed Conclusion: The novel hybrid benzoxazole-coumarins effectively induce Caspase-3 dependent apoptosis in HN-5 cancer cells, but also could circumvent the blockage of apoptotic cell death by induction of necroptosis. PMID- 27456664 TI - A right to health care? Participatory politics, progressive policy, and the price of loose language. AB - This article begins by clarifying and noting various limitations on the universal reach of the human right to health care under positive international law. It then argues that irrespective of the human right to health care established by positive international law, any system of positive international law capable of generating legal duties with prima facie moral force necessarily presupposes a universal moral human right to health care. But the language used in contemporary human rights documents or human rights advocacy is not a good guide to the content of this rather more modest universal moral human right to health care. The conclusion reached is that when addressing issues of justice as they inevitably arise with respect to health policy and health care, both within and between states, there is typically little to gain and much to risk by framing deliberation in terms of the human right to health care. PMID- 27456666 TI - Phase-modulating lasers toward on-chip integration. AB - Controlling laser-beam patterns is indispensable in modern technology, where lasers are typically combined with phase-modulating elements such as diffractive optical elements or spatial light modulators. However, the combination of separate elements is not only a challenge for on-chip miniaturisation but also hinders their integration permitting the switchable control of individual modules. Here, we demonstrate the operation of phase-modulating lasers that emit arbitrarily configurable beam patterns without requiring any optical elements or scanning devices. We introduce a phase-modulating resonator in a semiconductor laser, which allows the concurrent realisation of lasing and phase modulation. The fabricated devices are on-chip-sized, making them suitable for integration. We believe this work will provide a breakthrough in various laser applications such as switchable illumination patterns for bio-medical applications, structured illuminations, and even real three-dimensional or highly realistic displays, which cannot be realised with simple combinations of conventional devices or elements. PMID- 27456665 TI - Viperin inhibits rabies virus replication via reduced cholesterol and sphingomyelin and is regulated upstream by TLR4. AB - Viperin (virus inhibitory protein, endoplasmic reticulum-associated, IFN inducible) is an interferon-inducible protein that mediates antiviral activity. Generally, rabies virus (RABV) multiplies extremely well in susceptible cells, leading to high virus titres. In this study, we found that viperin was significantly up-regulated in macrophage RAW264.7 cells but not in NA, BHK-21 or BSR cells. Transient viperin overexpression in BSR cells and stable expression in BHK-21 cells could inhibit RABV replication, including both attenuated and street RABV. Furthermore, the inhibitory function of viperin was related to reduce cholesterol/sphingomyelin on the membranes of RAW264.7 cells. We explored the up stream regulation pathway of viperin in macrophage RAW264.7 cells in the context of RABV infection. An experiment confirmed that a specific Toll-like receptor 4 (TLR4) inhibitor, TAK-242, could inhibit viperin expression in RABV-infected RAW264.7 cells. These results support a regulatory role for TLR4. Geldanamycin, a specific inhibitor of interferon regulatory factor 3 (IRF3) (by inhibiting heat shock protein 90 (Hsp90) of the IRF3 phosphorylation chaperone), significantly delayed and reduced viperin expression, indicating that IRF3 is involved in viperin induction in RAW264.7 cells. Taken together, our data support the therapeutic potential for viperin to inhibit RABV replication, which appears to involve upstream regulation by TLR4. PMID- 27456667 TI - A rare case of multiple spinal epidural abscesses and cauda equina syndrome presenting to the emergency department following acupuncture. AB - BACKGROUND: Acupuncture is a form of traditional Chinese medicine being increasingly used as complementary therapy in many countries. It is relatively safe and rarely associated with deep infections. CASE PRESENTATION: In this case report, we describe a middle-aged Chinese patient who presented acutely to our emergency department with cauda equina syndrome secondary to acupuncture-related epidural abscesses, which were treated with surgical decompression and intravenous antibiotics. We also present a review of case reports of this rare condition in available literature. CONCLUSION: Emergency physicians should be aware that spinal abscesses may occur after acupuncture, with a broad spectrum of clinical presentations. If a history of recent acupuncture over the symptomatic area is elicited, a high index of suspicion should be maintained and appropriate imaging performed to establish the diagnosis. Treatment is directed by a number of factors, such as severity and duration of neurological deficit and progression of symptoms. PMID- 27456668 TI - UHPLC Quantitation Method for New Thiazolidinedione LPSF/GQ-02 and In Vitro/In Vivo Kinetic Studies. AB - BACKGROUND: LPSF/GQ-02 is a promising benzylidene thiazolidinedione that has demonstrated antidiabetic, antidyslipidemic, anti-atherosclerotic properties and can also treat non-alcoholic fatty liver disease. Despite all activity studies of the new compound, its pharmacokinetics are not yet described. OBJECTIVE: The aim of this study was to perform its first pharmacokinetic profile. METHODS: For this purpose a bioanalytical method for the quantitation of 5-(4- Chloro-benzylidene) 3-(4-methylbenzyl)-thiazolidine-2,4-dione (LPSF/GQ-02) was developed and validated. A Waters UPLC chromatographer using a BEH column (2.1x50mm, 1.7MUm particle), mobile phase water:acetonitrile (20:80) was used. The range of calibration curve in plasma was 1.9 to 250 ng/mL with r = 0.9997. LPSF/GQ-02 stability was evaluated in rat plasma and buffers at pH 1.2 and 7.4. The pharmacokinetic assay was carried out in male Wistar rats weighing 250-300 g. The animals received LPSF/GQ-02 at 3 mg/kg by intravenous route. The animals were used to perform a preliminary safety study concerning the evaluation of liver and kidney biomarkers (ALT, AST, urea, creatinine). RESULTS: The obtained pharmacokinetic parameters were elimination half-life of 4.44 h, Cl of 8.00 L/h.kg, Vd of 45.60 L/kg and MRT of 3.79h. No difference was observed for the liver and kidney biomarkers. CONCLUSION: The intravenous pharmacokinetic parameters are in agreement with a good future posology, even though the plasma concentrations from oral administration were not quantifiable in a dose of 12 mg/kg. The preliminary safety study demonstrated no acute effect of the drug in liver and kidneys. The LPSF/GQ-02 is a new thiazolidinedione that should continue being evaluated for future clinical use. PMID- 27456669 TI - Intracellular Retention of Three Quinuclidine Derivatives in Caco-2 Permeation Experiments: Mechanisms and Impact on Estimating Permeability and Active Efflux Ratio. AB - BACKGROUND: Three quinuclidine derivatives (FRM-1, FRM-2 and FRM-3) were subject to significant mass loss to cellular retention in Caco-2 permeation experiments. The apparent permeability coefficient (Papp) calculated with either 'sink' (Papp,sink) or 'non-sink' (Papp,nonsink) method was significantly biased. As a result, a simplified 3-compartmental distribution model was applied in this study to derive the 'intrinsic' Papp (Papp,int) and to understand the impact of cellular retention on estimating Papp and active efflux ratio (ER) values. METHODS: Time-courses of the amount of test compounds in the donor, receiver and cells were determined in the presence and absence of bafilomycin A1 (BFA, 100 nM) and / or cyclosporine A (CsA, 10 .M). A mathematical model was constructed to describe the mass transfer of test compounds among three compartments. The temporal profiles of directional Papp,sink, Papp,nonsink and the corresponding of ER values were compared with the counterpart parameters derived from data-fitting to the mathematical model. Simulations were performed for a better understanding of experimental observations. RESULTS: The mass recovery of test compounds deteriorated with incubation time and was direction dependent. Based on the directional Papp,sink values, the resulting ER is close to unity for FRM-1, and approximately 2 and 3.5 for FRM-2 and FRM-3. Treatment with BFA considerably enhanced mass recovery for FRM-1 and FRM-3 (by 5- and 2-fold) but elicited no impact on FRM-2, while ER values largely unchanged. Expectedly, Papp,nonsink was higher than Papp,sink, but the resulting ER was lower in most cases. In contrast, the model-derived Papp,int was much greater than the values of Papp,sink and Papp,nonsink. The model also quantitatively unveiled the respective contributions of lysosomal sequestration and nonspecific binding to the cellular retention of the compounds. CONCLUSION: Our work reveals the different mechanisms involved in cellular retention of these quinuclidine derivatives, and more importantly, demonstrates the value of kinetic analyses with mathematical modeling in minimizing the bias in Papp estimation when assumptions for conventional calculations are violated. PMID- 27456670 TI - Clinical significance of SLC2A9/GLUT9 rs11722228 polymorphisms in gout. AB - AIM: The main objective of this study is to elucidate the clinical significance of the SLC2A9/GLUT9 rs11722228 polymorphism among male gout patients. METHOD: We consecutively recruited all newly diagnosed male gout patients who were treatment naive from the rheumatology outpatient clinics of two Malaysian hospitals. Age matched healthy male adults were employed as controls. All subjects were tested for the SLC2A9/GLUT9 rs11722228 genotypes, serum uric acid (SUA), urine uric acid and creatinine levels. All gout subjects were examined for the presence of tophi and sonographically screened for renal calculi. RESULTS: A total of 73 male gout patients and 73 age-matched healthy male adults were recruited in this study. The genotypic frequencies of SLC2A9/GLUT9 rs1172228 did not differ significantly between the gout cases and the healthy controls. The gout subjects with the CC genotype had significantly higher SUA levels (P = 0.002), family history of gout (P < 0.050) and the occurrence of renal calculi (P = 0.026). The SUA-adjusted odds ratios (OR) of the occurrence of renal calculi in the CC genotype (OR = 1 [reference]) was significantly higher than the CT genotype (OR = 0.338, 95%CI: 0.141-0.813) and the TT genotype (OR = 0.271, 95%CI: 0.086-0.854). CONCLUSIONS: The genotypic distribution of SLC2A9/GLUT9 rs1172228 in male gout patients did not differ significantly from that of healthy male controls. However, the CC genotype in gout had significant associations with higher levels of SUA, renal calculi and a positive family history of gout. PMID- 27456672 TI - Technical comparison of four different extracorporeal photopheresis systems. AB - BACKGROUND: Extracorporeal photopheresis (ECP) is a therapeutic technique that combines leukapheresis and ultraviolet (UV)A irradiation of the leukapheresate after 8-methoxypsoralen treatment with subsequent retransfusion. It can be achieved with a single device (online) or by combining an apheresis machine with a separate UVA light source (offline). The comparability of both established methods is unknown. STUDY DESIGN AND METHODS: In a prospective setting, four ECP systems were evaluated: one with integrated UVA irradiation for online ECP (Therakos) and three with external UVA irradiation for offline ECP (Amicus, Optia, and Cobe Spectra). Apheresis variables and cell counts were determined by methods including flow cytometry. RESULTS: The duration of apheresis ranged from 120 minutes (Amicus, Optia) to 275 minutes (Therakos). Mononuclear cell (MNC) counts in the treatment bags were comparable between offline ECP methods (median, 57 * 108 - 66 * 108 ) and lower for online ECP (14 * 108 ). CD16+ monocytes were abundant in online ECP (82%) but rarer in offline ECP (median, 14% - 19%). Hematocrit ranged from 0.1% (Therakos) to 8% (Amicus). There were no side effects in any patients. DISCUSSION: All offline ECP systems studied yielded comparable cellular compositions and highly enriched populations of MNCs. In contrast, white blood cells from online ECP displayed enrichment of nonclassical monocytes. The relevance of these findings is unknown as there is no established biomarker to predict the therapeutic efficacy of these procedures. PMID- 27456673 TI - Major orthopaedic surgery for a haemophilia patient with inhibitors using a new bypassing agent. PMID- 27456671 TI - Protein kinase A modulation of CaV1.4 calcium channels. AB - The regulation of L-type Ca(2+) channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. Although much work has been done to understand this regulation in cardiac CaV1.2 Ca(2+) channels, relatively little is known about the closely related CaV1.4 L type Ca(2+) channels, which feature prominently in the visual system. Here we find that CaV1.4 channels are indeed modulated by PKA phosphorylation within the inhibitor of Ca(2+)-dependent inactivation (ICDI) motif. Phosphorylation of this region promotes the occupancy of calmodulin on the channel, thus increasing channel open probability (PO) and Ca(2+)-dependent inactivation. Although this interaction seems specific to CaV1.4 channels, introduction of ICDI1.4 to CaV1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems. Thus, this mechanism may not only play an important role in the visual system but may be generalizable across the L type channel family. PMID- 27456674 TI - An Australian stocks and flows model for asbestos. AB - All available data on asbestos consumption in Australia were collated in order to determine the most common asbestos-containing materials remaining in the built environment. The proportion of asbestos contained within each material and the types of products these materials are most commonly found in was also determined. The lifetime of these asbestos containing products was estimated in order to develop a model that projects stocks and flows of asbestos products in Australia through to the year 2100. The model is based on a Weibull distribution and was built in an excel spreadsheet to make it user-friendly and accessible. The nature of the products under consideration means both their asbestos content and lifetime parameters are highly variable, and so for each of these a high and low estimate is presented along with the estimate used in the model. The user is able to vary the parameters in the model as better data become available. PMID- 27456675 TI - Multi-criteria GIS-based siting of transfer station for municipal solid waste: The case of Kumasi Metropolitan Area, Ghana. AB - The increase in the quantity of municipal solid waste generated as a result of population growth in most urban areas has resulted in the difficulty of locating suitable land areas to be used as landfills. To curb this, waste transfer stations are used. The Kumasi Metropolitan Area, even though it has an engineered landfill, is faced with the problem of waste collection from the generation centres to the final disposal site. Thus in this study, multi-criteria decision analysis incorporated into a geographic information system was used to determine potential waste transfer station sites. The key result established 11 sites located within six different sub-metros. This result can be used by decision makers for site selection of the waste transfer stations after taking into account other relevant ecological and economic factors. PMID- 27456676 TI - Anatomic lung resections for benign pulmonary diseases by video-assisted thoracoscopic surgery (VATS). AB - PURPOSE: Based on increasing evidence of its benefits regarding perioperative and oncologic outcome, video-assisted thoracoscopic surgery (VATS) has gained increasing acceptance in the surgical treatment of early stage non-small cell lung cancer (NSCLC). However, the evidence for a VATS approach in anatomic lung resection for benign pulmonary diseases is still limited. METHODS: Between March 2011 and May 2014, data from 33 and 63 patients who received VATS anatomic lung resection for benign diseases (VATS-B) and early stage NSCLC (VATS-N), respectively, were analyzed retrospectively. For subgroup analyses, VATS-B was subdivided by operation time and underlying diseases. Subgroups were compared to VATS-N. RESULTS: Three patients from VATS-B and four from VATS-N experienced conversion to open surgery. Causes of conversion in VATS-B were intraoperative complications, whereas conversions in VATS-N were elective for oncological concerns (p < 0.05). Operation time and duration of postoperative mechanical ventilation were longer by tendency; postoperative stay on intensive care unit and chest tube duration were significantly longer in VATS-B. Subgroup analyses showed a longer operation time as a predictor for worse perioperative outcome regarding postoperative mechanical ventilation, postoperative stay on intensive care unit, chest tube duration, and length of hospital stay. Patients with longer operation time suffered from more postoperative complications. Differences in perioperative outcome data were not significantly dependent on the underlying benign diseases compared to VATS-N. CONCLUSIONS: VATS is feasible and safe in anatomic lung resection for benign pulmonary diseases. Not the underlying disease, but a longer operation time is a factor for worse postoperative outcome. PMID- 27456677 TI - Primary liver resection for patients with cirrhosis and hepatocellular carcinoma: the role of surgery in BCLC early (A) and intermediate stages (B). AB - AIM: This study aims to report the outcomes following primary liver resection (PLR) in patients with cirrhosis including stratification according to the Barcelona Clinic Liver Cancer (BCLC) classification. METHODS: Patients with cirrhosis and hepatocellular carcinoma (HCC) who had PLR between 2000 and 2013 were examined. Overall survival (OS), disease-free survival (DFS) and recurrence rate (RR) were analysed. Management after recurrence was reviewed as well as comparison to a series of 116 patients listed directly for liver transplant. RESULTS: Seventy-one patients underwent PLR. Median follow-up was 40 months. The 1-, 3- and 5-year OS and DFS for the series were 77, 69 and 61 % and 69, 39 and 28 % respectively. Overall recurrence was 59 % (44/71) and only 36 % (15/44) of those patients had a further potentially curative procedure. The 1-3-5-year OS and DFS in the BCLC-A (44 patients) were 86, 78 and 68 % and 78, 48 and 44 % respectively. The RR in BCLC-A was 45 % (20 patients) with half (11 patients) suitable for further treatment with curative intent. The 1-3-5-year OS and DFS in the BCLC-B (17 patients) were 81, 74 and 60 % and 58, 29 and 7 % respectively. The overall RR in BCLC-B was 76 % (13 patients). CONCLUSION: Recurrence following PLR for HCC in patients with cirrhosis is high with only a third of patients suitable for further potentially curative procedures. For patients with BCLC-A (or within Milan criteria), PLR provided a 68 % 5-year OS with 44 % of them free of disease. Surgery can offer satisfactory OS in carefully selected patients in the BCLC-B stage. PMID- 27456678 TI - Dorsal approach plus branch patch technique is the preferred method for liver transplanting small babies with monosegmental grafts. AB - PURPOSE: When living donor liver transplantation (LDLT) is performed on small infant patients, the incidence of hepatic artery complications (HACs) is high. Here, we present a retrospective analysis that focuses on our surgical procedure for hepatic arterial reconstruction and the outcomes of monosegmental LDLT. METHODS: Of the 275 patients who underwent LDLT between May 2001 and December 2015, 13 patients (4.7 %) underwent monosegmental LDLT. Hepatic artery reconstruction was performed under a microscope. The size discrepancy between the graft and the recipient's abdominal cavity was defined as the graft to recipient distance ratio (GRDR) between the left hepatic vein and the portal vein (PV) bifurcation on a preoperative computed tomography scan. HACs were defined as hepatic arterial hypoperfusion. RESULTS: Recipient hepatic arteries were selected for the branch patch technique in five cases (38.5 %), and the diameter was 2.2 +/- 0.6 mm. The anastomotic approaches selected were the dorsal position of the PV in seven cases (53.8 %) and the ventral position in six, and the GRDRs were 2.8 +/- 0.4 and 1.9 +/- 0.5, respectively (p = 0.012). The incidence rate of HACs caused by external factors, such as compression or inflammation around the anastomotic site, was significantly higher in monosegmental than in non monosegmental graft recipients (15.4 vs. 1.1 %, p < 0.001). CONCLUSION: Although monosegmental graft recipients experienced HACs caused by external factors around the anastomotic field, hepatic arterial reconstruction could be safely performed. Important components of successful hepatic arterial reconstructions include the employment of the branch patch technique and the selection of the dorsal approach. PMID- 27456679 TI - The earlier the better: health-related quality of life is inversely related to age of smoking cessation in older former Italian smokers. AB - BACKGROUND: Quitting smoking has several health benefits, including an improvement in health-related quality of life. It is not well established if there is a relationship between the age when people stop smoking and health related quality of life in older adults. AIMS: The primary aim was to investigate the relationship between health-related quality of life and the age when people quit smoking in a national representative sample of community-dwelling older Italian adults. The secondary aim was to describe the characteristics of older former smokers according to their age when they stopped smoking. METHODS: Data were drawn from the "Health and use of health care in Italy", a national cross sectional survey (2004-2005). Seven thousand five hundred and sixty-two former smokers, aged 65 years and older, were evaluated by age of smoking cessation. Socio-demographic characteristics, physical activity, the 12-Item Short-Form Health Survey (SF-12) score and its physical (PCS-12) and mental (MCS-12) component summary scores, disability and comorbidities were analyzed. RESULTS: Educational level, marital status and area of residence were associated with a different age of smoking cessation, as a higher level of disability and comorbidity. PCS-12 (beta -0.144; p < 0.001) and MCS-12 (beta -0.077; p < 0.001) component scores were lower in subjects who quit smoking later. The relationship was confirmed for the PCS-12 score even after adjustment for socio-demographic, disability and clinical variables (beta -0.031; p < 0.001), while it disappeared for the MCS-12 score (beta -0.010, p = 0.307), after adjustment for comorbidities. CONCLUSION: Physical and mental health-related quality of life is influenced by the age of smoking cessation in older individuals, but this relationship is influenced by comorbidities, particularly depression. Some individual characteristics are related to the age of the person when he/she quit smoking. PMID- 27456680 TI - Attitudes of neurology specialists toward older adults. AB - OBJECTIVE: Attitude of healthcare providers toward older people is very important in the aging world. Neurologists contact older adults very frequently. We aimed to investigate the attitudes of neurologists toward older adults. MEASUREMENTS: We recorded participants age; sex; duration of clinical practice in neurology; existence of older adult relatives; and history of geriatrics education, nursing home visits, older adult patient density in their clinical practice, and participation in voluntary public activities. UCLA Geriatrics Attitude Scale was used to evaluate participants' attitudes. RESULTS: A total of 100 neurologists participated in this study. Seventy-seven percent had positive, 3 % had neutral, and 20 % had negative attitudes. Twenty-seven percent of the participants had history of geriatrics education, and these participants tended to have a higher rate of positive attitudes. Neurologists with positive attitudes tended to be older than those with negative attitudes. Participants with history of living with older adult relatives had lower rates of positive attitudes. The most common diagnoses of the patients the participants encountered were stroke and dementia. Independent factors associated with positive attitudes were history of geriatrics education and older age. History of living with older relatives tended to have a negative effect. Most of the negative items of the attitude scale were associated with the natural course and behavior of the common diseases in neurology practice. CONCLUSIONS: Generalization of geriatrics education may translate into a better understanding and improved care for older patients. Development of instruments and implementation of qualitative studies to assess attitudes of neurologists toward older adults are needed. PMID- 27456682 TI - Histochemical study of rabbit medial pterygoid muscle during postnatal development. AB - The medial pterygoid muscle is a layered structure like the masseter muscle. This study aimed at investigating the regional differences in fiber type composition and fiber diameter of the medial pterygoid muscle in the rabbit from birth until 33 weeks of age. Histochemical analysis of the medial pterygoid muscle was performed during five developmental stages (4, 9, 12, 18, and 33 weeks after birth) in 30 male Japanese white rabbits. Six fiber types (I, IC, IIC, IIA, IIAB, and IIB) were identified by mATPase staining. An increase in diameter was observed in fiber types I and IC until 9 weeks of age, and in fiber types IIC, IIA, IIAB, and IIB until 33 weeks of age. No significant differences in fiber diameter were noted in the different regions of the pterygoid muscle. Moderate fast to slow fiber type shifts occurred from weeks 4-12; thereafter, a rapid slow to fast fiber type shift was observed. Significant differences in fiber type composition based on regional differences were noted at 4 weeks of age. However, there was no difference in fiber type composition between regions at 33 weeks. In conclusion, it was clear that the diameter and proportion of fast fibers had increased even after reaching sexual maturity in rabbits. In addition, the medial pterygoid muscle tissues appeared to be homogenous at 33 weeks of age with very few differences between regions. PMID- 27456683 TI - Adenosquamous carcinoma of the tongue: clinicopathologic study and review of the literature. AB - Adenosquamous carcinoma (ASC) of the tongue is an uncommon malignant oral neoplasm with mixed glandular and squamous differentiation and a propensity for aggressive clinical behavior. Here, we report a rare case of ASC of the lateral border of the tongue in a 65-year-old Japanese man. The patient was treated by radical operation and remained well for 6 months before developing metastasis of the hilar and pretracheal lymph nodes. Subsequently, the patient was treated with combined chemotherapy (nedaplatin plus docetaxel and S-1 for two cycles, intravenously) and radiotherapy. Radiation therapy of metastatic lymph nodes was performed at a total dose of 60 Gy and was delivered in 2 Gy fractions 5 days/week. The patient is currently tumor free and is being followed up carefully. This article describes a rare case of ASC of the tongue and its conventional histologic, immunohistochemical, and electron microscopic findings, together with a review of the literature. The findings provide important information to better understand the possible clinical and therapeutic approaches for this uncommon tumor of the tongue. PMID- 27456684 TI - Stain susceptibility of composite and ceramic CAD/CAM blocks versus direct resin composites with different resinous matrices. AB - To evaluate the stain susceptibility of CAD/CAM blocks and direct composite after long term exposure to various staining agents. 40 disk-shaped samples were fabricated from each of nine materials; six CAD/CAM (Vitablocs Mark II, Paradigm MZ100, Experimental Vita Hybrid Ceramic, Vita Enamic, Experimental Kerr and Lava Ultimate) and three direct composites (Filtek Supreme, Venus Diamond and Filtek Silorane). Samples were randomly divided into five groups (n = 8) according to different staining solutions (distilled water, tea, red wine, coffee and artificial saliva). Initial L*a*b* values were assessed using a calibrated digital spectrophotometer. Specimens were immersed in staining solutions and stored in an incubator at 37 degrees C for 120 days. L*a*b* values were assessed again and color change (?E) was calculated as difference between recorded L*a*b* values. ANOVA, and Duncan test were used to identify differences between groups (alpha = 0.05). Significant differences in ?E values were detected between materials (p = 0.000). Among all staining solutions, the highest ?E value was observed with red wine. The new CAD/CAM blocks (Vita Enamic, Vita Hybrid Ceramic and Lava Ultimate) showed the highest resistance to staining compared to the MZ100 composite resin blocks. Filtek Silorane, a direct composite, showed high stain resistance values compared to CAD/CAM materials and other direct composites. Ceramic and composite CAD/CAM blocks had lower staining susceptibility than methacrylate based direct composite. Staining susceptibility of the new resin based CAD/CAM materials Vita Enamic and Lava Ultimate was comparable to feldspathic ceramic blocks (Vitablocs Mark II). Filtek Silorane showed promising results that were comparable to some CAD/CAM blocks. PMID- 27456685 TI - The influence of cyclic stress on surface properties of soft liners. AB - : Soft polymers used under tissue-supported prostheses have limited service life because of surface degradation. PURPOSE: This paper evaluates the changes in surface properties and softness of soft relining materials after cyclic loading in water. MATERIALS AND METHODS: 3 polysiloxane (Silagum AM Comfort, Molloplast B, Mollosil Plus) and 2 acrylic-based (Vertex Soft, Astron LC Soft) proprietary soft relining materials and a vinyl polysiloxane (Imprint 2 Garant) as the reference impression material evaluated. A stainless steel block for detail reproduction was used on the basis of the apparatus recommended by the ISO 4823:1992 test method for preparing a standardized surface. A control group from each material was only subjected to water immersion. Non-destructive cyclic loading was carried out with a strain of 16.6 % and a frequency of 1.6 Hz 200,000 times in distilled water at 37 degrees C. The specimens were then duplicated and compared with the controls using roughness measurements, detail reproduction and Scanning Electron Microscope. Shore A hardness values before and after cycling were also measured. RESULTS: After degradation in the form of mechanical cycling in water, loss of substance and loss of surface detail was observed. Surface properties and Shore A hardness values of acrylic-based soft liners changed significantly (p < 0.05). CONCLUSIONS: The chemical composition of the soft relining materials seemed to affect their potential of preserving the surface texture and softness after mechanical cycling. Mechanical cycling influences the surface degradation process leading to changes of the surface texture. Polysiloxane-based materials preserved their softness, surface texture and surface smoothness better under cyclic loading compared to acrylic resin -based plasticized materials. PMID- 27456686 TI - Dental caries is negatively correlated with body mass index among 7-9 years old children in Guangzhou, China. AB - BACKGROUND: Evidence linking caries in primary dentition and children's anthropometric measures is contradictory. We aimed to evaluate the prevalence of primary dental caries and its relationship with body mass index (BMI) among 7-9 years old school children in urban Guangzhou, China. METHODS: This cross sectional study enrolled 32,461 pupils (14,778 girls and 17,683 boys) aged 7-9 years from 65 elementary schools in Guangzhou. Dental caries was detected according to criteria recommended by the World Health Organization (WHO). The total mean decayed, missing or filled teeth (dmft) of primary dentition were assessed. Weight and height were measured and BMI was calculated. Children were classified into underweight, normal weight, overweight and obesity groups by BMI based on Chinese criteria. Z-score of BMI-for-age (BAZ) was calculated by WHO standardized procedure. Multivariable odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using logistic regression. Restricted cubic spline regression was applied to evaluate the shape of the relationship between BAZ and primary dental caries. RESULTS: The prevalence of primary dental caries was 30.7 % in total sample. Regarding dmft values, the mean +/- standard deviation (SD) in the combined sample were 1.03 +/- 2.05 in boys and 0.93 +/- 1.92 in girls. Both indices decreased by age. Compared with normal BMI group, children in overweight and obesity groups have 27 % (OR = 0.73, 95 % CI: 0.66 0.81, P < 0.0001) and 34 % (OR = 0.66, 95 % CI: 0.59-0.74, P < 0.0001) lower odds for the presence of primary dental caries after adjustment for age and gender, respectively. Although in general, increased BAZ was associated with decreased risk of dental caries, full-range BAZ was associated with dental caries in an A shaped manner with a zenith at around -1.4. CONCLUSION: Higher BMI was associated with lower odds of caries; overweight and obese children were more likely to be primary dental caries free among 7-9 years in Guangzhou, China. PMID- 27456681 TI - The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. AB - Remarkable interest has risen in the idea that oxidative/nitrosative stress is mediated in the etiology of numerous human diseases. Oxidative/Nitrosative stress is the result of an disequilibrium in oxidant/antioxidant which reveals from continuous increase of Reactive Oxygen and Reactive Nitrogen Species production. The aim of this review is to emphasize with current information the importance of antioxidants which play the role in cellular responce against oxidative/nitrosative stress, which would be helpful in enhancing the knowledge of any biochemist, pathophysiologist, or medical personnel regarding this important issue. Products of lipid peroxidation have commonly been used as biomarkers of oxidative/nitrosative stress damage. Lipid peroxidation generates a variety of relatively stable decomposition end products, mainly alpha, beta unsaturated reactive aldehydes, such as malondialdehyde, 4-hydroxy-2-nonenal, 2 propenal (acrolein) and isoprostanes, which can be measured in plasma and urine as an indirect index of oxidative/nitrosative stress. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative/nitrosative stress or its consequences. They may act from directly scavenging free radicals to increasing antioxidative defences. Antioxidant deficiencies can develop as a result of decreased antioxidant intake, synthesis of endogenous enzymes or increased antioxidant utilization. Antioxidant supplementation has become an increasingly popular practice to maintain optimal body function. However, antoxidants exhibit pro-oxidant activity depending on the specific set of conditions. Of particular importance are their dosage and redox conditions in the cell. PMID- 27456687 TI - Injuries sustained by earthquake relief workers: a retrospective analysis of 207 relief workers during Nepal earthquake. AB - BACKGROUND: This study aimed to analyse the injuries sustained by rescue workers in earthquake relief efforts in high altitude areas for improving the ways of how to effectively prevent the injuries. METHODS: The clinical data of 207 relief workers from four military hospitals in Tibet, who were injured in the Tibetan disaster areas of China during '4.25' Nepal earthquake rescue period, was retrospectively analyzed. The demographic features, sites of injury and causes of injury were investigated. RESULTS: The most frequently injured sites were the ankle-foot and hand-wrist (n = 61, 26.5 %), followed by injuries in leg-knee-calf (n = 22, 9.6 %), head-neck (4.87 %), thoracic and abdominal region (2.6 %) and lower back (3.9 %). The specific high-altitude environment increased the challenges associated with earthquake relief. DISCUSSION: The specific plateau environment and climate increased the burden and challenge in earthquake relief. The injury distribution data shown in this study demonstrated that effective organization and personnel protection can reduce the injury occurrences. CONCLUSION: Relief workers were prone to suffering various injuries and diseases under specific high-altitude environment. PMID- 27456688 TI - The effects of liraglutide on both hypereosinophilic insulin allergy and the characteristics of anti-insulin antibodies in type 2 diabetes mellitus: a case report. AB - BACKGROUND: Liraglutide is one of the glucagon-like peptide-1 analogs; there are only a few reports of liraglutide being used for the treatment of insulin allergy. Furthermore, anti-insulin immunoglobulin G antibodies are occasionally detected in patients with diabetes. Hence, we report a case in which switching to liraglutide therapy ameliorated both the symptoms of insulin allergy with hypereosinophilia and the characteristics of insulin antibodies in a patient with type 2 diabetes mellitus. CASE PRESENTATION: We present the case of a 70-year-old Japanese man with type 2 diabetes who developed insulin allergy with hypereosinophilia. Anti-insulin antibodies, high glycated hemoglobin levels (approximately 12 %), and high serum insulin levels were detected. Because a change in his insulin treatment was inefficient, treatment with liraglutide to protect residual insulin secretion was started, resulting in improvements in his insulin allergy, serum glycated hemoglobin, insulin, and eosinophil levels. Scatchard plots revealed decreased binding capacity and increased affinity constant for high affinity sites of anti-insulin antibodies. CONCLUSIONS: Liraglutide might be useful for treating insulin allergy and anti-insulin antibodies in patients with type 2 diabetes. PMID- 27456690 TI - High-Flow Vascular Malformation in the Sigmoid Mesentery Successfully Treated with a Combination of Transarterial and Transvenous Embolization. AB - Mesenteric high-flow vascular malformation can cause various clinical symptoms and demand specific therapeutic interventions owing to its peculiar hemodynamics. We report a case of high-flow vascular malformation in the sigmoid mesentery which presented with ischemic colitis. The main trunk of the inferior mesenteric vein was occluded. After partially effective transarterial embolization, transvenous embolization was performed using a microballoon catheter advanced to the venous component of the lesion via the marginal vein. Complete occlusion of the lesion was achieved. Combination of transarterial and transvenous embolization may allow us to apply endovascular treatment to a wider variety of high-flow lesions in the area and possibly avoid the bowel resection. PMID- 27456689 TI - Guided Internet-delivered cognitive behavioural therapy in patients with non cardiac chest pain - a pilot randomized controlled study. AB - BACKGROUND: Patients with recurrent episodes of non-cardiac chest pain may experience cardiac anxiety and avoidance behavior, leading to increased healthcare utilization. These patients might benefit from help and support to evaluate the perception and management of their chest pain. The purpose of this study was to test the feasibility of a short guided Internet-delivered cognitive behavioural therapy (CBT) program and explore the effects on cardiac anxiety, fear of body sensations, depressive symptoms, and chest pain in patients with non cardiac chest pain, compared with usual care. METHODS: A pilot randomized controlled study was conducted. Fifteen patients with non-cardiac chest pain with cardiac anxiety or fear of body sensations, aged 22-76 years, were randomized to intervention (n = 7) or control (n = 8) groups. The four-session CBT program contained psychoeducation, physical activity, and relaxation. The control group received usual care. Data were collected before and after intervention. RESULTS: Five of seven patients in the intervention group completed the program, which was perceived as user-friendly with comprehensible language, adequate and varied content, and manageable homework assignments. Being guided and supported, patients were empowered and motivated to be active and complete the program. Patients in both intervention and control groups improved with regard to cardiac anxiety, fear of body sensations, and depressive symptoms, but no significant differences were found between the groups. CONCLUSIONS: The Internet-delivered CBT program seems feasible for patients with non-cardiac chest pain, but needs to be evaluated in larger groups and with a longer follow-up period. TRIAL REGISTRATION: Clinicaltrials.gov NCT02336880 . Registered on 8 January 2015. PMID- 27456691 TI - Highly efficient metallic optical incouplers for quantum well infrared photodetectors. AB - Herein, we propose a highly efficient metallic optical incoupler for a quantum well infrared photodetector (QWIP) operating in the spectrum range of 14~16 MUm, which consists of an array of metal micropatches and a periodically corrugated metallic back plate sandwiching a semiconductor active layer. By exploiting the excitations of microcavity modes and hybrid spoof surface plasmons (SSPs) modes, this optical incoupler can convert infrared radiation efficiently into the quantum wells (QWs) layer of semiconductor region with large electrical field component (Ez) normal to the plane of QWs. Our further numerical simulations for optimization indicate that by tuning microcavity mode to overlap with hybrid SSPs mode in spectrum, a coupled mode is formed, which leads to 33-fold enhanced light absorption for QWs centered at wavelength of 14.5 MUm compared with isotropic absorption of QWs without any metallic microstructures, as well as a large value of coupling efficiency (eta) of |Ez|(2) ~ 6. This coupled mode shows a slight dispersion over ~40 degrees and weak polarization dependence, which is quite beneficial to the high performance infrared photodetectors. PMID- 27456692 TI - The reporting and diagnosis of uterine fibroids in the UK: an observational study. AB - BACKGROUND: Uterine fibroids (UFs) are the most common benign tumour in women, and many undergo hysterectomy or uterus-preserving procedures (UPPs) to manage their symptoms. We aimed to validate the recording of UFs in a primary care database, The Health Improvement Network (THIN), and to determine the incidence of UFs in the UK. METHODS: In this observational study, women in THIN aged 15-54 years between January 2000 and December 2009 with no previous record of UFs, hysterectomy or UPPs were identified. Individuals were followed up until there was a Read code indicating UFs, they reached 55 years of age or died, or the study ended. Among those without a UF code, women were identified with a code for hysterectomy, UPPs or heavy menstrual bleeding (HMB). Anonymized patient profiles from each category were randomly selected and reviewed. Subsequently, primary care physicians were asked to complete questionnaires to verify the diagnosis for a randomly selected subgroup. RESULTS: In total, 737,638 women were identified who met the initial inclusion criteria. The numbers of women with a code for UFs, hysterectomy, UPPs and HMB were 9380, 11,002, 3220 and 60,915, respectively; the proportions of confirmed cases of UFs were 88.8, 29.7, 57.7 and 15.9 %. The estimated number of women with UFs was 23,140 (64.0 % without a recorded UF diagnosis). The overall incidence of UFs was 5.8 per 1000 woman-years. CONCLUSIONS: UFs were confirmed in a high proportion of women with UF Read codes. However, almost two-thirds of cases were identified among women with a code for hysterectomy, UPPs or HMB. These results show that UFs are under-recorded in UK primary care, and suggest that primary care physicians tend to code the symptoms of UFs more often than the diagnosis. PMID- 27456693 TI - Salvage robotic prostatectomy and high risk disease: what else can we do? PMID- 27456694 TI - Identification of hydrogeochemical processes in groundwater of Dawa River basin, southern Ethiopia. AB - Dawa River basin in southern Ethiopia is covered by volcanic, basement, and sedimentary rocks. Locating good quality groundwater is a challenge in most parts of the basin. Statistical analysis and graphical plots of 94 hydrochemical data of groundwater were used as a main tool to acquire an insight into the major processes that control groundwater chemistry. In the volcanic terrain groundwater is dilute (mean total dissolved solids (TDS): 152 mg/l), while salinity is the highest in the sedimentary terrain (mean TDS: 1750 mg/l). NO3 (-) varies from below the detection limit to 433 mg/l NO3 (-). In 26 % of the water samples, nitrate concentration is above the human-affected value, 5 mg/l NO3 (-). In 6 % of the samples, NO3 (-) concentration is above the limit recommended in drinking water, 50 mg/l NO3 (-), by WHO. Concentration range of the other major ions is also high and hydrochemical water types are diverse, suggesting the effect of various hydrogeochemical processes on the water chemistry. Chemical data analysis revealed that in the volcanic and most parts of the basement terrains silicate hydrolysis is the dominant process. Gypsum dissolution is the main process in the sedimentary terrain. Dissolution of gypsum is also important at few locations along dry riverbeds in the semiarid area where the effect of evaporation on the water chemistry is considerable. Loading of factors with K(+) and SO4 (2-), K(+) and NO3 (-), and NO3 (-) and correlation of SO4 (2-) with Cl(-), along with the observed high nitrate concentration, indicate the effect of surface contamination sources on the water quality. PMID- 27456695 TI - Effect of fly ash amendment on metolachlor and atrazine degradation and microbial activity in two soils. AB - The study reports the effect of Inderprastha (IP) and Badarpur (BP) fly ashes on degradation of metolachlor and atrazine in Inceptisol and Alfisol soils. Metolachlor dissipated at faster rate in Alfisol (t1/2 8.2-8.6 days) than in Inceptisol (t1/2 13.2-14.3 days). The fly ashes enhanced the persistence of metolachlor in both the soils; however, the extent of effect was more in Inceptisol (t1/2 16.6-33.8 days) than Alfisol (t1/2 8.4-12 days) and effect increased with fly ash dose. 2-Ethyl-6-methylacetanilide was detected as the only metabolite of metolachlor. Atrazine was more persistent in flooded soils (t1/2 10.8-20.3 days) than nonflooded soils (t1/2 3.7-12.6 days) and fly ash increased its persistence, but effect was more pronounced in the flooded Inceptisol (t1/2 23.7-31 days) and nonflooded Alfisol (t1/2 6.3-10.1 days). Increased herbicide sorption in the fly ash-amended soils might have contributed to the increased pesticide persistence. The IP fly ash inhibited microbial biomass carbon at 5 % amendment levels in both the soils, while BP fly ash slightly increased microbial biomass carbon (MBC) content. Dehydrogenase activity was inhibited by both fly ashes in both the soils with maximum inhibition observed in the IP fly ash amended Alfisol. No significant effect of fly ash amendment was observed on the fluorescein diacetate activity. PMID- 27456696 TI - PCBs in fish and their cestode parasites in Lake Victoria. AB - Polychlorinated biphenyls (PCBs) are classified as persistent organic pollutants (POPs) regulated by the Stockholm Convention (2001). Although their production and use was stopped almost three decades ago, PCBs are environmental persistent, toxic, and bioaccumulate in biota. We assessed the levels of 7 PCB congeners (IUPAC nos. 28, 52, 101, 118, 138, 153, and 180) in sediment and fish (Oreochromis niloticus, Lates niloticus, and Rastrineobola argentea) and evaluated the potential of cestode fish endoparasite (Monobothrioides sp., Proteocephalaus sp., and Ligula intestinalis) as biomonitors of PCBs in Lake Victoria, Kenya. The median concentration of Sigma7PCBs in sediments and fish were 2.2-96.3 MUg/kg dw and 300-3,000 MUg/kg lw, respectively. At all the sampling sites, CB138, CB153, and CB180 were the dominant PCB congeners in sediment and fish samples. Compared to the muscle of the piscine host, Proteocephalaus sp. (infecting L. niloticus) biomagnified PCBs *6-14 while Monobothrioides sp. (infecting O. niloticus) biomagnified PCBs *4-8. Meanwhile, L. intestinalis (infecting R. argentea) biomagnified PCBs *8-16 compared to the muscle of unparasitized fish. We demonstrate the occurrence of moderate to high levels of PCB in sediments and fish in Lake Victoria. We also provide evidence that fish parasites bioaccumulate higher levels of PCBs than their piscine hosts and therefore provide a promising biomonitor of PCBs. We urge further a long-term study to validate the use of the above cestode fish parasites as biomonitoring tools for PCBs. PMID- 27456697 TI - Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review. AB - BACKGROUND: Pharmacokinetic guided dosing of 5-fluorouracil chemotherapies to bring plasma 5-fluorouracil into a desired therapeutic range may lead to fewer side effects and better patient outcomes. High performance liquid chromatography and a high throughput nanoparticle immunoassay (My5-FU) have been used in conjunction with treatment algorithms to guide dosing. The objective of this study was to assess accuracy, clinical effectiveness and safety of plasma 5 fluorouracil guided dose regimen(s) versus standard regimens based on body surface area in colorectal cancer. METHODS: We undertook a systematic review. MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Library; Science Citation Index and Conference Proceedings (Web of Science); and NIHR Health Technology Assessment Programme were searched from inception to January 2014. We reviewed evidence on accuracy of My5-FU for estimating plasma 5 fluorouracil and on the clinical effectiveness of pharmacokinetic dosing compared to body surface area dosing. Estimates of individual patient data for overall survival and progression-free survival were reconstructed from published studies. Survival and adverse events data were synthesised and examined for consistency across studies. RESULTS: My5-FU assays were found to be consistent with reference liquid chromatography tandem mass spectrometry. Comparative studies pointed to gains in overall survival and in progression-free survival with pharmacokinetic dosing, and were consistent across multiple studies. CONCLUSIONS: Although our analyses are encouraging, uncertainties remain because evidence is mainly from outmoded 5-fluorouracil regimens; a randomised controlled trial is urgently needed to investigate new dose adjustment methods in modern treatment regimens. PMID- 27456698 TI - Early development of the malleus and incus in humans. AB - It is widely accepted by developmental biologists that the malleus and incus of the mammalian middle ear are first pharyngeal arch derivatives, a contention based originally on classical embryology that has now been backed up by molecular evidence from rodent models. However, it has been claimed in several studies of human ossicular development that the manubrium of the malleus and long process of the incus are actually derived from the second arch. This 'dual-arch' interpretation is commonly presented in otolaryngology textbooks, and it has been used by clinicians to explain the aetiology of certain congenital abnormalities of the human middle ear. In order to re-examine the origins of the human malleus and incus, we made three-dimensional reconstructions of the pharyngeal region of human embryos from 7 to 28 mm crown-rump length, based on serial histological sections from the Boyd Collection. We considered the positions of the developing ossicles relative to the pharyngeal pouches and clefts, and the facial and chorda tympani nerves. Confirming observations from previous studies, the primary union between first pharyngeal pouch and first cleft found in our youngest specimens was later lost, the external meatus developing rostroventral to this position. The mesenchyme of the first and second arches in these early embryos seemed to be continuous, but the boundaries of the developing ossicles proved to be very hard to determine at this stage. When first distinguishable, the indications were that both the manubrium of the malleus and the long process of the incus were emerging within the first pharyngeal arch. We therefore conclude that the histological evidence, on balance, favours the 'classical' notion that the human malleus and incus are first-arch structures. The embryological basis of congenital ossicular abnormalities should be reconsidered in this light. PMID- 27456699 TI - Fully automated macromolecule suppressed single voxel glutamate spectroscopy (FAMOUS SVGS). AB - PURPOSE: The aim of the study was to develop and validate a new localized (1)H MRS pulse sequence and automated post-processing software for the quantification of brain Glutamate (Glu) in clinical conditions at 7.0T in order to get reliable and reproducible results for acute intervention studies. METHODS: Here we describe a new localized proton MRS method "Fully Automated MacrOmolecUle Suppressed Single Voxel Glutamate Spectroscopy (FAMOUS SVGS)" for measuring Glu. FAMOUS SVGS method consists of a new pulse sequence with optimized switchable water, metabolites and outer volume suppression modules, as well as a frequency selective inversion pulse and automated post-processing of the five spectra obtained. FAMOUS SVGS method was first validated with glutamate phantoms and then validated with test-retest repeatability studies in the occipital cortex of five normal volunteers at 7.0T. RESULTS: Glutamate concentrations estimated from phantoms with FAMOUS SVGS method correlated well with actual concentrations. Test retest repeatability studies in human brain in vivo yielded less than 0.3 mM intra-subject variations in Glu concentrations. CONCLUSIONS: FAMOUS SVGS method enables Glu quantification in vivo at 7.0T with test-retest variability of less than 0.3 mM. We expect that we can reliably measure >=0.5 mM change in glutamate due to any acute intervention. PMID- 27456700 TI - Evaluation of potential drug- drug interactions among Palestinian hemodialysis patients. AB - BACKGROUND: The aims of this study are to find the prevalence of potential drug drug interactions (DDIs) in patients with Hemodialysis and identify factors associated with these interactions if present. METHODS: The study was an observational- retrospective cohort study that was conducted in ten hemodialysis units in the West bank, Palestine, between June and August 2015. The data collection form was completed by interviewing the patients in addition to reviewing their medical records. Potential DDIs were reviewed. SPSS program was used for data analysis. RESULTS: The study included 275 patients, a total of 930 potential interactions were identified in 245 (89.1 %) patients. Patients were prescribed 1-15 drugs with a mean (+/- SD) of 7.87 +/- 2.44, calcium carbonate was the most common drug prescribed. The most common potential interaction in 114 (41.5 %) patients was Calcium Carbonate/Amlodipine followed by Calcium Carbonate/Aspirin in 76 (27.6 %) cases. Most patients (89.9 %) of the patients had one or more comorbid diseases; hypertension, diabetes and gout were the most common. Univariate analysis showed that the number of potential DDIs were related to the number of diseases, the number of prescribed drugs (P value <0.0001) and the age of the patient (P value = 0.015). The results of multiple linear regression showed a significant positive association between number of potential DDIs with the total number of medications (r = 0.242; p < 0.001). CONCLUSION: The prevalence of potential drug- drug interactions among hemodialysis patients is very common; they are highly expected and depend on the number of drugs taken by the patients. Many of these potential interactions are considered as preventable drug- related problems, so screening for potential interactions and monitoring regularly is highly needed. PMID- 27456701 TI - Is real world evidence influencing practice? A systematic review of CPRD research in NICE guidances. AB - BACKGROUND: There is currently limited evidence regarding the extent Real World Evidence (RWE) has directly impacted the health and social care systems. The aim of this review is to identify national guidelines or guidances published in England from 2000 onwards which have referenced studies using the governmental primary care data provider the Clinical Practice Research Datalink (CPRD). METHODS: The methodology recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed. Four databases were searched and documents of interest were identified through a search algorithm containing keywords relevant to CPRD. A search diary was maintained with the inclusion/exclusion decisions which were performed by two independent reviewers. RESULTS: Twenty-five guidance documents were included in the final review (following screening and assessment for eligibility), referencing 43 different CPRD/GPRD studies, all published since 2007. The documents covered 12 disease areas, with the majority (N =7) relevant to diseases of the Central Nervous system (CNS). The 43 studies provided evidence of disease epidemiology, incidence/prevalence, pharmacoepidemiology, pharmacovigilance and health utilisation. CONCLUSIONS: A slow uptake of RWE in clinical and therapeutic guidelines (as provided by UK governmental structures) was noticed. However, there seems to be an increasing trend in the use of healthcare system data to inform clinical practice, especially as the real world validity of clinical trials is being questioned. In order to accommodate this increasing demand and meet the paradigm shift expected, organisations need to work together to enable or improve data access, undertake translational and relevant research and establish sources of reliable evidence. PMID- 27456702 TI - Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis. AB - Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1G93A mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1beta, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS. PMID- 27456704 TI - Left atrial collapse due to a giant false lumen in type B aortic dissection. PMID- 27456703 TI - The feasibility and safety of extracorporeal carbon dioxide removal to avoid intubation in patients with COPD unresponsive to noninvasive ventilation for acute hypercapnic respiratory failure (ECLAIR study): multicentre case-control study. AB - INTRODUCTION: The aim of the study was to evaluate the feasibility and safety of avoiding invasive mechanical ventilation (IMV) by using extracorporeal CO2 removal (ECCO2R) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) and acute hypercapnic respiratory failure refractory to noninvasive ventilation (NIV). METHODS: Case-control study. Patients with acute hypercapnic respiratory failure refractory to NIV being treated with a pump driven veno-venous ECCO2R system (iLA-Activve((r)); Novalung, Heilbronn, Germany) were prospectively observed in five European intensive care units (ICU). Inclusion criteria were respiratory acidosis (pH <= 7.35, PaCO2 > 45 mmHg) with predefined criteria for endotracheal intubation (ClinicalTrials.gov NCT01784367). The historical controls were patients with acute hypercapnic respiratory failure refractory to NIV who were treated with IMV. The matching criteria were main diagnosis, age, SAPS-II score and pH. RESULTS: Twenty-five cases (48.0 % male, mean age 67.3 years) were matched with 25 controls. Intubation was avoided in 14 patients (56.0 %) in the ECCO2R group with a mean extracorporeal blood flow of 1.3 L/min. Seven patients were intubated because of progressive hypoxaemia and four owing to ventilatory failure despite ECCO2R and NIV. Relevant ECCO2R associated adverse events were observed in 11 patients (44.0 %), of whom 9 (36.0 %) suffered major bleeding complications. The mean time on IMV, ICU stay and hospital stay in the case and control groups were 8.3 vs. 13.7, 28.9 vs. 24.0 and 36.9 vs. 37.0 days, respectively, and the 90-day mortality rates were 28.0 vs. 28.0 %. CONCLUSIONS: The use of veno-venous ECCO2R to avoid invasive mechanical ventilation was successful in just over half of the cases. However, relevant ECCO2R-associated complications occurred in over one-third of cases. Despite the shorter period of IMV in the ECCO2R group there were no significant differences in length of stay or in 28- and 90-day mortality rates between the two groups. Larger, randomised studies are warranted for further assessment of the effectiveness of ECCO2R. PMID- 27456705 TI - Design and Evaluation of the Psychometric Properties of a Paternal Adaptation Questionnaire. AB - The present study aimed to design and evaluate the psychometric properties of the Paternal Adaptation Questionnaire (PAQ). The study was a mixed (qualitative and quantitative) sequential exploratory study. In the qualitative phase, a preliminary questionnaire with 210 items emerged from in-depth interviews with 17 fathers and 15 key informants. In the quantitative phase, psychometric properties of the PAQ were assessed. Considering cutoff points as 1.5 for item impact, 0.49 for content validity ratio (CVR), and 0.7 for content validity index (CVI), items of the questionnaire were reduced from 210 to 132. Assessment of the content validity of the questionnaire demonstrated S-CVR = 0.68 and S-CVI = 0.92. Exploratory factor analysis resulted in the development of a PAQ with 38 items classified under five factors (ability in performing the roles and responsibilities; perceiving the parental development; stabilization in paternal position; spiritual stability and internal satisfaction; and challenges and concerns), which explained 52.19% of cumulative variance. Measurement of internal consistency reported a Cronbach's alpha of .89 for PAQ (.61-.86 for subscales), and stability assessment of the PAQ through the test-retest demonstrated Spearman's correlation coefficients and intraclass correlation coefficient of .96 (.81-.97 for subscales). It was identified that the PAQ is a valid and reliable instrument that could be used to assess fatherhood adaptation with the paternal roles and fathers' needs, as well as to design appropriate interventions and to evaluate their effectiveness. PMID- 27456706 TI - Genomic Analysis Reveals a Common Breakpoint in Amplifications of the Plasmodium vivax Multidrug Resistance 1 Locus in Thailand. AB - In regions of coendemicity for Plasmodium falciparum and Plasmodium vivax where mefloquine is used to treat P. falciparum infection, drug pressure mediated by increased copy numbers of the multidrug resistance 1 gene (pvmdr1) may select for mefloquine-resistant P. vivax Surveillance is not undertaken routinely owing in part to methodological challenges in detection of gene amplification. Using genomic data on 88 P. vivax samples from western Thailand, we identified pvmdr1 amplification in 17 isolates, all exhibiting tandem copies of a 37.6-kilobase pair region with identical breakpoints. A novel breakpoint-specific polymerase chain reaction assay was designed to detect the amplification. The assay demonstrated high sensitivity, identifying amplifications in 13 additional, polyclonal infections. Application to 132 further samples identified the common breakpoint in all years tested (2003-2015), with a decline in prevalence after 2012 corresponding to local discontinuation of mefloquine regimens. Assessment of the structure of pvmdr1 amplification in other geographic regions will yield information about the population-specificity of the breakpoints and underlying amplification mechanisms. PMID- 27456707 TI - Escherichia coli K1 Modulates Peroxisome Proliferator-Activated Receptor gamma and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis. AB - Escherichia coli K1 meningitis continues to be a major threat to neonatal health. Previous studies demonstrated that outer membrane protein A (OmpA) of E. coli K1 interacts with endothelial cell glycoprotein 96 (Ecgp96) in the blood-brain barrier to enter the central nervous system. Here we show that the interaction between OmpA and Ecgp96 downregulates peroxisome proliferator-activated receptor gamma (PPAR-gamma) and glucose transporter 1 (GLUT-1) levels in human brain microvascular endothelial cells, causing disruption of barrier integrity and inhibition of glucose uptake. The suppression of PPAR-gamma and GLUT-1 by the bacteria in the brain microvessels of newborn mice causes extensive pathophysiology owing to interleukin 6 production. Pretreatment with partial or selective PPAR-gamma agonists ameliorate the pathological outcomes of infection by suppressing interleukin 6 production in the brain. Thus, inhibition of PPAR gamma and GLUT-1 by E. coli K1 is a novel pathogenic mechanism in meningitis, and pharmacological upregulation of PPAR-gamma and GLUT-1 levels may provide novel therapeutic avenues. PMID- 27456708 TI - Unique Presentation of Orf Virus Infection in a Thermal-Burn Patient After Receiving an Autologous Skin Graft. AB - We describe a burn patient who developed skin lesions on her skin-graft harvest and skin-graft recipient (burn) sites. Orf virus infection was confirmed by a combination of diagnostic assays, including molecular tests, immunohistochemical analysis, pathologic analysis, and electron microscopy. DNA sequence analysis grouped this orf virus isolate among isolates from India. Although no definitive source of infection was determined from this case, this is the first reported case of orf virus infection in a skin graft harvest. Skin graft recipients with exposures to animals may be at risk for this viral infection. PMID- 27456709 TI - An Inactivated Rabies Virus-Based Ebola Vaccine, FILORAB1, Adjuvanted With Glucopyranosyl Lipid A in Stable Emulsion Confers Complete Protection in Nonhuman Primate Challenge Models. AB - The 2013-2016 West African Ebola virus (EBOV) disease outbreak was the largest filovirus outbreak to date. Over 28 000 suspected, probable, or confirmed cases have been reported, with a 53% case-fatality rate. The magnitude and international impact of this EBOV outbreak has highlighted the urgent need for a safe and efficient EBOV vaccine. To this end, we demonstrate the immunogenicity and protective efficacy of FILORAB1, a recombinant, bivalent, inactivated rabies virus-based EBOV vaccine, in rhesus and cynomolgus monkeys. Our results demonstrate that the use of the synthetic Toll-like receptor 4 agonist glucopyranosyl lipid A in stable emulsion (GLA-SE) as an adjuvant increased the efficacy of FILORAB1 to 100% protection against lethal EBOV challenge, with no to mild clinical signs of disease. Furthermore, all vaccinated subjects developed protective anti-rabies virus antibody titers. Taken together, these results support further development of FILORAB1/GLA-SE as an effective preexposure EBOV vaccine. PMID- 27456711 TI - Suppressing Electron Exposure Artifacts: An Electron Scanning Paradigm with Bayesian Machine Learning. AB - Electron microscopy of biological, polymeric, and other beam-sensitive structures is often hampered by deleterious electron beam interactions. In fact, imaging of such beam-sensitive materials is limited by the allowable radiation dosage rather that capabilities of the microscope itself, which has been compounded by the availability of high brightness electron sources. Reducing dwell times to overcome dose-related artifacts, such as radiolysis and electrostatic charging, is challenging due to the inherently low contrast in imaging of many such materials. These challenges are particularly exacerbated during dynamic time resolved, fluidic cell imaging, or three-dimensional tomographic reconstruction all of which undergo additional dosage. Thus, there is a pressing need for the development of techniques to produce high-quality images at ever lower electron doses. In this contribution, we demonstrate direct dose reduction and suppression of beam-induced artifacts through under-sampling pixels, by as much as 80% reduction in dosage, using a commercial scanning electron microscope with an electrostatic beam blanker and a dictionary learning in-painting algorithm. This allows for multiple sparse recoverable images to be acquired at the cost of one fully sampled image. We believe this approach may open new ways to conduct imaging, which otherwise require compromising beam current and/or exposure conditions. PMID- 27456710 TI - Do androgen deprivation and the biologically equivalent dose matter in low-dose rate brachytherapy for intermediate-risk prostate cancer? AB - The objective of this study was to investigate the impact of the biologically equivalent dose (BED) on treatment outcomes after iodine-125 low-dose-rate brachytherapy (LDR-BT) with or without supplemental external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for intermediate-risk prostate cancer (PCa). We retrospectively evaluated 292 Japanese patients. The impact of the BED and ADT on treatment outcomes was investigated. Cox proportional hazard models were used for univariate and multivariate analysis with biological progression-free survival (bPFS) and clinical progression-free survival (cPFS) as the primary outcome measures. The median follow-up was 66 months. The bPFS and cPFS rates at 5-/7-years were 91.6/87.7% and 95.9/94.0%, respectively. When stratified by BED levels, the bPFS rates at 5-/7-years were 92.1/89.3% for <178.0 Gy2, and 91.2/86.0% for >=178.0 Gy2 , respectively (P > 0.05). Based on ADT duration, the bPFS rates at 5-/7-years were 89.8/83.5%, 89.7/89.7%, and 97.5/97.5% for none, 1-3 months, and 4-12 months, respectively (P = 0.03). For the univariate analysis, the use of ADT and its duration were significant predictors for bPFS, whereas BED was not significant. A multivariate analysis did not indicate the use of ADT itself was significant, however, when covariates were accounted for by the duration of ADT, the longer use of ADT was found to significantly improve bPFS. Although cPFS was associated neither with the BED levels nor ADT duration (P > 0.05), ADT duration had a trend of improving cPFS (P = 0.053). The higher levels of BED did not significantly impact bPFS for intermediate-risk PCa after LDR-BT with or without supplemental EBRT and ADT. The longer duration of ADT could provide an additional benefit in the context of high dose irradiation generated by LDR-BT. PMID- 27456712 TI - Improvement of activated sludge resistance to shock loading by fungal enzyme addition during textile wastewater treatment. AB - The effects of the additions of the fungal enzymatic extract were investigated in relation to the treatment of real textile wastewater (RTW) by the activated sludge process (ASP). The used enzyme cocktail was produced by a new isolated fungal Chaetomium globosum IMA1. The system that was operated with enzyme addition showed a better chemical oxygen demand (COD) removal efficiency (95%) compared to the control system (75%). In addition, the improvement of color removal (OD620) efficiencies was around 15%, when the newly consortium fungal enzymes was added. As the organic loading rate (OLR) increased from 0.33 g to 0.66 g COD L-1 d-1, a decrease in the performance of the two reactors was observed by monitoring the quality of treated effluents. However, the ASP working with enzyme addition showed a strong resistance to shock loadings and restored after few days compared to the control system, which was strongly inhibited. In fact, the enzyme addition improved the sludge volume index (SVI) and the activity of microorganisms. A high activity of laccase (300 U.L-1) enzyme was observed throughout the decolorization process in the improved system. PMID- 27456713 TI - Public funding for abortion where broadly legal. AB - OBJECTIVE: The objective was to investigate public funding policies for abortion in countries with liberal or liberally interpreted laws (defined as permitting abortion for economic or social reasons or upon request). STUDY DESIGN: In May 2011-February 2012 and June 2013-December 2014, we researched online resources and conducted an email-based survey among reproductive health experts to determine countries' public funding policies for abortion. We categorized countries as follows: full funding for abortion (provided for free at government facilities, covered under state-funded health insurance); partial funding (partially covered by the government, covered for certain populations based on income or nonincome criteria, or less expensive in public facilities); funding for exceptional cases (rape/incest/fetal impairment, health/life of the woman or other limited cases) and no public funding. RESULTS: We obtained data for all 80 countries meeting inclusion criteria. Among the world's female population aged 15 49 in countries with liberal/liberally interpreted abortion laws, 46% lived in countries with full funding for abortion (34 countries), 41% lived in countries with partial funding (25 countries), and 13% lived in countries with no funding or funding for exceptional cases only (21 countries). Thirty-one of 40 high income countries provided full funding for abortion (n=20) or partial funding (n=11); 28 of 40 low- to middle-income countries provided full (n=14) or partial funding for abortion (n=14). Of those countries that did not provide public funding for abortion, most provided full coverage of maternity care. CONCLUSION: Nearly half of countries with liberal/liberally interpreted abortion laws had public funding for abortion, including most countries that liberalized their abortion law in the past 20 years. Outliers remain, however, including among developed countries where access to abortion may be limited due to affordability. IMPLICATIONS: Since cost of services affects access, country policies regarding public funding for services should be monitored, and advocacy should prioritize ensuring the affordability of care for low-income women. PMID- 27456715 TI - [Neurological complications and outcomes of bacterial meningitis in children]. AB - AIM: To analyze neurological complications and outcomes of bacterial meningitis (BM) in children. MATERIAL AND METHODS: Fifty-five patients with BM, aged from 2 months to 12 years, were examined. Bacteriological study, clinical and biochemical blood tests and blood serology and cerebrospinal fluid (CSF) tests as well as serum molecular-genetic study were performed. Neuroimaging methods (neurosonography, computed (X-ray) tomography and brain magnetic resonance imaging) were used. RESULTS AND SONCLUSION: A key role of generalized meningococcal infection in the development of BM in children was confirmed. Brain edema was an early and life-threatening complication of BM. It was found in 9% of the patients with meningococcal infection, 7.3% with pneumococcal meningitis and 3.6% with haemophilus meningitis. Changes in the brain structure were not found in 80% of the patients, in 20%, the residual stage of BM was characterized by cerebral destructive/proliferative or atrophic changes of different severity. The dissociation between clinical and neuroimaging parameters and poor outcomes of BM, related to the complicated premorbid state, concomitant somatic/neurological pathology, BM severity, late laboratory diagnosis and untimely etiotropic antibacterial treatment, were identified in 65.5%. PMID- 27456714 TI - Genetic variability in a frozen batch of MCF-7 cells invisible in routine authentication affecting cell function. AB - Common recommendations for cell line authentication, annotation and quality control fall short addressing genetic heterogeneity. Within the Human Toxome Project, we demonstrate that there can be marked cellular and phenotypic heterogeneity in a single batch of the human breast adenocarcinoma cell line MCF 7 obtained directly from a cell bank that are invisible with the usual cell authentication by short tandem repeat (STR) markers. STR profiling just fulfills the purpose of authentication testing, which is to detect significant cross contamination and cell line misidentification. Heterogeneity needs to be examined using additional methods. This heterogeneity can have serious consequences for reproducibility of experiments as shown by morphology, estrogenic growth dose response, whole genome gene expression and untargeted mass-spectroscopy metabolomics for MCF-7 cells. Using Comparative Genomic Hybridization (CGH), differences were traced back to genetic heterogeneity already in the cells from the original frozen vials from the same ATCC lot, however, STR markers did not differ from ATCC reference for any sample. These findings underscore the need for additional quality assurance in Good Cell Culture Practice and cell characterization, especially using other methods such as CGH to reveal possible genomic heterogeneity and genetic drifts within cell lines. PMID- 27456716 TI - [Features of the dynamics of clinical types of developmental delay in preschool children with residual brain damage]. AB - AIM: To study the features of the dynamics of different clinical variants of developmental delay (DD) in preschoolers with residual brain damage and analyze the relationship of these types with disease course and prognosis. MATERIAL AND METHODS: Eighty-six children (76 boys and 10 girls), aged 3-6 years, were examined. RESULTS AND CONCLUSION: The following clinical variants have been described: DD with speech impairments (motor and sensory-motor alalia); DD with hyperdynamic syndrome; DD with autistic syndrome; DD with affective instability syndrome; DD with neurotic syndromes (cerebroasthenic syndrome and other neurotic like conditions). It is assumed that a poor prognosis in preschool children with developmental delay is associated with manifestations of the autisticand alalia syndromes. PMID- 27456717 TI - [The efficacy of tenoten for children in the treatment of motor and speech disorders in children with perinatal damage of the central nervous system]. AB - AIM: To assess the therapeutic efficacy of tenoten for children in perinatal hypoxic CNS damage in children. MATERIAL AND METHODS: The study included 80 children (56 boys and 24 girls) between the ages of 3 and 3 years and 11 months with different variants (dysontogenetic or encephalopathic) of the effects on the perinatal nervous system. All children were divided into primary (n=50) and control (n=30) groups. Children of the primary group received a combination of conventional speech therapy methods with tenoten for children (1 tablet 3 times a day for 12 weeks). In the control group, children were not treated with tenoten for children. RESULTS AND CONCLUSION: The inclusion of tenoten in a comprehensive children's speech therapy program contributed significantly to the successful development of both general motor skills and spatial coordination as well as fine motor skills in the hand. In addition, tenoten significantly decreased signs of dysarthria and improved articulation, specifically in children with dysontogenetic variant of perinatal hypoxic CNS damage. Tenoten had a positive effect on child's behavior as well. PMID- 27456718 TI - [Possibilities of preventive treatment of tension-type headache in children and adolescents]. AB - AIM: To study clinical characteristics mechanisms and pathogenesis of the tension type headache (TTH) in children and adolescents treated with nooclerin. MATERIAL AND METHODS: The blind randomized placebo-controlled study of the efficacy of nooclerin (deanol aceglumate) indicated during 2 months as a preventive treatment of TTH was performed. Forty patients (15 male and 25 female), aged 9-16 years, were randomized into two equal groups to receive either nooclerin or placebo. RESULTS AND CONCLUSION: Nooclerin significantly reduced the frequency, duration and intensity of TTH. The treatment resulted in positive dynamics in daily activities, regression of fatigue symptoms and normalization of the sleep-wake cycle. PMID- 27456719 TI - [A psychovegetative symptom complex in the structure of didactogenic depression]. AB - AIM: To study clinical characteristics of didactogenic depression. MATERIAL AND METHODS: Eighty elementary and middle school students with psychogenic didactogenic depression were studied. RESULTS AND CONCLUSION: The following variants of didactogenic depression were described: timid, with "intellectual collapse", behavioral disturbances and with psychosomatic masking. Psychovegetative disturbances emerge to varying degrees in all variants. New features of somatic/autonomic symptoms in didactogenic depression and organization of psychocorrection are presented. PMID- 27456720 TI - [Uncompleted suicide attempts in adolescents]. AB - AIM: To analyze the characteristics of suicidal behavior, which was the reason of urgent admission to the psychiatric hospital, in adolescents. MATERIAL AND METHODS: Clinical and psychopathological analysis was performed for 143 adolescents, 55 boys and 88 girls, aged 15-17 years, admitted to a Moscow psychiatric hospital due to suicidal behavior. RESULTS AND CONCLUSION: Among all hospitalized on medical emergencies suicidal behavior was identified in 42%, repeated suicidal attempts were in 27% of boys and in 47% of girls. Mental disorders on admission and in the past history were found in 75%; 25% of the patients received psychiatric examination and treatment. Personality disorders and adaptation disorders were most prevalent; schizophrenia spectrum disorders made up 13%. Common features of suicidal behavior in adolescents were: the use of low fatal methods, mild expression of antivital feelings, short duration of pre suicidal stage, suddenness of commitment of suicidal actions, an additional stressful event (conflict situation) for the development of suicidal behavior. Significant differences in the methods of realization of suicidal intentions, preferable character of suicidal behavior (blackmailing/demonstrative in girls, brutal and compulsive in boys) and typology of psychopathological symptoms were established. PMID- 27456721 TI - [Projective method in the investigation of perception of external dangers in adolescents with mental disorders]. AB - AIM: To apply projective methods in the investigation of characteristics of external danger perception in adolescents with mental disorders and their healthy peers. MATERIAL AND METHODS: The clinical sample consisted of 42 inpatients (20 girls and 22 boys), aged 11-17 years, with schizophrenia spectrum disorders (ICD 10 items F20, F21, F25). The control group included 72 adolescents (50 girls, 22 boys), aged 11-17, pupils of secondary schools and colleges of Moscow and Moscow region, who had never been referred for psychiatric treatment. A complex of specially created projective methods for assessment of danger perception and psychometric methods for personality assessment scales were used. RESULTS AND CONCLUSION: Adolescents with mental disorders tend to increase the subjective danger level. In qualitative aspect, bizarre judgments about danger which reflect disease patterns, divergence between danger estimation and its interpretation, impulsivity of estimation and poor use of previous experience have been detected. Healthy adolescents perceive danger as a source of positive emotions, new experience and a reason for communication. Common traits in danger perception, including the distribution of results of danger situation selection and interpretations of uncertain hazards, in adolescents with mental disorders and their healthy peers were found. Several correlations between personality traits and subjective level of danger were identified. PMID- 27456722 TI - [The creative therapy by M. Burno in the psychotherapy of adolescents]. AB - Psychotherapeutic work with adolescents is a complex and challenging work. Clinical psychotherapy and creative psychotherapy (invented by M. Burno) have got an indisputable potential in use for the children and adolescents with mental disorders. A key feature of the psychotherapeutic approach for children and adolescents is obligatory taking into account all the aspects of mental ontogenesis/dysontogenesis of the patient. In the article we consider the basic clinical psychotherapeutic aspects of the new programme based on the creative psychotherapy (invented by M. Burno) to use in psychiatric departments for adolescents. PMID- 27456723 TI - [The assessment of neurocognitive functions in premature infants in the first year of life using Bayley Scales]. AB - AIM: To reveal the differences in neurocognitive development in premature infants and full-term infants in the first year of life. MATERIAL AND METHODS: The participants were 17 premature infants and 16 sex- and age-matched healthy full term infants. The gestational age of preterm infants was between 28 and 36 weeks. The Bayley Scales of Infant Development 3rd Edition were used to evaluate neurocognitive abilities in infants. ANCOVA with age as a covariate was used. RESULTS AND CONCLUSION: Preterm infants performed significantly (p<=0.05) worse than the full-term infants on cognitive scale, receptive language, gross motor and fine motor scales. No significant differences were found between preterm and full-term infants on the expressive language scale. Two-way ANOVA revealed no significant (p<=0.05) differences between female premature infants and full-term female infants on the gross motor scale in comparison to male infants. It has been proposed that the prematurity has a specific, but not a global, negative effect on the neurocognitive development in the first year of life with the gender effect on the development of gross motor skills. PMID- 27456724 TI - [The evaluation of the clinical efficacy of complex treatment and preventive orthodontic and rehabilitation measures in children with spastic cerebral paralysis]. AB - Based on the results of the comprehensive examination of 120 patients, the necessity of development and introduction of rehabilitation complex of therapeutic and preventive measures with regard to the type and severity of cerebral paralysis and patient's age in practice was shown. The main purpose of treatment and preventive measures was a complete social adaptation of children with spastic forms of cerebral paralysis, which was dependent on the integrity of speech functions. Rehabilitation measures were implemented by single multidisciplinary team with clear functional responsibilities of each member. The study determined the efficacy of treatment, preventive and rehabilitation measures in children with spastic forms of cerebral paralysis. It has been shown that the complex of treatment-and-preventive and rehabilitation measures for children with spastic forms of cerebral paralysis is positive and should be carried out continuously, from the early age to the maximum achievable level of correction of lost functions. PMID- 27456725 TI - [Neurologic disturbances in children with cleft lip and cleft palate]. AB - AIM: Neurological symptoms of genetic syndromes, including congenital cleft lip and palate (CLP) are well-studied while neurological characteristics of patients with non-syndromal CLP are not described. The authors studied neurological disturbances in CLP. MATERIAL AND METHODS: Twenty-one patients with CLP, mean age 12.0+/-4.7 years (the main group) were compared to healthy people (the control group). RESULTS AND CONCLUSION: Elements of bulbar syndrome (atrophy and deviation of the tongue, sagging of the soft palate, specific speech disturbances) and mimic innervation abnormalities (hypomimia or hypermimia, face asymmetry), microfocal neurological symptoms occurred significantly more frequently (p<0.01) in patients of the main group. Bulbar disorders, identified in 100% of the patients, were most characteristic of CLP. The neurological features of patients with CLP demonstrate the involvement of the brain stem, mimic innervation, bulbar cranial nerves and defects of the development of the neural tube. PMID- 27456726 TI - [The improvement of treatment efficacy in newborn full-term infants with severe birth asphyxia]. AB - AIM: To investigate the efficacy of cytoflavin as add-on to moderate controlled hypothermia in the treatment of newborn full-term infants with severe birth asphyxia. MATERIAL AND METHODS: Sixty full-term underweight children diagnosed with severe birth asphyxia (Apgar score 4-5) underwent moderate hypothermia for 72 hours. Depending on the regimen, the children were divided into two equal groups: the basic group received cytoflavin in dose of 2 ml/kg / day and the control group received the traditional scheme of therapy. RESULTS: The inclusion of cytoflavin increases the efficacy of therapy by reducing the severity of depression of consciousness (the increase in the average total score on the modified Glasgow Coma Scale pediatric/Saint Petersburg by 47.1% in children of the basic group compared with 27.9% in the control group, p=0.04) and more rapid recovery of vital functions (early extubation by 20.3%, p=0.03, and transition to enteral feeding earlier by 16.7% compared with the control group). The use of cytoflavin in newborns with severe asphyxia reduces lactic acidosis in the blood serum and normalizes EEG parameters as compared to the control group (p=0.02). CONCLUSION: Cytoflavin can be recommended as adjunctive therapy in full-term infants with severe intrapartum asphyxia. PMID- 27456727 TI - [Middle and anterior cerebral arteries dissection as a cause of ischemic stroke in a 7-year-old boy]. AB - Authors describe a 7-year-old boy, who developed a severe right-sided hemiparesis, aphasia, seizure, and confusion state during sport games. There was no headache. Allergic dermatitis in the past medical history and influenza vaccination 2 weeks before stroke were recorded. On the 12th day of disease, MRI of the brain revealed an acute infarction in the territory of left anterior and middle cerebral arteries with hemorrhagic transformation. MPA (15 day) showed occlusion of the left ACA and MCA. HR-MRI T1_db_fs weighted imaging (36 day) found intramural hematoma (IMH) in ACA and MCA with marked stenosis of the lumen. After 3 months, HR-MRI/MRA showed the complete regression of IMH, recanalization of the arterial lumen, prolonged irregular MCA stenosis. Neurological deficit regressed significantly. PMID- 27456729 TI - Histiocytosis Syndromes Classification, Diagnostic Features and Current Concepts. AB - The histiocytosis syndromes are broadly classified as those that feature dendritic cells and those that display only ordinary histiocytes in pathological lesions. The leukemias and lymphomas are malignant but the others defy simple assignment to basic pathological categorization. The ontogeny of histiocytes is considered, Langerhans cell histiocytosis and the hemophagocytic syndromes are discussed in detail and a conceptual context is presented. PMID- 27456730 TI - Treatment Options for Hodgkin's Disease During Pregnancy. AB - Treatment results of 47 pregnant women with Hodgkin's disease (HD) are analyzed using data reported in the literature since 1960. Twenty-three of the patients were treated with radiation during pregnancy and 17 of the 23 patients (74%) were reported to be long term disease-free survivors. All of these pregnancies resulted in normal deliveries and the babies were evaluated to have no abnormalities at birth. Termination of pregnancy was performed in 12 patients and 10 (83%) of them survived with no evidence of disease after subsequent treatment. In 12 patients, the treatment was initiated only after delivery and 9 (75%) of the 12 patients are disease-free survivors. The characteristics of the patients as well as an analysis of the results according to treatment approach practiced in each trimester of pregnancy are reported. The radiation dose to the fetus is evaluated and the factors affecting the dose are analyzed Experience with administering chemotherapy for HD during pregnancy is also reviewed. Twenty-six patients were treated during the first trimester. The patients treated with procarbazine, chlorambucil, cyclophosphamide or combination chemotherapy in the first trimester had abortions or malformed babies. When vinblastine was used during the first trimester in 13 patients, and nitrogen mustard in 3 patients, each of the 16 patients were reported to have delivered normal babies. When chemotherapy was used during the second or third trimesters, no abnormalities of the newborns were reported This review suggests that the cure rate of HD is unlikely to be compromised in pregnancy in spite of the fact that radiation or chemotherapy had to be modified in order to conserve the fetus. The treatment alternatives in each trimester are discussed and the consequences of administering radiation or chemotherapy during pregnancy are reviewed. PMID- 27456731 TI - Primary Gut Lymphomas. AB - Differences in behaviour and morphology between primary gut lymphomas and primary nodal lymphomas have recently become increasingly apparent. In this article we review the principal clinicopathological types of primary gut lymphomas and suggest an approach to their classification which is in accord with our own experience and, we believe, the recent literature on the subject. PMID- 27456732 TI - Effect of Cytotoxic Cells on Minimal Residual Leukemia. AB - The presence of minimal residual disease is indicated by the high frequency of relapses after twin bone marrow transplants and after allogeneic bone marrow transplants without graft versus host disease (up to 75% and 45% of cases, respectively). The graft versus leukemia effect may be mediated by IL-2 activation of natural killer cells (CD16 +, CD56 +, CD3-, CD8+/-) or cytotoxic T cells (CD3 +, CD56+/-). These activated killer cells can bind to targets and cause their lysis, and then recirculate to kill other targets. Killing can be blocked by anti-perforin antibodies and enhanced by protein kinase C-activation of effectors There are several studies indicating that a high percentage of leukemic cells can be killed by LAK-cells. However even in the most sensitive cases, lysis of all the cells cannot be achieved. The finding that leukemic clonogenic cells are generally sensitive to both NK and LAK cytotoxicity provides a more hopeful possibility The lack of tumor specific antigents, leukemic cell immunoheterogeneity and maturation asynchrony explains why antigen dependent T cell mediated cytotoxicity is only partly effective in eradicating residual leukemic cells. Future work should therefore include more studies of the mechanism of resistance to LAK cells, possibilities of further enchancing cytotoxicity and the mechanism of graft-versus-leukemia effect. PMID- 27456733 TI - Remission Induction in Patients with Lymphoid Malignancies Using Unconjugated CAMPATH-1 Monoclonal Antibodies. AB - CAMPATH-1 (CDw52) antigen is a heavily glycosylated, non-modulating glycoprotein expressed abundantly on the cell surface of nearly all normal and malignant lymphocytes but not on hemopoietic stem cells. A series of rat monoclonal antibodies (MAbs) with CDw52 specificity but of varying immunoglobulin isotype has been produced, and assessed for ability to deplete lymphoid cells in patients with lymphoproliferative disorders. Although all IgM, IgG2a and IgG2b rat MAbs were able to elicit lysis with human complement in vitro, only the IgG2b MAb (CAMPATH-1G) could elicit substantial lymphoid depletion in vivo. The efficacy of CAMPATH-1 G probably results from its ability to bind human Fc receptors and activate cell-mediated lysis of antibody-coated cells. Twenty-nine patients with lymphoid malignancies have received between 250 mg and 680 mg of CAMPATH-1G; nine of these attained complete remission A human MAb with CDw52 specificity has been produced by "grafting" the complementarity-determining regions (CDRs) of the rat MAb into human IgG1 heavy- and kappa light-chain genes. These constructs were transfected into a rat myeloma cell line. Sufficient human MAb (CAMPATH-1H) has been purified to treat two patients with non-Hodgkin's lymphoma in leukemic phase. Although each patient only received approximately 100 mg of MAb, remission was induced in both patients with recovery of normal hemopoiesis during the course of therapy CDw52 MAbs are the first MAbs to demonstrate consistent anti tumor effects in vivo and may have roles in the therapy of a wide range of lymphoid malignancies and as powerful immunosuppressive agents. PMID- 27456734 TI - Treatment of Adult T Cell Leukaemia by Extracorporeal Photochemotherapy. AB - Four patients with chronic or smouldering type adult T cell leukaemia (ATL) were treated by extracorporeal photochemotherapy (photopheresis). From 4 to 8 months after starting photo-pheresis, skin lesions with ATL cell infiltration began to disappear. Cell surface markers in three patients showed improvement. In one patient, a serial decrease of soluble interleukin-2 receptor levels (950 U/ml to 620) in the serum was observed after 4 months. This pilot study suggests that photopheresis may be successfully applied in ATL. It is still necessary to continue follow-up observations in these patients and to treat a larger number of cases, before definite conclusions can be drawn in the future. PMID- 27456735 TI - Immunophenotype of Abnormal Metaphases Demonstrating Multilineage Involvement in Myelodysplastic Syndromes. AB - Eight patients with myelodysplastic syndrome (MDS) and chromosome abnormalities were studied by a combined method which allows simultaneous analysis of the karyotype and immunophenotype of the same mitotic cell. To determine the cell lineages with abnormal karyotype, monoclonal antibodies in the alkaline phosphatase-antialkaline phosphatase (APAAP) staining methods were used All patients with MDS showed metaphases with abnormal karyotype in cells belonging to granulocytic/monocytic lineage. In 7 patients studied the leukaemic process also involved erythrocytic and/or megakaryocytic lineages. In 4 patients with 5q- chromosome it was evident that at least the granulocytic/monocytic and erythrocytic cell lineages participated in the clonal proliferation. One patient with 5q- chromosome at initial diagnosis showed a shift from megakaryocytic to a granulocytic/monocytic cell population at the time of acute leukaemia These findings indicate multi-lineage involvement in patients with MDS who have karyo typic abnormalities. PMID- 27456736 TI - Effect of Hemopoietic Growth Factors on the Proliferation of Acute Myeloid and Lymphoid Leukemias. AB - The effect of G-CSF, GM-CSF, IL-1 and IL-3 on the proliferation of acute leukemia cells (evaluated as (3)HTdR uptake) was investigated in short-term liquid cultures and compared with that observed on normal bone marrow (BM) populations enriched for immature cells. In acute myeloid leukemias (AML), a marked leukemic proliferation was induced in 10/18 cases by IL-3, in 9/18 by GM-CSF, in 7/18 by IL-1 and in 4/18 by G-CSF. In acute lymphoid leukemias (ALL), marked stimulation was observed in 7/11 cases with IL-3 and in 5/11 with GM-CSF, whereas IL-1 and G CSF were ineffective. Both in AML and ALL, the combination of several factors did not result in an additive synergistic effect. Purified normal BM cells responded to all four growth factors and their combinations produced an additive effect on cell proliferation which probably relates to the heterogeneity of the cell populations studied. The effect of a G-CSF, GM-CSF, IL-1 and IL-3 on the proliferation of acute leukemia cells by different growth factors suggests that caution should be exercised in their clinical use in these diseases. PMID- 27456737 TI - CD4 + T Cells from Lymph Nodes Involved by Hodgkin's Disease Showing Response in Autologous Mixed Lymphocyte Reaction, are Polyclonal. AB - Thirteen CD4 + T cell clones (TCCs) showing autologous mixed lymphocyte reaction (AMLR) and 12 CD4 + AMLR-negative TCCs derived from involved lymph nodes (LN) of 4 untreated patients with newly-diagnosed Hodgkin's disease (HD) were analyzed for some functional activities and for T cell receptor (TCR) gamma and beta gene rearrangement The majority of the AMLR-positive-, but only two AMLR-negative TCCs showed cytolytic potential when assayed by a lectin-dependent assay. In addition, the proportion of clones able to produce interleukin 2 (IL-2) was higher among AMLR-positive- than AMLR-negative TCCs and the amount of IL-2 synthesized by AMLR positive TCCs was significantly greater than that of AMLR-negative TCCs. In contrast, no difference in the profile of interleukin 4 (IL-4) and interferon gamma (IFN-gamma) production between AMLR-positive- and AMLR-negative TCCs was detected When AMLR-positive TCCs were analysed for their TCR beta and gamma gene rearrangements, a highly heterogeneous pattern was found. More importantly, TCCs derived from the same donor and displaying the same kind of TCR beta and gamma gene rearrangement showed different patterns of rearrangements, suggesting that CD4 + cells from LN involved by HD, displaying such an unusual functional profile, are polyclonal. PMID- 27456738 TI - Autologous Bone Marrow Transplantation in Hodgkin's Disease-A Single Centre U.K. Experience. AB - Twenty-five patients with relapsed or primary resistant Hodgkin's Disease were treated with high dose combination chemotherapy comprising cyclophosphamide, carmustine (BCNU) and etoposide followed by autologous bone marrow transplantation (ABMT). Sixteen (67%) of the twenty-four patients who survived the treatment schedule attained complete response (CR) and eleven of these remain disease free at a median time post ABMT of 16 months (range 6 to 27 months). Two of the patients who relapsed died at 7 and 17 months and the remaining three patients are alive with persistent disease at 12, 14 and 18 months. Four patients showed partial response. Three of these developed disease progression soon after the procedure and all died within ten months. The remaining patient achieved CR following further chemotherapy. There was a tendency for patients with bulky mediastinal disease, extra-nodal disease and heavy pre-treatment to fail to achieve CR. PMID- 27456739 TI - Pattern of Liver Disease Following High-Dose Cytosine Arabinoside (HDARAC) Therapy in Children with Acute Myeloid Leukemia. AB - The occurrence of liver disease and its relation to HBV markers were investigated in ten children with AML who were given HDARAC as late consolidation therapy. None of them developed jaundice or biochemical evidence of cholestasis. During therapy, SGPT values were normal in 5/10 patients, while in the other 5 a sharp increase was noted. These enzyme elevations followed an unusual timing, peaking just before each infusion of HDARAC. Evidence of long-lasting hepatocellular necrosis after therapy withdrawal was found in 8/8 cases. One child died of fulminant type B hepatitis and HBsAg positivity was found in 2/10 patients during therapy and 3/8 after withdrawal of the drug. Three children developed HBV antibodies during the observation period. We conclude that the use of HDARAC in childhood leukemia is not associated with major evidence of direct drug hepatotoxicity while it clearly affects the natural outcome of viral hepatitis. PMID- 27456740 TI - Involvement of HLA Antigens, Interleukin 2 Receptor and B-Cell Growth Factor in Interferon Action in Hairy Cell Leukemia. AB - Little is known about the mechanism(s) by which alpha-interferon (aIFN), when used as a biotherapeutic agent, suppresses the malignant cells and restores the normal phenotype of cells in patients with hairy cell leukemia (HCL). In previous studies using scanning electron microscopy (SEM) we found that alFN induced unique membrane alterations in target hairy cells in vitro. In addition, aIFN was shown to enhance the expression of HLA class II antigens on HCL cells, to induce the production of new proteins in such cells, and to lower the high levels of soluble IL-2 receptors in the serum of HCL patients. In the light of these results, and the fact that restoration of natural killer cell activity occurs in aIFN-treated patients well after the hematologic profile begins to improve, our studies have focused on the hypothesis that IFNs act directly on the target malignant cells, leading to the elimination of these cells either by inhibiting the proliferation of the malignant cells and/or triggering changes in the differentiation status of the malignant cells that lead to suppression (cytoconversion) of the malignant phenotype. We review the current hypotheses regarding alFN action on leukemic cells, with special reference to its potential antagonism with BCGF. PMID- 27456741 TI - Acute Nonlymphoblastic Leukemia: Treatment of Elderly Patients. AB - Forty-six elderly patients with acute non lymphoblastic leukemia (ANLL) were treated with a low toxicity drug combination (Oncovin, low dose Ara-C and Prednisone (OAP)) or with much more aggressive regimens. Complete remission was achieved in 6/23 patients treated with OAP and in 9/23 with aggressive chemotherapy (AC). The mean duration of remission was 18 and 27 weeks, respectively. Ten patients in the first group and 5 patients in the second group were resistant to therapy. During OAP treatment, 7 patients died, 6 during the induction phase and 1 in the consolidation phase, while 9 patients in the group treated aggressively died during the induction phase We conclude that aggressive regimens may be used in well selected elderly patients while patients with severe preexisting medical diseases may be treated with less aggressive drug combination. PMID- 27456742 TI - Acute Lymphoblastic Leukaemia Presenting as Bone Marrow Necrosis. AB - A young boy presented with recurrent anaemia which was initially attributed to malaria. On physical examination he was found to have generalized lymphadenopathy and hepatospleno-megaly. Peripheral blood showed neutropenia and bone marrow aspirate revealed bone marrow necrosis. Typical lymphoblasts were not seen in the peripheral blood until after intitiation of cytotoxic therapy. Needle aspirate of an enlarged lymph node and trephine biopsy established the diagnosis of acute lymphoblastic leukaemia. PMID- 27456743 TI - TdT-Positive, SmIg-Negative B Precursor Cell Leukemia with Burkitt Morphology: A Case Report. AB - The phenotypic marker profile and molecular analysis of ALL with typical FAB-L3 morphology of a 66-year-old lady are described. We detected the phenotypic expression of B cell-associated antigens (B4, BA1, HLA-DR) and terminal deoxynucleotidyl transferase, but not of surface and cytoplasmic immunoglobulin or cALLA antigen. Molecular analysis revealed that immunoglobulin heavy chain gene was in the rearranged form and that T cell beta-receptor gene was in the germ-line form Cytomorphology, immunophenotype and genotype indicated that her leukemic cells had characteristics of B-cell precursor ALL of Burkitt type. Cytogenetic investigation showed a normal karyotype, and neither rearrangement nor amplification of c-myc gene was detected To the best of our knowledge this type of TdT-positive, Smlg-negative FAB-L3 with immunological and molecular confirmation has as yet not been reported. PMID- 27456744 TI - Chronic B-Cell Malignancies in Patients with Lymphocytosis. PMID- 27456745 TI - Key Matrix Proteins Within the Pancreatic Islet Basement Membrane Are Differentially Digested During Human Islet Isolation. AB - Clinical islet transplantation achieves insulin independence in selected patients, yet current methods for extracting islets from their surrounding pancreatic matrix are suboptimal. The islet basement membrane (BM) influences islet function and survival and is a critical marker of islet integrity following rodent islet isolation. No studies have investigated the impact of islet isolation on BM integrity in human islets, which have a unique duplex structure. To address this, samples were taken from 27 clinical human islet isolations (donor age 41-59, BMI 26-38, cold ischemic time < 10 h). Collagen IV, pan laminin, perlecan and laminin-alpha5 in the islet BM were significantly digested by enzyme treatment. In isolated islets, laminin-alpha5 (found in both layers of the duplex BM) and perlecan were lost entirely, with no restoration evident during culture. Collagen IV and pan-laminin were present in the disorganized BM of isolated islets, yet a significant reduction in pan-laminin was seen during the initial 24 h culture period. Islet cytotoxicity increased during culture. Therefore, the human islet BM is substantially disrupted during the islet isolation procedure. Islet function and survival may be compromised as a consequence of an incomplete islet BM, which has implications for islet survival and transplanted graft longevity. PMID- 27456746 TI - Phylogenetic relationships among superfamilies of Neritimorpha (Mollusca: Gastropoda). AB - Despite the extraordinary morphological and ecological diversity of Neritimorpha, few studies have focused on the phylogenetic relationships of this lineage of gastropods, which includes four extant superfamilies: Neritopsoidea, Hydrocenoidea, Helicinoidea, and Neritoidea. Here, the nucleotide sequences of the complete mitochondrial genomes of Georissa bangueyensis (Hydrocenoidea), Neritina usnea (Neritoidea), and Pleuropoma jana (Helicinoidea) and the nearly complete mt genomes of Titiscania sp. (Neritopsoidea) and Theodoxus fluviatilis (Neritoidea) were determined. Phylogenetic reconstructions using probabilistic methods were based on mitochondrial (13 protein coding genes and two ribosomal rRNA genes), nuclear (partial 28S rRNA, 18S rRNA, actin, and histone H3 genes) and combined sequence data sets. All phylogenetic analyses except one converged on a single, highly supported tree in which Neritopsoidea was recovered as the sister group of a clade including Helicinoidea as the sister group of Hydrocenoidea and Neritoidea. This topology agrees with the fossil record and supports at least three independent invasions of land by neritimorph snails. The mitochondrial genomes of Titiscania sp., G. bangueyensis, N. usnea, and T. fluviatilis share the same gene organization previously described for Nerita mt genomes whereas that of P. jana has undergone major rearrangements. We sequenced about half of the mitochondrial genome of another species of Helicinoidea, Viana regina, and confirmed that this species shares the highly derived gene order of P. jana. PMID- 27456747 TI - Phylogeny, ecology, morphological evolution, and reclassification of the diatom orders Surirellales and Rhopalodiales. AB - The Surirellales and Rhopalodiales are large, widespread, and morphologically diverse groups of raphid pennate diatoms (Bacillariphyta) whose raphe, a structure that facilitates active motility, opens internally into a siliceous canal. We collected 202 representatives of the lineage and sequenced genes from the nuclear, plastid, and mitochondrial genomes to infer phylogenetic relationships as a basis for comparative study of ecology and morphological evolution as well as reclassification. The lineage was ancestrally marine, and we report the first evidence for a 'stepping stone' model of marine-freshwater transitions in which freshwater invasions were preceded by adaptation to intermediate brackish habitats. Phylogenetic comparative analyses also showed that the shift from an apical (e.g., Entomoneis) to transapical major axis of development (e.g., Surirella) did not have to proceed through subcircular intermediate forms (i.e., Campylodiscus). Rather, subcircular forms evolved both within lineages with longer apical axis or longer transapical axis. We also used the inferred phylogeny as a basis for genus-level reclassification of the lineage. Campylodiscus now includes the fastuosoid members of Surirella and Campylodiscus, but excludes other marine Campylodiscus which are now classified as Coronia. Surirella includes the Surirella striatula clade, Surirella Pinnatae group, and species formerly classified as Cymatopleura. We resurrected the genus Iconella to accommodate Stenopterobia and the robustoid members of Surirella and Campylodiscus. We broadened Epithemia to include members of the paraphyletic genus Rhopalodia. Finally, we discuss the challenges of constructing a classification that best leverages available phylogenetic data, while minimizing disruption to the research community and recognizing practical considerations stemming from the slow rate of progress on systematic studies of understudied organisms. PMID- 27456748 TI - Synthesis and deposition of basement membrane proteins by primary brain capillary endothelial cells in a murine model of the blood-brain barrier. AB - The brain vascular basement membrane is important for both blood-brain barrier (BBB) development, stability, and barrier integrity and the contribution hereto from brain capillary endothelial cells (BCECs), pericytes, and astrocytes of the BBB is probably significant. The aim of this study was to analyse four different in vitro models of the murine BBB for expression and possible secretion of major basement membrane proteins from murine BCECs (mBCECs). mBCECs, pericytes and glial cells (mainly astrocytes and microglia) were prepared from brains of C57BL/6 mice. The mBCECs were grown as monoculture, in co-culture with pericytes or mixed glial cells, or as a triple-culture with both pericytes and mixed glial cells. The integrity of the BBB models was validated by measures of transendothelial electrical resistance (TEER) and passive permeability to mannitol. The expression of basement membrane proteins was analysed using RT qPCR, mass spectrometry and immunocytochemistry. Co-culturing mBCECs with pericytes, mixed glial cells, or both significantly increased the TEER compared to the monoculture, and a low passive permeability was correlated with high TEER. The mBCECs expressed all major basement membrane proteins such as laminin-411, laminin-511, collagen [alpha1(IV)]2 alpha2(IV), agrin, perlecan, and nidogen 1 and 2 in vitro. Increased expression of the laminin alpha5 subunit correlated with the addition of BBB-inducing factors (hydrocortisone, Ro 20-1724, and pCPT cAMP), whereas increased expression of collagen IV alpha1 primarily correlated with increased levels of cAMP. In conclusion, BCECs cultured in vitro coherently form a BBB and express basement membrane proteins as a feature of maturation. Cover Image for this issue: doi: 10.1111/jnc.13789. PMID- 27456749 TI - Heparin-binding copolymer reverses effects of unfractionated heparin, enoxaparin, and fondaparinux in rats and mice. AB - The parenteral anticoagulants may cause uncontrolled and life-threatening bleeding. Protamine, the only registered heparin antidote, is partially effective against low-molecular weight heparins, completely ineffective against fondaparinux and may cause unacceptable toxicity. Therefore, we aimed to develop a synthetic compound for safe and efficient neutralization of all parenteral anticoagulants. We synthesized pegylated PMAPTAC block copolymers, and then, we selected a lead heparin-binding copolymer (HBC). We assessed the effectiveness of HBC in the model of arterial thrombosis electrically induced in the carotid artery of rats by measuring thrombus weight, bleeding time, activated partial thromboplastin time, activated clotting time, and anti-factor Xa activity. The intravital tissue distribution, the cardiorespiratory, and organ toxicity were monitored. HBC diminished antithrombotic and anticoagulant effects of unfractionated heparin. Moreover, it stopped bleeding and completely reversed the enhancement of clotting times and anti-factor Xa activity caused by enoxaparin or fondaparinux. We observed slight pulmonary congestion and cell infiltration, but the cardiorespiratory parameters remained unchanged. We found a strong signal of fluorescently-labeled HBC in the urine, and a weaker in the liver and in the kidney. No signs of hepatic or nephrotoxicity were observed in the blood biochemistry or histopathologic examination. We developed a copolymer efficiently neutralizing effects of heparins in the living organism, which shows a very promising efficacy/safety profile and may help in the management of uncontrolled bleeding resulting from an anticoagulant injection. HBC could enable the safe replacement of unfractionated heparin with low-molecular weight heparins in patients undergoing cardiac surgery and complex vascular procedures. PMID- 27456750 TI - Efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonists compared with exenatide and liraglutide in type 2 diabetes: a systemic review of randomised controlled trials. AB - BACKGROUND: Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promising results in the treatment of type 2 diabetes. Herein, we compared the efficacy and safety of once-weekly GLP-1RAs with exenatide and liraglutide separately. METHODS: We systematically surveyed the pertinent literature using various databases. The randomised controlled trials that compared once-weekly GLP 1RAs with exenatide and liraglutide in type 2 diabetes were included. Our main end-points were control of glycaemia, body weight, hypoglycaemia and gastrointestinal adverse events (AEs). RESULTS: Our analysis included eight trials involving 5531 patients. Exenatide-long-acting release (LAR), dulaglutide and taspoglutide were more effective than twice-daily exenatide in reducing glycosylated haemoglobin A1c (HbA1c) and fasting blood glucose (FBG) levels and achieving HbA1c targets (< 7.0% and <= 6.5%). Liraglutide was as effective as dulaglutide and more effective than exenatide-LAR and albiglutide in controlling glycaemia. With regard to the effectiveness in decreasing body weight, exenatide LAR, dulaglutide and taspoglutide were similar to exenatide whereas exenatide LAR, dulaglutide and albiglutide were inferior to liraglutide. Once-weekly GLP 1RAs, exenatide and liraglutide resulted in a similar incidence of hypoglycaemia and of gastrointestinal, serious, or other AEs. CONCLUSIONS: Once-weekly GLP-1RAs were more effective in controlling glycaemia and equally effective in decreasing body weight than twice-daily exenatide but were inferior to liraglutide in controlling these two parameters (dulaglutide was similar with liraglutide in controlling glycaemia). Once-weekly GLP-1RAs, exenatide and liraglutide had a similar risk of causing AEs. PMID- 27456751 TI - Preserving Dignity in Later Life. AB - This article examines how elders who receive social care in the community experience loss of dignity and how they preserve their dignity. Qualitative research revealed that loss of dignity is a major concern for these elders and that they preserve their dignity differently, ranging from actively engaging with life to detaching themselves from life. We conclude that, in later life, preserving dignity while receiving social care differs from preserving dignity in the context of health care, especially health care provided in institutional settings. Furthermore, preserving dignity in later life, while receiving social care, is a complex process, depending not only on performing activities and individual action and responsibility, but also on other actions, some of them involving a certain inactivity/passivity, and interactions with others, especially caregivers. This article offers some insights to developing better policies and care practices for promoting dignity in the context of community based social care. PMID- 27456753 TI - Activation of TGF-beta1 by AQP3-Mediated H2O2 Transport into Fibroblasts of a Bleomycin-Induced Mouse Model of Scleroderma. AB - Hydrogen peroxide (H2O2), the most important reactive oxygen species, mediates intracellular signal transmission and is transported into cells by aquaporin 3 (AQP3). However, it remains unclear whether AQP3 is involved in the pathogenesis of scleroderma. In this study, we examined the role of AQP3 in a bleomycin induced mouse model of scleroderma. We observed that H2O2 and AQP3 levels in mouse skin increased with the bleomycin injection period relative to phosphate buffered saline-injected control mice. AQP3 mRNA and protein levels were higher in bleomycin mice fibroblasts than in phosphate-buffered saline mice fibroblasts, and AQP3 immunofluorescence signals in the cytoplasm and cell membrane of bleomycin mice fibroblasts were much stronger than those in phosphate-buffered saline mice fibroblasts. Bleomycin-induced increases in H2O2, transforming growth factor-beta1, collagen type I, and collagen type III levels in bleomycin mice fibroblasts were blocked by silencing AQP3. In addition, silencing AQP3 decreased H2O2 levels, transforming growth factor-beta1 expression, and fibrosis in the scleroderma mouse model. These results demonstrate that AQP3-mediated transport of H2O2 into bleomycin mice fibroblasts activated transforming growth factor beta1, and silencing AQP3 is a potential approach for treating scleroderma. PMID- 27456754 TI - 5-Hydroxymethylcytosine Expression in Proliferative Nodules Arising within Congenital Nevi Allows Differentiation from Malignant Melanoma. AB - Differentiation of proliferative nodules in giant congenital nevi from melanoma arising within such nevi is an important diagnostic challenge. DNA methylation is a well-established epigenetic modification already observed in the earliest stages of carcinogenesis, which increases during melanoma progression. The ten eleven translocation enzymes catalyze the oxidation of 5-methylcytosine to 5 hydroxymethylcytosine (5-hmC), which has recently been reported as an epigenetic hallmark associated with tumor aggressiveness and poor prognosis in a wide variety of cancers. In this study, we analyzed 12 proliferative nodules and 13 melanomas both arising in giant congenital nevi and matched results with a control group including 67 benign and malignant melanocytic lesions. Proliferative nodules displayed high 5-hmC expression levels (90.65%) compared with melanomas with almost complete loss of this marker (7.87%). We showed that low 5-hmC levels in melanomas correlate with downregulation of isocitrate dehydrogenase and ten-eleven translocation families of enzymes implicated in the cytosine methylation cycle. Simultaneously, these enzymes were overexpressed in proliferative nodules leading to strong 5-hmC expression. We emphasize the significance of 5-hmC loss for discrimination of melanomas from benign proliferative nodules arising within giant congenital nevi, and for establishing the correct diagnosis in ambiguous cases when histological and immunohistochemical characteristics are not sufficiently specific. PMID- 27456755 TI - Prevalence and Age Distribution of Pemphigus and Pemphigoid Diseases in Germany. PMID- 27456756 TI - In Situ Mapping of Innate Lymphoid Cells in Human Skin: Evidence for Remarkable Differences between Normal and Inflamed Skin. AB - Although innate lymphoid cells (ILCs) have recently been identified also in skin, their role in this organ remains poorly understood. In this study, we aimed at developing a technique to assess ILCs in situ and to determine their topographical distribution in human skin. We collected lesional skin biopsies from patients with atopic dermatitis and psoriasis (both n = 13) and normal human skin from healthy controls. After establishing immunofluorescence ILC in situ stainings, we developed an analysis approach (gating combined with manual validation) to reliably identify ILCs. Topographical mapping was obtained by automated calculations of the distances between ILCs and different cellular/structural elements of the skin. Whereas normal human skin harbored a very scarce ILC population (mostly ILC1s and AHR+ILC3s), atopic dermatitis and psoriasis skin was infiltrated by clearly visible ILC subsets. We observed atopic dermatitis skin to contain not only ILC2s but also a prominent AHR+ILC3 population. Conversely, we encountered almost equal proportions of ILC1s and RORC+ILC3s in psoriasis skin. Distance calculations revealed ILCs to reside near the epidermis and in close proximity to T lymphocytes. ILC mapping in situ will provide valuable information about their likely communication partners in normal and diseased skin and forms the basis for the appropriate mechanistic studies. PMID- 27456757 TI - Presence of Hand Warts Is Associated with Subsequent Development of Cutaneous Squamous Cell Carcinoma in Psoriasis Patients Treated with Psoralen UVA (PUVA). PMID- 27456758 TI - Stathmin 1 plays a role in endometrial decidualisation by regulating hypoxia inducible factor-1alpha and vascular endothelial growth factor during embryo implantation. AB - The aim of the present study was to explore the potential mechanism underlying stathmin 1 (Stmn1) regulation of embryo implantation, as a continuation of previous proteomic research. Adult healthy female mice were mated naturally with fertile males. Murine uterine tissue was collected during the peri-implantation period. Local expression of Stmn1 during embryo implantation was detected by immunohistochemistry (IHC), which showed that Stmn1 was extensively expressed in endometrial glandular epithelium, vascular endothelium, luminal epithelium and the underlying stromal cells at the implantation site on Day 5. The role of Stmn1 during embryo implantation was evaluated by transient knockdown of Stmn1 in vivo using short interference (si) RNA, and some associated factors including Akt, phosphorylated (p-) Akt, hypoxia-inducible factor (HIF)-1alpha, prolactin (PRL), insulin-like growth factor binding protein (IGFBP) 1 and vascular endothelial growth factor (VEGF) were examined by western blotting analysis and ELISA. The number of embryos implanted after Stmn1-siRNA infusion into the lumen of one uterine horn was lower than that with normal pregnancies (2.2+/-1.5 vs 8.6+/-0.5 respectively; P<0.05). The expression of VEGF, HIF-1alpha, p-Akt and the decidualisation biomarkers PRL and IGFBP 1 was upregulated at the implantation site on Day 5, but downregulated after Stmn1-siRNA infusion. These findings suggest that during embryo implantation, knockdown of Stmn1 suppresses decidualisation by inhibiting the expression of p-Akt, HIF-1alpha and VEGF, thus leading to impaired embryo implantation. These findings provide clues for understanding the complicated process of embryo implantation and the potential role of Stmn1 during embryo implantation. PMID- 27456760 TI - Photoactivation of the Ni-SIr state to the Ni-SIa state in [NiFe] hydrogenase: FT IR study on the light reactivity of the ready Ni-SIr state and as-isolated enzyme revisited. AB - The Ni-SIr state of [NiFe] hydrogenase from Desulfovibrio vulgaris Miyazaki F was photoactivated to its Ni-SIa state by Ar(+) laser irradiation at 514.5 nm, whereas the Ni-SL state was light induced from a newly identified state, which was less active than any other identified state and existed in the "as-isolated" enzyme. PMID- 27456759 TI - Development and characterization of a long-acting nanoformulated abacavir prodrug. AB - AIM: A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half life and bioavailability. METHODS: Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice. RESULTS: MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks. CONCLUSION: MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen. PMID- 27456761 TI - OsMTOPVIB Promotes Meiotic DNA Double-Strand Break Formation in Rice. PMID- 27456762 TI - A decision support system for automatic sleep staging from EEG signals using tunable Q-factor wavelet transform and spectral features. AB - BACKGROUND: Automatic sleep scoring is essential owing to the fact that conventionally a large volume of data have to be analyzed visually by the physicians which is onerous, time-consuming and error-prone. Therefore, there is a dire need of an automated sleep staging scheme. NEW METHOD: In this work, we decompose sleep-EEG signal segments using tunable-Q factor wavelet transform (TQWT). Various spectral features are then computed from TQWT sub-bands. The performance of spectral features in the TQWT domain has been determined by intuitive and graphical analyses, statistical validation, and Fisher criteria. Random forest is used to perform classification. Optimal choices and the effects of TQWT and random forest parameters have been determined and expounded. RESULTS: Experimental outcomes manifest the efficacy of our feature generation scheme in terms of p-values of ANOVA analysis and Fisher criteria. The proposed scheme yields 90.38%, 91.50%, 92.11%, 94.80%, 97.50% for 6-stage to 2-stage classification of sleep states on the benchmark Sleep-EDF data-set. In addition, its performance on DREAMS Subjects Data-set is also promising. COMPARISON WITH EXISTING METHODS: The performance of the proposed method is significantly better than the existing ones in terms of accuracy and Cohen's kappa coefficient. Additionally, the proposed scheme gives high detection accuracy for sleep stages non-REM 1 and REM. CONCLUSIONS: Spectral features in the TQWT domain can discriminate sleep-EEG signals corresponding to various sleep states efficaciously. The proposed scheme will alleviate the burden of the physicians, speed-up sleep disorder diagnosis, and expedite sleep research. PMID- 27456763 TI - Source localization scale correction for Beamformer analysis. AB - BACKGROUND: Magnetoencephalography measurements are often processed by using imaging algorithms such as beamforming. The estimated source magnitude tends to suffer from unbalanced scaling across different brain locations. Hence, when examining current estimates for source activity it is vital to rescale the estimated source magnitude, in order to obtain a uniformly scaled image. NEW METHOD: We present a generalized scale correction method (Nempty) that uses empty room MEG measurements to evaluate the noise level. RESULTS: The location bias and spatial resolution of the estimated signal indicated that some scaling correction needs to be applied. Of all the scale correction methods that were tested, the best correction was achieved when using Nempty. COMPARISON WITH EXISTING METHODS: We show that a diagonal matrix does not reflect the true nature of the noise covariance matrix. Hence, diagonal matrix based methods are sub-optimal. CONCLUSION: We recommend adding empty room MEG measurements to each experimental recording session, for purposes of both scale correction and beamformer performance verification. PMID- 27456764 TI - An automated whisker tracking tool for the rat facial nerve injury paradigm. AB - BACKGROUND: The two-dimensional videographic analysis of vibrissal movements in behaving rodents has become a standard method to estimate the degree of functional impairment and recovery after facial nerve injuries quantitatively. The main limitation of the method is the time consuming, uneconomic process of manually tracking the vibrissae in video sequences. NEW METHOD: We developed a novel tool allowing automated detection of untagged vibrissae (two on each side of the snout). To compare the new method with the standard manual tracking approach, we used videos of unrestrained rats with unilateral section and immediate suture of the facial nerve performed two months earlier. RESULTS: Measurement agreement analyses showed that the two methods are equivalent for both "normal" high-amplitude vibrissal movements (non-operated side) and low amplitude whisking (reinnervated side). Spectral analysis revealed a significant deviation in the power spectra on the control and injured side, indicating that bilaterally coordinated whisker movements are not present two months after surgery. COMPARISON WITH EXISTING METHOD(S): The novel method yields results equal to those of the manual tracking approach. An advantage of our tool is the possibility to significantly increase sample size without additional labor cost. CONCLUSIONS: The novel tool can increase the efficacy and spectrum of functional measures used in facial nerve regeneration research. PMID- 27456765 TI - Giant quantum Hall plateaus generated by charge transfer in epitaxial graphene. AB - Epitaxial graphene has proven itself to be the best candidate for quantum electrical resistance standards due to its wide quantum Hall plateaus with exceptionally high breakdown currents. However one key underlying mechanism, a magnetic field dependent charge transfer process, is yet to be fully understood. Here we report measurements of the quantum Hall effect in epitaxial graphene showing the widest quantum Hall plateau observed to date extending over 50 T, attributed to an almost linear increase in carrier density with magnetic field. This behaviour is strong evidence for field dependent charge transfer from charge reservoirs with exceptionally high densities of states in close proximity to the graphene. Using a realistic framework of broadened Landau levels we model the densities of donor states and predict the field dependence of charge transfer in excellent agreement with experimental results, thus providing a guide towards engineering epitaxial graphene for applications such as quantum metrology. PMID- 27456766 TI - Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands. AB - BACKGROUND: Cytochrome P450 2U1 (CYP2U1) has been identified from the human genome and is highly conserved in the living kingdom. It is considered as an "orphan" protein as few data are available on its physiological function(s) and spectral characteristics. Its only known substrates reported so far are unsaturated fatty acids such as arachidonic acid (AA), and, more recently, N arachidonoylserotonin (AS) and some xenobiotics related to debrisoquine (Deb) and terfenadine. METHODS: We have expressed CYP2U1 in E. coli and performed UV-vis and EPR spectroscopy experiments with purified CYP2U1 alone and in the presence of substrates and imidazole and pyridine derivatives. Docking experiments using a 3D homology model of CYP2U1 were done to explain the observed spectroscopic data and the different regioselectivities of the oxidations of AA and AS. RESULTS: The UV-vis and EPR spectra of native recombinant human CYP2U1 revealed a predominant low-spin hexacoordinate FeIII state. Imidazole (Im) derivatives, such as miconazole, acted as FeIII ligands, contrary to ketoconazole, whereas the previously described substrates AS and Deb led to "reverse type I" difference UV vis spectra. These data, as well as the different regioselectivities of AA and AS oxidations, were supported by docking experiments performed on our previously reported CYP2U1 3D model. MAJOR CONCLUSION AND GENERAL SIGNIFICANCE: Our study describes for the first time the mode of interaction of several FeIII-heme ligands and substrates with the active site of CYP2U1 on the basis of spectroscopic and molecular docking data. The good agreement between these data validates the used CYP2U1 3D model which should help the design of new substrates or inhibitors of this orphan CYP. PMID- 27456767 TI - Deciphering hallmark processes of aging from interaction networks. AB - BACKGROUND: Aging is broadly considered to be a dynamic process that accumulates unfavourable structural and functional changes in a time dependent fashion, leading to a progressive loss of physiological integrity of an organism, which eventually leads to age-related diseases and finally to death. SCOPE OF REVIEW: The majority of aging-related studies are based on reductionist approaches, focusing on single genes/proteins or on individual pathways without considering possible interactions between them. Over the last few decades, several such genes/proteins were independently analysed and linked to a role that is affecting the longevity of an organism. However, an isolated analysis on genes and proteins largely fails to explain the mechanistic insight of a complex phenotype due to the involvement and integration of multiple factors. MAJOR CONCLUSIONS: Technological advance makes it possible to generate high-throughput temporal and spatial data that provide an opportunity to use computer-based methods. These techniques allow us to go beyond reductionist approaches to analyse large-scale networks that provide deeper understanding of the processes that drive aging. GENERAL SIGNIFICANCE: In this review, we focus on systems biology approaches, based on network inference methods to understand the dynamics of hallmark processes leading to aging phenotypes. We also describe computational methods for the interpretation and identification of important molecular hubs involved in the mechanistic linkage between aging related processes. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. PMID- 27456768 TI - Effect of donor age on the proliferation and multipotency of canine adipose derived mesenchymal stem cells. AB - Research into adipose tissue-derived mesenchymal stem cells (AD-MSCs) has demonstrated the feasibility of their use in clinical applications due to their ease of isolation and abundance in adipose tissue. We isolated AD-MSCs from young and old dogs, and the cells were subjected to sequential sub-passaging from passage 1 (P1) to P7. Canine AD-MSCs (cAD-MSCs) were examined for proliferation kinetics, expression of molecules associated with self-renewal, expression of cell surface markers, and differentiation potentials at P3. Cumulative population doubling level was significantly higher in cAD-MSCs of young donors than in those of old donors. In addition, expressions of CD73, CD80, Oct3/4, Nanog, cell survival genes and differentiation potentials were significantly higher in young donors than in old donors. The present study suggests that donor age should be considered when developing cell-based therapies for clinical application of cAD MSCs. PMID- 27456769 TI - Immunogenicity of recombinant Lactobacillus plantarum NC8 expressing goose parvovirus VP2 gene in BALB/c mice. AB - Goose parvovirus (GPV) continues to be a threat to goose farms and has significant economic effects on the production of geese. Current commercially available vaccines only rarely prevent GPV infection. In our study, Lactobacillus (L.) plantarum NC8 was selected as a vector to express the VP2 gene of GPV, and recombinant L. plantarum pSIP409-VP2/NC8 was successfully constructed. The molecular weight of the expressed recombinant protein was approximately 70 kDa. Mice were immunized with a 2 * 109 colony-forming unit/200 MUL dose of the recombinant L. plantarum strain, and the ratios and numbers of CD11c+, CD3+CD4+, CD3+CD8+, and interferon gamma- and tumor necrosis factor alpha-expressing spleen lymphocytes in the pSIP409-VP2/NC8 group were higher than those in the control groups. In addition, we assessed the capacity of L. plantarum SIP409-VP2/NC8 to induce secretory IgA production. We conclude that administered pSIP409-VP2/NC8 leads to relatively extensive cellular responses. This study provides information on GPV infection and offers a clear framework of options available for GPV control strategies. PMID- 27456770 TI - Extensive characterization of feline intra-abdominal adipose-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) isolated from various tissues have been well characterized for therapeutic application to clinical diseases. However, in contrast to MSCs from other animal species, the characteristics of feline MSCs have not been fully documented. In this study, we conducted extensive characterization of feline adipose tissue-derived MSCs (fAD-MSCs). Study fAD-MSCs were individually isolated from the intra-abdominal adipose tissues of six felines. The expression levels of cell surface markers and pluripotent markers were evaluated. Next, proliferation capacity was analyzed by performing cumulative population doubling level (CPDL) and doubling time (DT) calculation assays. Differentiation potentials of fAD-MSCs into mesodermal cell lineages were analyzed by examining specific staining and molecular markers. All fAD-MSCs positively expressed cell surface markers such as CD29, CD44, CD90, CD105, CD166, and MHC-I, while CD14, CD34, CD45, and CD73 were negatively expressed. The CPDL of the fAD-MSCs was maintained until passage 5 to 6 (P5 to P6), whereas DT increased after P3 to P4. Also, stem cell-specific pluripotent markers (Oct3/4, Nanog, and SSEA-4) were detected. Importantly, all fAD-MSCs demonstrated mesodermal differentiation capacity. These results suggest that fully characterized fAD-MSCs could be beneficial when considering the use of these cells in feline disease research. PMID- 27456771 TI - Porcine circovirus type 2 increases interleukin-1beta and interleukin-10 production via the MyD88-NF-kappa B signaling pathway in porcine alveolar macrophages in vitro. AB - Porcine alveolar macrophages (PAMs) represent the first line of defense in the porcine lung after infection with porcine circovirus type 2 (PCV2) via the respiratory tract. However, PCV2 infection impairs the microbicidal capability of PAMs and alters cytokine production and/or secretion. At present, the reason for the imbalance of cytokines has not been fully elucidated, and the regulatory mechanisms involved are unclear. In this study, we investigated the expression levels and regulation of interleukin-1beta (IL-1beta) and IL-10 in PAMs following incubation with PCV2 in vitro. Levels of IL-1beta and IL-10 increased in PAM supernatants, and the distribution of nuclear factor kappa B (NF-kappaB) p65staining in nucleus, expression of MyD88 and p-IkappaB in cytoplasm, and DNA binding activity of NF-kappaB increased after incubation with PCV2, while p65 expression in PAM cytoplasm decreased. However, when PAMs were co-incubated with PCV2 and small interfering RNA targeting MyD88, those effects were reversed. Additionally, mRNA expression levels of Toll-like receptors (TLR)-2, -3, -4, -7, 8, and -9 increased when PAMs were incubated with PCV2. These results show that PCV2 induces increased IL-1beta and IL-10 production in PAMs, and these changes in expression are related to the TLR-MyD88-NF-kappaB signaling pathway. PMID- 27456772 TI - Alginate encapsulation preserves the quality and fertilizing ability of Mediterranean Italian water buffalo (Bubalus bubalis) and Holstein Friesian (Bos taurus) spermatozoa after cryopreservation. AB - The use of artificial insemination (AI) in buffalo (Bubalus bubalis) is limited by poor ovarian activity during the hot season, seasonal qualitative patterns in semen, low resistance of sperm cells in the female tract, difficulties in estrus detection, and variable estrus duration. Although AI procedures are commonly used in bovine, use of AI has been limited in buffalo. In the zootechnical field, different studies have been conducted to develop techniques for improvement of fertilizing ability of buffalo spermatozoa after AI. In this study, for the first time, the use of alginate encapsulation and cryopreservation of buffalo spermatozoa is described, and the same procedure was performed with Holstein Friesian (Bos taurus) semen. Results obtained from in vitro analyses indicate that the encapsulation process does not have detrimental effects (compared to controls) on quality parameters (membrane integrity, progressive motility, path average velocity) in either species. Similarly, there were no detrimental effects after cryopreservation in either species. The fertilizing potential of encapsulated and cryopreserved semen was evaluated after AI in 25 buffalo and 113 bovine females. Pregnancy rates were not affected in either species. The results of this study show proof of concept for the use of frozen semen controlled release devices in buffalo. PMID- 27456773 TI - Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells. AB - The expression of stage-specific embryonic antigens (SSEAs) was determined in several types of canine cancer cells. Flow cytometry showed SSEA-1 expression in glioblastoma, melanoma, and mammary cancer cells, although none expressed SSEA-3 or SSEA-4. Expression of SSEA-1 was not detected in lymphoma, osteosarcoma, or hemangiosarcoma cell lines. Relatively stable SSEA-1 expression was observed between 24 and 72 h of culture. After 8 days in culture, sorted SSEA-1- and SSEA 1+ cells re-established SSEA-1 expression to levels comparable to those observed in unsorted cells. Our results document, for the first time, the expression of SSEA-1 in several canine cancer cell lines. PMID- 27456774 TI - Recurrence after exenteration for canine orbital malignant schwannoma. AB - A 14-year-old Maltese dog presented with progressive exophthalmos and external deviation of the right eye. Ultrasonography revealed the presence of a retrobulbar mass and fine-needle aspiration cytology was performed, which detected a malignant mass. There was no evidence of metastasis on thoracic and abdominal radiography. Computed tomography showed no invasion into the bony orbit and no metastasis to the lung or lymph nodes. Exenteration was performed to remove the mass completely. Malignant peripheral nerve sheath tumor was confirmed by histopathological examination. PMID- 27456775 TI - Surgical access via right thoracotomy facilitates tricuspid valve surgery in sheep. AB - In quadrupeds, the three-dimensional orientation of the heart with respect to the thorax is fundamentally different from that in humans. In this study, we assessed the best surgical approach to the tricuspid valve in sheep. Firstly, different surgical access sites to the tricuspid valve were tested in sheep cadavers, the anatomy was analyzed, and the optimal surgical approach to the tricuspid valve was determined. Secondly - along with cardiopulmonary bypass and cardioplegic arrest -the chosen approach was tested in six adult sheep in vivo. Anatomical analyses revealed that a left thoracotomy provided optimal access to the aorta and left heart. However, visualization of the right heart was significantly impaired. In contrast, a right thoracotomy provided good access to the right heart, but the ascending aorta was difficult to approach. Therefore, in the in vivo studies, arterial cannulation was performed through a carotid (n = 4) or femoral (n = 2) artery. In conclusion, a right-sided thoracotomy allows good visualization of all components of the tricuspid valve complex in sheep, but not of the ascending aorta. Consequently, peripheral vessels are preferred for arterial cannulation. This work may stimulate the investigation of pathomechanisms and/or novel treatment options for tricuspid valve pathologies. PMID- 27456776 TI - Molecular and phylogenetic analysis of Anaplasma spp. in sheep and goats from six provinces of China. AB - Members of the genus Anaplasma are important emerging tick-borne pathogens in both humans and animals in tropical and subtropical areas. Here, we investigated the presence of Anaplasma spp. in 621 sheep and 710 goats from six provinces of China. Polymerase chain reaction (PCR) and DNA sequencing were conducted to determine the prevalence of Anaplasma (A.) phagocytophilum, A. ovis and A. bovis targeting the 16S ribosomal RNA or the major surface protein 4 gene. PCR revealed Anaplasma in 39.0% (240/621) of sheep and 45.5% (323/710) of goats. The most frequently detected species was A. ovis (88/621, 14.2% for sheep; 129/710, 18.2% for goats), followed by A. bovis (60/621, 9.7% for sheep; 74/710, 10.4% for goats) and A. phagocytophilum (33/621, 5.3% for sheep; 15/710, 2.1% for goats). Additionally, eight sheep and 20 goats were found to be infected with three pathogens simultaneously. DNA sequencing confirmed the presence of these three Anaplasma species in the investigated areas, and phylogenetic analysis indicated that there was geographic segregation to a certain extent, as well as a relationship between the host and cluster of A. ovis. The results of the present study provide valuable data that helps understand the epidemiology of anaplasmosis in ruminants from China. PMID- 27456777 TI - Probiotic properties and adsorption of Enterococcus faecalis PSCT3-7 to vermiculite. AB - The probiotic properties of Enterococcus (E.) faecalis PSCT3-7, a new strain isolated from the intestines of pigs fed dietary fiber containing 50% sawdust, were investigated. E. faecalis PSCT3-7 tolerated a pH range of 3 to 8 and 0.3% bile salts, and it inhibited the growth of Salmonella Typhimurium in a concentration-dependent manner. In addition, E. faecalis showed resistance to several antibacterial agents. Vermiculite, a nutrient and microbial carrier, increased the bile tolerance of the strain. Scanning electron microscope images revealed good adsorption of E. faecalis PSCT3-7 onto vermiculite. E. faecalis PSCT3-7 represents a potential probiotic candidate to administer with vermiculite to swine. PMID- 27456778 TI - Genomic diversity of the Avian leukosis virus subgroup J gp85 gene in different organs of an infected chicken. AB - The genomic diversity of Avian leukosis virus subgroup J (ALV-J) was investigated in an experimentally infected chicken. ALV-J variants in tissues from four different organs of the same bird were re-isolated in DF-1 cells, and their gp85 gene was amplified and cloned. Ten clones from each organ were sequenced and compared with the original inoculum strain, NX0101. The minimum homology of each organ ranged from 96.7 to 97.6%, and the lowest homology between organs was only 94.9%, which was much lower than the 99.1% homology of inoculum NX0101, indicating high diversity of ALV-J, even within the same bird. The gp85 mutations from the left kidney, which contained tumors, and the right kidney, which was tumor-free, had higher non-synonymous to synonymous mutation ratios than those in the tumor-bearing liver and lungs. Additionally, the mutational sites of gp85 gene in the kidney were similar, and they differed from those in the liver and lung, implying that organ- or tissue-specific selective pressure had a greater influence on the evolution of ALV-J diversity. These results suggest that more ALV-J clones from different organs and tissues should be sequenced and compared to better understand viral evolution and molecular epidemiology in the field. PMID- 27456779 TI - Epizootiological characteristics of viable bacteria and fungi in indoor air from porcine, chicken, or bovine husbandry confinement buildings. AB - Microorganisms found in bioaerosols from animal confinement buildings not only foster the risk of spreading diseases among livestock buildings, but also pose health hazards to farm workers and nearby residents. This study identified the various microorganisms present in the air of swine, chicken, and cattle farms with different kinds of ventilation conditions in Korea. Microbial air samples were collected onto Petri dishes with bacterial or fungal growth media using a cascade impactor. Endotoxin levels in total dust were determined by the limulus amebocyte lysate kinetic QCL method. Prevalent Gram-positive bacteria were Staphylococcus (S.) lentus, S. chromogenes, Bacillus (B.) cereus, B. licheniformis, and Enterococcus faecalis, while the dominant fungi and Gram negative bacteria were Candida albicans and Sphingomonas paucimobilis, respectively. Considering no significant relationship between the indoor dust endotoxin levels and the isolation of Gram-negative bacteria from the indoor air, monitoring the indoor airborne endotoxin level was found to be also critical for risk assessment on health for animals or workers. The present study confirms the importance of microbiological monitoring and control on animal husbandry indoor air to ensure animal and worker welfare. PMID- 27456780 TI - Gastric volvulus with a large bochdalek hernia in an adult successfully treated with emergency endoscopic reduction followed by elective laparoscopic mesh repair: A case study. AB - We report a case of gastric volvulus with a large Bochdalek hernia successfully treated with emergency endoscopic reduction followed by elective laparoscopic mesh repair. The patient was a 71-year-old woman with no history of trauma. She was referred to our hospital because of nausea and vomiting after eating. Thoracic and abdominal CT showed gastric volvulus and a large Bochdalek hernia. The patient underwent emergency endoscopic reduction and elective laparoscopic surgery. The defect (10 * 12 cm) was reinforced with a Dual Mesh (expanded polytetrafluoroethylene) and fixed to the diaphragm with nonabsorbable sutures. The postoperative course was uneventful, and no complications or recurrence was found at the 2-year follow-up. The endoscopic reduction and elective laparoscopic procedure was performed successfully and resulted in significant clinical improvement in this case. PMID- 27456781 TI - Drosophila maleless gene counteracts X global aneuploid effects in males. AB - The loss of the entire X chromosome in Drosophila males generates a genome-wide aneuploid effect. We have employed a systems biology approach (microarray) to investigate the global aneuploid effect of the maleless (mle) mutation that disrupts the binding of male specific lethal (MSL) proteins that function in dosage compensation. A large number of the genes (144) that encode a broad spectrum of cellular transport proteins and transcription factors are located mainly in the autosomes of Drosophila melanogaster. We found several such targets to be sensitive to the aneuploid effect and conserved with the X chromosome in primitive Drosophila species and Anopheles gambiae. During evolution, they shifted gradually from their X-chromosomal positions to the autosomes in the species D. melanogaster, suggesting that the counteraction of trans-acting regulatory modifiers and their targets in two separate chromosomes is evolutionarily advantageous. These findings suggest a remarkable and previously unexpected level of complexity favoring natural compensation for the aneuploid effect. We propose that the MSL complex functions in dosage compensation in two separate steps. Initially, X-linked genes including X-linked trans-acting modifiers are hyperactivated in dosage compensated males. Later, these compensated modifiers eventually mitigate inverse aneuploid effects for the equality in expression of their autosomal targets in males and females. DATABASE: Microarray data are available at the Gene Expression Omnibus (GEO) web deposit of National Centre for Biotechnology Information (NCBI) with the accession number GSE78227. PMID- 27456782 TI - Novel homozygous sequence variants in the CDH3 gene encoding P-cadherin underlying hypotrichosis with juvenile macular dystrophy in consanguineous families. PMID- 27456783 TI - Pd(II)-Catalyzed Tandem Heterocyclization of 1-(1-Alkynyl)cyclopropyl Oxime Derivatives for the Synthesis of Functionalized Pyrroles. AB - An efficient approach for the synthesis of highly functionalized pyrroles has been developed by a Pd(TFA)2-catalyzed tandem heterocyclization of 1-(1 alkynyl)cyclopropyl oxime derivatives under mild conditions. The reaction first proceeded via an intramolecular nucleophilic attack followed by a ring-opening process and then intermolecular nucleophilic attack as well as protonation to afford the desired products in moderate to excellent yields. PMID- 27456784 TI - Comparative evaluation of cyclic fatigue resistance of four different nickel titanium rotary files with different cross-sectional designs and alloy properties. AB - OBJECTIVE: The purpose of the present study was to evaluate the cyclic fatigue resistance of F6 SkyTaper (Komet Brasseler, Lemgo, Germany), K3XF (SybronEndo, Orange, CA, USA), new generation OneShape (Micro Mega, Besancon, France) and TRUShape 3D conforming files (Dentsply Tulsa Dental Specialties, Tulsa, OK, USA). MATERIAL AND METHODS: Ten instruments from each group were selected and allowed to rotate using a low-torque motor in a stainless steel block with 1.5 mm diameter, 3 mm radius of 60 degrees angle of curvature at the manufacturer's recommended speed, and the number of cycles (NCF) from the beginning to the fracture was recorded. The data were analyzed using one-way ANOVA followed by post-hoc Tukey's test (P = 0.05). RESULTS: The ranking of the groups from the highest to the lowest NCF was as follows: F6 SkyTaper (959 +/- 92), K3XF (725 +/- 71), TRUShape (575 +/- 84) and OneShape (289 +/- 58). Statistically significant differences were detected between all groups (P < 0.05). CONCLUSION: Within the limitations of this study, F6 SkyTaper instruments presented the highest cyclic fatigue resistance among the tested instruments. The S-shaped cross-sectional design of F6 SkyTaper instruments could be the most important factor on the superior cyclic life span of these instruments. CLINICAL RELEVANCE: In endodontic practice, preferring the instruments with higher cyclic fatigue resistance would help to minimize the risk of instrument fractures; therefore especially during the preparation of curved canals, instruments with smaller core area and less cross-sectional metal mass, which could lead higher flexibility, can be proposed. PMID- 27456787 TI - Editor's notes. PMID- 27456785 TI - Estrogen Receptor Beta Selective Agonists as Agents to Treat Chemotherapeutic Induced Neuropathic Pain. AB - Chemotherapy-induced neuropathic pain (CINP) remains a major unmet medical need. Estrogen receptor beta (ERbeta)-selective agonists represent a novel strategy for treating CINP because they are neuroprotective and may also have anticancer activity. We confirmed that ERbeta-selective agonists have antiallodynic effects in the spinal nerve ligation model of neuropathic pain. We then showed that structurally diverse ERbeta-selective agonists also relieved allodynia in CINP caused by taxol, oxaliplatin, and vincristine. These effects were receptor subtype specific and mediated by ERbeta receptors as ERalpha-selective and nonselective estrogen agonists were inactive, a mixture of an ERbeta and ERalpha agonist was inactive, and ERbeta-selective antagonists blocked the effects of the ERbeta-selective agonists. The efficacy and potency of ERbeta-agonists was greater in male rats than females. To address the possibility that AC-186 might stimulate proliferation of cancers, rendering it unsuitable for treating CINP, we evaluated proliferative effects of AC-186 on prostate cancer cells and found it inhibited growth (LNCaP cells) or had no effect (PC3 cells) on these cells. Thus, ERbeta-selective agonists exhibit potential for treating CINP. PMID- 27456788 TI - Scanning sports. PMID- 27456789 TI - Coming in sportsmedicine. PMID- 27456790 TI - Brief Reports. PMID- 27456792 TI - Physician Certification in Sports Medicine: A Pathway in Continuing Education. PMID- 27456791 TI - Sportsmedicine forum. AB - A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Sportsmedicine Forum, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis 55435. PMID- 27456793 TI - Noteworthy. PMID- 27456795 TI - Running wild. PMID- 27456797 TI - Runner's Knee: What Is It and How Effective Is Conservative Management? AB - In brief: Forty-eight trained runners with runner's knee were examined, treated, and followed for eight months to identify the causes of this injury and its response to a particular regimen of conservative management. The subjects (41 men, 7 women), ranged in age from 20 to 40. Most trained from 40 to 80 km per week and had been running for four years or less; half had recently altered their training routine, the most common change being an increase in distance. Treatment consisted of prescribing appropriate running shoes alone (34%), orthoses alone (28%), shoes and orthoses (15%), appropriate running shoes plus ice application (19%), or icing alone (4%). Sixty-five percent of the subjects were symptom free within four weeks of starting treatment, a result at least equal to results cited in other reports. PMID- 27456798 TI - Stimulants and Athletic Performance (Part 2): Cocaine and Nicotine. AB - In brief: Cocaine and nicotine are among the stimulants that some athletes use in their quest for better performance or simple escape (amphetamines and caffeine were discussed in part 1 of this series [November, page 128]). Cocaine can cause paranoia and insomnia, and an overdose can lead to arrhythmias, coma, seizures, hyperthermia, and death. Nicotine affects several body systems and processes, and the impact of smoking on performance is negative in most cases. So far, little is known about how chewing tobacco influences performance. PMID- 27456799 TI - Implications of Smokeless Tobacco Use Among Athletes. AB - In brief: This literature review delineates the current status of smokeless tobacco. It discusses the prevalence and terminology as well as periodontal effects, buccal mucosal and soft-tissue alterations, leukoplakia, cancer, carcinogenic components, hemodynamic alterations, and potential addiction. It is clear that physicians and dentists should discourage their patients from using smokeless tobacco. Young people particularly may be influenced by popular sports figures and celebrities who convey the erroneous impression that smokeless tobacco is harmless. PMID- 27456800 TI - Painful Shoulder in Swimmers: A Diagnostic Challenge. AB - In brief: Painful shoulder can cause significant disability in swimmers, and in elite swimmers it may even force premature retirement. Treatment of this problem has been difficult, and surgery has been perceived as generally unsuccessful. The author asserts that "swimmer's shoulder" is not an anatomically based diagnosis and that the frequent lack of a specific diagnosis probably has hindered treatment. New investigative tools, such as arthrography and NMR imaging, have improved the chances of reaching an accurate diagnosis. The author lists the many regional problems that can cause shoulder pain, describes physical, clinical, and laboratory tests for use in diagnosis, and outlines approaches to management of the problem. PMID- 27456801 TI - The Caffeine Controversy: Effects on Endurance and Cholesterol. AB - In brief: Many endurance athletes use caffeine to enhance performance. This analysis of caffeine, endurance, and cholesterol considers whether and how caffeine is an ergogenic aid. It reviews the mechanisms of action and the pharmacological effects of caffeine; highlights eight studies of caffeine and exercise; surveys new research on exercise metabolism, coffee, cholesterol, and heart-attack risk; and offers a perspective on coffee consumption by athletes. The literature indicates that although caffeine in moderation is probably harmless, it does not predictably enhance performance, and the regular, heavy consumption of coffee may raise blood cholesterol and increase the risk of heart attack. Thus, coffee cannot be recommended for athletes. PMID- 27456802 TI - The Mandibular Orthopedic Repositioning Appliance and its Effect on Power Production in Conditioned Athletes. AB - In brief: Many athletes have used the mandibular orthopedic repositioning appliance (MORA) for alleged strength increases. In previous studies of the MORA, subjects were tested immediately after placement of the appliance. In this double blind study, the authors used a 72-hour adaptation period before examining the MORA's effect on the external muscle power of 11 university football players. Subjects were assigned to an experimental or a placebo/control group based on the degree of temporomandibular joint dysfunction. Before and after application of a MORA or a placebo mouthpiece, each subject's power was assessed in the seated press. Analysis of covariance was applied to the results and revealed no significant improvement for either group. PMID- 27456803 TI - Running Backward May Help Athletes Move Forward. AB - Some competitive and recreational athletes are running backward, believing that the activity will improve their ability to run forward. Crazy? Maybe not. Some researchers are finding that backward running may be an effective adjunct to forward running for both conditioning and rehabilitation. PMID- 27456804 TI - Quantifying Exercise Performance With SI Units. AB - The author argues that American exercise scientists and clinicians should voluntarily adopt the International System of Units, a refinement of the metric system. He shows how to use these units to describe two common exercise activities. PMID- 27456805 TI - Born to Jog: Exercise Programs for Preschoolers. AB - Exercise programs for infants and young children are popular, but are these types of programs necessary? PMID- 27456808 TI - Should Women Go Easy on Exercise? AB - Women who have been reading the lay press in recent months may get the idea that exercise is bad for them. But it ain't necessarily so. PMID- 27456806 TI - Aerobic Instructor Certification: Standards at Last? AB - The aerobic dance industry has made great strides toward getting organized. In response to a nationwide clamor for instructional standards, four major certifying bodies have emerged. PMID- 27456809 TI - Abstracts at a glance. PMID- 27456810 TI - Leverage and Strength. PMID- 27456812 TI - A novel approach to estimate the eruptive potential and probability in open conduit volcanoes. AB - In open conduit volcanoes, volatile-rich magma continuously enters into the feeding system nevertheless the eruptive activity occurs intermittently. From a practical perspective, the continuous steady input of magma in the feeding system is not able to produce eruptive events alone, but rather surplus of magma inputs are required to trigger the eruptive activity. The greater the amount of surplus of magma within the feeding system, the higher is the eruptive probability.Despite this observation, eruptive potential evaluations are commonly based on the regular magma supply, and in eruptive probability evaluations, generally any magma input has the same weight. Conversely, herein we present a novel approach based on the quantification of surplus of magma progressively intruded in the feeding system. To quantify the surplus of magma, we suggest to process temporal series of measurable parameters linked to the magma supply. We successfully performed a practical application on Mt Etna using the soil CO2 flux recorded over ten years. PMID- 27456813 TI - Quorum sensing systems differentially regulate the production of phenazine-1 carboxylic acid in the rhizobacterium Pseudomonas aeruginosa PA1201. AB - Pseudomonas aeruginosa strain PA1201 is a newly identified rhizobacterium that produces high levels of the secondary metabolite phenazine-1-carboxylic acid (PCA), the newly registered biopesticide Shenqinmycin. PCA production in liquid batch cultures utilizing a specialized PCA-promoting medium (PPM) typically occurs after the period of most rapid growth, and production is regulated in a quorum sensing (QS)-dependent manner. PA1201 contains two PCA biosynthetic gene clusters phz1 and phz2; both clusters contribute to PCA production, with phz2 making a greater contribution. PA1201 also contains a complete set of genes for four QS systems (LasI/LasR, RhlI/RhlR, PQS/MvfR, and IQS). By using several methods including gene deletion, the construction of promoter-lacZ fusion reporter strains, and RNA-Seq analysis, this study investigated the effects of the four QS systems on bacterial growth, QS signal production, the expression of phz1 and phz2, and PCA production. The possible mechanisms for the strain- and condition-dependent expression of phz1 and phz2 were discussed, and a schematic model was proposed. These findings provide a basis for further genetic engineering of the QS systems to improve PCA production. PMID- 27456814 TI - Dialectical Behaviour Therapy [DBT] with People with Intellectual Disabilities: A Systematic Review and Narrative Analysis. AB - BACKGROUND: There is mixed evidence regarding the effectiveness of psychological therapies for people with intellectual and developmental disorders. Although systematic reviews have supported the use of dialectical behaviour therapy with people with borderline personality disorder, there are no comparable reviews regarding DBT with people with intellectual and development disabilities. METHODS: Studies were identified using a systematic approach and were selected if they reported an intervention that included a DBT skills group and then assessed using the Evaluative Method for Determining Evidence Based Practice. RESULTS: Seven studies reported adaptations and outcomes of DBT for people with intellectual and development disabilities, four of which delivered full DBT programmes with three describing DBT skills groups. All studies were appraised with regard to methodological quality and the adaptations and results examined. CONCLUSIONS: The findings indicate that DBT and DBT skills groups can be adapted for people with intellectual and development disabilities, but further high quality research is needed to make conclusions about efficacy and effectiveness. PMID- 27456815 TI - An AIE-active fluorescence turn-on bioprobe mediated by hydrogen-bonding interaction for highly sensitive detection of hydrogen peroxide and glucose. AB - An AIE-active "turn-on" bioprobe is designed for hydrogen peroxide detection based on an imine-functionalized tetraphenylethene derivative. The linear fluorescence response enables quantification of hydrogen peroxide with superior sensitivity and selectivity. Meanwhile, glucose assay is also realized by taking advantage of GOx/glucose enzymatic reaction. PMID- 27456816 TI - Discovery and characterization of novel small-molecule CXCR4 receptor agonists and antagonists. AB - The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration, and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there have been no small molecule agonists reported. Herein, we describe the identification of a novel series of CXCR4 modulators, including the first small molecules to display agonist behavior against this receptor, using a combination of structure- and ligand-based virtual screening. These agonists produce robust calcium mobilization in human melanoma cell lines which can be blocked by the CXCR4 selective antagonist AMD3100. We also demonstrate the ability of these new agonists to induce receptor internalization, ERK activation, and chemotaxis, all hallmarks of CXCR4 activation. Our results describe a new series of biologically relevant small molecules that will enable further study of the CXCR4 receptor and may contribute to the development of new therapeutics. PMID- 27456817 TI - Phononic Structure Engineering: the Realization of Einstein Rattling in Calcium Cobaltate for the Suppression of Thermal Conductivity. AB - Phonons in condensed matter materials transmit energy through atomic lattices as coherent vibrational waves. Like electronic and photonic properties, an improved understanding of phononic properties is essential for the development of functional materials, including thermoelectric materials. Recently, an Einstein rattling mode was found in thermoelectric material Na0.8CoO2, due to the large displacement of Na between the [CoO2] layers. In this work, we have realized a different type of rattler in another thermoelectric material Ca3Co4O9 by chemical doping, which possesses the same [CoO2] layer as Na0.8CoO2. It remarkably suppressed the thermal conductivity while enhancing its electrical conductivity. This new type of rattler was investigated by inelastic neutron scattering experiments in conjunction with ab-initio molecular dynamics simulations. We found that the large mass of dopant rather than the large displacement is responsible for such rattling in present study, which is fundamentally different from skutterudites, clathrates as well as Na analogue. We have also tentatively studied the phonon band structure of this material by DFT lattice dynamics simulation, showing the relative contribution to phonons in the distinct layers of Ca3Co4O9. PMID- 27456818 TI - New cosurface capacitive stimulators for the development of active osseointegrative implantable devices. AB - Non-drug strategies based on biophysical stimulation have been emphasized for the treatment and prevention of musculoskeletal conditions. However, to date, an effective stimulation system for intracorporeal therapies has not been proposed. This is particularly true for active intramedullary implants that aim to optimize osseointegration. The increasing demand for these implants, particularly for hip and knee replacements, has driven the design of innovative stimulation systems that are effective in bone-implant integration. In this paper, a new cosurface based capacitive system concept is proposed for the design of implantable devices that deliver controllable and personalized electric field stimuli to target tissues. A prototype architecture of this system was constructed for in vitro tests, and its ability to deliver controllable stimuli was numerically analyzed. Successful results were obtained for osteoblastic proliferation and differentiation in the in vitro tests. This work provides, for the first time, a design of a stimulation system that can be embedded in active implantable devices for controllable bone-implant integration and regeneration. The proposed cosurface design holds potential for the implementation of novel and innovative personalized stimulatory therapies based on the delivery of electric fields to bone cells. PMID- 27456820 TI - Immunomodulatory and Anti-cancer Properties of Pharmacologically Relevant Mushroom Glycans. AB - The review of patents reveals that for decades, mushrooms have been regarded as an ethnic medicine and widely used in the treatment of various life-threatening diseases. One of the most important bioactive compounds isolated from these mushrooms are polysaccharides or glycans which exhibit potential immunomodulatory and anticancer properties. The immune stimulating properties of these glycans are linked to their origin, structure, composition, water solubility and conformations in solution. Moreover, modification of glycans to increase its size to a particulate form has also shown significant increase in its activity. Glycans are regarded as pathogen associated molecu- lar pattern (PAMP) like molecules which bind to specific pattern recognition receptors (PRRs) on the surface of immune cells. This binding induces the activation of a signaling cascade that directs the synthesis of a repertoire of immune effector molecules. Anticancer effects of glycans have been mostly associated with an increased immune activity while few cases are available which advocate its direct role on cancer cells. This review thereby provides a comprehensive outlook on the structure-function relationship of these pharmacologically relevant mushroom glycans. PMID- 27456819 TI - Molecular Markers Useful for Intraspecies Subtyping and Strain Differentiation of Dermatophytes. AB - Dermatophytosis is a very common skin disorder and the most frequent infection encountered by practicing dermatologists. The identification, pathogenicity, biology, and epidemiology of dermatophytes, the causative agents of dermatophytosis, are of interest for both dermatologists and medical mycologists. Recent advances in molecular methods have provided new techniques for identifying dermatophytes, including intraspecies variations. Intraspecies subtyping and strain differentiation have made possible the tracking of infections, the identification of common sources of infections, recurrence or reinfection after treatment, and analysis of strain virulence and drug resistance. This review describes molecular methods of intraspecies subtyping and strain differentiation, including analyses of mitochondrial DNA and non-transcribed spacer regions of ribosomal RNA genes, random amplification of polymorphic DNA, and microsatellite markers, along with their advantages and limitations. PMID- 27456821 TI - Food Biotechnology: A Step Towards Improving Nutritional Quality of Food for Asian Countries. AB - BACKGROUND: Food-based technologies established itself as a vast, inter disciplinary and multifaceted research area are at crossroads of scientific and technological advancements. The review of patents reveals that growing concerns over the source of nourishment for the burgeoning population, its quality, quantity and safety, along with associated human and environmental welfare has inspired global researchers to implement several new bio-based technologies. OBJECTIVE: Biotechnological interventions in food sector have been aimed at enhancing/modifying taste, aroma, shelf-life, texture and nutritional value of food products employing fermentation, enzyme technology, nanotechnology and molecular biology. The use of whole microbes as a source of nutrition and genetically modified microorganisms to be used as food or genetically modified food have been successfully attempted, which has addressed the mass population and malnutrition. Further, the processing techniques have been improved along with the proper utilization of food wastes for the generation of many useful byproducts. CONCLUSION: The article covers broadly the impact of biotechnological interventions in food sector. Techniques mostly discussed include not only the nutrient enriched food production but also byproduct utilization through proper improvisation of food waste into bioenergy, biomanure and other value added products, which is of great economic and environmental importance. This article reviews the overall aspects in relation to some of the recent advancements in food sector. PMID- 27456822 TI - Effect of Packaging on Shelf-life and Lutein Content of Marigold (Tagetes erecta L.) Flowers. AB - BACKGROUND: African marigold (Tagetes erecta L.) flowers are highly valued for their ornamental appeal as well as medicinal properties. However, their short shelf lives cause high post-harvest loss and limit their export potential. The review of patents and research articles revealed that different types of packaging designs/materials have been successfully employed for extension of shelf lives of cut flowers. OBJECTIVE: The current work focuses on designing of different packaging configurations and selection of best configuration for preservation of marigold cut flowers. METHODS: Ten packaging configurations, composed of four different packaging materials i.e., low density polyethylene (LDPE), polyethylene terephthalate, glassine paper and cellophane paper, were designed. Each pack, consisting of 20 +/- 1 g of marigold flowers along with non packaged control set were stored at 23 +/- 2 degrees C, 80% R.H., in an environmental chamber and the flowers were evaluated for their sensory attributes, phytochemical characteristics and physicochemical parameters of senescence to determine their shelf lives. RESULTS: Flowers packed in LDPE bag showed highest shelf life of 8 days with a lead of 4 days compared to control (shelf life - 4 days). This study also established for the first time the phenomenon of carotenogenesis in marigold cut flowers with significantly (P<0.01) higher production of lutein in LDPE packaged flowers. CONCLUSION: LDPE pack was the best design among the ten package designs, in preserving lutein content of marigold flowers and extending their shelf lives. This economically viable packaging can not only boost the export potential of this ornamental flower, but also allow utilization of nutraceutical potency of lutein. PMID- 27456823 TI - Acute Toxicity of the Pesticides, Dichlorvos and Lindane against the African air breathing catfish, Heterobranchus longifilis, Valenciennes, 1840 (Siluriformes: Clariidae). AB - BACKGROUND: This study raises the awareness to the use of toxic pesticides and reiterates the well-known danger of these pesticides. The acute toxicity of two pesticides, dichlorvos and lindane against the African air-breathing catfish, Heterobranchus longifilis fingerlings was investigated under static bioassay in the laboratory. Relevant patents relating to acute toxicity of pesticides against fish were reviewed. Invention concerning the detection of biomarkers in material from a living organism relates to a method of testing whether a living organism has been exposed to stress, such as pesticide exposure. METHODS: Range finding bioassays were conducted to get the range of concentrations for the definitive bioassays. The range of concentrations of test media for dichlorvos was 0.2 - 1.5 mg l-1 while that of lindane was 35 - 80 mg l-1. The median lethal concentrations were determined using probit analysis. RESULTS: The test pesticides were found to be differentially toxic to the test species. The 96h LC50 values of 0.8187 and 41.566 mg l-1 for dichlorvos and lindane respectively indicated that dichlorvos was highly toxic while lindane was slightly toxic to the test species. Computed toxicity factor showed that dichlorvos was 50.8 times more toxic than lindane. The unpaired t-test showed that dichlorvos was significantly (p < 0.05) more toxic than lindane. The physical and chemical parameters data showed that over the 96h periods, the test pesticides caused slight increase in temperature, dissolved oxygen and ammonia of the test media, when compared with the untreated control. But they differentially altered pH, conductivity and alkalinity. CONCLUSION: Since H. longifilis is sensitive to the test pesticides, it can therefore be considered as a good test species for the determination of acute toxicity and poisoning resulting from the pesticides and possibly for other compounds with similar intrinsic characteristics. PMID- 27456824 TI - Association of ABCB1 Gene Polymorphisms with Efficacy and Adverse Reaction to Risperidone or Paliperidone in Han Chinese Schizophrenic Patients. PMID- 27456825 TI - The use of Immunoglobulin Therapy in Primary Immunodeficiency Diseases. AB - Immunoglobulin therapy represents a lifesaving intervention for many patients with primary immunodeficiency (PID). Antibody defects represent approximately half of the well-known PIDs requiring immunoglobulin replacement therapy. Following immunoglobulin therapy in PID patients, protection against serious upper and lower respiratory tract infections and pulmonary function improves which leads to an increase in the quality of life of these patients. Successful treatment of PID patients depends on the type of immunodeficiency, regular monitoring of the patient, comorbidities of the patient, and the availability of the products. PMID- 27456826 TI - Sea ice and millennial-scale climate variability in the Nordic seas 90 kyr ago to present. AB - In the light of rapidly diminishing sea ice cover in the Arctic during the present atmospheric warming, it is imperative to study the distribution of sea ice in the past in relation to rapid climate change. Here we focus on glacial millennial-scale climatic events (Dansgaard/Oeschger events) using the sea ice proxy IP25 in combination with phytoplankton proxy data and quantification of diatom species in a record from the southeast Norwegian Sea. We demonstrate that expansion and retreat of sea ice varies consistently in pace with the rapid climate changes 90 kyr ago to present. Sea ice retreats abruptly at the start of warm interstadials, but spreads rapidly during cooling phases of the interstadials and becomes near perennial and perennial during cold stadials and Heinrich events, respectively. Low-salinity surface water and the sea ice edge spreads to the Greenland-Scotland Ridge, and during the largest Heinrich events, probably far into the Atlantic Ocean. PMID- 27456827 TI - Saliva-Induced Clotting Captures Streptococci: Novel Roles for Coagulation and Fibrinolysis in Host Defense and Immune Evasion. AB - Streptococcal pharyngitis is among the most common bacterial infections, but the molecular mechanisms involved remain poorly understood. Here we investigate the interactions among three major players in streptococcal pharyngitis: streptococci, plasma, and saliva. We find that saliva activates the plasma coagulation system through both the extrinsic and the intrinsic pathways, entrapping the bacteria in fibrin clots. The bacteria escape the clots by activating host plasminogen. Our results identify a potential function for the intrinsic pathway of coagulation in host defense and a corresponding role for fibrinolysis in streptococcal immune evasion. PMID- 27456828 TI - Salmonella Infection Enhances Erythropoietin Production by the Kidney and Liver, Which Correlates with Elevated Bacterial Burdens. AB - Salmonella infection profoundly affects host erythroid development, but the mechanisms responsible for this effect remain poorly understood. We monitored the impact of Salmonella infection on erythroid development and found that systemic infection induced anemia, splenomegaly, elevated erythropoietin (EPO) levels, and extramedullary erythropoiesis in a process independent of Salmonella pathogenicity island 2 (SPI2) or flagellin. The circulating EPO level was also constitutively higher in mice lacking the expression of signal-regulatory protein alpha (SIRPalpha). The expression level of EPO mRNA was elevated in the kidney and liver but not increased in the spleens of infected mice despite the presence of extramedullary erythropoiesis in this tissue. In contrast to data from a previous report, mice lacking EPO receptor (EPOR) expression on nonerythroid cells (EPOR rescued) had bacterial loads similar to those of wild-type mice following Salmonella infection. Indeed, treatment to reduce splenic erythroblasts and mature red blood cells correlated with elevated bacterial burdens, implying that extramedullary erythropoiesis benefits the host. Together, these findings emphasize the profound effect of Salmonella infection on erythroid development and suggest that the modulation of erythroid development has both positive and negative consequences for host immunity. PMID- 27456829 TI - The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis. AB - Giardia duodenalis is a noninvasive luminal pathogen that impairs digestive function in its host in part by reducing intestinal disaccharidase activity. This enzyme deficiency has been shown in mice to require CD8(+) T cells. We recently showed that both host immune responses and parasite strain affected disaccharidase levels during murine giardiasis. However, high doses of antibiotics were used to facilitate infections in that study, and we therefore decided to systematically examine the effects of antibiotic use on pathogenesis and immune responses in the mouse model of giardiasis. We found that antibiotic treatment did not overtly increase the parasite burden but significantly limited the disaccharidase deficiency observed in infected mice. Moreover, while infected mice had more activated CD8(+) alphabeta T cells in the small intestinal lamina propria, this increase was absent in antibiotic-treated mice. Infection also led to increased numbers of CD4(+) alphabeta T cells in the lamina propria and activation of T cell receptor gammadelta-expressing intraepithelial lymphocytes (IEL), but these changes were not affected by antibiotics. Finally, we show that activated CD8(+) T cells express gamma interferon (IFN-gamma) and granzymes but that granzymes are not required for sucrase deficiency. We conclude that CD8(+) T cells become activated in giardiasis through an antibiotic-sensitive process and contribute to reduced sucrase activity. These are the first data directly demonstrating activation of CD8(+) T cells and gammadelta T cells during Giardia infections. These data also demonstrate that disruption of the intestinal microbiota by antibiotic treatment prevents pathological CD8(+) T cell activation in giardiasis. PMID- 27456830 TI - Role of Serum Amyloid A, Granulocyte-Macrophage Colony-Stimulating Factor, and Bone Marrow Granulocyte-Monocyte Precursor Expansion in Segmented Filamentous Bacterium-Mediated Protection from Entamoeba histolytica. AB - Intestinal segmented filamentous bacteria (SFB) protect from ameba infection, and protection is transferable with bone marrow dendritic cells (BMDCs). SFB cause an increase in serum amyloid A (SAA), suggesting that SAA might mediate SFB's effects on BMDCs. Here we further explored the role of bone marrow in SFB mediated protection. Transient gut colonization with SFB or SAA administration alone transiently increased the H3K27 histone demethylase Jmjd3, persistently increased bone marrow Csf2ra expression and granulocyte monocyte precursors (GMPs), and protected from ameba infection. Pharmacologic inhibition of Jmjd3 H3K27 demethylase activity during SAA treatment or blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) signaling in SFB-colonized mice prevented GMP expansion, decreased gut neutrophils, and blocked protection from ameba infection. These results indicate that alteration of the microbiota and systemic exposure to SAA can influence myelopoiesis and susceptibility to amebiasis via epigenetic mechanisms. Gut microbiota-marrow communication is a previously unrecognized mechanism of innate protection from infection. PMID- 27456831 TI - Recombinant Mucin-Type Fusion Proteins with a Galalpha1,3Gal Substitution as Clostridium difficile Toxin A Inhibitors. AB - The capability of a recombinant mucin-like fusion protein, P-selectin glycoprotein ligand-1/mouse IgG2b (PSGL-1/mIgG2b), carrying Galalpha1,3Galbeta1,4GlcNAc determinants to bind and inhibit Clostridium difficile toxin A (TcdA) was investigated. The fusion protein, produced by a glyco-engineered stable CHO-K1 cell line and designated C-PGC2, was purified by affinity and gel filtration chromatography from large-scale cultures. Liquid chromatography-mass spectrometry was used to characterize O-glycans released by reductive beta-elimination, and new diagnostic ions to distinguish Galalpha1,3Gal from Galalpha1,4Gal-terminated O-glycans were identified. The C-PGC2 cell line, which was 20-fold more sensitive to TcdA than the wild-type CHO-K1, is proposed as a novel cell-based model for TcdA cytotoxicity and neutralization assays. The C-PGC2-produced fusion protein could competitively inhibit TcdA binding to rabbit erythrocytes, making it a high-efficiency inhibitor of the hemagglutination property of TcdA. The fusion protein also exhibited a moderate capability for neutralization of TcdA cytotoxicity in both C-PGC2 and CHO-K1 cells, the former with and the latter without cell surface Galalpha1,3Galbeta1,4GlcNAc sequences. Future studies in animal models of C. difficile infection will reveal its TcdA inhibitory effect and therapeutic potential in C. difficile-associated diseases. PMID- 27456832 TI - Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala. AB - Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection. PMID- 27456833 TI - Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms. AB - As the major cause of antibiotic-associated diarrhea, Clostridium difficile is a serious problem in health care facilities worldwide. C. difficile produces two large toxins, TcdA and TcdB, which are the primary virulence factors in disease. The respective functions of these toxins have been difficult to discern, in part because the cytotoxicity profiles for these toxins differ with concentration and cell type. The goal of this study was to develop a cell culture model that would allow a side-by-side mechanistic comparison of the toxins. Conditionally immortalized, young adult mouse colonic (YAMC) epithelial cells demonstrate an exquisite sensitivity to both toxins with phenotypes that agree with observations in tissue explants. TcdA intoxication results in an apoptotic cell death that is dependent on the glucosyltransferase activity of the toxin. In contrast, TcdB has a bimodal mechanism; it induces apoptosis in a glucosyltransferase-dependent manner at lower concentrations and glucosyltransferase-independent necrotic death at higher concentrations. The direct comparison of the responses to TcdA and TcdB in cells and colonic explants provides the opportunity to unify a large body of observations made by many independent investigators. PMID- 27456834 TI - Proinflammatory M1 Macrophages Inhibit RANKL-Induced Osteoclastogenesis. AB - In response to a defined panel of stimuli, immature macrophages can be classified into two major phenotypes: proinflammatory (M1) and anti-inflammatory (M2). Although both phenotypes have been implicated in several chronic inflammatory diseases, their direct role in bone resorption remains unclear. The present study investigated the possible effects of M1 and M2 macrophages on RANKL-induced osteoclastogenesis. In osteoclastogenesis assays using RAW264.7 cells or bone marrow cells as osteoclast precursors, addition of M1 macrophages significantly suppressed RANKL-induced osteoclastogenesis compared to nonstimulated conditions (M0), addition of M2 macrophages, or no macrophage addition (P < 0.05), suggesting that M1 macrophages can downregulate osteoclastogenesis. This effect was maintained when direct contact between M1 and osteoclast precursors was interrupted by cell culture insertion, indicating engagement of soluble factors released from M1. M1 macrophages developed from interferon gamma (IFN-gamma) knockout (IFN-gamma-KO) mice lost the ability to downregulate osteoclastogenesis. Antibody-based neutralization of interleukin-12 (IL-12), but not IL-10, produced by M1 macrophages also abrogated M1-mediated downregulation of osteoclastogenesis. Real-time PCR analyses showed that IFN-gamma suppressed gene expression of NFATc1, a master regulator of osteoclastogenesis, whereas IL-12 increased the apoptosis of osteoclasts, suggesting molecular mechanisms underlying the possible roles of IFN-gamma or IL-12 in M1-mediated inhibition of osteoclastogenesis. These findings were confirmed in an in vivo ligature-induced mouse periodontitis model in which adoptive transfer of M1 macrophages showed a significantly lower level of bone loss and less tartrate-resistant acid phosphatase (TRAP)-positive cell induction than M0 or M2 macrophage transfer. In conclusion, by its secretion of IFN-gamma and IL-12, M1, but not M0 or M2, was demonstrated to inhibit osteoclastogenesis. PMID- 27456835 TI - Microvascular and Macrovascular Disease and Risk for Major Peripheral Arterial Disease in Patients With Type 2 Diabetes. AB - OBJECTIVE: Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis in type 2 diabetes, but the relationship between other vascular diseases and PAD has been poorly investigated. We examined the impact of previous microvascular and macrovascular disease on the risk of major PAD in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We analyzed 10,624 patients with type 2 diabetes free from baseline major PAD in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) clinical trial. The primary composite outcome was major PAD defined as PAD induced death, peripheral revascularization, lower-limb amputation, or chronic ulceration. The secondary end points were the PAD components considered separately. RESULTS: Major PAD occurred in 620 (5.8%) participants during 5 years of follow-up. Baseline microvascular and macrovascular disease were both associated with subsequent risk of major PAD after adjustment for age, sex, region of origin, and randomized treatments. However, only microvascular disease remained significantly associated with PAD after further adjustment for established risk factors. The highest risk was observed in participants with a history of macroalbuminuria (hazard ratio 1.91 [95% CI 1.38-2.64], P < 0.0001) and retinal photocoagulation therapy (1.60 [1.11-2.32], P = 0.01). Baseline microvascular disease was also associated with a higher risk of chronic lower limb ulceration (2.07 [1.56-2.75], P < 0.0001) and amputation (1.59 [1.15-2.22], P = 0.006), whereas baseline macrovascular disease was associated with a higher rate of angioplasty procedures (1.75 [1.13-2.73], P = 0.01). CONCLUSIONS: Microvascular disease, particularly macroalbuminuria and retinal photocoagulation therapy, strongly predicts major PAD in patients with type 2 diabetes, but macrovascular disease does not. PMID- 27456836 TI - Do Electrochemiluminescence Assays Improve Prediction of Time to Type 1 Diabetes in Autoantibody-Positive TrialNet Subjects? AB - OBJECTIVE: To explore whether electrochemiluminescence (ECL) assays can help improve prediction of time to type 1 diabetes in the TrialNet autoantibody positive population. RESEARCH DESIGN AND METHODS: TrialNet subjects who were positive for one or more autoantibodies (microinsulin autoantibody, GAD65 autoantibody [GADA], IA-2A, and ZnT8A) with available ECL-insulin autoantibody (IAA) and ECL-GADA data at their initial visit were analyzed; after a median follow-up of 24 months, 177 of these 1,287 subjects developed diabetes. RESULTS: Univariate analyses showed that autoantibodies by radioimmunoassays (RIAs), ECL IAA, ECL-GADA, age, sex, number of positive autoantibodies, presence of HLA DR3/4 DQ8 genotype, HbA1c, and oral glucose tolerance test (OGTT) measurements were all significantly associated with progression to diabetes. Subjects who were ECL positive had a risk of progression to diabetes within 6 years of 58% compared with 5% for the ECL-negative subjects (P < 0.0001). Multivariate Cox proportional hazards models were compared, with the base model including age, sex, OGTT measurements, and number of positive autoantibodies by RIAs. The model with positivity for ECL-GADA and/or ECL-IAA was the best, and factors that remained significantly associated with time to diabetes were area under the curve (AUC) C peptide, fasting C-peptide, AUC glucose, number of positive autoantibodies by RIAs, and ECL positivity. Adding ECL to the Diabetes Prevention Trial risk score (DPTRS) improved the receiver operating characteristic curves with AUC of 0.83 (P < 0.0001). CONCLUSIONS: ECL assays improved the ability to predict time to diabetes in these autoantibody-positive relatives at risk for developing diabetes. These findings might be helpful in the design and eligibility criteria for prevention trials in the future. PMID- 27456837 TI - Health and Psychosocial Outcomes of a Telephonic Couples Behavior Change Intervention in Patients With Poorly Controlled Type 2 Diabetes: A Randomized Clinical Trial. AB - OBJECTIVE: To compare glycemic control and secondary outcomes of a 4-month telephonic couples behavioral intervention to individual intervention, and to education, for adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized trial with the following three arms: couples calls (CC) (n = 104); individual calls (IC) (n = 94); and diabetes education (DE) (n = 82). All arms had self-management education (two calls). CC and IC had 10 additional behavior change calls. CC addressed collaboration and relationships/communication. Participants consisted of 280 couples, among whom one partner had type 2 diabetes and an A1C level >=7.5%. Blinded assessments occurred at 4, 8, and 12 months. The primary outcome was change in A1C; and secondary outcomes were BMI, waist circumference, blood pressure, depressive symptoms, diabetes self-efficacy, and diabetes distress. RESULTS: Patients had a mean age of 56.8 years; 61.6% were male, and 30.4% were minorities. The baseline mean A1C level was 9.1%. Intention to-treat analyses found significant A1C reductions for all (12 months: CC -0.47%, IC -0.52%, DE -0.57%), with no differences between arms. Preplanned within-arm analyses were stratified by baseline A1C tertiles: lowest tertile (7.5-8.2%), no change from baseline; middle tertile (8.3-9.2%), only CC led to significantly lower A1C level; and highest tertile (>=9.3%), significant improvement for all interventions. For BMI, CC showed significant improvement, and CC and DE led to decreased waist circumference. The IC group showed greater blood pressure improvement. Results for secondary psychosocial outcomes favored the CC group. CONCLUSIONS: In adults with poorly controlled type 2 diabetes, a collaborative couples intervention resulted in significant, lasting improvement in A1C levels, obesity measures, and some psychosocial outcomes. For those with exceedingly high A1C levels, education alone was beneficial, but additional intervention is needed to achieve glycemic targets. PMID- 27456838 TI - Exogenous application of double-stranded RNA molecules from TMV p126 and CP genes confers resistance against TMV in tobacco. AB - MAIN CONCLUSION: External application of dsRNA molecules from Tobacco mosaic virus (TMV) p126 and CP genes confers significant resistance against TMV infection. Exogenously applied dsRNA exhibits a rapid systemic trafficking in planta , and it is processed successfully by DICER-like proteins producing small interfering RNAs. RNA interference (RNAi) is a sequence-specific, post transcriptional gene silencing mechanism, induced by double-stranded RNA (dsRNA), which protects eukaryotic cells against invasive nucleic acids like viruses and transposons. In the present study, we used a non-transgenic strategy to induce RNAi in Nicotiana tabacum cv. Xanthi plants against TMV. DsRNA molecules for the p126 (TMV silencing suppressor) and coat protein (CP) genes were produced by a two-step PCR approach followed by in vitro transcription. The application of TMV p126 dsRNA onto tobacco plants induced greater resistance against TMV infection as compared to CP dsRNA (65 vs. 50 %). This study also reported the fast systemic spread of TMV p126 dsRNA from the treated (local) to non-treated (systemic) leaves beginning from 1 h post-application, confirmed by both conventional and real-time RT-PCR. Furthermore, we employed a stem-loop RT-PCR and confirmed the presence of a putative viral siRNA for up to 9 days in local leaves and up to 6 days in systemic leaves post-application. The approach employed could represent a simple and environmentally safe way for the control of plant viruses in future agriculture. PMID- 27456840 TI - The Effects of Helmet Weight on Hybrid III Head and Neck Responses by Comparing Unhelmeted and Helmeted Impacts. AB - Most studies on football helmet performance focus on lowering head acceleration related parameters to reduce concussions. This has resulted in an increase in helmet size and mass. The objective of this paper was to study the effect of helmet mass on head and upper neck responses. Two independent test series were conducted. In test series one, 90 pendulum impact tests were conducted with four different headform and helmet conditions: unhelmeted Hybrid III headform, Hybrid III headform with a football helmet shell, Hybrid III headform with helmet shell and facemask, and Hybrid III headform with the helmet and facemask with mass added to the shell (n = 90). The Hybrid III neck was used for all the conditions. For all the configurations combined, the shell only, shell and facemask, and weighted helmet conditions resulted in 36%, 43%, and 44% lower resultant head accelerations (p < 0.0001), respectively, when compared to the unhelmeted condition. Head delta-V reductions were 1.1%, 4.5%, and 4.4%, respectively. In contrast, the helmeted conditions resulted in 26%, 41%, and 49% higher resultant neck forces (p < 0.0001), respectively. The increased neck forces were dominated by neck tension. In test series two, testing was conducted with a pneumatic linear impactor (n = 178). Fourteen different helmet makes and models illustrate the same trend. The increased neck forces provide a possible explanation as to why there has not been a corresponding reduction in concussion rates despite improvements in helmets ability to reduce head accelerations. PMID- 27456842 TI - The effect of pregnancy on the progression of diabetic retinopathy. AB - PURPOSE: To evaluate the progression and risk factors of diabetic retinopathy during and after pregnancy in patients with diabetes. METHODS: We checked the medical records of the patients with diabetes who were referred to the Diabetes Center, Tokyo Women's Medical University Hospital (Tokyo, Japan), and were pregnant between August 2004 and September 2010. The patients whose ophthalmic examinations records could not be found (n = 15) were excluded, and thus 93 patients (type 1 = 68, type 2 = 25) were included in the analyses. Data were obtained from the medical record and evaluated. RESULTS: The mean pre-pregnancy HbA1c was 7.1 +/- 0.8 %. All patients were encouraged to maintain HbA1c level of under 7.4 % before pregnancy. At baseline, the percentage of patients with no retinopathy was 78 %, with nonproliferative retinopathy 14 %, and with proliferative retinopathy, 8 %. Progression of retinopathy occurred in 16 (17 %) patients. Two (2 %) had loss of visual acuity and 1 (1 %) underwent laser treatment due to progression of retinopathy. Compared with patients who did not show progression, the patients with progression were characterized by longer duration of diabetes (p < 0.00001), presence of diabetic retinopathy before pregnancy (p < 0.00001) and higher blood pressure in the second trimester (p < 0.05). CONCLUSIONS: Frequent ophthalmic examination, especially in patients with a long history of diabetes, is recommended, as well as for patients with presence of diabetic retinopathy before pregnancy. In contrast to previous reports, the progression of retinopathy in this study was lower. This is probably due to our patients' pre-pregnancy tight glucose control and the high ratio of patients with no retinopathy at baseline. PMID- 27456839 TI - Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. AB - BACKGROUND: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research. DESIGN: A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. RESULTS: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally, on the cooperation between the urologist and nephrologist in the renal stone patients. CONCLUSIONS: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders, emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified. PMID- 27456843 TI - Radiating hemorrhage in exudative age-related macular degeneration. AB - PURPOSE: To investigate the characteristics of radiating hemorrhage secondary to exudative age-related macular degeneration (AMD) and its clinical significance. METHODS: This retrospective, observational case series included 288 eyes of 288 patients who initially presented with submacular hemorrhage secondary to exudative AMD. First, we estimated the incidence of radiating hemorrhage; we then compared the incidence of polypoidal choroidal vasculopathy (PCV) compared with that of the other subtypes of AMD. Optical coherence tomography (OCT) images were analyzed to identify the level of hemorrhage. The extent of submacular hemorrhage was compared between eyes with and without radiating hemorrhage. RESULTS: Radiating hemorrhage was identified in 41 eyes (14.2 %). In 36 of these eyes, the OCT scanning line included the area of radiating hemorrhage. In 31 of these, OCT showed avulsion of the outer retinal layers, including the outer nuclear layer and photoreceptor layer. The outer plexiform layer and inner retinal layer were relatively well preserved. The extent of submacular hemorrhage was significantly smaller in eyes with radiating hemorrhage (mean 4.2 +/- 2.9 disc areas) than in eyes without it (mean 8.3 +/- 6.2 disc areas) (P < 0.001). In addition, the incidence of radiating hemorrhage was significantly higher in eyes with submacular hemorrhage secondary to PCV (19.4 %) than in those with the other subtypes of AMD (7.5 %; P = 0.025). CONCLUSIONS: Radiating hemorrhage in exudative AMD was found to be a deep retinal hemorrhage generally accompanied with relatively small-sized submacular hemorrhage. The incidence of this type of hemorrhage was higher in PCV than in the other subtypes of AMD. PMID- 27456841 TI - Association of the tumor necrosis factor-alpha promoter polymorphism with change in triacylglycerol response to sequential meals. AB - BACKGROUND: Reported associations between Tumor Necrosis Factor-alpha (TNFA) and the postprandial triacylglycerol (TAG) response have been inconsistent, which could be due to variations in the TNFA gene, meal fat composition or participant's body weight. Hence, we investigated the association of TNFA polymorphism (-308G -> A) with body mass index (BMI) and postprandial lipaemia and also determined the impact of BMI on the association of the polymorphism with postprandial lipaemia. METHODS: The study participants (n = 230) underwent a sequential meal postprandial study. Blood samples were taken at regular intervals after a test breakfast (t = 0, 49 g fat) and lunch (t =330 min, 29 g fat) to measure fasting and postprandial lipids, glucose and insulin. The Metabolic Challenge Study (MECHE) comprising 67 Irish participants who underwent a 54 g fat oral lipid tolerance test was used as a replication cohort. The impact of genotype on postprandial responses was determined using general linear model with adjustment for potential confounders. RESULTS: The -308G -> A polymorphism showed a significant association with BMI (P = 0.03) and fasting glucose (P = 0.006), where the polymorphism explained 13 % of the variation in the fasting glucose. A 30 % higher incremental area under the curve (IAUC) was observed for the postprandial TAG response in the GG homozygotes than A-allele carriers (P = 0.004) and the genotype explained 19 % of the variation in the IAUC. There was a non-significant trend in the impact of BMI on the association of the genotype with TAG IAUC (P = 0.09). These results were not statistically significant in the MECHE cohort, which could be due to the differences in the sample size, meal composition, baseline lipid profile, allelic diversity and postprandial characterisation of participants across the two cohorts. CONCLUSIONS: Our findings suggest that TNFA -308G -> A polymorphism may be an important candidate for BMI, fasting glucose and postprandial TAG response. Further studies are required to investigate the mechanistic effects of the polymorphism on glucose and TAG metabolism, and determine whether BMI is an important variable which should be considered in the design of future studies. TRIAL REGISTRATION: NCT01172951 . PMID- 27456844 TI - A comparison of two methods for expert elicitation in health technology assessments. AB - BACKGROUND: When data needed to inform parameters in decision models are lacking, formal elicitation of expert judgement can be used to characterise parameter uncertainty. Although numerous methods for eliciting expert opinion as probability distributions exist, there is little research to suggest whether one method is more useful than any other method. This study had three objectives: (i) to obtain subjective probability distributions characterising parameter uncertainty in the context of a health technology assessment; (ii) to compare two elicitation methods by eliciting the same parameters in different ways; (iii) to collect subjective preferences of the experts for the different elicitation methods used. METHODS: Twenty-seven clinical experts were invited to participate in an elicitation exercise to inform a published model-based cost-effectiveness analysis of alternative treatments for prostate cancer. Participants were individually asked to express their judgements as probability distributions using two different methods - the histogram and hybrid elicitation methods - presented in a random order. Individual distributions were mathematically aggregated across experts with and without weighting. The resulting combined distributions were used in the probabilistic analysis of the decision model and mean incremental cost-effectiveness ratios and the expected values of perfect information (EVPI) were calculated for each method, and compared with the original cost effectiveness analysis. Scores on the ease of use of the two methods and the extent to which the probability distributions obtained from each method accurately reflected the expert's opinion were also recorded. RESULTS: Six experts completed the task. Mean ICERs from the probabilistic analysis ranged between L162,600-L175,500 per quality-adjusted life year (QALY) depending on the elicitation and weighting methods used. Compared to having no information, use of expert opinion decreased decision uncertainty: the EVPI value at the L30,000 per QALY threshold decreased by 74-86 % from the original cost-effectiveness analysis. Experts indicated that the histogram method was easier to use, but attributed a perception of more accuracy to the hybrid method. CONCLUSIONS: Inclusion of expert elicitation can decrease decision uncertainty. Here, choice of method did not affect the overall cost-effectiveness conclusions, but researchers intending to use expert elicitation need to be aware of the impact different methods could have. PMID- 27456845 TI - The Healthy Primary School of the Future: study protocol of a quasi-experimental study. AB - BACKGROUND: Unhealthy lifestyles in early childhood are a major global health challenge. These lifestyles often persist from generation to generation and contribute to a vicious cycle of health-related and social problems. This design article presents a study evaluating the effects of two novel healthy school interventions. The main outcome measure will be changes in children's body mass index (BMI). In addition, lifestyle behaviours, academic achievement, child well being, socio-economic differences, and societal costs will be examined. METHODS: In close collaboration with various stakeholders, a quasi-experimental study was developed, for which children of four intervention schools (n = 1200) in the southern part of the Netherlands are compared with children of four control schools (n = 1200) in the same region. The interventions started in November 2015. In two of the four intervention schools, a whole-school approach named 'The Healthy Primary School of the Future', is implemented with the aim of improving physical activity and dietary behaviour. For this intervention, pupils are offered an extended curriculum, including a healthy lunch, more physical exercises, and social and educational activities, next to the regular school curriculum. In the two other intervention schools, a physical-activity school approach called 'The Physical Activity School', is implemented, which is essentially similar to the other intervention, except that no lunch is provided. The interventions proceed during a period of 4 years. Apart from the effectiveness of both interventions, the process, the cost-effectiveness, and the expected legal implications are studied. Data collection is conducted within the school system. The baseline measurements started in September 2015 and yearly follow-up measurements are taking place until 2019. DISCUSSION: A whole-school approach is a new concept in the Netherlands. Due to its innovative, multifaceted nature and sound scientific foundation, these integrated programmes have the potential to form a template for primary schools worldwide. The effects of this approach may extend further than the outcomes associated with well-being and academic achievement, potentially impacting legal and cultural aspects in our society. TRIAL REGISTRATION: The study protocol was registered in the database ClinicalTrials.gov on 14-06-2016 with the reference number NCT02800616 . PMID- 27456846 TI - Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets. AB - BACKGROUND: Although males contribute half of the embryo's genome, only recently has interest begun to be directed toward the potential impact of paternal experiences on the health of offspring. While there is evidence that paternal malnutrition may increase offspring susceptibility to metabolic diseases, the influence of paternal factors on a daughter's breast cancer risk has been examined in few studies. METHODS: Male Sprague-Dawley rats were fed, before and during puberty, either a lard-based (high in saturated fats) or a corn oil-based (high in n-6 polyunsaturated fats) high-fat diet (60 % of fat-derived energy). Control animals were fed an AIN-93G control diet (16 % of fat-derived energy). Their 50-day-old female offspring fed only a commercial diet were subjected to the classical model of mammary carcinogenesis based on 7,12 dimethylbenz[a]anthracene initiation, and mammary tumor development was evaluated. Sperm cells and mammary gland tissue were subjected to cellular and molecular analysis. RESULTS: Compared with female offspring of control diet-fed male rats, offspring of lard-fed male rats did not differ in tumor latency, growth, or multiplicity. However, female offspring of lard-fed male rats had increased elongation of the mammary epithelial tree, number of terminal end buds, and tumor incidence compared with both female offspring of control diet-fed and corn oil-fed male rats. Compared with female offspring of control diet-fed male rats, female offspring of corn oil-fed male rats showed decreased tumor growth but no difference regarding tumor incidence, latency, or multiplicity. Additionally, female offspring of corn oil-fed male rats had longer tumor latency as well as decreased tumor growth and multiplicity compared with female offspring of lard-fed male rats. Paternal consumption of animal- or plant-based high-fat diets elicited opposing effects, with lard rich in saturated fatty acids increasing breast cancer risk in offspring and corn oil rich in n-6 polyunsaturated fatty acids decreasing it. These effects could be linked to alterations in microRNA expression in fathers' sperm and their daughters' mammary glands, and to modifications in breast cancer-related protein expression in this tissue. CONCLUSIONS: Our findings highlight the importance of paternal nutrition in affecting future generations' risk of developing breast cancer. PMID- 27456847 TI - Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. AB - BACKGROUND: Use of menopausal hormonal therapy (MHT)-containing estrogen and a synthetic progestin is associated with an increased risk of breast cancer. It is unclear if progesterone in combination with estrogen carries a lower risk of breast cancer. Limited data suggest differences between progesterone and progestins on cardiovascular risk factors, including cholesterol and glucose metabolism. Whether this translates to differences in cardiovascular outcomes is uncertain. We conducted a systematic review and meta-analysis to synthesize the existing evidence about the effect of progesterone in comparison to synthetic progestins, each in combination with estrogens, on the risk of breast cancer and cardiovascular events. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus through 17 May 2016 for studies that enrolled postmenopausal women using progesterone vs. synthetic progestins and reported the outcomes of interest. Study selection and data extraction were performed by two independent reviewers. Meta-analysis was conducted using the random effects model. RESULTS: We included two cohort studies and one population based case-control study out of 3410 citations identified by the search. The included studies enrolled 86,881 postmenopausal women with mean age of 59 years and follow-up range from 3 to 20 years. The overall risk of bias of the included cohort studies in the meta-analysis was moderate. There was no data on cardiovascular events. Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55-0.81. CONCLUSIONS: Observational studies suggest that in menopausal women, estrogen and progesterone use may be associated with lower breast cancer risk compared to synthetic progestin. PMID- 27456848 TI - Trial outcomes and information for clinical decision-making: a comparative study of opinions of health professionals. AB - BACKGROUND: Trials are robust sources of data for clinical practice; however, trial outcomes may not reflect what is important to communicate for decision making. The study compared clinicians' views of outcomes to include in a core outcome set for colorectal cancer (CRC) surgery, with what clinicians considered important information for clinical practice (core information). METHODS: Potential outcome/information domains were identified through systematic literature reviews, reviews of hospital information leaflets and interviews with patients. These were organized into six categories and used to design a questionnaire survey that asked surgeons and nurses from a sample of CRC centers to rate the importance of each domain as an outcome or as information on a nine point Likert scale. Respondents were re-surveyed (round 2) following group feedback (Delphi methods). Comparisons were made by calculating the difference in mean scores between the outcomes and information domains, and paired t tests were used to explore the difference between mean scores of the six outcome/information categories. RESULTS: Data sources identified 1216 outcome/information items for CRC surgery that informed a 94-item questionnaire. First-round questionnaires were returned from 63/81 (78 %) of centers. Clinicians rated 76/94 (84 %) domains of higher importance to measure in trials than information to communicate to patients in round 1. This was reduced to 24/47 (51 %) in round 2. The greatest difference was evident in domains regarding survival, which was rated much more highly as a trial outcome than an important piece of information for decision making (difference in mean 2.3, 95 % CI 1.9 to 2.8, p <0.0001). Specific complications and quality-of-life domains were rated similarly (difference in mean 0.18, 95 % CI -0.1 to 0.4, p = 0.2 and difference in mean 0.2, 95 % CI -0.1 to 0.5, p = 0.2, respectively). CONCLUSIONS: Whilst clinicians want to measure key outcomes in trials, they rate these as less important to communicate in decision-making with patients. This discrepancy needs to be explored and addressed to maximize the impact of trials on clinical practice. PMID- 27456850 TI - Anti-lipoapoptotic effects of Alisma orientalis extract on non-esterified fatty acid-induced HepG2 cells. AB - BACKGROUND: Liver steatosis was caused by lipid accumulation in the liver. Alisma orientale (AO) is recognized as a promising candidate with therapeutic efficacy for the treatment of nonalcoholic fatty liver disease (NAFLD). HepG2 hepatocyte cell line is commonly used for liver disease cell model. METHOD: The HepG2 cells were cultured with the NEFAs mixture (oleic and palmitic acids, 2:1 ratio) for 24 h to induce hepatic steatosis. Then different doses of Alisma orientale extract (AOE) was treated to HepG2 for 24 h. Incubated cells were used for further experiments. RESULTS: The AOE showed inhibitory effects on lipid accumulation in the Oil Red O staining and Nile red staining tests with no cytotoxicity at a concentration of 300 MUg/mL. Fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) mRNA and protein expression level were down-regulated after AOE treatment. Bcl-2 associated X protein (Bax) and c-Jun N-terminal kinase (JNK) mRNA expression level were decreased as well as p-JNK (activated form of JNK), Bax, cleaved caspase-9, caspase-3 protein expression level. Anti-apopototic B cell lymphoma 2 (Bcl-2) protein level increased after AOE treatment. In addition, inflammatory protein expression including p-p65, p65, COX-2 and iNOS were inhibited by AOE treatment. CONCLUSION: The results suggest that AOE has anti steatosis effects that involve lipogenesis, anti-lipoapoptosis, and anti inflammation in the NEFA-induced NAFLD pathological cell model. PMID- 27456851 TI - Outcome analysis for prediction of early and long-term survival in patients receiving intra-aortic balloon pumping after cardiac surgery. AB - BACKGROUND: Patients requiring an intra-aortic balloon pump (IABP) after cardiac surgery are critically ill and need a prolonged ICU stay. Considering limited health care resources, the early identification of patients with an extremely poor prognosis is important as a solid base for the decision whether further aggressive continuation or cessation of the therapy is recommendable. METHODS: From 2001 to 2007, 552 patients with low-output syndrome after open-heart surgery and IABP implantation in OR or within 24 h thereafter on ICU were retrospectively analyzed. RESULTS: The overall mortality at 30 and 180-day were 31 and 40 %, respectively. According to multivariate analyses, following factors were used to generate an IABP score: female gender, age >=70 years, simultaneous coronary and valve surgery, aortic cross-clamp time >120 min., need of norepinephrin more than 0.4 ug kg(-1) min(-1), postoperative dialysis, and maximal serum creatinine kinase >3000 mg mL(-1). The 30-day mortality continuously increased along the score (10.1 % for score = 0, n = 98; 11.8 % for score = 1, n = 144; 27.5 % for score = 2, n = 153; 40.4 % score = 3, n = 89; 65.2 % for score = 4, n = 46; 77.8 % for score = 5, n = 27) and reached 100 % for all patients with a score of 6 (n = 4). CONCLUSIONS: Prediction of 30 days mortality was possible with our scoring system based on multivariate analysis, and patients with scores of 4 or greater had remarkably worse early and late survival. PMID- 27456849 TI - Dendritic cells as gatekeepers of tolerance. AB - Dendritic cells (DC) are unique hematopoietic cells, linking innate and adaptive immune responses. In particular, they are considered as the most potent antigen presenting cells, governing both T cell immunity and tolerance. In view of their exceptional ability to present antigen and to interact with T cells, DC play distinct roles in shaping T cell development, differentiation and function. The outcome of the DC-T cell interaction is determined by the state of DC maturation, the type of DC subset, the cytokine microenvironment and the tissue location. Both regulatory T cells (Tregs) and DC are indispensable for maintaining central and peripheral tolerance. Over the past decade, accumulating data indicate that DC critically contribute to Treg differentiation and homeostasis. PMID- 27456852 TI - Wnt5a mediated canonical Wnt signaling pathway activation in orthodontic tooth movement: possible role in the tension force-induced bone formation. AB - Orthodontic tooth movement (OTM) is associated with bone remodeling mediated by orthodontic mechanical loading. Increasing studies reported that Wnt signaling played crucial roles in mechanical stimuli induced bone remodeling. However, little is known about the involvement of Wnt signaling in orthodontic force induced bone formation during OTM. In virtue of the OTM mice model as we previously reported, where new bone formation was determined by micro-CT and immunoreactivity of osteocalcin and osterix, we explored the activation of Wnt signaling pathway during OTM. Our results proved the nuclei translocation of beta catenin, suggesting the activation of canonical Wnt signaling pathway in the periodontal ligament cells (PDLCs) near the alveolar bone at the tension site (TS). Moreover, the immunoreactivity of Wnt5a, but not Wnt3a in PDLCs indicated the activation of canonical Wnt pathway might be mediated by Wnt5a, but not Wnt3a as in most cases. The co-location of Wnt5a and beta-catenin that was evidenced by double labeling immunofluorescence staining further supported the hypothesis. In addition, the high expression of FZD4 and LRP5 in PDLCs at TS of periodontium suggested that the activation of Wnt signaling pathway was mediated by these receptors. The negligible expression of ROR2 also indicated that canonical but not non-canonical Wnt signaling pathway was activated by Wnt5a, since previous studies demonstrated that the activation of canonical/non-canonical Wnt signaling pathway was largely dependent on the receptors. In summary, we here reported that Wnt5a mediated activation of canonical Wnt signaling pathway might contribute to the orthodontic force induced bone remodeling. PMID- 27456853 TI - p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines. AB - BACKGROUND: We recently demonstrated the cytotoxicity of liquid crystal precursors (hereafter referred to as "mesogenic compounds") in the human non small cell lung cancer (NSCLC) cell line A549 which carry wild-type p53. p53 mutations are observed in 50 % of NSCLC and contribute to their resistance to chemotherapy. To develop more effective and cancer-specific agents, in this study, we investigated the structure-activity relationships of mesogenic compounds with cytotoxic effects against multiple NSCLC cells. METHODS: The pharmacological effects of mesogenic compounds were examined in human NSCLC cells (A549, LU99, EBC-1, and H1299) and normal WI-38 human fibroblast. Analyses of the cell cycle, cell-death induction, and capsases expression were performed. RESULTS: The 3-ring compounds possessing terminal alkyl and hydroxyl groups (compounds C1-C5) showed cytotoxicity in NSCLC cells regardless of the p53 status. The compounds C1 and C3, which possess a pyrimidine at the center of the core, induced G2/M arrest, while the compounds without a pyrimidine (C2, C4, and C5) caused G1 arrest; all compounds produced caspase-mediated cell death. These events occurred in a p53-independent manner. Furthermore, it was suggested that compounds induced cell death through p53-independent DNA damage-signaling pathway. Compounds C2, C4, and C5 did not show strong cytotoxicity in WI-38 cells, whereas C1 and C3 did. However, the cytotoxicity of compound C1 against WI 38 cells was improved by modulating the terminal alkyl chain lengths of the compound. CONCLUSIONS: We showed the p53-indepdent structure-activity relationships of mesogenic compounds related to the cytotoxic effects. These structure-activity relationships will be helpful in the development of more effective and cancer-specific agents. PMID- 27456854 TI - miRNAs and sports: tracking training status and potentially confounding diagnoses. AB - BACKGROUND: The dependency of miRNA abundance from physiological processes such as exercises remains partially understood. We set out to analyze the effect of physical exercises on miRNA profiles in blood and plasma of endurance and strength athletes in a systematic manner and correlated differentially abundant miRNAs in athletes to disease miRNAs biomarkers towards a better understanding of how physical exercise may confound disease diagnosis by miRNAs. METHODS: We profiled blood and plasma of 29 athletes before and after exercise. With four samples analyzed for each individual we analyzed 116 full miRNomes. The study set up enabled paired analyses of individuals. Affected miRNAs were investigated for known disease associations using network analysis. RESULTS: MiRNA patterns in blood and plasma of endurance and strength athletes vary significantly with differences in blood outreaching variations in plasma. We found only moderate differences between the miRNA levels before training and the RNA levels after training as compared to the more obvious variations found between strength athletes and endurance athletes. We observed significant variations in the abundance of miR-140-3p that is a known circulating disease markers (raw and adjusted p value of 5 * 10(-12) and 4 * 10(-7)). Similarly, the levels of miR-140 5p and miR-650, both of which have been reported as makers for a wide range of human pathologies significantly depend on the training mode. Among the most affected disease categories we found acute myocardial infarction. MiRNAs, which are up-regulated in endurance athletes inhibit VEGFA as shown by systems biology analysis of experimentally validated target genes. CONCLUSION: We provide evidence that the mode and the extent of training are important confounding factors for a miRNA based disease diagnosis. PMID- 27456855 TI - Prevalence and predictors of hand involvement in Thai patients with systemic sclerosis. AB - AIM: Data regarding the clinical and radiographic hand involvement in Asian patients with systemic sclerosis (SSc) are limited. Thus, we determined the prevalence of clinical and radiographic hand involvement in Thai SSc patients, comparing diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). We also determined the factors associated with arthritis, contracture of fingers and digital ulcers. METHOD: SSc patients seen at the Rheumatology Clinic, Chiang Mai University, Thailand, from December 2012 to June 2013 were consecutively invited to enroll in the study. After study entry, demographic data, clinical features and hand radiographs were evaluated. RESULT: We studied 110 SSc patients (73 dcSSc) with mean +/- SD age of 53.2 +/- 9.2 years and disease duration from non Raynaud's phenomenon of 4.9 +/- 4.8 years. The prevalence of arthritis, finger contractures and digital ulcers were 10 (9.1%), 47 (42.7%), and 14 (12.7%), respectively. DcSSc patients had significantly more of the following hand complications than lcSSc patients: digital pitting scar (53.4% vs. 27.0%, P = 0.008), digital ulcer (17.8% vs. 2.7%, P = 0.032), traumatic ulcer (27.4% vs. 0%, P < 0.001), acrolysis (45.2% vs. 18.9%, P = 0.007) and flexion contracture (60.3% vs. 8.1%, P < 0.001). Radiographic finger contractures were more prevalent in the dcSSc subset. In multivariate logistic regression analysis, a positive rheumatoid factor was associated with arthritis; dcSSc, arthritis and modified Rodnan skin score (MRSS) > 18 were associated with contracture of fingers. Furthermore, hand MRSS > 4 was associated with digital ulcers. CONCLUSION: Our results confirm that dcSSc patients had more severe clinical hand complications than lcSSc. However, radiographic findings were similar among subgroups, except that more finger contractures were seen in dcSSc. Finally, the presence of rheumatoid factor is associated with arthritis, and high MRSS is associated with finger contractures and digital ulcers. PMID- 27456856 TI - Atomic-Scale Origin of Long-Term Stability and High Performance of p-GaN Nanowire Arrays for Photocatalytic Overall Pure Water Splitting. AB - The atomic-scale origin of the unusually high performance and long-term stability of wurtzite p-GaN oriented nanowire arrays is revealed. Nitrogen termination of both the polar (0001-) top face and the nonpolar (101-0) side faces of the nanowires is essential for long-term stability and high efficiency. Such a distinct atomic configuration ensures not only stability against (photo) oxidation in air and in water/electrolyte but, as importantly, also provides the necessary overall reverse crystal polarization needed for efficient hole extraction in p-GaN. PMID- 27456857 TI - Staying Alive: Measuring Intact Viable Microbes with Electrospray Ionization Mass Spectrometry. AB - Mass spectrometry has traditionally been the technology of choice for small molecule analysis, making significant inroads into metabolism, clinical diagnostics, and pharmacodynamics since the 1960s. In the mid-1980s, with the discovery of electrospray ionization (ESI) for biomolecule analysis, a new door opened for applications beyond small molecules. Initially, proteins were widely examined, followed by oligonucleotides and other nonvolatile molecules. Then in 1991, three intriguing studies reported using mass spectrometry to examine noncovalent protein complexes, results that have been expanded on for the last 25 years. Those experiments also raised the questions: How soft is ESI, and can it be used to examine even more complex interactions? Our lab addressed these questions with the analyses of viruses, which were initially tested for viability following electrospray ionization and their passage through a quadrupole mass analyzer by placing them on an active medium that would allow them to propagate. This observation has been replicated on multiple different systems, including experiments on an even bigger microbe, a spore. The question of analysis was also addressed in the early 2000s with charge detection mass spectrometry. This unique technology could simultaneously measure mass-to-charge and charge, allowing for the direct determination of the mass of a virus. More recent experiments on spores and enveloped viruses have given us insight into the range of mass spectrometry's capabilities (reaching 100 trillion Da), beginning to answer fundamental questions regarding the complexity of these organisms beyond proteins and genes, and how small molecules are integral to these supramolecular living structures. Graphical Abstract ?. PMID- 27456858 TI - Validity of the Portuguese CHO-KLAT in Brazil. AB - INTRODUCTION: It is essential to assess the health-related quality of life outcomes of boys with haemophilia in Brazil. The Canadian Haemophilia Outcomes Kids Life Assessment Tool (CHO-KLAT) was recently adapted for this population. AIM: To test the construct validity of the Portuguese version of the CHO-KLAT. METHODS: We recruited 50 boys, with moderate [factor VIII (FVIII) level 1-5%] or severe (FVIII level <1%) haemophilia, to participate in a descriptive study to establish a baseline understanding of the current status of boys with haemophilia in Brazil. All boys were required to complete the Brazilian CHO-KLAT and Brazilian Pediatric Quality of Life Inventory (PedsQL) by self-report. We examined the correlation between the CHO-KLAT and PedsQL scores to establish the construct validity of the Brazilian version of the CHO-KLAT. RESULTS: We obtained CHO-KLAT and PedsQL data from 35 boys with severe haemophilia and 15 with moderate haemophilia. They ranged in age from 7.3 to 18.0 years, with a mean of 13.0 years. They reported a mean CHO-KLAT score of 72.3 (range = 44.1-93.9). The mean PedsQL score was 79.9 (range = 45.7-96.7), with physical health (mean of 83.9) being better than psychosocial health (77.8). The Pearson's correlation between CHO-KLAT and PedsQL was 0.47 respectively (P < 0.001). The CHO-KLAT had a moderate and inverse relationship with the degree to which they were bothered by their haemophilia (rho = -0.53), while the PedsQL had a weaker relationship (rho = -0.27). CONCLUSION: The results confirm the validity of the Portuguese version of the CHO-KLAT. This measure is now available for clinical trials in boys with haemophilia in Brazil. PMID- 27456859 TI - Erratum to: Change in urinary storage symptoms following treatment for female stress urinary incontinence. PMID- 27456860 TI - Do symptom-based questions help screen COPD among Chinese populations? AB - Spirometry is required to confirm a chronic obstructive pulmonary disease (COPD) diagnosis, but it is difficult to perform in resource-limited settings. This study aimed to evaluate symptom-based questions for screening of individuals with COPD among Chinese populations. We recruited 3969 adult subjects from the First Affiliated Hospital of Nanjing Medical University. Spirometric measurements of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were collected to confirm the COPD diagnosis. A symptom-based questionnaire was administered to collect data related to COPD. The sensitivity and specificity together with the area under the curve (AUC) were calculated. The traditional IPAG eight-item questionnaire yielded an AUC of 0.80(95% CI: 0.78-0.82), with a sensitivity of 67.8% and specificity of 76.8%. After removing and adding questions, a revised eleven-item questionnaire exhibited a significantly increased diagnostic accuracy, with an AUC of 0.85(95% CI: 0.84-0.87). At the inflection point of the curve, it demonstrated a sensitivity of 82.5% and specificity of 72.9%. We showed that the revised symptom-based questionnaire could be used to screen individuals with a high likelihood of COPD among Chinese populations. Further validation is required before we claim it is a useful diagnostic for primary care populations. PMID- 27456861 TI - Dengue and chikungunya viruses in plasma are effectively inactivated after treatment with methylene blue and visible light. AB - BACKGROUND: Arboviruses, such as dengue viruses (DENV) and chikungunya virus (CHIKV), pose a risk to the safe transfusion of blood components, including plasma. Pathogen inactivation is an approach to manage this transfusion transmission risk, with a number of techniques being used worldwide for the treatment of plasma. In this study, the efficacy of the THERAFLEX MB-Plasma system to inactivate all DENV serotypes (DENV-1, DENV-2, DENV-3, DENV-4) or CHIKV in plasma, using methylene blue and light illumination at 630 nm, was investigated. STUDY DESIGN AND METHODS: Pooled plasma units were spiked with DENV 1, DENV-2, DENV-3 DENV-4, or CHIKV and treated with the THERAFLEX MB-Plasma system at four light illumination doses: 20, 40, 60, and 120 (standard dose) J/cm(2) . Pre- and posttreatment samples were collected and viral infectivity was determined. The reduction in viral infectivity was calculated for each dose. RESULTS: Treatment of plasma with the THERAFLEX MB-Plasma system resulted in at least a 4.46-log reduction in all DENV serotypes and CHIKV infectious virus. The residual infectivity for each was at the detection limit of the assay used at 60 J/cm(2) , with dose dependency also observed. CONCLUSIONS: Our study demonstrated the THERAFLEX MB-Plasma system can reduce the infectivity of all DENV serotypes and CHIKV spiked into plasma to the detection limit of the assay used at half of the standard illumination dose. This suggests this system has the capacity to be an effective option for managing the risk of DENV or CHIKV transfusion transmission in plasma. PMID- 27456862 TI - Prognostic value of MMP9 activity level in resected stage I B lung adenocarcinoma. AB - The clinical outcomes of patients with early-stage non-small cell lung cancer (NSCLC) have remained unsatisfactory after complete surgical resection. The objective of this study was to explore the prognostic value of matrix metalloproteinase 9 (MMP9) activity level in Chinese patients with stage I B lung adenocarcinoma. A sensitive and validated method was employed for determining the activity of MMP9 in human lung adenocarcinoma cells in vitro. Then, the association was examined between the level of MMP9 enzymatic activity and clinical outcomes. A total of 104 cases were stratified according to the IASLC/ATS/ERS classification scheme and activity of MMP9 was analyzed by SensoLyte(r) assay kit. The results showed that the MMP9 activity was the highest in solid predominant and micropapillary predominant subtypes, intermediate in acinar predominant and papillary predominant subtypes, and the lowest in lepidic predominant subtype. Multivariate analysis revealed that pathological subtype and activity of MMP9 were independent prognostic factors for disease-free survival (DFS), respectively (P = 0.005 and 0.029). Significant relationship existed between enzyme activity of MMP9 and prognosis. And the 30 months DFS of high- and low-level MMP9 activity tumors was 44.2% and 84.1% (P < 0.0001), respectively. High-level MMP9 activity is correlated with aggressive tumor behaviors and poor clinical outcomes in early-stage lung adenocarcinoma after complete resection. PMID- 27456863 TI - The Rivas Cohort Study: design and baseline characteristics of a Nicaraguan cohort. AB - BACKGROUND: A lack of advanced healthcare information systems and validated scientific cohorts in Nicaragua makes it difficult to estimate disease prevalences and other public health statistics. Although there is concern of an "epidemic" of chronic kidney disease (CKD) in this country, statistics regarding its magnitude are derived from only a small number of non-representative studies. Budgetary constraints and the logistical problems of maintaining a study cohort make longitudinal studies difficult. The Rivas Cohort was created to measure disease burden of CKD and other public health priorities in the Department of Rivas, Nicaragua. Using primarily volunteer research students and technologic innovation including GPS, digital photography and point of care biochemical analysis, the ability to establish a longitudinal chronic disease cohort is demonstrated. METHODS: Subjects were recruited from consecutive adjacent households in thirty-two randomly selected communities in the ten municipalities that comprise the Department of Rivas in southern Pacific coastal Nicaragua. The study was conducted in two phases. In the first phase, subjects were enrolled into the cohort and consented for future re-contact. In Phase II, conducted two years later, attempts were made to re-contact 400 of these subjects for additional data collection. Demographic, lifestyle, occupational, exposure and health data was collected for both phases of the study. Blood and urine testing and height, weight and blood pressure measurements were also performed. GPS coordinates of homes were recorded and maps of remote communities created. RESULTS: Of 1397 adults living in 533 households approached for participation a total of 1242 (89 %) were enrolled in the cohort. The median age is 41 years and 43 % are male, demographics in agreement with Nicaraguan census data for the Department of Rivas. During Phase II we attempted to re-contact 400 subjects for a follow-up study of CKD. It was possible to re-contact 84 % of these participants and of those re-contacted 95 % agreed to participate in the follow up study. Of subjects that were not successfully re-contacted the majority had either moved (32) or were not at home (22) at the time of the study team visits. CONCLUSION: The Rivas Cohort Study enrolled a representative sample of 1242 adults living in the Department of Rivas, Nicaragua. The high re-contact and participation rates at two years suggests that the cohort is suitable for long term studies and presents opportunities for investigations of disease prevalence, incidence, treatment and other public health matters. GPS coordinates and maps are available for future researchers who wish to use the cohort for additional studies. PMID- 27456864 TI - Improving mental health service users' with medical co-morbidity transition between tertiary medical hospital and primary care services: a qualitative study. AB - BACKGROUND: Mental health service users have high rates of medical co-morbidity but frequently experience problems accessing and transitioning between tertiary medical and primary care services. The aim of this study was to identify ways to improve service users' with medical co-morbidity care and experience during their transition between tertiary medical hospitals and primary care services. METHOD: Experience-based co-design (EBCD) qualitative study incorporating a focus group discussion. The study took place in a large tertiary medical service, incorporating three medical hospitals, and primary care services, in Melbourne, Australia. A purposive sample of service users and their caregivers and tertiary medical and primary care clinicians participated in the focus group discussion, in August 2014. A semi-structured interview guide was used to inform data collection. A thematic analysis of the data was undertaken. RESULTS: Thirteen participants took part in the focus group interview, comprising 5 service users, 2 caregivers and 6 clinicians. Five themes were abstracted from the data, illustrating participants' perspectives about factors that facilitated (clinicians' expertise, engagement and accessibility enhancing transition) and presented as barriers (improving access pathways; enhancing communication and continuity of care; improving clinicians' attitudes; and increasing caregiver participation) to service users' progress through tertiary medical and primary care services. A sixth theme, enhancing service users' transition, incorporated three strategies to enhance their transition through tertiary medical and primary care services. CONCLUSION: EBCD is a useful approach to collaboratively develop strategies to improve service users' with medical co-morbidity and their caregivers' transition between tertiary medical and primary care services. A whole-of-service approach, incorporating policy development and implementation, change of practice philosophy, professional development education and support for clinicians, and acceptance of the need for caregiver participation, is required to improve service users' transition. PMID- 27456866 TI - Erythromelalgia as a manifestation of autonomic nervous system involvement in multiple sclerosis. AB - Erythromelalgia is a rare condition characterized by burning pain, erythema and increased temperature of the hands or the feet. Its etiology is not completely understood but it is believed that the underlying cause is a peripheral vascular dysfunction that leads to simultaneous tissue hypoxia and hyperemia. We present a rare co-occurrence of erythromelalgia and multiple sclerosis in a patient with autonomic nervous system dysfunction and propose a causative interconnection. PMID- 27456865 TI - TRPV1 receptor in the human trigeminal ganglion and spinal nucleus: immunohistochemical localization and comparison with the neuropeptides CGRP and SP. AB - This work presents new data concerning the immunohistochemical occurrence of the transient receptor potential vanilloid type-1 (TRPV1) receptor in the human trigeminal ganglion (TG) and spinal nucleus of subjects at different ontogenetic stages, from prenatal life to postnatal old age. Comparisons are made with the sensory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). TRPV1-like immunoreactive (LI) material was detected by western blot in homogenates of TG and medulla oblongata of subjects at prenatal and adult stages of life. Immunohistochemistry showed that expression of the TRPV1 receptor is mostly restricted to the small- and medium-sized TG neurons and to the caudal subdivision of the spinal trigeminal nucleus (Sp5C). The extent of the TRPV1-LI TG neuronal subpopulation was greater in subjects at early perinatal age than at late perinatal age and in postnatal life. Centrally, the TRPV1 receptor localized to fibre tracts and punctate elements, which were mainly distributed in the spinal tract, lamina I and inner lamina II of the Sp5C, whereas stained cells were rare. The TRPV1 receptor colocalized partially with CGRP and SP in the TG, and was incompletely codistributed with both neuropeptides in the spinal tract and in the superficial laminae of the Sp5C. Substantial differences were noted with respect to the distribution of the TRPV1-LI structures described in the rat Sp5C and with respect to the temporal expression of the receptor during the development of the rat spinal dorsal horn. The distinctive localization of TRPV1 LI material supports the concept of the involvement of TRPV1 receptor in the functional activity of the protopathic compartment of the human trigeminal sensory system, i.e. the processing and neurotransmission of thermal and pain stimuli. PMID- 27456867 TI - Physician compensation for industry-sponsored clinical trials in multiple sclerosis influences patient trust. AB - BACKGROUND: Perceived physician financial conflicts of interest of can affect patient trust. Payment to physicians for industry sponsored clinical trials in multiple sclerosis is a relatively new potential source of physician conflict of interest. There is limited available data on how physician payment for trial involvement in multiple sclerosis clinical trials may influence patient trust. OBJECTIVE: To understand how patient trust is influenced by information about physician payment for multiple sclerosis clinical trials. METHODS: An anonymous online instrument was developed. RESULTS: 597 people with multiple sclerosis participated in the study. The study found that 61% of patients who had not previously participated in a clinical trial estimated that they would have lower levels of trust in their physician if the physician was paid for involvement in their clinical trial. Among former clinical trial participants, 38% self-reported a lower level of trust. Other potential physician-industry relationships, such as industry consulting or giving industry-sponsored talks, also adversely affected trust, though to a lesser extent than physician payment for subject participation in clinical trials. CONCLUSIONS: Results of this study demonstrate that physician payment for study participation in multiple sclerosis clinical trials is a potential conflict that can adversely affect patient trust. PMID- 27456868 TI - Spinal cord atrophy in neuromyelitis optica spectrum disorders. AB - Neuromyelitis optica spectrum disorders (NMOSDs) is an immune mediated inflammatory disease of the central nervous system (CNS) and often displays a monophasic or relapsing-remitting course. Spinal cord lesions is one of the predominant characteristics in NMOSD. Assessment of spinal cord atrophy (SCA) is of growing interest in monitoring disease progression in multiple sclerosis (MS), and correlates closely with the neurological disability. However, the studies of the SCA in NMOSD are still scarce. In this review, we describe the recent progress about the SCA in NMOSD, mainly the NMOSD with spinal cord lesions. PMID- 27456869 TI - Human endogenous retrovirus W in brain lesions: Rationale for targeted therapy in multiple sclerosis. AB - BACKGROUND OBJECTIVE: Attempts to identify a causative agent of Multiple Sclerosis (MS) among environmental viruses have consistently failed suggesting that development of MS is a result from gene-environment interactions. A new pathogenic player within human genes, a human endogenous retrovirus (HERV) was identified from MS cells, named MS-associated retrovirus element (MSRV) and unveiled homologous multicopy HERVs (HERV-W). As independent studies revealed biological features of HERV-W on immune-mediated inflammation and on remyelinating cells, the present study characterized the presence of HERV-W envelope protein (MSRV-Env) at the cellular level, in different MS lesion stages to extend and validate previous studies. METHODS: Immunohistological analysis of HERV-W envelope cellular expression in different lesion stages from a cohort of MS brains versus controls, using well-characterized and highly specific monoclonal antibodies. RESULTS: HERV-W envelope protein was detected in all MS brains and quite essentially in lesions. Immunohistochemistry showed dominant expression in macrophages and microglia, coinciding with areas of active demyelination, spread over the active lesions, or limited to the rim of active microglia in chronic active lesions or in few surviving astrocytes of inactive plaques. Weak expression was seen in MS normal appearing white matter. In active plaques, few lymphoid cells and astrocytes were also stained. This HERV-W expression was not observed in control brains. INTERPRETATION: HERV-W was expressed in demyelinated lesions from MS brains, which were all positive for this endogenous pathogenic protein. Pronounced HERV-W immunoreactivity in active MS lesions was intimately associated with areas of active demyelination throughout the successive stages of lesion evolution in MS brains. Based on its pathogenic potential, this HERV-W (MSRV) endogenous toxin thus appears to be a novel therapeutic target in MS. It also has a unique positioning as an early and lifelong expressed pathogenic agonist, acting upstream the pathways in which dysregulated physiological effectors are usually targeted by present therapeutic strategies for MS. PMID- 27456870 TI - Update on the cardiovascular profile of fingolimod in the therapy of relapsing remitting multiple sclerosis (MS). AB - BACKGROUND: Fingolimod (FTY720) has been approved as the first oral representative of the class of sphingosine-1-phosphate (S1P) receptor modulators for the treatment of relapsing-remitting multiple sclerosis (MS). Besides inducing vaso-relaxation, fingolimod can also influence electrical conduction in the myocardium and vascular endothelium by having a transient negative chronotropic effect on the sinus node. METHODS: Cardiac safety and tolerability of fingolimod in the cardiac sense were reviewed by analysing the data collected from the FREEDOMS and TRANSFORMS studies -both relevant studies for marketing authorisation, from their extension studies, as well as the clinical data collected from a practice-related MS patient cohort with cardiovascular risk factors and corresponding co-medication (FIRST study). RESULTS: The safety analyses on file gave no indication of any increased cardiovascular risk. The 2 3mmHg increase in blood pressure observed after the first dose of fingolimod has no therapeutic consequences. The first dose of 0.5mg fingolimod resulted in an average decrease in heart rate of 7-8beats/min. The onset of effect occurred approximately 1-2h after the first dose and the nadir was reached after approximately 4-5h. This negative chronotropic effect returned to normal after internalisation of the S1P1 receptors on maintenance therapy. There were no indications that patients with cardiac risk factors required closer observation beyond the monitoring recommended by the EMA following the first dose of fingolimod. Case study observations from the routine clinical setting show that patients accept this method of monitoring, which they assess as being a positive aspect of attentive medical care and concern. PMID- 27456871 TI - Prognostic factors associated with long-term disability and secondary progression in patients with Multiple Sclerosis. AB - BACKGROUND: Predicting the long-term prognosis of patients with multiple sclerosis (MS) remains an uncertain and difficult task, with most data having been obtained exclusively from Caucasian cohorts. OBJECTIVE: To investigate clinical prognostic factors in a Brazilian mixed-race cohort. METHODS: Demographic, clinical and therapeutic factors were investigated in 303 patients with relapsing-remitting MS in relation to the following outcomes: time until reaching Expanded Disability Status Scale (EDSS) 3 and EDSS 6, and until secondary progression. RESULTS: Benign course was significantly more frequent among Caucasians when compared to Afrodescendants. Patients with a malignant course had more than one relapse in the first year of the disease and reached EDSS 3 faster if treatment was not started. In the multivariate analysis, the following factors were associated with a significantly shorter time until the established outcomes: male gender, being of African descent, non-recovery after the first relapse, two or more relapses during the first year, a short interval between initial relapses, initial polysymptomatic presentation of pyramidal and cerebellar dysfunction and no treatment prior to reaching EDSS 3. CONCLUSIONS: Being of African descent was found to be an unfavorable factor for all outcomes, reinforcing the need to take ethnicity into consideration when defining treatment, particularly in mixed MS populations. PMID- 27456872 TI - Variations in multiple sclerosis practice within Europe - Is it time for a new treatment guideline? AB - In the past 5 years, the combination of developments in diagnostic strategy and approval of new disease-modifying therapies has provided an opportunity to achieve dramatic improvements in patient outcomes in multiple sclerosis (MS). However, across Europe there are several factors that may prevent patients from receiving the best therapy at the appropriate time, and there is variation among countries in terms of which of these factors are most relevant. Here, we review current MS clinical practices in a number of countries in the European Union to identify differences regarding initiation of treatment in patients with clinically isolated syndrome or relapsing-remitting MS, and differences in the timing of treatment switch or escalation. While recognizing that policy is not static in any country, we believe that patients' interests would be better served if a European treatment guideline was developed. Such a guideline could both inform and be informed by national policies, facilitating the dissemination of best clinical practice internationally. PMID- 27456873 TI - MEG evaluation of pico-Tesla external TMS on multiple sclerosis patients. AB - Magnetoencephalographic (MEG) recordings of 10 multiple sclerosis (MS) patients (2 men, 8 women, mean 41.3+/-9.5 years, mean disease duration 12.7+/-7.2 years) were obtained using a whole-head 122 - channel MEG system in a magnetically shielded room of low magnetic noise. Our experimental design was double-blind in order to look for possible effect of external pico - Tesla Transcranial Magnetic Stimulation (pT-TMS). The external pT-TMS was applied on the MS patients with proper field characteristics (magnetic field amplitude: 1-7.5pT, frequency: the alpha-rhythm of the patient 8-13Hz) which were obtained prior to the application of pT-TMS. Each MS patient had two separate recording sessions consisting of 3 runs in between where were given real or sham pT-TMS. It was then tried to predict the real and sham stimulation sessions based on the changes in the mean peak frequency difference (MPFD) observed in the brain of the patients in the 2 7Hz frequency band. After unblinding it was found a significant effect of an increase of frequencies in the range of 2-7Hz across the subjects followed by an improvement and normalization of the MEG. PMID- 27456874 TI - A study of dietary modification: Perceptions and attitudes of patients with multiple sclerosis. AB - BACKGROUND: Modifiable risk factors for multiple sclerosis (MS), including obesity and the gut microbiome, have been studied and have been found to be potentially relevant. Given this, there is a growing interest in diet modification as a means of impacting MS risk and disease course. OBJECTIVES: The aim of this study was to determine the current behaviors, level of interest, and relevant factors surrounding modification of diet in MS patients. METHODS: A total of 601 MS patients were mailed a dietary modification survey containing questions regarding subject demographics, disease course, and diet-related questions. RESULTS: Of the 199 survey responders, 17% admitted to currently attempting a diet for their MS and 91.5% were interested in diet modification as a means of benefiting their disease. Willingness to attempt diet therapy was not affected by demographic features or an individual's disease course. Over 85% of these patients were willing to attempt diet therapy for 3 months or longer. CONCLUSIONS: The majority of survey responders expressed interest in diet modification in attempts to improve or treat their MS. Our data demonstrate the feasibility of patient recruitment for future studies assessing therapeutic intervention by way of diet modification for MS disease. PMID- 27456876 TI - Refractory trigeminal neuralgia responsive to nabiximols in a patient with multiple sclerosis. AB - INTRODUCTION: Nabiximols is a cannabinoid compound approved for the treatment of multiple sclerosis (MS)-related spasticity. However, additional symptoms, such as pain, urinary urgency and sleep disturbance, may benefit from treatment. CASE REPORT: The present report describes a patient with secondary progressive MS and severe lower limbs spasticity who was started on treatment with nabiximols. The patient also suffered from trigeminal neuralgia, which he was not treating due to inefficacy or side effects of all previously tried medications. After nabiximols initiation the patient experienced a marked benefit on trigeminal neuralgia, which completely resolved, while spasticity responded only partially to treatment. CONCLUSION: Nabiximols mechanism of action is based on the interaction with CB1 and CB2 receptors, which are expressed by central nervous system neurons and are known to modulate pain among other effects. The present case indicates that nabiximols and other cannabinoids need to be further tested for the treatment of trigeminal neuralgia. PMID- 27456875 TI - The effect of vibrotactile biofeedback of trunk sway on balance control in multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis (MS) suffer from diminished balance control due to slowed sensory conduction and possibly delayed central processing. Vibrotactile biofeedback of trunk sway has been shown to improve balance control in patients with peripheral and central vestibular disorders. Here, the effects of vibrotactile feedback training on trunk sway and a possible carry-over effect was measured in MS patients during stance and gait. METHODS: Ten MS patients (mean age 46.8+/-7.7 years, 40% male) participated in a crossover study in which 7 different stance and gait tasks were trained with and without angle feedback for stance and angular velocity feedback for gait. An assessment sequence of 12 tasks was performed once before and twice after the training sequence. Trunk sway was measured with body-worn gyroscopes. Head mounted vibrotactile biofeedback of trunk sway was provided during one crossover training arm and the following second assessment sequence. RESULTS: Biofeedback generally leads to a decrease in sway but an increase in sway angular velocities during some stance tasks compared to training without biofeedback. Biofeedback while walking eyes open resulted in a decreased sway angular velocity. The greatest changes were found in the pitch direction of trunk sway. Effects diminished after biofeedback was removed. CONCLUSIONS: This study showed that vibrotactile biofeedback of trunk sway beneficially effects stance and provides significant improvement in gait compared to training without biofeedback in MS patients. PMID- 27456877 TI - Interleukin 7 receptor polymorphisms and the risk of multiple sclerosis: A meta analysis. AB - BACKGROUND: Multiple sclerosis (MS) is considered as the most common chronic inflammatory neurologic disorder diagnosed in young adults. Both environmental and genetic factors may influence risk of MS development. Interleukin 7 receptor (IL7R) is one of the most studied gene polymorphism on MS that may play a possible role in MS development. The most studied polymorphism of IL7R gene is "rs6897932" polymorphism on IL7Ralpha gene (IL7RA). METHODS: PubMed, Scopus, and Google scholar databases were searched for all of related studies on the association of IL7RA polymorphism with single nucleotide polymorphism (SNP) ID of "rs6897932" and the risk of MS through August 07, 2015. After exclusion of irrelevant articles, 11 eligible studies were selected, which were analyzed to determine an association between the MS and IL7R T244I polymorphism (rs6897932). For identification of this association, odds ratios (ORs) and 95% confidence interval (95% CI) were calculated. Four models of allelic (T vs. C), co-dominant genotype (TT vs. CC), dominant (TT+CT vs. CC), and recessive genotypes (TT vs. CT+CC) were considered to check the possible role of rs6897932 polymorphism in MS. A sensitivity analysis was conducted to find the reliability of this study. Furthermore, funnel plots were used to evaluate publication bias. RESULTS: A total of 11 case-control studies were identified through this meta-analysis, which containing 6752 cases and 7349 controls. In overall, the frequency of the C allele was found to be higher in patients with MS compared to healthy controls (75.66% vs. 72.19%). T allele was significantly associated with the decreased risk of MS in a random effect model (T vs. C: OR=0.84, 95% CI=0.77-0.92, P-value <0.001). In the co-dominant, dominant, and recessive genotypes models, a significant association between the IL7R T244I polymorphism and MS risk was demonstrated (TT vs. CC: OR=0.70, 95% CI=0.61-0.80, P-value <0.001; TT+CT vs. CC: OR=0.82, 95% CI=0.73-0.92, P-value <0.001; TT vs. CT+CC: OR=0.76, 95% CI=0.66 0.87, P-value <0.001). Sensitivity analysis revealed that this study is reliable. There was no evidence of publication bias. CONCLUSION: It was demonstrated that the IL7R T244I polymorphism was associated with susceptibility to MS. However, more well-designed studies with large sample size are needed to validate this association between this single nucleotide polymorphism and MS. PMID- 27456878 TI - Anti-N-methyl-d-aspartate receptor encephalitis in a patient with neuromyelitis optica spectrum disorders. AB - We described a female patient with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis occurring sequentially with neuromyelitis optica spectrum disorders (NMOSD). The 19-year-old patient initially presented a diencephalic syndrome with aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) and brain lesions which involving bilateral medial temporal lobes and periependymal surfaces of the third ventricle on magnetic resonance imaging (MRI). Ten months later, the patient developed cognitive impairment, psychiatric symptoms and dyskinesia with left basal ganglia lesions on brain MRI. Meanwhile, the anti-NMDAR antibodies were positive in the patient's serum and cerebrospinal fluid, while the screening tests for an ovarian teratoma and other tumors were all negative. Hence, the patient was diagnosed NMOSD and anti-NMDAR encephalitis followed by low-dose rituximab treatment with a good response. This case was another evidence for demyelinating syndromes overlapping anti-NMDAR encephalitis in Chinese patients. PMID- 27456879 TI - Adherence and persistence to drug therapies for multiple sclerosis: A population based study. AB - OBJECTIVE: We aimed to estimate the prevalence and predictors of optimal adherence and persistence to the disease-modifying therapies (DMT) for multiple sclerosis (MS) in 3 Canadian provinces. METHODS: We used population-based administrative databases in British Columbia (BC), Saskatchewan, and Manitoba. All individuals receiving DMT (interferon-B-1b, interferon-B-1a, and glatiramer acetate) between 1-January-1996 and 31-December-2011 (BC), 31-March-2014 (Saskatchewan), or 31-March-2012 (Manitoba) were included. One-year adherence was estimated using the proportion of days covered (PDC). Persistence was defined as time to DMT discontinuation. Regression models were used to assess predictors of adherence and persistence; results were pooled using random effects meta analysis. RESULTS: 4830 individuals were included. When results were combined, an estimated 76.4% (95% CI: 69.1-82.4%) of subjects exhibited optimal adherence (PDC >=80%). Median time to discontinuation of the initial DMT was 1.9 years (95% CI: 1.6-2.1) in Manitoba, 2.8 years (95% CI: 2.5-3.0) in BC, and 4.0 years (95% CI: 3.5-4.6) in Saskatchewan. Age, sex and socioeconomic status were not associated with adherence or persistence. Individuals who had >=4 physician visits during the year prior to the first DMT dispensation were more likely to exhibit optimal adherence compared to those with fewer (0-3) physician visits. CONCLUSIONS: We observed adherence that is higher than what has been reported for other chronic diseases, and other non-population-based MS cohorts. Closer examination as to why adherence appears to be relatively better in MS and how adherence influences disease outcomes could contribute to our understanding of MS, and prove useful in the management of other chronic diseases. PMID- 27456880 TI - Chronic lung disease and multiple sclerosis: Incidence, prevalence, and temporal trends. AB - OBJECTIVES: We aimed to estimate the incidence and prevalence of chronic lung disease (CLD), including asthma and chronic obstructive pulmonary disease, in the MS population versus a matched cohort from the general population. METHODS: We used population-based administrative data from four Canadian provinces to identify 44,452 persons with MS and 220,849 age-, sex- and geographically-matched controls aged 20 years and older. We employed a validated case definition to estimate the incidence and prevalence of CLD over the period 1995-2005, and used Poisson regression to assess temporal trends. RESULTS: In 2005, the crude incidence of CLD per 100,000 persons was 806 (95%CI: 701-911) in the MS population, and 757 in the matched population (95%CI: 712-803). In 2005, the crude prevalence of CLD was 13.5% (95%CI: 13.1-14.0%) in the MS population, and 12.4% (95%CI: 12.3-12.6%) in the matched population. Among persons aged 20-44 years, the average annual incidence of CLD was higher in the MS population than in the matched population (RR 1.15; 95%CI: 1.02-1.30), but did not differ between populations for those aged >=45 years. The incidence of CLD was stable, but the prevalence of CLD increased 60% over the study period. CONCLUSION: CLD is relatively common in the MS population. The incidence of CLD has been stable over time, but the prevalence of CLD has increased. Among persons aged 20-44 years, CLD is more common in the MS population than in a matched population. Given the prevalence of CLD in the MS population, further attention to the effects of CLD on outcomes in MS and approaches to mitigating those effects are warranted. PMID- 27456881 TI - Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis - A case report. AB - BACKGROUND: Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis associated with Interferon beta treatment. CASE PRESENTATION: We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved. CONCLUSION: Clinicians should be aware of the possibility of rhabdomyolysis occurring during Interferon-beta-1 alpha therapy. In cases where patients complain of severe myalgia, and in particular if weakness is reported, creatine kinase activity should be measured to prevent irreversible rhabdomyolysis during Interferon-beta-1-alpha therapy in patients with multiple sclerosis. PMID- 27456882 TI - Localized scleroderma en coup de sabre in the Neurology Clinic. AB - BACKGROUND: Localized scleroderma en coup de sabre (LScs) is a form of localized scleroderma thought to be an autoimmune disorder. Central nervous system involvement is not rare and neurological manifestations include seizures, focal neurological deficits, headache and neuropsychiatric changes. METHODS: Patients attending the Neurology Clinic with the final diagnosis of LScs with neurological manifestations were identified and clinical and imagiological records reviewed. RESULTS: Five patients (0.024%) had LScs with neurological involvement, presenting with transient focal neurologic deficits, seizures, headache or migraine with aura. Neuroimaging studies confirmed localized skin depression and showed bone thinning, white matter lesions, brain calcifications, sulcal effacement and meningeal enhancement. Three patients experienced clinical improvement after immunosuppressive therapy, and in two of these patients neuroimaging findings also improved. CONCLUSIONS: Recognizing typical dermatologic changes is keystone for the diagnosis of LScs with neurological involvement. It is a diagnosis of exclusion and extensive etiological diagnostic evaluation should be performed. Treatment options, including conservative follow up or immunosuppressive therapy, should be carefully considered. PMID- 27456883 TI - A lesion topography-based approach to predict the outcomes of patients with multiple sclerosis treated with Interferon Beta. AB - BACKGROUND: With increasing availability of effective disease-modifying treatments for multiple sclerosis (MS), an early identification of patients who do not adequately respond to Interferon Beta (IFNB) is relevant to decide the future strategy. OBJECTIVE: To investigate the predictive role of new lesion location on the risk of breakthrough disease in IFNB-treated patients with MS. METHODS: We analysed data from 392 patients starting IFNB and regularly followed up to 5 years. Before and after one year of IFNB treatment, all patients underwent a conventional brain and spinal cord magnetic resonancer imaging (MRI) scan with the same 1.5T magnet to obtain the count and location of new MRI lesions. Relapses and MRI activity occurred in the first year of IFNB treatment (year 0-1) were included in the set of potential predictors for relapses and disability worsening in the subsequent four years (year 2-5). RESULTS: We found that 96 (24.5%) patients had relapses and/or MRI activity in the first year of IFNB treatment, while 41.6% of the patients experienced relapses and 17.8% experienced disability worsening. from year 2 to 5. The risk of relapses (year 2 5) was associated with >=2 relapses (HR=5.65, p<0.001) and new T2-hyperintense lesions (for 2 new lesions: HR=1.96, p=0.011; for >=3 new lesions: HR=3.55, p<0.001) in the first year of treatment. Other than male sex (HR=2.01, p=0.01) and higher EDSS score (HR=2.17, p<0.001), the risk of disability worsening (year 2-5) was associated with >=2 relapses (HR=4.33, p<0.001) and new spinal cord or infratentorial lesions (HR=4.45,p<0.001) in the first year of treatment. CONCLUSIONS: Our findings suggest a dose-effect relationship between the lesion count and the risk of future relapses, while the occurrence of new MRI lesions in sites representing anatomical bottle-necks was better than lesion count at predicting the future risk of disability worsening despite IFNB treatment. PMID- 27456884 TI - Virtual reality in multiple sclerosis - A systematic review. AB - INTRODUCTION: Multiple sclerosis (MS) is an inflammatory disease in which the insulating cover of nerve cells in the brain and spinal cord are damaged. The methods used for motor rehabilitation of patients with neurological problems require the performance of several rehabilitation exercises. Recently, studies related to the use of video game consoles have proliferated in the field of motor rehabilitation. Virtual reality (VR) has been proposed as a potentially useful tool for motoring assessment and rehabilitation. OBJECTIVE: The purpose of this study was to investigate the results shown in previous studies on "Multiple Sclerosis" and "Virtual Reality". METHOD: A bibliographic review was performed without time limitations. The research was carried out using PubMed and BVS databases. Considering keywords, we included articles that showed the terms "Multiple Sclerosis" and "Virtual Reality". The review was according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines RESULTS: The initial search yielded 41 articles. After the duplicates were removed, two authors independently evaluated the title and abstract of each of the articles with the study inclusion criteria. From these, 31 articles were excluded based on the title and abstract. Finally, 10 articles were isolated that met the inclusion criteria. CONCLUSION: VR represents a motivational and effective alternative to traditional motor rehabilitation for MS patients. The results showed that VR programs could be an effective method of patients with MS rehabilitation in multiple cognitive and / or motor deficits. Additional research is needed to support the rehabilitation protocols with VR and increase the effects of treatment. PMID- 27456885 TI - The effectiveness of the Permission, Limited Information, Specific suggestions, Intensive Therapy (PLISSIT) model based sexual counseling on the sexual function of women with Multiple Sclerosis who are sexually active. AB - OBJECTIVE: This study was conducted to evaluate the effectiveness of sexual counseling based on the Permission, Limited Information, Specific Suggestion, Intensive Therapy (PLISSIT) model on the Sexual Dysfunction (SD) of married sexually active women who suffer from Multiple Sclerosis (MS). This is the first sexual intervention applied by a midwife as a health professional on MS patients in Iran where the cultural and religious limitations are important challenging issues. STUDY DESIGN: This randomized clinical trial was carried out in Iranian Community of Support for MS Patients in Tehran, Iran. The participating women who had a definite diagnosis of MS and SD, Expanded Disability Status Scale (EDSS) scores <7, and aged 18-55 years were randomly assigned to experimental (EG, n=43) and control group (CG, n=45). Participants in the EG group received 4 weekly sexual counseling sessions based on the PLISSIT model (90-120min per session). MAIN OUTCOME MEASURES: Sexual function was assessed three times (before the intervention, and 2 months and 3 months after the intervention) using the Female Sexual Function Index (FSFI). Chi-square test, Fisher's exact test, and Repeated Measures ANOVA were employed to analyze the data. RESULTS: The mean total FSFI score of the women in EG improved at 2 and 3 months after the intervention when it was compared with the FSFI score before the intervention (p<0.05). There was no significant difference in the total FSFI score when the data of 3 evaluations was compared in CG. A significant increase in the mean score of 6 subgroups was seen in EG (p<0.05) but not in CG. CONCLUSION: According to this study, utilizing the PLISSIT model as a framework for sexual counseling can improve sexual function in women who are sexually active and suffer from SD due to MS. PMID- 27456886 TI - Longstanding spastic paraparesis in a patient infected with hepatitis C virus and seropositive for aquaporin-4 antibody - Case report and review of the literature. AB - Nervous system involvement in Hepatitis C virus infection (HCV) has been associated to neuro-immunological deregulation, particularly in interferon-alpha treated patients. We present a case of optic and brainstem demyelinating disorder associated with aquaporin-4 (AQP4) antibodies. A 48 year-old woman, with previous diagnosis of non-treated hepatitis C, presented with a 10-year history of long standing gait disturbance. Neurological examination disclosed a grade 4 spastic paraparesis, lower limb hyperreflexia, right positive Hoffmann sign, bilateral Babinski sign and spastic gait only possible with bilateral support. Spinal cord magnetic resonance imaging (MRI) was normal. Brain MRI showed an asymmetric, bilateral pontine and left mesencephalic hypersignal in T2 and FLAIR, with no gadolinium enhancement. Visual evoked potential revealed bilateral pre-chiasmatic conduction delay. Blood tests showed a positive anti-HCV antibody and a positive AQP4 antibody. Cerebrospinal fluid (CSF) analysis was normal, with no oligoclonal bands. The patient started intravenous (IV) methylprednisolone followed by oral prednisolone; simultaneously, interferon-alpha and ribavirin. There was a slight clinical improvement within the first weeks. There are 7 cases describing association between HCV infection and central nervous system (CNS) demyelination with positive AQP4 antibody, 4 patients under interferon-alpha. AQP4 antibodies should be tested in patients infected with HCV and CNS demyelination. PMID- 27456887 TI - Relapse rates in patients with multiple sclerosis treated with fingolimod: Subgroup analyses of pooled data from three phase 3 trials. AB - BACKGROUND: Fingolimod is a once-daily, orally administered therapy for relapsing forms of MS. It has been shown to reduce relapse rates significantly in all phase II and phase III clinical trials when compared with placebo and intramuscular interferon beta-1a (IFNbeta-1a IM). METHODS: This study compared annualized relapse rates (ARRs) associated with fingolimod, placebo and IFNbeta-1a IM, in patient subgroups from the pooled FREEDOMS, FREEDOMS II, and TRANSFORMS populations. This provided a large data set in which the efficacy of fingolimod could be assessed across a range of patient subgroups, including clinically relevant subgroups not previously analysed. RESULTS: Compared with placebo, fingolimod was associated with significantly lower ARRs across all patient subgroups with relative reductions in ARRs ranging from 35% (patients who had previously received treatment for their MS for up to 1 year; P<0.05) to 69% (patients with symptoms for less than 3 years before study entry; P<0.001). Other relative reductions in ARR compared with placebo included 64% in patients aged 40 years or younger and 63% in those naive to treatment (P<0.001 for both). Compared with IFNbeta-1a IM, the greatest benefits to ARR were seen in patients aged 40 years or younger (55% relative ARR reduction, P<0.001) and in a small subgroup of patients who had previously received IFNbeta and glatiramer acetate (55% relative ARR reduction; P<0.05). Reductions in ARR compared with IFNbeta-1a IM were not statistically significant in men (33%, P=0.081), in patients aged over 40 years (23%, P=0.230) and in those who had received treatment prior to the study for 1 year or less (35%, P=0.108). Fingolimod was associated with significantly lower ARRs compared with placebo and with IFNbeta-1a IM irrespective of treatment status (treatment-naive and previously treated for MS), and regardless of type of previous therapy. CONCLUSIONS: Fingolimod provided consistent efficacy benefits over placebo and IFNbeta-1a IM across a range of subgroups of patients with relapsing MS. The magnitude of the beneficial effect of fingolimod over IFNbeta 1a IM may depend on age, sex, and duration of previous treatment. These findings suggest that most benefit will be gained by patients who start fingolimod early in the disease course, but the findings also suggest that fingolimod treatment will benefit patients later in the disease course when they have already accrued disability. PMID- 27456888 TI - The effects of thrombomodulin and activated protein C on the pathogenesis of multiple sclerosis. AB - BACKGROUND: Various molecules of the coagulation cascade are thought to have varying roles in the pathophysiology of multiple sclerosis (MS). We aimed to find new information about the effects of the coagulation cascade molecules to develop new therapeutic strategies for MS. MATERIALS AND METHODS: Patients with MS were chosen from among patients who were followed up at our hospital. We examined the thrombomodulin (TM) and activated protein C (APC) serum levels in patients with MS and the healthy controls. The patient groups were determined as relapsing remitting MS (RRMS) or secondary progressive MS (SPMS) according to the McDonald criteria and between ages of 18 and 70. RESULTS: A total of 244 participants, 122 patients with multiple sclerosis and 122 healthy volunteers were included in the study. There was no statistically significant difference in the APC and TM levels between the patients and the healthy controls (p>0.05), between the patients with RRMS and SPMS (p>0.05), and between the first day of acute relapse and 10th day of methylprednisolone therapy in the patients with RRMS (p=0.334; p=0.363). We detected a statistically positive correlation only between the expanded disability status scale (EDSS) scores and TM levels in the patient group (p=0.009). CONCLUSION: Treatment with methylprednisolone decreases EDSS score in RRMS relapse. The increase in EDSS is related to level of TM. The changes in level of TM and APC may be indicator for prognosis of MS or treatment modalities to MS. PMID- 27456889 TI - Longitudinal BMI trajectories in multiple sclerosis: Sex differences in association with disease severity. AB - BACKGROUND: Adolescent obesity is a risk factor for multiple sclerosis (MS), but little is known about changes in body mass index (BMI) after MS onset. OBJECTIVE: To assess the relationship between MS and longitudinal changes in BMI. METHODS: We analyzed prospectively collected BMIs in a cohort of patients with adult-onset MS and matched adult healthy controls (HC) gathered from the same hospital network central clinical data registry. RESULTS: We made three main observations. First, at baseline MS patients had a significantly higher BMI than HC (age- and sex- adjusted mean difference=0.57; 95% CI: 0.15, 0.99; p=0.008). Second, a significant age by MS status interaction was observed (p<0.0001), such that in MS, BMIs did not increase significantly higher in older individuals, whereas BMIs in HCs were higher with increasing age. Third, we observed sex-specific associations with disease severity: higher BMI was associated with higher cross sectional EDSS in women, but with lower EDSS in men (p=0.003, N=758). There were no longitudinal associations between BMI and EDSS in either sex or in the entire cohort (p=0.65, N=772). CONCLUSION: After MS onset, patients may not experience age-expected increases in BMI. BMI may have sex-specific associations with MS disability scores. More refined measures of body composition are warranted in future studies to distinguish adiposity from muscle mass. PMID- 27456890 TI - Erythroblastaemia in natalizumab-treated patients with multiple sclerosis. AB - BACKGROUND: Natalizumab is a monoclonal antibody that significantly reduces the occurrence of relapses in relapse-remitting multiple sclerosis (RRMS) patients. Early papers on the clinical use of natalizumab in RRMS patients reported erythroblastemia as occasional and transient. OBJECTIVES: to determine the prevalence and absolute count of erythroblasts (nucleated red blood cells, NRBCs) in peripheral blood of RRMS patients in different treatment groups and healthy controls from the same geographic area using the same equipment for laboratory analysis. METHODS: We retrospectively evaluated the samples of 203 consecutive RRMS patients including 26 subjects on natalizumab, 17 on fingolimod, 72 on interferon, 41 on glatiramer acetate, 47 treatment-naive and 240 healthy controls from the same geographic area. Blood samples were processed using an XN-9000 Hematology Analyzer and subsequent microscopic verification. In the natalizumab treated patients we performed an additional analysis in order to detect the expression of CD34+ cells in peripheral blood, as confirmation of a bone marrow mobilization. RESULTS: The prevalence of patients with NRBCs positivity was significantly higher in natalizumab-treated patients (92%) compared with the other treatment groups and healthy controls (0%) (p<0.0005). The median absolute NRBCs count was significantly higher in natalizumab-treated patients (median 0.020, p<0.0005) than in the other treatment groups and healthy controls. Natalizumab-treated patients also had higher levels of white blood cells than all other groups and lower haemoglobin levels than healthy subjects (p<0.01), but no morphologic alterations were evident at a subsequent review of red blood cells, platelets and white blood cells. CD34+ cells levels were consistent with mobilization of haematopoietic stem cells from the bone marrow (median 8 cells/uL, IQR 5-12). CONCLUSIONS: We confirm erythroblastaemia as a frequent finding of natalizumab treatment in RRMS patients. More extended knowledge and adequate long-term observation of this phenomenon are essential to better understand any pathological implication. PMID- 27456891 TI - Re-evaluating the incidence of natalizumab-associated progressive multifocal leukoencephalopathy. AB - OBJECTIVE: To estimate the prospective risk of developing PML during therapy with natalizumab in JCV-seropositive patients. METHODS: We analyzed postmarketing data about the incidence of PML on natalizumab, and quantified the risk by either applying the Kaplan-Meier estimator or, where this was not possible due to the unavailability of the respective raw data, using formulae yielding very similar figures. RESULTS: In JCV-seropositive patients with prior immunosuppressant (IS) use, the incidence of PML during months 25-48 of natalizumab therapy is about 19.5 per thousand. Without prior IS use, the incidence during months 25-48 is approximately 7.4 per thousand, and during months 49-72, it is approximately 10.8 per thousand. If one additionally assumes that the JCV index is in the range 0.9 1.5, then the incidence during months 49-72 is around 6.2 per thousand in comparison to 17.0 per thousand when the JCV index exceeds 1.5. CONCLUSIONS: Biogen's statistics concerning the risk of PML on natalizumab, while in principle helpful, underestimate the true incidence systematically and significantly; realistic estimates of the longterm risk of PML are nearly double those previously published, with some patient groups carrying a risk that is almost nine times higher. Fortunately, a refined risk-stratification algorithm with the incorporation of such markers as L-selectin and CSF lipid-specific IgM bands has the potential to make natalizumab a considerably safer drug. PMID- 27456892 TI - Editors' Welcome. PMID- 27456893 TI - Why do you have to be lucky to get the MS treatment you deserve? PMID- 27456895 TI - How much psychological distress is experienced at home by patients with palliative care needs in Germany? A cross-sectional study using the Distress Thermometer. AB - OBJECTIVE: The aims of the present study were (1) to describe the prevalence of psychosocial distress in palliative care patients living at home and the related factors, and (2) to test implementation of the Distress Thermometer (DT) within a home-based palliative care service. METHOD: Ours was a 15-month prospective study beginning in September of 2013 in western Germany with consecutive patients cared for by a home care palliative care service. The research was implemented during the first visit by the home care team. Patients were excluded if they were under 18 years of age, mentally or physically unable to complete the assessment questionnaires as judged by their healthcare worker, or unable to understand the German language. During the first encounter, the Distress Thermometer (DT), a Problem List (PL), and a structured questionnaire for evaluation were applied and sociodemographic and medical data collected. RESULTS: A total of 103 patients (response rate = 70%; mean age = 67; female = 54%; married = 67%; oncological condition = 91%; Karnofsky Performance Status [KPS] score 0-40 = 34%, 50-70 = 60%, >80 = 6%) were included. The incidence of distress (DT score >=4) was 89.3% (mean = 6.3 +/- 2.5). No statistical association was found between level of distress and sociodemographic or medical factors. The five most reported problems were "fatigue" (90%), "getting around" (84%), "eating" (63%), "bathing/dressing" (60%), and "sleep" (57%). The number of problems reported correlated with level of distress (rho = 0.34). The DT was comprehensible, and 80% considered its completion as unremarkable, while 14% found it "relieving." SIGNIFICANCE OF RESULTS: A significant proportion of patients treated at home reported symptoms of distress. The most oft-mentioned problems were physical and emotional in nature. The findings of our study highlight the importance of creating new concepts and structures in order to address the psychosocial needs of patients in home care with palliative needs. PMID- 27456894 TI - Factors Associated With Seeking Physician Care by Medicare Beneficiaries Who Receive All Their Primary Care From Nurse Practitioners. AB - BACKGROUND: A shortage of primary care physicians has led to the alternative strategy of nurse practitioners (NPs) as primary care providers for the growing elderly population. Many states have implemented policies that allow NPs to practice independently with no physician oversight. Little is known about the continuity of primary care provided by NPs. OBJECTIVE: To examine rate and correlates of switching from exclusive NP primary care to receiving some or all primary care from physicians. DESIGN: A retrospective cohort study. PARTICIPANTS: Medicare beneficiaries (n = 38 618) with diabetes, congestive heart failure, or chronic obstructive pulmonary disease who received all their primary care from NPs in 2007. MAIN MEASURES: Multivariable logistic regression model was used to assess patient and disease characteristics associated with switching from sole NP primary care in 2007 to receiving some or all primary care from physicians between 2008 and 2010. RESULTS: Of elderly patients receiving all their primary care from NPs in 2007, 53.8% switched to receiving some or all primary care from physicians in 2008-2010. The switching patients had less comorbidity before the switch and were more likely to reside in metropolitan areas, ZIP code areas with high education or states with the most restriction on NP scope of practice. In multivariable analyses, significant predictors of switching included one of the following within 30 days before the switch: emergency room visits (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.44-1.68), hospitalization (OR = 1.13, 95% CI = 1.02-1.25), new diagnosis of heart attacks (OR = 5.52, 95% CI = 4.33-7.02), pneumonia (OR = 4.84, 95% CI = 3.71-6.32), atrial fibrillation (OR = 3.99, 95% CI = 2.93-5.44), stroke (OR = 2.94, 95% CI = 2.31-3.74), or cancer (OR = 2.65, 95% CI = 1.94-3.63). CONCLUSIONS: About half of Medicare patients under exclusive NP primary care switched to physicians for some or all primary care over a 3-year period. Future study is needed to understand the reasons for switching. PMID- 27456896 TI - [Neurological presentations of bacterial meningitis in children: current possibilities of diagnosis and treatment]. AB - AIM: To improve clinical/laboratory diagnosis of bacterial meningitis (BM) in children. MATERIAL AND METHODS: Fifty-seven patients, aged from 4 months to 12 years, with BM were examined. Bacteriological study of the mucus from the nasopharynx, sterility tests of blood and cerebrospinal fluid (CNF), clinical and biochemical tests, serological study of paired samples of plasma - indirect hemagglutination test, latex agglutination assay, immunological study of plasma and CNF with the determination of interferon -alpha, -beta and -gamma, interferon procalcitonin and neopterin with ELISA were performed at admission and after CNF remediation. Molecular-genetic study of the blood serum and CNF using PCR, neurosonography, computed tomography and MRI of the brain were done as well. RESULTS AND CONCLUSION: Most of the patients had generalized meningococcus infection (64,9%). Hib-meningitis, pneumococcus meningitis and other forms were less frequent. Characteristics of neurological presentations of BM depending on the etiology, somatic complications and time from the manifestation of symptoms were described. Clinical/biochemical criteria of BM and correlations between procalcitonin, neopterin and interleukin-8 in the CNF and blood of the patients and disease severity as well as between the level of inflammatory reactions in the CNF and the BM form were established. These results are important for the development of informative biomarkers for the prognosis of BM course and outcome. PMID- 27456897 TI - [Hypovolemic hyponatremia at the onset of severe ischemic stroke as a predictor of adverse outcome]. AB - AIM: To study the prognostic value of disturbances of the water and electrolyte homeostasis in the acute stage of ischemic stroke (II) and their impact on the course and outcome. MATERIAL AND METHODS: Disturbances of the water and electrolyte homeostasis associated with plasma sodium fluctuations were studied in 150 patients with severe II. RESULTS: The poor outcome was associated with plasma osmolarity >297 mOsmol/L and plasma sodium concentration >155 mOsmol/L in the first day of severe II and with >303 mOsmol/L and >161 mOsmol/L, respectively, in the 3rd and 5th days. The prognosis was significantly worse in hypovolemia compared to normo- and hypervolemia. CONCLUSION: Hypovolemic hyponatremia as a presentation of hyperosmolar syndrome at the onset of severe II can be considered as a relatedly independent predictor of the fatal outcome. PMID- 27456898 TI - [Suicide and addictive characteristics of spouses with alcohol dependence according to the marriage dynamics]. AB - AIM: To explore how alcoholism of the husband impacts the dynamics of the marriage. The authors assume and justify the existence of isolated clinical/phenomenological types of marriages in these families: with permanently closed, primarily and secondary opened marriage systems. MATERIAL AND METHODS: It has been examined 125 families with special questionnaire. RESULTS AND CONCLUSION: Demonstrated that no common scenario exists for spouses, in particular, for co-dependent reaction of the wife. Assessment of autoaggresive patterns, addictive and co-dependent characteristics of spouses in respect of the variants of marriage dynamics were presented. This is of importance for effective prevention and treatment both of addiction and suicide as well as significantly expands current theoretical conceptions on "alcohol" marriages in general and codependence phenomenon in particular. PMID- 27456899 TI - [Photomatrix LED therapy in patients with post-stroke arthropathy of the shoulder joint]. AB - AIM: To assess the impact of quasi-monochromatic partially coherent infra-red radiation on the dynamics of recovery of the affected joint and the hemostatic system in patients with post-stroke arthropathy of the shoulder joint. MATERIAL AND METHODS: Fifty-five patients in the early, late and residual period of ischemic stroke were studied. Group I consisted of 27 patients who underwent 10 sessions of photomatrix therapy (wavelength 600 nm) on the affected joint, lasting for 10 minutes. In patients of group II (n=28), the duration of photomatrix therapy was 20 minutes. Patients of the comparison group (n=20) did not receive photomatrix therapy. RESULTS AND CONCLUSION: The results pointed to a significant reduction in the severity of pain, increase in the range of motion in the shoulder joint. All this was combined with a decrease in the severity of anxiety and depression, followed by a mild hypocoagulation effect and improvement of blood circulation in the paretic limb. The authors point out to the prospect of using this method for the prevention and treatment of post-stroke arthropathy. PMID- 27456900 TI - [Ultrasonography in evaluating the character of lesions of the median nerve in carpal tunnel syndrome]. AB - AIM: To correlate the cross-sectional area of the median nerve proximal and distal to carpal tunnel and the character of nerve lesion - axonotmesis and neurapraxiain in carpal tunnel syndrome. MATERIAL AND METHODS: Twenty-six hands with carpal tunnel syndrome and 30 hands of controls were examined. In all cases, median nerve cross-sectional areas were measured using ultrasonography and electromyography. The diagnosis and categorization of carpal tunnel syndrome were based on electrophysiological criteria. In all patients with confirmed carpal tunnel syndrome, needle electromyography of m. abductor pollicis brevis was used. Patients with carpal tunnel syndrome were divided into two groups according to the type of lesion of the median nerve - axonotmesis or neurapraxia. Correlation of ultrasound parameters with the character of the nerve lesion was evaluated. RESULTS AND CONCLUSION: Sensitivity and specificity of measurements of cross sectional area of the median nerve after tunnel in the diagnosis of carpal tunnel nerve lesion by axonotmesis type were estimated as 89% and 85%, respectively. Thresholds of cross-sectional area with respect to the character of lesions of the median nerve were established. PMID- 27456901 TI - [The possibility of using standardized self-report anxiety and depression scales in elderly patients: anxiety scales/questionnaires]. AB - AIM: To describe the specifics of using self-report anxiety scales in elderly patients, determine the parameters of their reliability and validity and develop recommendations on the use of these scales. MATERIAL AND METHODS: The study included 234 patients, aged over 50 years, with non-psychotic anxiety disorders. The following scales/questionnaires BAI, GAI, STAI, ZAS, HADS were used at baseline and 12 weeks after treatment. Conditions of testing, form and content of instructions were similar. Data analysis included the estimation of reliability and validity of these scales. Assessment made by the physician on the Hamilton anxiety scale (HAM-A) was used as "validity standard". RESULTS AND CONCLUSION: All scales (BAI, GAI, STAI, ZAS, HADS-A) can be used for screening diagnosis of anxiety in elderly people. The diagnostic sensitivity and specificity of the scales for subjective assessment of anxiety slightly decrease in advanced age and is sufficient for screening purposes. Based on the analysis, the authors have developed recommendations (common and specific for each scale) on the optimization of using self-report anxiety scales in advanced age. PMID- 27456902 TI - [Neurophysiological markers of generalized and focal epileptic seizures]. AB - AIM: To identify neurophysiological markers of focal and generalized epileptic seizures in the inter-epileptic period. MATERIAL AND METHODS: Sixty-four patients, including 36 with isolated generalized tonic-clonic seizures and 28 with focal seizures, were examined. The control group consisted of 27 healthy people. EEG-video monitoring and bioelectric activity analysis of the brain during wakefulness and day sleep, spectral EEG analysis, quantitative and quality indicators of sleep were used. RESULTS AND CONCLUSION: In generalized epileptic seizures, alpha rhythm is predominantly recorded in the left hemisphere. In wakefulness, the focal epileptiform activity develops during the first two stages of day sleep. In focal epileptic seizures, delta and beta-2 rhythms were recorded in the left hemisphere, regional epileptiform changes are aggravated during the 1st and 2nd stages of slow sleep initiated in the frontal regions. A focal component of the epileptiform activity in the inter-epileptic period in patients with different types of seizures should be taken into account in examination and treatment planning of patients who had difficulties with the diagnosis of epilepsy type. PMID- 27456903 TI - [A study of the effect of the genes of inflammatory proteins on basic personality dimensions]. AB - AIM: The present research examines the association between two basic dimensions of personality and genes of inflammatory cytokines and mediators reported to be elevated in schizophrenia and affective disorders. Genes of interleukin-1B (IL 1B), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) and alpha 1-antitrypsin (A1AT) were studied. MATERIAL AND METHODS: A total of 639 healthy subjects, aged from 17 to 69 years, participated in the study. The following polymorphisms were genotyped: IL-1B S-511T (rs16944) and S3954T (rs1143634), IL-6 G-174C (rs1800795), TNF-alpha G-308A (rs1800629), CRP (rs279452), A1AT 374G/A (rs709932). Basic personality dimensions Extraversion and Neuroticism were assessed using the Eysenck Personality Inventory. RESULTS AND CONCLUSION: The levels of Extraversion and Neuroticism were not associated with IL-1B, IL-6, TNF-alpha G and CRP polymorphisms. The association between the A1AT 374G/A polymorphism and Extraversion (r=0.036) was shown. There was a trend towards the association between the A1AT 374G/A polymorphism and Neuroticism (p=0,05) in women. Because this is the first study of the effect of IL-1B, IL-6, TNF-alpha and A1AT on personality dimensions, the results should be considered as preliminary and need to be replicated. PMID- 27456904 TI - [The effect of reamberin and alpha-lipoic acid on the tolerance to acute cerebral ischemia in experimental diabetes mellitus]. AB - AIM: To study an effect of reamberin and alpha-lipoic acid (alpha-LA) on the tolerance of mice with experimental diabetes mellitus (DM) to acute cerebrovascular accident (ACVA) in mice experiments. MATERIAL AND METHODS: The authors studied mice with alloxan diabetes and subtotal and total brain ischemia. In additional experimental series, an effect of reamberin and alpha-lipoic acid on the tolerance to acute hypoxic hypoxia and intensity of hyperglycemia in experimental DM was studied. RESULTS AND CONCLUSION: The increased vulnerability of animals to ACVA due to hyperglycemia and increased sensitivity to acute hypoxic hypoxia was established. Reamberin and alpha-lipoic acid administered for 14 days in doses, which are equivalent to therapeutic range in humans, enhance the tolerance to ACVA and acute hypoxic hypoxia in mice with alloxan diabetes. These medications also decrease the intensity of hyperglycemia during concurrent insulin replacement therapy. The increased tolerance to ACVA in mice with alloxan diabetes caused by reamberin and alpha-lipoic acid is associated with an antihypoxic effect of these medications and does not depend on their effect on the intensity of hyperglycemia. Reamberin outperformed alpha-lipoic acid in the antihypoxic activity, protection against ACVA and the rate of onset of glucose reducing effect in experimental diabetes mellitus. PMID- 27456905 TI - [Alcoholism at the end of 1980-s and beginning of 2010-s]. AB - AIM: To study the 20-years' clinical alteration and alcoholism basing on the changes in its clinical symptoms and course. MATERIAL AND METHODS: The study included 527 alcoholics with formed alcohol withdrawal syndrome: 181 alcoholics were examined in 1988-1990 (Group 1) and 346 alcoholics in 2011-2012 (Group 2). RESULTS AND CONCLUSION: In Group 1, vodka consumption dominated at all stages of alcoholism. Group 2 included 172 alcoholics with the domination of vodka consumption and 174 alcoholics with mixed consumption. It was shown that in comparison with Group 1 (1988-1990 patients) patients from Group 2 (2011-2012) had slower and mild development of alcoholism, especially those in the mixed consumption group. The authors suggest that the change of the clinical pattern in Group 2 was due to the change in the composition of consumed alcoholic beverages. PMID- 27456906 TI - [Pantogam augmentation in hyperkinetic behavior disorder treatment]. AB - A clinical case of a child with hyperkinetic conduct disorder is presented, with symptoms of hyperkinetic disorder itself closely intertwining with symptoms of conduct disorder. The qualitative changes in the child's condition are noted, including not only achieved control over the symptoms, but also improved social functioning level, achieved by means of Pantogam (neuroprotective drug) addition to atomoxetine therapy. The proposed strategy can contribute to improvement of treatment results for children with certain clinical types of hyperkinetic conduct disorder. PMID- 27456907 TI - [Multifocal motor neuropathy with conduction blocks]. AB - The article describes a case of multifocal motor neuropathy with conduction blocks in a female patient, aged 27 years. The development of the disease, results of neurological, laboratory, instrumental examinations, including electroneuromyography, and their role for the diagnosis and differential diagnosis are presented. PMID- 27456908 TI - [Experience of application of Russian biosimilar of interferon beta-1b for treatment of pediatric multiple sclerosis]. AB - AIM: To evaluate efficacy and safety of biosimilars of interferon beta-1b (Infibeta) in patients aged 14 to 17 years. MATERIAL AND METHODS: Interferon beta 1b (Infibeta) was appointed 9 children and adolescents (4 boys and 5 girls) between the ages of 14 to 17 years (mean age of onset of therapy 16.22+/-1.09). RESULTS: In the course of therapy there was a significant decrease in the annualrelapse rate (ARR) to 0.33+/-0.5 (from 0 to 1, r<=0,0001) and the of regression of neurological deficit on the EDSS scale up to +/-1.94+/-0.68 (1.5 to 3, p<=0.05). No cases of cancellation was not recorded due to poor tolerability or inefficiency. CONCLUSION: Although numerically small so far, but quite successful results on the use of Russian interferon beta-1b biosimilar (Infibeta) in children, we can recommend this treatment as sufficiently safe and effective. PMID- 27456909 TI - Mixed cellulose ester filter as a separator for air-diffusion cathode microbial fuel cells. AB - Separator is important to prevent bio-contamination of the catalyst layer of air diffusion cathode microbial fuel cells (MFCs). Mixed cellulose ester filter (MCEF) was examined as a separator for an air-cathode MFC in the present study. The MCEF-MFC produced a maximum power density of 780.7 +/- 18.7 mW/m2, which was comparable to 770.9 +/- 35.9 mW/m2 of MFC with Nafion membrane (NFM) as a separator. Long-term examination demonstrated a more stable performance of the MCEF-MFC than NFM-MFC. After 25 cycles, the maximum voltage of the MCEF-MFC decreased by only 1.3% from 425.1 +/- 4.3 mV (initial 5 cycles) to 419.5 +/- 2.3 mV (last 5 cycles). However, it was decreased by 9.1% from 424.8 +/- 5.7 to 386 +/- 2.5 mV for the NFM-MFC. The coulombic efficiency (CE) of the MCEF-MFC did not change (from 3.11 +/- 0.09% to 3.13 +/- 0.02%), while it decreased by 9.12% from 3.18 +/- 0.04% to 2.89 +/- 0.02% for the NFM-MFC. The MCEF separator was with less biofouling than the NFM separator over 60 days' operation, which might be the reason for the more table long-term performance of the MCEF-MFC. The results demonstrated that MCEF was feasible as a separator to set up good-performing and cost-effective air-diffusion cathode MFC. PMID- 27456911 TI - Coastal development and precipitation drive pathogen flow from land to sea: evidence from a Toxoplasma gondii and felid host system. AB - Rapidly developing coastal regions face consequences of land use and climate change including flooding and increased sediment, nutrient, and chemical runoff, but these forces may also enhance pathogen runoff, which threatens human, animal, and ecosystem health. Using the zoonotic parasite Toxoplasma gondii in California, USA as a model for coastal pathogen pollution, we examine the spatial distribution of parasite runoff and the impacts of precipitation and development on projected pathogen delivery to the ocean. Oocysts, the extremely hardy free living environmental stage of T. gondii shed in faeces of domestic and wild felids, are carried to the ocean by freshwater runoff. Linking spatial pathogen loading and transport models, we show that watersheds with the highest levels of oocyst runoff align closely with regions of increased sentinel marine mammal T. gondii infection. These watersheds are characterized by higher levels of coastal development and larger domestic cat populations. Increases in coastal development and precipitation independently raised oocyst delivery to the ocean (average increases of 44% and 79%, respectively), but dramatically increased parasite runoff when combined (175% average increase). Anthropogenic changes in landscapes and climate can accelerate runoff of diverse pathogens from terrestrial to aquatic environments, influencing transmission to people, domestic animals, and wildlife. PMID- 27456910 TI - Combined speed endurance and endurance exercise amplify the exercise-induced PGC 1alpha and PDK4 mRNA response in trained human muscle. AB - The aim of this study was to investigate the mRNA response related to mitochondrial biogenesis, metabolism, angiogenesis, and myogenesis in trained human skeletal muscle to speed endurance exercise (S), endurance exercise (E), and speed endurance followed by endurance exercise (S + E). Seventeen trained male subjects (maximum oxygen uptake (VO2-max): 57.2 +/- 3.7 (mean +/- SD) mL.min(-1).kg(-1)) performed S (6 * 30 sec all-out), E (60 min ~60% VO2-max), and S + E on a cycle ergometer on separate occasions. Muscle biopsies were obtained at rest and 1, 2, and 3 h after the speed endurance exercise (S and S + E) and at rest, 0, 1, and 2 h after exercise in E In S and S + E, muscle peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1alpha) and pyruvate dehydrogenase kinase-4 (PDK4) mRNA were higher (P < 0.05) 2 and 3 h after speed endurance exercise than at rest. Muscle PGC-1alpha and PDK4 mRNA levels were higher (P < 0.05) after exercise in S + E than in S and E, and higher (P < 0.05) in S than in E after exercise. In S and S + E, muscle vascular endothelial growth factor mRNA was higher (P < 0.05) 1 (S only), 2 and 3 h after speed endurance exercise than at rest. In S + E, muscle regulatory factor-4 and muscle heme oxygenase-1 mRNA were higher (P < 0.05) 1, 2, and 3 h after speed endurance exercise than at rest. In S, muscle hexokinase II mRNA was higher (P < 0.05) 2 and 3 h after speed endurance exercise than at rest and higher (P < 0.05) than in E after exercise. These findings suggest that in trained subjects, speed endurance exercise provides a stimulus for muscle mitochondrial biogenesis, substrate regulation, and angiogenesis that is not evident with endurance exercise. These responses are reinforced when speed endurance exercise is followed by endurance exercise. PMID- 27456912 TI - Critical Structure for Telescopic Movement of Honey bee (Insecta: Apidae) Abdomen: Folded Intersegmental Membrane. AB - The folded intersegmental membrane is a structure that interconnects two adjacent abdominal segments; this structure is distributed in the segments of the honey bee abdomen. The morphology of the folded intersegmental membrane has already been documented. However, the ultrastructure of the intersegmental membrane and its assistive role in the telescopic movements of the honey bee abdomen are poorly understood. To explore the morphology and ultrastructure of the folded intersegmental membrane in the honey bee abdomen, frozen sections were analyzed under a scanning electron microscope. The intersegmental membrane between two adjacent terga has a Z-S configuration that greatly influences the daily physical activities of the honey bee abdomen. The dorsal intersegmental membrane is 2 times thicker than the ventral one, leading to asymmetric abdominal motion. Honey bee abdominal movements were recorded using a high-speed camera and through phase contrast computed tomography. These movements conformed to the structural features of the folded intersegmental membrane. PMID- 27456915 TI - Acute Lymphoblastic Leukaemia in Infancy: Clinical and Biological Features. AB - The clinical and biological features of nineteen unselected cases of infant acute lymphoblastic leukaemia (ALL) are presented. All infants, eight male and eleven female. were 1 year of age or less at presentation of their disease and all showed the typical clinical features of ALL in infancy: hyperleucocytosis, organomegaly, frequent central nervous system (CNS) disease and one infant had cutaneous lesions. In the 17 cases which were successfully karyotyped, translocation of chromosome 11 involving band q23 were demonstrated in 16 cases (94%). The majority fell into the B precursor, or "null" ALL, category (CD10 negative, but CD19 and HLA DR positive), two cases, however, showed concomitant expression of B cell and myeloid (CD13 and CD33) markers. Two cases were CD10, HLA DR and CD19 positive and in one of these as well as one of the CD10 negative cases, 25-30%, of the blast cells expressed cytoplasmic Ig, M, a characteristic of pre-B cells. All cases, irrespective of phenotype or karyotype, showed rearrangement of the immunoglobulin heavy chain genes (IgH), but no light chain rearrangement. Together with the expression of B cell associated markers this, provided good evidence of their B lineage. No rearrangements of the beta or gamma chains of the T cell receptor complex (TcR) were seen in any case, nor was any rearrangement of the insulin receptor, which maps to band 19p13, seen in the cases with the t(11;19) translocation. The prognosis was uniformly poor. The majority of cases relapsed rapidly in the bone marrow whilst on therapy and within the first six months after diagnosis. Within the group of 19 infants studied, those with the t(11;19) translocation appeared to form a subgroup with the worst prognostic features (WBC averaging 591 * 10(9)/1, profound organomegaly and proven CNS disease in 4/7). 4/7 of this subgroup received no treatment and of the three who were treated, two relapsed within the first 11 months of treatment. PMID- 27456916 TI - Studies on the Clonogenicity of Human Myeloma Cells in vitro. AB - Myeloma is a disease of the B cell lineage which is characterized by the presence of excess numbers of isotypic plasma cells in the bone marrow and a serum paraprotein which is also isotypic for individual patients. These critieria may be accompanied by bone pain and often renal impairment. Until recently the median survival for patients treated with conventional chemotherapy was 2 years, however at the Royal Marsden Hospital (RMH) the use of VAMP (vincris-tine, 0.4 mg daily, days 1-4), adriamycin 9 mg/m(2) daily, days 1-4) and methylprednisolone (1 g/m(2) daily, days 1-5) followed by high-dose melphalan at 140 mg/m(2) or 200 mg/m(2) with autologous bone marrow transplantation has increased this survival time to 5 years in previously untreated patients(1,2). During the past 5 years the myeloma practice at the RMH has increased considerably and regular bone marrow aspirates from patients provide the material for in vitro studies. At present there: are approximately 160 patients whose disease is available for monitoring in vitro and approximately 15 myelomatous bone marrow are processed each week. The principal questions that need to be answered in myeloma is why do some patients fail to respond to chemotherapy and why does a further group become refractory to treatment at relapse. These problems encompass a need to examine drug-induced or endogenous drug resistance and to study the lineage of the disease. The development of an in vitro assay for myeloma colony formation by our group is enabling these questions to be investigated(3,4). PMID- 27456917 TI - The Reed-Sternberg Cell, An Activated T-cell? The Evidence Has Come Full Circle. AB - The origin of the malignant Reed-Sternberg (RS) cell in the most common histologic types of Hodgkin's disease (HD) has been controversial. Early attempts to study RS-cells in vitro for T-cell characteristics were not fruitful. Recent studies with more sensitive immunohistochemical methods have revealed that RS cells express T-lineage antigens in 25-60% of cases of all types of HD except nodular lymphocyte predominance which appears to be a B-cell disorder. All RS cells express lymphocyte activation antigens. This insight should permit a more complete understanding of the histopathology, clinical features and ctiology of HD through an investigation of lymphokines, growth factors and viruses associated with activated T and B lymphocytes. PMID- 27456918 TI - Oral Idarubicin in Elderly Acute Leukemia and Myelodyplastic Syndromes. AB - During the last five years, a new anthracycline 4:demethoxy daunorubicin or ldarubicin (IDR) has been found to be useful as an antileukemic agent. IDR is less cardiotoxic and has unequivocal biological activity when administered orally. Therefore, the choice of this oral agent to treat elderly acute non lymphoid leukemias (ANLL) or myelodysplastic syndromes (MDS) on an out-patient basis is attractive for obvious reasons. In this review we summarize the pharmacological characteristics of IDR, its use in the treatment off acute leukemia, and results reported until now in the literature and our sown results using oral IDR in elderly ANLL and MDS patients. IDR given orally at a total dose of 30 mg/m(2) to 90 mg/m(2) induced complete and partial overall responses, in approximately 50% of elderly ANLL and MDS. These results are comparable to those obtained in the same age category using low dose ARA-C, but with less drug toxicity for the patients. We believe that IDP given orally may be used as an additional tool in the conservative approach in elderly ANLL and MDS, which is a problematic category of patients to treat aggressively with combination intravenous chemotherapy. PMID- 27456919 TI - GM-CSF Stimulates Blast Cell Proliferation in Long-Term Culture of Bone Marrow from Patients with Myelodysplasia. AB - In long-term culture (LTBMC) of marrow from patients with myelodysplastic syndromes (MDS) abnormal patterns of growth, dysplastic cell morphology and cytogenetic changes present at initiation of culture persisted, providing a model in which to investigate the effects of hemopoeitic growth factors. In this model, rGM-CSF added weekly (100 u/ml) failed to increase the number of non-adherent cells, adherent cells or CFU-GM, but markedly increased the number or blast cells (from 11 +/- 5%) to 44 +/- 6% after 3.5 weeks), with a commensurate fall in the numbers of mature myeloid cells. In contrast, in LTBMC of normal marrow, rGM-CSF increased the non-adherent cell count by almost 5-fold. The increase was almost entirely due to enhanced production of myeloid precursors, predominantly mature myeloid cells, with a small increment in CFU-GM (2 fold: p < 0.05). These results suggest that in MDS GM-CSF enhances the "differentiation block" and may accelerate leukemic transformation. PMID- 27456920 TI - Differences Between Long- and Short-Term Survivors with Lymphoma Type of Adult T Cell Leukemia. AB - The clinical features at time of diagnosis of long-term survivors with lymphoma type of adult T-cell leukemia (ATL) were compared with those of short-term survivors. We had 51 Japanese patients with lymphoma type of ATL from 1981 to 1989 who had human T-cell leukemia virus type I (HTLV-I) antibody and monoclonal integration of HTLV-,I proviral DNA in the malignant cells. Of the 51 patients, 7 survived for more than 3 years, and they were classified as long-term survivors. Twenty-four patients died within 1 year and they were classified as short-term survivors. Differences between these two groups were investigated with the clinical findings recorded at the time of diagnosis. Findings that proved significant were serum lactate dehydrogenase (LDH) levels, calcium, total protein levels and the presence of B symptoms. Patients with lymphoma type of ATL are expected to be long-term survivors if they have no hypercalcemia or B symptoms with only mildly elevated serum LDH and total protein levels. PMID- 27456921 TI - The Pattern of Malignant Lymphoma in India: A Study of 1371 Cases. AB - A retrospective clinical and histopathological analysis was performed of 1371 patients with Non-Hodgkin's lymphomas presenting between January 1981 and December 1985. Pathologic material was reviewed and classified according to the modified Rappaport classification. The most common histologic type encountered was diffuse histiocytic lymphoma (29.5%), followed by diffuse poorly differentiated lymphoma (28%). A very low incidence of nodular lymphomas (10.6%) was seen. Twenty three percent of the patients had clinically stage 1 disease; 24.6% stage 11; 25.9% stage 111 and 26.2% stage IV disease. Bone marrow involvement was seen in 22.6% of patients. B symptoms were seen in 23.9% of patients. Primary extranodal lymphoma was seen in 307 (22.4%) patients. The commonest site of extranodal involvement was head and neck (36.1%) followed by gastrointestinal tract (24.4%). Treatment results could be analysed in only 599 patients. The response rate was 89% and complete response was seen in 67.5% patients. The overall survival for treated patients was 37.5% after 36 months, which is comparable to that reported by other investigators. This series is compared with different series reported from Asian as well as Western countries in order to highlight some common features as well as other major differences. PMID- 27456922 TI - A New Combination of Idarubicin, Etoposide and Cytarabine in Untreated Acute Non Lymphoblastic Leukemia. AB - Sixty-seven unselected adult patients with untreated acute non lymphotblastic leukemia (ANLL) ranging in age from 15 to 80 years received a new induction regimen consisting of Idarubicin, Etoposide and Cytarabine. Patients who entered complete remission (CR) were then allocated to 4 courses of post remission intensification. After this, patients under 50 years of age with a compatible donor were given allogeneic bone marrow transplantation (BMT) or autologous BMT (ABMT) in those without an HLA-compatible donor; the remainder, older than 50, did not receive further therapy. Fifty-six of 67 patients (83.5%) achieved CR (02.5% in young and 70.3% in old patients) and 40 (71 %) after the first course. Seven patients (of whom, 6 were > 50 years) died in aplasia during the induction phase and four additional patients (all elderly) died during post-remission intensification without recurrent disease. Subsequently, the younger patients received transplants (BMT: 4 pts; ABMT: 10 pts). Twelve: of the 52 (23%) who survived post remission intensification (BMT: 1; ABMT: 4; others: 7) are disease free survivors 9-67 months (median, 32 months) after achieving CR. In conclusion, this intensive chemotherapy regimen is highly effective both in young and odder patients but the post-remission intensification may be too aggressive for elderly patients. PMID- 27456923 TI - Immunocytochemical Analysis of Lymphoid Lesions Using -Fine Needle Aspiration Biopsy. AB - Sixty-four cases of mainly lymphoid lesions were investigated by fine needle aspiration. Both conventional smears and cytospin preparations were made from this material. Diagnoses based on cytological and immunocytological criteria were made in 57 of these cases and include reactive hyperplasia, non-Hodgkin's and Hodgkin's lymphoma and metastatic carcinoma. Five cases were inadequate for diagnostic purposes and in 2 cases no definite diagnosis could be made. These diagnoses were confirmed using tissue sections in 48/51 cases (with only 3 cytological diagnoses significantly altered by histology) and supported by supplementary clinical information in 8 cases. These results demonstrate the value of FNA biopsy in the investigation of lymphoid lesions using both conventional cytology and immunocytochemistry. PMID- 27456924 TI - Comparison of CHOP versus VEPA Therapy in Patients with Lymphoma Type of Adult T cell Leukemia. AB - Forty-six Japanese patients with lymphoma type of adult T-cell leukemia (ATL) were treated with one of the 4-drug combinations, CHOP or VEPA regimen. Fourteen patients were treated with CHOP, while 32 were treated with VEPA. The complete response i(CR) rate and the 5-year survival rate of patients treated with CHOP were 35.7% and 7.1%, respectively, while for those treated with VEPA the rates were 43.8% and 18.7%, respectively. Only two patients treated with CHOP survived for more than 1 year, while the others died within 1 year. On the other hand, 13 patients treated with VEPA survived for more than 1 year. The 32 VEF'A-treated patients were divided into two groups according to the duration of survival: (A) 13 surviving for more than 1 year, and (B) 19 surviving for less than 1 year. They were compared for pretreatment characteristics. The differences between the two groups related to hepatomegaly, the presence of B symptoms, lactic dehydrogenase (LDH) and calcium levels. The results indicate that these factors are important in predicting the response and survival of patients with lymphoma type of ATL. PMID- 27456925 TI - Factors Influencing the Efficacy of Platelet Transfusions in Acute Leukemia. AB - The efficacy of platelet transfusions was evaluated in a prospective study of 37 patients with acute leukemia. The patients received 495 platelet transfusions for chemotherapy-induced thrombocytopenia. Life table analysis was found to be useful for prediction of the platelet level after transfusion. Efficacy was positively correlated with platelet content in the concentrate, and inversely correlated with bleeding. Fever, contamination of the: concentrate by leukocytes, or previous platelet transfusions were not found to have any significant influence on the efficacy, as analyzed by multiple regression. Single-donor platelet preparations and multiple-donor preparations were equally efficient. It is nevertheless suggested that single-donor preparations should be preferred, due to reduced risk of blood-carried infections. PMID- 27456926 TI - Correlation between Intracellular and Extracellular Lysozyme in Acute (Myelo)Monocytic Leukemia. AB - The localization of myeloperoxidase (MPO) or lysozyme was studied in leukemic cells by electron microscopy in an attempt to investigate why the level of lysozyme activity increases in the serum of patients with acute (myelo)monocytic leukemia. The specimens were obtained from 3 patients with acute monocytic leukemia and 4 with acute myelomonocytic leukemia with extremely elevated serum lysozyme levels (more than 100 MUg/ml, normal: ~10ug/ml). The granules containing MPO or lysozyme, surrounded by microfilaments, were observed in the periphery of the cytoplasm. MPO positive granules were considered tot contain lysozyme. Some granules appeared to be degranulation from the cell-membrane of viable leukemic cells. This observation supports the concept that there is a mechanism by which lysozyme-positive granules degranulation from viable leukemic cells and as a result the level of lysozyme activity becomes elevated in the serum. It also appears that MPO is discharged into the serum at the same time as lysozyme: is released. PMID- 27456928 TI - Corrigendum. PMID- 27456927 TI - Changes in Utilization and Discard of Hepatitis C-Infected Donor Livers in the Recent Era. AB - The impact of interferon (IFN)-free direct-acting antiviral (DAA) hepatitis C virus (HCV) treatments on utilization and outcomes associated with HCV-positive deceased donor liver transplantation (DDLT) is largely unknown. Using the Scientific Registry of Transplant Recipients, we identified 25 566 HCV-positive DDLT recipients from 2005 to 2015 and compared practices according to the introduction of DAA therapies using modified Poisson regression. The proportion of HCV-positive recipients who received HCV-positive livers increased from 6.9% in 2010 to 16.9% in 2015. HCV-positive recipients were 61% more likely to receive an HCV-positive liver after 2010 (early DAA/IFN era) (aRR:1.45 1.611.79 , p < 0.001) and almost three times more likely to receive one after 2013 (IFN-free DAA era) (aRR:2.58 2.853.16 , p < 0.001). Compared to HCV-negative livers, HCV positive livers were 3 times more likely to be discarded from 2005 to 2010 (aRR:2.69 2.993.34 , p < 0.001), 2.2 times more likely after 2010 (aRR:1.80 2.162.58 , p < 0.001) and 1.7 times more likely after 2013 (aRR:1.37 1.682.04 , p < 0.001). Donor HCV status was not associated with increased risk of all-cause graft loss (p = 0.1), and this did not change over time (p = 0.8). Use of HCV positive livers has increased dramatically, coinciding with the advent of DAAs. However, the discard rate remains nearly double that of HCV-negative livers. Further optimization of HCV-positive liver utilization is necessary to improve access for all candidates. PMID- 27456929 TI - Intra-laboratory study to determine the reproducibility of LLNA:BrdU-ELISA for the prediction of the skin sensitizing potential of chemicals. AB - INTRODUCTION: The Local Lymph Node Assay (LLNA) has been designated as the first choice in vivo assay for identification the skin sensitization potential of new chemicals. The LLNA:BrdU-ELISA is a validated non-radioactive modification to the LLNA. An intra-laboratory reproducibility study for the LLNA:BrdU-ELISA was conducted to demonstrate its adequate performance in our laboratory. METHODS: Ten independent LLNA:BrdU-ELISAs with the preferred positive controls (PCs), i.e., 25% hexyl cinnamic aldehyde (HCA) and 25% eugenol, were conducted within a period of less than one year. In addition, different concentrations of 2,4 dinitrochlorobenzene (DNCB, an extreme sensitizer) (0.01, 0.1 and 0.3%), HCA (10, 25 and 50%) and eugenol (10, 25 and 50%), were tested to determine the EC1.6 values. Special Pathogen Free female CBA/J mice of 8-10weeks old were randomly allocated to the groups, each group having 4 mice. 25MUl of AOO (vehicle, acetone: olive oil=4:1, v/v) or HCA, eugenol, DNCB at the needed concentration was applied to the dorsum of each ear of the mice, daily for 3 consecutive days. A single intraperitoneal injection of 0.5ml of BrdU solution (10mg/ml) was given on day 5. On day 6, a pair of auricular lymph nodes from each mouse was excised, and BrdU ELISA analysis was conducted. RESULTS: The result for each group is expressed as the mean Stimulation Index (SI). The mean of the 10 mean SIs for 25% HCA (2.58+/-0.95) and 25% eugenol (3.51+/-1.25) was not significantly different to that from the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) (i.e., the data on the formal validation study for the LLNA:BrdU-ELISA by the ICCVAM) (3.03+/-2.00 for 25% HCA, 6.13+/-6.06 for 25% eugenol) (P>0.05), with even smaller Coefficient of Variations (CV) (36.8% for 25% HCA, 35.6% for 25% eugenol) than that from the ICCVAM (66.0% for 25% HCA, 98.8% for 25% eugenol). In addition, the EC1.6 values for HCA, eugenol and DNCB (15.2, 12.5 and 0.25%, respectively) were consistent with that from the ICCVAM (12.92, 8.85 and 0.34%, respectively). DISCUSSION: The results indicate that the reliability for our laboratory to conduct the LLNA:BrdU-ELISA is successfully determined. PMID- 27456930 TI - Gender and geographical variability in the exposure pattern and metabolism of deoxynivalenol in humans: a review. AB - Deoxynivalenol (DON, also known as vomitoxin) is a common mycotoxin found worldwide, especially in contaminated food. DON is toxic to a variety of cells and tissues in humans. Three kinds of conjugated products (DON-3-glucuronide, DON 15-glucuronide and DON-7-glucuronide) can be found as major metabolites in human urine. Females and males show different patterns of exposure levels, and human exposure to DON also shows some geographical differences because of different DON levels in cereal-based foods, food intake habits and UDP-glucuronosyltransferase expression. Specifically, the C12, 13-deepoxy metabolite was found predominantly in French adults but was rarely detected in UK adults. However, a cohort of Spanish individuals demonstrated even lower DON levels than the levels in the UK populations, whereas a very high DON exposure level was detected in South Africa and Linxian, China. Recent publications have further indicated that DON could be detected in the urine of pregnant women from different countries, which suggests that there is a potential risk to both mothers and foetuses. Additionally, phytochemicals have been shown to be less toxic to cells and laboratory animals in research studies and may also be used as food additives for reducing the toxic effects of DON. In this review, we provide global information on DON metabolism, human exposure and gender differences in humans. Also, control strategies for this mycotoxin are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27456931 TI - Increased Ubqln2 expression causes neuron death in transgenic rats. AB - Pathogenic mutation of ubiquilin 2 (UBQLN2) causes neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. How UBQLN2 mutations cause the diseases is not clear. While over-expression of UBQLN2 with pathogenic mutation causes neuron death in rodent models, deletion of the Ubqln2 in rats has no effect on neuronal function. Previous findings in animal models suggest that UBQLN2 mutations cause the diseases mainly through a gain rather than a loss of functions. To examine whether the toxic gain in UBQLN2 mutation is related to the enhancement of UBQLN2 functions, we created new transgenic rats over-expressing wild-type human UBQLN2. Considering that human UBQLN2 may not function properly in the rat genome, we also created transgenic rats over expressing rat's own Ubqln2. When over-expressed in rats, both human and rat wild type Ubqln2 caused neuronal death and spatial learning deficits, the pathologies that were indistinguishable from those observed in mutant UBQLN2 transgenic rats. Over-expressed wild-type UBQLN2 formed protein inclusions attracting the autophagy substrate sequestosome-1 and the proteasome component 26S proteasome regulatory subunit 7. These findings suggest that excess UBQLN2 is toxic rather than protective to neurons and that the enhancement of UBQLN2 functions is involved in UBQLN2 pathogenesis. Pathogenic mutation in ubiquilin 2 (UBQLN2) causes neurodegeneration in ALS and FTLD. Studies in rodent models suggest a gain of toxic function in mutant UBQLN2. We created new transgenic rats as a relevant model and examined whether enhancing wild-type UBQLN2 expression is implicated in the pathogenesis of mutant UBQLN2. We observed that over-expression of human or rat wild-type Ubqln2 caused protein aggregation and neuronal death in transgenic rats. Our findings suggest that excess UBQLN2 is toxic rather than protective to neurons and that uncontrolled enhancement of UBQLN2 function is involved in UBQLN2 pathogenesis. Read the Editorial Highlight for this article on page 159. PMID- 27456932 TI - Eliminating potential lead exposure in imported New Zealand wild game. PMID- 27456934 TI - The effects of resveratrol intervention on risk markers of cardiovascular health in overweight and obese subjects: a pooled analysis of randomized controlled trials. AB - BACKGROUND: Potential effects of resveratrol consumption on cardiovascular disease risk factors and body weight in overweight/obese adults have not been fully elucidated. Our present analysis was to evaluate the effects of resveratrol consumption on risk markers related to cardiovascular health in overweight/obese Individuals. METHODS: Multiple literature databases were systematically searched, and 21 studies were included. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI), and heterogeneity was assessed with the I2 test. Publication bias and subgroup analyses were also performed. RESULTS: There were variations in reporting quality of included studies. Resveratrol intervention significantly lowered total cholesterol (WMD, -0.19 mmol/L; 95% CI, -0.32 to -0.06; P = 0.004), systolic blood pressure (WMD, -2.26 mmHg; 95% CI, -4.82 to -0.49; P = 0.02), and fasting glucose (WMD, -0.22 mmol/L; 95% CI, -0.42 to -0.03; P = 0.03). Heterogeneity was noted for these outcomes (35.6%, 38.7% and 71.4%, respectively). Our subgroup analysis showed significant reductions in total cholesterol, systolic blood pressure, diastolic blood pressure, glucose, and insulin in subjects ingesting higher dose of resveratrol (>=300 mg/day). CONCLUSION: Our finding provides evidence that daily resveratrol consumption might be a candidate as an adjunct to pharmacological management to better prevent and control cardiovascular disease in overweight/obese individuals. PMID- 27456933 TI - Avoidance and Subversion of Eukaryotic Homeostatic Autophagy Mechanisms by Bacterial Pathogens. AB - Autophagy is a conserved lysosomal recycling process, which maintains cellular homeostasis during stress and starvation conditions by degrading and recycling proteins, lipids, and carbohydrates, ultimately increasing nutrient availability in eukaryotes. An additional function of autophagy, termed xenophagy, is to detect, capture, and destroy invading microorganisms, such as viruses, bacteria, and protozoa, providing autophagy with a role in innate immunity. Many intracellular pathogens have, however, developed mechanisms to avoid xenophagy and have evolved strategies to take advantage of select autophagic processes to undergo their intracellular life cycle. This review article will discuss the molecular mechanisms used by the intracellular bacterial pathogens Francisella spp. and Brucella spp. to manipulate components of the autophagic pathway, promoting cytosolic growth in the case of Francisella spp. and facilitating cellular egress and cell-to-cell spread in the case of Brucella spp. These examples highlight how successful, highly infectious bacterial pathogens avoid or subvert host autophagy mechanisms normally employed to maintain eukaryotic homeostasis. PMID- 27456935 TI - Diagnosis of Strongyloides stercoralis: Detection of parasite-derived DNA in urine. AB - Detecting infections of Strongyloides stercoralis is arduous and has low sensitivity. Clinically this is a major problem because chronic infections may disseminate in the host and lead to a life threatening condition. Epidemiologically, S. stercoralis is often missed in surveys as it is difficult to identify by standard stool examination procedures. We present, for the first time, evidence that the infection can be detected in filtered urine samples collected and processed in the field and subsequently assayed for the presence of parasite DNA. Urine specimens (~40mL) were collected from 125 test and control individuals living in rural and peri-urban regions of Northern Argentina. From the same individuals, fresh stool specimens were processed using three different copropological methods. Urine specimens were filtered in the field through a 12.5cm Whatman No. 3 filter. The filters were dried and packed individually in sealable plastic bags with desiccant and shipped to a laboratory where DNA was recovered from the filter and PCR-amplified with primers specific to a dispersed repetitive sequence. Prevalence of S. stercoralis infection by stool culture and direct examination was 35/125 (28%), In contrast, PCR-based detection of parasite specific trans-renal DNA in urine indicated that 56/125 (44.8%) carried the parasite. Of the patients that tested positive for urine-based parasite DNA, approximately half also tested positive in their stool specimens. There were 6.4% of cases where parasite larvae were seen in the stool but no DNA was amplified from the urine. As proof of principle, DNA amplification from urine residue reveals significantly more cases of S. stercoralis infection than the current standard stool examination techniques. Additional work is required to establish the relative utility, sensitivity and specificity of urine-based analysis compared to parasitological and nucleic acid detection from stool for clinical and epidemiological detection for S. stercoralis infection. PMID- 27456936 TI - Laboratory evaluation of differential attraction of Culex pipiens pallens to fruit-based sugar baits. AB - Mosquito adults usually need to obtain sugar from floral nectaries and damaged fruits/seed pods to replenish their energy reserves. The newly developed attractive toxic sugar baits have been successfully applied in controlling various mosquito species outdoors. However, the attraction of Culex pipiens pallens to different fruit-based sugar baits remains unknown. In the present study, we selected nine common fruit species, prepared the fruit-based sugar solutions, and investigated the attractiveness of different sugar baits to newly emerged Cx. pipiens pallens in the laboratory. The results showed that when tested against the 5% brown sugar solution, all the sugar baits were significantly attractive to both females and males. When tested together in the mesh-covered cage, there was a significant difference on the attractiveness between different fruit-based sugar baits. The most attractive fruit species included Broussonetia papyrifera, Cucumis melo, C. melo var. saccharinus, Amygdalus persica and Pyrus bretschneideri, and their seed pods could be potentially used as ingredients in ATSB for controlling mosquitoes outdoors. PMID- 27456938 TI - Comments on the association of immatures of Hemerodromia (Diptera, Empididae) and Simulium (Diptera, Simuliidae), and first record of this association in the Atlantic Forest (Brazil). AB - Larvae of Empididae (Diptera) prey on black fly immatures and its pupae can be collected from pupal cases of Simuliidae (Diptera). The aim of our work was to report the second record of association between immatures of Empididae and Simuliidae in the Neotropical Region and the first for the Atlantic Forest (Rio de Janeiro, Brazil). We collected 4982 pupae and exuviae of Simulium Latreille, (Diptera, Simuliidae) and found three with a pupa of Hemerodromia Meigen (Diptera, Empididae) inside. This shows that the use of black flies cocoons by dance flies occurs at extremely low frequencies, which might explain why this association is so rarely recorded. Our results are relevant for a better comprehension of the predator-prey relationship between these families. PMID- 27456937 TI - Evidence of Coxiella burnetii in Punjab province, Pakistan. AB - Coxiella burnetii causes query (Q) fever, an important zoonotic disease with worldwide significance. The role of environment in the ecology of C. burnetti, and its influence on seroconversion in animals has not been elucidated in Pakistan. We carried out a cross-sectional study in Punjab province to (1) determine the prevalence and distribution of C. burnetii in soil using an ISIIII gene-based real time-polymerase chain reaction (RT-PCR) assay, (2) analyze association between the occurrence of C. burnetii in soil and its predictors i.e. soil characteristics (macro- and micro-nutrients) and several likely risk factors including the seroconversion in small ruminants at places where its genome had or had not been detected, and (3) predict homology and genetic diversity of the identified strains using sequences originated from different hosts worldwide. A total of 2425 soil samples from nine districts of Punjab province were processed. C. burnetii DNA was detected in 47 samples (1.94%, 95% CI: +/-0.55) originating from 35 villages of studied districts (7.22%, 95% CI: +/-2.30). The highest prevalence was found in Attock (7.11%, 95% CI: +/-3.36), followed by Lahore (4.83%, 95% CI: +/-3.49), Sahiwal (4.70%, 95% CI: +/-2.6), Dera Ghazi Khan (2.33%, 95% CI: +/-2.02), Faisalabad (1.35%, 95% CI: +/-1.18) and Sheikhupura (0.68%, 95% CI: +/-0.94). The odds of detecting bacterial DNA in soil was increased with a unit increase in organic matter [2.511 (95% CI: 1.453-4.340), p=0.001] and sodium [1.013 (95% CI: 1.005-1.022), p=0.001], whereas, calcium [0.984 (95% CI: 0.975-0.994), p=0.002] and potassium [0.994 (95% CI: 0.990 0.999), p=0.011] had protective effect where a unit increase in each analyte decreased odds for its occurrence by 1.0% approximately. Likewise, for categorical variables (risk factors), the odds of detecting C. burnetii were higher at locations >500m away from a main road [1.95 (95% CI: 1.06-3.78), p=0.04]. The enzyme-linked immunosorbent assay (ELISA) revealed an increased prevalence of antibodies in sheep (17.9%, 95% CI: +/-5.54) compared with goats (16.4%, 95% CI: +/-4.34). When determining the association between soil DNA and C. burnetii antibodies in small ruminants, the odds of detecting these antibodies were significant in sheep at the livestock barns [2.81 (95% CI: 1.20-7.37), p=0.02]. The IS1111 gene-based sequence analysis revealed a clustering of the DNA into two distinct groups with much genetic divergence (0.76-68.70%): the first group that contained sequences from Lahore district clustered with human and buffalo origin isolates, whereas the second group that contained the sequences from the remaining study districts clustered with goat-, rodent- and human-origin isolates. This study provides the first evidence of the presence of C. burnetii in the environment in Punjab province, Pakistan. Future studies are needed to ascertain the bacteria's molecular epidemiology over a wide geographical area, type the isolates, and evaluates the potential risks to human populations, particularly farmers and veterinarians. PMID- 27456939 TI - Role of the Na+/K+-ATPase ion pump in male reproduction and embryo development. AB - Na+/K+-ATPase was one of the first ion pumps studied because of its importance in maintaining osmotic and ionic balances between intracellular and extracellular environments, through the exchange of three Na+ ions out and two K+ ions into a cell. This enzyme, which comprises two main subunits (alpha and beta), with or without an auxiliary polypeptide (gamma), can have specific biochemical properties depending on the expression of associated isoforms (alpha1beta1 and/or alpha2beta1) in the cell. In addition to the importance of Na+/K+-ATPase in ensuring the function of many tissues (e.g. brain, heart and kidney), in the reproductive tract this protein is essential for embryo development because of its roles in blastocoel formation and embryo hatching. In the context of male reproduction, the discovery of a very specific subunit (alpha4), apparently restricted to male germ cells, only expressed after puberty and able to influence sperm function (e.g. motility and capacitation), opened a remarkable field for further investigations regarding sperm biology. Therefore, the present review focuses on the importance of Na+/K+-ATPase on male reproduction and embryo development. PMID- 27456940 TI - Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma. AB - PURPOSE: Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance. MATERIALS AND METHODS: The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis. RESULTS: The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31+/-15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18+/-7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified. CONCLUSION: The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers. PMID- 27456941 TI - Efficacy and Safety of Regorafenib in Korean Patients with Advanced Gastrointestinal Stromal Tumor after Failure of Imatinib and Sunitinib: A Multicenter Study Based on the Management Access Program. AB - PURPOSE: The aim of this study was to confirm the efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors (GISTs) reported in the GRID phase III trial in Korean patients. MATERIALS AND METHODS: Fifty-seven Korean patientswith advanced GISTwho experienced both imatinib and sunitinib failure were enrolled in the management access program between December 2012 and November 2013 and treated with regorafenib (160 mg orally once daily in a 3 weeks on/1 week off). RESULTS: None of the patients achieved a complete or partial response while 25 patients (44%) showed stable disease for >= 12 weeks. With a median follow-up of 12.7 months (range, 0.2 to 27.6 months), the median progression-free survival and overall survival were 4.5 months (95% confidence interval [CI], 3.8 to 5.3) and 12.9 months (95% CI, 8.1 to 17.7), respectively. Interestingly, 15 patients (26%) experienced an exacerbation of their cancer related symptoms (abdominal pain in eight and abdominal distension in five) during the rest period for regorafenib, but all were ameliorated upon the resumption of regorafenib. The most common grade 3 or 4 adverse event was a hand foot skin reaction (25%). The regorafenib dose was reduced in 44 patients (77%) due to toxicity, which manifested mainly as a hand-foot skin reaction (n=31). CONCLUSION: This study confirmed the efficacy and safety of regorafenib for advanced GIST after imatinib and sunitinib failure in Korean patients. Considering the exacerbation of the cancer-related symptoms observed during the rest periods, further exploration of the continuous dosing schedule of regorafenib is warranted in future clinical trials. PMID- 27456943 TI - Current Trends of Lung Cancer Surgery and Demographic and Social Factors Related to Changes in the Trends of Lung Cancer Surgery: An Analysis of the National Database from 2010 to 2014. AB - PURPOSE: We investigated current trends in lung cancer surgery and identified demographic and social factors related to changes in these trends. MATERIALS AND METHODS: We estimated the incidence of lung cancer surgery using a procedure code based approach provided by the Health Insurance Review and Assessment Service (http://opendata.hira.or.kr). The population data were obtained every year from 2010 to 2014 from the Korean Statistical Information Service (http://kosis.kr/). The annual percent change (APC) and statistical significance were calculated using the Joinpoint software. RESULTS: From January 2010 to December 2014, 25,687 patients underwent 25,921 lung cancer surgeries, which increased by 45.1% from 2010 to 2014. The crude incidence rate of lung cancer surgery in each year increased significantly (APC, 9.5; p < 0.05). The male-to-female ratio decreased from 2.1 to 1.6 (APC, -6.3; p < 0.05). The incidence increased in the age group of >= 70 years for both sexes (male: APC, 3.7; p < 0.05; female: APC, 5.96; p < 0.05). Furthermore, the proportion of female patients aged >= 65 years increased (APC, 7.2; p < 0.05), while that of male patients aged < 65 years decreased (APC, -3.9; p < 0.05). The proportions of segmentectomies (APC, 17.8; p < 0.05) and lobectomies (APC, 7.5; p < 0.05) increased, while the proportion of pneumonectomies decreased (APC, -6.3; p < 0.05). Finally, the proportion of patients undergoing surgery in Seoul increased (APC, 1.1; p < 0.05), while the proportion in other areas decreased (APC, -1.5; p < 0.05). CONCLUSION: An increase in the use of lung cancer surgery in elderly patients and female patients, and a decrease in the proportion of patients requiring extensive pulmonary resection were identified. Furthermore, centralization of lung cancer surgery was noted. PMID- 27456942 TI - Adipose Stromal Cells from Visceral and Subcutaneous Fat Facilitate Migration of Ovarian Cancer Cells via IL-6/JAK2/STAT3 Pathway. AB - PURPOSE: Adipose stromal cells (ASCs) play an important regulatory role in cancer progression and metastasis by regulating systemic inflammation and tissue metabolism. This study examined whether visceral and subcutaneous ASCs (V- and S ASCs) facilitate the growth and migration of ovarian cancer cells. MATERIALS AND METHODS: CD45- and CD31- double-negative ASCs were isolated from the subcutaneous and visceral fat using magnetic-activated cell sorting. Ovarian cancer cells were cultured in conditioned media (CM) obtained from ASCs to determine the cancer promoting effects of ASCs. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, Boyden chamber assay, and western blotting were performed to determine the proliferative activity, migration ability, and activation of the JAK2/STAT3 pathway, respectively. RESULTS: CM from ASCs enhanced the migration of the ovarian cancer line, SKOV3, via activation of the JAK2/STAT3 signaling pathway. Interestingly, in response to ASC-CM, the ascites cells derived from an ovarian cancer patient showed an increase in growth and migration. The migration of ovarian cancer cells was suppressed by blocking the activation of JAK2 and STAT3 using a neutralizing antibody against interleukin 6, small molecular inhibitors (e.g., WP1066 and TG101348), and silencing of STAT3 using siRNA. Anatomical differences between S- and V-ASCs did not affect the growth and migration of the ovarian cancer cell line and ascites cells from the ovarian cancer patients. CONCLUSION: ASCs may regulate the progression of ovarian cancer, and possibly provide a potential target for anticancer therapy. PMID- 27456944 TI - Anti-cancer Effects of a Novel Quinoline Derivative 83b1 on Human Esophageal Squamous Cell Carcinoma through Down-Regulation of COX-2 mRNA and PGE2. AB - PURPOSE: 83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis. MATERIALS AND METHODS: A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2-derived prostaglandin E2 (PGE2) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450. RESULTS: 83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARdelta), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2-derived PGE2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft. CONCLUSION: The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARdelta, and down-regulation of the cancer related genes and molecules. PMID- 27456945 TI - Progressive Multifocal Leukoencephalopathy after Ibrutinib Therapy for Chronic Lymphocytic Leukemia. AB - Progressive multifocal leukoencephalopathy (PML) is a devastating neurological disease observed nearly exclusively in immunocompromised patients. Recently, the introduction of monoclonal antibodies significantly inhibiting the immune system such as rituximab has led to an increase in PML cases. Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton's tyrosine kinase inhibitors such as ibrutinib is steadily increasing. However, long-term experiences regarding possible side effects of these new substances are rare. Here, we report the development of eventually fatal PML possibly associated with ibrutinib therapy for CLL after multiple prior treatment lines, including rituximab. To the best of our knowledge, this is the first study to report such findings. Since the last course of rituximab was applied over 3 years ago, it is conceivable that the strong B cell inhibition by ibrutinib led to PML. With increased awareness of this potential side effect, further clinical studies are certainly warranted to evaluate this possible association. PMID- 27456946 TI - Blocking Interleukin-4 Receptor alpha Using Polyethylene Glycol Functionalized Superparamagnetic Iron Oxide Nanocarriers to Inhibit Breast Cancer Cell Proliferation. AB - PURPOSE: The specific targeting of interleukin-4 receptor alpha (IL4Ralpha) receptor offers a promising therapeutic approach for inhibition of tumor cell progression in breast cancer patients. In the current study, the in vitro efficacy of superparamagnetic iron oxide nanoparticles conjugated with anti IL4Ralpha blocking antibodies (SPION-IL4Ralpha) via polyethylene glycol polymers was evaluated in 4T1 breast cancer cells. MATERIALS AND METHODS: Cell viability, reactive oxygen species generation, and apoptosis frequency were assessed in vitro in 4T1 cancer cell lines following exposure to SPION-IL4Ralpha alone or combined with doxorubicin. In addition, immunofluorescence assessments and fluorimetrywere performed to confirm the specific targeting and interaction of the developed nanocarriers with IL4Ralpha receptors in breast cancer cells. RESULTS: Blocking of IL4Ralpha receptors caused a significant decrease in cell viability and induced apoptosis in 4T1 cells. In addition, combined treatment with SPION-IL4Ralpha+doxorubicin caused significant increases in cell death, apoptosis, and oxidative stress compared to either SPION-IL4Ralpha or doxorubicin alone, indicating the enhanced therapeutic efficacy of this combination. The decrease in fluorescence intensity upon immunofluorescence and fluorimetry assays combined with increased viability and decreased apoptosis following the blocking of IL4Ralpha receptors confirmed the successful binding of the synthesized nanocarriers to the target sites on murine 4T1 breast cancerous cells. CONCLUSION: These results suggest that SPION-IL4Ralpha nanocarriers might be used for successfulreduction of tumor growth and inhibition of progression of metastasis in vivo. PMID- 27456947 TI - Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma. AB - PURPOSE: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Recently, the overexpression of programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has been shown to correlate with poor prognosis in many cancers. However, the expression of PD-L1 or PD-1 ligand 2 (PD-L2) and clinical outcomes have not been fully investigated in HCC. MATERIALS AND METHODS: Formalin fixed paraffin-embedded samples were obtained from 85 patients with HCC who underwent surgery. The expression of PD-Ls (PD-L1, PD-L2) was evaluated by immunohistochemical analysis. RESULTS: The proportion of high expression groups of PD-L1 and PD-L2 was 27.1% and 23.5%, respectively. Univariate analysis revealed that tumor size (p < 0.001), histological differentiation (p=0.010), PD L1 expression (p < 0.001), and PD-L2 expression (p=0.039) were significant prognostic factors of overall survival in patients with HCC. Multivariate analysis revealed that overall tumor size (hazard ratio [HR], 4.131; 95% confidence interval [CI], 2.233 to 7.643; p < 0.001 and HR, 3.455; 95% CI, 1.967 to 6.067; p < 0.001) and PD-L1 expression (HR, 5.172; 95% CI, 2.661 to 10.054; p < 0.001 and HR, 3.730; 95% CI, 1.453 to 9.574; p=0.006) were independent prognostic values for overall and disease-free survival. Patients with high expression of PD-Ls had a significantly poorer survival than those with low expression (p < 0.001, p=0.034). CONCLUSION: The overexpression of PD-Ls in HCC patients is correlated with survival and tumor recurrence. Further evaluation of PD-1 and PD-Ls as therapeutic targets and predictive biomarkers for HCC is warranted. PMID- 27456948 TI - Expression of Myxovirus Resistance A (MxA) Is Associated with Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancers. AB - PURPOSE: The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been determined in breast cancers. Interferons can affect T-cell activity through direct and indirect mechanisms. Myxovirus resistance A (MxA) is an excellent marker of interferon activity. Here,we evaluated TILs and MxA expression in human epidermal growth factor receptor 2 (HER2)-positive breast cancers. MATERIALS AND METHODS: Ninety cases of hormone receptor (HR)+/HER2+ tumors and 78 cases of HR /HER2+ tumors were included. The TILs level was assessed using hematoxylin and eosin-stained full face sections, and MxA expressionwas evaluated by immunohistochemistrywith a tissue microarray. RESULTS: MxA protein expression was significantly higher in tumors with high histologic grade (p=0.023) and high levels of TILs (p=0.002). High levels of TILs were correlated with high histological grade (p=0.001), negative lymphovascular invasion (p=0.007), negative lymph node metastasis (p=0.007), absence of HR expression (p < 0.001), abundant tertiary lymphoid structures (TLSs) around ductal carcinoma in situ (p=0.018), and abundant TLSs around the invasive component (p < 0.001). High levels of TILs were also associated with improved disease-free survival, particularly in HR-/HER2+ breast cancers. However, MxA was not a prognostic factor. CONCLUSION: High expression of MxA in tumor cells was associated with high levels of TILs in HER2-positive breast cancers. Additionally, a high level of TILs was a prognostic factor for breast cancer, whereas the level of MxA expression had no prognostic value. PMID- 27456949 TI - Alcohol Intake and Risk of Thyroid Cancer: A Meta-Analysis of Observational Studies. AB - PURPOSE: The purpose of this study was to assess whether alcohol intake is associated with the risk of thyroid cancer by a meta-analysis of observational studies. MATERIALS AND METHODS: We searched PubMed and EMBASE in June of 2015 to locate eligible studies. We included observational studies such as cross sectional studies, case-control studies, and cohort studies reporting odd ratios (ORs) or relative risk (RRs) with 95% confidence intervals (CIs). RESULTS: We included 33 observational studies with two cross-sectional studies, 20 case controls studies, and 11 cohort studies, which involved a total of 7,725 thyroid cancer patients and 3,113,679 participants without thyroid cancer in the final analysis. In the fixed-effect model meta-analysis of all 33 studies, we found that alcohol intake was consistently associated with a decreased risk of thyroid cancer (OR or RR, 0.74; 95% CI, 0.67 to 0.83; I2=38.6%). In the subgroup meta analysis by type of study, alcohol intake also decreased the risk of thyroid cancer in both case-control studies (OR, 0.77; 95% CI, 0.65 to 0.92; I2=29.5%; n=20) and cohort studies (RR, 0.70; 95% CI, 0.60 to 0.82; I2=0%; n=11). Moreover, subgroup meta-analyses by type of thyroid cancer, gender, amount of alcohol consumed, and methodological quality of study showed that alcohol intake was significantly associated with a decreased risk of thyroid cancer. CONCLUSION: The current meta-analysis of observational studies found that, unlike most of other types of cancer, alcohol intake decreased the risk of thyroid cancer. PMID- 27456950 TI - A cure is possible: a study of 10-year survivors of brain metastases. AB - Little is known on the natural history, recurrence patterns, neurocognitive outcomes and prognostic factors associated with survival in long-term survivors (>=10 years) from brain metastasis (BM). In this study, the records of 1953 patients who underwent treatment for BM with a potential for >=10 years of follow up were reviewed. Cox regression analysis identified factors predictive for overall survival (OS). The median age at brain metastasis diagnosis was 60 years and the median OS was 6.4 months. The 1-year OS rate was 29.9, 12.1 % at 2 years, 3.0 % at 5 years, and 1.3 % at 10 years. On multivariable analysis, factors associated with worse OS included gender (males, HR 1.2), multiple brain metastases (HR 1.3), no surgery (HR 1.8), and no stereotactic radiosurgery (HR 1.8) (p < 0.0001 each). Fifty-six patients (2.9 %) survived >=5 years; 23 patients (1.2 %) survived >=10 years and the median survival for >=10 year survivors was 18.5 years. Six of the 10-year survivors had an intracranial recurrence, five occurred within 11 years from the first treatment. Presence of a solitary lesion or single lesion at the time of brain metastasis diagnosis was associated with improved survival. Eight of the >=10 year survivors (34.8 %) had no neurological symptoms at last follow-up; none of the 10-year survivors were documented to have a neurologic death. Our study demonstrates that patients with favorable prognostic features should undergo multimodality treatment. Albeit rare, patients who are alive 10 years after treatment for their brain metastases may be considered cured from their intracranial disease. PMID- 27456952 TI - Relation of Diagnostic Accuracy of Viral Respiratory Polymerase Chain Reaction to Specimen Number and Source in Severe Adenovirus Pneumonia: Antimicrobial Stewardship Implications. PMID- 27456954 TI - Innovative Targets For Asthma And COPD: Exploring The Existing And Screening The New!! AB - The inadequate benefits of the existing therapies and the new insights into the pathophysiology of inflammatory airway diseases like chronic obstructive pulmonary disease (COPD) and asthma have led to the breakthrough of newer targets and innovative compounds as the treatment alternatives. The enhanced interpretation of immune cell signalling and signal transduction pathways at the molecular level involved in this process allows the selection of new therapeutic targets and designing of new molecules to combat such multifactorial diseases. Pertaining to the marked variability in type of inflammation observed in their disease phenotypes, the blockade of a particular receptor or mediator yielding strong restorative effect in one patient may not be significant to other. Therefore, their management requires the prompt and phenotype specific optimized drug therapies and development of new and improved molecular compounds targeting the immune cell signalling. This whole process including the approval of such compounds as the standard drug therapies is time taking, expensive and complicated task. It ranges from the selection of novel anti-inflammatory drug target to the final approval of biologically active restorative molecules. Grounded on this, the current review gives a comprehensive idea of the basic immunological network involved in these inflammatory airway diseases at the cellular level along with the discussion of their potential therapeutic targets. It also follows brief over viewing of the drug development process generally employed for the exploration of such innovative targets leading to the discovery of novel anti-inflammatory molecules for these inflammatory airway diseases. PMID- 27456951 TI - Bone Marrow-Derived Progenitor Cells Are Functionally Impaired in Ischemic Heart Disease. AB - To determine whether the presence of ischemic heart disease (IHD) per se, or rather the co-presence of heart failure (HF), is the primum movens for less effective stem cell products in autologous stem cell therapy, we assessed numbers and function of bone marrow (BM)-derived progenitor cells in patients with coronary artery disease (n = 17), HF due to ischemic cardiomyopathy (n = 8), non ischemic HF (n = 7), and control subjects (n = 11). Myeloid and erythroid differentiation capacity of BM-derived mononuclear cells was impaired in patients with underlying IHD but not with non-ischemic HF. Migration capacity decreased with increasing IHD severity. Hence, IHD, with or without associated cardiomyopathy, is an important determinant of progenitor cell function. No depletion of hematopoietic and endothelial progenitor cells (EPC) within the BM was observed, while circulating EPC numbers were increased in the presence of IHD, suggesting active recruitment. The observed myelosuppression was not driven by inflammation and thus other mechanisms are at play. PMID- 27456955 TI - The special role of item-context associations in the direct-access region of working memory. AB - The three-embedded-component model of working memory (WM) distinguishes three representational states corresponding to three WM regions: activated long-term memory, direct-access region (DAR), and focus of attention. Recent neuroimaging research has revealed that access to the DAR is associated with enhanced hippocampal activity. Because the hippocampus mediates the encoding and retrieval of item-context associations, it has been suggested that this hippocampal activation is a consequence of the fact that item-context associations are particularly strong and accessible in the DAR. This study provides behavioral evidence for this view using an item-recognition task to assess the effect of non intentional encoding and maintenance of item-location associations across WM regions. Five pictures of human faces were sequentially presented in different screen locations followed by a recognition probe. Visual cues immediately preceding the probe indicated the location thereof. When probe stimuli appeared in the same location that they had been presented within the memory set, the presentation of the cue was expected to elicit the activation of the corresponding WM representation through the just-established item-location association, resulting in faster recognition. Results showed this same-location effect, but only for items that, according to their serial position within the memory set, were held in the DAR. PMID- 27456957 TI - Why Can't Surgeons Treat Older Patients the Same as Younger Patients? PMID- 27456956 TI - Gentisic acid sodium salt, a phenolic compound, is superior to norepinephrine in reversing cardiovascular collapse, hepatic mitochondrial dysfunction and lactic acidemia in Pseudomonas aeruginosa septic shock in dogs. AB - BACKGROUND: The development of lactic acidemia (LA) in septic shock (SS) is associated with an ominous prognosis. We previously showed that the mechanism of LA in SS may relate to impaired hepatic uptake of lactate, but the mechanism was not clear. Uptake of lactate by the liver occurs by a membrane-associated, pH dependent, antiport system known as the monocarboxylate transporter. In the hepatocyte, lactate can then be metabolized by oxidative phosphorylation or converted to glucose in the cytosol. In the present study, we examined (1) whether hepatic mitochondrial dysfunction accounted for decreased uptake of lactate in a canine model of Pseudomonas aeruginosa SS, (2) whether norepinephrine (NE) treatment by increasing mean arterial pressure (MAP) could improve mitochondrial dysfunction and LA in this model, and (3) whether gentisic acid sodium salt (GSS), a novel phenolic compound, was superior to NE in these effects. METHODS: In anesthetized/ventilated dogs, we infused the bacteria over ~10 h and measured hemodynamics in various treatment groups (see below). We then euthanized the animal and isolated the hepatic mitochondria. We measured hepatic mitochondrial oxygen consumption rates using the novel Seahorse XF24 analyzer under conditions that included: basal respiration, after the addition of adenosine- diphosphate to produce coupled respiration, and after the addition of a protonophore to produce maximal respiration. RESULTS: We found that in the septic control group, mean arterial pressure decreased over the course of the study, and that mitochondrial dysfunction developed in which there was a reduction in maximal respiration. Whereas both NE and GSS treatments reversed the reduction in mean arterial pressure and increased maximal respiration to similar extents in respective groups, only in the GSS group was there a reduction in LA. CONCLUSIONS: Hepatic mitochondrial dysfunction occurs in SS, but does not appear to be required for the development of LA in SS, since NE improved mitochondrial dysfunction without reversing LA. GSS, a phenolic compound restored mean arterial pressure, mitochondrial dysfunction, and LA in SS. This reduction in LA may be independent of its effect on improving hepatic mitochondrial function. PMID- 27456958 TI - Laparoscopic Management of Gallbladder Cancer: A Stepwise Approach. AB - BACKGROUND: In the era of laparoscopic cholecystectomy, incidentally discovered gallbladder cancer (IGBC) has become a common clinical presentation.1 A consensus exists that radical resection should be performed for IGBC patients with T1b or more advanced tumors.2 Although the oncologic safety of laparoscopic treatment for selected patients with gallbladder cancer (GBC) has been demonstrated, a laparoscopic approach for IGBC remains uncommonly practiced due to the technical challenge of the frequently reoperative cases.3 PATIENT: A 75-year-old man underwent laparoscopic cholecystectomy for the presumed diagnosis of chronic cholecystitis and sludge at an outside institution, and pathology showed a T3 gallbladder carcinoma with a positive margin at the cystic duct stump. Restaging computed tomography at the time of referral showed findings in the hepatoduodenal ligament and gallbladder fossa concerning residual tumor versus postoperative inflammation. After four cycles of gemcitabine and cisplatin, restaging showed interval resolution of the postoperative change, continued low tumor marker carbohydrate antigen 19-9, and no evidence of metastatic disease. Therefore, the decision was made to perform a laparoscopic radical resection TECHNIQUE: With the patient in French position, significant adhesions around the hepatoduodenal ligament had to be dissected. Lymph node stations 12 and 16 were removed after a Kocher maneuver and hepatoduodenal ligament lymphadenectomy, preserving an accessory right hepatic artery. The cystic duct stump was removed at the level of confluence with the common bile duct. The resulting defect was reconstructed with interrupted sutures. Using intraoperative ultrasonography (IOUS) guidance, an anatomic resection of segments 4b and 5 was performed. An alternative approach is a laparoscopic Glissonian approach that can facilitate a safe anatomic resection.4 An air cholangiogram detected no bile leak and confirmed biliary patency.5 The postoperative recovery was uneventful, and pathology showed residual adenocarcinoma in segments 4b, and 5 with 50 % tumor viability and negative margins. CONCLUSION: Because laparoscopic management of IGBC involves a challenging reoperative procedure, a systematic approach using accurate preoperative anatomic assessment, meticulous IOUS-guided surgery, and air cholangiogram is recommended to minimize the morbidity of this operation. PMID- 27456960 TI - Comment on: Tan WJ, Cima I, Choudhury Y, Wei X, Lim JCT, Thicke AA, Tan MH, Tan PH. A five-gene reverse transcription-PCR assay for pre-operative classification of breast fibroepithelial lesions. Breast Cancer Research 2016;18:31. PMID- 27456959 TI - Too much sitting and all-cause mortality: is there a causal link? AB - BACKGROUND: Sedentary behaviours (time spent sitting, with low energy expenditure) are associated with deleterious health outcomes, including all-cause mortality. Whether this association can be considered causal has yet to be established. Using systematic reviews and primary studies from those reviews, we drew upon Bradford Hill's criteria to consider the likelihood that sedentary behaviour in epidemiological studies is likely to be causally related to all cause (premature) mortality. METHODS: Searches for systematic reviews on sedentary behaviours and all-cause mortality yielded 386 records which, when judged against eligibility criteria, left eight reviews (addressing 17 primary studies) for analysis. Exposure measures included self-reported total sitting time, TV viewing time, and screen time. Studies included comparisons of a low sedentary reference group with several higher sedentary categories, or compared the highest versus lowest sedentary behaviour groups. We employed four Bradford Hill criteria: strength of association, consistency, temporality, and dose response. Evidence supporting causality at the level of each systematic review and primary study was judged using a traffic light system depicting green for causal evidence, amber for mixed or inconclusive evidence, and red for no evidence for causality (either evidence of no effect or no evidence reported). RESULTS: The eight systematic reviews showed evidence for consistency (7 green) and temporality (6 green), and some evidence for strength of association (4 green). There was no evidence for a dose-response relationship (5 red). Five reviews were rated green overall. Twelve (67 %) of the primary studies were rated green, with evidence for strength and temporality. CONCLUSIONS: There is reasonable evidence for a likely causal relationship between sedentary behaviour and all-cause mortality based on the epidemiological criteria of strength of association, consistency of effect, and temporality. PMID- 27456961 TI - Parental influences on children's mental health: the bad and the good sides of it. PMID- 27456962 TI - What change in body mass index is needed to improve metabolic health status in childhood obesity: protocol for a systematic review. AB - BACKGROUND: Childhood obesity is one of the most serious, global, public health challenges and has adverse health consequences in both the short-and long-term. The purpose of this study is to establish the change in body mass index (BMI) needed to achieve improvements in metabolic health status in obese children and adolescents attending lifestyle treatment interventions. METHODS: The following electronic databases will be searched from their inception: AMED, Embase, MEDLINE via OVID, Web of Science and CENTRAL via Cochrane library. Randomised controlled trials (RCTs) or cohort studies of lifestyle interventions (i.e. dietary, physical activity and/or behavioural therapy) for treating obesity in children and adolescents (4-18 years) will be included. Interventions that last less than 2 weeks and trials that include overweight participants or those with a secondary or syndromic cause of obesity will not be included. No language restrictions will be applied. Titles and abstracts will be assessed for eligibility by two reviewers, and data from full-text articles will be extracted using a standardised data extraction template. Reference lists of all included articles will be hand-searched for additional publications. A narrative synthesis of the findings will be presented, and meta-analysis will be conducted if considered appropriate. DISCUSSION: This will be the first systematic review of studies to establish the change in BMI required to improve metabolic health status in obese children and adolescents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016025317. PMID- 27456963 TI - Retrospective assessment of interobserver agreement and accuracy in classifications and measurements in subsolid nodules with solid components less than 8mm: which window setting is better? AB - OBJECTIVES: To compare interobserver agreements among multiple readers and accuracy for the assessment of solid components in subsolid nodules between the lung and mediastinal window settings. METHODS: Seventy-seven surgically resected nodules with solid components smaller than 8 mm were included in this study. In both lung and mediastinal windows, five readers independently assessed the presence and size of solid component. Bootstrapping was used to compare the interobserver agreement between the two window settings. Imaging-pathology correlation was performed to evaluate the accuracy. RESULTS: There were no significant differences in the interobserver agreements between the two windows for both identification (lung windows, k = 0.51; mediastinal windows, k = 0.57) and measurements (lung windows, ICC = 0.70; mediastinal windows, ICC = 0.69) of solid components. The incidence of false negative results for the presence of invasive components and the median absolute difference between the solid component size and the invasive component size were significantly higher on mediastinal windows than on lung windows (P < 0.001 and P < 0.001, respectively). CONCLUSIONS: The lung window setting had a comparable reproducibility but a higher accuracy than the mediastinal window setting for nodule classifications and solid component measurements in subsolid nodules. KEY POINTS: * Reproducibility was similar between the two windows in nodule classifications. * Reproducibility was similar between the two windows in solid component measurements. * Accuracy for solid component assessment was higher on lung windows. PMID- 27456964 TI - Aortic elasticity indices by magnetic resonance predict progression of ascending aorta dilation. AB - OBJECTIVES: Aortic distensibility and pulse-wave velocity (PWV) are under investigation as parameters by which to evaluate the indication for ascending aorta (AA) replacement. The maximum rate of systolic distension (MRSD) was proposed as a new index of aortic elasticity. The aim of this study was to assess the role of aortic elasticity parameters to predict AA growth rates in patients with AA dilation (AAD). METHODS: Magnetic resonance imaging (MRI) was performed annually in 65 patients with AA dilation (median follow-up 17 months; 25-75th percentile; range 12-30 months). A significant increase in AA diameter was defined as a >=2-mm increase. RESULTS: An increase in AA diameter was found in 42 (68 %) patients (AAD+ group) and absent in 20. Median increase was 0.16 (25-75th percentile; range 0.32-0.7) mm/month. The AAD+ group had a lower MRSD (4.6 +/- 2.2 vs 7.4 +/- 2.0, p < 0.001) but the same PWV and distensibility. MRSD showed 93.7 % specificity and 75.6 % sensitivity for prediction of increase. Patients with MRSD <= 6 had lower progression-free survival times (p < 0.002). After a follow-up of 4.1 years, patients who underwent surgical therapy had lower MRSD and distensibility than others. CONCLUSIONS: MRSD is an index of aorta elastic properties and is a valuable predictor for progression in AAD. KEY POINTS: * MRI derived parameters of aortic wall elasticity predict progression of ascending aorta dilation. * Maximal rate of systolic distension (MRSD) was the best predictor of progression. * Patients with MRSD <= 6 had lower progression-free survival (PFS) times. * Patients who underwent surgical therapy had lower MRSD and distensibility. * MRI-derived parameters identify patients with fast progression of Ascending Aorta Dilation. PMID- 27456965 TI - Comparison between gadolinium-enhanced 2D T1-weighted gradient-echo and spin-echo sequences in the detection of active multiple sclerosis lesions on 3.0T MRI. AB - OBJECTIVES: To compare the sensitivity of enhancing multiple sclerosis (MS) lesions in gadolinium-enhanced 2D T1-weighted gradient-echo (GRE) and spin-echo (SE) sequences, and to assess the influence of visual conspicuity and laterality on detection of these lesions. METHODS: One hundred MS patients underwent 3.0T brain MRI including gadolinium-enhanced 2D T1-weighted GRE and SE sequences. The two sets of contrast-enhanced scans were evaluated in random fashion by three experienced readers. Lesion conspicuity was assessed by the image contrast ratio (CR) and contrast-to-noise ratio (CNR). The intracranial region was divided into four quadrants and the impact of lesion location on detection was assessed in each slice. RESULTS: Six hundred and seven gadolinium-enhancing MS lesions were identified. GRE images were more sensitive for lesion detection (0.828) than SE images (0.767). Lesions showed a higher CR in SE than in GRE images, whereas the CNR was higher in GRE than SE. Most misclassifications occurred in the right posterior quadrant. CONCLUSIONS: The gadolinium-enhanced 2D T1-weighted GRE sequence at 3.0T MRI enables detection of enhancing MS lesions with higher sensitivity and better lesion conspicuity than 2D T1-weighted SE. Hence, we propose the use of gadolinium-enhanced GRE sequences rather than SE sequences for routine scanning of MS patients at 3.0T. KEY POINTS: * 2D SE and GRE sequences are useful for detecting active MS lesions. * Which of these sequences is more sensitive at high field remains uncertain. * GRE sequence showed better sensitivity for detecting active MS lesions than SE. * We propose GRE sequence for detecting active MS lesions at 3.0T. PMID- 27456967 TI - Building a Science of Animal Minds: Lloyd Morgan, Experimentation, and Morgan's Canon. AB - Conwy Lloyd Morgan (1852-1936) is widely regarded as the father of modern comparative psychology. Yet, Morgan initially had significant doubts about whether a genuine science of comparative psychology was even possible, only later becoming more optimistic about our ability to make reliable inferences about the mental capacities of non-human animals. There has been a fair amount of disagreement amongst scholars of Morgan's work about the nature, timing, and causes of this shift in Morgan's thinking. We argue that Morgan underwent two quite different shifts of attitude towards the proper practice of comparative psychology. The first was a qualified acceptance of the Romanesian approach to comparative psychology that he had initially criticized. The second was a shift away from Romanes' reliance on systematizing anecdotal evidence of animal intelligence towards an experimental approach, focused on studying the development of behaviour. We emphasize the role of Morgan's evolving epistemological views in bringing about the first shift - in particular, his philosophy of science. We emphasize the role of an intriguing but overlooked figure in the history of comparative psychology in explaining the second shift, T. Mann Jones, whose correspondence with Morgan provided an important catalyst for Morgan's experimental turn, particularly the special focus on development. We also shed light on the intended function of Morgan's Canon, the methodological principle for which Morgan is now mostly known. The Canon can only be properly understood by seeing it in the context of Morgan's own unique experimental vision for comparative psychology. PMID- 27456966 TI - Hepatic stiffness measurement by using MR elastography: prognostic values after hepatic resection for hepatocellular carcinoma. AB - PURPOSE: To evaluate prognostic value of hepatic stiffness (HS) measurement using MR elastography (MRE) in patients with hepatocellular carcinoma (HCC) treated by hepatic resection (HR). METHODS: We enrolled 144 patients with Barcelona Clinic Liver Cancer stage A HCCs initially treated by HR who underwent preoperative liver MRE between January 2010 and June 2013. HS values were measured using MRE. Receiver operating characteristics (ROC) and multivariate logistic regression analyses were used to determine significant predictive factors for posthepatecomy liver failure (PHLF). Overall survival (OS) was analyzed by evaluating prognostic factors using the Kaplan-Meier method and Cox proportional hazard regression model. RESULTS: After HR, 43 patients (29.9 %) experienced PHLF. HS values were significant predictive factors for PHLF. In ROC analysis, the area under the curve of HS was 0.740 (P = 0.001) for PHLF. Thirty-one patients had HS values >= 4.02 kPa; the estimated 1, 3, 5-year survival were 90.0 %, 74.7 % and 65.4 %, respectively, versus 98.1 %, 96.5 % and 96.5 % in 113 patients with HS values < 4.02 kPa (P = 0.015). An HS value >= 4.02 kPa was the only significant affecting factor for OS. CONCLUSION: HS values measured by MRE could predict PHLF development post-HR. Furthermore, an HS value >=4.02 kPa was a significant predicting factor for poor OS post-HR. KEY POINTS: * Hepatic stiffness value was a predictive factor for developing posthepatectomy liver failure * Hepatic stiffness value was a significant affecting factor for OS * Hepatic stiffness value >= 4.02 kPa was a predictive factor for poor OS. PMID- 27456968 TI - Red pitaya juice supplementation ameliorates energy balance homeostasis by modulating obesity-related genes in high-carbohydrate, high-fat diet-induced metabolic syndrome rats. AB - BACKGROUND: Red pitaya (Hylocereus polyrhizus) or known as buah naga merah in Malay belongs to the cactus family, Cactaceae. Red pitaya has been shown to give protection against liver damage and may reduce the stiffness of the heart. Besides, the beneficial effects of red pitaya against obesity have been reported; however, the mechanism of this protection is not clear. Therefore, in the present study, we have investigated the red pitaya-targeted genes in obesity using high carbohydrate, high-fat diet-induced metabolic syndrome rat model. METHODS: A total of four groups were tested: corn-starch (CS), corn-starch + red pitaya juice (CRP), high-carbohydrate, high-fat (HCHF) and high-carbohydrate, high-fat + red pitaya juice (HRP). The intervention with 5 % red pitaya juice was continued for 8 weeks after 8 weeks initiation of the diet. Retroperitoneal, epididymal and omental fat pads were collected and weighed. Plasma concentration of IL-6 and TNF alpha were measured using commercial kits. Gene expression analysis was conducted using RNA extracted from liver samples. A total of eighty-four genes related to obesity were analyzed using PCR array. RESULTS: The rats fed HCHF-diet for 16 weeks increased body weight, developed excess abdominal fat deposition and down regulated the expression level of IL-1alpha, IL-1r1, and Cntfr as compared to the control group. Supplementation of red pitaya juice for 8 weeks increased omental and epididymal fat but no change in retroperitoneal fat was observed. Red pitaya juice reversed the changes in energy balance homeostasis in liver tissues by regulation of the expression levels of Pomc and Insr. The increased protein expression levels of IL-6 and TNF-alpha in HCHF group and red pitaya treated rats confirmed the results of gene expression. CONCLUSION: Collectively, this study revealed the usefulness of this diet-induced rat model and the beneficial effects of red pitaya on energy balance homeostasis by modulating the anorectic, orexigenic and energy expenditure related genes. PMID- 27456969 TI - Locomotor deficits in recently concussed athletes and matched controls during single and dual-task turning gait: preliminary results. AB - BACKGROUND: There is growing evidence that mild traumatic brain injury (concussion) can affect locomotor characteristics for prolonged periods of time even when physical signs and symptoms are absent. While most locomotor deficits post-concussion have involved straight walking, turning gait has received little attention despite its pervasiveness in everyday locomotion and athletic competition. METHODS: This study longitudinally examined kinematic characteristics during preplanned turning in a small sample of recently concussed athletes (n = 4) and healthy matched control athletes (n = 4) to examine potential deficits during single and dual-task turning gait over the initial 6 weeks post-injury, with a one-year follow-up. Turning path kinematics (curvature, obstacle clearance, path length), stride kinematics (stride length, stride width, stride time), and inclination angles were calculated from motion capture of participants walking around an obstacle. RESULTS: Concussed athletes had larger dual-task costs in turning speed and stride time compared to healthy controls. After controlling for speed and turn curvature, recently concussed athletes increased their inclination towards the inside of the turn over time and decreased their stride time compared to controls indicating a prolonged recovery. Kinematic differences between groups were estimated to recover to healthy levels between 100 and 300 days post-injury, suggesting future prospective longitudinal studies should span 6-12 months post-injury. CONCLUSION: Turning gait should be included in future studies of concussion and may be a clinically useful tool. Future longitudinal studies should consider examining gait changes for up to 6-12 months post-injury. PMID- 27456970 TI - Comparison of the HER2, estrogen and progesterone receptor expression profile of primary tumor, metastases and circulating tumor cells in metastatic breast cancer patients. AB - BACKGROUND: The expression of HER2, estrogen (ER) and progesterone (PR) receptor can change during the course of the disease in breast cancer (BC). Therefore, reassessment of these markers at the time of disease progression might help to optimize treatment decisions. In this context, characterization of circulating tumor cells (CTCs) could be of relevance since metastatic tissue may be difficult to obtain for repeated analysis. Here we compared HER2/ER/PR expression profiles of primary tumors, metastases and CTCs. METHODS: Ninety-six patients with metastatic BC from seven University BC Centers in Germany were enrolled in this study. Blood was obtained at the time of first diagnosis of metastatic disease or disease progression and analyzed for CTCs using the AdnaTest BreastCancer (QIAGEN Hannover GmbH, Germany) for the expression of EpCAM, MUC-1, HER2, ER and PR. HER2 expression on CTCs was additionally assessed by immunocytochemistry using the CellSearch(r) assay. RESULTS: The detection rate for CTCs using the AdnaTest was 43 % (36/84 patients) with the expression rates of 50 % for HER2 (18/36 patients), 19 % for ER (7/36 patients) and 8 % for PR (3/36 patients), respectively. Primary tumors and CTCs displayed a concordant HER2, ER and PR status in 59 % (p = 0.262), 39 % (p = 0.51) and 44 % (p = 0.62) of cases, respectively. For metastases and CTCs, the concordance values were 67 % for HER2 (p = 0.04), 43 % for ER (p = 0.16) and 46 % for PR (p = 0.6). Using the CellSearch(r) assay, the CTC-positivity rate was 53 % (42/79 patients) with HER2 expressed in 29 % (12/42) of the patients. No significant concordance (58 % and 53 %) was found when HER2 on CTCs was compared with HER2 on primary tumors (p = 0.24) and metastases (p = 0.34). Interestingly, primary tumors and metastases were highly concordant for HER2 (84 %, p = 1.13E-08), ER (90 %, p = 3.26E-10) and PR (83 %, p = 2.09E-09) and ER-and PR-positive metastases were significantly found to be of visceral origin (p = 0.03, p = 0.02). CONCLUSION: Here we demonstrate that the molecular detection of HER2 overexpression in CTC is predictive of the HER2 status on metastases. Detailed analysis of ER and PR expression rates in tissue samples and CTCs may provide useful information for making treatment decisions. PMID- 27456971 TI - TOMM Trial 1 as a performance validity indicator in a criminal forensic sample. AB - OBJECTIVE: To determine the effectiveness of the Test of Memory Malingering Trial 1 (TOMM1) as a freestanding Performance Validity Test (PVT) as compared to the full TOMM in a criminal forensic sample. METHOD: Participants included 119 evaluees in a Midwestern forensic hospital. Criterion groups were formed based on passing/failing scores on other freestanding PVTs. This resulted in three groups: +MND (Malingered Neurocognitive Dysfunction), who failed two or more freestanding PVTs; possible MND (pMND), who failed one freestanding PVT; and -MND, who failed no other freestanding PVTs. All three groups were compared initially, but only +MND and -MND groups were retained for final analyses. TOMM1 performance was compared to standard TOMM performance using Receiver Operating Characteristic (ROC) analyses. RESULTS: TOMM1 was highly predictive of the standard TOMM decision rules (AUC = .92). Overall accuracy rate for TOMM1 predicting failure on 2 PVTs was quite robust as well (AUC = .80), and TOMM1 <= 39 provided acceptable diagnostic statistics (Sensitivity = .68, Specificity = .89). These results were essentially no different from the standard TOMM accuracy statistics. In addition, by adjusting for those strongly suspected of being inaccurately placed into the MND group (e.g. false negatives), TOMM1 diagnostics slightly improved (AUC = .84) at a TOMM1 <= 40 (sensitivity = .71, specificity = .94). CONCLUSIONS: Results support use of TOMM1 in a criminal forensic setting where accuracy, shorter evaluation times, and more efficient use of resources are often critical in informing legal decision-making. PMID- 27456972 TI - Recruitment of Arabidopsis RNA Helicase AtRH9 to the Viral Replication Complex by Viral Replicase to Promote Turnip Mosaic Virus Replication. AB - Positive-sense RNA viruses have a small genome with very limited coding capacity and are highly dependent on host components to fulfill their life cycle. Recent studies have suggested that DEAD-box RNA helicases play vital roles in many aspects of RNA metabolism. To explore the possible role of the RNA helicases in viral infection, we used the Turnip mosaic virus (TuMV)-Arabidopsis pathosystem. The Arabidopsis genome encodes more than 100 putative RNA helicases (AtRH). Over 41 Arabidopsis T-DNA insertion mutants carrying genetic lesions in the corresponding 26 AtRH genes were screened for their requirement in TuMV infection. TuMV infection assays revealed that virus accumulation significantly decreased in the Arabidopsis mutants of three genes, AtRH9, AtRH26, and PRH75. In the present work, AtRH9 was further characterized. Yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays showed that AtRH9 interacted with the TuMV NIb protein, the viral RNA-dependent RNA polymerase. Moreover, the subcellular distribution of AtRH9 was altered in the virus-infected cells, and AtRH9 was recruited to the viral replication complex. These results suggest that Arabidopsis AtRH9 is an important component of the TuMV replication complex, possibly recruited via its interaction with NIb. PMID- 27456974 TI - Simplified automatic method for measuring the visual field using the perimeter ZERK 1. AB - BACKGROUND: Currently available perimeters have limited capabilities of performing measurements of the visual field in children. In addition, they do not allow for fully automatic measurement even in adults. The patient in each case (in any type of perimeter) has at his disposal a button which he uses to indicate that he has seen a light stimulus. Such restrictions have been offset in the presented new perimeter ZERK 1. METHODS: The paper describes a new type of automated, computerized perimeter designed to test the visual field in children and adults. The new perimeter and proprietary software enable to carry out tests automatically (without the need to press any button). The presented full version of the perimeter has been tested on a head phantom. The next steps will involve clinical trials and a comparison with measurements obtained using other types of perimeters. RESULTS: The perimeter ZERK 1 enables automatic measurement of the visual field in two axes (with a span of 870 mm and a depth of 525 mm) with an accuracy of not less than 1(o) (95 LEDs on each arm) at a typical position of the patient's head. The measurement can be carried out in two modes: default/typical (lasting about 1 min), and accurate (lasting about 10 min). Compared with available and known types of perimeters, it has an open canopy, proprietary software and cameras tracking the eye movement, automatic control of fixation points, light stimuli with automatically preset light stimulus intensity in the following ranges: 550-700 mcd (red 620-630 nm), 1100-1400 mcd (green 515-530 nm), 200-400 mcd (blue 465-475 nm). CONCLUSIONS: The paper presents a new approach to the construction of perimeters based on automatic tracking of the eye movements in response to stimuli. The unique construction of the perimeter and the software allow for its mobile use in the examination of children and bedridden patients. PMID- 27456975 TI - Does an increase in visits to general practice indicate a malignancy? AB - BACKGROUND: An increase in a patient's visits to doctors usually raises concerns and may be a 'red flag' for a patient's deterioration of health. The aim of this study was to analyze whether an increase of patient-physician contacts is a first sign of a malignancy in a patient's near future. METHODS: This is a retrospective case-control study. From 153 German general practices' electronic patient records (EPR), cases with at least one new malignancy diagnosis and no-malignancy controls were matched for gender and age. We calculated (1) the number of contacts in the first quarter up to the sixth quarter before a malignancy diagnosis was made and (2) the inter-contact interval (ICI), i.e. the time lag between two consecutive patient-physician contacts measured in days. Differences between cases and controls were investigated in several analyses of variance, with group and time as main factors. RESULTS: A total of 3,310 cases and 3,310 controls could be included. The number of contacts for cases in the six quarters before a malignancy diagnosis increased from 4.8 contacts (SD 4.3) to 5.5 contacts (SD 4.8). The number of contacts for controls increased only marginally from 4.3 contacts (SD 3.6) to 4.5 (SD 4.2). The factor 'group' (cases vs. controls) was highly significant in the analyses of variance, also 'time' and the interaction 'group * time'. The effect size, however, was very small (R(2) being less than 0.02), which is the equivalent for about one additional contact per quarter in cases directly before a newly made malignancy diagnosis. CONCLUSION: An increase in contact frequency is a call for GPs to become more attentive towards these patients. It may raise the suspicion of an impending serious disease but the increase is not so dramatic and unique that it can be interpreted a reliable sign of a malignant diagnosis. PMID- 27456973 TI - Multidimensional assessment of empathic abilities in patients with insular glioma. AB - Recent studies have provided evidence that there are two possible systems for empathy: affective empathy (AE) and cognitive empathy (CE). Neuroimaging paradigms have proven that the insular cortex is involved in empathy processing, particularly in AE. However, these observations do not provide causal evidence for the role of the insula in empathy. Although impairments in empathy have been described following insular damage in a few case studies, it is not clear whether insular cortex is involved in CE and whether these two systems are impaired independently or laterally in patients with insular gliomas. In this study, we assessed 17 patients with an insular glioma, 17 patients with a noninsular glioma, and 30 healthy controls using a method that combined a self-report empathy questionnaire with the emotion recognition task, assessment of empathy for others' pain, and the emotional perspective-taking paradigm. We found that patients with an insular glioma had lower scores for empathic concern and perspective taking than did either healthy controls or lesion controls. The patients' abilities to recognize facial emotions, perceive others' pain, and understand the emotional perspectives of others were also significantly impaired. Furthermore, we did not observe a laterality effect on either AE or CE among those with insular lesions. These findings revealed that both AE and CE are impaired in patients with an insular glioma and that the insular cortex may be a central neuroanatomical structure in both the AE and CE systems. PMID- 27456977 TI - Arthritis and associated limitations in community-dwelling Canadians living with stroke. AB - BACKGROUND: Residual impairments and gait deviations post-stroke may lead to secondary musculoskeletal complications such as arthritis. This study explored the prevalence of arthritis and associated functional limitations in community dwelling Canadians with and without stroke. METHODS: Secondary analysis of the Canadian Community Health Survey; a population-based, cross-sectional survey conducted by Statistics Canada in 2011 and 2012. Respondents >50 years old who reported a stroke diagnosis (n = 1892) were age- and gender-matched with controls randomly selected from survey respondents who did not report a stroke (n = 1892). Stroke and control groups were compared on presence of arthritis (yes/no) and secondary variables including pain, perceived health and assistance required (5 point scales) using the Rao-Scott X(2) test. Within the stroke group, logistic regression was used to investigate the effect of arthritis on life satisfaction, pain limiting activities and perceived health with age, gender, BMI, comorbidities and socioeconomic status used as covariates in the model. RESULTS: A greater proportion of the stroke group (53%) reported arthritis compared to controls (43%). These groups also differed in reports of perceived health and pain. Within the stroke group, those with arthritis were significantly more likely to report pain limiting activities (OR 3.89) and less likely to report satisfaction with life (OR 0.59). CONCLUSIONS: This preliminary work suggests that arthritis is more prevalent in individuals with stroke compared to individuals without stroke and that this co-morbidity is associated with worse reports of pain and perceived health. A limitation is that it is not possible to determine if the arthritis pre-dated or followed the stroke. This work provides support for a longitudinal investigation of the development of secondary musculoskeletal issues post-stroke. PMID- 27456976 TI - Guided self-help cognitive behavioral intervention for VoicEs (GiVE): study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Cognitive behavior therapy for psychosis (CBTp) is an effective intervention for people who hear distressing voices (auditory hallucinations). However, there continues to be a problem of poor access to CBTp. Constraints on health care funding require this problem to be addressed without a substantial increase in funding. One solution is to develop guided self-help forms of CBTp to improve access, and a symptom-specific focus on, for example, distressing voices (auditory verbal hallucinations) has the potential to enhance effectiveness. We term this cognitive behavior therapy for distressing voices (CBTv). METHODS/DESIGN: This trial is an external pilot randomized controlled trial comparing the effects of 12-week guided self-help CBTv (with eight therapist support sessions) with a wait list control condition. Informed consent will be obtained from each participant. Half of the 30 participants will be randomized to receive guided self-help CBTv immediately; the remaining half will receive the intervention after a 12-week delay. All participants will continue with their usual treatment throughout the study. Outcomes will be assessed using questionnaires completed at baseline and 12 weeks postrandomization. Interviews will be offered to all those who receive therapy immediately to explore their experiences with the intervention. DISCUSSION: The outcomes of this trial, both quantitative and qualitative, will inform the design of a definitive randomized controlled trial of guided self-help CBTv. If this intervention is effective, it could help to increase access to CBT for those who hear distressing voices. TRIAL REGISTRATION: ISRCTN registration number ISRCTN77762753 . Registered on 23 July 2015. PMID- 27456978 TI - Gold(I)-Catalyzed Domino Cyclizations of Diynes for the Synthesis of Functionalized Cyclohexenone Derivatives. Total Synthesis of (-)-Gabosine H and ( )-6-epi-Gabosine H. AB - 1,6-Diynes with a t-butylcarbonate group in the propargylic position undergo gold(I)-catalyzed domino-cyclization which affords alpha-hydroxycyclohexenones. The described sequence can be applied on functionalized, highly oxygenated substrates, as examplified in the synthesis of (-)-gabosine H and its epimer. PMID- 27456979 TI - A paper/polymer hybrid microfluidic microplate for rapid quantitative detection of multiple disease biomarkers. AB - Enzyme linked immunosorbent assay (ELISA) is one of the most widely used laboratory disease diagnosis methods. However, performing ELISA in low-resource settings is limited by long incubation time, large volumes of precious reagents, and well-equipped laboratories. Herein, we developed a simple, miniaturized paper/PMMA (poly(methyl methacrylate)) hybrid microfluidic microplate for low cost, high throughput, and point-of-care (POC) infectious disease diagnosis. The novel use of porous paper in flow-through microwells facilitates rapid antibody/antigen immobilization and efficient washing, avoiding complicated surface modifications. The top reagent delivery channels can simply transfer reagents to multiple microwells thus avoiding repeated manual pipetting and costly robots. Results of colorimetric ELISA can be observed within an hour by the naked eye. Quantitative analysis was achieved by calculating the brightness of images scanned by an office scanner. Immunoglobulin G (IgG) and Hepatitis B surface Antigen (HBsAg) were quantitatively analyzed with good reliability in human serum samples. Without using any specialized equipment, the limits of detection of 1.6 ng/mL for IgG and 1.3 ng/mL for HBsAg were achieved, which were comparable to commercial ELISA kits using specialized equipment. We envisage that this simple POC hybrid microplate can have broad applications in various bioassays, especially in resource-limited settings. PMID- 27456980 TI - Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1. AB - We previously demonstrated that ABCD4 does not localize to peroxisomes but rather, the endoplasmic reticulum (ER), because it lacks the NH2-terminal hydrophilic region required for peroxisomal targeting. It was recently reported that mutations in ABCD4 result in a failure to release vitamin B12 from lysosomes. A similar phenotype is caused by mutations in LMBRD1, which encodes the lysosomal membrane protein LMBD1. These findings suggested to us that ABCD4 translocated from the ER to lysosomes in association with LMBD1. In this report, it is demonstrated that ABCD4 interacts with LMBD1 and then localizes to lysosomes, and this translocation depends on the lysosomal targeting ability of LMBD1. Furthermore, endogenous ABCD4 was localized to both lysosomes and the ER, and its lysosomal localization was disturbed by knockout of LMBRD1. To the best of our knowledge, this is the first report demonstrating that the subcellular localization of the ABC transporter is determined by its association with an adaptor protein. PMID- 27456981 TI - Dinutuximab: A Novel Immunotherapy in the Treatment of Pediatric Patients With High-Risk Neuroblastoma [Formula: see text]. AB - Therapy combining dinutuximab with granulocyte macrophage colony stimulating factor, interleukin 2, and isotretinoin has significant side effects; however, these complications are generally predictable and can be managed proactively. PMID- 27456982 TI - HPV16 detection by qPCR method in relation to quantity and quality of DNA extracted from archival formalin fixed and paraffin embedded head and neck cancer tissues by three commercially available kits. AB - The aim of the present study was to compare HPV16 detection by quantitative polymerase chain reaction (qPCR) in relation to the quantity and quality of DNA isolated from 21 formalin fixed and paraffin embedded (FFPE) head and neck cancer tissues by three commercially available kits: EX-WAXTM DNA Extraction Kit (M) (Merck Millipore, Darmstadt, Germany), QIAamp((r)) DNA FFPE Tissue (Q) (Qiagen, Hilden, Germany) and ReliaPrepTM FFPE gDNA Miniprep System (P) (Promega, Madison, USA). Quantity of extracted DNA was assessed spectrophometrically and fluorometrically. Its quality was analyzed using A260/280 and A260/230 ratios and the beta-actin fragment amplifiability in qPCR. HPV16 presence was detected by qPCR, using specific primers and TaqMan probe. HPV infection was found in 8 DNA samples extracted with M kit (38.1%) and in 7 (33.3%) isolated with Q and P kits. Three samples from M and Q kits were characterized by HPV16 positivity and lack of beta-actin amplifiability. They had significantly lower A260/280 ratio (M: 1.6+/-0.0, p=0.044 and Q: 1.7+/-0.0, p=0.016) compared to samples with both fragments amplification (M: 1.7+/-0.0 and Q: 1.9+/-0.0). Therefore, for HPV detection by qPCR in FFPE tissues we recommend ReliaPrepTM FFPE gDNA Miniprep System. PMID- 27456983 TI - Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy. AB - OBJECTIVE: The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial found that protease inhibitor monotherapy as a simplification strategy is well tolerated in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load. We sought to identify factors associated with the risk of viral load rebound in this trial. METHODS: PIVOT was a randomized controlled trial in HIV-positive adults with suppressed viral load for at least 24 weeks on combination therapy comparing a strategy of physician selected ritonavir-boosted protease inhibitor monotherapy versus ongoing triple therapy. In participants receiving monotherapy, we analysed time to confirmed viral load rebound and its predictors using flexible parametric survival models. RESULTS: Of 290 participants initiating protease inhibitor monotherapy (80% darunavir, 14% lopinavir, and 6% other), 93 developed viral load rebound on monotherapy. The risk of viral load rebound peaked at 9 months after starting monotherapy and then declined to approximately 5 per 100 person-years from 18 months onwards. Independent predictors of viral load rebound were duration of viral load suppression before starting monotherapy (hazard ratio 0.81 per additional year <50 copies/ml; P < 0.001), CD4 cell count (hazard ratio 0.73 per additional 100 cells/MUl for CD4 nadir; P = 0.008); ethnicity (hazard ratio 1.87 for nonwhite versus white, P = 0.025) but not the protease inhibitor agent used (P = 0.27). Patients whose viral load was analysed with the Roche TaqMan-2 assay had a 1.87-fold risk for viral load rebound compared with Abbott RealTime assay (P = 0.012). CONCLUSION: A number of factors can identify patients at low risk of rebound with protease inhibitor monotherapy, and this may help to better target those who may benefit from this management strategy. PMID- 27456984 TI - The cardiovascular risk management for people living with HIV in Europe: how well are we doing? AB - OBJECTIVES: HIV has become a chronic condition associated with comorbidities. We investigated cardiovascular risk and risk modification in a European HIV cohort. METHODS: EuroSIDA patients (from 1 January 2000) for whom cardiovascular risk could be calculated (DAD risk equation) were included in the analysis. Moderate to-high risk was defined as 5-year cardiovascular risk more than 5% and risk modification as two measurements meeting the European AIDS Clinical Society guidelines. Factors associated with risk development and modifications were investigated using Poisson regression. RESULTS: Of 8762 individuals, 32.1% were hypertensive, 45.0% had high cholesterol, 47.4% were current smokers, and 27.1% were overweight. A total of 1504 (17.2%) had a 5-year cardiovascular risk of more than 5%. Of 7258 individuals with a 5-year risk less than 5%, 1905 (26.2%) developed cardiovascular risk more than 5% (6.53/100 person-years). These patients were more likely to be older, men, living in East Europe, with traditional cardiovascular risk factors. MSM with longer exposure to antiretroviral therapy, low CD4 nadir, higher current CD4 and prior AIDs events were more likely to develop cardiovascular risk. Those on antihypertensive treatment and living in central Europe were less likely to develop cardiovascular risk. Of those clinically indicated for risk modification, 1205 of 2077 (58.0%) successfully modified BP; 1283 of 3919 (32.8%) stopped smoking; 277 of 1394 (19.9%) modified cholesterol and 543 of 2163 (25.1%) reduced their BMI. There was variation in modification of individual risk factors, by sex, age, HIV-related factors and region of follow-up. Risk modification for BP and smoking improved over time (P < 0.001). CONCLUSION: Cardiovascular risk was common. More than half modified their cardiovascular risk, and this improved over time. PMID- 27456985 TI - A meta-analysis assessing all-cause mortality in HIV-exposed uninfected compared with HIV-unexposed uninfected infants and children. AB - OBJECTIVE: Conduct a meta-analysis examining differential all-cause mortality rates between HIV-exposed uninfected (HEU) infants and children as compared with their HIV-unexposed uninfected (HUU) counterparts. DESIGN: Meta-analysis summarizing the difference in mortality between HEU and HUU infants and children. Reviewed studies comparing children in the two groups for all-cause mortality, in any setting, from 1994 to 2016 from six databases. METHODS: Meta-analyses were done estimating overall mortality comparing the two groups, stratified by duration of follow-up time from birth (0-12, 12-24 and >24 months) and by year enrollment ended in each study: less than 2002 compared with at least 2002, when single-dose nevirapine for prevention of mother-to-child transmission (PMTCT) commenced in low-income and middle-income countries. RESULTS: Included 22 studies, for a total of 29 212 study participants [n = 8840 (30.3%) HEU; n = 20 372 (37.7%) HUU]. Random effects models showed HEU had a more than 70% increased risk of mortality vs. HUU. Stratifying by age showed that HEU vs. HUU had a significant 60-70% increased risk of death at every age strata. There was a significant 70% increase in the risk of mortality between groups before the implementation of PMTCT, which remained after 2002 [risk ratio: 1.46; 95% confidence interval (CI): 1.14-1.87], when the availability of PMTCT services was widespread, suggesting that prenatal antiretroviral therapy, and healthier mothers, does not fully eliminate this increased risk in mortality. CONCLUSION: We show a consistent increase risk of mortality for HEU vs. HUU infants and children. Longitudinal research is needed to elucidate underlying mechanisms, such as maternal and infant health status and breast feeding practices, which may help explain these differences in mortality. PMID- 27456987 TI - A novel MIP mutation in familial congenital nuclear cataracts. AB - We screened 60 known genes which are involved in inherited cataract in a pregnant woman with a four-generation family history of autosomal dominant congenital nuclear cataract through next-generation sequencing (NGS) and identified a heterozygous mutation, c.508dupC (p.L170fs), in the major intrinsic protein (MIP) gene. This mutation results in a frame-shift in MIP and has not been previously reported. The correlation of the mutation with disease was validated by Sanger sequencing of DNA from the other affected or unaffected members of the family. Therefore, our data expand the mutation spectrum of MIP mutation, and suggest that NGS is an accurate, rapid, and cost-effective method in the genetic diagnosis of congenital nuclear cataract. PMID- 27456988 TI - Interstitial granulomatous dermatitis occurring in a patient with SAPHO syndrome one month after starting leflunomide, and subsequently disappearing with ustekinumab. PMID- 27456989 TI - Usefulness of transanal tube placement for prevention of anastomotic leakage following laparoscopic low anterior resection. AB - INTRODUCTION: Anastomotic leakage (AL) is a major complication of laparoscopic low anterior resection (LLAR) for rectal cancer. Although several recent reports have suggested that transanal tube placement can prevent AL, this practice is still controversial. Additionally, the mechanism by which a transanal tube prevents AL is unknown. The aim of this study was to evaluate the efficacy of transanal tube placement for prevention of AL following LLAR. METHODS: This was a retrospective study that included 69 patients who underwent LLAR between February 2012 and January 2016. After an anastomosis using a double stapling technique, a transanal tube was placed in 28 patients. A diverting stoma was created in 26 patients. Univariate and multivariate analyses of clinicopathological characteristics were performed. RESULTS: The overall incidence of AL was 15.9% (11/69). Univariate analysis showed that transanal tube placement (P = 0.022) and early postoperative diarrhea (P < 0.001) were associated with AL. The duration of the postoperative hospital stay for patients with transanal tube placement (13.1 +/- 4.1 days) was significantly shorter than for patients without a transanal tube (22.7 +/- 12.3 days; P < 0.001). However, transanal tube placement did not reduce postoperative diarrhea. Creation of a diverting stoma did not affect the incidence of AL. Multivariate analysis revealed that the absence of a transanal tube (odds ratio = 33.5, P = 0.018) and the occurrence of postoperative diarrhea (odds ratio = 86.3, P = 0.001) were independent risk factors for AL. CONCLUSION: Transanal tube placement prevents AL after LLAR. Furthermore, this protective effect may be due to a reduction in the unfavorable incidence of early postoperative diarrhea. PMID- 27456990 TI - Serum Alanine Aminotransferase and Hepatitis B DNA Flares in Pregnant and Postpartum Women with Chronic Hepatitis B. AB - OBJECTIVES: Alterations in the immune system during pregnancy have been associated with reactivation of hepatitis B virus (HBV) in chronic hepatitis B (CHB) women. However, the effects of pregnancy on CHB remain not well understood. The goal of this study was to examine flares in HBV DNA and serum alanine aminotransferase (ALT) during pregnancy and postpartum in CHB women untreated prior to pregnancy. METHODS: This was a multicenter retrospective study of 113 pregnancies in 101 CHB women who presented during pregnancy at two community gastroenterology clinics and two tertiary medical centers in the United States during 1997-2015. Outcomes analyzed included onset, severity, and resolution of flares in HBV and ALT that occurred prior to starting antiviral therapy, if antiviral therapy was subsequently initiated. Women who initiated antiviral therapy during pregnancy were not included in the analysis of postpartum flares. RESULTS: HBV DNA flares were observed in 9% (8/90) of women during pregnancy and 4% (2/48) of women during postpartum. Flares in ALT (99-2522 U/l) were observed in 6% (7/112) of women during pregnancy and 10% (5/51) of women within the first 3 months of delivery. Age, HBeAg positivity, baseline HBV DNA, baseline ALT, gravida, and parity were not found to be significant predictors of flare. CONCLUSIONS: Flares in HBV DNA and ALT can occur during late pregnancy and early postpartum in CHB women, and can be severe. Women with CHB should therefore be closely monitored during pregnancy and early postpartum. PMID- 27456992 TI - Coming in sportsmedicine. PMID- 27456994 TI - Full-Time Sports Medicine. PMID- 27456995 TI - Scanning sports. PMID- 27456991 TI - Genetic associations of the thyroid stimulating hormone receptor gene with Graves diseases and Graves ophthalmopathy: A meta-analysis. AB - Graves' disease (GD) is a common thyroid disease, and Graves ophthalmopathy(GO) is the most common extra-thyroidal manifestation of GD. Genetic associations of the thyroid stimulating hormone receptor (TSHR) gene with GD and GO have been studied in different population groups for a long time. We aimed to obtain a more precise estimation of the effects of TSHR single nucleotide polymorphisms (SNPs) on GD/GO using a meta-analysis. Publications were searched on Pub Med and EMBASE up to December 30, 2015. Eight studies involving three SNPs (rs179247, rs12101255, and rs2268458), which included 4790 cases and 5350 controls, met the selection criteria. The pooled odds ratios (OR) and the 95% confidence intervals (CI) were estimated. SNPs rs179247 (dominant model [GG + GA vs. AA]: OR = 0.66, 95%CI: 0.61-0.73, P = 0.000, I(2) = 0%) and rs12101255 (dominant model [TT + TC vs. CC]: OR = 1.67, 95%CI: 1.53-1.83, P = 0.000, I(2) = 0%) were significantly associated with GD in all of the genetic models. TSHR rs12101255 and rs2268458 polymorphisms had no association between GO and GD (GD without GO). The results indicate that rs179247 and rs12101255 are likely to be genetic biomarkers for GD. Further studies with different population groups and larger sample sizes are needed to confirm the genetic associations of the TSHR gene with GD/GO. PMID- 27456997 TI - What Is Sports Medicine? PMID- 27456998 TI - Abstracts at a glance. PMID- 27457000 TI - True Believers: Tourists and Racers. PMID- 27457001 TI - Noteworthy. PMID- 27457002 TI - Sportsmedicine forum. AB - A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Sportsmedicine Forum, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis 55435. PMID- 27457003 TI - Nutrition Education, Body Composition, and Dietary Intake of Female College Athletes. AB - In brief: This study examined the effects of nutrition education (through individual counseling) on the body composition and diet patterns of 39 female college athletes. Anthropometric and diet data were collected before and after the playing season. Ten of the athletes received individual nutrition counseling during the season and comprised group 1; the other 29 made up group 2. Neither group met the recommended dietary allowance for energy before or after the season, but group 1 significantly lowered fat and cholesterol levels and increased carbohydrate and fiber intakes. The findings suggest that individual counseling is effective in improving the diet quality of female athletes. PMID- 27457004 TI - Recent Developments in Cardiac Pacemakers: Rate-Responsive Pacing. AB - In brief: Over the last 30 years cardiac pacemakers have evolved from simple devices only capable of fixed-rate stimulation of a single chamber of the heart to more sophisticated units able to sense and stimulate electrical activity in both the atrium and the ventricle. These refinements have allowed for more physiologic pacing with maintenance of atrioventricular synchrony and cardiac output. Most recently, new technology has led to development of a single-chamber pacemaker that senses skeletal muscle activity and increases the heart rate in response to exercise. By increasing cardiac output with activity, this rate responsive pacemaker allows greater exercise tolerance. PMID- 27457005 TI - Exercise-Induced Skeletal Muscle Damage. AB - In brief: Delayed-onset muscle soreness is most likely caused by structural damage in skeletal muscle after eccentric exercise, in which muscles produce force while lengthening, as in running downhill. This damage may take as long as 12 weeks to repair. Therefore, athletes should allow plenty of time for recovery after events that cause extreme muscle soreness. Because prostaglandin E2 may be important in muscle repair, prostaglandin blockers, such as aspirin, may be useless or even detrimental in the treatment of delayed-onset muscle soreness. Eccentric exercise training may help prevent soreness. PMID- 27457006 TI - Low Back Pain in Athletes. AB - In brief: Low back pain in seasoned athletes is not common, but when present it can limit participation. While direct blows or hyperlor-dotic positions can cause low back pain in certain sports, the most common cause is overuse and resultant strains or sprains of the paravertebral muscles and ligaments. Such injuries cause acute pain and spasm, which sometimes do not appear for 24 hours or longer. Diagnosis is based on history, ruling out of systemic maladies, physical examination, and, if necessary, supplemental tests such as x-rays, myelograms, and bone scans. Treatment of low back pain due to overuse is, sequentially, bed rest and ice for 24 to 36 hours, heat and massage, analgesics as needed, and a lumbosacral support until flexion and strengthening exercises have returned the damaged part to normal. PMID- 27457007 TI - Blood Doping: Results and Consequences From the Laboratory and the Field. AB - In brief: Just as Roman gladiators drank the blood of foes to gain strength, modern Olympians have infused the blood of friends as well as their own to gain endurance. Blood doping, which tainted the triumphs of the 1984 US Olympic cyclists, has at last been banned. This literature review defines blood doping, discusses its use and rationale, and presents some of the research findings. The conclusion is that blood doping, properly performed, works in the laboratory, but there is insufficient evidence to show conclusively that it works in the field. PMID- 27457008 TI - Medical Aspects of Wrestling. PMID- 27457009 TI - Medical Problems of Wrestlers. AB - In brief: Wrestlers face a significant risk of injury and of contracting skin infections and respiratory and systemic illnesses. Because annual injury rates as high as 75% have been reported in wrestling, medical personnel should be present at all competitions. The article briefly describes mechanisms of injury and provides treatment guidelines for lacerations, cauliflower ear, and injuries to the spine, extremities, and ribs. Also provided is advice for the treatment and prevention of skin problems, including herpes gladiatorum, folliculitis, impetigo, fungal infections, and others. PMID- 27457010 TI - Basic Conditioning Principles for High School Wrestlers. AB - In brief: Tired wrestlers bore the crowd and disappoint themselves and their coaches. By contrast, skilled, aggressive wrestlers who are conditioned to attack and defend throughout a six-minute match can generate excitement equal to that of any athletic contest. To maintain the appropriate fitness required to perform at this level, a specific conditioning program is needed. This article describes a conditioning program based on a year-round schedule that helps wrestlers achieve and maintain their highest possible level of performance. PMID- 27457011 TI - Physicians Should Advise Wrestlers About Weight Loss. AB - Dehydration is one weight-loss method wrestlers use to 'make weight,' although the practice has potential hazards. The author discusses the role of the physician in advising school wrestlers about healthy nutrition habits. PMID- 27457012 TI - How Physicians Can Help High School Wrestlers Control Weight. AB - Four experts on high school wrestling offer advice for the team physician who must recommend safe weight-loss practices. PMID- 27457014 TI - Can Exercise Suppress Reproductive Hormones in Men? AB - Researchers examining the effects of exercise on hormones in men say that extremely strenuous activity over a long period of time, combined with anorectic behavior and a high-stress lifestyle, could lower testosterone levels. PMID- 27457013 TI - Treating the America's Cup Sailors. AB - Some physicians are taking part in efforts to win the America's Cup races, now taking place off the west coast of Australia, near Fremantle. But although 12 Meter yacht racing can be intense, sailors most often need treatment for minor injuries. PMID- 27457015 TI - The Federal Government: Keeping Tabs on the Nation's Fitness. AB - The federal government is increasingly looking to disease prevention as one way of reducing health care costs. If s no surprise that exercise and physical fitness are among the measures being promoted. PMID- 27457016 TI - FIMS: Providing International Leadership in Sports Medicine. AB - Many physicians and scientists think of sports medicine as a new field, but it has attracted worldwide interest since 1928, when FIMS, an international sports medicine federation, was organized. The author, the newly elected cochairman of the FIMS Scientific Commission, describes the organization. PMID- 27457017 TI - FIMS Meeting Offers World Forum for Sports Medicine Research. PMID- 27457018 TI - Breakfast of Champions. PMID- 27457019 TI - What Is Target Heart Rate? PMID- 27457021 TI - Post-Mortem Corneal Thickness Measurements with a Portable Optical Coherence Tomography System: a Reliability Study. AB - The purpose of this study was to determine the repeatability and reproducibility of post-mortem central corneal thickness (CCT) measurements by using a real-time, portable optical coherence tomography (OCT) system on an animal model, and to prospectively evaluate the time-course of post-mortem changes in CCT. Forty-six ocular globes of sheep (Ovis aries) were analyzed with a portable spectral-domain OCT device by two operators at different postmortem intervals (PMIs) as follows: immediately (i.e. within 10 minutes), at the 30(th) minute, at the 1(st), 6(th), 12(th), 24(th) and 48(th) hour, and later (up to the 96(th) hour). The coefficient of repeatability ranged from 0.3% to 3.5%, and coefficients of reproducibility ranged from 0.2% to 3.7% in the central region of the cornea. The intraclass correlation coefficients were particularly high at different PMIs, thus confirming good measurement reliability with the portable OCT. The average CCT decreased immediately and then increased thereafter, with two peaks at 6 and 24 hours after death. Our results suggest that portable OCT is a reliable tool for monitoring CCT variations after death and may be useful in characterizing corneas before explantation, detecting quantitative variations during post-mortem corneal degeneration or assessing changes in CCT for forensic implications. PMID- 27457022 TI - Treatment of acute bleeding in acquired haemophilia A with recombinant activated factor VII: analysis of 10-year Japanese postmarketing surveillance data. AB - INTRODUCTION: Patients with acquired haemophilia A (AHA) have autoantibodies against factor VIII (FVIII), and may develop spontaneous bleeding that requires treatment with FVIII inhibitor bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven(r) ). However, data regarding the use of rFVIIa are limited. AIM: To investigate the use, efficacy and safety of rFVIIa for the treatment of AHA by analysis of 10-year multicentre Japanese postmarketing surveillance data. METHODS: Treatment regimens, haemostatic efficacy and adverse events were recorded for rFVIIa therapy of AHA patients with bleeding episodes. Treatment was evaluated as markedly effective, effective, moderate or ineffective. RESULTS: Data were collected for 371 bleeding episodes in 132 patients. Bleeding improved after rFVIIa therapy in 92% of episodes (markedly effective in 41%, effective in 10%, moderate in 41%). The response rate was significantly better in patients who received an initial dose of >=90 MUg kg-1 than in those who received an initial dose of <90 MUg kg-1 . The response rate was also significantly better when rFVIIa was administered earlier after the onset of bleeding. Twelve serious adverse events were recorded in six patients, including five serious thromboembolic events in three patients who were all elderly with significant comorbidities. CONCLUSION: This is the largest, single country study of rFVIIa therapy in AHA patients reported to date. The Japanese surveillance data show comparable efficacy and safety to prior multinational studies. Doses of 90-120 MUg kg-1 and prompt initiation of treatment may be important to achieve good bleeding control. PMID- 27457026 TI - Imaging Art and Facts. PMID- 27457025 TI - Behaviour Problems in Children with Intellectual Disabilities in a Resource-Poor Setting in India - Part 1: Association with Age, Sex, Severity of Intellectual Disabilities and IQ. AB - BACKGROUND: Behaviour problems are most common in people with intellectual disabilities. Nature of behaviour problems can vary depending upon the age, sex and intellectual level (IQ). OBJECTIVES: This study examined the distribution of behaviour problems across intellectual disability categories and their association with IQ age and sex in children with intellectual disabilities. METHODS: This is a cross-sectional study design. A total of 104 participants (57 males and 47 females), aged 3-18 years, with intellectual disabilities were administered The Behavioural Assessment Scale for Indian Children with Mental Retardation (BASIC-MR). RESULTS: It was found that violent and destructive, temper tantrum and self-injurious behaviours were differently distributed with reference to intellectual disability levels (P > 0.05) but cumulative scores per se problem behaviours did not vary with the level of intellectual disabilities. IQ showed a significant positive correlation with destructive and violent and misbehaves with other; and a significant negative correlation with temper tantrums and self-injurious behaviours. Age was significantly, positively associated with violent and destructive, odd, and hyperactive behaviours and inversely with self-injurious problem behaviours. There was no significant relationship between the sex of the child and problem behaviours. There was no significant interactive effect of sex and level of intellectual disabilities of the child on problem behaviours. CONCLUSION: Behaviour problems, in general, are not equally distributed in all categories of intellectual disabilities. Relationship between behaviour problems and age, sex and IQ may not be uniform. But specific behaviours are more associated with specific age group and intellectual disability levels. PMID- 27457023 TI - Two functionally distinct kinetochore pools of BubR1 ensure accurate chromosome segregation. AB - The BubR1/Bub3 complex is an important regulator of chromosome segregation as it facilitates proper kinetochore-microtubule interactions and is also an essential component of the spindle assembly checkpoint (SAC). Whether BubR1/Bub3 localization to kinetochores in human cells stimulates SAC signalling or only contributes to kinetochore-microtubule interactions is debated. Here we show that two distinct pools of BubR1/Bub3 exist at kinetochores and we uncouple these with defined BubR1/Bub3 mutants to address their function. The major kinetochore pool of BubR1/Bub3 is dependent on direct Bub1/Bub3 binding and is required for chromosome alignment but not for the SAC. A distinct pool of BubR1/Bub3 localizes by directly binding to phosphorylated MELT repeats on the outer kinetochore protein KNL1. When we prevent the direct binding of BubR1/Bub3 to KNL1 the checkpoint is weakened because BubR1/Bub3 is not incorporated into checkpoint complexes efficiently. In conclusion, kinetochore localization supports both known functions of BubR1/Bub3. PMID- 27457024 TI - Subwavelength grating enabled on-chip ultra-compact optical true time delay line. AB - An optical true time delay line (OTTDL) is a basic photonic building block that enables many microwave photonic and optical processing operations. The conventional design for an integrated OTTDL that is based on spatial diversity uses a length-variable waveguide array to create the optical time delays, which can introduce complexities in the integrated circuit design. Here we report the first ever demonstration of an integrated index-variable OTTDL that exploits spatial diversity in an equal length waveguide array. The approach uses subwavelength grating waveguides in silicon-on-insulator (SOI), which enables the realization of OTTDLs having a simple geometry and that occupy a compact chip area. Moreover, compared to conventional wavelength-variable delay lines with a few THz operation bandwidth, our index-variable OTTDL has an extremely broad operation bandwidth practically exceeding several tens of THz, which supports operation for various input optical signals with broad ranges of central wavelength and bandwidth. PMID- 27457028 TI - Pulmonary thromboembolism in patient with coexistence of Behcet's disease and antiphospholipid syndrome. AB - Pulmonary thromboembolism (PTE) is rarely reported in Behcet's disease (BD) due to its distinctive thrombus-forming mechanism. In BD, the inflammation on vessel walls causes venous thrombosis. The thrombi are considered to be tethered to the inflamed walls making embolization less frequent. Thus, immunosuppressive agents are the mainstay of treatment. However, the necessity of anticoagulation therapy is controversial because of its uncertain efficacy of resolving thrombi and the possibility of fatal side effects of hemorrhage. A 25-year-old man with recurrent oral aphthae visited with abrupt onset of dyspnea and chest pain. Based on history, imaging studies and laboratory results, he was diagnosed with BD with vascular involvement and antiphospholipid syndrome (APS), causing PTE from deep vein thrombosis. The co-existing APS may have further promoted the thrombosis, shifting his blood profile toward the hypercoagulable state. Immunosuppressive therapy with glucocorticoid and azathioprine, and concomitant anticoagulation with warfarin were achieved successfully without any fatal complications. When atypical features of vascular involvement in BD develop, other coexisting diseases should be considered to design an optimal therapeutic plan. PMID- 27457030 TI - Abstract submission. PMID- 27457029 TI - Strange and scary memories of the intensive care unit: a qualitative, longitudinal study inspired by Ricoeur's interpretation theory. AB - AIMS AND OBJECTIVES: To describe the content of former intensive care unit patients' memories of delusions. BACKGROUND: Intensive care unit patients often have strange and frightening experiences during the critical stage of illness. Earlier studies have provided small-sample in-depth descriptions of patient experiences in intensive care unit, but large-scale studies are also needed to inform intensive care unit follow-up. METHODS: The study had a qualitative design using phenomenological hermeneutic analysis inspired by Ricoeur's interpretive theory. Patients were assessed with Confusion Assessment Method of the Intensive Care Unit for delirium in intensive care unit, and after discharge, memories of delusions were described by 114 of 325 patients in face-to-face (after two weeks) and telephone interviews (after two and six months) using the Intensive Care Unit Memory Tool. RESULTS: Four themes emerged: the ever-present family, dynamic spaces, surviving challenges and constant motion. Memories of delusions were a vivid mix of fact and fiction, demonstrating dynamic shifts in time, place and motion, but not dependent on the presence of delirium assessed by Confusion Assessment Method of the Intensive Care Unit. CONCLUSIONS: Analysis based on Ricoeurian phenomenological hermeneutics provided insights into themes in intensive care unit patients' memories of delusions. More studies are needed to understand the meaning of memories of delusions, the commonality of themes and the association between delusions and delirium after an intensive care unit stay. RELEVANCE TO CLINICAL PRACTICE: Understanding patients' memories of delusions is beneficial to nurses caring for patients that are anxious, upset or agitated. It opens a window to the world of the patient who is unable to communicate due to intubation and general weakness. We recommend the provision of nurse-led intensive care unit follow-up enabling patients to describe and discuss their intensive care unit experiences. PMID- 27457031 TI - Abstract Submission. PMID- 27457033 TI - Structural identification of triacylglycerol isomers using electron impact excitation of ions from organics (EIEIO). AB - Electron-induced dissociation or electron impact excitation of ions from organics (EIEIO) was applied to triacylglycerols (TAGs) for in-depth molecular structure analysis using MS. In EIEIO, energetic electrons (~10 eV) fragmented TAG ions to allow for regioisomeric assignment of identified acyl groups at the sn-2 or sn 1/3 positions of the glycerol backbone. In addition, carbon-carbon double bond locations within the acyl chains could also be assigned by EIEIO. Beyond the analysis of lipid standards, this technique was applied to edible oils and natural lipid extracts to demonstrate the power of this method to provide in depth structural elucidation of TAG molecular species. PMID- 27457034 TI - Controlling the phase locking of stochastic magnetic bits for ultra-low power computation. AB - When fabricating magnetic memories, one of the main challenges is to maintain the bit stability while downscaling. Indeed, for magnetic volumes of a few thousand nm(3), the energy barrier between magnetic configurations becomes comparable to the thermal energy at room temperature. Then, switches of the magnetization spontaneously occur. These volatile, superparamagnetic nanomagnets are generally considered useless. But what if we could use them as low power computational building blocks? Remarkably, they can oscillate without the need of any external dc drive, and despite their stochastic nature, they can beat in unison with an external periodic signal. Here we show that the phase locking of superparamagnetic tunnel junctions can be induced and suppressed by electrical noise injection. We develop a comprehensive model giving the conditions for synchronization, and predict that it can be achieved with a total energy cost lower than 10(-13) J. Our results open the path to ultra-low power computation based on the controlled synchronization of oscillators. PMID- 27457035 TI - Involvement of inhibition of RhoA/Rho kinase signaling in simvastatin-induced amelioration of neuropathic pain. AB - Small molecular G-protein plays a key role in several diseases. This study was designed to reveal the role of RhoA signaling in the pathophysiology of neuropathic pain in mice. Partial sciatic nerve injury caused thermal hyperalgesia, mechanical allodynia, and increased plasma membrane translocation of RhoA in the lumber spinal cord. GFAP-immunoreactivity (ir), Iba-1-ir, and Rho kinase 2 (ROCK2-ir) was also increased in the ipsilateral spinal dorsal horn of nerve-ligated mice. Moreover, partial nerve ligation increased the expression of phosphorylated myristoylated alanine-rich protein kinase C substrate (MARCKS)-ir in the ipsilateral spinal dorsal horn. Daily intrathecal administration of simvastatin, beginning 3days before nerve injury, completely blocked all these changes in nerve-ligated mice. Pharmacological inhibition of ROCK also attenuated the increased expression of GFAP-ir and phosphorylated MARCKS-ir. Together, it is suggested that astrogliosis initiated by the activation of RhoA/ROCK signaling results in MARCKS phosphorylation in nerve terminals, which leads to hyperalgesia in neuropathic pain. Furthermore, simvastatin exerts antihyperalgesic and antiallodynic effects through the inhibition of spinal RhoA activation. PMID- 27457036 TI - Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3 gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome. AB - Cognitive disability is an unavoidable feature of Down syndrome (DS), a genetic disorder due to the triplication of human chromosome 21. DS is associated with alterations of neurogenesis, neuron maturation and connectivity that are already present at prenatal life stages. Recent evidence shows that pharmacotherapies can have a large impact on the trisomic brain provided that they are administered perinatally. Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, performs many actions in the brain, including inhibition of DYRK1A, a kinase that is over-expressed in the DS brain and contributes to the DS phenotype. Young adults with DS treated with EGCG exhibit some cognitive benefits, although these effects disappear with time. We deemed it extremely important, however, to establish whether treatment with EGCG at the initial stages of brain development leads to plastic changes that outlast treatment cessation. In the current study, we exploited the Ts65Dn mouse model of DS in order to establish whether pharmacotherapy with EGCG during peak of neurogenesis in the hippocampal dentate gyrus (DG) enduringly restores hippocampal development and memory performance. Euploid and Ts65Dn mice were treated with EGCG from postnatal day 3 (P3) to P15. The effects of treatment were examined at its cessation (at P15) or after one month (at P45). We found that at P15 treated trisomic pups exhibited restoration of neurogenesis, total hippocampal granule cell number and levels of pre- and postsynaptic proteins in the DG, hippocampus and neocortex. However, at P45 none of these effects were still present, nor did treated Ts65Dn mice exhibit any improvement in hippocampus-dependent tasks. These findings show that treatment with EGCG carried out in the neonatal period rescues numerous trisomy-linked brain alterations. However, even during this, the most critical time window for hippocampal development, EGCG does not elicit enduring effects on the hippocampal physiology. PMID- 27457037 TI - The development of the nociceptive brain. AB - This review addresses the fundamental question of how we first experience pain, at the beginning of our lives. The brain is activated by peripheral tissue damaging stimulation from birth, but unlike other sensory systems, the pain system in healthy individuals cannot rely upon prolonged activity-dependent shaping through repeated noxious stimulation. Considering the importance of pain, remarkably little is known about when and how nociceptive cortical network activity characteristic of the mature adult brain develops. We begin this review by considering the underlying framework of connections in the infant brain. Since this developing brain connectome is necessary, if not sufficient, for pain experience, we discuss the structural and functional development of cortical and subcortical networks that contribute to this network. We then review specific information on the development of nociceptive processing in the infant brain, considering evidence from neurophysiological and hemodynamic measures separately, as the two are not always consistent. Finally we highlight areas that require further research and discuss how information gained from laboratory animal models will greatly increase our understanding in this area. PMID- 27457038 TI - Representing the consequences of our actions trial by trial: Complex and flexible encoding of feedback valence and magnitude. AB - In the last decades it has been shown that two components of the event-related potentials (ERPs), the feedback-related negativity (FRN) and the P300, reflect the evaluation of the outcomes of a given course of action. Within the reinforcement learning theory, the prevailing interpretation of the relationship between FRN and P300 is the classical "independent coding model". This model proposes that the FRN is only sensitive to feedback valence whereas the P300 is only sensitive to feedback magnitude. However, these predictions have recently been challenged and the question remains unsolved. The goal of the present study is to shed light on the effects of outcome valence and magnitude on the FRN and the feedback-P300. The electroencephalographic (EEG) activity was recorded while participants performed a perceptual discrimination task with two levels of difficulty, in which they could receive large or small rewards and penalties. We used receiver operating characteristics (ROC) analyses, which allowed us to analyze the relationship between the outcomes and EEG on a trial-by-trial basis. The results reveal that both components, which are contingent on feedback presentation, are sensitive to outcome valence. Regarding magnitude, this only affects the feedback P300, and only in conjunction with difficulty. Finally, we found that task difficulty has the opposite effect on these components, both in their latencies and discriminability. Our results suggest that the FRN and the feedback-P300 in fact reflect different performance monitoring processes in a flexible way that depends on the behavioral context. PMID- 27457039 TI - Acute Leukemia with a Translocation T(4;11)(q21;q23): a Distinct Clinicopathological Entity: Report of a Case with Cytogenetic Clonal Evolution and Review of 146 Cases of the Literature. AB - We present a cytogenetic clonal evolution that correlates morphological and immunological shifts in a case of a patient with a t(4;11) (q21;q23) acute leukemia. We take this opportunity to review 146 cases reported so far, with special reference to morphology, immunophenotyping, cytogenetics, clinical characteristics and evolution. Particular features are underlined, and prognosis, leukemic stem cell origin, chromosomal breakpoints and genes involved are discussed. A relationship between this type of leukemia and exposure to carcinogens is suggested by a high rate of secondary leukemia in adults and a high frequency in newborns and infants. PMID- 27457040 TI - Castleman's Disease and Interleukin 6. AB - Castleman's disease is a rare condition characterized by benign hyperplastic lymph nodes. Based on the morphological features, it has been divided into hyaline-vascular, plasma cell and intermediate types. The latter two types are frequently associated with a wide variety of clinical pictures such as fever, anemia with hypotransferrinemia, hyperimmunoglobulinemia and an increase in the concentration of C-reactive protein (CRP). Although immunological disturbances have been suggested to play important roles in the pathophysiology of Castleman's disease, the precise mechanisms for the generation of its clinical pictures are still unsettled. In this respect, we have reported a pediatric case with spontaneous production of high levels of B cell differentiation factor (BCDF) activity by the hyperplastic lymph node, and we demonstrated here the strong expression of interleukin 6 (IL-6) gene in the lymph node cells. On the other hand, recent studies have revealed that IL-6 is a multifunctional cytokine; IL-6 not only induces the immunoglobulin production but also induces the acute phase reaction, and functions as an endogeneous pyrogen. In the acute phase reaction, IL-6 may induce an increase in CRP concentration and hypotransferrinemia. These studies indicate that the overproduction of IL-6 by the hyperplastic lymph node may be closely related to the pathophysiology of Castleman's disease. Therefore, it is considered that this disease is a "disorder of IL-6 production". PMID- 27457041 TI - Peripheral T Cell Lymphoma: an Overview. AB - Peripheral T cell lymphoma (PTCL) is a term that encompasses a wide range of histological subtypes of Non-Hodgkin's lymphoma which arise from mature or post thymic T lymphocytes. These tumours account for 10-20% of all cases of non Hodgkin's lymphoma in the Western World. With the exception of HTLV1 associated lymphoma, there is little evidence that the incidence of PTCL is increasing. However, the diagnosis of PTCL is being made with greater frequency due to both an increased awareness of the entity and the more widespread use of phenotypic and genotypic studies for characterising lymphoid populations. The clinical course of PTCL is variable and less well documented than that for B cell lymphomas. As with B cell lymphomas, stage of disease is a major determinant of prognosis although the importance of histological subtype is still uncertain. Aggressive combination chemotherapy may result in complete remission and perhaps long term survival, but further prospective studies are urgently needed. PMID- 27457042 TI - Is IgD Myeloma a Separate Clinical Entity? Report of Six Cases Investigated by Isoelectric Focusing. AB - Six IgD myeloma patients whose monoclonal components were identified by isoelectric focusing are presented. They represented 4% of all patients with myeloma seen at our institute between 1982 and 1986. The patients did not display many of the features described as typical for IgD myeloma: in particular younger age group, decreased survival and increased incidence of lymphadenopathy, hepatosplenomegaly, extraosseous disease, anemia, renal failure and hypercalcemia. However males predominated, the concentrations of circulating monoclonal IgD were low and concentrations of serum and urinary monoclonal free light chains were high, findings previously reported in IgD myeloma. The concentrations of circulating IgD were at the lower end of ranges reported previously. The hypothesis that our patients represent the malignant equivalent of the normal "low secretory phenotype", possibly associated with improved survival, is discussed. The belief that IgD myeloma is a separate clinical entity is questioned. The sensitive, high-resolution technique of isoelectric focusing is recommended as the investigation of choice for the detection of monoclonal gammopathies in body fluids. PMID- 27457043 TI - Long-Term Results of CAP Therapy in Chronic Lymphocytic Leukemia. AB - This study was designed to study the efficacy and toxicity of an adriamycin containing regimen (CAP: cyclophosphamide, adriamycin, and prednisone) in patients with previously untreated chronic lymphocytic leukemia (CLL). CAP was given to clinical complete remission followed by 18 months of cyclophosphamide prednisone (CP) maintenance. Forty-seven patients with previously untreated CLL were treated. These patients initially presented with advanced stage (Rai III or IV) or had less advanced stage (Rai 0-II) patients and demonstrated evidence of disease progression. Patients received 750 mg/m(2) of cyclophosphamide intravenously on day 1, 50 mg/m(2) of adriamycin intravenously on day 1 and 100 mg/day of prednisone on days 1-5. Courses were repeated at 3-week intervals until clinical CR, at which time maintenance with cyclophosphamide and prednisone (CP) was commenced. A maximum cumulative dose of 450 mg/m(2) of adriamycin (9 courses of CAP) was given. Twenty (43%) of 47 patients obtained a CR and 11 (23%) obtained a partial remission. Bone marrow biopsy criteria were used to define response in addition to clinical and peripheral blood responses. All patients have been followed for 10 years. The median survival was 259 weeks. No patient remains in remission. No impact of response on survival was found. Surprisingly, the response rate and survival were higher and longer for patients with more advanced stages and higher tumor burdens. The median survival times for patients with Rai stage IV and Binet stage C disease were 93 months and 81 months, respectively. Although the regimen was well tolerated, three patients, each with an antecedent cardiac risk factor, developed congestive heart failure. Adriamycin containing regimens can be safely given to elderly patients with CLL and show promise in the treatment of advanced stage disease. PMID- 27457044 TI - Acute Promyelocytic Leukemia in Children: a Report on Eleven Cases. AB - We report 11 children (aged less than 20 years) with acute promyelocytic leukemia (APL), who represented 14% of our total number of patients with APL. There were 8 girls and 3 boys and the median age was 13.5 (range 3-19). Extramedullary leukemia was present in only 1 patient and hyperleukocytosis in 3 patients. Cytologically, 9 patients had "classical" APL, and 2 had the microgranular variant APL. Translocation (15;17) was present in all 4 karyotyped patients. Disseminated intravascular coagulation was seen in 8 patients at diagnosis, and was triggered by chemotherapy in 2 other cases. Induction chemotherapy was daunorubicin (DNR) alone in 6 patients, DNR + Ara C in 4 and zorubicin + Ara C in the remaining case. All patients received heparin during induction. Seven patients (64%) achieved complete remission (CR), 2 had resistant leukemia and 2 died during induction. Among the complete remitters, one received no further therapy and relapsed after 4 months, and another died of an unrelated cause after 4 weeks, while still in CR. The 5 others all relapsed after 3 to 13 months. Median survival was 5.5 months. Disease free survival (DFS) was significantly shorter than in our adult APL patients treated with the same regimens. APL is a rare disease in children and our results suggest that it may be associated with short remissions, especially when compared with adult APL. This could justify therapeutic reinforcement in these cases, such as allogeneic bone marrow transplantation, whenever possible, after CR has been achieved. PMID- 27457045 TI - Colony Stimulating Activities of GM-CSF, G-CSF and IL-3 on Blast Progenitors from Acute Myeloblastic Leukemia. AB - The colony stimulating activities (CSAs) of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), recombinant granulocyte colony-stimulating factor (rG-CSF) and recombinant interleukin-3 (rIL-3) on blast cells from various types of acute myeloblastic leukemia (AML) patients were studied using an in vitro blast colony assay. The stimulatory magnitude of rGM-CSF was highest in type M4 blasts but almost non-existent in type M1 blasts. Some preferential stimulatory action of rG-CSF was observed in type M2, M4 blasts and in overt leukemia in patients with refractory anemia with excess of blasts. On the other hand, the stimulatory activity of rIL-3 did not differ much with the AML subtype. Exposure to rGM-CSF, rG-CSF or rIL-3 did not alter the cellular phenotype or morphology of the leukemic blasts or the self-renewal capacity of blast progenitors. Simultaneous addition of rGM-CSF, rG-CSF and rIL-3, in various combinations, produced variable results and a simple additive effect was seen in 40% of the cases studied and either a significantly larger or smaller value in the remaining cases. Recombinant GM-CSF, rG-CSF and rIL-3 when added together did not reconstitute CSA of phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). PMID- 27457046 TI - Apoptosis is a Common Histopathological Finding in Myelodysplasia: the Correlate of Ineffective Haematopoiesis. AB - Twenty-three bone marrow biopsies from patients with myelodysplastic syndromes (MDS) with typical histological features were studied, and evidence of apoptosis of erythroid and immature myeloid precursors was seen by light microscopy in each case. This was quantified and found to be significantly greater than that seen in ten normal bone marrow biopsies (p < 0.01). There was no difference in the degree of apoptosis seen in the various sub-groups of MDS proposed by the French American-British (FAB) co-operative group. These results show apoptosis of haemopoietic precursors to be a characteristic histological finding in MDS, representing intramedullary death of these cells, a factor that may play a role in the pathogenesis of the cytopenias seen in this condition. PMID- 27457047 TI - Cell Suspensions from Collagenase Digestion of Bone Marrow Trephine Biopsy Specimens-its Use in Lymphoma. AB - Collagenase digestion allows cells to be released into suspension from bone marrow tissue. Discrete abnormal populations of lymphoid cells can be identified by cell morphology and immunological phenotyping techniques. Viable cells are also available for chromosomal analysis. This technique makes cells available for analysis in cases of dry bone marrow taps and has a particular use in the investigation of bone marrow involvement by malignant lymphoma. PMID- 27457048 TI - Mechanism of Decrease in Transferrin Receptor Synthesis by Interferon-alpha Treated Human Lymphoblastoid Cells. AB - To clarify the mechanism of antiproliferative action of interferon-alpha (IFN alpha) in hematological malignancy, we examined the transferrin receptor system in the lymphoblastoid cell line, Daudi cells treated with IFN-alpha. When cells were cultured with 10(4)U/ml of IFN-alpha, the number of surface transferrin receptors was decreased to 60% of that seen in the control culture. This decrease was not neutralized by co-incubation with the iron chelator, desferrioxamine (10 200 MUM), suggesting that the change in the level of chelatable iron did not account for the decrease in transferrin receptor numbers. When determined by metabolic labeling using (35)S-methionine, IFN-alpha markedly decreased the rate of transferrin receptor biosynthesis. Uptake of iron and the cellular ferritin content also decreased by 50% when incubated with 10(4)U/ml of IFN-alpha. These data indicate that IFN-alpha inhibits transferrin receptor biosynthesis in an iron-independent fashion and the subsequent cellular iron-deficiency state may play a role in the antiproliferative action of IFN-alpha. PMID- 27457049 TI - Unusual Association of Hairy Cell Leukemia and Monoclonal Large Granular Lymphocyte Proliferation. AB - The exceptional association of Hairy cell leukemia (HCL) and monoclonal large granular lymphocyte (LGL) proliferation is reported in the same patient. Immunophenotypic analysis, showed that most of the PBMC expressed CD3 and HNK-1 molecules, while in the bone marrow biopsy an infiltration by CD22 +/CD25 + lymphoid cells was detectable. The monoclonal rearrangement of betaTTCR genes in the PBMC, suggests that the increased LGL is not reactive. Nevertheless, a possible interaction between the two entities is proposed. The high sIL-2R serum levels, related to proliferation of hairy cells, might account for the lack of NK activity observed in the LGL. PMID- 27457051 TI - An Objective Evaluation of Mass Scaling Techniques Utilizing Computational Human Body Finite Element Models. AB - Biofidelity response corridors developed from post-mortem human subjects are commonly used in the design and validation of anthropomorphic test devices and computational human body models (HBMs). Typically, corridors are derived from a diverse pool of biomechanical data and later normalized to a target body habitus. The objective of this study was to use morphed computational HBMs to compare the ability of various scaling techniques to scale response data from a reference to a target anthropometry. HBMs are ideally suited for this type of study since they uphold the assumptions of equal density and modulus that are implicit in scaling method development. In total, six scaling procedures were evaluated, four from the literature (equal-stress equal-velocity, ESEV, and three variations of impulse momentum) and two which are introduced in the paper (ESEV using a ratio of effective masses, ESEV-EffMass, and a kinetic energy approach). In total, 24 simulations were performed, representing both pendulum and full body impacts for three representative HBMs. These simulations were quantitatively compared using the International Organization for Standardization (ISO) ISO-TS18571 standard. Based on these results, ESEV-EffMass achieved the highest overall similarity score (indicating that it is most proficient at scaling a reference response to a target). Additionally, ESEV was found to perform poorly for two degree-of-freedom (DOF) systems. However, the results also indicated that no single technique was clearly the most appropriate for all scenarios. PMID- 27457052 TI - Use of oral anticoagulation for patients who undergo invasive procedures. AB - The performance of invasive procedures in patients undergoing oral anticoagulation represents a risk. Without conclusive data on this issue, the recommendations on managing oral anticoagulation are generally weak, and its management is controversial and heterogeneous. We conducted a review of the evidence on the elective periprocedural management of oral anticoagulation following the publication of the 9th edition of the guidelines of the American College of Chest Physicians. Except for cases of procedures with minimal haemorrhagic risk, the use of oral anticoagulants is suspended with sufficient time so that it can be performed without a significant anticoagulant effect, which will depend on the half-life of the drug. For direct oral anticoagulants, the half-life is determined by the renal function. Recent studies have shown that the use of bridge therapy with heparin in patients who temporarily suspended the use of oral anticoagulation provided no benefits and increased the bleeding. However, there is no conclusive evidence against its use in patients with a high thromboembolic risk. PMID- 27457053 TI - Updated mortality study of a cohort of asbestos textile workers. AB - Limited information is available on risk of peritoneal mesothelioma after asbestos exposure, and in general on the risk of cancer after cessation of asbestos exposure. We updated to 2013 the follow-up of a cohort of 1083 female and 894 male textile workers with heavy asbestos exposure (up to 100 fb/mL), often for short periods. A total of 1019 deaths were observed, corresponding to a standardized mortality ratio (SMR) of 1.68 (95% confidence interval [CI]: 1.57 1.78). SMRs were 29.1 (95% CI: 21.5-38.6) for peritoneal cancer, 2.96 (95% CI: 2.50-3.49) for lung cancer, 33.7 (95% CI: 25.7-43.4) for pleural cancer, and 3.03 (95% CI: 1.69-4.99) for ovarian cancer. For pleural and peritoneal cancer, there was no consistent pattern of risk in relation to time since last exposure, whereas for lung cancer there was an indication of a decline in risk after 25 years since last exposure. The findings of this unique cohort provide novel data for peritoneal cancer, indicating that - as for pleural cancer - the excess risk does not decline up to several decades after cessation of exposure. PMID- 27457054 TI - Micronuclei as a marker for medical screening of subjects continuously occupationally exposed to low doses of ionizing radiation. AB - CONTEXT: Genotoxicity assays are widely employed in human biomonitoring studies to assess genetic damage inflicted by genotoxic agents. OBJECTIVE: Evaluation of micronuclei (MN) as a screening marker of occupational ionizing radiation (IR) exposure. MATERIALS AND METHODS: Using micronucleus test, peripheral blood lymphocytes (PBL) of 402 control and exposed subjects were screened for genetic damage. RESULTS: The mean frequencies of micronucleus test parameters were significantly higher in exposed persons. Increase of micronucleus yield with duration of exposure (DOE) by 0.303MN/year was revealed. DISCUSSION AND CONCLUSION: The obtained data encourage us to consider MN as valuable markers for preventive medical screening of occupationally exposed groups. PMID- 27457055 TI - Microsecond Response in Organic Electrochemical Transistors: Exceeding the Ionic Speed Limit. AB - Organic electrochemical transistors (OECTs) are transistors that can have extrinsic transconductances as high as 400 S m-1 , but they typically have response times on the order of 1 ms or longer. These response speeds are limited by ion transport. It is shown that OECTs can exceed the ionic response speed by a factor of 30 when operated in a high-speed bias regime. PMID- 27457056 TI - Microscopic Chain Motion in Polymer Nanocomposites with Dynamically Asymmetric Interphases. AB - Dynamics of the interphase region between matrix and bound polymers on nanoparticles is important to understand the macroscopic rheological properties of nanocomposites. Here, we present neutron scattering investigations on nanocomposites with dynamically asymmetric interphases formed by a high-glass transition temperature polymer, poly(methyl methacrylate), adsorbed on nanoparticles and a low-glass transition temperature miscible matrix, poly(ethylene oxide). By taking advantage of selective isotope labeling of the chains, we studied the role of interfacial polymer on segmental and collective dynamics of the matrix chains from subnanoseconds to 100 nanoseconds. Our results show that the Rouse relaxation remains unchanged in a weakly attractive composite system while the dynamics significantly slows down in a strongly attractive composite. More importantly, the chains disentangle with a remarkable increase of the reptation tube size when the bound polymer is vitreous. The glassy and rubbery states of the bound polymer as temperature changes underpin the macroscopic stiffening of nanocomposites. PMID- 27457057 TI - Simultaneous degradation of refractory organic pesticide and bioelectricity generation in a soil microbial fuel cell with different conditions. AB - In this study, the soil microbial fuel cells (MFCs) were constructed based on sandy soil to remove the refractory organic pesticide hexachlorobenzene (HCB) in topsoil by a simple method. The construction of membraneless single-chamber soil MFCs by setting up the cathode- and the anode-activated carbon, inoculating the sludge and adding the co-substrates can promote HCB removal significantly. The results showed that HCB removal efficiencies in the soils contaminated with 40, 80 and 200 mg/kg were 71.14%, 62.15% and 50.06%, respectively, which were 18.65%, 18.46% and 19.17% higher than the control, respectively. The electricity generation of soil MFCs in different HCB concentrations was analyzed. The highest power density reached was 70.8 mW/m2, and an internal resistance of approximately 960 Omega was obtained when an external resistance loading of 1000 Omega was connected. Meanwhile, the influences of temperature, substrate species and substrate concentrations on soil MFCs initial electricity production were investigated. The addition of the anionic surfactant sodium dodecyl sulfate (SDS) into the soil MFCs system contributed to the improvement in HCB removal efficiency. PMID- 27457058 TI - Serum Total Sialic Acid Level is Elevated in Hypothyroid Patients as an Atherosclerotic Risk Factor. AB - BACKGROUND: Serum total sialic acid (TSA) concentration is regarded as an indicator of the risks of atherosclerosis and cardiovascular diseases. The association between SA levels and atherosclerosis risk factors has not been assessed in patients with thyroid diseases. METHODS: Sixty newly diagnosed treatment-naive hypothyroid patients, 35 with subclinical and 25 with overt hypothyroidism, and 30 euthyroid individuals were analyzed. SA was measured in fasting blood samples, as were routine biochemical parameters, some atherosclerosis markers and carotid artery intima media thickness (CIMT). RESULTS: Mean SA (38.1 +/- 12.0 vs. 46.0 +/-15.8; P = 0.019) and CIMT (0.57 +/- 0.06 vs. 0.62 +/- 0.12; P = 0.013) were found to be higher in the patient group compared with the control group. Mean sialic acid was higher in overt hypothyroidism patients compared with subclinical hypothyroidism patients and the control group. No difference was found between the subclinical hypothyroidism group and the control group. Sialic acid level and CIMT had a positive correlation in both the entire population and the hypothyroidism group. The linear regression model established for mean CIMT level in the entire population showed that risk factors of LDL (B +/- SE = 0.454 +/- 0.206; P = 0.030), uric acid (B +/- SE = 1.902 +/- 0.686; P = 0.007), hs-CRP (B +/- SE = 1.003 +/- 0.380; P =0.010), and SA (B +/- SE = 2.419 +/- 0.450; P < 0.001) were independent predictors of CIMT level. CONCLUSION: Sialic acid level is elevated in hypothyroid patients. However, this elevation is not related to thyroid hormone levels and autoantibodies. Correlations between SA and atherosclerosis indicators, such as CIMT, LDL, hs-CRP, and uric acid, in hypothyroid individuals suggest that SA may be an indicator of atherogenesis in these patients. PMID- 27457059 TI - A qualitative study of professional and carer perceptions of the threats to safe hospital discharge for stroke and hip fracture patients in the English National Health Service. AB - BACKGROUND: Hospital discharge is a vulnerable transitional stage in patient care. This qualitative study investigated the views of healthcare professionals and patients about the threats to safe hospital discharge with aim of identifying contributory and latent factors. The study was undertaken in two regional health and social care systems in the English National Health Service, each comprising three acute hospitals, community and primary care providers and municipal social care services. The study focused on the threats to safe discharge for hip fracture and stroke patients as exemplars of complex care transitions. METHODS: A qualitative study involving narrative interviews with 213 representative stakeholders and professionals involved in discharge planning and care transition activities. Narratives were analysed in line with 'systems' thinking to identify proximal (active) and distal (latent) factors, and the relationships between them. RESULTS: Three linked categories of commonly and consistently identified threat to safe discharge were identified: (1) 'direct' patient harms comprising falls, infection, sores and ulceration, medicines-related issues, and relapse; (2) proximal 'contributing' factors including completion of tests, assessment of patient, management of equipment and medicines, care plan, follow-up care and patient education; and distal 'latent' factors including discharge planning, referral processes, discharge timing, resources constraints, and organisational demands. CONCLUSION: From the perspective of stakeholders, the study elaborates the relationship between patient harms and systemic factors in the context of hospital discharge. It supports the importance of communication and collaboration across occupational and organisational boundaries, but also the challenges to supporting such communication with the inherent complexity of the care system. PMID- 27457060 TI - An epidemiological analysis of acute flaccid paralysis in Khuzestan Province, southwest Iran, from 2006 to 2010. AB - OBJECTIVES: Investigations into the epidemiology of acute flaccid paralysis (AFP) are an essential strategic component of the Global Poliomyelitis Eradication Initiative of the World Health Organization (WHO), and are part of the certification process for polio eradication worldwide. This is an epidemiological report of AFP incidence in children less than 15 years old in southwest Iran. METHODS: This was a retrospective cohort study, carried out based on WHO guidelines, in which we reviewed non-polio AFP cases recorded from January 2006 to December 2010 in different regions of Khuzestan Province, southwest Iran. In this study, the records of all children under 15 years old with AFP were evaluated. RESULTS: During a 5-year period, 137 cases of AFP were reported (incidence rate, 2.21 per 100,000 children <15 years old). More than 50% (73 of 137) of the cases were boys, and 52.6% (72 of 137) were under 5 years of age, with a mean age of 5.39+/-3.98 years. The incidence of AFP was significantly higher in older children (p=0.001). The most common cause of paralysis was Guillain-Barre syndrome (117 of 137). None of the cases were diagnosed with acute poliomyelitis. CONCLUSIONS: In this study, we found that the incidence rate of AFP in the region was almost in agreement with the expected incidence of AFP in children less than 15 years old; therefore, the AFP surveillance program in Khuzestan Province is satisfactory in terms of reliability and effectiveness. Nevertheless, routine vaccination against polio and ensuring that patients with AFP receive follow-up are essential for eradicating polio. PMID- 27457061 TI - Epidemiologic research on lung damage caused by humidifier disinfectants. AB - In April 2011 a tertiary hospital located in Seoul, Korea reported several cases of severe respiratory distress of unknown origin in young adults. To find the route of transmission, causative agent and patient risk factors of the outbreak, an investigation of the epidemic was initiated. A hospital based case-control study was conducted to indicate that humidifier detergent use was the cause of the outbreak. This information led the Ministry of Health and Welfare of Korea issued an order that humidifier detergents should be withdrawn from the market. Here, we describe the major events of planning, execution, and interpretation of the study, and discussions between researchers and public authorities following the decision to perform an epidemiologic study, chronologically. PMID- 27457062 TI - Comparison of the tuberculin skin test and the QuantiFERON-TB Gold test in detecting latent tuberculosis in health care workers in Iran. AB - OBJECTIVES: The tuberculin skin test (TST) and the QuantiFERON-TB Gold test (QFT) are used to identify latent tuberculosis infections (LTBIs). The aim of this study was to determine the agreement between these two tests among health care workers in Iran. METHODS: This cross-sectional study included 177 tuberculosis (TB) laboratory staff and 67 non-TB staff. TST indurations of 10 mm or more were considered positive. The Student's t-test and the chi-square test were used to compare the mean score and proportion of variables between the TB laboratory staff and the non-TB laboratory staff. Kappa statistics were used to evaluate the agreement between these tests, and logistic regression was used to assess the risk factors associated with positive results for each test. RESULTS: The prevalence of LTBIs according to both the QFT and the TST was 17% (95% confidence interval [CI], 12% to 21%) and 16% (95% CI, 11% to 21%), respectively. The agreement between the QFT and the TST was 77.46%, with a kappa of 0.19 (95% CI, 0.04 to 0.34). CONCLUSIONS: Although the prevalence of LTBI based on the QFT and the TST was not significantly different, the kappa statistic was low between these two tests for the detection of LTBIs. PMID- 27457063 TI - Plague in Iran: its history and current status. AB - OBJECTIVES: Plague remains a public health concern worldwide, particularly in old foci. Multiple epidemics of this disease have been recorded throughout the history of Iran. Despite the long-standing history of human plague in Iran, it remains difficult to obtain an accurate overview of the history and current status of plague in Iran. METHODS: In this review, available data and reports on cases and outbreaks of human plague in the past and present in Iran and in neighboring countries were collected, and information was compiled regarding when, where, and how many cases occurred. RESULTS: This paper considers the history of plague in Persia (the predecessor of today's Iran) and has a brief review of plague in countries in the World Health Organization Eastern Mediterranean Region, including a range of countries in the Middle East and North Africa. CONCLUSIONS: Since Iran has experienced outbreaks of plague for several centuries, neighboring countries have reported the disease in recent years, the disease can be silent for decades, and the circulation of Yersinia pestis has been reported among rodents and dogs in western Iran, more attention should be paid to disease monitoring in areas with previously reported human cases and in high-risk regions with previous epizootic and enzootic activity. PMID- 27457064 TI - Dietary intakes of citrus fruit and risk of gastric cancer incidence: an adaptive meta-analysis of cohort studies. AB - OBJECTIVES: In the context of supplementary antioxidants having no anticancer effect, it is important to update the meta-analysis to evaluate whether there is an association between intake of citrus fruit and gastric cancer risk. METHODS: The list of articles to be searched was established using citation discovery tools provided by PubMed and Scopus. The effect size of each article to be used in meta-analysis was calculated using the interval-collapse method. Summary effect size (sES) and 95% confidence intervals (CI) were obtained by conducting this meta-analysis. Random effect dose-response meta-regression (DRMR) was performed to investigate the dose-response relationship. RESULTS: A total of five cohort studies were selected. The result was 13% reduction of gastric cancer according to the intake of citrus fruit (sES, 0.87; 95% CI, 0.76 to 0.99; I squared=69.6%). In subgroup analysis, it was found that the intake of citrus fruit inhibited cardia gastric cancer (CGC) (sES, 0.67; 95% CI, 0.55 to 0.81; I squared=46.1%) and as a result of DRMR, 100 g of citrus fruit intake per day inhibits CGC by 40% (relative risk, 0.60; 95% CI, 0.44 to 0.83). CONCLUSIONS: It is suggested that the intake of citrus fruit inhibits the development of CGC. This conclusion can be used as a primary prevention measure in the future when the incidence of CGC may be on the rise. PMID- 27457065 TI - Correlation between depressive symptoms and subjective mastication ability and ability to pronunciation among Korean elderly. AB - OBJECTIVES: The present study examines the relationship between depressive symptoms and subjective chewing and pronunciation ability in Korean seniors. Our goal is to provide the data required to develop appropriate oral health interventions programs for seniors. METHODS: The Center for Epidemiologic Studies Depression Scale (CES-D) is widely used depressive symptoms assessment. A Korean version was used for the 2009 Community Health Survey, which was consulted to extract the present study's participants comprising 50,694 Korean seniors (males, 20,582; females, 30,112) aged >=65 years. Those with a CES-D score >=16 were rated 'depressed.' SAS version 9.3 was used for the data analysis. RESULTS: Prevalence of depressive symptoms increased as the participants socioeconomic status decreased, number of health issues increased, health behavior worsened, and chewing and pronunciation discomfort increased. Males with chewing difficulties were found to have 1.45 times (95% confidence interval [CI], 1.29 to 1.63) greater risk of depressive symptoms than those without, while males with pronunciation discomfort were found to have 1.97 times greater risk of depressive symptoms than those without (95% CI, 1.76 to 2.20). Females with chewing difficulty were found to have 1.50 times (95% CI, 1.39 to 1.61) greater risk of depressive symptoms than those without, and females with pronunciation discomfort were found to have 1.55 times greater risk of depressive symptoms than those without (95% CI, 1.44 to 1.67). CONCLUSIONS: Intervention programs designed to help with oral health management and alleviate depressive symptoms in seniors are urgently needed. As the prevalence of depressive symptoms may vary geographically, research examining potential variance at city, district, and town levels would be beneficial. PMID- 27457066 TI - Preparation and Evaluation of a Novel Class of Amphiphilic Amines as Antitumor Agents and Nanocarriers for Bioactive Molecules. AB - PURPOSE: We describe a novel class of antitumor amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length. METHODS: We tested the lead compound, RC16, for cytotoxicity and mechanism of cell death in several cancer cell lines, anti tumor efficacy in mouse tumor models, and ability to encapsulate chemotherapy drugs. RESULTS: These compounds displayed strong cytotoxic activity against cell lines derived from both pediatric and adult cancers. The IC50 of the lead compound, RC16, for normal cells including human keratinocytes, human fibroblasts and human umbilical vein endothelial cells was tenfold higher than for tumor cells. RC16 exhibited significant antitumor effects in vivo using several human xenografts and a metastatic model of murine neuroblastoma by both intravenous and oral administration routes. The amphiphilic character of RC16 triggered a spontaneous molecular self-assembling in water with formation of micelles allowing complexation of Doxorubicin, Etoposide and Paclitaxel. These micelles significantly improved the in vitro antitumor activity of these drugs as the enhancement of their aqueous solubility also improved their biologic availability. CONCLUSIONS: RC16 and related amphiphilic amines may be useful as a novel cancer treatment. PMID- 27457067 TI - Immunological Characteristics of a Patient With Belatacept-Resistant Acute Rejection After Face Transplantation. PMID- 27457069 TI - The Yin and Yang of Microrna Assay Methods. AB - OBJECTIVE: microRNA assessments in biological samples can be performed by different methods that mainly rely on hybridization process, qPCR or RNA sequencing. With the aim to detect and validate microRNA biomarkers in tumor samples, we challenged the consistency of the quantitative results obtained with the different methods. METHODS: We measured microRNA concentrations in several biological samples such as cultured tumor cells or tumor tissues (frozen tissues or FFPE samples) using different microRNA assay methods, in particular hybridization to AffymetrixTM arrays, qPCR and digital droplet qPCR (BioradTM) based on Taqman microRNA assays (Life TechnologiesTM). We also compared our results to other data that have been obtained with different technical approaches and available in the literature. RESULTS: We found poor consistency for the microRNA amounts measured in the samples assayed by the different methods. Both technical platforms and microRNA assays protocols may be responsible for the observed inconsistencies. CONCLUSION: When assaying microRNAs for clinical purpose or fundamental researches it seems necessary to keep in mind the specific pitfalls of all the microRNA detection methods such as those we disclose here. Obviously, valid inter sample comparisons and meaningful multicenter studies can only be obtained when microRNA assessments are strictly performed with identical technical approaches and reagents. PMID- 27457068 TI - (-)-Epigallocatechin-3-O-gallate (EGCG) attenuates the hemodynamics stimulated by caffeine through decrease of catecholamines release. AB - A human study of the effects on hemodynamics of caffeine and epigallocatechin-3-O gallate (EGCG) was performed. Caffeine tablets (200 mg) were orally administered to healthy males aged between 25 and 35 years 30 min after oral administration of EGCG tablets (100 and 200 mg). The increase in BP induced by caffeine was inhibited when co-administrated with EGCG. We found that caffeine slightly decreased heart rate (HR) in the volunteers. Although EGCG enhanced HR reduction, the effect was not significant. In addition, caffeine increased blood catecholamine levels, but EGCG inhibited the increase in noradrenaline, adrenaline and dopamine levels induced by caffeine. Whether EGCG decreases the elevated HR and systolic perfusion pressure, and ventricular contractility induced by adrenergic agonists in the isolated rat heart was investigated. The modified Krebs-Henseleit solution was perfused through a Langendorff apparatus to the isolated hearts of rats. HR, systolic perfusion pressure, and developed maximal rates of contraction (+dP/dtmax) and relaxation (-dP/dtmax) were increased by epinephrine (EP) and isoproterenol (IP). In contrast, EGCG decreased the elevated HR, systolic perfusion pressure, and left ventricular +/-dp/dtmax induced by EP and/or IP. In conclusion, EGCG could attenuate the hemodynamics stimulated by caffeine through decreasing catecholamine release. PMID- 27457070 TI - Functions, Organization and Etiology: A Reply to Artiga and Martinez. AB - We reply to Artiga and Martinez's claim according to which the organizational account of cross-generation functions implies a backward looking interpretation of etiology, just as standard etiological theories of function do. We argue that Artiga and Martinez's claim stems from a fundamental misunderstanding about the notion of "closure", on which the organizational account relies. In particular, they incorrectly assume that the system, which is relevant for ascribing cross generation organizational function, is the lineage. In contrast, we recall that organizational closure refers to a relational description of a network of mutual dependencies, abstracted from time, in which production relations are irrelevant. From an organizational perspective, ascribing a function to an entity means locating it in the abstract system that realizes closure. In particular, the position of each entity within the relational system conveys an etiological explanation of its existence, because of its dependence on the effects exerted by other entities subject to closure. Because of the abstract relational nature of closure, we maintain that the organizational account of functions does not endorse a backward looking interpretation of etiology. As a consequence, it does not fall prey of epiphenomenalism. PMID- 27457071 TI - Mapping H4K20me3 onto the chromatin landscape of senescent cells indicates a function in control of cell senescence and tumor suppression through preservation of genetic and epigenetic stability. AB - BACKGROUND: Histone modification H4K20me3 and its methyltransferase SUV420H2 have been implicated in suppression of tumorigenesis. The underlying mechanism is unclear, although H4K20me3 abundance increases during cellular senescence, a stable proliferation arrest and tumor suppressor process, triggered by diverse molecular cues, including activated oncogenes. Here, we investigate the function of H4K20me3 in senescence and tumor suppression. RESULTS: Using immunofluorescence and ChIP-seq we determine the distribution of H4K20me3 in proliferating and senescent human cells. Altered H4K20me3 in senescence is coupled to H4K16ac and DNA methylation changes in senescence. In senescent cells, H4K20me3 is especially enriched at DNA sequences contained within specialized domains of senescence-associated heterochromatin foci (SAHF), as well as specific families of non-genic and genic repeats. Altered H4K20me3 does not correlate strongly with changes in gene expression between proliferating and senescent cells; however, in senescent cells, but not proliferating cells, H4K20me3 enrichment at gene bodies correlates inversely with gene expression, reflecting de novo accumulation of H4K20me3 at repressed genes in senescent cells, including at genes also repressed in proliferating cells. Although elevated SUV420H2 upregulates H4K20me3, this does not accelerate senescence of primary human cells. However, elevated SUV420H2/H4K20me3 reinforces oncogene-induced senescence associated proliferation arrest and slows tumorigenesis in vivo. CONCLUSIONS: These results corroborate a role for chromatin in underpinning the senescence phenotype but do not support a major role for H4K20me3 in initiation of senescence. Rather, we speculate that H4K20me3 plays a role in heterochromatinization and stabilization of the epigenome and genome of pre malignant, oncogene-expressing senescent cells, thereby suppressing epigenetic and genetic instability and contributing to long-term senescence-mediated tumor suppression. PMID- 27457072 TI - Knowledge of complications of diabetes mellitus among patients visiting the diabetes clinic at Sampa Government Hospital, Ghana: a descriptive study. AB - BACKGROUND: Diabetes mellitus (DM) appears to be a global epidemic and an increasingly major non-communicable disease threatening both affluent and non affluent society. The study aimed to determine the knowledge of diabetic complications among diabetes mellitus clients visiting the Diabetic Clinical at Sampa Government Hospital, Ghana. METHOD: This questionnaire-based descriptive study recruited a total 630 patients visiting the Diabetes Clinic at the Sampa Government Hospital. Structured questionnaire was used to obtain information such as socio-demographic and knowledge on complications of diabetes. RESULTS: Out of a total of 630 participants, 325 (51.5 %) knew diabetic foot as the most common complication followed by hypertension 223(35.4 %), neuropathy 184 (29.2 %), hypoactive sexual arousal 160(25.4 %), arousal disorder 135(21.5 %), eye diseases 112(17.7 %), heart disease 58(9.2 %), and renal disease 34(5.4 %). Comprehensive assessment of level of knowledge on the complications showed that majority 378(60.0 %) of T2D patients did not have knowledge on diabetes complications, 169(26.9 %) had inadequate knowledge on diabetics complication while 82(13.1 %) had adequate knowledge. The risk factors associated with the level of knowledge of diabetic complications were female gender adjusted odd ratio (AOR) =2.31 (1.56 3.41) married participants AOR = 3.37 (1.44-7.93), widowed AOR = 2.98 (1.10 8.08), basic level of education AOR =0.18 (0.082-0.50), Junior High School (JHS) and above of education level AOR = 0.035(0.017-0.75), 5-9 years of T2D duration AOR = 0.31(0.018-0.57), >=10 years T2D duration AOR = 0.042 (0.02-0.10) and urban dwellers AOR = 0.36 (0.22-0.68) respectively. CONCLUSION: Participants knew the individual complication of diabetic mellitus but lack an in-depth knowledge on the complications. Further expansion of diabetic educative programs like using mass media and involving national curriculum of education can improve self regulatory awareness of diabetic complications which may reduce the morbidity and mortality of diabetic patients. PMID- 27457073 TI - Streaming algorithms for identification of pathogens and antibiotic resistance potential from real-time MinION(TM) sequencing. AB - The recently introduced Oxford Nanopore MinION platform generates DNA sequence data in real-time. This has great potential to shorten the sample-to-results time and is likely to have benefits such as rapid diagnosis of bacterial infection and identification of drug resistance. However, there are few tools available for streaming analysis of real-time sequencing data. Here, we present a framework for streaming analysis of MinION real-time sequence data, together with probabilistic streaming algorithms for species typing, strain typing and antibiotic resistance profile identification. Using four culture isolate samples, as well as a mixed species sample, we demonstrate that bacterial species and strain information can be obtained within 30 min of sequencing and using about 500 reads, initial drug resistance profiles within two hours, and complete resistance profiles within 10 h. While strain identification with multi-locus sequence typing required more than 15x coverage to generate confident assignments, our novel gene-presence typing could detect the presence of a known strain with 0.5x coverage. We also show that our pipeline can process over 100 times more data than the current throughput of the MinION on a desktop computer. PMID- 27457074 TI - A cyclin D1-negative mantle cell lymphoma with an IGL-CCND2 translocation that relapsed with blastoid morphology and aggressive clinical behavior. AB - Mantle cell lymphoma (MCL) is a B cell neoplasm characterized by cyclin D1 overexpression; its prognosis is poor, especially when it exhibits a blastoid morphology. Cyclin D1-negative MCL is rare, and its pathogenesis and progression remain unclear. Herein, we describe a cyclin D1-negative, cyclin D2-positive MCL with a CCND2 and immunoglobulin lambda light chain (IGL) translocation. The patient was initially diagnosed with cyclin D1-negative MCL and achieved complete remission via combination chemotherapy and autologous stem cell transplantation. After relapsing, he was diagnosed with a blastoid variant of MCL that showed lymphoid cells with dispersed chromatin and more mitotic figures and higher p53 expression compared with the initial MCL. Despite salvage therapies, the disease became refractory, and the patient died 28 months after initiating chemotherapy. This case demonstrates that blastoid morphology in cyclin D1-negative MCL with IGL-CCND2 translocation indicates progression to a more aggressive neoplasm, similar to cyclin D1-positive MCL. PMID- 27457075 TI - Porcine placenta hydrolysates regulate calcium disturbance in MC3T3-E1 osteoblastic cells. AB - BACKGROUND: In bone metabolism, Ca(2+) disturbance and oxidative damage are the main biochemical factors related to pathology. Osteoblasts are bone-forming cells that also control bone endocrinology. Endocrine hormones and proteins are matured, folded, and secreted in the endoplasmic reticulum (ER). ER stress has emerged as a new pathological mechanism to explain bone disturbance. Here we studied the role of porcine placenta hydrolysates (PPHs) in the regulation of ER stress. METHODS: Cell viability was determined in vitro using trypan blue dye exclusion. ER stress and apoptosis were evaluated using immunoblotting and a caspase kit. The fluorescent Ca(2+)-binding dye Fura-2/AM was used to measure changes in intracellular Ca(2+) ([Ca(2+)]i). ROS levels, NADPH oxidase activity, and superoxide dismutase (SOD) activity were also measured. RESULTS: PPHs protected MC3T3-E1 osteoblastic cells against thapsigargin (Tg)-induced ER stress. Moreover, PPHs regulated caspase-12 and -3 activities, thereby protecting against cell death, and also regulated Tg-induced Ca(2+) release. The Ca(2+) chelator BAPT/AM also regulated caspase-12 and -3 activities and prevented Ca(2) stress-induced cell death. In the presence of PPHs or BAPTA/AM, Ca(2+)-related ROS were also regulated, as demonstrated by alterations in NADPH oxidase and SOD activity. CONCLUSIONS: PPHs appear to regulate bone metabolism disturbance by controlling Ca(2+) concentrations, and thus ER stress and ROS, in osteoblasts cultured in vitro. PMID- 27457076 TI - Gallbladder small cell carcinoma: a case report and literature review. AB - Gallbladder small cell carcinoma (SCC) comprises only 0.5 % of all gallbladder cancer and consists of aggressive tumors with poor survival outcomes against current treatments. These tumors are most common in elderly females, particularly those with cholecystolithiasis. We report the case of a 79-year-old woman with gallbladder small cell carcinoma. The patient had intermittent right upper quadrant abdominal pain and was admitted to our hospital due to suspected acute cholecystitis. She regularly received medical treatment for diabetes, hypertension, and dyslipidemia. On initial laboratory evaluation, the levels of aspartate aminotransferase (AST), total bilirubin, and C-reactive protein (CRP) were markedly elevated. She underwent computed tomography (CT) for screening. CT images showed a thick-walled gallbladder containing multiple stones and multiple 3-cm-sized round nodular lesions, which were suggestive of metastatic lymph nodes. After percutaneous transhepatic gallbladder drainage was performed, endoscopic ultrasound-guided fine needle aspiration of enlarged lymph nodes resulted in a diagnosis of small cell carcinoma or adenocarcinoma. However, we could not identify the primary lesion before the surgery because of no decisive factors. We performed cholecystectomy because there was a possibility of cholecystitis recurrence risk and also partial liver resection because we suspected tumor invasion. The final pathological diagnosis was neuroendocrine carcinoma of the gallbladder, small cell type. The tumor stage was IVb, T3aN1M1. The patient died 13 weeks after the surgery. In the present paper, we review the current available English-language literature of gallbladder SCC. PMID- 27457077 TI - Invasive liver abscess syndrome caused by Klebsiella pneumoniae with definite K2 serotyping in Japan: a case report. AB - BACKGROUND: Klebsiella pneumonia is a well-known human pathogen, and recently, a distinct invasive syndrome caused by K. pneumoniae serotypes K1 and K2 has been recognized in Southeast Asia. This syndrome is characterized by primary liver abscess and extrahepatic complications resulting from bacteremic dissemination. We report the first adult case of primary liver abscess caused by the definite K2 serotyped pathogen, with endogenous endophthalmitis in Japan. CASE PRESENTATION: A 64-year-old woman was admitted to a nearby hospital for a high fever and diarrhea. She had visual loss of her right eye, renal dysfunction, and thrombocytopenia within 24 h from admission. She was transferred to our institution. On admission, she had no alteration of mental status and normal vital signs; however, she had almost complete ablepsia of the right eye. Laboratory data showed severe inflammation, liver dysfunction, thrombocytopenia, an increased serum creatinine level, and coagulopathy. Computed tomography showed a low density area in the right lobe of the liver. Invasive liver abscess syndrome probably caused by K. pneumonia was highly suspected and immediately administered broad-spectrum antibiotics for severe sepsis. Concurrently, endogenous endophthalmitis was diagnosed, and we performed vitrectomy on the day of admission. The blood culture showed K. pneumoniae infection. Percutaneous drainage of the liver abscess was also performed. Although she was discharged in a good general condition on day 22, she had complete ablepsia of the right eye. The K2A gene was detected by polymerase chain reaction (PCR), which is consistent with the K2 serotype. PCR was also positive for the virulence-associated gene rmpA. Final diagnosis was invasive liver abscess syndrome caused by K2 serotype K. pneumonia. CONCLUSIONS: Although the primary liver abscess caused by K. pneumoniae with a hypermucoviscous phenotype is infrequently reported outside Southeast Asia, physicians should recognize this syndrome, and appropriate diagnosis and treatment is essential for saving patients' lives and preserving organ function, especially for visual acuity. PMID- 27457078 TI - Neuroendocrine tumor of the ampulla of Vater with distant cystic lymph node metastasis: a case report. AB - BACKGROUND: Neuroendocrine tumors (NETs) of the ampulla of Vater are rare and difficult to diagnose. We report a rare case of a small NET of the ampulla of Vater with metastasis to distant lymph nodes. CASE PRESENTATION: The patient was a 54-year-old man complaining of epigastric pain and melena. Upper gastrointestinal endoscopy revealed a bulging papilla with active bleeding, which was diagnosed as a well-differentiated NET of the ampulla of Vater. An approximately 10-mm hypervascular tumor at the ampulla of Vater and a 41-mm cyst adjacent to the wall of the jejunum were revealed by abdominal computed tomography. We performed pylorus-preserving pancreaticoduodenectomy with lymph node dissection. Macroscopic examination revealed a 9-mm tumor of the ampulla of Vater and a 52-mm cyst adjacent to the wall of the jejunum. Histological examination revealed that the cyst was a lymph node metastasis. The final diagnosis was non-functional NET G1 of the ampulla of Vater, designated T1N1M0 stage IIIB. Postoperatively, the patient underwent no treatment and has had no recurrence for 4 years. CONCLUSIONS: This case demonstrates that sporadic NETs of Vater's papilla have aggressive metastatic potential even with a small primary lesion, and radical resection with lymphadenectomy is recommended for all cases. PMID- 27457079 TI - [Revision surgery in episcleral glaucoma drainage devices]. AB - Episcleral glaucoma drainage devices (e.g., Ahmed or Baerveldt drainage device) are often used at a late stage in the care of glaucoma patients. At this stage other surgical techniques, such as trabeculectomy or viscocanaloplasty, have failed. However, the trend towards earlier implant surgery is supported by large randomized trials. Physicians should be aware of typical complications and, if possible, these should already be avoided by careful surgical technique. In this review article, we focus on postoperative hypotension, postoperative pressure increases, implant exposure, and possible corneal decompensation. PMID- 27457080 TI - Distinct catalytic activity and in vivo roles of the ExoIII and EndoIV AP endonucleases from Sulfolobus islandicus. AB - AP endonuclease cleaves the phosphodiester bond 5'- to the AP (apurinic or apyrimidinic) sites and is one of the major enzymes involved in base excision repair. So far, the properties of several archaeal AP endonuclease homologues have been characterized in vitro, but little is known about their functions in vivo. Herein, we report on the biochemical and genetic analysis of two AP endonucleases, SisExoIII and SisEndoIV, from the hyperthermophilic crenarchaeon Sulfolobus islandicus REY15A. Both SisExoIII and SisEndoIV exhibit AP endonuclease activity, but neither of them has 3'-5' exonuclease activity. SisExoIII and SisEndoIV have similar K M values on the substrate containing an AP site, but the latter cleaves the AP substrate at a dramatically higher catalytic rate than the former. Unlike other AP endonucleases identified in archaea, SisExoIII and SisEndoIV do not exhibit any cleavage activity on DNA having oxidative damage (8-oxo-dG) or uracil. Genetic analysis revealed that neither gene is essential for cell viability, and the growth of ?SiRe_2666 (endoIV), ?SiRe_0100 (exoIII), and ?SiRe_0100?SiRe_2666 is not affected under normal growth conditions. However, ?SiRe_2666 exhibits higher sensitivity to the alkylating agent methyl methanesulfonate (MMS) than ?SiRe_0100. Over-expression of SiRe_0100 can partially complement the sensitivity of ?SiRe_2666 to MMS, suggesting a backup role of SisExoIII in AP site processing in vivo. Intriguingly, over expression of SisEndoIV renders the strain more sensitive to MMS than the control. Taken together, we conclude that SisEndoIV, but not SisExoIII, is the main AP endonuclease that participates directly in base excision repair in S. islandicus. PMID- 27457082 TI - Age-based analysis of choroidal thickness and choroidal vessel diameter in primary open-angle glaucoma. PMID- 27457083 TI - Nerve Conduction Through Dendrites via Proton Hopping. AB - BACKGROUND: In our previous studies of nerve conduction conducted by proton hopping, we have considered the axon, soma, synapse and the nodes of Ranvier. The role of proton hopping described the passage of information through each of these units of a typical nerve system. The synapse projects information from the axon to the dendrite and their associated spines. METHODS: We have invoked the passage of protons via a hopping mechanism to illustrate the continuum of the impulse through the system, via the soma following the dendrites. This is proposed to be a continuum invoked by the proton hopping method. RESULTS: With the proposal of the activity through the dendrites, via proton hopping, a complete model of the nerve function is invoked. At each step to the way, a water pathway is present and is invoked in the proposed model as the carrier of the message via proton hopping. The importance of the dendrites is evident by the presence of a vast number of spines, each possessing the possibility to carry unique messages through the nervous system. CONCLUSION: With this model of the role of dendrites, functioning with the presence of proton hopping, a complete model of the nerve system is presented. The validity of this model will be available for further studies and models to assess it's validity. PMID- 27457081 TI - Substrate adaptabilities of Thermotogae mannan binding proteins as a function of their evolutionary histories. AB - The Thermotogae possess a large number of ATP-binding cassette (ABC) transporters, including two mannan binding proteins, ManD and CelE (previously called ManE). We show that a gene encoding an ancestor of these was acquired by the Thermotogae from the archaea followed by gene duplication. To address the functional evolution of these proteins as a consequence of their evolutionary histories, we measured the binding affinities of ManD and CelE orthologs from representative Thermotogae. Both proteins bind cellobiose, cellotriose, cellotetraose, beta-1,4-mannotriose, and beta-1,4-mannotetraose. The CelE orthologs additionally bind beta-1,4-mannobiose, laminaribiose, laminaritriose and sophorose while the ManD orthologs additionally only weakly bind beta-1,4 mannobiose. The CelE orthologs have higher unfolding temperatures than the ManD orthologs. An examination of codon sites under positive selection revealed that many of these encode residues located near or in the binding site, suggesting that the proteins experienced selective pressures in regions that might have changed their functions. The gene arrangement, phylogeny, binding properties, and putative regulatory networks suggest that the ancestral mannan binding protein was a CelE ortholog which gave rise to the ManD orthologs. This study provides a window on how one class of proteins adapted to new functions and temperatures to fit the physiologies of their new hosts. PMID- 27457084 TI - Echocardiography in Pregnancy: Part 2. AB - The prevalence of pregnant women with cardiovascular heart disease is increasing. Transthoracic echocardiography is safe during pregnancy, and it is an important diagnostic tool in pregnant women with established heart disease in order to monitor ventricular and valvular anatomy and function. In addition, it can be used to delineate cardiac anatomy in complex congenital heart disease and help stratify maternal risk during pregnancy. This review will focus on the use of echocardiography in the diagnosis and management of pregnant women with common congenital lesions and with prosthetic valves. PMID- 27457085 TI - Is Heart Rate a Norepiphenomenon in Heart Failure? AB - There has been an increased focus on heart rate as a target in the management of cardiovascular disease and more specifically in heart failure with preserved ejection fraction in recent years with several studies showing the benefit of a lower resting heart rate on outcomes. This review paper examines the pathophysiology behind the benefits of lowering heart rate in heart failure and also the evidence for and against the pharmacological agents available to achieve this. PMID- 27457086 TI - Changes in axial length, central cornea thickness, and anterior chamber depth after rhegmatogenous retinal detachment repair. AB - BACKGROUND: This study was designed to measure changes in anterior chamber depth (ACD), central cornea thickness (CCT), and axial length (AL) after scleral buckle (SB) surgery or pars plana vitrectomy (PPV) for the repair of rhegmatogenous retinal detachment (RD). METHODS: We prospectively reviewed the records of 245 eyes of 245 patients scheduled to undergo SB surgery and 238 eyes of 238 patients scheduled to undergo PPV. ACD, CCT, and AL were measured by spectral-domain optical coherence tomography (SD-OCT) and biometry, before surgery as well as 6 and 12 months postoperatively. RESULTS: For both SB and PPV surgeries, ACD was observed to decrease significantly postoperatively, with this trend continuing throughout the follow-up period (p < 0.005). CCT showed no significant difference after PPV or SB surgery. AL increased significantly after SB surgery but not PPV. CONCLUSION: Our results show that SB surgery altered the shape of the eye by changing both ACD and AL. PPV resulted in altered ACD. These findings should elucidate the changes to be expected after SB and PPV surgeries. PMID- 27457087 TI - A single amino acid substitution alter antigenicity of Glycosylated protein 4 of HP-PRRSV. AB - BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is an important pig endemic disease in pork-producing countries worldwide. The etiology, porcine reproductive and respiratory syndrome virus (PRRSV), is characterized by fast antigen variability. Glycosylated protein 4 (GP4) is a minor protein in PRRSV virion, but contributes to induce protective immune responses. However, the antigenic characterization of PRRSV GP4 and the role of the mutations in this protein in PRRSV evolution are not clear. METHODS: Peptides chip scanning and peptide based ELISA was used to analyze the antigenic characterization of HP PRRSV GP4. A total of 142 peptides printed on a chip were used to reveal the antigen reaction characteristics of the HP-PRRSV. The reactions of these peptides with HP-PRRSV-specific pig serum were scanned and quantified using the software PepSlide(r) Analyzer by fluorescence intensity. The active reaction regions (AR) were identified based on the scanning results and then the amino acids (aa) sequences of AR(s) is aligned among PRRSV strains for further identify the key aa site(s) impact the antigenicity of the protein. Peptide based ELISA is then reacted with PRRSV positive sera derived from pig inoculated with different PRRSV strains for further analysis the role of specific amino acid in AR. RESULTS: The intensity plot was used to show the reactions of the peptides with PRRSV serum and it showed that enormously different response happened to various parts of GP4. The highest reaction intensity value reached 6401.5 against one peptide with the sequence DIKTNTTAASDFVVL. An AR from S29 to G56 was identified. Sequence alignment revealed various mutations in site 43 and possibly played an important role in this AR. Peptides ELISA reaction with sera from pigs inoculated with different PRRSV strain revealed that the change of aa in site 43 reduced the reaction of the peptide with PRRSV positive sera derived from pigs inoculated with the peptide related PRRSV strains. CONCLUSION: In this study, one AR covering S29 to G56 was identified in GP4. The aa in site 43 play an important role in determining the antigenic character of GP4. The continual mutations (S -> G -> D -> N) occurred in this site alter the antigenicity of PRRSV GP4. PMID- 27457088 TI - Radiological description of cystic pancreatic tumors. AB - Although most cystic pancreatic lesions are pseudocysts, it is important to do a thorough differential diagnosis with true cystic tumors because cystic tumors are potentially malignant. Sometimes computed tomography and magnetic resonance imaging cannot establish the definitive diagnosis, making it necessary to perform other imaging tests such as endoscopic ultrasound, which in addition to morphological information, can also enable cytologic and biochemical analysis of the lesion through puncture and aspiration of its contents. Combining all these findings nearly always provides enough diagnostic information to allow the appropriate approach in each case. This article describes the specific morphological characteristics for each cystic pancreatic tumor on computed tomography, magnetic resonance imaging, and endoscopic ultrasound and reviews the guidelines for managing these types of lesions. PMID- 27457089 TI - Computed tomography protocols used in staging bronchopulmonary carcinoma: results of a national survey. AB - OBJECTIVES: To know the protocols used for staging bronchopulmonary carcinoma by computed tomography in Spain. MATERIAL AND METHODS: Radiologists in 129 hospitals were sent email questionnaires about the organization of their department, scanner type and manufacturer, study extension, techniques employed, and protocol for administering contrast material. RESULTS: A total of 109 hospitals responded with data from 91 teams. Most hospitals were affiliated with a university, and most departments were organized by organ-systems. Scanners were from four manufacturers, and 68% had either 16 or 64 detectors. In 61% of the hospitals, the dose of contrast agent is modified only in patients with extreme body weights, and in 22% the dose is not individualized. Most hospitals do contrast enhanced studies of the chest and upper abdomen, 42.4% through a single thoracoabdominal acquisition and 55.9% through independent chest and abdominal acquisitions; there was a significant association between these approaches and the scanner manufacturer's protocols and whether the hospital was affiliated with a university. The most commonly used technical parameters were 120kV with dose modulation and variable milliamperage. CONCLUSION: There is very little variability among hospitals in the type of scanner used, the study extension, and the technical parameters used to stage bronchopulmonary carcinoma. Most centers individualize the dose of contrast agent only in extreme weights. There is a broad division between using one or two acquisitions to image the thorax and abdomen, and the number of acquisitions is related to the scanner manufacturer and whether the hospital is affiliated with a university. PMID- 27457090 TI - Usefulness of ultrasonography is the evaluation of thyroid nodules. AB - OBJECTIVE: To evaluate the diagnostic capacity of ultrasonography (US) for differentiating between malignant and benign thyroid nodules and its usefulness in obviating unnecessary invasive procedures. PATIENTS AND METHODS: From January 2012 through December 2014, a total of 321 fine-needle aspiration biopsy (FNAB) procedures were done in 302 patients selected according to the criteria recommended by the American Association of Clinical Endocrinology guidelines and the American Thyroid Association guidelines. We analyzed the following characteristics on US: location, size, morphology, contour, consistency, echostructure, echogenicity, calcifications, and vascularization. We used univariate and multivariate analyses to investigate the relationship between the US findings and thyroid cancer. RESULTS: The prevalence of malignancy in our study population was 5.92%. The US findings that were significantly associated with a greater probability of malignancy were microcalcifications, central vascularization, and hypoechogenicity. The US findings that were associated with a lower risk of malignancy were areas of colloid degeneration and nodule heterogeneity. CONCLUSION: Our results suggest that decisions about whether to perform FNAB should be based on the presence of suspicious US findings found with our statistic model rather than on the size of the nodule. Thus, unnecessary FNAB procedures on nodules without suspicious US characteristics can be avoided. PMID- 27457091 TI - Hydroxysafflor yellow A inhibits TGF-beta1-induced activation of human fetal lung fibroblasts in vitro. AB - OBJECTIVE: Hydroxysafflor yellow A (HSYA) is one of the chemical component isolated from Chinese medicine Carthamus tinctorius L. Our preliminary study confirmed that HSYA attenuated bleomycin-induced pulmonary fibrosis in mice. In this study, we evaluated the effect of HSYA on TGF-beta1-induced activation of human fetal lung fibroblasts (MRC-5) and explored the underlying mechanisms of its activity. METHOD: MRC-5 cells activated by TGF-beta1 were incubated with HSYA and/or the TGF-beta type I receptor inhibitor, SB431542. TGF-beta1-induced cell proliferation, alpha-smooth muscle actin, collagen I alpha 1 and fibronectin expression, Smad, mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase/Akt signalling pathway activation were observed. KEY FINDINGS: Hydroxysafflor yellow A significantly inhibited TGF-beta1-induced cell proliferation and the expression, both mRNA and protein, of alpha-smooth muscle actin, collagen I alpha 1 and fibronectin. HSYA also suppressed TGF-beta1 activation of Smad signal transduction via inhibition of Smad2 and Smad3 phosphorylation, their nuclear translocation and the binding activity of Smad3 to type I collagen promoter in MRC-5 cells. In addition, HSYA inhibited TGF-beta1 induced phosphorylation of extracellular signal-regulated kinase (ERK). The inhibitory effects of HSYA were similar to SB431542. CONCLUSION: These findings suggest that HSYA inhibits TGF-beta1-induced activation of MRC-5 cells associated with TGF-beta1/Smad and ERK/MAPK signalling pathways. PMID- 27457094 TI - An Ito stochastic differential equations model for the dynamics of the MCF-7 breast cancer cell line treated by radiotherapy. AB - In this paper, a new mathematical model is proposed for studying the population dynamics of breast cancer cells treated by radiotherapy by using a system of stochastic differential equations. The novelty of the model is essentially in capturing the concept of the cell cycle in the modeling to be able to evaluate the tumor lifespan. According to the cell cycle, each cell belongs to one of three subpopulations G, S, or M, representing gap, synthesis and mitosis subpopulations. Cells in the M subpopulation are highly radio-sensitive, whereas cells in the S subpopulation are highly radio-resistant. Therefore, in the process of radiotherapy, cell death rates of different subpopulations are not equal. In addition, since flow cytometry is unable to detect apoptotic cells accurately, the small changes in cell death rate in each subpopulation during treatment are considered. Subsequently, the proposed model is calibrated using experimental data from previous experiments involving the MCF-7 breast cancer cell line. Consequently, the proposed model is able to predict tumor lifespan based on the number of initial carcinoma cells. The results show the effectiveness of the radiation under the condition of stability, which describes the decreasing trend of the tumor cells population. PMID- 27457092 TI - Stochastic multi-scale models of competition within heterogeneous cellular populations: Simulation methods and mean-field analysis. AB - We propose a modelling framework to analyse the stochastic behaviour of heterogeneous, multi-scale cellular populations. We illustrate our methodology with a particular example in which we study a population with an oxygen-regulated proliferation rate. Our formulation is based on an age-dependent stochastic process. Cells within the population are characterised by their age (i.e. time elapsed since they were born). The age-dependent (oxygen-regulated) birth rate is given by a stochastic model of oxygen-dependent cell cycle progression. Once the birth rate is determined, we formulate an age-dependent birth-and-death process, which dictates the time evolution of the cell population. The population is under a feedback loop which controls its steady state size (carrying capacity): cells consume oxygen which in turn fuels cell proliferation. We show that our stochastic model of cell cycle progression allows for heterogeneity within the cell population induced by stochastic effects. Such heterogeneous behaviour is reflected in variations in the proliferation rate. Within this set-up, we have established three main results. First, we have shown that the age to the G1/S transition, which essentially determines the birth rate, exhibits a remarkably simple scaling behaviour. Besides the fact that this simple behaviour emerges from a rather complex model, this allows for a huge simplification of our numerical methodology. A further result is the observation that heterogeneous populations undergo an internal process of quasi-neutral competition. Finally, we investigated the effects of cell-cycle-phase dependent therapies (such as radiation therapy) on heterogeneous populations. In particular, we have studied the case in which the population contains a quiescent sub-population. Our mean field analysis and numerical simulations confirm that, if the survival fraction of the therapy is too high, rescue of the quiescent population occurs. This gives rise to emergence of resistance to therapy since the rescued population is less sensitive to therapy. PMID- 27457095 TI - Locally dispersing populations in heterogeneous dynamic landscapes with spatiotemporal correlations. II. Habitat driven by voter dynamics. AB - We examine a spatially explicit population model on a dynamic landscape with suitable and unsuitable habitat driven by voter or contagion dynamics. We consider four cases, consisting of all combinations of local and global interactions for both population dispersal and habitat dynamics. For both local and global population dispersal, using local habitat dynamics always increases population density relative to the case with global habitat dynamics, due to the resulting segregation of habitat turnover, decrease in effective habitat turnover rate, and presence of stable habitat corridors. With global habitat dynamics, a population using local dispersal exhibits lower density than one with global dispersal due to local crowding as well as frequent disturbance due to habitat transitions. On the other hand, with local habitat dynamics, a population using local dispersal can exploit suitable habitat patches and use dynamic corridors to colonize new regions. The latter effect is not seen with static landscapes, where clustered habitat can lead to the isolation of suitable patches due to surrounding unsuitable habitat. PMID- 27457093 TI - The interplay of vaccination and vector control on small dengue networks. AB - Dengue fever is a major public health issue affecting billions of people in over 100 countries across the globe. This challenge is growing as the invasive mosquito vectors, Aedes aegypti and Aedes albopictus, expand their distributions and increase their population sizes. Hence there is an increasing need to devise effective control methods that can contain dengue outbreaks. Here we construct an epidemiological model for virus transmission between vectors and hosts on a network of host populations distributed among city and town patches, and investigate disease control through vaccination and vector control using variants of the sterile insect technique (SIT). Analysis of the basic reproductive number and simulations indicate that host movement across this small network influences the severity of epidemics. Both vaccination and vector control strategies are investigated as methods of disease containment and our results indicate that these controls can be made more effective with mixed strategy solutions. We predict that reduced lethality through poor SIT methods or imperfectly efficacious vaccines will impact efforts to control disease spread. In particular, weakly efficacious vaccination strategies against multiple virus serotype diversity may be counter productive to disease control efforts. Even so, failings of one method may be mitigated by supplementing it with an alternative control strategy. Generally, our network approach encourages decision making to consider connected populations, to emphasise that successful control methods must effectively suppress dengue epidemics at this landscape scale. PMID- 27457096 TI - Differences in density-dependence drive dual offspring size strategies in fish. AB - Offspring size reflects the optimal balance between female fecundity and allocation of energy to each offspring. Most fish, in particular teleost species, produce many small eggs, while others, notably elasmobranch species, have low fecundity and large offspring. No general explanation has yet been put forwards to explain these different strategies between species which occupy similar habitats. We approach the problem by (1) examining the differences between life history parameters of teleost fish and elasmobranchs and (2) an evolutionary model. We show that life history parameters characterising growth, mortality and reproductive output are almost similar between teleosts and elasmobranchs. We find that a model which accounts for density-dependence predicts dual offspring size strategies: either invariant with adult size or proportional to adult size. The model predicts that the invariant strategy is associated with an absence of density-dependence in early life whereas proportional offspring are subject to density-dependence throughout life. Parameterising the model using life history data regenerates the observed dual offspring size pattern. We conjecture that the life stage where density-dependent competition occurs is an important factor behind the observed difference in offspring size strategies. PMID- 27457097 TI - Comparing the effects of positive and negative feedback in information integration category learning. AB - Categorical learning is dependent on feedback. Here, we compare how positive and negative feedback affect information-integration (II) category learning. Ashby and O'Brien (2007) demonstrated that both positive and negative feedback are required to solve II category problems when feedback was not guaranteed on each trial, and reported no differences between positive-only and negative-only feedback in terms of their effectiveness. We followed up on these findings and conducted 3 experiments in which participants completed 2,400 II categorization trials across three days under 1 of 3 conditions: positive feedback only (PFB), negative feedback only (NFB), or both types of feedback (CP; control partial). An adaptive algorithm controlled the amount of feedback given to each group so that feedback was nearly equated. Using different feedback control procedures, Experiments 1 and 2 demonstrated that participants in the NFB and CP group were able to engage II learning strategies, whereas the PFB group was not. Additionally, the NFB group was able to achieve significantly higher accuracy than the PFB group by Day 3. Experiment 3 revealed that these differences remained even when we equated the information received on feedback trials. Thus, negative feedback appears significantly more effective for learning II category structures. This suggests that the human implicit learning system may be capable of learning in the absence of positive feedback. PMID- 27457098 TI - "You have to keep fighting": maintaining healthcare services and professionalism on the frontline of austerity in Greece. AB - BACKGROUND: Greece has been severely affected by the 2008 global economic crisis and its health system was, and still is, among the national institutions most shaped by its effects. METHODS: In 2014, this qualitative study examined these changes through in-depth interviews with 22 frontline healthcare professionals in five different locations in mainland Greece. These interviews with nurses, doctors and pharmacists explored perceptions of austerity and how ideas of professionalism were challenged and revised by these measures. RESULTS: Participants reported working conditions characterised by dramatic increases in public hospital admissions alongside decreases in personnel, consumables, materials, and also many hospital closures. Many drew on analogies of war and fighting to describe the effects of healthcare reforms on their working lives and professional conduct. Despite accounts of deteriorating conditions and numerous challenges, healthcare professionals presented themselves as making every effort to meet patients' needs, while battling to resist guidelines which they perceived diminished their roles to production-line operatives. CONCLUSIONS: Participants considered it their duty to defend their professional ethos and serve patients without compromising standards, even if this meant liberal interpretation and implementation of regulations. These professionals regarded themselves on the frontline of healthcare provision but also the frontline defence in a war on their professional standards from austerity. PMID- 27457099 TI - Current State of Antimicrobial Stewardship at Solid Organ and Hematopoietic Cell Transplant Centers in the United States. AB - OBJECTIVE To assess the extent of antimicrobial stewardship programs (ASPs) at solid organ transplant (SOT) and hematopoietic cell transplant (HCT) centers in the United States. DESIGN An 18-item voluntary survey was developed to gauge current antimicrobial stewardship practices in transplant patients, examine the availability and perceived usefulness of novel diagnostics and azole levels to guide therapy, and identify challenges for implementation of ASPs at these centers. PARTICIPANTS The survey was distributed electronically to infectious disease physicians and pharmacists at adult and pediatric SOT and HCT centers during May 1-22, 2015. Facilities were deidentified. RESULTS After duplicate removal, 71 (56%) of 127 unique transplant centers in 32 states were analyzed. Forty-four sites (62%) performed at least 100 SOT annually, and 40 (56%) performed at least 100 HCT annually. Top 5 stewardship activities encompassing transplant patients were formulary restriction, guideline development, prospective audit and feedback, education, and dose optimization. Respiratory viral panels (66/66 [100%]), azole levels (64/66 [97%]), and serum/bronchoalveolar lavage galactomannan (58/66 [88%]) were perceived as most useful to guide therapy. Apparent challenges to antimicrobial stewardship included undefined duration for certain infections (53/59 [90%]), diagnostic uncertainty (47/59 [80%]), the perception that antibiotic-resistant infections required escalation (42/59 [71%]), prescriber opposition (41/59 [69%]), and costly drugs (37/59 [63%]). CONCLUSIONS ASP activities were performed at many adult and pediatric SOT and HCT centers in the United States. Diagnostic and therapeutic uncertainty in transplant patients is challenging for ASPs. Collaborative research should examine the impact of antimicrobial stewardship practices in SOT and HCT. Infect Control Hosp Epidemiol 2016;1-6. PMID- 27457102 TI - A facile label-free aptasensor for detecting ATP based on fluorescence enhancement of poly(thymine)-templated copper nanoparticles. AB - A label-free fluorescence assay has been developed for sensitive and selective detection of adenosine triphosphate (ATP) by using poly(thymine) (poly T) templated copper nanoparticles (CuNPs) as fluorescent indicator. In our design, ATP aptamer was split into two fragments, both of which were elongated with poly T strands that can be utilized as efficient template for the formation of copper nanoparticles through the reduction of copper ions by sodium ascorbate. In the presence of ATP, the two split aptamers could be dragged to form aptamer-ATP aptamer complex, which drew the poly T strands close to each other and induced a remarkable fluorescence enhancement of poly T-templated CuNPs. Thus, an elevated fluorescence enhancement of poly T-templated CuNPs was obtained with the increase in ATP concentration. Under optimized conditions, a good linear range for ATP detection was realized from 100 nM to 100 MUM with a detection limit of 10.29 nM. In addition, the application of this biosensing system in complex biological matrix was demonstrated with satisfactory results. This assay provided a simple, label-free, cost-effective, and sensitive platform for the detection of ATP. PMID- 27457100 TI - Role of thigh muscle cross-sectional area and strength in progression of knee cartilage degeneration over 48 months - data from the Osteoarthritis Initiative. AB - OBJECTIVE: To determine in a 48-month longitudinal study the association of thigh muscle cross-sectional area (CSA) and strength on progression of morphologic knee cartilage degeneration using 3T magnetic resonance imaging (MRI). DESIGN: Seventy Osteoarthritis Initiative (OAI) subjects aged 50-60 years, with no radiographic evidence of osteoarthritis (OA) and constant muscle strength over 48 months as measured by isometric knee extension testing were included. Baseline right thigh muscle CSAs were assessed on axial T1-weighted magnetic resonance (MR) images, and extensor to flexor CSA ratios were calculated. Degenerative knee abnormalities at baseline and 48-months were graded on right knee 3T MRIs using a modified whole organ MRI score (WORMS). Statistical analysis employed Student's t tests and multivariable regression models adjusted for age, body mass index and gender. RESULTS: Extension strength was significantly and positively correlated with baseline thigh muscle CSA (r = 0.65, P < 0.001). Greater baseline total thigh muscle CSA was significantly associated with increase of cartilage WORMS scores over 48 months in patellar (P = 0.027) and trochlear (P = 0.038) compartments, but not in other knee compartments. Among specific muscle groups, CSA of extensors (P = 0.021) and vastus medialis (VM) (P = 0.047) were associated with patellar cartilage increase in WORMS. Baseline E/F ratio had a significant positive association with patellar WORMS cartilage score increase over 48 months, P = 0.0015. There were no other significant associations between muscle CSA/ratios and increase in WORMS scores. CONCLUSION: Maintenance of proper extensor to flexor muscle balance about the knee through decreased E/F ratios may slow patellofemoral cartilage deterioration, while higher extensor and VM CSA may increase patellofemoral cartilage loss. PMID- 27457103 TI - Direct and precise length measurement of single, stretched DNA fragments by dynamic molecular combing and STED nanoscopy. AB - A combination of DNA stretching method and super-resolution nanoscopy allows an accurate and precise measurement of the length of DNA fragments ranging widely in size from 117 to 23,130 bp. BstEII- and HindIII-treated lambdaDNA fragments were stained with an intercalating dye and then linearly stretched on a coverslip by dynamic molecular combing. The image of individual DNA fragments was obtained by stimulated emission depletion nanoscopy. For DNA fragments longer than ~1000 bp, the measured lengths of DNA fragments were consistently within ~0.5 to 1.0 % of the reference values, raising the possibility of this method in a wide range of applications including facile detection for copy number variations and trinucleotide repeat disorder. PMID- 27457104 TI - Plasma lipidomics reveals potential lipid markers of major depressive disorder. AB - Major depressive disorder (MDD) is a grave debilitating mental disease with a high incidence and severely impairs quality of life. Therefore, its physiopathological basis study and diagnostic biomarker discovery are extremely valuable. In this study, a non-targeted lipidomics strategy using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to reveal differential lipids between MDD (n = 60) and healthy controls (HCs, n = 60). Validation of changed lipid species was performed in an independent batch including 75 MDD and 52 HC using the same lipidomic method. Pronouncedly changed lipid species in MDD were discovered, which mainly were lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), 1-O-alkyl-2-acyl-PE (PE O), 1-O-alkyl-2-acyl-PC (PC O), sphingomyelin (SM), diacylglycerol (DG), and triacylglycerol (TG). Among these lipid species, LPC, LPE, PC, PE, PI, TG, etc. remarkably increased in MDD and showed pronounced positive relationships with depression severity, while 1-O-alkyl-2-acyl-PE and SM with odd summed carbon number significantly decreased in MDD and demonstrated negative relationships with depression severity. A combinational lipid panel including LPE 20:4, PC 34:1, PI 40:4, SM 39:1, 2, and TG 44:2 was defined as potential diagnostic biomarker with a good sensitivity and specificity for distinguishing MDD from HCs. Our study brings insights into lipid metabolism disorder in MDD and provides a specific potential biomarker for MDD diagnose. PMID- 27457105 TI - Erratum to: Multiplex detection of food allergens and gluten. PMID- 27457106 TI - Identification of fungal metabolites from inside Gallus gallus domesticus eggshells by non-invasively detecting volatile organic compounds (VOCs). AB - The natural porosity of eggshells allows hen eggs to become contaminated with microbes from the nesting material and environment. Those microorganisms can later proliferate due to the humid ambient conditions while stored in refrigerators, causing a potential health hazard to the consumer. The microbes' volatile organic compounds (mVOCs) are released by both fungi and bacteria. We studied mVOCs produced by aging eggs likely contaminated by fungi and fresh eggs using the non-invasive detection method of gas-phase sampling of volatiles followed by gas chromatography/mass spectrometry (GC/MS) analysis. Two different fungal species (Cladosporium macrocarpum and Botrytis cinerea) and two different bacteria species (Stenotrophomas rhizophila and Pseudomonas argentinensis) were identified inside the studied eggs. Two compounds believed to originate from the fungi themselves were identified. One fungus-specific compound was found in both egg and the fungi: trichloromethane. Graphical abstract Trichloromethane is a potential biomarker of fungal contamination of eggs. PMID- 27457108 TI - Iron-Catalyzed Acylation of Polyfunctionalized Aryl- and Benzylzinc Halides with Acid Chlorides. AB - FeCl2 (5 mol %) catalyzes a smooth and convenient acylation of functionalized arylzinc halides at 50 degrees C (2-4 h) and benzylic zinc chlorides at 25 degrees C (0.5-4 h) with a variety of acid chlorides leading to polyfunctionalized diaryl and aryl heteroaryl ketones. PMID- 27457107 TI - Prognostic significance of expression of cysteine-rich 61 and cyclooxygenase-2 in gastric cancer. AB - BACKGROUND: This study aimed to evaluate the clinical significance of cysteine rich 61 (Cyr-61/CCN1) and cyclooxygenase-2 (COX-2), and further explored their combined prognostic significance in gastric cancer. METHODS: This retrospective study examined the expressions of Cyr-61 and COX-2 in 82 surgically removed gastric cancer specimens and 43 non-tumor gastric mucosa specimens by immunohistochemical staining to identify the abnormal expression of Cyr-61 or COX 2 in gastric cancer. Crude survival curves were constructed by the Kaplan-Meier method and Cox proportional hazards regression analysis was performed to confirm the prognostic roles of Cyr-61/COX-2 as well as sex and histological grade. RESULTS: The expressions of Cyr-61 (p < 0.001) and COX-2 (p = 0.001) were both significantly up-regulated in gastric cancer samples compared with non-tumor gastric mucosa samples. The high expression of Cyr-61 or COX-2 was associated with invasion, lymph node metastasis, distant metastases, poor histological differentiation, advanced TNM stage and lower 5-year survival rate (all p < 0.05). Both Cyr-61 and COX-2 high expressions [hazard ratio (HR) = 31.8, 95 % confidence interval (CI) 4.09-246.8] was associated the higher risk of death during 5 years follow up than single Cyr-61 high expression (HR = 4.1, 95 % CI 1.5-11.6) or COX-2 high expression (HR = 2.9, 95 % CI 1.06-7.8). CONCLUSIONS: Cyr 61 and COX-2 expressions are associated with the progression of gastric cancer. Additionally, combined expressions of Cyr-61 and COX-2 has a higher prognostic value than single expression. PMID- 27457109 TI - Increasing access to care for young adults with cancer: Results of a quality improvement project using a novel telemedicine approach to supportive group psychotherapy. AB - OBJECTIVE: Young adults with cancer experience high levels of psychological distress. Group interventions for cancer patients have been effective in reducing levels of psychological distress but suffer from high levels of attrition and serve a limited geographic area. In a quality-improvement project, we converted an existing in-person support group to a telemedicine format in the hopes of improving attendance and reducing geographic disparities in access to care. METHOD: Eight young adults (18-40 years) with cancer were recruited from across Colorado. Participants received a tablet equipped with Wi-Fi and downloaded an HIPAA-compliant video-conferencing application. Participants attended six weekly supportive psychotherapy sessions. RESULTS: Participants found the group to be beneficial: the technology worked, they enjoyed the group format, and they would recommend it to others. The novel treatment interface allowed for low attrition rates due to the flexibility of a patient's location during the intervention. It allowed for provision of services to a geographically diverse population of medically ill young adults, as participants lived an average of 148 miles from the cancer center (range = 25-406 miles). SIGNIFICANCE OF RESULTS: Internet-based mental health care is an area of growing interest for providers, but few studies have evaluated its efficacy in patients with cancer, and even fewer in young adults with cancer. Incorporating technological advances into clinical practice will increase access to care, reduce geographic health disparities, and provide more consistent services. PMID- 27457111 TI - Nitrofurantoin vs other prophylactic agents in reducing recurrent urinary tract infections in adult women: a systematic review and meta-analysis. AB - BACKGROUND: The clinical and financial burden from bladder infections is significant. Daily antibiotic use is the recommended strategy for recurrent urinary tract infection prevention. Increasing antibiotic resistance rates, however, require immediate identification of innovative alternative prophylactic therapies. This systematic review aims to provide guidance on gaps in evidence to guide future research. OBJECTIVE: The objective of this review was to provide current pooled estimates of randomized control trials comparing the effects of nitrofurantoin vs other agents in reducing recurrent urinary tract infections in adult, nonpregnant women and assess relative adverse side effects. DATA SOURCES: Data sources included the following: MEDLINE, Jan. 1, 1946, to Jan. 31, 2015; Cochrane Central Register of Controlled Trials the Cochrane Database of Systematic Reviews, and web sites of the National Institute for Clinical Excellence, and the National Guideline Clearinghouse from 2000 to 2015. Randomized control trials of women with recurrent urinary tract infections comparing nitrofurantoin with any other treatment were included. STUDY DESIGN: A protocol for the study was developed a priori. Published guidance was followed for assessment of study quality. All meta-analyses were performed using random effects models with Stats Direct Software. Dual review was used for all decisions and data abstraction. RESULTS: Twelve randomized control trials involving 1063 patients were included. One study that had a serious flaw was rated poor in quality, one study rated good, and the remainder fair. No significant differences in prophylactic antibiotic treatment with nitrofurantoin and norfloxacin, trimethoprim, sulfamethoxazole/trimethoprim, methamine hippurate, estriol, or cefaclor were found in clinical or microbiological cure in adult nonpregnant women with recurrent urinary tract infections (9 randomized control trials, 673 patients, relative risk ratio, 1.06; 95% confidence interval, 0.89-1.27; I2, 65%; and 12 randomized control trials, 1063 patients, relative risk ratio, 1.06; 95% confidence interval, 0.90-1.26; I2, 76%, respectively). Duration of prophylaxis also did not have a significant impact on outcomes. There was a statistically significant difference in overall adverse effects, with nitrofurantoin resulting in greater risk than other prophylactic treatments (10 randomized control trials, 948 patients, relative risk ratio, 2.17; 95% confidence interval, 1.34-3.50; I2, 61%). Overall, the majority of nitrofurantoin adverse effects were gastrointestinal, with a significant difference for withdrawals (12 randomized control trials, 1063 patients, relative risk ratio, 2.14; 95% confidence interval, 1.28-3.56; I2, 8%). CONCLUSION: Nitrofurantoin had similar efficacy but a greater risk of adverse events than other prophylactic treatments. Balancing the risks of adverse events, particularly gastrointestinal symptoms, with potential benefits of decreasing collateral ecological damage should be considered if selecting nitrofurantoin. PMID- 27457110 TI - Junctional bradycardia is a potential risk factor of stroke. AB - BACKGROUND: This study aimed to determine the risk of thromboembolic events in patients with junctional bradycardia(JB). METHODS: We retrospectively reviewed electrocardiograms(ECGs) for 380,682 patients. Those with JB on an ECG at least twice over a >=3-month interval were included for analysis. We additionally included 138 CHADS2 score-matched patients(age, 68.4 +/- 15.7 years; male, 52.2%) in sinus rhythm as a control group. Between the JB patients(with or without retrograde P wave) and controls, we compared incidences of ischemic stroke and a composite of ischemic stroke, renal infarction, ischemic colitis, acute limb ischemia, and pulmonary embolism. RESULTS: Among 380,682 patients (age, 47.6 +/- 19.9 years; male, 49.3%), 69 patients (age, 68.5 +/- 16.5 years; male, 50.7%) exhibited JB on an ECG at least twice over a >=3-month interval; the overall prevalence of JB was 0.02%. The mean follow-up period was 27.2 +/- 26.2 months. Forty-five patients (65.2%) in the JB group had no retrograde P wave. Ischemic stroke incidence was significantly higher in JB patients without a retrograde P wave than in controls (6/45 patients [13.3%] and 3/138 patients [2.2%], respectively; P = 0.007). The incidence of composite thromboembolic events was also significantly higher in JB patients without a retrograde P wave than in controls (8/45 patients [17.8%] and 4/138 patients [2.9%], respectively; P = 0.011). In a Cox proportional hazards model, JB patients without a P wave showed a greater incidence of stroke (hazard ratio, 8.89 [2.20-33.01], P = 0.007) than controls and JB patients with a P wave. CONCLUSIONS: Junctional bradycardia is potentially associated with ischemic stroke, particularly in the absence of an identifiable retrograde P wave. PMID- 27457112 TI - Hospital delivery volume, severe obstetrical morbidity, and failure to rescue. AB - BACKGROUND: In the setting of persistently high risk for maternal death and severe obstetric morbidity, little is known about the relationship between hospital delivery volume and maternal outcomes. OBJECTIVE: The objectives of this analysis were (1) to determine maternal risk for severe morbidity during delivery hospitalizations by hospital delivery volume in the United States and (2) to characterize, by hospital volume, the risk for death in the setting of severe obstetric morbidity, a concept known as failure to rescue. STUDY DESIGN: This cohort study evaluated 50,433,539 delivery hospitalizations across the United States from 1998-2010. The main outcome measures were (1) severe morbidity that was defined as a composite of any 1 of 15 diagnoses that are representative of acute organ injury and critical illness and (2) failure to rescue that was defined as death in the setting of severe morbidity. RESULTS: The prevalence of severe morbidity rose from 471.2-751.5 cases per 100,000 deliveries from 1998 2010, which was an increase of 59.5%. Failure to rescue was highest in 1998 (1.5%), decreased to 0.6% in 2007, and rose to 0.9% in 2010. In models that were adjusted for comorbid risk and hospital factors, both low and high annualized delivery volume were associated with increased risk for failure to rescue and severe morbidity. However, the relative importance of hospital volume for both outcomes compared with other factors was relatively small. CONCLUSION: Although low-and high-delivery volume are associated with increased risk for both failure to rescue and severe maternal morbidity, other factors, in particular characteristics of individual centers, may be more important in the determination of outcomes. PMID- 27457113 TI - Maternal melatonin or N-acetylcysteine therapy regulates hydrogen sulfide generating pathway and renal transcriptome to prevent prenatal NG-Nitro-L arginine-methyl ester (L-NAME)-induced fetal programming of hypertension in adult male offspring. AB - BACKGROUND: Pregnancy is a critical time for fetal programming of hypertension. Nitric oxide deficiency during pregnancy causes hypertension in adult offspring. OBJECTIVE: We examined whether maternal melatonin or N-acetylcysteine therapy can prevent NG-nitro-L-arginine-methyl ester-induced fetal programming of hypertension in adult offspring. Next, we aimed to identify potential gatekeeper pathways that contribute to NG-nitro-L-arginine-methyl ester -induced programmed hypertension using the next generation RNA sequencing technology. STUDY DESIGN: Pregnant Sprague-Dawley rats were assigned to 4 groups: control, NG-nitro-L arginine-methyl ester, NG-nitro-L-arginine-methyl ester +melatonin, and NG-nitro L-arginine-methyl ester+N-acetylcysteine. Pregnant rats received NG-nitro-L arginine-methyl ester administration at 60 mg/kg/d subcutaneously during pregnancy alone, with additional 0.01% melatonin in drinking water, or with additional 1% N-acetylcysteine in drinking water during the entire pregnancy and lactation. Male offspring (n=8/group) were killed at 12 weeks of age. RESULTS: NG nitro-L-arginine-methyl ester exposure during pregnancy induced programmed hypertension in adult male offspring, which was prevented by maternal melatonin or N-acetylcysteine therapy. Protective effects of melatonin and N-acetylcysteine against NG-nitro-L-arginine-methyl ester-induced programmed hypertension were associated with an increase in hydrogen sulfide-generating enzymes and hydrogen sulfide synthesis in the kidneys. Nitric oxide inhibition by NG-nitro-L-arginine methyl ester in pregnancy caused >2000 renal transcripts to be modified during nephrogenesis stage in 1-day-old offspring kidney. Among them, genes belong to the renin-angiotensin system, and arachidonic acid metabolism pathways were potentially involved in the NG-nitro-L-arginine-methyl ester-induced programmed hypertension. However, melatonin and N-acetylcysteine reprogrammed the renin angiotensin system and arachidonic acid pathway differentially. CONCLUSION: Our results indicated that antioxidant therapy, by melatonin or N-acetylcysteine, in pregnant rats with nitric oxide deficiency can prevent programmed hypertension in male adult offspring. Early intervention with specific antioxidants that target redox imbalance in pregnancy to reprogram hypertension may well allow us to reduce the future burden of hypertension. The roles of transcriptome changes that are induced by NG-nitro-L-arginine-methyl ester in the offspring kidney require further clarification. PMID- 27457114 TI - Metabolic screening in patients with polycystic ovary syndrome is largely underutilized among obstetrician-gynecologists. AB - Women with polycystic ovary syndrome have substantially higher rates of insulin resistance, impaired glucose tolerance, type 2 diabetes, dyslipidemia, and metabolic syndrome when compared with women without the disease. Given the high prevalence of these comorbidities, guidelines issued by the American College of Obstetricians and Gynecologists and the Endocrine Society recommend that all women with polycystic ovary syndrome undergo screening for impaired glucose tolerance and dyslipidemia with a 2 hour 75 g oral glucose tolerance test and fasting lipid profile upon diagnosis and also undergo repeat screening every 2-5 years and every 2 years, respectively. Although a hemoglobin A1C and/or fasting glucose are widely used screening tests for diabetes, both the American College of Obstetricians and Gynecologists and the Endocrine Society preferentially recommend the 2 hour oral glucose tolerance test in women with polycystic ovary syndrome as a superior indicator of impaired glucose tolerance/diabetes mellitus. However, we found that gynecologists underutilize current recommendations for metabolic screening in women with polycystic ovary syndrome. In an online survey study targeting American College of Obstetricians and Gynecologists fellows and junior fellows, 22.3% of respondents would not order any screening test at the initial visit for at least 50% of their patients with polycystic ovary syndrome. The most common tests used to screen for impaired glucose tolerance in women with polycystic ovary syndrome were hemoglobin A1C (51.0%) and fasting glucose (42.7%). Whereas 54.1% would order a fasting lipid profile in at least 50% of their polycystic ovary syndrome patients, only 7% of respondents order a 2 hour oral glucose tolerance test. We therefore call for increased efforts to encourage obstetrician-gynecologists to address metabolic abnormalities in their patients with polycystic ovary syndrome. Such efforts should include education of physicians early in their careers, at the medical student and resident level. Efforts should also include implementation of continuing medical education activities, both locally and at the national level, to improve understanding of the metabolic implications of polycystic ovary syndrome. Electronic medical record systems should be utilized to generate prompts for appropriate screening tests in patients with a diagnosis of polycystic ovary syndrome. Because obstetrician-gynecologists may be the only physicians seen by many polycystic ovary syndrome patients, particularly those in their young reproductive years, such interventions could effectively promote optimal preventative health care and early diagnosis of metabolic comorbidities in these at-risk women. PMID- 27457115 TI - Follow-up of women with cervical cytological abnormalities showing atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion: a nationwide cohort study. AB - BACKGROUND: Atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion in abnormal cervical cytology among young women in cervical cancer screening is an increasing health burden, and comparative effectiveness studies of different management options for such diagnoses are needed. OBJECTIVE: The objective of the study was to compare the incidence of invasive cervical cancer, following different management options pursued after an atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion index smear. STUDY DESIGN: In this nationwide cohort study, we included all women aged 22-50 years and resident in Sweden 1989-2011 and with at least 1 cervical smear registered during the study period (n = 2,466,671). Follow-up of a first atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion cytological diagnosis within 25 months was classified as repeat cytology, colposcopy/biopsy, or without further assessment. Incidence rate ratios and 95% confidence intervals of subsequent cervical cancer within 6.5 years following atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion were estimated using Poisson regression by age group and management strategy. RESULTS: Women managed with repeat cytology within 6 months after atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cytology had a similar risk of cervical cancer compared with colposcopy/biopsy (incidence rate ratio, 1.1, 95% confidence interval, 0.5-2.5, and incidence rate ratio, 2.0, 95% confidence interval, 0.6-6.5, respectively) among women aged 22 27 years. For women aged 28 years and older, women managed with repeat cytology had a higher risk for cervical cancer than women managed with colposcopy/biopsy. CONCLUSION: Our findings suggest that women with a first cytological diagnosis of atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion up to age 27 years may indeed be safely followed up with repeat cytology within 6 months. A large amount of colposcopies that are currently performed in this group, therefore, could safely be discontinued. PMID- 27457116 TI - Adult Comorbidity Evaluation 27 score as a predictor of survival in endometrial cancer patients. AB - BACKGROUND: The incidence of endometrial cancer increases with age and is associated with medical comorbidities such as obesity and diabetes. Although a few cohort studies of <500 patients showed an association between comorbidity and survival in patients with endometrial cancer, the degree of association must be better described. The Adult Comorbidity Evaluation 27 is a validated comorbidity instrument that provides a score of 0-3 based on the number of and severity of medical comorbidities. OBJECTIVE: This study was performed to explore the association between medical comorbidities and survival of patients with endometrial cancer. STUDY DESIGN: Patients who were diagnosed with endometrial cancer from 2000-2012 were identified from the prospectively maintained Siteman Cancer Center tumor registry. Patients who underwent primary surgical treatment for endometrioid, serous, and clear cell endometrial carcinoma were included. Patients who primarily were treated with radiation, chemotherapy, or hormone therapy were excluded. Patients with uterine sarcomas or neuroendocrine tumors were excluded. Patients with missing Adult Comorbidity Evaluation 27 scores were also excluded from analysis. Information that included patient demographics, Adult Comorbidity Evaluation 27 score, tumor characteristics, adjuvant treatment, and survival data were extracted from the database. The association of Adult Comorbidity Evaluation 27 and overall and recurrence-free survival was explored in a multivariable Cox regression analysis after being controlled for variables that have been found to be associated significantly with survival in univariable analysis. RESULTS: A total of 2073 patients with a median age of 61 years (range, 20-94 years) at diagnosis were identified. The Adult Comorbidity Evaluation 27 score was 0, 1, 2, and 3 in 22%, 38%, 28%, and 12% of patients, respectively. Stage distribution was I (73%), II (5%), III (15%), and IV (7%), and grade distribution was 1 (52%), 2 (23%), and 3 (25%). Most patients had endometrioid histologic condition (87%) followed by serous (11%) and clear cell (3%) endometrial carcinoma. The median overall survival time for the entire cohort was 54 months (95% confidence interval, 3-154 months), and the median recurrence-free survival was 50 months (95% confidence interval, 2-154 months). On univariable analysis, age, race, marital status, stage, grade, histologic condition, and treatment type were associated significantly with overall survival and recurrence free survival. After adjustment for these covariates, patients with an Adult Comorbidity Evaluation 27 score of 2 had a 52% higher risk of death (95% confidence interval, 1.16-2.00); patients with an Adult Comorbidity Evaluation 27 score of 3 had a 2.35-fold increased risk of death (95% confidence interval, 1.73 3.21) compared with patients with an Adult Comorbidity Evaluation 27 score of 0. Similarly, patients with an Adult Comorbidity Evaluation 27 score of 2 had a 38% higher risk of recurrence (95% confidence interval, 1.07-1.78); patients with Adult Comorbidity Evaluation 27 score of 3 had a 2.05-fold increased risk of recurrence (95% confidence interval, 1.53-2.75) compared with patients with an Adult Comorbidity Evaluation 27 score of 0. We found no interaction between Adult Comorbidity Evaluation 27 score and age, stage, or treatment type. CONCLUSION: Our findings demonstrate the importance of comorbidities in the estimation of the prognosis of patients with endometrial cancer, even after adjustment for age and known tumor-specific prognostic factors such as stage, grade, histologic condition, and adjuvant treatment. PMID- 27457117 TI - Early-onset preeclampsia appears to discourage subsequent pregnancy but the risks may be overestimated. AB - BACKGROUND: Early-onset preeclampsia is associated with adverse maternal and perinatal outcomes. For women who consider another pregnancy after one complicated by early-onset preeclampsia, the likelihood of recurrence and the subsequent pregnancy outcome for themselves and their babies are pertinent considerations. OBJECTIVES: The purpose of this study was to determine the subsequent pregnancy rate after a nulliparous pregnancy that was complicated by early-onset preeclampsia and among those who have a subsequent pregnancy, the risk of recurrence by gestational week, and adverse pregnancy outcomes. STUDY DESIGN: This was a population-based record linkage cohort study. The study population included nulliparous women with a singleton pregnancy and early-onset preeclampsia (<34 weeks gestation) who gave birth in New South Wales Australia from 2001-2010 (the index birth), with follow-up data for a subsequent birth through 2012. Early-onset in the index birth was further categorized as <28 vs 28 33 weeks gestation. Subsequent pregnancy outcomes that were assessed included the pregnancy rate, preeclampsia recurrence, and maternal and perinatal morbidity and mortality rates. The risk of preeclampsia necessitating delivery at each gestational week for women who were at risk was plotted, and the net gain or loss of gestational age when comparing the index with the subsequent pregnancy was calculated. RESULTS: Among 361,031 nulliparous women with singleton pregnancies, 1473 (0.4%) had early-onset preeclampsia. Women with early-onset preeclampsia in their first pregnancy had a lower subsequent pregnancy rate (59.7%) than women without preeclampsia (67.7%). Of the 758 women with a subsequent singleton birth, 256 (33.8%) experienced preeclampsia in the next pregnancy; 57 women (7.5%) with recurrent early-onset preeclampsia were included. Cumulative rates of preeclampsia in the subsequent pregnancy were higher at every gestation from 23 weeks gestation when the index birth was <28 weeks compared with 28-33 weeks gestation. The cumulative rate and gestation-specific risk of recurrent preeclampsia rose most steeply at 32-38 weeks gestation. Most women (94.6%) progressed to a later gestational age in their subsequent pregnancy. The median overall increase in gestational age at delivery was 6 weeks (interquartile range, 4-8); among women with recurrent preeclampsia, the median increase was 5 weeks (interquartile range, 2-7). Women with index birth <28 weeks gestation compared with 28-33 weeks gestation were more likely to deliver preterm (38.8% vs 28.7%; relative risk, 1.35; 95% confidence interval, 1.04-1.75) and have a perinatal death (4.3% vs 1.2%; relative risk, 3.46; 95% confidence interval, 1.15-10.39) at the subsequent birth, but live born infants had similar rates of severe morbidity (17.1% vs 15.0%; relative risk, 1.14; 95% confidence interval, 0.73-1.79). CONCLUSION: Women with early-onset preeclampsia in a first pregnancy appear less likely than women without preeclampsia to have a subsequent pregnancy. Maternal and perinatal outcomes in the subsequent pregnancy are generally better than in the first; most women will not have recurrent preeclampsia, and those who do usually will give birth at a greater gestational age compared with their index birth. PMID- 27457118 TI - Immune activation enhances epithelial nerve growth in provoked vestibulodynia. AB - BACKGROUND: Provoked vestibulodynia manifests as allodynia of the vulvar vestibular mucosa. The exact mechanisms that result in altered pain sensation are unknown. Recently, we demonstrated the presence of secondary lymphoid tissue, which is the vestibule-associated lymphoid tissue in the vestibular mucosa, and showed that this tissue becomes activated in provoked vestibulodynia. OBJECTIVE: The purpose of this study was to examine whether expression of intraepithelial nerve fibers and nerve growth factor are related to immune activation in provoked vestibulodynia. STUDY DESIGN: Vestibular mucosal specimens were obtained from 27 patients with severe provoked vestibulodynia that was treated by vestibulectomy and from 15 control subjects. We used antibodies against the protein gene product 9.5, the neuron specific neurofilament, and nerve growth factor for immunohistochemistry to detect intraepithelial nerve fibers and nerve growth factor expressing immune cells in the vestibular mucosa. For intraepithelial nerve fibers, we determined their linear density (fiber counts per millimeter of the outer epithelial surface, protein gene product 9.5) or presence (neuron specific neurofilament). Nerve growth factor was analyzed by counting the staining-positive immune cells. Antibodies against CD20 (B lymphocytes) and CD3 (T lymphocytes) were used to identify and locate mucosal areas with increased density of lymphocytes and the presence of germinal centers (ie, signs of immune activation). B-cell activation index was used to describe the overall intensity of B-cell infiltration. RESULTS: We found more protein gene product 9.5-positive intraepithelial fibers in vestibulodynia than in the control samples (6.3/mm [range, 0.0-15.8] vs 2.0/mm [range, 0.0-12.0]; P=.006). Neuron specific neurofilament -positive intraepithelial fibers were found in 17 of 27 vestibulodynia cases (63.0%) and in none of the control cases. Protein gene product 9.5-positive intraepithelial fibers were more common in samples with more pronounced immune activation. The density of these fibers was higher in samples with than without germinal centers (6.1/mm [range, 4.3-15.8] vs 3.0/mm [range, 0.0-13.4]; P=.020). A positive correlation between the fiber density and B-cell activation index score of the sample was found (Spearman's Rho, 0.400; P=.004; R2=0.128). No significant difference, however, was found in the density or presence of nerve fibers between samples with high and low T-cell densities. We identified areas of minor and major vestibular glands in 16 of the patient samples and in 1 control sample. Protein gene product 9.5-positive nerve fibers were found more often in glandular epithelium surrounded by B-cell infiltration than in glands without B cells (P=.013). Also, the presence of neuron specific neurofilament-positive fibers in glandular epithelium was associated with B-cell infiltrates (P=.053). Nerve growth factor-positive immune cells were more common in mucosal areas with than without B-cell infiltration and intraepithelial nerve fibers. CONCLUSION: Excessive epithelial nerve growth in provoked vestibulodynia is associated with increased B-cell infiltration and the presence of germinal centers. This supports the fundamental role of immune activation in provoked vestibulodynia. PMID- 27457120 TI - The interdigitating Y-plasty procedure for the correction of transverse vaginal septa. AB - : Transverse vaginal septa are rare congenital abnormalities of the female genital tract, the surgical management of which is hardly described in the literature. While thicker septa might require complex reconstructive surgery, this paper proposes a simple technique for the surgical management of thin septa, utilising two interdigitating Y-plasties, without the need for excision of any septal tissue. The authors also present their series of eight consecutive cases where this technique was used, with no major complications or any cases of vaginal re-stenosis. This technique can also be used in imperforate hymen correction, therefore it might also be of interest to the general gynaecologist. TWEETABLE ABSTRACT: Interdigitating Y-plasties in transverse vaginal septa: presentation of a new technique. PMID- 27457121 TI - The relationship between functional magnetic resonance imaging activation, diffusion tensor imaging, and training effects. AB - While the relationship between diffusion tensor imaging (DTI) measurements and training effects is explored by Voelker et al. (this issue), a cursory discussion of functional magnetic resonance imaging (fMRI) measurements categorizes increased activation with findings of greater white matter integrity. Evidence of the relationship between fMRI activation and white matter integrity is conflicting, as is the relationship between fMRI activation and training effects. An examination of the changes in fMRI activation in response to training is helpful, but the relationship between DTI and fMRI activation, particularly in the context of white matter changes, must be examined further before general conclusions can be drawn. PMID- 27457122 TI - The Structure and Catalytic Mechanism of Sorghum bicolor Caffeoyl-CoA O Methyltransferase. AB - Caffeoyl-coenzyme A 3-O-methyltransferase (CCoAOMT) is an S-adenosyl methionine (SAM)-dependent O-methyltransferase responsible for methylation of the meta hydroxyl group of caffeoyl-coenzyme A (CoA) on the pathway to monolignols, with their ring methoxylation status characteristic of guaiacyl or syringyl units in lignin. In order to better understand the unique class of type 2 O methyltransferases from monocots, we have characterized CCoAOMT from sorghum (Sorghum bicolor; SbCCoAOMT), including the SAM binary complex crystal structure and steady-state enzyme kinetics. Key amino acid residues were validated with site-directed mutagenesis. Isothermal titration calorimetry data indicated a sequential binding mechanism for SbCCoAOMT, wherein SAM binds prior to caffeoyl CoA, and the enzyme showed allosteric behavior with respect to it. 5 Hydroxyferuloyl-CoA was not a substrate for SbCCoAOMT. We propose a catalytic mechanism in which lysine-180 acts as a catalytic base and deprotonates the reactive hydroxyl group of caffeoyl-CoA. This deprotonation is facilitated by the coordination of the reactive hydroxyl group by Ca(2+) in the active site, lowering the pKa of the 3'-OH group. Collectively, these data give a new perspective on the catalytic mechanism of CCoAOMTs and provide a basis for the functional diversity exhibited by type 2 plant OMTs that contain a unique insertion loop (residues 208-231) conferring affinity for phenylpropanoid-CoA thioesters. The structural model of SbCCoAOMT can serve as the basis for protein engineering approaches to enhance the nutritional, agronomic, and industrially relevant properties of sorghum. PMID- 27457123 TI - Integrative Analyses of Nontargeted Volatile Profiling and Transcriptome Data Provide Molecular Insight into VOC Diversity in Cucumber Plants (Cucumis sativus). AB - Plant volatile organic compounds, which are generated in a tissue-specific manner, play important ecological roles in the interactions between plants and their environments, including the well-known functions of attracting pollinators and protecting plants from herbivores/fungi attacks. However, to date, there have not been reports of holistic volatile profiling of the various tissues of a single plant species, even for the model plant species. In this study, we qualitatively and quantitatively analyzed 85 volatile chemicals, including 36 volatile terpenes, in 23 different tissues of cucumber (Cucumis sativus) plants using solid-phase microextraction combined with gas chromatography-mass spectrometry. Most volatile chemicals were found to occur in a highly tissue specific manner. The consensus transcriptomes for each of the 23 cucumber tissues were generated with RNA sequencing data and used in volatile organic compound gene correlation analysis to screen for candidate genes likely to be involved in cucumber volatile biosynthetic pathways. In vitro biochemical characterization of the candidate enzymes demonstrated that TERPENE SYNTHASE11 (TPS11)/TPS14, TPS01, and TPS15 were responsible for volatile terpenoid production in the roots, flowers, and fruit tissues of cucumber plants, respectively. A functional heteromeric geranyl(geranyl) pyrophosphate synthase, composed of an inactive small subunit (type I) and an active large subunit, was demonstrated to play a key role in monoterpene production in cucumber. In addition to establishing a standard workflow for the elucidation of plant volatile biosynthetic pathways, the knowledge generated from this study lays a solid foundation for future investigations of both the physiological functions of cucumber volatiles and aspects of cucumber flavor improvement. PMID- 27457124 TI - Genome-Wide Targets Regulated by the OsMADS1 Transcription Factor Reveals Its DNA Recognition Properties. AB - OsMADS1 controls rice (Oryza sativa) floral fate and organ development. Yet, its genome-wide targets and the mechanisms underlying its role as a transcription regulator controlling developmental gene expression are unknown. We identify 3112 gene-associated OsMADS1-bound sites in the floret genome. These occur in the vicinity of transcription start sites, within gene bodies, and in intergenic regions. Majority of the bound DNA contained CArG motif variants or, in several cases, only A-tracts. Sequences flanking the binding peak had a higher AT nucleotide content, implying that broader DNA structural features may define in planta binding. Sequences for binding by other transcription factor families like MYC, AP2/ERF, bZIP, etc. are enriched in OsMADS1-bound DNAs. Target genes implicated in transcription, chromatin remodeling, cellular processes, and hormone metabolism were enriched. Combining expression data from OsMADS1 knockdown florets with these DNA binding data, a snapshot of a gene regulatory network was deduced where targets, such as AP2/ERF and bHLH transcription factors and chromatin remodelers form nodes. We show that the expression status of these nodal factors can be altered by inducing the OsMADS1-GR fusion protein and present a model for a regulatory cascade where the direct targets of OsMADS1, OsbHLH108/SPT, OsERF034, and OsHSF24, in turn control genes such as OsMADS32 and OsYABBY5 This cascade, with other similar relationships, cumulatively contributes to floral organ development. Overall, OsMADS1 binds to several regulatory genes and, probably in combination with other factors, controls a gene regulatory network that ensures rice floret development. PMID- 27457125 TI - Flowering Time-Regulated Genes in Maize Include the Transcription Factor ZmMADS1. AB - Flowering time (FTi) control is well examined in the long-day plant Arabidopsis (Arabidopsis thaliana), and increasing knowledge is available for the short-day plant rice (Oryza sativa). In contrast, little is known in the day-neutral and agronomically important crop plant maize (Zea mays). To learn more about FTi and to identify novel regulators in this species, we first compared the time points of floral transition of almost 30 maize inbred lines and show that tropical lines exhibit a delay in flowering transition of more than 3 weeks under long-day conditions compared with European flint lines adapted to temperate climate zones. We further analyzed the leaf transcriptomes of four lines that exhibit strong differences in flowering transition to identify new key players of the flowering control network in maize. We found strong differences among regulated genes between these lines and thus assume that the regulation of FTi is very complex in maize. Especially genes encoding MADS box transcriptional regulators are up regulated in leaves during the meristem transition. ZmMADS1 was selected for functional studies. We demonstrate that it represents a functional ortholog of the central FTi integrator SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) of Arabidopsis. RNA interference-mediated down-regulation of ZmMADS1 resulted in a delay of FTi in maize, while strong overexpression caused an early-flowering phenotype, indicating its role as a flowering activator. Taken together, we report that ZmMADS1 represents a positive FTi regulator that shares an evolutionarily conserved function with SOC1 and may now serve as an ideal stating point to study the integration and variation of FTi pathways also in maize. PMID- 27457127 TI - Resolution enhancement using plasmonic metamask for wafer-scale photolithography in the far field. AB - Resolution enhancement in far-field photolithography is demonstrated using a plasmonic metamask in the proximity regime, in which Fresnel diffraction is dominant. The transverse magnetic component of the diffracted wave from the photomask, which reduces the pattern visibility and lowers the resolution, was successfully controlled by coupling with the anti-symmetric mode of the excited surface plasmon. We obtained a consistently finely-patterned photoresist surface at a distance of up to 15 MUm from the mask surface for 3-MUm-pitch slits because of conserved field visibility when propagating from the near-field to the proximity regime. We confirmed that sharp edge patterning is indeed possible when using a wafer-scale photomask in the proximity photolithography regime. Our plasmonic metamask method produces cost savings for ultra-large-scale high density display fabrication by maintaining longer photomask lifetimes and by allowing sufficient tolerance for the distance between the photomask and the photoresist. PMID- 27457126 TI - Photoperiod-H1 (Ppd-H1) Controls Leaf Size. AB - Leaf size is a major determinant of plant photosynthetic activity and biomass; however, it is poorly understood how leaf size is genetically controlled in cereal crop plants like barley (Hordeum vulgare). We conducted a genome-wide association scan for flowering time, leaf width, and leaf length in a diverse panel of European winter cultivars grown in the field and genotyped with a single nucleotide polymorphism array. The genome-wide association scan identified PHOTOPERIOD-H1 (Ppd-H1) as a candidate gene underlying the major quantitative trait loci for flowering time and leaf size in the barley population. Microscopic phenotyping of three independent introgression lines confirmed the effect of Ppd H1 on leaf size. Differences in the duration of leaf growth and consequent variation in leaf cell number were responsible for the leaf size differences between the Ppd-H1 variants. The Ppd-H1-dependent induction of the BARLEY MADS BOX genes BM3 and BM8 in the leaf correlated with reductions in leaf size and leaf number. Our results indicate that leaf size is controlled by the Ppd-H1- and photoperiod-dependent progression of plant development. The coordination of leaf growth with flowering may be part of a reproductive strategy to optimize resource allocation to the developing inflorescences and seeds. PMID- 27457128 TI - Loss-of-function screening to identify miRNAs involved in senescence: tumor suppressor activity of miRNA-335 and its new target CARF. AB - Significance of microRNAs (miRs), small non-coding molecules, has been implicated in a variety of biological processes. Here, we recruited retroviral insertional mutagenesis to obtain induction of an arbitrary noncoding RNAs, and coupled it with a cell based loss-of-function (5-Aza-2'-deoxycytidine (5Aza-dC)-induced senescence bypass) screening system. Cells that escaped 5-Aza-dC-induced senescence were subjected to miR-microarray analysis with respect to the untreated control. We identified miR-335 as one of the upregulated miRs. In order to characterize the functional significance, we overexpressed miR-335 in human cancer cells and found that it caused growth suppression. We demonstrate that the latter accounted for inhibition of 5-Aza-dC incorporation into the cell genome, enabling them to escape from induction of senescence. We also report that CARF (Collaborator of ARF) is a new target of miR-335 that regulates its growth suppressor function by complex crosstalk with other proteins including p16(INK4A), pRB, HDM2 and p21(WAF1). PMID- 27457129 TI - Monitoring the impact of a national school based deworming programme on soil transmitted helminths in Kenya: the first three years, 2012 - 2014. AB - BACKGROUND: In 2012, the Kenyan Ministries of Health and of Education began a programme to deworm all school-age children living in areas at high risk of soil transmitted helminths (STH) and schistosome infections. The impact of this school based mass drug administration (MDA) programme in Kenya is monitored by the Kenya Medical Research Institute (KEMRI) as part of a five-year (2012-2017) study. This article focuses on the impact of MDA on STH infections and presents the overall achieved reductions from baseline to mid-term, as well as yearly patterns of reductions and subsequent re-infections per school community. METHODS: The study involved a series of pre- and post-intervention, repeat cross-sectional surveys in a representative, stratified, two-stage sample of schools across Kenya. The programme contained two tiers of monitoring; a national baseline and mid-term survey including 200 schools, and surveys conducted among 60 schools pre- and post-intervention. Stool samples were collected from randomly selected school children and tested for helminth infections using Kato-Katz technique. The prevalence and mean intensity of each helminth species were calculated at the school and county levels and 95 % confidence intervals (CIs) were obtained by binomial and negative binomial regression, respectively, taking into account clustering by schools. RESULTS: The overall prevalence of STH infection at baseline was 32.3 % (hookworms: 15.4 %; Ascaris lumbricoides: 18.1 %; and Trichuris trichiura: 6.7 %). After two rounds of MDA, the overall prevalence of STH had reduced to 16.4 % (hookworms: 2.3 %; A. lumbricoides: 11.9 %; and T. trichiura: 4.5 %). The relative reductions of moderate to heavy intensity of infections were 33.7 % (STH combined), 77.3 % (hookworms) and 33.9 % (A. lumbricoides). For T. trichiura, however, moderate to heavy intensity of infections increased non-significantly by 18.0 % from baseline to mid-term survey. CONCLUSION: The school-based deworming programme has substantially reduced STH infections, but because of ongoing transmission additional strategies may be required to achieve a sustained interruption of transmission. PMID- 27457130 TI - Enhancing Intrinsic Stability of Hybrid Perovskite Solar Cell by Strong, yet Balanced, Electronic Coupling. AB - In the past few years, the meteoric development of hybrid organic-inorganic perovskite solar cells (PSC) astonished the community. The efficiency has already reached the level needed for commercialization; however, the instability hinders its deployment on the market. Here, we report a mechanism to chemically stabilize PSC absorbers. We propose to replace the widely used methylammonium cation (CH3NH3(+)) by alternative molecular cations allowing an enhanced electronic coupling between the cation and the PbI6 octahedra while maintaining the band gap energy within the suitable range for solar cells. The mechanism exploits establishing a balance between the electronegativity of the materials' constituents and the resulting ionic electrostatic interactions. The calculations demonstrate the concept of enhancing the electronic coupling, and hence the stability, by exploring the stabilizing features of CH3PH3(+), CH3SH2(+), and SH3(+) cations, among several other possible candidates. Chemical stability enhancement hence results from a strong, yet balanced, electronic coupling between the cation and the halides in the octahedron. This shall unlock the hindering instability problem for PSCs and allow them to hit the market as a serious low-cost competitor to silicon based solar cell technologies. PMID- 27457131 TI - Impact of nitrogen feeding regulation on polyhydroxyalkanoates production by mixed microbial cultures. AB - A sequencing batch reactor (SBR) is typically used for selecting mixed microbial cultures (MMC) for polyhydroxyalkanoate (PHA) production. Since many waste streams suitable as process feedstock for PHA production are nitrogen-deficient, a nutrient supply in the SBR is typically required to allow for efficient microbial growth. The scope of this study was to devise a nitrogen feeding strategy which allows controlling the nitrogen levels during the feast and famine regime of a lab-scale SBR, thereby selecting for PHA-storing microorganisms. At the beginning of the cycle the reactor was fed with a synthetic mixture of acetic and propionic acids at an overall organic load rate of 8.5gCODL-1d-1 (i.e. 260CmmolL-1d-1), whereas nitrogen (in the form of ammonium sulphate) was added either simultaneously to the carbon feed (coupled feeding strategy) or after the end of the feast phase (uncoupled feeding strategy). As a main result, PHA production was more than doubled (up to about 1300+/-64mgCODL-1) when carbon and nitrogen were separately fed and the higher PHA production also corresponded to an 82% increase in the polymer HV content (up to 20+/-1%, wtwt-1). Three SBR runs were performed with the uncoupled carbon and nitrogen feeding at different carbon to nitrogen (C/N) ratios (of 14.3, 17.9, and 22.3CmolNmol-1, respectively) which were varied by progressively reducing the concentration of the nitrogen feeding. In spite of a comparable PHA storage yield at 14.3 and 17.9CmolNmol-1 (0.41+/ 0.05 gCODPHA gCODVFA-1 and 0.38+/-0.05 gCODPHA gCODVFA-1, respectively), the storage response of the selected MMC significantly decreased when the C/N ratio was set at the highest investigated value. Notably, an increase in this parameter also resulted in a change in the HV content in the polymer regardless the composition of the organic acids solution. PMID- 27457132 TI - Cutaneous apocrine carcinoma on the scalp after cranial irradiation for acute lymphocytic leukaemia. PMID- 27457134 TI - Changes in default mode network as automaticity develops in a categorization task. AB - The default mode network (DMN) is a set of brain regions in which blood oxygen level dependent signal is suppressed during attentional focus on the external environment. Because automatic task processing requires less attention, development of automaticity in a rule-based categorization task may result in less deactivation and altered functional connectivity of the DMN when compared to the initial learning stage. We tested this hypothesis by re-analyzing functional magnetic resonance imaging data of participants trained in rule-based categorization for over 10,000 trials (Helie et al., 2010) [12,13]. The results show that some DMN regions are deactivated in initial training but not after automaticity has developed. There is also a significant decrease in DMN deactivation after extensive practice. Seed-based functional connectivity analyses with the precuneus, medial prefrontal cortex (two important DMN regions) and Brodmann area 6 (an important region in automatic categorization) were also performed. The results show increased functional connectivity with both DMN and non-DMN regions after the development of automaticity, and a decrease in functional connectivity between the medial prefrontal cortex and ventromedial orbitofrontal cortex. Together, these results further support the hypothesis of a strategy shift in automatic categorization and bridge the cognitive and neuroscientific conceptions of automaticity in showing that the reduced need for cognitive resources in automatic processing is accompanied by a disinhibition of the DMN and stronger functional connectivity between DMN and task-related brain regions. PMID- 27457133 TI - The role of the hippocampus in approach-avoidance conflict decision-making: Evidence from rodent and human studies. AB - The hippocampus (HPC) has been traditionally considered to subserve mnemonic processing and spatial cognition. Over the past decade, however, there has been increasing interest in its contributions to processes beyond these two domains. One question is whether the HPC plays an important role in decision-making under conditions of high approach-avoidance conflict, a scenario that arises when a goal stimulus is simultaneously associated with reward and punishment. This idea has its origins in rodent work conducted in the 1950s and 1960s, and has recently experienced a resurgence of interest in the literature. In this review, we will first provide an overview of classic rodent lesion data that first suggested a role for the HPC in approach-avoidance conflict processing and then proceed to describe a wide range of more recent evidence from studies conducted in rodents and humans. We will demonstrate that there is substantial, converging cross species evidence to support the idea that the HPC, in particular the ventral (in rodents)/anterior (in humans) portion, contributes to approach-avoidance conflict decision making. Furthermore, we suggest that the seemingly disparate functions of the HPC (e.g. memory, spatial cognition, conflict processing) need not be mutually exclusive. PMID- 27457135 TI - Individual differences in initial morphine sensitivity as a predictor for the development of opiate addiction in rats. AB - Individuals report a wide range of analgesia to similar doses of opiates, and not all opiate users become addicted. This suggests that there may be certain predispositions that influence one to develop opiate addiction. We investigated the relationship between the individual differences in initial morphine sensitivity and the subsequent development of opiate addiction-like behavior using a hot plate test and an intravenous morphine self-administration (MSA) paradigm in rats. Using a median split of initial morphine antinociception, animals were defined as low antinociception (LA) and high antinociception (HA) groups. Thus, the LA group represents the animals that were less sensitive to initial morphine antinociception as compared to those of the HA group. The animals were allowed to self-administer either saline or morphine (0.5mg/kg/infusion, 4hr/day) 5days per week for 3 weeks. Spontaneous locomotor activity was measured on self-administration days 10 and 15. Individual differences in initial morphine sensitivity were not correlated with the amount of morphine self-administered by the animals on day 1. In the second-week of MSA, the LA group exhibited increased morphine intake and locomotor hyperactivity as compared to those of the HA group. Therefore, certain animals that are less sensitive to initial morphine antinociception may be susceptible to developing opiate addiction. The current findings may have clinical implications for future research on the biological mechanisms of opiate addiction and preclinical medication development. PMID- 27457136 TI - The effect of surgery and intracerebral injections on motor skill learning in rats: results from a database analysis. AB - Male Long-Evans rats are often used to investigate neural mechanisms of learning in the motor system. Successful acquisition of a skilled motor task is influenced by various variables such as animal supplier and batch membership. In this retrospective analysis of our laboratory database, we investigate how head and brain surgery as well as intracerebral injections that were performed to address particular scientific questions affect motor learning. Overall, invasive interventions (n=90) slow the acquisition of a skilled-reaching task when compared to naive animals (n=184; P=0.01). With respect to subgroups, this detrimental effect widely differs between particular procedures: whereas epidural implantations of thin-film electrode arrays and punctual injection through pre implanted cannulas into primary motor cortex (M1) do not interfere with learning, skill acquisition is slowed after chronic infusion using osmotic minipumps into M1 and skill acquisition is lastingly impaired after bilateral cannula implantation within the dorsal striatum. In line with previous reports, breeder specific differences could be observed in the analysis of the overall population. In summary, interventions may impair learning-behavior in an unpredictable fashion. Thus, a comparison of behavioral data to a naive population is recommended to be aware of these drawbacks. PMID- 27457138 TI - Treating schizophrenia and supporting recovery: aligning clinician and patient goals. PMID- 27457139 TI - Monoamine oxidase inhibitors. PMID- 27457137 TI - Development and Testing of Shared Decision Making Interventions for Use in Emergency Care: A Research Agenda. AB - Decision aids are evidenced-based tools designed to increase patient understanding of medical options and possible outcomes, facilitate conversation between patients and clinicians, and improve patient engagement. Decision aids have been used for shared decision making (SDM) interventions outside of the ED setting for more than a decade. Their use in the ED has only recently begun to be studied. This article provides background on this topic and the conclusions of the 2016 Academic Emergency Medicine consensus conference SDM in practice work group regarding "Shared Decision Making in the Emergency Department: Development of a Policy-Relevant, Patient-Centered Research Agenda." The goal was to determine a prioritized research agenda for the development and testing of SDM interventions for use in emergency care that was most important to patients, clinicians, caregivers, and other key stakeholders. Using the nominal group technique, the consensus working group proposed prioritized research questions in six key domains: 1) content (i.e., clinical scenario or decision area), 2) level of evidence available, 3) tool design strategies, 4) risk communication, 5) stakeholders, and 6) outcomes. PMID- 27457141 TI - More than man's best friend: diagnostic dogs in psychiatry. PMID- 27457142 TI - Borderline personality disorder, depression, trauma and dissociation. PMID- 27457144 TI - From the President. PMID- 27457143 TI - Clozapine or antibiotic induced neutropenia? PMID- 27457147 TI - RANZCP award winners and new Fellows recognised during Congress. PMID- 27457146 TI - Congress welcomes 1300 delegates in Hong Kong and solidifies links with the Asian region. PMID- 27457148 TI - The College Medal of Honour - Professor Philip Boyce. PMID- 27457150 TI - The College Citation Conjoint Professor Bryanne E.W. Barnett AM. PMID- 27457149 TI - The Ian Simpson Award - Dr Matthew Eggleston. PMID- 27457151 TI - Engaging the next generation of psychiatrists. PMID- 27457154 TI - Parent Coping With Adolescent Trichotillomania. AB - Adolescents who struggle with trichotillomania (TTM; hairpulling disorder) are not alone, their parents also struggle. The focus of this qualitative study was to identify what parents (N = 30) perceive as stressful about parenting an adolescent with TTM and how they cope with these stressors. Parents described uncertainty about the course of the disorder and powerlessness in the ability to protect their adolescent from the reactions of others or assist them in curtailing the hairpulling as very distressing. Data analysis revealed eight coping strategies used to manage these stressors and the accompanying grief: (a) information gathering, (b) anticipatory guidance, (c) crying, (d) hypervigilance, (e) gaining emotional support from others, (f) acceptance, (g) goal revision, and (h) guiding rather than protecting their adolescent. The study findings can be used by school nurses to gain a deeper understanding of this disorder and to provide family-centered care in the school setting. PMID- 27457155 TI - Targeting the Dark Horse of complement: the first generation of functionally selective C5aR2 ligands. PMID- 27457157 TI - Editor's Notes. PMID- 27457159 TI - Scanning Sports. PMID- 27457158 TI - Noteworthy. PMID- 27457156 TI - Production of full-length soluble Plasmodium falciparum RH5 protein vaccine using a Drosophila melanogaster Schneider 2 stable cell line system. AB - The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has recently emerged as a leading candidate antigen against the blood-stage human malaria parasite. However it has proved challenging to identify a heterologous expression platform that can produce a soluble protein-based vaccine in a manner compliant with current Good Manufacturing Practice (cGMP). Here we report the production of full-length PfRH5 protein using a cGMP-compliant platform called ExpreS(2), based on a Drosophila melanogaster Schneider 2 (S2) stable cell line system. Five sequence variants of PfRH5 were expressed that differed in terms of mutagenesis strategies to remove potential N-linked glycans. All variants bound the PfRH5 receptor basigin and were recognized by a panel of monoclonal antibodies. Analysis following immunization of rabbits identified quantitative and qualitative differences in terms of the functional IgG antibody response against the P. falciparum parasite. The antibodies induced by one protein variant were shown to be qualitatively similar to responses induced by other vaccine platforms. This work identifies Drosophila S2 cells as a clinically-relevant platform suited for the production of 'difficult-to-make' proteins from Plasmodium parasites, and identifies a PfRH5 sequence variant that can be used for clinical production of a non-glycosylated, soluble full-length protein vaccine immunogen. PMID- 27457160 TI - new from ACSM. PMID- 27457163 TI - Coming in Sportsmedicine. PMID- 27457166 TI - Running Wild. PMID- 27457167 TI - Sportsmedicine Forum. AB - A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. PMID- 27457168 TI - Kids, Parents, and Sports: Some Questions and Answers. AB - In brief: This article summarizes the psychological research on youth sports and offers suggestions for advising young athletes, parents, and sports organizations. Specific topics include the psychological benefits and dangers of youth sports, competitive stress, and the optimum age for competition and sports specialization. PMID- 27457169 TI - Low Back Pain in a Tennis Player. AB - A group of experts met to discuss a case from the University of California, San Diego, School of Medicine. This case conference is part of a series featuring a variety of sports medicine topics. PMID- 27457170 TI - Acute Posttraumatic Pubic Symphysis Instability in an Athlete. AB - In brief: A 16-year-old high school football player and wrestler began experiencing groin and pubic pain, and a popping sensation with abduction movements, after sustaining an abduction injury to his lower extremities. Stress roentgenographs revealed instability of the pubic symphysis; there was no evidence of fracture or gross instability of the sacroiliac joints or the posterior sacrum. The patient was treated conservatively for one year, with an initial period of limited weight-bearing and rest followed by progressive stretching and strengthening exercises and a gradual return to full sports activity. PMID- 27457171 TI - Preparticipation Screening of Special Olympics Athletes. AB - In brief: Although preparticipation examinations are required for all Special Olympics athletes, information in the medical literature is limited concerning the difficulty in screening this group and in clearing them for competition. The results of 176 preparticipation exams are included in this report. The most striking finding was deficient visual acuity in half the athletes tested. Ruling out atlantoaxial subluxation in the athletes with Down's syndrome presented a special problem. The author suggests that the most effective method for screening Special Olympics athletes is a single-station/single-examiner format performed during school hours. She suggests improvements in the design of the consent forms to make physicians and parents aware of the special needs of these athletes. PMID- 27457172 TI - Resistance Training: Physiological Responses and Adaptations (Part 2 of 4). AB - In brief: Part 1 of this series of articles discussed basic concepts of resistance training. This article addresses selected physiological responses and adaptations to resistance training, including changes in muscle size, muscle enzymes, maximal oxygen consumption, connective tissue, and bone mineral content. Physiological responses and adaptations have been more thoroughly studied in endurance athletes than for those in resistance training programs. However, sufficient research has been conducted to discuss some of the specific responses and adaptations, which the authors do in this paper. PMID- 27457173 TI - Factors Associated With Shin Soreness in Athletes. AB - In brief: Twenty-five exercisers suffering from shin soreness were interviewed, examined, and monitored to identify factors associated with this injury. Twenty five uninjured persons who matched the injured subjects in age, sex, and activities served as controls. Injured subjects had a greater range of subtalar joint motion and increased ankle dorsiflexion, reported a significantly lower calcium intake, had raised their training intensity before injury, and were using worn or poorly made shoes when injured. Factors not associated with injury included number of months subjects had participated in weight-bearing exercise, exercise surface, amount of stretching, height-weight ratio, and menstrual status. This study is the first to indicate a possible relationship between nutrition and shin soreness. PMID- 27457174 TI - Energy Expenditure During Walking With Hand Weights. AB - In brief: Eleven obese adults (three men, eight women) performed three 30-minute walking sessions at 3.4 mph: normal walking, walking with increased arm movement, and walking with increased arm movement while holding hand weights. The purpose was to assess the additional energy expenditure induced by carrying hand weights. Walking with hand weights resulted in increased heart rate (127 vs 120 beats.min( 1)), increased VO2 (1.168 vs 1.086 L.min(-1)), and greater energy expenditure (171.5 vs 159.7 kcal) compared with normal walking. Fat use and recovery energy expenditures were similar in all exercise conditions. Increased arm movement while walking without weights resulted in no significant increases over normal walking. These results indicate that using hand weights increases the energy demands of walking, but only to a small degree. PMID- 27457175 TI - Proprioceptive Neuromuscular Facilitation Flexibility Techniques: Acute Effects on Arterial Blood Pressure. AB - In brief: For this study of the acute effects of stretching techniques on arterial blood pressure (ABP), 60 men were assigned to one of three treatment groups, each consisting of one modified proprioceptive neuromuscular facilitation (PNF) technique: hold-relax, contract-relax, and slow-reversal-hold-relax (SRHR). Flexibility and ABP data were collected from both baseline (passive stretch) and treatment measurements for each group. AH three treatments were more effective than the baseline stretch for increasing flexibility; the SRHR treatment provided the greatest flexibility. Increases in treatment ABPs were nonsignificant, compared with baseline measures. The authors conclude that the potential benefits of PNF may outweigh the risks of elevated ABP. PMID- 27457176 TI - Women's Weight Lifting: Elevating a Sport to World-Class Status. AB - The first women's world weight-lifting competition-held last fall in Daytona Beach, Florida-is evidence that the sport is growing and building its case for Olympic medal status. But little is known about the medical aspects of weight lifting for women. PMID- 27457178 TI - Where to Turn for Sports Injury Statistics. AB - THE PHYSICIAN AND SPORTSMEDICINE has developed the following list of government agencies, sports-related groups, and academic centers that are active in tracking sports injuries. While this is not a comprehensive list, it does provide a means for clinicians and researchers to obtain pertinent information on sports injuries. Organizations are arranged alphabetically. All correspondence should be addressed to the organization. We plan to update this list annually. Organizations that wish to be included should contact THE PHYSICIAN AND SPORTSMEDICINE, Injury Resource List, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27457177 TI - Pinning Down Bowling Injuries. AB - Bowling is not a physically taxing sport. But poor technique, the cumulative stress of pushing a heavy bowling ball thousands of times, or the wear and tear of poorly fitting equipment may produce or aggravate certain chronic conditions. PMID- 27457179 TI - Exercise Adviser. PMID- 27457181 TI - A Study of the Dynamics of the Heme Pocket and C-helix in CooA upon CO Dissociation Using Time-Resolved Visible and UV Resonance Raman Spectroscopy. AB - CooA is a CO-sensing transcriptional activator from the photosynthetic bacterium Rhodospirillum rubrum that binds CO at the heme iron. The heme iron in ferrous CooA has two axial ligands: His77 and Pro2. CO displaces Pro2 and induces a conformational change in CooA. The dissociation of CO and/or ligation of the Pro2 residue are believed to trigger structural changes in the protein. Visible time resolved resonance Raman spectra obtained in this study indicated that the nu(Fe His) mode, arising from the proximal His77-iron stretch, does not shift until 50 MUs after the photodissociation of CO. Ligation of the Pro2 residue to the heme iron was observed around 50 MUs after the photodissociation of CO, suggesting that the nu(Fe-His) band exhibits no shift until the ligation of Pro2. UV resonance Raman spectra suggested structural changes in the vicinity of Trp110 in the C-helix upon CO binding, but no or very small spectral changes in the time resolved UV resonance Raman spectra were observed from 100 ns to 100 MUs after the photodissociation of CO. These results strongly suggest that the conformational change of CooA is induced by the ligation of Pro2 to the heme iron. PMID- 27457182 TI - Local administration of siRNA through Microneedle: Optimization, Bio distribution, Tumor Suppression and Toxicity. AB - Although RNA interference may become a novel therapeutic approach for cancer treatment, target-site accumulation of siRNA to achieve therapeutic dosage will be a major problem. Microneedle represents a better way to deliver siRNAs and we have evaluated for the first time the capability of a silicon microneedle array for delivery of Gapdh siRNA to the skin in vivo and the results showed that the microneedle arrays could effectively deliver siRNA to relevant regions of the skin noninvasively. For the further study in this field, we evaluated the efficacy of the injectable microneedle device for local delivery of siRNA to the mouse xenograft. The results presented here indicate that local administration of siRNA through injectable microneedle could effectively deliver siRNA into the tumor region, and inhibit tumor progression without major adverse effects. PMID- 27457184 TI - Activated prothrombin complex concentrate in combination with tranexamic acid: a single centre experience for the treatment of mucosal bleeding and dental extraction in haemophilia patients with inhibitors. PMID- 27457183 TI - Escherichia coli Nissle 1917 protects gnotobiotic pigs against human rotavirus by modulating pDC and NK-cell responses. AB - Lactobacillus rhamnosus GG (LGG), a gram-positive lactic acid bacterium, is one of the most widely used probiotics; while fewer gram-negative probiotics including Escherichia coli Nissle 1917 (EcN) are characterized. A mechanistic understanding of their individual and interactive effects on human rotavirus (HRV) and immunity is lacking. In this study, noncolonized, EcN-, LGG-, and EcN + LGG-colonized neonatal gnotobiotic (Gn) pigs were challenged with HRV. EcN colonization is associated with a greater protection against HRV, and induces the highest frequencies of plasmacytoid dendritic cells (pDCs), significantly increased NK-cell function and decreased frequencies of apoptotic and TLR4+ mononuclear cells (MNCs). Consistent with the highest NK-cell activity, splenic CD172+ MNCs (DC enriched fraction) of EcN-colonized pigs produced the highest levels of IL-12 in vitro. LGG colonization has little effect on the above parameters, which are intermediate in EcN + LGG-colonized pigs, suggesting that probiotics modulate each other's effects. Additionally, in vitro EcN-treated splenic or intestinal MNCs produce higher levels of innate, immunoregulatory and immunostimulatory cytokines, IFN-alpha, IL-12, and IL-10, compared to MNCs of pigs treated with LGG. These results indicate that the EcN-mediated greater protection against HRV is associated with potent stimulation of the innate immune system and activation of the DC-IL-12-NK immune axis. PMID- 27457185 TI - Observation of temperature-gradient-induced magnetization. AB - Applying magnetic fields has been the method of choice to magnetize non-magnetic materials, but they are difficult to focus. The magneto-electric effect and voltage-induced magnetization generate magnetization by applied electric fields, but only in special compounds or heterostructures. Here we demonstrate that a simple metal such as gold can be magnetized by a temperature gradient or magnetic resonance when in contact with a magnetic insulator by observing an anomalous Hall-like effect, which directly proves the breakdown of time-reversal symmetry. Such Hall measurements give experimental access to the spectral spin Hall conductance of the host metal, which is closely related to other spin caloritronics phenomena such as the spin Nernst effect and serves as a reference for theoretical calculation. PMID- 27457187 TI - Changing my perspective: How the development of emergency medicine in Sri Lanka can inform the Australasian experience. AB - When compared to an Australasian ED, the two major differences in the emergency medicine practice at Teaching Hospital Karapitiya are which patients are selected at triage and how those selected present. These differences have caused me to reflect on emergency medicine practice in Australasia and wonder if this practice is sustainable. PMID- 27457186 TI - Perpendicular magnetic tunnel junction with a strained Mn-based nanolayer. AB - A magnetic tunnel junction with a perpendicular magnetic easy-axis (p-MTJ) is a key device for spintronic non-volatile magnetoresistive random access memory (MRAM). Co-Fe-B alloy-based p-MTJs are being developed, although they have a large magnetisation and medium perpendicular magnetic anisotropy (PMA), which make it difficult to apply them to a future dense MRAM. Here, we demonstrate a p MTJ with an epitaxially strained MnGa nanolayer grown on a unique CoGa buffer material, which exhibits a large PMA of more than 5 Merg/cm(3) and magnetisation below 500 emu/cm(3); these properties are sufficient for application to advanced MRAM. Although the experimental tunnel magnetoresistance (TMR) ratio is still low, first principles calculations confirm that the strain-induced crystal lattice distortion modifies the band dispersion along the tetragonal c-axis into the fully spin-polarised state; thus, a huge TMR effect can be generated in this p-MTJ. PMID- 27457188 TI - Lactococcus garvieae outbreaks in Brazilian farms Lactococcosis in Pseudoplatystoma sp. - development of an autogenous vaccine as a control strategy. AB - This study evaluated the control of streptococcosis outbreaks in Brazil, isolated from diseased sorubim and identified as Lactococcus garvieae by genetic sequencing. This report determined the potential for lactococcosis control in sorubim Pseudoplatystoma sp. with two vaccines: an aqueous-based, whole-cell inactivated vaccine (bacterin) and an oil-adjuvanted bacterin. Their efficacy was evaluated at 30 days post-vaccination (d.p.v.) by challenge with L. garvieae, and the antibody production response at 15, 30 and 60 d.p.v. and the non-specific immune response were compared amongst treatments. High protection levels (P < 0.05) were achieved with the oil-adjuvanted vaccine with a relative percentage survival value of 81.7% at 30 d.p.v. Additionally, the oil-adjuvanted vaccine increased the immunogenicity of the bacterin as indicated by greater agglutination antibody titres from 15 until 60 d.p.v. This is the first report of a positive effect of vaccine administration on the specific immunity of sorubim, and the study showed that a specific antibody plays an important role in sorubim defence against lactococcosis because the innate immune responses were similar in all of the studied animals. These results demonstrated that oil-adjuvanted vaccine can be an effective alternative for the protection of sorubim from L. garvieae disease. PMID- 27457189 TI - Efficient organic photomemory with photography-ready programming speed. AB - We propose a device architecture for a transistor-type organic photomemory that can be programmed fast enough for use in electrical photography. Following the strategies used in a flash memory where an isolated charge storage node or floating gate is employed, the proposed organic photomemory adopts an isolated photo-absorption zone that is embedded between upper and lower insulator layers without directly interfacing with a semiconductor channel layer. This isolated photo-absorption zone then allows the device to operate in electrically 'on' state, in which the high electric-field region can have a maximal spatial overlap with the illuminated area for efficient and facile light-programming. With the proposed approach, a significant threshold voltage shift is attained even with the exposure time as short as 5 ms. High quality dielectric layers prepared by initiated chemical vapor deposition ensure erasing to occur only with electrical signal in a controlled manner. Retention time up to 700 s is demonstrated. PMID- 27457191 TI - Ion Clouds in the Inductively Coupled Plasma Torch: A Closer Look through Computations. AB - We have computationally investigated the introduction of copper elemental particles in an inductively coupled plasma torch connected to a sampling cone, including for the first time the ionization of the sample. The sample is inserted as liquid particles, which are followed inside the entire torch, i.e., from the injector inlet up to the ionization and reaching the sampler. The spatial position of the ion clouds inside the torch as well as detailed information on the copper species fluxes at the position of the sampler orifice and the exhausts of the torch are provided. The effect of on- and off-axis injection is studied. We clearly show that the ion clouds of on-axis injected material are located closer to the sampler with less radial diffusion. This guarantees a higher transport efficiency through the sampler cone. Moreover, our model reveals the optimum ranges of applied power and flow rates, which ensure the proper position of ion clouds inside the torch, i.e., close enough to the sampler to increase the fraction that can enter the mass spectrometer and with minimum loss of material toward the exhausts as well as a sufficiently high plasma temperature for efficient ionization. PMID- 27457190 TI - The tendency for social submission predicts superior cognitive performance in previously isolated male mice. AB - The imposition of subordination may negatively impact cognitive performance in common social settings (e.g., the classroom), and likewise, laboratory studies of animals indicate that the stress associated with social defeat can impair cognitive performance. It is less clear whether an animal's predisposition for social subordination (i.e., a tendency that is expressed prior to experience with social defeat) is related to its cognitive abilities (e.g., "general" intelligence). Using genetically diverse CD-1 male mice, here we determined that in the absence of adult experience with social hierarchies or social defeat, the predisposition for social subordination was associated with superior general cognitive ability (aggregate performance across a battery of five learning tasks). The tendency for social subordination was not dependent on the mice' body weight, but both general cognitive ability and the tendency for social subordination were directly related to high stress reactivity (i.e., free corticosterone elevations induced by mild stress). This pattern of results suggests that submissive behavior and sensitivity to stress may be associated with superior cognitive potential, and this can reflect a native predisposition that precedes exposure to social pressures. More broadly, these results raise the possibility that socially subordinate animals evolved compensatory strategies to facilitate their survival, and that absent the imposition of subordination, normally submissive individuals may be better prepared for cognitive/academic achievement. PMID- 27457192 TI - Pre-B-Cell Acute Lymphoblastic Leukemia in Childhood. AB - The pre-B-cell (clgM) phenotype of childhood ALL comprises about one-fifth of newly diagnosed cases. It has a high frequency of chromosomal translocation, and is closely associated with the t(l;19)(q23;p13). The poor treatment outcome and high-risk features previously ascribed to this phenotype appear to be primarily due to the subset of cases with the t(l;19). Early results of at least one study suggest that aggressive treatment may even nullify the adverse prognostic implication of the t(l;19). Finally, molecular analyses of these cases have yielded exciting new information regarding the pathogenesis of pre-B-cell ALL with the t(l;19), and recombinant DNA technology (polymerase chain reaction) is likely to make molecular diagnosis and detection of minimal residual disease possible in the near future. PMID- 27457193 TI - Quantitative Phenotyping of Childhood Leukemia Identifies Variable and Invariable Cell Surface Antigens. AB - Cells obtained from 75 cases of childhood leukemia were subjected to flow cytometry analysis to estimate the density of several cell surface antigens and derive a quantitative immunological phenotype. Sixty-five cases of acute lymphoblastic leukemia (ALL) including 10 T-ALL, 6 non-T ALL designated groups I and II (HLA-DRCALLA), 48 non-T ALL termed groups III and IV (HLA-DRCALLA) and one B-ALL were studied; 10 cases of acute myeloblastic leukemia (AML) were also analysed. The estimation of the relative fluorescence index (RFI) on leukemic blasts led to the derivation of mean values for each marker in the leukemia subgroups. We have quantitated the levels of the antigens generally used in the classification of these leukemias (CALLA, CD5, CD20, CD13, HLA-DR and CD19) and of other cell surface antigens associated with leukemic cells. For example, CALLA (CD10) level was high (mean RFI value of 26.4) on the leukemic cells of non-T ALL groups III and IV. The CD5 antigen was present on T-ALL, as expected, with an RFI value of 4.5; however, low levels were observed on the more immature non-T ALL of groups I and II (RFI = 2.3 on only 27% of blast cells). The quantitative analysis of the cell surface antigens associated with non-T ALL has revealed molecules such as CALLA, HLA-DR, CD9 and CD44 present at high and variable levels and others such as CD19, CD38, 44G4, 44D7, 44H9 and 44H6 generally of lower intensity, less variable from one patient to another, and with similar mean levels of expression in the different subgroups. These invariable antigens are not altered by the lineage or stage of differentiation of the leukemic cells. The variable antigens could be correlated with the functional and/or differentiation status of the cells and could also be modified by the alterations of regulatory processes associated with malignancy. The quantitation of multiple leukemia associated antigens, whose structure and function are becoming rapidly established, should help in elucidating the function of these molecules in leukemogenesis and/or disease progression. PMID- 27457194 TI - Differential expression of TRAP Isoenzyme in B-CLL Cells Treated with Different Inducers. AB - Purified B-cells from normal tonsils and from the peripheral blood of eight patients with B-chronic lymphocytic leukemia (B-CLL) were treated in vitro with the protein kinase C (PKC) activators TPA, Bryostatin 1 (Bryo), mezerein, with the calcium ionophore A23187, and with the cytokines interleukin-1/2, interferon alpha/gamma, tumor necrosis factor. The induction of the lysosomal enzyme tartrate-resistant acid phosphatase (TRAP) was examined at the RNA (by Northern blotting analysis) and the protein level (by isoelectric focusing). TRAP mRNA and protein were induced by treatment with PKC activators while the combination of PKC stimulator and calcium ionophore was not effective, TRAP mRNA was detected as early as 2 hours after initiation of the culture. This induction of positivity for TRAP which is the enzymatic hallmark of hairy cell leukemia (HCL) by TPA or Bryo is consistent with the previously reported acquisition of HCL-type cellular features in TPA-driven CLL cells; CLL cells exposed to the double stimulus of TPA or Bryo + A23187 have previously been described to differentiate to plasmacytoid cells which is in accord with their remaining TRAP negative. The present data provide evidence that 1) B-CLL cells can be induced by direct stimulation of PKC to convert to HCL-type cells; 2) TPA/Bryo-exposed B-CLL cells display phenotypes different from those of cells treated with combinations containing calcium ionophore; 3) the phosphoinositol signal transduction pathway distal to PKC can be activated effectively in B-CLL cells; 4) Bryo, a new natural PKC activator, induces responses in CLL similar to those caused by TPA; 5) TRAP is an inducible indicator of cellular activation. These observations provide support for the idea that HCL and HCL-like cells might differentiate along a separate branch of B-cell lineage and might represent mature "activation end stage" cells. PMID- 27457195 TI - Detection of Activation Antigens on Chronic Lymphocytic Leukaemia Cells. AB - The peripheral blood mononuclear cells of patients with chronic lymphocytic leukaemia were characterized by the presence of a variety of cell surface differentiation antigens. The cells of 20 patients were found to be of B-cell phenotype when studied with antibodies directed against CD19, CD20, HLA-DR and sIg. Furthermore, a significant percentage of the cells gave a positive reaction with the monoclonal antibody to CD5. On the other hand, the CLL-cells did not express the CD21 antigen (C3d receptor, EBV receptor). We studied in parallel the presence of various activation antigens using 19 monoclonal antibodies grouped into 7 clusters (CD25, CD30, CD40, CD69, CD70, CD39, CD71). A significantly higher percentage of the CLL cells expressed activation antigens than lymphocytes from healthy controls. The percentage of CD3/HLA + DR + cells, compared to the healthy control lymphocytes was not increased in the CLL patients, and the activated cells in CLL were found to have characteristics of B-cells. Based on these results, we suggest that the CLL cells, like the cells in Hodgkin's disease and T-cell lymphoma, are not resting, but activated B-cells or the neoplastic abberrants of activated cells. PMID- 27457196 TI - Delayed Induction of Proto-Oncogene Expression in B-CLL Cells by Tumor Necrosis Factor. AB - In-vitro treatment of B-chronic lymphocytic leukaemia (B-CLL) cells with tumour necrosis factor (TNF) induced the transcription of the proto-oncogenes c-fos, c jun and c-myc. The products of these oncogenes appear to be involved in the signal transmission initiated via the phosphoinositol lipid and protein kinase C (PKC) signal transduction pathway. In contrast to the rapid induction of these oncogene products by the phorbol ester TPA (which directly activates PKC) alone or in combination with the calcium ionophore A23187, stimulation of c-fos, c-jun and c-myc mRNA expression by TNF is significantly delayed. A later onset of action mediated by TNF has similarly been reported for the induction of DNA synthesis and of gene expression following gene transfer in B-CLL cells. The delay in the response of B-CLL cells to TNF might be due to the delayed stimulation of the oncogene signal transmitters fos, jun and myc by TNF. The mechanism for this delay remains to be elucidated. PMID- 27457197 TI - Comparison of the DNA Content, Bromodeoxyuridine Incorporation and Ki-67 Antigen Expression in Human Acute Myeloid Leukemia. AB - The cell kinetics of twenty-two acute myeloid leukemias (AML) were investigated by means of flow cytometry evaluating the S-phase DNA content, bromodeoxyuridine labelling index (BrdUrd L.I.) and Ki-67 antigen expression. Eight patients showed a good correlation between the DNA content and BrdUrd L.I., while nine gave rise to divergent results. In the remaining five patients the S-phase DNA content could not be evaluated due to the presence of an additional aneuploid population. The Ki-67 antigen expression defined the extent of the growth fraction in all cases and allowed for better characterization of the cell cycle. These results suggest that the three methods explore only partly overlapping events; thus, it seems that a reliable picture of the cell kinetics in leukemic populations can only be achieved by combining all these methods. PMID- 27457198 TI - t(2;5) (p23;q35)-A Specific Chromosome Abnormality in Large Cell Anaplastic (Ki 1) Lymphoma. AB - Chromosome abnormalities of three patients with Ki-1 lymphoma are presented. In order to be included in the study each case fulfilled the following criteria: the majority of the tumour cells were positive for the Ki-1 antigen (CD30), and the cells were large with relatively abundant, slightly basophilic cytoplasm. In all cases, a major proportion of mitoses contained a complicated clonal chromosome abnormality. Two patients had a 2;5 translocation; and the third had break points at 14q32 and 2p12. The latter patient showed expression of B-cell antigens and had rearrangements in the immunoglobulin heavy chain and kappa light chain genes. The two patients with the 2;5 translocation were epithelial membrane antigen positive, but did not exhibit rearrangements of immunoglobulin/T-cell receptor genes or expression of T-/B-cell antigens. PMID- 27457199 TI - Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) Reduces Pancytopenia After Rescue Therapy in a Patient with Hodgkin's Lymphoma. AB - After several relapses, a stage IV lymphocyte depletion Hodgkin Lymphoma patient, with a bone marrow progenitor compartment depleted by several courses of chemotherapy, received further combination chemotherapy which caused severe and long-lasting pancytopenia. Because of an objective degree of tumor regression, a second identical course was administered, followed by Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) in an attempt to accelerate bone marrow recovery. This led to a significantly shorter period of neutropenia and thrombocytopenia with no additional red blood cell and platelet transfusion requirements. Furthermore, the neutropenic phase was not accompanied by septic complications. It is suggested that patients with solid tumors, even with a severely compromised bone marrow after several chemotherapy courses, may benefit from GM-CSF administration after rescue chemotherapy. PMID- 27457200 TI - A Novel Cell Line (NCU-L-1) from a Patient with Acute Lymphoblastic Leukemia, FAB, L3, Burkitt's Type. AB - A novel cultured cell line, NCU-L-1, was established from a 71-year-old Japanese woman with acute lymphoblastic leukemia, L3 FAB, Burkitt's type. The NCU-L-1 cells were shown to have a mature B-cell phenotype on the basis of immunologic surface marker analysis; including IgG Lambda surface immunoglobulins, CD19, CD20 and la-like antigen which were all detected on the cells. Intracytoplasmic immunoglobulin was not detected, but IgG was present in the cell culture supernatant. Cytogenetic studies revealed that the NCU-L-1 cells had t(2; 8) and an additional 14q+, a genotype which has not been identified previously in the usual Burkitt's cell lines. The NCU-L-1 cell line should prove to be useful for studying oncogenic events associated with the t(2; 8) translocation and karyotype evolution. PMID- 27457201 TI - Scabies Infestation following Autologous Bone Marrow Transplantation. PMID- 27457202 TI - Advanced signal analysis for the detection of periodic limb movements from bilateral ankle actigraphy. AB - Actigraphy can assist in the detection of periodic limb movements in sleep. Although several actigraphs have been previously reported to accurately detect periodic limb movements, many are no longer available; of the existing actigraphs, most sample too infrequently to accurately detect periodic limb movements. The purpose of this study was to use advanced signal analysis to validate a readily available actigraph that has the capability of sampling at relatively high frequencies. We simultaneously recorded polysomnography and bilateral ankle actigraphy in 96 consecutive patients presenting to our sleep laboratory. After pre-processing and conditioning, the bilateral ankle actigraphy signals were then analysed for 14 simple time, frequency and morphology-based features. These features reduced the signal dimensionality and aided in better representation of the periodic limb movement activity in the actigraph signals. These features were then processed by a Naive-Bayes binary classifier for distinguishing between normal and abnormal periodic limb movement indices. We trained the Naive-Bayes classifier using a training set, and subsequently tested its classification accuracy using a testing set. From our experiments, using a periodic limb movement index cut-off of 5, we found that the Naive-Bayes classifier had a correct classification rate of 78.9%, with a sensitivity of 80.3% and a specificity of 73.7%. The algorithm developed in this study has the potential of facilitating identification of periodic limb movements across a wide spectrum of patient populations via the use of bilateral ankle actigraphy. PMID- 27457203 TI - Fluorescence lifetime measurements in heterogeneous scattering medium. AB - Fluorescence lifetime in heterogeneous multiple light scattering systems is analyzed by an algorithm without solving the diffusion or radiative transfer equations. The algorithm assumes that the optical properties of medium are constant in the excitation and emission wavelength regions. If the assumption is correct and the fluorophore is a single species, the fluorescence lifetime can be determined by a set of measurements of temporal point-spread function of the excitation light and fluorescence at two different concentrations of the fluorophore. This method is not dependent on the heterogeneity of the optical properties of the medium as well as the geometry of the excitation-detection on an arbitrary shape of the sample. The algorithm was validated by an indocyanine green fluorescence in phantom measurements and demonstrated by an in vivo measurement. PMID- 27457204 TI - Secondary structure impacts patterns of selection in human lncRNAs. AB - BACKGROUND: Metazoans transcribe many long non-coding RNAs (lncRNAs) that are poorly conserved and whose function remains unknown. This has raised the questions of what fraction of the predicted lncRNAs is actually functional, and whether selection can effectively constrain lncRNAs in species with small effective population sizes such as human populations. RESULTS: Here we evaluate signatures of selection in human lncRNAs using inter-specific data and intra specific comparisons from five major populations, as well as by assessing relationships between sequence variation and predictions of secondary structure. In all analyses we included a reference of functionally characterized lncRNAs. Altogether, our results show compelling evidence of recent purifying selection acting on both characterized and predicted lncRNAs. We found that RNA secondary structure constrains sequence variation in lncRNAs, so that polymorphisms are depleted in paired regions with low accessibility and tend to be neutral with respect to structural stability. CONCLUSIONS: Important implications of our results are that secondary structure plays a role in the functionality of lncRNAs, and that the set of predicted lncRNAs contains a large fraction of functional ones that may play key roles that remain to be discovered. PMID- 27457205 TI - What Constitutes High-Quality Implementation of SEL Programs? A Latent Class Analysis of Second Step(r) Implementation. AB - With the increased number of schools adopting social-emotional learning (SEL) programming, there is increased emphasis on the role of implementation in obtaining desired outcomes. Despite this, the current knowledge of the active ingredients of SEL programming is lacking, and there is a need to move from a focus on "whether" implementation matters to "what" aspects of implementation matter. To address this gap, the current study utilizes a latent class approach with data from year 1 of a randomized controlled trial of Second Step(r) (61 schools, 321 teachers, over 7300 students). Latent classes of implementation were identified, then used to predict student outcomes. Teachers reported on multiple dimensions of implementation (adherence, dosage, competency), as well as student outcomes. Observational data were also used to assess classroom behavior (academic engagement and disruptive behavior). Results suggest that a three-class model fits the data best, labeled as high-quality, low-engagement, and low adherence classes. Only the low-engagement class showed significant associations with poorer outcomes, when compared to the high-quality class (not the low adherence class). Findings are discussed in terms of implications for program development and implementation science more broadly. PMID- 27457206 TI - Tuberculosis therapy for 2016 and beyond. AB - INTRODUCTION: Tuberculosis has been and remains arguably the most important infectious disease of all time. However, when compared to other diseases of similar human impact, relatively little progress has been made. Although there are many new drugs being developed for the first time in decades, it is unclear what role each of these new drugs will play. AREAS COVERED: The history of current therapy is reviewed as are the challenges associated with medications currently in use. Drugs that have recently been added to the armamentarium of therapy are reviewed as well as new candidate drugs. EXPERT OPINION: Developing new drugs to treat tuberculosis is of critical importance but even more important is developing strategies that ensure that there is no further amplification of drug resistance around the world especially in high burden low resource settings. Directly observed therapy is the cornerstone of protecting existing and future regimens and new technologies will potentially extend the reach of monitored therapy. Challenges remain including maintaining an adequate drug supply but the greatest challenge may be the issue of persistent organisms that require prolonged therapy. By discovering the triggers of persistence and identifying new drug targets can it be possible to radically shorten therapy. PMID- 27457208 TI - Enhancement of the Chaperone Activity of Alkyl Hydroperoxide Reductase C from Pseudomonas aeruginosa PAO1 Resulting from a Point-Specific Mutation Confers Heat Tolerance in Escherichia coli. AB - Alkyl hydroperoxide reductase subunit C from Pseudomonas aeruginosa PAO1 (PaAhpC) is a member of the 2-Cys peroxiredoxin family. Here, we examined the peroxidase and molecular chaperone functions of PaAhpC using a site-directed mutagenesis approach by substitution of Ser and Thr residues with Cys at positions 78 and 105 located between two catalytic cysteines. Substitution of Ser with Cys at position 78 enhanced the chaperone activity of the mutant (S78C-PaAhpC) by approximately 9 fold compared with that of the wild-type protein (WT-PaAhpC). This increased activity may have been associated with the proportionate increase in the high molecular-weight (HMW) fraction and enhanced hydrophobicity of S78C-PaAhpC. Homology modeling revealed that mutation of Ser(78) to Cys(78) resulted in a more compact decameric structure than that observed in WT-PaAhpC and decreased the atomic distance between the two neighboring sulfur atoms of Cys(78) in the dimer dimer interface of S78C-PaAhpC, which could be responsible for the enhanced hydrophobic interaction at the dimer-dimer interface. Furthermore, complementation assays showed that S78C-PaAhpC exhibited greatly improved the heat tolerance, resulting in enhanced survival under thermal stress. Thus, addition of Cys at position 78 in PaAhpC modulated the functional shifting of this protein from a peroxidase to a chaperone. PMID- 27457209 TI - Characterization of zinc oxide nanoparticle (nZnO) alginate beads in reducing gaseous emission from swine manure. AB - Hydrogen sulfide (H2S) and greenhouse gases' emission from livestock production facilities are of concern to human welfare and the environment. Application of nanoparticles (NPs) has emerged as a potential option for minimizing these gaseous emissions. Application of bare NPs, however, could have an adverse effect on plants, soil, human health, and the environment. To minimize NPs' exposure to the environment by recovering them, NPs were entrapped in polymeric beads for treating livestock manure. The objectives of the research were to understand the mechanism of gaseous reduction in swine manure treated for 33 days with zinc oxide nanoparticles (nZnO) or nZnO-entrapped alginate (alginate-nZnO) beads by different characterization techniques. Headspace gases from treated manure flasks were collected in 2-6-day intervals during the experimental period and were analyzed for methane (CH4), carbon dioxide (CO2), and H2S concentrations. The microbial analysis of manure was carried out using bacterial plate counts and Real-Time Polymerase Chain Reaction methods. Morphology and chemical composition of alginate-nZnO beads were analyzed by Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS), and X-ray Photoelectron Spectroscopy (XPS). Alginate-nZnO beads or bare nZnO proved to be an effective NP in reducing H2S (up to 99%), CH4 (49-72%), and CO2 (46-62%) from manure stored under anaerobic conditions and these reductions are likely due to the microbial inhibitory effect from nZnO, as well as chemical conversion. Both SEM-EDS and XPS analysis confirmed the presence of zinc sulfide (ZnS) in the beads, which is likely formed by reacting nZnO with H2S. PMID- 27457211 TI - Correlates of HIV and Inconsistent Condom Use Among Female Sex Workers in Ukraine. AB - While female sex workers (FSWs) carry one of the highest risks of HIV transmission, little is known about predictors of HIV and risky behavior of FSWs in Ukraine. In this study of 4806 Ukrainian FSWs, the prevalence of HIV was 5.6 %. FSWs had higher odds to be HIV infected if they had lower income, were older, injected drugs, experienced violence, and solicited clients on highways. Inconsistent condom use with clients was reported by 34.5 % of FSWs. FSWs who solicited clients at railway stations, via media, through previous clients and other FSWs, and on highways reported lower consistency of condom use. Furthermore, inconsistent condom use was related to younger age, alcohol use, having fewer clients, not being covered with HIV prevention, and experiences of violence. The present study expands on the rather limited knowledge of correlates of the HIV and inconsistent condom use among FSWs in Ukraine. PMID- 27457212 TI - Metabolomic Insight into Lipid and Protein Profile in Diabetes Using Mass Spectrometry. AB - In recent years, metabolomics has become a necessary tool for understanding the impact of external and pathological factors on the operation of biological systems. The first reports of metabolomics date back to the 1970s, however, the area only began to develop dynamically at the beginning of this century and has proved effective only during the present decade. The five primary tools used in this form of analysis are NMR spectrometry, HPLC, TLC-UV, GC-MS and LC-MS/MS, with MS as the most universal approach, particularly when used together with chromatographic separation and NMR. Diabetes mellitus type 2 (T2DM) is a rapidly growing problem with global consequences. The metabolomic approach has been extensively applied to examining T2DM, insulin resistance and obesity, not only to assess the development of the disease, but also to discover its potential biomarkers. The presented review summarizes current studies on lipidomic and proteomic profiles in the context of different types of diabetes mellitus disease (T1DM, T2DM and GDM), as determined by chromatography-coupled mass spectrometry. PMID- 27457210 TI - Detection of Novel QTLs Regulating Grain Size in Extra-Large Grain Rice (Oryza sativa L.) Lines. AB - BACKGROUND: Grain size is an important trait that affects rice yield. Although many genes that contribute to grain size have been cloned from mutants or by quantitative trait locus (QTL) analysis based on bi-parental mapping, the molecular mechanisms underlying grain-size determination remain poorly understood. In this study, we identified the lines with the largest grain size and detected novel QTLs affecting the grain size. RESULTS: We screened the National Institute for Agrobiological Sciences Genebank database and identified two rice lines, BG23 with the widest grain and LG10 with the longest grain. Using these two lines, we performed QTL analysis for grain size. Eight QTLs were detected during the QTL analyses using F2 populations derived from crosses between the large-grain lines BG23 or LG10 and the middle-size grain cultivars Nipponbare and Kasalath. Both BG23 and LG10 possessed large-grain alleles of four major QTLs: GW2, GS3, qSW5/GW5, and GW8. Other three minor QTLs were derived from BG23. However, these QTLs did not explain the differences in grain size between these two lines. Additionally, four QTLs for grain length or width were detected in an F2 population derived from a cross between BG23 and LG10; this population lacked the strong effects of the four major QTLs shared by both parent plants. Of these newly detected QTLs, the effects of two QTLs, GL3b and GL6, were confirmed by progeny testing. Comparison of the length of inner epidermal cells in plants homozygous for BG23 and LG10 alleles indicated that GL3b and GL6 genes regulate cell elongation and cell division, respectively. CONCLUSIONS: In this study, we detected 12 loci including 14 QTLs regulating grain size from two lines with largest grains available in Japanese stock. Of these loci, we confirmed the effect of two gene loci and mapped their candidate region. Identification of novel genes regulating grain size will contribute to our understanding of the molecular mechanisms controlling grain size. PMID- 27457213 TI - Vitamins B1, B2, B3 and B9 - Occurrence, Biosynthesis Pathways and Functions in Human Nutrition. AB - BACKGROUND: Vitamins are chemical compounds whose derivatives are involved in vital metabolic pathways of all living organisms. The complete endogenous biosynthesis of vitamins can be performed by many bacteria, yeast and plants, but humans need to acquire most of these essential nutrients with food. In recent years, new types of action of the well-recognized vitamins or their more sophisticated relationships have been reported. CONCLUSION: In this review we present the current knowledge of factors that can influence the yield and regulation of vitamin B1, B2, B3 and B9 biosynthesis in plants which can be important for human nutrition. A summary of modern methods applied for vitamin analysis in biological materials is also provided. Contributions of selected vitamins to the homeostasis of the human organism, as well as their relations to the progress or prevention of some important diseases such as cancer, cardiovascular diseases, diabetes and Alzheimer's disease are discussed in the light of recent investigations. Better understanding of the mechanisms of vitamin uptake by human tissues and possible metabolic or genetic backgrounds of vitamin deficiencies can open new perspectives on the medical strategies and biotechnological processes of food fortification. PMID- 27457214 TI - Vitamin E - Occurrence, Biosynthesis by Plants and Functions in Human Nutrition. AB - OBJECTIVE: This review examines various aspects of vitamin E, both in plant metabolism and with regard to its importance for human health. Vitamin E is the collective name of a group of lipidsoluble compounds, chromanols, which are widely distributed in the plant kingdom. Their biosynthetic pathway, intracellular distribution and antioxidant function in plants are well recognized, although their other functions are also considered. CONCLUSION: Analytical methods for the determination of vitamin E are discussed in detail. Furthermore, the vitamin E metabolism and its antioxidant action in humans are described. Other nonantioxidant functions of vitamin E are also presented, such as its anti-inflammatory effects, role in the prevention of cardiovascular diseases and cancer, as well as its protective functions against neurodegenerative and other diseases. PMID- 27457215 TI - Microalgal Fatty Acids and Their Implication in Health and Disease. AB - BACKGROUND: The fatty acids of seed plants and microalgae stored in triglyceride are all produced in the plastid and incorporated into triglycerides by a complex biochemical exchange between the plastid envelope and the endoplasmic reticulum. The oils of seed plants provide the basis for vegetal fat production and the microalgal fats represent an important part of the basal food web of the marine environment. The health-promoting properties of these various sources of fats and in particular the long-chain polyunsaturated fatty acids of marine microalgae are widely recognized. The omega-3 fatty acids are known to have benefits on health and disease. Indeed, alpha-linolenic, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are linked to the regulation of mechanisms involved in numerous biological functions associated with cardiovascular disease and cancer prevention. Most EPA and DHA sources for human nutrition are provided by decreasing global stocks of fish. This is one of the reasons why industrial research has been directed towards more sustainable sources of these "marine" lipids. The synthesis of fatty acids and triglycerides are in many respects similar in higher plants and marine algae, but there are also important differences. CONCLUSION: This mini-review covers the biochemistry of fatty acid and lipid synthesis in marine microalgae, and the potential health impact of the different fats is also discussed. PMID- 27457216 TI - Antineutrophil cytoplasmic antibody (ANCA) testing: Audit from a clinical immunology laboratory. AB - AIM: Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with small vessel vasculitis now termed 'ANCA associated vasculitis' (AAV). ANCAs are reported in diverse diseases where they have no clinical utility. We carried out an audit in a clinical immunology laboratory and assessed if use of ordering practices could have improved utility of ANCA. METHODS: All samples received for ANCA testing during 2014 were tested by indirect immunofluorescence (IIF) and automated enzyme-linked immunosorbent assay (ELISA). Clinical records of all samples positive by one or more assays were retrieved. We assessed the effect of applying proposed test ordering guidelines on performance of the tests. RESULTS: Of 1590 samples, 108 (6.8%) had a positive result by at least one method. IIF showed perinuclear pattern in 72 (21 were antinuclear antibody positive), cytoplasmic in 22, six had atypical pattern and eight were negative. By ELISA anti-myeloperoxidase antibodies were present in 33 samples, anti-proteinase 3 in 24, while five sera had both antibodies. ELISA and IIF were concordant in 45 samples. Twenty-seven patients had AAV of which 23 were both ELISA and IIF positive. Among these 27 with AAV all had at least one ordering criteria, while in 81 patients without AAV but with positive test, 38 had no ordering criteria. CONCLUSION: Reduction in false positive can be achieved by considering only those samples as ANCA positive that test positive both on IIF and ELISA and by following ordering guidelines before requesting ANCA testing, and by use of ordering criteria by clinicians. PMID- 27457218 TI - Introducing a Hydrogen-Bond Donor into a Weakly Nucleophilic Bronsted Base: Alkali Metal Hexamethyldisilazides (MHMDS, M=Li, Na, K, Rb and Cs) with Ammonia. AB - Alkali metal 1,1,1,3,3,3-hexamethyldisilazide (MHMDSs) are one of the most utilised weakly nucleophilic Bronsted bases in synthetic chemistry and especially in natural product synthesis. Like lithium organics, they aggregate depending on the employed donor solvents. Thus, they show different reactivity and selectivity as a function of their aggregation and solvation state. To date, monomeric LiHMDS with monodentate donor bases was only characterised in solution. Since the first preparation of LiHMDS in 1959 by Wannagat and Niederprum, all efforts to crystallise monomeric LiHMDS in the absence of chelating ligands failed. Herein, we present ammonia adducts of LiHMDS, NaHMDS, KHMDS, RbHMDS and CsHMDS with unprecedented aggregation motifs: 1) The hitherto missing monomeric key compound in the LiHMDS aggregation architectures. Monomeric crystal structures of trisolvated LiHMDS (1) and NaHMDS (2), showing unique intermolecular hydrogen bonds, 2) the unprecedented tetrasolvated KHMDS (3) and RbHMDS (4) dimers and 3) the disolvated CsHMDS (5) dimer with very close intermolecular Si-CH3 ???Cs s block "agostic" interactions have been prepared and characterised by single crystal X-ray structure analysis. PMID- 27457217 TI - Prognostic value of HMGB1 in early breast cancer patients under neoadjuvant chemotherapy. AB - The response to neoadjuvant chemotherapy in breast cancer patients is usually assessed by pCR and RCB score. However, the prognostic value of these parameters is still in discussion. We showed recently that an epirubicin/docetaxel therapy is associated with an increase in the cell death marker high-mobility group box 1 protein (HMGB1) in the circulation. Here, we investigate whether this increase correlates with the long-term outcome. Thirty-six early breast cancer patients under neoadjuvant epirubicin/docetaxel combination chemotherapy were included in this study. To determine the immediate effect of this treatment on HMGB1, we collected blood samples before and 24-96 h after the initial dose. This time course was then compared to the 5-year follow-up of the patients. HMGB1 levels varied before chemotherapy between 4.1 and 11.3 ng/mL and reacted differently in response to therapy. Some patients showed an increase while others did not show any changes. Therefore, we subdivided the patient collective into two groups: patients with an at least 1.1 ng/mL increase in HMGB1 and patients with smaller changes. The disease-free survival was longer in the HMGB1 increase group (56.2 months vs. 46.6 months), but this difference did not reach significance. The overall survival (OS) was significantly better in patients with an increase in HMGB1 (log rank P = 0.021). These data suggest that an immediate increase in HMGB1 levels correlates with improved outcome in early breast cancer patients receiving neoadjuvant chemotherapy, and may be a valuable complementary biomarker for early estimation of prognosis. PMID- 27457219 TI - Virus genomics and evolution: the transformative effect of new technologies and multidisciplinary collaboration on virus research and outbreak management. AB - The first Virus Genomics and Evolution Conference was held at the Wellcome Genome Campus in Hinxton, UK, 8-10 June 2016. PMID- 27457220 TI - Serum YKL-40 and gestational diabetes - an observational cohort study. AB - To examine serum YKL-40 in women developing gestational diabetes mellitus (GDM). In the present large observational cohort study of 1179 pregnant women, we determined serum YKL-40 four times during pregnancy (at gestational age 12, 20, 25, and 32 weeks). Pregnancy outcome was obtained from medical records. Sixty eight women (5.8%) developed GDM. Serum YKL-40 increased from gestational age (GA) 12 weeks and the following weeks in the women who developed GDM and was independent of BMI, parity, and maternal age (OR = 2.69, 95% CI: 1.45-5.00, p = 0.002). No association was found between serum YKL-40 and the oral glucose tolerance test results. In conclusion, YKL-40 significantly increased in pregnant women with GDM compared with women without GDM, probably reflecting the low-grade inflammation of GDM. However, we did not find an association between serum concentrations of YKL-40 in early pregnancy and the development of GDM and thus we conclude that YKL-40 alone is not usable as a biomarker for early prediction of GDM. PMID- 27457221 TI - Waitlist Outcomes of Liver Transplant Candidates Who Were Reprioritized Under Share 35. AB - Under Share 35, deceased donor (DD) livers are offered regionally to candidates with Model for End-Stage Liver Disease (MELD) scores >=35 before being offered locally to candidates with MELD scores <35. Using Scientific Registry of Transplant Recipients data from June 2013 to June 2015, we identified 1768 DD livers exported to regional candidates with MELD scores >=35 who were transplanted at a median MELD score of 39 (interquartile range [IQR] 37-40) with 30-day posttransplant survival of 96%. In total, 1764 (99.8%) exports had an ABO compatible candidate in the recovering organ procurement organization (OPO), representing 1219 unique reprioritized candidates who would have had priority over the regional candidate under pre-Share 35 allocation. Reprioritized candidates had a median waitlist MELD score of 31 (IQR 27-34) when the liver was exported. Overall, 291 (24%) reprioritized candidates had a comparable MELD score (within 3 points of the regional recipient), and 209 (72%) were eventually transplanted in 11 days (IQR 3-38 days) using a local (50%), regional (50%) or national (<1%) liver; 60 (21%) died, 13 (4.5%) remained on the waitlist and nine (3.1%) were removed for other reasons. Of those eventually transplanted, MELD score did not increase in 57%; it increased by 1-3 points in 37% and by >=4 points in 5.7% after the export. In three cases, OPOs exchanged regional exports within a 24-h window. The majority of comparable reprioritized candidates were not disadvantaged; however, 21% died after an export. PMID- 27457222 TI - Identification of host transcriptional networks showing concentration-dependent regulation by HPV16 E6 and E7 proteins in basal cervical squamous epithelial cells. AB - Development of cervical squamous cell carcinoma requires increased expression of the major high-risk human-papillomavirus (HPV) oncogenes E6 and E7 in basal cervical epithelial cells. We used a systems biology approach to identify host transcriptional networks in such cells and study the concentration-dependent changes produced by HPV16-E6 and -E7 oncoproteins. We investigated sample sets derived from the W12 model of cervical neoplastic progression, for which high quality phenotype/genotype data were available. We defined a gene co-expression matrix containing a small number of highly-connected hub nodes that controlled large numbers of downstream genes (regulons), indicating the scale-free nature of host gene co-expression in W12. We identified a small number of 'master regulators' for which downstream effector genes were significantly associated with protein levels of HPV16 E6 (n = 7) or HPV16 E7 (n = 5). We validated our data by depleting E6/E7 in relevant cells and by functional analysis of selected genes in vitro. We conclude that the network of transcriptional interactions in HPV16-infected basal-type cervical epithelium is regulated in a concentration dependent manner by E6/E7, via a limited number of central master-regulators. These effects are likely to be significant in cervical carcinogenesis, where there is competitive selection of cells with elevated expression of virus oncoproteins. PMID- 27457223 TI - Overweight and obesity and its socio-demographic correlates among urban Ethiopian women: evidence from the 2011 EDHS. AB - BACKGROUND: Evidences show that the burden of overweight and obesity is increasing in developing countries, particularly among urban women. Despite this worrying trend and the recognition of the emerging problem of chronic diseases in the recently launched Health Sector Transformation Plan of Ethiopia, little efforts are being made to address overweight and obesity. The present study aimed at assessing the prevalence and socio-demographic correlates of overweight and obesity among urban women. METHODS: This study was based on the 2011 Ethiopian Demographic Health Survey (EDHS) that used a two-stage stratified cluster sampling technique. A total of 3602 non-pregnant urban reproductive age women were included in the analysis. Simple descriptive, bivariate and multiple logistic regression analysis were employed as appropriate. RESULTS: The prevalence of overweight and obesity among urban Ethiopian women was found to be 435 (12.1 %) and 99 (2.8 %), respectively. Urban women in the age groups from 20 29 years [Adjusted Odds Ratio (AOR) = 2.3 95 % CI: 1.4, 3.9], 30-39 years (AOR = 5.0 95 % CI: 2.9, 8.8) and 40-49 years (AOR = 9.8 95 % CI: 5.1, 13.8) were significantly more likely to have overweight and obesity compared to the youngest age group (15 to 19 years). The odds of being overweight and obese was significantly higher among women in the richest quintile (AOR = 1.8 95 % CI: 1.1, 2.5), those with secondary and above education (AOR = 2.0 95 % CI: (1.3, 3.1) and married women (AOR = 2.0 95 % CI: (1.2, 3.3). CONCLUSIONS: The prevalence of overweight and obesity was found to be higher in urban women compared to the national average. Being married, older, belonging to the richest quintile, living in the three metropolises (Addis Ababa, Harari and Dire Dawa), and with secondary and above educational level are independent predictors of overweight and obesity. Programs that target on older, educated and well to do women, and those living in the big cities are expected to cope with this substantial public health concern. PMID- 27457225 TI - Editorial. PMID- 27457224 TI - Postural control and contingent negative variation during transient floor translation while standing with the ankle fixed. AB - BACKGROUND: Adaptation changes in postural muscle activity and anticipatory attention were investigated with the ankle joint fixed to change postural control strategies during transient floor translation. METHODS: For 15 healthy young adults, 40 transient floor translations (S2) in the anterior direction were applied 2 s after an auditory warning signal (S1), under conditions with or without fixation of the ankle. Activity of the frontal postural muscles (tibialis anterior (TA), rectus femoris (RF), rectus abdominis) and contingent negative variation (CNV, brain potential) were analyzed for 20 trials each of the early and latter halves under each fixation condition. RESULTS: With fixation, peak amplitude of muscle activity after S2 was significantly decreased in TA and increased in RF. These muscles showed marked adaptive decreases. The early component of CNV reduced with adaptation, particularly under fixation condition. Only in RF, background activity increased just before S2, with adaptation under fixation. A significant correlation was found between timings of CNV peak and RF activation just before S2 only after adaptation under fixation. CONCLUSION: These results suggest that the main activation muscle changes from TA to RF with fixation. Under such condition, attention would be focused on the knee with adaptation, and the need for heightening attention in the early stage may have declined. Correspondingly, the timing to heighten stiffness of the RF became later, and attention would have been paid to RF activation just before S2. PMID- 27457226 TI - Cerebello-cortical networks in orthostatic tremor. PMID- 27457227 TI - Resting state MRI: a new marker of prodromal neurodegeneration? PMID- 27457228 TI - Brain activity and Alzheimer's disease: a complex relationship. PMID- 27457229 TI - The flexible brain. PMID- 27457230 TI - Corrigendum. PMID- 27457231 TI - Expression of Ccdc85C, a causative protein for murine hydrocephalus, in the mammary gland tumors of dogs. AB - Coiled-coil domain containing 85c (Ccdc85c) is a causative gene for hemorrhagic hydrocephalus mouse which shows hydrocephalus with frequent brain hemorrhage and formation of subcortical band heterotopia. A previous study revealed that Ccdc85C protein is expressed in the systemic simple epithelial cells with proliferative activity in rats and suggested that Ccdc85C expression may be related to the cell proliferation of simple epithelial cells. To reveal the roles of Ccdc85C in the proliferative lesion, we examined the expression patterns of Ccdc85C in the mammary gland tumor of dogs, a common representative tumor derived from simple epithelial cells. In canine mammary gland tumors, Ccdc85C was expressed at the apical junctions of the luminal epithelial cells. Ccdc85C was also distributed throughout the entire cytoplasm of the myoepithelial cells. Ccdc85C expression was observed at the epithelial cells with luminal structures, but was not observed at the epithelial cells forming sheet growth pattern without luminal structure. In carcinomas, Ccdc85C expression in mammary tumor tissue tended to be weaker than that in surrounding normal mammary gland tissue. Ccdc85C is known to cause neurological diseases such as hydrocephalus, and subcortical heterotopia, and the present study is the first to demonstrate Ccdc85C expression in canine mammary tumors and a relationship between Ccdc85C expression and tumor malignancy. PMID- 27457232 TI - Surgical intervention strategies for congenital tracheal stenosis associated with a tracheal bronchus based on the location of stenosis. AB - PURPOSE: The aim of this study was to determine the appropriate surgical intervention strategies for congenital tracheal stenosis (CTS) associated with a tracheal bronchus based on the location of stenosis. METHODS: The medical records of 13 pediatric patients with CTS associated with a tracheal bronchus at a single institution between January 2006 and December 2015 were retrospectively reviewed. RESULTS: Type 1: tracheal stenosis above the right upper lobe bronchus (RULB) (n = 1). One patient underwent slide tracheoplasty and was successfully extubated. Type 2: tracheal stenosis below the RULB (n = 7). Tracheal end-to-end anastomosis was performed before 2014, and one patient failed to extubate. Posterior-anterior slide tracheoplasty was performed since 2014, and all three patients were successfully extubated. Type 3: tracheal stenosis above the RULB to the carina (n = 5). One patient underwent posterior-anterior slide tracheoplasty and was successfully extubated. Two patients with left-right slide tracheoplasty and another two patients with tracheal end-to-end anastomosis for the stenosis below the RULB could not be extubated. CONCLUSION: Tracheal end-to-end anastomosis or slide tracheoplasty can be selected for tracheal stenosis above the RULB according to the length of stenosis. Posterior-anterior slide tracheoplasty appears feasible for tracheal stenosis below the RULB or above the RULB to the carina. PMID- 27457234 TI - Who Are the Children Most Vulnerable to Social Exclusion? The Moderating Role of Self-Esteem, Popularity, and Nonverbal Intelligence on Cognitive Performance Following Social Exclusion. AB - Social exclusion has a profound emotional impact on children. However, there is still limited and partly conflicting experimental evidence for the possible effect of social exclusion on children's cognitive performance. In the present study, we tested the possibility that some children are more vulnerable than others to the negative effects of social exclusion on cognitive performance. We selected 4 potential candidates that could moderate the effects of social exclusion: relational self-esteem, peer ratings of popularity, rejection sensitivity and nonverbal intelligence. Individual differences in these 4 potential moderating factors were first assessed in a sample of 318 children (45.6 % females; mean age = 9.92 years). Then, in a subsequent experimental session, the participants were either socially included or excluded using a typical manipulation (i.e., the Cyberball paradigm). Following the manipulation, the children's cognitive performance was assessed using a logical reasoning test. The results showed that the children with lower scores for relational self-esteem (the bottom 37.46 % of the sample), lower popularity (43.49 %) or weaker nonverbal intelligence (37.80 %) performed worse on the logical reasoning test following social exclusion. Moreover, children with combined low self-esteem, popularity and nonverbal intelligence were the most affected by social exclusion. This study identified factors that make some children more vulnerable to the negative effects of social exclusion. Overall, the present work underscores the value of considering basic cognitive and relational individual differences when developing interventions aimed at preventing the negative effects of social exclusion among children. PMID- 27457233 TI - Relation between amount of bile ducts in portal canal and outcomes in biliary atresia. AB - BACKGROUND: There is no good prognostic indicator for biliary atresia (BA). We reviewed liver biopsies taken during the initial procedure to find a prognostic marker. METHODS: Thirty-two BA cases underwent Kasai operation from 1976 to 2009. We compared two groups at 1, 3, and 9 years. Group A required liver transplantation or died. Group B survived with their native liver. Biopsies were analyzed for liver fibrosis, portal-central vein bridging (P-C bridging), ductal plate malformation (DPM) and the number of the bile ducts in portal canal/measured surface area of the portal canal (BDP ratio). Statistical comparisons of the multiple data were evaluated by Mann-Whitney U test, Student's t test and Pearson's Chi-square test. Regression analysis with P < 0.05 was considered significant. RESULTS: BDP ratios (/mm(2)) were 2.4 +/- 1.5 in Group A1 (n = 9) vs 4.6 +/- 2.4 in Group B1 (n = 23) (P = 0.01); 2.6 +/- 1.4 in Group A3 (n = 14) vs 5.1 +/- 2.5 in Group B3 (n = 18) (P < 0.01), 3.0 +/- 2.2 in Group A9 (n = 15) vs 4.9 +/- 2.5 in Group B9 (n = 15) (P < 0.05). There was no significant difference in any other finding. CONCLUSION: The BDP ratio is a sound prognostic indicator in BA. PMID- 27457235 TI - Antitumor evaluation of two selected Pakistani plant extracts on human bone and breast cancer cell lines. AB - BACKGROUND: The medicinal plants Vincetoxicum arnottianum (VSM), Berberis orthobotrys (BORM), Onosma hispida (OHRM and OHAM) and Caccinia macranthera (CMM) are used traditionally in Pakistan and around the world for the treatment of various diseases including cancer, dermal infections, uterine tumor, wounds etc. The present study focuses on the investigation of the selected Pakistani plants for their potential as anticancer agents on human bone and breast cancer cell lines in comparison with non-tumorigenic control cells. METHODS: The antitumor evaluation was carried out on human bone (MG-63, Saos-2) and breast cancer cell lines (MCF-7, BT-20) in contrast to non-tumorigenic control cells (POB, MCF-12A) via cell viability measurements, cell cycle analysis, Annexin V/PI staining, microscopy based methods as well as migration/invasion determination, metabolic live cell monitoring and western blotting. RESULTS: After the first initial screening of the plant extracts, two extracts (BORM, VSM) revealed the highest potential with regard to its antitumor activity. Both extracts caused a significant reduction of cell viability in the breast and bone cancer cells in a concentration dependent manner. The effect of VSM is achieved primarily by inducing a G2/M arrest in the cell cycle and the stabilization of the actin stress fibers leading to reduced cell motility. By contrast BORM's cytotoxic properties were caused through the lysosomal-mediated cell death pathway indicated by an upregulation of Bcl-2 expression. CONCLUSIONS: The antitumor evaluation of certain medicinal plants presented in this study identified the methanolic root extract of Berberis orthobotrys and the methanolic extract of Vincetoxicum arnottianum as promising sources for exhibiting the antitumor activity. Therefore, the indigenous use of the herbal remedies for the treatment of cancer and cancer-related diseases has a scientific basis. Moreover, the present study provides a base for phytochemical investigation of the plant extracts. PMID- 27457236 TI - Curcumin as a MicroRNA Regulator in Cancer: A Review. AB - Curcumin is a natural dietary polyphenol for which anti-tumor effects have been documented. Anti-inflammatory and antioxidant properties of curcumin, along with its immunomodulatory, proapoptotic, and antiangiogenic properties, are often referred to as the main mechanisms underlying the anti-tumor effects. At the molecular level, inhibition of NF-kB, Akt/PI3K, and MAPK pathways and enhancement of p53 are among the most important anticancer alterations induced by curcumin. Recent evidence has suggested that epigenetic alterations are also involved in the anti-tumor properties of curcumin. Among these curcumin-induced epigenetic alterations is modulation of the expression of several oncogenic and tumor suppressor microRNAs (miRNAs). Suppression of oncomiRs such as miR-21, miR-17-5p, miR-20a, and miR-27a and over-expression of miR-34 a/c and epithelial-mesenchymal transition-suppressor miRNAs are among the most important effects of curcumin on miRNA homeostasis. The present review will summarize the findings of in vitro and experimental studies on the impact of curcumin and its analogues on the expression of miRNAs involved in different stages of tumor initiation, growth, metastasis, and chemo-resistance. PMID- 27457237 TI - Should There be Concern About Autoimmune Diabetes in Adults? Current Evidence and Controversies. AB - Autoimmune diabetes has a heterogeneous phenotype. Although often considered a condition starting in childhood, a substantial proportion of type 1 diabetes presents in adult life. This holds important implications for our understanding of the factors that modify the rate of progression through the disease prodrome to clinical diabetes and for our management of the disease. When autoimmune diabetes develops in adulthood, insulin treatment is often not required at the time of diagnosis, and this autoimmune non-insulin requiring diabetes is generally termed latent autoimmune diabetes in adults (LADA). Patients with LADA are generally leaner, younger at diabetes onset; have a greater reduction in C peptide; and have a greater likelihood of insulin treatment as compared with patients with type 2 diabetes. The LADA subset of patients with adult-onset autoimmune diabetes has highlighted many shortcomings in the classification of diabetes and invokes the case for more personalized data analysis in line with the move towards precision medicine. Perhaps most importantly, the issues highlight our persistent failure to engage with the heterogeneity within the most common form of autoimmune diabetes, that is adult-onset type 1 diabetes, both insulin-dependent and initially non-insulin requiring (LADA). This review discusses characteristics of autoimmune diabetes and specifically aims to illustrate the heterogeneity of the disease. PMID- 27457238 TI - A Review of Insulin-Dosing Formulas for Continuous Subcutaneous Insulin Infusion (CSII) for Adults with Type 1 Diabetes. AB - Dosing guidelines for patients with type 1 diabetes using continuous subcutaneous insulin infusion (CSII), which are historically based on clinical experience and retrospective studies of patients consuming an American diet, recommend that basal insulin should represent approximately 50 % of the total daily dose (TDD). Recent prospective studies in the USA and Japan conclude that the more appropriate proportion is closer to 30-40 % of TDD. In addition, currently used formulas for calculating the carbohydrate-to-insulin ratio (CIR) and correction factor (CF) may lead to underdosing of bolus insulin by as much as 12.8-50 % for a hypothetical patient. The discrepancies between traditional formulas and data from newer studies can be accounted for by the more rigorous design of the newer studies (e.g., prospective design, controlled diets, meal omission, and frequent glucose monitoring). International differences in diet composition may also be important to consider when developing dosing recommendations for CSII. PMID- 27457239 TI - Multiple lesions of gastrointestinal tract invasion by monomorphic epitheliotropic intestinal T-cell lymphoma, accompanied by duodenal and intestinal enteropathy-like lesions and microscopic lymphocytic proctocolitis: a case series. AB - BACKGROUND: In East Asia, monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), previously known as type II enteropathy-associated T-cell lymphoma (EATL), occurs more frequently than type I EATL, and coeliac disease is rare. CASE PRESENTATION: Here we present four cases of MEITL in Japanese patients, including the endoscopic and pathological findings of their duodenal and colorectal lesions. Tumor specimens obtained from duodenal, intestinal, and colorectal biopsies in all four patients showed a diffuse intramucosal infiltration of small to/or medium-sized lymphoma cells and numerous atypical intraepithelial lymphocytes (IELs). These cells were immunohistologically positive for CD103, CD3, CD7, CD8, CD56, and T-cell intracellular antigen-1. Upper and lower gastrointestinal and antegrade double-balloon endoscopy revealed foci of edematous mucosa, with or without villous atrophy, in the non-neoplastic mucosa. Histological studies demonstrated duodenal and intestinal enteropathy like lesions as well as microscopic (lymphocytic) proctocolitis with increased CD3- and CD8-positive and CD56-negative T-IELs in all four patients. The clinicopathological findings of the non-neoplastic lesions were similar to those characteristic of coeliac disease, suggesting that variants of coeliac disease may be present in the prodromal lesions of MEITL. CONCLUSIONS: Our study supports the need for random gastrointestinal biopsies to determine tumor spread, the features of MEITL in the particular patients, and the presence of prodromal non neoplastic lesions. PMID- 27457240 TI - The Role of Executive Control and Readiness to Change in Problematic Drinkers with Mild to Borderline Intellectual Disability. AB - BACKGROUND: Problematic alcohol use is associated with neuropsychological consequences, including cognitive biases. The goal of the study was to explore the moderating role of executive control and readiness to change on the relationship between alcohol use and cognitive biases in light and problematic drinkers with and without mild to borderline intellectual disability (MBID). METHOD: Participants (N = 112) performed the visual dot probe task to measure the strength of the cognitive biases. Executive control was measured using two computerised tasks for working memory capacity (Corsi block-tapping task) and inhibitory control (Go/No-go task). Readiness to change was measured using the Readiness to Change Questionnaire. RESULTS: No cognitive biases or executive dysfunctions were found in problematic drinkers. Working memory capacity and inhibitory control were impaired among individuals with MBID, irrespective of severity of alcohol use-related problems. Executive control and readiness to change did not moderate the relationship between alcohol use and cognitive biases. CONCLUSION: The results fail to support the dual-process models of addiction, but results need to be treated with caution given the problematic psychometric qualities of the visual dot probe task. Implementing a neurocognitive assessment and protocols in the treatment of substance use disorders seems premature. PMID- 27457241 TI - Corneal biomechanical changes in eyes with small incision lenticule extraction and laser assisted in situ keratomileusis. AB - BACKGROUND: Evaluating the corneal biomechanical changes using the Ocular Response Analyzer and the Corvis ST in eyes with incision lenticule extraction (SMILE) and laser assisted in situ keratomileusis (LASIK). METHODS: This is a retrospective study that included 50 eyes equally divided into two groups. The first group included eyes that underwent SMILE procedure using VisuMax(r) 500 kHz laser system (Carl Zeiss Meditec, Jena, Germany) and the second group included eyes that underwent LASIK procedure using the EX500 Allegretto excimer laser platform (Wavelight GmbH, Erlangen, Germany). The Ocular Response Analyzer (ORA) and the Corvis ST (CST) measured the corneal biomechanical changes before and after the procedures. RESULTS: The ORA showed significant decrease of corneal hysteresis (CH) and corneal resistance factor (CRF) in both groups postoperatively. The percentage of change of CH and CRF were found to be significantly higher in group II. There was no significant difference in the IOP with the ORA and the CST pre and postoperatively in either group. Using CST, the deformation amplitude and HC peak distances increased significantly in both groups. It was also noted that the mean percentage of change of the deformation amplitude was nearly five times higher in group II than group I. CONCLUSION: Both LASIK and SMILE substantially decreased the corneal biomechanical properties with greater reduction in the LASIK group. PMID- 27457242 TI - Perils of police action: a cautionary tale from US data sets. AB - OBJECTIVE: To count and characterise injuries resulting from legal intervention by US law enforcement personnel and injury ratios per 10 000 arrests or police stops, thus expanding discussion of excessive force by police beyond fatalities. DESIGN: Ecological. POPULATION: Those injured during US legal police intervention as recorded in 2012 Vital Statistics mortality census, 2012 Healthcare Cost and Utilization Project nationwide inpatient and emergency department samples, and two 2015 newspaper censuses of deaths. EXPOSURE: 2012 and 2014 arrests from Federal Bureau of Investigation data adjusted for non-reporting jurisdictions; street stops and traffic stops that involved vehicle or occupant searches, without arrest, from the 2011 Police Public Contact Survey (PPCS), with the percentage breakdown by race computed from pooled 2005, 2008 and 2011 PPCS surveys due to small case counts. RESULTS: US police killed or injured an estimated 55 400 people in 2012 (95% CI 47 050 to 63 740 for cases coded as police involved). Blacks, Native Americans and Hispanics had higher stop/arrest rates per 10 000 population than white non-Hispanics and Asians. On average, an estimated 1 in 291 stops/arrests resulted in hospital-treated injury or death of a suspect or bystander. Ratios of admitted and fatal injury due to legal police intervention per 10 000 stops/arrests did not differ significantly between racial/ethnic groups. Ratios rose with age, and were higher for men than women. CONCLUSIONS: Healthcare administrative data sets can inform public debate about injuries resulting from legal police intervention. Excess per capita death rates among blacks and youth at police hands are reflections of excess exposure. International Classification of Diseases legal intervention coding needs revision. PMID- 27457243 TI - Official government statistics of road traffic deaths in India under-represent pedestrians and motorised two wheeler riders. AB - BACKGROUND: Reliable data on traffic deaths are important for planning road safety programmes and evaluating progress. Although pedestrians comprise approximately 40% of traffic deaths in low-income and middle-income countries, official government statistics in India suggest that pedestrians comprise less than 10% of deaths. OBJECTIVE: To assess the accuracy of official tabulations of traffic deaths among various road users in India. METHOD: We reviewed police first information reports (FIRs) of traffic deaths in one district (Belgaum) in 2013 and 2014 and extracted information about crash victims. We validated the FIRs by linking with case files from four police stations in the district. Finally, we compared the information on types of road users killed based on FIRs with the district's official tabulations. RESULTS: We found that the distribution of deaths by types of road users reported in official tabulations differed substantially from the underlying police reports. While official tabulations reported that only 9% of deaths in 2013 were pedestrians and 37% were riders of motorised two wheelers, FIRs showed that these groups accounted for 21% and 49% of deaths, respectively. DISCUSSION: Official tabulations of traffic deaths in India do not correctly represent the types of roads users killed. Until the Indian National Crime Records Bureau has corrected the process of generating statistical tabulations from police reports, data on the types of road users killed in India should not be used for research and policy. In the interim, researchers and policy makers who need such information should extract it from police case files. PMID- 27457244 TI - The Utilization of the Monte Carlo Technique for Rational Drug Discovery. AB - Quantitative structure - activity relationships (QSARs) are built up for three endpoints (i) blood-brain barrier permeability; (ii) butyrylcholinesterase (BChE) inhibitory activity; and (iii) for biological effect of antibacterial drugs. The models are based on utilization of the Monte Carlo technique. The CORAL software available on the Internet has been utilized for the calculations. The principles of validation of models together with principles of selection of potential therapeutic agents are suggested. An original version of the definition for the domain of applicability as well as the mechanistic interpretation of model calculated with the Monte Carlo technique are described. Advantages and disadvantages of the utilized approach are discussed. PMID- 27457245 TI - Dispersal of human and plant pathogens biofilms via nitric oxide donors at 4 degrees C. AB - Recent studies suggest that nitric oxide donors capable of manipulating nitric oxide-mediated signaling in bacteria could induce dispersal of biofilms. Encased in extracellular polymeric substances, human and plant pathogens within biofilms are significantly more resistant to sanitizers. This is particularly a problem in refrigerated environments where food is processed. In an exercise aimed to study the potential of nitric oxide donors as biofilm dispersal in refrigerated conditions, we compared the ability of different nitric oxide donors (SNAP, NO aspirin and Noc-5) to dislodge biofilms formed by foodborne, human and plant pathogens treated at 4 degrees C. The donors SNAP and Noc-5 were efficient in dispersing biofilms formed by Salmonella enterica, pathogenic Escherichia coli and Listeria innocua. The biomasses were decreased up to 30 % when compared with the untreated controls. When the plant pathogens Pectobacterium sp. and Xanthomonas sp. were tested the dispersion was mainly limited to Pectobacterium carotovorum biofilms, decreasing up to 15 % after exposure to molsidomine. Finally, the association of selected nitric oxide donors with sanitizers (DiQuat, H2O2, peracetic acid and PhenoTek II) was effective in dispersing biofilms. The best dispersal was achieved by pre-treating P. carotovorum with molsidomine and then peracetic acid. The synergistic effect was estimated up to ~35 % in dispersal when compared with peracetic acid alone. The association of nitric oxide donors with sanitizers could provide a foundation for an improved sanitization procedure for cleaning refrigerate environments. PMID- 27457247 TI - Epilepsy as a risk factor for hepatic encephalopathy in patients with cirrhosis: a cohort study. AB - BACKGROUND: Epilepsy is associated with an increased mortality among cirrhosis patients, but the reasons are unknown. We aimed to determine whether epilepsy is a risk factor for developing hepatic encephalopathy (HE), which is a strong predictor of mortality. METHODS: We used data from three randomized 1-year trials of satavaptan in cirrhosis patients with ascites. With Cox regression, we compared the hazard rates of HE grade 1-4 between those cirrhosis patients who did or did not have epilepsy. We adjusted for confounding by gender, age, cirrhosis etiology, diabetes, history of HE, Model for Endstage Liver Disease (MELD) score, serum sodium, albumin, lactulose use, rifaximin use, and benzodiazepine/barbiturate sedation. In a supplementary analysis we examined the association between epilepsy and the hazard rate of HE grade 2-4. RESULTS: Of the 1120 cirrhosis patients with ascites, 21 (1.9 %) were diagnosed with epilepsy. These patients had better liver function at inclusion than the patients without epilepsy (median MELD score 7.9 vs. 11.4), and only one died during the trials. Nevertheless, seven patients with epilepsy had an HE episode during the follow up, and the adjusted hazard ratio of HE grade 1-4 for patients with epilepsy vs. controls was 2.12 (95 % CI 0.99-4.55). The corresponding hazard ratio of HE grade 2-4 was 3.83 (95 % CI 1.65-8.87). CONCLUSIONS: Our findings suggest that epilepsy is associated with an increased risk of HE in patients with cirrhosis. PMID- 27457246 TI - MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression. AB - BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and frequently progresses from an actinic keratosis (AK), a sun induced keratinocyte intraepithelial neoplasia (KIN). Epigenetic mechanisms involved in the phenomenon of progression from AK to cSCC remain to be elicited. METHODS: Expression of microRNAs in sun-exposed skin, AK and cSCC was analysed by Agilent microarrays. DNA methylation of miR-204 promoter was determined by bisulphite treatment and pyrosequencing. Identification of miR-204 targets and pathways was accomplished in HaCat cells. Immunofluorescence and immunohistochemistry were used to analyze STAT3 activation and PTPN11 expression in human biopsies. RESULTS: cSCCs display a marked downregulation of miR-204 expression when compared to AK. DNA methylation of miR-204 promoter was identified as one of the repressive mechanisms that accounts for miR-204 silencing in cSCC. In HaCaT cells miR-204 inhibits STAT3 and favours the MAPK signaling pathway, likely acting through PTPN11, a nuclear tyrosine phosphatase that is a direct miR-204 target. In non-peritumoral AK lesions, activated STAT3, as detected by pY705-STAT3 immunofluorescence, is retained in the membrane and cytoplasm compartments, whereas AK lesions adjacent to cSCCs display activated STAT3 in the nuclei. CONCLUSIONS: Our data suggest that miR-204 may act as a "rheostat" that controls the signalling towards the MAPK pathway or the STAT3 pathway in the progression from AK to cSCC. PMID- 27457248 TI - Women's experience of maternal morbidity: a qualitative analysis. AB - BACKGROUND: Maternal morbidity refers to pregnancy-related complications, ranging in severity from acute to chronic. In Ireland one in 210 maternities will experience a severe morbidity. Yet, how women internalize their experience of morbidity has gone largely unexplored. This study aimed to explore women's experiences of maternal morbidity. METHODS: A qualitative semi-structured interview format was utilized. Purposive sampling was used to recruit 14 women with a maternal morbidity before, during or after birth; nine women were diagnosed with one morbidity including hypertensive disorders, haemorrhage, placenta praevia and gestational diabetes whereas five women were diagnosed with two or more morbidities. Thematic analysis was employed as the analytic strategy. RESULTS: Four superordinate themes were identified: powerlessness, morbidity management, morbidity treatment and socio-behavioural responses to morbidities. Women were accepting of the uncontrollable nature of the adverse outcome experienced. While being treated for trauma, women were satisfied to relinquish their autonomy to ensure the safety of themselves and their babies. However, these events were debilitating. Women's inability to control their own bodies, as a result of the morbidity, contributed to high levels of frustration and anxiety. Morbidities impacted greatly on women's quality of life and sometimes these effects persisted for a prolonged period after delivery. Women felt that they were provided very little information on the practicalities of living with their condition; many were uncertain how to manage their morbidities in the home setting. CONCLUSION: Healthcare providers should ensure that women who experience a maternal morbidity are fully debriefed and have sufficient information on the morbidity including ongoing care and expectations prior to discharge. PMID- 27457249 TI - Histone deacetylases function as novel potential therapeutic targets for cancer. AB - Diverse cellular functions, including tumor suppressor gene expression, DNA repair, cell proliferation and apoptosis, are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) are enzymes involved in remodeling of chromatin by deacetylating the lysine residues. They play a pivotal role in epigenetic regulation of gene expression. Dysregulation of HDACs and aberrant chromatin acetylation and deacetylation have been implicated in the pathogenesis of various diseases, including cancer. Histone deacetylases have become a target for the development of drugs for treating cancer because of their major contribution to oncogenic cell transformation. Overexpression of HDACs correlates with tumorigenesis. Previous work showed that inhibition of HDACs results in apoptosis and the inhibition of cell proliferation in multiple cells. A significant number of HDAC inhibitors have been developed in the past decade. These inhibitors have strong anticancer effects in vitro and in vivo, inducing growth arrest, differentiation, and programmed cell death, inhibiting cell migration, invasion, and metastasis, and suppressing angiogenesis. In addition, HDAC-mediated deacetylation alters the transcriptional activity of nuclear transcription factors, including p53, E2F, c-Myc, and nuclear factor-kappaB, as well as the extracellular signal-regulated kinase1/2, phosphatidylinositol 3 kinase, Notch, and Wnt signaling pathways. This review highlights the role of HDACs in cancer pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets. PMID- 27457250 TI - The insect-specific Palm Creek virus modulates West Nile virus infection in and transmission by Australian mosquitoes. AB - BACKGROUND: Insect-specific viruses do not replicate in vertebrate cells, but persist in mosquito populations and are highly prevalent in nature. These viruses may naturally regulate the transmission of pathogenic vertebrate-infecting arboviruses in co-infected mosquitoes. Following the isolation of the first Australian insect-specific flavivirus (ISF), Palm Creek virus (PCV), we investigated routes of infection and transmission of this virus in key Australian arbovirus vectors and its impact on replication and transmission of West Nile virus (WNV). METHODS: Culex annulirostris, Aedes aegypti and Aedes vigilax were exposed to PCV, and infection, replication and transmission rates in individual mosquitoes determined. To test whether the virus could be transmitted vertically, progeny reared from eggs oviposited by PCV-inoculated Cx. annulirostris were analysed for the presence of PCV. To assess whether prior infection of mosquitoes with PCV could also suppress the transmission of pathogenic flaviviruses, PCV positive or negative Cx. annulirostris were subsequently exposed to WNV. RESULTS: No PCV-infected Cx. annulirostris were detected 16 days after feeding on an infectious blood meal. However, when intrathoracically inoculated with PCV, Cx. annulirostris infection rates were 100 %. Similar rates of infection were observed in Ae. aegypti (100 %) and Ae. vigilax (95 %). Notably, PCV was not detected in any saliva expectorates collected from any of these species. PCV was not detected in 1038 progeny reared from 59 PCV-infected Cx. annulirostris. After feeding on a blood meal containing 10(7) infectious units of WNV, significantly fewer PCV-infected Cx. annulirostris were infected or transmitted WNV compared to PCV negative mosquitoes. Immunohistochemistry revealed that PCV localized in the midgut epithelial cells, which are the first site of infection with WNV. CONCLUSIONS: Our results indicate that PCV cannot infect Cx. annulirostris via the oral route, nor be transmitted in saliva or vertically to progeny. We also provide further evidence that prior infection with insect-specific viruses can regulate the infection and transmission of pathogenic arboviruses. PMID- 27457251 TI - Understanding Differences in Administrative and Audited Patient Data in Cardiac Surgery: Comparison of the University HealthSystem Consortium and Society of Thoracic Surgeons Databases. AB - BACKGROUND: The University HealthSystem Consortium (UHC) administrative database has been used increasingly as a quality indicator for hospitals and even individual surgeons. We aimed to determine the accuracy of cardiac surgical data in the administrative UHC database vs data in the clinical Society of Thoracic Surgeons database. STUDY DESIGN: We reviewed demographic and outcomes information of patients with aortic valve replacement (AVR), mitral valve replacement (MVR), and coronary artery bypass grafting (CABG) surgery between January 1, 2012, and December 31, 2013. Data collected in aggregate and compared across the databases included case volume, physician specialty coding, patient age and sex, comorbidities, mortality rate, and postoperative complications. RESULTS: In these 2 years, the UHC database recorded 1,270 AVRs, 355 MVRs, and 1,473 CABGs. The Society of Thoracic Surgeons database case volumes were less by 2% to 12% (1,219 AVRs; 316 MVRs; and 1,442 CABGs). Errors in physician specialty coding occurred in UHC data (AVR, 0.6%; MVR, 0.8%; and CABG, 0.7%). In matched patients from each database, demographic age and sex information was identical. Although definitions differed in the databases, percentages of patients with at least one comorbidity were similar. Hospital mortality rates were similar as well, but postoperative recorded complications differed greatly. CONCLUSIONS: In comparing the 2 databases, we found similarity in patient demographic information and percentage of patients with comorbidities. The small difference in volumes of each operation type and the larger disparity in postoperative complications between the databases were related to differences in data definition, data collection, and coding errors. PMID- 27457253 TI - Impact of Income Inequality on the Nation's Health. AB - BACKGROUND: Income inequality in the United States has been increasing in recent decades. It is unclear whether income inequality has an independent effect on health outcomes, or whether it simply correlates with increasing levels of poverty. The goal of this study was to evaluate whether income inequality is significantly associated with US county health care expenditures and health care use. STUDY DESIGN: Cross-sectional analysis of county health expenditure data from the Health Resources and Services Administration's Area Resources File, county income inequality measures (Gini coefficient) from the Census' American Community Survey, and estimates of potentially preventable admissions and potentially discretionary procedures from the Nationwide Inpatient Sample (1998 to 2011). Datasets were linked via county Federal Information Processing Standard codes. Multivariable linear and Poisson regression analyses were performed at the county level adjusting for county characteristics. RESULTS: A total of 1,237 counties (of 3,144) were included. Income inequality was associated with higher health care expenditures, with each 1 percentage-point increase in county Gini coefficient associated with a US$40,008 increase in annual county Medicare cost (p = 0.003), and an increase of 174.7 total county Medicare inpatient days per year (p < 0.001). Even after accounting for poverty level and county characteristics, counties with higher inequality had higher potentially preventable admission (eg 4.86 rate ratio for low-birth-weight hospital admissions in the top income inequality quartile compared with bottom quartile; p < 0.001) and a higher incidence of potentially discretionary procedures (eg 1.79 rate ratio for prostatectomy for benign prostatic hyperplasia in the top income inequality quartile compared with bottom quartile; p < 0.001). CONCLUSIONS: Income inequality is independently associated with higher health care expenditures and more health care use, with increases in both potentially discretionary procedures and in potentially preventable admissions. PMID- 27457252 TI - Insurance Type and Solid Organ Transplantation Outcomes: A Historical Perspective on How Medicaid Expansion Might Impact Transplantation Outcomes. AB - BACKGROUND: The number of Medicaid beneficiaries has increased under the Affordable Care Act, improving access to solid organ transplantation in this disadvantaged patient cohort. It is unclear what impact Medicaid expansion will have on transplantation outcomes. We performed a retrospective cohort analysis to measure the frequency and variation in Medicaid transplantation and post transplantation survival in Medicaid patients. STUDY DESIGN: Adult heart, lung, liver, and renal transplant recipients between 2002 and 2011 (n = 169,194) reported to the Scientific Registry of Transplant Recipients were identified. Transplant recipients were classified based on insurance status (private, Medicare or Medicaid). Outcomes measures included 5-year post-transplantation survival, summarized using Kaplan-Meier curves and compared with log-rank tests. Organ-specific Cox proportional hazards models were used to adjust for donor and recipient factors. RESULTS: Medicaid patients comprised 8.6% of all organ transplant recipients. Fewer transplantations were performed than expected among Medicaid beneficiaries for all organs except liver (liver: observed to expected ratio = 1.21; 95% CI, 0.68-1.90; heart: observed to expected ratio = 0.89; 95% CI, 0.44-1.49; lung: observed to expected ratio = 0.57; 95% CI, 0.22-1.06; renal: observed to expected ratio = 0.32; 95% CI, 0.08-0.72). Medicaid transplant recipients were listed with more severe organ failure and experienced shorter transplant wait times. Post-transplantation survival was lower in Medicaid patients compared with private insurance for all organs. Post-transplantation survival in Medicaid patients was similar to Medicare patients for heart, liver, and renal but lower in lung. CONCLUSIONS: Medicaid organ transplant beneficiaries had significantly lower survival compared with privately insured beneficiaries. The more severe organ failure among Medicaid beneficiaries at the time of listing, suggested a pattern of late referral, which might account for worse outcomes. Implementation of the Affordable Care Act gives the opportunity to develop the necessary infrastructure to ensure timely transplantation referrals and improve long-term outcomes in this vulnerable population. PMID- 27457254 TI - Elimination of Routine Contact Precautions for Endemic Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus: A Retrospective Quasi-Experimental Study. AB - OBJECTIVE To evaluate the impact of discontinuation of contact precautions (CP) for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) and expansion of chlorhexidine gluconate (CHG) use on the health system. DESIGN Retrospective, nonrandomized, observational, quasi experimental study. SETTING Two California hospitals. PARTICIPANTS Inpatients. METHODS We compared hospital-wide laboratory-identified clinical culture rates (as a marker of healthcare-associated infections) 1 year before and after routine CP for endemic MRSA and VRE were discontinued and CHG bathing was expanded to all units. Culture data from patients and cost data on material utilization were collected. Nursing time spent donning personal protective equipment was assessed and quantified using time-driven activity-based costing. RESULTS Average positive culture rates before and after discontinuing CP were 0.40 and 0.32 cultures/100 admissions for MRSA (P=.09), and 0.48 and 0.40 cultures/100 admissions for VRE (P=.14). When combining isolation gown and CHG costs, the health system saved $643,776 in 1 year. Before the change, 28.5% intensive care unit and 19% medicine/surgery beds were on CP for MRSA/VRE. On the basis of average room entries and donning time, estimated nursing time spent donning personal protective equipment for MRSA/VRE before the change was 45,277 hours/year (estimated cost, $4.6 million). CONCLUSION Discontinuing routine CP for endemic MRSA and VRE did not result in increased rates of MRSA or VRE after 1 year. With cost savings on materials, decreased healthcare worker time, and no concomitant increase in possible infections, elimination of routine CP may add substantial value to inpatient care delivery. Infect Control Hosp Epidemiol 2016;1-8. PMID- 27457255 TI - Long-term Follow-up of Patients With Retinitis Pigmentosa Receiving Intraocular Ciliary Neurotrophic Factor Implants. AB - PURPOSE: To evaluate the long-term efficacy of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa. DESIGN: Long-term follow-up of a multicenter, sham controlled study. METHODS: Thirty-six patients at 3 CNTF4 sites were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoint (change in visual field sensitivity at 12 months) had been reported previously. Here we measure long-term visual acuity, visual field, and optical coherence tomography (OCT) outcomes in 24 patients either retaining or explanting the device at 24 months relative to sham-treated eyes. RESULTS: Eyes retaining the implant showed significantly greater visual field loss from baseline than either explanted eyes or sham eyes through 42 months. By 60 months and continuing through 96 months, visual field loss was comparable among sham-treated eyes, eyes retaining the implant, and explanted eyes, as was visual acuity and OCT macular volume. CONCLUSIONS: Over the short term, ciliary neurotrophic factor released continuously from an intravitreal implant led to loss of total visual field sensitivity that was greater than the natural progression in the sham-treated eye. This additional loss of sensitivity related to the active implant was reversible when the implant was removed. Over the long term (60-96 months), there was no evidence of efficacy for visual acuity, visual field sensitivity, or OCT measures of retinal structure. PMID- 27457256 TI - p16 Expression Is Not a Surrogate Marker for High-Risk Human Papillomavirus Infection in Periocular Sebaceous Carcinoma. AB - PURPOSE: To evaluate the role of high-risk human papillomavirus (HR-HPV) infection in periocular sebaceous carcinoma (SC) using multiple methods of detection, and to determine whether p16 overexpression is present and can be used as a surrogate marker for HR-HPV. DESIGN: Retrospective observational case series with laboratory investigations. METHODS: Unstained paraffin sections of 35 cases of periocular SC were analyzed with immunohistochemistry for p16 and subjected to polymerase chain reaction (PCR) for HR-HPV. A subset of 18 lesions that were p16 positive was further studied with a novel method of mRNA in situ hybridization (ISH) for the detection of transcriptionally active HR-HPV, an advanced technique with an enhanced sensitivity and specificity. RESULTS: The clinical findings were in keeping with those of comparable earlier studies. Strong immunohistochemical p16 positivity (meeting the criterion of >70% nuclear and cytoplasmic staining) was present in 29 of 35 cases of periocular SC (82.9%). The selected 18 p16 positive cases tested were negative for HR-HPV using mRNA ISH. PCR yielded unequivocal results with adequate DNA isolated in 24 cases, 23 of which were negative for HR-HPV. One case was positive for HPV type 16, which was found to be a false positive as collaterally determined by mRNA ISH negativity. CONCLUSION: No evidence was found for HR-HPV as an etiologic agent in the development of periocular SC using multiple modalities to maximize sensitivity and specificity and reduce the limitations of any single test. p16 overexpression is common in periocular SC but unrelated to HR-HPV status. Although p16 may be used as a surrogate marker for HR-HPV status in other tissue sites, this interpretation of p16 positivity is not applicable to periocular SC. PMID- 27457257 TI - Efficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 Hours. AB - PURPOSE: To compare the diurnal and nocturnal effects of latanoprostene bunod 0.024% solution with timolol maleate 0.5% solution on intraocular pressure (IOP) and ocular perfusion pressure. DESIGN: Prospective, open-label randomized crossover trial. METHODS: Twenty-five patients (aged 43-82 years) with ocular hypertension or early primary open-angle glaucoma were enrolled. Baseline IOP and blood pressure were measured in a sleep laboratory every 2 hours in the sitting and supine positions during the 16-hour diurnal/wake period and in the supine position during the 8-hour nocturnal/sleep period. Subjects were randomly assigned to bilateral treatments of latanoprostene bunod at 8 PM or timolol at 8 AM and 8 PM. The second laboratory recording occurred after the 4-week treatment. Subjects were crossed over to the comparator treatment for 4 weeks before the third laboratory recording. Mean IOP and calculated ocular perfusion pressure were compared for the diurnal and nocturnal periods. RESULTS: Twenty-one subjects completed the study. Both treatments reduced diurnal sitting and supine IOP compared to baseline by 2.3-3.9 mm Hg (all P < .001) with no statistically significant difference between the 2 treatments. Nocturnal IOP under latanoprostene bunod treatment was 2.5 +/- 3.1 mm Hg (mean +/- SD) less than baseline (P = .002) and 2.3 +/- 3.0 mm Hg less than timolol treatment (P = .004). Latanoprostene bunod treatment resulted in greater diurnal sitting and supine ocular perfusion pressures compared with baseline (P <= .006) and greater nocturnal ocular perfusion pressure compared with timolol treatment (P = .010). CONCLUSIONS: During the nocturnal period, latanoprostene bunod caused more IOP reduction and more increase of ocular perfusion pressure than timolol. PMID- 27457258 TI - Collective Synthesis of 3-Acylindoles, Indole-3-carboxylic Esters, Indole-3 sulfinic Acids, and 3-(Methylsulfonyl)indoles from Free (N-H) Indoles via Common N-Indolyl Triethylborate. AB - A general and direct C3 functionalization of free (N-H) indoles with readily available electrophiles such as acid chlorides, chloroformates, thionyl chloride, and methylsulfonyl chloride via a common N-indolyl triethylborate intermediate is reported. The reaction proceeds smoothly under mild conditions in up to 93% yield. Indoles with substituents at the C2, C4, C5, C6, and C7 positions are well tolerated. The easy accessibility of a variety of important 3-acylindoles, indole 3-carboxylic esters, indole-3-sulfinic acids, and 3-(methylsulfonyl)indoles demonstrates the high degree of compatibility and practicability of this method. PMID- 27457259 TI - A weird polyp, 8 years after the Whipple procedure. PMID- 27457260 TI - Limitations in Predicting Organ Confined Prostate Cancer in Patients with Gleason Pattern 4 on Biopsy: Implications for Active Surveillance. AB - PURPOSE: In prostate cancer biopsy Gleason score predicts stage and helps determine active surveillance suitability. Evidence suggests that small incremental differences in the quantitative percent of Gleason pattern 4 on biopsy stratify disease extent, biochemical failure following surgery and eligibility for active surveillance. We explored the overall quantitative percent of Gleason pattern 4 levels and adverse outcomes in patients with low and intermediate risk prostate cancer to whom active surveillance may be offered under expanded criteria. MATERIALS AND METHODS: We analyzed the records of patients with biopsy Gleason score 6 (3 + 3) or 7 (3 + 4) who underwent radical prostatectomy from January 2008 to August 2015. Age, prostate specific antigen, Gleason score, quantitative percent of Gleason pattern 4, overall percent positive cores (percent of prostate cancer) and clinical stage were explored as predictors of nonorgan confined disease and time to failure after radical prostatectomy. RESULTS: In 1,255 patients biopsy Gleason score 7 (3 + 4) was associated with T3 or greater disease at radical prostatectomy in 35.0% compared with Gleason score 6 (3 + 3) in 19.0% (p <0.001). On multivariate analysis for each quantitative percent of Gleason pattern 4 increase there were 2% higher odds of T3 or greater disease (OR 1.02, 95% CI 1.01-1.04, p <0.001). When stratified, patients with Gleason score 7 (3 + 4) only approximated the pT3 rates of Gleason score 6 (3 + 3) when prostate specific antigen was less than 8 ng/ml and the percent of prostate cancer was less than 15%. In those cases the quantitative percent of Gleason pattern 4 had less effect. Time to failure after radical prostatectomy was worse in Gleason score 7 (3 + 4) than 6 (3 + 3) cases. CONCLUSIONS: The quantitative percent of Gleason pattern 4 helps predict advanced disease and Gleason score 7 (3 + 4) is associated with worse outcomes. However, the impact of the quantitative percent of Gleason pattern 4 on adverse pathological and clinical outcomes is best used in combination with prostate specific antigen, age and disease volume since each has a greater impact on predicting nonorgan confined disease. The calculated absolute risk of T3 or greater can be used in shared decision making on prostate cancer treatment by patients and clinicians. PMID- 27457261 TI - Safety and Efficacy of En Bloc Renal Hilar Vascular Staple Ligation: A Meta Analysis. AB - PURPOSE: We reviewed the literature on the safety of en bloc ligation. We also performed a meta-analysis of the effect of using this technique with vascular staplers on perioperative factors compared to conventional renal pedicle dissection and isolated staple ligation of the renal artery and vein. MATERIALS AND METHODS: A literature search was performed to include all primary studies related to the safety of en bloc ligation of the renal hilum. After exclusion criteria were applied 9 studies were identified for review, of which 4 included a control group and were used in the meta-analysis. The primary end point was the incidence of arteriovenous fistula. Secondary end points were procedure duration, blood loss and the number of perioperative complications. RESULTS: None of the total population of 595 patients in whom en bloc ligation was performed for nephrectomy were diagnosed with arteriovenous fistula formation at an average postoperative followup of 26.5 months. When comparing en bloc and isolated ligation of the renal artery and vein, the meta-analysis showed a significant improvement in procedure duration for en bloc nephrectomy. There was no difference in estimated blood loss or the number of complications. CONCLUSION: En bloc ligation appears to be as safe as and potentially more beneficial in terms of perioperative factors than conventional renal pedicle dissection and isolated vascular ligation. PMID- 27457262 TI - Percutaneous Reduction and Fixation with Kirschner Wires versus Open Reduction Internal Fixation for the Management of Calcaneal Fractures: A Meta-Analysis. AB - The aim of our meta-analysis was to compare outcomes for two surgical treatments of calcaneal fractures, percutaneous reduction and fixation with Kirschner wires (PRFK) and open reduction internal fixation (ORIF), with the intent of evaluating the quality of evidence to inform practice. Search of MEDLINE, Cochrane and CNKI databases to identify randomized controlled trials (RCTs) comparing PRKF and ORIF on the following outcomes: post-operative function, complications and quality of the reduction. Odd ratios (OR) and weighted mean differences were pooled using either a fixed-effects or random-effects model, depending on the heterogeneity of the trials included in the analysis. Eighteen RCTs provided the data from 1407 patients. PRFK was associated with a lower risk of surgical wound complications, and ORIF with better post-operative function, angle of Gissane, calcaneal height, and calcaneal width. There were no statistically significant differences between the techniques with regards to post-operative Bohler's angle. PRFK does not provide a substantive advantage over ORIF for the treatment of calcaneal fractures in adults. PRFK may, however, yield comparable functional outcomes to ORIF for closed Sanders type II calcaneal fractures but with less complication related to surgical wound healing. PMID- 27457263 TI - Pine Needles for the Screening of Perfluorinated Alkylated Substances (PFASs) along Ski Tracks. AB - Perfluorinated alkylated substances (PFASs) are today considered persistent, toxic, and bioaccumulative contaminants. Perfluorooctansulfonate (PFOS) and perfluorooctanoic acid (PFOA) are currently listed as priority substances under the UNEP global convention for the regulation of POPs. A previous study reported higher levels of PFASs in pine needles near ski areas. Their application as stain repellents in modern outdoor clothes and in ski waxes is assumed to be a potential source. Pine trees (Pinus mugo in Slovakia and Pinus sylvestris in Norway) were chosen for sampling in ski resorts. Relative distributions, overall concentrations, trend estimates, elevation patterns, and distance from primary sources were assessed. PFOA was the predominant PFAS constituent in pine needles from Slovakia (8-93%). In Norway, the most-abundant PFAS was perfluorobutanoic acid (PFBA: 3-66%). A difference in product composition (particularly in ski waxes) and differences in Norwegian and Slovakian regulations are considered to be the primary reason for these differences. Open application of PFOA in industry and products has been banned in Norway since 2011. The replacement of PFOA with short-chain substitutes is thus considered the reason for the observed pattern differences in the analyzed pine needles. Regular monitoring and screening programs are recommended. PMID- 27457265 TI - Variable Temperature Infrared Spectroscopy Studies of Aromatic Acid Adsorbate Effects on Montmorillonite Dehydration. AB - Molecular interactions between benzoic, salicylic, and acetylsalicylic acids and water contained within montmorillonite clay interlayer spaces are characterized by using variable temperature diffuse reflection infrared Fourier transform spectroscopy (VT-DRIFTS). By using sample perturbation and difference spectroscopy, infrared (IR) spectral variations resulting from the removal of interlayer water are used to characterize aromatic acid local environment changes. Difference spectra features representing functional group perturbations are correlated with changes in IR absorptions associated with -O-H and -C = O stretching vibrations. Results suggest that adsorbate carboxylic acid functionalities participate in extensive hydrogen bonding and that the strengths of these interactions are diminished when clays are dehydrated. The nature of these interactions and their temperature-dependent properties are found to depend on adsorbate structure and concentration as well as the clay interlayer cation. PMID- 27457264 TI - Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice. AB - Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces beta-amyloid (Abeta) production and plaque formation after 6 weeks of treatment in 4.5-month-old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c-Jun N-terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Abeta metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Abeta pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD. PMID- 27457266 TI - Improving the Historical Knowledge and Writing of Students With or At Risk for LD. AB - In this study, we explored the potential of two forms of discussion (disciplinary vs. traditional) for 39 sixth- and seventh-grade students with or at risk for learning disabilities (LD), before writing historical arguments. Nine teachers who led small group discussions in six heterogeneous social studies classrooms implemented the intervention. Students who were involved in disciplinary discussions ( n = 19) scored statistically higher than their peers who engaged in traditional discussions ( n = 20) on a measure of historical knowledge (partial eta2 = .23); they also wrote essays with better persuasive quality (partial eta2 = .43) and greater evidence of historical thinking (partial eta2 = .40). A delayed posttest delivered 8 weeks after instruction ended revealed that students in the experimental condition continued to write in more historically sophisticated ways than did students in the comparison condition (partial eta2 = .19). Challenges, however, remain for struggling learners who must now meet basic and advanced disciplinary literacy goals. PMID- 27457267 TI - Quantum phase estimation using path-symmetric entangled states. AB - We study the sensitivity of phase estimation using a generic class of path symmetric entangled states |phi>|0> + |0>|phi>, where an arbitrary state |phi> occupies one of two modes in quantum superposition. With this generalization, we identify the fundamental limit of phase estimation under energy constraint that is characterized by the photon statistics of the component state |phi>. We show that quantum Cramer-Rao bound (QCRB) can be indefinitely lowered with super Poissonianity of the state |phi>. For possible measurement schemes, we demonstrate that a full photon-counting employing the path-symmetric entangled states achieves the QCRB over the entire range [0, 2pi] of unknown phase shift phi whereas a parity measurement does so in a certain confined range of phi. By introducing a component state of the form , we particularly show that an arbitrarily small QCRB can be achieved even with a finite energy in an ideal situation. This component state also provides the most robust resource against photon loss among considered entangled states over the range of the average input energy Nav > 1. Finally we propose experimental schemes to generate these path symmetric entangled states for phase estimation. PMID- 27457268 TI - Plant responses to tomato chlorotic mottle virus: Proteomic view of the resistance mechanisms to a bipartite begomovirus in tomato. AB - : Tomato chlorotic mottle virus (ToCMoV) is a widespread bipartite Begomovirus species found in tomato fields in Brazil. In this study, plant responses and putative mechanisms associated with the 'Tyking'-derived recessive resistance to ToCMoV were investigated. Changes in the protein profile in the inoculated plants of two near isogenic tomato lines resistant ('LAM 157') and susceptible ('Santa Clara') to ToCMoV were analyzed. Seedlings were biolistically inoculated with an infectious ToCMoV clone. Leaves from infected plants (confirmed by PCR) were sampled at 15days after inoculation. Proteins were extracted using phenol and analyzed by shotgun MS (2D-nanoUPLC/HDMSE). Out of the 534 identified proteins, 82 presented statistically significant differences in abundance, including 35 unique proteins displayed in the resistant tomato inoculated with ToCMoV. Proteins associated to chromatin structure, cytoskeleton structure, cuticle biosynthesis, and ubiquitin pathway were identified and their putative roles during virus infection process were discussed. The protein profile analysis allowed for the development of a hypothetical model showing how the resistant host cell responds to ToCMoV infection. The data obtained provide a better understanding of resistant mechanisms used by the host plant to contain viral infection and could be the basis for further investigation in other plant begomovirus pathosystems. BIOLOGICAL SIGNIFICANCE: In this study we propose a model of resistance to begomovirus in tomato and highlight host proteins, which could be targets for future investigations in plant-begomovirus pathosystems. PMID- 27457269 TI - Proteome analysis of acute kidney injury - Discovery of new predominantly renal candidates for biomarker of kidney disease. AB - : The main bottleneck in studies aiming to identify novel biomarkers in acute kidney injury (AKI) has been the identification of markers that are organ and process specific. Here, we have used different tissues from a controlled porcine renal ischemia/reperfusion (I/R) model to identify new, predominantly renal biomarker candidates for kidney disease. Urine and serum samples were analyzed in pre-ischemia, ischemia (60min) and 4, 11 and 16h post-reperfusion, and renal cortex samples after 24h of reperfusion. Peptides were analyzed on the Q ExactiveTM. In renal cortex proteome, we observed an increase in the synthesis of proteins in the ischemic kidney compared to the contralateral, highlighted by transcription factors and epithelial adherens junction proteins. Intersecting the set of proteins up- or down-regulated in the ischemic tissue with both serum and urine proteomes, we identified 6 proteins in the serum that may provide a set of targets for kidney injury. Additionally, we identified 49, being 4 predominantly renal, proteins in urine. As prove of concept, we validated one of the identified biomarkers, dipeptidyl peptidase IV, in a set of patients with diabetic nephropathy. In conclusion, we identified 55 systemic proteins, some of them predominantly renal, candidates for biomarkers of renal disease. BIOLOGICAL SIGNIFICANCE: The main bottleneck in studies aiming to identify novel biomarkers in acute kidney injury (AKI) has been the identification of markers that are predominantly renal. In fact, putative biomarkers for this condition have also been identified in a number of other clinical scenarios, such as cardiovascular diseases, chronic kidney failure or in patients being treated in intensive care units from a number of conditions. Here we propose a comprehensive, sequential screening procedure able to identify and validate potential biomarkers for kidney disease, using kidney ischemia/reperfusion as a paradigm for a kidney pathological event. PMID- 27457270 TI - Proteomic identification of putative biomarkers for early detection of sudden cardiac death in a family with a LMNA gene mutation causing dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is a severe heart disease characterized by progressive ventricular dilation and impaired systolic function of the left ventricle. We recently identified a novel pathogenic mutation in the LMNA gene in a family affected by DCM showing sudden death background. We now aimed to identify potential biomarkers of disease status, as well as sudden death predictors, in members of this family. We analysed plasma samples from 14 family members carrying the mutation, four of which (with relevant clinical symptoms) were chosen for the proteomic analysis. Plasma samples from these four patients and from four sex- and age-matched healthy controls were processed for their enrichment in low- and medium-abundance proteins (ProteoMinerTM) prior to proteomic analysis by 2D-DIGE and MS. 111 spots were found to be differentially regulated between mutation carriers and control groups, 83 of which were successfully identified by MS, corresponding to 41 different ORFs. Some proteins of interest were validated either by turbidimetry or western blot in family members and healthy controls. Actin, alpha-1-antytripsin, clusterin, vitamin-D binding protein and antithrombin-III showed increased levels in plasma from the diseased group. We suggest following these proteins as putative biomarkers for the evaluation of DCM status in LMNA mutation carriers. BIOLOGICAL SIGNIFICANCE: We developed a proteomic analysis of plasma samples from a family showing history of dilated cardiomyopathy caused by a LMNA mutation, which may lead to premature death or cardiac transplant. We identified a number of proteins augmented in mutation carriers that could be followed as potential biomarkers for dilated cardiomyopathy on these patients. PMID- 27457271 TI - The Twin Study of Negative Valence Emotional Constructs. AB - The Twin Study of Negative Valence Emotional Constructs is a multi-site study designed to examine the relationship between a broad selection of potential measures designed to assess putative endophenotypes for negative valence systems (NVS) and early symptoms of internalizing disorders (IDs). In this article, we describe the sample characteristics, data collection protocols, and measures used. Pre-adolescent Caucasian twin pairs were recruited through the Mid-Atlantic Twin Registry; data collection began in February of 2013. Enrolled twins completed various dimensional self-report measures along with cognitive, emotional, and psychophysiological tasks designed to assess NVS function. Parents also completed surveys about their twins and themselves. In addition, a subset of the twins also participated in a neuroimaging protocols. Data collection is in the final stages, and preliminary analyses are underway. The findings will potentially expand our understanding of the mechanisms by which genetic and environmental factors contribute to individual differences in NVS phenotypes and provide new insights into underlying risk factors for IDs. PMID- 27457273 TI - Entanglement classification with matrix product states. AB - We propose an entanglement classification for symmetric quantum states based on their diagonal matrix-product-state (MPS) representation. The proposed classification, which preserves the stochastic local operation assisted with classical communication (SLOCC) criterion, relates entanglement families to the interaction length of Hamiltonians. In this manner, we establish a connection between entanglement classification and condensed matter models from a quantum information perspective. Moreover, we introduce a scalable nesting property for the proposed entanglement classification, in which the families for N parties carry over to the N + 1 case. Finally, using techniques from algebraic geometry, we prove that the minimal nontrivial interaction length n for any symmetric state is bounded by . PMID- 27457272 TI - Distinct genomic architecture of Plasmodium falciparum populations from South Asia. AB - Previous whole genome comparisons of Plasmodium falciparum populations have not included collections from the Indian subcontinent, even though two million Indians contract malaria and about 50,000 die from the disease every year. Stratification of global parasites has revealed spatial relatedness of parasite genotypes on different continents. Here, genomic analysis was further improved to obtain country-level resolution by removing var genes and intergenic regions from distance calculations. P. falciparum genomes from India were found to be most closely related to each other. Their nearest neighbors were from Bangladesh and Myanmar, followed by Thailand. Samples from the rest of Southeast Asia, Africa and South America were increasingly more distant, demonstrating a high-resolution genomic-geographic continuum. Such genome stratification approaches will help monitor variations of malaria parasites within South Asia and future changes in parasite populations that may arise from in-country and cross-border migrations. PMID- 27457274 TI - Chemical Platform for the Preparation of Synthetic Orally Active Peptidomimetics with Hemoregulating Activity. AB - A novel chemical platform based on branched piperazine-2,5-dione derivatives (2,5 diketopiperazines) for creating orally available biologically active peptidomimetics has been developed. The platform includes a diketopiperazine scaffold with "built-in" functionally active peptide fragments covalently attached via linkers. The concept was applied to two hemostimulatory drugs, the dipeptide thymogen (GluTrp) and the tripeptide stemokin (IleGluTrp). Preparation of a series of respective derivatives is described. Of the five synthesized analogues, three demonstrated high hemostimulatory activity in vivo on intact mice and on ex vivo irradiated bone marrow cells. Prospects of further development of the concept are discussed. PMID- 27457275 TI - Predicting post-endoscopic retrograde cholangiopancreatography pancreatitis using the 4-h serum lipase level. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a complex therapeutic procedure that is complicated by pancreatitis in 3-5% of cases. The aim of this study is to determine whether a 4-h post-ERCP serum lipase level is superior to the serum amylase level in predicting the occurrence of post-ERCP pancreatitis (PEP). METHODS: We performed a retrospective review of prospectively collected data on 543 consecutive patients undergoing therapeutic ERCP at a single centre. Serum lipase and amylase levels were measured at 4-h post procedure and were recorded as a factor of the upper limit of normal: amylase factor (AF) and lipase factor (LF). Sensitivity and specificity were compared using receiver-operating characteristics and the Youden index (YI). RESULTS: A total of 506 procedures were considered for analysis. PEP occurred in 19 patients (3.8%). A LF of <10 was useful for the exclusion of PEP with a sensitivity of 100% and a specificity of 94%, YI = 0.94. In contrast, an AF <3 yielded a sensitivity of 79% and specificity of 94%, YI = 0.73. CONCLUSION: Serum lipase measured at 4-h post-ERCP better excludes PEP than serum amylase measured at the same time point. Patients with a LF <10 may be safely considered for same-day discharge. PMID- 27457276 TI - Anti-TIF1-gamma-positive young adult dermatomyositis with germ cell tumour. PMID- 27457277 TI - Vagal innervation is required for the formation of tertiary lymphoid tissue in colitis. AB - Tertiary lymphoid tissue (TLT) is lymphoid tissue that forms in adult life as a result of chronic inflammation in a tissue or organ. TLT has been shown to form in a variety of chronic inflammatory diseases, though it is not clear if and how TLT develops in the inflamed colon during inflammatory bowel disease. Here, we show that TLT develops as newly formed lymphoid tissue in the colon following dextran sulphate sodium induced colitis in C57BL/6 mice, where it can be distinguished from the preexisting colonic patches and solitary intestinal lymphoid tissue. TLT in the inflamed colon develops following the expression of lymphoid tissue-inducing chemokines and adhesion molecules, such as CXCL13 and VCAM-1, respectively, which are produced by stromal organizer cells. Surprisingly, this process of TLT formation was independent of the lymphotoxin signaling pathway, but rather under neuronal control, as we demonstrate that selective surgical ablation of vagus nerve innervation inhibits CXCL13 expression and abrogates TLT formation without affecting colitis. Sympathetic neuron denervation does not affect TLT formation. Hence, we reveal that inflammation in the colon induces the formation of TLT, which is controlled by innervation through the vagus nerve. PMID- 27457278 TI - Raman spectroscopic signature of fractionalized excitations in the harmonic honeycomb iridates beta- and gamma-Li2IrO3. AB - The fractionalization of elementary excitations in quantum spin systems is a central theme in current condensed matter physics. The Kitaev honeycomb spin model provides a prominent example of exotic fractionalized quasiparticles, composed of itinerant Majorana fermions and gapped gauge fluxes. However, identification of the Majorana fermions in a three-dimensional honeycomb lattice remains elusive. Here we report spectroscopic signatures of fractional excitations in the harmonic-honeycomb iridates beta- and gamma-Li2IrO3. Using polarization-resolved Raman spectroscopy, we find that the dynamical Raman response of beta- and gamma-Li2IrO3 features a broad scattering continuum with distinct polarization and composition dependence. The temperature dependence of the Raman spectral weight is dominated by the thermal damping of fermionic excitations. These results suggest the emergence of Majorana fermions from spin fractionalization in a three-dimensional Kitaev-Heisenberg system. PMID- 27457279 TI - Piscivorous fish exhibit temperature-influenced binge feeding during an annual prey pulse. AB - Understanding the limits of consumption is important for determining trophic influences on ecosystems and predator adaptations to inconsistent prey availability. Fishes have been observed to consume beyond what is sustainable (i.e. digested on a daily basis), but this phenomenon of hyperphagia (or binge feeding) is largely overlooked. We expect hyperphagia to be a short-term (1-day) event that is facilitated by gut volume providing capacity to store consumed food during periods of high prey availability to be later digested. We define how temperature, body size and food availability influence the degree of binge feeding by comparing field observations with laboratory experiments of bull trout (Salvelinus confluentus), a large freshwater piscivore that experiences highly variable prey pulses. We also simulated bull trout consumption and growth during salmon smolt outmigrations under two scenarios: 1) daily consumption being dependent upon bioenergetically sustainable rates and 2) daily consumption being dependent upon available gut volume (i.e. consumption is equal to gut volume when empty and otherwise 'topping off' based on sustainable digestion rates). One-day consumption by laboratory-held bull trout during the first day of feeding experiments after fasting exceeded bioenergetically sustainable rates by 12- to 87-fold at low temperatures (3 degrees C) and by ~1.3-fold at 20 degrees C. The degree of binge-feeding by bull trout in the field was slightly reduced but largely in agreement with laboratory estimates, especially when prey availability was extremely high [during a sockeye salmon (Oncorhynchus nerka) smolt outmigration and at a counting fence where smolts are funnelled into high densities]. Consumption by bull trout at other settings were lower and more variable, but still regularly hyperphagic. Simulations demonstrated the ability to binge-feed increased cumulative consumption (16-32%) and cumulative growth (19 110%) relative to only feeding at bioenergetically sustainable rates during the ~1-month smolt outmigration period. Our results indicate the ability for predators to maximize short-term consumption when prey are available can be extreme and is limited primarily by gut volume, then mediated by temperature; thus, predator-prey relationships may be more dependent upon prey availability than traditional bioenergetic models suggest. Binge-feeding has important implications for energy budgets of consumers as well as acute predation impacts on prey. PMID- 27457280 TI - Broccoli sprout extract prevents diabetic cardiomyopathy via Nrf2 activation in db/db T2DM mice. AB - To develop a clinic-relevant protocol for systemic up-regulation of NFE2-related factor 2 (Nrf2) to prevent diabetic cardiomyopathy (DCM), male db/db and age matched wild-type (WT) mice were given sulforaphane (SFN, an Nrf2 activator) and its natural source, broccoli sprout extract (BSE) by gavage every other day for 3 months, with four groups: vehicle (0.1 ml/10 g), BSE-low dose (estimated SFN availability at 0.5 mg/kg), BSE-high dose (estimated SFN availability at 1.0 mg/kg), and SFN (0.5 mg/kg). Cardiac function and pathological changes (hypertrophy, fibrosis, inflammation and oxidative damage) were assessed by echocardiography and histopathological examination along with Western blot and real-time PCR, respectively. Both BSE and SFN significantly prevented diabetes induced cardiac dysfunction, hypertrophy and fibrosis. Mechanistically, BSE, like SFN, significantly up-regulated Nrf2 transcriptional activity, evidenced by the increased Nrf2 nuclear accumulation and its downstream gene expression. This resulted in a significant prevention of cardiac oxidative damage and inflammation. For all these preventive effects, BSE at high dose provided a similar effect as did SFN. These results indicated that BSE at high dose prevents DCM in a manner congruent with SFN treatment. Therefore, it suggests that BSE could potentially be used as a natural and safe treatment against DCM via Nrf2 activation. PMID- 27457281 TI - Sulforhodamine 101, a widely used astrocyte marker, can induce cortical seizure like activity at concentrations commonly used. AB - Sulforhodamine 101 (SR101) is a preferential astrocyte marker widely used in 2 photon microscopy experiments. Here we show, that topical loading of two commonly used SR101 concentrations, 100 MUM and 250 MUM when incubated for 10 min, can induce seizure-like local field potential (LFP) activity in both anaesthetized and awake mouse sensori-motor cortex. This cortical seizure-like activity develops in less than ten minutes following topical loading, and when applied longer, these neuronal discharges reliably evoke contra-lateral hindlimb muscle contractions. Short duration (<1 min) incubation of 100 MUM and 250 MUM SR101 or application of lower concentrations 25 MUM and 50 MUM of SR101, incubated for 30 and 20 min, respectively, did not induce abnormal LFP activity in sensori-motor cortex, but did label astrocytes, and may thus be considered more appropriate concentrations for in vivo astrocyte labeling. In addition to label astrocytes SR101 may, at 100 MUM and 250 MUM, induce abnormal neuronal activity and interfere with cortical circuit activity. SR101 concentration of 50 MUM or lower did not induce abnormal neuronal activity. We advocate that, to label astrocytes with SR101, concentrations no higher than 50 MUM should be used for in vivo experiments. PMID- 27457282 TI - Apicoplast fatty acid synthesis is essential for pellicle formation at the end of cytokinesis in Toxoplasma gondii. AB - The apicomplexan protozoan Toxoplasma gondii, the causative agent of toxoplasmosis, harbors an apicoplast, a plastid-like organelle with essential metabolic functions. Although the FASII fatty acid biosynthesis pathway located in the apicoplast is essential for parasite survival, the cellular effects of FASII disruption in T. gondii had not been examined in detail. Here, we combined light and electron microscopy techniques - including focused ion beam scanning electron microscopy (FIB-SEM) - to characterize the effect of FASII disruption in T. gondii, by treatment with the FASII inhibitor triclosan or by inducible knockdown of the FASII component acyl carrier protein. Morphological analyses showed that FASII disruption prevented cytokinesis completion in T. gondii tachyzoites, leading to the formation of large masses of 'tethered' daughter cells. FIB-SEM showed that tethered daughters had a mature basal complex, but a defect in new membrane addition between daughters resulted in incomplete pellicle formation. Addition of exogenous fatty acids to medium suppressed the formation of tethered daughter cells and supports the notion that FASII is essential to generate lipid substrates required for the final step of parasite division. PMID- 27457283 TI - Association of TLR polymorphisms with bronchopulmonary dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a leading cause of morbidity and mortality during infancy. Evidence suggests that the Toll-like receptor (TLR) signaling pathway plays an integral role in lung inflammation and injury. This study aimed to detect single nucleotide polymorphisms (SNPs) in TLR pathway genes [TLR5 and Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP)] among preterm neonates and to determine their association with the development and severity of bronchopulmonary dysplasia. PMID- 27457284 TI - gr/gr-DAZ2-DAZ4-CDY1b deletion is a high-risk factor for male infertility in Tunisian population. AB - The azoospermia factor c (AZFc) region harbors multi-copy genes that are expressed in the testis. Deletions of this region lead to reduced copy numbers of these genes. In this present study we aimed to determine the frequency of AZFc subdeletion in infertile and fertile men from Tunisia and to identify whether deletions of DAZ and CDY1 gene copies are deleterious on spermatogenesis and on semen quality. We studied a group of 241 infertile men and 115 fertile healthy males using a sequence tagged site (STS)+/-method. To gain insight into the molecular basis of the heterogeneous phenotype observed in men with the deletion we defined the type of DAZ and CDY1 genes deleted. We reported in the present study and for the first time a new type of AZFc deletion (gr/gr-DAZ2-DAZ4-CDY1b) and hypothesis that this new deletion is the result of two successive events. We also demonstrated that this deletion constitutes a relative high-risk factor for male infertility in Tunisian population. PMID- 27457286 TI - Multiresidual LC-MS analysis of plasticizers used in PVC gaskets of lids and assessment of their migration into food sauces. AB - Plasticizers may migrate from polyvinyl chloride (PVC) gaskets into the foodstuffs mainly by direct contact during the packaging and sterilization procedure, but also by means of occasional contacts occurring during shipment and storage. The present work reports a reliable liquid chromatography-mass spectrometry (LC-MS) method able to quantify the main plasticizers used in the PVC closure gaskets for metal lids to verify their compliance in both food contact materials and foodstuffs. The atmospheric pressure chemical ionization in the positive ion mode resulted the best performing interface for the multiresidual detection of the plasticizers taken into account, followed by selected/multiple reaction monitoring, selected ion monitoring or full scan experiments, depending on the compounds to detect. The method was single laboratory validated, demonstrating to reach a good sensitivity, thus making possible to perform analysis without any preliminary sample purification or concentration step. It proved to be effectively applicable not only for the determination of plasticizers in PVC gaskets but also in complex food matrices. In particular, it was applied for monitoring plasticizer migration into sauces placed in contact with the lids in worst storage conditions, observing therefore their trend during the shelf-life. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27457285 TI - Therapeutic potential of cysteine-rich protein 61 in rheumatoid arthritis. AB - Cysteine-rich protein 61 (Cyr61)/CCN1, a product of an immediate early gene, can directly accommodate cell adhesion and migratory processes whilst simultaneously regulating the production of other cytokines and chemokines through paracrine and autocrine feedback loops. This intricate functionality of Cyr61 indicate its important role in targeting components of the infectious or chronic inflammatory disease processes including rheumatoid arthritis (RA). Recent work has focused on the role of Cyr61 in RA. For example, Cyr61 induced proIL-1beta production in FLS via the AKT-dependent NF-kappaB signaling pathway. Moreover, Cyr61-siRNA decreased the levels of matrix metalloproteinase (MMP)-3 and MMP-13, and induced apoptosis in RA-FLS cells. These results indicated that Cyr61 may represent a novel target for the treatment of RA. In this article we will introduce the molecular properties of Cyr61, discuss the function of Cyr61, and the therapeutic potential of modulating the Cyr61 in RA. PMID- 27457287 TI - Competition between diffusion and electroconvection at an ion-selective surface in intensive current regimes. AB - Considering diffusion near a solid surface and simplifying the shape of concentration profile in diffusion-dominated layer allowed Nernst and Brunner to propose their famous equation for calculating the solute diffusion flux. Intensive (overlimiting) currents generate electroconvection (EC), which is a recently discovered interfacial phenomenon produced by the action of an external electric field on the electric space charge formed near an ion-selective interface. EC microscale vortices effectively mix the depleted solution layer that allows the reduction of diffusion transport limitations. Enhancement of ion transport by EC is important in membrane separation, nano-microfluidics, analytical chemistry, electrode kinetics and some other fields. This paper presents a review of the actual understanding of the transport mechanisms in intensive current regimes, where the role of diffusion declines in the profit of EC. We analyse recent publications devoted to explore the properties of different zones of the diffusion layer. Visualization of concentration profile and fluid current lines are considered as well as mathematical modelling of the overlimiting transfer. PMID- 27457288 TI - Tuning of linear ADRC with known plant information. AB - Linear active disturbance rejection control (ADRC) is known for its simplicity and its performance in disturbance attenuation. Currently, tuning of linear ADRC (LADRC) is via the bandwidth idea. In this paper, tuning of LADRC with known plant information is investigated. It is shown that there are limitations using only two bandwidths to tune the LADRC controllers. To take advantage of the known plant information, a generalized ADRC (GADRC) method is proposed. Then the intrinsic link between the conventional LADRC and GADRC is analyzed. It is shown that the available plant model information used in GADRC can be utilized in the designs of the observer gain and the controller gain of the conventional LADRC. Simulation results demonstrate that with known plant information incorporated, the performance of a conventional LADRC can indeed be improved, especially for unstable, time-delayed and non-minimum phase processes. PMID- 27457289 TI - Role of Kekule and Non-Kekule Structures in the Radical Character of Alternant Polycyclic Aromatic Hydrocarbons: A TAO-DFT Study. AB - We investigate the role of Kekule and non-Kekule structures in the radical character of alternant polycyclic aromatic hydrocarbons (PAHs) using thermally assisted-occupation density functional theory (TAO-DFT), an efficient electronic structure method for the study of large ground-state systems with strong static correlation effects. Our results reveal that the studies of Kekule and non-Kekule structures qualitatively describe the radical character of alternant PAHs, which could be useful when electronic structure calculations are infeasible due to the expensive computational cost. In addition, our results support previous findings on the increase in radical character with increasing system size. For alternant PAHs with the same number of aromatic rings, the geometrical arrangements of aromatic rings are responsible for their radical character. PMID- 27457290 TI - Multimodal Plasmonic Assay of Copper(II) Ion via Stimuli-Responsive State Transformation of Silver Molecular Nanoparticles. AB - Molecular nanoparticles (MNPs) have gained increased attention recently due to their unique structures and properties. However, their applications remain largely unexplored. Herein, we present an Ag MNPs-based multimodal plasmonic assay. This assay relied on changes in optical properties due to stimuli responsive state trans-formation from MNPs to plasmonic nanoparticles (PNPs). As a proof-of-concept, naked-eye colorimetric assay, spectrophotometric assay and "turn-on" Raman assay of Cu(2+) were developed. The feasibility of this approach for real-world applications was demonstrated with the determination of Cu(2+) in human serum. This multimodal plasmonic assay exhibited several significant advantages, including selectivity, sensitivity, label-free nature, and multimodal capability. Because of these merits, Ag MNPs could be promising nanosensors for wide important applications such as diagnostics and environmental analysis. PMID- 27457291 TI - Peripheral T-Cell Lymphoma-A Brief Review. PMID- 27457292 TI - Can Long-Term Bone Marrow Culture Eliminate Leukemia Cells? AB - In chronic myeloid leukemia (CML) and acute myeloblastic leukemia (AML), experimental studies have shown growth advantage of the residual normal progenitor cells under long-term culture conditions. In some instances, this culture system has been used as a tool for purging bone marrow, before autotransplant. In this review, we discuss the efficiency of this technique, with respect to the persistence of sufficient numbers of normal stem and/or progenitor cells, capable of restoring hemopoiesis following pre-transplant conditioning regimens, and in relation to the elimination of leukemia cells, capable of causing relapse. Both issues are complex, and mostly still obscure. However if one considers the clinical outcome of patients receiving unpurged autografts, it is unlikely that long-term bone marrow cultures (LTBMCs) will be of substantial benefit in reducing leukemia relapse. Furthermore the clinical efficacy of this technique will in our opinion be difficult, if not impossible, to prove. PMID- 27457293 TI - Bone Marrow Transplantation as a Model for Immunotherapy in Leukemia. PMID- 27457294 TI - Spectrum of Reactivity with Three Monoclonal Antibodies-MHM6(CD23), L30(CD24) and UCHB1-in B-Cell Leukaemias. AB - Cells from patients with a range of B-cell leukaemias have been investigated for reactivity with three monoclonal antibodies-MHM6 (CD23), L30 (CD24) and UCHB1. Cells in suspension were studied by indirect immunofluorescence and fixed cells in cytospin preparations by an indirect immunoperoxidase technique. Positive results with CD23 were obtained in two thirds of patients with chronic lymphocytic leukaemia in contrast to one quarter of cases of other mature B lineage leukaemias and lymphomas; cells of acute lymphoblastic leukaemia gave negative results. L30 (CD24) had a wide spectrum of reactivity within the B lineage with negative reactions being common only in hairy cell leukaemia and multiple myeloma/plasma cell leukaemia. UCHB1 was most frequently and most strongly positive in prolymphocytic leukaemia. Our observations suggest that these reagents, in particular L30 (CD24) and MHM6 (CD23), provide useful additional information in the differential diagnosis of B-lineage lymphoproliferative disorders. PMID- 27457295 TI - Recombinant Alpha 2A Interferon-An Effective Maintenance Agent in Essential Thrombocythaemia. AB - Recombinant alpha 2a, 2b and 2c interferons have been shown to be effective short term agents in essential thrombocythaemia and thrombocythaemia associated with the other myeloproliferative disorders, including chronic granulocytic leukaemia, polycythaemia rubra vera and myelofibrosis. Few data exist on the use of the recombinant interferons as maintenance agents in patients with thrombocythaemia. We report on a cohort of 22 previously untreated patients, with essential thrombocythaemia, treated with recombinant alpha 2a interferon maintenance therapy for a minimum period of 6 months. Effective long-term control of platelet counts, without evidence of haematological toxicity, was achieved in 19 of 22 patients. No objective haemorrhagic or thrombotic event occurred in 298 patient months of interferon therapy. Three patients discontinued alpha interferon therapy due to adverse side-effects. Alpha 2a interferon is an effective maintenance agent in essential thrombocythaemia. PMID- 27457296 TI - Polymerase Chain Reaction Analysis of t(14;18) Junctional Regions in B-Cell Lymphomas. AB - The polymerase chain reaction (PCR) procedure was used for rapid and highly specific amplification of the t(14;18) bcl-2/JH DNA junctional regions in B-cell lymphomas. By using Taq-polymerase and relatively long oligonucleotide primers-a 33-mer for bcl-2 and an universal 25-mer complementary to the JH consensus sequence-the primer annealing and primer extension steps could be carried out at the same temperature (70 degrees C), thus markedly reducing the reaction time and significantly improving the specificity of the reaction. The specificity of the amplification allowed visual identification of the bcl-2/JH PCR-products in ethidium bromide stained agarose gels. DNA-sequence analysis of PCR-amplified, previously uncharacterized t(14; 18) junctional regions, confirmed the specificity of this assay. Moreover, preliminary data show that the procedure is capable of documenting the presence of occult lymphoma cells in both the peripheral blood and bone marrow. PMID- 27457297 TI - Distinctive Pattern of Expression of Activation and Resting B Cell Antigens on Normal and Neoplastic Human B Cells: Immunophenotypic Heterogeneity in Some Lymphomas. AB - The pattern of expression of four B cell antigen systems on mature human B cells and B cell lymphomas were studied. The L30 antigen was detected on small resting B cells, while the B cell activation antigens, CD10, CD25 and L29, were expressed differentially on activated B cells. The multiparameter-flowcytometric analysis of these four antigens revealed that mature B cells changed their pattern of expression in an activation-stage specific manner. Thus, the presence of L30, CD10, CD25 and L29 on mature human B cells correlated with distinct B cell populations at a particular stage of activation. Histo-pathologically well defined B cell lymphomas were also studied for the expression of these four antigens. Burkitt's lymphoma and diffuse small cleaved lymphoma were found to have an heterogeneous expression of these antigens, suggesting that certain types of non-Hodgkin's lymphoma (NHL) are immunophenotypically heterogeneous, and that this heterogeneity may reflect a different biology and behavior in vivo. PMID- 27457298 TI - An Analysis of Circulating CD4 Lymphocyte Subpopulations in B-Cell Chronic Lymphocytic Leukaemia. AB - The distribution of circulating CD4 lymphocyte subpopulations determined by reactivity with monoclonal antibodies anti-2H4 (CD45RA), anti-UCHL1 (CD45RO), anti-4B4 (CD29) and anti-Leu8, and analysed by dual colour immunofluorescence flow cytometry is described in a series of patients with B-CLL and in age-matched control subjects. The percentages and absolute numbers of CD4 cells reactive with anti-CD45RA, anti-CD45RO and anti-CD29 reagents were similar in the patient and control groups. In contrast, CD4+ Leu8+ cells (percentages and absolute numbers) were significantly reduced in B-CLL patients resulting in an inversion of the normal CD4+ Leu8+ :CD4+Leu8- ratio. The patients' clinical or therapeutic status did not appear to influence the levels of the respective CD4 subpopulations; nor was evidence of hypogammaglobulinaemia associated with specific numerical alterations in any of the CD4 subpopulations studied. It is proposed that, in B CLL, the alterations in the CD4Leu8 subpopulations are associated with the disease process, whereas the distributions of CD4+CD45RA+, CD4+ CD45RO+ and CD4+ CD29+ cells reflect the normal physiological levels of these subpopulations in elderly subjects. PMID- 27457299 TI - Splenic Rupture in Chronic Lymphoid Disorders: Possible Role of Opportunistic Infections. AB - Two patients with lymphoproliferative disorders, one with chronic lymphocytic leukemia and the other hairy cell leukemia, developed spontaneous rupture of the spleen during the course of their disease. In both cases, this rare complication occurred during systemic atypical infections with Salmonella Dublin and Candida tropicalis respectively. We suggest that severe infection may sometimes play a decisive role in the development of the splenic rupture in some patients who have splenomegaly due to these disorders. PMID- 27457300 TI - Rapid Remission Induction and Improved Disease Free Survival in Acute Myeloid Leukaemia Using Daunorubicin, ARA-C, and CCNU. AB - Thirty-four patients with acute myeloblastic leukaemia were treated with DAC, a schedule containing the nitrosourea CCNU (lomustine) 200 mg/m2 given on day one of treatment, together with a standard "3 + 7" remission induction schedule of daunorubicin (DR) and cytosine arabinoside (Ara-C). The results were compared with an historical control group of 24 patients who received 3 + 7 remission induction (DA). The DAC patients were older (median age 55 years) compared with the DA patients (median age 42 years), and had a higher frequency of poor prognosis features including secondary AML and prior myelodysplasia (11/34 DAC patients versus 1/24 patients receiving DA). Overall remission induction was the same for both groups (79%), but 89% of DAC patients who achieved remission did so with one course, compared with 37% of DA patients. The cytopenic phase following a single course of DAC was only slightly longer than that of a single course of DA (26 days vs. 19.5 days). DAC also gave a higher three year actuarial survival than DA (34% vs. 11%), and a lower relapse probability (44% vs. 74%). These results support the hypothesis that chemotherapy for AML may be favoured by including agents such as CCNU, which are active against both non-cycling and cycling leukaemic stem cells, in remission induction schedules. PMID- 27457301 TI - Molecular Structure of the Rearranged T-Cell Gamma Chain Gene in a Human Leukemia Which Expresses Its Product. AB - The gamma gene product is a component of the second T-cell receptor. We report a new case of acute lymphoblastic leukemia bearing a CD3+ CD4- CD5+ CD7+ CD8- WT31- immunophenpotype that expresses the gamma peptide. Immunoprecipitation studies using an anti Cgamma heteroantisera showed two different bands of 40 and 60 Kd. Southern analysis revealed Cgamma1 utilization in the productive rearrangement. The demonstration of Vdelta-Jdelta1 rearrangement in this leukemia suggests that the 60 Kd band could correspond to the product of the delta gene. The utilization of the Jgamma1.3 exon in this leukemia suggests that the T lymphocytes that undergo leukemic transformation are derived from a population different from the circulating gamma/delta lymphocytes, that preferentially use the Jgamma1.2 (JgammaP) exon. PMID- 27457302 TI - Polyclonal Bence Jones Proteinuria Associated with Reactive Plasmacytosis. AB - A 43 year old black male patient presented with progressive respiratory symptoms, fever and malaise of short duration accompanied by mild epistaxis. Physical examination revealed generalised lymphadenopathy and hepatosplenomegaly. Peripheral blood examination showed a striking plasmacytosis. Further investigation revealed Bence Jones proteinuria consisting of both kappa and lambda light chains. There was no monoclonal peak on serum electrophoresis and cytoplasmic immunoglobulin and gene rearrangement studies on the peripheral blood plasma cells demonstrated polyclonality. The possible role of Epstein-Barr virus in stimulating B cell proliferation in this case is discussed. PMID- 27457303 TI - Processing of stimulus content but not of emotional valence is altered in persons with Williams syndrome. AB - BACKGROUND: Individuals with Williams syndrome (WS) exhibit hypersociability and may respond atypically to emotional information in social and nonsocial stimuli. It is not yet clear whether these difficulties are specific to emotional content or stimulus type. This study examined the neural processes supporting social and emotional information processing in WS. METHOD: Visual event-related potentials were recorded in 19 adults with WS and 10 typical peers during a picture-viewing task requiring detection of smiling faces among other social and nonsocial images with positive and negative emotional content. RESULTS: The participant groups were not significantly different in affective processing of positive and negative stimuli and perceived faces as different from nonsocial images. Participants with WS showed subtle differences in face-specific perceptual processes (e.g. face inversion, N170 lateralisation), suggesting a more feature-based processing. They also demonstrated reduced attention and arousal modulation (P3, late positive potential) in response to faces vs. nonsocial images. These differences were independent of intelligence quotient. CONCLUSIONS: There was no evidence of greater than typical perceptual, attentional or affective processing of social information in WS. The results support the idea that altered face perception processes and not the increased salience of social stimuli or difficulties with emotion discrimination may contribute to the hypersocial phenotype in WS. PMID- 27457304 TI - ATX-101 (deoxycholic acid injection) for reduction of submental fat. AB - INTRODUCTION: The shape and contour of the chin and neck play an important role in facial esthetics. As such, excess fat within the submental area (double chin) can negatively affect facial esthetics and body image. Common treatments for submental contouring include invasive procedures such as surgical rejuvenation and targeted liposuction. Energy devices (lasers, radiofrequency, and ultrasound) may be used to improve submental skin laxity while cryolipolysis was recently cleared in the United States for use in the submental area. However, ATX-101 (deoxycholic acid injection) is the only injectable drug approved in the United States and Canada for reduction of submental fat. AREAS COVERED: The efficacy and safety of ATX-101 have been extensively evaluated in a global clinical development program including multiple Phase I/II studies and four large Phase III trials. Available data from ATX-101 trials are reviewed. Expert commentary: Injectables have been well established for facial rejuvenation. Extending injectable treatment into the chin and neck is a major advance for nonsurgical cosmetic correction. Overall, the evidence supports ATX-101 as a safe and effective, minimally invasive treatment alternative for reduction of submental fat that will provide a major tool for the esthetic physician. PMID- 27457305 TI - Effect of pre-analytical treatments on bovine milk acute phase proteins. AB - BACKGROUND: Samples for diagnostic procedures often require some form of pre analytical preparation for preservation or safe handling during transportation prior to analysis in the laboratory. This is particularly important for milk samples which frequently need preservatives to retain milk composition as close to that found in freshly collected samples as possible. METHODS: Milk samples were treated by heating at 56 degrees C for 30 min or preserved by addition of either potassium dichromate or bronopol respectively. Haptoglobin (Hp), mammary associated serum amyloid A3 (M-SAA3) and C-reactive protein (CRP) were measured in the various treatment groups and in control samples which were not treated, using enzyme linked immunoassays. The concentrations of each APP were compared between treated and non-treated groups using the Wilcoxon signed ranks tests. RESULTS: Heat treatment of samples was found to have a significant lowering effect on milk M-SAA3 and CRP but not Hp. The use of potassium dichromate and bronopol as preservatives in milk had no significant effects on milk Hp and M SAA3 concentration but lowered milk CRP values compared to controls. CONCLUSIONS: The observed effects of heating and preservative use on milk APP should be taken into consideration when assaying samples which have undergone heat treatment as a result of international transfer regulations involving biological samples or samples needing chemical preservation prior to transport to laboratory. PMID- 27457306 TI - A Qualitative Study of the Subjective Appraisal of Recovery Among People with Lived Experience of Schizophrenia in Poland. AB - The objective of this study was to explore definitions of recovery among Polish service users with lived experience of schizophrenia and to hear their recommendations regarding elements that should be considered in the planning of a recovery oriented psychosocial intervention. Four semi-structured focus groups were conducted in the Institute of Psychiatry and Neurology in Warsaw, Poland. A total of 28 service users' narratives were examined using the inductive thematic analysis approach. Five main recovery themes emerged from the combined users accounts, listed in order of frequency: psychological dimension of recovery, relationships with others, wellness strategies, clinical understanding of recovery and support systems. Service user recommendations referred to the above identified recovery themes as well as indications that the intervention should be flexible, individualized, and facilitative of personal growth. The findings indicate that for service users with lived experience of schizophrenia in Poland it is culturally feasible to embrace the person-oriented approach to practice and develop a recovery-oriented psychosocial intervention emphasizing psychological domains of recovery such as positive identity, personal strengths, or meaning and purpose in life alongside the other relevant recovery dimensions. Actions regarding the system level of change are also required. PMID- 27457307 TI - Where next in kidney cancer? PMID- 27457309 TI - ESMO European Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in Europe. AB - BACKGROUND: The management of cancer is predicated on the availability and affordability of anticancer therapies, which may be either curative or noncurative. AIM: The primary aims of the study were to evaluate (i) the formulary availability of licensed antineoplastic medicines across Europe; (ii) patient out-of-pocket costs for the medications and (iii) the actual availability of the medication for a patient with a valid prescription. MATERIALS AND METHODS: The survey tool was based on the previous ESMO studies that addressed the availability and accessibility of opioids for the management of cancer pain. A total of 185 field reporters from 49 countries were invited to participate. The preliminary set of data was posted on the ESMO website for open peer-review, and amendments have been incorporated into the final report. RESULTS: There are substantial differences in the formulary availability, out-of-pocket costs and actual availability for many anticancer medicines. The most profound lack of availability is in countries with lower levels of economic development, particularly in Eastern Europe, and these are largely related to the cost of targeted agents approved in the last 10 years. Discrepancies are less profound among medications on the WHO model essential medicines list (EML) for cancer and in curative settings. However, medicine shortages also affect WHO EML medicines, with relevant therapeutic implications for many patients. CONCLUSIONS: The cost and affordability of anticancer treatments with recent market approval is the major factor contributing to inequity of access to anticancer medications. This is especially true with regards to new medications used in the management of EGFR or ALK-mutated non-small-cell lung cancer, metastatic melanoma, metastatic renal cell cancer, RAS/RAF wild-type metastatic colorectal cancer, HER2 overexpressed breast cancer and castration-resistant metastatic prostate cancer. PMID- 27457312 TI - Editor's notes. PMID- 27457313 TI - QuilQuiz. PMID- 27457310 TI - Efficacy of the nanoparticle-drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator initiated phase I-IIa clinical trial. AB - BACKGROUND: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle-drug conjugate (NDC), which durably inhibits HIF1alpha and HIF2alpha in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. PATIENTS AND METHODS: Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m(2)) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. RESULTS: Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade >=3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. CONCLUSIONS: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing. PMID- 27457315 TI - Wrap-up. PMID- 27457311 TI - Efficacy and safety of golimumab in Indian patients with rheumatoid arthritis: Subgroup data from GO-MORE study. AB - AIM: To conduct a subgroup analysis of GO-MORE trial Part 1, comparing efficacy and safety of add-on subcutaneous golimumab therapy in rheumatoid arthritis (RA) patients enrolled from and outside India. METHODS: GO-MORE was an open-label, multicenter, prospective trial of add-on golimumab in biologic-naive RA patients, having active disease despite being on conventional DMARD regimen(s). Part 1 of the study was chosen as the focus of this subgroup analysis because a substantial number of Indian patients (106) were enrolled compared to no Indian patients in Part 2. The primary efficacy outcome was proportion of patients achieving good to moderate DAS28-ESR (Disease Activity Score of 28 joints calculated using erythrocyte sedimentation rate) European League Against Rheumatism (EULAR) response at month 6. RESULTS: Efficacy evaluable population comprised of 105 and 3175 patients from India and outside India, respectively. Safety analysis included 106 patients enrolled from India and 3251 from outside India. A higher proportion of Indian patients had a high disease activity as measured by DAS28 ESR than outside India patients. At month 6, the proportion of Indian and non Indian patients achieving DAS28-ESR, DAS28 - C-reactive protein, simplified disease activity index (SDAI) remission, and EuroQoL Quality-of-Life Questionnaire (EQ-5D) scores were comparable. Incidence of all adverse events was lower in Indian patients. There were no deaths, cases of tuberculosis or malignancy reported in the patients from India at month 6. CONCLUSIONS: The efficacy and safety results with add-on golimumab were consistent between RA patients from India and outside India, despite high baseline disease activity in the Indian patients. PMID- 27457316 TI - Forum. AB - A Forum for Our Readers Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Forum, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27457317 TI - Editorial. PMID- 27457308 TI - ESMO/ASCO recommendations for a Global Curriculum (GC) in medical oncology edition 2016. PMID- 27457318 TI - Scanning sports. PMID- 27457319 TI - Running wild. PMID- 27457320 TI - Coming in sportsmedicine. PMID- 27457321 TI - Varicose Veins in Active People. AB - In brief: Varicose veins can affect active HMM people of all ages, although the incidence gradually increases with age. Conservative treatment (eg, support stockings or exercise modification) often is sufficient, but in severe cases, injection therapy or ligation or removal of the varicose veins may be appropriate. Understanding the pathophysiology involved and the management options available can help physicians counsel patients with this common disorder. PMID- 27457322 TI - Knee Injuries in Sailboarding. AB - Sailboarding is an exciting sport, but it does involve some risk for injury. In this study of 21 knee injuries that occurred during sailboarding over a 2-year period, 12 were isolated medial collateral ligament (MCL) sprains, 4 were meniscus tears, and 5 involved joint instability. The MCL sprains were directly related to the use of the foot straps on the sailboard. Conservative treatment was successful for the MCL sprains; the meniscus tears were treated with arthroscopic surgery. Improved foot straps designed to release the foot more readily may help reduce knee injuries. PMID- 27457323 TI - Managing Plica Syndrome of the Knee. AB - In brief Plica syndrome of the knee-a potentially disabling condition-is caused when plicae (bands or pleats of synovial tissue) are aggravated by overuse or trauma. Symptoms include popping, clicking, effusion, swelling, pain, and Interference with normal excursion. Analysis of questionnaires from 66 patients revealed that both surgical and nonsurgical management relieved the symptoms. Plica syndrome should be included in the differential diagnosis of knee problems. PMID- 27457324 TI - Hypertension. AB - In brief Exercise can be an effective form of therapy for hypertension, recent research has shown. This article reviews the possible mechanisms by which exercise lowers blood pressure and gives physicians the necessary information to counsel hypertensive patients who want to start an exercise program. Some researchers are exploring the use of exercise testing to predict the onset of hypertension. PMID- 27457326 TI - Exercise adviser. PMID- 27457325 TI - Ventricular Tachycardia in a Marathoner. AB - In brief Young marathoners who run 60 miles per week may appear to be in great shape. But episodes of palpitations and light-headedness may signify a cardiovascular problem. Tests can reveal just how deceiving appearances can be. PMID- 27457327 TI - Neurovascular Complications Resulting From Corticosteroid Injections. AB - In brief Corticosteroid injections can be used effectively to treat shoulder problems, but they can be dangerous; direct injection into the nerve can result in a serious complication such as permanent axillary palsy. PMID- 27457328 TI - Exercise adviser. PMID- 27457329 TI - President Bush: He's Busy, but He Still Makes Time for Exercise. AB - An interview in the White House with Burton J. Lee III, MD, the physician to the President, reveals that George Bush is the Chief Exerciser as well as the Chief Executive. PMID- 27457330 TI - A Hard Look at Running Surfaces. AB - If running were controlled by OSHA, it probably would be banned. A runner hits the ground with a force of three to five times his or her body weight-a shock that is repeated over and over until the run ends. The type of surface can play a critical role in lessening the shock and therefore the risk of injury. PMID- 27457331 TI - Exercise for the Overweight Patient. AB - An exercise prescription for an overweight patient, if faithfully carried out, will dispel the curse of fat-right? Well, yes and no. Exercise isn't a big help in shedding excess pounds. But once a pound has fallen away, exercise helps keep it off. PMID- 27457332 TI - How To Communicate With Injured Athletes. AB - Athletes need a physician who is a careful listener and a willing negotiator. In this article experts give some useful advice on how to establish and maintain strong relationships with injured athletes. PMID- 27457333 TI - Babies on Wheels: Proceed With Caution. AB - Parents who like to run or bike can take their children along for the ride and often ask physicians about the safety of child carriers. The high number of injuries each year suggests that either some of the carriers are unsafe or that insufficient care is being exercised in their use. PMID- 27457334 TI - Exercise adviser. PMID- 27457335 TI - Emergencies. PMID- 27457337 TI - Assessing the accuracy and reliability of ultrasonographic three-dimensional parathyroid volume measurement in a patient with secondary hyperparathyroidism: a comparison with the two-dimensional conventional method. AB - PURPOSE: The purpose of this study was to investigate the accuracy and reliability of the semi-automated ultrasonographic volume measurement tool, virtual organ computer-aided analysis (VOCAL), for measuring the volume of parathyroid glands. METHODS: Volume measurements for 40 parathyroid glands were performed in patients with secondary hyperparathyroidism caused by chronic renal failure. The volume of the parathyroid glands was measured twice by experienced radiologists by two-dimensional (2D) and three-dimensional (3D) methods using conventional sonograms and the VOCAL with 30 degrees angle increments before parathyroidectomy. The specimen volume was also measured postoperatively. Intraclass correlation coefficients (ICCs) and the absolute percentage error were used for estimating the reproducibility and accuracy of the two different methods. RESULTS: The ICC value between two measurements of the 2D method and the 3D method was 0.956 and 0.999, respectively. The mean absolute percentage error of the 2D method and the 3D VOCAL technique was 29.56% and 5.78%, respectively. For accuracy and reliability, the plots of the 3D method showed a more compact distribution than those of the 2D method on the Bland-Altman graph. CONCLUSION: The rotational VOCAL method for measuring the parathyroid gland is more accurate and reliable than the conventional 2D measurement. This VOCAL method could be used as a more reliable follow-up imaging modality in a patient with hyperparathyroidism. PMID- 27457338 TI - Black phosphorus: a two-dimension saturable absorption material for mid-infrared Q-switched and mode-locked fiber lasers. AB - Black phosphorus (BP) as a novel class of two-dimension (2D) materials has recently attracted enormous attention as a result of its unique physical and chemical features. The remarkably strong light-matter interaction and tunable direct band-gap at a wide range make it an ideal candidate especially in the mid infrared wavelength region as the saturable absorber (SA). In this paper, the simple and effective liquid phase exfoliation (LPE) method was used to fabricate BP. By introducing the same BP SA into two specifically designed rare earth ions doped fluoride fiber lasers at mid-infrared wavebands, Q-switching with the pulse energy of 4.93 MUJ and mode-locking with the pulse duration of 8.6 ps were obtained, respectively. The operation wavelength of ~2970 nm for generated pulse is the reported longest wavelength for BP SA based fiber lasers. PMID- 27457339 TI - Investigating Effects of Acidic pH on Proliferation, Invasion and Drug-Induced Apoptosis in Lymphoblastic Leukemia. AB - Some studies have shown that extracellular pH in tumors, which results in tumor progression, is less than that in normal tissues. The aim of this study was to investigate the effects of extracellular acidic pH on proliferation, invasion, and drug-induced apoptosis in acute lymphoblastic cells. The cells were cultured in different pH (pH 6.6 and pH 7.4) for 12 days. Cell proliferation was assessed by MTT assay and cell invasion was assayed by invasion assay and gene expression analysis of MMP-9. Drug-induced apoptosis was evaluated after exposure to doxorubicin for 24 hours by annexin V/PI staining and gene expression analysis of BAX pro-apoptotic protein. The results indicated the enhanced growth and invasion of leukemic cells at pH 6.6 (P <= 0.05). Furthermore, the cells at pH 6.6 were resistant to apoptosis by doxorubicin (P <= 0.05). It can be concluded that acidic pH increases the proliferation, invasion and reduces the drug-induced apoptosis in acute lymphoblastic leukemia. Extracellular acidity can influence the behavior of leukemic cells and therefore, the manipulation of extracellular liquid can be selected as a therapeutic strategy for leukemia, especially for acute lymphoblastic leukemia. PMID- 27457340 TI - Impact of task design on task performance and injury risk: case study of a simulated drilling task. AB - Existing evidence is limited regarding the influence of task design on performance and ergonomic risk, or the association between these two outcomes. In a controlled experiment, we constructed a mock fuselage to simulate a drilling task common in aircraft manufacturing, and examined the effect of three levels of workstation adjustability on performance as measured by productivity (e.g. fuselage completion time) and quality (e.g. fuselage defective holes), and ergonomic risk as quantified using two common methods (rapid upper limb assessment and the strain index). The primary finding was that both productivity and quality significantly improved with increased adjustability, yet this occurred only when that adjustability succeeded in reducing ergonomic risk. Supporting the inverse association between ergonomic risk and performance, the condition with highest adjustability created the lowest ergonomic risk and the best performance while there was not a substantial difference in ergonomic risk between the other two conditions, in which performance was also comparable. Practitioner Summary: Findings of this study supported a causal relationship between task design and both ergonomic risk and performance, and that ergonomic risk and performance are inversely associated. While future work is needed under more realistic conditions and a broader population, these results may be useful for task (re)design and to help cost-justify some ergonomic interventions. PMID- 27457341 TI - Heart Rate Variability, Flow, Mood and Mental Stress During Yoga Practices in Yoga Practitioners, Non-yoga Practitioners and People with Metabolic Syndrome. AB - Heart Rate Variability (HRV) and respiratory sinus arrhythmia are directly associated with autonomic flexibility, self-regulation and well-being, and inversely associated with physiological stress, psychological stress and pathology. Yoga enhances autonomic activity, mitigates stress and benefits stress related clinical conditions, yet the relationship between autonomic activity and psychophysiological responses during yoga practices and stressful stimuli has not been widely explored. This experimental study explored the relationship between HRV, mood states and flow experiences in regular yoga practitioners (YP), non yoga practitioners (NY) and people with metabolic syndrome (MetS), during Mental Arithmetic Stress Test (MAST) and various yoga practices. The study found that the MAST placed a cardio-autonomic burden in all participants with the YP group showing the greatest reactivity and the most rapid recovery, while the MetS group had significantly blunted recovery. The YP group also reported a heightened experience of flow and positive mood states compared to NY and MetS groups as well as having a higher vagal tone during all resting conditions. These results suggest yoga practitioners have a greater homeostatic capacity and autonomic, metabolic and physiological resilience. Further studies are now needed to determine if regular yoga practice may improve autonomic flexibility in non-yoga practitioners and metabolic syndrome patients. Clinical Trial No 'ACTRN 2614001075673'. PMID- 27457342 TI - Trunk muscle activation characteristics in patients with severe haemophilia. AB - INTRODUCTION: Recurrent bleeding episodes in patients with haemophilia (PWH) lead to joint alterations and therewith disturbed muscle coordination patterns. Major weight-bearing joints are affected most. However, possible effects on trunk muscle activity have not been examined so far. The objective of this work was to study consequences of haemarthropathy on characteristics of trunk muscles in PWH while standing on surfaces with different mechanical properties. METHODS: Surface EMG of internal oblique (IO) and multifidus (MF) muscles were bilaterally recorded during a natural bilateral stance in 20 PWH with severe haemophilia A [age: 42 years (SD: 10)] and 25 non-haemophilic controls [NHC, 43 (12)]. Amplitude ratios, a symmetry index between sides and the co-activation ratio of IO over MF served as outcome measures and compared standing on three different surfaces (stable, soft, unsteady). RESULTS: PWH revealed markedly restricted lower extremity joints (P < 0.001), but without any hint of back pain. Neither result revealed significant main or interaction effects of 'group' (P > 0.24). Group-independent analyses showed amplitude ratios (MF: P < 0.05) as well as symmetry indices (MF: P < 0.02) significantly altered by 'surface' in NHC only. Effects of utilizing soft vs. unsteady surfaces were not detectable (P > 0.77). CONCLUSION: Utilizing unstable surfaces does not lead to altered trunk muscle activity in PWH. Differently than expected, a quite similar behaviour of lower trunk muscles in terms of applied indices can be found in PWH and NHC. Ascending alterations of muscle coordination in PWH could not be verified. PMID- 27457344 TI - Chronic Hepatitis C and Alcohol Abuse: The Single Center Experience of Novi Sad - Serbia. AB - BACKGROUND: Chronic ethyl alcohol consuming is well known independent negative predictor of unfavorable natural course and therapy outcome of Chronic Hepatitis C (CHC) infection. OBJECTIVE: The aim of the present study was to clarify the impact of alcohol consumption on fibrosis rate progression in patients with CHC and Sustained Virologic Response (SVR) rates in patients undergoing treatment with pegylated interferon and ribavirin. METHOD: This cross sectional retrospective study included 807 CHC patients underwent liver biopsy and hospitalized at Clinical center of Vojvodina, Novi Sad, Serbia. According to the alcohol consumption equal or greater than 50 g/day prior to liver biopsy, patients were divided into two groups. We compared demographic, clinical, virologic and histopathological markers of CHC, as well as response to antiviral therapy. RESULTS: We find statistically significant difference (p=0.001) in gender, but not in age (p=0.081), estimated duration of the CHC (p=0.470) and hepatitis C genotype (p=0.545) between two groups. Among patients with CHC who consume alcohol >=50 g/day there were significantly higher incidence of intravenous drug users (p=0.000). Binary logistic regression showed that the only independent predictors of moderate to severe fibrosis (fibrosis >=2) were age (p=0.000) and alcohol use (p=0.027). There was not statistically significant difference in SVR rate between two groups (p=0.810). CONCLUSION: We believe that this good result in treatment outcome was the consequence of proper selection of patients based primarily on regulations of Republic of Serbia on the necessity of abstinence from the use of alcohol and psychoactive substances at least one year before starting antiviral therapy. PMID- 27457345 TI - May Patients with Alcohol Liver Disease Benefit from Herbal Medicines? AB - Alcoholism is currently listed as the third leading cause of death. Chronic alcohol consumption brings serious medical complications like gastrointestinal, cardiovascular, musculoskeletal, respiratory system disorders. Liver can be seriously damage by alcohol misuse. Alcoholic Liver Disease (ALD) is the first important warning sign of alcohol abuse. Since effective therapies for ALD are still limited, natural products in the treatment of ALD become very important. In this regard, there have been done very few clinical trials with poor results. Silymarin, glycyrrhizin, garlic show some promising results in ALD patients while the in vivo and in vitro studies with green tee, quercetin and curcumin indicate positive effect on patients with ALD. PMID- 27457343 TI - Evaluation and Application of Dimethylated Amino Acids as Isobaric Tags for Quantitative Proteomics of the TGF-beta/Smad3 Signaling Pathway. AB - Isobaric labeling has become a widespread tool for quantitative proteomic studies. Here, we report the development and evaluation of several dimethylated amino acids as novel isobaric tags for quantitative proteomics. Four-plex dimethylated alanine (DiAla), valine (DiVal), and leucine (DiLeu) have been synthesized, sharing common features of peptide tagging and reporter ion production. DiAla and DiLeu are shown to achieve complete labeling. These two tags' impacts on peptide fragmentation and quantitation are further evaluated using HEK293 cell lysate. DiAla labeling generates more abundant backbone fragmentation whereas DiLeu labeling produces more intense reporter ions. Nonetheless, both tags enable accurate quantitative analysis of HEK293 cell proteomes. DiAla and DiLeu tags are then applied to study the TGF-beta/Smad3 pathway with four differentially treated mouse vascular smooth muscle (MOVAS) cells. Our MS data reveal proteome-wide changes of AdSmad3 as compared to the GFP control, consistent with previous findings of causing smooth muscle cell (SMC) dedifferentiation.1 Additionally, the other two novel mutations on the hub protein Smad3, Y226A, and D408H, show compromised TGF-beta/Smad3-dependent gene transcription and reversed phenotypic switch. These results are further corroborated with Western blotting and demonstrate that the novel DiAla and DiLeu isobaric tagging reagents provide useful tools for multiplex quantitative proteomics. PMID- 27457346 TI - The Role of Liver Biopsy to Assess Alcoholic Liver Disease. AB - Liver biopsy due to the limitations is not recommended for all patients with suspected Alcoholic Liver Disease (ALD) but useful for establishing the stage and severity of ALD, in case of aggressive forms or severe steatohepatitis requiring specific therapies, for distinguishing comorbid liver pathology. Procedure is invasive and that's why associated with some potential adverse effects and complications which may be minor (pain or vagal reactions, transient hypotension) or major such as visceral perforation, bile peritonitis or significant bleeding. The typical histological features in patients with ALD include steatosis, hepatocellular damage (ballooning and/or Mallory-Denk bodies), lobular inflammation with basically polymorphonuclear cells infiltration, with a variable degree of fibrosis and lobular distortion that may progress to cirrhosis which confers a high risk of complications (ascites, variceal bleeding, hepatic encephalopathy, renal failure and bacterial infections). PMID- 27457347 TI - Alcoholic Hepatitis: Pathogenesis, Diagnosis and Treatment. AB - Alcohol represents the oldest substance of abuse known and Alcoholic Liver Disease (ALD) is the most common cause of chronic liver disease worldwide. The ALD includes a wide spectrum of injury and may lead progressively from simple steatosis to frank cirrhosis. The ALD diagnosis may be hard and it is mainly defined by the history of chronic alcohol intake, physical and laboratory abnormalities suggestive of liver disease. Abstinence is the cornerstone of ALD therapy. Although the burden on health of ALD is not negligible, in the last decades few therapeutic advances have been made. Because of the complex pathogenetic mechanisms, the therapy of ALD and especially of severe Alcoholic Hepatitis (AH), represents a thorny problem in the clinical practice. In severe forms of acute AH, some specific drug treatments, including glucorticoids or pentoxifylline, have been defined and are, at the moment, recommended by international guidelines. On the contrary, specific long-term treatments of ALD, aimed at stopping the progression of fibrosis, are not yet approved. PMID- 27457348 TI - Hepatocellular Carcinoma in Alcoholic Liver Disease: Current Management and Recent Advances. AB - Hepatocellular Carcinoma (HCC) is a major healthcare problem. Almost ninety percent of HCCs develops on cirrhosis due to chronic viral hepatitis, Non Alcoholic Steatohepatitis (NASH) and alcohol abuse. Alcohol itself is defined a strong human carcinogenic agent. Some genetic polymorphisms in alcohol metabolizing systems and more recently, some sequence variations within the genes coding for patatin-like phospholipase encoding 3 (PNPLA3) and Transmembrane 6 superfamily 2 (TM6SF2), have been found to promote liver fibrosis in alcohol abuse, until HCC development. The current management of HCC is related to tumor burden and liver function and it does not differ in alcoholics, although in alcoholics the surveillance for HCC could be less effective because socioeconomic context, such as the recall policy, the stage at the diagnosis and the prognosis are not different compared to viral HCCs. On regards of loco-regional treatment options, there have not been significant advances in the last few years, though an increasing role will be probably reserved to radio embolization and irreversible electroporation in the next future. Sorafenib (SOR) is still the only drug approved as systemic therapy in patients with HCC, whereas immunotherapy represents a promising approach for the treatment of HCC. PMID- 27457349 TI - Effects of Exercise Training on Delaying Disease Progression in Patients with Chronic Kidney Disease: a Review of the Literature. AB - Chronic Kidney Disease (CKD) is an important public health problem throughout the world. The effects of exercise training are unclear in patients with CKD. This review aimed to evaluate the effects of exercise training to delay the progression of CKD and which training style is most effective. We developed individualized search strategies for the National Library of Medicine including the PubMed MeSH database to June 2015. We searched articles related to exercise training and kidney disease using the terms "CKD", "renal disease", "renal insufficiency", "renal failure", "end-stage renal disease (ESRD)" and "physical therapy". We searched only for reports in English and for full free papers. We also chose papers based on the references in the papers obtained by the search. Our search identified 6 different trials including 131 participants. Our review of these 6 studies suggests that aerobic exercise training may improve exercise capacity, and resistance training may also improve muscle function in patients with CKD. No cardiac events were reported in any of the published exercise training studies reviewed, suggesting the safety of exercise in patients with CKD. PMID- 27457350 TI - Clinical Trials Investigating Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer. AB - INTRODUCTION: Non-Small Cell Lung Cancer (NSCLC) is an aggressive malignancy with poor overall survival that accounts for up to 85% of lung cancer diagnoses. The use of immunotherapy in the form of checkpoint inhibition, to enhance the immune system's ability to attack malignant cells, has been a promising addition to treatment options in advanced NSCLC. RESULTS: Such therapeutic agents aimed at the Programmed Death 1 (PD-1) receptor or Programmed Death Ligand 1 (PD-L1) have revealed promising results against many types of cancer including NSCLC. Examples of these agents include nivolumab, pembrolizumab, BMS-936559, atezolizumab, and MEDI4736, of which the first two are approved by US FDA in the second line treatment of advanced NSCLC. DISCUSSION: Impressive improvements in objective responses from PD-1 blockade were found in both first line therapy as well as treatment after progression on platinum based therapy. In addition, the safety profile is favorable with significantly lower grade 3-4 adverse events compared to standard of care. The optimal selection criteria and factors that show an increased response to therapy are still being determined. PMID- 27457353 TI - Transition-Metal-Catalyzed Electrophilic Amination: Application of O Benzoylhydroxylamines in the Construction of the C-N Bond. AB - Transition-metal-catalyzed electrophilic amination has been developed into a powerful tool for C-N bond construction. So far, O-benzoylhydroxylamines are the most widely used electrophilic aminating reagents. Herein, we summarize the recent advances of O-benzoylhydroxylamines involved in electrophilic amination catalyzed by transition metals. Several pioneering studies and some of the relevant mechanisms are discussed in this review. PMID- 27457352 TI - Targeted TET oxidase activity through methyl-CpG-binding domain extensively suppresses cancer cell proliferation. AB - DNA methyltransferase (DNMT) inhibitors are epigenetic drugs used to treat myelodysplastic syndrome. They not only induce DNA demethylation but also have significant cytostatic and cytotoxic effects; however, the relationships between these characteristics have not been established yet due to the lack of a method to induce only DNA demethylation. Herein, we show that a fusion protein comprised of the methyl-CpG-binding domain (MBD) and the catalytic domain of Ten-eleven translocation protein 1 (TET1-CD) globally demethylates and upregulates a number of methylated genes. These upregulated genes frequently contained CpG islands (CGIs) within +/- 1000 bp of the transcription start site (TSS). Interestingly, 65% of the genes upregulated fivefold or more by MBD-TET1-CDwt were also reactivated after treatment with a DNMT inhibitor, 5-azacytidine (Aza-CR), suggesting that gene reactivation by both methods primarily shares the same mechanism, DNA demethylation. In order to examine whether DNA demethylation affects the growth of cancer cells, we have established a tetracycline inducible system that can regulate the expression of MBD-TET1-CDwt in a prostate cancer cell line, LNCaP. The induction of MBD-TET1-CDwt demethylated and upregulated glutathione S-transferase pi 1 (GSTP1), one of the hypermethylated genes in prostate cancer. In accordance with the reactivation of methylated genes, induction of MBD-TET1-CDwt extensively suppressed the growth of LNCaP cells through G1/S arrest. These results clearly indicate that TET oxidase activity recruited at methyl-CpG sites through MBD induces reactivation of hypermethylated genes by DNA demethylation and allows us to analyze the effect of only global DNA demethylation in a wide variety of cancer cells. PMID- 27457354 TI - Platelets contribute to growth and metastasis in hepatocellular carcinoma. AB - To determine the association of platelets with hepatocellular carcinoma (HCC) growth and its metastasis. We examined platelets, laboratory, and radiological data of consecutive 420 HCC and 1008 cirrhosis cases. Follow-up information of platelet count in cirrhosis to HCC, pre- to post-therapy, and post-therapy to HCC outcome was analyzed. Cytokine profiling was performed in HCC and cirrhosis (n = 10 each). On the basis of imaging, HCC was divided into six subgroups. Cytosmears of HCC were assessed for platelet clustering around tumor cells. An in vitro Matrigel invasion assay was performed on human HCC cell lines using graded concentration of platelets. Baseline platelet numbers and platelet/lymphocyte ratios (PLRs) were significantly higher (p < 0.001) in HCC than cirrhosis. IL-1, IL-6, FGF, G-CSF, thrombopoietin, and VEGF were higher in HCC than cirrhosis. Platelet counts were increased after HCC conversion of cirrhosis (p < 0.001) and decreased (p < 0.001) after therapy. Platelets and PLR in recurrence cases were higher than in responders at baseline. AFP, PIVKAII, platelets, and PLR increase (p < 0.001 each) with advancement in HCC growth. Multivariate analysis showed platelets (p = 0.002), PLR (p = 0.004), and AFP (p < 0.001) associated with distant metastasis. Platelet clustering seen in 75.7% of HCC group 3, 45% in group 2, and 12.5% in group 1 cases (p < 0.001). Invaded cells in Matrigel assay positively correlated with platelet concentration. Platelets can contribute to the development, growth, invasion, and metastasis of HCC. Rising platelet count after HCC therapy is indicative of incomplete response or recurrence. PMID- 27457355 TI - Does Lung Donation by Heart Donors Have an Impact on Survival in Heart Transplant Recipients? AB - Lung procurement is increasing during multiorgan recovery and substantially alters the explant process. This study evaluated whether lung donation by a heart donor affects survival in heart transplant recipients. Retrospective analysis of United Network for Organ Sharing (UNOS) adult heart transplantation data from 1998 to 2012 was performed. Lung donors (LDs) were defined as those having at least one lung procured and transplanted. Non-LDs had neither lung transplanted. Heart transplant recipients who had previous transplants, who had heterotopic transplants, who were waitlisted for other organs or who were temporarily delisted were excluded from the analysis. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed. Of 23 590 heart transplant recipients meeting criteria during the study period, 8638 (36.6%) transplants were from LDs. Donors in the LD group had less history of cigarette use (15.5% vs. 29.5%, p < 0.001). On univariate analysis, LDs were associated with improved patient survival (p < 0.001). On multivariate analysis, LDs were not significantly associated with patient survival (adjusted hazard ratio 0.98, 95% confidence interval 0.94-1.03). Analysis of the UNOS registry suggested that donor pulmonary status and lung procurement had no detrimental effect on survival in heart transplant recipients, supporting the present practice of using donor lungs whenever possible. PMID- 27457356 TI - Novel synthesis of holey reduced graphene oxide (HRGO) by microwave irradiation method for anode in lithium-ion batteries. AB - In this work, holey reduced graphene oxide (HRGO) was synthesized by the deposition of silver (Ag) nanoparticles onto the reduced graphene oxide (RGO) sheets followed by nitric acid treatment to remove Ag nanoparticles by microwave irradiation to form a porous structure. The HRGO were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), ultra violet-visible spectroscopy (UV Vis), thermogravimetric analysis (TGA), and Raman spectroscopy. These novel HRGO exhibited high rate capability with excellent cycling stability as an anode material for lithium-ion batteries. The results have shown an excellent electrochemical response in terms of charge/discharge capacity (423 mAh/g at 100 mA/g). The cyclic performance was also exceptional as a high reversible capacity (400 mAh/g at 100 mA/g) was retained for 100 charge/discharge cycles. This fascinating electrochemical performance can be ascribed to their specific porous structure (2-5 nm pores) and high surface area (457 m(2)/g), providing numerous active sites for Li(+) insertion, high electrical conductivity, low charge transfer resistance across the electrolyte-electrode interface, and improved structural stability against the local volume change during Li(+) insertion extraction. Such electrodes are envisioned to be mass scalable with relatively simple and low-cost fabrication procedures, thereby providing a clear pathway toward commercialization. PMID- 27457357 TI - The evolutionary scope and neurological disease linkage of yeast-prion-like proteins in humans. AB - BACKGROUND: Prions are proteinaceous particles that propagate alternative protein conformations/states to further copies of the same proteins, and are transmitted from cell-to-cell, and organism-to-organism. Prions are usually made of the beta sheet rich assemblies termed amyloid. The original prion protein PrP causes devastating neurodegenerative disorders in humans and other mammals. In the yeast Saccharomyces cerevisiae, many prion-forming proteins have been observed; a prominent feature of these proteins is an intrinsically disordered domain rich in glutamine (Q) and asparagine (N) residues. Several human proteins that are yeast prion-like, in particular those with poly-glutamine (poly-Q) expansions, have been experimentally implicated in human neurodegenerative diseases. RESULTS: Here, we have constructed a comprehensive list of human yeast-prion-like proteins that are linked to human neurological disease. Surprisingly, different methods to annotate yeast-prion-like proteins in humans have limited intersection. However, independent of annotation method, we find that human yeast-prion-like proteins as a group have a statistically significant genetic linkage to neurological disease, that is caused specifically by linkage to neurodegenerative diseases. This is despite: (i) no especially high expression of yeast-prion-like proteins in the central nervous system, or (ii) no general enrichment of intrinsically disordered proteins in neurological/neurodegenerative diseases. Cytoskeletal proteins are significantly overrepresented in the set of human yeast-prion-like neurological proteins. Whether involved in neurological pathomechanisms or not, yeast-prion like proteins in humans have very limited conservation outside of Deuterostomia (< ~10 %) with only a handful having prion-like character in both human and S. cerevisiae. The only such protein with a disease linkage is PUB1/TIA1, which functions as a stress granule component. Thus, the yeast-prion-like character of proteins linked to neurodegenerative diseases has not been conserved over the deep evolutionary time since the last common ancestor of yeasts and humans. CONCLUSION: Our results provide a comprehensive picture of yeast-prion-like proteins in humans and contribute to the strategic basis for experimental investigation of the link between yeast-prion-like protein character and neurological disease. REVIEWERS: Reviewed by Istvan Simon and Alexander Schleiffer. For the full reviews, please go to the Reviewers' comments section. PMID- 27457358 TI - Erratum to: Women-only drug treatment services and needs in Iran: the first review of current literature. PMID- 27457359 TI - Patching for corneal abrasion. AB - BACKGROUND: Published audits have demonstrated that corneal abrasions are a common presenting eye complaint. Eye patches are often recommended for treating corneal abrasions despite the lack of evidence for their use. This systematic review was conducted to determine the effects of the eye patch when used to treat corneal abrasions. OBJECTIVES: The objective of this review was to assess the effects of patching for corneal abrasion on healing and pain relief. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2016), EMBASE (January 1980 to May 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to May 2016), System for Information on Grey Literature in Europe (OpenGrey) (January 1995 to May 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 9 May 2016. We also searched the reference lists of included studies, unpublished 'grey' literature and conference proceedings and contacted pharmaceutical companies for details of unpublished trials. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared patching the eye with no patching to treat simple corneal abrasions. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Investigators were contacted for further information regarding the quality of trials. The primary outcome was healing at 24, 48 and 72 hours while secondary outcomes included measures of pain, quality of life and adverse effects. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We included 12 trials which randomised a total of 1080 participants in the review. Four trials were conducted in the United Kingdom, another four in the United States of America, two in Canada, one in Brazil and one in Switzerland. Seven trials were at high risk of bias in one or more domains and one trial was judged to be low risk of bias in all domains. The rest were a combination of low risk or unclear.People receiving a patch may be less likely to have a healed corneal abrasion after 24 hours compared to those not receiving a patch (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.79 to 1.00, 7 trials, 531 participants, low certainty evidence). Similar numbers of people in the patch and no-patch groups were healed by 48 hours (RR 0.97, 95% CI 0.91 to 1.02, 6 trials, 497 participants, moderate certainty evidence) and 72 hours (RR 1.01, 95% CI 0.97 to 1.05, 4 trials, 430 participants, moderate certainty evidence). Participants receiving a patch took slightly longer to heal but the difference was small and probably unimportant (mean difference (MD) 0.14 days longer, 95% CI 0 to 0.27 days longer, 6 trials, 642 participants, moderate certainty evidence).Ten trials reported pain scores. Most studies reported pain on a visual analogue scale (VAS). It was not possible to pool the data because it was skewed. In general, similar pain ratings were seen between patch and no-patch groups. Data from two trials reporting presence or absence of pain at 24 hours was inconclusive. There was a higher risk of reported pain in the patch group but wide confidence intervals compatible with higher or lower risk of pain (RR 1.51, 95% CI 0.86 to 2.65, 2 trials, 193 participants, low certainty evidence). Five trials compared analgesic use between the patch and no-patch groups. Data from three of these trials could be combined and suggested similar analgesic use in the patch and no-patch groups but with some uncertainty (RR 0.95, 95% CI 0.69 to 1.32, 256 participants, low certainty evidence). Frequently reported symptoms included photophobia, lacrimation, foreign body sensation and blurred vision but there was little evidence to suggest any difference in these symptoms in people with or without a patch.Activities of daily living (ADL) were assessed in one study involving children. There was little difference in ADL with the exception of walking which was reported to be more difficult with a patch on: VAS 1.7 cm (SD 2.1) versus 0.3 cm (SD 0.7).Complication rates were low across studies and there is uncertainty about the relative effects of patching or not patching with respect to these (RR 3.24, 95% CI 0.87 to 12.05, 8 trials, 660 participants, low certainty evidence). Three trials reporting rates of compliance to treatment found that 22% of participants did not have their eye patches during follow-up. No-patch groups generally received more adjuvant treatment with antibiotics or cycloplegics, or both, than the patch group. There were limited data on the effect of patching on abrasions greater than 10mm(2) in size. AUTHORS' CONCLUSIONS: Trials included in this review suggest that treating simple corneal abrasions with a patch may not improve healing or reduce pain. It must be noted that, in these trials, participants who did not receive a patch were more likely to receive additional treatment, for example with antibiotics. Overall we judged the certainty of evidence to be moderate to low. Further research should focus on designing and implementing better quality trials and examining the effectiveness of patching for large abrasions. PMID- 27457361 TI - Toward Better Oversight of NGS Tests. AB - The FDA has published two draft guidance documents aimed at streamlining its oversight of tests based on next-generation sequencing (NGS). One contains preliminary recommendations addressing the analytic validity of NGS-based tests for hereditary diseases; the other explains how test developers can obtain official recognition of their genetic variant databases, potentially speeding marketing clearance or approval. PMID- 27457360 TI - [Decline in renal function in old age : Part of physiological aging versus age related disease]. AB - The incidence and prevalence of chronic renal disease (CKD) in elderly patients are continuously increasing worldwide. Loss of renal function is not only considered to be part of the aging process itself but also reflects the multimorbidity of many geriatric patients. Calculating the glomerular filtration rate using specific algorithms validated for the elderly population and measuring the amount of proteinuria allow an estimation of renal function in elderly patients with high accuracy. Chronic renal failure has many clinical consequences and not only results in a delayed excretion of toxins cleared by the kidneys but also affects hematogenesis, water and electrolyte balance as well as mineral bone metabolism. Furthermore, CKD directly leads to and aggravates geriatric syndromes and in particular the onset of frailty. Therapeutic strategies to halt progression of CKD not only comprise treatment of the underlying disease but also efficient blood pressure and diabetic control and the avoidance of nephrotoxic medications. PMID- 27457362 TI - Anthelmintic activity of silver-extract nanoparticles synthesized from the combination of silver nanoparticles and M. charantia fruit extract. AB - BACKGROUND: Present study has been conducted to know the anthelmintic activity of polyaniline coated silver nanoparticles (AgNPs) synthesized from Momordica charantia fruit extract. METHODS: By reduction of AgNO3 in presence of NaBH4, silver nanoparticles were prepared. After mixing silver nanoparticles and extracts, coating was given on nanoparticles using polyaniline. Prepared nanoparticles were characterized by Visual, UV, FTIR spectroscopy, SEM techniques, and TEM analysis. RESULTS: The FTIR results implied that AgNPs were successfully synthesized and capped with bio-compounds present in the extract. The result showed that death times of worm were 35.12 +/- 0.5 and 59.3 +/- 0.3 minutes for M. charantia extract and Ag-nanoparticles individually. But when these two combined together, paralysis and death time fall drastically which were only 6.16 +/- 0.6 and 9.1 +/- 0.4 minutes respectively. Albendazole tablet was used as standard, which made worms death in 3.66 +/- 0.1 minutes. CONCLUSION: Ag Extract NPs showed strong anthelmintic activity against worm. This study has paved the way for further research to design new anthelmintic drug from the combination of M. charantia and AgNPs. PMID- 27457363 TI - Brief Report: The Effects of Equine-Assisted Activities on the Social Functioning in Children and Adolescents with Autism Spectrum Disorder. AB - Equine-assisted activities and therapies are increasing in popularity for treatment of ASD symptoms. This research evaluated effects of a 5-week programme of therapeutic riding on social functioning of children/adolescents (N = 15) with ASD. The effectiveness of the programme was evaluated using the autism spectrum quotient, the Vineland Adaptive Behaviour Scale and the empathising and systemising quotient. Results established that the TR intervention increased empathising and reduced maladaptive behaviours. The findings also indicated that specific adaptive behaviours like socialization and communication were not affected by the intervention. Thus, a complex picture of the effects of this intervention emerges: while TR does not change all of the child's behaviour, it can improve specific aspects of social functioning and also reduce maladaptive ASD traits. PMID- 27457364 TI - The Experiences of Late-diagnosed Women with Autism Spectrum Conditions: An Investigation of the Female Autism Phenotype. AB - We used Framework Analysis to investigate the female autism phenotype and its impact upon the under-recognition of autism spectrum conditions (ASC) in girls and women. Fourteen women with ASC (aged 22-30 years) diagnosed in late adolescence or adulthood gave in-depth accounts of: 'pretending to be normal'; of how their gender led various professionals to miss their ASC; and of conflicts between ASC and a traditional feminine identity. Experiences of sexual abuse were widespread in this sample, partially reflecting specific vulnerabilities from being a female with undiagnosed ASC. Training would improve teachers' and clinicians' recognition of ASC in females, so that timely identification can mitigate risks and promote wellbeing of girls and women on the autism spectrum. PMID- 27457365 TI - Brief Report: Character Strengths in Adults with Autism Spectrum Disorder Without Intellectual Impairment. AB - In the current study, we assessed character strengths in individuals with autism spectrum disorder (ASD, n = 32) and neurotypical controls (n = 32) using the Values in Action Inventory (VIA-IS, Peterson and Seligman 2004) and explored associations with levels of satisfaction with life (SWL). The most frequently endorsed signature strengths (i.e., five top-ranked strengths within an individual's strength ranking) were emotional (humour, love) and interpersonal strengths (kindness, fairness) in the control group, the most frequently endorsed signature strengths in the ASD group were intellectual strengths (open mindedness, creativity, love of learning). Interpersonal and emotional strengths had, however, the highest positive associations with SWL in the ASD group. PMID- 27457366 TI - Anti-MCV and anti-CCP antibodies-diagnostic and prognostic value in children with juvenile idiopathic arthritis (JIA). AB - The goal of the study was to evaluate the diagnostic and prognostic value of anti mutated citrullinated vimentin (anti-MCV) antibodies in juvenile idiopathic arthritis (JIA) comparing to anti-cyclic citrullinated peptide (anti-CCP). Thirty children with confirmed JIA diagnosis and 20 children as a control group were included into the study. Serum and synovial fluid levels of anti-CCP, anti-MCV, and immunoglobulin M rheumatoid factor (IgM-RF) antibodies have been assessed. Anti-MCV was positive in 11/30 (36.6 %), whereas anti-CCP positivity was found in 12/30 (40 %) children with JIA. Among 11 children with JIA positive for anti-MCV, five (45.5 %) were also positive for anti-CCP and among 18 JIA children negative for anti-CCP, six (33.33 %) were also anti-MCV positive. Six out of 30 JIA children were found to be IgM-RF positive. In general, two out of all those 11 anti-MCV-positive patients demonstrated oligoarthritis and 9/11 had polyarticular type of onset. Anti-MCV serum concentration correlated positively with anti-CCP (p = 0.004). Almost 60 % of children in early stage of JIA were anti-MCV positive. Levels of anti-CCP antibodies correlated positively with the disease activity (p = 0.0014) and radiological outcome (p = 0.00017). In all synovial fluid samples, the concentration of autoantibodies was under the cut-off values. The results of our study indicate that anti-MCV as well as anti-CCP antibodies may be helpful in the diagnosis of JIA, especially in the early course of the disease. Anti-MCV antibodies could identify a group of children with JIA which is negative for anti-CCP antibodies and RF. However, it appears that in JIA, anti CCP rather than anti-MCV antibodies have impact on radiographic changes. PMID- 27457367 TI - Training of Residential Social Care Staff to Meet the Needs of Older People with Intellectual Disabilities who Develop Age-Related Health Problems: An Exploratory Study. AB - BACKGROUND: Despite awareness of the age related health needs of people with intellectual disabilities little is known regarding how residential social care staff are prepared to meet such needs. METHODS: Data were gathered via semi structured interviews from 14 managers of supported living settings. Transcripts were thematically analysed. FINDINGS: Staff may work in supported living settings with no prior experience of care work, and previous knowledge/experience of supporting people in relation to their health is not required. Whilst health related training is provided there is a lack of specific training regarding healthy ageing, and training seems to be reactive to changing needs of tenants meaning that proactive monitoring for changes in health status may not occur. CONCLUSIONS: Whilst some training is provided for residential social care staff in relation to health and ageing a more proactive approach is required which should include a focus on healthy ageing. PMID- 27457368 TI - Drug Interaction and Serotonin Toxicity with Opioid Use: Another Reason to Avoid Opioids in Headache and Migraine Treatment. AB - Treatment of headache, specifically migraine attacks, has always been a challenging subject, especially for neurologist and pain specialists. Triptans are generally underutilized, despite being the gold standard abortive medication for migraine attacks. On the other hand, opioid analgesics are overused as a treatment for headache. One reason for this could be physician unfamiliarity with drug interactions between opioids and other medications, especially the possibility of serotonin toxicity. The general awareness of potential serotonin toxicity with using opioid analgesics is low. In this review, we will conduct a theoretic and evidence-based review of the potential for developing serotonin syndrome in patients who are using opioids analgesics, especially in combination with antidepressants, a common co-prescribed combination. We also review the current diagnostic criteria for serotonin syndrome and identify possible shortcomings of those criteria. Our aim is to increase the awareness of health care providers about potential drug interaction of opioid analgesics with other classes of medication. We place particular emphasis on tramadol since this drug is one of the most commonly used opioid analgesics for headache. The potential for developing serotonin syndrome is relatively high in the patients who are using opioid for pain control. The use of opioids in migraine headache is already discouraged due to the high risk of medication overuse headache and also an increase in headache-related disability (Katsarava et al. Neurology 62:788-790, 2004; Bigal and Lipton. Neurology 71:1821-8, 2008; Casucci and Cevoli. Neurol Sci. 34 Suppl 1:S125-8, 2013). This is another reason that physicians and health care providers should avoid using this class of medication for pain, specifically headache and migraine treatment. PMID- 27457369 TI - Evaluation of the effects of the low-level laser therapy on swelling, pain, and trismus after removal of impacted lower third molar. AB - BACKGROUND: In current study we aimed to examine the effect of a low-level laser therapy on the pain, mouth opening and swelling of patients whose impacted 3rd molar tooth was extracted in addition measurement volumetrically to the edema with 3dMD face system. METHODS: It was surveyed 15 patients who had bilateral symmetric lower 3rd molars. Surgical sides of patients were randomly separated into two groups: the study group and the control group. It was applied extra oral low-level laser therapy (LLLT, 0.3 W, 40 s, 4 J/cm(2)) to the study group (n = 15) after the surgical operation and on the 2nd day. Only routine postoperative recommendation (ice application) was made in the control (n = 15) group. The maximum mouth opening, pain level and facial swelling evaluated. 3dMD Face(r) (3dMD, Atlanta, GA) Photogrammetric System was used to evaluate volumetric changes of the swelling. RESULTS: There was no statistically significant difference in the edema and interincisal opening between the groups and the pain level in the laser group was significantly lower than in the control group on the 7(th) postoperative day. CONCLUSIONS: Although there were decreasing trismus, swelling, and pain level, with this LLLT, there was significant difference only in the 7th day pain level in the laser group compared with the control group. PMID- 27457370 TI - Epididymis of Viscacha (Lagostomus maximus maximus): A Morphological Comparative Study in Relation to Sexual Maturity. AB - The morphological variations and the androgen receptor (AR) expression were studied in viscacha epididymis in relation to sexual maturity. The animals were divided into immature, pre-pubertal and adult, according to their corporal weight and testicular histology. The epididymides were studied by light microscopy, immunohistochemistry for AR and morphometric analysis. In pre-pubertal and adult animals, four well-differentiated segments (initial, caput, corpus and cauda) were observed, while in immature animals, three segments were identified (initial caput segment, corpus and cauda). In each segment, the structural parameters and the relative cell distribution were different between the groups. The serum testosterone levels of pre-pubertal and adults showed a very significant increase related to sexual maturity. The AR expression in epithelial and fibromuscular stromal cells was different between the groups. In conclusion, the present work demonstrates that the morphological characteristics of the viscacha epididymis vary while sexual maturity is reached, the development of initial and caput is subsequent to corpus and cauda development and the androgens might play an important role during this process. PMID- 27457371 TI - Erratum to: MagicplexTM Sepsis Real-Time test to improve bloodstream infection diagnostics in children. PMID- 27457372 TI - Minification of fundus optical coherence tomographic images in gas-filled eye. AB - BACKGROUND: Optical coherence tomography (OCT) is being used increasingly to evaluate and manage a variety of retinal diseases, but not much is known about the minification of the OCT images in gas-filled eyes. The purpose of this study was to investigate the effect of gas-filled eyes on the size of the OCT images. METHODS: This was retrospective case series of 81 consecutive eyes of 79 patients who had macular hole surgery between April 2012 and September 2014. Images of the optic disc were taken with a spectral domain-OCT instrument 2 days after surgery in gas-filled, pseudophakic eyes and from the same eyes but fluid-filled one month after the surgery. The vertical length, horizontal width, and the area of the optic disc were measured in the OCT images. RESULTS: Clear images were obtained from 50 eyes of 49 patients (mean age 66.4 +/- 5.9 years). The mean vertical length and mean horizontal width of the optic disc in the gas-filled eyes were about 25 % shorter than that of fluid-filled eyes (vertical, 1213.8 +/- 170.5 and 1650.6 +/- 195.9 MUm, P < 0.01; horizontal, 1169.4 +/- 143.1 and 1526.4 +/- 219.9 MUm, P < 0.01). The mean area of the optic disc was 1.12 +/- 0.34 mm(2) in gas-filled eyes which was significantly smaller than that in fluid-filled eyes (1.88 +/- 0.37 mm(2)) by 40.4 %. CONCLUSIONS: The fundus images of gas-filled eyes are significantly smaller than that in the same fluid-filled eyes. The minification of the OCT images should be considered when analyzing images obtained from gas-filled eyes. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: UMIN000007517 . Date of registration: 3/21/2012. PMID- 27457373 TI - Variation in Venoms of Polybia Paulista Von Ihering and Polybia Occidentalis Olivier (Hymenoptera: Vespidae), Assessed by the FTIR-PAS Technique. AB - Wasps are able to synthesize toxic compounds known as venoms, which form a part of a mechanism to overcome prey and also to defend their colonies. Study of the compounds that constitute these substances is essential in order to understand how this defense mechanism evolved, since there is evidence that the venoms can vary both intra- and interspecifically. Some studies have used liquid and gas chromatography as a reliable technique to analyze these compounds. However, the use of Fourier transform infrared photoacoustic spectroscopy (FTIR-PAS) to analyze the variations in venom's chemical profile has been proposed recently. This study evaluated whether the FTIR-PAS technique is effective for assessing the role of environmental factors on intra- and interspecific differences in the venom of the wasps Polybia paulista Von Ihering and Polybia occidentalis Olivier by FTIR-PAS. The colonies were collected in three municipalities of Mato Grosso do Sul, Brazil, in different types of environments. The results showed that the venoms of P. paulista and P. occidentalis differed significantly in profile. In addition, the intraspecific differences in the venom's chemical profile of P. paulista are related to the type of environment where they nested, regardless of the geographical distance between the nests. The FTIR-PAS technique proved to be reliable and effective to evaluate the variations in the venom's chemical profile in social wasps. PMID- 27457374 TI - Tocilizumab and mesenteric arterial thrombosis: drug-drug interaction with anticoagulants metabolized by CYP 450 and/or by P-glycoprotein. PMID- 27457376 TI - Synthesis of homopropargylamines from 2-cyanoazetidines. AB - 2-Cyanoazetidines, easily accessible from beta-amino alcohols, undergo ring cleavage upon reaction with trimethylsilylazide and catalytic amounts of Bu2SnO, to give the corresponding homopropargylamines which are isolated as their N-Boc protected derivatives. The scope of this reaction, which constitutes a new way to access these highly relevant building blocks, is examined in detail. The proposed mechanism involves a tin-catalyzed cycloaddition of the nitrile moiety with the azide to give the corresponding tetrazole, which decomposes with the extrusion of two molecules of dinitrogen to produce an intermediate vinylidene carbene that finally evolves to give the alkyne. PMID- 27457375 TI - An association analysis of lipid profile and diabetic cardiovascular autonomic neuropathy in a Chinese sample. AB - BACKGROUND: Recent studies have shown that triglyceride (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) are related to the prevalence of cardiovascular autonomic neuropathy (CAN). However, little is known about the association of lipid profile with diabetic cardiovascular autonomic neuropathy (DCAN), or its severity in the Chinese population. The purpose of this study is to explore the extent of this phenomenon using a Chinese sample. METHODS: A subgroup analysis on 455 diabetic patients with undiagnosed DCAN was performed to evaluate the relationships of lipids profile and DCAN. DCAN was diagnosed if there were at least two abnormal cardiovascular autonomic reflex test results, based on short-term heart rate variability tests. Multivariable logistic regression (MLR)was carried out to control potential confounders for determining the independent association of variables with DCAN in different models. RESULTS: MLR analysis indicated that TG was significantly and independently associated with DCAN when controlling for confounding factors (P < 0.1 for two models). Additionally, TG combined with TC (LRS-1) and LDL (LRS-2) was associated with this outcome (P < 0.1 for LRS-1 and LRS-2). CONCLUSION: Our findings indicate that TG and the severity of lipids profile is significantly and independently associated with DCAN, respectively. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02461472 , retrospectively registered 2 Jun, 2015. PMID- 27457377 TI - Type 1 and type 2 diabetes in celiac disease: prevalence and effect on clinical and histological presentation. AB - BACKGROUND: Association between celiac disease and type 1 diabetes in adults is still somewhat unclear, and that between celiac disease and type 2 diabetes even less known. We studied these issues in a large cohort of adult celiac disease patients. METHODS: The prevalence of type 1 and type 2 diabetes in 1358 celiac patients was compared with the population-based values. Furthermore, patients with celiac disease and concomitant type 1 or type 2 diabetes and those with celiac disease only underwent comparisons of clinical and histological features and adherence to gluten-free diet. RESULTS: The prevalence of type 1 diabetes (men/women) was 8.0 % /1.8 % in celiac patients and 0.7 % /0.3 % in the population, and that of type 2 diabetes 4.3 % /2.5 % and 4.4 % /3.0 %, respectively. Celiac patients with concomitant type 1 diabetes were younger (45 years vs 65 years and 52 years, P < 0.001) and more often screen-detected (43 % vs 13 % and 14 %, P < 0.001), had less other gastrointestinal diseases (8 % vs 40 % and 25 %, P = 0.028), more thyroidal diseases (18 % vs 16 % and 13 %, P = 0.043) and lower dietary adherence (71 % vs 95 % and 96 %, P < 0.001) compared with celiac patients with concomitant type 2 diabetes and patients with celiac disease only. Patients with concomitant type 2 diabetes had more hypercholesterolemia than the other groups (8 % vs 6 % and 4 %, P = 0.024), and both diabetes groups more hypertension (47 % and 31 % vs 15 %, P < 0.001) and coronary artery disease (29 % and 18 % vs 3 %, P < 0.001) than the patients with celiac disease only. CONCLUSIONS: Type 1 diabetes was markedly overrepresented in celiac disease, especially in men, whereas the prevalence of type 2 diabetes was comparable with the population. Concomitant type 1 or type 2 diabetes predisposes celiac patients to severe co-morbidities and type 1 diabetes also to poor dietary adherence. PMID- 27457378 TI - Multi-genome analysis identifies functional and phylogenetic diversity of basidiomycete adenylate-forming reductases. AB - Among the invaluable benefits of basidiomycete genomics is the dramatically enhanced insight into the potential capacity to biosynthesize natural products. This study focuses on adenylate-forming reductases, which is a group of natural product biosynthesis enzymes that resembles non-ribosomal peptide synthetases, yet serves to modify one substrate, rather than to condense two or more building blocks. Phylogenetically, these reductases fall in four classes. The phylogeny of Heterobasidion annosum (Russulales) and Serpula lacrymans (Boletales) adenylate forming reductases was investigated. We identified a previously unrecognized phylogenetic branch within class III adenylate-forming reductases. Three representatives were heterologously produced and their substrate preferences determined in vitro: NPS9 and NPS11 of S. lacrymans preferred l-threonine and benzoic acid, respectively, while NPS10 of H. annosum accepted phenylpyruvic acid best. We also investigated two class IV adenylate-forming reductases of Coprinopsis cinerea, which each were active with l-alanine, l-valine, and l serine as substrates. Our results show that adenylate-forming reductases are functionally more diverse than previously recognized. As none of the natural products known from the species investigated in this study includes the identified substrates of their respective reductases, our findings may help further explore the diversity of these basidiomycete secondary metabolomes. PMID- 27457379 TI - Invasive Cutaneous Rhizopus Infections in an Immunocompromised Patient Population Associated with Hospital Laundry Carts. PMID- 27457380 TI - In vitro culture of Echinococcus multilocularis producing protoscoleces and mouse infection with the cultured vesicles. AB - BACKGROUND: Alveolar echinococcosis (AE) is a lethal zoonosis caused by the fox tapeworm Echinococcus multilocularis. The disease is difficult to treat and an effective therapeutic drug is urgently needed. Reliable models are essential for drug development. In this study, we developed both in vitro and in vivo models of larval E. multilocularis. RESULTS: The protoscoleces (PSC) of E. multilocularis from jirds were successfully cultured in a modified RPMI1640 based medium containing 25 % (v/v) fetal bovine serum (FBS). After 100 days of culture, PSC developed to larval vesicles (small unilocular cysts) and the fast growing vesicles produced PSC in brood capsules. In addition, mice were intraperitoneally injected with 30 cultured small vesicles and 100 % of the mice had resulting metacestode masses. CONCLUSIONS: Larval protoscoleces and vesicles of E. multilocularis grow healthily in vitro in the RPMI1640 based medium containing 25 % FBS. Echinococcus multilocularis in vitro and in vivo models provide a valuable platform for investigating the biology of the parasite and screening effective therapeutic drugs against AE. PMID- 27457383 TI - Nitrated Confined Imidodiphosphates Enable a Catalytic Asymmetric Oxa-Pictet Spengler Reaction. AB - The development of a highly enantioselective catalytic oxa-Pictet-Spengler reaction has proven a great challenge for chemical synthesis. We now report the first example of such a process, which was realized by utilizing a nitrated confined imidodiphosphoric acid catalyst. Our approach provides substituted isochroman derivatives from both aliphatic and aromatic aldehydes with high yields and excellent enantioselectivities. DFT calculations provide insight into the reaction mechanism. PMID- 27457382 TI - Foxp3 overexpression in tumor cells predicts poor survival in oral squamous cell carcinoma. AB - BACKGROUND: Forkhead Box P3 (Foxp3) is a regulatory T cells marker, and its expression correlates with prognosis in a number of malignancies. The aim of this study is to determine the relationship of Foxp3 expression with clinicopathological parameters and prognosis in oral squamous cell carcinoma (OSCC). METHODS: Foxp3 expression was examined using immunohistochemistry (IHC) in paraffin-embedded tissue samples from 273 OSCC patients. Statistical analysis was performed to evaluate the associations between Foxp3 expression, the clinicopathologic characteristics and prognostic factors in OSCC. RESULTS: Foxp3 protein expression was significantly associated with lymph node metastasis (P <0.01). Both univariate and multivariate analyses revealed that Foxp3 was an independent factor for both 5 years overall survival (OS) and relapse-free survival (RFS) (both P <0.01). Patients with Foxp3 overexpression had shorter OS and RFS. CONCLUSIONS: Our results determined that elevated Foxp3 protein expression was a predictive factor of outcome in OSCC and could act as a promising therapeutic target. PMID- 27457386 TI - [Not Available]. PMID- 27457384 TI - Conditioned medium derived from umbilical cord mesenchymal stem cells regenerates atrophied muscles. AB - We investigated the regenerative effects and regulatory mechanisms of human umbilical cord mesenchymal stem cells (UC-MSCs)-derived conditioned medium (CM) in atrophied muscles using an in vivo model. To determine the appropriate harvest point of UC-CM, active factor content was analyzed in the secretome over time. A muscle atrophy model was induced in rats by hindlimb suspension (HS) for 2 weeks. Next, UC-CM was injected directly into the soleus muscle of both hind legs to assess its regenerative efficacy on atrophy-related factors after 1 week of HS. During HS, muscle mass and muscle fiber size were significantly reduced by over 2 fold relative to untreated controls. Lactate accumulation within the muscles was similarly increased. By contrast, all of the above analytical factors were significantly improved in HS-induced rats by UC-CM injection compared with saline injection. Furthermore, the expression levels of desmin and skeletal muscle actin were significantly elevated by UC-CM treatment. Importantly, UC-CM effectively suppressed expression of the atrophy-related ubiquitin E3-ligases, muscle ring finger 1 and muscle atrophy F-box by 2.3- and 2.1-fold, respectively. UC-CM exerted its actions by stimulating the phosphoinositol-3-kinase (PI3K)/Akt signaling cascade. These findings suggest that UC-CM provides an effective stimulus to recover muscle status and function in atrophied muscles. PMID- 27457387 TI - [Not Available]. PMID- 27457385 TI - Coherent optical phonon oscillation and possible electronic softening in WTe2 crystals. AB - A rapidly-growing interest in WTe2 has been triggered by the giant magnetoresistance effect discovered in this unique system. While many efforts have been made towards uncovering the electron- and spin-relevant mechanisms, the role of lattice vibration remains poorly understood. Here, we study the coherent vibrational dynamics in WTe2 crystals by using ultrafast pump-probe spectroscopy. The oscillation signal in time domain in WTe2 has been ascribed as due to the coherent dynamics of the lowest energy A1 optical phonons with polarization- and wavelength-dependent measurements. With increasing temperature, the phonon energy decreases due to anharmonic decay of the optical phonons into acoustic phonons. Moreover, a significant drop (15%) of the phonon energy with increasing pump power is observed which is possibly caused by the lattice anharmonicity induced by electronic excitation and phonon-phonon interaction. PMID- 27457388 TI - [Not Available]. PMID- 27457389 TI - [Not Available]. PMID- 27457390 TI - [Not Available]. PMID- 27457391 TI - [Not Available]. PMID- 27457392 TI - [Posterm pregnancy]. AB - This review presents the up-to-date information from published resources on the issue of Posterm pregnancy (Medline, Cochrane Database, ACOG, RCOG, SOGC) and complements the presented guidelines. The most of resources are using the term "postterm pregnancy" for pregnancy reaching or exceeding 42+0 weeks and days of gestation, while late pregnancy is defined as a period in between 41+0 and 41+6.The exact determination of gestational age is necessary for exact diagnosis and appropriate management of late and postterm pregnancy, because these pregnancies have increased risk of perinatal morbidity and mortality. DESIGN: Review. PMID- 27457393 TI - [Induction of labor]. AB - Data published in this guideline are based on previous guideline issued by Society of Perinatal Medicine of Czech Gynecological and Obstetrical Society (CGPS) [55], international guidelines and data from peer-reviewed journals. The fundamental document for this guideline is guideline issued by The Society of Obstetricians and Gynaecologists of Canada (SOGS) Induction of labor, No. 296, 2013 (reviewed 2015) [61]. The literature review is added to the aforementioned document and some of its recommendations are further discussed in this guideline. DESIGN: Review of literature. PMID- 27457394 TI - [Current status and recommendations for intrapartum monitoring of fetal heart rate]. AB - Monitoring of fetal heart rate is one of the basic components of obstetrical care, in which the cardiotocography remains the gold standard and screening method in early diagnosis of fetal hypoxia, even after introduction of other selective methods of intrauterine monitoring of fetal well-being. The review article is divided into several parts: pathophysiology of fetal oxygenation, fetal heart rate and changes of fetal hemodynamics, and rules for fetal heart rate auscultation. The main principles of cardiotocographic monitoring and evaluation of ante- and intrapartrum recordings according to the FIGO criteria from 1986 and evaluation of intrapartum recordings according to the 2015 FIGO recommendations are mentioned. At the end a comparative table of 1986 FIGO and 2015 FIGO criteria is presented. DESIGN: Review. PMID- 27457395 TI - [Delivery of macrosomic fetus]. AB - Fetal macrosomia is associated with an increased risk of perinatal mortality and morbidity for both, mother and fetus. The frequency of these births is between 1.3 to 1.5%. Macrosomic fetuses are defined with a weight of 4500 g and more. Diagnosis and prediction of macrosomia or fetal birth weight is key to determine the tactics of delivery. It is based on the combination and assessment of medical history, clinical parameters and ultrasound biometry. The limit for elective caesarean section is considered the estimated fetal weight in healthy mothers of more than 5000 g. For mothers with diabetes an indication of the caesarean section should be considered for fetal weight of more than 4000 g. DESIGN: A review of the literature. PMID- 27457396 TI - [Assisted vaginal delivery]. AB - This article is meant to be a complement to the new statement "Assisted vaginal delivery" of the Section of perinatal and fetomaternal medicine (SPFM) of the Czech Society of Gynecology and Obstetrics CLS JEP, which is also published in this issue of Czech gynecology. The new statement has been formed as a synthesis of two previous separate statements of the SPFM "Vacuumextraction" and "Forceps delivery" and has also been updated based on new scientific knowledge. This review publication summarizes latest knowledge on vacuumextraction and forceps delivery and adds comments to certain points from the statement. DESIGN: A review of the literature. PMID- 27457397 TI - [Use of methotrexate in the ectopic pregnancy and pregnancy of unknown location]. AB - OBJECTIVE: There are only a few gynaecological departments in the Czech Republic that use medical treatment of the ectopic pregnancy (EP) or persistent pregnancy of unknown location (PUL). We have started using this method in 2008 at our clinic. The aim of this study was to assess the success rate of conservative medical treatment with methotrexate (MTX) in the dose of 1 mg/kg intramuscularly in patients with ectopic pregnancy or persistent pregnancy of unknown location and to compare the results of clinical history, clinical finding and laboratory results in a group of successful and a group of unsuccessful treatment. TYPE OF STUDY: Retrospective analysis. SETTING: Charles University in Prague, 1st Medical Faculty and Hospital Bulovka, Department of Obstetrics and Gynaecology, Prague. METHODS: Patients diagnosed with EP or persistent PUL diagnosed at the outpatient of our clinic in 01/2008 - 08/2014 who were hemodynamically stable and fulfilled the indication for medical treatment were enrolled in the study. Treatment success was decrease of free subunit of beta-hCG (beta-hCG) < 5 IU/L independent of the number of methotrexate doses administered. RESULTS: Two hundred and eleven patients were diagnosed with EP or PUL, sixty-three were eligible for our study and fulfilled the criteria for methotrexate treatment, fifty six women were finally analysed. From this number forty eight (86%) had clinically and laboratory diagnosed EP and eight (14%) were diagnosed with persistent PUL. Forty one patients (73%) had a successfull treatment (Group I) with the beta-hCG level decrease <5 IU/L in a mean time of 27 days. When comparing the data of successful and unsuccessful treatment (Group II) we found a difference in the non significant initial beta-hCG level. In Group I there was a median beta-hCG 538 IU/L (100-3852 IU/l), whereas in the unsuccessful Group II it was 1100 IU/L (300 3240 IU/l). Group I included more nuliparous women and more women with clinical histories of EP. Group II included more heavy smokers. The mean hematosalpinx diameter for group II, measured by transvaginal ultrasound, was larger. There were also more patients with endometriosis or deep infiltrating endometriosis in Group II, subsequently verified during laparoscopy, compared to Group I. There was no tubal rupture in these patients. CONCLUSION: The results of our study are comparable with foreign literature publications. We consider the pharmacological treatment of ectopic preganancy or persistent pregnancy of unknown location as effective and relatively safe for patients, with similar impact on a woman's fertility as laparoscopic salpingectomy. PMID- 27457398 TI - [Diagnosis of tuberous sclerosis complex focusing on prenatal period]. AB - Tuberous sclerosis is a disease with an autosomal dominant pattern of inheritance which is characterized by the development of benign tumours in many tissues and organs. Clinical signs are extremely variable, causing mutations in the gene TSC1 or TSC2. Complex formed by the products of the TSC genes regulates cell growth and proliferation by inhibition of mTORC1 signalling. Early diagnosis of TSC is very important to plan appropriate perinatal care. Using ultrasound and eventually MRI it is possible in the prenatal period to capture the following major features of tuberous sclerosis: cardiac rhabdomyo-ma, subependymal nodules, cortical tubers and renal angiomyolipomas. In connection with the syndrome of contiguous genes TSC2 / PKD1 can also be detect foetal renal cysts. Often these TSC-associated lesions represent an incidental finding during a routine ultrasound. In the period from the 20th week of pregnancy it is most often found cardiac rhabdomyoma/s as the first marker suggestive of tuberous sclerosis. In the case, where one of the parents is a carrier of already identified mutation in the TSC gene, it is possible to carry out targeted genetic testing of a sample of DNA isolated from cells of chorionic villi, amniocytes or tissue from aborted foe tuses. Significantly more time consuming is to perform molecular analysis of the TSC genes in foetuses with suspected tuberous sclerosis without the occurrence of illness in the family. After finding a causal mutation and its confirmation, it is possible to offer genetic testing for other persons at risk, prenatal (eventually preimplantation) diagnosis for future pregnancies. It is also necessary to consider the possibility of gonadal mosaicism. DESIGN: Review of the literature. PMID- 27457399 TI - [Czech Hospital in Uganda and quality of obstetric care]. AB - OBJECTIVE: The target was to evaluate the present state of obstetric care in Czech Hospital in Buikwe in Uganda. We evaluated a professional level of hospital physicians, their obstetric expertise and technical equipment of delivery theatre and mobile surgery and we provided a short 4 months evaluation of deliveries in main view of obstetric pathologies, frequency of caesarean sections and maternal mortality. METHODS AND RESULTS: In period from October 2014 to January 2015 there was evaluated a group of 374 women, admited to labour at delivery theatre. We evaluated parity of women, number and indications of caesarean sections, age of women and obstetric finding by admission. The most of our patients were primiparas and secundiparas, the caesarean section was performed in 23,8% of cases and the most frequent indication of it was threatened rupture of the uterus, state after caesarean section, cephalopelvic disproportion and obstructed labour. Two women died. By evaluation of quality of obstetric care we have found some serious lacks. Ugandan doctors are not obstetricians, they have no experience with vaginal obstetric operations, the Hospital has no fetal-monitor and no possibility for a transport of emergency cases. CONCLUSIONS: The Hospital needs expert help from Czech Republic, as doctors-obstetricians so as some equipment for delivery theatre and above all suitable car for urgent transport and for use of mobile surgery. PMID- 27457400 TI - [Not Available]. PMID- 27457401 TI - Gallic acid attenuates TGF-beta1-stimulated collagen gel contraction via suppression of RhoA/Rho-kinase pathway in hypertrophic scar fibroblasts. AB - AIMS: To examine the effect and molecular mechanism of gallic acid (GA) on transforming growth factor-beta1 (TGF-beta1)-stimulated hypertrophic scar fibroblast (HSF) contraction. MATERIALS AND METHODS: A fibroblast-populated collagen lattice (FPCL) was developed to examine the effect of GA on TGF-beta1 enhanced HSF contraction. The changes in crucial factors related to cell contraction including alpha-smooth muscle actin (alpha-SMA), F-actin, and the phosphorylation level of myosin light chain (MLC) were evaluated using western blot and immunostaining. The activation and expression of RhoA/ROCK after the TGF beta1 challenge and GA insult were evaluated using RhoA-G-LISA and RhoA-ELISA kit while the phosphorylation level of MYPT1 and the expression of ROCK1 and ROCK2 were examined by western blot, respectively. KEY FINDINGS: GA significantly suppressed TGF-beta1-stimulated HSF contraction in a dose- and time-dependent manner. Moreover, the TGF-beta1-enhanced alpha-SMA expression, F-actin formation, and MLC phosphorylation were obviously attenuated by GA. TGF-beta1 significantly stimulated RhoA activation but did not alter the expression of RhoA in the HSFs. However, both the activation and expression of RhoA decreased obviously with GA pretreatment followed by TGF-beta1 stimulation. Furthermore, GA inhibited ROCK activity but did not affect its expression after TGF-beta1 stimulation. SIGNIFICANCE: These results suggest that GA exhibited the potential to prevent HSF contraction after TGF-beta1 stimulation by down regulating the RhoA/ROCK signal cascade, followed by the inhibition of the expression of alpha-SMA, F actin formation, and phosphorylation of MLC. PMID- 27457402 TI - Label-Free Analysis of Single Viruses with a Resolution Comparable to That of Electron Microscopy and the Throughput of Flow Cytometry. AB - Viruses are by far the most abundant biological entities on our planet, yet existing characterization methods are limited by either their speed or lack of resolution. By applying a laboratory-built high-sensitivity flow cytometer (HSFCM) to precisely quantify the extremely weak elastically scattered light from single viral particles, we herein report the label-free analysis of viruses with a resolution comparable to that of electron microscopy and the throughput of flow cytometry. The detection of single viruses with diameters down to 27 nm is described. T7 and lambda bacteriophages, which differ in size by as little as 4 nm, could be baseline-resolved. Moreover, subtle structural differences of the same viral particles can be discriminated. Using monodisperse silica nanoparticles as the size reference standards, the virus sizes measured by the HSFCM are in agreement with the equivalent particle diameters derived from their structural dimensions. The HSFCM opens a new avenue for virus characterization. PMID- 27457403 TI - Air embolism following removal of hemodialysis catheter. AB - INTRODUCTION: Air embolism (AE) is a rare, but serious complication that can occur in the practice of hemodialysis. In contrast to careful techniques and meticulous care during insertions and manipulations of the central catheters, awareness of the risk of AE following catheter removal is less. We aimed to analyze the clinical characteristics of the all case reports with AE after catheter removal and summarize the mechanisms, clinical consequences, treatment and prevention of AE. METHODS: In addition to our case, MEDLINE database was searched for all case reports with AE following catheter removal, and the clinical, diagnostic and outcome data were analyzed. FINDINGS: A total of 10 patients (including our case) (M/F 6/4; median age 50.5 years) were found for the analysis. Procedures for prevention of AE were reported in a few patients (Trendelenburg position 2, airtight dressing 1). The time that elapsed between catheter removals and onset of AEs was ranged from seconds to 6 hours. The most common findings were dyspnea (90%), hypoxemia (70%), and cerebral dysfunction (70%). The most common sites where air could be detected were the left ventricle (40%), pulmonary artery (30%) and right ventricle (30%). Mortality was reported in 4 (40%) cases and the remaining 6 patients had complete recovery. Blocking of air portal was not reported in any of the fatal cases. DISCUSSION: AE following catheter removal carries a major risk of mortality. Great awareness and attention to preventive procedures and appropriate care after development of AE seem mandatory. PMID- 27457404 TI - Schizophrenia among patients with systemic lupus erythematosus: population-based cross-sectional study. AB - AIMS: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease involving multiple organs, including the central nervous system. Evidence of immune dysfunction exists also in schizophrenia, a psychiatric illness involving chronic or recurrent psychosis. The aim of our study was to investigate if there is an epidemiological association between SLE and schizophrenia. METHOD: A cross sectional study was conducted comparing patients with SLE with age and gender matched controls regarding the proportion of patients with comorbid schizophrenia. chi 2- and t-tests were used for univariate analysis, and interaction of schizophrenia with SLE across strata of covariates was checked. A logistic regression model was used for multivariate analysis. The study was performed utilising the medical database of Clalit Health Services in Israel. RESULTS: The study included 5018 patients with SLE and 25 090 controls. SLE patients had a female predominance, and a higher proportion of smoking compared with age and sex-matched controls. In multivariate analysis, SLE was found to be independently associated with schizophrenia while controlling for age, gender, socioeconomic status (SES) and smoking (OR 1.33, p = 0.042). CONCLUSIONS: We found a positive association between SLE and schizophrenia across patients of different age, gender and SES. This association can contribute to understanding the pathophysiology of the two disorders and may also have clinical implications for earlier as well as better diagnosis and treatment. PMID- 27457405 TI - On the origin of pure optical rotation in twisted-cross metamaterials. AB - We present an experimental and computational study of the response of twisted cross metamaterials that provide near dispersionless optical rotation across a broad band of frequencies from 19 GHz to 37 GHz. We compare two distinct geometries: firstly, a bilayer structure comprised of arrays of metallic crosses where the crosses in the second layer are twisted about the layer normal; and secondly where the second layer is replaced by the complementary to the original, i.e. an array of cross-shaped holes. Through numerical modelling we determine the origin of rotatory effects in these two structures. In both, pure optical rotation occurs in a frequency band between two transmission minima, where alignment of electric and magnetic dipole moments occurs. In the cross/cross metamaterial, the transmission minima occur at the symmetric and antisymmetric resonances of the coupled crosses. By contrast, in the cross/complementary-cross structure the transmission minima are associated with the dipole and quadrupole modes of the cross, the frequencies of which appear intrinsic to the cross layer alone. Hence the bandwidth of optical rotation is found to be relatively independent of layer separation. PMID- 27457406 TI - Socioeconomic and Racial Disparities in Parental Perception and Experience of Having a Medical Home, 2007 to 2011-2012. AB - OBJECTIVE: To evaluate whether socioeconomic (SES) and racial disparities in the parental perception and experience of having a medical home decreased from 2007 to 2011-2012. METHODS: We used nationally representative samples of children aged 1 to 17 from the 2007 (n = 83,293) and 2011-2012 (n = 87,774) National Surveys of Children's Health. Multivariable logistic regression was used to test associations between SES (income, employment, and education) and race/ethnicity to the medical home and its subcomponents (personal doctor or nurse, usual source of care, family-centered care, referrals, care coordination), controlling for a priori identified covariates. RESULTS: From 2007 to 2011-2012, fewer children overall had access to a medical home (56.9% vs 54.0%, aOR = 0.91, 95% confidence interval 0.86-0.96). There were no significant changes in SES and racial trends in access to the medical home during this time period. For example, parents of children <100% federal poverty level (FPL) were significantly less likely to report having a medical home than parents of children >=400% FPL in 2007 and 2011 2012; however, this disparity did not significantly change during the time period (aOR = 0.98, 95% confidence interval 0.75-1.27). There were also no significant changes in SES and racial/ethnic disparities over time for each medical home subcomponent. CONCLUSIONS: Despite widespread efforts to promote the medical home for all children, large SES and racial disparities in the parental perception and experience of having a medical home persisted from 2007 to 2011-2012. PMID- 27457408 TI - Manipulating Ce Valence in RE2Fe14B Tetragonal Compounds by La-Ce Co-doping: Resultant Crystallographic and Magnetic Anomaly. AB - Abundant and low-cost Ce has attracted considerable interest as a prospective alternative for those critically relied Nd/Pr/Dy/Tb in the 2:14:1-type permanent magnets. The (Nd, Ce)2Fe14B compound with inferior intrinsic magnetic properties to Nd2Fe14B, however, cannot provide an equivalent magnetic performance. Since Ce valence is sensitive to local steric environment, manipulating it towards the favorable trivalent state provides a way to enhance the magnetic properties. Here we report that such a desirable Ce valence can be induced by La-Ce co-doping into [(Pr, Nd)1-x(La, Ce)x]2.14Fe14B (0 <= x <= 0.5) compounds via strip casting. As verified by X-ray photoelectron spectroscopy results, Ce valence shifts towards the magnetically favorable Ce(3+) state in the composition range of x > 0.3, owing to the co-doping of large radius La(3+) into 2:14:1 phase lattice. As a result, both crystallographic and magnetic anomalies are observed in the same vicinity of x = 0.3, above which lattice parameters a and c, and saturation magnetization Ms increase simultaneously. Over the whole doping range, 2:14:1 tetragonal structure forms and keeps stable even at 1250 K. This finding may shed light on obtaining a favorable Ce valence via La-Ce co-doping, thus maintaining the intrinsic magnetic properties of 2:14:1-type permanent magnets. PMID- 27457407 TI - Versatile nourseothricin and streptomycin/spectinomycin resistance gene cassettes and their use in chromosome integration vectors. AB - An obstacle for the development of genetic systems for many bacteria is the limited number of antibiotic selection markers, especially for bacteria that are intrinsically antibiotic resistant or where utilization of such markers is strictly regulated. Here we describe the development of versatile cassettes containing nourseothricin, streptomycin/spectinomycin, and spectinomycin selection markers. The antibiotic resistance genes contained on these cassettes are flanked by loxP sites with allow their in vivo excision from the chromosome of target bacteria using Cre recombinase. The respective selection marker cassettes were used to derive mini-Tn7 elements that can be used for single-copy insertion of genes into bacterial chromosomes. The utility of the selection markers was tested by insertion of the resulting mini-Tn7 elements into the genomes of Burkholderia thailandensis and B. pseudomallei efflux pump mutants susceptible to aminoglycosides, aminocyclitols, and streptothricins, followed by Cre-mediated antibiotic resistance marker excision. The versatile nourseothricin, streptomycin/spectinomycin and spectinomycin resistance loxP cassette vectors described here extend the repertoire of antibiotic selection markers for genetic manipulation of diverse bacteria that are susceptible to aminoglycosides and aminocyclitols. PMID- 27457409 TI - Multicomponent Petasis-borono Mannich Preparation of Alkylaminophenols and Antimicrobial Activity Studies. AB - In this work we report the antibacterial activity of alkylaminophenols. A series of such compounds was prepared by a multicomponent Petasis-borono Mannich reaction starting from salicylaldehyde and its derivatives. The obtained compounds were tested against a large panel of microorganisms, Gram-positive and Gram-negative bacteria, and a yeast. Among the several tertiary amine derivatives tested, indoline-derived aminophenols containing a nitro group at the para-phenol position showed considerable activity against bacteria tested with minimal inhibitory concentrations as low as 1.36 MUm against Staphyloccocus aureus and Mycobacterium smegmatis. Cytotoxicity of the new para-nitrophenol derivatives was observed only at concentrations much higher than those required for antibacterial activity. PMID- 27457410 TI - Intergenerational Effects of Childhood Trauma: Evaluating Pathways Among Maternal ACEs, Perinatal Depressive Symptoms, and Infant Outcomes. AB - Maternal adverse childhood experiences (ACEs) have been associated with negative physical and mental health outcomes in adulthood. Less is known regarding how maternal ACEs relate to perinatal depressive symptoms or the intergenerational effect of maternal childhood trauma history on birth outcomes and infant functioning. To address this gap, an at-risk sample of 398 pregnant women was recruited from Women, Infants, and Children health clinics. Participants completed a prenatal ( M = 4.84 months before due date) and postnatal ( M = 6.76 months after birth) assessment and provided birth outcome data. At the prenatal assessment, mothers completed an ACEs measure which assessed experiences of childhood maltreatment and household dysfunction. Self-report measures of maternal depressive symptoms were obtained at both time points. Mothers reported on infant socioemotional functioning at 6 months. Maternal ACEs predicted higher levels of prenatal depressive symptoms. Childhood maltreatment experiences, in particular, predicted higher postnatal depressive symptoms and a smaller reduction in depressive symptoms across the perinatal period. Regarding intergenerational associations, maternal childhood maltreatment directly predicted higher levels of maladaptive infant socioemotional symptoms, whereas maternal household dysfunction indirectly related to infant socioemotional symptoms through maternal age at first pregnancy and infant birth weight. Limitations and future directions are discussed. PMID- 27457411 TI - Inflammatory myofibroblastic tumour: biology? PMID- 27457413 TI - A patient with Parkinson's disease and dermatomyositis with serum anti transcriptional intermediary factor 1-gamma antibody. PMID- 27457412 TI - IL-4 and IL-15 promotion of virtual memory CD8+ T cells is determined by genetic background. AB - Virtual memory (VM) CD8+ T cells are present in unimmunized mice, yet possess T cell receptors specific for foreign antigens. To date, VM cells have only been characterized in C57BL/6 mice. Here, we assessed the cytokine requirements for VM cells in C57BL/6 and BALB/c mice. As reported previously, VM cells in C57BL/6 mice rely mostly on IL-15 and marginally on IL-4. In stark contrast, VM cells in BALB/c mice rely substantially on IL-4 and marginally on IL-15. Further, NKT cells are the likely source of IL-4, because CD1d-deficient mice on a BALB/c background have significantly fewer VM cells. Notably, this NKT/IL-4 axis contributes to appropriate effector and memory T-cell responses to infection in BALB/c mice, but not in C57BL/6 mice. However, the effects of IL-4 are manifest prior to, rather than during, infection. Thus, cytokine-mediated control of the precursor population affects the development of virus-specific CD8+ T-cell memory. Depending upon the genetic background, different cytokines encountered before infection may influence the subsequent ability to mount primary and memory anti-viral CD8+ T-cell responses. PMID- 27457414 TI - Great hammerhead sharks swim on their side to reduce transport costs. AB - Animals exhibit various physiological and behavioural strategies for minimizing travel costs. Fins of aquatic animals play key roles in efficient travel and, for sharks, the functions of dorsal and pectoral fins are considered well divided: the former assists propulsion and generates lateral hydrodynamic forces during turns and the latter generates vertical forces that offset sharks' negative buoyancy. Here we show that great hammerhead sharks drastically reconfigure the function of these structures, using an exaggerated dorsal fin to generate lift by swimming rolled on their side. Tagged wild sharks spend up to 90% of time swimming at roll angles between 50 degrees and 75 degrees , and hydrodynamic modelling shows that doing so reduces drag-and in turn, the cost of transport-by around 10% compared with traditional upright swimming. Employment of such a strongly selected feature for such a unique purpose raises interesting questions about evolutionary pathways to hydrodynamic adaptations, and our perception of form and function. PMID- 27457415 TI - Altered neural response to rejection-related words in children exposed to maltreatment. AB - BACKGROUND: Children exposed to maltreatment show neural sensitivity to facial cues signalling threat. However, little is known about how maltreatment influences the processing of social threat cues more broadly, and whether atypical processing of social threat cues relates to psychiatric risk. METHODS: Forty-one 10- to 14-year-old children underwent a social rejection-themed emotional Stroop task during functional magnetic resonance imaging: 21 children with a documented history of maltreatment (11 F) and 19 comparison children with no maltreatment history (11 F). Groups were matched on age, pubertal status, gender, IQ, socioeconomic status, ethnicity and reading ability. Classic colour Stroop stimuli were also administered in the same paradigm to investigate potential differences in general cognitive control. RESULTS: Compared with their peers, children who had experienced maltreatment showed reduced activation in the Rejection versus Neutral condition, across circuitry previously implicated in abuse-related posttraumatic stress disorder (PTSD), including the left anterior insula, extending into left ventrolateral prefrontal cortex/orbitofrontal cortex; left amygdala; left inferior parietal cortex (STS); and bilateral visual association cortex, encompassing the cuneus and lingual gyrus. No group differences in neural or behavioural responses were found for the classic colour Stroop conditions. Significant negative associations between activity in bilateral cuneus and STS during the rejection-themed Stroop and higher self reported PTSD symptomatology, including dissociation, were observed in children exposed to maltreatment. CONCLUSION: Our findings indicate a pattern of altered neural response to social rejection cues in maltreated children. Compared to their peers, these children displayed relative hypoactivation to rejection cues in regions previously associated with PTSD, potentially reflecting an avoidant coping response. It is suggested that such atypical processing of social threat may index latent vulnerability to future psychopathology in general and PTSD in particular. PMID- 27457416 TI - Brain regions implicated in inhibitory control and appetite regulation are activated in response to food portion size and energy density in children. AB - OBJECTIVE: Large portions of energy-dense foods drive energy intake but the brain mechanisms underlying this effect are not clear. Our main objective was to investigate brain function in response to food images varied by portion size (PS) and energy density (ED) in children using functional magnetic resonance imaging (fMRI). METHODS AND DESIGN: Blood-oxygen-level-dependent (BOLD) fMRI was completed in 36 children (ages 7-10 years) after a 2-h fast while viewing food images at two levels of PS (Large PS, Small PS) and two levels of ED (High ED, Low ED). Children rated perceived fullness pre- and post-fMRI, as well as liking of images on visual analog scales post-fMRI. Anthropometrics were completed 4 weeks before the fMRI. Large PS vs Small PS and High ED vs Low ED were compared with region-of-interest analyses using Brain Voyager v 2.8. RESULTS: Region-of interest analyses revealed that activation in the right inferior frontal gyrus (P=0.03) was greater for Large PS vs Small PS. Activation was reduced for High ED vs Low ED in the left hypothalamus (P=0.03). Main effects were no longer significant after adjustment for pre-fMRI fullness and liking ratings (PS, P=0.92; ED, P=0.58). CONCLUSION: This is the first fMRI study to report increased activation to large portions in a brain region that is involved in inhibitory control. These findings may contribute to understanding why some children overeat when presented with large portions of palatable food. PMID- 27457418 TI - Interaction of lafutidine in binding to human serum albumin in gastric ulcer therapy: STD-NMR, WaterLOGSY-NMR, NMR relaxation times, Tr-NOESY, molecule docking, and spectroscopic studies. AB - In this study, lafutidine (LAF) was used as a model compound to investigate the binding mechanism between antiulcer drugs and human serum albumin (HSA) through various techniques, including STD-NMR, WaterLOGSY-NMR, (1)H NMR relaxation times, tr-NOESY, molecule docking calculation, FT-IR spectroscopy, and CD spectroscopy. The analyses of STD-NMR, which derived relative STD (%) intensities, and WaterLOGSY-NMR, determined that LAF bound to HSA. In particular, the pyridyl group of LAF was in close contact with HSA binding pocket, whereas furyl group had a secondary binding. Competitive STD-NMR and WaterLOGSY-NMR experiments, with warifarin and ibuprofen as site-selective probes, indicated that LAF preferentially bound to site II in the hydrophobic subdomains IIIA of HSA. The bound conformation of LAF at the HSA binding site was further elucidated by transferred NOE effect (tr-NOESY) experiment. Relaxation experiments provided quantitative information about the relationship between the affinity and structure of LAF. The molecule docking simulations conducted with AutoDock and the restraints derived from STD results led to three-dimensional models that were consistent with the NMR spectroscopic data. The presence of hydrophobic forces and hydrogen interactions was also determined. Additionally, FT-IR and CD spectroscopies showed that LAF induced secondary structure changes of HSA. PMID- 27457417 TI - Effects of macromolecular crowding on a small lipid binding protein probed at the single-amino acid level. AB - Macromolecular crowding is a distinctive feature of the cellular interior, influencing the behaviour of biomacromolecules. Despite significant advancements in the description of the effects of crowding on global protein properties, the influence of cellular components on local protein attributes has received limited attention. Here, we describe a residue-level systematic interrogation of the structural, dynamic, and binding properties of the liver fatty acid binding protein (LFABP) in crowded solutions. Two-dimensional NMR spectral fingerprints and relaxation data were collected on LFABP in the presence of polymeric and biomolecular crowders. Non-interacting crowders produced minimal site-specific spectral perturbations on ligand-free and lipid-bound LFABP. Conformational adaptations upon ligand binding reproduced those observed in dilute solution, but a perturbation of the free oleate state resulted in less favorable uptake. When LFABP engaged in direct interactions with background molecules, changes in local chemical environments were detected for residues of the internal binding pocket and of the external surface. Enhanced complexity was introduced by investigating LFABP in cell lysates, and in membrane-bounded compartments. LFABP was able to capture ligands from prokaryotic and eukaryotic cell lysates, and from artificial cells (water-in-oil emulsion droplets). The data suggest that promiscuous interactions are a major factor influencing protein function in the cell. PMID- 27457420 TI - A new classification for hereditary neurological disorders: A cure for the chaos! PMID- 27457419 TI - NF-E2, FLI1 and RUNX1 collaborate at areas of dynamic chromatin to activate transcription in mature mouse megakaryocytes. AB - Mutations in mouse and human Nfe2, Fli1 and Runx1 cause thrombocytopenia. We applied genome-wide chromatin dynamics and ChIP-seq to determine these transcription factors' (TFs) activities in terminal megakaryocyte (MK) maturation. Enhancers with H3K4me2-marked nucleosome pairs were most enriched for NF-E2, FLI and RUNX sequence motifs, suggesting that this TF triad controls much of the late MK program. ChIP-seq revealed NF-E2 occupancy near previously implicated target genes, whose expression is compromised in Nfe2-null cells, and many other genes that become active late in MK differentiation. FLI and RUNX were also the motifs most enriched near NF-E2 binding sites and ChIP-seq implicated FLI1 and RUNX1 in activation of late MK, including NF-E2-dependent, genes. Histones showed limited activation in regions of single TF binding, while enhancers that bind NF-E2 and either RUNX1, FLI1 or both TFs gave the highest signals for TF occupancy and H3K4me2; these enhancers associated best with genes activated late in MK maturation. Thus, three essential TFs co-occupy late-acting cis-elements and show evidence for additive activity at genes responsible for platelet assembly and release. These findings provide a rich dataset of TF and chromatin dynamics in primary MK and explain why individual TF losses cause thrombopocytopenia. PMID- 27457422 TI - Stable thermosensitive in situ gel-forming systems based on the lyophilizate of chitosan/alpha,beta-glycerophosphate salts. AB - In the present study, lyophilization was attempted to improve the long-term storage of CS/GP thermogelling systems for biopharmaceutical applications. After lyophilization, CS/alpha,beta-GP lyophilizate could not be dissolved in water, but some metal salts, such as NaCl, CaCl2, and MgCl2 surprisingly facilitated its dissolution. X-ray powder diffraction analysis suggested that calcium ions might preferentially form salts with alpha,beta-GP, inhibit the transfer of protons from CS to alpha,beta-GP, and then inhibit the aggregation of CS molecules during lyophilization. Comparison of the freshly prepared CS/alpha,beta-GP/salt solutions and the reconstituted solutions from lyophilizates showed that lyophilization clearly influenced the properties of reconstituted CS/alpha,beta GP/salt solutions such as gelation time, viscosity, and pH. Furthermore, the reconstituted CS/alpha,beta-GP/CaCl2 solutions maintained thermogelling properties and formed hydrogels at 37 degrees C within approximately 5min, but did not form hydrogels at 20 degrees C and 4 degrees C over 2 weeks. The model protein bovine serum albumin (BSA) was further incorporated into the CS/alpha,beta-GP/CaCl2 system. In vitro release experiments showed the sustained release of BSA from CS/alpha,beta-GP/CaCl2 hydrogels in a pH-sensitive manner, demonstrating that CS/alpha,beta-GP/CaCl2 may be useful as an in situ gel-forming system. PMID- 27457421 TI - Context-specific protection of TGFalpha null mice from osteoarthritis. AB - Transforming growth factor alpha (TGFalpha) is a growth factor involved in osteoarthritis (OA). TGFalpha induces an OA-like phenotype in articular chondrocytes, by inhibiting matrix synthesis and promoting catabolic factor expression. To better understand TGFalpha's potential as a therapeutic target, we employed two in vivo OA models: (1) post-traumatic and (2) aging related OA. Ten week old and six-month old male Tgfa null mice and their heterozygous (control) littermates underwent destabilization of the medial meniscus (DMM) surgery. Disease progression was assessed histologically using the Osteoarthritis Research Society International (OARSI) scoring system. As well, spontaneous disease progression was analyzed in eighteen-month-old Tgfa null and heterozygous mice. Ten-week old Tgfa null mice were protected from OA progression at both seven and fourteen weeks post-surgery. No protection was seen however in six-month old null mice after DMM surgery, and no differences were observed between genotypes in the aging model. Thus, young Tgfa null mice are protected from OA progression in the DMM model, while older mice are not. In addition, Tgfa null mice are equally susceptible to spontaneous OA development during aging. Thus, TGFalpha might be a valuable therapeutic target in some post-traumatic forms of OA, however its role in idiopathic disease is less clear. PMID- 27457423 TI - Fusion of an albumin-binding domain extends the half-life of immunotoxins. AB - Immunotoxins have documented potential as a cancer treatment due to their extreme potency; a single toxin molecule delivered to the cytosol may be sufficient to kill a cell. However, their short half-life in the circulatory system may be one of the key problems associated with the clinical use of immunotoxins and may continue to limit their therapeutic activity. Herein, we genetically fused an albumin-binding domain (ABD) to the human epidermal growth factor receptor 2 (HER2)-specific immunotoxin ZHER2-PE38 to extend the circulation time and thus improve the therapeutic outcome of this immunotoxin. Furthermore, the fusion of an ABD to the immunotoxin was found to promote non-covalent interactions between the immunotoxin and serum albumin, which rescue the immunotoxin from lysosomal degradation through a serum albumin-mediated interaction with the neonatal Fc receptor (FcRn). This manuscript reports the construction, purification, and characterization of the ABD-fused HER2-specific immunotoxin, ABD-ZHER2-PE38, both in vitro and in vivo. Compared with non-fused ZHER2-PE38, this new construct exhibits a clearly increased half-life in plasma (330.8 versus 13.5min, approximately 24.4-fold extension) and remarkably improved antitumor effects in an NCI-N87 subcutaneous xenograft model. Therefore, the new construct represents a potentially attractive therapeutic modality, and the proposed strategy may also have useful applications for current immunotoxin designs. PMID- 27457424 TI - Multi-isotopic signatures of organic and conventional Italian pasta along the production chain. AB - The variability of stable isotope ratios (delta(2) H, delta(13) C, delta(15) N, delta(18) O and delta(34) S) along the production chain of pasta (durum wheat, flour and pasta) produced by using both conventional and organic farming systems in four Italian regions in 2 years was investigated. The aim was to evaluate if and how the farming system and geographical origin affect stable isotope ratios determined along the production chain. Irrespective of the processing technology, 65% of the samples were correctly classified according to the farming system and 98% were correctly classified regarding the geographical region. When considering both farming system and geographical region simultaneously, 80% of the samples were correctly classified. The measured isotope parameters were thus primarily affected by the geographical origin. In conclusion, it is expected that the use of these parameters will allow the development of analytical control procedures that can be used to check the geographical origin of Italian organic and conventional pasta and its raw materials. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27457425 TI - Physician Assistant and Nurse Practitioner Malpractice Trends. AB - Trends in malpractice awards and adverse actions (e.g., revocation of provider license) following an act or omission constituting medical error or negligence were examined. The National Practitioner Data Bank was used to compare rates of malpractice reports and adverse actions for physicians, physician assistants (PAs), and nurse practitioners (NPs). During 2005 through 2014, there ranged from 11.2 to 19.0 malpractice payment reports per 1,000 physicians, 1.4 to 2.4 per 1,000 PAs, and 1.1 to 1.4 per 1,000 NPs. Physician median payments ranged from 1.3 to 2.3 times higher than PAs or NPs. Diagnosis-related malpractice allegations varied by provider type, with physicians having significantly fewer reports (31.9%) than PAs (52.8%) or NPs (40.6%) over the observation period. Trends in malpractice payment reports may reflect policy enactments to decrease liability. PMID- 27457426 TI - Search and You Shall Find: Geographic Characteristics Associated With Google Searches During the Affordable Care Act's First Enrollment Period. AB - Previous studies indicate that Internet searching was a major source of information for the public during the launch of the Affordable Care Act, but little is known about geographic variation in searching. Our objective was to examine factors associated with health insurance-related Google searches in 199 U.S. metro areas during the first open enrollment period (October 2013 through March 2014), by merging data from Google Trends with metro-area-level and state level characteristics. Our results indicate substantial geographic variation in the volumes of searching across the United States, and these patterns were related to local uninsurance rates. Specifically, areas with higher uninsurance rates were more likely to search in higher volumes for "Obamacare" and "health insurance," after adjusting for sociodemographic, political, and insurance market characteristics. The enormous political, advocacy, and media attention to the Affordable Care Act's launch may have contributed to heightened Internet search activity, particularly in areas characterized by higher uninsurance. PMID- 27457427 TI - Propacetamol-Induced Injection Pain Is Associated with Activation of Transient Receptor Potential Vanilloid 1 Channels. AB - Propacetamol (PPCM) is a prodrug of paracetamol (PCM), which was generated to increase water solubility of PCM for intravenous delivery. PPCM is rapidly hydrolyzed by plasma esterases to PCM and diethylglycine and shares some structural and metabolic properties with lidocaine. Although PPCM is considered to be comparable to PCM regarding its analgesic properties, injection pain is a common side effect described for PPCM but not PCM. Injection pain is a frequent and unpleasant side effect of numerous drugs in clinical use, and previous reports have indicated that the ligand gated ion channels transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) can mediate this effect on sensory neurons. This study aimed to investigate molecular mechanisms by which PPCM, in contrast to PCM, causes injection pain. Therefore, human TRPV1 and TRPA1 receptors were expressed in human embryonic kidney 293 cells and investigated by means of whole-cell patch clamp and ratiometric calcium imaging. PPCM (but not PCM) activated TRPV1, sensitized heat induced currents, and caused an increase in intracellular calcium. In TRPA1 expressing cells however, both PPCM and PCM evoked calcium responses but failed to induce inward currents. Intracutaneous injection of PPCM, but not of PCM, in human volunteers induced an intense and short-lasting pain and an increase in superficial blood flow, indicating activation of nociceptive C fibers and subsequent neuropeptide release. In conclusion, activation of human TRPV1 by PPCM seems to be a relevant mechanism for induction of pain upon intracutaneous injection and thus also for pain reported as an adverse side effect upon intravenous administration. PMID- 27457428 TI - Global sensitivity analysis of a model for venous valve dynamics. AB - Chronic venous disease is defined as dysfunction of the venous system caused by incompetent venous valves with or without a proximal venous obstruction. Assessing the severity of the disease is challenging, since venous function is determined by various interacting hemodynamic factors. Mathematical models can relate these factors using physical laws and can thereby aid understanding of venous (patho-)physiology. To eventually use a mathematical model to support clinical decision making, first the model sensitivity needs to be determined. Therefore, the aim of this study is to assess the sensitivity of the venous valve model outputs to the relevant input parameters. Using a 1D pulse wave propagation model of the tibial vein including a venous valve, valve dynamics under head up tilt are simulated. A variance-based sensitivity analysis is performed based on generalized polynomial chaos expansion. Taking a global approach, individual parameter importance on the valve dynamics as well as importance of their interactions is determined. For the output related to opening state of the valve, the opening/closing pressure drop (dpvalve,0) is found to be the most important parameter. The venous radius (rvein,0) is related to venous filling volume and is consequently most important for the output describing venous filling time. Finally, it is concluded that improved assessment of rvein,0 and dpvalve,0 is most rewarding when simulating valve dynamics, as this results in the largest reduction in output uncertainty. In practice, this could be achieved using ultrasound imaging of the veins and fluid structure interaction simulations to characterize detailed valve dynamics, respectively. PMID- 27457429 TI - Resection or degeneration of uncovertebral joints altered the segmental kinematics and load-sharing pattern of subaxial cervical spine: A biomechanical investigation using a C2-T1 finite element model. AB - The uncovertebral joint (UJ) is an important load-bearing structure in the subaxial cervical spine (SCS) and the medial wall of the intervertebral foramen (IVF). To investigate the UJ's role in load distribution and transmission under physiological loading, we developed and validated a detailed finite element model (C2-T1). Based on the initial model, two additional models were modified to simulate surgical resection and degeneration of UJs, to evaluate their influence on SCS kinematics and load distribution. The three models were subjected to 2Nm pure moment (flexion, extension, lateral bending, and axial rotation). Foraminal narrowing and potential nerve compression were evaluated. In the initial model, contact forces provided by the UJ were apparent in lateral bending and axial rotation. In axial rotation, the UJs and contralateral facet joints participated in joint activity, implying a possible restraint/counterbalance mechanism of these two joints. Peak vertebral stress was observed in the pedicle of vertebrae and was higher in the uncovertebral region than in the facet region. Resection of uncinate processes led to an apparent range of motion increase in lateral bending and axial rotation, while sagittal kinematics is influenced slightly. The load on other structures was slightly increased, but in axial rotation, resection of UJs changed the load distribution pattern. Degeneration of UJs significantly increased SCS stiffness and shielded other load-bearing structures. Peak IVF narrowing, but no nerve compression, was observed in axial rotation of the resection model. Thus, resection did not induce apparent secondary foraminal stenosis when other structures were still functional. PMID- 27457430 TI - Relation of Body Circumferences to Cardiometabolic Disease in Overweight-Obese Subjects. AB - Body circumferences have been proposed as potential anthropometric measures for the assessment of cardiometabolic risk as they are independently associated with insulin resistance and diabetes. The aim of this study was to validate neck and wrist circumference and waist-to-hip ratio as practical markers of metabolic dysfunction and atherosclerosis; 120 subjects who underwent coronary angiography and carotid Doppler ultrasound were enrolled in this cross-sectional study. Exclusion criteria were history of diabetes, acute myocardial infarction, body mass index (BMI) <18.5 or >=45.0 kg/m(2). Metabolic dysfunction was ascertained by the calculation of visceral adiposity index (VAI) and by diagnosis of metabolic syndrome (MS). Advanced atherosclerotic disease was defined as >=70% coronary lumen and/or >=50% carotid lumen stenosis. No association between body circumferences and VAI or MS was found in subjects with BMI <25 kg/m(2). VAI was significantly related to waist-to-hip ratio (R(2) = 0.09, p = 0.008), neck (R(2) = 0.09, p = 0.007), and wrist circumferences (R(2) = 0.05, p = 0.041) in subjects with BMI >=25 kg/m(2). In overweight subjects, higher gender-specific tertiles of wrist circumference were independently associated with an increased risk of MS (odds ratio 2.57, 95% confidence interval 1.11 to 5.96, p = 0.028). VAI was independently associated with carotid intima-media thickness: beta = 0.104, R(2) = 0.118, p = 0.003. Carotid intima-media thickness and MS, but not body circumferences, were associated with advanced atherosclerosis. In conclusion, these data indicate that anthropometric measurements, in particular wrist circumference, can be used as practical tools for assessment of metabolic risk in overweight-obese subjects but not as markers of advanced atherosclerosis. PMID- 27457431 TI - Usefulness of Left Ventricular Mass and Geometry for Determining 10-Year Prediction of Cardiovascular Disease in Adults Aged >65 Years (from the Cardiovascular Health Study). AB - Left ventricular (LV) mass and geometry are associated with risk of cardiovascular disease (CVD). We sought to determine whether LV mass and geometry contribute to risk prediction for CVD in adults aged >=65 years of the Cardiovascular Health Study. We indexed LV mass to body size, denoted as LV mass index (echo-LVMI), and we defined LV geometry as normal, concentric remodeling, and eccentric or concentric LV hypertrophy. We added echo-LVMI and LV geometry to separate 10-year risk prediction models containing traditional risk factors and determined the net reclassification improvement (NRI) for incident coronary heart disease (CHD), CVD (CHD, heart failure [HF], and stroke), and HF alone. Over 10 years of follow-up in 2,577 participants (64% women, 15% black, mean age 72 years) for CHD and CVD, the adjusted hazards ratios for a 1-SD higher echo-LVMI were 1.25 (95% CI 1.14 to 1.37), 1.24 (1.15 to 1.33), and 1.51 (1.40 to 1.62), respectively. Addition of echo-LVMI to the standard model for CHD resulted in an event NRI of -0.011 (95% CI -0.037 to 0.028) and nonevent NRI of 0.034 (95% CI 0.008 to 0.076). Addition of echo-LVMI and LV geometry to the standard model for CVD resulted in an event NRI of 0.013 (95% CI -0.0335 to 0.0311) and a nonevent NRI of 0.043 (95% CI 0.011 to 0.09). The nonevent NRI was also significant with addition of echo-LVMI for HF risk prediction (0.10, 95% CI 0.057 to 0.16). In conclusion, in adults aged >=65 years, echo-LVMI improved risk prediction for CHD, CVD, and HF, driven primarily by improved reclassification of nonevents. PMID- 27457432 TI - Genome interrogation for novel salinity tolerant Arabidopsis mutants. AB - Soil salinity is becoming an increasingly large problem in agriculture. In this study, we have investigated whether a capacity to withstand salinity can be induced in the salinity sensitive plant species Arabidopsis thaliana, and whether it can be maintained in subsequent generations. To this end, we have used zinc finger artificial transcription factor (ZF-ATFs) mediated genome interrogation. Already within a relatively small collection Arabidopsis lines expressing ZF ATFs, we found 41 lines that were tolerant to 100 mM NaCl. Furthermore, ZF-ATF encoding gene constructs rescued from the most strongly salinity tolerant lines were indeed found to act as dominant and heritable agents for salinity tolerance. Altogether, our data provide evidence that a silent capacity to withstand normally lethal levels of salinity exists in Arabidopsis and can be evoked relatively easily by in trans acting transcription factors like ZF-ATFs. PMID- 27457433 TI - Options for the Management of Chronic Myeloid Leukaemia-1990. AB - The management of the newly diagnosed patient with CML has become more complex in recent years. For the younger patient (aged <50 years) with an HLA-identical sibling allogeneic bone marrow transplantation should be considered and this may be best performed within one year of diagnosis. The probability of cure exceeds 50%. Other patients may be treated conventionally with hydroxyurea (in preference perhaps to busulphan) or with interferon-alpha; the latter drug induces Ph negativity in some patients but prolongation of life has not yet been proved. Autografting may achieve similar results: some patients autografted in chronic phase achieve long periods of Ph-negativity but the question of whether the procedure prolongs life for any patient is unresolved. Preliminary results of allografting with phenotypically matched unrelated donors suggest that the mortality of the procedure is greater than that of HLA-identical sibling transplants but that some patients will proved to have been cured. PMID- 27457434 TI - The Use of Genetic Markers in Studies of Myeloid Neoplasia. AB - We have focused this review on some aspects of the use of genetic markers in analyses of cell lineage relationships in myeloid leukemia relying predominantly on studies of women heterozygous for G6PD. We have emphasized the advantages of using markers which are extrinsic to the clonal process and if possible, combining them with markers intrinsic to the neoplastic clone. It is likely that additional intrinsic markers will become available as the multiple genetic defects leading to neoplastic transformation are elucidated. However, it is probable that these will prove to be markers of subclonal evolution and only by relying on cell markers that antedate the occurrence of neoplasia will it be possible to fully appreciate its multistep nature. PMID- 27457435 TI - 12-0-Tetradecanoyl Phorbol-13-Acetate (TPA) and Its Effect on Leukaemic Cells, In vitro-A Review. AB - The action of the promoting agent 12-0-tetradecanoyl phorbol-13-acetate (TPA), an active component of croton oil, on the cell membrane, is described. TPA primarily acts on Protein Kinase C (PKC), which is the prime target for this agent. PKC activation and calcium mobilization are the basic pathways for signal transduction and the regulation of differentiation, explaining how TPA affects cell growth and proliferation in some cell types. The effects of TPA on leukaemic cells in-vitro, is reviewed and the changes in cell surface features, membrane phenotype, regulation of growth and differentiation in leukaemic cells and particularly in B-cell neoplasias are described and discussed in detail. The importance of incubation of leukaemic cells with TPA, as a routine in-vitro test in leukaemia is emphasized, in the light of information reported in this review. PMID- 27457436 TI - The Challenge of Pediatric Hodgkin's Disease-Where is the Balance Between Cure and Long-Term Toxicity?: A report of the West German multicenter studies DAL-HD 78, DAL-HD-82 and DAL-HD-85. AB - From June 1978 until December 1989 more than 600 children under the age of 16 were treated for Hodgkin's disease in West Germany. In three consecutive multicenter studies (DAL-HD-78, HD-82, HD-85) a combined modality treatment concept was used. The aim of all these studies was to reduce the total dose and the extent of radiotherapy as well as the intensity of chemotherapy. In addition, the invasive abdominal staging procedures and the indications for splenectomy were reappraised, so that the number of laparotomies and splenectomies could be restricted to cases with an high probability of abdominal and/or splenic involvement. Special attention was directed to the effects of radio-and chemotherapy on thyroid and gonadal function as well as the development of secondary malignancies. We conclude, that patients treated for Hodgkin's disease with the combined modality treatment regimen (HD-78, HD-82), which included procarbazine, had a high probability of long term survival in first continuous complete remission (CCR). Omitting procarbazine (HD-85) significantly reduced the number of patients in first CCR in stages IIB to IV demonstrating the efficacy of this drug in the treatment of Hodgkin's disease. On the other hand, procarbazine appeared to be the major gonadotoxic drug causing predominantly testicular injury affecting mainly spermatogenesis. Few secondary malignancies have been observed, until now, however long term follow-up will be needed, to document side effects as well as the efficacy of the different therapeutic regimen. PMID- 27457437 TI - Breakpoints Involved in Deletions of the Long Arm of Chromosome 5 in Myelodysplasia and Acute Non-Lymphoblastic Leukemia do not Correlate with the Morphological Diagnosis. AB - Recent suggestions of a correlation between the extent of acquired deletions of the long arm of chromosome 5 [del(5q)] in association with myelodysplastic syndromes and acute non-lymphoblastic leukemia, and the morphological features, prompted us to review 34 patients with these conditions and del(5q). We found no correlation between the morphological diagnosis with which the patient presented and the extent of the deletion of 5q. All cases showed involvement of band 5q31, in common with most previously reported series. The consistent involvement of 5q31 is in keeping with the concept that a single gene at band 5q31 may be involved in the pathogenesis of these myeloid clonal expansions and that the deletion of genes in the long arm of chromosome 5, known to be involved in hemopoietic growth regulation, is unlikely to be the principal determinant of the hematological disorder. PMID- 27457438 TI - Inhibition of P210BCR/ABL Expression in K562 Cells by Electroporation with an Antisense Oligonucleotide. AB - We designed experiments to study the effects on P210BCR/ABL expression of introducing antisense oligonucleotides into K562 cells. We used two antisense oligonucleotides: one (AS1) is complementary to the first coding codon of the BCR/ABL mRNA and the two 5' and three 3' codons, and the other (AS2) to BCR coding codons 5 to 11 inclusive. To facilitate entry of the oligonucleotides the K562 cells were subjected to electroporation on three occasions at 24 hr intervals (0, 24 and 48 hr). P210BCR/ABL expression was assayed by in vivo phosphorylation followed by immune precipitation with a BCR antibody. Introduction of AS1 inhibited P210BCR/ABL expression at 72 and 96 hrs, whereas AS2 and the control oligonucleotide had no effect. AS1 also killed K562 cells. We conclude that selected antisense oligonucleotides can modify leukaemia-specific protein expression in K562 cells. This approach could prove valuable for purging CML bone marrow cells in vitro. PMID- 27457439 TI - Preliminary Experience with Short Course High-Dose Mitoxantrone in Combination with High-Dose Cytarabine in Patients with Acute Leukemia and Blastic Phase of Chronic Myelogenous Leukemia. AB - Mitoxantrone is effective therapy for patients with acute leukemia and blastic phase of chronic myelogenous leukemia (CML). In vitro mitoxantrone has a steep dose response curve, which suggests that higher doses given in a shorter duration may result in enhanced leukemic cell kill in vivo. Twenty-four patients with acute leukemia and blastic CML received mitoxantrone 20 mg/m2 I.V. daily * 2 with cytarabine 3 g/m2 I.V. once daily * 5 days. Diagnoses included 8 patients with previously untreated acute non-lymphocytic leukemia (ANLL), 9 patients with relapsed ANLL, 4 patients with refractory acute lymphoblastic leukemia (ALL) and 2 patients with blastic CML. Complete remission was achieved in 8 of 17 patients with ANLL, 1 of 4 patients with ALL and 0 of 2 with blastic CML. Extramedullary toxicity was acceptable and the median time to remission was 26 days (range 20 69). Short course high-dose mitoxantrone with high-dose cytarabine is effective and well-tolerated in patients with acute leukemia. PMID- 27457440 TI - Radon and Acute Lymphoblastic Leukaemia. AB - The incidence of Acute Lymphoblastic Leukaemia (A.L.L.) in an L.R.P. data collection survey has been compared with the indoor radon and gamma-ray exposure in 22 administrative counties in England and Wales. There is a strong correlation (r = 0.56, p < 0.01) for the incidence of childhood A.L.L. and indoor radon concentration. Weaker correlations were present in adults and no correlation with gamma-rays were obtained. A weak negative association of Hodgkin's Disease with indoor gamma-rays was found. This data adds to the accumulating evidence suggesting an association between indoor radon and acute leukaemia. PMID- 27457441 TI - Acute Myeloid Leukemia Expressing T-Cell Antigens: Clinico-Hematological Report on Six Cases. AB - In a series of 107 patients suffering from acute myeloid leukemia (AML), blast cells from six patients were found to simultaneously express CD2 and CD7 antigens along with CD13, CD33, and CDw 65 in various combinations. The frequency of the expression of both lymphoid markers recurred with a higher incidence than that anticipated by multiplying single antigens frequency. The clinical and hematologic features from CD2+/CD7 + AML patients were studied as well as compared with those of CD2-/CD7- AML patients observed in the same period. Morphologically, bone marrow smears from the AML hybrid subset showed a preponderant population of agranular blasts along with a minority of typical myeloid cells, characterized by larger amount of cytoplasm and, in three cases, by rare but distinct Auer Rods. In all cases more than 3% of blast cells were positive for myeloperoxidases and all samples were classified as M1 according to FAB classification. Clinically, CD2 + /CD7 + patients presented with a higher incidence of adenopathy and meningeal leukemia than did patients with CD2 + /CD7 AML and were characterized by poor response to therapy in terms of both achievement and duration of remission. We conclude that simultaneous expression of CD2 and CD7 in AML is a non random event, recurring in more than 5% of cases and is associated with distinct clinical and hematologic features. PMID- 27457442 TI - Relapse of Hodgkin's Disease After 14 Years of Complete Remission. AB - A 40 year old male patient with nodular lymphocyte predominance Hodgkin's disease had a nodal relapse of the mixed cellularity subtype 14 years after entering complete remission with total nodal irradiation. This case is unusual because of the very long disease-free interval and also because the histology at relapse changed to the mixed cellularity subtype. A review of the literature of late relapses in Hodgkin's disease is presented, and possible mechanisms involved in their development are discussed. Hodgkin's disease. PMID- 27457443 TI - Vincristine, Adriamycin and Dexamethasone (VAD) as Primary Therapy in Advanced Multiple Myeloma: A Single Centre Experience. AB - Vincristine, adriamycin and dexamethasone (VAD) combination chemotherapy was used as first line therapy in eleven patients with severe myeloma. Eight patients (73%) responded to VAD, six of them achieved complete remission (55%) with paraprotein concentrations falling to zero after a median of three treatment cycles. Median duration of response was 18.5 months with three patients remaining in CR for > 40 months. Median survival for all patients is greater than 62 months. Both infection (two deaths, both non-responders) and a significant decline in cardiac ejection fraction were encountered although only two patients required treatment for cardiac failure. The VAD regimen appears to be an effective first line treatment for severe myeloma producing prolonged survival and rapid response. Further trials with VAD induction followed by maintenance therapy appear to be justified. PMID- 27457445 TI - Universal Parameter Optimization of Density Gradient Ultracentrifugation Using CdSe Nanoparticles as Tracing Agents. AB - Density gradient ultracentrifugation (DGUC) has recently emerged as an effective nanoseparation method to sort polydispersed colloidal NPs mainly according to their size differences to reach monodispersed fractions (NPs), but its separation modeling is still lack and the separation parameters' optimization mainly based on experience of operators. In this paper, we gave mathematical descriptions on the DGUC separation, which suggested the best separation parameters for a given system. The separation parameters, including media density, centrifuge speed and time, which affected the separation efficiency, were discussed in details. Further mathematical optimization model was established to calculate and yield the "best" (optimized) linear gradient for a colloidal system with given size and density. The practical experiment results matched well with theoretical prediction, demonstrating the DGUC method, an efficient, practical, and predictable separation technique with universal utilization for colloid sorting. PMID- 27457446 TI - Lead intoxication in dogs: risk assessment of feeding dogs trimmings of lead-shot game. AB - BACKGROUND: Expanding lead-based bullets, commonly used for hunting of big game, produce a scattering of lead particles in the carcass around the wound channel. Trimmings around this channel, which are sometimes fed to dogs, may contain lead particles. The aim of this study was to assess potential health effects of feeding dogs such trimmings. RESULTS: Lead ingestion most commonly causes gastrointestinal and neurological clinical signs, although renal, skeletal, haematological, cardiovascular and biochemical effects have also been reported. Experimental data indicate that a daily dose of around 1 mg lead as lead acetate/kg body weight for ten days may be considered as a Lowest Observed Effect Level in dogs. Acute toxicity documentation from the Centers for Disease Control and Prevention indicates 300 mg/kg body weight as the lowest dose of lead acetate causing death in dogs after oral ingestion. Our assessment suggests that dogs fed trimmings of lead-shot game may be affected by the amounts of lead present, and that even deadly exposure could occasionally occur. The intestinal absorption of lead from bullets was assumed to be 10-80 % of that of lead acetate, reflecting both the variability in particle size and uncertainty about the bioavailability of metallic lead in dogs. CONCLUSIONS: Despite data gaps, this study indicates that feeding dogs trimmings of lead-shot game may represent a risk of lead intoxication. More research is needed to assess the exact consequences, if lead based bullets are still to be used. Meanwhile, we recommend that trimmings close to the wound channel should be made inaccessible to dogs, as well as to other domestic or wild animals. PMID- 27457448 TI - Familial Mediterranean fever patients homozygous for E148Q variant may have milder disease. AB - AIM: Familial Mediterranean fever (FMF) results from MEFV gene mutations. E148Q is a variant of unknown significance in MEFV. We aimed to define characteristics of FMF patients homozygous for E148Q, check for other MEFV variants in a subgroup, and compare the characteristics with FMF patients carrying other mutations. METHODS: Thirty FMF patients homozygous for E148Q were reviewed. MEFV variant analysis was performed with strip assay. All MEFV exons were screened by direct DNA sequencing in 14 randomly selected E148Q/E148Q patients. E148Q was also checked in 100 healthy adolescents. We compared the characteristics of FMF patients between three groups: E148Q/E148Q (n = 30), M694V/E148Q (n = 19) and exon 10/exon 10 MEFV mutations (n = 48). RESULTS: Among 30 FMF patients (E148Q/E148Q), the median age at disease onset and diagnosis were 60 (12-168) and 94 (41-196) months, respectively. Fifteen (50%) patients had mild, 14 (46.7%) moderate and one (3.3%) had severe disease. Twenty-two (73.3%) patients had complete, seven (23.3%) had incomplete response to colchicine, while only one was unresponsive. The detected MEFV variants in 14 E148Q/E148Q FMF patients were as follows: R314R (n = 9; 64.3%), E474E (n = 13; 92.9%), Q476Q (n = 13; 92.9%), D510D (n = 13; 92.9%), and P588P (n = 8; 57.1%). The E148Q allele frequency was 6.5% in healthy adolescents. When compared to FMF patients with other MEFV mutations, disease onset was later, disease was less severe and the ratio of patients responding completely to colchicine was higher in E148Q/E148Q patients. CONCLUSION: Patients homozygous for E148Q and negative for other pathogenic MEFV variants may display FMF phenotype and may experience moderate/severe disease activity, although the disease may be milder when compared to FMF patients with other mutations. PMID- 27457447 TI - The effects of body image impairment on the quality of life of non-operated Portuguese female IBD patients. AB - OBJECTIVES: Inflammatory bowel diseases (IBD) and their treatment are known to negatively impact on patients' body image, especially female patients. However, although there are broad evidences of body image impairment in female IBD patients, its negative impact on the quality of life (QoL) of non-operated women is not clearly and specifically studied. The aim of the current study was therefore to analyse, in a sample of non-operated female IBD patients, the factors that contribute to body image impairment and its impact on QoL. METHODS: Ninety-six non-operated women (39.7 % with CD and 60.3 % with UC), aged between 18 and 40 years old, completed an online survey with validated self-report measures, which included the Body Image Scale and the WHO Brief Quality of Life Assessment Scale. RESULTS: Negative body image was correlated with lower psychological and physical QoL and increased corticosteroids use, associated medical complications, body mass index (BMI), and IBD symptomatology. Regression analyses revealed that BMI and IBD symptomatology significantly predicted body image impairment. Furthermore, results from path analyses indicated that BMI and IBD symptomatology's effect on psychological and physical QoL was mediated through the negative effects of body image impairment. This model explained 31 % of psychological QoL and 41 % of physical QoL. CONCLUSIONS: These findings suggest that non-operated female patients are subject to pervasive and harmful effects of body image impairment on psychological and physical functioning. Therefore, psychological interventions aiming to target body dissatisfaction should be implemented in the health care of IBD, independently of patients' operative status. PMID- 27457449 TI - Letters. PMID- 27457451 TI - Brief reports. PMID- 27457453 TI - 'You Can't Steal Memories'. PMID- 27457452 TI - A need to know. PMID- 27457454 TI - 'Runner's Knee' Starts at the Foot. PMID- 27457455 TI - Violence in Sport. PMID- 27457456 TI - Basic Properties of Skeletal Muscle. PMID- 27457457 TI - Structure and Function of Skeletal Muscle. PMID- 27457458 TI - Cme credit quiz. PMID- 27457460 TI - What Makes a Superstar? A Physiological Profile. PMID- 27457459 TI - Boats, Speed Mean Injuries of Every Possible Type. PMID- 27457461 TI - Football Helmet Evaluation Based on Players' EEGs. PMID- 27457462 TI - Cardiovascular Response to Exercise Training. PMID- 27457463 TI - The Savage State of Sports. PMID- 27457464 TI - Choosing an Activity. PMID- 27457466 TI - The Role of Rest and Relaxation. PMID- 27457468 TI - Early intramedullary nailing of femoral shaft fracture on outcomes in patients with severe chest injury: A meta-analysis. AB - Early intramedullary nailing (IMN) within the first 24 hours for multiply injured patients with femoral fracture and concomitant severe chest injury is still controversial. This review aimed to investigate the association between early IMN and pulmonary complications in such patients. We searched the literature up to Jan 2016 in the main electronic databases (PubMed, Web of Science, Cochrane library databases) to identify eligible studies. Data were extracted and analyzed using a Mantel-Haenszel method with random-effects model to estimate pooled odds ratio (OR) and 95% confidence intervals (CIs). Seven retrospective cohort studies were identified eventually. The pooled estimates demonstrated that the application of early IMN did not significantly increase the risk of adult respiratory distress syndrome (ARDS) (OR, 0.65; 95% CI: 0.38-1.13), mortality (OR, 0.79; 95% CI: 0.43-1.47), pneumonia (OR, 0.92; 95% CI: 0.55-1.54), multiple organ failure (MOF) (OR, 0.87; 95% CI: 0.45-1.71) and pulmonary embolism (OR, 1.81; 95% CI: 0.28-11.83). In subgroup analysis according to the type of IMN (reamed or undreamed), we did not find any significant difference either. Our results indicated that early IMN of femoral shaft fracture was not associated with increased rates of pulmonary complications in severe chest-injured patients. PMID- 27457470 TI - The Cost-Effectiveness of Ranibizumab Treat and Extend Regimen Versus Aflibercept in the UK. AB - INTRODUCTION: Wet age-related macular degeneration (AMD) is a chronic eye condition that causes severe deterioration of vision and even blindness. Current wet AMD treatment in the UK involves the vascular endothelial growth factor inhibitors ranibizumab and aflibercept. Patients with wet AMD require frequent and long-term monitoring for treatment to be effective, contributing to a substantial resource burden at wet AMD centers. The European license for ranibizumab was recently updated with an individualized 'treat and extend' (T&E) regimen, comprising a structured monitoring and treatment protocol. This study evaluated the cost-effectiveness of ranibizumab T&E versus aflibercept within a UK setting. METHODS: An individual patient-level simulation model was developed utilizing treatment effects from a network meta-analysis of randomized controlled trials. The model was conducted from a UK National Health Service (NHS) perspective over a lifetime horizon and the base case utilized probabilistic sensitivity analysis to assess uncertainty in the model. Additional scenario analyses were conducted to assess the impact of changes to the model inputs. RESULTS: Ranibizumab T&E was found to be more effective and less costly than aflibercept, providing, on average, an additional 1.058 quality-adjusted life years (QALYs) and a cost-saving of L19,604 over a lifetime horizon. At list price, ranibizumab T&E was found to be cost-effective versus aflibercept in 100% of simulations at a willingness-to-pay threshold of L20,000 per QALY. The robustness of the results was tested in several scenario analyses; ranibizumab T&E was found to be more effective, and less costly, than aflibercept in the vast majority of cases. CONCLUSION: This evaluation suggests that treating patients with ranibizumab according to the T&E regimen could be a better use of NHS resources than aflibercept, and could, therefore, be considered as a first-line regimen for patients with wet AMD in the UK. FUNDING: Novartis Pharmaceuticals UK Limited. PMID- 27457469 TI - Long-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER Study. AB - INTRODUCTION: Latanoprostene bunod (LBN) is a novel nitric oxide (NO)-donating prostaglandin F2alpha analog. We evaluated the long-term safety and intraocular pressure (IOP)-lowering efficacy of LBN ophthalmic solution 0.024% over 1 year in Japanese subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: This was a single-arm, multicenter, open-label, clinical study. Subjects aged 20 years and older with a diagnosis of OAG or OHT instilled 1 drop of LBN ophthalmic solution 0.024% in the affected eye(s) once daily in the evening for 52 weeks and were evaluated every 4 weeks. Safety assessments included vital signs, comprehensive ophthalmic exams, and treatment-emergent adverse events (AEs). Absolute and percent reductions from baseline in IOP were also determined. RESULTS: Of 130 subjects enrolled, 121 (93.1%) completed the study. Mean age was 62.5 years, and mean (standard deviation) baseline IOP was 19.6 (2.9) and 18.7 (2.6) mmHg in study eyes and treated fellow eyes, respectively. Overall, 76/130 (58.5%) and 78/126 (61.9%) subjects experienced >=1 AEs in study eyes and treated fellow eyes, respectively. In both study eyes and treated fellow eyes, the most common AEs were conjunctival hyperemia, growth of eyelashes, eye irritation, and eye pain. At 52 weeks, 9% of treated eyes had an increase in iris pigmentation compared with baseline based on iris photographs. No safety concerns emerged based on vital signs or other ocular assessments. Mean reductions from baseline in IOP of 22.0% and 19.5% were achieved by week 4 in study and treated fellow eyes, respectively. These reductions were maintained through week 52 (P < 0.001 vs. baseline at all visits). CONCLUSION: Once daily LBN ophthalmic solution 0.024% was safe and well-tolerated in Japanese subjects with OAG or OHT when used for up to 1 year. Long-term treatment with LBN ophthalmic solution 0.024% provided significant and sustained IOP reduction. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01895972. FUNDING: Bausch & Lomb, Inc. a division of Valeant Pharmaceuticals International Inc. PMID- 27457471 TI - Impact of Warfarin on Atrial-Fibrillation Outcomes Related to Economic Consumption Patterns: Hospitalization, Cost, and Mortality may be Predictable and Modifiable at the Population Level. AB - INTRODUCTION: Warfarin reduces atrial fibrillation (AF)-related strokes and may impact mortality, hospitalizations, and costs. This study investigated the possibility that patterns of warfarin consumption are associated with the frequency of acute events. METHODS: Annual cost profiles of 9.2 million Medicare beneficiaries with AF were analyzed to identify patterns of benefits consumption from 2000 through 2010. Beneficiaries were divided into five consumption clusters based upon their annual cost profiles, ranging from crisis consumers at the high end to low consumers. Resource-utilization patterns and outcome differences were calculated between AF beneficiaries who received warfarin and those who did not. Propensity score-matched analysis was performed to reduce selection bias. RESULTS: The annual percentages of beneficiaries and expenditures that differentiated each cluster showed stable patterns. Warfarin use influenced consumption patterns and outcomes. The most important financial difference between higher and lower consumers was inpatient cost. AF beneficiaries on warfarin had lower annual cost profiles and had a higher propensity to persist in or migrate to consumption clusters with comparatively small reimbursement claims and lower hospitalization risks. AF beneficiaries not on warfarin had higher cost and mortality. CONCLUSIONS: These data signal that a nontrivial portion of acute events (hospitalization and mortality) are amenable to medical intervention (warfarin). When acute events are amenable to medical intervention and occur at a higher frequency because guidelines have not been applied evenly across affected populations, it is appropriate to define those occurrences as disparities associated with systemic failure in evidence-based medicine. Quality-improvement initiatives that reduce therapeutic disparities may result in lower cost and improved outcomes. FUNDING: No funding or sponsorship was received for this study or publication of this article. PMID- 27457472 TI - Environment-Wide Association Study of Blood Pressure in the National Health and Nutrition Examination Survey (1999-2012). AB - Identifying environmental exposures associated with blood pressure is a priority. Recently, we proposed the environment-wide association study to search for and replicate environmental factors associated with phenotypes. We conducted the environment-wide association study (EWAS) using the National Health and Nutrition Examination Surveys (1999-2012) which evaluated a total of 71,916 participants to prioritize environmental factors associated with systolic and diastolic blood pressure. We searched for factors on participants from survey years 1999-2006 and tentatively replicated findings in participants from years 2007-2012. Finally, we estimated the overall association and performed a second meta-analysis using all survey years (1999-2012). For systolic blood pressure, self-reported alcohol consumption emerged as our top finding (a 0.04 increase in mmHg of systolic blood pressure for 1 standard deviation increase in self-reported alcohol), though the effect size is small. For diastolic blood pressure, urinary cesium was tentatively replicated; however, this factor demonstrated high heterogeneity between populations (I(2) = 51%). The lack of associations across this wide of an analysis raises the call for a broader search for environmental factors in blood pressure. PMID- 27457473 TI - Residential Spaces and Timing of First Sexual Intercourse Among Never-Married Youths in Nigeria. AB - Youths in sub-Saharan Africa who initiate sex at an early age tend to be more vulnerable to HIV/AIDS and other sexually transmitted diseases because of the lack of accurate knowledge of preventive behaviors. Although sociocultural and economic factors associated with sexual initiation among youths have been studied extensively in Nigeria, little is known about the effect of place-based factors. Rural and urban disparities remain high in Nigeria, and these disparities are reinforced by stark regional inequalities between the north and south. Considering these underlying inequalities, we examined the extent to which rural and urban youths in northern and southern Nigeria differ with regard to the timing of sexual initiation using the 2013 Nigerian Demographic and Health Survey. Results from our event history analyses suggest that never-married male and female youths who lived in the urban north delayed their first sexual intercourse compared with their counterparts in the rural north, but those who lived in the rural south had their first sex earlier. Young males who lived in the urban south also experienced their first sex earlier than their counterparts in the rural north. Surprisingly, educated youths and those who had accurate knowledge about HIV/AIDS transmission experienced their first sex early. Clearly, the timing of sexual initiation among youths varies across different spatial and cultural contexts. Therefore, interventions aimed at discouraging early sexual initiation among young people in Nigeria may need to go beyond merely providing health information and services to addressing the livelihood needs of youths, especially those in rural settings. PMID- 27457474 TI - Stem-like features of cancer cells on their way to metastasis. AB - More than 90 % of cancer-related deaths are due to the development of a systemic metastatic disease. Clearly, much remains to be understood about the biological principles that govern human cancer metastasis, aiming at the ambitious objective to decrease metastasis-related mortality in patients. For many years, research on metastasis has been conducted in great part on experimental mouse models, mainly because of the difficulties in sampling, longitudinal studies, and molecular interrogation of a human metastatic disease. However, recently, extraordinary advances in microfluidic technologies are allowing the isolation and characterization of human circulating tumor cells (CTCs) that escaped a primary tumor mass and are in the process of seeding a distant metastasis. Analysis of human CTCs has now revealed important features of cancer metastasis, such as the high metastatic potential of CTC-clusters compared to single CTCs, the dynamic expression of epithelial and mesenchymal markers on CTCs during treatment, and the possibility to culture CTCs from patients for a real-time and individualized testing of drug susceptibility. Nevertheless, several aspects of CTC biology remain unsolved, such as the characterization of the stem-like cell population among human CTCs. Here, we focus on describing the latest findings in the CTC field, and discuss them in the context of cancer stem cell biology. Defining the molecular features of those few metastasis-initiating, stem-like CTCs holds the exceptional promise to develop metastasis-tailored therapies for patients with cancer. REVIEWERS: This article was reviewed by Elisa Cimetta, Luca Pellegrini and Sirio Dupont (nominated by LP). PMID- 27457476 TI - Special issue on endocrine disruption and reproductive health. PMID- 27457475 TI - Re-biopsy by endobronchial ultrasound procedures for mutation analysis of non small cell lung cancer after EGFR tyrosine kinase inhibitor treatment. AB - BACKGROUND: Re-biopsy for resistant non-small cell lung cancer (NSCLC) after treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) is important for selection of better therapy, but there have been no reports about the utility of endobronchial ultrasound (EBUS)-guided procedures for such purpose. The aim of this study was to evaluate the utility of EBUS guided re-biopsy for resistant NSCLC after treatment with EGFR-TKIs. METHODS: From January 2013 to December 2015, 53 consecutive patients who underwent EBUS guided re-biopsy for mutation analysis of NSCLC after EGFR-TKI treatment were assessed. RESULTS: Nine patients underwent EBUS-guided transbronchial needle aspiration (EBUS-TBNA) and 44 patients underwent EBUS with a guide sheath (EBUS GS) transbronchial biopsy. The technical success rates were 100 %. As for mutation analysis, all 9 specimens (100 %) from EBUS-TBNA and 33 specimens (75.0 %) from EBUS-GS were adequate for gene profiling. The remaining 11 specimens from EBUS-GS procedures were inadequate for mutation analysis owing to the absence of tumor component in the sample (n = 6) or insufficient specimen (n = 5). There were no related severe complications. CONCLUSIONS: Re-biopsy by both EBUS-TBNA and EBUS-GS were useful and safe sampling procedures for mutation analysis of EGFR-TKI resistant NSCLC. PMID- 27457477 TI - Dichlorodiphenyltrichloroethane exposure and anogenital distance in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) birth cohort study, South Africa. AB - Dichlorodiphenyltrichloroethane (DDT) is used for malaria control by 10 countries, nine of which are in Africa. Technical DDT contains various isomers with 65-80% insecticidal p,p'-DDT and 15-21% o,p'-DDT, an estrogenic chemical, while the persistent metabolite of p,p'-DDT, dichlorodiphenyldichloroethylene (p,p'-DDE), is an antiandrogen. In utero antiandrogenic exposure reduces anogenital distance in animal models and the anal position index in a single study. This study examined the associations between mother's serum DDT and DDE levels at delivery and anogenital distance in their children at birth and age 1 year. Data were collected as part of the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study located in rural South Africa. DDT and DDE concentrations were measured in blood samples collected from 752 mothers at delivery. Anogenital distance measurements, taken at birth (n = 671) and age 1 year (n = 674), included anofourchette and anoclitoral distances in girls, and anoscrotal and anopenile lengths in boys. We also measured anococcygeal and coccyx-fourchette distances in girls, while in boys, we measured anococcygeal and coccyx-scrotal distances as well as penile length and penile width. The anal position index is calculated for both sexes as anoscrotal/coccyx scrotal in boys and anofourchette/coccyx-fourchette in girls. We found no associations between p,p'-DDT/-DDE or o,p'-DDT and anogenital distance measurements at birth in either boys or girls. At 1 year, o,p'-DDE was negatively associated with anofourchette in girls (beta =-1.32 mm, 95% confidence interval (CI) = -2.27, -0.38) and positively associated with penile width in boys (beta = 0.30 mm, 95% CI = 0.00, 0.60). The results do not suggest an overt antiandrogenic or estrogenic effect on anogenital distance after long-term DDT exposure. These weak associations may be due to chance. PMID- 27457479 TI - [Erratum to: Multiple inappropriate defibrillator shocks due to insulation failure of a Biotronik Linox defibrillator lead with externalized conductor]. PMID- 27457478 TI - Comparison of two psycho-educational family group interventions for improving psycho-social outcomes in persons with spinal cord injury and their caregivers: a randomized-controlled trial of multi-family group intervention versus an active education control condition. AB - BACKGROUND: Over 12,000 individuals suffer a spinal cord injury (SCI) annually in the United States, necessitating long-term, complex adjustments and responsibilities for patients and their caregivers. Despite growing evidence that family education and support improves the management of chronic conditions for care recipients as well as caregiver outcomes, few systematic efforts have been made to involve caregivers in psycho-educational interventions for SCI. As a result, a serious gap exists in accumulated knowledge regarding effective, family based treatment strategies for improving outcomes for individuals with SCI and their caregivers. The proposed research aims to fill this gap by evaluating the efficacy of a structured adaptation of an evidence-based psychosocial group treatment called Multi-Family Group (MFG) intervention. The objective of this study is to test, in a randomized-controlled design, an MFG intervention for the treatment of individuals with SCI and their primary caregivers. Our central hypothesis is that by providing support in an MFG format, we will improve coping skills of persons with SCI and their caregivers as well as supportive strategies employed by caregivers. METHODS: We will recruit 32 individuals with SCI who have been discharged from inpatient rehabilitation within the previous 3 years and their primary caregivers. Patient/caregiver pairs will be randomized to the MFG intervention or an active SCI education control (SCIEC) condition in a two-armed randomized trial design. Participants will be assessed pre- and post-program and 6 months post-program. Intent to treat analyses will test two a priori hypotheses: (1) MFG-SCI will be superior to SCIEC for SCI patient activation, health status, and emotion regulation, caregiver burden and health status, and relationship functioning, and (2) MFG will be more effective for individuals with SCI and their caregivers when the person with SCI is within 18 months of discharge from inpatient rehabilitation compared to when the person is between 19 and 36 months post discharge. DISCUSSION: Support for our hypotheses will indicate that MFG-SCI is superior to specific education for assisting patients and their caregivers in the management of difficult, long-term, life adjustments in the months and years after SCI, with increased efficacy closer in time to the injury. TRIAL REGISTRATION: ClinicalTrials.gov NCT02161913 . Registered 10 June 2014. PMID- 27457481 TI - NMRFx Processor: a cross-platform NMR data processing program. AB - NMRFx Processor is a new program for the processing of NMR data. Written in the Java programming language, NMRFx Processor is a cross-platform application and runs on Linux, Mac OS X and Windows operating systems. The application can be run in both a graphical user interface (GUI) mode and from the command line. Processing scripts are written in the Python programming language and executed so that the low-level Java commands are automatically run in parallel on computers with multiple cores or CPUs. Processing scripts can be generated automatically from the parameters of NMR experiments or interactively constructed in the GUI. A wide variety of processing operations are provided, including methods for processing of non-uniformly sampled datasets using iterative soft thresholding. The interactive GUI also enables the use of the program as an educational tool for teaching basic and advanced techniques in NMR data analysis. PMID- 27457480 TI - Paeoniflorin inhibits excitatory amino acid agonist-and high-dose morphine induced nociceptive behavior in mice via modulation of N-methyl-D-aspartate receptors. AB - BACKGROUND: Pain, the most common reasons for physician consultation, is a major symptom in many medical conditions that can significantly interfere with a person's life quality and general functioning. Almost all painkillers have its untoward effects. Therefore, seeking for a safe medication for pain relieve is notable nowadays. Paeonia lactiflora is a well-known traditional Chinese medicine. Paeoniflorin is an active component found in Paeonia lactiflora, which has been reported to inhibit formalin-induced nociceptive behavior in mice. Aims of this present study were to investigate effects of paeoniflorin on excitatory amino acid agonist- or high-dose morphine-induced nociceptive behaviors in mice. RESULTS: Paeoniflorin (100, 200, 500 nmol, i.c.v.) alone and combined with glutamatergic antagonists (MK-801 14.8 pmol, or NBQX 5 nmol, i.t.) inhibited nociception. Those agents also inhibited the clonic seizure-like excitation induced by high-dose morphine (250 nmol, i.t) in mice. Antisense oligodeoxynucleotides of NMDA receptor subunits NR1, NR2A, NR2B significantly enhanced the inhibition of paeoniflorin on excitatory amino acid-and high-dose morphine-induced nociception. Docking energy data revealed that paeoniflorin had stronger binding activity in NR2A and NR2B than NR2C of NMDA receptors. CONCLUSIONS: Results of this study indicate that paeoniflorin-induced inhibition of excitatory amino acid agonist- and high-dose morphine-induced nociceptive behaviors might be due to modulation of NMDA receptors, specifically the NR2B subunit. PMID- 27457482 TI - Deep-sequencing revealing mutation dynamics in the miltefosine transporter gene in Leishmania infantum selected for miltefosine resistance. AB - Miltefosine is the first oral drug used in chemotherapy against leishmaniasis. In vitro studies found that resistance to miltefosine in Leishmania is often associated with the acquisition of point mutations in the miltefosine transporter, leading to a decrease in drug uptake. In this study, the dynamics of mutations upon miltefosine selection was studied by deep-sequencing of the miltefosine transporter gene. Deep-sequencing data revealed that no mutation was detected in the miltefosine transporter at sub-inhibitory concentrations of miltefosine. We show that the prevalence of mutated alleles was increasing when the drug pressure heightened, that more mutations were observed in highly resistant mutants, and that most mutations remained when parasites were cultured for a few passages in the absence of miltefosine. PMID- 27457483 TI - Ct2 Bladder Cancer. AB - The patient is an 80-year-old man who presented with gross hematuria. His past medical history indicates he was a cigarette smoker with 50 pack/years. He was successfully treated for carcinoma of the lung 7 years ago. He received chemotherapy, radiation, and surgery. He has mild COPD but has a good performance status. His laboratory studies do not indicate any abnormalities in terms of renal function. He does not have any significant cardiac disease. He has a medium build. He had prostate cancer and underwent a successful radical prostatectomy 10 years ago. His PSA is undetectable. He has some urinary incontinence and wears two pads/day. He underwent the appropriate investigations for gross hematuria. A CT scan of the abdomen and pelvis was normal with the exception of a 4-cm posterior mass in the bladder. There was no hydronephrosis and no enlarged lymph nodes. He underwent a transurethral resection of a solitary bladder tumor performed by another urologist. The tumor was described as large and sessile. It was located on the posterior wall and was approximately 4 cm. The bimanual examination did not reveal a mass. The pathology report stated that the tumor was a high-grade urothelial carcinoma with invasion into the muscularis propria. There was no lymphovascular invasion. I performed a reTURBT, and at that procedure, I did not identify any obvious tumor but the prior resection site was evident. I resected the prior tumor site quite extensively both in depth and width. The pathology revealed only focal carcinoma in situ. There was ample muscle in the specimen and there was some fat as well. As stated, they were free of any cancer. The patient is receptive to any treatment approach. PMID- 27457484 TI - Intravitreal ranibizumab for choroidal neovascularization in a patient with angioid streaks and multiple evanescent white dots. AB - BACKGROUND: To report a patient with angioid streaks (ASs) and coincident multiple evanescent white dot syndrome (MEWDS) who developed choroidal neovascularization (CNV). CASE PRESENTATION: A 20-year-old woman presented with reduced vision (20/100) in her left eye (LE). Based on a complete ophthalmologic examination the patient was diagnosed with ASs and coincident MEWDS. Two weeks later best-corrected visual acuity (BCVA) improved up to 20/25 and the MEWDS findings almost disappeared. Two months later BCVA dropped again (20/100) due to the development of CNV which was treated by a single intravitreal injection of ranibizumab (0.5 mg/0.05 mL). One month after this BCVA improved up to 20/40, and there was regression of the CNV. There was no need for retreatment at the last follow-up visit, 1 year after the ranibizumab injection, when the patient showed further recovery of BCVA up to 20/25. CONCLUSIONS: In this case of ASs, MEWDS completely resolved after 2 weeks, but 2 months later CNV developed. A single intravitreal injection of ranibizumab had a long-lasting effect. Larger series are necessary to clarify the pathogenesis of CNV in such cases and the role of intravitreal ranibizumab. PMID- 27457485 TI - MtDNA T4216C variation in multiple sclerosis: a systematic review and meta analysis. AB - MtDNA T4216C variation has frequently been investigated in Multiple Sclerosis (MS) patients; nonetheless, controversy has existed about the evidence of association of this variation with susceptibility to MS. The present systematic review and meta-analysis converge the results of the preceding publications, pertaining to association of mtDNA T4216C variation with susceptibility to MS, into a common conclusion. A computerized literature search in English was carried out to retrieve relevant publications from which required data were extracted. Using a fixed effect model, pooled odds ratio (OR), 95 % confidence interval (95 % CI), and P value were calculated for association of mtDNA T4216C variation with susceptibility to MS. The pooled results showed that there was a significant association between mtDNA T4216C variation and MS (OR = 1.38, 95 % CI = 1.13 1.67, P = 0.001). The present systematic review and meta-analysis suggest that mtDNA T4216C variation is a contributory factor in susceptibility to MS. PMID- 27457488 TI - First report of monogenean flatworms from Lake Tana, Ethiopia: gill parasites of the commercially important Clarias gariepinus (Teleostei: Clariidae) and Oreochromis niloticus tana (Teleostei: Cichlidae). AB - BACKGROUND: Lake Tana is the largest lake in Ethiopia and the source of the Blue Nile. The lake harbours unique endemic cyprinid fish species, as well as the commercially important endemic Nile tilapia subspecies Oreochromis niloticus tana and the North African catfish Clarias gariepinus. Its endemicity, especially within the Labeobarbus radiation, its conservation importance and its economic indispensability attract scientific interest to the lake's ichthyofauna. Fish parasites of Lake Tana, however, are hitherto poorly known, and no formal report exists on its monogenean flatworms. For sustainable aquaculture and fisheries development, it is essential to study monogenean fish parasites in these economically most important fish species. Moreover, it remains to be verified whether this unique ecosystem and its endemicity gave rise to a distinct parasite fauna as well. RESULTS: Nile tilapia and North African catfish hosts were collected from Lake Tana in 2013. Nine species of monogenean parasites of two orders, Gyrodactylidea Bychowsky, 1937 and Dactylogyridea Bychowsky, 1937, were recovered. Gyrodactylus gelnari Prikrylova, Blazek & Vanhove, 2012, Macrogyrodactylus clarii Gussev, 1961, Quadriacanthus aegypticus El-Naggar & Serag, 1986 and two undescribed Quadriacanthus species were recovered from C. gariepinus. Oreochromis niloticus tana hosted Cichlidogyrus cirratus Paperna, 1964, C. halli (Price & Kirk, 1967), C. thurstonae Ergens, 1981 and Scutogyrus longicornis (Paperna & Thurston, 1969). CONCLUSIONS: Except for M. clarii, all species represent new records for Ethiopia. This first study on the monogenean fauna of Lake Tana revealed that the lake's North African catfish, as well as its endemic Nile tilapia subspecies, harbour parasites that are known from these host species elsewhere in Africa. PMID- 27457487 TI - Genetic variations of DICKKOPF family genes might not be associated with gastric cancer susceptibility. AB - BACKGROUND: Recent studies have implicated that members of the DICKKOPF (DKK) were causally involved in large number of human cancers. This study was designed to investigate the relationship between the genetic variations of DKK family genes and the risk of gastric cancer (GC). METHODS: Six SNPs (single nucleotide polymorphisms) of DKK family genes, including rs2241529 in DKK1, rs3733635, rs17037102 and rs419764 in DKK2, rs3206824 in DKK3 and rs2073664 in DKK4, were selected and genotyped by restriction fragment length polymorphism (RFLP) and TaqMan SNP genotyping methods in 409 GC cases and 554 cancer-free controls in the Han population in eastern China. RESULTS: None of the six SNPs achieved significant association with the overall GC risk and stratified analysis by age, gender, smoking status, drinking status, tumor location and pathological classification confirmed these non-significant associations. CONCLUSIONS: Our study indicated that the studied six SNPs of DKKs would not be the risk factors for GC in this Han Chinese population. Studies of larger population for different ethnicities will be needed to warrant our findings. PMID- 27457486 TI - APOE genotype and stress response - a mini review. AB - The APOE gene is one of currently only two genes that have consistently been associated with longevity. Apolipoprotein E (APOE) is a plasma protein which plays an important role in lipid and lipoprotein metabolism. In humans, there are three major APOE isoforms, designated APOE2, APOE3, and APOE4. Of these three isoforms, APOE3 is most common while APOE4 was shown to be associated with age related diseases, including cardiovascular and Alzheimer's disease, and therefore an increased mortality risk with advanced age. Evidence accumulates, showing that oxidative stress and, correspondingly, mitochondrial function is affected in an APOE isoform-dependent manner. Accordingly, several stress response pathways implicated in the aging process, including the endoplasmic reticulum stress response and immune function, appear to be influenced by the APOE genotype. The investigation and development of treatment strategies targeting APOE4 have not resolved any therapeutic yet that could be entirely recommended. This mini-review provides an overview on the state of research concerning the impact of the APOE genotype on stress response-related processes, emphasizing the strong interconnection between mitochondrial function, endoplasmic reticulum stress and the immune response. Furthermore, this review addresses potential treatment strategies and associated pitfalls as well as lifestyle interventions that could benefit people with an at risk APOE4 genotype. PMID- 27457489 TI - A case of acquired haemophilia A complicated by peritonitis after distal gastrectomy. PMID- 27457490 TI - Successful treatment of multiple bilateral impactions - a case report. AB - BACKGROUND: Successful treatment of patients with multiple bilateral impactions can be an orthodontic challenge, but few reports on treatment planning and execution exist. CASE PRESENTATION: In this case report, we describe the successful orthodontic treatment of a 16.3-year old female patient without systemic or genetic disease with initially nine persisting deciduous and nine impacted permanent teeth with complete root formation and closed apices in both jaws. After extraction of the deciduous and surgical exposure of the impacted permanent teeth, the Easy-Way-CoilTM system was used in conjunction with a skeletal anchorage (maxilla, BENEfitTM system) to guide the eruption of all impacted teeth. After a total treatment time of only 22.8 months all impacted teeth could be aligned successfully and a stable and functional class I occlusion was achieved. In addition, there were no adverse treatment effects such as anchorage loss, root resorptions or periodontal problems and an esthetic result could be achieved. CONCLUSIONS: The presented treatment approach thus proved to be highly effective in cases with multiple bilateral impactions with minimal side effects and considerably reduced treatment time. PMID- 27457492 TI - Genetic Algorithm and Self-Organizing Maps for QSPR Study of Some N-aryl Derivatives as Butyrylcholinesterase Inhibitors. AB - BACKGROUND: Alzheimer's disease is the most common form of dementia, characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions, leading to altered and unsuitable activities. In this study, we focused on the influence of rndom selection (RS) and SOMs (self-organizing maps) data splitting on the external predictivity of quantitative structure property relationship (QSPR) models of some N-ary derivatives as butyrylcholinesterase (BChE) inhibitors. A QSPR model relates molecular descriptors to a chemical property can save time and money in drug discovery and development. Model validation is a critical step in QSPR model generation; for this purpose, it is necessary to carry out the data splitting on original data set. The GA is very useful for finding global minima for high dimensionality of the problem (e.g. variable selection in QSPR) when response surface has many local optima. METHODS: The molecular structures and experimental values for inhibition constants of BChE catalytic activities obtained from the literature. In this study, total number of 88 compounds was divided into training and test set by means of RS and SOM methods. The Chem3D module was used in order to create the 3D structures of compounds; geometry optimization, using the Polak-Ribiere algorithm. Using Dragon package over 1145 molecular descriptors such as 3D-MoRSE, GETAWAY and WHIM descriptors were derived to characterize the structures of ChEs inhibitors derivatives, properly. The constant variables, variables which have low correlation with response and collinear descriptors were omitted, and the number of descriptors was reduced to 422 in the data set. The QSAR models were constructed using stepwise-MLR and GA-MLR. RESULTS: The best MLR models with four, five and six variables were built to obtain the best QSAR model. The best multivariate linear models in both stepwise-MLR and GA-MLR methods had five variables. The best significant relationships, using comparison of Q2 of models, for logki values of BChE catalytic activity inhibition in the models obtained in S-MLR and GA-MLR methods are presented for all of the random sets and SOM set. CONCLUSION: The results of this study showed that a GA-MLR generally performs better than stepwise-MLR. The five variable models were chosen as the best models after evaluating the other models in both GA-MLR and S-MLR methods. The Q2 results indicate that the test set consists of compounds that are evenly distributed within the chemical space; hence, in QSPR modeling, rational splitting methods such as SOM rather than random selection should be used. Also, the Q2 comparison of GA-MLR and stepwise-MLR methods highlights the power of GA MLR for feature selection. According to the interpretation of QSPR descriptors indicates that, QSAR equation can be useful in designing new N-aryl derivatives as butyrylcholinesterase inhibitors compounds with improved inhibition catalytic activity. PMID- 27457491 TI - Evaluation of occurring complications after flow diverter treatment of elastase induced aneurysm in rabbits using micro-CT and MRI at 9.4 T. AB - INTRODUCTION: Flow diverters are increasingly being used to treat intracranial aneurysms. This study evaluates occurring complications of flow-diverting devices in the treatment of experimental aneurysms, involving the use of micro-CT and small animal MRI at 9.4 T, in correlation to angiographic and histological findings. METHODS: We previously published two preclinical studies, in which we assessed two different flow diverters in the treatment of elastase-induced aneurysms. Devices have been implanted across the aneurysm neck as well as in the abdominal aorta. From these studies, a total of 65 devices (prototype FD (n = 30) and Derivo embolization device (n = 35)) additionally underwent micro-CT and MRI after angiographic follow-up and before being histologically examined. RESULTS: The different architectures of both devices were precisely comparable due to high resolution micro-CT imaging. Micro-CT revealed wire fractures in nine cases (30 %) only with the prototype FD. In three cases (10 %), severe wire fractures correlated with an in-stent stenosis due to intimal hyperplasia. Other complications, like distal stent occlusions and post-stent stenosis, were seen in both groups and verified with both imaging techniques. Osseous metaplasia were correlated to calcifications seen with micro-CT. MRI enabled visualization of the position of the implanted devices relative to the aneurysm and revealed incomplete aneurysm neck coverage with the prototype FD in two cases (6.7 %). CONCLUSION: Micro-CT and 9.4-T MRI are valid to discover and understand occurring complications of flow diverters in the preclinical phase and can serve as evaluation tools to minimize complication rates of endovascular devices in the future. PMID- 27457493 TI - Targeted Quantitative Screening of Chromosome 18 Encoded Proteome in Plasma Samples of Astronaut Candidates. AB - This work was aimed at estimating the concentrations of proteins encoded by human chromosome 18 (Chr 18) in plasma samples of 54 healthy male volunteers (aged 20 47). These young persons have been certified by the medical evaluation board as healthy subjects ready for space flight training. Over 260 stable isotope-labeled peptide standards (SIS) were synthesized to perform the measurements of proteins encoded by Chr 18. Selected reaction monitoring (SRM) with SIS allowed an estimate of the levels of 84 of 276 proteins encoded by Chr 18. These proteins were quantified in whole and depleted plasma samples. Concentration of the proteins detected varied from 10-6 M (transthyretin, P02766) to 10-11 M (P4 ATPase, O43861). A minor part of the proteins (mostly representing intracellular proteins) was characterized by extremely high inter individual variations. The results provide a background for studies of a potential biomarker in plasma among proteins encoded by Chr 18. The SRM raw data are available in ProteomeXchange repository (PXD004374). PMID- 27457494 TI - Volcano electrical tomography unveils edifice collapse hazard linked to hydrothermal system structure and dynamics. AB - Catastrophic collapses of the flanks of stratovolcanoes constitute a major hazard threatening numerous lives in many countries. Although many such collapses occurred following the ascent of magma to the surface, many are not associated with magmatic reawakening but are triggered by a combination of forcing agents such as pore-fluid pressurization and/or mechanical weakening of the volcanic edifice often located above a low-strength detachment plane. The volume of altered rock available for collapse, the dynamics of the hydrothermal fluid reservoir and the geometry of incipient collapse failure planes are key parameters for edifice stability analysis and modelling that remain essentially hidden to current volcano monitoring techniques. Here we derive a high resolution, three-dimensional electrical conductivity model of the La Soufriere de Guadeloupe volcano from extensive electrical tomography data. We identify several highly conductive regions in the lava dome that are associated to fluid saturated host-rock and preferential flow of highly acid hot fluids within the dome. We interpret this model together with the existing wealth of geological and geochemical data on the volcano to demonstrate the influence of the hydrothermal system dynamics on the hazards associated to collapse-prone altered volcanic edifices. PMID- 27457496 TI - Timing of dornase alfa inhalation for cystic fibrosis. AB - BACKGROUND: Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane review. OBJECTIVES: To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day). SEARCH METHODS: Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings.Date of the most recent search: 25 April 2016. SELECTION CRITERIA: Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. MAIN RESULTS: We identified 115 trial reports representing 55 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second. Similarly, forced vital capacity and quality of life were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to 0.05), based on the pooled data from two small studies in children (seven to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial, morning versus evening inhalation had no impact on lung function or symptoms. AUTHORS' CONCLUSIONS: The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted. PMID- 27457498 TI - Association of human leukocyte antigen with postherpetic neuralgia in Koreans. AB - Postherpetic neuralgia (PHN), the most frequent complication of varicella-zoster virus reactivation, is characterized by pain that persists for more than 3 months, often for years after healing of zoster rash. A few studies revealing the association of human leukocyte antigen (HLA) with PHN have been reported, but only in the Japanese. The aim of this study was to investigate the primary HLA locus associated with PHN susceptibility in Koreans. We compared HLA-A, -B, -C, and DRB1 genotypes of 66 PHN patients with those of 54 herpes zoster (HZ) patients without developing PHN and 235 healthy controls. Frequencies of HLA B*13, B*44, B*15 (B75), DRB1*10:01, and DRB1*12:02 were increased, and those of HLA-C*01, C*12, and DRB1*01:01 were decreased in PHN patients compared to those in controls (each, p < 0.05). Among these alleles, only the frequency of HLA-B*44 was significantly increased in PHN patients compared to that in HZ patients and the change was due to HLA-B*44:03 (PHN vs controls, p = 0.043; PHN vs HZ, p = 0.012). The results suggest that HLA-B*44:03 or other closely linked gene of the major histocompatibility complex is associated with susceptibility to the development of PHN after HZ, but not with the onset of HZ. PMID- 27457497 TI - Prevalence of Staphylococcus aureus and of methicillin-resistant S. aureus clonal complexes in bulk tank milk from dairy cattle herds in Lombardy Region (Northern Italy). AB - Staphylococcus aureus is the most important causative agent of subclinical mastitis in cattle resulting in reduced milk production and quality. Methicillin resistant S. aureus (MRSA) strains has a clear zoonotic relevance, especially in the case of occupational exposure. The aim of the study was to evaluate the prevalence of S. aureus and MRSA in bulk tank milk (BTM) from dairy cattle herds in the Lombardy Region (Northern Italy) and to identify the main MRSA circulating genotypes. MRSA strains were characterized by susceptibility testing, multi-locus sequence typing (MLST), spa typing and SCCmec typing. A total 844 BTM samples were analysed and S. aureus and MRSA were detected in 47.2% and 3.8% of dairy herds, respectively. MLST showed that the majority (28/32) of isolates belonged to the typical livestock-associated lineages: ST398, ST97 and ST1. Interestingly, in this study we report for the first time the new ST3211, a single locus variant of ST(CC)22, with the newly described 462 aroE allele. Our study indicates high diffusion of S. aureus mastitis and low, but not negligible, prevalence of MRSA in the considered area, suggesting the need for planning specific control programmes for bovine mastitis caused by S. aureus, especially when MRSA is implicated. PMID- 27457495 TI - Associative and sensorimotor cortico-basal ganglia circuit roles in effects of abused drugs. AB - The mammalian forebrain is characterized by the presence of several parallel cortico-basal ganglia circuits that shape the learning and control of actions. Among these are the associative, limbic and sensorimotor circuits. The function of all of these circuits has now been implicated in responses to drugs of abuse, as well as drug seeking and drug taking. While the limbic circuit has been most widely examined, key roles for the other two circuits in control of goal-directed and habitual instrumental actions related to drugs of abuse have been shown. In this review we describe the three circuits and effects of acute and chronic drug exposure on circuit physiology. Our main emphasis is on drug actions in dorsal striatal components of the associative and sensorimotor circuits. We then review key findings that have implicated these circuits in drug seeking and taking behaviors, as well as drug use disorders. Finally, we consider different models describing how the three cortico-basal ganglia circuits become involved in drug related behaviors. This topic has implications for drug use disorders and addiction, as treatments that target the balance between the different circuits may be useful for reducing excessive substance use. PMID- 27457499 TI - Towards an Observation of Active Conformations in Asymmetric Catalysis: Interaction-Induced Conformational Preferences of a Chiral Thiourea Model Compound. AB - The observation of the active species is the goal of most spectroscopic investigations on enantioselective organocatalysts in solution. Although NMR spectroscopy is widely applied, it has low sensitivity for conformational changes or the chiral nature of the interactions. In the present work, we exemplify the use of vibrational circular dichroism (VCD) spectroscopy for the characterization of a chiral thiourea model compound in nonpolar and polar solvents, as well as for a detailed analysis of its interaction with a model reactant. We discuss solvent-induced conformational changes of the thiourea, and provide evidence for an unexpected binding topology between the thiourea and an acetate anion. The results clearly showcase the possibilities offered by using VCD spectroscopy in the characterization of chiral organocatalysts. PMID- 27457500 TI - Discussion: Tracing changes in atmospheric sources of lead contamination using lead isotopic compositions in Australian red wine Chemosphere (2016) 154, 40-47. Authors Kristensen LJ, Taylor MP, Evans AJ. PMID- 27457501 TI - Reply. PMID- 27457502 TI - Noninvasive assessment of the retina and the choroid using enhanced-depth imaging optical coherence tomography shows microvascular impairments in childhood obesity. PMID- 27457503 TI - Exotropic Duane syndrome with synergistic divergence. PMID- 27457504 TI - The solid state structures of the high and low temperature phases of dimethylcadmium. AB - The solid state structure of dimethylcadmium, a classic organometallic compound with a long history, has remained elusive for almost a century. X-ray crystallography and density functional theory reveal similar phase behaviour as in dimethylzinc. The high temperature tetragonal phase, alpha-Me2Cd, exhibits two dimensional disorder, while the low temperature monoclinic phase, beta-Me2Cd, is ordered. Both phases contain linearly coordinated cadmium atoms. While the methyl groups are staggered in the alpha-phase, they are eclipsed in the beta-phase. PMID- 27457506 TI - Highly Enantioselective Iron-Catalyzed cis-Dihydroxylation of Alkenes with Hydrogen Peroxide Oxidant via an Fe(III) -OOH Reactive Intermediate. AB - The development of environmentally benign catalysts for highly enantioselective asymmetric cis-dihydroxylation (AD) of alkenes with broad substrate scope remains a challenge. By employing [Fe(II) (L)(OTf)2 ] (L=N,N'-dimethyl-N,N'-bis(2-methyl 8-quinolyl)-cyclohexane-1,2-diamine) as a catalyst, cis-diols in up to 99.8 % ee with 85 % isolated yield have been achieved in AD of alkenes with H2 O2 as an oxidant and alkenes in a limiting amount. This "[Fe(II) (L)(OTf)2 ]+H2 O2 " method is applicable to both (E)-alkenes and terminal alkenes (24 examples >80 % ee, up to 1 g scale). Mechanistic studies, including (18) O-labeling, UV/Vis, EPR, ESI-MS analyses, and DFT calculations lend evidence for the involvement of chiral Fe(III) -OOH active species in enantioselective formation of the two C-O bonds. PMID- 27457505 TI - SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma. AB - The current lack of cancer stem cell (CSC) markers that are easily evaluated by blood samples prevents the establishment of new therapeutic strategies in hepatocellular carcinoma (HCC). Herein, we examined whether sex determining region Y-box 9 (SOX9) represents a new CSC marker, and whether osteopontin (OPN) can be used as a surrogate marker of SOX9 in HCC. In HCC cell lines transfected with a SOX9 promoter-driven enhanced green fluorescence protein gene, FACS isolated SOX9(+) cells were capable of self-renewal and differentiation into SOX9(-) cells, and displayed high proliferation capacity in vitro. Xenotransplantation experiments revealed that SOX9(+) cells reproduced, differentiated into SOX9(-) cells, and generated tumors at a high frequency in vivo. Moreover, SOX9(+) cells were found to be involved in epithelial-mesenchymal transition (EMT) and activation of TGFb/Smad signaling. Gain/loss of function experiments showed that SOX9 regulates Wnt/beta-catenin signaling, including cyclin D1 and OPN. Immunohistochemistry of 166 HCC surgical specimens and serum OPN measurements showed that compared to SOX9(-) patients, SOX9(+) patients had significantly poorer recurrence-free survival, stronger venous invasion, and higher serum OPN levels. In conclusion, SOX9 is a novel HCC-CSC marker regulating the Wnt/beta-catenin pathway and its downstream target, OPN. OPN is a useful surrogate marker of SOX9 in HCC. PMID- 27457507 TI - PPARalpha modulation of mesolimbic dopamine transmission rescues depression related behaviors. AB - Depressive disorders cause a substantial burden for the individual and the society. Key depressive symptoms can be modeled in animals and enable the development of novel therapeutic interventions. Chronic unavoidable stress disrupts rats' competence to escape noxious stimuli and self-administer sucrose, configuring a depression model characterized by escape deficit and motivational anhedonia associated to impaired dopaminergic responses to sucrose in the nucleus accumbens shell (NAcS). Repeated treatments that restore these responses also relieve behavioral symptoms. Ventral tegmental area (VTA) dopamine neurons encode reward and motivation and are implicated in the neuropathology of depressive-like behaviors. Peroxisome proliferator-activated receptors type-alpha (PPARalpha) acutely regulate VTA dopamine neuron firing via beta2 subunit-containing nicotinic acetylcholine receptors (beta2*nAChRs) through phosphorylation and this effect is predictive of antidepressant-like effects. Here, by combining behavioral, electrophysiological and biochemical techniques, we studied the effects of repeated PPARalpha stimulation by fenofibrate on mesolimbic dopamine system. We found decreased beta2*nAChRs phosphorylation levels and a switch from tonic to phasic activity of dopamine cells in the VTA, and increased phosphorylation of dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP 32) in the NAcS. We then investigated whether long-term fenofibrate administration to stressed rats reinstated the decreased DARPP-32 response to sucrose and whether this effect translated into antidepressant-like properties. Fenofibrate restored dopaminergic responses to appetitive stimuli, reactivity to aversive stimuli and motivation to self-administer sucrose. Overall, this study suggests PPARalpha as new targets for antidepressant therapies endowed with motivational anti-anhedonic properties, further supporting the role of an unbalanced mesolimbic dopamine system in pathophysiology of depressive disorders. PMID- 27457508 TI - Predictive Factors for HIV Seroconversion Among Individuals Attending a Specialized Center After an HIV Risk Exposure: A Case-Control Study. AB - OBJECTIVE: To better target our current prevention strategies, we assessed factors associated with HIV seroconversion in individuals attending a specialized center after a risk exposure. MATERIALS AND METHODS: We studied individuals from an HIV Unit's contact risk cohort at a tertiary care hospital in Barcelona, Spain, between 2003 and 2013 and performed a retrospective matched case-control study. Cases were individuals who seroconverted to HIV after at least 3 months since first follow-up visit for a contracting risk. Controls were HIV-negative individuals from the same cohort. Demographics and behavior variables were studied and compared using a McNemar test assessing factors associated with seroconversion. Univariate analysis and binary logistic regression were performed to develop a model for predicting probability of HIV seroconversion. We also evaluated sensitivity and specificity of our model and an area under Receiver Operating Characteristic (ROC) curve was estimated. RESULTS: Sixty-nine (2.2%) individuals seroconverted after a median (interquartile range) of 24 (9-34) months since last follow-up. Seroconverters were predominantly male (96%) and men who have sex with men (MSM) (94%). No differences were observed regarding risk of exposure. Being MSM [odds ratio (OR) 5.2 (1.4-20.2), p = .01], having a known HIV positive partner [OR 2.7 (1.2-6.2), p = .02], previous postexposure prophylaxis (PEP) [OR 3.9 (1.0-15.6), p = .05], and having previous sexually transmitted infections (STIs) [OR 4.6 (1.9-10.9), p = .001] were the factors independently associated with HIV seroconversion. The sensitivity and specificity of our model were 64.06% and 73.53%, respectively, and the area under ROC curve was 0.777. DISCUSSION: HIV seroconversions were observed frequently between individuals attending a specialized center because of a risk exposure. Being MSM, having had previous PEP, an HIV-positive sexual partner, and previous STI were predictive factors for HIV seroconversion. Closer and longer follow-up and/or pre-exposure prophylaxis should be considered to prevent HIV infections in this high-risk population. PMID- 27457509 TI - Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. AB - Diabetic nephropathy constitutes a devastating complication in patients with type 1 diabetes mellitus, and its diagnosis is traditionally based on microalbuminuria. The aim of this review is to update through the medical literature the suggested early natural course of diabetic nephropathy, the theories behind the pathways of its pathogenesis, and its diagnosis. Poor glycemic control, dyslipidemia, smoking, advanced glycation end products, and environmental and genetic clues play an important role in the development of diabetic nephropathy. Microalbuminuria has been traditionally considered as a primary early marker of microvascular complication unraveling the risk for progress to the advanced stages of chronic kidney disease, but because of our inability to make an early diagnosis of diabetic nephropathy in young patients as well as nonalbuminuric diabetic nephropathy, recently, other additional markers of renal injury like serum and urinary neutrophil gelatinase-associated lipocalin, chitinase-3-like protein 1, cystatin C, and plasma growth differentiation factor 15 have been proposed to unmask early renal dysfunction, even before microalbuminuria supervenes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27457510 TI - Physical trauma recorded in primary care is associated with the onset of psoriatic arthritis among patients with psoriasis. AB - OBJECTIVES: To evaluate the risk of psoriatic arthritis (PsA) among patients with psoriasis exposed to physical trauma. METHODS: A matched cohort study was performed using data from The Health Improvement Network (THIN). Patients with psoriasis exposed to trauma were randomly matched to up to five unexposed psoriasis controls based on gender, age, duration of psoriasis and the date of entry into THIN. Trauma exposure was stratified into subgroups of joint, bone, nerve and skin trauma. Cox proportional hazard models were used to estimate the HRs for developing PsA. For comparison, an identical analysis was performed in the entire THIN population evaluating rheumatoid arthritis (RA) risk following physical trauma. RESULTS: Patients with psoriasis exposed to trauma (N=15 416) and matched unexposed patients (N=55 230) were followed for a total of 425 120 person-years during which 1010 incident PsA cases were recorded. Adjusting for potential confounders, patients with psoriasis exposed to trauma had an increased risk of PsA compared with controls, with a multivariate HR of 1.32 (95% CI 1.13 to 1.54). In our subset analysis, bone and joint trauma were associated with multivariate HRs of 1.46 (95% CI 1.04 to 2.04) and 1.50 (95% CI 1.19 to 1.90), respectively; while nerve and skin trauma were not associated with a statistically significant increase in risk compared with controls. Patients exposed to trauma in the entire THIN population did not have an increased risk of developing RA: HR 1.04 (95% CI 0.99 to 1.10). CONCLUSIONS: Patients with psoriasis exposed to physical trauma are at an increased risk of developing PsA. PMID- 27457511 TI - Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. AB - BACKGROUND: The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD). METHODS: Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received riociguat (maximum 2.5 mg three times daily); the primary endpoint was safety and tolerability. RESULTS: In patients with PAH-CTD, riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2 years. Two-year survival of patients with PAH CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population. CONCLUSIONS: Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2 years in patients with PAH-CTD. TRIAL REGISTRATION NUMBERS: PATENT-1 (NCT00810693), PATENT-2 (NCT00863681). PMID- 27457512 TI - Disease activity states of the DAPSA, a psoriatic arthritis specific instrument, are valid against functional status and structural progression. AB - BACKGROUND: Recently, disease activity states were developed for the Disease Activity index for PSoriatic Arthritis (DAPSA). Here, we assess if different DAPSA disease activity states are associated with different degrees of functional impairment and different extents of joint damage progression in patients with psoriatic arthritis (PsA). METHODS: We used data from two pivotal trials of tumour necrosis factor (TNF) inhibitors in PsA (IMPACT II and GO-REVEAL) and identified patients in DAPSA remission (REM, <=4), and low, moderate or high disease activity (LDA, <=14; MDA, <=28; HDA, >28) at 6 months. Across these groups we compared the functional scores (Health Assessment Questionnaire Disability Index, HAQ and physical component scale of the Short Form-36, PCS), and 1-year structural progression (PsA-modified Sharp/van der Heijde Score). RESULTS: We identified 310 from GO-REVEAL and 130 from IMPACT II, with a mean (SD) baseline DAPSA of 48.8 (26.4) and 44.6 (17.9), respectively. HAQ scores increased across patients groups in the four DAPSA disease activity states, while PCS decreased (p<0.001 for both). The mean progression in the combined cohort was -0.47 for REM, -0.28 for LDA, -0.14 for MDA and 0.51 for HDA (p<0.001). This association was also significant in the individual trial cohorts, and in the subgroups of patients treated with TNF inhibitors or placebo. Higher DAPSA scores were significantly and independently associated with probability of structural progression in multiple analyses. CONCLUSIONS: Disease activity states of the PsA specific DAPSA score are highly valid for future use as endpoints in clinical trials or as targets in clinical practice. TRIAL REGISTRATION NUMBERS: IMPACT 2: NCT02152254; GO-REVEAL: NCT00265096. PMID- 27457514 TI - 2016 updated EULAR evidence-based recommendations for the management of gout. AB - BACKGROUND: New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. METHODS: The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. RESULTS: Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 umol/L) and <5 mg/dL (300 umol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. CONCLUSIONS: These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease. PMID- 27457518 TI - Correction. PMID- 27457515 TI - Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. AB - OBJECTIVES: Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS). METHODS: RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN) alpha/beta receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1beta-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays. RESULTS: HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1beta-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11. CONCLUSIONS: Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN driven autoimmune diseases. PMID- 27457513 TI - EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. AB - OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus. PMID- 27457516 TI - Direct observation of the Dirac nodes lifting in semimetallic perovskite SrIrO3 thin films. AB - Perovskite SrIrO3 has long been proposed as an exotic semimetal induced by the interplay between the spin-orbit coupling and electron correlations. However, its low-lying electronic structure is still lacking. We synthesize high-quality perovskite SrIrO3 (100) films by means of oxide molecular beam epitaxy, and then systemically investigate their low energy electronic structure using in-situ angle-resolved photoemission spectroscopy. We find that the hole-like bands around R and the electron-like bands around U(T) intersect the Fermi level simultaneously, providing the direct evidence of the semimetallic ground state in this compound. Comparing with the density functional theory, we discover that the bandwidth of states near Fermi level is extremely small, and there exists a pronounced mixing between the Jeff = 1/2 and Jeff = 3/2 states. Moreover, our data reveal that the predicted Dirac degeneracy protected by the mirror-symmetry, which was theoretically suggested to be the key to realize the non-trivial topological properties, is actually lifted in perovskite SrIrO3 thin films. Our findings pose strong constraints on the current theoretical models for the 5d iridates. PMID- 27457519 TI - Neuromuscular Control Mechanisms During Single-Leg Jump Landing in Subacute Ankle Sprain Patients: A Case Control Study. AB - BACKGROUND: Optimal neuromuscular control mechanisms are essential for preparing, maintaining, and restoring functional joint stability during jump landing and to prevent ankle injuries. In subacute ankle sprain patients, neither muscle activity nor kinematics during jump landing has previously been assessed. OBJECTIVE: To compare neuromuscular control mechanisms and kinematics between subacute ankle sprain patients and healthy persons before and during the initial contact phase of a 25-cm single-leg jump. DESIGN: Case-control study. SETTING: University hospital. PATIENTS: Fifteen patients with grade I or II acute ankle sprains were followed up after 4 weeks of conservative management not involving physical therapy. METHODS: Subjects performed alternately 3 single-leg forward jumps of 25 cm (toe-to-heel distance) barefoot. Their results were compared with the data of 15 healthy subjects. MAIN OUTCOME MEASUREMENTS: Electromyographic (EMG) activity of the musculus (m.) gastrocnemius lateralis, m. tibialis anterior, and m. peroneus longus as well as kinematics for ankle, knee, and hip joint were recorded for pre-initial contact (IC) phase, post-initial contact phase, and reflex-induced phase. RESULTS: The results showed that EMG activity of the 3 muscles did not differ between ankle sprain patients (n = 15) and healthy persons (n = 15) for any of the analyzed time intervals (all P > .05). However, during the pre-IC phase, ankle sprain patients presented less plantar flexion, as well as during the post-IC phase after jump landing, compared to healthy persons (P < .05). CONCLUSION: Taken together, these kinematic alterations of the ankle joint can lead to neuromuscular control mechanism disturbances through which functional instability might arise. LEVEL OF EVIDENCE: III. PMID- 27457520 TI - Estrogen Receptor alpha Promotes Breast Cancer by Reprogramming Choline Metabolism. AB - Estrogen receptor alpha (ERalpha) is a key regulator of breast growth and breast cancer development. Here, we report how ERalpha impacts these processes by reprogramming metabolism in malignant breast cells. We employed an integrated approach, combining genome-wide mapping of chromatin-bound ERalpha with estrogen induced transcript and metabolic profiling, to demonstrate that ERalpha reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline (Cho) metabolism. Cho phosphotransferase CHPT1, identified as a direct ERalpha-regulated gene, was required for estrogen-induced effects on Cho metabolism, including increased phosphatidylcholine synthesis. CHPT1 silencing inhibited anchorage-independent growth and cell proliferation, also suppressing early-stage metastasis of tamoxifen-resistant breast cancer cells in a zebrafish xenograft model. Our results showed that ERalpha promotes metabolic alterations in breast cancer cells mediated by its target CHPT1, which this study implicates as a candidate therapeutic target. Cancer Res; 76(19); 5634-46. (c)2016 AACR. PMID- 27457522 TI - Cardiac metastasis from lung cancer mimicking as perfusion defect on N-13 ammonia and FDG myocardial viability PET/CT scan. PMID- 27457521 TI - L-Tyrosine Confers Residualizing Properties to a d-Amino Acid-Rich Residualizing Peptide for Radioiodination of Internalizing Antibodies. AB - PURPOSE: The aims of the study were to develop and evaluate a novel residualizing peptide for labeling internalizing antibodies with (124)I to support clinical development using immuno-positron emission tomography (PET). METHODS: The anti epidermal growth factor receptor antibody ch806 was radiolabeled directly or indirectly with isotopes and various residualizing peptides. Azido-derivatized radiolabeled peptides were conjugated to dibenzylcyclooctyne-derivatized ch806 antibody via click chemistry. The radiochemical purities, antigen-expressing U87MG.de2-7 human glioblastoma cell-binding properties, and targeting of xenografts at 72 hours post injection of all radioconjugates were compared. Biodistribution of (124)I-PEG4-tptddYddtpt-ch806 and immuno-PET imaging were evaluated in tumor-bearing mice. RESULTS: Biodistribution studies using xenografts at 72 hours post injection showed that (131)I-PEG4-tptddYddtpt-ch806 tumor uptake was similar to (111)In-CHX-A"-DTPA-ch806. (125)I-PEG4-tptddyddtpt ch806 showed a lower tumor uptake value but higher than directly labeled (125)I ch806. (124)I-PEG4-tptddYddtpt-ch806 was produced at 23% labeling efficiency, 98% radiochemical purity, 25.9 MBq/mg specific activity, and 64% cell binding in the presence of antigen excess. Tumor uptake for (124)I-PEG4-tptddYddtpt-ch806 was similar to (111)In-CHX-A"-DTPA-ch806. High-resolution immuno-PET/magnetic resonance imaging of tumors showed good correlation with biodistribution data. CONCLUSIONS: The mixed d/l-enantiomeric peptide, dThr-dPro-dThr-dAsp-dAsp-Tyr dAsp-dAsp-dThr-dPro-dThr, is suitable for radiolabeling antibodies with radiohalogens such as (124)I for high-resolution immuno-PET imaging of tumors and for evaluation in early-phase clinical trials. PMID- 27457523 TI - Changing the trajectory of ischemic heart disease in women: Role of imaging. AB - Mortality from coronary artery disease in women declined from nearly 500,000 deaths in 2000 to 398,096 deaths in 2013. Despite these significant gains, cardiovascular disease mortality in women remains unacceptably high. Much additional progress in awareness, evaluation, and management of cardiovascular diseases is needed. Progress in cardiovascular imaging, over the past four decades, has substantially improved the evaluation and management of ischemic heart disease. Ischemic heart disease is now diagnosed early and with greater accuracy, leading to improved risk assessment and timely therapies. The next gains in ischemic heart disease mortality in women will probably be due to application of these imaging advances in a personalized fashion. Thoughtful leaders provide their viewpoints on the use of imaging in the evaluation and management of ischemic heart disease in women. PMID- 27457524 TI - Stress myocardial perfusion imaging in the elderly. PMID- 27457525 TI - The role of stress echocardiography in the evaluation of coronary artery disease and myocardial ischemia in women. AB - Considering the unfavorable prognosis of women with ischemic heart disease, an aggressive but safe approach to evaluate women presenting with chest pain is warranted so that coronary artery disease (CAD) can be identified and treated early. Stress echocardiography (SE) has matured into an invaluable technique for the noninvasive detection of obstructive epicardial CAD. Its versatility, accuracy, safety, noninvasiveness, and lack of radiation exposure make SE an attractive technique to apply to the assessment of women with known or suspected heart disease. This article focuses on the current evidence supporting the role of SE in the assessment of CAD and myocardial ischemia in women. PMID- 27457526 TI - The role of cardiac CT in women. AB - Due to the discrepancy between higher symptom burden and lower disease prevalence, the diagnosis of coronary artery disease (CAD) in women is challenging. Cardiac CT can be particularly useful in CAD diagnosis and risk stratification in women. In this review, we explore cardiac CT in women with and without symptoms and for adjudication of functional tests. Novel CT technologies such as fractional flow reserve and stress perfusion imaging and their potential for usefulness in women are also examined. PMID- 27457527 TI - The response of FDG uptake to immunosuppressive treatment on FDG PET/CT imaging for cardiac sarcoidosis. AB - BACKGROUND: Immunosuppression is used to treat cardiac sarcoidosis, despite limited data. FDG PET/CT is used for detecting cardiac inflammation in patients with CS, yet there is variability in interpretation of FDG PET/CT. Our aim was to compare quantitative and qualitative interpretation of FDG PET/CT for CS in defining the FDG response to immunosuppression. METHODS AND RESULTS: Patients with CS (N = 43 total studies from 17 patients) had serial FDG PET/CT studies before/after immunosuppression. FDG uptake was analyzed qualitatively (visually; FDG-positive segments) and quantitatively (SUVmax; cardiac metabolic volume and activity (CMV, CMA); volume above SUV thresholds 2.7 and 4.1 g/mL). Complete resolution of FDG uptake was common using CMA (10/17), CMV (10/17), but a 2.7 g/mL SUV threshold (13/17) and SUVmax (14/17) were more likely to define partial responses. In six patients imaged after a reduction in immunosuppression, 4/6 had a rebound quantitative FDG uptake. CONCLUSIONS: Quantitative interpretation of FDG PET/CT in CS can detect changes in FDG uptake in response to immunosuppression. Further studies are needed to see if quantitative changes in FDG uptake are associated with improved outcomes. PMID- 27457528 TI - The role of treadmill exercise testing in women. AB - Treadmill exercise electrocardiogram (ECG) is one of the most commonly used noninvasive tests for the assessment of ischemic heart disease (IHD). Sex specific challenges in diagnostic and prognostic tests methods for IHD outlined the importance of pretest probability evaluation and referral bias using risk prediction charts available for both asymptomatic and symptomatic women. Accordingly, exercise ECG has been indicated as the initial test for the symptomatic women at intermediate risk of IHD who has a normal resting ECG and is capable of maximal exercise. However, the difficulties of using exercise testing for diagnosing IHD in women have led to an initial speculation that stress imaging may be preferred to standard stress testing. This editorial analyzed a large body of evidence on the diagnostic and prognostic powers of treadmill ECG and exercise myocardial perfusion imaging (MPI) according to new advanced imaging technologies. PMID- 27457529 TI - The role of stress cardiac magnetic resonance in women. AB - Coronary artery disease (CAD) is the leading cause of death in women. Nevertheless, extensive evidence demonstrates under-diagnosis and under-treatment of women for suspected or known ischemic heart disease (IHD). Stress cardiac magnetic resonance (CMR) is becoming readily available and offers significant advantages over other stress imaging modalities. The high spatial and temporal resolution of CMR provides the unique ability to identify subendocardial ischemia, viability, and the presence of microvascular disease. Furthermore, CMR is free from ionizing radiation, and image quality is not compromised by attenuation artifacts or patient size. Over the past two decades, evidence-based data have demonstrated the high diagnostic and prognostic performance of stress CMR in the context of IHD, often superior to other stress imaging techniques. Importantly, ad hoc studies confirmed these results in women with known or suspected IHD. Stress CMR warrants consideration as the modality of choice for women requiring an imaging test for ischemia given its strong evidence base, superior test characteristics, comprehensive nature, and unique ability to characterize both epicardial and microvascular disease. PMID- 27457530 TI - Sympathetic nervous system, systolic heart failure, and central sleep apnea: Are we about to find the missing link? PMID- 27457532 TI - Neurofilament heavy chain expression and neuroplasticity in rat auditory cortex after unilateral and bilateral deafness. AB - Deafness induces many plastic changes in the auditory neural system. For instance, dendritic changes cause synaptic changes in neural cells. SMI-32, a monoclonal antibody reveals auditory areas and recognizes non-phosphorylated epitopes on medium- and high-molecular-weight subunits of neurofilament proteins in cortical pyramidal neuron dendrites. We investigated SMI-32-immunoreactive ( ir) protein levels in the auditory cortices of rats with induced unilateral and bilateral deafness. Adult male Sprague-Dawley rats were divided into unilateral deafness (UD), bilateral deafness (BD), and control groups. Deafness was induced by cochlear ablation. All rats were sacrificed, and the auditory cortices were harvested for real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analyses at 2, 4, 6, and 12 weeks after deafness was induced. Immunohistochemical staining was performed to evaluate the location of SMI-32-ir neurons. Neurofilament heavy chain (NEFH) mRNA expression and SMI-32-ir protein levels were increased in the BD group. In particular, SMI-32-ir protein levels increased significantly 6 and 12 weeks after deafness was induced. In contrast, no significant changes in protein level were detected in the right or left auditory cortices at any time point in the UD group. NEFH mRNA level decreased at 4 weeks after deafness was induced in the UD group, but recovered thereafter. Taken together, BD induced plastic changes in the auditory cortex, whereas UD did not affect the auditory neural system sufficiently to show plastic changes, as measured by neurofilament protein level. PMID- 27457531 TI - Mechanisms of sudden cardiac death. AB - Sudden cardiac death (SCD) continues to be a major public health problem and is thought to account for almost half of all cardiac deaths. Cardiac arrest and SCD are most commonly due to ventricular arrhythmias. Most patients who suffer cardiac arrest have underlying structural heart disease, with coronary artery disease (CAD) being the most common. In the setting of CAD, ventricular arrhythmias can result due to acute ischemia in the absence of preexisting myocardial scarring or in the presence of established scar from prior infarction without clinically significant ischemia. LV systolic dysfunction is an important predictor of risk for SCD in ischemic heart disease and in most nonischemic disorders, although other factors such as ventricular hypertrophy also play a role. Cardiac arrest and SCD can also occur due to primary electrical disorders in the absence of major structural abnormalities. PMID- 27457533 TI - Frontal-posterior coherence and cognitive function in older adults. AB - The reliable measurement of brain health and cognitive function is essential in mitigating the negative effects associated with cognitive decline through early and accurate diagnosis of change. The present research explored the relationship between EEG coherence for electrodes within frontal and posterior regions, as well as coherence between frontal and posterior electrodes and performance on standard neuropsychological measures of memory and executive function. EEG coherence for eyes-closed resting-state EEG activity was calculated for delta, theta, alpha, beta, and gamma frequency bands. Participants (N=66; mean age=67.15years) had their resting-state EEGs recorded and completed a neuropsychological battery that assessed memory and executive function, two cognitive domains that are significantly affected during aging. A positive relationship was observed between coherence within the frontal region and performance on measures of memory and executive function for delta and beta frequency bands. In addition, an inverse relationship was observed for coherence between frontal and posterior electrode pairs, particularly within the theta frequency band, and performance on Digit Span Sequencing, a measure of working memory. The present research supports a more substantial link between EEG coherence, rather than spectral power, and cognitive function. Continued study in this area may enable EEG to be applied broadly as a diagnostic measure of cognitive ability. PMID- 27457534 TI - Emotional facial activation induced by unconsciously perceived dynamic facial expressions. AB - Do facial expressions of emotion influence us when not consciously perceived? Methods to investigate this question have typically relied on brief presentation of static images. In contrast, real facial expressions are dynamic and unfold over several seconds. Recent studies demonstrate that gaze contingent crowding (GCC) can block awareness of dynamic expressions while still inducing behavioural priming effects. The current experiment tested for the first time whether dynamic facial expressions presented using this method can induce unconscious facial activation. Videos of dynamic happy and angry expressions were presented outside participants' conscious awareness while EMG measurements captured activation of the zygomaticus major (active when smiling) and the corrugator supercilii (active when frowning). Forced-choice classification of expressions confirmed they were not consciously perceived, while EMG revealed significant differential activation of facial muscles consistent with the expressions presented. This successful demonstration opens new avenues for research examining the unconscious emotional influences of facial expressions. PMID- 27457535 TI - Fabrication of a turbid optofluidic phantom device with tunable MUa and MU's to simulate cutaneous vascular perfusion. AB - Microfluidic devices are oftenly used to calibrate the imaging reconstruction, because they simulate the morphology of microvasculature. However, for lack of optical properties in microfluidics, the functional recovery of oximetry information cannot be verified. In this work, we describe the fabrication of a novel turbid optofluidic tissue phantom. It is designed to mimic the vascular perfusion and the turbid nature of cutaneous tissue. This phantom contains an interior hollow microfluidic structure with a diameter of phiave = 50 MUm. The microfluidic structure includes the geometry of an inlet, a river-like assay and an outlet. This structure can be perfused by hemoglobin solution to mimic the cutaneous micro-circulation. The multiple-layered phantom matrices exhibit the representative optical parameters of human skin cutis, namely the absorption coefficient MUa and the reduced scattering coefficient . The geometry of the generated microfluidic structure is investigated by using Spectral-Domain Optical Coherence Tomography. This optofluidic phantom bridges the gap between tissue equivalent phantoms and Lab-On-Chip devices. Perspectively, this device can be used to calibrate a variety of optical angiographic imaging approaches. PMID- 27457536 TI - Pseudomembranous colitis presenting as a mechanical large bowel obstruction. PMID- 27457537 TI - Behavioral Analysis of Visitors to a Medical Institution's Website Using Markov Chain Monte Carlo Methods. AB - BACKGROUND: Consistent with the "attention, interest, desire, memory, action" (AIDMA) model of consumer behavior, patients collect information about available medical institutions using the Internet to select information for their particular needs. Studies of consumer behavior may be found in areas other than medical institution websites. Such research uses Web access logs for visitor search behavior. At this time, research applying the patient searching behavior model to medical institution website visitors is lacking. OBJECTIVE: We have developed a hospital website search behavior model using a Bayesian approach to clarify the behavior of medical institution website visitors and determine the probability of their visits, classified by search keyword. METHODS: We used the website data access log of a clinic of internal medicine and gastroenterology in the Sapporo suburbs, collecting data from January 1 through June 31, 2011. The contents of the 6 website pages included the following: home, news, content introduction for medical examinations, mammography screening, holiday person-on duty information, and other. The search keywords we identified as best expressing website visitor needs were listed as the top 4 headings from the access log: clinic name, clinic name + regional name, clinic name + medical examination, and mammography screening. Using the search keywords as the explaining variable, we built a binomial probit model that allows inspection of the contents of each purpose variable. Using this model, we determined a beta value and generated a posterior distribution. We performed the simulation using Markov Chain Monte Carlo methods with a noninformation prior distribution for this model and determined the visit probability classified by keyword for each category. RESULTS: In the case of the keyword "clinic name," the visit probability to the website, repeated visit to the website, and contents page for medical examination was positive. In the case of the keyword "clinic name and regional name," the probability for a repeated visit to the website and the mammography screening page was negative. In the case of the keyword "clinic name + medical examination," the visit probability to the website was positive, and the visit probability to the information page was negative. When visitors referred to the keywords "mammography screening," the visit probability to the mammography screening page was positive (95% highest posterior density interval = 3.38 26.66). CONCLUSIONS: Further analysis for not only the clinic website but also various other medical institution websites is necessary to build a general inspection model for medical institution websites; we want to consider this in future research. Additionally, we hope to use the results obtained in this study as a prior distribution for future work to conduct higher-precision analysis. PMID- 27457539 TI - Safety and immunogenecity of a live attenuated Rift Valley fever vaccine (CL13T) in camels. AB - BACKGROUND: Rift Valley fever is an emerging zoonotic viral disease, enzootic and endemic in Africa and the Arabian Peninsula, which poses a significant threat to both human and animal health. The disease is most severe in ruminants causing abortions in pregnant animals, especially sheep animals and high mortality in young populations. High mortality rates and severe clinical manifestation have also been reported among camel populations in Africa, to attend however none of the currently available live vaccines against RVF have been tested for safety and efficacy in this species. In this study, the safety and efficacy (through a neutralizing antibody response) of the thermostable live attenuated RVF CL13T vaccine were evaluated in camels in two different preliminary experiments involving 16 camels, (that 12 camels and 4 pregnant camels). RESULTS: The study revealed that the CL13T vaccine was safe to use in camels and no abortions or teratogenic effects were observed. The single dose of the vaccine stimulated a strong and long-lasting neutralizing antibody response for up to 12 months. CONCLUSION: The presence of neutralization antibodies is likely to correlate with protection; however protection would need to be confirmed by challenge experiments using the virulent RVF virus. PMID- 27457538 TI - c-myb hyperactivity leads to myeloid and lymphoid malignancies in zebrafish. AB - The c-MYB transcription factor is a key regulator of hematopoietic cell proliferation and differentiation, and dysregulation of c-MYB activity often associates with various hematological disorders. Yet, its pathogenic role remains largely unknown due to lack of suitable animal models. Here, we report a detail characterization of a c-myb-gfp transgenic zebrafish harboring c-Myb hyperactivity (named c-mybhyper). This line exhibits abnormal granulocyte expansion that resembles human myelodysplastic syndrome (MDS) from embryonic stage to adulthood. Strikingly, a small portion of c-mybhyper adult fish develops acute myeloid leukemia-like or acute lymphoid leukemia-like disorders with age. The myeloid and lymphoid malignancies in c-mybhyper adult fish are likely caused by the hyperactivity of c-myb, resulting in the dysregulation of a number of cell cycle-related genes and hyperproliferation of hematopoietic precursor cells. Finally, treatment with c-myb target drug flavopiridol can relieve the MDS-like symptoms in both c-mybhyper embryos and adult fish. Our study establishes a zebrafish model for studying the cellular and molecular mechanisms underlying c Myb-associated leukemogenesis as well as for anti-leukemic drug screening. PMID- 27457540 TI - Determinants of Living Well With Aphasia in the First Year Poststroke: A Prospective Cohort Study. AB - OBJECTIVE: To determine factors that contribute to living well with aphasia in the first 12 months poststroke. DESIGN: Prospective longitudinal cohort study. SETTING: Hospitalized care, ambulatory care, and general community. PARTICIPANTS: A referred sample of people (N=58) with a first incidence of aphasia after stroke was assessed at 3, 6, 9, and 12 months postonset. Participants were recruited through speech-language pathologists in 2 capital cities in Australia. Presence of aphasia was determined through the Western Aphasia Battery-Revised by an experienced speech-language pathologist. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The main outcomes were the 5 domains of the Assessment for Living with Aphasia at 3, 6, 9, and 12 months poststroke. The independent variables included demographics, physical functioning, social network, mood, aphasia severity, and a self-rating of successfully living with aphasia at the same time points. Mixed effects modeling was used to determine which factors contributed to the trajectory of each of the 5 domains of participation, impairment, environment, personal factors, and life with aphasia. RESULTS: Higher household income, larger social network size, being a woman, and having milder aphasia were positively associated with the participation domain. Graduate or postgraduate educational levels, low mood, and poor physical functioning were negatively associated with the participation domain. Factors positively associated with other domains included higher income, self-ratings of successfully living with aphasia, and aphasia severity. Low mood was consistently negatively associated with all of the domains. CONCLUSIONS: Psychosocial determinants were the most significant predictors of living well with aphasia in the first 12 months postonset. Aphasia rehabilitation needs to attend more to these factors to optimize outcomes. PMID- 27457541 TI - 42,000-year-old worked and pigment-stained Nautilus shell from Jerimalai (Timor Leste): Evidence for an early coastal adaptation in ISEA. AB - In this paper, we describe worked and pigment-stained Nautilus shell artefacts recovered from Jerimalai, Timor-Leste. Two of these artefacts come from contexts dating to between 38,000 and 42,000 cal. BP (calibrated years before present), and exhibit manufacturing traces (drilling, pressure flaking, grinding), as well as red colourant staining. Through describing more complete Nautilus shell ornaments from younger levels from this same site (>15,900, 9500, and 5000 cal. BP), we demonstrate that those dating to the initial occupation period of Jerimalai are of anthropogenic origin. The identification of such early shell working examples of pelagic shell in Island Southeast Asia not only adds to our growing understanding of the importance of marine resources to the earliest modern human communities in this region, but also indicates that a remarkably enduring shell working tradition was enacted in this area of the globe. Additionally, these artefacts provide the first material culture evidence that the inhabitants of Jerimalai were not only exploiting coastal resources for their nutritional requirements, but also incorporating these materials into their social technologies, and by extension, their social systems. In other words, we argue that the people of Jerimalai were already practicing a developed coastal adaptation by at least 42,000 cal. BP. PMID- 27457542 TI - The evolutionary relationships and age of Homo naledi: An assessment using dated Bayesian phylogenetic methods. AB - Homo naledi is a recently discovered species of fossil hominin from South Africa. A considerable amount is already known about H. naledi but some important questions remain unanswered. Here we report a study that addressed two of them: "Where does H. naledi fit in the hominin evolutionary tree?" and "How old is it?" We used a large supermatrix of craniodental characters for both early and late hominin species and Bayesian phylogenetic techniques to carry out three analyses. First, we performed a dated Bayesian analysis to generate estimates of the evolutionary relationships of fossil hominins including H. naledi. Then we employed Bayes factor tests to compare the strength of support for hypotheses about the relationships of H. naledi suggested by the best-estimate trees. Lastly, we carried out a resampling analysis to assess the accuracy of the age estimate for H. naledi yielded by the dated Bayesian analysis. The analyses strongly supported the hypothesis that H. naledi forms a clade with the other Homo species and Australopithecus sediba. The analyses were more ambiguous regarding the position of H. naledi within the (Homo, Au. sediba) clade. A number of hypotheses were rejected, but several others were not. Based on the available craniodental data, Homo antecessor, Asian Homo erectus, Homo habilis, Homo floresiensis, Homo sapiens, and Au. sediba could all be the sister taxon of H. naledi. According to the dated Bayesian analysis, the most likely age for H. naledi is 912 ka. This age estimate was supported by the resampling analysis. Our findings have a number of implications. Most notably, they support the assignment of the new specimens to Homo, cast doubt on the claim that H. naledi is simply a variant of H. erectus, and suggest H. naledi is younger than has been previously proposed. PMID- 27457543 TI - The altitudinal mobility of wild sheep at the Epigravettian site of Kalavan 1 (Lesser Caucasus, Armenia): Evidence from a sequential isotopic analysis in tooth enamel. AB - Kalavan 1 is an Epigravettian hunting campsite in the Aregunyats mountain chain in northeastern Armenia (Lesser Caucasus). The site lies at an elevation of 1640 m in a bottleneck that controls the descent into the Barepat Valley from the alpine meadows above. The lithic and faunal assemblages show evidence of the production of hunting weapons, the hunting and targeting of wild sheep (Ovis orientalis), and the constitution of animal product reserves. A seasonal occupation of the site was proposed within a model of occupation by Epigravettian hunter-gatherers that involved a search for obsidian resources in high altitude sources from the spring to the summer and settling at Kalavan 1 at the end of summer or during autumn to coincide with the migration of wild herds from the alpine meadows to the valley. A key parameter of this model is wild sheep ethology, with a specifically seasonal vertical mobility, based on observations from contemporary mouflon populations from the surrounding areas. In this study, the vertical mobility of Paleolithic wild sheep was directly investigated through sequential isotope analysis (delta(18)O, delta(13)C) in teeth. A marked seasonality of birth is suggested that reflects a physiological adaptation to the strong environmental constraints of this mountainous region. Most importantly, a recurrent altitudinal mobility was demonstrated on a seasonal basis, which confirms that wild sheep migrated from lowland areas that they occupied in the winter and then moved to higher altitude meadows during the summer. Last, low inter-individual variability in the stable isotope sequences favors a hypothesis of accumulation for these faunal remains over a short time period. Overall, this new dataset strengthens the previous interpretations for Kalavan 1 and contributes to an understanding of the pattern of occupation of mountain territories by Epigravettian communities. PMID- 27457544 TI - Cutmark data and their implications for the planning depth of Late Pleistocene societies. AB - Cutmarks provide empirical evidence for the exploitation of animal resources by past human groups. Their study may contribute substantially to our knowledge of economic behavior, including the procurement of prey and the analysis of butchery sequences. Butchering practices can be investigated using cutmark illustrations recorded on bone templates. In this paper, quantitative data on cutmarks were derived from published and unpublished cutmark drawings for 27 French assemblages dated between the late Middle Paleolithic and the final Upper Paleolithic. The analysis of cutmark data on meaty long bones (humerus, radio-ulna, femur, tibia) highlights strong variations in cutmark length and orientation in the sample that potentially reflect significant shifts in meat processing strategies during the Late Pleistocene. The present study shows that long longitudinal cutmarks are considerably more frequent during the Late Glacial Maximum than in the early Upper Paleolithic. Although the number of studies is small, actualistic data generated in controlled settings indicate that long longitudinal cutmarks are commonly produced during filleting, an activity closely associated with meat preservation, as is the case with drying and smoking. Because they provide information on possible changes in the capacity for anticipation, these results have potentially important implications for the logistical and economic organization of Paleolithic hominins. PMID- 27457545 TI - What is Still Bay? Human biogeography and bifacial point variability. AB - 'Still Bay' is the name given to a cultural phase within the southern African Middle Stone Age, which remains critical to our understanding of modern human behavioural evolution. Although represented in only a handful of sites, the Still Bay is widespread geographically and, at certain localities, persisted over a substantial period of time. Many studies have focused on tracing the temporal range and geographic reach of the Still Bay, as well as inferring degrees of early modern human demographic connectedness from these parameters. Variation within the Still Bay, relative to the accuracy with which it can be identified, has received considerably less attention. However, demographic models based on the spread of the Still Bay in space and time hinge on the reliability with which it can be recognized in the archaeological record. Here we document patterns of bifacial point shape and size variation in some key Still Bay assemblages, and analyse these patterns using the statistical shape analysis tools of geometric morphometrics. Morphological variation appears to be geographically structured and is driven by the spatial separation between north-eastern and south-western clusters of sites. We argue that allometric variation is labile and reflects environmentally driven differences in point reduction, whereas shape differences unrelated to size more closely reflect technological and cultural fragmentation. Our results suggest that the biogeographic structure of Middle Stone Age populations was complex during the period associated with the Still Bay, and provide little support for heightened levels of cultural interconnectedness between distantly separated groups at this time. We briefly discuss the implications of our findings for tracing classic techno-traditions in the Middle Stone Age record of southern Africa, and for inferring underpinning population dynamics from these patterns. PMID- 27457546 TI - Reevaluating the functional implications of Australopithecus afarensis navicular morphology. AB - The longitudinal arch is a unique characteristic of the human foot, yet the timing and pattern of its evolution remain controversial, in part due to the disagreement among researchers over which skeletal traits are the best indicators of its presence or absence. The small size of the human navicular tuberosity has previously been linked to the presence of a longitudinal arch, implying that the large tuberosity of early hominins such as Australopithecus afarensis reflects a flat foot. However, this hypothesis is at odds with other evidence of pedal form and function, such as metatarsal, tarsal, and footprint morphology, which show that a longitudinal arch was probably present in A. afarensis. This study reevaluates the morphometric affinities of the A. afarensis naviculars among other Plio-Pleistocene fossil hominins and anthropoid primates (N = 170). Multivariate cluster analyses show that all fossil hominin naviculars, including those attributed to A. afarensis, are most similar to modern humans. A measure of navicular tuberosity size quantified as the ratio of the tuberosity volume to the surface area of the talar facet shows that Ateles has the largest navicular tuberosity among the anthropoid sample and that there is no difference between highly arboreal and terrestrial taxa in this metric (e.g., Hylobates and Gorilla beringei). Instead, a relatively large navicular tuberosity may reflect the development of leg musculature associated with ankle plantarflexion. The functional inferences derived from the morphology of the A. afarensis naviculars are consistent with the morphology of the Laetoli footprints. PMID- 27457547 TI - Marine and terrestrial foods as a source of brain-selective nutrients for early modern humans in the southwestern Cape, South Africa. AB - Many attempts have been made to define and reconstruct the most plausible ecological and dietary niche of the earliest members of the human species. While earlier models emphasise big-game hunting in terrestrial, largely savannah environments, more recent scenarios consider the role of marine and aquatic foods as a source of polyunsaturated fatty acids (PUFA) and other brain-selective nutrients. Along the coast of southern Africa, there appears to be an association between the emergence of anatomically modern humans and accumulation of some of the earliest shell middens during the Middle Stone Age (200-40 ka). Fragmentary fossil remains classified as those of anatomically modern humans, along with marine food residues and numerous material cultural indicators of increased social and behavioural complexity have been recovered from coastal sites. In this paper, new information on the nutrient content of marine and terrestrial foods available to early modern humans in the southwestern Cape is presented and compared with existing data on the nutritional value of some wild plant and animal foods in Africa. The results suggest that coastal foraging, particularly the collection of abundant and predictable marine molluscs, would have allowed early modern humans to exploit some of the richest and most accessible sources of protein, micronutrients and longer-chain omega-6 and omega-3 fatty acids. Reliable and accessible sources of omega-3 eicosapentaenoic and docosahexaenoic acid are considerably more restricted in terrestrial foods. PMID- 27457548 TI - Trabecular bone structural variation throughout the human lower limb. AB - Trabecular bone is responsive to mechanical loading, and thus may be a useful tool for interpreting past behaviour from fossil morphology. However, the ability to meaningfully interpret variation in archaeological and hominin trabecular morphology depends on the extent to which trabecular bone properties are integrated throughout the postcranium or are locally variable in response to joint specific loading. We investigate both of these factors by comparing trabecular bone throughout the lower limb between a group of highly mobile foragers and two groups of sedentary agriculturalists. Trabecular bone structure is quantified in four volumes of interest placed within the proximal and distal joints of the femur and tibia. We determine how trabecular structures correspond to inferred behavioural differences between populations and whether the patterns are consistent throughout the limb. A significant correlation was found between inferred mobility level and trabecular bone structure in all volumes of interest along the lower limb. The greater terrestrial mobility of foragers is associated with higher bone volume fraction, and thicker and fewer trabeculae (lower connectivity density). In all populations, bone volume fraction decreases while anisotropy increases proximodistally throughout the lower limb. This observation mirrors reductions in cortical bone mass resulting from proximodistal limb tapering. The reduction in strength associated with reduced bone volume fraction may be compensated for by the increased anisotropy in the distal tibia. A similar pattern of trabecular structure is found throughout the lower limb in all populations, upon which a signal of terrestrial mobility appears to be superimposed. These results support the validity of using lower limb trabecular bone microstructure to reconstruct terrestrial mobility levels from the archaeological and fossil records. The results further indicate that care should be taken to appreciate variation resulting from differences in habitual activity when inferring behaviour from the trabecular structure of hominin fossils through comparisons with modern humans. PMID- 27457549 TI - Re-evaluation of Pleistocene and Holocene long bone robusticity trends with regards to age-at-death estimates and size standardization procedures. AB - Long-term trends in robusticity of lower limb bones in the genus Homo through the Pleistocene until the present have been proposed, which have been interpreted as a consequence of decreasing levels of mobility and activity patterns, changes in lifestyle, and environmental factors. There has also long been evidence that skeletal strength increases over an individual's lifespan. This increase is caused by continuous bone remodeling that optimizes the structure of a bone to resist mechanical loadings and creates a balance between endosteal resorption and subperiosteal apposition. However, none of the previous studies of temporal trends in robusticity has considered both processes and analyzed how individual age-related robusticity might influence higher-level temporal trends. This paper therefore explores temporal trends in robusticity of lower limb long bones within the genus Homo and considers how individual ages-at-death can confound published evolutionary trends, given the fact that some aspects of relative bone strength tend to increase over individual lifespans. Cross-sectional diaphyseal properties of the midshaft and proximal femur and midshaft tibia of Pleistocene and early Holocene individuals, together with data on age-at-death are used to analyze changes in relative bone strength relative to individuals' ages and evolutionary time. The results show increasing bone strength in adulthood until the fourth decade and then a slight decrease, an observation that conforms to previously published results on recent human populations. However, no significant impact of age-at-death on the trends along an evolutionary trajectory has been detected. The evolutionary trends in femoral and tibial relative strength can be described as fluctuating, probably as a consequence of changing mobility patterns, environmentally and technologically influenced behaviors, and demographic processes. The differences between evolutionary trends published in several studies are explained primarily as a result of different ways of standardizing cross-sectional parameters for size, and differences in sample composition. PMID- 27457550 TI - Internal carotid arterial canal size and scaling in Euarchonta: Re-assessing implications for arterial patency and phylogenetic relationships in early fossil primates. AB - Primate species typically differ from other mammals in having bony canals that enclose the branches of the internal carotid artery (ICA) as they pass through the middle ear. The presence and relative size of these canals varies among major primate clades. As a result, differences in the anatomy of the canals for the promontorial and stapedial branches of the ICA have been cited as evidence of either haplorhine or strepsirrhine affinities among otherwise enigmatic early fossil euprimates. Here we use micro X-ray computed tomography to compile the largest quantitative dataset on ICA canal sizes. The data suggest greater variation of the ICA canals within some groups than has been previously appreciated. For example, Lepilemur and Avahi differ from most other lemuriforms in having a larger promontorial canal than stapedial canal. Furthermore, various lemurids are intraspecifically variable in relative canal size, with the promontorial canal being larger than the stapedial canal in some individuals but not others. In species where the promontorial artery supplies the brain with blood, the size of the promontorial canal is significantly correlated with endocranial volume (ECV). Among species with alternate routes of encephalic blood supply, the promontorial canal is highly reduced relative to ECV, and correlated with both ECV and cranium size. Ancestral state reconstructions incorporating data from fossils suggest that the last common ancestor of living primates had promontorial and stapedial canals that were similar to each other in size and large relative to ECV. We conclude that the plesiomorphic condition for crown primates is to have a patent promontorial artery supplying the brain and a patent stapedial artery for various non-encephalic structures. This inferred ancestral condition is exhibited by treeshrews and most early fossil euprimates, while extant primates exhibit reduction in one canal or another. The only early fossils deviating from this plesiomorphic condition are Adapis parisiensis with a reduced promontorial canal, and Rooneyia and Mahgarita with reduced stapedial canals. PMID- 27457551 TI - Trabecular architecture in the StW 352 fossil hominin calcaneus. AB - Australopithecus africanus has been interpreted as having a rigid lateral foot. One mechanism contributing to a rigid foot during push-off in humans is a calcaneocuboid joint (CCJ) with limited dorsiflexion and a "close-packed" talocalcaneal joint (TCJ). In contrast, apes likely have a greater CCJ range of motion and lack a close-packed TCJ. Differences in tarsal arthrokinematics may result in different joint loading environments. In Homo sapiens, we tested the hypothesis that dorsal and plantar CCJ and the TCJ show evidence of predictable habitual loading. In Pan troglodytes, Gorilla gorilla, Gorilla beringei, and Papio ursinus, we tested the hypothesis that only the dorsal CCJ shows evidence of predictable loading. Specifically, we predicted similarity in trabecular properties across the dorsal and plantar CCJ in H. sapiens, but dissimilarity in non-humans. Additionally, we investigated trabecular properties of an A. africanus calcaneus (StW 352) to evaluate joint loading patterns in this hominin and ultimately address the evolution of these properties in H. sapiens. Contrary to predictions, the H. sapiens dorsal CCJ has a significantly higher elongation index, bone volume fraction, trabecular thickness, and trabecular number than the plantar CCJ, while trabecular properties in non-humans do not always differ as predicted between regions. H. sapiens exhibits trabecular morphology indicative of less variable TCJ loading than other groups, having the most anisotropic and rod-like struts oriented in line with predicted principal loads. Multivariate analysis shows that the StW 352 dorsal CCJ matches P. ursinus best, while the plantar CCJ matches G. beringei best and the TCJ matches that of G. gorilla best. Overall patterns suggest that the StW 352 calcaneus experienced more variable loading than H. sapiens, but less variable loading than P. troglodytes, G. gorilla, G. beringei, and P. ursinus, consistent with a large range of foot movements, probably reflecting locomotor kinematics that are unlike those of living humans or apes. PMID- 27457552 TI - Neotropics provide insights into the emergence of New World monkeys: New dental evidence from the late Oligocene of Peruvian Amazonia. AB - Recent field efforts in Peruvian Amazonia (Contamana area, Loreto Department) have resulted in the discovery of a late Oligocene (ca. 26.5 Ma; Chambira Formation) fossil primate-bearing locality (CTA-61). In this paper, we analyze the primate material consisting of two isolated upper molars, the peculiar morphology of which allows us to describe a new medium-sized platyrrhine monkey: Canaanimico amazonensis gen. et sp. nov. In addition to the recent discovery of Perupithecus ucayaliensis, a primitive anthropoid taxon of African affinities from the alleged latest Eocene Santa Rosa locality (Peruvian Amazonia), the discovery of Canaanimico adds to the evidence that primates were well-established in the Amazonian Basin during the Paleogene. Our phylogenetic results based on dental evidence show that none of the early Miocene Patagonian taxa (Homunculus, Carlocebus, Soriacebus, Mazzonicebus, Dolichocebus, Tremacebus, and Chilecebus), the late Oligocene Bolivian Branisella, or the Peruvian Canaanimico, is nested within a crown platyrrhine clade. All these early taxa are closely related and considered here as stem Platyrrhini. Canaanimico is nested within the Patagonian Soriacebinae, and closely related to Soriacebus, thereby extending back the soriacebine lineage to 26.5 Ma. Given the limited dental evidence, it is difficult to assess if Canaanimico was engaged in a form of pitheciine-like seed predation as is observed in Soriacebus and Mazzonicebus, but dental microwear patterns recorded on one upper molar indicate that Canaanimico was possibly a fruit and hard-object eater. If Panamacebus, a recently discovered stem cebine from the early Miocene of Panama, indicates that the crown platyrrhine radiation was already well underway by the earliest Miocene, Canaanimico indicates in turn that the "homunculid" radiation (as a part of the stem radiation) was well underway by the late Oligocene. These new data suggest that the stem radiation likely occurred in the Neotropics during the Oligocene, and that several stem lineages independently reached Patagonia during the early Miocene. Finally, we are still faced with a "layered" pattern of platyrrhine evolution, but modified in terms of timing of cladogeneses. If the crown platyrrhine radiation occurred in the Neotropics around the Oligocene-Miocene transition (or at least during the earliest Miocene), it was apparently concomitant with the diversification of the latest stem forms in Patagonia. PMID- 27457553 TI - Wash effect of atmospheric trace metals wet deposition and its source characteristic in subtropical watershed in China. AB - In order to better understand air pollution in deve-loping regions, such as China, it is important to investigate the wet deposition behavior of atmospheric trace metals and its sources in the subtropical watershed. This paper studies the seasonal change of trace metal concentrations in precipitation and other potential sources in a typical subtropical watershed (Jiazhuhe watershed) located in the downstream of the Yangtze River of China. The results show that typical crustal elements (Al, Fe) and trace element (Zn) have high seasonal variation patterns and these elements have higher contents in precipitation as compared to other metals in Jiazhuhe watershed. In addition, there is no observed Pb in base flow in this study, and the concentration magnitudes of Al, Ba, Fe, Mn, Sr, and Zn in base flow are significantly higher than that of other metals. During different rainfall events, the dynamic export processes are also different for trace metals. The various trace metals dynamic export processes lead to an inconsistent mass first flush and a significant accumulative variance throughout the rainfall events. It is found that in this region, most of the trace metals in precipitation are from anthropogenic emission and marine aerosols brought by typhoon and monsoon. PMID- 27457554 TI - Estimation of the water quality of a large urbanized river as defined by the European WFD: what is the optimal sampling frequency? AB - Assessment of the quality of freshwater bodies is essential to determine the impact of human activities on water resources. The water quality status is estimated by comparing indicators with standard thresholds. Indicators are usually statistical criteria that are calculated on discrete measurements of water quality variables. If the time step of the measured time series is not sufficient to fully capture the variable's variability, the deduced indicator may not reflect the system's functioning. The goal of the present work is to assess, through a hydro-biogeochemical modeling approach, the optimal sampling frequency for an accurate estimation of 6 water quality indicators defined by the European Water Framework Directive (WFD) in a large human-impacted river, which receives large urban effluents (the Seine River across the Paris urban area). The optimal frequency depends on the sampling location and on the monitored variable. For fast varying compounds that originate from urban effluents, such as PO[Formula: see text], NH[Formula: see text] and NO[Formula: see text], a sampling time step of one week or less is necessary. To be able to reflect the highly transient character of bloom events, chl a concentrations also require a short monitoring time step. On the contrary, for variables that exert high seasonal variability, as NO[Formula: see text] and O 2, monthly sampling can be sufficient for an accurate estimation of WFD indicators in locations far enough from major effluents. Integrative water quality variables, such as O 2, can be highly sensitive to hydrological conditions. It would therefore be relevant to assess the quality of water bodies at a seasonal scale rather than at annual or pluri annual scales. This study points out the possibility to develop smarter monitoring systems by coupling both time adaptative automated monitoring networks and modeling tools used as spatio-temporal interpolators. PMID- 27457555 TI - Efficacy of Si fertilization to modulate the heavy metals absorption by barley (Hordeum vulgare L.) and pea (Pisum sativum L.). AB - Silicon-based fertilizers and soil amendments can have direct and indirect positive influences on cultivated plants. The solid forms of Si-based substances, the most widespread in use, are efficient only at high application rates due to their low level of solubility. Several types of Si-based substances such as fumed silica, slags from the iron and steel industry, modified slags, and a Si-rich product were tested using barley and pea as silicon accumulative and non accumulative plants, respectively, at two application rates. The plants were grown under toxic concentrations of heavy metals in a greenhouse. Si-rich materials high in water-soluble Si had a positive effect at both the low and high application rates, and for both plant species. This type of substance can be regarded as Si fertilizer, demonstrating greater efficiency at a low application rate and lessened efficiency at a high application rate for protection of the cultivated plants against accumulation of the heavy metals. PMID- 27457556 TI - Molybdenum (Mo) increases endogenous phenolics, proline and photosynthetic pigments and the phytoremediation potential of the industrially important plant Ricinus communis L. for removal of cadmium from contaminated soil. AB - Cadmium (Cd) in agricultural soil negatively affects crops yield and compromises food safety. Remediation of polluted soil is necessary for the re-establishment of sustainable agriculture and to prevent hazards to human health and environmental pollution. Phytoremediation is a promising technology for decontamination of polluted soil. The present study investigated the effect of molybdenum (Mo) (0.5, 1.0 and 2.0 ppm) on endogenous production of total phenolics and free proline, plant biomass and photosynthetic pigments in Ricinus communis plants grown in Cd (25, 50 and 100 ppm) contaminated soils and the potential for Cd phytoextraction. Mo was applied via seed soaking, soil addition and foliar spray. Foliar sprays significantly increased plant biomass, Cd accumulation and bioconcentration. Phenolic concentrations showed significantly positive correlations with Cd accumulation in roots (R 2 = 0.793, 0.807 and 0.739) and leaves (R 2 = 0.707, 721 and 0.866). Similarly, proline was significantly positively correlated with Cd accumulation in roots (R 2 = 0.668, 0.694 and 0.673) and leaves (R 2 = 0.831, 0.964 and 0.930). Foliar application was found to be the most effective way to deliver Mo in terms of increase in plant growth, Cd accumulation and production of phenolics and proline. PMID- 27457557 TI - Synthesis and Evaluation of Tricarbonyl (99m)Tc-Labeled 2-(4-Chloro)phenyl imidazo[1,2-a]pyridine Analogs as Novel SPECT Imaging Radiotracer for TSPO-Rich Cancer. AB - The 18-kDa translocator protein (TSPO) levels are associated with brain, breast, and prostate cancer progression and have emerged as viable targets for cancer therapy and imaging. In order to develop highly selective and active ligands with a high affinity for TSPO, imidazopyridine-based TSPO ligand (CB256, 3) was prepared as the precursor. (99m)Tc- and Re-CB256 (1 and 2, respectively) were synthesized in high radiochemical yield (74.5% +/- 6.4%, decay-corrected, n = 5) and chemical yield (65.6%) by the incorporation of the [(99m)Tc(CO)3(H2O)3]+ and (NEt4)2[Re(CO)3Br3] followed by HPLC separation. Radio-ligand 1 was shown to be stable (>99%) when incubated in human serum for 4 h at 37 degrees C with a relatively low lipophilicity (logD = 2.15 +/- 0.02). The rhenium-185 and -187 complex 2 exhibited a moderate affinity (Ki = 159.3 +/- 8.7 nM) for TSPO, whereas its cytotoxicity evaluated on TSPO-rich tumor cell lines was lower than that observed for the precursor. In vitro uptake studies of 1 in C6 and U87-MG cells for 60 min was found to be 9.84% +/- 0.17% and 7.87% +/- 0.23% ID, respectively. Our results indicated that (99m)Tc-CB256 can be considered as a potential new TSPO-rich cancer SPECT imaging agent and provides the foundation for further in vivo evaluation. PMID- 27457559 TI - Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase. AB - We report the first structure of heptaprenyl diphosphate synthase from Staphylococcus aureus (SaHepPPS), together with an investigation of its mechanism of action and inhibition. The protein is involved in the formation of menaquinone, a key electron transporter in many bacteria, including pathogens. SaHepPPS consists of a "catalytic " subunit (SaHepPPS-2) having two "DDXXD" motifs and a "regulatory" subunit (SaHepPPS-1) that lacks these motifs. High concentrations of the substrates, isopentenyl diphosphate and farnesyl diphosphate, inhibit the enzyme, which is also potently inhibited by bisphosphonates. The most active inhibitors (Ki ~200 nm) were N-alkyl analogues of zoledronate containing ~C6 alkyl side chains. They were modestly active against S. aureus cell growth, and growth inhibition was partially "rescued" by the addition of menaquinone-7. Because SaHepPPS is essential for S. aureus cell growth, its structure is of interest in the context of the development of menaquinone biosynthesis inhibitors as potential antibiotic leads. PMID- 27457560 TI - Effect of YH0618 soup on chemotherapy-induced toxicity in patients with cancer who have completed chemotherapy: study protocol for a randomized controlled trial. AB - BACKGROUND: The incidence of cancer has been staying at a high level worldwide in recent years. With advances in cancer diagnosis and therapy strategy, the survival rate of patients with cancer has been increasing, but the side effects of these treatments, especially chemotherapy, are obvious even when the chemotherapy ceases. YH0618, a prescription, has showed efficacy in reducing chemotherapy-induced toxicity through long clinical practice. However, there is no scientific research exploring the effects of YH0618 in patients with cancer. Therefore, using a randomized controlled trial, this study will explore the efficacy of YH0618 on ameliorating chemotherapy-induced toxicity including dermatologic toxicity, myelosuppression, hepatotoxicity and nephrotoxicity and improving fatigue in cancer patients who have completed chemotherapy. METHODS/DESIGN: This is a prospective assessor-blinded, parallel, randomized controlled trial. Patients with cancer at any stage who have completed chemotherapy within two weeks will be randomly divided into group A (YH0618) and group B (wait-list) using a 1:1 allocation ratio. The chemotherapeutic agents include taxanes or anthracyclines. Subjects assigned to group A will receive YH0618 soup 6 days a week for 6 weeks and uncontrolled follow-up for 6 weeks, while group B are required to wait for 6 weeks before receiving YH0618 intervention. The primary outcome of this study is the incidence of protocol specified grade >=2 dermatologic toxicities graded by NCI CTCAE Chinese version 4.0 and changes of fingernail color, face skin color and tongue color evaluated by the L*a*b system within 6 weeks. There are some secondary outcomes associated with dermatologic toxicity including fatigue and clinical objective examination. DISCUSSION: There are few scientific and safe methods in ameliorating chemotherapy-induced toxicity. The proposed study may provide direct and convincing evidence to support YH0618 as an adjuvant treatment for reducing chemotherapy-induced toxicity, which could be introduced into clinical settings. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-IOR-15006486 . Registered on 21 May 2015. PMID- 27457562 TI - Preliminary construction of integral analysis for characteristic components in complex matrices by in-house fabricated solid-phase microextraction fibers combined with gas chromatography-mass spectrometry. AB - Integral analysis plays an important role in study and quality control of substances with complex matrices in our daily life. As the preliminary construction of integral analysis of substances with complex matrices, developing a relatively comprehensive and sensitive methodology might offer more informative and reliable characteristic components. Flavoring mixtures belonging to the representatives of substances with complex matrices have now been widely used in various fields. To better study and control the quality of flavoring mixtures as additives in food industry, an in-house fabricated solid-phase microextraction (SPME) fiber was prepared based on sol-gel technology in this work. The active organic component of the fiber coating was multi-walled carbon nanotubes (MWCNTs) functionalized with hydroxyl-terminated polydimethyldiphenylsiloxane, which integrate the non-polar and polar chains of both materials. In this way, more sensitive extraction capability for a wider range of compounds can be obtained in comparison with commercial SPME fibers. Preliminarily integral analysis of three similar types of samples were realized by the optimized SPME-GC-MS method. With the obtained GC-MS data, a valid and well-fit model was established by partial least square discriminant analysis (PLS-DA) for classification of these samples (R2X=0.661, R2Y=0.996, Q2=0.986). The validity of the model (R2=0.266, Q2=-0.465) has also approved the potential to predict the "belongingness" of new samples. With the PLS-DA and SPSS method, further screening out the markers among three similar batches of samples may be helpful for monitoring and controlling the quality of the flavoring mixtures as additives in food industry. Conversely, the reliability and effectiveness of the GC-MS data has verified the comprehensive and efficient extraction performance of the in-house fabricated fiber. PMID- 27457561 TI - Repeatability of gradient ultrahigh pressure liquid chromatography-tandem mass spectrometry methods in instrument-controlled thermal environments. AB - The impact of viscous friction on eluent temperature and column efficiency in liquid chromatography is of renewed interest as the need for pressures exceeding 1000bar to use with columns packed with sub-2MUm particles has grown. One way the development of axial and radial temperature gradients that arise due to viscous friction can be affected is by the thermal environment the column is placed in. In this study, a new column oven integrated into an ultrahigh pressure liquid chromatograph that enables both still-air and forced-air operating modes is investigated to find the magnitude of the effect of the axial thermal gradient that forms in 2.1*100mm columns packed with sub-2MUm particles in these modes. Temperature increases of nearly 30K were observed when the generated power of the column exceeded 25W/m. The impact of the heating due to viscous friction on the repeatability of peak capacity, elution time, and peak area ratio to an internal standard for a gradient UHPLC-MS/MS method to analyze neurotransmitters was found to be limited. This result indicates that high speed UHPLC-MS/MS gradient methods under conditions of high viscous friction may be possible without the negative effects typically observed with isocratic separations under similar conditions. PMID- 27457564 TI - A Synergistic Treatment Strategy for Severe Obsessive Compulsive Disorder. PMID- 27457563 TI - Association of rs1137101 polymorphism in LEPR and susceptibility to knee osteoarthritis in a Northwest Chinese Han population. AB - BACKGROUND: Osteoarthritis (OA) is a complex arthritic condition in which the genetic factor plays a crucial role. A single nucleotide polymorphism (SNP), rs1137101 (Gln223Arg) of leptin receptor (LEPR) gene has been demonstrated to be associated with susceptibility to knee OA. However, this association in Chinese Han population has never been examined. The present study aimed to investigate whether Gln223Arg was related to knee OA susceptibility in a Northwest Chinese population with Han ethnicity. METHODS: Gln223Arg polymorphisms were genotyped in 587 patients with confirmed knee OA and in 628 age- and sex-matched healthy controls using polymerase chain reaction-restriction fragment length polymorphism analysis. Besides, LEPR genotypes were verified by direct DNA sequencing analysis on PCR products. RESULTS: The genotype and allele frequencies in LEPR SNP rs1137101 were significantly different between cases and control groups (chi square = 6.52, P = 0.038 for genotype and chi-square = 5.06, P = 0.024 for allele frequencies; respectively). Rs1137101 was correlated with knee OA in the dominant genetic model (GG + GA versus AA) (P = 0.016) and a higher G allele frequency existed (P = 0.024) among all patients with knee OA and controls. On stratification analysis, the genotype GG and G allele were associated with susceptibility to knee OA in females, both young (<=65 years) and old groups (>65 years) and patients with mild knee OA. CONCLUSIONS: Our finding suggested that the genetic variant of LEPR gene rs1137101 is independently related to knee OA susceptibility in Northwest Chinese population with Han ethnicity and may serve as a potential biomarker to determine risk of knee OA. PMID- 27457558 TI - Genetically modified laboratory mice with sebaceous glands abnormalities. AB - Sebaceous glands (SG) are exocrine glands that release their product by holocrine secretion, meaning that the whole cell becomes a secretion following disruption of the membrane. SG may be found in association with a hair follicle, forming the pilosebaceous unit, or as modified SG at different body sites such as the eyelids (Meibomian glands) or the preputial glands. Depending on their location, SG fulfill a number of functions, including protection of the skin and fur, thermoregulation, formation of the tear lipid film, and pheromone-based communication. Accordingly, SG abnormalities are associated with several diseases such as acne, cicatricial alopecia, and dry eye disease. An increasing number of genetically modified laboratory mouse lines develop SG abnormalities, and their study may provide important clues regarding the molecular pathways regulating SG development, physiology, and pathology. Here, we summarize in tabulated form the available mouse lines with SG abnormalities and, focusing on selected examples, discuss the insights they provide into SG biology and pathology. We hope this survey will become a helpful information source for researchers with a primary interest in SG but also as for researchers from unrelated fields that are unexpectedly confronted with a SG phenotype in newly generated mouse lines. PMID- 27457566 TI - Attentional avoidance of fearful facial expressions following early life stress is associated with impaired social functioning. AB - BACKGROUND: Early life stress is associated with poorer social functioning. Attentional biases in response to threat-related cues, linked to both early experience and psychopathology, may explain this association. To date, however, no study has examined attentional biases to fearful facial expressions as a function of early life stress or examined these biases as a potential mediator of the relation between early life stress and social problems. METHODS: In a sample of 154 children (ages 9-13 years) we examined the associations among interpersonal early life stressors (i.e., birth through age 6 years), attentional biases to emotional facial expressions using a dot-probe task, and social functioning on the Child Behavior Checklist. RESULTS: High levels of early life stress were associated with both greater levels of social problems and an attentional bias away from fearful facial expressions, even after accounting for stressors occurring in later childhood. No biases were found for happy or sad facial expressions as a function of early life stress. Finally, attentional biases to fearful faces mediated the association between early life stress and social problems. CONCLUSIONS: Attentional avoidance of fearful facial expressions, evidenced by a bias away from these stimuli, may be a developmental response to early adversity and link the experience of early life stress to poorer social functioning. PMID- 27457569 TI - Platelet PDGF and TGF-beta Levels in Myeloproliferative Disorders. AB - Myeloproliferative disorders mainly including essential thrombocythemia, polycythemia vera, chronic myeloid leukemia and myelofibrosis with myeloid metaplasia are clonal myeloproliferative diseases in which myelofibrosis is commonly observed. The pathogenesis of myelofibrosis still remains unclear. However it was proposed that an inappropriate release of PDGF from either megakaryocytes in bone marrow or platelets in circulation might promote medullary fibrosis. Recently the role of another peptide growth factor, namely TGF-beta, in the fibrotic process was emphasized. This review will focus on the different studies aimed at the evaluation of intraplatelet PDGF and TGF-beta content in patients with the various MPD, and outline the salient results lending support to the potential role of PDGF and TGF-beta in the promotion of myelofibrosis. PMID- 27457567 TI - Prognostic value of decreased FOXP1 protein expression in various tumors: a systematic review and meta-analysis. AB - The prognostic value of forkhead box protein P1 (FOXP1) protein expression in tumors remains controversial. Therefore, we conducted a systematic review and meta-analysis, searching the PubMed, Embase and Web of Science databases to identify eligible studies. In total, we analyzed 22 articles that examined 9 tumor types and included 2468 patients. Overall, decreased expression of FOXP1 protein was associated with favorable overall survival (OS) in lymphoma patients (HR = 0.38, 95%CI: 0.30-0.48, p < 0.001). In patients with solid tumors, decreased FOXP1 expression correlated with unfavorable OS (HR = 1.82, 95%CI: 1.18 2.83, p = 0.007). However, when FOXP1 protein expression was nuclear, decreased expression was also associated with favorable OS (HR = 0.53, 95%CI: 0.32-0.86, p = 0.011). Furthermore, decreased FOXP1 expression resulted in the best OS in patients with mucosa-associated lymphoid tissue (MALT) lymphomas (HR = 0.26, 95%CI: 0.11-0.59, p = 0.001), but the worst OS was observed in non-small cell lung cancer (NSCLC) patients (HR = 3.11, 95%CI: 1.87-5.17, p < 0.001). In addition, decreased FOXP1 expression was significantly correlated with an unfavorable relapse-free survival (RFS) in breast cancer patients (HR = 1.93, 95%CI: 1.33-2.80, p = 0.001). PMID- 27457568 TI - Music therapy in Huntington's disease: a protocol for a multi-center randomized controlled trial. AB - BACKGROUND: Huntington's disease is a progressive, neurodegenerative disease with autosomal dominant inheritance, characterized by motor disturbances, cognitive decline and behavioral and psychological symptoms. Since there is no cure, all treatment is aimed at improving quality of life. Music therapy is a non pharmacological intervention, aiming to improve the quality of life, but its use and efficacy in patients with Huntington's disease has hardly been studied. In this article, a protocol is described to study the effects of music therapy in comparison with a control intervention to improve quality of life through stimulating expressive and communicative skills. By targeting these skills we assume that the social-cognitive functioning will improve, leading to a reduction in behavioral problems, resulting in an overall improvement of the quality of life in patients with Huntington's disease. METHODS/DESIGN: The study is designed as a multi-center single-blind randomised controlled intervention trial. Sixty patients will be randomised using centre-stratified block-permuted randomisation. Patients will be recruited from four long-term care facilities specialized in Huntington's disease-care in The Netherlands. The outcome measure to assess changes in expressive and communication skills is the Behaviour Observation Scale Huntington and changes in behavior will be assessed by the Problem Behaviour Assesment-short version and by the BOSH. Measurements take place at baseline, then 8, 16 (end of intervention) and 12 weeks after the last intervention (follow up). DISCUSSION: This randomized controlled study will provide greater insight into the effectiveness of music therapy on activities of daily living, social cognitive functioning and behavior problems by improving expressive and communication skills, thus leading to a better quality of life for patients with Huntington's disease. TRIAL REGISTRATION: Netherlands Trial Register: NTR4904 , registration date Nov. 15, 2014. PMID- 27457570 TI - Thymosin beta4 Gene Expression in Leukemic Cells. AB - Thymosin beta4 (Tbeta4) was originally isolated as a thymic hormone from calf thymosin fraction 5 which exhibited both immune and endocrine functions in vivo and in vitro. Tbeta4 is a ubiquitous peptide located in various tissues of mammalian species and other vertebrate classes. Recent studies on the molecular cloning and sequence analysis of rat and human Tbeta4 cDNA have demonstrated that Tbeta4 lacks a signal peptide which makes it unlikely that Tbeta4 is a secretory peptide. The real function of Tbeta4 is presently unknown, however, we focus this review on the molecular biology of Tbeta4 with a special reference to the aspects of the Tbeta4 gene expression in leukemic cells and cell lines during growth and differentiation. PMID- 27457571 TI - Results of Therapy for Acute Myeloid Leukemia in First Relapse. AB - Fifty-four consecutive patients with acute myeloid leukemia (AML) in first relapse presenting at a single institution were studied to determine factors affecting response to re-induction therapy. For purposes of analysis, re treatment protocols were grouped into two categories, one with high dose and the other with standard dose cytosine arabinoside. Most regimens also included an anthracycline, mitoxantrone or amsacrine. Thirty-one of the 51 patients (61%) who received therapy achieved a second complete remission (CR-2). Median duration of CR-2 was 6 months (range 1-24+ months). Five patients remain in CR-2, three of whom received bone marrow transplants (median follow-up 24 months). The variables, age, gender, FAB subtype, leukocyte and platelet count, duration of CR 1, the initial and re-induction regimens were analyzed for prognostic value in attaining and maintaining CR-2. Only younger age (p < 0.001) and longer CR-1 duration (p < 0.05) were significantly correlated with greater likelihood of attaining CR-2 with univariate analysis, and only age was correlated with CR-2 rate using multivariate analysis (p = 0.018). Younger age was associated with longer CR-2 duration (p = 0.003) using multivariate analysis, a correlation that persisted when transplanted patients were excluded. There was no advantage to the use of high dose versus standard dose cytosine arabinoside in the reinduction regimen with respect to the ability to either achieve or sustain CR-2. Our data indicate that although the remission induction rate for AML in first relapse is high, remissions are brief and other strategies are required to improve outcome of patients in second remission. PMID- 27457572 TI - A Pilot Study Using Intravenous Immunoglobulin for the Prevention of Infection During Remission Induction in Acute Leukaemia. AB - Overwhelming infections cause significant morbidity and mortality in the immunocompromised host. There is considerable in vitro and in vivo evidence that the immune deficient state which accompanies acute leukaemia, and, is exacerbated by intensive chemotherapy, contributes to the infection risk in these patients. The most easily documented and corrected is that of impaired humoral immunity. In order to study the clinical significance of the deficit a double blind, randomised, placebo controlled pilot study was set up designed to test the feasibility, efficacy and toxicity of using prophylactic intravenous immunoglobulin to prevent infective complications in this patient group. Patients received 150 mg/kg of Pentaglobin, an immunoglobulin preparation specifically enriched in IgM and IgA, on days 0, 10 and 20 of the chemotherapy regimes. There were no adverse side effects. Patients in the placebo group had a 25% fall in IgM level whilst IgG and IgA remained unchanged. The treatment group maintained a stable IgM and IgG concentration throughout but had a rise in IgA. There was no difference in the total number of septicaemic episodes in each group but the placebo group had an increased number of non Staphylococcal infections (P < 0.04). We conclude that intravenous Pentaglobin protects patients against a fall in IgM during induction chemotherapy for acute leukaemia and decreases the number of non Staphylococcal infections. PMID- 27457573 TI - Prediction of Outcome in Diffuse Large Cell Lymphoma by the Major Histocompatibility Complex Class II (HLA-DR, DP, DQ) and Class I (HLA-A, B, C) Phenotype. AB - Ninety-nine consecutive diffuse large cell lymphoma (DLCL) patients were studied by immunohistochemistry to determine whether clinical outcome was predicted by major histocompatibility complex (MHC) antigen phenotypic expression. Statistically significantly shorter disease free survival (p = 0.005), but not overall survival (p = 0.47), was observed when patient lymphomas failed to express class I MHC antigens. We also observed significantly reduced survival of class II MHC HLA-DP negative patients (p = 0.038). This extends our previous finding of poor outcome with absent class II MHC HLA-DR in DLCL(1) to other MHC antigens and demonstrates that the phenomenon of defective class II antigen expression comprises 16% of these DLCL patients. Known clinical parameters predictive of prognosis were equally distributed between phenotypic groups. These findings indicate that aberrancy of immune phenotype in DLCL is critical to patient outcome and we speculate that loss of MHC expression may confound host immunosurveillance and tumor containment. PMID- 27457574 TI - Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Chemotherapy Related Neutropenia in Patients with Non-Hodgkin's Lymphomas-A Phase I/II Study of Dose and Mode of Administration. AB - The effect of mammalian glycosylated recombinant granulocyte-macrophage colony stimulating factor was investigated in 24 patients with newly diagnosed non Hodgkin's lymphoma in a phase I/II study. All patients received standard chemotherapy with CHOP. RhGM-CSF was administered after the first cycle for 5 days, and at one of four dose levels (2, 4, 8 and 16 MUg/kg). Patients were randomized to receive the drug either by continuous intravenous infusion or twice daily as subcutaneous injection. No significant difference in results was observed between subcutaneous administration of rhGM-CSF and continuous i.v. infusion and these patient groups could therefore be combined in the analysis. Administration of rhGM-CSF resulted in a significant dose-dependent increase of total WBC, mainly neutrophils, eosinophils and monocytes. The increase was observed in 18/24 patients, reaching a peak 24-72 (median 24) hours after the start of rhGM-CSF. The CHOP chemotherapy-induced leucocyte nadir occurred on day 12 (mean) compared to day 14 for the 127 historical controls. The WBC nadir values were higher (2.4 +/- 1.4) than for historical controls (1.8 +/- 1.1) and the leucopenic/neutropenic period was of shorter duration. Following the chemotherapy nadir a more rapid recovery of WBC was seen than in controls. GM-CSF was well tolerated, the side effects were mild and transient, and included myalgias, low grade fever, headache, chest/bone discomfort, nausea, erythema at injection site and superficial phlebitis. The encouraging results of this phase I/II study indicate the need for a prospective controlled study of GM-CSF in chemotherapy of malignant lymphoma. PMID- 27457575 TI - Mediastinal Clear Cell Lymphoma-A Distinct Entity of B-Cell Derived Lymphoma as Shown by Immunotyping and Analysis of Gene Rearrangements. AB - Mediastinal clear cell lymphoma (MCCL) is regarded as a distinct subtype of Non Hodgkin's-lymphoma. We have analyzed gene rearrangements of eight cases of newly diagnosed MCCL in order to verify their alignment to the B-cell lineage as suggested by immunotyping. The lymphoma cells shared a common immunophenotype which consisted of CD10-, CD19+, CD20+, and CD21-. Rearrangements of the heavy chain of the immunoglobulin gene were found in all eight cases studied. In contrast, the beta chain of the T-cell antigen receptor gene was not rearranged. No rearrangements of the kappa light chain gene were detected. There was no evidence for a t(14;18) or a t(8;14). In conclusion, MCCL seems to be a B-cell derived tumor, which is distinct from other known lymphomas both by its immunophenotype and genotype. PMID- 27457576 TI - High Dose, Short Duration Combination Chemotherapy (MEGA III) for Patients with High Grade Poor Prognosis Non-Hodgkin's Lymphoma-A Phase I/II Study. AB - 16 patients with histologically high grade poor prognosis non-Hodgkin's lymphoma were treated with high-dose, short duration combination chemotherapy (MEGA III). 14 patients had de novo disease and 2 patients primary refractory lymphoma. The 2 patients with primary refractory disease both died, 1 of disease progression and 1 of toxicity of the regimen. However, the complete response rate observed among the 14 de novo patients was nearly 85%. With a maximum follow-up period of 20 months, 2 patients have relapsed, one after 6 months and another after 7 months respectively. Toxicities were common and mainly related to mucositis and pancytopenia. The use of haemopoietic growth factors in these patients to shorten the periods of pancytopenia may reduce the mortality and morbidity of this regimen and should be explored. PMID- 27457577 TI - Phase II Trial of Fludarabine Phosphate in Multiple Myeloma Using a Loading Dose and Continuous Infusion Schedule. AB - A phase II trial of fludarabine phosphate using a bolus and continuous infusion regimen in previously treated multiple myeloma was performed. No responses were observed in eleven patients. There was no significant non-hematologic toxicity noted. Fludarabine phosphate is inactive in multiple myeloma using this schedule. PMID- 27457578 TI - Impaired Cytotoxic Activity of Interleukin 2 (IL 2)-cultured Large Granular Lymphocytes (LGL) in Childhood Acute Lymphoblastic Leukemia. Quantitative Measurement of IL 2 Receptor Expression of IL 2-cultured LGL. AB - Large granular lymphocytes (LGL) of the natural killer (NK) cell lineage were highly purified and their interleukin 2 (IL 2) receptors (IL 2R) were investigated in childhood acute lymphoblastic leukemia (ALL). Not only NK activity but also 3-day recombinant IL 2-cultured lymphokine activated killer (LAK) activity were decreased in ALL, despite normal percentages of LGL, CD16 (Leul1)(+) and CD56 (NKH1)(+) cells. The cytotoxic activity of IL 2-cultured LGL, but not IL 2-cultured T cells, was significantly decreased in ALL, indicating a selective defect of LGL among the killer cells. IL 2R (CD25) numbers/cell of 3 day IL 2-cultured LGL were not decreased in ALL by flow cytometric analysis. Scatchard plot analysis demonstrated that high affinity IL 2R numbers/cell of 3 day IL 2-cultured LGL were normal but the binding affinity level of the receptors in these cells in ALL was one-third of that in the similarly-cultured control cells, suggesting inadequate IL 2-IL 2R interaction is responsible, at least in part, for their reduced cytotoxic activity. PMID- 27457579 TI - Interactions Between Antibody-Coated Iron Micro-Particles and Leukemic Cells as seen by Electron Microscopy. AB - An electron microscopy study was performed to visualize the interactions between monoclonal antibodies (MoAbs) coated to ferromagnetic microparticles and leukemic cells. The properties of this specific reagent used for the efficient purging of residual leukemic cells from autografts before autologuous bone marrow transplantation (ABMT) have been previously reported. Incubation of a CD10+ NALM6 cell suspension with CD10 or CD8 MoAb conjugated particles was performed following a time-course schedule ranging from 0 to 90 min. at 4 degrees C and 37 degrees C. Transmission electron microscopy demonstrated that, although the CD10 MoAb-particles complex linked to the cell surface only at 4 degrees C, they readily penetrated into cells at 37 degrees C. In contrast, after incubation with CD8 MoAb-particles, no iron particles were seen at the cell surface, or within the cells no matter what the temperature and duration of the incubation were. This observation offers the unique opportunity to deliver a pharmaceutical agent crosslinked to the same magnetic carrier inside a cell, using an interesting site specific drug delivery concept. PMID- 27457580 TI - Immunophenotypes and Gene Rearrangements of the T-Cell Receptor in Two Patients with a Large Granular Lymphocyte Disorder. AB - Large granular lymphocyte disorder (LGLD) is a lymphoproliferative disease, characterized by moderate lymphocytosis with an excess of large granular lymphocytes, neutropenia, anemia, and a variable, but mostly chronic clinical course. We describe two patients with LGLD. One patient presented with symptomatic corticoster-oid-responsive hemolytic anemia, while the other had a chronic course not requiring therapy. The majority of lymphocytes from both patients were CD8 + T lymphocytes. However, the cells from the two patients differed in the molecular pattern of the T cell receptor (TCR), and this may explain the difference in their clinical course. PMID- 27457581 TI - Herpes simplex encephalitis is linked with selective mitochondrial damage; a post mortem and in vitro study. AB - Herpes simplex virus type-1 (HSV-1) encephalitis (HSE) is the most commonly diagnosed cause of viral encephalitis in western countries. Despite antiviral treatment, HSE remains a devastating disease with high morbidity and mortality. Improved understanding of pathogenesis may lead to more effective therapies. Mitochondrial damage has been reported during HSV infection in vitro. However, whether it occurs in the human brain and whether this contributes to the pathogenesis has not been fully explored. Minocycline, an antibiotic, has been reported to protect mitochondria and limit brain damage. Minocycline has not been studied in HSV infection. In the first genome-wide transcriptomic study of post mortem human HSE brain tissue, we demonstrated a highly preferential reduction in mitochondrial genome (MtDNA) encoded transcripts in HSE cases (n = 3) compared to controls (n = 5). Brain tissue exhibited a significant inverse correlation for immunostaining between cytochrome c oxidase subunit 1 (CO1), a MtDNA encoded enzyme subunit, and HSV-1; with lower abundance for mitochondrial protein in regions where HSV-1 was abundant. Preferential loss of mitochondrial function, among MtDNA encoded components, was confirmed using an in vitro primary human astrocyte HSV-1 infection model. Dysfunction of cytochrome c oxidase (CO), a mitochondrial enzyme composed predominantly of MtDNA encoded subunits, preceded that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Minocycline treated astrocytes exhibited higher CO1 transcript abundance, sustained CO activity and cell viability compared to non-treated astrocytes. Based on observations from HSE patient tissue, this study highlights mitochondrial damage as a critical and early event during HSV-1 infection. We demonstrate minocycline preserves mitochondrial function and cell viability during HSV-1 infection. Minocycline, and mitochondrial protection, offers a novel adjunctive therapeutic approach for limiting brain cell damage and potentially improving outcome among HSE patients. PMID- 27457584 TI - Incidence of acute otitis media in children below 6 years of age seen in medical practices in five East European countries. AB - BACKGROUND: Although acute otitis media (AOM) remains a major public health problem worldwide and brings economic burden on health care system and caregivers, little information is available about its epidemiology in Eastern Europe. METHODS: We conducted an epidemiological, prospective, observational, multi-centre cohort study (NCT01365390) in five East European countries (Estonia, Lithuania, Poland, Romania and Slovenia) between June 2011 and January 2013 to determine the incidence and clinical characteristics of AOM among children aged < 6 years during 1 year. RESULTS: AOM incidence was 160.7 cases (95 % confidence interval [CI]: 144.7-177.9) per 1000 person-years (PY) being the lowest in the < 1 year age group (92.3 cases [95 % CI: 59.7-136.2] per 1000 PY) and the highest in the 3- < 4 years age group (208.9 cases [95 % CI: 165.1-260.7] per 1000 PY). AOM incidence was similar across the countries, with the exception of Slovenia (340.3 cases [95 % CI: 278.3-412.0] per 1000 PY). There was a lower risk in breastfed children and a higher risk in those attending school/childcare or with allergies. AOM required 521 visits to the doctor. Antibiotics were prescribed for 276 (74.8 %) episodes with the lowest prescription rate in Estonia (51.4 %) and the highest in Romania (83.7 %). Complications were rare and hospitalisations occurred in 2 % of the cases. CONCLUSIONS: The disease burden of AOM in Eastern Europe is relevant and public health initiatives to reduce it should be considered. TRIAL REGISTRATION: ClinicalTrial.gov NCT01365390 . PMID- 27457582 TI - The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside. AB - At the beginning of the twenty-first century, 3-bromopyruvate (3BP), a simple alkylating chemical compound was presented to the scientific community as a potent anticancer agent, able to cause rapid toxicity to cancer cells without bystander effects on normal tissues. The altered metabolism of cancers, an essential hallmark for their progression, also became their Achilles heel by facilitating 3BP's selective entry and specific targeting. Treatment with 3BP has been administered in several cancer type models both in vitro and in vivo, either alone or in combination with other anticancer therapeutic approaches. These studies clearly demonstrate 3BP's broad action against multiple cancer types. Clinical trials using 3BP are needed to further support its anticancer efficacy against multiple cancer types thus making it available to more than 30 million patients living with cancer worldwide. This review discusses current knowledge about 3BP related to cancer and discusses also the possibility of its use in future clinical applications as it relates to safety and treatment issues. PMID- 27457585 TI - Gibberellin-Regulation and Genetic Variations in Leaf Elongation for Tall Fescue in Association with Differential Gene Expression Controlling Cell Expansion. AB - Leaf elongation rate (LER) is an important factor controlling plant growth and productivity. The objective of this study was to determine whether genetic variation in LER for a fast-growing ('K-31'), and a dwarf cultivar ('Bonsai') of tall fescue (Festuca arundinacea) and gibberellic acid (GA) regulation of LER were associated with differential expression of cell-expansion genes. Plants were treated with GA3, trinexapac-ethyl (TE) (GA inhibitor), or water (untreated control) in a hydroponic system. LER of 'K-31' was 63% greater than that of 'Bonsai', which corresponded with 32% higher endogenous GA4 content in leaf and greater cell elongation and production rates under the untreated control condition. Exogenous application of GA3 significantly enhanced LER while TE treatment inhibited leaf elongation due to GA3-stimulation or TE-inhibition of cell elongation and production rate in leaves for both cultivars. Real-time quantitative polymerase chain reaction analysis revealed that three alpha expansins, one beta-expansin, and three xyloglucan endotransglycosylase (XET) genes were associated with GA-stimulation of leaf elongation, of which, the differential expression of EXPA4 and EXPA7 was related to the genotypic variation in LER of two cultivars. Those differentially-expressed expansin and XET genes could play major roles in genetic variation and GA-regulated leaf elongation in tall fescue. PMID- 27457586 TI - Wildfires and water chemistry: effect of metals associated with wood ash. AB - The reactivity of metals associated with ash from wood collected from the Valles Caldera National Preserve, Jemez Mountains, New Mexico, was assessed through a series of laboratory experiments. Microscopy, spectroscopy, diffraction, and aqueous chemistry measurements were integrated to determine the chemical composition of wood ash and its effect on water chemistry. Climate change has caused dramatic impacts and stresses that have resulted in large-scale increases in wildfire activity in semi-arid areas of the world. Metals and other constituents associated with wildfire ash can be transported by storm event runoff and negatively affect the water quality in streams and rivers. Differences among ash from six tree species based on total concentrations of metals such as Ca, Al, Mg, Fe, and Mn were identified using non-metric multidimensional analysis. Metal-bearing carbonate and oxide phases were quantified by X-ray diffraction analyses and X-ray spectroscopy analyses. These metal-bearing carbonate phases were readily dissolved in the first 30 minutes of reaction with 18 MOmega water and 10 mM HCO3(-) in laboratory batch experiments which resulted in the release of metals and carbonates in the ash, causing water alkalinity to increase. However, metal concentrations decreased over the course of the experiment, suggesting that metals re-adsorb to ash. Our results suggest that the dissolution of metal-bearing carbonate and oxide phases in ash and metal re adsorption to ash are relevant processes affecting water chemistry after wildfire events. These results have important implications to better understand the impact of wildfire events on water quality. PMID- 27457587 TI - An overview of siderophores for iron acquisition in microorganisms living in the extreme. AB - Siderophores are iron-chelating molecules produced by microbes when intracellular iron concentrations are low. Low iron triggers a cascade of gene activation, allowing the cell to survive due to the synthesis of important proteins involved in siderophore synthesis and transport. Generally, siderophores are classified by their functional groups as catecholates, hydroxamates and hydroxycarboxylates. Although other chemical structural modifications and functional groups can be found. The functional groups participate in the iron-chelating process when the ferri-siderophore complex is formed. Classified as acidophiles, alkaliphiles, halophiles, thermophiles, psychrophiles, piezophiles, extremophiles have particular iron requirements depending on the environmental conditions in where they grow. Most of the work done in siderophore production by extremophiles is based in siderophore concentration and/or genomic studies determining the presence of siderophore synthesis and transport genes. Siderophores produced by extremophiles are not well known and more work needs to be done to elucidate chemical structures and their role in microorganism survival and metal cycling in extreme environments. PMID- 27457589 TI - Letters. PMID- 27457591 TI - Brief reports. PMID- 27457592 TI - Discover-or Reveal-Yourself Through Tennis. PMID- 27457593 TI - A Challenge and an Opportunity. PMID- 27457594 TI - Coping With Summer's Bummer-Sunburn. PMID- 27457595 TI - Coping With Your Patients' Summer Bummer-Sunburn. PMID- 27457596 TI - A Look Back Shows Much Left to Do. PMID- 27457588 TI - Iron uptake and transport across physiological barriers. AB - Iron is an essential element for human development. It is a major requirement for cellular processes such as oxygen transport, energy metabolism, neurotransmitter synthesis, and myelin synthesis. Despite its crucial role in these processes, iron in the ferric form can also produce toxic reactive oxygen species. The duality of iron's function highlights the importance of maintaining a strict balance of iron levels in the body. As a result, organisms have developed elegant mechanisms of iron uptake, transport, and storage. This review will focus on the mechanisms that have evolved at physiological barriers, such as the intestine, the placenta, and the blood-brain barrier (BBB), where iron must be transported. Much has been written about the processes for iron transport across the intestine and the placenta, but less is known about iron transport mechanisms at the BBB. In this review, we compare the established pathways at the intestine and the placenta as well as describe what is currently known about iron transport at the BBB and how brain iron uptake correlates with processes at these other physiological barriers. PMID- 27457597 TI - Leg Pains in Runners. PMID- 27457598 TI - Leg Pains in Runners. PMID- 27457599 TI - Cme credit quiz no. 19. PMID- 27457601 TI - Cme credit quiz no. 21. PMID- 27457600 TI - Effect of the Menstrual Cycle on Maximum Oxygen Uptake. PMID- 27457603 TI - Olympic Lifting Movements Endanger Adolescents. PMID- 27457602 TI - Legal Responsibilities and Sportsmedicine. PMID- 27457604 TI - Muscle Rehabilitation After Knee Surgery. PMID- 27457605 TI - Cardiac Effects of Running in Untrained College Men. PMID- 27457606 TI - In Activity Therapy, Patients Literally Move Toward Mental Health. PMID- 27457607 TI - Preventing Chest and Upper Abdominal Pain Associated With Exercise. PMID- 27457608 TI - Scanning sports. PMID- 27457609 TI - A need to know. PMID- 27457611 TI - Ion-Step Method for Surface Potential Sensing of Silicon Nanowires. AB - This paper presents a novel stimulus-response method for surface potential sensing of silicon nanowire (Si-NW) field-effect transistors. When an "ion-step" from low to high ionic strength is given as a stimulus to the gate oxide surface, an increase of double layer capacitance is therefore expected. Thus, a change of conductance through the Si-NWs is measured. The surface potential on the Si-NW gate is changed from negative for a bare SiO2 surface to neutral/positive when there is poly-l-lysine adsorption at certain pH, which also indicates a shift of point-of-zero charge pH after surface modification. This change is measured by a drop of current variation at the ion-step. The ion-step is performed to the Si-NW through a polydimethylsiloxane microfluidic chip with automatic sample switching. A reduction of the ion-step response from 2 nA to almost zero at pH 5.0 is observed by increasing the potassium ion concentration from 10 mM to 50 mM, which corresponds to a surface potential change of ~12 mV. We show that this method can be used as an alternative method for surface potential sensing, making it less sensitive to drift. PMID- 27457610 TI - Structure-guided development of heterodimer-selective GPCR ligands. AB - Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design of novel molecular probes and drugs. Here we report the structure guided design, chemical synthesis and biological investigations of bivalent ligands for dopamine D2 receptor/neurotensin NTS1 receptor (D2R/NTS1R) heterodimers. The compounds of types 1-3 consist of three different D2R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS1R agonist NT(8-13). The bivalent ligands show binding affinity in the picomolar range for cells coexpressing both GPCRs and unprecedented selectivity (up to three orders of magnitude), compared with cells that only express D2Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D2Rs but stimulating cAMP accumulation in D2R/NTS1R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1R-mediated beta-arrestin-2 recruitment at the D2R/NTS1R-coexpressing cells. PMID- 27457612 TI - Dabigatran Versus Warfarin for Direct Current Cardioversion in Atrial Fibrillation. AB - INTRODUCTION: Direct current cardioversion (DCCV) is considered as the most effective treatment for atrial fibrillation (AF). AF is associated with an increased risk of thromboembolism, and DCCV may increase this risk. The current recommendation is, therefore, to anticoagulate for at least 3 weeks before DCCV and 4 weeks after the procedure. METHODS: A retrospective study of patients referred for elective DCCV as treatment for AF in Hampshire Hospitals NHS Foundation Trust was performed to compare the safety and efficacy of dabigatran with warfarin in this setting. RESULTS: During a 12-month period, 129 patients were referred for DCCV for the treatment of AF and 107 patients received DCCV. Fifty-four patients were anticoagulated with dabigatran, 42 patients with warfarin, and 11 patients with other direct oral anticoagulants (DOACs) with choice of agent determined following an informed discussion with the patient. The average number of days between the date of referral for DCCV and the date of DCCV for patients who were on dabigatran was 51 days, while for warfarin, this was 82 (P = 0.001). The proportion of cancelation and rescheduling for warfarin patients was 21.4%, while for dabigatran, this was 5.5%. Patients were reviewed 6-20 weeks after DCCV; the success rate of DCCV for dabigatran patients was 61%, whilst for warfarin patients, this was 52%. The success rate went up to 69% for patients who received DCCV within 45 days of referral (P = 0.165). CONCLUSION: This retrospective study supports clinical experience that DCCV is more likely to be successful when there is a shorter duration between the onset of AF and the date of DCCV, and shows that the use of dabigatran in comparison with warfarin facilitates earlier DCCV. PMID- 27457613 TI - A Systematic Literature Review on the Cost-Effectiveness of Apixaban for Stroke Prevention in Non-valvular Atrial Fibrillation. AB - INTRODUCTION: Economic evaluations are becoming increasingly important due to limitations in economic resources, the expense of many new treatments, the need to allocate health spending as effectively as possible, and the need to inform decision makers. Based on the data from the apixaban studies (ARISTOTLE and AVERROES), several economic evaluations have been performed in various countries to demonstrate the efficacy of apixaban versus warfarin and aspirin or other new oral anticoagulants (NOACs) for preventing stroke in patients with non-valvular atrial fibrillation (NVAF).The aim of this study was to perform a systematic literature review of published economic evaluations with apixaban in the indication of stroke prevention in patients with NVAF. METHODS: A search in PubMed, Cochrane Library, Google Scholar, and Index Medicus Espanol was conducted in June 2015. Inclusion and exclusion criteria were established. The main characteristics were recorded for all relevant articles after being reviewed. In addition, a weighted version of the Drummond's checklist was used to further assess the quality of the selected studies. RESULTS: After review, 26 cost effectiveness analyses through Markov models were included; the identified economic evaluations represent different willingness-to-pay (WTP) thresholds, discount rates, medical costs, and healthcare systems. Apixaban was compared with warfarin/acenocoumarol in 7 of them (27%), with warfarin/NOACs in 14 (54%), with aspirin in 2 (8%), and with warfarin/aspirin in 3 (11%). Models were conducted from Europe (69%), USA (23%), Australia (4%), and Latin America (4%). All models reported cost/quality-adjusted life years (QALYs) gained, 92% reported using a payer perspective, and 8% using a societal perspective; the median quality score of the selected studies was 89 (out of 119), with a range of 55-103. In models performed in Europe, incremental cost-effectiveness ratios (ICERs) of apixaban versus warfarin ranged from ?5607/QALY to ?57,245/QALY, while ICERs versus aspirin ranged from being dominant to ?7334/QALY. In models carried out in the USA, ICERs of apixaban versus warfarin ranged from being dominant to $93,063/QALY. CONCLUSION: Different cost-effectiveness analyses suggest that apixaban is a cost-effective therapeutic option according to the WTP thresholds used in countries where cost-effectiveness analyses, were performed. FUNDING: BMS and Pfizer. PMID- 27457614 TI - The positive association of branched-chain amino acids and metabolic dyslipidemia in Chinese Han population. AB - BACKGROUND: It has been suggested that serum branched-chain amino acids (BCAAs) are associated with the incident, progression and prognostic of type 2 diabetes. However, the role of BCAAs in metabolic dyslipidemia (raised triglycerides (TG) and reduced high-density lipoprotein cholesterol (HDL-C)) remains poorly understood. This study aims to investigate 1) the association of serum BCAAs with total cholesterol (TC), TG, HDL-C and low-density lipoprotein cholesterol (LDL-C) and 2) the association between serum BCAAs levels and risk of metabolic dyslipidemia in a community population with different glucose homeostasis. METHODS: Demographics data and blood samples were collected from 2251 Chinese subjects from the Huaian Diabetes Protective Program (HADPP) study. After exclusion for cardiovascular disease (CVD), serious hepatic or nephritic diseases and others, 1320 subjects remained for analysis (789 subjects with hemoglobin A1c (HbA1c) > 5.7, 521 with HbA1c <= 5.7). Serum BCAAs level was measured by liquid chromatography-tandem mass spectrometry (LC MS/MS). The association of BCAAs with lipids or with the risk of metabolic dyslipidemia was analyzed. RESULTS: Elevated serum BCAAs (both total and individual BCAA) were positively associated with TG and inversely associated with HDL-C in the whole population. These correlations were still significant even after adjustment for confounding factors (r = 0.165, p < 0.001 for TG; and r = -0.126, p < 0.001 for HDL-C). For reduced HDL-C, we found higher odds risk (OR) of Valine (Val) in high HbA1c group than in the low one (OR = 1.055, p < 0.001 vs OR = 1.032, p = 0.059). Compared with that in the first quartile, the multivariable-adjusted OR (95 % CI) of the 4(th) quartile of serum total BCAAs level for reduced HDL-C was 3.689 (2.325, 5.854) in high HbA1c group and 2.329 (1.284, 4.227) in low group, for raised TG was 3.305 (2.120, 5.152) and 2.972 (1.706, 5.176), and for metabolic dyslipidemia was 3.703 (2.261, 6.065) and 3.702 (1.877, 7.304), respectively (all p < 0.01). CONCLUSION: Elevated serum BCAAs level are positively associated with incident metabolic dyslipidemia. In addition, glucose homeostasis could play a certain role in BCAAs related dyslipidemia. PMID- 27457615 TI - Oxymatrine inhibits aldosterone-induced rat cardiac fibroblast proliferation and differentiation by attenuating smad-2,-3 and-4 expression: an in vitro study. AB - BACKGROUND: We previously demonstrated oxymatrine, an alkaloid from the Chinese medicine radix Sophorae flavescentis, ameliorates hemodynamic disturbances and cardiac fibrosis; however, the underlying mechanisms are unclear. Here, we investigated the effect and mechanism of action of oxymatrine on aldosterone induced cardiac fibroblast to myofibroblast differentiation in vitro. METHODS: Cardiac fibroblasts were isolated purified from neonatal Sprague Dawley rats. The optimal concentration of aldosterone to stimulate cardiac fibroblast proliferation was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Cardiac fibroblasts were pretreated with 7.57 * 10(-4) mol/L or 3.78 * 10(-4) mol/L oxymatrine or without oxymatrine for 2 h, and then coincubated with 1 * 10(-8) mol/L aldosterone for 48 h. The MTT assay and Masson staining were used to detect the cardiac fibroblast proliferation and myofibroblast differentiation. The secretion of type I and III collagen was measured by commercial ELISA kits, and the hydroxyproline content was determined by the colorimetric assay. Western blotting assayed the Smad-2, Smad-3, and Smad 4 protein expression in cardiac fibroblasts. RESULTS: The present results confirmed that aldosterone induced cardiac fibroblast to myofibroblast proliferation and differentiation. The MTT assay and Masson staining indicated oxymatrine significantly inhibited aldosterone-induced cardiac fibroblast proliferation and myofibroblast differentiation. Oxymatrine significantly inhibited aldosterone-induced secretion of type I and III collagen, as indicated by commercial ELISA kits, and aldosterone-induced increase in hydroxyproline content, as indicated by a colorimetric assay. Western blotting revealed oxymatrine attenuated aldosterone-induced Smad-2, Smad-3, and Smad-4 expression in cardiac fibroblasts. CONCLUSION: Oxymatrine can inhibit cardiac fibroblast proliferation and differentiation into myofibroblasts via a mechanism linked to attenuation of the Smad signaling pathway. PMID- 27457616 TI - An Arginine Finger Regulates the Sequential Action of Asymmetrical Hexameric ATPase in the Double-Stranded DNA Translocation Motor. AB - Biological motors are ubiquitous in living systems. Currently, how the motor components coordinate the unidirectional motion is elusive in most cases. Here, we report that the sequential action of the ATPase ring in the DNA packaging motor of bacteriophage phi29 is regulated by an arginine finger that extends from one ATPase subunit to the adjacent unit to promote noncovalent dimer formation. Mutation of the arginine finger resulted in the interruption of ATPase oligomerization, ATP binding/hydrolysis, and DNA translocation. Dimer formation reappeared when arginine mutants were mixed with other ATPase subunits that can offer the arginine to promote their interaction. Ultracentrifugation and virion assembly assays indicated that the ATPase was presenting as monomers and dimer mixtures. The isolated dimer alone was inactive in DNA translocation, but the addition of monomer could restore the activity, suggesting that the hexameric ATPase ring contained both dimer and monomers. Moreover, ATP binding or hydrolysis resulted in conformation and entropy changes of the ATPase with high or low DNA affinity. Taking these observations together, we concluded that the arginine finger regulates sequential action of the motor ATPase subunit by promoting the formation of the dimer inside the hexamer. The finding of asymmetrical hexameric organization is supported by structural evidence of many other ATPase systems showing the presence of one noncovalent dimer and four monomer subunits. All of these provide clues for why the asymmetrical hexameric ATPase gp16 of phi29 was previously reported as a pentameric configuration by cryo-electron microscopy (cryo-EM) since the contact by the arginine finger renders two adjacent ATPase subunits closer than other subunits. Thus, the asymmetrical hexamer would appear as a pentamer by cryo-EM, a technology that acquires the average of many images. PMID- 27457617 TI - AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol. AB - The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling during Drosophila wing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed. PMID- 27457618 TI - Acetylation of Mitochondrial Trifunctional Protein alpha-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein alpha-subunit (MTPalpha) functions as a critical enzyme for fatty acid beta-oxidation, but whether dysregulation of MTPalpha is pathogenically connected to NAFLD is poorly understood. We show that MTPalpha is acetylated at lysine residues 350, 383, and 406 (MTPalpha-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPalpha-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPalpha. Replacement of MTPalpha-3K with either MTPalpha-3KR or MTPalpha-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTPalpha-3K mutant expression in mouse livers, and MTPalpha-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPalpha and MTPalpha-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPalpha regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD. PMID- 27457619 TI - Id3 Orchestrates Germinal Center B Cell Development. AB - Previous studies have demonstrated that E proteins induce activation-induced deaminase (AID) expression in activated B cells. Here, we examined the role of Id3 in germinal center (GC) cells. We found that Id3 expression is high in follicular B lineage cells but declines in GC cells. Immunized mice with Id3 expression depleted displayed a block in germinal center B cell maturation, showed reduced numbers of marginal zone B cells and class-switched cells, and were associated with decreased antibody titers and lower numbers of plasma cells. In vitro, Id3-depleted B cells displayed a defect in class switch recombination. Whereas AID levels were not altered in Id3-depleted activated B cells, the expression of a subset of genes encoding signaling components of antigen receptor , cytokine receptor-, and chemokine receptor-mediated signaling was significantly impaired. We propose that during the GC reaction, Id3 levels decline to activate the expression of genes encoding signaling components that mediate B cell receptor- and or cytokine receptor-mediated signaling to promote the differentiation of GC B cells. PMID- 27457620 TI - Structure-Activity Analysis of Gram-positive Bacterium-producing Lasso Peptides with Anti-mycobacterial Activity. AB - Lariatin A, an 18-residue lasso peptide encoded by the five-gene cluster larABCDE, displays potent and selective anti-mycobacterial activity. The structural feature is an N-terminal macrolactam ring, through which the C terminal passed to form the rigid lariat-protoknot structure. In the present study, we established a convergent expression system by the strategy in which larA mutant gene-carrying plasmids were transformed into larA-deficient Rhodococcus jostii, and generated 36 lariatin variants of the precursor protein LarA to investigate the biosynthesis and the structure-activity relationships. The mutational analysis revealed that four amino acid residues (Gly1, Arg7, Glu8, and Trp9) in lariatin A are essential for the maturation and production in the biosynthetic machinery. Furthermore, the study on structure-activity relationships demonstrated that Tyr6, Gly11, and Asn14 are responsible for the anti-mycobacterial activity, and the residues at positions 15, 16 and 18 in lariatin A are critical for enhancing the activity. This study will not only provide a useful platform for genetically engineering Gram-positive bacterium producing lasso peptides, but also an important foundation to rationally design more promising drug candidates for combatting tuberculosis. PMID- 27457621 TI - Editorial: How the Words We Use Affect the Care We Deliver. PMID- 27457622 TI - Value-based Healthcare: Part 1-Designing and Implementing Integrated Practice Units for the Management of Musculoskeletal Disease. PMID- 27457624 TI - CORR Insights(r): Are Bundled Payments a Viable Reimbursement Model for Revision Total Joint Arthroplasty? PMID- 27457623 TI - What Factors are Predictive of Patient-reported Outcomes? A Prospective Study of 337 Shoulder Arthroplasties. AB - BACKGROUND: Although shoulder arthroplasties generally are effective in improving patients' comfort and function, the results are variable for reasons that are not well understood. QUESTIONS/PURPOSES: We posed two questions: (1) What factors are associated with better 2-year outcomes after shoulder arthroplasty? (2) What are the sensitivities, specificities, and positive and negative predictive values of a multivariate predictive model for better outcome? METHODS: Three hundred thirty nine patients having a shoulder arthroplasty (hemiarthroplasty, arthroplasty for cuff tear arthropathy, ream and run arthroplasty, total shoulder or reverse total shoulder arthroplasty) between August 24, 2010 and December 31, 2012 consented to participate in this prospective study. Two patients were excluded because they were missing baseline variables. Forty-three patients were missing 2-year data. Univariate and multivariate analyses determined the relationship of baseline patient, shoulder, and surgical characteristics to a "better" outcome, defined as an improvement of at least 30% of the maximal possible improvement in the Simple Shoulder Test. The results were used to develop a predictive model, the accuracy of which was tested using a 10-fold cross-validation. RESULTS: After controlling for potentially relevant confounding variables, the multivariate analysis showed that the factors significantly associated with better outcomes were American Society of Anesthesiologists Class I (odds ratio [OR], 1.94; 95% CI, 1.03-3.65; p = 0.041), shoulder problem not related to work (OR, 5.36; 95% CI, 2.15-13.37; p < 0.001), lower baseline Simple Shoulder Test score (OR, 1.32; 95% CI, 1.23-1.42; p < 0.001), no prior shoulder surgery (OR, 1.79; 95% CI, 1.18-2.70; p = 0.006), humeral head not superiorly displaced on the AP radiograph (OR, 2.14; 95% CI, 1.15-4.02; p = 0.017), and glenoid type other than A1 (OR, 4.47; 95% CI, 2.24 8.94; p < 0.001). Neither preoperative glenoid version nor posterior decentering of the humeral head on the glenoid were associated with the outcomes. The model predictive of a better result was driven mainly by the six factors listed above. The area under the receiver operating characteristic curve generated from the cross-validated enhanced predictive model was 0.79 (generally values of 0.7 to 0.8 are considered fair and values of 0.8 to 0.9 are considered good). The false positive fraction and the true-positive fraction depended on the cutoff probability selected (ie, the selected probability above which the prediction would be classified as a better outcome). A cutoff probability of 0.68 yielded the best performance of the model with cross-validation predictions of better outcomes for 236 patients (80%) and worse outcomes for 58 patients (20%); sensitivity of 91% (95% CI, 88%-95%); specificity of 65% (95% CI, 53%-77%); positive predictive value of 92% (95% CI, 88%-95%); and negative predictive value of 64% (95% CI, 51%-76%). CONCLUSIONS: We found six easy-to-determine preoperative patient and shoulder factors that were significantly associated with better outcomes of shoulder arthroplasty. A model based on these characteristics had good predictive properties for identifying patients likely to have a better outcome from shoulder arthroplasty. Future research could refine this model with larger patient populations from multiple practices. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 27457625 TI - The Biotribology of PEEK-on-HXLPE Bearings Is Comparable to Traditional Bearings on a Multidirectional Pin-on-disk Tester. AB - BACKGROUND: All-polymer bearings involving polyetheretherketone (PEEK) have been proposed for orthopaedic applications because they may reduce stress shielding, reduce weight of the implants, reduce wear and risk of osteolysis, and prevent release of metal ions by replacing the metal articulating components. Little is known about the biotribology of all-polymer PEEK bearings, including the effects of cross-shear, which are relevant for implant longevity, especially in the hip, and increased temperature that may affect lubricant proteins and, hence, lubrication in the joint. QUESTIONS/PURPOSES: Using pin-on-disk in vitro testing, we asked: (1) Can all-polymer bearing couples involving PEEK have a comparable or lower wear rate than highly crosslinked UHMWPE (HXLPE) on CoCr bearing couples? (2) Is the wear rate of PEEK bearing couples affected by the amount of cross shear? (3) Is there a difference in wear mechanism and surface morphology for all polymer bearing surfaces compared with UHMWPE (HXLPE) on CoCr? METHODS: We simultaneously tested a total of 100 pin-on-disk couples (n = 10 per bearing couple) consisting of three traditional metal-on-UHMWPE and seven polymer-on polymer bearings for 2 million cycles under physiologically relevant conditions and in accordance with ASTM F732. Using analysis of variance, we analyzed the effect of bearing surface topography and cross-shear on wear rate. The changes in surface topography were evaluated using optical microscopy. Sample size was sufficient to provide 80% power to detect a difference of 1.4 mm3/MC in average wear rates of bearing couples. RESULTS: The combined wear rates of all-polymer bearing couples were not different than traditional bearing couples. With the numbers available, the PEEK and HXLPE bearing couple had a mean wear rate (WR: mean +/- SD) of 0.9 +/- 1.1 mm3/MC (95% confidence interval [CI], 0.2-1.5 mm3/MC), which was not different than the wear rate of the CoCr and HXLPE bearing couple (1.6 +/- 2.0 mm3/MC; 95% CI, 0.4-2.8 mm3/MC; mean difference = 0.73 mm3/MC, p = 0.36). Bearing couples with PEEK reinforced with a carbon fiber (CFR PEEK) counterface had higher wear rates (14.5 +/- 15.1 mm3/MC; 95% CI, 9.1-20.0 mm3/MC) than bearing couples with a PEEK (5.1 +/- 3.7 mm3/MC; 95% CI, 3.7-6.4 mm3/MC) or CoCr (4.1 +/- 2.7 mm3/MC; 95% CI, 3.2-5.1 mm3/MC) counterface (mean difference = 9.5 mm3/MC, p < 0.001; and mean difference = 10.4 mm3/MC, p < 0.001, respectively). PEEK and HXLPE were insensitive to the cross-shear scenario in the contact mechanics (WR: 0.3 +/- 0.1 mm3/MC for PEEK pins [95% CI, 0.2-0.3 mm3/MC] [representing full cross-shear condition] and 0.0 +/- 1.0 mm3/MC for PEEK disks [95% CI, -0.5 to 0.5 mm3/MC] [representing limited cross-shear condition], mean difference = 0.3 mm3/MC, p = 0.23; WR: 1.3 +/- 1.0 mm3/MC for HXLPE pins [95% CI, 0.7-1.9 mm3/MC] [full cross-shear] and 2.1 +/- 2.2 mm3/MC for HXLPE disks [95% CI, 0.8-3.3 mm3/MC] [limited cross-shear], mean difference = 0.8 mm3/MC, p = 0.24). Qualitatively, the surface morphology of UHMWPE appeared similar with PEEK or CoCr as a counterface, although it had a rougher appearance when coupled with carbon fiber-reinforced PEEK. No transfer film was detected on the specimens. CONCLUSIONS: Our in vitro pin-on-disk data suggest that all-polymer bearings, especially PEEK-on-HXLPE bearing couples, may represent a viable alternative to traditional bearings with respect to their wear performance. Our results warrant further testing of all-polymer bearing couples in physiologically relevant joint simulator tests. CLINICAL RELEVANCE: The in vitro pin-on-disk wear resistance of all-polymer bearings incorporating PEEK-on-HXLPE warrants further investigation using joint simulator testing for their validation as useful, metal-free alternatives to traditional CoCr-on-HXLPE bearings for use in orthopaedic applications. PMID- 27457628 TI - A new approach towards improved quality of life in fibromyalgia: a pilot study on the effects of an aquatic Ai Chi program. AB - BACKGROUND: Fibromyalgia syndrome (FMS) is a rheumatic disorder that presents with physical, psychological and social symptoms. OBJECTIVE: The aim of this study was to assess the effects of a program of water-based Ai Chi on the health related quality of life of subjects with FMS. METHODS: An experimental pilot study was performed with a sample of 20 female subjects diagnosed with FM and recruited from two different settings. Assessments were performed using the a visual analog scale and the Short Form-36 physical and mental health summary scores. Measurements took place at baseline and upon completion of 10 treatment sessions. RESULTS: After 10 treatment sessions, significant improvements (P < 0.05) were found in practically all the variables under study, with significant differences in values such as pain perception, vitality, mental health, as well as perceived overall improvement in quality of life. CONCLUSIONS: A water-based Ai Chi program may contribute to the improvement of mental and physical health and the quality of life in women with FMS. PMID- 27457626 TI - Economic Decision Model Suggests Total Shoulder Arthroplasty is Superior to Hemiarthroplasty in Young Patients with End-stage Shoulder Arthritis. AB - BACKGROUND: Young patients with severe glenohumeral arthritis pose a challenging management problem for shoulder surgeons. Two controversial treatment options are total shoulder arthroplasty (TSA) and hemiarthroplasty. This study aims to characterize costs, as expressed by reimbursements for episodes of acute care, and outcomes associated with each treatment. QUESTIONS/PURPOSES: We asked: for patients 30 to 50 years old with severe end-stage glenohumeral arthritis refractory to conservative management, (1) are more years of patient-derived satisfactory outcome by the Neer criteria and quality-adjusted life-years (QALYs) achieved using a TSA or a hemiarthroplasty; (2) does a TSA or a hemiarthroplasty result in a greater number of revision procedures; and (3) does a TSA or a hemiarthroplasty result in greater associated costs to society? METHODS: The incidence of glenohumeral arthritis among 30- to 50-year-old patients, outcomes, reoperation probabilities, and associated costs from TSA and hemiarthroplasty were derived from the literature. A Markov chain decision tree model was developed from these estimates with number of revisions, cost of management for patients to 70 years old as defined by reimbursement for acute-care episodes, years with "satisfactory" or "excellent" outcome by the modified Neer criteria, and QALYs gained as principle outcome measures. A Monte Carlo simulation was conducted with a cohort representing the at-risk population for shoulder arthritis between 30 and 50 years old in the United States. RESULTS: During the lifetime of a cohort of 5279 patients, hemiarthroplasty as the initial treatment resulted in 59,574 patient years of satisfactory or excellent results (11.29 per patient) and average QALYs gained of 6.55, whereas TSA as the initial treatment resulted in 85,969 patient years of satisfactory or excellent results (16.29 per patient) and average QALYs gained of 7.96. During the lifetime of a cohort of 5279 patients, a hemiarthroplasty as the initial treatment led to 2090 lifetime revisions (0.4 per patient), whereas a TSA as the initial treatment led to 1605 lifetime revisions (0.3 per patient). During the lifetime of a cohort of 5279 patients, a hemiarthroplasty as initial treatment resulted in USD 132,500,000 associated direct reimbursements (USD 25,000 per patient), whereas a TSA as initial treatment resulted in USD 125,500,000 associated direct reimbursements (USD 23,700 per patient). CONCLUSIONS: Treatment of end-stage glenohumeral arthritis refractory to conservative treatment in patients 30 to 50 years old in the United States with TSA, instead of hemiarthroplasty, would result in greater cost savings, avoid a substantial number of revision procedures, and result in greater years of satisfactory or excellent patient outcomes and greater QALYs gained. On a population level, TSA is the cost-effective treatment for glenohumeral arthritis in patients 30 to 50 years old. LEVEL OF EVIDENCE: Level II, economic and decision analysis study. PMID- 27457627 TI - Characterization of a midgut mucin-like glycoconjugate of Lutzomyia longipalpis with a potential role in Leishmania attachment. AB - BACKGROUND: Leishmania parasites are transmitted by phlebotomine sand flies and a crucial step in their life-cycle is the binding to the sand fly midgut. Laboratory studies on sand fly competence to Leishmania parasites suggest that the sand flies fall into two groups: several species are termed "specific/restricted" vectors that support the development of one Leishmania species only, while the others belong to so-called "permissive" vectors susceptible to a wide range of Leishmania species. In a previous study we revealed a correlation between specificity vs permissivity of the vector and glycosylation of its midgut proteins. Lutzomyia longipalpis and other four permissive species tested possessed O-linked glycoproteins whereas none were detected in three specific vectors examined. RESULTS: We used a combination of biochemical, molecular and parasitological approaches to characterize biochemical and biological properties of O-linked glycoprotein of Lu. longipalpis. Lectin blotting and mass spectrometry revealed that this molecule with an apparent molecular weight about 45-50 kDa corresponds to a putative 19 kDa protein with unknown function detected in a midgut cDNA library of Lu. longipalpis. We produced a recombinant glycoprotein rLuloG with molecular weight around 45 kDa. Anti-rLuloG antibodies localize the native glycoprotein on epithelial midgut surface of Lu. longipalpis. Although we could not prove involvement of LuloG in Leishmania attachment by blocking the native protein with anti-rLuloG during sand fly infections, we demonstrated strong binding of rLuloG to whole surface of Leishmania promastigotes. CONCLUSIONS: We characterized a novel O-glycoprotein from sand fly Lutzomyia longipalpis. It has mucin-like properties and is localized on the luminal side of the midgut epithelium. Recombinant form of the protein binds to Leishmania parasites in vitro. We propose a role of this molecule in Leishmania attachment to sand fly midgut. PMID- 27457629 TI - Reversible "triple-Q" elastic field structures in a chiral magnet. AB - The analytical solution of the periodic elastic fields in chiral magnets caused by presence of periodically distributed eigenstrains is obtained. For the skyrmion phase, both the periodic displacement field and the stress field are composed of three "triple-Q" structures with different wave numbers. The periodic displacement field, obtained by combining the three "triple-Q" displacement structures, is found to have the same lattice vectors with the magnetic skyrmion lattice. We find that for increasing external magnetic field, one type of "triple Q" displacement structure and stress structure undergo a "configurational reversal", where the initial and the final field configuration share similar pattern but with opposite direction of all the field vectors. The solution obtained is of fundamental significance for understanding the emergent mechanical properties of skyrmions in chiral magnets. PMID- 27457630 TI - Utilizing native fluorescence imaging, modeling and simulation to examine pharmacokinetics and therapeutic regimen of a novel anticancer prodrug. AB - BACKGROUND: Success of cancer prodrugs relying on a foreign gene requires specific delivery of the gene to the cancer, and improvements such as higher level gene transfer and expression. Attaining these objectives will be facilitated in preclinical studies using our newly discovered CNOB-GDEPT, consisting of the produrg: 6-chloro-9-nitro-5-oxo-5H-benzo-(a)-phenoxazine (CNOB) and its activating enzyme ChrR6, which generates the cytotoxic product 9-amino-6 chloro-5H-benzo[a]phenoxazine-5-one (MCHB). MCHB is fluorescent and can be noninvasively imaged in mice, and here we investigated whether MCHB fluorescence quantitatively reflects its concentration, as this would enhance its reporter value in further development of the CNOB-GDEPT therapeutic regimen. PK parameters were estimated and used to predict more effective CNOB administration schedules. METHODS: CNOB (3.3 mg/kg) was injected iv in mice implanted with humanized ChrR6 (HChrR6)-expressing 4T1 tumors. Fluorescence was imaged in live mice using IVIS Spectrum, and quantified by Living Image 3.2 software. MCHB and CNOB were quantified also by LC/MS/MS analysis. We used non-compartmental model to estimate PK parameters. Phoenix WinNonlin software was used for simulations to predict a more effective CNOB dosage regimen. RESULTS: CNOB administration significantly prolonged mice survival. MCHB fluorescence quantitatively reflected its exposure levels to the tumor and the plasma, as verified by LC/MS/MS analysis at various time points, including at a low concentration of 2 ng/g tumor. The LC/MS/MS data were used to estimate peak plasma concentrations, exposure (AUC0-24), volume of distribution, clearance and half-life in plasma and the tumor. Simulations suggested that the CNOB-GDEPT can be a successful therapy without large increases in the prodrug dosage. CONCLUSION: MCHB fluorescence quantifies this drug, and CNOB can be effective at relatively low doses. MCHB fluorescence characteristics will expedite further development of CNOB-GDEPT by, for example, facilitating specific gene delivery to the tumor, its prolonged expression, as well as other attributes necessary for successful gene-delivered enzyme prodrug therapy. PMID- 27457633 TI - Evaluation of a Technology to Support a Translational Diabetes Prevention Intervention. PMID- 27457632 TI - Role of Glycated Proteins in the Diagnosis and Management of Diabetes: Research Gaps and Future Directions. PMID- 27457634 TI - Making a Difference With Diabetes Research and Care. PMID- 27457635 TI - Metabolic Effects of Monounsaturated Fatty Acid-Enriched Diets Compared With Carbohydrate or Polyunsaturated Fatty Acid-Enriched Diets in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - OBJECTIVE: Dietary interventions in patients with type 2 diabetes (T2D) are important for preventing long-term complications. Although a healthy diet is crucial, there is still uncertainty about the optimal macronutrient composition. We performed a meta-analysis comparing diets high in cis-monounsaturated fatty acids (MUFA) to diets high in carbohydrates (CHO) or in polyunsaturated fatty acids (PUFA) on metabolic risk factors in patients with T2D. RESEARCH DESIGN AND METHODS: We systematically reviewed PubMed, MEDLINE, and Cochrane databases and prior systematic reviews and meta-analyses to identify interventions assessing HbA1c, fasting plasma glucose and insulin, LDL and HDL cholesterol, triglycerides, body weight, or systolic/diastolic blood pressure. Meta-analyses were conducted using both fixed- and random-effects models to calculate the weighted mean difference (WMD) and 95% CI. RESULTS: We identified 24 studies totaling 1,460 participants comparing high-MUFA to high-CHO diets and 4 studies totaling 44 participants comparing high-MUFA to high-PUFA diets. When comparing high-MUFA to high-CHO diets, there were significant reductions in fasting plasma glucose (WMD -0.57 mmol/L [95% CI -0.76, -0.39]), triglycerides (-0.31 mmol/L [ 0.44, -0.18]), body weight (-1.56 kg [-2.89, -0.23]), and systolic blood pressure (-2.31 mmHg [-4.13, -0.49]) along with significant increases in HDL cholesterol (0.06 mmol/L [0.02, 0.10]). When high-MUFA diets were compared with high-PUFA diets, there was a significant reduction in fasting plasma glucose (-0.87 mmol/L [-1.67, -0.07]). All of the outcomes had low to medium levels of heterogeneity, ranging from 0.0 to 69.5% for diastolic blood pressure (Phet = 0.011). CONCLUSIONS: Our meta-analysis provides evidence that consuming diets high in MUFA can improve metabolic risk factors among patients with T2D. PMID- 27457636 TI - Are There Clinical Implications of Racial Differences in HbA1c? Yes, to Not Consider Can Do Great Harm! AB - Studies that have compared HbA1c levels by race have consistently demonstrated higher HbA1c levels in African Americans than in whites. These racial differences in HbA1c have not been explained by measured differences in glycemia, sociodemographic factors, clinical factors, access to care, or quality of care. Recently, a number of nonglycemic factors and several genetic polymorphisms that operate through nonglycemic mechanisms have been associated with HbA1c Their distributions across racial groups and their impact on hemoglobin glycation need to be systematically explored. Thus, on the basis of evidence for racial differences in HbA1c, current clinical guidelines from the American Diabetes Association state: "It is important to take...race/ethnicity...into consideration when using the A1C to diagnose diabetes." However, it is not clear from the guidelines how this recommendation might be actualized. So, the critical question is not whether racial differences in HbA1c exist between African Americans and whites; the important question is whether the observed differences in HbA1c level are clinically meaningful. Therefore, given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative below, Dr. Herman provides his argument that the failure to acknowledge that HbA1c might be a biased measure of average glycemia and an unwillingness to rigorously investigate this hypothesis will slow scientific progress and has the potential to do great harm. In the counterpoint narrative that follows Dr. Herman's contribution, Dr. Selvin argues that there is no compelling evidence for racial differences in the validity of HbA1c as a measure of hyperglycemia and that race is a poor surrogate for differences in underlying causes of disease risk.-William T. CefaluEditor in Chief, Diabetes Care. PMID- 27457638 TI - "Prediabetes": Are There Problems With This Label? Yes, the Label Creates Further Problems! AB - The category of "prediabetes" defined by the American Diabetes Association comprises a range of intermediate hyperglycemia based on fasting or 2-h postload glucose or on HbA1c Over the recent past, the "cut points" identifying this stage have changed, i.e., a lower fasting glucose level is used. On one hand, it can be argued that the change to a lower cut point identifies a group of individuals still at higher risk and provides heightened awareness for a condition associated with higher risk for cardiovascular disease. In addition, identification of individuals at this stage may represent a chance of earlier intervention in the disease. However, the argument against this definition of "prediabetes" is that it disguises the differences in the three subcategories and creates problems in interpreting observations on interventions and outcomes. In addition, it can be argued that the enormous numbers of people identified with the criteria far exceeds the capacity of health care systems to respond through individual care, particularly without evidence that interventions benefit any category other than impaired glucose tolerance. Thus, there does not appear to be consensus on the definition using the cut points identified. Controversy also remains as to whether there are glycemic metrics beyond HbA1c that can be used in addition to HbA1c to help assess risk of an individual developing diabetes complications. Given the current controversy, a Point-Counterpoint debate on this issue is provided herein. In the point narrative below, Dr. Yudkin provides his argument that there are significant problems with this label. In the counterpoint narrative that follows Dr. Yudkin's contribution, Dr. Cefalu argues that the cut points are appropriate and do provide useful and important information in trying to reduce the future burden of diabetes.-William T. CefaluEditor in Chief, Diabetes Care. PMID- 27457637 TI - Are There Clinical Implications of Racial Differences in HbA1c? A Difference, to Be a Difference, Must Make a Difference. AB - Studies that have compared HbA1c levels by race have consistently demonstrated higher HbA1c levels in African Americans than in whites. These racial differences in HbA1c have not been explained by measured differences in glycemia, sociodemographic factors, clinical factors, access to care, or quality of care. Recently, a number of nonglycemic factors and several genetic polymorphisms that operate through nonglycemic mechanisms have been associated with HbA1c Their distributions across racial groups and their impact on hemoglobin glycation need to be systematically explored. Thus, on the basis of evidence for racial differences in HbA1c, current clinical guidelines from the American Diabetes Association state: "It is important to take...race/ethnicity...into consideration when using the A1C to diagnose diabetes." However, it is not clear from the guidelines how this recommendation might be actualized. So, the critical question is not whether racial differences in HbA1c exist between African Americans and whites; the important question is whether the observed differences in HbA1c level are clinically meaningful. Therefore, given the current controversy, we provide a Point-Counterpoint debate on this issue. In the preceding point narrative, Dr. Herman provides his argument that the failure to acknowledge that HbA1c might be a biased measure of average glycemia and an unwillingness to rigorously investigate this hypothesis will slow scientific progress and has the potential to do great harm. In the counterpoint narrative below, Dr. Selvin argues that there is no compelling evidence for racial differences in the validity of HbA1c as a measure of hyperglycemia and that race is a poor surrogate for differences in underlying causes of disease risk.-William T. CefaluEditor in Chief, Diabetes Care. PMID- 27457639 TI - "Prediabetes": Are There Problems With This Label? No, We Need Heightened Awareness of This Condition! AB - The category of "prediabetes" defined by the American Diabetes Association comprises a range of intermediate hyperglycemia based on fasting or 2-h postload glucose or on HbA1c Over the recent past, the "cut points" identifying this stage have changed, i.e., a lower fasting glucose level is used. On one hand, it can be argued that the change to a lower cut point identifies a group of individuals still at higher risk and provides heightened awareness for a condition associated with higher risk for cardiovascular disease. In addition, identification of individuals at this stage may represent a chance of earlier intervention in the disease. However, the argument against this definition of prediabetes is that it disguises the differences in the three subcategories and creates problems in interpreting observations on interventions and outcomes. In addition, it can be argued that the enormous numbers of people identified with the criteria far exceeds the capacity of health care systems to respond through individual care, particularly without evidence that interventions benefit any category other than impaired glucose tolerance. Thus, there does not appear to be consensus on the definition using the cut points identified. Controversy also remains as to whether there are glycemic metrics beyond HbA1c that can be used in addition to HbA1c to help assess risk of an individual developing diabetes complications. Given the current controversy, a Point-Counterpoint debate on this issue is provided herein. In the preceding point narrative, Dr. Yudkin provides his argument that there are significant problems with this label. In the counterpoint narrative below, Dr. Cefalu argues that the cut points are appropriate and do provide useful and important information in trying to reduce the future burden of diabetes.-William T. CefaluEditor in Chief, Diabetes Care. PMID- 27457641 TI - Comment on Koivusalo et al. Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL): A Randomized Controlled Trial. Diabetes Care 2016;39:24-30. PMID- 27457642 TI - Response to Comment on Koivusalo et al. Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL): A Randomized Controlled Trial. Diabetes Care 2016;39:24-30. PMID- 27457643 TI - Comment on Schwartz et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the beta-Cell-Centric Classification Schema. Diabetes Care 2016;39:179-186. PMID- 27457644 TI - Response to Comment on Schwartz et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the beta-Cell-Centric Classification Schema. Diabetes Care 2016;39:179-186. PMID- 27457645 TI - Comment on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392-399. PMID- 27457646 TI - Comment on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392-399. PMID- 27457647 TI - Comment on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392-399. PMID- 27457648 TI - Response to Comments on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392-399. PMID- 27457649 TI - Comment on Rosenstock and Ferrannini. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care 2015;38:1638-1642. PMID- 27457650 TI - Response to Comment on Rosenstock and Ferrannini. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care 2015;38:1638-1642. PMID- 27457651 TI - A theory-based evaluation of a dissemination intervention to improve childcare cooks' intentions to implement nutritional guidelines on their menus. AB - BACKGROUND: Childcare services represent a key setting to implement nutritional interventions to support the development of healthy eating behaviours in young children. Childcare-specific nutritional guidelines outlining recommendations for provision of food in care have been developed. Despite this, research suggests that few childcare services currently implement these guidelines. This study aimed to examine the impact of providing printed educational materials on childcare service cooks' intentions to use nutritional guidelines and provide fruit and vegetables on their menu. FINDINGS: A randomised controlled trial was conducted with 77 childcare services (38 control and 39 intervention). Intervention service cooks were mailed a two-page educational material together with a menu planning checklist. Intervention development and evaluation was guided by the theory of planned behaviour. Outcome data assessing intentions to use nutritional guidelines and serves of fruit and vegetables provided on menus (primary outcomes) as well as secondary outcomes (attitudes, behavioural regulation and social norms) were collected via a telephone interview with cooks. Relative to the comparison group, cooks in the intervention arm had significantly higher intentions to use the guidelines (p value 0.0005), accompanied by significant changes in perceived behavioural control (p value 0.0008) and attitudes (p value 0.0071). No significant difference in serves of fruit (p value 0.7278) and vegetables (p value 0.0573) was observed. CONCLUSIONS: The use of educational materials can improve childcare service cooks' intentions to use nutritional guidelines; however, as a standalone strategy, it may not improve provision of food on menus. PMID- 27457652 TI - Genome Characteristics of Two Novel Type I Methanotrophs Enriched from North Sea Sediments Containing Exclusively a Lanthanide-Dependent XoxF5-Type Methanol Dehydrogenase. AB - Microbial methane oxidizers play a crucial role in the oxidation of methane in marine ecosystems, as such preventing the escape of excessive methane to the atmosphere. Despite the important role of methanotrophs in marine ecosystems, only a limited number of isolates are described, with only four genomes available. Here, we report on two genomes of gammaproteobacterial methanotroph cultures, affiliated with the deep-sea cluster 2, obtained from North Sea sediment. Initial enrichments using methane as sole source of carbon and energy and mimicking the in situ conditions followed by serial subcultivations and multiple extinction culturing events over a period of 3 years resulted in a highly enriched culture. The draft genomes of the methane oxidizer in both cultures showed the presence of genes typically found in type I methanotrophs, including genes encoding particulate methane monooxygenase (pmoCAB), genes for tetrahydromethanopterin (H4MPT)- and tetrahydrofolate (H4F)-dependent C1-transfer pathways, and genes of the ribulose monophosphate (RuMP) pathway. The most distinctive feature, when compared to other available gammaproteobacterial genomes, is the absence of a calcium-dependent methanol dehydrogenase. Both genomes reported here only have a xoxF gene encoding a lanthanide-dependent XoxF5 type methanol dehydrogenase. Thus, these genomes offer novel insight in the genomic landscape of uncultured diversity of marine methanotrophs. PMID- 27457653 TI - Metatranscriptome analysis of active microbial communities in produced water samples from the Marcellus Shale. AB - Controlling microbial activity is a primary concern during the management of the large volumes of wastewater (produced water) generated during high-volume hydraulic fracturing. In this study we analyzed the transcriptional activity (metatranscriptomes) of three produced water samples from the Marcellus Shale. The goal of this study was to describe active metabolic pathways of industrial concern for produced water management and reuse, and to improve understanding of produced water microbial activity. Metatranscriptome analysis revealed active biofilm formation, sulfide production, and stress management mechanisms of the produced water microbial communities. Biofilm-formation and sulfate-reduction pathways were identified in all samples. Genes related to a diverse array of stress response mechanisms were also identified with implications for biocide efficacy. Additionally, active expression of a methanogenesis pathway was identified in a sample of produced water collected prior to holding pond storage. The active microbial community identified by metatranscriptome analysis was markedly different than the community composition as identified by 16S rRNA sequencing, highlighting the value of evaluating the active microbial fraction during assessments of produced water biofouling potential and evaluation of biocide application strategies. These results indicate biofouling and corrosive microbial processes are active in produced water and should be taken into consideration while designing produced water reuse strategies. PMID- 27457654 TI - Variables associated with physical health-related quality of life in Parkinson's disease patients presenting for deep brain stimulation. AB - Deep brain stimulation (DBS) benefits Parkinson's disease (PD) patient's quality of life specially in domains as mobility, activities of daily living (ADL) and bodily discomfort (BD), but little is known about the variables associated with these HRQOL domains in patients presenting for DBS. The objective is to evaluate variables associated with of HRQOL in a Brazilian sample of PD patients presenting for DBS treatment, specifically in the domains related with motor symptoms. In a cross-sectional study of 59 PD patients evaluated at outpatient Unit for Movement Disorders, multiple linear regression analysis was performed to identify independent variables associated with mobility, ADL and BD domains of the 39-item Parkinson's disease questionnaire (PDQ-39). UPDRS III "on" scores, duration of the disease, age, presence of comorbidities and anxiety and depressive symptoms quantified by hospital anxiety and depression scale (HADS), were the independent variables. In our results, HADS scores were independently associated to mobility domain: beta coefficient 1.36 (95 % CI 0.55-2.15) and BD domain: beta coefficient 1.57 (95 % CI 0.67-2.48). UPDRS III "on" scores were independently associated to mobility domain: 0.42 (95 % CI 0.03-0.81). The model of each multiple linear regression analysis explains 25 % of the mobility domain variability (p < 0.01) and 24 % of the BD domain variability (p < 0.01). Psychiatric symptoms were at least as relevant to quality of life as motor symptoms in PD patients presenting for DBS treatment. The effect of treating these psychiatric symptoms on patients' HRQOL deserves further investigation. PMID- 27457655 TI - Reversible disconnection syndrome in a case of acute tumefactive demyelinating lesion: a PET study. PMID- 27457656 TI - Health-related quality of life in patients with Gilles de la Tourette syndrome at the transition between adolescence and adulthood. AB - Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterised by tics and co-morbid behavioural problems, affecting predominantly male patients. Tic severity typically fluctuates over time, with a consistent pattern showing improvement after adolescence in a considerable proportion of patients. Both tics and behavioural co-morbidities have been shown to have the potential to affect patients' health-related quality of life (HR-QoL) in children and adults with persisting symptoms. In this study, we present the results of the first investigation of HR-QoL in patients with Gilles de la Tourette syndrome at the transition between adolescence and adulthood using a disease-specific HR-QoL measure, the Gilles de la Tourette Syndrome-Quality of Life-Children and Adolescents scale. Our results showed that patients with GTS and more severe co morbid anxiety symptoms reported lower HR-QoL across all domains, highlighting the impact of anxiety on patient's well-being at a critical stage of development. Routine screening for anxiety symptoms is recommended in all patients with GTS seen at transition clinics from paediatric to adult care, to implement effective behavioural and pharmacological interventions as appropriate. PMID- 27457657 TI - Choroidal thickness measurements in migraine patients during attack-free period. PMID- 27457658 TI - Delayed saccade to perceptually demanding locations in Parkinson's disease: analysis from the perspective of the speed-accuracy trade-off. AB - Parkinson's disease (PD) patients reportedly have shortened, normal, or prolonged latency of visually guided saccades (VGSs). This inconsistency seems to be partly derived from differences in experimental conditions, such as target eccentricity and direction. Another etiology may be a physiological saccade property, the speed-accuracy trade-off. VGS latency tends to increase along with its gain in certain conditions; however, this relationship has not been addressed in PD saccade studies. In this study, we measured VGS latency and gain in 47 PD patients and 48 normal controls (NCs). VGS was evoked by a target, which was presented at the central position initially and pseudo-randomly jumped to the horizontal (10 degrees or 20 degrees eccentricity) or vertical (10 degrees or 15 degrees ) meridian. For each target location, the logarithm of the latency (log-latency) was modeled with subject type (PD or NC), age, and gain in the linear-mixed regression analysis. Subsequently, for target locations where PD patients showed an abnormality, the log-latency was similarly modeled with additional clinical variables measured by the mini-mental state examination (MMSE) and unified Parkinson's disease rating scale Part III. PD saccade latency was prolonged and influenced by the MMSE score when targets were presented at the 20 degrees horizontal and upper vertical meridians. Furthermore, gain was a consistently significant variable in all models. The target locations of the delayed saccade corresponded to perceptually demanding locations, indicating that PD subclinical visual dysfunction prolonged the latency. The influence of the MMSE score supports this reasoning. Moreover, the speed-accuracy trade-off appeared to contribute to the accurate saccade analysis. PMID- 27457660 TI - Projections of increased and decreased dengue incidence under climate change. AB - Dengue is the world's most prevalent mosquito-borne disease, with more than 200 million people each year becoming infected. We used a mechanistic virus transmission model to determine whether climate warming would change dengue transmission in Australia. Using two climate models each with two carbon emission scenarios, we calculated future dengue epidemic potential for the period 2046 2064. Using the ECHAM5 model, decreased dengue transmission was predicted under the A2 carbon emission scenario, whereas some increases are likely under the B1 scenario. Dengue epidemic potential may decrease under climate warming due to mosquito breeding sites becoming drier and mosquito survivorship declining. These results contradict most previous studies that use correlative models to show increased dengue transmission under climate warming. Dengue epidemiology is determined by a complex interplay between climatic, human host, and pathogen factors. It is therefore naive to assume a simple relationship between climate and incidence, and incorrect to state that climate warming will uniformly increase dengue transmission, although in general the health impacts of climate change will be negative. PMID- 27457659 TI - Peripheral blood toll-like receptor 4 correlates with rapid virological response to pegylated-interferon and ribavirin therapy in hepatitis C genotype 1 patients. AB - BACKGROUND: Toll-like receptors (TLRs) are effectors of the innate immune system that are able to recognize hepatitis C virus (HCV) and give rise to an immune response. Failure of interferon (IFN)-alpha-based treatment is related to host immunity. Therefore, we sought to study the clinical importance of TLRs in HCV genotype 1 patients who received pegylated IFN (PEG-IFN) plus ribavirin (RBV) therapy. METHODS: We enrolled 79 treatment-naive patients with HCV genotype 1. Patients completed a 24- to 48-week course of response-guided therapy. Peripheral blood monocyte (PBMC) expression of mRNA for TLRs 2, 3, 4, 7, and 9 was quantified by real-time PCR before therapy. TLR mRNA expression is shown as a log ratio relative to GAPDH mRNA (log 2 (-(?Ct))). RESULTS: Forty-five patients (57.0 %) showed a rapid virological response (RVR). Univariate analysis revealed that TLR 2, 3, 4, 7, and 9 were significantly lower in the RVR group than in the non RVR group (P = 0.001, 0.014, < 0.001, 0.008, and 0.001, respectively). Multivariate analysis revealed that TLR 4 < -2 log (OR: 7.17, 95 % CI: 1.70 30.34, P = 0.007) was an independent predictor for RVR. In addition, levels of TLR 2, 3, 4, 7, and 9 were positively correlated with HCV viral load (P = 0.009, 0.013, < 0.001, 0.007, and 0.001, respectively). CONCLUSIONS: A low level of TLR 4 mRNA in PMBCs was correlated with RVR, which indicates that TLR4 may play a critical role in HCV recognition and activation of innate immunity. TLR expression levels were correlated with HCV viral load, indicating that TLR activation upon exposure to HCV may subsequently limit HCV replication. PMID- 27457662 TI - First preclinical support for the 'danger theory' in inhibitor development. PMID- 27457661 TI - Advance care planning for haemodialysis patients. AB - BACKGROUND: End-stage kidney disease (ESKD) is a chronic, debilitative and progressive illness that may need interventions such as dialysis, transplantation, dietary and fluid restrictions. Most patients with ESKD will require renal replacement therapy, such as kidney transplantation or maintenance dialysis. Advance care planning traditionally encompass instructions via living wills, and concern patient preferences about interventions such as cardiopulmonary resuscitation and feeding tubes, or circumstances around assigning surrogate decision makers. Most people undergoing haemodialysis are not aware of advance care planning and few patients formalise their wishes as advance directives and of those who do, many do not discuss their decisions with a physician. Advance care planning involves planning for future healthcare decisions and preferences of the patient in advance while comprehension is intact. It is an essential part of good palliative care that likely improves the lives and deaths of haemodialysis patients. OBJECTIVES: The objective of this review was to determine whether advance care planning in haemodialysis patients, compared with no or less structured forms of advance care planning, can result in fewer hospital admissions or less use of treatments with life-prolonging or curative intent, and if patient's wishes were followed at end-of-life. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 27 June 2016 through contact with the Information Specialist using search terms relevant to this review. We also searched the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Social Work Abstracts (OvidSP). SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at advance care planning versus no form of advance care planning in haemodialysis patients was considered for inclusion without language restriction. DATA COLLECTION AND ANALYSIS: Data extraction was carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals were translated before assessment. Where more than one publication of one study exists, reports were grouped together and the publication with the most complete data was used in the analyses. Where relevant outcomes are only published in earlier versions these data were used. Any discrepancies between published versions were highlighted. Non-randomised controlled studies were excluded. MAIN RESULTS: We included two studies (three reports) that involved 337 participants which investigated advance care planning for people with ESKD. Neither of the included studies reported outcomes relevant to this review. Study quality was assessed as suboptimal. AUTHORS' CONCLUSIONS: We found sparse data that were assessed at suboptimal quality and therefore we were unable to formulate conclusions about whether advance care planning can influence numbers of hospital admissions and treatment required by people with ESKD, or if patients' advance care directives were followed at end-of-life. Further well designed and adequately powered RCTs are needed to better inform patient and clinical decision making about advance care planning and advance directives among people with ESKD who are undergoing dialysis. PMID- 27457663 TI - Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient-three case reports. AB - Oncolytic virotherapy is a recent addition to cancer treatment. Here, we describe positive treatment outcomes in three patients using Rigvir virotherapy. One of the patients is diagnosed with melanoma stage IV M1c, one with small cell lung cancer stage IIIA, and one with histiocytic sarcoma stage IV. The diagnoses of all patients are verified by histology or cytology. All patients started Rigvir treatment within a few months after being diagnosed and are currently continuing Rigvir treatment. The degree of regression of the disease has been determined by computed tomography. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 1 during Rigvir((r)) treatment. Using current standard treatments, the survival of patients with the present diagnoses is low. In contrast, the patients described here were diagnosed 3.5, 7.0, and 6.6 years ago, and their condition has improved and been stabile for over 1.5, 6.5, and 4 years, respectively. These observations suggest that virotherapy using Rigvir can successfully be used in long-term treatment of patients with melanoma stage IV M1c, small cell lung cancer stage IIIA, and histiocytic sarcoma stage IV and therefore could be included in prospective clinical studies. PMID- 27457664 TI - Drug Resistance in Colorectal Cancer Cell Lines is Partially Associated with Aneuploidy Status in Light of Profiling Gene Expression. AB - A priority in solving the problem of drug resistance is to understand the molecular mechanism of how a drug induces the resistance response within cells. Because many cancer cells exhibit chromosome aneuploidy, we explored whether changes of aneuploidy status result in drug resistance. Two typical colorectal cancer cells, HCT116 and LoVo, were cultured with the chemotherapeutic drugs irinotecan (SN38) or oxaliplatin (QxPt), and the non- and drug-resistant cell lines were selected. Whole exome sequencing (WES) was employed to evaluate the aneuploidy status of these cells, and RNAseq and LC-MS/MS were implemented to examine gene expression at both mRNA and protein level. The data of gene expression was well-matched with the genomic conclusion that HCT116 was a near diploid cell, whereas LoVo was an aneuploid cell with the increased abundance of mRNA and protein for these genes located at chromosomes 5, 7, 12, and 15. By comparing the genomic, transcriptomic, and proteomic data, the LoVo cells with SN38 tolerance showed an increased genome copy in chromosome 14, and the expression levels of the genes on this chromosome were also significantly increased. Thus, we first observed that SN38 could impact the aneuploidy status in cancer cells, which was partially associated with the acquired drug resistance. PMID- 27457665 TI - Endogenous ouabain and aldosterone are coelevated in the circulation of patients with essential hypertension. AB - OBJECTIVE: In the setting of normal sodium (Na) intake, many patients with hypertension have inappropriately elevated plasma aldosterone (Aldo) levels and may be at increased risk for tissue damage. Moreover, other adrenocortical steroids, including endogenous ouabain can stimulate tissue damage. As endogenous ouabain is often elevated in chronically Na-loaded states, is a vasoconstrictor, raises blood pressure (BP), and also promotes tissue fibrosis, we investigated the extent to which plasma Aldo and endogenous ouabain were coelevated among naive hypertensive patients (NHP). We also investigated the impact of an acute salt load on these steroids, BP, and renal function. METHODS: NHP (590) were grouped in tertiles based on their baseline plasma Aldo (mean +/- SEM first 7.59 +/- 0.18, versus third 24.15 +/- 0.31 ng/dl). Baseline plasma renin activity (2.4 +/- 0.1 versus 1.2 +/- 0.1 ng/ml per h, P < 0.001), endogenous ouabain (268 +/- 14.9 pmol/l versus 239.0 +/- 13.6 pmol, P < 0.01) and DBP (91.9 +/- 0.76 versus 89.6 +/- 0.71 mmHg, P = 0.017) were higher in NHP in the third versus the first Aldo tertile, respectively. RESULTS: Acute Na loading showed that the BP of the third Aldo tertile NHP was especially salt-sensitive (slope of pressure natriuresis relationship 0.015 +/- 0.002 versus 0.003 +/- 0.001 MUEq/mmHg per min, P = 0.00024 after adjustment for sex, BMI, and age). Regression analyses showed that plasma Aldo and endogenous ouabain were linearly related (beta = 0.181, P = 0.0003). CONCLUSION: Among patients with essential hypertension, circulating endogenous ouabain and Aldo are typically coelevated and their BP is salt-sensitive. In conditions where Aldo is inappropriately elevated, both Aldo and endogenous ouabain may contribute to adverse cardiovascular and renal outcomes. PMID- 27457666 TI - Prevalence of orthostatic hypertension in the very elderly and its relationship to all-cause mortality. AB - OBJECTIVE: To investigate the association with mortality of orthostatic hypertension (OHYPER) amongst the oldest old. METHODS: Two waves of community dwelling residents born in 1920-1921 were examined at age of 85 (n = 1004) and 90 (n = 437). OHYPER, orthostatic hypotension (OHYPO), or orthostatic normotension (ONORMO) were so classified when difference of standing-sitting SBP either increased or decreased by at least 20 mmHg or not. RESULTS: Prevalence of OHYPO, ONORMO, and OHYPER was 5% (n = 48), 91% (n = 915), and 4% (n = 41) at age 85, and 9% (n = 39), 88% (n = 385), and 3% (n = 13) at age 90. There was a tendency for fewer men among OHYPER, and significantly more participants with financial hardship, higher weight, loneliness, and anemia (P < 0.05 for all) among the 85 year-olds, fewer with poor self-rated health, and more with anemia among the 90 year-olds. Sitting blood pressure was 157 +/- 22/75 +/- 11, 147 +/- 21/74 +/- 11, and 140 +/- 16/74 +/- 10 mmHg among OHYPO, ONORMO, and OHYPER at age 85 (P < 0.0001), and 166 +/- 28/75 +/- 10, 145 +/- 23/69 +/- 11, and 138 +/- 23/74 +/- 9 mmHg at age 90 (P < 0.0001). Ten-year survival were 27, 30, and 27%, respectively, at age 85 (log-rank P = 0.34). Five-year survival were 57, 67, and 55%, respectively, at age 90 (log-rank P = 0.14). In an adjusted Cox proportional hazards ratio model, OHYPER at age 85 was not associated with mortality (hazards ratio = 0.95, 95% confidence interval 0.65-1.39). The few OHYPER among 90-year olds precluded modeling. CONCLUSION: OHYPER is quite uncommon among community dwelling 85 and 90-year-olds and is not associated with increased mortality. PMID- 27457667 TI - Blood pressure status and the incidence of diabetic kidney disease in patients with hypertension and type 2 diabetes. AB - OBJECTIVE: Antihypertensive treatment and blood pressure (BP) reduction are known to retard the progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) but long-term real-life clinical data on the incidence of DKD are lacking. In this observational, prospective cohort study, we investigated the association between achievement and maintenance of recommended BP values and the incidence of DKD and its components over a 4-year follow-up in patients with T2DM and hypertension from the Italian Medical Diabetologists registry. METHODS: Clinical records from a total of 12 995 patients with normal renal function and urine albumin excretion at baseline and regular visits during a 4-year follow-up were retrieved and analyzed. The association between recommended, time-updated BP control (BPC) (i.e. >=75% of visits with SBP and DBP <140/85 mmHg) and the occurrence of renal outcomes was evaluated. RESULTS: At baseline, 28% of patients (n = 3612) had recommended BP values. Over the 4-year follow-up, 37% (n = 4845) developed DKD, 16% (n = 2061) low glomerular filtration rate and 27% (n = 3487) albuminuria. Patients who failed to achieve and maintain BPC over the study period showed an increased risk of developing DKD [odds ratio (OR) 1.38, P < 0.001], low glomerular filtration rate (OR 1.18, P = 0.03) and albuminuria (OR 1.47, P < 0.001) as compared with those with persistent BPC. These results were consistent after adjustment for covariates and in different subgroups. CONCLUSION: Long-term BPC is associated with a reduction in the incidence of DKD and its components in patients with hypertension and T2DM. PMID- 27457668 TI - Paternal programming of offspring cardiometabolic diseases in later life. AB - Early - intrauterine - environmental factors are linked to the development of cardiovascular disease in later life. Traditionally, these factors are considered to be maternal factors such as maternal under and overnutrition, exposure to toxins, lack of micronutrients, and stress during pregnancy. However, in the recent years, it became obvious that also paternal environmental factors before conception and during sperm development determine the health of the offspring in later life. We will first describe clinical observational studies providing evidence for paternal programming of adulthood diseases in progeny. Next, we describe key animal studies proving this relationship, followed by a detailed analysis of our current understanding of the underlying molecular mechanisms of paternal programming. Alterations of noncoding sperm micro-RNAs, histone acetylation, and targeted as well as global DNA methylation seem to be in particular involved in paternal programming of offspring's diseases in later life. PMID- 27457669 TI - Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice. AB - We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 * C57BL/6J D1 Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD 1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 * D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression. PMID- 27457670 TI - AutoStitcher: An Automated Program for Efficient and Robust Reconstruction of Digitized Whole Histological Sections from Tissue Fragments. AB - In applications involving large tissue specimens that have been sectioned into smaller tissue fragments, manual reconstruction of a "pseudo whole-mount" histological section (PWMHS) can facilitate (a) pathological disease annotation, and (b) image registration and correlation with radiological images. We have previously presented a program called HistoStitcher, which allows for more efficient manual reconstruction than general purpose image editing tools (such as Photoshop). However HistoStitcher is still manual and hence can be laborious and subjective, especially when doing large cohort studies. In this work we present AutoStitcher, a novel automated algorithm for reconstructing PWMHSs from digitized tissue fragments. AutoStitcher reconstructs ("stitches") a PWMHS from a set of 4 fragments by optimizing a novel cost function that is domain-inspired to ensure (i) alignment of similar tissue regions, and (ii) contiguity of the prostate boundary. The algorithm achieves computational efficiency by performing reconstruction in a multi-resolution hierarchy. Automated PWMHS reconstruction results (via AutoStitcher) were quantitatively and qualitatively compared to manual reconstructions obtained via HistoStitcher for 113 prostate pathology sections. Distances between corresponding fiducials placed on each of the automated and manual reconstruction results were between 2.7%-3.2%, reflecting their excellent visual similarity. PMID- 27457671 TI - Atmospheric chemical reactions of alternatives of polybrominated diphenyl ethers initiated by OH: A case study on triphenyl phosphate. AB - Many studies have been performed to evaluate the environmental risk caused by alternative flame retardants (AFRs) of polybrominated diphenyl ethers due to their ubiquitous occurrence in the environment. However, as an indispensable component of the environmental risk assessment, the information on atmospheric fate of AFRs is limited although some AFRs have been frequently and highly detected in the atmosphere. Here, a combined quantum chemical method and kinetics modeling were used to investigate atmospheric transformation mechanism and kinetics of AFRs initiated by OH in the presence of O2, taking triphenyl phosphate (TPhP) as a case. Results show that the pathway involving initial OH addition to phenyl of TPhP to form TPhP-OH adduct, and subsequent reaction of the TPhP-OH adduct with O2 to finally form phenol phosphate, is the most favorable for the titled reaction. The calculated overall reaction rate constant is 1.6*10( 12)cm(3) molecule(-1)s(-1), translating 7.6days atmospheric lifetime of TPhP. This clarifies that gaseous TPhP has atmospheric persistence. In addition, it was found that ice surface, as a case of ubiquitous water in the atmosphere, has little effect on the kinetics of the rate-determining step in the OH-initiated TPhP reaction. PMID- 27457672 TI - Impact of future urban growth on regional climate changes in the Seoul Metropolitan Area, Korea. AB - The influence of changes in future urban growth (e.g., land use changes) on the future climate variability in the Seoul metropolitan area (SMA), Korea was evaluated using the WRF model and an urban growth model (SLEUTH). The land use changes in the study area were simulated using the SLEUTH model under three different urban growth scenarios: (1) current development trends scenario (SC 1), (2) managed development scenario (SC 2) and (3) ecological development scenario (SC 3). The maximum difference in the ratio of urban growth between SC 1 and SC 3 (SC 1 - SC 3) for 50years (2000-2050) was approximately 6.72%, leading to the largest differences (0.01 degrees C and 0.03ms(-1), respectively) in the mean air temperature at 2m (T2) and wind speed at 10m (WS10). From WRF-SLEUTH modeling, the effects of future urban growth (or future land use changes) in the SMA are expected to result in increases in the spatial mean T2 and WS10 of up to 1.15 degrees C and 0.03ms(-1), respectively, possibly due to thermal circulation caused by the thermal differences between urban and rural regions. PMID- 27457673 TI - Assessment of full-scale biological nutrient removal systems upgraded with physico-chemical processes for the removal of emerging pollutants present in wastewaters from Mexico. AB - Two full-scale biological nutrient removal systems upgraded with three physico chemical processes (coagulation, chemical precipitation, and neutral Fenton) were evaluated in order to determine the removal of emerging pollutants (EPs) present in municipal wastewater from Mexico. Between 41 and 55 EPs were detected in the influents of two wastewater treatment plants (WWTPs), including personal care products (PPCPs), antibiotics, analgesics, antiepileptics, antilipidemics, antihypertensives, antiseptics, stimulants, and hormones. Emerging pollutants were detected at concentrations ranging from 0.69ng/L to 94,600ng/L. High concentrations of emerging pollutants were found during dry season. WWTP 1, integrated by oxidation ditches and UV light lamps, showed removal efficiencies of EPs between 20% and 22%. On the other hand, WWTP 2 consisted of anaerobic/anoxic/aerobic tanks coupled with two disinfection processes; chlorine dioxide and UV light lamps, for which the removal of EPs was significant (up to 80%). The concentrations of emerging pollutants in WWTP 1 effluent was found within a range 2 h and very low intrinsic clearance. It was found to be non-hepatotoxic and did not induce any significant DNA damage at high concentrations even up to 100 MUM. IIIM-019 showed satisfactory in-vivo pharmacokinetic properties. By increasing the dose from 2.5 mg/kg to 10 mg/kg, AUC0-t increased from 14935 ng h/ml to 81,478 ng h/ml. However the exposure of IIIM-019 in plasma suggested that the levels reached saturation at higher concentrations. The compound showed a good oral bioavailability of 58.7%. The results insinuate that IIIM-019 should undergo further development as a potential treatment for tuberculosis. PMID- 27457686 TI - The junction between self and other? Temporo-parietal dysfunction in neuropsychiatry. AB - The temporo-parietal junction (TPJ) is implicated in a variety of processes including multisensory integration, social cognition, sense of agency and stimulus-driven attention functions. Furthermore, manipulation of cortical excitation in this region can influence a diverse range of personal and interpersonal perceptions, from those involved in moral decision making to judgments about the location of the self in space. Synthesis of existing studies places the TPJ at the neural interface between mind and matter, where information about both mental and physical states is processed and integrated, contributing to self-other differentiation. After first summarising the functions of the TPJ according to existing literature, this narrative review aims to offer insight into the potential role of TPJ dysfunction in neuropsychiatric disorders, with a focus on the involvement of the right TPJ in controlling representations relating to the self and other. Problems with self-other distinctions may reflect or pose a vulnerability to the symptoms associated with Tourette syndrome, Schizophrenia, Autistic Spectrum Disorder and Obsessive Compulsive Disorder. Further study of this most fascinating neural region will therefore make a substantial contribution to our understanding of neuropsychiatric symptomatology and highlight significant opportunities for therapeutic impact. PMID- 27457687 TI - Remembering a visit to the psychology lab: Implications of Mild Cognitive Impairment. AB - Morris Moscovitch has emphasized the importance of sensitively and carefully measuring cognition in the real world. With this lesson in mind, we examined the real-world episodic memory problems of older adults with Mild Cognitive Impairment (MCI). MCI patients often complain of episodic memory problems and perform poorly on standardized neuropsychological measures, but we still do not know enough about their actual difficulties remembering real experiences. A few days after their visit to the laboratory for an experimental session, we telephoned 19 MCI patients and 34 healthy participants without warning to ask what they could recollect about 16 elements of their visit. The patients had difficulty remembering the details of their visit, and reported lower ratings of memory vividness compared to healthy participants. Patients' memory for the visit was commensurate with their performance on three standard clinical memory assessment measures (delayed 5 word recall from the Montreal Cognitive Assessment, long delay free recall from the California Verbal Learning Test-II and recall of the details of the Wechsler Memory Scale-III Logical Memory stories), providing evidence for the generalizability of the clinical measures. Putting these findings together with those from Moscovitch and colleagues (Murphy et al., 2008) can help us better understand the real-world memory implications of Mild Cognitive Impairment. PMID- 27457688 TI - Vulnerable children, stigmatised smokers: The social construction of target audiences in media debates on policies regulating smoking in vehicles. AB - Following restrictions on smoking in vehicles carrying children in several countries, legislation to safeguard minors from second-hand smoke exposure in vehicles is under-consideration or has been implemented across the United Kingdom. This article presents the first investigation into social constructions of children, smokers and smoking parents in newsprint media and coverage of debates about protecting children from exposure to second-hand smoke in vehicles. Using Scotland as an example, articles on children's exposure to second-hand smoke published between 1 January 2004 and 16 February 2014 in three Scottish newspapers were identified using Nexis UK. In all, 131 articles were thematically coded and analysed. Children were portrayed as vulnerable and requiring protection, with few articles highlighting children's ability to voice concerns about the dangers of smoking. Smokers and smoking parents were mainly portrayed in a factual manner, but also frequently as irresponsible and, in some cases, intentionally imposing harm. Individual smokers were blamed for their recklessness, with only a small number of articles mentioning the need to assist smokers in quitting. Supporters of legislation focused on corresponding discourse, whereas critics directed debates towards established arguments against policy, including individual freedom, privacy and problems of enforcement. Focusing on children's vulnerability to second-hand smoke might have increased support for legislation but risked a side effect of smokers being stigmatised. The media and supporters of public health policy are encouraged to consider appropriate approaches to raise awareness of the health harms of second-hand smoke to children while avoiding unintended stigmatisation of those in which they want to encourage behaviour change. PMID- 27457690 TI - Left bundle branch block in serious hyperkalaemia: rate-dependency? PMID- 27457689 TI - Ethnic differences in bone geometry between White, Black and South Asian men in the UK. AB - Relatively little is known about the bone health of ethnic groups within the UK and data are largely restricted to women. The aim of this study was to investigate ethnic differences in areal bone mineral density (aBMD), volumetric bone mineral density (vBMD), bone geometry and strength in UK men. White European, Black Afro-Caribbean and South Asian men aged over 40years were recruited from Greater Manchester, UK. aBMD at the spine, hip, femoral neck and whole body were measured by DXA. Bone geometry, strength and vBMD were measured at the radius and tibia using pQCT at the metaphysis (4%) and diaphysis (50% radius; 38% tibia) sites. Adjustments were made for age, weight and height. Black men had higher aBMD at the whole body, total hip and femoral neck compared to White and South Asian men independent of body size adjustments, with no differences between the latter two groups. White men had longer hip axis lengths than both Black and South Asian men. There were fewer differences in vBMD but White men had significantly lower cortical vBMD at the tibial diaphysis than Black and South Asian men (p<0.001). At the tibia and radius diaphysis, Black men had larger bones with thicker cortices and greater bending strength than the other groups. There were fewer differences between White and South Asian men. At the metaphysis, South Asian men had smaller bones (p=0.02) and lower trabecular vBMD at the tibia (p=0.003). At the diaphysis, after size-correction, South Asian men had similar sized bones but thinner cortices than White men; measures of strength were not broadly reduced in the South Asian men. Combining pQCT and DXA measurements has given insight into differences in bone phenotype in men from different ethnic backgrounds. Understanding such differences is important in understanding the aetiology of male osteoporosis. PMID- 27457691 TI - Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The poly-herbal formulation DB14201 is a new combination of ayurvedic ingredients for treatment of diabetes. The aim of present study was to investigate safety and in vivo efficacy of DB14201 extract. Further this work was aimed to develop, characterize and standardize DB14201 extract and develop it as a botanical drug. MATERIALS AND METHODS: The polyherbal extract was standardized using four chemical markers. The LC-MS/MS method was developed for identification and quantification of mangiferin, berberine, kaempferol and curcumin. The extract was standardized for heavy metal content, aflotoxins, and microbial tests. The mechanism of action of DB14201 extract was explored through glucose uptake by adipocytes, TNF-alpha production and free fatty acid release, in vitro, was studied using murine adipocytes (3T3-L1). The effect of extract on insulin release was evaluated using murine pancreatic beta cell (beta TC-6). The safety and in vivo efficacy of extract was studied using suitable animal model. Hematology and blood biochemistry parameters were also assessed. RESULTS: In vitro studies of DB14201 in murine adipocytes and murine pancreatic beta cells demonstrated the plausible mechanism of action of DB14201 could be through increase in glucose uptake and by stimulation of insulin release by RIN-5f cells. The microbial load, heavy metals were found to be within the AYUSH permissible limits and aflotoxins were absent. Preclinical efficacy studies in animal models proved the anti-diabetic potential of the extract. The preclinical acute dose toxicity study and 90-days repeated dose toxicity study of DB14201 extract in wistar rats by oral route indicated that the extract is safe up to 1000mg/kg dose. Hematology and blood biochemistry parameters were within the normal range. CONCLUSIONS: The data presented herein demonstrated anti diabetic potential of developed DB14201 extract and this study will serve as the benchmark for the further research on this polyherbal formulation. PMID- 27457692 TI - Evaluation of herb-drug interaction of a polyherbal Ayurvedic formulation through high throughput cytochrome P450 enzyme inhibition assay. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Arishtas are Ayurvedic formulation made with decoction of herbs. Arjunarishta formulation is being used in Ayurveda for cardio protective activity. Ashwagandharishta formulation possesses antioxidant, anti atherosclerotic and anti-stress properties. Ridayarishta, a novel empirical formulation was prepared using combination of selected ingredients from these two formulations to support healthy heart functions and to reduce stress. AIM OF THE STUDY: Aim of the Study was to investigate herb-drug interaction (HDI) of Ridayarishta formulation through human hepatic cytochrome P450 (CYP450) enzyme inhibition assay. MATERIALS AND METHODS: Ridayarishta formulation was phyto chemically standardized against arjunolic acid, arjunetin, berberine, piperine, resveratrol and withaferin-A using high performance thin layer chromatography (HPTLC) analysis. The formulation was standardized with respect to ethanol by gas chromatographic (GC) analysis. HDI was evaluated with Ridayarishta formulation and amlodipine besilate, atenolol, atorvastatin, metformin, glipizide glimepiride cocktail using high throughput CYP450 enzyme inhibition assay; against CYP1A2, 2C19, 2D6 and 3A4 isozymes. RESULTS: Contents of arjunolic acid, arjunetin, berberine, piperine, resveratrol and withaferin-A in Ridayarishta formulation were found to be 1.76+/-0.12, 1.51+/-0.09, 1.85+/-0.05, 3.2+/-0.12, 1.21+/-0.08, and 2.16+/-0.09ppm, respectively. Quantity of ethanol in Ridayarishta was found to be 7.95+/-0.023% (V/V). Ridayarishta showed significantly higher (P<0.001) IC50 value against CYP1A2 (IC50-13.80+/-1.96ug/mL), 2C19 (IC50-14.343+/ 2.28ug/mL), 2D6 (IC50-0.897+/-0.28ug/mL) and 3A4 (IC50-32.057+/-2.51ug/mL) compared to positive controls such as furafylline, tranylcypromine, quinidine and ketoconazole respectively. Cocktail of herbal formulation and cardio protective, antihypertensive, anti-diabetic drugs showed significantly (P<0.001and P<0.01) less or negligible HDI. CONCLUSION: Ridayarishta formulation alone and cocktail with amlodipine besilate, atenolol, atorvastatin, metformin, glipizide, glimepiride had negligible or insignificant effect on CYP450 inhibition. It may be concluded that consumption of Ridayarishta along with selective cardio protective, antihypertensive and anti-diabetic conventional medicine is safe with negligible or without any significant CYP450 (CYP1A2, 2C19, 2D6 and 3A4) inhibition mediated HDI. PMID- 27457693 TI - Ethnobotanical investigation on medicinal plants in the Vesuvio National Park (Campania, Southern Italy). AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper illustrates the results of an ethnobotanical study carried out in the Vesuvio National Park (VNP) (Campania, Southern Italy). It describes the medicinal uses of the plants in an ancient area rich in ethnobiodiversity investigated for the first time. AIM FOR THE STUDY: The main aim of the study was to understand at what extent current knowledge on medicinal plant uses is still alive in VNP. MATERIALS AND METHODS: The informations were collected using semi-structured and unstructured interviews performed on 136 persons living in the investigated area from March to November 2014 and from April to October 2015. The age of the informants ranged from 47 to 85 years old; more than half of the informants aged between 61 and 70. Local plant uses were listed and analyzed in a table and compared with uses in other localities in Italy and in other regions of the Mediterranean basin. RESULTS: In VNP were recorded a total number of 132 plant species, belonging to 110 genera and 51 families mentioned for medicinal purposes. Among the recorded 132 plant species, 70 are spontaneous or subspontaneous and 62 are cultivated above all in the kitchen gardens or in the apartments, as food or as ornamental. Herbs represent the majority, followed by trees and shrubs or subshrubs. The investigated plants were used to cure 116 different human health diseases and 4 veterinary problems. The majority of plants are used in the treatment of gastrointestinal, skin and respiratory problems. CONCLUSION: The number of medicinal plants reported in this paper reflects a well-preserved traditional popular knowledge (TPK) of the elderly people living in the rural areas and in the small villages of VNP. The conservation of TPK is owed to the persistence of an oral tradition that safeguard the use of plants as herbal medicine. We realized that while the use of some wild plants is decreasing, people continue to gather some cultivated and invasive plants for preparing remedies. Researches like this are necessary to protect ancient memories, to promote the transfer of information to the younger generations, to preserve ethno-biodiversity and to provide a starting point fur further biochemical investigations on medicinal entities. PMID- 27457694 TI - Evaluation of Cynodon dactylon for wound healing activity. AB - BACKGROUND AND AIMS: Research in the field of wound healing is very recent. The concept of wound healing is changing from day to day. Ayurveda is the richest source of plant drugs for management of wounds and Cynodon dactylon L. is one such. The plant is used as hemostatic and wound healing agent from ethnopharmacological point of view. Aim of the present study is scientific validation of the plant for wound healing activity in detail. MATERIALS AND METHODS: Aqueous extract of the plant was prepared and phytochemical constituents were detected by HPLC analysis. Acute and dermatological toxicity study of the extract was performed. Pharmacological testing of 15% ointment (w/w) of the extract with respect to placebo control and standard comparator framycetin were done on full thickness punch wound in Wister rats and effects were evaluated based on parameters like wound contraction size (mm2), tensile strength (g); tissue DNA, RNA, protein, hydroxyproline and histological examination. The ointment was applied on selected clinical cases of chronic and complicated wounds and efficacy was evaluated on basis of scoring on granulation, epithelialization, vascularity as well as routine hematological investigations. RESULTS: Significant results (p<0.05) were observed both in pharmacological and clinical studies. CONCLUSION: The present research with aqueous extract of Cynodon dactylon explores its potential wound healing activity in animal model and subsequent feasibility in human subjects. Phenolic acids and flavonoids present in c. dactylon supports its wound healing property for its anti-oxidative activity that are responsible for collagenesis. PMID- 27457695 TI - Ayurgenomics for stratified medicine: TRISUTRA consortium initiative across ethnically and geographically diverse Indian populations. AB - BACKGROUND: Genetic differences in the target proteins, metabolizing enzymes and transporters that contribute to inter-individual differences in drug response are not integrated in contemporary drug development programs. Ayurveda, that has propelled many drug discovery programs albeit for the search of new chemical entities incorporates inter-individual variability "Prakriti" in development and administration of drug in an individualized manner. Prakriti of an individual largely determines responsiveness to external environment including drugs as well as susceptibility to diseases. Prakriti has also been shown to have molecular and genomic correlates. We highlight how integration of Prakriti concepts can augment the efficiency of drug discovery and development programs through a unique initiative of Ayurgenomics TRISUTRA consortium. METHODS: Five aspects that have been carried out are (1) analysis of variability in FDA approved pharmacogenomics genes/SNPs in exomes of 72 healthy individuals including predominant Prakriti types and matched controls from a North Indian Indo-European cohort (2) establishment of a consortium network and development of five genetically homogeneous cohorts from diverse ethnic and geo-climatic background (3) identification of parameters and development of uniform standard protocols for objective assessment of Prakriti types (4) development of protocols for Prakriti evaluation and its application in more than 7500 individuals in the five cohorts (5) Development of data and sample repository and integrative omics pipelines for identification of genomic correlates. RESULTS: Highlight of the study are (1) Exome sequencing revealed significant differences between Prakriti types in 28 SNPs of 11 FDA approved genes of pharmacogenomics relevance viz. CYP2C19, CYP2B6, ESR1, F2, PGR, HLA-B, HLA-DQA1, HLA-DRB1, LDLR, CFTR, CPS1. These variations are polymorphic in diverse Indian and world populations included in 1000 genomes project. (2) Based on the phenotypic attributes of Prakriti we identified anthropometry for anatomical features, biophysical parameters for skin types, HRV for autonomic function tests, spirometry for vital capacity and gustometry for taste thresholds as objective parameters. (3) Comparison of Prakriti phenotypes across different ethnic, age and gender groups led to identification of invariant features as well as some that require weighted considerations across the cohorts. CONCLUSION: Considering the molecular and genomics differences underlying Prakriti and relevance in disease pharmacogenomics studies, this novel integrative platform would help in identification of differently susceptible and drug responsive population. Additionally, integrated analysis of phenomic and genomic variations would not only allow identification of clinical and genomic markers of Prakriti for application in personalized medicine but also its integration in drug discovery and development programs. PMID- 27457697 TI - C-reactive protein is a useful negative predictor of anastomotic leak in oesophago-gastric resection. AB - BACKGROUND: Post-operative C-reactive protein (CRP) has been investigated as a predictor of anastomotic leak (AL) following colorectal surgery, but its role in oesophago-gastric surgery is not yet established. METHODS: Clinical data and post operative CRP values of patients who underwent elective oesophago-gastric resection between January 2004 and July 2014 were analysed retrospectively. Only patients with an oesophageal anastomosis were included. AL was defined as leakage of contrast material seen on imaging or a leak confirmed intraoperatively on return to theatre. RESULTS: One hundred and forty-five patients were identified. Of the 145 patients, 13 (9%) developed AL. The CRP on post-operative days (POD) 2, 3 and 6 had the greatest diagnostic accuracy, with an area under the curve of 0.82, 0.80 and 0.91 respectively. Using a cut-off value of 209 mg/L on POD 2, the sensitivity was 100%, the specificity was 61%, the positive predictive value (PPV) was 21% and the negative predictive value (NPV) was 100%. Using a cut-off value of 190 mg/L on POD 3, the sensitivity was 100%, the specificity was 59%, the PPV was 21% and the NPV was 100%. Using a cut-off value of 154 mg/L on POD 6, the sensitivity was 100%, the specificity was 78%, the PPV was 29% and the NPV was 100%. CONCLUSION: Post-operative CRP is an accurate negative predictive test for the development of AL following oesophago-gastric surgery. It may help to discriminate between patients with a high risk of leak and those in which AL is unlikely to occur. PMID- 27457696 TI - Sameerpannag Ras Mixture (SRM) improved neurobehavioral deficits following acute ischemic stroke by attenuating neuroinflammatory response. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cerebral ischemic stroke is one of the leading causes of death and long-term disability worldwide. Unfortunately, due to the failure of most of drugs in clinical trials recently, attentions have moved towards the traditional system of medicines including Ayurveda. In Ayurveda, Sameerpannag Ras (SR) is a mineral and metallic origin based formulation which has been used for the treatment of arthritis and chronic systematic inflammatory disorder. The current study was designed to investigate the neuroprotective effects of Sameerpannag Ras Mixture (SRM), on the neurobehavioral dysfunction and associated neuroinflammation, induced by transient Internal Carotid Artery Occlusion (ICAO) in mice model. MATERIALS AND METHODS: In the present study, mice were treated with Sameerpannag Ras Mixture (SRM) at the dose of 40mg/kg body weight by oral gavages for 3 and 7days respectively, twice a day, after the induction of ICAO for 90min followed by reperfusion. The efficacy of SRM was examined by scoring neurological behavioral deficit using the standard neurological deficit score (NDS), grip strength and rotarod performance tests at different time intervals of post-ICAO. RESULTS: Post-ischemic treatment with Sameerpannag Ras Mixture (SRM) at 40mg/kg significantly reduced Neurological Deficit Score and improved the motor coordination at different time intervals post-ICAO. The analysis of RT-qPCR data showed that transient cerebral ischemia could induce the inflammatory response genes in the affected striatal region of ICAO group, as compared to sham group, on day3 and day7 post-ICAO. Interestingly, SRM treatment showed marked improvement in the ischemia-induced neurobehavioral deficits by attenuating ischemia-induced neuroinflammatory response at both gene and protein level. CONCLUSION: The present study suggests that Sameerpannag Ras Mixture (SRM) treatment ameliorates behavioral outcomes after mild ischemia through the suppression of a number of inflammatory response genes involved in neuronal damage. This is the first report of the molecular mechanism underlying the significant neuroprotective action of the Ayurvedic drug, Sameerpannag Ras Mixture (SRM), using a mild stroke in mice model. PMID- 27457698 TI - Lactose fermentation by engineered Saccharomyces cerevisiae capable of fermenting cellobiose. AB - Lactose is an inevitable byproduct of the dairy industry. In addition to cheese manufacturing, the growing Greek yogurt industry generates excess acid whey, which contains lactose. Therefore, rapid and efficient conversion of lactose to fuels and chemicals would be useful for recycling the otherwise harmful acid whey. Saccharomyces cerevisiae, a popular metabolic engineering host, cannot natively utilize lactose. However, we discovered that an engineered S. cerevisiae strain (EJ2) capable of fermenting cellobiose can also ferment lactose. This finding suggests that a cellobiose transporter (CDT-1) can transport lactose and a beta-glucosidase (GH1-1) can hydrolyze lactose by acting as a beta galactosidase. While the lactose fermentation by the EJ2 strain was much slower than the cellobiose fermentation, a faster lactose-fermenting strain (EJ2e8) was obtained through serial subcultures on lactose. The EJ2e8 strain fermented lactose with a consumption rate of 2.16g/Lh. The improved lactose fermentation by the EJ2e8 strain was due to the increased copy number of cdt-1 and gh1-1 genes. Looking ahead, the EJ2e8 strain could be exploited for the production of other non-ethanol fuels and chemicals from lactose through further metabolic engineering. PMID- 27457699 TI - A non-chromatographic protein purification strategy using Src 3 homology domains as generalized capture domains. AB - Protein purification using inverse phase transition of elastin-like polypeptide (ELP) domains is a useful alternative to chromatography. Genetic fusions of ELP domains to various proteins have the ability to reversibly transition between soluble monomers and micron-sized aggregates and this has been used to selectively purify many ELP fusions. Affinity domains can enhance this technology by using specific protein binding domains to enable ELP mediated affinity capture (EMAC) of proteins of interest (POI) that have been fused to corresponding affinity ligands. In this paper, we highlight the use of Src homology 3 (SH3) domains and corresponding peptide ligands in EMAC that have differential binding affinities towards SH3 for efficient capture and elution of proteins. Furthermore, differences between capture and elution of a monomeric and a multimeric protein were also studied. PMID- 27457701 TI - Life expectancy and causes of death in Bernese mountain dogs in Switzerland. AB - BACKGROUND: New regulations by the Swiss Federal Food Safety and Veterinary Office provide for the monitoring of breed health by Swiss breeding clubs. In collaboration with the Swiss Bernese Mountain Dog Club, the purpose of this study was to investigate the causes of death in purebred dogs registered by the club and born in 2001 and 2002. RESULTS: Of a total of 1290 Bernese mountain dogs (BMDs) born in 2001 and 2002 in Switzerland, data was collected from owners and veterinarians using a questionnaire designed for this study from 389 dogs (30.2 %). By the end of the study, 381/389 dogs (97.9 %) had died. The median life expectancy of all dogs was 8.4 years (IQR, 6.9-9.7). Female dogs had a significantly longer median survival (8.8 years; IQR, 7.1-10.3) than male dogs (7.7 years; IQR, 6.6-9.3) (P < 0.00). The cause of death was unknown in 89/381 dogs (23.4 %). For the remaining dogs, the most frequent causes of death were neoplasia (222/381, 58.3 %), degenerative joint disease (16/381, 4.2 %), spinal disorders (13/381, 3.4 %), renal injury (12/381, 3.1 %), and gastric or mesenteric volvulus (7/381, 1.8 %). However, large numbers of dogs were diagnosed with neoplasia without histopathologic or cytologic confirmation. Dogs with neoplasms had a shorter median survival than dogs with other disorders. The shortest median survival (6.8 years) was found for dogs with renal injury. CONCLUSIONS: Findings of this study confirm a high prevalence of neoplasia and associated low life expectancy in BMDs. The results underline a need for more widespread precise diagnostics and further research on malignant tumours in this breed to improve overall breed health. PMID- 27457700 TI - Extracellular K+ rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl- -dependent and independent mechanisms. AB - KEY POINTS: High dietary potassium (K+ ) intake dephosphorylates and inactivates the NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Using several ex vivo models, we show that physiological changes in extracellular K+ , similar to those occurring after a K+ rich diet, are sufficient to promote a very rapid dephosphorylation of NCC in native DCT cells. Although the increase of NCC phosphorylation upon decreased extracellular K+ appears to depend on cellular Cl- fluxes, the rapid NCC dephosphorylation in response to increased extracellular K+ is not Cl- -dependent. The Cl- -dependent pathway involves the SPAK/OSR1 kinases, whereas the Cl- independent pathway may include additional signalling cascades. ABSTRACT: A high dietary potassium (K+ ) intake causes a rapid dephosphorylation, and hence inactivation, of the thiazide-sensitive NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Based on experiments in heterologous expression systems, it was proposed that changes in extracellular K+ concentration ([K+ ]ex ) modulate NCC phosphorylation via a Cl- -dependent modulation of the with no lysine (K) kinases (WNK)-STE20/SPS-1-44 related proline alanine-rich protein kinase (SPAK)/oxidative stress-related kinase (OSR1) kinase pathway. We used the isolated perfused mouse kidney technique and ex vivo preparations of mouse kidney slices to test the physiological relevance of this model on native DCT. We demonstrate that NCC phosphorylation inversely correlates with [K+ ]ex , with the most prominent effects occurring around physiological plasma [K+ ]. Cellular Cl- conductances and the kinases SPAK/OSR1 are involved in the phosphorylation of NCC under low [K+ ]ex . However, NCC dephosphorylation triggered by high [K+ ]ex is neither blocked by removing extracellular Cl- , nor by the Cl- channel blocker 4,4'-diisothiocyano-2,2'-stilbenedisulphonic acid. The response to [K+ ]ex on a low extracellular chloride concentration is also independent of significant changes in SPAK/OSR1 phosphorylation. Thus, in the native DCT, [K+ ]ex directly and rapidly controls NCC phosphorylation by Cl- dependent and independent pathways that involve the kinases SPAK/OSR1 and a yet unidentified additional signalling mechanism. PMID- 27457702 TI - Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression. AB - The presence of high numbers of circulating clonal plasma cells (cPCs) in patients with smoldering multiple myeloma (SMM), detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to MM. The significance of quantifying cPCs via multiparameter flow cytometry, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. This study evaluated 100 patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013. Patients with ?150 cPCs (N=9) were considered to have high number of cPCs based on the 97% specificity and 78% PPV of progression to MM within 2 years of cPC assessment. The median TTP of patients with ?150 cPCs was 9 months compared with not reached for patients with <150 cPCs (P<0.001). Thus, quantification of cPCs via multiparametric flow cytometry identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage. PMID- 27457703 TI - Artificial plasma membrane models based on lipidomic profiling. AB - Phospholipid monolayers are often described as membrane models for analyzing drug lipid interactions. In many works, a single phosphatidylcholine is chosen, sometimes with one or two additional components. Drug penetration is studied at 30mN/m, a surface pressure considered as corresponding to the pressure in bilayers, independently of the density of lipid molecular packing. In this work, we have extracted, identified, and quantified the major lipids constituting the lipidome of plasma and mitochondrial membranes of retinoblastoma (Y79) and retinal pigment epithelium cells (ARPE-19), using liquid chromatography coupled to high-resolution mass spectrometry (LC-MS/MS). The results obtained from this lipidomic analysis were used in an attempt to build an artificial lipid monolayer with a composition mimicking that of the plasma membrane of Y79 cells, better than a single phospholipid. The variety and number of lipid classes and species in cell extracts monolayers exceeding by far those of the phospholipids chosen to mimic them, the pi-A isotherms of model monolayers differed from those of lipid extracts in shape and apparent packing density. We propose a model monolayer based on the most abundant species identified in the extracts, with a surface compressional modulus at 30mN/m close to the one of the lipid extracts. PMID- 27457705 TI - Can early allergen exposure prevent food allergy? PMID- 27457704 TI - Pentobarbital modifies the lipid raft-protein interaction: A first clue about the anesthesia mechanism on NMDA and GABAA receptors. AB - Recent studies have shown that anesthetic agents alter the physical properties of lipid rafts on model membranes. However, if this destabilization occurs in brain membranes, altering the lipid raft-protein interaction, remains unknown. We analyzed the effects produced by pentobarbital (PB) on brain plasma membranes and lipid rafts in vivo. We characterized for the first time the thermotropic behavior of plasma membranes, synaptosomes, and lipid rafts from rat brain. We found that the transition temperature from the ordered gel to disordered liquid phase of lipids is close to physiological temperature. We then studied the effect of PB on protein composition of lipid rafts. Our results show a reduction of the total protein associated to rafts, with a higher reduction of the NMDAR compared to the GABAA receptor. Both receptors are considered the main targets of PB. In general, our results suggest that lipid rafts could be plausible mediators in anesthetic action. PMID- 27457706 TI - The evolution of outpatient parenteral antibiotic therapy. PMID- 27457707 TI - Phase 1 Study of CEP-37250/KHK2804, a Tumor-specific Anti-glycoconjugate Monoclonal Antibody, in Patients with Advanced Solid Tumors. AB - BACKGROUND: CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types. OBJECTIVE: The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of CEP-37250/KHK2804 monotherapy in patients with advanced cancer in a first-in-human, phase 1 study. MATERIALS AND METHODS: In phase 1a, patients (n = 31) with solid tumors received increasing doses of CEP-37250/KHK2804 (0.03-1.0 mg/kg) intravenously once weekly using a standard 3 + 3 dose-escalation design. In phase 1b, two dose-expansion cohorts of patients with colorectal (n = 15) and pancreatic (n = 16) cancer, respectively, received the maximum tolerated dose (MTD). RESULTS: The MTD of CEP 37250/KHK2804 was 0.3 mg/kg weekly. Dose-limiting toxicities were infusion related reactions and increased serum transaminases. In the overall population (N = 62), the most frequent treatment-related adverse event (AE) was an infusion related reaction (45.2 %). Positive post-baseline CEP-37250/KHK2804 neutralizing antibodies were reported in 14 patients (22.6 %), almost exclusively in patients who developed infusion-related reactions. The most frequent treatment-related AE grade >=3 was increased AST or ALT in six patients (9.7 %). Three patients experienced treatment-related serious cardiac events (grade 4 ECG abnormality, grade 4 atrial fibrillation, and grade 3 acute myocardial infarction, respectively). Pharmacokinetic exposure to CEP-37250/KHK2804 increased proportionally to dose, with accumulation up to two fold with repeated administration. Mean elimination half-life was 34.1 to 70.3 hours over the dose range from 0.03 to 1.0 mg/kg. No patient had a complete or partial best response. Thirteen of 40 (32.5 %) evaluable patients had unconfirmed stable disease, four of which were confirmed (10.0 %). CONCLUSIONS: The study was stopped early due to the lack of efficacy. Additionally, safety concerns (i.e., cardiac issues, hepatic toxicity, and infusion-related reactions) made the benefit-risk assessment unfavorable for continued development of CEP-37250/KHK2804, which was halted indefinitely. [Study registered at ClinicalTrials.gov #NCT01447732]. PMID- 27457708 TI - Dielectric Huygens' Metasurface for High-Efficiency Hologram Operating in Transmission Mode. AB - Conventional metasurface holograms relying on metal antennas for phase manipulation suffer from strong Ohmic loss and incomplete polarization conversion. The efficiency is limited to rather small values when operating in transmission mode. Here, we implement a high-efficiency transmissive metasurface hologram by leveraging the recently developed Huygens' metasurface to construct an electric and magnetic sheet with a transmission efficiency up to 86% and optical efficiency of 23.6%. The high-efficiency originates from the simultaneous excitations of the Mie-type electric and magnetic dipole resonances in the meta atoms composed of silicon nanodisks. Our hologram shows high fidelity over a wide spectral range and promises to be an outstanding alternative for display applications. PMID- 27457709 TI - Older Cancer Patients' User Experiences With Web-Based Health Information Tools: A Think-Aloud Study. AB - BACKGROUND: Health information is increasingly presented on the Internet. Several Web design guidelines for older Web users have been proposed; however, these guidelines are often not applied in website development. Furthermore, although we know that older individuals use the Internet to search for health information, we lack knowledge on how they use and evaluate Web-based health information. OBJECTIVE: This study evaluates user experiences with existing Web-based health information tools among older (>= 65 years) cancer patients and survivors and their partners. The aim was to gain insight into usability issues and the perceived usefulness of cancer-related Web-based health information tools. METHODS: We conducted video-recorded think-aloud observations for 7 Web-based health information tools, specifically 3 websites providing cancer-related information, 3 Web-based question prompt lists (QPLs), and 1 values clarification tool, with colorectal cancer patients or survivors (n=15) and their partners (n=8) (median age: 73; interquartile range 70-79). Participants were asked to think aloud while performing search, evaluation, and application tasks using the Web-based health information tools. RESULTS: Overall, participants perceived Web based health information tools as highly useful and indicated a willingness to use such tools. However, they experienced problems in terms of usability and perceived usefulness due to difficulties in using navigational elements, shortcomings in the layout, a lack of instructions on how to use the tools, difficulties with comprehensibility, and a large amount of variety in terms of the preferred amount of information. Although participants frequently commented that it was easy for them to find requested information, we observed that the large majority of the participants were not able to find it. CONCLUSIONS: Overall, older cancer patients appreciate and are able to use cancer information websites. However, this study shows the importance of maintaining awareness of age-related problems such as cognitive and functional decline and navigation difficulties with this target group in mind. The results of this study can be used to design usable and useful Web-based health information tools for older (cancer) patients. PMID- 27457710 TI - Dental calcification stages as determinants of the peak growth period. AB - OBJECTIVE: The objective of this study was to investigate the diagnostic accuracy of dental maturation stages for identifying individual-specific skeletal maturation phases. SUBJECTS AND METHODS: Prior to initiating this study, 255 orthodontic patients comprising 145 girls and 110 boys from the Department of Orthodontics, Aristotle University of Thessaloniki, Greece were identified. Lateral cephalometric and panoramic radiographs were evaluated. Dental calcification stages were assessed according to the Demirjian method and skeletal maturation according to the cervical vertebral maturation stage (CVMS) method. Statistical assessments included Spearman Brown formula, descriptive statistics, Spearman's rho correlation coefficient, and positive likelihood ratios (LHRs). RESULTS: The highest (r = 0.725) correlations were found for second molars and the lowest correlation for canines (r = 0.463, p < 0.001). Positive LHR values exceeding ten were found to identify the pre-peak growth phase in conjunction with the second molar (stage D), second premolar (stage E), and first premolar (stages D and E). Only the second molar (stage F) yielded positive LHR values for identifying the peak growth phase. The positive LHR values for the second molar also facilitated identification of the post-peak growth phase (stage H). Taking the clinical diagnostic efficacy of the second molar into account in identifying these growth phases, we calculated the positive LHRs of the second molar to determine dental maturation stages for diagnosing CVMS II and III. Positive LHR values greater than 10 identified CVMS II (stage D). CONCLUSION: Evaluating dental maturation is a useful initial diagnostic step when assessing skeletal growth. The calcification stages of the second molar provide reliable diagnostic information with which to determine the pubertal growth spurt. PMID- 27457711 TI - Recent developments with the New Zealand regulated market approach to 'low-risk' psychoactive products. PMID- 27457713 TI - The Visual Aesthetics of Snowflakes. AB - In two experiments, participants evaluated the perceived beauty of snowflakes and solid objects. The snowflake silhouettes used as experimental stimuli were created from photographs of natural snowflakes. Both the snowflake silhouettes and computer-generated solid objects varied in complexity. In Experiment 1, 204 participants selected the single snowflake and single solid object that was the most beautiful. In Experiment 2, 33 participants rated the perceived complexity and beauty of the entire set of 100 snowflakes and solid objects. When considered as a group, the participants' results for the solid objects replicated previous findings: The most and least complex objects were perceived as being the most beautiful. This pattern did not necessarily occur, however, for individual participants. Some participants in Experiment 2, for example, found only complex solid objects to be most beautiful ( N = 10); other participants found only the simple solid objects to be most beautiful ( N = 11). Additional participants perceived both the most and least complex solid objects to be beautiful ( N = 10), while one participant only found moderately complex solid objects to be most beautiful. The results for the snowflakes were more uniform: 91% of participants perceived only the complex snowflakes as being most beautiful. PMID- 27457712 TI - Development and validation of a novel questionnaire for self-determination of the range of motion of wrist and elbow. AB - BACKGROUND: The aim of this study was to develop and validate a novel self administered questionnaire for assessing the patient's own range of motion (ROM) of the wrist and the elbow. METHODS: In a prospective clinical study from January 2015 to June 2015, 101 consecutive patients were evaluated with a novel, self administered, diagram-based, wrist motion assessment score (W-MAS) and elbow motion assessment score (E-MAS). The questionnaire was statistically evaluated for test-retest reliability, patient-physician agreement, comparison with healthy population, and influence of covariates (age, gender, affected side and involvement in workers' compensation cases). RESULTS: Assessment of patient physician agreement demonstrated almost perfect agreement (k > 0.80) with regard to six out of eight items. There was substantial agreement with regard to two items: elbow extension (k = 0.76) and pronation (k = 0.75). The assessment of the test-retest reliability revealed at least substantial agreement (k = 0.70). The questionnaire revealed a high discriminative power when comparing the healthy population with the study group (p = 0.007 or lower for every item). Age, gender, affected side and involvement in workers' compensation cases did not in general significantly influence the patient-physician agreement for the questionnaire. CONCLUSION: The W-MAS and E-MAS are valid and reliable self-administered questionnaires that provide a high level of patient-physician agreement for the assessments of wrist and elbow ROM. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 27457714 TI - Complementation of Cobalamin Auxotrophy in Synechococcus sp. Strain PCC 7002 and Validation of a Putative Cobalamin Riboswitch In Vivo. AB - The euryhaline cyanobacterium Synechococcus sp. strain PCC 7002 has an obligate requirement for exogenous vitamin B12 (cobalamin), but little is known about the roles of this compound in cyanobacteria. Bioinformatic analyses suggest that only the terminal enzyme in methionine biosynthesis, methionine synthase, requires cobalamin as a coenzyme in Synechococcus sp. strain PCC 7002. Methionine synthase (MetH) catalyzes the transfer of a methyl group from N(5)-methyl-5,6,7,8 tetrahydrofolate to l-homocysteine during l-methionine synthesis and uses methylcobalamin as an intermediate methyl donor. Numerous bacteria and plants alternatively employ a cobalamin-independent methionine synthase isozyme, MetE, that catalyzes the same methyl transfer reaction as MetH but uses N(5)-methyl 5,6,7,8-tetrahydrofolate directly as the methyl donor. The cobalamin auxotrophy of Synechococcus sp. strain PCC 7002 was complemented by using the metE gene from the closely related cyanobacterium Synechococcus sp. strain PCC 73109, which possesses genes for both methionine synthases. This result suggests that methionine biosynthesis is probably the sole use of cobalamin in Synechococcus sp. strain PCC 7002. Furthermore, a cobalamin-repressible gene expression system was developed in Synechococcus sp. strain PCC 7002 that was used to validate the presence of a cobalamin riboswitch in the promoter region of metE from Synechococcus sp. strain PCC 73109. This riboswitch acts as a cobalamin-dependent transcriptional attenuator for metE in that organism. IMPORTANCE: Synechococcus sp. strain PCC 7002 is a cobalamin auxotroph because, like eukaryotic marine algae, it uses a cobalamin-dependent methionine synthase (MetH) for the final step of l-methionine biosynthesis but cannot synthesize cobalamin de novo Heterologous expression of metE, encoding cobalamin-independent methionine synthase, from Synechococcus sp. strain PCC 73109, relieved this auxotrophy and enabled the construction of a truly autotrophic Synechococcus sp. strain PCC 7002 more suitable for large-scale industrial applications. Characterization of a cobalamin riboswitch expands the genetic toolbox for Synechococcus sp. strain PCC 7002 by providing a cobalamin-repressible expression system. PMID- 27457715 TI - The SaeRS Two-Component System Is a Direct and Dominant Transcriptional Activator of Toxic Shock Syndrome Toxin 1 in Staphylococcus aureus. AB - Toxic shock syndrome toxin 1 (TSST-1) is a Staphylococcus aureus superantigen that has been implicated in both menstrual and nonmenstrual toxic shock syndrome (TSS). Despite the important role of TSST-1 in severe human disease, a comprehensive understanding of staphylococcal regulatory factors that control TSST-1 expression remains incomplete. The S. aureus exotoxin expression (Sae) operon contains a well-characterized two-component system that regulates a number of important exotoxins in S. aureus, although regulation of TSST-1 by the Sae system has not been investigated. We generated a defined deletion mutant of the Sae histidine kinase sensor (saeS) in the prototypic menstrual TSS strain S. aureus MN8. Mutation of saeS resulted in a complete loss of TSST-1 expression. Using both luciferase reporter experiments and quantitative real-time PCR, we demonstrate that the Sae system is an important transcriptional activator of TSST 1 expression. Recombinant SaeR was able to bind directly to the tst promoter to a region containing two SaeR consensus binding sites. Although the stand-alone SarA transcriptional regulator has been shown to be both a positive and a negative regulator of TSST-1, deletion of sarA in S. aureus MN8 resulted in a dramatic overexpression of TSST-1. As expected, mutation of agr also reduced TSST-1 expression, but this phenotype appeared to be independent of Sae. A double mutation of saeS and sarA resulted in the loss of TSST-1 expression. This work indicates that the Sae system is a dominant and direct transcriptional activator that is required for expression of TSST-1. IMPORTANCE: The TSST-1 superantigen is an exotoxin, produced by some strains of S. aureus, that has a clear role in both menstrual and nonmenstrual TSS. Although the well-characterized agr quorum sensing system is a known positive regulator of TSST-1, the molecular mechanisms that directly control TSST-1 expression are only partially understood. Our studies demonstrate that the Sae two-component regulatory system is a positive transcriptional regulator that binds directly to the TSST-1 promoter, and furthermore, our data suggest that Sae is required for expression of TSST-1. This work highlights how major regulatory circuits can converge to fine-tune exotoxin expression and suggests that the Sae regulatory system may be an important target for antivirulence strategies. PMID- 27457716 TI - Identification and Regulation of Genes for Cobalamin Transport in the Cyanobacterium Synechococcus sp. Strain PCC 7002. AB - The cyanobacterium Synechococcus sp. strain PCC 7002 is a cobalamin auxotroph and utilizes this coenzyme solely for the synthesis of l-methionine by methionine synthase (MetH). Synechococcus sp. strain PCC 7002 is unable to synthesize cobalamin de novo, and because of the large size of this tetrapyrrole, an active transport system must exist for cobalamin uptake. Surprisingly, no cobalamin transport system was identified in the initial annotation of the genome of this organism. With more sophisticated in silico prediction tools, a btuB-cpdA-btuC btuF operon encoding components putatively required for a B12 uptake (btu) system was identified. The expression of these genes was predicted to be controlled by a cobalamin riboswitch. Global transcriptional profiling by high-throughput RNA sequencing of a cobalamin-independent form of Synechococcus sp. strain PCC 7002 grown in the absence or presence of cobalamin confirmed regulation of the btu operon by cobalamin. Perez et al. (A. A. Perez, Z. Liu, D. A. Rodionov, Z. Li, and D. A. Bryant, J Bacteriol 198:2743-2752, 2016, http://dx.doi.org/10.1128/JB.00475-16) developed a cobalamin-dependent yellow fluorescent protein reporter system in a Synechococcus sp. strain PCC 7002 variant that had been genetically modified to allow cobalamin-independent growth. This reporter system was exploited to validate components of the btu uptake system by assessing the ability of targeted mutants to transport cobalamin. The btuB promoter and a variant counterpart mutated in an essential element of the predicted cobalamin riboswitch were fused to a yfp reporter. The combined data indicate that the btuB-cpdA-btuF-btuC operon in this cyanobacterium is transcriptionally regulated by a cobalamin riboswitch. IMPORTANCE: With a cobalamin-regulated reporter system for expression of yellow fluorescent protein, genes previously misidentified as encoding subunits of a siderophore transporter were shown to encode components of cobalamin uptake in the cyanobacterium Synechococcus sp. strain PCC 7002. This study demonstrates the importance of experimental validation of in silico predictions and provides a general scheme for in vivo verification of similar cobalamin transport systems. A putative cobalamin riboswitch was identified in Synechococcus sp. strain PCC 7002. This riboswitch acts as a potential transcriptional attenuator of the btu operon that encodes the components of the cobalamin active-transport system. PMID- 27457717 TI - F-Type Bacteriocins of Listeria monocytogenes: a New Class of Phage Tail-Like Structures Reveals Broad Parallel Coevolution between Tailed Bacteriophages and High-Molecular-Weight Bacteriocins. AB - Listeria monocytogenes is a significant foodborne human pathogen that can cause severe disease in certain high-risk individuals. L. monocytogenes is known to produce high-molecular-weight, phage tail-like bacteriocins, or "monocins," upon induction of the SOS system. In this work, we purified and characterized monocins and found them to be a new class of F-type bacteriocins. The L. monocytogenes monocin genetic locus was cloned and expressed in Bacillus subtilis, producing specifically targeted bactericidal particles. The receptor binding protein, which determines target cell specificity, was identified and engineered to change the bactericidal spectrum. Unlike the F-type pyocins of Pseudomonas aeruginosa, which are related to lambda-like phage tails, monocins are more closely related to TP901-1-like phage tails, structures not previously known to function as bacteriocins. Monocins therefore represent a new class of phage tail-like bacteriocins. It appears that multiple classes of phage tails and their related bacteriocins have coevolved separately in parallel. IMPORTANCE: Phage tail-like bacteriocins (PTLBs) are structures widespread among the members of the bacterial kingdom that are evolutionarily related to the DNA delivery organelles of phages (tails). We identified and characterized "monocins" of Listeria monocytogenes and showed that they are related to the tail structures of TP901-1-like phages, structures not previously known to function as bacteriocins. Our results show that multiple types of envelope-penetrating machines have coevolved in parallel to function either for DNA delivery (phages) or as membrane-disrupting bacteriocins. While it has commonly been assumed that these structures were coopted from phages, we cannot rule out the opposite possibility, that ancient phages coopted complex bacteriocins from the cell, which then underwent adaptations to become efficient at translocating DNA. PMID- 27457718 TI - Mutagen Synergy: Hypermutability Generated by Specific Pairs of Base Analogs. AB - We tested pairwise combinations of classical base analog mutagens in Escherichia coli to study possible mutagen synergies. We examined the cytidine analogs zebularine (ZEB) and 5-azacytidine (5AZ), the adenine analog 2-aminopurine (2AP), and the uridine/thymidine analog 5-bromodeoxyuridine (5BrdU). We detected a striking synergy with the 2AP plus ZEB combination, resulting in hypermutability, a 35-fold increase in mutation frequency (to 53,000 * 10(-8)) in the rpoB gene over that with either mutagen alone. A weak synergy was also detected with 2AP plus 5AZ and with 5BrdU plus ZEB. The pairing of 2AP and 5BrdU resulted in suppression, lowering the mutation frequency of 5BrdU alone by 6.5-fold. Sequencing the mutations from the 2AP plus ZEB combination showed the predominance of two new hot spots for A.T->G.C transitions that are not well represented in either single mutagen spectrum, and one of which is not found even in the spectrum of a mismatch repair-deficient strain. The strong synergy between 2AP and ZEB could be explained by changes in the dinucleoside triphosphate (dNTP) pools. IMPORTANCE: Although mutagens have been widely studied, the mutagenic effects of combinations of mutagens have not been fully researched. Here, we show that certain pairwise combinations of base analog mutagens display synergy or suppression. In particular, the combination of 2-aminopurine and zebularine, analogs of adenine and cytidine, respectively, shows a 35-fold increased mutation frequency compared with that of either mutagen alone. Understanding the mechanism of synergy can lead to increased understanding of mutagenic processes. As combinations of base analogs are used in certain chemotherapy regimens, including those involving ZEB and 5AZ, these results indicate that testing the mutagenicity of all drug combinations is prudent. PMID- 27457719 TI - Health outcomes and the transition experience of HIV-infected adolescents after transfer to adult care in Quebec, Canada. AB - BACKGROUND: Little is known on outcomes after transition to adult care among adolescents with perinatal HIV infection. Though there is data from other chronic pediatric diseases suggesting increased morbidity and mortality following transfer to adult care, this has not well been studied among the first wave of survivors of perinatal HIV infection. The primary objective of this study was to determine outcomes after transition to adult care among a cohort of HIV-infected adolescents in Quebec, Canada. Secondary objectives were to document participant experiences with the transition process, identify barriers to successful transition, and potential changes to improve the transition process. METHODS: Clinic records were reviewed to identify all perinatally-infected youth who transitioned from the Centre Maternel et Infantile sur le Sida pediatric HIV clinic (Montreal) at age 18 to an adult care provider between 1999 and 2012. Transitioned patients were contacted using last available patient or parental listed phone number on hospital record, internet based telephone directory, or social media. A standardized questionnaire was administered by telephone or in person interview, and copies of current medical records obtained from treating physicians. RESULTS: Forty-five patients were transferred between 1999 and 2012, among whom 25 consented to the study, eight were lost to follow-up, eight refused participation, and four were deceased. Overall 76 % of patients remained engaged in care, defined by at least one physician visit within 6 months of the interview. Over 50 % reported difficulty with adherence to their current drug regimens. At one-year post-transfer, there was a decrease in the proportion of patients with CD4 count >500 cells/mm(3) from 64 to 29 %, and a statistically significant decrease in absolute CD4 count (mean 370 vs 524 cells/mm(3), p = 0.04.). The majority (92 %) of participants felt that 18 was too young an age to transfer to adult care, and provided suggestions for improving the transition process. CONCLUSIONS: This group of perinatally-infected youth remained engaged in care after transition, however difficulties with adherence and assuming responsibility for their own care were identified as issues in their post transition care. The high rate of mortality among them and the changes to their health status post-transition suggest that further work is necessary to document the health outcomes of this group in larger, more diverse cohort settings. PMID- 27457720 TI - The combination effects of body acupuncture and auricular acupressure compared to sham acupuncture for body weight control: study protocol for a randomized controlled trial. AB - BACKGROUND: Obesity is an increasingly prevalent chronic condition that is associated with serious morbidity and mortality. Excess body weight is a risk factor contributing to diseases such as hypertension, heart disease, hypercholesterolaemia, diabetes mellitus, cerebrovascular disease, gall bladder disease, and some types of cancer. Almost all the Western anti-obesity drugs have adverse effects or body weight is regained upon cessation of therapy. Recent studies have found that acupuncture had a similar efficacy as the Western anti obesity drugs with fewer reported adverse effects. However, these conclusions were limited due to the small sample size and low quality of methodologies of these studies. Therefore, we design this study to explore the effectiveness and safety of acupuncture on weight control. METHODS/DESIGN: This is a pilot single blinded, randomized, sham-controlled trial on acupuncture for body weight control. Seventy-two participants are randomly assigned to the acupuncture group or the control group. Tianshu (ST-25), Daheng (SP-15), Daimai (GB-26), Qihai (CV 6), Zhongwan (CV-12), Zusanli (ST-36), Fenglong (ST-40), and Sanyinjiao (SP-6) are selected as acupuncture points. For the acupuncture group, disposable acupuncture needles will be inserted at a depth of 10-25 mm into the points and electrical stimulation with dense-disperse waves at 50 Hz and 10 V will be applied on the abdominal points. The bodily needles will be retained for 30 minutes. For subjects assigned to the control group, Streitberger's non-invasive acupuncture needles will be applied to serve as the sham control at the same acupoints with the same stimulation modality, except that the needles are only adhered to the skin instead of inserted. The duration of the treatment is 8 weeks with two sessions per week, and the follow-up period is 8 weeks. The primary outcome is the change in body weight before and after treatment. The secondary outcomes include changes in body mass index, waist circumference, hip circumference, and body fat percentage during the treatment and follow-up period. DISCUSSION: The study will compare the efficacy and safety of acupuncture with sham acupuncture on weight control, in the hope of obtaining evidence for utilizing acupuncture for body weight control. TRIAL REGISTRATION: NCT02516878 . Registered on 30 July 2015. PMID- 27457721 TI - Psychological skills training and a mindfulness-based intervention to enhance functional athletic performance: design of a randomized controlled trial using ambulatory assessment. AB - BACKGROUND: Struggling to deliver performance in competitions is one of the main reasons why athletes seek the advice of sport psychologists. Psychologists apply a variety of intervention techniques, many of which are not evidence-based. Evidence-based techniques promote quality management and could help athletes, for example, to increase and maintain functional athletic behavior in competitions/games (i.e., being focused on task relevant cues and executing movements and actions in high quality). However, well-designed trials investigating the effectiveness of sport psychological interventions for performance enhancement are scarce. The planed study is founded by the Swiss National Science Foundation and examines the effectiveness of two interventions with elite and sub-elite athletes. A psychological skills training (PST) and a mindfulness-based intervention (MI), administered as group-program, will be compared to a waiting-list control group concerning how they enhance functional athletic behavior - which is a prerequisite for optimal performance. Furthermore, we will investigate underlying mechanisms (mediators) and moderators (e.g., task difficulty, individual characteristics, intervention-expectancy and intervention integrity). METHODS/DESIGN: The presented trial uses a randomized controlled design with three groups, comparing PST, MI and a waiting list control condition. Both group interventions will last 5 weeks, consist of four 2 h sessions and will be administered by a trained sport psychologist. Primary outcome is functional athletic behavior assessed using ambulatory assessment in a competition/game. As secondary outcomes competition anxiety, cognitive interference and negative outcome expectations will be assessed. Assessments are held at pre- and post intervention as well as at 2 months follow up. The study has been approved by the ethical committee of the Swiss Federal Institute of Sport. DISCUSSION: Both PST and MI are expected to help improve functional behavior in athletes. By examining potential mechanisms of change and moderators of outcome we will not only be able to answer the question whether the interventions work, but also how, under what conditions, and for whom. This study may also fill a gap in sport psychology research, considering the current lack of randomized controlled trials. In the future, researchers could use the presented study protocol as template to investigate similar topics in sport psychology. TRIAL REGISTRATION: ISRCTN11147748 , date of registration: 11 July 2016. PMID- 27457722 TI - Growth factor expression after supraspinatus tear: a quantitative polymerase chain reaction (PCR) study in rats. AB - INTRODUCTION: The objective of this study was to evaluate the temporal expression pattern of three different growth factors (VEGF, IL-1beta, and TGF-1beta) in a supraspinatus tendon lesion in an animal model. The hypothesis of this study is that there are variations in the expression of these factors in the first 8 weeks after injury. MATERIALS AND METHODS: A full thickness defect was made in the supraspinatus tendon of 40 rat shoulders. The animal were sacrificed at 0, 3, 7, 14 and 56 days after injury and three tissue samples were obtained: bone from the tendon footprint; the supraspinatus tendon stump, and a fragment of the myotendinous junction. After mRNA extraction, quantitative PCR analysis was performed, and the expression of three different growth factors were evaluated in each zone. RESULTS: There was an increased expression of IL-1beta during the first week after injury at all levels evaluated with a clear peak in the first day after injury. There was also a significant increase in TGF-1beta expression levels all along the first week in the three zones. There were no variations in VEGF expression in the three zones along the 8 weeks. CONCLUSION: IL-1beta was expressed predominantly in the initial stages after injury; TGF initiated its expression after the initial phase since day three, whereas VEGF remained basically unchanged during the entire process. PMID- 27457723 TI - Femoral shaft bowing in the coronal and sagittal planes on reconstructed computed tomography in women with medial compartment knee osteoarthritis: a comparison with radiograph and its predictive factors. AB - PURPOSE: To show the differences in lateral and anterior femoral shaft bowing (FSB) between radiographic and computed tomography (CT) images and to assess whether FSB is associated with various predictive factors in women with knee osteoarthritis (OA) using CT images. METHODS: We enrolled 135 Japanese women with medial compartment knee OA. Lateral and anterior FSB were measured by radiography and reconstructed CT. Age, body mass index (BMI), femorotibial angle (FTA), femoral length, and lumbar spine and femoral neck bone mineral density (BMD) were set as predictive factors for progression of knee OA. We compared predictive factors in the lateral FSB group having lateral angulations of >5 degrees with those in the nonbowing group and compared predictive factors in the anterior FSB group having anterior angulations of >11 degrees with those in the nonbowing group. Binomial logistic regression modeling was applied to determine independent predictors of both FSB. RESULTS: There were significant differences in both FSB between the radiographic and reconstructed CT images (P = 0.005 and P = 0.047, respectively). In binomial logistic regression analyses for lateral FSB on CT, age, BMI, and lumbar spine BMD were significant predictors, with odds ratios of 1.16, 1.22, and 0.03, respectively; for anterior FSB on CT, age was a significant predictor, with an odds ratio of 1.06. CONCLUSIONS: It is preferable to measure both FSB on reconstructed CT when planning reconstructive knee surgeries. Age, BMI, and lumbar spine BMD were predictors of lateral FSB progression, and age was a predictor of anterior FSB progression. Level of evidence Level III. PMID- 27457724 TI - Primary Baerveldt Shunt Implantation: Outcomes and Complications. AB - INTRODUCTION: This study is a retrospective case series to evaluate the outcomes and complications of Baerveldt glaucoma implant surgery (BGI) in patients without prior cataract or incisional glaucoma surgery. METHODS: Patients who underwent 350-mm2 BGI through the Glaucoma Service of the University of Illinois at Chicago between 2010 and 2015 were included in this study. Outcome measures included age, sex, ethnicity, operated eye, preoperative diagnosis, preoperative, and sequential postoperative intraocular pressure (IOP), visual acuity, glaucoma medications, and postoperative complication and interventions. Statistical analyses were performed using the two-sided Student t test for continuous variables. RESULTS: Thirty-seven patients were studied. IOP was consistently and statistically significantly lower at 3 months (17.4 +/- 6.4, p = 3 * 10-7), 6 months (13.9 +/- 5.1, p = 2 * 10-11), 1 year (12.2 +/- 4.0, p = 9 * 10-10), and 2 years (14.6 +/- 3.3, p = 0.0004) postoperatively compared to IOP at baseline (27.5 +/- 8.1). Fewer glaucoma medications were used at 3 months (2.8 +/- 1.3, p = 0.04), 6 months (2.6 +/- 1.2, p = 0.02), 1 year (2.7 +/- 1.7, p = 0.04), and 2 years (2.0 +/- 1.2, p = 0.03) postoperatively compared to baseline (3.4 +/- 1.1). A total of six cases (16%) had failure. A total of five patients (15%) had postoperative complications. Mean Snellen visual acuity was not statistically different at 6 months (0.5 +/- 0.6, p = 0.88) or 1 year (0.4 +/- 0.4, p = 0.57) postoperatively from baseline (0.5 +/- 0.6). CONCLUSIONS: Primary BGI is effective at reducing IOP and the medication burden in patients suffering glaucomatous optic neuropathy. Further randomized prospective studies are needed to compare various procedures in the primary surgical management of patients with uncontrolled glaucoma. FUNDING: This study was funded by an unrestricted grant from Research to Prevent Blindness. PMID- 27457725 TI - Supporting transvisibility and gender diversity in nursing practice and education: embracing cultural safety. AB - Many nursing education programs deserve a failing grade with respect to supporting gender diversity in their interactions with their students and in terms of the curricular content directed toward engaging in the safe and supportive nursing care of transgender clients. This situation contributes to transinvisibility in the nursing profession and lays a foundation for nursing practice that does not recognize the role that gender identity plays in the health and well-being of trans-clients and trans-nurses. This article seeks to raise readers' awareness about the problems inherent to transinvisibility and to propose several curricular and structural-level interventions that may serve to gradually increase the recognition of gender diversity in the planning and delivery of nursing education and practice. Contextualized in gender and intersectionality theory, cultural safety is presented as a viable and appropriate framework for engaging in these upstream approaches to addressing gender diversity in nursing education and practice. Among the structural interventions proposed are as follows: inclusive information systems, creation of gender neutral and safe spaces, lobbying for inclusion of competencies that address care of trans-persons in accreditation standards and licensure examinations and engaging in nursing research in this area. PMID- 27457727 TI - Anatomical approach to permanent His bundle pacing: Optimizing His bundle capture. AB - Permanent His bundle pacing is a physiological alternative to right ventricular pacing. In this article we describe our approach to His bundle pacing in patients with AV nodal and intra-Hisian conduction disease. It is essential for the implanters to understand the anatomic variations of the His bundle course and its effect on the type of His bundle pacing achieved. We describe several case examples to illustrate our anatomical approach to permanent His bundle pacing in this article. PMID- 27457726 TI - Homocysteine diminishes apolipoprotein A-I function and expression in patients with hypothyroidism: a cross-sectional study. AB - BACKGROUND: Hypothyroidism (HO) can significantly impair lipid metabolism and increase cardiovascular disease risk. Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. Our previous study demonstrated that HHcy significantly induced insulin resistance and impaired coronary artery endothelial function in patients with either hypertension or HO. In the present study, we studied whether plasma levels of high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) were altered in patients with HO, and if so, whether this change was mediated by HHcy. METHODS: A total of 258 subjects were enrolled and divided into the following three groups: control group (n = 94), HO group (n = 73), and subclinical hypothyroidism (SHO) group (n = 91). Additionally, all groups were subdivided based on the subjects' Hcy levels into HHcy (plasma Hcy level over 15 MUmol/l) and normal Hcy subgroups. The plasma levels of lipid indexes were measured. Statistical analyses were performed to evaluate the correlations between groups. RESULTS: The plasma Hcy levels were significantly higher in the HO group than in the SHO or control groups (all p < 0.05). Moreover, levels of Apo A-I and HDL-C were markedly reduced in the HHcy subgroup compared with the normal Hcy subgroup for patients with either HO (Apo A-I: p < 0.05; HDL-C: p < 0.01) or SHO (Apo A-I: p < 0.05; HDL-C: p < 0.01). In addition, the plasma Hcy levels were negatively correlated with levels of Apo A-I in all three groups (HO group: r = - 0.320, SHO group: r = - 0.337 and control group: r = - 0.317; all p < 0.01). CONCLUSIONS: Hcy levels were significantly increased in patients with HO or SHO. These increased Hcy levels may impair cardiovascular function via the inhibition of Apo A-1 expression and impairment of its antioxidant capacity. Our findings provide new insights into the pathogenesis of hypothyroidism-induced metabolic disorders. PMID- 27457728 TI - Left arm/left leg lead reversals at the cable junction box: A cause for an epidemic of errors. AB - Medical errors, especially due to misinterpretation of electrocardiograms (ECG), are extremely common in patients admitted to the hospital and significantly account for increased morbidity, mortality and health care costs in the United States. Inaccurate performance of an ECG can lead to invalid interpretation and in turn may lead to costly cardiovascular evaluation. We report a retrospective series of 58 sequential cases of ECG limb lead reversals in the ER due to inadvertent interchange in the lead cables at the point where they insert into the cable junction box of one ECG machine. This case series highlights recognition of ECG lead reversal originating in the ECG machine itself. This case series also demonstrates an ongoing need for education regarding standardization of ECG testing and for recognizing technical anomalies to deliver appropriate care for the patient. PMID- 27457729 TI - Electrophysiological observations of acute His bundle injury during permanent His bundle pacing. AB - BACKGROUND: Permanent His bundle pacing (HBP) is a physiological alternative to right ventricular pacing (RVP). Catheter manipulation during HBP can cause trauma to the His bundle during implantation. We sought to determine acute and long-term incidence of His bundle (HB) injury with HBP. METHODS: Patients undergoing permanent HBP at Geisinger Wyoming Valley Medical Center from 2006 to 2014 formed the study group. Patients with pre-existing His-Purkinje disease (HPD) were excluded from the study. Any development of new bundle branch block (BBB) or AV block (B) during acute HBP lead-induced block was recorded. Resolution of AVB and/or BBB was documented. RESULTS: HBP was attempted in 450 patients. In 358 patients without HPD, 28 (7.8%) developed acute HB injury in the form of complete AVB (4, 1.1%), RBBB (21, 5.9%) or LBBB (3, 0.8%) during HBP lead placement. In all 7 patients with AVB or LBBB, conduction completely recovered. The HB electrogram from the lead displayed injury current in all 7 patients. Lead induced RBBB resolved in 12 of 21 patients and persisted in 9 (2.5%) patients. Pacing from the HBP lead resulted in correction of acute conduction block in 27 of 28 patients and 8 of 9 patients with chronic RBBB. None of the patients with transient conduction block developed new conduction disease during follow-up of 21+/-19months. CONCLUSIONS: Despite acute trauma to HB in 7.8% of patients undergoing permanent HBP, complete resolution of conduction block occurred in 19 of 28 patients (68%). RBBB persisted in 9 patients (32%) but mostly normalized with HBP. PMID- 27457730 TI - When is Transplantation with a "Marginal Kidney" Justifiable? AB - The ability of kidney transplantation to improve quality of life has made this therapeutic modality the treatment of choice among renal replacement therapies; however, the continuing organ shortage has forced the use of marginal kidneys as a supplementary source of allografts. It has been repeatedly suggested that failed kidney transplant recipients have greater morbidity and mortality compared with dialysis patients with no renal transplant history. Achieving an optimal balance between the advantages of kidney transplant and disadvantages of allografts with marginal quality is a topic of controversy in transplant medicine. The major and potentially life-threatening complications of immunosuppressive therapies and shorter lifespan following graft failure necessitate a reappraisal of kidney transplant programs from expanded-criteria deceased donors, which can neither necessarily give dialysis patients a better quality of life nor a significant survival benefit, especially in settings with additional diminished graft survival due to HLA-mismatch. It should be offered just to those with short life expectancy and with HLA-matching. The last item is very important in countries without mandatory HLA-matching protocols for kidney transplantation programs. PMID- 27457731 TI - Dehydrogenation of anhydrous methanol at room temperature by o-aminophenol-based photocatalysts. AB - Dehydrogenation of anhydrous methanol is of great importance, given its ubiquity as an intermediate for the production of a large number of industrial chemicals. Since dehydrogenation of methanol is an endothermic reaction, heterogeneous or homogeneous precious-metal-based catalysts and high temperatures are usually required for this reaction to proceed. Here we report the photochemical dehydrogenation of anhydrous methanol at room temperature catalysed by o aminophenol (apH2), o-aminophenolate (apH(-)) and the non-precious metal complex trans-[Fe(II)(apH)2(MeOH)2]. Under excitation at 289+/-10 nm and in the absence of additional photosensitizers, these photocatalysts generate hydrogen and formaldehyde from anhydrous methanol with external quantum yields of 2.9+/-0.15%, 3.7+/-0.19% and 4.8+/-0.24%, respectively, which are the highest values reported so far to the best of our knowledge. Mechanistic investigations reveal that the photo-induced formation of hydrogen radicals triggers the reaction. PMID- 27457732 TI - Economical and environmentally-friendly approaches for usage of onion (Allium cepa L.) waste. AB - Onion (Allium cepa L.) is one of the most commonly cultivated crops across the globe, and its production is increasing every year due to increasing consumer demand. Simultaneously, huge amounts of waste are produced from different parts of the onion, which ultimately affect the environment in various ways. Hence, proper usage as well as disposal of this waste is important from the environmental aspect. This review summarizes various usage methods of onion waste material, and processes involved to achieve maximum benefits. Processing industries produce the largest amount of onion waste. Other sources are storage systems, domestic usage and cultivation fields. Particular emphasis has been given to the methods used for better extraction and usage of onion waste under specific topics: viz. organic synthesis, production of biogas, absorbent for pollutants and value added products. PMID- 27457733 TI - Tunable reactivity of geminal bis(silyl) enol derivatives leading to selective exo-IEDDA or Sakurai allylation with a beta,gamma-unsaturated ketoester. AB - Two contrasting pathways in a SnCl4-catalyzed reaction of geminal bis(silyl) enol derivatives with beta,gamma-unsaturated ketoesters have been achieved by tuning the R group in the enol moiety. While the electron-donating Bn-substituted enol ether undergoes an exo-selective inverse-electron-demand Diels-Alder (IEDDA) reaction to give dihydropyran, the electron-withdrawing Ac-substituted enol ester reacts as an allylsilane to provide a Sakurai-allylated product with predominant syn-selectivity. PMID- 27457734 TI - Letters. PMID- 27457735 TI - A need to know. PMID- 27457736 TI - Scanning sports. PMID- 27457739 TI - The Moral Minority. PMID- 27457737 TI - Brief reports. PMID- 27457740 TI - Medical School and Waning Physical Energies. PMID- 27457742 TI - Action Plan for Near Drownings. AB - In brief: The outcome of a near drowning depends on the patient's physical condition before the accident, the duration of submersion, the temperature of the water, and how much water entered the lungs and stomach. Dr. Podolsky describes the pathophysiology of drowning, a practical action plan for treating victims, and preventive measures. The key to successful management is shortening the duration and extent of hypoxemia. In addition, patients should be monitored in intensive care units for at least 24 hours, because potentially fatal complications may develop. Preventive measures include restricting access to unguarded pools and teaching the public basic cardiopulmonary resuscitation techniques. PMID- 27457743 TI - Blood Doping: An Update. AB - In brief: Blood doping-the process of withdrawing an athlete's blood, holding it 9 to 12 weeks until hemoglobin levels return to normal, and reintroducing it into the body immediately before an important contest-is a controversial Procedure, and its ethicality and legality are debated throughout the sports world. This review of the literature concludes that although five early studies did not provide sufficient objective evidence to support its use, the majority of 13 new studies support the physiological rationale and efficacy of the use of blood doping to increase endurance capacity. PMID- 27457744 TI - The Emotionally Disturbed Athlete. AB - In brief: In general, athletes have the same range of emotional illnesses as other persons, but the problem is complicated by the athlete's macho image and the fact that bizarre behavior is accepted and sometimes encouraged in sports. Two psychiatrists and two psychologists agreed that the most common emotional problem among athletes is depression, followed by abuse of alcohol or other drugs. Marital conflicts, anxiety reactions, and the threat of termination of a career at an early age are also common problems. Prevention must start early, and the panelists suggest that the role models in professional sports should be less violent. PMID- 27457745 TI - Medical Problems on a Professional Baseball Team. AB - In brief: This study presents a two-season analysis of medical problems on a class A professional baseball team. On the average, one or two problems were recorded per game. Fewer injuries-but more illnesses-occurred at the ginning and end of the season. Pitchers, catchers, second basemen, and right fielders had the most injuries, and musculoskeletal problems accounted for 86.4% of all injuries. Of the 382 new injuries, 82.2% were treated by the gainer, 13.1% by the team physician, and 4.7% by specialists. The data suggest hat most problems were handled adequately by the team trainer and a Primary care physician. PMID- 27457746 TI - Use of CAT Scan for a Cervical Vertebral Arch Fracture. AB - In brief: Cervical spine injuries are difficult to diagnose accurately with standard x-rays because the bony structures overlap one another. However, computerized axial tomography (CAT scanning) clearly shows the vertebral relationships. A CAT scan of the C-6 region of a 16-year-old high school running back who sustained an injury to the cervical spine revealed a fracture of the right vertebral arch that could not be seen on plain x-rays. The author says that because cervical and intracranial injuries can result in death or paralysis, players who experience numbness, tingling, paresthesia, and/or paralysis should be removed from sports activity. PMID- 27457747 TI - Physiological Characteristics of Masters Female Distance Runners. AB - In brief: Ten masters female long-distance runners (mean age 43.8 years) were assessed for body composition and cardiovascular endurance. The mean body fat was 18.3%, which is approximately 40% of the value for a control group of sedentary women. The only women exhibiting lower values for Percent body fat were much younger elite athletes. VO2 max averaged 43.41 ml.kg(-1) min(-1), which is 25% higher than that of normal women of comparative ages. The question of whether a lifetime of endurance training can offset the age- related decrease in Vo(2) max is still unknown, but the increased interest in masters competition may provide the data to answer this question. PMID- 27457748 TI - Salina Family Clinic Finds New Role for Exercise Physiologist. AB - In Salina, Kansas, an agricultural community of 40,000, an exercise Physiologist complements the family physician's responsibility in developing wellness programs by conducting stress tests, preparing exercise prescriptions, and counseling patients. PMID- 27457749 TI - The Computerization of Sportsmedicine. AB - The efficiency possible with computer technology is making sportsmedicine expertise available to a fitness-conscious public. Better communication between programmers and sportsmedicine practitioners is necessary, however, so that computer systems are fully understood by those using them. PMID- 27457750 TI - Fort Royal Club Med: French for Healthy Relaxation. AB - Set in the lush West Indies, Fort Royal is a Club Med with a difference-it is small and geared toward families. The daily sports offers sailing, diving, wind surfing, tennis, archery, and bicycling. PMID- 27457752 TI - Autonomous control for mechanically stable navigation of microscale implants in brain tissue to record neural activity. AB - Emerging neural prosthetics require precise positional tuning and stable interfaces with single neurons for optimal function over a lifetime. In this study, we report an autonomous control to precisely navigate microscale electrodes in soft, viscoelastic brain tissue without visual feedback. The autonomous control optimizes signal-to-noise ratio (SNR) of single neuronal recordings in viscoelastic brain tissue while maintaining quasi-static mechanical stress conditions to improve stability of the implant-tissue interface. Force displacement curves from microelectrodes in in vivo rodent experiments are used to estimate viscoelastic parameters of the brain. Using a combination of computational models and experiments, we determined an optimal movement for the microelectrodes with bidirectional displacements of 3:2 ratio between forward and backward displacements and a inter-movement interval of 40 s for minimizing mechanical stress in the surrounding brain tissue. A regulator with the above optimal bidirectional motion for the microelectrodes in in vivo experiments resulted in significant reduction in the number of microelectrode movements (0.23 movements/min) and longer periods of stable SNR (53 % of the time) compared to a regulator using a conventional linear, unidirectional microelectrode movement (with 1.48 movements/min and stable SNR 23 % of the time). PMID- 27457753 TI - Electrophysiological fingerprints of OFF bipolar cells in rat retina. AB - Retinal bipolar cells (BCs) divide photoreceptor output into different channels for the parallel extraction of temporal and chromatic stimulus properties. In rodents, five types of OFF BCs have been differentiated, based on morphological and functional criteria, but their electrophysiological characterization remains incomplete. This study analyzed OFF BCs with the patch clamp technique in acute slices of rat retina. Their specific voltage-dependent currents and glutamate responses are shown to represent individual fingerprints which define the signal processing and filtering properties of each cell type and allow their unequivocal identification. Two additions to the rat BC repertoire are presented: OFF BC-2', a variation of BC-2 with wider axonal arbours and prominent Na(+) currents, is described for the first time in rodents, and OFF BC-3b, previously identified in mouse, is electrophysiologically characterized in rat. Moreover, the glutamate responses of rat OFF BCs are shown to be differentially sensitive to AMPA- and kainate-receptor blockers and to modulation by nitric oxide (NO) through a cGMP dependent mechanism. These results contribute to our understanding of the diversity and function of bipolar cells in mammals. PMID- 27457754 TI - Is ragweed pollen allergenicity governed by environmental conditions during plant growth and flowering? AB - Pollen allergenicity is one of the main factors influencing the prevalence and/or severity of allergic diseases. However, how genotype and environment contribute to ragweed pollen allergenicity has still to be established. To throw some light on the factors governing allergenicity, in this work 180 ragweed plants from three Regions (Canada, France, Italy) were grown in both controlled (constant) and standard environmental conditions (seasonal changes in temperature, relative humidity and light). Pollen from single plants was characterized for its allergenic potency and for the underlying regulation mechanisms by studying the qualitative and quantitative variations of the main isoforms of the major ragweed allergen Amb a 1. Results showed a statistically higher variability in allergenicity of pollen from standard conditions than from controlled conditions growing plants. This variability was due to differences among single plants, regardless of their origin, and was not ascribed to differences in the expression and IgE reactivity of individual Amb a 1 isoforms but rather to quantitative differences involving all the studied isoforms. It suggests that the allergenic potency of ragweed pollen and thus the severity of ragweed pollinosis mainly depends on environmental conditions during plant growth and flowering, which regulate the total Amb a 1 content. PMID- 27457755 TI - Generation and protective efficacy of a cold-adapted attenuated avian H9N2 influenza vaccine. AB - To prevent H9N2 avian influenza virus infection in chickens, a long-term vaccination program using inactivated vaccines has been implemented in China. However, the protective efficacy of inactivated vaccines against antigenic drift variants is limited, and H9N2 influenza virus continues to circulate in vaccinated chicken flocks in China. Therefore, developing a cross-reactive vaccine to control the impact of H9N2 influenza in the poultry industry remains a high priority. In the present study, we developed a live cold-adapted H9N2 influenza vaccine candidate (SD/01/10-ca) by serial passages in embryonated eggs at successively lower temperatures. A total of 13 amino acid mutations occurred during the cold-adaptation of this H9N2 virus. The candidate was safe in chickens and induced robust hemagglutination-inhibition antibody responses and influenza virus-specific CD4(+) and CD8(+) T cell immune responses in chickens immunized intranasally. Importantly, the candidate could confer protection of chickens from homologous and heterogenous H9N2 viruses. These results demonstrated that the cold-adapted attenuated H9N2 virus would be selected as a vaccine to control the infection of prevalent H9N2 influenza viruses in chickens. PMID- 27457756 TI - Advantage of administering tacrolimus for improving prognosis of patients with polymyositis and dermatomyositis. AB - AIM: The purpose of this study was to investigate the therapeutic advantage of administering tacrolimus (TAC) in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: We retrospectively analyzed the clinical outcomes after initiating treatment in 66 patients with PM/DM (28 PM and 38 DM). After initiating treatment, the prognosis was compared between patients who received TAC in combination with prednisolone (PSL) (the concomitant TAC group), and patients who were treated with PSL alone. The therapeutic efficacy of TAC was also evaluated for patients in the concomitant TAC group as well as patients who started additional TAC treatment after relapse (the additional TAC group), by analyzing clinical results, including serum creatine kinase (CK) levels, muscle strength and the daily dose of PSL. RESULTS: Patients in the concomitant TAC group had significantly lower frequency of relapse and longer periods of remission than patients who were treated with PSL alone (P = 0.0001, P = 0.001, respectively). Significant decreases in CK levels were observed 1 month after starting TAC treatment in both the concomitant TAC group and the additional TAC group. Moreover, the significant effects of withdrawing PSL were also demonstrated in both groups. CONCLUSION: Concomitant use of TAC with PSL clearly provides a favorable outcome in patients with DM/PM. Furthermore, additional treatment with TAC is useful for improving prognosis even after recurrence. PMID- 27457757 TI - Insulin signalling mediates the response to male-induced harm in female Drosophila melanogaster. AB - Genetic manipulations in nutrient-sensing pathways are known to both extend lifespan and modify responses to environmental stressors (e.g., starvation, oxidative and thermal stresses), suggesting that similar mechanisms regulate lifespan and stress resistance. However, despite being a key factor reducing female lifespan and affecting female fitness, male-induced harm has rarely been considered as a stressor mediated by nutrient sensing pathways. We explored whether a lifespan-extending manipulation also modifies female resistance to male induced harm. To do so, we used long-lived female Drosophila melanogaster that had their insulin signalling pathway downregulated by genetically ablating the median neurosecretory cells (mNSC). We varied the level of exposure to males for control and ablated females and tested for interacting effects on female lifespan and fitness. As expected, we found that lifespan significantly declined with exposure to males. However, mNSC-ablated females maintained significantly increased lifespan across all male exposure treatments. Furthermore, lifespan extension and relative fitness of mNSC-ablated females were maximized under intermediate exposure to males, and minimized under low and high exposure to males. Overall, our results suggest that wild-type levels of insulin signalling reduce female susceptibility to male-induced harm under intense sexual conflict, and may also protect females when mating opportunities are sub-optimally low. PMID- 27457758 TI - In vivo and in vitro inhibition of rat liver glutathione transferases activity by extracts from Combretum zeyheri (Combretaceae) and Parinari curatellifolia (Chrysobalanaceae). AB - BACKGROUND: Parinari curatellifolia and Combretum zeyheri are medicinal plants used in Zimbabwe and other Southern African countries for stomach ailments, fever, body aches, wound healing, cancer and tuberculosis. Glutathione transferases (GSTs) are mammalian enzymes that play a significant role in the detoxification and metabolism of many xenobiotic and endogenous compounds and as such can interact with many exogenous compounds including herbal medicines. The effects of Parinari curatellifolia and Combretum zeyheri leaf extracts on glutathione transferases of male Sprague-Dawley rats were investigated in vivo and in vitro after oral administration of either leaf ethanol or water extracts of each plant. METHODS: For Parinari curatellifolia, 18 male Sprague-Dawley rats were administered with 0, 500 and 1000 mg/kg body weight of the leaf extracts in corn oil or saline. Animals were sacrificed after 96 h and the kidney and liver samples were removed and used to prepare the cytosolic fractions. GST activity was determined using 1-chloro-2, 4-dinitrobezene. For Combretum zeyheri, twenty four male Sprague-Dawley rats were randomly divided into two groups. These two groups were further divided into three groups of four animals each. They were given either the aqueous or ethanol extract at doses of C. zeyheri at 0, 50 mg/kg body weight and 200 mg/kg body weight. The extracts were administered orally by oral gavage for four consecutive days and the rats were sacrificed by cervical dislocation on the fifth day. RESULTS: In animals administered with C. zeyheri, GST activity was significantly increased by the 200 mg/kg aqueous extract in the kidneys and livers in vivo whilst the ethanolic extract at 200 mg/kg decreased enzyme activity significantly both organs. Both the ethanol and aqueous extracts inhibited GST activity in vitro with the ethanol extract being more potent inhibitor than ethacrynic acid, a standard GST inhibitor. The increased GST activity in vivo and versus inhibition in vitro suggests that metabolites may be responsible for the effects observed in vivo. For P. curatellifolia, a dose dependent decrease in GST activity was observed in vivo for the animals given the aqueous extract but no changes were observed with the ethanol extract. There was a concentration-dependent inhibition of cytosolic GSTs when P. curatellifolia leaf extracts in vitro. The ethanol extract of P. curatellifolia exhibited GST inhibitory activity in the liver with an IC50 value of 12 MUg/mL and for ethacrynic acid, the IC50 was found to be 10 MUg/mL. This showed that this extract was a potent inhibitor of GSTs in vitro. CONCLUSIONS: C. zeyheri had an inductive effect on GST activity when administered in aqueous solution but inhibited GST in vitro whilst P. curatellifolia inhibited GST activity in vivo. Induction of GSTs would be cytoprotective against the toxic effects electrophilic chemicals. Since GSTs are responsible for the synthesis of prostaglandins, the inhibition of GST activity of by these two plants in vivo maybe one of the reasons that makes the plants important for use in the treatment pain and fever in ethnopharmacology. PMID- 27457759 TI - Variation in the Gut Microbiota of Termites (Tsaitermes ampliceps) Against Different Diets. AB - Termites are well recognized for their thriving on recalcitrant lignocellulosic diets through nutritional symbioses with gut-dwelling microbiota; however, the effects of diet changes on termite gut microbiota are poorly understood, especially for the lower termites. In this study, we employed high-throughput 454 pyrosequencing of 16S V1-V3 amplicons to compare gut microbiotas of Tsaitermes ampliceps fed with lignin-rich and lignin-poor cellulose diets after a 2-week feeding period. As a result, the majority of bacterial taxa were shared across the treatments with different diets, but their relative abundances were modified. In particular, the relative abundance was reduced for Spirochaetes and it was increased for Proteobacteria and Bacteroides by feeding the lignin-poor diet. The evenness of gut microbiota exhibited a significant difference in response to the diet type (filter paper diets < corn stover diets < wood diets), while their richness was constant, which may be related to the lower recalcitrance of this biomass to degradation. These results have important implications for sampling and analysis strategies to probe the lignocellulose degradation features of termite gut microbiota and suggest that the dietary lignocellulose composition could cause shifting rapidly in the termite gut microbiota. PMID- 27457760 TI - Harvesting Microalgae with Different Sources of Starch-Based Cationic Flocculants. AB - In this study, starches obtained from wheat, potato, and corn were used to synthesize cationic starches (CS), and the flocculation efficiency of these materials was tested with Chlorella pyrenoidosa and Botryococcus braunii cultures under different conditions. Our results indicated that these three CS had differing degrees of substitution following identical synthesis conditions. The various CS functioned similarly in this study, and the desired harmless flocculation efficiency was obtained at low dosages, with CS to microalgal biomass ratios of approximately 89 and 119 mg g-1 for C. pyrenoidosa and B. braunii, respectively. Impressive harmless harvesting efficiencies were obtained at lower dosages with respect to appropriate stirring time before the settling, with ratios ranging from 58 to 78 mg g-1 for C. pyrenoidosa cultures. The cost of microalgae harvesting can be cut dramatically by choosing cheaper starches prior to the synthetic CS and by applying suitable flocculation procedures. PMID- 27457761 TI - In vitro activity of salinomycin and monensin derivatives against Trypanosoma brucei. AB - BACKGROUND: African trypanosomes are the causative agents of sleeping sickness in humans and nagana disease in livestock animals. As the few drugs available for treatment of the diseases have limited efficacy and produce adverse reactions, new and better tolerated therapies are required. Polyether ionophores have been shown to display anti-cancer, anti-microbial and anti-parasitic activity. In this study, derivatives of the polyether ionophores, salinomycin and monensin were tested for their in vitro activity against bloodstream forms of Trypanosoma brucei and human HL-60 cells. RESULTS: Most polyether ionophore derivatives were less trypanocidal than their corresponding parent compounds. However, two salinomycin derivatives (salinomycin n-butyl amide and salinomycin 2,2,2 trifluoroethyl ester) were identified that showed increased anti-trypanosomal activity with 50 % growth inhibition values in the mid nanomolar range and minimum inhibitory concentrations of below 1 MUM similar to suramin, a drug used in the treatment of sleeping sickness. In contrast, human HL-60 cells were considerably less sensitive towards all polyether ionophore derivatives. The cytotoxic to trypanocidal activity ratio (selectivity) of the two promising compounds was greater than 250. CONCLUSIONS: The data indicate that polyether ionophore derivatives are interesting lead compounds for rational anti trypanosomal drug development. PMID- 27457763 TI - Erratum to: Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program. PMID- 27457762 TI - Systems-level Proteomics of Two Ubiquitous Leaf Commensals Reveals Complementary Adaptive Traits for Phyllosphere Colonization. AB - Plants are colonized by a diverse community of microorganisms, the plant microbiota, exhibiting a defined and conserved taxonomic structure. Niche separation based on spatial segregation and complementary adaptation strategies likely forms the basis for coexistence of the various microorganisms in the plant environment. To gain insights into organism-specific adaptations on a molecular level, we selected two exemplary community members of the core leaf microbiota and profiled their proteomes upon Arabidopsis phyllosphere colonization. The highly quantitative mass spectrometric technique SWATH MS was used and allowed for the analysis of over two thousand proteins spanning more than three orders of magnitude in abundance for each of the model strains. The data suggest that Sphingomonas melonis utilizes amino acids and hydrocarbon compounds during colonization of leaves whereas Methylobacterium extorquens relies on methanol metabolism in addition to oxalate metabolism, aerobic anoxygenic photosynthesis and alkanesulfonate utilization. Comparative genomic analyses indicates that utilization of oxalate and alkanesulfonates is widespread among leaf microbiota members whereas, aerobic anoxygenic photosynthesis is almost exclusively found in Methylobacteria. Despite the apparent niche separation between these two strains we also found a relatively small subset of proteins to be coregulated, indicating common mechanisms, underlying successful leaf colonization. Overall, our results reveal for two ubiquitous phyllosphere commensals species-specific adaptations to the host environment and provide evidence for niche separation within the plant microbiota. PMID- 27457764 TI - Local radiotherapy alone following neoadjuvant chemotherapy and surgery in combined clinical stage II and III breast cancer. AB - PURPOSE: The outcomes and recurrence patterns for patients with combined clinical stage II and III breast cancer treated with local but not regional radiotherapy after neoadjuvant chemotherapy (NAC) and surgery are poorly documented. METHODS: We performed a retrospective review of a prospectively collected database comprised of breast cancer patients who received NAC at our institution. 172 patients met the specified criteria of receiving NAC, surgery inclusive of axillary nodal dissection and post-operative local (but not regional) radiotherapy. RESULTS: One hundred eleven patients (64.5 %) were of combined clinical stage II and 61 (35.5 %) stage III at diagnosis. 103 patients (59.9 %) were clinically node positive with 101 cN1. On post-NAC pathology 29 (16.9 %) patients had a complete response, 30 (17.6 %) were combined yp stage I, 104 (60.5 %) yp stage II and 9 (5.2 %) yp stage III. 77 (44.8 %) were node positive on post NAC pathology, all ypN1. 52.3 % were treated with breast conservation. At a median follow up of 67 months, 56 patients experienced breast cancer recurrence and 47 had died with breast cancer the dominant cause. Actuarial 5 and 10 year estimated freedom from locoregional recurrence (FFLRR), freedom from distant metastases (FFDM), disease free (DFS) and overall survival (OS) were 90 and 83.5, 74.5 and 64, 69.5 and 56, 79.5 and 65 % respectively. The most common pattern of failure was distant alone (without local or regional failure). Regional failure as the only site of first failure occurred in just three patients but was a component of first failure in a further twelve. Predictive factors on multivariate analysis for FFLRR were clinical stage II and estrogen receptor positivity. Prognostic factors were ypN0 stage and estrogen receptor positive status. CONCLUSIONS: Local radiotherapy alone may be reasonable for selected patients. Isolated distant recurrence is the dominant mode of failure for breast cancer patients who have received local radiotherapy without regional coverage following NAC. PMID- 27457765 TI - Role of water in the formation of macromolecular structures. AB - This review shows that water in biological systems is not just a passive liquid solvent but also a partner in the formation of the structure of proteins, nucleic acids and their complexes, thereby contributing to the stability and flexibility required for their proper function. Reciprocally, biological macromolecules affect the state of the water contacting them, so that it is only partly in the normal liquid state, being somewhat ordered when bound to macromolecules. While the compaction of globular proteins results from the reluctance of their hydrophobic groups to interact with water, the collagen superhelix is maintained by water forming a hydroxyproline-controlled frame around this coiled-coil macromolecule. As for DNA, its stability and rigidity are linked to water fixed by AT pairs in the minor groove: this leads to the enthalpic contribution of AT pairs exceeding that of GC pairs, but this is overbalanced by their greater entropy contribution, with the result that AT pairs melt at lower temperatures than GCs. Loss of this water drives transcription factor binding to the minor groove. PMID- 27457767 TI - A Retrospective Study of Drug Induced Cutaneous Adverse Reactions (CADR) in Patients Attending Tertiary Care Hospital. AB - OBJECTIVES: Find possible causative agents causing cutaneous adverse reactions; clinical patterns, causality and severity of Drug induced cutaneous adverse reactions (CADR) and treatment outcome. METHODS: Retrospective study was undertaken including cases of CADR. Causality, preventability and severity of Drug Induced cutaneous reactions were judged with the use of Naranjo's algorithm, WHO causality scale, modified Schumock and Thorton scale, and Hartwig's scale respectively. RESULTS: Among 275 total cADRs reported, Antimicrobials (46.55%) were the main drugs involved followed by Non steroidal anti-inflammatory drugs (NSAIDs) (25.09%) and Antifungal (9.82%). Urticaria (63.64%)followed by Erythema multiform(12.36%) was most frequently observed CDRs. Amongst all cADRs 50.18% were certain according to Naranjo's scale, none of them were preventable according to modified Schumock and Thorton scale. All reactions were moderate according to Hartwig's severity scale. CONCLUSION: It was observed that antibiotics and NSAIDs cause maximum number of CADRs. Therefore strict vigilance is required while using them. ?. PMID- 27457766 TI - The advantages of carbon dioxide laser applications in paediatric oral surgery. A prospective cohort study. AB - The aim of this study is to evaluate and demonstrate the advantages of the carbon dioxide laser in paediatric oral surgery patients in terms of less post-operative complications, healing without scaring, functional benefits, positive patient perception and acceptance of the treatment. One hundred fit and healthy paediatric patients (aged 4-15 years) were recruited to undergo laser surgery for different soft tissue conditions. The outcome of these laser treatments was examined. The Wong-Baker Faces Pain Rating Scale was employed to evaluate the pain before, immediately after laser treatment in the clinic and 1 day after post operatively at home. Post-operative complications and patients' perception and satisfaction were self-reported during a review telephone call the day after treatment. The patients were reviewed 2 weeks after surgery. Laser parameter was 1.62 W, measured by power meter, continuous wave mode with 50 % emission cycle. The beam spot size at the target tissue was 0.8 mm. The pain score pre-operative, during and immediately after laser treatment was rated 0. Whilst the pain score 1 day after surgery was rated between 0 and 2, the healing time was measured over 2 weeks. None of the patients reported post-operative complications after surgery. Patients' perception and acceptance were rated very good. Laser dentistry is a promising field in modern minimally invasive dentistry, which enables provision of better care for children and adolescents. In this cohort study, the use of the carbon dioxide laser therapy offers a desirable, acceptable and minimally invasive technique in the surgical management of soft tissues in paediatric oral surgery with minimal post-operative complications. PMID- 27457768 TI - Fatal Intoxications in the North of Portugal: 12 Years of Retrospective Analysis. AB - BACKGROUND: Fatal intoxications are a topic of great relevance in today's society. They typically occur by accidental or voluntary ingestion, but its characterization by a forensic perspective was not fully explored. OBJECTIVE: This study retrospectively reviews fatal intoxication cases autopsied at the northern forensic medicine services of Portugal, between 2001 and 2013. METHOD: For this purpose, we analyzed postmortem forensic medical reports with positive qualitative analysis for xenobiotics. RESULTS: A total of 27,778 autopsy reports were analyzed, of which 1,269 cases fulfilled the selection criteria, representing 4.6% of total number of individuals autopsied during the period under analysis. Men were involved in most of the cases (73.8%) and most individuals were adults with ages between 36 and 65 years old (57.0%). The highest incidences were medicines (22.9%) and alcohol (15.8%), followed by their association. Cases of fatal intoxications involving opioids come on fifth place (5.8%) namely due to accidental overdoses. Moreover, intoxications appeared as the leading cause of death in reports concerning accidental etiology, with drugs and alcohol associations having a great expression. CONCLUSION: Due to morbidity and relevant number of fatal cases, risk prevention measures, such as public health policies should be implemented to reduce the number of intoxications. PMID- 27457769 TI - Prevalence of overlap syndromes and symptoms in pediatric functional dyspepsia. AB - BACKGROUND: The purpose was to evaluate the overlap frequency of irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and overactive bladder syndrome (OBS), as well as other gastrointestinal and systemic symptoms, in functional dyspepsia (FD). Additionally, we sought to determine whether adult Rome III FD subtypes were uniquely related to overlap syndromes or symptoms. METHODS: The study was a retrospective review of 100 consecutive pediatric patients, age 8-17 years, diagnosed with FD. All had completed a standardized medical history including gastrointestinal and systemic symptoms as well as specific symptoms related to GERD and OBS. The frequency of overlap with IBS, GERD, and OBS were determined for the whole group and for those fulfilling adult FD subtype criteria. Individual symptoms were also compared by FD subtype. RESULTS: Overlap IBS was present in 33 % of the FD patients. At least one GERD symptom was present in 74 % of patients with 41 % reporting heartburn. At least one OBS symptom was present in 44 % of patients with 29 % reporting urinary urgency. Other than pain, the most common reported gastrointestinal symptom was nausea (86 %). Systemic symptoms were common. Overlap syndromes/symptoms did not vary by FD subtype. Postprandial distress syndrome was associated with pain with eating, weight loss, and waking at night to have a stool. CONCLUSIONS: FD is a heterogeneous condition in children and adolescents with significant variability in the presence of gastrointestinal and non-gastrointestinal symptoms and overlap syndromes. Varying symptom profiles need to be accounted for and analyzed in studies involving subjects with FD. PMID- 27457770 TI - A colorimetric sensor for the selective detection of fluoride ions. AB - A colorimetric receptor L was prepared. Receptor L can selectively sense F- based on distinct color changes among a series of ions. It can selectively sense F- through an intramolecular hydrogen bond interaction. A Job plot indicated a 1:1 complexation stoichiometry between receptor L and F- . The association constant for L-F- in CH3 CN was determined as 9.70 * 104 M-1 using a Stern-Volmer plot. PMID- 27457771 TI - [5+2] Cycloaddition of 2-(2-Aminoethyl)oxiranes with Alkynes via Epoxide Ring Opening: A Facile Access to Azepines. AB - A new FeCl3 and BF3 ?OEt2 co-catalyzed tandem hetero-[5+2] cycloaddition of 2-(2 aminoethyl)oxiranes with a wide range of alkynes, including terminal alkynes and alkyl-substituted internal alkynes is presented. This is the first example of rapid and facile production of diverse 2,3-dihydro-1H-azepines through a sequence of epoxide ring-opening, annulation, and dehydroxylation with broad substrate scope and exquisite selectivity control. PMID- 27457772 TI - Impacts of making sense of adversity on depression, posttraumatic stress disorder, and posttraumatic growth among a sample of mainly newly diagnosed HIV positive Chinese young homosexual men: the mediating role of resilience. AB - The experience of HIV, as a life-transforming event, might produce both negative and positive outcomes. Guided by the stress appraisal model, the present study investigated the hypothesized pathways in predicting symptomatology and posttraumatic growth (PTG) in a sample of Chinese male patients with HIV (PHIV) who were mainly newly diagnosed, young, and homosexual. In this cross-sectional study, 141 Chinese male PHIV (87.2% of them were homosexual) completed measures of making negative/positive sense of adversity, resilience, depression, posttraumatic stress disorder (PTSD), and PTG. The path analysis results showed that making negative sense of adversity was associated with depression and PTSD, partially mediated by low levels of resilience, whereas making positive sense of adversity was associated with PTG, partially mediated by resilience. The results suggest that negative and positive outcomes of trauma are impacted by making negative and positive sense of adversity, respectively, via two separate pathways, both mediated by resilience. Our findings contribute to an understanding of the cognitive process of symptomatology and PTG in the HIV context. Theoretical considerations, clinical implications, and future directions are discussed. PMID- 27457773 TI - Seroprevalence and associated risk factors of Toxocara infection in Korean, Manchu, Mongol, and Han ethnic groups in northern China. AB - Toxocariasis is a very prevalent zoonotic disease worldwide. Recently, investigators have focused more on Toxocara spp. seroprevalence in humans. Information regarding Toxocara seroprevalence in people from different ethnic backgrounds in China is limited. For this study, blood samples were collected from a total of 802 Han, 520 Korean, 303 Manchu, and 217 Mongol subjects from Jilin and Shandong provinces. The overall Toxocara seroprevalence was 16.07% (14.21% Han, 20.58% Korean, 11.22% Manchu, 18.89% Mongol). Living in suburban or rural areas, having dogs at home, exposure to soil, and consumption of raw/undercooked meat were risk factors for Toxocara infection. Exposure to soil was identified as the major risk factor for Toxocara seropositivity in all of the tested ethnicities. To the best of our knowledge, this is the first report concerning Toxocara infection in Manchus and Mongols in China. The present study provided baseline data for effective prevention strategies of toxocariasis in northeast China and recommends improvements in personal hygiene standards to achieve this goal. PMID- 27457775 TI - Correction: Beyond "turn-on" readout: from zero background to signal amplification by combination of magnetic separation and plasmon enhanced fluorescence. AB - Correction for 'Beyond "turn-on" readout: from zero background to signal amplification by combination of magnetic separation and plasmon enhanced fluorescence' by Suqin Gong and Yunsheng Xia, Chem. Commun., 2016, 52, 9660-9663. PMID- 27457774 TI - Policies for replacing long-term indwelling urinary catheters in adults. AB - BACKGROUND: Long-term indwelling catheters are used commonly in people with lower urinary tract problems in home, hospital and specialised health-care settings. There are many potential complications and adverse effects associated with long term catheter use. The effect of health-care policies related to the replacement of long-term urinary catheters on patient outcomes is unclear. OBJECTIVES: To determine the effectiveness of different policies for replacing long-term indwelling urinary catheters in adults. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In Process, MEDLINE Epub Ahead of Print, CINAHL, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 19 May 2016), and the reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials investigating policies for replacing long-term indwelling urinary catheters in adults were included. DATA COLLECTION AND ANALYSIS: At least two review authors independently performed data extraction and assessed risk of bias of all the included trials. Quality of evidence was assessed by adopting the GRADE approach. Any discrepancies were resolved by discussion between the review authors or an independent arbitrator. We contacted the authors of included trials to seek clarification where required. MAIN RESULTS: Three trials met the inclusion criteria, with a total of 107 participants in three different health care settings: A USA veterans administration nursing home; a geriatric centre in Israel; and a community nursing service in Hong Kong. Data were available for three of the pre-stated comparisons. Priefer and colleagues evaluated different time intervals between catheter replacement (n = 17); Firestein and colleagues evaluated the use of antibiotic prophylaxis at the time of replacement (n = 70); and Cheung and colleagues compared two different types of cleaning solutions (n = 20).All the included trials were small and under-powered. The reporting of the trials was inadequate and as a result, risk of bias assessment was judged to be unclear for the majority of the domains in two out of the three trials. There was insufficient evidence to indicate that (i) there was a lower incidence of symptomatic UTI in people whose catheter was changed both monthly and when clinically indicated (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.13 to 0.95; very low quality evidence) compared to only when clinically indicated, (ii) there was not enough evidence to assess the effect of antibiotic prophylaxis on reducing: positive urine cultures at 7 days (RR 0.91, 95% CI 0.79 to 1.04); infection (RR 1.41, 95% CI 0.55 to 3.65); or death (RR 2.12, 95% CI 0.20 to 22.30; very low quality evidence), (iii) there was no statistically significant difference in the incidence of asymptomatic bacteruria at 7 days (RR 0.80, 95% CI 0.42 to 1.52) between people receiving water or chlorhexidine solution for periurethral cleansing at the time of catheter replacement. However, none of the 16 participants developed a symptomatic catheter-associated urinary tract infection (CAUTI) at day 14.The following outcomes were considered critical for decision-making and were also selected for the 'Summary of findings' table: (i) participant satisfaction, (ii) condition-specific quality of life, (iii) urinary tract trauma, and (iv) formal economic analysis. However, none of the trials reported these outcomes.None of the trials compared the following comparisons: (i) replacing catheter versus other policy e.g. washouts, (ii) replacing in the home environment versus clinical environment, (iii) clean versus aseptic technique for replacing catheter, (iv) lubricant A versus lubricant B or no lubricant, and (v) catheter user versus carer versus health professional performing the catheter replacement procedure. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to assess the value of different policies for replacing long-term urinary catheters on patient outcomes. In particular, there are a number of policies for which there are currently no trial data; and a number of important outcomes which have not been assessed, including patient satisfaction, quality of life, urinary tract trauma, and economic outcomes. There is an immediate need for rigorous, adequately powered randomised controlled trials which assess important clinical outcomes and abide by the principles and recommendations of the CONSORT statement. PMID- 27457776 TI - Attitudes and barriers to providing dietary advice: perceptions of dental hygienists and oral health therapists. AB - OBJECTIVES: Effective dietary counselling in a dental setting can significantly reduce the risk of oral disease. However, studies suggest that dental professionals are not instigating dietary advice on a regular basis, and there is a lack of current information of the barriers experienced that limit the delivery of dietary advice. The aim of this study was to investigate the current attitudes and practice behaviours of dental hygienists and oral health therapists in NSW, Australia, regarding dietary advice, and identify the barriers that limit its delivery. METHODS: A convenience sample of dental hygienists and oral health therapists were surveyed using a mail-out questionnaire. The questionnaire investigated the demographic data of participants, the attitudes and practice behaviours of participants, the perceived barriers and current dietary resources accessed by participants. RESULTS: Of 987 dental hygienists and oral health therapists, 426 participants responded. The study results suggest that many dental hygienists and oral health therapists have positive beliefs regarding the importance of dietary counselling. However, there are a multitude of barriers preventing the delivery of dietary advice; these include time, patient compliance, patient knowledge of nutrition topics, personal counselling skills and practitioners' knowledge of nutrition. CONCLUSION: Whilst dental hygienists and oral health therapists recognize the importance of diet and have positive attitudes towards providing dietary advice to patients, this study identified many barriers preventing implementation in practice. This information may be used to develop targeted strategies aimed at overcoming these barriers and improving behaviours. PMID- 27457777 TI - Deeper Than the Epithelium: Role of Matrix and Fibroblasts in Pediatric and Adult Eosinophilic Esophagitis. PMID- 27457778 TI - Hepatoblastoma in Explanted Livers of Patients With Biliary Atresia. AB - OBJECTIVES: Surveillance of hepatic nodules for malignant transformation to hepatocellular carcinoma is important in the monitoring of patients with biliary atresia (BA). To date, only 2 published case reports describe the finding of hepatoblastoma (HB) in this setting. The present study aimed to investigate this association of HB and BA, and to assess the utility of alpha-fetoprotein (aFP) as a marker in the diagnosis. METHODS: A retrospective study of all patients who underwent isolated liver transplantation (LTx) for the primary diagnosis of BA at a single center, between January 1999 and June 2014, was conducted. Patient demographics, pre-LTx aFP levels, and histologic examination of native liver explants were reviewed. RESULTS: One hundred two (44% men, median age 11 months) patients underwent LTx for BA. Two (2%) explants examinations were confirmatory for concomitant HB; both patients had abnormally elevated aFP. Overall, 56 (55%) patients had available pre-LTx aFP levels. Recipients with persistently abnormal aFP levels (n = 20, 36%) were older at hepatoportoenterostomy (107 vs 68 days, P = 0.02) and younger at LTx surgery (359 vs 1713 days, P < 0.01), compared to patients with constantly normal levels (n = 24, 43%). CONCLUSIONS: In our cohort, HB was found to coexist in approximately 2% of patients with BA undergoing LTx, far exceeding the hypothetical anticipated incidence of 1:10 billion for the concomitant diagnoses. Elevated serum aFP levels may be sensitive but not specific for HB in this context. Further research is required to identify specific mechanisms and risk factors. PMID- 27457779 TI - Five-Year Follow-Up of High-Risk Infants with Family History of Allergy Who Were Exclusively Breast-Fed or Fed Partial Whey Hydrolysate, Soy, and Conventional Cow's Milk Formulas: Expression of Serious Concern. PMID- 27457782 TI - In Situ Generation of Co(III) -Salen Complexes for Copolymerization of Propylene Oxide and CO2. AB - A simple admixture of Co(II) -salcy complexes with [Cp2 Fe(III) ]PF6 resulted in reproduction of the results with isolated Co(III) -salcy complexes in the copolymerization of epoxide and carbon dioxide. By using this in situ-generated active species with bis(triphenylphosphoranilydene)ammonium 2,4-dinitrophenolate, a para-methoxy-substituted Co-salcy complex was proven to be more active than the parent tert-butyl-substituted system. In contrast, the Co(II) -salcy complex substituted with the more strongly electron-donating NMe2 group did not show any activity for this copolymerization. PMID- 27457780 TI - Prolonged withdrawal from cocaine self-administration affects prefrontal cortex- and basolateral amygdala-nucleus accumbens core circuits but not accumbens GABAergic local interneurons. AB - Withdrawal from extended-access cocaine self-administration leads to progressive intensification ('incubation') of cocaine craving. After prolonged withdrawal (1 2 months), when craving is high, expression of incubation depends on strengthening of excitatory inputs to medium spiny neurons (MSN) of the nucleus accumbens (NAc). These excitatory inputs interact with the intra-NAc GABAergic 'microcircuit', composed of MSN axon collaterals and GABAergic interneurons. Here, we investigated whether the increased glutamatergic neurotransmission observed after prolonged withdrawal is accompanied by altered GABAergic neurotransmission, focusing on NAc core. Rats self-administered cocaine or saline (6 hours/day) and then underwent >40 days of withdrawal. First, we investigated parvalbumin positive (PV+) interneurons, GABAergic fast-spiking interneurons that regulate MSN activity. Immunohistochemical studies revealed no significant change in PV signal intensity or the number of PV+ cells in cocaine rats versus saline controls. We then screened PV and other interneuron markers using immunoblotting. We detected no changes in levels of PV, calretinin, calbindin or neuronal nitric oxide synthase. Because expression of these markers is activity dependent, our results suggest no marked changes in interneuron activity. Finally, we utilized local field potential recording, which can detect GABA-mediated alterations at the circuit level, to investigate potential changes in two circuits implicated in cocaine craving: prelimbic prefrontal cortex to NAc core and basolateral amygdala to NAc core. We detected differential adaptations in these circuits, some of which may involve GABA. Overall, our results suggest that alterations in GABA transmission may accompany incubation of cocaine craving, but they are circuit specific and less pronounced than alterations in glutamate transmission. PMID- 27457783 TI - Bioactivation of Trimethoprim to Protein-Reactive Metabolites in Human Liver Microsomes. AB - The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the urine of patients taking TMP-SMX. However, the occurrence and extent of TMP covalent binding to proteins was unknown. To determine the ability of TMP to form protein adducts, we incubated [(14)C]TMP with human liver microsomes in the presence and absence of NADPH. We observed protein covalent binding that was NADPH dependent and increased with incubation time and concentration of both protein and TMP. The estimated covalent binding was 0.8 nmol Eq TMP/mg protein, which is comparable to the level of covalent binding for several other drugs that have been associated with covalent binding-induced toxicity and/or IADRs. NAC and selective inhibitors of CYP2B6 and CYP3A4 significantly reduced TMP covalent binding. These results demonstrate for the first time that TMP bioactivation can lead directly to protein adduct formation, suggesting that TMP has been overlooked as a potential contributor of TMP-SMX IADRs. PMID- 27457784 TI - Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans. AB - Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9. However, negligible quantities of M11 and M12 were detected when EPA was incubated with a panel of human microsomes from multiple tissues, hepatocytes, recombinant human cytochrome P450s (P450s), and non-P450 enzymatic systems. Given the reductive nature of M11 formation and the inability to define its source, the role of gut microbiota was investigated. Analysis of plasma from mice dosed with EPA following pretreatment with either antibiotic (ciprofloxacin) to inhibit gut bacteria or 1-aminobenzotriazole (ABT) to systemically inhibit P450s demonstrated that gut microbiota is responsible for the formation of M11. Incubations of EPA in human feces confirmed the role of gut bacteria in the formation of M11. Further, incubations of M11 with recombinant P450s showed that M12 is formed via N-dealkylation of M11 by CYP3A4, CYP2C19, and CYP1A2. Thus, in humans three major plasma metabolites of EPA were characterized: two primary metabolites, M9 and M11, formed directly from EPA via UGT1A9 and gut microbiota, respectively, and M12 formed as a secondary metabolite via P450s from M11. PMID- 27457785 TI - Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information. AB - Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrel-mediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model. Clopidogrel increased the AUC of pioglitazone (2.0-fold) and repaglinide (3.1-fold) but did not significantly change the AUC of pitavastatin (1.1-fold). In addition, the AUC of pioglitazone M4, a CYP2C8-mediated metabolite of pioglitazone, was reduced to 70% of the control by coadministration of clopidogrel. The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-beta-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1). In conclusion, a single 300 mg of clopidogrel mainly inhibits CYP2C8-mediated metabolism by clopidogrel acyl-beta-glucuronide, but its effect on the pharmacokinetics of OATP1B1 substrates is negligible. Clopidogrel is expected to have an effect not only on CYP2C8 substrates, but also dual CYP2C8/OATP1B1 substrates as seen in the case of repaglinide. PMID- 27457786 TI - Preoperative Cytologic Diagnosis of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: A Prospective Analysis. AB - BACKGROUND: The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has been proposed to replace noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) in recognition of the indolent behavior of this tumor. The ability to differentiate NIFTP from classical papillary thyroid carcinoma (cPTC) by fine-needle aspiration (FNA) would facilitate conservative management for NIFTP. The aim of this study was to determine if NIFTP can be distinguished prospectively from cPTC. METHODS: From June 2015 to January 2016, thyroid FNAs with a diagnosis of "malignant" or "suspicious for malignancy" were prospectively scored for features associated with NIFTP/FVPTC (microfollicular architecture) or cPTC (papillae, psammomatous calcifications, sheet-like architecture, and nuclear pseudoinclusions) and categorized as NIFTP/FVPTC, cPTC, or indeterminate. Results were correlated with subsequent histologic diagnoses. RESULTS: The study included 52 patients with 56 resected nodules with a cytologic diagnosis of "malignant" (43/56) or "suspicious for malignancy" (13/56). Forty-nine patients (94%) underwent initial total thyroidectomy. Histopathologic diagnoses included 42 cPTC, 8 NIFTP, 3 invasive FVPTC, 2 follicular adenomas, and 1 poorly differentiated carcinoma. Excluding 7 indeterminate cases, 89% (8/9) of nodules classified as NIFTP/FVPTC on FNA demonstrated follicular-patterned lesions on histology (5 NIFTP, 1 invasive FVPTC, 2 follicular adenomas). Cytopathologists prospectively identified cPTC in 95% (38/40) of cases. CONCLUSIONS: In thyroid FNAs with cytologic features concerning for PTC, NIFTP/FVPTC can be distinguished from cPTC in most cases by assessing a limited number of features. Therefore, it is both feasible and appropriate to attempt to separate NIFTP/FVPTC from cPTC on FNA to promote appropriate clinical management. PMID- 27457787 TI - Corrigendum to "Contamination of healthcare workers' mobile phones by epidemic viruses" [Clin Microbiol Infect (2016) 456.e1-456.e6]. PMID- 27457788 TI - Antibacterial effect of copper-bearing titanium alloy (Ti-Cu) against Streptococcus mutans and Porphyromonas gingivalis. AB - Formation of bacterial biofilms on dental implant material surfaces (titanium) may lead to the development of peri-implant diseases influencing the long term success of dental implants. In this study, a novel Cu-bearing titanium alloy (Ti Cu) was designed and fabricated in order to efficiently kill bacteria and discourage formation of biofilms, and then inhibit bacterial infection and prevent implant failure, in comparison with pure Ti. Results from biofilm based gene expression studies, biofilm growth observation, bacterial viability measurements and morphological examination of bacteria, revealed antimicrobial/antibiofilm activities of Ti-Cu alloy against the oral specific bacterial species, Streptococcus mutans and Porphyromonas gingivalis. Proliferation and adhesion assays with mesenchymal stem cells, and measurement of the mean daily amount of Cu ion release demonstrated Ti-Cu alloy to be biocompatible. In conclusion, Ti-Cu alloy is a promising dental implant material with antimicrobial/antibiofilm activities and acceptable biocompatibility. PMID- 27457789 TI - Are retailers compliant with zoning regulations that ban tobacco sales near schools in Changsha, China? AB - BACKGROUND: Tobacco retail sales are prohibited within 100 m of schools in many large cities in China. However, little is known about the enforcement of this zoning regulation. The objectives of this study were to estimate tobacco retailers' compliance with the regulation, examine the density of tobacco retail stores, describe the types of tobacco products sold in stores and how they are marketed, and determine if there are displays of warning messages in retail stores around schools and in neighbourhoods in Changsha, China. METHODS: Tobacco retail stores located within 200 m of 36 schools and 36 residential neighbourhoods were audited by trained students with a validated audit form. RESULTS: On average, there were about 3 tobacco retail stores within 100 m of the front entrance of schools. The density of the stores and the types of tobacco products sold in the stores were similar near schools and in neighbourhoods. Over one-fourth of the stores had exterior tobacco advertisements. Interior advertising was slightly less prevalent, and it was most prevalent among tobacco shops (62.5%). Tobacco displays that target children were pervasive, with about 83% of tobacco retail stores displaying cigarettes within 1 m of the floor and 59% displaying cigarettes within 0.3 m of toys and candy. About 40% of stores within 100 m of a school had a visible retail licence. Only 19.6% of the stores had a 'smoke-free' sign and 22.2% had a 'no sales to minors' sign. CONCLUSIONS: We observed low enforcement of the regulation that bans tobacco retail sales near schools and high prevalence of tobacco displays that target children in Changsha, China. Chinese officials should act to effectively enforce the regulation bans of tobacco sales near schools. In addition, regulations are urgently needed to limit tobacco marketing practices at the point of sale, especially those targeting youth. PMID- 27457790 TI - Efficacy and tolerability of a polysaccharide-resin-honey based cough syrup as compared to carbocysteine syrup for children with colds: a randomized, single blinded, multicenter study. AB - BACKGROUND: Available pediatric treatments for acute cough are limited by lack of demonstrated efficacy. The objective of this trial is to compare the effects of a polysaccharide-resin-honey based cough syrup, and carbocysteine syrups on nocturnal and daytime cough associated with childhood upper respiratory tract infections (URIs). METHODS: Using a single-blind randomization design, the study recruited children from 4 general pediatric community clinics. Participants included 150 children aged 2 to 5 years with an URI, nocturnal and daytime cough and illness duration of <=7 days. To be eligible, children had to be free of medication on the day before presentation. A survey was administered to parents on 4 consecutive days beginning from the day of presentation in clinic. Children received the study preparation on the first evening and then 3 times per day for 3 further days. Main outcome measures were cough frequency, cough severity, bothersome nature of cough, and quality of sleep for both child and parent. RESULTS: Both preparations were well tolerated and cough improved over the study period. After one night and on all survey days, there was a significantly better result for polysaccharide-resin-honey (P<0.05) for all the main outcome measures. The trend of improvement over the 4 days was steeper for polysaccharide-resin honey (P<0.05) with regards to all cough parameters. CONCLUSIONS: Both polysaccharide-resin-honey and carbocysteine cough syrups were well tolerated in children over 2 years of age. The polysaccharide-resin-honey syrup was associated with a more rapid and greater improvement in all clinical cough symptoms measured, beginning from the first night of therapy. Both nocturnal and daytime cough improved, as did sleep quality for both children and parents. PMID- 27457791 TI - CAIPIRINHA-accelerated T1w 3D-FLASH for small-bowel MR imaging in pediatric patients with Crohn's disease: assessment of image quality and diagnostic performance. AB - BACKGROUND: The "Controlled Aliasing In Parallel Imaging Results In Higher Acceleration" (CAPIRINHA) technique greatly accelerates T1w 3D fast low angle shot (FLASH) scans while maintaining high image quality. We studied image quality and conspicuity of inflammatory lesions on CAIPIRINHA-accelerated imaging for pediatric small-bowel magnetic resonance imaging (MRI). METHODS: Forty-four consecutive patients (mean 14+/-3 years, 18 girls) underwent small-bowel MRI (MR enterography, MRE) at 1.5 T including diffusion-weighted imaging (DWI), contrast enhanced CAIPIRINHA 3D-FLASH and standard 2D-FLASH imaging. Crohn's disease (CD) was confirmed in 26 patients, 18 patients served as control. Independent blinded readings were performed for grading of image quality and conspicuity of CD lesions on CAIPIRINHA FLASH and standard FLASH images in comparison to a reference standard comprising imaging and endoscopic data. RESULTS: CAIPIRINHA FLASH yielded significantly higher image quality with good inter-observer agreement (kappa=0.68) and showed better visual delineation in 40% of the assessed bowel lesions, as compared to standard FLASH. There was full agreement for identification of CD patients between CAIPIRINHA and standard FLASH. CAIPIRINHA FLASH detected two small-bowel lesions that were not seen on standard FLASH. DWI revealed additional inflammatory lesions inconspicuous on contrast enhanced imaging. MRE showed an overall diagnostic accuracy of 93%. CONCLUSION: We present first evidence that CAIPIRINHA greatly accelerates T1w imaging in paediatric MRE without trade-off in image quality or lesion conspicuity and is thus preferable to standard FLASH imaging. PMID- 27457792 TI - Hepatotoxicity induced by acute and chronic paracetamol overdose in children: Where do we stand? AB - BACKGROUND: There are few data on hepatotoxicity induced by acute or chronic paracetamol poisoning in the pediatric population. Paracetamol poisoning data can reveal the weaknesses of paracetamol poisoning management guidelines. METHODS: We retrospectively studied the patients of less than 18 years old with measurable paracetamol levels, who were brought to the emergency department (ED) of La Paz University Hospital, Madrid, Spain, for suspected paracetamol overdoses between 2005 and 2010. RESULTS: Ninety-two patients with suspected paracetamol poisoning were identified. In 2007, the incidence of paracetamol poisoning in the pediatric population was 0.8 [Poisson-95% confidence interval (CI): 0.03-3.69] per 10 000 inhabitants aged less than 18 years. The incidence in the same year was 1.53 (Poisson-95% CI: 0.24-5.57) per 10 000 patients in the pediatric ED. The most common cause of poisoning was attempted suicide (47.8%) in teenagers with a median age of 15 years, followed by accidental poisoning (42.2%) in babies with a median age of 2.65 years. Difference was seen in the frequency of hepatotoxicity between acute and chronic poisoning cases. Only 1 of 49 patients with acute poisoning showed hepatotoxicity [acute liver failure (ALF)], whereas 7 of 8 patients with chronic poisoning showed hepatotoxicity (3 cases of ALF). The average time to medical care was 6.83 hours for acute poisoning and 52.3 hours for chronic poisoning (P<0.001). CONCLUSIONS: Chronic paracetamol poisoning is a potential risk factor for hepatotoxicity and acute liver failure. Delays in seeking medical help might be a contributing factor. Clinicians should have a higher index of clinical suspicion for this entity. PMID- 27457793 TI - The role of exclusive enteral nutrition in the management of orofacial granulomatosis in children. AB - BACKGROUND: Orofacial granulomatosis (OFG) is a term used to describe a persistent, painless swelling of lips and orofacial region. It can be associated with ulceration, gingival hypertrophy and cobble stone appearance of the buccal mucosa. OFG is commonly associated with Crohn's disease and can precede the intestinal manifestation of the disease. Exclusive enteral nutrition (EEN) is a recognized treatment for induction of remission for Crohn's disease. The aim of this study was to review the use of EEN in the management of OFG in children. METHODS: Retrospective review of medical records of all children diagnosed with OFG between 2007 and 2012 was conducted. Presence of comorbidities, progression to inflammatory bowel disease (IBD) and response to EEN was evaluated. RESULTS: Twenty-nine children were included, mean age at diagnosis was 9 years (standard deviation 3.9) years. Ten children had isolated OFG and 19 had OFG and IBD, of which 12 presented with OFG and IBD and 7 developed IBD later. Median time to progression to IBD was 33 months (inter quartile range: 9.8-85.5). Twenty-two children completed 6 weeks of EEN, and 19 showed clinical improvement in the OFG appearance. CONCLUSION: EEN appears to be an effective treatment option for children with isolated OFG or OFG and IBD. PMID- 27457794 TI - Serological response and protection level evaluation in chickens exposed to grains coated with I2 Newcastle disease virus for effective oral vaccination of village chickens. AB - BACKGROUND: Conventional Newcastle disease (ND) vaccination strategies in village chicken production settings is impractical due to shortage of cold-chain, unsuitability of vaccine administration routes and demanding trained personnel and hence affected its adoption. Results from earlier works elsewhere showed that the heat stable vaccines such as NDI2 are thought to be promising for village chickens. This study investigated the suitability and efficacy of Ethiopian cereal grains as carriers for the orally administrated NDI2 vaccine in chickens. RESULTS: Of the 15 treatment groups, drinking water, cracked maize and parboiled barley induced significantly higher HI antibody titer than the other carrier grains and naive control. The higher mean HI titer of chickens in drinking-water, cracked maize and parboiled barley group resulted in 100 % survival rate. In general, there was an inverse relationship between chicken mortality (%) and mean HI titer. Chickens with higher HI antibody titers had better survival rate to the challenge experiment. Booster vaccination at age of day 35 and 105 induced progressively higher HI antibodies titers in all treatment groups. CONCLUSIONS: Vaccine coated parboiled grains could be a good carrier followed by cracked grains while untreated vaccine carrier grains had lower serological responses and protection levels. The current finding gives insights on suitable vaccine delivery system in villages with weak health and transportation infrastructure, unreliable electricity, and minimally trained health workers without catching chickens individually. PMID- 27457795 TI - Residential Stability Reduces Unmet Health Care Needs and Emergency Department Utilization among a Cohort of Homeless and Vulnerably Housed Persons in Canada. AB - This study examined the association of housing status over time with unmet physical health care needs and emergency department utilization among homeless and vulnerably housed persons in Canada. Homeless and vulnerably housed individuals completed interviewer-administered surveys on housing, unmet physical health care needs, health care utilization, sociodemographic characteristics, substance use, and health conditions at baseline and annually for 4 years. Generalized logistic mixed effects regression models examined the association of residential stability with unmet physical health care needs and emergency department utilization, adjusting for potential confounders. Participants were from Vancouver (n = 387), Toronto (n = 390), and Ottawa (n = 396). Residential stability was associated with lower odds of having unmet physical health needs (adjusted odds ratio (AOR), 0.82; 95 % confidence interval (CI), 0.67, 0.98) and emergency department utilization (AOR, 0.74; 95 % CI, 0.62, 0.88) over the 4-year follow-up period, after adjusting for potential confounders. Residential stability is associated with fewer unmet physical health care needs and lower emergency department utilization among homeless and vulnerably housed individuals. These findings highlight the need to address access to stable housing as a significant determinant of health disparities. PMID- 27457796 TI - Impact of the national prevention policy and scrum law changes on the incidence of rugby-related catastrophic cervical spine injuries in French Rugby Union. AB - BACKGROUND AND AIMS: Catastrophic cervical spine injuries are rare in rugby union but require close monitoring. The aim of this study was to analyse the incidence of severe cervical spine injuries and determine the impact of a national prevention programme and new scrum rules implemented by the French Rugby Union. METHODS: A prospective study was performed between 2006 and 2013 including all players affiliated to the French Rugby Union. All cervical spine injuries resulting in death, tetraplegia or a permanent neurological deficit were included. Prevention programmes were implemented from 2007 to 2013 and a change in scrum rules in 2010. To measure the impact of rule changes, results between 2006-2010 and 2010-2013 were compared using a Poisson regression. RESULTS: Altogether, 31 injuries were observed and the mean annual incidence was 1.6 per 100 000 players. There were significantly more injuries in senior players compared to junior players (3.5 vs 0.6 per 100 000 players; CI 95% (2.1 to 4.9) vs (0.1 to 1.0)). Incidence decreased from 1.8 in 2006 to 1.0 per 100 000 players in 2013 (p<0.0001). After 2010, there were significantly fewer injuries during scrums (p=0.02). In contrast, there were significantly more injuries in backs during 2010-2013 compared to 2006-2010 (p=0.003). CONCLUSIONS: The incidence of catastrophic cervical spine injuries has declined in French Rugby Union. The implementation of specific prevention programmes and scrum law changes has notably resulted in a decrease in scrum injuries in forwards. This prospective study should be continued to monitor the future progression of injuries and adapt prevention programmes accordingly. PMID- 27457797 TI - Fluzone(r) Intradermal Quadrivalent Influenza Vaccine. AB - INTRODUCTION: An intradermal version of Fluzone(r) split-virion inactivated trivalent influenza vaccine, containing 9 ug hemagglutinin per strain of A/H1N1, A/H3N2, and one B lineage virus (Fluzone Intradermal, Sanofi Pasteur), became available in the US during the 2011-2012 influenza season for adults 18-64 years of age. In advance of the 2015-2016 season, Fluzone Intradermal was replaced with Fluzone Intradermal Quadrivalent vaccine, which contains 9 ug hemagglutinin per strain of the two A-strain viruses and both B-strain lineage viruses (Victoria and Yamagata). AREAS COVERED: This literature review summarizes the history and mechanism of intradermal vaccination, discusses the clinical trial results supporting the immunogenicity and safety of Fluzone Intradermal Quadrivalent vaccine, and describes the unique microinjection system used to deliver Fluzone Intradermal Quadrivalent. Expert commentary: Fluzone Intradermal Quadrivalent may boost confidence in influenza vaccination with the addition of a second B-lineage strain. By using an innovative microinjection system, the vaccine is also designed to address some of the logistic challenges faced by healthcare providers administering immunizations. PMID- 27457798 TI - Tibial tunnel defect size as a risk factor in growth arrest following paediatric transphyseal anterior cruciate ligament reconstruction: an anatomical study. AB - BACKGROUND: There is ongoing controversy regarding growth disturbances in younger patients undergoing anterior cruciate ligament reconstructions. Animal models have shown that an injury of 7-9% of the physeal area is a risk factor for growth disturbances. METHODS: A total of 39 magnetic resonance imaging studies of the knee were examined. The proximal tibial physeal area was determined using a calibrated 'region of interest' ligature encompassing the tibial physis in the axial plane. The potential defect left by commonly used drill sizes was calculated as a percentage of the physeal area. RESULTS: A 7-mm drill leaves a mean defect of 1.45% physeal area (range: 1.11-1.89%, SD: 0.28, 95% CI: +/-0.09), 8-mm drill leaves a 1.84% mean defect (range: 1.43-2.49%, SD: 0.38, 95% CI: +/ 0.12) and a 9-mm drill leaves a 2.30% mean defect (range: 1.83-3.19%, SD: 0.58, 95% CI: +/-0.17). At 55 degrees , 7-mm drill leaves a mean defect of 1.96% (range: 1.32-2.28%, SD: 0.37, 95% CI: +/-0.12), 8-mm drill leaves a mean defect of 2.19% (range: 1.71-2.95%, SD: 0.46, 95% CI: +/-0.14) and a 9-mm drill leaves a mean defect of 2.76% (range: 2.16-3.73%, SD: 0.58, 95% CI: +/-0.18). There was a statistically significant difference in the tunnel area with a change of drill angle (7-mm drill P = 0.005, 8-mm drill P = 0.001, 9-mm drill P = 0.001). CONCLUSION: On the basis of this study in the context of animal model and observational evidence, the area of physeal injury using drill tunnels for anterior cruciate ligament reconstruction would not appear to contribute to potential growth disturbances. PMID- 27457799 TI - Amelioration of radiation-induced lung injury by halofuginone: An experimental study in Wistar-Albino rats. AB - To evaluate effects of halofuginone (H) on radiation-induced lung injury (RILI), 60 rats were divided into six groups: Group (G) 1 control, G2 radiotherapy (RT) only, G3 and G4 2. 5 and 5 MUg H and G5 and G6 RT + 2.5 and 5 MUg H groups, respectively. A single dose of 12 Gy RT was given to both lungs. H was applied intraperitoneally with daily doses, until animals were killed at 6 and 16 weeks after RT. At 6th and 16th weeks of RT, five rats from each group were killed. Lung tissues were dissected for light and electron microscopy. Chronic inflammation, fibrosis and transforming growth factor-beta (TGF)-beta scores of all study groups were significantly different at 6th and 16th week ( p < 0.001). Chronic inflammation, fibrosis and TGF-beta scores of G2 were higher than G5 and G6 at 6th and 16th weeks of RT. At 16th week, fibrosis and TGF-beta scores of G5 were higher than G6 ( p = 0.040 and 0.028, respectively). Electron microscopical findings also supported these results. Therefore, H may ameliorate RILI. The effect of the H was more prominent at higher dose and after long-term follow-up. These findings should be clarified with further studies. PMID- 27457800 TI - Biomarkers, lactate, and clinical scores as outcome predictors in systemic poisons exposures. AB - Acute exposure to systemic poisons represents an important challenge in clinical toxicology. We aimed to analyze the potential role of cardiac biomarkers, routine laboratory tests, and clinical scores as morbidity and in-hospital mortality predictors in patients intoxicated with various systemic poisons. We conducted a prospective study on adults acutely exposed to systemic poisons. We determined the PSS, Glasgow Coma Scale (GCS), and we performed electrocardiogram, laboratory tests, lactate and cardiac biomarkers (which were reassessed 4 h, respectively 6 h later). Of 120 patients included, 45% developed complications, 19.2% had a poor outcome, and 5% died. Multivariate logistic regression sustained lactate (odds ratio (OR) 1.58; confidence interval (CI) 95%: 0.97-2.59; p 0.066), MB isoenzyme of creatine kinase (6h-CKMB; OR 1.08; CI 95%: 1.02-1.16; p 0.018) as predictors for a poor outcome. A GCS < 10 (OR 0.113; CI 95%: 0.019-0.658; p 0.015) and 4h lactate (OR 4.87; CI 95%: 0.79-29.82; p 0.087) predicted mortality after systemic poisons exposure. Receiver operating characteristic analysis showed that brain natriuretic peptide (area under the curve (AUC), 0.96; CI 95%: 0.92-0.99; p < 0.001), lactate (AUC, 0.91; CI 95%: 0.85-0.97; p < 0.001), and 6h-CKMB have good discriminatory capacity for predicting a poor outcome. In conclusion, these biomarkers, lactate, and GCS can be used to predict morbidity and mortality after systemic poisons exposure. PMID- 27457801 TI - Assessment of a simplified spin and gradient echo (sSAGE) approach for human brain tumor perfusion imaging. AB - The goal of this study was to validate a simplified spin- and gradient-echo (sSAGE) approach to obtain T1-corrected dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) data in a clinical brain tumor population. A five echo SAGE sequence was used to acquire DSC-MRI data (n=8 patients, 3 primary glioma, and 5 brain metastases). The DeltaR2* and DeltaR2 time series obtained from a nonlinear fit of all echoes (SAGE) were compared to DeltaR2* and DeltaR2 time series obtained analytically (sSAGE) using three echoes (two GEs and one SE). Through the use of multiple echoes, both methods removed T1 leakage effects from the DeltaR2* and DeltaR2 time series, and the sSAGE DeltaR2* and DeltaR2 time series were highly correlated with those from SAGE, with average correlations of 0.9. The resulting hemodynamic parameters included GE and SE cerebral blood volume (CBV), cerebral blood flow (CBF), mean vessel diameter (mVD), volume transfer constant (Ktrans), and volume fraction of the extravascular extracellular space (ve). For each metric, there was good correlation (>0.86) between sSAGE and SAGE, with no significant differences. The sSAGE method provides T1-corrected GE and SE DSC-MRI parameters in an efficient and clinically feasible manner. PMID- 27457802 TI - Effects and mechanisms of melatonin on the proliferation and neural differentiation of PC12 cells. AB - Melatonin, a lipophilic molecule that is mainly synthesized in the pineal gland, performs various neuroprotective functions. However, the detailed role and mechanisms of promoting neuronal differentiation remains limited. This study demonstrated that 10 MUM melatonin led to significant increases in the proliferation and neurite outgrowth of PC12 cells. Increased expression of microtubule-associated protein 2 (MAP2, a neuron-specific protein) was also observed. However, luzindole (melatonin receptor antagonist) and PD98059 (MEK inhibitor) attenuated these increases. LY294002 (AKT inhibitor) inhibited melatonin-mediated proliferation in PC12 cells and did not affect melatonin induced neural differentiation. The expression of p-ERK1/2/ERK1/2 was increased by melatonin treatment for 14 days in PC12 cells, whereas luzindole or PD98059 reduced the melatonin-induced increase. These results suggest that the activation of both the MEK/ERK and PI3K/AKT signaling pathways could potentially contribute to melatonin-mediated proliferation, but that only the MEK/ERK pathway participates in the melatonin-induced neural differentiation of PC12 cells. Altogether, our study demonstrates for the first time that melatonin may exert a positive effect on neural differentiation via melatonin receptor signalling and that the MEK/ERK1/2 signalling may act down stream from the melatonin pathway. PMID- 27457804 TI - Molecular basis for the blue bioluminescence of the Australian glow-worm Arachnocampa richardsae (Diptera: Keroplatidae). AB - Bioluminescence is the emission of visible light by living organisms. Here we describe the isolation and characterisation of a cDNA encoding a MW ~ 59,000 Da luciferase from the Australian glow-worm, Arachnocampa richardsae. The enzyme is a member of the acyl-CoA ligase superfamily and produces blue light on addition of D-luciferin. These results are contrary to earlier reports (Lee, J., Photochem Photobiol 24, 279-285 (1976), Viviani, V. R., Hastings, J. W. & Wilson, T., Photochem Photobiol 75, 22-27 (2002)), which suggested glow-worm luciferase has MW ~ 36,000 Da and is unreactive with beetle luciferin. There are more than 2000 species of firefly, which all produce emissions from D-luciferin in the green to red regions of the electromagnetic spectrum. Although blue-emitting luciferases are known from marine organisms, they belong to different structural families and use a different substrate. The observation of blue emission from a D-luciferin using enzyme is therefore unprecedented. PMID- 27457803 TI - Serum- and glucocorticoid-inducible kinases in microglia. AB - Microglia are derived from myelogenous cells and contribute to immunological and inflammatory responses in central nervous system. They play important roles not only in infectious diseases and inflammation after stroke, but also in psychiatric diseases such as schizophrenia. While recent studies suggest the significances of serum- and glucocorticoid-inducible kinases (SGKs) in other immune cells such as macrophages, T cells and dendritic cells, their role in microglia remains unknown. Here we, for the first time, report that SGK1 and SGK3 are expressed in multiple microglial cell lines. An SGK inhibitor, gsk650394, inhibits cell viability. In addition, lipopolysaccharide-induced expression of inflammatory regulators iNOS and TNFalpha was enhanced by gsk650394. Furthermore, translocation of NF-kappaB was enhanced by gsk650394. Taken together, these findings suggest that SGKs may play an important role in regulating microglial viability and inflammatory responses. PMID- 27457805 TI - Liraglutide ameliorates palmitate-induced endothelial dysfunction through activating AMPK and reversing leptin resistance. AB - PURPOSE: Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, is an antidiabetic drug. It has been shown to improve endothelial dysfunction, but the mechanism remains somewhat unclear. Leptin can also improve endothelial function. Cardiovascular disease (CVD) is linked to hyperleptinemia, and leptin resistance, how liraglutide influences the effect of leptin on endothelial function, is never reported. We used palmitic acid (PA) to mimic hyperlipidemia in endothelial cells to explore the cardio-protective mechanism of liraglutide and its impact on the role of leptin. METHODS: Human umbilical vein endothelial cells (HUVECs) were incubated with PA for 16 h and then were treated with liraglutide for 30 min. RESULTS: PA elevated not only phosphorylation of JNK and IKKalpha/beta, but also the expression of IL-6 in HUVECs. These effects of PA were reversed by liraglutide. In addition, liraglutide increased phosphorylation of eNOS, AMPK, and the release of NO but had no effect on PKC phosphorylation. In addition, leptin elevated eNOS phosphorylation but was abrogated by PA. However, in the presence of liraglutide, leptin regained its function of elevating eNOS phosphorylation. Last, we found that liraglutide inhibited PA-elevated SOCS3, which is a marker of leptin resistance. CONCLUSIONS: GLP-1 impairs endothelial inflammatory signals, improves endothelial function, and reverses leptin resistance. PMID- 27457806 TI - Expression of Echmr gene from Eichhornia offers multiple stress tolerance to Cd sensitive Escherichia coli Deltagsh mutants. AB - The detoxification of heavy metals frequently involves conjugation to glutathione prior to compartmentalization and eflux in higher plants. We have expressed a heavy metal stress responsive (Echmr) gene from water hyacinth, which conferred tolerance to Cd sensitive Escherichia coli Deltagsh mutants against heavy metals and abiotic stresses. The recombinant E. coli Deltagsh mutant cells showed better growth recovery and survival than control cells under Cd (200 MUM), Pb(200 MUM), heat shock (50 degrees C), cold stress at 4 degrees C for 4 h, and UV-B (20 min) exposure. The enhanced expression of Echmr gene revealed by northern analysis during above stresses further advocates its role in multi-stress tolerance. Heterologous expression of EcHMR from Eichhornia rescued Cd(2+) sensitive E. coli mutants from Cd(2+) toxicity and induced better recovery post abiotic stresses. This may suggests a possible role of Echmr in Cd(II) and desiccation tolerance in plants for enhanced stress response. PMID- 27457807 TI - Integration of parafoveal orthographic information during foveal word reading: beyond the sub-lexical level? AB - Prior research has shown that processing of a given target word is facilitated by the simultaneous presentation of orthographically related stimuli in the parafovea. Here we investigate the nature of such spatial integration processes by presenting orthographic neighbours of target words in the parafovea, considering that neighbours have been shown to inhibit, rather than facilitate, recognition of target words in foveal masked priming research. In Experiment 1, we used the gaze-contingent boundary paradigm to manipulate the parafoveal information subjects received while they fixated a target word within a sentence. In Experiment 2, we used the Flanking Letters Lexical Decision paradigm to manipulate parafoveal information while subjects read isolated words. Parafoveal words were either a higher-frequency orthographic neighbour of targets words (e.g., blue-blur) or a high-frequency unrelated word (e.g., hand-blur). We found that parafoveal orthographic neighbours facilitated, rather than inhibited, processing of the target. Thus, the present findings provide further evidence that orthographic information is integrated across multiple words and suggest that either the integration process does not enable simultaneous access to those words' lexical representations, or that lexical representations activated by spatially distinct stimuli do not compete for recognition. PMID- 27457808 TI - Surface enhanced Raman scattering of monolayer MX2 with metallic nano particles. AB - Monolayer transition metal dichalcogenides MX2 (M = Mo, W; X = S) exhibit remarkable electronic and optical properties, making them candidates for application within flexible nano-optoelectronics. The ability to achieve a high optical signal, while quantitatively monitoring strain in real-time is the key requirement for applications in flexible sensing and photonics devices. Surface enhanced Raman scattering (SERS) allows us to achieve both simultaneously. However, the SERS depends crucially on the size and shape of the metallic nanoparticles (NPs), which have a large impact on its detection sensitivity. Here, we investigated the SERS of monolayer MX2, with particular attention paid to the effect of the distribution of the metallic NPs. We show that the SERS depends crucially on the distribution of the metallic NPs and also the phonon mode of the MX2. Moreover, strong coupling between MX2 and metallic NPs, through surface plasmon excitation, results in splitting of the and modes and an additional peak becomes apparent. For a WS2-Ag system the intensity of the additional peak increases exponentially with local strain, which opens another interesting window to quantitatively measure the local strain using SERS. Our experimental study may be useful for the application of monolayer MX2 in flexible nano-optoelectronics. PMID- 27457809 TI - Unexpected global impact of VTA dopamine neuron activation as measured by opto fMRI. AB - Dopamine neurons in the ventral tegmental area (VTA) are strongly implicated in cognitive and affective processing as well as in psychiatric disorders, including schizophrenia, depression, attention-deficit hyperactivity disorder and substance abuse disorders. In human studies, dopamine-related functions are routinely assessed using functional magnetic resonance imaging (fMRI) measures of blood oxygenation-level-dependent (BOLD) signals during the performance of dopamine dependent tasks. There is, however, a critical void in our knowledge about whether and how activation of VTA dopamine neurons specifically influences regional or global fMRI signals. Here, we used optogenetics in Th::Cre rats to selectively stimulate VTA dopamine neurons while simultaneously measuring global hemodynamic changes using BOLD and cerebral blood volume-weighted (CBVw) fMRI. Phasic activation of VTA dopamine neurons increased BOLD and CBVw fMRI signals in VTA-innervated limbic regions, including the ventral striatum (nucleus accumbens). Surprisingly, basal ganglia regions that receive sparse or no VTA dopaminergic innervation, including the dorsal striatum and the globus pallidus, were also activated. In fact, the most prominent fMRI signal increase in the forebrain was observed in the dorsal striatum that is not traditionally associated with VTA dopamine neurotransmission. These data establish causation between phasic activation of VTA dopamine neurons and global fMRI signals. They further suggest that mesolimbic and non-limbic basal ganglia dopamine circuits are functionally connected and thus provide a potential novel framework for understanding dopamine-dependent functions and interpreting data obtained from human fMRI studies. PMID- 27457810 TI - A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. AB - Induction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited central nervous system permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat-shock-like response but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer's disease, without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (>3 days) nuclear activation of the heat-shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome. PMID- 27457811 TI - Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study. AB - Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity. PMID- 27457812 TI - Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. AB - Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID. PMID- 27457813 TI - Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity. AB - Although the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent exome sequencing studies of SCZ have uncovered numerous single-nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes. Here we demonstrate loss-of-function effects of multiple rare coding SNVs found in SCZ subjects in the GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) gene using functional cell-based assays involving coexpression of GIT1 and PAK3 (p21 protein (Cdc42/Rac)-activated kinase 3). Most notably, a GIT1-R283W variant reported in four independent SCZ cases was defective in activating PAK3 as well as MAPK (mitogen-activated protein kinase). Similar functional deficits were found for a de novo SCZ variant GIT1-S601N. Additional assays revealed deficits in the capacity of GIT1-R283W to stimulate PAK phosphorylation in cultured hippocampal neurons. In addition, GIT1-R283W showed deficits in the induction of GAD1 (glutamate decarboxylase 1) protein expression. Extending these functional assays to 10 additional rare GIT1 variants revealed the existence of an allelic series with the majority of the SCZ case variants exhibiting loss of function toward MAPK activation in a manner correlated with loss of PAK3 activation. Taken together, we propose that rare variants in GIT1, along with other genetic and environmental factors, cause dysregulation of PAK3 leading to synaptic deficits in SCZ. PMID- 27457814 TI - SorCS2 is required for BDNF-dependent plasticity in the hippocampus. AB - SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2 deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75NTR, required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75NTR was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2-/- mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75NTR and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders. PMID- 27457816 TI - Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. PMID- 27457815 TI - Cellular and molecular basis for stress-induced depression. AB - Chronic stress has a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2+) glutamatergic neurons. Viral expression of p11 in D2+ PrL neurons alleviates the depression like behaviors exhibited by genetically manipulated mice with D2+ neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2+ PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses. PMID- 27457817 TI - Promoter region variation in NFE2L2 influences susceptibility to ototoxicity in patients exposed to high cumulative doses of cisplatin. AB - Ototoxicity is a disabling reaction to cisplatin chemotherapy. Much of the inter individual variability in the development of hearing impairment among cisplatin receiving patients has not been fully accounted for. In particular, little is known about the pharmacogenomics of cisplatin-induced ototoxicity. This study sought to investigate the role of variation in five candidate genes in a cohort of South African cancer patients. Five variants within the candidate genes were genotyped in 214 patients, of which SLC22A2 rs316019 and NFE2L2 rs6721961 associated with reduced rates of ototoxicity. In the patients who were exposed to cumulative cisplatin doses ?200 mg m-2 (n=113), the variant rs6721961 associated with ototoxicity according to three different grading scales of hearing loss (ASHA, P=0.005; Chang, P=0.028; CTCAE, P=0.004). The NFE2L2 promotor variant rs6721961 may therefore be protective against hearing loss in cisplatin-receiving cancer patients. PMID- 27457818 TI - Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. AB - Clonidine, an alpha2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions. PMID- 27457819 TI - [Acute pulmonary embolism and contraindication of anticoagulation : Bedside implantation of a new temporary vena cava inferior filter]. AB - Pulmonary embolism (PE), mostly caused by deep vein thrombosis, is a life threatening complication in critically ill patients in the intensive care unit. A potential strategy to prevent PE in patients with contraindication for anticoagulant therapy is the implantation of a vena cava filter (VCF), to provide fast and safe PE protection against ascending thrombi. We report the case of a 56 year-old woman with an intracranial hemorrhage, who developed a PE. Because of acute contraindications for anticoagulant therapy, bedside implantation of a new VCF was performed to overcome the period of absolute contraindications for anticoagulation. After explanation, several thrombi were found on the filter. PMID- 27457820 TI - [Limits of the meaningfulness of intensive care medicine : Position paper of the Ethics Section of DIVI]. PMID- 27457821 TI - [Hepatitis A immunity in refugees in Germany during the current exodus]. AB - BACKGROUND: Germany is facing a huge humanitarian challenge with rapidly rising numbers of refugees entering the country. Data on hepatitis A seroprevalence and infection in refugees and asylum seekers in Europe during the current refugee exodus is scarce. OBJECTIVES: To assess hepatitis A (HAV) seroprevalence and immunity in refugees arriving in northern Germany in 2015. MATERIALS AND METHODS: A cross-sectional study of 235 refugees seeking shelter in reception centers in Northern Germany in August 2015 was performed, as acute Hepatitis A had been detected in one refugee in this camp. In order to analyze acute HAV infection and overall immunity, serological screening for HAV antibodies (combined IgG and IgM) was performed. The immunity threshold was defined as <20 IU/l. In all positive screening results, separate IgM testing was performed to detect acute infections. RESULTS: Males accounted for 84.3 % of HAV screened refugees and the mean age of refugees was 29.1 +/- 11.2 years. Children and adolescents below the age of 18 years made up 8.8 % of the migrants. Overall HAV immunity within the cohort was 90 %, and a mild age-dependent increase in HAV immunity was observed, with 81.1 % immunity in children <18 years and a 100 % seropositivity in subjects >50 years. One 20-year-old female refugee had positive IgM results with high HAV antibodies, most likely due to subacute HAV infection. CONCLUSIONS: This comparably high rate of HAV protected refugees in our cohort supports the notion that the probability of large HAV outbreaks in current German refugee centers is low. However, depending on their current living situation, HAV vaccination should be considered for each refugee child, and healthcare providers and personnel working in refugee centers should be vaccinated against HAV. PMID- 27457822 TI - Unilateral nevoid acanthosis nigricans treated with CO2 laser. PMID- 27457823 TI - Amphetamine and morphine may produce acute-withdrawal related hypoactivity by initially activating a common dopamine pathway. AB - Rats given drugs of abuse such as amphetamine or morphine show longer-term effects, that is, signs of acute withdrawal, including hypoactivity, hypophagia, and blunted affect, sometime between 12 and 24h after treatment. This research explores the possibility that signs of acute withdrawal produced by different drugs of abuse are instigated by overlapping mechanisms. The specific objectives of the research were to see if amphetamine and morphine produced longer-term hypoactivity, and to see if any longer-term hypoactivity elicited by the drugs could be blocked by SCH23390, a dopamine D1 antagonist. Six groups of rats, with eight rats in each group, were exposed to a series of five-day tests. Near light onset of Test Day 1, each animal was given control administrations, consisting of a saline treatment (1.0ml/kg) followed 30m later by a saline posttreatment, and locomotor activity was monitored for the next 24h. On Test Day 3, each animal was given experimental administrations, and locomotor activity was again monitored for 24h. Each group received only one combination of experimental administrations across tests. Experimental administrations consisted of saline, amphetamine (2.0mg/kg), or morphine (5.0mg/kg), followed by saline or SCH23390 (0.05mg/kg). All administrations were subcutaneous. Amphetamine and morphine produced longer term hypoactivity, having similar time courses and magnitudes. SCH23390 blocked the longer-term hypoactivity produced by both drugs. Saline and SCH23390 produced no changes in longer-term activity in their own right. The time course of amphetamine-elicited longer-term hypoactivity resembled that of amphetamine elicited longer-term hypophagia observed in a prior study. Approximately 1/4 of the animals given amphetamine or morphine did not show longer-term hypoactivity ("low withdrawal" rats). Amphetamine and morphine may initiate the cascade of events resulting in signs of acute withdrawal by producing activation in a common pathway that uses dopamine as a neurotransmitter. Different signs of acute withdrawal (hypoactivity and hypophagia) may involve the short-term activation of the same common pathway. Low withdrawal rats may have a different vulnerability to amphetamine and may show differences in drug assessment outcomes relative to animals that manifest distinct signs of acute withdrawal. PMID- 27457824 TI - ActiviTeen: A Protocol for Deployment of a Consumer Wearable Device in an Academic Setting. AB - BACKGROUND: Regular physical activity (PA) can be an important indicator of health across an individual's life span. Consumer wearables, such as Fitbit or Jawbone, are becoming increasingly popular to track PA. With the increased adoption of activity trackers comes the increased generation of valuable individual-based data. Generated data has the potential to provide detailed insights into the user's behavior and lifestyle. OBJECTIVE: The primary objective of the described study is to evaluate the feasibility of individual data collection from the selected consumer wearable device (the Fitbit Zip). The rate of user attrition and barriers preventing the use of consumer wearable devices will also be evaluated as secondary objectives. METHODS: The pilot study will occur in two stages and employs a long-term review and analysis with a convenience sample of 30 students attending Research Triangle High School. For the first stage, students will initially be asked to wear the Fitbit Zip over the course of 4 weeks. During which time, their activity data and step count will be collected. Students will also be asked to complete a self-administered survey at the beginning and conclusion of the first stage. The second stage will continue to collect students' activity data and step count over an additional 3-month period. RESULTS: We are anticipating results for this study by the end of 2016. CONCLUSION: This study will provide insight into the data collection procedures surrounding consumer wearable devices and could serve as the future foundation for other studies deploying consumer wearable devices in educational settings. PMID- 27457825 TI - Biobased Polyamides: Recent Advances in Basic and Applied Research. AB - Polyamides represent a very important class of polymers for a wide range of applications. After establishing in the 1930s with Nylon and Perlon, their impact on many branches has been continuously growing. In the context of developing sustainable polymers from renewable resources, many polyamides have meanwhile been described, which are based on natural building blocks. In addition to their sustainability, these biobased starting materials can provide special structural features to the resulting polymers and their properties, e.g., side groups, functionalities, or stereoinformation. While some biopolyamides are known for decades and well established (e.g., PA-11, Rilsan), many other promising candidates have been described in fundamental research studies, which have high potential but whose capability-especially for large scale and/or high-performance materials-will have to be proved in the future. Other candidates are very interesting from a scientific point of view, but with less potential for a market establishment due to price and/or feasibility reasons. This article aims at collating the recent developments in the field of biopolyamides and elucidating their properties and potential for different applications. PMID- 27457826 TI - An Expansible Aortic Ring in Aortic Root Remodeling: Exact Position, Pulsatility, Effectiveness, and Stability in Three-Dimensional CT Study. AB - BACKGROUND: The aim of this study was to assess effectiveness, stability, position, and expansibility of an expansible aortic annuloplasty ring with computed tomography (CT). METHODS: Ten men (median age 51 years) scheduled for aortic root remodeling with implantation of external annuloplasty ring underwent contrast-enhanced CT of the aortic root preoperatively, postoperatively, and at a median of 21 months after operation. A reconstructed transverse double oblique view of the aortic base (AB) and of the new defined annuloplasty ring base (ARB; plane of the lower edge of the ring) in systole and diastole were obtained. The diameters, perimeter, and area were measured. In addition, the distances between AB and ARB in the nadir of each sinus were measured. RESULTS: We found 12% reduction of the postoperative AB and 19% of ARB perimeter in both systole (p = 0.004, p < 0.001, respectively) and diastole (p = 0.001, p < 0.001, respectively) compared with preoperative. There was 22% reduction of the postoperative AB area in systole and 24% in diastole (p = 0.002, p = 0.001, respectively) and 33% reduction of the ARB area in systole and 32% in diastole (p < 0.001 for both) compared with the preoperative period. Nearly all measured variables in the follow-up period showed a slight increase compared with the postoperative period; however, they did not reach statistical significance. The postoperative systolic diastolic differences in the three measured variables at the level of AB and ARB were statistically significant and were maintained throughout the follow-up period. The base of the ring was implanted 2 +/- 2 mm at the right, 0 +/- 1 mm at the left above the AB, and 2 (-3 to 2) mm at the noncoronary nadir below the AB. CONCLUSIONS: This study demonstrates imaging evidence of the effectiveness, stability, and pulsatility of the annuloplasty ring in aortic root remodeling in follow-up and describes the exact position of the ring at the base of the aortic root. PMID- 27457827 TI - Congenital Heart Surgery Case Mix Across North American Centers and Impact on Performance Assessment. AB - BACKGROUND: Performance assessment in congenital heart surgery is challenging due to the wide heterogeneity of disease. We describe current case mix across centers, evaluate methodology inclusive of all cardiac operations versus the more homogeneous subset of Society of Thoracic Surgeons benchmark operations, and describe implications regarding performance assessment. METHODS: Centers (n = 119) participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2010 through 2014) were included. Index operation type and frequency across centers were described. Center performance (risk-adjusted operative mortality) was evaluated and classified when including the benchmark versus all eligible operations. RESULTS: Overall, 207 types of operations were performed during the study period (112,140 total cases). Few operations were performed across all centers; only 25% were performed at least once by 75% or more of centers. There was 7.9-fold variation across centers in the proportion of total cases comprising high-complexity cases (STAT 5). In contrast, the benchmark operations made up 36% of cases, and all but 2 were performed by at least 90% of centers. When evaluating performance based on benchmark versus all operations, 15% of centers changed performance classification; 85% remained unchanged. Benchmark versus all operation methodology was associated with lower power, with 35% versus 78% of centers meeting sample size thresholds. CONCLUSIONS: There is wide variation in congenital heart surgery case mix across centers. Metrics based on benchmark versus all operations are associated with strengths (less heterogeneity) and weaknesses (lower power), and lead to differing performance classification for some centers. These findings have implications for ongoing efforts to optimize performance assessment, including choice of target population and appropriate interpretation of reported metrics. PMID- 27457828 TI - Identifying Patients at Higher Risk of Prolonged Air Leak After Lung Resection. AB - BACKGROUND: Predictive models of prolonged air leak have relied on information not always available preoperatively (eg, extent of resection, pleural adhesions). Our objective was to construct a model to identify patients at increased risk of prolonged air leak using preoperative factors exclusively. METHODS: From 2012 to 2014, data on consecutive patients undergoing pulmonary resection were collected prospectively. Prolonged air leak was defined as lasting longer than 7 days and requiring hospitalization. Factors associated with the primary outcome (p < 0.2) were included in a multivariate model. Regression coefficients were used to develop a weighted risk score for prolonged air leak. RESULTS: Of 225 patients, 8% (18/225) experienced a prolonged air leak. Male gender (p = 0.08), smoking history (p = 0.03), body mass index (BMI) 25 or below (p < 0.01), Medical Research Council (MRC) dyspnea score above 1 (p = 0.06), and diffusion capacity for carbon monoxide below 80% (Dlco) (p = 0.01) were selected for inclusion in the final model. Weighted scores were male gender (1 point), BMI 25 or below (0.5 point), smoker (2 points), Dlco% below 80% (2 points), and MRC dyspnea score above 1 (1 point). The area under the receiver operating characteristic curve was 0.8 (95% confidence interval [CI] = 0.7 to 0.9]. An air leak score above 4 points offered the best combination of sensitivity (83% [95% CI = 58 to 96]) and specificity (65% [95% CI = 58 to 71]). CONCLUSIONS: A subgroup of lung resection patients at higher risk for a prolonged air leak can be effectively identified with the use of widely available, preoperative factors. The proposed scoring system is simple, is clinically relevant to the informed consent, and allows preoperative patient selection for interventions to reduce the risk of prolonged air leak. PMID- 27457829 TI - Effects of False Lumen Procedures on Aorta Remodeling of Chronic DeBakey IIIb Aneurysm. AB - BACKGROUND: Although thoracic endovascular aortic repair is regularly used to treat chronic DeBakey type IIIb aneurysms, persistent retrograde flow into the false lumen through distal reentry tears is a common cause of failure. We sought to determine the safety and efficacy of the false lumen procedure (FLP) for aortic remodeling with chronic DeBakey IIIb aneurysms. METHODS: From 2012 to 2015, 25 patients with chronic DeBakey IIIb aneurysms underwent FLP using vascular plugs, stent grafts, coils, or glues. The FLP was performed as an adjunctive procedure after initial thoracic endovascular aortic repair in 9 patients, in combination with initial thoracic endovascular aortic repair in 13 patients, and as an isolated procedure in 3 patients. All patients were followed up for a mean duration of 10 months after the FLP. Outcomes included the degree of thrombosis and diameter change in the true lumen and false lumen. Diameters were measured at three levels: left subclavian artery, pulmonary artery bifurcation, and abdomen (celiac artery). RESULTS: No spinal cord injury, renal failure, or 30-day mortality was observed. Complete false lumen thrombosis after FLP was observed in 20 patients (80%). Compared with before FLP, the mean false lumen diameter for each level (before 22.23 +/- 10.18 mm versus after 17.56 +/- 10.84 mm; p < 0.001) significantly decreased, whereas the mean true lumen diameter for each level (20.45 +/- 5.33 mm versus 25.12 +/- 5.60 mm, p < 0.001) increased. CONCLUSIONS: False lumen procedures were safe, promoted complete thrombosis, and had favorable aortic remodeling in patients with chronic DeBakey IIIb aneurysms. PMID- 27457830 TI - Effect of Aortic Valve Replacement on Aortic Root Dilatation Rate in Patients With Bicuspid and Tricuspid Aortic Valves. AB - BACKGROUND: It remains unclear whether aortic valve replacement (AVR) has an effect on the aortic root dilatation rate in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). The present study evaluated the pre- and postoperative annual aortic root dilatation rates in BAV and TAV. METHODS: A total of 93 patients (67 +/- 11 years; 71% men) who underwent AVR between 2003 and 2013 and had at least 2 pre- and postoperative echocardiographic studies 1 year or more apart were included in this retrospective observational study. The sinus of Valsalva (SOV), sinotubular junction (STJ) and ascending aorta (AAo) were measured in the parasternal long-axis view. RESULTS: Patients with BAV (n = 22) were significantly younger and had less coronary artery disease than patients with TAV (n = 71). At all points in time, the aortic root diameters were larger in BAV compared with TAV. Preoperatively, the STJ and AAo grew significantly faster in BAV compared with TAV (STJ, 0.27 versus 0.04 mm/y; p = 0.021; AAo, 0.42 versus 0.15 mm/y; p = 0.019). After operation, there were no significant differences in aortic root dilatation rates between BAV and TAV (SOV, -0.01 versus 0.15 mm/y; p = 0.096; STJ, 0.08 versus 0.05 mm/y; p = 0.676; AAo, 0.28 versus 0.35 mm/y; p = 0.745). CONCLUSIONS: The annual aortic root dilatation rates were significantly higher in BAV compared with TAV before AVR. However, after AVR, aortic root dilatation rates were similar in BAV and TAV, suggesting an important role of hemodynamics on aortic root dilatation in BAV. PMID- 27457831 TI - Postoperative Adjuvant Therapy Improves Survival in Pathologic Nonresponders After Neoadjuvant Chemoradiation for Esophageal Squamous Cell Carcinoma: A Propensity-Matched Analysis. AB - BACKGROUND: The prognosis of patients with esophageal cancer who have poor response to chemoradiotherapy (ie, pathologic nonresponders [pNRs]) remains poor. We investigated whether the use of postoperative adjuvant therapy (AT) could improve survival in this patient group. METHODS: Among patients with esophageal squamous cell carcinoma who were treated with neoadjuvant chemoradiotherapy (nCRT) and operation between 2000 and 2012, pNRs (defined as those having a postoperative T stage of equal or greater pretreatment T stage or persistent nodal disease) were identified and divided into two groups according to their subsequent management (AT versus surveillance). Survival and recurrence were compared after propensity score matching for the following five factors: age, performance status, pathological lymph node status after treatment (ypN) status, severity of postoperative complications, and length of hospital stay (LOS). RESULTS: Of the 115 pNRs, 74 and 41 received AT and surveillance alone, respectively. Patients who received AT were younger, had less major postoperative complications, and a shorter LOS. A total of 32 pairs of well-balanced patients (n = 64) were selected by propensity matching. A significant benefit in terms of disease-free survival (DFS) was observed for pNRs treated with AT compared with those undergoing surveillance (3-year DFS rate: 45% versus 22.3%, p = 0.022). However, more patients in the AT group died of causes unrelated to cancer, resulting only in a borderline increase of overall survival (OS) [3-year OS rate: 34.4% versus 21.6%, p = 0.13]. CONCLUSIONS: Postoperative AT can improve DFS in pNRs after nCRT. However, its use should be carefully weighed against a potential increase in the risk of treatment-related death. PMID- 27457832 TI - Biomechanics of Failed Pulmonary Autografts Compared With Normal Pulmonary Roots. AB - BACKGROUND: Progressive dilatation of pulmonary autografts after the Ross operation may reflect inadequate remodeling of the native pulmonary root to adapt to systemic circulation. Understanding the biomechanics of autograft root dilatation may aid designing strategies to prevent dilatation. We have previously characterized normal human pulmonary root material properties; however, the mechanical properties of failed autografts are unknown. In this study, failed autograft roots explanted during reoperation were acquired, and their material properties were determined. METHODS: Failed pulmonary autograft specimens were obtained from patients undergoing reoperation after the Ross operation. Fresh human native pulmonary roots were obtained from the transplant donor network as controls. Biaxial stretch testing was performed to determine tissue mechanical properties. Tissue stiffness was determined at patient-specific physiologic stresses at pulmonary pressures. RESULTS: Nonlinear stress-strain response was present in both failed autografts and normal pulmonary roots. Explanted pulmonary autografts were less stiff than were their native pulmonary root counterparts at 8 mm Hg (134 +/- 42 vs 175 +/- 49 kPa, respectively) (p = 0.086) and 25 mm Hg (369 +/- 105 vs 919 +/- 353 kPa, respectively) (p = 0.006). Autograft wall stiffness at both 8 and 25 mm Hg was not correlated with age at the Ross procedure (p = 0.898 and p = 0.813, respectively) or with time in the systemic circulation (p = 0.609 and p = 0.702, respectively). CONCLUSIONS: Failed pulmonary autografts retained nonlinear response to mechanical loading typical of healthy human arterial tissue. Remodeling increased wall thickness but decreased wall stiffness in failed autografts. Increased compliance may explain progressive autograft root dilatation in autograft failures. PMID- 27457833 TI - Inner-Branched Endografts for the Treatment of Aortic Arch Aneurysms After Open Ascending Aortic Replacement for Type A Dissection. AB - BACKGROUND: The development of a postdissection aortic arch aneurysm after open ascending aortic replacement for type A dissection places the patient at increased risk for an open operation due to the need for redo sternotomy and total arch replacement. We conducted a computed tomography-based feasibility study to assess what proportion of these patients would be anatomically suitable for branched endograft repair of an arch aneurysm. We also aimed to identify ways to tailor the index operation to increase suitability for future endovascular repair. METHODS: Our study was conducted at the Aortic Centre, Lille University Hospital, Lille, France. Postoperative images were assessed for patients after open replacement of the ascending aorta for acute type A dissection in this center between 2009 and 2015 to determine suitability for use of an aortic arch inner-branched device. RESULTS: The assessment found 52 of 73 patients (71.2%) were anatomically suitable for treatment with the aortic arch inner-branched device. The only cause for absolute exclusion from suitability was the absence of a proximal landing zone in the ascending aorta. Reasons for this were the ascending aortic graft being too short (71.4%), the presence of a major kink in the graft (23.8%), and the graft diameter being too large (4.8%). CONCLUSIONS: Approximately 70% of patients with arch aneurysm formation after open ascending aortic replacement for type A dissection are anatomically suitable for treatment with the aortic arch inner-branched device. In the future, surgeons will be able to fashion the prosthetic graft at the time of the index operation to ensure it fulfills criteria for an adequate proximal landing zone. PMID- 27457834 TI - Management of Bilateral Spigelian Hernias. PMID- 27457835 TI - Carotid Artery Injury from Hemorrhage Control during Routine Tonsillectomy. PMID- 27457836 TI - Solitary Fibrous Tumor at the Anal Margin. PMID- 27457837 TI - An Unusual Cause of Subcutaneous Emphysema. PMID- 27457838 TI - Damage Control Laparotomy for Uterine Rupture Following Attempted Vaginal Birth after Cesarean. PMID- 27457839 TI - Anatomical Study about the Intra Individual Variability of the Superior Laryngeal Nerve: What is the Helpful Surgical Take-Away? PMID- 27457840 TI - Infectious Complications in Patients with Ventriculoperitoneal Shunts after Intra Abdominal Procedures. PMID- 27457841 TI - Case Discussion of Turnbull-Cutait Procedure for Complex Ano-vaginal Fistula: Revival of the Delayed Coloanal Pull-through Procedure and Its Application for the Modern Surgeon. PMID- 27457842 TI - Adult Intussusception Caused by Ileocecal Clostridium difficile Pseudomembranous Colitis. PMID- 27457843 TI - Sporadic, Primary Lymph Node Gastrinoma. PMID- 27457844 TI - Repair of Coloanal Anastomotic Dehiscence and Sinus Formation Using Intraluminal Application of Endo-SPONGE((r)). PMID- 27457845 TI - Ovarian Thyroid Cancer. PMID- 27457846 TI - Missed Extravasation Injury from Peripheral Infusion of Norepinephrine Resulting in Forearm Compartment Syndrome and Amputation. PMID- 27457847 TI - Duodenal Leiomyoma Causing Duodenojejunal Intussusception. PMID- 27457848 TI - Delayed Development of Extrathoracic Lung Herniation after Blunt Thoracic Trauma. PMID- 27457849 TI - Laparoscopic Gastrectomy for CDH-1 Mutation. PMID- 27457850 TI - Polycythemia Vera, an Unusual Suspect in the Case of Spontaneous Splenic Rupture. PMID- 27457851 TI - Esophageal Perforation in a Sword Swallower. PMID- 27457852 TI - Laparoscopic Duodenojejunostomy for Superior Mesenteric Artery Syndrome. PMID- 27457853 TI - Crossroads-2016 Southeastern Surgical Congress Presidential Address. PMID- 27457854 TI - Impact of Beta-Blockers on Nonhead Injured Trauma Patients. AB - Catecholamine surge after traumatic injury may lead to dysautonomia with increased morbidity. Small retrospective studies have shown potential benefit of beta-blockers (BB) in trauma patients with and without traumatic brain injury (TBI). This study evaluates a large multiply injured cohort without TBI that received BB. Patients were identified from the trauma registry from January 1, 2003 to December 31, 2011. Patients who received >1 dose of BB were compared to controls. Patients with TBI, length of stay (LOS) < 2 days, and prehospital BB were excluded. Outcomes were mortality, intensive care unit (ICU) LOS, and LOS. Stepwise multivariable regression was used to identify variables significantly associated with mortality. During the study period, 19,151 eligible patients were admitted. The mean age was 39 years. Most were male (74%) and most sustained blunt mechanism (75%). A total of 1854 (11%) patients received BB. BB patients had longer LOS (16 vs 6 days), ICU LOS (7 vs 1 days), and higher mortality (2.8 vs 0.5%) (all P < 0.001). Multivariable regression demonstrated no benefit to BB after adjusting for potential confounding characteristics [odds ratio (OR) 0.952; confidence interval (CI) 0.620-1.461]. In conclusion, in this largest study to date, patients receiving BB were older, more severely injured, and had a higher mortality. Unlike TBI patients, multivariable regression showed no benefit from BB in this population. PMID- 27457855 TI - Right Versus Left-Sided Colectomies: A Comparison of Outcomes. AB - Surgeons often consider that a right colectomy (RC) carries less risk than a left or sigmoid colectomy (L/SC). Our aim was to compare outcomes between RC and L/SC. Review of the Carolinas Medical Center National Surgical Quality Improvement Program data from 2013 to February 2015 was performed. Procedures were categorized as RC Versus L/SC based on current procedural terminology codes for both open and laparoscopic colectomies. Demographics and minor and major complications were evaluated using standard statistical methods. A total of 164 RC and 211 L/SC were studied. RC patients were older (63.9 +/- 14.2 vs 59.4 +/- 13.0, P < 0.001). Patients undergoing RC had more comorbidities, and 64.6 per cent had an American Society of Anesthesiologist (ASA) Class III or above Versus 51.7 per cent of those undergoing L/SC (P = 0.02). RC had significantly higher rates of postop urinary tract infection (7.3% vs 2.8%, P = 0.04) and postop transfusions (P = 0.01). Average length of stay was longer for RC (10.1 +/- 8.6 days vs 8.3 +/- 7.0 days, P < 0.01). After controlling for ASA class, preoperative hematocrit and surgical technique (lap Versus open), multivariate analysis indicated that there were no longer any significant differences in outcomes between RC and L/SC. There were no differences between the group complications including superficial or deep surgical site infections, anastomotic leak, myocardial infarction (MI), pneumonia, or 30-day mortality. RC patients tended to be sicker and had more medical complications postop with initial evaluation of the data. However, when controlling for ASA, hematocrit, and techniques, there were no differences in complications when RC was compared to L/SC. The belief that L/SC has a higher rate of complications compared to RC is not supported. PMID- 27457856 TI - Outcomes of Endoscopic Stenting for Traumatic Biliary and Pancreatic Fistulae. AB - The role of endoscopic retrograde cholangiopancreatography (ERCP) in the trauma patient is limited. Therefore, reporting of outcomes is sparse in the literature. The purpose of this study was to review outcomes of patients who underwent ERCP for traumatic biliopancreatic injury. We retrospectively reviewed 1550 ERCPs, from a prospectively maintained database, performed by a single surgical endoscopist consulted by the trauma surgical service for the management of traumatic fistulae. Referral was made for patients with high output (greater than 200 mL/d) and/or persistent (failure to resolve within 30 days) fistulae and traumatic biliary stricture. Primary end point was postprocedural complications. Secondary end points included patient characteristics, stents placed, and duration of stenting. Seventeen patients underwent a total of 31 ERCPs for biliary and/or pancreatic injury resulting from abdominal trauma (eight penetrating, nine blunt). Fourteen patients had ERCP after laparotomy, with a mean interval to ERCP of 74 days. In three patients, ERCP was the only intervention required. Fourteen biliary stents were placed, seven of which were metallic. Ten pancreatic stents were placed; one proximally migrated but was successfully retrieved. Four patients had both ducts simultaneously stented. The mean duration of stenting was 158 days. All fistulae resolved after stenting. There were no serious complications. PMID- 27457857 TI - A Single Surgeon's Experience with Enhanced Recovery after Surgery: An Army of One. AB - The benefits of enhanced recovery after surgery (ERAS) have been demonstrated for multiple surgical procedures in high-volume programs. However, resources required for its implementation may be daunting to individual surgeons. Patients undergoing elective abdominal procedures from June 2013 to April 2015 by a surgical oncologist before and after the implementation of an ERAS protocol were reviewed. A total of 179 patients were included. The mean age of the patients was 63 years, and a majority of them were females (53.6%), white (61.5%), had a Charlson score of 0 to 2 (45.8%), and a Clavien complication grade of 0 to I (60.1%). The univariate analysis revealed that the ERAS protocol was associated with shorter length of stay (LOS) (6.2 vs 9.6 days), lower cost ($21,674 vs $30,380), and lower mortality (0 vs 3.3%); P < 0.05. Differences were noted in LOS and costs for all procedures, the differences were the greatest for hepatic resection (3.8 vs 8.4 days and $16,770 vs $28,589), intestinal resection/stoma closure (4.8 vs 7.6 days and $18,391 vs $22,239), and other abdominal procedures (5.0 vs 10.8 and $17,713 vs $30,900); P < 0.05. The differences were less for patients undergoing procedures for which postoperative pathways were already in place such as pancreatic (9 vs 10.8 days and $30,524 vs $34,291) and colorectal (5.3 vs 6.5 days and $20,733 vs $25,150) surgeries. P > 0.05. An ERAS program can be instituted by an individual surgeon with the benefits of decreased LOS, cost, and mortality. PMID- 27457858 TI - What's in the Box? The Effectiveness of a Low-Volume Massive Transfusion Protocol. AB - Transfusion ratios approaching 1:1:1 of packed red blood cells (PRBCs) to fresh frozen plasma (FFP) to platelet have been shown to improve outcomes in trauma. There is little data available to describe in what quantity that ratio should be delivered. We hypothesized that lowering the total volume of products delivered in each protocol round would not adversely affect outcomes in the bleeding trauma patient. A retrospective review of 9732 trauma patients admitted to a rural Level I trauma center over a 3-year period was performed. Patients who received a massive transfusion (greater than 10 units of blood product transfused in the first 24 hours), between January 2012 and April 2015 were identified as the study cohort. In May of 2014, our institution switched from a massive transfusion protocol (MTP) that included 6 PRBCs:6 FFP:1 platelet to a lower volume massive transfusion protocol (LVMTP) that included 4 PRBC:4 FFP:1 platelet. Data collected included patient demographics, vital signs, and outcomes. A total of 131 patients met study criteria. MTP was activated on 65 per cent of patients (57/88), receiving a massive transfusion during the 28 months before implementation of the new protocol. In contrast, LVMTP was activated in 100 per cent of patients (43/43) receiving a massive transfusion in the 12 months after implementation of the new protocol. There was no significant difference in age (36.6 vs 37.2, P = 0.87), injury severity score (29.8 vs 32.3, P = 0.45), or per cent penetrating mechanism (43.9 vs 37.2%, P = 0.503) when comparing MTP to LVMTP. In addition, there was no significant difference in mortality (47.4 vs 41.9%, P = 0.584), lengths of stay (13.5 vs 17.1, P = 0.258), or vent days (6.4 vs 8.2, P = 0.236) when comparing MTP to LVMTP. A LVMTP is safe and effective for the resuscitation of the trauma patient. PMID- 27457859 TI - A Large Single-Center Experience of Open Lateral Abdominal Wall Hernia Repairs. AB - Lateral abdominal wall hernias may occur after a variety of procedures, including anterior spine exposure, urologic procedures, ostomy closures, or after trauma. Anatomically, these hernias are challenging and require a complete understanding of abdominal wall, interparietal and retroperitoneal, anatomy for successful repair. Mesh placement requires extensive dissection of often unfamiliar planes, and its fixation is difficult. We report our experience with open mesh repair of lateral abdominal wall hernias. A retrospective review of a prospectively maintained database was performed to identify patients with a classification of lateral abdominal wall hernia who underwent an open repair. A total of 61 patients underwent open lateral hernia repairs. Mean patient age was 58 years (range 25-78), with a mean body mass index of 32 kg/m(2) (range 19.0-59.1). According to the European Hernia Society classification, defects were located subcostal (L1, 14 patients), flank (L2, 33 patients), iliac (L3, 11 patients), and lumber (L4, 3 patients). Mean defect size was 78.6 cm(2), with a mean greatest single dimension of 9.2 cm (range 2-25 cm). Retromuscular or interparietal repair was performed in 50.8 per cent, preperitoneal in 41.0 per cent, intraperitoneal in 6.6 per cent, and onlay in 1.6 per cent. The rate of surgical site occurrence was 49.2 per cent, primarily seroma and surgical site infection rate was 13.1 per cent. With a mean follow-up of 15.4 months, seven patients (11.5%) have documented recurrence. Synthetic mesh reconstruction of lateral wall hernias is challenging. Our experience demonstrates the safety and success of repair using synthetic mesh primarily in the retromuscular, interparietal, or preperitoneal planes. PMID- 27457860 TI - Identifying Effectors of Outcomes in Patients with Large Umbilical Hernias. AB - Quality of life (QOL) has become an important focus of hernia repair outcomes. This study aims to identify factors which lead to ideal outcomes (asymptomatic and without recurrence) in large umbilical hernias (defect size >=9 cm(2)). Review of the prospective International Hernia Mesh Registry was performed. The Carolinas Comfort Scale was used to measure QOL at 1-, 6-, and 12-month follow up. Demographics, operative details, complications, and QOL data were evaluated using standard statistical methods. Forty-four large umbilical hernia repairs were analyzed. Demographics included: average age 53.6 +/- 12.0 and body mass index 34.9 +/- 7.2 kg/m(2). The mean defect size was 21.7 +/- 16.9 cm(2), and 72.7 per cent were performed laparoscopically. Complications included hematoma (2.3%), seroma (12.6%), and recurrence (9.1%). Follow-up and ideal outcomes were one month = 28.2 per cent, six months = 42.9 per cent, one year = 55.6 per cent. All patients who remained symptomatic at one and two years were significantly symptomatic before surgery. Symptomatic preoperative activity limitation was a significant predictor of nonideal outcomes at one year (P = 0.02). Symptomatic preoperative pain was associated with nonideal outcomes at one year, though the difference was not statistically significant (P = 0.06). Operative technique, mesh choice, and fixation technique did not impact recurrence or QOL. Repair of umbilical hernia with defects >=9 cm(2) had a surprising low rate of ideal outcomes (asymptomatic and no recurrence). All patients with nonideal long-term outcomes had preoperative pain and activity limitations. These data may suggest that umbilical hernia should be repaired when they are small and asymptomatic. PMID- 27457861 TI - Gluteal Fascial Advancement for Pilonidal Cyst Disease: A 10-year Review. AB - Elective excision of noninfected pilonidal cysts has historically been plagued by a high rate of complications, such as wound breakdown and recurrence. Debate remains regarding the most effective method of wound closure. We previously reported a small group of patients (n = 17 out of 83 patients) in which a novel technique decreased wound complications and recurrence. The purpose of this article was to build on that prior study by evaluating the utility of the gluteal fascial advancement method to decrease complications over a 10-year period. All patients who underwent elective pilonidal cyst excision from 2008 to 2015 were retrospectively reviewed (n = 150); this was added to the data from 2004 to 2007. Patients were divided into two cohorts: those who underwent elective excision with simple closure (n = 172) and those who underwent bilateral gluteal fascial advancement flaps (n = 61). Primary end points included recurrence and dehiscence. Overall demographic characteristics were statistically comparable between groups. The rate of recurrence was not significantly different between groups. However, wound closure using bilateral gluteal fascial advancement flaps was associated with a significantly lower rate of dehiscence when compared with standard primary closure (12% vs 40%, P < 0.001). The use of bilateral gluteal fascial advancement flaps is a superior method for closing elective pilonidal cyst excisions. PMID- 27457862 TI - Return to the System Within 30 Days of Discharge after Pediatric Appendectomy. AB - Postprocedural revisits, readmissions, and reoperations are commonly tracked quality metrics and have reimbursement and hospital-level comparison implications. Our purpose was to document these rates after pediatric appendectomy and to identify patient factors related to these metrics. This study included 3756 appendectomies performed at a single institution from 2009 to 2013. Data were prospectively collected and clinical events within 30 days of discharge were analyzed. Regression models identified factors associated with each metric. There were 328 returns to the emergency department (8.7%), 128 readmissions (3.4%), and 41 reoperations (1.0%). The main source of readmission was the emergency department (n = 118, 92%). Nearly two-thirds of readmissions were nonoperative (n = 87, 68%) and 12.5 per cent of readmissions were not related to the index appendectomy. Factors associated with readmission include procedure length >70 minutes [odds ratio (OR) 1.89, P = 0.043] and failed nonoperative management of perforated appendicitis (OR 2.97, P = 0.041). The most common indication for reoperation was intra-abdominal abscess (n = 20, 49%), 55 per cent of which were managed with image-guided drainage. In conclusion, although 30-day revisit, readmission, and reoperation rates after appendectomy are low, there are opportunities for improvement. Furthermore, many 30-day readmissions are not related to the index procedure and must be clearly identified to avoid inaccuracies with reimbursement and quality rankings. PMID- 27457863 TI - Vital Signs Strongly Predict Massive Transfusion Need in Geriatric Trauma Patients. AB - Early recognition of massive transfusion (MT) requirement in geriatric trauma patients presents a challenge, as older patients present with vital signs outside of traditional thresholds for hypotension and tachycardia. Although many systems exist to predict MT need in trauma patients, none have specifically evaluated the geriatric population. We sought to evaluate the predictive value of presenting vital signs in geriatric trauma patients for prediction of MT. We retrospectively reviewed geriatric trauma patients presenting to our Level I trauma center from 2010 to 2013 requiring full trauma team activation. The area under the receiver operating characteristic curve was calculated to assess discrimination of arrival vital signs for MT prediction. Ideal cutoffs with high sensitivity and specificity were identified. A total of 194 patients with complete data were analyzed. Of these, 16 patients received MT. There was no difference between the MT and non-MT groups in sex, age, or mechanism. Systolic blood pressure, pulse pressure, diastolic blood pressure, and shock index all were strongly predictive of MT need. Interestingly, we found that heart rate does not predict MT. MT in geriatric trauma patients can be reliably and simply predicted by arrival vital signs. Heart rate may not reflect serious hemorrhage in this population. PMID- 27457864 TI - Is there an Optimal Surgical Approach to Neuroendocrine Tumors of the Ampulla? A Single Institution Experience Over 15 Years. AB - Neuroendocrine tumors (NETs) of the ampulla of Vater are rare neoplasms accounting for a small fraction of gastroenteropancreatic NETs. The optimal surgical approach remains controversial. This study aimed to define the optimal approach in patients with ampullary NETs. Patients who underwent resection of ampullary NETs from 2000 to 2014 were analyzed. Fourteen patients with well differentiated, nonfunctional NETs were identified. The mean age was 60 +/- 15 years, and nine (64%) were male. The mean tumor size was 1.6 +/- 0.9 cm and the majority (61%) had an advanced tumor-node-metastasis stage. Eight (57%) patients underwent pancreaticoduodenectomy (PD) and six (43%) underwent transduodenal ampullectomy (TA). Although the mean tumor size was similar (1.7 vs 1.5 cm), the majority (75 vs 20%) of PD patients demonstrated a trend toward more aggressive tumors, characterized by advance T stage in 25 vs 0 per cent, lymph node positivity in 88 vs 17 per cent, and elevated proliferative index (Ki-67) in 25 vs 0 per cent. Complete resection (R0) was achieved in all PD patients versus 75 per cent in TA patients. There was no difference in major complication rate (50 vs 33%). In the TA group, one (17%) patient recurred and two (33%) patients died, whereas only one (13%) patient died in the PD group and no patients recurred. In conclusion, ampullary tumors can be aggressive tumors characterized by high regional lymph node involvement. A transduodenal approach may provide an inadequate oncological resection and thus has the potential to understage ampullary NETs. In the era of increasing therapeutic options for gastroenteropancreatic NETs, accurate staging is crucial and appropriate oncologic resection via PD for ampullary NETs should be considered. PMID- 27457865 TI - Analysis of Profit and Loss by Injury Severity over 20 Years at a University Level I Trauma Center. AB - We examined financial data from a University Level I Trauma Center from 1994 to 2014. We sought to investigate the hypothesis that lower injury severity correlates with increased profitability. We examined data from July 1994 to December 2014. This included hospital charges, Medicare cost data, final reimbursement, and payor source. Patients were separated into Injury Severity Score (ISS) groupings: 0 to 9, 10 to 14, 15 to 24, >24, and >14. Mean and standard deviation of mean are reported. We had complete data on 27,582 patients. Overall profit per case when subtracting costs from reimbursements was $1,932/case (total profit in unadjusted dollars = $53,475,828 or $2,673,791/year). When examined by ISS, profitability was significantly different between ISS 0 to 14 and 15 to 24, and > 24. When charge data were examined, the average loss per case was -$31,313 for the 27,582 patient data set. When using cost, and not charge data, overall trauma care had a positive margin. Severely injured patients (ISS > 14) were the most profitable, with a significantly higher profit per case than all other groupings. Only through examination of cost data can realistic determinations of trauma center profitability be made. If only charge data had been examined in this study, the overall loss from the 20-year period would have been $863,675,166 and not a profit of $53,475,828. PMID- 27457866 TI - Trauma Survival Margin Analysis: A Dissection of Trauma Center Performance through Initial Lactate. AB - Measurement of trauma center performance presently relies on W-score calculation and comparison to national data sets. A limitation to this practice is a skewing of the W score, as it determines overall performance of a trauma population that is often heavily weighted by patients of low acuity. The University of Virginia relative mortality metric (RMM) was formulated to provide higher resolution in identifying areas of performance improvement within subpopulations of a trauma center using traditional Trauma Injury Severity Score methodology. Lactic acidosis has been established as a risk factor for mortality in the setting of trauma. This study aims to compare survival margin, defined as the area between actual and predicted mortality curves, in patients with either normal or elevated initial lactate. W score and RMM were calculated and compared in these cohorts. Whereas the W score suggested increased survival within the high initial lactate group, the RMM demonstrated the expected finding of increased survival margin in the normal lactate cohort. The RMM is a potentially valuable tool for trauma centers to monitor and improve performance. In addition, these findings validate the use of lactate as a triage and risk adjustment tool in the trauma setting. PMID- 27457867 TI - A Case of Pancreatic Intraductal Tubular Carcinoma: A Rare Entity with Improved Prognosis. PMID- 27457868 TI - A Case of Iliac Crest Avulsion with Peritoneal Disruption and Bowel Herniation after Blunt Trauma: A Case Report and Review of Literature. PMID- 27457869 TI - Interparietal Hernia Complicating Retromuscular Ventral Hernia Repair. PMID- 27457870 TI - Reference values for spirometry and their use in test interpretation: A Position Statement from the Australian and New Zealand Society of Respiratory Science. AB - Traditionally, spirometry testing tended to be confined to the realm of hospital based laboratories but is now performed in a variety of health care settings. Regardless of the setting in which the test is conducted, the fundamental basis of spirometry is that the test is both performed and interpreted according to the international standards. The purpose of this Australian and New Zealand Society of Respiratory Science (ANZSRS) statement is to provide the background and recommendations for the interpretation of spirometry results in clinical practice. This includes the benchmarking of an individual's results to population reference data, as well as providing the platform for a statistically and conceptually based approach to the interpretation of spirometry results. Given the many limitations of older reference equations, it is imperative that the most up-to-date and relevant reference equations are used for test interpretation. Given this, the ANZSRS recommends the adoption of the Global Lung Function Initiative (GLI) 2012 spirometry reference values throughout Australia and New Zealand. The ANZSRS also recommends that interpretation of spirometry results is based on the lower limit of normal from the reference values and the use of Z scores where available. PMID- 27457871 TI - Malignant pleural mesothelioma. PMID- 27457872 TI - Management of malignant pleural mesothelioma-part 2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG). AB - Treatment of malignant pleural mesothelioma (MPM) depends on performance status of the patient, tumor stage, and histological differentiation. Chemotherapy (CHT) can be administered as first- and second-line treatment in unresectable MPM or as neoadjuvant or adjuvant treatment before or after surgery. A combination of an antifolate and platinum-based CHT is the only approved standard of care. Several targeted and immunotherapies are in evaluation and further studies are warranted to determine the therapeutic value of these new treatment options. Radiotherapy (RT) can be considered either as adjuvant treatment after surgery or for palliation of pain-related tumor growth. Recent data support the use of RT in a neoadjuvant setting. Macroscopic complete resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) is indicated in selected patients with good performance status. Surgery should only be applied as part of a multimodality treatment (MMT) in combination with chemo- and/or radiotherapy. In a large number of cases, palliative attempts are needed to improve quality of life and to achieve symptom control. PMID- 27457873 TI - Management of malignant pleural mesothelioma - part 3 : Data from the Austrian Mesothelioma Interest Group (AMIG) database. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor originating from the pleural cavity with a strong link to previous asbestos exposure. In order to determine the demographics, diagnostics, therapeutic strategies, and prognosis of MPM patients in Austria, the Austrian Mesothelioma Interest Group (AMIG) was founded in 2011. In this report the data from the AMIG MPM database collected to date are reported. METHODS: A prospective observational registry was initiated, including patients with histologically verified MPM diagnosed and treated at specialized centers in Austria. Patient inclusion started in January 2011 and follow-up was completed until September 2015. RESULTS: A total number of 210 patients were included. There were 167 male and 43 female patients with a mean age of 67.0 years (SD +/- 11.3) at the time of diagnosis. Asbestos exposure was confirmed in 109 (69.4 %) patients. The histological subtype was epithelioid in 141 (67.2 %), sarcomatoid in 16 (7.6 %), biphasic in 28 (13.3 %), and MPM not otherwise specified in 25 (11.9 %) patients. Of the patients, 30 (14.3 %) received best supportive care (BSC) only, 71 (33.8 %) chemotherapy (CHT) alone, four (1.9 %) radiotherapy (RT) alone, 23 (11.9 %) CHT/RT, two (0.9 %) surgery alone, and 76 (36.2 %) curative surgery within a multimodality treatment (MMT), which was more frequently performed for patients younger than 65 years and with early-stage disease (I + II). Median overall survival (OS) was 19.1 months (95 % CI 14.7-23.5). The 1-, 3-, and 5-year OS rates were 66 %, 30 %, and 23 %, respectively, and OS was significantly better in patients undergoing surgery within MMT (5-year survival 5 % vs. 40 %, p = 0.001). CONCLUSION: Patients with earlier disease stages, younger age, good performance status, and epithelioid histology were more likely to undergo MMT including surgery, which resulted in a more favorable outcome. PMID- 27457875 TI - Patient knowledge concerning age-related macular degeneration: an AMD questionnaire. AB - BACKGROUND: Age-related macular degeneration (AMD) is a disease with rising prevalence. This study evaluates patients' knowledge and the need for more patient information. METHODS: 271 patients with AMD were asked to complete a questionnaire concerning their knowledge about AMD. 150 patients were interviewed by a physician and 121 patients completed the questionnaire on their own. RESULTS: 79.4 % of patients had previous knowledge about AMD. Most patients, 97.3 %, got their information from physicians. 58 % of patients find their knowledge concerning AMD adequate. Only 23.9 % knew about aid organizations for patients with visual impairments. DISCUSSION: Though the majority of patients had good knowledge concerning AMD, there was a large percentage of patients who seemed to lack information. Physicians should actively ask their patients if they have any questions related to their disease. Medial focus on AMD and information about aid organizations could help patients to cope with their disease. CONCLUSION: A large number of patients seemed to need additional information. We suggest that ophthalmologists provide general information concerning AMD to their patients every 3 to 5 years. Information about aid organizations specializing in visual impairment could also be provided. Well-informed patients would be better able to follow their physician's instructions and would have a better understanding of their disease, particularly for the sake of therapy. PMID- 27457874 TI - [Guidelines for vaccination of immunocompromised individuals]. AB - Immunosuppression of various origins is associated with an increased risk of infection; therefore the prevention of infectious diseases by vaccination is especially important in immunocompromised patients. However, the response to vaccinations is often reduced in these risk groups and the application of live vaccines is contraindicated during immunosuppression.In the following expert statement, recommendations for vaccination were created on the basis of current evidence and theoretical/immunological considerations. A first, general part elaborates on efficacy and safety of vaccinations during immunosuppression, modes of action of immunosuppressive medications and recommended time intervals between immunosuppressive treatments and vaccinations. A core piece of this part is a graduation of immunosuppression into three stages, i. e. no relevant immunosuppression, mild to moderate and severe immunosuppression and the assignment of various medications (including biologicals) to one of those stages; this is followed by an overview of possible and necessary vaccinations in each of those stages.The second part gives detailed vaccination guidelines for common diseases and therapies associated with immunosuppression. Primary immune deficiencies, chronic kidney disease, diabetes mellitus, solid and hematological tumors, hematopoetic stem cell transplantation, transplantation of solid organs, aspenia, rheumatological-, gastroenterologic-, dermatologic-, neurologic diseases, biologicals during pregnancy and HIV infection are dealt with.These vaccination guidelines, compiled for the first time in Austria, aim to be of practical help for physicians to facilitate and improve vaccination coverage in immunocompromised patients and their household members and contact persons. PMID- 27457876 TI - Neuromuscular electrical stimulation of the thighs in cardiac patients with implantable cardioverter defibrillators. AB - BACKGROUND: The aim of this systematic review was to update scientific knowledge concerning the safety of neuromuscular electrical stimulation (NMES) to increase exercise capacity and prevent cardiac cachexia in patients with implantable cardioverter defibrillators (ICDs). METHODS: A systematic review including the electronic databases PubMed, MEDLINE, and SCOPUS was conducted for the time period from 1966 to March 31, 2016. RESULTS: Only four articles fulfilled the inclusion criteria (three original articles/safety studies and one case report). The three (safety) studies used NMES to increase muscle strength and/or endurance capacity of the thighs. NMES did not show electromagnetic interference (EMI) with ICD function. EMI was described in a case report of 2 patients with subpectoral ICDs and application of NMES on abdominal muscles. CONCLUSION: This review indicates that NMES may be applied in cardiac ICD patients if 1) individual risks (e. g., pacing dependency, acute heart failure, unstable angina, ventricular arrhythmic episode in the last 3 months) are excluded by performing a safety check before starting NMES treatment and 2) "passive" exercise using NMES is performed only for thighs and gluteal muscles in 3) compliant ICD patients (especially for home-based NMES) and 4) the treatment is regularly supervised by a physician and the device is examined after the first use of NMES to exclude EMI. Nevertheless, further studies including larger sample sizes are necessary to exclude any risk when NMES is used in this patient group. PMID- 27457877 TI - Biomaterials for Abrogating Metastasis: Bridging the Gap between Basic and Translational Research. AB - Herein lies the issue of how to best approach cancer metastasis therapeutics in a focused, directed and efficacious manner. The lack of standardized means to efficiently deliver therapeutic cargo to metastatic sites calls for a paradigm shift in the way we view and treat metastasis. It is crucial to leverage the potential of nanomedicine to differentially combat cancer spread at each stage of the disease (primary tumor growth and formation of metastases) while considering the optimal administration route. We propose to implement three possible strategies to treat cancer as a function of disease type and state, while leveraging the advancement in materials design and in particular nanotechnology: (1) local primary tumor abrogation; (2) primary tumor re-programming to prevent metastasis; and (3) combination (local and systemic) therapy when metastasis has already transpired. Herein, we highlight potential means to bridge the gap between basic and translational research as related to metastasis therapy. PMID- 27457878 TI - Relationships between water and paddlefish Polyodon spathula dentary elemental and stable-isotopic signatures: potential application for reconstructing environmental history. AB - The objectives of this study were to characterize relationships between water and paddlefish Polyodon spathula dentary Sr:Ca, delta18 O and stable hydrogen isotope ratio (deltaD) to determine the accuracy with which individual P. spathula could be assigned to their collection locations using dentary-edge Sr:Ca, deltaD and delta18 O. A laboratory experiment was also conducted to determine whether dentary Sr:Ca in age 0 year P. spathula would reflect shifts in water Sr:Ca to which fish were exposed. Significant linear relationships between water and dentary Sr:Ca, deltaD and delta18 O were observed, although the relationship between water and dentary delta18 O was weaker than those for Sr:Ca and deltaD. Classification success for individual fish to collection locations that differed in water Sr:Ca, deltaD and delta18 O ranged from 86 to 100% based on dentary-edge Sr:Ca, deltaD and delta18 O. Dentary Sr:Ca increased significantly in laboratory reared age 0 year P. spathula following 4 weeks of exposure to elevated water Sr:Ca; dentary Sr:Ca of fish held in water with elevated Sr:Ca was also significantly higher than that of control fish reared in ambient laboratory water. Results indicated that P. spathula dentaries reflect water signatures for commonly-applied natural chemical markers and strongly suggest that dentary microchemistry and stable-isotopic compositions will be applicable for reconstructing P. spathula environmental history in locations where sufficient spatial differences in water chemistry occur. PMID- 27457879 TI - The protective effect of a buckwheat-enriched diet on renal injury in high salt induced hypertension in rats. AB - An excess of dietary salt is the most common factor that contributes to the pathogenesis of hypertension. Dietary management is deemed critical to prevent and treat hypertension. We aimed at evaluating the preventive effect of the buckwheat (BW)-enriched diet on high salt-induced elevation of blood pressure (BP) and renal injury in order to provide a new focus on the design of strategies to prevent hypertension. Control, high salt (HS)-treated (8%), HS + tartary buckwheat (TB) (8% HS + 15% TB), and a group of HS + common buckwheat (CB) (8% HS + 15% CB) rats were used for 7 weeks. BP was monitored periodically during the study by the tail cuff method. HS intake caused a significant increase of BP, the level of serum Na(+) compared to the control group. BW significantly prevented the increase of BP, attenuated oxidative damage, and improved Na(+)/K(+)-ATPase activity in HS treated rats. These results show that a diet supplemented with whole BW has beneficial effects on hypertension, by decreasing blood pressure values and oxidative stress. PMID- 27457880 TI - The phylogeny of C/S1 bZIP transcription factors reveals a shared algal ancestry and the pre-angiosperm translational regulation of S1 transcripts. AB - Basic leucine zippers (bZIPs) form a large plant transcription factor family. C and S1 bZIP groups can heterodimerize, fulfilling crucial roles in seed development and stress response. S1 sequences also harbor a unique regulatory mechanism, termed Sucrose-Induced Repression of Translation (SIRT). The conservation of both C/S1 bZIP interactions and SIRT remains poorly characterized in non-model species, leaving their evolutionary origin uncertain and limiting crop research. In this work, we explored recently published plant sequencing data to establish a detailed phylogeny of C and S1 bZIPs, investigating their intertwined role in plant evolution, and the origin of SIRT. Our analyses clarified C and S1 bZIP orthology relationships in angiosperms, and identified S1 sequences in gymnosperms. We experimentally showed that the gymnosperm orthologs are regulated by SIRT, tracing back the origin of this unique regulatory mechanism to the ancestor of seed plants. Additionally, we discovered an earlier S ortholog in the charophyte algae Klebsormidium flaccidum, together with a C ortholog. This suggests that C and S groups originated by duplication from a single algal proto-C/S ancestor. Based on our observations, we propose a model wherein the C/S1 bZIP dimer network evolved in seed plants from pre-existing C/S bZIP interactions. PMID- 27457882 TI - Fluorocarbon Modified Low-Molecular-Weight Polyethylenimine for siRNA Delivery. AB - We report the synthesis and study of fluorocarbon (FC) modified polyethylenimine (PEI) for the purpose of siRNA delivery. Low-molecular-weight PEI (Mn = 600) was functionalized with fluorocarbon epoxides of varying length. All FC-modified samples with greater than 2.0 equiv of FC epoxide per PEI induced potent gene silencing in vitro. Compared to hydrocarbon (HC) analogues, the FC vectors showed greater general silencing efficacy, higher cell uptake, and reduced association with serum components. Collectively, the data suggest that modification of polyamines with FCs is a promising approach for the discovery of novel vectors for siRNA delivery. PMID- 27457881 TI - Tetrandrine identified in a small molecule screen to activate mesenchymal stem cells for enhanced immunomodulation. AB - Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-kappaB/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-alpha secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-alpha in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy. PMID- 27457883 TI - Comparative 3D analyses and palaeoecology of giant early amphibians (Temnospondyli: Stereospondyli). AB - Macroevolutionary, palaeoecological and biomechanical analyses in deep time offer the possibility to decipher the structural constraints, ecomorphological patterns and evolutionary history of extinct groups. Here, 3D comparative biomechanical analyses of the extinct giant early amphibian group of stereospondyls together with living lissamphibians and crocodiles, shows that: i) stereospondyls had peculiar palaeoecological niches with proper bites and stress patterns very different than those of giant salamanders and crocodiles; ii) their extinction may be correlated with the appearance of neosuchians, which display morphofunctional innovations. Stereospondyls weathered the end-Permian mass extinction, re-radiated, acquired gigantic sizes and dominated (semi) aquatic ecosystems during the Triassic. Because these ecosystems are today occupied by crocodilians, and stereospondyls are extinct amphibians, their palaeobiology is a matter of an intensive debate: stereospondyls were a priori compared with putative living analogous such as giant salamanders and/or crocodilians and our new results try to close this debate. PMID- 27457884 TI - Standardized Chinese Formula Xin-Ke-Shu inhibits the myocardium Ca(2+) overloading and metabolic alternations in isoproterenol-induced myocardial infarction rats. AB - Xin-Ke-Shu (XKS) is a traditional Chinese patent medicine used for treatment of coronary heart diseases in China. However, its mechanism of action is still unclear. In this paper, the mediation of XKS on the isoproterenol (ISO)-induced myocardial infarction (MI) rat were evaluated based on a tissue-targeted metabonomics in vitro/vivo. The result indicated that twelve metabolic pathways were involved in the therapeutic effect of XKS in vivo, where seven pathways were associated with the Ca(2+) overloading mechanism. In agreement with regulation on metabolic variations, XKS markedly reversed the over-expressions of three involved proteins including phospholipase A2 IIA (PLA2 IIA), calcium/calmodulin dependent protein kinase II (CaMK II) and Pro-Caspase-3. The metabolic regulations of XKS on H9c2 cell also partially confirmed its metabolic effect. These metabolic characteristics in vitro/vivo and western blotting analysis suggested that XKS protected from MI metabolic perturbation major via inhibition of Ca(2+) overloading mechanism. Furthermore, 11 active ingredients of XKS exerted steady affinity with the three proteins through the molecular docking study. Our findings indicate that the metabonomics in vitro/vivo combined with western blotting analysis offers the opportunity to gain insight into the comprehensive efficacy of TCMs on the whole metabolic network. PMID- 27457885 TI - Evaluation of coping strategies in established rheumatoid arthritis patients: emergence of concealment in an Asian cohort. AB - AIM: To evaluate coping strategies of Asian RA patients and their associations with health-related quality of life (HRQoL). METHODS: A cross-sectional sample of patients with established RA was evaluated using measures of coping (Coping in Rheumatoid Arthritis Questionnaire [C-RAQ]; appraisal of coping effectiveness and helplessness), HRQoL (Mental and Physical Components [MCS/PCS] of the Short Form 12v2; Rheumatoid Arthritis Impact of Disease score [RAID]) and clinical/laboratory assessments. Principal component analysis was conducted to identify coping strategies. Multiple linear regression analyses were performed to evaluate the associations between coping strategies and HRQoL outcomes. RESULTS: The study sample comprised 101 patients, 81% female, 72.3% Chinese, mean age 54.2 +/- 12.6 years. Five coping strategies were identified: Active problem solving (E = 5.36), Distancing (E = 2.30), Concealment (E = 1.89), Cognitive reframing (E = 1.55) and Emotional expression (E = 1.26). Concealment was consistently associated with PCS (rs = -0.23, P = 0.049), MCS (rs = -0.24, P = 0.04) and RAID (rs = 0.39, P < 0.001), and was significant in the multivariate model to explain lower disease-specific HRQoL (RAID) even after adjusting for disease activity, coping effectiveness and helplessness (beta = 0.20, P = 0.04). Emotional expression was associated with poorer physical HRQoL (PCS), after adjusting for disease severity, body mass index, coping effectiveness, helplessness and Concealment (beta = -0.39, P < 0.001). Perceived coping-related helplessness was significant in multivariate correlates for PCS (beta = -0.25, P = 0.036), MCS (beta = -0.29, P = 0.02) and RAID (beta = 0.53, P < 0.001), after adjusting for covariates. CONCLUSION: Concealment and Emotional expression are associated with lower disease-specific HRQoL and physical HRQoL respectively, with the former coping strategy likely to be culture-specific. Interventions should tailor psychosocial support needs to address not only coping strategies, but patients' perception of their coping. PMID- 27457888 TI - Editorial (Thematic Issue: Proceedings from the EMBO Workshop: ''Modern DNA Concepts and Tools for Safe Gene Transfer and Modificatio''). PMID- 27457887 TI - Location, location, location: the evolutionary history of CD1 genes and the NKR P1/ligand systems. AB - CD1 genes encode cell surface molecules that present lipid antigens to various kinds of T lymphocytes of the immune system. The structures of CD1 genes and molecules are like the major histocompatibility complex (MHC) class I system, the loading of antigen and the tissue distribution for CD1 molecules are like those in the class II system, and phylogenetic analyses place CD1 between class I and class II sequences, altogether leading to the notion that CD1 is a third ancient system of antigen presentation molecules. However, thus far, CD1 genes have only been described in mammals, birds and reptiles, leaving major questions as to their origin and evolution. In this review, we recount a little history of the field so far and then consider what has been learned about the structure and functional attributes of CD1 genes and molecules in marsupials, birds and reptiles. We describe the central conundrum of CD1 evolution, the genomic location of CD1 genes in the MHC and/or MHC paralogous regions in different animals, considering the three models of evolutionary history that have been proposed. We describe the natural killer (NK) receptors NKR-P1 and ligands, also found in different genomic locations for different animals. We discuss the consequence of these three models, one of which includes the repudiation of a guiding principle for the last 20 years, that two rounds of genome-wide duplication at the base of the vertebrates provided the extra MHC genes necessary for the emergence of adaptive immune system of jawed vertebrates. PMID- 27457886 TI - Activation strategies for invariant natural killer T cells. AB - Invariant natural killer T (iNKT) cells are a specialized T cell subset that plays an important role in host defense, orchestrating both innate and adaptive immune effector responses against a variety of microbes. Specific microbial lipids and mammalian self lipids displayed by the antigen-presenting molecule CD1d can activate iNKT cells through their semi-invariant alphabeta T cell receptors (TCRs). iNKT cells also constitutively express receptors for inflammatory cytokines typically secreted by antigen-presenting cells (APCs) after recognition of pathogen-associated molecular patterns (PAMPs), and they can be activated through these cytokine receptors either in combination with TCR signals, or in some cases even in the absence of TCR signaling. During infection, experimental evidence suggests that both TCR-driven and cytokine-driven mechanisms contribute to iNKT cell activation. While the relative contributions of these two signaling mechanisms can vary widely depending on the infectious context, both lipid antigens and PAMPs mediate reciprocal activation of iNKT cells and APCs, leading to downstream activation of multiple other immune cell types to promote pathogen clearance. In this review, we discuss the mechanisms involved in iNKT cell activation during infection, focusing on the central contributions of both lipid antigens and PAMP-induced inflammatory cytokines, and highlight in vivo examples of activation during bacterial, viral, and fungal infections. PMID- 27457889 TI - Transcriptomic Analysis of Compromise Between Air-Breathing and Nutrient Uptake of Posterior Intestine in Loach (Misgurnus anguillicaudatus), an Air-Breathing Fish. AB - Dojo loach (Misgurnus anguillicaudatus) is an air-breathing fish species by using its posterior intestine to breathe on water surface. So far, the molecular mechanism about accessory air-breathing in fish is seldom addressed. Five cDNA libraries were constructed here for loach posterior intestines form T01 (the initial stage group), T02 (mid-stage of normal group), T03 (end stage of normal group), T04 (mid-stage of air-breathing inhibited group), and T05 (the end stage of air-breathing inhibited group) and subjected to perform RNA-seq to compare their transcriptomic profilings. A total of 92,962 unigenes were assembled, while 37,905 (40.77 %) unigenes were successfully annotated. 2298, 1091, and 3275 differentially expressed genes (fn1, ACE, EGFR, Pxdn, SDF, HIF, VEGF, SLC2A1, SLC5A8 etc.) were observed in T04/T02, T05/T03, and T05/T04, respectively. Expression levels of many genes associated with air-breathing and nutrient uptake varied significantly between normal and intestinal air-breathing inhibited group. Intraepithelial capillaries in posterior intestines of loaches from T05 were broken, while red blood cells were enriched at the surface of intestinal epithelial lining with 241 +/- 39 cells per millimeter. There were periodic acid schiff (PAS)-positive epithelial mucous cells in posterior intestines from both normal and air-breathing inhibited groups. Results obtained here suggested an overlap of air-breathing and nutrient uptake function of posterior intestine in loach. Intestinal air-breathing inhibition in loach would influence the posterior intestine's nutrient uptake ability and endothelial capillary structure stability. This study will contribute to our understanding on the molecular regulatory mechanisms of intestinal air-breathing in loach. PMID- 27457890 TI - Generation of femtosecond gamma-ray bursts stimulated by laser-driven hosing evolution. AB - The promising ability of a plasma wiggler based on laser wakefield acceleration to produce betatron X-rays with photon energies of a few keV to hundreds of keV and a peak brilliance of 10(22)-10(23) photons/s/mm(2)/mrad(2)/0.1%BW has been demonstrated, providing an alternative to large-scale synchrotron light sources. Most methods for generating betatron radiation are based on two typical approaches, one relying on an inherent transverse focusing electrostatic field, which induces transverse oscillation, and the other relying on the electron beam catching up with the rear part of the laser pulse, which results in strong electron resonance. Here, we present a new regime of betatron gamma-ray radiation generated by stimulating a large-amplitude transverse oscillation of a continuously injected electron bunch through the hosing of the bubble induced by the carrier envelope phase (CEP) effect of the self-steepened laser pulse. Our method increases the critical photon energy to the MeV level, according to the results of particle-in-cell (PIC) simulations. The highly collimated, energetic and femtosecond gamma-ray bursts that are produced in this way may provide an interesting potential means of exploring nuclear physics in table top photo nuclear reactions. PMID- 27457892 TI - Regional differences, socio-demographics, and hidden population of HIV/AIDS in India. AB - This study examines the prevalence of HIV/AIDS in different regions of India, their socio-demographic indicators, and the presence of hidden population infected with HIV. Secondary data analyzed were obtained from national and international agencies. Considering the prevalence of HIV/AIDS in India, the low prevalence regions in the last decade have shown a steady increase in recent years. Productive age, urbanization, male gender, lower level of education, minority religions, low income, and mobile occupations are associated with HIV pandemic. The hidden population vulnerable to HIV/AIDS are: street children, homeless population, and refugees. These observations can help map the high-risk behavior groups and formulate targeted strategies to curb the HIV menace. PMID- 27457893 TI - Pyrenes, Peropyrenes, and Teropyrenes: Synthesis, Structures, and Photophysical Properties. AB - The design of a relatively simple and efficient method to extend the pi conjugation of readily available aromatics in one-dimension is of significant value. In this paper, pyrenes, peropyrenes, and teropyrenes were synthesized through a double or quadruple benzannulation reaction of alkynes promoted by Bronsted acid. This novel method does not involve cyclodehydrogenation (oxidative aryl-aryl coupling) to arrive at the newly incorporated large arene moieties. All of the target compounds were synthesized in moderate to good yields and were fully characterized with the structures unambiguously confirmed by X-ray crystallography. As expected, photophysical characterization clearly shows increasing red-shifts as a function of extended conjugation within the fused ring systems. PMID- 27457894 TI - Stressors and anxiety in dementia caregiving: multiple mediation analysis of rumination, experiential avoidance, and leisure. AB - BACKGROUND: Despite the robust associations between stressors and anxiety in dementia caregiving, there is a lack of research examining which factors contribute to explain this relationship. This study was designed to test a multiple mediation model of behavioral and psychological symptoms of dementia (BPSD) and anxiety that proposes higher levels of rumination and experiential avoidance and lower levels of leisure satisfaction as potential mediating variables. METHODS: The sample consisted of 256 family caregivers. In order to test a simultaneously parallel multiple mediation model of the BPSD to anxiety pathway, a PROCESS method was used and bias-corrected and accelerated bootstrapping method was used to test confidence intervals. RESULTS: Higher levels of stressors significantly predicted anxiety. Greater stressors significantly predicted higher levels of rumination and experiential avoidance, and lower levels of leisure satisfaction. These three coping variables significantly predicted anxiety. Finally, rumination, experiential avoidance, and leisure satisfaction significantly mediated the link between stressors and anxiety. The explained variance for the final model was 47.09%. Significant contrasts were found between rumination and leisure satisfaction, with rumination being a significantly higher mediator. CONCLUSIONS: The results suggest that caregivers' experiential avoidance, rumination, and leisure satisfaction may function as mechanisms through which BPSD influence on caregivers' anxiety. Training caregivers in reducing their levels of experiential avoidance and rumination by techniques that foster their ability of acceptance of their negative internal experiences, and increase their level of leisure satisfaction, may be helpful to reduce their anxiety symptoms developed by stressors. PMID- 27457911 TI - Comments on 'Comparison of dental hygienists and dentists: clinical and teledentistry identification of dental caries in children'. PMID- 27457910 TI - Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling. AB - Caffeine has cognitive-enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor independent form of LTP (CAF LTP) in the CA1 region of the hippocampus by promoting calcium-dependent secretion of BDNF, which subsequently activates TrkB mediated signaling required for the expression of CAF LTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAF LTP, a process that requires cytosolic free Ca2+ . Consistent with the involvement of IRS2 signals in caffeine-mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2-/- mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3-kinase (PI3K) pathway. These findings indicate that TrkB-IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine. PMID- 27457913 TI - Neuromuscular Responses to Short-Term Resistance Training With Traditional and Daily Undulating Periodization in Adolescent Elite Judoka. AB - Ullrich, B, Pelzer, T, Oliveira, S, and Pfeiffer, M. Neuromuscular responses to short-term resistance training with traditional and daily undulating periodization in adolescent elite judoka. J Strength Cond Res 30(8): 2083-2099, 2016-The influence of different periodization models on neuromuscular outcomes after short-term strength training periods has not been examined in adolescent athletes. Eleven elite judoka (age: 14.8 +/- 0.6 years, height: 163.2 +/- 7.5 cm, body mass: 57.3 +/- 11.1 kg, 5 boys/6 girls, and strength training experience: 2.7 +/- 1.1 years) performed two 4-week strength training mesocycles (each with 12 sessions) with either traditional (TP) or daily undulating (DUP) periodization. Both mesocycles were separated by a 7-week washout period and added to the regular judo training. Strength training was performed as lifting and lowering of weights using squats, knee flexion curl, clean & jerk, snatch, bench press, barbell bench pull, and lat pull-down. The mesocycles were equated for the number of repetitions and different intensity zones (50-90% of 1 repetition maximum [1RM]), addressing the optimization of strength, power, or velocity. Laboratory and 1RM testing was carried out 2 times during the baseline (T1 and T2), after the TP mesocycle (T3), after the washout period (T4), and after the DUP mesocycle (T5). Isometric knee extensor and knee flexor maximum voluntary contractive capacity (MVC), electromyographic-estimated neural drive of the quadriceps femoris, vastus lateralis (VL) muscle architecture, and 1RMs of all training exercises were measured. ANOVA revealed moderate (5.5-13.5%) but significant (p <= 0.05) temporal gains in knee extensor MVC, 1RMs, and VL architecture during both the mesocycles. Wilcoxon tests detected no significant differences for the percentage changes of any outcome between the mesocycles. For adolescent judoka, TP and DUP were equally adept in improving neuromuscular outcomes during short-term training periods. PMID- 27457912 TI - Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature that predicts poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of alpha-klotho, an FGF23 coreceptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform specific FGFR4 blocking antibody reduced hepatic and circulating levels of C reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD. PMID- 27457914 TI - Impact of Inertial Training on Strength and Power Performance in Young Active Men. AB - Naczk, M, Naczk, A, Brzenczek-Owczarzak, W, Arlet, J, and Adach, Z. Impact of inertial training on strength and power performance in young active men. J Strength Cond Res 30(8): 2107-2113, 2016-This study evaluated how 5 weeks of inertial training using 2 different loads influenced strength and power performance. Fifty-eight male physical education students were randomly divided into training and control groups. The 2 training groups (T0 and T10) performed inertial training 3 times per week for 5 weeks using the new Inertial Training and Measurement System (ITMS). Each training session included 3 exercise sets involving the knee extensors muscles. The T0 group used only the mass of the ITMS flywheel (19.4 kg), whereas the T10 group had an additional 10 kg on the flywheel. Before and after training, we evaluated maximum force and power of knee extensors muscles, countermovement jump (CMJ), squat jump (SJ), maximal power output achieved during ergometer test PVT, electromyography of quadriceps, and muscle mass. In T0 and T10, respectively, ITMS training induced significant increases in muscle force (25.2 and 23.3%), muscle power (33.2 and 27%), CMJ (3.8 and 6.7%), SJ (2.2 and 6.1%), PVT (8 and 7.4%), and muscle mass (9.8 and 15%). The changes did not significantly differ between T0 and T10. A 16% significant increase of electromyography amplitude (quadriceps muscle) was noted only in T0. The novel ITMS training method is effective for improving muscular strength and power. Improvements in PVT, CMJ, and SJ indicate that the increased strength and power elicited by ITMS training can translate to improvements in sport performance. The ITMS training can also be useful for building muscle mass. PMID- 27457915 TI - Wearable Lactate Threshold Predicting Device is Valid and Reliable in Runners. AB - Borges, NR and Driller, MW. Wearable lactate threshold predicting device is valid and reliable in runners. J Strength Cond Res 30(8): 2212-2218, 2016-A commercially available device claiming to be the world's first wearable lactate threshold predicting device (WLT), using near-infrared LED technology, has entered the market. The aim of this study was to determine the levels of agreement between the WLT-derived lactate threshold workload and traditional methods of lactate threshold (LT) calculation and the interdevice and intradevice reliability of the WLT. Fourteen (7 male, 7 female; mean +/- SD; age: 18-45 years, height: 169 +/- 9 cm, mass: 67 +/- 13 kg, V[Combining Dot Above]O2max: 53 +/- 9 ml.kg.min) subjects ranging from recreationally active to highly trained athletes completed an incremental exercise test to exhaustion on a treadmill. Blood lactate samples were taken at the end of each 3-minute stage during the test to determine lactate threshold using 5 traditional methods from blood lactate analysis which were then compared against the WLT predicted value. In a subset of the population (n = 12), repeat trials were performed to determine both inter-reliability and intrareliability of the WLT device. Intraclass correlation coefficient (ICC) found high to very high agreement between the WLT and traditional methods (ICC > 0.80), with TEMs and mean differences ranging between 3.9-10.2% and 1.3-9.4%. Both interdevice and intradevice reliability resulted in highly reproducible and comparable results (CV < 1.2%, TEM <0.2 km.h, ICC > 0.97). This study suggests that the WLT is a practical, reliable, and noninvasive tool for use in predicting LT in runners. PMID- 27457916 TI - Acute Effects of Contract-Relax Stretching vs. TENS in Young Subjects With Anterior Knee Pain: A Randomized Controlled Trial. AB - Valenza, MC, Torres-Sanchez, I, Cabrera-Martos, I, Valenza-Demet, G, and Cano Cappellacci, M. Acute effects of contract-relax stretching vs. TENS in young subjects with anterior knee pain: A randomized controlled trial. J Strength Cond Res 30(8): 2271-2278, 2016-The aim of this study was to examine the immediate effects on pressure point tenderness, range of motion (ROM), and vertical jump (VJ) of contract-relax stretching vs. transcutaneous electrical nerve stimulation (TENS) therapy in individuals with anterior knee pain (AKP). Eighty-four subjects with AKP were randomly assigned to 1 of 3 different intervention groups: a contract-relax stretching group (n = 28), a TENS intervention group (n = 28), and a control group (n = 28). The participants included in the sample were both sex (37.5% men vs. 62.5% women) at a mean age of 21 years, with mean values of height and weight of 169 cm and 64 kg, respectively. The main outcome measures were knee ROM, pressure pain threshold (PPT), and VJ. The participants were assessed at baseline and immediately after treatment. In the case of VJ, at baseline, immediately after the intervention, at 3 and at 6 minutes posttreatment. The data analysis showed that PPT scores of participants in the stretching and TENS group significantly increased from pretest to posttest (p <= 0.05). A significant increase pre- to posttreatment in ROM (p < 0.001) was also observed in both treatment groups. In VJ measures, TENS and stretching groups showed significant differences between preintervention and all postintervention values (p <= 0.05), whereas no significant differences were found in the control group. In conclusion, the results show significant pre-to-post-treatment effects in PPT, ROM, and VJ from both contract-relax stretching and TENS in young subjects with AKP. PMID- 27457917 TI - Differences in the Recurrence and Survival of Patients with Symptomatic and Asymptomatic Papillary Thyroid Carcinoma: An Observational Study of 11,265 Person Years of Follow-Up. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) generally has an indolent course and favorable prognosis. However, an optimal treatment strategy for asymptomatic PTC is not clear. We compared the recurrence and survival outcomes of patients with asymptomatic and symptomatic PTC and identified the associated risk factors. MATERIALS AND METHODS: Patients with previously untreated PTC of size <=2 cm and who underwent curative surgery were included in this analysis. Asymptomatic PTC was defined as a tumor detected only by ultrasonography, computed tomography (CT), magnetic resonance imaging, and/or 18F-fluorodeoxyglucose positron emission tomography/CT. Clinical factors, operative and pathologic findings, and posttreatment outcomes were compared between the aforementioned two groups. Univariate and multivariate analyses were performed to identify the factors associated with recurrence-free survival (RFS) and overall survival (OS). RESULTS: Out of 1419 patients, 1259 patients (88.7%) were asymptomatic. Patients with symptomatic PTC had significantly larger tumor size, palpability, extrathyroidal extension, high tumor and node stages, and were more likely to undergo treatment with radioactive iodine therapy compared with patients with asymptomatic PTC (p < 0.05 each). Recurrence was significantly higher in the symptomatic PTC group than in the asymptomatic group (p < 0.001). Asymptomatic PTC was an independent predictor of RFS and OS and had higher five-year rates than those associated with symptomatic tumors: 97.3% and 90.6% for RFS (p < 0.001) and 99.4% and 96.9% for OS (p < 0.001), respectively. CONCLUSION: Symptomatic PTC is associated with higher recurrence and lower overall survival rates than asymptomatic PTC. Symptomatic PTC may require total thyroidectomy and close posttreatment surveillance. PMID- 27457918 TI - Helicobacter pylori infection may increase the risk of progression of chronic hepatitis B disease among the Chinese population: a meta-analysis. AB - OBJECTIVES: Helicobacter pylori is a bacterium that infects over 50% of the human population worldwide. An increasing number of studies have demonstrated that H. pylori may cause liver diseases, and the underlying relationship between H. pylori infection and chronic hepatitis B has attracted much attention. This study aimed to examine the association between H. pylori infection and the progression of chronic hepatitis B in the Chinese population. METHODS: A search was performed of the PubMed/MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases, as well as the Chinese databases, China National Knowledge Infrastructure and Wanfang Data, for studies published between January 1, 1994 and November 1, 2015. RESULTS: In total, 2977 patients were included in the chronic hepatitis B group, while 1668 participants were included in the healthy control group. The prevalence of H. pylori among patients with chronic hepatitis B was significantly higher than that among those without chronic hepatitis B. The pooled odds ratio was 3.17. In the subgroup analysis, the odds ratio was 4.28 for hepatitis B virus (HBV)-related cirrhosis and 6.02 for hepatocellular carcinoma. CONCLUSION: These results indicate a strong relationship between H. pylori and chronic hepatitis B, particularly during HBV progression. PMID- 27457919 TI - Seroprevalence of vaccine-preventable diseases among young children in the United Arab Emirates. AB - OBJECTIVES: In the United Arab Emirates (UAE), many vaccine-preventable diseases are notifiable and are often reported despite high estimated immunization coverage. The serological assessment of immunity against these infections (serosurveillance) complements disease surveillance (notification). This study aimed to assess the yet unmeasured serological immunities to nine vaccine preventable infections among vaccinated Emirati children. METHODS: This cross sectional study involved children who attended the Well-Child Care Programme of the Ambulatory Healthcare Services (Al-Ain, UAE) between July 2014 and September 2015. Serological testing was performed in 227 Emirati children (49% females); subjects were aged (mean+/-standard deviation) 45+/-14 months (median 43, range 23-71 months). RESULTS: The seroprevalence rates varied markedly among the studied vaccine-preventable diseases, ranging from 39.2% (pertussis) to 98.3% (rubella). Other high seroprevalence rates were noted for measles (98.2%) and poliovirus (92%). The seroprevalence rate for mumps was 82.8%, for varicella was 68.3%, for diphtheria was 86.4%, for tetanus was 89.9%, and for Haemophilus influenzae type B was 84.1%. CONCLUSIONS: A large number of the studied children had low seroprevalence rates against pertussis, varicella, and mumps. Studies are needed to explore whether modifying the national immunization programme could improve these low seroprevalence estimates. PMID- 27457920 TI - When should antiviral drugs be used for the patient with an Ebola virus infection? PMID- 27457921 TI - DisSim: an online system for exploring significant similar diseases and exhibiting potential therapeutic drugs. AB - The similarity of pair-wise diseases reveals the molecular relationships between them. For example, similar diseases have the potential to be treated by common therapeutic chemicals (TCs). In this paper, we introduced DisSim, an online system for exploring similar diseases, and comparing corresponding TCs. Currently, DisSim implemented five state-of-the-art methods to measure the similarity between Disease Ontology (DO) terms and provide the significance of the similarity score. Furthermore, DisSim integrated TCs of diseases from the Comparative Toxicogenomics Database (CTD), which can help to identify potential relationships between TCs and similar diseases. The system can be accessed from http://123.59.132.21:8080/DisSim. PMID- 27457923 TI - Correction for Wang et al., Unveiling the biosynthetic puzzle of destruxins in Metarhizium species. PMID- 27457922 TI - Vimentin dephosphorylation at ser-56 is regulated by type 1 protein phosphatase in smooth muscle. AB - BACKGROUND: The intermediate filament protein vimentin undergoes reversible phosphorylation and dephosphorylation at Ser-56, which plays an important role in regulating the contraction-relaxation cycles of smooth muscle. The protein phosphatases that mediate vimentin dephosphorylation in smooth muscle have not been previously investigated. METHODS: The associations of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) with vimentin in mouse tracheal rings was evaluated by co-immunoprecipitation. Lentivirus-mediated shRNA against PP1 was used to assess the role of PP1 in vimentin dephosphorylation and the vimentin associated process in smooth muscle. RESULTS: Co-immunoprecipitation analysis showed that vimentin interacted with PP1, but barely with PP2A, in airway smooth muscle. Knockdown of PP1 by lentivirus-mediated shRNA increased the acetylcholine induced vimentin phosphorylation and smooth muscle contraction. Because vimentin phosphorylation is able to modulate p130 Crk-associated substrate (p130CAS) and actin polymerization, we also evaluated the role of PP1 in the biological processes. Silencing of PP1 also enhanced the agonist-induced the dissociation of p130CAS from vimentin and F/G-actin ratios (an index of actin polymerization). However, PP1 knockdown did not affect c-Abl tyrosine phosphorylation, an important molecule that controls actin dynamics. CONCLUSIONS: Taken together, these findings suggest that PP1 is a key protein serine/threonine phosphatase that controls vimentin Ser-56 dephosphorylation in smooth muscle. PP1 regulates actin polymerization by modulating the dissociation of p130CAS from vimentin, but not by affecting c-Abl tyrosine kinase. PMID- 27457924 TI - Highly sensitive detection of influenza virus by boron-doped diamond electrode terminated with sialic acid-mimic peptide. AB - The progression of influenza varies according to age and the presence of an underlying disease; appropriate treatment is therefore required to prevent severe disease. Anti-influenza therapy, such as with neuraminidase inhibitors, is effective, but diagnosis at an early phase of infection before viral propagation is critical. Here, we show that several dozen plaque-forming units (pfu) of influenza virus (IFV) can be detected using a boron-doped diamond (BDD) electrode terminated with a sialic acid-mimic peptide. The peptide was used instead of the sialyloligosaccharide receptor, which is the common receptor of influenza A and B viruses required during the early phase of infection, to capture IFV particles. The peptide, which was previously identified by phage-display technology, was immobilized by click chemistry on the BDD electrode, which has excellent electrochemical characteristics such as low background current and weak adsorption of biomolecules. Electrochemical impedance spectroscopy revealed that H1N1 and H3N2 IFVs were detectable in the range of 20-500 pfu by using the peptide-terminated BDD electrode. Our results demonstrate that the BDD device integrated with the receptor-mimic peptide has high sensitivity for detection of a low number of virus particles in the early phase of infection. PMID- 27457925 TI - Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1. AB - Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1-expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan- and dose-dependent. At concentrations <=0.25 uM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1-induced migration. Exposure to concentrations >=1 uM resulted in ERK(1/2)-dependent apoptosis and disruption of the F-actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1-deficient mice exhibited increased recruitment of eosinophils and CD3(+) T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF alpha in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis. PMID- 27457926 TI - Menopause accelerates biological aging. AB - Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further. PMID- 27457927 TI - Armed-conflict risks enhanced by climate-related disasters in ethnically fractionalized countries. AB - Social and political tensions keep on fueling armed conflicts around the world. Although each conflict is the result of an individual context-specific mixture of interconnected factors, ethnicity appears to play a prominent and almost ubiquitous role in many of them. This overall state of affairs is likely to be exacerbated by anthropogenic climate change and in particular climate-related natural disasters. Ethnic divides might serve as predetermined conflict lines in case of rapidly emerging societal tensions arising from disruptive events like natural disasters. Here, we hypothesize that climate-related disaster occurrence enhances armed-conflict outbreak risk in ethnically fractionalized countries. Using event coincidence analysis, we test this hypothesis based on data on armed conflict outbreaks and climate-related natural disasters for the period 1980 2010. Globally, we find a coincidence rate of 9% regarding armed-conflict outbreak and disaster occurrence such as heat waves or droughts. Our analysis also reveals that, during the period in question, about 23% of conflict outbreaks in ethnically highly fractionalized countries robustly coincide with climatic calamities. Although we do not report evidence that climate-related disasters act as direct triggers of armed conflicts, the disruptive nature of these events seems to play out in ethnically fractionalized societies in a particularly tragic way. This observation has important implications for future security policies as several of the world's most conflict-prone regions, including North and Central Africa as well as Central Asia, are both exceptionally vulnerable to anthropogenic climate change and characterized by deep ethnic divides. PMID- 27457928 TI - Complete in vitro generation of fertile oocytes from mouse primordial germ cells. AB - Reconstituting gametogenesis in vitro is a key goal for reproductive biology and regenerative medicine. Successful in vitro reconstitution of primordial germ cells and spermatogenesis has recently had a significant effect in the field. However, recapitulation of oogenesis in vitro remains unachieved. Here we demonstrate the first reconstitution, to our knowledge, of the entire process of mammalian oogenesis in vitro from primordial germ cells, using an estrogen receptor antagonist that promotes normal follicle formation, which in turn is crucial for supporting oocyte growth. The fundamental events in oogenesis (i.e., meiosis, oocyte growth, and genomic imprinting) were reproduced in the culture system. The most rigorous evidence of the recapitulation of oogenesis was the birth of fertile offspring, with a maximum of seven pups obtained from a cultured gonad. Moreover, cryopreserved gonads yielded functional oocytes and offspring in this culture system. Thus, our in vitro system will enable both innovative approaches for a deeper understanding of oogenesis and a new avenue to create and preserve female germ cells. PMID- 27457929 TI - PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61. AB - Phosphorylation regulates surface and synaptic expression of NMDA receptors (NMDARs). Both the tyrosine kinase Fyn and the tyrosine phosphatase striatal enriched protein tyrosine phosphatase (STEP) are known to target the NMDA receptor subunit GluN2B on tyrosine 1472, which is a critical residue that mediates NMDAR endocytosis. STEP reduces the surface expression of NMDARs by promoting dephosphorylation of GluN2B Y1472, whereas the synaptic scaffolding protein postsynaptic density protein 95 (PSD-95) stabilizes the surface expression of NMDARs. However, nothing is known about a potential functional interaction between STEP and PSD-95. We now report that STEP61 binds to PSD-95 but not to other PSD-95 family members. We find that PSD-95 expression destabilizes STEP61 via ubiquitination and degradation by the proteasome. Using subcellular fractionation, we detect low amounts of STEP61 in the PSD fraction. However, STEP61 expression in the PSD is increased upon knockdown of PSD-95 or in vivo as detected in PSD-95-KO mice, demonstrating that PSD-95 excludes STEP61 from the PSD. Importantly, only extrasynaptic NMDAR expression and currents were increased upon STEP knockdown, as is consistent with low STEP61 localization in the PSD. Our findings support a dual role for PSD-95 in stabilizing synaptic NMDARs by binding directly to GluN2B but also by promoting synaptic exclusion and degradation of the negative regulator STEP61. PMID- 27457930 TI - Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation. AB - Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca(2+) release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca(2+) leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with beta-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1-calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention. PMID- 27457932 TI - Flight paths of seabirds soaring over the ocean surface enable measurement of fine-scale wind speed and direction. AB - Ocean surface winds are an essential factor in understanding the physical interactions between the atmosphere and the ocean. Surface winds measured by satellite scatterometers and buoys cover most of the global ocean; however, there are still spatial and temporal gaps and finer-scale variations of wind that may be overlooked, particularly in coastal areas. Here, we show that flight paths of soaring seabirds can be used to estimate fine-scale (every 5 min, ~5 km) ocean surface winds. Fine-scale global positioning system (GPS) positional data revealed that soaring seabirds flew tortuously and ground speed fluctuated presumably due to tail winds and head winds. Taking advantage of the ground speed difference in relation to flight direction, we reliably estimated wind speed and direction experienced by the birds. These bird-based wind velocities were significantly correlated with wind velocities estimated by satellite-borne scatterometers. Furthermore, extensive travel distances and flight duration of the seabirds enabled a wide range of high-resolution wind observations, especially in coastal areas. Our study suggests that seabirds provide a platform from which to measure ocean surface winds, potentially complementing conventional wind measurements by covering spatial and temporal measurement gaps. PMID- 27457934 TI - Correction for Perry et al., Rapid behavioral maturation accelerates failure of stressed honey bee colonies. PMID- 27457931 TI - Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome. AB - How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14-24 y old. We found and replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial- and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence. PMID- 27457933 TI - Controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis. AB - Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex (MTBC), a wildly successful group of organisms and the leading cause of death resulting from a single bacterial pathogen worldwide. It is generally accepted that MTBC established itself in human populations in Africa and that animal-infecting strains diverged from human strains. However, the precise causal factors of TB emergence remain unknown. Here, we propose that the advent of controlled fire use in early humans created the ideal conditions for the emergence of TB as a transmissible disease. This hypothesis is supported by mathematical modeling together with a synthesis of evidence from epidemiology, evolutionary genetics, and paleoanthropology. PMID- 27457935 TI - Unraveling the drivers of MERS-CoV transmission. AB - With more than 1,700 laboratory-confirmed infections, Middle East respiratory syndrome coronavirus (MERS-CoV) remains a significant threat for public health. However, the lack of detailed data on modes of transmission from the animal reservoir and between humans means that the drivers of MERS-CoV epidemics remain poorly characterized. Here, we develop a statistical framework to provide a comprehensive analysis of the transmission patterns underlying the 681 MERS-CoV cases detected in the Kingdom of Saudi Arabia (KSA) between January 2013 and July 2014. We assess how infections from the animal reservoir, the different levels of mixing, and heterogeneities in transmission have contributed to the buildup of MERS-CoV epidemics in KSA. We estimate that 12% [95% credible interval (CI): 9%, 15%] of cases were infected from the reservoir, the rest via human-to-human transmission in clusters (60%; CI: 57%, 63%), within (23%; CI: 20%, 27%), or between (5%; CI: 2%, 8%) regions. The reproduction number at the start of a cluster was 0.45 (CI: 0.33, 0.58) on average, but with large SD (0.53; CI: 0.35, 0.78). It was >1 in 12% (CI: 6%, 18%) of clusters but fell by approximately one half (47% CI: 34%, 63%) its original value after 10 cases on average. The ongoing exposure of humans to MERS-CoV from the reservoir is of major concern, given the continued risk of substantial outbreaks in health care systems. The approach we present allows the study of infectious disease transmission when data linking cases to each other remain limited and uncertain. PMID- 27457936 TI - On the origin and evolutionary consequences of gene body DNA methylation. AB - In plants, CG DNA methylation is prevalent in the transcribed regions of many constitutively expressed genes (gene body methylation; gbM), but the origin and function of gbM remain unknown. Here we report the discovery that Eutrema salsugineum has lost gbM from its genome, to our knowledge the first instance for an angiosperm. Of all known DNA methyltransferases, only CHROMOMETHYLASE 3 (CMT3) is missing from E. salsugineum Identification of an additional angiosperm, Conringia planisiliqua, which independently lost CMT3 and gbM, supports that CMT3 is required for the establishment of gbM. Detailed analyses of gene expression, the histone variant H2A.Z, and various histone modifications in E. salsugineum and in Arabidopsis thaliana epigenetic recombinant inbred lines found no evidence in support of any role for gbM in regulating transcription or affecting the composition and modification of chromatin over evolutionary timescales. PMID- 27457937 TI - Early-life disease exposure and associations with adult survival, cause of death, and reproductive success in preindustrial humans. AB - A leading hypothesis proposes that increased human life span since 1850 has resulted from decreased exposure to childhood infections, which has reduced chronic inflammation and later-life mortality rates, particularly from cardiovascular disease, stroke, and cancer. Early-life cohort mortality rate often predicts later-life survival in humans, but such associations could arise from factors other than disease exposure. Additionally, the impact of early-life disease exposure on reproduction remains unknown, and thus previous work ignores a major component of fitness through which selection acts upon life-history strategy. We collected data from seven 18th- and 19th-century Finnish populations experiencing naturally varying mortality and fertility levels. We quantified early-life disease exposure as the detrended child mortality rate from infectious diseases during an individual's first 5 y, controlling for important social factors. We found no support for an association between early-life disease exposure and all-cause mortality risk after age 15 or 50. We also found no link between early-life disease exposure and probability of death specifically from cardiovascular disease, stroke, or cancer. Independent of survival, there was no evidence to support associations between early-life disease exposure and any of several aspects of reproductive performance, including lifetime reproductive success and age at first birth, in either males or females. Our results do not support the prevailing assertion that exposure to infectious diseases in early life has long-lasting associations with later-life all-cause mortality risk or mortality putatively linked to chronic inflammation. Variation in adulthood conditions could therefore be the most likely source of recent increases in adult life span. PMID- 27457938 TI - Profile of James M. Berger. PMID- 27457940 TI - Profile of Matthew O. Jackson. PMID- 27457939 TI - Kin of coauthorship in five decades of health science literature. AB - Family background-kinship-can propagate careers. The evidence for academic nepotism is littered with complex associations and disputed causal inferences. Surname clustering, albeit with very careful consideration of surnames' flows across regions and time periods, can be used to reflect family ties. We examined surname patterns in the health science literature, by country, across five decades. Over 21 million papers indexed in the MEDLINE/PubMed database were analyzed. We identified relevant country-specific kinship trends over time and found that authors who are part of a kin tend to occupy central positions in their collaborative networks. Just as kin build potent academic networks with their own resources, societies may do well to provide equivalent support for talented individuals with fewer resources, on the periphery of networks. PMID- 27457941 TI - Estimating watershed degradation over the last century and its impact on water treatment costs for the world's large cities. AB - Urban water systems are impacted by land use within their source watersheds, as it affects raw water quality and thus the costs of water treatment. However, global estimates of the effect of land cover change on urban water-treatment costs have been hampered by a lack of global information on urban source watersheds. Here, we use a unique map of the urban source watersheds for 309 large cities (population > 750,000), combined with long-term data on anthropogenic land-use change in their source watersheds and data on water treatment costs. We show that anthropogenic activity is highly correlated with sediment and nutrient pollution levels, which is in turn highly correlated with treatment costs. Over our study period (1900-2005), median population density has increased by a factor of 5.4 in urban source watersheds, whereas ranching and cropland use have increased by a factor of 3.4 and 2.0, respectively. Nearly all (90%) of urban source watersheds have had some level of watershed degradation, with the average pollutant yield of urban source watersheds increasing by 40% for sediment, 47% for phosphorus, and 119% for nitrogen. We estimate the degradation of watersheds over our study period has impacted treatment costs for 29% of cities globally, with operation and maintenance costs for impacted cities increasing on average by 53 +/- 5% and replacement capital costs increasing by 44 +/- 14%. We discuss why this widespread degradation might be occurring, and strategies cities have used to slow natural land cover loss. PMID- 27457942 TI - Reduced nighttime transpiration is a relevant breeding target for high water-use efficiency in grapevine. AB - Increasing water scarcity challenges crop sustainability in many regions. As a consequence, the enhancement of transpiration efficiency (TE)-that is, the biomass produced per unit of water transpired-has become crucial in breeding programs. This could be achieved by reducing plant transpiration through a better closure of the stomatal pores at the leaf surface. However, this strategy generally also lowers growth, as stomatal opening is necessary for the capture of atmospheric CO2 that feeds daytime photosynthesis. Here, we considered the reduction in transpiration rate at night (En) as a possible strategy to limit water use without altering growth. For this purpose, we carried out a genetic analysis for En and TE in grapevine, a major crop in drought-prone areas. Using recently developed phenotyping facilities, potted plants of a cross between Syrah and Grenache cultivars were screened for 2 y under well-watered and moderate soil water deficit scenarios. High genetic variability was found for En under both scenarios and was primarily associated with residual diffusion through the stomata. Five quantitative trait loci (QTLs) were detected that underlay genetic variability in En Interestingly, four of them colocalized with QTLs for TE. Moreover, genotypes with favorable alleles on these common QTLs exhibited reduced En without altered growth. These results demonstrate the interest of breeding grapevine for lower water loss at night and pave the way to breeding other crops with this underexploited trait for higher TE. PMID- 27457943 TI - Earth's oxygen cycle and the evolution of animal life. AB - The emergence and expansion of complex eukaryotic life on Earth is linked at a basic level to the secular evolution of surface oxygen levels. However, the role that planetary redox evolution has played in controlling the timing of metazoan (animal) emergence and diversification, if any, has been intensely debated. Discussion has gravitated toward threshold levels of environmental free oxygen (O2) necessary for early evolving animals to survive under controlled conditions. However, defining such thresholds in practice is not straightforward, and environmental O2 levels can potentially constrain animal life in ways distinct from threshold O2 tolerance. Herein, we quantitatively explore one aspect of the evolutionary coupling between animal life and Earth's oxygen cycle-the influence of spatial and temporal variability in surface ocean O2 levels on the ecology of early metazoan organisms. Through the application of a series of quantitative biogeochemical models, we find that large spatiotemporal variations in surface ocean O2 levels and pervasive benthic anoxia are expected in a world with much lower atmospheric pO2 than at present, resulting in severe ecological constraints and a challenging evolutionary landscape for early metazoan life. We argue that these effects, when considered in the light of synergistic interactions with other environmental parameters and variable O2 demand throughout an organism's life history, would have resulted in long-term evolutionary and ecological inhibition of animal life on Earth for much of Middle Proterozoic time (~1.8-0.8 billion years ago). PMID- 27457944 TI - Correction for Bastia et al., Phosphorylation of CMG helicase and Tof1 is required for programmed fork arrest. PMID- 27457946 TI - Deep ocean nutrients imply large latitudinal variation in particle transfer efficiency. AB - The "transfer efficiency" of sinking organic particles through the mesopelagic zone and into the deep ocean is a critical determinant of the atmosphere-ocean partition of carbon dioxide (CO2). Our ability to detect large-scale spatial variations in transfer efficiency is limited by the scarcity and uncertainties of particle flux data. Here we reconstruct deep ocean particle fluxes by diagnosing the rate of nutrient accumulation along transport pathways in a data-constrained ocean circulation model. Combined with estimates of organic matter export from the surface, these diagnosed fluxes reveal a global pattern of transfer efficiency to 1,000 m that is high (~25%) at high latitudes and low (~5%) in subtropical gyres, with intermediate values in the tropics. This pattern is well correlated with spatial variations in phytoplankton community structure and the export of ballast minerals, which control the size and density of sinking particles. These findings accentuate the importance of high-latitude oceans in sequestering carbon over long timescales, and highlight potential impacts on remineralization depth as phytoplankton communities respond to a warming climate. PMID- 27457945 TI - Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis. AB - Malignant osteolysis associated with inoperable primary bone tumors and multifocal skeletal metastases remains a challenging clinical problem in cancer patients. Nanomedicine that is able to target and deliver therapeutic agents to diseased bone sites could potentially provide an effective treatment option for different types of skeletal cancers. Here, we report the development of polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam) for the targeted treatment of malignant skeletal tumors. In vivo biodistribution of radiolabeled targeted Pam-NPs demonstrated enhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. In a murine model of focal malignant osteolysis, Pam functionalized, Doxo-loaded NPs (Pam-Doxo-NPs) significantly attenuated localized osteosarcoma (OS) progression compared with nontargeted Doxo-NPs. Importantly, we report on the first evaluation to our knowlege of Pam-Doxo-NPs in dogs with OS, which possess tumors of anatomic size and physiology comparable to those in humans. The repeat dosing of Pam-Doxo-NPs in dogs with naturally occurring OS indicated the therapeutic was well tolerated without hematologic, nonhematologic, and cardiac toxicities. By nuclear scintigraphy, the biodistribution of Pam-Doxo NPs demonstrated malignant bone-targeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment. PMID- 27457947 TI - Correction for Zou et al., Genetic and socioeconomic study of mate choice in Latinos reveals novel assortment patterns. PMID- 27457948 TI - The enigma of the apparent disappearance of Eurasian highly pathogenic H5 clade 2.3.4.4 influenza A viruses in North American waterfowl. AB - One of the major unresolved questions in influenza A virus (IAV) ecology is exemplified by the apparent disappearance of highly pathogenic (HP) H5N1, H5N2, and H5N8 (H5Nx) viruses containing the Eurasian hemagglutinin 2.3.4.4 clade from wild bird populations in North America. The introduction of Eurasian lineage HP H5 clade 2.3.4.4 H5N8 IAV and subsequent reassortment with low-pathogenic H?N2 and H?N1 North American wild bird-origin IAVs in late 2014 resulted in widespread HP H5Nx IAV infections and outbreaks in poultry and wild birds across two-thirds of North America starting in November 2014 and continuing through June 2015. Although the stamping out strategies adopted by the poultry industry and animal health authorities in Canada and the United States-which included culling, quarantining, increased biosecurity, and abstention from vaccine use-were successful in eradicating the HP H5Nx viruses from poultry, these activities do not explain the apparent disappearance of these viruses from migratory waterfowl. Here we examine current and historical aquatic bird IAV surveillance and outbreaks of HP H5Nx in poultry in the United States and Canada, providing additional evidence of unresolved mechanisms that restrict the emergence and perpetuation of HP avian influenza viruses in these natural reservoirs. PMID- 27457950 TI - QnAs with John Rogers. PMID- 27457949 TI - Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor. AB - Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria. PMID- 27457951 TI - Mechanical signaling coordinates the embryonic heartbeat. AB - In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, beta glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts-consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats. PMID- 27457952 TI - Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation. AB - Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34(+) cord blood cells in long-term culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models. PMID- 27457953 TI - Dual role of CO in the stability of subnano Pt clusters at the Fe3O4(001) surface. AB - Interactions between catalytically active metal particles and reactant gases depend strongly on the particle size, particularly in the subnanometer regime where the addition of just one atom can induce substantial changes in stability, morphology, and reactivity. Here, time-lapse scanning tunneling microscopy (STM) and density functional theory (DFT)-based calculations are used to study how CO exposure affects the stability of Pt adatoms and subnano clusters at the Fe3O4(001) surface, a model CO oxidation catalyst. The results reveal that CO plays a dual role: first, it induces mobility among otherwise stable Pt adatoms through the formation of Pt carbonyls (Pt1-CO), leading to agglomeration into subnano clusters. Second, the presence of the CO stabilizes the smallest clusters against decay at room temperature, significantly modifying the growth kinetics. At elevated temperatures, CO desorption results in a partial redispersion and recovery of the Pt adatom phase. PMID- 27457955 TI - Crystal structure of a nuclear actin ternary complex. AB - Actin polymerizes and forms filamentous structures (F-actin) in the cytoplasm of eukaryotic cells. It also exists in the nucleus and regulates various nucleic acid transactions, particularly through its incorporation into multiple chromatin remodeling complexes. However, the specific structure of actin and the mechanisms that regulate its polymeric nature inside the nucleus remain unknown. Here, we report the crystal structure of nuclear actin (N-actin) complexed with actin related protein 4 (Arp4) and the helicase-SANT-associated (HSA) domain of the chromatin remodeler Swr1. The inner face and barbed end of N-actin are sequestered by interactions with Arp4 and the HSA domain, respectively, which prevents N-actin from polymerization and binding to many actin regulators. The two major domains of N-actin are more twisted than those of globular actin (G actin), and its nucleotide-binding pocket is occluded, freeing N-actin from binding to and regulation by ATP. These findings revealed the salient structural features of N-actin that distinguish it from its cytoplasmic counterpart and provide a rational basis for its functions and regulation inside the nucleus. PMID- 27457954 TI - Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray. AB - The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects. PMID- 27457956 TI - Transcription factors of the alternative NF-kappaB pathway are required for germinal center B-cell development. AB - The NF-kappaB signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-kappaB in these cells. The NF kappaB signaling cascade is comprised of two branches, the canonical and alternative NF-kappaB pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-kappaB2, in late B-cell development is incompletely understood. Using conditional deletion of relb and nfkb2 in GC B cells, we here report that ablation of both RELB and NF-kappaB2, but not of the single transcription factors, resulted in the collapse of established GCs. RELB/NF-kappaB2 deficiency in GC B cells was associated with impaired cell-cycle entry and reduced expression of the cell-surface receptor inducible T-cell costimulator ligand that promotes optimal interactions between B and T cells. Analysis of human tonsillar tissue revealed that plasma cells and their precursors in the GC expressed high levels of NF-kappaB2 relative to surrounding lymphocytes. Accordingly, deletion of nfkb2 in murine GC B cells resulted in a dramatic reduction of antigen specific antibody-secreting cells, whereas deletion of relb had no effect. These results demonstrate that the transcription factors of the alternative NF-kappaB pathway control distinct stages of late B-cell development, which may have implications for B-cell malignancies that aberrantly activate this pathway. PMID- 27457957 TI - The neural chaperone proSAAS blocks alpha-synuclein fibrillation and neurotoxicity. AB - Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated alpha-synuclein into the Lewy bodies present in Parkinson's disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson's disease. Recombinant proSAAS potently inhibits the fibrillation of alpha-synuclein in an in vitro assay; residues 158-180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks alpha-synuclein induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks alpha-synuclein-induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks beta-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease. PMID- 27457958 TI - Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor. AB - Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor beta, which likely regulates RHEB shuttling between GDP-bound and GTP bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity. PMID- 27457959 TI - Chromosomal landscape of UV damage formation and repair at single-nucleotide resolution. AB - UV-induced DNA lesions are important contributors to mutagenesis and cancer, but it is not fully understood how the chromosomal landscape influences UV lesion formation and repair. Genome-wide profiling of repair activity in UV irradiated cells has revealed significant variations in repair kinetics across the genome, not only among large chromatin domains, but also at individual transcription factor binding sites. Here we report that there is also a striking but predictable variation in initial UV damage levels across a eukaryotic genome. We used a new high-throughput sequencing method, known as CPD-seq, to precisely map UV-induced cyclobutane pyrimidine dimers (CPDs) at single-nucleotide resolution throughout the yeast genome. This analysis revealed that individual nucleosomes significantly alter CPD formation, protecting nucleosomal DNA with an inward rotational setting, even though such DNA is, on average, more intrinsically prone to form CPD lesions. CPD formation is also inhibited by DNA-bound transcription factors, in effect shielding important DNA elements from UV damage. Analysis of CPD repair revealed that initial differences in CPD damage formation often persist, even at later repair time points. Furthermore, our high-resolution data demonstrate, to our knowledge for the first time, that CPD repair is significantly less efficient at translational positions near the dyad of strongly positioned nucleosomes in the yeast genome. These findings define the global roles of nucleosomes and transcription factors in both UV damage formation and repair, and have important implications for our understanding of UV-induced mutagenesis in human cancers. PMID- 27457960 TI - Stochastic ice stream dynamics. AB - Ice streams are narrow corridors of fast-flowing ice that constitute the arterial drainage network of ice sheets. Therefore, changes in ice stream flow are key to understanding paleoclimate, sea level changes, and rapid disintegration of ice sheets during deglaciation. The dynamics of ice flow are tightly coupled to the climate system through atmospheric temperature and snow recharge, which are known exhibit stochastic variability. Here we focus on the interplay between stochastic climate forcing and ice stream temporal dynamics. Our work demonstrates that realistic climate fluctuations are able to (i) induce the coexistence of dynamic behaviors that would be incompatible in a purely deterministic system and (ii) drive ice stream flow away from the regime expected in a steady climate. We conclude that environmental noise appears to be crucial to interpreting the past behavior of ice sheets, as well as to predicting their future evolution. PMID- 27457961 TI - Computational investigation of cold denaturation in the Trp-cage miniprotein. AB - The functional native states of globular proteins become unstable at low temperatures, resulting in cold unfolding and impairment of normal biological function. Fundamental understanding of this phenomenon is essential to rationalizing the evolution of freeze-tolerant organisms and developing improved strategies for long-term preservation of biological materials. We present fully atomistic simulations of cold denaturation of an alpha-helical protein, the widely studied Trp-cage miniprotein. In contrast to the significant destabilization of the folded structure at high temperatures, Trp-cage cold denatures at 210 K into a compact, partially folded state; major elements of the secondary structure, including the alpha-helix, are conserved, but the salt bridge between aspartic acid and arginine is lost. The stability of Trp-cage's alpha-helix at low temperatures suggests a possible evolutionary explanation for the prevalence of such structures in antifreeze peptides produced by cold-weather species, such as Arctic char. Although the 310-helix is observed at cold conditions, its position is shifted toward Trp-cage's C-terminus. This shift is accompanied by intrusion of water into Trp-cage's interior and the hydration of buried hydrophobic residues. However, our calculations also show that the dominant contribution to the favorable energetics of low-temperature unfolding of Trp-cage comes from the hydration of hydrophilic residues. PMID- 27457962 TI - Reply to Yang et al.: GCTA produces unreliable heritability estimates. PMID- 27457963 TI - GCTA-GREML accounts for linkage disequilibrium when estimating genetic variance from genome-wide SNPs. PMID- 27457964 TI - Orteronel Switch Maintenance Therapy in Metastatic Castration Resistant Prostate Cancer After First-Line Docetaxel: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (SAKK 08/11). AB - BACKGROUND: We tested whether a switch maintenance treatment with orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration-resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel. METHODS: Men with mCRPC and non-progressive disease after a cumulative dose of >=300 mg/m2 docetaxel for first line treatment were randomized 1:1 to receive orteronel 300 mg twice daily or placebo. The primary endpoint was event-free survival (EFS) defined as the time from randomization to death or the combination of at least two of radiographic, clinical, or PSA progression. Ninety-six patients per arm were planned to demonstrate an improvement of median EFS from 4 months on placebo to 6.7 months on orteronel (hazard ratio (HR) 0.6; type I error 5% and power 90%). RESULTS: Forty-seven patients (23 orteronel, 24 placebo) were randomized before premature closure of the trial because of discontinuation of clinical development of orteronel. Median EFS was 8.5 months with orteronel and 2.9 months with placebo (P = 0.001; HR 0.32; 95%CI 0.15-0.65). Median radiographic progression-free survival (rPFS) was 8.5 and 2.8 months (P = 0.02; HR 0.42; 95%CI 0.20-0.91) in the orteronel and placebo arm, respectively. PSA decline >=50% was seen in 57% on orteronel and 4% on placebo. Toxicity was mainly mild, one patient on orteronel developed transient grade 3 adrenal insufficiency and one grade 4 pneumonitis. CONCLUSIONS: Orteronel significantly prolongs EFS in men with mCRPC who achieve disease stabilization with docetaxel. The concept of switch maintenance therapy in mCRPC warrants further research. Prostate 76:1519-1527, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27457965 TI - Impact of mitral geometry and global afterload on improvement of mitral regurgitation after trans-catheter aortic valve implantation. AB - OBJECTIVE: To assess the impact of mitral geometry, left ventricular (LV) remodelling and global LV afterload on mitral regurgitation (MR) after trans catheter aortic valve implantation (TAVI). METHODS: In this study, 60 patients who underwent TAVI were evaluated by 3D echocardiography at baseline, 1 month and 6 months after procedure. The proportional change in MR following TAVI was determined by examining the percentage change in vena contracta (VC) at 6 months. Patients having a significant reduction of at least 30% in VC were defined as good responders (GR) and the remaining patients were defined as poor responders (PR). RESULTS: After 6 months of TAVI, 27 (45%) patients were GR and 33 (55%) were PR. There was a significant decrease in 3DE-derived mitral annular diameter and area (P = 0.001), mitral valve tenting area (TA) (P = 0.05), and mitral papillary muscle dyssynchrony index (DSI) (P = 0.05) in the GR group. 3DE-derived LVESV (P = 0.016), LV mass (P = 0.001) and LV DSI, (P = 0.001) were also improved 6 months after TAVI. In addition, valvulo-arterial impedance (ZVA) was significantly higher at baseline in patients with PR (P = 0.028). 3DE-derived mitral annular area (beta: 0.47, P = 0.04), mitral papillary DSI (beta: -0.65, P = 0.012) and ZVA (beta: 0.45, P = 0.028) were the strongest independent parameters that could predict the reduction of functional MR after TAVI. CONCLUSION: GR patients demonstrate more regression in mitral annulus area and diameter after significant decrease in high LVEDP and trans-aortic gradients with TAVI. PR patients appear to have increased baseline ZVA, mitral valve tenting and restriction in mitral valve coaptation. These factors are important for predicting the impact of TAVI on pre-existing MR. PMID- 27457966 TI - Right heart function deteriorates in breast cancer patients undergoing anthracycline-based chemotherapy. AB - BACKGROUND: Cardiotoxicity from anthracycline-based chemotherapy is an important cause of early and late morbidity and mortality in breast cancer patients. Left ventricular (LV) function is assessed for patients receiving anthracycline-based chemotherapy to identify cardiotoxicity. However, animal studies suggest that right ventricular (RV) function may be a more sensitive measure to detect LV dysfunction. The purpose of this pilot study was to determine if breast cancer patients undergoing anthracycline-based chemotherapy experience RV dysfunction. METHODS: Forty-nine breast cancer patients undergoing anthracycline-based chemotherapy at the Ottawa Hospital between November 2007 and March 2013 and who had 2 echocardiograms performed at least 3months apart were retrospectively identified. Right atrial area (RAA), right ventricular fractional area change (RV FAC) and RV longitudinal strain of the free wall (RV LSFW) were evaluated according to the American Society of Echocardiography guidelines. RESULTS: The majority (48/49) of patients were females with an average age of 53.4 (95% CI: 50.1-56.7years). From baseline to follow-up study, average LV ejection fraction (LVEF) decreased from 62.22 (95% CI: 59.1-65.4) to 57.4% (95% CI: 54.0-60.9) (P=0.04). During the same time period, the mean RAA increased from 12.1cm(2) (95% CI: 11.1-13.0cm(2)) to 13.8cm(2) (95% CI: 12.7-14.9cm(2)) (P=0.02), mean RV FAC decreased (P=0.01) from 48.3% (95% CI: 44.8-51.74) to 42.1% (95% CI: 38.5-45.6%), and mean RV LSFW worsened from -16.2% (95% CI: -18.1 to -14.4%) to -13.81% (95% CI: -15.1 to -12.5%) (P=0.04). CONCLUSION: This study demonstrates that breast cancer patients receiving anthracycline-based chemotherapy experience adverse effects on both right atrial size and RV function. Further studies are required to determine the impact of these adverse effects on right heart function and whether this represents an earlier marker of cardiotoxicity. PMID- 27457967 TI - Focused cardiac ultrasound is feasible in the general practice setting and alters diagnosis and management of cardiac disease. AB - BACKGROUND: Ultrasound-assisted examination of the cardiovascular system with focused cardiac ultrasound by the treating physician is non-invasive and changes diagnosis and management of patient's with suspected cardiac disease. This has not been reported in a general practice setting. AIM: To determine whether focused cardiac ultrasound performed on patients aged over 50 years changes the diagnosis and management of cardiac disease by a general practitioner. DESIGN AND SETTING: A prospective observational study of 80 patients aged over 50years and who had not received echocardiography or chest CT within 12months presenting to a general practice. METHOD: Clinical assessment and management of significant cardiac disorders in patients presenting to general practitioners were recorded before and after focused cardiac ultrasound. Echocardiography was performed by a medical student with sufficient training, which was verified by an expert. Differences in diagnosis and management between conventional and ultrasound assisted assessment were recorded. RESULTS AND CONCLUSION: Echocardiography and interpretation were acceptable in all patients. Significant cardiac disease was detected in 16 (20%) patients, including aortic stenosis in 9 (11%) and cardiac failure in 7 (9%), which were missed by clinical examination in 10 (62.5%) of these patients. Changes in management occurred in 12 patients (15% overall and 75% of those found to have significant cardiac disease) including referral for diagnostic echocardiography in 8 (10%), commencement of heart failure treatment in 3 (4%) and referral to a cardiologist in 1 patient (1%).Routine focused cardiac ultrasound is feasible and frequently alters the diagnosis and management of cardiac disease in patients aged over 50years presenting to a general practice. PMID- 27457968 TI - Blood pressure-lowering effects of long chain n-3 fatty acids from meals enriched with liquid fish oil and from microencapsulated powder. AB - BACKGROUND: Diet plays an important role in the etiology of hypertension. Blood pressure (BP)-lowering properties of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) are promising. The aim was to investigate whether different formulations of fish oil differently affect blood pressure in community-dwelling adults. The hypothesis was that fish oil formulations would improve BP in comparison with a placebo. METHODS: In this 4-week randomized, placebo controlled, doubly-blinded dietary intervention study, participants (N = 99, >50 years) from the capital area of Iceland were randomized into three groups. Group 1 (n = 38) received 6 meals/week fortified with a liquid fish oil and placebo powder. Group 2 (n = 30) received conventional (unfortified) meals and microencapsulated powder. Group 3 (n = 31) was the control group which received conventional meals and placebo powder. Calculated on a weekly basis, the amount of EPA + DHA provided was 1.5 g/d. Systolic (SBP) and diastolic BP (DBP) were measured before and after the intervention period. RESULTS: Seventy-seven subjects finished the study (77.8%). Drop-out rates were not different between groups. According to multivariate statistics, endpoint SBP was lower in Group 1 ( 7.0 mmHg, p = 0.037) and in Group 2 (-7.2 mmHg, p = 0.037) as compared with Group 3. There was no significant difference in DBP between the groups. CONCLUSION: Our study shows that LC n-3 PUFA from microencapsulated powder are equally effective to meaningfully reduce SBP as LC n-3 PUFA from meals enriched with liquid fish oil in comparison with a control group. PMID- 27457969 TI - "Happy goat says": The effect of a food selection inhibitory control training game of children's response inhibition on eating behavior. AB - Recent studies suggest that when inhibitory control is lacking, people are more inclined to indulge in high-calorie food, but inhibitory control can be trained. In this study, a daily-life training game was used to train children and investigate whether strengthening or weakening inhibitory control influences food intake in opposite directions. The baseline of response inhibition was measured by the go/no-go task, and the baseline of food intake was measured by a bogus food taste task. Then, participants performed a food selection training game named "Happy goat says" with three within-subject conditions: the first type of instruction was always paired without a go signal (inhibition manipulation); the second type of instruction was always presented with a go signal (impulsivity manipulation); and the third type of instruction was presented either with a go or no-go signal, both in 50% of the time (control manipulation). Following these manipulations, they went through the go/no-go task and bogus food taste task. In the pre-training food taste task, commission errors were positively correlated with body mass index. Relative to a control group playing Lego blocks (n = 20), the trained group showed a performance improvement on the go/no-go task. The intake of food in the inhibition manipulation was significantly less in the post training food taste task. These findings demonstrate that children can gain control over the consumption of high-calorie food after a daily-life response inhibition training game. PMID- 27457970 TI - Characterizing and improving the sensory and hedonic responses to polyphenol-rich aronia berry juice. AB - Interest in nutrient-rich berry juices is growing, but their high polyphenol levels render them sensorily unappealing. Fifty adults, who were assessed for sensory phenotype and dietary behaviors, provided sensory and palatability ratings of juices from 'Viking' aronia berries for each of seven harvest weeks. By peak harvest, juice preference increased two-fold, averaging neither like/dislike. This hedonic shift was associated with: increases in juice sugars paralleling increases in perceived sweetness (maximum = weak); reductions in percent acidity paralleling reductions in sourness (minimum = moderate), astringency (minimum = to just above weak) and bitterness (minimum = just below weak). About 25% of adults liked the aronia juice, including adults who also liked an aqueous citric acid solution (average rating = moderately sour) or those who reported adventurous eating behaviors. Bitter taste phenotype, measured by propylthiouracil or quinine bitterness, failed to explain significant variation in juice sensation or preference. We also collected sensory and preference ratings from juice collected at peak harvest blended with sugar and/or sweet olfactory flavoring (10 ppm ethyl butyrate). Increasing juice sweetness by adding 5% sucrose decreased sourness and improved preference from weak dislike to weak like. Adding sweet olfactory flavoring decreased juice sourness without changing preference. Adding sweet flavoring and 3% sucrose resulted in reduction of sourness and improvements in preference ratings comparable to 5% added sucrose. Neither added sugar nor flavoring blocked juice astringency. In summary, these findings suggest that aronia juice, even from berries picked at peak harvest, appealed to only a few adults (sour likers or adventurous eaters). Although enhanced sweetness, with added sugar and sweet olfactory flavoring, improved aronia juice preference, broader sensory approaches are required to blunt astringency for greater consumer appeal. PMID- 27457971 TI - Insulin secretion impairment in Sirt6 knockout pancreatic beta cells is mediated by suppression of the FoxO1-Pdx1-Glut2 pathway. AB - Sirtuin 6 (Sirt6), a chromatin associated class III deacetylase, controls whole body energy homeostasis and has a critical role in glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells. However, its underlying molecular mechanism remains poorly understood. To gain further insights, we studied the pathway by which Sirt6 regulates GSIS utilizing mice lacking Sirt6 in their beta cells (betaS6KO). Further, we overexpressed wild type or deacetylase-inactive mutant Sirt6 in isolated islets as well as in MIN6 cells. We confirmed that betaS6KO mice developed glucose intolerance with severely impaired GSIS. Gene expression analysis of knockout islets and overexpression studies demonstrated that Sirt6 deacetylates forkhead box protein O1 (FoxO1) to trigger its nuclear export and releases its transcriptional repression of key glucose sensing genes such as Pdx1 and Glut2. Ectopic overexpression of Sirt6 in knockout islets resulted in rescue of the defective insulin secretion and restoration of the expression of Pdx1 and Glut2. These results show that Sirt6 in pancreatic beta cells deacetylates FoxO1 and subsequently increases the expression of Pdx1 and Glut2 to maintain the glucose-sensing ability of pancreatic beta cells and systemic glucose tolerance. PMID- 27457972 TI - Active surveillance is suitable for intermediate term follow-up of renal oncocytoma diagnosed by percutaneous core biopsy. AB - OBJECTIVES: To evaluate the intermediate outcome of conservative management in patients with biopsy-proven oncocytoma. PATIENTS AND METHODS: Patients with oncocytoma diagnosed on percutaneous core biopsy between January 2000 to December 2014 were identified from the renal biopsy database of a large specialist urologic pathology laboratory. After review of patient clinical records, the study cohort comprised only of patients enrolled in active surveillance. Clinicopathological and follow-up details were reviewed for each case, in particular: type and interval of surveillance imaging, tumour growth, definitive intervention and reason for intervention. Where possible, correlation was made between the final surgical and the initial biopsy specimens. RESULTS: Fifty three patients diagnosed with oncocytoma on core biopsy were initially placed on active surveillance with median follow-up of 34 months (range 6-109). The median age at diagnosis was 65 years (range 20-85) and median tumour size was 30 mm (range 13 87). Mean average tumour growth was 1.4 mm per annum (median 0 mm/year) with the majority (36 of 53, 68%) exhibiting minimal growth (less than 2 mm per annum) or partial regression. Forty seven of the 53 patients remained on active surveillance with no significant progression. Six patients elected to undergo definitive intervention (five surgical excision, one ablation). Renal oncocytoma was confirmed in all five patients who underwent surgical excision of their lesions. CONCLUSIONS: The majority of oncocytomas in this study showed minimal growth rate or regression. Patients with biopsy proven oncocytoma can be conservatively managed with active surveillance. PMID- 27457973 TI - Isolation and identification of Vibrio cholerae and Vibrio parahaemolyticus from prawn (Penaeus monodon) seafood: Preservation strategies. AB - Bacterial diseases are one of the major problems which affects the production, development and expansion of aqua culture. Vibrio sp. are widespread in marine and estuarine environments. The several pathogenic species are commonly associated with outbreaks of Vibrio species and it is mainly associated with food poisonings. In this research, the occurrence of Vibrio sp. was studied by the isolation and it is confirmed by the biochemical methods. The growth rate was studied by changing the different operating parameters. Isolation studies were done by using enrichment and selective plating methods. The different biochemical test was carried out and inferred that the isolated organisms were Vibrio choleraee and Vibrio parahaemolyticus. The antibiotic study was also performed to find out the resistant and sensitivity of the Vibrio species. From the results, it was observed that this can be able to correlate the growth of vibrio species to a limited condition and other environmental parameters for which it will be able to find the remedial measures to prevent the growth and spreading of the diseases. Also the different preservation method was carried out to suppress the growth rate of Vibrio sp. PMID- 27457974 TI - Molecular detection of virulence genes in Pseudomonas aeruginosa isolated from children with Cystic Fibrosis and burn wounds in Iran. AB - Pseudomonas aeruginosa possesses various virulence factors which contribute to the bacterial invasion and toxicity. Moreover, children suffered from Cystic Fibrosis (CF) and burn wounds are at a high risk of various bacterial infections. The aim of this study was to determine the prevalence of virulent genes in P. aeruginosa isolated from children with CF and burn wounds and comparing their virulence genes to figure out the role of every virulent factor in the infections. P. aeruginosa were isolated from sputum, oropharyngeal swabs, and broncho-alveolar lavage (BAL) specimens from CF and burn wounds between June 2013 and June 2014 in Tehran's hospitals. Bacterial genomic DNAs were extracted and uniplex, duplex and multiplex PCR were performed for detection of toxA, algD and plcN, exoS, lasB, plcH genes, respectively. The prevalence rate of virulence genes in P. aeruginosa isolated from CF was; toxA (63.1%), algD (64.6%), plcH (87.7%), plcN (60%), lasB (95.4%) and exoS (70.8%) and virulence genes in P. aeruginosa from burn patients were: toxA (36.9%), algD (70.1%), plcH (79%), plcN (63.1%), lasB (82%) and exoS (21.1%). The prevalence of three virulent genes in P. aeruginosa was higher in CF comparing to burn wound infections. We found that the number of toxA, lasB and exoS were significantly higher in the bacteria which were isolated from children with CF. This finding shows that these virulence factors play an important role in CF infections by P. aeroginosa. PMID- 27457976 TI - Radiotherapy infrastructure and human resources in Switzerland : Present status and projected computations for 2020. AB - PURPOSE: The purpose of this study was to evaluate the present status of radiotherapy infrastructure and human resources in Switzerland and compute projections for 2020. MATERIALS AND METHODS: The European Society of Therapeutic Radiation Oncology "Quantification of Radiation Therapy Infrastructure and Staffing" guidelines (ESTRO-QUARTS) and those of the International Atomic Energy Agency (IAEA) were applied to estimate the requirements for teleradiotherapy (TRT) units, radiation oncologists (RO), medical physicists (MP) and radiotherapy technologists (RTT). The databases used for computation of the present gap and additional requirements are (a) Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) for cancer incidence (b) the Directory of Radiotherapy Centres (DIRAC) of the IAEA for existing TRT units (c) human resources from the recent ESTRO "Health Economics in Radiation Oncology" (HERO) survey and (d) radiotherapy utilization (RTU) rates for each tumour site, published by the Ingham Institute for Applied Medical Research (IIAMR). RESULTS: In 2015, 30,999 of 45,903 cancer patients would have required radiotherapy. By 2020, this will have increased to 34,041 of 50,427 cancer patients. Switzerland presently has an adequate number of TRTs, but a deficit of 57 ROs, 14 MPs and 36 RTTs. By 2020, an additional 7 TRTs, 72 ROs, 22 MPs and 66 RTTs will be required. In addition, a realistic dynamic model for calculation of staff requirements due to anticipated changes in future radiotherapy practices has been proposed. This model could be tailor-made and individualized for any radiotherapy centre. CONCLUSION: A 9.8 % increase in radiotherapy requirements is expected for cancer patients over the next 5 years. The present study should assist the stakeholders and health planners in designing an appropriate strategy for meeting future radiotherapy needs for Switzerland. PMID- 27457977 TI - Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis-stimulating agent in monkeys and rats. AB - EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025mg/kg. The study findings at 0.2mg/kg for rats and 0.3mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical studies. PMID- 27457978 TI - Dynamics of glucosinolate-myrosinase system during Plutella xylostella interaction to a novel host Lepidium latifolium L. AB - Plutella xylostella L. is a notorious pest of cruciferous crops causing worldwide losses of $4-5 billion per year. Developing classical biological control to this pest include an introduction of host plants that act as natural enemies showing deviation from the preference-performance regimen in the evolutionary ecology of plant-insect interactions. The present study was designed to understand the role of glucosinolate-myrosinase system during P. xylostella interactions with a novel host. Adult moth preference and larval performance study were conducted on a novel host Lepidium latifolium L. (LL) that has high sinigrin content and was compared with its laboratory host Arabidopsis thaliana (AT). The glucosinolate myrosinase system was studied in a time course experiment during larval feeding in choice and no-choice experiments. Adult moths visit and prefers LL over AT for oviposition. Conversely, LL leaves were not preferred and proved detrimental for P. xylostella larvae. Aliphatic and indolic glucosinolates were found to decrease significantly (p<=0.05) in AT during initial 12h of P. xylostella challenge, whereas, they were not affected in LL. Also, MYB transcription factor expression and myrosinase activity in LL do not suggest a typical host response to a specialist insect. This preference-performance mismatch of P. xylostella on LL mediated by glucosinolate pattern suggests that this novel plant could be utilized in P. xylostella management. PMID- 27457979 TI - Phosphatidylinositol 4-phosphate 5-kinases 1 and 2 are involved in the regulation of vacuole morphology during Arabidopsis thaliana pollen development. AB - The pollen grains arise after meiosis of pollen mother cells within the anthers. A series of complex structural changes follows, generating mature pollen grains capable of performing the double fertilization of the female megasporophyte. Several signaling molecules, including hormones and lipids, have been involved in the regulation and appropriate control of pollen development. Phosphatidylinositol 4-phophate 5-kinases (PIP5K), which catalyze the biosynthesis of the phosphoinositide PtdIns(4,5)P2, are important for tip polar growth of root hairs and pollen tubes, embryo development, vegetative plant growth, and responses to the environment. Here, we report a role of PIP5Ks during microgametogenesis. PIP5K1 and PIP5K2 are expressed during early stages of pollen development and their transcriptional activity respond to auxin in pollen grains. Early male gametophytic lethality to certain grade was observed in both pip5k1(-/ ) and pip5k2(-/-) single mutants. The number of pip5k mutant alleles is directly related to the frequency of aborted pollen grains suggesting the two genes are involved in the same function. Indeed PIP5K1 and PIP5K2 are functionally redundant since homozygous double mutants did not render viable pollen grains. The loss of function of PIP5K1 and PIP5K2results in defects in vacuole morphology in pollen at the later stages and epidermal root cells. Our results show that PIP5K1, PIP5K2 and phosphoinositide signaling are important cues for early developmental stages and vacuole formation during microgametogenesis. PMID- 27457980 TI - Asada-Halliwell pathway maintains redox status in Dioscorea alata tuber which helps in germination. AB - Reactive Oxygen Species (ROS) are important regulatory molecules governing physiological processes. In the present study a biochemical and proteome level comparison of two contrasting growth stages of Dioscorea alata tuber namely germinating and mature tuber was performed in order to understand the tuber physiology and biochemistry. Existence of all the component enzymes [APx (ascorbate peroxidase), GR (glutathione reductase), DHAR (dehydroascorbate reductase), MDHAR (mono-dehydroascorbate reductase)] and major products [ascorbate (ASC) and glutathione (GSH)] of the cycle showed an operational Asada Halliwell cycle in the tuber. A 2.65 fold increase in ASC content & a 3.8 fold increase in GR activity fortified the redox milieu during germination. In contrast a 5 fold higher H2O2 content (due to 3.08 fold lower APx activity) and accumulation of reactive nitrogen species (RNS) such as nitric oxide (NO, 2.4 fold) and S-nitrosothiol (SNO, 2.08 fold) contributed to overall oxidative conditions in the mature tuber. The carbonic anhydrase (CA, 7.5 fold), DHAR (5.31 fold) and MDHAR (7 fold) activities were higher in the germinating tuber in comparison with the mature tuber. GSNO negatively regulated the CA (3.6 & 3.95 fold), MDHAR (7.5 & 1.5 fold) and APx (2.3 & 1.81 fold) while another NO donor, CysNO negatively regulated the DHAR (2.24 & 1.32 fold) activity in the mature and germinating stages respectively indicating again that the lesser inhibition by NO (via nitrosylation) may be because of overall reducing environment in the germinating tuber. Increased SNO leading to S-nitrosylation of dioscorin was confirmed by Biotin switch assay. This is the first report showing dioscorin nitrosylation. The present analysis showed differential redox regulation and also suggests the physiological relevance of CA, DHAR, MDHAR, APx & GR in tuber germination for the first time. These enzymes may be used as potential markers of tuber germination in future. PMID- 27457981 TI - Membrane-bound NAC transcription factors in maize and their contribution to the oxidative stress response. AB - NAC membrane-bound transcription factors (NTM1-like, NTL proteins) participate in the regulation of plant development and the abiotic stress response. While their function has been thoroughly explored in Arabidopsis thaliana, this is not the case in maize. Seven ZmNTL genes were identified by an in silico scan of relevant genome sequence. All seven included a NAC domain at their N terminus, and an alpha-helical membrane-bound structure domain in their C terminal region. Based on their gene structure and content of conserved motifs, the seven sequences were distributed into four clades. Six of the seven ZmNTLs were associated with the plasma membrane, and the remaining one with the endoplasmic reticulum. ZmNTL2-7 were more strongly transcribed in the stem than in either the leaf or root, while ZmNTL1 transcript abundance was highest in the leaf. When the plants were exposed to either abscisic acid or hydrogen peroxide treatment, all seven genes were up regulated in the root and stem and down-regulated in the leaf. The heterologous expression of ZmNTL1-DeltaTM, 2-DeltaTM and 5-DeltaTM in A. thaliana reduced the level of sensitivity of the plant to hydrogen peroxide. PMID- 27457982 TI - Identification and characterization of contrasting sunflower genotypes to early leaf senescence process combining molecular and physiological studies (Helianthus annuus L.). AB - Leaf senescence is a complex mechanism ruled by multiple genetic and environmental variables that affect crop yields. It is the last stage in leaf development, is characterized by an active decline in photosynthetic rate, nutrients recycling and cell death. The aim of this work was to identify contrasting sunflower inbred lines differing in leaf senescence and to deepen the study of this process in sunflower. Ten sunflower genotypes, previously selected by physiological analysis from 150 inbred genotypes, were evaluated under field conditions through physiological, cytological and molecular analysis. The physiological measurement allowed the identification of two contrasting senescence inbred lines, R453 and B481-6, with an increase in yield in the senescence delayed genotype. These findings were confirmed by cytological and molecular analysis using TUNEL, genomic DNA gel electrophoresis, flow sorting and gene expression analysis by qPCR. These results allowed the selection of the two most promising contrasting genotypes, which enables future studies and the identification of new biomarkers associated to early senescence in sunflower. In addition, they allowed the tuning of cytological techniques for a non-model species and its integration with molecular variables. PMID- 27457983 TI - Proteomic analysis of the mature Brassica stigma reveals proteins with diverse roles in vegetative and reproductive development. AB - The stigma, the specialized apex of the Brassicaceae gynoecium, plays a role in pollen capture, discrimination, hydration, germination, and guidance. Despite this crucial role in reproduction, the global proteome underlying Brassicaceae stigma development and function remains largely unknown. As a contribution towards the characterization of the Brassicaceae dry stigma global proteome, more than 2500 Brassica napus mature stigma proteins were identified using three different gel-based proteomics approaches. Most stigma proteins participated in Metabolic Processes, Responses to Stimulus or Stress, Cellular or Developmental Processes, and Transport. The stigma was found to express a wide variety of proteins with demonstrated roles in cellular and organ development including proteins known to be involved in cellular expansion and morphogenesis, embryo development, as well as gynoecium and stigma development. Comparisons to a corresponding proteome from a very morphologically different Poaceae dry stigma showed a very similar distribution of proteins among different functional categories, but also revealed evident distinctions in protein composition especially in glucosinolate and carotenoid metabolism, photosynthesis, and self incompatibility. To our knowledge, this study reports the largest Brassicaceae stigma protein dataset described to date. PMID- 27457984 TI - Photosynthetic responses mediate the adaptation of two Lotus japonicus ecotypes to low temperature. AB - Lotus species are important forage legumes due to their high nutritional value and adaptability to marginal conditions. However, the dry matter production and regrowth rate of cultivable Lotus spp. is drastically reduced during colder seasons. In this work, we evaluated the chilling response of Lotus japonicus ecotypes MG-1 and MG-20. No significant increases were observed in reactive oxygen species and nitric oxide production or in lipid peroxidation, although a chilling-induced redox imbalance was suggested through NADPH/NADP(+) ratio alterations. Antioxidant enzyme catalase, ascorbate peroxidase, and superoxide dismutase activities were also measured. Superoxide dismutase, in particular the chloroplastic isoform, showed different activity for different ecotypes and treatments. Stress-induced photoinhibition also differentially influenced both ecotypes, with MG-1 more affected than MG-20. Data showed that the D2 PSII subunit was more affected than D1 after 1 d of low temperature exposure, although its protein levels recovered over the course of the experiment. Interestingly, D2 recovery was accompanied by improvements in photosynthetic parameters (Asat and Fv/Fm) and the NADPH/NADP(+) ratio. Our results suggest that the D2 protein is involved in the acclimation response of L. japonicus to low temperature. This may provide a deeper insight into the chilling tolerance mechanisms of the Lotus genus. PMID- 27457985 TI - Constitutive over-expression of rice ClpD1 protein enhances tolerance to salt and desiccation stresses in transgenic Arabidopsis plants. AB - Caseinolytic proteases (Clps) perform the important role of removing protein aggregates from cells, which can otherwise prove to be highly toxic. ClpD system is a two-component protease complex composed of a regulatory ATPase module ClpD and a proteolytic component ClpP. Under desiccation stress condition, rice ClpD1 (OsClpD1) gene encoding for the regulatory subunit, was represented by four variant transcripts differing mainly in the expanse of their N-terminal amino acids. These transcripts were expressed in a differential manner in response to salt, mannitol and polyethylene glycol stresses in rice. Purified OsClpD1.3 protein exhibited intrinsic chaperone activity, shown using citrate synthase as substrate. Arabidopsis (Col-0) plants over-expressing OsClpD1.3 open reading frame downstream to CaMV35S promoter (ClpD1.3 plants) showed higher tolerance to salt and desiccation stresses as compared to wild type plants. ClpD1.3 seedlings also showed enhanced growth during the early stages of seed germination under unstressed, control conditions. The free proline levels and starch breakdown activities were higher in the ClpD1.3 seedlings as compared to the wild type Arabidopsis seedlings. It thus emerges that increasing the potential of ClpD1 chaperoning activity may be of advantage in protection against abiotic stresses. PMID- 27457986 TI - Hierarchies of plant stiffness. AB - Plants must meet mechanical as well as physiological and reproductive requirements for survival. Management of internal and external stresses is achieved through their unique hierarchical architecture. Stiffness is determined by a combination of morphological (geometrical) and compositional variables that vary across multiple length scales ranging from the whole plant to organ, tissue, cell and cell wall levels. These parameters include, among others, organ diameter, tissue organization, cell size, density and turgor pressure, and the thickness and composition of cell walls. These structural parameters and their consequences on plant stiffness are reviewed in the context of work on stems of the genetic reference plant Arabidopsis thaliana (Arabidopsis), and the suitability of Arabidopsis as a model system for consistent investigation of factors controlling plant stiffness is put forward. Moving beyond Arabidopsis, the presence of morphological parameters causing stiffness gradients across length-scales leads to beneficial emergent properties such as increased load bearing capacity and reversible actuation. Tailoring of plant stiffness for old and new purposes in agriculture and forestry can be achieved through bioengineering based on the knowledge of the morphological and compositional parameters of plant stiffness in combination with gene identification through the use of genetics. PMID- 27457987 TI - Mutations in exocyst complex subunit SEC6 gene impaired polar auxin transport and PIN protein recycling in Arabidopsis primary root. AB - Polar auxin transport, which is critical for land plant pattern formation and directional growth, is largely depended on asymmetric distribution of PIN proteins at the plasma membrane (PM). Endocytosis and recycling processes play important roles in regulating PIN protein distribution and abundance at the PM. Two subunits (SEC8, EXO70A1) of exocyst, an octameric vesicle-tethering complex, have been reported to be involved in PIN protein recycling in Arabidopsis. However, the function of exocyst complex in PIN protein recycling and polar auxin transport remains incompletely understood. In this study, we utilized two SEC6 down-regulation mutants (PRsec6-1 and PRsec6-2) to investigate the role of exocyst subunit SEC6 in the primary root development, polar auxin transport and PIN proteins recycling. We found that in PRsec6 mutants: 1. Primary root growth was retarded, and lateral root initiation were compromised. 2. Primary roots were sensitive to exogenous auxin 1-napthalene acetic acid (NAA) but not 2,4 dichlorophenoxy (2.4-D). 3. Recycling of PIN1 and PIN2 proteins from the Brefeldin A (BFA) compartment to the PM was delayed. 4. Vesicles accumulated in the primary root tip cells, especially accumulated in the cytosol closed to the PM. These results further demonstrated that the exocyst complex plays an important role in PIN protein recycling and polar auxin transport in Arabidopsis primary root. PMID- 27457988 TI - Tissue-specific expression of Arabidopsis NPR1 gene in rice for sheath blight resistance without compromising phenotypic cost. AB - Rice sheath blight disease, caused by the fungus Rhizoctonia solani, is considered the second most important disease of rice after blast. NPR1 (non expressor of PR1) is the central regulator of systemic acquired resistance (SAR) conferring broad spectrum resistance to various pathogens. Previous reports have indicated that constitutive expression of the Arabidopsis thaliana NPR1 (AtNPR1) gene results in disease resistance in rice but has a negative impact on growth and agronomic traits. Here, we report that green tissue-specific expression of AtNPR1 in rice confers resistance to the sheath blight pathogen, with no concomitant abnormalities in plant growth and yield parameters. Elevated levels of NPR1 activated the defence pathway in the transgenic plants by inducing expression of endogenous genes such as PR1b, RC24, and PR10A. Enhanced sheath blight resistance of the transgenic plants was evaluated using three different bioassay systems. A partially isolated toxin from R. solani was used in the bioassays to measure the resistance level. Studies of the phenotype and yield showed that the transgenic plants did not exhibit any kind of phenotypic imbalances. Our results demonstrate that green tissue-specific expression of AtNPR1 is an effective strategy for controlling the sheath blight pathogen. The present work in rice can be extended to other crop plants severely damaged by the pathogen. PMID- 27457989 TI - BcIEB1, a Botrytis cinerea secreted protein, elicits a defense response in plants. AB - BcIEB1 is a very abundant protein in the secretome of Botrytis cinerea but it has no known function and no similarity to any characterized protein family. Previous results suggested that this protein is an elicitor of the plant defense system. In this work we have generated loss-of-function B. cinerea mutants lacking BcIEB1 and we have expressed the protein in yeast to assay its activity on plants. Analysis of the Deltabcieb1 mutants did not result in any observable phenotype, including no difference in the virulence on a variety of hosts. However, when BcIEB1 was applied to plant tissues it produced necrosis as well as a whole range of symptoms: inhibition of seedling growth in Arabidopsis and tobacco, ion leakage from tobacco leaf disks, a ROS burst, cell death and autofluorescence in onion epidermis, as well as the expression of defense genes in tobacco. Moreover, tobacco plants treated with BcIEB1 showed an increased systemic resistance to B. cinerea. A small 35-amino acids peptide derived from a conserved region of BcIEB1 is almost as active on plants as the whole protein. These results clearly indicate that BcIEB1 elicits plant defenses, probably as a consequence of its recognition as a pathogen associated molecular pattern. PMID- 27457990 TI - ABI3 mediates dehydration stress recovery response in Arabidopsis thaliana by regulating expression of downstream genes. AB - ABI3, originally discovered as a seed-specific transcription factor is now implicated to act beyond seed physiology, especially during abiotic stress. In non-seed plants, ABI3 is known to act in desiccation stress signaling. Here we show that ABI3 plays a role in dehydration stress response in Arabidopsis. ABI3 gene was upregulated during dehydration stress and its expression was maintained during subsequent stress recovery phases. Comparative gene expression studies in response to dehydration stress and stress recovery were done with genes which had potential ABI3 binding sites in their upstream regulatory regions. Such studies showed that several genes including known seed-specific factors like CRUCIFERIN1, CRUCIFERIN3 and LEA-group of genes like LEA76, LEA6, DEHYDRIN LEA and LEA-LIKE got upregulated in an ABI3-dependent manner, especially during the stress recovery phase. ABI3 got recruited to regions upstream to the transcription start site of these genes during dehydration stress response through direct or indirect DNA binding. Interestingly, ABI3 also binds to its own promoter region during such stress signaling. Nucleosomes covering potential ABI3 binding sites in the upstream sequences of the above-mentioned genes alter positions, and show increased H3 K9 acetylation during stress-induced transcription. ABI3 thus mediates dehydration stress signaling in Arabidopsis through regulation of a group of genes that play a role primarily during stress recovery phase. PMID- 27457991 TI - The C3H-type zinc finger protein GDS1/C3H42 is a nuclear-speckle-localized protein that is essential for normal growth and development in Arabidopsis. AB - Eukaryotic C3H-type zinc finger proteins (Znfs) comprise a large family of regulatory proteins involved in many aspects of plant stress response, growth and development. However, compared to mammalian, only a few plant Znfs have been functionally characterized. Here, T-DNA inserted gds1 (growth, development and splicing 1) mutant, displayed abnormal growth throughout the lifecycle owing to the reduction of cell size and number. Inverse PCR analysis revealed that the abnormal growth was caused by the disruption of At3g47120, which encodes a C3H42 protein belonging to the C-X7-C-X5-C-X3-H class of the Znf family. GDS1 was ubiquitously transcribed, but shows high levels of expression in young seedling and unexpanded new leaves. In gds1, the transcripts of many growth- and development-related genes were down-regulated, and the auxin response was dramatically reduced. A fluorescence-based assay revealed that the GDS1 protein was localized to the nucleus, prominently in the speckle compartments. Its arginine/serine dipeptide-rich-like (RS-like) domain was essential for nuclear localization. In addition, the SR1, SRm102 and U1-70K components of the U1 spliceosome interacted with GDS1 in the nuclear speckle compartments. Taken together, these suggest that GDS1, a nuclear-speckle-associated Znf, might play a significant role in splicing during plant growth and development. PMID- 27457992 TI - Enhanced accumulation of phytosterols and phenolic compounds in cyclodextrin elicited cell suspension culture of Daucus carota. AB - In this work, suspension-cultured cells of Daucus carota were used to evaluate the effect of beta-cyclodextrins on the production of isoprenoid and phenolic compounds. The results showed that the phytosterols and phenolic compounds were accumulated in the extracellular medium (15100MUgL(-1) and 477.46MUgL(-1), respectively) in the presence of cyclodextrins. Unlike the phytosterol and phenolic compound content, beta-carotene (1138.03MUgL(-1)), lutein (25949.54MUgL( 1)) and alpha-tocopherol (8063.82MUgL(-1)) chlorophyll a (1625.13MUgL(-1)) and b (9.958 (9958.33MUgL(-1)) were mainly accumulated inside the cells. Therefore, cyclodextrins were able to induce the cytosolic mevalonate pathway, increasing the biosynthesis of phytosterols and phenolic compounds, and accumulate them outside the cells. However, in the absence of these cyclic oligosaccharidic elicitors, carrot cells mainly accumulated carotenoids through the methylerythritol 4-phosphate pathway. Therefore, the use of cyclodextrins would allow the extracellular accumulation of both phytosterols and phenolic compounds by diverting the carbon flux towards the cytosolic mevalonate/phenylpropanoid pathway. PMID- 27457993 TI - Brassinosteroid's multi-modular interaction with the general stress network customizes stimulus-specific responses in Arabidopsis. AB - Adaptation to fluctuating environmental conditions is a universal feature of plant life, governed by fundamental mechanisms optimizing resource allocation. This balance is achieved in part through tightly regulated communication networks among growth and stress response signaling pathways. Understanding the communication modules between brassinosteroids (BRs), the ubiquitous hormones known to control growth and stress adaptation, and the general stress response (GSR), a rapid and transient transcriptional output in response to perturbations, provides an optimal platform to unravel new facet(s) of plant stress adaptation. Here, we explore communication facets of BR with GSR via in planta quantification of the GSR in Arabidopsis expressing luciferase driven by a functional GSR cis element, the Rapid Stress Response Element (4xRSRE:LUC). We establish that application of exogenous BR suppresses microbe-associated molecular pattern activated GSR, but enhances the wound-triggered GSR. The enhanced wound-activated GSR in BR-treated plants results in a greater wound-induced resistance to Botrytis cinerea. A combination of molecular genetics using BR signaling mutants and application of an activator of BR signaling, bikinin, confirms these results and places the chief point of BR-GSR interaction downstream of potential membrane receptor circuitry. These results support a multi-modular interaction between BRs and stress signaling, instrumental in customizing stimulus-specific responses in Arabidopsis. PMID- 27457994 TI - Wound signaling of regenerative cell reprogramming. AB - Plants are sessile organisms that must deal with various threats resulting in tissue damage, such as herbivore feeding, and physical wounding by wind, snow or crushing by animals. During wound healing, phytohormone crosstalk orchestrates cellular regeneration through the establishment of tissue-specific asymmetries. In turn, hormone-regulated transcription factors and their downstream targets coordinate cellular responses, including dedifferentiation, cell cycle reactivation and vascular regeneration. By comparing different examples of wound induced tissue regeneration in the model plant Arabidopsis thaliana, a number of key regulators of developmental plasticity of plant cells have been identified. We present the relevance of these findings and of the dynamic establishment of differential auxin gradients for cell reprogramming after wounding. PMID- 27457995 TI - Saponin determination, expression analysis and functional characterization of saponin biosynthetic genes in Chenopodium quinoa leaves. AB - Quinoa (Chenopodium quinoa Willd.) is a highly nutritious pseudocereal with an outstanding protein, vitamin, mineral and nutraceutical content. The leaves, flowers and seed coat of quinoa contain triterpenoid saponins, which impart bitterness to the grain and make them unpalatable without postharvest removal of the saponins. In this study, we quantified saponin content in quinoa leaves from Ecuadorian sweet and bitter genotypes and assessed the expression of saponin biosynthetic genes in leaf samples elicited with methyl jasmonate. We found saponin accumulation in leaves after MeJA treatment in both ecotypes tested. As no reference genes were available to perform qPCR in quinoa, we mined publicly available RNA-Seq data for orthologs of 22 genes known to be stably expressed in Arabidopsis thaliana using geNorm, NormFinder and BestKeeper algorithms. The quinoa ortholog of At2g28390 (Monensin Sensitivity 1, MON1) was stably expressed and chosen as a suitable reference gene for qPCR analysis. Candidate saponin biosynthesis genes were screened in the quinoa RNA-Seq data and subsequent functional characterization in yeast led to the identification of CqbAS1, CqCYP716A78 and CqCYP716A79. These genes were found to be induced by MeJA, suggesting this phytohormone might also modulate saponin biosynthesis in quinoa leaves. Knowledge of the saponin biosynthesis and its regulation in quinoa may aid the further development of sweet cultivars that do not require postharvest processing. PMID- 27457996 TI - Deciphering and modifying LAFL transcriptional regulatory network in seed for improving yield and quality of storage compounds. AB - Increasing yield and quality of seed storage compounds in a sustainable way is a key challenge for our societies. Genome-wide analyses conducted in both monocot and dicot angiosperms emphasized drastic transcriptional switches that occur during seed development. In Arabidopsis thaliana, a reference species, genetic and molecular analyses have demonstrated the key role of LAFL (LEC1, ABI3, FUS3, and LEC2) transcription factors (TFs), in controlling gene expression programs essential to accomplish seed maturation and the accumulation of storage compounds. Here, we summarize recent progress obtained in the characterization of these LAFL proteins, their regulation, partners and target genes. Moreover, we illustrate how these evolutionary conserved TFs can be used to engineer new crops with altered seed compositions and point out the current limitations. Last, we discuss about the interest of investigating further the environmental and epigenetic regulation of this network for the coming years. PMID- 27457997 TI - Identification of a peroxisomal-targeted aldolase involved in chlorophyll biosynthesis and sugar metabolism in rice. AB - Chlorophyll plays remarkable and critical roles in photosynthetic light harvesting, energy transduction and plant development. In this study, we identified a rice Chl-deficient mutant, ygdl-1 (yellow green and droopy leaf-1), which showed yellow-green leaves throughout plant development with decreased content of Chls and carotene and an increased Chl a/b ratio. The ygdl-1 mutant also exhibited severe defects in chloroplast development, including disorganized grana stacks. Sequence analysis revealed that the mutant contained a T-DNA insertion within the promoter of a fructose-1,6-bisphosphate aldolase (OsAld-Y), which dramatically reduced the OsAld-Y mRNA level, and its identity was verified by transgenic complementation. Real-time PCR analysis showed that the expression levels of genes associated with chlorophyll biosynthesis and chloroplast development were concurrently altered in the ygdl-1 mutant. The expression of OsAld-Y-GFP fusion protein in tobacco epidermal cells showed that OsAld-Y was localized to the peroxisome. In addition, the analysis of primary carbon metabolites revealed the significantly reduced levels of sucrose and fructose in the mutant leaves, while the glucose content was similar to wild-type plants. Our results suggest that the OsAld-Y participates in Chl accumulation, chloroplast development and plant growth by influencing the photosynthetic rate of leaves and the sugar metabolism of rice. PMID- 27457998 TI - Longer Paced QRS Duration is Associated With Increased Prevalence of Right Ventricular Pacing-Induced Cardiomyopathy. AB - INTRODUCTION: Pacing-induced cardiomyopathy (PICM) is an important cause of heart failure in patients exposed to frequent right ventricular (RV) pacing. While echocardiography is diagnostic, the optimal surveillance strategy remains unknown. We sought to identify clinical and electrocardiographic factors associated with the presence of PICM to guide further testing. METHODS AND RESULTS: We retrospectively studied 1,750 consecutive patients undergoing pacemaker implantation 2003-2012. Patients were included if baseline LVEF was normal, single chamber ventricular or dual chamber pacemaker (but not ICD or cardiac resynchronization therapy device) was implanted, frequent (>=20%) RV pacing was present and repeat echocardiogram was available following implantation. PICM was defined as >=10% decrease in LVEF, resulting in LVEF <50%. Patients with alternative causes of cardiomyopathy were excluded. Clinical and electrocardiographic indicators of PICM were identified using multivariate logistic regression. Of 184 patients meeting study criteria, 42 (22.8%) developed PICM, with decrease in mean LVEF from 62.1% to 35.3% over mean follow-up 2.5 years. Longer follow-up paced QRS duration was associated with the presence of PICM (multivariate odds ratio 1.34 per 10 millisecond increase, 95% CI 1.06-1.63, p = 0.01). Paced QRS duration >=150 milliseconds was 95% sensitive for PICM. Only half of patients with PICM had heart failure signs or symptoms at the time of echocardiographic diagnosis. CONCLUSION: Patients with frequent RV pacing and paced QRS duration >=150 milliseconds should be screened by echocardiogram to assess for PICM. Patients with paced QRS duration <150 milliseconds likely do not require screening, in the absence of heart failure signs or symptoms. PMID- 27457999 TI - Targeting GH-1 splicing as a novel pharmacological strategy for growth hormone deficiency type II. AB - Isolated growth hormone deficiency type II (IGHD II) is a rare genetic splicing disorder characterized by reduced growth hormone (GH) secretion and short stature. It is mainly caused by autosomal dominant-negative mutations within the growth hormone gene (GH-1) which results in missplicing at the mRNA level and the subsequent loss of exon 3, producing the 17.5-kDa GH isoform: a mutant and inactive GH protein that reduces the stability and the secretion of the 22-kDa GH isoform, the main biologically active GH form. At present, patients suffering from IGHD II are treated with daily injections of recombinant human GH (rhGH) in order to reach normal height. However, this type of replacement therapy, although effective in terms of growth, does not prevent the toxic effects of the 17.5-kDa mutant on the pituitary gland, which may eventually lead to other hormonal deficiencies. As the severity of the disease inversely correlates with the 17.5 kDa/22-kDa ratio, increasing the inclusion of exon 3 is expected to ameliorate disease symptoms. This review focuses on the recent advances in experimental and therapeutic strategies applicable to treat IGHD II in clinical and preclinical contexts. Several avenues for alternative IGHD II therapy will be discussed including the use of small interfering RNA (siRNA) and short hairpin RNA (shRNA) constructs that specifically target the exon 3-deleted transcripts as well as the application of histone deacetylase inhibitors (HDACi) and antisense oligonucleotides (AONs) to enhance full-length GH-1 transcription, correct GH-1 exon 3 splicing and manipulate GH pathway. PMID- 27458000 TI - Implementation of Sexually Transmitted Infection Interventions. AB - Although community-wide, multilevel interventions are widely regarded as the most effective method for addressing complex health issues such as sexually transmitted infections (STIs), there is a dearth of research about the implementation of interventions of this nature. The aim of this study was to determine the implementation of locally developed and evidence-based STI interventions across an urban community using the Institute of Medicine's intervention spectrum as a framework, to highlight collaborations, and to identify barriers to the implementation of community-wide, multilevel interventions. Semistructured interviews were conducted ( N = 20) with staff from schools, after-school programs, community organizations, and clinics in a Midwestern metropolitan area. Results indicate that interventions were implemented at all levels of the Institute of Medicine's intervention spectrum, although selective interventions that served a small number of youth were most common. Most interventions were locally developed or adapted from evidence-based programs. Despite reported collaboration between agencies, there was relatively little community-wide coordination of STI interventions due to factors such as community norms and competition for limited funding. These findings offer further insight into the gap between best practice recommendations and the implementation of community-wide, multilevel interventions. Implications for intervention development and implementation are discussed. PMID- 27458001 TI - How Do Stages of Change for Physical Activity Relate to Employee Sign-Up for and Completion of a Worksite Physical Activity Competition? AB - INTRODUCTION: This study evaluated whether stages of change for physical activity (PA) predict sign-up, participation, and completion in a PA competition. METHOD: Deidentified data were provided to evaluate a PA competition between 16 different institutions from a public university system. Employees who completed a health assessment (HA) prior to the start of the PA competition ( n = 6,333) were included in the study. Participants completed a self-report HA and logged their PA throughout the competition. Multivariable logistic regression models tested whether stages of change predicted PA competition sign-up and completion. An ordinal logistic regression model tested whether stages of change predicted number of weeks of PA competition participation. RESULTS: Stages of change predicted PA competition sign-up and completion, but not weeks of participation. The odds for PA competition sign-up were 1.64 and 1.98 times higher for employees in preparation and action/maintenance (respectively) compared with employees in precontemplation/contemplation. The odds for PA competition completion were 4.17 times higher for employees in action/maintenance compared with employees in precontemplation/contemplation/preparation. CONCLUSION: The PA competition was more likely to reach employees in preparation, action, or maintenance stages than precontemplation/contemplation. Most of the completers were likely participating in regular PA prior to the competition. PMID- 27458002 TI - Fine-needle aspiration cytology of a mammary myofibroblastoma: A case report on the role of immunohistochemistry and cell block preparations and a review of the literature. AB - Myofibroblastoma (MFB) is a benign tumor of the mammary stroma with predominant myofibroblastic differention. The cytologic reports of MFB are very few in the available literature. From the cytodiagnostic point of view about 21 cases of MFB with cytological evaluation by fine-needle aspiration cytology (FNAC) have been encountered in the English-language literature: A 35-year-old woman presented with lump in the left breast. FNAC showed mild degree of pleomorphism with occasional groups with fibrous stroma and tumoral cells. A few benign epithelial cell groups were seen. Hematoxylin-eosin-stained sections of cell block preparation from the aspirate showed fascicles of spindle cells forming whorl structures. Three months later, excision biopsy was performed. The diagnosis was a classic variant of MFB. On immunohistochemical examination, sections were found to be highly positive for vimentin, CD34, and bcl- 2. In light of these findings, cell block material was retrospectively reviewed both morphologically and immunhistochemically. The findings of resection and cell block material were found to be very similar. MFB may cause a potential diagnostic pitfall while interpreting FNAC due to its wide differential diagnosis spectrum. We concluded that cytology and cell block findings complement each other. Diagn. Cytopathol. 2016;44:1064-1069. (c) 2016 Wiley Periodicals, Inc. PMID- 27458003 TI - Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. AB - This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (>=grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (>=90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451. PMID- 27458005 TI - Inhibiting TLR9 and other UNC93B1-dependent TLRs paradoxically increases accumulation of MYD88L265P plasmablasts in vivo. AB - The MYD88(L265P) mutation is found in 2% to 10% of chronic lymphocytic leukemia, 29% of activated B-cell type diffuse large B-cell lymphoma and 90% of Waldenstrom macroglobulinemia, making it conceptually attractive to treat these malignancies with inhibitors of endosomal Toll-like receptors (TLR9, TLR7) that activate MYD88. Here we show that genetic inhibition of endosomal TLRs has the opposite effect on accumulation of MYD88(L265P) B cells in vitro and in vivo. Activated mature B cells from wild-type, Unc93b1(3d/3d)-mutant, or Tlr9-deficient mice were transduced with retrovirus encoding MYD88(L265P) and analyzed either in vitro or after transplantation into Rag1(-/-) recipient mice. Unc93b1(3d/3d) mutation, which blocks TLR9 and TLR7 signaling, or Tlr9 deficiency suppressed MYD88(L265P) B-cell growth in vitro but paradoxically increased in vivo accumulation of MYD88(L265P) B cells as CD19(low) plasmablasts by 10- to 100-fold. These results reveal an unexpected, powerful inhibitory effect of TLR9 on MYD88(L265P) B-cell proliferation and differentiation that appears independent of TLR7, and they provide a preclinical indicator for caution in clinical trials of TLR7/9 inhibitors for MYD88(L265P) B-cell malignancies. PMID- 27458004 TI - Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. AB - In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response. PMID- 27458006 TI - Cognitive Capitalism: Economic Freedom Moderates the Effects of Intellectual and Average Classes on Economic Productivity. AB - Cognitive ability stimulates economic productivity. However, the effects of cognitive ability may be stronger in free and open economies, where competition rewards merit and achievement. To test this hypothesis, ability levels of intellectual classes (top 5%) and average classes (country averages) were estimated using international student assessments (Programme for International Student Assessment; Trends in International Mathematics and Science Study; and Progress in International Reading Literacy Study) (N = 99 countries). The ability levels were correlated with indicators of economic freedom (Fraser Institute), scientific achievement (patent rates), innovation (Global Innovation Index), competitiveness (Global Competitiveness Index), and wealth (gross domestic product). Ability levels of intellectual and average classes strongly predicted all economic criteria. In addition, economic freedom moderated the effects of cognitive ability (for both classes), with stronger effects at higher levels of freedom. Effects were particularly robust for scientific achievements when the full range of freedom was analyzed. The results support cognitive capitalism theory: cognitive ability stimulates economic productivity, and its effects are enhanced by economic freedom. PMID- 27458008 TI - Genetics: Are circRNAs involved in cancer pathogenesis? PMID- 27458007 TI - Improving early diagnosis of symptomatic cancer. AB - Much time, effort and investment goes into the diagnosis of symptomatic cancer, with the expectation that this approach brings clinical benefits. This investment of resources has been particularly noticeable in the UK, which has, for several years, appeared near the bottom of international league tables for cancer survival in economically developed countries. In this Review, we examine expedited diagnosis of cancer from four perspectives. The first relates to the potential for clinical benefits of expedited diagnosis of symptomatic cancer. Limited evidence from clinical trials is available, but the considerable observational evidence suggests benefits can be obtained from this approach. The second perspective considers how expedited diagnosis can be achieved. We concentrate on data from the UK, where extensive awareness campaigns have been conducted, and initiatives in the primary-care setting, including clinical decision support, have all occurred during a period of considerable national policy change. The third section considers the most appropriate patients for cancer investigations, and the possible community settings for identification of such patients; UK national guidance for selection of patients for investigation is discussed. Finally, the health economics of expedited diagnosis are reviewed, although few studies provide definitive evidence on this topic. PMID- 27458009 TI - Haematological cancer: High-risk SMM - early action required. PMID- 27458010 TI - Isolated Unilateral Tongue Atrophy: A Possible Late Complication of Juxta Cephalic Radiation Therapy. AB - BACKGROUND Isolated unilateral hypoglossal nerve injury is extremely rare. It may be caused by radiation therapy targeting neoplasms of the cephalic region. CASE REPORT A 51-year-old man with synovial sarcoma of the left upper arm status post extensive radiation therapy in 1980 presented in late 2014 with gradual onset of speech difficulty and difficulty moving his tongue for a couple of weeks. Neurological examination revealed isolated left-sided unilateral tongue atrophy. Postradiation residual extensive cicatrix with erythema over the whole left upper extremity extending to the neck on the affected side was noticed. On head magnetic resonance imaging (MRI) before and after administration of gadolinium, he was found to have asymmetrically fatty striations, atrophy, and fibrosis in the left tongue consistent with radiation toxicity. The patient's tongue weakness persisted without improvement. CONCLUSIONS The diagnosis of unilateral hypoglossal nerve injury is usually difficult. Detailed neurological examinations and thorough investigations including head MRI are very helpful. Previous exposure to radiation therapy is a potential cause of hypoglossal nerve injury. To our knowledge, this is the first case report that presents isolated unilateral tongue atrophy as a late complication of juxta cephalic radiation therapy. PMID- 27458011 TI - Manganese-Substituted Polyoxometalate as an Effective Shuttle Redox Mediator in Z Scheme Water Splitting under Visible Light. AB - In the present study, a polyoxometalate is for the first time applied as a shuttle redox in two-step (Z-Scheme) photocatalytic water splitting. Photocatalytic H2 evolution using a Mn-substituted polyoxometalate [SiW11 O39 Mn(II) (H2 O)](6-) as an electron donor proceeded over a Ru-loaded SrTiO3 :Rh photocatalyst under visible light with relatively high selectivity, accompanied by the stoichiometric production of its oxidized form [SiW11 O39 Mn(III) (H2 O)](5-) . Photocatalytic O2 evolution using the oxidized [SiW11 O39 Mn(III) (H2 O)](5-) as an electron acceptor proceeded over PtOx -loaded WO3 photocatalyst under visible light with relatively high quantum efficiency and selectivity, whereas the loading of effective PtOx cocatalyst was necessary to facilitate the reduction of polyoxometalate. Finally, a two-step water splitting into H2 and O2 was demonstrated under visible light using the couple of Mn-substituted polyoxometalate as shuttle redox between Ru/SrTiO3 :Rh and PtOx /WO3 photocatalysts, under mildly acidic conditions with pH~4.5. PMID- 27458012 TI - Unusual records of deepwater teleosteans trawled off the western coast of Mexico. AB - The first records of three midwater species for the Mexican ichthyofauna (Holtbyrnia laticauda, Brama dussumieri and Cubiceps baxteri), caught off the coast of Baja California, Mexico, in mid 2014, are reported. As far as is known, they are the first verified specimens, geo-referenced and catalogued in a reference fish collection for the west coast of Mexico. The species' known distributions were extended northward in the eastern Pacific Ocean, ranging from 3495 to 8300 km. PMID- 27458013 TI - Mycotoxin Patulin Suppresses Innate Immune Responses by Mitochondrial Dysfunction and p62/Sequestosome-1-dependent Mitophagy. AB - Innate immune responses are important for pathogen elimination and adaptive immune response activation. However, excess inflammation may contribute to immunopathology and disease progression (e.g. inflammation-associated hepatocellular carcinoma). Immune modulation resulting from pattern recognition receptor-induced responses is a potential strategy for controlling immunopathology and related diseases. This study demonstrates that the mycotoxin patulin suppresses Toll-like receptor- and RIG-I/MAVS-dependent cytokine production through GSH depletion, mitochondrial dysfunction, the activation of p62-associated mitophagy, and p62-TRAF6 interaction. Blockade of autophagy restored the immunosuppressive activity of patulin, and pharmacological activation of p62-dependent mitophagy directly reduced RIG-I-like receptor dependent inflammatory cytokine production. These results demonstrated that p62 dependent mitophagy has an immunosuppressive role to innate immune response and might serve as a potential immunomodulatory target for inflammation-associated diseases. PMID- 27458014 TI - The Import of Proteins into the Mitochondrion of Toxoplasma gondii. AB - Outside of well characterized model eukaryotes, relatively little is known about the translocons that transport proteins across the two membranes that surround the mitochondrion. Apicomplexans are a phylum of intracellular parasites that cause major diseases in humans and animals and are evolutionarily distant from model eukaryotes such as yeast. Apicomplexans harbor a mitochondrion that is essential for parasite survival and is a validated drug target. Here, we demonstrate that the apicomplexan Toxoplasma gondii harbors homologues of proteins from all the major mitochondrial protein translocons present in yeast, suggesting these arose early in eukaryotic evolution. We demonstrate that a T. gondii homologue of Tom22 (TgTom22), a central component of the translocon of the outer mitochondrial membrane (TOM) complex, is essential for parasite survival, mitochondrial protein import, and assembly of the TOM complex. We also identify and characterize a T. gondii homologue of Tom7 (TgTom7) that is important for parasite survival and mitochondrial protein import. Contrary to the role of Tom7 in yeast, TgTom7 is important for TOM complex stability, suggesting the role of this protein has diverged during eukaryotic evolution. Together, our study identifies conserved and modified features of mitochondrial protein import in apicomplexan parasites. PMID- 27458015 TI - CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells. AB - High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 degrees C) and association (37 degrees C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [(3)H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD. PMID- 27458016 TI - Structural Basis of Host Autophagy-related Protein 8 (ATG8) Binding by the Irish Potato Famine Pathogen Effector Protein PexRD54. AB - Filamentous plant pathogens deliver effector proteins to host cells to promote infection. The Phytophthora infestans RXLR-type effector PexRD54 binds potato ATG8 via its ATG8 family-interacting motif (AIM) and perturbs host-selective autophagy. However, the structural basis of this interaction remains unknown. Here, we define the crystal structure of PexRD54, which includes a modular architecture, including five tandem repeat domains, with the AIM sequence presented at the disordered C terminus. To determine the interface between PexRD54 and ATG8, we solved the crystal structure of potato ATG8CL in complex with a peptide comprising the effector's AIM sequence, and we established a model of the full-length PexRD54-ATG8CL complex using small angle x-ray scattering. Structure-informed deletion of the PexRD54 tandem domains reveals retention of ATG8CL binding in vitro and in planta This study offers new insights into structure/function relationships of oomycete RXLR effectors and how these proteins engage with host cell targets to promote disease. PMID- 27458017 TI - Degradation of Glucan Primers in the Absence of Starch Synthase 4 Disrupts Starch Granule Initiation in Arabidopsis. AB - Arabidopsis leaf chloroplasts typically contain five to seven semicrystalline starch granules. It is not understood how the synthesis of each granule is initiated or how starch granule number is determined within each chloroplast. An Arabidopsis mutant lacking the glucosyl-transferase, STARCH SYNTHASE 4 (SS4) is impaired in its ability to initiate starch granules; its chloroplasts rarely contain more than one large granule, and the plants have a pale appearance and reduced growth. Here we report that the chloroplastic alpha-amylase AMY3, a starch-degrading enzyme, interferes with granule initiation in the ss4 mutant background. The amy3 single mutant is similar in phenotype to the wild type under normal growth conditions, with comparable numbers of starch granules per chloroplast. Interestingly, the ss4 mutant displays a pleiotropic reduction in the activity of AMY3. Remarkably, complete abolition of AMY3 (in the amy3 ss4 double mutant) increases the number of starch granules produced in each chloroplast, suppresses the pale phenotype of ss4, and nearly restores normal growth. The amy3 mutation also restores starch synthesis in the ss3 ss4 double mutant, which lacks STARCH SYNTHASE 3 (SS3) in addition to SS4. The ss3 ss4 line is unable to initiate any starch granules and is thus starchless. We suggest that SS4 plays a key role in granule initiation, allowing it to proceed in a way that avoids premature degradation of primers by starch hydrolases, such as AMY3. PMID- 27458018 TI - Amyloid-beta(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity. AB - The accumulation of amyloid beta peptide(1-42) (Abeta(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of Abeta(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. Abeta may be present in an aggregated form prior to cellular uptake. Alternatively, monomeric peptide may enter the endocytic pathway and conditions in the endocytic compartments may induce the aggregation process. Our study aims to answer the question whether aggregate formation is a prerequisite or a consequence of Abeta endocytosis. We visualized aggregate formation of fluorescently labeled Abeta(1 42) and tracked its internalization by human neuroblastoma cells and neurons. beta-Sheet-rich Abeta(1-42) aggregates entered the cells at low nanomolar concentration of Abeta(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed Abeta(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that Abeta(1-42) monomers bound rapidly to the plasma membrane and formed aggregates there. These structures were subsequently taken up and accumulated in endocytic vesicles. This process correlated with metabolic inhibition. Our data therefore imply that the formation of beta-sheet-rich aggregates is a prerequisite for Abeta(1-42) uptake and cytotoxicity. PMID- 27458019 TI - Presynaptic N-Methyl-d-aspartate (NMDA) Receptor Activity Is Increased Through Protein Kinase C in Paclitaxel-induced Neuropathic Pain. AB - Painful peripheral neuropathy is a severe adverse effect of chemotherapeutic drugs such as paclitaxel (Taxol). The glutamate N-methyl-d-aspartate receptors (NMDARs) are critically involved in the synaptic plasticity associated with neuropathic pain. However, paclitaxel treatment does not alter the postsynaptic NMDAR activity of spinal dorsal horn neurons. In this study, we determined whether paclitaxel affects presynaptic NMDAR activity by recording excitatory postsynaptic currents (EPSCs) of dorsal horn neurons in spinal cord slices. In paclitaxel-treated rats, the baseline frequency of miniature EPSCs (mEPSCs) was significantly increased; the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) completely normalized this frequency. Also, AP5 significantly reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation and reversed the reduction in the paired-pulse ratio of evoked EPSCs in paclitaxel-treated rats. Blocking GluN2A-containing, but not GluN2B-containing, NMDARs largely decreased the frequency of mEPSCs and the amplitude of evoked EPSCs of dorsal horn neurons in paclitaxel-treated rats. Furthermore, inhibition of protein kinase C fully reversed the increased frequency of mEPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats. Paclitaxel treatment significantly increased the protein level of GluN2A and phosphorylated GluN1 in the dorsal root ganglion. In addition, intrathecal injection of AP5 or systemic administration of memantine profoundly attenuated pain hypersensitivity induced by paclitaxel. Our findings indicate that paclitaxel treatment induces tonic activation of presynaptic NMDARs in the spinal cord through protein kinase C to potentiate nociceptive input from primary afferent nerves. Targeting presynaptic NMDARs at the spinal cord level may be an effective strategy for treating chemotherapy induced neuropathic pain. PMID- 27458020 TI - ATP/ADP Turnover and Import of Glycolytic ATP into Mitochondria in Cancer Cells Is Independent of the Adenine Nucleotide Translocator. AB - Non-proliferating cells oxidize respiratory substrates in mitochondria to generate a protonmotive force (Deltap) that drives ATP synthesis. The mitochondrial membrane potential (DeltaPsi), a component of Deltap, drives release of mitochondrial ATP(4-) in exchange for cytosolic ADP(3-) via the electrogenic adenine nucleotide translocator (ANT) located in the mitochondrial inner membrane, which leads to a high cytosolic ATP/ADP ratio up to >100-fold greater than matrix ATP/ADP. In rat hepatocytes, ANT inhibitors, bongkrekic acid (BA), and carboxyatractyloside (CAT), and the F1FO-ATP synthase inhibitor, oligomycin (OLIG), inhibited ureagenesis-induced respiration. However, in several cancer cell lines, OLIG but not BA and CAT inhibited respiration. In hepatocytes, respiratory inhibition did not collapse DeltaPsi until OLIG, BA, or CAT was added. Similarly, in cancer cells OLIG and 2-deoxyglucose, a glycolytic inhibitor, depolarized mitochondria after respiratory inhibition, which showed that mitochondrial hydrolysis of glycolytic ATP maintained DeltaPsi in the absence of respiration in all cell types studied. However in cancer cells, BA, CAT, and knockdown of the major ANT isoforms, ANT2 and ANT3, did not collapse DeltaPsi after respiratory inhibition. These findings indicated that ANT was not mediating mitochondrial ATP/ADP exchange in cancer cells [corrected]. We propose that suppression of ANT contributes to low cytosolic ATP/ADP, activation of glycolysis, and a Warburg metabolic phenotype in proliferating cells. PMID- 27458021 TI - The Roles of Puf6 and Loc1 in 60S Biogenesis Are Interdependent, and Both Are Required for Efficient Accommodation of Rpl43. AB - Puf6 and Loc1 have two important functional roles in the cells, asymmetric mRNA distribution and ribosome biogenesis. Puf6 and Loc1 are localized predominantly in the nucleolus. They bind ASH1 mRNA, repress its translation, and facilitate the transport to the daughter cells. Asymmetric mRNA distribution is important for cell differentiation. Besides their roles in mRNA localization, Puf6 and Loc1 have been shown to be involved in 60S biogenesis. In puf6Delta or loc1Delta cells, pre-rRNA processing and 60S export are impaired and 60S subunits are underaccumulated. The functional studies of Puf6 and Loc1 have been focused on ASH1 mRNA pathway, but their roles in 60S biogenesis are still not clear. In this study, we found that Puf6 and Loc1 interact directly with each other and both proteins interact with the ribosomal protein Rpl43 (L43e). Notably, the roles of Puf6 and Loc1 in 60S biogenesis are interdependent, and both are required for efficient accommodation of Rpl43. Loc1 is further required to maintain the protein level of Rpl43. Additionally, the recruitment of Rpl43 is required for the release of Puf6 and Loc1. We propose that Puf6 and Loc1 facilitate Rpl43 loading and are sequentially released from 60S after incorporation of Rpl43 into ribosomes in yeast. PMID- 27458022 TI - Structure engineering of filled protein microbeads to tailor release of oil droplets in gastric digestion. AB - Oil-soluble components can be encapsulated in an O/W1/W2 microsystem, in which they are dissolved in oil droplets dispersed in a gelled microbead (W1), which forms a barrier between the oil droplets and the aqueous continuous phase (W2). We investigated the rate and mechanism of breakdown of protein microbeads in a simulated gastric system, and studied the influence of microbead protein concentration, gelling method (cold-set, slow and fast heat-set), and further processing (freeze-drying), on the breakdown process. Breakdown rate decreased with increasing protein content of the beads, for the same method of production. Due to the porosity of the slowly-heated heat-set beads, breakdown occurred evenly throughout the entire bead. Cold-set microbeads of 10% protein broke down slightly slower than the heat-set microbeads of 15%. The denser surface of the 10% beads slowed down the diffusion of the enzymes into the bead's interior, causing the beads to be broken down from the outside inward. All these beads broke down within one hour. Increasing the rate of temperature increase during the heating step dramatically slowed breakdown. There was no significant breakdown of rapidly heated beads within 138 minutes, even though no difference in microstructure between rapidly and slowly heated beads was visible with electron microscopy. Freeze-drying of the beads also slowed their breakdown. After 132 minutes more than half the measured particle volume of were intact beads. Freeze-drying changed the microstructure of the beads irreversibly: rehydrating the dried beads did not result in a breakdown behaviour similar to that of unprocessed beads. PMID- 27458024 TI - Synthesis and Characterization of Hexagonal Boron Nitride as a Gate Dielectric. AB - Two different growth modes of large-area hexagonal boron nitride (h-BN) film, a conventional chemical vapor deposition (CVD) growth mode and a high-pressure CVD growth mode, were compared as a function of the precursor partial pressure. Conventional self-limited CVD growth was obtained below a critical partial pressure of the borazine precursor, whereas a thick h-BN layer (thicker than a critical thickness of 10 nm) was grown beyond a critical partial pressure. An interesting coincidence of a critical thickness of 10 nm was identified in both the CVD growth behavior and in the breakdown electric field strength and leakage current mechanism, indicating that the electrical properties of the CVD h-BN film depended significantly on the film growth mode and the resultant film quality. PMID- 27458023 TI - Manic symptom severity correlates with COMT activity in the striatum: A post mortem study. AB - OBJECTIVES: The enzyme catechol-O-methyltransferase (COMT), which catalyses the degradation of dopamine and norepinephrine, is posited to participate in the pathophysiology of bipolar disorder (BD) and schizophrenia. In support of this notion, rich evidence has documented that the severity of various BD and schizophrenia symptoms is moderated by rs4680, a single nucleotide polymorphism of the COMT gene featuring a valine (Val)-to-methionine (Met) substitution that results in lower catalytic activity. Nevertheless, the specific relevance of COMT enzymatic activity in the pathophysiology of BD and schizophrenia dimensions remains elusive. METHODS: We measured COMT catalytic activity in post-mortem prefrontal cortices, striata and cerebella of schizophrenia and BD patients, as well as non-affected controls. These values were then correlated with rs4680 genotypes and psychopathology scores in the last week of life. RESULTS: No direct correlation between COMT activity and rs4680 genotypes was found; however, the severity of manic symptoms was highly correlated with COMT activity in the striatum, irrespective of the diagnostic group. CONCLUSIONS: These results suggest that COMT striatal activity, but not rs4680 genotype, may serve as a biomarker for manic symptoms. Future studies are warranted to confirm these findings and assess the neurobiological links between COMT striatal activity and manic symptoms. PMID- 27458025 TI - The right temporoparietal junction encodes efforts of others during action observation. AB - Smooth social interactions require a deep understanding of others' intentions and feelings. In the present study, to investigate brain regions that respond to inference of others' effort level, we recorded brain activity during action observation of different effort levels using functional magnetic resonance imaging (fMRI). We used a dumbbell curl movement to depict a movement requiring effort. To dissociate the factors of effort level of the actor and weight of the dumbbell, we used four combinations of dumbbell weight and actor physique: a thin actor or a built actor lifting a heavy or light dumbbell. During observation of dumbbell curls, the bilateral front-parietal action observation network (AON) was activated. This included the premotor cortices, parietal cortices, visual areas 5/superior temporal cortices (STS), amygdalae, hippocampi, right dorsolateral and ventrolateral frontal cortices. When we evaluated brain regions associated with the actor's effort level, activity in the right temporoparietal junction (TPJ) and STS was observed. However, activity in the front-parietal AON was independent of the actor's effort during action observation. This finding suggests that the right TPJ and STS play an important role in the inference of others' effort levels during the observation of others' movements. PMID- 27458026 TI - Baseline Predictors of Treatment Outcomes in Children With Multidrug-Resistant Tuberculosis: A Retrospective Cohort Study. AB - BACKGROUND: Globally, >30 000 children fall sick with multidrug-resistant (MDR) tuberculosis every year. Without robust pediatric data, clinical management follows international guidelines that are based on studies in adults and expert opinion. We aimed to identify baseline predictors of death, treatment failure, and loss to follow-up among children with MDR tuberculosis disease treated with regimens tailored to their drug susceptibility test (DST) result or to the DST result of a source case. METHODS: This retrospective cohort study included all children <=15 years old with confirmed and probable MDR tuberculosis disease who began tailored regimens in Lima, Peru, between 2005 and 2009. Using logistic regression, we examined associations between baseline patient and treatment characteristics and (1) death or treatment failure and (2) loss to follow-up. RESULTS: Two hundred eleven of 232 (90.9%) children had known treatment outcomes, of whom 163 (77.2%) achieved cure or probable cure, 29 (13.7%) were lost to follow-up, 10 (4.7%) experienced treatment failure, and 9 (4.3%) died. Independent baseline predictors of death or treatment failure were the presence of severe disease (adjusted odds ratio [aOR], 4.96; 95% confidence interval [CI], 1.61-15.26) and z score <=-1 (aOR, 3.39; 95% CI, 1.20-9.54). We did not identify any independent predictors of loss to follow-up. CONCLUSIONS: High cure rates can be achieved in children with MDR tuberculosis using tailored regimens containing second-line drugs. However, children faced significantly higher risk of death or treatment failure if they had severe disease or were underweight. These findings highlight the need for early interventions that can improve treatment outcomes for children with MDR tuberculosis. PMID- 27458027 TI - PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET. AB - The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pair is a major immune checkpoint pathway exploited by cancer cells to develop and maintain immune tolerance. With recent approvals of anti-PD-1 and anti-PD-L1 therapeutic antibodies, there is an urgent need for noninvasive detection methods to quantify dynamic PD-L1 expression in tumors and to evaluate the tumor response to immune modulation therapies. To address this need, we assessed [(64)Cu]atezolizumab for the detection of PD-L1 expression in tumors. Atezolizumab (MPDL3208A) is a humanized, human and mouse cross-reactive, therapeutic PD-L1 antibody that is being investigated in several cancers. Atezolizumab was conjugated with DOTAGA and radiolabeled with copper-64. The resulting [(64)Cu]atezolizumab was assessed for in vitro and in vivo specificity in multiple cell lines and tumors of variable PD-L1 expression. We performed PET CT imaging, biodistribution, and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-hPD-L1) and in controls (CHO). Specificity of [(64)Cu]atezolizumab was further confirmed in orthotopic tumor models of human breast cancer (MDAMB231 and SUM149) and in a syngeneic mouse mammary carcinoma model (4T1). We observed specific binding of [(64)Cu]atezolizumab to tumor cells in vitro, correlating with PD-L1 expression levels. Specific accumulation of [(64)Cu]atezolizumab was also observed in tumors with high PD-L1 expression (CHO hPD-L1 and MDAMB231) compared to tumors with low PD-L1 expression (CHO, SUM149). Collectively, these studies demonstrate the feasibility of using [(64)Cu]atezolizumab for the detection of PD-L1 expression in different tumor types. PMID- 27458028 TI - Using CRISPR-Cas9 to quantify the contributions of O-glycans, N-glycans and Glycosphingolipids to human leukocyte-endothelium adhesion. AB - There is often interest in dissecting the relative contributions of the N glycans, O-glycans and glycosphingolipids (GSLs) in regulating complex biological traits like cell signaling, adhesion, development and metastasis. To address this, we developed a CRISPR-Cas9 toolkit to selectively truncate each of these commonly expressed glycan-types. Here, O-glycan biosynthesis was truncated by knocking-out Core 1 beta3Gal-T Specific Molecular Chaperone (COSMC), N-glycans by targeting the beta1,2 GlcNAc-transferase (MGAT1) and GSLs by deleting UDP-glucose ceramide glucosyltransferase (UGCG). These reagents were applied to reveal the glycoconjugates regulating human myeloid cell adhesion to selectins under physiological shear-flow observed during inflammation. These functional studies show that leukocyte rolling on P- and L-selectin is ablated in cells lacking O glycans, with N-glycan truncation also increasing cell rolling velocity on L selectin. All three glycan families contributed to E-selectin dependent cell adhesion with N-glycans contributing to all aspects of the leukocyte adhesion cascade, O-glycans only being important during initial recruitment, and GSLs stabilizing slow cell rolling and the transition to firm arrest. Overall, the genome editing tools developed here may be broadly applied in studies of cellular glycosylation. PMID- 27458030 TI - Cutaneous lupus erythematosus induced by golimumab therapy. PMID- 27458029 TI - Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development. AB - Histone deacetylases (HDACs) catalyze the removal of acetyl molecules from histone and non-histone substrates playing important roles in chromatin remodeling and control of gene expression. Class I HDAC1 is a critical regulator of cell cycle progression, cellular proliferation and differentiation during development; it is also regulated by many post-translational modifications (PTMs). Herein we characterize a new mitosis-specific phosphorylation of HDAC1 driven by Aurora kinases A and B. We show that this phosphorylation affects HDAC1 enzymatic activity and it is critical for the maintenance of a proper proliferative and developmental plan in a complex organism. Notably, we find that Aurora-dependent phosphorylation of HDAC1 regulates histone acetylation by modulating the expression of genes directly involved in the developing zebrafish central nervous system. Our data represent a step towards the comprehension of HDAC1 regulation by its PTM code, with important implications in unravelling its roles both in physiology and pathology. PMID- 27458031 TI - Hard and soft tissue changes following alveolar ridge preservation: a systematic review. AB - OBJECTIVE: Two focused questions were addressed within this systematic review. Q1) What is the effect of alveolar ridge preservation on linear and volumetric alveolar site dimensions, keratinised measurements, histological characteristics and patient-based outcomes when compared to unassisted socket healing. Q2) What is the size effect of these outcomes in three different types of intervention (guided bone regeneration, socket grafting and socket seal). MATERIALS AND METHODS: An electronic search (MEDLINE, EMBASE, Cochrane Central Register LILACS, Web of Science) and hand-search was conducted up to June 2015. Randomised controlled trials (RCT) and controlled clinical trials (CCT); with unassisted socket healing as controls: were eligible in the analysis for Q1. RCTs, CCTs and large prospective case series with or without an unassisted socket healing as control group were eligible in the analysis for Q2. RESULTS: Nine papers (8 RCTs and 1 CCTs) were included in the analysis for Q1 and 37 papers (29 RCTs, 7 CCTs and 1 case series) for Q2. The risk for bias was unclear or high in most of the studies. Q1: the standardised mean difference (SMD) in vertical mid-buccal bone height between ARP and a non-treated site was 0.739 mm (95% CI: 0.332 to 1.147). The SMD when proximal vertical bone height and horizontal bone width was compared was 0.796mm (95% CI: -1.228 to 0.364) and 1.198 mm (95% CI: -0.0374 to 2.433). Examination of ARP sites revealed significant variation in vital and trabecular bone percentages and keratinised tissue width and thickness. Adverse events were routinely reported, with three papers reporting a high level of complications in the test and control groups and two papers reporting greater risks associated with ARP. No studies reported on variables associated with the patient experience in either the test or the control group. Q2: A pooled effect reduction (PER) in mid-buccal alveolar ridge height of -0.467 mm (95% CI: -0.866 to -0.069) was recorded for GBR procedures and -0.157 mm (95% CI: -0.554 to 0.239) for socket grafting. A proximal vertical bone height reduction of -0.356 mm (95% CI: -0.490 to -0.222) was recorded for GBR, with a horizontal dimensional reduction of -1.45 mm (95% CI: -1.892 to -1.008) measured following GBR and -1.613 mm (95% CI: 1.989 to -1.238) for socket grafting procedures. Five papers reported on histological findings after ARP. Two papers indicated an increase in the width of the keratinised tissue following GBR, with two papers reporting a reduction in the thickness of the keratinised tissue following GBR. Histological examination revealed extensive variations in the treatment protocols and biomaterials materials used to evaluate extraction socket healing. GBR studies reported a variation in total bone formation of 47.9 +/- 9.1% to 24.67 +/- 15.92%. Post operative complications were reported by 29 papers, with the most common findings soft tissue inflammation and infection. CONCLUSION: ARP results in a significant reduction in the vertical bone dimensional change following tooth extraction when compared to unassisted socket healing. The reduction in horizontal alveolar bone dimensional change was found to be variable. No evidence was identified to clearly indicate the superior impact of a type of ARP intervention (GBR, socket filler and socket seal) on bone dimensional preservation, bone formation, keratinised tissue dimensions and patient complications. PMID- 27458032 TI - Commentary: Basic Research in HIV Vaccinology Is Hampered by Reductionist Thinking. PMID- 27458033 TI - Induction of PSMA and Internalization of an Anti-PSMA mAb in the Vascular Compartment. AB - : Angiogenesis is critical for tumor growth and survival and involves interactions between cancer and endothelial cells. Prostate-specific membrane antigen (PSMA/FOLH1) is expressed in the neovasculature of several types of cancer. However, the study of neovascular PSMA expression has been impeded as human umbilical vein endothelial cell (HUVEC) cultures are PSMA-negative and both tumor xenografts and patient-derived xenograft (PDX) models are not known to express PSMA in their vasculature. Therefore, PSMA expression was examined in HUVECs, in vitro and in vivo, and we tested the hypothesis that cancer cell-HUVEC crosstalk could induce the expression of PSMA in HUVECs. Interestingly, conditioned media from several cancer cell lines induced PSMA expression in HUVECs, in vitro, and these lines induced PSMA, in vivo, in a HUVEC coimplantation mouse model. Furthermore, HUVECs in which PSMA expression was induced were able to internalize J591, a mAb that recognizes an extracellular epitope of PSMA as well as nanoparticles bearing a PSMA-binding ligand/inhibitor. These findings offer new avenues to study the molecular mechanism responsible for tumor cell induction of PSMA in neovasculature as well as the biological role of PSMA in neovasculature. Finally, these data suggest that PSMA-targeted therapies could synergize with antiangiogenic and/or other antitumor agents and provide a promising model system to test therapeutic modalities that target PSMA in these settings. IMPLICATIONS: Cancer cells are able to induce PSMA expression in HUVECs, in vitro and in vivo, allowing internalization of PSMA-specific mAbs and nanoparticles bearing a PSMA-binding ligand/inhibitor. Mol Cancer Res; 14(11); 1045-53. (c)2016 AACR. PMID- 27458034 TI - Entanglement as a resource to distinguish orthogonal product states. AB - It is known that there are many sets of orthogonal product states which cannot be distinguished perfectly by local operations and classical communication (LOCC). However, these discussions have left the following open question: What entanglement resources are necessary and/or sufficient for this task to be possible with LOCC? In m ? n, certain classes of unextendible product bases (UPB) which can be distinguished perfectly using entanglement as a resource, had been presented in 2008. In this paper, we present protocols which use entanglement more efficiently than teleportation to distinguish some classes of orthogonal product states in m ? n, which are not UPB. For the open question, our results offer rather general insight into why entanglement is useful for such tasks, and present a better understanding of the relationship between entanglement and nonlocality. PMID- 27458035 TI - The Roles of Histone Demethylase UTX and JMJD3 (KDM6B) in Cancers: Current Progress and Future Perspectives. AB - Aberrant epigenetic reprogramming occurs frequently in the development of tumors. Histone H3 lysine 27 trimethylation (H3K27me3) exerts a repressive epigenetic mark on a large number of genes. UTX and JMJD3 are the only two histone demethylases which activate gene expression via demethylating H3K27me3 to H3K27me2 or H3K27me1. Current studies show that dysregulation of these two proteins are heavily linked to oncogenesis in various tissue types. Accumulating evidence suggested that there is remarkable therapeutic potential of targeting JMJD3 or UTX in different types of cancer. Herein, we shall give a brief review on the functional roles of JMJD3 and UTX in cancers and evaluate the available compounds and agents targeting UTX and JMJD3. Finally, we also discuss the several modalities that target UTX and JMJD3 for cancer therapy. This review will help to develop novel strategies to abolish or restore effects of UTX and JMJD3 in the pathogenesis of cancer. PMID- 27458036 TI - Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme. AB - The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs. The present review focuses on the role of XOR as a drug-metabolizing enzyme, specifically for drugs with anticancer, antimicrobial, antiviral, immunosuppressive or vasodilator activities, as well as drugs acting on metabolism or inducing XOR expression. XOR has an activating role that is essential to the pharmacological action of quinone drugs, cyadox, antiviral nucleoside analogues, allopurinol, nitrate and nitrite. XOR activity has a degradation function toward thiopurine nucleotides, pyrazinoic acid, methylxanthines and tolbutamide, whose half-life may be prolonged by the use of XOR inhibitors. In conclusion, to avoid potential drug interaction risks, such as a toxic excess of drug bioavailability or a loss of drug efficacy, caution is suggested in the use of XOR inhibitors, as in the case of hyperuricemic patients affected by gout or tumor lysis syndrome, when it is necessary to simultaneously administer therapeutic substances that are activated or degraded by the drug metabolizing activity of XOR. PMID- 27458037 TI - Cryptococcosis in Acquired Immunodeficiency Syndrome Patients Clinically Confirmed and/or Diagnosed at Necropsy in a Teaching Hospital in Brazil. AB - Cryptococcosis occurs in acquired immunodeficiency syndrome (AIDS) patients with poor compliance to antiretroviral therapy or unaware of their human immunodeficiency virus status who present severe immunosuppression at admission. Consequently, high mortality rates are observed due to disseminated fungal infection. This report presents clinical and postmortem data of AIDS patients with cryptococcosis in a teaching hospital in Brazil. Retrospectively, medical and necropsy records of AIDS patients with cryptococcosis clinically confirmed and/or postmortem verified were reviewed. Clinical data were compared with those of patients presenting a good outcome to evaluate disseminated fungal infection and the agreement between clinical and postmortem diagnosis. At admission, most of the 45 patients with cryptococcal meningitis who died, presented more altered consciousness (P = 0.0047), intracranial increased pressure (P = 0.047), and severe malnutrition (P = 0.0006) than the survivors. Of 29 (64.4%) patients with cryptococcal meningitis, 23 died before week 2 on antifungal therapy, and the other six during the next 3 months. The remaining 16 (35.6%) cases had other diagnoses and died soon after. At necropsy, 31 (68.9%) presented disseminated infection involving two or more organs, whereas 14 (31.1%) cases had meningeal or pulmonary localized infection. The agreement of 64.4% between clinical and postmortem diagnosis was similar to some studies. However, other reports have shown figures ranging from 34% to 95%. Currently, a progressive worldwide decrease of autopsies is worrying because the role of postmortem examination is pivotal to verify or identify the death causes, which contributes to improve the quality of clinical diagnosis and medical training. PMID- 27458038 TI - An Outbreak of Fearsome Photos and Headlines: Ebola and Local Newspapers in West Africa. PMID- 27458039 TI - Changes in Health-Seeking Behavior Did Not Result in Increased All-Cause Mortality During the Ebola Outbreak in Western Area, Sierra Leone. AB - Little is known about the residual effects of the west African Ebola virus disease (Ebola) epidemic on non-Ebola mortality and health-seeking behavior in Sierra Leone. We conducted a retrospective household survey to estimate mortality and describe health-seeking behavior in Western Area, Sierra Leone, between May 25, 2014, and February 16, 2015. We used two-stage cluster sampling, selected 30 geographical sectors with probability proportional to population size, and sampled 30 households per sector. Survey teams conducted face-to-face interviews and collected information on mortality and health-seeking behavior. We calculated all-cause and Ebola-specific mortality rates and compared health-seeking behavior before and during the Ebola epidemic using chi2 and Fisher's exact tests. Ninety six deaths, 39 due to Ebola, were reported in 898 households. All-cause and Ebola specific mortality rates were 0.52 (95% confidence interval [CI] = 0.29-0.76) and 0.19 (95% CI = 0.01-0.38) per 10,000 inhabitants per day, respectively. Of those households that reported a sick family member during the month before the survey, 86% (73/85) sought care at a health facility before the epidemic, compared with 58% (50/86) in February 2015 (P = 0.013). Reported self-medication increased from 4% (3/85) before the epidemic to 23% (20/86) during the epidemic (P = 0.013). Underutilization of health services and increased self-medication did not show a demonstrable effect on non-Ebola-related mortality. Nevertheless, the residual effects of outbreaks need to be taken into account for the future. Recovery efforts should focus on rebuilding both the formalized health system and the population's trust in it. PMID- 27458040 TI - A Case of Scrub Typhus Complicated by Adult Respiratory Distress Syndrome and Successful Management with Extracorporeal Membrane Oxygenation. AB - A 67-year-old woman was diagnosed as having scrub typhus with pneumonitis. On admission, she was started on a combination therapy with levofloxacin and doxycycline. However, the patient developed severe acute respiratory distress syndrome (ARDS) on the 2nd day, and as a result, she underwent extracorporeal membrane oxygenation (ECMO). She was weaned from ECMO on the 10th day, as her respiratory status gradually improved. She was discharged without sequelae on the 23rd day. The outcome suggests that the use of ECMO should be considered for patients with ARDS induced from scrub typhus. PMID- 27458041 TI - Agreement Between the Douleur Neuropathique in 4 Questions and Leeds Assessment of Neuropathic Symptoms and Signs Questionnaires to Classify Neuropathic Pain Among Patients with Leprosy. AB - Neuropathic pain (NP) often occurs during the course of leprosy, and screening tools to differentiate NP from non-NP are often used. However, their performance varies in different settings. The most frequently used scales are the Douleur Neuropathique in 4 questions (DN4) and the Leeds assessment of neuropathic symptoms and signs (LANSS) questionnaires. Thus, we conducted a study to evaluate the agreement between DN4 and LANSS questionnaires to classify NP in 195 leprosy patients attending two reference centers in Sergipe, Brazil. The DN4 and LANSS classified 166 and 110 patients, respectively, as having NP. One hundred and seven (54.8%) were classified as NP by both questionnaires; 59 (30.2%) solely by the DN4 questionnaire and three (1.5%) solely by the LANSS. The agreement of the questionnaires was 66.2% (weak agreement, Kappa = 0.30). Although both questionnaires identified a high proportion of NP, the development of more robust instruments is necessary to ensure the accuracy of diagnosis of leprosy patients classified as having NP. PMID- 27458042 TI - Assessing Latrine Use in Rural India: A Cross-Sectional Study Comparing Reported Use and Passive Latrine Use Monitors. AB - Although large-scale programs, like India's Total Sanitation Campaign (TSC), have improved latrine coverage in rural settings, evidence suggests that actual use is suboptimal. However, the reliability of methods to assess latrine use is uncertain. We assessed the reliability of reported use, the standard method, by comparing survey-based responses against passive latrine use monitors (PLUMs) through a cross-sectional study among 292 households in 25 villages in rural Odisha, India, which recently received individual household latrines under the TSC. PLUMs were installed for 2 weeks and householders responded to surveys about their latrine use behavior. Reported use was compared with PLUM results using Bland-Altman (BA) plots and concordance statistics. Reported use was higher than corresponding PLUM-recorded events across the range of comparisons. The mean reported "usual" daily events per household (7.09, 95% confidence interval [CI] = 6.51, 7.68) was nearly twice that of the PLUM-recorded daily average (3.62, 95% CI = 3.29, 3.94). There was poor agreement between "usual" daily latrine use and the average daily PLUM-recorded events (rhoc = 0.331, 95% CI = 0.242, 0.427). Moderate agreement (rhoc = 0.598, 95% CI = 0.497, 0.683) was obtained when comparing daily reported use during the previous 48 hours with the average daily PLUM count. Reported latrine use, though already suggesting suboptimal adoption, likely exaggerates the actual level of uptake of latrines constructed under the program. Where reliance on self-reports is used, survey questions should focus on the 48 hours prior to the date of the survey rather than asking about "usual" latrine use behavior. PMID- 27458044 TI - Considerations for the Assessment of Salt Intake by Urinary Sodium Excretion in Hypertensive Patients. PMID- 27458045 TI - Cation Intercalation in Manganese Oxide Nanosheets: Effects on Lithium and Sodium Storage. AB - The rapid development of advanced energy-storage devices requires significant improvements of the electrode performance and a detailed understanding of the fundamental energy-storage processes. In this work, the self-assembly of two dimensional manganese oxide nanosheets with various metal cations is introduced as a general and effective method for the incorporation of different guest cations and the formation of sandwich structures with tunable interlayer distances, leading to the formation of 3D Mx MnO2 (M=Li, Na, K, Co, and Mg) cathodes. For sodium and lithium storage, these electrode materials exhibited different capacities and cycling stabilities. The efficiency of the storage process is influenced not only by the interlayer spacing but also by the interaction between the host cations and shutter ions, confirming the crucial role of the cations. These results provide promising ideas for the rational design of advanced electrodes for Li and Na storage. PMID- 27458046 TI - Multifocal tuberculous osteomyelitis in a 3-year-old child. AB - Multifocal skeletal tuberculosis accounts for less than 1% of all tuberculous lesions in children. A 3-year-old unimmunised child presented with painless symmetrical swelling of both arms, pallor and hepatosplenomegaly. A skeletal survey demonstrated lytic lesions of the metadiaphysis of both humeri, a rib and the sacrum. The possibility of Langerhans cell histiocytosis or multifocal fibrous dysplasia was considered; however, acid-fast bacilli were detected in the biopsy specimen and real-time polymerase chain reaction confirmed Mycobacterium tuberculosis infection. Culture for M. tuberculosis was negative. The patient responded to anti-tuberculous therapy. PMID- 27458047 TI - ICRF-193, an anticancer topoisomerase II inhibitor, induces arched telophase spindles that snap, leading to a ploidy increase in fission yeast. AB - ICRF-193 [meso-4,4-(2,3-butanediyl)-bis(2,6-piperazinedione)] is a complex stabilizing inhibitor of DNA topoisomerase II (topo II) that is used as an effective anticancer drug. ICRF-193 inhibits topo II catalytic activity in vitro and blocks nuclear division in vivo. Here, we examined the effects of ICRF-193 treatment on chromatin behavior and spindle dynamics using detailed live mitotic cell analysis in the fission yeast, Schizosaccharomyces pombe. Time-lapse movie analysis showed that ICRF-193 treatment leads to an elongation of presumed chromatin fibers connected to kinetochores during mid-mitosis. Anaphase spindles begin to arch, and eventually spindle poles come together abruptly, as if the spindle snapped at the point of spindle microtubule overlap in telophase. Segregating chromosomes appeared as elastic clumps and subsequently pulled back and merged. The snapped spindle phenotype was abolished by microtubule destabilization after thiabendazole treatment, accompanied by unequal chromosome segregation or severe defects in spindle extension. Thus, we conclude that ICRF 193-treated, unseparated sister chromatids pulling toward opposite spindle poles produce the arched and snapped telophase spindle. ICRF-193 treatment increased DNA content, suggesting that the failure of sister chromatids to separate properly in anaphase, causes the spindle to break in telophase, resulting in polyploidization. PMID- 27458048 TI - Octadecylsilane/Nylon-6 composite as a thin-film microextraction sorbent for the determination of bisphenol A in water samples. AB - We report on the fabrication of a thin-film composite for the extraction of bisphenol A from aqueous solutions. Nylon-6, C18 particles, and polyethylene glycol were used to prepare the thin film sorbent. Bisphenol A was used as a model compound to evaluate the extraction efficiency of the sorbent. High performance liquid chromatography with UV detection was used for the analysis. The extraction yield of the sorbent was compared with other thin films fabricated using different sorbents including nanoclay, LiChrolut EN, and multiwalled carbon nanotubes. Experimental parameters affecting the extraction performance (extraction time, desorption condition, sample stirring, and ionic strength of the sample solution) were investigated. The detection limit and the dynamic range of the method were 0.05 and 0.15-50 MUg/L, respectively. The relative standard deviation of the method at two concentration levels (0.5 and 20 MUg/L) was less than 7.2%. Finally, a polycarbonate baby bottle, river water, and wastewater samples were analyzed by the method. PMID- 27458049 TI - Two cases of erosive oral lichen planus with autoantibodies to desmoglein 3. AB - Oral lichen planus (OLP) is a chronic inflammatory disorder of the oral mucosa of unknown etiology. Clinically, the erosive type of OLP (erosive OLP) can show features similar to those of pemphigus vulgaris (PV), an autoimmune blistering disorder in which desmoglein (Dsg)3 is targeted. In addition to clinical and histopathological findings, immunological studies, including direct immunofluorescence (IF), indirect IF and enzyme-linked immunosorbent assay (ELISA) that detect autoantibodies to Dsg3, are helpful in differentiating erosive OLP from PV. Here, we show two cases of erosive OLP with autoantibodies to Dsg3. Patient 1 was a 68-year-old woman with chronic erosions of the oral mucosa, in which elevated levels of immunoglobulin (Ig)G autoantibodies to Dsg1 and Dsg3 were detected by ELISA. Patient 2 was an 85-year-old woman with white striae with erosions on the lateral sides of the buccal mucosa with elevated levels of IgG autoantibodies to Dsg3 detected by ELISA. Histopathological findings from both cases showed lichenoid dermatitis, and both direct and indirect IF showed no tissue-bound IgG autoantibodies. From these findings, the diagnosis of erosive OLP was made. Immunological assays revealed both cases to have IgG-directing calcium-independent linear epitopes on Dsg3, which are suggestive of non-pathogenic autoantibodies. In addition, autoantibodies to Dsg3 in patient 2 reacted with a prosequence-possessing precursor form of Dsg3 but not with the mature form of the molecule. The present study suggests that erosive OLP may develop anti-Dsg3 autoantibodies, which should be carefully assessed. PMID- 27458050 TI - Physics of Fluid Transport in Hybrid Biporous Capillary Wicking Microstructures. AB - The mass transport capacity (i.e., the capillary limit,) of homogeneous wicks is limited by the inverse relation between the capillary pressure and permeability. Hybrid wicks with two or more distinct pore sizes have been proposed as alternative geometries to enhance the capillary limit. In this study, the impact of the two hybridization schemes-in-plane and out-of-plane-on the capillary transport of hybrid wicks is studied. Experimental data from in-plane hybrid wicks in conjunction with a theoretical model show that local changes in the curvature of the liquid-vapor meniscus (i.e., pore size) do not result in a higher mass flow rate than that of a comparable homogeneous wick. Instead, a global change in the curvature of the liquid-vapor meniscus (as occurring in out of-plane hybrid wicks) is necessary for obtaining mass flow rates greater than that of a homogeneous wick. Therefore, the physics of capillary limit and dryout in out-of-plane hybrid wicks is investigated using a hybrid wick consisting of a 1-MUm-thick highly porous mesh suspended over a homogeneous array of micropillars. A study of the dryout process within the structure revealed that the presence of the mesh strongly alters the dryout mechanism. Visualization studies showed that out-of-plane hybrid wicks remain operational only as long as the liquid is constrained within the mesh pores; recession of the meniscus just below the mesh results in instantaneous local dryout. To maintain liquid within the mesh structure, the mesh thickness was increased, and it was determined that the mesh thickness plays the key role in the performance of an out-of-plane hybrid wick. PMID- 27458051 TI - Mitochondrial Mg(2+) homeostasis decides cellular energy metabolism and vulnerability to stress. AB - Cellular energy production processes are composed of many Mg(2+) dependent enzymatic reactions. In fact, dysregulation of Mg(2+) homeostasis is involved in various cellular malfunctions and diseases. Recently, mitochondria, energy producing organelles, have been known as major intracellular Mg(2+) stores. Several biological stimuli alter mitochondrial Mg(2+) concentration by intracellular redistribution. However, in living cells, whether mitochondrial Mg(2+) alteration affect cellular energy metabolism remains unclear. Mg(2+) transporter of mitochondrial inner membrane MRS2 is an essential component of mitochondrial Mg(2+) uptake system. Here, we comprehensively analyzed intracellular Mg(2+) levels and energy metabolism in Mrs2 knockdown (KD) cells using fluorescence imaging and metabolome analysis. Dysregulation of mitochondrial Mg(2+) homeostasis disrupted ATP production via shift of mitochondrial energy metabolism and morphology. Moreover, Mrs2 KD sensitized cellular tolerance against cellular stress. These results indicate regulation of mitochondrial Mg(2+) via MRS2 critically decides cellular energy status and cell vulnerability via regulation of mitochondrial Mg(2+) level in response to physiological stimuli. PMID- 27458053 TI - Experimental analysis of radiographer exposure to the static field from a 1.5-T magnetic resonance imaging machine. AB - INTRODUCTION: This study measures the exposure of occupational therapists from a 1.5-T magnetic resonance imaging (MRI) machine. METHOD: A total of 14 time-series on each of the chest, head and hand were taken before and after different MRI procedures. The peak values were noted in each case together with an average of all data recorded in the time-series. RESULTS: The highest exposure recorded was observed on the hand, followed by the head and the chest. The overall maximum exposure (1479.40 mT) recorded was observed on the hand during a change of coil. It was also observed that the recorded exposure of experienced radiographers working in the MRI environment was less than that of junior staff due to different practices. CONCLUSION: This study is of significant importance in Malta since it is the first conducted in a MRI environment, especially because the results were compared with limits imposed by EU Directive 2013/35/EU which has to be implemented by July 2016. PMID- 27458052 TI - Severe glucose-6-phosphate dehydrogenase deficiency leads to susceptibility to infection and absent NETosis. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells in human subjects, causing hemolytic anemia linked to impaired nicotinamide adenine dinucleotide phosphate (NADPH) production and imbalanced redox homeostasis in erythrocytes. Because G6PD is expressed by a variety of hematologic and nonhematologic cells, a broader clinical phenotype could be postulated in G6PD-deficient patients. We describe 3 brothers with severe G6PD deficiency and susceptibility to bacterial infection. OBJECTIVE: We sought to study the molecular pathophysiology leading to susceptibility to infection in 3 siblings with severe G6PD deficiency. METHODS: Blood samples of 3 patients with severe G6PD deficiency were analyzed for G6PD enzyme activity, cellular oxidized nicotinamide adenine dinucleotide phosphate/NADPH levels, phagocytic reactive oxygen species production, neutrophil extracellular trap (NET) formation, and neutrophil elastase translocation. RESULTS: In these 3 brothers strongly reduced NADPH oxidase function was found in granulocytes, leading to impaired NET formation. Defective NET formation has thus far been only observed in patients with the NADPH oxidase deficiency chronic granulomatous disease, who require antibiotic and antimycotic prophylaxis to prevent life-threatening bacterial and fungal infections. CONCLUSION: Because severe G6PD deficiency can be a phenocopy of chronic granulomatous disease with regard to the cellular and clinical phenotype, careful evaluation of neutrophil function seems mandatory in these patients to decide on appropriate anti infective preventive measures. Determining the level of G6PD enzyme activity should be followed by analysis of reactive oxygen species production and NET formation to decide on required antibiotic and antimycotic prophylaxis. PMID- 27458054 TI - TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: From muscular dystrophy to tumours. AB - TRIM32 is a member of the TRIpartite Motif family characterised by the presence of an N-terminal three-domain-module that includes a RING domain, which confers E3 ubiquitin ligase activity, one or two B-box domains and a Coiled-Coil region that mediates oligomerisation. Several TRIM32 substrates were identified including muscular proteins and proteins involved in cell cycle regulation and cell motility. As ubiquitination is a versatile post-translational modification that can affect target turnover, sub-cellular localisation or activity, it is likely that diverse substrates may be differentially affected by TRIM32-mediated ubiquitination, reflecting its multi-faceted roles in muscle physiology, cancer and immunity. With particular relevance for muscle physiology, mutations in TRIM32 are associated with autosomal recessive Limb-Girdle Muscular Dystrophy 2H, a muscle-wasting disease with variable clinical spectrum ranging from almost asymptomatic to wheelchair-bound patients. In this review, we will focus on the ability of TRIM32 to mark specific substrates for proteasomal degradation discussing how the TRIM32-proteasome axis may (i) be important for muscle homeostasis and for the pathogenesis of muscular dystrophy; and (ii) define either an oncogenic or tumour suppressive role for TRIM32 in the context of different types of cancer. PMID- 27458055 TI - Identification of the interactome between fish plasma proteins and Edwardsiella tarda reveals tissue-specific strategies against bacterial infection. AB - Elucidating the complex pathogen-host interaction is essential for a comprehensive understanding of how these remarkable agents invade their hosts and how the hosts defend against these invaders. During the infection, pathogens interact intensively with host to enable their survival, which can be revealed through their interactome. Edwardsiella tarda is a Gram-negative bacterial pathogen causing huge economic loss in aquaculture and a spectrum of intestinal and extraintestinal diseases in humans. E. tarda is an ideal model for host pathogen investigation as it infects fish in three distinct steps: entering the host, circulating through the blood and establishing infection. We adopted a previous established proteomic approach that inactivated E. tarda cells and covalent crosslink fish plasma proteins were used to capture plasma proteins and bacterial outer membrane proteins, respectively. By the combinatorial use of proteomic and biochemical approaches, six plasma proteins and seven outer membrane proteins (OMPs) were identified. Interactions among these proteins were validated with protein-array, far-Western blotting and co-immunoprecipitation. At last, seventeen plasma protein-bacteria protein-protein interaction were confirmed to be involved in the interaction network, forming a complex interactome. Compared to our previous results, different host proteins were detected, whereas some of the bacterial proteins were similar, which indicates that hosts adopt tissue-specific strategies to cope with the same pathogen during infection. Thus, our results provide a robust demonstration of both bacterial initiators and host receptors or interacting proteins to further explore infection and anti-infective mechanisms between hosts and microbes. PMID- 27458056 TI - Suppression of TWIST1 enhances the sensitivity of colon cancer cells to 5 fluorouracil. AB - The 5-fluorouracil (5FU)-based adjuvant chemotherapy improves the survival of patients with colorectal cancer, however the main obstacle affecting its effectiveness is a drug resistance. Our study aimed to investigate the impact of TWIST1 silencing on the sensitivity of cancer cells to 5FU. The suppression of TWIST1 expression in human colon cancer HT29 and HCT116 cell lines was achieved by transduction with lentiviral vector carrying the TWIST1 silencing sequence (pLL3.7-shTWIST1). The suppression of TWIST1 expression induced changes in the expression pattern of epithelial to mesenchymal transition markers, reduced the cells proliferation rate, increased their sensitivity to serum withdrawn, and increased the cytotoxic effect of 5FU. However, significantly higher 5FU cytotoxicity was observed in HT29 cell cultures. Cells with silenced TWIST1 displayed altered expression of enzymes metabolizing 5FU. The expression level of dihydropyrimidine dehydrogenase, and thymidylate synthase decreased significantly in HT29 shTWIST1 cells, but not in HCT116 shTWIST1 cells. On the other hand, significant increases in the expression levels of thymidine phosphorylase, and uridine phosphorylase 1 were seen in both cell lines with suppressed expression of TWIST1. The changes in enzymes expression were mirrored by enzymatic activities. In conclusion, our observations point to TWIST1 as a target protein to enhance the sensitivity of colorectal cancer cells to 5FU. PMID- 27458057 TI - Perovskite CH3NH3PbI3(Cl) Single Crystals: Rapid Solution Growth, Unparalleled Crystalline Quality, and Low Trap Density toward 10(8) cm(-3). AB - Single crystal reflects the intrinsic physical properties of a material, and single crystals with high-crystalline quality are highly desired for the acquisition of high-performance devices. We found that large single crystals of perovskite CH3NH3PbI3(Cl) could be grown rapidly from chlorine-containing solutions. Within 5 days, CH3NH3PbI3(Cl) single crystal as large as 20 mm * 18 mm * 6 mm was harvested. As a most important index to evaluate the crystalline quality, the full width at half-maximum (fwhm) in the high-resolution X-ray rocking curve (HR-XRC) of as-grown CH3NH3PbI3(Cl) single crystal was measured as 20 arcsec, which is far superior to so far reported CH3NH3PbI3 single crystals (~1338 arcsec). The unparalleled crystalline quality delivered a low trap-state density of down to 7.6 * 10(8) cm(-3), high carrier mobility of 167 +/- 35 cm(2) V(-1) s(-1), and long transient photovoltaic carrier lifetime of 449 +/- 76 MUs. The improvement in the crystalline quality, together with the rapid growth rate and excellent carrier transport property, provides state-of-the-art single crystalline hybrid perovskite materials for high-performance optoelectronic devices. PMID- 27458058 TI - Less with More: Hospitalization Cost and Event Rates with Quadripolar versus Bipolar CRT-D System. AB - BACKGROUND: This is a comparative effectiveness study for cardiac resynchronization therapy defibrillator (CRT-D) therapy enabled by quadripolar (QUAD) versus bipolar (BIP) left ventricular (LV) leads. Heart failure (HF) hospitalization (HFH) rates, associated costs, and 30-day readmissions after index HFH were compared. METHODS: Patients with de novo LV leads implanted as part of a CRT-D system between January 2011 and August 2013 with >=1-year follow up were included. Medical history, dates, and locations of HFH were collected thereafter. Patients were divided based on LV lead model: QUAD or BIP. Universal billing records (UB-04) for each HFH and ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) diagnoses/procedure codes were used to classify hospitalizations as HF or non-HF and calculate concurrent U.S. national-average medicare reimbursement. Rates, associated payer costs, and 30-day readmissions were then compared using nonparametric bootstrapping. RESULTS: Baseline characteristics (N = 69 QUAD and N = 56 BIP) were similar. The inpatient HFH for the QUAD group (0.20/patient-year) was lower than the BIP group (0.31/patient-year, incidence rate ratio [IRR] = 0.62, P = 0.036). The overall HFH rate for the inpatient or outpatient setting for QUAD (0.29/patient-year) was lower than the BIP group (0.42/patient-year, IRR = 0.69, P = 0.055). Average cost of HFH in QUAD ($4,428/patient-year) was lower than BIP ($7,354/patient-year), a 39.8% cost reduction (P = 0.026). The 30-day readmission rate was also lower in QUAD compared to BIP (19% vs 28%, IRR = 0.68, P = 0.18). CONCLUSION: This U.S. economic comparative study demonstrated that QUAD exhibited lower postimplant inpatient HFH rates and reduced healthcare utilization compared to BIP systems. PMID- 27458059 TI - Within-day associations between sedentary behavior and affect in middle-aged women. PMID- 27458060 TI - Randomized clinical trial: benefits of aerobic physical activity for 24 weeks in postmenopausal women with nonalcoholic fatty liver disease. AB - OBJECTIVE: The aim of the study was to evaluate the effectiveness of aerobic physical activity in reducing the frequency of hepatic steatosis and metabolic and cardiovascular risk in postmenopausal women with nonalcoholic fatty liver disease (NAFLD). METHODS: Forty sedentary postmenopausal women (mean age 55.3 +/- 8.0 y) with biopsy-proven NAFLD were randomly divided into two groups: an exercising group (19 participants) and a control group (nonexercising, 21 participants). The exercise group underwent a supervised aerobic physical activity program of 120 min/wk for 24 weeks. The anthropometric parameters; body composition; hepatic, lipid, and glycemic profiles; homeostasis model assessment of insulin resistance index; cytokines; transient elastography (FibroScan; liver stiffness/controlled attenuation parameter); and cardiopulmonary exercise test were evaluated at baseline and after 24 weeks of protocol. RESULTS: At baseline there were no significant differences in anthropometric, metabolic, and inflammatory parameters-stiffness and liver fat content by FibroScan between the groups. After 24 weeks, we observed a decrease of waist circumference, an increase of high-density lipoprotein cholesterol levels (P < 0.05), and improved cardiopulmonary functional capacity in the exercise group. In addition, the controlled attenuation parameter analysis showed no significant decrease of hepatic steatosis in the exercise group. With regard to the systemic inflammation, there were, however, no significant differences in the cytokines between the groups. CONCLUSIONS: An aerobic physical activity program of 24 weeks in NAFLD postmenopausal women showed improvement in some variables such as waist circumference, high-density lipoprotein cholesterol, and cardiopulmonary performance that may be beneficial in improving cardiovascular risk factors in this population. PMID- 27458061 TI - Human hemokinin-1 promotes migration of melanoma cells and increases MMP-2 and MT1-MMP expression by activating tumor cell NK1 receptors. AB - Receptors and their regulatory peptides are aberrantly expressed in tumors, suggesting a potential tumor therapy target. Human hemokinin-1 (hHK-1) is a tachykinin peptide ligand of the neurokinin-1 (NK1) receptor which is overexpressed in melanoma and other tumor tissues. Here, we investigated the role of hHK-1 and the NK1 receptor in melanoma cell migration. NK1 receptor expression was associated with melanoma metastatic potential. Treatment with hHK-1 significantly enhanced A375 and B16F10 melanoma cell migration and an NK1 receptor antagonist L732138 blocked this effect. MMP-2 and MT1-MMP expression were up-regulated in hHK-1-treated melanoma cells and cell signaling data suggested that hHK-1 induced phosphorylation of ERK1/2, JNK and p38 by way of PKC or PKA. Kinase activation led to increased MMP-2 and MT1-MMP expression and melanoma cell migration induced by hHK-1. Thus, hHK-1 and the NK1 receptor are critical to melanoma cell migration and each may be a promising chemotherapeutic target. PMID- 27458062 TI - Benign Prostatic Hyperplasia, Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease: Is Metaflammation the Link? AB - PURPOSE: The prevalence of prostatic inflammation (PI) is very frequent in patients affected by benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). To investigate the relationship between prostatic inflammation (PI) and the presence of MetS and non-alcoholic fatty liver disease (NAFLD) in a cohort of patients affected by BPH/LUTS. METHODS: We conducted a prospective study from January 2012 to June 2014 on 264 consecutive patients, who underwent transurethral resection of the prostate for bladder outlet obstruction. Metabolic syndrome (MetS) has been defined according to the International Diabetes Federation (IDF). Prior to surgery, each patient has been evaluated for the presence of MetS and NAFLD. All surgical specimens were investigated for the presence of an inflammatory infiltrate, according to the Irani score. RESULTS: The prevalence of patients affected by MetS alone was 13.8% (32/232), 13.8% (32/232) by NAFLD alone, and 42.7% (99/232) by both diseases. The rate of subjects affected by MetS + NAFLD and severe PI was significantly greater than those with only one metabolic alteration (75.8% vs. 24.2%, P < 0.01). The multivariate logistic regression analysis revealed that FLI was independently associated with high PI (Irani score >= 4) (odds ratio [OR]: 1.04; P < 0.01). Further, the combination between MetS and NAFLD was associated severe PI (OR: 4.5; P < 0.01) while not MetS as a single alteration. CONCLUSIONS: Patients with BPH/LUTS and metabolic aberration exhibited grater PI. The coexistence of MetS and NAFLD exerted a greater detrimental effect on prostate gland by increasing severity of inflammation. Prostate 76:1528-1535, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27458063 TI - Cortisol coregulation in fish. AB - Cortisol coregulation, which is the up- or down-regulation of partners' physiological stress responses, has been described for individuals with strong attachment bonds, e.g. parents and their children, and romantic relationship partners. Research into moderating effects on cortisol coregulation suggests stronger covariation among distressed partners. Whether cortisol coregulation is unique to humans or can also be found in other species that share universal features of the vertebrate stress response remains unexplored. Using a repeated measures approach and non-invasive waterborne hormone analysis, we test the hypothesis that dyads of three-spined stickleback fish (Gasterosteus aculeatus) coregulate their cortisol levels in shared environments. Dyadic cortisol levels were unrelated when cohabiting (home tank), but significantly covaried when sharing a more stressful (as indicated by higher cortisol levels) environment (open field). Time-lag analysis further revealed that open field cortisol levels were predicted by partner's cortisol levels prior to the shared experience. To our knowledge, this study provides the first evidence for coregulatory processes on cortisol responses in a non-human animal that lacks strong bonds and social attachment relationships, suggesting a shared evolutionary origin of cortisol coregulation in vertebrates. From an adaptive perspective, cortisol coregulation may serve to reduce risk in challenging, potentially threatening situations. PMID- 27458064 TI - Ibuprofen in paediatrics: pharmacology, prescribing and controversies. AB - Ibuprofen, a propionic acid derivative, is a non-steroidal anti-inflammatory drug. The oral formulation is widely used in paediatric practice and after paracetamol it is one of the most common drugs prescribed for children in hospital. The treatment of fever with antipyretics such as ibuprofen is controversial as fever is the normal response of the body to infection and unless the child becomes distressed or symptomatic, fever alone should not be routinely treated. Combined treatment with paracetamol and ibuprofen is commonly undertaken but almost certainly is not helpful. This article aims to describe the indications and mode of action of the drug, outline its pharmacokinetics and highlight the important key messages regarding its use in clinical practice. PMID- 27458065 TI - Value of a coordinated management of osteoporosis via Fracture Liaison Service for the treatment of orthogeriatric patients. AB - INTRODUCTION: The prevalence of osteoporosis in female patients over 75 years of age is 59.2 %. In Germany ~6.3-7.8 million patients are affected by osteoporosis. In 77 % of german patients osteoporosis is not treated adequately. Even after fragility fractures only 16-21 % of female patients and 3 % of male patients are supplied with a specific osteoporosis therapy. Establishing a Fracture Liaison Services (FLS) is a possible addition to co-management for an efficient treatment of osteoporosis in orthogeriatric patients. MATERIALS AND METHODS: According to a treatment algorithm adapted to the DVO guideline 2014, data of 251 (77 male, 173 female) patients were collected over 3 months. For the assessment specific and standardized questionnaires were used. There was also a basic laboratory testing for osteoporosis done. RESULTS: The average age of female patients was 76.1 years, in male patients 76.6 years. Thirty-seven patients had vertebral fractures, 25 patients proximal humerus fractures, 18 distal radius fractures and a total of 78 proximal femur fractures were recorded. Eighteen percent of the 251 patients have already been treated with a basic and 11 % with a specific osteoporosis medication. Approximately 40 % of the orthogeriatric patients were diagnosed with osteoporosis for the first time in our clinic. Less than 1 % of the patients had a vitamin D level over 40 ng/ml and 32 % had a vitamin D level under 10 ng/ml. Sixty-five percent of the discharged patients received a basic osteoporosis therapy and 25 % an additional specific therapy. DISCUSSION: Due to the demographic development osteoporosis-associated fractures steadily increase. In addition to the surgical treatment of fractures, osteological diagnosis and treatment are essential components of successful treatment and critical to the prevention of further fractures. A combination of orthogeriatric center and fracture liaison service allows a more efficient treatment of osteoporosis by close supervision of orthogeriatric patients by the physicians involved. PMID- 27458066 TI - The protective effect of Shenfu injection against elderly severe pneumonia. AB - OBJECTIVE: The purpose of this study is to investigate the effect of Shenfu injection (SFI) on the tumor necrosis factor-alpha (TNF-alpha) and the interleukin (IL-6, IL-8, IL-10) of elderly patients who suffered from severe pneumonia. METHODS: From June 2012 to September 2014, we performed in our department 89 cases of elderly patients with severe pneumonia. These patients were randomly divided into two groups: the treatment group (45 cases) and the control group (44 cases). The control group was given the treatment of anti infection, reducing sputum, and support therapy, while the treatment group was fed by SFI intravenously based on the control group. The TNF-alpha and the interleukin were detected by enzyme-linked immunosorbent assay (ELISA). Meanwhile, the changes in the inflammatory response indicators, the blood gas analysis, and the parameters of vital signs were measured and compared before and after therapy. RESULTS: Prior to treatment, there is no significant difference between the treatment group and the control group (p > 0.05); after the treatment for 7 days, the levels of TNF-alpha, IL-6, and IL-8 were significantly decreased, while the level of IL-10 was obviously increased. The APACHE II score was significantly decreased in comparison to that before the treatment (p < 0.05), and the time of mechanical ventilation, the duration of time in ICU, and the application time of vasoactive drugs were notably shortened. CONCLUSION: The application of Shenfu injection exhibited a positive and effective effect on removing the inflammation media during the treatment of elderly severe pneumonia. PMID- 27458067 TI - Variation in blood pressure among adolescent schoolchildren in an urban slum of Kolkata, West Bengal. AB - BACKGROUND: High blood pressure in childhood is a potential risk factor for cardiovascular and cerebrovascular diseases. The roots of essential hypertension in adults may be initiated in childhood. This study was conducted to investigate blood pressure profiles of adolescent schoolchildren in the practice field area of the Urban Health Centre, Chetla, Kolkata. OBJECTIVES: This cross-sectional study was carried out to determine the prevalence of hypertension in adolescent schoolchildren, to compare the blood pressure between boys and girls, and to study the association between selected variables and blood pressure. MATERIALS AND METHODS: The study was conducted among adolescent schoolchildren aged 10-19 years in two randomly selected secondary schools situated in the practice field area of the Urban Health Centre, Chetla, Kolkata. All students aged 10-19 years present on the day of the visit were included in the study; the sample was 129. A predesigned questionnaire was used to carry out the study. Measurements of height, weight, body mass index (BMI) and blood pressure were made using standardised physical instruments following standard operative guidelines. The data were collected and analysed using appropriate statistical methods. RESULTS: The prevalence of hypertension was found to be 10.1% (11.1% in boys and 8.8% in girls). The prevalence of pre-hypertension was 20.2% (16.7% in boys and 24.6% in girls). Hypertension was found to be significantly associated with physical exercise (p<0.05) and salt intake (p<0.05); BMI was also significantly associated with both systolic blood pressure (p<0.05) and diastolic blood pressure (p<0.05). There was a significant (p<0.05) positive correlation of systolic blood pressure and diastolic blood pressure with BMI (r=0.303, p<0.05; r=0.262, p<0.05), age (r=0.326, p<0.05; r=0.267, p<0.05) and height (r=0.322, p<0.05; r=0.174, p<0.05). There was a negative correlation between hypertension and physical exercise (r= 0.313, p<0.05) and a positive correlation between hypertension and salt intake (r=0.298, p<0.05). CONCLUSIONS: The prevalence of pre-hypertension and hypertension together in adolescents was 30.3%. To avoid the consequences and sequelae of hypertension, prevention should start from childhood by encouraging physical exercise, promoting low salt intake, advising on maintaining normal body weight, and checking up on blood pressure at regular intervals. PMID- 27458068 TI - Suprachoroidal haemorrhage following intravitreal injection. PMID- 27458069 TI - Hunt is accused of "underhand" cover up over health department finances. PMID- 27458070 TI - Unfair Lineups Make Witnesses More Likely to Confuse Innocent and Guilty Suspects. AB - Eyewitness-identification studies have focused on the idea that unfair lineups (i.e., ones in which the police suspect stands out) make witnesses more willing to identify the police suspect. We examined whether unfair lineups also influence subjects' ability to distinguish between innocent and guilty suspects and their ability to judge the accuracy of their identification. In a single experiment (N = 8,925), we compared three fair-lineup techniques used by the police with unfair lineups in which we did nothing to prevent distinctive suspects from standing out. Compared with the fair lineups, doing nothing not only increased subjects' willingness to identify the suspect but also markedly impaired subjects' ability to distinguish between innocent and guilty suspects. Accuracy was also reduced at every level of confidence. These results advance theory on witnesses' identification performance and have important practical implications for how police should construct lineups when suspects have distinctive features. PMID- 27458071 TI - In vitro assessment of plutonium uptake and release using the human macrophage like THP-1 cells. AB - Plutonium (Pu) intake by inhalation is one of the major potential consequences following an accident in the nuclear industry or after improvised nuclear device explosion. Macrophages are essential players in retention and clearance of inhaled compounds. However, the extent to which these phagocytic cells are involved in these processes highly depends on the solubility properties of the Pu deposited in the lungs. Our objectives were to develop an in vitro model representative of the human pulmonary macrophage capacity to internalize and release Pu compounds in presence or not of the chelating drug diethylenetriaminepentaacetate (DTPA). The monocyte cell line THP-1 was used after differentiation into macrophage-like cells. We assessed the cellular uptake of various forms of Pu which differ in their solubility, as well as the release of the internalized Pu. Results obtained with differentiated THP-1 cells are in good agreement with data from rat alveolar macrophages and fit well with in vivo data. In both cell types, Pu uptake and release depend upon Pu solubility and in all cases DTPA increases Pu release. The proposed model may provide a good complement to in vivo animal experiments and could be used in a first assessment to predict the fraction of Pu that could be potentially trapped, as well as the fraction available to chelating drugs. PMID- 27458072 TI - Consensus of classification trees for skin sensitisation hazard prediction. AB - Since March 2013, it is no longer possible to market in the European Union (EU) cosmetics containing new ingredients tested on animals. Although several in silico alternatives are available and achievements have been made in the development and regulatory adoption of skin sensitisation non-animal tests, there is not yet a generally accepted approach for skin sensitisation assessment that would fully substitute the need for animal testing. The aim of this work was to build a defined approach (i.e. a predictive model based on readouts from various information sources that uses a fixed procedure for generating a prediction) for skin sensitisation hazard prediction (sensitiser/non-sensitiser) using Local Lymph Node Assay (LLNA) results as reference classifications. To derive the model, we built a dataset with high quality data from in chemico (DPRA) and in vitro (KeratinoSensTM and h-CLAT) methods, and it was complemented with predictions from several software packages. The modelling exercise showed that skin sensitisation hazard was better predicted by classification trees based on in silico predictions. The defined approach consists of a consensus of two classification trees that are based on descriptors that account for protein reactivity and structural features. The model showed an accuracy of 0.93, sensitivity of 0.98, and specificity of 0.85 for 269 chemicals. In addition, the defined approach provides a measure of confidence associated to the prediction. PMID- 27458073 TI - Dual-energy computed tomography as a diagnostic tool for gout during intercritical periods. AB - AIM: The aim of this study is to evaluate the diagnostic yield of dual-energy computed tomography (DECT) in detection of uric acid accumulation in joints or periarticular structures in patients suspected of having gout, in their intercritical period. METHODS: Patients with a history of recurrent, short-lived mono- or oligo-arthralgia or arthritis, referred to the rheumatology clinic for diagnosis of their condition, were included in this retrospective evaluation. RESULTS: DECT confirmed the diagnosis of gout in 30 of 50 patients (60%). A positive DECT was present in 12 of 16 cases (75%) with serum uric acid > 8.5 mg/dL, compared to seven of 13 cases (54%) and two of five cases (40%) with levels of 6.1-8.5 mg/dL and <= 6 mg/dL, respectively. The diagnostic impact of screening hands and feet were highest (78% and 56%, respectively). Follow-up data were available for 24 of the 30 patients with urate deposits identified by DECT. Twenty-one were treated with urate-lowering agents, all responded with lowering of serum uric acid and cessation of flares. Follow-up data were available for 16 of the 20 patients with no urate deposits identified by DECT. Gout was diagnosed in two of them by synovial fluid examination during subsequent flares. Both positive and negative predictive values of DECT for diagnosing gout in this patient population were 87%. Following DECT, treatment regimen was modified to gout-specific therapy in 52% of the patients. DISCUSSION: The ability to make a definite diagnosis of gout by DECT imaging in a substantial number of asymptomatic patients in the intercritical period should help in treatment decision-making and improve patient adherence to long-term urate-lowering therapy. PMID- 27458075 TI - Acceptance of Shaken Baby Syndrome and Abusive Head Trauma as Medical Diagnoses. AB - OBJECTIVE: To assess the current general acceptance within the medical community of shaken baby syndrome (SBS), abusive head trauma (AHT), and several alternative explanations for findings commonly seen in abused children. STUDY DESIGN: This was a survey of physicians frequently involved in the evaluation of injured children at 10 leading children's hospitals. Physicians were asked to estimate the likelihood that subdural hematoma, severe retinal hemorrhages, and coma or death would result from several proposed mechanisms. RESULTS: Of the 1378 physicians surveyed, 682 (49.5%) responded, and 628 were included in the final sample. A large majority of respondents felt that shaking with or without impact would be likely or highly likely to result in subdural hematoma, severe retinal hemorrhages, and coma or death, and that none of the alternative theories except motor vehicle collision would result in these 3 findings. SBS and AHT were comsidered valid diagnoses by 88% and 93% of the respondents, respectively. CONCLUSIONS: Our empirical data confirm that SBS and AHT are still generally accepted by physicians who frequently encounter suspected child abuse cases, and are considered likely sources of subdural hematoma, severe retinal hemorrhages, and coma or death in young children. Other than a high-velocity motor vehicle collision, no alternative theories of causation for these findings are generally accepted. PMID- 27458074 TI - Inequality and ethics in paediatric HIV remission research: From Mississippi to South Africa and back. AB - In 2013, physician-researchers announced that a baby in Mississippi had been 'functionally cured' of HIV [Persaud, D., Gay, H., Ziemniak, C. F., Chen, Y. H., Piatak, M., Chun, T.-W., ... Luzuriaga, K. (2013b, March). Functional HIV cure after very early ART of an infected infant. Paper presented at the 20th conference on retroviruses and opportunistic infections, Atlanta, GA]. Though the child later developed a detectable viral load, the case remains unprecedented, and trials to build on the findings are planned [National Institute of Allergy and Infectious Diseases. (2014). 'Mississippi baby' now has detectable HIV, researchers find. Retrieved from http://www.niaid.nih.gov/news/newsreleases/2014/pages/mississippibabyhiv.aspx ]. Whether addressing HIV 'cure' or 'remission', scrutiny of this case has focused largely on scientific questions, with only introductory attention to ethics. The social inequalities and gaps in care that made the discovery possible - and their ethical implications for paediatric HIV remission - have gone largely unexamined. This paper describes structural inequalities surrounding the 'Mississippi baby' case and a parallel case in South Africa, where proof-of-concept studies are in the early stages. We argue that an ethical programme of research into infant HIV remission ought to be 'structurally competent', and recommend that paediatric remission studies consider including a research component focused on social protection and barriers to care. PMID- 27458076 TI - Duodenal-jejunal bypass surgery induces hepatic lipidomic alterations associated with ameliorated hepatic steatosis in mice. AB - OBJECTIVE: Bariatric surgery induces weight loss and improvement of insulin resistance; one aspect of both is an amelioration of hepatic steatosis. This study was undertaken to assess the changes in the hepatic lipidome after duodenal jejunal bypass (DJB) surgery. METHODS: A DJB surgical model was developed and characterized in diet-induced obese mice. In comparison with sham-operated mice, an unbiased lipidomic profiling of hepatic lipids was performed together with measurements of gene expression within key pathways of hepatic lipid metabolism. RESULTS: In the liver of DJB mice, a dramatic reduction (by 77%) in hepatic triacylglycerols was observed. Global lipidomic profiling identified marked decreases of triacylglycerols comprised of medium length fatty acids and with low double bond content. Specific diacylglycerol species were also among the most dramatic decreases in hepatic lipids, whereas lysophosphatidic acids and phosphatidic acids were increased. Expression of fatty acid transporter and lipogenic genes was down-regulated. CONCLUSIONS: From in-depth analysis of hepatic lipid composition, specific lipid intermediates were identified that are preferentially changed following DJB surgery. These changes were most likely due to DJB-induced weight loss, and only further studies will be able to distinguish weight loss-dependent from weight loss-independent changes. PMID- 27458077 TI - Accuracy of flow cytometry and cytomorphology for the diagnosis of meningeal involvement in lymphoid neoplasms: A systematic review. AB - Central nervous system (CNS) involvement by lymphoid neoplasms is a relatively infrequent event that demands accurate identification. The purpose of this article is to review studies comparing diagnostic accuracy of flow cytometry (FCM) and cytomorphology (CM) for meningeal involvement from lymphoid neoplasms. Primary publications from the last 26 years were identified searching MedLine, Scopus, and Web of Science and systematically scanning bibliographies of identified articles. Only studies reporting complete results were included. We assessed study quality using the QUADAS-2 tool. For each study, we extracted informations regarding study population, technical details about sample preparation, data analysis, and results. Twenty-seven studies were included. A great heterogeneity regarding study populations and analytical procedures was observed among studies. Percentages of samples giving a positive result with both FCM and CM range from 0.3% to 42.9% among studies, whereas double negative samples go from 0% to 96.3%. Samples with positive FCM but negative CM are reported by 89% (24/27) of the studies with rates ranging from 3.5% to 61.5% of total specimens. On the contrary, samples with positive CM and negative FCM are found in 48% (13/27) of the studies with percentages ranging from 0.5% to 10%. Despite all the differences observed among studies, almost all of them state that employing flow cytometry along with conventional cytology increases the number of positive CSF samples for lymphoma involvement, although a few cases remain in whom only morphology can correctly identify malignant cells. Diagn. Cytopathol. 2016;44:841-856. (c) 2016 Wiley Periodicals, Inc. PMID- 27458078 TI - Reducing Radiation Exposure During CRT Implant Procedures: Single-Center Experience With Low-Dose Fluoroscopy Settings and a Sensor-Based Navigation System (MediGuide). AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) implant procedures are often complex and prolonged, resulting in substantial ionizing radiation (IR) exposure to the patient and operator. We assessed the impact of lower-dose fluoroscopy settings and a sensor-based electromagnetic tracking system (MediGuideTM, MDG) on reducing IR exposure during CRT implantation. METHODS: A single-center 2-group cohort study was conducted on 348 consecutive patients, age 66.4 +/- 11.0 years, 80.4% male, with CRT implant procedures from 2013 to 2015. Patients were arbitrarily assigned to MDG (N = 239) versus no MDG (N = 109) guidance. Lower-dose fluoroscopy settings were adopted in January 2015 (3 instead of 6 fps; 23 instead of 40 nGy/pulse; N = 101). RESULTS: Overall, MDG was associated with an 82.1% reduction in IR exposure (393 MUGray.m2 vs. 2191 MUGray.m2 , P < 0.001). Lower-dose fluoroscopy resulted in a 59.5% reduction in IR-exposure without MDG (1055 MUGray.m2 vs. 2608 MUGray.m2 , P < 0.001) and 81.8% reduction with MDG (108 MUGray.m2 vs. 595 MUGray.m2 , P < 0.001). Low-dose fluoroscopy combined with MDG was associated with a 95.9% lower exposure to IR when compared to standard fluoroscopy without MDG (108 MUGray.m2 vs. 2608 MUGray.m2 , P < 0.001). Procedures with MDG were shorter (96 minutes vs. 123 minutes, P < 0.001) and associated with a trend towards a higher success rate (94.6% vs. 89.0%, P = 0.062), with fewer coronary sinus cannulation failures (2.1% vs. 6.4%, P = 0.040). CONCLUSION: Low-dose fluoroscopy settings are highly effective (>50%) in reducing IR exposure during CRT implant procedures. When combined with MDG, >95% reduction in IR exposure is achieved. Moreover, MDG shortens procedural duration and may improve acute procedural outcomes. PMID- 27458079 TI - Reductionist perspectives and the notion of information. AB - Reductionism is the dominant stance of biology. According to this perspective, biological phenomena have to fit with physical explanations. Some biologists thought that the introduction of the idea of program was a sound way to overcome both physicalism and reductionism. We argue instead that the introduction of information theory into biology did not liberate biology from reductionism. We argue that the adoption of information in biology is an erroneous transposition from a specific mathematical domain to one where it does not belong. Indeed, the mathematical framework of the information theory is too rigid and discrete to fit with biological phenomena. Therefore, information in biology represents an inappropriate metaphor. Then, we make explicit the use of metaphors and the choice of explanation mode. We argue that the choice of explanation is not neutral. Furthermore, the use of metaphors in science becomes dangerous when they take the place of theories and they lose their paradoxical content. PMID- 27458080 TI - Anti-inflammatory effects of dabrafenib on polyphosphate-mediated vascular disruption. AB - The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Previous studies have reported polyphosphate (PolyP)-mediated vascular inflammatory responses such as disruption of vascular integrity. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. This study illustrates drug repositioning with dabrafenib (DAB) for the modulation of PolyP-mediated vascular inflammatory responses in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Dabrafenib suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-kappaB, tumor necrosis factor-alpha, and interleukin-6. Furthermore, dabrafenib demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of dabrafenib on various systemic inflammatory diseases, such as sepsis or septic shock. PMID- 27458081 TI - Assessing the impact of educational intervention in patients with hypertension. AB - BACKGROUND: It is accepted that patient education can be beneficial in the treatment of chronic diseases. We conducted an educational intervention (EI) in hypertensive patients seen at Primary Care centres (PCC) and specialised Hypertension Units (SHU). OBJECTIVES: To assess patient's knowledge of hypertension and to verify the impact of this educational initiative. METHODS: A multicentre quasi-experimental study with the participation of 120 patients with hypertension. EI consisted of oral and written information which included the definition of hypertension, causes, cardiovascular risk factors and means of control. A self-administered questionnaire was used to assess patient's knowledge before and after EI. RESULTS: Sixty-two (52%) patients were from PCC and 58 (48%) from SHU (mean age: 61 +/- 13.3 years, 59% were women). There were no differences in baseline characteristics between patients attending at PCC and SHU. The definition of hypertension (blood pressure >=140 mmHg and/or >=90 mmHg was known by 48% and 99% of the participants before and after EI, respectively (p < 0.001). Poor baseline knowledge about the risks of hypertension was related to kidneys (54%) and eyes (58%). After EI this knowledge increased to 100% (p < 0.001 and p < 0.001, respectively). A significant improvement in knowledge about medication was observed (51% before and 87% after EI; p = 0.004). CONCLUSIONS: This study shows a positive impact of EI to improve patients' knowledge about hypertension. However, further studies are needed to assess if EI produces behaviour changes in the long term, as this might enhance optimal blood pressure control to prevent kidney disease or delay its progression. PMID- 27458082 TI - Ligand binding to an Allergenic Lipid Transfer Protein Enhances Conformational Flexibility resulting in an Increase in Susceptibility to Gastroduodenal Proteolysis. AB - Non-specific lipid transfer proteins (LTPs) are a family of lipid-binding molecules that are widely distributed across flowering plant species, many of which have been identified as allergens. They are highly resistant to simulated gastroduodenal proteolysis, a property that may play a role in determining their allergenicity and it has been suggested that lipid binding may further increase stability to proteolysis. It is demonstrated that LTPs from wheat and peach bind a range of lipids in a variety of conditions, including those found in the gastroduodenal tract. Both LTPs are initially cleaved during gastroduodenal proteolysis at three major sites between residues 39-40, 56-57 and 79-80, with wheat LTP being more resistant to cleavage than its peach ortholog. The susceptibility of wheat LTP to proteolyic cleavage increases significantly upon lipid binding. This enhanced digestibility is likely to be due to the displacement of Tyr79 and surrounding residues from the internal hydrophobic cavity upon ligand binding to the solvent exposed exterior of the LTP, facilitating proteolysis. Such knowledge contributes to our understanding as to how resistance to digestion can be used in allergenicity risk assessment of novel food proteins, including GMOs. PMID- 27458084 TI - A new fish cell line derived from the caudal fin of freshwater angelfish Pterophyllum scalare: development and characterization. AB - In this study, a new cell line derived from the caudal fin of the freshwater angelfish Pterophyllum scalare was developed and characterized. The cell line was designated angelfish fin (AFF) and subcultured 44 times since its development. These cells grew well in Leibovitz's -15 medium supplemented with 10% foetal bovine saline (FBS) at 28 degrees C and the modal chromosome number (2n) was 48. The AFF cell-line is mainly comprised of epithelial cells as confirmed by immunocytological technique using anti-cytokeratin antibodies, an epithelial cell marker. This cell line was tested for growth in a temperatures range from 20 to 37 degrees C and at various FBS concentrations of 5-20% at 28 degrees C. The cell line was cryopreserved at different passage levels and revived successfully with 80% survival rate. Polymerase chain reaction amplification and sequencing of partial mitochondrial 16s rRNA and coI genes confirmed that the AFF cell-line originated from angelfish. Mycoplasma sp. contamination was not detected in AFF cells and checked by Hoechst 33258 fluorescence staining. At the 42nd passage the cells were transfected with 2 MUg of pAcGFP1-N1 expression vector. The AFF cells exhibited cytotoxic effects when exposed to the bacterial extra cellular products from Serratia marcescens and Proteus hauseri. The AFF cells and cells from kidney and brain did not show cytopathic effect when exposed to cyprinid herpes virus2 and viral nervous necrosis virus. The newly developed AFF cell line will be useful for the isolation of viruses affecting angelfishes, such as iridoviruses, in the future. PMID- 27458083 TI - A novel peptide ADAM8 inhibitor attenuates bronchial hyperresponsiveness and Th2 cytokine mediated inflammation of murine asthmatic models. AB - A disintegrin and metalloproteinase 8 (ADAM8) has been identified as a signature gene associated with moderate and severe asthma. Studies in mice have demonstrated that the severity of asthma can be reduced by either transgenic knock-out or by antibodies blocking ADAM8 function, highlighting ADAM8 as potential drug target for asthma therapy. Here, we examined the therapeutic effect of an ADAM8 inhibitor peptide (BK-1361) that specifically blocks cellular ADAM8 activity in ovalbumin-sensitized and challenged Balb/c mice. We found that BK-1361 (25 MUg/g body weight) attenuated airway responsiveness to methacholine stimulation by up to 42%, concomitantly reduced tissue remodeling by 50%, and decreased inflammatory cells (e.g. eosinophils down by 54%)/inflammatory factors (e.g. sCD23 down by 50%)/TH2 cytokines (e.g. IL-5 down by 70%)/ADAM8-positive eosinophils (down by 60%) in the lung. We further verified that BK-1361 specifically targets ADAM8 in vivo as the peptide caused significantly reduced levels of soluble CD23 in wild-type but not in ADAM8-deficient mice. These findings suggest that BK-1361 blocks ADAM8-dependent asthma effects in vivo by inhibiting infiltration of eosinophils and TH2 lymphocytes, thus leading to reduction of TH2-mediated inflammation, tissue remodeling and bronchial hyperresponsiveness. Taken together, pharmacological ADAM8 inhibition appears as promising novel therapeutic strategy for the treatment of asthma. PMID- 27458086 TI - Virtual membrane for filtration of particles using surface acoustic waves (SAW). AB - Surface acoustic wave (SAW) based particle manipulation is contactless, versatile, non-invasive and biocompatible making it useful for biological studies and diagnostic technologies. In this work, we present a sensitive particle sorting system, termed the virtual membrane, in which a periodic acoustic field with a wavelength on the order of particle dimensions permits size-selective filtration. Polystyrene particles that are larger than approximately 0.3 times the acoustic half-wavelength experience a force repelling them from the acoustic field. If the particle size is such that, at a given acoustic power and flow velocity, this repulsive force is dominant over the drag force, these particles will be prohibited from progressing further downstream (i.e. filtered), while smaller particles will be able to pass through the force field along the pressure nodes (akin to a filter's pores). Using this mechanism, we demonstrate high size selectivity using a standing SAW generated by opposing sets of focused interdigital transducers (FIDTs). The use of FIDTs permits the generation of a highly localized standing wave field, here used for filtration in MUl min(-1) order flow rates at 10s of mW of applied power. Specifically, we demonstrate the filtration of 8 MUm particles from 5 MUm particles and 10.36 MUm particles from 7.0 MUm and 5.0 MUm particles, using high frequency SAW at 258 MHz, 192.5 MHz, and 129.5 MHz, respectively. PMID- 27458087 TI - Structural Characterization of Cross-Linked Species in Trastuzumab Emtansine (Kadcyla). AB - The antibody-drug conjugate, trastuzumab emtansine (Kadcyla), is produced by attachment of the antitubulin drug, DM1, to lysine amines via a heterobifunctional linker, SMCC (succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate). Following the reaction of the N-hydroxysuccinimide activated linker with antibody lysines to produce a linker-modified intermediate (Tmab-MCC), DM1 is added to yield the desired product. In addition to the expected distribution of drug-linked forms (from 0 to 8), mass spectrometry also demonstrates the presence of a second distribution shifted by about +222 Da. This series is consistent with the presence of a population containing a bound linker without DM1 ("unconjugated linker"). Extended characterization of trastuzumab emtansine was performed using capillary isoelectic focusing, CE-SDS, peptide mapping, and LC/MS following (18)O labeling of peptide digests to identify this family of product variants. These studies demonstrate that the presence of these +222 Da species is due to an unexpected reaction of the maleimide moiety in the MCC linker with antibody lysine residues to produce cross-linked species that cannot conjugate to DM1. PMID- 27458085 TI - GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine. AB - BACKGROUND: Recurrent abdominal pain is a common and costly health-care problem attributed, in part, to visceral hypersensitivity. Increasing evidence suggests that gut bacteria contribute to abdominal pain perception by modulating the microbiome-gut-brain axis. However, specific microbial signals remain poorly defined. gamma-aminobutyric acid (GABA) is a principal inhibitory neurotransmitter and a key regulator of abdominal and central pain perception from peripheral afferent neurons. Although gut bacteria are reported to produce GABA, it is not known whether the microbial-derived neurotransmitter modulates abdominal pain. METHODS: To investigate the potential analgesic effects of microbial GABA, we performed daily oral administration of a specific Bifidobacterium strain (B. dentiumATCC 27678) in a rat fecal retention model of visceral hypersensitivity, and subsequently evaluated pain responses. KEY RESULTS: We demonstrate that commensal Bifidobacterium dentium produces GABA via enzymatic decarboxylation of glutamate by GadB. Daily oral administration of this specific Bifidobacterium (but not a gadB deficient) strain modulated sensory neuron activity in a rat fecal retention model of visceral hypersensitivity. CONCLUSIONS & INFERENCES: The functional significance of microbial-derived GABA was demonstrated by gadB-dependent desensitization of colonic afferents in a murine model of visceral hypersensitivity. Visceral pain modulation represents another potential health benefit attributed to bifidobacteria and other GABA producing species of the intestinal microbiome. Targeting GABAergic signals along this microbiome-gut-brain axis represents a new approach for the treatment of abdominal pain. PMID- 27458088 TI - Ultrasonography in Diagnosis of Congenital Absence of the Vas Deferens. AB - BACKGROUND Congenital absence of the vas deferens is an important cause of obstructive azoospermia, and the lack of an imaging diagnostic test is a critical problem. The aim of this study is to discuss the use of ultrasonography in congenital absence of vas deferens, including dysplasia of the epididymis and the seminal vesical. MATERIAL AND METHODS Five fresh spermatic cord specimens were detected by ultrasonography (US) to evaluate the image of the spermatic cord segment of the vas deferens. Fifty normal males had scrotal US to confirm whether the normal spermatic cord segment of the vas deferens can be detected and to measure the internal and external diameter on the long axis view. Forty-six males clinically diagnosed as having congenital absence of vas deferens underwent scrotal US to evaluate the spermatic cord segment of the vas deferens and the epididymis. The seminal vesicals were detected with transrectal ultrasonography. We evaluated images of the vas deferens, epididymis, and seminal vesical. RESULTS Scrotal ultrasonography can distinguish the vas deferens from the other cord-like structures in the spermatic cord, and the vas deferens has a characteristic image. Scrotal ultrasonography detected all 50 normal males and measured the diameter. No statistically significant difference was found between the left and right measurements. In the 46 patients, the following anomalies were observed: 1) 42 cases of congenital bilateral absence of vas deferens; 2) 2 cases of congenital unilateral absence of the vas deferens; and 3) 1 case of congenital segmental absence of the vas deferens. All 46 cases were accompanied with epididymis and seminal vesical anomalies. CONCLUSIONS The spermatic cord segment of the vas deferens can be detected by US, which is a valuable tool in diagnosis of congenital absence of the vas deferens. Seminal vesical and epididymis anomalies often associated with congenital absence of the vas deferens were revealed by ultrasonography. PMID- 27458089 TI - Quantum information tapping using a fiber optical parametric amplifier with noise figure improved by correlated inputs. AB - One of the important functions in a communication network is the distribution of information. It is not a problem to accomplish this in a classical system since classical information can be copied at will. However, challenges arise in quantum system because extra quantum noise is often added when the information content of a quantum state is distributed to various users. Here, we experimentally demonstrate a quantum information tap by using a fiber optical parametric amplifier (FOPA) with correlated inputs, whose noise is reduced by the destructive quantum interference through quantum entanglement between the signal and the idler input fields. By measuring the noise figure of the FOPA and comparing with a regular FOPA, we observe an improvement of 0.7 +/- 0.1 dB and 0.84 +/- 0.09 dB from the signal and idler outputs, respectively. When the low noise FOPA functions as an information splitter, the device has a total information transfer coefficient of Ts+Ti = 1.5 +/- 0.2, which is greater than the classical limit of 1. Moreover, this fiber based device works at the 1550 nm telecom band, so it is compatible with the current fiber-optical network for quantum information distribution. PMID- 27458091 TI - Control of Earth-like magnetic fields on the transformation of ferrihydrite to hematite and goethite. AB - Hematite and goethite are the two most abundant iron oxides in natural environments. Their formation is controlled by multiple environmental factors; therefore, their relative concentration has been used widely to indicate climatic variations. In this study, we aimed to test whether hematite and goethite growth is influenced by ambient magnetic fields of Earth-like values. Ferrihydrite was aged at 95 degrees C in magnetic fields ranging from ~0 to ~100 MUT. Our results indicate a large influence of the applied magnetic field on hematite and goethite growth from ferrihydrite. The synthesized products are a mixture of hematite and goethite for field intensities <~60 MUT. Higher fields favour hematite formation by accelerating ferrimagnetic ferrihydrite aggregation. Additionally, hematite particles growing in a controlled magnetic field of ~100 MUT appear to be arranged in chains, which may be reduced to magnetite keeping its original configuration, therefore, the presence of magnetic particles in chains in natural sediments cannot be used as an exclusive indicator of biogenic magnetite. Hematite vs. goethite formation in our experiments is influenced by field intensity values within the range of geomagnetic field variability. Thus, geomagnetic field intensity could be a source of variation when using iron (oxyhydr-)oxide concentrations in environmental magnetism. PMID- 27458090 TI - Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling. AB - 1. Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that disrupt hepatic xenobiotic and intermediary metabolism, leading to metabolic syndrome and nonalcoholic steatohepatitis (NASH). 2. Since phenobarbital indirectly activates Constitutive Androstane Receptor (CAR) by antagonizing growth factor binding to the epidermal growth factor receptor (EGFR), we hypothesized that PCBs may also diminish EGFR signaling. 3. The effects of the PCB mixture Aroclor 1260 on the protein phosphorylation cascade triggered by EGFR activation were determined in murine (in vitro and in vivo) and human models (in vitro). EGFR tyrosine residue phosphorylation was decreased by PCBs in all models tested. 4. The IC50 values for Aroclor 1260 concentrations that decreased Y1173 phosphorylation of EGFR were similar in murine AML-12 and human HepG2 cells (~2-4 MUg/mL). Both dioxin and non-dioxin-like PCB congeners decreased EGFR phosphorylation in cell culture. 5. PCB treatment reduced phosphorylation of downstream EGFR effectors including Akt and mTOR, as well as other phosphoprotein targets including STAT3 and c-RAF in vivo. 6. PCBs diminish EGFR signaling in human and murine hepatocyte models and may dysregulate critical phosphoprotein regulators of energy metabolism and nutrition, providing a new mechanism of action in environmental diseases. PMID- 27458092 TI - Crystal structures of RidA, an important enzyme for the prevention of toxic side products. AB - The YjgF/YER057c/UK114 family proteins are highly conserved across all three domains of life, and most of them currently have no clearly defined biological roles. In vitro, these proteins were found to hydrolyze the enamine/imine intermediates generated from serine or threonine, and were renamed Reactive Intermediate Deaminase A (RidA). RidA was recently discovered in Arabidopsis thaliana, and by deaminating the toxic enamine/imine intermediates, it prevents the inactivation of many functionally important pyridoxal 5'-phosphate (PLP) containing enzymes in plants such as branched-chain aminotransferase BCAT (IlvE). In this study, we determined the crystal structure of Arabidopsis thaliana RidA in the apo form, as well as RidA complexed with the ligand pyruvate. RidA forms the trimeric, barrel-like quaternary structure and inter-subunit cavities, and resembles most RidA family members. Each pyruvate molecule binds to the interface between two subunits, and the recognition of pyruvate is achieved by the interactions with R165 and T167. From sequence alignment and structural superposition, we identified a series of key residues responsible for the trimer assembly, whose importance was confirmed by enzymatic assays. This study provides structural insight into RidA functions in plants. PMID- 27458093 TI - Correlation between horizontal mucosal thickness and probing depths at healthy and diseased implant sites. AB - OBJECTIVES: To assess the horizontal mucosal thickness (hMT) at healthy and diseased implant sites and correlate these measurements with respective probing depths (PD). MATERIALS AND METHODS: In 60 patients, hMT was assessed at the buccal aspect of healthy (n = 36) and diseased (peri-implant mucositis: n = 26; peri-implantitis: n = 167) implant sites using a validated ultrasonic A-scanner (Pirop(r) Ultrasonic Biometer A- Scan, Echo-Son, Krancowa, Poland) equipped with a specially designed tissue probe. The corresponding PD values were measured at the mid-buccal aspects. RESULTS: Median hMT (1.10 mm) at healthy implant sites was significantly lower when compared with diseased sites (1.68 mm; 1.61 mm) (P < 0.001, respectively). These values did not markedly differ by implant location (i.e., upper/lower jaws) or position (i.e., anterior/posterior sites). The regression model failed to reveal a significant linear association between hMT and PD values at healthy and diseased implant sites. CONCLUSION: This study has pointed to a significant increase of hMT values at diseased implant sites. PMID- 27458094 TI - Knockdown of PFTAIRE Protein Kinase 1 (PFTK1) Inhibits Proliferation, Invasion, and EMT in Colon Cancer Cells. AB - PFTK1 is a member of the cyclin-dependent kinase (CDK) family and is upregulated in many types of tumors. However, its expression and role in colon cancer remain unclear. In this study, we aimed to investigate the expression and function of PFTK1 in colon cancer. Our results showed that PFTK1 was highly expressed in colon cancer cell lines. The in vitro experiments demonstrated that knockdown of PFTK1 inhibited the proliferation, migration, and invasion of colon cancer cells as well as the epithelial-to-mesenchymal transition (EMT) progress. Furthermore, knockdown of PFTK1 suppressed the expression of Shh as well as Smo, Ptc, and Gli 1 in colon cancer cells. Taken together, these results suggest that knockdown of PFTK1 inhibited the proliferation and invasion of colon cancer cells as well as the EMT progress by suppressing the Sonic hedgehog signaling pathway. Therefore, these findings reveal that PFTK1 may be a potential therapeutic target for the treatment of colon cancer. PMID- 27458095 TI - MicroRNA-15a Inhibits Proliferation and Induces Apoptosis in CNE1 Nasopharyngeal Carcinoma Cells. AB - Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer, frequently occurring in Southeast Asia and Southern China. Several microRNAs (miRNAs) have been shown to have an inhibitive effect on NPC, while the effect of miR-15a on NPC remains unclear. Thus, our study aimed to investigate the potential effect of miR-15a on NPC cell proliferation, apoptosis, and possible functional mechanism. Human NPC CNE1 cells were transfected with miR-15a mimics, miR-15a inhibitors, or a control. Afterward, cell viability and apoptosis were assayed by using CCK-8, BrdU assay, and flow cytometry. Moreover, Western blot was used to detect the expression changes of proliferation and apoptosis of related proteins. As a result, miR-15a overexpression significantly reduced cell proliferation (p < 0.01 or p < 0.001) and induced cell apoptosis (p < 0.001), while miR-15a suppression got the opposite result for cell proliferation and apoptosis. In addition, miR 15a overexpression upregulated the protein levels of p27, GSK-3beta, Bax, procaspase 3, and active caspase 3, whereas miR-15a suppression downregulated these proteins. The protein level of p21 was not significantly regulated by miR 15a overexpression or suppression. These results indicated that miR-15a played a role for inhibition of proliferation and induction of apoptosis in CNE1 cells. PMID- 27458096 TI - Knockdown of HPIP Inhibits the Proliferation and Invasion of Head-and-Neck Squamous Cell Carcinoma Cells by Regulating PI3K/Akt Signaling Pathway. AB - Hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) is a corepressor for the transcription factor PBX. Previous studies showed that HPIP is frequently overexpressed in many tumors. However, the role of HPIP in head-and-neck squamous cell carcinoma (HNSCC) has not yet been determined. Thus, we decided to investigate the effects and mechanisms of HPIP in HNSCC. Our results demonstrated that HPIP is highly expressed in human HNSCC cell lines and provides the first evidence that knockdown of HPIP obviously inhibits proliferation and migration/invasion in HNSCC cells in vitro, as well as inhibits tumor growth in vivo. Furthermore, knockdown of HPIP significantly inhibits the expression of p-PI3K and p-Akt in human HNSCC cells. In conclusion, our study demonstrated that knockdown of HPIP significantly inhibits the proliferation and migration/invasion of HNSCC cells by suppressing the PI3K/Akt signaling pathway. Therefore, HPIP may be a novel potential therapeutic target for the treatment of HNSCC. PMID- 27458097 TI - Knockdown of Long Noncoding RNA PCAT6 Inhibits Proliferation and Invasion in Lung Cancer Cells. AB - As a newly identified oncogenic long noncoding RNA (lncRNA), prostate cancer associated transcript 6 (PCAT6) promoted cellular proliferation and colony formation of prostate cancer. However, the biological function of PCAT6 in lung cancer is still largely unknown. In this study, we found that PCAT6 is significantly increased in cancer tissues compared to normal tissues and positively correlates with metastasis of lung cancer in patients. We then examined PCAT6 expression in lung cancer cell lines and identified that PCAT6 expression was significantly elevated in lung cancer cells compared to normal human bronchial epithelial (NHBE) cells, especially in CL1-5 and H446 cells. PCAT6 knockdown significantly inhibited cellular proliferation and metastasis, as well as induced early apoptosis of lung cancer cells. Molecular analysis revealed that PCAT6 regulated the expression of two pivotal cancer-related proteins, c-Myc and p53, in lung cancer cells. However, PCAT6 was not directly combined with c Myc and p53 as confirmed by RNA immunoprecipitation. Finally, a retrospective study further revealed that PCAT6 negatively correlates with overall survival of lung cancer patients. In conclusion, these results suggest that PCAT6 could play an oncogenic role in lung cancer progression and may serve as a biomarker for prognosis of lung cancer patients. PMID- 27458098 TI - Downregulation of CREB Promotes Cell Proliferation by Mediating G1/S Phase Transition in Hodgkin Lymphoma. AB - The cyclic-AMP response element-binding protein (CREB), a well-known nuclear transcription factor, has been shown to play an essential role in many cellular processes, including differentiation, cell survival, and cell proliferation, by regulating the expression of downstream genes. Recently, increased expression of CREB was frequently found in various tumors, indicating that CREB is implicated in the process of tumorigenesis. However, the effects of CREB on Hodgkin lymphoma (HL) remain unknown. To clarify the role of CREB in HL, we performed knockdown experiments in HL. We found that downregulation of CREB by short hairpin RNA (shRNA) resulted in enhancement of cell proliferation and promotion of G1/S phase transition, and these effects can be rescued by expression of shRNA-resistant CREB. Meanwhile, the expression level of cell cycle-related proteins, such as cyclin D1, cyclin E1, cyclin-dependent kinase 2 (CDK2), and CDK4, was elevated in response to depletion of CREB. Furthermore, we performed chromatin immunoprecipitation (ChIP) assay and confirmed that CREB directly bound to the promoter regions of these genes, which consequently contributed to the regulation of cell cycle. Consistent with our results, a clinical database showed that high expression of CREB correlates with favorable prognosis in B-cell lymphoma patients, which is totally different from the function of CREB in other cancers such as colorectal cancer, acute myeloid leukemia, and some endocrine cancers. Taken together, all of these features of CREB in HL strongly support its role as a tumor suppressor gene that can decelerate cell proliferation by inhibiting the expression of several cell cycle-related genes. Our results provide new evidence for prognosis prediction of HL and a promising therapeutic strategy for HL patients. PMID- 27458099 TI - Knockdown of PFTK1 Expression by RNAi Inhibits the Proliferation and Invasion of Human Non-Small Lung Adenocarcinoma Cells. AB - PFTK1 (PFTAIRE protein kinase 1), also named CDK14 (cyclin-dependent kinase 14), is a member of the cell division cycle 2 (CDC2)-related protein kinase family. It is highly expressed in several malignant tumors. However, the role of PFTK1 in the progression of non-small cell lung cancer (NSCLC) is still elusive. In this study, we aimed to explore the expression and function of PFTK1 in NSCLC cells. Our results showed that PFTK1 was significantly upregulated in human NSCLC cell lines. Silencing the expression of PFTK1 inhibited the proliferation of NSCLC cells. In addition, silencing the expression of PFTK1 endowed NSCLC cells with decreased migration and invasion abilities, as well as epithelial-mesenchymal transition (EMT) progress in A549 cells. A mechanistic study showed that knockdown of PFTK1 inhibited the expression of beta-catenin, cyclin D1, and c-Myc in A549 cells. In summary, we report that small interfering RNA (siRNA)-PFTK1 might inhibit the proliferation and invasion of NSCLC cells by suppressing the Wnt/beta-catenin signaling pathway. Therefore, PFTK1 may represent a novel therapeutic target for the treatment of NSCLC. PMID- 27458100 TI - Knockdown of HVEM, a Lymphocyte Regulator Gene, in Ovarian Cancer Cells Increases Sensitivity to Activated T Cells. AB - Ovarian cancer is highly malignant with a gradually increasing incidence and a high mortality rate. Immunosuppression is induced in ovarian cancer, although the mechanism detail is not clear. It has been indicated that HVEM (herpesvirus entry mediator) B- and T-lymphocyte attenuator (BTLA) negatively regulates the immune responses of T lymphocytes. Here, HVEM mRNA was found to be elevated in ovarian cancer tissue samples and primary ovarian cancer cells in comparison with benign tissue samples. We then knocked down HVEM expression in an ovarian cancer cell line, OVCAR3, by lentivirus-based small hairpin RNA (shRNA). Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis showed that HVEM-shRNA had no effect on the proliferation, early apoptosis, or cell cycle distribution of OVCAR3. We then isolated activated T cells and performed coculture experiments in Transwell. Remarkably, HVEM-silenced ovarian cancer cells (primary ovarian cancer cells and OVCAR3) increased the number of T cells and the secretion of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), while activated T cells promoted the apoptosis of HVEM-silenced ovarian cancer cells. The current study partially explains the immune escape mechanism of ovarian cancer cells and provides a possible target for immunotherapy. PMID- 27458101 TI - Knockdown of Upregulated Gene 11 (URG11) Inhibits Proliferation, Invasion, and beta-Catenin Expression in Non-Small Cell Lung Cancer Cells. AB - Upregulated gene 11 (URG11), a new gene upregulated by hepatitis B virus X protein, was found to be involved in the development and progression of several tumors. However, the role of URG11 in human non-small cell lung cancer (NSCLC) has not yet been determined. Therefore, the aim of the present study was to explore the role of URG11 in human NSCLC. Our results found that URG11 was highly expressed in human NSCLC tissues compared with matched normal lung tissues, and higher levels were found in NSCLC cell lines in comparison to the normal lung cell line. Moreover, we also found that knockdown of URG11 significantly inhibited proliferation, migration/invasion of NSCLC cells, as well as suppressed tumor growth in vivo. Furthermore, knockdown of URG11 suppressed the expression of beta-catenin, c-Myc, and cyclin D1 in NSCLC cells. Taken together, the study reported here provided evidence that URG11 downregulation suppresses proliferation, invasion, and beta-catenin expression in NSCLC cells. Thus, URG11 may be a novel potential therapeutic target for NSCLC. PMID- 27458102 TI - Knockdown of Zinc Transporter ZIP5 by RNA Interference Inhibits Esophageal Cancer Growth In Vivo. AB - We recently found that SLC39A5 (ZIP5), a zinc transporter, is overexpressed in esophageal cancer. Downregulation of ZIP5 inhibited the proliferation, migration, and invasion of the esophageal cancer cell line KYSE170 in vitro. In this study, we found that downregulation of SLC39A5 (ZIP5) by interference resulted in a significant reduction in esophageal cancer tumor volume and weight in vivo. COX2 (cyclooxygenase 2) expression was decreased and E-cadherin expression was increased in the KYSE170K xenografts, which was caused by the downregulation of ZIP5. However, we did not find that the downregulation of ZIP5 caused a change in the relative expressions of cyclin D1, VEGF (vascular endothelial growth factor), MMP9 (matrix metalloprotein 9), and Bcl-2 (B-cell lymphoma/leukmia-2) mRNA or an alteration in the average level of zinc in the peripheral blood and xenografts in vivo. Collectively, these findings indicate that knocking down ZIP5 by small interfering RNA (siRNA) might be a novel treatment strategy for esophageal cancer with ZIP5 overexpression. PMID- 27458105 TI - A global measure of sickness behaviour: Development of the Sickness Questionnaire. AB - Symptoms after inflammatory activation, so-called sickness behaviour, overlap with trans-diagnostic complaints. As no self-report questionnaire to assess sickness behaviour exists, we aimed to develop such an instrument, the Sickness Questionnaire. Items responsive to experimentally induced inflammatory activation (randomized double-blind study endotoxin (0.6 ng/kg) versus placebo, n = 52) were selected and the statistical properties were examined in 172 primary care patients. A principal component analysis indicated a one-factor solution (Cronbach's alpha = .86). This 10-item scale correlated with depression ( beta = .41, p < .001), anxiety ( beta = .36, p < .001), self-rated health ( beta = .28, p < .001) and a single item of feeling sick ( beta = .55, p < .001). The results support the adequacy of Sickness Questionnaire as a brief assessment instrument of perceived sickness behaviour. PMID- 27458104 TI - Effectiveness of a Communication for Behavioral Impact (COMBI) Intervention to Reduce Salt Intake in a Vietnamese Province Based on Estimations From Spot Urine Samples. AB - This study evaluated the effectiveness of the Communication for Behavioral Impact (COMBI)-Eat Less Salt intervention conducted in Viet Tri, Vietnam. The behavior change intervention was implemented in four wards and four communes for one year, which included mass media communication, school interventions, community programs, and focus on high-risk groups. Mean sodium excretion was estimated from spot urine samples using different equations. A subsample provided 24-hour urine to validate estimates from spot urine. Information about salt-related knowledge and behaviors was also collected. There were 513 participants at both baseline and follow-up. Mean sodium excretion estimated from spot urines fell significantly from 8.48 g/d at baseline to 8.05 g/d at follow-up (P=.001). All spot equations demonstrated a significant reduction in sodium levels; however, the change was smaller than the measured 24-hour urine. Participants showed improved knowledge and behaviors following the intervention. The COMBI intervention was effective in lowering average population salt intake and improving knowledge and behaviors. PMID- 27458106 TI - Depression and anxiety in patients receiving interferon-alpha: The role of illness perceptions. AB - Development of psychiatric symptoms during interferon-alpha therapy may be influenced by psychological factors. We examined illness perceptions using the Revised Illness Perceptions Questionnaire in 55 patients with chronic hepatitis C virus infection, due to receive interferon-alpha. The Hospital Anxiety and Depression Scale was used to assess the development of symptoms. Negative identity, consequences and emotional representation beliefs were significantly associated with both higher depression and anxiety scores. Negative illness perceptions play a predictive role in the development of interferon-alpha-induced psychiatric symptoms. PMID- 27458107 TI - When childbirth becomes a tragedy: What is the role of hospital organization? AB - In this autoethnographic study, I analyse my birthing event, in order to point out some relevant cultural aspects of the experience. I explore the role of expectations, childbirth place, medicalization and relationships with healthcare professionals and partner. My experience and the analysis of the context where childbirth takes place leads to the conclusion that hospital organization is central to women's experiences of giving birth, but the hospital culture is still too centred on the security that medical interventions guarantee, relegating people to a passive position. Health services should address personal agency, in order to guarantee more respectful childbirth care. PMID- 27458108 TI - Do coping strategies mediate the association between Type D personality and quality of life among people with multiple sclerosis? AB - The aim of this study is to explore whether different coping strategies are able to mediate the association between Type D personality and quality of life. We collected information from 156 consecutive patients (response rate: 72.9%; 75.0% women; median age: 40 +/- 3 years). Patients completed the Type D Scale-14, the Coping Self-Efficacy Scale and the Short-Form Health Survey for measuring physical and mental quality of life. The mediating effect of coping was analysed using correlations, linear regressions and the Sobel z-test. In the mental quality of life, all three studied coping strategies mediated the association between Type D personality and quality of life. PMID- 27458109 TI - Organosulfate Formation through the Heterogeneous Reaction of Sulfur Dioxide with Unsaturated Fatty Acids and Long-Chain Alkenes. AB - The heterogeneous reaction between SO2 and unsaturated compounds results in the efficient production of organosulfates for several fatty acids and long-chain alkenes. The presence of an acid group, the physical state of the reactants (solid or liquid), the nature of the double bond (cis, trans, terminal), and the use of light irradiation all have an impact on the reaction rate. The reaction was investigated using different set-ups (coated flow tube, aerosol flow tube, and diffuse reflectance infrared Fourier transform cell). The reaction products were identified by high-resolution mass spectrometry and the impact of this reaction on organosulfate formation in the atmosphere is discussed. PMID- 27458110 TI - Characterization of a homologue of mammalian serine racemase from Caenorhabditis elegans: the enzyme is not critical for the metabolism of serine in vivo. AB - Free d-serine (d-Ser) plays a crucial role in regulating brain function in mammals. In various organisms, including mammals, d-Ser is biosynthesized by Ser racemase, a synthetic enzyme that produces d-Ser from l-Ser. Ser racemase also exhibits dehydratase activity toward several hydroxyamino acids. Thus, this enzyme is unique in that it possesses the capability to both synthesize and degrade d-Ser; however, the physiological significance of its degradative activity remains unclear. In contrast to the physiological roles of d-Ser in mammals, little is known about the role of this amino acid in lower organisms, including the nematode Caenorhabditis elegans. It is known that a mammalian Ser racemase homologue (T01H8.2) from C. elegans exhibits racemase activity. Here, the enzymatic properties of recombinant T01H8.2 were characterized and compared with those of recombinant human Ser racemase. Furthermore, the levels of several d- and l-amino acids were measured in wild-type C. elegans and in a mutant in which the T01H8.2 gene is partially deleted and thereby inactivated. The results indicate that T01H8.2 also shows dehydratase activity toward several hydroxyamino acids, although the enzyme is not critical for Ser metabolism in vivo. The possible physiological roles of T01H8.2 are discussed. PMID- 27458111 TI - Proteomic analysis of vascular smooth muscle cells in physiological condition and in pulmonary arterial hypertension: Toward contractile versus synthetic phenotypes. AB - Vascular smooth muscle cells (VSMCs) are highly specialized cells that regulate vascular tone and participate in vessel remodeling in physiological and pathological conditions. It is unclear why certain vascular pathologies involve one type of vessel and spare others. Our objective was to compare the proteomes of normal human VSMC from aorta (human aortic smooth muscle cells, HAoSMC), umbilical artery (human umbilical artery smooth muscle cells, HUASMC), pulmonary artery (HPASMC), or pulmonary artery VSMC from patients with pulmonary arterial hypertension (PAH-SMC). Proteomes of VSMC were compared by 2D DIGE and MS. Only 19 proteins were differentially expressed between HAoSMC and HPASMC while 132 and 124 were differentially expressed between HUASMC and HAoSMC or HPASMC, respectively (fold change 1.5<= or -1.5>=, p < 0.05). As much as 336 proteins were differentially expressed between HPASMC and PAH-SMC (fold change 1.5<= or 1.5>=, p < 0.05). HUASMC expressed increased amount of alpha-smooth muscle actin compared to either HPASMC or HAoSMC (although not statistically significant). In addition, PAH-SMC expressed decreased amount of smooth muscle myosin heavy chain and proliferation rate was increased compared to HPASMC thus supporting that PAH SMC have a more synthetic phenotype. Analysis with Ingenuity identified paxillin and (embryonic lethal, abnormal vision, drosophila) like 1 (ELAVL1) as molecules linked with a lot of proteins differentially expressed between HPASMC and PAH SMC. There was a trend toward reduced proliferation of PAH-SMC with paxillin-si RNA and increased proliferation with ELAVL1-siRNA. Thus, VSMCs have very diverse protein content depending on their origin and this is in link with phenotypic differentiation. Paxillin targeting may be a promising treatment of PAH. ELAVL1 also participate in the regulation of PAH-SMC proliferation. PMID- 27458112 TI - Involvement of genes encoding apoptosis regulatory factors (FAS, FASL, TRAIL, BCL2, TNFR1 and TNFR2) in the pathogenesis of autoimmune thyroid diseases. AB - Apoptosis is necessary for the maintenance of self-tolerance by eliminating autoreactive immune cells in the periphery. To clarify the association between the pathogenesis of autoimmune thyroid disease (AITD) and genes encoding apoptosis regulatory factors, we genotyped the FAS -1377G/A, -670A/G, FASL 844C/T, TRAIL -716C/T, BCL2 -938C/A, +127G/A, TNFR1 -383A/C and TNFR2 +676T/G polymorphisms. The frequencies of the FASL -844CC and BCL2 -938AA genotypes were significantly lower in AITD patients than in control subjects (P=0.0101 and 0.0307, respectively). The frequency of the TNFR2 +676TT genotype was significantly lower in Graves' disease (GD) patients than in controls (P=0.0284). The serum sFasL level was significantly higher in GD and Hashimoto's disease (HD) patients than in control subjects (P=0.0003 and 0.0017, respectively). The serum sFasL levels in control subjects were significantly lower than those in intractable GD, GD in remission, and HD without treatment (P=0.0310, 0.0007 and 0.0002, respectively). The serum sFasL levels in HD with treatment were significantly lower than those in HD without treatment (P=0.0490). The polymorphisms in genes encoding apoptosis regulatory factors (FASL, BCL2) and serum levels of sFasL may be associated with immune dysregulation. PMID- 27458113 TI - Plasma, subcutaneous tissue and bone concentrations of ceftiofur sodium after regional limb perfusion in horses. AB - REASONS FOR PERFORMING STUDY: Regional limb perfusion (RLP) is an effective treatment option for injuries and infections of the distal limb in horses. Using ceftiofur sodium in RLP has been studied due to its superior spectrum of Gram positive organisms compared to aminoglycosides, but it is not known if this antimicrobial drug adequately penetrates subcutaneous tissue and bone. OBJECTIVE: To determine the concentration of ceftiofur in plasma, subcutaneous tissue and bone in horses after RLP. STUDY DESIGN: Experimental prospective study. METHODS: Six healthy horses were used in this study. Under standing sedation, an Esmarch tourniquet was applied to both proximal metacarpi and RLP was performed in each forelimb by injecting either ceftiofur sodium (experimental limb) or saline (control limb) i.v. in the lateral palmar digital vein. The experimental limb was injected with 2 g ceftiofur diluted to 60 mL with sterile saline. The control limb was injected with 60 mL of sterile saline. The tourniquet was left in place for 30 min post injection. Plasma, subcutaneous tissue and cortical bone samples were collected immediately after tourniquet removal (0.5 h), 12 and 24 h post injection. Ceftiofur concentrations and its active metabolite desfuroylceftiofur were analysed using high performance liquid chromatography-tandem mass spectrometry and the results were compared between control and experimental limbs using a Wilcoxon signed rank test. RESULTS: The median plasma concentrations were greater than the minimum inhibitory concentration (MIC) for common pathogens (1 MUg/mL) at 0 and 12 h post RLP. The median subcutaneous tissue concentrations were greater than MIC (1 MUg/g) at all 3 time points in the experimental limb. The median bone concentration was above MIC (1 MUg/g) at time 0 in the experimental limb but was below MIC at 12 and 24 h in the experimental limb. CONCLUSIONS: Ceftiofur administration via RLP maintained plasma concentrations above MIC for 12 h. Subcutaneous tissue concentrations above MIC were maintained for 24 h. Bone concentrations were only above MIC immediately after tourniquet removal. Further research is needed to evaluate ceftiofur administration via RLP and its implications in disease states. PMID- 27458114 TI - US probes first apparent non-sexual person-to-person Zika transmission and first domestic outbreak. PMID- 27458116 TI - Commentary: Sudden Cardiac Risk Stratification with Electrocardiographic Indices A Review on Computational Processing, Technology Transfer, and Scientific Evidence. PMID- 27458115 TI - Doppler ultrasound of the placenta and maternal and fetal vessels during normal gestation in captive agoutis (Dasyprocta prymnolopha, Wagler, 1831). AB - The use of ultrasound for pregnancy monitoring is critical for the evaluation of hemodynamic parameters essential to fetal viability. In the present study, using B-mode and Doppler ultrasound, we characterized the placenta, subplacenta, maternal, and fetal vessels during normal gestation of healthy agoutis raised in captivity. In total, 30 agoutis were obtained from the Center for the Study and Preservation of Wild Animals, Center of Agricultural Sciences, Federal University of Piaui (Nucleo de Estudos e Preservacao de Animais Silvestres-NEPAS, Centro de Ciencias Agrarias-CCA, Universidade Federal do Piaui-UFPI). These animals were subjected to B-mode and Doppler ultrasound examinations to evaluate their maternal and fetal hemodynamic profiles. The placenta was located in the mesometrial region and had a discoid, ellipsoid, or globular aspect. With spectral Doppler, characteristic systolic and diastolic flow was observed in the umbilical artery. This flow increased during pregnancy. A cross-sectional view revealed a goblet-shaped placenta. The uteroplacental blood flow was characterized by a marked increase in systolic peak velocity during pregnancy, the presence of a rapid deceleration ramp, and a relatively high diastolic speed. The fetal aortic vascular flow was predominantly systolic and diastolic. The caudal vena cava blood flow was characterized by a systolic peak followed by a decreased diastolic wave throughout pregnancy. In the present study, we characterized the morphologic and hemodynamic interactions of the placenta/subplacenta with maternal and fetal vessels in agoutis at 30, 45, 60, 75, and 90 days gestation using B-mode and Doppler ultrasound. We determined the approximation and separation of the blood flow values of the umbilical artery, subplacental flow, uteroplacental artery, fetal aorta, and fetal vena cava. We believe these values may contribute to an understanding of the gestational biology and aid delivery prediction in this species. PMID- 27458117 TI - Opposing ends of the spectrum: Exploring trust in scientific and religious authorities. AB - Given the ethical questions that surround emerging science, this study is interested in studying public trust in scientific and religious authorities for information about the risks and benefits of science. Using data from a nationally representative survey of American adults, we employ regression analysis to better understand the relationships between several variables-including values, knowledge, and media attention-and trust in religious organizations and scientific institutions. We found that Evangelical Christians are generally more trusting of religious authority figures to tell the truth about the risks and benefits of science and technology, and only slightly less likely than non Evangelicals to trust scientific authorities for the same information. We also found that many Evangelicals use mediated information and science knowledge differently than non-Evangelicals, with both increased knowledge and attention to scientific media having positive impacts on trust in scientific authorities among the latter, but not the former group. PMID- 27458118 TI - POPDC proteins as potential novel therapeutic targets in cancer. AB - Popeye domain-containing (POPDC) proteins are a novel class of cAMP-binding molecules that affect cancer cell behaviour and correlate with poor clinical outcomes. They are encoded by the POPDC genes POPDC1, POPDC2, and POPDC3. The deletion of POPDC genes and the suppression of POPDC proteins correlate with enhanced cancer cell proliferation, migration, invasion, metastasis, drug resistance, and poor patient survival in various human cancers. Overexpression of POPDC proteins inhibits cancer cell migration and invasion in vitro. POPDC proteins present promising anticancer therapeutic targets and here we review their roles in promoting cancer progression and highlight their potential as anticancer therapeutic targets. PMID- 27458120 TI - Journal strict stylistic requirements: Implications for junior researchers. PMID- 27458119 TI - Augmentation of glycolytic metabolism by meclizine is indispensable for protection of dorsal root ganglion neurons from hypoxia-induced mitochondrial compromise. AB - To meet energy demands, dorsal root ganglion (DRG) neurons harbor high mitochondrial content, which renders them acutely vulnerable to disruptions of energy homeostasis. While neurons typically rely on mitochondrial energy production and have not been associated with metabolic plasticity, new studies reveal that meclizine, a drug, recently linked to modulations of energy metabolism, protects neurons from insults that disrupt energy homeostasis. We show that meclizine rapidly enhances glycolysis in DRG neurons and that glycolytic metabolism is indispensable for meclizine-exerted protection of DRG neurons from hypoxic stress. We report that supplementation of meclizine during hypoxic exposure prevents ATP depletion, preserves NADPH and glutathione stores, curbs reactive oxygen species (ROS) and attenuates mitochondrial clustering in DRG neurites. Using extracellular flux analyzer, we show that in cultured DRG neurons meclizine mitigates hypoxia-induced loss of mitochondrial respiratory capacity. Respiratory capacity is a measure of mitochondrial fitness and cell ability to meet fluctuating energy demands and therefore, a key determinant of cellular fate. While meclizine is an 'old' drug with long record of clinical use, its ability to modulate energy metabolism has been uncovered only recently. Our findings documenting neuroprotection by meclizine in a setting of hypoxic stress reveal previously unappreciated metabolic plasticity of DRG neurons as well as potential for pharmacological harnessing of the newly discovered metabolic plasticity for protection of peripheral nervous system under mitochondria compromising conditions. PMID- 27458121 TI - On the use of peroxy-caged luciferin (PCL-1) probe for bioluminescent detection of inflammatory oxidants in vitro and in vivo - Identification of reaction intermediates and oxidant-specific minor products. AB - Peroxy-caged luciferin (PCL-1) probe was first used to image hydrogen peroxide in living systems (Van de Bittner et al., 2010 [9]). Recently this probe was shown to react with peroxynitrite more potently than with hydrogen peroxide (Sieracki et al., 2013 [11]) and was suggested to be a more suitable probe for detecting peroxynitrite under in vivo conditions. In this work, we investigated in detail the products formed from the reaction between PCL-1 and hydrogen peroxide, hypochlorite, and peroxynitrite. HPLC analysis showed that hydrogen peroxide reacts slowly with PCL-1, forming luciferin as the only product. Hypochlorite reaction with PCL-1 yielded significantly less luciferin, as hypochlorite oxidized luciferin to form a chlorinated luciferin. Reaction between PCL-1 and peroxynitrite consists of a major and minor pathway. The major pathway results in luciferin and the minor pathway produces a radical-mediated nitrated luciferin. Radical intermediate was characterized by spin trapping. We conclude that monitoring of chlorinated and nitrated products in addition to bioluminescence in vivo will help identify the nature of oxidant responsible for bioluminescence derived from PCL-1. PMID- 27458122 TI - Regulation of Neurospora Catalase-3 by global heterochromatin formation and its proximal heterochromatin region. AB - Catalase-3 (CAT-3) constitutes the main catalase activity in growing hyphae of Neurospora crassa, and its activity increases during exponential growth or is induced under different stress conditions. Although extensive progress has been made to identify catalase regulators, the regulation mechanism of CAT-3 at the chromatin level still remains unclear. Here, we aim at investigating the molecular regulation mechanisms of cat-3 at the chromatin level. We found that CAT-3 protein levels increased in mutants defective in proper global heterochromatin formation. Bioinformatics analysis identified a 5-kb AT-rich sequence adjacent to the cat-3 promoter as a heterochromatin region because of its enrichment of H3K9me3 and HP1. Expression of CAT-3 was induced by H2O2 treatment in wild-type and such change occurred along with the accumulation of histone H3 acetylation at 5-kb heterochromatin boundaries and cat-3 locus, but without alteration of its H3K9me3 repressive modification. Moreover, disruption of 5-kb heterochromatin region results in elevated cat-3 expression, and higher levels of cat-3 expression were promoted by the combination with global heterochromatin defective mutants. Interestingly, the molecular weight and activity bands of CAT-3 protein are different in heterochromatin defective mutants compared with those in wild-type, suggesting that its N-terminal processing and modification may be altered. Our study indicates that the local chromatin structure creates a heterochromatin repressive environment to repress nearby gene expression. PMID- 27458123 TI - Inhibition of endoplasmic reticulum stress and oxidative stress by vitamin D in endothelial cells. AB - Endoplasmic reticulum (ER) stress and oxidative stress promote endothelial dysfunction and atherosclerosis. Since vitamin D has been shown in several studies to lower the risk of cardiovascular disease, we examined the effects of vitamin D on ER stress and oxidative stress in endothelial cells. ER stress was measured using the placental secreted alkaline phosphatase assay and oxidative stress was measured by hydroethidine fluorescence. Expression of ER stress markers, including glucose-regulated protein 78, c-jun N-terminal kinase 1 phosphorylation, and eukaryotic initiation factor 2alpha phosphorylation, as well as X-box binding protein-1 splicing were measured in tunicamycin (TM)-treated human umbilical endothelial cells (HUVEC) treated with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and other vitamin D analogs. When TM and 1,25-(OH)2D3 were added simultaneously, 1,25-(OH)2D3 prevented ER stress. However, the effect was much stronger when cells were pre-treated with 1,25-(OH)2D3 for 24-h. However, ER stress was not inhibited by 25-OH vitamin D3 (25-OHD3) or the vitamin D analog EB1089. Both ZK191784 and the vitamin D metabolite 24,25-dihydroxyvitamin D3 were as effective as 1,25-(OH)2D3 in preventing ER stress. Similar effects were observed dextrose-induced stress. All of the compounds tested, except for 25 OHD3, inhibited dextrose-induced (27.5mM) oxidative stress and ER stress. Although TM with and without 1,25-(OH)2D3 had no effect on VDR expression, inhibition of VDR expression via siRNA prevented 1,25-(OH)2D3, ZK191784, EB1089, and 24,25-dihydroxyvitamin D3 from inhibiting dextrose-mediated SO generation. Furthermore, each vitamin D analog, with the exception of 25-OHD3, prevented dextrose-induced toxicity. These results suggest that vitamin D has a protective effect on vascular endothelial cells. PMID- 27458125 TI - Endovascular Removal of Intracardiac Thrombus Prior to Radical Nephrectomy and Inferior Vena Cava Thrombectomy. AB - We report a case of a 54-year-old patient with a T3c renal mass with intracardiac extension of the thrombus to the level of the pulmonary valve. The patient was not a candidate for cardiopulmonary bypass due to recent pulmonary embolism. Under transesophageal echocardiogram guidance, the intracardiac thrombus was removed percutaneously via transvenous mechanical thrombectomy. The patient was effectively downstaged to T3b and underwent successful radical nephrectomy and inferior vena cava thrombectomy without the use of cardiopulmonary bypass. PMID- 27458124 TI - Prorenin/renin receptor blockade promotes a healthy fat distribution in obese mice. AB - OBJECTIVE: Administration of the handle region peptide (HRP), a (pro)renin receptor blocker, decreases body weight gain and visceral adipose tissue (VAT) in high-fat/high-carbohydrate (HF/HC) diet-fed mice. The objective of this study was to elucidate potential mechanisms implicated in these observations. METHODS: Mice were given a normal or a HF/HC diet along with saline or HRP for 10 weeks. RESULTS: In HF/HC-fed mice, HRP increased the expression of several enzymes implicated in lipogenesis and lipolysis in subcutaneous fat (SCF) while the expression of the enzyme implicated in the last step of lipogenesis decreased in VAT. A reduction was also observed in circulating free fatty acids in these animals which was accompanied by normalized adipocyte size in VAT and increased adipocyte size in SCF. ''Beiging'' is the evolution of a white adipose tissue toward a brown-like phenotype characterized by an increased mitochondrial density and small lipid droplets. HRP increased the expression of' "beiging" markers in SCF of HF/HC diet-fed mice. CONCLUSIONS: HRP treatment may favor healthy fat storage in SCF by activating a triglyceride/free fatty acid cycling and "beiging," which could explain the body weight and fat mass reduction. PMID- 27458126 TI - Improving Distress in Dialysis (iDiD): A tailored CBT self-management treatment for patients undergoing dialysis. AB - BACKGROUND: There is significant psychological distress in adults with end-stage kidney disease (ESKD). However, psychological treatments tailored to address the unique challenges of kidney failure are absent. We identified psychological correlates of distress in ESKD to develop a cognitive-behavioural therapy (CBT) treatment protocol that integrates the mental health needs of patients alongside their illness self-management demands. METHODS: Studies which examined relationships between distress and psychological factors that apply in the context of ESKD including: health threats, cognitive illness representations and illness management behaviours were narratively reviewed. Review findings were translated into a CBT formulation model to inform the content of a renal-specific seven session CBT treatment protocol, which was commented on and refined by patient representatives. RESULTS: Health threats related to distress were grouped into four themes including: acute ESKD events, loss of role, uncertainty and illness self-management. Having pessimistic illness and treatment perceptions were associated with elevated distress. Non-adherence and avoidance behaviours were related to feelings of distress, whereas cognitive reappraisal, acceptance, social support and assertiveness were associated with less distress. CONCLUSIONS: The dialysis-specific CBT formulation identifies the importance of targeting ESKD specific correlates of distress to allow the delivery of integrated mental and physical health care. The 'Improving Distress in Dialysis (iDiD)' treatment protocol now requires further evaluation in terms of content, feasibility and potential efficacy. PMID- 27458127 TI - Fast, robust and high-resolution glycosylation profiling of intact monoclonal IgG antibodies using nanoLC-chip-QTOF. AB - Optimal glycosylation of immunoglobulins is essential in the generation of therapeutic biologicals with respect to efficacy, pharmacokinetics and immunogenic properties. This challenge in the field of biopharmaceuticals requires technologies for fast, robust and quantitative analysis of glycosylation. Current analyses of monoclonal antibody glycosylation are proteolysis-based mass spectrometry methods, which provide detailed structural information, but suffer a number of drawbacks such as lengthy sample preparation with the possibility to introduce artifacts. Here, we describe a fast, robust and high-resolution nanoLC-chip-QTOF method for quantitative analysis of intact monoclonal IgG glycosylation profiling. The method is able to detect hypoglycosylation, i.e. the lack of whole glycans, which is an important advantage over the well-established methods for free N-glycan or glycopeptide analysis. Moreover, the method is highly amenable to automation and because no digestion steps are involved, it provides direct relative quantitative information of both glycans on each IgG attachment site. We demonstrate that the ease and robustness make this technique ideally suited for quality control of the production process of mAb biopharmaceuticals, and provides new opportunities to study the clinical impact of mAb-glycosylation in patients with monoclonal gammopathies. PMID- 27458128 TI - Biomolecules damage and redox status abnormalities in Fabry patients before and during enzyme replacement therapy. AB - Fabry disease (FD) is caused by deficient activity of the lysosomal enzyme alpha galactosidase A. Its substrates, mainly globotriaosylceramide (Gb3), accumulate and seem to induce other pathophysiological findings of FD. Once enzyme replacement therapy (ERT) is not completely efficient on preventing disease progress in FD patients, elucidating the underlying mechanisms in FD pathophysiology is essential to the development of additional therapeutic strategies. We investigated 58 Fabry patients (23 male and 35 female) subdivided into two groups (at diagnosis and during long-term ERT) and compared them to healthy individuals. Fabry patients at diagnosis presented altered glutathione (GSH) metabolism (higher GSH levels, lower glutathione peroxidase - GPx - and normal glutathione reductase - GR - activities), higher lipid peroxidation levels (thiobarbituric acid reactive species - TBARS - and malondialdehyde - MDA), nitric oxide (NO(.)) equivalents and urinary Gb3. Fabry patients on ERT presented GSH metabolism similar to controls, although lipid peroxidation and urinary levels of NO(.) equivalents remained higher whereas Gb3 levels were lower than at diagnosis but still higher than controls. These data demonstrated that redox impairment occurs in Fabry patients before and after ERT, probably as a consequence of Gb3 accumulation, providing targets to future therapy approaches using antioxidants in combination with ERT in FD. PMID- 27458129 TI - Esophagogastric junction distensibility identifies achalasia subgroup with manometrically normal esophagogastric junction relaxation. AB - BACKGROUND: Manometric criteria to diagnose achalasia are absent peristalsis and incomplete relaxation of the esophagogastric junction (EGJ), determined by an integrated relaxation pressure (IRP) >15 mm Hg. However, EGJ relaxation seems normal in a subgroup of patients with typical symptoms of achalasia, no endoscopic abnormalities, stasis on timed barium esophagogram (TBE), and absent peristalsis on high-resolution manometry (HRM). The aim of our study was to further characterize these patients by measuring EGJ distensibility and assessing the effect of achalasia treatment. METHODS: Impedance planimetry (EndoFLIP) was used to measure EGJ distensibility and compared to previous established data of 15 healthy subjects. In case the EGJ distensibility was impaired, achalasia treatment followed. Eckardt score, HRM, TBE, and EGJ distensibility measurements were repeated >3 months after treatment. KEY RESULTS: We included 13 patients (5 male; age 19-59 years) with typical symptoms of achalasia, Eckardt score of 7 (5 7). High-resolution manometry showed absent peristalsis with low basal EGJ pressure of 10 (5.8-12.9) mm Hg and IRP of 9.3 (6.1-12) mm Hg. Esophageal stasis was 4.6 (2.7-6.9) cm after 5 minutes. Esophagogastric junction distensibility was significantly reduced in patients compared to healthy subjects (0.8 [0.7-1.2] mm2 /mm Hg vs 6.3 [3.8-8.7] mm2 /mm Hg). Treatment significantly improved the Eckardt score (7 [5-7] to 2 [1-3.5]) and EGJ distensibility (0.8 [0.7-1.2] mm2 /mm Hg to 3.5 [1.5-6.1] mm2 /mm Hg). CONCLUSIONS & INFERENCES: A subgroup of patients with clinical and radiological features of achalasia but manometrically normal EGJ relaxation has an impaired EGJ distensibility and responds favorably to achalasia treatment. Our data suggest that this condition can be considered as achalasia and treated as such. PMID- 27458131 TI - A mitochondrial-derived vesicle HOPS to endolysosomes using Syntaxin-17. AB - Damaged mitochondrial content is packaged in mitochondrial-derived vesicles (MDVs), which are targeted for degradation through an unclear mechanism. McLelland et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201603105) show that the SNARE Syntaxin-17 mediates MDV fusion with endolysosomes, promoting the delivery of mitochondrial cargo to lysosomes for degradation. PMID- 27458130 TI - Novel role for the midbody in primary ciliogenesis by polarized epithelial cells. AB - The primary cilium is a membrane protrusion that is crucial for vertebrate tissue homeostasis and development. Here, we investigated the uncharacterized process of primary ciliogenesis in polarized epithelial cells. We show that after cytokinesis, the midbody is inherited by one of the daughter cells as a remnant that initially locates peripherally at the apical surface of one of the daughter cells. The remnant then moves along the apical surface and, once proximal to the centrosome at the center of the apical surface, enables cilium formation. The physical removal of the remnant greatly impairs ciliogenesis. We developed a probabilistic cell population-based model that reproduces the experimental data. In addition, our model explains, solely in terms of cell area constraints, the various observed transitions of the midbody, the beginning of ciliogenesis, and the accumulation of ciliated cells. Our findings reveal a biological mechanism that links the three microtubule-based organelles-the midbody, the centrosome, and the cilium-in the same cellular process. PMID- 27458132 TI - Tissue homogeneity requires inhibition of unequal gene silencing during development. AB - Multicellular organisms can generate and maintain homogenous populations of cells that make up individual tissues. However, cellular processes that can disrupt homogeneity and how organisms overcome such disruption are unknown. We found that ~100-fold differences in expression from a repetitive DNA transgene can occur between intestinal cells in Caenorhabditis elegans These differences are caused by gene silencing in some cells and are actively suppressed by parental and zygotic factors such as the conserved exonuclease ERI-1. If unsuppressed, silencing can spread between some cells in embryos but can be repeat specific and independent of other homologous loci within each cell. Silencing can persist through DNA replication and nuclear divisions, disrupting uniform gene expression in developed animals. Analysis at single-cell resolution suggests that differences between cells arise during early cell divisions upon unequal segregation of an initiator of silencing. Our results suggest that organisms with high repetitive DNA content, which include humans, could use similar developmental mechanisms to achieve and maintain tissue homogeneity. PMID- 27458133 TI - The importance of serine metabolism in cancer. AB - Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine alone is sufficient to support cancer cell proliferation, whereas some cancer cells increase serine synthesis from glucose and require de novo serine synthesis even in the presence of abundant extracellular serine. Recent studies cast new light on the role of serine metabolism in cancer, suggesting that active serine synthesis might be required to facilitate amino acid transport, nucleotide synthesis, folate metabolism, and redox homeostasis in a manner that impacts cancer. PMID- 27458134 TI - Deciphering dynamics of clathrin-mediated endocytosis in a living organism. AB - Current understanding of clathrin-mediated endocytosis (CME) dynamics is based on detection and tracking of fluorescently tagged clathrin coat components within cultured cells. Because of technical limitations inherent to detection and tracking of single fluorescent particles, CME dynamics is not characterized in vivo, so the effects of mechanical cues generated during development of multicellular organisms on formation and dissolution of clathrin-coated structures (CCSs) have not been directly observed. Here, we use growth rates of fluorescence signals obtained from short CCS intensity trace fragments to assess CME dynamics. This methodology does not rely on determining the complete lifespan of individual endocytic assemblies. Therefore, it allows for real-time monitoring of spatiotemporal changes in CME dynamics and is less prone to errors associated with particle detection and tracking. We validate the applicability of this approach to in vivo systems by demonstrating the reduction of CME dynamics during dorsal closure of Drosophila melanogaster embryos. PMID- 27458135 TI - mito-QC illuminates mitophagy and mitochondrial architecture in vivo. AB - Autophagic turnover of mitochondria, termed mitophagy, is proposed to be an essential quality-control (QC) mechanism of pathophysiological relevance in mammals. However, if and how mitophagy proceeds within specific cellular subtypes in vivo remains unclear, largely because of a lack of tractable tools and models. To address this, we have developed "mito-QC," a transgenic mouse with a pH sensitive fluorescent mitochondrial signal. This allows the assessment of mitophagy and mitochondrial architecture in vivo. Using confocal microscopy, we demonstrate that mito-QC is compatible with classical and contemporary techniques in histochemistry and allows unambiguous in vivo detection of mitophagy and mitochondrial morphology at single-cell resolution within multiple organ systems. Strikingly, our model uncovers highly enriched and differential zones of mitophagy in the developing heart and within specific cells of the adult kidney. mito-QC is an experimentally advantageous tool of broad relevance to cell biology researchers within both discovery-based and translational research communities. PMID- 27458136 TI - Syntaxin-17 delivers PINK1/parkin-dependent mitochondrial vesicles to the endolysosomal system. AB - Mitochondria are considered autonomous organelles, physically separated from endocytic and biosynthetic pathways. However, recent work uncovered a PINK1/parkin-dependent vesicle transport pathway wherein oxidized or damaged mitochondrial content are selectively delivered to the late endosome/lysosome for degradation, providing evidence that mitochondria are indeed integrated within the endomembrane system. Given that mitochondria have not been shown to use canonical soluble NSF attachment protein receptor (SNARE) machinery for fusion, the mechanism by which mitochondrial-derived vesicles (MDVs) are targeted to the endosomal compartment has remained unclear. In this study, we identify syntaxin 17 as a core mitochondrial SNARE required for the delivery of stress-induced PINK1/parkin-dependent MDVs to the late endosome/lysosome. Syntaxin-17 remains associated with mature MDVs and forms a ternary SNARE complex with SNAP29 and VAMP7 to mediate MDV-endolysosome fusion in a manner dependent on the homotypic fusion and vacuole protein sorting (HOPS) tethering complex. Syntaxin-17 can be traced to the last eukaryotic common ancestor, hinting that the removal of damaged mitochondrial content may represent one of the earliest vesicle transport routes in the cell. PMID- 27458137 TI - Vitamin D Enhances the Efficacy of Irinotecan through miR-627-Mediated Inhibition of Intratumoral Drug Metabolism. AB - Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D-regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4 mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer cells. We show that calcitriol enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. When miR-627 is inhibited, calcitriol fails to enhance the activity of irinotecan. In addition, overexpression of miR-627 or siRNA knockdown of CYP3A4 enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. In contrast, overexpression of CYP3A4 abolished the effects of calcitriol on the activity of irinotecan. Using a nude mouse xenograft model, we demonstrated that calcitriol inhibited CYP3A4 and enhanced the in vivo antitumor activity of irinotecan without causing side effects. Our study identified a novel target for improving cancer therapy, i.e., modulating the intratumoral CYP3A4-mediated drug metabolism with vitamin D. This strategy could enhance the therapeutic efficacy without eliciting the side effects. Mol Cancer Ther; 15(9); 2086-95. (c)2016 AACR. PMID- 27458138 TI - Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma. AB - Melanoma is molecularly and structurally heterogeneous, with some tumor cells existing under hypoxic conditions. Our cell growth assays showed that under controlled hypoxic conditions, BRAF(V600E) melanoma cells rapidly became resistant to vemurafenib. By employing both a three-dimensional (3D) spheroid model and a two-dimensional (2D) hypoxic culture system to model hypoxia in vivo, we identified upregulation of HGF/MET signaling as a major mechanism associated with vemurafenib resistance as compared with 2D standard tissue culture in ambient air. We further confirmed that the upregulation of HGF/MET signaling was evident in drug-resistant melanoma patient tissues and mouse xenografts. Pharmacologic inhibition of the c-Met/Akt pathway restored the sensitivity of melanoma spheroids or 2D hypoxic cultures to vemurafenib. Mol Cancer Ther; 15(10); 2442-54. (c)2016 AACR. PMID- 27458139 TI - Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer. AB - Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with full-length trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity enhanced serotype 5 oncolytic adenovirus, Ad5/3-Delta24-tras, coding for human trastuzumab antibody heavy- and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3 Delta24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-Delta24 or commercial trastuzumab in HER2 positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-Delta24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-Delta24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. Mol Cancer Ther; 15(9); 2259-69. (c)2016 AACR. PMID- 27458140 TI - Receptor Tyrosine Kinase Phosphorylation Pattern-Based Multidrug Combination Is an Effective Approach for Personalized Cancer Treatment. AB - Receptor tyrosine kinases (RTK) are key signaling molecules in regulating cancer cell growth and are important cancer drug targets. Despite the success of specific RTK-targeting therapy in certain cancer treatments, the overall response rates are limited to the drug target-stratified populations. We have systematically studied RTK activations in a panel of cancer cell lines, primary cancers, and cancer xenografts and found that different combinations of RTKs were activated in different cancer cells regardless of their tissue origins. Combinations of specific RTK inhibitors (RTKi) preferentially inhibited proliferation of the cancer cells with corresponding RTK activation profiles. We also found that the activations of RTKs were regulated by both cell-autonomous and environment-dependent mechanisms and demonstrated that inhibition of all activated RTKs was essential to completely block cancer cell proliferation. In addition, c-Myc downregulation was identified as an indicator for the effectiveness of the RTKi combination treatments. Our findings demonstrated that the RTK activation profile is a valid biomarker for diagnosis and stratification of cancers, and a corresponding combination of RTKis is a promising strategy to treat cancers, particularly the single RTKi therapy-resistant cancers, selectively and effectively. Mol Cancer Ther; 15(10); 2508-20. (c)2016 AACR. PMID- 27458142 TI - One in 10 adults has tinnitus and risk increases with noise exposure, study shows. PMID- 27458141 TI - A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer. AB - mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m(2) i.v. every two weeks with lenalidomide given orally days 1-21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcgammaRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m(2) with lenalidomide 25 mg daily, days 1-21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244-50. (c)2016 AACR. PMID- 27458143 TI - The differential impact of preoperative comorbidity on perioperative outcomes following thoracoscopic and open lobectomies. AB - OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) lobectomy is quickly becoming the standard of care for many patients with early-stage non-small-cell lung cancer (NSCLC) and benign lung conditions. There is a lack of published data defining the differential impact of preoperative patient comorbidity on outcomes following VATS and OPEN lobectomies, which would be beneficial for procedure selection and clinical decision-making. METHODS: A retrospective analysis of the 2008-2011 Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP) database was performed. Demographic and clinical data on patients >=18 years having undergone VATS or OPEN lobectomy were included. Measured outcomes included postoperative length of stay (PO-LOS), in-hospital mortality and perioperative pulmonary complications. PO-LOS was further analysed using multivariable logistic regression and cumulative incidence models. RESULTS: VATS lobectomies were associated with shorter PO-LOS and fewer complications even after censoring for inpatient mortality. Furthermore, VATS lobectomy patients had improved PO-LOS compared with OPEN lobectomy patients, even with greater comorbidity. Logistic regression modelling for PO-LOS >=14 days identified independent predictors of prolonged PO-LOS, including male gender, non-elective admission, lower hospital lobectomy volume, several Elixhauser comorbidities and performance of OPEN lobectomy. CONCLUSIONS: The expected postoperative length of stay for a patient treated by OPEN lobectomy is approximately equal to that of a VATS lobectomy patient with an additional 2-3 comorbidities. The VATS approach remains advantageous with respect to PO-LOS, regardless of the number of comorbidities. PMID- 27458144 TI - Successful graft treatment of severe stenosis of the left subclavian artery in a patient with double aortic arch. PMID- 27458146 TI - Simpler psychological treatment is as effective as CBT for depression and is cheaper, study shows. PMID- 27458145 TI - WNT Stimulation Dissociates a Frizzled 4 Inactive-State Complex with Galpha12/13. AB - Frizzleds (FZDs) are unconventional G protein-coupled receptors that belong to the class Frizzled. They are bound and activated by the Wingless/Int-1 lipoglycoprotein (WNT) family of secreted lipoglycoproteins. To date, mechanisms of signal initiation and FZD-G protein coupling remain poorly understood. Previously, we showed that FZD6 assembles with Galphai1/Galphaq (but not with Galphas, Galphao and Ga12/13), and that these inactive-state complexes are dissociated by WNTs and regulated by the phosphoprotein Dishevelled (DVL). Here, we investigated the inactive-state assembly of heterotrimeric G proteins with FZD4, a receptor important in retinal vascular development and frequently mutated in Norrie disease or familial exudative vitreoretinopathy. Live-cell imaging experiments using fluorescence recovery after photobleaching show that human FZD4 assembles-in a DVL-independent manner-with Galpha12/13 but not representatives of other heterotrimeric G protein subfamilies, such as Galphai1, Galphao, Galphas, and Galphaq The FZD4-G protein complex dissociates upon stimulation with WNT-3A, WNT-5A, WNT-7A, and WNT-10B. In addition, WNT-induced dynamic mass redistribution changes in untransfected and, even more so, in FZD4 green fluorescent protein transfected cells depend on Galpha12/13 Furthermore, expression of FZD4 and Galpha12 or Galpha13 in human embryonic kidney 293 cells induces WNT-dependent membrane recruitment of p115-RHOGEF (RHO guanine nucleotide exchange factor, molecular weight 115 kDa), a direct target of Galpha12/13 signaling, underlining the functionality of an FZD4-Galpha12/13-RHO signaling axis. In summary, Galpha12/13-mediated WNT/FZD4 signaling through p115-RHOGEF offers an intriguing and previously unappreciated mechanistic link of FZD4 signaling to cytoskeletal rearrangements and RHO signaling with implications for the regulation of angiogenesis during embryonic and tumor development. PMID- 27458148 TI - Open contracting for health services. PMID- 27458147 TI - Addition of lysophospholipids with large head groups to cells inhibits Shiga toxin binding. AB - Shiga toxin (Stx), an AB5 toxin, binds specifically to the neutral glycosphingolipid Gb3 at the cell surface before being transported into cells. We here demonstrate that addition of conical lysophospholipids (LPLs) with large head groups inhibit Stx binding to cells whereas LPLs with small head groups do not. Lysophosphatidylinositol (LPI 18:0), the most efficient LPL with the largest head group, was selected for in-depth investigations to study how the binding of Stx is regulated. We show that the inhibition of Stx binding by LPI is reversible and possibly regulated by cholesterol since addition of methyl-beta-cyclodextrin (mbetaCD) reversed the ability of LPI to inhibit binding. LPI-induced inhibition of Stx binding is independent of signalling and membrane turnover as it occurs in fixed cells as well as after depletion of cellular ATP. Furthermore, data obtained with fluorescent membrane dyes suggest that LPI treatment has a direct effect on plasma membrane lipid packing with shift towards a liquid disordered phase in the outer leaflet, while lysophosphoethanolamine (LPE), which has a small head group, does not. In conclusion, our data show that cellular treatment with conical LPLs with large head groups changes intrinsic properties of the plasma membrane and modulates Stx binding to Gb3. PMID- 27458149 TI - On the histogenesis of mixed germ cell-sex cord stromal tumour of the gonads. AB - AIMS: The origin of testicular mixed germ cell-sex cord stromal tumour (MGC-SCST) is uncertain, and the nature of this neoplasm is controversial. It has not been established whether the germ cells in testicular MGC-SCST are neoplastic or whether they are merely entrapped within an unclassified sex cord stromal tumour or related testicular neoplasm. In this investigation, we present additional evidence regarding the nature of the germ cells in testicular MGC-SCST. METHODS: We obtained 25 cases of MGC-SCST, 13 of which involved the testis and 12 occurred in the ovary for histological examination. Although the majority of the cases studied were archival, materials were available for immunocytochemical examination in 10 instances. RESULTS: We found that 10 of 13 testicular MGC-SCSTs studied had a sex cord component resembling unclassified sex cord stromal tumour. In two MGC-SCSTs that had prominent entrapped tubules, an intratubular component was identified. A total of 12 ovarian MGC-SCSTs were examined, and these neoplasms were more diverse in their histological appearance than the testicular examples. The germ cells often resembled those of dysgerminoma. Formation of imperfect follicular-like structures was a frequent feature in ovarian cases. CONCLUSIONS: In this investigation, we provide further evidence that the germ cells in testicular MGC-SCSTs are neoplastic; however, in the great majority of tumours, these cells are low-grade. Some testicular MGC-SCSTs arise from an intratubular component. We believe that the majority of ovarian and some testicular MGC-SCSTs arise more directly from simultaneous transformation of germ cells and sex cord derivatives. PMID- 27458150 TI - Epstein-Barr virus and regulatory T cells in Egyptian paediatric patients with acute B lymphoblastic leukaemia. AB - OBJECTIVE: Acute B lymphoblastic leukaemia (B-ALL) is the most common type of childhood malignancy worldwide but little is known of its origin. Recently, many studies showed both a high incidence of Epstein-Barr virus (EBV) infection and high levels of CD4+CD25+Foxp3+(Treg cells) in children with B-ALL. In our study, we investigated the possible relationship between EBV infection and the onset of B-ALL, and its relation to expression of CD4+, CD25high+Foxp3+ T regulatory cells. SUBJECT AND METHODS: We analysed expression and mean fluorescence intensity (MFI) of Treg cells in peripheral blood of 45 children with B-ALL and in 40 apparently healthy children as a control, using flow cytometry. Serum anti EBV viral capsid antigen (VCA) IgG, anti-EBV nuclear antigen (EBNA) IgG (for latent infection) and anti-EBV VCA IgM (for acute infection) were investigated using ELISA. RESULTS: Analysis of the Treg cells population in patients and controls revealed that expression of CD4+ CD25high+ T lymphocytes was higher in patients than in controls (mean+/-SD 15.7+/-4.1 and 10.61+/-2.6 in patients and controls, respectively, and MFI of Foxp3 was 30.1+/-7.1 and 16.7+/-3.7 in patients and controls, respectively (p<0.001)). There was a high incidence of latent EBV infection in patients (31%) compared with controls (10%) while the incidence of acute infection was 12% in patients and 0% in the control group. To study the role of latent EBV infection in the pathogenesis of acute B-ALL, OR was calculated (OR=4.06, coefficient index 1.2-13.6). CONCLUSIONS: These findings suggest a possible role for Treg cells and EBV in the pathogenesis of B-ALL. Further studies are needed on the possible mechanisms of tumour genesis related to Treg cells and EBV in children with B-ALL. PMID- 27458151 TI - Three are charged in $1bn US Medicare fraud case. PMID- 27458152 TI - High expression of cholesterol biosynthesis genes is associated with resistance to statin treatment and inferior survival in breast cancer. AB - There is sufficient evidence that statins have a protective role against breast cancer proliferation and recurrence, but treatment predictive biomarkers are lacking. Breast cancer cell lines displaying diverse sensitivity to atorvastatin were subjected to global transcriptional profiling and genes significantly altered by statin treatment were identified. Atorvastatin treatment strongly inhibited proliferation in estrogen receptor (ER) negative cell lines and a commensurate response was also evident on the genome-wide transcriptional scale, with ER negative cells displaying a robust deregulation of genes involved in the regulation of cell cycle progression and apoptosis. Interestingly, atorvastatin upregulated genes involved in the cholesterol biosynthesis pathway in all cell lines, irrespective of sensitivity to statin treatment. However, the level of pathway induction; measured as the fold change in transcript levels, was inversely correlated to the effect of statin treatment on cell growth. High expression of cholesterol biosynthesis genes before treatment was associated with resistance to statin therapy in cell lines and clinical biopsies. Furthermore, high expression of cholesterol biosynthesis genes was independently prognostic for a shorter recurrence-free and overall survival, especially among ER positive tumors. Dysregulation of cholesterol biosynthesis is therefore predictive for both sensitivity to anti-cancer statin therapy and prognosis following primary breast cancer diagnosis. PMID- 27458153 TI - Upregulation of brain-derived neurotrophic factor in advanced gastric cancer contributes to bone metastatic osteolysis by inducing long pentraxin 3. AB - The brain-derived neurotrophic factor (BDNF) activates its receptor, tropomyosin receptor kinase B (TrkB; also called NTRK2) that has been shown to promote the malignant progression of several cancers. In this study, we investigated the clinical and biological significance of the BDNF/TrkB axis in the progression of human gastric cancer. The increased co-expression of the BDNF/TrkB axis was significantly correlated with bone metastatic properties in advanced gastric cancers. BDNF acting via TrkB receptors increased the levels of long pentraxin 3 (PTX3) that was related to bone metastatic status of gastric cancer by enhancing gastric cancer-osteoblastic niche interactions. In bone metastatic gastric cancer, PTX3 knockdown using small interfering RNA significantly inhibited BDNF induced interactions of cancer cells with osteoblasts. Moreover, BDNF-derived PTX3 induction supported subsequent osteoclastogenesis, and this effect was significantly reversed by PTX3 silencing. These findings suggest that a functional interaction between BDNF/TrkB and PTX3 enhances the osteolysis of bone metastatic gastric cancer, thereby providing potential prognostic factors for the development of bone metastasis of gastric cancer. PMID- 27458154 TI - Oncogenic effects of urotensin-II in cells lacking tuberous sclerosis complex-2. AB - Lymphangioleiomyomatosis (LAM) is a destructive lung disease that can arise sporadically or in adults suffering from the tumor syndrome tuberous sclerosis complex (TSC). Microscopic tumors ('LAM nodules') in the lung interstitium arise from lymphatic invasion and metastasis. These consist of smooth muscle-like cells (LAM cells) that exhibit markers of neural crest differentiation and loss of the tumor suppressor protein 'tuberous sclerosis complex-2' (TSC2). Consistent with a neural phenotype, expression of the neuropeptide urotensin-II and its receptor was detected in LAM nodules. We hypothesized that loss of TSC2 sensitizes cells to the oncogenic effects of urotensin-II. TSC2-deficient Eker rat uterine leiomyoma ELT3 cells were stably transfected with empty vector or plasmid for the expression of TSC2. Urotensin-II increased cell viability and proliferation in TSC2-deficient cells, but not in TSC2-reconstituted cells. When exposed to urotensin-II, TSC2-deficient cells exhibited greater migration, anchorage independent cell growth, and matrix invasion. The effects of urotensin-II on TSC2 deficient cells were blocked by the urotensin receptor antagonist SB657510, and accompanied by activation of Erk mitogen-activated protein kinase and focal adhesion kinase. Urotensin-II-induced proliferation and migration were reproduced in TSC2-deficient human angiomyolipoma cells, but not in those stably expressing TSC2. In a mouse xenograft model, SB657510 blocked the growth of established ELT3 tumors, reduced the number of circulating tumor cells, and attenuated the production of VEGF-D, a clinical biomarker of LAM. Urotensin receptor antagonists may be selective therapeutic agents for the treatment of LAM or other neural crest-derived neoplasms featuring loss of TSC2 or increased expression of the urotensin receptor. PMID- 27458156 TI - MALAT1 promotes osteosarcoma development by targeting TGFA via MIR376A. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non coding RNA (lncRNA) that contributes to the initiation and development of many solid tumors, including osteosarcoma (OS). Here, we showed that MALAT1 was increased in human OS cell lines and tissues and promoted OS cell growth, while MALAT1 knockdown suppressed OS cell growth. We also detected downregulation of MIR376A, a suppressor of OS growth, and upregulation of TGFA, a promoter of OS growth, in OS tissues. TGFA expression was positively correlated with MALAT1 expression, and both were negatively correlated with MIR376A expression. There was a direct interaction between MIR376A and MALAT1 via a putative MIR376A binding site within the MALAT1 3'-untranslated region (3'-UTR). There was also a direct interaction between MIR376A and the TGFA 3'-UTR. Thus, MALAT1 may promote OS cell growth through inhibition of MIR376A, leading to increased expression of TGFA. Our results suggest a MALAT1/MIR376A/TGFA axis mediates OS cell proliferation and tumor progression. PMID- 27458157 TI - PAX3 is a novel tumor suppressor by regulating the activities of major signaling pathways and transcription factor FOXO3a in thyroid cancer. AB - Paired box 3 (PAX3) is expressed early during embryonic development in spatially restricted domains in the nervous system and in some mesodermally-derived structure. In recent years, it is found to be overexpressed in different types of cancer tissues and cell lines including glioblastomas, neuroblastomas, melanomas, rhabdomyosarcomas, Ewing sarcomas and gastric cancers, suggesting that it may function as an oncogene in these cancers. However, its role in thyroid cancer remains totally unclear. The aim of this study was to explore the functions and related molecular mechanism of PAX3 in thyroid tumorigenesis. Using quantitative RT-PCR (qRT-PCR) and Methylation-specific PCR (MSP) assays, we demonstrated that PAX3 was frequently down-regulated by promoter methylation in both primary thyroid cancer tissues and thyroid cancer cell lines. In addition, our data showed that ectopic expression of PAX3 dramatically inhibited thyroid cancer cell proliferation, colony formation, migration and invasion, induced cell cycle arrest and apoptosis and retarded tumorigenic potential in nude mice. Mechanically, PAX3 exerted its tumor suppressor function by inhibiting the activity of major signaling pathways including the phosphatidylinositol-3-kinase (PI3K)/Akt and MAPK/Erk pathways, and enhancing expression and activity of transcription factor FOXO3a. Altogether, our findings provided insight into the role of PAX3 as a novel functional tumor suppressor in thyroid cancer through modulating the activities of PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a, and demonstrated that epigenetic alterations such as promoter methylation should be a major mechanism of PAX3 inactivation in this cancer. PMID- 27458158 TI - Association between single nucleotide polymorphisms in the TSPYL6 gene and breast cancer susceptibility in the Han Chinese population. AB - We investigated the associations between single nucleotide polymorphisms (SNPs) in the testis-specific Y-encoded-like protein 6 (TSPYL6) gene and breast cancer (BC) susceptibility in the Han Chinese population. A total of 183 BC patients and 195 healthy women were included in the study. Six SNPs in TSPYL6 were genotyped and the association with BC risk analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used to identify SNPs that correlated with BC susceptibility. Rs11896604 was associated with a decreased risk of BC based on dominant and genotype models. Rs843706 was associated with an increased risk of BC based on a recessive model. Rs11125529 was associated with decreased BC susceptibility based on a genotype model. Finally, rs843711 inversely correlated with clinical stage III/IV BC. Our findings reveal a significant association between SNPs in the TSPYL6 gene and BC risk in a Han Chinese population. PMID- 27458159 TI - Tristetraprolin functions in cytoskeletal organization during mouse oocyte maturation. AB - Tristetraprolin (TTP), a member of TIS11 family containing CCCH tandem zinc finger, is one of the best characterized RNA-binding proteins. However, to date, the role of TTP in mammalian oocytes remains completely unknown. In the present study, we report the altered maturational progression and cytokinesis, upon specific knockdown of TTP in mouse oocytes. Furthermore, by confocal scanning, we observe the failure to form cortical actin cap during meiosis of TTP-depleted oocytes. Loss of TTP in oocytes also results in disruption of meiotic spindle morphology and chromosome alignment. In support of these findings, incidence of aneuploidy is accordingly increased when TTP is abated in oocytes. Our results suggest that TTP as a novel cytoskeletal regulator is required for spindle morphology/chromosome alignment and actin polymerization in oocytes. PMID- 27458160 TI - The mTOR/AP-1/VEGF signaling pathway regulates vascular endothelial cell growth. AB - Vascular restenosis is a common adverse event following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The atypical Ser/Thr protein kinase mammalian target of rapamycin (mTOR) plays an important role in cell differentiation and apoptosis. Vascular restenosis caused by excessive endothelial cell proliferation can be inhibited by local application of the mTOR inhibitor rapamycin (RAPA); however, RAPA can also suppress normal vascular endothelial cell growth by blocking mTOR/VEGF signaling, although the underlying mechanism is still unclear. Here, endogenous mTOR, AP-1, and VEGF were inhibited or overexpressed to investigate the mechanism underlying the effects of RAPA. Inhibition of AP-1 or mTOR with AP-1-siRNA or RAPA treatment respectively, decreased vascular endothelial cell proliferation, upregulation of AP-1 or mTOR increased cell proliferation, and VEGF overexpression increased, while RAPA induced mTOR inhibition decreased vascular endothelial cell proliferation, the results indicate that combining mTOR downregulation and VEGF upregulation might both inhibit restenosis and maintain normal vascular endothelial cell growth after PCI or CABG, suggest the mTOR/AP-1/VEGF pathway might play a crucial role in regulating vascular endothelial cell growth. PMID- 27458161 TI - Crosstalk between integrin alphavbeta3 and ERalpha contributes to thyroid hormone induced proliferation of ovarian cancer cells. AB - Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin alphavbeta3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10-7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin alphav or beta3 by RNAi blocked thyroid hormone induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor alpha (ERalpha). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin alphav and phosphorylation of ERalpha. The specific ERalpha antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERalpha phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin alphav and phosphorylated ERalpha was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERalpha and integrin alphav are dissimilar. Chromatin immunoprecipitation results showed that T4 induced binding of integrin alphav monomer to ERalpha promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin alphav and ERalpha, mimicking functions of E2. PMID- 27458162 TI - Hypoxia-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated sodium iodide symporter gene delivery. AB - Adoptively transferred mesenchymal stem cells (MSCs) home to solid tumors. Biologic features within the tumor environment can be used to selectively activate transgenes in engineered MSCs after tumor invasion. One of the characteristic features of solid tumors is hypoxia. We evaluated a hypoxia-based imaging and therapy strategy to target expression of the sodium iodide symporter (NIS) gene to experimental hepatocellular carcinoma (HCC) delivered by MSCs.MSCs engineered to express transgenes driven by a hypoxia-responsive promoter showed robust transgene induction under hypoxia as demonstrated by mCherry expression in tumor cell spheroid models, or radioiodide uptake using NIS. Subcutaneous and orthotopic HCC xenograft mouse models revealed significant levels of perchlorate sensitive NIS-mediated tumoral radioiodide accumulation by tumor-recruited MSCs using 123I-scintigraphy or 124I-positron emission tomography. Functional NIS expression was further confirmed by ex vivo 123I-biodistribution analysis. Administration of a therapeutic dose of 131I in mice treated with NIS-transfected MSCs resulted in delayed tumor growth and reduced tumor perfusion, as shown by contrast-enhanced sonography, and significantly prolonged survival of mice bearing orthotopic HCC tumors. Interestingly, radioiodide uptake into subcutaneous tumors was not sufficient to induce therapeutic effects. Our results demonstrate the potential of using tumor hypoxia-based approaches to drive radioiodide therapy in non-thyroidal tumors. PMID- 27458163 TI - Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors. AB - Since epidermal growth factor receptor (EGFR) is commonly deregulated in pre malignant lung epithelium, targeting EGFR may arrest the development of lung cancer. Here, we showed that honokiol (2.5-7.5 MUM), a bioactive compound of Magnolia officinalis, differentially suppressed proliferation (up to 93%) and induced apoptosis (up to 61%) of EGFR overexpressing tumorigenic bronchial cells and these effects were paralleled by downregulation of phospho-EGFR, phospho-Akt, phospho-STAT3 and cell cycle-related proteins as early as 6-12 h post-treatment. Autocrine secretion of EGF sensitized 1170 cells to the effects of honokiol. Molecular docking studies indicated that honokiol binds to the tyrosine kinase domain of EGFR although it was less efficient than erlotinib. However, the anti proliferative and pro-apoptotic activities of honokiol were stronger than those of erlotinib. Upon combinatory treatment, honokiol sensitized bronchial cells and erlotinib resistant H1650 and H1975 cells to erlotinib. Furthermore, in a mouse lung tumor bioassay, intranasal instillation of liposomal honokiol (5 mg/kg) for 14 weeks reduced the size and multiplicity (49%) of lung tumors and the level of total- and phospho-EGFR, phospho-Akt and phospho-STAT3. Overall, our results indicate that honokiol is a promising candidate to suppress the development and even progression of lung tumors driven by EGFR deregulation. PMID- 27458164 TI - Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling. AB - Fms-like tyrosine kinase (FLT3) is a frequently mutated oncogene in acute myeloid leukemia (AML). FLT3 inhibitors display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, a better understanding of FLT3 downstream signal transduction pathways will help to identify an alternative target for the treatment of AML patients carrying oncogenic FLT3. Activation of FLT3 results in phosphorylation of FLT3 on several tyrosine residues that recruit SH2 domain containing signaling proteins. We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. SLAP2 binding sites in FLT3 mainly overlap with those of SRC. SLAP2 over expression in murine proB cells or myeloid cells inhibited oncogenic FLT3-ITD-mediated cell proliferation and colony formation in vitro, and tumor formation in vivo. Microarray analysis suggests that higher SLAP2 expression correlates with a gene signature similar to that of loss of oncogene function. Furthermore, FLT3-ITD positive AML patients with higher SLAP2 expression displayed better prognosis compared to those with lower expression of SLAP2. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5. Finally, SLAP2 accelerated FLT3 degradation through enhanced ubiquitination. Collectively, our data suggest that SLAP2 acts as a negative regulator of FLT3 signaling and therefore, modulation of SLAP2 expression levels may provide an alternative therapeutic approach for FLT3 ITD positive AML. PMID- 27458165 TI - MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A. AB - MicroRNA expression profiling assays have shown that miR-34b/c and miR-449a are down-regulated in nasopharyngeal carcinoma (NPC); however, the targets and functions of miR-34b/c and miR-449a in the pathologenesis of NPC remain elusive. In this study, we verified miR-34b/c and miR-449a were significantly reduced with the advance of NPC. Overexpression of miR-34b-3 and miR-449a suppressed the growth of NPC cells in culture and mouse tumor xenografts. Using tandem mass tags for quantitative labeling and LC-MS/MS analysis to investigate protein changes after restoring expression of miR-34b-3, 251 proteins were found to be down regulated after miR-34b-3 transfection. Through 3 replicate experiments, we found that miR-34b-3 regulated the expression of 15 potential targeted genes mainly clustered in the key enzymes of glycolysis metabolism, including lactate dehydrogenase A (LDHA). Further investigation revealed that miR-34b-3 and miR 449a negatively regulated LDHA by binding to the 3' untranslated regions of LDHA. Furthermore, LDHA overexpression rescued the miR-34b-3 and miR-449a induced tumor inhibition effect in CNE2 cells. In addition, miR-34b-3 and miR-449a suppressed LDH activity and reduced LD content, which were directly induced by downregulation of the LDHA. Our findings suggest that miR-34b-3 and miR-449a suppress the development of NPC through regulation of glycolysis via targeting LDHA and may be potential therapeutic targets for the treatment of NPC. PMID- 27458166 TI - Efficacy and safety of proprotein convertase subtilisin/kexin type 9 monoclonal antibody in adults with familial hypercholesterolemia. AB - Proprotein convertase-subtilisin/kexin type 9 (PCSK9) monoclonal antibody is a new therapy to reduce low-density lipoprotein cholesterol (LDL-C) level in patients with familial hypercholesterolemia (FH). This pooled analysis aimed to estimate the efficacy and safety of PCSK9 antibody therapy in FH. Reports of randomized controlled trials (RCTs) comparing PCSK9 antibody to placebo were retrieved by a search of MEDLINE via PubMed, EMBASE, the Cochrane Library databases, ClinicalTrials.gov and Clinical Trial Results (up to November 30, 2015) with no language restriction. Data were abstracted by a standardized protocol. We found eight RCTs (1,879 patients with FH) for the pooled analysis. As compared with placebo, PCSK9 antibody therapy remarkably reduced LDL-C level (mean reduction: -48.54 %, 95 % CI: -53.19 to -43.88), total cholesterol (mean reduction: -31.08%, 95 % CI: -35.20 to -26.95), lipoprotein (a) (mean reduction: 20.44%, 95 % CI: -25.21 to -15.66), and apolipoprotein B (mean reduction: 36.32%, 95 % CI: -40.75 to -31.90) and elevated the level of high-density lipoprotein cholesterol (mean change: 6.29 %, 95 % CI: 5.12 to 7.46) and apolipoprotein A1(mean change: 4.86%, 95 % CI: 3.77 to 5.95). Therapy with and without PCSK9 antibodies did not differ in rate of adverse events (pooled rate: 50.86 % vs. 48.63%; RR: 1.03; 95 % CI: 0.92 to 1.15; P = 0.64; heterogeneity P = 0.13; I2= 40%) or serious adverse events (pooled rate: 7.14% vs. 6.74%; RR: 1.05; 95 % CI: 0.70 to 1.58; P = 0.80; heterogeneity P = 0.69; I2= 0%). PCSK9 antibody may be an effective and safe treatment for FH. PMID- 27458167 TI - A network meta-analysis: the overall and progression-free survival of glioma patients treated by different chemotherapeutic interventions combined with radiation therapy (RT). AB - Different chemotherapy drugs are generally introduced in clinical practices combining with therapy for glioma treatment. However, these chemotherapy drugs have rarely been compared with each other and the optimum drug still remains to be proved. In this research, medical databases were consulted, PubMed, Embase and Cochrane Library included. As primary outcomes, hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with their corresponding 95% credential intervals (CrI) were reported. A network meta-analysis was conducted; the surface under the cumulative ranking curve (SUCRA) was utilized for treatment rank and a cluster analysis based on SUCRA values was performed. This research includes 14 trials with 3,681 subjects and eight interventions. In terms of network meta-analysis, placebo was proved to be inferior to the combination of temozolomide (TMZ), nimustine (ACNU) and cisplatin (CDDP). Also, bevacizumab (BEV) in conjunction with TMZ were significantly more effective than placebo with an HR of 0.40. The estimated probabilities from SUCRA verified the above outcomes, confirming that the combination of TMZ, ACNU and CDDP exhibited the highest ranking probability of 0.889 with respect to OS, while BEV in combination with TMZ - with a probability of 0.772 - ranked the first place with respect to PFS. According to the results of this network meta-analysis, the combination of (1) TMZ, ACNU and CDDP; (2) BEV in combination with TMZ and (3) cilengitide in combination with TMZ, are considered as the preferable choices of chemotherapy drugs for glioma treatment. PMID- 27458168 TI - Bendamustine for the treatment of relapsed or refractory peripheral T cell lymphomas: A French retrospective multicenter study. AB - Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and few therapeutic options. We aimed to assess the efficacy of bendamustine in real life cohort of patients.Between November 2009 and March 2015, 138 PTCL patients were treated with bendamustine in 27 centers. Population median age was 64 (28 89) years with male/female ratio of 1.4. There were mainly angio-immunoblastic (AITL = 71), PTCL-not otherwise specified (PTCL-NOS = 40) and anaplastic large cell lymphoma (ALCL = 8). The majority of patients (96%) had disseminated disease and extranodal localizations (77%). Median number of chemotherapy lines prior to bendamustine was 2 (1-8). Median duration of response (DoR) after the last chemotherapy prior to bendamustine was 4.3 months (1-70) and 50% of patients had refractory disease.Median number of administered bendamustine cycles was 2 (1-8) and 72 patients (52%) received less than 3 mostly because of disease progression. Median dose was 90 (50-150) mg/m2. Overall response rate (ORR) was 32.6% with complete response (CR) rate of 24.6% and median DoR was 3.3 months (1-39). AITL patients were more sensitive than PTCL-NOS patients (ORR: 45.1 versus 20%, p = 0.01). Median PFS and OS were 3.1 (0.2-46.3) and 4.4 (0.2-55.4) months. On multivariate analysis, refractory disease (p = 0.001) and extranodal localization (p = 0.028) adversely influenced ORR. Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22, 17 and 23% of cases respectively.Bendamustine as single agent could be considered as a therapeutic option for relapsed or refractory PTCL, particularly in chemosensitive or AITL patients. Combinations of bendamustine with other drugs warrant further evaluation. PMID- 27458169 TI - Epigenetics in myeloid derived suppressor cells: a sheathed sword towards cancer. AB - Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells composed of progenitors and precursors to myeloid cells, are deemed to participate in the development of tumor-favoring immunosuppressive microenvironment. Thus, the regulatory strategies targeting MDSCs' expansion, differentiation, accumulation and function could possibly be effective "weapons" in anti-tumor immunotherapies. Epigenetic mechanisms, which involve DNA modification, covalent histone modification and RNA interference, result in the heritable down-regulation or silencing of gene expression without a change in DNA sequences. Epigenetic modification of MDSC's functional plasticity leads to the remodeling of its characteristics, therefore reframing the microenvironment towards countering tumor growth and metastasis. This review summarized the pertinent findings on the DNA methylation, covalent histone modification, microRNAs and small interfering RNAs targeting MDSC in cancer genesis, progression and metastasis. The potentials as well as possible obstacles in translating into anti-cancer therapeutics were also discussed. PMID- 27458170 TI - Carfilzomib/pomalidomide single-agent or in combination with other agents for the management of relapsed/refractory multiple myeloma: a meta-analysis of 37 trials. AB - PURPOSE: The use of carfilzomib/pomalidomide single-agent or in combination with other agents in patients with refractory/relapsed multiple myeloma (RRMM) was not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the efficacy and safety of carfilzomib (CFZ) and pomalidomide (POM). RESULTS: Based on our research criteria, we identified 37 prospective studies that evaluated 1160 patients. Analysis of subgroup differences between carfilzomib single-agent and CFZ/DEX dual combination showed significantly(P < 0.001, I2 = 96.3%), suggesting the overall response rate (ORR) of 66% attained from CFZ/DEX dual combination seemed to be higher than that of 28% from carfilzomib single-agent. And, the same trend favoring CFZ/DEX dual combination was found in >=VGPR and CBR analysis. The ORR of 31% attained from POM/DEX dual combination was superior to that of 19% from pomalidomide single-agent(P < 0.001, I2 = 94.4%). And, the same trend favoring POM/DEX dual combination was found in >=VGPR and CBR analysis. However, the ORR of 83% attained from POM/BOR/DEX triplet combination was superior to that of 31% from POM/DEX dual combination(P < 0.001, I2 = 99.1%). And, the same trend favoring POM/BOR/DEX triplet combination was found in >=VGPR analysis. METHODS: We searched published reports including carfilzomib and (or) pomalidomide therapy for RRMM who had received bortezomib and (or) lenalidomide. CONCLUSION: Pomalidomide/Carfilzomib plus dexamethasone seemed to attain a superior response rate compared with pomalidomide/carfilzomib single-agent. Furthermore, the combination of pomalidomide, bortezomib and dexamethasone resulted in a much higher response rate compared with pomalidomide plus dexamethasone regimen. These results needed more validation in future trials. PMID- 27458172 TI - The effect of alendronate soaking and ultraviolet treatment on bone-implant interface. AB - OBJECTIVE: Rapid and stable fixation of dental implants is crucial for successful treatment. Herein, we examined whether the simultaneous treatment of titanium implants with ultraviolet (UV) and alendronate (ALN) synergistically improved the bone-to-implant contact. MATERIALS AND METHODS: We assessed the in vitro effects of UV radiation-treated (UV+/ALN-), ALN-soaked (UV-/ALN+), and UV radiation/ALN treated (UV+/ALN+) titanium implants on cell proliferation, cytotoxicity, cell adhesion, and osteoblast differentiation using MG-63 osteoblast-like cells by the assays of MTS, live/dead, scanning electron microscopy (SEM), alkaline phosphatase (ALP) activity, and alizarin red S (AR-S) staining, respectively. Furthermore, in vivo bone formation at the bone-implant interface efficiency determined using a rabbit tibia implantation. Implants were divided into 3 experimental groups (UV+/ALN-, UV-/ALN+, UV+/ALN+) and the non-treated control (UV-/ALN-) group and transplanted into the proximal tibia of rabbits. At 1, 2, 4, and 8 weeks post-operation, bone formation at the bone-implant interface was evaluated by micro-computed tomography and histological analysis. RESULTS: MG-63 cells cultured on UV+/ALN+ implants showed significantly higher cell proliferation, ALP activity, and calcium mineralization than those cultured on other implants (P < 0.05). Furthermore, SEM observation showed the highest increase in cell attachment and growth on the UV+/ALN+ implants. In vivo, experimental groups at all time points showed greater peri-implant bone formation than the control group. At 8 weeks post-implantation, in the UV+/ALN+ group, significantly higher bone formation was observed than the UV+/ALN- or UV-/ALN+ group, respectively (P < 0.05). CONCLUSIONS: Treatment of titanium surfaces with UV and ALN may synergistically enhance osteoblastic differentiation and mineralization in vitro and enhance bone formation at the bone-implant interface in vivo. These data suggest that UV and ALN treatment may improve the osseointegration of titanium implants. PMID- 27458171 TI - Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer. AB - Persistent STAT3 activation is seen in many tumor cells and promotes malignant transformation. Here, we investigated whether capsazepine (Capz), a synthetic analogue of capsaicin, exerts anticancer effects by inhibiting STAT3 activation in prostate cancer cells. Capz inhibited both constitutive and induced STAT3 activation in human prostate carcinoma cells. Capz also inhibited activation of the upstream kinases JAK1/2 and c-Src. The phosphatase inhibitor pervanadate reversed Capz-induced STAT3 inhibition, indicating that the effect of Capz depends on a protein tyrosine phosphatase. Capz treatment increased PTPepsilon protein and mRNA levels. Moreover, siRNA-mediated knockdown of PTPepsilon reversed the Capz-induced induction of PTPepsilon and inhibition of STAT3 activation, indicating that PTPepsilon is crucial for Capz-dependent STAT3 dephosphorylation. Capz also decreased levels of the protein products of various oncogenes, which in turn inhibited proliferation and invasion and induced apoptosis. Finally, intraperitoneal Capz administration decreased tumor growth in a xenograft mouse prostate cancer model and reduced p-STAT3 and Ki-67 expression. These data suggest that Capz is a novel pharmacological inhibitor of STAT3 activation with several anticancer effects in prostate cancer cells. PMID- 27458173 TI - Oral health status in older immigrants in a medium-sized Swedish city. AB - AIM: The aim of the study was to investigate oral health and oral care habits among older immigrants to Sweden from countries outside the Nordic region. METHOD: Participants >=60 years of age from senior social centers for immigrants were invited to attend oral examinations. Data was collected on the number of teeth, dentures, caries, periodontal status, saliva secretion, and plaque scores. Participants also described their general health and oral care habits. RESULTS: Fourteen men and 28 women, median age 71.5 years, participated. Seventeen percent were edentulous, women often than men. Three out of four had caries and 63% had gingival bleeding. Two-thirds brushed their teeth twice per day and 60% had visited dental services in the last 2 years. CONCLUSION: The group had a high prevalence of oral diseases and discomfort. They used dental services and brushed their teeth less frequently than Swedish populations of the same age. PMID- 27458174 TI - Simultaneous Preconcentration of Copper and Cadmium by Dispersive Liquid-Liquid Microextraction Using N,N'-Bis (2-Hydroxy-5-Bromo-Benzyl)1,2 Diaminopropane and Their Determination by Flame Atomic Absorption Spectrometry. AB - In the present study, the simultaneous preconcentration of copper and cadmium based on dispersive liquid-liquid microextraction as a prior step to their determination using flame atomic absorption spectrometry was developed. Carbon tetrachloride and N,N'-bis(2-hydroxy-5-bromo-benzyl)1,2 diaminopropane were used as the extraction solvent and chelating ligand, respectively. Some parameters that influence the extraction efficiency-e.g., sample pH, volume of extraction solvent (carbon tetrachloride), concentration of the chelating ligand, effect of salt addition, and sample volume-were investigated and optimized. With a preconcentration factor of 10, the LODs (3sigma) for Cd and Cu were 0.69 and 1.98 MUg/L, respectively. The accuracy of the developed method was evaluated by analyzing SLRS-5 river water and SRM 1573a tomato leaves certified reference materials. Results obtained were in good agreement with the certified values. The proposed method was successfully applied to river water, seawater, and black tea samples. Good spike recoveries, varying within the range of 97.5 to 116.9%, confirmed the good performance of the method in real sample analysis. PMID- 27458175 TI - Integrative Analysis of Microarray Data to Reveal Regulation Patterns in the Pathogenesis of Hepatocellular Carcinoma. AB - Background/Aims: The integration of multiple profiling data and the construction of a transcriptional regulatory network may provide additional insights into the molecular mechanisms of hepatocellular carcinoma (HCC). The present study was conducted to investigate the deregulation of genes and the transcriptional regulatory network in HCC. Methods: An integrated analysis of HCC gene expression datasets was performed in Gene Expression Omnibus. Functional annotation of the differentially expression genes (DEGs) was conducted. Furthermore, transcription factors (TFs) were identified, and a global transcriptional regulatory network was constructed. Results: An integrated analysis of eight eligible gene expression profiles of HCC led to 1,835 DEGs. Consistent with the fact that the cell cycle is closely related to various tumors, the functional annotation revealed that genes involved in the cell cycle were significantly enriched. A transcriptional regulatory network was constructed using the 62 TFs, which consisted of 872 TF-target interactions between 56 TFs and 672 DEGs in the context of HCC. The top 10 TFs covering the most downstream DEGs were ZNF354C, NFATC2, ARID3A, BRCA1, ZNF263, FOXD1, GATA3, FOXO3, FOXL1, and NR4A2. This network will appeal to future investigators focusing on the development of HCC. Conclusions: The transcriptional regulatory network can provide additional information that is valuable in understanding the underlying molecular mechanism in hepatic tumorigenesis. PMID- 27458176 TI - Irritable Bowel Syndrome, Particularly the Constipation-Predominant Form, Involves an Increase in Methanobrevibacter smithii, Which Is Associated with Higher Methane Production. AB - Background/Aims: Because Methanobrevibacter smithii produces methane, delaying gut transit, we evaluated M. smithii loads in irritable bowel syndrome (IBS) patients and healthy controls (HC). Methods: Quantitative real-time polymerase chain reaction for M. smithii was performed on the feces of 47 IBS patients (Rome III) and 30 HC. On the lactulose hydrogen breath test (LHBT, done for 25 IBS patients), a fasting methane result >=10 ppm using 10 g of lactulose defined methane-producers. Results: Of 47, 20 had constipation (IBS-C), 20 had diarrhea (IBS-D) and seven were not sub-typed. The M. smithii copy number was higher among IBS patients than HC (Log105.4, interquartile range [IQR; 3.2 to 6.3] vs 1.9 [0.0 to 3.4], p<0.001), particularly among IBS-C compared to IBS-D patients (Log106.1 [5.5 to 6.6] vs 3.4 [0.6 to 5.7], p=0.001); the copy number negatively correlated with the stool frequency (R=-0.420, p=0.003). The M. smithii copy number was higher among methane-producers than nonproducers (Log106.4, IQR [5.7 to 7.4] vs 4.1 [1.8 to 5.8], p=0.001). Using a receiver operating characteristic curve, the best cutoff for M. smithii among methane producers was Log106.0 (sensitivity, 64%; specificity, 86%; area under curve [AUC], 0.896). The AUC for breath methane correlated with the M. smithii copy number among methane producers (r=0.74, p=0.008). Abdominal bloating was more common among methane producers (n=9/11 [82%] vs 5/14 [36%], p=0.021). Conclusions: Patients with IBS, particularly IBS C, had higher copy numbers of M. smithii than HC. On LHBT, breath methane levels correlated with M. smithii loads. PMID- 27458177 TI - Impact of Long-Term Proton Pump Inhibitor Therapy on Gut Microbiota in F344 Rats: Pilot Study. AB - Background/Aims: To evaluate changes in gut microbiota composition following long term proton pump inhibitor (PPI) treatment. Methods: Twenty-four-week-old F344 rats were fed diets with (n=6) or without (n=5) lansoprazole for 50 weeks. Profiles of luminal microbiota in the terminal ileum were then analyzed. Pyrosequencing of the 16S rRNA gene was performed using an FLX genome sequencer (454 Life Sciences/Roche). Results: Rats treated with lansoprazole showed significantly reduced body weights compared to controls (lansoprazole-treated rats and controls, 322.3+/-15.3 g vs 403.2+/-5.2 g, respectively, p<0.001). However, stool frequencies and consistencies did not differ between the two groups. The composition of the gut microbiota in lansoprazole-treated rats was quite different from that of the controls. In the controls, the microbiota profiles obtained from the terminal ileum showed a predominance of Proteobacteria (93.9%) due to the abundance of Escherichia and Pasteurella genera. Conversely, lansoprazole-treated rats showed an elevated population of Firmicutes (66.9%), which was attributed to an increased ratio of Clostridium g4 to Lactobacillus genera. Conclusions: This preliminary study suggests that long-term administration of PPI may cause weight loss and changes to the microbiota in the terminal ileum. PMID- 27458178 TI - The Combination of Periostin Overexpression and Microvascular Invasion Is Related to a Poor Prognosis for Hepatocellular Carcinoma. AB - Background/Aims: Periostin is an extracellular matrix protein and is known to be related to the metastatic potential and prognosis of cancer. However, few studies have investigated the expression level of periostin and its association with prognoses in hepatocellular carcinoma. Therefore, we analyzed periostin overexpression in hepatocellular carcinoma and its implication for prognoses. Methods: We evaluated 149 patients who underwent surgical resection between 2006 and 2010. Tissue microarrays were constructed from hepatocellular carcinoma tissue and adjacent nontumor tissue, and immunohistochemistry was performed. Results: A high periostin level was observed more frequently in cases of multiple tumors (odds ratio [OR], 2.826; 95% confidence interval [CI], 1.224 to 6.527; p=0.013), positive microvascular invasion (OR, 2.974; 95% CI, 1.431 to 6.181; p=0.003), and advanced stage disease (OR, 3.032; 95% CI, 1.424 to 6.452; p=0.003). Patients with high periostin expression had significantly (p=0.002) lower overall survival rates than those with low periostin expression (90.3%, 66.1%, and 56.2% vs 97.7%, 85.1%, and 77.5% at 1, 3, and 5 years). Conclusions: We found that a combination of periostin overexpression and microvascular invasion in hepatocellular carcinoma was correlated with a poor prognosis and can be a good prognostic marker for hepatocellular carcinoma. PMID- 27458179 TI - Two Distinct Types of Hypercontractile Esophagus: Classic and Spastic Jackhammer. AB - Hypercontractile esophagus (nicknamed jackhammer esophagus) is a recently defined disease within the esophageal motility disorders classification. Responses to treatments for jackhammer esophagus have been inconsistent in previous trials, possibly due to its heterogeneous manifestation. Thus, we reviewed 10 patients diagnosed with jackhammer esophagus and compared their clinical and manometric features at baseline. Additionally, manometric and symptomatic responses after treatment with known smooth muscle relaxants, including anticholinergic drugs (cimetropium bromide and scopolamine butylbromide) and a phosphodiesterase-5 inhibitor (sildenafil) were compared. We observed two distinct subgroups in the findings: one with hypercontractility and normal distal latencies ("classic jackhammer esophagus," n=7) and the other with hypercontractility and short distal latencies ("spastic jackhammer esophagus," n=3). The two types also differed in their responses to medications in that symptoms improved upon treatment with an anticholinergic agent in classic jackhammer esophagus patients, while spastic jackhammer esophagus was unresponsive to both the anticholinergic drugs and the phosphodiesterase-5 inhibitor. In conclusion, hypercontractile esophagus may be a heterogeneous disease with different underlying pathophysiologies. We introduced two novel terms, "classic jackhammer esophagus" and "spastic jackhammer esophagus," to distinguish the two types. PMID- 27458181 TI - India is urged to resist US pressure to rein in its affordable medicines policies. PMID- 27458180 TI - Helicobacter pylori Infection with Atrophic Gastritis Is an Independent Risk Factor for Advanced Colonic Neoplasm. AB - Background/Aims: Helicobacter pylori is a major risk factor for atrophic gastritis (AG) and gastric cancer. The correlation between H. pylori, AG and colorectal neoplasm (CRN) has only been examined in a limited number of studies, and findings have been inconclusive. We aimed to investigate the association between H. pylori infection status, AG and advanced CRN. Methods: This cross sectional study investigated the relationship between the presence of serum anti H. pylori IgG antibodies, AG, and advanced CRN in 6,351 consecutive asymptomatic subjects who underwent a screening colonoscopy. Results: A total of 316 participants (5.0%) had advanced CRN. H. pylori seropositivity was 61.3%. In a univariate analysis, the presence of H. pylori infection was associated with advanced CRN (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.17 to 1.91; p=0.001). H. pylori infection was associated with an increased risk of advanced CRN after adjusting for clinically relevant confounders (OR, 1.34; 95% CI, 1.04 to 1.72; p=0.023). H. pylori-related AG was significantly associated with the risk of advanced CRN (OR, 1.40; 95% CI, 1.03 to 1.91; p=0.030), whereas H. pylori infection without AG was not. Conclusions: H. pylori infection increased the risk of advanced CRN, especially when it was combined with AG. Strict colonoscopy screening and surveillance may be warranted in those with H. pylori-positive AG. PMID- 27458182 TI - Transthoracic echocardiographic imaging in diagnosis of post-operative left ventricular pseudoaneurysm. PMID- 27458183 TI - Multimodality imaging and histopathology of cardiac myeloid sarcoma. PMID- 27458184 TI - Left main artery compression by haematoma following acute aortic root dissection: identification by optical coherence tomography. PMID- 27458185 TI - Chronological observations of left ventricular-coronary sinus shunt formation after mitral prosthetic valve endocarditis. PMID- 27458186 TI - Comprehensive assessment of Valsalva sinus ruptured by using 4D flow cardiac magnetic resonance. PMID- 27458187 TI - Reactive underwater object inspection based on artificial electric sense. AB - Weakly electric fish can perform complex cognitive tasks based on extracting information from blurry electric images projected from their immediate environment onto their electro-sensitive skin. In particular they can be trained to recognize the intrinsic properties of objects such as their shape, size and electric nature. They do this by means of novel perceptual strategies that exploit the relations between the physics of a self-generated electric field, their body morphology and the ability to perform specific movement termed probing motor acts (PMAs). In this article we artificially reproduce and combine these PMAs to build an autonomous control strategy that allows an artificial electric sensor to find electrically contrasted objects, and to orbit around them based on a minimum set of measurements and simple reactive feedback control laws of the probe's motion. The approach does not require any simulation models and could be implemented on an autonomous underwater vehicle (AUV) equipped with artificial electric sense. The AUV has only to satisfy certain simple geometric properties, such as bi-laterally (left/right) symmetrical electrodes and possess a reasonably high aspect (length/width) ratio. PMID- 27458188 TI - High aspect ratio tungsten grating on ultrathin Si membranes for extreme UV lithography. AB - Extreme ultraviolet lithography is one of the modern lithography tools for high volume manufacturing with 22 nm resolution and beyond. But critical challenges exist to the design and fabrication of large-scale and highly efficient diffraction transmission gratings, significantly reducing the feature sizes down to 22 nm and beyond. To achieve such a grating, the surface flatness, the line edge roughness, the transmission efficiency and aspect ratio should be improved significantly. Delachat et al (2015 Nanotechnology 26 108262) develop a full process to fabricate a tungsten diffraction grating on an ultrathin silicon membrane with higher aspect ratio up to 8.75 that met all the aforementioned requirements for extreme ultraviolet lithography. This process is fully compatible with standard industrial extreme ultraviolet lithography. PMID- 27458189 TI - Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA mediated excitotoxicity. AB - Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults including stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, the molecular mechanisms regulating c-Jun abundance in neurons are poorly understood. Here, we show that the synaptic component Proline rich 7 (PRR7) accumulates in the nucleus of hippocampal neurons following NMDAR activity. We find that PRR7 inhibits the ubiquitination of c-Jun by E3 ligase SCF(FBW) (7) (FBW7), increases c-Jun-dependent transcriptional activity, and promotes neuronal death. Microarray assays show that PRR7 abundance is directly correlated with transcripts associated with cellular viability. Moreover, PRR7 knockdown attenuates NMDAR-mediated excitotoxicity in neuronal cultures in a c Jun-dependent manner. Our results show that PRR7 links NMDAR activity to c-Jun function and provide new insights into the molecular processes that underlie NMDAR-dependent excitotoxicity. PMID- 27458191 TI - AMPKalpha1: SUMO Wrestling Runx2 as a Strategy to Inhibit Arteriosclerotic Calcification. PMID- 27458190 TI - Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing. AB - The transmembrane recognition complex (TRC40) pathway mediates the insertion of tail-anchored (TA) proteins into membranes. Here, we demonstrate that otoferlin, a TA protein essential for hair cell exocytosis, is inserted into the endoplasmic reticulum (ER) via the TRC40 pathway. We mutated the TRC40 receptor tryptophan rich basic protein (Wrb) in hair cells of zebrafish and mice and studied the impact of defective TA protein insertion. Wrb disruption reduced otoferlin levels in hair cells and impaired hearing, which could be restored in zebrafish by transgenic Wrb rescue and otoferlin overexpression. Wrb-deficient mouse inner hair cells (IHCs) displayed normal numbers of afferent synapses, Ca2+ channels, and membrane-proximal vesicles, but contained fewer ribbon-associated vesicles. Patch-clamp of IHCs revealed impaired synaptic vesicle replenishment. In vivo recordings from postsynaptic spiral ganglion neurons showed a use-dependent reduction in sound-evoked spiking, corroborating the notion of impaired IHC vesicle replenishment. A human mutation affecting the transmembrane domain of otoferlin impaired its ER targeting and caused an auditory synaptopathy. We conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells. PMID- 27458192 TI - A New Editor of Smooth Muscle Phenotype. PMID- 27458193 TI - Consistently Inconsistent-Bone Marrow Mononuclear Stem Cell Therapy Following Acute Myocardial Infarction: A Decade Later. PMID- 27458194 TI - Adiponectin: Just Along for the Ride? PMID- 27458195 TI - General Overview of the 13th TECAM Conference: Time for a Global Initiative in 2016. PMID- 27458196 TI - Abandoning M1/M2 for a Network Model of Macrophage Function. PMID- 27458197 TI - The Need for Speed: Mice, Men, and Myocardial Kinetic Reserve. PMID- 27458198 TI - Renal Sympathetic Hyperactivity in Hypertension: True or False? PMID- 27458199 TI - Response by Grassi et al to Letter Regarding Article, "The Sympathetic Nervous System Alterations in Human Hypertension". PMID- 27458200 TI - Correction. PMID- 27458201 TI - An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting. AB - The CRISPR/Cas9 system is a powerful genome editing tool and has been widely used for biomedical research. However, many challenges, such as off-target effects and lack of easy solutions for multiplex targeting, are still limiting its applications. To overcome these challenges, we first developed a highly efficient doxycycline-inducible Cas9-EGFP vector. This vector allowed us to track the cells for uniform temporal control and efficient gene disruption, even in a polyclonal setting. Furthermore, the inducible CRISPR/Cas9 system dramatically decreased off target effects with a pulse exposure of the genome to the Cas9/sgRNA complex. To target multiple genes simultaneously, we established simple one-step cloning approaches for expression of multiple sgRNAs with improved vectors. By combining our inducible and multiplex genome editing approaches, we were able to simultaneously delete Lysine Demethylase (KDM) 5A, 5B and 5C efficiently in vitro and in vivo This user friendly and highly efficient toolbox provides a solution for easy genome editing with tight temporal control, minimal off-target effects and multiplex targeting. PMID- 27458202 TI - eIF2beta is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control. AB - In protein synthesis translation factor eIF2 binds initiator tRNA to ribosomes and facilitates start codon selection. eIF2 GDP/GTP status is regulated by eIF5 (GAP and GDI functions) and eIF2B (GEF and GDF activities), while eIF2alpha phosphorylation in response to diverse signals is a major point of translational control. Here we characterize a growth suppressor mutation in eIF2beta that prevents eIF5 GDI and alters cellular responses to reduced eIF2B activity, including control of GCN4 translation. By monitoring the binding of fluorescent nucleotides and initiator tRNA to purified eIF2 we show that the eIF2beta mutation does not affect intrinsic eIF2 affinities for these ligands, neither does it interfere with eIF2 binding to 43S pre-initiation complex components. Instead we show that the eIF2beta mutation prevents eIF5 GDI stabilizing nucleotide binding to eIF2, thereby altering the off-rate of GDP from eIF2*GDP/eIF5 complexes. This enables cells to grow with reduced eIF2B GEF activity but impairs activation of GCN4 targets in response to amino acid starvation. These findings provide support for the importance of eIF5 GDI activity in vivo and demonstrate that eIF2beta acts in concert with eIF5 to prevent premature release of GDP from eIF2gamma and thereby ensure tight control of protein synthesis initiation. PMID- 27458203 TI - SNP calling from RNA-seq data without a reference genome: identification, quantification, differential analysis and impact on the protein sequence. AB - SNPs (Single Nucleotide Polymorphisms) are genetic markers whose precise identification is a prerequisite for association studies. Methods to identify them are currently well developed for model species, but rely on the availability of a (good) reference genome, and therefore cannot be applied to non-model species. They are also mostly tailored for whole genome (re-)sequencing experiments, whereas in many cases, transcriptome sequencing can be used as a cheaper alternative which already enables to identify SNPs located in transcribed regions. In this paper, we propose a method that identifies, quantifies and annotates SNPs without any reference genome, using RNA-seq data only. Individuals can be pooled prior to sequencing, if not enough material is available from one individual. Using pooled human RNA-seq data, we clarify the precision and recall of our method and discuss them with respect to other methods which use a reference genome or an assembled transcriptome. We then validate experimentally the predictions of our method using RNA-seq data from two non-model species. The method can be used for any species to annotate SNPs and predict their impact on the protein sequence. We further enable to test for the association of the identified SNPs with a phenotype of interest. PMID- 27458204 TI - Contiguous and accurate de novo assembly of metazoan genomes with modest long read coverage. AB - Genome assemblies that are accurate, complete and contiguous are essential for identifying important structural and functional elements of genomes and for identifying genetic variation. Nevertheless, most recent genome assemblies remain incomplete and fragmented. While long molecule sequencing promises to deliver more complete genome assemblies with fewer gaps, concerns about error rates, low yields, stringent DNA requirements and uncertainty about best practices may discourage many investigators from adopting this technology. Here, in conjunction with the platinum standard Drosophila melanogaster reference genome, we analyze recently published long molecule sequencing data to identify what governs completeness and contiguity of genome assemblies. We also present a hybrid meta assembly approach that achieves remarkable assembly contiguity for both Drosophila and human assemblies with only modest long molecule sequencing coverage. Our results motivate a set of preliminary best practices for obtaining accurate and contiguous assemblies, a 'missing manual' that guides key decisions in building high quality de novo genome assemblies, from DNA isolation to polishing the assembly. PMID- 27458205 TI - Histone H2B mono-ubiquitylation maintains genomic integrity at stalled replication forks. AB - Histone modifications play an important role in regulating access to DNA for transcription, DNA repair and DNA replication. A central player in these events is the mono-ubiquitylation of histone H2B (H2Bub1), which has been shown to regulate nucleosome dynamics. Previously, it was shown that H2Bub1 was important for nucleosome assembly onto nascent DNA at active replication forks. In the absence of H2Bub1, incomplete chromatin structures resulted in several replication defects. Here, we report new evidence, which shows that loss of H2Bub1 contributes to genomic instability in yeast. Specifically, we demonstrate that H2Bub1-deficient yeast accumulate mutations at a high frequency under conditions of replicative stress. This phenotype is due to an aberrant DNA Damage Tolerance (DDT) response upon fork stalling. We show that H2Bub1 normally functions to promote error-free translesion synthesis (TLS) mediated by DNA polymerase eta (Poleta). Without H2Bub1, DNA polymerase zeta (Polzeta) is responsible for a highly mutagenic alternative mechanism. While H2Bub1 does not appear to regulate other DDT pathways, error-free DDT mechanisms are employed by H2Bub1-deficient cells as another means for survival. However, in these instances, the anti-recombinase, Srs2, is essential to prevent the accumulation of toxic HR intermediates that arise in an unconstrained chromatin environment. PMID- 27458206 TI - OGT restrains the expansion of DNA damage signaling. AB - O-linked N-acetylglucosamine linkage (O-GlcNAcylation) to serine or threonine residues regulates numerous biological processes; however, its role in DNA damage response remains elusive. Here, we found that O-GlcNAcylation is induced by DNA damage response. O-GlcNAc transferase (OGT), the solo enzyme for O-GlcNAcylation, relocates to the sites of DNA damage and induces the O-GlcNAcylation of histone H2AX and mediator of DNA damage checkpoint 1 (MDC1). The O-GlcNAcylation negatively regulates DNA double-strand break-induced phosphorylation of H2AX and MDC1 by restraining the expansion of these phosphorylation events from the sites of DNA damage. Therefore, our study reveals the molecular mechanism and biological function of OGT-dependent O-GlcNAcylation in response to DNA damage. PMID- 27458207 TI - Visualizing the phage T4 activated transcription complex of DNA and E. coli RNA polymerase. AB - The ability of RNA polymerase (RNAP) to select the right promoter sequence at the right time is fundamental to the control of gene expression in all organisms. However, there is only one crystallized structure of a complete activator/RNAP/DNA complex. In a process called sigma appropriation, bacteriophage T4 activates a class of phage promoters using an activator (MotA) and a co-activator (AsiA), which function through interactions with the sigma(70) subunit of RNAP. We have developed a holistic, structure-based model for sigma appropriation using multiple experimentally determined 3D structures (Escherichia coli RNAP, the Thermus aquaticus RNAP/DNA complex, AsiA /sigma(70) Region 4, the N-terminal domain of MotA [MotA(NTD)], and the C-terminal domain of MotA [MotA(CTD)]), molecular modeling, and extensive biochemical observations indicating the position of the proteins relative to each other and to the DNA. Our results visualize how AsiA/MotA redirects sigma, and therefore RNAP activity, to T4 promoter DNA, and demonstrate at a molecular level how the tactful interaction of transcriptional factors with even small segments of RNAP can alter promoter specificity. Furthermore, our model provides a rational basis for understanding how a mutation within the beta subunit of RNAP (G1249D), which is far removed from AsiA or MotA, impairs sigma appropriation. PMID- 27458208 TI - Genome-wide analysis reveals positional-nucleosome-oriented binding pattern of pioneer factor FOXA1. AB - The compaction of nucleosomal structures creates a barrier for DNA-binding transcription factors (TFs) to access their cognate cis-regulatory elements. Pioneer factors (PFs) such as FOXA1 are able to directly access these cis-targets within compact chromatin. However, how these PFs interplay with nucleosomes remains to be elucidated, and is critical for us to understand the underlying mechanism of gene regulation. Here, we have conducted a computational analysis on a strand-specific paired-end ChIP-exo (termed as ChIP-ePENS) data of FOXA1 in LNCaP cells by our novel algorithm ePEST. We find that FOXA1 chromatin binding occurs via four distinct border modes (or footprint boundary patterns), with a preferential footprint boundary patterns relative to FOXA1 motif orientation. In addition, from this analysis three fundamental nucleotide positions (oG, oS and oH) emerged as major determinants for blocking exo-digestion and forming these four distinct border modes. By integrating histone MNase-seq data, we found an astonishingly consistent, 'well-positioned' configuration occurs between FOXA1 motifs and dyads of nucleosomes genome-wide. We further performed ChIP-seq of eight chromatin remodelers and found an increased occupancy of these remodelers on FOXA1 motifs for all four border modes (or footprint boundary patterns), indicating the full occupancy of FOXA1 complex on the three blocking sites (oG, oS and oH) likely produces an active regulatory status with well-positioned phasing for protein binding events. Together, our results suggest a positional nucleosome-oriented accessing model for PFs seeking target motifs, in which FOXA1 can examine each underlying DNA nucleotide and is able to sense all potential motifs regardless of whether they face inward or outward from histone octamers along the DNA helix axis. PMID- 27458209 TI - Pharmacokinetic and Pharmacodynamic Evaluation of a Weight-Based Dosing Regimen of Cefoxitin for Perioperative Surgical Prophylaxis in Obese and Morbidly Obese Patients. AB - The objective of this study was to determine the pharmacokinetics and pharmacodynamics (PK/PD) of a weight-based cefoxitin dosing regimen for surgical prophylaxis in obese patients. Patients received a single dose of cefoxitin at 40 mg/kg based on total body weight. Cefoxitin samples were obtained over 3 h from serum and adipose tissue, and concentrations were determined by validated high performance liquid chromatography. Noncompartmental pharmacokinetic analysis was performed, followed by Monte Carlo simulations to estimate probability of target attainment (PTA) for Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis over 4-h periods postdose. Thirty patients undergoing bariatric procedures were enrolled. The body mass index (mean +/- standard deviation [SD])was 45.9 +/- 8.0 kg/m(2) (range, 35.0 to 76.7 kg/m(2)); the median cefoxitin dose was 5 g (range, 4.0 to 7.5 g). The mean maximum concentrations were 216.15 +/- 41.80 MUg/ml in serum and 12.62 +/- 5.89 in tissue; the mean tissue/serum ratio was 8% +/- 3%. In serum, weight-based regimens achieved >=90% PTA (goal time during which free [unbound] drug concentrations exceed pathogen MICs [fT>MIC] of 100%) for E. coli and S. aureus over 2 h and for B. fragilis over 1 h; in tissue this regimen failed to achieve goal PTA at any time point. The 40 mg/kg regimens achieved higher PTAs over longer periods in both serum and tissue than did the standard 2-g doses. However, although weight-based cefoxitin regimens were better than fixed doses, achievement of desired pharmacodynamic targets was suboptimal in both serum and tissue. Alternative dosing regimens and agents should be explored in order to achieve more favorable antibiotic performance during surgical prophylaxis in obese patients. PMID- 27458210 TI - Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration. AB - Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant Staphylococcus aureus As rhabdomyolysis has been reported upon coadministration of FA with statins, we aimed to elucidate the underlying molecular mechanisms that contribute to FA-statin drug-drug interactions. Because of the association between rhabdomyolysis and increased exposure to statins, we investigated if cytochrome P450 (CYP) enzymes and transporters involved in the disposition of various statins are inhibited by FA. FA was found to inhibit BCRP and OATP1B1 but not P-gp. In overexpressing cell systems, FA inhibited BCRP mediated efflux (50% inhibitory concentration [IC50], ~50 to 110 MUM) and OATP1B1 mediated uptake (IC50, ~4 to 35 MUM) of statins at clinically relevant concentrations achievable in the intestine and liver (based on a 550-mg oral dose of FA, the expected maximum theoretical gastrointestinal concentration is ~4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 MUM or 11 MUM, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC50, ~17 to 195 MUM). These data suggest that FA inhibits at least 3 major dispositional pathways (BCRP, OATP1B1, and CYP3A) and thus affects the clearance of several statins. We confirmed that FA is eliminated via phase 1 metabolism (primarily via CYP3A); however, there is also some phase 2 metabolism (mediated primarily by UGT1A1). Taken together, these data provide evidence for molecular mechanisms that may explain the occurrence of rhabdomyolysis when FA is administered with statins. PMID- 27458211 TI - Use of Comparative Genomics To Characterize the Diversity of Acinetobacter baumannii Surveillance Isolates in a Health Care Institution. AB - Despite the increasing prevalence of the nosocomial pathogen Acinetobacter baumannii, little is known about which genomic components contribute to clinical presentation of this important pathogen. Most whole-genome comparisons of A. baumannii have focused on specific genomic regions associated with phenotypes in a limited number of genomes. In this work, we describe the results of a whole genome comparative analysis of 254 surveillance isolates of Acinetobacter species, 203 of which were A. baumannii, isolated from perianal swabs and sputum samples collected as part of an infection control active surveillance program at the University of Maryland Medical Center. The collection of surveillance isolates includes both carbapenem-susceptible and -resistant isolates. Based on the whole-genome phylogeny, the A. baumannii isolates collected belong to two major phylogenomic lineages. Results from multilocus sequence typing indicated that one of the major phylogenetic groups of A. baumannii was comprised solely of strains from the international clonal lineage 2. The genomic content of the A. baumannii isolates was examined using large-scale BLAST score ratio analysis to identify genes that are associated with carbapenem-susceptible and -resistant isolates, as well as genes potentially associated with the source of isolation. This analysis revealed a number of genes that were exclusive or at greater frequency in each of these classifications. This study is the most comprehensive genomic comparison of Acinetobacter isolates from a surveillance study to date and provides important information that will contribute to our understanding of the success of A. baumannii as a human pathogen. PMID- 27458212 TI - Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs. AB - Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in Med-G6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates. PMID- 27458213 TI - Eradication of Staphylococcus aureus Catheter-Related Biofilm Infections Using ML:8 and Citrox. AB - Staphylococci are a leading cause of catheter-related infections (CRIs) due to biofilm formation. CRIs are typically managed by either device removal or systemic antibiotics, often in combination with catheter lock solutions (CLSs). CLSs provide high concentrations of the antimicrobial agent at the site of infection. However, the most effective CLSs against staphylococcal biofilm associated infections have yet to be determined. The purpose of this study was to evaluate the efficacy and suitability of two newly described antimicrobial agents, ML:8 and Citrox, as CLSs against Staphylococcus aureus biofilms. ML:8 (1% [vol/vol]) and Citrox (1% [vol/vol]), containing caprylic acid and flavonoids, respectively, were used to treat S. aureus biofilms grown in vitro using newly described static and flow biofilm assays. Both agents reduced biofilm viability >97% after 24 h of treatment. Using a rat model of CRI, ML:8 was shown to inactivate early-stage S. aureus biofilms in vivo, while Citrox inactivated established, mature in vivo biofilms. Cytotoxicity and hemolytic activity of ML:8 and Citrox were equivalent to those of other commercially available CLSs. Neither ML:8 nor Citrox induced a cytokine response in human whole blood, and exposure of S. aureus to either agent for 90 days was not associated with any increase in resistance. Taken together, these data reveal the therapeutic potential of these agents for the treatment of S. aureus catheter-related biofilm infections. PMID- 27458214 TI - First Report of German Cockroaches (Blattella germanica) as Reservoirs of CTX-M 15 Extended-Spectrum-beta-Lactamase- and OXA-48 Carbapenemase-Producing Enterobacteriaceae in Batna University Hospital, Algeria. AB - Here we report the isolation of extended-spectrum beta-lactamase (ESBL)- and carbapenemase-producing Enterobacteriaceae from German cockroaches caught in the burn unit of Batna University Hospital in Algeria. Nine of 12 isolates harbored the blaCTX-M-15 ESBL gene. One Enterobacter cloacae isolate belonging to sequence type 528 coexpressed the blaOXA-48, blaCTX-M-15, and blaTEM genes. Our findings indicate that cockroaches may be one of the most dangerous reservoirs for ESBL and carbapenemase producers in hospitals. PMID- 27458215 TI - Amikacin Optimal Exposure Targets in the Hollow-Fiber System Model of Tuberculosis. AB - Aminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). However, formal pharmacokinetic/pharmacodynamic (PK/PD) studies to identify amikacin exposures and dosing schedules that optimize Mycobacterium tuberculosis killing have not been performed. It is believed that aminoglycosides do not work well under acidic conditions, which, if true, would mean poor sterilizing activity against semidormant bacilli at low pH. We performed time-kill studies to compare the bactericidal effect of amikacin in log-phase-growth bacilli with the sterilizing effect in semidormant bacilli at pH 5.8 in broth. In log-phase M. tuberculosis at normal pH versus semidormant M. tuberculosis at pH 5.8, the maximal kill (Emax) estimate and 95% confidence interval (CI) were 5.39 (95% CI, 4.91 to 5.63) versus 4.88 (CI, 4.46 to 5.22) log10 CFU/ml, while the concentration mediating 50% of Emax (EC50) was 1.0 (CI, 0. 0.86 to 1.12) versus 0.60 (CI, 0.50 to 0.66) times the MIC, respectively. Thus, the optimal exposures and kill rates identified for log-phase M. tuberculosis will be optimal even for semidormant bacilli. Next, we performed exposure-response and dose-scheduling studies in the hollow-fiber system model of tuberculosis using log-phase M. tuberculosis We recapitulated the amikacin concentration-time profiles observed in lungs of patients treated over 28 days. The PK/PD index linked to M. tuberculosis kill was the peak concentration (Cmax)-to-MIC ratio (r(2) > 0.99), closely followed by the area under the concentration-time curve from 0 to 24 h (AUC0-24)-to-MIC ratio (r(2) = 0.98). The EC90 was a Cmax/MIC ratio of 10.13 (95% CI, 7.73 to 12.48). The EC90 is the dosing target for intermittent therapy that optimizes cure in TB programs for MDR-TB patients. PMID- 27458216 TI - Development of a Novel High-Density [3H]Hypoxanthine Scintillation Proximity Assay To Assess Plasmodium falciparum Growth. AB - The discovery and development of new antimalarial drugs are becoming imperative because of the spread of resistance to current clinical treatments. The lack of robustly validated antimalarial targets and the difficulties with the building in of whole-cell activity in screening hits are hampering target-based approaches. However, phenotypic screens of structurally diverse molecule libraries are offering new opportunities for the identification of novel antimalarials. Several methodologies can be used to determine the whole-cell in vitro potencies of antimalarial hits. The [(3)H]hypoxanthine incorporation assay is considered the "gold standard" assay for measurement of the activity of antimalarial compounds against intraerythrocytic forms of Plasmodium falciparum However, the method has important limitations, as the assay is not amenable for high-throughput screening since it remains associated with the 96-well plate format. We have overcome this drawback by adapting the [(3)H]hypoxanthine incorporation method to a 384-well high-density format by coupling a homogeneous scintillation proximity assay (SPA) and thus eliminating the limiting filtration step. This SPA has been validated using a diverse set of 1,000 molecules, including both a representative set from the Tres Cantos Antimalarial Set (TCAMS) of compounds and molecules inactive against whole cells. The results were compared with those from the P. falciparum lactate dehydrogenase whole-cell assay, another method that is well established as a surrogate for parasite growth and is amenable for high-throughput screening. The results obtained demonstrate that the SPA-based [(3)H]hypoxanthine incorporation assay is a suitable design that is adaptable to high-throughput antimalarial drug screening and that maintains the features, robustness, and reliability of the standard filtration hypoxanthine incorporation method. PMID- 27458217 TI - Short Palate, Lung, and Nasal Epithelial Clone 1 Has Antimicrobial and Antibiofilm Activities against the Burkholderia cepacia Complex. AB - The opportunistic bacteria of the Burkholderia cepacia complex (Bcc) are extremely pathogenic to cystic fibrosis (CF) patients, and acquisition of Bcc bacteria is associated with a significant increase in mortality. Treatment of Bcc infections is difficult because the bacteria are multidrug resistant and able to survive in biofilms. Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) is an innate defense protein that is secreted by the upper airways and pharynx. While SPLUNC1 is known to have antimicrobial functions, its effects on Bcc strains are unclear. We therefore tested the hypothesis that SPLUNC1 is able to impair Bcc growth and biofilm formation. We found that SPLUNC1 exerted bacteriostatic effects against several Bcc clinical isolates, including B. cenocepacia strain J2315 (50% inhibitory concentration [IC50] = 0.28 MUM), and reduced biofilm formation and attachment (IC50 = 0.11 MUM). We then determined which domains of SPLUNC1 are responsible for its antimicrobial activity. Deletions of SPLUNC1's N terminus and alpha6 helix did not affect its function. However, deletion of the alpha4 helix attenuated antimicrobial activity, while the corresponding alpha4 peptide displayed antimicrobial activity. Chronic neutrophilia is a hallmark of CF lung disease, and neutrophil elastase (NE) cleaves SPLUNC1. However, we found that the ability of SPLUNC1 to disrupt biofilm formation was significantly potentiated by NE pretreatment. While the impact of CF on SPLUNC1-Bcc interactions is not currently known, our data suggest that understanding this interaction may have important implications for CF lung disease. PMID- 27458218 TI - Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109. AB - We report that the tuberculosis drug SQ109 [N-adamantan-2-yl-N'-((E)-3,7-dimethyl octa-2,6-dienyl)-ethane-1,2-diamine] has potent activity against the intracellular amastigote form of Leishmania mexicana (50% inhibitory concentration [IC50], ~11 nM), with a good selectivity index (>500). It is also active against promastigotes (IC50, ~500 nM) and acts as a protonophore uncoupler, in addition to disrupting Ca(2+) homeostasis by releasing organelle Ca(2+) into the cytoplasm, and as such, it is an interesting new leishmaniasis drug hit candidate. PMID- 27458220 TI - In Vitro Activity of Delafloxacin Tested against Isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. AB - Delafloxacin, an investigational anionic fluoroquinolone, is active against a broad range of Gram-positive and Gram-negative bacteria. In this study, 200 Streptococcus pneumoniae (plus 30 levofloxacin-resistant isolates), 200 Haemophilus influenzae, and 100 Moraxella catarrhalis isolates selected primarily from the United States (2014) were tested against delafloxacin and comparator agents. Delafloxacin was the most potent agent tested. MIC50 and MIC90 values against all S. pneumoniae isolates were 0.008 and 0.015 MUg/ml. Delafloxacin susceptibility was not affected by beta-lactamase status against H. influenzae and M. catarrhalis. PMID- 27458219 TI - Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis. AB - Understanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and alpha-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control. PMID- 27458221 TI - Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Treating Pulmonary Mycobacterium abscessus Infection. AB - In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, a kill rate of 0.09 (95% confidence interval, -0.04 to 0.03) log10 CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed. PMID- 27458222 TI - Acquisition of a High Diversity of Bacteria during the Hajj Pilgrimage, Including Acinetobacter baumannii with blaOXA-72 and Escherichia coli with blaNDM-5 Carbapenemase Genes. AB - Pilgrims returning from the Hajj (pilgrimage to Mecca) can be carriers of multidrug-resistant bacteria (MDR). Pharyngeal and rectal swab samples were collected from 98 pilgrims before and after they traveled to the Hajj in 2014 to investigate the acquisition of MDR bacteria. The bacterial diversity in pharyngeal swab samples was assessed by culture with selective media. There was a significantly higher diversity of bacteria in samples collected after the return from the Hajj than in those collected before (P = 0.0008). Surprisingly, Acinetobacter baumannii strains were isolated from 16 pharyngeal swab samples (1 sample taken during the Hajj and 15 samples taken upon return) and 26 post-Hajj rectal swab samples, while none were isolated from samples taken before the Hajj. Testing of all samples by real-time PCR targeting blaOXA-51 gave positive results for only 1% of samples taken during the Hajj, 21/90 (23.3%) pharyngeal swab samples taken post-Hajj, and 35/90 (38.9%) rectal swab samples taken post-Hajj. One strain of A. baumannii isolated from the pharynx was resistant to imipenem and harbored a blaOXA-72 carbapenemase gene. Multilocus sequence typing analysis of 43 A. baumannii isolates revealed a huge diversity of 35 sequence types (STs), among which 18 were novel STs reported for the first time in this study. Moreover, we also found one Escherichia coli isolate, collected from a rectal swab sample from a pilgrim taken after the Hajj, which harbored blaNDM-5, blaCTX M-15, blaTEM-1, and aadA2 (ST2659 and ST181). In conclusion, pilgrims are at a potential risk of acquiring and transmitting MDR Acinetobacter spp. and carbapenemase-producing Gram-negative bacteria during the Hajj season. PMID- 27458223 TI - Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects. AB - Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCtau). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCtau and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCtau values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCtau and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased delamanid absorption and not to CYP induction. PMID- 27458224 TI - Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients. AB - Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0-24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0-24, and trough concentrations. The primary node for failure had two competing variables, Cmax of <67 mg/liter and AUC0-24 of <568.30 mg . h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R(2) = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of >=67 mg/liter versus 3/15 (20%) in those with a Cmax of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0-24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model. PMID- 27458225 TI - A High-Throughput Approach To Identify Compounds That Impair Envelope Integrity in Escherichia coli. AB - The envelope of Gram-negative bacteria constitutes an impenetrable barrier to numerous classes of antimicrobials. This intrinsic resistance, coupled with acquired multidrug resistance, has drastically limited the treatment options against Gram-negative pathogens. The aim of the present study was to develop and validate an assay for identifying compounds that increase envelope permeability, thereby conferring antimicrobial susceptibility by weakening of the cell envelope barrier in Gram-negative bacteria. A high-throughput whole-cell screening platform was developed to measure Escherichia coli envelope permeability to a beta-galactosidase chromogenic substrate. The signal produced by cytoplasmic beta galactosidase-dependent cleavage of the chromogenic substrate was used to determine the degree of envelope permeabilization. The assay was optimized by using known envelope-permeabilizing compounds and E. coli gene deletion mutants with impaired envelope integrity. As a proof of concept, a compound library comprising 36 peptides and 45 peptidomimetics was screened, leading to identification of two peptides that substantially increased envelope permeability. Compound 79 reduced significantly (from 8- to 125-fold) the MICs of erythromycin, fusidic acid, novobiocin and rifampin and displayed synergy (fractional inhibitory concentration index, <0.2) with these antibiotics by checkerboard assays in two genetically distinct E. coli strains, including the high-risk multidrug-resistant, CTX-M-15-producing sequence type 131 clone. Notably, in the presence of 0.25 MUM of this peptide, both strains were susceptible to rifampin according to the resistance breakpoints (R > 0.5 MUg/ml) for Gram-positive bacterial pathogens. The high-throughput screening platform developed in this study can be applied to accelerate the discovery of antimicrobial helper drug candidates and targets that enhance the delivery of existing antibiotics by impairing envelope integrity in Gram-negative bacteria. PMID- 27458226 TI - Characterization of Spectinomycin Resistance in Streptococcus suis Leads to Two Novel Insights into Drug Resistance Formation and Dissemination Mechanism. AB - Spectinomycin is an aminocyclitol antibiotic used clinically to treat a variety of infections in animals. Here, we characterized drug resistance prevalence in clinical Streptococcus suis isolates and discovered a novel resistance mechanism in which the s5 mutation (Gly26Asp) results in high spectinomycin resistance. Additionally, a novel integrative and conjugative element encompassing a multidrug resistance spw_like-aadE-lnu(B)-lsa(E) cluster and a cadmium resistance operon were identified, suggesting a possible cause for the wide dissemination of spectinomycin resistance in S. suis. PMID- 27458227 TI - The Antimicrobial Peptides P-113Du and P-113Tri Function against Candida albicans. AB - Two antimicrobial P-113 peptide derivatives, P-113Du and P-113Tri, were investigated in this study. Notably, P-113Du and P-113Tri contained significant fractions of alpha-helix conformation and were less sensitive to high salt and low pH than P-113. Moreover, compared to P-113, these peptides exhibited increased antifungal activity against planktonic cells, biofilm cells, and clinical isolates of Candida albicans and non-albicans Candida spp. These results suggest that P-113Du and P-113Tri are promising candidates for development as novel antifungal agents. PMID- 27458228 TI - Tolerability and Plasma Drug Level Monitoring of Prolonged Subcutaneous Teicoplanin Treatment for Bone and Joint Infections. AB - Teicoplanin is a key drug for the treatment of multiresistant staphylococcal bone and joint infections (BJI), yet can only be administered via a parenteral route. The objective of this study was to evaluate the safety and tolerability of subcutaneous (s.c.) teicoplanin for that indication over 42 days. Thirty patients with Gram-positive cocci BJI were included. Once the target of 25 to 40 mg/liter trough serum concentration was achieved, treatment was switched from an intravenous to an s.c. route. No discontinuation of teicoplanin related to injection site reaction and no severe local adverse event were observed. On multivariate analysis, better tolerability was observed at the beginning of treatment, in patients over 70 years old, and for dosages less than 600 mg. In conclusion, we recommend s.c. administration of teicoplanin when needed. PMID- 27458229 TI - Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection. AB - Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 +/- 0.47 versus 0.15 +/- 0.06 h(-1), respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of <=0.008 mg/liter and <=0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively. PMID- 27458230 TI - Identification of Novel Plasmodium falciparum Hexokinase Inhibitors with Antiparasitic Activity. AB - Plasmodium falciparum, the deadliest species of malaria parasites, is dependent on glycolysis for the generation of ATP during the pathogenic red blood cell stage. Hexokinase (HK) catalyzes the first step in glycolysis, transferring the gamma-phosphoryl group of ATP to glucose to yield glucose-6-phosphate. Here, we describe the validation of a high-throughput assay for screening small-molecule collections to identify inhibitors of the P. falciparum HK (PfHK). The assay, which employed an ADP-Glo reporter system in a 1,536-well-plate format, was robust with a signal-to-background ratio of 3.4 +/- 1.2, a coefficient of variation of 6.8% +/- 2.9%, and a Z'-factor of 0.75 +/- 0.08. Using this assay, we screened 57,654 molecules from multiple small-molecule collections. Confirmed hits were resolved into four clusters on the basis of structural relatedness. Multiple singleton hits were also identified. The most potent inhibitors had 50% inhibitory concentrations as low as ~1 MUM, and several were found to have low micromolar 50% effective concentrations against asexual intraerythrocytic-stage P. falciparum parasites. These molecules additionally demonstrated limited toxicity against a panel of mammalian cells. The identification of PfHK inhibitors with antiparasitic activity using this validated screening assay is encouraging, as it justifies additional HTS campaigns with more structurally amenable libraries for the identification of potential leads for future therapeutic development. PMID- 27458231 TI - Exploiting Interkingdom Interactions for Development of Small-Molecule Inhibitors of Candida albicans Biofilm Formation. AB - A rapid decline in the development of new antimicrobial therapeutics has coincided with the emergence of new and more aggressive multidrug-resistant pathogens. Pathogens are protected from antibiotic activity by their ability to enter an aggregative biofilm state. Therefore, disrupting this process in pathogens is a key strategy for the development of next-generation antimicrobials. Here, we present a suite of compounds, based on the Pseudomonas aeruginosa 2-heptyl-4(1H)-quinolone (HHQ) core quinolone interkingdom signal structure, that exhibit noncytotoxic antibiofilm activity toward the fungal pathogen Candida albicans In addition to providing new insights into what is a clinically important bacterium-fungus interaction, the capacity to modularize the functionality of the quinolone signals is an important advance in harnessing the therapeutic potential of signaling molecules in general. This provides a platform for the development of potent next-generation small-molecule therapeutics targeting clinically relevant fungal pathogens. PMID- 27458232 TI - Crystal Structure of the Metallo-beta-Lactamase GOB in the Periplasmic Dizinc Form Reveals an Unusual Metal Site. AB - Metallo-beta-lactamases (MBLs) are broad-spectrum, Zn(II)-dependent lactamases able to confer resistance to virtually every beta-lactam antibiotic currently available. The large diversity of active-site structures and metal content among MBLs from different sources has limited the design of a pan-MBL inhibitor. GOB-18 is a divergent MBL from subclass B3 that is expressed by the opportunistic Gram negative pathogen Elizabethkingia meningoseptica This MBL is atypical, since several residues conserved in B3 enzymes (such as a metal ligand His) are substituted in GOB enzymes. Here, we report the crystal structure of the periplasmic di-Zn(II) form of GOB-18. This enzyme displays a unique active-site structure, with residue Gln116 coordinating the Zn1 ion through its terminal amide moiety, replacing a ubiquitous His residue. This situation contrasts with that of B2 MBLs, where an equivalent His116Asn substitution leads to a di-Zn(II) inactive species. Instead, both the mono- and di-Zn(II) forms of GOB-18 are active against penicillins, cephalosporins, and carbapenems. In silico docking and molecular dynamics simulations indicate that residue Met221 is not involved in substrate binding, in contrast to Ser221, which otherwise is conserved in most B3 enzymes. These distinctive features are conserved in recently reported GOB orthologues in environmental bacteria. These findings provide valuable information for inhibitor design and also posit that GOB enzymes have alternative functions. PMID- 27458233 TI - Modulation of Staphylococcus aureus Biofilm Matrix by Subinhibitory Concentrations of Clindamycin. AB - Staphylococcus aureus biofilms are extremely difficult to treat. They provide a protected niche for the bacteria, rendering them highly recalcitrant toward host defenses as well as antibiotic treatment. Bacteria within a biofilm are shielded from the immune system by the formation of an extracellular polymeric matrix, composed of polysaccharides, extracellular DNA (eDNA), and proteins. Many antibiotics do not readily penetrate biofilms, resulting in the presence of subinhibitory concentrations of antibiotics. Here, we show that subinhibitory concentrations of clindamycin triggered a transcriptional stress response in S. aureus via the alternative sigma factor B (sigma(B)) and upregulated the expression of the major biofilm-associated genes atlA, lrgA, agrA, the psm genes, fnbA, and fnbB Our data suggest that subinhibitory concentrations of clindamycin alter the ability of S. aureus to form biofilms and shift the composition of the biofilm matrix toward higher eDNA content. An understanding of the molecular mechanisms underlying biofilm assembly and dispersal in response to subinhibitory concentrations of clinically relevant antibiotics such as clindamycin is critical to further optimize antibiotic treatment strategies of biofilm-associated S. aureus infections. PMID- 27458234 TI - Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction. AB - RATIONALE: Abnormalities in nitric oxide signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to nitric oxide in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use. OBJECTIVE: Determine whether inhaled nitrite improves hemodynamics in HFpEF. METHODS AND RESULTS: In a double-blind, randomized, placebo-controlled, parallel group trial, subjects with HFpEF (n=26) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise before and after treatment with inhaled sodium nitrite (90 mg) or placebo. The primary end point was the pulmonary capillary wedge pressure during exercise. Before study drug administration, HFpEF subjects displayed an increase in pulmonary capillary wedge pressure with exercise from 20+/-6 to 34+/-7 mm Hg (P<0.0001). After study drug administration, exercise pulmonary capillary wedge pressure was substantially improved by nitrite as compared with placebo (baseline-adjusted mean 25+/-5 versus 31+/-6 mm Hg; analysis of covariance P=0.022). Inhaled nitrite reduced resting pulmonary capillary wedge pressure (-4+/-3 versus -1+/-2 mm Hg; P=0.002), improved pulmonary artery compliance (+1.5+/-1.1 versus +0.6+/-0.9 mL/mm Hg), and decreased mean pulmonary artery pressures at rest (-7+/-4 versus -3+/-4 mm Hg; P=0.007) and with exercise (-10+/-6 versus -5+/-6 mm Hg; P=0.05). Nitrite reduced right atrial pressures, with no effect on cardiac output or stroke volume. CONCLUSIONS: Acute administration of inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF. Further study is warranted to evaluate chronic effects of inhaled nitrite in HFpEF. CLINICAL TRIAL REGISTRATION: This single center randomized clinical trial is registered at clinicaltrials.gov (NCT02262078). PMID- 27458235 TI - Glutathione-mediated mesoporous carbon as a drug delivery nanocarrier with carbon dots as a cap and fluorescent tracer. AB - This work describes a novel and general redox-responsive controlled drug delivery release nanocarrier with mesoporous carbon nanoparticles (MCNs) gated by customized fluorescent carbon dots (CDs). The modification of MCNs with a disulfide unit enables the system to be sensitive to intracellular glutathione (GSH). The CDs anchoring onto the surface of the MCNs via an electrostatic interaction block the mesopores and thus prevent the leakage of doxorubicin (DOX) loaded inside the channel of the MCNs. Upon the addition of GSH at the physiological environment, the integrity of the system is disrupted due to the dissociation of the disulfide bond; meanwhile stripping the CDs opens the gate and thus triggers the rapid release of the encapsulated DOX. The fluorescence of the CDs is quenched/'turned off' when linking to the MCNs, while it is restored/'turned on' when detaching the CDs from the surface of the MCNs. Thus the fluorescent CDs serve as both a controllable drug release gatekeeper and a fluorescent probe for the visualization of the drug delivery process. By combining these inherent capabilities, the present drug delivery system may be a promising route for designing custom-made visual controlled-release nanodevices specifically governed by in situ stimulus in the cells. PMID- 27458236 TI - Experience With the Wearable Cardioverter-Defibrillator in Patients at High Risk for Sudden Cardiac Death. AB - BACKGROUND: This study evaluated the wearable cardioverter-defibrillator (WCD) for use and effectiveness in preventing sudden death caused by ventricular tachyarrhythmia or fibrillation. METHODS: From April 2010 through October 2013, 6043 German WCD patients (median age, 57 years; male, 78.5%) were recruited from 404 German centers. Deidentified German patient data were used for a retrospective, nonrandomized analysis. RESULTS: Ninety-four patients (1.6%) were treated by the WCD in response to ventricular tachyarrhythmia/fibrillation. The incidence rate was 8.4 (95% confidence interval, 6.8-10.2) per 100 patient-years. Patients with implantable cardioverter-defibrillator explantation had an incidence rate of 19.3 (95% confidence interval, 12.2-29.0) per 100 patient years. In contrast, an incidence rate of 8.2 (95% confidence interval, 6.4-10.3) was observed in the remaining cardiac diagnosis groups, including dilated cardiomyopathy, myocarditis, and ischemic and nonischemic cardiomyopathies. Among 120 shocked patients, 112 (93%) survived 24 hours after treatment, whereas asystole was observed in 2 patients (0.03%) with 1 resulting death. CONCLUSIONS: This large cohort represents the first nationwide evaluation of WCD use in patients outside the US healthcare system and confirms the overall value of the WCD in German treatment pathways. PMID- 27458238 TI - Releasing the brakes to fight cancer: The recent discovery of checkpoints has boosted the field of cancer immunotherapy. PMID- 27458237 TI - SPATA2 promotes CYLD activity and regulates TNF-induced NF-kappaB signaling and cell death. AB - K63- and Met1-linked ubiquitylation are crucial posttranslational modifications for TNF receptor signaling. These non-degradative ubiquitylations are counteracted by deubiquitinases (DUBs), such as the enzyme CYLD, resulting in an appropriate signal strength, but the regulation of this process remains incompletely understood. Here, we describe an interaction partner of CYLD, SPATA2, which we identified by a mass spectrometry screen. We find that SPATA2 interacts via its PUB domain with CYLD, while a PUB interaction motif (PIM) of SPATA2 interacts with the PUB domain of the LUBAC component HOIP SPATA2 is required for the recruitment of CYLD to the TNF receptor signaling complex upon TNFR stimulation. Moreover, SPATA2 acts as an allosteric activator for the K63- and M1-deubiquitinase activity of CYLD In consequence, SPATA2 substantially attenuates TNF-induced NF-kappaB and MAPK signaling. Conversely, SPATA2 is required for TNF-induced complex II formation, caspase activation, and apoptosis. Thus, this study identifies SPATA2 as an important factor in the TNF signaling pathway with a substantial role for the effects mediated by the cytokine. PMID- 27458240 TI - Attitudes and preferences in patients with acromegaly on long-term treatment with somatostatin analogues. AB - INTRODUCTION: Patients with acromegaly can be treated with surgery, medical therapy and/or radiation therapy. For the patients not being cured with surgery, treatment with somatostatin analogues (SSAs) is the primary therapy. SSA can be taken by self- or partner-administered injections in addition to being given by a nurse at a clinic. The aim was to assess if patients with acromegaly prefer self injections and to investigate their attitudes towards long-term medical therapy. METHOD: All patients in the southern medical region of Sweden with a diagnosis of acromegaly and treated with SSA were eligible for the study (n = 24). The study is based on a questionnaire asking about the patients' attitudes and preferences for injections with SSA, including their attitudes towards self-injection with SSA. RESULTS: The patients' (23 included) median age was 68.5 years and the patients had been treated with SSA for 13 (1-38) years. One patient was currently self-injecting. All of the other patients were receiving injections from a nurse at a clinic. Three patients preferred self-injections, one preferred partner injections and 19 patients did not prefer self- or partner injections. The most frequent arguments to not preferring self-injections were 'feeling more secure with an educated nurse' and 'preferring regular contact with a specialised nurse'. CONCLUSION: Patients with acromegaly prefer regular contact with the endocrine team to the independence offered by self-injections. These findings might mirror the patients' desires for continuity and safety. We need to address patients' concerns regarding injections with SSA and support them in their choices. PMID- 27458239 TI - Structural role of the T94I rhodopsin mutation in congenital stationary night blindness. AB - Congenital stationary night blindness (CSNB) is an inherited and non-progressive retinal dysfunction. Here, we present the crystal structure of CSNB-causing T94I2.61 rhodopsin in the active conformation at 2.3 A resolution. The introduced hydrophobic side chain prolongs the lifetime of the G protein activating metarhodopsin-II state by establishing a direct van der Waals contact with K2967.43, the site of retinal attachment. This is in stark contrast to the light activated state of the CSNB-causing G90D2.57 mutation, where the charged mutation forms a salt bridge with K2967.43 To find the common denominator between these two functional modifications, we combined our structural data with a kinetic biochemical analysis and molecular dynamics simulations. Our results indicate that both the charged G90D2.57 and the hydrophobic T94I2.61 mutation alter the dark state by weakening the interaction between the Schiff base (SB) and its counterion E1133.28 We propose that this interference with the tight regulation of the dim light photoreceptor rhodopsin increases background noise in the visual system and causes the loss of night vision characteristic for CSNB patients. PMID- 27458241 TI - Eight sages over five centuries share oxygen's discovery. AB - During the last century, historians have discovered that between the 13th and 18th centuries, at least six sages discovered that the air we breathe contains something that we need and use. Ibn al-Nafis (1213-1288) in Cairo and Michael Servetus (1511-1553) in France accurately described the pulmonary circulation and its effect on blood color. Michael Sendivogius (1566-1636) in Poland called a part of air "the food of life" and identified it as the gas made by heating saltpetre. John Mayow (1641-1679) in Oxford found that one-fifth of air was a special gas he called "spiritus nitro aereus." Carl Wilhelm Scheele (1742-1786) in Uppsala generated a gas he named "fire air" by heating several metal calcs. He asked Lavoisier how it fit the phlogiston theory. Lavoisier never answered. In 1744, Joseph Priestley (1733-1804) in England discovered how to make part of air by heating red calc of mercury. He found it brightened a flame and supported life in a mouse in a sealed bottle. He called it "dephlogisticated air." He published and personally told Lavoisier and other chemists about it. Lavoisier never thanked him. After 9 years of generating and studying its chemistry, he couldn't understand whether it was a new element. He still named it "principe oxigene." He was still not able to disprove phlogiston. Henry Cavendish (1731-1810) made an inflammable gas in 1766. He and Priestley noted that its flame made a dew. Cavendish proved the dew was pure water and published this in 1778, but all scientists called it impossible to make water, an element. In 1783, on June 24th, Lavoisier was urged to try it, and, when water appeared, he realized that water was not an element but a compound of two gases, proving that oxygen was an element. He then demolished phlogiston and began the new chemistry revolution. PMID- 27458242 TI - Adventures in education. PMID- 27458243 TI - Making physiology learning memorable: a mobile phone-assisted case-based instructional strategy. AB - The goal of the present study was to determine whether an active learning/teaching strategy facilitated with mobile technologies can improve students' levels of memory retention of key physiological concepts. We used a quasiexperimental pretest/posttest nonequivalent group design to compare the test performances of second-year medical students (n = 311) taught by conventional didactic methods (traditional group) with those involved in a case-based problem solving learning approach facilitated with mobile phones as web-based "clickers" (experimental group). Using their cell phones, students answered the same questions about the key physiological concepts three times. A pretest to determine their baseline knowledge was followed by two followup tests after 1 wk and 2 mo, respectively. The experimental group scored a mean of 93.2% correct items after 1 wk and 84.8% correct items after 2 mo [95% confidence intervals: (89.4, 97.0) and (79.4, 90.3), respectively]. Compared with their colleagues in the traditional group who scored 33.3% [95% confidence interval: (18.9, 47.8)] and 38.5% [95% confidence interval: (23.6, 53.4)] correct items, respectively, this was a significant increase of ~50% (P < 0.0001). Furthermore, for the experimental group, Cohen's effect size (d) values of d = 1.67 (1-wk posttest) and d = 1.38 (2-mo posttest) suggested a very high practical significance. In contrast, in the traditional group, Cohen's d values of d = 0.04 (1-wk posttest) and d = 0.15 (2-mo posttest) assumed a very low practical significance. PMID- 27458244 TI - PVALB diminishes [Ca2+] and alters mitochondrial features in follicular thyroid carcinoma cells through AKT/GSK3beta pathway. AB - We have identified previously a panel of markers (C1orf24, ITM1 and PVALB) that can help to discriminate benign from malignant thyroid lesions. C1orf24 and ITM1 are specifically helpful for detecting a wide range of thyroid carcinomas, and PVALB is particularly valuable for detecting the benign Hurthle cell adenoma. Although these markers may ultimately help patient care, the current understanding of their biological functions remains largely unknown. In this article, we investigated whether PVALB is critical for the acquisition of Hurthle cell features and explored the molecular mechanism underlying the phenotypic changes. Through ectopic expression of PVALB in thyroid carcinoma cell lines (FTC 133 and WRO), we demonstrated that PVALB sequesters free cytoplasmic Ca(2+), which ultimately lowers calcium levels and precludes endoplasmic reticulum (ER) Ca(2+) refilling. These results were accompanied by induced expression of PERK, an ER stress marker. Additionally, forced expression of PVALB reduces Ca(2+) inflow in the mitochondria, which can in turn cause changes in mitochondria morphology, increase mitochondria number and alter subcellular localization. These findings share striking similarity to those observed in Hurthle cell tumors. Moreover, PVALB inhibits cell growth and induces cell death, most likely through the AKT/GSK-3beta. Finally, PVALB expression coincides with Ca(2+) deposits in HCA tissues. Our data support the hypothesis that the loss of PVALB plays a role in the pathogenesis of thyroid tumors. PMID- 27458245 TI - Impaired exercise tolerance, mitochondrial biogenesis, and muscle fiber maintenance in miR-133a-deficient mice. AB - Exercise promotes multiple beneficial effects on muscle function, including induction of mitochondrial biogenesis. miR-133a is a muscle-enriched microRNA that regulates muscle development and function. The role of miR-133a in exercise tolerance has not been fully elucidated. In the current study, mice that were deficient in miR-133a demonstrated low maximal exercise capacity and low resting metabolic rate. Transcription of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, peroxisome proliferator-activated receptor-gamma coactivator 1-beta, nuclear respiratory factor-1, and transcription factor A, mitochondrial were lower in miR-133a deficient muscle, which was consistent with lower mitochondrial mass and impaired exercise capacity. Six weeks of endurance exercise training increased the transcriptional level of miR-133a and stimulated mitochondrial biogenesis in wild type mice, but failed to improve mitochondrial function in miR-133a-deficient mice. Further mechanistic analysis showed an increase in the miR-133a potential target, IGF-1 receptor, along with hyperactivation of Akt signaling, in miR-133a deficient mice, which was consistent with lower transcription of the mitochondrial biogenesis regulators. These findings indicate an essential role of miR-133a in skeletal muscle mitochondrial biogenesis, exercise tolerance, and response to exercise training.-Nie, Y., Sato, Y., Wang, C., Yue, F., Kuang, S., Gavin, T. P. Impaired exercise tolerance, mitochondrial biogenesis, and muscle fiber maintenance in miR-133a-deficient mice. PMID- 27458246 TI - Antitumor Effect of Programmed Death-1 (PD-1) Blockade in Humanized the NOG-MHC Double Knockout Mouse. AB - PURPOSE: Humanized mouse models using NOD/Shi-scid-IL2rgammanull (NOG) and NOD/LtSz-scid IL2rgammanull (NSG) mouse are associated with several limitations, such as long incubation time for stem cell engraftment and the development of xenograft versus host disease in mice injected with peripheral blood mononuclear cells (PBMCs). To solve problems, we used humanized major histocompatibility class I- and class II-deficient NOG mice (referred to as NOG-dKO) to evaluate the antitumor effect of anti-programmed death-1 (PD-1) antibody. EXPERIMENTAL DESIGN: Humanized NOG-dKO mice, in which human PBMCs and human lymphoma cell line SCC-3, or glioblastoma cell line U87 were transplanted, were used as an immunotherapy model to investigate the effect of anti-PD-1 antibody. A biosimilar anti-PD-1 mAb generated in our laboratory was administered to humanized NOG-dKO mice transplanted with tumors. RESULTS: Within 4 weeks after transplantation, human CD45+ cells in antibody-treated mice constituted approximately 70% of spleen cells. The injection of anti-PD-1 antibody reduced by more 50% the size of SCC-3 and U87 tumors. In addition, induction of CTLs against SCC-3 cells and upregulation of natural killer cell activity was observed in the antibody-treated group. Tumor-infiltrating lymphocyte profiling showed that more exhausted marker (PD1+TIM3+LAG3+) positive T cells maintained in anti-PD-1 antibody-treated tumor. A greater number of CD8+ and granzyme-producing T cells infiltrated the tumor in mice treated with the anti-PD-1 antibody. CONCLUSIONS: These results suggest that NOG-dKO mice might serve as a good humanized immunotherapy model to evaluate the efficacy of anti-PD-1 antibody prior to the clinical treatment. Clin Cancer Res; 23(1); 149-58. (c)2016 AACR. PMID- 27458247 TI - GRM1 is An Androgen-Regulated Gene and its Expression Correlates with Prostate Cancer Progression in Pre-Clinical Models. AB - PURPOSE: We recently demonstrated that glutamate receptor GRM1 was expressed at high levels in castration-resistant prostate cancer (CR-PCa) tissues and cells. Herein, we determined the relationship between GRM1 and AR, PSA, and tumor growth, remission, and recurrence in preclinical PCa models. The effect of alterations in GRM1 expression was also investigated on PCa cell growth, migration and invasion. EXPERIMENTAL DESIGN: We used quantitative gene expression and immunohistochemistry to define the temporal association between GRM1 expression and AR, PSA, and tumor growth during CR progression in CWR22 (n = 59) and LuCaP 35 (n = 12) PCa xenografts. The effect of alterations in GRM1 expression levels on growth, migration, and invasion was investigated in GRM1 overexpressed or -silenced PCa cell lines. The effect of DHT on GRM1 expression was determined in the presence or absence of the antiandrogen bicalutamide. RESULTS: We found that GRM1 transcript and tissue expression directly correlated with growth and AR and PSA expression in hormone-sensitive (HS), castrated, and CR tumor xenografts. GRM1 overexpression or silencing directly correlated with PCa cell proliferation, migration, and invasion. DHT increased GRM1 expression via an AR-dependent manner in HS- and CR-PCa cell lines. CONCLUSIONS: This is a first report of GRM1 as an androgen and AR-target gene. GRM1 expression directly correlated with tumor growth, regression, and recurrence and may contribute to CR progression of PCa in preclinical models. Further studies are needed to define the utility of GRM1 as a druggable target or biomarker for PCa. PMID- 27458248 TI - Implications of the Bystander and Abscopal Effects of Radiation Therapy. AB - Siva and colleagues have demonstrated that localized thoracic radiation resulted in DNA damage at out-of-field sites. Although these interesting findings require validation, we discuss the important clinical implications of these data, especially in the era of immune therapies. Clin Cancer Res; 22(19); 4763-5. (c)2016 AACRSee related article by Siva et al., p. 4817. PMID- 27458249 TI - Gene Expression Analysis Reveals the Concurrent Activation of Proapoptotic and Antioxidant-Defensive Mechanisms in Flavokawain B-Treated Cervical Cancer HeLa Cells. AB - Flavokawain B (FKB) is known to possess promising anticancer abilities. This is demonstrated in various cancer cell lines including HeLa cells. Cervical cancer is among the most widely diagnosed cancer among women today. Though FKB has been shown to be effective in treating cancer cells, the exact molecular mechanism is still unknown. This study is aimed at understanding the effects of FKB on HeLa cells using a microarray-based mRNA expression profiling and proteome profiling of stress-related proteins. The results of this study suggest that FKB induced cell death through p21-mediated cell cycle arrest and activation of p38. However, concurrent activation of antioxidant-related pathways and iron sequestration pathway followed by activation of ER-resident stress proteins clearly indicate that FKB failed to induce apoptosis in HeLa cells via oxidative stress. This effect implies that the protection of HeLa cells by FKB from H2O2-induced cell death is via neutralization of reactive oxygen species. PMID- 27458250 TI - Physical Activity as a Nonpharmacological Symptom Management Approach in Myeloproliferative Neoplasms: Recommendations for Future Research. AB - PURPOSE: Essential thrombocythemia, polycythemia vera, and myelofibrosis are rare chronic hematological malignancies known as myeloproliferative neoplasms (MPNs) and are characterized by deregulated myeloid lineage cell production, splenomegaly, and heterogeneous symptom profiles. MPN patients suffer from a significant symptom burden (eg, fatigue, depressive symptoms, early satiety) and an impaired overall quality of life (QoL). Current treatments typically include pharmacological approaches, which may come with additional side effects and may be limited by treatment-associated toxicities (ie, cytopenias). Nonpharmacological approaches such as physical activity may be beneficial for reducing symptom burden and improving QoL. To date, no studies have examined physical activity as a nonpharmacological approach in MPN patients despite preliminary evidence supporting its benefit in other hematological cancers. The purpose of this article is to (1) review the literature related to physical activity and specific hematological cancer subtypes and to (2) make suggestions for future research involving physical activity in MPN patients as a symptom management strategy. METHODS: A brief review of studies examining physical activity in leukemias, lymphomas, and myelomas (excluding stem-cell transplant patients) was conducted. RESULTS: There is preliminary evidence to suggest that physical activity may be an effective approach to improve patient-reported outcomes (fatigue, depression, anxiety, sleep), physical fitness (cardiovascular fitness, balance, body composition), and overall QoL in other hematological cancers. CONCLUSIONS: Based on encouraging findings in other hematological cancers, future research should examine the feasibility and effectiveness of physical activity in MPN patients. PMID- 27458251 TI - Scaffolding protein IQGAP1: an insulin-dependent link between caveolae and the cytoskeleton in primary human adipocytes? AB - The ubiquitously expressed IQ motif-containing GTPase activating protein-1 (IQGAP1) is a scaffolding protein implicated in an array of cellular functions, in particular by binding to cytoskeletal elements and signaling proteins. A role of IQGAP1 in adipocytes has not been reported. We therefore investigated the cellular IQGAP1 interactome in primary human adipocytes. Immunoprecipitation and quantitative mass spectrometry identified caveolae and caveolae-associated proteins as the major IQGAP1 interactors alongside cytoskeletal proteins. We confirmed co-localization of IQGAP1 with the defining caveolar marker protein caveolin-1 by confocal microscopy and proximity ligation assay. Most interestingly, insulin enhanced the number of IQGAP1 interactions with caveolin-1 by five-fold. Moreover, we found a significantly reduced abundance of IQGAP1 in adipocytes from patients with type 2 diabetes compared with cells from nondiabetic control subjects. Both the abundance of IQGAP1 protein and mRNA were reduced, indicating a transcriptional defect in diabetes. Our findings suggest a novel role of IQGAP1 in insulin-regulated interaction between caveolae and cytoskeletal elements of the adipocyte, and that this is quelled in the diabetic state. PMID- 27458252 TI - Ablation of CD44 induces glycolysis-to-oxidative phosphorylation transition via modulation of the c-Src-Akt-LKB1-AMPKalpha pathway. AB - Cluster of differentiation 44 (CD44) is a transmembrane glycoprotein that has been identified as a cancer stem cell marker in various cancer cells. Although many studies have focused on CD44 as a cancer stem cell marker, its effect on cancer cell metabolism remains unclear. To investigate the role of CD44 on cancer cell metabolism, we established CD44 knock-down cells via retroviral delivery of shRNA against CD44 in human breast cancer cells. Silencing of CD44 decreased the glycolytic phenotype of cancer cells, affecting glucose uptake, ATP production, and lactate production. We also found that ablation of the CD44-induced lactate dehydrogenase (LDH) isoenzyme results in a shift to LDH1 due to LDHA down regulation and LDHB up-regulation, implying the importance of LDH isoenzyme modulation on cancer metabolism. The expression of glycolysis-related proteins including hypoxia inducible factor-1alpha (HIF-1alpha) and LDHA was decreased by CD44 silencing. These effects were due to the up-regulation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)alpha activity by reduction in c-Src and Akt activity in CD44 knock-down cells. Finally, induction of LKB1/AMPKalpha activity blocked the expression of HIF-1alpha and its target gene, LDHA. Inversely, LDHB expression was repressed by HIF-1alpha. Collectively, these results indicate that the CD44 silencing-induced metabolic shift is mediated by the regulation of c-Src/Akt/LKB1/AMPKalpha/HIF-1alpha signaling in human breast cancer cells. PMID- 27458253 TI - Association of P16-RBSP3 inactivation with phosphorylated RB1 overexpression in basal-parabasal layers of normal cervix unchanged during CACX development. AB - To understand the molecular mechanism of RB1 phosphorylation in basal-parabasal layers of normal cervix and during cervical cancer (CACX) development, we analyzed the alterations (expression/methylation/deletion/mutation) of RB1/phosphorylated RB1 (p-RB1) (ser807/811 and ser567) and two RB1 phosphorylation inhibitors, P16 and RBSP3, in disease-free normal cervical epithelium (n = 9), adjacent normal cervical epithelium of tumors (n = 70), cervical intraepithelial neoplasia (CIN; n = 28), CACX (n = 102) samples and two CACX cell lines. Immunohistochemical analysis revealed high/medium expression of RB1/p-RB1 (ser807/811 and ser567) and low expression of P16 and RBSP3 in proliferating basal-parabasal layers of majority of normal cervical epitheliums, irrespective of HPV16 infection. Interestingly, 35-52% samples showed high/medium expression of P16 in basal-parabasal layers of normal and had significant association with deleterious non-synonimous SNPs of P16. Methylation of P16 and RBSP3 in basal-parabasal layers of normal cervix (32 and 62%, respectively) showed concordance with their respective expressions in basal-parabasal layers. The methylation frequency of P16 and RBSP3 in basal-parabasal layers of normal did not change significantly in CIN and CACX. The deletion frequency of P16 and RB1 increased significantly with CACX progression. While, deletion of RBSP3 was high in CIN and comparable during CACX progression. P16 showed scattered and infrequent mutation in CACX. The alteration of P16 and RBSP3 was synergistic and showed association with overexpression of p-RB1 in tumors and associated with poor prognosis of patients. Thus, our data suggest that overexpression of p-RB1 in basal-parabasal layers of normal cervical epithelium was due to methylation/low functional-linked non-synonimous SNPs of P16 and RBSP3. This pattern was maintained during cervical carcinogenesis by additional deletion/mutation. PMID- 27458254 TI - A Systematic Review and Meta-Analysis Comparing Carer Focused and Dyadic Multicomponent Interventions for Carers of People With Dementia. AB - OBJECTIVE: The aim of this study was to compare the efficacy of two approaches: multicomponent interventions that focus on working with the carer and dyadic interventions that work with both the carer and the person with dementia. METHOD: A systematic review involving a search of Medline, EMBASE, and PsycINFO in October 2015 was performed. Randomized controlled trials involving carers of people with dementia and comparing multicomponent interventions with usual care were included. RESULTS: Pooling of all studies demonstrated that multicomponent interventions can reduce depressive symptoms, improve quality of life, reduce carer impact, and reduce behavioral and psychological symptoms of dementia as well as caregiver upset with these symptoms. We were unable to find a significant difference in the effects of dyadic interventions in comparison with carer focused interventions for these outcomes. DISCUSSION: Although effect sizes associated with intervention are small, multicomponent interventions are relatively inexpensive to deliver, acceptable, and widely applicable. PMID- 27458255 TI - Phenotypical heterogeneity linked to adipose tissue dysfunction in patients with Type 2 diabetes. AB - Adipose tissue (AT) inflammation leads to increased free fatty acid (FFA) efflux and ectopic fat deposition, but whether AT dysfunction drives selective fat accumulation in specific sites remains unknown. The aim of the present study was to investigate the correlation between AT dysfunction, hepatic/pancreatic fat fraction (HFF, PFF) and the associated metabolic phenotype in patients with Type 2 diabetes (T2D). Sixty-five consecutive T2D patients were recruited at the Diabetes Centre of Sapienza University, Rome, Italy. The study population underwent clinical examination and blood sampling for routine biochemistry and calculation of insulin secretion [homoeostasis model assessment of insulin secretion (HOMA-beta%)] and insulin-resistance [homoeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (ADIPO-IR)] indexes. Subcutaneous (SAT) and visceral (VAT) AT area, HFF and PFF were determined by magnetic resonance. Some 55.4% of T2D patients had non-alcoholic fatty liver disease (NAFLD); they were significantly younger and more insulin resistant than non-NAFLD subjects. ADIPO-IR was the main determinant of HFF independently of age, sex, HOMA-IR, VAT, SAT and predicted severe NAFLD with the area under the receiver operating characteristic curve (AUROC)=0.796 (95% confidence interval: 0.65-0.94, P=0.001). PFF was independently associated with increased total adiposity but did not correlate with AT dysfunction, insulin resistance and secretion or NAFLD. The ADIPO-IR index was capable of predicting NAFLD independently of all confounders, whereas it did not seem to be related to intrapancreatic fat deposition; unlike HFF, higher PFF was not associated with relevant alterations in the metabolic profile. In conclusion, the presence and severity of AT dysfunction may drive ectopic fat accumulation towards specific targets, such as VAT and liver, therefore evaluation of AT dysfunction may contribute to the identification of different risk profiles among T2D patients. PMID- 27458256 TI - Vitellogenin2: spermatozoon specificity and immunoprotection in mud crabs. AB - As the precursor of vitellin (Vn), vitellogenin (Vg) has initially been considered as a female-specific protein involved in vitellogenesis, while it was also present in males induced by hormones or organs manipulation. Distinct from vtg1 we previously found in female mud crab Scylla paramamosain, vtg2 was intriguingly detected in male testis under normal physiological conditions in this study. Sequence analysis showed that vtg2 and vtg1 were actually two isoforms of Vg caused by different types of alternative splicing. PCR and in situ hybridization analysis revealed that vtg2 was localized only in the testicular spermatozoa, while Vn was detected in both the spermatozoa of the testis and seminal vesicle. Therefore, we speculated that Vn was initially translated in testicular spermatozoa, then migrated with spermatozoa, and finally stored in the seminal vesicle, where spermatozoa gradually accomplished maturation. We presumed that vtg2/Vn might act as an immune-relevant molecule in the male reproduction system. In the subsequent experiment, the expression of vtg2/Vn in testis was significantly induced in response to lipopolysaccharide (LPS) and lipoteichoic acid (LTA) injection at both transcriptional and translational levels. In the light of the results presented above, we deemed that vtg2/Vn is a novel candidate of immune-relevant molecules involved in immunoprotection during the spermatozoon maturation, and this research helps to open a new avenue for further exploring the role of Vg. PMID- 27458257 TI - The Standard Model: how far can it go and how can we tell? AB - The Standard Model of particle physics encapsulates our current best understanding of physics at the smallest distances and highest energies. It incorporates quantum electrodynamics (the quantized version of Maxwell's electromagnetism) and the weak and strong interactions, and has survived unmodified for decades, save for the inclusion of non-zero neutrino masses after the observation of neutrino oscillations in the late 1990s. It describes a vast array of data over a wide range of energy scales. I review a selection of these successes, including the remarkably successful prediction of a new scalar boson, a qualitatively new kind of object observed in 2012 at the Large Hadron Collider. New calculational techniques and experimental advances challenge the Standard Model across an ever-wider range of phenomena, now extending significantly above the electroweak symmetry breaking scale. I will outline some of the consequences of these new challenges, and briefly discuss what is still to be found.This article is part of the themed issue 'Unifying physics and technology in light of Maxwell's equations'. PMID- 27458258 TI - Time-reversal constraint limits unidirectional photon emission in slow-light photonic crystals. AB - Photonic crystal waveguides are known to support C-points-point-like polarization singularities with local chirality. Such points can couple with dipole-like emitters to produce highly directional emission, from which spin-photon entanglers can be built. Much is made of the promise of using slow-light modes to enhance this light-matter coupling. Here we explore the transition from travelling to standing waves for two different photonic crystal waveguide designs. We find that time-reversal symmetry and the reciprocal nature of light places constraints on using C-points in the slow-light regime. We observe two distinctly different mechanisms through which this condition is satisfied in the two waveguides. In the waveguide designs, we consider a modest group velocity of vg~c/10 is found to be the optimum for slow-light coupling to the C-points.This article is part of the themed issue 'Unifying physics and technology in light of Maxwell's equations'. PMID- 27458259 TI - Unification of force and substance. AB - Maxwell's mature presentation of his equations emphasized the unity of electromagnetism and mechanics, subsuming both as 'dynamical systems'. That intuition of unity has proved both fruitful, as a source of pregnant concepts, and broadly inspiring. A deep aspect of Maxwell's work is its use of redundant potentials, and the associated requirement of gauge symmetry. Those concepts have become central to our present understanding of fundamental physics, but they can appear to be rather formal and esoteric. Here I discuss two things: the physical significance of gauge invariance, in broad terms; and some tantalizing prospects for further unification, building on that concept, that are visible on the horizon today. If those prospects are realized, Maxwell's vision of the unity of field and substance will be brought to a new level.This article is part of the themed issue 'Unifying physics and technology in light of Maxwell's equations'. PMID- 27458260 TI - Emergent gauge fields and the high-temperature superconductors. AB - The quantum entanglement of many states of matter can be represented by electric and magnetic fields, much like those found in Maxwell's theory. These fields 'emerge' from the quantum structure of the many-electron state, rather than being fundamental degrees of freedom of the vacuum. I review basic aspects of the theory of emergent gauge fields in insulators in an intuitive manner. In metals, Fermi liquid (FL) theory relies on adiabatic continuity from the free electron state, and its central consequence is the existence of long-lived electron-like quasi-particles around a Fermi surface enclosing a volume determined by the total density of electrons, via the Luttinger theorem. However, long-range entanglement and emergent gauge fields can also be present in metals. I focus on the 'fractionalized Fermi liquid' (FL*) state, which also has long-lived electron like quasi-particles around a Fermi surface; however, the Luttinger theorem on the Fermi volume is violated, and this requires the presence of emergent gauge fields, and the associated loss of adiabatic continuity with the free electron state. Finally, I present a brief survey of some recent experiments in the hole doped cuprate superconductors, and interpret the properties of the pseudogap regime in the framework of the FL* theory.This article is part of the themed issue 'Unifying physics and technology in light of Maxwell's equations'. PMID- 27458261 TI - Beyond the standard model of particle physics. AB - The Large Hadron Collider (LHC) at CERN and its experiments were conceived to tackle open questions in particle physics. The mechanism of the generation of mass of fundamental particles has been elucidated with the discovery of the Higgs boson. It is clear that the standard model is not the final theory. The open questions still awaiting clues or answers, from the LHC and other experiments, include: What is the composition of dark matter and of dark energy? Why is there more matter than anti-matter? Are there more space dimensions than the familiar three? What is the path to the unification of all the fundamental forces? This talk will discuss the status of, and prospects for, the search for new particles, symmetries and forces in order to address the open questions.This article is part of the themed issue 'Unifying physics and technology in light of Maxwell's equations'. PMID- 27458262 TI - Unifying physics and technology in light of Maxwell's equations. PMID- 27458263 TI - Maxwell electromagnetism as an emergent phenomenon in condensed matter. AB - The formulation of a complete theory of classical electromagnetism by Maxwell is one of the milestones of science. The capacity of many-body systems to provide emergent mini-universes with vacua quite distinct from the one we inhabit was only recognized much later. Here, we provide an account of how simple systems of localized spins manage to emulate Maxwell electromagnetism in their low-energy behaviour. They are much less constrained by symmetry considerations than the relativistically invariant electromagnetic vacuum, as their substrate provides a non-relativistic background with even translational invariance broken. They can exhibit rich behaviour not encountered in conventional electromagnetism. This includes the existence of magnetic monopole excitations arising from fractionalization of magnetic dipoles; as well as the capacity of disorder, by generating defects on the lattice scale, to produce novel physics, as exemplified by topological spin glassiness or random Coulomb magnetism.This article is part of the themed issue 'Unifying physics and technology in light of Maxwell's equations'. PMID- 27458264 TI - Hair Follicle and Sebaceous Gland De Novo Regeneration With Cultured Epidermal Stem Cells and Skin-Derived Precursors. AB - : : Stem cell-based organ regeneration is purported to enable the replacement of impaired organs in the foreseeable future. Here, we demonstrated that a combination of cultured epidermal stem cells (Epi-SCs) derived from the epidermis and skin-derived precursors (SKPs) was capable of reconstituting functional hair follicles and sebaceous glands (SG). When Epi-SCs and SKPs were mixed in a hydrogel and implanted into an excisional wound in nude mice, the Epi-SCs formed de novo epidermis along with hair follicles, and SKPs contributed to dermal papilla in the neogenic hair follicles. Notably, a combination of culture expanded Epi-SCs and SKPs derived from the adult human scalp were sufficient to generate hair follicles and hair. Bone morphogenetic protein 4, but not Wnts, sustained the expression of alkaline phosphatase in SKPs in vitro and the hair follicle-inductive property in vivo when SKPs were engrafted with neonatal epidermal cells into excisional wounds. In addition, Epi-SCs were capable of differentiating into sebocytes and formed de novo SGs, which excreted lipids as do normal SGs. Thus our results indicate that cultured Epi-SCs and SKPs are sufficient to generate de novo hair follicles and SGs, implying great potential to develop novel bioengineered skin substitutes with appendage genesis capacity. SIGNIFICANCE: In postpartum humans, skin appendages lost in injury are not regenerated, despite the considerable achievement made in skin bioengineering. In this study, transplantation of a combination of culture-expanded epidermal stem cells and skin-derived progenitors from mice and adult humans led to de novo regeneration of functional hair follicles and sebaceous glands. The data provide transferable knowledge for the development of novel bioengineered skin substitutes with epidermal appendage regeneration capacity. PMID- 27458265 TI - Concise Review: In Vitro Formation of Bone-Like Nodules Sheds Light on the Application of Stem Cells for Bone Regeneration. AB - : : Harnessing the differentiation of stem cells into bone-forming cells represents an intriguing avenue for the creation of functional skeletal tissues. Therefore, a profound understanding of bone development and morphogenesis sheds light on the regenerative application of stem cells in orthopedics and dentistry. In this concise review, we summarize the studies deciphering the mechanisms that govern osteoblast differentiation in the context of in vitro formation of bone like nodules, including morphologic and molecular events as well as cellular contributions to mineral nucleation, occurring during osteogenic differentiation of stem cells. This article also highlights the limitations of current translational applications of stem cells and opportunities to use the bone-like nodule model for bone regenerative therapies. SIGNIFICANCE: Harnessing the differentiation of stem cells into bone-forming cells represents an intriguing avenue for the creation of functional skeletal tissues. Therefore, a profound understanding of bone development and morphogenesis sheds light on the regenerative application of stem cells in orthopedics and dentistry. In this concise review, studies deciphering the mechanisms that govern osteoblast commitment and differentiation are summarized. This article highlights the limitations of current translational applications of stem cells and the opportunities to use the bone-like nodule model for bone regenerative therapies. PMID- 27458266 TI - Adult Human Peripheral Blood Mononuclear Cells Are Capable of Producing Neurocyte or Photoreceptor-Like Cells That Survive in Mouse Eyes After Preinduction With Neonatal Retina. AB - : : Adult human peripheral blood mononuclear cells (hPBMCs) exhibit pluripotency in vitro and so may be a valuable cell source for regenerative therapies. The efficacy of such therapies depends on the survival, differentiation, migration, and integration capacity of hPBMCs in specific tissues. In this study, we examined these capacities of transplanted hPBMCs in mouse retina as well functional improvement after transplant. We isolated hPBMCs and preinduced them for 4 days in media preconditioned with postnatal day 1 rat retina explants. Preinduction increased the proportions of hPBMCs expressing neural stem cell, neural progenitor cell, or photoreceptor markers as revealed by immunofluorescent staining, flow cytometry, and quantitative real-time polymerase chain reaction. Preinduced hPBMCs were transplanted into the subretinal space of retinal degenerative slow (RDS) and retinal degeneration 1 (RD1) mice. At 1, 3, and 6 months after transplantation, treated eyes of RDS mice were collected and cell phenotype was studied by immunofluorescent staining. Preinduced hPBMCs survived in the subretinal space; migrated away from the injection site and into multiple retinal layers; and expressed neural stem cell, neuronal, and photoreceptor markers. Finally, we assessed RD1 retinal function after subretinal transplantation and found significant improvement at 3 months after transplantation. The ease of harvesting, viability in vivo, capacity to express neuronal and photoreceptor proteins, and capacity for functional enhancement suggest that hPBMCs are potential candidates for cell replacement therapy to treat retinal degenerative diseases. SIGNIFICANCE: This study provides support for the use of peripheral blood mononuclear cells (PBMCs) as a potential source of pluripotent stem cells for treating retinal degeneration. First, this study demonstrated that PBMCs can differentiate into retinal neuron-like cells in vitro and in vivo. Second, some transplanted cells expressed markers for neural progenitors, mature neurons, or photoreceptors at 1, 3, and 6 months after subretinal injection. Finally, this study showed that PBMC transplantation can improve the function of a degenerated retina. PMID- 27458267 TI - Photo Quiz: Fever, Rash, and Polyarthralgia in a 5-Year-Old Male. PMID- 27458268 TI - The Brief Case: Recurrent Granulomatous Mastitis Due to Corynebacterium kroppenstedtii. PMID- 27458269 TI - May Newly Defined Subgenotypes Va and Vb of Newcastle Disease Virus in Poultry Be Considered Two Different Genotypes? PMID- 27458270 TI - Reply to "May Newly Defined Subgenotypes Va and Vb of Newcastle Disease Virus in Poultry Be Considered Two Different Genotypes?". PMID- 27458271 TI - Correction for Alcala et al., Comparison of GenomEra C. difficile and Xpert C. difficile as Confirmatory Tests in a Multistep Algorithm for Diagnosis of Clostridium difficile Infection. PMID- 27458272 TI - Correction for Kim et al., Identification of Mycobacterial Antigens in Human Urine by Use of Immunoglobulin G Isolated from Sera of Patients with Active Pulmonary Tuberculosis. PMID- 27458273 TI - Correction for Escribano et al., Microsatellite (STRAf) Genotyping Cannot Differentiate between Invasive and Colonizing Aspergillus fumigatus Isolates. PMID- 27458274 TI - Correction for Guinea et al., Aspergillus citrinoterreus, a New Species of Section Terrei Isolated from Samples of Patients with Nonhematological Predisposing Conditions. PMID- 27458275 TI - Correction for Molina-Moya et al., Evaluation of GenoFlow DR-MTB Array Test for Detection of Rifampin and Isoniazid Resistance in Mycobacterium tuberculosis. PMID- 27458276 TI - Closing the Brief Case: Recurrent Granulomatous Mastitis Due to Corynebacterium kroppenstedtii. PMID- 27458277 TI - Answer to August 2016 Photo Quiz. PMID- 27458279 TI - National Comprehensive Cancer Network Recommendations on Molecular Profiling of Advanced Bladder Cancer. PMID- 27458280 TI - Categorization of Cancer Survivors: Why We Need It. PMID- 27458281 TI - Reply to M. Nishino. PMID- 27458282 TI - Reply to S. Rastogi et al. PMID- 27458283 TI - Differential Sensitivity to Crizotinib: Does EML4-ALK Fusion Variant Matter? PMID- 27458284 TI - Reply to E. Roca et al. PMID- 27458285 TI - Reply to K. Lin et al. PMID- 27458286 TI - Management of Chronic Pain in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. AB - PURPOSE: To provide evidence-based guidance on the optimum management of chronic pain in adult cancer survivors. METHODS: An ASCO-convened expert panel conducted a systematic literature search of studies investigating chronic pain management in cancer survivors. Outcomes of interest included symptom relief, pain intensity, quality of life, functional outcomes, adverse events, misuse or diversion, and risk assessment or mitigation. RESULTS: A total of 63 studies met eligibility criteria and compose the evidentiary basis for the recommendations. Studies tended to be heterogeneous in terms of quality, size, and populations. Primary outcomes also varied across the studies, and in most cases, were not directly comparable because of different outcomes, measurements, and instruments used at different time points. Because of a paucity of high-quality evidence, many recommendations are based on expert consensus. RECOMMENDATIONS: Clinicians should screen for pain at each encounter. Recurrent disease, second malignancy, or late-onset treatment effects in any patient who reports new-onset pain should be evaluated, treated, and monitored. Clinicians should determine the need for other health professionals to provide comprehensive pain management care in patients with complex needs. Systemic nonopioid analgesics and adjuvant analgesics may be prescribed to relieve chronic pain and/or to improve function. Clinicians may prescribe a trial of opioids in carefully selected patients with cancer who do not respond to more conservative management and who continue to experience distress or functional impairment. Risks of adverse effects of opioids should be assessed. Clinicians should clearly understand terminology such as tolerance, dependence, abuse, and addiction as it relates to the use of opioids and should incorporate universal precautions to minimize abuse, addiction, and adverse consequences. Additional information is available at www.asco.org/chronic pain-guideline and www.asco.org/guidelineswiki. PMID- 27458287 TI - Trabectedin in Soft Tissue Sarcoma: Have We Hit the Bull's-eye? PMID- 27458289 TI - Can Observational Data Replace Randomized Trials? PMID- 27458290 TI - Reply to K. Lin et al. PMID- 27458288 TI - Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma. AB - PURPOSE: We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. PATIENTS AND METHODS: Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m(2), 50 mg/m(2), or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. RESULTS: The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (>= 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. CONCLUSION: Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1 week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated. PMID- 27458292 TI - Reply to O. Corli et al and M. Lucchesi et al. PMID- 27458291 TI - Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis. AB - PURPOSE: Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer. METHODS: We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab. RESULTS: Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis. CONCLUSION: Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab. PMID- 27458293 TI - Two-Step Approach for Persisting Pain: Learning From Children. PMID- 27458294 TI - Good and Bad Responses to a Pain Therapy: How to Discriminate Between Them? PMID- 27458296 TI - Reply to P. de Boissieu et al. PMID- 27458295 TI - Trends in Obesity Prevalence in Adults With a History of Cancer: Results From the US National Health Interview Survey, 1997 to 2014. AB - PURPOSE: Obesity after a diagnosis of specific cancers has been associated with worse prognosis. We examined the trend in obesity prevalence among cancer survivors in the United States in the past two decades and compared trends with those of adults without a history of cancer. PATIENTS AND METHODS: This was a population-based nationally representative sample of 538,969 noninstitutionalized US adults 18 to 85 years old with and without a history of cancer who participated in annual cross-sectional National Health Interview Surveys from 1997 to 2014. Obesity was defined as body mass index >= 30 kg/m(2) for non-Asians and body mass index >= 27.5 kg/m(2) for Asians. RESULTS: Among 32,447 cancer survivors identified, the most common cancer diagnoses were breast (n = 6,948), prostate (n = 3,984), and colorectal (n = 2,546). From 1997 to 2014, the prevalence of obesity increased from 22.4% to 31.7% in cancer survivors and from 20.9% to 29.5% in adults without a history of cancer (P for trend < .001, both groups). Over this period, the estimated rate of annual increase in obesity prevalence was higher in women and men with a history of cancer compared with those without a history of cancer (all P for interaction < .001). The estimated rate of annual increase in obesity prevalence was 3.1% in female and 3.7% in male colorectal cancer survivors, 3.0% in breast cancer survivors, and 2.1% in prostate cancer survivors (all P < .001). In subgroup analyses, populations with the highest rates of increasing obesity burden were colorectal cancer survivors, breast cancer survivors, and non-Hispanic blacks. CONCLUSION: From 1997 to 2014, obesity increased more rapidly among adult cancer survivors compared with the general population. Colorectal and breast cancer survivors and non-Hispanic blacks were identified as being at the highest risk for obesity. PMID- 27458297 TI - Accuracy of Prostate-Specific Antigen Values in Prostate Cancer Registries. PMID- 27458298 TI - Patient Navigation in Breast Cancer Treatment and Survivorship: A Systematic Review. AB - PURPOSE: Patient navigation is an intervention approach that improves cancer outcomes by reducing barriers and facilitating timely access to cancer care. Little is known about the benefits of patient navigation during breast cancer treatment and survivorship. This systematic review evaluates the efficacy of patient navigation in improving treatment and survivorship outcomes in women with breast cancer. METHODS: The review included experimental and quasi-experimental studies of patient navigation programs that target breast cancer treatment and breast cancer survivorship. Articles were systematically obtained through electronic database searches of PubMed/MEDLINE, PsycINFO, Web of Science, CINAHL, and Cochrane Library. The Effective Public Health Practice Project Quality Assessment Tool was used to evaluate the methodologic quality of individual studies. RESULTS: Thirteen studies met the inclusion criteria. Most were of moderate to high quality. Outcomes targeted included timeliness of treatment initiation, adherence to cancer treatment, and adherence to post-treatment surveillance mammography. Heterogeneity of outcome assessments precluded a meta analysis. Overall, results demonstrated that patient navigation increases surveillance mammography rates, but only minimal evidence was found with regard to its effectiveness in improving breast cancer treatment outcomes. CONCLUSION: This study is the most comprehensive systematic review of patient navigation research focused on improving breast cancer treatment and survivorship. Minimal research has indicated that patient navigation may be effective for post treatment surveillance; however, more studies are needed to draw definitive conclusions about the efficacy of patient navigation during and after cancer treatment. PMID- 27458299 TI - Pseudoprogression and Measurement Variability. PMID- 27458301 TI - Reply to O. Corli et al and M. Lucchesi et al. PMID- 27458302 TI - Change in Pattern of HER2 Fluorescent in Situ Hybridization (FISH) Results in Breast Cancers Submitted for FISH Testing: Experience of a Reference Laboratory Using US Food and Drug Administration Criteria and American Society of Clinical Oncology and College of American Pathologists Guidelines. AB - Purpose In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio >= 2.0, 1.3% (n = 35) with a FISH ratio >= 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal >= 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal >= 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed. PMID- 27458303 TI - Reply to S. Rastogi et al. PMID- 27458300 TI - Recommendations for Premature Ovarian Insufficiency Surveillance for Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Report From the International Late Effects of Childhood Cancer Guideline Harmonization Group in Collaboration With the PanCareSurFup Consortium. AB - PURPOSE: Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. PATIENTS AND METHODS: The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer. RESULTS AND CONCLUSION: The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer. PMID- 27458304 TI - Serum Vitamin D and Prostate Cancer Prognosis: The Story Continues. PMID- 27458305 TI - Impact of Depression in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy With Cytoreductive Surgery. PMID- 27458306 TI - Evaluating Quality Metrics for the Care of Patients With Blood Cancer Who Are Near Death. PMID- 27458308 TI - Dangers of Excluding Margin Status From a Ductal Carcinoma In Situ Prognostic Score. PMID- 27458307 TI - Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. AB - Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC. PMID- 27458309 TI - Industry-Academic Relationship in a New Era of Drug Discovery. AB - The pharmaceutical industry is entering a renewed period of productivity as a result of advances in the understanding of human biology, particularly in the areas of genetics and immunology. The relationship between industry and academia needs to evolve to maximize the opportunity. In four areas-target identification, the molecule itself, experimental medicine, and larger-scale clinical testing there are specific needs for academic partnerships that should be open and transparent and include talent, skills, and career development. PMID- 27458310 TI - Programmed Cell Death Ligand-1 Blockade in Urothelial Bladder Cancer: To Select or Not to Select. PMID- 27458311 TI - Estimating the Influence of Obesity on Cancer Risk: Stratification by Smoking Is Critical. PMID- 27458312 TI - Celebrating Research, Our Future and Dental Hygienists! PMID- 27458313 TI - Cultural Competency in Dental Hygiene Curricula. AB - PURPOSE: The purpose of this study was to determine the degree to which U.S. dental hygiene programs are incorporating cultural competency education into the dental hygiene curriculum and to identify associated program characteristics. METHODS: A 19 item survey was electronically administered to all 334 U.S. dental hygiene program directors. The questionnaire solicited information on teaching and evaluation methodologies relative to cultural competency education (CCE), as well as director's perceptions and program demographic information. RESULTS: An overall response rate of 27% was obtained. The majority of participating programs (92%) reported incorporating CCE into the curriculum in some form. Most responding directors indicated that CCE has been effectively integrated into the curriculum. A variety of curricular methods are being employed to teach CCE with lectures being the most common method utilized. Results of this study suggest that an overwhelming number of responding programs (98%) participate in community outreach/service learning projects. However, nearly half (42%) indicated that their students are not evaluated for culture competency knowledge, skills and attitudes. CONCLUSION: These findings imply that responding programs are incorporating CCE into the curriculum using a variety of teaching methodologies with an emphasis on community outreach/service learning projects. It is important to consider whether or not community outreach/service learning projects improve dental hygiene students' cultural competency skills, attitudes and knowledge. Future research efforts should aim to describe the value and effectiveness of such programs at achieving cultural competence. PMID- 27458314 TI - Oral Health and Hospital-Acquired Pneumonia in Elderly Patients: A Review of the Literature. AB - PURPOSE: The U.S. spends an average of $6.5 billion each year to treat patients who suffer from pneumonia. Pneumonia currently has the highest morbidity and mortality rates of all nosocomial infections, is hypothesized to account for 15% of all hospital-acquired illnesses and is responsible for 13 to 48% of all nursing home-associated illnesses. For years, researchers have tried to develop methods to prevent pneumonia because of its detrimental effects on the body, but only in the last decade have they been able to uncover possible methods to do so. Inadequate oral hygiene care is one of the ways that elderly patients contract hospital-acquired pneumonia (HAP). Proper oral disease prevention could possibly be considered the standard of care in long-term stay facilities to reduce and prevent elderly patients from contracting HAP. The purpose of this literature review is to explore the relationship between oral health care practices and HAP. PMID- 27458315 TI - An Assessment Model for Evaluating Outcomes in Federally Qualified Health Centers' Dental Departments: Results of a 5 Year Study. AB - PURPOSE: The purpose of this report was to establish baseline data on 10 oral health performance indicators over 5 fiscal years (2007 to 2008 through 2011 to 2012) for an Iowa health center. The baseline data provides an assessment model and reports outcomes based on the use of the model. Performance indicators show evidence of provider performance, accountability to stakeholders and provide the benchmarks required for dental management to develop future goals to improve oral health outcomes for atrisk populations. METHODS: Using descriptive statistic, this report extrapolated data from the Iowa Health Center's computer management systems software, HealthPro, and Centricity electronic medical records, and analyzed using IBM(r) SPSS(r) 19. This report describes the change in utilization for number and type of visits for uninsured and Medicaid patients over 5 fiscal years (a fiscal year is measured from November 1 through October 31). RESULTS: The number of patients receiving at least 1 dental visit in a measurement year showed n=81,673 procedures with 21% (17,167) being unduplicated patients. Preventive averaged 46%, restorative 18%, urgent care 22% and other procedures 14%. CONCLUSION: Federally qualified health centers (FQHCs) with a dental component serve populations with the greatest health disparities. This population includes ethnic and racial minorities, uninsured, underinsured, rural residents, Medicaid and Medicare. Establishing baseline data for FQHCs provides a foundational tool that will allow dental management to analyze successes as well as deficiencies in the goal to provide increased utilization to oral health care for at-risk populations. PMID- 27458316 TI - Evaluating the Impact of Expanded Practice Dental Hygienists in Oregon: An Outcomes Assessment. AB - PURPOSE: Currently the dental hygiene practice model in Oregon includes the Expanded Practice Dental Hygienist (EPDH), which allows dental hygienists with an Expanded Practice Permit (EPP) to provide care to limited access populations without the supervision of a dentist. The number and types of services provided by EPDH practitioners is thus far undocumented. The purpose of this study is to conduct an outcomes assessment of EPDH practitioners in order to quantify the impact, defined by count of services, on the access to care crisis in Oregon. METHODS: A 16 question confidential survey was developed and approved by the Pacific University institutional review board. The mail-based survey was sent to 181 EPDHs in Oregon in November 2011 (all EPDHs except pilot testers and one author). A second mailing was sent to non-respondents. Data were analyzed using descriptive statistics and chi-square analysis in SPSS. RESULTS: The response rate was 39% (n=71). Approximately 41% (n=29) of the respondents were currently using their EPP to provide care to limited access patients with an additional 21% (n=15) planning to start their own expanded practice. The majority of practicing EPDHs provide care in residential care facilities (n=21) and in school settings (n=13). Of the current practicing EPP holders, 76% practice <=10 hours per week, and 66% make <$10,000 per year. Total services reported in an average month from all responding EPDH practitioners were: 254 adult prophylaxes, 1,003 child prophylaxes, 106 adult fluorides, 901 child fluorides and 1,994 fluoride varnishes, among many other preventive procedures. CONCLUSION: To a limited extent, the amount and type of services provided by EPDHs has now been quantified, and EPDHs are making an impact on the access to care crisis in Oregon. Continued outcomes assessment is needed to further quantify the impact of EPDHs. PMID- 27458317 TI - Assessing Evidence-Based Practice Knowledge, Attitudes, Access and Confidence Among Dental Hygiene Educators. AB - PURPOSE: To assess U.S. dental hygiene educators' evidence-based practice (EBP) knowledge, attitude, access and confidence and determine whether a correlation exists between assessment scores and level of education, length teaching and teaching setting (didactic, clinical or both). METHODS: A cross-sectional survey was conducted with a sample of dental hygiene faculty from all 334 U.S. dental hygiene schools. ANOVA and Pearson correlation coefficient statistical analysis were utilized to investigate relationships between demographic variables and application of evidence-based principles of patient care. RESULTS: This study involved a non-probability sample (n=124), since the total faculty among all U.S. dental hygiene schools was not determined. Analysis demonstrated a positive correlation between EBP knowledge, access and confidence scores indicating that as knowledge scores increased, so did confidence and access scores (r=0.313, p<0.01 and r=0.189, p<0.05, respectively). Study findings also revealed that faculty who held advanced educational degrees scored significantly higher in EBP knowledge (F3,120=2.81, p<0.04) and confidence (F3,120=7.26, p<0.00). CONCLUSION: This study suggests the level of EBP knowledge, attitude, access and confidence increases with additional education. Therefore, more EBP training may be necessary for faculty who do not possess advanced education. Results of the study indicate that further incorporation of EBP into dental hygiene curricula may occur as dental hygiene educators' knowledge of EBP increases, which in turn could enhance students' acquisition of EBP skills and their application of EBP principles toward patient care. PMID- 27458318 TI - National Dental Hygiene Research Agenda. PMID- 27458319 TI - A lambda 3 mm and 1 mm line survey toward the yellow hypergiant IRC +10420: N rich chemistry and IR flux variations. AB - AIMS: Our knowledge of the chemical properties of the circumstellar ejecta of the most massive evolved stars is particularly poor. We aim to study the chemical characteristics of the prototypical yellow hypergiant star, IRC +10420. For this purpose, we obtained full line surveys at 1 and 3 mm atmospheric windows. METHODS: We have identified 106 molecular emission lines from 22 molecular species. Approximately half of the molecules detected are N-bearing species, in particular HCN, HNC, CN, NO, NS, PN, and N2H+. We used rotational diagrams to derive the density and rotational temperature of the different molecular species detected. We introduced an iterative method that allows us to take moderate line opacities into account. RESULTS: We have found that IRC +10420 presents high abundances of the N-bearing molecules compared with O-rich evolved stars. This result supports the presence of a N-rich chemistry, expected for massive stars. Our analysis also suggests a decrease of the 12C/13C ratio from ? 7 to ~ 3.7 in the last 3800 years, which can be directly related to the nitrogen enrichment observed. In addition, we found that SiO emission presents a significant intensity decrease for high-J lines when compared with older observations. Radiative transfer modeling shows that this variation can be explained by a decrease in the infrared (IR) flux of the dust. The origin of this decrease might be an expansion of the dust shell or a lower stellar temperature due to the pulsation of the star. PMID- 27458320 TI - Retention of 14C-labeled multiwall carbon nanotubes by humic acid and polymers: Roles of macromolecule properties. AB - Developing methods to measure interactions of carbon nanotubes (CNTs) with soils and sediments and understanding the impact of soil and sediment properties on CNT deposition are essential for assessing CNT environmental risks. In this study, we utilized functionalized carbon-14 labeled nanotubes to systematically investigate retention of multiwall CNTs (MWCNTs) by 3 humic acids, 3 natural biopolymers, and 10 model solid-phase polymers, collectively termed macromolecules. Surface properties, rather than bulk properties of macromolecules, greatly influenced MWCNT retention. As shown via multiple linear regression analysis and path analysis, aromaticity and surface polarity were the two most positive factors for retention, suggesting retention was regulated by pi-pi stacking and hydrogen bonding interactions. Moreover, MWCNT deposition was irreversible. These observations may explain the high retention of MWCNT in natural soils. Moreover, our findings on the relative contribution of each macromolecule property on CNT retention provide information on macromolecule selection for removal of MWCNTs from wastewater and provide a method for measuring CNT interactions with organic macromolecules. PMID- 27458321 TI - Speed-of-Sound Measurements in (Argon + Carbon Dioxide) over the Temperature Range from (275 to 500) K at Pressures up to 8 MPa. AB - The speed of sound of two (argon + carbon dioxide) mixtures was measured over the temperature range from (275 to 500) K with pressures up to 8 MPa utilizing a spherical acoustic resonator. The compositions of the gravimetrically prepared mixtures were (0.50104 and 0.74981) mole fraction carbon dioxide. The vibrational relaxation of pure carbon dioxide led to high sound absorption, which significantly impeded the sound-speed measurements on carbon dioxide and its mixtures; pre-condensation may have also affected the results for some measurements near the dew line. Thus, in contrast to the standard operating procedure for speed-of-sound measurements with a spherical resonator, non-radial resonances at lower frequencies were taken into account. Still, the data show a comparatively large scatter, and the usual repeatability of this general type of instrument could not be realized with the present measurements. Nonetheless, the average relative combined expanded uncertainty (k = 2) in speed of sound ranged from (0.042 to 0.056)% for both mixtures, with individual state-point uncertainties increasing to 0.1%. These uncertainties are adequate for our intended purpose of evaluating thermodynamic models. The results are compared to a Helmholtz energy equation of state for carbon capture and storage applications; relative deviations of (-0.64 to 0.08)% for the (0.49896 argon + 0.50104 carbon dioxide) mixture, and of (-1.52 to 0.77)% for the (0.25019 argon + 0.74981 carbon dioxide) mixture were observed. PMID- 27458322 TI - EUV-induced oxidation of carbon on TiO2. AB - Previously we reported estimates of the maximum etch rates of C on TiO2 by oxidizers including NO, O3 and H2O2 when irradiated by a spatially-non-uniform beam of extreme ultraviolet (EUV) radiation at 13.5 nm (Faradzhev et al., 2013). Here we extend that work by presenting temporally and spatially resolved measurements of the C etching by these oxidizers as a function of EUV intensity in the range (0.3 to 3) mW/mm2 [(0.2 to 2) * 1016 photons s-1 cm-2]. We find that the rates for NO scale linearly with intensity and are smaller than those for O3, which exhibit a weak, sub-linear intensity dependence in this range. We demonstrate that these behaviors are consistent with adsorption of the oxidizing precursor on the C surface followed by a photon-stimulated reaction resulting in volatile C-containing products. The kinetics of photon-induced C etching by hydrogen peroxide, however, appear to be more complex. The spatially resolved measurements reveal that C removal by H2O2 begins at the edges of the C spot, where the light intensity is the lowest, and proceeds toward the center of the spot. This localization of the reaction may occur because hydroxyl radicals are produced efficiently on the catalytically active TiO2 surface. PMID- 27458323 TI - Efficient access to sp3-rich tricyclic amine scaffolds through Diels-Alder reactions of azide-containing silyloxydienes. AB - The preparation of sp3-rich scaffolds to obtain more natural product-like libraries for incorporation into screening decks is challenging. Here, we describe the use of a Diels-Alder reaction between an enone and an azide containing silyloxydiene to gain efficient access to complex tricyclic amine scaffolds. Derivatization of these scaffolds provided a library of 80 amines, amides, sulfonamides, quinolines and indolenines, all in >20 mg quantities and >90% purities. These library compounds displayed properties more similar to alkaloid natural products than to drugs and commercial drug-like libraries, as shown by a high proportion of sp3 carbon centers. PMID- 27458324 TI - Changes in Inmates' Substance Use and Dependence From Pre-Incarceration to One Year Post-Release. AB - PURPOSE: To assess changes in inmates' misuse of substances from pre- to post incarceration. METHODS: In Study 1, professionals (n = 162) and laypersons (n = 50) predicted how jail inmates' substance misuse would change from pre incarceration to post-release. In Study 2, a longitudinal study of 305 jail inmates, we examined actual changes in substance use and dependence from pre incarceration to the first year post-incarceration, as well as whether changes varied as a function of demographic, criminal justice, treatment, and personality factors. RESULTS: Professionals and laypersons predicted little change in substance misuse whereas, in fact, inmates' frequency of substance use and dependence decreased substantially from pre-incarceration to post-release. Sharper decreases were observed for inmates who were female, younger, more educated, serving longer sentences, enrolled in substance abuse treatment, high in shame-proneness, and low in criminogenic thinking. Race, first time incarceration, transfer to other correctional facilities, mandated community supervision (probation), and guilt-proneness did not predict changes in substance use or dependence. CONCLUSIONS: Although substance misuse decreased, this remains a population high in need of substance abuse treatment both upon arrest and at one year post-incarceration; 60% of former inmates met at least one DSM-IV criterion for substance dependence at one year post-release. PMID- 27458325 TI - Thermoreversible and Injectable ABC Polypeptoid Hydrogels: Controlling the Hydrogel Properties through Molecular Design. AB - A series of ABC triblock copolypeptoids [i.e., poly(N-allyl glycine)-b-poly(N methyl glycine)-b-poly(N-decyl glycine) (AMD)] with well-defined structure and varying composition have been synthesized by sequential primary amine-initiated ring-opening polymerization of the corresponding N-substituted N-carboxyanhydride monomers (Al-NCA, Me-NCA, and De-NCA). The ABC block copolypeptoids undergo sol to-gel transitions with increasing temperature in water and biological media at low concentrations (2.5-10 wt %). The sol-gel transition is rapid and fully reversible with a narrow transition window, evidenced by the rheological measurements. The gelation temperature (Tgel) and mechanical stiffness of the hydrogels are highly tunable: Tgel in the 26.2-60.0 degrees C range, the storage modulus (G') and Young's modulus (E) in the 0.2-780 Pa and 0.5-2346 Pa range, respectively, at the physiological temperature (37 degrees C) can be readily accessed by controlling the block copolypeptoid composition and the polymer solution concentration. The hydrogel is injectable through a 24 gauge syringe needle and maintains their shape upon in contact with surfaces or water baths that are kept above the sol-gel transition temperature. The hydrogels exhibit minimal cytotoxicity toward human adipose derived stem cells (hASCs), evidenced from both alamarBlue and PicoGreen assays. Furthermore, quantitative PCR analysis revealed significant up-regulation of the Col2a1 gene and down-regulation of ANGPT1 gene, suggesting that the hydrogel exhibit biological activity in inducing chondrogenesis of hASCs. It was also demonstrated that the hydrogel can be used to quantitatively encapsulate water-soluble enzymes (e.g., horseradish peroxidase) by manipulating the sol-gel transition. The enzymatic activity of HRP remain unperturbed after encapsulation at 37 degrees C for up to 7 d, suggesting that the hydrogel does not adversely affect the enzyme structure and thereby the enzymatic activity. These results suggest that the polypeptoid hydrogel a promising synthetic platform for tissue engineering or protein storage applications. PMID- 27458327 TI - A 5-D Localization Method for a Magnetically Manipulated Untethered Robot using a 2-D Array of Hall-effect Sensors. AB - This paper introduces a new five-dimensional localization method for an untethered meso-scale magnetic robot, which is manipulated by a computer controlled electromagnetic system. The developed magnetic localization setup is a two-dimensional array of mono-axial Hall-effect sensors, which measure the perpendicular magnetic fields at their given positions. We introduce two steps for localizing a magnetic robot more accurately. First, the dipole modeled magnetic field of the electromagnet is subtracted from the measured data in order to determine the robot's magnetic field. Secondly, the subtracted magnetic field is twice differentiated in the perpendicular direction of the array, so that the effect of the electromagnetic field in the localization process is minimized. Five variables regarding the position and orientation of the robot are determined by minimizing the error between the measured magnetic field and the modeled magnetic field in an optimization method. The resulting position error is 2.1+/ 0.8 mm and angular error is 6.7+/-4.3 degrees within the applicable range (5 cm) of magnetic field sensors at 200 Hz. The proposed localization method would be used for the position feedback control of untethered magnetic devices or robots for medical applications in the future. PMID- 27458326 TI - In Their Own Voices: Breaking the Vicious Cycle of Addiction, Treatment and Criminal Justice Among People who Inject Drugs in Ukraine. AB - AIMS: To understand how perceived law enforcement policies and practices contribute to the low rates of utilization of opioid agonist therapies (OAT) among people who inject drugs (PWIDs) in Ukraine. METHODS: Qualitative data from 25 focus groups (FGs) with 199 opioid-dependent PWIDs in Ukraine examined domains related to lived or learned experiences with OAT, police, arrest, incarceration, and criminal activity were analyzed using grounded theory principles. FINDINGS: Most participants were male (66%), in their late 30s, and previously incarcerated (85%) mainly for drug-related activities. When imprisoned, PWIDs perceived themselves as being "addiction-free". After prison-release, the confluence of police surveillance, societal stress contributed to participants' drug use relapse, perpetuating a cycle of searching for money and drugs, followed by re arrest and re-incarceration. Fear of police and arrest both facilitated OAT entry and simultaneously contributed to avoiding OAT since system-level requirements identified OAT clients as targets for police harassment. OAT represents an evidence-based option to 'break the cycle', however, law enforcement practices still thwart OAT capacity to improve individual and public health. CONCLUSION: In the absence of structural changes in law enforcement policies and practices in Ukraine, PWIDs will continue to avoid OAT and perpetuate the addiction cycle with high imprisonment rates. PMID- 27458328 TI - Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers with Isotopically-Labeled Grignard Reagents. AB - In this manuscript we highlight the potential of stereospecific nickel-catalyzed cross-coupling reactions for applications in the pharmaceutical industry. Using an inexpensive and sustainable nickel catalyst, we report a gram-scale Kumada cross-coupling reaction. Reactions are highly stereospecific and proceed with inversion at the benzylic position. We also expand the scope of our reaction to incorporate isotopically labeled substituents. PMID- 27458329 TI - Risk Judgment by General Dental practitioners: Rational but Uninformed. AB - BACKGROUND: Decisions by dentists to administer antibiotic prophylaxis to prevent infectious complications in patients involves professional risk assessment. While recommendations for rational use have been published, several studies have shown that dentists have low adherence to these recommendations. OBJECTIVE: To examine general dental practitioners' (GDPs') assessments of the risk of complications if not administering antibiotic prophylaxis in connection with dental procedures in patients with specific medical conditions. METHODS: Postal questionnaires in combination with telephone interviews. Risk assessments were made using visual analogue scales (VAS), where zero represented "insignificant risk" and 100 represented a "very significant risk". RESULTS: Response rate: 51%. The mean risk assessments were higher for GDPs who administered antibiotics (mean = 54, SD = 23, range 26-72 mm on the VAS) than those who did not (mean = 14, SD = 12, range 7-31 mm) (P < 0.05). Generally, GDPs made higher risk assessments for patients with medical conditions that are included in recommendations than those with conditions that are not included. Overall, risk assessments were higher for tooth removal than for scaling or root canal treatment, even though the risk assessments should be considered equal for these interventions. CONCLUSIONS: GDPs' risk assessments were rational but uninformed. They administered antibiotics in a manner that was consistent with their risk assessments. Their risk assessments, however, were overestimated. Inaccurate judgments of risk should not be expected to disappear in the presence of new information. To achieve change, clinicians must be motivated to improve behaviour and an evidence based implementation strategy is required. PMID- 27458330 TI - Differential Transcriptional Changes in Mice Exposed to Chemically Distinct Diesel Samples. AB - Epidemiological studies have linked exposure to ambient particulate matter (PM) with increased asthmatic symptoms. Diesel exhaust particles (DEP) are a predominant source of vehicle derived ambient PM, and experimental studies have demonstrated that they may have adjuvant potential when given with an antigen. We previously compared 3 DEP samples: N-DEP, A-DEP, and C-DEP in a murine ovalbumin (OVA) mucosal sensitization model and reported the adjuvant activity to be: C-DEP ~ A-DEP > N-DEP. The present study analyzed gene expression changes from the lungs of these mice. Transcription profiling demonstrated that all the DEP samples altered cytokine and toll-like receptor pathways regardless of type, with or without antigen sensitization. Further analysis of DEP exposure with OVA showed that all DEP treatments altered networks involved in immune and inflammatory responses. The A- and C-DEP/OVA treatments induced differential expression of apoptosis pathways in association with stronger adjuvant responses, while expression of cell cycle control and DNA damage pathways were also altered in the C-DEP/OVA treatment. This comprehensive approach using gene expression analysis to examine changes at a pathway level provides detailed information on events occurring in the lung after DEP exposure, and confirms that the most bioactive sample induced many more individual genes and changes in immunoregulatory and homeostatic pathways. PMID- 27458331 TI - Examining the Relationship Between Trauma Centrality and Posttraumatic Stress Disorder Symptoms: A Moderated Mediation Approach. AB - BACKGROUND AND OBJECTIVES: The degree to which a traumatic event is seen as central to one's sense of self (trauma centrality) has been associated with posttraumatic stress disorder (PTSD) symptoms. Based on cognitive models of PTSD that highlight the role that maladaptive appraisals play in generating PTSD symptoms, we hypothesized that appraising a trauma as violating one's core beliefs and goals mediates the link between trauma centrality and PTSD symptoms. Further, we reasoned that coping ability moderates the direct and indirect link as those with better coping ability will have more adaptive appraisals. DESIGN: Hypotheses were examined in a cross-sectional sample of 367 undergraduates who have experienced a traumatic event. METHODS: Data were collected via an online survey. RESULTS: Overall, results of the moderated mediation analysis were consistent with the hypothesized mediating role for appraised violations and moderating role for coping ability. CONCLUSIONS: Findings highlight the importance of considering individual differences and trauma appraisals in understanding the relationship between trauma centrality and PTSD - trauma centrality may be related to PTSD symptoms more so among people with poorer coping ability who appraise a trauma as violating their core beliefs and goals. PMID- 27458332 TI - The Embodied Self in Parkinson's Disease: Feasibility of a Single Tango Intervention for Assessing Changes in Psychological Health Outcomes and Aesthetic Experience. AB - BACKGROUND: Dance is an embodied activity with benefits for mobility, balance, and quality of life (QoL) of persons affected by Parkinson's Disease (PD). It is enjoyable and likely to support adherence to movement prescriptions. The objective of this study was to assess the feasibility of measuring changes in psychological outcomes, specifically well-being, body self-efficacy, outcome expectations, and experienced beauty after a single Argentine Tango intervention in a workshop format. To anchor experienced beauty in a theory, the article introduces a model of embodied aesthetics featuring active art-making as a central aspect of healing in arts-based interventions. METHODS: In a single-group pre-post design, we tested the feasibility of measuring psychological changes of 34 PD patients from Southern Germany after an introductory workshop in Argentine Tango. They participated in a 90 min Tango for PD intervention and completed the Heidelberg State Inventory (HSI-24; (Koch et al., 2007)), the Body Self-Efficacy Scale (BSE; (Fuchs and Koch, 2014)) with a sub-dimension on aesthetic experience, and the Credibility-Expectancy Questionnaire (CEQ; (Devilly and Borkovec, 2000)) before and after the intervention. A subgroup completed the therapeutic factors of arts therapies-scale, a new measure to elaborate on the aesthetic experience. We analyzed pre-post-differences with a t-test for paired samples. RESULTS AND DISCUSSION: The study supports the feasibility of measuring health-related psychological changes from a single Argentine Tango intervention for PD patients, as well as acceptance and appropriateness of the intervention for the patient group. After the tango intervention, well-being, body self-efficacy, and outcome expectancies increased. Participants also experienced an increase in beauty of their movements and other aesthetic aspects. We suspect that, in addition to the functional and psychological factors identified so far, the aesthetic experience in dance may be an important therapeutic factor mediating several outcomes of dance and other arts-based interventions. A controlled study for evidence-based testing of targeted variables can now follow to examine the new hypotheses. PMID- 27458333 TI - Editorial: The Functional Organization of the Auditory System. PMID- 27458334 TI - "Bird Song Metronomics": Isochronous Organization of Zebra Finch Song Rhythm. AB - The human capacity for speech and vocal music depends on vocal imitation. Songbirds, in contrast to non-human primates, share this vocal production learning with humans. The process through which birds and humans learn many of their vocalizations as well as the underlying neural system exhibit a number of striking parallels and have been widely researched. In contrast, rhythm, a key feature of language, and music, has received surprisingly little attention in songbirds. Investigating temporal periodicity in bird song has the potential to inform the relationship between neural mechanisms and behavioral output and can also provide insight into the biology and evolution of musicality. Here we present a method to analyze birdsong for an underlying rhythmic regularity. Using the intervals from one note onset to the next as input, we found for each bird an isochronous sequence of time stamps, a "signal-derived pulse," or pulse(S), of which a subset aligned with all note onsets of the bird's song. Fourier analysis corroborated these results. To determine whether this finding was just a byproduct of the duration of notes and intervals typical for zebra finches but not dependent on the individual duration of elements and the sequence in which they are sung, we compared natural songs to models of artificial songs. Note onsets of natural song deviated from the pulse(S) significantly less than those of artificial songs with randomized note and gap durations. Thus, male zebra finch song has the regularity required for a listener to extract a perceived pulse (pulse(P)), as yet untested. Strikingly, in our study, pulses(S) that best fit note onsets often also coincided with the transitions between sub-note elements within complex notes, corresponding to neuromuscular gestures. Gesture durations often equaled one or more pulse(S) periods. This suggests that gesture duration constitutes the basic element of the temporal hierarchy of zebra finch song rhythm, an interesting parallel to the hierarchically structured components of regular rhythms in human music. PMID- 27458335 TI - A Simplified In vitro Experimental Model Encompasses the Essential Features of Sleep. AB - In this paper, we show that neuronal assemblies plated on Micro Electrode Arrays present synchronized, low frequency firing patterns similar to in vivo slow wave oscillations, which are a key parameter of sleep-like state. Although neuronal cultures lack the characteristic high-frequency waves of wakefulness, it is possible to modulate their spontaneous firing pattern through the administration of specific neurotransmitters such as acetylcholine. We thus stimulated the cortical cultures with an agonist of acetylcholine receptor, Carbachol, which caused a desynchronization of the spontaneous firing of the cultures. We recorded and monitored the cultures for a period of over 31 h. We analyzed the electrophysiological signals by exploiting novel methodological approaches, taking into account the different temporal scales of the recorded signals, and considering both spikes and local field potentials. Supporting the electrophysiological analysis results, gene expressions of targeted genes showed the activation of specific markers involved in sleep-wake rhythms. Our results demonstrate that the Carbachol treatment induces desynchronization of neuronal activity, altering sleep-like properties in an in vitro model. PMID- 27458337 TI - Atypical Brain Mechanisms of Prediction According to Uncertainty in Autism. AB - Resistance to change is often reported in autism and may arise from an inability to predict events in uncertain contexts. Using EEG recorded in 12 adults with autism and age-matched controls performing a visual target detection task, we characterized the influence of a certain context (targets preceded by a predictive sequence of three distinct stimuli) or an uncertain context (random targets) on behavior and electrophysiological markers of predictive processing. During an uncertain context, adults with autism were faster than controls to detect targets. They also had an enhancement in CNV amplitude preceding all random stimuli-indexing enhanced preparatory mechanisms, and an earlier N2 to targets-reflecting faster information processing-compared to controls. During a certain context, both controls and adults with autism presented an increase in P3 amplitude to predictive stimuli-indexing information encoding of the predictive sequence, an enhancement in CNV amplitude preceding predictable targets corresponding to the deployment of preparatory mechanisms, and an earlier P3 to predictable targets-reflecting efficient prediction building and implementation. These results suggest an efficient extraction of predictive information to generate predictions in both controls and adults with autism during a certain context. However, adults with autism displayed a failure to decrease mu power during motor preparation accompanied by a reduced benefit in reaction times to predictable targets. The data reveal that patients with autism over-anticipate stimuli occurring in an uncertain context, in accord with their sense of being overwhelmed by incoming information. These results suggest that adults with autism cannot flexibly modulate cortical activity according to changing levels of uncertainty. PMID- 27458338 TI - Corrigendum: Commentary: Evaluation of Models of Parkinson's Disease. AB - [This corrects the article on p. 161 in vol. 10, PMID: 27147953.]. PMID- 27458336 TI - Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD). AB - Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan-McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-beta2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. beta2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 MUm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are only partially proven, and not all are "clean" of different confounding factors. The associations described in this review emphasize again how little we know about the etiology and pathogenesis of ASD. It is obvious that we need more epidemiologic data to establish many of these associations, but if proven, they might be promising avenues for prevention. PMID- 27458339 TI - Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase Treated Dorsal Root Entry Zone Following Dorsal Root Crush. AB - While the peripheral branch of dorsal root ganglion neurons (DRG) can successfully regenerate after injury, lesioned central branch axons fail to regrow across the dorsal root entry zone (DREZ), the interface between the dorsal root and the spinal cord. This lack of regeneration is due to the limited regenerative capacity of adult sensory axons and the growth-inhibitory environment at the DREZ, which is similar to that found in the glial scar after a central nervous system (CNS) injury. We hypothesized that transduction of adult DRG neurons using adeno-associated virus (AAV) to express a constitutively-active form of the GTPase Rheb (caRheb) will increase their intrinsic growth potential after a dorsal root crush. Additionally, we posited that if we combined that approach with digestion of upregulated chondroitin sulfate proteoglycans (CSPG) at the DREZ with chondroitinase ABC (ChABC), we would promote regeneration of sensory axons across the DREZ into the spinal cord. We first assessed if this strategy promotes neuritic growth in an in vitro model of the glial scar containing CSPG. ChABC allowed for some regeneration across the once potently inhibitory substrate. Combining ChABC treatment with expression of caRheb in DRG significantly improved this growth. We then determined if this combination strategy also enhanced regeneration through the DREZ after dorsal root crush in adult rats in vivo. After unilaterally crushing C4-T1 dorsal roots, we injected AAV5-caRheb or AAV5-GFP into the ipsilateral C5-C8 DRGs. ChABC or PBS was injected into the ipsilateral dorsal horn at C5-C8 to digest CSPG, for a total of four animal groups (caRheb + ChABC, caRheb + PBS, GFP + ChABC, GFP + PBS). Regeneration was rarely observed in PBS-treated animals, whereas short-distance regrowth across the DREZ was observed in ChABC-treated animals. No difference in axon number or length between the ChABC groups was observed, which may be related to intraganglionic inflammation induced by the injection. ChABC-mediated regeneration is functional, as stimulation of ipsilateral median and ulnar nerves induced neuronal c-Fos expression in deafferented dorsal horn in both ChABC groups. Interestingly, caRheb + ChABC animals had significantly more c-Fos(+) nuclei indicating that caRheb expression in DRGs promoted functional synaptogenesis of their axons that regenerated beyond a ChABC-treated DREZ. PMID- 27458340 TI - Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer's Disease. AB - We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain's main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain's main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal. PMID- 27458341 TI - Altered Co-Translational Processing Plays a Role in Huntington's Pathogenesis-A Hypothesis. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG codon repeat region in the HTT gene's first exon that results in huntingtin protein aggregation and neuronal cell death. The development of therapeutic treatments for HD is hindered by the fact that while the etiology and symptoms of HD are understood, the molecular processes connecting this genotype to its phenotype remain unclear. Here, we propose the novel hypothesis that the perturbation of a co-translational process affects mutant huntingtin due to altered translation-elongation kinetics. These altered kinetics arise from the shift of a proline-induced translational pause site away from Htt's localization sequence due to the expansion of the CAG-repeat segment between the poly-proline and localization sequences. Motivation for this hypothesis comes from recent experiments in the field of protein biogenesis that illustrate the critical role that temporal coordination of co-translational processes plays in determining the function, localization, and fate of proteins in cells. We show that our hypothesis is consistent with various experimental observations concerning HD pathology, including the dependence of the age of symptom onset on CAG repeat number. Finally, we suggest three experiments to test our hypothesis. PMID- 27458343 TI - Dystrophin Distribution and Expression in Human and Experimental Temporal Lobe Epilepsy. AB - OBJECTIVE: Dystrophin is part of a protein complex that connects the cytoskeleton to the extracellular matrix. In addition to its role in muscle tissue, it functions as an anchoring protein within the central nervous system such as in hippocampus and cerebellum. Its presence in the latter regions is illustrated by the cognitive problems seen in Duchenne Muscular Dystrophy (DMD). Since epilepsy is also supposed to constitute a comorbidity of DMD, it is hypothesized that dystrophin plays a role in neuronal excitability. Here, we aimed to study brain dystrophin distribution and expression in both, human and experimental temporal lobe epilepsy (TLE). METHOD: Regional and cellular dystrophin distribution was evaluated in both human and rat hippocampi and in rat cerebellar tissue by immunofluorescent colocalization with neuronal (NeuN and calbindin) and glial (GFAP) markers. In addition, hippocampal dystrophin levels were estimated by Western blot analysis in biopsies from TLE patients, post-mortem controls, amygdala kindled (AK)-, and control rats. RESULTS: Dystrophin was expressed in all hippocampal pyramidal subfields and in the molecular-, Purkinje-, and granular cell layer of the cerebellum. In these regions it colocalized with GFAP, suggesting expression in astrocytes such as Bergmann glia (BG) and velate protoplasmic astrocytes. In rat hippocampus and cerebellum there were neither differences in dystrophin positive cell types, nor in the regional dystrophin distribution between AK and control animals. Quantitatively, hippocampal full length dystrophin (Dp427) levels were about 60% higher in human TLE patients than in post-mortem controls (p < 0.05), whereas the level of the shorter Dp71 isoform did not differ. In contrast, AK animals showed similar dystrophin levels as controls. CONCLUSION: Dystrophin is ubiquitously expressed by astrocytes in the human and rat hippocampus and in the rat cerebellum. Hippocampal full-length dystrophin (Dp427) levels are upregulated in human TLE, but not in AK rats, possibly indicating a compensatory mechanism in the chronic epileptic human brain. PMID- 27458344 TI - Probing Corticospinal Recruitment Patterns and Functional Synergies with Transcranial Magnetic Stimulation. AB - BACKGROUND: On the one hand, stimulating the motor cortex at different spots may activate the same muscle and result in a muscle-specific cortical map. Maps of different muscles, which are functionally coupled, may present with a large overlap but may also show a relevant variability. On the other hand, stimulation of the motor cortex at one spot with different stimulation intensities results in a characteristic input-output (IO) curve for one specific muscle but may simultaneously also activate different, functionally coupled muscles. A comparison of the cortical map overlap of synergistic muscles and their IO curves has not yet been carried out. OBJECTIVE: The aim of this study was to probe functional synergies of forearm muscles with transcranial magnetic stimulation by harnessing the convergence and divergence of the corticospinal output. METHODS: We acquired bihemispheric cortical maps and IO curves of the extensor carpi ulnaris, extensor carpi radialis, and extensor digitorum communis muscles by subjecting 11 healthy subjects to both monophasic and biphasic pulse waveforms. RESULTS: The degree of synergy between pairs of forearm muscles was captured by the overlap of the cortical motor maps and the respective IO curves which were influenced by the pulse waveform. Monophasic and biphasic stimulation were particularly suitable for disentangling synergistic muscles in the right and left hemisphere, respectively. CONCLUSION: Combining IO curves and different pulse waveforms may provide complementary information on neural circuit dynamics and corticospinal recruitment patterns of synergistic muscles and their neuroplastic modulation. PMID- 27458342 TI - Function Over Form: Modeling Groups of Inherited Neurological Conditions in Zebrafish. AB - Zebrafish are a unique cell to behavior model for studying the basic biology of human inherited neurological conditions. Conserved vertebrate genetics and optical transparency provide in vivo access to the developing nervous system as well as high-throughput approaches for drug screens. Here we review zebrafish modeling for two broad groups of inherited conditions that each share genetic and molecular pathways and overlap phenotypically: neurodevelopmental disorders such as Autism Spectrum Disorders (ASD), Intellectual Disability (ID) and Schizophrenia (SCZ), and neurodegenerative diseases, such as Cerebellar Ataxia (CATX), Hereditary Spastic Paraplegia (HSP) and Charcot-Marie Tooth Disease (CMT). We also conduct a small meta-analysis of zebrafish orthologs of high confidence neurodevelopmental disorder and neurodegenerative disease genes by looking at duplication rates and relative protein sizes. In the past zebrafish genetic models of these neurodevelopmental disorders and neurodegenerative diseases have provided insight into cellular, circuit and behavioral level mechanisms contributing to these conditions. Moving forward, advances in genetic manipulation, live imaging of neuronal activity and automated high-throughput molecular screening promise to help delineate the mechanistic relationships between different types of neurological conditions and accelerate discovery of therapeutic strategies. PMID- 27458346 TI - Over-Expression of Meteorin Drives Gliogenesis Following Striatal Injury. AB - A number of studies have shown that damage to brain structures adjacent to neurogenic regions can result in migration of new neurons from neurogenic zones into the damaged tissue. The number of differentiated neurons that survive is low, however, and this has led to the idea that the introduction of extrinsic signaling factors, particularly neurotrophic proteins, may augment the neurogenic response to a level that would be therapeutically relevant. Here we report on the impact of the relatively newly described neurotrophic factor, Meteorin, when over expressed in the striatum following excitotoxic injury. Birth-dating studies using bromo-deoxy-uridine (BrdU) showed that Meteorin did not enhance injury induced striatal neurogenesis but significantly increased the proportion of new cells with astroglial and oligodendroglial features. As a basis for comparison we found under the same conditions, glial derived neurotrophic factor significantly enhanced neurogenesis but did not effect gliogenesis. The results highlight the specificity of action of different neurotrophic factors in modulating the proliferative response to injury. Meteorin may be an interesting candidate in pathological settings involving damage to white matter, for example after stroke or neonatal brain injury. PMID- 27458348 TI - The Development of Muscle Fatigue Suppresses Auditory Sensory Gating (P50) during Sustained Contraction. AB - Our aim was to study the influence of fatigue development on sensory gating during a muscle load. The fatiguing task was sustained contraction of a handgrip dynamometer with 7 and 30% maximum voluntary contraction (MVC). The suppression of P50, an auditory event-related potential, was used as the sensory gating index in the paired-click paradigm with a 500 ms interstimulus interval; the difference between the P50 amplitudes of the first and the second stimuli of the pair was used as the sensory gating index. We found that the 30% MVC fatigue development strongly decreased sensory gating, sometimes totally suppressing it. We concluded that central fatigue impaired motor performance and strongly suppressed inhibitory processes, as shown by the decreased P50 amplitude to the second stimulus. Therefore, muscle central fatigue influences sensory gating, similar to schizophrenia spectrum disorders. PMID- 27458347 TI - Dynamics of Population Activity in Rat Sensory Cortex: Network Correlations Predict Anatomical Arrangement and Information Content. AB - To study the spatiotemporal dynamics of neural activity in a cortical population, we implanted a 10 * 10 microelectrode array in the vibrissal cortex of urethane anesthetized rats. We recorded spontaneous neuronal activity as well as activity evoked in response to sustained and brief sensory stimulation. To quantify the temporal dynamics of activity, we computed the probability distribution function (PDF) of spiking on one electrode given the observation of a spike on another. The spike-triggered PDFs quantified the strength, temporal delay, and temporal precision of correlated activity across electrodes. Nearby cells showed higher levels of correlation at short delays, whereas distant cells showed lower levels of correlation, which tended to occur at longer delays. We found that functional space built based on the strength of pairwise correlations predicted the anatomical arrangement of electrodes. Moreover, the correlation profile of electrode pairs during spontaneous activity predicted the "signal" and "noise" correlations during sensory stimulation. Finally, mutual information analyses revealed that neurons with stronger correlations to the network during spontaneous activity, conveyed higher information about the sensory stimuli in their evoked response. Given the 400-MUm-distance between adjacent electrodes, our functional quantifications unravel the spatiotemporal dynamics of activity among nearby and distant cortical columns. PMID- 27458345 TI - Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue. AB - The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate "realistic" models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems. PMID- 27458349 TI - Impact of Short Social Training on Prosocial Behaviors: An fMRI Study. AB - Efficient brain-computer interfaces (BCIs) are in need of knowledge about the human brain and how it interacts, plays games, and socializes with other brains. A breakthrough can be achieved by revealing the microfoundations of sociality, an additional component of the utility function reflecting the value of contributing to group success derived from social identity. Building upon our previous behavioral work, we conduct a series of functional magnetic resonance imaging (fMRI) experiments (N = 10 in the Pilot Study and N = 15 in the Main Study) to measure whether and how sociality alters the functional activation of and connectivity between specific systems in the brain. The overarching hypothesis of this study is that sociality, even in a minimal form, serves as a natural mechanism of sustainable cooperation by fostering interaction between brain regions associated with social cognition and those related to value calculation. We use group-based manipulations to induce varying levels of sociality and compare behavior in two social dilemmas: Prisoner's Dilemma and variations of Ultimatum Game. We find that activation of the right inferior frontal gyrus, a region previously associated with cognitive control and modulation of the valuation system, is correlated with activity in the medial prefrontal cortex (mPFC) to a greater degree when participants make economic decisions in a game with an acquaintance, high sociality condition, compared to a game with a random individual, low sociality condition. These initial results suggest a specific biological mechanism through which sociality facilitates cooperation, fairness and provision of public goods at the cost of individual gain. Future research should examine neural dynamics in the brain during the computation of utility in the context of strategic games that involve social interaction for a larger sample of subjects. PMID- 27458350 TI - Brain Plasticity in Blind Subjects Centralizes Beyond the Modal Cortices. AB - It is well established that the human brain reorganizes following sensory deprivations. In blind individuals, visual processing regions including the lateral occipital cortex (LOC) are activated by auditory and tactile stimuli as demonstrated by neurophysiological and neuroimaging investigations. The mechanisms for such plasticity remain unclear, but shifts in connectivity across existing neural networks appear to play a critical role. The majority of research efforts to date have focused on neuroplastic changes within visual unimodal regions, however we hypothesized that neuroplastic alterations may also occur in brain networks beyond the visual cortices including involvement of multimodal integration regions and heteromodal cortices. In this study, two recently developed graph-theory based functional connectivity analyses, interconnector analyses and local and distant connectivity, were applied to investigate functional reorganization in regional and distributed neural-systems in late onset blind (LB) and congenitally blind (CB) cohorts each compared to their own group of sighted controls. While functional network alterations as measured by the degree of differential links (DDL) occurred in sensory cortices, neuroplastic changes were most prominent within multimodal and association cortices. Subjects with LB showed enhanced multimodal integration connections in the parieto opercular, temporoparietal junction (TPJ) and ventral premotor (vPM) regions, while CB individuals exhibited increased superior parietal cortex (SPC) connections. This study reveals the critical role of recipient multi-sensory integration areas in network reorganization and cross-modal plasticity in blind individuals. These findings suggest that aspects of cross-modal neuroplasticity and adaptive sensory-motor and auditory functions may potentially occur through reorganization in multimodal integration regions. PMID- 27458351 TI - Endocannabinoids and Heterogeneity of Glial Cells in Brain Function. PMID- 27458352 TI - Innate Fear-Induced Weight Regulation in the C57BL/6J Mouse. AB - Regulation of body weight is an important strategy for small prey animals to avoid capture. Field and laboratory studies have shown that prey animals reduce body size when subjected to long-term predator stimuli. However, the causes of predator-induced weight regulation are highly variable and the underlying mechanisms remain unclear. Understanding this phenomenon is important for gaining a better understanding of how animals regulate body weight under ethologically relevant conditions and has implications for obesity. Here we expose inbred C57BL/6J mice to a fear-inducing odorant (2,4,5-trimethylthiazole; mT) to model predation-induced weight regulation. Eight week-old mice were put on a 45% high fat diet (HFD) or chow diet (5% fat) and exposed daily to mT, an equally aversive dose of butyric acid (BA), or a neutral control scent (almond). mT-exposed mice in both diet groups gained significantly less weight over a 6-week period than BA exposed mice. This differential weight gain appears unlikely to be due to differences in food intake and activity level, or brown adipose thermogenesis between the mT and BA groups. However, following chronic mT exposure we find increases in DeltaFosB protein, a marker for long-term neural plasticity, in the dorsomedial hypothalamus (DMH)-an area previously implicated in chronic stress and defensive responses, as well as weight regulation. This study establishes a simplified and robust laboratory model of predation-mediated weight regulation with inbred lab mice and fear-inducing odor, and suggests a likely, yet undetermined, metabolic adaptation as contributing to this response. PMID- 27458353 TI - Early-Life Stress Paradigm Transiently Alters Maternal Behavior, Dam-Pup Interactions, and Offspring Vocalizations in Mice. AB - Animal models can help elucidate the mechanisms through which early-life stress (ELS) has pathophysiological effects on the developing brain. One model that has been developed for rodents consists of limiting the amount of bedding and nesting material during the first postnatal weeks of pup life. This ELS environment has been shown to induce "abusive" behaviors by rat dams towards pups, while mouse dams have been hypothesized to display "fragmented care". Here, as part of an ongoing study of gene-environment interactions that impact brain development, we analyzed long observation periods of wild-type C57Bl/6J dams caring for wild-type and Met heterozygous pups. Met encodes for the MET receptor tyrosine kinase, which is involved in cortical and hippocampal synaptogenesis. Dams with limited resources from postnatal day (P)2 to P9 preserved regular long on-nest periods, and instead increased the number of discrete dam-pup interactions during regular off-nest periods. Immediately after dams entered the nest during off-nest periods in this ELS environment, pups responded to these qualitatively different interactions with an increased number of ultrasonic vocalizations (USV) and audible vocalizations (AV), communication signals that have been associated with aversive and painful stimuli. After returning to control conditions, nest entry behaviors normalized, and dams did not show altered anxiety-like or contextual fear learning behaviors after pup weaning. Furthermore, female mice that had undergone ELS as pups did not show atypical nest entry behaviors in control conditions in adulthood, suggesting that these specific maternal behaviors are not learned during the ELS period. The results suggest that atypical responses of both mother and pups during exposure to this ELS environment likely contribute to long-term negative outcomes in mice, and that these responses more closely resemble the effects of limited bedding on rat dams and pups than was previously suggested. Discerning how different early-life stressors mediate changes in maternal-pup interactions can help elucidate the mechanisms of ELS on brain development and behavior. PMID- 27458354 TI - The Running Wheel Enhances Food Anticipatory Activity: An Exploratory Study. AB - Rodents anticipate rewarding stimuli such as daily meals, mates, and stimulant drugs. When a single meal is provided daily at a fixed time of day, an increase in activity, known as food anticipatory activity (FAA), occurs several hours before feeding time. The factors affecting the expression of FAA have not been well-studied. Understanding these factors may provide clues to the undiscovered anatomical substrates of food entrainment. In this study we determined whether wheel-running activity, which is also rewarding to rodents, modulated the robustness of FAA. We found that access to a freely rotating wheel enhanced the robustness of FAA. This enhancement was lost when the wheel was removed. In addition, while prior exposure to a running wheel alone did not enhance FAA, the presence of a locked wheel did enhance FAA as long as mice had previously run in the wheel. Together, these data suggest that FAA, like wheel-running activity, is influenced by reward signaling. PMID- 27458355 TI - Differences in Insula and Pre-/Frontal Responses during Reappraisal of Food in Lean and Obese Humans. AB - Brain regions involved in the reappraisal of tasty but unhealthy foods are of special interest for the development of new therapeutic interventions for obesity, such as non-invasive brain stimulation or neurofeedback. Here, we visually presented food items (i.e., high/low caloric) to obese and lean individuals during electroencephalogram (EEG) recordings, while they either admitted or regulated their food desire. During admitting the desire for low and high calorie foods, obese as well as lean individuals showed higher activity in the left dorsolateral prefrontal cortex (DLPFC), whereas the right frontal operculum was involved in the reappraisal of the same foods, suggesting interplay between executive control and gustatory regions. Only in lean participants, we found an interaction between calorie content and the regulate/admit conditions in bilateral anterior insular cortices, suggesting that the anterior insula, assumed to primarily host gustatory processes, also underpins higher cognitive processes involved in food choices, such as evaluating the foods' calorie content for its reappraisal. PMID- 27458356 TI - Corrigendum: The Influence of Menstrual Cycle and Androstadienone on Female Stress Reactions: An fMRI Study. AB - [This corrects the article on p. 44 in vol. 10, PMID: 26909031.]. PMID- 27458357 TI - Early Blindness Results in Developmental Plasticity for Auditory Motion Processing within Auditory and Occipital Cortex. AB - Early blind subjects exhibit superior abilities for processing auditory motion, which are accompanied by enhanced BOLD responses to auditory motion within hMT+ and reduced responses within right planum temporale (rPT). Here, by comparing BOLD responses to auditory motion in hMT+ and rPT within sighted controls, early blind, late blind, and sight-recovery individuals, we were able to separately examine the effects of developmental and adult visual deprivation on cortical plasticity within these two areas. We find that both the enhanced auditory motion responses in hMT+ and the reduced functionality in rPT are driven by the absence of visual experience early in life; neither loss nor recovery of vision later in life had a discernable influence on plasticity within these areas. Cortical plasticity as a result of blindness has generally be presumed to be mediated by competition across modalities within a given cortical region. The reduced functionality within rPT as a result of early visual loss implicates an additional mechanism for cross modal plasticity as a result of early blindness competition across different cortical areas for functional role. PMID- 27458358 TI - Influence of Transcranial Direct Current Stimulation to the Cerebellum on Standing Posture Control. AB - Damage to the vestibular cerebellum results in dysfunctional standing posture control. Patients with cerebellum dysfunction have a larger sway in the center of gravity while standing compared with healthy subjects. Transcranial direct current stimulation (tDCS) is a noninvasive technique for selectively exciting or inhibiting specific neural structures with potential applications in functional assessment and treatment of neural disorders. However, the specific stimulation parameters for influencing postural control have not been assessed. In this study, we investigated the influence of tDCS when applied over the cerebellum on standing posture control. Sixteen healthy subjects received tDCS (20 min, 2 mA) over the scalp 2 cm below the inion. In Experiment 1, all 16 subjects received tDCS under three stimulus conditions, Sham, Cathodal, and Anodal, in a random order with the second electrode placed on the forehead. In Experiment 2, five subjects received cathodal stimulation only with the second electrode placed over the right buccinator muscle. Center of gravity sway was measured twice for 60 s before and after tDCS in a standing posture with eyes open and legs closed, and average total locus length, locus length per second, rectangular area, and enveloped area were calculated. In Experiment 1, total locus length and locus length per second decreased significantly after cathodal stimulation but not after anodal or sham stimulation, while no tDCS condition influenced rectangular or enveloped areas. In Experiment 2, cathodal tDCS again significantly reduced total locus length and locus length per second but not rectangular and enveloped areas. The effects of tDCS on postural control are polarity-dependent, likely reflecting the selective excitation or inhibition of cerebellar Purkinje cells. Cathodal tDCS to the cerebellum of healthy subjects can alter body sway (velocity). PMID- 27458359 TI - Electrophysiological Correlates of Emotional Content and Volume Level in Spoken Word Processing. AB - For visual stimuli of emotional content as pictures and written words, stimulus size has been shown to increase emotion effects in the early posterior negativity (EPN), a component of event-related potentials (ERPs) indexing attention allocation during visual sensory encoding. In the present study, we addressed the question whether this enhanced relevance of larger (visual) stimuli might generalize to the auditory domain and whether auditory emotion effects are modulated by volume. Therefore, subjects were listening to spoken words with emotional or neutral content, played at two different volume levels, while ERPs were recorded. Negative emotional content led to an increased frontal positivity and parieto-occipital negativity-a scalp distribution similar to the EPN-between ~370 and 530 ms. Importantly, this emotion-related ERP component was not modulated by differences in volume level, which impacted early auditory processing, as reflected in increased amplitudes of the N1 (80-130 ms) and P2 (130-265 ms) components as hypothesized. However, contrary to effects of stimulus size in the visual domain, volume level did not influence later ERP components. These findings indicate modality-specific and functionally independent processing triggered by emotional content of spoken words and volume level. PMID- 27458360 TI - COMT Val(158)Met Polymorphism Is Associated with Verbal Working Memory in Neurofibromatosis Type 1. AB - Neurofibromatosis type I (NF1) is a neurogenetic disease marked by multiple cognitive and learning problems. Genetic variants may account for phenotypic variance in NF1. Here, we investigated the association between the catechol-O methyltransferase (COMT) Val(158)Met polymorphism and working memory and arithmetic performance in 50 NF1 individuals. A significant association of the COMT polymorphism was observed only with verbal working memory, as measured by the backward digit-span task with an advantageous performance for Met/Met carriers. To study how genetic modifiers influence NF1 cognitive performance might be of importance to decrease the unpredictability of the cognitive profile among NF1 patients. PMID- 27458361 TI - Editorial: What Determines Social Behavior? Investigating the Role of Emotions, Self-Centered Motives, and Social Norms. PMID- 27458362 TI - The Role of Cognitive and Perceptual Loads in Inattentional Deafness. AB - The current study examines the role of cognitive and perceptual loads in inattentional deafness (the failure to perceive an auditory stimulus) and the possibility to predict this phenomenon with ocular measurements. Twenty participants performed Air Traffic Control (ATC) scenarios-in the Laby ATC-like microworld-guiding one (low cognitive load) or two (high cognitive load) aircraft while responding to visual notifications related to 7 (low perceptual load) or 21 (high perceptual load) peripheral aircraft. At the same time, participants were played standard tones which they had to ignore (probability = 0.80), or deviant tones (probability = 0.20) which they had to report. Behavioral results showed that 28.76% of alarms were not reported in the low cognitive load condition and up to 46.21% in the high cognitive load condition. On the contrary, perceptual load had no impact on the inattentional deafness rate. Finally, the mean pupil diameter of the fixations that preceded the target tones was significantly lower in the trials in which the participants did not report the tones, likely showing a momentary lapse of sustained attention, which in turn was associated to the occurrence of inattentional deafness. PMID- 27458363 TI - Neural Correlates of the Appraisal of Attachment Scenes in Healthy Controls and Social Cognition-An fMRI Study. AB - The human attachment system is activated in situations of danger such as potential separation, threats of loss of a significant other and potential insecurity on the availability of the attachment figure. To date, however, a precise characterization of the neural correlates of the attachment system in healthy individuals is lacking. This functional magnetic resonance imaging (fMRI) study aims at characterizing the distinctive neural substrates activated by the exposure to attachment vs. non-attachment scenes. Healthy participants (N = 25) were presented scenes from the Adult Attachment Projective Picture System (AAP), a validated set of standardized attachment-related pictures extended by a control picture stimulus set consisting of scenes without attachment-related content. When compared to the control neutral pictures, attachment scenes activated the inferior parietal lobes (IPLs), the middle temporal gyrus (MTG), and the anterior medial prefrontal cortex (mPFC). These areas are associated with reasoning about mental representations, semantic memory of social knowledge, and social cognition. This neural activation pattern confirms the distinctive quality of this stimulus set, and suggests its use as a potential neuroimaging probe to assess social cognition/mentalizing related to attachment in healthy and clinical populations. PMID- 27458364 TI - Active SAmpling Protocol (ASAP) to Optimize Individual Neurocognitive Hypothesis Testing: A BCI-Inspired Dynamic Experimental Design. AB - The relatively young field of Brain-Computer Interfaces has promoted the use of electrophysiology and neuroimaging in real-time. In the meantime, cognitive neuroscience studies, which make extensive use of functional exploration techniques, have evolved toward model-based experiments and fine hypothesis testing protocols. Although these two developments are mostly unrelated, we argue that, brought together, they may trigger an important shift in the way experimental paradigms are being designed, which should prove fruitful to both endeavors. This change simply consists in using real-time neuroimaging in order to optimize advanced neurocognitive hypothesis testing. We refer to this new approach as the instantiation of an Active SAmpling Protocol (ASAP). As opposed to classical (static) experimental protocols, ASAP implements online model comparison, enabling the optimization of design parameters (e.g., stimuli) during the course of data acquisition. This follows the well-known principle of sequential hypothesis testing. What is radically new, however, is our ability to perform online processing of the huge amount of complex data that brain imaging techniques provide. This is all the more relevant at a time when physiological and psychological processes are beginning to be approached using more realistic, generative models which may be difficult to tease apart empirically. Based upon Bayesian inference, ASAP proposes a generic and principled way to optimize experimental design adaptively. In this perspective paper, we summarize the main steps in ASAP. Using synthetic data we illustrate its superiority in selecting the right perceptual model compared to a classical design. Finally, we briefly discuss its future potential for basic and clinical neuroscience as well as some remaining challenges. PMID- 27458365 TI - Taxonomy of Individual Variations in Aesthetic Responses to Fractal Patterns. AB - In two experiments, we investigate group and individual preferences in a range of different types of patterns with varying fractal-like scaling characteristics. In Experiment 1, we used 1/f filtered grayscale images as well as their thresholded (black and white) and edges only counterparts. Separate groups of observers viewed different types of images varying in slope of their amplitude spectra. Although with each image type, the groups exhibited the "universal" pattern of preference for intermediate amplitude spectrum slopes, we identified 4 distinct sub-groups in each case. Sub-group 1 exhibited a typical peak preference for intermediate amplitude spectrum slopes ("intermediate"; approx. 50%); sub-group 2 exhibited a linear increase in preference with increasing amplitude spectrum slope ("smooth"; approx. 20%), while sub-group 3 exhibited a linear decrease in preference as a function of the amplitude spectrum slope ("sharp"; approx. 20%). Sub-group 4 revealed no significant preference ("other"; approx. 10%). In Experiment 2, we extended the range of different image types and investigated preferences within the same observers. We replicate the results of our first experiment and show that individual participants exhibit stable patterns of preference across a wide range of image types. In both experiments, Q-mode factor analysis identified two principal factors that were able to explain more than 80% of interindividual variations in preference across all types of images, suggesting a highly similar dimensional structure of interindividual variations in preference for fractal-like scaling characteristics. PMID- 27458366 TI - A Hierarchical Bayesian Model for Crowd Emotions. AB - Estimation of emotions is an essential aspect in developing intelligent systems intended for crowded environments. However, emotion estimation in crowds remains a challenging problem due to the complexity in which human emotions are manifested and the capability of a system to perceive them in such conditions. This paper proposes a hierarchical Bayesian model to learn in unsupervised manner the behavior of individuals and of the crowd as a single entity, and explore the relation between behavior and emotions to infer emotional states. Information about the motion patterns of individuals are described using a self-organizing map, and a hierarchical Bayesian network builds probabilistic models to identify behaviors and infer the emotional state of individuals and the crowd. This model is trained and tested using data produced from simulated scenarios that resemble real-life environments. The conducted experiments tested the efficiency of our method to learn, detect and associate behaviors with emotional states yielding accuracy levels of 74% for individuals and 81% for the crowd, similar in performance with existing methods for pedestrian behavior detection but with novel concepts regarding the analysis of crowds. PMID- 27458367 TI - Exploring fMRI Results Space: 31 Variants of an fMRI Analysis in AFNI, FSL, and SPM. PMID- 27458368 TI - Decreased Self-Appraisal Accuracy on Cognitive Tests of Executive Functioning Is a Predictor of Decline in Mild Cognitive Impairment. AB - OBJECTIVE: Mild cognitive impairment (MCI) in older individuals is associated with increased risk of progression to dementia. The factors predicting progression are not yet well established, yet cognitive performance, particularly for memory, is known to be important. Anosognosia, meaning lack of awareness of one's impaired function, is commonly reported in dementia and is often also a feature of MCI, but its association with risk of progression is not well understood. In particular, self-appraisal measures provide an autonomous measure of insight abilities, without the need of an informant. METHODS: The present study examined the utility of self-appraisal accuracy at baseline for predicting cognitive decline in 51 patients using an informant-free assessment method. Baseline task performance scores were compared to self-assessments of performance to yield a discrimination score (DS) for tasks tapping into memory and executive functions. RESULTS: Linear regression revealed that a larger DS for executive function tasks in MCI predicted functional decline, independent of age, education, and baseline memory and executive task scores. CONCLUSION: These findings indicate that objective estimates of self-appraisal can be used to quantify anosognosia and increase predictive accuracy for decline in MCI. PMID- 27458369 TI - An Alpha and Theta Intensive and Short Neurofeedback Protocol for Healthy Aging Working-Memory Training. AB - The present study tested the effects of an intensive and short alpha and theta neurofeedback (NF) protocol in working memory (WM) performance in a healthy elder population and explored the effects of a multimodal approach, by supplementing NF with cognitive tasks. Participants were allocated to four groups: NF (N = 9); neurofeedback supplemented with cognitive training (NFCT) (N = 8); cognitive training (CT) (N = 7) and sham neurofeedback (Sham-NF) (N = 6). The intervention consisted in 30-min sessions for 8 days. The NF group presented post intervention increases of alpha and theta relative power as well as performance in the matrix rotation task. In addition, a successful up training of frontal theta showed positive correlation with an improvement of post-training alpha and a better performance in the matrix rotation task. The results presented herein suggest that an intensive and short NF protocol enables elders to learn alpha and theta self-modulation and already presents moderate improvements in cognition and basal EEG. Also, CT group showed moderate performance gains on the cognitive tasks used during the training sessions but no clear improvements on neurophysiology and behavioral measurements were observed. This study represents a first attempt to study the effects of an intensive and short NF protocol in WM performance of elders. The evidence presented here suggests that an intensive and short NF intervention could be a valid alternative for introduction of older populations to NF methodologies. PMID- 27458370 TI - Mechanisms of Abeta Clearance and Degradation by Glial Cells. AB - Glial cells have a variety of functions in the brain, ranging from immune defense against external and endogenous hazardous stimuli, regulation of synaptic formation, calcium homeostasis, and metabolic support for neurons. Their dysregulation can contribute to the development of neurodegenerative disorders, including Alzheimer's disease (AD). One of the most important functions of glial cells in AD is the regulation of Amyloid-beta (Abeta) levels in the brain. Microglia and astrocytes have been reported to play a central role as moderators of Abeta clearance and degradation. The mechanisms of Abeta degradation by glial cells include the production of proteases, including neprilysin, the insulin degrading enzyme, and the endothelin-converting enzymes, able to hydrolyse Abeta at different cleavage sites. Besides these enzymes, other proteases have been described to have some role in Abeta elimination, such as plasminogen activators, angiotensin-converting enzyme, and matrix metalloproteinases. Other relevant mediators that are released by glial cells are extracellular chaperones, involved in the clearance of Abeta alone or in association with receptors/transporters that facilitate their exit to the blood circulation. These include apolipoproteins, alpha2macroglobulin, and alpha1-antichymotrypsin. Finally, astrocytes and microglia have an essential role in phagocytosing Abeta, in many cases via a number of receptors that are expressed on their surface. In this review, we examine all of these mechanisms, providing an update on the latest research in this field. PMID- 27458371 TI - Effects of Physical Exercise Combined with Nutritional Supplements on Aging Brain Related Structures and Functions: A Systematic Review. AB - Age-related decline in gray and white brain matter goes together with cognitive depletion. To influence cognitive functioning in elderly, several types of physical exercise and nutritional intervention have been performed. This paper systematically reviews the potential additive and complementary effects of nutrition/nutritional supplements and physical exercise on cognition. The search strategy was developed for EMBASE, Medline, PubMed, Cochrane, CINAHL, and PsycInfo databases and focused on the research question: "Is the combination of physical exercise with nutrition/nutritional supplementation more effective than nutrition/nutritional supplementation or physical exercise alone in effecting on brain structure, metabolism, and/or function?" Both mammalian and human studies were included. In humans, randomized controlled trials that evaluated the effects of nutrition/nutritional supplements and physical exercise on cognitive functioning and associated parameters in healthy elderly (>65 years) were included. The systematic search included English and German language literature without any limitation of publication date. The search strategy yielded a total of 3129 references of which 67 studies met the inclusion criteria; 43 human and 24 mammalian, mainly rodent, studies. Three out of 43 human studies investigated a nutrition/physical exercise combination and reported no additive effects. In rodent studies, additive effects were found for docosahexaenoic acid supplementation when combined with physical exercise. Although feasible combinations of physical exercise/nutritional supplements are available for influencing the brain, only a few studies evaluated which possible combinations of nutrition/nutritional supplementation and physical exercise might have an effect on brain structure, metabolism and/or function. The reason for no clear effects of combinatory approaches in humans might be explained by the misfit between the combinations of nutritional methods with the physical interventions in the sense that they were not selected on sharing of similar neuronal mechanisms. Based on the results from this systematic review, future human studies should focus on the combined effect of docosahexaenoic acid supplementation and physical exercise that contains elements of (motor) learning. PMID- 27458373 TI - Role of miR-211 in Neuronal Differentiation and Viability: Implications to Pathogenesis of Alzheimer's Disease. AB - Alzheimer's disease (AD) is an age-related irreversible neurodegenerative disorder characterized by extracellular beta Amyloid(Abeta) deposition, intracellular neurofibrillary tangles and neuronal loss. The dysfunction of neurogenesis and increased degeneration of neurons contribute to the pathogenesis of AD. We now report that miR-211-5p, a small non-coding RNA, can impair neurite differentiation by directly targeting NUAK1, decrease neuronal viability and accelerate the progression of Abeta-induced pathologies. In this study, we observed that during embryonic development, the expression levels of miR-211-5p were down-regulated in the normal cerebral cortexes of mice. However, in APPswe/PS1DeltaE9 double transgenic adult mice, it was up-regulated from 9 months of age compared to that of the age-matched wild type mice. Studies in primary cortical neuron cultures demonstrated that miR-211-5p can inhibit neurite growth and branching via NUAK1 repression and decrease mature neuron viability. The impairments were more obvious under the action of Abeta. Our data showed that miR 211-5p could inhibit cortical neuron differentiation and survival, which may contribute to the synaptic failure, neuronal loss and cognitive dysfunction in AD. PMID- 27458374 TI - Upper-Extremity Dual-Task Function: An Innovative Method to Assess Cognitive Impairment in Older Adults. AB - BACKGROUND: Difficulties in orchestrating simultaneous tasks (i.e., dual-tasking) have been associated with cognitive impairments in older adults. Gait tests have been commonly used as the motor task component for dual-task assessments; however, many older adults have mobility impairments or there is a lack of space in busy clinical settings. We assessed an upper-extremity function (UEF) test as an alternative motor task to study the dual-task motor performance in older adults. METHODS: Older adults (>=65 years) were recruited, and cognitive ability was measured using the Montreal cognitive assessment (MoCA). Participants performed repetitive elbow flexion with their maximum pace, once single-task, and once while counting backward by one (dual-task). Single- and dual-task gait tests were also performed with normal speed. Three-dimensional kinematics was measured both from upper-extremity and lower-extremity using wearable sensors to determine UEF and gait parameters. Parameters were compared between the cognitively impaired and healthy groups using analysis of variance tests, while controlling for age, gender, and body mass index (BMI). Correlations between UEF and gait parameters for dual-task and dual-task cost were assessed using linear regression models. RESULTS: Sixty-seven older adults were recruited (age = 83 +/- 10 years). Based on MoCA, 10 (15%) were cognitively impaired. While no significant differences were observed in the single-task condition, within the dual-task condition, the cognitively impaired group showed significantly less arm flexion speed (62%, d = 1.51, p = 0.02) and range of motion (27%, d = 0.93, p = 0.04), and higher speed variability (88%, d = 1.82, p < 0.0001) compared to the cognitively intact group, when adjusted with age, gender, and BMI. Significant correlations were observed between UEF speed parameters and gait stride velocity for dual-task condition (r = 0.55, p < 0.0001) and dual-task cost (r = 0.28, p = 0.03). CONCLUSION: We introduced a novel test for assessing dual-task performance in older adults that lasts 20 s and is based on upper-extremity function. Our results confirm significant associations between upper-extremity speed, range of motion, and speed variability with both the MoCA score and the gait performance within the dual-task condition. PMID- 27458375 TI - Development of Cerebral Microbleeds in the APP23-Transgenic Mouse Model of Cerebral Amyloid Angiopathy-A 9.4 Tesla MRI Study. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by extracellular deposition of amyloid beta (Abeta) around cerebral arteries and capillaries and leads to an increased risk for vascular dementia, spontaneous lobar hemorrhage, convexal subarachnoid hemorrhage, and transient focal neurological episodes, which might be an indicator of imminent spontaneous intracerebral hemorrhage. In CAA cerebral microbleeds (cMBs) with a cortical/juxtacortical distribution are frequently observed in standard magnetic resonance imaging (MRI). In vivo MRI of transgenic mouse models of CAA may serve as a useful tool to investigate translational aspects of the disease. MATERIALS AND METHODS: APP23-transgenic mice demonstrate cerebrovascular Abeta deposition with subsequent neuropathological changes characteristic for CAA. We performed a 9.4 Tesla high field MRI study using T2, T2* and time of flight-magnetic resonance angiograpy (TOF-MRA) sequences in APP23-transgenic mice and wildtype (wt) littermates at the age of 8, 12, 16, 20 and 24 months, respectively. Numbers, size, and location of cMBs are reported. RESULTS: T2* imaging demonstrated cMBs (diameter 50-300 MUm) located in the neocortex and, to a lesser degree, in the thalamus. cMBs were detected at the earliest at 16 months of age. Numbers increased exponentially with age, with 2.5 +/- 2 (median +/- interquartilrange) at 16 months, 15 +/- 6 at 20 months, and 31.5 +/- 17 at 24 months of age, respectively. CONCLUSION: We report the temporal and spatial development of cMBs in the aging APP23-transgenic mouse model which develops characteristic pathological patterns known from human CAA. We expect this mouse model to serve as a useful tool to non-invasively monitor mid- and longterm translational aspects of CAA and to investigate experimental therapeutic strategies in longitudinal studies. PMID- 27458376 TI - Review of Sparse Representation-Based Classification Methods on EEG Signal Processing for Epilepsy Detection, Brain-Computer Interface and Cognitive Impairment. AB - At present, the sparse representation-based classification (SRC) has become an important approach in electroencephalograph (EEG) signal analysis, by which the data is sparsely represented on the basis of a fixed dictionary or learned dictionary and classified based on the reconstruction criteria. SRC methods have been used to analyze the EEG signals of epilepsy, cognitive impairment and brain computer interface (BCI), which made rapid progress including the improvement in computational accuracy, efficiency and robustness. However, these methods have deficiencies in real-time performance, generalization ability and the dependence of labeled sample in the analysis of the EEG signals. This mini review described the advantages and disadvantages of the SRC methods in the EEG signal analysis with the expectation that these methods can provide the better tools for analyzing EEG signals. PMID- 27458378 TI - Deliberate Practice as a Theoretical Framework for Interprofessional Experiential Education. AB - OBJECTIVE: The theory of deliberate practice has been applied to many skill-based performance activities. The primary aim of this project was to integrate synergistic principles from deliberate practice and consensus-derived competencies for interprofessional education into a framework upon which educational models to advance interprofessional experiential education (IEE) might be built. METHODS: CINAHL, ERIC, and MEDLINE databases were searched using the keywords "deliberate practice" and "interprofessional education," both individually and in combination. Relevant articles were selected from the catalog based on support for the premise of the project. Defining characteristics of deliberate practice were distilled with particular emphasis on their application to the Interprofessional Education Collaborative's (IPEC) core competencies. Recommendations for IEE development were identified through the synthesis of deliberate practice principles and IPEC competencies. RESULTS: There is a high degree of synergy between deliberate practice principles and IPEC competencies. Our synthesis of the literature yielded a cyclical four-step process to advance IEE: (1) implement an IEE plan guided by the student's strengths/weaknesses and in consideration of the collaborative practice skills they wish to develop, (2) engage in IPE experiences that will challenge targeted skills according to the IEE plan, (3) embed frequent opportunities for student reflection and preceptor/team feedback within IEE plan, and (4) revise the IEE plan and the IPE experience based on insights gained during step 3. CONCLUSION: The cyclical four step process synthesized through this literature review may be used to guide the development of new IEE models. The purposeful development of IEE models grounded in a theory that has already been operationalized in other skill-based performance areas is an important step to address expanding accreditation standards throughout the health professions mandating interprofessional education for pre-licensure health professional students. PMID- 27458377 TI - Disrupted Brain Functional Network Architecture in Chronic Tinnitus Patients. AB - PURPOSE: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated the disruptions of multiple brain networks in tinnitus patients. Nonetheless, several studies found no differences in network processing between tinnitus patients and healthy controls (HCs). Its neural bases are poorly understood. To identify aberrant brain network architecture involved in chronic tinnitus, we compared the resting-state fMRI (rs-fMRI) patterns of tinnitus patients and HCs. MATERIALS AND METHODS: Chronic tinnitus patients (n = 24) with normal hearing thresholds and age-, sex-, education- and hearing threshold matched HCs (n = 22) participated in the current study and underwent the rs-fMRI scanning. We used degree centrality (DC) to investigate functional connectivity (FC) strength of the whole-brain network and Granger causality to analyze effective connectivity in order to explore directional aspects involved in tinnitus. RESULTS: Compared to HCs, we found significantly increased network centrality in bilateral superior frontal gyrus (SFG). Unidirectionally, the left SFG revealed increased effective connectivity to the left middle orbitofrontal cortex (OFC), left posterior lobe of cerebellum (PLC), left postcentral gyrus, and right middle occipital gyrus (MOG) while the right SFG exhibited enhanced effective connectivity to the right supplementary motor area (SMA). In addition, the effective connectivity from the bilateral SFG to the OFC and SMA showed positive correlations with tinnitus distress. CONCLUSIONS: Rs-fMRI provides a new and novel method for identifying aberrant brain network architecture. Chronic tinnitus patients have disrupted FC strength and causal connectivity mostly in non-auditory regions, especially the prefrontal cortex (PFC). The current findings will provide a new perspective for understanding the neuropathophysiological mechanisms in chronic tinnitus. PMID- 27458372 TI - Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease. AB - Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein alpha subunit (Galphaolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells' own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID- 27458379 TI - Anti-nociceptive Activity of Ethnomedicinally Important Analgesic Plant Isodon rugosus Wall. ex Benth: Mechanistic Study and Identifications of Bioactive Compounds. AB - Isodon rugosus Wall. ex Benth. is extensively used as traditional medicine for the management of various types of pain including tooth ache, gastric pain, abdominal pain, ear ache, and generalized body pain. The current study is designed to scientifically verify the purported uses of I. rugosus as analgesic agent and to figure out its possible mechanism of action. Bioactive compounds responsible for analgesic activity were identified using GC and GC-MS analysis. Analgesic potentials were evaluated using acetic acid induced writhing, hot plate test, and formalin induced paw licking test. In acetic acid induced writhing chloroform fraction (Ir.Chf) exhibited 53% analgesia while formalin test displayed 61% inhibition at phase-I and 45% at phase-II respectively at a dose of 100 mg/kg. Similarly, in hot plate test Ir.Chf displayed average reaction time of 7 min at 15, 30, 45, and 60 min intervals. The possible mechanism of action was found to be the central pathway via opioidergic receptors as the mice showed morphine like analgesic activity at pre-administration of naloxone (opioid antagonist) in hot plate and formalin tests. In GC-MS analysis, 83 compounds were identified among which eight compounds including benzyl alcohol, sebacic acid, myristic acid, phytol, sugiol, Tocopherol, alpha-Amyrin, and stigmasterol were sorted out as previously reported analgesic compounds. Current study revealed that analgesic potential of I. rugosus can attributed to the presence of analgesic compounds. It may also be concluded that opioids receptors are involved in the analgesic mechanism of I. rugosus due to effective antagonism of nalaxone. PMID- 27458381 TI - Cerebral Regulation in Different Maximal Aerobic Exercise Modes. AB - We investigated cerebral responses, simultaneously with peripheral and ratings of perceived exertion (RPE) responses, during different VO2MAX-matched aerobic exercise modes. Nine cyclists (VO2MAX of 57.5 +/- 6.2 ml.kg(-1).min(-1)) performed a maximal, controlled-pace incremental test (MIT) and a self-paced 4 km time trial (TT4km). Measures of cerebral (COX) and muscular (MOX) oxygenation were assessed throughout the exercises by changes in oxy- (O2Hb) and deoxy hemoglobin (HHb) concentrations over the prefrontal cortex (PFC) and vastus lateralis (VL) muscle, respectively. Primary motor cortex (PMC) electroencephalography (EEG), VL, and rectus femoris EMG were also assessed throughout the trials, together with power output and cardiopulmonary responses. The RPE was obtained at regular intervals. Similar motor output (EMG and power output) occurred from 70% of the duration in MIT and TT4km, despite the greater motor output, muscle deoxygenation (? MOX) and cardiopulmonary responses in TT4km before that point. Regarding cerebral responses, there was a lower COX (? O2Hb concentrations in PFC) at 20, 30, 40, 50 and 60%, but greater at 100% of the TT4km duration when compared to MIT. The alpha wave EEG in PMC remained constant throughout the exercise modes, with greater values in TT4km. The RPE was maximal at the endpoint in both exercises, but it increased slower in TT4km than in MIT. Results showed that similar motor output and effort tolerance were attained at the closing stages of different VO2MAX-matched aerobic exercises, although the different disturbance until that point. Regardless of different COX responses during most of the exercises duration, activation in PMC was preserved throughout the exercises, suggesting that these responses may be part of a centrally coordinated exercise regulation. PMID- 27458380 TI - The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity. AB - Different from other epithelia, the intestinal epithelium has the complex task of providing a barrier impeding the entry of toxins, food antigens, and microbes, while at the same time allowing for the transfer of nutrients, electrolytes, water, and microbial metabolites. These molecules/organisms are transported either transcellularly, crossing the apical and basolateral membranes of enterocytes, or paracellularly, passing through the space between enterocytes. Accordingly, the intestinal epithelium can affect energy metabolism, fluid balance, as well as immune response and tolerance. To help accomplish these complex tasks, the intestinal epithelium has evolved many sensing receptor mechanisms. Yet, their roles and functions are only now beginning to be elucidated. This article explores one such sensing receptor mechanism, carried out by the extracellular calcium-sensing receptor (CaSR). In addition to its established function as a nutrient sensor, coordinating food digestion, nutrient absorption, and regulating energy metabolism, we present evidence for the emerging role of CaSR in the control of intestinal fluid homeostasis and immune balance. An additional role in the modulation of the enteric nerve activity and motility is also discussed. Clearly, CaSR has profound effects on many aspects of intestinal function. Nevertheless, more work is needed to fully understand all functions of CaSR in the intestine, including detailed mechanisms of action and specific pathways involved. Considering the essential roles CaSR plays in gastrointestinal physiology and immunology, research may lead to a translational opportunity for the development of novel therapies that are based on CaSR's unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators. It is possible that, through targeting of intestinal CaSR with a combination of specific nutrients, oral solutions that are both inexpensive and practical may be developed to help in conditioning the gut microenvironment and in maintaining digestive health. PMID- 27458382 TI - A Critical Role of TRPM7 As an Ion Channel Protein in Mediating the Mineralization of the Craniofacial Hard Tissues. AB - Magnesium ion (Mg(2+)) is the fourth most common cation in the human body, and has a crucial role in many physiological functions. Mg(2+) homeostasis is an important contributor to bone development, however, its roles in the development of dental mineralized tissues have not yet been well known. We identified that transient receptor potential cation channel, subfamily M, member 7 (TRPM7), was significantly upregulated in the mature ameloblasts as compared to other ameloblasts through our whole transcript microarray analyses of the ameloblasts. TRPM7, an ion channel for divalent metal cations with an intrinsic serine/threonine protein kinase activity, has been characterized as a key regulator of whole body Mg(2+) homeostasis. Semi-quantitative PCR and immunostaining for TRMP7 confirmed its upregulation during the maturation stage of enamel formation, at which ameloblasts direct rapid mineralization of the enamel matrix. The significantly hypomineralized craniofacial structures, including incisors, molars, and cranial bones were demonstrated by microCT analysis, von Kossa and trichrome staining in Trpm7 (Deltakinase/+) mice. A previously generated heterozygous mouse model with the deletion of the TRPM7 kinase domain. Interestingly, the skeletal phenotype of Trpm7 (Deltakinase/+) mice resembled those found in the tissue-nonspecific alkaline phosphatase (Alpl) KO mice, thus we further examined whether ALPL protein content and alkaline phosphatase (ALPase) activity in ameloblasts, odontoblasts and osteoblasts were affected in those mice. While ALPL protein in Trpm7 (Deltakinase/+) mice remained at the similar level as that in wt mice, ALPase activities in the Trpm7 (Deltakinase/+) mice were almost nonexistent. Supplemented magnesium successfully rescued the activities of ALPase in ameloblasts, odontoblasts and osteoblasts of Trpm7 (Deltakinase/+) mice. These results suggested that TRPM7 is essential for mineralization of enamel as well as dentin and bone by providing sufficient Mg(2+) for the ALPL activity, underlining the key importance of ALPL for biomineralization. PMID- 27458384 TI - User Experience May be Producing Greater Heart Rate Variability than Motor Imagery Related Control Tasks during the User-System Adaptation in Brain-Computer Interfaces. AB - Brain-computer interface (BCI) is technology that is developing fast, but it remains inaccurate, unreliable and slow due to the difficulty to obtain precise information from the brain. Consequently, the involvement of other biosignals to decode the user control tasks has risen in importance. A traditional way to operate a BCI system is via motor imagery (MI) tasks. As imaginary movements activate similar cortical structures and vegetative mechanisms as a voluntary movement does, heart rate variability (HRV) has been proposed as a parameter to improve the detection of MI related control tasks. However, HR is very susceptible to body needs and environmental demands, and as BCI systems require high levels of attention, perceptual processing and mental workload, it is important to assess the practical effectiveness of HRV. The present study aimed to determine if brain and heart electrical signals (HRV) are modulated by MI activity used to control a BCI system, or if HRV is modulated by the user perceptions and responses that result from the operation of a BCI system (i.e., user experience). For this purpose, a database of 11 participants who were exposed to eight different situations was used. The sensory-cognitive load (intake and rejection tasks) was controlled in those situations. Two electrophysiological signals were utilized: electroencephalography and electrocardiography. From those biosignals, event-related (de-)synchronization maps and event-related HR changes were respectively estimated. The maps and the HR changes were cross-correlated in order to verify if both biosignals were modulated due to MI activity. The results suggest that HR varies according to the experience undergone by the user in a BCI working environment, and not because of the MI activity used to operate the system. PMID- 27458383 TI - P4-ATPases as Phospholipid Flippases-Structure, Function, and Enigmas. AB - P4-ATPases comprise a family of P-type ATPases that actively transport or flip phospholipids across cell membranes. This generates and maintains membrane lipid asymmetry, a property essential for a wide variety of cellular processes such as vesicle budding and trafficking, cell signaling, blood coagulation, apoptosis, bile and cholesterol homeostasis, and neuronal cell survival. Some P4-ATPases transport phosphatidylserine and phosphatidylethanolamine across the plasma membrane or intracellular membranes whereas other P4-ATPases are specific for phosphatidylcholine. The importance of P4-ATPases is highlighted by the finding that genetic defects in two P4-ATPases ATP8A2 and ATP8B1 are associated with severe human disorders. Recent studies have provided insight into how P4-ATPases translocate phospholipids across membranes. P4-ATPases form a phosphorylated intermediate at the aspartate of the P-type ATPase signature sequence, and dephosphorylation is activated by the lipid substrate being flipped from the exoplasmic to the cytoplasmic leaflet similar to the activation of dephosphorylation of Na(+)/K(+)-ATPase by exoplasmic K(+). How the phospholipid is translocated can be understood in terms of a peripheral hydrophobic gate pathway between transmembrane helices M1, M3, M4, and M6. This pathway, which partially overlaps with the suggested pathway for migration of Ca(2+) in the opposite direction in the Ca(2+)-ATPase, is wider than the latter, thereby accommodating the phospholipid head group. The head group is propelled along against its concentration gradient with the hydrocarbon chains projecting out into the lipid phase by movement of an isoleucine located at the position corresponding to an ion binding glutamate in the Ca(2+)- and Na(+)/K(+)-ATPases. Hence, the P4-ATPase mechanism is quite similar to the mechanism of these ion pumps, where the glutamate translocates the ions by moving like a pump rod. The accessory subunit CDC50 may be located in close association with the exoplasmic entrance of the suggested pathway, and possibly promotes the binding of the lipid substrate. This review focuses on properties of mammalian and yeast P4-ATPases for which most mechanistic insight is available. However, the structure, function and enigmas associated with mammalian and yeast P4-ATPases most likely extend to P4-ATPases of plants and other organisms. PMID- 27458385 TI - Arterial Stiffening in Western Diet-Fed Mice Is Associated with Increased Vascular Elastin, Transforming Growth Factor-beta, and Plasma Neuraminidase. AB - Consumption of excess fat and carbohydrate (Western diet, WD) is associated with alterations in the structural characteristics of blood vessels. This vascular remodeling contributes to the development of cardiovascular disease, particularly as it affects conduit and resistance arteries. Vascular remodeling is often associated with changes in the elastin-rich internal elastic lamina (IEL) and the activation of transforming growth factor (TGF)-beta. In addition, obesity and type II diabetes have been associated with increased serum neuraminidase, an enzyme known to increase TGF-beta cellular output. Therefore, we hypothesized that WD-feeding would induce structural modifications to the IEL of mesenteric resistance arteries in mice, and that these changes would be associated with increased levels of circulating neuraminidase and the up-regulation of elastin and TGF-beta in the arterial wall. To test this hypothesis, a WD, high in fat and sugar, was used to induce obesity in mice, and the effect of this diet on the structure of mesenteric resistance arteries was investigated. 4-week old, Post weaning mice were fed either a normal diet (ND) or WD for 16 weeks. Mechanically, arteries from WD-fed mice were stiffer and less distensible, with marginally increased wall stress for a given strain, and a significantly increased Young's modulus of elasticity. Structurally, the wall cross-sectional area and the number of fenestrae found in the internal elastic lamina (IEL) of mesenteric arteries from mice fed a WD were significantly smaller than those of arteries from the ND fed mice. There was also a significant increase in the volume of elastin, but not collagen in arteries from the WD cohort. Plasma levels of neuraminidase and the amount of TGF-beta in mesenteric arteries were elevated in mice fed a WD, while ex vivo, cultured vascular smooth muscle cells exposed to neuraminidase secreted greater amounts of tropoelastin and TGF-beta than those exposed to vehicle. These data suggest that consumption of a diet high in fat and sugar causes stiffening of the vascular wall in resistance arteries through a process that may involve increased neuraminidase and TGF-beta activity, elevated production of elastin, and a reduction in the size and number of fenestrae in the arterial IEL. PMID- 27458386 TI - Intra-Parenchymal Renal Resistive Index Variation (IRRIV) Describes Renal Functional Reserve (RFR): Pilot Study in Healthy Volunteers. AB - An increase of glomerular filtration rate after protein load represents renal functional reserve (RFR) and is due to afferent arteriolar vasodilation. Lack of RFR may be a risk factor for acute kidney injury (AKI), but is cumbersome to measure. We sought to develop a non-invasive, bedside method that would indirectly measure RFR. Mechanical abdominal pressure, through compression of renal vessels, decreases blood flow and activates the auto-regulatory mechanism which can be measured by a fall in renal resistive index (RRI). The study aims at elucidating the relationship between intra-parenchymal renal resistive index variation (IRRIV) during abdominal pressure and RFR. In healthy volunteers, pressure was applied by a weight on the abdomen (fluid-bag 10% of subject's body weight) while RFR was measured through a protein loading test. We recorded RRI in an interlobular artery after application of pressure using ultrasound. The maximum percentage reduction of RRI from baseline was compared in the same subject to RFR. We enrolled 14 male and 16 female subjects (mean age 38 +/- 14 years). Mean creatinine clearance was 106.2 +/- 16.4 ml/min/1.73 m(2). RFR ranged between -1.9 and 59.7 with a mean value of 28.9 +/- 13.1 ml/min/1.73 m(2). Mean baseline RRI was 0.61 +/- 0.05, compared to 0.49 +/- 0.06 during abdominal pressure; IRRIV was 19.6 +/- 6.7%, ranging between 3.1% and 29.2%. Pearson's coefficient between RFR and IRRIV was 74.16% (p < 0.001). Our data show the correlation between IRRIV and RFR. Our results can lead to the development of a "stress test" for a rapid screen of RFR to establish renal susceptibility to different exposures and the consequent risk for AKI. PMID- 27458387 TI - Erythropoietin Does Not Enhance Skeletal Muscle Protein Synthesis Following Exercise in Young and Older Adults. AB - PURPOSE: Erythropoietin (EPO) is a renal cytokine that is primarily involved in hematopoiesis while also playing a role in non-hematopoietic tissues expressing the EPO-receptor (EPOR). The EPOR is present in human skeletal muscle. In mouse skeletal muscle, EPO stimulation can activate the AKT serine/threonine kinase 1 (AKT) signaling pathway, the main positive regulator of muscle protein synthesis. We hypothesized that a single intravenous EPO injection combined with acute resistance exercise would have a synergistic effect on skeletal muscle protein synthesis via activation of the AKT pathway. METHODS: Ten young (24.2 +/- 0.9 years) and 10 older (66.6 +/- 1.1 years) healthy subjects received a primed, constant infusion of [ring-13C(6)] L-phenylalanine and a single injection of 10,000 IU epoetin-beta or placebo in a double-blind randomized, cross-over design. 2 h after the injection, the subjects completed an acute bout of leg extension resistance exercise to stimulate skeletal muscle protein synthesis. RESULTS: Significant interaction effects in the phosphorylation levels of the members of the AKT signaling pathway indicated a differential activation of protein synthesis signaling in older subjects when compared to young subjects. However, EPO offered no synergistic effect on vastus lateralis mixed muscle protein synthesis rate in young or older subjects. CONCLUSIONS: Despite its ability to activate the AKT pathway in skeletal muscle, an acute EPO injection had no additive or synergistic effect on the exercise-induced activation of muscle protein synthesis or muscle protein synthesis signaling pathways. PMID- 27458388 TI - No Smoke without Tobacco: A Global Overview of Cannabis and Tobacco Routes of Administration and Their Association with Intention to Quit. AB - Cannabis and tobacco are common drugs of abuse worldwide and are often used in combination through various routes of administration (ROAs). Here, we aimed to provide an overview of how cannabis and tobacco routes varied across countries and assess the impact of tobacco-based ROAs on motivation to use less cannabis, and less tobacco, in different models. A cross-sectional online survey (Global Drugs Survey 2014) was completed by 33,687 respondents (mean age = 27.9; % female = 25.9) who smoked cannabis at least once in the last 12 months. Most common ROA, frequency of cannabis/tobacco use, and questions about motivation to use less cannabis/tobacco were recorded. Tobacco-based ROA were used by 65.6% of respondents. These were most common in Europe (77.2-90.9%) and Australasia (20.7 51.6%) and uncommon in the Americas (4.4-16.0%). Vaporizer use was most common in Canada (13.2%) and the United States (11.2%). Using a non-tobacco ROA was associated with a 10.7% increase in odds for "desire to use less" tobacco (OR: 1.107, 95% CI: 1.003, 1.221), 80.6% increase in odds for "like help to use less tobacco" (OR: 1.806, 95% CI: 1.556, 2.095), and a 103.9% increase in the odds for "planning to seek help to use less tobacco" (OR: 2.039, 95% CI: 1.638, 2.539), in comparison to using a tobacco-based ROA. Associations between ROA and intentions to use less cannabis were inconsistent. Results support considerable global variation in cannabis and tobacco ROA. Tobacco routes are common, especially "joints with tobacco," especially in Europe, but not in the Americas. Non-tobacco based routes are associated with increased motivation to change tobacco use. Interventions addressing tobacco and cannabis need to accommodate this finding and encourage non-tobacco routes. PMID- 27458389 TI - Effect of Deep Brain Stimulation on Regional Cerebral Blood Flow in Patients with Medically Refractory Tourette Syndrome. AB - In this study, alterations in brain perfusion have been investigated in patients with Tourette syndrome (TS) compared with control subjects. In addition, we investigated the effects of deep brain stimulation (DBS) in both globus pallidus internus (GPi) and centromedian-parafascicular/ventralis oralis internus nuclei of the thalamus (CM/Voi) and sham (SHAM) stimulation on cerebral blood flow. In a prospective controlled, randomized, double-blind setting, five severely affected adult patients with TS with predominant motor or vocal tics (mean total tic score on the Yale Global Tic Severity Scale: 39) underwent serial brain perfusion single photon emission computed tomography with (99m)Tc-ECD. Results were compared with data from six age-matched control subjects. All patients were investigated at four different time points: once before DBS implantation (preOP) and three times postoperatively. Postoperative scans were performed in a randomized order, each after 3 months of either GPi, CM/Voi, or SHAM stimulation. At each investigation, patients were injected at rest while awake, but scanned during anesthesia. This procedure ensured that neither anesthesia nor movement artifacts influenced our results. Control subjects were investigated only once at baseline (without DBS or anesthesia). At baseline, cerebral blood flow was significantly reduced in patients with TS (preOP) compared with controls in the central region, frontal, and parietal lobe, specifically in Brodmann areas 1, 4 9, 30, 31, and 40. Significantly increased perfusion was found in the cerebellum. When comparing SHAM stimulation to preOP condition, we found significantly decreased perfusion in basal ganglia and thalamus, but increased perfusion in different parts of the frontal cortex. Compared with SHAM condition both GPi and thalamic stimulation resulted in a significant decrease in cerebral blood flow in basal ganglia and cerebellum, while perfusion in the frontal cortex was significantly increased. Our results provide substantial evidence that, in TS, brain perfusion is altered in the frontal cortex and the cerebellum and that these changes can be reversed by both GPi and CM/Voi DBS. PMID- 27458390 TI - Perspectives on Games, Computers, and Mental Health: Questions about Paradoxes, Evidences, and Challenges. AB - In the field of mental health, games and computerized games present questions about paradoxes, evidences, and challenges. This perspective article offers perspectives and personal opinion about these questions, evidences, and challenges with an objective of presenting several ideas and issues in this rapidly developing field. First, games raise some questions in the sense of the paradox between a game and an issue, as well as the paradox of using an amusing game to treat a serious pathology. Second, games also present evidence in the sense that they involve relationships with others, as well as learning, communication, language, emotional regulation, and hedonism. Third, games present challenges, such as the risk of abuse, the critical temporal period that may be limited to childhood, their important influence on sociocognitive learning and the establishment of social norms, and the risk of misuse of games. PMID- 27458391 TI - Editorial: Frontiers in Brain-Based Therapeutic Interventions and Biomarker Research in Child and Adolescent Psychiatry. PMID- 27458392 TI - The Role of Semantic Diversity in Word Recognition across Aging and Bilingualism. AB - Frequency effects are pervasive in studies of language, with higher frequency words being recognized faster than lower frequency words. However, the exact nature of frequency effects has recently been questioned, with some studies finding that contextual information provides a better fit to lexical decision and naming data than word frequency (Adelman et al., 2006). Recent work has cemented the importance of these results by demonstrating that a measure of the semantic diversity of the contexts that a word occurs in provides a powerful measure to account for variability in word recognition latency (Johns et al., 2012, 2015; Jones et al., 2012). The goal of the current study is to extend this measure to examine bilingualism and aging, where multiple theories use frequency of occurrence of linguistic constructs as central to accounting for empirical results (Gollan et al., 2008; Ramscar et al., 2014). A lexical decision experiment was conducted with four groups of subjects: younger and older monolinguals and bilinguals. Consistent with past results, a semantic diversity variable accounted for the greatest amount of variance in the latency data. In addition, the pattern of fits of semantic diversity across multiple corpora suggests that bilinguals and older adults are more sensitive to semantic diversity information than younger monolinguals. PMID- 27458393 TI - Distinct Effects of Lexical and Semantic Competition during Picture Naming in Younger Adults, Older Adults, and People with Aphasia. AB - Producing a word requires selecting among a set of similar alternatives. When many semantically related items become activated, the difficulty of the selection process is increased. Experiment 1 tested naming of items with either multiple synonymous labels ("Alternate Names," e.g., gift/present) or closely semantically related but non-equivalent responses ("Near Semantic Neighbors," e.g., jam/jelly). Picture naming was fastest and most accurate for pictures with only one label ("High Name Agreement"), slower and less accurate in the Alternate Names condition, and slowest and least accurate in the Near Semantic Neighbors condition. These results suggest that selection mechanisms in picture naming operate at two distinct levels of processing: selecting between similar but non equivalent names requires two selection processes (semantic and lexical), whereas selecting among equivalent names only requires one selection at the lexical level. Experiment 2 examined how these selection mechanisms are affected by normal aging and found that older adults had significantly more difficulty in the Near Semantic Neighbors condition, but not in the Alternate Names condition. This suggests that aging affects semantic processing and selection more strongly than it affects lexical selection. Experiment 3 examined the role of the left inferior frontal gyrus (LIFG) in these selection processes by testing individuals with aphasia secondary to stroke lesions that either affected the LIFG or spared it. Surprisingly, there was no interaction between condition and lesion group: the presence of LIFG damage was not associated with substantively worse naming performance for pictures with multiple acceptable labels. These results are not consistent with a simple view of LIFG as the locus of lexical selection and suggest a more nuanced view of the neural basis of lexical and semantic selection. PMID- 27458395 TI - A Three-Stage Model for the Acquisition of Anticipatory Planning Skills for Grip Selection during Object Manipulation in Young Children. PMID- 27458394 TI - Traditional Masculinity and Femininity: Validation of a New Scale Assessing Gender Roles. AB - Gender stereotype theory suggests that men are generally perceived as more masculine than women, whereas women are generally perceived as more feminine than men. Several scales have been developed to measure fundamental aspects of gender stereotypes (e.g., agency and communion, competence and warmth, or instrumentality and expressivity). Although omitted in later version, Bem's original Sex Role Inventory included the items "masculine" and "feminine" in addition to more specific gender-stereotypical attributes. We argue that it is useful to be able to measure these two core concepts in a reliable, valid, and parsimonious way. We introduce a new and brief scale, the Traditional Masculinity Femininity (TMF) scale, designed to assess central facets of self-ascribed masculinity-femininity. Studies 1-2 used known-groups approaches (participants differing in gender and sexual orientation) to validate the scale and provide evidence of its convergent validity. As expected the TMF reliably measured a one dimensional masculinity-femininity construct. Moreover, the TMF correlated moderately with other gender-related measures. Demonstrating incremental validity, the TMF predicted gender and sexual orientation in a superior way than established adjective-based measures. Furthermore, the TMF was connected to criterion characteristics, such as judgments as straight by laypersons for the whole sample, voice pitch characteristics for the female subsample, and contact to gay men for the male subsample, and outperformed other gender-related scales. Taken together, as long as gender differences continue to exist, we suggest that the TMF provides a valuable methodological addition for research into gender stereotypes. PMID- 27458396 TI - Zebra Finch Song Phonology and Syntactical Structure across Populations and Continents-A Computational Comparison. AB - Learned bird songs are often characterized by a high degree of variation between individuals and sometimes between populations, while at the same time maintaining species specificity. The evolution of such songs depends on the balance between plasticity and constraints. Captive populations provide an opportunity to examine signal variation and differentiation in detail, so we analyzed adult male zebra finch (Taeniopygia guttata) songs recorded from 13 populations across the world, including one sample of songs from wild-caught males in their native Australia. Cluster analysis suggested some, albeit limited, evidence that zebra finch song units belonged to universal, species-wide categories, linked to restrictions in vocal production and non-song parts of the vocal repertoire. Across populations, songs also showed some syntactical structure, although any song unit could be placed anywhere within the song. On the other hand, there was a statistically significant differentiation between populations, but the effect size was very small, and its communicative significance dubious. Our results suggest that variation in zebra finch songs within a population is largely determined by species-wide constraints rather than population-specific features. Although captive zebra finch populations have been sufficiently isolated to allow them to genetically diverge, there does not appear to have been any divergence in the genetically determined constraints that underlie song learning. Perhaps more surprising is the lack of locally diverged cultural traditions. Zebra finches serve as an example of a system where frequent learning errors may rapidly create within-population diversity, within broad phonological and syntactical constraints, and prevent the formation of long-term cultural traditions that allow populations to diverge. PMID- 27458397 TI - Characterization of Vulnerable and Resilient Spanish Adolescents in Their Developmental Contexts. AB - Research on resilience and vulnerability can offer very valuable information for optimizing design and assessment of interventions and policies aimed at fostering adolescent health. This paper used the adversity level associated with family functioning and the positive adaptation level, as measured by means of a global health score, to distinguish four groups within a representative sample of Spanish adolescents aged 13-16 years: maladaptive, resilient, competent and vulnerable. The aforementioned groups were compared in a number of demographic, school context, peer context, lifestyles, psychological and socioeconomic variables, which can facilitate or inhibit positive adaptation in each context. In addition, the degree to which each factor tended to associate with resilience and vulnerability was examined. The majority of the factors operated by increasing the likelihood of good adaptation in resilient adolescents and diminishing it in vulnerable ones. Overall, more similarities than differences were found in the factors contributing to explaining resilience or vulnerability. However, results also revealed some differential aspects: psychological variables showed a larger explicative capacity in vulnerable adolescents, whereas factors related to school and peer contexts, especially the second, showed a stronger association with resilience. In addition, perceived family wealth, satisfaction with friendships and breakfast frequency only made a significant contribution to the explanation of resilience. The current study provides a highly useful characterization of resilience and vulnerability phenomena in adolescence. PMID- 27458398 TI - Children with Attention Deficit/Hyperactivity Disorder and Reading Disability: A Review of the Efficacy of Medication Treatments. AB - Reading is a multifaceted skillset that has the potential to profoundly impact a child's academic performance and achievement. Mastery of reading skills is often an area of difficulty for children during their academic journey, particularly for children with Attention Deficit/Hyperactivity Disorder (ADHD), Specific Learning Disorder with Impairment in Reading (SLD-R), or children with a comorbid diagnosis of both ADHD and SLD-R. ADHD is characterized by executive functioning and impulse control deficits, as well as inattention and impulsivity. Among the academic struggles experienced by children with ADHD are challenges with word reading, decoding, or reading comprehension. Similarly, children with SLD-R frequently encounter difficulties in the development of appropriate reading skills. SLD-R incorporates dysfunctions in basic visual and auditory processes that result in difficulties with decoding and spelling words. There have been limited empirical studies investigating the efficacy of interventions to improve the reading ability of children with both ADHD and SLD-R. Research studies that have focused on reading interventions for children from this population have predominantly included the use of medication treatments with stimulants (e.g., methylphenidate) and non-stimulants (e.g., atomoxetine). This review paper will present and integrate findings from empirical studies on successful medication treatments for children with comorbid ADHD and SLD-R. Furthermore, this paper will extend findings from empirically successful medication treatments to provide directions for future research. PMID- 27458399 TI - Visual Online Control of Goal-Directed Aiming Movements in Children. AB - The present study investigated whether the initial impulse of goal-directed movements was visually monitored by 5- to 12-years-old children (n = 36) in a manner similar to adults (n = 12). The participants moved a cursor toward a fixed target. In some trials, the cursor was unpredictably translated by 20 mm following movement initiation. The results showed that even the youngest children visually monitor the initial impulse of goal-directed movements. This monitoring and the error correction process that it triggers seem automatic because it occurs even when the cursor jump is not consciously detected. Finally, it appears that this process does not fully mature before late childhood, which suggests that a putative dedicated channel for processing visual hand information develops during childhood. PMID- 27458401 TI - Editorial: The Balanced Triad of Perception, Action, and Cognition. PMID- 27458400 TI - Age-Related Differences in Lexical Access Relate to Speech Recognition in Noise. AB - Vocabulary size has been suggested as a useful measure of "verbal abilities" that correlates with speech recognition scores. Knowing more words is linked to better speech recognition. How vocabulary knowledge translates to general speech recognition mechanisms, how these mechanisms relate to offline speech recognition scores, and how they may be modulated by acoustical distortion or age, is less clear. Age-related differences in linguistic measures may predict age-related differences in speech recognition in noise performance. We hypothesized that speech recognition performance can be predicted by the efficiency of lexical access, which refers to the speed with which a given word can be searched and accessed relative to the size of the mental lexicon. We tested speech recognition in a clinical German sentence-in-noise test at two signal-to-noise ratios (SNRs), in 22 younger (18-35 years) and 22 older (60-78 years) listeners with normal hearing. We also assessed receptive vocabulary, lexical access time, verbal working memory, and hearing thresholds as measures of individual differences. Age group, SNR level, vocabulary size, and lexical access time were significant predictors of individual speech recognition scores, but working memory and hearing threshold were not. Interestingly, longer accessing times were correlated with better speech recognition scores. Hierarchical regression models for each subset of age group and SNR showed very similar patterns: the combination of vocabulary size and lexical access time contributed most to speech recognition performance; only for the younger group at the better SNR (yielding about 85% correct speech recognition) did vocabulary size alone predict performance. Our data suggest that successful speech recognition in noise is mainly modulated by the efficiency of lexical access. This suggests that older adults' poorer performance in the speech recognition task may have arisen from reduced efficiency in lexical access; with an average vocabulary size similar to that of younger adults, they were still slower in lexical access. PMID- 27458402 TI - Holding Back the Tears: Individual Differences in Adult Crying Proneness Reflect Attachment Orientation and Attitudes to Crying. AB - Despite being a universal human attachment behavior, little is known about individual differences in crying. To facilitate such examination we first recommend shortened versions of the attitudes and proneness sections of the Adult Crying Inventory using two independent samples. Importantly, we examine attachment orientation differences in crying proneness and test the mediating role of attitudes toward crying in this relationship. Participants (Sample 1 N = 623, Sample 2 N = 781), completed online measures of adult attachment dimensions (avoidance and anxiety), attitudes toward crying, and crying proneness. Exploratory factor analyses in Sample 1 revealed four factors for crying attitudes: crying helps one feel better; crying is healthy; hatred of crying; and crying is controllable; and three factors for crying proneness: threat to self; sadness; and joy. Confirmatory factor analyses in Sample 2 replicated these structures. Theoretically and statistically justified short forms of each scale were created. Multiple mediation analyses revealed similar patterns of results across the two samples, with the attitudes "crying is healthy" and "crying is controllable" consistently mediating the positive links between attachment anxiety and crying proneness, and the negative links between attachment avoidance and crying proneness. Results are discussed in relation to attachment and emotion regulation literature. PMID- 27458403 TI - Development of Embodied Sense of Self Scale (ESSS): Exploring Everyday Experiences Induced by Anomalous Self-Representation. AB - The scientific exploration of the self has progressed, with much attention focused on the Embodied Sense of Self (ESS). Empirical studies have suggested the mechanisms for self-representation. On the other hand, less attention has been paid to the subjectivity itself of the self. With reference to previous studies, the current study collected items that reflect the ESS and statistically extracted three factors for it: Ownership, Agency, and Narrative. The developed questionnaire [Embodied Sense of Self Scale (ESSS)] showed good enough validity and reliability for practical use. Furthermore, ESSS discriminated schizophrenia, a disorder of the ESS, from controls. We discuss the factorial structure of ESS and the relationship among factors on the basis of the current results. PMID- 27458404 TI - Color Discrimination Is Affected by Modulation of Luminance Noise in Pseudoisochromatic Stimuli. AB - Pseudoisochromatic stimuli have been widely used to evaluate color discrimination and to identify color vision deficits. Luminance noise is one of the stimulus parameters used to ensure that subject's response is due to their ability to discriminate target stimulus from the background based solely on the hue between the colors that compose such stimuli. We studied the influence of contrast modulation of the stimulus luminance noise on threshold and reaction time color discrimination. We evaluated color discrimination thresholds using the Cambridge Color Test (CCT) at six different stimulus mean luminances. Each mean luminance condition was tested using two protocols: constant absolute difference between maximum and minimum luminance of the luminance noise (constant delta protocol, CDP), and constant contrast modulation of the luminance noise (constant contrast protocol, CCP). MacAdam ellipses were fitted to the color discrimination thresholds in the CIE 1976 color space to quantify the color discrimination ellipses at threshold level. The same CDP and CCP protocols were applied in the experiment measuring RTs at three levels of stimulus mean luminance. The color threshold measurements show that for the CDP, ellipse areas decreased as a function of the mean luminance and they were significantly larger at the two lowest mean luminances, 10 cd/m(2) and 13 cd/m(2), compared to the highest one, 25 cd/m(2). For the CCP, the ellipses areas also decreased as a function of the mean luminance, but there was no significant difference between ellipses areas estimated at six stimulus mean luminances. The exponent of the decrease of ellipse areas as a function of stimulus mean luminance was steeper in the CDP than CCP. Further, reaction time increased linearly with the reciprocal of the length of the chromatic vectors varying along the four chromatic half-axes. It decreased as a function of stimulus mean luminance in the CDP but not in the CCP. The findings indicated that visual performance using pseudoisochromatic stimuli was dependent on the Weber's contrast of the luminance noise. Low Weber's contrast in the luminance noise is suggested to have a reduced effect on chromatic information and, hence, facilitate desegregation of the hue-defined target from the background. PMID- 27458405 TI - Organizational Climate for Successful Aging. AB - Research on successful aging at work has neglected contextual resources such as organizational climate, which refers to employees' shared perceptions of their work environment. We introduce the construct of organizational climate for successful aging (OCSA) and examine it as a buffer of the negative relationship between employee age and focus on opportunities (i.e., beliefs about future goals and possibilities at work). Moreover, we expected that focus on opportunities, in turn, positively predicts job satisfaction, organizational commitment, and motivation to continue working after official retirement age. Data came from 649 employees working in 120 companies (M age = 44 years, SD = 13). We controlled for organizational tenure, psychological climate for successful aging (i.e., individuals' perceptions), and psychological and organizational age discrimination climate. Results of multilevel analyses supported our hypotheses. Overall, our findings suggest that OCSA is an important contextual resource for successful aging at work. PMID- 27458406 TI - "It's Always the Judge's Fault": Attention, Emotion Recognition, and Expertise in Rhythmic Gymnastics Assessment. AB - In many sports, such as figure skating or gymnastics, the outcome of a performance does not rely exclusively on objective measurements, but on more subjective cues. Judges need high attentional capacities to process visual information and overcome fatigue. Also their emotion recognition abilities might have an effect in detecting errors and making a more accurate assessment. Moreover, the scoring given by judges could be also influenced by their level of expertise. This study aims to assess how rhythmic gymnastics judges' emotion recognition and attentional abilities influence accuracy of performance assessment. Data will be collected from rhythmic gymnastics judges and coaches at different international levels. This study will employ an online questionnaire consisting on an emotion recognition test and attentional test. Participants' task is to watch a set of videotaped rhythmic gymnastics performances and evaluate them on the artistic and execution components of performance. Their scoring will be compared with the official scores given at the competition the video was taken from to measure the accuracy of the participants' evaluations. The proposed research represents an interdisciplinary approach that integrates cognitive and sport psychology within experimental and applied contexts. The current study advances the theoretical understanding of how emotional and attentional aspects affect the evaluation of sport performance. The results will provide valuable evidence on the direction and strength of the relationship between the above-mentioned factors and the accuracy of sport performance evaluation. Importantly, practical implications might be drawn from this study. Intervention programs directed at improving the accuracy of judges could be created based on the understanding of how emotion recognition and attentional abilities are related to the accuracy of performance assessment. PMID- 27458407 TI - Effects of Internet-Based Self-Efficacy Intervention on Secondary Traumatic Stress and Secondary Posttraumatic Growth among Health and Human Services Professionals Exposed to Indirect Trauma. AB - BACKGROUND: Although the evidence for the associations among self-efficacy, secondary traumatic stress (STS) and secondary posttraumatic growth (SPTG) is mounting, there is a lack of the experimental evidence for the influence of self efficacy on positive and negative mental health outcomes among professionals indirectly exposed to trauma. PURPOSE: This study investigated the effects of an internet-based self-efficacy intervention (the experimental condition), compared to an education (the active control condition) on STS and SPTG among workers exposed to traumatic events indirectly, through their clients. We hypothesized that the group assignment (experimental vs. control) would affect STS and SPTG indirectly, with a mediating role of self-efficacy beliefs. METHODS: Participants were 168 health and human services professionals (78% women), exposed indirectly to a traumatic event at work. They were randomly assigned to either a 4-session internet-based self-efficacy intervention (n = 87) or an education control group (n = 81) which received information about coping resources and consequences of stressors at work or at home. STS, SPTG, and self-efficacy were measured at the baseline (Time 1), 1-month follow-up (Time 2) and 2-month follow-up (Time 3). RESULTS: Analysis of covariance showed that the group assignment had a significant effect on STS (Time 2) and self-efficacy (Time 2), with lower STS and higher self-efficacy reported by the self-efficacy intervention participants. Compared to the experimental group, the active control (education) group participants reported higher SPTG at Time 2. Mediation analyses indicated that the group assignment had indirect effects on STS and SPTG at Time 3. Workers who experienced increases in self-efficacy (Time 2) through the intervention were more likely to report lower STS and higher SPTG at Time 3. CONCLUSION: Elucidating the mediating processes that explain why an intervention for secondary trauma works is essential in order to develop more effective support systems that promote improved mental health outcomes among health and human services professionals. Prevention programs for workers exposed indirectly to traumatic events may target self-efficacy enhancement and education. PMID- 27458408 TI - The Sex Differences in Regulating Unpleasant Emotion by Expressive Suppression: Extraversion Matters. AB - Males are known for more suppression of emotional displays than females. However, when the emotion regulation effect of expressive suppression is greater in males, and how this sex difference varies with emotion display-related personality (e.g., extraversion), are undetermined. Event-related potentials were recorded while male and female participants different in extraversion were required to attend to or suppress emotional expression to negative pictures. Sex and extraversion did not modulate self-reported emotional experience. However, late positive potential (LPP) amplitudes showed an extraversion-moderated sex difference in the 2000-3000 ms and the 3000-4000 ms time epochs. LPP amplitudes were decreased during suppression versus viewing conditions in ambivert males, while this effect was absent in ambivert females. However, the LPP amplitudes of extraverts were similar for suppression and viewing conditions, irrespective of sex and timing. Regardless of early, middle, or late time windows, LPP amplitudes were positively related to self-reported emotion. These results suggest a male advantage for using expressive suppression for emotion regulation in non extraverted, ambivert individuals. PMID- 27458409 TI - Examining the Importance of the Teachers' Emotional Support for Students' Social Inclusion Using the One-with-Many Design. AB - The importance of high quality teacher-student relationships for students' well being has been long documented. Nonetheless, most studies focus either on teachers' perceptions of provided support or on students' perceptions of support. The degree to which teachers and students agree is often neither measured nor taken into account. In the current study, we will therefore use a dyadic analysis strategy called the one-with-many design. This design takes into account the nestedness of the data and looks at the importance of reciprocity when examining the influence of teacher support for students' academic and social functioning. Two samples of teachers and their students from Grade 4 (age 9-10 years) have been recruited in primary schools, located in Turkey and Romania. By using the one-with-many design we can first measure to what degree teachers' perceptions of support are in line with students' experiences. Second, this level of consensus is taken into account when examining the influence of teacher support for students' social well-being and academic functioning. PMID- 27458410 TI - The Relation between Effortful Control and Language Competence-A Small But Mighty Difference between First and Second Language Learners. AB - The present longitudinal study evaluates the effect of effortful control (EC) as a core dimension of temperament on early language competence. We assume that first and second language competence is influenced by EC, and that immigrant children with low EC are thus at risk of an unfavorable language development. The sample consisted of n = 351 dual language learners (DLLs) with an immigrant background and n = 78 monolingual children. Language competence was measured with a standardized language test at age 4.9 years and at age 6.3 years. EC was captured with the Child Behavior Questionnaire, completed by teachers. Results of regression analyses revealed a significant effect of EC on second language development. DLLs with lower EC were found to have not only lower language competence at the beginning and the end of kindergarten but also a less favorable language development. Comparisons between the effect of EC on first and second language provide evidence that EC plays a bigger role in subsequent second language competence compared to first language competence. Overall, the results emphasize the small yet significant role of EC in the second language development of DLLs. PMID- 27458411 TI - Emerging Executive Functioning and Motor Development in Infants at High and Low Risk for Autism Spectrum Disorder. AB - Existing evidence suggests executive functioning (EF) deficits may be present in children with autism spectrum disorder (ASD) by 3 years of age. It is less clear when, prior to 3 years, EF deficits may emerge and how EF unfold over time. The contribution of motor skill difficulties to poorer EF in children with ASD has not been systematically studied. We investigated the developmental trajectory of EF in infants at high and low familial risk for ASD (HR and LR) and the potential associations between motor skills, diagnostic group, and EF performance. Participants included 186 HR and 76 LR infants. EF (A-not-B), motor skills (Fine and Gross Motor), and cognitive ability were directly assessed at 12 months and 24 months of age. Participants were directly evaluated for ASD at 24 months using DSM-IV-TR criteria and categorized as HR-ASD, HR-Negative, and LR-Negative. HR ASD and HR-Negative siblings demonstrated less improvement in EF over time compared to the LR-Negative group. Motor skills were associated with group and EF performance at 12 months. No group differences were found at 12 months, but at 24 months, the HR-ASD and HR-Negative groups performed worse than the LR-Negative group overall after controlling for visual reception and maternal education. On reversal trials, the HR-ASD group performed worse than the LR-Negative group. Motor skills were associated with group and EF performance on reversal trials at 24 months. Findings suggest that HR siblings demonstrate altered EF development and that motor skills may play an important role in this process. PMID- 27458412 TI - Loneliness and Schizotypy Are Distinct Constructs, Separate from General Psychopathology. AB - Loneliness is common in youth and associated with a significantly increased risk of psychological disorders. Although loneliness is strongly associated with psychosis, its relationship with psychosis proneness is unclear. Our aim in this paper was to test the hypothesis that loneliness and schizotypal traits, conveying risk for schizophrenia spectrum disorders, are similar but separate constructs. Pooling data from two non-clinical student samples (N = 551) we modeled the structure of the relationship between loneliness and trait schizotypy. Loneliness was assessed with the University of California, Los Angeles Loneliness Scale (UCLA-3), whilst negative (Social Anhedonia) and positive (Perceptual Aberrations) schizotypal traits were assessed with the Wisconsin Schizotypy Scales-Brief (WSS-B). Fit statistics indicated that the best fitting model of UCLA-3 scores comprises three correlated factors (Isolation, Related Connectedness, and Collective Connectedness), consistent with previous reports. Fit statistics for a two factor model of positive and negative schizotypy were excellent. Next, bi-factor analysis was used to model a general psychopatholgy factor (p) across the three loneliness factors and separate negative and positive schizotypy traits. The results showed that all items (except 1) co-loaded on p. However, with the influence of p removed, additional variance remained within separate sub-factors, indicating that loneliness and negative and positive trait schizotypy are distinct and separable constructs. Similarly, once shared variance with p was removed, correlations between sub factors of loneliness and schizotypal traits were non-significant. These findings have important clinical implications since they suggest that loneliness should not be conflated with the expression of schizotypy. Rather, loneliness needs to be specifically targeted for assessment and treatment in youth at risk for psychosis. PMID- 27458413 TI - Early Literacy and Numeracy Skills in Bilingual Minority Children: Toward a Relative Independence of Linguistic and Numerical Processing. AB - Many studies have suggested that the concept of "number" is relatively independent from linguistic skills, although an increasing number of studies suggest that language abilities may play a pivotal role in the development of arithmetic skills. The condition of bilingualism can offer a unique perspective into the role of linguistic competence in numerical development. The present study was aimed at evaluating the relationship between language skills and early numeracy through a multilevel investigation in monolingual and bilingual minority children attending preschool. The sample included 156 preschool children. Of these, 77 were bilingual minority children (mean age = 58.27 +/- 5.90), and 79 were monolinguals (mean age = 58.45 +/- 6.03). The study focused on three levels of analysis: group differences in language and number skills, concurrent linguistic predictors of early numeracy and, finally, profile analysis of linguistic skills in children with impaired vs. adequate numeracy skills. The results showed that, apart from the expected differences in linguistic measures, bilinguals differed from monolinguals in numerical skills with a verbal component, such as semantic knowledge of digits, but they did not differ in a pure non-verbal component such as quantity comparison. The multigroup structural equation model indicated that letter knowledge was a significant predictor of the verbal component of numeracy for both groups. Phonological awareness was a significant predictor of numeracy skills only in the monolingual group. Profile analysis showed that children with a selective weakness in the non-verbal component of numeracy had fully adequate verbal skills. Results from the present study suggest that only some specific components of language competence predict numerical processing, although linguistic proficiency may not be a prerequisite for developing adequate early numeracy skills. PMID- 27458414 TI - U Can Touch This: How Tablets Can Be Used to Study Cognitive Development. AB - New technological devices, particularly those with touch screens, have become virtually omnipresent over the last decade. Practically from birth, children are now surrounded by smart phones and tablets. Despite being our constant companions, little is known about whether these tools can be used not only for entertainment, but also to collect reliable scientific data. Tablets may prove particularly useful for collecting behavioral data from those children (1-10 years), who are, for the most part, too old for studies based on looking times and too young for classical psychophysical testing. Here, we analyzed data from six studies that utilized touch screen tablets to deliver experimental paradigms in developmental psychology. In studies 1 and 2, we employed a simple sorting and recall task with children from the ages of 2-8. Study 3 (ages 9 and 10) extended these tasks by increasing the difficulty of the stimuli and adding a staircase based perception task. A visual search paradigm was used in study 4 (ages 2-5), while 1- to 3-year-olds were presented with an extinction learning task in study 5. In study 6, we used a simple visuo-spatial paradigm to obtain more details about the distribution of reaction times on touch screens over all ages. We collected data from adult participants in each study as well, for comparison purposes. We analyzed these data sets in regard to four metrics: self-reported tablet usage, completeness of data, accuracy of responses and response times. In sum, we found that children from the age of two onwards are very capable of interacting with tablets, are able to understand the respective tasks and are able to use tablets to register their answers accordingly. Results from all studies reiterated the advantages of data collection through tablets: ease of use, high portability, low-cost, and high levels of engagement for children. We illustrate the great potential of conducting psychological studies in young children using tablets, and also discuss both methodological challenges and their potential solutions. PMID- 27458415 TI - The Benefits of Merging Leadership Research and Emotions Research. AB - A closer merging of the literature on emotions with the research on leadership may prove advantageous to both fields. Leadership researchers will benefit by incorporating the research on emotional labor, emotional regulation, and happiness. Emotions researchers will be able to more fully consider how leadership demands influence emotional processes. In particular, researchers can better understand how the workplace context and leadership demands influence affective events. The leadership literature on charisma, transformational leadership, leader-member exchange, and other theories have the potential to shed light on how rhetorical techniques and other leadership techniques influence emotional labor, emotional contagion, moods, and overall morale. Conversely, the literature on emotional labor and emotional contagion stands to provide insights into what makes leaders charismatic, transformational, or capable of developing high quality leader-follower relationships. This review examines emotions and leadership at five levels: within person, between persons, interpersonal, groups and teams, and organizational wide and integrates research on emotions, emotional contagion, and leadership to identify opportunities for future research for both emotions researchers and leadership researchers. PMID- 27458416 TI - Pay What You Want! A Pilot Study on Neural Correlates of Voluntary Payments for Music. AB - Pay-what-you-want (PWYW) is an alternative pricing mechanism for consumer goods. It describes an exchange situation in which the price for a given good is not set by the seller but freely chosen by the buyer. In recent years, many enterprises have made use of PWYW auctions. The somewhat contra-intuitive success of PWYW has sparked a great deal of behavioral work on economical decision making in PWYW contexts in the past. Empirical studies on the neural basis of PWYW decisions, however, are scarce. In the present paper, we present an experimental protocol to study PWYW decision making while simultaneously acquiring functional magnetic resonance imaging data. Participants have the possibility to buy music either under a traditional "fixed-price" (FP) condition or in a condition that allows them to freely decide on the price. The behavioral data from our experiment replicate previous results on the general feasibility of the PWYW mechanism. On the neural level, we observe distinct differences between the two conditions: In the FP-condition, neural activity in frontal areas during decision-making correlates positively with the participants' willingness to pay. No such relationship was observed under PWYW conditions in any neural structure. Directly comparing neural activity during PWYW and the FP-condition we observed stronger activity of the lingual gyrus during PWYW decisions. Results demonstrate the usability of our experimental paradigm for future investigations into PWYW decision-making and provides first insights into neural mechanisms during self determined pricing decisions. PMID- 27458417 TI - A Rolling Stone Gathers No Moss-The Long Way from Good Intentions to Physical Activity Mediated by Planning, Social Support, and Self-Regulation. AB - BACKGROUND: Although many people know that an active lifestyle contributes to health they fail to translate their intentions into action. This has been explained by deficits in self-management and resources, such as enabling social support, planning, and self-regulation in the face of barriers. The present study examines the role of perceived social support, planning, and self-regulation in facilitating physical activity. METHODS: In a prospective online study, intention was assessed at baseline (Time 1), planning and social support at 4-week follow up (Time 2), self-regulation and physical activity at 6-month follow-up (Time 3). A path analysis was conducted to shed light on mediating psychological mechanisms contributing to maintenance of physical activity. RESULTS: Perceived support (Time 2), planning (Time 2), and self-regulation (Time 3) mediated the link from intention (Time 1) to physical activity (Time 3); the specific and total indirect effects were significant. CONCLUSIONS: Findings suggest that perceived social support, planning, and self-regulation can bridge the intention-behavior gap. Behavior change interventions should target those mechanisms in vulnerable individuals. PMID- 27458418 TI - Modeling the Overalternating Bias with an Asymmetric Entropy Measure. AB - Psychological research has found that human perception of randomness is biased. In particular, people consistently show the overalternating bias: they rate binary sequences of symbols (such as Heads and Tails in coin flipping) with an excess of alternation as more random than prescribed by the normative criteria of Shannon's entropy. Within data mining for medical applications, Marcellin proposed an asymmetric measure of entropy that can be ideal to account for such bias and to quantify subjective randomness. We fitted Marcellin's entropy and Renyi's entropy (a generalized form of uncertainty measure comprising many different kinds of entropies) to experimental data found in the literature with the Differential Evolution algorithm. We observed a better fit for Marcellin's entropy compared to Renyi's entropy. The fitted asymmetric entropy measure also showed good predictive properties when applied to different datasets of randomness-related tasks. We concluded that Marcellin's entropy can be a parsimonious and effective measure of subjective randomness that can be useful in psychological research about randomness perception. PMID- 27458419 TI - Self-Reported Responses to Player Profile Questions Show Consistency with the Use of Complex Attentional Strategies by Expert Horseshoe Pitchers. AB - The advantages on an external focus of attention have been demonstrated for a variety of sport tasks. The constrained action hypothesis (Wulf et al., 2001) argues that focusing externally on the movement effect results in the use of automated processes for movement control. In contrast, focusing internally in an attempt to control the movements of the body disrupts normally automated processes and degrades performance. Research on experts, however, suggests that they may adopt more complex attentional strategies. The present study provided a unique opportunity to examine expert horseshoe players' attentional strategies as indicated by their self-reported responses to questions included in a National Horseshoe Pitchers Association (NHPA) player profile questionnaire. Responses submitted by 83 top NHPA players were examined to determine the frequency of references to the use of internal and external focus points and identify categories related to attentional strategies. Results indicated that the large majority of players reported using focus points that are consistent with an external focus of attention and that their thoughts corresponded to one or more categories related to technique, mental focus or concentration, general success, use of external focus cues, and emotional control. The findings are consistent with the view that experts may adopt complex attentional strategies that encompass both an external focus and thoughts about a variety of other performance related factors. PMID- 27458420 TI - Affective Norms for 718 Polish Short Texts (ANPST): Dataset with Affective Ratings for Valence, Arousal, Dominance, Origin, Subjective Significance and Source Dimensions. AB - Affective sciences are of burgeoning interest and are attracting more and more research attention. Three components of stimuli meaning have traditionally been distinguished: valence (degree of pleasantness), arousal (degree of intensity of sensations), and dominance (degree of control over sensations). Recently, another three dimensions have been introduced to measure qualities connected to the emotion-duality model: origin (the main component originating in the heart or in the mind), subjective significance (the degree of the subjective goal's relevance), and source (the location of the stimuli evoking the state). All six affective dimensions were assessed in our study of 718 Polish short texts (sentences of 5-23 words and 36-133 characters in length) describing situations or states in a way that can be referenced to an individual's experience. Assessments were carried out by 148 psychology students (all women for 108 sentences) and 2,091 students of different faculties (social science, engineering, life science, and science) from Warsaw colleges and universities (1,061 women and 1,030 men for all 718 sentences). Assessing sets of sentences for emotional response is especially useful for researchers interested in emotion elicitation through the use of a phrase such as "imagine that ..." or by simply reading emotionally charged material that is more complex and that provides better context than single pictures or words. PMID- 27458421 TI - The Neurocognitive Performance of Visuospatial Attention in Children with Obesity. AB - The present study investigates the behavioral performance and event-related potentials (ERPs) in children with obesity and healthy weight children when performing a visuospatial attention task. Twenty-six children with obesity (obese group) and 26 healthy weight children (control group) were recruited. Their behavioral performance during a variant of the Posner paradigm was measured, and brain ERPs were recorded concurrently. The behavioral data revealed that the obese group responded more slowly, especially in the invalid condition, and exhibited a deficit in attentional inhibition capacity as compared to the control group. In terms of cognitive electrophysiological performance, although the obese group did not show significant differences on P3 latency elicited by the target stimuli when compared to the control group, they exhibited smaller P3 amplitudes when performing the visuospatial attention task. These results broaden previous findings, and indicate that childhood obesity is associated with a reduced ability to modulate the executive function network which supports visuospatial attention. PMID- 27458423 TI - What Do True Gender Ratios and Stereotype Norms Really Tell Us? AB - We present a Focused Review on work that was conducted to compare perceived distributions of men and women in occupations and other social roles with actual real world distributions. In previous work, we showed that means for the two sources were similar and the correlation between them was high. However, in the present paper, although we argue that comparing subjective gender stereotype norms and real world data about gender ratios is an interesting endeavor, we also discuss the limits to and difficulties in trying to determine the causal relationship between them. Most crucially, we argue that our data does not allow us to deduce with certainty that subjective gender norms are based directly on gender ratios. PMID- 27458422 TI - Semantic Neighborhood Effects for Abstract versus Concrete Words. AB - Studies show that semantic effects may be task-specific, and thus, that semantic representations are flexible and dynamic. Such findings are critical to the development of a comprehensive theory of semantic processing in visual word recognition, which should arguably account for how semantic effects may vary by task. It has been suggested that semantic effects are more directly examined using tasks that explicitly require meaning processing relative to those for which meaning processing is not necessary (e.g., lexical decision task). The purpose of the present study was to chart the processing of concrete versus abstract words in the context of a global co-occurrence variable, semantic neighborhood density (SND), by comparing word recognition response times (RTs) across four tasks varying in explicit semantic demands: standard lexical decision task (with non-pronounceable non-words), go/no-go lexical decision task (with pronounceable non-words), progressive demasking task, and sentence relatedness task. The same experimental stimulus set was used across experiments and consisted of 44 concrete and 44 abstract words, with half of these being low SND, and half being high SND. In this way, concreteness and SND were manipulated in a factorial design using a number of visual word recognition tasks. A consistent RT pattern emerged across tasks, in which SND effects were found for abstract (but not necessarily concrete) words. Ultimately, these findings highlight the importance of studying interactive effects in word recognition, and suggest that linguistic associative information is particularly important for abstract words. PMID- 27458424 TI - The Interpretation of Scholars' Interpretations of Confidence Intervals: Criticism, Replication, and Extension of Hoekstra et al. (2014). AB - Hoekstra et al. (Psychonomic Bulletin & Review, 2014, 21:1157-1164) surveyed the interpretation of confidence intervals (CIs) by first-year students, master students, and researchers with six items expressing misinterpretations of CIs. They asked respondents to answer all items, computed the number of items endorsed, and concluded that misinterpretation of CIs is robust across groups. Their design may have produced this outcome artifactually for reasons that we describe. This paper discusses first the two interpretations of CIs and, hence, why misinterpretation cannot be inferred from endorsement of some of the items. Next, a re-analysis of Hoekstra et al.'s data reveals some puzzling differences between first-year and master students that demand further investigation. For that purpose, we designed a replication study with an extended questionnaire including two additional items that express correct interpretations of CIs (to compare endorsement of correct vs. nominally incorrect interpretations) and we asked master students to indicate which items they would have omitted had they had the option (to distinguish deliberate from uninformed endorsement caused by the forced-response format). Results showed that incognizant first-year students endorsed correct and nominally incorrect items identically, revealing that the two item types are not differentially attractive superficially; in contrast, master students were distinctively more prone to endorsing correct items when their uninformed responses were removed, although they admitted to nescience more often that might have been expected. Implications for teaching practices are discussed. PMID- 27458425 TI - The Conductor As Visual Guide: Gesture and Perception of Musical Content. AB - Ensemble conductors are often described as embodying the music. Researchers have determined that expressive gestures affect viewers' perceptions of conducted ensemble performances. This effect may be due, in part, to conductor gesture delineating and amplifying specific expressive aspects of music performances. The purpose of the present study was to determine if conductor gesture affected observers' focus of attention to contrasting aspects of ensemble performances. Audio recordings of two different music excerpts featuring two-part counterpoint (an ostinato paired with a lyric melody, and long chord tones paired with rhythmic interjections) were paired with video of two conductors. Each conductor used gesture appropriate to one or the other musical element (e.g., connected and flowing or detached and crisp) for a total of sixteen videos. Musician participants evaluated 8 of the excerpts for Articulation, Rhythm, Style, and Phrasing using four 10-point differential scales anchored by descriptive terms (e.g., disconnected to connected, and angular to flowing.) Results indicated a relationship between gesture and listeners' evaluations of musical content. Listeners appear to be sensitive to the manner in which a conductor's gesture delineates musical lines, particularly as an indication of overall articulation and style. This effect was observed for the lyric melody and ostinato excerpt, but not for the chords and interjections excerpt. Therefore, this effect appears to be mitigated by the congruence of gesture to preconceptions of the importance of melodic over rhythmic material, of certain instrument timbres over others, and of length between onsets of active material. These results add to a body of literature that supports the importance of the visual component in the multimodal experience of music performance. PMID- 27458426 TI - Longitudinal Brain Magnetic Resonance Imaging CO2 Stress Testing in Individual Adolescent Sports-Related Concussion Patients: A Pilot Study. AB - BACKGROUND: Advanced neuroimaging studies in concussion have been limited to detecting group differences between concussion patients and healthy controls. In this small pilot study, we used brain magnetic resonance imaging (MRI) CO2 stress testing to longitudinally assess cerebrovascular responsiveness (CVR) in individual sports-related concussion (SRC) patients. METHODS: Six SRC patients (three males and three females; mean age = 15.7, range = 15-17 years) underwent longitudinal brain MRI CO2 stress testing using blood oxygen level-dependent (BOLD) MRI and model-based prospective end-tidal CO2 targeting under isoxic conditions. First-level and second-level comparisons were undertaken using statistical parametric mapping (SPM) to score the scans and compare them to an atlas of 24 healthy control subjects. RESULTS: All tests were well tolerated and without any serious adverse events. Anatomical MRI was normal in all study participants. The CO2 stimulus was consistent between the SRC patients and control subjects and within SRC patients across the longitudinal study. Individual SRC patients demonstrated both quantitative and qualitative patient specific alterations in CVR (p < 0.005) that correlated strongly with clinical findings, and that persisted beyond clinical recovery. CONCLUSION: Standardized brain MRI CO2 stress testing is capable of providing a longitudinal assessment of CVR in individual SRC patients. Consequently, larger prospective studies are needed to examine the utility of brain MRI CO2 stress testing as a clinical tool to help guide the evaluation, classification, and longitudinal management of SRC patients. PMID- 27458427 TI - New 3D-Culture Approaches to Study Interactions of Bone Marrow Adipocytes with Metastatic Prostate Cancer Cells. AB - Adipocytes are a major component of the bone marrow that can critically affect metastatic progression in bone. Understanding how the marrow fat cells influence growth, behavior, and survival of tumor cells requires utilization of in vitro cell systems that can closely mimic the physiological microenvironment. Herein, we present two new three-dimensional (3D) culture approaches to study adipocyte tumor cell interactions in vitro. The first is a transwell-based system composed of the marrow-derived adipocytes in 3D collagen I gels and reconstituted basement membrane-overlayed prostate tumor cell spheroids. Tumor cells cultured under these 3D conditions are continuously exposed to adipocyte-derived factors, and their response can be evaluated by morphological and immunohistochemical analyses. We show via immunofluorescence analysis of metabolism-associated proteins that under 3D conditions tumor cells have significantly different metabolic response to adipocytes than tumor cells grown in 2D culture. We also demonstrate that this model allows for incorporation of other cell types, such as bone marrow macrophages, and utilization of dye-quenched collagen substrates for examination of proteolysis-driven responses to adipocyte- and macrophage-derived factors. Our second 3D culture system is designed to study tumor cell invasion toward the adipocytes and the consequent interaction between the two cell types. In this model, marrow adipocytes are separated from the fluorescently labeled tumor cells by a layer of collagen I. At designated time points, adipocytes are stained with BODIPY and confocal z-stacks are taken through the depth of the entire culture to determine the distance traveled between the two cell types over time. We demonstrate that this system can be utilized to study effects of candidate factors on tumor invasion toward the adipocytes. We also show that immunohistochemical analyses can be performed to evaluate the impact of direct interaction of prostate tumor cells with adipocytes. Our models underline the importance of using the appropriate culture conditions to mimic physiological interactions between marrow adipocytes and metastatic tumor cells. These systems have a potential to be utilized for analyses of various factors that may be regulated by the adipocytes in bone. Their application likely extends beyond metastatic prostate cancer to other tumors that colonize the bone marrow microenvironment. PMID- 27458428 TI - Depletion of Myostatin b Promotes Somatic Growth and Lipid Metabolism in Zebrafish. AB - Myostatin (MSTN) is a negative regulator of myogenesis in vertebrates. Depletion of mstn resulted in elevated muscle growth in several animal species. However, the report on the complete ablation of mstn in teleost fish has not yet become available. In this study, two independent mstnb-deficient mutant lines in zebrafish were generated with the TALENs technique. In the mstnb-deficient zebrafish, enhanced muscle growth with muscle fiber hyperplasia was achieved. Beginning at the adult stage (80 days postfertilization), the mstnb-deficient zebrafish exhibited increased circumferences and body weights compared with the wild-type sibling control fish. Although the overall total lipid/body weight ratios remained similar between the mstnb-deficient zebrafish and the control fish, the distribution of lipids was altered. The size of the visceral adipose tissues became smaller while more lipids accumulated in skeletal muscle in the mstnb-deficient zebrafish than in the wild-type control fish. Based on the transcriptional expression profiles, our results revealed that lipid metabolism, including lipolysis and lipogenesis processes, was highly activated in the mstnb deficient zebrafish, which indicated the transition of energy metabolism from protein-dependent to lipid-dependent in mstnb-deficient zebrafish. Our mstnb deficient model could be valuable in understanding not only the growth trait regulation in teleosts but also the mechanisms of teleost energy metabolism. PMID- 27458429 TI - Sensing of Porcine Reproductive and Respiratory Syndrome Virus-Infected Macrophages by Plasmacytoid Dendritic Cells. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) represents a macrophage (MO)-tropic virus which is unable to induce interferon (IFN) type I in its target cells. Nevertheless, infected pigs show a short but prominent systemic IFN alpha (IFN-alpha) response. A possible explanation for this discrepancy is the ability of plasmacytoid dendritic cells (pDC) to produce IFN-alpha in response to free PRRSV virions, independent of infection. Here, we show that the highly pathogenic PRRSV genotype 1 strain Lena is unique in not inducing IFN alpha production in pDC, contrasting with systemic IFN-alpha responses found in infected pigs. We also demonstrate efficient pDC stimulation by PRRSV Lena infected MO, resulting in a higher IFN-alpha production than direct stimulation of pDC by PRRSV virions. This response was strain-independent, required integrin mediated intercellular contact, intact actin filaments in the MO and was partially inhibited by an inhibitor of neutral sphingomyelinase. Although infected MO-derived exosomes stimulated pDC, an efficient delivery of the stimulatory component was dependent on a tight contact between pDC and the infected cells. In conclusion, with this mechanism the immune system can efficiently sense PRRSV, resulting in production of considerable quantities of IFN-alpha. This is adding complexity to the immunopathogenesis of PRRSV infections, as IFN-alpha should alert the immune system and initiate the induction of adaptive immune responses, a process known to be inefficient during infection of pigs. PMID- 27458430 TI - Produce from Africa's Gardens: Potential for Leafy Vegetable and Fruit Fermentations. AB - A rich variety of indigenous fruits and vegetables grow in Africa, which contribute to the nutrition and health of Africa's populations. Fruits and vegetables have high moisture and are thus inherently prone to accelerated spoilage. Food fermentation still plays a major role in combating food spoilage and foodborne diseases that are prevalent in many of Africa's resource disadvantaged regions. Lactic acid fermentation is probably the oldest and best accepted food processing method among the African people, and is largely a home based process. Fermentation of leafy vegetables and fruits is, however, underutilized in Africa, although such fermented products could contribute toward improving nutrition and food security in this continent, where many are still malnourished and suffer from hidden hunger. Fermentation of leafy vegetables and fruits may not only improve safety and prolong shelf life, but may also enhance the availability of some trace minerals, vitamins and anti-oxidants. Cassava, cow peas, amaranth, African nightshade, and spider plant leaves have a potential for fermentation, as do various fruits for the production of vinegars or fruit beers and wines. What is needed to accelerate efforts for production of fermented leaves and vegetables is the development of fermentation protocols, training of personnel and scale-up of production methods. Furthermore, suitable starter cultures need to be developed and produced to guarantee the success of the fermentations. PMID- 27458431 TI - Paracoccin Induces M1 Polarization of Macrophages via Interaction with TLR4. AB - The fungal human pathogen Paracoccidioides brasiliensis contains paracoccin (PCN), a multi-domain protein that has lectin and N-acetyl-glucosaminidase activities, which account for its effects on the growth and morphogenesis of the fungus and on the activation of host macrophages through its interaction with TLR N-glycans. With the purpose of detailing the knowledge on the effects of PCN on macrophages, we used recombinant PCN expressed in Pichia pastoris (p-rPCN) to stimulate isolated murine peritoneal macrophages. The activation of these cells manifested through the release of high levels of inflammatory mediators, such as nitric oxide, TNF-alpha, IL-12p40, and IL-6. Furthermore, peritoneal macrophages stimulated with p-rPCN increased the relative expression of STAT1, SOCS3, and iNOS2 mRNA (M1 polarization markers). However, the expression of Arginase-1, Ym 1, and FIZZ1 (M2 polarization markers) remained at basal levels. Interestingly, the observed M1 macrophages' polarization triggered by p-rPCN was abolished in cells obtained from knockout Toll-like receptor-4 mice. In this case, the p-rPCN induced production of pro-inflammatory mediators was blocked too. These results demonstrate that the classical activation of macrophages induced by paracoccin depends on TLR4. Taken together, the results of our study indicate that paracoccin acts as a TLR agonist able to modulate immunity and exerts biological activities that favor its applicability as an immunotherapeutic agent to combat systemic fungal infections. PMID- 27458432 TI - Overcoming the Barrier of Low Efficiency during Genetic Transformation of Streptococcus mitis. AB - OBJECTIVE: Streptococcus mitis is a predominant oral colonizer, but difficulties in genetic manipulation of this species have hampered our understanding of the mechanisms it uses for colonization of oral surfaces. The aim of this study was to reveal optimal conditions for natural genetic transformation in S. mitis and illustrate its application in direct genome editing. METHODS: Luciferase reporter assays were used to assess gene expression of the alternative sigma factor (sigma(X)) in combination with natural transformation experiments to evaluate the efficiency by which S. mitis activates the competence system and incorporates exogenous DNA. Optimal amounts and sources of donor DNA (chromosomal, amplicon, or replicative plasmid), concentrations of synthetic competence-stimulating peptide, and transformation media were assessed. RESULTS: A semi-defined medium showed much improved results for response to the competence stimulating peptide when compared to rich media. The use of a donor amplicon with large homology flanking regions also provided higher transformation rates. Overall, an increase of transformation efficiencies from 0.001% or less to over 30% was achieved with the developed protocol. We further describe the construction of a markerless mutant based on this high efficiency strategy. CONCLUSION: We optimized competence development in S. mitis, by use of semi-defined medium and appropriate concentrations of synthetic competence factor. Combined with the use of a large amplicon of donor DNA, this method allowed easy and direct editing of the S. mitis genome, broadening the spectrum of possible downstream applications of natural transformation in this species. PMID- 27458433 TI - Exploitation of Endophytic Bacteria to Enhance the Phytoremediation Potential of the Wetland Helophyte Juncus acutus. AB - This study investigated the potential of indigenous endophytic bacteria to improve the efficiency of the wetland helophyte Juncus acutus to deal with a mixed pollution consisting of emerging organic contaminants (EOCs) and metals. The beneficial effect of bioaugmentation with selected endophytic bacteria was more prominent in case of high contamination: most of the inoculated plants (especially those inoculated with the mixed culture) removed higher percentages of organics and metals from the liquid phase in shorter times compared to the non inoculated plants without exhibiting significant oxidative stress. When exposed to the lower concentrations, the tailored mixed culture enhanced the performance of the plants to decrease the organics and metals from the water. The composition of the root endophytic community changed in response to increased levels of contaminants while the inoculated bacteria did not modify the community structure. Our results indicate that the synergistic relationships between endophytes and the macrophyte enhance plants' performance and may be exploited in constructed wetlands treating water with mixed contaminations. Taking into account that the concentrations of EOCs used in this study are much higher than the average contents of typical wastewaters, we can conclude that the macrophyte J. acutus with the aid of a mixed culture of tailored endophytic bacteria represents a suitable environmentally friendly alternative for treating pharmaceuticals and metals. PMID- 27458435 TI - Surveillance of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli in Dairy Cattle Farms in the Nile Delta, Egypt. AB - INTRODUCTION: Industrial livestock farming is a possible source of multi resistant Gram-negative bacteria, including producers of extended spectrum beta lactamases (ESBLs) conferring resistance to 3rd generation cephalosporins. Limited information is currently available on the situation of ESBL producers in livestock farming outside of Western Europe. A surveillance study was conducted from January to May in 2014 in four dairy cattle farms in different areas of the Nile delta, Egypt. MATERIALS AND METHODS: In total, 266 samples were collected from 4 dairy farms including rectal swabs from clinically healthy cattle (n = 210), and environmental samples from the stalls (n = 56). After 24 h pre enrichment in buffered peptone water, all samples were screened for 3rd generation cephalosporin-resistant Escherichia coli using BrillianceTM ESBL agar. Suspected colonies of putatively ESBL-producing E. coli were sub-cultured and subsequently genotypically and phenotypically characterized. Susceptibility testing using the VITEK-2 system was performed. All suspect isolates were genotypically analyzed using two DNA-microarray based assays: CarbDetect AS-1 and E. coli PanType AS-2 kit (ALERE). These tests allow detection of a multitude of genes and their alleles associated with resistance toward carbapenems, cephalosporins, and other frequently used antibiotics. Serotypes were determined using the E. coli SeroGenotyping AS-1 kit (ALERE). RESULTS: Out of 266 samples tested, 114 (42.8%) ESBL-producing E. coli were geno- and phenotypically identified. 113 of 114 phenotypically 3rd generation cephalosporin-resistant isolates harbored at least one of the ESBL resistance genes covered by the applied assays [blaCTX-M15 (n = 105), blaCTX-M9 (n = 1), blaTEM (n = 90), blaSHV (n = 1)]. Alarmingly, the carbapenemase genes blaOXA-48 (n = 5) and blaOXA-181 (n = 1) were found in isolates that also were phenotypically resistant to imipenem and meropenem. Using the array-based serogenotyping method, 66 of the 118 isolates (55%) could be genotypically assigned to O-types. CONCLUSION: This study is considered to be a first report of the high prevalence of ESBL-producing E. coli in dairy farms in Egypt. ESBL-producing E. coli isolates with different underlying resistance mechanisms are common in investigated dairy cattle farms in Egypt. The global rise of ESBL- and carbapenemase-producing Gram-negative bacteria is a big concern, and demands intensified surveillance. PMID- 27458434 TI - Dissimilar Fitness Associated with Resistance to Fluoroquinolones Influences Clonal Dynamics of Various Multiresistant Bacteria. AB - Fitness cost associated with resistance to fluoroquinolones was recently shown to vary across clones of methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Klebsiella pneumoniae. The resulting dissimilar fitness should have influenced the clonal dynamics and thereby the rates of resistance for these pathogens. Moreover, a similar mechanism was recently proposed for the emergence of the H30 and H30R lineages of ESBL-producing E. coli and the major international clone (ribotype 027) of Clostridium difficile. Furthermore, several additional international clones of various multiresistant bacteria are suspect to have been selected by an analogous process. An ability to develop favorable mutations in the gyrase and topoisomerase IV genes seems to be a prerequisite for pathogens to retain fitness while showing high-level resistance to fluoroquinolones. Since, the consumption of other "non fluoroquinolone" groups of antibiotics have also contributed to the rise in resistance rates a more judicious use of antibiotics in general and of fluoroquinolones in particular could ameliorate the international resistance situation. PMID- 27458436 TI - "Candidatus Propionivibrio aalborgensis": A Novel Glycogen Accumulating Organism Abundant in Full-Scale Enhanced Biological Phosphorus Removal Plants. AB - Enhanced biological phosphorus removal (EBPR) is widely used to remove phosphorus from wastewater. The process relies on polyphosphate accumulating organisms (PAOs) that are able to take up phosphorus in excess of what is needed for growth, whereby phosphorus can be removed from the wastewater by wasting the biomass. However, glycogen accumulating organisms (GAOs) may reduce the EBPR efficiency as they compete for substrates with PAOs, but do not store excessive amounts of polyphosphate. PAOs and GAOs are thought to be phylogenetically unrelated, with the model PAO being the betaproteobacterial "Candidatus Accumulibacter phosphatis" (Accumulibacter) and the model GAO being the gammaproteobacterial "Candidatus Competibacter phosphatis". Here, we report the discovery of a GAO from the genus Propionivibrio, which is closely related to Accumulibacter. Propionivibrio sp. are targeted by the canonical fluorescence in situ hybridization probes used to target Accumulibacter (PAOmix), but do not store excessive amounts of polyphosphate in situ. A laboratory scale reactor, operated to enrich for PAOs, surprisingly contained co-dominant populations of Propionivibrio and Accumulibacter. Metagenomic sequencing of multiple time-points enabled recovery of near complete population genomes from both genera. Annotation of the Propionivibrio genome confirmed their potential for the GAO phenotype and a basic metabolic model is proposed for their metabolism in the EBPR environment. Using newly designed fluorescence in situ hybridization (FISH) probes, analyses of full-scale EBPR plants revealed that Propionivibrio is a common member of the community, constituting up to 3% of the biovolume. To avoid overestimation of Accumulibacter abundance in situ, we recommend the use of the FISH probe PAO651 instead of the commonly applied PAOmix probe set. PMID- 27458438 TI - Unanticipated Geochemical and Microbial Community Structure under Seasonal Ice Cover in a Dilute, Dimictic Arctic Lake. AB - Despite most lakes in the Arctic being perennially or seasonally frozen for at least 40% of the year, little is known about microbial communities and nutrient cycling under ice cover. We assessed the vertical microbial community distribution and geochemical composition in early spring under ice in a seasonally ice-covered lake in southwest Greenland using amplicon-based sequencing that targeted 16S rRNA genes and using a combination of field and laboratory aqueous geochemical methods. Microbial communities changed consistently with changes in geochemistry. Composition of the abundant members responded strongly to redox conditions, shifting downward from a predominantly heterotrophic aerobic community in the suboxic waters to a heterotrophic anaerobic community in the anoxic waters. Operational taxonomic units (OTUs) of Sporichthyaceae, Comamonadaceae, and the SAR11 Clade had higher relative abundances above the oxycline and OTUs within the genus Methylobacter, the phylum Lentisphaerae, and purple sulfur bacteria (PSB) below the oxycline. Notably, a 13 fold increase in sulfide at the oxycline was reflected in an increase and change in community composition of potential sulfur oxidizers. Purple non-sulfur bacteria were present above the oxycline and green sulfur bacteria and PSB coexisted below the oxycline, however, PSB were most abundant. For the first time we show the importance of PSB as potential sulfur oxidizers in an Arctic dimictic lake. PMID- 27458437 TI - Extracellular Vesicle-Associated Transitory Cell Wall Components and Their Impact on the Interaction of Fungi with Host Cells. AB - Classic cell wall components of fungi comprise the polysaccharides glucans and chitin, in association with glycoproteins and pigments. During the last decade, however, system biology approaches clearly demonstrated that the composition of fungal cell walls include atypical molecules historically associated with intracellular or membrane locations. Elucidation of mechanisms by which many fungal molecules are exported to the extracellular space suggested that these atypical components are transitorily located to the cell wall. The presence of extracellular vesicles (EVs) at the fungal cell wall and in culture supernatants of distinct pathogenic species suggested a highly functional mechanism of molecular export in these organisms. Thus, the passage of EVs through fungal cell walls suggests remarkable molecular diversity and, consequently, a potentially variable influence on the host antifungal response. On the basis of information derived from the proteomic characterization of fungal EVs from the yeasts Cryptoccocus neoformans and Candida albicans and the dimorphic fungi Histoplasma capsulatum and Paracoccidioides brasiliensis, our manuscript is focused on the clear view that the fungal cell wall is much more complex than previously thought. PMID- 27458439 TI - Industrial Acetogenic Biocatalysts: A Comparative Metabolic and Genomic Analysis. AB - Synthesis gas (syngas) fermentation by anaerobic acetogenic bacteria employing the Wood-Ljungdahl pathway is a bioprocess for production of biofuels and biocommodities. The major fermentation products of the most relevant biocatalytic strains (Clostridium ljungdahlii, C. autoethanogenum, C. ragsdalei, and C. coskatii) are acetic acid and ethanol. A comparative metabolic and genomic analysis using the mentioned biocatalysts might offer targets for metabolic engineering and thus improve the production of compounds apart from ethanol. Autotrophic growth and product formation of the four wild type (WT) strains were compared in uncontrolled batch experiments. The genomes of C. ragsdalei and C. coskatii were sequenced and the genome sequences of all four biocatalytic strains analyzed in comparative manner. Growth and product spectra (acetate, ethanol, 2,3 butanediol) of C. autoethanogenum, C. ljungdahlii, and C. ragsdalei were rather similar. In contrast, C. coskatii produced significantly less ethanol and its genome sequence lacks two genes encoding aldehyde:ferredoxin oxidoreductases (AOR). Comparative genome sequence analysis of the four WT strains revealed high average nucleotide identity (ANI) of C. ljungdahlii and C. autoethanogenum (99.3%) and C. coskatii (98.3%). In contrast, C. ljungdahlii WT and C. ragsdalei WT showed an ANI-based similarity of only 95.8%. Additionally, recombinant C. ljungdahlii strains were constructed that harbor an artificial acetone synthesis operon (ASO) consisting of the following genes: adc, ctfA, ctfB, and thlA (encoding acetoacetate decarboxylase, acetoacetyl-CoA:acetate/butyrate:CoA transferase subunits A and B, and thiolase) under the control of thlA promoter (P thlA ) from C. acetobutylicum or native pta-ack promoter (P pta-ack ) from C. ljungdahlii. Respective recombinant strains produced 2-propanol rather than acetone, due to the presence of a NADPH-dependent primary-secondary alcohol dehydrogenase that converts acetone to 2-propanol. Furthermore, the ClosTron(TM) system was used to construct an adhE1 integration mutant. These results provide extensive insights into genetic features of industrially relevant bacterial biocatalysts and expand the toolbox for metabolic engineering of acetogenic bacteria able to ferment syngas. PMID- 27458441 TI - Editorial: Anthropogenic Impacts on the Microbial Ecology and Function of Aquatic Environments. PMID- 27458440 TI - Diversity and Expression of Bacterial Metacaspases in an Aquatic Ecosystem. AB - Metacaspases are distant homologs of metazoan caspase proteases, implicated in stress response, and programmed cell death (PCD) in bacteria and phytoplankton. While the few previous studies on metacaspases have relied on cultured organisms and sequenced genomes, no studies have focused on metacaspases in a natural setting. We here present data from the first microbial community-wide metacaspase survey; performed by querying metagenomic and metatranscriptomic datasets from the brackish Baltic Sea, a water body characterized by pronounced environmental gradients and periods of massive cyanobacterial blooms. Metacaspase genes were restricted to ~4% of the bacteria, taxonomically affiliated mainly to Bacteroidetes, Alpha- and Betaproteobacteria and Cyanobacteria. The gene abundance was significantly higher in larger or particle-associated bacteria (>0.8 MUm), and filamentous Cyanobacteria dominated metacaspase gene expression throughout the bloom season. Distinct seasonal expression patterns were detected for the three metacaspase genes in Nodularia spumigena, one of the main bloom formers. Clustering of normalized gene expression in combination with analyses of genomic and assembly data suggest functional diversification of these genes, and possible roles of the metacaspase genes related to stress responses, i.e., sulfur metabolism in connection to oxidative stress, and nutrient stress induced cellular differentiation. Co-expression of genes encoding metacaspases and nodularin toxin synthesis enzymes was also observed in Nodularia spumigena. The study shows that metacaspases represent an adaptation of potentially high importance for several key organisms in the Baltic Sea, most prominently Cyanobacteria, and open up for further exploration of their physiological roles in microbes and assessment of their ecological impact in aquatic habitats. PMID- 27458442 TI - Mississippi River Plume Enriches Microbial Diversity in the Northern Gulf of Mexico. AB - The Mississippi River (MR) serves as the primary source of freshwater and nutrients to the northern Gulf of Mexico (nGOM). Whether this input of freshwater also enriches microbial diversity as the MR plume migrates and mixes with the nGOM serves as the central question addressed herein. Specifically, in this study physicochemical properties and planktonic microbial community composition and diversity was determined using iTag sequencing of 16S rRNA genes in 23 samples collected along a salinity (and nutrient) gradient from the mouth of the MR, in the MR plume, in the canyon, at the Deepwater Horizon wellhead and out to the loop current. Analysis of these datasets revealed that the MR influenced microbial diversity as far offshore as the Deepwater Horizon wellhead. The MR had the highest microbial diversity, which decreased with increasing salinity. MR bacterioplankton communities were distinct compared to the nGOM, particularly in the surface where Actinobacteria and Proteobacteria dominated, while the deeper MR was also enriched in Thaumarchaeota. Statistical analyses revealed that nutrients input by the MR, along with salinity and depth, were the primary drivers in structuring the microbial communities. These results suggested that the reduced salinity, nutrient enriched MR plume could act as a seed bank for microbial diversity as it mixes with the nGOM. Whether introduced microorganisms are active at higher salinities than freshwater would determine if this seed bank for microbial diversity is ecologically significant. Alternatively, microorganisms that are physiologically restricted to freshwater habitats that are entrained in the plume could be used as tracers for freshwater input to the marine environment. PMID- 27458443 TI - Proteomic Analysis of the Hydrogen and Carbon Monoxide Metabolism of Methanothermobacter marburgensis. AB - Hydrogenotrophic methanogenic archaea are efficient H2 utilizers, but only a few are known to be able to utilize CO. Methanothermobacter thermoautotrophicus is one of the hydrogenotrophic methanogens able to grow on CO, albeit about 100 times slower than on H2 + CO2. In this study, we show that the hydrogenotrophic methanogen Methanothermobacter marburgensis, is able to perform methanogenic growth on H2/CO2/CO and on CO as a sole substrate. To gain further insight in its carboxydotrophic metabolism, the proteome of M. marburgensis, grown on H2/CO2 and H2/CO2/CO, was analyzed. Cultures grown with H2/CO2/CO showed relative higher abundance of enzymes involved in the reductive acetyl-CoA pathway and proteins involved in redox metabolism. The data suggest that the strong reducing capacity of CO negatively affects hydrogenotrophic methanogenesis, making growth on CO as a sole substrate difficult for this type of methanogens. M. marburgensis appears to partly deal with this by up-regulating co-factor regenerating reactions and activating additional pathways allowing for formation of other products, like acetate. PMID- 27458444 TI - GABA Production in Lactococcus lactis Is Enhanced by Arginine and Co-addition of Malate. AB - Lactococcus lactis NCDO 2118 was previously selected for its ability to decarboxylate glutamate to gamma-aminobutyric acid (GABA), an interesting nutritional supplement able to improve mood and relaxation. Amino acid decarboxylation is generally considered as among the biochemical systems allowing lactic acid bacteria to counteracting acidic stress and obtaining metabolic energy. These strategies also include arginine deiminase pathway and malolactic fermentation but little is known about their possible interactions of with GABA production. In the present study, the effects of glutamate, arginine, and malate (i.e., the substrates of these acid-resistance pathways) on L. lactis NCDO 2118 growth and GABA production performances were analyzed. Both malate and arginine supplementation resulted in an efficient reduction of acidity and improvement of bacterial biomass compared to glutamate supplementation. Glutamate decarboxylation was limited to narrow environmental conditions (pH < 5.1) and physiological state (stationary phase). However, some conditions were able to improve GABA production or activate glutamate decarboxylation system even outside of this compass. Arginine clearly stimulated glutamate decarboxylation: the highest GABA production (8.6 mM) was observed in cultures supplemented with both arginine and glutamate. The simultaneous addition of arginine, malate, and glutamate enabled earlier GABA production (i.e., during exponential growth) at relatively high pH (6.5). As far as we know, no previous study has reported GABA production in such conditions. Although further studies are needed to understand the molecular basis of these phenomena, these results represent important keys suitable of application in GABA production processes. PMID- 27458445 TI - Marine Biotoxins: Occurrence, Toxicity, Regulatory Limits and Reference Methods. AB - Harmful algal blooms are natural phenomena caused by the massive growth of phytoplankton that may contain highly toxic chemicals, the so-called marine biotoxins causing illness and even death to both aquatic organisms and humans. Their occurrence has been increased in frequency and severity, suggesting a worldwide public health risk. Marine biotoxins can accumulate in bivalve molluscs and regulatory limits have been set for some classes according to European Union legislation. These compounds can be distinguished in water- and fat-soluble molecules. The first group involves those of Paralytic Shellfish Poisoning and Amnesic Shellfish Poisoning, whereas the toxins soluble in fat can cause Diarrheic Shellfish Poisoning and Neurotoxic Shellfish Poisoning. Due to the lack of long-term toxicity studies, establishing tolerable daily intakes for any of these marine biotoxins was not possible, but an acute reference dose can be considered more appropriate, because these molecules show an acute toxicity. Dietary exposure assessment is linked both to the levels of marine biotoxins present in bivalve molluscs and the portion that could be eaten by consumers. Symptoms may vary from a severe gastrointestinal intoxication with diarrhea, nausea, vomiting, and abdominal cramps to neurological disorders such as ataxia, dizziness, partial paralysis, and respiratory distress. The official method for the detection of marine biotoxins is the mouse bioassay (MBA) showing some limits due to ethical restrictions and insufficient specificity. For this reason, the liquid chromatography-mass spectrometry method has replaced MBA as the reference technique. However, the monitoring of algal blooms producing marine biotoxins should be regularly assessed in order to obtain more reliable, accurate estimates of bloom toxicity and their potential impacts. PMID- 27458446 TI - A Central Role for STAT3 in Gammaherpesvirus-Life Cycle and -Diseases. AB - Having co-evolved with humans, herpesviruses have adapted to exploit the host molecular machinery to ensure viral persistence. The cellular protein Signal Transducer and Activator of Transcription 3 (STAT3) is a leading example. STAT3 is a prominent transcription factor that functions in a variety of physiologic processes including embryonic development, inflammation, immunity, and wound healing. Generally activated via growth factor and cytokine signaling, STAT3 can transcriptionally drive oncoproteins, pro-survival and pro-proliferative proteins as well as angiogenic factors, thereby contributing to cancer. As in most non viral cancers, STAT3 is constitutively active in EBV-related B and epithelial cell cancers and in animal models of KSHV-cancers. Again, similar to non-viral cancers, STAT3 contributes to gammaherpesvirus (EBV and KSHV)-mediated cancers by driving cell proliferation, invasion and angiogenesis. Being herpesviruses, EBV and KSHV establish latency in humans with episodic lytic activation. Importantly, both viruses activate STAT3 almost immediately upon infection of primary cells. In the setting of infection of primary B cells by EBV, this rapidly activated STAT3 plays a key role in suppressing the DNA damage response (DDR) to EBV oncogene triggered replication stress, thereby facilitating B cell proliferation and ultimately establishment of latency. STAT3 also contributes to maintenance of latency by curbing lytic activation of EBV and KSHV in latent cells that express high levels of STAT3. In this way, gammaherpesviruses exploit STAT3 to overcome cellular anti-proliferative and anti-lytic barriers to promote viral persistence. These investigations into gammaherpesviruses and STAT3 have simultaneously revealed a novel function for STAT3 in suppression of the DDR, a process fundamental to physiologic cell proliferation as well as development of cancer. PMID- 27458447 TI - A Recombinant Trivalent Fusion Protein F1-LcrV-HSP70(II) Augments Humoral and Cellular Immune Responses and Imparts Full Protection against Yersinia pestis. AB - Plague is one of the most dangerous infections in humans caused by Yersinia pestis, a Gram-negative bacterium. Despite of an overwhelming research success, no ideal vaccine against plague is available yet. It is well established that F1/LcrV based vaccine requires a strong cellular immune response for complete protection against plague. In our earlier study, we demonstrated that HSP70(II) of Mycobacterium tuberculosis modulates the humoral and cellular immunity of F1/LcrV vaccine candidates individually as well as in combinations in a mouse model. Here, we made two recombinant constructs caf1-lcrV and caf1-lcrV hsp70(II). The caf1 and lcrV genes of Y. pestis and hsp70 domain II of M. tuberculosis were amplified by polymerase chain reaction. Both the recombinant constructs caf1-lcrV and caf1-lcrV-hsp70(II) were cloned in pET28a vector and expressed in Escherichia coli. The recombinant fusion proteins F1-LcrV and F1 LcrV-HSP70(II) were purified using Ni-NTA columns and formulated with alum to evaluate the humoral and cell mediated immune responses in mice. The protective efficacies of F1-LcrV and F1-LcrV-HSP70(II) were determined following challenge of immunized mice with 100 LD50 of Y. pestis through intraperitoneal route. Significant differences were noticed in the titers of IgG and it's isotypes, i.e., IgG1, IgG2b, and IgG3 in anti- F1-LcrV-HSP70(II) sera in comparison to anti F1-LcrV sera. Similarly, significant differences were also noticed in the expression levels of IL-2, IFN-gamma and TNF-alpha in splenocytes of F1-LcrV HSP(II) immunized mice in comparison to F1-LcrV. Both F1-LcrV and F1-LcrV HSP70(II) provided 100% protection. Our research findings suggest that F1-LcrV fused with HSP70 domain II of M. tuberculosis significantly enhanced the humoral and cellular immune responses in mouse model. PMID- 27458449 TI - The Small Colony Variant of Listeria monocytogenes Is More Tolerant to Antibiotics and Has Altered Survival in RAW 264.7 Murine Macrophages. AB - Small Colony Variant (SCV) cells of bacteria are a slow-growing phenotype that result from specific defects in the electron transport chain. They form pinpoint colonies on agar plates and have a variety of phenotypic characteristics, such as altered carbon metabolism, decreased toxin and lytic enzyme production, aminoglycoside resistance, and increased intracellular persistence. They are clinically relevant in Staphylococcus aureus and Pseudomonas aeruginosa, serving as a reservoir for recurrent or prolonged infections. Here, we found that a SCV mutant in the foodborne pathogen Listeria monocytogenes (strain SCV E18), similar to the high persister mutant phenotype, survived significantly better than the wild type when exposed over a 48-h period to concentrations above Minimal Inhibitory Concentration for most tested antibiotics. SCV E18 survived more poorly than the wildtype in unactivated RAW264.7 macrophage cells, presumably because of its reduced listeriolysin O expression, however, it survived better in reactive oxygen species producing, phorbol 12-myristate 13-acetate-activated macrophages. Although SCV E18 was sensitive to oxygen as it entered the stationary phase, it was significantly more tolerant to H2O2 than the wild type, which may result from a shift in metabolism, however, further investigation is needed to resolve this. SCV E18 is a spontaneous mutant with a point mutation in the hemA gene. A wild type copy of hemA was complemented on plasmid pSOG30222, which restored the wild type phenotype. The results reported here suggest that the SCV of L. monocytogenes could be of clinical importance and highlight a need for adequate clinical screening for this phenotype, as it could affect antibiotic treatment outcomes. PMID- 27458448 TI - Bacillus cereus Biofilms-Same, Only Different. AB - Bacillus cereus displays a high diversity of lifestyles and ecological niches and include beneficial as well as pathogenic strains. These strains are widespread in the environment, are found on inert as well as on living surfaces and contaminate persistently the production lines of the food industry. Biofilms are suspected to play a key role in this ubiquitous distribution and in this persistency. Indeed, B. cereus produces a variety of biofilms which differ in their architecture and mechanism of formation, possibly reflecting an adaptation to various environments. Depending on the strain, B. cereus has the ability to grow as immersed or floating biofilms, and to secrete within the biofilm a vast array of metabolites, surfactants, bacteriocins, enzymes, and toxins, all compounds susceptible to act on the biofilm itself and/or on its environment. Within the biofilm, B. cereus exists in different physiological states and is able to generate highly resistant and adhesive spores, which themselves will increase the resistance of the bacterium to antimicrobials or to cleaning procedures. Current researches show that, despite similarities with the regulation processes and effector molecules involved in the initiation and maturation of the extensively studied Bacillus subtilis biofilm, important differences exists between the two species. The present review summarizes the up to date knowledge on biofilms produced by B. cereus and by two closely related pathogens, Bacillus thuringiensis and Bacillus anthracis. Economic issues caused by B. cereus biofilms and management strategies implemented to control these biofilms are included in this review, which also discuss the ecological and functional roles of biofilms in the lifecycle of these bacterial species and explore future developments in this important research area. PMID- 27458450 TI - Prioritized Expression of BDH2 under Bulk Translational Repression and Its Contribution to Tolerance to Severe Vanillin Stress in Saccharomyces cerevisiae. AB - Vanillin is a potent fermentation inhibitor derived from the lignocellulosic biomass in biofuel production, and high concentrations of vanillin result in the pronounced repression of bulk translation in Saccharomyces cerevisiae. Studies on genes that are efficiently translated even in the presence of high concentrations of vanillin will be useful for improving yeast vanillin tolerance and fermentation efficiency. The BDH1 and BDH2 genes encode putative medium-chain alcohol dehydrogenase/reductases and their amino acid sequences are very similar to each other. Although BDH2 was previously suggested to be involved in vanillin tolerance, it has yet to be clarified whether Bdh1/Bdh2 actually contribute to vanillin tolerance and reductions in vanillin. Therefore, we herein investigated the effects of Bdh1 and Bdh2 on vanillin tolerance. bdh2Delta cells exhibited hypersensitivity to vanillin and slower reductions in vanillin than wild-type cells and bdh1Delta cells. Additionally, the overexpression of the BDH2 gene improved yeast tolerance to vanillin more efficiently than that of BDH1. Only BDH2 mRNA was efficiently translated under severe vanillin stress, however, both BDH genes were transcriptionally up-regulated. These results reveal the importance of Bdh2 in vanillin detoxification and confirm the preferential translation of the BDH2 gene in the presence of high concentrations of vanillin. The BDH2 promoter also enabled the expression of non-native genes under severe vanillin stress and furfural stress, suggesting its availability to improve of the efficiency of bioethanol production through modifications in gene expression in the presence of fermentation inhibitors. PMID- 27458451 TI - A First Insight into the Gut Microbiota of the Sea Turtle Caretta caretta. PMID- 27458452 TI - The Candida albicans Pho4 Transcription Factor Mediates Susceptibility to Stress and Influences Fitness in a Mouse Commensalism Model. AB - The Pho4 transcription factor is required for growth under low environmental phosphate concentrations in Saccharomyces cerevisiae. A characterization of Candida albicans pho4 mutants revealed that these cells are more susceptible to both osmotic and oxidative stress and that this effect is diminished in the presence of 5% CO2 or anaerobiosis, reflecting the relevance of oxygen metabolism in the Pho4-mediated response. A pho4 mutant was as virulent as wild type strain when assayed in the Galleria mellonella infection model and was even more resistant to murine macrophages in ex vivo killing assays. The lack of Pho4 neither impairs the ability to colonize the murine gut nor alters the localization in the gastrointestinal tract. However, we found that Pho4 influenced the colonization of C. albicans in the mouse gut in competition assays; pho4 mutants were unable to attain high colonization levels when inoculated simultaneously with an isogenic wild type strain. Moreover, pho4 mutants displayed a reduced adherence to the intestinal mucosa in a competitive ex vivo assays with wild type cells. In vitro competitive assays also revealed defects in fitness for this mutant compared to the wild type strain. Thus, Pho4, a transcription factor involved in phosphate metabolism, is required for adaptation to stress and fitness in C. albicans. PMID- 27458453 TI - Characterization of Microbial Mat Microbiomes in the Modern Thrombolite Ecosystem of Lake Clifton, Western Australia Using Shotgun Metagenomics. AB - Microbialite-forming communities interact with the environment and influence the precipitation of calcium carbonate through their metabolic activity. The functional genes associated with these metabolic processes and their environmental interactions are therefore critical to microbialite formation. The microbiomes associated with microbialite-forming ecosystems are just now being elucidated and the extent of shared pathways and taxa across different environments is not fully known. In this study, we profiled the microbiome of microbial communities associated with lacustrine thrombolites located in Lake Clifton, Western Australia using metagenomic sequencing and compared it to the non-lithifying mats associated with surrounding sediments to determine whether differences in the mat microbiomes, particularly with respect to metabolic pathways and environmental interactions, may potentially contribute to thrombolite formation. Additionally, we used stable isotope biosignatures to delineate the dominant metabolism associated with calcium carbonate precipitation in the thrombolite build-ups. Results indicated that the microbial community associated with the Lake Clifton thrombolites was predominantly bacterial (98.4%) with Proteobacteria, Cyanobacteria, Bacteroidetes, and Actinobacteria comprising the majority of annotated reads. Thrombolite-associated mats were enriched in photoautotrophic taxa and functional genes associated with photosynthesis. Observed delta(13)C values of thrombolite CaCO3 were enriched by at least 3.50/00 compared to theoretical values in equilibrium with lake water DIC, which is consistent with the occurrence of photoautotrophic activity in thrombolite associated microbial mats. In contrast, the microbiomes of microbial communities found on the sandy non-lithifying sediments of Lake Clifton represented distinct microbial communities that varied in taxa and functional capability and were enriched in heterotrophic taxa compared to the thrombolite-associated mats. This study provides new insight into the taxa and functional capabilities that differentiate potentially lithifying mats from other non-lithifying types and suggests that thrombolites are actively accreting and growing in limited areas of Lake Clifton. PMID- 27458454 TI - Anti-biofilm Activities from Resveratrol against Fusobacterium nucleatum. AB - Fusobacterium nucleatum is a Gram-negative, anaerobic bacterium that plays an important role in dental plaque biofilm formation. In this study, we evaluate the effect of resveratrol, a phytoalexin compound, on F. nucleatum biofilm formation. The effects of different concentrations of resveratrol on biofilms formed on 96 well microtiter plates at different time points were determined by the MTT assay. The structures and thicknesses of the biofilm were observed by confocal laser scanning microscopy (CLSM), and gene expression was investigated by real-time PCR. The results showed that resveratrol at sub-MIC levels can significantly decrease biofilm formation, whereas it does not affect the bacterial growth rate. It was observed by CLSM images that the biofilm was visually decreased with increasing concentrations of resveratrol. Gene expression was down regulated in the biofilm in the presence of resveratrol. Our results revealed that resveratrol can effectively inhibit biofilm formation. PMID- 27458455 TI - Pathogenesis and Phylogenetic Analyses of Two Avian Influenza H7N1 Viruses Isolated from Wild Birds. AB - The emergence of human infections with a novel H7N9 influenza strain has raised global concerns about a potential human pandemic. To further understand the character of other influenza viruses of the H7 subtype, we selected two H7N1 avian influenza viruses (AIVs) isolated from wild birds during routine surveillance in China: A/Baer's Pochard/Hunan/414/2010 (BP/HuN/414/10) (H7N1) and A/Common Pochard/Xianghai/420/2010 (CP/XH/420/10) (H7N1). To better understand the molecular characteristics of these two isolated H7N1 viruses, we sequenced and phylogenetically analyzed their entire genomes. The results showed that the two H7N1 strains belonged to a Eurasian branch, originating from a common ancestor. Phylogenetic analysis of their hemagglutinin (HA) genes showed that BP/HuN/414/10 and CP/XH/420/10 have a more distant genetic relationship with A/Shanghai/13/2013 (H7N9), with similarities of 91.6 and 91.4%, respectively. To assess the replication and pathogenicity of these viruses in different hosts, they were inoculated in chickens, ducks and mice. Although, both CP/XH/420/10 and BP/HuN/414/10 can infect chickens, ducks and mice, they exhibited different replication capacities in these animals. The results of this study demonstrated that two low pathogenic avian influenza (LPAI) H7N1 viruses of the Eurasian branch could infect mammals and may even have the potential to infect humans. Therefore, it is important to monitor H7 viruses in both domestic and wild birds. PMID- 27458456 TI - A Novel H1N2 Influenza Virus Related to the Classical and Human Influenza Viruses from Pigs in Southern China. AB - Southern China has long been considered to be an epicenter of pandemic influenza viruses. The special environment, breeding mode, and lifestyle in southern China provides more chances for wild aquatic birds, domestic poultry, pigs, and humans to be in contact. This creates the opportunity for interspecies transmission and generation of new influenza viruses. In this study, we reported a novel reassortant H1N2 influenza virus from pigs in southern China. According to the phylogenetic trees and homology of the nucleotide sequence, the virus was confirmed to be a novel triple-reassortant H1N2 virus containing genes from classical swine (PB2, PB1, HA, NP, and NS genes), triple-reassortant swine (PA and M genes), and recent human (NA gene) lineages. It indicated that the novel reassortment virus among human and swine influenza viruses occurred in pigs in southern China. The isolation of the novel reassortant H1N2 influenza viruses provides further evidence that pigs are "mixing vessels," and swine influenza virus surveillance in southern China will provide important information about genetic evaluation and antigenic variation of swine influenza virus to formulate the prevention and control measures for the viruses. PMID- 27458457 TI - Corrigendum: Distinct Transcriptomic Features Are Associated with Transitional and Mature B-Cell Populations in the Mouse Spleen. AB - [This corrects the article on p. 30 in vol. 6, PMID: 25717326.]. PMID- 27458458 TI - Of Amoebae and Men: Extracellular DNA Traps as an Ancient Cell-Intrinsic Defense Mechanism. AB - Since the discovery of the formation of DNA-based extracellular traps (ETs) by neutrophils as an innate immune defense mechanism (1), hundreds of articles describe the involvement of ETs in physiological and pathological human and animal conditions [reviewed in Ref. (2), and the previous Frontiers Research Topic on NETosis: http://www.frontiersin.org/books/NETosis_At_the_Intersection_of_Cell_Biology_Micr biology_and_Immunology/195]. Interestingly, a few reports reveal that ETs can be formed by immune cells of more ancient organisms, as far back as the common ancestor of vertebrates and invertebrates (3). Recently, we reported that the Sentinel cells of the multicellular slug of the social amoeba Dictyostelium discoideum also produce ETs to trap and kill slug-invading bacteria [see Box 1; and Figure 1 Ref. (4)]. This is a strong evidence that DNA-based cell-intrinsic defense mechanisms emerged much earlier than thought, about 1.3 billion years ago. Amazingly, using extrusion of DNA as a weapon to capture and kill uningestable microbes has its rationale. During the emergence of multicellularity, a primitive innate immune system developed in the form of a dedicated set of specialized phagocytic cells. This professionalization of immunity allowed the evolution of sophisticated defense mechanisms including the sacrifice of a small set of cells by a mechanism related to NETosis. This altruistic behavior likely emerged in steps, starting from the release of "dispensable" mitochondrial DNA by D. discoideum Sentinel cells. Grounded in this realization, one can anticipate that in the near future, many more examples of the invention and fine-tuning of ETs by early metazoan ancestors will be identified. Consequently, it can be expected that this more complete picture of the evolution of ETs will impact our views of the involvement and pathologies linked to ETs in human and animals. PMID- 27458459 TI - Platelets: New Bricks in the Building of Neutrophil Extracellular Traps. AB - In addition to being key elements in hemostasis and thrombosis, platelets have an important role in the inflammatory and innate immune response. This activity is associated with their capability to recognize pathogens through the expression of toll-like receptors, the secretion of various cytokines, chemokines, and growth factors stored within their granules, and the expression of cell adhesion molecules that allows interaction with other immune cells, mainly neutrophils and monocytes. As part of the first line of defense, neutrophils control invading pathogens by phagocytosis, the release of antimicrobial proteins during degranulation, or through the formation of web-like structures named neutrophil extracellular traps (NETs). NETs are formed by chromatin, proteases, and antimicrobial proteins, and their main function is to trap and kill bacteria, virus, and fungi, avoiding their dissemination. Besides microorganisms, NET formation is also triggered by proinflammatory molecules and platelets. The uncontrolled formation of NETs might exert tissue damage and has been involved in a pathogenic mechanism of autoimmune and prothrombotic clinical conditions. In this review, we discuss the role of platelets in NET generation highlighting the mediators, stimuli, and molecular mechanisms involved in this phenomenon, both in human and murine models. PMID- 27458460 TI - Molecular Cloning and Functional Characterization of a Novel Isoflavone 3'-O methyltransferase from Pueraria lobata. AB - Pueraria lobata roots accumulate 3'-, 4'- and 7-O-methylated isoflavones and many of these methylated compounds exhibit various pharmacological activities. Either the 4'- or 7-O-methylation activity has been investigated at molecular levels in several legume species. However, the gene encoding the isoflavone 3'-O methyltransferase (OMT) has not yet been isolated from any plant species. In this study, we reported the first cDNA encoding the isoflavone 3'-OMT from P. lobata (designated PlOMT4). Heterologous expressions in yeast and Escherichia coli cells showed that the gene product exhibits an enzyme activity to methylate the 3' hydroxy group of the isoflavone substrate. The transcript abundance of PlOMT4 matches well with its enzymatic product in different organs of P. lobata and in the plant roots in response to methyl jasmonate elicitation. Integration of the biochemical with metabolic and transcript data supported the proposed function of PlOMT4. The identification of PlOMT4 would not only help to understand the isoflavonoid metabolism in P. lobata but also potentially provide an enzyme catalyst for methylating existing drug candidates to improve their hydrophobicity. PMID- 27458461 TI - Systematic Investigation of FLOWERING LOCUS T-Like Poaceae Gene Families Identifies the Short-Day Expressed Flowering Pathway Gene, TaFT3 in Wheat (Triticum aestivum L.). AB - To date, a small number of major flowering time loci have been identified in the related Triticeae crops, bread wheat (Triticum aestivum), durum wheat (T. durum), and barley (Hordeum vulgare). Natural genetic variants at these loci result in major phenotypic changes which have adapted crops to the novel environments encountered during the spread of agriculture. The polyploid nature of bread and durum wheat means that major flowering time loci in which recessive alleles confer adaptive advantage in related diploid species have not been readily identified. One such example is the PPD-H2 flowering time locus encoded by FLOWERING LOCUS T 3 (HvFT3) in the diploid crop barley, for which recessive mutant alleles confer delayed flowering under short day (SD) photoperiods. In autumn-sown barley, such alleles aid the repression of flowering over the winter, which help prevent the development of cold-sensitive floral organs until the onset of inductive long day (LD) photoperiods the following spring. While the identification of orthologous loci in wheat could provide breeders with alternative mechanisms to fine tune flowering time, systematic identification of wheat orthologs of HvFT3 has not been reported. Here, we characterize the FT gene families in six Poaceae species, identifying novel members in all taxa investigated, as well as FT3 homoeologs from the A, B and D genomes of hexaploid (TaFT3) and tetraploid wheat. Sequence analysis shows TaFT3 homoeologs display high similarity to the HvFT3 coding region (95-96%) and predicted protein (96 97%), with conservation of intron/exon structure across the five cereal species investigated. Genetic mapping and comparative analyses in hexaploid and tetraploid wheat find TaFT3 homoeologs map to the long arms of the group 1 chromosomes, collinear to HvFT3 in barley and FT3 orthologs in rice, foxtail millet and brachypodium. Genome-specific expression analyses show FT3 homoeologs in tetraploid and hexaploid wheat are upregulated under SD photoperiods, but not under LDs, analogous to the expression of HvFT3. Collectively, these results indicate that functional wheat orthologs of HvFT3 have been identified. The molecular resources generated here provide the foundation for engineering a novel major flowering time locus in wheat using forward or reverse genetics approaches. PMID- 27458462 TI - Mitigation of NaCl Stress by Arbuscular Mycorrhizal Fungi through the Modulation of Osmolytes, Antioxidants and Secondary Metabolites in Mustard (Brassica juncea L.) Plants. AB - Present work was carried out to investigate the possible role of arbuscular mycorrhizal fungi (AMF) in mitigating salinity-induced alterations in Brassica juncea L. Exposure to NaCl stress altered the morphological, physio-biochemical attributes, antioxidant activity, secondary metabolites and phytohormones in the mustard seedlings. The growth and biomass yield, leaf water content, and total chlorophyll content were decreased with NaCl stress. However, AMF-inoculated plants exhibited enhanced shoot and root length, elevated relative water content, enhanced chlorophyll content, and ultimately biomass yield. Lipid peroxidation and proline content were increased by 54.53 and 63.47%, respectively with 200 mM NaCl concentration. Further increase in proline content and decrease in lipid peroxidation was observed in NaCl-treated plants inoculated with AMF. The antioxidants, superoxide dismutase, ascorbate peroxidase, glutathione reductase, and reduced glutathione were increased by 48.35, 54.86, 43.85, and 44.44%, respectively, with 200 mM NaCl concentration. Further increase in these antioxidants has been observed in AMF-colonized plants indicating the alleviating role of AMF to salinity stress through antioxidant modulation. The total phenol, flavonoids, and phytohormones increase with NaCl treatment. However, NaCl-treated plants colonized with AMF showed further increase in the above parameters except ABA, which was reduced with NaCl+AMF treatment over the plants treated with NaCl alone. Our results demonstrated that NaCl caused negative effect on B. juncea seedlings; however, colonization with AMF enhances the NaCl tolerance by reforming the physio-biochemical attributes, activities of antioxidant enzymes, and production of secondary metabolites and phytohormones. PMID- 27458464 TI - Phloroglucinol and Terpenoid Derivatives from Hypericum cistifolium and H. galioides (Hypericaceae). AB - A new simple phloroglucinol derivative characterized as 1-(6-hydroxy-2,4 dimethoxyphenyl)-2-methyl-1-propanone (1) was isolated from Hypericum cistifolium (Hypericaceae) as a major constituent of the non-polar plant extract. Minor amounts of this new compound, in addition to two known structurally related phloroglucinol derivatives (2 and 3), and two new terpenoid derivatives characterized, respectively, as 2-benzoyl-3,3-dimethyl-4R,6S-bis-(3-methylbut-2 enyl)-cyclohexanone (4a) and 2-benzoyl-3,3-dimethyl-4S,6R-bis-(3-methylbut-2 enyl)-cyclohexanone (4b), were isolated from a related species, H. galioides Lam. The chemical structures were established using 2D-NMR spectroscopy and mass spectrometry. These compounds were evaluated in vitro for antimicrobial activity against a panel of pathogenic microorganisms and anti-inflammatory activity through inhibition of COX-1, COX-2, and 5-LOX catalyzed LTB4 formation. PMID- 27458463 TI - De Novo Transcriptional Analysis of Alfalfa in Response to Saline-Alkaline Stress. AB - Saline-alkaline stress, caused by high levels of harmful carbonate salts and high soil pH, is a major abiotic stress that affects crop productivity. Alfalfa is a widely cultivated perennial forage legume with some tolerance to biotic and abiotic stresses, especially to saline-alkaline stress. To elucidate the mechanism underlying plant saline-alkaline tolerance, we conducted transcriptome analysis of whole alfalfa seedlings treated with saline-alkaline solutions for 0 day (control), 1 day (short-term treatment), and 7 days (long-term treatment) using ion torrent sequencing technology. A transcriptome database dataset of 53,853 unigenes was generated, and 2,286 and 2,233 genes were differentially expressed in the short-term and long-term treatment, respectively. Gene ontology analysis revealed 14 highly enriched pathways and demonstrated the differential response of metabolic pathways between the short-term and long-term treatment. The expression levels of 109 and 96 transcription factors were significantly altered significantly after 1 day and 7 days of treatment, respectively. Specific responses of peroxidase, flavonoids, and the light pathway component indicated that the antioxidant capacity was one of the central mechanisms of saline alkaline stress tolerance response in alfalfa. Among the 18 differentially expressed genes examined by real time PCR, the expression levels of eight genes, including inositol transporter, DNA binding protein, raffinose synthase, ferritin, aldo/keto reductase, glutathione S-transferase, xyloglucan endotrans glucosylase, and a NAC transcription factor, exhibited different patterns in response to saline and alkaline stress. The expression levels of the NAC transcription factor and glutathione S-transferase were altered significantly under saline stress and saline-alkaline stress; they were upregulated under saline-alkaline stress and downregulated under salt stress. Physiology assays showed an increased concentration of reactive oxygen species and malondialdehyde and a decreased content of chlorophyll, indicating that anti-oxidation and detoxification play an important role in response to saline-alkaline stress. Overall, the transcriptome analysis provided novel insights into the saline alkaline stress tolerance response mechanisms in alfalfa. PMID- 27458465 TI - Genomic Analysis Reveals Contrasting PIFq Contribution to Diurnal Rhythmic Gene Expression in PIF-Induced and -Repressed Genes. AB - Members of the PIF quartet (PIFq; PIF1, PIF3, PIF4, and PIF5) collectively contribute to induce growth in Arabidopsis seedlings under short day (SD) conditions, specifically promoting elongation at dawn. Their action involves the direct regulation of growth-related and hormone-associated genes. However, a comprehensive definition of the PIFq-regulated transcriptome under SD is still lacking. We have recently shown that SD and free-running (LL) conditions correspond to "growth" and "no growth" conditions, respectively, correlating with greater abundance of PIF protein in SD. Here, we present a genomic analysis whereby we first define SD-regulated genes at dawn compared to LL in the wild type, followed by identification of those SD-regulated genes whose expression depends on the presence of PIFq. By using this sequential strategy, we have identified 349 PIF/SD-regulated genes, approximately 55% induced and 42% repressed by both SD and PIFq. Comparison with available databases indicates that PIF/SD-induced and PIF/SD-repressed sets are differently phased at dawn and mid morning, respectively. In addition, we found that whereas rhythmicity of the PIF/SD-induced gene set is lost in LL, most PIF/SD-repressed genes keep their rhythmicity in LL, suggesting differential regulation of both gene sets by the circadian clock. Moreover, we also uncovered distinct overrepresented functions in the induced and repressed gene sets, in accord with previous studies in other examined PIF-regulated processes. Interestingly, promoter analyses showed that, whereas PIF/SD-induced genes are enriched in direct PIF targets, PIF/SD-repressed genes are mostly indirectly regulated by the PIFs and might be more enriched in ABA-regulated genes. PMID- 27458466 TI - A Reliable Protocol for In situ microRNAs Detection in Feeding Sites Induced by Root-Knot Nematodes. AB - Galls induced by Meloidogyne spp. in plant roots are a complex organ formed by heterogeneous tissues; within them there are 5-8 giant cells (GCs) that root-knot nematodes use for their own nurturing. Subtle regulatory mechanisms likely mediate the massive gene repression described at early infection stages in galls, particularly in giant cells. Some of these mechanisms are mediated by microRNAs (miRNAs); hence we describe a reliable protocol to detect miRNAs abundance within the gall tissues induced by Meloidogyne spp. Some methods are available to determine the abundance of specific miRNAs in different plant parts; however, galls are complex organs formed by different tissues. Therefore, detection of miRNAs at the cellular level is particularly important to understand specific regulatory mechanisms operating within the GCs. In situ hybridization (ISH) is a classical, robust and accurate method that allows the localization of specific RNAs directly on plant tissues. We present for the first time an adapted and standardized ISH protocol to detect miRNAs in GCs induced by nematodes based on tissue embedded in paraffin and on-slide ISH of miRNAs. It can be adapted to any laboratory with no more requirements than a microtome and an optical microscope and it takes 10 days to perform once plant material has been collected. It showed to be very valuable for a quick detection of miRNAs expression pattern in tomato. We tested the protocol for miR390, as massive sequencing analysis showed that miR390 was induced at 3 dpi (days post-infection) in Arabidopsis galls and miR390 is 100% conserved between Arabidopsis and tomato. Successful localization of miR390 in tomato GCs constitutes a validation of this method that could be easily extended to other crops and/or syncytia induced by cyst nematodes. Finally, the protocol also includes guidance on troubleshooting. PMID- 27458467 TI - Genetic Linkage Map Construction and QTL Analysis of Two Interspecific Reproductive Isolation Traits in Sponge Gourd. AB - The hybrids between Luffa acutangula (L.) Roxb. and L.cylindrica (L.) Roem. have strong heterosis effects. However, some reproductive isolation traits hindered their normal hybridization and fructification, which was mainly caused by the flowering time and hybrid pollen sterility. In order to study the genetic basis of two interspecific reproductive isolation traits, we constructed a genetic linkage map using an F2 population derived from a cross between S1174 [L. acutangula (L.) Roxb.] and 93075 [L. cylindrica (L.) Roem.]. The map spans 1436.12 CentiMorgans (cM), with an average of 8.11 cM among markers, and consists of 177 EST-SSR markers distributed in 14 linkage groups (LG) with an average of 102.58 cM per LG. Meanwhile, we conducted colinearity analysis between the sequences of EST-SSR markers and the genomic sequences of cucumber, melon and watermelon. On the basis of genetic linkage map, we conducted QTL mapping of two reproductive isolation traits in sponge gourd, which were the flowering time and hybrid male sterility. Two putative QTLs associated with flowering time (FT) were both detected on LG 1. The accumulated contribution of these two QTLs explained 38.07% of the total phenotypic variance (PV), and each QTL explained 15.36 and 22.71% of the PV respectively. Four QTLs for pollen fertility (PF) were identified on LG 1 (qPF1.1 and qPF1.2), LG 3 (qPF3) and LG 7 (qPF7), respectively. The percentage of PF explained by these QTLs varied from 2.91 to 16.79%, and all together the four QTLs accounted for 39.98% of the total PV. Our newly developed EST-SSR markers and linkage map are very useful for gene mapping, comparative genomics and molecular marker-assisted breeding. These QTLs for interspecific reproductive isolation will also contribute to the cloning of genes relating to interspecific reproductive isolation and the utilization of interspecific heterosis in sponge gourd in further studies. PMID- 27458468 TI - Transient Expression of Candidatus Liberibacter Asiaticus Effector Induces Cell Death in Nicotiana benthamiana. AB - Candidatus Liberibacter asiaticus "Las" is a phloem-limited bacterial plant pathogen, and the most prevalent species of Liberibacter associated with citrus huanglongbing (HLB), a devastating disease of citrus worldwide. Although, the complete sequence of the Las genome provides the basis for studying functional genomics of Las and molecular mechanisms of Las-plant interactions, the functional characterization of Las effectors remains a slow process since remains to be cultured. Like other plant pathogens, Las may deliver effector proteins into host cells and modulate a variety of host cellular functions for their infection progression. In this study, we identified 16 putative Las effectors via bioinformatics, and transiently expressed them in Nicotiana benthamiana. Diverse subcellular localization with different shapes and aggregation patterns of the effector candidates were revealed by UV- microscopy after transient expression in leaf tissue. Intriguingly, one of the 16 candidates, Las5315mp (mature protein), was localized in the chloroplast and induced cell death at 3 days post inoculation (dpi) in N. benthamiana. Moreover, Las5315mp induced strong callose deposition in plant cells. This study provides new insights into the localizations and potential roles of these Las effectors in planta. PMID- 27458469 TI - Mannitol Stress Directs Flavonoid Metabolism toward Synthesis of Flavones via Differential Regulation of Two Cytochrome P450 Monooxygenases in Coleus forskohlii. AB - Cytochrome P450 monooxygenases (CYP450s) are known to play important roles in biosynthesis of all secondary metabolites, including flavonoids. Despite this, few CYP450s have been functionally characterized in model plants and roles of fewer CYP450s are known in non-model, medicinal, and aromatic plants. Our study in Coleus forskohlii indicates that flavone synthase (CYP93B) and flavonoid 3' monooxygenase (CYP706C) are key enzymes positioned at a metabolic junction, to execute the biosynthesis of different sub-classes of flavonoids (flavones, flavonol, anthocynanin, isoflavones etc.) from a common precursor. Such branch points are favored targets for artificially modulating the metabolic flux toward specific metabolites, through genetic manipulation or use of elicitors that differentially impact the expression of branch point genes. Genkwanin, the only flavone reported from C. forskohlii, is known to possess anti-inflammatory activity. It is biosynthesized from the general flavonoid precursor: naringenin. Two differentially expressed cytochrome P450 genes (CfCYP93B, CfCYP706C), exhibiting maximum expression in leaf tissues, were isolated from C. forskohlii. Mannitol treatment resulted in increased expression of CfCYP93B and decrease in expression of CfCYP706C. Metabolite quantification data showed that genkwanin content increased and anthocyanin levels decreased in response to mannitol treatment. Alignment, phylogenetic analysis, modeling, and molecular docking analysis of protein sequences suggested that CfCYP93B may be involved in conversion of naringenin to flavones (possibly genkwanin via apigenin), while CfCYP706C may act on common precursors of flavonoid metabolism and channel the substrate toward production of flavonols or anthocynanins. Decrease in expression of CfCYP706C and increase in accumulation of genkwanin suggested that mannitol treatment may possibly lead to accumulation of genkwanin via suppression of a competitive branch of flavonoids in C. forskohlii. PMID- 27458470 TI - Physiological Traits Associated with Wheat Yield Potential and Performance under Water-Stress in a Mediterranean Environment. AB - Different physiological traits have been proposed as key traits associated with yield potential as well as performance under water stress. The aim of this paper is to examine the genotypic variability of leaf chlorophyll, stem water-soluble carbohydrate content and carbon isotope discrimination (Delta(13)C), and their relationship with grain yield (GY) and other agronomical traits, under contrasting water conditions in a Mediterranean environment. The study was performed on a large collection of 384 wheat genotypes grown under water stress (WS, rainfed), mild water stress (MWS, deficit irrigation), and full irrigation (FI). The average GY of two growing seasons was 2.4, 4.8, and 8.9 Mg ha(-1) under WS, MWS, and FI, respectively. Chlorophyll content at anthesis was positively correlated with GY (except under FI in 2011) and the agronomical components kernels per spike (KS) and thousand kernel weight (TKW). The WSC content at anthesis (WSCCa) was negatively correlated with spikes per square meter (SM2), but positively correlated with KS and TKW under WS and FI conditions. As a consequence, the relationships between WSCCa with GY were low or not significant. Therefore, selecting for high stem WSC would not necessary lead to genotypes of GY potential. The relationship between Delta(13)C and GY was positive under FI and MWS but negative under severe WS (in 2011), indicating higher water use under yield potential and MWS conditions. PMID- 27458471 TI - Whole-Genome Mapping Reveals Novel QTL Clusters Associated with Main Agronomic Traits of Cabbage (Brassica oleracea var. capitata L.). AB - We describe a comprehensive quantitative trait locus (QTL) analysis for 24 main agronomic traits of cabbage. Field experiments were performed using a 196-line double haploid population in three seasons in 2011 and 2012 to evaluate important agronomic traits related to plant type, leaf, and head traits. In total, 144 QTLs with LOD threshold >3.0 were detected for the 24 agronomic traits: 25 for four plant-type-related traits, 64 for 10 leaf-related traits, and 55 for 10 head related traits; each QTL explained 6.0-55.7% of phenotype variation. Of the QTLs, 95 had contribution rates higher than 10%, and 51 could be detected in more than one season. Major QTLs included Ph 3.1 (max R (2) = 55.7, max LOD = 28.2) for plant height, Ll 3.2 (max R (2) = 31.7, max LOD = 13.95) for leaf length, and Htd 3.2 (max R (2) = 28.5, max LOD = 9.49) for head transverse diameter; these could all be detected in more than one season. Twelve QTL clusters were detected on eight chromosomes, and the most significant four included Indel481-scaffold18376 (3.20 Mb), with five QTLs for five traits; Indel64-scaffold35418 (2.22 Mb), six QTLs for six traits; scaffold39782-Indel84 (1.78 Mb), 11 QTLs for 11 traits; and Indel353-Indel245 (9.89 Mb), seven QTLs for six traits. Besides, most traits clustered within the same region were significantly correlated with each other. The candidate genes at these regions were also discussed. Robust QTLs and their clusters obtained in this study should prove useful for marker-assisted selection (MAS) in cabbage breeding and in furthering our understanding of the genetic control of these traits. PMID- 27458472 TI - Harnessing Diversity in Wheat to Enhance Grain Yield, Climate Resilience, Disease and Insect Pest Resistance and Nutrition Through Conventional and Modern Breeding Approaches. AB - Current trends in population growth and consumption patterns continue to increase the demand for wheat, a key cereal for global food security. Further, multiple abiotic challenges due to climate change and evolving pathogen and pests pose a major concern for increasing wheat production globally. Triticeae species comprising of primary, secondary, and tertiary gene pools represent a rich source of genetic diversity in wheat. The conventional breeding strategies of direct hybridization, backcrossing and selection have successfully introgressed a number of desirable traits associated with grain yield, adaptation to abiotic stresses, disease resistance, and bio-fortification of wheat varieties. However, it is time consuming to incorporate genes conferring tolerance/resistance to multiple stresses in a single wheat variety by conventional approaches due to limitations in screening methods and the lower probabilities of combining desirable alleles. Efforts on developing innovative breeding strategies, novel tools and utilizing genetic diversity for new genes/alleles are essential to improve productivity, reduce vulnerability to diseases and pests and enhance nutritional quality. New technologies of high-throughput phenotyping, genome sequencing and genomic selection are promising approaches to maximize progeny screening and selection to accelerate the genetic gains in breeding more productive varieties. Use of cisgenic techniques to transfer beneficial alleles and their combinations within related species also offer great promise especially to achieve durable rust resistance. PMID- 27458474 TI - TreeWatch.net: A Water and Carbon Monitoring and Modeling Network to Assess Instant Tree Hydraulics and Carbon Status. AB - TreeWatch.net is an initiative that has been developed to watch trees grow and function in real-time. It is a water- and carbon-monitoring and modeling network, in which high-quality measurements of sap flow and stem diameter variation are collected on individual trees. Automated data processing using a cloud service enables instant visualization of water movement and radial stem growth. This can be used to demonstrate the sensitivity of trees to changing weather conditions, such as drought, heat waves, or heavy rain showers. But TreeWatch.net's true innovation lies in its use of these high-precision harmonized data to also parameterize process-based tree models in real-time, which makes displaying the much-needed mechanisms underlying tree responses to climate change possible. Continuous simulation of turgor to describe growth processes and long-term time series of hydraulic resistance to assess drought-vulnerability in real-time are only a few of the opportunities our approach offers. TreeWatch.net has been developed with the view to be complementary to existing forest monitoring networks and with the aim to contribute to existing dynamic global vegetation models. It provides high-quality data and real-time simulations in order to advance research on the impact of climate change on the biological response of trees and forests. Besides its application in natural forests to answer climate change related scientific and political questions, we also envision a broader societal application of TreeWatch.net by selecting trees in nature reserves, public areas, cities, university areas, schoolyards, and parks to teach youngsters and create public awareness on the effects of changing weather conditions on trees and forests in this era of climate change. PMID- 27458473 TI - Comparison between Arabidopsis and Rice for Main Pathways of K(+) and Na(+) Uptake by Roots. AB - K(+) is an essential macronutrient for plants. It is acquired by specific uptake systems located in roots. Although the concentrations of K(+) in the soil solution are widely variable, K(+) nutrition is secured by uptake systems that exhibit different affinities for K(+). Two main systems have been described for root K(+) uptake in several species: the high-affinity HAK5-like transporter and the inward-rectifier AKT1-like channel. Other unidentified systems may be also involved in root K(+) uptake, although they only seem to operate when K(+) is not limiting. The use of knock-out lines has allowed demonstrating their role in root K(+) uptake in Arabidopsis and rice. Plant adaptation to the different K(+) supplies relies on the finely tuned regulation of these systems. Low K(+)-induced transcriptional up-regulation of the genes encoding HAK5-like transporters occurs through a signal cascade that includes changes in the membrane potential of root cells and increases in ethylene and reactive oxygen species concentrations. Activation of AKT1 channels occurs through phosphorylation by the CIPK23/CBL1 complex. Recently, activation of the Arabidopsis HAK5 by the same complex has been reported, pointing to CIPK23/CBL as a central regulator of the plant's adaptation to low K(+). Na(+) is not an essential plant nutrient but it may be beneficial for some plants. At low concentrations, Na(+) improves growth, especially under K(+) deficiency. Thus, high-affinity Na(+) uptake systems have been described that belong to the HKT and HAK families of transporters. At high concentrations, typical of saline environments, Na(+) accumulates in plant tissues at high concentrations, producing alterations that include toxicity, water deficit and K(+) deficiency. Data concerning pathways for Na(+) uptake into roots under saline conditions are still scarce, although several possibilities have been proposed. The apoplast is a significant pathway for Na(+) uptake in rice grown under salinity conditions, but in other plant species different mechanisms involving non-selective cation channels or transporters are under discussion. PMID- 27458475 TI - An Integrated Biochemical, Proteomics, and Metabolomics Approach for Supporting Medicinal Value of Panax ginseng Fruits. AB - Panax ginseng roots are well known for their medicinal properties and have been used in Korean and Chinese traditional medicines for 1000s of years. However, the medicinal value of P. ginseng fruits remain poorly characterized. In this study, we used an integrated biochemical, proteomics, and metabolomics approach to look into the medicinal properties of ginseng fruits. DPPH (1,1-diphenyl-2 picrylhydrazyl) and ABTS [2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid)] assays showed higher antioxidant activities in ginseng fruits than leaves or roots. Two-dimensional gel electrophoresis (2-DE) profiling of ginseng fruit proteins (cv. Cheongsun) showed more than 400 spots wherein a total of 81 protein spots were identified by mass spectrometry using NCBInr, UniRef, and an in-house developed RNAseq (59,251 protein sequences)-based databases. Gene ontology analysis showed that most of the identified proteins were related to the hydrolase (18%), oxidoreductase (16%), and ATP binding (15%) activities. Further, a comparative proteome analysis of four cultivars of ginseng fruits (cvs. Yunpoong, Gumpoong, Chunpoong, and Cheongsun) led to the identification of 22 differentially modulated protein spots. Using gas chromatography-time of flight mass spectrometry (GC-TOF MS), 66 metabolites including amino acids, sugars, organic acids, phenolic acids, phytosterols, tocopherols, and policosanols were identified and quantified. Some of these are well known medicinal compounds and were not previously identified in ginseng. Interestingly, the concentration of almost all metabolites was higher in the Chunpoong and Gumpoong cultivars. Parallel comparison of the four cultivars also revealed higher amounts of the medicinal metabolites in Chunpoong and Gumpoong cultivars. Taken together, our results demonstrate that ginseng fruits are a rich source of medicinal compounds with potential beneficial health effects. PMID- 27458476 TI - Soybean Cyst Nematode Resistance Emerged via Artificial Selection of Duplicated Serine Hydroxymethyltransferase Genes. AB - A major soybean (Forrest cultivar) quantitative trait locus (QTL) gene, Rhg4, which controls resistance to soybean cyst nematodes (SCN), encodes the enzyme serine hydroxylmethyltransferase (SHMT). The resistant allele possesses two critical missense mutations (P130R and N358Y) compared to that of the sensitive allele, rhg4. To understand the evolutionary history of this gene, sequences of 117 SHMT family members from 18 representative plant species were used to reconstruct their phylogeny. According to this phylogeny, the plant SHMT gene family can be divided into two groups and four subgroups (Ia, Ib, IIa, and IIb). Belonging to the Subgroup Ia lineage, the rhg4 gene evolved from a recent duplication event in Glycine sp.. To further explore how the SCN-resistant allele emerged, both the rhg4 gene and its closest homolog, the rhg4h gene, were isolated from 33 cultivated and 68 wild soybean varieties. The results suggested that after gene duplication, the soybean rhg4 gene accumulated a higher number of non-synonymous mutations than rhg4h. Although a higher number of segregating sites and gene haplotypes were detected in wild soybeans than in cultivars, the SCN-resistant Rhg4 allele (represented by haplotype 4) was not found in wild varieties. Instead, a very similar allele, haplotype 3, was observed in wild soybeans at a frequency of 7.4%, although it lacked the two critical non synonymous substitutions. Taken together, these findings support that the SCN resistant Rhg4 allele likely emerged via artificial selection during the soybean domestication process, based on a SCN-sensitive allele inherited from wild soybeans. PMID- 27458477 TI - Above-Ground Dimensions and Acclimation Explain Variation in Drought Mortality of Scots Pine Seedlings from Various Provenances. AB - Seedling establishment is a critical part of the life cycle, thus seedling survival might be even more important for forest persistence under recent and future climate change. Scots pine forests have been disproportionally more affected by climate change triggered forest-dieback. Nevertheless, some Scots pine provenances might prove resilient to future drought events because of the species' large distributional range, genetic diversity, and adaptation potential. However, there is a lack of knowledge on provenance-specific survival under severe drought events and on how acclimation alters survival rates in Scots pine seedlings. We therefore conducted two drought-induced mortality experiments with potted Scots pine seedlings in a greenhouse. In the first experiment, 760 three year-old seedlings from 12 different provenances of the south-western distribution range were subjected to the same treatment followed by the mortality experiment in 2014. In the second experiment, we addressed the question of whether acclimation to re-occurring drought stress events and to elevated temperature might decrease mortality rates. Thus, 139 four-year-old seedlings from France, Germany, and Poland were subjected to different temperature regimes (2012-2014) and drought treatments (2013-2014) before the mortality experiment in 2015. Provenances clearly differed in their hazard of drought-induced mortality, which was only partly related to the climate of their origin. Drought acclimation decreased the hazard of drought-induced mortality. Above-ground dry weight and height were the main determinants for the hazard of mortality, i.e., heavier and taller seedlings were more prone to mortality. Consequently, Scots pine seedlings exhibit a considerable provenance-specific acclimation potential against drought mortality and the selection of suitable provenances might thus facilitate seedling establishment and the persistence of Scots pine forest. PMID- 27458479 TI - Editorial: Systems Biology of Transcription Regulation. PMID- 27458478 TI - Reprogramming, Circular Reasoning and Self versus Non-self: One-Stop Shopping with RNA Editing. AB - Transcription of genetic information from archival DNA into RNA molecule working copies is vital for proper cellular function and is highly accurate. In turn, RNAs serve structural, enzymatic, and regulatory roles, as well as being informational templates for the ribosomal translation of proteins. Following RNA synthesis, maturing of RNA molecules occurs through various RNA processing events. One component of the collection of processes involving RNA species, broadly defined as RNA metabolism, is the RNA-editing pathway and is found in all animals. Acting specifically on RNA substrates with double-stranded character, RNA editing has been shown to regulate a plethora of genomic outputs, including gene recoding, RNA splicing, biogenesis and targeting actions of microRNAs and small interfering RNAs, and global gene expression. Recent evidence suggests that RNA modifications mediated via RNA editing influence the biogenesis of circular RNAs and safeguard against aberrant innate immune responses generated to endogenous RNA sources. These novel roles have the potential to contribute new insights into molecular mechanisms underlying pathogenesis mediated by mishandling of double-stranded RNA. Here, we discuss recent advances in the field, which highlight novel roles associated with the RNA-editing process and emphasize their importance during cellular RNA metabolism. In addition, we highlight the relevance of these newly discovered roles in the context of neurological disorders and the more general concept of innate recognition of self versus non-self. PMID- 27458480 TI - Retrospective analysis on the agreement between skin prick test and serum food specific IgE antibody results in adults with suspected food allergy. AB - BACKGROUND: Food allergy is a common clinical problem in adults. Given logistical barriers to conducting food challenges, the use of skin prick test (SPT) and specific IgE (sIgE) are important in establishing the diagnosis. The purpose of this study is to investigate the agreement of SPT and sIgE results in adults presenting to an allergy clinic with suspected food allergy. METHODS: Retrospective analysis of medical records at the University of Alberta Allergy Clinic between September 2013 and May 2015 was performed. Demographic, medical history as well as SPT and specific IgE results were recorded. Agreement of SPT and sIgE for individual food allergens was analyzed by Kappa statistics. RESULTS: Data from 260 patients was collected. The population was predominantly female, often having other atopic diseases. Very few food challenges were performed; IgE mediated food allergy was diagnosed in a minority (29.6 %) of cases. Kappa values which reached statistical significance were moderate for peanut K = 0.535 (p = 0.0002, CI 0.364-0.707), walnut K = 0.408 (p = 0.001 CI 0.159-0.657), pecan K = 0.530 (p = 0.001 CI 0.211-0.848), and lobster K = 0.543 (p = 0.004 CI 0.197 0.889), substantial for pistachio K = 0.657 (p = 0.023 CI 0.224-1.000), codfish K = 0.770 (p = 0.0002 CI 0.558-0.983), shrimp K = 0.627 (p = 0.0006 CI 0.383-0.871) and egg white K = 0.625 (p = 0.002 CI 0.293-0.957), almost perfect for cashew K = 0.894 (p = 0.0008 CI 0.693-1.000) and salmon K = 0.874 (p = 0.004 CI 0.705 1.000). CONCLUSIONS: The agreement between SPT and sIgE results on adults being evaluated for food allergy is at least moderate or better for peanut, walnut, pecan, pistachio, cashew, lobster, shrimp, codfish, salmon and egg white. This should be reassuring for patients who have contraindications or restricted access to either test as the results for the above allergens will likely agree. These findings may suggest that these tests could possibly be interchangeable in adults being evaluated for suspected food allergy and will aid primary care physicians in the triage of patients requiring allergist care. PMID- 27458481 TI - A promising antitumor activity of evodiamine incorporated in hydroxypropyl-beta cyclodextrin: pro-apoptotic activity in human hepatoma HepG2 cells. AB - BACKGROUND: Evodiamine has gained wide interests recently because of its antitumor activities. However, a superior bioavailability is required to achieve better efficacy due to its poor water solubility. The aim of this study was to enhance the evodiamine's aqueous solubility by preparing evodiamine/hydroxypropyl beta-cyclodextrin (EVO/HP-beta-CD) inclusion complex, which is incorporated evodiamine into HP-beta-CD, and compare the antitumor activities before and after inclusion with HP-beta-CD in human hepatoma HepG2 cells. RESULTS: The EVO/HP-beta CD inclusion complexes were prepared by the kneading method and structurally characterized. P-glycoprotein ATPase assays firstly demonstrated that evodiamine was a substrate of P-glycoprotein, while HP-beta-CD and EVO/HP-beta-CD inclusion complexes inhibited P-glycoprotein by blocking P-glycoprotein ATPase activity. The EVO/HP-beta-CD inclusion complexes may be a promising anticancer drug candidate without drug resistance. After given evodiamine or EVO/HP-beta-CD inclusion complexes intervention, cell viability evaluation indicated that the half inhibition concentration of evodiamine and EVO/HP-beta-CD inclusion complexes on HepG2 cells was 8.516 and 0.977 MUM, respectively. The caspase-3 enzyme activity analysis and Annexin V/PI double-staining revealed that EVO/HP beta-CD inclusion complexes possessed better antitumor activities than evodiamine. Additionally, Hoechst 33258 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay demonstrated that EVO/HP-beta CD inclusion complexes induced HepG2 cell apoptosis more effectively than evodiamine. CONCLUSIONS: The improved antitumor activities of evodiamine were attributed to the enhanced solubility and P-glycoprotein inhibition by HP-beta CD. These results are promising for the drug administration of EVO/HP-beta-CD inclusion complexes to enhance the bioavailability of evodiamine in vivo. PMID- 27458482 TI - Identity Transformation During the Transition to Parenthood Among Same-Sex Couples: An Ecological, Stress-Strategy-Adaptation Perspective. AB - This article reviews the current research on the potential stressors associated with identity transformation experienced by same-sex couples during the transition to parenthood and the coping strategies they employ. By integrating disparate findings into an ecological, stress-strategy-adaptation framework, we demonstrate that the identity transformation experiences among same-sex couples during the transition to parenthood (a) involve various adaptive processes of navigating different stressors via their human agency within multiple nested contexts; (b) are products of the intersections of individual characteristics, relational dynamics, LGBT community culture, and heterosexual sociostructural norms; and (c) are complicated by social contextual factors such as social class, race/ethnicity, family structure, and the sociocultural environment associated with geographic location. Last, several avenues for future inquiry are suggested. PMID- 27458483 TI - Features of respiratory support during laparoscopic correction of inguinal hernias in children. AB - INTRODUCTION: The objectives were to study the changes in the mechanics of respiration in children undergoing surgery depending on the value of intra abdominal pressure (IAP) during laparoscopic procedures, and to compare the effects of different mechanical ventilation modes - pressure controlled (PCV) and volume controlled (VCV) ventilation - on the mechanics of respiration considering carboxyperitoneum conditions (CP). AIM: To study the changes in the mechanics of respiration in operated children depending on the value of intra-abdominal pressure during laparoscopic procedures. MATERIAL AND METHODS: Fifty-two children aged 1-12 years undergoing laparoscopic surgery on inguinal hernias were randomly allocated to receive mechanical ventilation using either VCV (n = 24) or PCV (n = 28) mode. Respiratory mechanics were measured before application of carboxyperitoneum (initial data) and after the gas had been pumped into the abdominal cavity, at the following intra-abdominal pressure values: 6 mm Hg, 8 mm Hg, 10 mm Hg, 12 mm Hg, 14 mm Hg. RESULTS: Elevation of intra-abdominal pressure due to carboxyperitoneum conditions had a negative effect on the mechanics of respiration. Changes in the respiratory mechanics were restrictive in nature in both groups. The patients who were receiving pressure controlled ventilation showed a decrease in tidal volume, exhaled minute volume, and dynamic lung compliance, which affected the gas exchange at intra-abdominal pressure values >= 12 mm Hg. Patients who were receiving volume controlled ventilation showed an increase in peak inspiratory pressure and mean airway pressure and a decrease in dynamic lung compliance in response to higher intra-abdominal pressure. A significant increase of concentration of exhaled carbon dioxide (etCO2) was registered at IAP >= 12 mm Hg. CONCLUSIONS: Application of carboxyperitoneum causes increased intra-abdominal pressure and restrictive disorders in respiratory mechanics. Intra-abdominal pressure readings within 8-12 mm Hg allow laparoscopic procedures to be performed without significant gas exchange disorders in children older than 1 year. PMID- 27458484 TI - Surgical treatment of GERD. Comperative study of WTP vs. Toupet fundoplication - results of 151 consecutive cases. AB - INTRODUCTION: Gastroesophageal reflux disease (GERD) is recognized as one of the most common disorders of the upper gastrointestinal tract (GIT). The best choice of management for advanced GERD is laparoscopic surgery. AIM: To compare and evaluate the results of surgical treatment of GERD patients operated on using two different techniques. MATERIAL AND METHODS: Between 2001 and 2012, 353 patients (211 female and 142 male), aged 17-76 years (mean 44), underwent laparoscopic antireflux surgery. The study included patients who underwent a Toupet fundoplication or Wroblewski Tadeusz procedure (WTP). RESULTS: The mean age of the group was 47.77 years (17-80 years). Forty-nine (32.45%) patients had severe symptoms, 93 (61.58%) had mild symptoms and 9 (5.96%) had a single mild but intolerable sign of GERD. Eighty-six (56.95%) patients had a Toupet fundoplication and 65 (43.04%) had a WTP. The follow-up period was 18-144 months. The average operating time for Toupet fundoplication and the WTP procedure was 164 min (90-300 min) and 147 min (90-210 min), respectively. The perioperative mortality rate was 0.66%. The average post-operative hospitalization period was 5.4 days (2-16 post-operative days (POD) = Toupet) vs. 4.7 days (2-9 POD = WTP). No reoperations were performed. No major surgical complications were identified. CONCLUSIONS: Wroblewski Tadeusz procedure due to a low percentage of post operative complications, good quality of life of patients and a zero recurrence rate of hiatal hernia should be a method of choice. PMID- 27458485 TI - Ultrasound-guided foam sclerotherapy of great saphenous vein with 2% polidocanol one-year follow-up results. AB - INTRODUCTION: Ultrasound-guided foam sclerotherapy (UGFS) of varicose veins is a useful treatment option. It is a relatively safe method in the case of limited, small varicose veins. In theory, a justified concern could be raised that the injection of an active drug into the large superficial venous vessels may potentially cause life-threatening consequences. AIM: To assess the safety and efficacy of UGFS using a 2% solution of polidocanol (Aethoxysklerol 2%) in the case of great saphenous vein incompetence. MATERIAL AND METHODS: Fifty-two patients with great saphenous vein incompetence underwent ultrasound-guided foam sclerotherapy. The efficacy criterion was the elimination of reflux measured ultrasonographically and withdrawal or decrease of complaints: 1 week, and 1, 3, 6 and 12 months after the treatment. Complications of sclerotherapy were reported during follow-up. RESULTS: Decrease or withdrawal of complaints of chronic venous insufficiency was reported in 96% of cases (50 patients). Disappearance or decrease of varicose veins was noted in all patients (100%). During examination after 12 months, full success of ultrasound was achieved in 38 (73%) cases, and 11 (21%) patients presented a partial desired effect according to the consensus from Tegernsee. Persistence of reflux longer than 1 s in the treated great saphenous vein was reported in 3 (6%) cases. Serious complications, such as deep vein thrombosis, pulmonary embolism, dyspnea, anaphylaxis, or neurological abnormalities, were not recorded. CONCLUSIONS: Ultrasound-guided foam sclerotherapy of incompetent great saphenous vein and varicosities with 2% polidocanol was found to be an effective and safe method of treatment during 1 year of observation. However, longer observation is necessary. PMID- 27458486 TI - Arthroscopically assisted anterior cruciate ligament reconstruction with bone patellar tendon-bone autograft without wound drainage: short- to middle-term outcome. AB - INTRODUCTION: Several studies have suggested that anterior cruciate ligament reconstruction (ACLR) without wound drainage has no impact on long-term follow up. AIM: To investigate a prospective patient series as measured by the patient administered disease-specific questionnaire Knee injury and Osteoarthritis Outcome Score (KOOS). MATERIAL AND METHODS: The study included 101 consecutive patients (71 men and 30 women) with a mean age of 30 years (SD 10, range: 15-62 years), who had undergone primary single incision arthroscopic bone-patellar tendon-bone autograft (BPTB) ACLR without wound drainage. All patients completed KOOS questionnaires, preoperatively and at a mean follow-up of 1.4 years (range: 0.4-3.4). Satisfactory clinical outcome (function recovery - FR) was defined as the lower threshold for the 95% CI of 18-34-year old males and corresponded to a KOOS score > 90 for Pain, 84 for Symptoms, 91 for Activities of Daily Living (ADL), 80 for Sports/Recreation, and 81 for Quality of Life (QOL). A non satisfactory result was defined as treatment failure (TF) and corresponded to a QOL score < 44. RESULTS: All patients achieved 90 degrees of knee flexion on the first postoperative day and full extension 2 weeks postoperatively. A full range of motion was achieved in less than 6 weeks postoperatively. No postoperative complications were reported. Score improvement at follow-up was observed in the KOOS subscales Pain, Symptoms and ADL. Criteria for FR were fulfilled by 52% of patients for Pain, 47% for Symptoms, 62% for ADL, 34% for Sports/Recreation and 15% for QOL, whereas criteria for TF were fulfilled by 29% of patients. CONCLUSIONS: The study demonstrated that the primary ACLRs without wound drainage did not have any negative impact for patient-reported recovery. PMID- 27458487 TI - Laparoscopic peritoneal lavage: our experience and review of the literature. AB - INTRODUCTION: Over the years various therapeutic techniques for diverticulitis have been developed. Laparoscopic peritoneal lavage (LPL) appears to be a safe and useful treatment, and it could be an effective alternative to colonic resection in emergency surgery. AIM: This prospective observational study aims to assess the safety and benefits of laparoscopic peritoneal lavage in perforated sigmoid diverticulitis. MATERIAL AND METHODS: We surgically treated 70 patients urgently for complicated sigmoid diverticulitis. Thirty-two (45.7%) patients underwent resection of the sigmoid colon and creation of a colostomy (Hartmann technique); 21 (30%) patients underwent peritoneal laparoscopic lavage; 4 (5.7%) patients underwent colostomy by the Mikulicz technique; and the remaining 13 (18.6%) patients underwent resection of the sigmoid colon and creation of a colorectal anastomosis with a protective ileostomy. RESULTS: The 66 patients examined were divided into 3 groups: 32 patients were treated with urgent surgery according to the Hartmann procedure; 13 patients were treated with resection and colorectal anastomosis; 21 patients were treated urgently with laparoscopic peritoneal lavage. We had no intraoperative complications. The overall mortality was 4.3% (3 patients). In the LPL group the morbidity rate was 33.3%. CONCLUSIONS: Currently it cannot be said that LPL is better in terms of mortality and morbidity than colonic resection. These data may, however, be proven wrong by greater attention in the selection of patients to undergo laparoscopic peritoneal lavage. PMID- 27458488 TI - Single stage bilateral uniportal videothoracoscopic sympathicotomy for hyperhidrosis: can it be managed as an outpatient procedure? AB - INTRODUCTION: The videothoracoscopic approach is minimally invasive with benefits that include less postoperative pain and shorter hospital stay. It is also a safe procedure which can be performed on an outpatient basis. AIM: To determine whether videothoracoscopic sympathicotomy can be performed safely in most patients as an outpatient procedure. MATERIAL AND METHODS: Between July 2005 and October 2015, a total of 92 patients underwent bilateral and single port thoracoscopic sympathicotomy in our department on an outpatient basis. The level of sympathicotomy was T2 in 2 (2.2%) patients, T2 to T3 in 31 (33%) patients, T2 to T4 in 46 (50%) patients and T3 to T4 in 12 (13%) patients. Demographic data, length of postoperative stay, substitution index (SI), admission rate (AR) and readmission rate (RR), complications and patient satisfaction were reviewed retrospectively. RESULTS: Two (2.2%) patients suffered from chest pain, while 4 (4.3%) patients complained about pain at the port site. Mean discharge time after surgery was 5.1 h (range: 4-6 h), mean duration of hospital stay was 0.15 days (0 3 days) postoperatively and the mean operation time was 43.6 min (15-130 min). In 8 (8.6%) patients, pneumothorax was detected on postoperative chest X-ray, while 5 (5.4%) patients required chest tube drainage. Mild or moderate compensatory sweating developed in 32 (34.7%) patients. No recurrence was observed, and the satisfaction rate was 96.7%. Substitution index and admission rate were 91.3% and 11% respectively, while RR was 0%. CONCLUSIONS: Bilateral video-assisted thoracoscopic sympathicotomy can be performed safely in most patients as an outpatient procedure. PMID- 27458489 TI - Patient comfort during flexible and rigid cystourethroscopy. AB - INTRODUCTION: Cystourethroscopy (CS) is an endoscopic method used to visualize the urethra and the bladder. AIM: In this study, we prospectively evaluated pain in men undergoing cyclic cystoscopic assessment with rigid and flexible instruments after transurethral resection of bladder tumor (TURB). MATERIAL AND METHODS: One hundred and twenty male patients who were under surveillance after a TURB procedure due to urothelial cell carcinoma and who had undergone at least one rigid cystourethroscopy in the past were enrolled in the trial. Patients were prospectively randomized to age-matched groups for flexible (group F) or rigid (group R) CS. Patient's comfort was evaluated on an 11-grade scale, ranging from 0 (free from pain) to 10 points (unbearable pain). RESULTS: The patients described the pain during the previous rigid CS as ranging from 4 to 10 (mean: 6.8) in group F and from 0 to 10 (mean: 5.8) in group R. Group R patients described the pain during the current rigid CS as ranging from 0 to 10 (mean: 5.7). No mean change in the grade was observed between the two pain descriptions (no change 11 patients, weaker pain 25 patients, stronger pain 24 patients, gamma 0.51, p < 0.0001). Group F described the pain as 1 to 5 (mean: 2.1). In the case of flexible CS the pain experience was greatly lowered compared to the previous rigid CS. All flexible CS patients reported lowered pain (by 1 to 9 grades). Patients' age did not influence the comfort of the flexible CS or the change in pain level. CONCLUSIONS: Flexible CS is better tolerated than rigid cystoscopy by male patients regardless of patients' age. PMID- 27458490 TI - Minimally invasive repair of pectus excavatum (MIRPE) in adults: is it a proper choice? AB - INTRODUCTION: The Nuss procedure is suitable for prepubertal and early pubertal patients but can also be used in adult patients. AIM: To determine whether the minimally invasive technique (MIRPE) can also be performed successfully in adults. MATERIAL AND METHODS: Between July 2006 and January 2016, 836 patients (744 male, 92 female) underwent correction of pectus excavatum with the MIRPE technique at our institution. The mean age was 16.8 years (2-45 years). There were 236 adult patients (28.2%) (> 18 years) - 20 female, 216 male. The mean age among the adult patients was 23.2 years (18-45 years). The recorded data included length of hospital stay, postoperative complications, number of bars used, duration of the surgical procedure and signs of pneumothorax on the postoperative chest X-ray. RESULTS: The MIRPE was performed in 236 adult patients. The average operative time was 44.4 min (25-90 min). The median postoperative stay was 4.92 +/-2.81 days (3-21 days) in adults and 4.64 +/-1.58 (2-13) in younger patients. The difference was not statistically significant (p = 0.637). Two or more bars were used in 36 (15.8%) adult patients and in 44 (7.5%) younger patients. The difference was not statistically significant either (p = 0.068). Regarding the overall complications, complication rates among the adult patients and younger patients were 26.2% and 11.8% respectively. The difference was statistically significant (p = 0.007). CONCLUSIONS: MIRPE is a feasible procedure that produces good long-term results in the treatment of pectus excavatum in adults. PMID- 27458491 TI - Two-port laparoscopic appendectomy with the help of a needle grasper: better cosmetic results and fewer trocars than conventional laparoscopic appendectomy. AB - INTRODUCTION: The two-port laparoscopic appendectomy technique (TPLA) lays between the conventional three-port trocar procedure and single-port laparoscopic appendectomy surgery. During TPLA, the appendix is suspended with stitches, resulting in perforation risk and difficulty in exploration. AIM: We used a needle grasper in TPLA to hang and manipulate the appendix. MATERIAL AND METHODS: Thirty-four patients (10 female, 24 male) who underwent TPLA between February 2015 and November 2015 were analyzed retrospectively for patient demographics, duration of operation, laparotomy or conventional laparoscopy necessity, drain use, complications, and hospital stay periods. The needle grasper was inserted at the right under the abdominal quadrant (McBurney point) without an incision to hang and manipulate the appendix. RESULTS: The mean age was 25.19 +/-8.464 years; the mean body mass index (BMI) was 23.50 +/-3.246 kg/m(2). ASA scores were 1 and 2. The operations were completed without any additional trocar in 34 patients. The mean operation time was 57.03 +/-3.814 min. There were no intraoperative complications in any patients. Three patients required a drain; all were discharged after drain removal. Thirty-one patients were discharged on the 1(st) postoperative day; three patients with drains were discharged on the 2(nd) day. The mean hospital stay period was 1.18 +/-0.535 days. CONCLUSIONS: Using the needle grasper, the appendix was held and suspended and the mesoappendix was cauterized and skeletonized successfully in TPLA. Inserting a needle grasper into the abdominal cavity at the McBurney point to manipulate the appendix helps and does not leave a visible scar. PMID- 27458492 TI - Acute limb ischemia caused by incorrect deployment of a clip-based arterial closure device. AB - Failure of a vascular closure device most commonly results in a hemorrhage or pseudoaneurysm formation. In this paper a rare case of severe acute limb ischemia following incorrect deployment of a clip-based closure device (Starclose SE, Abbott Vascular) in a 31-year-old woman is presented. Symptoms of acute limb ischemia occurred at the start of the ambulation, 6 h after completion of the procedure. Because of the severity of ischemia the patient was treated surgically, and limb perfusion was successfully restored. An attempt of closure of an inadvertently punctured narrow superficial femoral artery was identified as the cause of this complication. PMID- 27458493 TI - Laparoscopic and natural orifice transluminal restorative proctocolectomy: no abdominal incision for specimen extraction or ileostomy. AB - The aim of this study was to demonstrate the feasibility of laparoscopic restorative proctocolectomy (LRPC) without additional abdominal incisions. Two sisters with familial adenomatous polyposis were enrolled. The colon and rectum were mobilized entirely through the five abdominal trocars. The terminal ileum and distal rectum were transected with endoscopic staplers. The entire colorectal specimen was extracted transanally. A circular stapler anvil was introduced transanally. The J-pouch was created intracorporeally. The rectal stump was re closed and a pouch-anal anastomosis was created using a circular stapler. We used a transanal tube for decompression of the pouch instead of a diverting ileostomy. The patients were discharged on the 10(th) and 12(th) days uneventfully. Both were doing well with their pouches after 18.5 and 12.1 months of follow-up. With the help of transanal specimen extraction and transanal tube decompression, additional abdominal incisions can be avoided following LRPC. PMID- 27458494 TI - Diagnosis and management of early gastric band slip after laparoscopic adjustable gastric banding. AB - Laparoscopic adjustable gastric banding (LAGB) used to be a very popular bariatric procedure at a certain time for the treatment of obesity as it has many advantages and is associated with low morbidity and mortality rates. Complications are often late and are rarely seen by general surgeons due to the limited number of patients, and physicians should be aware of the symptoms. We present a case of a 40-year-old female patient who underwent LAGB and was admitted for a huge gastric pouch dilatation on postoperative day 5. She had a history of food consumption on the fourth day after surgery. She was diagnosed with early gastric band slippage (EGBS). The band was repositioned and gastrogastric sutures were placed to prevent reprolapse of the band. The EGBS is an immediate postoperative complication. Diagnosis of EGBS can be made with oral contrast X-ray studies, and surgical intervention is necessary. PMID- 27458495 TI - MULTILINEAR TENSOR REGRESSION FOR LONGITUDINAL RELATIONAL DATA. AB - A fundamental aspect of relational data, such as from a social network, is the possibility of dependence among the relations. In particular, the relations between members of one pair of nodes may have an effect on the relations between members of another pair. This article develops a type of regression model to estimate such effects in the context of longitudinal and multivariate relational data, or other data that can be represented in the form of a tensor. The model is based on a general multilinear tensor regression model, a special case of which is a tensor autoregression model in which the tensor of relations at one time point are parsimoniously regressed on relations from previous time points. This is done via a separable, or Kronecker-structured, regression parameter along with a separable covariance model. In the context of an analysis of longitudinal multivariate relational data, it is shown how the multilinear tensor regression model can represent patterns that often appear in relational and network data, such as reciprocity and transitivity. PMID- 27458497 TI - How Do You Deactivate Painful Scars in Your Practice? PMID- 27458496 TI - A Randomized Exploratory Study to Evaluate Two Acupuncture Methods for the Treatment of Headaches Associated with Traumatic Brain Injury. AB - Background: Headaches are prevalent among Service members with traumatic brain injury (TBI); 80% report chronic or recurrent headache. Evidence for nonpharmacologic treatments, such as acupuncture, are needed. Objective: The aim of this research was to determine if two types of acupuncture (auricular acupuncture [AA] and traditional Chinese acupuncture [TCA]) were feasible and more effective than usual care (UC) alone for TBI-related headache. Materials and Methods:Design: This was a three-armed, parallel, randomized exploratory study. Setting: The research took place at three military treatment facilities in the Washington, DC, metropolitan area. Patients: The subjects were previously deployed Service members (18-69 years old) with mild-to-moderate TBI and headaches. Intervention: The interventions explored were UC alone or with the addition of AA or TCA. Outcome Measures: The primary outcome was the Headache Impact Test (HIT). Secondary outcomes were the Numerical Rating Scale (NRS), Pittsburgh Sleep Quality Index, Post-Traumatic Stress Checklist, Symptom Checklist-90-R, Medical Outcome Study Quality of Life (QoL), Beck Depression Inventory, State-Trait Anxiety Inventory, the Automated Neuropsychological Assessment Metrics, and expectancy of outcome and acupuncture efficacy. Results: Mean HIT scores decreased in the AA and TCA groups but increased slightly in the UC-only group from baseline to week 6 [AA, -10.2% (-6.4 points); TCA, -4.6% (-2.9 points); UC, +0.8% (+0.6 points)]. Both acupuncture groups had sizable decreases in NRS (Pain Best), compared to UC (TCA versus UC: P = 0.0008, d = 1.70; AA versus UC: P = 0.0127, d = 1.6). No statistically significant results were found for any other secondary outcome measures. Conclusions: Both AA and TCA improved headache-related QoL more than UC did in Service members with TBI. PMID- 27458498 TI - Coaching mental health peer advocates for rural LGBTQ people. AB - Lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) people are affected by mental health disparities, especially in rural communities. We trained peer advocates in rural areas in the fundamentals of mental health, outreach, education, and support for this population. The peer advocates were coached by licensed mental health professionals. We evaluated this process through iterative qualitative analysis of semi-structured interviews and written logs from coaches and advocates. The six major themes comprising the results centered on (1) coaching support, (2) peer advocate skills and preparation, (3) working with help seekers, (4) negotiating diversity, (5) logistical challenges in rural contexts, and (6) systemic challenges. We concluded that peer advocacy for LGBTQ people with mental distress offers an affirmative, community-based strategy to assist the underserved. To be successful, however, peer advocates will likely require ongoing training, coaching, and infrastructural support to negotiate contextual factors that can influence provision of community resources and support to LGBTQ people within rural communities. PMID- 27458499 TI - On Various Nonlinearity Measures for Boolean Functions. AB - A necessary condition for the security of cryptographic functions is to be "sufficiently distant" from linear, and cryptographers have proposed several measures for this distance. In this paper, we show that six common measures, nonlinearity, algebraic degree, annihilator immunity, algebraic thickness, normality, and multiplicative complexity, are incomparable in the sense that for each pair of measures, MU1, MU2, there exist functions f1, f2 with f1 being more nonlinear than f2 according to MU1, but less nonlinear according to MU2. We also present new connections between two of these measures. Additionally, we give a lower bound on the multiplicative complexity of collision-free functions. PMID- 27458500 TI - Successful use of cyclosporine as treatment for eosinophilic cystitis: a case report. AB - BACKGROUND: Eosinophilic cystitis is a rare inflammatory disorder characterized by eosinophilic infiltration of all layers of the urinary bladder wall. Due to lack of consensus and potential for side effect from various therapeutic options, treatment of the disease is often challenging. CASE PRESENTATION: A 64-year old woman with hypertensive nephropathy resulting in stage III chronic kidney disease, obstructive sleep apnea, and obstructive lung disease presented with a 4 month history of dysuria, urgency, frequency, and persistent hematuria. Based on eosinophilic infiltration on bladder wall biopsy in the absence of any evidence of infection, malignancy, or immune disorder, she was diagnosed with eosinophilic cystitis. Despite multiple medication regimens, her symptoms persisted, requiring high-dose prednisone with steroid-related side effects. After four months, she was started on cyclosporine, which led to symptomatic improvement and reduction in prednisone dosage. At that time, repeat urine cytology and cystoscopy did not reveal friable tissues or eosinophiluria. CONCLUSION: This case illustrates the utility of using cyclosporine to treat eosinophilic cystitis in adult patient with multiple comorbid conditions. PMID- 27458502 TI - Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management. AB - Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day (diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease (NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD. PMID- 27458503 TI - Lipogenesis in Huh7 cells is promoted by increasing the fructose: Glucose molar ratio. AB - AIM: To determine whether hepatocyte lipogenesis, in an in vitro cell culture model, is modulated by adjusting culture media monosaccharide content and concentration. METHODS: Hepatocytes (Huh7), demonstrating glucose and fructose uptake and lipid biosynthesis, were incubated in culture media containing either glucose alone (0.65-0.72 mmol/L) or isosmolar monosaccharide (0.72 mmol/L) comprising fructose:glucose (F:G) molar ratios ranging from 0.58-0.67. Following a 24-h incubation, cells were harvested and analyzed for total protein, triglyceride (TG) and cholesterol (C) content. Significant differences (P < 0.05) among groups were determined using analysis of variance followed by Dunnett's test for multiple comparisons. RESULTS: After a 24 h incubation period, Huh7 cell mass and viability among all experimental groups were not different. Hepatocytes cultured with increasing concentrations of glucose alone did not demonstrate a significant change either in C or in TG content. However, when the culture media contained increasing F:G molar ratios, at a constant total monosaccharide concentration, synthesis both of C and of TG increased significantly [F:G ratio = 0.58, C/protein (MUg/MUg) = 0.13; F:G = 0.67, C/protein = 0.18, P < 0.01; F:G ratio = 0.58, TG/protein (MUg/MUg) = 0.06; F:G ratio = 0.67, TG/protein = 0.11, P < 0.01]. CONCLUSION: In an in vitro hepatocyte model, glucose or fructose plus glucose support total cell mass and lipogenic activity. Increasing the fructose:glucose molar ratio (but not glucose alone) enhances triglyceride and cholesterol synthesis. These investigations demonstrate fructose promotes hepatocellular lipogenesis, and they provide evidence supporting future, in vivo studies of fructose's role in the development of hepatic steatosis and non alcoholic fatty liver disease. PMID- 27458504 TI - Aluminum potassium sulfate and tannic acid sclerotherapy for Goligher Grades II and III hemorrhoids: Results from a multicenter study. AB - AIM: To show that aluminum potassium sulfate and tannic acid (ALTA) sclerotherapy has a high success rate for Grade II and III hemorrhoids. METHODS: This study was based on the clinical data of 604 patients with hemorrhoids who underwent ALTA sclerotherapy between January 2009 and February 2015. The objective of this study was to assess the efficacy of this treatment for Grades II and III hemorrhoids. Preoperative and postoperative symptoms, complications and success rate were all assessed retrospectively. Follow-up consisted of a simple questionnaire, physical examination and an anoscopy. Patients were followed-up at one day, one week, two weeks, one month, one year, two years, three years, four years and five years after the ALTA sclerotherapy. RESULTS: One hundred and sixty-nine patients were diagnosed with Grade II hemorrhoids and 435 patients were diagnosed with Grade III hemorrhoids. The one year, three year and five year cumulative success rates of ALTA sclerotherapy for Grades II and III hemorrhoids were 95.9% and 93.1%; 89.3% and 83.7%; and 89.3% and 78.2%, respectively. No significant differences were observed in the cumulative success rates after ALTA sclerotherapy between Grades II and III hemorrhoids (P = 0.09). There were forty-seven post-operative complications (low grade fever; anal pain; urinary retention; rectal ulcer; and others). No serious or life-threatening complications occurred and all cases improved through conservative treatment. At univariate analysis there were no predictive factors of failure. CONCLUSION: ALTA sclerotherapy has had a high success rate for Grade II and III hemorrhoids during five years of post-operative treatment. However, additional studies are needed to evaluate the efficacy of this ALTA sclerotherapy in the management of hemorrhoidal disease. PMID- 27458501 TI - Eosinophilic esophagitis: published evidences for disease subtypes, indications for patient subpopulations, and how to translate patient observations to murine experimental models. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus and commonly classified as a Th2-type allergy. Major advances in our understanding of the EoE pathophysiology have recently been made, but clinicians struggle with highly unpredictable therapy responses indicative of phenotypic diversity within the patient population. Here, we summarize evidences for the existence of EoE subpopulations based on diverse inflammatory characteristics of the esophageal tissue in EoE. Additionally, clinical characteristics of EoE patients support the concept of disease subtypes. We conclude that clinical and experimental evidences indicate that EoE is an umbrella term for conditions that are unified by esophageal eosinophilia but that several disease subgroups with various inflammatory esophageal patterns and/or different clinical features exist. We further discuss strategies to study the pathophysiologic differences as observed in EoE patients in murine experimental EoE. Going forward, models of EoE that faithfully mimic EoE subentities as defined in humans will be essential because mechanistic studies on triggers which regulate the onset of diverse EoE subpopulations are not feasible in patients. Understanding how and why different EoE phenotypes develop will be a first and fundamental step to establish strategies that integrate individual variations of the EoE pathology into personalized therapy. PMID- 27458505 TI - Transjugular intrahepatic portosystemic shunt combined with esophagogastric variceal embolization in the treatment of a large gastrorenal shunt. AB - AIM: To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) combined with stomach and esophageal variceal embolization (SEVE) in cirrhotic patients with a large gastrorenal vessel shunt (GRVS). METHODS: Eighty-one cirrhotic patients with gastric variceal bleeding (GVB) associated with a GRVS were enrolled in the study and accepted TIPS combined with SEVE (TIPS + SEVE), by which portosystemic pressure gradient (PPG), biochemical, TIPS-related complications, shunt dysfunction, rebleeding, and death were evaluated. RESULTS: The PPGs before TIPS were greater than 12 mmHg in 81 patients. TIPS + SEVE treatment caused a significant decrease in PPG (from 37.97 +/- 6.36 mmHg to 28.15 +/- 6.52 mmHg, t = 19.22, P < 0.001). The percentage of reduction in PPG was greater than 20% from baseline. There were no significant differences in albumin, alanine aminotransferase, aspartate aminotransferase, bilirubin, prothrombin time, or Child-Pugh score before and after operation. In all patients, rebleeding rates were 3%, 6%, 12%, 18%, and 18% at 1, 3, 6, 12, and 18 mo, respectively. Five patients (6.2%) were diagnosed as having hepatic encephalopathy. The rates of shunt dysfunction were 0%, 4%, 9%, 26%, and 26%, at 1, 3, 6, 12, and 18 mo, respectively. The cumulative survival rates in 1, 3, 6, 12, and 18 mo were 100%, 100%, 95%, 90%, and 90%, respectively. CONCLUSION: Our preliminary results indicated that the efficacy and safety of TIPS + SEVE were satisfactory in cirrhotic patients with GVB associated with a GRVS (GVB + GRVS). PMID- 27458506 TI - Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report. AB - The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R. PMID- 27458507 TI - Association between celiac disease and chronic hepatitis C. AB - Celiac disease is characterized by a gluten-induced damage of the small bowel in sensitive individuals that may cause malabsorption. Non-intestinal inflammatory diseases may trigger immunologic gluten intolerance in susceptible people and the HCV virus may be considered as a suitable candidate. Interferon therapy could precipitate symptom onset in subjects with silent celiac disease. In fact, symptoms such as diarrhea, anemia, and weight loss may occur during interferon therapy and are associated with serological positivity of anti-tranglutaminase antibodies. To date, considering the available literature data, it is very difficult to support a firm association between HCV chronic hepatitis and celiac disease. Thus, such a serological screening in HCV patients before starting interferon therapy should not be recommended. However, serology for celiac disease must be considered in patients who develop diarrhea and/or weight loss during such therapy. PMID- 27458509 TI - Creation of a murine orthotopic hepatoma model with intra-abdominal metastasis. AB - AIM: To create an orthotopic hepatoma model with local metastasis monitored with ultrasound could be created as a platform for testing new treatments. BACKGROUND: Hepatoma accounts for 25% of liver tumors in children with poor overall survival. Intraabdominal metastasis are present in 35% of patients at time of diagnosis. We hypothesized that an orthotopic tumor model with local metastasis could be created as a platform for testing treatment modalities and could be monitored with ultrasound. PATIENTS AND METHODS: One million human hepatoma cells (Hep3B) were injected into the left lobe of the liver of immunocompromised mice. Tumor volume was monitored with high frequency-ultrasound until it reached 1,000mm(3). At that time animals were sacrificed and examined for gross metastatic disease. Tumor sections were analyzed with hematoxylin and eosin (H&E) staining. RESULTS: Tumor formed in 8/15 mice. The tumor was detected as small as 19.59mm(3) on ultrasound. Of the forming tumors, tumor size was 145+/-177.93mm(3) at 60 days post-injection, 665+/-650.39mm(3) at 67 days, and reached >1000mm(3) by 76.6+/ 9.9 days. At necropsy, four mice (50%) had tumor only within the liver, four (50%) had additional tumors in omentum, pelvis and peritoneum. H&E showed tumor within the normal liver parenchyma, with multiple mitotic figures, small areas of necrosis, and hemorrhage within the tumor. CONCLUSION: We have successfully established an orthotopic hepatoma murine model, with a local metastatic rate of 50%. Non-invasive tumor monitoring is feasible via ultrasound. PMID- 27458508 TI - Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases. AB - Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies. PMID- 27458510 TI - Changes in portal blood flow and liver functions in cirrhotics during Ramadan fasting in the summer; a pilot study. AB - AIM: Assessment of short term changes in portal blood flow and long term changes in liver functions in cirrhotic patients who chose to fast during the month of Ramadan in summer. BACKGROUND: During Ramadan, healthy Muslims obligated to fast from predawn to sunset. PATIENTS AND METHODS: Forty cirrhotic patients intended to fast during the month of Ramadan in the year 2014, were examined by Congestion index (CI) as a non-invasive indicator of short term changes in the portal blood flow, while liver function tests were determined as an indicator of long term changes in liver functions. RESULTS: A total of 38 patients completed the whole month fasting and two patients discontinued fasting due to variceal bleeding. The complicated patients were 7. CI showed a statistically significant increase from fasting to postprandial status (P<0.001), with statistically significant increases from fasting to postprandial status in Child class A (P<0.001), and B (P<0.001). We did not find a statistical significance between patients with complications and those without complications (P=0.6). There was a statistically significant rise in the serum bilirubin after Ramadan. Deterioration noticed as advanced Child classes, development of lower limb edema, increasing ascites, increasing jaundice and overt encephalopathy. CONCLUSION: Cirrhotic patients showed significant short-term changes in the portal blood flow. However, these changes are not linked to complications or deterioration of liver functions and accommodated especially in patients with Child class A and B. Child class C patients should not fast. PMID- 27458511 TI - Postoperative pain relief after laparoscopic cholecystectomy: intraperitoneal sodium bicarbonate versus normal saline. AB - AIM: The aim of this study was to determine the effect of sodium bicarbonate irrigation versus normal saline irrigation in patients undergoing a laparoscopic cholecystectomy. BACKGROUND: Pain in patients undergoing laparoscopic cholecystectomy is the most common complaint, especially in the abdomen, back, and shoulder region. PATIENTS AND METHODS: In a double blind randomized clinical trial, 150 patients were assigned to the three groups (50 patients in each group). Group A received intraperitoneal irrigation normal saline (NS). Groups B and C received irrigation sodium bicarbonate and none irrigation, respectively. Pain was assessed using a visual analog scale (VAS) for 6, 18 and 24 hours postoperatively, as well as one week after the surgery. Data analysis was performed using SPSS ver18 and chi-square, Fisher's Exact Test, on-way ANOVA and repeated measure ANOVA tests. RESULTS: Patients in groups showed no significant difference in terms of age, gender, past medical history and smoking history (p>0.05). Left shoulder tip pain was significantly lower only between the sodium bicarbonate group and non-washing group at 6, 18, and 24 hours postoperatively (P=0.04, P=0.02 and P=0.009 respectively). There was no significant difference between the three treatment groups in right shoulder tip pain, back pain and port site incisional pain. CONCLUSION: In laparoscopic cholecystectomy, peritoneal irrigation with sodium bicarbonate may reduce the intensity of postoperative shoulder tip pain and is an effective method for improving the quality of life within the early recovery period. PMID- 27458512 TI - Synthesis and evaluation of multi-wall carbon nanotube-paclitaxel complex as an anti-cancer agent. AB - AIM: The aim of this study was to design multi-walled carbon nanotubes (MWCNTs) loaded with paclitaxel (PTX) anti-cancer drug and investigate its anti-cancerous efficacy of human gastric cancer. BACKGROUND: Carbon nanotubes (CNTs) represent a novel nano-materials applied in various fields such as drug delivery due to their unique chemical properties and high drug loading. PATIENTS AND METHODS: In this study, multi-walled carbon nanotubes (MWCNTs) pre-functionalized covalently with a paclitaxel (PTX) as an anti-cancer drug and evaluated by different analyses including, scanning electron microscope (SEM), particle size analyzer and cellular analyses. RESULTS: A well conjugated of anti-cancer drug on the carbon nanotube surfaces was shown. This study demonstrates that the MWCN-PTX complex is a potentially useful system for delivery of anti-cancer drugs. The flow cytometry, CFU and MTT assay results have disclosed that MWCNT/PTXs might promote apoptosis in MKN-45 gastric adenocarcinoma cell line. CONCLUSION: According to results, our simple method can be designed a candidate material for chemotherapy. It has presented a few bio-related applications including, their successful use as a nano-carriers for drug transport. PMID- 27458513 TI - Molecular diagnosis and anti-microbial resistance patterns among Shigella spp. isolated from patients with diarrhea. AB - AIM: This study aims to determine the serogroup distribution and molecular diagnosis, as well as antimicrobial resistance profiles among Shigella spp. isolated from patients with diarrhea in Kerman, southeast of Iran. BACKGROUND: Shigella species are frequent cause of bacterial dysentery worldwide. Previous studies have been reported that S. sonnei and S. flexneri are the most prevalent serogroups in various parts of Iran. PATIENTS AND METHODS: A total of 624 stool samples were randomly collected from patients with diarrhea from June 2013 to August 2014. Biochemical and serological characterizations were performed for identifying Shigella spp. In addition, the multiplex PCR assay was carried out for the detection and differentiation of three pathogenic Shigella spp. Antibiotic susceptibility testing was performed according to the Clinical Laboratory Standards Institute (CLSI) guidelines. RESULTS: Fifty six (9%) Shigella strains were isolated from stool samples. The most common species were S. flexneri 31(55.4%), followed by S . sonnei 18(32.1%) and S. boydii 7(12.5%). S. dysentery was not detected in the present study. All the isolates that identified by serological test as Shigella spp. were confirmed by the multiplex PCR method. The highest rate of resistance was observed for ampicillin and trimethoprim-sulphamethoxazole antibiotics with 52(92.9%) resistant, followed by tetracycline 44(78.6%) and cefotaxime 33(58.9%). All Shigella isolates were susceptible to ciprofloxacin. A significant relationship was found between the Shigella species and cefotaxime resistance (p<0.05). CONCLUSION: S. flexneri was found as the most prevalent serogroup causing shigellosis. The high rate of resistance to third-generation cephalosporins limits the treatment options available for the management of shigellosis in Kerman, Iran. PMID- 27458514 TI - Development of systemic sclerosis in patients with autoimmune hepatitis: an emerging overlap syndrome. AB - AIM: We described two case reports of AIH/SSc overlap syndrome and reviewed literatures regarding this issue. BACKGROUND: AIH is a chronic hepatitis of unknown aetiology characterized by continuing hepatocellular necrosis and inflammation. AIH overlap syndromes have been reported with other autoimmune diseases. PATIENTS AND METHODS: According to the classification criteria for SSc, we conducted a retrospective chart review of 35 cases with biopsy-proven AIH over the past 5 years at our institution. We reviewed the MEDLINE database using the appropriate key-words. RESULTS: A chart review of 35 cases (M/F ratio 1:2, mean age 47.6+/-10.3 years) revealed nine patients (9/35, 25.7%) with CTD (four males and three females with a mean age of 45.1+/-8.4 years). All patients had ANA. Four patients were SSA/Ro positive UCTD (1/35, 2.85%), and six patients developed SLE (6/35, 17.1%). Only two female patients (2/35, 5.7%) with specific SSc AAb developed a systemic sclerosis. We described a patient with AIH who was diagnosed with diffuse systemic sclerosis-sine scleroderma with positive anti-centromere B and SSA/Ro52 KDa antibodies. We also reported a patient with AIH who was diagnosed limited SSc with contemporary presence of anti-centromere A and anti RNA polymerase III antibody. CONCLUSION: We suggest that SSc may be considered to be one of the manifestations associated with AIH. Patients with AIH may have an increased risk to develop SSc and should be followed, especially when Raynaud phenomenon was found. PMID- 27458515 TI - Pregnancy with autoimmune hepatitis. AB - AIM: The aim of this study was to review our experience with gestations in autoimmune hepatitis patients. BACKGROUND: There are only limited data describing pregnancy in patients with autoimmune hepatitis. PATIENTS AND METHODS: Retrospective analysis of pregnancies with autoimmune hepatitis followed in Centro Hospitalar do Porto, Portugal in the last ten years. RESULTS: We reported nine pregnancies in seven patients with autoimmune hepatitis. Two patients had documented liver cirrhosis prior to the pregnancy. In this study, 66.7% of patients were treated with azathioprine and 88.9% with prednisolone. Clinical improvements were observed in 11.1% of pregnancies and 22.2% exacerbations were diagnosed. There were six live births and two preterm deliveries (preterm delivery rate of 33%). We also report three first trimester miscarriages (early gestation miscarriage rate of 33%). There were no neonatal or maternal deaths. CONCLUSION: The favorable obstetric outcome is a realistic expectation in patients with autoimmune hepatitis. Tight monitoring and control of asymptomatic and unpredictable exacerbations, which are unrelated to the severity of the underlying disease, are essential to the prognosis of the current pregnancy. PMID- 27458516 TI - Clinical characteristics and response to therapy of autoimmune hepatitis in an urban Latino population. AB - AIM: We hypothesized that AIH outcomes might be different in our patient population that consists of a large number of Latinos. BACKGROUND: Literature has suggested that the presentation and outcome of autoimmune hepatitis can be different among different ethnicity and communities. PATIENTS AND METHODS: We performed a retrospective chart review of Latino patients with AIH diagnosed between 2002-2012. Complete and partial remissions were defined as normalization of liver enzyme values, or achieving less than twice the upper limit normal (ULN), respectively. RESULTS: A total of 28 patients were identified. 26 (93%) were female. 13 (46%) had an acute presentation, one with type 2 AIH and 3 with ANA seronegative disease. The average pathologic stage (Ishak score) was 3.44+/ 1.67 (range: 0-6). Complete and partial remission was achieved in 20 (71%) and 5 (18%) patients respectively. Ten patients (38%) required maintenance prednisone either alone (2), or in combination with Azathioprine (6) or Mycophenolate Mofetil (2). Remission in the majority of patients, including 14 (50%) who were cirrhotic. Six of 14 (43%) cirrhotic patients were asymptomatic at the time of diagnosis. CONCLUSION: In an urban Latino population, cirrhosis was the initial presentation of AIH in a significant percentage of patients raising concerns regarding insufficient screening for AIH in this patient population. A large number of patients required continuous prednisone to avoid relapse. PMID- 27458517 TI - Hepatitis A virus vaccination in Iranian soldiers needs more attention. PMID- 27458518 TI - Argon plasma coagulation is not effective in every vascular lesion. PMID- 27458519 TI - Recent advances in functional bowel disorders. PMID- 27458520 TI - Modification of Shape Memory Polymer Foams Using Tungsten, Aluminum Oxide, and Silicon Dioxide Nanoparticles. AB - Shape memory polymer (SMP) foams were synthesized with three different nanoparticles (tungsten, silicon dioxide, and aluminum oxide) for embolization of cerebral aneurysms. Ultra-low density SMP foams have previously been utilized for aneurysm occlusion, resulting in a rapid, stable thrombus. However, the small cross section of foam struts can potentially lead to fracture and particulate generation, which would be a serious adverse event for an embolic device. The goal of this study was to improve the mechanical properties of the system by physically incorporating fillers into the SMP matrix. Thermal and mechanical characterization suggested minimal changes in thermal transition of the SMP nanocomposites and improved mechanical strength and toughness for systems with low filler content. Actuation profiles of the three polymer systems were tuned with filler type and content, resulting in faster SMP foam actuation for nanocomposites containing higher filler content. Additionally, thermal stability of the SMP nanocomposites improved with increasing filler concentration, and particulate count remained well below accepted standard limits for all systems. Extraction studies demonstrated little release of silicon dioxide and aluminum oxide from the bulk over 16 days. Tungstun release increased over the 16 day examination period, with a maximum measured concentration of approxiately 2.87 MUg/mL. The SMP nanocomposites developed through this research have the potential for use in medical devices due to their tailorable mechanical properties, thermal resisitivity, and actuation profiles. PMID- 27458521 TI - The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation. AB - A biomaterial with both antithrombin and antiplatelet properties is the ideal surface for use in extracorporeal circulation (ECC) as it targets both fibrin generation and platelet adhesion. A hemocompatible surface coating avoids the need for systemic anticoagulation by providing a local anticoagulant effect at the polymer-blood interface. Previous work has demonstrated the potential use of argatroban, a direct thrombin inhibitor, as a nonthrombogenic material for extracorporeal devices. The work reported here focuses on the characterization of argatroban linked to a polyurethane-silicone polymer, CarboSil(r). Chemical immobilization, the amount of argatroban, incubation times, and saturation point were evaluated to achieve maximal antithrombin activity at the polymer surface. Cross-linked polymer coatings reacted with 10 and 30 umole of argatroban were prepared and tested. These coatings resulted in argatroban activity levels of 0.131 uM and 0.446 uM, respectively. After refining the cross-linking process, argatroban activity increased by approximately 3.6 fold. Maintenance of activity and leaching from the polymer surface were also evaluated. Using the refined process for linking argatroban to polymer, the resulting polymer was applied as a surface coating to the inner lumen of poly(vinyl chloride) ECC circuit tubing and its antithrombin effect evaluated using a 4 h rabbit ECC model. Following 4 h of blood exposure, the argatroban circuit demonstrated significantly less thrombus formation compared to the control CarboSil(r) coating with a 4.1 cm2 thrombus average area for the control coating compared to 1.2 cm2 for the argatroban coating (n=4). There was no significant change in thrombin time from baseline in plasma from animals in which the argatroban coated circuit was used, with a thrombin time of 16.2 s at t=0 and 14.5 s after 4 h. These results demonstrate the potential efficacy of immobilized argatroban as a hemocompatible biomaterial for extracorporeal life support devices. PMID- 27458522 TI - Physician-level variation in the diagnosis of myocardial infarction and the use of angiography among Veterans with elevated troponin. AB - BACKGROUND: Cardiac troponin assays have improved the ability to detect myocardial damage. However, ascertaining whether troponin elevation is due to myocardial infarction (MI) or secondary to another process can be challenging. Our aim is to evaluate provider-level variation in the diagnosis of MI and the use of invasive coronary angiography (ICA) among patients with undifferentiated elevations in cardiac troponin. METHODS: We analyzed data from all patients with elevated troponin levels in a single Veterans Affairs (VA) Medical Center between 2006 and 2007. One of several cardiologists prospectively evaluated each patient's presentation and course of care. We compared the frequency of MI diagnosis and ICA use between physicians using univariate odds ratios (OR). RESULTS: Among 761 patients, 34.0 % were diagnosed with MI and 25.9 % underwent ICA. The unadjusted rates of MI (23.9 to 56.7 %, P = 0.02) and ICA (17.3 to 73.3 %, P < 0.001) differed between physicians. Comparing the patient cohorts for each physician, baseline characteristics were similar except for chest pain. In multivariate regression, factors associated with the use of cardiac ICA included an abnormal electrocardiograph (ECG) (OR = 1.89, P = 0.014), level of troponin (OR = 1.71, P = 0.004), chest pain (OR = 8.60, P < 0.001), and care by non-VA physicians (OR = 4.45, P = 0.006). One physician had a lower ICA use (OR = 0.56, P = 0.017). In multivariate regression of MI, no physician-level variation was observed. CONCLUSION: Among patients with elevated troponin, the likelihood of being diagnosed with MI and undergoing ICA is dependent on their clinical presentation. After adjustment, physician-level variation in care was observed for the use of ICA, but not for the diagnosis of MI. PMID- 27458523 TI - Prevalence of pale, soft, and exudative (PSE) condition in chicken meat used for commercial meat processing and its effect on roasted chicken breast. AB - BACKGROUND: Studies on prevalence of pale, soft, exudative (PSE) condition in Sri Lankan poultry industry is minimal. Hence, the objective of present study was to determine the incidence of PSE chicken meat in a commercial meat processing plant and to find out its consequences on meat quality traits of roasted chicken breast. METHOD: A total of 60 breast fillets were randomly selected, evaluated based on color L* value, and placed into 1 of 2 categories; PSE (L* > 58) or normal meat (L* <= 58). A total of 20 breast fillets (10 PSE and 10 normal) were then analyzed for color, pH, and water holding capacity (WHC). After processing those into roasted chicken breast, cooking loss, color, pH, WHC, and texture values were evaluated. A sensory evaluation was conducted using 30 untrained panelists. RESULTS: The incidence of PSE meat was 70 % in the present experiment. PSE fillets were significantly lighter and had lower pH values compared with normal fillets. Correlation between the lightness and pH was negative (P < 0.05). Although there was no significant difference in color, texture, and WHC values between the 2 groups after processing into roasted chicken breast (P > 0.05), an approximately 3 % higher cooking loss was observed in PSE group compared to its counterpart (P < 0.05). Moreover, cooking loss and lightness values showed a significant positive correlation. Nevertheless, there were no significant differences in sensory parameters between the 2 products (P > 0.05). CONCLUSIONS: These results indicated that an economical loss can be expected due to the significantly higher cooking loss observed in roasted breast processed from PSE meat. PMID- 27458524 TI - Mental health, life functioning and risk factors among people exposed to frequent natural disasters and chronic poverty in Vietnam. AB - BACKGROUND: People living in low- and middle-income countries (LMIC) are at increased risk for exposure to major natural disasters, which places them at increased risk for mental health problems. Evidence is less clear, however, regarding the effects of less severe but more frequent natural disasters, which are likely to increase due to global climate change. AIMS: To examine the mental health and life functioning, and their predictors, of people living in central coastal Vietnam, an area characterized by high risk for natural disasters and poverty. METHOD: 1000 individuals were randomly selected from 5 provinces in central coastal Vietnam. Individuals were assessed cross-sectionally for exposure to major storms and other traumatic events (Post-traumatic Diagnostic Scale; PDS), financial stress (Chronic Financial Stress Scale), depression (PHQ-9), anxiety (GAD-7), PTSD (PDS), somatic syndrome (SCL-90-R), alcohol dependency (ICD 10), self-perceived general physical health (SF 36), and functional impairment (PDS life functioning section); caseness was determined using the various measures' algorithms. RESULTS: 22.7% percent of the sample (n=227) met caseness criteria in one or more mental health domains, and 22.1% (n=221) reported moderate to severe functional impairment. Lifetime exposure to typhoons and other major storms was 99% (n=978), with 77% (n=742) reporting traumatic major storm exposure. Moderate to high levels of financial stress were reported by 30% (n=297). Frequency of exposure to major storms was not associated with increased risk for mental health problems but traumatic exposure to a major storm was. Overall, the strongest predictor of mental health problems was financial stress. Number of traumatic typhoons and other major storms in turn were significant predictors (r2 = .03) of financial stress. The primary predictor of alcohol dependency was male gender, highlighting the importance of gender roles in development of alcohol abuse in countries like Vietnam. CONCLUSIONS: Individuals living in central coastal Vietnam have elevated rates of PTSD, somatic syndrome, and functional impairment but not depression or anxiety. Financial stress was the strongest predictor of mental health problems. Results suggest the importance of conducting broad assessments when providing mental health support for disaster impacted communities. Study results suggest that one indirect consequence of predicted global climate change may be increased prevalence of mental health problems in communities such as that assessed in the present study, due to increased risk for traumatic storm-related exposure and through indirect effects on financial stress, but not through a general increased risk for major storms. Such results also indicate that when supporting LMIC communities that have experienced natural disasters, it will be important to consider the broader community context including poverty, in addition to the direct effects of the disaster. PMID- 27458525 TI - Programmed cell death ligand-1 (PD-L1) expression by immunohistochemistry: could it be predictive and/or prognostic in non-small cell lung cancer? AB - Blockade of immune checkpoints has recently emerged as a novel therapeutic strategy in various tumors. In particular, monoclonal antibodies targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been most studied in lung cancer, and PD-1 inhibitors are now established agents in the management of non-small cell lung cancer (NSCLC). The reports on high-profile clinical trials have shown the association of PD-L1 expression by immunohistochemistry (IHC) with higher overall response rates to the PD-1/PD-L1 axis blockade suggesting that PD L1 expression may serve as a predictive marker. Unfortunately, however, each PD-1 or PD-L1 inhibitor is coupled with a specific PD-L1 antibody, IHC protocol and scoring system for the biomarker assessment, making the head-to-head comparison of the studies difficult. Similarly, multiple clinical series that correlated PD L1 expression with clinicopathologic and/or molecular variables and/or survival have reported conflicting results. The discrepancy could be explained by the differences in ethnicity and/or histologic types included in the studies, but it appears to be attributed in part to the differences in PD-L1 IHC methods. Thus, orchestrated efforts to standardize the PD-L1 IHC are warranted to establish the IHC as a predictive and/or prognostic biomarker in NSCLC. PMID- 27458526 TI - Immuno-oncology combinations: raising the tail of the survival curve. AB - There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design. PMID- 27458527 TI - Nonmuscle invasive bladder cancer: a primer on immunotherapy. AB - Intravesical Bacillus Calmette-Guerin (BCG) has long been the gold standard treatment of nonmuscle invasive bladder cancer. Recently, there has been an emergence of novel immunotherapeutic agents, which have shown promise in the treatment of urothelial cell carcinoma. These agents aim to augment, modify, or enhance the immune response. Such strategies include recombinant BCG, monoclonal antibodies, vaccines, gene therapy, and adoptive T-cell therapy. Here, we review the emerging immunotherapeutics in the treatment of nonmuscle invasive bladder cancer. PMID- 27458528 TI - Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? AB - Vascular endothelial growth factor (VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors (VEGFRs), they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells (DCs), macrophages, and lymphocytes further express certain types of VEGF receptors. VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness. This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment. PMID- 27458529 TI - Liquid biopsies for liquid tumors: emerging potential of circulating free nucleic acid evaluation for the management of hematologic malignancies. AB - Circulating free nucleic acids; cell free DNA and circulating micro-RNA, are found in the plasma of patients with hematologic and solid malignancies at levels higher than that of healthy individuals. In patients with hematologic malignancy cell free DNA reflects the underlying tumor mutational profile, whilst micro-RNAs reflect genetic interference mechanisms within a tumor and potentially the surrounding microenvironment and immune effector cells. These circulating nucleic acids offer a potentially simple, non-invasive, repeatable analysis that can aid in diagnosis, prognosis and therapeutic decisions in cancer treatment. PMID- 27458530 TI - New generation of breast cancer clinical trials implementing molecular profiling. AB - The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block specific molecular aberrations. This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. This paradigm shift impacts the field of clinical trials, since the classical approach of having clinico pathological disease characteristics dictating the patients' enrolment in oncology trials shifts towards the implementation of molecular profiling as pre screening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been developed new, innovative trial designs that could be classified as follows: i) longitudinal cohort studies that implement (or not) "nested" downstream trials, 2) studies that assess the clinical utility of molecular profiling, 3) "master" protocol trials, iv) "basket" trials, v) trials following an adaptive design. In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology trials implementing molecular profiling. Emphasis is put on the field of breast cancer clinical trials. PMID- 27458531 TI - Genetic and molecular changes in ovarian cancer. AB - Epithelial ovarian cancer represents the most lethal gynecological malignancy in the developed world, and can be divided into five main histological subtypes: high grade serous, endometrioid, clear cell, mucinous and low grade serous. These subtypes represent distinct disease entities, both clinically and at the molecular level. Molecular analysis has revealed significant genetic heterogeneity in ovarian cancer, particularly within the high grade serous subtype. As such, this subtype has been the focus of much research effort to date, revealing molecular subgroups at both the genomic and transcriptomic level that have clinical implications. However, stratification of ovarian cancer patients based on the underlying biology of their disease remains in its infancy. Here, we summarize the molecular changes that characterize the five main ovarian cancer subtypes, highlight potential opportunities for targeted therapeutic intervention and outline priorities for future research. PMID- 27458532 TI - Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang. AB - Acute myeloid leukemia (AML) is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow (BM) niche is critical to the maintenance and retention of hematopoietic stem cells (HSC), including leukemia stem cells (LSC), and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy-induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDF1/CXCL12, Wnt/beta-catenin, VCAM/VLA-4/NF-kappaB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors. PMID- 27458533 TI - Characterization of FGFR signaling pathway as therapeutic targets for sarcoma patients. AB - The fibroblast growth factor receptor (FGFR) family plays important roles in regulating cell growth, proliferation, survival, differentiation and angiogenesis. Deregulation of the FGF/FGFR signaling pathway has been associated with multiple development syndromes and cancers, and thus therapeutic strategies targeting FGFs and FGFR in human cancer are currently being explored. However, few studies on the FGF/FGFR pathway have been conducted in sarcoma, which has a poor outcome with traditional treatments such as surgery, chemotherapy, and radiotherapy. Hence, in the present review, we provide an overview of the role of the FGF/FGFR pathway signal in sarcoma and FGFR inhibitors, which might be new targets for the treatment of sarcomas according to recent research. PMID- 27458535 TI - Modulation of B-cell receptor and microenvironment signaling by a guanine exchange factor in B-cell malignancies. AB - OBJECTIVE: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B cell malignancies. METHODS: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-1 over-expressing and a control transfected cell line. RESULTS: Cells over expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. CONCLUSIONS: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells. PMID- 27458534 TI - Influence of obesity and bariatric surgery on gastric cancer. AB - Esophageal and gastric cancer (GC) are related to obesity and bariatric surgery. Risk factors, such as gastroesophageal reflux and Helicobacter pylori, must be investigated and treated in obese population. After surgery, GC reports are anecdotal and treatment is not standardized. This review aims to discuss GC related to obesity before and after bariatric surgery. PMID- 27458536 TI - The oncofetal protein IMP3 is an indicator of early recurrence and poor outcome in mucoepidermoid carcinoma of salivary glands. AB - OBJECTIVE: Mucoepidermoid carcinoma (MEC) is the most common primary malignancy of the salivary glands. Insulin-like growth factor-II mRNA-binding protein-3 (IMP3) is an important prognostic factor in some cancers and a tool that differentiates between benign and malignant pancreatic lesions. This study aimed to identify a relationship between the expression of IMP3 and the outcome of salivary gland MEC, as well as to differentiate MEC from pleomorphic adenoma (PA). METHODS: Tissue specimens from 70 cases of salivary gland MEC, 40 cases of PA, and 10 cases with normal salivary gland were examined immunohistochemically for IMP3. The association among the expression of IMP3, clinicopathological characteristics and patient's survival was assessed. RESULTS: IMP3 was present in 51.4% of MEC but absent in PA and normal salivary gland tissues. IMP3 expression was associated with age > 60 years, submandibular gland tumors, tumor size > 4 cm, high-grade tumors, lymph node metastasis, involvement of surgical margins, perineural invasion, distant metastasis, advanced TNM stage, tumor relapse, and death ( P<0.05). Increased expression of IMP3, tumors of the submandibular gland, and lymph node metastasis were independent prognostic factors of -free survival (DFS). In addition, IMP3 was a strong predictor of overall survival (OS) together with distant metastasis and intermediate and high-grade tumors. CONCLUSIONS: IMP3 expression is highly important in evaluating the outcome of MEC. IMP3 can be used to differentiate MEC from PA of salivary glands. PMID- 27458537 TI - A Proof of Concept Study to Detect Urease Producing Bacteria in Lungs Using Aerosolized 13C-Urea. AB - This is a "proof of concept" study to determine whether inhalation of 13C-urea can be safely used to detect the presence of urease producing bacteria in the airways of patients with cystic fibrosis (CF) by detecting 13CO2 in breath. This was a prospective, 2-part, open label, single-center, single-arm, single administration, dose-escalation investigational device exemption trial. First, the safety of 20 and 50 mg inhaled 13C-urea was evaluated in 6 healthy adult participants. Then, 3 adult CF participants colonized with Pseudomonas aeruginosa were enrolled for each dose of inhaled 13C-urea. The safety of inhaled 13C-urea was assessed by spirometry and physical examination. 13C-urea was administered using a jet nebulizer, followed by serial spirometry (10 min and 30 min post inhalation) and collection of exhaled breath at 5, 10, and 15 min post inhalation. There was no clinical significant change in any of the spirometry values compared to baseline in healthy participants and CF patients. Mean of 13CO2/12CO2 delta over baseline (DOB) values in CF participants at 5, 10, and 15 min post inhalation was as follows: 20 mg dose 40/00 (2.20/00-4.90/00), 10/00 (1.00/00-1.40/00), and 10/00 (0.40/00-1.50/00); 50 mg dose: 100/00 (6.20/00 14.50/00), 30/00 (2.10/00-4.30/00), and 1.50/00 (0.60/00-2.30/00). Inhaled 13C urea for detection of urease producing bacteria was safe, and preliminary data suggest that 13CO2/12CO2 DOB values may be higher in CF patients with P. aeruginosa at 5-10 min after inhalation of 13C-urea. A future direction is to investigate use of inhaled 13C-urea in young children who have difficulty producing sputum for culturing. PMID- 27458538 TI - Rituximab Desensitization in Pediatric Patients: Results of a Case Series. AB - Rituximab is a monoclonal antibody (mAb) primarily used to treat oncologic and autoinflammatory conditions. Although hypersensitivity reactions (HSRs) and desensitization protocols to mAbs have been well described in adults, the experience in the pediatric population is very limited. We sought to determine the safety and efficacy of desensitization to rituximab in the pediatric population at our institution. We retrospectively reviewed the experience with HSRs and desensitization to rituximab during a 5-year period in our tertiary care pediatric center, including reaction evaluation, premedication regimens, and desensitization procedures and protocols. A total of 17 desensitizations to rituximab were performed in three patients. A 14-year-old patient underwent successful desensitization to rituximab using a published adult protocol without incident. Two younger patients (ages 7 years and 23 months) experienced significant reactions during initial desensitization attempts. Therefore, we designed a modified desensitization protocol to rituximab, with particular attention to the rate of infusion as mg/kg/h. This new patient weight-based protocol was successfully used in a total of 13 desensitizations in these two patients. Desensitization to rituximab was a safe and effective procedure in our pediatric population. We present a new patient weight-based desensitization protocol for pediatric patients who develop HSRs to rituximab, with particular usefulness for younger pediatric patients and potential utility in pediatric patients with HSRs to other mAbs. PMID- 27458539 TI - Macrolides for Acute Wheezing Episodes in Preschool Children. AB - The National Asthma Education and Prevention Program's Expert Panel Report 3, Guidelines for the Diagnosis and Management of Asthma does not recommend antibiotics for the management of acute episodes of asthma exacerbation. Macrolides seem to have some potential effect beyond or in addition to their antibacterial effect. It has been reported that macrolides may potentially benefit patients with chronic inflammatory airway diseases due to their antibacterial, antiviral, and/or anti-inflammatory effects. This review presents recent data on use of azithromycin in prevention and management of acute exacerbation of respiratory symptoms in infants and young children. PMID- 27458540 TI - Normative values of quantitative sensory testing in Hispanic Latino population. AB - BACKGROUND: Quantitative Sensory Testing (QST) is more often used because of the increasing recognition of small fiber neuropathy. METHODS: We studied QST in a systematic way in an age-stratified cohort of 83 neurological-free Hispanic Latinamerican patients. Predefined standardized stimuli were applied using the method of limits. RESULTS: WDT range from 2.2 to 3.3 degrees C in hands, and from 4.0 degrees C up to 6.6 degrees C in feet. Cold detection threshold range from 2.2 to 3.6 degrees C in hands, and from 2.6 degrees C to 4.5 degrees C in feet. Heat-induced pain (HP) was induced at lower temperatures than previously reported, with a range from 41.8 degrees C to 44.5 degrees C in hands and from 43.2 to 45.7 degrees C in feet. Similar to HP, cold pain was also induced at much higher temperatures, between 21.4-17.3 degrees C in hands and 21.5-16.5 degrees C in feet. Vibratory stimuli ranged from 0.8 to 1.7 MU/sec in hands and from 1.4 to 3.5 MU/sec in feet. CONCLUSION: Temperature and vibration thresholds were similar to those previously reported in other populations except for pain thresholds that were lower in this population than in the Caucasian population. PMID- 27458541 TI - Parental bonding and neuropsychological performance are associated with episodic simulation of future events in trauma-exposed patients with major depressive disorder. AB - INTRODUCTION: Major depressive disorder (MDD) and trauma-related disorders are associated with deficits in remembering the past and imagining the future (i.e., episodic simulation). We examined parental bonding and neuropsychological performance in relation to episodic simulation in trauma-exposed patients with recurrent MDD. METHODS: Trauma-exposed patients with MDD (n = 21) and matched controls (n = 20) completed a future-oriented Autobiographical Interview, the Parental Bonding Instrument, and a standardized neuropsychological battery. RESULTS: Patients with major depressive disorder generated fewer episodic details for future neutral events compared to controls. Although higher reported levels of maternal care were associated with increased specificity of negative future events among the patient group, higher maternal overprotection was related to decreased specificity of negative and positive future events. Higher levels of performance on measures of intelligence, verbal memory, executive functioning, and sustained attention were associated with increased specificity of future events. CONCLUSIONS: Maternal relations during childhood and neuropsychological performance are related to the specificity of episodic simulation in adult patients with MDD. Childhood experience continues to influence memory performance into adulthood. PMID- 27458542 TI - fMRI exploration of pedagogical benefits of repeated testing: when more is not always better. AB - INTRODUCTION: The testing effect refers to superior retention when study is followed by a test rather than followed by another study. Most research to date on why the testing effect occurs has been behavioral, but we employed neuroimaging methods in this study in order to shed light on the underlying processes. METHODS: Subjects were scanned while studying, restudying, and taking cued-recall tests of word pairs (with no feedback). We analyzed the BOLD responses by back sorting the encoding and test trials based on whether the subsequent test was correct or incorrect. We compared the subsequent memory patterns in initial study, restudy, and test trials. RESULTS: Overall, brain activity during test trials was a better predictor of later performance than brain activity during restudy trials. For test trials, we separately examined brain regions associated with the retrieval attempt process during successful retrieval and regions associated with the re-encoding process during retrieval in terms of prediction of subsequent memory. Regions associated with retrieval attempts were found to always predict subsequent memory success (the greater the activation, the more likely the correct recall); however, the regions associated with re-encoding would sometimes predict subsequent failure, specifically when subjects had correctly recalled the associated word several times already. CONCLUSIONS: These results suggest that whether a testing effect advantage is observed depends on both on the retrieval process and the re-encoding process which follows that retrieval. PMID- 27458543 TI - Methylene blue and normobaric hyperoxia combination therapy in experimental ischemic stroke. AB - INTRODUCTION: Ischemic stroke is a global burden that contributes to the disability and mortality of millions of patients. This study aimed to evaluate the efficacy of combined MB (methylene blue) and NBO (normobaric hyperoxia) therapy in experimental ischemic stroke. METHODS: Rats with transient (60 min) MCAO (middle cerebral artery occlusion) were treated with: (1) air + vehicle (N = 8), (2) air + MB (N = 8), (3) NBO + vehicle (N = 7), and (4) NBO + MB (N = 9). MB (1 mg/kg) was administered at 30 min, again on days 2, 7, and 14 after stroke. NBO was given during MRI (30-150 min) on day 0, and again 1 h each during MRI on subsequent days. Serial diffusion, perfusion and T2 MRI were performed to evaluate lesion volumes. Foot-fault and cylinder tests were performed to evaluate sensorimotor function. RESULTS: The major findings were: (1) NBO + MB therapy showed a greater decrease in infarct volume compared to NBO alone, but similar infarct volume compared to MB alone, (2) NBO + MB therapy accelerated sensorimotor functional recovery compared to NBO or MB alone, (3) Infarct volumes on day 2 did not change significantly from those on day 28 for all four groups, but behavioral function continued to show improved recovery in the NBO + MB group. CONCLUSIONS: These findings support the hypothesis that combined NBO + MB further improves functional outcome and reduces infarct volume compared to either treatment alone and these improvements extended up to 28 days. PMID- 27458544 TI - Epigenetic marks as the link between environment and development: examination of the associations between attachment, socioeconomic status, and methylation of the SLC6A4 gene. AB - BACKGROUND: Epigenetic processes act as a link between environment and individual development. This pilot study examined the association between socioeconomic status (SES), attachment, and methylation of the promoter region of the serotonin transporter gene (SLC6A4). METHODS: Attachment classification and SLC6A4 methylation was determined in 100 late adolescents. We hypothesized that (1) SES would interact with methylation to predict higher unresolved loss (UL) or trauma scores on the Adult Attachment Interview; (2) across SES, participants with unresolved attachment would have lower levels of methylation than organized or secure participants; and (3) within the unresolved classification, SES would predict methylation. RESULTS: Results showed that lower methylation and low-SES were associated with higher UL, and higher methylation and low-SES were associated with higher unresolved trauma. Across SES, unresolved participants had lower levels of methylation than organized participants. Within the unresolved category, low-SES unresolved participants had higher levels of methylation than mid/upper-SES participants. SES was unrelated to methylation within the secure and organized categories. CONCLUSIONS: These results suggest that the quality of attachment relationships may impact epigenetic processes. PMID- 27458545 TI - Prevalence estimates of major neurocognitive disorders in a rural Nigerian community. AB - OBJECTIVE: There is paucity of information on major neurocognitive disorders in sub-Saharan Africa where the number of individuals with neurocognitive disorders is expected to increase due to demographic transition. This study aims to report on the prevalence estimates of dementia and MCI (mild cognitive impairment) in a rural community in southwest Nigeria. MATERIALS AND METHODS: This was a two-stage cross-sectional study of persons aged 65 years and above resident in Lalupon community, Oyo State. The Identification and IDEA (Intervention for Dementia in Elderly Africans) Study Questionnaire was used for initial screening by trained community health care workers, utilized followed by cognitive assessment using the validated IDEA cognitive screen. Functional and cognitive assessment of selected individuals was carried out during the second stage. Information obtained was used for consensus diagnosis and participants were categorized into normal, MCI and dementia using standard criteria. RESULTS: Six hundred and thirteen participants completed the study with 111 (18.1%) diagnosed as MCI while 17 (2.8%) had dementia. The age-adjusted prevalence estimates were 18.4% (95% CI: 14.9-21.9%) and 2.9% (95% CI 1.6-4.4%) for MCI and dementia, respectively. Probable Alzheimer's disease and amnestic MCI predominated. Individuals with dementia were older than both MCI and normal cases while those with MCI had significantly fewer years of schooling than the other diagnostic categories. CONCLUSION: Almost one out of five older persons in Lalupon community had major neurocognitive impairment with MCI being six-times more common than dementia. Alzheimer's disease was the most common dementia sub-type. PMID- 27458546 TI - Synergistic association of STX1A and VAMP2 with cryptogenic epilepsy in North Indian population. AB - INTRODUCTION: "Common epilepsies", merely explored for genetics are the most frequent, nonfamilial, sporadic cases in hospitals. Because of their much debated molecular pathology, there is a need to focus on other neuronal pathways including the existing ion channels. METHODS: For this study, a total of 214 epilepsy cases of North Indian ethnicity comprising 59.81% generalized, 40.19% focal seizures, and based on epilepsy types, 17.29% idiopathic, 37.38% cryptogenic, and 45.33% symptomatic were enrolled. Additionally, 170 unrelated healthy individuals were also enrolled. Here, we hypothesize the involvement of epilepsy pathophysiology genes, that is, synaptic vesicle cycle, SVC genes (presynapse), ion channels and their functionally related genes (postsynapse). An interactive analysis was initially performed in SVC genes using multifactor dimensionality reduction (MDR). Further, in order to understand the influence of ion channels and their functionally related genes, their interaction analysis with SVC genes was also performed. RESULTS: A significant interactive two-locus model of STX1A_rs4363087|VAMP2_rs2278637 (presynaptic genes) was observed among SVC variants in all epilepsy cases (P 1000-value = 0.054; CVC = 9/10; OR = 2.86, 95%CI = 1.88-4.35). Further, subgroup analysis revealed stronger interaction for the same model in cryptogenic epilepsy patients only (P 1000-value = 0.012; CVC = 10/10; OR = 4.59, 95%CI = 2.57-8.22). However, interactive analysis of presynaptic and postsynaptic genes did not show any significant association. CONCLUSIONS: Significant synergistic interaction of SVC genes revealed the possible functional relatedness of presynapse with pathophysiology of cryptogenic epilepsy. Further, to establish the clinical utility of the results, replication in a large and similar phenotypic group of patients is warranted. PMID- 27458547 TI - A systematic review of reviews on the prevalence of anxiety disorders in adult populations. AB - BACKGROUND: A fragmented research field exists on the prevalence of anxiety disorders. Here, we present the results of a systematic review of reviews on this topic. We included the highest quality studies to inform practice and policy on this issue. METHOD: Using PRISMA methodology, extensive electronic and manual citation searches were performed to identify relevant reviews. Screening, data extraction, and quality assessment were undertaken by two reviewers. Inclusion criteria consisted of systematic reviews or meta-analyses on the prevalence of anxiety disorders that fulfilled at least half of the AMSTAR quality criteria. RESULTS: We identified a total of 48 reviews and described the prevalence of anxiety across population subgroups and settings, as reported by these studies. Despite the high heterogeneity of prevalence estimates across primary studies, there was emerging and compelling evidence of substantial prevalence of anxiety disorders generally (3.8-25%), and particularly in women (5.2-8.7%); young adults (2.5-9.1%); people with chronic diseases (1.4-70%); and individuals from Euro/Anglo cultures (3.8-10.4%) versus individuals from Indo/Asian (2.8%), African (4.4%), Central/Eastern European (3.2%), North African/Middle Eastern (4.9%), and Ibero/Latin cultures (6.2%). CONCLUSIONS: The prevalence of anxiety disorders is high in population subgroups across the globe. Recent research has expanded its focus to Asian countries, an increasingly greater number of physical and psychiatric conditions, and traumatic events associated with anxiety. Further research on illness trajectories and anxiety levels pre- and post-treatment is needed. Few studies have been conducted in developing and under-developed parts of the world and have little representation in the global literature. PMID- 27458548 TI - The Longitudinal Effects of Adolescent Volunteering on Secondary School Completion and Adult Volunteering. AB - This study explores the longitudinal effect of adolescent volunteering behaviour on young adult volunteering and the completion of secondary school. Utilising data from the Australian sample of the International Youth Development Study, frequency of volunteering in Grade 9 (mean age = 15 years) and in young adulthood (mean age = 21 years), and completion of secondary school were measured. Mixed effect logistic regression analyses revealed that adolescent volunteering was associated with an increased likelihood of volunteering in young adulthood (Odds Ratio [OR] 1.29; 95% Confidence Interval [CI] 1.20 - 1.39; N = 2,648) and of Grade 12 completion (OR 1.14; CI 1.03 - 1.28; N = 2,648), after controlling for family socioeconomic status and adolescent school adjustment. These findings suggest that adolescent volunteering may lead to further involvement in young adult volunteering and have a positive effect on school completion. PMID- 27458550 TI - Chronic eosinophilic leukemia, NOS with t(5;12)(q31;p13)/ETV6-ACSL6 gene fusion: a novel variant of myeloid proliferative neoplasm with eosinophilia. AB - The 2008 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues introduced a category for myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1. Many of these patients are responsive to tyrosine kinase inhibitor (TKI) therapy. In this case report , we report a unique case of chronic eosinophlic leukemia with novel t(5;12) (q23-31;p13)/ETV6-ACSL6 gene fusion, in which patient was resistant to TKI therapy. This important finding is a novel addition to the above entity in WHO 2008 classification. The ACSL6 gene encodes a long-chain acyl-CoA synthetase, an enzyme that plays an essential role in lipid metabolism and ATP generation pathways in cells. The EBV6-ACSL6 rearrangement is present in diverse types of hematopoietic malignancies. As yet, it is not clear how ACSL6, a gene involved in fatty acid synthesis, contributes to clonal expansion of myeloid progenitor cells. Therefore, elucidating the contribution of ACSL6 to leukemogenesis may allow the development of novel treatment for those resistant to TKI therapy. PMID- 27458549 TI - Ontology-based Vaccine and Drug Adverse Event Representation and Theory-guided Systematic Causal Network Analysis toward Integrative Pharmacovigilance Research. AB - Compared with controlled terminologies (e.g., MedDRA, CTCAE, and WHO-ART), the community-based Ontology of AEs (OAE) has many advantages in adverse event (AE) classifications. The OAE-derived Ontology of Vaccine AEs (OVAE) and Ontology of Drug Neuropathy AEs (ODNAE) serve as AE knowledge bases and support data integration and analysis. The Immune Response Gene Network Theory explains molecular mechanisms of vaccine-related AEs. The OneNet Theory of Life treats the whole process of a life of an organism as a single complex and dynamic network (i.e., OneNet). A new "OneNet effectiveness" tenet is proposed here to expand the OneNet theory. Derived from the OneNet theory, the author hypothesizes that one human uses one single genotype-rooted mechanism to respond to different vaccinations and drug treatments, and experimentally identified mechanisms are manifestations of the OneNet blueprint mechanism under specific conditions. The theories and ontologies interact together as semantic frameworks to support integrative pharmacovigilance research. PMID- 27458551 TI - Prenatal diagnosis and assessment of congenital spinal anomalies: Review for prenatal counseling. AB - The last two decades have seen continuous advances in prenatal ultrasonography and in utero magnetic resonance imaging. These technologies have increasingly enabled the identification of various spinal pathologies during early stages of gestation. The purpose of this paper is to review the range of fetal spine anomalies and their management, with the goal of improving the clinician's ability to counsel expectant parents prenatally. PMID- 27458552 TI - Evaluation of bone remodeling in regard to the age of scaphoid non-unions. AB - AIM: To analyse bone remodeling in regard to the age of scaphoid non-unions (SNU) with immunohistochemistry. METHODS: Thirty-six patients with symptomatic SNU underwent surgery with resection of the pseudarthrosis. The resected material was evaluated histologically after staining with hematoxylin-eosin (HE), tartrate resistant acid phosphatase (TRAP), CD 68, osteocalcin (OC) and osteopontin (OP). Histological examination was performed in a blinded fashion. RESULTS: The number of multinuclear osteoclasts in the TRAP-staining correlated with the age of the SNU and was significantly higher in younger SNU (P = 0.034; r = 0.75). A higher number of OP-immunoreactive osteoblasts significantly correlated with a higher number of OC-immunoreactive osteoblasts (P = 0.001; r = 0.55). Furthermore, a greater number of OP-immunoreactive osteoblasts correlated significantly with a higher number of OP-immunoreactive multinuclear osteoclasts (P = 0.008; r = 0.43). SNU older than 6 mo showed a significant decrease of the number of fibroblasts (P = 0.04). Smoking and the age of the patients had no influence on bone remodeling in SNU. CONCLUSION: Multinuclear osteoclasts showed a significant decrease in relation to the age of SNU. However, most of the immunhistochemical findings of bone remodeling do not correlate with the age of the SNU. This indicates a permanent imbalance of bone formation and resorption as indicated by a concurrent increase in both osteoblast and osteoclast numbers. A clear histological differentiation into phases of bone remodeling in SNU is not possible. PMID- 27458553 TI - Computerized tomography based "patient specific blocks" improve postoperative mechanical alignment in primary total knee arthroplasty. AB - AIM: To compare the postoperative mechanical alignment achieved after total knee arthroplasty (TKA) using computer tomography (CT) based patient specific blocks (PSB) to conventional instruments (CI). METHODS: Total 80 knees were included in the study, with 40 knees in both the groups operated using PSB and CI. All the knees were performed by a single surgeon using the same cruciate sacrificing implants. In our study we used CT based PSB to compare with CI. Postoperative mechanical femoro-tibial angle (MFT angle) was measured on long leg x-rays using picture archiving and communication system (PACS). We compared mechanical alignment achieved using PSB and CI in TKA using statistical analysis. RESULTS: The PSB group (group 1) included 17 females and seven males while in CI group (group 2) there were 15 females and eight males. The mean age of patients in group 1 was 60.5 years and in group 2 it was 60.2 years. The mean postoperative MFT angle measured on long-leg radiographs in group 1 was 178.23 degrees (SD = 2.67 degrees , range: 171.9 degrees to 182.5 degrees ) while in group 2, the mean MFT angle was 175.73 degrees (SD = 3.62 degrees , range: 166.0 degrees to 179.8 degrees ). There was significant improvement in postoperative mechanical alignment (P value = 0.001), in PSB group compared to CI. Number of outliers were also found to be less in group operated with PSB (7 Knee) compared to those operated with CI (17 Knee). CONCLUSION: PSB improve mechanical alignment after total knee arthroplasty, compared to CI. This may lead to lower rates of revision in the PSB based TKA as compared to the conventional instrumentation. PMID- 27458554 TI - Constrained fixed-fulcrum reverse shoulder arthroplasty improves functional outcome in epileptic patients with recurrent shoulder instability. AB - AIM: To report the results of fixed-fulcrum fully constrained reverse shoulder arthroplasty for the treatment of recurrent shoulder instability in patients with epilepsy. METHODS: A retrospective review was conducted at a single facility. Cases were identified using a computerized database and all clinic notes and operative reports were reviewed. All patients with epilepsy and recurrent shoulder instability were included for study. Between July 2003 and August 2011 five shoulders in five consecutive patients with epilepsy underwent fixed-fulcrum fully constrained reverse shoulder arthroplasty for recurrent anterior shoulder instability. The mean duration of epilepsy in the cohort was 21 years (range, 5 51) and all patients suffered from grand mal seizures. RESULTS: Mean age at the time of surgery was 47 years (range, 32-64). The cohort consisted of four males and one female. Mean follow-up was 4.7 years (range, 4.3-5 years). There were no further episodes of instability, and no further stabilisation or revision procedures were performed. The mean Oxford shoulder instability score improved from 8 preoperatively (range, 5-15) to 30 postoperatively (range, 16-37) (P = 0.015) and the mean subjective shoulder value improved from 20 (range, 0-50) preoperatively to 60 (range, 50-70) postoperatively (P = 0.016). Mean active forward elevation improved from 71 degrees preoperatively (range, 45 degrees 130 degrees ) to 100 degrees postoperatively (range, 80 degrees -90 degrees ) and mean active external rotation improved from 15 degrees preoperatively (range, 0 degrees -30 degrees ) to 40 degrees (20 degrees -70 degrees ) postoperatively. No cases of scapular notching or loosening were noted. CONCLUSION: Fixed-fulcrum fully constrained reverse shoulder arthroplasty should be considered for the treatment of recurrent shoulder instability in patients with epilepsy. PMID- 27458555 TI - Trochanter/calcar preserving reconstruction in tumors involving the femoral head and neck. AB - AIM: To evaluate the results of hip reconstruction with extensive excision for tumor confined to the femoral head and neck. METHODS: We designed a resection preserving the greater trochanter and lower portion of calcar femorale, and utilized conventional total hip prosthesis. We retrospectively reviewed 7 patients, who underwent a wide resection and reconstruction using conventional hip prosthesis. There were 3 men and 4 women and their mean age was 42.5 years (22 to 65 years). The histologic diagnosis of each patient was low-grade osteosarcoma, diffuse large B-cell lymphoma, liposclerosing myxofibroma, intraosseous lipoma, chondroblastoma, giant cell tumor and focal intramedullary fibrosis. RESULTS: One patient with lymphoma died due to disease dissemination at 10 mo postoperatively and the remaining 6 patients were followed for a mean of 4.7 years (3 to 6 years). All patients were able to return to their daily activities and no patient had local recurrence. No radiographic signs of loosening, wear, and osteolysis were found at the last follow-up. CONCLUSION: Trochanter/calcar-preserving resection of the proximal femur and reconstruction using conventional total hip prosthesis, is a satisfactory treatment for tumors confined to the femoral head and neck. PMID- 27458556 TI - Extensor pollicis brevis tendon can hyperextend thumb interphalangeal joint in absence of extensor pollicis longus: Case report and review of the literature. AB - We are reporting a case of extensor pollicis longus tendon rupture which did not require tendon transfer owing to the ability of the intact extensor pollicis brevis (EPB) to fully hyperextend the thumb interphalangeal joint. The thumb metacarpophalangeal joint was also able to be fully actively extended by the EPB. Previous anatomical studies have demonstrated that the insertional anatomy of the EPB tendon is highly variable and sometimes inserts onto the extensor hood and distal phalanx, which is likely the mechanism by which our patient was able to fully extend the thumb interphalangeal joint. Despite the potential for the EPB to extend the IP joint of the thumb, virtually all previously reported cases of extensor pollicis longus (EPL) tendon rupture had deficits of thumb IP extension requiring tendon transfer. This case highlights the potential ability of the EPB tendon to completely substitute for the function of the EPL tendon in providing thumb IP joint extension. PMID- 27458557 TI - Hemorrhagic lumbar synovial facet cyst secondary to transforaminal epidural injection: A case report and review of the literature. AB - A 64-year-old-female presented with progressive left foot weakness, low back and radicular pain after a left sided S1 transforaminal epidural steroid injection (ESI). Magnetic resonance imaging revealed left side L5-S1 large extradural heterogeneous mass with layering areas suggesting different stages of hematoma formation. Past medical history was significant for peripheral vascular disease and transient ischemic attacks, for which she took aspirin and clopidogrel (antiplatelet agent). These medications were discontinued one week prior to ESI. Although synovial cysts associated with facet arthropathy are common, hemorrhagic cyst is not. To the best of the authors' knowledge, this is the first reported case of symptomatic hemorrhagic lumbar facet synovial cyst following ESI on a patient taking anti-platelet medications. PMID- 27458558 TI - Operative stabilization of the remaining mobile segment in ankylosed cervical spine in systemic onset - juvenile idiopathic arthritis: A case report. AB - We describe a case of a 19-year-old young man with oligoarthritis type of juvenile idiopathic arthritis, who presented with several month duration of lower neck pain and progressive muscular weakness of all four limbs. X-rays of the cervical spine demonstrated spontaneous apophyseal joint fusion from the occipital condyle to C6 and from C7 to Th2 with marked instability between C6 and C7. Surgical intervention began with anterolateral approach to the cervical spine performing decompression, insertion of cage and anterior vertebral plate and screws, followed by posterior approach and fixation. Care was taken to restore sagittal balance. The condition was successfully operatively managed with multisegmental, both column fixation and fusion, resulting in pain cessation and resolution of myelopathy. Postoperatively, minor swallowing difficulties were noted, which ceased after three days. Patient was able to move around in a wheelchair on the sixth postoperative day. Stiff neck collar was advised for three months postoperatively with neck pain slowly decreasing in the course of first postoperative month. On the follow-up visit six months after the surgery patient exhibited no signs of spastic tetraparesis, X-rays of the cervical spine revealed solid bony fusion at single mobile segment C6-C7. He was able to gaze horizontally while sitting in a wheelchair. Signs of myelopathy with stiff neck and single movable segment raised concerns about intubation, but were successfully managed using awake fiber-optic intubation. Avoidance of tracheostomy enabled us to perform an anterolateral approach without increasing the risk of wound infection. Regarding surgical procedure, the same principles are obeyed as in management of fracture in ankylosing spondylitis or Mb. Forestrier. PMID- 27458559 TI - Update on kidney transplantation in human immunodeficiency virus infected recipients. AB - Improved survival of human immunodeficiency virus (HIV) infected patients with chronic kidney disease following the introduction of antiretroviral therapy resulted in the need to revisit the topic of kidney transplantation in these patients. Large cohort studies have demonstrated favorable outcomes and proved that transplantation is a viable therapeutic option. However, HIV-infected recipients had higher rates of rejection. Immunosuppressive therapy did not negatively impact the course of HIV infection. Some of the immunosuppressive drugs used following transplantation exhibit antiretroviral effects. A close collaboration between infectious disease specialists and transplant professionals is mandatory in order to optimize transplantation outcomes in these patients. Transplantation from HIV(+) donors to HIV(+) recipients has been a subject of intense debate. The HIV Organ Policy Equity act provided a platform to research this area further and to develop guidelines. The first HIV(+) to HIV(+) kidney transplant in the United States and the first HIV(+) to HIV(+) liver transplant in the world were recently performed at the Johns Hopkins University Medical Center. PMID- 27458561 TI - Renal biopsy: Still a landmark for the nephrologist. AB - Renal biopsy was performed for the first time more than one century ago, but its clinical use was routinely introduced in the 1950s. It is still an essential tool for diagnosis and choice of treatment of several primary or secondary kidney diseases. Moreover, it may help to know the expected time of end stage renal disease. The indications are represented by nephritic and/or nephrotic syndrome and rapidly progressive acute renal failure of unknown origin. Nowadays, it is performed mainly by nephrologists and radiologists using a 14-18 gauges needle with automated spring-loaded biopsy device, under real-time ultrasound guidance. Bleeding is the major primary complication that in rare cases may lead to retroperitoneal haemorrhage and need for surgical intervention and/or death. For this reason, careful evaluation of risks and benefits must be taken into account, and all procedures to minimize the risk of complications must be observed. After biopsy, an observation time of 12-24 h is necessary, whilst a prolonged observation may be needed rarely. In some cases it could be safer to use different techniques to reduce the risk of complications, such as laparoscopic or transjugular renal biopsy in patients with coagulopathy or alternative approaches in obese patients. Despite progress in medicine over the years with the introduction of more advanced molecular biology techniques, renal biopsy is still an irreplaceable tool for nephrologists. PMID- 27458560 TI - Reclassification of membranoproliferative glomerulonephritis: Identification of a new GN: C3GN. AB - This review revises the reclassification of the membranoproliferative glomerulonephritis (MPGN) after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and pathogenesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized: The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecific treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in finding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies. PMID- 27458562 TI - Management of nocturnal enuresis - myths and facts. AB - Nocturnal enuresis often causes considerable distress or functional impairment to patient and their parents necessitating a multidisciplinary approach from paediatrician, paediatric nephrologist, urologists and psychiatrist. Mechanisms of monosymptomatic nocturnal enuresis are mainly nocturnal polyuria, bladder overactivity and failure to awaken from sleep in response to bladder sensations. Goal oriented and etiology wise treatment includes simple behavioral intervention, conditioning alarm regimen and pharmacotherapy with desmopressin, imipramine and anticholinergic drugs. Symptoms often recurs requiring change over or combination of different modes of treatment. PMID- 27458563 TI - Constitutive renal Rel/nuclear factor-kappaB expression in Lewis polycystic kidney disease rats. AB - AIM: To determine the temporal expression and pattern of Rel/nuclear factor (NF) kappaB proteins in renal tissue in polycystic kidney disease (PKD). METHODS: The renal expression of Rel/NF-kappaB proteins was determined by immunohistochemistry, immunofluorescence and immunoblot analysis in Lewis polycystic kidney rats (LPK, a genetic ortholog of human nephronopthsis-9) from postnatal weeks 3 to 20. At each timepoint, renal disease progression and the mRNA expression of NF-kappaB-dependent genes (TNFalpha and CCL2) were determined. NF-kappaB was also histologically assessed in human PKD tissue. RESULTS: Progressive kidney enlargement in LPK rats was accompanied by increased renal cell proliferation and interstitial monocyte accumulation (peaking at weeks 3 and 10 respectively), and progressive interstitial fibrosis (with alpha smooth muscle actin and Sirius Red deposition significantly increased compared to Lewis kidneys from weeks 3 to 6 onwards). Rel/NF-kappaB proteins (phosphorylated-p105, p65, p50, c-Rel and RelB) were expressed in cystic epithelial cells (CECs) of LPK kidneys as early as postnatal week 3 and sustained until late-stage disease at week 20. From weeks 10 to 20, nuclear p65, p50, RelB and cytoplasmic IkappaBalpha protein levels, and TNFalpha and CCL2 expression, were upregulated in LPK compared to Lewis kidneys. NF-kappaB proteins were consistently expressed in CECs of human PKD. The DNA damage marker gamma-H2AX was also identified in the CECs of LPK and human polycystic kidneys. CONCLUSION: Several NF-kappaB proteins are consistently expressed in CECs in human and experimental PKD. These data suggest that the upregulation of both the canonical and non-canonical pathways of NF kappaB signaling may be a constitutive and early pathological feature of cystic renal diseases. PMID- 27458564 TI - Diabetes mellitus increases the prevalence of anemia in patients with chronic kidney disease: A nested case-control study. AB - AIM: To compare anemia prevalence between matched chronic kidney disease (CKD) patients with and without diabetes mellitus (DM) and to assess factors associated with anemia development. METHODS: This is a nested case-control study of 184 type 2 diabetic and 184 non-diabetic CKD patients from a prospectively assembled database of a Nephrology outpatient clinic, matched for gender, age and estimated glomerular filtration rate (eGFR). Prevalence of anemia (hemoglobin: Men: < 13 g/dL, women: < 12 g/dL and/or use of recombinant erythropoietin) was examined in comparison, in the total population and by CKD Stage. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with anemia. RESULTS: The total prevalence of anemia was higher in diabetics (47.8% vs 33.2%, P = 0.004). Accordingly, prevalence was higher in diabetics in CKD Stage 3 (53.5% vs 33.1%, P < 0.001) and particularly in Stage 3a (60.4% vs 26.4%, P < 0.001), whereas it was non-significantly higher in Stage 4 (61.3% vs 48.4%; P = 0.307). Serum ferritin was higher in diabetics in total and in CKD stages, while serum iron was similar between groups. In multivariate analyses, DM (OR = 2.206, 95%CI: 1.196-4.069), CKD Stages 3a, 3b, 4 (Stage 4: OR = 12.169, 95%CI: 3.783 39.147) and serum iron (OR = 0.976, 95%CI: 0.968-0.985 per mg/dL increase) were independently associated with anemia. CONCLUSION: Prevalence of anemia progressively increases with advancing stages of CKD and is higher in diabetic than matched non-diabetic CKD patients and diabetes is independently associated with anemia occurrence. Detection and treatment of anemia in diabetic CKD patients should be performed earlier than non-diabetic counterparts. PMID- 27458565 TI - Metformin associated lactic acidosis in Auckland City Hospital 2005 to 2009. AB - AIM: To determine the incidence, clinical characteristics and outcomes of patients with metformin associated lactic acidosis (MALA). METHODS: Auckland City Hospital drains a population of just over 400000 people. All cases presenting with metabolic acidosis between July 2005 and July 2009 were identified using clinical coding. A retrospective case notes review identified patients with MALA. Prescribing data for metformin was obtained from the national pharmaceutical prescribing scheme. RESULTS: There were 42 cases of metabolic lactic acidosis over 1718000 patient years. There were 51000 patient years of metformin prescribed to patients over the study period. There were thirty two cases of lactic acidosis due to sepsis, seven in patients treated with metformin. Ten cases of MALA were identified. The incidence of MALA was estimated at 19.46 per 100000 patient year exposure to metformin. The relative risk of lactic acidosis in patients on metformin was 13.53 (95%CI: 7.88-21.66) compared to the general population. The mean age of patients with MALA was 63 years, range 40-83 years. A baseline estimated glomerular filtration rate was obtained in all patients and ranged from 23-130 mL/min per 1.73 m(2). Only two patients had chronic kidney disease G4. Three patients required treatment with haemodialysis. Two patients died. CONCLUSION: Lactic acidosis is an uncommon but significant complication of use of metformin which carries a high risk of morbidity. PMID- 27458566 TI - Skin disorders in peritoneal dialysis patients: An underdiagnosed subject. AB - AIM: To examine all skin changes in peritoneal dialysis (PD) patients followed up in our unit. METHODS: Patients on PD program for at least three months without any known chronic skin disease were included in the study. Patients with already diagnosed skin disease, those who have systemic diseases that may cause skin lesions, patients with malignancies and those who did not give informed consent were excluded from the study. All patients were examined by the same predetermined dermatologist with all findings recorded. The demographic, clinical and laboratory data including measures of dialysis adequacy of patients were recorded also. Statistical Package for Social Sciences (SPSS) for Windows 16.0 standard version was used for statistical analysis. RESULTS: Among the patients followed up in our PD unit, those without exclusion criteria who gave informed consent, 38 patients were included in the study with male/female ratio and mean age of 26/12 and 50.3 +/- 13.7 years, respectively. The duration of CKD was 7.86 +/- 4.16 years and the mean PD duration was 47.1 +/- 29.6 mo. Primary kidney disease was diabetic nephropathy in 11, nephrosclerosis in six, uropathologies in four, chronic glomerulonephritis in three, chronic pyelonephritis in three, autosomal dominant polycystic kidney disease in three patients while cause was unknown in eight patients. All patients except for one patient had at least one skin lesion. Loss of lunula, onychomycosis and tinea pedis are the most frequent skin disorders recorded in the study group. Diabetic patients had tinea pedis more frequently (P = 0.045). No relationship of skin findings was detected with primary renal diseases, comorbidities and medications that the patients were using. CONCLUSION: Skin abnormalities are common in in PD patients. The most frequent skin pathologies are onychomycosis and tinea pedis which must not be overlooked. PMID- 27458567 TI - Measurement of the intestinal permeability in chronic kidney disease. AB - AIM: To evaluate methods measuring the intestinal per-meability in chronic kidney disease (CKD) and clarify whether there is an increased intestinal permeability in CKD. METHODS: We reviewed the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol and performed a systematic literature search through MEDline and EMBASE. All controlled trials and cohort studies using non-invasive methods to assess intestinal permeability in CKD patients were included. Excluded were: Conference abstracts and studies including patients younger than 18 years or animals. From the included studies we summarized the used methods and their advantages and disadvantages. For the comparison of their results we divided the included studies in two categories based on their included patient population, either assessing the intestinal permeability in mild to moderate CKD patients or in end stage renal disease (ESRD) patients. Results were graphically displayed in two plots, one comparing the intestinal permeability in mild to moderate CKD patients to healthy controls and one comparing the intestinal permeability in ESRD patients to healthy controls. RESULTS: From the 480 identified reports, 15 met our inclusion criteria. Methods that were used to assess the intestinal permeability varied from markers measured in plasma to methods based on calculating the urinary excretion of an orally administered test substance. None of the applied methods has been validated in CKD patients and the influence of decreased renal function on the different methods remains unclear to a certain extent. Methods that seem the least likely to be influenced by decreased renal function are the quantitative PCR (qPCR) for bacterial DNA in blood and D lactate. Considering the results published by the included studies; the studies including patients with mild to moderate CKD conducted conflicting results. Some studies did report an increase in intestinal permeability whilst other did not find a significant increased permeability. However, despite the variety in used methods among the different studies, all studies measuring the intestinal permeability in ESRD point out a significant increased intestinal permeability. Results should nevertheless be interpreted with caution due to the possible influence of a decreased glomerular filtration rate on test results. CONCLUSION: The intestinal permeability in CKD: (1) could be measured by qPCR for bacterial DNA in blood and D-lactate; and (2) seems to be increased in ESRD. PMID- 27458568 TI - Pulmonary Malformations: Predictors of Neonatal Respiratory Distress and Early Surgery. AB - OBJECTIVES: The objective of our study is to retrospectively analyze a single centre series of antenatally detected pulmonary malformations (PM) and to evaluate their postnatal outcome. MATERIALS AND METHODS: We retrospectively reviewed all prenatally diagnosed PM patients referred to our Centre in the period between January 1999 and December 2014. All cases were diagnosed by one of our Maternal-Fetal Specialists by US examination. Congenital pulmonary airway malformation (CPAM) volume ratio (CVR), development of fetal complications, need for fetal therapy, need for neonatal resuscitation and timing of surgery were analyzed. RESULTS: A total of 70 fetuses were diagnosed with a PM in the period of study. An initial CVR higher than 1.6 was found in 16/70 patients (22.8%); 14/16 developed fetal complications (p less than .0001). Fifty-six fetuses (80%) did not develop any complications during pregnancy. To all complicated cases a prenatal treatment was offered, carried out in 12 (1 termination, 1 refusal). Survival rate was 100%. Sixty-three fetuses (90%) were asymptomatic at birth and did not require any neonatal resuscitation. Six patients submitted to fetal therapy and one untreated presented with neonatal respiratory distress, required mechanical ventilation at birth and early surgery in the neonatal period (7/70, 10%). CONCLUSION: CVR > 1.6 and the presence of fetal complications can be considered as predictors of respiratory distress at birth and of the need for early surgery. Nevertheless, the vast majority of PM are asymptomatic at birth and only a small group of fetuses require prenatal and postnatal treatment and support. PMID- 27458569 TI - Management of Intestinal Strictures Post Conservative Treatment of Necrotizing Enterocolitis: The Long Term Outcome. AB - OBJECTIVES: Evaluating the long-term outcome of the surgical management for intestinal strictures developing after necrotizing enterocolitis (NEC). PATIENTS AND METHODS: This is a retrospective study of all patients with an intestinal stricture after completion of conservative management for NEC. They were treated during the eight years period from 1st January 2008 to 31st December 2015. RESULTS: During the study period 67 infants had an operation for NEC, of which 55 had emergency surgery. The remaining twelve infants (6 males) had a stricture and were included in the study group. Their median gestational age was 35 (range 27 40) weeks and the median weight was 2180 (range 770 - 3290) g. The onset of NEC was seen at a median of 2 (range 1- 47) days. The median peak C-reactive protein (CRP) level was 73.1 (range 25.2 - 232) mg/dl. Isolated strictures were seen in 9 (75%) patients. Two-third of all strictures (n=15) were located in the colon. Surgery was done at a median of 5 (range 3 - 13) weeks after diagnosing NEC. Primary anastomosis was the procedure of choice; only one needed a temporary colostomy. This cohort had no mortality during a median follow up of 6.25 (range 0.5 - 7.6) years, whilst the overall death rate for NEC was 15 (22 %). Two fifth of the group developed a neurological / sensory impairment. CONCLUSION: One fifth of the surgical workload for NEC is related to post-NEC strictures. Most strictures are located in the colonic region. In the long-term no mortality and no surgical co-morbidities were observed. PMID- 27458570 TI - Erratum: Thoracoscopic Patch Repair of Congenital Diaphragmatic Hernia in a Neonate Using Spiral Tacks: A Case Report. AB - [This corrects the article on p. 31 in vol. 4, PMID: 26290813.]. PMID- 27458571 TI - Sickle Cells Abolish Melanoma Tumorigenesis in Hemoglobin SS Knockin Mice and Augment the Tumoricidal Effect of Oncolytic Virus In Vivo. AB - Insights from the study of cancer resistance in animals have led to the discovery of novel anticancer pathways and opened new venues for cancer prevention and treatment. Sickle cells (SSRBCs) from subjects with homozygous sickle cell anemia (SCA) have been shown to target hypoxic tumor niches, induce diffuse vaso occlusion, and potentiate a tumoricidal response in a heme- and oxidant-dependent manner. These findings spawned the hypothesis that SSRBCs and the vasculopathic microenvironment of subjects with SCA might be inimical to tumor outgrowth and thereby constitute a natural antitumor defense. We therefore implanted the B16F10 melanoma into humanized hemoglobin SS knockin mice which exhibit the hematologic and vasculopathic sequelae of human SCA. Over the 31-day observation period, hemoglobin SS mice showed no significant melanoma outgrowth. By contrast, 68-100% of melanomas implanted in background and hemoglobin AA knockin control mice reached the tumor growth end point (p < 0.0001). SS knockin mice also exhibited established markers of underlying vasculopathy, e.g., chronic hemolysis (anemia, reticulocytosis) and vascular inflammation (leukocytosis) that differed significantly from all control groups. Genetic differences or normal AA gene knockin do not explain the impaired tumor outgrowth in SS knockin mice. These data point instead to the chronic pro-oxidative vasculopathic network in these mice as the predominant cause. In related studies, we demonstrate the ability of the sickle cell component of this system to function as a therapeutic vehicle in potentiating the oncolytic/vasculopathic effect of RNA reovirus. Sickle cells were shown to efficiently adsorb and transfer the virus to melanoma cells where it induced apoptosis even in the presence of anti-reovirus neutralizing antibodies. In vivo, SSRBCs along with their viral cargo rapidly targeted the tumor and initiated a tumoricidal response exceeding that of free virus and similarly loaded normal RBCs without toxicity. Collectively, these data unveil two hitherto unrecognized findings: hemoglobin SS knockin mice appear to present a natural barrier to melanoma tumorigenesis while SSRBCs demonstrate therapeutic function as a vehicle for enhancing the oncolytic effect of free reovirus against established melanoma. PMID- 27458572 TI - Predicting Biochemical Disease-Free Survival after Prostate Stereotactic Body Radiotherapy: Risk-Stratification and Patterns of Failure. AB - BACKGROUND AND PURPOSE: To determine appropriate risk-stratification factors for prostate cancer patients undergoing stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Between 2006 and 2010, 515 patients with organ-confined prostate cancer were treated with a regimen of five-fraction SBRT to dose of 35 36.25 Gy. By NCCN criteria, 324 patients were low risk, 153 were intermediate risk, and 38 were high risk. Patients were defined as unfavorable intermediate risk if Gleason 4 + 3 = 7 or >1 intermediate-risk factors (cT2b, c, PSA 10-20, Gleason 3 + 4 = 7). Cox regression analysis was used to determine risk factors significantly associated biochemical failure, and patterns of failure analyzed. RESULTS: With median follow-up of 84 months, the 8-year disease-free survival was 93.6, 84.3, and 65.0% for low, intermediate, and high-risk group patients, respectively. Based on the above definition, 106 favorable intermediate-risk patients had excellent outcomes, with no significant difference compared to low risk patients (7-year DFS 95.2 vs. 93.2%, respectively). The 47 unfavorable intermediate-risk patients had worse outcomes, similar to high-risk patients (7 year DFS 68.2 vs. 65.0%, respectively). Gleason score was the only significant factor associated with biochemical failure on multivariate analysis (p = 0.0003). CONCLUSION: Patients with favorable intermediate-risk disease have excellent outcomes, comparable to low-risk patients. Patients with unfavorable intermediate risk disease have significantly worse outcomes after SBRT, and should be considered for clinical trials or treatment intensification. PMID- 27458574 TI - Retrograde Endopyelotomy with Cutting BalloonTM for Treatment of Ureteropelvic Junction Obstruction in Infants. AB - PURPOSE: The aim of this study is to analyze results of retrograde endopyelotomy with cutting balloon for treatment of ureteropelvic junction obstruction (UPJO) in infants. METHODS: We routinely treat patients with UPJO under 18 months of age with retrograde high-pressure balloon dilatation of the pelviureteric junction (PUJ). During the procedure, in these cases where narrowing at the PUJ persists, endopyelotomy with cutting balloon is performed. Endopyelotomy is performed over guidewire with 5-mm Cutting BalloonTM under fluoroscopic control. Double-J stents is left in situ for 4 weeks. We retrospectively analyzed the postoperative, clinical, and radiological outcome infants treated with cutting balloon endopyelotomy between 2007 and 2015. RESULTS: Sixteen patients required cutting balloon endopyelotomy to achieve complete resolution of narrowing of the waist observed during high-pressure balloon dilatation of the PUJ. Mean operative time was 35 +/- 21 min (mean +/- SD) and hospital stay was <24 h in all patients. Complete resolution of the narrowing at the PUJ under fluoroscopy was achieved in all cases, with no perioperative complications. One patient presented with urinary tract infection, postoperatively (Clavien grade II). Preoperatively, all cases had grade IV SFU hydronephrosis with parenchymal thinning. During follow up, resolution of the hydronephrosis was observed in 11 patients (grade I SFU). In four infants, there was an improvement of the hydronephrosis (grade II SFU) and the renogram curve. In one case, an open pyeloplasty was required due to persistent hydronephrosis and obstructive curve. CONCLUSION: We believe that endopyelotomy with cutting balloon could be a valid and safe option in minimally invasive management of UPJO in infants. PMID- 27458575 TI - The Precautionary Principle, Evidence-Based Medicine, and Decision Theory in Public Health Evaluation. AB - The precautionary principle (PP) has been used in the evaluation of the effectiveness and/or cost-effectiveness of interventions designed to prevent future harms in a range of activities, particularly in the area of the environment. Here, we provide details of circumstances under which the PP can be applied to the topic of harm reduction in Public Health. The definition of PP that we use says that the PP reverses the onus of proof of effectiveness between an intervention and its comparator when the intervention has been designed to reduce harm. We first describe the two frameworks used for health-care evaluation: evidence-based medicine (EBM) and decision theory (DT). EBM is usually used in treatment effectiveness evaluation, while either EBM or DT may be used in evaluating the effectiveness of the prevention of illness. For cost effectiveness, DT is always used. The expectation in Public Health is that interventions employed to reduce harm will not actually increase harm, where "harm" in this context does not include opportunity cost. That implies that an intervention's effectiveness can often be assumed. Attention should therefore focus on its cost-effectiveness. This view is consistent with the conclusions of DT. It is also very close to the PP notion of reversing the onus of proof, but is not consistent with EBM as normally practiced, where the onus is on showing a new practice to be superior to usual practice with a sufficiently high degree of certainty. Under our definitions, we show that where DT and the PP differ in their evaluation is in cost-effectiveness, but only for decisions that involve potential catastrophic circumstances, where the nation-state will act as if it is risk-averse. In those cases, it is likely that the state will pay more, and possibly much more, than DT would allow, in an attempt to mitigate impending disaster. That is, the rules that until now have governed all cost-effectiveness analyses are shown not to apply to catastrophic situations, where the PP applies. PMID- 27458573 TI - Mycobacterium leprae Activates Toll-Like Receptor-4 Signaling and Expression on Macrophages Depending on Previous Bacillus Calmette-Guerin Vaccination. AB - Toll-like receptor (TLR)-1 and TLR2 have been shown to be receptors for Mycobacterium leprae (M. leprae), yet it is unclear whether M. leprae can signal through alternative TLRs. Other mycobacterial species possess ligands for TLR4 and genetic association studies in human populations suggest that people with TLR4 polymorphisms may be protected against leprosy. Using human embryonic kidney (HEK)-293 cells co-transfected with TLR4, we demonstrate that M. leprae activates TLR4. We used human macrophages to show that M. leprae stimulation of cytokine production is diminished if pre-treated with TLR4 neutralizing antibody. TLR4 protein expression was up-regulated on macrophages derived from non-bacillus Calmette-Guerin (BCG) vaccinated healthy volunteers after incubation with M. leprae, whereas it was down-regulated in macrophages derived from BCG-vaccinated donors. Finally, pre-treatment of macrophages derived from BCG-naive donors with BCG reversed the effect of M. leprae on TLR4 expression. This may be a newly described phenomenon by which BCG vaccination stimulates "non-specific" protection to the human immune system. PMID- 27458576 TI - Psychological Distress among Ebola Survivors Discharged from an Ebola Treatment Unit in Monrovia, Liberia - A Qualitative Study. AB - INTRODUCTION: A consequence of the West Africa Ebola outbreak 2014-2015 was the unprecedented number of Ebola survivors discharged from the Ebola Treatment Units (ETUs). Liberia alone counted over 5,000 survivors. We undertook a qualitative study in Monrovia to better understand the mental distress experienced by survivors during hospitalization and reintegration into their community. METHODS: Purposively selected Ebola survivors from ELWA3, the largest ETU in Liberia, were invited to join focus group discussions. Verbal-informed consent was sought. Three focus groups with a total of 17 participants were conducted between February and April 2015. Thematic analysis approach was applied to analyze the data. RESULTS: The main stressors inside the ETU were the daily exposure to corpses, which often remained several hours among the living; the patients' isolation from their families and worries about their well-being; and sometimes, the perception of disrespect by ETU staff. However, most survivors reported how staff motivated patients to drink, eat, bathe, and walk. Additionally, employing survivors as staff fostered hope, calling patients by their name increased confidence and familiarity, and organizing prayer and singing activities brought comfort. When Ebola virus disease survivors returned home, the experience of being alive was both a gift and a burden. Flashbacks were common among survivors. Perceived as contagious, many were excluded from their family, professional, and social life. Some survivors faced divorce, were driven out of their houses, or lost their jobs. The subsequent isolation prevented survivors from picking up daily life, and the multiple losses affected their coping mechanisms. However, when available, the support of family, friends, and prayer enabled survivors to cope with their mental distress. For those excluded from society, psychosocial counseling and the survivor's network were ways to give a meaning to life post Ebola. CONCLUSION: Exposure to death in the ETU and stigma in the communities induced posttraumatic stress reactions and symptoms of depression among Ebola survivors. Distress in the ETU can be reduced through timely management of corpses. Coping mechanisms can be strengthened through trust relationships, religion, peer/community support, and community-based psychosocial care. Mental health disorders need to be addressed with appropriate specialized care and follow-up. PMID- 27458577 TI - Toward the Development of a Sustainable Scientific Research Culture in Azerbaijan (2011-2015). AB - This review especially describes the dangerous pathogens research program in Azerbaijan (AJ) funded by the US Defense Threat Reduction Agency under the Cooperative Biological Engagement Program (CBEP) from 2011 through 2015. The objectives of the CBEP are to prevent the proliferation of biological weapons; to consolidate and secure collections of dangerous pathogens in central repositories; to strengthen biosafety and biosecurity of laboratory facilities; and to improve partner nations' ability to detect, diagnose, report, and respond to outbreaks of disease caused by especially dangerous pathogens. One of the missions of the CBEP is therefore to increase the research skills and proficiency of partner country scientists. The program aims to fulfill this mission by sponsoring scientific research projects that exercise the modern diagnostic techniques available in the CBEP-engaged laboratories and the enhanced disease surveillance/control programs. To strengthen the local scientists' ability to develop research ideas, write grant proposals, and conduct research independently, in-country CBEP integrating contractor personnel have mentored scientists across AJ and conducted workshops to address technical gaps. As a result of CBEP engagement, seven research projects developed and led by AJ scientists have been funded, and five projects are currently in various stages of implementation. The Defense Threat Reduction Agency has also sponsored AJ scientist participation at international scientific conferences to introduce and integrate them into the global scientific community. The efforts summarized in this review represent the first steps in an ongoing process that will ultimately provide AJ scientists with the skills and resources to plan and implement research projects of local and regional relevance. PMID- 27458579 TI - Increase of Incidence and Mortality of Ovarian Cancer during 2003-2012 in Jiangsu Province, China. AB - PURPOSE: The objective of this study is to investigate and analyze the epidemiologic characteristics and time trends of ovarian cancer incidence and mortality in Jiangsu Province of China during 2003-2012. METHOD: Data were collected from eligible cancer registries in Jiangsu Province. Crude rates, age specific rates, truncated age-standardized rate, and proportions of ovarian cancer were calculated. The Segi's World Population was used to calculate age standardized rates for world (ASW). Poisson distribution was used to analyze the differences between urban and rural areas. Joinpoint regression was performed to estimate the annual percent change (APC) of ovarian cancer incidence/mortality. RESULTS: A total number of 4,401 new cases and 1,918 deaths were identified during period 2003-2012. The incidence and mortality ASW was 3.64/100,000 and 1.52/100,000, respectively. ASW of incidence was 4.48/100,000 in urban areas, while 3.04/100,000 in rural areas. The mortality of ASW was slight higher in urban areas than in rural areas. Age-specific incidence showed a peak at the age group of 60-64 years, whereas mortality peaked at age group of 65-69 years. A significant increase of incidence was observed from 2003 to 2006, with an APC of 34.0% (95% CI: 9.7, 63.7), the increasing rate declined since 2006 (APC = 3.3%, 95% CI: -3.5, 10.5). The mortality showed a gentle upward trend as compared with incidence, with an APC of 9.9% (95% CI: 7.7, 12.2) per year, continuously from 2003 to 2012. It is apparent that both incidence and mortality presented a rising trend in all areas, but urban were higher than that in rural areas. CONCLUSION: Ovarian cancer is a highly lethal disease which is becoming a significant public health problem in Chinese women. It is vital to improve the understanding of current status of ovarian cancer. Moreover, prevention and control policies should be formulated to reduce the disease burden of ovarian cancer in China. PMID- 27458580 TI - Occupational Health and Safety of Finnish Dairy Farmers Using Automatic Milking Systems. AB - INTRODUCTION: Conventional pipeline and parlor milking expose dairy farmers and workers to adverse health outcomes. In recent years, automatic milking systems (AMS) have gained much popularity in Finland, but the changes in working conditions when changing to AMS are not well known. The aim of this study was to investigate the occupational health and safety risks in using AMS, compared to conventional milking systems (CMS). METHODS: An anonymous online survey was sent to each Finnish dairy farm with an AMS in 2014. Only those dairy farmers with prior work experience in CMS were included in the final analysis consisting of frequency distributions and descriptive statistics. RESULTS: We received 228 usable responses (131 male and 97 female; 25.2% response rate). The majority of the participants found that AMS had brought flexibility to the organization of farm work, and it had increased leisure time, quality of life, productivity of dairy work, and the attractiveness of dairy farming among the younger generation. In addition, AMS reduced the perceived physical strain on the musculoskeletal system as well as the risk of occupational injuries and diseases, compared to CMS. However, working in close proximity to the cattle, particularly training of heifers to use the AMS, was regarded as a high-risk work task. In addition, the daily cleaning of the AMS and manual handling of rejected milk were regarded as physically demanding. The majority of the participants stated that mental stress caused by the monotonous, repetitive, paced, and hurried work had declined after changing to AMS. However, many indicated increased mental stress because of the demanding management of the AMS. Nightly alarms caused by the AMS, lack of adequately skilled hired labor or farm relief workers, and the 24/7 standby for the AMS were issues that also caused mental stress. CONCLUSION: Based on this study, AMS may have significant potential in the prevention of adverse health outcomes in milking of dairy cows. In addition, AMS may improve the productivity of dairy work and sustainability of dairy production. However, certain characteristics of the AMS require further attention with regard to occupational health and safety risks. PMID- 27458578 TI - The Elevated Susceptibility to Diabetes in India: An Evolutionary Perspective. AB - India has rapidly become a "diabetes capital" of the world, despite maintaining high rates of under-nutrition. Indians develop diabetes at younger age and at lower body weights than other populations. Here, we interpret these characteristics in terms of a "capacity-load" model of glucose homeostasis. Specifically, we assume that glycemic control depends on whether the body's "metabolic capacity," referring to traits, such as pancreatic insulin production and muscle glucose clearance, is able to resolve the "metabolic load" generated by high levels of body fat, high dietary glycemic load, and sedentary behavior. We employ data from modern cohorts to support the model and the interpretation that elevated diabetic risk among Indian populations results from the high metabolic load imposed by westernized lifestyles acting on a baseline of low metabolic capacity. We attribute this low metabolic capacity to the low birth weight characteristic of Indian populations, which is associated with short stature and low lean mass in adult life. Using stature as a marker of metabolic capacity, we review archeological and historical evidence to highlight long-term declines in Indian stature associated with adaptation to several ecological stresses. Underlying causes may include increasing population density following the emergence of agriculture, the spread of vegetarian diets, regular famines induced by monsoon failure, and the undermining of agricultural security during the colonial period. The reduced growth and thin physique that characterize Indian populations elevate susceptibility to truncal obesity, and increase the metabolic penalties arising from sedentary behavior and high glycemic diets. Improving metabolic capacity may require multiple generations; in the meantime, efforts to reduce the metabolic load will help ameliorate the situation. PMID- 27458581 TI - Exploring Instructive Physiological Signaling with the Bioelectric Tissue Simulation Engine. AB - Bioelectric cell properties have been revealed as powerful targets for modulating stem cell function, regenerative response, developmental patterning, and tumor reprograming. Spatio-temporal distributions of endogenous resting potential, ion flows, and electric fields are influenced not only by the genome and external signals but also by their own intrinsic dynamics. Ion channels and electrical synapses (gap junctions) both determine, and are themselves gated by, cellular resting potential. Thus, the origin and progression of bioelectric patterns in multicellular tissues is complex, which hampers the rational control of voltage distributions for biomedical interventions. To improve understanding of these dynamics and facilitate the development of bioelectric pattern control strategies, we developed the BioElectric Tissue Simulation Engine (BETSE), a finite volume method multiphysics simulator, which predicts bioelectric patterns and their spatio-temporal dynamics by modeling ion channel and gap junction activity and tracking changes to the fundamental property of ion concentration. We validate performance of the simulator by matching experimentally obtained data on membrane permeability, ion concentration and resting potential to simulated values, and by demonstrating the expected outcomes for a range of well-known cases, such as predicting the correct transmembrane voltage changes for perturbation of single cell membrane states and environmental ion concentrations, in addition to the development of realistic transepithelial potentials and bioelectric wounding signals. In silico experiments reveal factors influencing transmembrane potential are significantly different in gap junction-networked cell clusters with tight junctions, and identify non-linear feedback mechanisms capable of generating strong, emergent, cluster-wide resting potential gradients. The BETSE platform will enable a deep understanding of local and long-range bioelectrical dynamics in tissues, and assist the development of specific interventions to achieve greater control of pattern during morphogenesis and remodeling. PMID- 27458582 TI - Fusion to Hydrophobin HFBI Improves the Catalytic Performance of a Cytochrome P450 System. AB - Cytochrome P450 monooxygenases (P450) are heme-containing enzymes that oxidize a broad range of substrates in the presence of molecular oxygen and NAD(P)H. For their activity, most P450s rely on one or two redox proteins responsible for the transfer of electrons from the cofactor NAD(P)H to the heme. One of the challenges when using P450s in vitro, especially when non-physiological redox proteins are applied, is the inefficient transfer of electrons between the individual proteins resulting in non-productive consumption of NAD(P)H - referred to as uncoupling. Herein, we describe the improvement of the coupling efficiency between a P450 and its redox partner - diflavin reductase - by fusing both enzymes individually to the hydrophobin HFBI - a small self-assembling protein of the fungus Trichoderma reesei. The separated monooxygenase (BMO) and reductase (BMR) domains of P450 BM3 from Bacillus megaterium were chosen as a P450 reductase model system and individually fused to HFBI. The fusion proteins could be expressed in soluble form in Escherichia coli. When HFBI-fused BMO and BMR were mixed in vitro, substantially higher coupling efficiencies were measured as compared with the respective non-fused enzymes. Consequently, myristic acid conversion increased up to 20-fold (after 6 h) and 5-fold (after 24 h). Size exclusion chromatography demonstrated that in vitro the hydrophobin-fused enzymes build multimeric protein assemblies. Thus, the higher activity is hypothesized to be due to HFBI-mediated self-assembly arranging BMO and BMR in close spatial proximity in aqueous solution. PMID- 27458583 TI - Enzymes in Fish and Seafood Processing. AB - Enzymes have been used for the production and processing of fish and seafood for several centuries in an empirical manner. In recent decades, a growing trend toward a rational and controlled application of enzymes for such goals has emerged. Underlying such pattern are, among others, the increasingly wider array of enzyme activities and enzyme sources, improved enzyme formulations, and enhanced requirements for cost-effective and environmentally friendly processes. The better use of enzyme action in fish- and seafood-related application has had a significant impact on fish-related industry. Thus, new products have surfaced, product quality has improved, more sustainable processes have been developed, and innovative and reliable analytical techniques have been implemented. Recent development in these fields are presented and discussed, and prospective developments are suggested. PMID- 27458584 TI - A Prospective, Randomized, Double-Blinded, Double-Dummy Pilot Study to Assess the Preemptive Effect of Triple Therapy with Aprepitant, Dexamethasone, and Promethazine versus Ondansetron, Dexamethasone and Promethazine on Reducing the Incidence of Postoperative Nausea and Vomiting Experienced by Patients Undergoing Craniotomy Under General Anesthesia. AB - INTRODUCTION: Postoperative nausea and vomiting (PONV) is among the most common distressing complications of surgery under anesthesia. Previous studies have demonstrated that patients who undergo craniotomy have incidences of nausea and vomiting as high as 50-70%. The main purpose of this pilot study is to assess the incidence of PONV by using two different prophylactic regimens in subjects undergoing a craniotomy. Thus, we designed this study to assess the efficacy and safety of triple therapy with the combination of dexamethasone, promethazine, and aprepitant versus ondansetron to reduce the incidence of PONV in patients undergoing craniotomy. MATERIALS AND METHODS: This is a prospective, single center, two-armed, randomized, double-dummy, double-blind, pilot study. Subjects were randomly assigned to one of the two treatment groups. Subjects received 40 mg of aprepitant pill (or matching placebo pill) 30-60 min before induction of anesthesia and 4 mg of ondansetron IV (or 2 ml of placebo saline solution) at induction of anesthesia. In addition, all subjects received 25 mg of promethazine IV and 10 mg of dexamethasone IV at induction of anesthesia. Assessments of PONV commenced for the first 24 h after surgery and were subsequently assessed for up to 5 days. RESULTS: The overall incidence of PONV during the first 24 h after surgery was 31.0% (n = 15) in the aprepitant group and 36.2% (n = 17) for the ondansetron group. The median times to first emetic and significant nausea episodes were 7.6 (2.9, 48.7) and 14.3 (4.4, 30.7) hours, respectively, for the aprepitant group and 6.0 (2.2, 29.5) and 9.6 (0.7, 35.2) hours, respectively, for the ondansetron group. There were no statistically significant differences between these groups. No adverse events directly related to study medications were found. CONCLUSION: This pilot study showed similar effectiveness when comparing the two PONV prophylaxis regimens. Our data showed that both treatments could be effective regimens to prevent PONV in patients undergoing craniotomy under general anesthesia. Future trials testing new PONV prophylaxis regimens in this surgical population should be performed to gain a better understanding of how to best provide prophylactic treatment. PMID- 27458585 TI - Treatment of Acute Liver Failure in Resource-Constrained Settings without Transplantation Facilities Can Be Improved. PMID- 27458586 TI - Meningioma Genomics: Diagnostic, Prognostic, and Therapeutic Applications. AB - There has been a recent revolution in our understanding of the genetic factors that drive meningioma, punctuating an equilibrium that has existed since Cushing's germinal studies nearly a century ago. A growing appreciation that meningiomas share similar biologic features with other malignancies has allowed extrapolation of management strategies and lessons from intra-axial central nervous system neoplasms and systemic cancers to meningiomas. These features include a natural proclivity for invasion, frequent intratumoral heterogeneity, and correlation between biologic profile and clinical behavior. Next-generation sequencing has characterized recurrent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA, which are collectively present in ~80% of sporadic meningiomas. Genomic features of meningioma further associate with tumor location, histologic subtype, and possibly clinical behavior. Such genomic decryption, along with advances in targeted pharmacotherapy, provides a maturing integrated view of meningiomas. We review recent advances in meningioma genomics and probe their potential applications in diagnostic, therapeutic, and prognostic frontiers. PMID- 27458588 TI - Editorial: Function and Flexibility: Friend or Foe? PMID- 27458587 TI - Feature Selection Methods for Early Predictive Biomarker Discovery Using Untargeted Metabolomic Data. AB - Untargeted metabolomics is a powerful phenotyping tool for better understanding biological mechanisms involved in human pathology development and identifying early predictive biomarkers. This approach, based on multiple analytical platforms, such as mass spectrometry (MS), chemometrics and bioinformatics, generates massive and complex data that need appropriate analyses to extract the biologically meaningful information. Despite various tools available, it is still a challenge to handle such large and noisy datasets with limited number of individuals without risking overfitting. Moreover, when the objective is focused on the identification of early predictive markers of clinical outcome, few years before occurrence, it becomes essential to use the appropriate algorithms and workflow to be able to discover subtle effects among this large amount of data. In this context, this work consists in studying a workflow describing the general feature selection process, using knowledge discovery and data mining methodologies to propose advanced solutions for predictive biomarker discovery. The strategy was focused on evaluating a combination of numeric-symbolic approaches for feature selection with the objective of obtaining the best combination of metabolites producing an effective and accurate predictive model. Relying first on numerical approaches, and especially on machine learning methods (SVM-RFE, RF, RF-RFE) and on univariate statistical analyses (ANOVA), a comparative study was performed on an original metabolomic dataset and reduced subsets. As resampling method, LOOCV was applied to minimize the risk of overfitting. The best k-features obtained with different scores of importance from the combination of these different approaches were compared and allowed determining the variable stabilities using Formal Concept Analysis. The results revealed the interest of RF-Gini combined with ANOVA for feature selection as these two complementary methods allowed selecting the 48 best candidates for prediction. Using linear logistic regression on this reduced dataset enabled us to obtain the best performances in terms of prediction accuracy and number of false positive with a model including 5 top variables. Therefore, these results highlighted the interest of feature selection methods and the importance of working on reduced datasets for the identification of predictive biomarkers issued from untargeted metabolomics data. PMID- 27458589 TI - Canine Butterfly Glioblastomas: A Neuroradiological Review. AB - In humans, high-grade gliomas may infiltrate across the corpus callosum resulting in bihemispheric lesions that may have symmetrical, winged-like appearances. This particular tumor manifestation has been coined a "butterfly" glioma (BG). While canine and human gliomas share many neuroradiological and pathological features, the BG morphology has not been previously reported in dogs. Here, we describe the magnetic resonance imaging (MRI) characteristics of BG in three dogs and review the potential differential diagnoses based on neuroimaging findings. All dogs presented for generalized seizures and interictal neurological deficits referable to multifocal or diffuse forebrain disease. MRI examinations revealed asymmetrical (2/3) or symmetrical (1/3), bihemispheric intra-axial mass lesions that predominantly affected the frontoparietal lobes that were associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and fluid-attenuated inversion recovery signal intensities, variable contrast enhancement (2/3), and mass effect. All tumors demonstrated classical histopathological features of glioblastoma multiforme (GBM), including glial cell pseudopalisading, serpentine necrosis, microvascular proliferation as well as invasion of the corpus callosum by neoplastic astrocytes. Although rare, GBM should be considered a differential diagnosis in dogs with an MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma. PMID- 27458590 TI - Resolvins and omega three polyunsaturated fatty acids: Clinical implications in inflammatory diseases and cancer. AB - Inflammation is a central process in several disorders and contributes to cancer progression. Inflammation involves a complex cascade of pro-inflammatory and anti inflammatory signaling events with protein and lipid mediators. Recent advances in lipid detection have revealed the importance of lipid mediators in inflammation. Omega three polyunsaturated fatty acids (omega-3 PUFA) are found naturally in fish oil and have been extensively studied in multiple inflammatory diseases with improved outcomes. Resolvins are thought to be the active metabolites of omega-3 PUFA, and are responsible for facilitating the resolving phase of acute inflammation. Clinically, resolvins have been associated with resolution of acute kidney injury and acute lung injury, micro and macro vascular response to injury, and inhibition of microglia-activated inflammation in neurodegenerative disorders. In addition to inflammatory diseases, omega-3 PUFA and resolvins appear to modulate cancer progression. omega-3 PUFA intake has been associated with reduced inflammation in colorectal cancer, and favorable phenotype in breast cancer. Resolvins offer promising therapeutic potential as they may modulate inflammation with minimal side-effects, in contrast to currently available anti-inflammatory medications. This review describes the roles of omega-3 PUFA and resolvins in the inflammatory cascade, various inflammatory diseases, and specific cancers. Additionally, it will discuss the clinical therapeutic potential of resolvins as targets in inflammatory diseases and cancers. PMID- 27458591 TI - Role of urocortin in pregnancy: An update and future perspectives. AB - The activities of corticotropin-releasing factor (CRF) and related peptides are mediated a number of receptors with seven transmembrane domains that are coupled to the Gs and Gq proteins. These receptors are known as CRF-Rs. In vitro studies have evidenced that urocortin (UCN) and CRF provoke an increase in the contractility of the uterus which is induced by endometrial prostaglandin F2a. Furthermore, through trophoblasts, it stimulates the secretion of adrenocorticotropic hormone (ACTH) and prostaglandin PGE2 and has a vasodilatory effect on the placenta. While it is well known that the placenta produces considerable quantities of CRF, several studies have, however, excluded that the placenta can generate significant quantities of UCN. In the short term, the human fetal adrenal gland produces more cortisol and dehydroepiandrosterone sulfate. The gestational tissues express UCN3 and UCN2 mRNA in cytotrophoblast and syncytiotrophoblast cells, while UCN2 is only to be found in the maternal and fetal vessels and amniotic cells. Nevertheless, gestational tissues express UCN2 and UCN3 differentially and do not stimulate placental ACTH secretion. In term pregnancies, maternal plasma levels of CRF and UCN are lower than at the beginning of pregnancy and are correlated to labor onset. Conversely, they do not decrease in post-term pregnancies. This evidence would seem to indicate that the fine-regulated expression of these neuropeptides is important in determining the duration of human gestation. In this scenario, low concentrations of UCN in the amniotic fluid at mid-term may be considered a sign of predisposition to preterm birth. PMID- 27458592 TI - Neuromuscular electrical stimulation and testosterone did not influence heterotopic ossification size after spinal cord injury: A case series. AB - Neuromuscular electrical stimulation (NMES) and testosterone replacement therapy (TRT) are effective rehabilitation strategies to attenuate muscle atrophy and evoke hypertrophy in persons with spinal cord injury (SCI). However both interventions might increase heterotopic ossification (HO) size in SCI patients. We present the results of two men with chronic traumatic motor complete SCI who also had pre-existing HO and participated in a study investigating the effects of TRT or TRT plus NMES resistance training (RT) on body composition. The 49-year old male, Subject A, has unilateral HO in his right thigh. The 31-year-old male, Subject B, has bilateral HO in both thighs. Both participants wore transdermal testosterone patches (4-6 mg/d) daily for 16 wk. Subject A also underwent progressive NMES-RT twice weekly for 16 wk. Magnetic resonance imaging scans were acquired prior to and post intervention. Cross-sectional areas (CSA) of the whole thigh and knee extensor skeletal muscles, femoral bone, and HO were measured. In Subject A (NMES-RT + TRT), the whole thigh skeletal muscle CSA increased by 10%, the knee extensor CSA increased by 17%, and the HO + femoral bone CSA did not change. In Subject B (TRT), the whole thigh skeletal muscle CSA increased by 13% in the right thigh and 6% in the left thigh. The knee extensor CSA increased by 7% in the right thigh and did not change in the left thigh. The femoral bone and HO CSAs in both thighs did not change. Both the TRT and NMES-RT + TRT protocols evoked muscle hypertrophy without stimulating the growth of pre-existing HO. PMID- 27458593 TI - Colitis cystica profunda of the rectum: An unexpected operative finding. AB - Colitis cystic profunda is a rare entity benign condition of the colon and rectum that can mimic suspicious polyps or malignancy. The commonest sites of affectation are the rectum and the sigmoid colon but it can be unusually widely distributed in the colon. The aetiology of this condition is not fully elucidated and confident diagnosis can only be made on histological features. We hereby describe a patient who presented with significant rectal symptoms and an unexpected finding of a submucosal mucous cyst mimicking a suspicious rectal polyp and highlighted its significance and the review of the literature. PMID- 27458594 TI - Spontaneous calcaneal fracture in patients with diabetic foot ulcer: Four cases report and review of literature. AB - Spontaneous calcaneal fractures in diabetic patients without obvious trauma may occur, sometimes accompanying diabetic foot ulcers. In the current study we report four cases who were hospitalized for diabetic foot ulcer with concomitant calcaneal fractures. There were four diabetic patients (one type 1 and three type 2) who registered with diabetic foot ulcers with coexisting calcaneal fractures, all of which were classified as Type A according to Essex Lopresti Calcaneal Fracture Classification. Two of the patients with renal failure were in a routine dialysis program, as well as vascular compromise and osteomyelitis in all of the patients. The diabetic foot ulcer of the 61 years old osteoporotic female patient healed with local debridement, vacuum assisted closure and then epidermal growth factor while the calcaneal fracture was then followed by elastic bandage. In two patients could not prevent progression of diabetic foot ulcers and calcaneal fractures to consequent below-knee amputation. The only patient with type 1 diabetes mellitus improved with antibiotic therapy and split thickness skin grafting, while the calcaneal fracture did not heal. In the current study we aimed to emphasize the spontaneous calcaneal fractures as possible co-existing pathologies in patients with diabetic foot ulcers. After all the medical treatment, amputation below knee had to be performed in 2 patients. It should be noted that other accompanying conditions such as impaired peripheral circulation, osteomyelitis, chronic renal failure, and maybe osteoporosis is a challenge of the recovery of calcaneal fractures and accelerate the progress to amputation in diabetic patients. PMID- 27458595 TI - Extensive laryngeal infiltration from a neglected papillary thyroid carcinoma: A case report. AB - Papillary carcinoma of the thyroid is the commonest type of thyroid cancer. Laryngeal infiltration from papillary thyroid carcinoma is extremely rare, with only a few cases of partial invasion described in the literature. We present a very unusual case of complete infiltration of both thyroid and cricoid cartilages from a neglected papillary thyroid carcinoma in a 59-year-old male. This sequel resulted from refusal of the patient to undergo treatment when initially diagnosed. An invasion to such an extent has not been described in the literature before, and in this case warranted a total laryngectomy followed by radioactive iodine. Prompt management of papillary carcinomas is crucial for avoiding such complications. Future guidelines should include management options for the patients who deny treatment initially. PMID- 27458596 TI - Staphylococcal bullous impetigo in a neonate. AB - An otherwise healthy, full-term neonate presented at day 15 of life to the pediatric emergency with generalized papulo-pustular rash for 2 d. This was finally diagnosed as bullous impetigo caused by Staphylococcus aureus (S. aureus). The skin lesions decreased significantly after starting antibiotic therapy and drainage of blister fluid. There was no recurrence of the lesions on follow-up. This case of generalized pustular eruption due to S. aureus in a neonate is reported, as it poses a diagnostic dilemma and can have serious consequences if left untreated. PMID- 27458597 TI - Rituximab for Sjogren syndrome-associated type II mixed cryoglobulinemic cerebral vasculitis. PMID- 27458598 TI - Autoantibodies against glutamate receptor delta2 after allogenic stem cell transplantation. AB - OBJECTIVE: To report on a Caucasian patient who developed steroid-responsive transverse myelitis, graft vs host disease of the gut, and anti-GluRdelta2 after allogenic stem cell transplantation. METHODS: Histoimmunoprecipitation (HIP) with the patient's serum and cryosections of rat and porcine cerebellum followed by mass spectrometry was used to identify the autoantigen. Correct identification was verified by indirect immunofluorescence using recombinant GluRdelta2 expressed in HEK293 cells. RESULTS: The patient's serum produced a granular staining of the cerebellar molecular layer (immunoglobulin G1 and immunoglobulin G3; endpoint titer: 1:1,000) but did not react with other CNS tissues or 28 established recombinant neural autoantigens. HIP revealed a unique protein band at ~110 kDa that was identified as GluRdelta2. The patient's serum also stained GluRdelta2 transfected but not mock-transfected HEK293 cells. Control sera from 38 patients with multiple sclerosis, 85 patients with other neural autoantibodies, and 205 healthy blood donors were negative for anti-GluRdelta2. Preadsorption with lysate from HEK293-GluRdelta2 neutralized the patient's tissue reaction whereas control lysate had no effect. In addition to anti-GluRdelta2, the patient's serum contained immunoglobulin G autoantibodies against the pancreatic glycoprotein CUZD1, which are known to be markers of Crohn disease. CONCLUSIONS: In the present case, the development of anti-GluRdelta2 was associated with transverse myelitis, which was supposedly triggered by the stem cell transplantation. Similar to encephalitis in conjunction with anti-GluRdelta2 reported in a few Japanese patients, the patient's neurologic symptoms ameliorated after steroid therapy. PMID- 27458599 TI - No association of tobacco use and disease activity in multiple sclerosis. AB - OBJECTIVE: To study whether tobacco use is associated with MRI and clinical disease activity in patients with multiple sclerosis (MS). METHODS: Prospective cohort study of 87 patients with relapsing-remitting MS originally included in a randomized placebo-controlled trial of omega-3 fatty acids in MS (the OFAMS Study). Serum levels of cotinine (biomarker of tobacco use) were analyzed at baseline and every 6 months for 2 years. MRI activity was assessed at baseline and monthly for 9 months and after 12 and 24 months. RESULTS: Fifty-three patients (61%) had serum cotinine levels >=85 nmol/L on >=60% of the measurements and were considered tobacco users and 34 (39%) had cotinine levels <85 nmol/L, consistent with non-tobacco use. There was no association between tobacco use and the occurrence of new gadolinium-enhancing T1 lesions, new or enlarging T2 lesions, or their aggregate (combined unique activity). Furthermore, there was no association between cotinine levels and MRI activity for the tobacco users, and tobacco users did not have more relapses or Expanded Disability Status Scale progression. CONCLUSION: Our results indicate that tobacco use does not directly influence MRI activity or relapse rate in MS. This may implicate that the reported association between smoking and MS disease progression could be mediated through other mechanisms. PMID- 27458600 TI - Next-generation sequencing of tissue: A logical extension. PMID- 27458601 TI - Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. AB - OBJECTIVES: To evaluate the presence of antibodies to conformation-intact myelin oligodendrocyte glycoprotein (MOG) in a subgroup of adult patients with clinically definite multiple sclerosis (MS) preselected for a specific clinical phenotype including severe spinal cord, optic nerve, and brainstem involvement. METHODS: Antibodies to MOG were investigated using a cell-based assay in 3 groups of patients: 104 preselected patients with MS (group 1), 55 age- and sex-matched, otherwise unselected patients with MS (group 2), and in 22 brain-biopsied patients with demyelinating diseases of the CNS (n = 19 with MS), 4 of whom classified as MS type II (group 3). Recognized epitopes were identified with mutated variants of MOG. RESULTS: Antibodies to MOG were found in about 5% (5/104) of preselected adult patients with MS. In contrast, in groups 2 and 3, none of the patients tested positive for MOG antibodies. Patients with MS with antibodies to MOG predominantly manifested with concomitant severe brainstem and spinal cord involvement and had a severe disease course with high relapse rates and failure to several disease-modifying therapies. Three of them had been treated with plasma exchange with a favorable response. All anti-MOG-positive patients with MS showed typical MS lesions on brain MRI. Longitudinal analysis up to 9 years revealed fluctuations and reappearance of anti-MOG reactivity. Epitope mapping indicated interindividual heterogeneity, yet intraindividual stability of the antibody response. CONCLUSIONS: Antibodies to MOG can be found in a distinct subgroup of adult MS with a specific clinical phenotype and may indicate disease heterogeneity. PMID- 27458602 TI - Infliximab is a plausible alternative for neurologic complications of Behcet disease. AB - OBJECTIVE: We evaluated the effectiveness of infliximab in patients with neuro Behcet syndrome for whom other immunosuppressive medications had failed. METHODS: Patients whose common immunosuppressive medications fail in recurrent neuro Behcet syndrome need an alternative. We report our experience with the tumor necrosis factor alpha blocker infliximab for long-term treatment of neuro-Behcet syndrome. We recruited patients within a multidisciplinary referral practice of Behcet disease and prospectively followed everyone with a neurologic symptom(s). Patients (n = 16) with >=2 neurologic bouts (excluding purely progressive disease) while on another immunosuppressive treatment were switched to and successfully sustained on infliximab (5 mg/kg in weeks 0, 2, and 6, then once every 8 weeks; minimum follow-up duration >=12 months). Infliximab was stopped within 2 months after initiation in one patient because of pulmonary and CNS tuberculosis. RESULTS: Patients had stepwise worsening due to relapses in the Expanded Disability Status Scale modified for neuro-Behcet syndrome before switching to infliximab (median score of 5.0, range 2.0-7.0; median neuro-Behcet syndrome duration 29.1 months, range 5.0-180.7). Median duration of preinfliximab immunosuppressive medication use was 20.0 months (range 3.0-180.7). In all 15 patients, during infliximab treatment (median score 4.0, range 2.0-7.0; median duration 39.0 months, range 16.0-104.9 months), neurologic relapses were completely aborted and there was no further disability accumulation. CONCLUSION: We observed a significant beneficial effect of infliximab in neuro-Behcet syndrome. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with neuro-Behcet syndrome whose other immunosuppressive medications failed, infliximab prevents further relapses and stabilizes disability. PMID- 27458603 TI - Integrating MRI brain imaging studies of pre-reading children with current theories of developmental dyslexia: A review and quantitative meta-analysis. AB - The neurobiological substrates that cause people with dyslexia to experience difficulty in acquiring accurate and fluent reading skills are still largely unknown. Although structural and functional brain anomalies associated with dyslexia have been reported in adults and school-age children, these anomalies may represent differences in reading experience rather than the etiology of dyslexia. Conducting MRI studies of pre-readers at risk for dyslexia is one approach that enables us to identify brain alterations that exist before differences in reading experience emerge. The current review summarizes MRI studies that examine brain differences associated with risk for dyslexia in children before reading instruction and meta-analyzes these studies. In order to link these findings with current etiological theories of dyslexia, we focus on studies that take a modular perspective rather than a network approach. Although some of the observed differences in pre-readers at risk for dyslexia may still be shaped by language experiences during the first years of life, such studies underscore the existence of reading-related brain anomalies prior to reading onset and could eventually lead to earlier and more precise diagnosis and treatment of dyslexia. PMID- 27458604 TI - Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model. AB - BACKGROUND AND AIMS: The human intestinal peptide transporter 1, hPepT1, is expressed in the small intestine at low levels in the healthy colon and upregulated during inflammatory bowel disease. hPepT1 plays a role in mouse colitis and human studies have demonstrated that chronic intestinal inflammation leads to colorectal cancer (colitis-associated cancer; CAC). Hence, we assessed here the role of PepT1 in CAC. METHODS: Mice with hPepT1 overexpression in intestinal epithelial cells (TG) or PepT1 (PepT1-KO) deletion were used and CAC was induced by AOM/DSS. RESULTS: TG mice had larger tumor sizes, increased tumor burdens, and increased intestinal inflammation compared to WT mice. Conversely, tumor number and size and intestinal inflammation were significantly decreased in PepT1-KO mice. Proliferating crypt cells were increased in TG mice and decreased in PepT1-KO mice. Analysis of human colonic biopsies revealed an increased expression of PepT1 in patients with colorectal cancer, suggesting that PepT1 might be targeted for the treatment of CAC. The use of an anti-inflammatory tripeptide KPV (Lys-Pro-Val) transported by PepT1 was able to prevent carcinogenesis in WT mice. When administered to PepT1-KO mice, KPV did not trigger any of the inhibitory effect on tumorigenesis observed in WT mice. CONCLUSIONS: The observations that pepT1 was highly expressed in human colorectal tumor and that its overexpression and deletion in mice increased and decreased colitis associated tumorigenesis, respectively, suggest that PepT1 is a potential therapeutic target for the treatment of colitis associated tumorigenesis. PMID- 27458606 TI - Epidemiology of Bloodstream Infections in a Multicenter Retrospective Cohort of Liver Transplant Recipients. AB - Although some studies have examined the epidemiology of bloodstream infections after liver transplantation, they were based in single centers and did not identify bloodstream infections treated in other hospitals. METHODS: We retrospectively examined a cohort of 7912 adult liver transplant recipients from 24 transplant centers using 2004 to 2012 International Classification of Diseases, Ninth Revision, Clinical Modification billing data from 3 State Inpatient Databases, and identified bloodstream infections, inpatient death, and cumulative 1-year hospital costs. Multilevel Cox regression analyses were used to determine factors associated with bloodstream infections and death. RESULTS: Bloodstream infections were identified in 29% (n = 2326) of liver transplant recipients, with a range of 19% to 40% across transplant centers. Only 63% of bloodstream infections occurring more than 100 days posttransplant were identified at the original transplant center. Bloodstream infections were associated with posttransplant laparotomy (adjusted hazard ratio [aHR], 1.52), prior liver transplant (aHR, 1.42), increasing age (aHR, 1.07/decade), and some comorbidities. Death was associated with bloodstream infections with and without septic shock (aHR, 10.96 and 3.71, respectively), transplant failure or rejection (aHR, 1.41), posttransplant laparotomy (aHR, 1.40), prior solid-organ transplant (aHR, 1.48), increasing age (aHR, 1.15/decade), and hepatitis C cirrhosis (aHR, 1.20). The risk of bloodstream infections and death varied across transplant centers. Median 1-year cumulative hospital costs were higher for patients who developed bloodstream infections within 1 year of transplant compared with patients who were bloodstream infection-free (US $229 806 vs US $111 313; P < 0.001). CONCLUSIONS: Bloodstream infections are common and costly complications after liver transplantation that are associated with a markedly increased risk of death. The incidence and risk of developing bloodstream infections may vary across transplant centers. PMID- 27458605 TI - Microbiota-inducible Innate Immune, Siderophore Binding Protein Lipocalin 2 is Critical for Intestinal Homeostasis. AB - BACKGROUND & AIMS: Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD. METHODS: Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration. WT and Lcn2 knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S rRNA gene pyrosequencing and, their colitogenic potential by co-housing with Il-10KO mice. Acute (dextran sodium sulfate) and chronic (IL-10R neutralization and T-cell adoptive transfer) colitis was induced in WT and Lcn2KO mice with or without antibiotics. RESULTS: Lcn2 expression was dramatically induced upon inflammation and was dependent upon presence of a gut microbiota and MyD88 signaling. Use of bone-marrow chimeric mice revealed non-immune cells are the major contributors of circulating Lcn2. Lcn2KO mice exhibited elevated levels of entA-expressing gut bacteria burden and, moreover, a broadly distinct bacterial community relative to WT littermates. Lcn2KO mice developed highly colitogenic T-cells and exhibited exacerbated colitis upon exposure to DSS or neutralization of IL-10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota of Lcn2KO mice, via cohousing, resulted in severe colitis in Il-10KO mice. CONCLUSION: Lcn2 is a bacterially-induced, MyD88-dependent, protein that play an important role in gut homeostasis and a pivotal role upon challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota. PMID- 27458607 TI - TREM2 p.R47H substitution is not associated with dementia with Lewy bodies. AB - Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.(1,2) At autopsy, alpha-synuclein-positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease-related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.(2) The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD). A recent genetic association study examining known hits from PD and AD identified variants at both the alpha-synuclein (SNCA) and APOE loci as influencing the individual risk to DLB.(3) These findings would suggest that DLB may be a distinct disease with shared genetic risk factors with PD and AD. PMID- 27458608 TI - Exploring Willingness of Elder Chinese in Houston to Participate in Clinical Research. AB - BACKGROUND AND OBJECTIVES: Inadequate minority participation in clinical research can threaten the applicability and strength of scientific findings. Previous research suggests that trial participation rates are lowest among Asian Americans, compared to other groups. This study explored barriers to clinical research participation among elder Chinese living in Houston, Texas. Additionally we administered the Trust in Medical Researchers Scale (TIMRS), used previously in researching trust in medical researchers as related to research participation. DESIGN: In this mixed methods study, a semi-structured interview, including the TIMRS were administered to 30 adults of Chinese ancestry aged 50 years or older recruited from a Chinese community center. Interviews were conducted in English, Mandarin and Cantonese and independently coded and analyzed using thematic content analysis. TIMRS scores were calculated for participants. RESULTS: Participants were 70% female, 70% were 60 or elder, all were foreign born and on average lived in the US for 21.8 years. Participants perceived risks to research participation and preferred language concordant research staff. Interviewees were more willing to participate if they perceived personal and community health related benefits. The overall TIMRS score was 23.9 (+/-5.0), lower than the overall TIMRS for Whites in a previous study (P<0.001). CONCLUSIONS: The barriers and facilitators to research participation confirmed previous research among Asians. Our participant TIMRS scores were consistent with decreased levels of trust observed in the original TIMRS study for African Americans as compared and lower than Whites. Employing strategies that utilize language concordant staff who build trust with participants may aid in recruiting elder Chinese, especially if the research is personally relevant to those being recruited. PMID- 27458609 TI - Reslizumab: Maintenance treatment for eosinophilic asthma inadequately controlled on corticosteroids. AB - The starting point for this drug was the growing realization that eosinophils appeared to be associated with a severe form of asthma in which patients were subject to exacerbations of their condition that could not be adequately managed using inhaled and/or oral corticosteroids. Studies of the pathophysiology of eosinophils revealed that they produce many bioactive compounds that contribute to the pathophysiology of a number of diseases including asthma. Interleukin-5 (IL-5) in particular is an important factor in some forms of severe asthma. A rat antibody to IL-5 (39D10) was humanized producing the product now know as reslizumab. However, initial studies of this antibody in patients with asthma were unsuccessful. It was only when the importance of the eosinophilic asthma endotype was recognized that reslizumab was found to indeed reduce the severity and exacerbations of asthma in patients who were inadequately treated by inhaled and/ or oral corticosteroids. These studies have determined that reslizumab is a valuable drug for the management of such patients provided that they have an eosinophil count of > 400 cells/mcL. Because a very small percentage of patients receiving reslizumab may experience anaphylaxis, reslizumab must be only given in a facility with adequate facilities and by a health professional trained in the management of anaphylaxis. PMID- 27458611 TI - Cancer Therapeutic Resistance: Progress and Perspectives (April 7-8, 2016 - Barcelona, Spain). AB - At the Cancer Therapeutic Resistance: Progress and Perspectives conference, in Barcelona, Spain, April 7-8, 2016, researchers, clinicians and students gathered to discuss our current understanding of intrinsic and acquired resistance of tumors to cancer therapies and to explore how to translate strategies to predict risk or overcome resistance to the clinic. The sessions covered a wide range of topics, including cancer omics, molecular classification, clinically relevant tumor models, biomarkers and novel therapeutic targets, and personalized medicine, with talks from many international experts in the field. This report highlights the main presentations that demonstrate the progress being made in predicting and identifying drug resistance in patients with cancer, personalized approaches to direct treatment and understanding the mechanisms involved. With better models of human cancer and powerful high-throughput screening techniques, translation to the clinic leading to tangible benefits for patients is attainable. PMID- 27458610 TI - Riboflavin for corneal cross-linking. AB - Corneal collagen cross-linking (CXL) with riboflavin and ultraviolet A (UVA) radiation is the first therapeutic modality that appears to arrest the progression of keratoconus and other corneal ectasias. Riboflavin is central to the process, acting as a photosensitizer for the production of oxygen singlets and riboflavin triplets. These free radicals drive the CXL process within the proteins of the corneal stroma, altering its biomechanical properties. Riboflavin also absorbs the majority of the UVA radiation, which is potentially cytotoxic and mutagenic, within the anterior stroma, preventing damage to internal ocular structures, such as the corneal endothelium, lens and retina. Clinical studies report cessation of ectatic progression in over 90% of cases and the majority document significant improvements in visual, keratometric and topographic parameters. Clinical follow-up is limited to 5-10 years, but suggests sustained stability and enhancement in corneal shape. Sight-threatening complications are rare. The optimal stromal riboflavin dosage for CXL is as yet undetermined. PMID- 27458612 TI - The European League Against Rheumatism (EULAR) - 17th Annual European Congress of Rheumatology (June 8-11, 2016 - London, UK). AB - The 2016 Annual European Congress of Rheumatology, an annual conference organized by the European League Against Rheumatism (EULAR), took place in London, U.K. Over 4,000 abstracts were submitted this year with over 199 sessions and poster tours on offer. The congress has become a major event in the field of rheumatology with participants attending from around the world. The oral sessions, poster displays and lectures cover a broad spectrum of topics, including the latest understanding of disease processes, as well as recent advances in diagnosis and patient care. PMID- 27458613 TI - American Diabetes Association - 76th Scientific Sessions (June 10-14, 2016 - New Orleans, Louisiana, USA). AB - The 76th American Diabetes Association (ADA) Scientific Sessions took place in New Orleans, Louisiana, USA. The meeting brought together scientists and professionals from a wide range of disciplines in the field of diabetes and provided a platform for networking, allowing experts and researchers to share ideas and learn about the significant advances in diabetes research, treatment and care. Over the course of the 5 days, participants received exclusive access to more than 2,500 original research presentations. PMID- 27458614 TI - The effect of EDTA root conditioning on periodontal surgery outcome: A meta analysis. AB - OBJECTIVE: Chemical root conditioning is a procedure to remove the smear layer, which influences periodontal healing. The purpose of this study was to determine the effect of using ethylenediaminetetraacetic acid (EDTA) as a root conditioning agent on periodontal surgery outcomes. METHOD AND MATERIALS: The databases searched from their earliest records to February 2015 included Pubmed, Embase, the Cochrane library, and ISI Web of Science. Quality assessment of the methodologies of all the included studies and data was performed with Review Manager software. Probing depth (PD) and clinical attachment level (CAL) were analyzed using inverse variance. RESULTS: The evaluation of the three articles that met the inclusion criteria showed that the differences between the EDTA groups and the control groups were not statistically significant (6 months PD: mean difference [MD] = -0.15 mm, Z = 1.09, P = .27; CAL: MD = 0.15 mm, Z = 0.89, P = .37). CONCLUSION: EDTA was not able to significantly improve the PD and CAL. A positive outcome of using EDTA as a root conditioning agent was not evident. Thus, future research should focus on EDTA in combination with other drugs or a better alternative drug to EDTA. PMID- 27458615 TI - A "chemical nose" biosensor for detecting proteins in complex mixtures. AB - A growing understanding of the fundamental role of proteins in diseases has advanced the development of quantitative protein assays in the medical field. Current techniques for protein analysis include enzyme-linked immunosorbent assays (ELISA), flow cytometry, mass spectrometry, and immunohistochemistry. However, many of these conventional strategies require specialized training, expensive antibodies, or sophisticated equipment, raising assay costs and limiting their application to laboratory analysis. Here, we present the application of a "chemical nose" type colorimetric gold nanoparticle sensor for detection, quantification, and identification of single proteins, protein mixtures, and proteins within the complex environment of human serum. The unique interactions between a mixture of two different gold nanoparticle morphologies (spherical and branched) and six separate proteins (bovine serum albumin, human serum albumin, immunoglobulin G, fibrinogen, lysozyme, and hemoglobin) generated distinguishable protein- and concentration-dependent absorption spectra, even at nanomolar concentrations. Furthermore, we show that this response is sensitive to the relative abundance of different proteins in solution, permitting analysis of protein mixtures. Finally, we demonstrate the ability to distinguish human serum samples with and without a clinically relevant two-fold increase in immunoglobulin G, without the use of expensive reagents or complicated sample processing. PMID- 27458616 TI - Simultaneous realization of high catalytic activity and stability for catalytic cracking of n-heptane on highly exposed (010) crystal planes of nanosheet ZSM-5 zeolite. AB - Nanosheet ZSM-5 zeolite with highly exposed (010) crystal planes demonstrates high reactivity and good anti-coking stability for the catalytic cracking of n heptane, which is attributed to the synergy of high external surface area and acid sites, fully accessible channel intersection acid sites, and hierarchical porosity caused by the unique morphology. PMID- 27458618 TI - Thematic Abstract Review. Antibiotics and Implant Therapy. PMID- 27458617 TI - Revolution to Evolution and Back Again. PMID- 27458619 TI - CardioPulse: Leaders in cardiovascular medicine of today: Professor David Wood, Imperial College, London. PMID- 27458620 TI - CardioPulse: Prevention of global cardiovascular disease. PMID- 27458621 TI - CardioPulse: The plunging mortality of cardiovascular disease in Israel. PMID- 27458622 TI - [Cardiovascular disease in rheumatic diseases]. AB - The representatives of immunoinflammatory diseases are rheumatic ones, such as primarily rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus, and other systemic connective diseases, which are characterized by a high risk for untimely death. The high risk of untimely death in these diseases has been found to be associated with the severity of an immunoinflammatory process that gives rise to severe irreversible damage to vital organs and systems and with the development of a wide spectrum of comorbidities (infections, interstitial lung disease, malignant tumors, osteoporotic fractures, etc.). Among them, diseases of the cardiovascular system, which are most commonly caused by the early development and.accelerated progression of atherosclerotic coronary lesions, hold a central.position. The paper gives the data available in the recent literature on the impact.of antirheumatic therapy (disease-modifying antirheumatic drugs and biological agents) on' the cardiovascular system. PMID- 27458623 TI - [Interleukin-6 inhibition and cardiovascular disease in patients with rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a' disease conferring high risk for cardiovascular events (CVE). Systemic inflammation underlying RA favors development of CVE. The safety of biological agents, acting on the cardiovascular system has been inadequately investigated. On the one hand, they decrease RA activity and, on the other, may increase the risk of CVE. This review analyzes' the literature data predominantly published in recent years on the effect of an IL-6 receptor inhibitor on the cardiovascular system. Tocilizumab is shown to be a promising agent to reduce cardiovascular risk the findings need to be clinically verified. Long-term prospective investigations should be conducted to determine more exactly the impact of IL-6 receptor inhibition on. the development of CVE. PMID- 27458625 TI - CardioPulse: The second Postgraduate Course in Heart Failure: 2016-2017. PMID- 27458624 TI - [Cardiovascular risk in patients with psoriatic arthritis]. AB - Psoriatic arthritis (PsA) is a chronic.immune-mediated disease that is observed in 8-30% of psoriatic patients. It has been recently established that PsA and psoriasis are closely associated with the high prevalence of metabolic syndrome, hypertension; abdominal obesity, and a risk for cardiovascular diseases (CVD), including fatal myocardial infarction (Ml) and acute cerebrovascular accidents, which shortens lifespan in the patients compared to the general population. The authors state their belief that the synergic effect of traditional risk factors (RFs) for CYD and systemic inflammation underlie the development of atherosclerosis in PsA. It is pointed out that the risk of CYD may be reduced not only provided that the traditional RFs for CVD are monitored, but also systemic inflammation is validly suppressed. The cardioprotective abilities of methotrexate and tumor necrosis factor-a (TNF-a) inhibitors are considered; the data of investigations showing that the treatment of PsA patients with TNF-a inhibitors results in a reduction in carotid artery intima-media thickness are given. lt is noted that there is a need for the early monitoring of traditional RFs for CVD in patients with PsA and for the elaboration of interdisciplinary national guidelines. PMID- 27458626 TI - [Anemic syndrome in rheumatoid arthritis: Diagnostic approaches and treatment opportunities]. AB - Anemia of chronic disease (ACD) is a leading cause of anemic syndrome in patients with rheumatoid arthritis (RA). Enhanced hepcidin production mainly stimulated by excess interleukin-6 levels is a key pathodgentic component of ACD (frequently known as anemia of inflammation) by causing the degradation of the transmembrane protein ferroportin, hepcidin impairs iron metabolism. On the basis of the material of recent publications the review gives present-day views on the pathodgenesis of ACD in RA, approaches to the diagnosis and differential diagnosis of ACD, especially in its concomitance with iron-deficiency anemia, as well as approaches to therapy for the type of anemic syndrome with the complex mechanism for its development. PMID- 27458627 TI - [The problem of cardiac safety of nonsteroidal anti-inflammatory drugs]. AB - The paper considers an update on the mechanisms for the development of adverse reactions of nonsteroidal anti-inflammatory drugs on the cardiovascular system. PMID- 27458628 TI - CardioPulse: Leaders in cardiovascular medicine today: Prof. Marc Pfeffer PhD MD. PMID- 27458629 TI - [Probiotics as stimulators of immune response against pathogens in the respiratory tract]. AB - This review analyzes whether.it is expedient to use oral probiotics for the stimulation of immune response against pathogens in the respiratory tract. It considers a relationship between.mucosal microbial colonization in different biotopes of the body and mucosal.immunity in the respiratory tract. The principal and terminological controversial issues of colonic dysbiosis and the possibilities of using the medicines and products containing live commensals/symbionts to correct microbiota disturbances are examined. There are data on the degree of resistance and resilience of the colonic microbial community exposed to destabilizing factors, antibiotics in particular. The properties of probiotics that have been proven to enhance host response against pathogens and the phenomena that characterize these probiotics as immunomodifiers and distinguish them from other immunostimulating/immunomodulating agents are described. Criteria for choosing effective and safe oral probiotics to stimulate an immune response in the respiratory tract are formulated. Finally, we review the data on the clinical and immunomodulatory effects of dietary supplement containing a combination of three probiotic strains (Lactobacillus gasseri PA 16/8, Bifidobacterium bifidum MF 20/5 and Bifidobacterium longum SP 07/3) with vitamins and minerals as an agent to prevent and reduce the severity of acute and recurrent respiratory tract infections. PMID- 27458630 TI - CardioPulse: Settling scores with a failing heart. PMID- 27458631 TI - [Wasting syndrome in HIV-infected patients]. AB - The review of literature analyzes scientific data on wasting syndrome in HIV infected patients. It considers its etiology, diagnosis,and therapeutic approaches. PMID- 27458632 TI - CardioPulse; Pocket-sized ultrasound for nurses in heart failure? PMID- 27458633 TI - [In memory of Evegeny Evgenevich Gogin]. PMID- 27458634 TI - CardioPulse: Transcatheter aortic valve replacement.The American perspective on transcatheter aortic valve replacement. PMID- 27458635 TI - CardioPulse: Active surveillance for latent rheumatic heart disease in Nepal. PMID- 27458636 TI - CardioPulse: A new European Society of Cardiology research database: Atlas of Cardiology. PMID- 27458637 TI - Scalable Semi-Automatic Annotation for Multi-Camera Person Tracking. AB - This paper proposes a generic methodology for the semi-automatic generation of reliable position annotations for evaluating multi-camera people-trackers on large video data sets. Most of the annotation data are automatically computed, by estimating a consensus tracking result from multiple existing trackers and people detectors and classifying it as either reliable or not. A small subset of the data, composed of tracks with insufficient reliability, is verified by a human using a simple binary decision task, a process faster than marking the correct person position. The proposed framework is generic and can handle additional trackers. We present results on a data set of $sim 6$ h captured by 4 cameras, featuring a person in a holiday flat, performing activities such as walking, cooking, eating, cleaning, and watching TV. When aiming for a tracking accuracy of 60 cm, 80% of all video frames are automatically annotated. The annotations for the remaining 20% of the frames were added after human verification of an automatically selected subset of data. This involved $sim 2.4$ h of manual labor. According to a subsequent comprehensive visual inspection to judge the annotation procedure, we found 99% of the automatically annotated frames to be correct. We provide guidelines on how to apply the proposed methodology to new data sets. We also provide an exploratory study for the multi-target case, applied on the existing and new benchmark video sequences. PMID- 27458639 TI - [Health insurance demise continues. But where is the limit?]. PMID- 27458638 TI - Inducing stable reversion to achieve cancer control. AB - How can we stop cancer progression? Current strategies depend on modelling progression as the balanced outcome of mutations in, and expression of, tumour suppressor genes and oncogenes. New treatments emerge from successful attempts to tip that balance, but secondary mutational escape from those treatments has become a major impediment because it leads to resistance. In this Opinion article, we argue for a return to an earlier stratagem: tumour cell reversion. Treatments based on selection and analysis of stable revertants could create more durable remissions by reducing the selective pressure that leads to rapid drug resistance. PMID- 27458640 TI - [Government puts pressure on contract physician association]. PMID- 27458641 TI - [Acceptance of a health care card for refugees progresses only sluggishly. Communities are reluctant]. PMID- 27458642 TI - [Recipe for pension sought. Reform proposals from A to Z]. PMID- 27458643 TI - [New immunotherapy uses defense cells against hematologic cancer. "Living medicine instead of roentgen rays]. PMID- 27458644 TI - [Nursing Plus Specialty Congress 2016]. PMID- 27458645 TI - [Factors in wound healing]. PMID- 27458646 TI - Ni- and Mn-Promoted Mesoporous Co3O4: A Stable Bifunctional Catalyst with Surface Structure-Dependent Activity for Oxygen Reduction Reaction and Oxygen Evolution Reaction. AB - Efficient bifunctional catalysts for electrochemical oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are highly desirable due to their wide applications in fuel cells and rechargeable metal air batteries. However, the development of nonprecious metal catalysts with comparable activities to noble metals is still challenging. Here we report a one-step wet-chemical synthesis of Ni-/Mn-promoted mesoporous cobalt oxides through an inverse micelle process. Various characterization techniques including powder X-ray diffraction (PXRD), N2 sorption, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) confirm the successful incorporation of Ni and Mn leading to the formation of Co-Ni(Mn)-O solid solutions with retained mesoporosity. Among these catalysts, cobalt oxide with 5% Ni doping demonstrates promising activities for both ORR and OER, with an overpotential of 399 mV for ORR (at -3 mA/cm(2)) and 381 mV (at 10 mA/cm(2)) for OER. Furthermore, it shows better durability than precious metals featuring little activity decay throughout 24 h continuous operation. Analyses of cyclic voltammetry (CV), X-ray photoelectron spectroscopy (XPS), Raman, and O2-temperature-programmed desorption (O2-TPD) reveal that redox activity of Co(3+) to Co(4+) is crucial for OER performance, while the population of surface oxygen vacancies and surface area determine ORR activities. The comprehensive investigation of the intrinsic active sites for ORR and OER by correlating different physicochemical properties to the electrochemical activities is believed to provide important insight toward the rational design of high-performance electrocatalysts for ORR and OER reactions. PMID- 27458647 TI - Pd-Catalyzed Ligand-Free Synthesis of Arylated Heteroaromatics by Coupling of N Heteroaromatic Bromides with Iodobenzene Diacetate, Iodosobenzene, or Diphenyliodonium Salts. AB - An efficient method for synthesizing arylated heteroaromatics has been reported via Pd-catalyzed ligand-free cross-coupling of N-heteroaromatic bromides with iodine(III) reagents under mild conditions. Iodobenzene diacetate, iodosobenzene, and diphenyliodonium salts act as ideal arylated sources in this reaction, producing bioactive aromatic-substituted pyridines and quinolines in moderate to high yields. PMID- 27458648 TI - Intraoral 3D Scanning in Cleft Care. PMID- 27458649 TI - Hearing Loss in Children With Craniofacial Microsomia. AB - OBJECTIVE: To evaluate the association between craniofacial phenotype and hearing loss in children with craniofacial microsomia. DESIGN: Retrospective cohort study. SETTING: Tertiary care children's hospital. PATIENTS: Individuals with craniofacial microsomia. MAIN OUTCOME MEASURES: Ear-specific audiograms and standardized phenotypic classification of facial characteristics. RESULTS: A total of 79 participants were included in the study. The mean age was 9 years (range, 1 to 23 years) and approximately 60% were boys. Facial anomalies were bilateral in 39 participants and unilateral in 40 participants (24 right, 16 left). Microtia (hypoplasia of the ear) was the most common feature (94%), followed by mandibular hypoplasia (76%), soft tissue deficiency (60%), orbital hypoplasia or displacement (53%), and facial nerve palsy (32%). Sixty-five individuals had hearing loss (12 bilateral and 53 unilateral). Hearing loss was conductive in 73% of affected ears, mixed in 10%, sensorineural in 1%, and indeterminate in 16%. Hypoplasia of the ear or mandible was frequently associated with ipsilateral hearing loss, although contralateral hearing loss occurred in 8% of hemifaces. CONCLUSIONS: Hearing loss is strongly associated with malformations of the ipsilateral ear in craniofacial microsomia and is most commonly conductive. Hearing loss can occur contralaterally to the side with malformations in children with apparent hemifacial involvement. Children with craniofacial microsomia should receive early diagnostic hearing assessments. PMID- 27458650 TI - Cp2ZrMeCl: A Reagent for Asymmetric Methyl Addition. AB - The use of Cp2ZrMeCl is described as a source of nucleophilic methyl in asymmetric catalysis. This easily prepared reagent is bench stable, weighable in air, and generally useful in highly enantioselective copper-catalyzed addition reactions at room temperature. Methyl is successfully (generally >90% ee) added in 1,4-additions to cyclic and acyclic alpha,beta-unsaturated ketones to provide tertiary and quaternary centers. Examples of catalyst controlled diastereoselective 1,6-addition and dynamic kinetic asymmetric allylic alkylation reactions are also reported. The reagent is used in the catalytic asymmetric synthesis of naturally occurring fragrance (R)-(-)-muscone (82% yield, 91% ee). PMID- 27458651 TI - Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors. AB - Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure-activity relationship (SAR), cocrystal structure in complex with HBV capsid proteins and in vivo pharmacological study of the 4-methyl HAP analogues. In particular, the (2S,4S) 4,4-difluoroproline substituted analogue 34a demonstrated high oral bioavailability and liver exposure and achieved over 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model. PMID- 27458652 TI - Ligand Layer Engineering To Control Stability and Interfacial Properties of Nanoparticles. AB - The use of mixed ligand layers including poly(ethylene glycol)-based ligands for the functionalization of nanoparticles is a very popular strategy in the context of nanomedicine. However, it is challenging to control the composition of the ligand layer and maintain high colloidal and chemical stability of the conjugates. A high level of control and stability are crucial for reproducibility, upscaling, and safe application. In this study, gold nanoparticles with well-defined mixed ligand layers of alpha-methoxypoly(ethylene glycol)-omega-(11-mercaptoundecanoate) (PEGMUA) and 11-mercaptoundecanoic acid (MUA) were synthesized and characterized by ATR-FTIR spectroscopy and gel electrophoresis. The colloidal and chemical stability of the conjugates was tested by dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and UV/vis spectroscopy based experiments, and their interactions with cells were analyzed by elemental analysis. We demonstrate that the alkylene spacer in PEGMUA is the key feature for the controlled synthesis of mixed layer conjugates with very high colloidal and chemical stability and that a controlled synthesis is not possible using regular PEG ligands without the alkylene spacer. With the results of our stability tests, the molecular structure of the ligands can be clearly linked to the colloidal and chemical stabilization. We expect that the underlying design principle can be generalized to improve the level of control in nanoparticle surface chemistry. PMID- 27458653 TI - Spatial Distribution and Air-Water Exchange of Organic Flame Retardants in the Lower Great Lakes. AB - Organic flame retardants (OFRs) such as polybrominated diphenyl ethers (PBDEs) and novel halogenated flame retardants (NHFRs) are ubiquitous, persistent, and bioaccumulative contaminants that have been used in consumer goods to slow combustion. In this study, polyethylene passive samplers (PEs) were deployed throughout the lower Great Lakes (Lake Erie and Lake Ontario) to measure OFRs in air and water, calculate air-water exchange fluxes, and investigate spatial trends. Dissolved Sigma12BDE was greatest in Lake Ontario near Toronto (18 pg/L), whereas gaseous Sigma12BDE was greatest on the southern shoreline of Lake Erie (11 pg/m(3)). NHFRs were generally below detection limits. Air-water exchange was dominated by absorption of BDEs 47 and 99, ranging from -964 pg/m(2)/day to -30 pg/m(2)/day. Sigma12BDE in air and water was significantly correlated with surrounding population density, suggesting that phased-out PBDEs continued to be emitted from population centers along the Great Lakes shoreline in 2012. Correlation with dissolved Sigma12BDE was strongest when considering population within 25 km while correlation with gaseous Sigma12BDE was strongest when using population within 3 km to the south of each site. Bayesian kriging was used to predict dissolved Sigma12BDE over the lakes, illustrating the utility of relatively highly spatially resolved measurements in identifying potential hot spots for future study. PMID- 27458654 TI - The performance of hybrid titania/silica-derived xerogels as active antifouling/fouling-release surfaces against the marine alga Ulva linza: in situ generation of hypohalous acids. AB - Mixed titania/silica xerogels were prepared using titanium tetraisopropoxide (TTIP) and tetraethoxy orthosilicate (TEOS). Xerogel properties were modified by incorporating n-octyltriethoxysilane (C8). The xerogels catalyze the oxidation of bromide and chloride with hydrogen peroxide (H2O2) to produce hypohalous acids at pH 7 and pH 8. The antifouling/ fouling-release performance of a TTIP/C8/TEOS xerogel in the presence and absence of H2O2 was evaluated for the settlement of zoospores of the marine alga Ulva linza and for the removal of sporelings (young plants). In the absence of H2O2, differences in the settlement of zoospores and removal of sporelings were not significant relative to a titanium-free C8/TEOS xerogel. Addition of H2O2 gave a significant reduction in zoospore settlement and sporeling removal relative to the C8/TEOS xerogel and relative to peroxide-free conditions. The impact of TTIP on xerogel characteristics was evaluated by comprehensive contact angle analysis, scanning electron microscopy, and X-ray photoelectron spectroscopy. PMID- 27458655 TI - Multi-omics reveals global effects of mutant p53 gain-of-function. PMID- 27458656 TI - Forming Nanoparticle Monolayers at Liquid-Air Interfaces by Using Miscible Liquids. AB - One standard way of forming monolayers (MLs) of nanoparticles (NPs) is to drop cast a NP dispersion made using one solvent onto a second, immiscible solvent; after this upper solvent evaporates, the NP ML can be transferred to a solid substrate by liftoff. We show that this previously universal use of only immiscible solvent pairs can be relaxed and close-packed, hexagonally ordered NP monolayers can self-assemble at liquid-air interfaces when some miscible solvent pairs are used instead. We demonstrate this by drop-casting an iron oxide NP dispersion in toluene on a dimethyl sulfoxide (DMSO) liquid substrate. The NPs are energetically stable at the DMSO surface and remain there even with solvent mixing. Excess NPs coagulate and precipitate in the DMSO, and this limits NPs at the surface to approximately 1 ML. The ML domains at the surface nucleate independently, which is in contrast to ML growth at the receding edge of the drying drop, as is common in immiscible solvent pair systems and seen here for the toluene/diethylene glycol immiscible solvent pair system. This new use of miscible solvent pairs can enable the formation of MLs for a wider range of NPs. PMID- 27458658 TI - Phytyl Fatty Acid Esters in the Pulp of Bell Pepper (Capsicum annuum). AB - Phytyl fatty acid esters (PFAE) are esters of fatty acids with the isoprenoid alcohol phytol (3,7R,11R,15-tetramethylhexadec-2E-enol). In this study, PFAE were identified and quantified in bell pepper using gas chromatography with mass spectrometry (GC-MS). All red (n = 14) and yellow (n = 6) samples contained six or seven PFAE at 0.9-11.2 mg/100 g fresh weight. By contrast, PFAE were not detected in green bell pepper samples (n = 3). PFAE might eventually be a source for bioavailable phytol, which can be transformed into phytanic acid by humans. Phytanic acid cannot be properly degraded by patients who suffer from Refsum's disease (tolerable daily intake (TDI) <= 10 mg of phytanic acid). The phytol moiety of the PFAE (0.4-5.4 mg/100 g fresh weight) would contribute up to ~50% to the TDI with the consumption of only one portion of bell pepper fruit pulp. PMID- 27458657 TI - Binding Isotherms and Time Courses Readily from Magnetic Resonance. AB - Evidence is presented that binding isotherms, simple or biphasic, can be extracted directly from noninterpreted, complex 2D NMR spectra using principal component analysis (PCA) to reveal the largest trend(s) across the series. This approach renders peak picking unnecessary for tracking population changes. In 1:1 binding, the first principal component captures the binding isotherm from NMR detected titrations in fast, slow, and even intermediate and mixed exchange regimes, as illustrated for phospholigand associations with proteins. Although the sigmoidal shifts and line broadening of intermediate exchange distorts binding isotherms constructed conventionally, applying PCA directly to these spectra along with Pareto scaling overcomes the distortion. Applying PCA to time domain NMR data also yields binding isotherms from titrations in fast or slow exchange. The algorithm readily extracts from magnetic resonance imaging movie time courses such as breathing and heart rate in chest imaging. Similarly, two step binding processes detected by NMR are easily captured by principal components 1 and 2. PCA obviates the customary focus on specific peaks or regions of images. Applying it directly to a series of complex data will easily delineate binding isotherms, equilibrium shifts, and time courses of reactions or fluctuations. PMID- 27458659 TI - Prevalence, clinical and echocardiographic characteristics of various flow and gradient patterns in mild or moderate aortic stenosis with normal left ventricular ejection fraction. AB - BACKGROUND/OBJECTIVES: Paradoxical low-flow aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF) has only been described in severe AS. Controversy surrounds prognosis and management but no studies have reported this phenomenon in mild or moderate AS. We investigated the prevalence of flow and gradient patterns in this population, characterising their clinical and echocardiographic profile. METHODS: Consecutive subjects (n=1362) with isolated AS: mild (n=462, aortic valve area>=1.5cm(2), 2.5m/s=50%) were studied. Subjects with low-flow (stroke volume index<35ml/m(2)) were identified. Univariate and multivariate analyses were employed to compare the flow and gradient patterns. RESULTS: In mild AS, 130 (28%) had low-flow. Lower left ventricular mass index (LVMI) (97.0+/-28.5vs116.4+/-2.3g/m(2),p<0.001), higher percentage of concentric remodelling (40%vs6%,p<0.001) and hypertrophy (43%vs40%,p<0.001) and lower end-systolic wall stress (ESWS) (57.6+/-1.60vs67.7+/ 19.6dyn/cm(2),p=0.014) were independently associated with low-flow. Similarly, in moderate AS, 297 (33%) had low-flow. Older age (73.4+/-14.8vs69.5+/ 16.5,p=0.027), lower LVMI (88.6+/-25.9vs118.0+/-36.5,p<0.001), higher percentage of concentric remodelling (46%vs8%,p<0.001) and lower ESWS (59.9+/-18.3vs70.5+/ 19.7,p<0.001) were independently associated with low-flow. Despite moderate AS, most had lower mean pressure gradients, especially subjects with concentric remodelling. In the entire cohort, low-flow patients had more concentric remodelling (43%vs7%,p<0.001) and less eccentric hypertrophy (2%vs27%,p<0.001) compared to normal flow. CONCLUSIONS: Low-flow AS with normal LVEF is observed in mild or moderate AS, in up to a third of the cases. These patients had different LV structure compared to normal-flow, with more concentric remodelling. Further studies are warranted. PMID- 27458660 TI - Does an ideal prototype of a twin mother exist? AB - Objective To evaluate the association of a set (or the lack thereof) of pre gravid maternal features with a better outcome in terms of gestational age and birth weight of twins. Methods Analysis of a Slovenian population-based cohort of all dichorionic twin pairs born at >=22 weeks during an 11-year period from 2002 to 2013. The independent variables included tall stature (>=170 cm), multiparity, and normal pregravid body mass index (BMI). The outcome variables included gestational age and total twin birth weight. Results We studied 3232 dichorionic twins. Being "tall", multiparous, and with a normal pregravid BMI was significantly associated with a higher total twin birth weight, more advanced gestational age, fewer sets with a total twin birth weight <3000 g, fewer births at <=32 weeks, more pairs with a total twin birth weight >5000 g and more pairs born at >=37 weeks. In contrast, women with the converse features had a significantly worse outcome. Being just multiparous was different only in the incidence of total twin birth weight >5000 g. Conclusion Maternal stature >170 cm, being multiparous, and having a normal pregravid BMI is association with improved outcomes in terms of gestational age and birth weight of twins. PMID- 27458661 TI - Antinociceptive activity of Tibouchina pereirae, an endemic plant from the Brazilian semiarid region. AB - The anti-nociceptive activity of an extract of Tibouchina pereirae Aubl (AETP) was investigated using two models of chemically induced pain, viz. the acetic acid-induced writhing and the formalin test, respectively, with dipyrone and indomethacin as reference drugs, respectively. In the acetic acid-induced writhing test, AETP application (100 mg/kg) caused a significant reduction of writhing produced by acetic acid. In the formalin test, AETP reduced the formalin effects significantly only in the late phase. These findings thus indicate the involvement of AETP only in peripheral antinociceptive mechanisms. In addition, AETP exhibited good antioxidant activity (EC50 approx. 15 MUg/mL) in the DPPH free radical scavenging assay. PMID- 27458662 TI - Volatile oil profile of some lamiaceous plants growing in Saudi Arabia and their biological activities. AB - A comparative investigation of hydro-distilled essential oils from aerial parts of Mentha longifolia L. (ML), Mentha microphylla K.Koch (MM), Mentha australis R.Br. (MA), and Teucrium polium L. (TP) growing in Al Madinah Al Munawwarah, Saudi Arabia, was carried out. The total numbers of identified constituents were 22, 23, 14, and 20 in ML, MM, MA, and TP oils, representing 93.0, 99.3, 78.1, and 81.1% of the total oil composition, respectively. Pulegone (40.7%) and cineole (33.4%) were the major components in ML, whereas carvone (64.6%) was the major one in MM. Furthermore, beta-linalool (22.9%) and alpha-terpineol (12%) were the major components in MA, whereas, (E)-3-caren-2-ol accounted for 12.1% in TP. The essential oils of TP and MA exhibited promising activities against Leishmania donovani promastigotes with IC50 values of 2.3 and 3.7 MUg/mL, respectively. In contrast, MA essential oils exhibited antifungal activities towards Candida krusei and C. glabrata with IC50 values of 1 and 1.2 MUg/mL, respectively. PMID- 27458663 TI - Anticalins directed against vascular endothelial growth factor receptor 3 (VEGFR 3) with picomolar affinities show potential for medical therapy and in vivo imaging. AB - Members of the vascular endothelial growth factor receptor (VEGFR) family play a central role in angiogenesis as well as lymphangiogenesis and are crucial for tumor growth and metastasis. In particular, VEGFR-3 expression is induced in endothelial cells during tumor angiogenesis. We report the design of anticalins that specifically recognize the ligand-binding domains 1 and 2 of VEGFR-3. To this end, a library of the lipocalin 2 scaffold with 20 randomized positions distributed across its binding site was subjected to phage display selection and enzyme linked immunosorbent assay (ELISA) screening using the VEGF-C binding fragment (D1-2) or the entire extracellular region (D1-7) of VEGFR-3 as target proteins. Promising anticalin candidates were produced in Escherichia coli and biochemically characterized. Three variants with different receptor binding modes were identified, and two of them were optimized with regard to target affinity as well as folding efficiency. The resulting anticalins show dissociation constants down to the single-digit picomolar range. Specific recognition of VEGFR-3 on cells was demonstrated by immunofluorescence microscopy. Competitive binding versus VEGF-C was demonstrated for two of the anticalins with Ki values in the low nanomolar range. Based on these data, VEGFR-3 specific anticalins provide promising reagents for the diagnosis and/or therapeutic intervention of tumor associated vessel growth. PMID- 27458664 TI - Glycated albumin: correlation to HbA1c and preliminary reference interval evaluation. PMID- 27458665 TI - Commutable samples with assigned target concentrations may help us harmonise general chemistry results. PMID- 27458666 TI - Large Magnetoresistance in Single-Radical Molecular Junctions. AB - Organic radicals are promising building blocks for molecular spintronics. Little is known about the role of unpaired electrons for electron transport at the single-molecule level. Here, we examine the impact of magnetic fields on electron transport in single oligo(p-phenyleneethynylene) (OPE)-based radical molecular junctions, which are formed with a mechanically controllable break-junction technique at a low temperature of 4.2 K. Surprisingly huge positive magnetoresistances (MRs) of 16 to 287% are visible for a magnetic field of 4 T, and the values are at least 1 order of magnitude larger than those of the analogous pristine OPE (2-4%). Rigorous analysis of the MR and of current-voltage and inelastic electron-tunneling spectroscopy measurements reveal an effective reduction of the electronic coupling between the current-carrying molecular orbital and the electrodes with increasing magnetic field. We suggest that the large MR for the single-radical molecular junctions might be ascribed to a loss of phase coherence of the charge carriers induced by the magnetic field. Although further investigations are required to reveal the mechanism underlying the strong MR, our findings provide a potential approach for tuning charge transport in metal-molecule junctions with organic radicals. PMID- 27458667 TI - Electrical stimulation ventilatory feedback facilitates maintenance of a prolonged expiration pattern during exercise: A proof-of-concept study in healthy adults. AB - This study aimed at verifying the safety and effects of electrical stimulation ventilatory feedback (ESVF) to provide feedback during expiration, which may assist with breathing control in patients with chronic obstructive pulmonary disease (COPD). Because this is a new therapy, we examined the feasibility of the therapy in healthy adults. The 23 healthy adult participants were randomized into two groups: a stimulation group that received ESVF and a placebo group with the ESVF device attached, but not activated. Sensory stimulation was provided at a frequency of 20 Hz and pulse duration of 200 MUs. During breathing training, participants practiced a prolonged expiration pattern and were instructed to maintain the breathing pattern during exercise. A variety of parameters such as respiratory time from the gas analyzer monitor and quantitative load were measured during lower-extremity cycle ergometer exercise. The primary outcome was the expiratory to inspiratory time ratio, which was significantly higher in the stimulation group than in the placebo group, both during and after exercise. No side effects were reported during the use of electrical stimulation. Therefore, ESVF is safe and facilitates maintenance of a prolonged expiration pattern during and after exercise. PMID- 27458668 TI - Oncogenes and Anti-oncogenes in the Evolution of Human Leukemia/Lymphoma. PMID- 27458669 TI - Hairy Cell Leukemia and Its T Cell Interactions. PMID- 27458670 TI - Gastrointestinal Non-Hodgkin's Lymphoma. AB - The records of 77 patients with gastrointestinal Non-Hodgkin's Lymphoma (GI-NHL) diagnosed from 1972 to 1988 were reviewed. There were 47 male and 30 female patients, median age 56 years (range 20-82 years). Twenty-four patients had stage I disease at presentation, 25 stage II, 8 stage III and 20 stage IV. The primary site was stomach for 32 patients, small bowel for 30, colon for 10, and 5 patients had multiple areas of involvement. Six patients had low grade histology, 59 intermediate grade and 12 high grade histology. Forty-two stage I and II patients underwent laparotomy; 30 had complete surgical resection, and 42 had chemotherapy. Only 21 stage III and IV patients underwent laparotomy; 15 had bowel resection and 24 had chemotherapy. Forty-one patients had evaluable disease prior to chemotherapy. Fifty-six percent achieved complete remission and 32% partial remission. At a median follow up of 46 months the median survival is 31 months, and predicted 5 and 10 year survivals are 61% and 42% respectively. Survival correlated most strongly with stage of disease at presentation (p = 0.003). Projected 10 year survival for stage I is 84%, stage II 52%, stage III 38% and no stage IV patients are alive at 10 years. Survival was significantly longer for stage I and II patients who underwent complete surgical resection (p = 0.003), but surgery did not alter survival for stage III or IV patients. Sex, the presence of B symptoms, histologic subtype or site of primary GI-NHL did not demonstrate significant correlation with prognosis. PMID- 27458671 TI - Primary Thrombocythemia in Japan: A Survey of 225 Patients. AB - Data on 225 Japanese patients with primary or essential thrombocythemia (ET) were analyzed in an attempt to characterize the clinical and laboratory features in subgroups with thrombosis (T), hemorrhages (H), thrombohemorrhagic events (TH) or a non-thrombohemorrhagic (O) group, and in order to examine survival and the incidence of blastic transformation in the entire group and in the different subgroups. Higher platelet and leukocyte counts were related to hemorrhage (H and TH), prolonged activated partial thromboplastin times and high LDH levels to H while elevated FDP levels were more frequently linked to T. Increased spontaneous platelet aggregation (SPA) was noted in 80.3% of the entire group, independent of whether there was a tendency for thrombohemorrhagic events or not. Bleeding time, as measured by the Duke method, and hemoglobin levels were not different in the various subgroups. Transformation occurred in 11 patients (1.9% per year); seven developed acute leukemia (myeloblastic 4, lymphoblastic 2, megakaryoblastic 1) at a rate of 1.2% per year; and 4 developed other types of chronic myeloproliferative disorders. Nineteen patients died (3.3% per year), six from leukemia (32%), 4 from bleeding (21%) and 9 from unrelated diseases (47%). Survival was estimated to be 65% at ten years, and was significantly longer in females, younger individuals, and the groups with lower leukocyte counts, but did not differ between the subgroups when platelet count and hemoglobin level were considered. Survival was similar in patients with platelet counts between 700 1000 * 10(9)/L and in those with an even higher platelet count. These findings suggest that (1) young female patients with low leukocyte counts may survive longer, (2) SPA is not indicative of either a thrombotic or an hemorrhagic tendency and (3) the limit of the platelet count for establishing the diagnosis of this disorder could perhaps be lowered to 700 * 10(9)/L. PMID- 27458672 TI - Identification of CD3 Associated T Cell Receptor as a Diagnostic Tool in T Cell Acute Lymphoblastic Lymphoma or Leukemia. AB - By using several monoclonal antibodies (mAb) reacting either with the constant or variable regions of the T cell receptors (TcR) alphabeta and gammadelta or various CD molecules, differences between two clinically related entities e.g. T cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL) have been demonstrated. We studied a panel of fifteen T-ALL and fifteen T-LL because of their cell surface expression of the CD3-TcR molecules. The results indicated that TcR gammadelta is more frequently expressed in T-ALL (10 out of the 15 patients tested) than TcR alphabeta. This is in contrast to the results obtained with T-LL where the vast majority showed TcR alphabeta (13 out of the 15 patients). We discuss the significance of these findings which may imply that the leukemic cells are of a different origin in these two diseases. In addition analysis of TcR variable regions expressed by the leukemic blasts showed that in most cases they had rearranged functional Vdelta1 gene to Jdelta1 or Jdelta2 segments (8 out of 11 patients) whereas in a unique case Vdelta2 gene segment was evident. Taken together these results and those showing that T-ALL cells coexpress the CD1a, b and c molecules strengthen the possibility that despite the fact that these leukemic cells express the CD3-TcR complex at their surface their normal counterparts are not found in peripheral blood. PMID- 27458673 TI - C-Jun is Induced to High Continuous Expression During Differentiation of Hematopoietic Cells and is Regulated Independently from C-Fos. AB - The c-jun proto-oncogene is usually expressed at a low level in most cell types but is induced rapidly and transiently in response to stimuli. The present results show that stimulation of U-937 cells to macrophage differentiation by a phorbol ester or vitamin D3 induced a continuous high level expression of c-jun mRNA and protein. High level expression of c-jun mRNA was also observed in various other human differentiated hematopoietic cells, represented by normal macrophages, HL-60 promyelocytic cells differentiated towards macrophages or granulocytes and in myeloma, but not in immature cell lines. These results might suggest a role of c-jun in the differentiation of several hematopoietic lineages. In U-937, a differential regulation of c-jun and c-fos was demonstrated both with respect to kinetics and to the level of regulation. Furthermore, in subclones of U-937, where maturation and growth arrest could be separated, c-jun was induced in the absence of c-fos and vice versa. Expression of c-jun and c-fos mRNA correlated with maturation and growth arrest, respectively, in these clones. cAMP generating agents, which induced c-jun and c-fos, did, however, not induce terminal differentiation, indicating that other signals, e.g. those associated with down-regulation of c-myb and c-myc, are also required. PMID- 27458674 TI - Diffuse Large-Cell Lymphoma in the Elderly: Does a Clinically Indolent Subset Exist? AB - Among 63 patients with intermediate or high grade non Hodgkin's lymphoma (NHL) seen at our institution in a five-year period, 19 were aged 70 years or older. For various reasons, four of these patients were either not treated or received only minimal treatment. Three of the patients remain well without evidence of disease for 1 to 3 years, and the fourth has relapsed in an indolent fashion after 3 years. These observations suggest that existence of a subset of patients with histologically aggressive non-Hodgkin's lymphoma whose disease behaves mildly. Because of the high incidence of treatment-related morbidity and mortality in elderly lymphoma patients treated with combination chemotherapy, it is important to try to identify prospectively this subset of patients clinically and to avoid overtreatment in this category of cases. PMID- 27458675 TI - Translocation t(12;13)(p13.3;q12.2) is Not Restricted to Lymphoid Malignancies; Report of a Further Case with Hypereosinophilia. AB - We report two cases of t(12;13)(p13;q12). One was found in a lymphoid disorder, as previously described, while the second was observed in a myeloproliferative syndrome with hypereosinophilia. As t(12;13) has already been described in association with hypereosinophilia in a case of acute lymphoblastic leukaemia, we suggest that the association of t(12;13) with hypereosinophilia is not random. PMID- 27458676 TI - Primary Liver Lymphoma: A Case Report with Review of Literature. AB - Primary non-Hodgkin's lymphoma of the liver is exceedingly rare and until now only 53 cases have been recorded. Most extranodal non-Hodgkin's lymphomas are in the head and neck region and the gastrointestinal tract. We report a patient with primary non-Hodgkin's lymphoma of the liver and also review the relevant literature. PMID- 27458678 TI - Phenobarbital for Neonatal Seizures: Response Rate and Predictors of Refractoriness. AB - Background Phenobarbital is the first-line choice for neonatal seizures treatment, despite a response rate of approximately 45%. Failure to respond to acute anticonvulsants is associated with poor neurodevelopmental outcome, but knowledge on predictors of refractoriness is limited. Objective To quantify response rate to phenobarbital and to establish variables predictive of its lack of efficacy. Methods We retrospectively evaluated newborns with electrographically confirmed neonatal seizures admitted between January 1999 and December 2012 to the neonatal intensive care unit of Parma University Hospital (Italy), excluding neonates with status epilepticus. Response was categorized as complete (cessation of clinical and electrographic seizures after phenobarbital administration), partial (reduction but not cessation of electrographic seizures with the first bolus, response to the second bolus), or absent (no response after the second bolus). Multivariate analysis was used to identify independent predictors of refractoriness. Results Out of 91 newborns receiving phenobarbital, 57 (62.6%) responded completely, 15 (16.5%) partially, and 19 (20.9%) did not respond. Seizure type (p = 0.02), background electroencephalogram (EEG; p <= 0.005), and neurologic examination (p <= 0.005) correlated with response to phenobarbital. However, EEG (p <= 0.02) and seizure type (p <= 0.001) were the only independent predictors. Conclusion Our results suggest a prominent role of neurophysiological variables (background EEG and electrographic-only seizure type) in predicting the absence of response to phenobarbital in high-risk newborns. PMID- 27458679 TI - Aging bones: A short history of osteoporosis, by Gerald N. Grob. PMID- 27458681 TI - Editorial. PMID- 27458680 TI - Factors affecting the seroconversion rate of 12-month-old babies after the first injection of measles vaccine in the southeast of Iran. AB - Within the past few years, several measles outbreaks have occurred in the southeast of Iran. To learn about the effectiveness of the immunization services for producing a serologic response against measles, this follow-up study was designed and implemented in the southeast of Iran. In Iran, all routine immunization services provided by the public sector are free of charge. The follow-up study was designed and implemented in 5 Urban Health Centers located in 3 districts of Sistan-va-BaluchestanProvince, Iran. In the pre-vaccination phase, 270 12-month-old babies were blood sampled; and in the post-vaccination phase, 4 to 7 weeks after Measles, Mumps, Rubella (MMR) vaccination, 236 of them were blood sampled (34 dropouts), and their sera were tested for IgG anti-measles antibodies, using indirect ELISA, in the National Reference Measles Laboratory. Out of the 236 participants, who had been blood sampled in the post-vaccination phase, 10 (3.7%) were excluded from the calculations of seroconversion rate, because they had protective levels of antibody before the vaccination. The seroconversion rate for the remaining 226 participants was 91.2% (95% confidence interval: 86.7 to 94.5). Among the variables studied, stunting (height-for-age z score < -2) showed a strong relationship with the remaining seronegative after the vaccination (odds ratio = 5.6; 95% confidence interval: 1.7-18.2). The chance of seroconversion was inversely related to the mothers' levels of education (up to 9 y of education vs. above nine years) (odds ratio = 0.2; 95% confidence interval: 0.06-0.4). In the study population, the seroconversion rates for anti measles antibodies after MMR vaccination are acceptable, even though in order to achieve the elimination goal, higher standards need to be achieved. PMID- 27458682 TI - The role of SISCOM in preoperative evaluation for patients with epilepsy surgery: A meta-analysis. AB - PURPOSE: To assess the specific value of subtraction ictal and inter-ictal SPECT co-registered to MRI (SISCOM) in identifying the epileptogenic zone (EZ) and predicting postoperative outcomes in epileptic surgical patients. METHOD: A meta analysis of studies published from January 1995 to June 2015 was conducted through a comprehensive literature search, and 11 studies were included. R software was first used to calculate a pooled positive rate, concordant rate and positive predictive value (PPV) for good outcomes. Stata software was then used to explore the relationship between SISCOM localization and surgical outcomes, including a subgroup analysis for extra-temporal lobe epilepsy. RESULTS: The unweighted positive and concordant rates of SISCOM were 85.9% and 65.3%, respectively. In 142 MRI-negative patients, the SISCOM positive rate was 83.8%. The pooled PPV of 178 surgical patients with concordant SISCOM was 56%. In the meta-analysis of 275 surgical patients, the seizure-free odds ratio was 3.28 times higher in concordant than in non-concordant SISCOM patients [95%CI (1.90, 5.67)]. For extra-temporal lobe epilepsy, the seizure-free odds ratio was 2.44 times higher in concordant than in non-concordant SISCOM patients [95%CI (1.34, 4.43)]. CONCLUSION: Our data indicate that SISCOM has moderate sensitivity in localizing the epileptogenic zone and can provide complementary information when MRI is negative. Furthermore, SISCOM localization concordant with the gold standard demonstrates slightly higher predictive value for good surgical outcomes. Further research is required to explore the influence of SISCOM localization results in temporal lobe versus extra-temporal lobe epilepsy. PMID- 27458683 TI - Evidence-based practice use of quick-release bromocriptine across the natural history of type 2 diabetes mellitus. AB - OBJECTIVES: To provide an evidence-based practice overview on the clinical use of bromocriptine-quick release (QR) across the natural history of type 2 diabetes mellitus (T2DM). METHODS: Articles for inclusion were selected after a comprehensive literature search of English-language PubMed articles and identification of other relevant references through other sources. Inclusion criteria were animal studies examining the mechanism of action and efficacy of bromocriptine, and clinical studies examining the safety and efficacy of bromocriptine-QR in patients with T2DM, without a time limitation. RESULTS: The brain plays a key role in total body metabolism, in particular ensuring that sufficient levels of glucose are available for proper neural functioning. The hypothalamic suprachiasmatic nucleus (SCN), the body's biological clock, plays a key role in the regulation of seasonal and diurnal variations of insulin sensitivity. A daily surge of dopaminergic activity in the SCN upon waking enables insulin sensitivity throughout the day. When this is disrupted (e.g. by a high fat/sugar diet, stress, altered [diminished] exercise, altered sleep/wake cycle, diabetes), insulin resistance persists throughout the day and overnight. Improving the morning surge in dopaminergic activity with the short-acting dopamine D2 receptor agonist bromocriptine-QR can safely and effectively improve glycemic control, while improving cardiovascular disease risk factors and related adverse events, and reducing sympathetic tone, as demonstrated by 5 reports of the Cycloset Safety Trial and 3 additional clinical studies of bromocriptine-QR. CONCLUSIONS: In patients with T2DM, the dopamine D2 receptor agonist bromocriptine-QR has been shown to be well tolerated, efficacious, and a logical treatment option. PMID- 27458684 TI - Age-Related Variations in Ventricular Response Rate in Individuals with Persistent or Permanent Atrial Fibrillation. PMID- 27458685 TI - Osteoprotective Effects of Polysaccharide-Enriched Hizikia fusiforme Processing Byproduct In Vitro and In Vivo Models. AB - The traditional manufacturing method used to produce goods from Hizikia fusiforme, utilizes extraction steps with hot water. The byproduct (of hot water extraction) is rich in polysaccharide and is considered a waste. To evaluate the osteogenic effects of the byproduct of H. fusiforme (HFB), osteogenic cells and animal models were used to test it effects on osteogenesis. The HFB-treated mouse myoblast C2C12 cells exhibited significant dose dependently elevated alkaline phosphatase (ALP) activity and slightly increased bone morphogenetic protein-2 (BMP-2). HFB also suppressed the formation of tartrate-resistant acid phosphatase (TRAP) activity and TRAP staining in the bone marrow-derived macrophages (BMM) cells that had been stimulated with the receptor activator of the nuclear factor kB ligand/macrophage colony-stimulating factor kB ligand. In addition, HFB also increased the phosphorylation of extracellular signal-regulated protein kinase (p ERK) level. Finally, osteogenic effects of HFB were clearly confirmed in the three in vivo models: zebrafish, ovariectomized mice, and mouse calvarial bones. HFB accelerated the rate of skeletal development in zebrafish and prevented much of the mouse femoral bone density loss of ovariectomized mice. Moreover, HFB enhanced woven bone formation over the periosteum of mouse calvarial bones. Our result showed that HFB functions as a bone resorption inhibitor as well as an activator of bone formation in vivo and in osteogenic in vitro cell systems. PMID- 27458687 TI - The relationship between physical activity level and cardiovascular disease biomarkers in healthy, normal-weight 3- to 6-year-old children and their parents. AB - To determine if physical activity is linked to cardiovascular biomarkers in preschool children at risk, we need information on these biomarkers in healthy normal-weight children. In this population, multi-level modelling analyses found no correlation between accelerometer recorded physical activity and fasting lipids, adiponectin, or insulin sensitivity. Exploratory analyses found positive correlations between adiponectin and time spent in light physical activity, and between triglyceride and time spent in sedentary behaviour; these findings need to be confirmed in longitudinal prospective studies. PMID- 27458688 TI - Quinoline-degrading strain Pseudomonas aeruginosa KDQ4 isolated from coking activated sludge is capable of the simultaneous removal of phenol in a dual substrate system. AB - Quinoline is a refractory organic compound in the treatment of coking wastewater. The isolation of high efficiency quinoline-degrading bacteria from activated sludge and the evaluation of their degradation characteristics in the presence of phenol or in the actual coking wastewater are important for the improvement of effluent quality. The novel bacterial strain Pseudomonas aeruginosa KDQ4 was isolated from a quinoline enrichment culture obtained from the activated sludge of a coking wastewater treatment plant. The optimum temperature and initial pH for quinoline degradation were 33-38 degrees C and 8-9, respectively. KDQ4 completely degraded 400 mg/L of quinoline within 24 h and 800 mg/L of phenol within 30 h. In the dual-substrate system, the removal efficiencies of quinoline and phenol at the same initial concentration (200 mg/L) by KDQ4 were 89% and 100% within 24 h, respectively, indicating that KDQ4 could simultaneously and quickly degrade quinoline and phenol in a coexistence system. Moreover, KDQ4 was able to adapt to actual coking wastewater containing high quinoline and phenol concentrations and rapidly remove them. KDQ4 also exhibited heterotrophic nitrification and aerobic denitrification potential under aerobic conditions. These results suggested a potential bioaugmentation role for KDQ4 in the removal of nitrogen-heterocyclic compounds and phenolics from coking wastewater. PMID- 27458689 TI - Delirium After Major Elective Noncardiac Surgery: Successful Aging After Elective Surgery Study. PMID- 27458690 TI - Effect of Inula viscosa on the pellicle's protective properties and initial bioadhesion in-situ. AB - OBJECTIVES: The present in situ study investigated the effect of Inula viscosa tea on the pellicle's acid protective properties and on initial oral biofilm formation. DESIGN: Biofilm formation was performed on bovine enamel slabs on individual maxillary splints. Following 1min of pellicle formation, eight subjects rinsed for 10min with Inula viscosa tea and the splints remained for 8h intraorally. Samples carried after 1-min rinsing with CHX (0.2%) or without rinse served as controls. BacLightTM staining, 4',6-diamidino-2-phenylindole (DAPI) staining and fluorescence in situ hybridization (FISH) were used for fluorescence microscopic detection of adherent bacteria. For investigation of acid protective properties, three subjects rinsed for 10min with Inula viscosa tea after 1min pellicle formation and kept the splints intraorally for further 19min. Physiological 30-min pellicles and native enamel samples served as controls. After HCl incubation of the samples ex-vivo over 120s (pH 2.0, 2.3, 3.0) calcium- and phosphate release were quantified photometrically. Potential influences on the pellicle's ultrastructure by Inula viscosa tea were evaluated by transmission electron microscopy (TEM). RESULTS: Application of Inula viscosa tea yielded a significant reduction of adherent bacteria on all enamel samples as detected by fluorescence microscopy. For calcium- and phosphate release no significant effect was recorded. TEM investigation indicated a modification of the pellicle's ultrastructure, but no enhanced protection against erosive noxae. CONCLUSION: Rinsing with Inula viscosa tea influences the bacterial colonization on enamel in situ over 8h but has no impact on acid protective properties of the pellicle. PMID- 27458691 TI - Peripheral Blood Epstein-Barr Viral Nucleic Acid Surveillance as a Marker for Posttransplant Cancer Risk. AB - Several viruses, such as Epstein-Barr virus, are now known to be associated with several human cancers, but not all patients with these viral infections develop cancer. In transplantation, such viruses often have a prolonged time gap from infection to cancer development, and many are preceded by a period of circulating and detectable nucleic acids in the peripheral blood compartment. The interpretation of a viral load as a measure of posttransplant risk of developing cancer depends on the virus, the cancer and associated pathogenic factors. This review describes the current state of knowledge regarding the utility and limitations of peripheral blood nucleic acid testing for Epstein-Barr virus in surveillance and risk prediction for posttransplant lymphoproliferative disorders. PMID- 27458692 TI - The geometric curvature of the spine during the sirshasana, the yoga's headstand. AB - This study analysed the behaviour of the geometric curvature of the spine during sirshasana. The position of dorsal retroreflective markers was computed via stereophotogrammetric analysis in six males and five females (29.4 +/- 8.8 years, 63.0 +/- 11.4 kg, 1.66 +/- 0.08 m [average +/- standard deviation]). The spinal points were projected onto the sagittal and frontal planes of the trunk, a polynomial was fitted to the data and the two-dimensional geometric curvature was quantified. The inferior lumbar lordosis decreased compared to the orthostatic position and gait, which may favour the posterior protrusion of the lumbar spinal nucleus pulposus in people with posterior herniation. The lateral deviation at the middle of the thoracic spine increases during sirshasana, which may reflect increased difficulties for postural control and spinal loads. It could be useful for promoting positive spinal structural and functional chronic adaptations for healthy participants, if the yoga programme is carefully planned and the spinal alignment is carefully monitored during a headstand. However, it may aggravate some spinal diseases, especially scoliosis. PMID- 27458693 TI - Challenges in laboratory diagnosis of acute viral central nervous system infections in the era of emerging infectious diseases: the syndromic approach. AB - INTRODUCTION: Many acute viral infections of the central nervous system (CNS) remain without etiological diagnosis. Specific treatment is available for only few of them; however, accurate diagnosis is essential for patient's life and public health. AREAS COVERED: In the current article, the main parameters playing a role for a successful etiological diagnosis of acute CNS infections are analysed and the syndromic approach based on clinical and demographic data combined with surrogated indicators is discussed. For the development of a relevant test panel, knowledge on the microbes causing CNS infections in a particular geographic region is essential. The modern screening strategies covering a large panel of potential causative agents are described. Examples of the successful application of next generation sequencing in the identification of etiological agents, including novel and emerging viruses, are given. Expert commentary: Knowledge on epidemiology of the viruses, expertise on syndromic grouping of the etiological agents and advances in technology enable the laboratory diagnosis of acute CNS infections, and the rapid identification, containment and mitigation of probable outbreaks. PMID- 27458694 TI - Role of thrombin in the pathogenesis of central nervous system inflammatory diseases. AB - Thrombin initiates proinflammatory signaling responses through activation of protease-activated receptors (PARs) in in vitro and in vivo systems. Proinflammatory signaling function of thrombin increases secretion of proinflammatory cytokines and chemokines, triggers vascular permeability, promotes leukocyte migration, and induces adhesion molecule expression. Thrombin as a potent signaling molecule is strongly implicated in a number of proinflammatory disorders including severe sepsis, cancer, cardiovascular disease, and of special interest in this review neurodegenerative disorders. This review summarizes the role of thrombin in the pathogenesis of central nervous system (CNS) inflammatory diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), promoting greater understanding and clinical management of these diseases. J. Cell. Physiol. 232: 482-485, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27458695 TI - Triggered-release drug delivery nanosystems for cancer therapy by intravenous injection: where are we now? PMID- 27458696 TI - Computed Tomography Perfusion Imaging Detection of Microcirculatory Dysfunction in Small Intestinal Ischemia-Reperfusion Injury in a Porcine Model. AB - OBJECTIVE: To evaluate multi-slice computed tomography (CT) perfusion imaging (CTPI) for identifying microcirculatory dysfunction in small intestinal ischemia reperfusion (IR) injury in a porcine model. MATERIALS AND METHODS: Fifty-two pigs were randomly divided into 4 groups: (1) the IR group (n = 24), where intestinal ischemia was induced by separating and clamping the superior mesenteric artery (SMA) for 2 h, followed by reperfusion for 1, 2, 3, and 4 h (IR-1h, IR-2h, IR-3h, and IR-4h; n = 6, respectively); (2) the sham-operated (SO) group (n = 20), where the SMA was separated without clamping and controlled at postoperative 3, 4, 5, and 6 h (SO-3h, SO-4h, SO-5h, and SO-6h; n = 5, respectively); (3) the ischemia group (n = 4), where the SMA was separated and clamped for 2 h, without reperfusion, and (4) baseline group (n = 4), an additional group that was not manipulated. Small intestinal CTPI was performed at corresponding time points and perfusion parameters were obtained. The distal ileum was resected to measure the concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) and for histopathological examination. RESULTS: The perfusion parameters of the IR groups showed significant differences compared with the corresponding SO groups and the baseline group (before ischemia). The blood flow (BF), blood volume (BV), and permeability surface (PS) among the 4 IR groups were significantly different. BF and BV were significantly negatively correlated with MDA, and significantly positively correlated with SOD in the IR groups. Histopathologically, the effects of the 2-h ischemic loops were not significantly exacerbated by reperfusion. CONCLUSION: CTPI can be a valuable tool for detecting microcirculatory dysfunction and for dynamic monitoring of small intestinal IR injury. PMID- 27458697 TI - Strategies for immunohistochemical protein localization using antibodies: What did we learn from neurotransmitter transporters in glial cells and neurons. AB - Immunocytochemistry and Western blotting are still major methods for protein localization, but they rely on the specificity of the antibodies. Validation of antibody specificity remains challenging mostly because ideal negative controls are often unavailable. Further, immunochemical labeling patterns are also influenced by a number of other factors such as postmortem changes, fixation procedures and blocking agents as well as the general assay conditions (e.g., buffers, temperature, etc.). Western blotting similarly depends on tissue collection and sample preparation as well as the electrophoretic separation, transfer to blotting membranes and the immunochemical probing of immobilized molecules. Publication of inaccurate information on protein distribution has downstream consequences for other researchers because the interpretation of physiological and pharmacological observations depends on information on where ion channels, receptors, enzymes or transporters are located. Despite numerous reports, some of which are strongly worded, erroneous localization data are being published. Here we describe the extent of the problem and illustrate the nature of the pitfalls with examples from studies of neurotransmitter transporters. We explain the importance of supplementing immunochemical observations with other measurements (e.g., mRNA levels and distribution, protein activity, mass spectrometry, electrophysiological recordings, etc.) and why quantitative considerations are integral parts of the quality control. Further, we propose a practical strategy for researchers who plan to embark on a localization study. We also share our thoughts about guidelines for quality control. GLIA 2016;64:2045 2064. PMID- 27458698 TI - Effects of resveratrol on carbon monoxide-induced cardiotoxicity in rats. AB - Carbon monoxide (CO) poisoning leads to tissue hypoxia resulting in cardiovascular disturbances. Resveratrol (RES) is considered a natural cardioprotective agent especially in the setting of ischemia/reperfusion injury. In the present study, the cardioprotective potential of RES against CO-induced cardiotoxicity was evaluated. 45 male Wistar rats, animals were randomly assigned to 5 experimental groups. The first group served as negative control and was not exposed to CO. All remaining rats were exposed to CO 3000ppm for 60min. The second group received normal saline following CO exposure, while groups 3, 4 and 5 were injected intraperitoneally with different doses of RES (1, 5 and 10mg/kg, respectively). Histopathological examination showed that RES administration reduced myocardial lesions compared to control groups. Myocardial Akt expression was significantly increased in rats treated with the highest dose of RES (p<0.05) compared to CO-exposed non-treated animals. Caspase-3 activity in rat cardiomyocytes of RES-treated animals was significantly decreased in a dose dependent manner. ECG findings did not differ significantly among CO-exposed groups. In conclusion, the present study offers evidence of a protective effect of RES administration on CO-induced cardiotoxicity via Akt up-regulation and attenuation of caspase-3 activity in rat hearts. PMID- 27458699 TI - Phycoremediation and adsorption isotherms of cadmium and copper ions by Merismopedia tenuissima and their effect on growth and metabolism. AB - The current study tends to investigate the removal of cadmium and copper ions by Merismopedia tenuissima, grown in different concentrations of cadmium and copper ions, as well to investigate their effects on growth and metabolism. Sorption isotherms of Langmuir and Freundlich were obtained for the quantitative description of cadmium and copper uptake by M. tenuissima. Langmuir model adequately to describe the data of biosorption for these metals. However, the Freundlich model could work well in case of Cu(2+) only. M. tenuissima appears to be more efficient for removing Cd(2+) ions than Cu(2+). However, the affinity constant of Cu(2+) on the biomass of M. tenuissima was higher than Cd(2+) indicating that M. tenuissima is more tolerant to Cd(2+) phytotoxicity than Cu(2+). FTIR analysis of algae with and without biosorption revealed the presence of carboxyl, amino, amide and hydroxyl groups, which were responsible for biosorption of Cd(+2) and Cu(+2) ions. PMID- 27458700 TI - The influence of aripiprazole and olanzapine on neurotransmitters level in frontal cortex of prenatally stressed rats. AB - OBJECTIVES: The study aims to verify whether alterations in the level of neurotransmitters have occurred in prenatally stressed rats (animal model of schizophrenia), and whether aripiprazole (ARI) and olanzapine (OLA) modify this level. METHODS: The effects of ARI (1.5mg/kg) and OLA (0.5mg/kg) were studied by means of microdialysis in freely moving rats (observation time 120min). The level of neurotransmitters (DA, 5-HT, NA) and their metabolites (DOPAC, HVA, 5-HIAA) was analyzed by HPLC with coulochemical detection. RESULTS: Obtained results indicate that after a single administration of ARI and OLA in the prenatally stressed rats the increase of DA, DOPAC, and 5-HT was observed. In turn ARI administration increase the level of HVA and 5-HIAA and also decrease the level of NA. After OLA administration the level of NA and HVA increased and no significant change in 5-HIAA was observed. CONCLUSION: Alterations observed as a result of ARI and OLA administration may be pivotal in identifying animal models of mental disorders and in the analysis of neuroleptics effectiveness. PMID- 27458701 TI - Mutagenic and genotoxic potential of native air borne particulate matter from industrial area of Rourkela city, Odisha, India. AB - In this study, we examined potential adverse health effect of particulate matter (PM) collected from industrial areas of Rourkela, Odisha, India. Results indicate that PM in these areas contains benzo[a]pyrene in addition to other unidentified molecules. Ames test revealed the above PM to be highly mutagenic. Further studies of PM in HaCaT cells suggest its DNA damaging potential which may lead to apoptosis. Generation of reactive oxygen and nitrogen species following PM exposure may be an early event in the PM induced apoptosis. In addition, the activity of cytochrome P450 (CYP450), the key xenobiotic metabolism enzyme, was found to be increased following PM exposure indicating its role in PM induced toxicity. To confirm this, we used genetic and pharmacological inhibitors of CYP450 like CYP1B1 siRNA and Clotrimazole. Interestingly, we found that the use of these inhibitors significantly suppressed the PM induced apoptosis in HaCaT cells, which confirm the crucial role of CYP1B1 in the toxic manifestation of PM. For further analysis, blood samples were collected from the volunteer donor and analyzed for immunophenotypes and comet assay to survey any change in immune cells and DNA damage in blood cells respectively. The study was performed with 55 blood samples including 32 from industrial areas and 23 people from non industrial zone of Rourkela city. Samples had a mean+/-SD age of 35+/-6.2years (35 men and 20 women). Our investigation did not observe any significant alteration in lymphocytes (P=0.671), B cell (P=0.104), cytotoxic T cell (P=0.512), helper T cell (P=0.396), NK cell (P=0.675) and monocytes (P=0.170) of blood cells from these two groups. Taken together; this study first time reports the possible health hazards of PM from industrial areas of Odisha, India. PMID- 27458702 TI - Effect of GADD45a on olaquindox-induced apoptosis in human hepatoma G2 cells: Involvement of mitochondrial dysfunction. AB - Olaquindox, a quinoxaline 1, 4-dioxide derivative, has been widely used as a feed additive for promoting animal growth in China. The aim of present study was to investigate the effect of grow arrest and DNA damage 45 alpha (GADD45a) on olaquindox-induced apoptosis in HepG2 cells. The result showed that olaquindox induced the decrease of cell viability in a dose dependent manner. Compared to the control group, olaquindox treatment at 400 and 800MUg/mL increased the expression level of GADD45a protein and reactive oxygen species (ROS) production, decreased mitochondrial membrane potential (MMP), and subsequently increased the expression of Bax while decreased the expression of Bcl-2, leading to the release of cytochrome c (Cyt c). However, knockdown of GADD45a enhanced olaquindox induced ROS production, disrupted MMP and subsequently caused Cyt c release, then further increased olaquindox- induced cell apoptosis by increasing the activities of caspase-9, caspase-3, and poly (ADP-ribose) polymerase (PARP). In conclusion, the results revealed that GADD45a played a critical role in olaquindox-induced apoptosis in HepG2 cells, which may embrace the regulatory ability on the mitochondrial apoptosis pathway. PMID- 27458703 TI - Nano-encapsulated chlorophyllin significantly delays progression of lung cancer both in in vitro and in vivo models through activation of mitochondrial signaling cascades and drug-DNA interaction. AB - Chlorophyllin (CHL), a sodium-copper-salt derived from chlorophyll, has been widely used as a food-dye, also reportedly having some anti-cancer effect. We tested if PLGA-loaded CHL (NCHL) could have additional protective abilities through its faster and targeted drug delivery in cancer cells. Physico-chemical characterization of NCHL was done through atomic-force microscopy and UV spectroscopy. NCHL demonstrated greater ability of drug uptake and strong anti cancer potentials in non-small cell lung cancer cells, A549, as revealed from data of% cell viability, generation of reactive-oxygen-species and expression of bax, bcl2, caspase3, p53 and cytochrome c proteins. Circular dichroic spectral data indicated strong binding of NCHL with calf-thymus-DNA, causing a conformational/structural change in DNA. Further, NCHL could cross the blood brain-barrier in mice and showed greater efficacy in recovery process of tissue damage, reduction in chromosomal aberrations and% of micronuclei in co-mutagens (Sodiumarsenite+Benzo[a]Pyrene)-treated mice at a much reduced dose, indicating its use in therapeutic oncology. PMID- 27458704 TI - Intramolecular Charge Transfer and Solvation of Photoactive Molecules with Conjugated Push-Pull Structures. AB - A comparative investigation on the photophysical properties and solvation-related ICT dynamics of three push-pull compounds containing different donors including carbazole, triphenylamine and phenothiazine, was performed. The steady-state spectra and theoretical calculations show the charge transfers from the central donors to the acceptors at each side. The characterization of the extent of charge transfer was determined by various means, including estimation of the dipole moment, the electron density distribution of HOMO and LUMO, CDD and change in Gibb's free energy, which show the charge transfer strength to be in the order PDHP > BDHT > PDHC. This suggests that the electron-donating ability of the donor groups plays a crucial role in the charge transfer in these compounds. The TA data show the excited-state relaxation dynamics follow a sequential model: FC >ICT->ICT'->S0 , and are affected by the solvent polarity. The results presented here demonstrate that the compound with a higher degree of ICT characteristic interacts more strongly with stronger polar solvent molecules, which can accelerate the solvation and spectral evolution to lower energy levels. The A-pi D-pi-A architectures with prominent ICT characteristics based on carbazole, triphenylamine and phenothiazine might be potential scaffolds for light harvesting and photovoltaic devices. These results are of value for understanding structure-property relationships and the rational design of functional materials for photoelectric applications. PMID- 27458706 TI - Editorial Comment to Spherical cap surface model: A novel method for predicting renal function after partial nephrectomy. PMID- 27458707 TI - Reconstructive option after radical mutilating surgery in children with genitourinary rhabdomyosarcoma: When sparing the bladder is not an option. AB - OBJECTIVES: To present versatile surgical reconstructive techniques and their outcomes in pediatric patients with genitourinary rhabdomyosarcoma. METHODS: We retrospectively analyzed the oncological and urological outcomes of seven patients treated between 1992 and 2014 according to the Cooperative Weichteilsarkom Studiengruppe protocols. Intergroup Rhabdomyosarcoma Study staging: local, six patients; and IV, one patient. HISTOLOGY: embryonal, five patients; unclassified, one patient; triton tumor one patient. Surgical treatment included: cystectomy, uterectomy and partial vaginectomy, one patient; radical cystectomy, two patients; cystectomy, one patient; cystectomy with partial prostatectomy, one patient; partial cystectomy, one patient; and partial prostatectomy, one patient. RESULTS: All patients were alive in complete remission at last follow up. In four cases, ileal conduit with ureteral reimplantation with serous-lined extramural tunnel (Abol-Enein technique) was carried out, which was followed by conversion into ileal continent bladder with continent appendiceal stoma for clean intermittent catheterization in three patients. In one boy, partial cystectomy and continent reconstruction was carried out during a single surgical procedure. One child with incontinent urinary diversion is still awaiting a continence solution. One child after partial prostatectomy is continent without any voiding disturbances. CONCLUSIONS: The timing and extent of radical surgery for treatment of genitourinary rhabdomyosarcoma depend on the local anatomical conditions, and the response to previous chemo- and radiotherapy. Cystectomy followed by various reconstructive techniques still remains an important option in the local treatment. PMID- 27458708 TI - Immunohistochemical loss of 5-hydroxymethylcytosine expression in acute myeloid leukaemia: relationship to somatic gene mutations affecting epigenetic pathways. AB - AIMS: Genes affecting epigenetic pathways are frequently mutated in myeloid malignancies, including acute myeloid leukaemia (AML). The genes encoding TET2, IDH1 and IDH2 are among the most commonly mutated genes, and cause defective conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), impairing demethylation of DNA, and presumably serving as driver mutations in leukaemogenesis. The aim of this study was to correlate 5hmC immunohistochemical loss with the mutation status of genes involved in epigenetic pathways in AML. METHODS AND RESULTS: Immunohistochemical staining with an anti-5hmC antibody was performed on 41 decalcified, formalin-fixed paraffin-embedded (FFPE) bone marrow biopsies from patients with AML. Archived DNA was subjected to next-generation sequencing for analysis of a panel of genes, including TET2, IDH1, IDH2, WT1 and DNMT3A. TET2, IDH1, IDH2, WT1 and DNMT3A mutations were found in 46% (19/41) of the cases. Ten of 15 cases (67%) with TET2, IDH1, IDH2 or WT1 mutations showed deficient 5hmC staining, whereas nine of 26 cases (35%) without a mutation in these genes showed loss of 5hmC. It is of note that all four cases with TET2 mutations showed deficient 5hmC staining. CONCLUSIONS: Overall, somatic mutations in TET2, IDH1, IDH2, WT1 and DNMT3A were common in our cohort of AML cases. Immunohistochemical staining for 5hmC was lost in the majority of cases harbouring mutations in these genes, reflecting the proposed relationship between dysfunctional epigenetic pathways and leukaemogenesis. PMID- 27458709 TI - Progesterone-induced miR-133a inhibits the proliferation of endometrial epithelial cells. AB - AIM: This study aimed to understand the role of miR-133a in progesterone actions, explore the regulative mechanism of the progesterone receptor, and investigate the effects of miR-133a on the progesterone-inhibited proliferation of mouse endometrial epithelial cells. METHODS: The expression of miR-133a induced by progesterone was detected by quantitative real-time PCR both in vivo and in vitro. Ishikawa subcell lines stably transfected with progesterone receptor subtypes were used to determine the receptor mechanism of progesterone inducing miR-133a. Specific miR-133a mimics or inhibitors were transfected into mouse uteri and primary cultured endometrial epithelial cells to overexpress or downregulate the miR-133a. The roles of miR-133a in the cell cycle and proliferation of endometrial epithelial cells were analysed by flow cytometry and Edu incorporation analysis. The protein levels of cyclinD2 in uterine tissue sections and primary cultured endometrial epithelial cells were determined by immunohistochemistry and Western blot analysis. RESULTS: Progesterone could induce miR-133a expression in a PRB-dependent manner in endometrial epithelial cells. miR-133a inhibited endometrial epithelial cell proliferation by arresting cell cycle at the G1 -S transition. Moreover, miR-133a acted as an inhibitor in downregulating cyclinD2 in endometrial epithelial cells. CONCLUSION: We showed for the first time that progesterone-induced miR-133a inhibited the proliferation of endometrial epithelial cells by downregulating cyclinD2. Our research indicated an important mechanism for progesterone inhibiting the proliferation of endometrial epithelial cells by inducing special miRNAs to inhibit positive regulatory proteins in the cell cycle. PMID- 27458711 TI - Ruthenium(II)-Catalyzed Traceless C-H Functionalization Using an N-N Bond as an Internal Oxidant. AB - A previously elusive Ru(II) -catalyzed N-N bond-based traceless C-H functionalization strategy is reported. An N-amino (i.e., hydrazine) group is used for the directed C-H functionalization with either an alkyne or an alkene, affording an indole derivative or olefination product. The synthesis features a broad substrate scope, superior atom and step economy, as well as mild reaction conditions. PMID- 27458710 TI - Structure of Alcohol Oxidase from Pichia pastoris by Cryo-Electron Microscopy. AB - The first step in methanol metabolism in methylotrophic yeasts, the oxidation of methanol and higher alcohols with molecular oxygen to formaldehyde and hydrogen peroxide, is catalysed by alcohol oxidase (AOX), a 600-kDa homo-octamer containing eight FAD cofactors. When these yeasts are grown with methanol as the carbon source, AOX forms large crystalline arrays in peroxisomes. We determined the structure of AOX by cryo-electron microscopy at a resolution of 3.4 A. All residues of the 662-amino acid polypeptide as well as the FAD are well resolved. AOX shows high structural homology to other members of the GMC family of oxidoreductases, which share a conserved FAD binding domain, but have different substrate specificities. The preference of AOX for small alcohols is explained by the presence of conserved bulky aromatic residues near the active site. Compared to the other GMC enzymes, AOX contains a large number of amino acid inserts, the longest being 75 residues. These segments are found at the periphery of the monomer and make extensive inter-subunit contacts which are responsible for the very stable octamer. A short surface helix forms contacts between two octamers, explaining the tendency of AOX to form crystals in the peroxisomes. PMID- 27458712 TI - Outbreak of pulmonary Pseudomonas aeruginosa and Stenotrophomonas maltophilia infections related to contaminated bronchoscope suction valves, Lyon, France, 2014. AB - In April 2014, pulmonary Pseudomonas aeruginosa and Stenotrophomonas maltophilia co-infections potentially related to bronchoscopic procedures were identified in the intensive care units of a university hospital in Lyon, France. A retrospective cohort of 157 patients exposed to bronchoscopes from 1 December 2013 to 17 June 2014 was analysed. Environmental samples of suspected endoscopes were cultured. Bronchoscope disinfection was reviewed. Ten cases of pulmonary P. aeruginosa/S. maltophilia co-infections were identified, including two patients with secondary pneumonia. Eight cases were linked to bronchoscope A1 and two to bronchoscope A2. Cultures deriving from suction valves were positive for P. aeruginosa/S. maltophilia. Exposure to bronchoscopes A1 and A2 was independently coupled with increased risk of co-infection (adjusted odds ratio (aOR) = 84.6; 95% confidence interval (CI): 9.3-771.6 and aOR = 11.8, 95% CI: 1.2-121.3). Isolates from suction valves and clinical samples presented identical pulsotypes. The audit detected deficiencies in endoscope disinfection. No further cases occurred after discontinuation of the implicated bronchoscopes and change in cleaning procedures. This outbreak of pulmonary P. aeruginosa/S. maltophilia co infections was caused by suction valve contamination of two bronchoscopes of the same manufacturer. Our findings underscore the need to test suction valves, in addition to bronchoscope channels, for routine detection of bacteria. PMID- 27458713 TI - AtRAD5A is a DNA translocase harboring a HIRAN domain which confers binding to branched DNA structures and is required for DNA repair in vivo. AB - DNA lesions such as crosslinks represent obstacles for the replication machinery. Nonetheless, replication can proceed via the DNA damage tolerance pathway also known as postreplicative repair pathway. SNF2 ATPase Rad5 homologs, such as RAD5A of the model plant Arabidopsis thaliana, are important for the error-free mode of this pathway. We able to demonstrate before, that RAD5A is a key factor in the repair of DNA crosslinks in Arabidopsis. Here, we show by in vitro analysis that AtRAD5A protein is a DNA translocase able to catalyse fork regression. Interestingly, replication forks with a gap in the leading strand are processed best, in line with its suggested function. Furthermore AtRAD5A catalyses branch migration of a Holliday junction and is furthermore not impaired by the DNA binding of a model protein, which is indicative of its ability to displace other proteins. Rad5 homologs possess HIRAN (Hip116, Rad5; N-terminal) domains. By biochemical analysis we were able to demonstrate that the HIRAN domain variant from Arabidopsis RAD5A mediates structure selective DNA binding without the necessity for a free 3'OH group as has been shown to be required for binding of HIRAN domains in a mammalian RAD5 homolog. The biological importance of the HIRAN domain in AtRAD5A is demonstrated by our result that it is required for its function in DNA crosslink repair in vivo. PMID- 27458714 TI - An Integrative Review of the Structures and Processes Related to Nurse Supervisory Performance in Long-Term Care. AB - BACKGROUND: Understanding the structures and processes related to the supervisor performance of regulated nurses (registered nurses [RN] and registered practical nurses [RPN]) is critical in order to discern how administrators of long-term care (LTC) homes can facilitate and better support nurses given their important contribution to nurse assistants' job satisfaction and resident outcomes. AIMS: The aim of this integrative review is to identify the structures and processes related to supervisory performance of regulated nurses in LTC. METHODS: An electronic search of six databases for studies published in English between 2000 and September 2015 was conducted by a librarian. The inclusion criteria were studies focused on RN or RPN supervisory performance in LTC, which included a structure or process related to supervisory performance of the nurse. Screening, quality assessment using the Mixed Methods Assessment Tool, and data extraction for the included studies were conducted independently by two reviewers. RESULTS: A total of 22 studies were included in the review. Six nurse structures (e.g., nurses' "perceptions of their supervisory role and authority" as well as their "personal qualities"), and eight organizational structures (e.g., "organizational support (culture) for supervisory and management practices" and "staffing levels") were identified. Six processes of effective supervisory performance were identified, such as "being flexible, understanding, considerate listeners and encourage staff input" as well as "respect, value, recognize, acknowledge and motivate" nursing assistants they supervise. LINKING EVIDENCE TO ACTION: The results highlight the nuanced and complex nature of nurses' supervisory performance and the multifaceted approach required to support effective nurse supervisors in LTC. Future research should examine how resident-related structures, as well as other moderators and mediators, may influence supervisory performance. Developing detailed models of effective supervision can inform future interventions targeting modifiable processes related to supervisory performance to thereby change practice and optimize supervisory performance in LTC. PMID- 27458715 TI - Molecular epidemiology of co-infection with hepatitis B virus and human immunodeficiency virus (HIV) among adult patients in Harare, Zimbabwe. AB - The objective of this study was to determine the prevalence of co-infection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) and the genetic characteristics of both viruses among pre-HIV-treatment patients in Harare, Zimbabwe. This cross-sectional survey involved 176 remnant plasma samples collected from consenting HIV patients (median age 35 [18-74]) between June and September 2014. HBV seromarkers were determined by high-sensitivity chemiluminescence assays. Molecular evolutionary analyses were conducted on the basal core promoter/precore (BCP/PC) and S regions of HBV, as well as part of the HIV pol region. Of the 176 participants (65.7% female), 19 (10.8%) were positive for HBsAg (median 0.033 IU/ml (IQR 0.01-415). The HBsAg incidence was higher in men than women (P = 0.009). HBsAg-positive subjects had lower median CD4 counts (P = 0.016). HBV DNA was detectable in 12 HBsAg-positive samples (median 3.36 log cp/ml (2.86-4.51), seven being amplified and sequenced. All isolates were subgenotype A1 without HBV drug resistance mutations but each had at least one BCP/PC mutation. PreS deletion mutants and small S antigen variants M133I/T and D144G were identified. Of the 164 HIV isolates successfully genotyped, 163 (99.4%) were HIV-1 subtype C and only one was HIV-1 subtype F1. Sixteen (9.8%) had at least one drug resistance mutation, predominantly non-nucleoside reverse transcriptase inhibitor-related mutations, observed mostly among female participants. This study shows that co-infection with HBV is present among HIV patients enrolling into HIV care in Zimbabwe, suggesting that HBV screening and monitoring programmes be strengthened in this context. J. Med. Virol. 89:257-266, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27458716 TI - The Role of MAPT Haplotype H2 and Isoform 1N/4R in Parkinsonism of Older Adults. AB - BACKGROUND AND OBJECTIVE: Recently, we have shown that the Parkinson's disease (PD) susceptibility locus MAPT (microtubule associated protein tau) is associated with parkinsonism in older adults without a clinical diagnosis of PD. In this study, we investigated the relationship between parkinsonian signs and MAPT transcripts by assessing the effect of MAPT haplotypes on alternative splicing and expression levels of the most common isoforms in two prospective clinicopathologic studies of aging. MATERIALS AND METHODS: using regression analysis, controlling for age, sex, study and neuropathology, we evaluated 976 subjects with clinical, genotyping and brain pathology data for haplotype analysis. For transcript analysis, we obtained MAPT gene and isoform-level expression from the dorsolateral prefrontal cortex for 505 of these subjects. RESULTS: The MAPT H2 haplotype was associated with lower total MAPT expression (p = 1.2x10-14) and global parkinsonism at both study entry (p = 0.001) and proximate to death (p = 0.050). Specifically, haplotype H2 was primarily associated with bradykinesia in both assessments (p<0.001 and p = 0.008). MAPT total expression was associated with age and decreases linearly with advancing age (p<0.001). Analysing MAPT alternative splicing, the expression of 1N/4R isoform was inversely associated with global parkinsonism (p = 0.008) and bradykinesia (p = 0.008). Diminished 1N/4R isoform expression was also associated with H2 (p = 0.001). CONCLUSIONS: Overall, our results suggest that age and H2 are associated with higher parkinsonism score and decreased total MAPT RNA expression. Additionally, we found that H2 and parkinsonism are associated with altered expression levels of specific isoforms. These findings may contribute to the understanding of the association between MAPT locus and parkinsonism in elderly subjects and in some extent to age-related neurodegenerative diseases. PMID- 27458717 TI - Ambient Air Pollutant Exposures and Hospitalization for Kawasaki Disease in Taiwan: A Case-Crossover Study (2000-2010). AB - BACKGROUND: Kawasaki disease (KD) is an acute and multi-systemic vasculitis that occurs predominantly in infants and young children. Although the etiological agent of KD remains unclear, limited studies have reported that windborne environmental factors may trigger KD. OBJECTIVES: We conducted a time-stratified case-crossover study to assess the associations between air pollutants and KD in Taiwan. METHODS: We identified children < 5 years old with a diagnosis of KD from the Longitudinal Health Insurance Database 2000 (LHID2000) between 2000 and 2010. We obtained data regarding carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), particulate matter with aerodynamic diameter < 10 MUm (PM10), and sulfate dioxide (SO2) from 70 monitoring stations and used inverse distance weighting to calculate average daily exposures for the residential postal code of each case. We performed conditional logistic regression to estimate associations between KD and each air pollutant according to interquartile range (IQR) increases and quartiles of exposure on the day of hospitalization versus 3-4 reference days during the same month for each case. Additionally, we estimated associations with single-day exposures lagged 1-2 days. RESULTS: We identified 695 KD hospital admissions during the study period. An IQR increase (28.73 ppb) of O3 was positively associated with KD after adjusting for temperature, humidity, northward wind, and eastward wind [adjusted odds ratio = 1.21; 95% confidence interval (CI): 1.01, 1.44]. There were no significant associations between KD and CO, NO2, PM10, or SO2. The association with O3 was limited to exposure on the day of hospitalization and to exposure during the summer months (June-August). CONCLUSIONS: Our results provide new evidence that exposure to O3 may increase the risk of KD in children. However, further investigation is needed to confirm the association and identify a potential biological mechanism. PMID- 27458718 TI - Detailed analyses of the bacterial populations in processed cocoa beans of different geographic origin, subject to varied fermentation conditions. AB - The quality of chocolate is influenced by several parameters, one of which is bacterial diversity during fermentation and drying; a crucial factor for the generation of the optimal cocoa flavor precursors. Our understanding of the bacterial populations involved in chocolate fermentation can be improved by the use of high-throughput sequencing technologies (HTS), combined with PCR amplification of the 16S rRNA subunit. Here, we have conducted a high-throughput assessment of bacterial diversity in four processed samples of cocoa beans from different geographic origins. As part of this study, we also assessed whether different DNA extraction methods could affect the quality of our data. The dynamics of microbial populations were analyzed postharvest (fermentation and sun drying) and shipment, before entry to the industrial process. A total of 691,867 high quality sequences were obtained by Illumina MiSeq sequencing of the two bacterial 16S rRNA hypervariable regions, V3 and V4, following paired-read assembly of the raw reads. Manual curation of the 16S database allowed us to assign the correct taxonomic classifications, at species level, for 83.8% of those reads. This approach revealed a limited biodiversity and population dynamics for both the lactic acid bacteria (LAB) and acetic acid bacteria (AAB), both of which are key players during the acetification and lactic acid fermentation phases. Among the LAB, the most abundant species were Lactobacillus fermentum, Enterococcus casseliflavus, Weissella paramesenteroides, and Lactobacillus plantarum/paraplantarum. Among the AAB, Acetobacter syzygii, was most abundant, then Acetobacter senegalensis and Acetobacter pasteriuanus. Our results indicate that HTS approach has the ability to provide a comprehensive view of the cocoa bean microbiota at the species level. PMID- 27458719 TI - The Effect of Different Foot Orthosis Inverted Angles on Plantar Pressure in Children with Flexible Flatfeet. AB - Although orthotic modification using the inverted technique is available for the treatment of flatfoot, empirical evidence for the biomechanical effects of inverted-angle foot orthoses (FOs) is lacking. The aim of this study was to evaluate the effects of different FO inversion angles on plantar pressure during gait in children with flatfoot. Twenty-one children with flexible flatfeet (mean age 9.9 years) were enrolled in this study. The plantar pressures were measured for the rearfoot; medial and lateral midfoot; and medial, central, and lateral forefoot as participants walked on a treadmill while wearing shoes only and shoes with the following 3 orthotic conditions: (i) orthosis with no inverted angle, (ii) orthosis with a 15 degrees inverted angle, and (iii) orthosis with a 30 degrees inverted angle. A one-way repeated measures analysis of variance (ANOVA) with the Bonferroni-adjusted post-hoc test was used to compare the mean values of each orthotic condition. Compared with the shoe only condition, the peak pressure decreased significantly under the medial forefoot and rearfoot with all FOs (p <0.05). However, no significant differences in the peak pressure under the medial forefoot and rearfoot were observed between the FOs. The peak pressure under the medial midfoot increased significantly with all FOs, and a maximal increase in the peak pressure was obtained with a 30 degrees inverted angle orthosis. Furthermore, the contact area under the medial midfoot and rearfoot increased significantly with all FOs, compared with the shoe only condition (p <0.05). Again, no significant differences were observed between the FOs. For plantar pressure redistribution, a FO with a low inverted angle could be effective, accommodative, and convenient for children with flatfoot. PMID- 27458720 TI - Doing well while fighting river blindness: the alignment of a corporate drug donation programme with responsibilities to shareholders. AB - OBJECTIVE: Using the example of Merck's donations of ivermectin, to show how tax incentives and non-profit collaborators can make corporate largesse consistent with obligations to maximise returns to shareholders. METHODS: We obtained information from publicly available data and estimated Merck's tax deductions according to the US Internal Revenue Code. Reviews of Merck-Kitasato contracts and personal interviews provided additional information regarding key lessons from this collaboration. RESULTS: Our best estimate of the direct cost to Merck of the ivermectin tablets donated during 2005-2011 is around US$ 600 million, well below the stated value of US$ 3.8 billion. Our calculation of tax write-offs reduces the net cost to around US$ 180 million in that period. Indirect market benefits and effects on goodwill further enhanced the compatibility of Merck's donation programme with the company's profit-maximising objective. The case offers lessons for effective management of collaborations with public and non profit organisations. CONCLUSION: Merck's role in the donation of ivermectin for the treatment of onchocerciasis is widely and justly acknowledged as a prime example of corporate largesse in the public interest. It is nevertheless important to note that several public and non-profit collaborators, and United States taxpayers, played significant roles in increasing Merck's incentives, and indeed ability, to conduct the donation programme that changed so many lives in poor countries, while meeting its responsibilities to shareholders. Overall, the record indicates responsible corporate management of Merck's ivermectin programme and demonstrates the feasibility of socially responsible policies in a manner compatible with obligations to shareholders. PMID- 27458721 TI - The Loss of Myocardial Benefit following Ischemic Preconditioning Is Associated with Dysregulation of Iron Homeostasis in Diet-Induced Diabetes. AB - Whether the diabetic heart benefits from ischemic preconditioning (IPC), similar to the non-diabetic heart, is a subject of controversy. We recently proposed new roles for iron and ferritin in IPC-protection in Type 1-like streptozotocin induced diabetic rat heart. Here, we investigated iron homeostasis in Cohen diabetic sensitive rat (CDs) that develop hyperglycemia when fed on a high sucrose/low-copper diet (HSD), but maintain normoglycemia on regular-diet (RD). Control Cohen-resistant rats (CDr) maintain normoglycemia on either diet. The IPC procedure improved the post-ischemic recovery of normoglycemic hearts (CDr-RD, CDr-HSD and CDs-RD). CDs-HSD hearts failed to show IPC-associated protection. The recovery of these CDs-HSD hearts following I/R (without prior IPC) was better than their RD controls. During IPC ferritin levels increased in normoglycemic hearts, and its level was maintained nearly constant during the subsequent prolonged ischemia, but decayed to its baseline level during the reperfusion phase. In CDs-HSD hearts the baseline levels of ferritin and ferritin-saturation with iron were notably higher than in the controls, and remained unchanged during the entire experiment. This unique and abnormal pattern of post-ischemic recovery of CDs-HSD hearts is associated with marked changes in myocardial iron homeostasis, and suggests that iron and iron-proteins play a causative role/s in the etiology of diabetes-associated cardiovascular disorders. PMID- 27458722 TI - Clarifying the Impact of Untreated and Treated Dental Caries on Oral Health Related Quality of Life among Adolescents. AB - The aim of the present study was to investigate the effect of dental caries experience and the components of the decayed, missing and filled teeth (DMFT) index on oral health-related quality of life (OHRQoL) among adolescents in southern Brazil. A cross-sectional study was conducted with 509 adolescents aged 11-14 years enrolled at public schools in the municipality of Osorio (southern Brazil). A calibrated examiner performed the clinical examination for caries (World Health Organization: DMFT index), malocclusion (Dental Aesthetic Index) and traumatic dental injuries [Andreasen et al., 2007]. The participants answered the Brazilian version of the Child Perceptions Questionnaire (CPQ11-14) - Impact Short Form, and their parents/guardians answered a structured questionnaire addressing demographic and socioeconomic characteristics. Data analysis involved Poisson regression with robust variance, with the calculation of rate ratios adjusted for potential confounding variables. High severity of dental caries experience exerted a significant impact on OHRQoL, even after controlling for socioeconomic and clinical factors (rate ratio 1.30; 95% confidence interval, CI 1.12-1.51). All OHRQoL domains were affected by untreated dental caries. The multivariate analysis demonstrated that the CPQ11-14 scores were 33% higher among adolescents with untreated caries (rate ratio 1.33; 95% CI 1.17-1.50) and 24% higher among those with missing teeth (rate ratio 1.24; 95% CI 1.06-1.47). No difference in OHRQoL was found between adolescents with filled teeth and those without dental caries. In conclusion, dental caries experience, untreated dental caries and missing teeth exerted a negative impact on OHRQoL among the adolescents. PMID- 27458723 TI - Reversible CO2 Capture by Conjugated Ionic Liquids through Dynamic Covalent Carbon-Oxygen Bonds. AB - The strong chemisorption of CO2 is always accompanied by a high absorption enthalpy, and traditional methods to reduce the absorption enthalpy lead to decreased CO2 capacities. Through the introduction of a large pi-conjugated structure into the anion, a dual-tuning approach for the improvement of CO2 capture by anion-functionalized ionic liquids (ILs) resulted in a high capacity of up to 0.96 molCO2 mol-1IL and excellent reversibility. The increased capacity and improved desorption were supported by quantum chemical calculations, spectroscopic investigations, and thermogravimetric analysis. The increased capacity may be a result of the strengthened dynamic covalent bonds in these pi electron-conjugated structures through anion aggregation upon the uptake of CO2 , and the improved desorption originates from the charge dispersion of interaction sites through the large pi-electron delocalization. These results provide important insights into effective strategies for CO2 capture. PMID- 27458724 TI - International Evidence-Based Medicine Survey of the Veterinary Profession: Information Sources Used by Veterinarians. AB - Veterinarians are encouraged to use evidence to inform their practice, but it is unknown what resources (e.g. journals, electronic sources) are accessed by them globally. Understanding the key places veterinarians seek information can inform where new clinically relevant evidence should most effectively be placed. An international survey was conducted to gain understanding of how veterinary information is accessed by veterinarians worldwide. There were 2137 useable responses to the questionnaire from veterinarians in 78 countries. The majority of respondents (n = 1835/2137, 85.9%) undertook clinical work and worked in a high income country (n = 1576/1762, 89.4%). Respondents heard about the survey via national veterinary organisations or regulatory bodies (31.5%), online veterinary forums and websites (22.7%), regional, discipline-based or international veterinary organisations (22.7%) or by direct invitation from the researchers or via friends, colleagues or social media (7.6%). Clinicians and non clinicians reportedly used journals most commonly (65.8%, n = 1207/1835; 75.6%, n = 216/286) followed by electronic resources (58.7%, n = 1077/1835; 55.9%, n = 160/286), respectively. Respondents listed a total of 518 journals and 567 electronic sources that they read. Differences in veterinarian preference for resources in developed, and developing countries, were found. The nominated journals most read were the Journal of the American Veterinary Medical Association (12.7% of nominations) for clinicians and the Veterinary Record (5.7%) for non-clinicians. The most accessed electronic resource reported was the Veterinary Information Network (25.6%) for clinicians and PubMed (7.4%) for non clinicians. In conclusion, a wide array of journals and electronic resources appear to be accessed by veterinarians worldwide. Veterinary organisations appear to play an important role in global communication and outreach to veterinarians and consideration should be given to how these channels could be best utilised for effective dissemination of key research findings. PMID- 27458725 TI - Effects of Photoperiod Extension on Clock Gene and Neuropeptide RNA Expression in the SCN of the Soay Sheep. AB - In mammals, changing daylength (photoperiod) is the main synchronizer of seasonal functions. The photoperiodic information is transmitted through the retino hypothalamic tract to the suprachiasmatic nuclei (SCN), site of the master circadian clock. To investigate effects of day length change on the sheep SCN, we used in-situ hybridization to assess the daily temporal organization of expression of circadian clock genes (Per1, Per2, Bmal1 and Fbxl21) and neuropeptides (Vip, Grp and Avp) in animals acclimated to a short photoperiod (SP; 8h of light) and at 3 or 15 days following transfer to a long photoperiod (LP3, LP15, respectively; 16h of light), achieved by an acute 8-h delay of lights off. We found that waveforms of SCN gene expression conformed to those previously seen in LP acclimated animals within 3 days of transfer to LP. Mean levels of expression for Per1-2 and Fbxl21 were nearly 2-fold higher in the LP15 than in the SP group. The expression of Vip was arrhythmic and unaffected by photoperiod, while, in contrast to rodents, Grp expression was not detectable within the sheep SCN. Expression of the circadian output gene Avp cycled robustly in all photoperiod groups with no detectable change in phasing. Overall these data suggest that synchronizing effects of light on SCN circadian organisation proceed similarly in ungulates and in rodents, despite differences in neuropeptide gene expression. PMID- 27458726 TI - What Are the Optimal Monitoring Techniques in Head and Neck Microvascular Reconstruction? AB - PURPOSE: We evaluated the outcomes for widely used systems in terms of accuracy, salvage rates, and added cost compared to conventional monitoring. METHODS: We performed a narrative review of the literature (high-impact report). RESULTS: The overall free flap success for head and neck reconstruction is at least 95% using any type of monitoring. Salvage rates in decreasing frequency of monitoring techniques are 85% with near-infrared spectroscopy (NIRS), 81% with implantable Doppler, and 61.5% with conventional monitoring. False-positive rates in increasing frequency are 0% for NIRS, 0.4% for conventional monitoring, and <10% for implantable Doppler. Current data show implantable Doppler to be potentially cost-effective for institutions with a failure rate of at least 6%. Buried flaps may be monitored with conventional monitoring using an exteriorized paddle, or using implantable Doppler. CONCLUSIONS: The cost-effectiveness of advanced flap monitoring systems beyond conventional monitoring is related to the success rate of each institution. Cost-effectiveness studies are necessary to determine at what point NIRS becomes advantageous. PMID- 27458728 TI - Saliva Crystallization Occurs in Female Bornean Orangutans (Pongo pygmaeus): Could It Be a New Option for Monitoring of Menstrual Cycle in Captive Great Apes? AB - Saliva crystallization was previously studied in both humans and animals with various results. The study aimed to confirm of the presence of saliva crystallization in female Bornean orangutans (Pongo pygmaeus), to evaluate the quality of samples which were collected from animals and processed by keepers, and to test preliminarily if the saliva crystallization could be connected with menstrual cycle and could serve as a cheap, quick and simple method for the basic monitoring of their reproductive status. The research was carried out from September 2014 to January 2015. Sampling of saliva was done in three female orangutans from three zoological gardens (Dvur Kralove, Usti nad Labem, Bojnice) daily, mostly by tongue prints on glass slides with ground edges or by sampling directly from the mouth using plastic spoons from which the saliva was transferred onto glass slides. Samples were evaluated by light microscopy with *400 magnification. The quality of the sample and type of crystallization was assessed for two different approaches. In total, 246 samples were evaluated. We confirmed the presence of saliva crystallization in orangutans. The quality of samples was variable however acceptable. Unfortunately, it was impossible to detect exact fertile period in two females. However in one orangutan female, when the crystallization was evaluated by the approach typically used in humans, we discovered that saliva crystallization during the fertile period significantly differed from saliva crystallization in the non-fertile period. This points out the possibility of using saliva crystallization for detection of the fertile period in orangutans. However, further research was recommended. PMID- 27458729 TI - Numerical Study on the Heat Transfer of Carbon Dioxide in Horizontal Straight Tubes under Supercritical Pressure. AB - Cooling heat transfer of supercritical CO2 in horizontal straight tubes with wall is numerically investigated by using FLUENT. The results show that almost all models are able to present the trend of heat transfer qualitatively, and the stand k-epsilon with enhanced wall treatment model shows the best agreement with the experimental data, followed by LB low Re turbulence model. Then further studies are discussed on velocity, temperature and turbulence distributions. The parameters which are defined as the criterion of buoyancy effect on convection heat transfer are introduced to judge the condition of the fluid. The relationships among the inlet temperature, outlet temperature, the mass flow rate, the heat flux and the diameter are discussed and the difference between the cooling and heating of CO2 are compared. PMID- 27458727 TI - Host Gut Motility Promotes Competitive Exclusion within a Model Intestinal Microbiota. AB - The gut microbiota is a complex consortium of microorganisms with the ability to influence important aspects of host health and development. Harnessing this "microbial organ" for biomedical applications requires clarifying the degree to which host and bacterial factors act alone or in combination to govern the stability of specific lineages. To address this issue, we combined bacteriological manipulation and light sheet fluorescence microscopy to monitor the dynamics of a defined two-species microbiota within a vertebrate gut. We observed that the interplay between each population and the gut environment produces distinct spatiotemporal patterns. As a consequence, one species dominates while the other experiences sudden drops in abundance that are well fit by a stochastic mathematical model. Modeling revealed that direct bacterial competition could only partially explain the observed phenomena, suggesting that a host factor is also important in shaping the community. We hypothesized the host determinant to be gut motility, and tested this mechanism by measuring colonization in hosts with enteric nervous system dysfunction due to a mutation in the ret locus, which in humans is associated with the intestinal motility disorder known as Hirschsprung disease. In mutant hosts we found reduced gut motility and, confirming our hypothesis, robust coexistence of both bacterial species. This study provides evidence that host-mediated spatial structuring and stochastic perturbation of communities can drive bacterial population dynamics within the gut, and it reveals a new facet of the intestinal host-microbe interface by demonstrating the capacity of the enteric nervous system to influence the microbiota. Ultimately, these findings suggest that therapeutic strategies targeting the intestinal ecosystem should consider the dynamic physical nature of the gut environment. PMID- 27458730 TI - The Clinical and Public Health Challenges of Diabetes Prevention: A Search for Sustainable Solutions. AB - In an Editorial accompanying PLOS Medicine's Special Issue on Diabetes Prevention, Guest Editors Nicholas Wareham and William Herman discuss some of the challenges for researchers and policy makers in developing effective and equitable solutions to the worldwide problem of type 2 diabetes. PMID- 27458731 TI - Gold-Based Cubic Nanoboxes with Well-Defined Openings at the Corners and Ultrathin Walls Less Than Two Nanometers Thick. AB - We report a facile synthesis of Au-based cubic nanoboxes as small as 20 nm for the outer edge length, together with well-defined openings at the corners and walls fewer than 10 atomic layers (or <2 nm) in thickness. The success relies on the selective formation of Ag2O at the corners of Ag nanocubes, followed by the conformal deposition of Au on the side faces in a layer-by-layer fashion. When six atomic layers of Au are formed on the side faces to generate Ag@Au6L core shell nanocubes, we can selectively remove the Ag2O patches at the corner sites using a weak acid, making it possible to further remove the Ag core by H2O2 etching without breaking the ultrathin Au shell. This synthetic approach works well for Ag nanocubes of 38 and 18 nm in edge length, and the wall thickness of the nanoboxes can be controlled down to 2 nm. The resultant Au nanoboxes exhibit strong plasmonic absorption in the near-infrared region, consistent with computational simulations. PMID- 27458732 TI - Investigation of Ester- and Amide-Linker-Based Porous Organic Polymers for Carbon Dioxide Capture and Separation at Wide Temperatures and Pressures. AB - Organic compounds, such as covalent organic framework, metal-organic frameworks, and covalent organic polymers have been under investigation to replace the well known amine-based solvent sorption technology of CO2 and introduce the most efficient and economical material for CO2 capture and storage. Various organic polymers having different function groups have been under investigation both for low and high pressure CO2 capture. However, search for a promising material to overcome the issues of lower selectivity, less capturing capacity, lower mass transfer coefficient and instability in materials performance at high pressure and various temperatures is still ongoing process. Herein, we report synthesis of six covalent organic polymers (COPs) and their CO2, N2, and CH4 adsorption performances at low and high pressures up to 200 bar. All the presented COPs materials were characterized by using elemental analysis method, Fourier transform infrared spectroscopy (FTIR) and solid state nuclear magnetic resonance (NMR) spectroscopy techniques. Physical properties of the materials such as surface areas, pore volume and pore size were determined through BET analysis at 77 K. All the materials were tested for CO2, CH4, and N2 adsorption using state of the art equipment, magnetic suspension balance (MSB). Results indicated that, amide based material i.e. COP-33 has the largest pore volume of 0.2 cm(2)/g which can capture up to the maximum of 1.44 mmol/g CO2 at room temperature and at pressure of 10 bar. However, at higher pressure of 200 bar and 308 K ester-based compound, that is, COP-35 adsorb as large as 144 mmol/g, which is the largest gas capturing capacity of any COPs material obtained so far. Importantly, single gas measurement based selectivity of COP-33 was comparatively better than all other COPs materials at all condition. Nevertheless, overall performance of COP-35 rate of adsorption and heat of adsorption has indicated that this material can be considered for further exploration as efficient and cheaply available solid sorbent material for CO2 capture and separation. PMID- 27458734 TI - Styrene as 4pi-Component in Zn(II)-Catalyzed Intermolecular Diels-Alder/Ene Tandem Reaction. AB - A mild Zn-catalyzed intermolecular Diels-Alder/ene tandem reaction with styrene as a 4pi-component is reported. A variety of dihydronaphthalene products could be prepared in moderate to good yields. Moreover, a combination of DFT calculations and experiments was performed to further understand the mechanism of this unique tandem reaction. PMID- 27458735 TI - ATR checkpoint suppression by repetitive DNA. PMID- 27458733 TI - Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis. AB - Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) alpha and beta or the proton coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRalpha and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRalpha and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3 d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents. PMID- 27458736 TI - Direct Measurements of Fermi Level Pinning at the Surface of Intrinsically n-Type InGaAs Nanowires. AB - Surface effects strongly dominate the intrinsic properties of semiconductor nanowires (NWs), an observation that is commonly attributed to the presence of surface states and their modification of the electronic band structure. Although the effects of the exposed, bare NW surface have been widely studied with respect to charge carrier transport and optical properties, the underlying electronic band structure, Fermi level pinning, and surface band bending profiles are not well explored. Here, we directly and quantitatively assess the Fermi level pinning at the surfaces of composition-tunable, intrinsically n-type InGaAs NWs, as one of the prominent, technologically most relevant NW systems, by using correlated photoluminescence (PL) and X-ray photoemission spectroscopy (XPS). From the PL spectral response, we reveal two dominant radiative recombination pathways, that is, direct near-band edge transitions and red-shifted, spatially indirect transitions induced by surface band bending. The separation of their relative transition energies changes with alloy composition by up to more than ~40 meV and represent a direct measure for the amount of surface band bending. We further extract quantitatively the Fermi level to surface valence band maximum separation using XPS, and directly verify a composition-dependent transition from downward to upward band bending (surface electron accumulation to depletion) with increasing Ga-content x(Ga) at a crossover near x(Ga) ~ 0.2. Core level spectra further demonstrate the nature of extrinsic surface states being caused by In rich suboxides arising from the native oxide layer at the InGaAs NW surface. PMID- 27458740 TI - Quantifying Carbon-14 for Biology Using Cavity Ring-Down Spectroscopy. AB - A cavity ring-down spectroscopy (CRDS) instrument was developed using mature, robust hardware for the measurement of carbon-14 in biological studies. The system was characterized using carbon-14 elevated glucose samples and returned a linear response up to 387 times contemporary carbon-14 concentrations. Carbon-14 free and contemporary carbon-14 samples with varying carbon-13 concentrations were used to assess the method detection limit of approximately one-third contemporary carbon-14 levels. Sources of inaccuracies are presented and discussed, and the capability to measure carbon-14 in biological samples is demonstrated by comparing pharmacokinetics from carbon-14 dosed guinea pigs analyzed by both CRDS and accelerator mass spectrometry. The CRDS approach presented affords easy access to powerful carbon-14 tracer techniques that can characterize complex biochemical systems. PMID- 27458741 TI - Ribosomal DNA locus variation and REMAP analysis of the diploid and triploid complexes of Lilium lancifolium. AB - Lilium lancifolium Thunb. (2n = 2x = 24) is a cytologically conspicuous species with both diploids and triploids in nature. Cytological and molecular genetic analyses were carried out in both diploids and triploids that were collected from 55 geographical locations in Korea, Japan, and China. While the 5S rRNA gene loci were located at duplicated loci on the long arm of chromosome 2, the 45S rRNA gene loci were present in chromosomes 1, 2, 4, 6, 7, and 11. While the loci on chromosomes 1 and 7 were constant, the loci on chromosomes 2, 4, 6, 7, and 11 were variable in some plants so that the L. lancifolium accessions were grouped into 7 cytotypes in diploids and 12 cytotypes in triploids. REMAP marker analysis revealed that the diploids were classified into seven clusters, and the triploids were classified into a large cluster. Geographic, cytological, and genetic differentiations were not related in both the diploid and triploid accessions of L. lancifolium. Thus, current genetic variations occurred prior to the geographic differentiation in both diploids and triploids, and the 45S rDNA cytotype variations occurred after geographic differentiation in the current habitats of L. lancifolium. PMID- 27458742 TI - Treatment-resistant Schizophrenia and Global Cortical Atrophy in a Patient with Turner Syndrome. PMID- 27458743 TI - Electroconvulsive Therapy Induces Transient Sensitivity for a Serotonin Syndrome: A Case Report. AB - Introduction: Serotonin syndrome is a potentially life-threatening condition with delirium, vegetative and neuromuscular symptoms as well as neural hyperexcitability. The main causes are combinations of serotonergic drugs, excessive dosages of serotonergic agents or the recreational use of certain drugs. Methods and Results: We report a case of a patient who started developing serotonin syndrome after a cumulative dose of only 900 mg lithium carbonate given in temporal association with electroconvulsive therapy (ECT). The patient tolerated the serotonergic combination of escitalopram and lithium well a few weeks after ECT. Discussion: Generally, hypersensitivity to psychotropic medications during a course of ECT is rare and hypothetically attributed to a possible and reversible alteration of the blood brain barrier. Consecutively, drugs with assumed central nervous side effects should be started at low dosages and slow titration within the first two days after ECT because even low plasma concentrations may not be tolerated. Importantly and as in other cases, the liability appeared to be of transient nature. In cases of non-tolerance immediately after ECT, a re-exposure after several weeks seems justified. PMID- 27458745 TI - Mental Health Nursing. PMID- 27458744 TI - Young women's sexual involvement in emerging adulthood. AB - Using data from the Relationship Dynamics and Social Life Study, this study examined the association of peer, family, attitudinal, aspirational, and attainment factors relevant to 820 young women's (aged 18-19) number of sexual partners. Overall, this study found that perceived peer norms and early onset of sexual initiation had a positive and statistically significant association with the respondents' number of lifetime sexual partners. While high school performance and college aspirations were inversely associated with the number of lifetime partners, their current level of educational attainment was not. Finally, racial disparities in the accrual of partners were contingent upon the respondents' attitude to premarital abstinence and educationally related factors. Understanding risk and protective factors may help public health policy planners and health care professionals formulate a more effective ecologically based approach to mitigate sexual health risks and social repercussion related to dating for young women. PMID- 27458746 TI - The Control of Single-color and Multiple-color Visual Search by Attentional Templates in Working Memory and in Long-term Memory. AB - The question whether target selection in visual search can be effectively controlled by simultaneous attentional templates for multiple features is still under dispute. We investigated whether multiple-color attentional guidance is possible when target colors remain constant and can thus be represented in long term memory but not when they change frequently and have to be held in working memory. Participants searched for one, two, or three possible target colors that were specified by cue displays at the start of each trial. In constant-color blocks, the same colors remained task-relevant throughout. In variable-color blocks, target colors changed between trials. The contralateral delay activity (CDA) to cue displays increased in amplitude as a function of color memory load in variable-color blocks, which indicates that cued target colors were held in working memory. In constant-color blocks, the CDA was much smaller, suggesting that color representations were primarily stored in long-term memory. N2pc components to targets were measured as a marker of attentional target selection. Target N2pcs were attenuated and delayed during multiple-color search, demonstrating less efficient attentional deployment to color-defined target objects relative to single-color search. Importantly, these costs were the same in constant-color and variable-color blocks. These results demonstrate that attentional guidance by multiple-feature as compared with single-feature templates is less efficient both when target features remain constant and can be represented in long-term memory and when they change across trials and therefore have to be maintained in working memory. PMID- 27458747 TI - Proactive, but Not Reactive, Distractor Filtering Relies on Local Modulation of Alpha Oscillatory Activity. AB - Filter mechanisms that prevent irrelevant information from consuming the limited storage capacity of visual STM are critical for goal-directed behavior. Alpha oscillatory activity has been related to proactive filtering of anticipated distraction. Yet, distraction in everyday life is not always anticipated, necessitating rapid, reactive filtering mechanisms. Currently, the oscillatory mechanisms underlying reactive distractor filtering remain unclear. In the current EEG study, we investigated whether reactive filtering of distractors also relies on alpha-band oscillatory mechanisms and explored possible contributions by oscillations in other frequency bands. To this end, participants performed a lateralized change detection task in which a varying and unpredicted number of distractors were presented both in the relevant hemifield, among targets, and in the irrelevant hemifield. Results showed that, whereas proactive distractor filtering was accompanied by lateralization of alpha-band activity over posterior scalp regions, reactive distractor filtering was not associated with modulations of oscillatory power in any frequency band. Yet, behavioral and post hoc ERP analyses clearly showed that participants selectively encoded relevant information. On the basis of these results, we conclude that reactive distractor filtering may not be realized through local modulation of alpha-band oscillatory activity. PMID- 27458749 TI - Does Contralateral Delay Activity Reflect Working Memory Storage or the Current Focus of Spatial Attention within Visual Working Memory? AB - During the retention of visual information in working memory, event-related brain potentials show a sustained negativity over posterior visual regions contralateral to the side where memorized stimuli were presented. This contralateral delay activity (CDA) is generally believed to be a neural marker of working memory storage. In two experiments, we contrasted this storage account of the CDA with the alternative hypothesis that the CDA reflects the current focus of spatial attention on a subset of memorized items set up during the most recent encoding episode. We employed a sequential loading procedure where participants memorized four task-relevant items that were presented in two successive memory displays (M1 and M2). In both experiments, CDA components were initially elicited contralateral to task-relevant items in M1. Critically, the CDA switched polarity when M2 displays appeared on the opposite side. In line with the attentional activation account, these reversed CDA components exclusively reflected the number of items that were encoded from M2 displays, irrespective of how many M1 items were already held in working memory. On trials where M1 and M2 displays were presented on the same side and on trials where M2 displays appeared nonlaterally, CDA components elicited in the interval after M2 remained sensitive to a residual trace of M1 items, indicating that some activation of previously stored items was maintained across encoding episodes. These results challenge the hypothesis that CDA amplitudes directly reflect the total number of stored objects and suggest that the CDA is primarily sensitive to the activation of a subset of working memory representations within the current focus of spatial attention. PMID- 27458750 TI - Neural Entrainment in Drum Rhythms with Silent Breaks: Evidence from Steady-state Evoked and Event-related Potentials. AB - The fusion of rhythm, beat perception, and movement is often summarized under the term "entrainment" and becomes obvious when we effortlessly tap our feet or snap our fingers to the pulse of music. Entrainment to music involves a large network of brain structures, and neural oscillations at beat-related frequencies can help elucidate how this network is connected. Here, we used EEG to investigate steady state evoked potentials (SSEPs) and event-related potentials (ERPs) during listening and tapping to drum clips with different rhythmic structures that were interrupted by silent breaks of 2-6 sec. This design allowed us to address the question of whether neural entrainment processes persist after the physical presence of musical rhythms and to link neural oscillations and event-related neural responses. During stimulus presentation, SSEPs were elicited in both tasks (listening and tapping). During silent breaks, SSEPs were only present in the tapping task. Notably, the amplitude of the N1 ERP component was more negative after longer silent breaks, and both N1 and SSEP results indicate that neural entrainment was increased when listening to drum rhythms compared with an isochronous metronome. Taken together, this suggests that neural entrainment to music is not solely driven by the physical input but involves endogenous timing processes. Our findings break ground for a tighter linkage between steady-state and transient evoked neural responses in rhythm processing. Beyond music perception, they further support the crucial role of entrained oscillatory activity in shaping sensory, motor, and cognitive processes in general. PMID- 27458748 TI - Global Visual Motion Sensitivity: Associations with Parietal Area and Children's Mathematical Cognition. AB - Sensitivity to global visual motion has been proposed as a signature of brain development, related to the dorsal rather than ventral cortical stream. Thresholds for global motion have been found to be elevated more than for global static form in many developmental disorders, leading to the idea of "dorsal stream vulnerability." Here we explore the association of global motion thresholds with individual differences in children's brain development, in a group of typically developing 5- to 12-year-olds. Good performance was associated with a relative increase in parietal lobe surface area, most strongly around the intraparietal sulcus and decrease in occipital area. In line with the involvement of intraparietal sulcus, areas in visuospatial and numerical cognition, we also found that global motion performance was correlated with tests of visuomotor integration and numerical skills. Individual differences in global form detection showed none of these anatomical or cognitive correlations. This suggests that the correlations with motion sensitivity are unlikely to reflect general perceptual or attentional abilities required for both form and motion. We conclude that individual developmental variations in global motion processing are not linked to greater area in the extrastriate visual areas, which initially process such motion, but in the parietal systems that make decisions based on this information. The overlap with visuospatial and numerical abilities may indicate the anatomical substrate of the "dorsal stream vulnerability" proposed as characterizing neurodevelopmental disorders. PMID- 27458751 TI - Representational Account of Memory: Insights from Aging and Synesthesia. AB - The representational account of memory envisages perception and memory to be on a continuum rather than in discretely divided brain systems [Bussey, T. J., & Saksida, L. M. Memory, perception, and the ventral visual-perirhinal-hippocampal stream: Thinking outside of the boxes. Hippocampus, 17, 898-908, 2007]. We tested this account using a novel between-group design with young grapheme-color synesthetes, older adults, and young controls. We investigated how the disparate sensory-perceptual abilities between these groups translated into associative memory performance for visual stimuli that do not induce synesthesia. ROI analyses of the entire ventral visual stream showed that associative retrieval (a pair-associate retrieved in the absence of a visual stimulus) yielded enhanced activity in young and older adults' visual regions relative to synesthetes, whereas associative recognition (deciding whether a visual stimulus was the correct pair-associate) was characterized by enhanced activity in synesthetes' visual regions relative to older adults. Whole-brain analyses at associative retrieval revealed an effect of age in early visual cortex, with older adults showing enhanced activity relative to synesthetes and young adults. At associative recognition, the group effect was reversed: Synesthetes showed significantly enhanced activity relative to young and older adults in early visual regions. The inverted group effects observed between retrieval and recognition indicate that reduced sensitivity in visual cortex (as in aging) comes with increased activity during top-down retrieval and decreased activity during bottom-up recognition, whereas enhanced sensitivity (as in synesthesia) shows the opposite pattern. Our results provide novel evidence for the direct contribution of perceptual mechanisms to visual associative memory based on the examples of synesthesia and aging. PMID- 27458752 TI - A Causal Role for Primary Motor Cortex in Perception of Observed Actions. AB - It has been proposed that motor system activity during action observation may be modulated by the kinematics of observed actions. One purpose of this activity during action observation may be to predict the visual consequence of another person's action based on their movement kinematics. Here, we tested the hypothesis that the primary motor cortex (M1) may have a causal role in inferring information that is present in the kinematics of observed actions. Healthy participants completed an action perception task before and after applying continuous theta burst stimulation (cTBS) over left M1. A neurophysiological marker was used to quantify the extent of M1 disruption following cTBS and stratify our sample a priori to provide an internal control. We found that a disruption to M1 caused a reduction in an individual's sensitivity to interpret the kinematics of observed actions; the magnitude of suppression of motor excitability predicted this change in sensitivity. PMID- 27458753 TI - The Default Computation of Negated Meanings. AB - Negation is a fundamental component of human reasoning and language. Yet, current neurocognitive models, conceived to account for the cortical representation of meanings (e.g., writing), hardly accommodate the representation of negated meanings (not writing). One main hypothesis, known as the two-step model, proposes that, for negated meanings, the corresponding positive representation is first fully activated and then modified to reflect negation. Recast in neurobiological terms, this model predicts that, in the initial stage of semantic processing, the neural representation of a stimulus' meaning is indistinguishable from the neural representation of that meaning following negation. Although previous work has shown that pragmatic and task manipulations can favor or hinder a two-step processing, we just do not know how the brain processes an utterance as simple as "I am not writing." We implemented two methodologies based on chronometric TMS to measure motor excitability (Experiment 1) and inhibition (Experiment 2) as physiological markers of semantic access to action-related meanings. We used elementary sentences (Adverb + Verb) and a passive reading task. For the first time, we defined action word-related motor activity in terms of increased excitability and concurrently reduced inhibition. Moreover, we showed that this pattern changes already in the earliest stage of semantic processing, when action meanings were negated. Negation modifies the neural representation of the argument in its scope, as soon as semantic effects are observed in the brain. PMID- 27458754 TI - iTRAQ-Based Proteomics Revealed the Bactericidal Mechanism of Sodium New Houttuyfonate against Streptococcus pneumoniae. AB - Sodium new houttuyfonate (SNH), an addition product of active ingredient houttuynin from the plant Houttuynia cordata Thunb., inhibits a variety of bacteria, yet the mechanism by which it induces cell death has not been fully understood. In the present study, we utilized iTRAQ-based quantitative proteomics to analyze the protein alterations in Streptococcus pneumoniae in response to SNH treatment. Numerous proteins related to the production of reactive oxygen species (ROS) were found to be up-regulated by SNH, suggesting that ROS pathways may be involved as analyzed via bioinformatics. As reported recently, cellular reactions stimulated by ROS including superoxide anion (O2(*-)), hydrogen peroxide (H2O2), and hydroxyl radicals (OH(*)) have been implicated as mechanisms whereby bactericidal antibiotics kill bacteria. We then validated that SNH killed S. pneumoniae in a dose-dependent manner accompanied by the increasing level of H2O2. On the other hand, the addition of catalase, which can neutralize H2O2 in cells, showed a significant recovery in bacterial survival. These results indicate that SNH indeed induced H2O2 formation to contribute to the cell lethality, providing new insights into the bactericidal mechanism of SNH and expanding our understanding of the common mechanism of killing induced by bactericidal agents. PMID- 27458756 TI - Multifunctional Three-Dimensional Europium Metal-Organic Framework for Luminescence Sensing of Benzaldehyde and Cu(2+) and Selective Capture of Dye Molecules. AB - A multifunctional three-dimensional lanthanide metal-organic framework has been rationally constructed. Highly selective sensing of benzaldehyde and Cu(2+) ions makes it a potential bifunctional sensor. Also, it could serve as a good candidate material for the removal of dyes from effluents based on the size exclusion. PMID- 27458755 TI - Functional implication of Dclk1 and Dclk1-expressing cells in cancer. AB - Doublecortin like kinase protein 1 (Dclk1) is a microtubule-associated protein with C-terminal serine/threonine kinase domain. Originally designated Doublecortin and CaM kinase-like 1 protein (Dcamkl1) or KIAA0369, Dclk1 was first described as a marker for radial glia cells in the context of microtubule polymerization and neuronal migration, possibly contributing to early neurogenesis. Additionally, Dclk1 was proposed as a marker of quiescent gastrointestinal and pancreatic stem cells, but in recent years has been recognized as a marker for tuft cells in the gastrointestinal tract. While Dclk1+ tuft cells are now considered as niche or sensory cells in the normal gut, growing evidence supports a role for Dclk1 function in a variety of malignancies, modulating the activity of multiple key pathways, including Kras signaling. Here, we review the recent advances in understanding of the importance of Dclk1 function in tumorigenesis and cancer. PMID- 27458757 TI - Influence of static stretching on hamstring flexibility in healthy young adults: Systematic review and meta-analysis. AB - The aim of the current study was to investigate the influence of static stretching on hamstring flexibility in healthy young adults by means of systematic review and meta-analysis. The search strategy included MEDLINE, PEDro, Cochrane CENTRAL, EMBASE, LILACS, and manual search from inception to June 2015. Randomized and controlled clinical trials studies that have compared static stretching to control group, and evaluated range of motion (ROM), were included. On the other hand, studies that have worked with special population such as children, elderly people, athletes, and people with any dysfunction/disease were excluded, as well as articles that have used contralateral leg as control group or have not performed static stretching. The meta-analysis was divided according to three types of tests. Nineteen studies were included out of the 813 articles identified. In all tests, the results favored static stretching compared to control group: passive straight leg raise (12.04; 95% CI: 9.61 to 14.47), passive knee extension test (8.58; 95% CI: 6.31 to 10.84), and active knee extension test (8.35; 95% CI: 5.15 to 11.55). In conclusion, static stretching was effective in increasing hamstring flexibility in healthy young adults. PMID- 27458758 TI - Evaluation of the cytotoxic activity of Hypericum spp. on human glioblastoma A1235 and breast cancer MDA MB-231 cells. AB - Cytotoxic activity of 16 Hypericum ethanolic extracts was evaluated by MTT assay on two human cancer cell lines: glioblastoma A1235 and breast cancer MDA MB-231. Morphology and the type of induced cell death were determined using light and fluorescence microscopy. The majority of Hypericum extracts had no significant cytotoxic effect on MDA MB-231 cells. Eight extracts exhibited mild cytotoxic effect on A1235 cells after 24 h incubation, ranging from 8.0% (H. patulum) to 21.7% (H. oblongifolium). After 72 h of treatment, the strongest inhibition of A1235 viability was observed for extracts of H. androsaemum (26.4-43.9%), H. balearicum (25.8-36.3%), H. delphicum (14.8-27.4%) and H. densiflorum (11.2 24.1%). Micro-scopic examination of cells showed apoptosis as the dominant type of cell death. Due to observed high viability of treated cells, we propose that cytotoxic effects of Hypericum extracts could be related to alternations/interruptions in the cell cycle. PMID- 27458759 TI - Boswellic acid disables signal transduction of IL-6-STAT-3 in Ehrlich ascites tumor bearing irradiated mice. AB - Boswellic acid (BA) is known for its ability to trigger apoptosis as well as to inhibit angiogenesis in tumor tissue. In this study, we investigated the effect of BA on the IL-6-STAT-3 signalling pathway in irradiated mice bearing solid tumors of Ehrlich ascites carcinoma (EAC). For this, we administered BA (25 mg.(kg body mass)(-1).day(-1), by intraperitoneal injection) to mice with EAC, and then exposed them to 4 Gy of gamma radiation. Data analyses of the results revealed a specific impact from BA on IL-6R mRNA and survivin mRNA in EACs and irradiated EAC-bearing mice. Also, significant improvements were observed in the protein expression of JAK-1, P-JAK-1, STAT-3, P-STAT-3, and caspase-3, as well as VEGF and IL-6 levels. We propose that BA interfered with IL-6-STAT-3 signal transduction, thereby preventing the activation of caspase-3 and subsequently triggering the process of apoptosis. However, the alternative angiogenesis pathway, which includes the over-expression of VEGF and which depends on IL-6 STAT-3 signalling, was inhibited by the action of BA. Thus, we recommend that therapeutic strategies for cancer should include treatment with BA. PMID- 27458760 TI - Environment effect on spectral and charge distribution characteristics of some drugs of folate derivatives. AB - Molecular surrounding media as an important factor can effect on the operation of wide variety of drugs. For more study in this paper, spectral properties of Methotrexate and Folinic acid have been studied in various solvents. Our results show that the photo-physical of solute molecules depend strongly on solute solvent interactions and active groups in their chemical structures. In order to investigate the contribution of specific and nonspecific interactions on the various properties of drug molecules, the linear solvation energy relationships concept is used. Moreover, charge distribution characteristics of used samples with various resonance structures in solvent environments were calculated by means of solvatochromic method. The high value of dipole moments in excited state show that local intramolecular charge transfer can occur by excitation. These results about molecular interactions can be extended to biological systems and can indicate completely the behaviors of Methotrexate and Folinic acid in polar solvents such as water in body system. PMID- 27458761 TI - Cu(I) complexes of bis(methyl)(thia/selena) salen ligands: Synthesis, characterization, redox behavior and DNA binding studies. AB - Mononuclear cuprous complexes 1 and 2, [{CH3E(o-C6H4)CH=NCH2}2Cu]ClO4; E=S/Se, have been synthesized by the reaction of bis(methyl)(thia/selena) salen ligands and [Cu(CH3CN)4]ClO4. Both the products were characterized by elemental analysis, ESI-MS, FT-IR, 1H/13C/77Se NMR, and cyclic voltammetry. The complexes possess tetrahedral geometry around metal center with the N2S2/N2Se2 coordination core. Cyclic voltammograms of complexes 1 and 2 displayed reversible anodic waves at E1/2=+0.08V and +0.10V, respectively, corresponding to the Cu(I)/Cu(II) redox couple. DNA binding studies of both the complexes were performed applying absorbance, fluorescence and molecular docking techniques. Competitive binding experiment of complexes with ct-DNA against ethidium bromide is performed to predict the mode of binding. The results indicate the groove binding mode of complexes 1 and 2 to DNA. The binding constants revealed the strong binding affinity of complexes towards ct-DNA. PMID- 27458762 TI - Molecular characteristics of a fluorescent chemosensor for the recognition of ferric ion based on photoresponsive azobenzene derivative. AB - Metal ion recognition is of great significance in biological and environmental detection. So far, there is very few research related to the ferric ion sensing based on photoresponsive azobenzene derivatives. In this work, we report a highly selective fluorescent "turn-off" sensor for Fe3+ ions and the molecular sensing characteristics based on an azobenzene derivative, N-(3,4,5-octanoxyphenyl)-N'-4 [(4-hydroxyphenyl)azophenyl]1,3,4-oxadiazole (AOB-t8). The binding association constant was determined to be 6.07*103M-1 in ethanol and the stoichiometry ratio of 2:2 was obtained from Job's plot and MS spectra. The AOB-t8 might be likely to form the dimer structure through the chelation of ferric ion with the azobenzene moiety. Meanwhile, it was found that the photoisomerization property of AOB-t8 was regulated by the binding with Fe3+. With the chelation of Fe3+, the regulated molecular rigidity and the perturbed of electronic state and molecular geometry was suggested to be responsible for the accelerated isomerization of AOB-t8 to UV irradiation and the increased fluorescence lifetime of both trans- and cis-AOB-t8 Fe(III). Moreover, the reversible sensing of AOB-t8 was successfully observed by releasing the iron ion from AOB-t8-Fe(III) with the addition of citric acid. PMID- 27458774 TI - Optical anisotropy and sign reversal in layer-by-layer assembled films from chiral nanoparticles. AB - Chiral anisotropy and related optical effects at the nanoscale represent some of the most dynamic areas of nanomaterials today. Translation of optical activity of chiral semiconductor and metallic nanoparticles (NPs) into optoelectronic devices requires preparation of thin films from chiral NPs on both flat and curved surfaces. In this paper we demonstrate that chiral NP films can be made via layer by-layer assembly (LBL) using negatively charged chiral CdS NPs, stabilized by d- and l-cysteine and positively charged polyelectrolytes, as building blocks. LBL coatings from NPs combine simplicity of preparation and strong optical activity. Circular extinction measurements using circular dichroism instruments indicate that the film possess four chiroptical bands at 280, 320, 350, and 390 nm. The latter two bands at 390 and 350 nm are associated with the band gap transitions (chiral excitons), while the former two are attributed to transitions involving surface ligands. When NPs are assembled in LBL films, the rotatory activity and the sign for circular extinction associated with the electronic transition in the inorganic core of the NPs is conserved. However, this is not true for circular extinction bands at short wavelengths: the sign of the rotatory optical activity is reversed. This effect is attributed to the change of the conformation of surface ligands in the polyelectrolyte matrix, which was confirmed both by semi empirical and density functional (DFT) quantum mechanical calculations. Circular dichroism spectra calculated using a DFT algorithm closely match the experimental spectra of CdS NPs. These findings indicate that the spectroscopic methods sensitive to chirality of the surface ligands can be used to investigate fine structural changes in the surface layer of nanocolloids. Strong rotatory optical activity of nanostructured semiconductor films opens the possibilities for new polarization-based optical devices. PMID- 27458775 TI - Effect of ski boot rear stiffness (SBRS) on maximal ACL force during injury prone landing movements in alpine ski racing: A study with a musculoskeletal simulation model. AB - A common anterior cruciate ligament (ACL) injury situation in alpine ski racing is landing back-weighted after a jump. Simulated back-weighted landing situations showed higher ACL-injury risk for increasing ski boot rear stiffness (SBRS) without considering muscles. It is well known that muscle forces affect ACL tensile forces during landing. The purpose of this study is to investigate the effect of different SBRS on the maximal ACL tensile forces during injury prone landings considering muscle forces by a two-dimensional musculoskeletal simulation model. Injury prone situations for ACL-injuries were generated by the musculoskeletal simulation model using measured kinematics of a non-injury situation and the method of Monte Carlo simulation. Subsequently, the SBRS was varied for injury prone landings. The maximal ACL tensile forces and contributing factors to the ACL forces were compared for the different SBRS. In the injury prone landings the maximal ACL tensile forces increased with increasing SBRS. It was found that the higher maximal ACL force was caused by higher forces acting on the tibia by the boot and by higher quadriceps muscle forces both due to the higher SBRS. Practical experience suggested that the reduction of SBRS is not accepted by ski racers due to performance reasons. Thus, preventive measures may concentrate on the reduction of the quadriceps muscle force during impact. PMID- 27458777 TI - Synthetic drugs for the treatment of vitiligo: a patent review (2010-2015). AB - INTRODUCTION: Vitiligo is one of the most important acquired depigmentation disorders, with an average worldwide prevalence of 0.5-2.0%. The exact etiology of vitiligo is not fully understood, but the principle theories focus on the mechanism responsible for the destruction of melanocytes, which is proposed to be autoimmune, neurogenic, or self-destructive. There is no cure for vitiligo and the results of current treatments vary between individuals, being unsatisfactory in most cases. Despite being a cosmetic disease, the disorder can be psychologically devastating and stigmatizing. AREAS COVERED: In this review, the authors summarize new synthetic drugs for the treatment of vitiligo developed between 2010 and 2015, which include MC1 R agonists and peptides, as well as considering new approaches and strategies using existing drugs. EXPERT OPINION: In conclusion, we found significant advancement in this field of research, demonstrating the growing interest of academic and industrial groups in developing successful products for the treatment of vitiligo. New therapeutic options could contribute to improving the quality of life of patients and advance the search for a truly effective treatment of vitiligo. PMID- 27458778 TI - Scope and Mechanism of Cooperativity at the Intersection of Organometallic and Supramolecular Catalysis. AB - The scope and mechanism of the microenvironment-catalyzed C(sp(3))-C(sp(3)) reductive elimination from transition metal complexes [Au(III), Pt(IV)] is explored. Experiments detailing the effect of structural perturbation of neutral and anionic spectator ligands, reactive alkyl ligands, solvent, and catalyst structure are disclosed. Indirect evidence for a coordinatively unsaturated encapsulated cationic intermediate is garnered via observation of several inactive donor-arrested inclusion complexes, including a crystallographically characterized encapsulated Au(III) cation. Finally, based on stoichiometric experiments under catalytically relevant conditions, a detailed mechanism is outlined for the dual supramolecular and platinum-catalyzed C-C coupling between methyl iodide and tetramethyltin. Determination of major platinum species present under catalytic conditions and subsequent investigation of their chemistry reveals an unexpected interplay between cis-trans isomerism and the supramolecular catalyst in a Pt(II)/Pt(IV) cycle, as well as several off-cycle reactions. PMID- 27458780 TI - Acquisition and consolidation of novel morphology in human neocortex: A neuromagnetic study. AB - Research into neurobiological mechanisms of morphosyntactic processing of language has suggested specialised systems for decomposition and storage, which are used flexibly during the processing of complex polymorphemic words (such as those formed through affixation, e.g., boy + s = noun + plural marker or boy + ish = noun plus attenuator). However, neural underpinnings of acquisition of novel morphology are still unknown. We implicitly trained our participants with new derivational affixes through a word-picture association task and investigated the neural processes underlying formation of neural memory traces for new affixes. The participants' brain activity was recorded using magnetoencephalography (MEG), as they passively listened to the newly trained and untrained suffixes combined with real word and pseudoword stems. The MEG recording was repeated after a night's sleep using the same stimuli, to test the effects of overnight consolidation. The newly trained suffixes combined with real stems elicited stronger source activity in the left inferior frontal gyrus (LIFG) at ~50 msec after the suffix onset than untrained suffixes, suggesting memory trace formation for the newly learned suffixes already on the same day. The following day, the suffix learning effect spread to the left superior temporal gyrus (STG) where it was again manifest as a response enhancement, particularly at ~200-300 msec after the suffix onset, which might reflect an additional effect of overnight consolidation. Overall, the results demonstrate the rapid and dynamic processes of both immediate build-up and longer-term consolidation of neocortical memory traces for novel morphology, taking place after a short period of exposure to novel morphology and involving fronto-temporal perisylvian language circuitry. PMID- 27458779 TI - Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data. AB - BACKGROUND: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. OBJECTIVE: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. METHODS: From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). RESULTS: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and >= 20%, respectively (88 statistics, five studies). CONCLUSION: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta regression of published data. Environ Health Perspect 125:296-305; http://dx.doi.org/10.1289/EHP426. PMID- 27458781 TI - Cell-penetrating self-nanoemulsifying drug delivery systems (SNEDDS) for oral gene delivery. AB - OBJECTIVE: The aim of study was to investigate whether cell-penetrating peptides could amplify cellular uptake of plasmid DNA (pDNA) loaded self-nanoemulsifying drug delivery systems (SNEDDS) by mucosal epithelial cells, thereby enhancing transfection efficiency. METHODS: HIV-1 Tat peptide-oleoyl conjugate (TAT-OL) was synthesized through amide bond formation between HIV-1 Tat-protein 49-57 (TAT) and oleoyl-chloride (OL). SNEDDS formulation contained 29.7% each of Cremophor EL, Capmul MCM and Crodamol, 9.9% propylene glycol and 1% TAT-OL. SNEDDS with OL instead of TAT-OL served as control. RESULTS: Fluorescent-microscopy demonstrated 0.5% (m/v) nanoemulsions were suitable for subsequent studies. Mucus diffusion of nanoemulsion loaded with fluorescein diacetate (FDA) was 1.5-fold increased by incorporation of TAT-OL. Confocal microscopy confirmed that droplets of nanoemulsions were successfully internalized. Furthermore, quantitative analysis showed that addition of TAT-OL increases uptake of nanoemulsions by 2.3- and 2.6 folds after 2 and 4 hours of incubation, respectively. Cellular internalization pathways were found with substantial decrease in uptake in presence of indomethacin and chlorpromazine. Transfection efficiency investigated on HEK-293 cells was found to be 1.7- and 1.8-fold higher for SNEDDS loaded with TAT-OL compared to Lipofectin and control, respectively. CONCLUSION: In comparison to prevailing lipid and polymer-based delivery systems, these novel cell-penetrating SNEDDS likely represent most effective, simplistic and expedite dosage form for mucosal gene delivery. PMID- 27458782 TI - Capture and Reversible Storage of Volatile Iodine by Novel Conjugated Microporous Polymers Containing Thiophene Units. AB - Conjugated microporous polymers having thiophene building blocks (SCMPs), which originated from ethynylbenzene monomers with 2,3,5-tribromothiophene, were designedly synthesized through Pd(0)/CuI catalyzed Sonogashira-Hagihara cross coupling polymerization. The morphologies, structure and physicochemical properties of the as-synthesized products were characterized through scanning electron microscope (SEM), thermogravimeter analysis (TGA), (13)C CP/MAS solid state NMR and Fourier transform infrared spectroscope (FTIR) spectra. Nitrogen sorption-desorption analysis shows that the as-synthesized SCMPs possesses a high specific surface area of 855 m(2) g(-1). Because of their abundant porosity, pi conjugated network structure, as well as electron-rich thiophene building units, the SCMPs show better adsorption ability for iodine and a high uptake value of 222 wt % was obtained, which can compete with those nanoporous materials such as silver-containing zeolite, metal-organic frameworks (MOFs) and conjugated microporous polymers (CMPs), etc. Our study might provide a new possibility for the design and synthesis of functional CMPs containing electron-rich building units for effective capture and reversible storage of volatile iodine to address environmental issues. PMID- 27458783 TI - Cantharimide and Its Derivatives from the Blister Beetle Mylabris phalerata Palla. AB - Eleven new monoterpenoids including three 1-methyl cantharimide-type derivatives (1-3), five 1,2-dimethyl cantharimide-type derivatives (4, 5, 7-9), and three 1 hydroxymethyl-2-methyl cantharimide-type derivatives (10-12), together with seven known cantharimides (6, 13-18), were isolated from Mylabis phalerata Palla. The planar structures and absolute configurations of compounds 1-14 were fully elucidated on the basis of spectroscopic analysis, ECD spectra, single-crystal X ray diffraction analysis, and chemical methods. Compounds 6, 15, 16, and 18 were found to be potent inhibitors of HBV virus, with IC50 values of 62, 42, 58, and 19 MUM. PMID- 27458784 TI - Adaptive thermostability of light-harvesting complexes in marine picocyanobacteria. AB - Marine Synechococcus play a key role in global oceanic primary productivity. Their wide latitudinal distribution has been attributed to the occurrence of lineages adapted to distinct thermal niches, but the physiological and molecular bases of this ecotypic differentiation remain largely unknown. By comparing six strains isolated from different latitudes, we showed that the thermostability of their light-harvesting complexes, called phycobilisomes (PBS), varied according to the average sea surface temperature at strain isolation site. Comparative analyses of thermal unfolding curves of the three phycobiliproteins (PBP) constituting PBS rods suggested that the differences in thermostability observed on whole PBSs relied on the distinct molecular flexibility and stability of their individual components. Phycocyanin was the least thermostable of all rod PBP, constituting a fragility point of the PBS under heat stress. Amino-acid composition analyses and structural homology modeling notably revealed the occurrence of two amino-acid substitutions, which might have a role in the observed differential thermotolerance of this phycobiliprotein among temperature ecotypes. We hypothesize that marine Synechococcus ancestors occurred first in warm niches and that during the colonization of cold, high latitude thermal niches, their descendants have increased the molecular flexibility of PBP to maintain optimal light absorption capacities, this phenomenon likely resulting in a decreased stability of these proteins. This apparent thermoadaptability of marine Synechococcus has most probably contributed to the remarkable ubiquity of these picocyanobacteria in the ocean. PMID- 27458786 TI - Synthesis of Cyclic Azomethine Imines by Cycloaddition Reactions of N-Isocyanates and N-Isothiocyanates. AB - Various nitrogen-substituted iso(thio)cyanates engage in [3 + 2]-cycloaddition reactions to form azomethine imines containing triazolone, triazole-thione, and pyrazole-thione cores. First, iminoisothiocyanates are shown to undergo aminothiocarbonylation reactions with strained alkenes, and a comparison with recently reported reactions of iminoisocyanates highlights their reduced reactivity. In contrast, amino(thio)carbonylation reactions of imines with iminoisocyanates and iminoisothiocyanates proved more efficient, providing access to triazolone and triazole-thione cores. The dipole products can be converted to valuable heterocyclic cores through simple derivatization reactions. PMID- 27458785 TI - The antibiotic resistome of swine manure is significantly altered by association with the Musca domestica larvae gut microbiome. AB - The overuse of antibiotics as veterinary feed additives is potentially contributing to a significant reservoir of antibiotic resistance in agricultural farmlands via the application of antibiotic-contaminated manure. Vermicomposting of swine manure using housefly larvae is a promising biotechnology for waste reduction and control of antibiotic pollution. To determine how vermicomposting influences antibiotic resistance traits in swine manure, we explored the resistome and associated bacterial community dynamics during larvae gut transit over 6 days of treatment. In total, 94 out of 158 antibiotic resistance genes (ARGs) were significantly attenuated (by 85%), while 23 were significantly enriched (3.9-fold) following vermicomposting. The manure-borne bacterial community showed a decrease in the relative abundance of Bacteroidetes, and an increase in Proteobacteria, specifically Ignatzschineria, following gut transit. ARG attenuation was significantly correlated with changes in microbial community succession, especially reduction in Clostridiales and Bacteroidales. Six genomes were assembled from the manure, vermicompost (final product) and gut samples, including Pseudomonas, Providencia, Enterococcus, Bacteroides and Alcanivorax. Transposon-linked ARGs were more abundant in gut-associated bacteria compared with those from manure and vermicompost. Further, ARG-transposon gene cassettes had a high degree of synteny between metagenomic assemblies from gut and vermicompost samples, highlighting the significant contribution of gut microbiota through horizontal gene transfer to the resistome of vermicompost. In conclusion, the larvae gut microbiome significantly influences manure-borne community succession and the antibiotic resistome during animal manure processing. PMID- 27458787 TI - Cancer-associated chromosomal deletions: Size makes a difference. PMID- 27458788 TI - Creation of cell micropatterns using a newly developed gel micromachining technique. AB - Creation of cell micropatterns comprising heterogeneous cell populations is an important technique for tissue engineering, medical transplantation, drug discovery, and regenerative medicine. This paper presents a novel gel patterning technique similar to general micromachining for creating cell micropatterns using alginate gel to inhibit cell adhesion. The alginate thin-film micropattern was formed on a glass plate by photolithography and wet etching. Cell micropatterns were subsequently created along the alginate micropattern on the glass plate. This technique permits the creation of cell micropatterns with arbitrary geometry because hydrogel materials promoting or inhibiting cell adhesion can be patterned precisely. Moreover, this technique permits processing of the culture surface during cultivation because none of the materials used such as hydrogels and hydrogel-etching solutions exhibit cytotoxicity. A cell micropattern comprising different cell types was successfully created using the presented technique. This technique will be conducive to further improvement of the fabrication of artificial tissues formed by heterogeneous cells. PMID- 27458789 TI - The Synergic Effect of Atomic Hydrogen Adsorption and Catalyst Spreading on Ge Nanowire Growth Orientation and Kinking. AB - Hydride precursors are commonly used for semiconductor nanowire growth from the vapor phase and hydrogen is quite often used as a carrier gas. Here, we used in situ scanning electron microscopy and spatially resolved Auger spectroscopy to reveal the essential role of atomic hydrogen in determining the growth direction of Ge nanowires with an Au catalyst. With hydrogen passivating nanowire sidewalls the formation of inclined facets is suppressed, which stabilizes the growth in the ?111? direction. By contrast, without hydrogen gold diffuses out of the catalyst and decorates the nanowire sidewalls, which strongly affects the surface free energy of the system and results in the ?110? oriented growth. The experiments with intentional nanowire kinking reveal the existence of an energetic barrier, which originates from the kinetic force needed to drive the droplet out of its optimum configuration on top of a nanowire. Our results stress the role of the catalyst material and surface chemistry in determining the nanowire growth direction and provide additional insights into a kinking mechanism, thus allowing to inhibit or to intentionally initiate spontaneous kinking. PMID- 27458790 TI - All-Dielectric Colored Metasurfaces with Silicon Mie Resonators. AB - The photonic resonances hosted by nanostructures provide vivid colors that can be used as color filters instead of organic colors and pigments in photodetectors and printing technology. Metallic nanostructures have been widely studied due to their ability to sustain surface plasmons that resonantly interact with light. Most of the metallic nanoparticles behave as point-like electric multipoles. However, the needs of an another degree of freedom to tune the color of the photonic nanostructure together with the use of a reliable and cost-effective material are growing. Here, we report a technique to imprint colored images based on silicon nanoparticles that host low-order electric and magnetic Mie resonances. The interplay between the electric and magnetic resonances leads to a large palette of colors. This all-dielectric fabrication technique offers the advantage to use cost-effective, reliable, and sustainable materials to provide vivid color spanning the whole visible spectrum. The interest and potential of this all-dielectric printing technique are highlighted by reproducing at a micrometer scale a Mondrian painting. PMID- 27458791 TI - Dipolar Self-Assembling in Mixtures of Propylene Carbonate and Dimethyl Sulfoxide as Revealed by the Orientational Entropy. AB - This article presents the results of static dielectric studies performed on mixtures of two strongly polar liquids important from a technological point of view: propylene carbonate (PC) and dimethyl sulfoxide (DMSO). The dielectric data were analyzed in terms of the molar orientational entropy increment induced by the probing electric field. It was found that the two polar liquids in the neat state reveal quite different molecular organization in terms of dipole-dipole self-assembling: PC exhibits a dipolar coupling of the head-to-tail type, whereas in DMSO one observes extreme restriction of dipolar association in any form. In PC + DMSO mixtures, the disintegration of the dipolar ensembles of PC molecules takes place and the progress of that process is strictly proportional to the concentration of DMSO. The static permittivity of mixtures of such differently self-organized liquids exhibits a positive deviation from the additive rule and the deviation develops symmetrically within the concentration scale. PMID- 27458792 TI - Donor Graft MicroRNAs: A Newly Identified Player in the Development of New-onset Diabetes After Liver Transplantation. AB - New-onset diabetes after liver transplantation (NODALT) is a frequent complication with an unfavorable outcome. We previously demonstrated a crucial link between donor graft genetics and the risk of NODALT. We selected 15 matched pairs of NODALT and non-NODALT liver recipients using propensity score matching analysis. The donor liver tissues were tested for the expression of 10 microRNAs (miRNAs) regulating human hepatic glucose homeostasis. The biological functions of potential target genes were predicted using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Both miR-103 and miR-181a were significantly highly expressed in the NODALT group as compared to the non-NODALT group. The predicted target genes (e.g. Irs2, Pik3r1, Akt2, and Gsk3b) were involved in glucose import and the insulin signaling pathway. We also observed dysregulation of miRNAs (e.g. let-7, miR-26b, miR-145, and miR-183) in cultured human hepatocytes treated with tacrolimus or high glucose, the two independent risk factors of NODALT identified in this cohort. The hepatic miRNA profiles altered by tacrolimus or hyperglycemia were associated with insulin resistance and glucose homeostatic imbalance as revealed by enrichment analysis. The disease susceptibility miRNA expressive pattern could be imported directly from the donor and consolidated by the transplant factors. PMID- 27458795 TI - Upper airway viruses and bacteria and clinical outcomes in children with cough. AB - BACKGROUND: Cough is symptomatic of a broad range of acute and chronic pediatric respiratory illnesses. No studies in children have tested for an extended panel of upper airway respiratory viruses and bacteria to identify whether they predict cough outcomes, irrespective of clinical diagnosis at the time of acute respiratory illness (ARI). We therefore determined whether upper airway microbes independently predicted hospitalization and persistent cough 28-days later in children presenting with an ARI, including cough as a symptom. METHODS: A cohort study of children aged <15-years were followed for 28-days after presenting to a pediatric emergency department with an ARI where cough was also a symptom. Socio demographic factors, presenting clinical features and a bilateral anterior nasal swab were collected at enrolment. Polymerase chain reaction assays tested for seven respiratory bacteria and 17 viruses. Predictors of hospitalization and persistent cough at day-28 were evaluated in logistic regression models. RESULTS: Eight hundred and seventeen children were included in the analysis; median age 27.7-months. 116 (14.2%, 95%CI 11.8, 16.6) children were hospitalized and 163 (20.0%, 95%CI 17.2, 22.7) had persistent cough at day-28. Hospitalized children were more likely to have RSV A or B detected on nasal swab than those not admitted (adjusted relative risk (aRR) 1.8, 95%CI 1.0, 3.3). M. catarrhalis was the only microbial difference between children with and without cough persistence (aRR for those with cough at day 28: 2.1, 95%CI 1.3, 3.1). DISCUSSION: An etiologic role for M. catarrhalis in the pathogenesis of persistent cough post ARI is worth exploring, especially given the burden of chronic cough in children and its relationship with chronic lung disease. Pediatr Pulmonol. 2017;52:373 381. (c) 2016 Wiley Periodicals, Inc. PMID- 27458796 TI - Object vision to hand action in macaque parietal, premotor, and motor cortices. AB - Grasping requires translating object geometries into appropriate hand shapes. How the brain computes these transformations is currently unclear. We investigated three key areas of the macaque cortical grasping circuit with microelectrode arrays and found cooperative but anatomically separated visual and motor processes. The parietal area AIP operated primarily in a visual mode. Its neuronal population revealed a specialization for shape processing, even for abstract geometries, and processed object features ultimately important for grasping. Premotor area F5 acted as a hub that shared the visual coding of AIP only temporarily and switched to highly dominant motor signals towards movement planning and execution. We visualize these non-discrete premotor signals that drive the primary motor cortex M1 to reflect the movement of the grasping hand. Our results reveal visual and motor features encoded in the grasping circuit and their communication to achieve transformation for grasping. PMID- 27458797 TI - A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. AB - Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons. PMID- 27458799 TI - A filter at the entrance of the Golgi that selects vesicles according to size and bulk lipid composition. AB - When small phosphatidylcholine liposomes are added to perforated cells, they bind preferentially to the Golgi suggesting an exceptional avidity of this organelle for curved membranes without stereospecific interactions. We show that the cis golgin GMAP-210 accounts for this property. First, the liposome tethering properties of the Golgi resembles that of the amphipathic lipid-packing sensor (ALPS) motif of GMAP-210: both preferred small (radius < 40 nm) liposomes made of monounsaturated but not saturated lipids. Second, reducing GMAP-210 levels or redirecting its ALPS motif to mitochondria decreased liposome capture by the Golgi. Extensive mutagenesis analysis suggests that GMAP-210 tethers authentic transport vesicles via the same mechanism whereby the ALPS motif senses lipid packing defects at the vesicle surface through its regularly spaced hydrophobic residues. We conclude that the Golgi uses GMAP-210 as a filter to select transport vesicles according to their size and bulk lipid composition. PMID- 27458800 TI - Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. AB - Newly born cells either continue to proliferate or exit the cell division cycle. This decision involves delaying expression of Cyclin E that promotes DNA replication. ORC1, the Origin Recognition Complex (ORC) large subunit, is inherited into newly born cells after it binds to condensing chromosomes during the preceding mitosis. We demonstrate that ORC1 represses Cyclin E gene (CCNE1) transcription, an E2F1 activated gene that is also repressed by the Retinoblastoma (RB) protein. ORC1 binds to RB, the histone methyltransferase SUV39H1 and to its repressive histone H3K9me3 mark. ORC1 cooperates with SUV39H1 and RB protein to repress E2F1-dependent CCNE1 transcription. In contrast, the ORC1-related replication protein CDC6 binds Cyclin E-CDK2 kinase and in a feedback loop removes RB from ORC1, thereby hyper-activating CCNE1 transcription. The opposing effects of ORC1 and CDC6 in controlling the level of Cyclin E ensures genome stability and a mechanism for linking directly DNA replication and cell division commitment. PMID- 27458801 TI - Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress induced NF-kappaB activation. AB - Nuclear factor kappa B (NF-kappaB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a 'nuclear-to-cytoplasmic' NF-kappaB activation signaling pathway; however, the early nuclear signaling cascade linking DNA damage and NF-kappaB activation is poorly understood. Here we report that Src-associated-substrate-during-mitosis-of 68kDa/KH domain containing, RNA binding, signal transduction associated 1 (Sam68/KHDRBS1) is a key NF-kappaB regulator in genotoxic stress-initiated signaling pathway. Sam68 deficiency abolishes DNA damage-stimulated polymers of ADP-ribose (PAR) production and the PAR-dependent NF-kappaB transactivation of anti-apoptotic genes. Sam68 deleted cells are hypersensitive to genotoxicity caused by DNA damaging agents. Upregulated Sam68 coincides with elevated PAR production and NF-kappaB-mediated anti-apoptotic transcription in human and mouse colon cancer. Knockdown of Sam68 sensitizes human colon cancer cells to genotoxic stress-induced apoptosis and genetic deletion of Sam68 dampens colon tumor burden in mice. Together our data reveal a novel function of Sam68 in the genotoxic stress-initiated nuclear signaling, which is crucial for colon tumorigenesis. PMID- 27458804 TI - Retraction: Drug-Eluting Stents for Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials. PMID- 27458803 TI - Multiplexed coding by cerebellar Purkinje neurons. AB - Purkinje cells (PC), the sole output neurons of the cerebellar cortex, encode sensorimotor information, but how they do it remains a matter of debate. Here we show that PCs use a multiplexed spike code. Synchrony/spike time and firing rate encode different information in behaving monkeys during saccadic eye motion tasks. Using the local field potential (LFP) as a probe of local network activity, we found that infrequent pause spikes, which initiated or terminated intermittent pauses in simple spike trains, provide a temporally reliable signal for eye motion onset, with strong phase-coupling to the beta/gamma band LFP. Concurrently, regularly firing, non-pause spikes were weakly correlated with the LFP, but were crucial to linear encoding of eye movement kinematics by firing rate. Therefore, PC spike trains can simultaneously convey information necessary to achieve precision in both timing and continuous control of motion. PMID- 27458802 TI - Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. AB - Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2(tm1.1Bird/y)). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (>=P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1(CreER);Mecp2(fl/y)or Cx3cr1(Cr)(eER); Mecp2(LSL/y)) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types. PMID- 27458805 TI - Prognostic Value of Pleural Lavage Cytology in Patients with Lung Cancer Resection: An Updated Meta-Analysis. AB - OBJECTIVE: Pleural lavage cytology (PLC) is considered as a possible tool for assessing prognosis of lung cancer patients. We aimed to comprehensively review the prognosis value of PLC in patients undergoing surgical resection. METHODS: We searched 4 electronic databases for relevant studies comparing positive PLC and negative PLC. The primary outcomes included survival rate and recurrence rate at maximum follow-up. RESULTS: The meta-analysis included 28 studies, with a total of 20,714 patients. For the overall survival rate of all stages, the results demonstrated that positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: hazard ratio (HR) 2.89 (95% confidence interval [CI] 2.48-3.37), 2.70 (1.90-3.83), and 2.89 (2.52-3.31), respectively. For the stage I survival rate, the combined results also suggested that positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: HR 3.29 (95% CI 2.55-4.25), 4.85 (2.31-10.20), and 3.16 (2.53-3.94), respectively. Furthermore, a meta-analysis of 14 studies included 14,279 patients showed that positive pre-resection, post-resection and pooled PLC were associated with an increased risk of overall recurrence: risk ratio (RR) 2.45 (95% CI 1.91 3.15), 2.37 (1.11-5.09), and 2.37 (95% CI 2.00-2.80), respectively. Positive PLC was also associated with a high pleural recurrence (RR 4.77; 95% CI 3.13-7.26) or distant recurrence (RR 2.33; 95% CI 1.65-3.29). CONCLUSIONS: Both positive pre- resection and post-resection PLC are associated with not only higher tumor recurrence but also unfavorable survival outcomes in patients with lung cancer resection. This technique can therefore act as a strong prognostic factor for tumor recurrence and adverse survival rates. PMID- 27458806 TI - Dual Role of a Biosynthetic Enzyme, CysK, in Contact Dependent Growth Inhibition in Bacteria. AB - Contact dependent growth inhibition (CDI) is the phenomenon where CDI+ bacterial strain (inhibitor) inhibits the growth of CDI-strain (target) by direct cell to cell contact. CDI is mediated by cdiBAI gene cluster where CdiB facilitates the export of CdiA, an exotoxin, on the cell surface and CdiI acts as an immunity protein to protect CDI+ cells from autoinhibition. CdiA-CT, the C-terminal region of the toxin CdiA, from uropathogenic Escherichia coli strain 536 (UPEC536) is a latent tRNase that requires binding of a biosynthetic enzyme CysK (O-acetylserine sulfyhydrylase) for activation in the target cells. CdiA-CT can also interact simultaneously with CysK and immunity protein, CdiI, to form a ternary complex in UPEC536. But the role of CysK in the ternary complex is not clear. We studied the hydrodynamic, thermodynamic and kinetic parameters of binary and ternary complexes using AUC, ITC and SPR respectively, to investigate the role of CysK in UPEC536. We report that CdiA-CT binds CdiI and CysK with nanomolar range affinity. We further report that binding of CysK to CdiA-CT improves its affinity towards CdiI by ~40 fold resulting in the formation of a more stable complex with over ~130 fold decrease in dissociation rate. Thermal melting experiments also suggest the role of CysK in stabilizing CdiA-CT/CdiI complex as Tm of the binary complex shifts ~10 degrees C upon binding CysK. Hence, CysK acts a modulator of CdiA-CT/CdiI interactions by stabilizing CdiA-CT/CdiI complex and may play a crucial role in preventing autoinhibition in UPEC536. This study reports a new moonlighting function of a biosynthetic enzyme, CysK, as a modulator of toxin/immunity interactions in UPEC536 inhibitor cells. PMID- 27458807 TI - Setting the Stage for Notch: The Drosophila Su(H)-Hairless Repressor Complex. AB - Notch signaling is iteratively used throughout development to maintain stem cell potential or in other instances allow differentiation. The central transcription factor in Notch signaling is CBF-1/RBP-J, Su(H), Lag-1 (CSL)-Su(H) in Drosophila which functions as a molecular switch between transcriptional activation and repression. Su(H) represses transcription by forming a complex with the corepressor Hairless (H). The Su(H)-repressor complex not only competes with the Notch intracellular domain (NICD) but also configures the local chromatin landscape. In this issue, Yuan and colleagues determined the structure of the Su(H)/H complex, showing that a major conformational change within Su(H) explains why the binding of NICD and H is mutually exclusive. PMID- 27458808 TI - An Exploration of Social Functioning in Young People with Eating Disorders: A Qualitative Study. AB - Previous research indicates adults with eating disorders (EDs) report smaller social networks, and difficulties with social functioning, alongside demonstrating difficulties recognising and regulating emotions in social contexts. Concurrently, those recovered from the illness have discussed the vital role offered by social support and interaction in their recovery. To date, little is known about the social skills and social networks of adolescents with EDs and this study aimed to conduct focus groups to explore the social functioning of 17 inpatients aged 12-17. Data were analysed using thematic analysis and six core themes were identified: group belonging, self-monitoring, social sensitivity, impact of hospitalisation, limited coping strategies and strategies for service provision. Key areas for service provision were: management of anxiety, development and/or maintenance of a social network and development of inter and intrapersonal skills. The most salient finding was that adolescents with EDs reported social difficulties which appeared to persist over and above those typically experienced at this point in the lifespan and therefore a key area for future focus is the development of appropriate coping strategies and solutions to deal with these reported difficulties. PMID- 27458809 TI - Supported Telemonitoring and Glycemic Control in People with Type 2 Diabetes: The Telescot Diabetes Pragmatic Multicenter Randomized Controlled Trial. AB - BACKGROUND: Self-monitoring of blood glucose among people with type 2 diabetes not treated with insulin does not appear to be effective in improving glycemic control. We investigated whether health professional review of telemetrically transmitted self-monitored glucose results in improved glycemic control in people with poorly controlled type 2 diabetes. METHODS AND FINDINGS: We performed a randomized, parallel, investigator-blind controlled trial with centralized randomization in family practices in four regions of the United Kingdom among 321 people with type 2 diabetes and glycated hemoglobin (HbA1c) >58 mmol/mol. The supported telemonitoring intervention involved self-measurement and transmission to a secure website of twice-weekly morning and evening glucose for review by family practice clinicians who were not blinded to allocation group. The control group received usual care, with at least annual review and more frequent reviews for people with poor glycemic or blood pressure control. HbA1c assessed at 9 mo was the primary outcome. Intention-to-treat analyses were performed. 160 people were randomized to the intervention group and 161 to the usual care group between June 6, 2011, and July 19, 2013. HbA1c data at follow-up were available for 146 people in the intervention group and 139 people in the control group. The mean (SD) HbA1c at follow-up was 63.0 (15.5) mmol/mol in the intervention group and 67.8 (14.7) mmol/mol in the usual care group. For primary analysis, adjusted mean HbA1c was 5.60 mmol/mol / 0.51% lower (95% CI 2.38 to 8.81 mmol/mol/ 95% CI 0.22% to 0.81%, p = 0.0007). For secondary analyses, adjusted mean ambulatory systolic blood pressure was 3.06 mmHg lower (95% CI 0.56-5.56 mmHg, p = 0.017) and mean ambulatory diastolic blood pressure was 2.17 mmHg lower (95% CI 0.62-3.72, p = 0.006) among people in the intervention group when compared with usual care after adjustment for baseline differences and minimization strata. No significant differences were identified between groups in weight, treatment pattern, adherence to medication, or quality of life in secondary analyses. There were few adverse events and these were equally distributed between the intervention and control groups. In secondary analysis, there was a greater number of telephone calls between practice nurses and patients in the intervention compared with control group (rate ratio 7.50 (95% CI 4.45-12.65, p < 0.0001) but no other significant differences between groups in use of health services were identified between groups. Key limitations include potential lack of representativeness of trial participants, inability to blind participants and health professionals, and uncertainty about the mechanism, the duration of the effect, and the optimal length of the intervention. CONCLUSIONS: Supported telemonitoring resulted in clinically important improvements in control of glycaemia in patients with type 2 diabetes in family practice. Current Controlled Trials, registration number ISRCTN71674628. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 71674628. PMID- 27458811 TI - Human Papillomavirus Vaccine Uptake in Adolescent Boys: An Evidence Review. AB - BACKGROUND: Despite evidence-based guidelines recommending routine vaccination against human papillomavirus (HPV) for adolescent boys, ages 11-12 years, vaccine uptake among this population remains low. AIMS: To examine reasons for low HPV quadrivalent vaccine uptake and methods available to increase vaccine uptake among adolescent males, ages 11-12 years. METHODS AND RESULTS: Of 341 identified studies, 30 were included from three databases. The 30 studies were grouped into six categories: population-specific, problem-specific, educational interventions, theory-specific, political implications, and foundational guidelines and Websites. DISCUSSION: Among eight studies, low vaccine uptake was attributed to lack of parental, adolescent, and physician knowledge of HPV4 vaccine availability and recommendations. HPV4 vaccine educational interventions for parents and adolescents were the most effective for promoting vaccine uptake. Theory applications and gain-framed messages were shown to be effective for assessing HPV vaccine attitudes and perceptions. Political implication studies reveal the need for political and financial measures to encourage HPV vaccine acceptability among the population. IMPLICATIONS FOR CLINICIANS: To promote HPV vaccine uptake among adolescent males, providers must remain current with HPV vaccine recommendations and offer parental and adolescent HPV education focusing on benefits of vaccine acceptance and risks of vaccine refusal. LINKING EVIDENCE TO ACTION: The results of this review inform our understanding of effective educational strategies to positively impact HPV vaccine uptake in adolescent males. Based on this review, clinicians can employ several evidence-based educational strategies to facilitate HPV vaccine uptake. PMID- 27458810 TI - Human Cytomegalovirus DNA Quantification and Gene Expression in Gliomas of Different Grades. AB - Gliomas are the most common type of primary brain tumors. The most aggressive type, Glioblastoma multiforme (GBM), is one of the deadliest human diseases, with an average survival at diagnosis of about 1 year. Previous evidence suggests a link between human cytomegalovirus (HCMV) and gliomas. HCMV has been shown to be present in these tumors and several viral proteins can have oncogenic properties in glioma cells. Here we have investigated the presence of HCMV DNA, RNA and proteins in fifty-two gliomas of different grades of malignancy. The UL83 viral region, the early beta 2.7 RNA and viral protein were detected in 73%, 36% and 57% by qPCR, ISH and IHC, respectively. Positivity of the viral targets and viral load was independent of tumor type or grade suggesting no correlation between viral presence and tumor progression. Our results demonstrate high prevalence of the virus in gliomas from Brazilian patients, contributing to a better understanding of the association between HCMV infection and gliomas worldwide and supporting further investigations of the virus oncomodulatory properties. PMID- 27458812 TI - Testing for dabigatran and rivaroxaban by clinical laboratories. AB - Rivaroxaban and dabigatran are among the newest anticoagulants, and measuring their concentration in patients is a new challenge for clinical laboratories. We analyzed data from the ECAT proficiency program to determine how well the assays are performing in clinical laboratories internationally. Most laboratories received a passing grade (Z score <3) for the results of their dabigatran and rivaroxaban testing. Failing Z scores were not associated with any particular method. With dabigatran, some homemade calibrators gave higher results than the commercially available calibrators. There were no significant differences among the instruments or the 5 reagents in use, but results showed inter-laboratory variability that could have clinical significance. The 3 reagents with the lowest number of users had poor inter-laboratory precision. Ten different anti-Xa reagents were in use for rivaroxaban testing. One reagent gave lower results than other reagents at 100 ng/mL but not at 300 ng/mL. There were no significant differences among the different rivaroxaban calibrators or instruments. In conclusion, inter-laboratory precision could be improved for both dabigatran and rivaroxaban assays. Homemade dabigatran calibrators differed from commercially available calibrators, and there was a statistically significant difference between some of the rivaroxaban reagents. About 10% of results received failing Z scores or passed but fell in a range that require the laboratory to investigate for bias or other inaccuracy in their method. Am. J. Hematol. 91:E464-E467, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27458813 TI - Glioblastoma Multiforme and Adult Neurogenesis in the Ventricular-Subventricular Zone: A Review. AB - Brain cancers account for <1,5% of all new cancer cases reported in the United States each year. Due to their invasive and heterogeneous nature, in addition to their resistance to multimodal treatments, these tumors are usually fatal. Gliomas, and in particular high-grade astrocytomas such as glioblastoma multiforme (GBM), are the most common and lethal primary tumors of the central nervous system. The median survival of most patients is less than 1 year after application of multimodal therapies. The question is why are these cancers so injurious? And above all, how is it possible for a so carefully orchestrated area like the brain to develop such tumors? This brings us to the study of glioma stem cells, their specialized niches (perivascular and hypoxic), and the neurogenic phenomena that takes place within the adult ventricular-subventricular zone: a structure that lies at the intersection between brain development and gliomagenesis. J. Cell. Physiol. 232: 1596-1601, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27458814 TI - Lingual palpation for porcine cysticercosis: a rapid epidemiological tool for estimating prevalence and community risk in Africa. AB - OBJECTIVE: To assess the association between the prevalence of tongue cyst positive and antigen-positive pigs across different settings in Africa, to evaluate whether examining pigs for cysts could be used as a rapid surveillance tool for identifying geographical areas with a higher probability of high transmission of cysticercosis. METHODS: Published data were collated from 26 study sites across Africa that reported the prevalence of porcine cysticercosis by both lingual and serological examinations. The study sites were located in 10 countries across Africa. RESULTS: Seroprevalence rates ranged from 4% to 41%. Despite the varied study sites, the relationship between the two variables was highly consistent and suggests identification of tongue cysts may be useful for cysticercosis surveillance. We found that all areas with more than 10% of pigs having cysts in their tongues had at least 30% seroprevalence (PPV of 100%), although this cut-off is less reliable at predicting that an area is of low transmission (NPV of 84%). CONCLUSION: Assessing the prevalence of tongue cyst positive pigs is a potential rapid epidemiological tool for identifying areas at high risk of cysticercosis, although further refinement and validation is required using standardised data sets. PMID- 27458815 TI - Titanium-Substituted Polyoxotantalate Clusters Exhibiting Wide pH Stabilities: [Ti2 Ta8 O28 ](8-) and [Ti12 Ta6 O44 ](10.). AB - Two new substituted polyoxotantalate clusters, [Ti2 Ta8 O28 ](8-) and [Ti12 Ta6 O44 ](10-) , considerably expand the pH range where tantalates persist in aqueous solution. The structures of [Ti2 Ta8 O28 ](8-) and [Ti12 Ta6 O44 ](10-) are reported as tetramethylammonium salts after synthesis at hydrothermal conditions in aqueous solution. These Ti-substituted polyoxotantalate clusters have analogues among recently discovered niobates, but are slightly larger and more persistent in solution. Most importantly, they exhibit a much wider range of pH stability than the familiar hexatantalate cluster, which is the only other tantalate known to be stable at highly basic pH conditions. These molecules are kinetically stable to near-neutral pH, making them excellent synthons for further development into materials and catalysts, and an significant advance in adapting tantalates for use in aqueous solutions. PMID- 27458798 TI - A century of trends in adult human height. AB - Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries. PMID- 27458816 TI - Induction of Genes Expressed in Endothelial Cells of the Corpus Callosum in the Chronic Cerebral Hypoperfusion Rat Model. AB - BACKGROUND: Cerebrovascular white matter lesions (WMLs) are associated with cognitive impairment in patients with subcortical vascular dementia. We performed a comprehensive gene expression analysis to elucidate genes associated with WML development in a chronic cerebral hypoperfusion rat model. METHODS: Brains of rats with bilateral carotid ligation (2VO, n = 10) and sham-operated rats (n = 5 10/group) were removed on days 1, 7, or 28 after surgery. Total RNA isolated from the corpus callosum was evaluated by microarray analysis and quantitative reverse transcription-polymerase chain reaction. RESULTS: On days 7 and 28, WMLs exhibited histologic changes. On day 7, 16 genes were differentially expressed between groups. mRNA levels of Ptprb, Kcnj8, Crispld2, Bcl6b, and Gja5 were differentially expressed in 2VO rats on day 7, but then returned to normal, whereas mRNA levels of Vwf and Trappc6a were upregulated after day 7. Immunohistochemistry showed that GJA5 and vWF were detected in endothelial cells, KCNJ8 in endothelial cells and astrocytes, CRISPLD2 in neurons and astrocytes, and TRAPPC6A in neurons. CONCLUSION: Our findings indicate novel genes that may be associated with WML development in the chronic cerebral hypoperfusion rat model, and suggest an important role of neurovascular dysfunction in the pathophysiology. PMID- 27458817 TI - Higher Fluorosis Severity Makes Enamel Less Resistant to Demineralization. AB - Fluorotic teeth could either be more resistant or more susceptible to the caries process than sound ones due to their higher enamel fluoride concentration and higher porosity (subsurface hypomineralization), respectively; however, there is no consensus on this subject. In this study, a total of 49 human unerupted third molars presenting Thylstrup and Fejerskov (TF) fluorosis scores 0-4 were used. Two enamel slabs were obtained from each tooth. The rest of the tooth crown was powdered, and the enamel was separated from the dentine. In purified powdered enamel, the calcium (Ca), inorganic phosphate (Pi), and fluoride (F) concentrations were determined. The F concentration gradient throughout the enamel and in the enamel volume was determined in one slab. The other enamel slab was isolated with acid-resistant varnish, subjecting the exposed enamel surface half to a pH-cycling model to evaluate its demineralization resistance and to calculate the demineralization area. The nonexposed surface was used to determine the natural hypomineralization area found in fluorotic enamel and normalize the demineralization data. The hypomineralization and demineralization areas were assessed by cross-sectional microhardness. For statistical analyses, the data for TF1 and 2, and for TF3 and 4 were pooled. Concentrations of powered enamel Ca and Pi were not significantly different (p > 0.05) among groups TF0, TF1-2 and TF3-4, but a higher F concentration was found in fluorotic enamel (p < 0.05). Highly fluorotic teeth (TF3-4) presented a greater hypomineralization subsurface area and demonstrated lower demineralization resistance than sound enamel (p < 0.05). The findings suggest that a higher severity of fluorosis makes enamel less resistant to the caries process due to its greater subsurface mineral area exposed to demineralization and deeper acid diffusion through the enamel. PMID- 27458818 TI - Multiscale Approach to the Study of the Electronic Properties of Two Thiophene Curcuminoid Molecules. AB - We studied the electronic and conductance properties of two thiophene-curcuminoid molecules, 2-thphCCM (1) and 3-thphCCM (2), in which the only structural difference is the position of the sulfur atoms in the thiophene terminal groups. We used electrochemical techniques as well as UV/Vis absorption studies to obtain the values of the HOMO-LUMO band gap energies, showing that molecule 1 has lower values than 2. Theoretical calculations show the same trend. Self-assembled monolayers (SAMs) of these molecules were studied by using electrochemistry, showing that the interaction with gold reduces drastically the HOMO-LUMO gap in both molecules to almost the same value. Single-molecule conductance measurements show that molecule 2 has two different conductance values, whereas molecule 1 exhibits only one. Based on theoretical calculations, we conclude that the lowest conductance value, similar in both molecules, corresponds to a van der Waals interaction between the thiophene ring and the electrodes. The one order of magnitude higher conductance value for molecule 2 corresponds to a coordinate (dative covalent) interaction between the sulfur atoms and the gold electrodes. PMID- 27458819 TI - A Systematic Review and Meta-Analysis of Circulating Biomarkers Associated with Failure of Arteriovenous Fistulae for Haemodialysis. AB - BACKGROUND: Arteriovenous fistula (AVF) failure is a significant cause of morbidity and expense in patients on maintenance haemodialysis (HD). Circulating biomarkers could be valuable in detecting patients at risk of AVF failure and may identify targets to improve AVF outcome. Currently there is little consensus on the relationship between circulating biomarkers and AVF failure. The aim of this systematic review was to identify circulating biomarkers associated with AVF failure. METHODS: Studies evaluating the association between circulating biomarkers and the presence or risk of AVF failure were systematically identified from the MEDLINE, EMBASE and Cochrane Library databases. No restrictions on the type of study were imposed. Concentrations of circulating biomarkers of routine HD patients with and without AVF failure were recorded and meta-analyses were performed on biomarkers that were assessed in three or more studies with a composite population of at least 100 participants. Biomarker concentrations were synthesized into inverse-variance random-effects models to calculate standardized mean differences (SMD) and 95% confidence intervals (CI). RESULTS: Thirteen studies comprising a combined population of 1512 participants were included after screening 2835 unique abstracts. These studies collectively investigated 48 biomarkers, predominantly circulating molecules which were assessed as part of routine clinical care. Meta-analysis was performed on twelve eligible biomarkers. No significant association between any of the assessed biomarkers and AVF failure was observed. CONCLUSION: This paper is the first systematic review of biomarkers associated with AVF failure. Our results suggest that blood markers currently assessed do not identify an at-risk AVF. Further, rigorously designed studies assessing biological plausible biomarkers are needed to clarify whether assessment of circulating markers can be of any clinical value. PROSPERO registration number CRD42016033845. PMID- 27458820 TI - Clinical Severity, Age, and Sex Overcome Cardiometabolic Morbidities but Not Stroke as Predictors of Mortality in Elderly Inpatients: Data From the REgistro POliterapie Societa Italiana di Medicina Interna Registry. PMID- 27458822 TI - Phenotypes Associated with Knockouts of Eight Dense Granule Gene Loci (GRA2-9) in Virulent Toxoplasma gondii. AB - Toxoplasma gondii actively invades host cells and establishes a parasitophorous vacuole (PV) that accumulates many proteins secreted by the dense granules (GRA proteins). To date, at least 23 GRA proteins have been reported, though the function(s) of most of these proteins still remains unknown. We targeted gene knockouts at ten GRA gene loci (GRA1-10) to investigate the cellular roles and essentiality of these classical GRA proteins during acute infection in the virulent type I RH strain. While eight of these genes (GRA2-9) were successfully knocked out, targeted knockouts at the GRA1 and GRA10 loci were not obtained, suggesting these GRA proteins may be essential. As expected, the Deltagra2 and Deltagra6 knockouts failed to form an intravacuolar network (IVN). Surprisingly, Deltagra7 exhibited hyper-formation of the IVN in both normal and lipid-free growth conditions. No morphological alterations were identified in parasite or PV structures in the Deltagra3, Deltagra4, Deltagra5, Deltagra8, or Deltagra9 knockouts. With the exception of the Deltagra3 and Deltagra8 knockouts, all of the GRA knockouts exhibited defects in their infection rate in vitro. While the single GRA knockouts did not exhibit reduced replication rates in vitro, replication rate defects were observed in three double GRA knockout strains (Deltagra4Deltagra6, Deltagra3Deltagra5 and Deltagra3Deltagra7). However, the virulence of single or double GRA knockout strains in CD1 mice was not affected. Collectively, our results suggest that while the eight individual GRA proteins investigated in this study (GRA2-9) are not essential, several GRA proteins may provide redundant and potentially important functions during acute infection. PMID- 27458823 TI - Optimal configuration of respiratory navigator gating for the quantification of left ventricular strain using spiral cine displacement encoding with stimulated echoes (DENSE) MRI. AB - PURPOSE: To determine the optimal respiratory navigator gating configuration for the quantification of left ventricular strain using spiral cine displacement encoding with stimulated echoes (DENSE) MRI. MATERIALS AND METHODS: Two dimensional spiral cine DENSE was performed on a 3 Tesla MRI using two single navigator configurations (retrospective, prospective) and a combined "dual navigator" configuration in 10 healthy adults and 20 healthy children. The adults also underwent breathhold DENSE as a reference standard for comparisons. Peak left ventricular strains, signal-to-noise ratio (SNR), and navigator efficiency were compared. Subjects also underwent dual-navigator gating with and without visual feedback to determine the effect on navigator efficiency. RESULTS: There were no differences in circumferential, radial, and longitudinal strains between navigator-gated and breathhold DENSE (P = 0.09-0.95) (as confidence intervals, retrospective: [-1.0%-1.1%], [-7.4%-2.0%], [-1.0%-1.2%]; prospective: [-0.6% 2.7%], [-2.8%-8.3%], [-0.3%-2.9%]; dual: [-1.6%-0.5%], [-8.3%-3.2%], [-0.8% 1.9%], respectively). The dual configuration maintained SNR compared with breathhold acquisitions (16 versus 18, P = 0.06). SNR for the prospective configuration was lower than for the dual navigator in adults (P = 0.004) and children (P < 0.001). Navigator efficiency was higher (P < 0.001) for both retrospective (54%) and prospective (56%) configurations compared with the dual configuration (35%). Visual feedback improved the dual configuration navigator efficiency to 55% (P < 0.001). CONCLUSION: When quantifying left ventricular strains using spiral cine DENSE MRI, a dual navigator configuration results in the highest SNR in adults and children. In adults, a retrospective configuration has good navigator efficiency without a substantial drop in SNR. Prospective gating should be avoided because it has the lowest SNR. Visual feedback represents an effective option to maintain navigator efficiency while using a dual navigator configuration. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:786-794. PMID- 27458824 TI - Pattern of late gadolinium enhancement predicts arrhythmic events in patients with non-ischemic cardiomyopathy. AB - BACKGROUND: Left ventricular late gadolinium enhancement (LV-LGE) by cardiac magnetic resonance (CMR) imaging has been associated with adverse clinical outcomes in patients with non-ischemic cardiomyopathy (NICM). However, an association between the characteristics of the LGE and arrhythmic risk has not been demonstrated consistently. This study evaluated the impact of the LV-LGE characteristics on the arrhythmia risk in patients with NICM. METHODS: This study enrolled 365 consecutive patients (54+/-15years) with NICM who underwent CMR imaging. All patients were monitored for the following outcomes: major arrhythmic events (MA), including sustained ventricular tachycardia, an appropriate implantable cardioverter-defibrillator intervention, ventricular fibrillation and sudden cardiac death. RESULTS: During 44.3+/-36.4months of follow-up, 44 (12.1%) patients experienced MA. LV-LGE was observed in 40 (90.9%) and 221 (68.8%) patients with and without MA, respectively. LV-LGE was more frequently observed in the MA group (p=0.002). The age- and sex-adjusted hazard ratio (HR) of MA was increased in patients with LGE extent>=8% (HR 8.45, 95% confidence interval (CI) 2.91-24.6), and those with subendocardial (HR 6.98, 95% CI 1.74-28.0) and subepicardial LGE patterns (HR 7.2, 95% CI 1.61-35.6). In multivariable models adjusted for other clinical variables, only the subepicardial LGE pattern had 7.2 (95% CI, 1.61-32.6, p=0.01) time increase in the MA risk. CONCLUSIONS: LV-LGE in patients with NICM is not uncommon. The subepicardial pattern of the LV-LGE was an independent predictor of MA, suggesting that specific patterns of the LV-LGE are closely related to the severity of arrhythmic events. PMID- 27458821 TI - Glial Na(+) -dependent ion transporters in pathophysiological conditions. AB - Sodium dynamics are essential for regulating functional processes in glial cells. Indeed, glial Na(+) signaling influences and regulates important glial activities, and plays a role in neuron-glia interaction under physiological conditions or in response to injury of the central nervous system (CNS). Emerging studies indicate that Na(+) pumps and Na(+) -dependent ion transporters in astrocytes, microglia, and oligodendrocytes regulate Na(+) homeostasis and play a fundamental role in modulating glial activities in neurological diseases. In this review, we first briefly introduced the emerging roles of each glial cell type in the pathophysiology of cerebral ischemia, Alzheimer's disease, epilepsy, Parkinson's disease, Amyotrophic Lateral Sclerosis, and myelin diseases. Then, we discussed the current knowledge on the main roles played by the different glial Na(+) -dependent ion transporters, including Na(+) /K(+) ATPase, Na(+) /Ca(2+) exchangers, Na(+) /H(+) exchangers, Na(+) -K(+) -Cl(-) cotransporters, and Na(+) HCO3- cotransporter in the pathophysiology of the diverse CNS diseases. We highlighted their contributions in cell survival, synaptic pathology, gliotransmission, pH homeostasis, and their role in glial activation, migration, gliosis, inflammation, and tissue repair processes. Therefore, this review summarizes the foundation work for targeting Na(+) -dependent ion transporters in glia as a novel strategy to control important glial activities associated with Na(+) dynamics in different neurological disorders. GLIA 2016;64:1677-1697. PMID- 27458826 TI - Metabolic consequences of adipose tissue dysfunction and not adiposity per se increase the risk of cardiovascular events and mortality in patients with type 2 diabetes. AB - OBJECTIVES: To quantify the risk of obesity and its associated metabolic dysfunction on the development of cardiovascular events and mortality in patients with type 2 diabetes. METHODS: In 1827 patients with type 2 diabetes enrolled in the Secondary Manifestations of ARTerial disease (SMART) cohort study, the risk of higher BMI, waist circumference and intra-abdominal fat on the development of cardiovascular events (composite of myocardial infarction, stroke, and vascular mortality) was quantified using Cox regression. Second, risk of cardiovascular events related to obesity associated metabolic dysfunction (>=3 adapted NCEP metabolic syndrome criteria) was quantified for tertiles of intra-abdominal fat. RESULTS: 217 patients died from cardiovascular causes and 338 patients developed the composite endpoint of cardiovascular events during a median follow-up of 7.0years (interquartile range 3.9 to 10.5years). No increased risk for cardiovascular events and mortality was observed per SD higher BMI, waist circumference and intra-abdominal fat (HR varying from 1.00, 95% CI 0.88-1.14 to 1.13, 95% CI 0.96-1.33). Compared to the first tertile of intra-abdominal fat without metabolic dysfunction, the presence of metabolic dysfunction increased the risk of cardiovascular events in all tertiles of intra-abdominal fat with the highest risk observed for metabolic dysfunction in the first tertile of intra abdominal fat (HR 2.47, 95% CI 1.32-4.62). CONCLUSIONS: Body-mass index, waist circumference and intra-abdominal fat are not related to the risk of cardiovascular events and mortality in patients with type 2 diabetes. Instead, in these patients the metabolic consequences of adipose tissue dysfunction are more important than strict measures of adiposity when estimating cardiovascular risk. PMID- 27458827 TI - The relationship between multilevel models and non-parametric multilevel mixture models: Discrete approximation of intraclass correlation, random coefficient distributions, and residual heteroscedasticity. AB - Multilevel data structures are common in the social sciences. Often, such nested data are analysed with multilevel models (MLMs) in which heterogeneity between clusters is modelled by continuously distributed random intercepts and/or slopes. Alternatively, the non-parametric multilevel regression mixture model (NPMM) can accommodate the same nested data structures through discrete latent class variation. The purpose of this article is to delineate analytic relationships between NPMM and MLM parameters that are useful for understanding the indirect interpretation of the NPMM as a non-parametric approximation of the MLM, with relaxed distributional assumptions. We define how seven standard and non-standard MLM specifications can be indirectly approximated by particular NPMM specifications. We provide formulas showing how the NPMM can serve as an approximation of the MLM in terms of intraclass correlation, random coefficient means and (co)variances, heteroscedasticity of residuals at level 1, and heteroscedasticity of residuals at level 2. Further, we discuss how these relationships can be useful in practice. The specific relationships are illustrated with simulated graphical demonstrations, and direct and indirect interpretations of NPMM classes are contrasted. We provide an R function to aid in implementing and visualizing an indirect interpretation of NPMM classes. An empirical example is presented and future directions are discussed. PMID- 27458825 TI - Practical approach on frail older patients attended for acute heart failure. AB - Acute heart failure (AHF) is a multi-organ dysfunction syndrome. In addition to known cardiac dysfunction, non-cardiac comorbidity, frailty and disability are independent risk factors of mortality, morbidity, cognitive and functional decline, and risk of institutionalization. Frailty, a treatable and potential reversible syndrome very common in older patients with AHF, increases the risk of disability and other adverse health outcomes. This position paper highlights the need to identify frailty in order to improve prognosis, the risk-benefits of invasive diagnostic and therapeutic procedures, and the definition of older person-centered and integrated care plans. PMID- 27458828 TI - Incidental Finding of Lung Herniation After Cardiopulmonary Resuscitation. PMID- 27458829 TI - Absent quadriceps reflex with distant toe flexor response: An underrecognized neurological sign. AB - As opposed to finger flexion response upon tapping the styloid process with absent brachioradialis reflex (inverted brachioradialis reflex), toe flexion response upon patellar percussion with absent quadriceps reflex is a quite underrecognized neurological sign, and has been reported only once in the literature. Similar to the inverted brachioradialis reflex, this sign can also be useful for neurological localization. We hereby report a patient presenting with signs and symptoms of lumbar radiculopathy in the setting of an anterior epidural mass compressing the cauda equina at L2-L4, without evidence of myelopathy. Upon examination, the patient had bilateral absent quadriceps reflexes with a right toe flexor response when the right patella was percussed. An absent quadriceps reflex with distant toe flexor response is proposed as a lower extremity equivalent of the inverted brachioradialis reflex, likely localizing to L3-L4 levels. Spindle hypersensitivity due to lack of reciprocal inhibition from antagonist muscles is hypothesized as a possible underlying mechanism. Further observations should help clarify the most common underlying etiology (radicular vs. radiculomyelopathy). Neurologists should be able to recognize this sign, as it can be helpful for neurological localization. PMID- 27458830 TI - Molecular Detection of Pseudogymnoascus destructans (Ascomycota: Pseudeurotiaceae) and Unidentified Fungal Dermatitides on Big Brown Bats ( Eptesicus fuscus ) Overwintering inside Buildings in Canada. AB - Big brown bats ( Eptesicus fuscus ) overwintering outside the underground environment are not believed to play a role in the epidemiology of the disease white-nose syndrome (WNS), caused by the fungus Pseudogymnoascus destructans (Pd). Using quantitative real-time PCR (qPCR), we provide molecular evidence for Pd on four big brown bats overwintering in heated buildings in New Brunswick, Canada. Two of the affected individuals also had very mild, focal, pustular, fungal dermatitis identified microscopically. A third bat, which was qPCR Pd negative, had similar fungal lesions. Despite determining that these fungal lesions were caused by a suspected ascomycete, the intralesional fungi were not confirmed to be Pd. These findings demonstrate that bats overwintering in heated buildings and other above-ground sites may have subclinical or preclinical WNS, or be contaminated with Pd, and could play a role in local dispersal of Pd. Our inability to determine if the ascomycetes causing pustular lesions were Pd highlights the need for ancillary diagnostic tests, such as in situ hybridization or immunohistochemistry, so that Pd can be detected directly within a lesion. As the host-pathogen relationship for Pd evolves, and where bat species are exposed to the fungus under varying temperature regimes, lesions may become less stereotypic and such tests could help define these changes. PMID- 27458831 TI - PREVALENCE, GENETIC ANALYSES, AND RISK FACTORS ASSOCIATED WITH HEARTWORM (DIROFILARIA IMMITIS) IN WILD COYOTES (CANIS LATRANS) FROM FLORIDA, USA. AB - We detected heartworm (Dirofilaria immitis) in 37.2% of 212 coyotes ( Canis latrans ) collected from 28 counties in Florida, US, between February 2010 and April 2014. Adult coyotes had a higher prevalence (45.6% of 103) than juveniles (29% of 80), and there was no significant difference in prevalence between adult male and female coyotes. Adults demonstrated a higher prevalence of heartworm in northern counties (56% of 91) than in southern counties (23.1% of 121) and a higher prevalence in urban areas (58.1% of 31) than in rural areas (33.3% of 63). There was no significant difference in mean body weight between infected and uninfected adult males or females. Intensity ranged from 1 to 144 (x =21.29, SD=23.89, n=77). Mixed-sex heartworm infections were found in 88.9% of positive hosts, where the female-to-male ratio of worms was 1.14:1 (n=27). No pathologic changes attributable to heartworm infection were seen. A subsample of heartworms was confirmed to be D. immitis by targeted PCR amplification and DNA sequencing. Of 25 samples submitted for genotyping eight sequence haplotypes were found, all of which were distinct from all publicly available sequences derived from heartworms collected from domestic dogs ( Canis lupus familiaris). These sequences revealed more polymorphisms than did previous samples of D. immitis, which provides a broader foundation for the possibility that the heartworms will develop resistance to anthelmintics. PMID- 27458832 TI - Intestinal Parasites in the Critically Endangered Przewalski's Gazelle ( Procapra przewalskii ) in China, with the Description of a New Species of Eimeria (Apicomplexa: Eimeriidae). AB - We used a flotation technique to survey fecal samples from 27 Przewalski's gazelles ( Procapra przewalskii Buchner, 1891) for intestinal parasites. Samples were collected from the Qinghai Lake region, Qinghai-Tibet plateau, China, in April 2015. We report parasites belonging to two nematode (Nematodirus, Marshallagia) genera and one apicomplexan (Eimeria) genus; one of the latter was a new species from the critically endangered Przewalski's gazelle. Sporulated oocysts of the new eimerian were spheroidal; they had a thick, outer wall without a micropyle, but with a distinct polar granule and an oocyst residuum. Oocysts measured a mean of 18.6(+/-0.8)*17.3(+/-0.9) MUm in length and width, with a mean 1.1(+/-0.1) length/width ratio and a spheroidal oocyst residuum that had a mean width of 2.0(+/-0.7) MUm. Sporocysts were ovoid, measuring a mean of 9.4(+/ 0.6)*5.5(+/-0.5) MUm in length and width, with a mean 1.7(+/-0.2) length/width ratio. A Stieda body and sporocyst residuum were present, but a substieda body was absent. Sporozoites each had a small anterior refractile body and a larger, posterior refractile body; a small nucleus was visible between them. PMID- 27458833 TI - Removal of Lipid from Serum Increases Coherence between Brucellosis Rapid Agglutination Test and Enzyme-linked Immunosorbent Assay in Bears in Alaska, USA. AB - In cases of chronic Brucella spp. infection, results of the rose bengal plate test (RBPT) and indirect enzyme-linked immunosorbent assay (ELISA) should be coherent, as reported in controlled conditions in the literature. We compared RBPT and ELISA results in 58 Alaska grizzly bears ( Ursus arctos horribilis), eight Kodiak brown bears ( Ursus arctos middendorffi), and six Alaska Peninsula brown bears ( Ursus arctos gyas). Of the 72 bears tested, 42 (58%) were ELISA positive and 53 (73%) were RBPT positive. However, the coherence between the tests was only fair (K=0.37, SE=0.11), suggesting that either the serologic results were not compatible with Brucella spp. infection or that there was a technical problem with the tests. To address a potential technical problem, we performed a 30-min chloroform/centrifugation cleanup. Following cleanup, the ELISA identified 43 positives (59%) and the RBPT identified 47 (65%), and the coherence between the tests was much improved (K=0.80, SE=0.07). We recommend cleaning wildlife sera with a high lipid content before performing RBPT and performing RBPT and ELISA in parallel to assess coherence. Our results suggest that Alaskan brown bears have been exposed to Brucella spp. PMID- 27458834 TI - Psychological Assessment Training in Clinical Psychology Doctoral Programs. AB - We surveyed American Psychological Association-accredited clinical psychology doctoral programs' (n = 83) training in psychological assessment-specifically, their coverage of various assessment topics and tests in courses and practica, and whether the training was optional or required. We report results overall and separately per training model (clinical science, scientist-practitioner, and practitioner-focused). Overall, our results suggest that psychological assessment training is as active, or even more active, than in previous years. Areas of increased emphasis include clinical interviewing and psychometrics; multimethod, outcomes, health, and collaborative or therapeutic assessment; and different types of cognitive and self-report personality tests. All or almost all practice focused programs offered training with the Thematic Apperception Test and Rorschach compared to about half of the scientist-practitioner programs and a third of the clinical science programs. Although almost all programs reported teaching multimethod assessment, what constitutes different methods of assessing psychopathology should be clarified in future studies because many programs appear to rely on one method-self-report (especially clinical science programs). Although doctoral programs covered many assessment topics and tests in didactic courses, there appears to be a shortage of program-run opportunities for students to obtain applied assessment training. Finally, we encourage doctoral programs to be familiar with (a) internships' assessment expectations and opportunities, (b) the professional guidelines for assessment training, and PMID- 27458835 TI - Characteristics and mechanism of perverted head-shaking nystagmus in central lesions: Video-oculography analysis. AB - OBJECTIVE: Perverted downbeat head-shaking nystagmus (pdHSN) has been considered a sign of central pathology. Two hypotheses have been advanced as the mechanisms of pdHSN without proper validation. This study aimed to elucidate the mechanism of pdHSN. METHODS: Eighteen patients with pdHSN due to central lesions were subjected to analyses of their oculographic characteristics. The peak velocity, temporal features including the duration and time constant (TC), rotational axis of pdHSN were analyzed. To determine the most relevant mechanism of pdHSN, we compared the TCs of pdHSN with those of downbeat nystagmus after vertical head shaking in four subjects, and with the TCs of horizontal head-shaking nystagmus (HSN) in three subjects who had both horizontal and downbeat nystagmus after head shaking. RESULTS: The duration of pdHSN ranged from 14 to 25s and the estimated TC was from 3.9 to 7.8s. When the data were pooled after the intensities of the nystagmus in each patient were normalized, the TC was 5.2 (95% CI=5.0-5.4) seconds from nonlinear regression test. The rotational vectors of pdHSN (n=8) were mostly aligned between the anterior semicircular canals. The estimated TC of downbeat nystagmus after vertical head-shaking (5.8s) was similar to that of pdHSN (6.0s) in four subjects tested. In contrast, the TC of horizontal HSN (10.9s) was significantly larger than that of pdHSN (4.9s) in three subjects. CONCLUSIONS: The characteristics of TCs of HSN in our patients with central lesions suggest that pdHSN is due to enhanced activities of the central anterior canal pathway. SIGNIFICANCE: pdHSN is a sign indicative of central pathology causing cerebellar dysfunction, especially when it associated with other neuro otological signs. PMID- 27458836 TI - MUNIX: Reproducibility and clinical correlations in Amyotrophic Lateral Sclerosis. AB - OBJECTIVE: To study the reproducibility, diagnostic yield to detect denervation, and clinical correlations of the Motor Unit Number Index (MUNIX) in subjects with Amyotrophic Lateral Sclerosis (ALS). METHODS: MUNIX evaluation was performed in three muscles twice on the same day to assess reproducibility. Cut-off values for the MUNIX were based on data from 51 healthy subjects (controls) to evaluate the sensitivity of the technique to detect denervation in 30 subjects with ALS. RESULTS: The method had good reproducibility. The variability was greater in the ALS group. In 23 ALS subjects (77%), low MUNIX values were detected. Most of the muscles with low MUNIX had also low compound muscle action potential (CMAP) and strength, but these parameters were normal in 9% of muscles. According to ROC curve analysis, MUNIX was generally accurate (AUC=0.9504) for discriminating between healthy individuals and subjects with at least one denervated muscle. CONCLUSIONS: MUNIX variability was higher in the ALS group. The method showed good diagnostic performance for the detection of denervation in a sample of patients with ALS. SIGNIFICANCE: This study demonstrated that in addition to being a quantitative tool MUNIX can detect denervation in subjects with ALS. PMID- 27458837 TI - Somatosensory temporal discrimination threshold in Parkinson's disease parallels disease severity and duration. AB - OBJECTIVE: To investigate whether the somatosensory temporal discrimination threshold (STDT) is already altered at the clinical onset of Parkinson's disease (PD) and whether STDT abnormalities correlate with disease progression we tested STDT values in patients with different severity of disease. METHODS: We prospectively and consecutively enrolled 63 PD patients: 26 drug-naive PD patients with symptom onset no longer than two years prior to inclusion in the study (early-phase), 37 PD patients with varying degrees of disease severity and 51 age-matched healthy subjects. The STDT was tested on the index finger of both hands, and on both sides of the face. Twelve out of 26 early phase PD patients were re-tested two years after the initial diagnosis. RESULTS: PD patients as a whole displayed higher STDT values than healthy subjects. STDT values did not significantly differ between early-phase PD patients and healthy subjects, whereas they were significantly higher in patients with mild/moderate and advanced PD. In early-phase PD patients STDT values at the two years-follow up assessment did not statistically differ from those obtained at baseline. Considering the whole group of PD patients STDT abnormalities significantly correlated with duration and severity of the disease. CONCLUSIONS: STDT increases as disease progresses. In early-phase PD patients STDT values are still statistically similar to those of healthy subjects, thus implying that dopaminergic depletion alone may not be sufficient to cause STDT abnormalities. SIGNIFICANCE: Our study gives new insight into the sensory abnormalities in PD. PMID- 27458838 TI - Nerve ultrasound in CMT2E/CMT1F due to NEFL mutation: Confirmation of an axonal pathology. PMID- 27458839 TI - Impact of ground soybean and starch levels on the quality of meat from feedlot young Nellore bulls. AB - Twenty-eight young Nellore bulls (395+/-32kg initial body weight) were assigned to a completely randomized design (2*2 factorial design with 7 animals per treatment) to evaluate effects on the quality of meat. Diet treatments consisted of high (about 25%) or low (about 16%) starch levels, with or without ground soybean addition. Shear force was decreased in the meat from animals fed a low starch diet (P=0.0016). Meat from animals fed a high-starch diet had increased total concentrations of unsaturated (P=0.0029) and monounsaturated fatty acids (P=0.0253). Polyunsaturated fatty acid content increased in the meat from animals fed a diet containing soybean (P=0.0121). High starch diets (>25%) decreased the concentration of saturated fatty acids and increased the amount of unsaturated fatty acids in the meat from young Nellore bulls. PMID- 27458840 TI - Differential enrichment of TTF-I and Tip5 in the T-like promoter structures of the rDNA contribute to the epigenetic response of Cyprinus carpio during environmental adaptation. AB - To ensure homeostasis, ectothermic organisms adapt to environmental variations through molecular mechanisms. We previously reported that during the seasonal acclimatization of the common carp Cyprinus carpio, molecular and cellular functions are reprogrammed, resulting in distinctive traits. Importantly, the carp undergoes a drastic rearrangement of nucleolar components during adaptation. This ultrastructural feature reflects a fine modulation of rRNA gene transcription. Specifically, we identified the involvement of the transcription termination factor I (TTF-I) and Tip-5 (member of nucleolar remodeling complex, NoRC) in the control of rRNA transcription. Our results suggest that differential Tip5 enrichment is essential for silencing carp ribosomal genes and that the T0 element is key for regulating the ribosomal gene during the acclimatization process. Interestingly, the expression and content of Tip5 were significantly higher in winter than in summer. Since carp ribosomal gene expression is lower in the winter than in summer, and considering that expression concomitantly occurs with nucleolar ultrastructural changes of the acclimatization process, these results indicate that Tip5 importantly contributes to silencing the ribosomal genes. In conclusion, the current study provides novel evidence on the contributions of TTF-I and NoRC in the environmental reprogramming of ribosomal genes during the seasonal adaptation process in carp. PMID- 27458842 TI - Luminescent Rhenium(I) Pyridyldiaminocarbene Complexes: Photophysics, Anion Binding, and CO2-Capturing Properties. AB - A series of luminescent isocyanorhenium(I) complexes with chelating acyclic diaminocarbene ligands (N^C) has been synthesized and characterized. Two of these carbene complexes have also been structurally characterized by X-ray crystallography. These complexes show blue-to-red phosphorescence, with the emission maxima not only considerably varied with a change in the number of ancillary isocyanide ligands but also extremely sensitive to the electronic and steric nature of the substituents on the acyclic diaminocarbene ligand. A detailed study with the support of density functional theory calculations revealed that the lowest-energy absorption and phosphorescence of these complexes in a degassed CH2Cl2 solution are derived from the predominantly metal-to-ligand charge-transfer [dpi(Re) -> pi*(N^C)] excited state. The unprecedented anion binding and CO2-capturing properties of the acyclic diaminocarbene have also been described. PMID- 27458841 TI - Targeting cell membrane adaptation as a novel antimicrobial strategy. AB - Emergence of antibiotic resistance is an example of the incredible plasticity of bacteria to survive in all environments. The search for new antibiotics active against traditional targets is more challenging due not only to the lack of novel natural products to fulfill the current clinical needs against multidrug resistant (MDR) bacteria, but also for the possible 'collateral' effects on the human microbiota. Thus, non-traditional approaches to combat MDR bacteria have been proposed. Here, we discuss the possibility of targeting the membrane response to the antibiotic attack (cell membrane adaptation) as a viable strategy to increase the activity of current antimicrobials, enhance the activity of the innate immune system and prevent development of resistance during therapy using the three-component regulatory system LiaFSR of enterococci as a model. PMID- 27458844 TI - Diabetes increases morbidity and mortality rates in peptic ulcer bleeding: An updated systematic review and meta-analysis. AB - BACKGROUND/AIMS: To elucidate the relationship between diabetes mellitus (DM) and the risk of peptic ulcer complications. MATERIALS AND METHODS: Fixed effects and random effects models were used for calculating pooled relative risks (RRs) and/or odds ratios (ORs). Subgroup and sensitivity analyses were also performed. RESULTS: Nineteen high-quality investigations were included in the present study. In an analysis of morbidity rates in primary peptic ulcer bleeding (PUB), we calculated a summary OR of 1.433 (95% CI=1.280-1.604) in the random effects model comparing incidence in diabetes patients and in those without diabetes. In addition, a meta-analysis using the fixed effects model indicated a higher 30-day mortality in PUB in DM patients (OR=1.442, 95% CI=1.245-1.671) than in patients without DM. Further subgroup analyses demonstrated that DM patients in prospective cohort studies had an increased risk of 30-day mortality in PUB (RR=1.407, 95% CI=1.177-1.681). A similar result was obtained in a retrospective cohort subgroup, in which DM significantly increased mortality rates in PUB (OR=1.521, 95% CI=1.171-1.976). CONCLUSION: We provided convincing evidence by a meta-analysis that DM was associated with a 43.3% increase in morbidity rates in PUB and a 44.2% increase in the risk of 30-day mortality in PUB patients. PMID- 27458845 TI - Endoscopic evaluation of acute intestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation. AB - BACKGROUND/AIMS: Acute graft-versus-host disease (GVHD) is a common complication of haematopoietic cell transplantation (HCT), with the gastrointestinal tract (GIT) as one of the main target organs. There is a lack of consensus regarding the site in GIT with the highest sensitivity for biopsy. The present study aimed to determine the endoscopic and histological findings in acute GVHD. MATERIALS AND METHODS: The data of 111 patients who had received allogeneic HCT were retrospectively reviewed. RESULTS: Allogeneic HCT was performed in 111 patients, of whom 27 (24.3%) had developed acute GVHD. Nineteen of the 111 patients with intestinal symptoms were evaluated for intestinal involvement, and 17 were diagnosed with acute intestinal GVHD. Upper endoscopic findings had a sensitivity of 64.7%, a specificity of 50%, a positive predictive value of 91.6% and a negative predictive value of 14.2%. The diagnostic accuracy of upper endoscopy was 63.1%. Lower endoscopic findings had a sensitivity of 40% and a specificity of 0%. The diagnostic accuracy of upper endoscopy with duodenal biopsy and sigmoidoscopy was 94.1%. CONCLUSION: Endoscopic findings are nonspecific in acute intestinal GVHD. There is little agreement between endoscopic findings and histopathology; thus, biopsies are essential. In patients with intestinal symptoms after HCT, upper endoscopy with duodenal biopsy and sigmoidoscopy has an acceptable diagnostic yield for intestinal involvement. PMID- 27458846 TI - Association between single nucleotide polymorphisms in prospective genes and susceptibility to ankylosing spondylitis and inflammatory bowel disease in a single centre in Turkey. AB - BACKGROUND/AIMS: To establish the prevalence of the single nucleotide polymorphisms (SNPs) of endoplasmic reticulum aminopeptidase 1 (ERAP1), IL-23 receptor (IL-23R), signal transducer and activator of transcription 3 (STAT-3) and Janus kinase 2 (JAK-2) in ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) in a Turkish population. MATERIALS AND METHODS: A total of 562 subjects who presented at the Ankara University internal medicine departments of rheumatology and gastroenterology outpatient clinics were recruited in this study, including 365 patients with AS, 197 patients with IBD and 230 healthy controls. ERAP1, IL-23R, STAT-3 and JAK-2) were genotyped in competitive allele specific polymerase chain reactions. RESULTS: The ERAP1 (rs26653) polymorphism was found to increase the disease risk in patients with AS and IBD compared with the control group (p=0.02 and p=0.01, respectively). In addition, this polymorphism revealed a significant relationship with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI) in patients with AS (r=0.829, p < 0.001 and r=0.731, p < 0.001, respectively). CONCLUSION: The ERAP1 gene polymorphism might be a risk factor in the pathogenesis of AS and IBD. In contrast, IL-23R gene polymorphisms may serve a protective role in AS and IBD. PMID- 27458847 TI - An unusual cause of paediatric abdominal pain: Mesenteric masses accompanied with volvulus. AB - BACKGROUND/AIMS: Volvulus caused by mesenteric masses is rare and may result in serious consequences. This study aimed to better characterize volvulus caused by mesenteric masses in children. MATERIALS AND METHODS: A retrospective study was conducted in 24 patients who underwent surgical treatment between January 1994 and January 2014 in one single institution. RESULTS: There were 10 boys and 14 girls. The most frequent findings were abdominal pain (100%), emesis (91.7%) and nausea (83.3%). Physical examination showed positive ileus signs in majority cases, and palpable mass was found in half of the patients. Ultrasound and CT scans revealed mesenteric masses in 21 and 24 patients, and 'whirlpool sign' was observed in 19 and 22 patients, respectively. Emergency laparotomy was performed in all patients. Histological examination revealed that 18 cystic masses were lymphangioma, 5 solid cases were lipoma and the remaining one was lipoblastoma. The postoperative course was uneventful in 22 patients, and postoperative obstruction and incision infection occurred in 2 patients. There was no evidence of recurrence at follow-up. CONCLUSION: Volvulus caused by mesenteric masses is a rare but potentially life-threatening cause of abdominal pain, which should be considered in the differential diagnosis of paediatric acute abdominal pain. PMID- 27458848 TI - Outpatient treatment in uncomplicated acute diverticulitis: 5-year experience. AB - BACKGROUND/AIMS: Most cases of diverticular inflammation are mild and require only medical treatment with liquid diet and antibiotics. Until recently, this treatment required admission to hospitals, which consequently entailed costs. In most cases, treatment was conservative, and less than a quarter of patients admitted actually underwent surgery. In the last year, the outpatient treatment of these patients with uncomplicated diverticulitis has proven effective and safe. The aim of the present study was to describe our experience after 5 years of outpatient treatment with oral antibiotics. MATERIALS AND METHODS: We conducted a retrospective revision study between January 2010 and December 2014. We included all patients admitted to the Emergency Department of the University General Hospital of Elche with a diagnosis of uncomplicated acute diverticulitis based on medical history, physical examination and abdominopelvic computed tomography (CT) scanning. Outpatient treatment consisted of oral antibiotics for 10 days (metronidazole 500 mg/8 h and ciprofloxacin 500 mg/12 h), a liquid diet and oral analgesics (acetaminophen 1 g/6 h). RESULTS: During the period from January 2010 to December 2014, 224 patients were treated on an outpatient basis at a success rate of over 92%. Only 18 patients (8%) required admission after outpatient treatment. CONCLUSION: Outpatient treatment of uncomplicated acute diverticulitis was demonstrated to be safe and effective. PMID- 27458849 TI - Glutathione and glutathione S-transferase levels in patients with liver metastases of colorectal cancer and other hepatic disorders. AB - BACKGROUND/AIMS: Glutathione and glutathione S-transferases (GST) are involved in cell defence against reactive oxygen species, which induces oxidative stress and are associated with different chronic diseases. The aim of the present study was to determine the differences in reduced glutathione (GSH) and GST levels in patients with different liver diseases. MATERIALS AND METHODS: Overall, 114 patients were enrolled in this study: 58 patients with colorectal cancer (18 without and 40 with liver metastases), 27 with liver steatosis, 29 with alcoholic cirrhosis and a group of 40 healthy volunteers. The levels of GSH and GST in blood serum were evaluated by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's guidelines. RESULTS: Significant differences in GSH and GST levels were observed in most of the groups compared to the healthy volunteers (GSH: 52.72 ug/mL, GST: 0.53 ng/mL): with hepatic steatosis (GSH: 17.04 ug/mL, p < 0.001; GST: 5.89 ng/mL, p < 0.001), alcoholic cirrhosis (GSH: 62.04 ug/mL, p < 0.003; GST: 0.94 ng/mL, p < 0.001) and liver metastases (GSH: 37.84 ug/mL, p < 0.001, GST: 1.25 ng/mL, p=0.747). CONCLUSION: The different GSH and GST levels in patients with colorectal cancer liver metastases, liver steatosis and alcoholic cirrhosis indicate the differences in antioxidative system damage and its compensatory possibilities and could serve as potential biomarkers for its correction. PMID- 27458850 TI - Insight into the natural history of primary biliary cirrhosis: A systemic review of data from placebo-controlled clinical trials. AB - BACKGROUND/AIMS: The natural history of primary biliary cirrhosis (PBC) is extremely variable. The extraction and analysis of available information from placebo-treated patients in randomized controlled trials of PBC treatment would facilitate the study of the natural history of PBC. The aim of the present study was to determine important clinical information regarding the natural history of PBC patients without effective treatment. MATERIALS AND METHODS: A search of the PubMed, EMBASE and Cochrane Library databases was performed by two authors. Twelve randomized placebo-controlled clinical trials for PBC patients without decompensated cirrhosis were retrieved for further review. Pooled estimates of biochemical measurements, histological scores and clinical outcomes associated with PBC were calculated in the placebo group. RESULTS: Placebo-treated PBC patients displayed a significant decrease in serum alkaline phosphatase and very slight fluctuations in the other biochemical parameters during the 2-year follow up. Meanwhile, histological progression was observed in 39.4% of the placebo treated patients, and a moderate deterioration in histological scores was noted after 2 years. The pooled 2-year rates of death, transplantation and development of varices were 11.4%, 8.7% and 10.6%, respectively, in placebo-treated PBC patients. CONCLUSION: This review provides a foundation for further epidemiologic investigations in untreated patients and ursodeoxycholic acid-resistant patients with PBC. Biochemical responses after 2 years may provide some information on disease progression and therapeutic response in PBC. PMID- 27458851 TI - Effect of coronary-caval shunt combined with partial pericardial devascularisation on oesophageal and gastric variceal bleeding caused by portal hypertension. AB - BACKGROUND/AIMS: To investigate the effect of coronary-caval shunt combined with partial pericardial devascularisation on oesophageal and gastric variceal bleeding caused by portal hypertension. MATERIALS AND METHODS: Between January 2005 and January 2015, coronary-caval shunt operations combined with partial pericardial devascularisation were performed electively on 15 cirrhotic patients with portal hypertension. All of these patients had a history of oesophageal and gastric variceal bleeding. The clinical and follow-up data of these patients were reviewed retrospectively. Another 15 patients receiving non-surgical treatments in a similar follow-up period were used as controls to compare the preventive effects of different treatment strategies on rebleeding. RESULTS: All of the 15 surgical procedures were performed successfully, and no severe complications occurred. Among these, autogenous splenic veins were used as bridge vessels in 6 cases, whereas the coronary vein and inferior vena cava were anastomosed directly in 9 cases. All surgical patients were followed up from 5 months to 10 years with an average of 63 months; 2 patients died due to liver failure induced by reactivation of hepatitis B virus and oesophageal/gastric variceal rebleeding, respectively. The rebleeding rates for surgical and non-surgical patients were 6.7% and 66.7% (p < 0.05), respectively, whereas the 5-year survival rates for the two groups were 85.7% and 33.3% (p < 0.05), respectively. CONCLUSION: Patients with oesophageal and gastric variceal bleeding caused by portal hypertension may benefit from a coronary-caval shunt combined with partial pericardial devascularisation due to decreased coronary vein pressure, unaffected hepatic blood inflow, and reduced incidence of rebleeding. PMID- 27458852 TI - Role of oxidative stress and insulin resistance in disease severity of non alcoholic fatty liver disease. AB - BACKGROUND/AIMS: Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to find the relation between oxidative stress parameters and histopathological findings in NAFLD patients with and without insulin resistance (IR). MATERIALS AND METHODS: Thirty-two patients with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied (M/F: 17/15; mean age 46.5+/-11.4 years). Twenty-one NAFLD patients with IR were compared with 11 patients without IR. The fasting insulin level was measured, and the insulin resistance index was calculated using the homeostasis model assessment (HOMA) method. Malondialdehyde (MDA) and superoxide dismutase (SOD) activities were measured in tissue and serum specimens. Glutathione (GH) was measured in tissue homogenates. Nitric oxide (NO), vitamin E and C levels were measured in serum. RESULTS: Patients with IR had significantly higher tissue MDA levels (p=0.001) and significantly decreased tissue SOD and GH levels (p=0.001 and 0.002, respectively) than those without IR. The steatosis grade, necroinflammatory grade and stage were significantly higher in patients with IR (p=0.035, 0.003 and 0.001, respectively). HOMA IR significantly correlated with the necroinflammatory grade, stage, tissue MDA, SOD and GH (p=0.013, 0.001, 0.008, 0.001 and 0.001, respectively). Serum MDA (beta=1.88, p=0.002), serum SOD (beta=0.57, p=0.006), tissue MDA (beta=0.22, p=0.006), tissue SOD (beta=1.48, p=0.071) and stage (beta=2.81, p=0.003) were independently associated with increased HOMA IR. Increased MDA [OR: 1.51; 95% CI: (1.03-2.22); p=0.034] was a risk factor for non alcoholic steatohepatitis (NASH), and increased SOD activity had a preventive effect against NASH [OR: 0.008; 95% CI: (0.001-0.98); p=0.04]. CONCLUSION: This study shows that insulin resistance in NAFLD correlates with enhanced oxidative stress. Histopathological disease severity significantly correlated with oxidative stress parameters. These data show that NAFLD patients with IR may have increased risk for disease progression. PMID- 27458853 TI - Galactin-3 and brain natriuretic peptide versus conventional echocardiography in the early detection of cirrhotic cardiomyopathy. AB - BACKGROUND/AIMS: Cirrhotic cardiomyopathy (CCM) is defined as an abnormal heart structure and function in cirrhotic patients. CCM includes systolic and diastolic dysfunction, electrophysiological abnormalities, and structural changes, both microscopic and macroscopic. Currently, there is no one diagnostic test that can identify patients with CCM. Evaluation of the validity of galactin-3 and brain natriuretic peptide (BNP) as biomarkers in the early detection of CCM in comparison to conventional echocardiography. MATERIALS AND METHODS: A case control study was carried out in the Departments of internal medicine and tropical Medicine, Assuit University, Egypt. Seventy-one subjects were divided into the following three groups: 26 cirrhotic patients without ascites, 25 cirrhotic patients with ascites, and 20 healthy controls. All groups underwent clinical examination, and laboratory investigation including BNP, galactin-3, and echocardiography. RESULTS: There was a significant difference between the three groups (p < 0.001) with regard to corrected QT (cQT), BNP and galactin-3. Left ventricular diastolic dysfunction with different grades was the most recorded cardiac abnormality in the patient group I and II (88.5% and 96%; respectively) with significantly increased frequency and severity in ascetic patients and with the advancement of liver cirrhosis. BNP and galactin-3 were sensitive and specific biomarkers for the detection of diastolic dysfunction in cirrhotic patients (77.6%, 95.5%, 89.9% and 86.4%; respectively). CONCLUSION: Diastolic dysfunction is a common cardiac abnormality in cirrhotic patients that worsens with the advancement of cirrhosis. BNP and galactin-3 had higher sensitivity and specificity in the early detection of CCM compared with those of conventional echocardiography. PMID- 27458854 TI - Combination of DKK1 and AFP improves diagnostic accuracy of hepatocellular carcinoma compared with either marker alone. AB - BACKGROUND/AIMS: The Wnt/beta-catenin pathway plays a prominent role in hepatocellular carcinoma (HCC). The Dickkopf (DKK) proteins (DKK1-4) are known Wnt antagonists; the overexpression of DKK1 has been demonstrated in HCC, and increased DKK3 methylation in the HCC tissue is associated with worse prognosis. Thus, the aim of our study was to demonstrate the diagnostic accuracy of serum DKK1 and DKK3 in HCC in comparison with that of serum alpha-fetoprotein (AFP). MATERIALS AND METHODS: We included consecutive 40 HCC patients, 54 cirrhosis patients, and 39 healthy controls. Serum DKK1 and DKK3 levels were measured by an enzyme-linked immunosorbent assay, and serum AFP levels were measured by a chemiluminescence assay. RESULTS: The AFP levels differed in each group and could help differentiate between groups (p < 0.001). The DKK1 levels could help differentiate the HCC group from cirrhosis and control groups (p < 0.001), and the DKK3 levels could help differentiate HCC and cirrhosis groups from the control group (p < 0.001). Combined usage of DKK1 and AFP increased the diagnostic yield, with a sensitivity, specificity, positive predictive value, and negative predictive value of 87.5%, 92.3%, 92.1%, and 87.8%, respectively. CONCLUSION: Although AFP is superior to DKK1 and DKK3 in the diagnosis of HCC, the combination of DKK1 and AFP showed a better diagnostic yield than AFP alone. PMID- 27458855 TI - Impact of psoas muscle index on short-term outcome after living donor liver transplantation. AB - BACKGROUND/AIMS: Living donor liver transplantation is an operation with high morbidity and mortality rates. The purpose of this study was to examine factors affecting the short-term outcome after living donor liver transplantation. MATERIALS AND METHODS: Forty-seven adult patients who underwent living donor liver transplantation from September 2001 to December 2014 were included. Short term post-transplant outcomes were evaluated in terms of the onset of postoperative complications of grade 3a and above (Clavien-Dindo classification) and postoperative 120-day mortality. Univariate and multivariate analyses were used to determine possible predictive factors among perioperative variables such as preoperative psoas muscle index (PMI), blood laboratory test results, perioperative nutritional therapy, and operative factors. RESULTS: Lower PMI (lower than the first quartile of PMI of donors), higher blood urea nitrogen level (>=14 mg/dL), and blood type incompatibility were independent risk factors for the development of postoperative complications. The 120-day survival rates were significantly lower for the lower PMI group (n=30, 66.7%) than for the higher PMI group (n=17, 94.1%, p=0.034). CONCLUSION: A significant correlation was observed between preoperative PMI and short-term postoperative outcomes. Sarcopenia estimated by PMI may serve as a measure of patient frailty and a target for risk stratification. PMID- 27458856 TI - An abdominal and unexpected cause of persistent fever in a 3-year old boy. PMID- 27458857 TI - DRESS syndrome in a patient with chronic hepatic encephalopathy. PMID- 27458858 TI - Non-alcoholic fatty liver disease in chronic hepatitis B patients. PMID- 27458859 TI - Noninvasive indirect serum markers of liver fibrosis in patients with chronic viral hepatitis. PMID- 27458860 TI - Worsening jaundice induced by biliary drainage. PMID- 27458861 TI - Early combined immunosupression for the management of Crohn's disease. PMID- 27458862 TI - To chromo or not to chromo: That is the question! PMID- 27458863 TI - Protecting Transgender Rights Promotes Transgender Health. PMID- 27458864 TI - Mental Health Nursing. PMID- 27458865 TI - [Not Available]. PMID- 27458866 TI - Myxovirus resistance 1 gene polymorphisms and outcomes of viral hepatitis B and C infections in Moroccan patients. AB - Host genetic factors may influence the establishment of chronicity or spontaneous clearance in viral hepatitis B and C infections. More light was shed on the role played by interferon-stimulated genes in the innate immunity. Myxovirus resistance 1 (MX1) is one of those key genes that have reported to inhibit several viruses. The present study aims to explore the possible association of 88G/T and -123C/A promoter variants of MX1 with susceptibility to chronic hepatitis B and C and/or with spontaneous clearance in a Moroccan population. The -88G/T and -123C/A SNPs were genotyped by PCR-RFLP in 538 individuals stratified into HBV chronically infected patients (n = 120), HCV-chronically infected patients (n = 115), HBV spontaneously resolved subjects (n = 114), HCV spontaneously resolved group (n = 52), and healthy controls (n = 137). A significant association of -123C allele with HBV spontaneous clearance has been found (P = 0.002, OR = 2.34; 95%CI [1.36-4]). In addition, a significant correlation between the MX1-GC haplotype and HBV spontaneous clearance (P < 0.001) was found. No significant association of -88G/T and -123C/A polymorphisms with regard to HCV infection was observed in this study. Here, we show that for North African patients with chronic hepatitis, MX1 gene variation at position 123 may influence the outcome of HBV infection but not HCV infection. J. Med. Virol. 89:647-652, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27458867 TI - Just in case it rains: building a hydrophobic biofilm the Bacillus subtilis way. AB - Over the millennia, diverse species of bacteria have evolved multiple independent mechanisms to structure sessile biofilm communities that confer protection and stability to the inhabitants. The Gram-positive soil bacterium Bacillus subtilis biofilm presents as an architecturally complex, highly hydrophobic community that resists wetting by water, solvents, and biocides. This remarkable property is conferred by a small secreted protein called BslA, which self-assembles into an organized lattice at an interface. In the biofilm, production of BslA is tightly regulated and the resultant protein is secreted into the extracellular environment where it forms a very effective communal barrier allowing the resident B. subtilis cells to shelter under the protection of a protein raincoat. PMID- 27458868 TI - Evaluation of forest decontamination using radiometric measurements. AB - An experiment has been conducted to evaluate the additional dose reduction by clear felling contaminated forestry in Fukushima Prefecture, Japan, and using the timber to cover the areas with wood chips. A portable gamma spectrometry system, comprising a backpack containing a 3 * 3" NaI(Tl) detector with digital spectrometer and GPS receiver, has been used to map dose rate and radionuclide activity concentrations before, after and at stages during this experiment. The data show the effect of the different stages of the experiment on dose rate at different locations around the site. The spectrometric data have allowed the assessment of the contributions of natural and anthropogenic radionuclides to the dose rate at different parts of the site before and after the experiment. This has clearly demonstrated the value of radiometric methods in evaluating remediation, and the effect of other environmental processes. The value of spectrometric methods which directly measure radionuclide concentrations has also been shown, especially through the identification of the contribution of natural and anthropogenic activity to the measured dose rate. The experiment has shown that clearing trees and applying wood chips can reduce dose rates by 10-15% beyond that achieved by just clearing the forest litter and natural redistribution of radiocaesium. PMID- 27458869 TI - Effect of low molecular weight organic acids on the uptake of 226Ra by corn (Zea mays L.) in a region of high natural radioactivity in Ramsar-Iran. AB - To study the benefit of including citric and oxalic acid treatments for phytoremediation of 226Ra contaminated soils a greenhouse experiment with corn was conducted. A soil was sampled from a region of high natural 226Ra radioactivity in Ramsar, Iran. After cultivation of corn seed and using organic acid treatments at 1, 10 and 100 mM concentrations, plants (shoots and roots) were harvested, digested and prepared to measure 226Ra activity. Simultaneously, sequential selective extraction were performed to estimate the partitioning of 226Ra among geochemical extraction. Results showed that the maximum uptake of 226Ra in plants was observed in citric acid (6.3%) and then oxalic acid (6%) at 100 mM concentration. These treatments increased radium uptake by a factor of 1.5 than the control. Enhancement of radium uptake by plants was related to soil pH reduction of organic acids in comparison to control. Also, the maximum uptake of this radionuclide in all treatments was obtained in roots compared to shoots. 226Ra fractionations results revealed that 91.8% of radium was in the residual phase of the soil and the available fractions were less than 2%. As the main percent of 226Ra was in the residual phase of the soil in this region, it seems that organic acids had not significant effect on the uptake of 226Ra for phytoremediation by corn in this condition. PMID- 27458870 TI - Bioengineering of differentiated hepatocytes with human factor IX-expressing plasmids in vitro. AB - For somatic gene therapy of hemophilia B, hepatocytes as the main cellular host for expression of hFIX are attractive targets. In gene therapy protocols, an efficient expression vector equipped with cis-regulatory elements such as introns is required. With this in mind, hFIX-expressing plasmids equipped with different combinations of 2 human beta-globin (hBG) introns inside the hFIX-cDNA and Kozak element were used for bioengineering of HepG2 cells as a model for differentiated hepatocytes and CHO cells a cell line generally used to produce recombinant hFIX (rhFIX). In HepG2 cells, the highest hFIX secretion level occurred for the intron less plasmid with 8.5 to 53.8- fold increases, while in CHO cells, the hBG intron I containing plasmid induced highest hFIX secretion level with 2.3 to 14.3-fold increases as compared to other plasmids. The first hBG intron appears to be more effective than the second one in both cell lines. The expression level was further increased upon the inclusion of the Kozak element. The highest hFIX activity was obtained from the cells that carrying the intron-less plasmids with 470 mU/ml and 25 mU/ml for HepG2 and CHO cells respectively. Secretion of active hFIX by all constructs was documented except for hBG intron-II containing construct in both cell lines. HepG2 cells were able to secret higher hFIX levels by 0.6 to 112.2-fold increases with activity by 5.3 to 16.4-fold increases compared to CHO cells transfected with the same constructs. Presence of both hBG intron-I and II inside the hFIX-cDNA provides properly spliced hFIX transcripts in both cell lines. In conclusion, the advantages of hBG introns as attractive cis-regulatory elements to obtain higher expression level of hFIX particularly in CHO cells were demonstrated. Hepatocytes could be effectively bioengineered with the use of plasmid vectors and this strategy may provide a potential in-vitro source of functional hepatocytes for ex-vivo gene therapy of hemophilias and production of rhFIX in vitro. PMID- 27458871 TI - Synthesis and Characterization of Ru Cubic Nanocages with a Face-Centered Cubic Structure by Templating with Pd Nanocubes. AB - Nanocages have received considerable attention in recent years for catalytic applications owing to their high utilization efficiency of atoms and well-defined facets. Here we report, for the first time, the synthesis of Ru cubic nanocages with ultrathin walls, in which the atoms are crystallized in a face-centered cubic (fcc) rather than hexagonal close-packed (hcp) structure. The key to the success of this synthesis is to ensure layer-by-layer deposition of Ru atoms on the surface of Pd cubic seeds by controlling the reaction temperature and the injection rate of a Ru(III) precursor. By selectively etching away the Pd from the Pd@Ru core-shell nanocubes, we obtain Ru nanocages with an average wall thickness of 1.1 nm or about six atomic layers. Most importantly, the Ru nanocages adopt an fcc crystal structure rather than the hcp structure observed in bulk Ru. The synthesis has been successfully applied to Pd cubic seeds with different edge lengths in the range of 6-18 nm, with smaller seeds being more favorable for the formation of Ru shells with a flat, smooth surface due to shorter distance for the surface diffusion of the Ru adatoms. Self-consistent density functional theory calculations indicate that these unique fcc-structured Ru nanocages might possess promising catalytic properties for ammonia synthesis compared to hcp Ru(0001), on the basis of strengthened binding of atomic N and substantially reduced activation energies for N2 dissociation, which is the rate determining step for ammonia synthesis on hcp Ru catalysts. PMID- 27458872 TI - FXR1: Linking cellular quiescence, immune genes and cancer. PMID- 27458873 TI - (19)F NMR-Guided Design of Glycomimetic Langerin Ligands. AB - C-type lectin receptors (CLRs) play a pivotal role in pathogen defense and immune homeostasis. Langerin, a CLR predominantly expressed on Langerhans cells, represents a potential target receptor for the development of anti-infectives or immunomodulatory therapies. As mammalian carbohydrate binding sites typically display high solvent exposure and hydrophilicity, the recognition of natural monosaccharide ligands is characterized by low affinities. Consequently, glycomimetic ligand design poses challenges that extend to the development of suitable assays. Here, we report the first application of (19)F R2-filtered NMR to address these challenges for a CLR, i.e., Langerin. The homogeneous, monovalent assay was essential to evaluating the in silico design of 2-deoxy-2 carboxamido-alpha-mannoside analogs and enabled the implementation of a fragment screening against the carbohydrate binding site. With the identification of both potent monosaccharide analogs and fragment hits, this study represents an important advancement toward the design of glycomimetic Langerin ligands and highlights the importance of assay development for other CLRs. PMID- 27458874 TI - Communication about vaccination: A shared responsibility. AB - Vaccine hesitancy is an important issue to be addressed, due to the risk of decrease of vaccination coverage and consequent control of preventable diseases. While it is not considered a specific determinant, poor or inadequate communication can contribute to vaccine hesitancy and negatively influence vaccination uptake. As a contribution to the ongoing discussion regarding this theme and in the perspective of the implementation of the upcoming national vaccination plan in Italy, the Erice Declaration was drafted by experts in the field of immunization following a 5-day residential, independent workshop regarding communication topics in vaccinology. The aim of the current letter is to present to the broader international audience such a contribution, proposing the identification of the main actions that should be taken into account and prioritized in order to improve communication in the domain of vaccination. PMID- 27458875 TI - Rehabilitation of ataxic gait following cerebellar lesions: Applying theory to practice. AB - Damage to the cerebellum can result in ataxic gait, which affects the ability to walk safely and independently. Physiotherapy is the main treatment for ataxic gait, but there is limited high-quality evidence for interventions used. This review explores the neural mechanisms of the symptoms of ataxic gait, by discussing the cerebellum's role in coordination, motor learning, anticipatory postural control, balance reactions and adapting gait to meet environmental demands. It discusses mechanisms that occur at cellular level throughout the whole cerebellum and then focuses on difficulties that arise from damage to specific lobes of the cerebellum. Physiotherapy-based interventions, such as balance training, developing postural control, specific gait training, and use of compensatory orthotics and aids, are discussed in relation to the theoretical understanding of cerebellar functioning. Consideration is given to difficulties of using trial-and-error-based learning, which will impact on teaching techniques and strategies used during gait rehabilitation. This theoretical understanding will aid physiotherapists to target their assessment, treatment, management, and goal setting with individuals who have difficulties with ataxic gait following a cerebellar lesion. PMID- 27458876 TI - Adverse effects of oral second-line antituberculosis drugs in children. AB - INTRODUCTION: Increasing numbers of children with drug-resistant tuberculosis are accessing second-line antituberculosis drugs; these are more toxic than first line drugs. Little is known about the safety of new antituberculosis drugs in children. Knowledge of adverse effects, and how to assess and manage these, is important to ensure good adherence and treatment outcomes. AREAS COVERED: A Pubmed search was performed to identify articles addressing adverse effects of second-line antituberculosis drugs; a general search was done for the new drugs delamanid and bedaquiline. This review discusses adverse effects associated with oral second-line antituberculosis drugs. The spectrum of adverse effects caused by antituberculosis drugs is wide; the majority are mild or moderate, but these are important to manage as it could lead to non-adherence to treatment. Adverse effects may be more common in HIV-infected than in HIV-uninfected children. EXPERT OPINION: Although children may experience fewer adverse effects from oral second-line antituberculosis drugs than adults, evidence from prospective studies of the incidence of adverse events in children is limited. Higher doses of second line drugs, new antituberculosis drugs, and new drug regimens are being evaluated in children: these call for strict pharmacovigilance in children treated in the near future, as adverse effect profiles may change. PMID- 27458877 TI - Therapeutic significance of quinolines: a patent review (2013-2015). AB - INTRODUCTION: Quinoline is a versatile bicyclic heterocyclic scaffold with immense therapeutic potential. Some of the compounds containing quinoline nucleus are agents of choice for the treatment of various ailments, particularly cancer and malaria. Furthermore, several quinoline derivatives exhibit a broad spectrum of antimicrobial, anti-inflammatory, and antidiabetic activities, quite a few of which are under clinical investigation to combat potentially lethal diseases/disorders. AREAS COVERED: The present review summarizes inventions developed towards finding new chemotherapeutic agents based on the quinoline skeleton. It presents an outline of patents filed between 2013 and 2015, relating to the anticancer, antimicrobial, anti-inflammatory and other biological activities exhibited by quinoline derivatives. EXPERT OPINION: Several molecules containing quinoline skeleton are clinically significant drugs, extensively used for the treatment of various human diseases/disorders. The clinical success of some of these compounds and the versatile character of the quinoline nucleus attracted medicinal chemists in the development of newer chemotherapeutic agents. The considerably high number of patents filed in a relatively short period of time indicates the increasing importance of this pharmacophore. The development of facile synthetic strategies is anticipated to facilitate the generation of chemical libraries that could serve as a source of new chemical entities. PMID- 27458878 TI - Adhesiveless Transfer Printing of Ultrathin Microscale Semiconductor Materials by Controlling the Bending Radius of an Elastomeric Stamp. AB - High-performance electronic devices integrated onto unconventional substrates provide opportunities for use in diverse applications, such as wearable or implantable forms of electronic devices. However, the interlayer adhesives between the electronic devices and substrates often limit processing temperature or cause electrical or thermal resistance at the interface. This paper introduces a very simple but effective transfer printing method that does not require an interlayer adhesive. Controlling the bending radius of a simple flat stamp enables picking up or printing of microscale semiconductor materials onto rigid, curvilinear, or flexible surfaces without the aid of a liquid adhesive. Theoretical and experimental studies reveal the underlying mechanism of the suggested approach. Adhesiveless printing of thin Si plates onto diverse substrates demonstrates the capability of this method. PMID- 27458879 TI - Ecotoxicological assessment of pyriproxyfen under environmentally realistic exposure conditions of integrated vector management for Aedes aegypti control in Brazil. AB - There is increasing concern to control Aedes aegypti mosquito exposure in developing countries such as Brazil. Thus, integrated approaches using a combination of chemical, pyriproxyfen larvicide, and biological, Xiphophorus maculatus, larvivorous fish species approaches are necessary and important to initiate more effective control against mosquito borne diseases. This study describes the toxicological effects of pyriproxyfen larvicide on the fish Xiphophorus maculatus, the larvivorous fish species employed to destroy A. aegypti larvae mosquito species. The toxicological profile of pyriproxyfen was evaluated to determine compatible concentrations for the use of this chemical in conjunction with X. maculatus as an integrated approach against A. aegypti mosquito larvae. According to the behavioral responses of fish, the no-observed effect concentration (NOEC) and lowest-observed-effect concentration (LOEC) of pyriproxyfen were determined to be 2.5 and 5 ug/L, respectively. Bioassays indicated that although pyriproxyfen was not lethal to X. maculatus, the application of this compound at a concentration reported to control the emergence of A. aegypti larvae may decrease the swimming performance of larvivorous fish and their ability to ingest A. aegypti L4 larvae. Data show that integration of biological larvivorous fish and chemical larvicides is more effective when the appropriate larvicide concentration is utilized. PMID- 27458880 TI - Hexafluoro-2-propanol-Promoted Intermolecular Friedel-Crafts Acylation Reaction. AB - The intermolecular Friedel-Crafts acylation was carried out in hexafluoro-2 propanol to yield aryl and heteroaryl ketones at room temperature without any additional reagents. PMID- 27458890 TI - Thermodynamic Control of Two-Dimensional Molecular Ionic Nanostructures on Metal Surfaces. AB - Bulk molecular ionic solids exhibit fascinating electronic properties, including electron correlations, phase transitions, and superconducting ground states. In contrast, few of these phenomena have been observed in low-dimensional molecular structures, including thin films, nanoparticles, and molecular blends, not in the least because most of such structures have been composed of nearly closed-shell molecules. It is therefore desirable to develop low-dimensional ionic molecular structures that can capture potential applications. Here, we present detailed analysis of monolayer-thick structures of the canonical TTF-TCNQ (tetrathiafulvalene 7,7,8,8-tetracyanoquinodimethane) system grown on low-index gold and silver surfaces. The most distinctive property of the epitaxial growth is the wide abundance of stable TTF/TCNQ ratios, in sharp contrast to the predominance of a 1:1 ratio in the bulk. We propose the existence of the surface phase diagram that controls the structures of TTF-TCNQ on the surfaces and demonstrate phase transitions that occur upon progressively increasing the density of TCNQ while keeping the surface coverage of TTF fixed. Based on direct observations, we propose the binding motif behind the stable phases and infer the dominant interactions that enable the existence of the rich spectrum of surface structures. Finally, we also show that the surface phase diagram will control the epitaxy beyond monolayer coverage. Multiplicity of stable surface structures, the corollary rich phase diagram, and the corresponding phase transitions present an interesting opportunity for low-dimensional molecular systems, particularly if some of the electronic properties of the bulk can be preserved or modified in the surface phases. PMID- 27458891 TI - Mutation-Induced Changes in the Protein Environment and Site Energies in the (M)L214G Mutant of the Rhodobacter sphaeroides Bacterial Reaction Center. AB - This work focuses on the low-temperature (5 K) photochemical (transient) hole burned (HB) spectra within the P870 absorption band, and their theoretical analysis, for the (M)L214G mutant of the photosynthetic Rhodobacter sphaeroides bacterial reaction center (bRC). To provide insight into system-bath interactions of the bacteriochlorophyll a (BChl a) special pair, i.e., P870, in the mutated bRC, the optical line shape function for the P870 band is calculated numerically. On the basis of the modeling studies, we demonstrate that (M)L214G mutation leads to a heterogeneous population of bRCs with modified (increased) total electron phonon coupling strength of the special pair BChl a and larger inhomogeneous broadening. Specifically, we show that after mutation in the (M)L214G bRC a large fraction (~50%) of the bacteriopheophytin (HA) chromophores shifts red and the 800 nm absorption band broadens, while the remaining fraction of HA cofactors retains nearly the same site energy as HA in the wild-type bRC. Modeling using these two subpopulations allowed for fits of the absorption and nonresonant (transient) HB spectra of the mutant bRC in the charge neutral, oxidized, and charge-separated states using the Frenkel exciton Hamiltonian, providing new insight into the mutant's complex electronic structure. Although the average (M)L214G mutant quantum efficiency of P(+)QA(-) state formation seems to be altered in comparison with the wild-type bRC, the average electron transfer time (measured via resonant transient HB spectra within the P870 band) was not affected. Thus, mutation in the vicinity of the electron acceptor (HA) does not tune the charge separation dynamics. Finally, quenching of the (M)L214G mutant excited states by P(+) is addressed by persistent HB spectra burned within the B band in chemically oxidized samples. PMID- 27458892 TI - Fish gut microbiota analysis differentiates physiology and behavior of invasive Asian carp and indigenous American fish. PMID- 27458893 TI - Association Between Duration of Human Immunodeficiency Virus (HIV)-1 Viral Suppression Prior to Renal Transplantation and Acute Cellular Rejection. AB - Renal transplant has become an important option for human immunodeficiency virus (HIV)-infected patients with end-stage renal disease; however, these patients experience a high rate of acute cellular rejection (ACR). Guidelines do not currently exist for the optimal duration of viral suppression prior to transplantation. In a retrospective cohort analysis of 47 HIV-infected renal transplant recipients, we compared the rate of ACR between patients based on the length of time of viral suppression prior to transplantation. Of the patients who achieved viral suppression for >6 months but less than 2 years prior to transplantation (n = 15), 60% experienced ACR compared to 41% of patients suppressed at least 2 years or more (n = 32) prior to transplant (p = 0.21). Patients suppressed <2 years experienced ACR at 2.48 times the rate of those suppressed 2 years or longer. Induction immunosuppression, HLA mismatch and panel reactive antibodies (PRAs) did not significantly differ between the two groups. PMID- 27458894 TI - Early Postoperative Complications After Shoulder Arthroplasty in Patients With Epilepsy. AB - Epilepsy is the most common serious neurological disorder in the United States, but little is known about its effect in the perioperative shoulder surgery setting. The authors sought to determine whether patients with epilepsy undergoing shoulder arthroplasty would be at increased risk for in-hospital adverse events, prolonged length of stay, and nonroutine disposition. Using the National Inpatient Sample (2002-2011), 422,371 adults undergoing shoulder arthroplasty were identified, 3714 (0.9%) of whom had epilepsy. Comparisons of perioperative outcomes were performed by multivariable logistic regression modeling. The authors found that patients with epilepsy were more likely to experience postoperative adverse events (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.54-1.84), including mechanical ventilation (OR, 3.91; 95% CI, 2.81-5.44), gastrointestinal complication (OR, 3.86; 95% CI, 2.78-5.37), deep venous thrombosis (OR, 3.23; 95% CI, 2.22-4.69), pneumonia (OR, 1.66; 95% CI, 1.35-2.04), posthemorrhagic anemia (OR, 1.57; 95% CI, 1.42-1.73), transfusion (OR, 1.56; 95% CI, 1.41-1.72), and acute renal failure (OR, 1.34; 95% CI, 1.04 1.74). An epilepsy diagnosis was also associated with increased odds for prolonged hospital stay (OR, 1.39; 95% CI, 1.28-1.52) and nonroutine discharge (OR, 1.80; 95% CI, 1.67-1.94). This study concludes that patients with epilepsy are at higher risk for early postoperative complications and resource use following shoulder arthroplasty surgery. Awareness of these risks may allow more targeted perioperative management of these patients to optimize postoperative outcomes and limit complications. [Orthopedics. 2016; 39(6):e1075-e1079.]. PMID- 27458895 TI - Lateral Capsular Meniscal Tear in a Cross-country Runner. AB - Tears of the meniscal capsular junction present unique diagnostic and treatment challenges for practitioners because they are rich in blood supply yet often not visualized on magnetic resonance imaging. The authors report the case of a young man with a meniscal capsular junction tear, difficulties related to his diagnosis, and his short-term outcomes following surgical treatment. An 18-year old male cross-country runner presented to the authors for nonradiating lateral right knee pain after a failed course of physical therapy. This tear was only definitively diagnosed after inconclusive magnetic resonance imaging, an ultrasound-guided cortisone injection, and a direct arthroscopic visualization. He underwent an uncomplicated repair of his meniscal capsular junction tear with injection into the repair of bone marrow aspirate concentration taken from his iliac crest. At his 6-month follow-up visit, he had returned to cross-country running, achieved satisfactory Knee Outcome Scores, and reported minimal pain per the visual analog scale. This case is unique in that meniscal capsular junction tears often occur at the posteromedial portion. Given the rarity of these injuries, future studies should focus on longer-term outcomes following surgical repair of meniscal capsular junction tears and which techniques may portend to superior outcomes. [Orthopedics. 2016; 39(6):e1201-e1204.]. PMID- 27458896 TI - Hip Pain After a Femoral Fracture: It Is Not Always Related to the Implant. AB - The source of continued hip pain following fixation of traumatic femoral shaft fracture is not always clear. Intra-articular hip pathology is often overlooked when evaluating the etiology of residual pain. The purpose of this study was to describe cases of intra-articular hip pathology following traumatic femoral shaft fracture. This was a retrospective case series of patients presenting to a private practice orthopedic clinic from 2012 to 2015. Three patients presented with symptomatic intra-articular hip pathology following traumatic ipsilateral femoral shaft fracture. Patients who underwent hip arthroscopy with allograft labral reconstruction were identified retrospectively. Validated, subjective outcome scores administered included the Modified Harris Hip Score (MHHS), Lower Extremity Functional Scale (LEFS), visual analog scale (VAS) for pain, and VAS scale for patient satisfaction. Three patients were identified with residual, disabling groin pain after femoral shaft fracture fixation following a traumatic motor vehicle accident. All 3 patients were found to have a symptomatic ipsilateral labral tear. In 2 of the patients, an indentation on the lateral femoral head was appreciated, which was hypothesized to be caused by a subluxation event. All 3 patients were treated with arthroscopic hip surgery. At final follow-up, all 3 patients showed significant improvement in MHHS, VAS pain scores, level of satisfaction, and LEFS. Residual pain following ipsilateral femoral shaft fracture is not always related to implant. Intra-articular hip pathology should be considered in patients with lingering hip pain. [Orthopedics. 2016; 39(6):e1080-e1084.]. PMID- 27458897 TI - A Simple Method for Fixation of Proximal Opening-Wedge Osteotomy of the First Metatarsal for Correction of Hallux Valgus. AB - A simple, inexpensive technique for fixation of proximal opening-wedge osteotomy of the first metatarsal for correction of moderate or severe hallux valgus (HV) is described. After the opening-wedge osteotomy and bone grafting of the first metatarsal have been performed, 2 Kirschner wires are introduced for internal fixation and removed 8 weeks postoperatively. Twenty-three patients with symptomatic HV who had a proximal medial opening-wedge osteotomy of the first metatarsal in combination with a distal soft tissue procedure and bunionectomy were evaluated retrospectively. All osteotomies healed without complications and satisfaction was achieved in 22 patients. Hallux varus developed in 1 patient. Preoperatively, mean HV angle (HVA) was 41 degrees (range, 35 degrees -61 degrees ) and mean 1-2 intermetatarsal angle (IMA) was 19 degrees (range, 16 degrees -24 degrees ). Postoperatively, mean HVA was 14 degrees (range, 10 degrees -17 degrees ) and mean 1-2 IMA was 7 degrees (range, 5 degrees -9 degrees ). The mean decrease in the HVA was 27 degrees (P<.001) and the mean decrease in the 1-2 IMA was 12 degrees (P<.001). [Orthopedics. 2016; 39(6):e1213 e1217.]. PMID- 27458898 TI - Stress Fractures of the Distal Femur Involving Small Nonossifying Fibromas in Young Athletes. AB - Small nonossifying fibromas (ie, fibrocortical defects) are incidental findings commonly seen on radiographs of young patients evaluated for extremity pain or sport-related trauma. Although pathological fractures have been reported in larger lesions, the subcentimeter, intracortical defects are not generally thought to predispose to pathological fractures. The authors report on 2 young athletes who presented with knee pain after initiating conditioning exercise programs (cross-training). Both were diagnosed with transverse metaphyseal stress fractures involving fibrous cortical defects of the distal femur. Initial radiographs were interpreted without evidence of fractures. However, subsequent magnetic resonance imaging was informative, suggesting that magnetic resonance imaging may have value in identifying potential stress reactions in young athletes. In addition, subsequent plain radiographs of both patients showed subperiosteal new bone formation in these nondisplaced fractures, suggesting that serial radiographs and close clinical follow-up are warranted for patients with persistent symptoms. The authors propose that, in the appropriate clinical setting, the presence of a small nonossifying fibroma may be a clinical indication that further evaluation is needed when plain radiographs show normal findings, as the defect could be an unrecognized area of fracture initiation. [Orthopedics. 2016; 39(6):e1197-e1200.]. PMID- 27458899 TI - The 50 Most Cited Articles in Rotator Cuff Repair Research. AB - Analysis of the number of citations within a given specialty provides information on the classic publications of that specialty. The goals of this study were to identify the 50 most cited articles on rotator cuff repair and to analyze various characteristics of these articles. The ISI Web of Science (Thomson Reuters, Philadelphia, Pennsylvania) was used to conduct a search for the term rotator cuff repair. The 50 most cited articles were retrieved, and the following objective characteristics of each article were recorded: number of times cited, citation density, journal, country of origin, and language. The following subjective characteristics of each article were also recorded: article type (clinical vs basic science), article subtype, and level of evidence for clinical articles. Of the 50 most cited articles on rotator cuff repair, the number of citations ranged from 138 to 677 (mean, 232+/-133 citations) and citation density ranged from 3.8 to 53.5 citations per year (mean, 16.9+/-9.2 citations per year). The articles were published between 1974 and 2011, with most of the articles published in the 2000s (29 articles), followed by the 1990s (16 articles). The articles originated from 8 countries, with the United States accounting for 30 articles (60%). Overall, 66% of the articles were clinical and 34% were basic science. The most common article subtype was the clinical case series (48%). Of the 33 clinical articles, 24 (73%) were level IV. Among the 50 most cited articles on rotator cuff repair, the case series was the most common article subtype, showing the effect that publication of preliminary outcomes and new surgical techniques has had on surgeons performing rotator cuff repair. [Orthopedics. 2016; 39(6):e1045-e1051.]. PMID- 27458900 TI - Early-term deliveries as an independent risk factor for long-term respiratory morbidity of the offspring. AB - OBJECTIVE: Newborns exhibit the lowest immediate respiratory morbidity rates when born following 39 completed weeks of gestation. We sought to determine whether early-term delivery (37-38 + 6 weeks' gestation) impacts on long-term pediatric respiratory morbidity. STUDY DESIGN: In this population-based prospective cohort analysis, all term singleton deliveries occurring between 1991 and 2013 at a single tertiary medical center were included. Gestational age upon delivery was sub-divided into: early (37-38 + 6 weeks' gestation), full (39-40 + 6 weeks' gestation), late (41-41 + 6 weeks' gestation), and post-term (>42 weeks) deliveries. The incidence of long-term hospitalizations (up to the age of 18 years) of the offspring due to a set of predefined respiratory morbidities was evaluated. Survival curves were used to compare cumulative morbidity incidence. A Cox hazards regression model was used to control for confounders. RESULTS: During the study period, 229,142 term deliveries met the inclusion criteria. Of those, 24% (n = 55,202) occurred at early term. Hospitalizations up to the age of 18 years, as a result of complications in the respiratory system were significantly more common in the early-term group as compared with full and late-term delivery groups. In the Cox regression model, while controlling for multiple confounders, early-term delivery exhibited an independent association with long-term respiratory morbidity (adjusted HR = 1.24, CI 1.19-1.29, P < 0.001). CONCLUSION: Deliveries occurring at early term are associated with higher rates of pediatric respiratory hospitalizations compared with full and late-term deliveries. Pediatr Pulmonol. 2017;52:198-204. (c) 2016 Wiley Periodicals, Inc. PMID- 27458901 TI - Demineralized bone matrix fibers formable as general and custom 3D printed mold based implants for promoting bone regeneration. AB - INTRODUCTION: Bone repair frequently requires time-consuming implant construction, particularly when using un-formed implants with poor handling properties. We therefore developed osteoinductive, micro-fibrous surface patterned demineralized bone matrix (DBM) fibers for engineering both defect matched and general three-dimensional implants. METHODS AND RESULTS: Implant molds were filled with demineralized human cortical bone fibers there were compressed and lyophilized, forming mechanically strong shaped DBM scaffolds. Enzyme linked immunosorbent assays and mass spectrometry confirmed that DBM fibers contained abundant osteogenic growth factors (bone morphogenetic proteins, insulin-like growth factor-I) and extracellular matrix proteins. Mercury porosimetry and mechanical testing showed interconnected pores within the mechanically stable, custom DBM fiber scaffolds. Mesenchymal stem cells readily attached to the DBM and showed increasing metabolic activity over time. DBM fibers further increased alkaline phosphatase activity in C2C12 cells. In vivo, DBM implants elicited osteoinductive potential in a mouse muscle pouch, and also promoted spine fusion in a rat arthrodesis model. SIGNIFICANCE: DBM fibers can be engineered into custom-shaped, osteoinductive and osteoconductive implants with potential for repairing osseous defects with precise fitment, potentially reducing operating time. By providing pre-formed and custom implants, this regenerative allograft may improve patient outcomes following surgical bone repair, while further advancing personalized orthopedic and craniomaxillofacial medicine using three-dimensional-printed tissue molds. PMID- 27458903 TI - Preliminary experience using a tunica vaginalis flap as the dorsal component of Bracka's urethroplasty. AB - OBJECTIVE: To evaluate clinical use of a tunica vaginalis flap as the dorsal component of a two-stage urethroplasty in boys with cripple hypospadias. PATIENTS AND METHODS: We performed the first stage of a Bracka two-stage urethroplasty, using a tunica vaginalis flap as the dorsal component in six boys with cripple hypospadias. We analysed their clinical characteristics and the results of this technique. RESULTS: The mean (range) age of the boys was 57 (34-120) months. The mean (range) number of previous procedures the boys had undergone was 4 (3-5). At the 6-month follow-up, all the boys presented significant fibrosis of the dorsal graft rendering it unusable for tubularisation. CONCLUSIONS: Exposure to the external environment seems to induce retraction and fibrosis of the tunica vaginalis. We believe one should be very cautious about using tunica vaginalis as the dorsal component of a two-stage urethroplasty, as significant fibrosis might well render the flap unusable. PMID- 27458902 TI - Surgical prophylaxis with gram-negative activity for reduction of surgical site infections after microvascular reconstruction for head and neck cancer. AB - BACKGROUND: The purpose of this study was to determine the incidence of and risk factors for surgical site infections in microvascular reconstruction for patients with head and neck cancer. METHODS: One hundred seventeen patients with head and neck cancer undergoing microvascular reconstruction received postoperative surgical infection prophylaxis and were followed for 30 days. Surgical infection prophylaxis was categorized by empiric spectrum of activity. Risk factors for surgical site infection development and cumulative incidence of surgical site infections were characterized. RESULTS: Thirty-seven patients developed surgical site infection (cumulative surgical site infection incidence of 31.6%). Risk factors identified in logistic regression include alcohol use (odds ratio [OR] = 2.704; 95% confidence interval [CI] = 1.029-7.106), increased surgical duration (OR = 1.403; 95% CI = 1.185-1.661), American Society of Anesthesiologists (ASA) class IV (OR = 3.075; 95% CI = 1.000-9.459), and lack of postoperative gram negative coverage (OR = 15.139; 95% CI = 3.083-74.347). CONCLUSION: Alcohol use, longer surgical duration, and lack of gram-negative postoperative prophylactic coverage are modifiable risk factors for surgical site infection development. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: First-1454, 2016. PMID- 27458904 TI - Epigenetics, cellular memory and gene regulation. AB - The field described as 'epigenetics' has captured the imagination of scientists and the lay public. Advances in our understanding of chromatin and gene regulatory mechanisms have had impact on drug development, fueling excitement in the lay public about the prospects of applying this knowledge to address health issues. However, when describing these scientific advances as 'epigenetic', we encounter the problem that this term means different things to different people, starting within the scientific community and amplified in the popular press. To help researchers understand some of the misconceptions in the field and to communicate the science accurately to each other and the lay audience, here we review the basis for many of the assumptions made about what are currently referred to as epigenetic processes. PMID- 27458905 TI - 'Model organisms' in the light of evolution. AB - Paul Katz argues that is time to stop using the term 'model' to describe subject species in biology. PMID- 27458906 TI - Camouflage. AB - Nokelainen and Stevens introduce strategies of concealment among animals and plants. PMID- 27458907 TI - Dimensionality reduction in neuroscience. AB - The nervous system extracts information from its environment and distributes and processes that information to inform and drive behaviour. In this task, the nervous system faces a type of data analysis problem, for, while a visual scene may be overflowing with information, reaching for the television remote before us requires extraction of only a relatively small fraction of that information. We could care about an almost infinite number of visual stimulus patterns, but we don't: we distinguish two actors' faces with ease but two different images of television static with significant difficulty. Equally, we could respond with an almost infinite number of movements, but we don't: the motions executed to pick up the remote are highly stereotyped and related to many other grasping motions. If we were to look at what was going on inside the brain during this task, we would find populations of neurons whose electrical activity was highly structured and correlated with the images on the screen and the action of localizing and picking up the remote. PMID- 27458908 TI - Culture shapes 7-month-olds' perceptual strategies in discriminating facial expressions of emotion. AB - Emotional facial expressions are thought to have evolved because they play a crucial role in species' survival. From infancy, humans develop dedicated neural circuits [1] to exhibit and recognize a variety of facial expressions [2]. But there is increasing evidence that culture specifies when and how certain emotions can be expressed - social norms - and that the mature perceptual mechanisms used to transmit and decode the visual information from emotional signals differ between Western and Eastern adults [3-5]. Specifically, the mouth is more informative for transmitting emotional signals in Westerners and the eye region for Easterners [4], generating culture-specific fixation biases towards these features [5]. During development, it is recognized that cultural differences can be observed at the level of emotional reactivity and regulation [6], and to the culturally dominant modes of attention [7]. Nonetheless, to our knowledge no study has explored whether culture shapes the processing of facial emotional signals early in development. The data we report here show that, by 7 months, infants from both cultures visually discriminate facial expressions of emotion by relying on culturally distinct fixation strategies, resembling those used by the adults from the environment in which they develop [5]. PMID- 27458909 TI - Brain development is similar in Neanderthals and modern humans. AB - While the braincase of adult Neanderthals had a similar volume to that of modern humans from the same period, differences in endocranial shape suggest that brain morphology differed between modern humans and Neanderthals. When and how these differences arose during evolution and development is a topic of ongoing research, with potential implications for species-specific differences in brain and cognitive development, and in life history [1,2]. Earlier research suggested that Neanderthals followed an ancestral mode of brain development, similar to that of our closest living relatives, the chimpanzees [2-4]. Modern humans, by contrast, were suggested to follow a uniquely derived mode of brain development just after birth, giving rise to the characteristically globular shape of the adult human brain case [2,4,5]. Here, we re-examine this hypothesis using an extended sample of Neanderthal infants. We document endocranial development during the decisive first two years of postnatal life. The new data indicate that Neanderthals followed largely similar modes of endocranial development to modern humans. These findings challenge the notion that human brain and cognitive development after birth is uniquely derived [2,4]. PMID- 27458910 TI - Evolution: Bioluminescent Courtship as an Engine of Diversity. AB - A new study finds that the evolution of bioluminescent sexual displays drives high species richness across animal lineages, providing a crucial link between microevolutionary and macroevolutionary explanations of biodiversity. PMID- 27458911 TI - Circadian Rhythms: Does Burning the Midnight Oil Leave You Weak? AB - A new study shows that nocturnal light exposure rapidly disrupts the central circadian clock as well as reduces motor performance and bone health. These findings provide a striking example of the costs of living in a disrupted light/dark cycle. PMID- 27458912 TI - Neuroscience: Impaired Decision-Making in Parkinson's Disease. AB - When making decisions we combine previously acquired knowledge with the available current information to optimize our choices. A new study shows that Parkinson patients are impaired in using their prior knowledge leading to suboptimal decisions when current information is ambiguous. PMID- 27458913 TI - Neuroscience: Incepting Associations. AB - A recent study has used real-time fMRI neurofeedback to induce color-specific activity patterns in early visual cortex as participants viewed achromatic gratings. This procedure resulted in an association between the color and the displayed grating orientation, suggesting that early visual cortex can support associative learning of this type. PMID- 27458914 TI - Decision-Making: Are Plants More Rational than Animals? AB - A new study presents a novel experimental design and allows a test of risk sensitivity in plants. Faced with a choice between constant and variable resource supply, they make a rational decision for the option that maximizes fitness, a fact rarely observed in animals. PMID- 27458915 TI - Visual Space: Adaptation to Texture Density Reduces Perceived Object Size. AB - A recent study shows that visual adaptation to dense textures, while causing an increase in the perceived sparseness of a subsequently viewed less-dense texture, paradoxically reduces the perceived size of an object, revealing a dissociation between the internal spatial representations of textures and objects. PMID- 27458916 TI - Evo-Devo: Universal Toll Pass for the Extension Highway? AB - The distinction between long-germ and short-germ insects is a classic one in evo devo, yet a common genetic mechanism may underlie germband extension in all insects, even all arthropods. PMID- 27458917 TI - CRISPR-Cas: Spacer Diversity Determines the Efficiency of Defense. AB - Bacterial CRISPR-Cas systems acquire short sequences, called spacers, from viruses and plasmids, leading to adaptive immunity. The diversity of spacers within natural bacterial populations is very high. New data now explain how spacer diversity strengthens resistance of the bacterial population to phage infection. PMID- 27458918 TI - Animal Evolution: The Hard Problem of Cartilage Origins. AB - Our skeletons evolved from cartilaginous tissue, but it remains a mystery how cartilage itself first arose in evolution. Characterization of cartilage in cuttlefish and horseshoe crabs reveals surprising commonalities with chordate chondrocytes, suggesting a common evolutionary origin. PMID- 27458919 TI - Ionic Liquid Ordering at an Oxide Surface. AB - The interaction of the ionic liquid [C4 C1 Im][BF4 ] with anatase TiO2 , a model photoanode material, has been studied using a combination of synchrotron radiation photoelectron spectroscopy and near-edge X-ray absorption fine structure spectroscopy. The system is of interest as a model for fundamental electrolyte-electrode and dye-sensitized solar cells. The initial interaction involves degradation of the [BF4 ]- anion, resulting in incorporation of F into O vacancies in the anatase surface. At low coverages, [C4 C1 Im][BF4 ] is found to order at the anatase(101) surface via electrostatic attraction, with the imidazolium ring oriented 32+/-4 degrees from the anatase TiO2 surface. As the coverage of ionic liquid increases, the influence of the oxide surface on the topmost layers is reduced and the ordering is lost. PMID- 27458920 TI - Continuous Monitoring of Specific mRNA Expression Responses with a Fluorescence Resonance Energy Transfer-Based DNA Nano-tweezer Technique That Does Not Require Gene Recombination. AB - This letter discusses the feasibility of continuously monitoring specific mRNA expression responses in a living cell with a probe structured as a fluorescence resonance energy transfer (FRET)-based DNA nano-tweezer (DNA-NT). The FRET-based DNA-NT, self-assembled from three single-stranded DNAs, alters its structure from an open state to a closed state in recognition of a target mRNA, resulting in the closing of the distal relation of previously modified FRET-paired fluorescent dyes and generating a FRET signal. The expressions of glucose transporters (GLUT) 1 and 4 in a mouse hepato-carcinoma (Hepa 1-6 cells) were selected as the target model. Live-cell imaging analysis of Hepa 1-6 cells with both FRET-based DNA-NTs indicated that the behaviors of the FRET signals integrated in each individual cell were similar to those measured with the conventional mass analysis technique of semiquantitative real-time (RT) polymerase chain reaction (PCR). From these results, it is concluded that continuous monitoring of gene expression response without gene recombination is feasible with a FRET-based DNA-NT, even in a single cell manner. PMID- 27458921 TI - Exploring Explanations of Subglacial Bedform Sizes Using Statistical Models. AB - Sediments beneath modern ice sheets exert a key control on their flow, but are largely inaccessible except through geophysics or boreholes. In contrast, palaeo ice sheet beds are accessible, and typically characterised by numerous bedforms. However, the interaction between bedforms and ice flow is poorly constrained and it is not clear how bedform sizes might reflect ice flow conditions. To better understand this link we present a first exploration of a variety of statistical models to explain the size distribution of some common subglacial bedforms (i.e., drumlins, ribbed moraine, MSGL). By considering a range of models, constructed to reflect key aspects of the physical processes, it is possible to infer that the size distributions are most effectively explained when the dynamics of ice-water sediment interaction associated with bedform growth is fundamentally random. A 'stochastic instability' (SI) model, which integrates random bedform growth and shrinking through time with exponential growth, is preferred and is consistent with other observations of palaeo-bedforms and geophysical surveys of active ice sheets. Furthermore, we give a proof-of-concept demonstration that our statistical approach can bridge the gap between geomorphological observations and physical models, directly linking measurable size-frequency parameters to properties of ice sheet flow (e.g., ice velocity). Moreover, statistically developing existing models as proposed allows quantitative predictions to be made about sizes, making the models testable; a first illustration of this is given for a hypothesised repeat geophysical survey of bedforms under active ice. Thus, we further demonstrate the potential of size-frequency distributions of subglacial bedforms to assist the elucidation of subglacial processes and better constrain ice sheet models. PMID- 27458923 TI - Retraction: Association of Polymorphism rs198977 in Human Kallikrein-2 Gene (KLK2) with Susceptibility of Prostate Cancer: A Meta-Analysis. PMID- 27458922 TI - Is It Time to Change Our Reference Curve for Femur Length? Using the Z-Score to Select the Best Chart in a Chinese Population. AB - OBJECTIVE: To use Z-scores to compare different charts of femur length (FL) applied to our population with the aim of identifying the most appropriate chart. METHODS: A retrospective study was conducted in Beijing. Fifteen hospitals in Beijing were chosen as clusters using a systemic cluster sampling method, in which 15,194 pregnant women delivered from June 20th to November 30th, 2013. The measurements of FL in the second and third trimester were recorded, as well as the last measurement obtained before delivery. Based on the inclusion and exclusion criteria, we identified FL measurements from 19996 ultrasounds from 7194 patients between 11 and 42 weeks gestation. The FL data were then transformed into Z-scores that were calculated using three series of reference equations obtained from three reports: Leung TN, Pang MW et al (2008); Chitty LS, Altman DG et al (1994); and Papageorghiou AT et al (2014). Each Z-score distribution was presented as the mean and standard deviation (SD). Skewness and kurtosis and were compared with the standard normal distribution using the Kolmogorov-Smirnov test. The histogram of their distributions was superimposed on the non-skewed standard normal curve (mean = 0, SD = 1) to provide a direct visual impression. Finally, the sensitivity and specificity of each reference chart for identifying fetuses <5th or >95th percentile (based on the observed distribution of Z-scores) were calculated. The Youden index was also listed. A scatter diagram with the 5th, 50th, and 95th percentile curves calculated from and superimposed on each reference chart was presented to provide a visual impression. RESULTS: The three Z-score distribution curves appeared to be normal, but none of them matched the expected standard normal distribution. In our study, the Papageorghiou reference curve provided the best results, with a sensitivity of 100% for identifying fetuses with measurements < 5th and > 95th percentile, and specificities of 99.9% and 81.5%, respectively. CONCLUSIONS: It is important to choose an appropriate reference curve when defining what is normal. The Papageorghiou reference curve for FL seems to be the best fit for our population. Perhaps it is time to change our reference curve for femur length. PMID- 27458924 TI - Crowdsourcing: It Matters Who the Crowd Are. The Impacts of between Group Variations in Recording Land Cover. AB - Volunteered geographical information (VGI) and citizen science have become important sources data for much scientific research. In the domain of land cover, crowdsourcing can provide a high temporal resolution data to support different analyses of landscape processes. However, the scientists may have little control over what gets recorded by the crowd, providing a potential source of error and uncertainty. This study compared analyses of crowdsourced land cover data that were contributed by different groups, based on nationality (labelled Gondor and Non-Gondor) and on domain experience (labelled Expert and Non-Expert). The analyses used a geographically weighted model to generate maps of land cover and compared the maps generated by the different groups. The results highlight the differences between the maps how specific land cover classes were under- and over estimated. As crowdsourced data and citizen science are increasingly used to replace data collected under the designed experiment, this paper highlights the importance of considering between group variations and their impacts on the results of analyses. Critically, differences in the way that landscape features are conceptualised by different groups of contributors need to be considered when using crowdsourced data in formal scientific analyses. The discussion considers the potential for variation in crowdsourced data, the relativist nature of land cover and suggests a number of areas for future research. The key finding is that the veracity of citizen science data is not the critical issue per se. Rather, it is important to consider the impacts of differences in the semantics, affordances and functions associated with landscape features held by different groups of crowdsourced data contributors. PMID- 27458925 TI - Incorporation of a Nuclear Localization Signal in pH Responsive LAH4-L1 Peptide Enhances Transfection and Nuclear Uptake of Plasmid DNA. AB - The major intracellular barriers associated with DNA delivery using nonviral vectors are inefficient endosomal/lysosomal escape and poor nuclear uptake. LAH4 L1, a pH responsive cationic amphipathic peptide, is an efficient DNA delivery vector that promotes the release of nucleic acid into cytoplasm through endosomal escape. Here we further enhance the DNA transfection efficiency of LAH4-L1 by incorporating nuclear localizing signal (NLS) to promote nuclear importation. Four NLSs were investigated: Simian virus 40 (SV40) large T-antigen derived NLS, nucleoplasmin targeting signal, M9 sequence, and the reverse SV40 derived NLS. All peptides tested were able to form positively charged nanosized complexes with DNA. Significant improvement in DNA transfection was observed in slow-dividing epithelial cancer cells (Calu-3), macrophages (RAW264.7), dendritic cells (JAWSII), and thymidine-induced growth-arrested cells, but not in rapidly dividing cells (A549). Among the four NLS-modified peptides, PK1 (modified with SV40 derived NLS) and PK2 (modified with reverse SV40 derived NLS) were the most consistent in improving DNA transfection; up to a 10-fold increase in gene expression was observed for PK1 and PK2 over the unmodified LAH4-L1. Additionally PK1 and PK2 were shown to enhance cellular uptake as well as nuclear entry of DNA. Overall, we show that the incorporation of SV40 derived NLS, in particular, to LAH4-L1 is a promising strategy to improve DNA delivery efficiency in slow dividing cells and dendritic cells, with development potential for in vivo applications and as a DNA vaccine carrier. PMID- 27458926 TI - A Lack of Bioactive Predictability for Marker Compounds Commonly Used for Herbal Medicine Standardization. AB - The use of botanical medicine by practitioners and the general public has dramatically increased in recent years. Most of these botanical therapeutics are obtained through commercial manufacturers or nutraceutical companies. The current standard of practice that manufacturers typically use to standardize botanicals is done based on the level of a well-known, abundant marker compound present in the botanical. This study evaluated the putative correlation between the level of a marker compound and the biological activity of eight common botanicals. Overall, the standardization of a botanical based on a marker compound was found not to be a reliable method when compared to in vitro bioactivity. A marker compound is often not the biologically active component of a plant and therefore the level of such a marker compound does not necessarily correlate with biological activity or therapeutic efficacy. PMID- 27458930 TI - Yellow Painting (Abstraction): Ad Reinhardt. PMID- 27458927 TI - Chemical, microscopic, and microbiological analysis of a functionalized poly ether-ether-ketone-embedding antibiofilm compounds. AB - Poly-ether-ether-ketone (PEEK) is currently introduced as an alternative material for orthopedic implants due to its biocompatibility and low elastic modulus compared to titanium. Also, a sulphonation treatment can functionalize PEEK to embed therapeutical substances. The objective of this work was to functionalize a PEEK film to incorporate novel lactam-based antibiofilms compounds. PEEK samples were functionalized by sulphuric acid treatment and then dissolved in dimethylsulfoxide, where lactams were added to be incorporated into the polymer. A dip-coating technique was used to synthesize a thin film on a glass-based substrate. The degree of sulfonation (DS) and the incorporation of lactams into sulphonated PEEK (sPEEK) were analyzed by Fourier transform infrared spectroscopy, nuclear magnetic resonance, thermogravimetric analysis (TGA), and scanning electron microscopy. A DS of 65% was obtained and TGA curves confirmed the presence of SO3 H and lactams in the sPEEK structure. The growth of Streptococcus mutans biofilm decreased on sPEEK surface containing lactams when compared to sPEEK free of lactams. That indicated the antibiofilm activity of those compounds was maintained after incorporation into sPEEK. Planktonic growth analysis showed no long distant effects of sPEEK containing lactams, indicating that no systemic effects should be expected upon clinical uses of medical devices produced with lactam-treated sPEEK. Results revealed that inclusion of lactams into sPEEK represents a good alternative for the production of biomaterials resistant to bacterial accumulation. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3015-3020, 2016. PMID- 27458939 TI - The Potential to Advance Health Care in the US Criminal Justice System. PMID- 27458940 TI - A PIECE OF MY MIND. A Word From Our Sponsors. PMID- 27458941 TI - Whole Brain Radiotherapy for Brain Metastases: Is the Debate Over? PMID- 27458942 TI - Improving Birth Outcomes Key to Improving Global Health. PMID- 27458943 TI - Trisomy 13 and 18--Treatment Decisions in a Stable Gray Zone. PMID- 27458944 TI - Visual Inspection and the US Preventive Services Task Force Recommendation on Skin Cancer Screening. PMID- 27458945 TI - Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. AB - IMPORTANCE: Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial. OBJECTIVE: To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT. DESIGN, SETTING, AND PARTICIPANTS: At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. INTERVENTIONS: The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. MAIN OUTCOMES AND MEASURES: The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3 month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival. RESULTS: There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P < .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, -48.7%; 95% CI, -87.6% to -9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, -34.4%; 95% CI, -74.4% to 5.5%; P = .04). CONCLUSIONS AND RELEVANCE: Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00377156. PMID- 27458946 TI - Temporal Trends in Late Preterm and Early Term Birth Rates in 6 High-Income Countries in North America and Europe and Association With Clinician-Initiated Obstetric Interventions. AB - IMPORTANCE: Clinicians have been urged to delay the use of obstetric interventions (eg, labor induction, cesarean delivery) until 39 weeks or later in the absence of maternal or fetal indications for intervention. OBJECTIVE: To describe recent trends in late preterm and early term birth rates in 6 high income countries and assess association with use of clinician-initiated obstetric interventions. DESIGN: Retrospective analysis of singleton live births from 2006 to the latest available year (ranging from 2010 to 2015) in Canada, Denmark, Finland, Norway, Sweden, and the United States. EXPOSURES: Use of clinician initiated obstetric intervention (either labor induction or prelabor cesarean delivery) during delivery. MAIN OUTCOMES AND MEASURES: Annual country-specific late preterm (34-36 weeks) and early term (37-38 weeks) birth rates. RESULTS: The study population included 2,415,432 Canadian births in 2006-2014 (4.8% late preterm; 25.3% early term); 305,947 Danish births in 2006-2010 (3.6% late preterm; 18.8% early term); 571,937 Finnish births in 2006-2015 (3.3% late preterm; 16.8% early term); 468,954 Norwegian births in 2006-2013 (3.8% late preterm; 17.2% early term); 737,754 Swedish births in 2006-2012 (3.6% late preterm; 18.7% early term); and 25,788,558 US births in 2006-2014 (6.0% late preterm; 26.9% early term). Late preterm birth rates decreased in Norway (3.9% to 3.5%) and the United States (6.8% to 5.7%). Early term birth rates decreased in Norway (17.6% to 16.8%), Sweden (19.4% to 18.5%), and the United States (30.2% to 24.4%). In the United States, early term birth rates decreased from 33.0% in 2006 to 21.1% in 2014 among births with clinician-initiated obstetric intervention, and from 29.7% in 2006 to 27.1% in 2014 among births without clinician-initiated obstetric intervention. Rates of clinician-initiated obstetric intervention increased among late preterm births in Canada (28.0% to 37.9%), Denmark (22.2% to 25.0%), and Finland (25.1% to 38.5%), and among early term births in Denmark (38.4% to 43.8%) and Finland (29.8% to 40.1%). CONCLUSIONS AND RELEVANCE: Between 2006 and 2014, late preterm and early term birth rates decreased in the United States, and an association was observed between early term birth rates and decreasing clinician-initiated obstetric interventions. Late preterm births also decreased in Norway, and early term births decreased in Norway and Sweden. Clinician-initiated obstetric interventions increased in some countries but no association was found with rates of late preterm or early term birth. PMID- 27458947 TI - Survival and Surgical Interventions for Children With Trisomy 13 and 18. AB - IMPORTANCE: Trisomy 13 and 18 are genetic diagnoses with characteristic physical features, organ anomalies, and neurodevelopmental disability. Most children with these disorders die shortly after birth, although limited data suggest some children survive longer. Surgeries are controversial, and little evidence is available about outcomes. OBJECTIVE: To describe survival and utilization of any type of surgery among children with trisomy 13 and 18 born over a 21-year period in Ontario, Canada. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used linked health administrative databases to identify children born in Ontario between April 1, 1991, and March 31, 2012, with a diagnosis code for trisomy 13 or 18 on a hospital record in the first year of life. Survival was calculated from birth and death dates; children living on March 31, 2013, were censored at their last clinical encounter. EXPOSURES: All procedures classified as occurring in an operating room through March 31, 2013, were categorized as major, intermediate, or minor surgeries. MAIN OUTCOMES AND MEASURES: Survival and surgical procedure utilization. RESULTS: The cohorts included 174 children with trisomy 13 (mean [SD] birth weight, 2.5 [0.7] kg; 98 [56.3%] female); and 254 children with trisomy 18 (mean birth weight, 1.8 [0.7] kg; 157 [61.8%] female), with follow-up times of 0 to more than 7000 days. Median (interquartile range [IQR]) survival times were 12.5 (2-195) days for trisomy 13 and 9 (2-92) days for trisomy 18. Mean 1-year survival for trisomy 13 was 19.8% (95% CI, 14.2%-26.1%) and 12.6% (95% CI, 8.9%-17.1%) for trisomy 18. Ten-year survival for trisomy 13 was 12.9% (95% CI, 8.4%-18.5%) and 9.8% (95% CI, 6.4%-14.0%) for trisomy 18. Survival did not change over the study period. Forty-one children (23.6%) with trisomy 13 and 35 children (13.8%) with trisomy 18 underwent surgeries, ranging from myringotomy to complex cardiac repair. Median age at first surgery for trisomy 13 was 92 (IQR, 30.5-384.5) days and for trisomy 18, it was 205.5 (IQR, 20.0-518.0) days. Kaplan-Meier curves showed 1-year survival after first surgery of 70.7% (95% CI, 54.3%-82.2%; n = 23) for trisomy 13 and 68.6% (95% CI, 50.5% 81.2%; n = 29) for trisomy 18. CONCLUSIONS AND RELEVANCE: Among children born with trisomy 13 or 18 in Ontario, early mortality was the most common outcome, but 10% to 13% survived for 10 years. Among children who underwent surgical interventions, 1-year survival was high. PMID- 27458948 TI - Screening for Skin Cancer: US Preventive Services Task Force Recommendation Statement. AB - IMPORTANCE: Basal and squamous cell carcinoma are the most common types of cancer in the United States and represent the vast majority of all cases of skin cancer; however, they rarely result in death or substantial morbidity, whereas melanoma skin cancer has notably higher mortality rates. In 2016, an estimated 76,400 US men and women will develop melanoma and 10,100 will die from the disease. OBJECTIVE: To update the 2009 US Preventive Services Task Force (USPSTF) recommendation on screening for skin cancer. EVIDENCE REVIEW: The USPSTF reviewed the evidence on the effectiveness of screening for skin cancer with a clinical visual skin examination in reducing skin cancer morbidity and mortality and death from any cause; its potential harms, including any harms resulting from associated diagnostic follow-up; its test characteristics when performed by a primary care clinician vs a dermatologist; and whether its use leads to earlier detection of skin cancer compared with usual care. FINDINGS: Evidence to assess the net benefit of screening for skin cancer with a clinical visual skin examination is limited. Direct evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations. Information on harms is similarly sparse. The potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment. CONCLUSIONS AND RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults (I statement). PMID- 27458949 TI - Screening for Skin Cancer in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - IMPORTANCE: Skin cancer, primarily melanoma, is a leading cause of morbidity and mortality in the United States. OBJECTIVE: To provide an updated systematic review for the US Preventive Services Task Force regarding clinical skin cancer screening among adults. DATA SOURCES: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials were searched for relevant studies published from January 1, 1995, through June 1, 2015, with surveillance through February 16, 2016. STUDY SELECTION: English-language studies conducted in asymptomatic populations 15 years and older at general risk for skin cancer. DATA EXTRACTION AND SYNTHESIS: Relevant data were abstracted, and study quality was rated. MAIN OUTCOMES AND MEASURES: Melanoma incidence and mortality, harms from cancer screening, diagnostic accuracy, and stage distribution. RESULTS: No randomized clinical trials were identified. There was limited evidence on the association between skin cancer screening and mortality. A German ecologic study (n = 360,288) found a decrease of 0.8 per 100,000 melanoma deaths in a region with population-based skin cancer screening compared with no change or slight increases in comparison regions. The number of excisions needed to detect 1 skin cancer from clinical visual skin examinations varied by age and sex; for example, 22 for women 65 years or older compared with 41 for women aged 20 to 34 years. In 2 studies of performing visual skin examination, sensitivity to detect melanoma was 40.2% and specificity was 86.1% when conducted by primary care physicians (n = 16,383). Sensitivity was 49.0% and specificity was 97.6% when skin examinations were performed by dermatologists (n = 7436). In a case-control study of melanoma (n = 7586), cases diagnosed with thicker lesions (>0.75 mm) had an odds ratio of 0.86 (95% CI, 0.75-0.98) for receipt of a physician skin examination in the prior 3 years compared with controls. Eight cohort studies (n = 236,485) demonstrated a statistically significant relationship between the degree of disease involvement at diagnosis and melanoma mortality, regardless of the characterization of the stage or lesion thickness. Tumor thickness greater than 4.0 mm was associated with increased melanoma mortality compared with thinner lesions, and late stage at diagnosis was associated with increased all-cause mortality. CONCLUSIONS AND RELEVANCE: Only limited evidence was identified for skin cancer screening, particularly regarding potential benefit of skin cancer screening on melanoma mortality. Future research on skin cancer screening should focus on evaluating the effectiveness of targeted screening in those considered to be at higher risk for skin cancer. PMID- 27458950 TI - Partnering Behavioral Modification With Bariatric Surgery. PMID- 27458951 TI - Cutaneous Necrosis of the Ears. PMID- 27458952 TI - Clinical Criteria to Identify Patients With Sepsis. PMID- 27458953 TI - Clinical Criteria to Identify Patients With Sepsis. PMID- 27458954 TI - Defining Septic Shock. PMID- 27458955 TI - Clinical Criteria to Identify Patients With Sepsis--Reply. PMID- 27458956 TI - Defining Septic Shock. PMID- 27458957 TI - Definitions for Sepsis and Septic Shock. PMID- 27458958 TI - Defining Septic Shock--Reply. PMID- 27458959 TI - Definitions for Sepsis and Septic Shock. PMID- 27458960 TI - Definitions for Sepsis and Septic Shock. PMID- 27458961 TI - Definitions for Sepsis and Septic Shock. PMID- 27458962 TI - Definitions for Sepsis and Septic Shock--Reply. PMID- 27458963 TI - Composition of the Sepsis Definitions Task Force. PMID- 27458964 TI - Composition of the Sepsis Definitions Task Force. PMID- 27458965 TI - Composition of the Sepsis Definitions Task Force. PMID- 27458966 TI - Composition of the Sepsis Definitions Task Force--Reply. PMID- 27458967 TI - Composition of the Sepsis Definitions Task Force--Reply. PMID- 27458969 TI - Exercise and the Heart. PMID- 27458970 TI - JAMA PATIENT PAGE. Screening for Skin Cancer. PMID- 27458971 TI - Caging and Uncaging Genetics. AB - It is important for biology to understand if observations made in highly reductionist laboratory settings generalise to harsh and noisy natural environments in which genetic variation is sorted to produce adaptation. But what do we learn by studying, in the laboratory, a genetically diverse population that mirrors the wild? What is the best design for studying genetic variation? When should we consider it at all? The right experimental approach depends on what you want to know. PMID- 27458973 TI - Leveraging Genetics to Advance Type 2 Diabetes Prevention. AB - In this Perspective, Jose Florez discusses how information from genetics and genomics may be able to contribute to prevention of type 2 diabetes and predicting individual responses to behavioral and other interventions. PMID- 27458972 TI - Altered Blood Biomarker Profiles in Athletes with a History of Repetitive Head Impacts. AB - The long-term health effects of concussion and sub-concussive impacts in sport are unknown. Growing evidence suggests both inflammation and neurodegeneration are pivotal to secondary injury processes and the etiology of neurodegenerative diseases. In the present study we characterized circulating brain injury and inflammatory mediators in healthy male and female athletes according to concussion history and collision sport participation. Eighty-seven university level athletes (male, n = 60; female, n = 27) were recruited before the start of the competitive season. Athletes were healthy at the time of the study (no medications, illness, concussion or musculoskeletal injuries). Dependent variables included 29 inflammatory and 10 neurological injury analytes assessed in the peripheral blood by immunoassay. Biomarkers were statistically evaluated using partial least squares multivariate analysis to identify possible relationships to self-reported previous concussion history, number of previous concussions and collision sport participation in male and female athletes. Multiple concussions were associated with increases in peripheral MCP-1 in females, and MCP-4 in males. Collision sport participation was associated with increases in tau levels in males. These results are consistent with previous experimental and clinical findings that suggest ongoing inflammatory and cerebral injury processes after repetitive mild head trauma. However, further validation is needed to correlate systemic biomarkers to repetitive brain impacts, as opposed to the extracranial effects common to an athletic population such as exercise and muscle damage. PMID- 27458974 TI - Quantitative Analysis of Endocytic Recycling of Membrane Proteins by Monoclonal Antibody-Based Recycling Assays. AB - In this report, we present an analysis of several recycling protocols based on labeling of membrane proteins with specific monoclonal antibodies (mAbs). We analyzed recycling of membrane proteins that are internalized by clathrin dependent endocytosis, represented by the transferrin receptor, and by clathrin independent endocytosis, represented by the Major Histocompatibility Class I molecules. Cell surface membrane proteins were labeled with mAbs and recycling of mAb:protein complexes was determined by several approaches. Our study demonstrates that direct and indirect detection of recycled mAb:protein complexes at the cell surface underestimate the recycling pool, especially for clathrin dependent membrane proteins that are rapidly reinternalized after recycling. Recycling protocols based on the capture of recycled mAb:protein complexes require the use of the Alexa Fluor 488 conjugated secondary antibodies or FITC conjugated secondary antibodies in combination with inhibitors of endosomal acidification and degradation. Finally, protocols based on the capture of recycled proteins that are labeled with Alexa Fluor 488 conjugated primary antibodies and quenching of fluorescence by the anti-Alexa Fluor 488 displayed the same quantitative assessment of recycling as the antibody-capture protocols. J. Cell. Physiol. 232: 463-476, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27458975 TI - Reasons Charcot-Marie-Tooth disease due to mutations in the MME gene should not be named AR-CMT2T. PMID- 27458976 TI - Procollagen C-Proteinase Enhancer 1 (PCPE-1) as a Plasma Marker of Muscle and Liver Fibrosis in Mice. AB - Current non-invasive diagnostic methods of fibrosis are limited in their ability to identify early and intermediate stages of fibrosis and assess the efficacy of therapy. New biomarkers of fibrosis are therefore constantly sought for, leading us to evaluate procollagen C-proteinase enhancer 1 (PCPE-1), a fibrosis-related extracellular matrix glycoprotein, as a plasma marker of fibrosis. A sandwich ELISA that permitted accurate measurements of PCPE-1 concentrations in mouse plasma was established. Tissue fibrosis was assessed using histochemical, immunofluorescence, and immunoblotting analyses for type I collagen and PCPE-1. The normal plasma concentration of PCPE-1 in 6 weeks to 4 months old mice was ~200 ng/ml (189.5 +/- 11.3 to 206.8 +/- 13.8 ng/ml). PCPE-1 plasma concentrations in four and 8.5 months old mdx mice displaying fibrotic diaphragms increased 27 and 40% respectively relatively to age-matched control mice, an increase comparable to that of the N-propeptide of procollagen type III (PIIINP), a known blood marker of fibrosis. PCPE-1 plasma levels in mice with CCl4-induced liver fibrosis increased 34 to 50% relatively to respective controls and reflected the severity of the disease, namely increased gradually during the progression of fibrosis and went down to basal levels during recovery, in parallel to changes in the liver content of collagen I and PCPE-1. The results favor PCPE-1 as a potential new clinically valuable fibrosis biomarker. PMID- 27458977 TI - The Clinical Significance of miR-34a in Pancreatic Ductal Carcinoma and Associated Molecular and Cellular Mechanisms. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor prognosis and resistance to chemotherapy. This study was to identify the biomarkers associated with the progression, poor prognosis and chemoresistance of PDAC. METHODS: miR 34a and miR-150 levels in the plasma and tissues from PDAC patients were measured by real-time PCR. Xenograft PDAC tumor models were established in mice by inoculation of CD133+ stem cells isolated from PDAC tumors. Protein expression was measured by Western blot. RESULTS: The plasma miR-34a and miR-150 levels were significantly lower in PDAC patients than in patients with benign pancreatic lesions and in healthy subjects. The miR-34a and miR-150 levels in the tumor tissues were significantly lower than in pancreatic tissues with benign lesions. The protein levels of CD133, Notch1, Notch2 and Notch4 receptors in PDAC tumor tissues were significantly higher than in pancreatic tissues with benign lesions. miR-34a injection significantly inhibited the tumor growth of PDAC tumors and sensitized the anticancer effects of 5-fluorouracil (5-FU). miR-34a significantly inhibited Notch1, Notch2 and Notch4 expression in xenograft tumor tissues in vivo and BxPC-3 cells in vitro. miR-34a and miR-150 significantly induced apoptosis and inhibited proliferation, invasion and migration in BxPC-3 cells. miR-34a, but not miR-150, significantly sensitized the anticancer effect of 5-FU in BxPC-3 cells in vitro. CONCLUSION: A loss of expression of miR-34a, but not of miR-150, is associated with disease progression and poor prognosis in PDAC patients, and may be involved in the chemoresistance of PDAC cells. PMID- 27458978 TI - Heterostructures through Divergent Edge Reconstruction in Nitrogen-Doped Segmented Graphene Nanoribbons. AB - Atomically precise engineering of defined segments within individual graphene nanoribbons (GNRs) represents a key enabling technology for the development of advanced functional device architectures. Here, the bottom-up synthesis of chevron GNRs decorated with reactive functional groups derived from 9-methyl-9H carbazole is reported. Scanning tunneling and non-contact atomic force microscopy reveal that a thermal activation of GNRs induces the rearrangement of the electron-rich carbazole into an electron-deficient phenanthridine. The selective chemical edge-reconstruction of carbazole-substituted chevron GNRs represents a practical strategy for the controlled fabrication of spatially defined GNR heterostructures from a single molecular precursor. PMID- 27458979 TI - Ecological Hypothesis of Dentin and Root Caries. AB - Recent advances regarding the caries process indicate that ecological phenomena induced by bacterial acid production tilt the de- and remineralization balance of the dental hard tissues towards demineralization through bacterial acid-induced adaptation and selection within the microbiota - from the dynamic stability stage to the aciduric stage via the acidogenic stage [Takahashi and Nyvad, 2008]. Dentin and root caries can also be partly explained by this hypothesis; however, the fact that these tissues contain a considerable amount of organic material suggests that protein degradation is involved in caries formation. In this review, we compiled relevant histological, biochemical, and microbiological information about dentin/root caries and refined the hypothesis by adding degradation of the organic matrix (the proteolytic stage) to the abovementioned stages. Bacterial acidification not only induces demineralization and exposure of the organic matrix in dentin/root surfaces but also activation of dentin-embedded and salivary matrix metalloproteinases and cathepsins. These phenomena initiate degradation of the demineralized organic matrix in dentin/root surfaces. While a bacterial involvement has never been confirmed in the initial degradation of organic material, the detection of proteolytic/amino acid-degrading bacteria and bacterial metabolites in dentin and root caries suggests a bacterial digestion and metabolism of partly degraded matrix. Moreover, bacterial metabolites might induce pulpitis as an inflammatory/immunomodulatory factor. Root and dentin surfaces are always at risk of becoming demineralized in the oral cavity, and exposed organic materials can be degraded by host-derived proteases contained in saliva and dentin itself. New approaches to the prevention and treatment of root/dentin caries are required. PMID- 27458980 TI - Successful treatment of a disseminated infection with extensively drug-resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin-based multidrug regimen. AB - Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor-derived, disseminated infection with colistin resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts. PMID- 27458981 TI - Monocyte Chemotactic Protein-1, Fractalkine, and Receptor for Advanced Glycation End Products in Different Pathological Types of Lupus Nephritis and Their Value in Different Treatment Prognoses. AB - BACKGROUND: Early diagnosis is important for the outcome of lupus nephritis (LN). However, the pathological type of lupus nephritis closely related to the clinical manifestations; therefore, the treatment of lupus nephritis depends on the different pathological types. OBJECTIVE: To assess the level of monocyte chemotactic protein (MCP-1), fractalkine (Fkn), and receptor for advanced glycation end product (RAGE) in different pathological types of lupus nephritis and to explore the value of these biomarkers for predicting the prognosis of lupus nephritis. METHODS: Patients included in this study were assessed using renal biopsy. Class III and class IV were defined as the proliferative group, class V as non-proliferative group, and class V+III and class V+IV as the mixed group. During the follow-up, 40 of 178 enrolled patients had a poor response to the standard immunosuppressant therapy. The level of markers in the different response groups was tested. RESULTS: The levels of urine and serum MCP-1, urine and serum fractalkine, and serum RAGE were higher in the proliferative group, and lower in the non-proliferative group, and this difference was significant. The levels of urine and serum MCP-1 and serum RAGE were lower in the poor response group, and these differences were also significant. The relationship between urine MCP-1 and urine and serum fractalkine with the systemic lupus erythematosus disease activity index was evaluated. CONCLUSION: The concentration of cytokines MCP-1, fractalkine, and RAGE may be correlated with different pathology type of lupus nephtitis. Urine and serum MCP-1 and serum RAGE may help in predicting the prognosis prior to standard immunosuppressant therapy. PMID- 27458982 TI - Coalescent Simulation and Paleodistribution Modeling for Tabebuia rosealba Do Not Support South American Dry Forest Refugia Hypothesis. AB - Studies based on contemporary plant occurrences and pollen fossil records have proposed that the current disjunct distribution of seasonally dry tropical forests (SDTFs) across South America is the result of fragmentation of a formerly widespread and continuously distributed dry forest during the arid climatic conditions associated with the Last Glacial Maximum (LGM), which is known as the modern-day dry forest refugia hypothesis. We studied the demographic history of Tabebuia rosealba (Bignoniaceae) to understand the disjunct geographic distribution of South American SDTFs based on statistical phylogeography and ecological niche modeling (ENM). We specifically tested the dry forest refugia hypothesis; i.e., if the multiple and isolated patches of SDTFs are current climatic relicts of a widespread and continuously distributed dry forest during the LGM. We sampled 235 individuals across 18 populations in Central Brazil and analyzed the polymorphisms at chloroplast (trnS-trnG, psbA-trnH and ycf6-trnC intergenic spacers) and nuclear (ITS nrDNA) genomes. We performed coalescence simulations of alternative hypotheses under demographic expectations from two a priori biogeographic hypotheses (1. the Pleistocene Arc hypothesis and, 2. a range shift to Amazon Basin) and other two demographic expectances predicted by ENMs (3. expansion throughout the Neotropical South America, including Amazon Basin, and 4. retraction during the LGM). Phylogenetic analyses based on median joining network showed haplotype sharing among populations with evidence of incomplete lineage sorting. Coalescent analyses showed smaller effective population sizes for T. roseoalba during the LGM compared to the present-day. Simulations and ENM also showed that its current spatial pattern of genetic diversity is most likely due to a scenario of range retraction during the LGM instead of the fragmentation from a once extensive and largely contiguous SDTF across South America, not supporting the South American dry forest refugia hypothesis. PMID- 27458983 TI - Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes. AB - The CXCR4 chemokine receptor is implicated in a number of diseases including HIV infection and cancer development and metastasis. Previous studies have demonstrated that configurationally restricted bis-tetraazamacrocyclic metal complexes are high-affinity CXCR4 antagonists. Here, we present the synthesis of Cu(2+) and Zn(2+) acetate complexes of six cross-bridged tetraazamacrocycles to mimic their coordination interaction with the aspartate side chains known to bind them to CXCR4. X-ray crystal structures for three new Cu(2+) acetate complexes and two new Zn(2+) acetate complexes demonstrate metal-ion-dependent differences in the mode of binding the acetate ligand concomitantly with the requisite cis-V configured cross-bridged tetraazamacrocyle. Concurrent density functional theory molecular modelling studies produced an energetic rationale for the unexpected [Zn(OAc)(H2 O)](+) coordination motif present in all of the Zn(2+) cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)](+) structures of known unbridged and side-bridged tetraazamacrocyclic Zn(2+) -containing CXCR4 antagonists. PMID- 27458984 TI - Functional anisotropic panglial networks in the lateral superior olive. AB - Astrocytes form large gap junctional networks that contribute to ion and neurotransmitter homeostasis. Astrocytes concentrate in the lateral superior olive (LSO), a prominent auditory brainstem center. Compared to the LSO, astrocyte density is lower in the region dorsal to the LSO (dLSO) and in the internuclear space between the LSO, the superior paraolivary nucleus (SPN). We questioned whether astrocyte networks exhibit certain properties that reflect the precise neuronal arrangement. Employing whole-cell patch-clamp and concomitant injection of a gap junction-permeable tracer, we analyzed size and orientation of astrocyte networks in LSO, dLSO, and SPN-LSO in acute brainstem slices of mice at postnatal days 10-20. The majority of LSO networks exhibited an oval topography oriented orthogonally to the tonotopic axis, whereas dLSO networks showed no preferred orientation. This correlated with the overall astrocyte morphology in both regions, i.e. LSO astrocyte processes were oriented mainly orthogonally to the tonotopic axis. To assess the spread of small ions within LSO networks, we analyzed the diffusion of Na(+) signals between cells using Na(+) imaging. We found that Na(+) not only diffused between SR101(+) astrocytes, but also from astrocytes into SR101(-) cells. Using PLP-GFP mice for tracing, we could show that LSO networks contained astrocytes and oligodendrocytes. Together, our results demonstrate that LSO astrocytes and LSO oligodendrocytes form functional anisotropic panglial networks that are oriented predominantly orthogonally to the tonotopic axis. Thus, our results point toward an anisotropic ion and metabolite diffusion and a limited glial crosstalk between neighboring isofrequency bands in the LSO. GLIA 2016;64:1892-1911. PMID- 27458985 TI - Relationship Between Oral Dysfunction, Physical Disability, and Depressive Mood in Community-Dwelling Elderly Adults in Japan. PMID- 27458986 TI - A short note on the maximal point-biserial correlation under non-normality. AB - The aim of this paper is to derive the maximal point-biserial correlation under non-normality. Several widely used non-normal distributions are considered, namely the uniform distribution, t-distribution, exponential distribution, and a mixture of two normal distributions. Results show that the maximal point-biserial correlation, depending on the non-normal continuous variable underlying the binary manifest variable, may not be a function of p (the probability that the dichotomous variable takes the value 1), can be symmetric or non-symmetric around p = .5, and may still lie in the range from -1.0 to 1.0. Therefore researchers should exercise caution when they interpret their sample point-biserial correlation coefficients based on popular beliefs that the maximal point-biserial correlation is always smaller than 1, and that the size of the correlation is always further restricted as p deviates from .5. PMID- 27458987 TI - Music Therapy for Motor and Nonmotor Symptoms of Parkinson's Disease: A Prospective, Randomized, Controlled, Single-Blinded Study. PMID- 27458988 TI - Using generalizability analysis to estimate parameters for anatomy assessments: A multi-institutional study. AB - With integrated curricula and multidisciplinary assessments becoming more prevalent in medical education, there is a continued need for educational research to explore the advantages, consequences, and challenges of integration practices. This retrospective analysis investigated the number of items needed to reliably assess anatomical knowledge in the context of gross anatomy and histology. A generalizability analysis was conducted on gross anatomy and histology written and practical examination items that were administered in a discipline-based format at Indiana University School of Medicine and in an integrated fashion at the University of Alabama School of Medicine and Rush University Medical College. Examination items were analyzed using a partially nested design s*(i:o) in which items were nested within occasions (i:o) and crossed with students (s). A reliability standard of 0.80 was used to determine the minimum number of items needed across examinations (occasions) to make reliable and informed decisions about students' competence in anatomical knowledge. Decision study plots are presented to demonstrate how the number of items per examination influences the reliability of each administered assessment. Using the example of a curriculum that assesses gross anatomy knowledge over five summative written and practical examinations, the results of the decision study estimated that 30 and 25 items would be needed on each written and practical examination to reach a reliability of 0.80, respectively. This study is particularly relevant to educators who may question whether the amount of anatomy content assessed in multidisciplinary evaluations is sufficient for making judgments about the anatomical aptitude of students. Anat Sci Educ 10: 109-119. (c) 2016 American Association of Anatomists. PMID- 27458989 TI - Incidence and etiology of hospitalized acute respiratory infections in the Egyptian Delta. AB - INTRODUCTION: Acute Respiratory Infections (ARI) are responsible for nearly two million childhood deaths worldwide. A limited number of studies have been published on the epidemiology of viral respiratory pathogens in Egypt. METHODS: A total of 6113 hospitalized patients >1 month of age with suspected ARI were enrolled between June 23, 2009 and December 31, 2013. Naso- and oropharyngeal specimens were collected and tested for influenza A and B, respiratory syncytial virus, human metapneumovirus, adenovirus, and parainfluenza viruses 1-3. Blood specimens from children 1-11 months were cultured and bacterial growth was identified by polymerase chain reaction. Results from a healthcare utilization survey on the proportion of persons seeking care for ARI was used to calculate adjusted ARI incidence rates in the surveillance population. RESULTS: The proportion of patients with a viral pathogen detected decreased with age from 67% in patients age 1-11 months to 19% in patients >=65 years of age. Influenza was the dominant viral pathogen detected in patients >=1 year of age (13.9%). The highest incidence rates for hospitalized ARI were observed in children 1-11 months (1757.9-5537.5/100 000 population) and RSV was the most commonly detected pathogen in this age group. CONCLUSION: In this study population, influenza is the largest viral contributor to hospitalized ARIs and children 1-11 months of age experience a high rate of ARI hospitalizations. This study highlights a need for surveillance of additional viral pathogens and alternative detection methods for bacterial pathogens, which may reveal a substantial proportion of as yet unidentified etiologies in adults. PMID- 27458990 TI - ICU sedation with dexmedetomidine after severe traumatic brain injury. AB - OBJECTIVE: To comprehensively describe the use of dexmedetomidine in a single institutional series of adult ICU patients with severe TBI. This study describes the dexmedetomidine dosage and infusion times, as well as the physiological parameters, neurological status and daily narcotic requirements before, during and after dexmedetomidine infusion. METHODS: This study identified 85 adult patients with severe TBI who received dexmedetomidine infusions in the Trauma ICU at Vanderbilt University Medical Center between 2006-2010. Demographic, haemodynamic, narcotic use and sedative use data were systematically obtained from the medical record and analysed for changes associated with dexmedetomidine infusion. RESULTS: During infusion with dexmedetomidine, narcotic and sedative use decreased significantly (p < 0.001 and p < 0.05). Median MAP, SBP, DBP and HR also decreased significantly during infusion when compared to pre-infusion values (p < 0.001). Despite the use of dexmedetomidine, RASS and GCS scores improved from pre-infusion to infusion time periods. CONCLUSIONS: The findings demonstrate that initiation of dexmedetomidine infusion is not associated with a decline in neurological functioning in adults with severe TBI. Although there was an observed decrease in haemodynamic parameters during infusion with dexmedetomidine, the change was not clinically significant and the requirements for narcotics and additional sedatives were minimized. PMID- 27458992 TI - Pulmonary MRI of neonates in the intensive care unit using 3D ultrashort echo time and a small footprint MRI system. AB - PURPOSE: To determine the feasibility of pulmonary magnetic resonance imaging (MRI) of neonatal lung structures enabled by combining two novel technologies: first, a 3D radial ultrashort echo time (UTE) pulse sequence capable of high spatial resolution full-chest imaging in nonsedated quiet-breathing neonates; and second, a unique, small-footprint 1.5T MRI scanner design adapted for neonatal imaging and installed within the neonatal intensive care unit (NICU). MATERIALS AND METHODS: Ten patients underwent MRI within the NICU, in accordance with an approved Institutional Review Board protocol. Five had clinical diagnoses of bronchopulmonary dysplasia (BPD), and five had putatively normal lung function. Pulmonary imaging was performed at 1.5T using 3D radial UTE and standard 3D fast gradient recalled echo (FGRE). Diagnostic quality, presence of motion artifacts, and apparent severity of lung pathology were evaluated by two radiologists. Quantitative metrics were additionally used to evaluate lung parenchymal signal. RESULTS: UTE images showed significantly higher signal in lung parenchyma (P < 0.0001) and fewer apparent motion artifacts compared to FGRE (P = 0.046). Pulmonary pathology was more severe in patients diagnosed with BPD relative to controls (P = 0.001). Infants diagnosed with BPD also had significantly higher signal in lung parenchyma, measured using UTE, relative to controls (P = 0.002). CONCLUSION: These results demonstrate the technical feasibility of pulmonary MRI in free-breathing, nonsedated infants in the NICU at high, isotropic resolutions approaching that achievable with computed tomography (CT). There is potential for pulmonary MRI to play a role in improving how clinicians understand and manage care of neonatal and pediatric pulmonary diseases. J. Magn. Reson. Imaging 2016. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:463-471. PMID- 27458993 TI - Effect of quinine and artesunate combination therapy on platelet count of children with severe malaria. AB - BACKGROUND: There are several case reports of quinine-induced thrombocytopenia but no clinical trials to ascertain its incidence and significance in severe malaria. OBJECTIVES: The primary objective was to assess the effect of quinine on the platelet count in children with severe malaria and to compare it with artesunate combination therapy (ACT), and the secondary objective was to assess outcome of treatment with quinine and ACT. METHODS: An open-labelled, randomised, controlled trial was undertaken in 100 children aged 6 months to 12 years who were diagnosed with malaria by microscopy and/or rapid diagnostic test kits with at least one WHO clinical or laboratory criterion for severe malaria. All subjects were commenced on either quinine or ACT. Clindamycin was added to artesunate as a combination drug (ACT). It was also given to patients on quinine to avoid its confounding effect on the results. Platelet counts were undertaken every 24 hours for 7 consecutive days, temperature and coma score (Blantyre coma score >=3 in children <4 years or Glasgow coma score >=13 in children >4 years) was recorded 6-hourly and peripheral smears were taken 12-hourly until two consecutively negative smears were obtained. The primary outcome was a fall in the platelet count by >=20% from the time of drug initiation until day 7. The secondary outcome was comparison of the efficacy, parasite clearance time, fever clearance time, coma recovery time and adverse effects of quinine vs ACT. RESULTS: 30.4% patients in the quinine group (n = 48) had >=20% fall in platelet count and 10.8% of patients in the ACT group (n = 46) (P = 0.02). Despite the fall in platelet count, there was no bleeding. The efficacy of ACT was significantly better than quinine but the other treatment outcomes showed insignificant difference. CONCLUSION: Quinine should be used with caution in patients with severe malaria because of the potential risk of quinine-induced thrombocytopenia. PMID- 27458994 TI - Fatal anaphylactic reactions to lignocaine. AB - Fatal anaphylactic reactions to lignocaine are very rare. In this review of published reports, the main objective is to determine the characteristics of fatal allergic reactions to lignocaine and describe the forensic investigations of anaphylaxis related deaths. From 1957 to 2012, there were seven reports of single case and one report of 8 cases with sufficient information for review. Fatal anaphylactic reactions to lignocaine were generally characterised by fast onset of symptoms (within seconds to <30min of drug exposure) and rapid progression to cardiopulmonary arrest and death (23min to ~1h). Features of cardiovascular, respiratory and neurological system involvements were often seen. Autopsy might reveal laryngeal oedema, pulmonary oedema, cerebral oedema, eosinophil infiltrates in many organs and other changes. Elevated blood tryptase level caused by mast cell degranulation was also used to diagnose acute anaphylaxis. PMID- 27458995 TI - Targeted toxicological screening for acidic, neutral and basic substances in postmortem and antemortem whole blood using simple protein precipitation and UPLC HR-TOF-MS. AB - A broad targeted screening method based on broadband collision-induced dissociation (bbCID) ultra-performance liquid chromatography high-resolution time of-flight mass spectrometry (UPLC-HR-TOF-MS) was developed and evaluated for toxicological screening of whole blood samples. The acidic, neutral and basic substances covered by the method were identified in postmortem and antemortem whole blood samples from forensic autopsy cases, clinical forensic cases and driving under the influence of drugs (DUID) cases by a reverse target database search. The screening method covered 467 substances. Validation was performed on spiked whole blood samples and authentic postmortem and antemortem whole blood samples. For most of the basic drugs, the established cut-off limits were very low, ranging from 0.25ng/g to 50ng/g. The established cut-off limits for most neutral and acidic drugs, were in the range from 50ng/g to 500ng/g. Sample preparation was performed using simple protein precipitation of 300MUL of whole blood with acetonitrile and methanol. Ten microliters of the reconstituted extract were injected and separated within a 13.5min UPLC gradient reverse-phase run. Positive electrospray ionization (ESI) was used to generate the ions in the m/z range of 50-1000. Fragment ions were generated by bbCID. Identification was based on retention time, accurate mass, fragment ion(s) and isotopic pattern. A very sensitive broad toxicological screening method using positive electrospray ionization UPLC-HR-TOF-MS was achieved in one injection. This method covered basic substances, substances traditionally analyzed in negative ESI (e.g., salicylic acid), small highly polar substances such as beta- and gamma hydroxybutyric acid (BHB and GHB, respectively) and highly non-polar substances such as amiodarone. The new method was shown to combine high sensitivity with a very broad scope that has not previously been reported in toxicological whole blood screening when using only one injection. PMID- 27458996 TI - Volatile organic compounds in polyethylene bags-A forensic perspective. AB - Polyethylene bags, though not recommended, are sometimes used in some countries as improvised packaging for items sent to be analysed for the presence of volatile organic compounds, namely ignitable liquids residues. Sometimes items made of polyethylene constitute the samples themselves. It is well known what kind of volatile organic compounds are produced as a result of polyethylene thermal decomposition, but there is a lack of information relating to if some volatile compounds are present in unheated/unburned items made of polyethylene in detectable amounts and, if so, what those compounds are. The aim of this presented research was to answer these questions. 28 different bags made of polyethylene, representing 9 brands, were purchased in local shops and analysed according to the procedure routinely used for fire debris. The results proved that in almost all bags a distinctive mixture of compounds is present, comprising of n-alkanes and n-alkenes with an even number of carbon atoms in their molecules. Some other compounds (e.g., limonene, 2,2,4,6,6-pentamethylheptane) are also often present, but the presence of even n-alkanes and n-alkenes constitutes the most characteristic feature. PMID- 27458997 TI - Correlation of the functional difficulties questionnaire (FDQ-9) with dynamic balance using the SMART instrumented wobbleboard. AB - OBJECTIVES: To investigate concurrent validity of the Functional Difficulties Questionnaire (FDQ-9) using balance tasks on the SMARTwobbleboard. Poor balance is associated with reduced physical activity which may impact on quality of life. There is a requirement to use simple tests to assess balance so that suitable interventions can be employed to ameliorate poor balance and enhance uptake of physical activity. DESIGN: Observational study employing 30 healthy volunteers who completed the FDQ-9 and undertook three balance tasks on the SMARTwobbleboard: double leg stance eyes open (DLSEO); double leg stance eyes closed (DLSEC) and single leg stance eyes open (SLSEO). RESULTS: There were moderate significant correlations between the FDQ-9 and DLSEO and SLSEO. There were significant between group differences in dynamic balance for participants with FDQ-9 <= 18 (indicative of no functional difficulties) and FDQ-9 >= 19 (indicative of one or more functional difficulties) for DLSEO and SLSEO. CONCLUSIONS: Significant moderate correlations were recorded between the FDQ-9 and the SMARTwobbleboard in healthy adults indicating a relationship between dynamic balance and questionnaire scores (DLSEO and SLSEO). Initial findings contribute to the concurrent validity of the FDQ-9 which could also be used as a simple tool for assessing balance. PMID- 27458998 TI - Transcripts in the Plasmodium Apicoplast Undergo Cleavage at tRNAs and Editing, and Include Antisense Sequences. AB - The apicoplast, an organelle found in Plasmodium and many other parasitic apicomplexan species, is a remnant chloroplast that is no longer able to carry out photosynthesis. Very little is known about primary transcripts and RNA processing in the Plasmodium apicoplast, although processing in chloroplasts of some related organisms (chromerids and dinoflagellate algae) shows a number of unusual features, including RNA editing and the addition of 3' poly(U) tails. Here, we show that many apicoplast transcripts are polycistronic and that there is extensive RNA processing, often involving the excision of tRNA molecules. We have identified major RNA processing sites, and have shown that these are associated with a conserved sequence motif. We provide the first evidence for the presence of RNA editing in the Plasmodium apicoplast, which has evolved independently from editing in dinoflagellates. We also present evidence for long, polycistronic antisense transcripts, and show that in some cases these are processed at the same sites as sense transcripts. Together, this research has significantly enhanced our understanding of the evolution of chloroplast RNA processing in the Apicomplexa and dinoflagellate algae. PMID- 27459000 TI - Correction to Bis(trin-hexylsilyl oxide) Silicon Phthalocyanine: A Unique Additive in Ternary Bulk Heterojunction Organic Photovoltaic Devices. PMID- 27458999 TI - Draft genome sequence of an inbred line of Chenopodium quinoa, an allotetraploid crop with great environmental adaptability and outstanding nutritional properties. AB - Chenopodium quinoa Willd. (quinoa) originated from the Andean region of South America, and is a pseudocereal crop of the Amaranthaceae family. Quinoa is emerging as an important crop with the potential to contribute to food security worldwide and is considered to be an optimal food source for astronauts, due to its outstanding nutritional profile and ability to tolerate stressful environments. Furthermore, plant pathologists use quinoa as a representative diagnostic host to identify virus species. However, molecular analysis of quinoa is limited by its genetic heterogeneity due to outcrossing and its genome complexity derived from allotetraploidy. To overcome these obstacles, we established the inbred and standard quinoa accession Kd that enables rigorous molecular analysis, and presented the draft genome sequence of Kd, using an optimized combination of high-throughput next generation sequencing on the Illumina Hiseq 2500 and PacBio RS II sequencers. The de novo genome assembly contained 25 k scaffolds consisting of 1 Gbp with N50 length of 86 kbp. Based on these data, we constructed the free-access Quinoa Genome DataBase (QGDB). Thus, these findings provide insights into the mechanisms underlying agronomically important traits of quinoa and the effect of allotetraploidy on genome evolution. PMID- 27459002 TI - Divergent evolution for diverse substrate recognition by family 31 glycoside hydrolases. AB - Carbohydrates make up an important component of our diet, contributing a significant portion to our total caloric intake. The ability to harvest these molecules for energy is reliant on the activity of carbohydrate-active enzymes. Family 31 alpha-glucosidases are a group of glycoside hydrolases that has been shown to play a key role in the metabolic process of hydrolyzing dietary starch into monomers of glucose. The purpose of the research presented here is to explore evolutionary changes that occurred within this family of glycoside hydrolases, and to relate these divergences to observed structural differences in relation to predicted substrate preferences. Here we report specific single amino acid changes that are believed to have arisen through evolution, and are directly related to the ability of these enzymes to bind different starch-based glycans. Through phylogenetic analysis we observed a number of evolutionary adaptions that we believe resulted in duplicated genes that allow for the efficient utilization of dietary starch. PMID- 27459001 TI - Synthesis of Oxorhenium(V) and Oxotechnetium(V) Complexes That Bind to Amyloid beta Plaques. AB - Alzheimer's disease is characterized by the presence of amyloid plaques in the brain. The primary constituents of the plaques are aggregated forms of the amyloid-beta (Abeta) peptide. With the goal of preparing technetium-99(m) complexes that bind to Abeta plaques with the potential to be diagnostic imaging agents for Alzheimer's disease, new tetradentate ligands capable of forming neutral and lipophilic complexes with oxotechentium(V) and oxorhenium(V) were prepared. Nonradioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. Two planar tetradentate N3O ligands were prepared that form charge-neutral complexes with oxorhenium(v) as well as a ligand featuring a styrylpyridyl functional group designed to bind to Abeta plaques. All three ligands formed complexes with oxorhenium(V), and each complex was characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The oxorhenium(V) complex with a styrylpyridyl functional group binds to Abeta plaques present in post-mortem human brain tissue. The chemistry was extrapolated to technetium-99(m) at the tracer level for two of the ligands. The resulting oxotechnetium(V) complexes were sufficiently lipophilic and charge neutral to suggest that they have the potential to cross the blood-brain barrier but exhibited modest stability with respect to exchange with histidine. The chemistry presented here identifies a strategy to integrate styrylpyridyl functional groups into tetradentate ligands capable of forming complexes with [M?O](3+) cores (M = Re or Tc). PMID- 27459004 TI - [Not Available]. PMID- 27459003 TI - Hepatitis B virus X protein impairs alpha-interferon signaling via up-regulation of suppressor of cytokine signaling 3 and protein phosphatase 2A. AB - Hepatitis B Virus (HBV) causes liver cirrhosis and hepatocellular carcinoma. Standard therapy includes treatment with interferon (IFN); however, its efficacy is limited. HBV has been reported to impair IFN signaling; however, the mechanism is unclear. Here, the relationship between HBV X protein (HBx) and IFN signaling was investigated by establishing HepG2 cells, stably expressing HBx (HepG2/HBx) via retrovirus-mediated gene transfer. Subsequently, IFN negative-regulator expression and its mechanism were studied. HepG2/HBx cells showed reduced expression of IFN-stimulated genes and expressed higher levels of suppressor of cytokine signaling 3 (SOCS3) and protein phosphatase 2A (PP2A) suppressor compared with control cells. Knockdown of SOCS3 and PP2A restored IFN sensitivity. Moreover, HepG2/HBx cells showed higher phosphorylation levels of signal transducers and activators of transcription 3 and endoplasmic reticulum stress, which are inducers of SOCS3 and PP2A, respectively. Additionally, HBx knockdown restored IFN sensitivity in HepG2.2.15.7 cells. It was also confirmed that SOCS3 and PP2A expression levels were up-regulated in the liver of patients with HBV infection. The results of this study demonstrated that HBx impairs IFN signaling via increased expression of SOCS3 and PP2A, a novel mechanistic insight, providing a potential therapeutic target to enhance the efficiency of IFN therapy. J. Med. Virol. 89:267-275, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27459005 TI - "Iodine Allergy" - The Neverending Story. PMID- 27459006 TI - [Not Available]. PMID- 27459007 TI - [Not Available]. PMID- 27459008 TI - [Not Available]. PMID- 27459009 TI - [Not Available]. PMID- 27459010 TI - [Not Available]. PMID- 27459011 TI - [Not Available]. PMID- 27459012 TI - [Not Available]. PMID- 27459013 TI - [Not Available]. PMID- 27459014 TI - [Not Available]. PMID- 27459015 TI - [Not Available]. PMID- 27459016 TI - [Not Available]. PMID- 27459019 TI - Clonal Transmission of Gram-Negative Bacteria with Carbapenemases NDM-1, VIM-1, and OXA-23/72 in a Bulgarian Hospital. AB - We characterized 72 isolates with reduced susceptibility to carbapenems (50 Acinetobacter spp., 13 Proteus mirabilis, five Escherichia coli, one Morganella morganii, one Enterobacter cloacae, one Providencia rettgeri, and one Pseudomonas aeruginosa) from a hospital in Sofia, Bulgaria. Different beta-lactamase genes were identified by polymerase chain reaction and sequencing. Bacterial strain typing was performed by enzymatic macrorestriction and pulsed-field gel electrophoresis (PFGE) typing as well as multilocus sequence typing for selected isolates. The majority of Acinetobacter baumannii (46/50) and one Acinetobacter pittii isolate harbored carbapenemase genes blaOXA-23 or blaOXA-72; two A. baumannii contained both genes. PFGE typing of all A. baumannii showed the presence of nine different clones belonging to eight sequence types ST350, ST208, ST436, ST437, ST449, ST231, ST502, and ST579. Molecular characterization of the remaining isolates confirmed the presence of one NDM-1-producing E. coli-ST101 clone (five isolates) and one P. mirabilis clone (13 isolates) with VIM-1 and CMY 99. Furthermore, NDM-1 was identified in P. rettgeri and M. morganii and VIM-2 in the P. aeruginosa isolate. The permanent introduction of OXA-23/72 carbapenemase producing A. baumannii clones into the hospital and the repeated occurrence of one VIM-1-producing P. mirabilis and one NDM-1-producing E. coli-ST101 clone over a period of more than 1 year is of concern and requires intensified investigations. PMID- 27459018 TI - Antifungal adjuvants: Preserving and extending the antifungal arsenal. AB - As the rates of systemic fungal infections continue to rise and antifungal drug resistance becomes more prevalent, there is an urgent need for new therapeutic options. This issue is exacerbated by the limited number of systemic antifungal drug classes. However, the discovery, development, and approval of novel antifungals is an extensive process that often takes decades. For this reason, there is growing interest and research into the possibility of combining existing therapies with various adjuvants that either enhance activity or overcome existing mechanisms of resistance. Reports of antifungal adjuvants range from plant extracts to repurposed compounds, to synthetic peptides. This approach would potentially prolong the utility of currently approved antifungals and mitigate the ongoing development of resistance. PMID- 27459020 TI - Effectiveness of abatacept for patients with Sjogren's syndrome associated with rheumatoid arthritis. An open label, multicenter, one-year, prospective study: ROSE (Rheumatoid Arthritis with Orencia Trial toward Sjogren's syndrome Endocrinopathy) trial. AB - OBJECTIVE: To clarify the efficacy and safety of abatacept for secondary Sjogren's syndrome (SS) associated with rheumatoid arthritis (RA). METHODS: The primary endpoint of this open-labeled, prospective, observational multicenter study for secondary SS with RA was the remission rate of Simplified Disease Activity Index (SDAI) at 52 weeks after initiation of abatacept. The secondary endpoints included Saxon's test and Schirmer's test. Adverse events and adherence rate during the study period were also analyzed. RESULTS: Thirty-six patients (all females) were enrolled in this study. The mean SDAI decreased significantly from 20.6 +/- 11.2 (+/-SD) at baseline to 10.0 +/- 10.5 at 52 weeks (p < 0.05). Patients with SDAI remission increased from 0 (0 week) to 12 patients (33.3%) at 52 weeks. Saliva volume assessed by Saxon's test increased significantly from 2136 +/- 1809 (0 week) to 2397 +/- 1878 (24 weeks) mg/2 min (n = 34, p < 0.05). Saliva volume increased significantly from 2945 +/- 2090 (0 week) to 3419 +/- 2121 (24 weeks) mg/2 min in 11 patients with Greenspan grade 1 or 2 of labial salivary gland biopsy (p < 0.05), but no change was noted in 18 patients with Greenspan grade 3 or 4. Tear volume by Schirmer's test increased significantly from 4.2 +/- 4.8 (0 week) to 6.4 +/- 7.8 (24 weeks) mm/5 min (n = 30, p < 0.05). The adherence rate to abatacept was 80.6% (29/36) over the 52-week period. Twelve adverse events occurred in 10 of the 36 patients, and 7 of these events were infections. CONCLUSION: Abatacept seems to be effective for both RA and SS related manifestations. PMID- 27459021 TI - Water Splitting and CO2 Reduction under Visible Light Irradiation Using Z-Scheme Systems Consisting of Metal Sulfides, CoOx-Loaded BiVO4, and a Reduced Graphene Oxide Electron Mediator. AB - Metal sulfides are highly active photocatalysts for water reduction to form H2 under visible light irradiation, whereas they are unfavorable for water oxidation to form O2 because of severe self-photooxidation (i.e., photocorrosion). Construction of a Z-scheme system is a useful strategy to split water into H2 and O2 using such photocorrosive metal sulfides because the photogenerated holes in metal sulfides are efficiently transported away. Here, we demonstrate powdered Z schematic water splitting under visible light and simulated sunlight irradiation by combining metal sulfides as an H2-evolving photocatalyst, reduced graphene oxide (RGO) as an electron mediator, and a visible-light-driven BiVO4 as an O2 evolving photocatalyst. This Z-schematic photocatalyst composite is also active in CO2 reduction using water as the sole electron donor under visible light. PMID- 27459022 TI - Limits and opportunities to community health worker empowerment: A multi-country comparative study. AB - BACKGROUND: In LMICs, Community Health Workers (CHW) increasingly play health promotion related roles involving 'Empowerment of communities'. To be able to empower the communities they serve, we argue, it is essential that CHWs themselves be, and feel, empowered. We present here a critique of how diverse national CHW programs affect CHW's empowerment experience. METHODS: We present an analysis of findings from a systematic review of literature on CHW programs in LMICs and 6 country case studies (Bangladesh, Ethiopia, Indonesia, Kenya, Malawi, Mozambique). Lee & Koh's analytical framework (4 dimensions of empowerment: meaningfulness, competence, self-determination and impact), is used. RESULTS: CHW programs empower CHWs by providing CHWs, access to privileged medical knowledge, linking CHWs to the formal health system, and providing them an opportunity to do meaningful and impactful work. However, these empowering influences are constantly frustrated by - the sense of lack/absence of control over one's work environment, and the feelings of being unsupported, unappreciated, and undervalued. CHWs expressed feelings of powerlessness, and frustrations about how organisational processual and relational arrangements hindered them from achieving the desired impact. CONCLUSIONS: While increasingly the onus is on CHWs and CHW programs to solve the problem of health access, attention should be given to the experiences of CHWs themselves. CHW programs need to move beyond an instrumentalist approach to CHWs, and take a developmental and empowerment perspective when engaging with CHWs. CHW programs should systematically identify disempowering organisational arrangements and take steps to remedy these. Doing so will not only improve CHW performance, it will pave the way for CHWs to meet their potential as agents of social change, beyond perhaps their role as health promoters. PMID- 27459023 TI - Understanding HIV-related stigma in older age in rural Malawi. AB - The combination of HIV- and age-related stigma exacerbates prevalence of HIV infection and late diagnosis and initiation of anti-retroviral therapy among older populations (Moore, 2012; Richards et al. 2013). Interventions to address these stigmas must be grounded in understanding of situated systems of beliefs about illness and older age. This study analyses constructions of HIV and older age that underpinned the stigmatisation of older adults with HIV in rural Balaka, Malawi. It draws on data from a series of in-depth interviews (N = 135) with adults aged 50-~90 (N = 43) in 2008-2010. Around 40% (n = 18) of the sample had HIV. Dominant understandings of HIV in Balaka pertained to the sexual transmission of the virus and poor prognosis of those infected. They intersected with understandings of ageing. Narratives about older age and HIV in older age both centred on the importance of having bodily, moral and social power to perform broadly-defined "work". Those who could not work were physically and socially excluded from the social world. This status, labelled as "child-like", was feared by all participants. In participants' narratives, growing old involves a gradual decline in the power required to produce one's membership of the social world through work. HIV infection in old age is understood to accelerate this decline. Understandings of the sexual transmission of HIV, in older age, imply the absence of moral power and in turn, loss of social power. The prognosis of those with HIV, in older age, reflects and causes amplified loss of bodily power. In generating dependency, this loss of bodily power infantilises older care recipients and jeopardises their family's survival, resulting in further loss of social power. This age-and HIV-related loss of power to produce social membership through work is the discrediting attribute at the heart of the stigmatisation of older people with HIV. PMID- 27459024 TI - Recombinant human granulocyte macrophage colony stimulating factor (hGM-CSF): Possibility of nanoparticle-mediated delivery in cancer immunotherapy. AB - Most of the cancer treatment strategies from chemotherapy to radiotherapy render cancer cells apoptotic and these apoptotic cancer cells accumulate at the tumor sites. The accumulation of apoptotic cancer cells often result in inflammation and autoimmune responses causing serious health implications. Macrophages, which are effective immune combatants, can help in the clearance of these deleterious occupants. Granulocyte macrophage colony stimulating factor (GM-CSF) is a key cytokine, modulator of immune system and responsible for growth and differentiation of granulocytes and macrophages. In this regard, supply of recombinant GM-CSF can enhance the capability of macrophages for clearance of apoptotic cancer cells. However, delivery of the cytokine in vivo can suffer from certain disadvantages like faster depletion, less stability and low targeting efficiency. We believe that the stability and sustained release of GM-CSF can be improved through its encapsulation inside appropriately designed nanoparticles. PMID- 27459025 TI - The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes. AB - INTRODUCTION: There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion. AREAS COVERED: In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM. EXPERT OPINION: Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety. PMID- 27459027 TI - Physiotherapists' perspectives on aerobic exercise early after stroke: A preliminary study. AB - Aerobic exercise is recognized as part of comprehensive stroke rehabilitation in best-practice and clinical guidelines, yet many individuals remain physically inactive during their hospitalization. The purpose of this study was to identify the perspectives of physiotherapists on aerobic exercise prescription and implementation at in-patient stroke rehabilitation centers with and without a structured aerobic exercise program. A survey was conducted at three Canadian rehabilitation centers to evaluate physiotherapist perceptions of individuals recovering from stroke, the practice environment, and their training on aerobic exercise in stroke. Physiotherapists at centers without a structured aerobic exercise program (n = 10) reported the lack of necessary resources and therapeutic support staff and the individuals' physical impairment as the greatest barriers. In contrast, physiotherapists at the center with a structured aerobic exercise program (n = 6) reported therapy selection (insufficient time in a single physiotherapy session) and concern for the individuals' cardiovascular risk and cognitive impairment as the greatest barriers. Both groups of physiotherapists indicated that fatigue was a barrier. Only physiotherapists at the center with a structured aerobic exercise program had received continuing education on aerobic exercise in stroke. The lack of resources at rehabilitation centers without a structured aerobic exercise program needs to be addressed. There remains a need for continuing education on aerobic training in stroke, specifically on assessment and prescription using a standardized approach. PMID- 27459028 TI - Molecular switch of EZH2 in hypoxia. PMID- 27459026 TI - p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes. AB - INTRODUCTION: Spontaneous preterm birth (PTB) and preterm premature rupture of the membranes (pPROM) remain as a major clinical and therapeutic problem for intervention and management. Current strategies, based on our knowledge of pathways of preterm labor, have only been effective, in part, due to major gaps in our existing knowledge of risks and risk specific pathways. Areas covered: Recent literature has identified physiologic aging of fetal tissues as a potential mechanistic feature of normal parturition. This process is affected by telomere dependent and p38 mitogen activated protein kinase (MAPK) induced senescence activation. Pregnancy associated risk factors can cause pathologic activation of this pathway that can cause oxidative stress induced p38 MAPK activation leading to senescence and premature aging of fetal tissues. Premature aging is associated with sterile inflammation capable of triggering preterm labor or preterm premature rupture of membranes. Preterm activation of p38MAPK can be considered as a key contributor to adverse pregnancies. Expert opinion: This review considers p38MAPK activation as a potential target for therapeutic interventions to prevent adverse pregnancy outcomes mediated by stress factors. In this review, we propose multiple strategies to prevent p38MAPK activation. PMID- 27459029 TI - A combined analysis of genome-wide expression profiling of bipolar disorder in human prefrontal cortex. AB - Numbers of gene expression profiling studies of bipolar disorder have been published. Besides different array chips and tissues, variety of the data processes in different cohorts aggravated the inconsistency of results of these genome-wide gene expression profiling studies. By searching the gene expression databases, we obtained six data sets for prefrontal cortex (PFC) of bipolar disorder with raw data and combinable platforms. We used standardized pre processing and quality control procedures to analyze each data set separately and then combined them into a large gene expression matrix with 101 bipolar disorder subjects and 106 controls. A standard linear mixed-effects model was used to calculate the differentially expressed genes (DEGs). Multiple levels of sensitivity analyses and cross validation with genetic data were conducted. Functional and network analyses were carried out on basis of the DEGs. In the result, we identified 198 unique differentially expressed genes in the PFC of bipolar disorder and control. Among them, 115 DEGs were robust to at least three leave-one-out tests or different pre-processing methods; 51 DEGs were validated with genetic association signals. Pathway enrichment analysis showed these DEGs were related with regulation of neurological system, cell death and apoptosis, and several basic binding processes. Protein-protein interaction network further identified one key hub gene. We have contributed the most comprehensive integrated analysis of bipolar disorder expression profiling studies in PFC to date. The DEGs, especially those with multiple validations, may denote a common signature of bipolar disorder and contribute to the pathogenesis of disease. PMID- 27459030 TI - Frequency-specific alterations in functional connectivity in treatment-resistant and -sensitive major depressive disorder. AB - Major depressive disorder (MDD) may involve alterations in brain functional connectivity in multiple neural circuits and present large-scale network dysfunction. Patients with treatment-resistant depression (TRD) and treatment sensitive depression (TSD) show different responses to antidepressants and aberrant brain functions. This study aims to investigate functional connectivity patterns of TRD and TSD at the whole brain resting state. Seventeen patients with TRD, 17 patients with TSD, and 17 healthy controls matched with age, gender, and years of education were recruited in this study. The brain was divided using an automated anatomical labeling atlas into 90 regions of interest, which were used to construct the entire brain functional networks. An analysis method called network-based statistic was used to explore the dysconnected subnetworks of TRD and TSD at different frequency bands. At resting state, TSD and TRD present characteristic patterns of network dysfunction at special frequency bands. The dysconnected subnetwork of TSD mainly lies in the fronto-parietal top-down control network. Moreover, the abnormal neural circuits of TRD are extensive and complex. These circuits not only depend on the abnormal affective network but also involve other networks, including salience network, auditory network, visual network, and language processing cortex. Our findings reflect that the pathological mechanism of TSD may refer to impairment in cognitive control, whereas TRD mainly triggers the dysfunction of emotion processing and affective cognition. This study reveals that differences in brain functional connectivity at resting state reflect distinct pathophysiological mechanisms in TSD and TRD. These findings may be helpful in differentiating two types of MDD and predicting treatment responses. PMID- 27459031 TI - Decreased anticipated pleasure correlates with increased salience network resting state functional connectivity in adolescents with depressive symptomatology. AB - Previous studies have found dysfunctional resting state functional connectivity (RSFC) in depressed patients. Examining RSFC might aid biomarker discovery for depression. However RSFC in young people at risk of depression has yet to be examined. 35 healthy adolescents (13-18 yrs old.) were recruited. 17 scoring high on the Mood and Feelings Questionnaire (MFQ > 27 (High Risk: HR), and 18 scoring low on the MFQ < 15 (Low Risk: LR) matched on age and gender. We selected seed regions in the salience network (SN: amygdala and pregenual anterior cingulate cortex (pgACC)) and the central executive network (CEN: dorsal medial prefrontal cortex (dmPFC)). Mood and anhedonia measures were correlated with brain connectivity. We found decreased RSFC in the HR group between the amygdala and the pgACC and hippocampus and precuneus. We also found decreased RSFC in the HR group between the pgACC and the putamen and between the dmPFC and the precuneus. The pgACC RSFC with the insula/orbitofrontal cortex correlated inversely with the anticipation of pleasure in all subjects. Increased RSFC was observed between the pgACC and the prefrontal cortex and the amygdala and the temporal pole in the HR group compared to the LR group. Our findings are the first to show that adolescents with depression symptoms have dysfunctional RSFC between seeds in the SN and CEN with nodes in the Default Mode Network. As increased connectivity between the pgACC and the insula correlated with decreased ability to anticipate pleasure, we suggest this might be mechanism underlying the risk of experiencing anhedonia, a suggested biomarker for depression. PMID- 27459032 TI - Usefulness of percutaneous elastography by acoustic radiation force impulse for the non-invasive diagnosis of chronic pancreatitis. AB - OBJECTIVE: To determine the accuracy of the acoustic radiation force impulse (ARFI) technique for the diagnosis of chronic pancreatitis. MATERIALS AND METHODS: We present an observational, single-center study that included patients with suspected chronic pancreatitis in the period between October 2012 and September 2015 who underwent endoscopic ultrasound (EUS) and were classified according to the standard and Rosemont criteria. The same group of patients was assessed by the ARFI technology using ACUSON S2000TM equipment with Virtual TouchTM Quantification software for the assessment of pancreatic stiffness by obtaining the shear wave velocity (SWV) in the head, body and tail of the pancreas. Data were analyzed using ANOVA and nonparametric correlation methods. Diagnostic accuracy was obtained by analyzing receiver operating characteristic (ROC) curve. RESULTS: A total of thirty-three patients were studied (45.5% women); mean age was 58.3 +/- 11.8 years. Seventeen with a diagnosis of chronic pancreatitis and sixteen classified as normal according to standard criteria. A significant difference was detected between the means of SWV in pancreatic body of patients without (SWV: 1.27 m/s) and with chronic pancreatitis (SWV 1.57 m/s), p = 0.037. The area under the ROC curve was 71.3% (95% CI 0.532-0.895) and the accuracy of ARFI for diagnosing chronic pancreatitis was 69.7% for a SWV of 1.4 m/s in the pancreatic body. The SWV means in head (r = 0.421, p < 0.05) and body (r = 0.455, p < 0.05) of the pancreas showed a significant correlation with the number of EUS criteria for chronic pancreatitis. CONCLUSION: Quantification of pancreatic stiffness with ARFI elastography technique has proven to be useful for the non-invasive diagnosis of chronic pancreatitis. PMID- 27459033 TI - More than 40% of those not taking antiseizure medication with recent seizures reported that epilepsy or its treatment interfered with their recent activities, 2010 and 2013 US National Health Interview Surveys. AB - From the combined 2010 and 2013 National Health Interview Surveys, we estimated US national age-standardized prevalence of adults with active epilepsy who reported that a nervous system/sensory organ condition caused a limitation (e.g., walking; memory; or physical, mental, or emotional problems) and, separately, that epilepsy interfered with their activities (e.g., working, schooling, or socializing) during the 30days preceding the survey. Sixty-one percent of adults who took antiseizure medication and had recent seizures and 51% of those who took medication and had no seizures reported having limitations caused by a nervous system/sensory organ condition. Sixty-two percent of adults who took antiseizure medication and had recent seizures and 20% of those who took medication and had no seizures reported that epilepsy or its treatment interfered with their recent activities. Forty-one percent of those who did not take medication and had recent seizures also reported that epilepsy interfered with their activities. To reduce activity limitations in people with epilepsy, health and social service providers can ensure that adequate policies and practices that promote access to high quality care and social participation are in effect in organizations and communities. PMID- 27459034 TI - Efficacy and tolerability of perampanel in ten patients with Lafora disease. AB - Lafora disease (LD) is a fatal intractable adolescence-onset progressive myoclonus epilepsy. Recently, two single-case studies reported drastic reductions in seizures and myoclonus with the AMPA antagonist perampanel and improved activities of daily living. We proceeded to study the effect of perampanel on 10 patients with genetically confirmed LD with disease duration ranging from 2 to 27years. Open-label perampanel was added to ongoing medications to a mean dose of 6.7mg/day. Seizures, myoclonus, functional disability, and cognition scores were measured for the third and ninth months following initiation and compared with those of the month prior to the start of therapy. Three patients withdrew because of inefficacy or side effects. Four had significant reduction in seizures of greater than 74% from baseline. Seven had major improvement in myoclonus with group-adjusted sum score of myoclonus intensity reduced from 7.01 at baseline to 5.67 and 5.18 at 3 and 9months, respectively. There was no significant improvement in disability and cognition. While not universal, perampanel adjunctive therapy appears to confer particular benefit not commonly seen with other antiepileptic drugs on seizures and myoclonus in LD. Improvement in the extremely disabling myoclonus of LD is a major benefit in this devastating disease. PMID- 27459035 TI - Bioaccumulation of metals in the trees of Novi Sad, Serbia. AB - In urban and industrial areas, higher plants are used as biomonitors of exposure. The objective of this study was to assess metals accumulation in leaves of dendroflora for the city of Novi Sad, Serbia, in May and September. The investigation was conducted at three sites in the urban area of Novi Sad. Determination of metals concentration for Al, As, Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd, and Pb in the sample was performed by inductively coupled plasma-optical emission spectrometry (ICP/OES). In the leaves of the examined tree species the highest concentrations were obtained for: Al, Fe, Mn, and Zn. The highest mean concentrations of metals were present in leaves of Aesculus hippocastanum in September. Trees from Liman and the Danube Park contained higher mean concentrations of metals in the leaves. In A. hippocastanum and Platanus hybrida an increase of al., As, Cr, Fe, and Pb concentrations occurred from May to September, with higher concentrations of Al and Fe noted in May. However, in Celtis australis, Juglans regia, and Tilia platypyllos there was a reduction in Al, Mn, Fe, and Zn from May to September. The basis for these findings requires further investigation, but diverse washing procedures may account partially for these observations. PMID- 27459036 TI - Remarkably high homoselectivity in [2 + 2] photodimerization of trans-cinnamic acids in multicomponent systems. AB - [2 + 2] homoadducts were exclusively obtained with total regio- and stereo selectivities when a suspension of several solid photoactive trans-cinnamic acids in cyclohexane was stirred and irradiated. PMID- 27459037 TI - Hypolipidemic effects of Myrica rubra extracts and main compounds in C57BL/6j mice. AB - The present study evaluated the antihyperlipidemic activity of myricetin, myricetrin, the alcohol fraction (AF) and the ethyl acetate fraction (EF) obtained from the bark of Myrica rubra (MR) in high-fat and high-cholesterol (HFHC) induced hyperlipidemic C57BL/6j mice. Mice were treated with myricetin, myricetrin, AF and EF with a dose of 130 mg per kg per day for 35 days. After treatment, serum parameters including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), total bile acids (TBA), etc., were examined. The results revealed that EF showed the highest weight lowering activity (P < 0.01). All tested samples decreased the levels of the TC, TG, LDL C, TBA and LPS (lipopolysaccharide) content in the serum of mice to different extents. Liver fat deposition was significantly reduced after myricetin, myricetrin, AF and EF therapy (P < 0.01). Additionally, the cell size of epididymal adipose tissue was also decreased in myricetin, AF and EF groups (P < 0.05). The antihyperlipidemic activity of these samples may be attributed to the inhibition of lipid synthesis via suppressing the expression of HMGCR (3-hydroxy 3-methylglutaryl coenzyme A reductase) and ACC1 (acetyl-CoA carboxylase), promoting the metabolism and excretion of lipids via up-regulating the expression of SREBP2 (sterol regulatory element binding proteins), LDLR (low density lipoprotein receptor), UCP2 (uncoupling protein 2) and CYP7A1 (cholesterol 7alpha hydroxylase). These results may provide a powerful foundation for seeking and utilizing Myrica rubra bio-active compounds for the treatment of hyperlipidemia and cardiovascular diseases. PMID- 27459050 TI - Kinetic and Thermodynamic Evaluation of Kynurenic Acid Binding to GluR1270-300 Polypeptide by Surface Plasmon Resonance Experiments. AB - This work clearly demonstrates an evaluation process that is easily performed and is simply based on the fitting of temperature-dependent surface plasmon resonance (SPR) sensorgrams to provide detailed thermodynamic characterization of biologically relevant interactions. The reversible binding of kynurenic acid (KYNA) on human glutamate receptor (GluR1) polypeptide (GluR1270-300)-modified gold surface has been studied at various temperatures under physiological conditions by two-dimensional SPR experiments. The registered sensorgrams were fitted by using different kinetic models without application of any commercial software. Assuming that the association of GluR1270-300-KYNA complex is first order in both reactants, the association (ka) and dissociation (kd) constants as well as the equilibrium constants (KA) and the Gibbs free-energy change (DeltaG degrees ) were given at 10, 20, 30, and 40 degrees C. Moreover, the enthalpy (DeltaH degrees = -27.91 kJ mol(-1)), entropy (DeltaS degrees = -60.33 J mol( 1) K(-1)), and heat capacity changes (DeltaCp = -1.28 kJ mol(-1) K(-1)) of the model receptor-ligand system were also calculated using a spreadsheet program. Negative values of DeltaG degrees and DeltaH degrees indicate the exothermic formation of a stable GluR1270-300-KYNA complex, because the |DeltaH| > |TDeltaS| relation suggests an enthalpy-driven binding process. The negative DeltaH degrees and DeltaS degrees values strongly support the formation of a salt bridge between KYNA and the positively charged residues of the polypeptide (Arg, Lys) at pH 7.4, confirmed by molecular docking calculations as well. PMID- 27459051 TI - Disentangling Multichannel Photodissociation Dynamics in Acetone by Time-Resolved Photoelectron-Photoion Coincidence Spectroscopy. AB - For the investigation of photoinduced dynamics in molecules with time-resolved pump-probe photoionization spectroscopy, it is essential to obtain unequivocal information about the fragmentation behavior induced by the laser pulses. We present time-resolved photoelectron-photoion coincidence (PEPICO) experiments to investigate the excited-state dynamics of isolated acetone molecules triggered by two-photon (269 nm) excitation. In the complex situation of different relaxation pathways, we unambiguously identify three distinct pump-probe ionization channels. The high selectivity of PEPICO detection allows us to observe the fragmentation behavior and to follow the time evolution of each channel separately. For channels leading to fragment ions, we quantitatively obtain the fragment-to-parent branching ratio and are able to determine experimentally whether dissociation occurs in the neutral molecule or in the parent ion. These results highlight the importance of coincidence detection for the interpretation of time-resolved photochemical relaxation and dissociation studies if multiple pathways are present. PMID- 27459052 TI - Cytotoxic heteroleptic heptacoordinate salan zirconium(iv)-bis-chelates - synthesis, aqueous stability and X-ray structure analysis. AB - Herein we report the synthesis and structural characterization of a series of novel Zr(iv)salan complexes. The initial metalation product [(L1)2Zr] is highly water sensitive while ligand exchanged [L1Zr(dipic)] hydrolyses slowly with a bis hydroxo Zr(iv) species identified by MS as an intermediate. [L1Zr(dipic)] is cytotoxic in the range of cisplatin against two human carcinoma cell lines. PMID- 27459049 TI - Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury. AB - Commercialization of multiwalled carbon nanotubes (MWCNT)-based applications has been hampered by concerns regarding their lung toxicity potential. Hyaluronic acid (HA) is a ubiquitously found polysaccharide, which is anti-inflammatory in its native high molecular weight form. HA-functionalized smart MWCNTs have shown promise as tumor-targeting drug delivery agents and can enhance bone repair and regeneration. However, it is unclear whether HA functionalization could reduce the pulmonary toxicity potential of MWCNTs. Using in vivo and in vitro approaches, we investigated the effectiveness of MWCNT functionalization with HA in increasing nanotube biocompatibility and reducing lung inflammatory and fibrotic effects. We utilized three-dimensional cultures of differentiated primary human bronchial epithelia to translate findings from rodent assays to humans. We found that HA functionalization increased stability and dispersion of MWCNTs and reduced postexposure lung inflammation, fibrosis, and mucus cell metaplasia compared with nonfunctionalized MWCNTs. Cocultures of fully differentiated bronchial epithelial cells (cultivated at air-liquid interface) and human lung fibroblasts (submerged) displayed significant reduction in injury, oxidative stress, as well as pro-inflammatory gene and protein expression after exposure to HA-functionalized MWCNTs compared with MWCNTs alone. In contrast, neither type of nanotubes stimulated cytokine production in primary human alveolar macrophages. In aggregate, our results demonstrate the effectiveness of HA functionalization as a safer design approach to eliminate MWCNT-induced lung injury and suggest that HA functionalization works by reducing MWCNT-induced epithelial injury. PMID- 27459053 TI - Defining the clonal dynamics leading to mouse skin tumour initiation. AB - The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene targeted cells to induce tumour formation is dependent not only on their long term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin. PMID- 27459056 TI - Perspective on cystic fibrosis and physical activity: Is there a difference compared to healthy individuals? AB - OBJECTIVES: The aim of this study was to compare habitual physical activity between cystic fibrosis (CF) patients and healthy controls and to investigate possible predictors for reduced physical activity in CF patients. METHODS: Sixty six patients with CF (3-44 years) and 65 healthy controls (3-55 years) were asked to wear an accelerometer (Actigraph GT1M) for 9 days (at least 10 hr/day). Physical activity was classified in five categories from very low to very strenuous. RESULTS: In general, there was no difference in physical activity between CF patients and healthy controls. However, young school-aged 6-13 years old children with CF spent less time with strenuous and very strenuous activity than healthy controls (adjusted difference in activity -0.43 (-0.69, -0.17)). Patients with very low lung function were significantly less active, but other CF associated conditions did not affect physical activity. CONCLUSIONS: While we found similar levels of physical activity measured by accelerometry in patients with CF compared to healthy controls in general, young school-aged children showed less engagement in strenuous activities than their healthy counterparts. As the reduced physical activity in young school children was not likely to be explained by the disease state, strenuous physical activity may be enhanced by advocating exercise and sport. Pediatr Pulmonol. 2016;51:1020-1030. (c) 2016 Wiley Periodicals, Inc. PMID- 27459055 TI - Cryo-EM structure of the spliceosome immediately after branching. AB - Precursor mRNA (pre-mRNA) splicing proceeds by two consecutive transesterification reactions via a lariat-intron intermediate. Here we present the 3.8 A cryo-electron microscopy structure of the spliceosome immediately after lariat formation. The 5'-splice site is cleaved but remains close to the catalytic Mg2+ site in the U2/U6 small nuclear RNA (snRNA) triplex, and the 5' phosphate of the intron nucleotide G(+1) is linked to the branch adenosine 2'OH. The 5'-exon is held between the Prp8 amino-terminal and linker domains, and base pairs with U5 snRNA loop 1. Non-Watson-Crick interactions between the branch helix and 5'-splice site dock the branch adenosine into the active site, while intron nucleotides +3 to +6 base-pair with the U6 snRNA ACAGAGA sequence. Isy1 and the step-one factors Yju2 and Cwc25 stabilize docking of the branch helix. The intron downstream of the branch site emerges between the Prp8 reverse transcriptase and linker domains and extends towards the Prp16 helicase, suggesting a plausible mechanism of remodelling before exon ligation. PMID- 27459057 TI - Nonparameningeal head and neck rhabdomyosarcoma in children and adolescents: Lessons from the consecutive International Society of Pediatric Oncology Malignant Mesenchymal Tumor studies. AB - BACKGROUND: This article reports risk factors and long-term outcome in localized nonparameningeal head and neck rhabdomyosarcomas in children and adolescents from a combined dataset from 3 consecutive international trials. METHODS: Data from 140 children (9.3% of total) prospectively enrolled in the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT)-84/89/95 studies were analyzed. RESULTS: Primary site was: superficial face in 46%; oral cavity (21%); neck (19%); and salivary glands (14%). Local control was achieved in 96%, but 49% relapsed (locoregionally 91%). At median follow-up of 10 years, 5-year overall survival (OS) was 74.7% (67.4% to 81.9%) and event-free survival 48.9% (40.6% to 57.2%), although this improved with successive studies. Radiotherapy (RT) as first-line treatment was independently prognostic for event-free survival (relative risk [RR] = 0.4 [range, 0.2-0.7]; p < .01) even if it did not impact OS (RR = 1 [range, 0.5-2]). CONCLUSION: High rates of locoregional relapse were seen in head and neck rhabdomyosarcoma that should be prevented by more frequent use of RT in this primary. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 24-31, 2017. PMID- 27459059 TI - Focusing on Phagocytes. PMID- 27459058 TI - A standardized evaluation of artefacts from metallic compounds during fast MR imaging. AB - OBJECTIVES: Metallic compounds present in the oral and maxillofacial regions (OMRs) cause large artefacts during MR scanning. We quantitatively assessed these artefacts embedded within a phantom according to standards set by the American Society for Testing and Materials (ASTM). METHODS: Seven metallic dental materials (each of which was a 10-mm3 cube embedded within a phantom) were scanned [i.e. aluminium (Al), silver alloy (Ag), type IV gold alloy (Au), gold palladium-silver alloy (Au-Pd-Ag), titanium (Ti), nickel-chromium alloy (NC) and cobalt-chromium alloy (CC)] and compared with a reference image. Sequences included gradient echo (GRE), fast spin echo (FSE), gradient recalled acquisition in steady state (GRASS), a spoiled GRASS (SPGR), a fast SPGR (FSPGR), fast imaging employing steady state (FIESTA) and echo planar imaging (EPI; axial/sagittal planes). Artefact areas were determined according to the ASTM F2119 standard, and artefact volumes were assessed using OsiriX MD software (Pixmeo, Geneva, Switzerland). RESULTS: Tukey-Kramer post hoc tests were used for statistical comparisons. For most materials, scanning sequences eliciting artefact volumes in the following (ascending) order FSE-T1/FSE-T2 < FSPGR/SPGR < GRASS/GRE < FIESTA < EPI. For all scanning sequences, artefact volumes containing Au, Al, Ag and Au-Pd-Ag were significantly smaller than other materials (in which artefact volume size increased, respectively, from Ti < NC < CC). The artefact specific shape (elicited by the cubic sample) depended on the scanning plane (i.e. a circular pattern for the axial plane and a "clover-like" pattern for the sagittal plane). CONCLUSIONS: The availability of standardized information on artefact size and configuration during MRI will enhance diagnosis when faced with metallic compounds in the OMR. PMID- 27459054 TI - Genomic insights into the origin of farming in the ancient Near East. AB - We report genome-wide ancient DNA from 44 ancient Near Easterners ranging in time between ~12,000 and 1,400 bc, from Natufian hunter-gatherers to Bronze Age farmers. We show that the earliest populations of the Near East derived around half their ancestry from a 'Basal Eurasian' lineage that had little if any Neanderthal admixture and that separated from other non-African lineages before their separation from each other. The first farmers of the southern Levant (Israel and Jordan) and Zagros Mountains (Iran) were strongly genetically differentiated, and each descended from local hunter-gatherers. By the time of the Bronze Age, these two populations and Anatolian-related farmers had mixed with each other and with the hunter-gatherers of Europe to greatly reduce genetic differentiation. The impact of the Near Eastern farmers extended beyond the Near East: farmers related to those of Anatolia spread westward into Europe; farmers related to those of the Levant spread southward into East Africa; farmers related to those of Iran spread northward into the Eurasian steppe; and people related to both the early farmers of Iran and to the pastoralists of the Eurasian steppe spread eastward into South Asia. PMID- 27459060 TI - Brassinosteroid/Abscisic Acid Antagonism in Balancing Growth and Stress. AB - In this issue of Developmental Cell, Gui et al. (2016) show that an abscisic acid inducible remorin protein in rice directly interacts with critical brassinosteroid signaling components to attenuate the brassinosteroid response, thus illuminating one aspect of the brassinosteroid/abscisic acid antagonism. PMID- 27459061 TI - A Death Trap for Microglia. AB - Microglia, immune cells of the brain, originate from erythromyeloid precursors, far from the central nervous system. Xu et al. (2016) in this issue of Developmental Cell and Casano et al. (2016) recently in Cell Reports show that apoptotic neurons act as bait to "trap" microglia into colonizing the developing brain. PMID- 27459062 TI - The Software and Hardware of Macrophages: A Diversity of Options. AB - Macrophages play important immune and homeostatic roles that depend on the ability to receive and interpret specific signals from environmental stimuli. Here we describe the different activation states these cells can exhibit in response to signals and how these states affect and can be affected by bacterial pathogens. PMID- 27459063 TI - Microglia: Phagocytosing to Clear, Sculpt, and Eliminate. AB - Microglia are the primary phagocytes of the central nervous system. They eliminate excess functional connections between neurons to sculpt neuronal circuits during development and throughout adulthood. Understanding how microglia recognize and prune synapses during development is providing insight into synapse loss and dysfunction in disease. PMID- 27459064 TI - Creating a Buzz about Macrophages: The Fly as an In Vivo Model for Studying Immune Cell Behavior. AB - Drosophila macrophages exhibit functional parallels with their vertebrate counterparts in both their early developmental roles and later diverse roles in health and disease. This, together with the fly's genetic tractability and opportunities for live imaging, has recently established Drosophila as a powerful model to study macrophage behavior in vivo. PMID- 27459065 TI - Illuminating Phagocyte Biology: The View from Zebrafish. AB - Many phagocyte behaviors, including vascular rolling and adhesion, migration, and oxidative bursting, are better measured in seconds or minutes than hours or days. Zebrafish is ideally suited for imaging such rapid biology within the intact animal. We discuss how this model has revealed unique insights into various aspects of phagocyte physiology. PMID- 27459066 TI - Diffusion Barriers, Mechanical Forces, and the Biophysics of Phagocytosis. AB - Phagocytes recognize and eliminate pathogens, alert other tissues of impending threats, and provide a link between innate and adaptive immunity. They also maintain tissue homeostasis, consuming dead cells without causing alarm. The receptor engagement, signal transduction, and cytoskeletal rearrangements underlying phagocytosis are paradigmatic of other immune responses and bear similarities to macropinocytosis and cell migration. We discuss how the glycocalyx restricts access to phagocytic receptors, the processes that enable receptor engagement and clustering, and the remodeling of the actin cytoskeleton that controls the mobility of membrane proteins and lipids and provides the mechanical force propelling the phagocyte membrane toward and around the phagocytic prey. PMID- 27459068 TI - Leading from the Back: The Role of the Uropod in Neutrophil Polarization and Migration. AB - Cell motility is required for diverse biological processes including development, homing of immune cells, wound healing, and cancer cell invasion. Motile neutrophils exhibit a polarized morphology characterized by the formation of leading-edge pseudopods and a highly contractile cell rear known as the uropod. Although it is known that perturbing uropod formation impairs neutrophil migration, the role of the uropod in cell polarization and motility remains incompletely understood. Here we discuss cell intrinsic mechanisms that regulate neutrophil polarization and motility, with a focus on the uropod, and examine how relationships among regulatory mechanisms change when cells change their direction of migration. PMID- 27459070 TI - Stimulating Contributions to Public Goods through Information Feedback: Some Experimental Results. AB - In traditional public good experiments participants receive an endowment from the experimenter that can be invested in a public good or kept in a private account. In this paper we present an experimental environment where participants can invest time during five days to contribute to a public good. Participants can make contributions to a linear public good by logging into a web application and performing virtual actions. We compared four treatments, with different group sizes and information of (relative) performance of other groups. We find that information feedback about performance of other groups has a small positive effect if we control for various attributes of the groups. Moreover, we find a significant effect of the contributions of others in the group in the previous day on the number of points earned in the current day. Our results confirm that people participate more when participants in their group participate more, and are influenced by information about the relative performance of other groups. PMID- 27459067 TI - The Dynamics of Apoptotic Cell Clearance. AB - The phagocytic clearance of dying cells in a tissue is a highly orchestrated series of intercellular events coordinated by a complex signaling network. Recent data from genetic, biochemical, and live-imaging approaches have greatly enhanced our understanding of the dynamics of cell clearance and how the process is orchestrated at the cellular and tissue levels. We discuss how networks regulating apoptotic cell clearance are integrated to enable a rapid, efficient, and high-capacity clearance system within tissues. PMID- 27459071 TI - Avoiding bile duct injury in cholecystectomy through anatomical appreciation. PMID- 27459069 TI - HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine. AB - The histone deacetylase (HDAC) family regulates many biological pathways through the deacetylation of lysine residues on histone and nonhistone proteins. Mammals have 18 HDACs that are classified into four classes. Class I, II, and IV are zinc dependent, while class III is nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase or sirtuins. HDAC8, a class I HDAC family member, has been shown to have low deacetylation activity compared to other HDACs in vitro. Recent studies showed that several sirtuins, with low deacetylase activities, can actually hydrolyze other acyl lysine modifications more efficiently. Inspired by this, we tested the activity of HDAC8 using a variety of different acyl lysine peptides. Screening a panel of peptides with different acyl lysine modifications, we found that HDAC8 can catalyze the removal of acyl groups with 2-16 carbons from lysine 9 of the histone H3 peptide (H3K9). Interestingly, the catalytic efficiencies (kcat/Km) of HDAC8 on octanoyl, dodecanoyl, and myristoyl lysine are several-fold better than that on acetyl lysine. The increased catalytic efficiencies of HDAC8 on larger fatty acyl groups are due to the much lower Km values. T-cell leukemia Jurkat cells treated with a HDAC8 specific inhibitor, PCI 34051, exhibited an increase in global fatty acylation compared to control treatment. Thus, the de-fatty-acylation activity of HDAC8 is likely physiologically relevant. This is the first report of a zinc-dependent HDAC with de-fatty-acylation activity, and identification of HDAC8 de-fatty-acylation targets will help to further understand the function of HDAC8 and protein lysine fatty acylation. PMID- 27459072 TI - Clinical fellowships: time to critically appraise their real value. PMID- 27459073 TI - Clinical fellows: valuable or not? Opinions of Australian and New Zealand urology trainees and consultants. PMID- 27459074 TI - Difficulties of sourcing Australian health data: the case of breast reconstruction. PMID- 27459075 TI - The John Loewenthal Society Scientific Meeting, March 2016. PMID- 27459076 TI - Medicine in small doses. PMID- 27459077 TI - 25, 50 & 75 years ago. PMID- 27459078 TI - Perioperative Medicine for the Junior Clinician. PMID- 27459079 TI - Intra-anal pilonidal sinus disease: a unique diagnosis possibly pointing to the occiput. PMID- 27459080 TI - Colosplenic fistula as a complication of splenic abscess. PMID- 27459081 TI - Management of recurrent carpal tunnel disease with reverse radial forearm fasciocutaneous flap and external neurolysis. PMID- 27459082 TI - Congenital transmesenteric hernia presenting with intestinal obstruction in an adult: a case report. PMID- 27459083 TI - An association between conversion of laparoscopic cholecystectomy to open surgery and intra-abdominal organ injury. PMID- 27459085 TI - Origins of Wetting. AB - This feature article provides an overview of wetting phenomena. Much of the analysis done on wetting in the last 100 years assumes that the phenomena are determined by molecular interactions within the interfacial area between the liquid and solid. However, there is now ample evidence that wetting is controlled by interactions in the vicinity of the contact line where the liquid and solid meet. Recent experiments and modeling that demonstrate this are reviewed. PMID- 27459084 TI - Highly Uniform Carbon Nanotube Field-Effect Transistors and Medium Scale Integrated Circuits. AB - Top-gated p-type field-effect transistors (FETs) have been fabricated in batch based on carbon nanotube (CNT) network thin films prepared from CNT solution and present high yield and highly uniform performance with small threshold voltage distribution with standard deviation of 34 mV. According to the property of FETs, various logical and arithmetical gates, shifters, and d-latch circuits were designed and demonstrated with rail-to-rail output. In particular, a 4-bit adder consisting of 140 p-type CNT FETs was demonstrated with higher packing density and lower supply voltage than other published integrated circuits based on CNT films, which indicates that CNT based integrated circuits can reach to medium scale. In addition, a 2-bit multiplier has been realized for the first time. Benefitted from the high uniformity and suitable threshold voltage of CNT FETs, all of the fabricated circuits based on CNT FETs can be driven by a single voltage as small as 2 V. PMID- 27459086 TI - The effect of heparinized decellularized scaffolds on angiogenic capability. AB - The immobilization of heparin, a new and versatile approach to the surface modification of decellularized tissues, has the potential to greatly improve the hemocompatibility of engineered tissue constructs derived from decellularized organs. We report on porcine decellularized liver scaffolds (DLSs) heparinized by the end-point attachment (EPA) technique. The heparinized DLSs (HEP-DLSs) have the ability to bind and slowly release heparin-binding growth factors. We hypothesized that DLS-immobilized heparin acts as an antithrombotic coating reagent and binds vascular endothelial growth factor (VEGF) to induce angiogenesis in the DLSs. Human umbilical vein endothelial cells (HUVECs) seeded on HEP-VEGF-DLSs attached and remained bioactive. Using the chicken chorioallantoic membrane (CAM) assay, we found that the HEP-VEGF-DLSs induced a significant and rapid enhancement of angiogenesis compared with native DLSs. Scaffolds were implanted in the greater omentum of rats and evaluated after 7, 14, 21, and 28 days. There were significant increases in the numbers of blood vessels in the HEP-VEGF-DLSs compared with native DLSs at all time-points. The modified method introduced in this article could overcome obstacles faced by conventional matrices that lack the ability to induce rapid and sufficient vascularization. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3021-3030, 2016. PMID- 27459087 TI - [Not Available]. AB - High temperatures have a direct impact on body functions. Heat waves increase mortality risks due to myocardial infarction, stroke, and pulmonary disease. Cold temperatures also increase mortality, but with a longer latency. A recent study found only a small difference between the minimal mortality temperature (MMT) and the temperatures at which mortality rose steeply, although the majority of deaths occurred at temperatures below MMT. Global climate change with increasing temperatures seriously threatens health, work capacity, and generation of household incomes, particularly among poor people in hot countries. In Sweden, heat waves increase mortality in vulnerable groups of elderly people and patients with chronic heart and lung diseases, as well as those performing intensive physical work in hot environments. The medical profession can play an important role not only in prevention of climate change, but also in adaptation to climate change with the goal of minimizing health risks. PMID- 27459088 TI - [Not Available]. PMID- 27459089 TI - [Not Available]. PMID- 27459090 TI - [Not Available]. PMID- 27459091 TI - Accuracy of ultrasonography for renal stone detection and size determination: is it good enough for management decisions? AB - OBJECTIVES: To determine the sensitivity and specificity of ultrasonography (US) for detecting renal calculi and to assess the accuracy of US for determining the size of calculi and how this can affect counselling decisions. MATERIALS AND METHODS: We retrospectively identified all patients at our institution with a diagnosis of nephrolithiasis who underwent US followed by non-contrast computed tomography (CT) within 60 days. Data on patient characteristics, stone size (maximum axial diameter) and stone location were collected. The sensitivity, specificity and size accuracy of US was determined using CT as the standard. RESULTS: A total of 552 US and CT examinations met the inclusion criteria. Overall, the sensitivity and specificity of US was 54 and 91%, respectively. There was a significant association between sensitivity of US and stone size (P < 0.001), but not with stone location (P = 0.58). US significantly overestimated the size of stones in the 0-10 mm range (P < 0.001). Assuming patients with stones 0-4 mm in size will be selected for observation and those with stones >=5 mm could be counselled on the alternative of intervention, we found that in 14% (54/384) of cases where CT would suggest observation, US would lead to a recommendation for intervention. By contrast, when CT results would suggest intervention as management, US would suggest observation in 39% (65/168) of cases. An average of 22% (119/552) of patients could be inappropriately counselled. Stones classified as 5-10 mm according to US had the highest probability (43% [41/96]) of having their management recommendation changed when CT was performed. The use of plain abdominal film of kidney, ureter and bladder and US increases sensitivity (78%), but 37% (13/35) of patients may still be counselled inappropriately to undergo observation. CONCLUSIONS: Using US to guide clinical decision-making for residual or asymptomatic calculi is limited by low sensitivity and inability to size the stone accurately. As a result, one in five patients may be inappropriately counselled when using US alone. PMID- 27459092 TI - Comprehensive N-Glycan Profiling of Avian Immunoglobulin Y. AB - Recent exploitation of the avian immune system has highlighted its suitability for the generation of high-quality, high-affinity antibodies to a wide range of antigens for a number of therapeutic and biotechnological applications. The glycosylation profile of potential immunoglobulin therapeutics is species specific and is heavily influenced by the cell-line/culture conditions used for production. Hence, knowledge of the carbohydrate moieties present on immunoglobulins is essential as certain glycan structures can adversely impact their physicochemical and biological properties. This study describes the detailed N-glycan profile of IgY polyclonal antibodies from the serum of leghorn chickens using a fully quantitative high-throughput N-glycan analysis approach, based on ultra-performance liquid chromatography (UPLC) separation of released glycans. Structural assignments revealed serum IgY to contain complex bi-, tri- and tetra-antennary glycans with or without core fucose and bisects, hybrid and high mannose glycans. High sialic acid content was also observed, with the presence of rare sialic acid structures, likely polysialic acids. It is concluded that IgY is heavily decorated with complex glycans; however, no known non-human or immunogenic glycans were identified. Thus, IgY is a potentially promising candidate for immunoglobulin-based therapies for the treatment of various infectious diseases. PMID- 27459093 TI - Temporal Variability of Zooplankton (2000-2013) in the Levantine Sea: Significant Changes Associated to the 2005-2010 EMT-like Event? AB - In this study, we investigated, for the first time, the potential impact of environmental changes on zooplankton abundance over a fourteen year period (2000 2013) at an offshore station in the Eastern Mediterranean Sea (the Levantine basin, offshore Lebanon). Samples were collected monthly and analyzed using the semi-automated system ZooScan. Salinity, temperature and phytoplankton abundance (nano and microphytoplankton) were also measured. Results show no significant temporal trend in sea surface temperature over the years. Between 2005-2010, salinity in the upper layer (0-80 m) of the Levantine basin increased (~0.3 degrees C). During this 5 year period, total zooplankton abundance significantly increased. These modifications were concomitant to the activation of Aegean Sea as a source of dense water formation as part of the "Eastern Mediterranean Transient-like" event. The results of the present study suggested that zooplankton benefited from enhanced phytoplankton production during the mixing years of the event. Changes in the phenology of some taxa were observed accordingly with a predominantly advanced peak of zooplankton abundance. In conclusion, long-term changes in zooplankton abundance were related to the Levantine thermohaline circulation rather than sea surface warming. Sampling must be maintained to assess the impact of long-term climate change on zooplankton communities. PMID- 27459094 TI - Constituents from the Roots of Actinidia chinensis and Their Cytochrome P450 Enzyme Inhibitory Activities. AB - A newly discovered triterpenoid, (2alpha,3beta)-2,3,23-trihydroxyurs-13(18)-en-28 oic acid (1), along with twelve known compounds (2 - 13), were isolated from the roots of Actinidia chinensis Planch (Actinidiaceae). Their chemical structures were determined by 1D- and 2D-NMR spectra and mass spectrometry (MS). The crude extracts and six main constituents (8 - 13) were tested for cytochrome P450 (CYPs) enzyme inhibitory activity. The results showed that, except for compound 8, compounds 9 - 13 had different inhibitory effects on the cytochrome P450 (CYPs) enzyme, and compound 9 significantly inhibited the catalytic activities of CYP3A4 to < 10% of its control activities. PMID- 27459096 TI - SNP Identification through Transcriptome Analysis of the European Brown Hare (Lepus europaeus): Cellular Energetics and Mother's Curse. AB - The European brown hare (Lepus europaeus, Pallas 1778) is an important small game species in Europe. Due to its size and position in the food chain, as well as its life history, phenotypic variation and the relatively recent speciation events, brown hare plays an important role in the structure of various ecosystems and has emerged as an important species for population management and evolutionary studies. In order to identify informative SNPs for such studies, heart and liver tissues of three samples from the European lineage and a three-sample pool from the Anatolian lineage were subjected to RNA-Sequencing analysis. This effort resulted in 9496 well-assembled protein-coding sequences with close homology to human. After applying very stringent filtering criteria, 66185 polymorphic sites were identified in 7665 genes/cds and 2050 of those polymorphic sites are potentially capable of distinguishing the European from the Anatolian lineage. From these distinguishing mutations we focused on those in genes that are involved in cellular energy production, namely the glycolysis, Krebs cycle and the OXPHOS machinery. A selected set of SNPs was also validated by Sanger sequencing. By simulating the three European individuals as one pool, no substantial informative-SNP identification was lost, making it a cost-efficient approach. To our knowledge this is the first attempt to correlate the differentiation in both nuclear and mitochondrial genome between the two different lineages of L. europaeus with the observed spatial partitioning of the lineages of the species, proposing a possible mechanism that is maintaining the reproductive isolation of the lineages. PMID- 27459095 TI - Multiscale Simulations Suggest a Mechanism for the Association of the Dok7 PH Domain with PIP-Containing Membranes. AB - Dok7 is a peripheral membrane protein that is associated with the MuSK receptor tyrosine kinase. Formation of the Dok7/MuSK/membrane complex is required for the activation of MuSK. This is a key step in the complex exchange of signals between neuron and muscle, which lead to neuromuscular junction formation, dysfunction of which is associated with congenital myasthenic syndromes. The Dok7 structure consists of a Pleckstrin Homology (PH) domain and a Phosphotyrosine Binding (PTB) domain. The mechanism of the Dok7 association with the membrane remains largely unknown. Using multi-scale molecular dynamics simulations we have explored the formation of the Dok7 PH/membrane complex. Our simulations indicate that the PH domain of Dok7 associates with membranes containing phosphatidylinositol phosphates (PIPs) via interactions of the beta1/beta2, beta3/beta4, and beta5/beta6 loops, which together form a positively charged surface on the PH domain and interact with the negatively charged headgroups of PIP molecules. The initial encounter of the Dok7 PH domain is followed by formation of additional interactions with the lipid bilayer, and especially with PIP molecules, which stabilizes the Dok7 PH/membrane complex. We have quantified the binding of the PH domain to the model bilayers by calculating a density landscape for protein/membrane interactions. Detailed analysis of the PH/PIP interactions reveal both a canonical and an atypical site to be occupied by the anionic lipid. PH domain binding leads to local clustering of PIP molecules in the bilayer. Association of the Dok7 PH domain with PIP lipids is therefore seen as a key step in localization of Dok7 to the membrane and formation of a complex with MuSK. PMID- 27459097 TI - Viral load and ganciclovir (GCV) concentration in cerebrospinal fluid of patients successfully treated with GCV or valGCV for human herpesvirus 6 encephalitis/myelitis following umbilical cord blood transplantation. AB - We describe successful treatment of 3 cases of human herpesvirus 6 (HHV-6) encephalitis/myelitis following cord blood transplantation (CBT). Ganciclovir (GCV) (10 mg/kg/day) reduced HHV-6 load to undetectable levels in cerebrospinal fluid (CSF). Early dose reduction in the presence of HHV-6 detectable in CSF resulted in an increased HHV-6 load. GCV was capably shifted to valganciclovir (VGCV) with an almost equivalent concentration. GCV/VGCV may be effective for HHV 6 encephalitis/myelitis after CBT, although HHV-6 load in CSF should be monitored. PMID- 27459098 TI - Conditional rod photoreceptor ablation reveals Sall1 as a microglial marker and regulator of microglial morphology in the retina. AB - Neurodegeneration has been shown to induce microglial activation and the infiltration of monocyte-derived macrophages into the CNS, resulting in the coexistence of these two populations within the same lesion, though their distinct features remain elusive. To investigate the impact of rod photoreceptor degeneration on microglial activation, we generated a toxin-mediated genetic model of rod degeneration. Rod injury induced microglial proliferation and migration toward the photoreceptors. Bone marrow transplantation revealed the invasion of monocyte-derived macrophages into the retina, with microglia and the infiltrating macrophages showing distinct distribution patterns in the retina. By comparing the gene expression profiles of the activated microglia and infiltrating macrophages, we identified microglia-specific genes, including Ak1, Ctsf, Sall1, Phlda3, and Spns2. An analysis of Sall1gfp knock-in mice showed GFP expression in the microglia of developing and mature healthy retinas. DTA injury induced the expansion of Sall1gfp(+) microglia, whereas Ly6C(+) monocyte-derived macrophages were mostly Sall1gfp(-) , supporting the idea that Sall1 is exclusively expressed in microglia within the retinal phagocyte pool. We evaluated the contribution of microglia to the phagocyte pool in rd1 mutant retinas and found that Sall1gfp(+) microglia constituted the majority of phagocytes. A Sall1 deficiency did not affect microglial colonization of the retina and the cortex, but it did change their morphology from a ramified to a more amoeboid appearance. The morphological defects observed in Sall1-deficient microglia were not rescued by the presence of wild-type non-microglial cells, suggesting that Sall1 functions cell-autonomously in microglia. Taken together, our data indicate that Sall1 regulates microglial morphology during development. GLIA 2016;64:2005-2024. PMID- 27459099 TI - Molecular Responses to Small Regulating Molecules against Huanglongbing Disease. AB - Huanglongbing (HLB; citrus greening) is the most devastating disease of citrus worldwide. No cure is yet available for this disease and infected trees generally decline after several months. Disease management depends on early detection of symptoms and chemical control of insect vectors. In this work, different combinations of organic compounds were tested for the ability to modulate citrus molecular responses to HLB disease beneficially. Three small-molecule regulating compounds were tested: 1) L-arginine, 2) 6-benzyl-adenine combined with gibberellins, and 3) sucrose combined with atrazine. Each treatment contained K phite mineral solution and was tested at two different concentrations. Two trials were conducted: one in the greenhouse and the other in the orchard. In the greenhouse study, responses of 42 key genes involved in sugar and starch metabolism, hormone-related pathways, biotic stress responses, and secondary metabolism in treated and untreated mature leaves were analyzed. TGA5 was significantly induced by arginine. Benzyladenine and gibberellins enhanced two important genes involved in biotic stress responses: WRKY54 and WRKY59. Sucrose combined with atrazine mainly upregulated key genes involved in carbohydrate metabolism such as sucrose-phosphate synthase, sucrose synthase, starch synthase, and alpha-amylase. Atrazine also affected expression of some key genes involved in systemic acquired resistance such as EDS1, TGA6, WRKY33, and MYC2. Several treatments upregulated HSP82, which might help protect protein folding and integrity. A subset of key genes was chosen as biomarkers for molecular responses to treatments under field conditions. GPT2 was downregulated by all small molecule treatments. Arginine-induced genes involved in systemic acquired resistance included PR1, WRKY70, and EDS1. These molecular data encourage long term application of treatments that combine these regulating molecules in field trials. PMID- 27459100 TI - Overexpression of KIF11 in Gastric Cancer with Intestinal Mucin Phenotype. AB - OBJECTIVE: Gastric cancer (GC) is one of the most common human cancers. A useful method of gastric cancer stem cell (CSC) characterization is spheroid colony formation. Previously, we reported that KIF11 expression is >2-fold in spheroid body-forming GC cells compared with parental cells. Here, we analyzed the expression and distribution of KIF11 in human GC by immunohistochemistry. METHODS: Expression of KIF11 in 165 GC cases was determined using immunohistochemistry. For mucin phenotypic expression analysis of GC, immunostaining of MUC5AC, MUC6, MUC2 and CD10 was evaluated. RNA interference was used to inhibit KIF11 expression in GC cell lines. RESULTS: In total, 119 of 165 GC cases (72%) were positive for KIF11. Expression of KIF11 was not associated with any clinicopathologic characteristics; however, it was observed frequently in GC exhibiting an intestinal phenotype. Both the number and size of spheres formed by MKN-74 cells were significantly reduced following transfection of KIF11 targeting siRNA compared with negative-control siRNA. Furthermore, levels of phosphorylated Erk1/2 were lower in KIF11 siRNA-transfected cells than with negative-control siRNA-transfected cells. CONCLUSION: These results indicate that KIF11 is involved in intestinal mucin phenotype GC. PMID- 27459101 TI - Dual Task Gait Performance in Frail Individuals with and without Mild Cognitive Impairment. AB - BACKGROUND: Several studies have stated that frailty is associated with cognitive impairment. Based on various studies, cognition impairment has been considered as a component of frailty. Other authors have shown that physical frailty is associated with low cognitive performance. Dual task gait tests are used as a strong predictor of falls in either dementia or frailty. Consequently, it is important to investigate dual task walking tests in elderly populations including control robust oldest old, frail oldest old with mild cognitive impairment (MCI) and frail oldest old without MCI. METHODS: Dual task walking tests were carried out to examine the association between frailty and cognitive impairment in a population with advanced age. Forty-one elderly men and women participated in this study. The subjects from control, frail with MCI and frail without MCI groups, completed the 5-meter walk test at their own gait velocity. Arithmetic and verbal dual task walking performance was also assessed. Kinematic data were acquired from a unique tri-axial inertial sensor. RESULTS: The spatiotemporal and frequency parameters related to gait disorders did not show any significant differences between frail with and without MCI groups. CONCLUSIONS: The evaluation of these parameters extracted from the acceleration signals led us to conclude that these results expand the knowledge regarding the common conditions in frailty and MCI and may highlight the idea that the impairment in walking performance does not depend of frailty and cognitive status. PMID- 27459102 TI - Is Social Network Diversity Associated with Tooth Loss among Older Japanese Adults? AB - BACKGROUND: We sought to examine social network diversity as a potential determinant of oral health, considering size and contact frequency of the social network and oral health behaviors. METHODS: Our cross-sectional study was based on data from the 2010 Japan Gerontological Evaluation Study. Data from 19,756 community-dwelling individuals aged 65 years or older were analyzed. We inquired about diversity of friendships based on seven types of friends. Ordered logistic regression models were developed to determine the association between the diversity of social networks and number of teeth (categorized as >=20, 10-19, 1 9, and 0). RESULTS: Of the participants, 54.1% were women (mean age, 73.9 years; standard deviation, 6.2). The proportion of respondents with >=20 teeth was 34.1%. After adjusting for age, sex, socioeconomic status (income, education, and occupation), marital status, health status (diabetes and mental health), and size and contact frequency of the social network, an increase in the diversity of social networks was significantly associated with having more teeth (odds ratio = 1.08; 95% confidence interval, 1.04-1.11). Even adjusted for oral health behaviors (smoking, curative/preventive dental care access, use of dental floss/fluoride toothpaste), significant association was still observed (odds ratio = 1.05 (95% confidence interval, 1.02-1.08)). CONCLUSION: Social connectedness among people from diverse backgrounds may increase information channels and promote the diffusion of oral health behaviors and prevent tooth loss. PMID- 27459104 TI - Retraction: Association of CYP2A6*4 with Susceptibility of Lung Cancer: A Meta Analysis. PMID- 27459103 TI - The Phospholipid:Diacylglycerol Acyltransferase Lro1 Is Responsible for Hepatitis C Virus Core-Induced Lipid Droplet Formation in a Yeast Model System. AB - Chronic infection with the hepatitis C virus frequently induces steatosis, which is a significant risk factor for liver pathogenesis. Steatosis is characterized by the accumulation of lipid droplets in hepatocytes. The structural protein core of the virus induces lipid droplet formation and localizes on the surface of the lipid droplets. However, the precise molecular mechanisms for the core-induced formation of lipid droplets remain elusive. Recently, we showed that the expression of the core protein in yeast as a model system could induce lipid droplet formation. In this study, we probed the cellular factors responsible for the formation of core-induced lipid-droplets in yeast cells. We demonstrated that one of the enzymes responsible for triglyceride synthesis, a phospholipid:diacylglycerol acyltransferase (Lro1), is required for the core induced lipid droplet formation. While core proteins inhibit Lro1 degradation and alter Lro1 localization, the characteristic localization of Lro1 adjacent to the lipid droplets appeared to be responsible for the core-induced lipid droplet formation. RNA virus genomes have evolved using high mutation rates to maintain their ability to replicate. Our observations suggest a functional relationship between the core protein with hepatocytes and yeast cells. The possible interactions between core proteins and the endoplasmic reticulum membrane affect the mobilization of specific proteins. PMID- 27459105 TI - Unraveling the Mechanism and Regioselectivity of the B12-Dependent Reductive Dehalogenase PceA. AB - PceA is a cobalamin-dependent reductive dehalogenase that catalyzes the dechlorination of perchloroethylene to trichloroethylene and then to cis dichloroethylene as the sole final product. The reaction mechanism and the regioselectivity of this enzyme are investigated by using density functional calculations. Four different substrates, namely, perchloroethylene, trichloroethylene, cis-dichloroethylene, and chlorotheylene, have been considered and were found to follow the same reaction mechanism pattern. The reaction starts with the reduction of Co(II) to Co(I) through a proton-coupled electron transfer process, with the proton delivered to a Tyr246 anion. This is followed by concerted C-Cl bond heterolytic cleavage and proton transfer from Tyr246 to the substrate carbon atom, generating a Co(III) -Cl intermediate. Subsequently, a one electron transfer leads to the formation of the Co(II) -Cl product, from which the chloride and the dehalogenated product can be released from the active site. The substrate reactivity follows the trend perchloroethylene>trichloroethylene?cis-dichloroethylene?chlorotheylene. The barriers for the latter two substrates are significantly higher compared with those for perchloroethylene and trichloroethylene, implying that PceA does not catalyze their degradation. In addition, the formation of cis-dichloroethylene has a lower barrier by 3.8 kcal mol(-1) than the formation of trans dichloroethylene and 1,1-dichloroethylene, reproducing the regioselectivity. These results agree quite well with the experimental findings, which show cis dichloroethylene as the sole product in the PceA-catalyzed dechlorination of perchloethylene and trichloroethylene. PMID- 27459106 TI - Vicariously. PMID- 27459107 TI - The stability and validity of automated vocal analysis in preverbal preschoolers with autism spectrum disorder. AB - Theory and research suggest that vocal development predicts "useful speech" in preschoolers with autism spectrum disorder (ASD), but conventional methods for measurement of vocal development are costly and time consuming. This longitudinal correlational study examines the reliability and validity of several automated indices of vocalization development relative to an index derived from human coded, conventional communication samples in a sample of preverbal preschoolers with ASD. Automated indices of vocal development were derived using software that is presently "in development" and/or only available for research purposes and using commercially available Language ENvironment Analysis (LENA) software. Indices of vocal development that could be derived using the software available for research purposes: (a) were highly stable with a single day-long audio recording, (b) predicted future spoken vocabulary to a degree that was nonsignificantly different from the index derived from conventional communication samples, and (c) continued to predict future spoken vocabulary even after controlling for concurrent vocabulary in our sample. The score derived from standard LENA software was similarly stable, but was not significantly correlated with future spoken vocabulary. Findings suggest that automated vocal analysis is a valid and reliable alternative to time intensive and expensive conventional communication samples for measurement of vocal development of preverbal preschoolers with ASD in research and clinical practice. Autism Res 2017, 10: 508 519. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27459108 TI - Modulation of Visual Cortex Excitability by Continuous Theta Burst Stimulation Depends on Coil Type. AB - Subthreshold continuous theta burst stimulation of the visual cortex has been reported to cause inhibitory effects on phosphene threshold. In contrast, we observed no inhibition in a former study applying higher stimulation intensities. The main discrepancies between our experiments and the former studies were stimulation intensity and coil type. We aimed at investigating the role of these factors on the modulatory effects of continuous theta burst stimulation applied to the visual cortex. In a between-group-design, we used either a figure-of-eight coil or a round coil, respectively. We measured phosphene thresholds prior and after continuous theta burst stimulation applied at 80% of individual phosphene threshold. With the figure-of-eight-coil, phosphene thresholds significantly decreased following stimulation. This is in line with the results of our former study but contrary to the increase observed in the other two studies. Using a round coil, no significant effect was observed. A correlation analysis revealed an inhibitory effect in subjects with higher phosphene thresholds only. Furthermore, the slope of the baseline phosphene threshold seems to predict the direction of modulation, independent from coil type. Thus, modulatory effects of continuous theta burst stimulation seem to depend on coil type and psychophysics parameters, probably due to different cortex volumes stimulated. Stochastic resonance phenomena might account for the differences observed. PMID- 27459109 TI - Endocrine and cardiovascular rhythms differentially adapt to chronic phase-delay shifts in rats. AB - Disturbances in regular circadian oscillations can have negative effects on cardiovascular function, but epidemiological data are inconclusive and new data from animal experiments elucidating critical biological mechanisms are needed. To evaluate the consequences of chronic phase shifts of the light/dark (LD) cycle on hormonal and cardiovascular rhythms, two experiments were performed. In Experiment 1, male rats were exposed to either a regular 12:12 LD cycle (CONT) or rotating 8-h phase-delay shifts of LD every second day (SHIFT) for 10 weeks. During this period, blood pressure (BP) was monitored weekly, and daily rhythms of melatonin, corticosterone, leptin and testosterone were evaluated at the end of the experiment. In Experiment 2, female rats were exposed to the identical shifted LD schedule for 12 weeks, and daily rhythms of BP, heart rate (HR) and locomotor activity were recorded using telemetry. Preserved melatonin rhythms were found in the pineal gland, plasma, heart and kidney of SHIFT rats with damped amplitude in the plasma and heart, suggesting that the central oscillator can adapt to chronic phase-delay shifts. In contrast, daily rhythms of corticosterone, testosterone and leptin were eliminated in SHIFT rats. Exposure to phase shifts did not lead to increased body weight and elevated BP. However, a shifted LD schedule substantially decreased the amplitude and suppressed the circadian power of the daily rhythms of BP and HR, implying weakened circadian control of physiological and behavioural processes. The results demonstrate that endocrine and cardiovascular rhythms can differentially adapt to chronic phase delay shifts, promoting internal desynchronization between central and peripheral oscillators, which in combination with other negative environmental stimuli may result in negative health effects. PMID- 27459110 TI - Coordinate regulation of autophagy and the ubiquitin proteasome system by MTOR. AB - Proteins in eukaryotic cells are continually being degraded to amino acids either by the ubiquitin proteasome system (UPS) or by the autophagic-lysosomal pathway. The breakdown of proteins by these 2 degradative pathways involves totally different enzymes that function in distinct subcellular compartments. While most studies of the UPS have focused on the selective ubiquitination and breakdown of specific cell proteins, macroautophagy/autophagy is a more global nonselective process. Consequently, the UPS and autophagy were traditionally assumed to serve distinct physiological functions and to be regulated in quite different manners. However, recent findings indicate that protein breakdown by these 2 systems is coordinately regulated by important physiological stimuli. The activation of MTORC1 by nutrients and hormones rapidly suppresses proteolysis by both proteasomes and autophagy, which helps promote protein accumulation, whereas in nutrient-poor conditions, MTORC1 inactivation causes the simultaneous activation of these 2 degradative pathways to supply the deprived cells with a source of amino acids. Also this selective breakdown of key anabolic proteins by the UPS upon MTORC1 inhibition can help limit growth-related processes (e.g., cholesterol biosynthesis). Thus, the collaboration of these 2 degradative systems, together with the simultaneous control of protein translation by MTORC1, provide clear advantages to the organism in both growth and starvation conditions. PMID- 27459111 TI - Left atrial active contractile function parameters assessed by cardiac MR are sensitive to myocardial iron. AB - PURPOSE: To determine the impact of myocardial iron overload on left atrial (LA) volume and function using MR in patients with systemic iron overload. MATERIALS AND METHODS: Thirty-eight patients with systemic iron overload disease and 10 controls underwent 1.5 Tesla MR performing steady state free precession short axis cine-series of the LA. Three-dimensional-volumetry was assessed to calculate LA volumes and function. Parameters were indexed (i) to body surface area. The myocardial transverse relaxation rate R2* was determined in the ventricular septum using a multi-echo GRE sequence (breathhold; electrocardiography triggered; 12 echoes; echo time = 1.3-25.7 ms). RESULTS: Significantly decreased active atrial emptying fraction (AAEF) (23% [95%-range, 7-34] versus 36% [95% range, 14-49], P = 0.009), active atrial emptying volume (AAEVi) (5.5 mL/m2 [95% range, 2-11] versus 11.9 mL/m2 [95%-range, 3-23], P = 0.008), and active peak emptying rate (APERi) (46 mL/s/m2 [95%-range, 29-69] versus 75 mL/s/m2 [95% range, 45-178], P < 0.001) were found for patients with myocardial iron overload (R2* > 40 s-1 ) compared with patients with normal myocardial iron levels (R2* < 40 s-1 ). Receiver operating characteristics (ROC) analysis revealed higher potential to indicate myocardial iron overload for the AAEF (area under the ROC curve [AUC] = 0.84; P < 0.0001), APERi (AUC = 0.87; P < 0.0001), and AAEVi (AUC = 0.80; P < 0.0001) compared with LA ejection fraction (LAEF) (AUC = 0.68; P = 0.02) with equal sensitivities and specificities of 82% (AAEF), 79% (APERi), 73% (AAEVi), and 57% (LAEF). CONCLUSION: MR parameters of active LA contractile function were associated with myocardial iron overload. This cross-sectional study suggests impaired active LA contractile function to be sensitive to myocardial iron toxicity. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:535-541. PMID- 27459112 TI - Neuroprotective effect of crude polysaccharide isolated from the fruiting bodies of Morchella importuna against H2O2-induced PC12 cell cytotoxicity by reducing oxidative stress. AB - Oxidative stress played an essential role in neuronal cell injury through several apoptotic mechanisms associated with many neurodegenerative diseases. Reducing oxidative stress through antioxidants might be a possible strategy that could retard the disease's progression. In order to investigate the neuroprotective role of MIP (the crude polysaccharide extracted from the fruiting bodies of Morchella importuna), the antioxidative activity of MIP against the H2O2-induced cytotoxicity and the underlying preventative mechanisms in rat pheochromocytoma (PC12) cells were illustrated. It was shown that MIP could considerably enhance the viability of PC12 cells exposure to H2O2 and increased the activities of antioxidant enzyme like CAT, GSH-Px and SOD. It also reduced the content of malondialdehyde MDA and caspase-3 activation. In addition, MIP inhibited cell apoptosis via down-regulation of the NF-kappaB pathway and the p38-JNK pathway as well as activating of the extracellular signal-regulated kinase (ERK). Accordingly, MIP can be used as a promising neuroprotective compound for nervous diseases treatment. PMID- 27459113 TI - Preventive and curative effect of Pistacia lentiscus oil in experimental colitis. AB - AIM: to investigate the anti-inflammatory effect of the Pistacia lentiscus oil in experimental colitis model. MATERIALS AND METHODS: Colitis was induced in male rats by instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in all groups. The experimental groups consisted of: 5 rats received Lentisc oil 2months before colitis induction (preventive group), 5 rats received the oil on the day of colitis induction (curative group) and 5 control rats. Lentisc oil was extracted from the ripe fruit of the plant by the cold press method and was analyzed by spectro-chromatography. Lentisc oil has been inserted with a standard diet at the dose of 30mg oil/100g of food/rat. RESULTS: The lentisc oil sample is composed mainly by Oleic acid (47.96%), Palmitic acid (27.94%) and Linoleic acid (20.22%).There was a significant difference between control rats and treated rats with lentisc oil concerned body mass (p=0.009), bleeding index (p=0.005 and p=0.018) and diarrhea (p=0.012). Histological examination revealed a clear difference between the control and preventive groups with disappearance of erosion, decreased of cryptitis, irregular crypts and crypt loss in the preventive group. Curative group showed a significant decrease of ulceration, hyperplasia, cryptitis, irregular crypts and crypt loss compared to the control group. There was an attenuation of inflammation in the preventive group compared to the curative group without statistically significant. CONCLUSION: Lentisc oil administration could provide a protective effect on intestinal inflammation in colitis rats induced by TNBS mainly when it is administered at a young age in preventive mode. This beneficial effect would involve a modification of arachidonic acid metabolism. PMID- 27459114 TI - Protective effect of grape seed and skin extract against diabetes-induced oxidative stress and renal dysfunction in virgin and pregnant rat. AB - The present work deal with the effect of alloxan-induced diabetes on kidney oxidative stress and dysfunction of virgin and pregnant rat as well as the protection that may be afforded by high dosage GSSE (4g/kg) treatment. Diabetes affected negatively several kidney function parameters as creatinemia, uremia, uricemia and proteinuria without affecting kidney index. Diabetes also induced an oxidative stress characterized by increased lipid and protein oxidation, a drop in antioxidant enzyme defenses as catalase, superoxide-dismutase, glutathione peroxidase, an alteration in transition metals as free iron, copper, selenium and associated enzymes and an increase in calpain and acetyl-cholinesterase activities. Tremendously, GSSE treatment protected efficiently against all the deleterious effects of diabetes-induced kidney dysfunction in both virgin and pregnant animals. High dosage GSSE is a safe and potent anti-oxidant that may be further tested in clinical trials for the long-term preservation of kidney function especially in multiple pregnancies. PMID- 27459115 TI - Over-expression of microRNA-940 promotes cell proliferation by targeting GSK3beta and sFRP1 in human pancreatic carcinoma. AB - Increasing study reports that Wnt/beta-catenin signaling pathway plays an essential role in numerous cancers growth, progression and metastasis. Aberrant miR-940 expression has been studied in gastric and breast cancer. However, the molecular mechanism of miR-940 enhancing proliferation and metastatic ability in human pancreatic carcinoma is far from to know. Real-time PCR was used to quantify miR-940 expression. Luciferase reporter assays here were performed to verify the activity of Wnt/beta-catenin signaling pathway and targeting gene relationships, and immunofluorescence assay was applied to observe beta-catenin expressed intensity. Bioinformatics analysis together with in vivo and vitro functional analysis indicated the potential targeting genes of miR-940. Specimens from 15 pairs of patients with human pancreatic carcinoma were involoved to confirm the relationship between miR-940 expression and the GSK3beta/sFRP1 through real-time PCR and western blot assays. Bioinformatics combined with cell luciferase function researches determined the possible regulation of miR-940 on the 3'-UTR of the GSK3beta and sFRP1 genes, resulting in the Wnt/beta-catenin signaling activation. Further, miR-940 knockdown significantly recovered GSK3beta and sFRP1 expression and relieved Wnt/beta-catenin-mediated cell invasion, migration, metastasis and proliferation. The ectopic up-regulation of miR-940 significantly suppressed GSK3beta/sFRP1 expression and promoted pancreatic carcinoma proliferation and invasion. Our study suggested mechanistic relationship between miR-940 and Wnt/beta-catenin in the development and progression of pancreatic carcinoma through regulation of GSK3beta and sFRP1. PMID- 27459116 TI - HMSH2 and HMSH6 gene expression profiles in colorectal adenocarcinoma in patients up to 50 years of age. AB - Lynch syndrome, previously called hereditary non-polyposis colorectal cancer (HNPCC), is a major mortality threat. It is an autosomal dominant disease which is caused by a germline mutation in the DNA mismatch repair (MMR), especially in patients aged up to 50 years. Such mutation more frequently occurs in the hMSH2 gene (38-40%) and less frequently in the hMSH6 gene (14-16%). These mutations, when associated with the patient's lifestyle, may reveal a considerable variability in the disease manifestations, such as the degrees of penetrance and clinical aggressiveness. The aim of this study is to analyze the expression of DNA MMR genes, and correlate this expression with the clinical and anatomopathological findings of the neoplasia in patients aged between 39 and 49 years. A total of 45 patients were included: (48.9%) males and (51.1%) females, and they all underwent resection of a colorectal adenocarcinoma. The tissue microarray technique was used to analyze the relative and absolute expression of hMSH2 and hMSH6. Amsterdam II criteria for the diagnosis of HNPCC were obtained from the data provided by medical records and interviews with patients. hMSH2 and hMSH6 was expressed in all patients, which correlated between each other (RHO=0.669 and p<0.001) but not to age. There is a positive correlation between the expressions of males (RHO=0.673 and p=0.001) and females (RHO=0.006 and p<0.001). It is possible to evaluate the expression of MMR genes in embedded anatomopathological samples. Gene expressions correlated between each other and to the sex of the patients, but no difference in relation to age. PMID- 27459117 TI - Fucoidan-induced ID-1 suppression inhibits the in vitro and in vivo invasion of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a fast growing tumor associated with a high tendency for vascular invasion and distant metastasis. Recently, we reported that fucoidan displays inhibitory effect on proliferation and invasion of HCC cells. In this study, we investigated the anti-metastatic effect of fucoidan on HCC cells and the key signal that modulates metastasis. The anti-metastatic effect of fucoidan was evaluated in vitro using an invasion assay with human HCC cells (Huh 7, SNU-761, and SNU-3085) under both normoxic (20% O2 and 5% CO2, at 37 degrees C) and hypoxic (1% O2, 5% CO2, and 94% N2, at 37 degrees C) conditions. Complementary DNA (cDNA) microarray analysis was performed to find the molecule which is significantly suppressed by fucoidan. In vivo study using a distant metastasis model by injecting SNU-761 cells into spleen via portal vein was performed to confirm the inhibitory effect by small interfering RNA (siRNA) transfection. Immunoblot analyses were used to investigate the signaling pathway. Fucoidan significantly suppressed the invasion of human HCC cells (Huh-7, SNU 761, and SNU-3085). Using cDNA microarray analysis, we found the molecule, ID-1, which was significantly suppressed by fucoidan treatment. Downregulation of ID-1 by siRNA significantly decreased invasion of HCC cells, both in vitro and in vivo (both P<0.05) in a NDRG-1/CAP43-dependent manner. In immunoblot assay, downregulation of ID-1 by siRNA decreased the expressions of epithelial mesenchymal transition markers including CK19, vimentin, MMP2, and fibronectin. Immunofluorescence study also revealed that actin rearrangement was inhibited when ID-1 was down-regulated in HCC cells. Interestingly, in SNU-761 cells, the ID-1 expressions under hypoxic conditions were lower as compared to those under normoxic conditions. Under hypoxic conditions, HIF-1alpha up-regulated NDRG 1/CAP43, while HIF-2alpha down-regulated ID-1, which might be a compensatory phenomenon against hypoxia-induced HCC invasion. In conclusion, NDRG-1/CAP43 dependent down-regulation of ID-1 suppressed HCC invasion both in vitro and in vivo, which was modulated by fucoidan treatment. Moreover, the compensatory down regulation of ID-1 against hypoxia-induced HCC invasion was observed. ID-1 is a novel therapeutic target for the treatment of metastatic HCC. PMID- 27459118 TI - The apoptotic and autophagic properties of two natural occurring prodrugs, hyperoside and hypoxoside, against pancreatic cancer cell lines. AB - Pancreatic cancer is only the 12th most common cancer, but the fourth leading cause of cancer-related deaths in the world. This is due to late prognosis, poor response to chemotherapy and early metastases. Natural prodrugs may play an important role in the treatment of pancreatic cancer. The main aim of this study was to determine the cytotoxicity of five natural prodrugs, namely harpagoside, hyperoside, hypoxoside, oleuropein and polydatin, by investigating apoptosis and autophagy as possible mechanism/s of action. Hypoxoside and hyperoside have shown selective cytotoxicity at IC50 values of ~25 and 50MUM against INS-1 and MIA PaCa 2 pancreatic cancer cells, respectively. Hypoxoside and hyperoside induced G2/M phase arrest and caspase-3 activation in INS-1 and MIA PaCa-2 cells, respectively. Hoechst/phalloidin staining confirmed morphological changes, including condensed chromatin multinucleation, membrane blebbing and loss of cytoskeletal arrangement in INS-1 and MIA PaCa-2 cells. Acridine orange staining was absent in INS-1 (hypoxoside) and MIA PaCa-2 (hyperoside) treated cells, whereas LC3B expression was not significantly increased. INS-1 and MIA PaCa-2 treated cells favour the cell death pathway, apoptosis, over the cell survival pathway, autophagy. PMID- 27459119 TI - Combination treatment with Rhizoma Paridis and Rhizoma Curcuma longa extracts and 10-hydroxycamptothecin enhances the antitumor effect in H22 tumor model by increasing the plasma concentration. AB - The combination of Western medicine and Chinese prescription is the most effective tumor therapy in China market. In our previous report, a new prescription composed by Rhizoma Paridis and Rhizoma Curcuma longa called LouHuang preparation (LH) shows good antitumor activity. 10-Hydroxycamptothecin (HCPT) as a chemotherapy agent is used for treatment of solid tumors in clinical. In this study, we investigated the combination effect of LH and HCPT on H22 tumor cells in vitro and in vivo. In vitro test, combination of LH and HCPT presented a synergistic effect on H22 cancer cells. Because of the toxicity of HCPT in normal dosage with intraperitoneal injection, we chose a low dose in the study. LH increased the tumor inhibition rate of HCPT in H22 tumor model from 39% to 55% and showed additive effect by the q value method. The concentration of HCPT in plasma was detected by HPLC-FLD method and increased from 60 to 75ng/mL when combined with LH. For the absorption research, LH significantly enhanced the absorption transport of HCPT from 7019.04 to 11569.02ng/cm2, while improved the permeation flux (F) and apparent permeability (Papp) of HCPT from 10.62 to 21.47 (ng/cm2min) and 9.92-20.07 (10-6cm/s), respectively. The study indicates that LH could boost the efficacy of HCPT by increasing the plasma concentration regardless of the formulation and combined administration of HCPT and LH might be used as an adjuvant drug for treatment of liver cancer. PMID- 27459120 TI - Thymoquinone: An edible redox-active quinone for the pharmacotherapy of neurodegenerative conditions and glial brain tumors. A short review. AB - There exist few efficient agents in the neurological and neurosurgical armamentarium for treatment of neurotrauma, refractory seizures and high grade glial tumors. Pathophysiological conditions of diverse neural injuries have converging common pathways including oxidative stress and apoptosis. Targeted therapies have been throughly investigated, but limited success has been achieved until now. Phytochemical drugs may provide easily achievable and cheap adjunctive sources. Thymoquinone is an edible quinone obtained from Nigella sativa seed oil and exerts powerful antiinflammatory, antioxidant and antitumor activities in experimental models. Recently emerging studies conducted with animal models suggest that thymoquinone - bearing a very simple molecular structure - significantly crosses the blood brain barrier and exerts neuromodulatory activities. Indeed, in animal studies, the following actions of thymoquinone were demonstrated: 1-Protection against ischemic brain damage. 2-Reduction of epileptic seizures and associated cerebral oxidative injury. 3-Reduction of morphine tolerance and associated oxidative brain damage. 4-Anxiolytic effects and reduction of immobility stress-associated cerebral oxidative injury. 5 Reduction of diabetes-induced cerebral oxidative stress, 6-Reduction of cerebral oxidative injuries induced by noxious exposures including toluene, lead and ionizing radiation. Substantial in vitro data suggest that thymoquinone may be beneficial in treatment of glial tumors. However, there is no clinical study investigating its antitumor effects. In fact, thymoquinone suppresses growth and invasion, and induces apoptosis of glial tumor cells via degrading tubulins and inhibiting 20S proteasome, telomerase, autophagy, FAK and metalloproteinases. A simple and easily available agent may be a promising adjunctive treatment option in neurological and neurosurgical practice. PMID- 27459121 TI - Hair growth promoting activity of cedrol isolated from the leaves of Platycladus orientalis. AB - Platycladus orientalis (L.) Franco is traditionally known to potentiate hair growth promotion. However, there has been no report on its main active ingredient responsible for the hair growth activity. In the current work, cedrol as a major constituent from P. orientalis was evaluated for its potential on hair growth in vivo. Different concentrations of cedrol (10, 20 and 30mg/mL) were applied topically over the shaved skin of C57BL/6 mice and monitored for 21days. Results indicated that cedrol significantly promoted hair growth in a dose-dependent manner, particularly for the female mice. Both male and female mice groups treated with 30mg/mL cedrol required shorter time than the blank control and 2% minoxidil groups at different growth stages. Compared with the blank control (8.87mm) and 2% minoxidil (9.94mm) groups at 21days, the hair length of female mice treated with 30mg/mL cedrol showed a remarkable increase with the value of 11.07mm. Hair in male and female mice groups treated with 30mg/mL cedrol was heavier than the 2% minoxidil (38.2 and 35.9mg, respectively) groups with the weight of 42.6 and 45.2mg, respectively. Further observation of the hair follicle demonstrated that cedrol exerted a remarkable effect on the hair follicle length. These findings suggested that cedrol may be the main active ingredient of P. orientalis and have the potential of becoming a new hair growth promoter. PMID- 27459122 TI - In vitro-Scientific evaluation on antimicrobial, antioxidant, cytotoxic properties and phytochemical constituents of traditional coastal medicinal plants. AB - In the present study, evaluation of antimicrobial, antioxidant, phytochemical constituents and toxicological properties of six coastal medicinal plants (CMP's) such as Ipomea biloba, Cantharanthus roseus, Cymbopogon citratus, Vitex negundo, Thespesia populnea and Pandanus tectorius was done. The maximum antimicrobial activity was recorded by methanolic extracts of V. negundo and T. populnea against bacterial and fungal pathogens. Similarly, methanolic extracts of V. negundo and T. populnea evidenced highest antioxidant properties. The extract of T. populnea showed the maximum cytotoxicity against Artemia salina with the LC50 value of 478.11MUg/ml. The hemolytic property of CMP's extracts was V. negundo (8.91%), T. populnea (21%) and C. citratus (64%) also the hemolytic index did not show any hemolysis of human erythrocytes. Furthermore, the TLC separation of V. negundo and T. populnea extracts exhibited the presence of Flavonoids (Rf-0.74) and Terpenoids (Rf-0.64). The present findings propose the promising clinical applications of selected CMP's. PMID- 27459123 TI - Conceptualization and Pilot Testing of a Core Competency-Based Training Workshop in Suicide Risk Assessment and Management: Notes From the Field. AB - OBJECTIVES: As professional psychology training programs and continuing education have moved toward competency based approaches, it has become equally important to develop uniform, evidence-based approaches for suicide risk assessment and management. The present article presents a workshop curriculum based on established core competencies in suicide risk assessment and management. METHOD: Drawing on theories suicide risk formation, the workshop features an integration of didactic, process, and experiential components. We present pilot data from 2 small group workshops (n = 17): 1 from a clinical psychology doctoral program and 1 from a university counseling center. RESULTS: Workshop participation yielded increases in (a) the ability to recognize appropriate clinician responses to suicidal client statements, (b) self-perceptions of general capacity to interface with suicidal patients and mastery of the 10 core competencies, (c) factual knowledge concerning suicide risk assessment and management, and (d) the self rated ability to assess and manage a suicidal patient. CONCLUSION: We discuss statistical and generalizability limitations as well as implications for future modification, implementation, and provision of this training method. PMID- 27459125 TI - Reply. PMID- 27459124 TI - Chemokines and their receptors: insights from molecular modeling and crystallography. AB - Chemokines are small secreted proteins that direct cell migration in development, immunity, inflammation, and cancer. They do so by binding and activating specific G protein coupled receptors on the surface of migrating cells. Despite the importance of receptor:chemokine interactions, their structural basis remained unclear for a long time. In 2015, the first atomic resolution insights were obtained with the publication of X-ray structures for two distantly related receptors bound to chemokines. In conjunction with experiment-guided molecular modeling, the structures suggest a conserved receptor:chemokine complex architecture, while highlighting the diverse details and functional roles of individual interaction epitopes. Novel findings promote the development and detailed structural interpretation of the canonical two-site hypothesis of receptor:chemokine recognition, and suggest new avenues for pharmacological modulation of chemokine receptors. PMID- 27459126 TI - Development and validation of an UPLC-PDA method for the determination of corilagin in rat plasma and its application to pharmacokinetic study. AB - Corilagin, which was isolated from several medical herbs, has been reported to exert many pharmacological activities. A simple and rapid liquid ultra performance liquid chromatography (UPLC) coupled to photodiode array (PDA) method has been developed to quantify corilagin in rat plasma. In this study, plasma samples were prepared by ethyl acetate extraction. Separation was performed on a HSS T3 (100mm*2.1mm, 1.8MUm) column by using a mobile phase of acetonitrile and water with 0.1% trifluoroacetic acid (v/v). Corilagin and internal standard epicatechin were detected at a wavelength of 266nm. The calibration curve was linear (r>0.998) over a concentration range of 0.2MUg/mL to 20MUg/mL with a lower quantification limit of 0.2MUg/mL. Both intra and inter-day precision values were within 5.7% and extraction recovery were greater than 81.0%. Stability tests showed that corilagin and IS remained stable during the analytical procedure. The validated UPLC-PDA method was then used to analyze the pharmacokinetics of corilagin administered to rats intravenously (10mg/kg) or orally (50mg/kg). Oral bioavailability of corilagin was calculated to be 10.7%, indicating that this component is not suitable for oral administration. The results provide basis for further preclinical studies on corilagin. PMID- 27459127 TI - Thermally Induced Reversible Double Phase Transitions in an Organic-Inorganic Hybrid Iodoplumbate C4H12NPbI3 with Symmetry Breaking. AB - A one-dimensional (1D) organic-inorganic hybrid iodoplumbate crystal (1, C4H12NPbI3, TMAPbI3) can undergo two reversible phase transitions as the temperature decreases. Its dynamic phase-transition behaviors were carefully studied by dielectric measurements, thermal analysis, and variable-temperature crystallographic studies. These results indicate that the phase transitions possess a disorder-order feature with a noncentrosymmetrical intermediate phase structure. Due to the existence of the ordered motion and reorientation of the C4H12N(+) cation, 1 undergoes two phase transitions: the first one from space group P63/m at room temperature to Pm at 163 K with symmetry breaking, and the second one from space group Pm at 163 K to P61 at 142 K with partial symmetry restoration. Our results indicate that there is an existence of a transitional structure with a low symmetry space group during the disorder-order-type phase transitions, which can provide us valuable information to deeply understand the disorder-order phase transition in organic-inorganic hybrids. PMID- 27459128 TI - Tuning the Morphology and Crystal Structure of Li2O2: A Graphene Model Electrode Study for Li-O2 Battery. AB - The performance and the cyclability of the Li-O2 batteries are strongly affected by the morphology and crystal structure of Li2O2 produced during discharge. In order to explore the details of growth and electrochemical decomposition of Li2O2, and its relationship with the cell performance, graphene films were used as model carbon electrodes and compared with electrodeposited Pd nanoparticles (NPs) on graphene. Multiple methods, including transmission/scanning electron microscopy (TEM/SEM), Raman spectroscopy, electrochemical impedance spectroscopy (EIS), and coin cell charge/discharge test, were employed for material characterization and reaction monitoring. The results showed that the presence of Pd NPs significantly changed the growth, morphology, and crystal structure of Li2O2 and reduced the charge overpotential by 1060 mV. All of these changes are ascribed to the stronger binding energy between LiO2 and the Pd surface, resulting in the generation of amorphous Li2O2 with higher ionic conductivity of Li(+) and O2(2-), which in turn improve the cell charging performance. PMID- 27459130 TI - Summary of the 12th International Phytotechnology Conference: Phytotechnologies for Sustainable Development, Manhattan, Kansas, September 27-30, 2015. PMID- 27459131 TI - Oxidative Annulation of Arenecarboxylic and Acrylic Acids with Alkynes under Ambient Conditions Catalyzed by an Electron-Deficient Rhodium(III) Complex. AB - It has been established that an electron-deficient Cp(E) rhodium(III) complex catalyzes the oxidative [4+2] annulation of substituted arenecarboxylic and acrylic acids with alkynes under ambient conditions (at RT-40 degrees C, under air) without using excess amounts of substrates to produce the corresponding substituted isocoumarins and alpha-pyrones in high yields. Minor modification of reaction conditions depending on the coordination ability of alkynes realized the high efficiency. PMID- 27459129 TI - Activation and modulation of recombinant glycine and GABAA receptors by 4 halogenated analogues of propofol. AB - BACKGROUND AND PURPOSE: Glycine receptors are important players in pain perception and movement disorders and therefore important therapeutic targets. Glycine receptors can be modulated by the intravenous anaesthetic propofol (2,6 diisopropylphenol). However, the drug is more potent, by at least one order of magnitude, on GABAA receptors. It has been proposed that halogenation of the propofol molecule generates compounds with selective enhancement of glycinergic modulatory properties. EXPERIMENTAL APPROACH: We synthesized 4-bromopropofol, 4 chloropropofol and 4-fluoropropofol. The direct activating and modulatory effects of these drugs and propofol were compared on recombinant rat glycine and human GABAA receptors expressed in oocytes. Behavioural effects of the compounds were compared in the tadpole loss-of-righting assay. KEY RESULTS: Concentration response curves for potentiation of homomeric alpha1, alpha2 and alpha3 glycine receptors were shifted to lower drug concentrations, by 2-10-fold, for the halogenated compounds. Direct activation by all compounds was minimal with all subtypes of the glycine receptor. The four compounds were essentially equally potent modulators of the alpha1beta3gamma2L GABAA receptor with EC50 between 4 and 7 MUM. The EC50 for loss-of-righting in Xenopus tadpoles, a proxy for loss of consciousness and considered to be mediated by actions on GABAA receptors, ranged from 0.35 to 0.87 MUM. CONCLUSIONS AND IMPLICATIONS: We confirm that halogenation of propofol more strongly affects modulation of homomeric glycine receptors than alpha1beta3gamma2L GABAA receptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABAA receptors. We infer that 4 bromopropofol, 4-chloropropofol and 4-fluoropropofol are not selective homomeric glycine receptor modulators. PMID- 27459132 TI - Preventing Opioid Prescription Theft and Ensuring SeCure Transfer of Personal Health Information when Patients Transition from the Hospital to a Nursing Home. PMID- 27459133 TI - Dynamic 3D MR-Defecography. PMID- 27459134 TI - Trehalose as antifungal target: The picture is still incomplete. PMID- 27459135 TI - Accessing spin-crossover behaviour in iron(ii) complexes of N-confused scorpionate ligands. AB - The first examples of a class of N-confused tris(pyrazolyl)methane 'scorpionate' ligands have been prepared. The magnetic properties of their iron(ii) tetrafluoroborate complexes are dictated by changing one substituent per ligand rather than three as is typical for normal scorpionate ligands. PMID- 27459136 TI - Distribution of hip pain in patients with idiopathic osteonecrosis of the femoral head. AB - OBJECTIVE: To determine the distribution of referred hip pain in patients with idiopathic osteonecrosis of the femoral head (ION). METHODS: We prospectively documented 119 hips in 90 patients with ION (mean age 51 years). Patients identified the location of pain originating in their hip on a drawing of the body. Osteoarthritis of the hip (OA) was used as a historical cohort. RESULTS: Referral of pain originating from the hip in patients with ION was 93% (111 hips) to the groin, 68% (81 hips) to the knee, 36% (43 hips) to the anterior thigh, 34% (40 hips) to the buttock, 18% (22 hips) to the lower leg, 9% (11 hips) to the greater trochanter, and 8% (9 hips) to the low back. About 97% (115 hips) of pain was located in the hip region (groin, buttock, and greater trochanter) and 77% (92 hips) showed referred pain (anterior thigh, knee, lower leg, and low back). Pain from ION was significantly more frequent in the knee and lower leg, but significantly less frequent in the lower back than pain from OA. CONCLUSION: We should be aware of ION masquerading as pain in the knee or anterior thigh. PMID- 27459137 TI - Complicated Outcomes After Emergent Lower Extremity Surgery in Patients With Solid Organ Transplants. AB - The complications of emergent or urgent surgery in solid organ transplant recipients are unclear. The goal of this nonrandomized retrospective case study, conducted at a large public university teaching hospital, was to determine the following: (1) 90-day postsurgical complications in solid organ transplant recipients who undergo fracture surgery of the lower extremities; (2) 90-day and 1-year mortality rates for this cohort; (3) correlation of particular postsurgical complications with the 90-day or 1-year mortality rate; and (4) correlation of body mass index with the 90-day or 1-year mortality rate. Subjects included 36 solid organ transplant recipients who underwent surgical treatment for 37 emergent or urgent lower extremity fractures within 72 hours of presentation to the emergency department. Patients were followed for all medical and surgical complications for 90 days and for all-cause mortality for 1 year. Within 90 days of surgery, patients had complications that included acute renal failure (15, 40.5%), deep venous thrombosis (3, 8.1%), pulmonary embolus (2, 5.4%), pneumonia (7, 18.9%), superficial surgical site infection (3, 8.1%), and nonorthopedic sepsis (4, 10.8%). In addition, 3 (8.1%) and 5 (13.9%) patients died within 90 days and 1 year, respectively. Hospital readmission correlated with a higher 1-year mortality rate (odds ratio, 14.000; P=.016). Higher body mass index correlated with higher 90-day (odds ratio, 1.425; P=.035) and 1-year (odds ratio, 1.334; P=.033) mortality rates. Solid organ transplant recipients with lower extremity fracture have high 90-day and 1-year mortality rates and may have multiple complications within 90 days of treatment. [Orthopedics. 2016; 39(6):e1063-e1069.]. PMID- 27459138 TI - A New Culture of Transparency: Industry Payments to Orthopedic Surgeons. AB - Under the Physician Payments Sunshine Act, "payments or transfers of value" by biomedical companies to physicians must be disclosed through the Open Payments Program. Designed to provide transparency of financial transactions between medication and device manufacturers and health care providers, the Open Payments Program shows financial relationships between industry and health care providers. Awareness of this program is crucial because its interpretation or misinterpretation by patients, physicians, and the general public can affect patient care, clinical practice, and research. This study evaluated nonresearch payments by industry to orthopedic surgeons. A retrospective cross-sectional review of the first wave of Physician Payments Sunshine Act data (August through December 2013) was performed to characterize industry payments to orthopedic surgeons by subspecialty, amount, type, origin, and geographic distribution. During this 5-month period, orthopedic surgeons (n=14,828) received $107,666,826, which included 3% of those listed in the Open Payments Program and 23% of the total amount paid. Of orthopedic surgeons who received payment, 45% received less than $100 and 1% received $100,000 or more. Median payment (interquartile range) was $119 ($34-$636), and mean payment was $7261+/-95,887. The largest payment to an individual orthopedic surgeon was $7,849,711. The 2 largest payment categories were royalty or license fees (68%) and consulting fees (13%). During the study period, orthopedic surgeons had substantial financial ties to industry. Of orthopedic surgeons who received payments, the largest proportion (45%) received less than $100 and only 1% received large payments (>=$100,000). The Open Payments Program offers insight into industry payments to orthopedic surgeons. [Orthopedics. 2016; 39(6):e1058-e1062.]. PMID- 27459139 TI - Total Knee Arthroplasty After Knee Arthroscopy in Patients Older Than 50 Years. AB - Several orthopedic registries have described the incidence of total knee arthroplasty (TKA) in patients who have undergone knee arthroscopy. Patient risk factors may play a role in the conversion rate from knee arthroscopy to TKA. This study quantifies the incidence of conversion of knee arthroscopy to TKA from a US mixed-payer database and describes some common patient risk factors for conversion. The medical records of more than 50 million patients who were treated between 1998 and 2014 were mined with a commercially available software platform. During the study period, a total of 68,090 patients older than 50 years underwent knee arthroscopy for partial meniscectomy, chondroplasty, or debridement. Reported rates of TKA at 1, 2, and 3 years after arthroscopy were 10.1%, 13.7%, and 15.6%, respectively. Obesity, depressive disorder, rheumatoid arthritis, diabetes, and age 70 years and older were associated with increased relative risk of conversion to TKA at 2 years. When obesity was combined individually with the top 5 other risk factors, no combination produced a higher relative risk than that of obesity alone. Patients who were 50 to 54 years of age had the lowest incidence of conversion to TKA (8.3%, P<.001). Men had a lower incidence of conversion to TKA (11.3%) than women (15.8%, P<.001). This information can help surgeons to counsel patients on the incidence of TKA after knee arthroscopy and identify preoperative risk factors that increase risk. [Orthopedics. 2016; 39(6):e1041-e1044.]. PMID- 27459140 TI - Pediatric Diaphyseal Femur Fractures: Submuscular Plating Compared With Intramedullary Nailing. AB - This study compared the radiographic and clinical outcomes of pediatric diaphyseal femur fractures treated by submuscular plating, flexible retrograde intramedullary nailing, or rigid antegrade intramedullary nailing with a trochanteric entry point in skeletally immature patients who were 8 years and older. A retrospective review was conducted of skeletally immature patients 8 years and older who were treated for femur fracture with submuscular plating, flexible intramedullary nailing, or rigid intramedullary nailing from 2001 to 2014 with a minimum 12-week follow-up. Treatment outcomes were compared for statistical significance, including time to union, malunion, nonunion, heterotopic ossification, avascular necrosis, time to full weight bearing, limb length discrepancy, residual limp, painful hardware, and infection. The study identified 198 femur fractures in 196 patients (mean age, 11.9 years). Each femur fracture was treated with submuscular plating (35), flexible intramedullary nailing (61), or rigid intramedullary nailing (102). Mean follow-up across the cohort was 48 weeks, ranging from 12 to 225 weeks. Flexible nailing was associated with an increased incidence of malunion (P<.0001) and hardware irritation (P=.0204) and longer time to full weight bearing (P=.0018). Rigid nailing was associated with an increased incidence of limp at 12-week followup (P=.0412). Additionally, 23.5% of patients who were treated with rigid nailing had heterotopic ossification. Of all surgical methods, submuscular plating allowed for the most rapid return to full weight bearing (mean, 7 weeks) and offered the fastest healing rate (mean, 6 weeks). Submuscular plating resulted in faster times to union and full weight bearing, with minimal complication rates. Rigid intramedullary nailing with trochanteric entry resulted in a lower incidence of malunion and hardware-related complications; however, these patients had an increased incidence of heterotopic ossification and residual limp postoperatively. Flexible retrograde intramedullary nailing resulted in the highest rates of malunion and hardware irritation and the longest time to full weight bearing. [Orthopedics. 2016; 39(6):353-358.]. PMID- 27459141 TI - Accuracy and Reproducibility of the Femoral Tunnel With Different Viewing Techniques in the ACL Reconstruction. AB - The purpose of this study was to compare the accuracy and reproducibility of the femoral tunnel location among 3 different viewing techniques used during outside in anterior cruciate ligament (ACL) reconstruction with 3- dimensional (3-D) computed tomography (CT): (1) an anterolateral (AL) or anteromedial (AM) portal with a 30 degrees arthroscope (A group) vs (2) a posterolateral (PL) portal with a 70 degrees arthroscope (PL group) vs (3) a trans-septal (TS) portal with a 30 degrees arthroscope (TS group). A total of 106 patients undergoing outside-in ACL reconstruction were recruited. Patients were divided into 3 groups according to viewing technique (A group=36 patients; PL group=35 patients; TS group=35 patients). Femoral tunnel locations were evaluated with the quadrant method and the anatomic coordinate axes measurement (ACAM) method in the medial wall of the lateral femoral condyle using 3-D reconstructed CT. The accuracy and reproducibility of the femoral tunnel locations were compared among the 3 techniques. The accuracy of the tunnel location was higher in the TS group by the quadrant method as well as the ACAM method. The reproducibility of the femoral tunnel position in the TS group was the highest, and the femoral tunnel locations of the TS group were more compactly distributed compared with those of the A and PL groups. The accuracy and reproducibility of the femoral tunnel location could be improved with a TS portal viewed using a 30 degrees arthroscope. Anteromedial/anterolateral and PL portals viewed using a 70 degrees arthroscope showed no difference. [Orthopedics. 2016; 39(6):e1085-e1091.]. PMID- 27459142 TI - Venous Thromboembolism After Knee Arthroscopy in Undiagnosed Familial Thrombophilia. AB - Venous thromboembolism is uncommon after knee arthroscopy, and there are no guidelines for thromboprophylaxis in elective routine knee arthroscopy. Preoperative evaluation of common thrombophilias should provide guidance for postarthroscopy thromboprophylaxis in otherwise healthy patients who are at high risk for venous thromboembolism. This study assessed 10 patients with venous thromboembolism after total hip or knee arthroplasty. Patients were assessed if venous thromboembolism occurred within 6 months after knee arthroscopy (n=10) or total hip or knee arthroplasty (n=21). This study assessed gene mutations (factor V Leiden, prothrombin G20210A, plasminogen activator inhibitor, methylenetetrahydrofolate reductase) and serologic thrombophilias (high levels of factors VIII and XI, homocysteine, anticardiolipin immunoglobulin G and immunoglobulin M antibodies, and lupus anticoagulant; low antigenic protein C, S, and free S; and antithrombin III deficiency). The same coagulation data were obtained for normal subjects (n=110). The major thrombophilias in the arthroscopy group were factor V Leiden heterozygosity (40%), high factor VIII level (50%), and high homocysteine (30%). The respective values in control subjects were 2% (P=.0004), 7% (P=.0011), and 5% (P=.02). When the arthroscopy group was compared with the 21 patients who had venous thromboembolism after total hip or knee arthroplasty, the sole difference was factor V Leiden heterozygosity, which was 40% vs 0%, respectively (P=.007). Although venous thromboembolism after knee arthroscopy is uncommon, to identify high-risk patients and guide postoperative thromboprophylaxis, the authors suggest routine preoperative measurement of 3 common familial thrombophilias: factor V Leiden, factor VIII, and homocysteine. [Orthopedics. 2016; 39(6):e1052-e1057.]. PMID- 27459143 TI - Timing of Hip Fracture Surgery and 30-Day Outcomes. AB - The goal of this study was to determine the proportion of patients admitted with a hip fracture to participating American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) hospitals who were treated within the United Kingdom's National Institute for Health and Care Excellence (NICE) time-to hip-fracture-surgery benchmark. The secondary goals were to identify factors associated with missing the benchmark and to determine whether the benchmark was associated with improved 30-day patient outcomes. Patients aged 60 years or older who underwent hip fracture surgery between 2005 and 2013 were identified from the ACS-NSQIP database. Of the 26,066 patients who met the enrollment criteria, 71.4% were treated within the NICE benchmark. Many variables, including sex, race, procedure type, and hip fracture diagnosis, were statistically significant predictors of missing the benchmark (P<.001). Meeting the NICE benchmark was not associated with reductions in major complications (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.83-1.05; P=.234); however, it was associated with reductions in 30-day mortality (OR, 0.88; 95% CI, 0.78-0.99; P=.028), minor complications (OR, 0.92; 95% CI, 0.84-0.995; P=.038), and postoperative length of stay (beta=-0.77; P<.001). Current practice at participating ACS-NSQIP hospitals is compatible with the NICE time-to-surgery benchmark. However, the findings highlight the importance of further prospective investigation to monitor the effect of early-treatment benchmarks on 30-day patient outcomes. [Orthopedics. 2016; 39(6):361-368.]. PMID- 27459144 TI - Metal in Total Hip Arthroplasty: Wear Particles, Biology, and Diagnosis. AB - Total hip arthroplasty (THA) has been performed for nearly 50 years. Between 2006 and 2012, more than 600,000 metal-on-metal THA procedures were performed in the United States. This article reviews the production of metal wear debris in a metal-on-metal articulation and the interaction of cobalt and chromium ions that ultimately led to a dramatic decline in the use of metal-on-metal THA articulations. Additionally, the article reviews mechanisms of metal wear, the biologic reaction to cobalt and chromium ions, the clinical presentation of failing metal-on-metal articulations, and current diagnostic strategies. Further, the article discusses the use of inflammatory markers, metal ion levels, radiographs, metal artifact reduction sequence magnetic resonance imaging, and ultrasound for failed metal-on-metal THA procedures. When adopting new technologies, orthopedic surgeons must weigh the potential increased benefits against the possibility of new mechanisms of failure. Metal-on-metal bearings are a prime example of the give and take between innovation and clinical results, especially in the setting of an already successful procedure such as THA. [Orthopedics. 2016; 39(6):371-379.]. PMID- 27459145 TI - Precursor Triggering Synthesis of Self-Coupled Sulfide Polymorphs with Enhanced Photoelectrochemical Properties. AB - Heteronanostructures have attracted intensive attention due to their electronic coupling effects between distinct components. Despite tremendous advances of nanostructure fabrication, combining independent polymorphs by forming heterojunction is still challenging but fascinating, such as copper sulfides (Cu2 xS), exhibiting varying band gaps and crystal structures with various stoichiometries. Herein, self-coupled Cu2-xS polymorphs (Cu1.94S-CuS) by a facile one-pot chemical transformation route have been reported for the first time. Unprecedentedly, a manganous precursor plays a crucial role in inducing and directing the formation of such a dumbbell-like architecture, which combines 1D Cu1.94S with 2D CuS. During the transformation, Mn2+ ions mediate the Cu+ ions diffusion and phase conversion process particularly. Furthermore, this self coupled polymorphic structure exhibits significantly enhanced photoelectrochemical properties compared with the individual Cu1.94S nanocrystals and CuS nanoplates, originating from the unique heterointerfaces constructed by intrinsic band alignment and the enhanced contact between high conductivity hexagonal planes and the working electrode revealed by density functional theory (DFT) calculations. So we anticipate this emerging interfacial charge separation could provide useful hints for applications in optoelectronic devices or photocatalysis. PMID- 27459146 TI - Successful delivery after surgical repair of uterine rupture at 15 weeks of gestation: case report and brief review. AB - OBJECTIVE: Second-trimester uterine rupture is a rare disorder and it is unclear if it should be managed with caesarean section, repair or hysterectomy. This article provides a case report of second-trimester uterine rupture repair, and reviews the risk factors, signs and symptoms, suturing technique and newborn outcome. METHODS: PubMed was searched using the terms 'uterine rupture', 'second trimester' and 'repair' Only cases of second-trimester uterine rupture repair that led to successful prolongation of pregnancy were included. RESULTS: The main risk factor of uterine rupture is previous caesarean section (5/10, 50%). Eight of 10 cases presented with abdominal pain and three cases presented in shock. Haemoperitoneum was present in five cases. The mean and median gestational age at delivery were 33.4 and 33.5 weeks, respectively (range 28-37 weeks), with mean and median delayed interval delivery of 95.5 and 91 days, respectively (range 14 147 days). Neonatal outcome was good for 10 of 11 newborns. Despite the early onset of uterine rupture, there were no cases of extremely preterm delivery. One early preterm infant, seven moderate-to-late preterm infants and one term infant were delivered. CONCLUSIONS: The lack of extremely preterm deliveries and good neonatal outcomes encourage attempts to repair the uterus after second-trimester rupture. PMID- 27459148 TI - Reliability and validity of a smartphone pulse rate application for the assessment of resting and elevated pulse rate. AB - : Purpose/hypothesis: This study was designed to investigate the test-retest reliability, concurrent validity, and the standard error of measurement (SEm) of a pulse rate assessment application (Azumio(r)'s Instant Heart Rate) on both Android(r) and iOS(r) (iphone operating system) smartphones as compared to a FT7 Polar(r) Heart Rate monitor. Number of subjects: 111. MATERIALS/METHODS: Resting (sitting) pulse rate was assessed twice and then the participants were asked to complete a 1-min standing step test and then immediately re-assessed. The smartphone assessors were blinded to their measurements. RESULTS: Test-retest reliability (intraclass correlation coefficient [ICC 2,1] and 95% confidence interval) for the three tools at rest (time 1/time 2): iOS(r) (0.76 [0.67-0.83]); Polar(r) (0.84 [0.78-0.89]); and Android(r) (0.82 [0.75-0.88]). Concurrent validity at rest time 2 (ICC 2,1) with the Polar(r) device: IOS(r) (0.92 [0.88 0.94]) and Android(r) (0.95 [0.92-0.96]). Concurrent validity post-exercise (time 3) (ICC) with the Polar(r) device: iOS(r) (0.90 [0.86-0.93]) and Android(r) (0.94 [0.91-0.96]). The SEm values for the three devices at rest: iOS(r) (5.77 beats per minute [BPM]), Polar(r) (4.56 BPM) and Android(r) (4.96 BPM). CONCLUSIONS: The Android(r), iOS(r), and Polar(r) devices showed acceptable test-retest reliability at rest and post-exercise. Both the smartphone platforms demonstrated concurrent validity with the Polar(r) at rest and post-exercise. CLINICAL RELEVANCE: The Azumio(r) Instant Heart Rate application when used by either platform appears to be a reliable and valid tool to assess pulse rate in healthy individuals. PMID- 27459147 TI - Agroinfiltration contributes to VP1 recombinant protein degradation. AB - There is a growing interest in applying tobacco agroinfiltration for recombinant protein production in a plant based system. However, in such a system, the action of proteases might compromise recombinant protein production. Protease sensitivity of model recombinant foot-and-mouth disease (FMD) virus P1 polyprotein (P1) and VP1 (viral capsid protein 1) as well as E. coli glutathione reductase (GOR) were investigated. Recombinant VP1 was more severely degraded when treated with the serine protease trypsin than when treated with the cysteine protease papain. Cathepsin L- and B-like as well as legumain proteolytic activities were elevated in agroinfiltrated tobacco tissues and recombinant VP1 was degraded when incubated with such a protease-containing tobacco extract. In silico analysis revealed potential protease cleavage sites within the P1, VP1 and GOR sequences. The interaction modeling of the single VP1 protein with the proteases papain and trypsin showed greater proximity to proteolytic active sites compared to modeling with the entire P1-polyprotein fusion complex. Several plant transcripts with differential expression were detected 24 hr post agroinfiltration when the RNA-seq technology was applied to identify changed protease transcripts using the recently available tobacco draft genome. Three candidate genes were identified coding for proteases which included the Responsive-to-Desiccation-21 (RD21) gene and genes for coding vacuolar processing enzymes 1a (NbVPE1a) and 1b (NbVPE1b). The data demonstrates that the tested recombinant proteins are sensitive to protease action and agroinfiltration induces the expression of potential proteases that can compromise recombinant protein production. PMID- 27459149 TI - Stress Cardiac MRI in Women With Myocardial Infarction and Nonobstructive Coronary Artery Disease. AB - BACKGROUND: In a prospective study, cardiac MRI (CMR) and intravascular ultrasound were performed in women with myocardial infarction (MI) and nonobstructive coronary artery disease (MINOCA). Forty participants underwent adenosine-stress CMR (sCMR). HYPOTHESIS: Abnormal perfusion may co-localize with ischemic late gadolinium enhancement (LGE) and T2-weighted signal hyperintensity (T2+), suggesting microvascular dysfunction contributed to MI. METHODS: Qualitative perfusion analysis was performed by 2 independent readers. Abnormal myocardial perfusion reserve index (MPRI) was defined as global average <=1.84. RESULTS: Abnormal rest perfusion was present in 10 patients (25%) and stress perfusion abnormalities in 25 (63%). Abnormal stress perfusion was not associated with LGE but tended to occur with T2+. Among patients with abnormal perfusion and LGE, the LGE pattern was ischemic in half. The locations of abnormal perfusion and LGE matched in 75%, T2+ in 100%. Abnormal stress perfusion was not associated with plaque disruption and matched in location in 63%. MPRI was abnormal in 10 patients (25%) and was not associated with LGE, T2+ or plaque disruption. CONCLUSIONS: Abnormal perfusion on sCMR is common among women with MINOCA. Abnormal perfusion usually co-localized with LGE and/or T2+ when present. Variability in LGE pattern leads to uncertainty about whether the finding of abnormal perfusion was cause or consequence of the tissue state leading to LGE. Low MPRI, possibly indicating diffuse microvascular disease, was observed with and without LGE and T2+. Multiple mechanisms may lead to abnormal perfusion on sCMR. Microvascular dysfunction may contribute to the pathogenesis of and coexist with other causes of MINOCA. PMID- 27459150 TI - Identification of biotransformation products of citalopram formed in activated sludge. AB - Citalopram (CTR) is a worldwide highly consumed antidepressant which has demonstrated incomplete removal by conventional wastewater treatment. Despite its global ubiquitous presence in different environmental compartments, little is known about its behaviour and transformation processes during wastewater treatment. The present study aims to expand the knowledge on fate and transformation of CTR during the biological treatment process. For this purpose, batch reactors were set up to assess biotic, abiotic and sorption losses of this compound. One of the main objectives of the study was the identification of the formed transformation products (TPs) by applying suspect and non-target strategies based on liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). The complementary use of reversed phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC) for the identification of polar TPs, and the application of in-house developed quantitative structure-retention relationship (QSRR) prediction models, in addition to the comprehensive evaluation of the obtained MS/MS spectra, provided valuable information to support identification. In total, fourteen TPs were detected and thirteen of them were tentatively identified. Four compounds were confirmed (N-desmethylCTR, CTR amide, CTR carboxylic acid and 3-oxo-CTR) through the purchase of the corresponding reference standard. Probable structures based on diagnostic evidence were proposed for the additional nine TPs. Eleven TPs are reported for the first time. A transformation pathway for the biotransformation of CTR was proposed. The presence of the identified TPs was assessed in real wastewater samples through retrospective analysis, resulting in the detection of five compounds. Finally, the potential ecotoxicological risk posed by CTR and its TPs to different trophic levels of aquatic organisms was evaluated by means of risk quotients. PMID- 27459151 TI - Oxidative degradation of triclosan by potassium permanganate: Kinetics, degradation products, reaction mechanism, and toxicity evaluation. AB - In this study, we systematically investigated the potential applicability of potassium permanganate for removal of triclosan (TCS) in water treatment. A series of kinetic experiments were carried out to study the influence of various factors, including the pH, oxidant doses, temperature, and presence of typical anions (Cl(-), SO4(2-), NO3(-)), humic acid (HA), and fulvic acid (FA) on triclosan removal. The optimal reaction conditions were: pH = 8.0, [TCS]0:[KMnO4]0 = 1:2.5, and T = 25 degrees C, where 20 mg/L of TCS could be completely degraded in 120 s. However, the rate of TCS (20 MUg/L) oxidation by KMnO4 ([TCS]0:[KMnO4]0 = 1:2.5) was 1.64 * 10(-3) mg L(-1).h(-1), lower than that at an initial concentration of 20 mg/L (2.24 * 10(3) mg L(-1).h(-1)). A total of eleven products were detected by liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-Q-TOF-MS) analysis, including phenol and its derivatives, benzoquinone, an organic acid, and aldehyde. Two main reaction pathways involving CO bond cleavage (-C(8)O(7)-) and benzene ring opening (in the less chlorinated benzene ring) were proposed, and were further confirmed based on frontier electron density calculations and point charges. Furthermore, the changes in the toxicity of the reaction solution during TCS oxidation by KMnO4 were evaluated by using both the luminescent bacteria Photobacterium phosphoreum and the water flea Daphnia magna. The toxicity of 20 mg/L triclosan to D. magna and P. phosphoreum after 60 min was reduced by 95.2% and 43.0%, respectively. Phenol and 1,4 benzoquinone, the two representative degradation products formed during permanganate oxidation, would yield low concentrations of DBPs (STHMFP, 20.99 278.97 MUg/mg; SHAAFP, 7.86 * 10(-4)-45.77 MUg/mg) after chlorination and chloramination. Overall, KMnO4 can be used as an effective oxidizing agent for TCS removal in water and wastewater treatment. PMID- 27459153 TI - Old and new acetylcholinesterase inhibitors for Alzheimer's disease. AB - INTRODUCTION: To date, pharmacological treatment of Alzheimer's disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease. AREAS COVERED: On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far. EXPERT OPINION: Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer's disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people. PMID- 27459152 TI - Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. AB - OBJECTIVE: Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy. DESIGN: Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components. RESULTS: Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals. CONCLUSIONS: These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease. PMID- 27459155 TI - Selective conversion of organic pollutant p-chlorophenol to formic acid using zeolite Fenton catalyst. AB - Effective remediation technologies which can converse the harmful organic pollutants to high-value chemicals are crucial both for wastewater treatment and energy regeneration. This study provides an evidence that extracting useful chemicals from wastewater is feasible through selective conversion of p chlorophenol to high value formic acid as an example. The reported system works with a readily available Fe-containing ZSM-5 catalyst, water as the solvent and hydrogen peroxide as the oxidant. The yield of formic acid reached up to 50.7% when the Si/Al ratio of ZSM-5 was 80 and the Fe-content was 1.4%. By X-ray adsorption fine structure (XAFS), NH3 temperature-programmed desorption (NH3-TPD) technique, the pyridine adsorption Fourier-transition infrared (Py-IR) spectroscopy and adsorption measurements, it was concluded that the controllable degradation of p-CP could be approached through selective adsorption, the moderate Bronsted acid sites for H2O2 activation and the properly selective conversion control due to extra-framework coordination unsaturated sites (CUS) of Fe. This approach might provide a new avenue for the field of organic pollutant remediation. PMID- 27459154 TI - Spatio-temporal Analysis of the Genetic Diversity of Arctic Rabies Viruses and Their Reservoir Hosts in Greenland. AB - There has been limited knowledge on spatio-temporal epidemiology of zoonotic arctic fox rabies among countries bordering the Arctic, in particular Greenland. Previous molecular epidemiological studies have suggested the occurrence of one particular arctic rabies virus (RABV) lineage (arctic-3), but have been limited by a low number of available samples preventing in-depth high resolution phylogenetic analysis of RABVs at that time. However, an improved knowledge of the evolution, at a molecular level, of the circulating RABVs and a better understanding of the historical perspective of the disease in Greenland is necessary for better direct control measures on the island. These issues have been addressed by investigating the spatio-temporal genetic diversity of arctic RABVs and their reservoir host, the arctic fox, in Greenland using both full and partial genome sequences. Using a unique set of 79 arctic RABV full genome sequences from Greenland, Canada, USA (Alaska) and Russia obtained between 1977 and 2014, a description of the historic context in relation to the genetic diversity of currently circulating RABV in Greenland and neighboring Canadian Northern territories has been provided. The phylogenetic analysis confirmed delineation into four major arctic RABV lineages (arctic 1-4) with viruses from Greenland exclusively grouping into the circumpolar arctic-3 lineage. High resolution analysis enabled distinction of seven geographically distinct subclades (3.I - 3.VII) with two subclades containing viruses from both Greenland and Canada. By combining analysis of full length RABV genome sequences and host derived sequences encoding mitochondrial proteins obtained simultaneously from brain tissues of 49 arctic foxes, the interaction of viruses and their hosts was explored in detail. Such an approach can serve as a blueprint for analysis of infectious disease dynamics and virus-host interdependencies. The results showed a fine-scale spatial population structure in Greenland arctic foxes based on mitochondrial sequences, but provided no evidence for independent isolated evolutionary development of RABV in different arctic fox lineages. These data are invaluable to support future initiatives for arctic fox rabies control and elimination in Greenland. PMID- 27459156 TI - Hypoxia drives apoptosis independently of p53 and metallothionein transcript levels in hemocytes of the whiteleg shrimp Litopenaeus vannamei. AB - The cellular mechanisms used by the shrimp Litopenaeus vannamei to respond to hypoxia have been studied from the energetic metabolism and antioxidant angles. We herein investigated the participation of p53 and metallothionein (MT) in the apoptotic process in response to hypoxia in shrimp hemocytes. The Lvp53 or LvMT genes were efficiently silenced by injection of double stranded RNA for p53 or MT. The effects of silencing on apoptosis were measured as caspase-3 activity and flow cytometry in hemocytes after 24 and 48 h of hypoxia (1.5 mg DO L(-1)). Hemocytes from unsilenced animals had significantly higher apoptosis levels upon both times of hypoxia. The apoptotic levels were diminished but not suppressed in dsp53-silenced but not dsMT-silenced hemocytes after 24 h of hypoxia, indicating a contribution of Lvp53 to apoptosis. Apoptosis in normoxia was significantly higher in dsp53-and dsMT-silenced animals compared to the unsilenced controls, pointing to a possible cytoprotective role of LvMT and Lvp53 during the basal apoptotic program in normoxia. Overall, these results indicate that hypoxia augments apoptosis in shrimp hemocytes and high mRNA levels of Lvp53 and LvMT are not necessary for this response. PMID- 27459157 TI - An improved method to determine PM-bound nitro-PAHs in ambient air. AB - Nowadays, no a standard method for the determination of particulate bound nitro PAHs (NPAHs) has been developed. Existing methods include complex sampling and extraction procedures. Moreover, their sensitivity does not allow to analyze daily PM10 samples, affecting the temporal resolution of NPAH concentrations. In this study an analytical method for the quantification of NPAHs on half 47 mm filter samples of daily PM10 was developed and validated. NPAHs were recovered by microwave-assisted extraction, and analyzed by using a gas chromatography-triple quadrupole mass spectrometry in MRM mode. The analytical performance for 14 NPAHs (2-nitrofluorene, 9-nitroanthracene, 9-nitrophenantrene, 3-nitrophenantrene, 2 nitroanthracene, 3-nitrofluoranthene, 1-nitropyrene, 2,7-dinitrofluorene, 7 nitrobenzo[a]anthracene, 6-nitrochrysene, 1,3-dinitropyrene, 1,8-dinitropyrene, 1,6-dinitropyrene, 6-nitrobenza[a]pyrene) was investigated. Recovery extraction percentage exceeded 95% for all target compounds in the range between 0.25 and 10 ng/mL. The repeatability, expressed as Relative Standard Deviation percentage (RSD%) of five determinations, was less than 10% for target compounds except for 2,7-dinitrofluorene, 1,3- and 1,8-dinitropyrene (RSD% < 15%). The limit of detection (LOD) ranged from 12 to 84 pg/mL for most of NPAHs, except for dinitro pyrenes and nitro-benzo(a)anthracene for which the LOD reached 1.8 ng/mL. The method developed was applied to real samples in order to evaluate the levels of NPAHs in the urban and industrial area of Taranto (South of Italy). The analysis of PM10 samples collected at four industrial and one urban sites, highlighted that in proximity of critical emission source as the biggest European steel plant and under certain weather conditions, combustion processes were the main source of NPAHs in atmosphere. PMID- 27459158 TI - Effects of subinhibitory ciprofloxacin concentrations on the abundance of qnrS and composition of bacterial communities from water supply reservoirs. AB - We used a short-term microcosm approach to investigate the influence of two different subinhibitory concentrations of ciprofloxacin (0.01 and 0.1 MUg/ml) on both the abundance of a plasmid-mediated quinolone resistance determinant (qnrS) and the structure and composition of bacterial communities from impaired and pristine water supply reservoirs. The results showed that the abundance of the qnrS gene increases in water samples exposed to both subinhibitory concentrations of ciprofloxacin, especially in water samples from La Llosa del Cavall, which represents the pristine system. Subinhibitory ciprofloxacin concentrations also induced changes in bacterial community composition as indicated by the relative abundances of each operational taxonomic unit (OTU) across treatments. Therefore, our findings may be of significant importance because subinhibitory ciprofloxacin concentrations may promote antibiotic resistance and affect bacterial community composition in environmental settings. PMID- 27459159 TI - Evaluation of the binding of perfluorinated compound to pepsin: Spectroscopic analysis and molecular docking. AB - In this paper, we investigated the binding mode of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) to pepsin using spectroscopies and molecular docking methods. Fluorescence quenching study indicated that their different ability to bind with pepsin. Meanwhile, time-resolved fluorescence measurements established that PFOA and PFNA quenched the fluorescence intensity of pepsin through the mechanism of static quenching. The thermodynamic parameters showed that hydrophobic forces were the main interactions. Furthermore, UV-vis, FTIR, three-dimensional fluorescence and molecular docking result indicated that PFCs impact the conformation of pepsin and PFOA was more toxic than PFNA. The conformational transformation of PFOA/PFNA-pepsin was confirmed through the quantitative analysis of the CD spectra. The present studies offer the theory evidence to analyze environmental safety and biosecurity of PFCs on proteases. PMID- 27459160 TI - Removal of trace nonylphenol from water in the coexistence of suspended inorganic particles and NOMs by using a cellulose-based flocculant. AB - A flocculation method was used for the removal of trace nonylphenol (NP) from synthetic surface water containing natural organic matters (humic acid, HA) and suspended inorganic particles (kaolin). A polymeric flocculant (CMCND), with enhanced cationic property and unique switchable hydrophobic/hydrophilic characteristic, was specially designed for this application. CMCND showed a high efficiency for trace NP removal, turbidity and UV254 abatements: under optimized conditions (pH: 4; T: 35 degrees C; dosage: 40 mg/L), the removal of NP reached up to 79%. By using dosage-pH flocculation diagrams and correlation analyses as tools, kaolin and HA were found to exert synergistic effects on NP removal, with the aid of CMCND; the synergistic effect of HA is higher due to pi-pi stacking. Zeta potential-dosage profiles clearly demonstrated charge neutralization predominated at pH 4, due to the strong cationic groups in the flocculant. Floc size monitoring displayed that the delayed phase transformation process (from hydrophilicity to hydrophobicity) of CMCND at 35 degrees C enhanced NP removal. In addition, spectral analyses clarified the interactions among CMCND, NP, kaolin and HA: charge attraction and hydrophobic interaction between CMCND and NP played the key roles. The findings are of significance for removing endocrine-disrupting chemicals in environmental remediation. PMID- 27459161 TI - Effects of environmental conditions on aerobic degradation of a commercial naphthenic acid. AB - Naphthenic acids (NAs) are problematic constituents in energy-derived waters, and aerobic degradation may provide a strategy for mitigating risks to aquatic organisms. The overall objective of this study was to determine the influence of concentrations of N (as ammonia) and P (as phosphate), and DO, as well as pH and temperatures on degradation of a commercial NA in bench-scale reactors. Commercial NAs provided replicable compounds necessary to compare influences of environmental conditions on degradation. NAs were quantified using high performance liquid chromatography. Microbial diversity and relative abundance were measured in treatments as explanatory parameters for potential effects of environmental conditions on microbial populations to support analytically measured NA degradation. Environmental conditions that positively influenced degradation rates of Fluka NAs included nutrients (C:N 10:1-500:1, C:P 100:1 5000:1), DO (4.76-8.43 mg L(-1)), pH (6-8), and temperature (5-25 degrees C). Approximately 50% removal of 61 +/- 8 mg L(-1) was achieved in less than 2 d after NA introduction, achieving the method detection limit (5 mg L(-1)) by day 6 of the experiment in treatments with a C:N:P ratio of 100:10:1, DO > 8 mg L(-1), pH ~8-9, and temperatures >23 degrees C. Microbial diversity was lowest in lower temperature treatments (6-16 degrees C), which may have resulted in observed slower NA degradation. Based on results from this study, when macro- and micronutrients were available, DO, pH, and temperature (within environmentally relevant ranges) influenced rates of aerobic degradation of Fluka NAs. This study could serve as a model for systematically evaluating environmental factors that influence NA degradation in field scenarios. PMID- 27459162 TI - "Inside These Fences Is Our Own Little World": Prison-Based HIV Testing and HIV Related Stigma Among Incarcerated Men and Women. AB - Correctional facilities offer opportunities to provide comprehensive HIV services including education, testing, treatment, and coordination of post- release care. However, these services may be undermined by unaddressed HIV stigma. As part of a prison-based HIV testing study, we interviewed 76 incarcerated men and women from the North Carolina State prison system. The sample was 72% men, median age 31.5 years (range: 19 to 60). Thematic analysis revealed high levels of HIV-related fear and stigma, homophobia, incomplete HIV transmission knowledge, beliefs that HIV is highly contagious within prisons ("HIV miasma"), and the View of HIV testing as protective. Interviewees described social distancing behaviors and coping mechanisms they perceived to be protective, including knowing their HIV status and avoiding contact with others and shared objects. Interviewees endorsed universal testing, public HIV status disclosure, and segregation of HIV-positive inmates. Intensified education and counseling efforts are needed to ameliorate entrenched HIV-transmission fears and stigmatizing beliefs. PMID- 27459163 TI - A Randomized Study of Incentivizing HIV Testing for Parolees in Community Aftercare. AB - HIV risk-behaviors are high in criminal justice populations and more efforts are necessary to address them among criminal justice-involved substance abusers. This study examines the role of incentives in promoting HIV testing among parolees. Participants were randomly assigned to either an incentive (n = 104) or education group (control; n = 98), where the incentive group received a voucher for testing for HIV. Bivariate comparisons showed that a larger proportion of those in the incentive group received HIV testing (59% versus 47%), but this was not statistically significant (p = .09). However, in a multivariate logistic regression model controlling for covariates likely to influence HIV-testing behavior, those in the incentive group had increased odds of HIV testing in comparison to those in the education group (OR = 1.99, p < .05, CI [1.05, 3.78]). As a first of its kind, this study provides a foundation for further research on the utility of incentives in promoting HIV testing and other healthy behaviors in criminal justice populations. PMID- 27459164 TI - Willingness to Self-Pay for Pre-exposure Prophylaxis in Men Who Have Sex With Men: A National Online Survey in Taiwan. AB - High cost of pre-exposure prophylaxis (PrEP) is a major concern for acceptability. This study determined the willingness of men who have sex with men to self-pay for PrEP and factors associated with the likelihood of condom use if taking PrEP. The Taiwan 2014 MSM Online Sex Survey was conducted and data such as demographics, attitudes toward PrEP, and sexual behaviors in the previous 3 months were collected. Of the 1,151 MSM who participated, 56% were willing to take PrEP, but only 23% were willing to self-pay $340 for PrEP. Willingness to self-pay for PrEP was significantly associated with the previous receipt of nonoccupational post-exposure prophylaxis (adjusted odds ratio [AOR], 3.02, 95%CI [1.49, 6.12]), and positive attitudes toward PrEP (AOR, 3.02, 95%CI [2.19, 4.17]). Of MSM who are willing to use PrEP, 73.6% would maintain condom use if taking PrEP. If PrEP is made available in Taiwan, more efforts should be focused on increasing awareness of MSM who are practicing risky behaviors. PMID- 27459165 TI - I Want Your Sext: Sexting and Sexual Risk in Emerging Adult Minority Men. AB - Sexting, sending, or receiving sexually suggestive or explicit messages/photos/videos, have not been studied extensively. The aims of this study is to understand factors associated with sexting among minority (e.g., African- American, Hispanic) emerging adult males and the association between sexting and sexual risk. We recruited 119 emerging adult heterosexual males and assessed sexting and sexual risk behaviors. Fifty-four percent of participants sent a sext, and 70% received a sext. Participants were more likely to sext with casual partners than with steady partners. Multiple regression analyses showed that participants who sent sexts to steady partners had significantly more unprotected vaginal intercourse and oral sex. Participants who sent sexts to casual partners had significantly more partners, and participants who received sexts from casual partners had significantly more unprotected oral sex and sex while on substances. We found that sexting is a frequent and reciprocal behavior among emerging adults, and there were different patterns of significance for sexts with casual and steady partners. PMID- 27459166 TI - Friends, Sisters, and Wives: Social Support and Social Risks in Peer Relationships Among Men Who Have Sex With Men (MSM) in India. AB - Globally, men who have sex with men (MSM) are at high risk for HIV. Many HIV prevention efforts rely on community outreach and mobilization to engage MSM. This study examines peer relationships and their potential role in HIV prevention through 31 focus group discussions (FGDS) and 121 in-depth interviews (IDIs) with 363 MSM across 15 sites in India. Results indicate that MSM receive social support in friendships, sex-worker collaborations, constructed kin relationships, and romantic partnerships. Access to these relationships, however, is uneven across MSM, and can carry risks of disclosure of same-sex behavior and exclusion based on HIV- positive status. Positive peer relationships can serve as the basis of community empowerment, education, and couple-based interventions for MSM, and peer counselors can also provide a buffer against the social risks of peer relationships and facilitate linkage to care and continued engagement in treatment. These insights can improve HIV interventions for MSM in India and elsewhere. PMID- 27459167 TI - Evaluating the Relationship-Oriented Information, Motivation, and Behavioral Skills Model of HIV Preventive Behaviors in Young Men Who Have Sex With Men. AB - Most HIV infections among young men who have sex with men (YMSM) occur within primary partnerships. Research on YMSM's knowledge, motivation, and behavioral skills regarding relationship-related HIV prevention, and how these correspond to HIV risk and partnership characteristics, is limited. We examined links among the Relationship-Oriented Information- Motivation-Behavioral Skills (RELO-IMB) model, relationship characteristics, and HIV risk in 96 YMSM. Condomless sex with a primary partner was associated with low relationship-related HIV preventive information, motivation, and behavioral skills. Lack of HIV testing and alcohol use before sex were associated with low behavioral skills. In multivariate analyses, behavioral skills were the only consistent predictor of these outcomes. Regarding relationship characteristics, feeling trapped in the relationship or being physically abused by a partner was associated with low motivation and behavioral skills. The RELO-IMB model can be used to understand HIV risk in relationships and points to targets for relationship-specific HIV prevention education for YMSM. PMID- 27459168 TI - Factors Associated With Condom Use for HIV Prevention Among Nepalese Labor Migrant Couples. AB - Information about factors associated with condom use among Nepalese labor migrant couples that are considered being at high risk of HIV infection is not clearly understood. Therefore, we carried out a cross-sectional study to identify the factors associated with condom use among Nepalese labor migrant couples. A total of 266 wives of Nepalese labor migrants were invited for an interview. Hierarchical logistic regression analysis was performed to analyze data. We found that almost 39% of the women reported having used a condom while having sex with their husbands. Age was the only husband-related factor independently associated with condom use. School education, knowledge about HIV/AIDS, discussion of HIV with peers and sexual negotiation with the husband were the wife-related factors independently associated with condom use. Our findings highlight a clear need to develop effective HIV prevention interventions targeting illiterate labor migrant couples, with a particular emphasis on increasing women's ability to negotiate condom use. PMID- 27459169 TI - Reply to Wolkewitz: When to Use Cumulative Risk-Based Versus Rate-Based Approaches in the Analysis of Hospital-Acquired Infection Risk Factors? That Depends on the Question. PMID- 27459171 TI - Serum PAI-1 and PAI-1 4G/5G Polymorphism in Hepatitis C Virus-Induced Cirrhosis and Hepatitis C Virus-Induced Hepatocellular Carcinoma Patients. AB - Association between variable agent-induced hepatocellular carcinoma (HCC) and both PAI-1 4G/5G polymorphism and plasminogen activator inhibitor (PAI-1) levels compared to healthy controls have been reported in earlier studies. We aimed to assess serum PAI-1 and PAI-1 4G/5G polymorphism in hepatitis C virus (HCV) induced HCC, HCV-induced liver cirrhosis, and viral infection-free apparently healthy control subjects. Forty nine HCC, 52 cirrhosis, and 105 controls were genotyped for PAI-1 4G/5G using an allele-specific polymerase chain reaction analysis. In addition, for 31 HCC, 24 cirrhosis, and 28 controls, serum PAI-1 level was measured by enzyme-linked immunosorbent assay (ELISA). There was no significant difference in PAI-1 4G/5G genotype distribution between cirrhosis and controls (p = 0.33, p = 0.15, and p = 0.38 for the codominant, dominant, and recessive models, respectively) or between HCC and cirrhosis (p = 0.5, p = 0.24, and p = 0.69 for the codominant, dominant, and recessive models, respectively). Serum PAI-1 was significantly higher in cirrhosis than controls and significantly lower in HCC than cirrhosis (p < 0.001 for both). Serum PAI-1 did not differ significantly among the three PAI-1 4G/5G genotypes in controls, cirrhosis, and HCC (p = 0.29, p = 0.28, and p = 0.73 respectively). We documented higher serum PAI-1 in HCV-induced HCC than viral infection-free controls, but interestingly, lower than HCV-induced liver cirrhosis patients. This was not genotype related. Further studies will be needed to clearly elucidate the underlying mechanism. PMID- 27459172 TI - Bio-inspired immobilization of metal oxides on monolithic microreactor for continuous Knoevenagel reaction. AB - A facile method is reported to construct monolithic microreactor with high catalytic performance for Knoevenagel reaction. The microreactor is based on hierarchically porous silica (HPS) which has interconnected macro- and mesopores. Then the HPS is surface modified by pyrogallol (PG) polymer. Al(NO3)3 and Mg(NO3)2 are loaded on the surface of HPS through coordination with -OH groups of PG. After thermal treatment, Al(NO3)3 and Mg(NO3)2 are converted Al2O3 and MgO. The as-synthesized catalytic microreactor shows a high and stable performance in Knoevenagel reaction. The microreactor possess large surface area and interconnected pore structures which are beneficial for reactions. Moreover, this economic, facile and eco-friendly surface modification method can be used in loading more metal oxides for more reactions. PMID- 27459170 TI - Intrahepatic regulation of antiviral T cell responses at initial stages of viral infection. AB - It is generally accepted that the appropriate boost of early immune response will control viral replications and limit the immune-mediated pathology in viral hepatitis. However, poor immunity results in viral persistence, chronic inflammation and finally liver cirrhosis and carcinoma. As a peripheral non lymphoid organ of immune surveillance, the liver continually encounters hundreds of molecules from the blood, including nutrients, toxins and pathogens. In this way, the liver maintains immune tolerance under healthy conditions, but responds quickly to the hepatotropic pathogens during the early stages of an infection. Although our knowledge of liver cell compositions and functions has been improved significantly in recent years, the intrahepatic immune regulation of antiviral T cells at the initial stage is complex and not well elucidated. Here, we summarize the role of liver cell subpopulations in regulating antiviral T cell response at the initial stages of viral infection. A better understanding of early hepatic immune regulation will pave the way for the development of novel therapies and vaccine design for human viral hepatitis. PMID- 27459173 TI - Augmented delivery of gemcitabine in lung cancer cells exploring mannose anchored solid lipid nanoparticles. AB - Gemcitabine (GmcH) is an effective anti-cancer agent used in the chemotherapy of lung cancer. However, the clinical applications of GmcH has been impeded primarily due to its low blood residence time, unfavorable pharmacokinetic and pharmacodynamic (PK/PD) profile, and poor penetration in the complex environment of lung cancer cells. Thus, the present study aims to formulate GmcH loaded mannosylated solid lipid nanoparticles (GmcH-SLNs) for improving its drug uptake into the lung cancer cells. GmcH-SLNs were prepared by emulsification and solvent evaporation process, and surface modification was done with mannose using ring opening technique. The cellular toxicity and cell uptake studies were performed in A549 lung adenocarcinoma cell line. The developed nanoformulation appears to be proficient in targeted delivery of GmcH with improved therapeutic effectiveness and enhanced safety. PMID- 27459174 TI - Shape Analysis of DNA-Au Hybrid Particles by Analytical Ultracentrifugation. AB - Current developments in nanotechnology have increased the demand for nanocrystal assemblies with well-defined shapes and tunable sizes. DNA is a particularly well suited building block in nanoscale assemblies because of its scalable sizes, conformational variability, and convenient self-assembly capabilities via base pairing. In hybrid materials, gold nanoparticles (AuNPs) can be assembled into nanoparticle structures with programmable interparticle distances by applying appropriate DNA sequences. However, the development of stoichiometrically defined DNA/NP structures is still challenging since product mixtures are frequently obtained and their purification and characterization is the rate-limiting step in the development of DNA-NP hybrid assemblies. Improvements in nanostructure fractionation and characterization techniques offer great potential for nanotechnology applications in general. This study reports the application of analytical ultracentrifugation (AUC) for the characterization of anisotropic DNA linked metal-crystal assemblies. On the basis of transmission electron microscopy data and the DNA primary sequence, hydrodynamic bead models are set up for the interpretation of the measured frictional ratios and sedimentation coefficients. We demonstrate that the presence of single DNA strands on particle surfaces as well as the shape factors of multiparticle structures in mixtures can be quantitatively described by AUC. This study will significantly broaden the possibilities to analyze mixtures of shape-anisotropic nanoparticle assemblies. By establishing insights into the analysis of nanostructure mixtures based on fundamental principles of sedimentation, a wide range of potential applications in basic research and industry become accessible. PMID- 27459187 TI - Effect of Surface and Salt Properties on the Ion Distribution around Spherical Nanoparticles: Monte Carlo Simulations. AB - Nanoparticle surface charge properties represent key parameters to predict their fate, reactivity, and complexation in natural, biological, and industrial dispersions. In this context, we present here an original approach to better understand the surface charge electrostatic properties of spherical nanoparticles (NPs). The ion distribution around one nanoparticle is investigated using Monte Carlo simulations and by adjusting a wide range of parameters including NP properties (surface charge density and site distribution), salt concentration (ionic strength and cation concentration), and salt valency (mono-, di-, and trivalent salt). A canonical Metropolis Monte Carlo method is used to reach equilibrium states and a primitive Coulomb model is applied to describe the electrostatic interactions between explicit discrete sites, counterions, and salt particles. Our results show that the presence of explicit surface charges on the NP and in solution has a strong influence on the local ion distribution and on the effective surface charge of the nanoparticles. The increase of surface charge density reduces the NP effective charge by the formation of a condensation layer around the nanoparticle. However, a limit of condensation is achieved due to steric effects and electrostatic repulsions. The presence of di- and trivalent cations is also found to strongly modify the effective charge and improve condensation state as long as electrostatic repulsion between the cations close to the surface are not so strong. At high trivalent cation concentration, the NP effective charge is greatly reduced and the local environment around the nanoparticle becomes more structured with the formation of a multi layer structure composed by anions and cations. PMID- 27459188 TI - Influence of Protonation State on the Excited State Dynamics of a Photobiologically Active Ru(II) Dyad. AB - The influence of ligand protonation on the photophysics of a ruthenium (Ru) dyad bearing the 2-(1-pyrenyl)-1H-imidazo[4,5-f][1,10]-phenanthroline (ippy) ligand was investigated by time-resolved transient absorption spectroscopy. It was found that changes in the protonation state of the imidazole group led to changes in the electronic configuration of the lowest lying excited state. Formation of the fully deprotonated imidazole anion resulted in excited state signatures that were consistent with a low-lying intraligand (IL) triplet state. This assignment was supported by time-dependent density functional theory (TDDFT) calculations. IL triplet states have been suggested to be potent mediators of photodynamic effects. Thus, these results are of interest in the design of Ru metal complexes as photosensitizers (PSs) for photodynamic therapy (PDT). PMID- 27459189 TI - Finite-Element Analysis of Bone Stresses on Primary Impact in a Large-Animal Model: The Distal End of the Equine Third Metacarpal. AB - OBJECTIVE: To assess whether the transient stresses of foot impact with the ground are similar to those found during midstance loading and if the location of high stress correlate with the sites most commonly associated with mechanically induced osteoarthritis (OA). We compared impact stresses in subchondral bone between two subject-specific, three-dimensional, finite-element models of the equine metacarpophalangeal (MCP) joint-one with advanced OA and one healthy, and with similar published data on the stresses that occur at midstance. METHODS: Two right MCP joints (third metacarpal and proximal phalanx) were scanned using micro computed tomography (MUCT). Images were segmented, and meshed using modified 10 node quadratic tetrahedral elements. Bone material properties were assigned based on the bone density. An impact velocity of 3.55 m/s was applied to each model and contact pressures and stress distribution were calculated for each. In a separate iteration, the third metacarpal was loaded statically. A sampling grid of 160 equidistant points was superimposed over selected slices, and average peak stresses were calculated for 6 anatomical regions. Within-region maximal peak and average von Mises stresses were compared between healthy and OA bones in both midstance and impact loading. RESULTS: Average impact stresses across all regions, in both locations (palmar and dorsal) were greater in the OA model. Highest impact stresses were located in the dorsal medial condyle in the healthy (12.8 MPa) and OA (14.1MPa) models, and were lowest in the palmar medial and lateral parasagittal grooves in the healthy (5.94 MPa) and OA (7.07 MPa) models. The healthy static model had higher peak (up to 49.7% greater) and average (up to 38.6% greater) stresses in both locations and across all regions compared to the OA static model. CONCLUSIONS: Under simulated footfall a trot, loading on the dorsal aspect of the third metacarpal at impact created stresses similar to those found during midstance. The high accelerations that occur under impact loading are likely responsible for creating the high stresses, as opposed to midstance loading where the high stresses are the result of high mass loading. Although the stress magnitudes were found to be similar among the two loading conditions, the location of the high stress loading occurred in sites that are not typically associated with osteoarthritic changes. PMID- 27459190 TI - Reply to letter regarding in-office cup biopsies for pharyngolaryngeal tumors. PMID- 27459191 TI - Bark and Ambrosia Beetles Show Different Invasion Patterns in the USA. AB - Non-native bark and ambrosia beetles represent a threat to forests worldwide. Their invasion patterns are, however, still unclear. Here we investigated first, if the spread of non-native bark and ambrosia beetles is a gradual or a discontinuous process; second, which are the main correlates of their community structure; third, whether those correlates correspond to those of native species. We used data on species distribution of non-native and native scolytines in the continental 48 USA states. These data were analyzed through a beta-diversity index, partitioned into species richness differences and species replacement, using Mantel correlograms and non-metric multidimensional scaling (NMDS) ordination for identifying spatial patterns, and regression on distance matrices to test the association of climate (temperature, rainfall), forest (cover area, composition), geographical (distance), and human-related (import) variables with beta-diversity components. For both non-native bark and ambrosia beetles, beta diversity was mainly composed of species richness difference than species replacement. For non-native bark beetles, a discontinuous invasion process composed of long distance jumps or multiple introduction events was apparent. Species richness differences were primarily correlated with differences in import values while temperature was the main correlate of species replacement. For non native ambrosia beetles, a more continuous invasion process was apparent, with the pool of non-native species arriving in the coastal areas that tended to be filtered as they spread to interior portions of the continental USA. Species richness differences were mainly correlated with differences in rainfall among states, while rainfall and temperature were the main correlates of species replacement. Our study suggests that the different ecology of bark and ambrosia beetles influences their invasion process in new environments. The lower dependency that bark beetles have on climate allowed them to potentially colonize more areas within the USA, while non-native ambrosia beetles, being dependent on rainfall, are typically filtered by the environment. PMID- 27459192 TI - Lack of Association between Missense Variants in GRHL3 (rs2486668 and rs545809) and Susceptibility to Non-Syndromic Orofacial Clefts in a Han Chinese Population. AB - BACKGROUND: Grainyhead-like-3 (GRHL3) was recently identified as the second gene that, when mutated, can leads to Van der Woude syndrome, which is characterized by orofacial clefts (OFC) and lower lip pits. In addition, a missense variant (rs41268753) in GRHL3 confers risk for non-syndromic cleft palate cases of European ancestry. Together with interferon regulatory factor 6 (IRF6), GRHL3 may be associated with the risk of NSOFC which awaits for being verified across different ethnic populations. OBJECTIVE: The aim of this study was to investigate the possible relationship between common functional variants in GRHL3 and susceptibility to NSOFC, especially cleft palate cases, in a Han Chinese population, one of the ethnic groups with the highest birth prevalence of orofacial clefting. METHODS: Because the allele frequency for rs41268753 minor alleles was zero in our Chinese population, we selected functional single nucleotide polymorphisms (SNPs) spanning GRHL3 with minor allele frequencies (MAFs) > 5% in the Han Chinese population. Two SNPs which meet the above criteria were then genotyped in a case-control cohort comprising 1145 individuals using the TaqMan 5'-exonuclease allelic discrimination assay. RESULTS: SNPs rs2486668 and rs545809 were used in this study. Overall genotype and allele distributions of both SNPs in general and stratified genotyping analyses revealed no statistically significant differences between cases and controls. Further logistic regression analyses using different genetic models failed to reveal any evidence that these markers influence risk to NSOFC. CONCLUSIONS: The variant rs41268753 in GRHL3 increases the risk for cleft palate in European population, but our findings failed to detect the link between two GRHL3 SNPs (rs2486668 and rs545809) and risk to NSOFC in the Han Chinese cohort. Although the present study did not provide any evidence that common functional variants in GRHL3 may contribute to NSOFC etiology in this Chinese population, further studies with a larger sample size, additional SNPs, and a more diverse ethnic cohort are still warranted. PMID- 27459193 TI - Rapid Discrimination of Malignant Breast Lesions from Normal Tissues Utilizing Raman Spectroscopy System: A Systematic Review and Meta-Analysis of In Vitro Studies. AB - PURPOSE: The aim of this study is to evaluate the diagnostic accuracy of Raman spectroscopy system in the detection of malignant breast lesions through a systemic review and meta-analysis of published studies. METHODS: We conducted a comprehensive literature search of PubMed and Embase from 2000 to June 2015. Published studies that evaluated the diagnostic performance of Raman spectroscopy in distinguishing malignant breast lesions from benign lesions and normal tissues were included in our study. The pooled sensitivity, specificity, diagnostic odds ratio, and the area under the curve of summary receiver-operating characteristic curves was derived. A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies guidelines was used to assess the quality of included studies. RESULTS: The initial search produced a total of 157 articles after removing duplicates. Nine studies (8 in vitro and 1 in vivo) were eligible in this meta analysis. We analyzed the eight in vitro studies with 1756 lesions, the pooled sensitivity and specificity of Raman spectroscopy system for the diagnosis of malignant breast lesions were 0.92 (95% CI 0.86-0.96) and 0.97 (97% CI 0.93 0.98), respectively. Diagnostic odds ratio was 266.70 (95% CI 89.38-795.79), and the area under the curve of summary receiver-operating characteristic curves was 0.98 (95% CI 0.97-0.99). Significant heterogeneity was found between studies. There was no evidence of considerable publication bias. CONCLUSIONS: Raman spectroscopy system is an optical diagnostic technology with great value for detecting malignant breast lesions. At the same time, it has advantages of being non-invasive, real-time, and easy to use. Thus it deserves to be further explored for intra-operatory breast tumor margin detection. PMID- 27459194 TI - Complete analytic anharmonic hyper-Raman scattering spectra. AB - We present the first computational treatment of the complete second-order vibrational perturbation theory applied to hyper-Raman scattering spectroscopy. The required molecular properties are calculated in a fully analytic manner using a recently developed program [Ringholm, Jonsson and Ruud, J. Comp. Chem., 2014, 35, 622] that utilizes recursive routines. For some of the properties, these calculations are the first analytic calculations of their kind at their respective levels of theory. We apply this approach to the calculation of the hyper-Raman spectra of methane, ethane and ethylene and compare these to available experimental data. We show that the anharmonic corrections have a larger effect on the vibrational frequencies than on the spectral intensities, but that the inclusion of combination and overtone bands in the anharmonic treatment can improve the agreement with the experimental data, although the quality of available experimental data limits a detailed comparison. PMID- 27459195 TI - Cardiomyocyte Circadian Oscillations Are Cell-Autonomous, Amplified by beta Adrenergic Signaling, and Synchronized in Cardiac Ventricle Tissue. AB - Circadian clocks impact vital cardiac parameters such as blood pressure and heart rate, and adverse cardiac events such as myocardial infarction and sudden cardiac death. In mammals, the central circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, synchronizes cellular circadian clocks in the heart and many other tissues throughout the body. Cardiac ventricle explants maintain autonomous contractions and robust circadian oscillations of clock gene expression in culture. In the present study, we examined the relationship between intrinsic myocardial function and circadian rhythms in cultures from mouse heart. We cultured ventricular explants or dispersed cardiomyocytes from neonatal mice expressing a PER2::LUC bioluminescent reporter of circadian clock gene expression. We found that isoproterenol, a beta adrenoceptor agonist known to increase heart rate and contractility, also amplifies PER2 circadian rhythms in ventricular explants. We found robust, cell autonomous PER2 circadian rhythms in dispersed cardiomyocytes. Single-cell rhythms were initially synchronized in ventricular explants but desynchronized in dispersed cells. In addition, we developed a method for long-term, simultaneous monitoring of clock gene expression, contraction rate, and basal intracellular Ca2+ level in cardiomyocytes using PER2::LUC in combination with GCaMP3, a genetically encoded fluorescent Ca2+ reporter. In contrast to robust PER2 circadian rhythms in cardiomyocytes, we detected no rhythms in contraction rate and only weak rhythms in basal Ca2+ level. In summary, we found that PER2 circadian rhythms of cardiomyocytes are cell-autonomous, amplified by adrenergic signaling, and synchronized by intercellular communication in ventricle explants, but we detected no robust circadian rhythms in contraction rate or basal Ca2+. PMID- 27459197 TI - The missing large impact craters on Ceres. AB - Asteroids provide fundamental clues to the formation and evolution of planetesimals. Collisional models based on the depletion of the primordial main belt of asteroids predict 10-15 craters >400 km should have formed on Ceres, the largest object between Mars and Jupiter, over the last 4.55 Gyr. Likewise, an extrapolation from the asteroid Vesta would require at least 6-7 such basins. However, Ceres' surface appears devoid of impact craters >~280 km. Here, we show a significant depletion of cerean craters down to 100-150 km in diameter. The overall scarcity of recognizable large craters is incompatible with collisional models, even in the case of a late implantation of Ceres in the main belt, a possibility raised by the presence of ammoniated phyllosilicates. Our results indicate that a significant population of large craters has been obliterated, implying that long-wavelength topography viscously relaxed or that Ceres experienced protracted widespread resurfacing. PMID- 27459196 TI - Conservation of Distinct Genetically-Mediated Human Cortical Pattern. AB - The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p<10-3), and are biologically meaningful on several fronts. For example, close genetic relationships are seen in cortical regions within the same lobes and, the frontal lobe, a region showing great evolutionary expansion and functional complexity, has the most distant genetic relationship with other lobes. The frontal lobe also exhibits the most distinct expression pattern relative to the other regions, implicating a number of genes with known functions mediating immune and related processes. Our analyses reflect one of the first attempts to provide an assessment of the biological consistency of a genetic phenomenon involving the brain that leverages very different types of data, and therefore is not just statistical replication which purposefully use very similar data sets. PMID- 27459198 TI - Premedication Methods in Nasal Endoscopy: A Prospective, Randomized, Double-Blind Study. AB - OBJECTIVES: To identify the optimal pharmacological method of preparing patients for nasal endoscopy. METHODS: Twenty healthy volunteers were enrolled in this prospective, randomized, double-blind study. Four types of medications were applied in their nostrils with binary combinations of spray bottles on four different days in a random order: placebo (normal saline [NS]+NS), decongestant (NS+oxymetazoline), anesthetic (NS+lidocaine), and decongestant plus anesthetic (oxymetazoline+lidocaine). Rigid nasal endoscopy was performed 10 minutes after spray application. The volunteers evaluated the discomfort caused by each spray application, and nasal pain scores due to the passage of the endoscope. The physicians quantified nasal decongestion using a visual analogue scale. Endoscopy duration as well as pulse and mean blood pressure (MBP) before spray application, 10 minutes after the application, and immediately after endoscopic examination were also recorded. RESULTS: The discomfort caused by lidocaine was significantly higher than that caused by the other sprays (P<0.001). The lowest pain score related to endoscopy was obtained for oxymetazoline+lidocaine (P<0.001). Nasal decongestion was best achieved with NS+oxymetazoline (P<0.001). Endoscopy duration was the shortest for oxymetazoline+ lidocaine (P<0.05). Statistically significant MBP changes were only seen with the application of NS+oxymetazoline (P<0.05). However, neither MBP nor pulse rate change was significant clinically. CONCLUSION: Application of decongestant and anesthetic sprays together seems to be the best method of pharmacological preparation of patients for nasal endoscopy. PMID- 27459199 TI - Does Herpes Virus Reactivation Affect Prognosis in Idiopathic Sudden Sensorineural Hearing Loss? AB - OBJECTIVES: Several etiologies have been proposed to underlie idiopathic sudden sensorineural hearing loss (ISSNHL), including viral infection, vascular disturbance, and immune-mediated mechanisms. However, none of these mechanisms are conclusive. Should ISSNHL be caused by reactivation of a viral infection, antiviral treatment would be an important option. Thus, in this study, we reported the prognosis according to serologic test results of herpes viruses in patients with ISSNHL. We also evaluated treatment response with acyclovir and corticosteroids versus corticosteroids alone in herpes simplex virus (HSV) seropositive ISSNHL patients. METHODS: We compared hematologic examinations and the results of audiometry testing in 232 patients with ISSNHL. Statistical analyses for initial hearing impairment, progression of hearing impairment, recovery of hearing loss, and laboratory results were performed in all patients. All statistical analyses were performed using SPSS software. RESULTS: The 232 ISSNHL patients were divided into two subgroups according to HSV immunoglobulin M (IgM) serologic results (seropositive or seronegative). When the seropositive group was compared to the seronegative group, age, gender, body mass index (BMI), white blood cell, absolute neutrophil count, absolute monocyte count, and platelet count were not significantly different. Initial hearing level, final recovery hearing level, and recovery time were also not significantly different between the two groups (P>0.05). Though there were no significant differences in age, gender, BMI, or viral HSV IgM titer, the two groups had similar initial hearing level, final recovery hearing level, and recovery time. The difference in hearing threshold before and after treatment was larger (18.7+/-37.1) in the group receiving antiviral medication than in the corticosteroids group (11.0+/ 44.5), but this difference was not significant (P=0.619). CONCLUSION: There was no significant difference of prognosis between the patients with and without reactivation of HSV. In addition, there seems to be no benefit for the treatment of acyclovir combined with the corticosteroids in the patients with ISSNHL. PMID- 27459200 TI - Differences of the Voice Parameters Between the Population of Different Hearing Tresholds: Findings by Using the Multi-Dimensional Voice Program. AB - OBJECTIVES: To compare voice parameters in subjects with different hearing level. METHODS: The evaluation consisted of Multi-Dimensional Voice Program (MDVP) and electroglottography. Group 1 consisted of normal hearing subjects which is bilateral average hearing better than 25 decibels (dB) whereas group 2 consisted of patients who have bilateral average hearing between the 25 and 60 dB and group 3 consisted of patients who have bilateral average hearing between the 60 and 90 dB. The evaluations were performed on males and females separately. RESULTS: In female subjects, fundamental frequency (F0), absolute jitter, %jitter and soft phonation index (SPI) were significantly different between the group 1 and group 2. Also, we detected significant difference on maximum phonation time (MPT), fundamental frequency, absolute jitter and %jitter, and variable F0 (vF0) values between group 1 and group 3. Male subjects demonstrated significant difference between the group 1 and group 2 in MPT, absolute jitter, %jitter, vF0, and SPI parameters. Between the group 3 and group 1; differences in absolute jitter, %jitter, shimmer, %shimmer, vF0, and SPI were also significant. CONCLUSION: This study concluded that even mild to moderate hearing losses may affect voice patterns in adults and also females and males react differently to hearing loss in some parameters. PMID- 27459201 TI - Pathologic Evaluation of Routine Nasopharynx Punch Biopsy in the Adult Population: Is It Really Necessary? AB - OBJECTIVES: To retrospectively evaluate the patients who underwent nasopharyngeal biopsy with imaging and biopsy results, who have or don't have symptoms for nasopharyngeal pathology and to determine the ratio of the nasopharyngeal cancer cases and other pathologic conditions. METHODS: In this retrospective study, 983 patients who underwent endoscopic nasopharyngeal biopsy for symptomatic nasopharyngeal lesions were included. All pathological results, benign or malign was recorded and classified due to the patients' presenting symptoms such as symptomatic for nasopharyngeal pathology or asymptomatic. Computed tomography (CT) or magnetic resonance imaging (MRI) reports were also recorded separately as group A for malignancy or group B for not malignancy. RESULTS: Forty-five (4.6%) of 983 biopsies were malignant. In this group, there is no statistically significant difference between symptomatic and asymptomatic group. For malignant pathologies, the sensitivity of MRI was found 88.2% and CT was 61.5%. CONCLUSION: For early diagnosis of nasopharyngeal cancer, all patients admitted to Ear, Nose and Throat (ENT) referral clinics should be examined endoscopically irrespective of their complaints and suspicious cases should be investigated by imaging especially by MRI. If MRI report clearly indicates Thornwaldt cyst or reactive lymphoid hyperplasia and this result is compatible with endoscopic findings, biopsy may not be necessary. Apart from these cases, all suspected lesions should be biopsied. PMID- 27459202 TI - Bioengineered Livers: A New Tool for Drug Testing and a Promising Solution to Meet the Growing Demand for Donor Organs. AB - BACKGROUND: Organ engineering is a new innovative strategy to cope with two problems: the need for physiological models for pharmacological research and donor organs for transplantation. A functional scaffold is generated from explanted organs by removing all cells (decellularization) by perfusing the organ with ionic or nonionic detergents via the vascular system. Subsequently the acellular scaffold is reseeded with organ-specific cells (repopulation) to generate a functional organ. SUMMARY: This review gives an overview of the state of the art describing the decellularization process, the subsequent quality assessment, the repopulation techniques and the functional assessment. It emphasizes the use of scaffolds as matrix for culturing human liver cells for drug testing. Further, it highlights the techniques for transplanting these engineered scaffolds in allogeneic or xenogeneic animals in order to test their biocompatibility and use as organ grafts. Key Messages: The first issue is the so called decellularization, which is best explored and resulted in a multitude of different protocols. The most promising approach seems to be the combination of pulsatile perfusion of the liver with Triton X-100 and SDS via hepatic artery and portal vein. Widely accepted parameters of quality control include the quantitative assessment of the DNA content and the visualization of eventually remaining nuclei confirmed by HE staining. Investigations regarding the composition of the extracellular matrix focused on histological determination of laminin, collagen, fibronectin and elastin and remained qualitatively. Repopulation is the second issue which is addressed. Selection of the most suitable cell type is a highly controversial topic. Currently, the highest potential is seen for progenitor and stem cells. Cells are infused into the scaffold and cultured under static conditions or in a bioreactor allowing dynamic perfusion of the scaffold. The quality of repopulation is mainly assessed by routine histology and basic functional assays. These promising results prompted to consider the use of a liver scaffold repopulated with human cells for pharmacological research. Transplantation of the (repopulated) scaffold is the third topic which is not yet widely addressed. Few studies report the heterotopic transplantation of repopulated liver tissue without vascular anastomosis. Even fewer studies deal with the heterotopic transplantation of a scaffold or a repopulated liver lobe. However, observation time was still limited to hours, and long-term graft survival has not been reported yet. These exciting results emphasize the potential of this new and promising strategy to create physiological models for pharmacological research and to generate liver grafts for the transplant community to treat organ failure. However, the scientific need for further development in the field of liver engineering is still tremendous. PMID- 27459203 TI - The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans. AB - The mitochondrial unfolded protein response (UPRmt) is a surveillance pathway that defends proteostasis in the "powerhouse" of the cell. Activation of the UPRmt protects against stresses imposed by reactive oxygen species, respiratory chain deficits, and pathologic bacteria. Consistent with the UPRmt's role in adaption, we found that either its pharmacological or genetic activation by ethidium bromide (EtBr) or RNAi of the mitochondrial AAA-protease spg-7 was sufficient to reduce death in an anoxia-based Caenorhabditis elegans model of ischemia-reperfusion injury. The UPRmt-specific transcription factor atfs-1 was necessary for protection and atfs-1 gain-of-function (gf) mutants were endogenously protected from both death and dysfunction. Neurons exhibited less axonal degeneration following non-lethal anoxia-reperfusion (A-R) when the UPRmt was pre-activated, and consistent with the concept of mitochondrial stress leading to cell non-autonomous (ie. "remote") effects, we found that restricted activation of the UPRmt in neurons decreased A-R death. However, expression of the atfs-1(gf) mutant in neurons, which resulted in a robust activation of a neuronal UPRmt, did not upregulate the UPRmt in distal tissues, nor did it protect the worms from A-R toxicity. These findings suggest that remote signaling requires additional component(s) acting downstream of de facto mitochondrial stress. PMID- 27459204 TI - Specificity of a Polyclonal Fecal Elastase ELISA for CELA3. AB - INTRODUCTION: Elastase is a proteolytic pancreatic enzyme that passes through the gastrointestinal tract undergoing only limited degradation. ELISA tests to determine stool elastase concentrations have therefore been developed for the diagnosis of exocrine pancreatic insufficiency. Five different isoforms of pancreatic elastase (CELA1, CELA2A, CELA2B, CELA3A, CELA3B) are encoded in the human genome. We have investigated three different polyclonal antisera that are used in a commercial fecal elastase ELISA to determine their specificity for different pancreatic elastase isoforms. MATERIAL AND METHODS: Different polyclonal rabbit antisera against human elastase peptides (BIOSERV Diagnostics GmbH, Germany) were tested by Western blot analysis of human pancreatic juice, in HEK-293 cells expressing Elastase constructs, and in the protein content of porcine pancreatin, used for treatment of exocrine pancreatic insufficiency. RESULTS: In human pancreatic juice the polyclonal antisera detected proteins at the corresponding size of human pancreatic elastase isoforms (~29kDa). Transiently expressed GFP fusion protein of elastase isoform CELA3A (CELA3A-GFP), but not CELA2A (CELA2A-GFP) could be precipitated from HEK-293 cell lysates with the elastase antisera. We detected no cross-reactivity with elastases in the porcine pancreatic extracts (pancreatin) used for enzyme replacement therapy. CONCLUSION: The polyclonal antisera used in a commercial fecal elastase ELISA are specific for the human pancreatic elastase isoform CELA3 and do not cross-react with elastase contained in pig pancreatin. While pancreatic elastase 1 (CELA1) is not expressed in the adult human pancreas, possible differences between the other isoforms regarding their cellular expression, pathophysiological role and relevance in exocrine pancreatic insufficiency deserve further investigation. PMID- 27459205 TI - Correction: The Relationship between Serum Ferritin Levels and Insulin Resistance in Pre- and Postmenopausal Korean Women: KNHANES 2007-2010. AB - [This corrects the article DOI: 10.1371/journal.pone.0157934.]. PMID- 27459206 TI - Plant diversity and root traits benefit physical properties key to soil function in grasslands. AB - Plant diversity loss impairs ecosystem functioning, including important effects on soil. Most studies that have explored plant diversity effects belowground, however, have largely focused on biological processes. As such, our understanding of how plant diversity impacts the soil physical environment remains limited, despite the fundamental role soil physical structure plays in ensuring soil function and ecosystem service provision. Here, in both a glasshouse and a long term field study, we show that high plant diversity in grassland systems increases soil aggregate stability, a vital structural property of soil, and that root traits play a major role in determining diversity effects. We also reveal that the presence of particular plant species within mixed communities affects an even wider range of soil physical processes, including hydrology and soil strength regimes. Our results indicate that alongside well-documented effects on ecosystem functioning, plant diversity and root traits also benefit essential soil physical properties. PMID- 27459207 TI - Role of Cell Membrane-Vector Interactions in Successful Gene Delivery. AB - Cationic polymers have been investigated as nonviral vectors for gene delivery due to their favorable safety profile when compared to viral vectors. However, nonviral vectors are limited by poor efficacy in inducing gene expression. The physicochemical properties of cationic polymers enabling successful gene expression have been investigated in order to improve expression efficiency and safety. Studies over the past several years have focused on five possible rate limiting processes to explain the differences in gene expression: (1) endosomal release, (2) transport within specific intracellular pathways, (3) protection of DNA from nucleases, (4) transport into the nucleus, and (5) DNA release from vectors. However, determining the relative importance of these processes and the vector properties necessary for optimization remain a challenge to the field. In this Account, we describe over a decade of studies focused on understanding the interaction of cationic polymer and cationic polymer/oligonucleotide (polyplex) interactions with model lipid membranes, cell membranes, and cells in culture. In particular, we have been interested in how the interaction between cationic polymers and the membrane influences the intracellular transport of intact DNA to the nucleus. Recent advances in microfluidic patch clamp techniques enabled us to quantify polyplex cell membrane interactions at the cellular level with precise control over material concentrations and exposure times. In attempting to relate these findings to subsequent intracellular transport of DNA and expression of protein, we needed to develop an approach that could distinguish DNA that was intact and potentially functional for gene expression from the much larger pool of degraded, nonfunctional DNA within the cell. We addressed this need by developing a FRET oligonucleotide molecular beacon (OMB) to monitor intact DNA transport. The research highlighted in this Account builds to the conclusion that polyplex transported DNA is released from endosomes by free cationic polymer intercalated into the endosomal membrane. This cationic polymer initially interacts with the cell plasma membrane and appears to reach the endosome by lipid cycling mechanisms. The fraction of cells displaying release of intact DNA from endosomes quantitatively predicts the fraction of cells displaying gene expression for both linear poly(ethylenimine) (L-PEI; an effective vector) and generation five poly(amidoamine) dendrimer (G5 PAMAM; an ineffective vector). Moreover, intact OMB delivered with G5 PAMAM, which normally is confined to endosomes, was released by the subsequent addition of L-PEI with a corresponding 10-fold increase in transgene expression. These observations are consistent with experiments demonstrating that cationic polymer/membrane partition coefficients, not polyplex/membrane partition coefficients, predict successful gene expression. Interestingly, a similar partitioning of cationic polymers into the mitochondrial membranes has been proposed to explain the cytotoxicity of these materials. Thus, the proposed model indicates the same physicochemical property (partitioning into lipid bilayers) is linked to release from endosomes, giving protein expression, and to cytotoxicity. PMID- 27459208 TI - N-Heterocyclic Carbene-Polyethylenimine Platinum Complexes with Potent in Vitro and in Vivo Antitumor Efficacy. AB - The current interest for platinum N-heterocyclic carbene complexes in cancer research stems from their impressive toxicity reported against a range of different human cancer cells. To date, the demonstration of their in vivo efficacy relative to that of established platinum-based drugs has not been specifically addressed. Here, we introduce an innovative approach to increase the NHC-Pt complex potency whereby multiple NHC-Pt(II) complexes are coordinated along a polyethylenimine polymer (PEI) chain. We show that such NHC-Pt(II)-PEI conjugates induce human cancer cell death in vitro and in vivo in a xenograft mouse model with no observable side effects in contrast to oxaliplatin. Additional studies indicate nucleus and mitochondria targeting and suggest various mechanisms of action compared to classical platinum-based anticancer drugs. PMID- 27459209 TI - Punishment Learning in U.S. Veterans With Posttraumatic Stress Disorder. AB - Learning processes have been implicated in the development and course of posttraumatic stress disorder (PTSD); however, little is currently known about punishment-based learning in PTSD. The current study investigated impairments in punishment-based learning in U.S. veterans. We expected that veterans with PTSD would demonstrate greater punishment-based learning compared to a non-PTSD control group. We compared a PTSD group with and without co-occurring depression (n = 27) to a control group (with and without trauma exposure) without PTSD or depression (n = 29). Participants completed a computerized probabilistic punishment-based learning task. Compared to the non-PTSD control group, veterans with PTSD showed significantly greater punishment-based learning. Specifically, there was a significant Block * Group interaction, F(1, 54) = 4.12, p = .047, eta(2) = .07. Veterans with PTSD demonstrated greater change in response bias for responding toward a less frequently punished stimulus across blocks. The observed hypersensitivity to punishment in individuals with PTSD may contribute to avoidant responses that are not specific to trauma cues. PMID- 27459210 TI - Semiconductor plasmonic nanolasers: current status and perspectives. AB - Scaling down semiconductor lasers in all three dimensions holds the key to the development of compact, low-threshold, and ultrafast coherent light sources, as well as integrated optoelectronic and plasmonic circuits. However, the minimum size of conventional semiconductor lasers utilizing dielectric cavity resonators (photonic cavities) is limited by the diffraction limit. To date, surface plasmon amplification by stimulated emission of radiation (spaser)-based plasmonic nanolaser is the only photon and plasmon-emitting device capable of this remarkable feat. Specifically, it has been experimentally demonstrated that the use of plasmonic cavities based on metal-insulator-semiconductor (MIS) nanostructures can indeed break the diffraction limit in all three dimensions. In this review, we present an updated overview of the current status for plasmonic nanolasers using the MIS configuration and other related metal-cladded semiconductor microlasers. In particular, by using composition-varied indium gallium nitride/gallium nitride core-shell nanorods, it is possible to realize all-color, single-mode nanolasers in the full visible wavelength range with ultralow continuous-wave (CW) lasing thresholds. The lasing action in these subdiffraction plasmonic cavities is achieved via a unique auto-tuning mechanism based on the property of weak size dependence inherent in plasmonic nanolasers. As for the choice of metals in the plasmonic structures, epitaxial silver films and giant colloidal silver crystals have been shown to be the superior constituent materials for plasmonic cavities due to their low plasmonic losses in the visible and near-infrared (NIR) spectral regions. In this review, we also provide some perspectives on the challenges and opportunities in this exciting new research frontier. PMID- 27459211 TI - How can we make the learning curve of endoscopic submucosal dissection for (Western) endoscopists less steep? PMID- 27459212 TI - Prevention of rebleeding: high-dose PPIs, second-look endoscopy or both? PMID- 27459213 TI - Serrated colorectal neoplasia: detection, characterization ... what next? PMID- 27459214 TI - How can endoscopic R0 resection be ensured for relatively small gastric gastrointestinal stromal tumors? PMID- 27459215 TI - Use of patency capsules in patients with established Crohn's disease. PMID- 27459216 TI - Which approach should be used for endoscopic ultrasound-guided biliary drainage? PMID- 27459217 TI - Reply to Fabbri et al. PMID- 27459220 TI - French comment on article: Measures to improve microbial quality surveillance of gastrointestinal endoscopes. PMID- 27459221 TI - French comment on article: Video-based supervision for training of endoscopic submucosal dissection. PMID- 27459222 TI - French comment on article: High-dose omeprazole infusion compared with scheduled second-look endoscopy for prevention of peptic ulcer rebleeding: a randomized controlled trial. PMID- 27459223 TI - French comment on article: A multicenter prospective study of the real-time use of narrow-band imaging in the diagnosis of premalignant gastric conditions and lesions. PMID- 27459224 TI - French comment on article: Diagnosis of sessile serrated adenomas/polyps with image-enhanced endoscopy: a systematic review and meta-analysis. PMID- 27459225 TI - French comment on article: Prevalence, distribution and risk of sessile serrated adenomas/polyps at a center with a high adenoma detection rate and experienced pathologists. PMID- 27459226 TI - French comment on article: Prophylactic clipping for the prevention of bleeding following wide-field endoscopic mucosal resection of laterally spreading colorectal lesions: an economic modeling study. PMID- 27459227 TI - Video Comment on Bahin et al. PMID- 27459228 TI - A step change in the transfer of interspecific variation into wheat from Amblyopyrum muticum. AB - Despite some notable successes, only a fraction of the genetic variation available in wild relatives has been utilized to produce superior wheat varieties. This is as a direct result of the lack of availability of suitable high-throughput technologies to detect wheat/wild relative introgressions when they occur. Here, we report on the use of a new SNP array to detect wheat/wild relative introgressions in backcross progenies derived from interspecific hexaploid wheat/Ambylopyrum muticum F1 hybrids. The array enabled the detection and characterization of 218 genomewide wheat/Am. muticum introgressions, that is a significant step change in the generation and detection of introgressions compared to previous work in the field. Furthermore, the frequency of introgressions detected was sufficiently high to enable the construction of seven linkage groups of the Am. muticum genome, thus enabling the syntenic relationship between the wild relative and hexaploid wheat to be determined. The importance of the genetic variation from Am. muticum introduced into wheat for the development of superior varieties is discussed. PMID- 27459229 TI - Relationship between repetitive behaviour and fear across normative development, autism spectrum disorder, and down syndrome. AB - The present study had two aims: first to compare levels of restricted and repetitive behaviours (RRB) across two groups of typically developing (TD) children, and two disorders: Autism Spectrum Disorder (ASD) and Down syndrome (DS), and second to explore the relationship between fear and repetitive behaviours in these four groups. Parents of 41 offspring with ASD (Mage = 123.39 months, SDage = 27.67), 38 offspring with DS (Mage = 125.37 months, SDage = 45.71), 45 typically developing children matched to the mental age (MA) of the DS group (TD MA; Mage = 51.13 months, SDage = 22.1), and 42 chronological age (TD CA; Mage = 117.93 months, SDage = 22.91) matched TD children, completed measures of RRB and fear. ANOVAs revealed differences across the four groups on the RRB subscale scores: "Just Right" F(3,162) = 16.62, P < 0.001; Rigid Routines F(3,162) = 52.76, P < 0.001; Sensory behaviours F(3,162) = 23.26, P < 0.001. Post hoc comparisons revealed that children with ASD had the highest RRB levels followed by DS, TD MA, and TD CA children. In children with ASD, higher levels of fear were related to higher RRB levels. Similar, albeit less strong, patterns of associations was found among DS and TD MA children but not in older TD CA children. This study provided evidence of a fear-RRB association in children with ASD, DS, and two groups of TD children. Autism Res 2017, 10: 502-507. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27459231 TI - Variation in Essential Oil Yield and Composition of Dorema aucheri Boiss., an Endemic Medicinal Plant Collected from Wild Populations in Natural Habitats. AB - In the present research, variability in essential oil (EO) composition of five Dorema aucheri populations collected from natural habitats in different regions of Iran, were investigated. The EO content of populations varied from 0.28 to 0.68%. According to gas chromatography/mass spectrometry analysis, beta caryophyllene (7.17 - 35.73%), thymol (23.45 - 29.64%), beta-gurjunene (2.58 - 5.89%), carvacrol (1.32 - 2.67%) and cuparene (1.97 - 2.98%) were the major components. Hierarchical cluster, principal component and canonical correspondence analyses classified the studied populations into three groups based on major EO components. The environmental parameters of the collected sites were also evaluated. According to the results, it might be suggested that sandy soils with high mean annual precipitation were major environmental factors influencing the amount of beta-caryophyllene, while thymol, cuparene and caryophyllen oxide increased in silty and clay soils. Finally, the population collected in high altitudes and clay soils had higher amount of beta-gurjunene. PMID- 27459232 TI - Ureteral double-J stents performances toward encrustation after long-term indwelling in a dynamic in vitro model. AB - Three different single-lumen double-J ureteral stents of different materials were studied and compared after the insertion into a dynamic in vitro model with sterile artificial urine up to 6 months. The aim was to evaluate, at selected time steps of 1, 3, and 6 months, the material performances of the stents in preventing the formation of inorganic encrustations. Morphological, compositional, and qualitative analyses were carried out both before stent insertion and after stent permanence for the different time steps, showing an increasing level of encrustation which remains particularly low in the case of two polyurethane stents. Mechanical tests show that both the polyurethane stents and the chitosan one do not decrease the tensile strength after 6 months of indwelling. Evaluation of the wetting behavior of the stent outer surfaces indicates a hydrophilic behavior in most of the cases, which is generally preserved after immersion in artificial urine for the different time steps. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2244 2253, 2017. PMID- 27459233 TI - Design and Room-Temperature Operation of GaAs/AlGaAs Multiple Quantum Well Nanowire Lasers. AB - We present the design and room-temperature lasing characteristics of single nanowires containing coaxial GaAs/AlGaAs multiple quantum well (MQW) active regions. The TE01 mode, which has a doughnut-shaped intensity profile and is polarized predominantly in-plane to the MQWs, is predicted to lase in these nanowire heterostructures and is thus chosen for the cavity design. Through gain and loss calculations, we determine the nanowire dimensions required to minimize loss for the TE01 mode and determine the optimal thickness and number of QWs for minimizing the threshold sheet carrier density. In particular, we show that there is a limit to the minimum and maximum number of QWs that are required for room temperature lasing. Based on our design, we grew nanowires of a suitable diameter containing eight uniform coaxial GaAs/AlGaAs MQWs. Lasing was observed at room temperature from optically pumped single nanowires and was verified to be from TE01 mode by polarization measurements. The GaAs MQW nanowire lasers have a threshold fluence that is a factor of 2 lower than that previously demonstrated for room-temperature GaAs nanowire lasers. PMID- 27459234 TI - Enantioselective Syntheses of Lignin Models: An Efficient Synthesis of beta-O-4 Dimers and Trimers by Using the Evans Chiral Auxiliary. AB - We describe an efficient five-step, enantioselective synthesis of (R,R)- and (S,S)-lignin dimer models possessing a beta-O-4 linkage, by using the Evans chiral aldol reaction as a key step. Mitsunobu inversion of the (R,R)- or (S,S) isomers generates the corresponding (R,S)- and (S,R)-diastereomers. We further extend this approach to the enantioselective synthesis of a lignin trimer model. These lignin models are synthesized with excellent ee (>99 %) and high overall yields. The lignin dimer models can be scaled up to provide multigram quantities that are not attainable by using previous methodologies. These lignin models will be useful in degradation studies probing the selectivity of enzymatic, microbial, and chemical processes that deconstruct lignin. PMID- 27459235 TI - Donor-derived tuberculosis (TB): isoniazid-resistant TB transmitted from a lung transplant donor with inadequately treated latent infection. AB - Donor-derived tuberculosis (TB) is an increasingly recognized complication of solid organ transplantation. We report a case of isoniazid-resistant pulmonary TB in a lung transplant recipient. The patient acquired the infection from the lung donor who was previously empirically treated with isoniazid for latent TB. The case highlights the caveat that, while adequate treatment of latent TB with isoniazid is presumed, meticulous screening of donors is required. PMID- 27459236 TI - Effectiveness of a Proactive Primary Care Program on Preserving Daily Functioning of Older People: A Cluster Randomized Controlled Trial. AB - OBJECTIVES: To determine the effectiveness of a proactive primary care program on the daily functioning of older people in primary care. DESIGN: Single-blind, three-arm, cluster-randomized controlled trial with 1-year follow-up. SETTING: Primary care setting, 39 general practices in the Netherlands. PARTICIPANTS: Community-dwelling people aged 60 and older (N = 3,092). INTERVENTIONS: A frailty screening intervention using routine electronic medical record data to identify older people at risk of adverse events followed by usual care from a general practitioner; after the screening intervention, a nurse-led care program consisting of a comprehensive geriatric assessment, evidence-based care planning, care coordination, and follow-up; usual care. MEASUREMENTS: Primary outcome was daily functioning measured using the Katz-15 (6 activities of daily living (ADLs), 8 instrumental activities of daily living (IADLs), one mobility item (range 0-15)); higher scores indicate greater dependence. Secondary outcomes included quality of life, primary care consultations, hospital admissions, emergency department visits, nursing home admissions, and mortality. RESULTS: The participants in both intervention arms had less decline in daily functioning than those in the usual care arm at 12 months (mean Katz-15 score: screening arm, 1.87, 95% confidence interval (CI) = 1.77-1.97; screening and nurse-led care arm, 1.88, 95% CI = 1.80-1.96; control group, 2.03, 95% CI = 1.92-2.13; P = .03). No differences in quality of life were observed. CONCLUSION: Participants in both intervention groups had less decline than those in the control group at 1-year follow-up. Despite the statistically significant effect, the clinical relevance is uncertain at this point because of the small differences. Greater customizing of the intervention combined with prolonged follow-up may lead to more-robust results. PMID- 27459237 TI - Stimulating Influenza Vaccination via Prosocial Motives. AB - OBJECTIVE: Americans do not vaccinate nearly enough against Influenza (flu) infection, despite severe health and economic burden of influenza. Younger people are disproportionately responsible for transmission, but do not suffer severely from the flu. Thus, to achieve herd immunity, prosocial motivation needs to be a partial driver of vaccination decisions. Past research has not established the causal role of prosociality in flu vaccination, and the current research evaluates such causal relationship by experimentally eliciting prosociality through messages about flu victims. METHODS: In an experimental study, we described potential flu victims who would suffer from the decision of others to not vaccinate to 3952 Internet participants across eight countries. We measured sympathy, general prosociality, and vaccination intentions. The study included two identifiable victim conditions (one with an elderly victim and another with a young victim), an unidentified victim condition, and a no message condition. RESULTS: We found that any of the three messages increased flu vaccination intentions. Moreover, this effect was mediated by enhanced prosocial motives, and was stronger among people who were historical non-vaccinators. In addition, younger victim elicited greater sympathy, and describing identifiable victims increased general sympathy and prosocial motives. CONCLUSIONS: These findings provide direct experimental evidence on the causal role of prosocial motives in flu vaccination, by showing that people can be prompted to vaccinate for the sake of benefiting others. PMID- 27459238 TI - Intensive voluntary wheel running may restore circadian activity rhythms and improves the impaired cognitive performance of arrhythmic Djungarian hamsters. AB - Circadian rhythms are highly important not only for the synchronization of animals and humans with their periodic environment but also for their fitness. Accordingly, the disruption of the circadian system may have adverse consequences. A certain number of animals in our breeding stock of Djungarian hamsters are episodically active throughout the day. Also body temperature and melatonin lack 24-h rhythms. Obviously in these animals, the suprachiasmatic nuclei (SCN) as the central pacemaker do not generate a circadian signal. Moreover, these so-called arrhythmic (AR) hamsters have cognitive deficits. Since motor activity is believed to stabilize circadian rhythms, we investigated the effect of voluntary wheel running. Hamsters were bred and kept under standardized housing conditions with food and water ad libitum and a 14 L/10 D lighting regimen. AR animals were selected according to their activity pattern obtained by means of passive infrared motion detectors. In a first step, the daily activity behavior was investigated for 3 weeks each without and with running wheels. To estimate putative photic masking effects, hamsters were exposed to light (LPs) and DPs and also released into constant darkness for a minimum of 3 weeks. A novel object recognition (NOR) test was performed to evaluate cognitive abilities both before and after 3 weeks of wheel availability. The activity patterns of hamsters with low wheel activity were still AR. With more intense running, daily patterns with higher values in the dark time were obtained. Obviously, this was due to masking as LPs did suppress and DPs induced motor activity. When transferred to constant darkness, in some animals the daily rhythm disappeared. In other hamsters, namely those which used the wheels most actively, the rhythm was preserved and free-ran, what can be taken as indication of a reconstitution of circadian rhythmicity. Also, animals showing a 24-h activity pattern after 3 weeks of extensive wheel running were able to recognize the novel object in the NOR test but not so before. The results show that voluntary exercise may reestablish circadian rhythmicity and improve cognitive performance. PMID- 27459230 TI - The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. AB - Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989 1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis. PMID- 27459239 TI - Role for DUSP1 (dual-specificity protein phosphatase 1) in the regulation of autophagy. AB - Accumulating evidence suggests that mitogen-activated protein kinases (MAPKs) regulate macroautophagy/autophagy. However, the involvement of dual-specificity protein phosphatases (DUSPs), endogenous inhibitors for MAPKs, in autophagy remains to be determined. Here we report that DUSP1/MKP-1, the founding member of the DUSP family, plays a critical role in regulating autophagy. Specifically, we demonstrate that DUSP1 knockdown by shRNA in human ovarian cancer CAOV3 cells and knockout in murine embryonic fibroblasts, increases both basal and rapamycin increased autophagic flux. Overexpression of DUSP1 had the opposite effect. Importantly, knockout of Dusp1 promoted phosphorylation of ULK1 at Ser555, and BECN1/Beclin 1 at Ser15, and the association of PIK3C3/VPS34, ATG14, BECN1 and MAPK, leading to the activation of the autophagosome-initiating class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Furthermore, knockdown and pharmacological inhibitor studies indicated that DUSP1-mediated suppression of autophagy reflected inactivation of the MAPK1-MAPK3 members of the MAPK family. Knockdown of DUSP1 sensitized CAOV3 cells to rapamycin-induced antigrowth activity. Moreover, CAOV3-CR cells, a line that had acquired cisplatin resistance, exhibited an elevated DUSP1 level and were refractory to rapamycin induced autophagy and cytostatic effects. Knockdown of DUSP1 in CAOV3-CR cells restored sensitivity to rapamycin. Collectively, this work identifies a previously unrecognized role for DUSP1 in regulating autophagy and suggests that suppression of DUSP1 may enhance the therapeutic activity of rapamycin. PMID- 27459241 TI - Asthma after bronchiolitis: The outcome and risk factors depend on the age definition of bronchiolitis. PMID- 27459240 TI - Three-Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence-Structure Analysis of its Disease-Causing Variations. AB - Defective mitochondrial proteins are emerging as major contributors to human disease. Nicotinamide nucleotide transhydrogenase (NNT), a widely expressed mitochondrial protein, has a crucial role in the defence against oxidative stress. NNT variations have recently been reported in patients with familial glucocorticoid deficiency (FGD) and in patients with heart failure. Moreover, knockout animal models suggest that NNT has a major role in diabetes mellitus and obesity. In this study, we used experimental structures of bacterial transhydrogenases to generate a structural model of human NNT (H-NNT). Structure based analysis allowed the identification of H-NNT residues forming the NAD binding site, the proton canal and the large interaction site on the H-NNT dimer. In addition, we were able to identify key motifs that allow conformational changes adopted by domain III in relation to its functional status, such as the flexible linker between domains II and III and the salt bridge formed by H-NNT Arg882 and Asp830. Moreover, integration of sequence and structure data allowed us to study the structural and functional effect of deleterious amino acid substitutions causing FGD and left ventricular non-compaction cardiomyopathy. In conclusion, interpretation of the function-structure relationship of H-NNT contributes to our understanding of mitochondrial disorders. PMID- 27459242 TI - Meaning and Posttraumatic Growth Among Survivors of the September 2013 Colorado Floods. AB - In the wake of significant adversity, a range of recovery outcomes are possible, from prolonged distress to minimal effects on functioning and even psychological growth. Finding meaning in one's life is thought to facilitate optimal recovery from such adversity. Research on psychological growth and recovery often focuses on the daily hassles or significant traumas of convenience samples or on people's psychological recovery from medical illness. A small body of research is developing to test theories of growth among survivors of natural disasters. The present study of 57 survivors of the 2013 Colorado floods tested the incremental relations between posttraumatic growth (PTG) and dimensions of meaning in life, vitality, and perceived social support. The most consistent relations observed were among the one dimension of meaning-search for meaning-perceived social support, and PTG. Despite the limitations of this study, we conclude that search for meaning in life may be an important part of recovery from natural disasters, floods being one example. PMID- 27459243 TI - Stable, Fast UV-Vis-NIR Photodetector with Excellent Responsivity, Detectivity, and Sensitivity Based on alpha-In2Te3 Films with a Direct Bandgap. AB - Photoelectric conversion is of great importance to extensive applications. However, thus far, photodetectors integrated with high responsivity, excellent detectivity, large phototo-dark current ratio, fast response speed, broad spectral range, and good stability are rarely achieved. Herein, we deposited large-scale and high-quality polycrystalline indium sesquitelluride (alpha In2Te3) films via pulsed-laser deposition. Then, we demonstrated that the photodetectors made of the prepared alpha-In2Te3 films possess stable photoswitching behavior from 370 to 1064 nm and short response time better than ca. 15 ms. At a source-drain voltage of 5 V, the device achieves a high responsivity of 44 A/W, along with an outstanding detectivity of 6 * 10(12) cm H(1/2) W(-1) and an excellent sensitivity of 2.5 * 10(5) cm(2)/W. All of these figures-of-merit are the best among those of the reported alpha-In2Te3 photodetectors. In fact, they are comparable to the state-of-the-art commercial Si and Ge photodetectors. For the first time, we established the theoretical evidence that alpha-In2Te3 possesses a direct bandgap structure, which reasonably accounts for the superior photodetection performances above. Importantly, the device exhibits a good stability against the multiple photoswitching operation and ambient environment, along with no obvious voltage-scan hysteresis. These excellent figures-of-merit, together with the broad spectral range and good stability, underscore alpha-In2Te3 as a promising candidate material for next generation photodetection. PMID- 27459244 TI - Quantification of the vascular endothelial growth factor with a bioluminescence resonance energy transfer (BRET) based single molecule biosensor. AB - Neovascular pathologies in the eye like age-related macular degeneration (AMD), the diabetic retinopathie (DR), retinopathie of prematurity (ROP) or the retinal vein occlusion (RVO) are caused through a hypoxia induced upregulation of the vascular endothelial growth factor (VEGF). So far a correlation of intraocular VEGF concentrations to the impact of the pathologies is limited because of invasive sampling. Therefore, a minimally invasive, repeatable quantification of VEGF levels in the eye is needed to correlate the stage of VEGF induced pathologies as well as the efficacy of anti-VEGF treatment. Here we describe the development of three variants of enhanced BRET2 (eBRET2) based, single molecule biosensors by fusing a Renilla luciferase mutant with enhanced light output (RLuc8) to the N-terminus and a suitable eBRET2 acceptor fluorophore (GFP2) to the C-terminus of a VEGF binding domain, directly fused or separated with two different peptide linkers for the quantification of VEGF in vitro. The VEGF binding domain consists of a single chain variable fragment (scFv) based on ranibizumab in which the light- and the heavy- F(ab) chains were connected with a peptide linker to generate one open reading frame (orf). All three variants generate measureable eBRET2 ratios by transferring energy from the luciferase donor to the GFP2 acceptor, whereas only the directly fused and the proline variant permit VEGF quantification. The directly fused biosensor variant allows the quantification of VEGF with higher sensitivity, compared to the widely used ELISA systems and a wide dynamic quantification range in vitro. Our system demonstrates not only an additional in vitro application on VEGF quantification but also a promising step towards an applicable biosensor in an implantable device able to quantify VEGF reliably after implantation in vivo. PMID- 27459246 TI - Yeast surface display of dehydrogenases in microbial fuel-cells. AB - Two dehydrogenases, cellobiose dehydrogenase from Corynascus thermophilus and pyranose dehydrogenase from Agaricus meleagris, were displayed for the first time on the surface of Saccharomyces cerevisiae using the yeast surface display system. Surface displayed dehydrogenases were used in a microbial fuel cell and generated high power outputs. Surface displayed cellobiose dehydrogenase has demonstrated a midpoint potential of -28mV (vs. Ag/AgCl) at pH=6.5 and was used in a mediator-less anode compartment of a microbial fuel cell producing a power output of 3.3MUWcm(-2) using lactose as fuel. Surface-displayed pyranose dehydrogenase was used in a microbial fuel cell and generated high power outputs using different substrates, the highest power output that was achieved was 3.9MUWcm(-2) using d-xylose. These results demonstrate that surface displayed cellobiose dehydrogenase and pyranose dehydrogenase may successfully be used in microbial bioelectrochemical systems. PMID- 27459245 TI - Estimating the harms and benefits of prostate cancer screening as used in common practice versus recommended good practice: A microsimulation screening analysis. AB - BACKGROUND: Prostate-specific antigen (PSA) screening and concomitant treatment can be implemented in several ways. The authors investigated how the net benefit of PSA screening varies between common practice versus "good practice." METHODS: Microsimulation screening analysis (MISCAN) was used to evaluate the effect on quality-adjusted life-years (QALYs) if 4 recommendations were followed: limited screening in older men, selective biopsy in men with elevated PSA, active surveillance for low-risk tumors, and treatment preferentially delivered at high volume centers. Outcomes were compared with a base model in which annual screening started at ages 55 to 69 years and were simulated using data from the European Randomized Study of Screening for Prostate Cancer. RESULTS: In terms of QALYs gained compared with no screening, for 1000 screened men who were followed over their lifetime, recommended good practice led to 73 life-years (LYs) and 74 QALYs gained compared with 73 LYs and 56 QALYs for the base model. In contrast, common practice led to 78 LYs gained but only 19 QALYs gained, for a greater than 75% relative reduction in QALYs gained from unadjusted LYs gained. The poor outcomes for common practice were influenced predominantly by the use of aggressive treatment for men with low-risk disease, and PSA testing in older men also strongly reduced potential QALY gains. CONCLUSIONS: Commonly used PSA screening and treatment practices are associated with little net benefit. Following a few straightforward clinical recommendations, particularly greater use of active surveillance for low-risk disease and reducing screening in older men, would lead to an almost 4-fold increase in the net benefit of prostate cancer screening. Cancer 2016;122:3386-3393. (c) 2016 American Cancer Society. PMID- 27459247 TI - Is diffusion tensor imaging useful in the assessment of the sciatic nerve and its pathologies? Our clinical experience. AB - OBJECTIVE: To evaluate the usefulness of diffusion tensor imaging (DTI) in the clinical setting as a complementary tool to conventional MRI in the study and assessment of the sciatic nerve and its pathologies. METHODS: 17 patients diagnosed with different types of sciatic neuropathy and 10 healthy controls underwent a conventional MRI and a DTI study in a 3-T MR scanner (Achieva((r)) 3 T X-Series; Philips Healthcare, Netherlands). RESULTS: In the control group, we were able to track and visualize the common sciatic nerve and its main branches from hip to foot. In the patient group, the affected sciatic nerves presented statistically significant lower fractional anisotropy values and higher apparent diffusion coefficient values when compared with controls, suggesting nerve damage. In all cases, DTI offered complementary information for diagnosis and/or confirmation of the suspected pathology. When compared with conventional MRI, DTI showed higher sensitivity for nerve damage detection. CONCLUSION: DTI offers a significant improvement and an important complement to visualize the sciatic nerve and its main branches. In patients with sciatic nerve pathology DTI allows to a better detection and characterization of the nerve damage. ADVANCES IN KNOWLEDGE: DTI enables in vivo dissection of the sciatic nerve white matter fibres; its use offers a significant improvement and complement to conventional MRI. PMID- 27459248 TI - Application of FLASH-3D dynamic contrast-enhanced imaging for diagnosis of endometrial carcinoma. AB - OBJECTIVE: To investigate the application and value of fast low-angle shot three dimensional (FLASH-3D) dynamic contrast-enhanced MRI for the pre-operative staging of endometrial carcinoma. METHODS: This prospective study enrolled 48 patients with complete clinical data and pathologically confirmed endometrial carcinoma from July 2012 to March 2014. After routine MRI examination, subjects underwent FLASH-3D dynamic contrast-enhanced examination. The dynamically enhanced features of the uterine wall and tumours were analyzed. FLASH-3D pre operative staging and findings in relation to myometrial invasion were compared with post-operative pathological results in a double-blind manner. RESULTS: There were 48 cases of pathologically proven endometrial carcinoma, including 34 patients with Stage I (Stage Ia 22 cases and Stage Ib 12 cases), 9 with Stage II, 3 with Stage III and 2 with Stage IV. The staging accuracy for endometrial carcinoma was 81% (39/48) using FLASH-3D dynamic contrast-enhanced sequences. The sensitivity, specificity and accuracy for the determination of deep myometrial invasion were 84%, 90% and 88%, respectively. There was no significant difference compared with the results of post-operative pathology (p > 0.05). CONCLUSION: FLASH-3D dynamic contrast-enhanced imaging may be valuable for the early diagnosis and pre-operative staging of endometrial carcinoma. Its high accuracy for assessing deep myometrial invasion makes FLASH-3D imaging an important tool for selecting the optimal therapeutic protocol and for prognosis estimation. ADVANCES IN KNOWLEDGE: FLASH-3D can significantly improve the accurate assessment of the depth of tumour invasion into the myometrium and may thus help to guide clinical surgical choices and post-operative evaluation. FLASH-3D is thus a promising technique for the routine examination of female pelvic tumours. PMID- 27459249 TI - Short-term follow-up MRI after unplanned resection of malignant soft-tissue tumours; quantitative measurements on dynamic contrast enhanced and diffusion weighted MR images. AB - OBJECTIVE: To determine the diagnostic availability of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MR images for evaluating residual tumours at short-term follow-up after unplanned excision of malignant soft-tissue tumours. METHODS: From January 2013 to September 2014, 38 patients underwent first follow up MRI, including DCE and DW imaging (DWI), within 3 months of unplanned malignant soft-tissue tumour excision. The presence or absence of definite nodule formation, focal fluid/haematoma collection, oedema and fascial thickening around or at tumour beds were evaluated using conventional MR images. The volume transfer constant between blood plasma and extracellular/extravascular space (EES) (Ktrans), rate constant between EES and blood plasma (Kep), volume of EES space per unit volume of tissue and initial area under the concentration curve (iAUC) values with time-concentration curve (TCC) plots were obtained on DCE images, and apparent diffusion coefficient (ADC) values were measured on ADC maps. All data were statistically analyzed. RESULTS: Of the 21 patients who underwent re-excision, 12 patients had a residual tumor and 9 did not. All conventional MRI variables, except definite nodule formation, were insignificantly related to the presence of residual tumour. However, ADC values were found to be significantly associated with the presence of residual tumour, as were the DCE MRI variables, Ktrans, Kep and iAUC. In particular, TCC pattern and Kep were most significantly associated with residual tumour. CONCLUSION: Additional DCE images may be useful for determining the presence of residual tumours in tumour beds during short-term follow-up after inadequate malignant soft-tissue tumour excision. ADVANCES IN KNOWLEDGE: The addition of DCE MRI and quantitative analysis of the images obtained might be useful for determining the presence of residual tumour in a tumour bed during short-term follow-up after inadequate excision of a malignant soft-tissue tumour, although DWI was also found to be helpful. PMID- 27459250 TI - Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model. AB - OBJECTIVE: To investigate the distribution and clearance of retained gadolinium (Gd) in various parts of the brain after intravenously administering a Gd-based contrast agent (GBCA) in normal and renal failure mouse models. METHODS: Two different mouse models: normal (n = 12) and renal failure (n = 12) were used. Clinical GBCAs (Gd-DTPA-BMA, 5 mmol kg(-1), or Gd-DOTA, 5 mmol kg(-1)) were intravenously administered five times per week for 4 weeks. Both groups were divided into two subgroups based on the time point for sample collection: 3 days (3d) and 45 days (45d) after the last injection. Normal saline (5 ml kg(-1)) was intravenously administered to mice of the control groups in the same manner. Samples of the following parts of the mouse brain were obtained on dissection: olfactory bulb, cerebral cortex, hippocampus, thalamus, mid-brain, cerebellum, pons and medulla. (158)Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry. RESULTS: The olfactory bulb had the highest Gd concentration in both Gd-DTPA-BMA and Gd-DOTA groups. Gd retention was higher in the Gd-DTPA-BMA group than in the Gd-DOTA group (p < 0.01). In the Gd DTPA-BMA group, Gd retention in the 3d subgroups of normal and renal failure models were similar (p = 0.4). At 45d, Gd in the Gd-DTPA-BMA group was not eliminated from the renal failure model (p = 0.1), while that in the Gd-DOTA group was eliminated from both the normal and renal failure mouse models (p < 0.01). CONCLUSION: Gd distributions in the brain for both groups were similar, regardless of the renal function and GBCA type. The Gd concentration was highest in the olfactory bulb of both groups. In the Gd-DOTA group, Gd was eliminated from the brain in both mouse models, while in the Gd-DTPA-BMA group, Gd clearance was limited. ADVANCES IN KNOWLEDGE: Gd concentration in the brain was not affected by renal function. The clearance of Gd from linear GBCA was limited in both the normal and impaired renal function mouse models. PMID- 27459251 TI - Erratum: Structural Ultrasound of the Medial Temporal Lobe in Alzheimer's Disease. PMID- 27459252 TI - A Partially Fluorinated, Water-Stable Cu(II)-MOF Derived via Transmetalation: Significant Gas Adsorption with High CO2 Selectivity and Catalysis of Biginelli Reactions. AB - A partially fluorinated, angular tetracarboxylic acid linker (H4L) incorporating a pendant amine moiety forms a three-dimensional Zn(II) framework, 1. The structure consists of paddle-wheel Zn2(CO2)4 secondary building units (SBUs) and Zn12(CO2)24 supramolecular building blocks (SBBs). Thermal stability of 1 is found to be low. However, it undergoes transmetalation reaction with Cu(II) at room temperature without losing crystallinity affording an isostructural framework, 1Cu. Framework 1Cu is thermally robust and allows generation of the solvent-free porous framework 1Cu' upon activation with coordinatively unsaturated metal centers. Framework 1Cu' exhibits water stability and at 77 K, adsorbs 2.56 wt % of H2 up to 1 bar that significantly increases to 4.01 wt % at 13 bar. Also, this framework gives a high adsorption of 164.70 cc/g of CH4 (11.7 wt %) at 303 K and 60 bar. The channel surfaces decorated with -NH2 group and unsaturated metal centers in 1Cu' allow a promising 36.4 wt % of CO2 adsorption at 1 bar and 273 K. Moreover, it exhibits pronounced selectivity of CO2 adsorption over N2 and H2 at 273 K. Finally, the versatility of 1Cu' is shown by its excellent heterogeneous catalytic activity in the Biginelli coupling reactions involving an aldehyde, urea, and ethylacetoacetate to afford dihydroprimidinones. PMID- 27459253 TI - Hydro-climatic forcing of dissolved organic carbon in two boreal lakes of Canada. AB - The boreal forest of the northern hemisphere represents one of the world's largest ecozones and contains nearly one third of the world's intact forests and terrestrially stored carbon. Long-term variations in temperature and precipitation have been implied in altering carbon cycling in forest soils, including increased fluxes to receiving waters. In this study, we use a simple hydrologic model and a 40-year dataset (1971-2010) of dissolved organic carbon (DOC) from two pristine boreal lakes (ELA, Canada) to examine the interactions between precipitation and landscape-scale controls of DOC production and export from forest catchments to surface waters. Our results indicate that a simplified hydrologically-based conceptual model can enable the long-term temporal patterns of DOC fluxes to be captured within boreal landscapes. Reconstructed DOC exports from forested catchments in the period 1901-2012 follow largely a sinusoidal pattern, with a period of about 37years and are tightly linked to multi-decadal patterns of precipitation. By combining our model with long-term precipitation estimates, we found no evidence of increasing DOC transport or in-lake concentrations through the 20th century. PMID- 27459254 TI - On the sources of PBDEs in coastal marine sediments off Baja California, Mexico. AB - Polybrominated diphenyl ethers (PBDEs) are widely distributed compounds in all types of matrices. In the northern portion of the Southern California Bight (SCB), there were reports of some of the largest PBDE concentrations in marine mammals and mussels. Because of this, we decided to analyze the status of PBDEs in the southern part of the SCB. An analysis of 91 samples of marine surface sediment was carried out. All of the 91 samples contained measurable amounts of PBDEs, which is a manifestation of the widespread distribution of these chemical substances. However, the levels detected are between one and two orders of magnitude smaller than those reported in southern California. Currents appear to control the distribution of PBDEs along the coast and the sedimentation sites with largest concentrations are favored by local bathymetry. Maximum concentrations were located in the middle and deeper platforms ranging from 0.02 to 5.90 (with a median 0.71) ng.g(-1) d.w. Deca-BDE mixture is largely predominant in the sediments followed by the penta-BDE mixture. The mass balance for the latitudinal strata shows the largest concentrations in the north where the largest population centers are present and with a very clear southward gradient. The mass balance calculation values showed about 36kg of PBDEs for the north, 22kg for the center, and 10kg for the south strata. In terms of depth, the PBDEs are mainly located on the middle and deep platforms rather than near point discharges, which is different than that reported by other authors. PMID- 27459255 TI - Association of land use and its change with beach closure in the United States, 2004-2013. AB - Land use and its change have great influences on water quality. However, their impacts on microbial contamination of beach water have rarely been investigated and their relationship with beach actions (e.g., advisories or closure) is still unknown. Here, we analyzed beach closure data obtained from 2004 to 2013 for >500 beaches in the United States, and examined their associations with land use around beaches in 2006 and 2011, as well as the land use change between 2006 and 2011. The results show that the number of beach closures due to elevated indicators of health risk is negatively associated with the percentages of forest, barren land, grassland and wetland, while positively associated with the percentages of urban area. The results from multi-level models also indicate the negative association with forest area but positive association with urban area and agriculture. The examination of the change of land use and the number of beach closures between 2006 and 2011 indicates that the increase in the number of beach closures is positively associated with the increase in urban (beta=1.612, p<0.05) and agricultural area including pasture (beta=0.098, p<0.05), but negatively associated with the increase in forest area (beta=-1.789, p<0.05). The study suggests that urbanization and agriculture development near beaches have adverse effects on beach microbial water quality, while afforestation may protect beach water quality and reduce the number of beach closures. PMID- 27459256 TI - Daphnia as a refuge for an antibiotic resistance gene in an experimental freshwater community. AB - Mechanisms that enable the maintenance of antibiotic resistance genes in the environment are still greatly unknown. Here we show that the tetracycline resistance gene tet(A) is largely removed from the pelagic aquatic bacterial community through filter feeding by Daphnia obtusa while it becomes detectable within the microbiome of the daphniids themselves, where it was not present prior to the experiment. We moreover show that a multitude of Daphnia-associated bacterial taxa are potential carriers of tet(A) and postulated that the biofilm like structures, where bacteria grow in, may enable horizontal transfer of such genes. This experiment highlights the need to take ecological interactions and a broad range of niches into consideration when studying and discussing the fate of antibiotic resistance genes in nature. PMID- 27459257 TI - Characteristics and outcomes of older adults with long-standing versus late-onset asthma. AB - OBJECTIVE: To examine the effect of age of onset on clinical characteristics and outcomes in a cohort of older patients with long-standing (LSA) and late-onset asthma (LOA). METHODS: In all, 452 patients 60 years of age and older with persistent asthma were recruited. We defined LOA as asthma developing at age 40 or later and LSA as developing before age 40. We compared airway obstruction as assessed by spirometry, as well as asthma control using the Asthma Control Questionnaire (ACQ), quality of life using the Mini Asthma Quality of Life Questionnaire (AQLQ), and asthma-related emergency department visits and hospitalizations among patients with LSA vs. LOA. RESULTS: Patients with LOA, were less likely to have FEV1 <70% of predicted (23% vs. 40%, p = 0.0002), to have FEV1/FVC<0.7 (27% vs. 38%, p = 0.01), or to have been intubated in the past (5% vs. 14%, p = 0.0007), and were also less likely to report a history of allergic conditions (64% vs 76%, p = 0.007). There was no significant difference in the level of asthma control, quality of life, or health care utilization. CONCLUSIONS: Older adults with LOA have different clinical and physiological characteristics and outcomes compared to those with LSA. Some of these differences may represent sequelae of longstanding disease, however LOA may also represent a different clinical phenotype that could influence management approaches. PMID- 27459264 TI - Internalized Stigma Among People Who Inject Drugs. AB - BACKGROUND: Perceived experiences of stigma have been found to be associated with poorer psychosocial outcomes and engagement in risk practices among people who inject drugs. Yet the extent to which people internalize or accept the stigma surrounding their injecting drug use, and whether this is associated with risky injecting practices, is not well known. OBJECTIVES: The aim of this study was to assess the extent of internalized stigma among a sample of people who inject drugs in Australia and identify socio-demographic, injecting risk, and mental health correlates. METHODS: People who inject drugs were recruited from a needle and syringe program located in Sydney, Australia to complete a brief survey. The survey included measures of internalized stigma, severity of drug dependence, self-esteem, depression, and shared use of injecting equipment. RESULTS: The sample comprised 102 people who inject drugs. Internalized stigma was higher among participants who reported being depressed in the past month, and was also associated with greater severity of drug dependence and diminished self-esteem. There was no relationship between internalized stigma and shared use of needles or other injecting equipment in the past month. Conclusions/Importance: Findings underscore the need for further investigation of internalized stigma among people who inject drugs. In particular, future research should assess the impact of implicit (i.e., subconscious) internalized stigma on mental health. PMID- 27459265 TI - Response to Wu et al. - Cost-effectiveness analysis of infant pneumococcal vaccination in Malaysia and Hong Kong. AB - A recently published paper that assessed the comparative cost-effectiveness of the 2 pneumococcal conjugate vaccines (PCVs) in Malaysia and Hong Kong reported that the 13-valent PCV vaccine (PCV13) is a better choice compared to the 10 valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV or PCV10) from both a payer and societal perspective as well as under various scenarios. However, the analysis relied on a large number of assumptions that were either erroneous or did not take into account the most recent body of evidence available. A rigorous evaluation of the underlying assumptions is necessary to present a fair and balanced analysis for decision making. PMID- 27459267 TI - Association of inflammatory bowel disease with ankylosing spondylitis and rheumatoid arthritis: A nationwide population-based study. AB - OBJECTIVES: Tantalizing connections between autoimmune rheumatic diseases (ARDs) and inflammatory bowel disease (IBD) have become evident with regard to their genetic and immunologic background. However, the association between these two disease entities remains unclear. The aim of this study is to investigate the association between each ARD and IBD. METHODS: A nationwide population-based cross-sectional study was performed using the Korean National Health Insurance Claims database. The data of patients with IBD and age- and sex-matched controls between 2009 and 2013 were collected from the database. The prevalence of ARDs, including systemic lupus erythematosus (SLE), inflammatory myositis (polymyositis and dermatomyositis), systemic sclerosis (SSc), Sjogren's syndrome (SjS), ankylosing spondylitis (AS), and rheumatoid arthritis (RA), was determined. The associations between each ARD and IBD were analyzed using multivariate logistic regression models. RESULTS: A total of 40,843 IBD patients (28,197 patients with ulcerative colitis and 12,646 with Crohn's disease) and 122,529 controls were enrolled. The nonstratified analysis revealed that patients with IBD had significant risk of being concomitantly affected by AS (odds ratio [OR] 5.140, 95% confidence interval [95% CI] 4.069-6.492) and RA (OR: 3.474, 95% CI: 2.671 4.519) after adjusting for age and sex. No significant association was observed between IBD and other ARDs including SLE, inflammatory myositis, SSc, and SjS. CONCLUSION: IBD is significantly associated with AS and RA in the large-scaled population-based study. This result suggests that etiopathogenesis of IBD might be shared with AS and RA. PMID- 27459266 TI - Cytokine Profile of Children Hospitalized with Virologically-Confirmed Dengue during Two Phase III Vaccine Efficacy Trials. AB - BACKGROUND: Two large-scale efficacy studies with the recombinant yellow fever 17D-dengue virus, live-attenuated, tetravalent dengue vaccine (CYD-TDV) candidate undertaken in Asia (NCT01373281) and Latin America (NCT01374516) demonstrated significant protection against dengue disease during two years' active surveillance (active phase). Long-term follow up of participants for breakthrough disease leading to hospitalization is currently ongoing (hospital phase). METHODOLOGY/PRINCIPAL FINDINGS: We assessed the cytokine profile in acute sera from selected participants hospitalized (including during the active phase) up to the beginning of the second year of long-term follow up for both studies. The serum concentrations of 38 cytokines were measured in duplicate using the Milliplex Human Cytokine MAGNETIC BEAD Premixed 38 Plex commercial kit (Millipore, Billerica, MA, USA). Partial least squares discriminant analyses did not reveal any difference in the overall cytokine profile of CYD-TDV and placebo recipients hospitalized for breakthrough dengue regardless of stratification used. In addition, there was no difference in the cytokine profile for breakthrough dengue among those aged <9 years versus those aged >= 9 years. CONCLUSIONS/SIGNIFICANCE: These exploratory findings show that CYD-TDV does not induce a particular immune profile versus placebo, corroborating the clinical profile observed. PMID- 27459268 TI - Quantum Confinement of Surface Electrons by Molecular Nanohoop Corrals. AB - Quantum confinement of two-dimensional surface electronic states has been explored as a way for controllably modifying the electronic structures of a variety of coinage metal surfaces. In this Letter, we use scanning tunneling microscopy and spectroscopy (STM/STS) to study the electron confinement within individual ring-shaped cycloparaphenylene (CPP) molecules forming self-assembled films on Ag(111) and Au(111) surfaces. STM imaging and STS mapping show the presence of electronic states localized in the interiors of CPP rings, inconsistent with the expected localization of molecular electronic orbitals. Electronic energies of these states show considerable variations correlated with the molecular shape. These observations are explained by the presence of localized states formed due to confinement of surface electrons by the CPP skeletal framework, which thus acts as a molecular electronic "corral". Our experiments suggest an approach to robust large-area modification of the surface electronic structure via quantum confinement within molecules forming self assembled layers. PMID- 27459269 TI - Microstrain distribution mapping on CuInSe2 thin films by means of electron backscatter diffraction, X-ray diffraction, and Raman microspectroscopy. AB - The investigation of the microstructure in functional, polycrystalline thin films is an important contribution to the enhanced understanding of structure-property relationships in corresponding devices. Linear and planar defects within individual grains may affect substantially the performance of the device. These defects are closely related to strain distributions. The present work compares electron and X-ray diffraction as well as Raman microspectroscopy, which provide access to microstrain distributions within individual grains. CuInSe2 thin films for solar cells are used as a model system. High-resolution electron backscatter diffraction and X-ray microdiffraction as well as Raman microspectroscopy were applied for this comparison. Consistently, microstrain values were determined of the order of 10(-4) by these three techniques. However, only electron backscatter diffraction, X-ray microdiffraction exhibit sensitivities appropriate for mapping local strain changes at the submicrometer level within individual grains in polycrystalline materials. PMID- 27459271 TI - Yeast cell surface display: An efficient strategy for improvement of bioethanol fermentation performance. AB - The cell surface serves as a functional interface between the inside and the outside of the cell. Within the past 20 y the ability of yeast (Saccharomyces cerevisiae) to display heterologous proteins on the cell surface has been demonstrated. Furthermore, S. cerevisiae has been both developed and applied in expression of various proteins on the cell surface. Using this novel and useful strategy, proteins and peptides of various kinds can be displayed on the yeast cell surface by fusing the protein of interest with the glycosylphosphatidylinositol (GPI)-anchoring system. Consolidated bioprocessing (CBP) using S. cerevisiae represents a promising technology for bioethanol production. However, further work is needed to improve the fermentation performance. There is some excellent previous research regarding construction of yeast biocatalyst using the surface display system to decrease cost, increase efficiency of ethanol production and directly utilize starch or biomass for fuel production. In this commentary, we reviewed the yeast surface display system and highlighted recent work. Additionally, the strategy for decrease of phytate phosphate content in dried distillers grains with solubles (DDGS) by display of phytase on the yeast cell surface is discussed. PMID- 27459272 TI - Importance of Addressing Driving with Older Adults in Primary Care and the Role of Occupational Therapy. PMID- 27459270 TI - A novel intrinsically disordered outer membrane lipoprotein of Aggregatibacter actinomycetemcomitans binds various cytokines and plays a role in biofilm response to interleukin-1beta and interleukin-8. AB - Intrinsically disordered proteins (IDPs) do not have a well-defined and stable 3 dimensional fold. Some IDPs can function as either transient or permanent binders of other proteins and may interact with an array of ligands by adopting different conformations. A novel outer membrane lipoprotein, bacterial interleukin receptor I (BilRI) of the opportunistic oral pathogen Aggregatibacter actinomycetemcomitans binds a key gatekeeper proinflammatory cytokine interleukin (IL)-1beta. Because the amino acid sequence of the novel lipoprotein resembles that of fibrinogen binder A of Haemophilus ducreyi, BilRI could have the potential to bind other proteins, such as host matrix proteins. However, from the tested host matrix proteins, BilRI interacted with neither collagen nor fibrinogen. Instead, the recombinant non-lipidated BilRI, which was intrinsically disordered, bound various pro/anti-inflammatory cytokines, such as IL-8, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and IL-10. Moreover, BilRI played a role in the in vitro sensing of IL-1beta and IL-8 because low concentrations of cytokines did not decrease the amount of extracellular DNA in the matrix of bilRI- mutant biofilm as they did in the matrix of wild-type biofilm when the biofilms were exposed to recombinant cytokines for 22 hours. BilRI played a role in the internalization of IL-1beta in the gingival model system but did not affect either IL-8 or IL-6 uptake. However, bilRI deletion did not entirely prevent IL-1beta internalization, and the binding of cytokines to BilRI was relatively weak. Thus, BilRI might sequester cytokines on the surface of A. actinomycetemcomitans to facilitate the internalization process in low local cytokine concentrations. PMID- 27459273 TI - Similar Impact of Clopidogrel or Ticagrelor on Carotid Atherosclerotic Plaque Inflammation. AB - BACKGROUND: Platelets play an important role in inflammation. Inhibitors of the P2Y12 receptor, which is involved in platelet activation, may have a direct effect on carotid atherosclerotic plaque inflammation. HYPOTHESIS: We compared the effects of clopidogrel and ticagrelor therapy for carotid atherosclerotic plaque inflammation using 18 F-fluorodeoxyglucose ( 18 FDG) positron emission tomography (PET) imaging. METHODS: Fifty patients with acute coronary syndrome and >=1 18 FDG uptake in the carotid artery (target-to-background ratio [TBR] >=1.6) were randomized to either clopidogrel or ticagrelor groups. Of these, 46 completed PET examinations at baseline and at 6 months. The primary endpoint was the percent change in TBR of the index vessel at the most diseased segment (MDS). RESULTS: Baseline characteristics were similar between the 2 groups. At 6-month follow-up, low-density lipoprotein cholesterol and C-reactive protein significantly decreased in both groups (P < 0.001). The TBR of the index vessel and aorta significantly decreased in both groups (P < 0.01). The percent change in the MDS TBR of the index vessel was numerically but not significantly lower in the clopidogrel group than in the ticagrelor group (-9.5 +/- 14.6% vs -13.5 +/- 19.3%; P = 0.427). Likewise, the percent change in the whole-vessel TBR of the index vessel was not different between the 2 groups (P = 0.166). Similar findings were observed for changes in the MDS TBR (P = 0.412) or whole-vessel TBR of the aorta (P = 0.363). CONCLUSIONS: Carotid atherosclerotic plaque inflammation significantly decreases to a similar degree following 6 months of either clopidogrel or ticagrelor treatment. PMID- 27459274 TI - Catalytic Carbonylative Spirolactonization of Hydroxycyclopropanols. AB - A palladium-catalyzed cascade carbonylative spirolactonization of hydroxycyclopropanols has been developed to efficiently synthesize oxaspirolactones common to many complex natural products of important therapeutic value. The mild reaction conditions, high atom economy, broad substrate scope, and scalability of this new method were highlighted in expedient total syntheses of the Turkish tobacco natural products alpha-levantanolide and alpha levantenolide in two and four steps, respectively. The hydroxycyclopropanol substrates are readily available in one step via a Kulinkovich reaction of the corresponding lactones. Mechanistic studies utilizing high-resolution electrospray ionization mass spectrometry (ESI-MS) identified several key intermediates in the catalytic cycle, as well as those related to catalyst decomposition and competitive pathways. PMID- 27459275 TI - ATP-binding cassette transmembrane transporters and their epigenetic control in cancer: an overview. AB - INTRODUCTION: Members of the ATP-binding cassette (ABC) transmembrane transporters control the passage of several substrates across cell membranes, including drugs. This means that ABC transporters may exert a significant influence on the kinetics and dynamics of pharmacological agents, being responsible for the occurrence of multidrug-resistant (MDR) phenotype. Pharmacogenetic analyses have shed light on gene expression and polymorphisms as possible markers predictive of transporter activity. However, a non-negligible part of the variability in drug pharmacokinetics and pharmacodynamics still remains. Further research has demonstrated that different epigenetic mechanisms exert a coordinated control over ABC genes, and on the corresponding MDR phenotype. Areas covered: DNA methylation and histone modifications (namely acetylation, methylation, phosphorylation, etc.) significantly impact gene expression, as well as noncoding RNA molecules that are involved in the post transcriptional control of the ABC transporters ABCB1, ABCC1 and ABCG2. We describe the epigenetic mechanisms of gene expression control for ABC transporters and their relevant association with the MDR phenotype in human cancer. Expert opinion: The clinical meaning of those observations is discussed in the review, highlighting the importance of the epigenetic control of the ABC transporters for the clinical therapeutic outcomes that despite their effects and applications, requires further investigation. PMID- 27459276 TI - Obesity and health-related decisions: An empirical model of the determinants of weight status across the transition from adolescence to young adulthood. AB - We estimate a structural dynamic model of the determinants of obesity. In addition to including many of the well-recognized endogenous factors mentioned in the literature as obesity determinants, we also model the individual's residential location as a choice variable, which is the main contribution of this paper to the literature. This allows us to control for an individual's self selection into communities that possess the types of amenities in the built environment, which in turn affect their obesity-related behaviors such as physical activity (PA) and fast food consumption. We specify reduced form equations for a set of endogenous demand decisions, together with an obesity structural equation. The whole system of equations is jointly estimated by a semi parametric full information log-likelihood method that allows for a general pattern of correlation in the errors across equations. Our model predicts a reduction in adult obesity of 7 percentage points as a result of a continued high level PA from adolescence into adulthood; a reduction of 0.7 (3) percentage points in adult obesity as a result of one standard deviation reduction in weekly fast food consumption for women (men); and a reduction of 0.02 (0.05) in adult obesity as a result of one standard deviation change in several neighborhood amenities for women (men). Another key finding is that controlling for residential self-selection has substantive implications. To our knowledge, this has not been yet documented within a full information maximum likelihood framework. PMID- 27459278 TI - Asymmetric Synthesis of Chiral alpha-Methyl-alpha,beta-diamino Acid Derivatives via Group-Assisted Purification Chemistry Using N-Phosphonyl Imines and a Ni(II) Complexed Alanine Schiff Base. AB - The Mannich reaction between chiral N-phosphonyl imines and a Ni(II)-complexed alanine Schiff base (Ala-Ni) is reported. With a chiral phosphonyl auxiliary, a single isomer of alpha-methyl-alpha,beta-diamino acid derivative containing vicinal chiral centers, including a chiral quaternary carbon center, can be obtained simply by washing the crude mixture with cosolvents. The absolute stereochemistry of the enantiomerically pure product has been unambiguously determined by X-ray crystallographic analysis. PMID- 27459277 TI - Dual-Modality Positron Emission Tomography/Optical Image-Guided Photodynamic Cancer Therapy with Chlorin e6-Containing Nanomicelles. AB - Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise in nanomedicine. Herein, we develop an organic photodynamic therapy (PDT) system based on polyethylene glycol (PEG)-coated nanomicelles conjugated with ~20% chlorin e6 (PEG-Ce 6 nanomicelles), which functions as an optical imaging agent, as well as a PDT agent. The formed PEG-Ce 6 nanomicelles with the size of ~20 nm were highly stable in various physiological solutions for a long time. Moreover, Ce 6 can also be a (64)Cu chelating agent for in vivo positron emission tomography (PET). By simply mixing, more than 90% of (64)Cu was chelator-free labeled on PEG-Ce 6 nanomicelles, and they also showed high stability in serum conditions. Both fluorescence imaging and PET imaging revealed that PEG-Ce 6 nanomicelles displayed high tumor uptake (13.7 +/- 2.2%ID/g) after intravenous injection into tumor-bearing mice at the 48 h time point. In addition, PEG-Ce 6 nanomicelles exhibited excellent PDT properties upon laser irradiation, confirming the theranostic properties of PEG-Ce 6 nanomicelles for imaging and treatment of cancer. In addition, PDT was not shown to render any appreciable toxicity. This work presents a theranostic platform based on polymer nanomicelles with great potential in multimodality imaging-guided photodynamic cancer therapy. PMID- 27459279 TI - Genetic Structure of Water Chestnut Beetle: Providing Evidence for Origin of Water Chestnut. AB - Water chestnut beetle (Galerucella birmanica Jacoby) is a pest of the water chestnut (Trapa natans L.). To analyze the phylogeny and biogeography of the beetle and provide evidence for the origin of T. natans in China, we conducted this by using three mitochondrial genes (COI, COII and Cytb) and nuclear ITS2 ribosomal DNA of G. birmanica. As for mtDNA genes, the beetle could be subdivided into three groups: northeastern China (NEC), central-northern-southern China (CC NC-SC) and southwestern China (SWC) based on SAMOVA, phylogenetic analyses and haplotype networks. But for ITS2, no obvious lineages were obtained but individuals which were from NEC region clustered into one clade, which might be due to sequence conservation of ITS2. Significant genetic variation was observed among the three groups with infrequent gene flow between groups, which may have been restricted due to natural barriers and events in the Late Pleistocene. Based on our analyses of genetic variation in the CC-NC-SC geographical region, the star-like haplotype networks, approximate Bayesian computation, niche modelling and phylogeographic variation of the beetle, we concluded that the beetle population has been lasting in the lower, central reaches of the Yangtze River Basin with its host plant, water chestnut, which is consistent with archaeological records. Moreover, we speculate that the CC-NC-SC population of G. birmanica may have undergone a period of expansion coincident with domestication of the water chestnut approximately 113,900-126,500 years ago. PMID- 27459293 TI - A New Method for Nonlocal Means Image Denoising Using Multiple Images. AB - The basic principle of nonlocal means is to denoise a pixel using the weighted average of the neighbourhood pixels, while the weight is decided by the similarity of these pixels. The key issue of the nonlocal means method is how to select similar patches and design the weight of them. There are two main contributions of this paper: The first contribution is that we use two images to denoise the pixel. These two noised images are with the same noise deviation. Instead of using only one image, we calculate the weight from two noised images. After the first denoising process, we get a pre-denoised image and a residual image. The second contribution is combining the nonlocal property between residual image and pre-denoised image. The improved nonlocal means method pays more attention on the similarity than the original one, which turns out to be very effective in eliminating gaussian noise. Experimental results with simulated data are provided. PMID- 27459294 TI - Proton Affinity of Isomeric Dipeptides Containing Lysine and Non-Proteinogenic Lysine Homologues. AB - Conformational effects on the proton affinity of oligopeptides have been studied using six alanine (A)-based acetylated dipeptides containing a basic probe that is placed closest to either the C- or the N-terminus. The basic probe includes Lysine (Lys) and two nonproteinogenic Lys-homologues, ornithine (Orn) and 2,3 diaminopropionic acid (Dap). The proton affinities of the peptides have been determined using the extended Cooks kinetic method in a triple quadrupole mass spectrometer. Computational studies have been carried out to search for the lowest energy conformers and to calculate theoretical proton affinities as well as various molecular properties using the density functional theory. The dipeptides containing a C-terminal probe, ALys, AOrn, and ADap, were determined to have a higher proton affinity by 1-4 kcal/mol than the corresponding dipeptides containing an N-terminal probe, LysA, OrnA, and DapA. For either the C probe peptides or the N-probe peptides, the proton affinity reduces systematically as the side-chain of the probe residue is shortened. The difference in the proton affinities between isomeric peptides is largely associated with the variation of the conformations. The peptides with higher values of the proton affinity adopt a relatively compact conformation such that the protonated peptides can be stabilized through more efficient internal solvation. PMID- 27459295 TI - Spectroscopic Survey of Electronic Transitions of C6H, (13)C6H, and C6D. PMID- 27459296 TI - Salvage surgery after head and neck squamous cell carcinoma treated with bioradiotherapy. AB - BACKGROUND: The purpose of this study was to describe the results and complications of primary site salvage surgery after head and neck squamous cell carcinoma (HNSCC) treated with bioradiotherapy. METHODS: We conducted a retrospective chart review of 268 patients treated with bioradiotherapy between March 2006 and December 2013 at the Hospital Universitari de Bellvitge-ICO. RESULTS: Fifty-nine patients developed local recurrence or had residual disease with a 1-year and 3-year overall survival of 47% and 15.4%, respectively. Salvage surgery was feasible in 22 patients (37.3%). There were 16 complications in these 22 patients (72.7%), 11 (50%) of which were major. Bilateral neck dissection was identified as a risk factor for complications. CONCLUSION: Salvage surgery after bioradiotherapy is associated with a high rate of complications. Neck dissection seems to be related to an increased rate of complications with no survival improvement. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 116-121, 2017. PMID- 27459297 TI - Trends in One-Year Outcomes of Dialysis-Requiring Acute Kidney Injury in Denmark 2005-2012: A Population-Based Nationwide Study. AB - BACKGROUND: Dialysis-requiring acute kidney injury (AKI) is associated with substantial mortality and risk of end-stage renal disease (ESRD). Despite considerable growth in incidence of severe AKI, information pertaining to trends in outcomes remains limited. We evaluated time trends in one year risks of ESRD and death in patients with dialysis-requiring AKI over an eight year period in Denmark. METHODS: In a retrospective nationwide study based on national registers, all adults requiring acute renal replacement therapy between 2005 and 2012 were identified. Patients with preceding ESRD were excluded. Through individual-level cross-referencing of administrative registries, information pertaining to comorbidity, preceding surgical interventions, and concurrent other organ failure and sepsis was ascertained. Comparisons of period-specific one year odds ratios for ESRD and death were calculated in a multiple logistic regression model. RESULTS: A total of 13,819 patients with dialysis-requiring AKI were included in the study. Within one year, 1,017 (7.4%) patients were registered with ESRD, and 7,908 (57.2%) patients died. The one-year rate of ESRD decreased from 9.0% between 2005 and 2006 to 6.1% between 2011 and 2012. Simultaneously, the one-year mortality rate decreased from 58.2% between 2005 and 2006 to 57.5% between 2011 and 2012. Consequently, the adjusted odds ratios for the period 2011 2012 (with the period 2005-2006 as reference) were 0.75 (0.60-0.95, p = 0.015) and 0.87 (95% CI 0.78-0.97, p = 0.010) for ESRD and death, respectively. CONCLUSIONS: In a nationwide retrospective study on time trends in one year outcomes following dialysis-requiring AKI, risk of all-cause mortality and ESRD decreased over a period of 8 years. PMID- 27459298 TI - A Selective Irreversible Inhibitor of Furin Does Not Prevent Pseudomonas Aeruginosa Exotoxin A-Induced Airway Epithelial Cytotoxicity. AB - Many bacterial and viral pathogens (or their toxins), including Pseudomonas aeruginosa exotoxin A, require processing by host pro-protein convertases such as furin to cause disease. We report the development of a novel irreversible inhibitor of furin (QUB-F1) consisting of a diphenyl phosphonate electrophilic warhead coupled with a substrate-like peptide (RVKR), that also includes a biotin tag, to facilitate activity-based profiling/visualisation. QUB-F1 displays greater selectivity for furin, in comparison to a widely used exemplar compound (furin I) which has a chloromethylketone warhead coupled to RVKR, when tested against the serine trypsin-like proteases (trypsin, prostasin and matriptase), factor Xa and the cysteine protease cathepsin B. We demonstrate QUB-F1 does not prevent P. aeruginosa exotoxin A-induced airway epithelial cell toxicity; in contrast to furin I, despite inhibiting cell surface furin-like activity to a similar degree. This finding indicates additional proteases, which are sensitive to the more broad-spectrum furin I compound, may be involved in this process. PMID- 27459299 TI - Healthy ageing of cloned sheep. AB - The health of cloned animals generated by somatic-cell nuclear transfer (SCNT) has been of concern since its inception; however, there are no detailed assessments of late-onset, non-communicable diseases. Here we report that SCNT has no obvious detrimental long-term health effects in a cohort of 13 cloned sheep. We perform musculoskeletal assessments, metabolic tests and blood pressure measurements in 13 aged (7-9 years old) cloned sheep, including four derived from the cell line that gave rise to Dolly. We also perform radiological examinations of all main joints, including the knees, the joint most affected by osteoarthritis in Dolly, and compare all health parameters to groups of 5-and 6 year-old sheep, and published reference ranges. Despite their advanced age, these clones are euglycaemic, insulin sensitive and normotensive. Importantly, we observe no clinical signs of degenerative joint disease apart from mild, or in one case moderate, osteoarthritis in some animals. Our study is the first to assess the long-term health outcomes of SCNT in large animals. PMID- 27459300 TI - Expression of a Recombinant Anti-HIV and Anti-Tumor Protein, MAP30, in Nicotiana tobacum Hairy Roots: A pH-Stable and Thermophilic Antimicrobial Protein. AB - In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP) with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents. PMID- 27459301 TI - A Rare Variant of Turner Syndrome in Four Sequential Generations: Effect of the Interplay of Growth Hormone Treatment and Estrogens on Body Proportion. AB - BACKGROUND: Terminal Xp deletion leads to SHOX haploinsufficiency, and when it exceeds Xp22.33 it causes a variant of Turner syndrome (TS) in which gonadal function is preserved and short stature constitutes the major clinical feature. CASE REPORT: We present a family with vertical transmission of TS that affected six women in four sequential generations. The karyotype was defined as a combination of terminal Xp deletion and terminal Xq duplication: 46,X,rec(X)inv(p21.1q27.3). All affected women had short stature, but had developed spontaneous puberty and normal fertility. Generation IV exclusively received recombinant human growth hormone (rhGH). We investigated the effect of rhGH treatment on skeletal growth and body proportion via the comparison of auxological data from an untreated 39.7-year-old mother to her 14.8-year-old rhGH treated daughter. The adult height of the daughter was substantially better than that of the mother [160.3 cm (-0.8 SDS) and 150.0 cm (-2.7 SDS), respectively]; however, the disproportion progressed following rhGH treatment and ultimately led to a worse trunk-to-extremities ratio compared with the mother (4.8 and 3.7 SDS, respectively). CONCLUSION: This rare family confirms the vertical transmission of TS spanning multiple generations. The combination of endogenous estrogen production and exogenous rhGH administration in women with SHOX haploinsufficiency may worsen their body disproportion. PMID- 27459303 TI - Patterns of Assemblage Structure Indicate a Broader Conservation Potential of Focal Amphibians for Pond Management. AB - Small freshwater ponds host diverse and vulnerable biotic assemblages but relatively few conspicuous, specially protected taxa. In Europe, the amphibians Triturus cristatus and Pelobates fuscus are among a few species whose populations have been successfully restored using pond restoration and management activities at the landscape scale. In this study, we explored whether the ponds constructed for those two target species have wider conservation significance, particularly for other species of conservation concern. We recorded the occurrence of amphibians and selected aquatic macro-invertebrates (dragonflies; damselflies; diving beetles; water scavenger beetles) in 66 ponds specially constructed for amphibians (up to 8 years post construction) and, for comparison, in 100 man-made ponds (created by local people for cattle or garden watering, peat excavation, etc.) and 65 natural ponds in Estonia. We analysed nestedness of the species assemblages and its dependence on the environment, and described the co occurrence patterns between the target amphibians and other aquatic species. The assemblages in all ponds were significantly nested, but the environmental determinants of nestedness and co-occurrence of particular species differed among pond types. Constructed ponds were most species-rich irrespective of the presence of the target species; however, T. cristatus was frequent in those ponds and rare elsewhere, and it showed nested patterns in every type of pond. We thus conclude that pond construction for the protected amphibians can serve broader habitat conservation aims in the short term. However, the heterogeneity and inconsistent presence of species of conservation concern observed in other types of ponds implies that long-term perspectives on pond management require more explicit consideration of different habitat and biodiversity values. We also highlight nestedness analysis as a tool that can be used for the practical task of selecting focal species for habitat conservation. PMID- 27459304 TI - Hexa-peri-hexabenzocoronene with Different Acceptor Units for Tuning Optoelectronic Properties. AB - Hexa-peri-hexabenzocoronene (HBC)-based donor-acceptor dyads were synthesized with three different acceptor units, through two pathways: 1) "pre functionalization" of monobromo-substituted hexaphenylbenzene prior to the cyclodehydrogenation; and 2) "post-functionalization" of monobromo-substituted HBC after the cyclodehydrogenation. The HBC-acceptor dyads demonstrated varying degrees of intramolecular charge-transfer interactions, depending on the attached acceptor units, which allowed tuning of their photophysical and optoelectronic properties, including the energy gaps. The two synthetic pathways described here can be complementary and potentially be applied for the synthesis of nanographene acceptor dyads with larger aromatic cores, including one-dimensionally extended graphene nanoribbons. PMID- 27459302 TI - Aversive Behavior in the Nematode C. elegans Is Modulated by cGMP and a Neuronal Gap Junction Network. AB - All animals rely on their ability to sense and respond to their environment to survive. However, the suitability of a behavioral response is context-dependent, and must reflect both an animal's life history and its present internal state. Based on the integration of these variables, an animal's needs can be prioritized to optimize survival strategies. Nociceptive sensory systems detect harmful stimuli and allow for the initiation of protective behavioral responses. The polymodal ASH sensory neurons are the primary nociceptors in C. elegans. We show here that the guanylyl cyclase ODR-1 functions non-cell-autonomously to downregulate ASH-mediated aversive behaviors and that ectopic cGMP generation in ASH is sufficient to dampen ASH sensitivity. We define a gap junction neural network that regulates nociception and propose that decentralized regulation of ASH signaling can allow for rapid correlation between an animal's internal state and its behavioral output, lending modulatory flexibility to this hard-wired nociceptive neural circuit. PMID- 27459305 TI - The theory and application of space microbiology: China's experiences in space experiments and beyond. AB - Microorganisms exhibit high adaptability to extreme environments of outer space via phenotypic and genetic changes. These changes may affect astronauts in the space environment as well as on Earth because mutant microbes will inevitably return with the spacecraft. However, the role and significance of these phenotypic changes and the underlying mechanisms are important unresolved questions in the field of space biology. By reviewing, especially the Chinese studies, we propose a space microbial molecular effect theory, that is, the space environment affects the nature of genes and the molecular structure of microorganisms to produce phenotypic changes. In this review, we discussed three basic theories for the research of space microbiology, including (1) space microbial pathogenicity and virulence mutations and the human mutualism theory; (2) space microbial drug-resistance mutations and metabolism associated with space pharmaceuticals theory; (3) space corrosion, microbial decontamination, and new materials technology theory. PMID- 27459306 TI - Is Time an Important Problem in Management of Hypertension and Hypercholesterolemia by Using an Amlodipine-Atorvastatin Single Pill Combination? AB - BACKGROUND Is the timing of dosing for amlodipine and atorvastatin important with regard to therapeutic efficacy? To answer this question, we designed an outpatient, practice-based, case-control study lasting 8 weeks. MATERIAL AND METHODS Two hundred patients were divided into 2 groups: in Group I, patients were provided with a single pill containing amlodipine/atorvastatin (5/20 mg) to be taken each night at 10 pm, and in Group II, patients were taking amlodipine (5 mg) and atorvastatin (20 mg) each morning at 7 am. RESULTS Our results indicated no obvious difference in blood pressure control between the 2 groups. Taking amlodipine at night not only lowered blood pressure, but it also provided better control during the peak blood pressure in the morning. Hypercholesterolemia control in the 2 groups was also not significantly different, taking atorvastatin in the morning was as effective as dosing at night in patients with hypercholesterolemia. While the carotid IMT, hs-CRP, and LVMI were significantly lower after treatment, no differences were found between the 2 groups. Although no obvious difference was found in adverse drug reactions between the 2 groups, compliance was much better in the single-pill group than in patients taking the 2 medications separately. CONCLUSIONS In conclusion, single-pill amlodipine atorvastatin taken at night can lower blood pressure and reduce the morning peak blood pressure levels the next day. Additionally, this dosing method could improve patient adherence to the therapy. PMID- 27459307 TI - Correction: Developing a Triple Transgenic Cell Line for High-Efficiency Porcine Reproductive and Respiratory Syndrome Virus Infection. AB - [This corrects the article DOI: 10.1371/journal.pone.0154238.]. PMID- 27459308 TI - Patchy Supramolecular Bottle-Brushes Formed by Solution Self-Assembly of Bis(urea)s and Tris(urea)s Decorated by Two Incompatible Polymer Arms. AB - In an attempt to design urea-based Janus nanocylinders through a supramolecular approach, nonsymmetrical bis(urea)s and tris(urea)s decorated by two incompatible polymer arms, namely, poly(styrene) (PS) and poly(isobutylene) (PIB), were synthesized using rather straightforward organic and polymer chemistry techniques. Light scattering experiments revealed that these molecules self assembled in cyclohexane by cooperative hydrogen bonds. The extent of self assembly was limited for the bis(urea)s. On the contrary, reasonably anisotropic 1D structures (small nanocylinders) could be obtained with the tris(urea)s (Nagg ~ 50) which developed six cooperative hydrogen bonds per molecule. (1)H transverse relaxation measurements and NOESY NMR experiments in cyclohexane revealed that perfect Janus nanocylinders with one face consisting of only PS and the other of PIB were not obtained. Nevertheless, phase segregation between the PS and PIB chains occurred to a large extent, resulting in patchy cylinders containing well separated domains of PIB and PS chains. Reasons for this behavior were proposed, paving the way to improve the proposed strategy toward true urea based supramolecular Janus nanocylinders. PMID- 27459309 TI - An Examination of the Surface and Sub-Surface of Modern and Historical Platinum Photographic Prints Using Low Vacuum High-Resolution Scanning Electron Microscopy. AB - Photographic prints of platinum metal on paper supports are some of the most exquisite and expressive in the world of fine art photography. Platinum prints were produced from about 1890 to 1920 in the USA and Europe. The chemical and material nature of these valuable prints is of great interest to many who are interested in their long-term preservation, in the intersection of science and art, and in the scientific and technical study of cultural heritage. This paper presents the results of a characterization study using newer electron microscopy techniques. In this study, a low vacuum high-resolution scanning electron microscope was used to study the surface and sub-surface of historic and modern platinum and/or palladium print samples. Using environmental SEM pressures allowed us to investigate the actual top surface and sub-surface with cross sections without any preparation; no coatings of carbon or other material. Cross sections were prepared using an argon plasma cross-polishing system. This study shows that the photographic image of platinum prints is composed of platinum nanoparticles embedded in the upper layers of the paper's cellulosic fibers. PMID- 27459310 TI - Perceived Support From Multiple Sources: Associations With PTSD Symptoms. AB - Perceived social support is negatively associated with severity of posttraumatic stress disorder (PTSD), but the literature lacks data about specific sources of support. Using 2 service member (SM) samples (n = 207 and 465), this study examined perceived support from family/friends and the broader public. SMs perceived high support from both sources. In multivariate regressions, perceived support from the broader public was not significantly associated with severity of PTSD symptoms, but it demonstrated a nearly identical effect size (beta = -.21) as support from family/friends (beta = -.23) in a sample of active duty and National Guard/Reserve SMs. We found that, SMs perceived high levels of support from the broader public, with modest evidence that such perceptions may relate to severity of PTSD. PMID- 27459311 TI - Family history and the risk of colorectal cancer: The importance of patients' history of colonoscopy. AB - Registry-based studies on the risk of colorectal cancer (CRC) for persons with a family history (FH) typically did not control for important covariates, such as history of colonoscopy. We aimed to quantify the association between FH and CRC risk, carefully accounting for potential confounders. We conducted a population based case-control study in Germany. A total of 4,313 patients with a first diagnosis of CRC (cases) and 3,153 controls recruited from 2003 to 2014 were included. We used multiple logistic regression analyses to assess the association between FH and risk of CRC with odds ratios (OR) and the resulting 95% confidence intervals (95% CI). A total of 582 cases (13.5%) and 321 (10.2%) controls reported a history of CRC in a first-degree relative, which was associated with a 41% increase in risk of CRC (OR: 1.41, 95% CI 1.22-1.63) after adjustment for sex and age. The OR substantially increased to 1.73 (95% CI, 1.48-2.03) after comprehensive adjustment including previous colonoscopies. Irrespective of their FH status, persons with history of colonoscopies had a lower CRC risk compared with persons without previous colonoscopies and without family history (OR: 0.25, 95% CI, 0.22-0.28 for persons without FH and OR 0.45, 95% CI, 0.36-0.56 for persons with FH). In an era of widespread use of colonoscopy, adjusting for previous colonoscopy is therefore crucial for deriving valid estimates of FH related CRC risk. Colonoscopy reduces the risk of CRC among those with FH far below levels of people with no FH and no colonoscopy. PMID- 27459312 TI - Intraductal Tubulopapillary Neoplasm of the Pancreas Masquerading as Pancreatic Neuroendocrine Carcinoma: Review of the Literature with a Case Report. AB - BACKGROUND: Intraductal tubulopapillary neoplasm of the pancreas (ITPN) is a rare tumor which was first described in 2009. We report a case with cytologic and histologic findings and discuss the pitfalls in diagnosing this entity on cytology. CASE: An 82-year-old female presented with a pancreatic body mass measuring 3.3 cm. Endoscopic ultrasound-guided fine-needle aspiration showed cells in cohesive clusters with high-grade nuclear atypia. Immunohistochemistry (IHC) showed the neoplastic cells to be positive for CK19, CD56 and chromogranin (focal). Ki-67 was high at 50-60%, and chymotrypsin was negative. On the basis of this pattern of staining, the cytologic diagnosis rendered was 'favors high-grade neuroendocrine carcinoma'. Distal pancreatic resection revealed a cystic 4-cm mass. Histologically, the tumor was seen arising from the duct with a solid growth pattern, tubule formation and papillary structures. IHC showed the tumor to be negative for chromogranin, synaptophysin, CD56, trypsin and chymotrypsin. The Ki-67 index was 70%. The final diagnosis was noninvasive ITPN. CONCLUSION: We review the literature and discuss the cytomorphologic features and IHC patterns characteristic of this new entity on cytology material in addition to the pitfalls of the cytologic diagnosis. PMID- 27459313 TI - Urotensin II inhibits autophagy in renal tubular epithelial cells and induces extracellular matrix production in early diabetic mice. AB - AIMS/INTRODUCTION: Urotensin II (UII) and autophagy have been considered as important components in the pathogenesis of diabetic nephropathy. The present study explores whether UII can regulate autophagy in the kidney, and its effect in diabetes. MATERIALS AND METHODS: Immunohistochemistry and western blot were carried out on the kidney tissues of diabetic UII receptor (UT) gene knockout mice, wild-type diabetic mice and normal control mice. For the in vitro experiment, HK-2 cells were treated with UII (10-7 mol/L) in the presence or absence of UT antagonist, SB-657510, (10-6 mol/L) or autophagy inducer, rapamycin (10-3 mol/L), for 12 h. Markers for autophagy (LC3-II, p62/SQSTM1) and extracellular matrix (fibronectin, collagen IV) were analyzed. RESULTS: In diabetic UT knockout mice, expression of LC3-II is increased and p62 was reduced in comparison with that of the normal diabetic mice. Fibronectin and collagen IV were downregulated in diabetic UT knockout mice when compared with that of the normal diabetic mice. For the in vitro cell experiment, UII was shown to inhibit expression LC3-II and increase expression of p62 in comparison with that of the normal control. Treatment with SB-657510 can block UII-induced downregulation of LC3-II and upregulation of p62 while inhibiting UII-induced upregulation of fibronectin and collagen IV. Adding autophagy inducer, rapamycin, also inhibited UII-induced upregulation of fibronectin and collagen IV. CONCLUSIONS: The present study is the first to show that UII can downregulate autophagy in the kidney while accompanying the increased production of extracellular matrix in early diabetes. Our in vitro study also showed that upregulation of autophagy can decrease UII-induced production of extracellular matrix in HK-2 cells. PMID- 27459314 TI - Overexpression of Lnk in the Ovaries Is Involved in Insulin Resistance in Women With Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) progression involves abnormal insulin signaling. SH2 domain-containing adaptor protein (Lnk) may be an important regulator of the insulin signaling pathway. We investigated whether Lnk was involved in insulin resistance (IR). Thirty-seven women due to receive laparoscopic surgery from June 2011 to February 2012 were included from the gynecologic department of the Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. Samples of polycystic and normal ovary tissues were examined by immunohistochemistry. Ovarian cell lines underwent insulin stimulation and Lnk overexpression. Expressed Lnk underwent coimmunoprecipitation tests with green fluorescent protein-labeled insulin receptor and His-tagged insulin receptor substrate 1 (IRS1), and their colocalization in HEK293T cells was examined. Ovarian tissues from PCOS patients with IR exhibited higher expression of Lnk than ovaries from normal control subjects and PCOS patients without IR; mainly in follicular granulosa cells, the follicular fluid and plasma of oocytes in secondary follicles, and atretic follicles. Lnk was coimmunoprecipitated with insulin receptor and IRS1. Lnk and insulin receptor/IRS1 locations overlapped around the nucleus. IR, protein kinase B (Akt), and ERK1/2 activities were inhibited by Lnk overexpression and inhibited further after insulin stimulation, whereas IRS1 serine activity was increased. Insulin receptor (Tyr1150/1151), Akt (Thr308), and ERK1/2 (Thr202/Tyr204) phosphorylation was decreased, whereas IRS1 (Ser307) phosphorylation was increased with Lnk overexpression. In conclusion, Lnk inhibits the phosphatidylinositol 3 kinase-AKT and MAPK-ERK signaling response to insulin. Higher expression of Lnk in PCOS suggests that Lnk probably plays a role in the development of IR. PMID- 27459315 TI - Leaf Protein and Mineral Concentrations across the "Miracle Tree" Genus Moringa. AB - The moringa tree Moringa oleifera is a fast-growing, drought-resistant tree cultivated across the lowland dry tropics worldwide for its nutritious leaves. Despite its nutritious reputation, there has been no systematic survey of the variation in leaf nutritional quality across M. oleifera grown worldwide, or of the other species of the genus. To guide informed use of moringa, we surveyed protein, macro-, and micro- nutrients across 67 common garden samples of 12 Moringa taxa, including 23 samples of M. oleifera. Moringa oleifera, M. concanensis, M. stenopetala, an M. concanensis X oleifera hybrid, and M. longituba were highest in protein, with M. ruspoliana having the highest calcium levels. A protein-dry leaf mass tradeoff may preclude certain breeding possibilities, e.g. maximally high protein with large leaflets. These findings identify clear priorities and limitations for improved moringa varieties with traits such as high protein, calcium, or ease of preparation. PMID- 27459316 TI - Judicious Ligand Design in Ruthenium Polypyridyl CO2 Reduction Catalysts to Enhance Reactivity by Steric and Electronic Effects. AB - A series of RuII polypyridyl complexes of the structural design [RuII (R tpy)(NN)(CH3 CN)]2+ (R-tpy=2,2':6',2''-terpyridine (R=H) or 4,4',4''-tri-tert butyl-2,2':6',2''-terpyridine (R=tBu); NN=2,2'-bipyridine with methyl substituents in various positions) have been synthesized and analyzed for their ability to function as electrocatalysts for the reduction of CO2 to CO. Detailed electrochemical analyses establish how substitutions at different ring positions of the bipyridine and terpyridine ligands can have profound electronic and, even more importantly, steric effects that determine the complexes' reactivities. Whereas electron-donating groups para to the heteroatoms exhibit the expected electronic effect, with an increase in turnover frequencies at increased overpotential, the introduction of a methyl group at the ortho position of NN imposes drastic steric effects. Two complexes, [RuII (tpy)(6-mbpy)(CH3 CN)]2+ (trans-[3]2+ ; 6-mbpy=6-methyl-2,2'-bipyridine) and [RuII (tBu-tpy)(6-mbpy)(CH3 CN)]2+ (trans-[4]2+ ), in which the methyl group of the 6-mbpy ligand is trans to the CH3 CN ligand, show electrocatalytic CO2 reduction at a previously unreactive oxidation state of the complex. This low overpotential pathway follows an ECE mechanism (electron transfer-chemical reaction-electron transfer), and is a direct result of steric interactions that facilitate CH3 CN ligand dissociation, CO2 coordination, and ultimately catalytic turnover at the first reduction potential of the complexes. All experimental observations are rigorously corroborated by DFT calculations. PMID- 27459317 TI - Genetic Basis for Variation in Wheat Grain Yield in Response to Varying Nitrogen Application. AB - Nitrogen (N) is a major nutrient needed to attain optimal grain yield (GY) in all environments. Nitrogen fertilisers represent a significant production cost, in both monetary and environmental terms. Developing genotypes capable of taking up N early during development while limiting biomass production after establishment and showing high N-use efficiency (NUE) would be economically beneficial. Genetic variation in NUE has been shown previously. Here we describe the genetic characterisation of NUE and identify genetic loci underlying N response under different N fertiliser regimes in a bread wheat population of doubled-haploid lines derived from a cross between two Australian genotypes (RAC875 * Kukri) bred for a similar production environment. NUE field trials were carried out at four sites in South Australia and two in Western Australia across three seasons. There was genotype-by-environment-by-treatment interaction across the sites and also good transgressive segregation for yield under different N supply in the population. We detected some significant Quantitative Trait Loci (QTL) associated with NUE and N response at different rates of N application across the sites and years. It was also possible to identify lines showing positive N response based on the rankings of their Best Linear Unbiased Predictions (BLUPs) within a trial. Dissecting the complexity of the N effect on yield through QTL analysis is a key step towards elucidating the molecular and physiological basis of NUE in wheat. PMID- 27459318 TI - Determinants of tobacco-related health literacy: A qualitative study with early adolescents. AB - BACKGROUND: Today's adolescents are used to a constant information flow, but many face difficulties in processing health-related information due to low health literacy. There is still need for deeper understanding on the determinants of health literacy in relation to adolescents to guide the development of health literacy instruments and interventions. PURPOSE: The purpose of this study was to explore, from the perspective of early adolescents, the determinants of health literacy in the context of tobacco-related health communication. DESIGN: A qualitative descriptive study. SETTING: Two schools located in the south of Finland. One school represented a typical Finnish public school with students following general curriculum and the other represented a Finnish public school with students with special educational needs. PARTICIPANTS: Purposively selected sample of 10-13-year-old early adolescents (n=39) from the two schools to obtain a varied group of early adolescents representing different kinds of literacy levels. METHODS: We conducted 10 focus groups with early adolescents and analyzed the data using the theoretical thematic analysis method. We used a combination of the determinants presented in three adolescent-specific health literacy models as the theoretical framework of deductive analysis. The remaining data extracts were coded inductively. We sorted the codes under sub-themes that represented different determinants of health literacy. These were further divided between three themes: "personal", "external", and "mediating" determinants. Finally, we named the themes with an expression that embodied the early adolescents' views and experiences. RESULTS: Early adolescents' descriptions revealed that the list of determinants presented in the three adolescent-specific health literacy models is not comprehensive enough. Early adolescents brought up how their motives, self efficacy, and role expectations determine their health literacy in addition to the other personal determinants presented in the previous models. Their descriptions also suggest that external determinants include interpersonal relations with authorities, idols and random people, and the socio-cultural atmosphere as new factors. New mediating determinants that have a separate influence on health literacy were recognized based on early adolescents' descriptions as well. CONCLUSION: Our findings give a new, adolescent-oriented insight on the determinants of adolescents' health literacy. Based on the findings, there are additional personal, external, and mediating determinants that are not included in the current adolescent-specific health literacy models. These newly found determinants require attention and further exploration. The acquired knowledge can be used for strengthening existing adolescent-specific health literacy models, and as a basis of health literacy instrument and intervention development. PMID- 27459319 TI - Capillarity-Driven Welding of Semiconductor Nanowires for Crystalline and Electrically Ohmic Junctions. AB - Semiconductor nanowires (NWs) have been demonstrated as a potential platform for a wide-range of technologies, yet a method to interconnect functionally encoded NWs has remained a challenge. Here, we report a simple capillarity-driven and self-limited welding process that forms mechanically robust and Ohmic inter-NW connections. The process occurs at the point-of-contact between two NWs at temperatures 400-600 degrees C below the bulk melting point of the semiconductor. It can be explained by capillarity-driven surface diffusion, inducing a localized geometrical rearrangement that reduces spatial curvature. The resulting weld comprises two fused NWs separated by a single, Ohmic grain boundary. We expect the welding mechanism to be generic for all types of NWs and to enable the development of complex interconnected networks for neuromorphic computation, battery and solar cell electrodes, and bioelectronic scaffolds. PMID- 27459320 TI - Visible-Light Microscopic Discovery of Up to 150 MUm Long Helical Amyloid Fibrils Built of the Dodecapeptide H-(Val-Ala-Leu)4 -OH and of Decapeptides Derived from Insulin. AB - In the formation of amyloid fibrils from small peptides, the appearance of superhelices of (P)- or (M)-helicity has been observed for the first time; high concentrations of the peptides and extended periods of incubation at physiological pH appear to be important for this phenomenon. In view of the general importance of peptide and protein aggregation, we give a brief overview with selected examples for demonstration. PMID- 27459321 TI - Fabrication and physical properties of glass-fiber-reinforced thermoplastics for non-metal-clasp dentures. AB - Recently, non-metal-clasp dentures (NMCDs) made from thermoplastic resins such as polyamide, polyester, polycarbonate, and polypropylene have been used as removable partial dentures (RPDs). However, the use of such RPDs can seriously affect various tissues because of their low rigidity. In this study, we fabricated high-rigidity glass-fiber-reinforced thermoplastics (GFRTPs) for use in RPDs, and examined their physical properties such as apparent density, dynamic hardness, and flexural properties. GFRTPs made from E-glass fibers and polypropylene were fabricated using an injection-molding. The effects of the fiber content on the GFRTP properties were examined using glass-fiber contents of 0, 5, 10, 20, 30, 40, and 50 mass%. Commercially available denture base materials and NMCD materials were used as controls. The experimental densities of GFRTPs with various fiber contents agreed with the theoretical densities. Dynamic micro indentation tests confirmed that the fiber content does not affect the GFRTP surface properties such as dynamic hardness and elastic modulus, because most of the reinforcing glass fibers are embedded in the polypropylene. The flexural strength increased from 55.8 to 217.6 MPa with increasing glass-fiber content from 0 to 50 mass%. The flexural modulus increased from 1.75 to 7.42 GPa with increasing glass-fiber content from 0 to 50 mass%, that is, the flexural strength and modulus of GFRTP with a fiber content of 50 mass% were 3.9 and 4.2 times, respectively, those of unreinforced polypropylene. These results suggest that fiber reinforcement has beneficial effects, and GFRTPs can be used in NMCDs because their physical properties are better than those of controls. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2254 2260, 2017. PMID- 27459322 TI - A Sequence of Flushing and Drying of Breeding Habitats of Aedes aegypti (L.) Prior to the Low Dengue Season in Singapore. AB - In dengue-endemic areas, transmission shows both a seasonal and interannual variability. To investigate how rainfall impacts dengue seasonality in Singapore, we carried out a longitudinal survey in the Geylang neighborhood from August 2014 to August 2015. The survey comprised of twice-weekly random inspections to outdoor breeding habitats and continuous monitoring for positive ones. In addition, observations of rainstorms were collected. Out of 6824 inspected habitats, 67 contained Aedes aegypti, 11 contained Aedes albopictus and 24 contained Culex spp. The main outdoors habitat of Aedes aegypti was storm drains (54/67). We found that 80% of breeding sites in drains (43/54) were lost after intense rainstorms related to the wet phase of the Northeast monsoon (NE) between November 2014 and early January 2015. Subsequently, 95% (41/43) of these flushed drains had dried out during the dry phase of the NE in late January-February 2015. A return in the outdoor breeding of Aedes aegypti was observed after the onset of Southwest monsoon (SW) between May and August 2015. There was also a reduction in productivity of breeding habitats for larvae and pupae after the onset of the NE. In wet equatorial regions like Singapore, rainfall varies with the monsoons. A monsoon-driven sequence of flushing and drying shapes the outdoor seasonal abundance of Aedes aegypti. This finding can be used to optimize vector control strategies and better understand dengue in the context of climate change. PMID- 27459323 TI - Treatment of Thoracolumbar Fractures by Percutaneous Pedicle Screw Fixation Technique Combined with Three-step Reduction. AB - Purpose To evaluate the efficacy of percutaneous pedicle screw fixation technique combined with three-step reduction in the treatment of thoracolumbar fracture. Methods This is a retrospective study, based on medical records from the archives of the Fifth People's Hospital of Fudan University, from January 2012 to January 2015. The 49 patients with thoracolumbar fracture were treated with percutaneous pedicle screw fixation technique combined with three-step reduction. The treatment plan was determined by the AO classification and the Thoracolumbar Injury Classification and Severity classification. Baseline data included patient demographics, mechanism of injuries, fracture level, and neurologic status. Kyphotic angle correction and vertebral body height (VBH) restoration were used to assess radiologic outcome. Blood loss, operative complications, hospital stay, and pain score on the visual analog scale (VAS) were used to assess safety and clinical outcomes. Result A total of 49 patients with 51 thoracolumbar burst fractures were treated with percutaneous pedicle screw fixation technique combined with three-step reduction. There was significant improvement in kyphotic angle correction (p < 0.05) and restoration of anterior vertebral height (p < 0.05) after each reduction procedure. These improvements remained statistically significant at the latest follow-up for restoration of anterior VBH (p < 0.05) and kyphotic angle correction (p < 0.05). The preoperative VAS score was 8.2 +/- 1.3, and the postoperative VAS score (3 days after the operation) was 3.5 +/- 0.7. Conclusion Percutaneous pedicle screw internal fixation technique combined with three-step reduction is a relatively safe and effective technique for treating selected thoracolumbar burst fractures, and it yields satisfactory results. PMID- 27459324 TI - What the USPSTF "Insufficient" Skin Cancer Screening Recommendation Means for Primary Care Clinicians and Dermatologists. PMID- 27459325 TI - A redox-sensitive, oligopeptide-guided, self-assembling, and efficiency-enhanced (ROSE) system for functional delivery of microRNA therapeutics for treatment of hepatocellular carcinoma. AB - Lack of efficient adjuvant therapy contributes to a high incidence of recurrence and metastasis of hepatocellular carcinoma (HCC). A novel therapeutic is required for adjuvant treatment of HCC. We developed a polymer-based nanosystem (ROSE) for functional gene therapy by synthesizing a supramolecular complex self-assembled from polycations and functional adamantyl modules. The ROSE system condensing tumor suppressor microRNA-34a (miR-34a) therapeutics becomes ROSE/miR-34a nanoparticles that could facilitate gene transfection in HCC cells with satisfied stability and efficiency, possibly due to proton sponge effect by polycations, PEGlyation protection, and controlled release by breakdown of disulfide bonds. Meanwhile, modification with a targeting oligopeptide SP94 in ROSE/miR-34a enables approximately higher affinity for LM3 HCC cells than hepatocytes in vitro and greater HCC specificity in vivo. Furthermore, ROSE/miR-34a nanoparticles significantly inhibits HCC cell proliferation and in vivo tumor growth, representing a notable effect improvement over conventional gene delivery strategies. ROSE/miR-34a, featuring redox-responsiveness, oligopeptide-guided specificity, self-assembly, and enhanced transfection, is therefore a potential therapeutic agent in future adjuvant therapy for HCC treatment. PMID- 27459326 TI - Trend Analysis of Substance Abuse Treatment Admissions in New Orleans From 2000 2012: A Population-Based Comparison Pre- and Post-Hurricane Katrina. AB - BACKGROUND: Substance abuse treatment following a natural disaster is often met with challenges. If treatment is available, facilities may be unequipped to service an influx of patients or provide specialized care for unique populations. OBJECTIVES: This paper seeks to evaluate trends in substance abuse treatment over time and assess changes pre- and post-Hurricane Katrina. METHODS: Substance abuse treatment admission data (N = 42,678) from New Orleans, Louisiana, for years 2000 through 2012 were obtained from the Treatment Episode Data Set. Admissions were examined to evaluate demographic, socioeconomic, psychiatric, and criminality trends in substance abuse treatment and assess changes following Hurricane Katrina. RESULTS: Treatment admissions have decreased from 2000 to 2012. About one in five admissions had a psychiatric illness in addition to a substance abuse problem. A staggering 76% of admissions with a psychiatric illness were referred by the criminal justice system post-Katrina as compared to pre-Katrina. Rates of alcohol and marijuana admissions have remained stable from 2000 to 2012. Cocaine/crack admissions have declined and admissions who abused heroin have increased over time. CONCLUSIONS: Treatment admissions stabilized following Hurricane Katrina; however, since 2009, they have begun to decline. Targeted exploration of factors affecting admission to treatment in New Orleans with populations such as the homeless, those with a psychiatric illness in addition to a substance abuse problem, and those referred by the criminal justice system is essential. The results of this study assist in identifying variations in substance abuse treatment characteristics for those admitted to treatment in New Orleans. PMID- 27459327 TI - Adults' Explanations for Intimate Partner Violence During Childhood and Associated Effects. AB - OBJECTIVES: Exposure to intimate partner violence (IPV) is known to challenge children's optimal development. This study sought to associate participants' beliefs about IPV held during childhood with their adjustment as adults, and to compare their beliefs from childhood to their beliefs in early adulthood. METHOD: A nationally representative sample of 703 Swedish young adults reported on their past and present beliefs about the causes of their parents' IPV. Standardized measures assessed their mental health (anxiety, depression, and traumatic stress symptoms) and the quality of their relationships as adults. RESULTS: The most common explanations for IPV were that the perpetrator suffered from physical or mental illness, had relationship problems, or was distressed. Participants were less likely to blame themselves for IPV or to believe that the perpetrator was cruel when they were adults, compared to their reports of themselves as children. Women were more likely to attribute mental or physical illness as the cause of the perpetrator's IPV. Childhood beliefs that the perpetrator was debilitated (from mental illness or substance abuse) and cruel (took pleasure in violence and/or despised the child) were associated with greater mental health problems and poorer relationship quality in adulthood. CONCLUSION: Evaluation of children's harmful beliefs about IPV could be useful in adapting intervention services aimed at ameliorating negative personal causal attributions. PMID- 27459328 TI - Ultrahigh resolution metabolomics for S-containing metabolites. AB - The advent of the genome-editing era greatly increases the opportunities for synthetic biology research that aims to enhance production of potentially useful bioactive metabolites in heterologous hosts. A wide variety of sulfur (S) containing metabolites (S-metabolites) are known to possess bioactivities and health-promoting properties, but finding them and their chemical assignment using mass spectrometry-based metabolomics has been difficult. In this review, we highlight recent advances on the targeted metabolomic analysis of S-metabolites (S-omics) in plants using ultrahigh resolution mass spectrometry. The use of exact mass and signal intensity differences between 32S-containing monoisotopic ions and counterpart 34S isotopic ions exploits an entirely new method to characterize S-metabolites. Finally, we discuss the availability of S-omics for synthetic biology. PMID- 27459329 TI - When French Adult Grandchildren Become the Primary Caregivers of Their Grandparents with Dementia: A Desperate or an Overlooked Generation? PMID- 27459330 TI - Is Regioselectivity in the Enzyme-Catalyzed Hydroperoxidation of Arachidonic Acid Necessarily Determined by Hydrogen Abstraction? The Case of Rabbit Leu597Ala/Ile663Ala ALOX15 Mutant. AB - Molecular dynamics simulations and quantum mechanics/molecular mechanics calculations were performed on the in silico Leu597Ala/Ile663Ala double mutant of rabbit ALOX15 (12/15 lipoxygenase). The computational results suggested that subtle steric hindrance by the conserved Leu597 and C-terminal Ile663 residues disturbed H10 abstractions in wildtype ALOX15 (which abstracts H13), but if these two bulky residues were mutated to smaller ones, H10 abstraction was no longer impeded and the regioselectivity of the initial H-abstraction step was changed. However, site-directed mutagenesis with HPLC analysis of the products of the whole oxidation process showed that the regioselectivity of the hydroperoxidation was not altered. This disagreement may be explained by the conformational reorganization of the system needed to rotate the -OO. group from an antarafacial to a suprafacial arrangement prior to back-hydrogen transfer. After H10 abstraction and O2 insertion, the evolution of the peroxy radical at C12 was sterically impeded, whereas peroxyl group rotation at C15 (after H13 abstraction) could easily evolve to a suprafacial arrangement, which thus led to the final product. For this reason, the global regiospecificity was not affected in the mutant. These findings exemplify that the regioselectivity of initial hydrogen abstraction and the regioselectivity of the final product do not necessarily coincide (in fact, they can be opposite) for the hydroperoxidation of arachidonic acid catalyzed by a lipoxygenase. PMID- 27459331 TI - Randomized phase 2 trial of a coordinated breast cancer follow-up care program. AB - BACKGROUND: Previous research has demonstrated that cancer survivors often fail to receive recommended care and also undergo unnecessary care; this reduces care quality and increases costs. METHODS: This phase 2 trial randomized 100 stage 0 to IIIa breast cancer patients who had primary care providers within a large Massachusetts-based hospital network (with accessible online records) to either coordinated follow-up care (CC), which entailed a tailored survivorship care plan (SCP) and patient navigator calls every 3 months, or standard care (SC), which did not include an SCP or patient navigation, for 1 year after the completion of their last chemotherapy, surgery, or radiation treatment. The primary endpoint was the frequency of redundant examinations (>1 breast/chest wall examination per patient within any 30-day period in the absence of a new breast or chest wall complaint) over the year of follow-up. The total number of non-plastic surgery visits in the year of follow-up was a secondary endpoint. RESULTS: Two patients (both on CC) were ineligible, and 2 patients (1 per arm) had a recurrence or died during follow-up; this left 96 for analysis (47 in the CC arm and 49 in the SC arm). Twenty-two of the 47 CC patients (47%; 95% confidence interval, 32%-62%) and 19 of the 49 SC patients (39%; 95% confidence interval, 25%-54%) had 1 or more redundant breast/chest wall examinations during the year. The median number of non-plastic surgery visits was 12 for CC patients and 8 for SC patients. CONCLUSIONS: Early-stage breast cancer patients visit health care providers very frequently during their first year of follow-up and often receive unnecessary breast/chest wall examinations. An SCP and patient navigator calls did not reduce this surrogate for redundant care. Cancer 2016;122:3546-3554. (c) 2016 American Cancer Society. PMID- 27459333 TI - Question and Answers. PMID- 27459334 TI - Structural, Electronic, and Computational Studies of Heteroleptic Cu(I) Complexes of 6,6'-Dimesityl-2,2'-bipyridine with Ferrocene-Appended Ethynyl-2,2'-bipyridine Ligands. AB - Optical characterization and computational modeling of three ferrocene-appended ethynyl-2,2'-bipyridine ligands and the associated heteroleptic copper(I) complexes of 6,6'-dimesityl-2,2'-bipyridine are reported. These dyes have been studied using electrochemical analysis, electronic absorption, and Raman and resonance Raman spectroscopies, coupled with density functional theoretical approaches. For the complexes, optical spectra are dominated by a low energy copper(I) centered metal to ligand charge transfer (MLCT) transition; this is modulated by the presence of pendant ferrocene units and the extent of conjugation of the ferrocenyl bipyridine backbone. Electronic tuning due to ferrocene is shown to result in a redshift of the MCLT transition of up to ~0.2 eV, while an elongation of conjugation appears to result in an increased MLCT intensity of around 50%. PMID- 27459332 TI - MicroRNA expression profiling of Leishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy. AB - Leishmania is an obligate intracellular parasite that replicates inside phagolysosomes or parasitophorous vacuoles (PV) of the monocyte/macrophage lineage. It reprograms macrophages and produces a metabolic state conducive to successful infection and multiplication. MicroRNAs (miRNAs), a class of small 22 to 24 nucleotide noncoding regulatory RNAs alter the gene expression and consequently proteome output by targeting mRNAs, may play a regulatory role in modulating host cell functions. In the present study, we demonstrate the novel regulatory role of host microRNA, MIR30A-3p in modulation of host cell macroautophagy/autophagy after infection with L. donovani. Our in vitro studies showed that MIR30A-3p expression was significantly enhanced after L. donovani infection in a time-dependent manner. Transient transfection with a MIR30A-3p inhibitor followed by L. donovani infection promoted the autophagic response and decreased the intracellular parasite burden in both THP-1 cells and human monocyte-derived macrophages (HsMDM). BECN1/Beclin 1, the mammalian ortholog of yeast Vps30/Atg6, is a key autophagy-promoting protein that plays a key role in the regulation of cell death and survival. We report BECN1-dependent modulation of host cell autophagy in response to L. donovani infection. Pretreatment of L. donovani-infected macrophages with the MIR30A-3p mimic decreased and with antagomir increased the expression of BECN1 protein. We demonstrate that BECN1 is a potential target of MIR30A-3p and this miRNA negatively regulates BECN1 expression. Our present study reveals for the first time a novel role of MIR30A 3p in regulating autophagy-mediated L. donovani elimination by targeting BECN1. The present study has significant impact for the treatment of visceral leishmaniasis. PMID- 27459335 TI - Lactobacillus delbrueckii subsp lactis CIDCA 133 modulates response of human epithelial and dendritic cells infected with Bacillus cereus. AB - It is known that probiotic microorganisms are able to modulate pathogen virulence. This ability is strain dependent and involves multiple interactions between microorganisms and relevant host's cell populations. In the present work we focus on the effect of a potentially probiotic lactobacillus strain (Lactobacillus delbrueckii subsp. lactis CIDCA 133) in an in vitro model of Bacillus cereus infection. Our results showed that infection of intestinal epithelial HT-29 cells by B. cereus induces nuclear factor kappa B (NF-kappaB) pathway. Noteworthy, the presence of strain L. delbrueckii subsp.lactis CIDCA 133 increases stimulation. However, B. cereus-induced interleukin (IL)-8 production by epithelial cells is partially abrogated by L. delbrueckii subsp. lactis CIDCA 133. These findings suggest that signalling pathways other than that of NF-kappaB are involved. In a co-culture system (HT-29 and monocyte-derived dendritic cells), B. cereus was able to translocate from the epithelial (upper) to the dendritic cell compartment (lower). This translocation was partially abrogated by the presence of lactobacilli in the upper compartment. In addition, infection of epithelial cells in the co-culture model, led to an increase in the expression of CD86 by dendritic cells. This effect could not be modified in the presence of lactobacilli. Interestingly, infection of enterocytes with B. cereus triggers production of proinflammatory cytokines by dendritic cells (IL-8, IL-6 and tumour necrosis factor alpha (TNF-alpha)). The production of TNF-alpha (a protective cytokine in B. cereus infections) by dendritic cells was increased in the presence of lactobacilli. The present work demonstrates for the first time the effect of L. delbrueckii subsp. lactis CIDCA 133, a potentially probiotic strain, in an in vitro model of B. cereus infection. The presence of the probiotic strain modulates cell response both in infected epithelial and dendritic cells thus suggesting a possible beneficial effect of selected lactobacilli strains on the course of B. cereus infection. PMID- 27459336 TI - Inflammation-related pro-apoptotic activity of exopolysaccharides isolated from Lactococcus lactis subsp. lactis. AB - Exopolysaccharides (EPS) have attracted attention recently for possible use in suppressing early stage breast cancer. In this study, a mannan EPS produced by Lactococcus lactis subsp. lactis was found to affect the production of inflammatory cytokines. EPS (300 MUg/ml) can significantly enhance tumour necrosis factor alpha and inducible NO synthase release in MCF-7 cells compared to control cells in a concentration-dependent manner. Also the intracellular calcium level was found to increase with the concentration of EPS. After EPS treatment, a significant reduction in mitochondrial potential was observed, as was nuclear condensation and cell shrinkage. These results may be helpful in further understanding the anti-tumour properties of lactic acid bacteria. PMID- 27459337 TI - Above vs. belowground plant biomass along a barrier island: Implications for dune stabilization. AB - Coastal regions are inherently and increasingly vulnerable and geomorphologically unstable, yet are invaluable economic and residential hubs. Dunes are dynamic buffers to erosion and the most natural, economical, and effective defense for coastal communities. Vegetation is integral to dune structure as it facilitates accretion and stabilization. Differences in the vegetation and root density likely translate to variability in coastal erosion prevention, but this notion has been largely unconsidered. We directly compared stabilizing factors, depth and density, of the root systems of two dominant mid-Atlantic dune plant species, native American beach grass (Ammophila breviligulata) and invasive Asiatic sand sedge (Carex kobomugi). Despite high plant density, C. kobomugi is targeted for removal in restoration efforts as its roots are assumed to provide less effective stabilization than A. breviligulata. We collected 30 cores and hand dug 14 A. breviligulata ramets at Island Beach State Park, New Jersey to examine biomass, root:shoot ratios, and root density. C. kobomugi had a more extensive root system with a root:shoot ratio of 11.36:1 compared to 1.62:1 for A. breviligulata. Similarly, cores 60 cm deep and 7.6 cm wide were sufficient to attain fully intact A. breviligulata roots, which did not extend deeper than 40 cm, but insufficient for C. kobomugi roots which extended beyond the sampling system vertically and horizontally. Scaling these findings to m(-2), aboveground biomass is relatively equal, but C. kobomugi had over 700% more root mass m(-2) than A. breviligulata. These results have strong implications for dune management. The root system of C. kobomugi may be better adapted to stabilize dunes and thus protect coastal areas during small and large-scale perturbations than previously supposed. This is a unique situation whereby the creation of monocultures will hyperstabilize dunes and make them more resistant to erosion at the cost of reduced biodiversity within the framework of resiliency. PMID- 27459338 TI - Factors associated with potentially inappropriate medication use in elderly Koreans in an outpatient setting: a population-based study. PMID- 27459339 TI - Oral Magnesium Treatment Reduces Anemia and Levels of Inflammatory Markers in Experimental Diabetes. AB - Magnesium has been reported to improve glucose utilization in diabetes mellitus. However, information on its effects on anemic and inflammatory markers in diabetes mellitus is limited. This study investigated the effect of oral magnesium (Mg) treatment on some markers of anemia and inflammation in 25 male Wistar rats. Rats (200 +/- 15 g) were randomly divided into five groups (n = 5). Group 1 was control (received orally 0.2 mL distilled water daily), group 2 (Diabetic Untreated), group 3 (Diabetic Mg treated-100 mg/kg bw), group 4 (Diabetic Mg treated-250 mg/kg bw), group 5 (Diabetic Insulin treated-1 IU/kg bw). Diabetes was induced with a single dose of alloxan (100 mg/kg intraperitoneal (i.p.)). All treatments were done for 14 days. Anemic and inflammatory markers were investigated on blood samples obtained from each animal using standard laboratory methods. Significant increase (p < 0.05) in total white blood cell (WBC) count was observed in diabetic untreated rats (7.67 +/- 0.397 * 109/L) compared to control (5.88 +/- 0.25 * 109/L), DMg 100 (5.86 +/- 0.74 * 109/L) and DMg 250 (5.06 +/- 0.78 * 109/L). Hemoglobin concentration, packed cell volume (PCV) and red blood cell (RBC) count was decreased (p < 0.05) in DU compared to control, DMg 100, and DI rats. Erythrocyte sedimentation rate (ESR) was significantly increased (p < 0.05) in DU compared to control, DMg 100, DMg 250, and DI groups. Fibrinogen level was increased (p < 0.05) in DU rats (0.44 +/ 0.02 g/dL) compared to control(0.26 +/- 0.02 g/dL). Values obtained in DMg 100 (0.30 +/- 0.03 g/dL), DMg 250 (0.22 +/- 0.04 g/dL), and DI (0.36 +/- 0.02 g/dL) rats were comparable to control (0.26 +/- 0.02 g/dL). Total protein, albumin, and globulin levels were decreased in DU rats compared to normal control, DMg 100, DMg 250, and DI rats. In conclusion, anemia and increased hematologic and metabolic inflammatory markers may be associated with untreated diabetes mellitus. Treatment of alloxan-induced diabetic rats with magnesium improved the anemic state and reduced hematologic and metabolic inflammatory markers. PMID- 27459340 TI - Effect of nitrogen deficiency on ascorbic acid biosynthesis and recycling pathway in cucumber seedlings. AB - L-Ascorbic acid (AsA, ascorbate) is one of the most abundant natural antioxidants, and it is an important factor in the nutritional quality of cucumber. In this work, key enzymes involved in the ascorbic acid biosynthesis and recycling pathway in cucumber seedlings under nitrogen deficiency were investigated at the levels of transcription and enzyme activity. The activities of myo-inositol oxygenase (MIOX) and transcript levels of MIOXs increased dramatically, while the activities of ascorbate oxidase (AO) and glutathione reductase (GR) and transcript levels of AOs and GR2 decreased significantly in N limited leaves, as did the ascorbate concentration, in nitrogen-deficient cucumber seedlings. The activities of other enzymes and transcript levels of other genes involved in the ascorbate recycling pathway and ascorbate synthesis pathways decreased or remained unchanged under nitrogen deficiency. These results indicate that nitrogen deficiency induced genes involved in the ascorbate glutathione recycling and myo-inositol pathway in cucumber leaves. Thus, the AO, GR and MIOX involved in the pathways might play roles in AsA accumulation. PMID- 27459341 TI - Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES. AB - BACKGROUND: Ribavirin is a key component of several hepatitis C virus (HCV) treatment regimens. However, its utility in combination with newer directly acting anti-viral agents regimens is unclear. AIM: To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimen +/- ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens. METHODS: We used Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA. RESULTS: We identified 1235 persons on PrOD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on PrOD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in PrOD group without ribavirin, HCV genotype 1a without cirrhosis (SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group. CONCLUSIONS: In HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except PrOD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established. PMID- 27459343 TI - Oxide Charge Engineering of Atomic Layer Deposited AlOxNy/Al2O3 Gate Dielectrics: A Path to Enhancement Mode GaN Devices. AB - Nitrogen incorporation to produce negative fixed charge in Al2O3 gate insulator layers is investigated as a path to achieve enhancement mode GaN device operation. A uniform distribution of nitrogen across the resulting AlOxNy films is obtained using N2 plasma enhanced atomic layer deposition (ALD). The flat band voltage (Vfb) increases to a significantly more positive value with increasing nitrogen concentration. Insertion of a 2 nm thick Al2O3 interlayer greatly decreases the trap density of the insulator/GaN interface, and reduces the voltage hysteresis and frequency dispersion of gate capacitance compared to single-layer AlOxNy gate insulators in GaN MOSCAPs. PMID- 27459342 TI - Chemical exchange saturation transfer of the cervical spinal cord at 7 T. AB - High-magnetic-field (7 T) chemical exchange saturation transfer (CEST) MRI provides information on the tissue biochemical environment. Multiple sclerosis (MS) affects the entire central nervous system, including the spinal cord. Optimal CEST saturation parameters found via simulation were implemented for CEST MRI in 10 healthy controls and 10 patients with MS, and the results were examined using traditional asymmetry analysis and a Lorentzian fitting method. In addition, T1 - and T2 *-weighted images were acquired for lesion localization and the transmitted B1 (+) field was evaluated to guide imaging parameters. Distinct spectral features for all tissue types studied were found both up- and downfield from the water resonance. The z spectra in healthy subjects had the expected z spectral shape with CEST effects apparent from 2.0 to 4.5 ppm. The z spectra from patients with MS demonstrated deviations from this expected normal shape, indicating this method's sensitivity to known pathology as well as to tissues appearing normal on conventional MRI. Examination of the calculated CESTasym revealed increased asymmetry around the amide proton resonance (Deltaomega = 3.5 ppm), but it was apparent that this measure is complicated by detail in the CEST spectrum upfield from water, which is expected to result from the nuclear Overhauser effect. The z spectra upfield (negative ppm range) were also distinct between healthy and diseased tissue, and could not be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1 ppm, the Lorentzian differences (and z spectra) for lesions and normal-appearing white matter were distinct from those for healthy white matter. The increased frequency separation and signal-to-noise ratio, in concert with prolonged T1 at 7 T, resulted in signal enhancements necessary to detect subtle tissue changes not possible at lower field strengths. This study presents CEST imaging metrics that may be sensitive to the extensive and temporally varying biochemical neuropathology of MS in the spinal cord. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27459344 TI - Microbial production of plant hormones: Opportunities and challenges. AB - Plant hormones are a class of organic substances which are synthesized during the plant metabolism. They have obvious physiological effect on plant growth at very low concentrations. Generally, plant hormones are mainly divided into 5 categories: auxins, cytokinins, ethylene, gibberellins (GAs) and abscisic acid (ABA). With the deepening of research, some novel plant hormones such as brassinosteroid and salicylates have been found and identified. The plant hormone products are mainly obtained through plant extraction, chemical synthesis as well as microbial fermentation. However, the extremely low yield in plants and relatively complex chemical structure limit the development of the former 2 approaches. Therefore, more attention has been paid into the microbial fermentative production. In this commentary, the developments and technological achievements of the 2 important plant hormones (GAs and ABA) have been discussed. The discovery, producing strains, fermentation technologies, and their accumulation mechanisms are first introduced. Furthermore, progresses in the industrial mass scale production are discussed. Finally, guidelines for future studies for GAs and ABA production are proposed in light of the current progress, challenges and trends in the field. With the widespread use of plant hormones in agriculture, we believe that the microbial production of plant hormones will have a bright future. PMID- 27459345 TI - Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives. AB - Poylcyclic tetrahydroxanthones comprise a large class of cytototoxic natural products. No mechanism of action has been described for any member of the family. We report the synthesis of kibdelone C and several simplified analogs. Both enantiomers of kibdeleone C show low nanomolar cytotoxicity toward multiple human cancer cell lines. Moreover, several simplified derivatives with improved chemical stability display higher activity than the natural product itself. In vitro studies rule out interaction with DNA or inhibition of topoisomerase, both of which are common modes of action for polycyclic aromatic compounds. However, celluar studies reveal that kibdelone C and its simplified derivatives disrupt the actin cytoseketon without directly binding actin or affecting its polymerization in vitro. PMID- 27459346 TI - Vaginal HIV-1 shedding among HIV-1 infected women in the current era of combined antiretroviral therapy: A cross sectional study. PMID- 27459347 TI - Transferring Desirable Genes from Agropyron cristatum 7P Chromosome into Common Wheat. AB - Wheat-Agropyron cristatum 7P disomic addition line II-5-1, derived from the distant hybridization between A. cristatum (2n = 4x = 28, PPPP) and the common wheat cv. Fukuhokomugi (Fukuho), displays numerous desirable agronomic traits, including enhanced thousand-grain weight, smaller flag leaf, and enhanced tolerance to drought. In order to transfer these traits into common wheat, II-5-1 was induced by 60Co-gamma ray, leading to the creation of 18 translocation lines and three deletion lines. Genomic in situ hybridization (GISH) and fluorescence in situ hybridization (FISH) indicated that multiple wheat chromosomes were involved in the translocation events, including chromosome 2A, 3A, 5A, 7A, 3B, 5B, 7B, 3D and 7D. A. cristatum 7P chromosome was divided into 15 chromosomal bins with fifty-five sequence-tagged site (STS) markers specific to A. cristatum 7P chromosome. Seven and eight chromosomal bins were located on 7PS and 7PL, respectively. The above-mentioned translocation and deletion lines each contained different, yet overlapping 7P chromosomal fragments, covering the entire A. cristatum 7P chromosome. Three translocation lines (7PT-13, 7PT-14 and 7PT-17) and three deletion lines (del-1, del-2 and del-3), which contained the common chromosomal bins 7PS1-3, displayed higher thousand-grain weigh than Fukuho, suggesting that potential genes conferring high thousand-grain weigh might be located on these chromosomal bins. Therefore, wheat-A. cristatum 7P translocation lines with elite traits will be useful as novel germplasms for wheat genetic improvement. PMID- 27459348 TI - Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma - an update. AB - INTRODUCTION: The development of monoclonal antibody-based biologics targeted at inhibition of the Th2 cytokines IL-4, IL-5 and IL-13 represent potentially effective treatments for patients with the glucocorticoid refractory eosinophilic asthma phenotype. Areas covered: Asthma exhibits marked heterogeneity both clinically and at the molecular phenotypic level, requiring specifically targeted treatments to block the key pathways of the disease. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of reproducible and straightforward discriminatory biomarkers may aid identification of those patients most likely to benefit from treatment with these expensive interventions. This narrative review is based on English-language original articles in PubMed or Med-Line that reported significant clinical findings published in the last two years on the evidence demonstrating the effectiveness or otherwise of the targeting of IL-4, IL-5, or IL-13 in carefully selected patients with severe refractory asthma. Expert commentary: The use of a baseline peripheral blood eosinophilia as a simple reproducible biomarker to identify patients with particular sub-phenotypes of asthma to guide the effective use of biologic therapy represents a significant step forward. PMID- 27459349 TI - Effects of Nurse-Led Multifactorial Care to Prevent Disability in Community Living Older People: Cluster Randomized Trial. AB - BACKGROUND: To evaluate the effects of nurse-led multifactorial care to prevent disability in community-living older people. METHODS: In a cluster randomized trail, 11 practices (n = 1,209 participants) were randomized to the intervention group, and 13 practices (n = 1,074 participants) were randomized to the control group. Participants aged >= 70 years were at increased risk of functional decline based on a score >= 2 points on the Identification of Seniors at Risk- Primary Care, ISAR-PC. Participants in the intervention group received a systematic comprehensive geriatric assessment, and individually tailored multifactorial interventions coordinated by a trained community-care registered nurse (CCRN) with multiple follow-up home visits. The primary outcome was the participant's disability as measured by the modified Katz activities of daily living (ADL) index score (range 0-15) at one year follow-up. Secondary outcomes were health related quality of life, hospitalization, and mortality. RESULTS: At baseline, the median age was 82.7 years (IQR 77.0-87.1), the median modified Katz-ADL index score was 2 (IQR 1-5) points in the intervention group and 3 (IQR 1-5) points in the control group. The follow-up rate was 76.8% (n = 1753) after one year and was similar in both trial groups. The adjusted intervention effect on disability was 0.07 (95% confidence interval -0.22 to 0.07; p = 0.33). No intervention effects were found for the secondary outcomes. CONCLUSIONS: We found no evidence that a one-year individualized multifactorial intervention program with nurse-led care coordination was better than the current primary care in community-living older people at increased risk of functional decline in The Netherlands. TRIAL REGISTRATION: Netherlands Trial Register NTR2653. PMID- 27459350 TI - Developmental validation of the Yfiler((r)) Plus PCR Amplification Kit: An enhanced Y-STR multiplex for casework and database applications. AB - Y-chromosomal loci have proven useful in solving investigations where low levels of male DNA are present in a high female DNA background. An intrinsic limitation of Y-STRs compared with autosomal STRs is a reduced power of discrimination due to a lack of recombination throughout most of the Y-chromosome. Thus, in an effort to increase the power of discrimination we have developed a new 6-dye, 27 plex Y-STR system that includes the 17 loci from the Yfiler((r)) and Yfiler((r)) Direct kits (DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 (Y GATA C4), and Y GATA H4) plus three highly polymorphic Y-STR loci (DYS460, DYS481, and DYS533), and seven rapidly mutating Y-STR loci (DYF387S1a/b, DYS449, DYS518, DYS570, DYS576, DYS627) which allow for improved discrimination of related individuals. The Yfiler((r)) Plus PCR Amplification Kit is a dual application assay designed to amplify DNA from extracted casework and database samples from storage cards and swab lysates via direct amplification. Compared to the Yfiler PCR Amplification Kit, the new multiplex shows increased discrimination of male lineages and also improved performance in inhibited samples, improved balance in male DNA samples mixed with female DNA at ratios >1:1000, and faster time to results. The Yfiler Plus Kit shows very high concordance to the Yfiler Kit but discordance with the PowerPlex((r)) Y23 Kit at the DYS481 locus was observed in 2 out of 30 samples tested. This developmental validation work follows the SWGDAM guidelines and demonstrates that the assay is robust and suitable for use on forensic casework and database samples. PMID- 27459351 TI - Prediction of radioactive iodine remnant ablation failure in patients with differentiated thyroid cancer: A cohort study of 740 patients. AB - BACKGROUND: The purpose of this study was to detect parameters that could serve as predictors of radioactive iodine (I-131) ablation failure in patients with low risk and intermediate-risk differentiated thyroid carcinoma (DTC). METHODS: Our cohort study included 740 patients with DTC who received postoperative I-131 remnant ablation. Anthropometric, biochemical, and pathohistological parameters were analyzed and correlated with ablation outcome using multivariable logistic regression models. RESULTS: Treatment failure rates were higher in patients <53 years, with N1a classification, and lymph node capsular invasion. In patients with N1a disease, thyroglobulin (Tg) > 2.4 ng/mL predicted treatment failure with 93.8% sensitivity and 52.5% specificity, and in patients with N1b disease, Tg > 14.9 ng/mL with 77.8% sensitivity and 92.9% specificity. I-131 activity was not associated with treatment outcome. CONCLUSION: Patients < 53 years old, with higher Tg levels, N1a classification, and lymph node capsular invasion have a higher risk of ablation failure. Stimulated Tg is an excellent predictor of treatment failure in patients with N1 disease. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 109-115, 2017. PMID- 27459352 TI - Fluorescent Probe Encapsulated in Avidin Protein to Eliminate Nonspecific Fluorescence and Increase Detection Sensitivity in Blood Serum. AB - Quantitative detection of trace amounts of a biomarker in protein rich human blood plasma using fluorescent probes is a great challenge as the real signal is usually obscured by nonspecific fluorescence. This problem occurs because most of the fluorescent dyes bind very tightly with blood proteins to produce a large fluorescence increase, resulting in overestimation of the biomarker concentrations and false positive diagnosis. In this paper, we report that biotinylated fluorescent probes encapsulated in avidin protein can generate very specific fluorescence in blood serum by blocking out nonspecific dye-protein interactions. We applied our novel probe design to detect two different types of biomolecules, hydrogen sulfide and nitroreductase. Our Avidin conjugated probes achieved quantitative analyte detection in blood serum; whereas concentrations were overestimated up to 320-fold when bare fluorescent probes were employed. As compared to conventional approaches where fluorescent probes are encapsulated into polymers and nanoparticles, our simple approach successfully overcomes many key issues such as dye leakage, long preparation steps, inconsistent dye-host ratios, difficulty in constructing in situ in a complex medium, and limited application to detect only small metabolites. PMID- 27459362 TI - Holistic Comfort Interventions for Pediatric Nursing Procedures: A Systematic Review. AB - Comfort interventions for children during invasive nursing procedures have been well documented in the literature. It is important, however, to distinguish between the provision of holistic comfort management and pain alleviation. Holistic comfort focuses on treating the child's whole procedural experience and includes more than simply reducing pain. In this literature review, 33 intervention studies were examined. These studies focused on evaluating comfort effects from nursing interventions on pain, anxiety, fear, and distress. Four themes of procedural comfort intervention emerged: music therapy, amusement and entertainment, caregiver facilitation, and a multifaceted approach. Important findings of this review, gaps in the literature, and implications for future research are discussed. PMID- 27459364 TI - Liquid Surface X-ray Studies of Gold Nanoparticle-Phospholipid Films at the Air/Water Interface. AB - Amphiphilic phospholipids and nanoparticles functionalized with hydrophobic capping ligands have been extensively investigated for their capacity to self assemble into Langmuir monolayers at the air/water interface. However, understanding of composite films consisting of both nanoparticles and phospholipids, and by extension, the complex interactions arising between nanomaterials and biological membranes, remains limited. In this work, dodecanethiol-capped gold nanoparticles (Au-NPs) with an average core diameter of 6 nm were incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monolayers with surface densities ranging from 0.1 to 20% area coverage at a surface pressure of 30 mN/m. High resolution liquid surface X-ray scattering studies revealed a phase separation of the DPPC and Au-NP components of the composite film, as confirmed with atomic force microscopy after the film was transferred to a substrate. At low Au-NP content, the structural organization of the phase-separated film is best described as a DPPC film containing isolated islands of Au-NPs. However, increasing the Au-NP content beyond 5% area coverage transforms the structural organization of the composite film to a long-range interconnected network of Au-NP strands surrounding small seas of DPPC, where the density of the Au-NP network increases with increasing Au-NP content. The observed phase separation and structural organization of the phospholipid and nanoparticle components in these Langmuir monolayers are useful for understanding interactions of nanoparticles with biological membranes. PMID- 27459363 TI - Intestinal bacteria are necessary for doxorubicin-induced intestinal damage but not for doxorubicin-induced apoptosis. AB - Doxorubicin (DOXO) induces significant, but transient, increases in apoptosis in the stem cell zone of the jejunum, followed by mucosal damage involving a decrease in crypt proliferation, crypt number, and villus height. The gastrointestinal tract is home to a vast population of commensal bacteria and numerous studies have demonstrated a symbiotic relationship between intestinal bacteria and intestinal epithelial cells (IEC) in maintaining homeostatic functions of the intestine. However, whether enteric bacteria play a role in DOXO induced damage is not well understood. We hypothesized that enteric bacteria are necessary for induction of apoptosis and damage associated with DOXO treatment. Conventionally raised (CONV) and germ free (GF) mice were given a single injection of DOXO, and intestinal tissue was collected at 6, 72, and 120 h after treatment and from no treatment (0 h) controls. Histology and morphometric analyses quantified apoptosis, mitosis, crypt depth, villus height, and crypt density. Immunostaining for muc2 and lysozyme evaluated Paneth cells, goblet cells or dual stained intermediate cells. DOXO administration induced significant increases in apoptosis in jejunal epithelium regardless of the presence of enteric bacteria; however, the resulting injury, as demonstrated by statistically significant changes in crypt depth, crypt number, and proliferative cell number, was dependent upon the presence of enteric bacteria. Furthermore, we observed expansion of Paneth and goblet cells and presence of intermediate cells only in CONV and not GF mice. These findings provide evidence that manipulation and/or depletion of the enteric microbiota may have clinical significance in limiting chemotherapy-induced mucositis. PMID- 27459366 TI - Computational Mechanistic Study of Thionation of Carbonyl Compounds with Lawesson's Reagent. AB - The thionation reaction of carbonyl compounds with Lawesson's reagent (LR) has been studied using density functional theory methods and topological analyses. After dissociation of LR, the reaction takes place through a two-step mechanism involving (i) a concerted cycloaddition between one monomer and the carbonyl compound to form a four-membered intermediate and (ii) a cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. Topological analyses confirmed the concertedness and asynchronicity of the process. The second step is the rate-limiting one, and the whole process resembles the currently accepted mechanism for the lithium salt-free Wittig reaction. No zwitterionic intermediates are formed during the reaction, although stabilizing electrostatic interactions are present in initial stages. Phenyl(thioxo)phosphine oxide formed in the thionation reaction is capable of performing a second thionation, although with energy barriers higher than the first one. The driving force of the thionation reactions is the formation of trimers from the resulting monomers. In agreement with experimental observations, the amides are the most reactive when compared with esters, aldehydes, and ketones and the reaction is slightly influenced by the polarity of the solvent. Whereas for amides and esters substituents have little effect, aldehydes and ketones are influenced by both steric and electronic effects. PMID- 27459367 TI - Conformation of Alkali Metal Ion-Benzo-12-Crown-4 Complexes Investigated by UV Photodissociation and UV-UV Hole-Burning Spectroscopy. AB - We measure UV photodissociation (UVPD) spectra of benzo-12-crown-4 (B12C4) complexes with alkali metal ions, M(+).B12C4 (M = Li, Na, K, Rb, and Cs), in the 36300-37600 cm(-1) region. Thanks to the cooling of ions to ~10 K, all the M(+).B12C4 complexes show sharp vibronic bands in this region. For UV-UV hole burning (HB) spectroscopy, we first check if our experimental system works well by observing UV-UV HB spectra of the K(+) complex with benzo-18-crown-6 (B18C6), K(+).B18C6. In the UV-UV HB spectra of the K(+).B18C6 complex, gain signals are also observed; these are due to vibrationally hot K(+).B18C6 complex produced by the UV excitation of cold K(+).B18C6 complex. Then we apply UV-UV HB spectroscopy to the M(+).B12C4 complexes, and only one conformer is found for each complex except for the Li(+) complex, which has two conformers. The vibronic structure around the origin band of the UVPD spectra is quite similar for all the complexes, indicating close resemblance of the complex structure. The most stable structures calculated for the M(+).B12C4 (M = Li, Na, K, Rb, and Cs) complexes also have a similar conformation among them, which coincides with the UVPD results. In these conformers the metal ions are too big to be included in the B12C4 cavity, even for the Li(+) ion. In solution, it was reported that 12-crown 4 (12C4) shows the preference of Na(+) ion among alkali metal ions. From the similarity of the structure for the M(+).B12C4 complexes, it is suggested that the solvation of free metal ions, not of the M(+).12C4 complexes, may lead to the selectivity of Na(+) ion for 12C4 in solution. PMID- 27459365 TI - Stromal Myofibroblasts Are Associated with Poor Prognosis in Solid Cancers: A Meta-Analysis of Published Studies. AB - OBJECTIVE: Published studies have evaluated the impact of stromal myofibroblasts on prognosis in solid cancers. However, the results of these studies remain controversial. We therefore performed a meta-analysis to address this issue. METHODS: The PubMed, ISI Web of Science and Embase databases were searched through November 30th, 2015 by two investigators, and a total of 17 studies that contained 2606 patients were included. Stromal myofibroblasts were quantified in solid cancers using alpha-smooth muscle actin staining. Pooled Odds Ratio with 95% Confidence Intervals were calculated, and publication bias was analyzed. RESULTS: The results of this study suggest that in solid cancers, a high density of stromal myofibroblasts is significantly associated with poor 3- and 5-year overall survival (pooled odds ratio (95% confidence interval): 1.33 (1.10-1.60) for 3-year overall survival and 1.68 (1.22-2.32) for 5-year overall survival). In addition, a high density of stromal myofibroblasts also predicted poor 3- and 5 year disease-free survival (1.30 (1.05-1.60) for 3-year disease-free survival and 1.36 (1.01-1.83) for 5-year disease-free survival). However, stromal myofibroblasts were not associated with 3- and 5-year cancer-specific survival. No publication bias was found for all analyses. CONCLUSIONS: The results of this study suggest that a high density of stromal myofibroblasts is associated with poor survival in solid cancers. More studies were required to investigate the prognostic value of stromal myofibroblasts in different types of solid cancers. PMID- 27459368 TI - Capacity-limiting mechanisms in Li/O2 batteries. AB - A continuum model of an aprotic lithium/oxygen battery is validated against experimental first-discharge data and used to examine how the apparent cell capacity is affected by macroscopic multicomponent mass transfer, interfacial kinetics, and electronic conduction or tunneling through the discharge product. The model accounts for the three-phase nature of the positive electrode in detail, including an explicit discharge-product layer whose properties and volume distribution generally depend on the local discharge depth. Several hypothetical positive-electrode reaction mechanisms involving different product morphologies and electron-transfer sites are explored within the theoretical framework. To match experimental discharge-voltage vs. capacity and capacity vs. discharge current trends qualitatively, the discharge-product layer must be assumed to have electronic resistivity several orders of magnitude lower than typical insulators, supporting the notion that the presence of lithium peroxide does not wholly prevent electrons from reaching dissolved reactants. The discharge product also appears to allow charge transport over length scales longer than electron tunneling permits. 'Sudden death' of voltage in lithium/oxygen cells is explained by macroscopic oxygen-diffusion limitations in the positive electrode at high rates, and by pore clogging associated with discharge-product formation at low rates. PMID- 27459370 TI - Improved Electrochromic Performance of Poly(3,4-ethylenedioxythiophene) by Incorporating a Three-Dimensionally Ordered Macroporous Structure. AB - In this paper, three-dimensionally ordered macroporous (3DOM) poly(3,4 ethylenedioxythiophene) (PEDOT) films were electropolymerized from an ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim]PF6 ). The electrochromic performances of the 3DOM PEDOT films were studied. The 3DOM films exhibited high transmittance modulation (41.2 % at lambda=580 nm), high ionic fast switching speeds (0.7 and 0.7 s for coloration and bleaching, respectively), and enhanced cycling stability relative to that exhibited by the dense PEDOT film. The relationship between the declining behavior of the transmittance modulation and the nanostructure of the film was investigated. A three-period decay process was proposed to understand the declining behavior. The 3D interconnected macroporous nanostructure is beneficial for fast ion and electron transportation, high ion accessibility, and maintenance of structure integrity, which result in enhanced cycling stability and fast switching speeds. PMID- 27459369 TI - Functional Characterization of CYP94-Genes and Identification of a Novel Jasmonate Catabolite in Flowers. AB - Over the past decades much research focused on the biosynthesis of the plant hormone jasmonyl-isoleucine (JA-Ile). While many details about its biosynthetic pathway as well about its physiological function are established nowadays, knowledge about its catabolic fate is still scarce. Only recently, the hormonal inactivation mechanisms became a stronger research focus. Two major pathways have been proposed to inactivate JA-Ile: i) The cleavage of the jasmonyl-residue from the isoleucine moiety, a reaction that is catalyzed by specific amido-hydrolases, or ii), the sequential oxidation of the omega-end of the pentenyl side-chain. This reaction is catalyzed by specific members of the cytochrome P450 (CYP) subfamily CYP94: CYP94B1, CYP94B3 and CYP94C1. In the present study, we further investigated the oxidative fate of JA-Ile by expanding the analysis on Arabidopsis thaliana mutants, lacking only one (cyp94b1, cyp94b2, cyp94b3, cyp94c1), two (cyp94b1xcyp94b2, cyp94b1xcyp94b3, cyp94b2xcyp94b3), three (cyp94b1xcyp94b2xcyp94b3) or even four (cyp94b1xcyp94b2xcyp94b3xcyp94c1) CYP94 functionalities. The results obtained in the present study show that CYP94B1, CYP94B2, CYP94B3 and CYP94C1 are responsible for catalyzing the sequential omega oxidation of JA-Ile in a semi-redundant manner. While CYP94B-enzymes preferentially hydroxylate JA-Ile to 12-hydroxy-JA-Ile, CYP94C1 catalyzes primarily the subsequent oxidation, yielding 12-carboxy-JA-Ile. In addition, data obtained from investigating the triple and quadruple mutants let us hypothesize that a direct oxidation of unconjugated JA to 12-hydroxy-JA is possible in planta. Using a non-targeted metabolite fingerprinting analysis, we identified unconjugated 12-carboxy-JA as novel jasmonate derivative in floral tissues. Using the same approach, we could show that deletion of CYP94-genes might not only affect JA-homeostasis but also other signaling pathways. Deletion of CYP94B1, for example, led to accumulation of metabolites that may be characteristic for plant stress responses like systemic acquired resistance. Evaluation of the in vivo function of the different CYP94-enzymes on the JA-sensitivity demonstrated that particularly CYP94B-enzymes might play an essential role for JA-response, whereas CYP94C1 might only be of minor importance. PMID- 27459371 TI - How stable is the human gut microbiota? And why this question matters. PMID- 27459373 TI - The influence of different debridement methods on the prognosis of elderly patients with diabetic foot ulcers and sepsis. AB - BACKGROUND: We evaluated the influence of different debridement methods on the prognosis of elderly patients with diabetic foot ulcers complicated with sepsis. METHODS: Retrospective study was adopted to study 65 hospitalized elderly patients with Wagner Grade-4 diabetic foot ulcer and sepsis in Vascular Disease Department of Shanghai TCM-Integrated Hospital. Thirty-two cases were included in the thorough debridement group and the other 33 were included in the minor debridement group. We compared the mortality rates on the 7th day and 14th day after debridement, and monitored changes of sepsis-related organ failure assessment (SOFA) Score as well as C-reactive protein (CRP), procalcitonin (PCT) and D-Dimer (D-D) levels. Cox regression analysis and Kaplan-Meier analysis were used to analyze the mortality rates. Binary logistic regression analysis was employed to screen relevant prognostic factors to see the prognostic value of SOFA Score, PCT and D-D. RESULTS: Fatality rates of the thorough debridement group on the 7th day and 14th day of the debridement were higher than those in the minor debridement group and such a difference has statistical significance. The CRP, PCT, and D-D of patients within seven days after thorough debridement were obviously higher than those of patients after minor debridement. CONCLUSIONS: Damage control should be provided for elderly patients with diabetic foot ulcers and sepsis when debridement is being performed. Palliative debridement methods such as small-scale incision and drainage are less likely to affect systematic inflammatory response and coagulation function, and thus can buy time for further treatment to improve clinical effect. PMID- 27459372 TI - Rotavirus and Serotonin Cross-Talk in Diarrhoea. AB - Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNANSP4) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNAVP4, siRNAVP6 and siRNAVP7. Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p < 0.05) less diarrhoea, lower diarrhoea severity score and lower total diarrhoea output as compared to mock-treated mice (n = 9). Similarly, Ondansetron-treated mice had better weight gain than mock treated animals (p < 0.05). A most surprising finding was that the serotonin receptor antagonist significantly (p < 0.05) also attenuated total viral shedding. In summary, we show that intracellularly expressed NSP4 stimulates release of serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron. PMID- 27459374 TI - IUNS News. PMID- 27459376 TI - Influence of Morphology on the Mechanical Properties of Polymer Nanocomposites Filled with Uniform or Patchy Nanoparticles. AB - In this work we perform molecular-dynamics simulations, both on the coarse grained and the chemistry-specific levels, to study the influence of morphology on the mechanical properties of polymer nanocomposites (PNCs) filled with uniform spherical nanoparticles (which means without chemical modification) and patchy spherical nanoparticles (with discrete, attractive interaction sites at prescribed locations on the particle surface). Through the coarse-grained model, the nonlinear decrease of the elastic modulus (G') and the maximum of the viscous modulus (G") around the shear strain of 10% is clearly reproduced. By turning to the polybutadiene model, we examine the effect of the shear amplitude and the interaction strength among uniform NPs on the aggregation kinetics. Interestingly, the change of the G' as a function of the aggregation time exhibited a maximum value at intermediate time attributed to the formation of a polymer-bridged filler network in the case of strong interaction between NPs. By imposing a dynamic periodic shear, we probe the change of the G' as a function of the strain amplitude while varying the interaction strength between uniform NPs and its weight fraction. A continuous filler network is developed at a moderate shear amplitude, which is critically related to the interaction strength between NPs and the weight fraction of the fillers. In addition, we study the self assembly of the patchy NPs, which form the typical chain-like and sheet-like structures. For the first time, the effect of these self-assembled structures on the viscoelastic and stress-strain behavior of PNCs is compared. In general, in the coarse-grained model we focus on the size effect of the rough NPs on the Payne effect, while some other parameters such as the dynamic shear flow, the interaction strength between NPs, the weight fraction, and the chemically heterogeneous surface of the NPs are explored for the chemistry-specific model. PMID- 27459375 TI - Exercise Training and Weight Gain in Obese Pregnant Women: A Randomized Controlled Trial (ETIP Trial). AB - BACKGROUND: The effectiveness of exercise training for preventing excessive gestational weight gain (GWG) and gestational diabetes mellitus (GDM) is still uncertain. As maternal obesity is associated with both GWG and GDM, there is a special need to assess whether prenatal exercise training programs provided to obese women reduce the risk of adverse pregnancy outcomes. Our primary aim was to assess whether regular supervised exercise training in pregnancy could reduce GWG in women with prepregnancy overweight/obesity. Secondary aims were to examine the effects of exercise in pregnancy on 30 outcomes including GDM incidence, blood pressure, blood measurements, skinfold thickness, and body composition. METHODS AND FINDINGS: This was a single-center study where we randomized (1:1) 91 pregnant women with a prepregnancy body mass index (BMI) >= 28 kg/m2 to exercise training (n = 46) or control (standard maternity care) (n = 45). Assessments were done at baseline (pregnancy week 12-18) and in late pregnancy (week 34-37), as well as at delivery. The exercise group was offered thrice weekly supervised sessions of 35 min of moderate intensity endurance exercise and 25 min of strength training. Seventeen women were lost to follow-up (eight in the exercise group and nine in the control group). Our primary endpoint was GWG from baseline testing to delivery. The principal analyses were done as intention-to-treat analyses, with supplementary per protocol analyses where we assessed outcomes in the women who adhered to the exercise program (n = 19) compared to the control group. Mean GWG from baseline to delivery was 10.5 kg in the exercise group and 9.2 kg in the control group, with a mean difference of 0.92 kg (95% CI -1.35, 3.18; p = 0.43). Among the 30 secondary outcomes in late pregnancy, an apparent reduction was recorded in the incidence of GDM (2009 WHO definition) in the exercise group (2 cases; 6.1%) compared to the control group (9 cases; 27.3%), with an odds ratio of 0.1 (95% CI 0.02, 0.95; p = 0.04). Systolic blood pressure was significantly lower in the exercise group (mean 120.4 mm Hg) compared to the control group (mean 128.1 mm Hg), with a mean difference of -7.73 mm Hg (95% CI 13.23, -2.22; p = 0.006). No significant between-group differences were seen in diastolic blood pressure, blood measurements, skinfold thickness, or body composition in late pregnancy. In per protocol analyses, late pregnancy systolic blood pressure was 115.7 (95% CI 110.0, 121.5) mm Hg in the exercise group (significant between-group difference, p = 0.001), and diastolic blood pressure was 75.1 (95% CI 71.6, 78.7) mm Hg (significant between-group difference, p = 0.02). We had planned to recruit 150 women into the trial; hence, under recruitment represents a major limitation of our results. Another limitation to our study was the low adherence to the exercise program, with only 50% of the women included in the intention-to-treat analysis adhering as described in the study protocol. CONCLUSIONS: In this trial we did not observe a reduction in GWG among overweight/obese women who received a supervised exercise training program during their pregnancy. The incidence of GDM in late pregnancy seemed to be lower in the women randomized to exercise training than in the women receiving standard maternity care only. Systolic blood pressure in late pregnancy was also apparently lower in the exercise group than in the control group. These results indicate that supervised exercise training might be beneficial as a part of standard pregnancy care for overweight/obese women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01243554. PMID- 27459377 TI - The Spatiotemporal Stability of Dominant Frequency Sites in In-Silico Modeling of 3-Dimensional Left Atrial Mapping of Atrial Fibrillation. AB - BACKGROUND: We previously reported that stable rotors were observed in in-silico human atrial fibrillation (AF) models, and were well represented by dominant frequency (DF). We explored the spatiotemporal stability of DF sites in 3D-AF models imported from patient CT images of the left atrium (LA). METHODS: We integrated 3-D CT images of the LA obtained from ten patients with persistent AF (male 80%, 61.8 +/- 13.5 years old) into an in-silico AF model. After induction, we obtained 6 seconds of AF simulation data for DF analyses in 30 second intervals (T1-T9). The LA was divided into ten sections. Spatiotemporal changes and variations in the temporal consistency of DF were evaluated at each section of the LA. The high DF area was defined as the area with the highest 10% DF. RESULTS: 1. There was no spatial consistency in the high DF distribution at each LA section during T1-T9 except in one patient (p = 0.027). 2. Coefficients of variation for the high DF area were highly different among the ten LA sections (p < 0.001), and they were significantly higher in the four pulmonary vein (PV) areas, the LA appendage, and the peri-mitral area than in the other LA sections (p < 0.001). 3. When we conducted virtual ablation of 10%, 15%, and 20% of the highest DF areas (n = 270 cases), AF was changed to atrial tachycardia (AT) or terminated at a rate of 40%, 57%, and 76%, respectively. CONCLUSIONS: Spatiotemporal consistency of the DF area was observed in 10% of AF patients, and high DF areas were temporally variable. Virtual ablation of DF is moderately effective in AF termination and AF changing into AT. PMID- 27459378 TI - Time Perception in Mild Cognitive Impairment: Interval Length and Subjective Passage of Time. AB - OBJECTIVES: Patients with mild cognitive impairment (MCI) may have difficulties in time perception, which in turn might contribute to some of their symptoms, especially memory deficits. The aim of this study was to evaluate perception of interval length and subjective passage of time in MCI patients as compared to healthy controls. METHODS: Fifty-five MCI patients and 57 healthy controls underwent an experimental protocol for time perception on interval length, a questionnaire for the subjective passage of time and a neuropsychological evaluation. RESULTS: MCI patients presented no changes in the perception of interval length. However, for MCI patients, time seemed to pass more slowly than it did for controls. This experience was significantly correlated with memory deficits but not with performance in executive tests, nor with complaints of depression or anxiety. CONCLUSIONS: Memory deficits do not affect the perception of interval length, but are associated with alterations in the subjective passage of time. (JINS, 2016, 22, 755-764). PMID- 27459379 TI - Chronic Effects of Blast-Related TBI on Subcortical Functional Connectivity in Veterans - Erratum. PMID- 27459380 TI - The Moderating Effect of State Anger on Treatment Outcome in Female Adolescents With PTSD. AB - Trauma experienced in childhood and adolescence negatively affects the development of adaptive regulation of emotions and is associated with greater symptoms of anger. Prior research has suggested that high levels of anger may impede the outcome of treatment in adults with posttraumatic stress disorder (PTSD). The current study investigated whether high levels of anger resulted in poorer treatment outcomes in adolescent girls with PTSD. Participants included 61 female adolescent survivors of sexual abuse or assault who were randomized to either prolonged exposure for adolescents (PE-A) or client-centered therapy (CCT) for traumatized children for 8-14 weekly sessions. Participants were followed for 12 months posttreatment. High levels of state anger at baseline were associated with less improvement in PTSD symptoms in the CCT group than the PE-A group (d = 0.62). The moderating effects of state anger on improvement in PTSD symptoms was significant with emotion regulation difficulties, which may underlie anger symptoms (d = 0.58) in the model. The results of this study suggessted that high state anger was less of an impediment to treatment of PTSD for those receiving PE A than those receiving less differentiated approaches such as CCT. PMID- 27459381 TI - Leukocyte trafficking is not affected by multikinase inhibitors sunitinib or sorafenib in mice. AB - Sunitinib and sorafenib are broad-spectrum tyrosine kinase inhibitors (TKI) targeting, for example, VEGF1-3, PDGFRb, RET, FLT3, CD117 (c-KIT) and CSF-1R cell membrane receptors thus suppressing tumor angiogenesis and cancer cell growth. Recently it has been suggested that the kinases targeted by Sunitinib and/or Sorafenib regulate leukocyte transmigration, which might in part be responsible for the often-observed reduction in tumor-associated myeloid derived suppressor cells and regulatory T cells. The aim of the current study is to determine whether sunitinib or sorafenib inhibit leukocyte extravasation. Sunitinib, sorafenib, or vehicle treated animals did not show any difference in leukocyte trafficking either in peritonitis or in vivo homing experiments, although sunitinib treatment effectively inhibited growth of B16 melanoma tumors in WT, SCID and SCID beige mice. Inhibition of tumor growth was associated with an increased number of infiltrating CD11b+ cells in the tumor, while the numbers of CD8, Gr-1 and F4/80 expressing cells were unchanged. In conclusion, the findings suggest that despite multiple targets with a potential role in leukocyte extravasation, neither sunitinib nor sorafenib effectively inhibits this process in vivo. Thus, the observed specific effect on CD11b cells among tumor infiltrating leukocytes is most likely an indirect effect. PMID- 27459382 TI - Artificial Swimmers Propelled by Acoustically Activated Flagella. AB - Recent studies have garnered considerable interest in the field of propulsion to maneuver micro- and nanosized objects. Acoustics provide an alternate and attractive method to generate propulsion. To date, most acoustic-based swimmers do not use structural resonances, and their motion is determined by a combination of bulk acoustic streaming and a standing-wave field. The resultant field is intrinsically dependent on the boundaries of their resonating chambers. Though acoustic based propulsion is appealing in biological contexts, existing swimmers are less efficient, especially when operating in vivo, since no predictable standing-wave can be established in a human body. Here we describe a new class of nanoswimmer propelled by the small-amplitude oscillation of a flagellum-like flexible tail in standing and, more importantly, in traveling acoustic waves. The artificial nanoswimmer, fabricated by multistep electrodeposition techniques, compromises a rigid bimetallic head and a flexible tail. During acoustic excitation of the nanoswimmer the tail structure oscillates, which leads to a large amplitude propulsion in traveling waves. FEM simulation results show that the structural resonances lead to high propulsive forces. PMID- 27459383 TI - Correction: Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor. AB - [This corrects the article DOI: 10.1371/journal.pone.0155030.]. PMID- 27459384 TI - Comparison of Insulin Resistance and beta-Cell Dysfunction Between the Young and the Elderly in Normal Glucose Tolerance and Prediabetes Population: A Prospective Study. AB - Insulin resistance and beta-cell function are different between the young and elderly diabetes individuals, which are not well elaborated in the nondiabetic persons. The aims of this study were to compare insulin resistance and beta-cell function between young and old adults from normal glucose tolerance (NGT) to prediabetes [which was subdivided into isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), and a combination of both (IFG/IGT)], and compare the prevalence of diabetes mellitus (DM) in the above prediabetes subgroups between different age groups after 3 years. A total of 1 374 subjects aged below 40 or above 60 years old with NGT or prediabetes were finally included in this study. Insulin resistance and beta-cell function from homeostasis model assessment (HOMA) and interactive, 24-variable homeostatic model of assessment (iHOMA2) were compared between different age groups. The rate of transition to diabetes between different age groups in all pre-diabetes subgroups was also compared. Compared with the old groups, young i-IFG and IFG/IGT groups exhibit higher log HOMA-IR and log HOMA2-S, whereas the young i IGT groups experienced comparable log HOMA-IR and log HOMA2-S when compared with old i-IFG and IFG/IGT groups. Three prediabetes subgroups all had similar log HOMA-B and log HOMA2-B between different age groups. In addition, the prevalence of diabetes in young i-IFG was statistically higher than that in old i-IFG after 3 years. Age is negatively related to log HOMA2-B in both age groups. Considering an age-related deterioration of beta-cell function, young i-IFG, young i-IGT, and young IFG/IGT all suffered a greater impairment in insulin secretion than the old groups. Young i-IFG and IFG/IGT have more severe insulin resistance than the old groups. In addition, young i-IFG characterized with a higher incidence of DM than the old i-IFG. These disparities highlight that the prevention to slow progression from prediabetes to type 2 diabetes should be additionally focused in young prediabetes individuals, especially young i-IFG. PMID- 27459385 TI - CYP2J2-Derived EETs Attenuated Angiotensin II-Induced Adventitial Remodeling via Reduced Inflammatory Response. AB - BACKGROUND: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling. METHODS: We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling. RESULTS: CYP/sEH system was found to exist in human adventitia, and involved in adventitial remodeling process. Exogenous EETs administration significantly inhibited Ang II-induced AFs activation, characterized by differentiation, proliferation, migration, and collagen synthesis. These protective effects were partially reversed by PPARx03B3; antagonist GW9662 pretreatment or SOCS3 siRNA transfection. EETs suppressed Ang II-induced Ix03BA;Balpha phosphorylation, subsequent NF-x03BA;B nuclear translocation via PPARx03B3; dependent signaling pathway in AFs. Additionally, EETs reduced Ang II-induced JAK2, STAT3 phosphorylation and subsequent phosphor STAT3 nuclear translocation, which were mediated by SOCS3 induction but independent of PPARx03B3; activation. Furthermore, rAAV-CYP2J2 gene delivery reduced vessel wall thickening, AFs differentiation, proliferation and collagen deposition in aortic adventitia induced by Ang II infusion, which were mediated by NF-x03BA;B and SOCS3/JAK/STAT signaling pathways in blood pressure dependent and independent manner, respectively. CONCLUSION: We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARx03B3; dependent NF-x03BA;B and PPARx03B3;-independent SOCS3/JAK/STAT inflammatory signaling pathways. PMID- 27459386 TI - The Expression of Programmed Death-1 on CD4+ and CD8+ T Lymphocytes in Patients with Type 2 Diabetes and Severe Sepsis. AB - OBJECTIVE: To investigate the expression of Programmed death-1 (PD-1) on T lymphocytes in patients with type 2 diabetes mellitus (T2DM) and severe sepsis, we determined PD-1 expression on CD4+ and CD8+ T lymphocytes of patients with T2DM, severe sepsis, and T2DM combined with severe sepsis. RESEARCH DESIGN AND METHODS: This prospective and observational study included 50 healthy controls, 80 cases of T2DM without infection (T2DM group), 88 cases of severe sepsis without T2DM (SS group), and 77 cases of severe sepsis combined with T2DM (SS+T2DM group). Expression of peripheral blood PD-1+ CD4+ T cells and PD-1+ CD8+ T cells were compared between these 4 groups. Then, 28-day survival of the SS and SS+T2DM patients was assessed, and the expression of PD-1 on T cells was also compared between survivors and non-survivors. RESULTS: Percentages of PD-1+ CD4+ T cells and PD-1+ CD8+ T cells were higher in the T2DM group than in the healthy control group, and were highest in the SS and SS+T2DM groups. However, the expression of PD-1 on T cells and the mortality showed no significant difference between the SS and SS+T2DM groups. The expression of PD-1 on T cells was higher in non-survivors than survivors, but within the survivor group or non-survivor group, no difference can be detected between those with T2DM and those without T2DM. CONCLUSION: The expression of PD-1 on T cells was increased in both T2DM and severe septic patients, but combining T2DM did not cause a further increase on the PD-1 expression in patients with severe sepsis. PMID- 27459387 TI - A Novel Bufalin Derivative Exhibited Stronger Apoptosis-Inducing Effect than Bufalin in A549 Lung Cancer Cells and Lower Acute Toxicity in Mice. AB - BF211 is a synthetic molecule derived from bufalin (BF). The apoptosis-inducing effect of BF211 was stronger than that of BF while the acute toxicity of BF211 was much lower than that of BF. BF211 exhibited promising concentration-dependent anti-cancer effects in nude mice inoculated with A549 cells in vivo. The growth of A549 tumor xenografts was almost totally blocked by treatment with BF211 at 6 mg/kg. Notably, BF and BF211 exhibited differences in their binding affinity and kinetics to recombinant proteins of the alpha subunits of Na+/K+-ATPase. Furthermore, there was a difference in the effects of BF or BF211 on inhibiting the activity of porcine cortex Na+/K+-ATPase and in their time-dependent effects on intracellular Ca2+ levels in A549 cells. The time-dependent effects of BF or BF211 on the activation of Src, which was mediated by the Na+/K+-ATPase signalosome, in A549 cells were also different. Both BF and BF211 could induce apoptosis-related cascades, such as activation of caspase-3 and the cleavage of PARP (poly ADP-ribose polymerase) in A549 cells, in a concentration-dependent manner; however, the effects of BF211 on apoptosis-related cascades was stronger than that of BF. The results of the present study supported the importance of binding to the Na+/K+-ATPase alpha subunits in the mechanism of cardiac steroids and also suggested the possibility of developing new cardiac steroids with a stronger anti-cancer activity and lower toxicity as new anti-cancer agents. PMID- 27459388 TI - Perilesional Inflammation in Neurocysticercosis - Relationship Between Contrast Enhanced Magnetic Resonance Imaging, Evans Blue Staining and Histopathology in the Pig Model. AB - BACKGROUND: Disease manifestations in neurocysticercosis (NCC) are frequently due to inflammation of degenerating Taenia solium brain cysts. Exacerbated inflammation post anthelmintic treatment is associated with leakage of the blood brain barrier (BBB) using Evans blue (EB) staining. How well EB extravasation into the brain correlates with magnetic resonance imaging (MRI) using gadolinium (Gd) enhancement as a contrast agent and pericystic inflammation was analyzed in pigs harboring brain cysts of Taenia solium. METHODOLOGY/PRINCIPAL FINDINGS: Three groups of 4 naturally infected pigs were assessed. The first and second groups were treated with both praziquantel plus albendazole and sacrificed two and five days post treatment, respectively. A third untreated group remained untreated. Pigs were injected with EB two hours prior to evaluation by Gd enhanced T1-MRI, and euthanized. The EB staining for each cyst capsule was scored (EB grades were 0: 0%; 1: up to 50%; 2: over 50% but less than 100%; 3: 100%). Similarly, the Gd enhancement around each cyst was qualitatively and quantitatively scored from the MRI. The extent of pericystic inflammation on histology was scored in increasing severity as IS1, IS2, IS3 and IS4. Grade 3 EB staining and enhancement was only seen in treated capsules. Also, treated groups had higher Gd intensity than the untreated group. Grades of enhancement correlated significantly with Gd enhancement intensity. EB staining was correlated with Gd enhancement intensity and with IS4 in the treated groups. These correlations were stronger in internally located cysts compared to superficial cysts in treated groups. SIGNIFICANCE: EB staining and Gd enhancement strongly correlate. The intensity of enhancement determined by MRI is a good indication of the degree of inflammation. Similarly, EB staining highly correlates with the degree of inflammation and may be applied to study inflammation in the pig model of NCC. PMID- 27459389 TI - HKDC1 Is a Novel Hexokinase Involved in Whole-Body Glucose Use. AB - In a recent genome-wide association study, hexokinase domain-containing protein 1, or HKDC1, was found to be associated with gestational glucose levels during 2 hour glucose tolerance tests at 28 weeks of pregnancy. Because our understanding of the mediators of gestational glucose homeostasis is incomplete, we have generated the first transgenic mouse model to begin to understand the role of HKDC1 in whole-body glucose homeostasis. Interestingly, deletion of both HKDC1 alleles results in in utero embryonic lethality. Thus, in this study, we report the in vivo role of HKDC1 in whole-body glucose homeostasis using a heterozygous deleted HKDC1 mouse model (HKDC1(+/-)) as compared with matched wild-type mice. First, we observed no weight, fasting or random glucose, or fasting insulin abnormalities with aging in male and female HKDC1(+/-) mice. However, during glucose tolerance tests, glucose levels were impaired in both female and male HKDC1(+/-) mice at 15, 30, and 120 minutes at a later age (28 wk of age). These glucose tolerance differences also existed in the female HKDC1(+/-) mice at earlier ages but only during pregnancy. And finally, the impaired glucose tolerance in HKDC1(+/-) mice was likely due to diminished whole-body glucose use, as indicated by the decreased hepatic energy storage and reduced peripheral tissue uptake of glucose in HKDC1(+/-) mice. Collectively, these data highlight that HKDC1 is needed to maintain whole-body glucose homeostasis during pregnancy but also with aging, possibly through its role in glucose use. PMID- 27459391 TI - A Red-Emitting Luminescent Material Capable of Detecting Low Water Content in Organic Solvents. AB - A new red-emitting luminescent material was prepared from a gel formed by simply mixing EuCl3 ?6 H2 O and 4'-para-phenylcarboxyl-2,2':6',2''-terpyridine (Hcptpy) in a molar ratio of 1:2 in anhydrous ethanol at room temperature. It shows bright red luminescence dominated by the (5) D0 ->(7) F2 transition of Eu(3+) , a long lifetime (1.16 ms), a high absolute quantum yield (48.2 %), and good thermostability (stable up to 500 degrees C). In addition, the luminescence of the material can be easily quenched by contact with water, which makes it suitable for detecting low contents of water (0.1-1.5 vol %) in common organic solvents such as diethyl ether and THF. PMID- 27459390 TI - The neural circuits recruited for the production of signs and fingerspelled words. AB - Signing differs from typical non-linguistic hand actions because movements are not visually guided, finger movements are complex (particularly for fingerspelling), and signs are not produced as holistic gestures. We used positron emission tomography to investigate the neural circuits involved in the production of American Sign Language (ASL). Different types of signs (one-handed (articulated in neutral space), two-handed (neutral space), and one-handed body anchored signs) were elicited by asking deaf native signers to produce sign translations of English words. Participants also fingerspelled (one-handed) printed English words. For the baseline task, participants indicated whether a word contained a descending letter. Fingerspelling engaged ipsilateral motor cortex and cerebellar cortex in contrast to both one-handed signs and the descender baseline task, which may reflect greater timing demands and complexity of handshape sequences required for fingerspelling. Greater activation in the visual word form area was also observed for fingerspelled words compared to one handed signs. Body-anchored signs engaged bilateral superior parietal cortex to a greater extent than the descender baseline task and neutral space signs, reflecting the motor control and proprioceptive monitoring required to direct the hand toward a specific location on the body. Less activation in parts of the motor circuit was observed for two-handed signs compared to one-handed signs, possibly because, for half of the signs, handshape and movement goals were spread across the two limbs. Finally, the conjunction analysis comparing each sign type with the descender baseline task revealed common activation in the supramarginal gyrus bilaterally, which we interpret as reflecting phonological retrieval and encoding processes. PMID- 27459392 TI - Epidemiological Risk Factors and Perinatal Outcomes of Congenital Anomalies. AB - Objectives To identify the epidemiological risk factors for congenital anomalies (CAs) and the impact of these fetal malformations on the perinatal outcomes. Methods This prospective cohort study comprised 275 women whose fetuses had CAs. Maternal variables to establish potential risk factors for each group of CA and perinatal outcomes were evaluated. The primary outcome was CA. Secondary outcomes included: fetal growth restriction (FGR); fetal distress (FD); premature rupture of membranes (PROM); oligohydramnios or polyhydramnios; preterm delivery (PTD); stillbirth; cesarean section; low birth weight; Apgar score < 7 at the 1st and 5th minutes; need for assisted ventilation at birth; neonatal infection; need for surgical treatment; early neonatal death; and hospitalization time. Chi-square (chi(2)) test and multilevel regression analysis were applied to compare the groups and determine the effects of maternal characteristics on the incidence of CAs. Results The general prevalence of CAs was of 2.4%. Several maternal characteristics were associated to CAs, such as: age; skin color; level of education; parity; folic acid supplementation; tobacco use; and history of previous miscarriage. There were no significant differences among the CA groups in relation to FGR, FD, PROM, 1-minute Apgar score > 7, and need for assisted ventilation at birth. On the other hand, the prevalence of the other considered outcomes varied significantly among groups. Preterm delivery was significantly more frequent in gastrointestinal tract/abdominal wall defects. The stillbirth rate was increased in all CAs, mainly in isolated fetal hydrops (odds ratio [OR]: 27.13; 95% confidence interval [95%CI]: 2.90-253.47). Hospitalization time was higher for the urinary tract and congenital heart disease groups (p < 0.01). Neonatal death was significantly less frequent in the central nervous system anomalies group. Conclusion It was possible to identify several risk factors for CAs. Adverse perinatal outcomes were presented in all CA groups, and may differ according to the type of CA considered. PMID- 27459393 TI - Cytokine secreted by S100A9 via TLR4 in monocytes delays neutrophil apoptosis by inhibition of caspase 9/3 pathway. AB - Dysregulation of neutrophil apoptosis causes pathogenesis and aggravation of allergy. S100A9 exists as one of the proteins in the neutrophils, triggering inflammatory responses by activating the immune cells. In this study, we investigated whether S100A9 affects constitutive neutrophil apoptosis by activating the monocytes in normal and allergic subjects. Supernatant from human monocytic THP-1 cells after treatment with S100A9 suppressed normal neutrophil apoptosis by inhibiting the activations of caspase 9 and caspase 3. S100A9 upregulated the release of MCP-1, IL-6, and IL-8 in THP-1 cells. An increase in cytokine was suppressed by CLI-095, a Toll-like receptor (TLR) 4 inhibitor, PP2, a Src inhibitor, rottlerin, a PKCdelta inhibitor, MAP kinase inhibitors, including PD98059, SB202190, and SP600125, and BAY-11-7085, an NF-kappaB inhibitor. Src, PKCdelta, ERK1/2, p38 MAPK, and JNK were phosphorylated by S100A9. The phosphorylation of Src and PKCdelta was suppressed by CLI-095, and the activation of ERK1/2, p38 MAPK, and JNK was inhibited by CLI-095, PP2, and rottlerin. S100A9 induced NF-kappaB activity, and the activation was suppressed by CLI-095, PP2, rottlerin, and MAPK kinase inhibitors. In normal and allergic subjects, supernatant from normal and allergic monocytes after stimulation with S100A9 suppressed normal and allergic neutrophil apoptosis, respectively; MCP-1, IL-6, and IL-8 in the supernatant was increased by S100A9. The cytokine secretion induced by S100A9 is related to TLR4, Src, PKCdelta, ERK1/2, p38 MAPK, JNK, and NF-kappaB. Taken together, S100A9 induces anti-apoptotic effect on normal and allergic neutrophils by increasing cytokine secretion of monocytes. These findings may help us to better understand neutrophil apoptosis regulated by S100A9 and pathogenesis of allergic diseases. PMID- 27459394 TI - Skin Cancer-The Importance of Prevention. PMID- 27459395 TI - Self-perceptions of romantic appeal in adolescents with a cleft lip and/or palate. AB - During adolescence, romantic relationships are a key developmental milestone. Coupled with the increasing salience of appearance and social acceptance, adolescents with an appearance-altering condition may feel particularly vulnerable when it comes to romantic relationships. This study aimed to explore the prevalence of romantic experiences among adolescents with a cleft lip and/or palate (CL/P), and to investigate how these experiences could be related to depressive symptoms and global self-worth. The study included 661 Norwegian adolescents with CL/P, who were compared to a large national sample. The prevalence of romantic relationships was lower among adolescents with CL/P compared to the reference group, although the overall impact on depressive symptoms and global self-worth appeared to be low. This study is one of few to explore the impact of a congenital visible condition on experiences of romantic relationships and provides preliminary insight into a significant, yet complex topic. PMID- 27459396 TI - Dangerous Beliefs: College Alcohol Beliefs Are Associated With Increased Risk of Regretted Sexual Encounters. AB - This study explored the relative impact of college alcohol beliefs (CABs; i.e., the extent to which the student views alcohol as part of the fabric of college life), descriptive norms, injunctive norms, positive alcohol expectancies, and sensation seeking on college students' (N = 415) risk for engaging in regretted sexual encounters (RSE). Overall, 12% of our sample reported having experienced RSE within the past 30 days. When pitted against the other traditional predictors of college student drinking and its consequences, such as positive alcohol expectancies, descriptive and injunctive norms, and sensation seeking, CABs emerged as the strongest correlate of RSE other than drinking itself, and explained significant additional variance in RSE beyond these other predictors. Mediation analyses revealed that CABs had a significant indirect effect on RSE through typical weekly drinking. This pattern of findings indicates that college alcohol beliefs are, from a public health perspective, dangerous beliefs, that warrant serious consideration in the development of new approaches to college student drinking and its consequences. PMID- 27459397 TI - Simulating Spatial Microwave Manipulation of Polyatomic Asymmetric-Top Molecules Using a Multi-Level Approach. AB - A numerical approach that employs a multi-level dressed state method to determine the AC-Stark shifts of molecular rotational energy levels is described. This approach goes beyond the two-level approximation often employed for simpler molecules, such as ammonia and acetonitrile, and is applicable to a variety of molecules. The calculations are used to develop experiments aimed at focusing, guiding, decelerating and trapping neutral, polyatomic, asymmetric-top molecules by using microwave fields. Herein, numerical calculations are performed for acetonitrile and 4-aminobenzonitrile. Based on these results, trajectory simulations are performed to predict the outcome of microwave focusing experiments in the TE1,1,p mode of a cylindrically symmetric microwave resonator. Simulations show that, for such an experimental setup, microwave focusing and guiding of 4-aminobenzonitrile requires starting longitudinal velocities close to, or below, 100 m s-1 , that is, much lower than values obtained with standard molecular beam techniques, such as supersonic expansion. Therefore, alternative beam-generation techniques, for example, buffer-gas-cooled molecular beams, are required to extend microwave manipulation methods to larger and more complex molecules. PMID- 27459398 TI - Attentional Control Scale for Children: Factor Structure and Concurrent Validity Among Children and Adolescents Referred for Anxiety Disorders. AB - OBJECTIVE: The present study examined the factor structure and concurrent validity of the Attentional Control Scale for Children (ACS-C; Muris, de Jong, & Engelen, 2004), a youth self-rating scale of attentional control. METHOD: A multisource assessment approach was used with 186 children and adolescents referred to an anxiety disorders specialty clinic. RESULTS: Exploratory factor analysis yielded a 2-factor structure with internally consistent and moderately correlated subscales of Attentional Focusing and Attentional Shifting. Total ACS C and subscale scores demonstrated significant associations with youth and parent ratings of youth anxiety symptoms, youth self ratings of depressive symptoms, and youth diagnosis of attention deficit-hyperactivity disorder. CONCLUSIONS: These findings support use of the ACS-C as a self-rating scale of attentional control among referred youth. Future research is encouraged to examine retest reliability of the ACS-C and to evaluate whether its internal structure could be enhanced by removing or modifying items that performed poorly. PMID- 27459399 TI - High Quality Factor Mechanical Resonators Based on WSe2 Monolayers. AB - Suspended monolayer transition metal dichalcogenides (TMD) are membranes that combine ultralow mass and exceptional optical properties, making them intriguing materials for opto-mechanical applications. However, the low measured quality factor of TMD resonators has been a roadblock so far. Here, we report an ultrasensitive optical readout of monolayer TMD resonators that allows us to reveal their mechanical properties at cryogenic temperatures. We find that the quality factor of monolayer WSe2 resonators greatly increases below room temperature, reaching values as high as 1.6 * 10(4) at liquid nitrogen temperature and 4.7 * 10(4) at liquid helium temperature. This surpasses the quality factor of monolayer graphene resonators with similar surface areas. Upon cooling the resonator, the resonant frequency increases significantly due to the thermal contraction of the WSe2 lattice. These measurements allow us to experimentally study the thermal expansion coefficient of WSe2 monolayers for the first time. High Q-factors are also found in resonators based on MoS2 and MoSe2 monolayers. The high quality-factor found in this work opens new possibilities for coupling mechanical vibrational states to two-dimensional excitons, valley pseudospins, and single quantum emitters and for quantum opto-mechanical experiments based on the Casimir interaction. PMID- 27459400 TI - Tobacco assessment in completed lung cancer treatment trials. PMID- 27459401 TI - Difference in suitable mechanical properties of three-dimensional, synthetic scaffolds for self-renewing mouse embryonic stem cells of different genetic backgrounds. AB - We evaluated whether the genetic background of embryonic stem cells (ESCs) affects the properties suitable for three-dimensional (3D) synthetic scaffolds for cell self-renewal. Inbred R1 and hybrid B6D2F1 mouse ESC lines were cultured for 7 days in hydrogel scaffolds with different properties derived from conjugating 7.5, 10, 12.5, or 15% (wt/vol) vinylsulfone-functionalized three-, four-, or eight-arm polyethylene glycol (PEG) with dicysteine-containing crosslinkers with an intervening matrix metalloproteinase-specific cleavage sites. Cell proliferation and expression of self-renewal-related genes and proteins by ESCs cultured in feeder-free or containing 2D culture plate or 3D hydrogel were monitored. As a preliminary experiment, the E14 ESC-customized synthetic 3D microenvironment did not maintain self-renewal of either the R1 or B6D2F1 ESCs. The best R1 cell proliferation (10.04 vs. 0.16-4.39; p < 0.0001) was observed in the four-arm 7.5% PEG-based hydrogels than those with other properties, whereas the F1 ESCs showed better proliferation when they were embedded in the three-arm 10% hydrogels. Self-renewal-related gene and protein expression by ESCs after feeder-free 3D culture was generally maintained compared with the feeder-containing 2D culture, but expression patterns and quantities differed. However, the feeder-free 3D culture yielded better expression than the feeder-free 2D culture. In conclusion, genetic background determined the suitability of hydrogel scaffolds for self-renewal of ESCs, which requires customization for the mechanical properties of each cell line. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2261-2268, 2017. PMID- 27459402 TI - Crash course in pallidus-habenula signaling. PMID- 27459403 TI - Treatment synergy in axon regeneration. PMID- 27459404 TI - More than meets the eye. PMID- 27459406 TI - Corrigendum: A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. PMID- 27459405 TI - A polarizing question: do M1 and M2 microglia exist? AB - Microglial research has entered a fertile, dynamic phase characterized by novel technologies including two-photon imaging, whole-genome transcriptomic and epigenomic analysis with complementary bioinformatics, unbiased proteomics, cytometry by time of flight (CyTOF; Fluidigm) cytometry, and complex high-content experimental models including slice culture and zebrafish. Against this vivid background of newly emerging data, investigators will encounter in the microglial research literature a body of published work using the terminology of macrophage polarization, most commonly into the M1 and M2 phenotypes. It is the assertion of this opinion piece that microglial polarization has not been established by research findings. Rather, the adoption of this schema was undertaken in an attempt to simplify data interpretation at a time when the ontogeny and functional significance of microglia had not yet been characterized. Now, terminology suggesting established meaningful pathways of microglial polarization hinders rather than aids research progress and should be discarded. PMID- 27459407 TI - Corrigendum: Hedgehog signaling promotes basal progenitor expansion and the growth and folding of the neocortex. PMID- 27459408 TI - Addendum: The schizophrenia risk gene product miR-137 alters presynaptic plasticity. PMID- 27459409 TI - Event-triggered Hinfinity filter design for delayed neural network with quantization. AB - This paper is concerned with Hinfinity filter design for a class of neural network systems with event-triggered communication scheme and quantization. Firstly, a new event-triggered communication scheme is introduced to determine whether or not the current sampled sensor data should be broadcasted and transmitted to quantizer, which can save the limited communication resource. Secondly, a logarithmic quantizer is used to quantify the sampled data, which can reduce the data transmission rate in the network. Thirdly, considering the influence of the constrained network resource, we investigate the problem of Hinfinity filter design for a class of event-triggered neural network systems with quantization. By using Lyapunov functional and linear matrix inequality (LMI) techniques, some delay-dependent stability conditions for the existence of the desired filter are obtained. Furthermore, the explicit expression is given for the designed filter parameters in terms of LMIs. Finally, a numerical example is given to show the usefulness of the obtained theoretical results. PMID- 27459410 TI - Functional Toxicogenomic Assessment of Triclosan in Human HepG2 Cells Using Genome-Wide CRISPR-Cas9 Screening. AB - There are thousands of chemicals used by humans and detected in the environment for which limited or no toxicological data are available. Rapid and cost effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic screening to identify the potential molecular mechanism of a widely used antimicrobial triclosan (TCS) in HepG2 cells. Resistant genes at IC50 (the concentration causing a 50% reduction in cell viability) were significantly enriched in the adherens junction pathway, MAPK signaling pathway, and PPAR signaling pathway, suggesting a potential role in the molecular mechanism of TCS-induced cytotoxicity. Evaluation of the top ranked resistant genes, FTO (encoding an mRNA demethylase) and MAP2K3 (a MAP kinase kinase family gene), revealed that their loss conferred resistance to TCS. In contrast, sensitive genes at IC10 and IC20 were specifically enriched in pathways involved with immune responses, which was concordant with transcriptomic profiling of TCS at concentrations of 3 days/week) had the lowest risk of mortality compared with abstainers and women who consumed substantially more than 1 drink per day. PMID- 27459456 TI - Breast Cancer Research in the Nurses' Health Studies: Exposures Across the Life Course. AB - OBJECTIVES: To review the contribution of the Nurses' Heath Study (NHS) and the NHS II in identifying risk and protective factors for breast cancer incidence and survival. METHODS: We conducted a narrative review of NHS and NHS II articles on breast cancer incidence and survival published from 1976 to 2016, with a focus on exogenous and endogenous hormones; lifestyle factors, including diet, physical activity, and aspirin use; intermediate markers of risk; and genetic factors. RESULTS: With the investigation of individual risk factors, as well as their incorporation into risk prediction models, the NHS has contributed to the identification of ways in which women may reduce breast cancer risk, including limiting alcohol consumption, reducing the duration of postmenopausal estrogen plus-progestin use, avoiding weight gain, and increasing vegetable consumption. In addition, the NHS has helped elucidate the roles of several biomarkers and contributed to the identification of risk alleles. CONCLUSIONS: The NHS has contributed to our understanding of lifestyle, hormonal, and genetic risk factors for breast cancer, highlighting the importance of exposures across the life course, and has helped identify lifestyle changes that may reduce risk and improve survival after a diagnosis of breast cancer. PMID- 27459457 TI - Epidemiological Assessments of Skin Outcomes in the Nurses' Health Studies. AB - OBJECTIVES: To review the contribution of the Nurses' Health Studies (NHSs) to identifying epidemiological factors associated with multiple skin diseases, including skin cancer, psoriasis, and other inflammatory and autoimmune skin diseases. METHODS: We carried out a narrative review of NHS articles published between 1976 and 2016. RESULTS: The NHSs have identified environmental and lifestyle factors related to psoriasis, supporting obesity and smoking as psoriasis risk factors; associations between psoriasis and diabetes, myocardial infarction, and Crohn's disease, supporting psoriasis as a systemic disorder; and associations of pigmentary traits, ultraviolet radiation, and lifestyle factors such as citrus consumption with risk of skin cancer. Genetic studies have identified novel genetic loci for skin pigmentation (e.g., IRF4, SLC24A4, NID1, and EDNRB) and skin cancer (e.g., TET2 and HERC2-OCA2). Work continues on highly prevalent but less studied skin conditions such as rosacea, acne, and atopic dermatitis. The NHS results have influenced public health policies on indoor tanning devices. CONCLUSIONS: The NHSs have provided invaluable resources on skin disease population science and contributed to the etiological understanding of multiple skin disorders. PMID- 27459458 TI - Nurses' Health Study Contributions on the Epidemiology of Less Common Cancers: Endometrial, Ovarian, Pancreatic, and Hematologic. AB - OBJECTIVES: To review the contributions of the Nurses' Health Study (NHS) to epidemiologic knowledge of endometrial, ovarian, pancreatic, and hematologic cancers. METHODS: We reviewed selected NHS publications from 1976 to 2016, including publications from consortia and other pooled studies. RESULTS: NHS studies on less common cancers have identified novel risk factors, such as a reduced risk of endometrial cancer in women of advanced age at last birth, and have clarified or prospectively confirmed previously reported associations, including an inverse association between tubal ligation and ovarian cancer. Through biomarker research, the NHS has furthered understanding of the pathogenesis of rare cancers, such as the role of altered metabolism in pancreatic cancer risk and survival. NHS investigations have also demonstrated the importance of the timing of exposure, such as the finding of a positive association of early life body fatness, but not of usual adult body mass index, with non-Hodgkin lymphoma risk. CONCLUSIONS: Evidence from the NHS has informed prevention strategies and contributed to improved survival from less common but often lethal malignancies, including endometrial, ovarian, pancreatic, and hematologic cancers. PMID- 27459459 TI - Diet Assessment Methods in the Nurses' Health Studies and Contribution to Evidence-Based Nutritional Policies and Guidelines. AB - OBJECTIVES: To review the contribution of the Nurses' Health Studies (NHSs) to diet assessment methods and evidence-based nutritional policies and guidelines. METHODS: We performed a narrative review of the publications of the NHS and NHS II between 1976 and 2016. RESULTS: Through periodic assessment of diet by validated dietary questionnaires over 40 years, the NHSs have identified dietary determinants of diseases such as breast and other cancers; obesity; type 2 diabetes; cardiovascular, respiratory, and eye diseases; and neurodegenerative and mental health disorders. Nutritional biomarkers were assessed using blood, urine, and toenail samples. Robust findings, from the NHSs, together with evidence from other large cohorts and randomized dietary intervention trials, have contributed to the evidence base for developing dietary guidelines and nutritional policies to reduce intakes of trans fat, saturated fat, sugar sweetened beverages, red and processed meats, and refined carbohydrates while promoting higher intake of healthy fats and carbohydrates and overall healthful dietary patterns. CONCLUSIONS: The long-term, periodically collected dietary data in the NHSs, with documented reliability and validity, have contributed extensively to our understanding of the dietary determinants of various diseases, informing dietary guidelines and shaping nutritional policy. PMID- 27459460 TI - Determinants and Consequences of Obesity. AB - OBJECTIVES: To review the contribution of the Nurses' Health Studies (NHS and NHS II) in addressing hypotheses regarding risk factors for and consequences of obesity. METHODS: Narrative review of the publications of the NHS and NHS II between 1976 and 2016. RESULTS: Long-term NHS research has shown that weight gain and being overweight or obese are important risk factors for type 2 diabetes, cardiovascular diseases, certain types of cancers, and premature death. The cohorts have elucidated the role of dietary and lifestyle factors in obesity, especially sugar-sweetened beverages, poor diet quality, physical inactivity, prolonged screen time, short sleep duration or shift work, and built environment characteristics. Genome-wide association and gene-lifestyle interaction studies have shown that genetic factors predispose individuals to obesity but that such susceptibility can be attenuated by healthy lifestyle choices. This research has contributed to evolving clinical and public health guidelines on the importance of limiting weight gain through healthy dietary and lifestyle behaviors. CONCLUSIONS: The NHS cohorts have contributed to our understanding of the risk factors for and consequences of obesity and made a lasting impact on clinical and public health guidelines on obesity prevention. PMID- 27459461 TI - Acute Gastroenteritis and Recreational Water: Highest Burden Among Young US Children. AB - OBJECTIVES: To provide summary estimates of gastroenteritis risks and illness burden associated with recreational water exposure and determine whether children have higher risks and burden. METHODS: We combined individual participant data from 13 prospective cohorts at marine and freshwater beaches throughout the United States (n = 84 411). We measured incident outcomes within 10 days of exposure: diarrhea, gastrointestinal illness, missed daily activity (work, school, vacation), and medical visits. We estimated the relationship between outcomes and 2 exposures: body immersion swimming and Enterococcus spp. fecal indicator bacteria levels in the water. We also estimated the population attributable risk associated with these exposures. RESULTS: Water exposure accounted for 21% of diarrhea episodes and 9% of missed daily activities but was unassociated with gastroenteritis leading to medical consultation. Children aged 0 to 4 and 5 to 10 years had the most water exposure, exhibited stronger associations between levels of water quality and illness, and accounted for the largest attributable illness burden. CONCLUSIONS: The higher gastroenteritis risk and associated burden in young children presents important new information to inform future recreational water quality guidelines designed to protect public health. PMID- 27459462 TI - Epidemiology of Major Neurodegenerative Diseases in Women: Contribution of the Nurses' Health Study. AB - OBJECTIVES: To review the contribution of the Nurses' Health Study (NHS) to identifying the role of lifestyle, diet, and genetic or biological factors in several neurodegenerative diseases, including cognitive decline, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. METHODS: We completed a narrative review of the publications of the NHS and NHS II between 1976 and 2016. RESULTS: In primary findings for cognitive function, higher intake of nuts, moderate alcohol consumption, and higher physical activity levels were associated with better cognitive function. Flavonoids, physical activity, and postmenopausal hormone therapy were related to cognitive decline over 2 to 6 years. The NHS also has been integral in establishing Epstein-Barr virus infection, inadequate vitamin D nutrition, cigarette smoking, and obesity as risk factors for multiple sclerosis and inverse associations between cigarette smoking and caffeine and risk of Parkinson's disease. Increased risk of amyotrophic lateral sclerosis has been associated with cigarette smoking and decreased risk associated with obesity. CONCLUSIONS: The NHS has provided invaluable resources on neurodegenerative diseases and contributed to their etiological understanding. We anticipate that the NHS cohorts will continue to make important contributions to the field of neurodegenerative diseases. PMID- 27459464 TI - Effectiveness of patient-targeted interventions to promote cancer screening among ethnic minorities: A systematic review. AB - BACKGROUND: Cancer is a major public health problem due to its incidence, morbidity and mortality. A large proportion of cancer cases and deaths could be prevented through the implementation of cancer screening programmes. However, there are social inequalities in patient access to these programmes, especially in underserved communities and minority populations. OBJECTIVE: To identify, characterise and analyse the effectiveness of patient-targeted healthcare interventions to promote cancer screening programmes in ethnic minorities. METHODS: A comprehensive search of bibliographic databases was conducted. The results of our systematic review were reported in accordance with the PRISMA guidelines. RESULTS: Seventeen articles were identified and included in the review. Sixteen of the seventeen studies were conducted in the United States and one was conducted in Israel. Fifteen of the seventeen interventions selected were effective in increasing cancer screening rates. Moreover, five of the seventeen studies found an improvement in cancer knowledge, awareness, self-efficacy, attitudes, intention and perceptions, and three studies found a positive change in health beliefs and barriers. The results show that culturally adapted interventions appear to increase the rate of participation in cancer screening. In addition, the effectiveness of the interventions seems to be related to the use of small media, one-on-one interactions, small group education sessions, reminder strategies, and strategies for reducing structural barriers and out-of pocket costs. CONCLUSION: Culturally adapted patient-targeted healthcare interventions can help to reduce racial or ethnic inequalities in access to cancer screening programmes. Further research is needed to develop interventions to promote adherence to cancer screening programmes with repeat testing and vigorous economic evaluation methodologies. PMID- 27459463 TI - Biotic Control of Surface pH and Evidence of Light-Induced H+ Pumping and Ca2+-H+ Exchange in a Tropical Crustose Coralline Alga. AB - Presently, an incomplete mechanistic understanding of tropical reef macroalgae photosynthesis and calcification restricts predictions of how these important autotrophs will respond to global change. Therefore, we investigated the mechanistic link between inorganic carbon uptake pathways, photosynthesis and calcification in a tropical crustose coralline alga (CCA) using microsensors. We measured pH, oxygen (O2), and calcium (Ca2+) dynamics and fluxes at the thallus surface under ambient (8.1) and low (7.8) seawater pH (pHSW) and across a range of irradiances. Acetazolamide (AZ) was used to inhibit extracellular carbonic anhydrase (CAext), which mediates hydrolysis of HCO3-, and 4,4' diisothiocyanatostilbene-2,2'-disulphonate (DIDS) that blocks direct HCO3- uptake by anion exchange transport. Both inhibited photosynthesis, suggesting both diffusive uptake of CO2 via HCO3- hydrolysis to CO2 and direct HCO3- ion transport are important in this CCA. Surface pH was raised approximately 0.3 units at saturating irradiance, but less when CAext was inhibited. Surface pH was lower at pHSW 7.8 than pHSW 8.1 in the dark, but not in the light. The Ca2+ fluxes were large, complex and temporally variable, but revealed net Ca2+ uptake under all conditions. The temporal variability in Ca2+ dynamics was potentially related to localized dissolution during epithallial cell sloughing, a strategy of CCA to remove epiphytes. Simultaneous Ca2+ and pH dynamics suggest the presence of Ca2+/H+ exchange. Rapid light-induced H+ surface dynamics that continued after inhibition of photosynthesis revealed the presence of a light-mediated, but photosynthesis-independent, proton pump. Thus, the study indicates metabolic control of surface pH can occur in CCA through photosynthesis and light-inducible H+ pumps. Our results suggest that complex light-induced ion pumps play an important role in biological processes related to inorganic carbon uptake and calcification in CCA. PMID- 27459465 TI - ABO blood group and risk of cancer: A register-based cohort study of 1.6 million blood donors. AB - INTRODUCTION: The associations between ABO blood group and cancer risk have been studied repeatedly, but results have been variable. Consistent associations have only been reported for pancreatic and gastric cancers. MATERIALS AND METHODS: We estimated associations between different ABO blood groups and site-specific cancer risk in a large cohort of healthy blood donors from Sweden and Denmark. RESULTS: A total of 1.6 million donors were followed over 27 million person-years (20 million in Sweden and 7 million in Denmark). We observed 119,584 cancer cases. Blood groups A, AB and B were associated either with increased or decreased risk of cancer at 13 anatomical sites (p<=0.05), compared to blood group O. Consistent with assessment using a false discovery rate approach, significant associations with ABO blood group were observed for cancer of the pancreas, breast, and upper gastrointestinal tract (mouth, salivary glands, pharynx, esophageal adenocarcinoma and stomach). DISCUSSION: Our study reconfirms the association between ABO blood group and cancer risk and exact underlying mechanisms involved needs further research. PMID- 27459476 TI - Diffusion of H2 and D2 Confined in Single-Walled Carbon Nanotubes: Quantum Dynamics and Confinement Effects. AB - We present quantum dynamics calculations of the diffusion constant of H2 and D2 along a single-walled carbon nanotube at temperatures between 50 and 150 K. We calculate the respective diffusion rates in the low-pressure limit by adapting well-known approaches and methods from the chemical dynamics field using two different potential energy surfaces to model the C-H interaction. Our results predict a usual kinetic isotope effect, with H2 diffusing faster than D2 in the higher temperature range but a reverse trend at temperatures below 50-70 K. These findings are consistent with experimental observation in similar systems and can be explained by the different effective size of both isotopes resulting from their different zero-point energy. PMID- 27459477 TI - Direct and Osmolarity-Dependent Effects of Glycine on Preimplantation Bovine Embryos. AB - Concentrations of glycine (Gly) in embryo culture media are often lower (~0.1 mM) than those in oviductal or uterine fluids (>=1.2 mM). The objective of this study was to determine direct and osmolarity-dependent effects of physiological concentrations of Gly on blastocyst formation and hatching, cell allocation to the trophectoderm (TE) and inner cell mass (ICM), and metabolic activity of bovine embryos. In experiment 1, zygotes were cultured with 100 or 120 mM NaCl and 0 or 1 mM Gly for the first 72 h of culture. Blastocyst formation and hatching were improved (P<0.05) when embryos were cultured with 100 compared to 120 mM NaCl. Inclusion of 1 mM Gly improved (P<0.05) blastocyst formation compared to 0 mM Gly, but this effect was only significant (P<0.05) for embryos cultured with 120 mM NaCl, suggesting bovine embryos can utilize Gly as an osmolyte. In experiment 2, embryos were cultured with 0.1, 1.1, 2.1, or 4.1 mM Gly (100 mM NaCl) for the final 96 h of culture. Blastocyst development was not affected (P>0.05) by Gly, but hatching (0.1 mM Gly, 18.2%) was improved (P<0.05) when embryos were cultured with 1.1 (31.4%) or 2.1 (29.4%) mM Gly. Blastocyst, TE, and ICM cell numbers were not affected (P>0.05) by Gly in either experiment. Blastocysts produced alanine, glutamine, pyruvate, and urea and consumed aspartate, but this metabolic profile was not affected (P>0.05) by Gly. In conclusion, Gly (1.0 mM) improves the development of both early and late stage embryos, but beneficial effects are more pronounced for early embryos exposed to elevated osmolarity. PMID- 27459478 TI - Asymmetric Construction of Pyrrolidines Bearing a Trifluoromethylated Quaternary Stereogenic Center via Cu(I) -Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides with beta-CF3 -beta,beta-Disubstituted Nitroalkenes. AB - A direct and convenient method has been developed for the synthesis of optically active pyrrolidines bearing a quaternary stereogenic center containing a CF3 group at the C-3 position of the pyrrolidine ring. The synthesis system, Cu(I) /Si-FOXAP-catalyzed exo-selective 1,3-dipolar cycloaddition of azomethine ylides with beta-CF3 -beta,beta-disubstituted nitroalkenes, provides pyrrolidines with high diastereoselectivities (up to >98:2 d.r.) and excellent enantioselectivities (up to >99.9 ee) and performs well for a broad scope of substrates under mild conditions. PMID- 27459479 TI - Charting the Chemical Reactivity Space of 2,3-Substituted Furo[2,3-b]pyridines Synthesized via the Heterocyclization of Pyridine-N-oxide Derivatives. AB - A concise strategy for the synthesis of 2,3-substituted furo[2,3-b]pyridines is described. Mild, metal-free conditions were successfully applied to produce a range of 2-(alkyl or aryl)-3-ethylcarboxylate-furo[2,3-b]pyridines in yields of 50-91%. Then, the chemical reactivity of this heterocyclic framework was explored to develop straightforward methods for its functionalization. The pyridine moiety reactivity was successfully explored by C-H amination and borylation reactions, although C-H fluorination and radical C-H arylation processes were not as efficient. In addition, while the furopyridine core proved stable under basic conditions, the ring-opening reaction of the furan moiety with hydrazine generated a valuable new pyridine-dihydropyrazolone scaffold. PMID- 27459480 TI - Metabolomics of Breast Cancer Using High-Resolution Magic Angle Spinning Magnetic Resonance Spectroscopy: Correlations with 18F-FDG Positron Emission Tomography Computed Tomography, Dynamic Contrast-Enhanced and Diffusion-Weighted Imaging MRI. AB - PURPOSE: Our goal in this study was to find correlations between breast cancer metabolites and conventional quantitative imaging parameters using high resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) and to find breast cancer subgroups that show high correlations between metabolites and imaging parameters. MATERIALS AND METHODS: Between August 2010 and December 2013, we included 53 female patients (mean age 49.6 years; age range 32-75 years) with a total of 53 breast lesions assessed by the Breast Imaging Reporting and Data System. They were enrolled under the following criteria: breast lesions larger than 1 cm in diameter which 1) were suspicious for malignancy on mammography or ultrasound (US), 2) were pathologically confirmed to be breast cancer with US-guided core-needle biopsy (CNB) 3) underwent 3 Tesla MRI with dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) and positron emission tomography-computed tomography (PET-CT), and 4) had an attainable immunohistochemistry profile from CNB. We acquired spectral data by HR MAS MRS with CNB specimens and expressed the data as relative metabolite concentrations. We compared the metabolites with the signal enhancement ratio (SER), maximum standardized FDG uptake value (SUV max), apparent diffusion coefficient (ADC), and histopathologic prognostic factors for correlation. We calculated Spearman correlations and performed a partial least squares discriminant analysis (PLS-DA) to further classify patient groups into subgroups to find correlation differences between HR-MAS spectroscopic values and conventional imaging parameters. RESULTS: In a multivariate analysis, the PLS-DA models built with HR-MAS MRS metabolic profiles showed visible discrimination between high and low SER, SUV, and ADC. In luminal subtype breast cancer, compared to all cases, high SER, ADV, and SUV were more closely clustered by visual assessment. Multiple metabolites were correlated with SER and SUV in all cases. Multiple metabolites showed correlations with SER and SUV in the ER positive, HER2 negative, and Ki-67 negative groups. CONCLUSION: High levels of PC, choline, and glycine acquired from HR-MAS MRS using CNB specimens were noted in the high SER group via DCE MRI and the high SUV group via PET-CT, with significant correlations between choline and SER and between PC and SUV. Further studies should investigate whether HR-MAS MRS using CNB specimens can provide similar or more prognostic information than conventional quantitative imaging parameters. PMID- 27459481 TI - [Risk factors and prevention of postoperative pancreatitis after pancreatectomy]. AB - AIM: to improve the results of pancreatic resections through decrease of postoperative pancreatitis incidence. MATERIAL AND METHODS: It was analyzed 207 patients who underwent pancreatic surgery for pancreatic tumor (n=137) or chronic pancreatitis (n=70). 22 risk factors of postoperative pancreatitis were analyzed in 112 patients retrospectively. In prospective study of 95 patients the efficacy of lornoxicam to prevent postoperative pancreatitis was assessed. 68 parameters of immune state were studied to estimate effect of lornoxicam. RESULTS: Significant factors were mellow pancreatic parenchyma, tumoral disease, pancreatic duct diameter over 3 mm, pancreatric duct index over 0.2, body mass index over 27 kg/m2. Likelihood of postoperative pancreatitis was 40%, 63%, 74.3% and 88.9% if 2, 3, 4 and 5 factors were combined respectively. Preventive use of lornoxicam reduced significantly incidence of postoperative pancreatitis (p=0.042). Incidence of pancreatic fistula and arrosive bleeding was decreased insignificantly due to small number of observations. CONCLUSION: Assessment of significant risk factors and use of medical prevention are available to decrease likelihood of postoperative pancreatitis. PMID- 27459482 TI - [Early diagnosis of mild acute pancreatitis]. AB - AIM: to analyze the efficacy of early detection of patients with mild acute pancreatitis. MATERIAL AND METHODS: 61 patients with acute pancreatitis who do not require intensive care were analyzed. Severity of condition was assessed using integral scales, i.e. modified index of severe pancreatitis severity (MITOP), BISAP, HAPS, SOFA, SIRS, CTSI and Atlanta classification (2012). RESULTS: Verification of mild course of disease according to MITOP scores <=0.23 and BISAP scores <=1 for the first 24 hours after admission and CTSI scores <=3 within first 72 hours had high accuracy [AUC (CI 95%) 0.79 (0.66-0.91); 0.76 (0.66-0.87) and 0.99 (0.97-1.00) respectively], sensitivity and specificity (88.8 and 43.7%; 71.1 and 75.0%; 100 and 83.3% respectively). CONCLUSION: MITOP and BISAP scales are reliable to diagnose early mild acute pancreatitis. Their high positive diagnostic value (81.6 and 88.8%) allows to detect patients who do not require intensive care. PMID- 27459483 TI - [Mannheim peritonitis index as a surgical criterion for perforative duodenal ulcer]. AB - AIM: to define the correlation between Mannheim peritonitis index scores and outcomes of different radical and palliative interventions for perforative duodenal ulcer. MATERIAL AND METHODS: Treatment of 386 patients with perforative duodenal ulcer is presented. Different surgical techniques were analyzed including stomach resection, various methods of vagotomy with/without drainage, ulcer suturing and ulcerative edges excision with suturing in patients with Mannheim index scores <21, 21-29 and over 29. Clavien-Dindo classification was used to analyze postoperative complications. RESULTS: In 64.3% of cases mortality was caused by peritonitis and peritonitis-associated complications. Surgical features resulted unfavorable outcome only in 35.7% of cases. Severe complications requiring re-operation were predominantly observed after stomach resection. CONCLUSION: Mannheim peritonitis index is sensitive method allowing prognosis the outcomes in patients with perforative duodenal ulcer. Radical interventions are advisable in Mannheim index scores <21, in other cases palliative surgery for example suturing or edges excision with suturing is preferred. If radical surgery is performed with strict indications (Mannheim index scores <21) volume and type of surgery do not significantly influence on mortality rate. PMID- 27459484 TI - [Surgical treatment of patients with gastrointestinal stromal tumor of the stomach]. AB - AIM: to evaluate objectively the effectiveness of currently used diagnostic and curative approaches to gastrointestinal stromal tumors (GIST). MATERIAL AND METHODS: Early and remote results of treatment of 49 patients with gastric GISTs were presented. Herewith in 20 (40.8%) patients the disease was complicated by gastrointestinal bleeding. 43 (87.7%) of 49 patients with gastric GIST were operated. Conventional surgery was performed in 24 (55.8%) cases, laparoscopic interventions - in 12 (28%) cases, endoscopic endoluminal - in 7 (16.2%). 6 (14.2%) patients were not operated. RESULTS: Intraoperative complications were observed in 2 (4.65%) patients. In postoperative period complications occurred also in 2 (4.65%) patients. In long-term postoperative period tumoral process progression was observed in 3 (8.3%) patients. Recurrence was diagnosed in 2 (5.6%) patients. PMID- 27459485 TI - [Laparotomy closure in advanced peritonitis]. AB - AIM: to improve the results of advanced peritonitis management. MATERIAL AND METHODS: 743 patients with advanced peritonitis were studied. Patients were divided into 2 groups depending on treatment strategy. RESULTS: Programmed relaparotomy combined with removable draining musculoaponeurotic seams during laparotomy closure decreased mortality from 47.8+/-2.7% to 24.1+/-2.3% (p<0.001) and provided 4-fold reduction of postoperative suppuration incidence (p<0.001). Refusal from removable draining musculoaponeurotic seams and use of only cutaneous seams in persistent abdominal hypertension were associated with further decrease of mortality to 15.8+/-2.7% (p<0.05). CONCLUSION: Programmed relaparotomy combined with removable draining musculoaponeurotic seams are advisable for advanced peritonitis management. Laparotomy closure with only cutaneous seams is indicated in case of persistent abdominal hypertension. Large eventration always requires abdominal wall repair. APACHE-III scale scores have significant prognostic value in patients with advanced peritonitis. PMID- 27459486 TI - [Chylothorax in practice of thoracic and cardiovascular surgeon]. AB - AIM: to improve the results and current pathogenetic treatment of chylorrhea. MATERIAL AND METHODS: Thirty seven patients with chylothorax have been treated for the period 2004-2014. In 34 cases traumatic chylothorax developed after surgery and in 3 cases - after intensive care for therapeutic diseases and great veins catheterization. Chylothorax was predominantly diagnosed by X-ray method. Herewith, hydrothorax was established and its nature was defined using laboratory survey. Presence of neutral fat in pleural drainage is the sign of chylothorax. Pathogenetic treatment was often delayed (up to 4.5 months) due to poor awareness of physicians about this pathological process. 6 patients underwent thoracic duct ligation above diaphragm due to ineffective therapy. RESULTS: Medical therapy had good clinical effect in 83.8% of cases. Postoperatively 1 patient died for single lung inflammation on background of postoperative chylothorax after right-sided pneumonectomy. In other cases chylothora was eliminated with no recurrence in remote postoperative period. It is difficult to recognize injury of thoracic duct or its great branches during surgery. In these cases prolonged thoracic duct ligation above diaphragm is indicated. PMID- 27459487 TI - [Errors in crural perforant veins ligation]. AB - AIM: to assess topographic features and technical aspects of perforant veins ligation in patients with trophic disorders due to varicose disease. RESULTS: There were 13-16 perforant veins of anterior tibial group and 3-8 veins of posterior tibial group which were predominantly localized along Linton line. Also there were 4-6 perforant veins of peroneal group. Postoperative control revealed that 41.63% of veins were missed during surgery regardless method of ligation. Anatomical analysis showed that relationship with deep fascia cruris is determinant factor for errors and dangers of remote ligation of perforant veins and creates high risk of deep vein injury. One of available method to avoid errors during ligation is thorough examination of the wound and use of Turner Warwick test to confirm dissection of perforant vein and its incompetence. 100% effect of ligation was achieved in all cases after this test. Perforant veins ligation is single pathogenetic treatment for varicose disease class C4-C6. Perforant veins should be ligated under visual control. Intraoperative tests are also advisable. PMID- 27459488 TI - [The technologies of inpatient care substitution in surgery]. AB - It was analyzed the introduction of inpatient care substitution technologies in multi-disciplinary Polyclinic OAO "Gazprom". Organizational principles of outpatient surgical interventions under general and combined anesthesia are represented. Also it was described surgical features to decrease incidence of intra- and postoperative complications. System of active postoperative management was presented to define early different features of disease. Also main directions of development of this technology were suggested. PMID- 27459489 TI - [Cytoflavin rationale for the use in treatment of patients with postsurgical hypothyroidism]. AB - The aim of the study was to assess the effectiveness of cytoflavin inclusion in complex treatment of patients with hypoparathyroidism occurring after thyroid surgery. To do this, an analysis of treatment of 54 patients who received surgical treatment for thyroid diseases of various etiologies. Depending on the scheme of post-operative medical therapy, the patients were divided into 2 groups: group I patients (27 persons) received basic therapy according to regulatory documents, II of the group (27 patients) in addition cytoflavin intravenous drip of 10 ml to 200 ml 0.9% NaCl for 7 days. In addition to standard clinical and laboratory examination, all patients were studied and the level of active ionized Ca2+ and PTH, oxidation products of the modified protein, lipid peroxidation and antioksidazation system dynamics - 1, 3 and 7 days after surgery. It was revealed that in the first days after the surgical treatment of patients significantly reduced the levels of ionized Ca2+ and PTH that may be regarded as signs of postoperative hypoparathyroidism, as well as the activation of the system of lipid peroxidation and antioxidant system depression. Turning cytoflavin in drug regimens improved the efficiency of the treatment, which was manifested in arresting to 7 days of monitoring signs of hypoparathyroidism, improve tissue oxygenation and restoring the balance by reducing the activity of the system of lipid peroxidation and antioxidant system strengthening. PMID- 27459490 TI - [PAD prevalence in Russian Federation]. AB - BACKGROUND: Currently there is no data on peripheral arterial disease prevalence in Russia. AIM: To estimate prevalence of patients with symptomatic low limb ischemia (LLI) in Russian Federation on 2014. PATIENTS AND METHODS: "League for patient' protection" had sent questionnaires for all regional health departments asking to name prevalence of ICD-10 codes I70.2 (atherosclerosis of arteries of extremities) and I73.1 (thromboangiitis obliterans (Buerger)) on 2014. The figures were listed separately for ischemia I-IIa and III-IV (critical limb ischemia, CLI) (Pokrovsky, 1976). Also were mentioned major amputations and mortality. RESULTS: Total number of received questionnaires was 44, we've got information from all RF' federal regions with a population of appr. 71 million people. There were 174 125 cases of symptomatic LLI. Prevalence of symptomatic LLI among Russian population aged more than 40 years was 0.51%. Prevalence of intermittent claudication was 0.36% and of critical limb ischemia - 0.13%. Rate of major amputations was 6.9%. CONCLUSION: World PAD prevalence among people older than 25 years is 8.3%. The same figure in our study was only 0.5%. This is due to the fact that we considered only symptomatic LLI and only with codes I70.2 and I73.1. Prevalence of symptomatic patients among all PAD patients is 10-35%. So the real number of PAD patients in Russian might be 1.5-5%. We can conclude that PAD is still unrevealed in Russia. Another conclusion could be that the treatment results are less than satisfactory. Finally there is urgent necessity for special PAD register in RF. PMID- 27459491 TI - [Right-sided hemicolectomy with gastropancreatoduodenectomy for complicated right sided locally-advanced colon cancer in elder patient]. PMID- 27459492 TI - [External duodenal fistula management]. PMID- 27459493 TI - [Surgical treatment of false aneurysm of internal carotid artery after carotid endarterectomy]. PMID- 27459494 TI - [Roadmap of surgeons training]. PMID- 27459496 TI - Dissolution Mechanism of Upconverting AYF4:Yb,Tm (A = Na or K) Nanoparticles in Aqueous Media. AB - The dissolution of upconverting AYF4:Yb,Tm (A = Na or K) nanoparticles (UCNPs) in aqueous media was systematically studied. UCNPs with a cubic structure and sizes of between 10 and 33 nm were synthesized solvothermally in ethylene glycol at 200 degrees C. The UCNPs of both compositions showed an upconversion fluorescence emission characteristic of Tm(3+). The effects of the A cation, the particle size, the temperature, the pH, and the composition of the aqueous medium on the dissolution of the UCNPs were evaluated. The degree of dissolution was determined from the fraction of dissolved fluoride (F(-)) using potentiometry. Unexpectedly, the composition of aqueous media had the most significant effect on the dissolution of the UCNPs. The highest degree of dissolution and rate were measured for the phosphate-buffered saline (PBS), which can be explained by the formation of stable lanthanide compounds with phosphates. The degree of dissolution was much lower in water and in the phthalate buffer, which was attributed to the release of F(-) as a result of the hydrolysis of the UCNPs' surfaces. PMID- 27459495 TI - Legionella pneumophila Type IV Effectors YlfA and YlfB Are SNARE-Like Proteins that Form Homo- and Heteromeric Complexes and Enhance the Efficiency of Vacuole Remodeling. AB - Legionella pneumophila is a Gram-negative bacterium that can colonize both freshwater protozoa and human alveolar macrophages, the latter infection resulting in Legionnaires' disease. The intracellular lifecycle of L. pneumophila requires extensive manipulation of its host cell, which is carried out by effector proteins that are translocated into the host cell through the Dot/Icm type IV secretion system. This study focuses on a pair of highly similar type IV substrates called YlfA/LegC7 and YlfB/LegC2 that were initially identified in a screen for proteins that cause growth inhibition in yeast. Analysis of truncation mutants revealed that the hydrophobic residues in the Ylf amino termini were required for localization of each protein to the membranes of host cells. Central and carboxy terminal coiled coil domains were found to mediate binding of YlfA and YlfB to themselves and to each other. In vivo, a DeltaylfA DeltaylfB double mutant strain of L. pneumophila was shown to be defective in establishing a vacuole that supports bacterial replication. This phenotype was subsequently correlated with a decrease in the association of endoplasmic reticulum (ER) derived vesicles with vacuoles containing DeltaylfA DeltaylfB mutant bacteria. These data suggest that the Ylf proteins are membrane-associated effectors that enhance remodeling of the L. pneumophila -containing vacuole by promoting association and possibly fusion of ER-derived membrane vesicles with the bacterial compartment. PMID- 27459497 TI - A medley of flavours. PMID- 27459498 TI - Tympanoplasty: does dry or wet temporalis fascia graft matter? AB - OBJECTIVES: To evaluate the success rate of dry and wet temporalis fascia grafts in type I underlay tympanoplasty. METHODS: A prospective, randomised study was conducted. One hundred adult patients (males and females) with chronic suppurative otitis media (mucosal type) were divided into 2 groups of 50 each: one group underwent dry graft tympanoplasty and the other underwent wet graft tympanoplasty. Fibroblast count was calculated in dry and wet grafts. RESULTS: The dry graft and wet graft groups had overall surgical success rates of 82 and 90 per cent, respectively; this finding was not statistically significant. A statistically significant high fibroblast count was observed in wet grafts, but it did not correlate with surgical success. CONCLUSION: A dry or wet temporalis fascia graft does not influence the outcome of tympanoplasty type I. PMID- 27459499 TI - Attitudes towards and personal use of complementary and alternative medicine amongst clinicians working in audiovestibular disciplines. AB - OBJECTIVE: Literature indicates that complementary and alternative medicine is used by patients with auditory and vestibular symptoms. This study sought to determine the prevalence of complementary and alternative medicine uptake, and examine attitudes towards complementary and alternative medicine in clinicians working with audiovestibular disorder patients. METHOD: The Holistic Complementary and Alternative Medicine Questionnaire and a devised questionnaire about recent and lifetime use of complementary and alternative medicine were used. RESULTS: Fifty-four individuals, including audiologists, ENT surgeons, nurses and rehabilitationists, completed the questionnaires (67 per cent response rate). Lifetime prevalence of complementary and alternative medicine uptake was 44 per cent, and 12-month prevalence was 22 per cent. Uptake was more common in females, but there was no significant difference in use when comparing age, seniority or profession. Attitudes towards complementary and alternative medicine were mildly adverse, but sizeable standard deviation indicates wide-ranging attitudes. CONCLUSION: Clinicians working with patients with audiovestibular disorders have a range of attitudes towards complementary and alternative medicine. Personal uptake of complementary and alternative medicine was lower than that of the general UK population, but remains sizeable. PMID- 27459500 TI - Muscle-tendon unit scaling methods of Hill-type musculoskeletal models: An overview. AB - This article gives an overview of the state of the art in scaling methods of generic Hill-type muscle model parameters in view of different applications and implementation of experimental data. This article establishes the requirements used to alter a generic model toward subject-specific musculoskeletal models. This article aims to improve model transparency by a structured description of scaling methods and the associated limitations in musculoskeletal models and highlight the importance of selecting a scaling method supporting the purpose of the model. PMID- 27459501 TI - Effects of a drill diameter on the temperature rise in a bone during implant site preparation under clinical conditions. AB - Heat, generated during the drilling of a dental implant site preparation, leads to a temperature rise and consequently to a thermal injury of the bone tissue surrounding the implant site, which can cause the subsequent implant failure. In this article, we present new findings related to the temperature rise during implant site drilling under real conditions on a bovine rib bone specimen. The experiments were designed with the help of a full-factorial design in randomized complete blocks, where the main effects of the drill diameter in combination with the drilling force and the drilling speed, and their interactions, on the temperature rise were determined. The temperature rise in the bone under real conditions was measured as the implant site was being prepared by a dentist using intermittent, graduated drilling and external irrigation. Results show that the drill diameter has statistically significant effect, independent of the drilling procedure used. Among the examined drilling parameters, the drill diameter has the greatest effect, where an increase in the drill diameter first causes a decrease in the temperature rise and further increase in the drill diameter causes its increase. During the continuous and one-step drilling, the temperatures of the bones were up to 40.5 degrees C and during the drilling under actual conditions up to 30.11 degrees C. PMID- 27459502 TI - Mothers after Gestational Diabetes in Australia (MAGDA): A Randomised Controlled Trial of a Postnatal Diabetes Prevention Program. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for type 2 diabetes. We evaluated the effectiveness of a group-based lifestyle modification program in mothers with prior GDM within their first postnatal year. METHODS AND FINDINGS: In this study, 573 women were randomised to either the intervention (n = 284) or usual care (n = 289). At baseline, 10% had impaired glucose tolerance and 2% impaired fasting glucose. The diabetes prevention intervention comprised one individual session, five group sessions, and two telephone sessions. Primary outcomes were changes in diabetes risk factors (weight, waist circumference, and fasting blood glucose), and secondary outcomes included achievement of lifestyle modification goals and changes in depression score and cardiovascular disease risk factors. The mean changes (intention-to-treat [ITT] analysis) over 12 mo were as follows: -0.23 kg body weight in intervention group (95% CI -0.89, 0.43) compared with +0.72 kg in usual care group (95% CI 0.09, 1.35) (change difference -0.95 kg, 95% CI -1.87, -0.04; group by treatment interaction p = 0.04); -2.24 cm waist measurement in intervention group (95% CI -3.01, -1.42) compared with -1.74 cm in usual care group (95% CI -2.52, -0.96) (change difference -0.50 cm, 95% CI -1.63, 0.63; group by treatment interaction p = 0.389); and +0.18 mmol/l fasting blood glucose in intervention group (95% CI 0.11, 0.24) compared with +0.22 mmol/l in usual care group (95% CI 0.16, 0.29) (change difference -0.05 mmol/l, 95% CI -0.14, 0.05; group by treatment interaction p = 0.331). Only 10% of women attended all sessions, 53% attended one individual and at least one group session, and 34% attended no sessions. Loss to follow-up was 27% and 21% for the intervention and control groups, respectively, primarily due to subsequent pregnancies. Study limitations include low exposure to the full intervention and glucose metabolism profiles being near normal at baseline. CONCLUSIONS: Although a 1-kg weight difference has the potential to be significant for reducing diabetes risk, the level of engagement during the first postnatal year was low. Further research is needed to improve engagement, including participant involvement in study design; it is potentially more effective to implement annual diabetes screening until women develop prediabetes before offering an intervention. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000338066. PMID- 27459503 TI - Comparison of Adding Treatment of PTSD During and After Shelter Stay to Standard Care in Residents of Battered Women's Shelters: Results of a Randomized Clinical Trial. AB - This study explored the acceptability, feasibility, and initial efficacy of an expanded version of a PTSD treatment developed for residents of battered women's shelters, Helping to Overcome PTSD through Empowerment (HOPE) in women who received standard shelter services (SSSs). A Phase I randomized clinical trial comparing HOPE + SSSs (n = 30) to SSSs (n = 30) was conducted. Primary outcome measures included the Clinician-Administered PTSD Scale (Blake et al., 1995) and the Revised Conflict Tactic Scales (Straus, Hamby, Boney-McCoy, & Sugarman, ). Participants were followed at 1-week, and 3- and 6-months posttreatment. Only 2 women dropped out of HOPE + SSS treatment. Latent growth curve analyses found significant treatment effects for PTSD from intimate partner violence (IPV) (beta = -.007, p = .021), but not for future IPV (beta = .002, p = .709) across follow up points. Significant effects were also found for secondary outcomes of depression severity (beta = -.006, p = .052), empowerment (beta = .155, p = .022), and resource gain (beta = .158, p = .036). Additionally, more women in HOPE + SSSs were employed at 3- and 6-month follow-up compared to those in SSSs only. Results showed the acceptability and feasibility of adding IPV-related treatment to standard services. They also suggested that HOPE may be a promising treatment for residents of battered women's shelters. Further research with a larger sample, utilizing more diverse shelter settings and a more rigorous control condition, is needed to confirm these findings. PMID- 27459505 TI - Formation of Nanoscale Composites of Compound Semiconductors Driven by Charge Transfer. AB - Composites are a class of materials that are formed by mixing two or more components. These materials often have new functional properties compared to their constituent materials. Traditionally composites are formed by self-assembly due to structural dissimilarities or by engineering different layers or structures in the material. Here we report the synthesis of a uniform and stoichiometric composite of CdO and SnTe with a novel nanocomposite structure stabilized by the dissimilarity of the electronic band structure of the constituent materials. The composite has interesting electronic properties which range from highly n-type in CdO to semi-insulating in the intermediate composition range to highly p-type in SnTe. This can be explained by the overlap of the conduction and valence band of the constituent compounds. Ultimately, our work identifies a new class of composite semiconductors in which nanoscale self organization is driven and stabilized by charge transfer between constituent materials. PMID- 27459504 TI - Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer. AB - Prediction of tumor recurrence after curative resection is critical for determining the prognosis of patients with gastric cancer (GC). The initiation and progression of GC are associated with inappropriate immune responses caused by chronic inflammation of the gastric mucosa. To identify immunoregulatory molecules involved in GC progression, GC cell lines and 200 pairs of tumor and normal tissues from patients with GC were analyzed for gene expression, amplification and methylation as well as function of a differentially expressed gene. The transcriptome analysis revealed that marginal zone B and B1 cell specific protein (MZB1) was expressed at significantly decreased levels in primary GC tissues when compared with the corresponding normal gastric mucosa. PCR array analysis exploring genes expressed cooperatively with MZB1 revealed that differential expression of MZB1 mRNA in GC cell lines correlated positively with the levels of the mRNAs encoding estrogen receptor 1 and desumoylating isopeptidase 1. Hypermethylation of the MZB1 promoter was frequent in cell lines with decreased levels of MZB1 mRNA. siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines. Low MZB1 expression was an independent prognostic factor for recurrence after curative gastrectomy and was associated significantly with increased hematogenous recurrence. MZB1 acts as a suppressor of GC. Low MZB1 expression in the primary GC tissue is predictive of recurrence after curative resection. PMID- 27459506 TI - Management of high-risk HPV-positive women for detection of cervical (pre)cancer. AB - INTRODUCTION: Primary HPV-testing has been shown to provide a superior detection of women at risk of cervical (pre)cancer compared to cytology-based screening. However, as most high-risk HPV infections are harmless, additional triage testing of HPV-positive women is necessary to identify those with cervical (pre)cancer. In this paper, we compare the performance, advantages and limitations of clinically relevant available triage strategies for HPV-positive women. AREAS COVERED: Many different colposcopy triage strategies, comprising both microscopy based and molecular (virus/host-related) markers, have been suggested: Pap cytology, p16/Ki-67 dual-stained cytology, HPV16/18 genotyping, viral DNA methylation and host cell DNA methylation. Literature search was limited to triage strategies that have achieved at least phase 2 of the five-phase framework for biomarker development and studies including large cohorts (>=100 hrHPV positive women). Triage markers were stratified by sample type (cervical scrape, self-collected sample) and by study population (screening, non-attendee, referral). Expert commentary: At present, repeat Pap cytology and Pap cytology combined with HPV16/18 genotyping are the only triage strategies that have been robustly shown to be ready for implementation. Other strategies such as p16/Ki-67 dual-stained cytology and host cell DNA methylation analysis, with or without additional HPV16/18 genotyping, are attractive options for the near future. PMID- 27459508 TI - DNA-stabilized Ag-Au bimetallic clusters: the effects of alloying and embedding on optical properties. AB - Global geometry optimization and time-dependent density functional theory calculations have been used to study the structural evolution and optical properties of AgnAun (n = 2-6) nanoalloys both as individual clusters and as clusters stabilized with the fragments of DNA of different size. We show that alloying can be used to control and tune the level of interaction between the metal atoms of the cluster and the organic fragments of the DNA ligands. For instance, gold and silver atoms are shown to exhibit synergistic effects in the process of charge transfer from the nucleobase to the cluster, with the silver atoms directly connected to the nitrogen atoms of cytosine increasing their positive partial charge, while their more electronegative neighbouring gold atoms host the excess negative charge. This allows the geometrical structures and optical absorption spectra of small bimetallic clusters to retain many of their main features upon aggregation with relatively large DNA fragments, such as a cytosine-based 9-nucleotide hairpin loop, which suggests a potential synthetic route to such hybrid metal-organic compounds, and opens up the possibility of bringing the unique tunable properties of bimetallic nanoalloys to biological applications. PMID- 27459507 TI - The Migrant Paradox in Children and the Role of Schools in Reducing Health Disparities: A Cross-Sectional Study of Migrant and Native Children in Beijing, China. AB - Migrants usually exhibit similar or better health outcomes than native-born populations despite facing socioeconomic disadvantages and barriers to healthcare use; this is known as the "migrant paradox." The migrant paradox among children is highly complex. This study explores whether the migrant paradox exists in the health of internal migrant children in China and the role of schools in reducing children's health disparities, using a multi-stage stratified cluster sampling method. Participants were 1,641 student and parent pairs from Grades 4, 5, and 6 of eight primary schools in Beijing. The following school types were included: state schools with migrant children comprising over 70% of total children (SMS), private schools with migrant children comprising over 70% (PMS), and state schools with permanent resident children comprising over 70% (SRS). Children were divided into Groups A, B, C or D by the type of school they attended (A and B were drawn from SRSs, C was from SMSs, and D was from PMSs) and whether they were in the migrant population (B, C, and D were, but A was not). Related information was collected through medical examination and questionnaires completed by parents and children. Prevalence of caries, overweight and obesity, poor vision, and self reported incidence of colds and diarrhea in the previous month were explored as health outcomes. The results partially demonstrated the existence of the migrant paradox and verified the role of schools in lowering health disparities among children; there are theoretical and practical implications for improving the health of migrant children. PMID- 27459509 TI - Fluorogenic Enhancement of an in Vitro-Selected Peptide Ligand by Replacement of a Fluorescent Group. AB - To prepare a fluorogenic peptide ligand which binds to an arbitrary target, we previously succeeded in seeking a fluorogenic ligand to calmodulin using in vitro selection. In this study the environment-sensitive fluorescent group in the selected peptide ligand was replaced with other fluorescent groups to find the possibility to increase the fluorogenic activity. Surface plasmon resonance measurement exhibited that the binding affinity was held even after the replacement. However, the replacement significantly affected the fluorogenic activity. It depended on the kind of incorporated fluorophors and linker length. As a result, the incorporation of 4-N,N-dimethylamino-1,8-naphthalimide enhanced the fluorescence intensity over 100-fold in the presence of target calcium-bound calmodulin. This study demonstrated that the functionality of in vitro selected peptide can be tuned with keeping the binding affinity. PMID- 27459511 TI - Soil compartment is a major determinant of the impact of simulated rainfall on desert microbiota. AB - Although desert soils support functionally important microbial communities that affect plant growth and influence many biogeochemical processes, the impact of future changes in precipitation patterns on the microbiota and their activities is largely unknown. We performed in-situ experiments to investigate the effect of simulated rainfall on bacterial communities associated with the widespread perennial shrub, Rhazya stricta in Arabian desert soils. The bacterial community composition was distinct between three different soil compartments: surface biological crust, root-attached, and the broader rhizosphere. Simulated rainfall had no significant effect on the overall bacterial community composition, but some population-level responses were observed, especially in soil crusts where Betaproteobacteria, Sphingobacteria, and Bacilli became more abundant. Bacterial biomass in the nutrient-rich crust increased three-fold one week after watering, whereas it did not change in the rhizosphere, despite its much higher water retention. These findings indicate that between rainfall events, desert-soil microbial communities enter into stasis, with limited species turnover, and reactivate rapidly and relatively uniformly when water becomes available. However, microbiota in the crust, which was relatively enriched in nutrients and organic matter, were primarily water-limited, compared with the rhizosphere microbiota that were co-limited by nutrients and water. PMID- 27459510 TI - CD103+ Conventional Dendritic Cells Are Critical for TLR7/9-Dependent Host Defense against Histoplasma capsulatum, an Endemic Fungal Pathogen of Humans. AB - Innate immune cells shape the host response to microbial pathogens. Here we elucidate critical differences in the molecular response of macrophages vs. dendritic cells (DCs) to Histoplasma capsulatum, an intracellular fungal pathogen of humans. It has long been known that macrophages are permissive for Histoplasma growth and succumb to infection, whereas DCs restrict fungal growth and survive infection. We used murine macrophages and DCs to identify host pathways that influence fungal proliferation and host-cell viability. Transcriptional profiling experiments revealed that DCs produced a strong Type I interferon (IFN-I) response to infection with Histoplasma yeasts. Toll-like receptors 7 and 9 (TLR7/9), which recognize nucleic acids, were required for IFN-I production and restriction of fungal growth in DCs, but mutation of TLR7/9 had no effect on the outcome of macrophage infection. Moreover, TLR7/9 were essential for the ability of infected DCs to elicit production of the critical cytokine IFNgamma from primed CD4+ T cells in vitro, indicating the role of this pathway in T cell activation. In a mouse model of infection, TLR7/9 were required for optimal production of IFN-I and IFNgamma, host survival, and restriction of cerebral fungal burden. These data demonstrate the critical role of this pathway in eliciting an appropriate adaptive immune response in the host. Finally, although other fungal pathogens have been shown to elicit IFN-I in mouse models, the specific host cell responsible for producing IFN-I has not been elucidated. We found that CD103+ conventional DCs were the major producer of IFN-I in the lungs of wild-type mice infected with Histoplasma. Mice deficient in this DC subtype displayed reduced IFN-I production in vivo. These data reveal a previously unknown role for CD103+ conventional DCs and uncover the pivotal function of these cells in modulating the host immune response to endemic fungi. PMID- 27459512 TI - Letter to the Editor regarding in-office cup biopsy. PMID- 27459514 TI - TM4SF1 Regulates Pancreatic Cancer Migration and Invasion In Vitro and In Vivo. AB - BACKGROUND/AIMS: The cell surface protein transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors and plays a major role in the development of cancer. We aimed to investigate the effects of TM4SF1 on the migration and invasion of pancreatic cancer in vitro and in vivo and explore its related molecular mechanisms. METHODS: qRT-PCR and immunohistochemical analyses were used to measure the expression of TM4SF1 in pancreatic cancer tissues and adjacent tissues. TM4SF1 was silenced using siRNA and shRNA to investigate the role of this protein in the proliferation and metastasis of pancreatic cancer cells. MTS and Transwell assays were used to examine the effect of TM4SF1 on pancreatic cancer cell lines. The expression and activity of MMP-2 and MMP-9 were determined by qRT-PCR, western blots and gelatin zymography. In vivo, orthotopic pancreatic tumor models were used to examine the formation of metastasis. RESULTS: qRT-PCR and immunohistochemical analyses showed that TM4SF1 was highly expressed in pancreatic cancer tissues compared with the adjacent tissues. In in vitro experiments the silencing of TM4SF1 reduced cell migration and invasion and down-regulated the expression and activity of MMP-2 and MMP-9. However, no significant difference in cell proliferation was detected after silencing TM4SF1. Additionally, knocking down TM4SF1 decreased the formation of lung and liver metastases in orthotopic pancreatic tumor models. CONCLUSION: Our results demonstrate that the expression of TM4SF1 is higher in pancreatic cancer tissues and pancreatic cancer cell lines than controls. Knockdown of TM4SF1 inhibited the migration and invasion of pancreatic cancer cells by regulating the expression and activity of MMP-2 and MMP-9, which suggests that TM4SF1 may play a significant role in metastasis in pancreatic cancer. PMID- 27459513 TI - Effects of Corroded and Non-Corroded Biodegradable Mg and Mg Alloys on Viability, Morphology and Differentiation of MC3T3-E1 Cells Elicited by Direct Cell/Material Interaction. AB - This study investigated the effect of biodegradable Mg and Mg alloys on selected properties of MC3T3-E1 cells elicited by direct cell/material interaction. The chemical composition and morphology of the surface of Mg and Mg based alloys (Mg2Ag and Mg10Gd) were analysed by scanning electron microscopy (SEM) and EDX, following corrosion in cell culture medium for 1, 2, 3 and 8 days. The most pronounced difference in surface morphology, namely crystal formation, was observed when Pure Mg and Mg2Ag were immersed in cell medium for 8 days, and was associated with an increase in atomic % of oxygen and a decrease of surface calcium and phosphorous. Crystal formation on the surface of Mg10Gd was, in contrast, negligible at all time points. Time-dependent changes in oxygen, calcium and phosphorous surface content were furthermore not observed for Mg10Gd. MC3T3-E1 cell viability was reduced by culture on the surfaces of corroded Mg, Mg2Ag and Mg10Gd in a corrosion time-independent manner. Cells did not survive when cultured on 3 day pre-corroded Pure Mg and Mg2Ag, indicating crystal formation to be particular detrimental in this regard. Cell viability was not affected when cells were cultured on non-corroded Mg and Mg alloys for up to 12 days. These results suggest that corrosion associated changes in surface morphology and chemical composition significantly hamper cell viability and, thus, that non-corroded surfaces are more conducive to cell survival. An analysis of the differentiation potential of MC3T3-E1 cells cultured on non-corroded samples based on measurement of Collagen I and Runx2 expression, revealed a down regulation of these markers within the first 6 days following cell seeding on all samples, despite persistent survival and proliferation. Cells cultured on Mg10Gd, however, exhibited a pronounced upregulation of collagen I and Runx2 between days 8 and 12, indicating an enhancement of osteointegration by this alloy that could be valuable for in vivo orthopedic applications. PMID- 27459515 TI - [Unilateral Gigantic Exophthalmos in Haemorrhagic Exacerbation of an Orbital Meningioma]. PMID- 27459516 TI - [Lymphoma of the Conjunctiva with Simultaneous Infection with Chlamydia trachomatis]. PMID- 27459518 TI - [Systematic Review of the Application of Complementary and Alternative Medicine and their Potential Therapeutic Benefits in the Treatment of Ophthalmology Patients]. AB - Purpose A systematic review was carried out of the reported therapeutic effects of complementary and alternative medicine methods as supplementary or primary treatments for patients suffering from glaucoma, cataract or age-related macular degeneration (AMD). Material and Methods For the years 1990 to 2013, the following databases were screened for reports of the application of complementary and alternative treatments: PubMed, Cochrane Library, EMBASE, CAMbase and AMED. Both randomised and prospective non-randomised patient trials were included in the review; results were evaluated in the following classes: "phytotherapy", "acupuncture/acupressure", "biofeedback" and "other alternative treatments". The studies were evaluated by measures of clinical effect, statistical significance (p value and/or confidence interval) and the underlying trial design. Results 30 clinical trials were included, including 13 on glaucoma, 5 on cataract and 12 on AMD patients. These trials were based on patient numbers of 6 - 332, 27 - 157 and 6 - 328 patients, respectively. Phytotherapy was applied in 14 trials, including 6 on glaucoma patients (all 6 with a controlled design, and 3 of which reporting statistically significant results); 5 trials were on cataract patients (3 with a controlled design and 2 with a significant result) and 3 on AMD patients (only 1 with a controlled design, with a significant result). Acupuncture/acupressure was investigated in 9 trials, 5 on glaucoma patients (3 with a controlled design, 1 with a significant result); no acupuncture/acupressure trial was found in cataract patients, but 4 trials in AMD patients (none with a controlled design). Biofeedback was studied in 4 trials, all on AMD patients (only one with a controlled design, without statistically significant findings). Conclusion Despite its rigorous inclusion criteria, this review identified several clinical trials on complementary and alternative medicine in ophthalmological patients. Phytotherapeutic methods gave significant results in half of the reported controlled trials, whereas there were few significant benefits with acupuncture or acupressure. PMID- 27459517 TI - [The 2-Scale Model of the National Eye Institute Visual Function Questionnaire (NEI-VFQ) to Assess Vision-Related Quality of Life]. AB - Aim This study addresses the examination of the factorial validity of the National Eye Institute Visual Function Questionnaire 39 (NEI-VFQ 39) and the neuro-ophthalmological supplement in a German sample. Method Eighty-one patients with visual field defects affecting at least one eye answered the NEI-VFQ 39 and the supplement. Theoretical factor structures reported in the manuals were examined in confirmatory factor analysis. Because of a misfit, items retained after item analysis were subjected to exploratory factor analysis. Results The originally postulated factor structures could not be replicated. Many items revealed floor effects. The 21 remaining items could be assigned to two factors - "visual functioning" and "socio-emotional impairment". Conclusion The weakness of the theoretical factors can be avoided by using the 2-scale model. PMID- 27459519 TI - Heat Sensitivity of wMel Wolbachia during Aedes aegypti Development. AB - The wMel strain of Wolbachia bacteria is known to prevent dengue and Zika virus transmission in the mosquito vector Aedes aegypti. Accordingly, the release of wMel-infected A. aegypti in endemic regions has been recommended by the World Health Organization as a potential strategy for controlling dengue and Zika outbreaks. However, the utility of this approach could be limited if high temperatures in the aquatic habitats where A. aegypti develop are detrimental to Wolbachia. We exposed wMel-infected A. aegypti eggs and larvae to fluctuating daily temperatures of 30-40 degrees C for three, five, or seven days during their development. We found that Wolbachia levels in females emerging from heat treatments were significantly lower than in the controls that had developed at 20 30 degrees C. Notably, seven days of high temperatures starting at the egg stage reduced Wolbachia levels in emerging females to less than 0.1% of the wMel control levels. However, after adult females returned to 20-30 degrees C for 4-7 days, they experienced differing degrees of Wolbachia recovery. Our findings suggest that the spread of Wolbachia in wild A. aegypti populations and any consequent protection from dengue and Zika viruses might be limited in ecosystems that experience periods of extreme heat, but Wolbachia levels recover partially after temperatures return to normal. PMID- 27459520 TI - Synthesis and Isolation of the Titanium-Scandium Endohedral Fullerenes-Sc2 TiC@Ih -C80 , Sc2 TiC@D5h -C80 and Sc2 TiC2 @Ih -C80 : Metal Size Tuning of the Ti(IV) /Ti(III) Redox Potentials. AB - The formation of endohedral metallofullerenes (EMFs) in an electric arc is reported for the mixed-metal Sc-Ti system utilizing methane as a reactive gas. Comparison of these results with those from the Sc/CH4 and Ti/CH4 systems as well as syntheses without methane revealed a strong mutual influence of all key components on the product distribution. Whereas a methane atmosphere alone suppresses the formation of empty cage fullerenes, the Ti/CH4 system forms mainly empty cage fullerenes. In contrast, the main fullerene products in the Sc/CH4 system are Sc4 C2 @C80 (the most abundant EMF from this synthesis), Sc3 C2 @C80 , isomers of Sc2 C2 @C82 , and the family Sc2 C2 n (2 n=74, 76, 82, 86, 90, etc.), as well as Sc3 CH@C80 . The Sc-Ti/CH4 system produces the mixed-metal Sc2 TiC@C2 n (2 n=68, 78, 80) and Sc2 TiC2 @C2 n (2 n=80) clusterfullerene families. The molecular structures of the new, transition-metal-containing endohedral fullerenes, Sc2 TiC@Ih -C80 , Sc2 TiC@D5h -C80 , and Sc2 TiC2 @Ih -C80 , were characterized by NMR spectroscopy. The structure of Sc2 TiC@Ih -C80 was also determined by single-crystal X-ray diffraction, which demonstrated the presence of a short Ti=C double bond. Both Sc2 TiC- and Sc2 TiC2 -containing clusterfullerenes have Ti-localized LUMOs. Encapsulation of the redox-active Ti ion inside the fullerene cage enables analysis of the cluster-cage strain in the endohedral fullerenes through electrochemical measurements. PMID- 27459521 TI - The Effect of Skin Debris on Gunshot Residue Sampling and Detection. AB - These experiments were designed to determine whether skin debris (desquamated epithelial cells and apparent skin oils) affects gunshot residue (GSR) particle detection on the sticky tape lift samples prepared for scanning electron microscopy (SEM). A dabbing experiment showed that GSR particles accumulate not only on the adhesive surface of the sampler, but also on the epithelial cell surfaces. Samplers were loaded with target GSR followed by dabbing 30 times on the back of a hand. Backscatter electron images were taken at 20 kV and for some at 30 kV of the same areas. The samplers were then treated with a sodium/calcium hypochlorite solution (bleach) to remove skin debris and again imaged in the SEM. Comparison of these images shows more GSR particles will likely be revealed at 30 kV than 20 kV and more particles revealed by the bleach treatment in an automated SEM system. PMID- 27459522 TI - Acquired Hemophilia Treated Using Low-Dose of Rituximab. PMID- 27459523 TI - Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial. AB - CONTEXT: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS. OBJECTIVE: The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS. DESIGN: This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial. SETTINGS: University hospitals and private clinical research centers were included. PARTICIPANTS: Women with PCOS aged 18-45 years participated. INTERVENTION: Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days. MAIN OUTCOME MEASURE: Change from baseline in the area under the LH serum concentration-time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured. RESULTS: Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6-67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9-40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0-5.1) (all nominal P < .05). CONCLUSIONS: The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS. PMID- 27459524 TI - Deep Sequencing Reveals Spatially Distributed Distinct Hot Spot Mutations in DICER1-Related Multinodular Goiter. AB - CONTEXT: Nontoxic multinodular goiter (MNG) occurs frequently, but its genetic etiology is not well established. Familial MNG and MNG occurring with ovarian Sertoli-Leydig cell tumor are associated with germline DICER1 mutations. We recently identified second somatic DICER1 ribonuclease (RNase) IIIb mutations in two MNGs. OBJECTIVE: The objective of the study was to investigate the occurrence of somatic DICER1 mutations and mutational clonality in MNG. PATIENTS: MNGs from 15 patients (10 with and five without germline DICER1 mutations) were selected based on tissue availability. DESIGN: Core biopsies/scrapings (n = 70) were obtained, sampling areas of follicular hyperplasia, hyperplasia within colloid pools, unremarkable thyroid parenchyma, and areas of thyroid parenchyma, not classified. After capture with a Fluidigm access array, the coding sequence of DICER1 was deep sequenced using DNA from each core/scraping. RESULTS: All germline DICER1-mutated cases were found to harbor at least one RNase III mutation. Specifically, we identified 12 individually distinct DICER1 RNase IIIb hot spot mutations in 32 of the follicular hyperplasia or hyperplasia within colloid pools cores/scrapings. These mutations are predicted to affect the metal ion binding residues at positions p.Glu1705, p.Asp1709, p.Gly1809, p.Asp1810, and p.Glu1813. Somatic RNase IIIb mutations were identified in the 10 DICER1 germline mutated MNGs as follows: two cases contained one somatic mutation, five cases contained two mutations, and three cases contained three distinct somatic hot spot mutations. No RNase IIIb mutations were identified in the MNGs from individuals without germline DICER1 mutations. CONCLUSIONS: This study demonstrates that nodules within MNG occurring in DICER1 syndrome are associated with spatially distributed somatic DICER1 RNase IIIb mutations. PMID- 27459525 TI - FKBP5 mRNA Expression Is a Biomarker for GR Antagonism. AB - CONTEXT: Endogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for the treatment of Cushing's syndrome. Currently there is an unmet clinical need for a direct biochemical method for monitoring the immediate effectiveness of mifepristone in patients with Cushing's syndrome. The glucocorticoid induction of FK506-binding protein 5 (FKBP5) expression is rapid and has been shown to be attenuated by GR antagonists in a range of in vitro and in vivo models. OBJECTIVE: The objective of the study was to develop a quantitative PCR assay for FKBP5 mRNA expression in blood and apply it to measure the inhibition of glucocorticoid-induced FKBP5 expression by GR antagonists in healthy human subjects. METHODS: Briefly, blood samples were acquired from a phase I study in which healthy human subjects were administered either a single dose of the GR agonist prednisone with and without coadministration of a single oral dose of mifepristone or glucocorticoid receptor antagonist (CORT125134) or multiple daily doses of CORT125134 over 14 days with coadministration of prednisone with the final dose. FKBP5 mRNA levels were analyzed by quantitative PCR in blood samples collected at selected time points. SETTING: The study was conducted at Quotient Clinical (Nottingham, United Kingdom). RESULTS: Oral administration of the glucocorticoid prednisone to healthy human subjects resulted in a time-dependent increase of FKBP5 mRNA to peak levels of approximately 12-fold compared with unstimulated levels within 4 hours of steroid administration, followed by a reduction to baseline levels within 24 hours. Furthermore, oral administration of mifepristone or the selective GR antagonist CORT125134 had the desired effect of inhibiting prednisone-mediated activation of GR as seen by a reduction of FKBP5 mRNA levels. CONCLUSIONS: The inhibition of FKBP5 mRNA expression by a selective GR antagonist is a potential clinical biomarker of GR antagonism. PMID- 27459526 TI - Weight Loss Partially Restores Glucose-Driven Betatrophin Response in Humans. AB - CONTEXT: Recently a potential role of betatrophin was shown in the postprandial switch from lipid to glucose metabolism. OBJECTIVE: The objective of the study was to analyze whether obesity is associated with altered postprandial betatrophin response and whether this could be restored by weight loss. Design, Setting, Participants, and Intervention: Oral glucose load was performed in 12 lean individuals at baseline as well as in 20 obese subjects before and after a 12-week structured weight-loss program at an endocrinology research center. Euglycemic hyperinsulinemic clamps were performed in the obese cohort. The effect of insulin and different glucose concentrations on betatrophin expression were analyzed in 3T3-L1 adipocytes. MAIN OUTCOME MEASURE: Circulating betatrophin levels during a glucose challenge were measured. RESULTS: The betatrophin level decreases after an oral glucose intake (P < .001). This correlates with the increase of glucose levels (r = -0.396; P < .05). Hyperinsulinemia results in an increase of betatrophin. In vitro experiments in 3T3-L1 adipocytes confirmed that insulin and low glucose concentration increases betatrophin expression, whereas a further elevation of glucose levels blunts this effect. Obese subjects are characterized by lower fasting betatrophin (600.6 +/- 364.4 vs 759.5 +/- 197.9 pg/mL; P < .05) and a more pronounced betatrophin suppression during the glucose challenge. The impaired betatrophin response in obese subjects is restored after weight loss and is comparable with lean individuals. CONCLUSIONS: Obesity is associated with increased betatrophin suppression after an oral glucose load, which is driven by increased hyperglycemia. Given the metabolic properties of betatrophin, this may indicate that betatrophin is tightly linked to obesity associated metabolic disturbances. In line with such an assumption, weight loss almost completely eliminated this phenomenon. PMID- 27459527 TI - Impact of Levothyroxine in Miscarriage and Preterm Delivery Rates in First Trimester Thyroid Antibody-Positive Women With TSH Less Than 2.5 mIU/L. AB - BACKGROUND: Thyroid disease during pregnancy is associated with multiple adverse maternal and fetal outcomes. In particular, multiple observational studies have demonstrated an association between the presence of thyroid antibodies in euthyroid women in the first trimester of miscarriage and an increased rate of spontaneous miscarriage and preterm delivery. The present study is a prospective intervention trial of the effect of levothyroxine on the rate of miscarriage and preterm delivery in euthyroid thyroid-antibody positive women in the first trimester of pregnancy. METHODS: A total of 8530 women in the first trimester of pregnancy in Southern Italy were screened for TSH and thyroid antibodies. Group A consisted of 198 euthyroid thyroid antibody positive women treated with levothyroxine, group B consisted of 195 untreated euthyroid thyroid antibody positive women, and group C consisted of 197 untreated thyroid antibody negative women. RESULTS: The rate of miscarriage did not differ between the 3 groups (11.6%, 14.9%, and 8.1 %, P = .11). The rate of preterm delivery between the 3 groups was 6.9%, 10.8%, and 2.8% and was statistically significant (P = .01). The rate of preterm delivery was significantly different between groups B and C (P = .02) but was not significantly different between groups A and B (P = .27). CONCLUSIONS: In conclusion, the present study found that levothyroxine intervention had no impact on the rate of miscarriage and preterm delivery in euthyroid thyroid antibody positive women. PMID- 27459528 TI - One-Hour Postload Hyperglycemia Confers Higher Risk of Hepatic Steatosis to HbA1c Defined Prediabetic Subjects. AB - CONTEXT: Individuals with glycated hemoglobin (HbA1c)-defined prediabetes (HbA1c value of 5.7-6.4%) and 1-hour plasma glucose >=155 mg/dL during an oral glucose tolerance test have an increased risk of developing type 2 diabetes. OBJECTIVE: To evaluate the degree to which HbA1c-defined prediabetes and 1-hour postload glucose >=155 mg/dL individually and jointly associate with hepatic steatosis and related biomarkers. DESIGN AND PATIENTS: A cross-sectional analysis was performed on 1108 White individuals. SETTING: Ambulatory care. MAIN OUTCOME MEASURES: Anthropometric and metabolic characteristics including hepatic steatosis assessed by ultrasonography. RESULTS: Compared with the normal group (HbA1c <5.7%), HbA1c defined prediabetic and diabetic individuals exhibit higher values of fasting, 1 hour, and 2-hour postload glucose; fasting and 2-hour postload insulin; triglycerides; uric acid; homeostasis model of assessment for insulin resistance; liver insulin resistance index; liver enzymes; and inflammatory biomarkers; and lower levels of high-density lipoprotein cholesterol and IGF-1. Prediabetic and diabetic subjects have increased risk of hepatic steatosis (1.5- and 2.46-fold, respectively). Stratifying participants according to HbA1c and 1-hour postload glucose, we found that individuals with HbA1c-defined prediabetes and 1-hour postload glucose >=155 mg/dL have significantly higher risk of hepatic steatosis as compared with individuals with HbA1c-defined prediabetes but 1-hour postload glucose <155 mg/dL. Individuals with HbA1c-defined prediabetes and 1-hour postload glucose >=155 mg/dL exhibit higher values of liver enzymes; fasting, 1 hour, and 2-hour postload glucose; insulin; triglycerides; uric acid; and inflammatory biomarkers; and lower levels of high-density lipoprotein and IGF-1. CONCLUSIONS: These data suggest that a value of 1-hour postload glucose >=155 mg/dL may be helpful to identify a subset of individuals within HbA1c-defined glycemic categories at higher risk of hepatic steatosis. PMID- 27459530 TI - Dopamine Agonists Can Reduce Cystic Prolactinomas. AB - CONTEXT: Cystic prolactinomas are considered resistant to volume reduction by dopamine agonists (DAs). Although several individual case reports and small case series have suggested that DAs may reduce these lesions, larger series using standardized imaging metrics are lacking. OBJECTIVE: The objectives of the study were to assess the efficacy of DAs on cyst size in patients with predominantly cystic prolactinomas and to characterize the clinical course and treatment outcomes in these patients. DESIGN: This study was a retrospective review. SETTING: The study was conducted at a tertiary referral center. SUBJECTS: The study comprised 30 adults with cystic prolactinomas treated at Massachusetts General Hospital. INTERVENTION(S): The interventions included treatment with Das and transsphenoidal surgery. MAIN OUTCOME MEASURE(S): Cyst volume calculated by a commercial software and pituitary hormone function were measured. RESULTS: Median age was 31.5 years (interquartile range [IR] 24.5-39.2), and 24 of 30 were female. Median length of follow-up was 3.05 years (IR 1.04-5.28). Twenty-three of 30 patients received initial treatment with DAs. Median cyst volume for these patients was 435 mm3 (IR 255-1785). Persistent cyst reduction occurred in 20 of 22 patients after DA treatment. Median cyst volume reduction was 83.5% (IR 48.8 96.2). Median time to cyst reduction was 24.6 weeks (range 2.6-73). Chiasm compression resolved in four of five patients, and nongonadal anterior hypopituitarism improved in five of six. Transsphenoidal surgery was ultimately performed in 15 of 30 patients. CONCLUSIONS: Significant cyst reduction occurred in the majority of patients treated with DAs, including those with larger lesions and chiasm compression. This study is the first formal analysis of cyst reduction with DAs in patients with cystic prolactinomas, and contrary to long-held assumptions, our results suggest that medical therapy may be effective in many such patients. PMID- 27459529 TI - Genome-Wide Expression Screening Discloses Long Noncoding RNAs Involved in Thyroid Carcinogenesis. AB - CONTEXT: Long noncoding RNAs (lncRNAs) regulate pathological processes, yet their potential roles in papillary thyroid carcinoma (PTC) are poorly understood. OBJECTIVE: To profile transcriptionally dysregulated lncRNAs in PTC and identify lncRNAs associated with clinicopathological characteristics. DESIGN: We performed RNA sequencing of 12 paired PTC tumors and matched noncancerous tissues and correlated the expression of lncRNAs with clinical parameters. The 2 most significantly dysregulated lncRNAs were studied in an Ohio PTC cohort (n = 109) and in PTC data (n = 497) from The Cancer Genome Atlas. SETTING: A combination of laboratory-based studies and computational analysis using clinical data and samples and a publically available database. MAIN OUTCOME MEASURES: Correlation between expression values and clinical parameters. RESULTS: We identified 218 lncRNAs showing differential expression in PTC (fold change >= 2.0, P < .01). Significant correlation was observed between the expression of 2 lncRNAs (XLOC_051122 and XLOC_006074) and 1) lymph node metastasis (N stage) and 2) BRAF(V600E) mutation. Among patients with wild-type BRAF, the expression of these 2 lncRNAs showed significantly higher levels in the patients with lymph node metastasis. In silico analysis of these lncRNAs pinpointed cell movement and cellular growth and proliferation as targeted functions. CONCLUSIONS: Comprehensive expression screening identified 2 novel lncRNAs associated with risk factors of adverse prognosis in PTC patients. These lncRNAs may be novel players in PTC carcinogenesis. PMID- 27459531 TI - Hysterectomy, Oophorectomy, and Risk of Thyroid Cancer. AB - CONTEXT: Estrogen has been suggested as a risk factor for thyroid cancer. OBJECTIVE: The aim of this study is to examine the associations between hysterectomy, bilateral salpingo-oophorectomy (BSO), and incidence of thyroid cancer. DESIGN: This was a prospective cohort study. SETTING: The study was conducted at 40 clinical centers in the United States. PARTICIPANTS: A total of 127 566 women aged 50-79 were enrolled in the Women's Health Initiative during 1993-1998. MAIN OUTCOME MEASURES: Hysterectomy and BSO were self-reported. Incident thyroid cancer cases were confirmed by medical record review. RESULTS: Three hundred forty-four incident thyroid cancer cases were identified during an average of 14.4 years of follow-up. Compared with women without hysterectomy, women with hysterectomy, regardless of ovarian status, had a significantly higher risk of thyroid cancer (hazard ratio 1.46 [95% confidence interval 1.16-1.85]). Hysterectomy with BSO was not associated with a lower risk for thyroid cancer compared with hysterectomy alone. Among women with hysterectomy alone, hormone therapy use was associated with lower risk of thyroid cancer (hazard ratio 0.47 [95% confidence interval 0.28-0.78]). However, we did not observe significant associations between hormone therapy use and thyroid cancer in women without hysterectomy or women with hysterectomy plus BSO. CONCLUSION: Our large prospective study observed that hysterectomy, regardless of oophorectomy status, was associated with increased risk of thyroid cancer among postmenopausal women. In addition, our data did not support the hypotheses that exogenous estrogen is a risk factor or that estrogen deprivation is a protective factor for thyroid cancer. Further research is needed to clarify whether these apparent associations may be due to shared risk factors between indications for hysterectomy and thyroid cancer. PMID- 27459532 TI - Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors. AB - CONTEXT: Somatostatin analogs are established in the treatment of neuroendocrine tumors (NETs) including small intestinal NET; however, the molecular mechanisms are not well known. Here, we examined the direct effects of lanreotide in NET cell line models. SETTING AND DESIGN: The cell lines HC45 and H727 were treated with 10nM lanreotide for different time periods and alterations of the proteome were analyzed by in-depth high-resolution isoelectric focusing tandem liquid chromatography-mass spectrometry. We next investigated whether the observed suppression of survivin was mediated by adenomatous polyposis coli (APC) and possible effects on tumor proliferation in vitro. Expression of survivin was assessed by immunohistochemistry in 112 NET cases and compared with patient outcome. RESULTS: We quantified 6451 and 7801 proteins in HC45 and H727, respectively. After short time lanreotide treatment APC was increased and survivin reduced. Overexpression of APC in H727 cells decreased, and APC knock down elevated the survivin level. The lanreotide regulation of APC-survivin could be suppressed by small interfering RNA against somatostatin receptor 2. Although lanreotide only gave slight inhibition of proliferation, targeting of survivin with the small molecule YM155 dramatically reduced proliferation. Moderate or high as compared with low or absent total survivin expression was associated with shorter progression-free survival, independent of tumor stage, grade, and localization. CONCLUSIONS: We report a proteome-wide analysis of changes in response to lanreotide in NET cell lines. This analysis suggests a connection between somatostatin analog, APC, and survivin levels. Survivin is a possible prognostic factor and a new potential therapeutic target in NETs. PMID- 27459533 TI - Metformin Increases Cortisol Regeneration by 11betaHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus. AB - CONTEXT: The mechanism of action of metformin remains unclear. Given the regulation of the cortisol-regenerating enzyme 11betahydroxysteroid dehydrogenase 1 (11betaHSD1) by insulin and the limited efficacy of selective 11betaHSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11betaHSD1 activity. OBJECTIVE: To determine whether metformin regulates 11betaHSD1 activity in vivo in obese men with and without type 2 diabetes mellitus. DESIGN: Double-blind, randomized, placebo controlled, crossover study. SETTING: A hospital clinical research facility. PARTICIPANTS: Eight obese nondiabetic (OND) men and eight obese men with type 2 diabetes (ODM). INTERVENTION: Participants received 28 days of metformin (1 g twice daily), placebo, or (in the ODM group) gliclazide (80 mg twice daily) in random order. A deuterated cortisol infusion at the end of each phase measured cortisol regeneration by 11betaHSD1. Oral cortisone was given to measure hepatic 11betaHSD1 activity in the ODM group. The effect of metformin on 11betaHSD1 was also assessed in human hepatocytes and Simpson-Golabi-Behmel syndrome adipocytes. MAIN OUTCOME MEASURES: The effect of metformin on whole-body and hepatic 11betaHSD1 activity. RESULTS: Whole-body 11betaHSD1 activity was approximately 25% higher in the ODM group than the OND group. Metformin increased whole-body cortisol regeneration by 11betaHSD1 in both groups compared with placebo and gliclazide and tended to increase hepatic 11betaHSD1 activity. In vitro, metformin did not increase 11betaHSD1 activity in hepatocytes or adipocytes. CONCLUSIONS: Metformin increases whole-body cortisol generation by 11betaHSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11betaHSD1 inhibitors. PMID- 27459534 TI - Reciprocal Feedback Between miR-181a and E2/ERalpha in Myometrium Enhances Inflammation Leading to Labor. AB - CONTEXT: The initiation of term and preterm labor is associated with an up regulated inflammatory response in myometrium; however, the underlying signaling pathways remain incompletely defined. OBJECTIVE: To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR). DESIGN AND SETTING: Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility. PATIENTS: Myometrial tissues from 15 term pregnant women undergoing elective cesarean section (not in labor) and 10 term pregnant women undergoing emergency cesarean section (in labor) were used. RESULTS: Expression of the highly conserved microRNA, miR-181a, was significantly decreased in mouse and human myometrium during late gestation. By contrast, the putative miR-181a targets, TNF-alpha, and estrogen receptor (ER)-alpha, and the validated target, c Fos, key factors in the inflammatory response leading to parturition, were coordinately up-regulated. In studies using human myometrial cells, overexpression of miR-181a mimics repressed basal as well as IL-1beta-induced TNF alpha, C-C motif chemokine ligand 2 and 8 expression, whereas the expression of the antiinflammatory cytokine, IL-10, was increased. Overexpression of miR-181a dramatically inhibited both spontaneous and IL-1beta-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERalpha and decreased its expression, whereas estradiol-17beta reciprocally inhibited expression of mature miR-181a in myometrial cells. CONCLUSIONS: Thus, increased estradiol 17beta/ERalpha signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERalpha and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences. PMID- 27459536 TI - Urinary Haptoglobin Predicts Rapid Renal Function Decline in Asians With Type 2 Diabetes and Early Kidney Disease. AB - CONTEXT: A recent study suggested that urinary haptoglobin may be a novel biomarker to improve predictive performance of albuminuria in type 2 diabetes mellitus (T2DM). However, the finding has not been externally validated. OBJECTIVE: The objective of the study was to evaluate whether urinary haptoglobin improves predictive performance of albuminuria in Asian T2DM with an estimated glomerular filtration rate (eGFR) of 30 mL/min per 1.73 m2 or greater. DESIGN AND PARTICIPANTS: This was a prospective study with 269 T2DM nonprogressors (eGFR changes 0.2 [-0.7 to 1.0] mL/min per 1.73 m2 per y) and 153 T2DM progressors (eGFR decline -7.1 [-10.6 to -5.1] mL/min per 1.73 m2 per y) included. MAIN OUTCOME: The main outcome was an eGFR decline of 3 mL/min per 1.73 m2 or greater per year by trajectory slope. RESULTS: Urinary haptoglobin level increased 11 fold in progressors as compared with nonprogressors at baseline. In comparison with subjects in the lowest quartile, those with haptoglobin in the third and fourth quartiles had 2.25- (1.11-4.59) and 5.41 (2.63-11.1)-fold increased odds for renal progression, whereas those with an albuminuria level in the third and fourth quartiles had 2.53- (1.17-5.51) and 9.01 (4.00-20.5)-fold increased odds. Notably, urinary haptoglobin predicted renal progression independent of albuminuria. Addition of haptoglobin significantly improved the predictive performance of albuminuria beyond traditional risk factors as reflected by a significant increase in the net reclassification index and integrated discrimination index. In the chronic kidney disease stage 3 subpopulation, urinary haptoglobin outperformed albuminuria for the prediction of rapid renal function decline. CONCLUSIONS: Our data confirmed that urinary haptoglobin may improve the predictive performance of albuminuria for renal progression in Asians with T2DM. Moreover, it may potentially outperform albuminuria for the prediction of rapid renal function decline in the T2DM chronic kidney disease stage 3 subpopulation. PMID- 27459535 TI - Endogenous Estrogen Regulates Somatostatin-Induced Rebound GH Secretion in Postmenopausal Women. AB - BACKGROUND: Systemic concentrations of T, estradiol (E2), GH, IGF-1, and IGF binding protein-3 decline in healthy aging individuals. Conversely, T and E2 stimulate GH and IGF-1 production in hypogonadal patients. HYPOTHESIS: Because E2 stimulates GH secretion, putatively via the nuclear estrogen receptor-alpha and E2 and GH fall with menopause, we postulated that diminished endogenous E2 contributes to low GH output in older women. LOCATION: The study was conducted at the Mayo Center for Clinical and Translational Science. STUDY DESIGN: This was a randomized, double-blind, controlled study in 60 healthy postmenopausal women treated with the following: 1) double placebo; 2) anastrozole, a potent inhibitor of aromatase-enzyme activity, which mediates E2 synthesis from T; and/or 3) fulvestrant, a selective estrogen receptor-alpha antagonist. METHODS: GH pulse generation was quantified by frequent GH sampling before and after short-term iv somatostatin infusion, thought to induce hypothalamic GHRH-mediated rebound-like GH secretion. RESULTS: On anastrozole, E2 fell from 3.1 +/- 0.35 pg/mL to 0.36 +/ 0.04 pg/mL, and estrone from 13 +/- 1.4 pg/mL to 1.9 +/- 0.01 pg/mL (P < .001) by mass spectrometry. Estrogen values were unchanged by fulvestrant. T concentrations did not change. One-hour peak GH rebound after somatostatin infusion declined markedly during both estrogen-deprivation schedules (P < .001). Mean (150 min) maximal GH rebound decreased comparably (P < .001). Measures of GH rebound correlated negatively with computed tomography-estimated abdominal visceral fat (all P < .05). CONCLUSION: These data suggest a previously unrecognized dependence of hypothalamo-pituitary GH regulation on low levels of endogenous estrogen after menopause. PMID- 27459537 TI - GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves beta-Cell Function in Type 2 Wolfram Syndrome. AB - CONTEXT: Type 2 Wolfram syndrome (T2-WFS) is a neuronal and beta-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying beta-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. OBJECTIVE: Unraveling the mechanisms of beta-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA). DESIGN AND SETTING: A case report and in vitro mechanistic studies. PATIENT AND METHODS: We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of beta-cell dysfunction and the effects of GLP-1-RA. RESULTS: Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects. CONCLUSION: NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to beta-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores beta-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation. PMID- 27459538 TI - Adipose and Circulating CCL18 Levels Associate With Metabolic Risk Factors in Women. AB - CONTEXT: Cardiometabolic complications in obesity may be linked to white adipose tissue (WAT) dysfunction. Transcriptomic studies of Sc WAT have reported that CCL18, encoding the CC chemokine ligand 18 (CCL18), is increased in obesity/insulin resistance but its functional role is unknown. OBJECTIVE: Our objectives were to determine if CCL18 is secreted from Sc WAT and if secreted and/or serum levels associate with metabolic phenotypes. We also planned to define the primary cellular source and if CCL18 exerts effects on adipocytes. DESIGN: This is a cohort study. SETTING: The study took place in an outpatient academic clinic. PARTICIPANTS: A total of 130 obese women scheduled for bariatric surgery and 35 nonobese controls were included. METHODS: Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp or homeostasis model assessment. CCL18 was analyzed in serum/WAT incubates by ELISA. Effects of recombinant CCL18 was determined in cultures of primary human adipocytes and the monocyte cell line THP-1 differentiated into M0/M1/M2 macrophages. MAIN OUTCOME MEASURE: Association with metabolic risk factors was measured. RESULTS: CCL18 was secreted from WAT and the levels correlated positively with insulin resistance, Adult Treatment Panel III risk score and plasma triglycerides, independent of body mass index and better than other established adipocytokines. In 80 obese women, S-CCL18 levels were significantly higher in insulin resistant compared with insulin sensitive subjects. In WAT CCL18 mRNA was expressed in macrophages and correlated positively with immune-related genes, particularly those enriched in M2 macrophages. While CCL18 increased cyto-/chemokine expression in M0/M2-THP-1 cells, human adipocytes showed no responses in vitro. CONCLUSIONS: Circulating and WAT-secreted CCL18 correlates with insulin resistance and metabolic risk score. Because CCL18 is macrophage-specific and associates with adipose immune gene expression, it may constitute a marker of WAT inflammation. PMID- 27459539 TI - MicroRNA-145 Mediates Steroid-Induced Necrosis of the Femoral Head by Targeting the OPG/RANK/RANKL Signaling Pathway. AB - OBJECTIVE: To investigate the role of microRNA-145 (miR-145) in steroid-induced necrosis of the femoral head (SINFH) by evaluating its effects on the OPG/RANK/RANKL signaling pathway. METHODS: A rat model of SINFH was constructed via injection of the lentiviral vector pLV-shRNA-miR-145. Pathological observation was performed via tartrate-resistant acid phosphatase (TRAP) staining, and serum OPG levels were detected by ELISA. The mRNA expression levels of miR-145, OPG, RANK and RANKL in THP-1 cells were assessed by RT-PCR, and the protein expression levels of OPG, RANK and RANKL were assessed by western blotting. RESULTS: The expression of miR-145 in the lentivirus-mediated miR-145 group was significantly up-regulated compared with that in the control and normal groups (both P < 0.01). Serum OPG levels were decreased in SINFH rats compared with control and normal rats. The mRNA and protein expression levels of OPG in THP-1 cells decreased after transfection (all P < 0.05). By contrast, the mRNA and protein expression levels of RANK and RANKL in THP-1 cells increased after transfection (all P < 0.05). After transfection of 293T cells with an miR-145 overexpression vector, miR-145 expression in 293T cells increased significantly, while OPG mRNA and protein expression decreased significantly (all P < 0.05). CONCLUSION: MiR-145 plays a role in the occurrence of SINFH by targeting the OPG/RANK/RANKL signaling pathway. PMID- 27459540 TI - The Case for Skin Cancer Screening With Total-Body Skin Examinations. PMID- 27459541 TI - Endocrine Response Phenotypes Are Altered by Charcoal-Stripped Serum Variability. AB - Charcoal-stripped bovine serum (CSS) is a critical reagent in the study of steroid hormones. However, CSS has high lot-to-lot variability, including residual growth factor and steroid hormone content. Assessing and reporting this variability is challenging but may affect experimental outcomes and data reproducibility. We hypothesized that CSS lot variability would affect endocrine response phenotypes in breast cancer cells, and we tested the effects of five individual CSS lots on endocrine response in MCF-7 and MDA MB 134VI (MM134) cells. Based on the effects of antiestrogens on MCF-7 cell proliferation, we defined CSS lots as having complete vs partial hormone deprivation. In partial deprivation CSS, the absolute effects of residual estrogens on cell proliferation were modest, but these effects masked the partial agonist activity of 4 hydroxytamoxifen in MM134 cells. Importantly, this effectively reversed the interpretation of tamoxifen-resistance in MM134 cells. Variable effects of CSS lots on endocrine resistance phenotypes were also observed in MCF-7 cells. In this context, we observed that partial vs complete deprivation CSS allowed for the development of unique early endocrine resistance phenotypes that correlated with the presence or absence of residual estrogenic hormones. We evaluated the methods of CSS preparation and identified factors contributing to the extent of hormone deprivation. Our observations suggest that CSS lot-to-lot variability has substantial effects on endocrine response phenotypes and that this ubiquitous factor in study methodology may confound reproducibility. Renewed vigilance in testing and reporting CSS phenotypes will greatly aid in interpreting and reproducing endocrine response and resistance data by the community. PMID- 27459542 TI - Efficient Batch-Mode Parahydrogen-Induced Polarization of Propane. AB - We report on a simple approach for efficient NMR proton hyperpolarization of propane using the parahydrogen-induced polarization (PHIP) technique, which yielded ~6.2 % proton polarization using ~80 % parahydrogen, a record level achieved with any hyperpolarization technique for propane. Unlike in previously developed approaches designed for continuous-flow operation, where reactants (propene and parahydrogen) are simultaneously loaded for homogeneous or heterogeneous pairwise addition of parahydrogen, here a batch-mode method is applied: propene is first loaded into the catalyst-containing solution, which is followed by homogeneous hydrogenation via parahydrogen bubbling delivered at ~7.1 atm. The achieved nuclear spin polarization of this contrast agent potentially useful for pulmonary imaging is approximately two orders of magnitude greater than that achieved in the continuous-flow homogeneous catalytic hydrogenation, and a factor of 3-10 more efficient compared to the typical results of heterogeneous continuous-flow hydrogenations. PMID- 27459544 TI - Analysis of the application of the generalized monod kinetics model to describe the human corneal oxygen-consumption rate during soft contact lens wear. AB - This work is an analysis of the application of the generalized Monod kinetics model describing human corneal oxygen consumption during soft contact lens wear to models previously used by Chhabra et al. (J Biomed Mater Res B Appl Biomater, 2009a;90:202-209, Optom Vis Sci 2009b;86:454-466) and Larrea and Buchler (Invest Ophthalmol Vis Sci 2009;50:1076-1080). We use oxygen tension from in vivo estimations provided by Bonanno [Bonanno et al., Invest Ophthalmol Vis Sci 2002;43:371-376, and Bonanno et al 2009]. We consider four hydrogel and six silicone hydrogel lenses. The cornea is considered a single homogeneous layer, with constant oxygen permeability regardless of the type of lens worn. Our calculations yield different values for the maximum oxygen consumption rate Qc,max , whith differents oxygen tensions (high and low pc ) at the cornea-tears interface. Surprisingly, for both models, we observe an increase in oxygen consumption near an oxygen tension of 105 mmHg until a maximum is reached, then decreasing for higher levels of oxygen pressure. That is, when lowering the pressure of oxygen, the parameter Qc,max initially increases depending on the intensity of the change in pressure. Which, it could be related with the variation of the pH. Furthermore, it is also noted that to greater reductions in pressure, this parameter decreases, possibly due to changes in the concentration of glucose related to the anaerobic respiration. The averaged in vivo human corneal oxygen consumption rate of 1.47 * 10-4 cm3 of O2 /cm3 tissue s, with Monod kinetics model, considering all the lenses studied, is smaller than the average oxygen consumption rate value obtained using the Larrea and Buchler model. The impact that these calculations have on the oxygen partial pressure available at different depths in the corneal tissue is presented and discussed, taking into consideration previous models used in this study. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2269-2281, 2017. PMID- 27459543 TI - Mechanistic insight into protein modification and sulfur mobilization activities of noncanonical E1 and associated ubiquitin-like proteins of Archaea. AB - Here we provide the first detailed biochemical study of a noncanonical E1-like enzyme with broad specificity for cognate ubiquitin-like (Ubl) proteins that mediates Ubl protein modification and sulfur mobilization to form molybdopterin and thiolated tRNA. Isothermal titration calorimetry and in vivo analyses proved useful in discovering that environmental conditions, ATP binding, and Ubl type controlled the mechanism of association of the Ubl protein with its cognate E1 like enzyme (SAMP and UbaA of the archaeon Haloferax volcanii, respectively). Further analysis revealed that ATP hydrolysis triggered the formation of thioester and peptide bonds within the Ubl:E1-like complex. Importantly, the thioester was an apparent precursor to Ubl protein modification but not sulfur mobilization. Comparative modeling to MoeB/ThiF guided the discovery of key residues within the adenylation domain of UbaA that were needed to bind ATP as well as residues that were specifically needed to catalyze the downstream reactions of sulfur mobilization and/or Ubl protein modification. UbaA was also found to be Ubl-automodified at lysine residues required for early (ATP binding) and late (sulfur mobilization) stages of enzyme activity revealing multiple layers of autoregulation. Cysteine residues, distinct from the canonical E1 'active site' cysteine, were found important in UbaA function supporting a model that this noncanonical E1 is structurally flexible in its active site to allow Ubl~adenylate, Ubl~E1-like thioester and cysteine persulfide(s) intermediates to form. PMID- 27459545 TI - High Specificity in Circulating Tumor Cell Identification Is Required for Accurate Evaluation of Programmed Death-Ligand 1. AB - BACKGROUND: Expression of programmed-death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) is typically evaluated through invasive biopsies; however, recent advances in the identification of circulating tumor cells (CTCs) may be a less invasive method to assay tumor cells for these purposes. These liquid biopsies rely on accurate identification of CTCs from the diverse populations in the blood, where some tumor cells share characteristics with normal blood cells. While many blood cells can be excluded by their high expression of CD45, neutrophils and other immature myeloid subsets have low to absent expression of CD45 and also express PD-L1. Furthermore, cytokeratin is typically used to identify CTCs, but neutrophils may stain non-specifically for intracellular antibodies, including cytokeratin, thus preventing accurate evaluation of PD-L1 expression on tumor cells. This holds even greater significance when evaluating PD-L1 in epithelial cell adhesion molecule (EpCAM) positive and EpCAM negative CTCs (as in epithelial-mesenchymal transition (EMT)). METHODS: To evaluate the impact of CTC misidentification on PD-L1 evaluation, we utilized CD11b to identify myeloid cells. CTCs were isolated from patients with metastatic NSCLC using EpCAM, MUC1 or Vimentin capture antibodies and exclusion-based sample preparation (ESP) technology. RESULTS: Large populations of CD11b+CD45lo cells were identified in buffy coats and stained non-specifically for intracellular antibodies including cytokeratin. The amount of CD11b+ cells misidentified as CTCs varied among patients; accounting for 33-100% of traditionally identified CTCs. Cells captured with vimentin had a higher frequency of CD11b+ cells at 41%, compared to 20% and 18% with MUC1 or EpCAM, respectively. Cells misidentified as CTCs ultimately skewed PD-L1 expression to varying degrees across patient samples. CONCLUSIONS: Interfering myeloid populations can be differentiated from true CTCs with additional staining criteria, thus improving the specificity of CTC identification and the accuracy of biomarker evaluation. PMID- 27459547 TI - Usefulness of repeat review of head magnetic resonance images during presurgical epilepsy conferences. AB - Surgical epilepsy conferences are an important part of the process of determining whether a patient is a candidate for resective epilepsy surgery. At these conferences, repeat review (re-review) of the magnetic resonance images (MRIs) of the patient's head often occurs. This study assessed how often radiologic re review at a presurgical epilepsy conference resulted in a changed interpretation of the head MRI. Charts were reviewed for 239 patients who had been presented at presurgical epilepsy conferences between 2008 and 2012. Of the 233 patients whose MRIs were re-reviewed, resective surgery was performed in 94 patients (40.3%). Forty-one patients (17.6%) had a previously undiagnosed finding, and 18 of the 41 (43.9%) underwent resective surgery. For 4 of the 41 patients (9.8%) with a previously undiagnosed pertinent finding, re-review detected abnormalities that were not amenable to surgical resection (autoimmunity or significant bilateral pathology). PMID- 27459546 TI - LC/MS/MS analysis of alpha-tocopherol and coenzyme Q10 content in lyophilized royal jelly, beebread and drone homogenate. AB - This study shows the results of application liquid chromatography-tandem mass spectrometry (LC/MS/MS) for assay of the content of alpha-tocopherol and coenzyme Q10 in bee products of animal origin, i.e. royal jelly, beebread and drone homogenate. The biological matrix was removed using extraction with n-hexane. It was found that drone homogenate is a rich source of coenzyme Q10 . It contains only 8 +/- 1 ug/g of alpha-tocopherol and 20 +/- 2 ug/g of coenzyme Q10 . The contents of assayed compounds in royal jelly were 16 +/- 3 and 8 +/- 0.2 ug/g of alpha-tocopherol and coenzyme Q10 , respectively. Beebread appeared to be the richest of alpha-tocopherol. Its level was 80 +/- 30 ug/g, while the level of coenzyme Q10 was only 11.5 +/- 0.3 ug/g. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27459550 TI - Olympic Officials Should Tell Women "High T" Is No Hurdle. PMID- 27459551 TI - The Lesser Evil of E-Cigarettes. PMID- 27459552 TI - Genetic Resurrection. PMID- 27459553 TI - The New Allergy Shot. PMID- 27459554 TI - $1.4 Billion. PMID- 27459555 TI - Divide and Conquer. PMID- 27459556 TI - Your Brain on Physics. PMID- 27459557 TI - Model Airplane. PMID- 27459558 TI - Can We Learn How to Forget? PMID- 27459561 TI - Bionic is Better. PMID- 27459560 TI - Zika-Proofing the Olympics. PMID- 27459562 TI - Toothless Beaks for the Win. PMID- 27459563 TI - Waste Not, Want Not. PMID- 27459564 TI - The Acupuncture Myth. PMID- 27459565 TI - The End of Passwords. PMID- 27459566 TI - The Emptiest Place in Space. PMID- 27459567 TI - Health Check for Humanity. PMID- 27459568 TI - The Coding Revolution. PMID- 27459569 TI - Teach the Prof How to Teach. PMID- 27459570 TI - The Secret to Speed. PMID- 27459572 TI - The Seven-Year Mission to Fetch 60 Grams of Asteroid. PMID- 27459571 TI - The Huntington's Paradox. PMID- 27459573 TI - Zombie Neuroscience. PMID- 27459575 TI - The Quack of the Gaps Problem. PMID- 27459579 TI - Aggressiveness of End-of-Life Care for Hospitalized Individuals with Cancer with and without Dementia: A Nationwide Matched-Cohort Study in France. AB - OBJECTIVES: To compare the aggressiveness of end-of-life care in hospitalized individuals with cancer with and without dementia in France. DESIGN: Nationwide register-based matched-cohort study. SETTING: Hospital facilities in France. PARTICIPANTS: All individuals with cancer aged 65 and older with a diagnosis of dementia who died between January 1, 2010 and December 31, 2013, matched one-to one with individuals with cancer without dementia (n = 26,782 matched pairs). RESULTS: Older individuals with cancer with dementia were less likely to receive aggressive treatment in their last month of life than those who were not diagnosed with dementia. Dementia was associated with significantly greater likelihood of receiving chemotherapy (2.8% vs 8.5%, P < .001, adjusted odds ratio (aOR) = 0.33, 95% confidence interval (CI) = 0.31-0.36) in the month before death. Individuals with dementia were also less likely to receive radiation therapy (aOR = 0.49, 95% CI = 0.43-0.56), blood transfusions (aOR = 0.67, 95% CI = 0.64-0.70), artificial nutrition (aOR = 0.79, 95% CI = 0.73-0.85), and invasive ventilation (aOR = 0.62, 95% CI = 0.57-0.68), although they were more likely to remain hospitalized over their entire last month of life (aOR = 1.42, 95% CI = 1.37-1.48) and to have more than one emergency department visit (aOR = 1.22, 95% CI = 1.12-1.34). CONCLUSION: Older hospitalized adults with cancer with dementia are less likely to receive aggressive cancer treatment near the end of life than those without dementia. This discrepancy raises important ethical questions for clinicians and healthcare policy-makers. PMID- 27459580 TI - Gnotobiotic Miniature Pig Interbreed Somatic Cell Nuclear Transfer for Xenotransplantation. AB - Transgenic animal producing technology has improved consistently over the last couple of decades. Among the available methods, somatic cell nuclear transfer (SCNT) technology was officially the most popular. However, SCNT has low efficiency and requires a highly skilled individual. Additionally, the allo-SCNT nuclear reprogramming mechanism is poorly understood in the gnotobiotic miniature pig, which is a candidate for xenotransplantation, making sampling in oocytes very difficult compared to commercial hybrid pigs. Therefore, interbreed SCNT (ibSCNT), which is a combination of miniature pig and commercial pig (Landrace based), was analyzed and was found to be similar to SCNT in terms of the rate of blastocyst formation (12.6% +/- 2.9% vs. 15.5% +/- 2.2%; p > 0.05). However, a significantly lower fusion rate was observed in the ibSCNT compared to normal SCNT with Landrace pig somatic cells (29.6% +/- 0.8% vs. 65.0% +/- 4.9%). Thus, the optimization of fusion parameters was necessary for efficient SCNT. Our results further revealed that ibSCNT by the whole-cell intracytoplasmic injection (WCICI) method had a significantly higher blastocyst forming efficiency than the electrofusion method (31.1 +/- 8.5 vs. 15.5% +/- 2.2%). The nuclear remodeling and the pattern of changes in acetylation at H3K9 residue were similar in both SCNT and ibSCNT embryos. PMID- 27459581 TI - PDE4 Inhibition by Rolipram Promotes Neuronal Differentiation in Human Bone Marrow Mesenchymal Stem Cells. AB - Increased intracellular cyclic adenosine monophosphate (cAMP) can promote axonal elongation and facilitate neuronal repair, while decreased cAMP is associated with losses in neuronal regenerative capacity. Rolipram, which upregulates intracellular cAMP by blocking phosphodiesterase-4 (PDE4) enzyme activity, can mitigate diverse neurological disorders. In this study, we investigated whether rolipram induces neuronal differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs). Rolipram-treated MSCs (Roli-MSCs) had significantly increased expression of the neuroprogenitor proteins Nestin, Musashi, GFAP, and Sox-2. When Roli-MSCs were differentiated with neuronal induction media (Roli-dMSCs), they exhibited cell body and dendritic morphologies similar to those of neurons. The neurite number and length of Roli-dMSCs were significantly increased compared to those of differentiated MSCs (dMSCs). Compared with undifferentiated hBM-MSCs, the Roli-dMSCs and dMSCs showed significantly increased expression of the neuronal-specific marker genes Nestin, Musashi, CD133, GFAP, NF-M, MAP-2, KCNH1, KCNH5, SCN3A, and CACNA1A, and decreased expression of other lineage-specific markers Adiponectin, ALP, FABP4, and MMP13. The Roli-dMSCs also showed a higher expression of the neuronal markers Nestin, Musashi, Sox-2, NF-M, and Tuj-1 compared to those of the undifferentiated hBM-MSCs, measured by immunocytochemistry and immunoblotting assay. Thus, we have shown that rolipram ameliorates neuronal differentiation by the regulation of neuroprogenitor expression in hBM-MSCs, and rolipram treatment of MSCs may improve the therapeutic efficacy of stem cell therapy for neurodegenerative disorders. PMID- 27459582 TI - MicroRNA-145 Inhibitor Significantly Improves the Development of Bovine Somatic Cell Nuclear Transfer Embryos In Vitro. AB - Directly regulating the translation of POU5F1, SOX2, KLF4, and miRNA-145 plays an important role in maintaining the pluripotency of stem cells and the development of early embryos. In the present study, the expression model of miRNA-145 on bovine somatic cell nuclear transfer (SCNT) and in vitro fertilized (IVF) embryos were investigated and compared. Results indicated that (1) the expression level of miRNA-145 was significantly higher in SCNT embryos than that in IVF embryos after the eight-cell stage; (2) miRNA-145 negatively regulated the POU5F1, SOX2, and KLF4 in bovine embryos; (3) decreasing the expression of miRNA-145 by the miRNA-145 inhibitor significantly enhanced the expression of these three genes and the blastocyst formation rate; it also increased the total cell number and inner cell mass ratio of the bovine day 7 SCNT embryos. In conclusion, decreasing miRNA-145 expression might be a feasible means to enhance SCNT efficiency in bovines. PMID- 27459583 TI - MEF2 Transcription Factor Regulates Osteogenic Differentiation of Dental Pulp Stem Cells. AB - The myocyte enhancer factor-2 (MEF2) is a member of the MADS-box family. It controls the expression of genes that are critical for biological processes such as proliferation, cell death, and differentiation. Some studies have shown that MEF2 expression is enhanced in osteogenic progenitor cells established from bone marrow stromal cells with other types of mesenchymal progenitor cells. However, the effect of MEF2 on dental pulp stem cells (DPSCs) is unclear. In this study, we investigate the effect of MEF2 on regulating osteogenic differentiation and proliferation of DPSCs. We find that MEF2 is stably expressed in DPSCs, and the expression is increased time-dependently along with cell osteogenic differentiation. MEF2 expression also increases the alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) activity, and enhances mineralization in DPSCs. SB202190, inhibitor of p38, blocks the p38/MEF2 pathway and osteogenic differentiation. In addition, MEF2 overexpression inhibits DPSC proliferation. In summary, our data indicate that MEF2 not only regulates DPSCs as an inhibitor of cell proliferation but is also a promoter of osteogenic differentiation through the p38/MEF2 signaling pathway. PMID- 27459584 TI - Production of Pigs by Hand-Made Cloning Using Mesenchymal Stem Cells and Fibroblasts. AB - Mesenchymal stem cells (MSCs) exhibited self-renewal and less differentiation, making the MSCs promising candidates for adult somatic cell nuclear transfer (SCNT). In this article, we tried to produce genome identical pigs through hand made cloning (HMC), with MSCs and adult skin fibroblasts as donor cells. MSCs were derived from either adipose tissue or peripheral blood (aMSCs and bMSCs, respectively). MSCs usually showed the expression pattern of CD29, CD73, CD90, and CD105 together with lack of expression of the hematopoietic markers CD34and CD45. Flow cytometry results demonstrated high expression of CD29 and CD90 in both MSC lines, while CD73, CD34, and CD45 expression were not detected. In contrary, in reverse transcription-polymerase chain reaction (RT-PCR) analysis, CD73 and CD34 were detected indicating that human antibodies CD73 and CD34 were not suitable to identify porcine cell surface markers and porcine MSC cellular surface markers of CD34 might be different from other species. MSCs also had potential to differentiate successfully into chondrocytes, osteoblasts, and adipocytes. After HMC, embryos reconstructed with aMSCs had higher blastocyst rate on day 5 and 6 than those reconstructed with bMSCs and fibroblasts (29.6% +/ 1.3% and 41.1% +/- 1.4% for aMSCs vs. 23.9% +/- 1.2% and 35.5% +/- 1.6% for bMSCs and 22.1% +/- 0.9% and 33.3% +/- 1.1% for fibroblasts, respectively). Live birth rate per transferred blastocyst achieved with bMSCs (1.59%) was the highest among the three groups. This article was the first report to compare the efficiency among bMSCs, aMSCs, and fibroblasts for boar cloning, which offered a realistic perspective to use the HMC technology for commercial breeding. PMID- 27459585 TI - Lizard tail regeneration as an instructive model of enhanced healing capabilities in an adult amniote. AB - The ability to regenerate damaged or lost tissues has remained the lofty goal of regenerative medicine. Unfortunately, humans, like most mammals, suffer from very minimal natural regenerative capabilities. Certain non-mammalian animal species, however, are not so limited in their healing capabilities, and several have attracted the attention of researchers hoping to recreate enhanced healing responses in humans. This review focuses on one such animal group with remarkable regenerative abilities, the lizards. As the closest relatives of mammals that exhibit enhanced regenerative abilities as adults, lizards potentially represent the most relevant model for direct comparison and subsequent improvement of mammalian healing. Lizards are able to regenerate amputated tails and exhibit adaptations that both limit tissue damage in response to injury and initiate coordinated regenerative responses. This review summarizes the salient aspects of lizard tail regeneration as they relate to the overall regenerative process and also presents the relevant information pertaining to regrowth of specific tissues, including skeletal, muscular, nervous, and vascular tissues. The goal of this review is to introduce the topic of lizard tail regeneration to new audiences with the hope of expanding the knowledge base of this underutilized but potentially powerful model organism. PMID- 27459586 TI - Higher sexual interest with androgen receptor inhibitor monotherapy than with castration plus an androgen receptor inhibitor in prostate cancer patients treated with curative radiotherapy, but otherwise small health-related quality of life differences: A randomised prospective 18-month follow-up study. AB - PURPOSE: To prospectively study differences in health-related quality of life (HRQoL) in patients with localised/locally advanced prostate cancer (PC) treated with curative intended radiation therapy and randomised to androgen receptor inhibitor monotherapy treatment versus castration plus an androgen receptor inhibitor used continuously. Time to Prostate Specific Antigen (PSA) relapse, time to symptomatic metastasis and overall survival (OS) were also described for the two groups. PATIENTS AND METHODS: From 2005 to 2011, a total of 110 patients were randomised at a ratio of 1:1. HRQoL was assessed at six time points: before randomisation, before radiotherapy (RT) start and 9, 12, 15 and 18 months after randomisation, using the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) and EORTC QLQ-PR25. RESULTS: At the 3-month follow-up, statistically significant differences between the two groups were found for overall quality of life (p = 0.006), fatigue (p = 0.023), sexual interest (p < 0.001) and urinary problems (p = 0.036). Small clinical differences were noted for overall quality of life, role functioning, fatigue, pain, sleeping problems and urinary problems. At that assessment point, clinical differences between the groups were substantial regarding sexual interest and moderate regarding sexual functioning (the latter indicated only by patients reporting having sexual interest at baseline). All statistical and clinical differences favoured the androgen receptor inhibitor monotherapy arm. At 18 months after randomisation, statistically significant differences were found for cognitive functioning (p = 0.040) and sexual interest (p = 0.011), both favouring the androgen receptor inhibitor monotherapy arm. CONCLUSION: The results suggest that neo-adjuvant androgen receptor inhibitor monotherapy might be preferred compared to castration plus an androgen receptor inhibitor before curative intended RT in men with localised/locally advanced PC, with higher levels of HRQoL, especially concerning sexual interest. HRQoL differences over time were small. The observation time and study sample were too small for evaluating time to PSA progression and OS. Further studies are needed to confirm the results. The study was registered in, identification number NCT02382094. PMID- 27459587 TI - Improving performance by anchoring movement and "nerves". AB - Golf's governing bodies' recent decision to ban all putting styles "anchoring one end of the club against the body" bridges an important practical problem with psychological theory. We report the first experiment testing whether anchoring provides technical and/or psychological advantage in competitive performance. Many "greats" of professional golf from Arnold Palmer and Jack Nicklaus to Tiger Woods have argued against anchoring, believing that it takes "nerves" out of competitive performance and therefore artificially levels the playing field. To shed more light on the issue, we tested participants' performance with anchored and unanchored putters under low and high pressure when controlling for the putter length. We found no statistically significant evidence for a technical advantage due to anchoring but a clear psychological advantage: participants who anchored their putters significantly outperformed unanchored counterparts under high, but not low, pressure. Results provide tentative evidence for the ban's justification from a competitive standpoint. However, before any definite conclusions can be made, more research is needed when using high-level golfers. PMID- 27459588 TI - Electronic Structure and Luminescence of Quasi-Freestanding MoS2 Nanopatches on Au(111). AB - Monolayers of transition metal dichalcogenides are interesting materials for optoelectronic devices due to their direct electronic band gaps in the visible spectral range. Here, we grow single layers of MoS2 on Au(111) and find that nanometer-sized patches exhibit an electronic structure similar to their freestanding analogue. We ascribe the electronic decoupling from the Au substrate to the incorporation of vacancy islands underneath the intact MoS2 layer. Excitation of the patches by electrons from the tip of a scanning tunneling microscope leads to luminescence of the MoS2 junction and reflects the one electron band structure of the quasi-freestanding layer. PMID- 27459589 TI - Microstructural investigations of carbon foams derived from modified coal-tar pitch. AB - This work reports the microstructural evaluation of carbon foams derived from coal-tar pitch precursors treated with H2SO4 and HNO3 and finally annealed at 1000 degrees C and 2000 degrees C. Our experimental investigations combine scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM) imaging, X-ray photoelectron spectroscopy (XPS) and micro-spot near-edge X-ray absorption fine structure (MU-NEXAFS) spectroscopy. This set of complementary techniques provides detailed structural and chemical information of the surface and the bulk of the carbon foams. The high-resolution microscopy data indicate the formation of carbonaceous amorphous microspheres (average diameters of 0.28+/-0.01MUm) embedded in the partially graphitized carbon foam matrix at 1000 degrees C. The microspheres are enriched with sp bonded species and their microstructural characteristics depend on the reagent (nitric vs. sulfuric acid) used for pitch treatment. A complete chemical transformation of the microspheres at temperatures >1000 degrees C occurs and at 2000 degrees C they are spectroscopically identical with the bulk material (sp(2) and sp(3)-hybridised forms of carbon). The microstructure-property relationship is exemplified by the compressive strength measurements. These results allow a better description of coal-tar pitch-derived carbon foams at the atomic level, and may account for a better understanding of the processes during graphitization step. PMID- 27459590 TI - Facile Fabrication of Cyclodextrin-Modified Magnetic Particles for Effective Demulsification from Various Types of Emulsions. AB - Effective oil-water phase separation from various emulsions, especially those stabilized by surfactant, is of great importance. Although superhydrophobic and superoleophilic materials have attracted considerable attention in recent years, they are incapable of directly separating all types of oil-water mixtures. To separate various types of emulsions, one of the most important features of particles is that they can be dispersed in the continuous phase for delivery and target dispersed phases. In this study, cyclodextrin-modified magnetic composite particles (M-CDs) have been fabricated for this goal, based on their special interfacial activity and response to an external magnetic field. Though M-CDs are hydrophilic, the intelligent M-CDs can switch from hydrophilicity to hydrophobicity spontaneously, due to the formation of CD-oil inclusion complexes (ICs) at the oil-water interface. Physicochemical characterization reveals that M CDs can adsorb at the oil-water interface and locate at the droplet surface as an effective Pickering emulsifier. By applying an external magnetic field, M-CDs are removed from the droplet surface and a rapid oil-water phase separation occurs. Our M-CDs can demulsify, for the first time, surfactant-free or surfactant stabilized oil-in-water (O/W) and water-in-oil (W/O) emulsions directly, with high separation efficiency. Furthermore, the recycled MNPs still show high demulsification efficiency. In view of the sustainability of cyclodextrin and effective recycling ability of MNPs, M-CDs provides a new opportunity to develop an environmentally friendly interfacial material for practical applications in wastewater treatment. PMID- 27459591 TI - Faculty development to support interprofessional education in healthcare professions: A realist synthesis. AB - Interprofessional collaboration is expected of healthcare providers to effect positive patient care experiences, reduce healthcare costs, and improve population health. While interprofessional education (IPE) is essential to graduate collaboration-ready healthcare professionals, faculty have limited experience and expertise in facilitating IPE, slowing adoption of this strategy. Faculty who are expected to develop, implement, and facilitate IPE activities in health professions need support and training to be successful. Faculty development programmes specific to IPE are examined through a comprehensive realist synthesis. The review began by identification of the mechanisms underpinning the intervention and then continued through a search for evidence relevant to the identified mechanisms. From 1,749 citations reviewed, 15 articles and book chapters were synthesised. The findings demonstrate that through the mechanisms-roles and role modelling, valuing diversity, reflection, group process, and knowledge, skills, and attitudes for IPE-positive outcomes can be achieved. Outcomes of increasing capacity and sustainability of IPE programmes, forming networks of individuals concerned with IPE, and evaluating and assessing of outcomes of IPE, may all be achieved through these mechanisms. The contextual factors include attitudes and expectations, programme logistics, leadership, and commitment, which interact with the mechanisms to impact the outcomes. Multiple context-mechanism-outcome configurations were revealed and analysed which help to explain how faculty development for IPE works in varying settings. PMID- 27459592 TI - Innovative Bimolecular-Based Advanced Logic Operations: A Prime Discriminator and An Odd Parity Checker. AB - Herein, a novel logic operation of prime discriminator is first performed for the function of identifying the prime numbers from natural numbers less than 10. The prime discriminator logic operation is developed by DNA hybridizations and the conjugation of graphene oxide and single-stranded DNA as a reacting platform. On the basis of the similar reaction principle, an odd parity checker is also developed. The odd parity checker logic operation can identify the even numbers and odd numbers from natural numbers less than 10. Such advanced logic operations with digital recognition ability can provide a new field of vision toward prototypical DNA-based logic operations and promote the development of advanced logic circuits. PMID- 27459593 TI - Cross-Linked Quaternized Poly(styrene-b-(ethylene-co-butylene)-b-styrene) for Anion Exchange Membrane: Synthesis, Characterization and Properties. AB - Poly(styrene-b-(ethylene-co-butylene)-b-styrene) triblock copolymer (SEBS) was selected for functionalization and cross-linking reaction to prepare the anion exchange membrane. The cross-linked quaternized SEBS (QSEBS-Cn) membranes were synthesized by simultaneous of quaternization and cross-linking of chloromethylated SEBS with alpha,omega-difunctional tertiary amines. The spacer groups of (-CH2-)n in diamines did affect the functionalization, micromorphology and properties of the resulting QSEBS-Cn membranes. The ionic conductivity of QSEBS-Cn membranes greatly increased and methanol resistance slightly decreased with increasing the length of spacer groups in the cross-linked structures from (CH2)- to -(CH2)6-. Compared to the un-cross-linked QSEBS, the QSEBS-Cn membranes behaved much higher mechanical property, service temperature, chemical stability and thermal stability. Moreover, the hybrid composite membrane of QSEBS-C6 with 0.5% of graphene oxide could also be in situ prepared. This hybrid membrane had both relatively high ionic conductivity of 2.0 * 10(-2) S.cm(-1) and high selectivity of 7.6 * 10(4) S.s.cm(-3) at 60 degrees C due to its low methanol permeability. PMID- 27459594 TI - The robo-pigeon based on the multiple brain regions synchronization implanted microelectrodes. AB - Almost all multichannel microelectrodes are only applied to the same nucleus. The multiple brain regions synchronization implanted microelectrodes can be implanted in the several brain regions at the same time, when used in the robo-animal, which can reduce the operation process, shorten animals operation time. Due to electrode position relatively fixed, errors caused by each separately implanted electrode were reduced and the animal control effect was greatly increased compared to the original electrodes. The electrode fixed time was also extended. This microelectrode provided beneficial reference function for the study of the free state of small animals in different brain regions. PMID- 27459595 TI - Dynamic analysis of the human brain with complex cerebral sulci. AB - The brain is one of the most vulnerable organs inside the human body. Head accidents often appear in daily life and are easy to cause different level of brain damage inside the skull. Once the brain suffered intense locomotive impact, external injuries, falls, or other accidents, it will result in different degrees of concussion. This study employs finite element analysis to compare the dynamic characteristics between the geometric models of an assumed simple brain tissue and a brain tissue with complex cerebral sulci. It is aimed to understand the free vibration of the internal brain tissue and then to protect the brain from injury caused by external influences. Reverse engineering method is used for a Classic 5-Part Brain (C18) model produced by 3B Scientific Corporation. 3D optical scanner is employed to scan the human brain structure model with complex cerebral sulci and imported into 3D graphics software to construct a solid brain model to simulate the real complex brain tissue. Obtaining the normal mode analysis by inputting the material properties of the true human brain into finite element analysis software, and then to compare the simplified and the complex of brain models. PMID- 27459596 TI - Effects of protein and phosphate buffer concentrations on thermal denaturation of lysozyme analyzed by isoconversional method. AB - Thermal denaturation of lysozymes was studied as a function of protein concentration, phosphate buffer concentration, and scan rate using differential scanning calorimetry (DSC), which was then analyzed by the isoconversional method. The results showed that lysozyme thermal denaturation was only slightly affected by the protein concentration and scan rate. When the protein concentration and scan rate increased, the denaturation temperature (Tm) also increased accordingly. On the contrary, the Tm decreased with the increase of phosphate buffer concentration. The denaturation process of lysozymes was accelatated and the thermal stability was reduced with the increase of phosphate concentration. One part of degeneration process was not reversible where the aggregation occurred. The other part was reversible. The apparent activation energy (Ea) was computed by the isoconversional method. It decreased with the increase of the conversion ratio (alpha). The observed denaturation process could not be described by a simple reaction mechanism. It was not a process involving 2 standard reversible states, but a multi-step process. The new opportunities for investigating the kinetics process of protein denaturation can be supplied by this novel isoconversional method. PMID- 27459597 TI - Morphological study of dynamic culture of thermosensitive collagen hydrogel in constructing tissue engineering complex. AB - ABSTACT The purpose of this study is to research the morphologies and functional characteristics of the cell-scaffold complex in vitro constructed under dynamic culture conditions. BMSCs were isolated from the long bones of Fischer344 rats, and performed in vitro amplification to the third generation as seed cells, together with thermosensitive collagen hydrogel (TCH) as cell adhesion matrix, and poly-L-lactic acid (PLLA) as scaffold, to construct cell-scaffold complex. The cell-scaffold complexes in the experiment group and the control group were then performed dynamic culture and static culture. After 7 d of in vitro culture, the complexes in the 2 groups were performed gross observation and SEM; meanwhile, the total DNA content in the complex was detected on D0,1,3, and 7 of culture. After cultured using these 2 ways, collagen could both wrap the PLLA scaffold, forming dense film-like structures on the PLLA surface. The total DNA contents in the cell-scaffold complex of the experiment group on D1,3, and 7 were significantly higher than the control group (P < 0.05). Compared with D0, the total DNA contents on D1,3, and 7 in both groups were gradually increased, but only the total DNA contents on D7 showed statistically significant difference than D0 (P < 0.05). TCH -PLLA fiber joint-constructed complex extracellular matrix had good biocompatibility, and dynamic culture could promote the distribution of BMSCs on the surface and inside the structure, thus promoting cell proliferation, so it could be used for the in vitro construction of tissue engineering complex. PMID- 27459598 TI - Molecular modification of proanthocyanidins. AB - Regioselective enzymatic acylation of proanthocyanidin is proposed and investigated as a method by which to improve the solubility of proanthocyanidins in the oil phase and maintain its oxidation resistance. Experimental results indicate that butanol functions as the best solvent in the studied reaction, in which Lipase Novozym435 is used as biological catalyst enzyme and the molar ratio of lauric acid to proanthocyanidins is 4:1. To increase the esterification conversion, we propose the addition of molecular sieve at 5 h. The product was separated by TLC, and results indicate an optimal solvent ratio of ethyl acetate: petroleum ether: acetic acid = 2:3:0.5. This condition can effectively separate the ester and proanthocyanidins, achieving an esterification yield of 60.9%. PMID- 27459599 TI - Erratum. PMID- 27459600 TI - Geochemical hunting of lithogenic and anthropogenic impacts on polymetallic distribution (Bregalnica river basin, Republic of Macedonia). AB - The main subject of this investigation was the assessment of the lithogenic and anthropogenic distribution of 69 elements in the sediments and fluvisol in the Bregalnica river basin. Alluvial soil and fluvisol samples were collected from the total of eighteen locations along the course of the Bregalnica river and additional thirteen samples were collected from its tributaries. The matrix elements accumulation patterns followed the order: Fe > Na > Al > Ca > Mg > K > Ti > P. The potentially toxic elements, such as As, Cd, Pb, and Zn, have enriched content in the sediments in the medium course of the river, where the main anthropogenic introduction activities occurred. By multivariate analysis the dominant geochemical associations were extracted, as follows: F1: Y-Eu-Lu-Cr-V-La Gd-Nb-Co-Hf-Zr-Ga-Mg-Fe-Sr-Ta-Sn-Li-Na-Rb-Ni-Ge-Be-Cs; F2: As-W-Ba-Ag-Cu-Tl-Zn-Sb Mo-In-Cd-Te-Bi-Pb and F3: I-Sc-Br-K. Lead and zinc contents were strongly correlated with the hydrothermal exploitations, especially in the area of Neogene clastite and vulcanite. These elements occur as dominant geochemical markers of the anthropogenic impacts of polymetallic enrichments due to the hydrothermal ore exploitation (Factor 2). The impact of Oligocene volcanism (Kratovo-Zletovo region) was observed in the lithological enrichments of Pb, Zn, Cu, As, Sb, Mo and Bi. Despite the natural distribution along the course of the Bregalnica river, an exceptional anomaly in the iron distribution of the old polymetallic unused mineralization was detected in Zone 1 (Berovo region). PMID- 27459601 TI - Reduction-Triggered Self-Assembly of Nanoscale Molybdenum Oxide Molecular Clusters. AB - Understanding the formation mechanism of giant molecular clusters is essential for rational design and synthesis of cluster-based nanomaterials with required morphologies and functionalities. Here, typical synthetic reactions of a 2.9 nm spherical molybdenum oxide cluster, {Mo132} (formula: [Mo(VI)72Mo(V)60O372(CH3COO)30(H2O)72](42-)), with systematically varied reaction parameters have been fully explored to determine the morphologies and concentration of products, reduction of metal centers, and chemical environments of the organic ligands. The growth of these clusters shows a typical sigmoid curve, suggesting a general multistep self-assembly mechanism for the formation of giant molecular clusters. The reaction starts with a lag phase period when partial Mo(VI) centers of molybdate precursors are reduced to form {Mo(V)2(acetate)} structures under the coordination effect of the acetate groups. Once the concentration of {Mo(V)2(acetate)} reaches a critical value, it triggers the co-assembly of Mo(V) and Mo(VI) species into the giant clusters. PMID- 27459602 TI - Worse health-related quality of life and hip function in female patients with elevated chromium levels. AB - Background and purpose - Blood metal ion levels can be an indicator for detecting implant failure in metal-on-metal (MoM) hip arthroplasties. Little is known about the effect of bilateral MoM implants on metal ion levels and patient-reported outcomes. We compared unilateral patients and bilateral patients with either an ASR hip resurfacing (HR) or an ASR XL total hip replacement (THR) and investigated whether cobalt or chromium was associated with a broad spectrum of patient outcomes. Patients and methods - From a registry of 1,328 patients enrolled in a multicenter prospective follow-up of the ASR Hip System, which was recalled in 2010, we analyzed data from 659 patients (311 HR, 348 THR) who met our inclusion criteria. Cobalt and chromium blood metal ion levels were measured and a 21-item patient-reported outcome measures (PROMs) questionnaire was used mean 6 years after index surgery. Results - Using a minimal threshold of >=7 ppb, elevated chromium ion levels were found to be associated with worse health related quality of life (HRQoL) (p < 0.05) and hip function (p < 0.05) in women. These associations were not observed in men. Patients with a unilateral ASR HR had lower levels of cobalt ions than bilateral ASR HR patients (p < 0.001) but similar levels of chromium ions (p = 0.09). Unilateral ASR XL THR patients had lower chromium and cobalt ion levels (p < 0.005) than bilateral ASR XL THR patients. Interpretation - Chromium ion levels of >=7 ppb were associated with reduced functional outcomes in female MoM patients. PMID- 27459603 TI - Estimation of Tau and Phosphorylated Tau181 in Serum of Alzheimer's Disease and Mild Cognitive Impairment Patients. AB - The elevated level of cerebrospinal fluid (CSF) Tau and phosphorylated Tau181 (p Tau181) proteins are well established hallmarks of Alzheimer's disease (AD). Elevated level of p-Tau181 can differentiate AD from other neurodegenerative disease. However, the expression level of these proteins in serum of AD patient is not well set up. This study sought to evaluate the level of Tau and p-Tau181 in serum of AD, and mild cognitive impairment (MCI) patients for an alternative approach to establish protein-based markers by convenient way. Blood samples were collected from 39 AD patients, 37 MCI patients and 37 elderly individuals as controls. The levels of Tau and p-Tau181 in the serum of the different groups were measured by label free real time Surface Plasmon Resonance technology by using specific antibodies, and were further confirmed by the conventional western blot method. An appropriate statistical analysis, including Receiver Operating Characteristic (ROC), was performed. The concentrations of serum Tau and p-Tau181 were significantly higher (p<0.00001) in AD (Tau; 47.49+/-9.00ng/MUL, p-Tau181; 0.161+/-0.04 ng/MUL) compared to MCI (Tau; 39.26+/-7.78 ng/MUL, p-Tau181; 0.135+/ 0.02 ng/MUL) and were further higher compared to elderly controls (Tau; 34.92+/ 6.58 ng/MUL, p-Tau181; 0.122+/-0.01 ng/ MUL). A significant (p<0.0001) downhill correlation was found between Tau as well as p-Tau181 levels with HMSE and MoCA score. This study for the first time reports the concentration of Tau and p Tau181 in serum of AD and MCI patients. The cutoff values of Tau and p-Tau181 of AD and MCI patients with sensitivity and specificity reveal that serum level of these proteins can be used as a predictive marker for AD and MCI. PMID- 27459605 TI - CATO: The Clone Alignment Tool. AB - High-throughput cloning efforts produce large numbers of sequences that need to be aligned, edited, compared with reference sequences, and organized as files and selected clones. Different pieces of software are typically required to perform each of these tasks. We have designed a single piece of software, CATO, the Clone Alignment Tool, that allows a user to align, evaluate, edit, and select clone sequences based on comparisons to reference sequences. The input and output are designed to be compatible with standard data formats, and thus suitable for integration into a clone processing pipeline. CATO provides both sequence alignment and visualizations to facilitate the analysis of cloning experiments. The alignment algorithm matches each of the relevant candidate sequences against each reference sequence. The visualization portion displays three levels of matching: 1) a top-level summary of the top candidate sequences aligned to each reference sequence, 2) a focused alignment view with the nucleotides of matched sequences displayed against one reference sequence, and 3) a pair-wise alignment of a single reference and candidate sequence pair. Users can select the minimum matching criteria for valid clones, edit or swap reference sequences, and export the results to a summary file as part of the high-throughput cloning workflow. PMID- 27459606 TI - Fast and Efficient Screening for Wheat Loss-of-Gene Mutants Using Multiplexed Melt Curve Analyses. AB - This study describes a new approach in the screening for loss-of-gene mutants in Heavy Ion Bombardment (HIB) mutant populations of genetically complex organisms such as hexaploid bread wheat using multiplexed single-color (SYBR Green) melt curve analyses. The assay was set up for three target genes to test its validity and applicability. For each gene, three genome-specific primer pairs (one for each genome) with distinct melt curves were developed and multiplexed. This allowed screening for "single null mutants" (plants with the target gene deleted in one of the three genomes) for all three genomes in a single reaction. The first two genes (alpha-Amylase 3 and Epsilon Cyclase) were used to test the approach as HIB null lines for all three genomes were already available for these. The third assay was successfully applied to identify new single null lines of the target gene alpha-Amylase 2 in an in-house HIB wheat collection. The use of SYBR Green greatly reduced the time and/or cost investment compared to other techniques and the approach proved highly suitable for high-throughput applications. PMID- 27459607 TI - Silver-Catalyzed Isocyanide-Isocyanide [3+2] Cross-Cycloaddition Involving 1,2 Group Migration: Efficient Synthesis of Trisubstituted lmidazoles. AB - Imidazole ring is an important five-membered aromatic heterocycle that is widely present in natural products and synthetic molecules. The isocyanide-isocyanide [3+2] cross-cycloaddition reaction constitutes a straightforward method to access imidazoles starting from the easily available chemicals. So far, only three successive reports are known and all lead to the formation of 1,4-disubstituted imidazoles. Here, we report the first isocyanide-isocyanide [3+2] cross cycloaddition reaction allowing for the formation of 1,4,5-trisubstituted imidazoles under silver catalysis. An unexpected 1,2-migration of sulfonyl, alkoxycaybonyl, and carbamoyl groups took place during the cyclization process that is responsible for the formation of trisubstituted imidazoles. This report displayed a mechanistically novel synthetic method toward a variety of imidazole derivatives, which are otherwise difficult to access by conventional methods. PMID- 27459604 TI - Systemic delivery of adeno-associated viral vectors. AB - For diseases like muscular dystrophy, an effective gene therapy requires bodywide correction. Systemic viral vector delivery has been attempted since early 1990s. Yet a true success was not achieved until mid-2000 when adeno-associated virus (AAV) serotype-6, 8 and 9 were found to result in global muscle transduction in rodents following intravenous injection. The simplicity of the technique immediately attracts attention. Marvelous whole body amelioration has been achieved in rodent models of many diseases. Scale-up in large mammals also shows promising results. Importantly, the first systemic AAV-9 therapy was initiated in patients in April 2014. Recent studies have now begun to reveal molecular underpinnings of systemic AAV delivery and to engineer new AAV capsids with superior properties for systemic gene therapy. PMID- 27459608 TI - Highly Enantio- and Diastereoselective [4 + 2] Cycloaddition of 5H-oxazol-4-ones with N-Maleimides. AB - An organocatalytic asymmetric reaction between 5H-oxazol-4-ones and N-substituted maleimides is disclosed. Employing Takemoto's chiral tertiary amine-thiourea as the catalyst, [4 + 2] annulation reactions were performed with high chemoselectivity, leading to a series of biologically important chiral oxo bridged piperidone-fused succinimides in good to excellent enantioselectivities (up to >99% ee) and >19:1 dr. PMID- 27459609 TI - A story of cooperation and friendship in Europe with good outcomes. PMID- 27459610 TI - [Acute Ph-negative lymphoblastic leukemias in adults: Risk factors in the use of the ALL-2009 protocol]. AB - AIM: to analyze well-known risk factors (RFs), such as age, immunophenotype, baseline leukocytosis, enhanced lactate dehydrogenase (LDH) activity, time to achieve complete remission, a risk group, and cytogenetic abnormalities) in patients with acute lymphoblastic leukemia (ALL) in the use of the ALL-2009 protocol. SUBJECTS AND METHODS: The protocol covered 298 patients (137 women (including 13 pregnant women) and 161 men) aged 15 to 55 years (median age 28 years) with Ph-negative ALL. The phenotype was unknown in 6 patients. Three (1%) were ascertained to have a biphenotypic variant. 182 (62.4%) patients were found to have B-cell ALL (early pre-B ALL (n=51); common ALL (n=92), and pre-B ALL (n=39); 107 (36.6%) patients had T-cell ALL (early T-ALL (n=56); thymic T-ALL (n=41), and mature T-ALL (n=10). According to the baseline clinical and laboratory parameters (leukocytosis of 30.109/l and more for B-ALL; and that of 100.109/l and more for T-ALL; phenotype V-I for B-ALL, phenotype T-I-II-IV for T ALL; LDH activity was more than twice the normal values; the presence of translocation t(4;11)), the high-risk group included most patients with B-ALL (n=110 (72.8%)) and T-ALL (n=76 (76%)). Thirty-five patients with T-ALL underwent autologous bone marrow transplantation (BMT). Allogeneic BMT was performed in 18 (7%) of the 258 patients who had undergone an induction phase. RESULTS: Five-year overall survival for all the patients included in the investigation was 59%; relapse-free survival was 65%, which was significantly different in the patients with B-ALL and in those with T-ALL: the overall survival rates were 53.3 and 67.5% (p=0.1); the relapse-free survival was 56 and 79% (p=0.005), respectively. Multivariate analysis including the well-known RFs demonstrated that the latter for T-ALL were of no independent prognostic value and only the patient's age was identified for B-ALL (p=0.013). CONCLUSION: A lower chemotherapeutic load and a small number of allogeneic BMTs did not affect total positive treatment results in adult patients with ALL, by complying with the principle achieving the continuity of cytostatic effects and by preserving the total cytostatic loading dose. The results of the Russian investigation casts some doubt on the necessity of using very intensive consolidation cycles and performing a large number of allogeneic BMTs in adult patients with ALL. PMID- 27459611 TI - [Diagnosis of latent polycythemia vera: A clinician's opinion]. AB - AIM: to identify the clinical features of latent polycythemia vera (PV) as an independent nosological entity. SUBJECTS AND METHODS: The investigation enrolled 81 patients (50 with extensive (manifest) PV and 31 with latent PV) who had visited the Outpatient Department, Hematology Research Center, Ministry of Health of Russia, in 2014 to October 2015. RESULTS: The gender distribution of the patients was statistically comparable in the analyzed groups. The patients with manifest PV were slightly older than those with latent PV: the median age in the compared groups was 56 and 44 years, respectively. Red blood cell counts, hemoglobin concentrations, and packed cell volume were higher in the patients with manifest PV. Blood platelet counts were higher in the latent PV group. There were no differences in the number of white blood cells in the compared groups. All the patients were JAK2 V617F mutation carriers. The JAK2 allele load was significantly higher in the manifest PV group than in the latent PV group. The compared patient groups differed in the rate of thromboses in the history or at diagnosis. In the patients with latent PV, thromboses were detected in 38% of cases versus 16% in those with manifest PV. In latent PV, there were mainly venous thromboses; abdominal vascular thromboses were diagnosed with a high frequency. Arterial thromboses were revealed in only 2 cases. CONCLUSION: Chronic myeloproliferative disease that is characterized by the JAK2 V617F mutation, borderline hemoglobin counts, and morphological features of a bone marrow trephine biopsy specimen, which are specific for PV, is an independent PV variant, namely: latent PV. PMID- 27459612 TI - [Aberrant methylation of the promoter regions of the SOX7 and p15INK4b genes and Wnt signaling pathway antagonists in patients with acute myeloid leukemias]. AB - AIM: to investigate the methylation status of the SOX7 and p15NK4b genes and Wnt signaling pathway antagonists in patients with acute myeloid leukemia (AML) in order to assess the association of the rate of aberrant methylation (AM) with the morphological variant and pattern of chromosomal aberrations, as well as the impact of the methylation status on survival. SUBJECTS AND METHODS: The data of 57 AML patients aged 20 to 79 years were analyzed. The methylation status of the genes was studied by methylation-specific polymerase chain reaction. RESULTS: The signs of the AM of >=1 gene were detected in 52 (91.2%) of the 57 patients. The most common finding was AM of simultaneously 2 or 3 genes: in 29.8 and 21.1% of the patients, respectively. Concurrent methylation of 3-5 genes proved to be a more frequent finding in AML patients with myelodysplasia: in 7 (70%) of 10 patients. The proportion of patients with methylation of 5 genes was considerably higher in a group of patients with a complex karyotype: 50% versus 8.3% among other patients (odds ratio: 11.0; 95% confidence interval 2.0 to 61.6; p=0.01). There were no differences in the median overall and relapse-free survival rates in patients with a normal karyotype and without FLT3 and NPM mutations, who received induction therapy, in relation to the number of genes with AM. CONCLUSION: AM of the p15NK4b and SOX7 genes and Wnt signaling pathway antagonists is detected in the majority of patients with AML, which allows hypomethylating agents to be recommended for the treatment of patients who cannot use intensive cytostatic therapy for different reasons. The detection of a large number of genes with the aberrant methylation status in most AML patients with myelodysplasia or a complex karyotype serves as the basis for initiating trials to evaluate the efficiency of a combination of 5-azacytidine and cytostatics. PMID- 27459613 TI - [Therapy for primary mediastinal large B-cell lymphoma in accordance with the R DA-EPOCH-21 program: The first results]. AB - AIM: to evaluate the efficiency of the R-DA-EPOCH-21 + R-DHAP protocol and autologous hematopoietic stem cell transplantation (a BEAM conditioning mode) in first-line therapy for primary mediastinal large B-cell lymphoma (PMBCL). SUBJECTS AND METHODS: In 2013 to 2016, the investigation enrolled 57 patients with newly diagnosed PMBCL (according to the 2008 WHO criteria). The results were analyzed in 40 patients who had completed their treatment. RESULTS: All the 40 patients (14 men and 26 women) (median age, 27 years (19 to 67 years)) received 6 cycles of polychemotherapy (PCT) in accordance with the R-DA-EPOCH-21 regimen. After induction PCT cycles, 32/40 (80%) patients achieved complete remission. Partial remission was stated in 8/40 (20%) patients who had further 2 cycles of chemotherapy using the R-DHAP program and autologous hematopoietic stem cell transplantation (a BEAM conditioning mode). Two-year overall and relapse-free survival rates were 100% and 96%, respectively; the median follow-up was 17 months. CONCLUSION: The R-DA-EPOCH regimen allows complete remission in 80% of the cases and two-year survival in 100%. If there are unfavorable factors at onset and in partial remission, it is appropriate to intensify treatment at early stages, by using high-dose chemotherapy and autologous hematopoietic stem transplantation. PMID- 27459614 TI - [Late myelotoxicity of high-dose chemotherapy according to the modified NHL-BFM 90 program in adult patients with diffuse large B-cell lymphoma]. AB - AIM: to evaluate late myelotoxicity (MT) relate to high-dose chemotherapy (CT) according to the modified NHL-BFM-90 (mNHL-BFM-90) program in adult patients with diffuse large B-cell lymphoma (DLBCL). SUBJECTS AND METHODS: The results of a complex clinical, laboratory, and instrumental examination, including cytologic, histologic, and routine cytogenetic studies of the bone marrow (BM), were analyzed in 40 DLBCL patients treated according to the mNHL-BFM-90 program in the National Research Center for Hematology (NRCH), Ministry of Health of the Russian Federation (MHRF), in 2002 to 2009; among them, there were 20 men and 20 women (median age, 57 years). A comparison group consisted of 19 patients who had received high-dose SNOR/R-SNOR-21 CT in HRC, MHRF, in the same period of time; out of them, there were 8 men and 11 women (median age, 70 years). The median posttherapy follow-up period was 6 years. The results of BM studies were analyzed before and 5-10 years after treatment in complete remission. The cytological and histological studies of BM determined its cellularity, the sizes of erythroid, granulocytic, and megakaryocytic lineages, their ratios, the signs of dysplasia, and stromal dysplastic changes. Routine BM cytogenetic study was conducted to identify karyological problems. Only myelopoietic changes that had been revealed for the first time 5-10 years after completion of CT were kept in mind as late MT. Cases of baseline and post-CT changes and those of baseline and no post-CT changes were not taken into account. RESULTS: Cytopenic syndromes (having no signs of myelopoietic lineage dysplasia or needing no blood component replacement transfusions) were revealed in 52% of the patients in the high-dose CT; thrombocytopenia amounted to 46%. In the late follow-up period, the patient group after high-dose mNHL-BFM-90 CT were found to have BM hypocellularity in 15 (38%) cases, a narrowing of erythroid and megakaryocytic lineages in 13 (33%) and 19 (48%) cases, respectively, and obvious secondary stromal changes in 17 (43%). The first 6 patients underwent routine BM cytogenetic study; all the patients were ascertained to have a normal karyotype; in this connection further BM study was stopped. CONCLUSION: The late MT of high-dose mNHL-BFM 90 CT is statistically significantly higher than that of the standard CHOP/R-CHOP-21 therapy. However, signs of myelodysplastic syndromes and those of cytopenia requiring blood component transfusions were observed in none patient. PMID- 27459615 TI - [Subcutaneous panniculitis-like T-cell lymphoma: The authors' experience of diagnosis and treatment]. AB - The paper gives the data of clinical, histological, immunohistochemical, and molecular studies and the results of positron emission tomography in 3 cases of subcutaneous panniculitis-like T-cell lymphoma (SPTCL). It shows the high efficiency of a GEM-P regimen in the treatment of patients with SPTCL. PMID- 27459616 TI - [Diffuse large B-cell lymphoma with monoclonal immunoglobulin secretion]. AB - AIM: to provide the clinical characteristics of patients with diffuse large B cell lymphoma (DLBCL) with monoclonal immunoglobulin secretion and to evaluate the efficiency of intensified mNHL-BFM-90 or R-DA-EPOCH/R-HMA therapy programs in patients with Ig-secreting DLBCL. SUBJECTS AND METHODS: A clinical trial was conducted in 93 patients with newly diagnosed DLBCL, among whom 21 (22.6%) were found to have monoclonal immunoglobulin secretion. RESULTS: Ig-secreting DLBCL is shown to be characterized by bone marrow involvement (p<0.001), as well as generalized injury (Ann Arbor Stage 4) and a high risk in accordance with the international prognostic index (p=0.001 and p=0.026, respectively). Analysis of overall and event-free survival rates has indicated that the patients have a poor prognosis versus those with non-Ig-secreting DLBCL and poor prognostic factors even when implementing intensified therapy programs, such as mNHL-BFM-90 or R-DA EPOCH/R-HMA ones. CONCLUSION: The investigation has demonstrated that there is a high association of the secretion of monoclonal paraproteins with bone marrow involvement in DLBCL (p<0.001). The intensified therapy using the mNHL-BFM-90 and R-DA-EPOCH/R-HMA programs involving autologous hematopoietic stem cell transplantation also permits the patients with Ig-secreting DLBCL to achieve long term sustained remissions in not all cases. PMID- 27459618 TI - [Perianal infection in patients with hemoblastosis: Risk factors and possibilities of prevention]. AB - AIM: to identify poor prognostic factors for perianal infection (PI) in patients with hemoblastosis and to define an effective tactic for preventive and therapeutic measures. SUBJECTS AND METHODS: The prospective study enrolled 72 patients (37 men and 35 women; mean age, 47 years) with hemoblastosis that was complicated by the development of one of the following forms of PI: abscess, infiltrate, multiple ulcers. Different clinical and laboratory characteristics of the patients were examined to identify risk factors for PI. The species-specific concordance of microorganisms isolated from the anus and blood in the development of PI was assessed to record the latter as a source of sepsis. Treatment policy was defined according to the clinical form of PI. RESULTS: Acute myeloid leukemias and lymphomas were the most common background diseases in 30 (41.7%) and 22 (30.6%) patients, respectively. During induction chemotherapy cycles, perianal tissue infection occurred twice more frequently (66%) than totally at the onset of hemoblastosis (13%) and after achievement of remission (during consolidation and maintenance therapy) (21%; Fisher's exact test; p=0.01). PI in agranulocytosis was more than twice as common as in its absence: 69.4% vs 30.6% (p=0.01) and was responsible for sepsis in 9 (18%) of 50 patients. The main source of perianal tissue infection in patients with granulocytopenia was anal fissures and fistulas and ulcers of the anal canal: 44 (88%) cases of the 50 cases. In PI as an abscess, the average white blood cell count was 5 times higher (p=0.01) than that in PI as an infiltrate (or multiple ulcers): 6.6.109/l and 1.2.109 g/l. Abscess formation was observed in 16 (22.2%) patients and an indication for surgical drain. The inflammatory infiltrate was found to develop in 48 (66.7%) patients; multiple ulcers were seen in 8 (11.1%); in this group, parenteral antimicrobial therapy proved to be effective in 36 (78%) patients. 29 patients were operated on for anal fissures and fistulas at intercycle intervals. After continuing CT, PI recurrences were observed in 4 (9.1%) patients. In the operated versus medically treated patients, the risk of complications associated with abnormalities in the perianal area during continued CT was 5 times statistically significantly lower (odds ratio=0.2; 95% confidence interval 0.1 to 0.5; p=0.04; Cochran-Mantel test). CONCLUSION: Induction CT cycles, the status of granulocytopenia, and the presence of infection sources in the anal canal as an anal fissure, skin ulcerations, or a fistula should be considered as independent statistically significant prognostic risk factors for PI. The number of granulocytes determines the form of inflammation, the course of infection, and the chance of developing sepsis. The effective prevention encompassing surgical treatment for anal canal diseases reduces the risk of septic complications and the number of paraproctitis recurrences, contributing to the implementation of a planned CT program in patients with hemoblastosis. PMID- 27459617 TI - [Follicular lymphoma. High-dose immunochemotherapy with autologous blood stem cell transplantation: Results of the first prospective study in Russia]. AB - AIM: to evaluate the efficiency of high-dose chemotherapy (HDCT) with further autologous blood stem cell transplantation (auto-BSCT) in the first-line therapy of patients with follicular lymphoma (FL) and poor prognostic factors. SUBJECTS AND METHODS: In 2000 to 2015, the National Research Center for Hematology, Ministry of Health of the Russian Federation, performed therapy in 39 patients with FL and poor prognostic factors (a total of 215 patients with FL). The R-CHOP treatment was done as induction therapy. Sequential HCT and further auto-BSCT were performed in 29 (74%) of the 39 patients, who had shown a partial tumor response to the induction therapy or achieved partial remission after 4-6 cycles of CT, but had poor prognostic factors. 22 of the 29 patients underwent auto-BSCT in first-line therapy after induction R-CHOP regimens. Among them, there were 17 men with a median age of 46 years (31-68 years). 21 of the 22 patients were recorded to have Stage IV by the Ann Arbor staging classification. Bulky peritoneal and retroperitoneal tumors larger than 7 cm were detectable at disease onset in 14 of the 22 cases. Two patients were noted to have phenomena of leukemization. 16 patients had bone marrow (BM) involvement. According to the Follicular Lymphoma International Prognostic Index-1 (FLIPI-1), the patients were divided into 3 groups: 1) a low risk (n=5); 2) an intermediate risk (n=3); a high risk (n=14). B-symptoms were observed in 16 cases. 16 patients were diagnosed with cytological grade I-II FL and 6 had grade IIIA. According to the tumor proliferative pattern, the distribution turned out to be as follows: nodular (n=6), nodular-diffuse (n=13), and diffuse (n=3). The proliferative activity index averaged 30% (8-90%). Serum and urine proteins were immmunochemically assayed in 18 cases, out of them 8 patients were diagnosed as having serum beta2 microglobulin concentrations above normal as a poor prognostic factor. In 14 of the 22 patients, the activity of lactate dehydrogenase was greater than normal (266-7806 U/l). RESULTS: Out of the 22 patients, 20 who have undergone auto-BSCT in first-line therapy are survivors and have remission of the underlying disease: 18 and 2 patients achieved complete and partial remission, respectively. The follow-up period was 7 to 178 months (median, 32 months). After auto-BSCT in the first remission, 2 patients developed disease recurrences: an early recurrence after 9 months in one case and a late recurrence 6 years after completion of therapy in the other. CONCLUSION: The first prospective study of intensive therapy for FL in Russia has demonstrated that HDCT with further auto-BSCT in first-line therapy allows complete remission in patients with poor prognostic factors and higher overall and progression-free survival rates. PMID- 27459619 TI - [Molecular serological characteristics of weak D antigen types of the Rhesus system]. AB - AIM: to estimate the spread of weak D antigen types of the Rhesus system in the citizens of the Russian Federation and a possibility of serologically identifying these types. SUBJECTS AND METHODS: The red blood cells and DNA of people with weakened expression of D antigen were investigated using erythrocyte agglutination reaction in salt medium (2 methods); agglutination reaction in the gel columns containing IgM + IgG anti-D antibodies, indirect antiglobulin test with IgG anti-D antibodies (2 methods); polymerase chain reaction to establish the type of weak D. RESULTS: A rhesus phenotype was determined in 5100 people in 2014-2015. The weakened agglutinable properties of red blood cells were detected in 102 (2%) examinees. 63 examinees underwent genotyping to identify the variants of the weak D antigen, which identified 6 weak D types. There were the most common weak D types 3 (n=31 (49.2%)) and weak D type 1 (n=18 (28.6%)), including weak D type 1.1 in one (1.6%) case. The other 4 weak D antigen types were as follows: weak D type 2 (14.3% (n=9)), weak D type 15 (4.8% (n=3)), weak D type 4.2 (DAR) (1.6% (n=1)) and weak D type 6 (1.6% (n=1)). The antiglobulin test in the gel column containing antiglobulin serum was the most sensitive serological assay to identify the weak D antigen. Only a molecular test could establish weak D type 15 in 2 samples of red blood cells with Ccdee and ccdEe phenotypes. CONCLUSION: The weak D antigen could be serologically identified in 96.8% of cases. When testing for weak D, particular attention should be given to people with the D-negative phenotype who had the C or E antigens. Our investigations conducted for the first time in Russia will be able to improve the immunological safety of red blood cell-containing medium transfusions for patients. PMID- 27459620 TI - [The specific features of pain syndrome in patients with hemophilia]. AB - AIM: to study the nature of pain in hemophilic arthropathy and its prevention ways used by patients with hemophilia. SUBJECTS AND METHODS: A prospective, multicenter, cross-sectional study was conducted to interview 136 patients with hemophilia A or B. The survey included 32 points, including questions about drug and nondrug pain treatment, as well as questionnaires to assess the severity of pain and its impact on daily life (Brief Pain Inventory) and those to identify a neuropathic pain component (PainDetect questionnaire). RESULTS: 83 (75%) patients with hemophilia experienced acute pain associated with bleeding into the large joints; 44 (39%) patients had chronic pain that had lasted longer than six months; 33% assessed the moderate pain experienced in the past 24 hours as severe (more than 5-8 of the 10 scores). In addition to the above, only 32% of the respondents indicated that they had painless intervals within the last 24 hours. 75% of the hemophilia patients mentioned to have limited daily activities. 74% reported their partial or complete disability when pain occurred. 77% of the respondents pointed out that when having pain, they had experienced great difficulty walking. 55% of the hemophilia patients had sleep disorders because of pain. When acute pain occurred, only 91 (81%) respondents injected a factor VIII or IX preparation, 37% of the respondents used narcotic analgesics; 51% received different nonsteroidal anti-inflammatory drugs; 13% took paracetamol. Some patients indicated that they used alcohol and illegal narcotic drugs to relieve pain. Attention is drawn to the fact that the hemophilia patients very frequently took painkillers: 60% of the respondents used analgesics every month; of them 49% had them every week, 11% every day. Most patients (n=83 (74%)) stated that they treated pain (prescribed drugs) themselves; 49 (44%) patients held they were dissatisfied with their pain treatment. When the question as to how the analgesic you used could "remove' pain was asked, only 12 (10%) patients answered that this could fully relieve the pain; 31 (26%) patients told that the pain was not reduced even by half. The study has shown that a neuropathic pain component is very common in hemophilia patients (31%). CONCLUSION: Pain in patients with hemophilia is a serious problem that negatively affects their quality of life, including their working capacity. The prevention and treatment of pain in hemophilia patients should involve the following: organization of educational activities and pain services; adequate treatment of acute pain; detection and prevention of a neuropathic pain component. PMID- 27459621 TI - [The new endothelin receptor antagonist macitentan: Prospects for therapy of pulmonary arterial hypertension]. AB - Pulmonary arterial hypertension (PAH) is a clinical group of severe and rare diseases with similar morphological, hemodynamic, and therapeutic characteristics. One of the novel drugs to treat PAH is macitentan, a new double endothelin ETA and ETB receptor antagonist that is characterized by special physicochemical properties, ensuring the penetration of the drug into tissues and its improved receptor-binding properties. The SERAPHIN trial has demonstrated that therapy with macitentan 10 mg versus placebo statistically significantly reduces the risk of poor outcomes and death by 45%. The treatment with macitentan 10 is observed to be highly effective regardless of the presence/absence of basic PAH-specific therapy. The drug considerably improves clinically important outcomes, including 6-minute walk distance and WHO functional class. Macitentan exerts a steady-state therapeutic effect, by improving pulmonary hemodynamics. Macitentan 10 mg statistically significantly reduces the risk of PAH, frequency of its related hospitalizations, and the number of days spent in hospital. The drug has a favorable safety profile; its most common side effects are headache, nasopharyngitis, and anemia. Macitentan is an effective first-line drug to improve long-term outcomes in patients with newly and previously diagnosed PAH. PMID- 27459622 TI - [A rare case of myeloproliferative disease with t(8;13)(p11;q12) associated with eosinophilia and lymphadenopathy]. AB - Myeloproliferative disease associated with FGFR1 rearrangement (8p11), which is included in the 2008 WHO Classification of Myeloid Neoplasms, is a rare and extremely aggressive abnormality. The paper describes a clinical case of a 39 year-old female patient who was detected to have leukocytosis (as high as 47.2.109/l), absolute eosinophilia (as high as 3.1.109/l), and enlarged peripheral lymph nodes during her visit to a doctor. The bone marrow (BM) showed the changes typically encountered in myeloproliferative disease with eosinophilia. The patient was found to have t(8;13)(p11;q12) translocation associated with the rearrangement of the FGFR1 gene located at the 8p11 locus. Molecular and cytogenetic examinations failed to reveal BCR-ABL chimeric transcript, Jak2 V617F mutation, and deletions and translocations involving PDGFRA (4q12) and PDGFRB (5q32-33). The similar changes in the karyotype were also found in the lymph node cells. The undertaken treatment with hydroxyurea and the tyrosine kinase inhibitor dasatinib turned out to be ineffective. The patient underwent allogeneic BM transplantation from a HLA-identical sibling. Graft rejection occurred 6 months later. Allogeneic BM transplantation from the same donor (100% donor chimerism; FGFR1/8r11 translocation was not detected), which was complicated by the development of chronic graft-versus-host reaction, was performed again in March 2015. The patient is being followed up and continues to receive immunosuppressive therapy. PMID- 27459623 TI - [Transformation of secondary myelodysplastic syndrome to atypical chronic myeloid leukemia in a female patient with acute myeloid leukemia]. AB - Secondary myeloid neoplasia may be a complication of intensive cytostatic therapy. The most common types of secondary neoplasias are acute myeloid leukemia and myelodysplastic syndrome. The development of secondary atypical chronic myeloid leukemia (aCML) is an extremely rare phenomenon. The paper describes transformation of secondary myelodysplastic syndrome to aCML 6 months after its diagnosis. The development of aCML was accompanied by additional chromosomal aberration as monosomy of chromosome 17. No mutations in the JAK2, MPL, and CalR genes were detected. It is concluded that the clinical course of secondary myeloid neoplasias is variable. PMID- 27459624 TI - [Laparoscopic splenectomy in immune thrombocytopenic purpura in pregnant women]. AB - The paper describes 4 cases of laparoscopic splenectomy in pregnant women with immune thrombocytopenic purpura. No complications of surgery were noted in all the patients. The postoperative period was marked by sustained clinical and hematological remission that made it possible to discontinue prednisolone therapy and to ensure an uncomplicated course of pregnancy and labor. PMID- 27459625 TI - Communicating nutraceuticals: A multi-stakeholder perspective from a developing nation. AB - Nutraceuticals, a combination of nutrition and pharmaceutical, have grown rapidly as a product globally. Nutraceuticals can be advertised directly to consumers as well as prescribed, and thus involve multiple stakeholders in the marketing communication process. The present study investigates the marketing communication aspects of nutraceuticals using 216 semistructured in-depth interviews including all stakeholders in the process such as company/brand, physicians, pharmacists, and consumers. The findings bring out the role of each participant in the communication process and a comprehensive picture of the same. The insights would facilitate the nutraceutical brands to understand and implement marketing effective communication strategies. PMID- 27459626 TI - Transient versus Static Electron Spin Relaxation in Mn(2+) Complexes Relevant as MRI Contrast Agents. AB - The zero-field splitting (ZFS) parameters of the [Mn(EDTA)(H2O)](2-).2H2O and [Mn(MeNO2A)(H2O)].2H2O systems were estimated by using DFT and ab initio CASSCF/NEVPT2 calculations (EDTA = 2,2',2",2'''-(ethane-1,2 diylbis(azanetriyl))tetraacetate; MeNO2A = 2,2'-(7-methyl-1,4,7-triazonane-1,4 diyl)diacetate). Subsequent molecular dynamics calculations performed within the atom-centered density matrix propagation (ADMP) approach provided access to the transient and static ZFS parameters, as well as to the correlation time of the transient ZFS. The calculated ZFS parameters present a reasonable agreement with the experimental values obtained from the analysis of (1)H relaxation data. The correlation times calculated for the two systems investigated turned out to be very short (tauc ~ 0.02-0.05 ps), which shows that the transient ZFS is modulated by molecular vibrations. On the contrary, the static ZFS is modulated by the rotation of the complexes in solution, which for the small complexes investigated here is characterized by rotational correlation times of tauR ~ 35-60 ps. As a result, electron spin relaxation in small Mn(2+) complexes is dominated by the static ZFS. PMID- 27459627 TI - Wicking Enhancement in Three-Dimensional Hierarchical Nanostructures. AB - Wicking, the absorption of liquid into narrow spaces without the assistance of external forces, has drawn much attention due to its potential applications in many engineering fields. Increasing surface roughness using micro/nanostructures can improve capillary action to enhance wicking. However, reducing the structure length scale can also result in significant viscous forces to impede wicking. In this work, we demonstrate enhanced wicking dynamics by using nanostructures with three-dimensional (3D) hierarchical features to increase the surface area while mitigating the obstruction of liquid flow. The proposed structures were engineered using a combination of interference lithography and hydrothermal synthesis of ZnO nanowires, where structures at two length scales were independently designed to control wicking behavior. The fabricated hierarchical 3D structures were tested for water and ethanol wicking properties, demonstrating improved wicking dynamics with intermediate nanowire lengths. The experimental data agree with the derived fluid model based on the balance of capillary and vicious forces. The hierarchical wicking structures can be potentially used in applications in water harvesting surfaces, microfluidics, and integrated heat exchangers. PMID- 27459628 TI - Application of Circulating Tumor DNA as a Non-Invasive Tool for Monitoring the Progression of Colorectal Cancer. AB - BACKGROUND: Liquid biopsy has been proposed to be a promising noninvasive tool to obtain information on tumor progression. Through a clinical observation of a case series of 6 consecutive patients, we aim to determine the value of circulating tumor DNA (ctDNA) for monitoring the tumor burden during the treatment of colorectal cancer (CRC). MATERIALS AND METHODS: We used capture sequencing of 545 genes to identify somatic alternations in primary tumor tissues of the six CRC patients who underwent radical surgery and in 23 plasma samples collected at serial time points. We compared the mutation patterns and variant allele frequencies (VAFs) between the matched tissue and the plasma samples and evaluated the potential advantage of using ctDNA as a better tumor load indicator to detect disease relapse over carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9 and imaging studies. RESULTS: We identified low-frequency mutations with a mean VAF of 0.88% (corresponding to a mean tumor burden of 0.20ng/mL) in the preoperative plasmas of four patients with locally advanced CRC and a subset of mutations shared by their primary tumors. The tumor loads appeared a sudden decrease upon surgery or other adjuvant treatments and then generally maintained at low levels (0.092ng/mL) until disease recurred. ctDNA increased by 13-fold when disease relapsed in one patient while the CEA and CA 19-9 levels remained normal. In this patient, all six somatic mutations identified in the preoperative plasma were detected in the recrudescent plasma again, with five mutations showing allele fraction increase. CONCLUSIONS: We described a multi-time-point profile of ctDNA of CRC patients during the course of comprehensive treatment and observed a correlation of ctDNA level with the clinically evaluated tumor progression. This demonstrated a new strategy by analyzing the heterogeneous ctDNA to evaluate and monitor the tumor burden in the treatment and follow-up of CRC patients, with potentially better potency than conventional biomarkers. PMID- 27459629 TI - Clue to Understanding the Janus Behavior of Eumelanin: Investigating the Relationship between Hierarchical Assembly Structure of Eumelanin and Its Photophysical Properties. AB - The contradictory biological function of eumelanin (photoprotection vs photosensitization) has long been a topic of debate in a wide range of disciplines such as chemistry, physics and biology. For understanding full spectrum of eumelanin's photobiological aspect, revealing how eumelanin's complex structural organization dictates its photophysical properties is critical step. Here, we report a practical approach to controlling the hierarchically assembled structure of natural eumelanin, which leads to disassembly of its structure into subunits and oxidized subunits, respectively. Based on the well-characterized model system, it was possible to systematically determine how the photophysical properties of eumelanin are ruled by its hierarchical assembly organization. Particularly, our experiments reveal that the chemical oxidation of eumelanin's subunits, which leads to delamination of their stacked layer structure, is critical to significantly increase their photochemical reactivity to generate ROS under UV irradiation. This result provides clear experimental evidence that oxidative degradation of eumelanin, which might be induced by phagosomal enzymatic activity in the process of melanomagenesis, is responsible for triggering the negative photobiological role of eumelanin such as ROS source needed for development of malignant melanoma. PMID- 27459630 TI - Growth hormone receptor gene variant and three-dimensional mandibular morphology. AB - OBJECTIVE: To examine the relationship between three-dimensional mandibular morphology and growth hormone receptor (GHR) gene variants in a healthy Japanese population. MATERIALS AND METHODS: The subjects, who were unrelated Japanese orthodontic patients, consisted of 64 men and 114 women. Using the Taqman genotyping assay, GHR gene rs6184 and rs6180 variants were detected in genomic DNA extracted from saliva. Mandibular volume and length were measured from cone beam computed tomography images that were analyzed using Analyze image-processing software. The relationship between GHR gene variants and three-dimensional mandibular morphology was statistically examined. RESULTS: Statistical significance for the relationship between the distance between the left and right coronoid processes and rs6180 was noted (P < .05). CONCLUSION: Our results indicate that the GHR variant rs6180 is associated with the distance between the left and right coronoid process in the Japanese subjects. PMID- 27459631 TI - Prescribing Exercise and Lifestyle Training for High Risk Women in Pregnancy and Early Post-partum-Is It Worth It? AB - In a Perspective, Jane Norman and Rebecca Reynolds discuss two randomized controlled trials aimed at testing behavioral interventions for women at risk of gestational diabetes. PMID- 27459632 TI - An investigation into mature adults' attitudinal reluctance to register as organ donors. AB - BACKGROUND: Mature adults (age 50-64) make up a large proportion of organ transplant recipients, and waiting list candidates yet are underrepresented in terms of actual donors. Understanding the reasons why mature adults fail to register as deceased organ donors is critical in achieving the goal of increasing the actionable supply of organs available for transplant. Conceptual models propose certain factors such as bodily integrity, ick (i.e., disgust), jinx (i.e., superstition), medical mistrust, salience, self-efficacy, and stake are associated with organ donation registration attitudes. Moreover, the age myth, or the belief that one's age prevents them from becoming an organ donor, was examined among mature adults between the ages of 50-64. METHOD: An online survey was disseminated to mature adults (N=709). RESULTS: Results indicated jinx, salience, self-efficacy, and stake each predicted organ donation attitudes among mature adults. Moreover, results indicated that age myth accounted for attitudes toward registering as an organ donor among non-registered mature adults after controlling for non-cognitive and vested interest constructs. CONCLUSION: This study demonstrates the age myth is negatively associated with attitudes toward registering as organ donors. The results are discussed with an emphasis on both the theoretical and practical implications of study findings. PMID- 27459633 TI - Enhanced Signal and Quantitative Detection of Anti-Interferon-Gamma Antibody by Using a Nanometer Biolinker. AB - For rapid screening and quantification of an antisera antibody, a nanometer bithiophene-based conductive biolinker can enhanced signal performance and can be used to verify the interaction of an anti-IFN-gamma antibody with an IFN-gamma protein. The experimental measurements take a generic approach which takes advantage of the functionality of thiophene-based linkers for biosensors. Effects associated with using bithiophene as a biolinker for surface plasmon resonance (SPR) spectroscopy are examined in this paper. By using an atomic force microscope (AFM), it was observed that the morphology of the bithiophene modified gold sensor surface became smoother than the original gold surface. We compared the response and concentration of the anti-IFN-gamma antibody on a bithiophene coated and dextran-coated biochip as well as on different thickness-modified surfaces under SPR relevant conditions. The results indicate that a response to IFN-gamma molecules immobilized on a sensor using a bithiophene biolinker improved more than 8-fold when compared to that of a sensor using a dextran biolinker. Furthermore, the regeneration ability of the sensor surface shows good repeatability as only less than a 1% decrease was found after repeating the experimental work over 6 cycles. The characteristics provided us with a good platform for rapid screening, real-time monitoring and quantitative concentration of the autoimmune antibody activities. PMID- 27459635 TI - Aquaporin gene therapy for cholestasis. PMID- 27459636 TI - Probing the pseudo-1-D ion diffusion in lithium titanium niobate anode for Li-ion battery. AB - Comprehensive understanding of the charge transport mechanism in the intrinsic structure of an electrode material is essential in accounting for its electrochemical performance. We present here systematic experimental and theoretical investigations of Li(+)-ion diffusion in a novel layered material, viz. lithium titanium niobate. Lithium titanium niobate (exact composition Li0.55K0.45TiNbO5.1.06H2O) is obtained from sol-gel synthesized potassium titanium niobate (KTiNbO5) by an ion-exchange method. The Li(+)-ions are inserted and de-inserted preferentially into the galleries between the octahedral layers formed by edge and corner sharing TiO6 and NbO6 octahedral units and the effective chemical diffusion coefficient, is estimated to be 3.8 * 10(-11) cm(2) s(-1) using the galvanostatic intermittent titration technique (GITT). Calculations based on density functional theory (DFT) strongly confirm the anisotropic Li(+)-ion diffusion in the interlayer galleries and that Li(+)-ions predominantly diffuse along the crystallographic b-direction. The preferential Li(+)-ion diffusion along the b-direction is assisted by line-defects, which are observed to be higher in concentration along the b-direction compared to the a- and c-directions, as revealed by high resolution electron microscopy. The Li-Ti niobate can be cycled to low voltages (~0.2 V) and show stable and satisfactory battery performance over 100 cycles. Due to the possibility of cycling to low voltages, cyclic voltammetry and X-ray photoelectron spectroscopy convincingly reveal the reversibility of Ti(3+) <-> Ti(2+) along with Ti(4+) <-> Ti(3+) and Nb(5+) <-> Nb(4+). PMID- 27459634 TI - A prospective study of dietary patterns and cancer mortality among Blacks and Whites in the REGARDS cohort. AB - Marked racial differences exist in dietary patterns and obesity, as well as cancer mortality. This study aims to assess whether dietary patterns are associated with cancer mortality overall and by race. We identified 22,041 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Dietary patterns were categorized into: Convenience (Chinese and Mexican foods, pasta, pizza), Plant-based (fruits, vegetables), Southern (added fats, fried foods, sugar-sweetened beverages), Sweets/Fats (sugary foods) and Alcohol/Salads (alcohol, green-leafy vegetables, salad dressing). Using Cox regression, we examined the association between quartiles of dietary patterns and cancer mortality, adjusted for potential confounders, overall among all participants and stratified by race. A total of 873 cancer deaths were observed over the 10-year observation period: 582 (66.7%) in Whites and 291 (33.3%) in Blacks. Greater adherence to the Southern dietary pattern was associated with an increased risk of cancer mortality (4th vs. 1st quartile HR: 1.67; 95% CI: 1.32 2.10) overall, especially among Whites (4th vs. 1st quartile HR: 1.59; 95% CI: 1.22-2.08). The convenience (HR: 0.73; 95% CI: 0.56-0.94) and Plant-based (HR: 0.72; 95% CI: 0.55-0.93) dietary patterns were associated with up to a 28% reduced risk of cancer mortality, but only among Whites. Greater adherence to the Southern dietary pattern increased the risk of cancer mortality, while greater adherence to the convenience and Plant-based diets reduced the risk of cancer mortality among Whites. Racial differences were observed in the association between dietary patterns and cancer mortality, but warrant further study. PMID- 27459637 TI - The Synergy between Metal Facet and Oxide Support Facet for Enhanced Catalytic Performance: The Case of Pd-TiO2. AB - The demand for catalyst with higher activity and higher selectivity is still a central issue in current material science community. On the basis of first principles calculations, we demonstrate that the catalytic performance of the Pd TiO2 hybrid nanostructures can be selectively promoted or depressed by choosing the suitable shaped Pd and TiO2 nanocrystals. To be more specific, the catalytic activities of Pd nanoparticles enclosed by (100) or (111) facets can be promoted more significantly when dosed on the TiO2(001) than on TiO2(101) under irradiation. Such theoretical prediction has then been further verified by the experimental observations in which the Pd(100)-TiO2(001) composites exhibit the highest catalytic performance toward the activation of oxygen among all the other shaped hybrid nanostructures. As a result, the selection of facets of support materials can provide an extra tuning parameter to control the catalytic activities of metal nanoparticles. This research opened up a new direction for designing and preparing catalysts with enhanced catalytic performance. PMID- 27459638 TI - Present day management of inherited bleeding disorders in pregnancy. AB - INTRODUCTION: How specifically to prevent post-partum haemorrhage (PPH) remains a challenge in pregnant women with an inherited bleeding disorder. There exists a morbidity of 5-10% of patients as well as increased mortality. AREAS COVERED: This review will survey the literature based on Medline review and various society monographs. Numerous societies have developed guidelines in hopes of reducing the risk of PPH. The guidelines are congruent in stating that the von Willebrand factor (VWF) /Factor VIII (FVIII) level must be > 50% to both permit safely epidural analgesia but also to prevent PPH. However, specific guidance is lacking in terms of how high and long a level should be achieved. Recent studies report a high rate of PPH in these treated patients despite aiming for levels > 50-100% suggesting that a postpartum post-replacement VWF/FVIII level of 50-100% is inadequate and follow up dosing should maintain higher levels then typically achieved per 'guidelines'. Expert commentary: Future studies to reduce PPH in women in the third trimester with levels < 50% should incorporate concurrent post partum antifibrinolytic agent therapy and/or double utertonics and/or aiming for a higher trough factor level closer to 200% than 100% and maintaining such a level for several days postpartum. PMID- 27459639 TI - Methods for Predicting Diabetes Phase III Efficacy Outcome From Early Data: Superior Performance Obtained Using Longitudinal Approaches. PMID- 27459640 TI - Serum Levels of Insulin-Like Growth Factor-1 and Obsessive-Compulsive Disorder: A Case-Control Study. AB - BACKGROUND/AIMS: Recent findings suggest an involvement of insulin-like growth factor-1 (IGF-1) in the pathogenesis of many psychiatric disorders; however, there is a lack of data regarding IGF-1 in patients with obsessive-compulsive disorder (OCD). The aims of the present study were (1) to analyze putative alterations of IGF-1 serum content in patients with OCD compared to patients with major depressive disorder (MDD) and healthy controls, and (2) to analyze putative changes of IGF-1 levels during drug treatment in subjects with OCD compared to patients with MDD. METHODS: We recruited 40 OCD patients, 37 MDD patients, and 43 healthy controls. All participants were adults. Serum IGF-1 levels were measured by the ELISA method on venous blood samples collected at baseline and after 10 +/ 1 weeks of drug treatment. RESULTS: IGF-1 levels were increased in OCD patients compared to controls (149.9 +/- 60.2 vs. 121.2 +/- 51.6 ng/ml; p = 0.040). No correlations were observed between baseline IGF-1 levels, clinical features, and response to treatment at follow-up in OCD or MDD patients. No changes in serum IGF-1 were observed after drug treatment. CONCLUSION: Our results show for the first time that serum IGF-1 levels are altered in patients with OCD. Further research on the role of IGF-1 in OCD is warranted. PMID- 27459641 TI - Life-Course Approach to Chronic Disease: The Active and Healthy Aging Perspective. PMID- 27459643 TI - Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability. AB - Transcranial focused ultrasound technology used to transiently open the blood brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier. PMID- 27459644 TI - Mammalian Target of Rapamycin Signaling Pathway Changes with Intestinal Epithelial Cells Renewal Along Crypt-Villus Axis. AB - BACKGROUND/AIMS: Understanding the mechanism that involves in regulating epithelial cells renewal is the fundamental of regulating intestinal mucosa development and functions and related diseases. The mechanistic target of rapamycin (mTOR) signaling pathway involves in controlling various major processes by integrating intracellular and extracellular cues. The present experiment was conducted to test the correlation between the mTOR signaling pathway and intestinal epithelial cells renewal along crypt-villus axis (CVA). METHODS: Intestinal epithelial cells were sequentially isolated from the jejunum of piglets along CVA, and the amount or phosphorylation level of proteins involved in cell cycle, mTOR signaling pathway, gene expression, and the antioxidant capacity in the isolated cells were measured. RESULTS: The results showed that the amount of proteins involved in cell cycle decreased from crypt to villus tip. The amount or phosphorylation level of proteins related to mTOR signaling pathway in intestinal epithelial cells mainly decreased during maturation along CVA. The amount of proteins involved in gene expression and the antioxidant capacity also decreased from crypt to the top of villi. CONCLUSIONS: These results indicate that the mTOR signaling pathway may be involved in regulating the intestinal epithelial cells renewal along CVA and it may partly through affecting the antioxidant capacity and gene expression of intestinal epithelial cells. Further histological verification is needed to confirm the results of the present experiments. PMID- 27459645 TI - CO2-Responsive Polymer-Functionalized Au Nanoparticles for CO2 Sensor. AB - Metallic nanoparticles (NPs) coated with stimuli-responsive polymers (SRPs) exhibit tunable optical properties responding to external stimuli and show promising sensing applications. We present a new CO2-responsive polymer, poly(N (3-amidino)-aniline) (PNAAN), coated gold NPs (AuNPs) synthesized by directly reducing HAuCl4 with a CO2-responsive monomer N-(3-amidino)-aniline (NAAN). The amidine group of PNAAN can be protonated into a hydrophilic amidinium group by dissolved CO2 (dCO2). This induces the PNAAN to swell and detach from the AuNP surface, resulting in AuNP aggregation and color change. By monitoring the UV absorbance change of AuNPs, a sensitive dCO2 sensor with a linear range of 0.0132 to 0.1584 hPa and a limit of detection (LOD) of 0.0024 hPa is developed. This method shows dramatic improvement in sensitivity and convenience of sample preparation compared with the previously reported dCO2 sensor. PMID- 27459646 TI - Evidence of the effect of rural background on rural practise in Australian dental practitioners: Does gender play a role? AB - BACKGROUND: People residing outside the capital cities have poorer oral health than their city counterparts. Health workforce shortages and stability issues can have negative health effects on rural populations. There has been an increasing proportion of women entering the dental practitioner workforce in Australia. This study investigated whether dental practitioners who have a rural background are more likely to work in a rural area than those who do not have a rural background; and whether the gender of dental practitioners plays a role. METHODS: A self-administered questionnaire was sent to a sample of dental practitioners via their professional dental associations. Practice location was assigned as either 'urban' or 'rural' using the Australian Standard Geographical Classification - Remoteness Area categories and measured with demographic characteristics of the respondents. Prevalence ratios (PR) were estimated using Poisson regression with robust standard errors. RESULTS: Participants with a rural background were more than twice as likely (male PR = 2.23, 95% confidence interval (CI) = 0.79-6.26; female PR = 2.82, 95% CI = 1.35-5.87) to practise in a rural area than those with an urban background. CONCLUSIONS: Dental practitioners with rural backgrounds were more than twice as likely to work in a rural practice as their urban counterparts. PMID- 27459647 TI - An Entry to Mixed NHC-Fischer Carbene Complexes and Zwitterionic Group 6 Metal Alkenyls. AB - The addition of NHCs to alpha,beta-unsaturated Cr(0) and W(0) (Fischer) carbene complexes is strongly dependent on the electrophilicity of the carbene carbon. Electrophilic alkoxy-carbene complexes quantitatively react with NHCs to yield stable zwitterionic (racemic) Cr(0) - and W(0) -alkenyls with total regio- and E stereoselectivity. Less electrophilic aminocarbenes react with NHCs to promote the displacement of a CO ligand and yield "mixed" NHC/Fischer biscarbenes in a process that is unprecedented in group 6 metal-carbene chemistry. In fact, the compounds prepared, are some of the scarce examples of Fischer bisylidenes reported in the literature. The electrochemistry of the zwitterionic Cr(0) - and W(0) -alkenylcomplexes made, show that these compounds have a strong reductor character, which is demonstrated in their reactions towards [Ph3 C][PF6 ]. The oxidation processes lead to new types of cationic Fischer mono- and biscarbene complexes having a charged NHC fragment in their structures, in a new example of the use of electron-transfer reactions as a method to prepare novel group 6 (Fischer) carbene complexes. PMID- 27459648 TI - Insect Pollinators in Iowa Cornfields: Community Identification and Trapping Method Analysis. AB - Availability of mass flowering plants in landscapes dominated by agriculture can have a strong positive impact on the density of generalist, native pollinators. Row-crop production in Iowa accounts for 75% of the arable acres, with corn, Zea mays, representing the majority of hectares planted. To date, there has been no description of the insect pollinator community found within Iowa cornfields. We report a field study to determine the optimal sampling methodology to characterize the community of insect pollinators within cornfields. During 2012 and 2013, 3,616 insect pollinators representing 51 species were captured using bee bowls, and 945 individuals representing 10 species were captured using sticky cards. We examined the effects of trap type, height, and bowl color on the described community. Bee bowls captured a more abundant and species rich community than sticky cards with all species captured on sticky cards also present in bee bowls. Traps deployed at the height of the tassels describe a more abundant and species rich community of pollinators than traps at ear height (2x as many individuals) or ground height (4x as many individuals). Blue bowls captured more bees than white (2.75x as many individuals) or yellow bowls (3.5x as many individuals); and yellow bowls captured more flies than white (2x as many individuals) or blue (2.3x as many individuals). To provide the most complete description of the community of insect pollinators using cornfields as a resource, we suggest sampling-using bee bowls at the height of the tassels using all three bee bowl colors. PMID- 27459649 TI - Response to Paul Regal. PMID- 27459650 TI - Grim Provider and Supplier Gross Margins of 1.8%-3.7% if CMS-1670-P Is Finalized As Proposed. AB - DISCLOSURES: The author provides consulting services to the pharmaceutical industry, including manufacturers, health plans, employers, and specialty pharmacies, and is a member of the editorial advisory board of Specialty Pharmacy News. The author reports no financial or other conflicts of interest related to the subject of this letter. PMID- 27459651 TI - Antihyperlipidemic Medication Treatment Patterns and Statin Adherence Among Patients with ASCVD in a Managed Care Plan After Release of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol. AB - BACKGROUND: The American College of Cardiology (ACC) and American Heart Association (AHA) released a new blood cholesterol treatment guideline in November 2013. It is unknown how the new recommendations have affected cholesterol medication use and adherence in a commercial health plan. OBJECTIVE: To evaluate the effect of the 2013 guideline release on antihyperlipidemic treatment patterns and statin adherence in patients with atherosclerotic cardiovascular disease (ASCVD) compared with a historical control group. METHODS: This study was a historical cohort analysis of adult patients (aged 21-75 years) with clinical ASCVD enrolled in a SelectHealth commercial health plan. Patients were included in the guideline implementation cohort if they had a medical claim with an ICD-9-CM diagnosis of ASCVD in the year before the November 2013 ACC/AHA guideline release. The index date was defined as the first outpatient medical claim with an ICD-9-CM for ASCVD in the first 6 months after the guideline was released. Patients were required to have continuous enrollment for >= 1 year before and after the index date. These same criteria were applied to patients exactly 4 years earlier to identify a historical control group. Patients meeting these criteria formed the antihyperlipidemic treatment patterns cohort. Of these, patients who also had >=1 pharmacy claim for a statin in the 1-year pre- and post index periods were included in the statin adherence cohort. Antihyperlipidemic treatment patterns were assessed using pharmacy claims for antihyperlipidemic medications in the 1-year pre- and post-index periods. Antihyperlipidemic medication claims were classified as a nonstatin cholesterol medication, low intensity statin, moderate-intensity statin, or high-intensity statin. To address differences in pre-index antihyperlipidemic medications between the guideline implementation and historical control groups, patients were randomly matched 1:1 based on pre-index classification in a post hoc analysis. Post-index antihyperlipidemic classifications were compared between groups using a Stuart Maxwell test. The change in mean statin adherence (proportion of days covered [PDC]) was compared within and between groups using paired and independent t tests, respectively. The proportion of adherent patients (PDC >= 0.80) in the pre and post-index periods was compared between groups using a chi-square test. A multivariable logistic regression was used to compare the likelihood of being adherent in the post-index period while controlling for pre-index adherence and other potential confounders. RESULTS: A total of 7,818 adult members with ASCVD in the index period and 1 year before the index period were identified. Of those, 1,841 patients met the criteria to be included in the analysis, and 1,526 patients were matched on antihyperlipidemic classification and included in the antihyperlipidemic treatment patterns analysis. Baseline characteristics were similar, although the guideline implementation group was younger (58.3 vs. 60.5 years, P < 0.001), and more were male (74.8% vs. 71.3%, P = 0.106) than the historical control group. In the matched cohort, there was a significant difference in the post-index antihyperlipidemic classification (P < 0.001), which appeared to be a result of the difference in nonstatin cholesterol medications (guideline 6.9% vs. historical 13.0%) and high-intensity statins (guideline 23.7% vs. historical 16.3%). Of the 1,841 patients in the antihyperlipidemic treatment patterns cohort, 919 patients met inclusion criteria for the statin adherence analysis. Although PDC decreased over time in both groups, significantly more patients in the guideline implementation group were adherent in the post-index period than the historical control group (66.5% vs. 57.3%, respectively; P = 0.005). Additionally, patients in the guideline implementation group were more likely than the historical control to be adherent in the post-index period when adjusting for potential confounders (OR = 1.49, 95% CI = 1.10-2.03; P = 0.011). CONCLUSIONS: Since the release of the updated ACC/AHA treatment guideline, more commercial health plan patients with ASCVD used high-intensity statins and fewer used nonstatin cholesterol medications than historical controls. Additionally, since the guideline release, more patients are adherent to statin therapy than historical controls. This study provides managed care organizations with valuable information regarding the effect of the 2013 ACC/AHA guideline. DISCLOSURES: No outside funding or services were received for this work. Outside of the current study, Bellows has received research funding from Biogen Idec, Regeneron Pharmaceuticals, Myriad Genetic Laboratories, Shire Development, and Bristol Myers Squibb and an honorariam from Avanir Pharmaceuticals. Voelker received summer intern support from Pfizer and the AMCP Foundation during the time of this study. The remaining authors have nothing to disclose. All authors contributed to study concept and design and to the revision of the manuscript. Bellows, Olsen, and Voelker collected the data, assisted by Wander; data interpretation was performed primarily by Bellows, along with Olsen and Voelker and assisted by Wander. The manuscript was primarily written by Bellows, along with the other authors. PMID- 27459652 TI - Impact of the 2013 Cholesterol Guideline on Patterns of Lipid-Lowering Treatment in Patients with Atherosclerotic Cardiovascular Disease or Diabetes After 1 Year. AB - BACKGROUND: The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults emphasizes evidence-based treatment with moderate- to high-dose statins for patients at high risk for atherosclerotic cardiovascular disease (ASCVD). Whether this new guideline influenced patterns of treatment 1 year after its dissemination is unknown. OBJECTIVE: To compare patterns of lipid-lowering treatment before and 1 year after the release of the 2013 cholesterol guideline in 2 high-risk groups: patients with ASCVD and patients with diabetes mellitus. METHODS: Using pharmacy and medical claims from a large U.S. health insurance organization, 610,535 patients with ASCVD (n = 301,440) or diabetes mellitus (n = 309,095) were identified, and statin treatment rates and statin intensity were examined before and 1 year after the dissemination of the 2013 cholesterol guideline. A standardized difference of at least 10% was required to declare the effect size meaningful. RESULTS: Overall, there was no change in statin treatment rates for patients with ASCVD (48.0% before guideline vs. 47.3% after, standardized difference 1.4%) or diabetes (50% vs. 51.5% after, standardized difference 2.4%). Statin initiation rates among patients not on statins before the 2013 guideline were 10.1% in patients with ASCVD and 14.3% in patients with diabetes, but these gains were offset by 13.0% and 12.2% statin discontinuation rates among ASCVD and diabetes patients, respectively. Among patients taking statins 1 year after the guideline was issued, 80% of patients with ASCVD and aged <= 75 years were not on guideline-recommended high-intensity statin therapy, whereas most patients with ASCVD and aged > 75 years or patients with diabetes were on moderate- or high intensity statin treatment. CONCLUSIONS: One year after dissemination of the 2013 cholesterol guideline, overall treatment rates with statins among patients with ASCVD and diabetes did not change appreciably, and many patients remained either untreated or undertreated. DISCLOSURES: No outside funding supported this research. Chan is supported by grants from the National Heart Lung and Blood Institute (1R01HL123980 and K23HL102224). Tran, Stockl, Lew, and Solow are employed by Optum. Kao and Caglar were employed by Optum when this study was conducted. Chan serves as an advisor and consultant to OptumRx but received no compensation for work on this manuscript. Stockl is also employed by the Journal of Managed Care & Specialty Pharmacy. Spertus reports personal fees from United Healthcare and grants from Lilly, outside of the submitted work. None of the authors have any other financial conflicts of interest to report. Tran and Chan supervised this study, had full access to all of the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. Study design and concept were contributed by Tran and Chan. Tran and Kao collected the data, with analysis and interpretation performed by all the authors. Statistical analysis was performed by Caglar and Kao, and Tran and Chan drafted the manuscript. All authors were involved in the critical revision of the manuscript. PMID- 27459653 TI - Health Outcomes of Population-Based Pharmacy Outreach to Increase Statin Use for Prevention of Cardiovascular Disease in Patients with Diabetes. AB - BACKGROUND: In 2003, Group Health implemented a pharmacy-based, systemwide outreach effort to increase the preventive use of statins and angiotensin converting enzyme inhibitors in enrollees at risk for cardiovascular disease, including all enrollees with diabetes. OBJECTIVE: To estimate the associations between the use of statins and major vascular events and the total costs in 2006 2010 for enrollees with diabetes, using a pharmacy-based, systemwide outreach. METHODS: In a 14-year (1997-2010) longitudinal cohort study design, the study population consisted of 6,975 Group Health enrollees with type 1 or type 2 diabetes, who were enrolled continuously and had no statin use before the Group Health outreach in 1997-2002. Health outcomes were all-cause mortality, cardiovascular mortality, myocardial infarction, and stroke. Statin exposure was measured by cumulative statin use since 2003, weighted by the effect of the statin type and dose on the lowering of low-density lipoprotein levels. Regression models estimated associations between cumulative statin use, health outcomes, and total costs in 2006-2010. RESULTS: Among enrollees with no statin use before outreach began in 2003, about half had no or low exposure to statins by the end of 2005. In 2006-2010, cumulative statin use was greater among enrollees with risk factors for cardiovascular disease. Greater statin use was related to lower cardiovascular deaths and incidence of stroke and myocardial infarction, greater but nonsignificant all-cause mortality, and unrelated to total costs. CONCLUSIONS: Population-based pharmacy outreach increased statin use for eligible enrollees with diabetes, which was related to better cardiovascular outcomes. Generally, statin use was unrelated to all-cause mortality and total costs. DISCLOSURES: This study was funded by Grant No. R21 HS019501 from the Agency for Healthcare Research and Quality (AHRQ) and was conducted as part of the AHRQ announcement Optimizing Prevention and Healthcare Management for the Complex Patient (R21; RFA-HS-10-009). Ralston and Anderson are employees of Group Health and the Group Health Research Institute, which provided the data for this study. Study concept and design were contributed by Grembowski, Ralston, and Anderson. Anderson assisted with data collection and analysis, and data interpretation was performed by Anderson, along with Grembowski and Ralston. The manuscript was prepared by Grembowski, along with Ralston and Anderson. PMID- 27459654 TI - Biosimilar Naming Conventions: Pharmacist Perceptions and Impact on Confidence in Dispensing Biologics. AB - BACKGROUND: The approval of the first biosimilar in the United States has placed increased pressure on the FDA to provide guidance on the naming convention that will be assigned to current and future biosimilars. The release of the FDA draft guidance on nonproprietary naming of biosimilars in August 2015 established a naming convention for all biologic products, including biosimilars. However, the draft guidance is nonbinding while the FDA continues to receive input from stakeholders, and it does not address the naming convention that will be used for products designated as interchangeable biologics. OBJECTIVES: To (a) determine pharmacist perceptions of biosimilar naming conventions and their impact on confidence to dispense biosimilars and (b) measure the burden that is created by laws and regulations requiring pharmacists to complete postdispense notifications. METHODS: A cross-sectional survey of 781 members of the Academy of Managed Care Pharmacy and the Hematology/Oncology Pharmacy Association was conducted using an online survey software program. RESULTS: Participants reported preferring a biosimilar naming convention that uses a nonproprietary base with a designated suffix (48.1%), compared with the use of a nonproprietary base alone (26.3%), nonproprietary base plus a prefix (14.2%), or a unique brand name (11.4%). However, when participants were asked to report their confidence levels when dispensing a biosimilar in place of the reference biologic, more participants reported high levels of confidence when the products shared the same nonproprietary name (62.9%). A majority of participants (64.9%) reported perceptions of increased burden when required to provide a postdispense notification to prescribers when dispensing biosimilars. CONCLUSIONS: According to the survey used in this study, pharmacists prefer the use of a naming convention for biosimilars that includes a nonproprietary proper name with a designated suffix; however, levels of confidence in substituting a biosimilar for the reference biologic are highest when products share the same nonproprietary name. In addition, the results of this study suggest that the naming convention and postdispense notification requirements may affect the willingness of some pharmacists to dispense interchangeable biologics. This effect will be minimized if interchangeable biologics share the same nonproprietary name as the reference biologics. DISCLOSURES: Funding for this study was provided by the Academy of Managed Care Pharmacy. The author reports no conflicts of interest. Tomaszewski was responsible for all aspects of project and manuscript development. PMID- 27459655 TI - Biologics, Pharmacovigilance, and Patient Safety: It's All in the Name. AB - The most appropriate naming convention for biologics and biosimilars has been an area of significant debate. The ultimate decision will have an impact on patient safety, pharmacovigilance program effectiveness, and, potentially, the overall adoption of biosimilars in the United States. This article reviews some of the advantages and disadvantages of various naming approaches. For clarity in communication, optimal pharmacovigilance, and patient safety, it is recommended that biosimilars be named with a common USAN (United States Adopted Name) with the reference product, along with a suffix that is memorable, such as one associated with the original manufacturer of the product. This approach supports the FDA's mission of protecting patient safety and public health, while minimizing the possibility of inadvertent switching of products and facilitating effective pharmacovigilance. DISCLOSURES: No funding supported the writing of this article. Stevenson reports consulting fees from Amgen, Inc., AbbVie, and Pfizer and is employed by Visante. Green is employed by and owns stock in Amgen, Inc. Article concept was contributed primarily by Stevenson, along with Green. The manuscript was written and revised primarily by Stevenson, along with Green. Both authors contributed equally to data interpretation. PMID- 27459656 TI - The Risk of Pneumonia in Older Adults Using Nonbenzodiazepine Hypnotics. AB - BACKGROUND: Previous studies have shown an increased risk of pneumonia with benzodiazepines (BZD) and an increased risk of any infection with non-BZD hypnotics, but no analysis has specifically investigated the risk of pneumonia with non-BZD hypnotic use. OBJECTIVE: To evaluate the risk of pneumonia associated with non-BZD hypnotic use in the elderly. METHODS: This was a retrospective case-control study of members aged 65 years and older enrolled in an integrated health care system. Cases were identified as patients aged 65 years and older with a diagnosis of pneumonia from January 2011 to December 2012. Controls were matched in a 4:1 ratio to cases based on age, gender, and active enrollment. Non-BZD hypnotic exposure was evaluated for all cases and controls 1 year before the index date. Proximity of exposure to index date and duration of use were analyzed. Conditional logistic regression adjusted for covariates was performed. RESULTS: We identified 51,029 cases with pneumonia and matched 188,391 controls without pneumonia. Of the cases with pneumonia, 5.5% (2,790) of cases had exposure to a non-BZD hypnotic, compared with 3.4% (6,345) of controls. Non BZD hypnotic exposure was associated with an increased risk of pneumonia (OR = 1.14; 95% CI = 1.08-1.20). When exposure was stratified by proximity to index date, only current exposure was associated with an increased risk of pneumonia (OR = 1.27; 95% CI = 1.18-1.36). Short-term exposure was associated with a relatively higher risk of pneumonia (OR = 1.57; 95% CI = 1.39-1.77) compared with long-term use (OR = 1.16; 95% CI = 1.06-1.25). CONCLUSIONS: Current use of non BZD hypnotics in older adults is associated with an increased risk of pneumonia. The findings of this study provide additional support for reducing the use of non BZD hypnotics in older adults and for pursuing safer alternatives for treating insomnia. DISCLOSURES: No outside funding supported this study. At the time of this study, Jung was a PGY2 resident in drug information at Kaiser Permanente Drug Information Services. All authors are employed by Kaiser Permanente and report no other potential financial conflicts of interest. Study concept and design were contributed by Jung, Spence, Lee, and Gibbs. Jung, Spence, and Hui were responsible for data collection, and data interpretation was performed by Jung and Spence, with assistance from Escasa, Lee, and Hui. The manuscript was primarily written by Jung, along with Spence and Escasa, and revised by Spence, Escasa, and Lee, along with the other authors. PMID- 27459657 TI - Clopidogrel-Proton Pump Inhibitor Drug-Drug Interaction and Risk of Adverse Clinical Outcomes Among PCI-Treated ACS Patients: A Meta-analysis. AB - BACKGROUND: Uncertainty regarding clopidogrel effectiveness attenuation because of a drug-drug interaction with proton pump inhibitors (PPI) has led to conflicting guidelines on concomitant therapy. In particular, the effect of this interaction in patients who undergo a percutaneous coronary intervention (PCI), a population known to have increased risk of adverse cardiovascular events, has not been systematically evaluated. OBJECTIVE: To synthesize the evidence of the effect of clopidogrel-PPI drug interaction on adverse cardiovascular outcomes in a PCI patient population. METHODS: We conducted a systematic literature review for studies reporting clinical outcomes in patients who underwent a PCI and were initiated on clopidogrel with or without a PPI. Studies were included in the analysis if they reported at least 1 of the clinical outcomes of interest (major adverse cardiovascular event [MACE], cardiovascular death, all-cause death, myocardial infarction, stroke, stent thrombosis, and bleed events). We excluded studies that were not exclusive to PCI patients or had no PCI subgroup analysis and/or did not report at least a 6-month follow-up. Statistical and clinical heterogeneity were evaluated and HRs and 95% CIs for adverse clinical events were pooled using the DerSimonian and Laird random-effects meta-analysis method. RESULTS: We identified 12 studies comprising 50,277 PCI patients that met our inclusion and exclusion criteria. Our analysis included retrospective analyses of randomized controlled trials (2), health registries (3), claims databases (2), and institutional records (5); no prospective studies of PCI patients were identified. On average, patients were in their mid-60s, male, and had an array of comorbidities, including hyperlipidemia, diabetes, hypertension, and smoking history. Concomitant therapy following PCI resulted in statistically significant increases in composite MACE (HR = 1.28; 95% CI = 1.24-1.32), myocardial infarction (HR = 1.51; 95% CI = 1.40-1.62), and stroke (HR = 1.46; 95% CI = 1.15 1.86). However, concomitant therapy had no statistically significant effect on stent thrombosis, mortality measured by all-cause or cardiovascular death, or major bleeding before or after the grouping of studies that reported a major or minor bleed outcome. Only 1 study reported on gastrointestinal bleed, and pooled analysis could not be conducted. Statistical testing suggested heterogeneity among studies, but subgroup analysis did not reveal a clear source. CONCLUSIONS: Based on the results from this meta-analysis of retrospective analyses of randomized controlled trials and observational studies, concomitant clopidogrel PPI therapy following PCI appears to be significantly associated with adverse cardiovascular events. Further research on the effect of individual PPIs is needed. DISCLOSURES: Serbin, Guzauskas, and Veenstra were supported by the NIH Common Fund and NIA (1U01AG047109-01, Veenstra, PI) via the Personalized Medicine Economics Research (PriMER) project. The authors do not report any conflicting interests. All authors contributed to the study concept and design. Serbin took the lead in data collection; data interpretation was performed primarily by Serbin, with assistance from the other authors. The manuscript was written primarily by Serbin, along with Guzauskas, and revised by Guzauskas and Veenstra, with assistance from Serbin. PMID- 27459658 TI - Factors Influencing the Use of Second-Generation Antipsychotics in Children with Psychosis. AB - BACKGROUND: In 2011, the U.S. Department of Health and Human Services sent a letter to state Medicaid directors explaining the need for oversight of psychiatric prescriptions for children with mental health disorders. The National Committee for Quality Alliance proposed 3 quality measures for rating managed care organizations (MCOs) that involve use of second-generation or atypical antipsychotics in children. In order to ensure appropriate use and to effectively manage the use of second-generation antipsychotics in children, MCOs need to better understand the factors that influence medication treatment decisions for children. OBJECTIVES: To (a) determine how patient-level and physician-level factors influence decisions to prescribe second-generation antipsychotics to children (aged under 18 years) diagnosed with psychosis and (b) evaluate how the influence of these factors may differ between primary care providers and psychiatrists. METHODS: This study employed a cross-sectional survey of 193 primary care providers and psychiatrists. A web-based patient simulation survey using a fractional factorial design was administered via a commercial vendor. Respondents were presented with simulated patient profiles described by various levels of factors considered to be essential to decision making. Respondents were asked to make treatment recommendations for each profile evaluated. In addition to treatment recommendations, demographics and beliefs about products were measured. Modified Poisson regression accounting for multilevel data was used to identify the factors that significantly affect treatment recommendations. RESULTS: Psychiatrists were more likely to recommend second-generation antipsychotics than primary care practitioners (unadjusted RR = 1.36, 95% CI = 1.23-1.51). Social factors such as foster status or parental concern were not found to be significant predictors of prescribing second-generation antipsychotics. The percentage of a provider's patients using second-generation antipsychotics (RR = 1.002, 95% CI = 1.0002-1.003), patient age (aged 4 years: RR = 0.75, 95% CI = 0.68-0.84; aged 10 years: RR = 0.94, 95% CI = 0.91-0.99; reference group: aged 15 years), and patient disease severity (severe: RR = 1.11, 95% CI = 1.04-1.18; moderate: RR = 1.10, 95% CI = 1.05-1.17; reference group: mild) significantly predicted prescription behavior among primary care providers and psychiatrists. Primary care providers were about twice as likely to recommend antipsychotics if they believed the use of antipsychotics was a labeled indication (RR = 2.16, 95% CI = 1.56-2.98) or a medically accepted use (RR = 1.88, 95% CI = 1.33-2.67), when compared with physicians who believed there was no evidence available. This effect was not significant among psychiatrists. Primary care providers, but not psychiatrists, were also significantly influenced by patient white blood cell (WBC) count. Patients with healthy WBC counts were 1.11 times as likely (95% CI = 1.05-1.17) to receive antipsychotics from primary care providers compared with those with low WBC count. Patient body mass index (BMI) was not found to significantly influence prescribing behavior. Nearly 50% of patients did not receive recommendations for psychosocial care. Primary care providers recommended antipsychotic polypharmacy in 23% of the patient profiles, while psychiatrists did so in 42% of the profiles. CONCLUSIONS: This study provides valuable insight into physician-prescribing practices for antipsychotics. The lack of significance of foster status and parental concern, after controlling for other factors, shows that physicians base their decisions on clinical factors more than social factors. Results for patient BMI and frequency of recommendations of polypharmacy are concerning. The general lack of awareness of evidence supporting use of antipsychotics is also highly concerning. The effects of patient BMI, beliefs about evidence supporting use, and prescribing practices with regard to psychosocial care and antipsychotic polypharmacy provide actionable results for managed care programs looking to improve their quality metrics. The results of this study further demonstrate the need for the immediate implementation of the various proposed quality metrics in this area and for new practice guidelines to raise the current standard of care. DISCLOSURES: No outside funding supported this research. Bentley reports the receipt of grants from PQA and the NACDS Foundation. Patel is employed by Medical Marketing Economics. The authors report no other conflicting interests, potential or otherwise. Study concept and design were contributed by Ramachandran, Banahan, West-Strum, and Bentley. Ramachandran, Banahan, and Patel collected data; data interpretation was performed primarily by Ramachandran, Banahan, and Patel, along with Bentley and West-Strum. The manuscript was primarily written by Ramachandran, along with Banahan and Bentley, and revised by Banahan, Bentley, West-Strum, and Patel. PMID- 27459659 TI - Nephrotoxic Medication Exposure in U.S. Adults with Predialysis Chronic Kidney Disease: Health Services Utilization and Cost Outcomes. AB - BACKGROUND: Nephrotoxic medication exposure increases risks for acute kidney injury, permanent renal function loss, and costly preventable adverse drug events. Exposure to medications associated with inducing acute tubular nephritis or tubular toxicity versus nonexposure among those with predialysis renal disease a population vulnerable to increased risk of kidney injury-may affect health services utilization and cost outcomes. Few studies quantify nephrotoxic medication exposure in chronic kidney disease (CKD) and associated costs. OBJECTIVE: To examine exposure to medications associated with inducing acute tubular nephritis or tubular toxicity versus nonexposure and the effect on health services utilization and cost outcomes in a nationally representative sample of adults with predialysis CKD. METHODS: This retrospective study used Medical Expenditure Panel Survey (MEPS) household component longitudinal files (years 2006-2012; panels 11-16). Participants included 809 MEPS respondents aged > 18 years with predialysis CKD, after excluding those participants with cancer, kidney stone, renal dialysis, or transplant procedures (approximately 14.7 million U.S. noninstitutionalized individuals). Two groups were created to evaluate the main measures: (1) participants prescribed 1 or more medications associated with risk of acute tubular nephritis and/or tubular toxicity (termed "nephrotoxic exposure") and (2) participants with nonexposure. Medications cited in published literature as associated with tubular kidney damage were used. Multivariable regression models assessed the pattern of nephrotoxic medication exposure and its effect on health services utilization and expenses. RESULTS: Nephrotoxic medication exposure occurred in 72% of adult MEPS respondents. Of those, 47.2% and 52.8% were prescribed 1 and at least 2 nephrotoxic medications, respectively. Coexistent chronic conditions included hypertension (72.3%), diabetes (49.5%), coronary heart disease (33%), arthritis (23.6%), and chronic obstructive pulmonary disease (17.6%). Eligible MEPS respondents aged >= 65 years, from the U.S. South region, and with Charlson Comorbidity Index (CCI) score > 0 were 75% (vs. aged 18-45 years), 83% (vs. Northeast), and 72%-96% (vs. CCI = 0) more likely to be exposed to nephrotoxic medications. Uninsured participants showed 55% less likelihood of nephrotoxic exposure, compared with privately insured participants. Higher utilization was shown in the nephrotoxic medication exposure group (vs. nonexposure): prescription fills (52.8 vs. 26.8, P < 0.001), emergency department visits (56.2 vs. 29.3 per 1,000 patient months, P < 0.001), and hospitalization (51.8 vs. 23.4 per 1,000 patient months, P < 0.001). Unadjusted all-cause expenses were greater for the following categories: medical ($119,935 vs. $11,462, P < 0.001), prescription drug ($4,828 vs. $2,816, P < 0.001), and total health expenses ($24,663 vs. $14,277, P < 0.001). Adjusted all-cause expenses were greater for total (29.7% greater, P = 0.003), prescription medications (56.6% greater, P < 0.001), and medical (23.4% greater, P = 0.036), but there were no differences in predialysis CKD-related utilization and expenses. CONCLUSIONS: Increased vigilance is needed when prescribing nephrotoxic medications in predialysis CKD, particularly in patients with comorbid conditions and the elderly. Nephrotoxic medication exposure in predialysis CKD has the potential for increased health services utilization and cost outcomes. DISCLOSURES: There was no grant or intramural funding for this research. The authors have no conflicts of interest, financial or otherwise, to disclose. Study concept and design were primarily contributed by Davis-Ajami, along with Fink and Wu. Davis-Ajami took the lead in data collection, along with Wu, and data interpretation was performed by David-Ajami, Wu, and Fink. All authors participated in manuscript preparation and revision. PMID- 27459660 TI - Factors Associated with Adherence to Adjuvant Endocrine Therapy Among Privately Insured and Newly Diagnosed Breast Cancer Patients: A Quantile Regression Analysis. AB - BACKGROUND: Adherence to adjuvant endocrine therapy (AET) for estrogen receptor positive breast cancer remains suboptimal, which suggests that women are not getting the full benefit of the treatment to reduce breast cancer recurrence and mortality. The majority of studies on adherence to AET focus on identifying factors among those women at the highest levels of adherence and provide little insight on factors that influence medication use across the distribution of adherence. OBJECTIVE: To understand how factors influence adherence among women across low and high levels of adherence. METHODS: A retrospective evaluation was conducted using the Truven Health MarketScan Commercial Claims and Encounters Database from 2007-2011. Privately insured women aged 18-64 years who were recently diagnosed and treated for breast cancer and who initiated AET within 12 months of primary treatment were assessed. Adherence was measured as the proportion of days covered (PDC) over a 12-month period. Simultaneous multivariable quantile regression was used to assess the association between treatment and demographic factors, use of mail order pharmacies, medication switching, and out-of-pocket costs and adherence. The effect of each variable was examined at the 40th, 60th, 80th, and 95th quantiles. RESULTS: Among the 6,863 women in the cohort, mail order pharmacies had the greatest influence on adherence at the 40th quantile, associated with a 29.6% (95% CI = 22.2-37.0) higher PDC compared with retail pharmacies. Out-of-pocket cost for a 30-day supply of AET greater than $20 was associated with an 8.6% (95% CI = 2.8-14.4) lower PDC versus $0-$9.99. The main factors that influenced adherence at the 95th quantile were mail order pharmacies, associated with a 4.4% higher PDC (95% CI = 3.8-5.0) versus retail pharmacies, and switching AET medication 2 or more times, associated with a 5.6% lower PDC versus not switching (95% CI = 2.3-9.0). CONCLUSIONS: Factors associated with adherence differed across quantiles. Addressing the use of mail order pharmacies and out-of-pocket costs for AET may have the greatest influence on improving adherence among those women with low adherence. DISCLOSURES: This research was supported by a Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellowship grant from the National Cancer Institute (grant number F31 CA174338), which was awarded to Farias. Additionally, Farias was funded by a Postdoctoral Fellowship at the University of Texas School of Public Health Cancer Education and Career Development Program through the National Cancer Institute (NIH Grant R25 CA57712). The other authors declare no conflicts of interest. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Farias was primarily responsible for the study concept and design, along with Hansen and Zeliadt and with assistance from the other authors. Farias, Hansen, and Zeliadt took the lead in data interpretation, assisted by the other authors. The manuscript was written by Farias, along with Thompson and assisted by the other authors, and was revised by Ornelas, Li, and Farias, with assistance from the other authors. PMID- 27459661 TI - Real-World Treatment Patterns and Costs for Patients with Renal Cell Carcinoma Initiating Treatment with Sunitinib and Pazopanib. AB - BACKGROUND: Sunitinib and pazopanib are among the most prescribed targeted therapies for the systemic management of advanced renal cell carcinoma (RCC), but published cost comparisons between the 2 agents are few and limited by methodological and population differences. Also, sunitinib is administered on a 4 week on/2-week off cycle, and pazopanib is taken continuously. Thus, appropriate use and cost comparisons between the 2 drugs require methodological approaches to account for these differences. One way to accomplish this is to substitute expected for observed days supply. Recognizing the effects of nonrepresentative days supply values is important for assessing real-world treatment patterns and costs. OBJECTIVES: To (a) characterize demographic and clinical characteristics among patients with RCC newly initiating sunitinib or pazopanib, using a large administrative claims dataset; (b) characterize treatment patterns, persistence, and costs for each treatment group; and (c) assess the effect on treatment patterns and costs for sunitinib by substituting 42 days for prescriptions with 28- or 30-day supplies to account for sunitinib's 4-week on/2-week off dosing schedule. METHODS: This was a retrospective cohort study using health care claims data from the Truven MarketScan Research Databases, which include enrollment information and medical and pharmacy claims. Baseline patient demographic and clinical characteristics and treatment patterns (continuation, discontinuation, switching, or interruption; days supply; and persistence) were compared. Health care costs were calculated as mean daily index medication costs and as total, medical, and medication (all-cause and RCC-related) costs over the 12 months post index period. Inclusion criteria were continuous health plan enrollment between 6 months pre-index and 12 months post-index; no RCC medications 6 months pre-index; >= 2 RCC diagnoses within +/-180 days of index; and age >= 20 years. For demographic and clinical characteristics, treatment patterns, and costs, means (+/- standard deviations) for continuous data and relative frequencies for categorical data were reported. Chi-square tests or Student t-tests were used to evaluate differences other than costs. A generalized linear model with gamma distribution and log link was used for evaluating costs, controlling for patient demographic and pre-index clinical characteristics, persistence days, and index medication. All statistical tests were 2-tailed with significance set at P < 0.05 for all comparisons except for interactions with significance set at P < 0.10. The effects of substituting 42 days supply for sunitinib prescription records with 28 or 30 days supply were determined. RESULTS: In total, 609 (15.1% of the sunitinib overall sample) sunitinib patients and 183 (8.3% of the pazopanib overall sample) pazopanib patients were included. Demographic and clinical characteristics were similar for each treatment cohort. The persistence periods and number of prescriptions filled were also similar. Without substitution, significant differences were observed between treatment groups in patterns of index medication use (overall P = 0.0409), with fewer patients taking sunitinib continuing treatment than patients taking pazopanib. However, with substitution, treatment patterns differed significantly (overall P = 0.0026), but with more sunitinib patients than pazopanib patients continuing treatment. Without substitution, unadjusted daily mean index medication costs were significantly different for sunitinib ($216) versus pazopanib ($177, P < 0.0001). Substitution of sunitinib days supply eliminated the significant differences in daily index medication costs between treatment groups. The 1-year RCC-related and all-cause medication, medical, and total unadjusted costs were not significantly different between treatment groups, and substitution had no effect on these costs. After adjustment for possible confounding factors, these cost results were similar to those found with unadjusted analyses. CONCLUSIONS: In this study, patients with RCC who were initiating sunitinib and pazopanib had similar demographic and clinical characteristics and drug persistence patterns. The effect of substituting days supply values was demonstrated as an approach to considering differences in dosing cycles. Substitution significantly reduced sunitinib mean daily index medication costs and eliminated or reversed the direction of significant differences in costs between drugs during the persistence period. No significant differences were observed in unadjusted or adjusted 1-year costs. DISCLOSURES: This study was funded and conducted fully by Pfizer. All authors are employees of Pfizer. This work was presented in part as posters at the 2015 Genitourinary Cancers Symposium, of the American Society of Clinical Oncology; Rosen Shingle Creek, Orlando, FL; February 26-28, 2015, and the 20th Annual International Meeting of the International Society for Pharmacoeconomics and Outcomes Research; Philadelphia, PA; May 16-20, 2015. All authors contributed to study concept and design and to data interpretation. Mardekian was primarily responsible for data collection, along with Harnett. MacLean and Harnett worked on the manuscript, which was revised by MacLean and Mardekian. PMID- 27459662 TI - Estimating the Economic Impact of Adding Panobinostat to a U.S. Formulary for Relapsed and/or Refractory Multiple Myeloma: A Budget Impact and Cost-Benefit Model. AB - BACKGROUND: Multiple myeloma is an incurable B-cell malignancy with a natural history that involves alternating periods of remission and subsequent relapse. For relapsed and/or refractory multiple myeloma (RRMM), the typical patient currently receives more lines of therapy than has been feasible in the past, translating into longer progression-free survival (PFS). Consequently, cost issues have become more prominent because patients may be offered newer and more expensive therapies during a more prolonged overall treatment course. OBJECTIVE: To estimate the economic impact of adding panobinostat to a U.S. health plan formulary as a treatment option with bortezomib and dexamethasone for patients with RRMM previously treated with a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), using a budget impact and cost-benefit model. METHODS: Total costs of commonly used salvage therapy regimens were combined with market share data and population prevalence estimates of RRMM to yield the total cost of treatment, from the perspective of a U.S. third-party payer (commercial or Medicare) with a time horizon of 1 year. Comparator treatment regimens included bortezomib-dexamethasone, lenalidomide-dexamethasone, lenalidomide bortezomib-dexamethasone, carfilzomib monotherapy, carfilzomib-lenalidomide dexamethasone, and pomalidomide-dexamethasone. Costs (2015 U.S. dollars) included drug costs for oral oncology agents, medical and administration costs for injectable oncology agents, costs of adverse event (AE) prophylaxis and monitoring, and costs of grade 3/4 AEs. RESULTS: In a hypothetical health plan with 1 million members, the annual number of RRMM patients with previous PI and IMiD treatments was estimated at 16 and 118 for a commercial and Medicare plan, respectively. Introduction of panobinostat as part of the panobinostat-bortezomib dexamethasone regimen was not expected to result in a substantial budget impact to either commercial or Medicare plans, with an incremental cost < $0.01 per member per month. Panobinostat-bortezomib-dexamethasone had a low cost per treated patient per month without progression, owing to the minimal increase in expenditure over existing bortezomib-based regimens and long median PFS, compared with median duration of treatment. CONCLUSIONS: Adding panobinostat to a plan formulary as a treatment option is expected to be cost neutral (and potentially cost saving in the context of new and more expensive treatment regimens). With a low cost per month without progression, panobinostat-bortezomib-dexamethasone represents good value for the money. DISCLOSURES: Funding for this study was sponsored by Novartis, East Hanover, New Jersey. Bloudek and Kish are employees of Xcenda, a consulting company contracted by Novartis to conduct this analysis. Roy, Globe, and Kuriakose are employees of Novartis. Siegel is on the advisory boards and speaker's bureau of Celgene, Onyx/Amgen, Millennium/Takeda, and Novartis and is on the advisory boards of Merck. Jagannath is a consultant to Sanofi, Bristol-Meyers Squibb, and Celgene. Orloski is a contractor to Xcenda and provided medical writing support, which was funded by Novartis. Study design and concept were contributed by Bloudek, Roy, and Kish, assisted by Globe. Bloukek took the lead in data collection, along with Kish, and data interpretation was performed by Siegal, Jagannath, Globe, and Kuriakose. The manuscript was written primarily by Orloski, along with Roy and Kish, and revised by Roy, along with Siegal, Jagannath, Globe, Orloski, and Kuriakose. PMID- 27459663 TI - Cost-Effectiveness of Double Reading versus Single Reading of Mammograms in a Breast Cancer Screening Programme. AB - OBJECTIVES: The usual practice in breast cancer screening programmes for mammogram interpretation is to perform double reading. However, little is known about its cost-effectiveness in the context of digital mammography. Our purpose was to evaluate the cost-effectiveness of double reading versus single reading of digital mammograms in a population-based breast cancer screening programme. METHODS: Data from 28,636 screened women was used to establish a decision-tree model and to compare three strategies: 1) double reading; 2) double reading for women in their first participation and single reading for women in their subsequent participations; and 3) single reading. We calculated the incremental cost-effectiveness ratio (ICER), which was defined as the expected cost per one additionally detected cancer. We performed a deterministic sensitivity analysis to test the robustness of the ICER. RESULTS: The detection rate of double reading (5.170/00) was similar to that of single reading (4.780/00; P = .768). The mean cost of each detected cancer was ?8,912 for double reading and ?8,287 for single reading. The ICER of double reading versus single reading was ?16,684. The sensitivity analysis showed variations in the ICER according to the sensitivity of reading strategies. The strategy that combines double reading in first participation with single reading in subsequent participations was ruled out due to extended dominance. CONCLUSIONS: From our results, double reading appears not to be a cost-effective strategy in the context of digital mammography. Double reading would eventually be challenged in screening programmes, as single reading might entail important net savings without significantly changing the cancer detection rate. These results are not conclusive and should be confirmed in prospective studies that investigate long-term outcomes like quality adjusted life years (QALYs). PMID- 27459664 TI - Retinal Ganglion Cell and Inner Plexiform Layer Loss Correlate with Visual Acuity Loss in LHON: A Longitudinal, Segmentation OCT Analysis. AB - PURPOSE: Describe changes in the retina as vision loss progresses in Leber's Hereditary Optic Neuropathy (LHON) using spectral-domain optical coherence tomography (SD-OCT) autosegmentation, and determine if relationship exists between retinal changes and vision loss. METHODS: From patient records we identified nine LHON patients who underwent periodic neuro-ophthalmologic examinations and high-resolution SD-OCT as part of their care. We describe the impact of LHON progression on each retinal layer, and the relationship between these structural changes and visual acuity using generalized estimating equations and nonparametric tests. RESULTS: The thickness of the ganglion cell layer (GCL) and inner plexiform layer (IPL) decreased immediately or soon after symptom onset, and this decrease was associated with worsening vision: in the GCL a 1-mm3 volume loss was associated with a 3.2 increase in logMAR visual acuity (95% confidence interval [CI]: 2.1-4.1); in the IPL a 1-mm3 volume loss was associated with a 4.9 increase in visual acuity (95%CI: 6.5-3.2). The retinal nerve fiber layer (RNFL) also thinned, but not until after the GCL and IPL, and only in the papillomacular bundle (PMB) and temporal layers was thinning associated with vision loss. CONCLUSIONS: For the first time these analyses describe a structure function relationship between the retinal changes that occur in LHON patients as their disease progresses and vision worsens. The structural changes in the GCL, IPL, and RNFL preceded structural changes in the other retinal layers. This analysis suggests that the first 6 months after diagnosis define a target for therapeutic intervention, and this can inform treatment guidelines for ongoing therapeutic trials. PMID- 27459665 TI - Assessment of Optic Pathway Structure and Function in Patients With Compression of the Optic Chiasm: A Correlation With Optical Coherence Tomography. AB - PURPOSE: The purpose of this study was to investigate correlations between retinal fiber thickness measured by optical coherence tomography (OCT) and anterograde functional and structural differences in the optic pathway of patients with compression of the optic chiasm. Our hypothesis was that loss of visual acuity caused by chronic compressive pathologies may lead to an irreversible decline in vision because of permanent neurodegeneration of the optic radiations and visual cortex. METHODS: Quantitative OCT, functional magnetic resonance imaging (MRI) and diffusion tensor MRI measurements were made in 17 patients being surgically treated for chiasmal compression. RESULTS: In our study we found that surgically irreversible visual field defects and reduced retinal nerve fiber layer thickness were significantly associated with lower fractional diffusion anisotropy and higher diffusivities in optic radiations and less functional MRI activation in the visual cortex. CONCLUSIONS: Damage to the retinal nerve fiber layer is associated with downstream structural and functional degradation of the optic pathway. This may be related to trans-synaptic degeneration and the fact that these factors are important potential imaging biomarkers for predicting visual recovery after surgical decompression. PMID- 27459666 TI - Erratum. PMID- 27459668 TI - Construction and characterization of a full-length cDNA infectious clone of emerging porcine Senecavirus A. AB - A full-length cDNA infectious clone, pKS15-01-Clone, was constructed from an emerging Senecavirus A (SVA; strain KS15-01). To explore the potential use as a viral backbone for expressing marker genes, the enhanced green fluorescent protein (EGFP)-tagged reporter virus (vKS15-01-EGFP) was generated using reverse genetics. Compared to the parental virus, the pKS15-01-Clone derived virus (vKS15 01-Clone) replicated efficiently in vitro and in vivo, and induced similar levels of neutralizing antibody and cytokine responses in infected animals. In contrast, the vKS15-01-EGFP virus showed impaired growth ability and induced lower level of immune response in infected animals. Lesions on the dorsal snout and coronary bands were observed in all pigs infected by parental virus KS15-01, but not in pigs infected with vKS15-01-Clone or vKS15-01-EGFP viruses. These results demonstrated that the infectious clone and EGFP reporter virus could be used as important tools in further elucidating the SVA pathogenesis and development of control measures. PMID- 27459669 TI - Review article: Effectiveness of ultra-brief interventions in the emergency department to reduce alcohol consumption: A systematic review. AB - To assess the effectiveness of ultra-brief interventions (ultra-BI) or technology involved preventive measures in the ED to reduce alcohol harm and risky drinking. Medline, Embase, PsycINFO, CINAHL and EBM reviews were searched for articles published between 1996 and 2015. Randomised controlled trials and quasi randomised trials, which compared an ultra-BI with screening, standard care or minimal intervention for adults and adolescents at risk for alcohol-related harm presenting to an ED, were included. Outcomes of interest were frequency of alcohol consumption, quantity of alcohol consumed, binge drinking and ED representation. Thirteen studies (nine single centre and four multicentre) were included. Six studies showed a significant reduction in the quantity consumed with intermediate effect size at 3 months (d = -0.40) and small effect size at 12 months (d = -0.15). Two studies showed a significant reduction in binge drinking with small effect size at 3 months (d = -0.12) and 12 months (d = -0.09). No studies showed an effect on frequency of alcohol consumption or ED representation. Heterogeneity in study design, definition of risky, harmful or hazardous alcohol use, intervention types, outcomes, outcome timeframes and outcome measures prevented the performance of quantitative meta-analysis. Despite its limited effectiveness in reducing alcohol use in the short-term, with the large number of people attending EDs with risky drinking, the use of an effective ultra-BI would have the potential to have a measurable population effect. PMID- 27459670 TI - The Effects of Heteroatoms Si and S on Tuning the Optical Properties of Rhodamine and Fluorescein-Based Fluorescence Probes: A Theoretical Analysis. AB - The effects of the incorporated heteroatoms Si and S on tuning the optical properties of rhodamine- and fluorescein-based fluorescence probes is investigated using DFT and time-dependent DFT with four different functionals. As previously proposed, the large redshift (90 nm) produced by a Si atom in both the absorption and emission spectra can be attributed to the sigma*-pi* conjugation between the sigma* orbital of the Si atom and the pi* orbital of the adjacent carbon atoms. However, the presence of a Si atom does not alter the fluorescence quenching mechanism of the nonfluorescent forms of the investigated compounds. For the first time, these theoretical results indicate that the n orbital of the S atom plays an important role in determining the optical properties of the nonfluorescent form of rhodamine-based fluorescence probes. It alters the fluorescence quenching mechanism by lowering the energy of the dark npi* state, which is due to breakage of the C10-S52 bond upon photoexcitation. PMID- 27459672 TI - Tissue phantom-based breast cancer detection using continuous near-infrared sensor. AB - Women's health is seriously threatened by breast cancer. Taking advantage of efficient diagnostic instruments to identify the disease is very meaningful in prolonging life. As a cheap noninvasive radiation-free technology, Near-infrared Spectroscopy is suitable for general breast cancer examination. A discrimination method of breast cancer is presented using the deference between absorption coefficients and applied to construct a blood oxygen detection device based on Modified Lambert-Beer theory. Combined with multi-wavelength multi-path near infrared sensing technology, the proposed method can quantitatively distinguish the normal breast from the abnormal one by measuring the absorption coefficients of breast tissue and the blood oxygen saturation. An objective judgment about the breast tumor is made according to its high absorption of near-infrared light. The phantom experiment is implemented to show the presented method is able to recognize the absorption differences between phantoms and demonstrates its feasibility in the breast tumor detection. PMID- 27459671 TI - Tau Protein Mediates APP Intracellular Domain (AICD)-Induced Alzheimer's-Like Pathological Features in Mice. AB - Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (Abeta) and APP Intracellular Domain (AICD) peptides. Abeta plays a pivotal role in Alzheimer's disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner. Since AD is a tauopathy and tau has been shown to mediate Abeta-induced toxicity, we examined the role of tau in AICD induced pathological features. We report that ablating endogenous tau protects AICD-Tg mice from deficits in adult neurogenesis, seizure severity, short-term memory deficits and neurodegeneration. Deletion of tau restored abnormal phosphorylation of NMDA receptors, which is likely to underlie hyperexcitability and associated excitotoxicity in AICD-Tg mice. Conversely, overexpression of wild type human tau aggravated receptor phosphorylation, impaired adult neurogenesis, memory deficits and neurodegeneration. Our findings show that tau is essential for mediating the deleterious effects of AICD. Since tau also mediates Abeta induced toxic effects, our findings suggest that tau is a common downstream factor in both amyloid-dependent and-independent pathogenic mechanisms and therefore could be a more effective drug target for therapeutic intervention in AD. PMID- 27459673 TI - Four Weeks of Classical Altitude Training Increases Resting Metabolic Rate in Highly Trained Middle-Distance Runners. AB - High altitude exposure can increase resting metabolic rate (RMR) and induce weight loss in obese populations, but there is a lack of research regarding RMR in athletes at moderate elevations common to endurance training camps. The present study aimed to determine whether 4 weeks of classical altitude training affects RMR in middle-distance runners. Ten highly trained athletes were recruited for 4 weeks of endurance training undertaking identical programs at either 2200m in Flagstaff, Arizona (ALT, n = 5) or 600m in Canberra, Australia (CON, n = 5). RMR, anthropometry, energy intake, and hemoglobin mass (Hbmass) were assessed pre- and posttraining. Weekly run distance during the training block was: ALT 96.8 +/- 18.3km; CON 103.1 +/- 5.6km. A significant interaction for Time*Group was observed for absolute (kJ.day-1) (F-statistic, p-value: F(1,8)=13.890, p = .01) and relative RMR (F(1,8)=653.453, p = .003) POST training. No significant changes in anthropometry were observed in either group. Energy intake was unchanged (mean +/- SD of difference, ALT: 195 +/- 3921kJ, p = .25; CON: 836 +/- 7535kJ, p = .75). A significant main effect for time was demonstrated for total Hbmass (g) (F(1,8)=13.380, p = .01), but no significant interactions were observed for either variable [Total Hbmass (g): F(1,8)=1.706, p = .23; Relative Hbmass (g.kg-1): F(1,8)=0.609, p = .46]. These novel findings have important practical application to endurance athletes routinely training at moderate altitude, and those seeking to optimize energy management without compromising training adaptation. Altitude exposure may increase RMR and enhance training adaptation,. During training camps at moderate altitude, an increased energy intake is likely required to support an increased RMR and provide sufficient energy for training and performance. PMID- 27459675 TI - From the ADAA President. PMID- 27459674 TI - The relationship between levels of resilience and coping styles in chiropractic students and perceived levels of stress and well-being. AB - OBJECTIVE: The aim of this study was to explore the relationship between chiropractic students' coping styles and levels of resilience with their physical injuries, perceived levels of stress, and well-being. METHODS: A questionnaire was distributed to the entire student body of the chiropractic program at Murdoch University, and gathered demographic variables and responses to the Connor Davidson Resilience Scale, Perceived Levels of Stress Scale, Everyday Feelings Questionnaire, and Coping Inventory for Stressful Situations. Linear regression analysis was used to calculate for significant relationships. RESULTS: Of 244 students, 194 (81%) completed the surveys. Being female and not having recovered from an injury within 12 months was significantly associated with lower levels of well-being and higher levels of stress. Being female, possessing an increased use of an emotional-based coping style, and having lower levels of well-being were associated with higher levels of stress (R2 = 0.65, F(6,164) = 50.47, p < .001). Lower levels of well-being were associated with being female, higher perceived levels of stress, lower levels of resilience, and an increased use emotional coping styles (R2 = 0.64, F[6,164] = 49.5, p < .001). CONCLUSION: It is possible to identify chiropractic students at the university who are at risk of experiencing low levels of well-being and high levels of stress. These students may benefit from interventions aimed at enhancing their coping style choices and increasing their resilience levels. Future studies are recommended to see if these findings are consistent across chiropractic programs nationally and internationally. PMID- 27459676 TI - WHITHER KETAMINE AS AN ANTIDEPRESSANT: PANACEA OR TOXIN? PMID- 27459677 TI - The p-wave superconductivity in the presence of Rashba interaction in 2DEG. AB - We investigate the effect of the Rashba interaction on two dimensional superconductivity. The presence of the Rashba interaction lifts the spin degeneracy and gives rise to the spectrum of two bands. There are intraband and interband pairs scattering which result in the coupled gap equations. We find that there are isotropic and anisotropic components in the gap function. The latter has the form of cos phik where . The former is suppressed because the intraband and the interband scatterings nearly cancel each other. Hence, -the system should exhibit the p-wave superconductivity. We perform a detailed study of electron-phonon interaction for 2DEG and find that, if only normal processes are considered, the effective coupling strength constant of this new superconductivity is about one-half of the s-wave case in the ordinary 2DEG because of the angular average of the additional in the anisotropic gap function. By taking into account of Umklapp processes, we find they are the major contribution in the electron-phonon coupling in superconductivity and enhance the transition temperature Tc. PMID- 27459678 TI - The formate bio-economy. AB - In this review we discuss the concept of the formate bio-economy: formate can be produced efficiently from various available resources and can be consumed by microbes as the sole carbon source for the production of value-added chemicals, directly addressing major challenges in energy storage and chemical production. We show that the formate assimilation pathways utilized by natural formatotrophs are either inefficient or are constrained to organisms that are difficult to cultivate and engineer. Instead, adapting model industrial organisms to formatotrophic growth using synthetic, specially tailored formate-assimilation routes could prove an advantageous strategy. Several studies have started to tackle this challenge, but a fully active synthetic pathway has yet to be established, leaving room for future undertakings. PMID- 27459679 TI - Potential of Agarose/Silk Fibroin Blended Hydrogel for in Vitro Cartilage Tissue Engineering. AB - An osteoarthritis pandemic has accelerated exploration of various biomaterials for cartilage reconstruction with a special emphasis on silk fibroin from mulberry (Bombyx mori) and non-mulberry (Antheraea assamensis) silk worms. Retention of positive attributes of the agarose standard and nullification of its negatives are central to the current agarose/silk fibroin hydrogel design. In this study, hydrogels of mulberry and non-mulberry silk fibroin blended with agarose were fabricated and evaluated in vitro for two weeks for cartilaginous tissue formation. The fabricated hydrogels were physicochemically characterized and analyzed for cell viability, proliferation, and extra cellular matrix deposition. The amalgamation of silk fibroin with agarose impacted the pore size, as illustrated by field emission scanning electron microscopy studies, swelling behavior, and in vitro degradation of the hydrogels. Fourier transform infrared spectroscopy results indicated the blend formation and confirmed the presence of both components in the fabricated hydrogels. Rheological studies demonstrated enhanced elasticity of blended hydrogels with G' > G". Biochemical analysis revealed significantly higher levels of sulfated glycosaminoglycans (sGAGs) and collagen (p <= 0.01) in blended hydrogels. More specifically, the non-mulberry silk fibroin blend showed sGAG and collagen content (~1.5-fold) higher than that of the mulberry blend (p <= 0.05). Histological and immunohistochemical analyses further validated the enhanced deposition of sGAG and collagen, indicating maintenance of chondrogenic phenotype within constructs after two weeks of culture. Real-time PCR analysis further confirmed up-regulation of cartilage specific aggrecan, sox-9 (~1.5-fold) and collagen type II (~2-fold) marker genes (p <= 0.01) in blended hydrogels. The hydrogels demonstrated immunocompatibility, which was evidenced by minimal in vitro secretion of tumor necrosis factor-alpha (TNF-alpha) by murine macrophages. Taken together, the results suggest promising attributes of blended hydrogels and particularly the non-mulberry silk fibroin/agarose blends as alternative biomaterial for cartilage tissue engineering. PMID- 27459680 TI - Hexokinase 2; Tangled between sphingolipid and sugar metabolism. PMID- 27459681 TI - The antimicrobial agents triclocarban and triclosan as potent modulators of reproduction in Potamopyrgus antipodarum (Mollusca: Hydrobiidae). AB - In this study, we assessed the chronic effects of the two antimicrobial substances triclocarban (TCC) and triclosan (TCS) on reproduction of a mollusk species by using the reproduction test with the New Zealand mudsnail Potamopyrgus antipodarum. Snails coming from a laboratory culture were exposed for 28 days to nominal concentrations ranging from 0.1 up to 10 ug/L for both chemicals (measured 0.082-8.85 ug TCC/L; 0.068-6.26 ug TCS/L). At the end of the experiment, snails were dissected and embryos in the brood pouch were counted to assess the individualized reproductive success of adult snails. Exposure to TCC resulted in an inverted u-shaped concentration-response relationship, with a stimulation of reproduction at low concentrations followed by an inhibition at higher concentrations. The no observed effect concentration (NOEC) and the lowest observed effect concentration (LOEC) were 0.082 and 0.287 ug/L, respectively. TCS caused significantly increased embryo numbers at all tested concentrations, except in the group of 0.170 ug/L. Therefore, the NOEC for TCS was 0.170 ug/L and the LOEC was 0.660 ug/L. These results indicate that TCC and TCS may cause reproductive effects at environmentally relevant concentrations indicating a potential risk for aquatic organisms in the environment. PMID- 27459682 TI - Effects of end products on fermentation profiles in Clostridium carboxidivorans P7 for syngas fermentation. AB - Clostridium carboxidivorans P7 is a strict anaerobic bacterium capable of converting syngas to biofuels. However, its fermentation profiles is poorly understood. Here, various end-products, including acetic acid, butyric acid, hexanoic acid, ethanol and butanol were supplemented to evaluate their effects on fermentation profiles in C. carboxidivorans at two temperatures. At 37 degrees C, fatty acids addition likely led to more corresponding alcohols production. At 25 degrees C, C2 and C4 fatty acids supplementation resulted in more corresponding higher fatty acids, while supplemented hexanoic acid increased yields of C2 and C4 fatty acids and hexanol. Supplementation of ethanol or butanol caused increased production of C2 and C4 acids at both temperatures; however, long-chain alcohols were still more likely produced at lower temperature. In conclusion, fermentation profiles of C. carboxidivorans can be changed in respond to pre added end-products and carbon flow may be redirected to desired products by controlling culture conditions. PMID- 27459683 TI - Performance and microbial community of simultaneous anammox and denitrification (SAD) process in a sequencing batch reactor. AB - A sequencing batch reactor (SBR) was used to test the simultaneous anammox and denitrification process. Optimal nitrogen removal was achieved with chemical oxygen demand (COD) of 150mg/L, during which almost all of ammonia, nitrite and nitrate could be removed. Organic matter was a key factor to regulate the synergy of anammox and denitrification. Both experimental DeltaNO2(-)-N/DeltaNH4(+)-N and DeltaNO3(-)-N/DeltaNH4(+)-N values deviated from their theoretical values with increasing COD. Denitrifying bacteria exhibited good diversity and abundance, but the diversity of anammox bacteria was less abundant. Brocadia sinica was able to grow in the presence of organic matter and tolerate high nitrite concentration. Anammox bacteria were predominant at low COD contents, while denitrifying bacteria dominated the microbial community at high COD contents. Anammox and denitrifying bacteria could coexist in one reactor to achieve the simultaneous carbon and nitrogen removal through the synergy of anammox and denitrification. PMID- 27459685 TI - The B(C6F5)3-Catalyzed Tandem Meinwald Rearrangement-Reductive Amination. AB - A system of three coupled catalytic cycles enabling the one-pot transformation of epoxides to amines via Meinwald rearrangement, imine condensation, and imine reduction is described. This assisted tandem catalysis is catalyzed by B(C6F5)3 resulting in the first tandem Meinwald rearrangement-reductive amination protocol. The reaction proceeds in nondried solvents and yields beta functionalized amines. In particular, beta-diarylamines are obtained in high yields. PMID- 27459684 TI - Determination of the intrinsic reactivities for carbon dioxide gasification of rice husk chars through using random pore model. AB - Rice husk is abundantly available and environmentally friendly, and char-CO2 gasification is of great importance for the biomass gasification process. The intrinsic reaction rates of carbon dioxide gasification with rice husk chars derived from different pyrolysis temperatures were investigated in this study by conducting thermogravimetric analysis (TGA) measurements. The effects of gasification temperature and reactant partial pressure on the char-CO2 gasification were investigated and the random pore model (RPM) was used to determine the intrinsic kinetic parameters based on the experimental data. The results obtained from this study show that the activation energy, reaction order and pre-exponential factor varied in the ranges of 226.65-232.28kJ/mol, 0.288 0.346 and 2.38*10(5)-2.82*10(5)1/sPa(n) for the rice husk chars pyrolyzed at 700 900 degrees C, respectively. All the determination coefficients between the RPM predictions and experimental results were higher than 0.906, indicating the RPM is reliable for determining and evaluating the intrinsic reactivities of rice husk chars. PMID- 27459686 TI - Pharmacokinetic/pharmacodynamic properties and efficacy/safety of U-500R from randomized clinical studies. PMID- 27459687 TI - Immunophenotypic and Ultrastructural Analysis of Mast Cells in Hermansky-Pudlak Syndrome Type-1: A Possible Connection to Pulmonary Fibrosis. AB - Hermansky-Pudlak Syndrome type-1 (HPS-1) is an autosomal recessive disorder caused by mutations in HPS1 which result in reduced expression of the HPS-1 protein, defective lysosome-related organelle (LRO) transport and absence of platelet delta granules. Patients with HPS-1 exhibit oculocutaneous albinism, colitis, bleeding and pulmonary fibrosis postulated to result from a dysregulated immune response. The effect of the HPS1 mutation on human mast cells (HuMCs) is unknown. Since HuMC granules classify as LROs along with platelet granules and melanosomes, we set out to determine if HPS-1 cutaneous and CD34+ culture-derived HuMCs have distinct granular and cellular characteristics. Cutaneous and cultured CD34+-derived HuMCs from HPS-1 patients were compared with normal cutaneous and control HuMCs, respectively, for any morphological and functional differences. One cytokine-independent HPS-1 culture was expanded, cloned, designated the HP proMastocyte (HPM) cell line and characterized. HPS-1 and idiopathic pulmonary fibrosis (IPF) alveolar interstitium showed numerous HuMCs; HPS-1 dermal mast cells exhibited abnormal granules when compared to healthy controls. HPS-1 HuMCs showed increased CD63, CD203c and reduced mediator release following FcERI aggregation when compared with normal HuMCs. HPM cells also had the duplication defect, expressed FcERI and intracytoplasmic proteases and exhibited less mediator release following FcERI aggregation. HPM cells constitutively released IL-6, which was elevated in patients' serum, in addition to IL-8, fibronectin-1 (FN-1) and galectin-3 (LGALS3). Transduction with HPS1 rescued the abnormal HPM morphology, cytokine and matrix secretion. Microarray analysis of HPS-1 HuMCs and non-transduced HPM cells confirmed upregulation of differentially expressed genes involved in fibrogenesis and degranulation. Cultured HPS-1 HuMCs appear activated as evidenced by surface activation marker expression, a decrease in mediator content and impaired releasibility. The near-normalization of constitutive cytokine and matrix release following rescue by HPS1 transduction of HPM cells suggests that HPS-1 HuMCs may contribute to pulmonary fibrosis and constitute a target for therapeutic intervention. PMID- 27459688 TI - Reliability of MR-Based Volumetric 3-D Analysis of Pelvic Muscles among Subjects with Low Back with Leg Pain and Healthy Volunteers. AB - AIM: Lately, the diagnostic value of magnetic resonance imaging, Lasegue sign and classic neurological signs have been considered not accurate enough to distinguish the radicular from non-radicular low back with leg pain (LBLP) and a calculation of the symptomatic side muscle volume has been indicated as a probable valuable marker. However, only the multifidus muscle volume has been calculated so far. The main objective of the study was to verify whether LBLP subjects presented symptomatic side pelvic muscle atrophy compared to healthy volunteers. The second aim was to assess the inter-rater reliability of 3-D manual method for segmenting and measuring the volume of the gluteus maximus, gluteus medius, gluteus minimus and piriformis muscles in both LBLP patients and healthy subjects. METHOD: Two independent raters analyzed MR images of LBLP and healthy subjects towards muscle volume of four pelvic muscles, i.e. the piriformis, gluteus minimus, gluteus medius and gluteus maximus. For both sides, the MR images of the muscles without adipose tissue infiltration were manually segmented in 3-D medical images. RESULTS: Symptomatic muscle atrophy was confirmed in only over 50% of LBLP subjects (gluteus maximus (p<0.001), gluteus minimus (p<0.01) and piriformis (p<0.05)). The ICC values indicated that the inter-rater reproducibility was greater than 0.90 for all measurements (LBLP and healthy subjects), except for the measurement of the right gluteus medius muscle in LBLP patients, which was equal to 0.848. CONCLUSION: More than 50% of LBLP subjects presented symptomatic gluteus maximus, gluteus minimus and piriformis muscle atrophy. 3-D manual segmentation reliably measured muscle volume in all the measured pelvic muscles in both healthy and LBLP subjects. To answer the question of what kind of muscle atrophy is indicative of radicular or non radicular pain further studies are required. PMID- 27459689 TI - Significance of Epicardial and Intrathoracic Adipose Tissue Volume among Type 1 Diabetes Patients in the DCCT/EDIC: A Pilot Study. AB - INTRODUCTION: Type 1 diabetes (T1DM) patients are at increased risk of coronary artery disease (CAD). This pilot study sought to evaluate the relationship between epicardial adipose tissue (EAT) and intra-thoracic adipose tissue (IAT) volumes and cardio-metabolic risk factors in T1DM. METHOD: EAT/IAT volumes in 100 patients, underwent non-contrast cardiac computed tomography in the Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study were measured by a certified reader. Fat was defined as pixels' density of -30 to -190 Hounsfield Unit. The associations were assessed using-Pearson partial correlation and linear regression models adjusted for gender and age with inverse probability sample weighting. RESULTS: The weighted mean age was 43 years (range 32-57) and 53% were male. Adjusted for gender, Pearson correlation analysis showed a significant correlation between age and EAT/IAT volumes (both p<0.001). After adjusting for gender and age, participants with greater BMI, higher waist to hip ratio (WTH), higher weighted HbA1c, elevated triglyceride level, and a history of albumin excretion rate of equal or greater than 300 mg/d (AER>=300) or end stage renal disease (ESRD) had significantly larger EAT/IAT volumes. CONCLUSION: T1DM patients with greater BMI, WTH ratio, weighted HbA1c level, triglyceride level and AER>=300/ESRD had significantly larger EAT/IAT volumes. Larger sample size studies are recommended to evaluate independency. PMID- 27459690 TI - Photocatalytic Carbon Dioxide Reduction at p-Type Copper(I) Iodide. AB - A p-type semiconductor, CuI, has been synthesized, characterized, and tested as a photocatalyst for CO2 reduction under UV/Vis irradiation in presence of isopropanol as a hole scavenger. Formation of CO, CH4 , and/or HCOOH was observed. The photocatalytic activity of CuI was attributed to the very low potential of the conduction band edge (i.e., -2.28 V vs. NHE). Photocurrents generated by the studied material confirm a high efficiency of the photoinduced interfacial electrontransfer processes. Our studies show that p-type semiconductors may be effective photocatalysts for CO2 reduction, even better than extensively studied n-type titanium dioxide, owing to the low potential of the conduction band edge. PMID- 27459691 TI - Exposure reduces negative bias in self-rated performance in public speaking fearful participants. AB - BACKGROUND AND OBJECTIVES: Individuals with public speaking anxiety (PSA) under rate their performance compared to objective observers. The present study examined whether exposure reduces the discrepancy between self and observer performance ratings and improved observer-rated performance in individuals with PSA. METHODS: PSA participants gave a speech in front of a small audience and rated their performance using a questionnaire before and after completing repeated exposures to public speaking. Non-anxious control participants gave a speech and completed the questionnaire one time only. Objective observers watched videos of the speeches and rated performance using the same questionnaire. RESULTS: PSA participants underrated their performance to a greater degree than did controls prior to exposure, but also performed significantly more poorly than did controls when rated objectively. Bias significantly decreased and objective rated performance significantly increased following completion of exposure in PSA participants, and on one performance measure, anxious participants no longer showed a greater discrepancy between self and observer performance ratings compared to controls. LIMITATIONS: The study employed non-clinical student sample, but the results should be replicated in clinical anxiety samples. CONCLUSIONS: These findings indicate that exposure alone significantly reduces negative performance bias among PSA individuals, but additional exposure or additional interventions may be necessary to fully correct bias and performance deficits. PMID- 27459692 TI - The impact of appraisals on intrusive memories. AB - BACKGROUND AND OBJECTIVES: Intrusive memories are a core feature of posttraumatic stress disorder (PTSD). Cognitive models posit that PTSD symptoms are stimulated by maladaptive appraisals about symptoms. This study aimed to test the causal pathway of maladaptive appraisals about the meaning of intrusions on subsequent intrusive memories. METHODS: Forty-five healthy participants were presented with a traumatic film, and were subsequently told either (a) intrusions are indicative of poor psychological functioning, (b) intrusions are not indicative of psychological functioning, or (c) no instructions. Participants subsequently completed a measure of cognitive performance to index potential interference by intrusions, as well as a scale of intrusive memories. RESULTS: Participants who were told that intrusions are indicative of negative psychological state subsequently reported more intrusive memories than those who were told that intrusions have no particular significance. LIMITATIONS: Inferences are reduced by lack of group differences in appraisals reported by participants. A stronger index of intrusions would have been achieved through diary keeping in the period after the experimental session. CONCLUSIONS: This finding provides initial causal evidence that appraising intrusions as maladaptive may directly enhance the occurrence of intrusions following encoding of an aversive event, and in this sense is supportive of cognitive models of PTSD. PMID- 27459693 TI - Response to 'Comments on 'The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study''. PMID- 27459694 TI - Comment on 'The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study'. PMID- 27459695 TI - Comment on 'The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study'. PMID- 27459696 TI - Metalloproteolytic receptor shedding...platelets "acting their age". AB - Whilst significant effort has been focused on development of tools and approaches to clinically modulate activation processes that consume platelets, the platelet receptors that initiate activation processes remain untargeted. The modulation of receptor levels is also linked to underlying platelet aging processes which influence normal platelet lifespan and also the functionality and survival of stored platelets that are used in transfusion. In this review, we will focus on platelet adhesion receptors initiating thrombus formation, and discuss how regulation of levels of these receptors impact platelet function and platelet survival. PMID- 27459697 TI - Deciphering Transcriptome and Complex Alternative Splicing Transcripts in Mammary Gland Tissues from Cows Naturally Infected with Staphylococcus aureus Mastitis. AB - Alternative splicing (AS) contributes to the complexity of the mammalian proteome and plays an important role in diseases, including infectious diseases. The differential AS patterns of these transcript sequences between the healthy (HS3A) and mastitic (HS8A) cows naturally infected by Staphylococcus aureus were compared to understand the molecular mechanisms underlying mastitis resistance and susceptibility. In this study, using the Illumina paired-end RNA sequencing method, 1352 differentially expressed genes (DEGs) with higher than twofold changes were found in the HS3A and HS8A mammary gland tissues. Gene ontology and KEGG pathway analyses revealed that the cytokine-cytokine receptor interaction pathway is the most significantly enriched pathway. Approximately 16k annotated unigenes were respectively identified in two libraries, based on the bovine Bos taurus UMD3.1 sequence assembly and search. A total of 52.62% and 51.24% annotated unigenes were alternatively spliced in term of exon skipping, intron retention, alternative 5' splicing and alternative 3' splicing. Additionally, 1,317 AS unigenes were HS3A-specific, whereas 1,093 AS unigenes were HS8A specific. Some immune-related genes, such as ITGB6, MYD88, ADA, ACKR1, and TNFRSF1B, and their potential relationships with mastitis were highlighted. From Chromosome 2, 4, 6, 7, 10, 13, 14, 17, and 20, 3.66% (HS3A) and 5.4% (HS8A) novel transcripts, which harbor known quantitative trait locus associated with clinical mastitis, were identified. Many DEGs in the healthy and mastitic mammary glands are involved in immune, defense, and inflammation responses. These DEGs, which exhibit diverse and specific splicing patterns and events, can endow dairy cattle with the potential complex genetic resistance against mastitis. PMID- 27459698 TI - HCV Health Policy Developments in Response to the National Viral Hepatitis Action Plan: A Brief Update. AB - Hepatitis C virus (HCV) kills 366,000 people worldwide and 17,000 people in the United States each year. In 2011, the U.S. Department of Health and Human Services (HHS) published a national viral hepatitis action plan to control and combat HCV in the United States. This article provides a brief update of HCV health policy developments that have emerged since publication of HHS's national viral hepatitis action plan and concludes with a discussion of the public health impact of these recent HCV health policy developments. PMID- 27459699 TI - Wood-Derived Materials for Green Electronics, Biological Devices, and Energy Applications. AB - With the arising of global climate change and resource shortage, in recent years, increased attention has been paid to environmentally friendly materials. Trees are sustainable and renewable materials, which give us shelter and oxygen and remove carbon dioxide from the atmosphere. Trees are a primary resource that human society depends upon every day, for example, homes, heating, furniture, and aircraft. Wood from trees gives us paper, cardboard, and medical supplies, thus impacting our homes, school, work, and play. All of the above-mentioned applications have been well developed over the past thousands of years. However, trees and wood have much more to offer us as advanced materials, impacting emerging high-tech fields, such as bioengineering, flexible electronics, and clean energy. Wood naturally has a hierarchical structure, composed of well oriented microfibers and tracheids for water, ion, and oxygen transportation during metabolism. At higher magnification, the walls of fiber cells have an interesting morphology-a distinctly mesoporous structure. Moreover, the walls of fiber cells are composed of thousands of fibers (or macrofibrils) oriented in a similar angle. Nanofibrils and nanocrystals can be further liberated from macrofibrils by mechanical, chemical, and enzymatic methods. The obtained nanocellulose has unique optical, mechanical, and barrier properties and is an excellent candidate for chemical modification and reconfiguration. Wood is naturally a composite material, comprised of cellulose, hemicellulose, and lignin. Wood is sustainable, earth abundant, strong, biodegradable, biocompatible, and chemically accessible for modification; more importantly, multiscale natural fibers from wood have unique optical properties applicable to different kinds of optoelectronics and photonic devices. Today, the materials derived from wood are ready to be explored for applications in new technology areas, such as electronics, biomedical devices, and energy. The goal of this study is to review the fundamental structures and chemistries of wood and wood derived materials, which are essential for a wide range of existing and new enabling technologies. The scope of the review covers multiscale materials and assemblies of cellulose, hemicellulose, and lignin as well as other biomaterials derived from wood, in regard to their major emerging applications. Structure properties-application relationships will be investigated in detail. Understanding the fundamental properties of these structures is crucial for designing and manufacturing products for emerging applications. Today, a more holistic understanding of the interplay between the structure, chemistry, and performance of wood and wood-derived materials is advancing historical applications of these materials. This new level of understanding also enables a myriad of new and exciting applications, which motivate this review. There are excellent reviews already on the classical topic of woody materials, and some recent reviews also cover new understanding of these materials as well as potential applications. This review will focus on the uniqueness of woody materials for three critical applications: green electronics, biological devices, and energy storage and bioenergy. PMID- 27459700 TI - Transplantation of Endothelial Cells to Mitigate Acute and Chronic Radiation Injury to Vital Organs. AB - Current therapeutic approaches for treatment of exposure to radiation involve the use of antioxidants, chelating agents, recombinant growth factors and transplantation of stem cells (e.g., hematopoietic stem cell transplantation). However, exposure to high-dose radiation is associated with severe damage to the vasculature of vital organs, often leading to impaired healing, tissue necrosis, thrombosis and defective regeneration caused by aberrant fibrosis. It is very unlikely that infusion of protective chemicals will reverse severe damage to the vascular endothelial cells (ECs). The role of irradiated vasculature in mediating acute and chronic radiation syndromes has not been fully appreciated or well studied. New approaches are necessary to replace and reconstitute ECs in organs that are irreversibly damaged by radiation. We have set forth the novel concept that ECs provide paracrine signals, also known as angiocrine signals, which not only promote healing of irradiated tissue but also direct organ regeneration without provoking fibrosis. We have developed innovative technologies that enable manufacturing and banking of human GMP-grade ECs. These ECs can be transplanted intravenously to home to and engraft to injured tissues where they augment organ repair, while preventing maladaptive fibrosis. In the past, therapeutic transplantation of ECs was not possible due to a shortage of availability of suitable donor cell sources and preclinical models, a lack of understanding of the immune privilege of ECs, and inadequate methodologies for expansion and banking of engraftable ECs. Recent advances made by our group as well as other laboratories have breached the most significant of these obstacles with the development of technologies to manufacture clinical-scale quantities of GMP-grade and human ECs in culture, including genetically diverse reprogrammed human amniotic cells into vascular ECs (rAC-VECs) or human pluripotent stem cells into vascular ECs (iVECs). This approach provides a path to therapeutic EC transplantation that can be infused concomitantly or sequentially with hematopoietic stem cell transplantation more than 24 h after irradiation to support multi-organ regeneration, thereby improving immediate and long-term survival, while limiting long-term morbidity resulting from nonregenerative damage repair pathways. PMID- 27459701 TI - A Review of Radiation-Induced Coagulopathy and New Findings to Support Potential Prevention Strategies and Treatments. AB - Results from our recent studies have led to the novel hypothesis that radiation induced coagulopathy (RIC) and associated hemorrhage occurring as part of the acute radiation syndrome (ARS) is a major cause of death resulting from radiation exposure in large mammals, including humans. This article contains information related to RIC, as well as potential strategies for the prevention and treatment of RIC. In addition, new findings are reported here on the occurrence of RIC biomarkers in humans exposed to radiation. To determine whether irradiated humans have RIC biomarkers, blood samples were obtained from radiotherapy patients who received treatment for different types of malignancies. Blood samples from allogeneic hematopoietic cell transplantation (allo-HCT) patients obtained before, during and after irradiation indicated that exposure led to prolonged clot formation times, increased levels of thrombin-antithrombin III (TAT) complex and increased circulating nucleosome/histone (cNH) levels, which suggest potential coagulopathies in the allo-HCT patients. Since these allo-HCT patients received chemotherapy prior to radiotherapy, it is possible that the chemical agents could have influenced the observed results. Frozen plasma samples from radiotherapy patients with prostate, lung and breast cancer were also obtained for analyses of cNH levels. The results indicated that some of these patients had very high cNH blood levels. Analysis of cNH levels in plasma samples from irradiated ferrets also indicated increased cNH levels compared to preirradiation baseline levels. The results from irradiated animals and some radiotherapy patients suggest the possibility that anti-histone antibodies, which block the toxic effects of elevated cNH levels in the blood, might be useful as therapeutic agents for adverse biological radiation-induced effects. The detection of increased levels of cNH in some radiotherapy patient blood samples demonstrates its potential as a biomarker for diagnosing and/or predicting the propensity for developing coagulopathies/hemorrhage, offering possible treatment options with personalized medicine therapies for cancer patients. PMID- 27459702 TI - Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model. AB - Intestinal radiation toxicity occurs during and after abdominopelvic radiotherapy. Endothelial cells play a significant role in modulating radiation induced intestinal damage. We demonstrated that the endothelial cell surface receptor thrombomodulin (TM), a protein with anticoagulant, anti-inflammatory and antioxidant properties, mitigates radiation-induced lethality in mice. The goal of this study was to determine whether recombinant TM (Solulin) can protect the intestine from toxicity in a clinically relevant rat model. A 4 cm loop of rat small bowel was exposed to fractionated 5 Gy X radiation for 9 consecutive days. The animals were randomly assigned to receive daily subcutaneous injections of vehicle or Solulin (3 mg/kg/day or 10 mg/kg/day) for 27 days starting 4 days before irradiation. Early intestinal injury was assessed two weeks after irradiation by quantitative histology, morphometry, immunohistochemistry and luminol bioluminescence imaging. Solulin treatment significantly ameliorated intestinal radiation injury, made evident by a decrease in myeloperoxidase (MPO) activity, transforming growth factor beta (TGF-beta) immunoreactivity, collagen-I deposition, radiation injury score (RIS) and intestinal serosal thickening. These findings indicate the need for further development of Solulin as a prophylactic and/or therapeutic agent to mitigate radiation-induced intestinal damage. PMID- 27459704 TI - Radiation-Induced Microvascular Injury as a Mechanism of Salivary Gland Hypofunction and Potential Target for Radioprotectors. AB - Radiation therapy is commonly used to treat patients with head and neck squamous cell carcinoma (HNSCC). One of the major side effects of radiotherapy is injury to the salivary glands (SG), which is thought to be mediated by microvascular dysfunction leading to permanent xerostomia. The goal of this study was to elucidate the mechanism of radiation-induced microvasculature damage and its impact on SG function. We measured bovine aortic endothelial cell (BAEC) apoptosis and ceramide production in response to 5 Gy irradiation, either alone or with reactive oxygen species (ROS) scavengers. We then investigated the effect of a single 15 Gy radiation dose on murine SG function. BAECs exposed to 5 Gy underwent apoptosis with increased ceramide production, both prevented by ROS scavengers. Among the 15 Gy irradiated mice, there was considerable weight loss, alopecia and SG hypofunction manifested by reduced saliva production and lower lysozyme levels. All of these effects, except for the lysozyme levels, were prevented by pretreatment with ROS scavengers. Microvessel density was significantly lower in the SG of irradiated mice compared to the control group, and this effect was significantly attenuated by pretreatment with Tempol. This study demonstrates that radiation-induced SG hypofunction is to a large extent mediated by microvascular dysfunction involving ceramide and ROS generation. These findings strongly suggest that ROS scavengers may serve as potential radioprotectors of SG function in patients undergoing radiotherapy for HNSCC. PMID- 27459706 TI - Through-the-scope enteral metal stent placement using a short-type single-balloon enteroscope for malignant surgically reconstructed jejunal stenosis (with video). PMID- 27459703 TI - Extracellular Vesicles and Vascular Injury: New Insights for Radiation Exposure. AB - This article reviews our current knowledge about cell-derived extracellular vesicles (EVs), including microparticles and exosomes, and their emergence as mediators of a new important mechanism of cell-to-cell communication. Particular emphasis has been given to the increasing involvement of EVs in the field of radiation-induced vascular injury. Although EVs have been considered for a long time as cell "dust", they in fact precisely reflect the physiological state of the cells. The role of microparticles and exosomes in mediating vascular dysfunction suggests that they may represent novel pathways in short- or long distance paracrine intercellular signaling in vascular environment. In this article, the mechanisms involved in the biogenesis of microparticles and exosomes, their composition and participation in the pathogenesis of vascular dysfunction are discussed. Furthermore, this article highlights the concept of EVs as potent vectors of biological information and protagonists of an intercellular communication network. Special emphasis is made on EV-mediated microRNA transfer and on the principal consequences of such signal exchange on vascular injury and radiation-induced nontargeted effect. The recent progress in elucidating the biology of EVs has provided new insights for the field of radiation, advancing their use as diagnostic biomarkers or in therapeutic interventions. PMID- 27459705 TI - Cardiometabolic Risk Factor Changes Observed in Diabetes Prevention Programs in US Settings: A Systematic Review and Meta-analysis. AB - BACKGROUND: The Diabetes Prevention Program (DPP) study showed that weight loss in high-risk adults lowered diabetes incidence and cardiovascular disease risk. No prior analyses have aggregated weight and cardiometabolic risk factor changes observed in studies implementing DPP interventions in nonresearch settings in the United States. METHODS AND FINDINGS: In this systematic review and meta-analysis, we pooled data from studies in the United States implementing DPP lifestyle modification programs (focused on modest [5%-7%] weight loss through >=150 min of moderate physical activity per week and restriction of fat intake) in clinical, community, and online settings. We reported aggregated pre- and post-intervention weight and cardiometabolic risk factor changes (fasting blood glucose [FBG], glycosylated hemoglobin [HbA1c], systolic or diastolic blood pressure [SBP/DBP], total [TC] or HDL-cholesterol). We searched the MEDLINE, EMBASE, Cochrane Library, and Clinicaltrials.gov databases from January 1, 2003, to May 1, 2016. Two reviewers independently evaluated article eligibility and extracted data on study designs, populations enrolled, intervention program characteristics (duration, number of core and maintenance sessions), and outcomes. We used a random effects model to calculate summary estimates for each outcome and associated 95% confidence intervals (CI). To examine sources of heterogeneity, results were stratified according to the presence of maintenance sessions, risk level of participants (prediabetes or other), and intervention delivery personnel (lay or professional). Forty-four studies that enrolled 8,995 participants met eligibility criteria. Participants had an average age of 50.8 years and body mass index (BMI) of 34.8 kg/m2, and 25.2% were male. On average, study follow-up was 9.3 mo (median 12.0) with a range of 1.5 to 36 months; programs offered a mean of 12.6 sessions, with mean participant attendance of 11.0 core sessions. Sixty percent of programs offered some form of post-core maintenance (either email or in person). Mean absolute changes observed were: weight -3.77 kg (95% CI: -4.55; 2.99), HbA1c -0.21% (-0.29; -0.13), FBG -2.40 mg/dL (-3.59; -1.21), SBP -4.29 mmHg (-5.73, -2.84), DBP -2.56 mmHg (-3.40, 1.71), HDL +0.85 mg/dL (-0.10, 1.60), and TC -5.34 mg/dL (-9.72, -0.97). Programs with a maintenance component achieved greater reductions in weight (additional -1.66kg) and FBG (additional -3.14 mg/dl). Findings are subject to incomplete reporting and heterogeneity of studies included, and confounding because most included studies used pre-post study designs. CONCLUSIONS: DPP lifestyle modification programs achieved clinically meaningful weight and cardiometabolic health improvements. Together, these data suggest that additional value is gained from these programs, reinforcing that they are likely very cost-effective. PMID- 27459708 TI - Monte Carlo Study of Degenerate Behavior of AB Diblock Copolymer/Nanoparticle under Cylindrical Confinement. AB - Degenerate behavior (i.e., forming different self-assembled structures for a given block copolymer (BCP) under the same confinement) commonly exists in various confined systems. Understanding degenerate behavior is crucial for precise control over the structures formed by self-assembly systems under confinement. In this study, the degenerate behavior of a self-assembled AB diblock copolymer/nanoparticle (NP) mixture in a cylindrical pore is studied using Monte Carlo simulation. We find that the degenerate behavior of such a mixture depends on the introduction of the NP. Under different pore sizes, four typical degenerate structures [i.e., single helices (S-helices), double helices (D-helices), parallel cylinders, and stacked toroids] can be obtained if the NP content is zero. However, when the NP content in the mixture is increased, it is found that the number of degenerate structures decreases, that is, only blocky structures can be obtained in the case of high NP content. Moreover, the probability of forming S-helices decreases, whereas the probability of forming D helices increases with increase in the NP content. Analysis of the interactive enthalpy densities and the chain conformation of the systems indicates that entropy plays an important role in the degenerate structure formation. This study provides some new insights into the degenerate behavior of a BCP/NP mixture under confinement, which can offer a theoretical reference for further experiments. PMID- 27459709 TI - Vaccination policies of Utah family practice clinics. AB - BACKGROUND AND PURPOSE: The purpose of this study was to collect information regarding healthcare worker (HCW) vaccination policies in Utah family practice clinics. METHODS: The study was conducted in Utah family practice clinics in the most densely populated counties in the state and was a cross-sectional descriptive design. Data were collected from 91 family practice clinic managers. Descriptive statistics were performed, as well as a content analysis for open ended items. CONCLUSIONS: HCWs are employed in environments where infectious diseases can be easily spread from person to person, thus, vaccinations can be instrumental in protecting the health of HCWs and patients alike. In Utah, 56.8% of family practice clinics had either no vaccination policy for HCWs or had a policy with no consequences for noncompliance. Utah family practice clinics need to implement changes to create and maintain HCW vaccination policies. IMPLICATIONS FOR PRACTICE: Nurse practitioners can be leaders and change agents by working with their county and state health departments to create state-wide policies that mirror the position statements from the American Nurses Association and the American Association of Nurse Practitioners. PMID- 27459707 TI - Telomere structure and maintenance gene variants and risk of five cancer types. AB - Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs <=3.08 * 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk. PMID- 27459710 TI - Natural Genetic Variation and Candidate Genes for Morphological Traits in Drosophila melanogaster. AB - Body size is a complex character associated to several fitness related traits that vary within and between species as a consequence of environmental and genetic factors. Latitudinal and altitudinal clines for different morphological traits have been described in several species of Drosophila and previous work identified genomic regions associated with such variation in D. melanogaster. However, the genetic factors that orchestrate morphological variation have been barely studied. Here, our main objective was to investigate genetic variation for different morphological traits associated to the second chromosome in natural populations of D. melanogaster along latitudinal and altitudinal gradients in Argentina. Our results revealed weak clinal signals and a strong population effect on morphological variation. Moreover, most pairwise comparisons between populations were significant. Our study also showed important within-population genetic variation, which must be associated to the second chromosome, as the lines are otherwise genetically identical. Next, we examined the contribution of different candidate genes to natural variation for these traits. We performed quantitative complementation tests using a battery of lines bearing mutated alleles at candidate genes located in the second chromosome and six second chromosome substitution lines derived from natural populations which exhibited divergent phenotypes. Results of complementation tests revealed that natural variation at all candidate genes studied, invected, Fasciclin 3, toucan, Reticulon-like1, jing and CG14478, affects the studied characters, suggesting that they are Quantitative Trait Genes for morphological traits. Finally, the phenotypic patterns observed suggest that different alleles of each gene might contribute to natural variation for morphological traits. However, non-additive effects cannot be ruled out, as wild-derived strains differ at myriads of second chromosome loci that may interact epistatically with mutant alleles. PMID- 27459711 TI - Proteomics and metabolomics in biomarker discovery for cardiovascular diseases: progress and potential. AB - INTRODUCTION: The process of discovering novel biomarkers and potential therapeutic targets may be shortened using proteomic and metabolomic approaches. AREAS COVERED: Several complementary strategies, each one presenting different advantages and limitations, may be used with these novel approaches. In vitro studies show how cells involved in cardiovascular disease react, although the phenotype of cultured cells differs to that occurring in vivo. Tissue analysis either in human specimens or animal models may show the proteins that are expressed in the pathological process, although the presence of structural proteins may be confounding. To identify circulating biomarkers, analyzing the secretome of cultured atherosclerotic tissue, analysis of blood cells and/or plasma may be more straightforward. However, in the latter approach, high abundant proteins may mask small molecules that could be potential biomarkers. The study of sub-proteomes such as high-density lipoproteins may be useful to circumvent this limitation. Regarding metabolomics, most studies have been performed in small populations, and we need to perform studies in large populations in order to discover robust biomarkers. Expert commentary: It is necessary to involve the clinicians in these areas to improve the design of clinical studies, including larger populations, in order to obtain consistent novel biomarkers. PMID- 27459712 TI - Response to Timo E. Strandberg. PMID- 27459713 TI - Gut Taste Stimulants Alter Brain Activity in Areas Related to Working Memory: a Pilot Study. AB - BACKGROUND/AIMS: Taste perception is one of the most important primary oral reinforcers, driving nutrient and energy intake as well as toxin avoidance. Taste receptors in the gastrointestinal tract might as well impact appetitive or aversive behavior and thus influence learning tasks and a close relation of neural taste processing and working memory networks seems plausible. METHODS: In the present pilot study, we determined the effects of five taste qualities "bitter" (quinine), "sweet" (glucose), "sour" (citric acid), "salty" (NaCl) and "umami" (monosodium glutamate, MSG) on working memory processing using functional MRI and their effect on plasma insulin and glucose levels. On six separate occasions, subjects received one of the following test substances dissolved in 200 mL tap water via a nasogastric tube (to circumvent the oral cavity): 1) 2g citric acid corresponding to 52 mM, 2) 2g NaCl; 171 mM, 3) 0.017g quinine; 0.26 mM, 4) 1g monosodium glutamate; 30 mM, 5) 25g glucose; 694 mM and 6) 200 mL tap water (placebo). RESULTS: The taste qualities "bitter" and "umami" significantly altered brain activation patterns in the primary gustatory cortex as well as in subcortical structures, previously reported to be involved in emotional learning and memory. In contrast, glucose did not reveal any statistically significant brain activation difference. Working memory performance was not different over the six treatments. Plasma insulin and glucose levels were not affected by the different taste substances (MSG, quinine, NaCl and citric acid). CONCLUSIONS: in this pilot trial, we demonstrate that acute intragastric administration of different taste substances does not affect working memory performance in humans. However, "umami" and "bitter" have effects on brain areas involved in neural working memory, overpowering the effects of "sweet", "salty" and "sour" reception. PMID- 27459714 TI - Training Standards Statements of Family Medicine Postgraduate Training - A Review of Existing Documents Worldwide. AB - INTRODUCTION: For the effective and safe management of complex care needs for patients in community settings, high quality family medicine (FM) training programmes are needed. In less primary care oriented countries, training standards statements for FM postgraduate training are less commonly found. The aim of this study was to review international training standards statements in FM postgraduate training and to catalogue these statements to be used as a best practice standard guide for FM training programs in Germany. MATERIALS AND METHODS: A structured three-tiered search was performed: a systematic literature search in MEDLINE(r); a search of international indicator databases; and a search in grey literature, consisting of a survey of international experts and a search in "Google (Scholar)". From all identified documents, training standards statements were extracted, translated and summarized into categories referring to the same quality aspect. RESULTS: The search strategy revealed 25 relevant documents (MEDLINE(r) n = 15, databases n = 2, experts n = 7, "Google" n = 1), containing 337 training standards statements. These were summarized into 80 statements. They covered structure quality (n = 35); process quality (n = 43); and two training standards statements referred to outcome quality (n = 2). CONCLUSION: A broad range of internationally sourced training standards statements for FM postgraduate training could be identified from countries with well-established primary care systems. Only few statements internationally referred to outcome quality, expressing the difficulty in assessing outcome. The resulting inventory of training standards statements for FM postgraduate training can serve as a resource for institutions seeking to formalise and systematise FM training at regional or national levels. PMID- 27459716 TI - Switching the Photochromic Activity of Acenaphthylene Derivatives through a Tandem Nucleophile-Promoted Addition Reaction. AB - New acenaphthylene-based dithienylethenes have been prepared. Surprisingly they did not show photochromism. However, they readily underwent a tandem addition of a nucleophile and an electrophile, leading to a small library of dearomatized colourless analogues, which, on the contrary, were endowed with photochromic activity. In the absence of the electrophile, the intermediate obtained by C attack readily aromatizes to give, surprisingly, a final product of direct aromatic nucleophilic substitution, which was not photochromically active. PMID- 27459715 TI - Corticostriatal and Dopaminergic Response to Beer Flavor with Both fMRI and [(11) C]raclopride Positron Emission Tomography. AB - BACKGROUND: Cue-evoked drug-seeking behavior likely depends on interactions between frontal activity and ventral striatal (VST) dopamine (DA) transmission. Using [(11) C]raclopride (RAC) positron emission tomography (PET), we previously demonstrated that beer flavor (absent intoxication) elicited VST DA release in beer drinkers, inferred by RAC displacement. Here, a subset of subjects from this previous RAC-PET study underwent a similar paradigm during functional magnetic resonance imaging (fMRI) to test how orbitofrontal cortex (OFC) and VST blood oxygenation level-dependent (BOLD) responses to beer flavor are related to VST DA release and motivation to drink. METHODS: Male beer drinkers (n = 28, age = 24 +/ 2, drinks/wk = 16 +/- 10) from our previous PET study participated in a similar fMRI paradigm wherein subjects tasted their most frequently consumed brand of beer and Gatorade((r)) (appetitive control). We tested for correlations between BOLD activation in fMRI and VST DA responses in PET, and drinking-related variables. RESULTS: Compared to Gatorade, beer flavor increased wanting and desire to drink, and induced BOLD responses in bilateral OFC and right VST. Wanting and desire to drink correlated with both right VST and medial OFC BOLD activation to beer flavor. Like the BOLD findings, beer flavor (relative to Gatorade) again induced right VST DA release in this fMRI subject subset, but there was no correlation between DA release and the magnitude of BOLD responses in frontal regions of interest. CONCLUSIONS: Both imaging modalities showed a right-lateralized VST response (BOLD and DA release) to a drug-paired conditioned stimulus, whereas fMRI BOLD responses in the VST and medial OFC also reflected wanting and desire to drink. The data suggest the possibility that responses to drug-paired cues may be rightward biased in the VST (at least in right-handed males) and that VST and OFC responses in this gustatory paradigm reflect stimulus wanting. PMID- 27459717 TI - Achieving NHAS 90/90/80 Objectives by 2020: An Interactive Tool Modeling Local HIV Prevalence Projections. AB - BACKGROUND: Tools using local HIV data to help jurisdictions estimate future demand for medical and support services are needed. We present an interactive prevalence projection model using data obtainable from jurisdictional HIV surveillance and publically available data. METHODS: Using viral load data from Georgia's enhanced HIV/AIDS Reporting System, state level death rates for people living with HIV and the general population, and published estimates for HIV transmission rates, we developed a model for projecting future HIV prevalence. Keeping death rates and HIV transmission rates for undiagnosed, in care/viral load >200, in care/viral load<200, and out of care (no viral load for 12 months) constant, we describe results from simulations with varying inputs projecting HIV incidence and prevalence from 2014 to 2024. RESULTS: In this model, maintaining Georgia's 2014 rates for diagnosis, transitions in care, viral suppression (VS), and mortality by sub-group through 2020, resulted in 85% diagnosed, 59% in care, and 44% VS among diagnosed (85%/58%/44%) with a total of 67 815 PLWH, 33 953 in care, and more than 1000 new cases per year by 2020. Neither doubling the diagnosis rate nor tripling rates of re-engaging out of care PLWH into care alone were adequate to reach 90/90/80 by 2020. We demonstrate a multicomponent scenario that achieved NHAS goals and resulted in 63 989 PLWH, 57 546 in care, and continued annual prevalence increase through 2024. CONCLUSIONS: Jurisdictions can use this HIV prevalence prediction tool, accessible at https://dph.georgia.gov/hiv-prevalence-projections to assess local capacity to meet future HIV care and social services needs. In this model, achieving 90/90/80 by 2020 in Georgia slowed but did not reverse increases in HIV prevalence, and the number of HIV-infected persons needing care and support services more than doubled. Improving the HIV care infrastructure is imperative. PMID- 27459719 TI - Acute Encephalopathy in Children Associated with Influenza A: A Retrospective Case Series. PMID- 27459718 TI - Subclinical Inflammation and Endothelial Dysfunction in Young Patients with Diabetes: A Study from United Arab Emirates. AB - BACKGROUND: The impact of obesity and dyslipidemia on cardiovascular health in adolescents and young adults with diabetes is incompletely understood. This study evaluated the effects of these co-morbidities on markers of inflammation and endothelial dysfunction in young patients with the disease. METHODS: The study investigated sets of inflammatory, endothelial, and adipocyte biomarkers in 79 patients with type 1 diabetes, 55 patients with type 2 diabetes, and 47 controls. RESULTS: Mean (+/-SD) age was 20+/-6 y (median = 17, range = 12-31). Patients with diabetes had higher levels of cytoadhesive molecules (sICAM-1 and sVCAM-1, p<0.001), adiponectin (p<0.001), and haptoglobin (p = 0.023). Their heart rate variability assessment revealed lower standard deviation of beat-to-beat intervals and lower total power (p<=0.019), reflecting autonomous nervous dysfunction. Hemoglobin A1c >8.0% (estimated average blood glucose >10 mmol/L) was associated with higher adiponectin (p<0.001) and obesity was associated with lower adiponectin (p<0.001); thus, obesity damped the effect of hyperglycemia on adiponectin. Obesity was associated with higher sICAM-1 (p<=0.015), tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), and high-sensitivity C reactive protein (hs-CRP), p<0.001. Similarly, high-density lipoprotein (HDL) <1.02 mmol/L was associated with higher sICAM-1, TNFalpha, IL-6, and hsCRP (p<=0.009) and lower adiponectin (p<0.001). Adiponectin correlated negatively with the inflammatory biomarkers in patients with diabetes. CONCLUSION: Subclinical inflammation and endothelial dysfunction are common among young patients with diabetes. Poor diabetes control is associated with higher adiponectin. Obesity and dyslipidemia are associated with lower adiponectin and higher inflammatory and endothelial biomarkers. Intuitively, these predictors of cardiovascular disease are amenable to proper glycemic control, nutritional choices, and regular exercise. PMID- 27459720 TI - A Systematic Review of Human Bat Rabies Virus Variant Cases: Evaluating Unprotected Physical Contact with Claws and Teeth in Support of Accurate Risk Assessments. AB - In the United States and Canada, the most recent documented cases of rabies have been attributed to bat rabies viruses (RABV). We undertook this systematic review in an effort to summarize and enhance understanding of the risk of infection for individuals who have been potentially exposed to a suspect or confirmed rabid bat. United States rabies surveillance summaries documented a total of 41 human bat-rabies virus variant verified non-transplant cases between 1990 and 2015. All cases were fatal. Seven (17.1%) of 41 cases reported a bite from a bat. Ten (24.3%) cases had unprotected physical contact (UPC); these included seven cases that had a bat land or crawl on them (contact with claws) and one case that touched a bat's teeth. Seven (17.1%) cases had probable UPC. Insectivorous bat teeth are extremely sharp and highly efficient for predation upon arthropod prey. Bats also have sharp claws on the end of their thumbs and feet. One of the most common bat RABV variants has an ability to replicate in non-neural cells. Questioning individuals about unprotected contact with bat teeth and claws (including a bat landing or crawling on a person) may help identify additional exposures. PMID- 27459722 TI - Vibronic Spectroscopy of Sympathetically Cooled CaH. AB - We report the measurement of the 11 Sigma->21 Sigma transition of CaH+ by resonance-enhanced photodissociation of CaH+ that is co-trapped with laser-cooled Ca+ . We observe four resonances that we assign to transitions from the vibrational v=0 ground state to the v'=1-4 excited states based on theoretical predictions. A simple theoretical model that assumes instantaneous dissociation after resonant excitation yields results in good agreement with the observed spectral features except for the unobserved v'=0 peak. This discrepancy is attributed to an insufficient understanding of the dissociation process, and further experimental and theoretical studies are required to confirm the assignment. The resolution of our experiment is limited by the mode-locked excitation laser, but this survey spectroscopy enables future rotationally resolved studies with applications in astrochemistry and precision measurement. PMID- 27459721 TI - Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized, Placebo-Controlled Study. AB - Insulin independence after total pancreatectomy and islet autotransplant (TPIAT) for chronic pancreatitis is limited by a high rate of postprocedure beta cell apoptosis. Endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are increased by dipeptidyl peptidase 4 inhibitor therapy (sitagliptin) may protect against beta cell apoptosis. To determine the effect of sitagliptin after TPIAT, 83 adult TPIAT recipients were randomized to receive sitagliptin (n = 54) or placebo (n = 29) for 12 months after TPIAT. At 12 and 18 months after TPIAT, participants were assessed for insulin independence; metabolic testing was performed with mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Insulin independence did not differ between the sitagliptin and placebo groups at 12 months (42% vs. 45%, p = 0.82) or 18 months (36% vs. 44%, p = 0.48). At 12 months, insulin dose was 9.0 (standard error 1.7) units/day and 7.9 (2.2) units/day in the sitagliptin and placebo groups, respectively (p = 0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) units/day, respectively (p = 0.32). Hemoglobin A1c levels and insulin secretory measures were similar in the two groups, as were adverse events. In conclusion, sitagliptin could be safely administered but did not improve metabolic outcomes after TPIAT. PMID- 27459723 TI - Crushed Ice Ingestion Does Not Improve Female Cycling Time Trial Performance in the Heat. AB - This study examined the effects of precooling via ice ingestion on female cycling performance in hot, humid conditions. Ten female endurance athletes, mean age (28 +/- 6 y), height (167.6 +/- 6.5 cm) and body-mass (68.0 +/- 11.5 kg) participated in the study. Participants completed an 800 kJ cycle time-trial in hot, humid conditions (34.9 +/- 0.3 degrees C, 49.8 +/- 3.5% RH). This was preceded by the consumption of 7 g?kg-1 of crushed ice (ICE) or water (CON). There was no difference in performance time (CON 3851 +/- 449 s; ICE 3767 +/- 465 s), oxygen consumption (CON 41.6 +/- 7.0 ml?kg?min-1; ICE 42.4 +/- 6.0 ml?kg?min-1) or respiratory exchange ratio (CON 0.88 +/- 0.05; ICE 0.90 +/- 0.06) between conditions (p > .05, d < 0.5). Core and skin temperature following the precooling period were lower in ICE (Tc 36.4 +/- 0.4 degrees C; Tsk 31.6 +/- 1.2 degrees C) compared with CON (Tc 37.1 +/- 0.4 degrees C; Tsk 32.4 +/- 0.7 degrees C) and remained lower until the 100 kJ mark of the cycle time-trial (p < .05, d > 1.0). Sweat onset occurred earlier in CON (228 +/- 113 s) compared with ICE (411 +/- 156 s) (p < .05, d = 1.63). Mean thermal sensation (CON 1.8 +/- 2.0; ICE 1.2 +/- 2.5, p < .05, d = 2.51), perceived exertion (CON 15.3 +/- 2.9; ICE 14.9 +/- 3.0, p < .05, d = 0.38) and perceived thirst (CON 5.6 +/- 2.2; ICE 4.6 +/- 2.4, p < .05, d = 0.98) were lower in ICE compared with CON. Crushed ice ingestion did not improve cycling performance in females, although perceptual responses were reduced. PMID- 27459724 TI - Impaired fornix-hippocampus integrity is linked to peripheral glutathione peroxidase in early psychosis. AB - Several lines of evidence implicate the fornix-hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix-hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix-hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms. PMID- 27459725 TI - 15q13.3 homozygous knockout mouse model display epilepsy-, autism- and schizophrenia-related phenotypes. AB - The 15q13.3 microdeletion syndrome is caused by a 1.5-MB hemizygous microdeletion located on 15q13.3 affecting seven genes: FAN1; MTMR10; TRPM1; miR-211; KLF13; OTUD7A; and CHRNA7. The 15q13.3 microdeletion increases the risk of intellectual disability, epilepsy, autism spectrum disorder and schizophrenia, though the clinical profile varies considerably. Two mouse models of this syndrome, with hemizygous deletion of the orthologous region in the murine genome, have recently been shown to recapitulate a number of the behavioral and physiological deficits that characterize the human condition. Still, little is known of the underlying biological mechanisms. Eleven human cases with homozygous deletion of the 15q13.3 region have been reported, all with severe functional and physiological impairments. We therefore hypothesized that a 15q13.3 homozygous knockout would confer more pronounced behavioral and physiological deficits in mice than the 15q13.3 hemizygous deletion. Here we report the characterization of a 15q13.3 knockout mouse. We observed marked deficits including altered seizure susceptibility, autistic behavior-related phenotypes, and auditory sensory processing. Several of these deficits, albeit less pronounced, were also found in the 15q13.3 hemizygous littermates indicating a gene-dosage dependency. Our findings strongly indicate that studies of the hemi- and homozygous 15q13.3 mouse strains will facilitate understanding of the biological mechanisms of severe mental disorders. PMID- 27459727 TI - Estimated Costs of Sporadic Gastrointestinal Illness Associated with Surface Water Recreation: A Combined Analysis of Data from NEEAR and CHEERS Studies. AB - BACKGROUND: The burden of illness can be described by addressing both incidence and illness severity attributable to water recreation. Monetized as cost, attributable disease burden estimates can be useful for environmental management decisions. OBJECTIVES: We characterize the disease burden attributable to water recreation using data from two cohort studies using a cost of illness (COI) approach and estimate the largest drivers of the disease burden of water recreation. METHODS: Data from the NEEAR study, which evaluated swimming and wading in marine and freshwater beaches in six U.S. states, and CHEERS, which evaluated illness after incidental-contact recreation (boating, canoeing, fishing, kayaking, and rowing) on waterways in the Chicago area, were used to estimate the cost per case of gastrointestinal illness and costs attributable to water recreation. Data on health care and medication utilization and missed days of work or leisure were collected and combined with cost data to construct measures of COI. RESULTS: Depending on different assumptions, the cost of gastrointestinal symptoms attributable to water recreation are estimated to be $1,220 for incidental-contact recreation (range $338-$1,681) and $1,676 for swimming/wading (range $425-2,743) per 1,000 recreators. Lost productivity is a major driver of the estimated COI, accounting for up to 90% of total costs. CONCLUSIONS: Our estimates suggest gastrointestinal illness attributed to surface water recreation at urban waterways, lakes, and coastal marine beaches is responsible for costs that should be accounted for when considering the monetary impact of efforts to improve water quality. The COI provides more information than the frequency of illness, as it takes into account disease incidence, health care utilization, and lost productivity. Use of monetized disease severity information should be included in future studies of water quality and health. Citation: DeFlorio-Barker S, Wade TJ, Jones RM, Friedman LS, Wing C, Dorevitch S. 2017. Estimated costs of sporadic gastrointestinal illness associated with surface water recreation: a combined analysis of data from NEEAR and CHEERS Studies. Environ Health Perspect 125:215-222; http://dx.doi.org/10.1289/EHP130. PMID- 27459726 TI - A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology. AB - It has been proposed that vulnerability to nicotine addiction is moderated by variation at the MU-opioid receptor locus (OPRM1), but results from human studies vary and prospective studies based on genotype are lacking. We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A>G (A118G). Here we use this model system together with a cohort of German youth to examine the role of the OPRM1 A118G variation on nicotine reward. Nicotine reinforcement was examined in the humanized mouse model using i.v. self administration. Male (n=17) and female (n=26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2 h sessions of nicotine self-administration. Furthermore, male (n=104) and female (n=118) subjects homozygous for the A allele or carrying the G allele from the Mannheim Study of Children at Risk were evaluated for pleasurable and unpleasant experiences during their initial smoking experience. A significant sex-by genotype effect was observed for nicotine self-administration. Male 118GG mice demonstrated higher nicotine intake than male 118AA mice, suggesting increased nicotine reinforcement. In contrast, there was no genotype effect in female mice. Human male G allele carriers reported increased pleasurable effects from their first smoking experience, as compared to male homozygous A, female G and female homozygous A allele carriers. The 118G allele appears to confer greater sensitivity to nicotine reinforcement in males, but not females. PMID- 27459728 TI - Ventricular repolarization time, location of pacing stimulus and current pulse amplitude conspire to determine arrhythmogenicity in mice. AB - AIM: In this study, we investigate the impact of altered action potential durations (APD) on ventricular repolarization time and proarrhythmia in mice with and without genetic deletion of the K+ -channel-interacting protein 2 (KChIP2-/- and WT respectively). Moreover, we examine the interrelationship between the dispersion of repolarization time and current pulse amplitude in provoking ventricular arrhythmia. METHODS: Intracardiac pacing in anesthetized mice determined refractory periods and proarrhythmia susceptibility. Regional activation time (AT), APD and repolarization time (=AT + APD) were measured in isolated hearts using floating microelectrodes. RESULTS: Proarrhythmia in WT and KChIP2-/- was not sensitive to changes in refractory periods. Action potentials were longer in KChIP2-/- hearts compared to WT hearts. Isolated WT hearts had large apico-basal dispersion of repolarization time, whereas hearts from KChIP2-/ mice had large left-to-right ventricular dispersion of repolarization time. Pacing from the right ventricle in KChIP2-/- mice in vivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice. CONCLUSION: Large heterogeneity of repolarization time is proarrhythmic when pacing is delivered from the location of earlier repolarization time. Ventricular repolarization time, location of the pacing stimulus and the amplitude of the stimulating current pulse are critical parameters underlying arrhythmia vulnerability. PMID- 27459729 TI - Identification and Characterization of Novel Matrix-Derived Bioactive Peptides: A Role for Collagenase from Santyl(r) Ointment in Post-Debridement Wound Healing? AB - Debridement, the removal of diseased, nonviable tissue, is critical for clinicians to readily assess wound status and prepare the wound bed for advanced therapeutics or downstream active healing. Removing necrotic slough and eschar through surgical or mechanical methods is less specific and may be painful for patients. Enzymatic debridement agents, such as Clostridial collagenase, selectively and painlessly degrade devitalized tissue. In addition to its debriding activities, highly-purified Clostridial collagenase actively promotes healing, and our past studies reveal that extracellular matrices digested with this enzyme yield peptides that activate cellular migratory, proliferative and angiogenic responses to injury in vitro, and promote wound closure in vivo. Intriguingly, while collagenase Santyl(r) ointment, a sterile preparation containing Clostridial collagenases and other non-specific proteases, is a well accepted enzymatic debridement agent, its role as an active healing entity has never been established. Based on our previous studies of pure Clostridial collagenase, we now ask whether the mixture of enzymes contained within Santyl(r) produces matrix-derived peptides that promote cellular injury responses in vitro and stimulate wound closure in vivo. Here, we identify novel collagen fragments, along with collagen-associated peptides derived from thrombospondin-1, multimerin 1, fibronectin, TGFbeta-induced protein ig-h3 and tenascin-C, generated from Santyl(r) collagenase-digested human dermal capillary endothelial and fibroblastic matrices, which increase cell proliferation and angiogenic remodeling in vitro by 50-100% over controls. Using an established model of impaired healing, we further demonstrate a specific dose of collagenase from Santyl(r) ointment, as well as the newly-identified and chemically-synthesized ECM-derived peptides significantly increase wound re-epithelialization by 60-100% over saline-treated controls. These results not only confirm and extend our earlier studies using purified collagenase- and matrix-derived peptides to stimulate healing in vitro and in vivo, but these Santyl(r)-generated, matrix derived peptides may also represent exciting new opportunities for creating advanced wound healing therapies that are enabled by enzymatic debridement and potentially go beyond debridement. PMID- 27459730 TI - Functional conservation and divergence of GmCHLI genes in polyploid soybean. AB - Polyploidy is prevalent in nature. As the fate of duplicated genes becomes more complicated when the encoded proteins function as oligomers, functional investigations into duplicated oligomer-encoding genes in polyploid genomes will facilitate our understanding of how traits are expressed. In this study, we identified GmCHLI1, a gene encoding the I subunit of magnesium (Mg)-chelatase, which functions in hexamers as responsible for the semi-dominant etiolation phenotype in soybean. Four GmCHLI copies derived from two polyploidy events were identified in the soybean genome. Further investigation with regard to expression patterns indicated that these four copies have diverged into two pairs; mutation in the other copy of the pair that includes GmCHLI1 also resulted in a chlorophyll-deficient phenotype. Protein interaction assays showed that these four GmCHLIs can interact with each other, but stronger interactions were found with mutated subunits. The results indicate that, in polyploidy, deficiency in each copy of duplicated oligomer-encoding genes could result in a mutant phenotype due to hetero-oligomer formation, which is different from the model of allelic dosage or functional redundancy. In addition, we interestingly found an increase in isoflavonoids in the heterozygous etiolated plants, which might be useful for improving soybean seed quality. PMID- 27459731 TI - Analysis of androgenetic alopecia in Amerindian people (Mapuche) from southern Chile. PMID- 27459732 TI - Recovery of Lower Extremity Performance After Hip Fracture Depends on Prefracture and Postdischarge Mobility: A Subgroup Analysis of a Randomized Rehabilitation Trial. PMID- 27459733 TI - Nephrotoxicity Associated with Concomitant Use of Ledipasvir-Sofosbuvir and Tenofovir in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection. AB - Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, with superior efficacy and safety compared to interferon based therapies. Despite these improvements, drug interactions with DAAs exist and may be clinically relevant in human immunodeficiency virus (HIV)-coinfected patients. We present a case of nephrotoxicity associated with concomitant use of tenofovir disoproxil fumarate (TDF) and ledipasvir-sofosbuvir (LDV-SOF). A 56 year-old woman with HIV infection who had been taking efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) for 6 years developed acute kidney injury 8 weeks after initiating LDV-SOF for the treatment of HCV infection. Her serum creatinine concentration peaked at 10 mg/dL, compared with her baseline concentration of 0.9-1 mg/dL. Kidney biopsy revealed acute tubular necrosis and acute interstitial nephritis. Both LDV-SOF and TDF were discontinued, and the patient's serum creatinine concentration decreased to 1.3 mg/dL over the following 6 weeks. We postulate that this adverse drug reaction may have been secondary to the known interaction between ledipasvir and TDF, which results in increased TDF exposure. Despite knowledge of this interaction, LDV-SOF is commonly prescribed in patients with HIV-HCV coinfection, as patients who received LDV-SOF- and TDF-containing regimens in trials have not demonstrated adverse clinical consequences related to this interaction. This case highlights the rare but potentially serious nephrotoxicity that can result from TDF toxicity and serves as a reminder to clinicians to implement close renal function monitoring in patients receiving both LDV-SOF and TDF. Clinicians prescribing LDV SOF to HCV-HIV-coinfected patients receiving TDF should be cautious about use with concomitant nephrotoxic medications and monitor markers of tubular dysfunction, including urinary phosphorus excretion, and renal injury at baseline and week 4 of therapy. Tenofovir alafenamide and alternative DAAs may also have a role in the management of patients at high risk for renal adverse effects from TDF. PMID- 27459734 TI - Identification and Characterization of Microsatellite Loci in Maqui (Aristotelia chilensis [Molina] Stunz) Using Next-Generation Sequencing (NGS). AB - Maqui (Aristotelia chilensis [Molina] Stunz) is a small dioecious tree native to South America with edible fruit characterized by very high antioxidant capacity and anthocyanin content. To preserve maqui as a genetic resource it is essential to study its genetic diversity. However, the complete genome is unknown and only a few gene sequences are available in databases. Simple sequence repeats (SSR) markers, which are neutral, co-dominant, reproducible and highly variable, are desirable to support genetic studies in maqui populations. By means of identification and characterization of microsatellite loci from a maqui genotype, using 454 sequencing technology, we develop a set of SSR for this species. Obtaining a total of 165,043 shotgun genome sequences, with an average read length of 387 bases, we covered 64 Mb of the maqui genome. Reads were assembled into 4,832 contigs, while 98,546 reads remained as singletons, generating a total of 103,378 consensus genomic sequences. A total of 24,494 SSR maqui markers were identified. Of them, 15,950 SSR maqui markers were classified as perfects. The most common SSR motifs were dinucleotide (31%), followed by tetranucleotide (26%) and trinucleotide motifs (24%). The motif AG/CT (28.4%) was the most abundant, while the motif AC (89 bp) was the largest. Eleven polymorphic SSRs were selected and used to analyze a population of 40 maqui genotypes. Polymorphism information content (PIC) ranged from 0.117 to 0.82, with an average of 0.58. Non-significant groups were observed in the maqui population, showing a panmictic genetic structure. In addition, we also predicted 11150 putative genes and 3 microRNAs (miRNAs) in maqui sequences. This results, including partial sequences of genes, some miRNAs and SSR markers from high throughput next generation sequencing (NGS) of maqui genomic DNA, constitute the first platform to undertake genetic and molecular studies of this important species. PMID- 27459735 TI - Impaired T cell function in malignant pleural effusion is caused by TGF-beta derived predominantly from macrophages. AB - Malignant pleural effusion (MPE) is an indication of advanced cancer. Immune dysfunction often occurs in MPE. We aimed to identify the reason for impaired T cell activity in MPE from lung cancer patients and to provide clues toward potential immune therapies for MPE. The surface inhibitory molecules and cytotoxic activity of T cells in MPE and peripheral blood (PB) were analyzed using flow cytometry. Levels of inflammatory cytokines in MPE and PB were tested using ELISA. TGF-beta expression in tumor-associated macrophages (TAMs) was also analyzed. The effect of TAMs on T cells was verified in vitro. Lastly, changes in T cells were evaluated following treatment with anti-TGF-beta antibody. We found that expression levels of Tim-3, PD-1 and CTLA-4 in T cells from MPE were upregulated compared with those from PB, but levels of IFN-gamma and Granzyme B were downregulated (p < 0.05). The amount of TGF-beta was significantly higher in MPE than in PB (p < 0.05). TGF-beta was mainly produced by TAMs in MPE. When T cells were co-cultured with TAMs, expression levels of Tim-3, PD-1 and CTLA-4 were significantly higher than controls, whereas levels of IFN-gamma and Granzyme B were significantly decreased, in a dose-dependent manner (p < 0.05). In vitro treatment with anti-TGF-beta antibody restored the impaired T cell cytotoxic activity in MPE. Our results indicate that macrophage-derived TGF-beta plays an important role in impaired T cell cytotoxicity. It will therefore be valuable to develop therapeutic strategies against TGF-beta pathway for MPE therapy of lung cancer. PMID- 27459736 TI - An Audit of Nursing Documentation at Three Public Hospitals in Jamaica. AB - PURPOSE: Nursing documentation provides an important indicator of the quality of care provided for hospitalized patients. This study assessed the quality of nursing documentation on medical wards at three hospitals in Jamaica. METHODS: This cross-sectional study audited a multilevel stratified sample of 245 patient records from three type B hospitals. An audit instrument which assessed nursing documentation of client history, biological data, client assessment, nursing standards, discharge planning, and teaching facilitated data collection. Descriptive statistics were conducted using IBM SPSS, Version 19 (IBM Inc., Armonk, NY, USA). FINDINGS: Records from three hospitals (Hospital 1, n = 119, 48.6%; Hospital 2, n = 56, 22.9%; Hospital 3, n = 70, 28.6%) were audited. Documented evidence of the patient's chief complaint (81.6%), history of present illness (78.8%), past health (79.2%), and family health (11.0%) were noted; however, less than a third of the dockets audited recorded adequate assessment data (e.g., occupation or living accommodations of patients). The audit noted 90% of records had a physical assessment completed within 24 hr of admission and entries timed, dated, and signed by a nurse. Less than 5% of dockets had evidence of patient teaching, and 13.5% had documented evidence of discharge planning conducted within 72 hr of admission. CONCLUSIONS: This study highlights the weakness in nursing documentation and the need for increased training and continued monitoring of nursing documentation at the hospitals studied. Additional research regarding the factors that affect nursing documentation practice could prove useful. CLINICAL RELEVANCE: The study provides valuable information for the development of strategic risk management programs geared at improving the quality of care delivered to clients and presents an opportunity for nurse leaders to implement structured interventions geared at improving nursing documentation in Jamaica. In light of Jamaica's epidemiologic transition of chronic diseases, gaps in nurses' documentation of client assessment, patient teaching, and discharge planning should be addressed with urgency. Patient teaching and discharge planning enable the clients to participate more effectively in their health maintenance process. PMID- 27459737 TI - [Toward understanding and regulation of gut ecosystem by metabologenomics]. PMID- 27459738 TI - Health Law and Medical Practice. PMID- 27459739 TI - [Personalities of medical history. Heinrich Irenaeus Quincke]. PMID- 27459740 TI - How Has the Affordable Care Act Affected Health Insurers' Financial Performance? AB - Starting in 2014, the Affordable Care Act transformed the market for individual health insurance by changing how insurance is sold and by subsidizing coverage for millions of new purchasers. Insurers, who had no previous experience under these market conditions, competed actively but faced uncertainty in how to price their products. This issue brief uses newly available data to understand how health insurers fared financially during the ACA's first year of full reforms. Overall, health insurers' financial performance began to show some strain in 2014, but the ACA's reinsurance program substantially buffered the negative effects for most insurers. Although a quarter of insurers did substantially worse than others, experience under the new market rules could improve the accuracy of pricing decisions in subsequent years. PMID- 27459741 TI - [Personalities of medical history. Willem Einthoven]. PMID- 27459742 TI - Factors Affecting Health Insurance Enrollment Through the State Marketplaces: Observations on the ACA's Third Open Enrollment Period. AB - Issue: Nearly 12.7 million individuals signed up for coverage in the Affordable Care Act's (ACA) health insurance marketplaces during the third open enrollment period, and by the end of March there were 11.1 million consumers with active coverage. States that operate their own marketplaces posted a year-to-year enrollment gain of 8.8 percent. To maintain membership and attract new consumers, the state-based marketplaces must sponsor enrollment assistance programs and conduct consumer outreach. These marketplaces relied heavily on such efforts during the third enrollment period, despite declining funding. Goal: To learn which outreach strategies, assistance programs, and other factors marketplace officials viewed as having exerted the greatest influence on enrollment. Methods: Survey of officials representing each of the 17 state-based marketplaces (15 responses). Key findings and conclusions: The cost of coverage and low health insurance literacy pose significant barriers to enrollment for many consumers. Marketplaces sought to overcome them by encouraging consumers to obtain in-person enrollment assistance from ACA-created assistance programs and from insurance brokers, and by partnering with community organizations for outreach activities. Many marketplaces also enhanced their web portals to make them easier to navigate and to give consumers better tools with which to evaluate their coverage options. PMID- 27459743 TI - [Central Nervous System Tumor: Glioma]. PMID- 27459744 TI - [Current Progress of Chemotheraphy for Glimoa]. PMID- 27459745 TI - Medical-Legal Partnerships and the Promise and Challenge of Physician Advocacy: An Interview with Megan Sandel. PMID- 27459746 TI - [Long-Term Efficacy of BCNU Wafers for Malignant Gliomas]. PMID- 27459747 TI - [Bevacizumab Treatment for Malignant Glioma Based on Basic Research and Clinical Trial]. PMID- 27459748 TI - [5-ALA Sonodynamic Therapy for Malignant Glioma]. PMID- 27459749 TI - E2C(R2) Periodic Benefit-Risk Evaluation Report and E2C(R2) Periodic Benefit Risk Evaluation Report--Questions and Answers; International Council for Harmonisation; Guidances for Industry; Availability. Notice. AB - The Food and Drug Administration (FDA or Agency) is announcing the availability of guidances for industry entitled ''E2C(R2) Periodic Benefit-Risk Evaluation'' (E2C(R2) guidance) and ''E2C(R2) Periodic Benefit-Risk Evaluation Report- Questions and Answers'' (E2C(R2) Q&A guidance). These guidances were prepared under the auspices of the International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation. The E2C(R2) draft guidance, issued April 11, 2012, updated and combined two ICH guidances, ''E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs'' (E2C guidance) and ''Addendum to E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs'' (addendum to the E2C guidance). The E2C(R2) guidance is intended to describe the format, content, and timing of a Periodic Benefit-Risk Evaluation Report (PBRER) for an approved drug or biologic, and it finalizes the draft guidance. The E2C(R2) Q&A guidance is a supplementary guidance that is intended to clarify key issues in the E2C(R2) guidance. PMID- 27459750 TI - Final Priority--Training of Interpreters for Individuals Who Are Deaf or Hard of Hearing and Individuals Who Are Deaf-Blind Program. Final priority. AB - Rehabilitative Services announces a final priority under the Training of Interpreters for Individuals Who Are Deaf or Hard of Hearing and Individuals Who Are Deaf-Blind program. The Assistant Secretary may use this priority for competitions in fiscal year 2016 and later years. We take this action to provide training and technical assistance to better prepare novice interpreters to become highly qualified nationally certified sign language interpreters. PMID- 27459751 TI - Physical Medicine Devices; Reclassification of Iontophoresis Device Intended for Any Other Purposes. Final order. AB - The Food and Drug Administration (FDA) is issuing a final order to reclassify iontophoresis devices intended for any other purposes, which are preamendments class III devices (regulated under product code EGJ), into class II (special controls) and to amend the device identification to clarify that devices intended to deliver specific drugs are not considered part of this regulatory classification. PMID- 27459752 TI - Will these shirts protect you from Zika? With fears on the rise we put treated clothing to the test. PMID- 27459753 TI - Is There a Cure for High Drug Prices? A Special Investigation From Consumer Reports Best Buy Drugs. PMID- 27459755 TI - [META-ANALYSIS OF CLINICAL STUDIES ON THE USE OF STATINS FOR PREVENTION OF ATRIAL FIBRILLATION SOON AFTER CORONARY BYPASS SURGERY]. AB - BACKGROUND: Atrial fibrillation (AF) develops in the early postoperative period in each third patient undergoing coronary bypass surgery (CBPS). Multifactorial pathogenesis of postoperative AF is unclear. The concept of postoperative inflammation as a potential basic mechanism of this condition has been implied in many studies. Pre- and postoperative treatment with antiinflammatory statins proved beneficial as a means for reducing the frequency of AF. MATERIALS AND METHODS: The meta-analysis is based on the results of 15 clinical studies carried out in the last 15 years. They included 9369 patients of whom 5598 (59.75%) used statins and 3771 (49.25%) did not receive them. The following endpoints were evaluated in the early postoperative periods: fiequency of AF, overall lethality, frequency of cerebral circulation disorders and myocardial infarction. Odds ratio (OR) and 95% CI were calculated, levels of inflammation markers before and after surgery and duration of hospitalization were determined. RESULTS: Statins decreased the frequency of AF soon after CBPS (OR 0,481 at 95% CI 0,345-0,672; p = 0,000), they did not influence overall lethality (OR 0,837 at 95% CI 0,501 1,399: p = 0,497) and frequency of myocardial infarction (OR 1,001 at 95% CI 0,702-1,426; p = 0,997), but decreased frequency of cerebral circulation disorders (OR 0,067 at 95% Cl 0,037- 0,121; p = 0,000). Also, they reduced duration of hospitalization and serum levels of inflammation markers. CONCLUSION: Results of clinical studies available to date leave no doubt that statins produce anti-inflammatory and anti-arrhythmic effects. Meta-analysis of relevant studies confirmed on the whole the positive role of statin therapy prior to CBPS. PMID- 27459756 TI - [NEWS IN ETIOLOGY AND PATHOGENESIS OF IRRITATED BOWEL SYNDROME]. AB - The concept of irritated bowel syndrome as a complex of functional disorders that can not be explained by organic changes and are totally due to intestinal motility and visceral sensitivity needs revision. The development of this syndrome also depends on a number of pathogenetic and etiological factors, such as inflammation of intestinal mucosa, changes of its permeability, previous infection, altered microflora, gene polymorphism, and food hypersensitivity. PMID- 27459757 TI - [TYPE 2 DIABETES MELLITUS AND DEPRESSION]. AB - The clinical significance of type 2 diabetes mellitus is not confined to metabolic disorders. A serious problem is also affective pathology that occurs in the majority (30-70%) of patients. However, diagnostics and correction of anxiety and depressive disorders associated with diabetes are often given insufficient attention. Many studies showed relationship between affective disorders and low adherence to the prescribed treatment resulting in general deterioration of clinical prognosis of diabetes. This review article describes the basic mechanisms behind the interrelation of affective disorders and diabetes. The role of persistent subclinical inflammation in diabetes and depression is discussed. The influence of emotional stress on the activation of the hypothalamic-pituitary adrenal axis on the overproduction of cortisol is emphasized. The similarity of some structural changes in the brain tissue in diabetes and depression is discussed. Effect of endocrine disruption in the emotional sphere is demonstrated. Mechanisms responsible for the development of diabetes and its complications provoked by depression are considered. PMID- 27459758 TI - [DELAYED CORONARY SURGERY FOR THE TREATMENT OF ACUTE MYOCARDIAL INFARCTION WITH ELEVATED ST SEGMENT]. AB - AIM: To develop algorithms of reperfusion therapy (RT) based on the assessment of the initial risk of death determining the priority use of delayed transdermal coronary surgery (TCS) unavailable in the early period. We compared effectiveness of different strategies for the treatment of 1245 patients with acute myocardial infarction (MI) and elevated ST segment in 2003-2007 including various TCS modalities at recommended time (n = 88), delayed TCS within 24-72 hr after the onset of MI (n = 194), thrombolytic therapy without subsequent TCS (n = 275), and conservative therapy (N = 688). The general and cardiovascular lethality was evaluated among 474 patients 5 years after discharge. The results suggest that unavailability of TCS in recommended time in case of enhanced risk of death does not exclude the possibility of its delayed application. TCS 24-72 hr after the onset of MI prevents complications and the fatal outcome the frequency of which remains high remains high not only in the early but also in the late post infarction period. Delayed TCS can be effectively used to treat patients in case of their late admission or referral from other hospitals where X-ray endovascular methods for the treatment of acute MI are not used. PMID- 27459759 TI - [NERVOUS SYSTEM LESIONS ASSOCIATED WITH RELAPSING POLYCHONDRITIS: ANALYSIS OF ORIGINAL OBSERVATIONS]. AB - Three clinical cases are described including two of relapsing polychondritis with lesions in the central and peripheral nervous system (one of long-standing aseptic lymphocytic meningitis and one of cranial neuropathy of 2, 5, 7, and 8 pairs) and the third case of the optic nerve lesion with amblyopia. The two former cases were successfully treated with high doses of corticosteroids, the third one with moderate doses of the same medications. The data from the current literature concerning variants of clinical manifestations, methods for diagnostics and treatment of neurologic manifestations of relapsing polychondritis are discussed. PMID- 27459760 TI - [CLINICAL AND PATHOGENETIC PECULIARITIES OF DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION]. AB - The purpose of the study was to examine the relationship between functional parameters, arterial rigidity, lipid profile, markers of systemic inflammation and endothelial dysfunction in patients with COPD and COPD + coronary heart disease. We examined 110 subjects divided into 3 groups. G group 1 included 40 patients with severe and very severe COPD, group 2 consisted of 40 patients with severe and very severe COPD + coronary artery disease, the control group was comprised of 30 healthy volunteers. We studied parameters of respiratory function, the level of blood oxygenation, the main characteristics of arterial rigidity plasma lipid, TNF-alpha, CRP, fibrinogen, sPECAM-1 levels and the expression of CD38/ADP-ribosylcyclase in peripheral blood lymphocytes. The study revealed increased rigidity of the central arteries in the patients of groups 1and 2 regardless of the duration of observation and the presence of coronary artery disease, as evidenced by the increase of the pulse wave velocity in the aorta. Patients of both groups had elevated levels of TNF-alpha, CRP and fibrinogen indicating systemic inflammatory response. Taken together, the enhanced expression of CD38 in peripheral blood lymphocytes, elevated concentration of soluble CD31 (sPECAM-1) in both groups related to bronchial obstruction and neutrophil elastase activity as well as increased rigidity of the vascular bed gives evidence that the CD38 and sCD31 relationship plays a role in the formation of endothelial dysfunction, and dysregulation of vascular tone in COPD patients. Disorders of lipid metabolism combined with increased rigidity of the vascular wall, elevated levels of markers of systemic inflammation and endothelia dysfunction, suggest that patients with COPD are at risk of cardiovascular events. PMID- 27459761 TI - [THE INFLUENCE OF ADIPONECTIN AND LEPTIN LEVELS ON MYOCARDIAL REMODELING IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND GOUT]. AB - BACKGROUND: There is a growing number of patients with type 2 diabetes mellitus. As a component of the metabolic syndrome, type 2 diabetes is often associated with hyperuricemia and gout. These diseases worsen prognosis of concomitant cardiovascular disorders. PURPOSE: To assess the relationship between adiponectin and leptin levels and echocardiographic parameters in patients with type 2 diabetes mellitus, gout, and a combination thereof. MATERIALS AND METHODS: The study involved 30 men aged 41 to 70 years divided into 3 groups. The first group included 10 patients with type 2 diabetes, the second one 10 patients with gout, and the third group consisted of 10 men with a combination of type 2 diabetes and gout. In all patients the levels of glucose, immunoreactive insulin, HOMA-IR, adiponectin, and leptin were measured. All patients underwent echocardiography. RESULTS: The study revealed hyperglycemia in patients with type 2 diabetes and its combination with gout. Patients of all three groups had increased insulin resistance, insulin and leptin levels, decreased concentration of adiponectin. The thickness of interventricular sepum in systole and diastole, posterior wall of the left ventricle in diastole, myocarduial mass of the left ventricle, the size of the left atrium and the right ventricle increased in patients of all three groups. CONCLUSION: The study demonstrated compensatory hyperinsulinemia and insulin resistance, hypoadiponectinemia, hyperleptinemia, left ventricular hypertrophy, diastolic dysfunction, and intact ventricular contractility in patients with type 2 diabetes, gout, and their combination. Hypoadiponectinemia and hyperleptinemia play a role in remodeling of myocardium in these patients. PMID- 27459762 TI - [MULTIDISCIPLINARY TEAM APPROACH FOR DIABETIC FOOT PATIENTS IN AN OUT-PATIENT CLINIC]. AB - AIM: To assess the effectiveness of multidisciplinary team approach in daily practice of diabetic foot. MATERIALS AND METHODS: 376 diabetic patients (446 ulcers) treated in a diabetic foot department in 2014 were examined. All patients were screened for diabetic peripheral polyneuropathy and blood insufficiency of lower extremities in order to diagnose the type of diabetic foot ulcer: neuropathic or neuroischemic. Patients were treated by a multidisciplinary team. The number of healed ulcers, minor and major amputations was analyzed. RESULTS: 80% of diabetic foot ulcers were neuropathic with normal blood supply, 20% had signs of ischemia. 77.8% of the ulcers healed in the general group during the study period. 13 amputations (2.9%) were done in the study group: 7 minor amputations (1.6%), 2 below the knee (0.4%), and 4 above knee (0.9%). Two patients died from cardiovascular events (0.4%). The comparative analysis of outcomes of neuropathic and neuroischemic ulcers showed that 84% of neuropathic ulcers healed. Minor amputations were done in 1% of the cases, no major amputations were performed. In patients with neuroischemic ulcers, 60% of them healed, minor amputations were made in 3.4% of cases (2.3% below knee, 4.6% above knee). CONCLUSION: The majority of diabetic ulcers in the study group were neuropathic with normal blood supply. The main risk factor of major amputations is ischemia of the affected limb. The multidisciplinary team approach in daily practice of the diabetic foot department of an out-patient clinic is instrumental in healing ulcers and minimizing the risk of major amputations. PMID- 27459763 TI - [AGE-SPECIFIC PECULIARITIES OF CLINICAL PICTURE AND EVOLUTION OF ACUTE CHOLECYSTITIS]. AB - The problem of acute cholecystitis is now becoming ever more urgent bearing in mind a rise in morbidity and poor treatment results especially in elderly patients. Hence, the importance of studying age-specific peculiarities of clinical picture and evolution of this condition. The present study included 1273 patients with acute cholecystitis divided in 2 groups. It was shown that patients of advanced age more frequently suffer complicated cholecystitis. It is concluded that patients aged 60 years and more make up a high-risk group characterized by mildly manifest clinical symptoms and hospitalization at the late stages of the disease. PMID- 27459764 TI - [EFFECT OF CORTEXIN ON THE QUALITY OF LIFE IN THE EARLY REHABILITATIVE PERIOD AFTER HEMISPHERIC ISCHEMIC STROKE]. AB - AIM: To study the neuroprotective effect of a repeated course of low dose cortexin therapy on the quality of life in the early rehabilitative period after hemispheric ischemic stroke (IS). MATERIALS AND METHODS: 90 patients were divided into group 1 treated with cortexin (10 mg i/m twice daily (morning and afternoon) in addition to basal treatment, group 2 given the repeated course of the same treatment, and control group (basal therapy alone). The standard SF-36 questionnaire was used to assess the quality of life. RESULTS: Treatment of patients following acute hemispheric ischemic stroke with cortexin (10 mg i/m twice daily) and the repeated course of the same treatment after 10 days resulted in the accelerated and more complete normalization of the quality of life in the early rehabilitation petriod (starting from days 21-27 days after the onset of disease) than in the patients given a single course of cortexin therapy or basal treatment alone. PMID- 27459765 TI - [OSGOOD-SCHLATTER DISEASE]. AB - Osgood-Schlatter disease is a specific disorder related to osteochondropathies that affects young subjects and is localized in the tuberositas tibiae. The disease frequently develops after injuries including loading ones. It is apparent as gradual swelling of the knee joint(s) that becomes painful. Pain increases during walking, lower limb flexion an extension or stair climbing but may die down at rest. Diagnostics is based on the clinical picture. Radiodiagnostic methods my be helpful but their efficacy is inferior to that of clinical examination. Anti-inflammatory and chondroprotective therapy, immobilization of the affected joint, controlled exercises, and balneotherapy are indicated. PMID- 27459766 TI - [HYPEREOSINOPHILIC SYNDROME ASSOCIATED WITH SEPSIS DUE TO PAECILOMYCES FUNGI DISSEMINATED INTO THE LIVER]. AB - A 49 year old woman with signs of chronic sepsis, hepatomegaly, and high eosinophil count was under long-term examination including consultations with an oncologist, parasitologist, and hematologist, diagnostic laparotomy, and studies of liver biopsies. Seeding blood samples onto Saburo's medium resulted in the growth of Paecilomyces variotii Bainier colonies. Counting mature spherules of the fungus revealed 59000 spherules per 1 mcl compared with the normal value of 1000-6000 which suggested paecilomycotic etiology of sepsis. The histological study of liver biopsies demonstrated hemorrhagic foci and eosinophilic infiltrates around fungal spherules. The clinical recovery of the patient was achieved after 3 courses of pulsed terbinafine therapy (500 mg/d every other day for 14 days during a month) in combination with vitamins and i/v infusion of 100 ml of a fluconazole solution (2 mg/ml) every third day (10 procedures during a course of therapy). PMID- 27459767 TI - [V.I. GEDROITS, A SURGEON AND A FOLLOWER OF CESARE ROUX OF LAUSANNE]. AB - The paper overviews personality formation of the woman surgeon Vera Ignat'evna Gedroits (1870-1932), a follower of the world-famous Cesare Roux of Lausanne. PMID- 27459768 TI - Interactive effects of shelter and conspecific density shape mortality, growth, and condition in juvenile reef fish. AB - How landscape context influences density-dependent processes is important, as environmental heterogeneity can confound estimates of density dependence in demographic parameters. Here we evaluate 19 populations in a shoaling temperate reef fish (Trachinops caudimaculatus) metapopulation within a heterogeneous seascape (Port Phillip Bay, Australia) to show empirically that shelter availability and population density interact to influence juvenile mortality, growth and condition. Although heterogeneity in shelter availability obscured the underlying patterns of density dependence in different ways, the combination of habitat and its interaction with density were two to six times more important than density alone in explaining variation in demographic parameters for juveniles. These findings contradict many small-scale studies and highlight the need for landscape-scale observations of how density dependence interacts with resource availability and competition to better understand how demographic parameters influence the dynamics of metapopulations in heterogeneous environments. PMID- 27459769 TI - Link flexibility: evidence for environment-dependent adaptive foraging in a food web time-series. AB - Temporal variability in the distribution of feeding links in a food web can be an important stabilizing factor for these complex systems. Adaptive foraging and prey choice have been hypothesized to cause this link flexibility as organisms adjust their behavior to variation in the prey community. Here, we analyze a 10 yr time series of monthly aphid-parasitoid-secondary-parasitoid networks and show that interaction strengths for polyphagous secondary parasitoids are generally biased toward the larger host species within their fundamental niche; however, in months of higher competition for hosts, size-based biases are reduced. The results corroborate a previous hypothesis stating that host selectivity of parasitoids should be correlated to the relative likelihood of egg limitation vs. time limitation. Our results evince adaptation of foraging behavior to varying conditions affects the distribution of host-parasitoid link strengths, where link rewiring may be integral to stability in complex communities. PMID- 27459770 TI - Feeding guild of non-host community members affects host-foraging efficiency of a parasitic wasp. AB - Interactions between predator and prey, or parasitoid and host, are shaped by trait- and density-mediated processes involving other community members. Parasitoids that lay their eggs in herbivorous insects locate their hosts through infochemicals such as herbivore-induced plant volatiles (HIPVs) and host-produced kairomones. Hosts are frequently accompanied by non-host herbivores that are unsuitable for the parasitoid. These non-hosts may interfere with host location primarily through trait-mediated processes, by their own infochemicals, and their induction of the emission of plant volatiles. Although it is known that single non-hosts can interfere with parasitoid host location, it is still unknown whether the observed effects are due to species specific characteristics or to the feeding habits of the non-host herbivores. Here we addressed whether the feeding guild of non-host herbivores differentially affects foraging of the parasitoid Cotesia glomerata for its common host, caterpillars of Pieris brassicae feeding on Brassica oleracea plants. We used different phloem-feeding and leaf-chewing non-hosts to study their effects on host location by the parasitoid when searching for host-infested plants based on HIPVs and when searching for hosts on the plant using infochemicals. To evaluate the ultimate effect of these two phases in host location, we studied parasitism efficiency of parasitoids in small plant communities under field-tent conditions. We show that leaf-chewing non-hosts primarily affected host location through trait-mediated effects via plant volatiles, whereas phloem-feeding non-hosts exerted trait mediated effects by affecting foraging efficiency of the parasitoid on the plant. These trait-mediated effects resulted in associational susceptibility of hosts in environments with phloem feeders and associational resistance in environments with non-host leaf chewers. PMID- 27459771 TI - Drought, pollen and nectar availability, and pollination success. AB - Pollination success of animal-pollinated flowers depends on rate of pollinator visits and on pollen deposition per visit, both of which should vary with the pollen and nectar "neighborhoods" of a plant, i.e., with pollen and nectar availability in nearby plants. One determinant of these neighborhoods is per flower production of pollen and nectar, which is likely to respond to environmental influences. In this study, we explored environmental effects on pollen and nectar production and on pollination success in order to follow up a surprising result from a previous study: flowers of Ipomopsis aggregata received less pollen in years of high visitation by their hummingbird pollinators. A new analysis of the earlier data indicated that high bird visitation corresponded to drought years. We hypothesized that drought might contribute to the enigmatic prior result if it decreases both nectar and pollen production: in dry years, low nectar availability could cause hummingbirds to visit flowers at a higher rate, and low pollen availability could cause them to deposit less pollen per visit. A greenhouse experiment demonstrated that drought does reduce both pollen and nectar production by I. aggregata flowers. This result was corroborated across 6 yr of variable precipitation and soil moisture in four unmanipulated field populations. In addition, experimental removal of pollen from flowers reduced the pollen received by nearby flowers. We conclude that there is much to learn about how abiotic and biotic environmental drivers jointly affect pollen and nectar production and availability, and how this contributes to pollen and nectar neighborhoods and thus influences pollination success. PMID- 27459772 TI - Nectar microbes can reduce secondary metabolites in nectar and alter effects on nectar consumption by pollinators. AB - Secondary metabolites that are present in floral nectar have been hypothesized to enhance specificity in plant-pollinator mutualism by reducing larceny by non pollinators, including microorganisms that colonize nectar. However, few studies have tested this hypothesis. Using synthetic nectar, we conducted laboratory and field experiments to examine the effects of five chemical compounds found in nectar on the growth and metabolism of nectar-colonizing yeasts and bacteria, and the interactive effects of these compounds and nectar microbes on the consumption of nectar by pollinators. In most cases, focal compounds inhibited microbial growth, but the extent of these effects depended on compound identity, concentration, and microbial species. Moreover, most compounds did not substantially decrease sugar metabolism by microbes, and microbes reduced the concentration of some compounds in nectar. Using artificial flowers in the field, we also found that the common nectar yeast Metschnikowia reukaufii altered nectar consumption by small floral visitors, but only in nectar containing catalpol. This effect was likely mediated by a mechanism independent of catalpol metabolism. Despite strong compound-specific effects on microbial growth, our results suggest that the secondary metabolites tested here are unlikely to be an effective general defense mechanism for preserving nectar sugars for pollinators. Instead, our results indicate that microbial colonization of nectar could reduce the concentration of secondary compounds in nectar and, in some cases, reduce deterrence to pollinators. PMID- 27459773 TI - Experimental simulation of pollinator decline causes community-wide reductions in seedling diversity and abundance. AB - Pollinator decline can disrupt the mutualistic interactions between plants and pollinators and potentially affect the maintenance of plant populations. However, there is still little knowledge on how changes in pollinator abundance can affect seedling recruitment, which is essential for population persistence. We experimentally simulated a community-wide reduction in pollinator availability during four years to examine its effects on seedling recruitment in 10 perennial herbs in a Norwegian hay meadow. Our experimental reduction in pollinator availability significantly reduced community-wide seedling diversity. Overall seedling abundance was also consistently lower under reduced pollinator availability, although this effect was only significant when the most abundant plant species in the community was excluded from the analysis. Despite an overall negative effect on seedling abundance, the experimental reduction in pollinator availability had contrasting effects on individual plant species. This tended to cause a larger change in seedling species composition in the experimental than in the control plots after the four study years. Our study demonstrates for the first time a direct causal link between reduced pollinator availability and reduced plant diversity and abundance. PMID- 27459774 TI - Flexible foraging shapes the topology of plant-pollinator interaction networks. AB - In plant-pollinator networks, foraging choices by pollinators help form the connecting links between species. Flexible foraging should therefore play an important role in defining network topology. Factors such as morphological trait complementarity limit a pollinator's pool of potential floral resources, but which potential resource species are actually utilized at a location depends on local environmental and ecological context. Pollinators can be highly flexible foragers, but the effect of this flexibility on network topology remains unclear. To understand how flexible foraging affects network topology, we examined differences between sets of locally realized interactions and corresponding sets of potential interactions within 25 weighted plant-pollinator networks in two different regions of the United States. We examined two possible mechanisms for flexible foraging effects on realized networks: (1) preferential targeting of higher-density plant resources, which should increase network nestedness, and (2) context-dependent resource partitioning driven by interspecific competition, which should increase modularity and complementary specialization. We found that flexible foraging has strong effects on realized network topology. Realized connectance was much lower than connectance based on potential interactions, indicating a local narrowing of diet breadth. Moreover, the foraging choices pollinators made, which particular plant species to visit and at what rates, resulted in networks that were significantly less nested and significantly more modular and specialized than their corresponding networks of potential interactions. Preferentially foraging on locally abundant resources was not a strong driver of the realization of potential interactions. However, the degree of modularity and complementary specialization both increased with the number of competing pollinator species and with niche availability. We therefore conclude that flexible foraging affects realized network topology more strongly through resource partitioning than through focusing on high-density resources. PMID- 27459775 TI - Site fidelity by bees drives pollination facilitation in sequentially blooming plant species. AB - Plant species can influence the pollination and reproductive success of coflowering neighbors that share pollinators. Because some individual pollinators habitually forage in particular areas, it is also possible that plant species could influence the pollination of neighbors that bloom later. When flowers of a preferred forage plant decline in an area, site-fidelity may cause individual flower feeders to stay in an area and switch plant species rather than search for preferred plants in a new location. A newly blooming plant species may quickly inherit a set of visitors from a prior plant species, and therefore experience higher pollination success than it would in an area where the first species never bloomed. To test this, we manipulated the placement and timing of two plant species, Delphinium barbeyi and later-blooming Gentiana parryi. We recorded the responses of individually marked bumble bee pollinators. About 63% of marked individuals returned repeatedly to the same areas to forage on Delphinium. When Delphinium was experimentally taken out of bloom, most of those site-faithful individuals (78%) stayed and switched to Gentiana. Consequently, Gentiana flowers received more visits in areas where Delphinium had previously flowered, compared to areas where Delphinium was still flowering or never occurred. Gentiana stigmas received more pollen in areas where Delphinium disappeared than where it never bloomed, indicating that Delphinium increases the pollination of Gentiana when they are separated in time. Overall, we show that individual bumble bees are often site-faithful, causing one plant species to increase the pollination of another even when separated in time, which is a novel mechanism of pollination facilitation. PMID- 27459776 TI - Demographic shifts related to mycoheterotrophy and their fitness impacts in two Cephalanthera species. AB - Evolutionary losses of photosynthesis in terrestrial plants all originate in photosynthetic ancestors. The adaptive context under which this transition happens has remained elusive because of the rarity of plants in which both photosynthetic and non-photosynthetic forms exist as a polymorphism. Here, we report on demographic patterns in photosynthetic ("green") and nonphotosynthetic ("albino") individuals within populations of two such species, Cephalanthera damasonium and C. longifolia, which also acquire nutrition from their mycorrhizal hosts (partial mycoheterotrophy). We hypothesized that demographic shifts in albinos relative to greens would include compensatory patterns with respect to fitness, such that maladaptive changes to survival or reproduction would be adaptively countered by changes to other parameters, such as growth probabilities. We tracked individuals in two populations of C. damasonium for 3 yr, and in one population of C. longifolia for 14 yr. We then analyzed vital rates for both phenotypes using general linear mixed models (GLMMs) and multi state capture mark-recapture models (CMR), and used these models to develop size classified, function-based population projection matrices. We estimated fitness as the deterministic population growth rate (lambda) for each phenotype, and explored the impact of shifts in demographic patterns to albinism via life table response experiments (LTREs). Mortality differed between greens and albinos, but not similarly across species. Albinos generally sprouted less than greens, and flowered more when small but less at other times. Albinos typically had a higher probability of fruiting, although their lower flower numbers yielded lower numbers of fruits overall. Fitness did not differ significantly among phenotypes. Thus, we did not find significant evidence that albinism is adaptive or maladaptive; however, if in fact it is the latter, then we did find evidence of incomplete compensation for declines in survival and reproduction from growth transitions, particularly to small flowering size classes in C. damasonium, and to large vegetative size classes in C. longifolia. These patterns indicate some support for the idea that albinism may lead to the speciation of mycoheterotrophic plants. PMID- 27459777 TI - Environmental and trait variability constrain community structure and the biodiversity-productivity relationship. AB - There is still considerable debate about which mechanisms drive the relationship between biodiversity and ecosystem function (BEF). Although most scientists agree on the existence of two underlying mechanisms, complementarity and selection, experimental studies keep producing contrasting results on the relative contributions of the two effects. We present a spatially explicit resource competition model and investigate how the strength of these effects is influenced by trait and environmental variability, resource distribution, and species pool size. Our results demonstrate that the increase of biomass production with increasing species numbers depends on the concurrence of environmental and trait variability: BEF relationships are stronger if functionally different species coexist in a landscape with heterogeneous resource supply. These large biodiversity effects arise from complementarity effects, whereas selection effects are maximized when broad trait ranges coincide with narrow ranges of resource supply ratios. Our results will therefore help to resolve the debate on complementarity and selection mechanisms. PMID- 27459778 TI - Trophic interactions determine the effects of drought on an aquatic ecosystem. AB - Species interactions can be important mediators of community and ecosystem responses to environmental stressors. However, we still lack a mechanistic understanding of the indirect ecological effects of stress that arise via altered species interactions. To understand how species interactions will be altered by environmental stressors, we need to know if the species that are vulnerable to such stressors also have large impacts on the ecosystem. As predators often exhibit certain traits that are linked to a high vulnerability to stress (e.g., large body size, long generation time), as well as having large effects on communities (e.g., top-down trophic effects), predators may be particularly likely to mediate ecological effects of environmental stress. Other functional groups, like facilitators, are known to have large impacts on communities, but their vulnerability to perturbations remains undocumented. Here, we use aquatic insect communities in bromeliads to examine the indirect effects of an important stressor (drought) on community and ecosystem responses. In a microcosm experiment, we manipulated predatory and facilitative taxa under a range of experimental droughts, and quantified effects on community structure and ecosystem function. Drought, by adversely affecting the top predator, had indirect cascading effects on the entire food web, altering community composition and decomposition. We identified the likely pathway of how drought cascaded through the food web from the top-down as drought -->predator --> shredder --> decomposition. This stress-induced cascade depended on predators exhibiting both a strong vulnerability to drought and large impacts on prey (especially shredders), as well as shredders exhibiting high functional importance as decomposers. PMID- 27459779 TI - The role of competition--colonization tradeoffs and spatial heterogeneity in promoting trematode coexistence. AB - Competition - colonization tradeoffs occur in many systems, and theory predicts that they can strongly promote species coexistence. However, there is little empirical evidence that observed competition - colonization tradeoffs are strong enough to maintain diversity in natural systems. This is due in part to a mismatch between theoretical assumptions and biological reality in some systems. We tested whether a competition - colonization tradeoff explains how a diverse trematode guild coexists in California horn snail populations, a system that meets the requisite criteria for the tradeoff to promote coexistence. A field experiment showed that subordinate trematode species tended to have higher colonization rates than dominant species. This tradeoff promoted coexistence in parameterized models but did not fully explain trematode diversity and abundance, suggesting a role of additional diversity maintenance mechanisms. Spatial heterogeneity is an alternative way to promote coexistence if it isolates competing species. We used scale transition theory to expand the competition - colonization tradeoff model to include spatial variation. The parameterized model showed that spatial variation in trematode prevalence did not isolate most species sufficiently to explain the overall high diversity, but could benefit some rare species. Together, the results suggest that several mechanisms combine to maintain diversity, even when a competition - colonization tradeoff occurs. PMID- 27459780 TI - Parasites alter freshwater communities in mesocosms by modifying invasive crayfish behavior. AB - Parasites can alter communities by reducing densities of keystone hosts, but few studies have examined how trait-mediated indirect effects of parasites can alter ecological communities. We test how trematode parasites (Microphallus spp.) that affect invasive crayfish (Orconectes rusticus) behavior alter how crayfish impact lake littoral communities. O. rusticus drive community composition in north temperate lakes, and predatory fish can reduce crayfish activity and feeding. In laboratory studies, Microphallus parasites also alter O. rusticus behavior: infected O. rusticus eat fewer macroinvertebrates and are bolder near predatory fish than uninfected individuals. We used a 2 x 2 factorial experiment to test how predatory fish and parasites affect O. rusticus impacts in large mesocosms over 4 weeks. We predicted (1) that when predators were absent, infected crayfish would have lower impacts than uninfected crayfish on macrophytes and macroinvertebrates (as well as reduced growth and higher mortality). However, (2) when predators were present but unable to consume crayfish, infected crayfish would have greater impacts (as well as greater growth and lower mortality) than uninfected crayfish because of increased boldness. Because of its effect on crayfish feeding behavior, we also predicted (3) that infection would alter macrophyte and macroinvertebrate community composition. In contrast to our first hypothesis, we found that infected and uninfected crayfish had similar impacts on lower trophic levels when predators were absent. Across all treatments, infected crayfish were more likely to be outside shelters and had greater growth than uninfected crayfish, suggesting that the reduced feeding observed in short-term experiments does not occur over longer timescales. However, in support of the second hypothesis, when predatory fish were present, infected crayfish ate more macroinvertebrates than did uninfected crayfish, likely due to increased boldness. We also observed a trend for greater macrophyte consumption associated with infection and a trend indicating infection might alter macroinvertebrate community composition. Our results suggest that parasites can alter aquatic communities in mesocosms merely by modifying host behavior. PMID- 27459781 TI - Ontogenetic shifts in a freshwater cleaning symbiosis: consequences for hosts and their symbionts. AB - Animal fitness is influenced by diverse assemblages of internal and external symbionts. These assemblages often change throughout host ontogeny, but the mechanisms that underlie these changes and their consequences for host fitness are seldom revealed. Here we examine a cleaning symbiosis between crayfish and an assemblage of ectosymbiotic branchiobdellidan worms to uncover what mechanisms drive changes in symbiont composition during host ontogeny and the consequences of these changes for both the host and symbionts. In surveys of a North Carolina river, the dominant worm species shifted from Cambarincola philadelphicus to Cambarincola ingens as crayfish (Cambarus bartonii) increased in size. We demonstrate that this shift is a function of host regulation by small crayfish and exclusion by a dominant symbiont on large crayfish. In a controlled lab experiment, small crayfish often removed their symbionts but C. ingens was removed at a higher rate than C. philadelphicus. In contrast, C. ingens had higher survivorship and reproduction than C. philadelphicus on large crayfish. We also measured the effect of each worm species on crayfish growth through ontogeny; neither worm species had an effect on small crayfish but both species had similar positive effects on the growth of large crayfish relative to controls. Evidence from another experiment suggested that intraguild predation by C. ingens caused a decline in C. philadelphicus on large crayfish. We have shown that shifts in partner fitness are a function of host size and that these shifts can involve the succession of symbionts. Further, our results suggest that changes in the outcome of symbioses can remain robust throughout host ontogeny despite interactive mechanisms that lead to shifts in symbiont community structure. PMID- 27459782 TI - Effects of intraspecific diversity on survivorship, growth, and recruitment of the eastern oyster across sites. AB - Intraspecific diversity, particularly of foundation species, can significantly affect population, community, and ecosystem processes. Examining how genetic diversity relates to demographic traits provides a key mechanistic link from genotypic and phenotypic variation of taxa with complex life histories to their population dynamics. We conducted a field experiment to assess how two metrics of intraspecific diversity (cohort diversity, the number of independent juvenile cohorts created from different adult source populations, and genetic relatedness, genetic similarity among individuals within and across cohorts) affect the survivorship, growth, and recruitment of the foundation species Crassostrea virginica. To assess the effects of both cohort diversity and genetic relatedness on oyster demographic traits under different environmental conditions, we manipulated juvenile oyster diversity and predator exposure (presence/absence of a cage) at two sites differing in resource availability and predation intensity. Differences in predation pressure between sites overwhelmingly determined post settlement survivorship of oysters. However, in the absence of predation (i.e., cage treatment), one or both metrics of intraspecific diversity, in addition to site, influenced long-term survivorship, growth, and recruitment. While both cohort diversity and genetic relatedness were negatively associated with long term survivorship, genetic relatedness alone showed a positive association with growth and cohort diversity alone showed a positive association with recruitment. Thus, our results demonstrate that in the absence of predation, intraspecific diversity can affect multiple demographic traits of a foundation species, but the relative importance of these effects depends on the environmental context. Moreover, the magnitude and direction of these effects vary depending on the diversity metric, cohort diversity or genetic relatedness, suggesting that although they are inversely related in this system, each captures sufficiently different components of intraspecific diversity. Given the global loss of oyster reef habitat and rapid decline in oyster population size, our results are particularly relevant to management and restoration. In addition, aquaculture, which commonly excludes predators during early life history stages, may benefit from incorporation of oyster cohort diversity into standard practice. PMID- 27459783 TI - Chemolithoautotrophy supports macroinvertebrate food webs and affects diversity and stability in groundwater communities. AB - The prevailing paradigm in subterranean ecology is that below-ground food webs are simple, limited to one or two trophic levels, and composed of generalist species because of spatio-temporally patchy food resources and pervasive energy limitation. This paradigm is based on relatively few studies of easily accessible, air-filled caves. However, in some subterranean ecosystems, chemolithoautotrophy can subsidize or replace surface-based allochthonous inputs of photosynthetically derived organic matter (OM) as a basal food resource and promote niche specialization and evolution of higher trophic levels. Consequently, the current subterranean trophic paradigm fails to account for variation in resources, trophic specialization, and food chain length in some subterranean ecosystems. We reevaluated the subterranean food web paradigm by examining spatial variation in the isotopic composition of basal food resources and consumers, food web structure, stygobiont species diversity, and chromophoric organic matter (CDOM), across a geochemical gradient in a large and complex groundwater system, the Edwards Aquifer in Central Texas (USA). Mean delta13C values of stygobiont communities become increasingly more negative along the gradient of photosynthetic OM sources near the aquifer recharge zone to chemolithoautotrophic OM sources closer to the freshwater-saline water interface (FWSWI) between oxygenated freshwater and anoxic, sulfide-rich saline water. Stygobiont community species richness declined with increasing distance from the FWSWI. Bayesian mixing models were used to estimate the relative importance of photosynthetic OM and chemolithoautorophic OM for stygobiont communities at three biogeochemically distinct sites. The contribution of chemolithoautotrophic OM to consumers at these sites ranged between 25% and 69% of total OM utilized and comprised as much as 88% of the diet for one species. In addition, the food web adjacent to the FWSWI had greater trophic diversity when compared to the other two sites. Our results suggest that diverse OM sources and in situ, chemolithoautotrophic OM production can support complex groundwater food webs and increase species richness. Chemolithoautotrophy has been fundamental for the long term maintenance of species diversity, trophic complexity, and community stability in this subterranean ecosystem, especially during periods of decreased photosynthetic production and groundwater recharge that have occurred over geologic time scales. PMID- 27459784 TI - Plant community and soil chemistry responses to long-term nitrogen inputs drive changes in alpine bacterial communities. AB - Bacterial community composition and diversity was studied in alpine tundra soils across a plant species and moisture gradient in 20 y-old experimental plots with four nutrient addition regimes (control, nitrogen (N), phosphorus (P) or both nutrients). Different bacterial communities inhabited different alpine meadows, reflecting differences in moisture, nutrients and plant species. Bacterial community alpha-diversity metrics were strongly correlated with plant richness and the production of forbs. After meadow type, N addition proved the strongest determinant of bacterial community structure. Structural Equation Modeling demonstrated that tundra bacterial community responses to N addition occur via changes in plant community composition and soil pH resulting from N inputs, thus disentangling the influence of direct (resource availability) vs. indirect (changes in plant community structure and soil pH) N effects that have remained unexplored in past work examining bacterial responses to long-term N inputs in these vulnerable environments. Across meadow types, the relative influence of these indirect N effects on bacterial community structure varied. In explicitly evaluating the relative importance of direct and indirect effects of long-term N addition on bacterial communities, this study provides new mechanistic understandings of the interaction between plant and microbial community responses to N inputs amidst environmental change. PMID- 27459785 TI - Soil moisture mediates alpine life form and community productivity responses to warming. AB - Climate change is expected to alter primary production and community composition in alpine ecosystems, but the direction and magnitude of change is debated. Warmer, wetter growing seasons may increase productivity; however, in the absence of additional precipitation, increased temperatures may decrease soil moisture, thereby diminishing any positive effect of warming. Since plant species show individual responses to environmental change, responses may depend on community composition and vary across life form or functional groups. We warmed an alpine plant community at Niwot Ridge, Colorado continuously for four years to test whether warming increases or decreases productivity of life form groups and the whole community. We provided supplemental water to a subset of plots to alleviate the drying effect of warming. We measured annual above-ground productivity and soil temperature and moisture, from which we calculated soil degree days and adequate soil moisture days. Using an information-theoretic approach, we observed that positive productivity responses to warming at the community level occur only when warming is combined with supplemental watering; otherwise we observed decreased productivity. Watering also increased community productivity in the absence of warming. Forbs accounted for the majority of the productivity at the site and drove the contingent community response to warming, while cushions drove the generally positive response to watering and graminoids muted the community response. Warming advanced snowmelt and increased soil degree days, while watering increased adequate soil moisture days. Heated and watered plots had more adequate soil moisture days than heated plots. Overall, measured changes in soil temperature and moisture in response to treatments were consistent with expected productivity responses. We found that available soil moisture largely determines the responses of this forb-dominated alpine community to simulated climate warming. PMID- 27459786 TI - Evaluating the ecological impacts of salvage logging: can natural and anthropogenic disturbances promote coexistence? AB - Salvage logging following windthrow is common throughout forests worldwide even though the practice is often considered inimical to forest recovery. Because salvaging removes trees, crushes seedlings, and compacts soils, many warn this practice may delay succession, suppress diversity, and alter composition. Here, over 8 yr following windthrow, we experimentally evaluate how salvaging affects tree succession across 11 gaps in Eastern deciduous forests of Pennsylvania, wherein each gap was divided into salvaged and control (unsalvaged) halves. Our gaps vary in size and windthrow severity, and we explicitly account for this variation as well as variation in soil disturbance (i.e., scarification) resulting from salvaging so that our results would be generalizable. Salvage logging had modest and ephemeral impacts on tree succession. Seedling richness and density declined similarly over time in both salvaged and unsalvaged areas as individuals grew into saplings. The primary impact of salvaging on succession occurred where salvaging scarified soils. Here, salvaging caused 41 to 82% declines in sapling abundance, richness, and diversity, but these differences largely disappeared within 5 yr. Additionally, we documented interactions between windthrow severity and scarification. Specifically, low-severity windthrow and scarification combined reinforced dominance by shade-tolerant and browse-tolerant species (Acer pensylvanicum, Fagus grandifolia). In contrast, high windthrow severity and scarification together reduced the density of a fast-growing pioneer tree (Prunus pensylvanica) and non-tree vegetation cover by 75% and 26%, respectively. This reduction enhanced the recruitment of two mid-successional tree species, Acer rubrum and Prunus serotina, by 2 and 3-fold, respectively. Thus, our findings demonstrate that salvaging creates novel microsites and mitigates competing vegetation, thereby enhancing establishment of important hardwoods and promoting tree species coexistence. Our results, coupled with an assessment of 27 published post-windthrow salvage studies, suggest short-term studies may overestimate the impact of salvaging on regeneration. We conclude that the ecological costs and benefits of salvaging depend upon the variation in canopy and soil disturbance severity as well as the timescale at which effects are evaluated. Thus, our findings are inconsistent with the view that salvaging inexorably undermines plant diversity; rather we suggest salvaging can promote tree species coexistence within various contexts. PMID- 27459787 TI - Phylogenetic impoverishment of plant communities following chronic human disturbances in the Brazilian Caatinga. AB - Chronic disturbances, such as selective logging, firewood extraction and extensive grazing, may lead to the taxonomic and phylogenetic impoverishment of remaining old-growth forest communities worldwide; however, the empirical evidence on this topic is limited. We tested this hypothesis in the Caatinga vegetation--a seasonally dry tropical forest restricted to northeast Brazil. We sampled 11,653 individuals (adults, saplings, and seedlings) from 51 species in 29 plots distributed along a gradient of chronic disturbance. The gradient was assessed using a chronic disturbance index (CDI) based on five recognized indicators of chronic disturbances: proximity to urban center, houses and roads and the density of both people and livestock. We used linear models to test if mean effective number of lineages, mean phylogenetic distance and phylogenetic dispersion decreased with CDI and if such relationships differed among ontogenetic stages. As expected, the mean effective number of lineages and the mean phylogenetic distance were negatively related to CDI, and such diversity losses occurred irrespective of ontogeny. Yet the increase in phylogenetic clustering in more disturbed plots was only evident in seedlings and saplings, mostly because clades with more descendent taxa than expected by chance (e.g., Euphorbiaceae) thrived in more disturbed plots. This novel study indicates that chronic human disturbances are promoting the phylogenetic impoverishment of the irreplaceable woody flora of the Brazilian Caatinga forest. The highest impoverishment was observed in seedlings and saplings, indicating that if current chronic disturbances remain, they will result in increasingly poorer phylogenetically forests. This loss of evolutionary history will potentially limit the capacity of this ecosystem to respond to human disturbances (i.e., lower ecological resilience) and particularly their ability to adapt to rapid climatic changes in the region. PMID- 27459788 TI - Enhanced facilitation at the extreme end of the aridity gradient in the Atacama Desert: a community-level approach. AB - Plant facilitation is now recognized as an important process in severe environments. However, there is still no agreement on how facilitation changes as conditions become increasingly severe. The classic stress gradient hypothesis (SGH) predicts a monotonic increase in facilitation, which rises in frequency as conditions approach the extreme end of the environmental gradient. However, few studies have evaluated the validity of the SGH at the community level, the level at which it was formulated. Moreover, few studies have tested the SGH at either extreme of the gradient, and very few have excluded the effect of livestock on community response to stress. In line with the SGH, we hypothesized that several spatial pattern summary statistics would change monotonically from the least to the most arid sites, indicating increasingly aggregated patterns. In this study, we performed an evaluation of the SGH both within communities of shrub species and across a large portion of the Atacama Desert, and we isolated the abiotic component of the SGH. Our environmental gradient covered an extreme aridity gradient (< 20-130 mm annual precipitation). To perform point pattern analysis, we established 13 sites with environmental conditions representing four distinct levels of this gradient. Further, we conducted species co-occurrence analyses at 19 sites along the gradient. Both sets of analyses showed stronger positive spatial associations among plants at the most extreme end of the gradient. This was true regardless of whether we included all individuals, only small individuals located around large ones, or individuals in species pairs. Moreover, species tended to show greater co-occurrence as environmental severity increased. This increase in aggregation in the plant community seems to correlate with an increase in the strength of positive interspecific interactions, rather than greater clustering within each species. These monotonic increases in species co occurrence and spatial association in more severe environments are consistent with some of the predictions of SGH, and collectively these results suggest that as the climate becomes more arid, positive species pairs interactions tend to be prevalent in the community. PMID- 27459789 TI - Predation risk increases immune response in a larval dragonfly (Leucorrhinia intacta). AB - Predators often negatively affect prey performance through indirect, non consumptive effects. We investigated the potential relationship between predator induced stress and prey immune response. To test this, we administered a synthetic immune challenge into dragonfly larvae (Leucorrhinia intacta) and assessed a key immune response (level of encapsulation) in the presence and absence of a caged predator (Anax junius) at two temperatures (22 degrees C and 26 degrees C). We hypothesized that immune response would be lowered when predators were present due to lowered allocation of resources to immune function and leading to reduced encapsulation of the synthetic immune challenge. Contrary to our expectations, larvae exposed to caged predators had encapsulated monofilaments significantly more than larvae not exposed to caged predators. Levels of encapsulation did not differ across temperatures, nor interact with predator exposure. Our results suggest that the previously observed increase in mortality of L. intacta exposed to caged predators is not driven by immune suppression. In situations of increased predation risk, the exposure to predator cues may induce higher levels of melanin production, which could lead to physiological damage and high energetic costs. However, the costs and risks of increased allocations to immune responses and interactions with predation stress remain unknown. PMID- 27459790 TI - Suppression of savanna ants alters invertebrate composition and influences key ecosystem processes. AB - In almost every ecosystem, ants (Hymenoptera: Formicidae) are the dominant terrestrial invertebrate group. Their functional value was highlighted by Wilson (1987) who famously declared that invertebrates are the "little things that run the world." However, while it is generally accepted that ants fulfil important functions, few studies have tested these assumptions and demonstrated what happens in their absence. We report on a novel large-scale field experiment in undisturbed savanna habitat where we examined how ants influence the abundance of other invertebrate taxa in the system, and affect the key processes of decomposition and herbivory. Our experiment demonstrated that ants suppressed the abundance and activity of beetles, millipedes, and termites, and also influenced decomposition rates and levels of herbivory. Our study is the first to show that top-down control of termites by ants can have important ecosystem consequences. Further studies are needed to elucidate the effects ant communities have on other aspects of the ecosystem (e.g., soils, nutrient cycling, the microbial community) and how their relative importance for ecosystem function varies among ecosystem types (e.g., savanna vs. forest). PMID- 27459791 TI - Seasonal variation in the relative dominance of herbivore guilds in an African savanna. AB - African savannas are highly seasonal with a diverse array of both mammalian and invertebrate herbivores, yet herbivory studies have focused almost exclusively on mammals. We conducted a 2-yr exclosure experiment in South Africa's Kruger National Park to measure the relative impact of these two groups of herbivores on grass removal at both highly productive patches (termite mounds) and in the less productive savanna matrix. Invertebrate and mammalian herbivory was greater on termite mounds, but the relative importance of each group changed over time. Mammalian offtake was higher than invertebrates in the dry season, but can be eclipsed by invertebrates during the wet season when this group is more active. Our results demonstrate that invertebrates play a substantial role in savanna herbivory and should not be disregarded in attempts to understand the impacts of herbivory on ecosystems. PMID- 27459792 TI - [Effects of aluminium chloride on the methylation of app in hippocampal of rats]. AB - OBJECTIVE: To study the effect of aluminum chloride on amyloid precursor protein ( APP ) promoter methylation and the content of amyloid beta-protein (Abeta) in hippocampus of rats. METHODS: Forty male SPF grade SD rats were divided into four groups: control group (0.9% NaCl), 10 mg/kg AlCl3 group, 20 mg/kg AlCl3 group, and 30 mg/kg AlCl3 group, respectively. After treatment for 8 weeks, the APP methylation level and expressions of APP mRNA was detected by methylation specific PCR and quantitative real time PCR, respectively. The content of APP and Abeta were detected with enzym-linked immunosorbent assay (ELISA). RESULTS: With the increase of the content of aluminium chloride, the escape latency were significantly prolong (P < 0.05), numbers of traversing flat in AlCl3 20 mg/kg and AlCl3 30 mg/kg group high and were significantly decreased (P < 0.05), the methylation level of APP contaminated by AlCl3 were decreased (chi2 = 27.61, P < 0.05), the level of APP methylation in 30 mg/kg AlCl3 group was lower than three groups (P < 0.01). With the increase of aluminium chloride, the level of APP methylation were decreased (chi2 = 19.08, P < 0.01). With the increase of the content of aluminium chloride, the methylation level of APP treated with 20 mg/kg AlCl3 and 30 mg/kg AlCl3 were decreased compared with control group (P < 0.05), the level of APP methylation in 30 mg/kg AlCl3 group was lower than 10mg/kg AlCl3 group (P < 0.05), the APP mRNA expression level in AlCl3 group was of statistical significance compared to the control group (F = 8.973, P < 0.05), the level of APP mRNA in 30 mg/kg AlCl3 were higher than 10 mg/kg AlCl3 (P < 0.05). Compared with the control group, the content of APP and Abeta in hippocampus of AlCl3 group were increased (F = 11.14, P = 0. 032, F = 17.82, P = 0.018), and 30 mg/kg AlCl3 group were higher than 10 mg/kg AlCl3 (P < 0.05), the content of APP in 20 mg/kg AlCl3 group were higher than 10 mg/kg AlCl3 (P < 0.05). The result of immunohistochemistry revealed that the grey scale in hippocampus, which suggested that the deposition of Abeta was the most in 20 mg/kg AlCl3 group and 30 mg/kg AlCl3 group. CONCLUSION: Aluminium chloride might cause APP promoter methylation decline, affect the APP mRNA and APP expression increased and result in Abeta deposition in hippocampal. PMID- 27459793 TI - [Effects of BDE-209 exposure on differentiation capacity of human embryonic stem cells]. AB - OBJECTIVE: To study the effects of decabrominated biphenyl ether (BDE-209) exposure on differentiation capacity of human embryonic stem cells. METHODS: Human embryonic stem cell line FY-hES-10 cells were exposed to the concentrations of 0 (solvent control), 1, 10 to 100 nmol/L BDE-209 for 96 h and then were differentiated into embryoid bodies (EBs) in vitro. The RNA of EBs derived from FY-hES-10 cells at Day 10 was collected. OCT4,three-layer differentiation-related genes (AFP,SMA and PAX6) and oxidative stress-related genes (HIF1a, HIF2a and SOD1) expression was detected by Q-PCR. The contents of SOD was measured by using kit. RESULTS: Compared with the solvent control group, the expression levels of OCT4, SMA, HIF1a and HIF2a in BDE-209 exposure groups were increased, the expression levels of AFP, PAX6 and SOD1 were decreased, with statistically significant differences (P < 0.05). With the increase of the BDE-209 dose, the expression levels of OCT4 showed an increasing trend while the expression levels of SOD1 and the activity of the SOD showed a decreasing trend. CONCLUSION: BDE 209 may interfere with differentiation capacity of human embryonic stem cells resulting in developmental toxicity. PMID- 27459794 TI - [Role of nuclear factor E2 related factor 2 signaling pathway in malignant transformation induced by sodium arsenite]. AB - OBJECTIVE: To construct the malignant transformation model of human bronchial epithelial (HBE) cell line by exposing to low level of sodium arsenite and determine if the nuclear factor E2 related factor 2 (Nrf2) signaling pathway is involved in this process. METHODS: HBE cells were continuously exposed to 2.5 micromol/L sodium arsenite and malignant transformation occurred as evidenced by the MTT assay, colony formation assay and cell migration assay. Western blot was used to evaluate the expression of Nrf2, quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (10-1) during sodium arsenite-induced transformation of HBE cells. RESULTS: MTT assay demonstrated that the proliferation of HBE cells was out of control with increasing passages of sodium arsenite exposure. In As-HBE-T25 and As-HBE-T50 cells, the cell invasion ability was 2.04 and 4.17 times than that in normal HBE cells and colony formation rate was 1.33% depedent manner (P < 0.5). Also, the expresion of QO1 and HO-1, downstream of Nrf2 target proteins, were also decreased with the expression of Nrf2. CONCLUSION: The transformation of HBE cells induced by chronic exposure to sodium arsenite is mediated by decreased Nrf2 level and its downstream NQO1 and HO-1 protein, which subsequently promote the malignant proliferation. PMID- 27459795 TI - [Comparison BMC assessed by dual-energy X-ray absorptiometry and multi-frequency bioelectrical impedance in Chinese overweight and obesity adults]. AB - OBJECTIVE: To compare consistency of Body Mineral Content (BMC, kg) assessed by Multi-frequency Bioelectrical Impedance Analysis ( MF-BIA) and Dual Energy X-ray Absorptiometry (DXA) measurement, providing evidence for MF-BIA accurate application in Chinese overweight/obese adults. METHODS: A total of 1323 overweight/obesity adults aged 22-55 years were recruited voluntarily. All the subjects received the measurement of BMC both using MF-BIA and DXA. To evaluate the agreement of BMC measured by MF-BIA and DXA using interclass correlation coefficients (ICC), then establish correction prediction models. RESULTS: The mean difference of BMC between two methods was significant different with 0, overweight male subgroup was 0.28 kg, and 0.38 kg for obesity male, 0.24 kg for overweight female and 0.36 kg for obesity female, respectively (P < 0.05). The ICC of BMC between MF-BIA and DXA measurement were statistically significant in all subgroups (P < 0.01). The ICC for overweight male subgroup was 0.787, 0.796 for obesity male, 0.741 for overweight female and 0.788 for obesity female, respectively. Correction prediction model: overweight male population: BMC (DXA method) = -0.297 + 1.005 x BMC (MF-BIA method). Obese male population: BMC (DXA method) =0.302 + 0.799 x BMC (MF-BIA method). Overweight female groups: BMC (DXA method) = 0.780 + 0.598 x BMC (MF-BIA method). Obese female group: BMC (DXA method) = 0.755 + 0.597 x BMC (MF-BIA method). Upon examination, correction prediction models were better. Co ONCLUSION: The correlation and agreement of BMC measured by BIA and DXA are weak in Chinese overweight/obese adults. Therefore, consideration should be given to BMC measured by BIA method in Chinese overweight/obese adults. It should be corrected or adjusted to reduce errors compared with DXA method. PMID- 27459796 TI - [Optimization of primary hepatocytes model and study on the cytotoxicity of styrene and styrene oxide]. AB - OBJECTIVE: To establish a model in vitro for primary cultured mouse hepatocytes with high viability and function, and evaluate the acute toxicity of the primary hepatocytes exposed to the chemicals such as styrene and styrene oxide (SO). METHODS: Based on the classical method, the two-step collagenase digestion method was optimized by reverse and intermittent perfusion, restriction of digestion time as well as purification of percoll liquid. Hepatocytes were isolated from BALB/C mouse by an improved isolated method and then cultured in monolayer and sandwich configuration. The primary cultured hepatocytes model was assessed by various indexes including cell morphology, cell viability, intracellular glycogen granules, as well as albumin (ALB), lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and blood urine nitrogen (BUN) levels in the supernatant. In addition, the primary cultured hepatocytes were treated with various concentrations from 0.2 to 25 micromol/L of styrene and styrene oxide during different time from 3 to 48 hours. The cytotoxicity induced by the two toxicants was assessed by CCK-8 and LDH assays. RESULTS: On average, the isolation using this improved method resulted in the cell viability of (90.3 +/- 5.2) %, the cell purity of (95.3 +/- 4.2)% and the yield of (2.4 +/- 0.9) x 10(7) viable cells. More than 90% cells showed a typical morphological feature of hepatocytes in sandwich configuration within 7 days, and contained a large number of glycogen granules on the third day. The ALB secretion, ALT and LDH leakage and BUN synthesis as well as cell viability fluctuated during 8 days, and they stayed at stable levels between 3 to 7 days in sandwich configuration. But they fluctuated during 6 days in monolayer configuration. In comparison with the monolayer configuration, the levels of ALB and BUN were distinctly increased and the levels of LDH and ALT were significantly decreased in sandwich configuration. The levels of ALB [ (1.42 +/- 0.20) g/L ] and BUN [(1.97 +/- 0.22) mmol/L] as well as cell viability were the highest, while the levels of LDH [ (7.30 +/- 2.33) U/L] and ALT [ (6.51 +/- 1.86) U/L] were the lowest in sandwich configuration on the third day. The relative low cytotoxicity and high cell survival rate ( more than 90%) were shown in treated hepatocytes with styrene and styrene oxide within 6 hours by CCK-8 and LDH measurements, and there was no distinct difference in the determination of cytotoxicity between the two methods. With the prolonged exposure time, the cell survival rate was lower by CCK-8 assay (less than 85%) than the one by LDH assay. The relative obvious cytotoxicity and low cell survival rate (about 85%) by CCK-8 method were revealed in treated cells with 5 micromol/L of styrene and styrene oxide for 24 hours, but there was no significant difference between CCK-8 and LDH assays. With the increase of the concentrations, the cell survival rate was lower by CCK-8 assay (less than 80%) compared with LDH assay. CONCLUSION: The improved two-step collagenase digestion method combination with sandwich culture method might maintain the morphology and function of primary cultured mouse hepatocytes for seven days. The cytotoxic effects of styrene and styrene oxide might be accurately evaluated by means of primary cultured hepatocyte model from 3 to 7 days. The chemicals might have major adverse effects on the functions of the organelles in hepatocytes such as mitochondria, but little influence to the cell membrane damage. PMID- 27459797 TI - [Association of leptin receptor gene polymorphrism with metabolic syndrome in older Han adults from major cities in China]. AB - OBJECTIVE: To investigate the relationship of leptin receptor gene rs1137100 and rs1137101 single nucleotide polymorphrism (SNP) with metabolic syndrome (MS) in older Han adults from major cities in China. METHODS: A total of 2082 older Han adults were selected from 18 major cities including 15 provinces/municipalities of China National Nutrition and Health Survey in 2002. According to the MS definition proposed by Joint Interim Statement (JIS), the subjects were divided into MS and control groups. Plasma leptin and insulin levels were measured. The genotypes of rs1137100 and rs1137101 were detected by Taqman method. Association of genotypes of leptin receptor gene SNPs with MS was investigated. RESULTS: The MS group showed higher body mass index (BMI), waist circumference, fasting serum glucose, systolic blood pressure (SBP) and diastolic blood pressure (DBP), triglycerides (TG), serum total cholesterol (TC), insulin, homeostasis model of assessment for insulin resistence index (HOMA-IR) and leptin levels than those of control individuals, while the high density lipoprotein cholesterol (HDL-c) was significantly lower than the control group. The, GG, AA, GA genotypes distribution and the A allele frequency of rs1137100 and rs1137101 were similar between the two groups. The DBP and SBP level were obviously higher in AA genotype. The HDL-c concentration Was significantly lower in AA and GA + AA genotype. The AA and GA genotypes carriers in rs1137100 had similar risk for MS when comparing with the GG genotypes, and the OR values were 1.23 (95% CI 0.90 1.67) and 2.23 (95% CI 0.83-6.44), respectively. The AA and GA genotypes carriers in rs1137101 had similar risk for MS when comparing with the GG genotypes, and the OR values were 1.23 (95% CI 0.90-1.67) and 2.23 (95% CI 0.83-6.44), respectively. CONCLUSION: Leptin receptor genes rs1137100 and rs1137101 are not associated with pathogenesis of MS in older Han adults, but it may relate with hypertension or lipid abnormality. PMID- 27459798 TI - [Effect of dietary cholesterol intake on stroke incidence among Chinese adults: evidence from China Health and Nutrition Survey]. AB - OBJECTIVE: To examine the longitudinal association between dietary cholesterol intake and stroke incidence in Chinese adults. METHODS: The data were from 5833 non-stroke participants aged 30-98 in 1997 and more than one repeated measurements in the following five waves (2000, 2004, 2006, 2009 and 2011) of the China Health and Nutrition Survey. 5805 participants were included eventually after removing those with abnormal dietary cholesternul intake. Dietary cholesterol and energy intake was assessed with 3 d - 24 h dietary recalls in all the waves. Self-reported hypertension, diabetes mellitus, alcohol drinking, smoking, and standardized measurement of waist circumstance were collected also. Time-dependent Cox proportional hazard regression models were constructed to estimate relative risks (RR) with 95% confidence intervals (CI). RESULTS: During the mean 11. 3 years follow-up, 198 stroke events of 5805 participants were ascertained. The quintiles dietary cholesterol intake were 70.0, 146.9, 218.3, 297.8 and 425.9 mg/d. After adjusted for potential confounders, the time dependent cholesterol intake, baseline cholesterol intake and the mean cholesterol intake during 1997-2011 were insignificantly associated with stroke. The relative risks and 95% confidence intervals were 1. 000 (0.999 - 1.001), 1.000 (0.999 - 1.001 ) and 0.999 (0.998 - 1.001) respectively. The cholesterol intake quintiles were insignificantly associated with stroke incidence. The relative risks and 95% confidence intervals versus lowest quintile were 0.812 (0.504 - 1.310), 0.644 (0.389 - 1.066) 0.913 (0.576 - 1.446) and 0.692 (0.416 - 1.152) respectively. CONCLUSION: Effect of dietary cholesterol intake on stroke incidence might was insignificant in Chinese adults. PMID- 27459799 TI - [Analysis of the dietary factors on sarcopenia in elderly in Beijing]. AB - OBJECTIVE: To analyze the dietary factors on sarcopenia in elderly in Beijing and provide nutritional recommendations for the sarcopenia. METHOD: A total of 830 participants aged 60 and above and without serious diseases were selected from two representative communities in Beijing. A cross-sectional research design was used, including inquiry investigation, dietary surveys (food frequency questionnaire) anthropometry, muscle mass and functional assessment. RESULTS: The prevalence of sarcopenia was 20.1% in this area, the men was 17.1%, while the women was 21.6% (P > 0.05). The prevalence of sarcopenia in the five age groups has significant statistically difference (chi2 = 19.03, P = 0.0008) and increased with age rising (Z = -4.18, P < 0.0001). The prevalence of sarcopenia would be downward if the time of exercise prolonged and body mass index (BMI) increased (P < 0.05). The prevalence of sarcopenia in the group of meat consumption <35, 35 70, > 70 g/d was 24.5%,19.9% and 15. 3% (chi2 = 6.02, P = 0.0492), respectively (trend test for groups comparison, Z = 2.45, P =0.0141). The prevalence of sarcopenia in the group of egg consumption <35, 35-60, >60 g/d was 25.8%, 18.7% and 11.3% (chi2 = 6.50, P = 0.0388), respectively ( trend test for groups comparison, Z =2. 55, P = 0.0109). The prevalence of sarcopenia in the group of energy consumption < 1612, 1612-2109, > 2109 kcal/d was 25.8%,19.5% and 15. 0% (x2 = 8. 19 , P = 0. 0158), respectively (trend test for groups comparison, Z = 2.87, P = 0.0042). The prevalence of sarcopenia in the group of protein consumption < 58.2, 58.2 - 78.4, > 78.4 g/d was 25.3%, 18.2% and 16.7% (chi2 = 5.97, P = 0. 0505 ) , respectively (Z = 2.28, P = 0.0227). After controlling the influence of age, BMI, exercise and education, meat consumption (beta = -0.1703, P = 0.0119), egg consumption (beta = -0.1545, P = 0.0302) and the high quality protein consumption (beta = -0.1805, P = 0.0302) were negatively related with sarcopenia. CONCLUSION: Animal food, such as meet and egg, is an important protective factor for sarcopenia. Therefore, it is the first important thing for the elderly to ensure adequate energy intake, then you should increase the animal food intake which contains high quality protein to prevent sarcopenia. PMID- 27459800 TI - [Analysis of physical activity and sedentary behaviors in children and adolescents from 12 provinces/municipalities in China]. AB - OBJECTIVE: To evaluate the pattern and level of physical activity (PA) and sedentary behaviors in Chinese children and adolescents. METHODS: The data of present study were derived from China Health and Nutrition Survey in 2011. Subjects aged 7-18 years with completed demographic, PA and sedentary behavior data were included to analyze the proportions of participations in PA outside school, PA in school, domestic PA, PA in travel and sedentary behaviors. In subjects with PA and sedentary behaviors, PA and sedentary behavior levels were estimated by age, gender, residence areus and household income. RESULTS: Amony the five types of activities studies, the proportion of children and adolescents with sedentary behaviors was highest (97.9%), while that of PA outside school was lowest (33.6%), the distribution of participations of various PA and sedentary behaviors were similor regardless of age and gender. The median levels of PA outside school and sedentary behaviors in children and adolescents having corresponding activities were the highest, 39.9 and 36.1 MET-h/week, respectively, which suggested that the time on sedentary behaviors was long. The differences in levels of various PA and sedentary behaviors by age, gender and residence were observed (all P < 0.05). CONCLUSION: In general, PA is deficient in Chinese children and adolescents. The promotion programmes to increas PA level need to be strengthened. PMID- 27459801 TI - [Consumption status and trend of added sugar containing food among Chinese from 2002 to 2012]. AB - OBJECTIVE: To understand the status and trend of added sugar containing food consumption from 2002 to 2012. METHODS: Using dietary data from the Chinese Nutrition and Health Survey in 2002 and the Chinese Nutrition and Health Surveillance in 2010-2012, to analyze the consumption status of added sugar containing food in these two years and to compare the difference between the past ten years in China. RESULTS: From 2002 to 2012, consumption rate of added sugar containing food increased from 20.4% to 26.9%, the consumption rate of all ages in 2012 was higher than in 2002 (t = -3.75, P = 0.0133), female higher than male (t = 0.86, P = 0.3991). The percentage of total calories from added sugar containing food was decreasing from 9.48% in 2002 to 9.09% in 2012, the difference was statistically significant (t = 4.16, P < 0.0001). From 2002 to 2012, species composition ratio of sugar-sweetened beverages (11.7% and 8.5%), dairy products (8.1% and 15.0%), instants food (26.6% and 39.0%) was increasing in some degree. CONCLUSION: The consumption level of added sugar in China is low, which still under the recommended limits (10%) of WHO, but the consumption rate of food containing added sugar is increasing generally. PMID- 27459802 TI - [Association between dietary calcium/dairy intakes and overweight/obesity]. AB - OBJECTIVE: To investigate the intakes of dietary calcium/dairy and the current prevalence of overweight and obesity among children and adolescents aged 7-15 in Longquanyi District, Chengdu, and to explore the association of dietary calcium and dairy intake with overweight/obesity. METHODS: 1738 children and adolescents were recruited in the cross-sectional study using cluster random sampling method. Information on dietary calcium and dairy intakes was collected using 24-hour dietary recall and food frequency questionnaire (FFQ). Height, weight and waist circumference were measured to calculate body mass index (BMI)/waist-to-height ratio (WHtR) and body mass index standard deviation (BMI SDS). Overweight/obesity was defined based on the criteria of Working Group on Obesity in China (WGOC). Participants were grouped into 3 categories indicating lower, moderate and higher intakes of dietary calcium and dairy, respectively. The association of dietary calcium and dairy consumption with (BMI SDS) /WHtR and the prevalence of overweight/obesity was analyzed after being stratified by gender and age. RESULTS: The prevalence of overweight/obesity in boys and girls were 11.92%/7.04% and 8.04%/6.30%, respectively. The intake of dietary calcium and dairy in girls were much higher than that in boys (P < 0.0001). Among boys aged 7-9 years, those with higher consumption of dairy had the higher BMI SDS (P = 0.01). Among boys aged 10-12 years, those with higher consumption of dietary calcium had the lowest prevalence of overweight (P = 0.03). However, similar results were not observed among girls. CONCLUSIONS: Dietary calcium and dairy intakes seemed to be related to overweight/ obesity in boys, however the associations were inconsistent among different age groups. Associations between consumption of calcium, dairy and overweight/obesity were not found among girls. PMID- 27459803 TI - [Relationship between dietary pattern and maternal state of fatty acids during pregnancy in three regions of China]. AB - OBJECTIVE: To investigate the dietary pattern during pregnancy and the compositions of fatty acids of phosphatidylcholine (PC) during pregnancy in different regions of China. METHOD: 35 Health women of each region were recruited from three different geographical regions in China: Jurong (an inland region close to freshwater), Rizhao (a coastal region) and Xushui (an inland region with limited access to freshwater). All women were long-term residents of their respective region. Their dietary status (including consumption frequency of food and consumption of culinary oil) during second trimester pregnancy was recorded and the fatty acid composition of PC in plasma during late pregnancy (34 weeks gestation) was quantified by GC. RESULTS: The consumption frequency of marine fish in Rizhao was significant higher than in other two regions. The main n-3 polyunsaturated fatty acids of PC in plasma was docosahexaenoic acid (DHA) in all regions. The composition of DHA in three regions were (3.31 +/- 0.77) %, (3.74 +/ 1.21) % and (2.44 +/- 0.63) %, respectively. The composition of DHA in Xushui was significant lower than in other two regions (P < 0.017). There was positive relationship between consumption frequency of marine fish and composition of DHA of PC in plasma (r = 0.337, P < 0.05). CONCLUSION: There was relationship between pregnant women's fatty acids composition of PC in plasma and their dietary. The consumption of food with high content of n-3 long chain polyunsaturated fatty acids during pregnancy would be more practical for DHA store of pregnant women. PMID- 27459804 TI - [Survey and analysis of the intakes of energy and macronutrients in rural boarding school students]. AB - OBJECTIVE: To preliminarily survey the intakes of energy and macronutrients in rural boarding school students and analyse the affect factors of discrepancies between different sex and age groups. METHODS: A total of 1834 rural boarding junior high school first grade students were selected from 16 provinces, and stratified cluster sampling method was used. The method of weight recording and three days dietary recall were used to investigate the diet of boarding school students. RESULTS: The ratios which reached the EER of energy intakes in boy and girl groups were 37.0% and 46.7% (P < 0.05) respectively, and the proportion of the intakes level of EER among the age groups of 11y ~ and 14y ~ for both boys and girls were 93.4%, 81.1% (P < 0.05) and 102.1%, 87.1% (P < 0.05) respectively. The ratios which reached the EAR of protein intakes in boy and girl groups were 57.7% and 61.4% ( P > 0.05) respectively, and the proportion of the intakes level of EAR among the age groups of 11y ~ and 14y ~ for both boys and girls were 124.8%, 107.3% (P > 0.05) and 134.8%, 112.1% (P < 0.05) respectively. The ratios which reached the EAR of total carbohydrate intakes in boy and girl groups were 85.0% and 77.5% (P < 0.05) respectively, and the proportion of the intakes level of EAR among the age groups of 11y ~ and 14y ~ for both boys and girls were 202.0% and 240.0% (P < 0.05), 180.1% and 205.4% (P < 0.05 ) respectively. The ratios which reached the AMDR of total fat intakes in boy and girl groups were 25.4% and 22.0% (P > 0.05) respectively, and among the age groups of 11y ~ and 14y ~ for both boys and girls were 21.8% and 30.5% (P < 0.05), 20.2% and 25.5% (P > 0.05) respectively. CONCLUSIONS: Double burden of nutrient might exist in the rural boarding schools. The status of nutrition could be improved evidently, by fulfilling the relative national policies, promoting the balance of the nutrition supplying in schools, and enriching the boarding students' knowledge of nutrition. PMID- 27459805 TI - [Comparison of 24 hour dietary recalls with a food frequency questionnaire in evaluating dietary fat intakes]. AB - OBJECTIVE: To compare the difference and correlation of dietary fat intakes measures from the food-frequency questionnaire (FFQ) with measures from 24 hour dietary recalls (24HDRs), and provide evidence for the future research of dietary fat. METHODS: A total of 511 participants, selected from Zhejiang province, were asked to complete an FFQ and 24HDRs. The consumption of energy, fat, fatty acids, the percentages of energy from fat were calculated with the FFQ and 24HDRs and the results were analyzed. RESULTS: There was no difference between FFQ and 24HDRs in energy, fat, fatty acids and the percentages of energy from fat. Sperman's rank correlation coefficient between the two methods were 0.51 in energy, 0.58 in fat and 0. 57 in the percentages of energy from fat. The proportion of subjects who were assigned to the same or adjacent quintile groups were 80.73% for energy, 84.81% for fat and 83. 38% for the percentages of energy from fat. CONCLUSION: An effective FFQ can evaluate dietary fat consumption and rank participants well. Selecting the simple and easy FFQ method to assess the dietary fat intake would he a good choice when research the relationship between dietary fat and chronic disease in the future. PMID- 27459806 TI - [Total dietary exposure assessment of emerging brominated flame retardants in Beijing]. AB - OBJECTIVE: To estimate the exposure characteristic of six emerging brominated flame retardant for Beijing residents by dietary intake. METHODS: 2,3,5,6 tetrabromo-p-xylene (pTBX), pentabromotoluene (PBT), 1, 2, 3, 4, 5-pentabromo-6- ethylbenzene (PBEB), hexahromobenzene (HBB), hexachlorocyclopentadienyl- dibromocyclooctane (DBHCTD) and 1,2-bis(2 ,4 ,6-tribromo phenoxy) ethane (BTBPE) were detected by atmospheric pressure gas chromatography tandem mass spectrometry (APGC-MS/MS) in total dietary samples from Beijing. Dietary intake assessments of human exposure were carried out according to results of determination. RESULTS: PBT, PBEB, HBB and BTBPE were occurred with concentration between 1.2-29.4 pg/g wet weight. The detection rates of HBB and BTBPE in animal--origin samples were higher than those in plant-origin samples, and there were significant differences (P < 0.05). The exposure level of Beijing residents to six emerging brominated flame retardants were 296.8 pg/(kg-d). CONCLUSION: The exposure level of emerging brominated flame retardants by dietary intake in Beijing is relatively low, and meat is the main source of BTBPE dietary intake. PMID- 27459807 TI - [Relevant factors of early puberty timing in urban primary schools in Chongqing]. AB - OBJECTIVE: To investigate the status of puberty timing and relevant factors of early puberty timing in children from grade one to four in urban primary schools of Chongqing. METHODS: According to the purposive sample method, four urban primary schools in Chongqing were selected and of which 1471 children from grade one to four who have obtained informed consent were recruited. Questionnaire survey on social-demographic characteristics and family environment (e.g., age, parents' relationship, diet and lifestyle, etc), and Pubertal Development Scale (PDS) survey and physical examination (measurements of height, weight, pubertal development status, etc) were conducted. P25, P50, P75 ages of each important pubertal event were calculated by probit regression. Univariate and multivariate analysis were used to analyze relevant factors. RESULTS: The detection rate of early puberty timing was 17.7%, and the median ages of the onset of breast and testicular development were 10.77 and 11.48 years old, respectively. Multivariate logistic regression showed that early puberty timing occurred more likely in girls than in boys (OR = 0.561, 95% CI 0.406-0.774), and bad relationship between parents (OR = 1.320, 95% CI 1.007-1.729) and hair-products-use (OR = 1.685, 95%, CI 1.028-2.762) were risk factors of early puberty timing. CONCLUSION: Early onset of puberty in urban Chongqing is still exist. Gender, parents' relationship, and hair-products-use have an essential impact on early puberty timing. PMID- 27459808 TI - [Effects of diets with different n-6/n-3 fatty acids on cardiovascular risk factors in mice fed high-fat diets]. AB - To investigate effects of diets with different fatty acid composition on serum lipid profiles, inflammation, oxidative stress and endothelial function in mice fed high-fat diets. METHODS: Male KM mice were randomly divided into five groups and were fed normal control diet, high-fat lard diet, high-fat diets with n-6/n-3 polyunsaturated fatty acid (PUFA) ratios of 1:1, 5:1 nd 2:1 for fiv weeks, respectively. The levels of serum triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C ) iterlekin-6 (IL-6), alonildehyde (MDA), hypersensitive C-reactive protein (hs CRP), tumor ncrosis factor alpha (TNF-alpha), lipid lphaproxide (LPO), 8-iso postaglandin F2aalpha (8-iso-PGlphaF2u), oxidialphaed low-density lipoprotein (ox LDL), free faty acid (FFA), E-selectin (ES) and von Willebrand factor (vWF) were measured. RESULTS: The levels of serum LDL-C and non-HDL-C in the lard group were significantly higher than those in the other groups (P < 0.05). Th e ard group had. significntly higher serum TG and TC concentrations compared to 1:1 and 5: groups P <0. 05). The evels of serum FFA in 20:1 group wre significantly higher than those in 1:1 and 5:1 groups P < 0.05). Co mpred with the lard and 20:1 groups,the 1:1 and 5:1 groups displayed lower levels of inflammatory cytokines, oxidative stress and ES. The 5:1 group sgnificantly decreased the level of serum vWF compared to lard and 20:1 groups P < 0.05). CONCLUSION: diet with low n-6/n-3 PUFA ratio could improve lipid metabolism, inflammation, oxidative stress and endothelial function compared to high-fat diets with lard and higher n-6/n-3 PUFA ratio. The diet with low n-6/n-3 PUFA ratio can improve cardiovascular disease risk factors to prevent cardiovascular disease. PMID- 27459809 TI - [Inhibition effect on Microcystis aeruginosa PCC7806 as well as separation and identification of algicidal substances isolated from Salvinia natans (L.) All]. AB - OBJECTIVE: To study the inhibition effect of Salvinia natans ( L. ) All. on harmful algae. METHODS: With Microcystis aeruginosa as the subjects, deionized water, ethanol, acetone, ethyl acetate as solvent, four kinds of crude extracts from Salvinia natans (L.) All. were prepared, and their alga-inhibiting actions were verified, respectively. The crude extracts of Salvinia natans (L.) All. with better inhibition effect were selected. The components of algal inhibiting material through macroporous resin purification were obtained, and determined by gas chromatography-mass spectrometry (GC-MS). RESULTS: The algicidal effect as follows: ethyl acetate extract > acetone crude extract > ethanol crude extract > water crude extract. Meanwhile, the inhibitory substances of Salvinia natans (L.) All. may be: diacetone alcohol, methyl isobutenyl ketone, 5-methyl-2-(1 methylethyl)-1-hexanol, pentadecanal, 14-heptadecenal, cumene, butyl acetate, ascorbyl dipalmitate, 1, 2-benzenedicarboxylic acid, mono (2- ethylhexyl) ester, dibutyl phthalate and phthalic acid, butyl undecane ester. CONCLUSION: The algal inhibiting effect research of Salvinia natans (L.) All., as well as its separation and identification of allelochemicals supplys theoretical basis and practical evidence not only for algae control, but also exploitation of algal inhibiting agent. PMID- 27459810 TI - [Joint inhibitory effects researches on Microcystis aeruginosa and Chlorella pyrenoidosa of phenolic acids]. AB - OBJECTIVE: To investigate the inhibitory effects of single and compound phenolic acids on mixed algae. METHODS: Salicylic acid, cinnamic acid and pyrogallic acid were chosen individually or in pairs to act on mixed algae of Microcystis aeruginosa and Chlorella pyrenoidosa. RESULTS: Three phenolic acids that singled or paired showed certain inhibitory effects on the mixed algae, of which were pyrogallic acid > salicylic acid > cinnamic acid in single phenolic acid, the EC50s of the three phenolic acids on the mixture of Microcystis aeruginosa and Chlorella pyrenoidosa were 7.87, 64.90 and 89.34 mg/L at the day 6; and inhibition of the paired phenolic acid group was pyrogallic acid & salicylic acid group > pyrogallic acid & cinnamic acid group > salicylic acid & cinnamic acid, the first 2 groups had synergistic algal inhibitory effects and the last paired group showed additive action. CONCLUSION: Some specifically combined phenolic acids can lead to synergistic inhibiting effects on algae, which has better environmental safety for application due to the use of single phenolic acid was massively decreased. PMID- 27459811 TI - [Change in plasma nesfatin-1 concentration within high-fat diet induced nonalcoholic fatty liver disease rat models]. AB - OBJECTIVE: To investigate the change of plasma nesfatin-1 concentration in a nonalcoholic fatty liver disease rat model induced by high-fat diet, and explore its effect on the dysfunction of glucose and lipid metabolism. METHODS: The nonalcoholic fatty liver disease rat model was established through introduction of a high-fat diet, and four weeks later, the intraperitoneal glucose tolerance test was conducted. Serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total cholesterol (TC) triglyceride (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin, and insulin (INS) were measured via enzyme-linked immunosorbent assay (ELISA), the histological changes of the liver was observed via HE staining, and the protein expressions of beta-catenin, p-beta-catenin and cyclin D1 in the liver were detected using western blot and compared with beta actin. RESULTS: The bodyweight, liver weight, liver index, and area under the curve of the intraperitoneal glucose tolerance test were all higher in the model rats than those in the controls. Compared with the control, serum concentrations of ALT, TBIL, IBIL, TC and LDL-C in the model rats were all increased. The plasma nesfatin-1 level was increased in model rats while the plasma concentrations of leptin and insulin were decreased, and a negative correlation was found between the plasma concentration of nesfatin-1 and leptin. Inflammation and hepatocyte steatosis were detected in the livers of model rats, and the protein expression of cyclinD1 was upregulated while the phosphorylation of beta-catenin was decreased in the livers of the model rats. CONCLUSION: Post-creation of nonalcoholic fatty liver disease rat models through high fat diets, changes were observed in plasma nesfatin-1 concentration, perhaps a vital part of glucose and lipid metabolism dysfunction. PMID- 27459812 TI - [Identification of icaritin metabolites in rat plasma by UPLC-QTOF-MS]. AB - OBJECTIVE: To identify metabolites of icaritin in rat plasma by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF-MS). METHODS: Acetonitrile was employed to precipitate protein in rat plasma. The separation was carried out on a BEH C18 column (2.1 mm x 50 mm,1.7 microm) using a gradient mobile phase of acetonitrile, water and ammonium formate. High resolution mass spectrometry was applied for qualitative analysis in positive and negative ion modes, respectively. The metabolites were predicted by the PALLAS software and identified in the UNIFI database. RESULTS: Twenty-four metabolites of icaritin in rat plasma which were generated by reactions of hydroxylation, hydrogenation, epoxidation, acetylation, demethylation, dehydroxylation, sulfation conjugation, glucuronidation and glycosylation, were identified. CONCLUSION: A rapid and efficient UPLC-QTOF-MS method is established for the identification of icaritin metabolites in rat plasma, which provided support for the preclinical safety evaluation of icaritin. PMID- 27459813 TI - [Determination of 17 plasticizers in dairy food]. AB - OBJECTIVE: A method was established for determination of 17 kinds of plasticizers in infant formula by solid-phase extraction coupled with UPLC-MS/MS. METHODS: The plasticizers were extracted from the infant formula with acetonitrile, and purified by solid phase extraction column named OASIS Prime HLB. The analytes were then separated by the chromatographic column (BEH Phenyl, 2.1 mm x 100 mm x 1.7 microm). The ion fragment information analytes were obtained using ultra high performance liquid chromatography-tandem mass spectrometry under multiple reaction monitoring mode and the isotope internal standards were used to quantify by calibration curves. RESULTS: The method showed a good linearity (R2 > 0.9990) in the range of 0.5-500 microg/L for 17 plasticizers analytes with average recovery rates of 89.8%-119.0% (n = 6) and the relative standard deviation (RSD) within 3.62%-12.60%. The limits of quantification (LOQ) were between 1 microg/kg and 14 microg/kg. CONCLUSION: The method is simple, sensitive and accurate, and the sample pretreatment is very convenient especially, is suitable for the determination of 17 plasticizers in infant formula and dairy products. PMID- 27459814 TI - [Determination of 3-hydroxyisovaleryl carnitine in plasma and urinary excretion by ultra-performance liquid chromatography-tandem mass spectrometry]. AB - OBJECTIVE: An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS ) method was developed for the determination of 3-hydroxyisovaleryl carnitine in plasma and urinary excretion. METHODS: Plasma and urinary excretion samples were centrifugated with high speed at 3000 x g for 10 minutes, and the MCX solid phase extraction column was used to filter and purify the liquid samples. The following procedures were elution, wash-out, redissolve, detection. The chromatographic separation was achieved on a Waters Acquity UPLC BEH C18 column (2.1 mm x 50 mm, 1.7 microm), with a mobile phase composed of 0.1% formic acid in water-methanol with gradient elution. Analyte quantification was performed in the positive electrospray ionization mode and multiple monitoring. The quantification and qualification were performed using the internal standard of 3-hydroxyisovaleryl carnitine, then the evaluation for accuracy and precision were followed. RESULTS: The linear range of 3-hydroxyisovaleryl carnitine were 0.1-20.0 microg/L in the plasma and 5.0-200 microg/L in urine, with both the linear correlation coefficient above 0. 99. Moreover, in three standard levels, rate of recovery in plasma and urine ranged from 78.6% to 115.6%. The RSD of six parallel determination for the 3HIA-carnitine in plasma and urine were 4.80% and 5.70% respectively. The detection and quantification limits for plasma and urine were 0.04 microg/L, 0.1 microg/L and 0.03 microg/L, 0.08 microg/L, respectively. CONCLUSION: The sample preparation method is simple and fast, and the method can be used to analyze 3-hydroxyisovaleryl carnitine in plasma and urinary excretion efficiently and sensitively. PMID- 27459815 TI - [Optimization for determination methods of alpha-, beta- carotene in vegetables]. AB - OBJECTIVE: To optimize the determination method of carotene in order to separate the alpha and beta carotene. METHODS: The homogenized samples were extracted with ethanol before saponification, and then extracted with petroleum ether followed by wash, dry and concentration. At last, the separation was performed on the high performance liquid chromatographic with YMC Carotenoid C30 column (3 microm 4.6 mm x 150 mm). The mobile phase was consisted of A (methanol: acetonitrile: water = 73.5: 24.5:2) and B (methyl tert-butyl ether), with a linear gradient elution. The detection wavelength was 450 nm. RESULTS: The C30-HPLC column was used throughout the experiment exhibiting a significant benefit for the separation of carotienes and isomers. Multifactor analysis of variance showed that heating by the anhydrous ethyl alcohol before the saponification was more suitable for extracting the carotenoids from vegetables. Under the optimal condition, the linear range of alpha-carotene was 0.495-9.90 microg/mL, and all-trans-beta carotene was 0.552-10.4 microg/mL, with the linear correlation coefficient were above 0. 999. The relative standard deviation for the alpha and beta carotene were less than 10% (n = 6). The average spike recoveries for alpha and beta carotene in vegetables were 81.6%-93.3%. The detection and quantification limits for alpha and beta carotene were 0.5 microg/100 g and 1.5 microg/100 g, respectively, when taking 5g samples. CONCLUSION: The method is accurate, reliable, and fit for analyzing alpha-carotene and beta-carotene in fresh vegetables. PMID- 27459816 TI - [Determination of 6 kinds of plant growth regulator in bean sprout by ultra high performance liquid chromatography-tandem mass spectrometry]. AB - OBJECTIVE: A method for the simultaneous determination of 6 plant growth regulator (PGR) residues in bean sprout was developed by ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). 6-Benzylaminopurine, isopentennyladenine, 4-chlorophenoxyacetic acid, 4-fluorophenoxyacetic acid, indole-3- acetic acid and indole-3-butyric acid were concerned. METHODS: Bean sprout samples were extracted by acetonitrile and QuEChERS extraction kit, purified by C18 powers. After centrifugation, the sample liquids was diluted 10 times by ultrapure water. The chromatographic analysis was carried out on an waters acquity UPLC BEH C18 column( 100 mm x 2.1 mm, 1.7 microm). The analyzer confirmed and quantified by mass spectrum of triple quadrupole in the multiple reaction monitoring (MRM) mode and quantified by matrix-matched external standard method. RESULTS: The calibration curves showed good linearity in each range with correlation coefficients greater than 0.998. 3 levels spiked recoveries were carried out using blank bean sprout extraction as substrate, the recoveries ranged from 84.2% to 107.5%, the relative standard deviations (RSDs) ranged from 3.08% to 12.71%. The qualitative limits of detections (S/N = 3) were 0.03-3.0 microg/kg and the quantitative limits(S/N = 10) were 0.1-10.0 microg/kg for the 6 PGRs. CONSLUSION: The method is simple and easy to operate, with less organic reagent, high sensitivity and good stability. It is suitable for the detection of 6 kinds of plant growth regulators in bean sprouts. PMID- 27459817 TI - [Usefulness and Limitation of Thyroglobulin Measurement in Fine Needle Aspirates (FNA-Tg) for Diagnosis of Neck Lymph Node Metastasis from Thyroid Carcinoma]. AB - BACKGROUND: Preoperative diagnosis of lymph node metastasis from thyroid carcinoma is usually confirmed by using fine needle aspiration cytology (FNAC) when thyroid carcinoma is suspected based on the clinical findings. However, the result of FNAC sometimes leads to a false negative, especially in cases of hypocellular lesions such as metastases with cystic change. Thyroglobulin measurement in fine needle aspirates (FNA-Tg) has been shown to be a useful technique to detect the protein specifically secreted by thyroid follicular cells. Elevated FNA-Tg levels in an extra-thyroidal lesion means that the lesion comprises thyroid-originated tissue, most of which suggests the metastasis from thyroid carcinoma. Thus, FNA-Tg is expected to improve the sensitivity of FNAC for the aforementioned purpose. PATIENTS AND METHODS: From 2008 to 2012, 49 extra thyroidal lesions from 43 patients with thyroid carcinoma were examined using both FNAC and FNA-Tg, followed by surgical resection with a histopathological diagnosis. The results were retrospectively reviewed and analyzed. RESULTS: Among 49 lesions, 47 were metastatic lymph nodes from thyroid carcinoma (46 papillary carcinoma and one follicular carcinoma), one was a metastatic lymph node from submandibular gland adenocarcinoma, and one was an ectopic thyroid gland. In the 47 cases of thyroid carcinoma, the sensitivity of FNAC was 57.4% (27/47), whereas that of FNA-Tg was 76.6% (36/47). When both methods were combined, the sensitivity increased to 93.6% (44/47). Metastasis from submandibular gland adenocarcinoma was considered to be an example of a false positive from FNAC, whereas an ectopic thyroid gland was an FNA-Tg false positive. Three lesions were negative for both FNAC and FNA-Tg, although metastases were suspected by imaging studies and confirmed by histopathological diagnosis, which were consistent with examples of a false negative from both FNAC and FNA-Tg findings. CONCLUSIONS: FNAC reflects whether the lesion has malignant cells, whereas FNA-Tg reflects whether the lesion has thyroid-originated tissue that specifically secrets thyroglobulin. Therefore, FNAC and FNA-Tg are considered to be complementary to each other for the preoperative diagnosis of lymph node metastasis from thyroid carcinoma. FNA-Tg was validated to improve the preoperative diagnostic sensitivity especially when combined with FNAC, however, it is attended with the possibility of a false positive or negative finding, which requires caution in interpretation of the findings. PMID- 27459818 TI - [Detection of the Presence of Middle-ear Effusion with Wideband Absorbance Tympanometry]. AB - This study evaluated the ability of wideband absorbance (AB) to predict the presence of middle-ear effusion (MEE) in ears with a flat (type B) 226 Hz tympanogram (TG). AB measures were obtained in a no MEE group of 8 ears with a flat TG and a MEE group of 19 ears also with a flat TG. AB was significantly small at frequencies 2 and 4 kHz in the MEE group than in the no MEE group. Based on our results, it appeared that AB could detect MEE with higher specificity than conventional tympanometry. The presence or absence of MEE could be distinguished based on the average AB using 1, 2, and 4 kHz, with 40% as the cutoff point. PMID- 27459819 TI - [Sequential Chemoradiotherapy for Advanced Head and Neck Cancer: A Clinical Study with 33 Cases]. AB - A total of 33 patients with advanced head and neck cancer (AHNC) treated with sequential chemoradiotherapy (SCRT) were retrospectively evaluated at Gunma University Hospital between 2009 and 2011. The regimen of SCRT was docetaxel, cisplatin, and fluorouracil (TPF)-based induction chemotherapy (ICT), accompanied by docetaxel and cisplatin-based concurrent chemoradiotherapy (CCRT), and oral administration of TS-1 after that. The response rate was 61%, the 3-year overall survival rate was 42%, the non-tumor-bearing survival rate was 27%, and the tumor bearing survival rate was 15%. Fourteen of 33 patients were tumor-free, and their 3-year overall survival rate was surprisingly 86%. On the other hand, 3-year overall survival rate in the remaining 19 patients was significantly low. To select good response cases for ICT was important. In such cases, TPF should be applied repeatedly, which achieved a 61% response rate even in AHNC. A long-term TS-1 oral medication suppressed cancer regrowth and contributed to long-term survival. PMID- 27459820 TI - [Four Cases of Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders in the Head and Neck Region]. AB - Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA LPD) comprise lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune diseases, especially rheumatoid arthritis (RA) treated with methotrexate (MTX). MTX has been increasingly administered to patients with RA, resulting in methotrexate-associated lymphoproliferative disorder (MTX-LPD) in patients. We report herein on four cases of patients with RA, who diagnosed with head and neck region. In two cases (one case MTX and another case tacrolimus) drug therapy was discontinued, when the patients were diagnosed as having OIIA-LPD in only a few local findings. These patients have followed good clinical courses for 24 months. In the other two cases, consultations were performed for cervical lymphadenopathy by the Division of Rheumatology. In one case drug therapy was discontinued and a good clinical course was followed. In case of the other patient, however, who had undergone tacrolimus therapy after MTX therapy was discontinued, she relapsed and died. In the case of patients with an autoimmune disease such as RA who are taking MTX, tacrolimus, or anti TNF-alpha therapy, when cervical lymphadenopathy and extranodal disease are detected, OIIA-LPD should be suspected. We should cooperate with a hematologist-oncologist, a rheumatologist, and pathologist in such a case. PMID- 27459821 TI - The 'Deadliest Catch' No More. PMID- 27459822 TI - Reducing Electrical Hazards. PMID- 27459823 TI - Can Industrial Chemical Exposure Cause Hearing Loss? PMID- 27459824 TI - Dateline Atlanta. PMID- 27459825 TI - Strategic Planning in Hard Times: Why Safety Incentive Programs are a Budget Trimming Tool. PMID- 27459826 TI - Keys to Employee Engagement. PMID- 27459827 TI - Working Against Time: Nine Steps to Implementing a Successful AED Program. PMID- 27459828 TI - CPR and AEDs--Two Important Acronyms for Your Workplace First Aid Program. PMID- 27459829 TI - Weighing BSEE's Well Control Rule. PMID- 27459830 TI - Seven Ways to Go Back to Basics With Your Safety Program. PMID- 27459831 TI - Three Steps to Minimize the Risk of HAIs in Your Facility. PMID- 27459832 TI - FMCSA's New Training Standards for Entry-Level Drivers. PMID- 27459833 TI - It's Not Just the Heat--How OSHA Enforces Occupational Exposures to Hot Environments. PMID- 27459834 TI - Understanding the Ramifications of Heat in Work Environments. PMID- 27459835 TI - Use PPE in the Workplace and Keep Your 'Eyes' on the Prize. PMID- 27459836 TI - Selecting the Right Gas Detection Solution. PMID- 27459837 TI - Boomeranging: Five Methods For Revitalizing an Aging Workforce. PMID- 27459838 TI - Motoneuron diseases: impact on health professionals. AB - The approach to patients affected by motor neuron disease (MND) and their caregivers requires specific training for the care-team. In fact, the progression of the disease, with the decline of physical--and sometimes cognitive--function, the increasing difficulties in speaking, breathing, and swallowing and the need of invasive choices, as the artificial nutrition and tracheostomy, constitute a challenge for the health professionals, often generating distress. For this reason, their cohesion and sharing abilities are fundamental. Psychologist assumes a strategic role in supporting and facilitating the analysis of clinical cases and of the team's intra/interpersonal dynamics. For this aim, he/she needs specific training and instruments. We here present a semi-structured interview- the Motor Neuron Disease-Psychological Interview (MoNeDi-PI)--which may guide in the psychological assessment of patients affected by MNDs and their caregivers. It can also be a handy reference tool for other members of the healthcare team providing necessary information about the patient and caregiver in order to optimize clinical decision making about which health interventions to apply. PMID- 27459839 TI - [Basopil Activation Test (BAT) as a novel method for monitoring occupational exposure to Beta-lactams and intermediates of production]. AB - BACKGROUND: Cutaneous tests and specific IgE are used in the diagnosis of allergy due to beta-lactans, although drug administration at therapeutic dosage is considered gold standard in drug allergy. OBJECTIVES: The diagnostic approach in symptomatic workers is more critical when they are exposed because of work, unlike reactions to drug in case of therapy. There is not a general consensus about markers in workers occupationally exposed to drugs. Indeed, basophil activation test (BAT) is a new and promising laboratory tool, particularly useful to test intermediate molecules involved in the production. In this article we show our experience on the health surveillance of workers exposed to beta lactams and intermediate molecule (7-ZACA) in a pharmaceutical industry. METHODS: We studied 15 workers divided into 3 groups: 5 exposed and symptomatic (group A), 5 exposed and asymptomatic (group B), 5 non exposed and asymptomatic (group C). RESULTS: BAT was positive for 7-ZACA in three subjects of group A, and in one subject of group B and one of group C. There was e concordance between clinical history, respiratory symptoms, and results of texts. It was possible to determine allergic nature of symptoms and sensitization in a preclinical phase, correctly discriminating symptoms related to irritants from the allergic ones. CONCLUSIONS: BAT, a simple and quick diagnostic procedure if compared to challenge, can be used as a useful and practical tool by occupational doctors for prevention measures, evaluation of ability to a specific job and reallocation of workers. PMID- 27459840 TI - [Risk of deterministic effects after exposure to low doses of ionizing radiation: retrospective study among health workers in view of a new publication of International Commission on Radiological Protection]. AB - The new recommended equivalent (publication n. 118 of International Commission on Radiological Protection) dose limit for occupational exposure of the lens of the eye is based on prevention of radiogenic cataracts, with the underlying assumption of a nominal threshold which has been adjusted from 2,5 Gy to 0.5 Gy for acute or protracted exposure. The study aim was to determine the prevalence of ocular lens opacity among healthcare workers (radiologic technologists, physicians, physician assistants) with respect to occupational exposures to ionizing radiations. Therefore, we conducted another retrospective study to explore the relationship between occupational exposure to radiation and opacity lens increase. Healthcare data (current occupational dosimetry, occupational history) are used to investigate risk of increase of opacity lens of eye. The sample of this study consisted of 148 health-workers (64 M and 84 W) aged from 28 to 66 years coming from different hospitals of the ASL of Potenza (clinic, hospital and institute with scientific feature). On the basis of the evaluation of the dosimetric history of the workers (global and effective dose) we agreed to ascribe the group of exposed subjects in cat A (equivalent dose > 2 mSV) and the group of non exposed subjects in cat B (workers with annual absorbed level of dose near 0 mSv). The analisys was conducted using SPSS 15.0 (Statistical Package for Social Science). A trend of increased ocular lens opacity was found with increasing number for workers in highest category of exposure (cat. A, Yates' chi squared test = 13,7 p = 0,0002); variable significantly related to opacity lens results job: nurse (Chi(2)Y = 14,3 p = 0,0002) physician (Chi(2)Y = 2.2 p = 0,1360) and radiologic technologists (Chi(2)Y = 0,1 p = 0,6691). In conclusion our provides evidence that exposure to relatively low doses of ionizing radiation may be harmful to the lens of the eye and may increase a long-term risk of cataract formation; similary necessary to monitor the "equivalent dose" for the lens for the workers in highest category of exposure. PMID- 27459841 TI - Upper airway and eye involvement in polyurethane shoe sole production workers. AB - OBJECTIVES: This cross-sectional study was aimed to investigate the prevalence of work-related upper and lower airway and eye symptoms in 118 workers in polyurethane shoe soles (PSS) production. METHODS: Workplace monitoring of methylene diphenyl diisocyanate (MDI) and solvents was performed. Subjects completed a study-specific questionnaire and underwent anterior rhinoscopy, skin prick tests for common aeroallergens, spirometry, nasal peak inspiratory (NPIF) and expiratory flow (NPEF). RESULTS: MDI and solvent levels were below threshold limit value-time-weighted average (TLW-TWA) except for two measures of dichloromethane and tetrachloroethylene, respectively, and in one measure of acetonitrile, which were higher then TLW-TWA. In exposed workers the prevalence of cough (p < 0.05) and nasal congestion at rhinoscopy (p = 0.05) was more frequent than in non-exposed workers. Occupational exposure (OR 4.5, 95% CI 1.2 16.5) and a low FEV1 (OR 2.6, 95% CI 1.1-6.3) were significant predictors of cough. CONCLUSIONS: In workers exposed to low levels of MDI and solvents in polyurethane shoe sole production there was a high prevalence of cough and nasal congestion. An improvement in the exhaust ventilation system and other preventive measures were needed. PMID- 27459842 TI - [Not Available]. AB - The working posture is part of the risk factors for the development of muscle skeletal disorders. Compared to postural problems of the trunk and upper limbs, those related to the lower limbs have been so far undervalued in the context of preventive medicine and ergonomics. The risk assessment tools for the lower limbs posture are inhomogeneous and incomplete. The classification of postures, the quantification of the risk, the correlation with organizational and individual aspects, and interventions for the prevention and management of the risk are aspects yet to be explored. PMID- 27459843 TI - [Not Available]. AB - The legislative developments that led to the Three-year Degree of the Health Professions poses any health professional in the position of having to comply with the ethical and legal duty to obtain valid informed consent from the patient prior to treatment. In the present work, attention was focused on the figure of the occupational therapist. MATERIALS AND METHODS: Informed consent forms have been developed according to the specific disease from which the patient undergoing occupational therapy is affected. The following categories of sick were identified: amputation, developmental age, orthopedy, spinal cord injury, neurology, psychiatry, geriatry and oncology. RESULTS AND CONCLUSION: The consent forms are particularly well suited to obtaining valid consent from the patient and, at the same time, allow the occupational therapist to obtain all the information he/she needs to carry out the treatment in safety. This results improved patient compliance to therapy by facilitating a better empathic relationship with the therapist. PMID- 27459844 TI - Analysis of reaching movements of upper arm in robot assisted exercises. Kinematic assessment of robot assisted upper arm reaching single-joint movements. AB - Robot-mediated therapy (RMT) has been a very dynamic area of research in recent years. Robotics devices are in fact capable to quantify the performances of a rehabilitation task in treatments of several disorders of the arm and the shoulder of various central and peripheral etiology. Different systems for robot aided neuro-rehabilitation are available for upper limb rehabilitation but the biomechanical parameters proposed until today, to evaluate the quality of the movement, are related to the specific robot used and to the type of exercise performed. Besides, none study indicated a standardized quantitative evaluation of robot assisted upper arm reaching movements, so the RMT is still far to be considered a standardised tool. In this paper a quantitative kinematic assessment of robot assisted upper arm reaching movements, considering also the effect of gravity on the quality of the movements, is proposed. We studied a group of 10 healthy subjects and results indicate that our advised protocol can be useful for characterising normal pattern in reaching movements. PMID- 27459845 TI - Part 3. Modeling of Multipollutant Profiles and Spatially Varying Health Effects with Applications to Indicators of Adverse Birth Outcomes. AB - The highly intercorrelated nature of air pollutants makes it difficult to examine their combined effects on health. As such, epidemiological studies have traditionally focused on single-pollutant models that use regression-based techniques to examine the marginal association between a pollutant and a health outcome. These relatively simple, additive models are useful for discerning the effect of a single pollutant on a health outcome with all other pollutants held to fixed values. However, pollutants occur in complex mixtures consisting of highly correlated combinations of individual exposures. For example, evidence for synergy among pollutants in causing health effects has been recently reviewed by Mauderly and Samet (2009). Also, studies cited in the Ozone Criteria Document (U.S. Environmental Protection Agency [U.S. EPA*] 2006) confirmed that synergisms between ozone and other pollutants have been demonstrated in laboratory studies involving humans and animals. Thus, the highly correlated nature of air pollution exposures makes marginal, single-pollutant models inadequate. This issue was raised in a report by the National Research Council (NRC 2004), which called for a multipollutant approach to air quality management. Here we present and apply a series of statistical approaches that treat patterns of covariates as a whole unit, stochastically grouping pollutant patterns into clusters and then using these cluster assignments as random effects in a regression model. Using this approach, the effect of a multipollutant pattern, or profile, is determined in a manner that takes into account the uncertainty in the clustering process. The models are set in a Bayesian framework, and in general, Markov chain Monte Carlo (MCMC) techniques (Gilks et al. 1998). For interpretation purposes, a best clustering is derived, and the uncertainty related to this best clustering is determined by utilizing model averaging techniques, in a manner such that consistent clustering obtained by the estimation process generally yields smaller standard errors while inconsistent clustering is generally associated with larger errors. These multivariate methods are applied to a range of different problems related to air pollution exposures, namely an association of multipollutant profiles with indicators of poverty and to an assessment of the association between measures of various air pollutants, patterns of socioeconomic status (SES), and birth outcomes. All of these studies involve an examination of regional-level exposures, at the census tract (CT) and census block group (CBG) levels, and individual-level outcomes throughout Los Angeles (LA) County. Results indicate that effects of pollutants vary spatially and vary in a complex interconnected manner that cannot be discerned using standard additive line ar models. Results obtaine d from these studies can be used to efficiently use limited resources to inform policies in targeting are as where air pollution reductions result in maximum health benefits. PMID- 27459846 TI - Ensembles of randomized trees using diverse distributed representations of clinical events. AB - BACKGROUND: Learning deep representations of clinical events based on their distributions in electronic health records has been shown to allow for subsequent training of higher-performing predictive models compared to the use of shallow, count-based representations. The predictive performance may be further improved by utilizing multiple representations of the same events, which can be obtained by, for instance, manipulating the representation learning procedure. The question, however, remains how to make best use of a set of diverse representations of clinical events - modeled in an ensemble of semantic spaces - for the purpose of predictive modeling. METHODS: Three different ways of exploiting a set of (ten) distributed representations of four types of clinical events - diagnosis codes, drug codes, measurements, and words in clinical notes - are investigated in a series of experiments using ensembles of randomized trees. Here, the semantic space ensembles are obtained by varying the context window size in the representation learning procedure. The proposed method trains a forest wherein each tree is built from a bootstrap replicate of the training set whose entire original feature set is represented in a randomly selected set of semantic spaces - corresponding to the considered data types - of a given context window size. RESULTS: The proposed method significantly outperforms concatenating the multiple representations of the bagged dataset; it also significantly outperforms representing, for each decision tree, only a subset of the features in a randomly selected set of semantic spaces. A follow-up analysis indicates that the proposed method exhibits less diversity while significantly improving average tree performance. It is also shown that the size of the semantic space ensemble has a significant impact on predictive performance and that performance tends to improve as the size increases. CONCLUSIONS: The strategy for utilizing a set of diverse distributed representations of clinical events when constructing ensembles of randomized trees has a significant impact on predictive performance. The most successful strategy - significantly outperforming the considered alternatives - involves randomly sampling distributed representations of the clinical events when building each decision tree in the forest. PMID- 27459847 TI - Erratum to: Calnexin, an ER stress-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer. PMID- 27459848 TI - Genotypic characterization of drug resistant Mycobacterium tuberculosis in Quebec, 2002-2012. AB - BACKGROUND: The increasing emergence of drug-resistant tuberculosis presents a threat to the effective control of tuberculosis (TB). Rapid detection of drug resistance is more important than ever to address this scourge. The purpose of this study was to genotypically characterize the first-line antitubercular drug resistant isolates collected over 11 years in Quebec. RESULTS: The main mutations found in our resistant strains collection (n = 225) include: the S315T substitution in katG (50.2 %), the -15 C/T mutation in the inhA promoter (29 %); the S531L substitution in rpoB (43 %); the deletion 8 bp 446 / + R140S in pncA (72.9 %); the M306I (35.7 %) and M306V (21.4 %) substitutions in embB. Ten of the mutations in katG and 4 mutations identified in pncA were previously undescribed. CONCLUSION: Screening of mutations conferring resistance to first-line antituberculous drugs using DNA-sequencing approach seems to be feasible and would drastically shorten the time to determine the resistance profile compared to the proportion method. PMID- 27459849 TI - Role of phenolics from Spondias pinnata bark in amelioration of iron overload induced hepatic damage in Swiss albino mice. AB - BACKGROUND: Crude Spondias pinnata bark extract was previously assessed for its antioxidant, anticancer and iron chelating potentials. The isolated compounds gallic acid (GA) and methyl gallate (MG) were evaluated for their curative potential against iron overload-induced liver fibrosis and hepatocellular damage. METHODS: In vitro iron chelation property and in vivo ameliorating potential from iron overload induced liver toxicity of GA and MG was assessed by different biochemical assays and histopathological studies. RESULTS: MG and GA demonstrated excellent reducing power activities but iron chelation potential of MG is better than GA. Oral MG treatment in mice displayed excellent efficacy (better than GA) to significantly restore the levels of liver antioxidants, serum markers and cellular reactive oxygen species in a dose-dependent fashion. Apart from these, MG exceptionally prevented lipid peroxidation and protein oxidation whereas GA demonstrated better activity to reduce collagen content, thereby strengthening its position as an efficient drug against hepatic damage/fibrosis, which was further supported by histopathological studies. Alongside, MG efficiently eliminated the cause of liver damage, i.e., excess iron, by chelating free iron and reducing the ferritin-bound iron. CONCLUSIONS: The present study confirmed the curative effect of GA and MG against iron overload hepatic damage via their potent antioxidant and iron-chelating potential. PMID- 27459851 TI - Initiating and continuing participation in citizen science for natural history. AB - BACKGROUND: Natural history has a long tradition in the UK, dating back to before Charles Darwin. Developing from a principally amateur pursuit, natural history continues to attract both amateur and professional involvement. Within the context of citizen science and public engagement, we examine the motivations behind citizen participation in the national survey activities of the Open Air Laboratories (OPAL) programme, looking at: people's experiences of the surveys as 'project-based leisure'; their motivations for taking part and barriers to continued participation; where they feature on our continuum of engagement; and whether participation in an OPAL survey facilitated their movement between categories along this continuum. The paper focuses on a less-expected but very significant outcome regarding the participation of already-engaged amateur naturalists in citizen science. RESULTS: Our main findings relate to: first, how committed amateur naturalists (already-engaged) have also enjoyed contributing to OPAL and the need to respect and work with their interest to encourage broader and deeper involvement; and second, how new (previously-unengaged) and relatively new participants (casually-engaged) have gained confidence, renewed their interests, refocussed their activities and/or gained validation from participation in OPAL. Overall, we argue that engagement with and enthusiasm for the scientific process is a motivation shared by citizens who, prior to participating in the OPAL surveys, were previously-unengaged, casually-engaged or already-engaged in natural history activities. CONCLUSIONS: Citizen science has largely been written about by professional scientists for professional scientists interested in developing a project of their own. This study offers a qualitative example of how citizen science can be meaningful to participants beyond what might appear to be a public engagement data collection exercise. PMID- 27459850 TI - New strategies for improving stem cell therapy in ischemic heart disease. AB - Stem cell therapy is a promising approach to the treatment of ischemic heart disease via replenishing cell loss after myocardial infarction. Both preclinical studies and clinical trials have indicated that cardiac function improved consistently, but very modestly after cell-based therapy. This mainly attributed to low cell survival rate, engraftment and functional integration, which became the major challenges to regenerative medicine. In recent years, several new cell types have been developed to regenerate cardiomyocytes and novel delivery approaches helped to increase local cell retention. New strategies, such as cell pretreatment, gene-based therapy, tissue engineering, extracellular vesicles application and immunologic regulation, have surged and brought about improved cell survival and functional integration leading to better therapeutic effects after cell transplantation. In this review, we summarize these new strategies targeting at challenges of cardiac regenerative medicine and discuss recent evidences that may hint their effectiveness in the future clinical settings. PMID- 27459853 TI - Rapidly progressive Kaposi's Sarcoma in an Iraqi boy received Valproic acid: a case report and review of literature. AB - BACKGROUND: Kaposi's sarcoma (KS), an endothelial neoplasm, is associated with human herpes virus (HHV) -8 infection. KS has four clinical sub-types: Mediterranean/classic, African/endemic, human immunodeficiency virus (HIV) associated/epidemic, and transplantation-related/iatrogenic. Immunosuppression is an important cofactor in KS process. Classic KS (CKS) is exceedingly rare in children and when occurs, it is much more disseminated than adults. The epidemic, HIV-associated and the iatrogenic forms of childhood KS are a result of a profound and acquired T-cell deficiency. To our knowledge, this is the first paediatric KS case report from Iraq. Our patient was showing an unusual aggressive course of the disease while receiving Valproic acid (VPA) of the potential immune-suppressive effect. CASE PRESENTATION: A six-year-old Iraqi boy, who had cerebral palsy (CP) and epilepsy since the age of 9-months, had received VPA to control his seizures. He developed skin discoloration followed by nodules that disseminated proximally from the lower extremities to the groin, face, ears and oral cavity, and then he died from severe respiratory distress after 110 days from the disease evolution. KS diagnosis was proved by a skin biopsy. As the patient was of Arab-Asian ethnicity and was HIV-seronegative status, accordingly, his condition best fitted the classic form of KS. However, recent studies showed the link of VPA with the reactivation of HHV-8. Moreover, accumulated experimental and clinical data elucidated that VPA induces T-cell suppression. Given that there was a lack of facilities to perform the laboratory immunological diagnostic tests in Iraq, the VPA-induced effect on immunity in our case (iatrogenic KS) could not be evaluated. CONCLUSIONS: Our report demonstrates a rare, rapidly progressing paediatric KS case and highlights the possible role of the 5-years' administration of VPA and its challenging effect on cellular immunity based on recent studies. Thus, VPA could have promoted the development of the KS in our patient. This report also recalls the need of paediatricians to consider KS especially when the skin lesion appears at the child's foot even in countries outside the geographical map of the disease. PMID- 27459852 TI - HAE Pathophysiology and Underlying Mechanisms. AB - Remarkable progress in understanding the pathophysiology and underlying mechanisms of hereditary angioedema has led to the development of effective treatment for this disorder. Progress in three separate areas has catalyzed our understanding of hereditary angioedema. The first is the recognition that HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor. This observation has led to a detailed understanding of the SERPING1 mutations responsible for this deficiency as well as the molecular regulation of C1 inhibitor expression and function. The second is that the fundamental cause of swelling is enhanced contact system activation leading to increased generation of bradykinin. Substantial progress has been made in defining the parameters regulating bradykinin generation and catabolism as well as the receptors that transduce the biologic effects of kinins. The third is the understanding that tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions. This knowledge is driving increased attention to the role of endothelial biology in determining disease activity in hereditary angioedema. While there has been considerable progress made, large gaps still remain in our knowledge. Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the bradykinin B1 receptor. The phenotypic variability of hereditary angioedema has been extensively documented but never understood. The mechanisms discussed in this chapter likely contribute to this variability. Future progress in understanding these mechanisms should provide new means to improve the diagnosis and treatment of hereditary angioedema. PMID- 27459854 TI - Predicting dementia in primary care patients with a cardiovascular health metric: a prospective population-based study. AB - BACKGROUND: Improving cardiovascular health possibly decreases the risk of dementia. Primary care practices offer a suitable setting for monitoring and controlling cardiovascular risk factors in the older population. The purpose of the study is to examine the association of a cardiovascular health metric including six behaviors and blood parameters with the risk of dementia in primary care patients. METHODS: Participants (N = 3547) were insurants aged >=55 of the largest German statutory health insurance company, who were enrolled in a six year prospective population-based study. Smoking, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose were assessed by general practitioners at routine examinations. Using recommended cut-offs for each factor, the patients' cardiovascular health was classified as ideal, moderate, or poor. Behaviors and blood parameters sub-scores, as well as a total score, were calculated. Dementia diagnoses were retrieved from health insurance claims data. Results are presented as hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: Over the course of the study 296 new cases of dementia occurred. Adjusted for age, sex, and education, current smoking (HR = 1.77, 95% CI 1.09-2.85), moderate (1.38, 1.05-1.81) or poor (1.81, 1.32-2.47) levels of physical activity, and poor fasting glucose levels (1.43, 1.02-2.02) were associated with an increased risk of dementia. Body mass index, blood pressure, and cholesterol were not associated with dementia. Separate summary scores for behaviors and blood values, as well as a total score showed no association with dementia. Sensitivity analyses with differently defined endpoints led to similar results. CONCLUSIONS: Due to complex relationships of body-mass index and blood pressure with dementia individual components cancelled each other out and rendered the sum-scores meaningless for the prediction of dementia. PMID- 27459857 TI - The soil microbiome at the Gi-FACE experiment responds to a moisture gradient but not to CO2 enrichment. AB - The soil bacterial community at the Giessen free-air CO2 enrichment (Gi-FACE) experiment was analysed by tag sequencing of the 16S rRNA gene. No substantial effects of CO2 levels on bacterial community composition were detected. However, the soil moisture gradient at Gi-FACE had a significant effect on bacterial community composition. Different groups within the Acidobacteria and Verrucomicrobia phyla were affected differently by soil moisture content. These results suggest that modest increases in atmospheric CO2 may cause only minor changes in soil bacterial community composition and indicate that the functional responses of the soil community to CO2 enrichment previously reported at Gi-FACE are due to factors other than changes in bacterial community composition. The effects of the moisture gradient revealed new information about the relationships between poorly known Acidobacteria and Verrucomicrobia and soil moisture content. This study contrasts with the relatively small number of other temperate grassland free-air CO2 enrichment microbiome studies in the use of moderate CO2 enrichment and the resulting minor changes in the soil microbiome. Thus, it will facilitate the development of further climate change mitigation studies. In addition, the moisture gradient found at Gi-FACE contributes new knowledge in soil microbial ecology, particularly regarding the abundance and moisture relationships of the soil Verrucomicrobia. PMID- 27459856 TI - Performance of rapid diagnostic test, blood-film microscopy and PCR for the diagnosis of malaria infection among febrile children from Korogwe District, Tanzania. AB - BACKGROUND: Rapid diagnostic tests (RDT) and light microscopy are still recommended for diagnosis to guide the clinical management of malaria despite difficult challenges in rural settings. The performance of these tests may be affected by several factors, including malaria prevalence and intensity of transmission. The study evaluated the diagnostic performance of malaria RDT, light microscopy and polymerase chain reaction (PCR) in detecting malaria infections among febrile children at outpatient clinic in Korogwe District, northeastern Tanzania. METHODS: The study enrolled children aged 2-59 months with fever and/or history of fever in the previous 48 h attending outpatient clinics. Blood samples were collected for identification of Plasmodium falciparum infection using histidine-rich-protein-2 (HRP-2)-based malaria RDT, light microscopy and conventional PCR. RESULTS: A total of 867 febrile patients were enrolled into the study. Malaria-positive samples were 85/867 (9.8 %, 95 % CI, 7.9-12.0 %) by RDT, 72/867 (8.3 %, 95 % CI, 6.5-10.1 %) by microscopy and 79/677 (11.7 %, 95 % CI, 9.3-14.3 %) by PCR. The performance of malaria RDT compared with microscopy results had sensitivity and positive predictive value (PPV) of 88.9 % (95 % CI, 79.3-95.1 %) and 75.3 % (95 % CI, 64.8-84.0 %), respectively. Confirmation of P. falciparum infection with PCR analysis provided lower sensitivity and PPV of 88.6 % (95 % CI, 79.5-94.7 %) and 84.3 % (95 % CI, 74.7 91.4 %) for RDT compared to microscopy. CONCLUSION: Diagnosis of malaria infection is still a challenge due to variation in results among diagnostic methods. HRP-2 malaria RDT and microscopy were less sensitive than PCR. Diagnostic tools with high sensitivity are required in areas of low malaria transmission. PMID- 27459858 TI - In vitro effects of 6 % hydroxyethyl starch 130/0.42 solution on feline whole blood coagulation measured by rotational thromboelastometry. AB - BACKGROUND: The artificial colloid, hydroxyethyl starch (HES), is recommended for intravascular volume expansion and colloid-osmotic pressure enhancement in dogs and cats. A well-known side effect of HES solutions in humans and dogs is coagulopathy. However, HES-associated coagulopathy has thus far not been investigated in cats. The goal of this study was to assess the in vitro effects of 6 % HES 130/0.42 on feline whole blood samples using rotational thromboelastometry (ROTEM). A further goal was to develop feline reference intervals for ROTEM at our institution. In this in vitro experimental study, blood samples of 24 adult healthy cats were collected by atraumatic jugular phlebotomy following intramuscular sedation. Baseline ROTEM analyses (using ex tem, in-tem and fib-tem assays) were performed in duplicate. Additionally, ROTEM analyses were performed on blood samples after dilution with either Ringer's acetate (RA) or 6 % HES 130/0.42 (HES) in a 1:6 dilution (i.e. 1 part solution and 6 parts blood). RESULTS: Coefficients of variation of duplicate measures were below 12 % in all ex-tem assays, 3 of 4 in-tem assays but only 1 of 3 fib-tem assays. Reference intervals were similar albeit somewhat narrower than those previously published. Dilution with both solutions lead to significantly prolonged CT (in-tem), CFT (ex-tem and in-tem), and reduced MCF (ex-tem, in-tem, and fib-tem) and alpha (ex-tem and in-tem). Compared to RA, dilution with HES caused a significant prolongation of CT in fib-tem (P = 0.016), CFT in ex-tem (P = 0.017) and in-tem (P = 0.019), as well as a reduction in MCF in in-tem (P = 0.032) and fib-tem (P = 0.020), and alpha in ex-tem (P = 0.014). However, only a single parameter (CFT in ex-tem) was outside of the established reference interval after dilution with HES. CONCLUSIONS: In vitro hemodilution of feline blood with RA and HES causes a small but significant impairment of whole blood coagulation, with HES leading to a significantly greater effect on coagulation than RA. Further studies are necessary to evaluate the in vivo effects and the clinical significance of these findings. PMID- 27459859 TI - Acute promyelocytic leukemia with the translocation t(15;17)(q22;q21) associated with t(1;2)(q42~43;q11.2~12): a case report. AB - BACKGROUND: Acute promyelocytic leukemia is characterized by a typical reciprocal translocation t(15;17)(q22;q21). Additional chromosomal abnormalities are reported in only 23-43 % of cases of acute promyelocytic leukemia. CASE PRESENTATION: Here we report the case of a 46-year-old Syrian Alawis woman with acute promyelocytic leukemia with the typical t(15;17) translocation, but with a second clone presenting a t(1;2)(q42~43;q11.2~12) translocation as an additional abnormality. To the best of our knowledge, an association between these chromosomal abnormalities has not previously been described in the literature. Our patient started treatment with all-trans retinoic acid 10 days after diagnosis but died the same day of treatment initiation due to hemolysis, intracranial hemorrhage, thrombocytopenia, and disseminated intravascular coagulation. CONCLUSION: The here reported combination of aberrations in a case of acute promyelocytic leukemia seems to indicate an adverse prognosis, and possibly shows that all-trans retinoic acid treatment may be contraindicated in such cases. PMID- 27459860 TI - Effects of Self-directed Exercise Programmes on Individuals with Type 2 Diabetes Mellitus: A Systematic Review Evaluating Their Effect on HbA1c and Other Metabolic Outcomes, Physical Characteristics, Cardiorespiratory Fitness and Functional Outcomes. AB - BACKGROUND: Type two diabetes mellitus (T2DM) is caused and progressed by an individual's lifestyle and, therefore, its optimal day-to-day management may involve the patient taking responsibility for this, including fulfilling a planned and prescribed exercise regime used as part of the treatment. A prescription of exercise designed to meet a patient's individual needs with minimal supervision from healthcare practitioners would facilitate this. However, the optimal prescription of exercise in the population remains unclear. OBJECTIVE: This review examines the effects planned self-directed exercise has on glycosylated haemoglobin and other outcomes in individuals with T2DM and aims to identify the most suitable forms of planned self-directed exercise for individuals with T2DM that can be carried out independently. METHODS: A search of the electronic databases PubMed, SPORTDiscus, CINAHL, EMBASE, Cochrane (Trials) and ClinicalTrials.gov was conducted along with reference lists of previous reviews. Randomised controlled trials published in English between January 1990 and February 2015 examining participants diagnosed with T2DM only were included. Studies were critically appraised using the PEDro (Physiotherapy Evidence Database) scale and data were presented on standardised tables. RESULTS: Twenty eight articles that used five element gymnastics, a games console exercise intervention (Wii fit plus) or aerobic, resistance or combined training were included. CONCLUSION: This review comprehensively summarised the effects planned self-directed exercise interventions had on individuals with T2DM. The review found that self-directed exercise was found to be beneficial for individuals with T2DM for improving glycosylated haemoglobin, physical characteristics, cardiorespiratory fitness, functional measures and other metabolic outcomes. PMID- 27459862 TI - Impact of Endurance Exercise Training in the Fasted State on Muscle Biochemistry and Metabolism in Healthy Subjects: Can These Effects be of Particular Clinical Benefit to Type 2 Diabetes Mellitus and Insulin-Resistant Patients? AB - Exercise training intervention is a cornerstone in the care of type 2 diabetes mellitus (T2DM) and insulin resistance (IR), and it is pursued in order to optimize exercise interventions for these patients. In this regard, the nutritional state of patients during exercise (being in the fed or fasted state) can be of particular interest. The aim of the present review is to describe the impact of endurance exercise (training) in the fasted versus fed state on parameters of muscle biochemistry and metabolism linked to glycemic control or insulin sensitivity in healthy subjects. From these data it can then be deduced whether exercise training in the fasted state may be relevant to patients with T2DM or IR. In healthy subjects, acute endurance exercise in the fasted state is accompanied by lower blood insulin and elevated blood free fatty acid concentrations, stable blood glucose concentrations (in the first 60-90 min), superior intramyocellular triacylglycerol oxidation and whole-body lipolysis, and muscle glycogen preservation. Long-term exercise training in the fasted state in healthy subjects is associated with greater improvements in insulin sensitivity, basal muscle fat uptake capacity, and oxidation. Therefore, promising results of exercise (training) in the fasted state have been found in healthy subjects on parameters of muscle biochemistry and metabolism linked to insulin sensitivity and glycemic control. Whether exercise training intervention in which exercise sessions are organized in the fasted state may be more effective in improving insulin sensitivity or glycemic control in T2DM patients and insulin-resistant individuals warrants investigation. PMID- 27459863 TI - The Effects of Ischemic Preconditioning on Human Exercise Performance: A Counterpoint. PMID- 27459864 TI - Using the Evidence Available to Inform Practice and Direct Future Research. PMID- 27459861 TI - Impact of Aging on Endurance and Neuromuscular Physical Performance: The Role of Vascular Senescence. AB - The portion of society aged >=60 years is the fastest growing population in the Western hemisphere. Aging is associated with numerous changes to systemic physiology that affect physical function and performance. We present a narrative review of the literature aimed at discussing the age-related changes in various metrics of physical performance (exercise economy, anaerobic threshold, peak oxygen uptake, muscle strength, and power). It also explores aging exercise physiology as it relates to global physical performance. Finally, this review examines the vascular contributions to aging exercise physiology. Numerous studies have shown that older adults exhibit substantial reductions in physical performance. The process of decline in endurance capacity is particularly insidious over the age of 60 years and varies considerably as a function of sex, task specificity, and individual training status. Starting at the age of 50 years, aging also implicates an impressive deterioration of neuromuscular function, affecting muscle strength and power. Muscle atrophy, together with minor deficits in the structure and function of the nervous system and/or impairments in intrinsic muscle quality, plays an important role in the development of neuromotor senescence. Large artery stiffness increases as a function of age, thus triggering subsequent changes in pulsatile hemodynamics and systemic endothelial dysfunction. For this reason, we propose that vascular senescence has a negative impact on cerebral, cardiac, and neuromuscular structure and function, detrimentally affecting physical performance. PMID- 27459855 TI - Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. AB - BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 * 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 * 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 * 10(-4)) identified in the general populations, and rs113824616 (P = 7 * 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk. PMID- 27459865 TI - Author's Reply to Sabour and Ghassemi "Submaximal Step Tests to Estimate Maximal Oxygen Uptake in Healthy Adults: Methodological Issues About Validity and Reliability". PMID- 27459868 TI - Notice of Retraction: Therapeutic Effects of Umbilical Cord Blood Derived Mesenchymal Stem Cell-Conditioned Medium on Pulmonary Arterial Hypertension in Rats. PMID- 27459866 TI - Relationships Between Training Load Indicators and Training Outcomes in Professional Soccer. AB - BACKGROUND: In professional senior soccer, training load monitoring is used to ensure an optimal workload to maximize physical fitness and prevent injury or illness. However, to date, different training load indicators are used without a clear link to training outcomes. OBJECTIVE: The aim of this systematic review was to identify the state of knowledge with respect to the relationship between training load indicators and training outcomes in terms of physical fitness, injury, and illness. METHODS: A systematic search was conducted in four electronic databases (CINAHL, PubMed, SPORTDiscus, and Web of Science). Training load was defined as the amount of stress over a minimum of two training sessions or matches, quantified in either external (e.g., duration, distance covered) or internal load (e.g., heart rate [HR]), to obtain a training outcome over time. RESULTS: A total of 6492 records were retrieved, of which 3304 were duplicates. After screening the titles, abstracts and full texts, we identified 12 full-text articles that matched our inclusion criteria. One of these articles was identified through additional sources. All of these articles used correlations to examine the relationship between load indicators and training outcomes. For pre season, training time spent at high intensity (i.e., >90 % of maximal HR) was linked to positive changes in aerobic fitness. Exposure time in terms of accumulated training, match or combined training, and match time showed both positive and negative relationships with changes in fitness over a season. Muscular perceived exertion may indicate negative changes in physical fitness. Additionally, it appeared that training at high intensity may involve a higher injury risk. Detailed external load indicators, using electronic performance and tracking systems, are relatively unexamined. In addition, most research focused on the relationship between training load indicators and changes in physical fitness, but less on injury and illness. CONCLUSION: HR indicators showed relationships with positive changes in physical fitness during pre-season. In addition, exposure time appeared to be related to positive and negative changes in physical fitness. Despite the availability of more detailed training load indicators nowadays, the evidence about the usefulness in relation to training outcomes is rare. Future research should implement continuous monitoring of training load, combined with the individual characteristics, to further examine their relationship with physical fitness, injury, and illness. PMID- 27459867 TI - The influence of the winter North Atlantic Oscillation index on hospital admissions through diseases of the circulatory system in Lisbon, Portugal. AB - The aim of this paper is to analyze the relationship between North Atlantic Oscillation (NAO), meteorological variables, air pollutants, and hospital admissions due to diseases of circulatory systems in Lisbon (Portugal) during winter months (2003-2012). This paper is one of the few studies analyzing the impact of NAO on health through its influence on thermal stress and air pollution and is the first to be conducted in Lisbon. This study uses meteorological data (synthetized into a thermal comfort index), air pollutant metrics, and the NAO index (all clustered in 10-day cycles to overcome daily variability of the NAO index). The relationship between morbidity, thermal comfort index, NAO index, and air pollutants was explored through several linear models adjusted to seasonality through a periodic function. The possible indirect effect between the NAO index and hospital admissions was tested, assuming that NAO (independent variable) is affecting hospital admissions (outcome variable) through thermal discomfort and/or pollution levels (tested as individual mediators). This test was conducted through causal mediation analysis and adjusted for seasonal variation. The results from this study suggest a possible indirect relationship between NAO index and hospital admissions. Although NAO is not significantly associated with hospital admissions, it is significantly associated with CO, PM2.5, NO, and SO2 levels, which in turn increase the probability of hospitalization. The discomfort index (built with temperature and relative humidity) is significantly associated with hospital admissions, but its variability is not explained by the NAO index. This study highlights the impacts of the atmospheric circulation patterns on health. Furthermore, understanding the influence of the atmospheric circulation patterns can support the improvement of the existing contingency plans. PMID- 27459870 TI - 50 years of Rett syndrome, 1966-2016 : From parents to clinicians to scientists, and for parents, clinicians, and scientist. PMID- 27459869 TI - A binary concrete crack self-healing system containing oxygen-releasing tablet and bacteria and its Ca2+-precipitation performance. AB - A strategy to supply molecular oxygen for microbial calcium precipitation was developed for the first time. Firstly, a controlled oxygen-releasing tablet (ORT) containing CaO2 and lactic acid with a suitable ratio of 9:1 was developed. It can provide a stable oxygen supply and maintain pH in the range of 9.5-11.0 for 45 days while contacting with water. In the presence of oxygen, a self-healing bacterium H4 spores germinated more effectively and maintained high metabolic activity. Furthermore, H4 vegetative cells induced 50 % more calcium precipitation than that obtained without oxygen supply. Finally, a binary self healing system containing bacterial spores and ORT was established. The calcium precipitation experiments showed that H4 in the binary self-healing system precipitated 27.5 mM calcium with oxygen supply after 32 days and dissolved oxygen (DO) concentration of the solution decreased from 15 to 4 mg l-1, while only 6.9 mM calcium precipitation was obtained without oxygen supply. This work can disclose the effect of oxygen on microbial calcium precipitation and further lay a foundation for the establishment of ternary self-healing system containing bacteria, ORT, and nutrients, which will be promising for the self-healing of cracks deep inside the concrete structure. PMID- 27459871 TI - Natriuretic peptides as biomarkers of cardiac endocrine function in heart failure: new challenges and perspectives. AB - Several studies indicated that B-type natriuretic peptide (BNP) assay is able to detect patients even in the early phases of heart failure (HF), when the myocardial remodeling process may be still reversible. BNP assay may assist the physician to initiate appropriate and prompt pharmacological treatments. However, clinical relevance and result interpretation of BNP assay for the guide of therapy or in particular clinical conditions, such as renal failure or treatment with inhibitors of enzymes degrading BNP in HF patients, are still debated. The aim of this article is to discuss some still controversial issues concerning the clinical use of measurement of cardiac natriuretic peptides, and also to provide a general overview and some perspectives related to pathophysiological mechanisms of HF. PMID- 27459872 TI - [Study of the Consumers' preference on the universal health coverage development strategy through health mutual in Ziguinchor Region, Southwest of Senegal]. AB - In Senegal, the informal and rural sector that accounts for over 80% of the population is covered only up to 7% by a health insurance system. That is why, for the implementation of development strategy of the universal health coverage (UHC) through mutual health insurance providers, the Government of Senegal has focused on this sector. The objective of this study was to assess the consumer's preference on the UHC development strategies through mutual health insurance providers. This was a qualitative and exploratory study based on a literature review, and indepth interview with the heads of households. It was also based on focus groups of people with and without health mutual membership, and the Expert Committee meetings. The results showed that the most critical attributes in the decision-making of consumers to join the health mutual in Ziguinchor were the membership units; the content of the benefit package, the payment modalities of the premium, the premium amount, the availability of transportation, the co payment level, convention arrangement with health facilities, and health mutual governance. For a successful implementation of the UHC development strategy through health mutual organizations, policymakers should explore the possibility of introducing the modality of payment in kind, the revision of the co-payment amount, and the promotion of equity through the introduction of a differentiated premium contribution by income. They should also establish a crossborder strategy with The Gambia and Guinea-Bissau to improve health care access to people living in the borders. The promotion of innovative funding and risk equalization between health insurance schemes is also recommended. In areas where the microfinance institutions are well organized and structured their substitution to health mutuals should be an option the decision-makers have to explore. PMID- 27459873 TI - Evaluation of new laboratory tests to discriminate bacterial from nonbacterial chronic obstructive pulmonary disease exacerbations. AB - INTRODUCTIONS: Discriminating bacterial from nonbacterial acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is difficult, causing antibiotics overuse and bacterial resistance. Sputum cultures are of limited use because results take time. In our hospital, only leukocyte concentration and CRP are laboratory parameters evaluated in AECOPD. We evaluated additional tests to discriminate bacterial vs. nonbacterial AECOPD: 5-part leukocyte differentiation (hematology analyzer), leukocyte differentiation using flow cytometry (Leukoflow, Cytodiff), Leuko64 kit, and procalcitonin. METHODS: Retrospectively, patients were classified as bacterial or nonbacterial AECOPD. ROC analyses tested how the additional tests discriminate these groups. RESULTS: Twenty-two AECOPD were classified as bacterial and 23 as nonbacterial. From the additional tests, basophil percentage (Cytodiff) has superior AUC (0.800). At a cutoff resulting in >=90% sensitivity, neutrophil/lymphocyte ratio (AUC:0.755) and CD4-positive T cells (Leukoflow, AUC:0.747) have the highest specificity (57%). Both neutrophil mean volume and standard deviation (Cell Population Data, DxH800 hematology analyzer) had good combined sensitivity and specificity (AUC:0.846/0.804, 91% sensitivity, 69% specificity). Addition of leukocyte populations and procalcitonin to CRP in regression models (AUC: 0.907/0.876/0.890) increased specificity compared to CRP alone (71% or 73% vs. 39%). CONCLUSION: No additional test has sufficient accuracy on its own to predict bacterial AECOPD. Combining CRP with several parameters from the additional tests may improve this. PMID- 27459874 TI - Evaluation of the iPLEX(r) ADME PGx Pro Panel and allele frequencies of pharmacogenetic markers in Danes. AB - OBJECTIVES: The iPlex(r) ADME PGx Pro Panel was developed to investigate 191 polymorphisms including single nucleotide polymorphisms (SNPs), insertion deletions (INDELS), and copy number variations (CNV) relevant for absorption, distribution, metabolism, and excretion (ADME) of drugs. The purpose of this study was to perform a technical evaluation of the iPlex(r) ADME PGx Pro Panel by genotyping 50 unrelated Danes and estimate preliminary genotype frequencies among Danes. DESIGN AND METHODS: The investigations were performed by the use of PCR, single base extension (SBE) and Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS). RESULTS: The typing quality of 161 SNP assays was categorized as well performing or acceptable, whereas 22 SNP assays were categorized as either questionable or unacceptable. The frequencies of the genotypes observed in the Danish population were compared to those of the European reference population from the 1000 Genome Project. Three SNPs (rs737865, rs35167514, and rs34305973) showed statistically significantly differences between the frequencies of the 1000 Genomes Europeans and the Danes. The CNV assays could only be used as a guideline. CONCLUSION: In conclusion, the iPlex(r) ADME PGx Pro Panel is a cost-effective way of genotyping genes relevant for ADME. PMID- 27459875 TI - Call to action: greater investment in the registered nurse role is required to improve care outcomes for dementia patients living in residential aged care and their families. PMID- 27459876 TI - Rapid one-step construction of a Middle East Respiratory Syndrome (MERS-CoV) infectious clone system by homologous recombination. AB - BACKGROUND: Viral Infectious clone systems serve as robust platforms to study viral gene or replicative function by reverse genetics, formulate vaccines and adapt a wild type-virus to an animal host. Since the development of the first viral infectious clone system for the poliovirus, novel strategies of viral genome construction have allowed for the assembly of viral genomes across the identified viral families. However, the molecular profiles of some viruses make their genome more difficult to construct than others. Two factors that affect the difficulty of infectious clone construction are genome length and genome complexity. RESULTS: This work examines the available strategies for overcoming the obstacles of assembling the long and complex RNA genomes of coronaviruses and reports one-step construction of an infectious clone system for the Middle East Respiratory Syndrome coronavirus (MERS-CoV) by homologous recombination in S. cerevisiae. CONCLUSIONS: Future use of this methodology will shorten the time between emergence of a novel viral pathogen and construction of an infectious clone system. Completion of a viral infectious clone system facilitates further study of a virus's biology, improvement of diagnostic tests, vaccine production and the screening of antiviral compounds. PMID- 27459877 TI - Fulminant Budd-Chiari syndrome due to ecstasy. PMID- 27459878 TI - Extensive ulcerative duodenitis caused by ischemia. PMID- 27459879 TI - The association of the vitamin D status with the persistence of anti-HBs antibody at 20years after primary vaccination with recombinant hepatitis B vaccine in infancy. AB - BACKGROUND AND OBJECTIVE: Vitamin D has potent immunoregulatory effects due to the expression of its receptor on the majority of immune cells. The aim was to evaluate the association of the vitamin D status with the persistence of anti-HBs antibody and immune response to booster immunization at 20years after primary vaccination with hepatitis B (HB) vaccine. METHODS: Blood samples were collected from 300 adults 20years after completion of the primary HB vaccination in infancy. The serum levels of vitamin D and anti-HBs antibody were measured by ELISA. A single booster dose of a recombinant HB vaccine was administered to a total of 138 subjects, whose anti-HBs titer was<10IU/L. The sera of revaccinated subjects were re-tested for anti-HBs antibody, 4weeks after booster vaccination. RESULTS: At 20years after primary vaccination, the mean vitamin D concentrations were significantly higher in seroprotective subjects as compared to non seroprotective individuals (P<0.01). The levels of anti-HBs were significantly increased with advanced concentrations of vitamin D (P<0.01). Overall, 125/138 (90.6%) of the revaccinated subjects showed an anamnestic response to booster vaccination. The concentrations of vitamin D were significantly higher in subjects with an anamnestic response to booster vaccination as compared with subjects without this response (P<0.01). CONCLUSION: Vitamin D status may influence the persistence of anti-HBs antibody and durability of protection after primary vaccination with a recombinant HB vaccine in infancy. PMID- 27459880 TI - Dairy product consumption and the risk of type 2 diabetes in the elderly. PMID- 27459881 TI - Main biomarkers associated with age-related plasma zinc decrease and copper/zinc ratio in healthy elderly from ZincAge study. AB - PURPOSE: Zinc (Zn) plays an essential role in many biological processes including immune response. Impaired Zn status promotes immune dysfunction, and it has been associated with enhanced chronic inflammation during aging. It has been suggested that the measurement of circulating Zn by itself could not reflect the real Zn status of an individual. It is therefore necessary to identify other determinants associated with plasma Zn to better understanding how physiopathological conditions during aging may affect the concentration of this metal. METHODS: We have investigated the association between Zn levels and some biomarkers in 1090 healthy elderly from five European countries to increase the accuracy in the assessment of the Zn status. Stepwise multivariate linear regression models were used to analyze the influence of factors such as age, dietary intake, inflammatory mediators, laboratory parameters and polymorphisms previously associated with Zn homeostasis. RESULTS: Plasma Zn decrement was most strongly predicted by age, while positive correlations were found with albumin, RANTES and Zn intake after adjustment for multiple confounders. HSP70 +1267 AA genotype was an independent factor associated with Zn plasma concentrations. Cu/Zn ratio was positively associated with markers of systemic inflammation and age and negatively associated with albumin serum levels. CONCLUSIONS: Our findings show the most important independent determinants of plasma Zn concentration and Cu/Zn ratio variability in elderly population and suggest that the decline with age of Zn circulating levels is more dependent on physiopathological changes occurring with aging rather than to its nutritional intake. PMID- 27459882 TI - Emerging from their burrow: Hedgehog pathway inhibitors for cancer. AB - INTRODUCTION: Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins and mechanisms important to cancer development or survival. The Hedgehog Pathway (HhP) is a signal transduction pathway and its constitutive activation is tumorigenic in basal cell carcinoma (BCC). The HhP enables phenotypic flexibility, and channels tumor stroma interactions. As a result, it is over-expressed in numerous cancers as well as in the tumor microenvironment and may represent a promising therapeutic target. AREAS COVERED: In this article, we review the rationale for targeting HhP and its role as an oncogenic driver, in tumor epithelial-to-mesenchymal transition (EMT), and in the tumor microenvironment and describe the results of preclinical and clinical studies involving HhP inhibitors. EXPERT OPINION: HhP activation plays an important role in both the tumor microenvironment and tumor EMT which can lead to treatment resistance for a number of different malignancies. In addition to standard use in BCC, several HhP inhibitors are in preclinical, early, and mid-stage clinical development for other solid and hematologic malignancies. PMID- 27459883 TI - Fluorescent biosensors enabled by graphene and graphene oxide. AB - During the past few years, graphene and graphene oxide (GO) have attracted numerous attentions for the potential applications in various fields from energy technology, biosensing to biomedical diagnosis and therapy due to their various functionalization, high volume surface ratio, unique physical and electrical properties. Among which, graphene and graphene oxide based fluorescent biosensors enabled by their fluorescence-quenching properties have attracted great interests. The fluorescence of fluorophore or dye labeled on probes (such as molecular beacon, aptamer, DNAzymes and so on) was quenched after adsorbed on to the surface of graphene. While in the present of the targets, due to the strong interactions between probes and targets, the probes were detached from the surface of graphene, generating dramatic fluorescence, which could be used as signals for detection of the targets. This strategy was simple and economy, together with great programmable abilities of probes; we could realize detection of different kinds of species. In this review, we first briefly introduced the history of graphene and graphene oxide, and then summarized the fluorescent biosensors enabled by graphene and GO, with a detailed account of the design mechanism and comparison with other nanomaterials (e.g. carbon nanotubes and gold nanoparticles). Following that, different sensing platforms for detection of DNAs, ions, biomolecules and pathogens or cells as well as the cytotoxicity issue of graphene and GO based in vivo biosensing were further discussed. We hope that this review would do some help to researchers who are interested in graphene related biosening research work. PMID- 27459884 TI - Interactions between avidin and graphene for development of a biosensing platform. AB - Fundamental understanding of interactions at the interface of biological molecules, such as proteins, and nanomaterials is crucial for developing various biocompatible hybrid materials and biosensing platforms. Biosensors comprising of graphene-based conductive nanomaterials offer the advantage of higher sensitivity and reliable diagnosis mainly due to their superior specific surface area and ballistic conductivity. Furthermore, conductive nanocomposite structures that immobilize proteins can synergize the properties of both transducers and molecular recognition elements improving the performance of the biosensing device. Here we report for the first time, using a combined molecular dynamics simulations and experimental approach, the interactions between avidin and graphene for the development of a sensing platform that can be used for the detection of biological macromolecules such as mismatch repair proteins through biotinylated DNA substrates. We find that the interactive forces between avidin and graphene are mainly hydrophobic, along with some van der Waals, electrostatic and hydrogen bonding interactions. Notably, the structure and function of the avidin molecule are largely preserved after its adsorption on the graphene surface. The MD results agree well with scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS) analysis of avidin immobilized on a graphenated polypyrrole (G-PPy) conductive nanocomposite confirming the adsorption of avidin on graphene nanoplatelets as observed from the Fourier transform infrared spectroscopy (FTIR). PMID- 27459885 TI - In-tube collision-induced dissociation for selected ion flow-drift tube mass spectrometry, SIFDT-MS: a case study of NO(+) reactions with isomeric monoterpenes. AB - RATIONALE: Soft chemical ionisation techniques including selected ion flow tube mass spectrometry, SIFT-MS, and proton transfer reaction mass spectrometry, PTR MS, cannot currently quantify individual isomers present simultaneously in samples, a notable example being atmospheric monoterpenes. A possible solution lies in integrating in-tube collision-induced dissociation, CID, into a selected ion flow-drift tube mass spectrometry, SIFDT-MS, instrument. METHODS: In-tube CID was implemented by applying electrostatic potential difference between the resistive glass flow-drift tube downstream end and the nose cone of a quadrupole mass spectrometer. The resulting inhomogeneous electric field accelerates the product ions along the last 1 mm before the nose cone and causes their dissociation in collisions with molecules of the buffer gas (4% air, 96% helium, 2 mbar). Mass spectra of the product ions of NO(+) reactions with 3-carene, beta pinene, (S)-limonene and their mixture were obtained for variable potential difference. RESULTS: Potential difference up to 47.7 V resulted in dramatic changes in the mass spectra due to fragmentation of the monoterpene radical molecular cations. The main observed fragments correspond to logical losses from different isomeric structures. Fragmentation increases with the potential difference and can be interpreted as single collision dissociation on air molecules at centre-of-mass energies of several eV. Combination of fragmentation patterns at different CID enables distinction of isomers in the mixture on the basis of pseudoinversion. CONCLUSIONS: In-tube CID represents a simple and low cost extension to SIFDT-MS that allows real-time identification of isomeric products of ion-molecule reactions on the basis of their structural differences and corresponding changes in fragmentation patterns with CID energy without significantly changing the net reaction time important for absolute quantification. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27459887 TI - Evidence for plasmid DNA exchange after polyplex mixing. AB - The self-assembly of a plasmid DNA (pDNA) with cationic polymers or cationic liposomes forms nanosized supramolecular structures called lipoplexes, polyplexes and lipopolyplexes. Here, we report that when two polyplex preparations made using the same polymer and the same pDNA but labelled with two different fluorophores are mixed together, pDNA molecules are exchanged. Indeed, when Flu pDNA complexed with histidinylated lPEI (Flu-pDNA/His-lPEI) polyplexes are mixed with Cy5-pDNA complexed with histidinylated lPEI (Cy5-pDNA/His-lPEI) polyplexes, a high quantity of polyplexes emitting dual fluorescence is observed and FRET indicates that one single polyplex contains two kinds of fluorescent pDNA molecules. This phenomenon depends on the polymer-type and the strength of the pDNA/polymer interaction. No exchange is observed with polylysine polyplexes, caged His-lPEI polyplexes, lipoplexes, lipopolyplexes or when His-lPEI polyplexes are mixed with lipoplexes. Our results suggest that aggregation or collapse of polyplexes occurs after their interaction leading to their unpackaging followed by the formation of new polyplexes with the exchange of pDNA. PMID- 27459886 TI - Review of Beet pseudoyellows virus genome structure built the consensus genome organization of cucumber strains and highlighted the unique feature of strawberry strain. AB - The complete nucleotide sequences of Beet pseudoyellows virus (BPYV)-MI (cucumber isolate; Matsuyama, Idai) genomic RNAs 1 and 2 were determined and compared with the previously sequenced Japanese cucumber strain (BPYV-JC) and a strawberry strain (BPYV-S). The RNA 2 of BPYV-MI showed 99 % nucleotide sequence identity with both BPYV-JC and -S having highly conserved eight ORFs. In contrast, the RNA1 of BPYV-MI showed sequence identities of 98 and 86 % with BPYV-JC and -S, respectively. Phylogenetic analysis of RNA-dependent RNA polymerase (RdRp) coding sequences from three fully sequenced BPYV strains and five partially sequenced cucurbit-infecting BPYV strains from Japan and South Africa has shown that cucurbit-infecting strains are closer to each other than to BPYV-S. In addition, the strawberry strain BPYV-S has an ORF2 in the downstream of RdRp gene in RNA1, but all the cucumber strains, BPYV-JC, -MI, and those from South Africa, lacked the ORF2 of RNA1, highlighting the difference between common BPYV cucumber strains and a unique strawberry strain. PMID- 27459889 TI - Perceived Safety at Work in the Wake of Terror: The Importance of Security Measures and Emergency Preparedness. AB - OBJECTIVES: We aimed to explore how perceived safety after terrorism is connected to views on security measures and emergency preparedness in a workplace setting. METHODS: Using a questionnaire-based, cross-sectional study of ministerial employees in Norway who were targeted in a terrorist attack in 2011 (n=3344), we investigated how employees' perceived safety at work 9 to 10 months after the attack was associated with their perceptions of whether security measures were sufficiently prioritized at work, whether there had been sufficient escape and evacuation training, and whether they were confident with evacuation procedures. RESULTS: We found strong evidence of increasing perceived safety at work the more employees believed security measures were sufficiently prioritized at work (partially confounded by post-traumatic stress disorder), and the better their knowledge of evacuation procedures (modified by gender and education). CONCLUSIONS: The present study suggests that employers may enhance perceived safety at work for terror-exposed employees by showing a commitment to security measures and by ensuring employees know evacuation procedures well. More research is needed to investigate causality patterns behind the associations found in this cross-sectional study. (Disaster Med Public Health Preparedness. 2016;10:805 811). PMID- 27459890 TI - Development of PDF-ECG: Further steps towards the long-term preservation of clinical electrocardiograms. PMID- 27459891 TI - Routes to the preparation of mixed monolayers of fluorinated and hydrogenated alkanethiolates grafted on the surface of gold nanoparticles. AB - The use of binary blends of hydrogenated and fluorinated alkanethiolates represents an interesting approach to the construction of anisotropic hybrid organic-inorganic nanoparticles since the fluorinated and hydrogenated components are expected to self-sort on the nanoparticle surface because of their reciprocal phobicity. These mixed monolayers are therefore strongly non-ideal binary systems. The synthetic routes we explored to achieve mixed monolayer gold nanoparticles displaying hydrogenated and fluorinated ligands clearly show that the final monolayer composition is a non-linear function of the initial reaction mixture. Our data suggest that, under certain geometrical constraints, nucleation and growth of fluorinated domains could be the initial event in the formation of these mixed monolayers. The onset of domain formation depends on the structure of the fluorinated and hydrogenated species. The solubility of the mixed monolayer nanoparticles displayed a marked discontinuity as a function of the monolayer composition. When the fluorinated component content is small, the nanoparticle systems are fully soluble in chloroform, at intermediate content the nanoparticles become soluble in hexane and eventually they become soluble in fluorinated solvents only. The ranges of monolayer compositions in which the solubility transitions are observed depend on the nature of the thiols composing the monolayer. PMID- 27459888 TI - Mechanistic understanding of the effect of Dengzhan Shengmai capsule on the pharmacokinetics of clopidogrel in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Dengzhan Shengmai capsule (DZSM) is known in China for its remarkable curative effect as a treatment of cardiovascular diseases, such as coronary heart disease and ischemic stroke. DZSM is a Chinese herbal compound preparation that consists of four ingredients, including Erigeron breviscapus (Vaniot) Hand.-Mazz., Panax ginseng C.A. Mey, Ophiopogon japonicas (Thunb.) Ker-Gawl. and Schisandra chinensis (Turcz.) Baill., and was indexed in the Chinese Pharmacopoeia 2010. DZSM and clopidogrel are often co-prescribed in the clinic to prevent the recurrence of stroke or other cardiovascular and cerebrovascular diseases. However, the effect of DZSM on the pharmacokinetics of clopidogrel remains unclear. AIM OF THE STUDY: The purpose of the study is to explore the pharmacokinetics and potential interaction between DZSM and clopidogrel and the underlying mechanism. MATERIALS AND METHODS: Rats were used to investigate the effect of DZSM on the pharmacokinetics of clopidogrel and its active metabolite in vivo. The plasma concentrations were simultaneously determined using LC-MS/MS. The effects of DZSM on the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel were investigated using MDCKII-MDR1 cells and rat liver microsomes, respectively. RESULTS: After pretreatment with DZSM, the Cmax and AUC0-infinity of clopidogrel increased from 0.4+/-0.1 to 1.7+/-0.6ng/mL and 0.9+/-0.4 to 2.0+/-0.2ng/mLh, respectively. The Cmax and AUC0-infinity of the derivatized active metabolite of clopidogrel decreased from 8.2+/-1.2 to 2.8+/-0.5ng/mL and 18.2+/-5.6 to 6.4+/-3.7ngh/mL, respectively. In MDCKII-MDR1 cells, the P-gp-mediated efflux transport of clopidogrel was significantly inhibited by the DZSM extract. In rat liver microsomes, DZSM inhibited clopidogrel metabolism with an IC50 of 0.02mg/mL. CONCLUSIONS: DZSM significantly affects the pharmacokinetics of clopidogrel and its active metabolite by inhibiting the P-gp-mediated efflux transport and CYP450 mediated metabolism of clopidogrel. Thus, caution is needed when DZSM is co administered with clopidogrel in the clinic because the interaction of these drugs may result in altered plasma concentrations of clopidogrel and its active metabolite. PMID- 27459892 TI - The fascial suspension of the prostate: A cadaveric study. AB - AIMS: Analysis and description of the supporting fascial structure around the prostate and urethra, which needs to be preserved or restored during radical prostatectomy (RP). METHODS: Anatomical dissection of 10 male cadavers was performed and the supporting fascial structures of bladder neck, prostate, and proximal urethra were investigated. The cadavers were embalmed according to Thiel's method, which preserves a natural texture and color of tissues. RESULTS: Anteriorly, the puboprostatic ligament (PL), the dorsal vein complex, and the urethropelvic ligament form an integral structure that suspends and stabilizes the prostatic apex. Laterally, the fascia originates from the fascial tendinous arch of the pelvis and stabilizes the prostate in the central position. In the posterolateral aspect, we could demonstrate a tendineous dorsal raphe, which represents an important stabilization structure of the urethra. CONCLUSIONS: The anterior and posterior pelvic fascial structure seems to be important stabilizer for the prostate and proximal urethra. Their preservation or reconstruction during RP is mandatory to restore the anatomic and functional continuity of the bladder neck and urethra. Neurourol. Urodynam. 36:1131-1135, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27459893 TI - Messages from the Malaysian Diabetes Registries on Diabetes Care in Malaysian public healthcare facilities. AB - A persistent and increasing prevalence of diagnosed and undiagnosed diabetes mellitus has recently been reported in the National Health and Morbidity Survey 2015. This commentary recapitulates the relevant and valuable lessons in the Malaysian national diabetes registries to inform the healthcare stakeholders and policy makers on potential areas of clinical practice improvement and future researches. Under performance of the process measures and sub-optimal control of HbA1c, blood pressure and lipids profile were prevalent (<40% achieved treatment targets). Although these had improved slightly from 2009 to 2012, diabetes co morbidities (hypertension and dyslipidaemia) and complications had also increased. Prevalence of insulin use had doubled, and lipid lowering agent use had increased about 50% in 2012 compared to 2009. We identified six clinical areas for urgent attention and improvement, and three potential areas for future research. PMID- 27459895 TI - Three-dimensional macro-structures of two-dimensional nanomaterials. AB - If two-dimensional (2D) nanomaterials are ever to be utilized as components of practical, macroscopic devices on a large scale, there is a complementary need to controllably assemble these 2D building blocks into more sophisticated and hierarchical three-dimensional (3D) architectures. Such a capability is key to design and build complex, functional devices with tailored properties. This review provides a comprehensive overview of the various experimental strategies currently used to fabricate the 3D macro-structures of 2D nanomaterials. Additionally, various approaches for the decoration of the 3D macro-structures with organic molecules, polymers, and inorganic materials are reviewed. Finally, we discuss the applications of 3D macro-structures, especially in the areas of energy, environment, sensing, and electronics, and describe the existing challenges and the outlook for this fast emerging field. PMID- 27459897 TI - Rashba Effect and Carrier Mobility in Hybrid Organic-Inorganic Perovskites. AB - The outstanding photovoltaic performance in hybrid organic-inorganic perovskites (HOIPs) relies on their desirable carrier transport properties. In the HOIPs, strong spin-orbit coupling (SOC) and structural inversion asymmetry give rise to a giant spin splitting in the conduction and valence bands, that is, the Rashba effect (RE), a subject intensively studied in spintronics. Here we show that this giant RE can manifest itself in charge transport and is the key to understanding carrier mobility and its temperature dependence in the HOIPs. The RE greatly enhances acoustic-phonon scattering (APS) and alters the temperature dependence of carrier mobility from T(-3/2) to T(-1). Meanwhile, it reduces polar-optical phonon scattering (POPS). In CH3NH3PbI3, the carrier mobility is limited by the APS for temperatures up to 100 K, above which the POPS becomes dominant. The effective polar coupling is moderate, alpha = 1.1, indicating that band conduction is still a valid description of charge transport. Our results account for the observed carrier transport behaviors over the entire temperature range and highlight the importance of SOC in charge transport in the HOIPs. PMID- 27459896 TI - Unbiased measurements of reconstruction fidelity of sparsely sampled magnetic resonance spectra. AB - The application of sparse-sampling techniques to NMR data acquisition would benefit from reliable quality measurements for reconstructed spectra. We introduce a pair of noise-normalized measurements, and , for differentiating inadequate modelling from overfitting. While and can be used jointly for methods that do not enforce exact agreement between the back-calculated time domain and the original sparse data, the cross-validation measure is applicable to all reconstruction algorithms. We show that the fidelity of reconstruction is sensitive to changes in and that model overfitting results in elevated and reduced spectral quality. PMID- 27459894 TI - Discovery and Total Synthesis of Streptoaminals: Antimicrobial [5,5] Spirohemiaminals from the Combined-Culture of Streptomyces nigrescens and Tsukamurella pulmonis. AB - A series of lipidic spirohemiaminals, designated streptoaminals, is reported. These were discovered by surveying the unique molecular signatures identified in the mass spectrometry data of the combined-culture broth of Streptomyces nigrescens HEK616 and Tsukamurella pulmonis TP-B0596. Mass spectrometry analysis showed that streptoaminals appeared as a cluster of ion peaks, which were separated by 14 mass unit intervals, implying the presence of alkyl chains of different lengths. The chemical structures of these compounds were elucidated by spectroscopic analysis and total synthesis. Streptoaminals with globular structures showed broad antimicrobial activities, whereas the planar structures of the 5-alkyl-1,2,3,4-tetrahydroquinolines found in the same combined-culture did not. This work shows the application of microbes as reservoirs for a range of chemical scaffolds. PMID- 27459898 TI - Gold-Nanosponge-Based Multistimuli-Responsive Drug Vehicles for Targeted Chemo Photothermal Therapy. AB - Gold-nanosponge-based multistimuli-responsive drug vehicles are constructed for combined chemo-photothermal therapy with pinpointed drug delivery and release capabilities and minimized nonspecific systemic spread of drugs, remarkably enhancing the therapeutic efficiency while minimizing acute side effects. PMID- 27459900 TI - Flu vaccination reduces hospital admissions for cardiovascular disease in people with diabetes, study shows. PMID- 27459899 TI - Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry. AB - PURPOSE: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study. EXPERIMENTAL DESIGN: Tissue microarrays from 1,076 patients with colorectal cancer from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1, and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semiquantitative pathologist scoring of the cores as input and applied to three independent clinical cohorts. RESULTS: This classifier demonstrated 87% concordance with the gold-standard transcriptome based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular colorectal cancer subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild-type metastatic cancers of the canonical epithelial-like subtypes. CONCLUSIONS: This study shows that a practical and robust immunohistochemical assay can be employed to identify molecular colorectal cancer subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of colorectal cancer samples, both in the format of an automated image analysis pipeline to score tumor core staining, and as a classifier based on semiquantitative pathology scoring. Clin Cancer Res; 23(2); 387-98. (c)2016 AACR. PMID- 27459901 TI - Electrochemical deposition of conductive and adhesive polypyrrole-dopamine films. AB - Electrode surfaces have been widely modified with electrically conductive polymers, including polypyrrole (PPY), to improve the performance of electrodes. To utilize conductive polymers for electrode modification, strong adhesion between the polymer films and electrode substrates should be ensured with high electrical/electrochemical activities. In this study, PPY films were electrochemically polymerized on electrodes (e.g., indium tin oxide (ITO)) with dopamine as a bio-inspired adhesive molecule. Efficient and fast PPY electrodeposition with dopamine (PDA/PPY) was found; the resultant PDA/PPY films exhibited greatly increased adhesion strengths of up to 3.7 +/- 0.8 MPa and the modified electrodes had electrochemical impedances two to three orders of magnitude lower than that of an unmodified electrode. This electrochemical deposition of adhesive and conductive PDA/PPY offers a facile and versatile electrode modification for various applications, such as biosensors and batteries. PMID- 27459902 TI - CT image biomarkers to improve patient-specific prediction of radiation-induced xerostomia and sticky saliva. AB - BACKGROUND AND PURPOSE: Current models for the prediction of late patient-rated moderate-to-severe xerostomia (XER12m) and sticky saliva (STIC12m) after radiotherapy are based on dose-volume parameters and baseline xerostomia (XERbase) or sticky saliva (STICbase) scores. The purpose is to improve prediction of XER12m and STIC12m with patient-specific characteristics, based on CT image biomarkers (IBMs). METHODS: Planning CT-scans and patient-rated outcome measures were prospectively collected for 249 head and neck cancer patients treated with definitive radiotherapy with or without systemic treatment. The potential IBMs represent geometric, CT intensity and textural characteristics of the parotid and submandibular glands. Lasso regularisation was used to create multivariable logistic regression models, which were internally validated by bootstrapping. RESULTS: The prediction of XER12m could be improved significantly by adding the IBM "Short Run Emphasis" (SRE), which quantifies heterogeneity of parotid tissue, to a model with mean contra-lateral parotid gland dose and XERbase. For STIC12m, the IBM maximum CT intensity of the submandibular gland was selected in addition to STICbase and mean dose to submandibular glands. CONCLUSION: Prediction of XER12m and STIC12m was improved by including IBMs representing heterogeneity and density of the salivary glands, respectively. These IBMs could guide additional research to the patient-specific response of healthy tissue to radiation dose. PMID- 27459904 TI - A detailed proteomic profiling of plasma membrane from zebrafish brain. AB - Zebrafish (Danio rerio) is a well-established model organism in developmental biology and disease modeling. In recent years, an increasing amount of studies used zebrafish to analyze the genetic changes underlying various neurological disorders. The brain plasma membrane proteome represents the major subsets of signaling proteins and promising drug targets, but is often understudied due to traditional experimental difficulties including problems with solubility, detergent removal, or low abundance. Here, we report a comprehensive dataset of the proteins identified in the enriched plasma membrane of the zebrafish brain by applying sequential trypsin/chymotrypsin digestion with multidimensional LC MS/MS. A total number of 97 017 peptide groups corresponding to 9201 proteins were identified. These were annotated in various molecular functions or neurological disorders. The dataset of the current study provides a useful data source for further utilizing zebrafish in basic and clinical neuroscience. PMID- 27459903 TI - Bioanalytical assay development and validation for simultaneous quantification of five schisandra lignans in rat primary hepatocytes based on LC-MS/MS: application to a real-time uptake study for Schisandra Lignan Extract. AB - Schisandra lignans, mainly including schizandrol A, schizandrol B, schisantherin A, schizandrin A, schizandrin B, etc., are the major active ingredients of Schisandra chinensis. In the present study, a robust liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the simultaneous quantification of schisandra lignans in rat primary hepatocytes. Lovastatin was used as an internal standard, and chromatographic separation was achieved on a Shimadzu C18 column with a gradient elution at the flow rate of 0.2 mL/min. All of the analytes were detected in multiple reaction monitoring mode with positive electrospray ionization since the sodium adduct ion [M + Na]+ was observed as the most intensive peak in the MS spectrum. For schizandrol A, schisantherin A and schizandrin A, the dynamic range was within 2-1000 ng/mg protein, and the linear range of schizandrol B and schizandrin B was from 5 to 1000 ng/mg protein. The intra- and inter-day precision was <15% and the accuracy (relative error) ranged from -15 to 15%. No significant variation was observed in the stability tests. The validated method was then successfully applied to the time-dependent uptake study for the Schisandra Lignan Extract in rat primary hepatocytes. PMID- 27459905 TI - Incremental predictive value of mean platelet volume/platelet count ratio in in hospital stroke after acute myocardial infarction. AB - Stroke is a serious complication after acute myocardial infarction (AMI) and is associated with an increased risk of death. Though the pathophysiological mechanisms are not exactly known, increased inflammation and platelet reactivity could play an important role in the occurrence of stroke during AMI. We aimed to investigate the relationship between both mean platelet volume (MPV), a parameter of platelet function, and C-reactive protein (CRP) and the occurrence of in hospital ischemic stroke (IHS) after AMI. Data were obtained from a French regional survey for AMI that included 5976 patients admitted to an intensive care unit (ICU) between 2001 and 2010. Patients were divided into two groups according to the occurrence of IHS. MPV, platelet count (PC), and CRP were routinely measured at admission to the ICU; 99 (1.6%) IHSs were recorded during hospitalization after admission for AMI. In multivariate analysis, IHS was independently associated with a history of stroke (OR: 1.99%, CI: 1.1-3.49, p = 0.01), impaired left ventricular ejection fraction <40% (OR: 1.88, 95% CI: 1.20 2.94, p = 0.006), impaired renal function (OR: 1.94, 95% CI: 1.27-2.95, p = 0.002), CRP > 10 mg/l (OR: 2.19, 95% CI: 1.44-3.33, p < 0.001), and MPV/PC ratio (OR: 1.04, 95% CI: 1.01-1.08, p = 0.023). Compared with the first to fourth quintiles, the last quintile of the MPV/PC ratio was associated with higher rates of IHS on survival curve analysis (p = 0.014). At hospital admission, a high MPV/PC ratio and a high level of CRP might help to identify patients at increased risk of IHS. Moreover, these results provide new insights into the potential role played by increased inflammation and platelet reactivity in the occurrence of stroke after AMI. PMID- 27459906 TI - Combined Detoxification and In-situ Product Removal by a Single Resin During Lignocellulosic Butanol Production. AB - Phragmites australis (an invasive plant in North America) was used as feedstock for ABE (acetone-butanol-ethanol) fermentation by Clostridium saccharobutylicum. Sulphuric acid pretreated phragmites hydrolysate (SAEH) without detoxification inhibited butanol production (0.73 g/L butanol from 30 g/L sugars). The treatment of SAEH with resin L-493 prior the fermentation resulted in no inhibitory effects and an ABE titer of 14.44 g/L, including 5.49 g/L butanol was obtained, corresponding to an ABE yield and productivity of 0.49 g/g and 0.60 g/L/h, respectively. Dual functionality of the resin was realized by also using it as an in-situ product removal agent. Integrating in-situ product removal allowed for the use of high substrate concentrations without the typical product inhibition. Resin-detoxified SAEH was supplemented with neat glucose and an effective ABE titer of 33 g/L (including 13.7 g/L acetone, 16.4 g/L butanol and 1.9 g/L ethanol) was achieved with resin-based in-situ product removal, corresponding to an ABE yield and productivity of 0.41 g/g and 0.69 g/L/h, respectively. Both detoxification of the substrate and the products was achieved by the same resin, which was added prior the fermentation. Integrating hydrolysate detoxification and in-situ butanol removal in a batch process through single resin can potentially simplify cellulosic butanol production. PMID- 27459907 TI - Coix seed emulsion synergistically enhances the antitumor activity of gemcitabine in pancreatic cancer through abrogation of NF-kappaB signaling. AB - Clinical outcomes in patients with pancreatic cancer (PC) continue to be dismal, in part due to de novo and acquired chemoresistance. In the present study, we provide preclinical evidence that pre-treatment with coix seed emulsion, an injectable agent extracted from coix seeds, synergistically sensitized PC cell lines (BxPC-3, PANC-1 and AsPC-1) to gemcitabine, both in vitro and in vivo. Such pretreatment led to significant induction of pro-apoptosis proteins, including caspase-3, cleaved-PARP and Bax (P<0.05), after lower doses of gemcitabine compared to monotherapy. We also showed that coix seed emulsion suppressed the constitutive and gemcitabine-induced activation of nuclear factor-kappaB (NF kappaB), as shown with the use of electrophoretic mobility shift, reporter and immunoblotting analyses. Coix seed emulsion pretreatment also downregulated the NF-kappaB-dependent anti-apoptotic molecules Bcl-2, survivin and cyclooxygenase 2. In vivo, coix seed emulsion combined with gemcitabine had a much greater antitumor effect than the effect of either agent alone, consistent with the downregulation of the proliferation index, and the results of immunostaining for Ki-67, or for the NF-kappaB subunit p65. Overall, our data demonstrated that coix seed emulsion abrogated gemcitabine-induced activation of NF-kappaB, and synergistically sensitized PC cells to gemcitabine therapy. PMID- 27459908 TI - [Clinical records as a tool for enhancing medical care]. PMID- 27459909 TI - [Assessment of maternal satisfaction with epidural analgesia for pain control during labour]. AB - BACKGROUND: To determine the level of satisfaction and the sociodemographic characteristics of patients who receive epidural analgesia during labour. MATERIAL AND METHODS: A SERVQHOS questionnaire administered, with consecutive sampling, to 140 patients who had received an epidural anaesthetic for pain control during labour between January and June 2014, at the Hospital San Pedro. RESULTS: A total of 140 questionnaires were completed. The mean overall satisfaction (SERVQHOS scale) was 4.4 with standard deviation (SD):+/-0.9, with the best results being obtained in the subjective items: (4.3; SD 0.81) compared to the objective items (4; SD: 0.9). The large majority (84.3%) showed satisfaction with the epidural anaesthetic, and 100% would ask for it again. No significant differences were found in epidural satisfaction or pain perception related to socioeconomic variables (age, nationality, employment conditions, education level or marital status). As regards nationality, 119 (85%) were Spanish, and 14.3% (20) of other nationalities, with 1 patient not answering the nationality question. As regards marital status, 79.3% (111) were married, 1.4% (2), single, and 2.9% (4) were widows or separated, and 2.9% (4) did not answer. The mean age was 33.3 years (SD: 4.4). Prior to the administration of the epidural anaesthetic 93.2% of the Spanish citizens group described the pain as severe compared to 95% of the other nationalities group, but this difference had no statistical significance (p=.279). CONCLUSION: The level of satisfaction reported by the patients with this technique was high, with subjective items (good manners and trust) being appreciated more. PMID- 27459910 TI - Skin aging caused by intrinsic or extrinsic processes characterized with functional proteomics. AB - The skin provides protection against environmental stress. However, intrinsic and extrinsic aging causes significant alteration to skin structure and components, which subsequently impairs molecular characteristics and biochemical processes. Here, we have conducted an immunohistological investigation and established the proteome profiles on nude mice skin to verify the specific responses during aging caused by different factors. Our results showed that UVB-elicited aging results in upregulation of proliferating cell nuclear antigen and strong oxidative damage in DNA, whereas chronological aging abolished epidermal cell growth and increased the expression of caspase-14, as well as protein carbonylation. Network analysis indicated that the programmed skin aging activated the ubiquitin system and triggered obvious downregulation of 14-3-3 sigma, which might accelerate the loss of cell growth capacity. On the other hand, UVB stimulation enhanced inflammation and the risk of skin carcinogenesis. Collectively, functional proteomics could provide large-scale investigation of the potent proteins and molecules that play important roles in skin subjected to both intrinsic and extrinsic aging. PMID- 27459911 TI - Client and clinical staff perceptions of barriers to and enablers of the uptake and delivery of behavioural interventions for urinary incontinence: qualitative evidence synthesis. AB - AIM: To evaluate factors influencing uptake and delivery of behavioural interventions for urinary incontinence from the perspective of clients and clinical staff. BACKGROUND: Behavioural interventions are recommended as first line therapy for the management of urinary incontinence. Barriers to and enablers of uptake and delivery of behavioural interventions have not been reviewed. DESIGN: Qualitative evidence synthesis. DATA SOURCES: MEDLINE, EMBASE, CINAHL, PsychInfo, AMED (inception to May 2013); Proceedings of the International Continence Society (ICS) (2006-2013). REVIEW METHODS: Studies where data were collected from clients or staff about their experiences or perceptions of behavioural interventions were included. Two reviewers independently screened records on title and abstract. Full-text papers were obtained for records identified as potentially relevant by either reviewer. Two reviewers independently filtered all full-text papers for inclusion, extracted findings and critically appraised studies. We used an approach akin to Framework, using a matrix of pre-specified themes to classify the data and facilitate its presentation and synthesis. RESULTS: Seven studies involving 200 participants identified clients' views. Findings identified from at least one study of moderate quality included increased fear of accidents and convenience of treatment. Factors enabling participation included realistic goals and gaining control. Six studies involving 427 participants identified staff views. Findings identified from at least one study of moderate quality included staff education and perceptions of treatment effectiveness. Enabling factors included teamwork and experience of success. CONCLUSION: There is little detailed exploration of clients' experiences of, and responses to, behavioural interventions. Evidence for staff relates predominantly to prompted voiding in long-term residential care. Studies of the uptake and delivery of other behavioural interventions in other settings are warranted. PMID- 27459912 TI - Is the size of the pancreas useful in diagnosing chronic pancreatitis? An ultrasound based, retrospective study. AB - BACKGROUND/OBJECTIVES: According to the widely accepted "Cambridge Classification", one of the morphological criteria for chronic pancreatitis (CP) is enlargement of the pancreas. Increased size seems to be an obvious feature of an inflammatory disease. However, it has never been validated so far, if CP is indeed accompanied by significant enlargement of the pancreas. METHODS: In this retrospective study, reference values for the size of the pancreas (head, body and tail measured in the transverse plane by transabdominal ultrasound) were established from 921 patients without pancreatic disease. Measurements were performed by a single investigator. Subsequently, the size of the pancreas from 72 patients with CP was compared to age- and sex-matched controls. RESULTS: Calculating the 5th and 95th percentile, reference values of the pancreatic size were as follows: head 1.5-3.1 cm (mean: 2.2); body 0.6-1.6 cm (mean: 1.1); tail 1.4-3.0 cm (mean: 2.1). The size of the pancreas correlated significantly with body height, weight and body mass index. Patients with CP had only a slightly but statistically significantly larger pancreas than controls. Mean values from the CP group were still between the 5th and 95th percentile of matched controls. CONCLUSIONS: Although the pancreas from patients with CP was statistically significantly larger compared to controls, the difference was only marginally. According to these data, it is at least questionable if pancreatic size is a helpful parameter for sonographic evaluation to discriminate chronic pancreatitis from healthy pancreas. PMID- 27459913 TI - Pancreatic juice cytology as sensitive test for detecting pancreatic malignancy in intraductal papillary mucinous neoplasm of the pancreas without mural nodule. AB - OBJECTIVE: Recent studies reported that mural nodule (MN) was the most associated with malignant intraductal papillary mucinous neoplasms (IPMNs). However, IPMNs without MN cannot be diagnosed as malignant if only MN is determined to be indicator of malignancy. This study aimed to investigate role of pancreatic juice cytology for IPMNs without MN. METHODS: Medical records of 50 patients with histologically proven malignant IPMNs were reviewed. Exclusively for non-invasive cancer, extent of high-grade dysplasia along the main pancreatic duct (MPD) was determined microscopically. RESULTS: Thirty-six percent IPMNs had no MN. Cyst and main MPD diameter were significantly smaller in IPMN without MN compared to those in IPMN with MN (23 +/- 14.1 vs 35 +/- 13.2 mm, p = 0.010; 6.6 +/- 4.3 vs 10.9 +/ 6.1 mm, p = 0.006). Sensitivity of pancreatic juice cytology was higher in IPMN without MN compared to that in IPMN with MN (94% vs 53%, p = 0.004) although it could be affected by selection bias of study patients. Absence of MN was determined to be an independent factor associated with true positive cytology (OR = 24.3, p = 0.005). Extent of high-grade dysplasia was significantly longer in IPMN with true positive cytology compared to that in IPMN with false negative cytology (46.8 +/- 20.5 vs 26.4 +/- 11.0 mm, p = 0.005), and tended to be longer in IPMN without MN compared to that in IPMN with MN (47.0 +/- 19.0 vs 36.0 +/- 20.1 mm, p = 0.16). CONCLUSIONS: Sensitivity of pancreatic juice cytology was excellent in IPMN without MN. Pancreatic juice cytology may be a sensitive test for detection of pancreatic malignancy in IPMN without MN compared to high-risk imaging features. PMID- 27459914 TI - Overexpression of seven in absentia homolog 2 protein in human breast cancer tissues is associated with the promotion of tumor cell malignant behavior in in vitro. AB - Seven in absentia homolog 2 (SIAH2), a homologue of Drosophila seven in absentia (Sina), has emerged as an oncogene and plays important roles in cancer development and progression. This study further assessed the role of SIAH2 in breast cancer and the underlying molecular events. The data showed that SIAH2 protein was overexpressed in invasive breast cancer (IBC) compared to the expression noted in normal or ductal carcinoma in situ (DCIS) tissues, expression of which is associated with malignant behaviors. SIAH2 may function differently in different molecular subtypes (e.g., luminal- vs. basal-like type) of breast cancer. Manipulation of SIAH2 expression led to a 'cross-talk' of the ERK and PI3K pathway, which could be one of the mechanisms by which SIAH2 regulates viability, apoptosis, and invasion capacity in these breast cancer cell lines. PMID- 27459915 TI - Vibrio parahaemolyticus and Vibrio vulnificus in South America: water, seafood and human infections. AB - The bacterial species, Vibrio parahaemolyticus and Vibrio vulnificus, are ubiquitous in estuaries and coastal waters throughout the world, but they also happen to be important human pathogens. They are concentrated by filter-feeding shellfish which are often consumed raw or undercooked, providing an important potential route of entry for an infective dose of these bacteria. Vibrio parahaemolyticus can cause abdominal cramping, nausea, diarrhoea, vomiting, chills and fever. Vibrio vulnificus can cause similar gastrointestinal-related symptoms, but can also spread to the bloodstream, resulting in primary septicaemia, and it can also cause disease via wound infections. The objective of this article is to summarize, for the first time, the incidence and importance of V. parahaemolyticus and V. vulnificus in South America, in environmental waters and seafood, especifically molluscan shellfish, as well as human infection cases and outbreaks. It appears that infections from V. parahaemolyticus have been more strongly related to shellfish ingestion and have been more frequently reported on the Pacific coast of South America. Conversely, V. vulnificus has been more frequently acquired by water contact with open wounds and its presence has been more heavily reported along the Atlantic coast of South America, and while documented to cause serious mortality, have been relatively few in number. The impacts of El Nino Southern Oscillation (ENSO) have been observed to cause an increase in V. parahaemolyticus outbreaks on the Pacific coast of South America. The implementation of a regulated monitoring approach, along with the use of faster, more accurate and virulence-specific detection approaches, such as PCR confirmation, should be considered to detect the presence of pathogenic Vibrio strains in environmental and seafood samples for protection of public health. Furthermore, improved clinical surveillance with suspected cases should be implemented. This review highlights the need for more research and monitoring of vibrios in South America, in water, shellfish and clinical samples. PMID- 27459916 TI - A case of acute encephalopathy with biphasic seizures and late reduced diffusion: Utility of arterial spin labeling sequence. AB - A 1-year-old boy was admitted because of febrile status epilepticus (FSE). A secondary cluster of seizures was seen on day 5 after onset, and the patient eventually displayed developmental delay. Conventional magnetic resonance imaging (MRI) showed no abnormal findings on day 1 after onset, but showed reduced diffusion in the subcortical regions of bilateral frontal lobes on day 5 after onset. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was diagnosed. Arterial spin labeling (ASL) revealed reduced cerebral blood flow (CBF) in bilateral frontal lobes on day 1 after onset and showed increased CBF in the corresponding region in the subacute phase. Outcomes after prolonged febrile seizures are usually good, but mental deficit and/or epilepsy often remain in AESD. Discriminating between these syndromes is difficult, because no useful biomarkers have been identified. Reduced CBF in bilateral frontal lobes was observed on ASL on day 1 of FSE in the present case, and this finding may be predictive of developing AESD. PMID- 27459918 TI - Erratum to "Skin infection after infiltration by Nocardia cerradoensis". PMID- 27459919 TI - Costs and cost-efficacy analysis of the 2016 GESIDA/Spanish AIDS National Plan recommended guidelines for initial antiretroviral therapy in HIV-infected adults. AB - INTRODUCTION: GESIDA and the AIDS National Plan panel of experts suggest preferred (PR), alternative (AR), and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for the year 2016. The objective of this study is to evaluate the costs and the efficacy of initiating treatment with these regimens. METHODS: Economic assessment of costs and efficiency (cost/efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48 in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied, only taking into account differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting is Spain and the costs correspond to those of 2016. A sensitivity deterministic analysis was conducted, building three scenarios for each regimen: base case, most favourable, and least favourable. RESULTS: In the base case scenario, the cost of initiating treatment ranges from 4663 Euros for 3TC+LPV/r (OR) to 10,894 Euros for TDF/FTC+RAL (PR). The efficacy varies from 0.66 for ABC/3TC+ATV/r (AR) and ABC/3TC+LPV/r (OR), to 0.89 for TDF/FTC+DTG (PR) and TDF/FTC/EVG/COBI (AR). The efficiency, in terms of cost/efficacy, ranges from 5280 to 12,836 Euros per responder at 48 weeks, for 3TC+LPV/r (OR), and RAL+DRV/r (OR), respectively. CONCLUSION: Despite the overall most efficient regimen being 3TC+LPV/r (OR), among the PR and AR, the most efficient regimen was ABC/3TC/DTG (PR). Among the AR regimes, the most efficient was TDF/FTC/RPV. PMID- 27459920 TI - An attenuated immune response by Schwann cells and macrophages inhibits nerve regeneration in aged rats. AB - Although peripheral nerves are capable of regeneration, advanced age decreases the potential for functional recovery after injury. The cellular mechanisms for this are not currently understood. Here, we performed sciatic nerve grafting with young (2 months old) and aged (18 months old) Brown-Norway male rats, in which 1 cm nerve grafts from young or aged rats were sutured into nerves of young or aged rats. Axons were allowed to regenerate until the nerve grafts and distal nerves were harvested at 1, 3, and 7 days and 2 and 6 weeks. At 6 weeks, our data suggested that young nerve grafts supported regeneration better than aged nerve grafts. In addition, myelin debris clearance was inhibited in young nerves when grafted into aged rats, but clearance was faster when aged nerves were grafted into young rats. Further analysis revealed that aged macrophages have delayed migration into injured nerve, and macrophages and Schwann cells from aged rats were less phagocytic for myelin debris in vitro. To understand these impairments, expression levels of pro- and anti-inflammatory cytokines were analyzed at 1 day after injury. Based on these levels, there was not a clear polarization to either an M1 or M2 phenotype; however, expression levels of IL-6, IL-10, CCL2 (MCP1), and Arg-1 were decreased in aged nerves. Taken together, both macrophages and Schwann cells had attenuated responses to nerve injury in aged rats, leading to inefficient clearance of debris and impaired axonal regeneration. PMID- 27459921 TI - Altered temporal dynamics of neural adaptation in the aging human auditory cortex. AB - Neural response adaptation plays an important role in perception and cognition. Here, we used electroencephalography to investigate how aging affects the temporal dynamics of neural adaptation in human auditory cortex. Younger (18-31 years) and older (51-70 years) normal hearing adults listened to tone sequences with varying onset-to-onset intervals. Our results show long-lasting neural adaptation such that the response to a particular tone is a nonlinear function of the extended temporal history of sound events. Most important, aging is associated with multiple changes in auditory cortex; older adults exhibit larger and less variable response magnitudes, a larger dynamic response range, and a reduced sensitivity to temporal context. Computational modeling suggests that reduced adaptation recovery times underlie these changes in the aging auditory cortex and that the extended temporal stimulation has less influence on the neural response to the current sound in older compared with younger individuals. Our human electroencephalography results critically narrow the gap to animal electrophysiology work suggesting a compensatory release from cortical inhibition accompanying hearing loss and aging. PMID- 27459917 TI - Autophagy is induced in the skeletal muscle of cachectic cancer patients. AB - Basal rates of autophagy can be markedly accelerated by environmental stresses. Recently, autophagy has been involved in cancer-induced muscle wasting. Aim of this study has been to evaluate if autophagy is induced in the skeletal muscle of cancer patients. The expression (mRNA and protein) of autophagic markers has been evaluated in intraoperative muscle biopsies. Beclin-1 protein levels were increased in cachectic cancer patients, suggesting autophagy induction. LC3B-I protein levels were not significantly modified. LC3B-II protein levels were significantly increased in cachectic cancer patients suggesting either increased autophagosome formation or reduced autophagosome turnover. Conversely, p62 protein levels were increased in cachectic and non-cachectic cancer patients, suggesting impaired autophagosome clearance. As for mitophagy, both Bnip3 and Nix/Bnip3L show a trend to increase in cachectic patients. In the same patients, Parkin levels significantly increased, while PINK1 was unchanged. At gene level, Beclin-1, p-62, BNIP3, NIX/BNIP3L and TFEB mRNAs were not significantly modulated, while LC3B and PINK1 mRNA levels were increased and decreased, respectively, in cachectic cancer patients. Autophagy is induced in the skeletal muscle of cachectic cancer patients, although autophagosome clearance appears to be impaired. Further studies should evaluate whether modulation of autophagy could represent a relevant therapeutic strategy in cancer cachexia. PMID- 27459922 TI - Association between shift work history and performance on the trail making test in middle-aged and elderly humans: the EpiHealth study. AB - Shift work has been proposed to promote cognitive disturbances in humans; however, conflicting evidence is also present. By using data from 7143 middle aged and elderly humans (45-75 years) who participated in the Swedish EpiHealth cohort study, the present analysis sought to investigate whether self-reported shift work history would be associated with performance on the trail making test (TMT). The TMT has been proposed to be a useful neuropsychological tool to evaluate humans' executive cognitive function, which is known to decrease with age. After adjustment for potential confounders (e.g., age, education, and sleep duration), it was observed that current and recent former shift workers (worked shifts during the past 5 years) performed worse on the TMT than nonshift workers. In contrast, performance on the TMT did not differ between past shift workers (off from shift work for more than 5 years) and nonshift workers. Collectively, our results indicate that shift work history is linked to poorer performance on the TMT in a cohort of middle-aged and elderly humans. PMID- 27459924 TI - Enhanced resting-state functional connectivity between core memory-task activation peaks is associated with memory impairment in MCI. AB - Resting-state functional connectivity (FC) is altered in Alzheimer's disease (AD) but its predictive value for episodic memory impairment is debated. Here, we aimed to assess whether resting-state FC in core brain regions activated during memory-task functional magnetic resonance imaging is altered and predictive of memory performance in AD and amnestic mild cognitive impairment (aMCI). Twenty three elderly cognitively healthy controls (HC), 76 aMCI subjects, and 19 AD dementia patients were included. We computed resting-state FC between 18 meta analytically determined peak coordinates of brain activation during successful memory retrieval. Higher FC between the parahippocampus, parietal cortex, and the middle frontal gyrus was observed in both AD and mild cognitive impairment compared to HC (false-discovery rate-corrected p < 0.05). The increase in FC between the parahippocampus and middle frontal gyrus was associated with reduced episodic memory in aMCI, independent of amyloid-beta positron emission tomography binding and apolipoprotein E epsilon4-carrier status. In conclusion, increased parahippocampal-prefrontal FC is predictive of impaired episodic memory in aMCI and may reflect a dysfunctional change within the episodic memory-related neural network. PMID- 27459923 TI - Neurofilament-labeled pyramidal neurons and astrocytes are deficient in DNA methylation marks in Alzheimer's disease. AB - There is increasing evidence that epigenetic alterations may play a role in Alzheimer's disease (AD); yet, there is little information regarding epigenetic modifications in specific cell types. We assessed DNA methylation (5 methylcytosine [5mC]) and hydroxymethylation (5-hydroxymethylcytosine [5hmC]) marks specifically in neuronal and glial cell types in the inferior temporal gyrus of human AD cases and age-matched controls. Interestingly, neurofilament (NF)-labeled pyramidal neurons that are vulnerable to AD pathology are deficient in extranuclear 5mC in AD cases compared with controls. We also found that fewer astrocytes exhibited nuclear 5mC and 5hmC marks in AD cases compared with controls. However, there were no alterations in 5mC and 5hmC in disease-resistant calretinin interneurons or microglia in AD, and there was no alteration in the density of 5mC- or 5hmC-labeled nuclei in near-plaque versus plaque-free regions in late-AD cases. 5mC and 5hmC were present in a high proportion of neurofibrillary tangles, suggesting no loss of DNA methylation marks in tangle bearing neurons. We provide evidence that epigenetic dysregulation may be occurring in astrocytes and NF-positive pyramidal neurons in AD. PMID- 27459925 TI - Longitudinal noninvasive magnetic resonance imaging of brain microhemorrhages in BACE inhibitor-treated APP transgenic mice. AB - Currently, several immunotherapies and BACE (Beta Site APP Cleaving Enzyme) inhibitor approaches are being tested in the clinic for the treatment of Alzheimer's disease. A crucial mechanism-related safety concern is the exacerbation of microhemorrhages, which are already present in the majority of Alzheimer patients. To investigate potential safety liabilities of long-term BACE inhibitor therapy, we used aged amyloid precursor protein (APP) transgenic mice (APP23), which robustly develop cerebral amyloid angiopathy. T2*-weighted magnetic resonance imaging (MRI), a translational method applicable in preclinical and clinical studies, was used for the detection of microhemorrhages throughout the entire brain, with subsequent histological validation. Three dimensional reconstruction based on in vivo MRI and serial Perls' stained sections demonstrated a one-to-one matching of the lesions thus allowing for their histopathological characterization. MRI detected small Perls' positive areas with a high spatial resolution. Our data demonstrate that volumetric assessment by noninvasive MRI is well suited to monitor cerebral microhemorrhages in vivo. Furthermore, 3 months treatment of aged APP23 with the potent BACE inhibitor NB-360 did not exacerbate microhemorrhages in contrast to Abeta antibody beta1. These results substantiate the safe use of BACE inhibitors regarding microhemorrhages in long-term clinical studies for the treatment of Alzheimer's disease. PMID- 27459926 TI - No evidence for increased brain iron deposition in patients with ischemic white matter disease. AB - Besides specific iron accumulation in some neurodegenerative disorders, increased iron deposition in cerebral deep gray matter (DGM) is found in multiple sclerosis. As this is considered largely a white matter (WM) disease, we speculated that patients with more severe ischemic WM hyperintensities (WMH) might also have an increased iron concentration in DGM structures and tested this assumption by using magnetic resonance imaging-based quantitative R2* relaxometry. WMH severity was measured in 61 patients with acute transient neurological symptoms (mean age: 71.5 +/- 8.3 years) undergoing 3-Tesla magnetic resonance imaging. Despite a 6-year higher age of patients with more severe (i.e., early confluent or confluent) WMH, their DGM R2* rates did not differ from patients with punctate or no WMH. In the globus pallidum, R2* rates were even lower in patients with severe WMH. WMH volume was not correlated with R2* levels in any of the analyzed DGM structures. These findings argue against WM damage per se causing increased DGM iron deposition in multiple sclerosis and suggest no role of iron accumulation in ischemic small vessel disease. PMID- 27459927 TI - Spatial training promotes short-term survival and neuron-like differentiation of newborn cells in Abeta1-42-injected rats. AB - Neurogenesis plays a role in hippocampus-dependent learning and impaired neurogenesis may correlate with cognitive deficits in Alzheimer's disease. Spatial training influences the production and fate of newborn cells in hippocampus of normal animals, whereas the effects on neurogenesis in Alzheimer like animal are not reported until now. Here, for the first time, we investigated the effect of Morris water maze training on proliferation, survival, apoptosis, migration, and differentiation of newborn cells in beta-amyloid-treated Alzheimer like rats. We found that spatial training could preserve a short-term survival of newborn cells generated before training, during the early phase, and the late phase of training. However, the training had no effect on the long-term survival of mature newborn cells generated at previously mentioned 3 different phases. We also demonstrated that spatial training promoted newborn cell differentiation preferentially to the neuron direction. These findings suggest a time-independent neurogenesis induced by spatial training, which may be indicative for the cognitive stimulation in Alzheimer's disease therapy. PMID- 27459928 TI - Knockdown of microRNA-195 contributes to protein phosphatase-2A inactivation in rats with chronic brain hypoperfusion. AB - Reduction of protein phosphatase-2A (PP2A) activity is a common clinical feature of Alzheimer's disease and vascular dementia. In this study, we observed that chronic brain hypoperfusion induced by bilateral common carotid artery occlusion of rats led to PP2A inactivation based on the increase in tyrosine-307 phosphorylation and leucine-309 demethylation of PP2AC and the depression in PP2ABalpha. Knockdown of miR-195 using overexpression of its antisense molecule oligonucleotide (pre-AMO-miR-195) delivered by a lentivirus (lenti-pre-AMO-miR 195) increased tyrosine-307 phosphorylation and decreased both PP2ABalpha expression and leucine-309 methylation; these effects were prevented by the overexpression of miR-195 using lenti-pre-miR-195 and controlled by an increase in methylesterase (PME-1) and a decrease in leucine carboxyl methyltransferase-1. In vitro studies demonstrated that miR-195 regulated PME-1 expression by binding to the Ppme1 gene 3'-untranslated region (3'UTR) domain. Masking the miR-195 binding sites in the amyloid precursor protein (APP) and beta-site APP cleaving enzyme 1 genes prevented miR-195-induced leucine carboxyl methyltransferase-1 elevation. We concluded that the miR-195 downregulation in chronic brain hypoperfusion involved PP2A inactivity, which was mediated by the post transcriptional regulation PME-1, APP, and beta-site APP cleaving enzyme 1 expression. PMID- 27459930 TI - Summative effects of vascular risk factors on cortical thickness in mild cognitive impairment. AB - Vascular risk factors (VRFs) increase the risk of Alzheimer's disease (AD) and contribute to neurodegenerative processes. The purpose of this study was to investigate whether increasing number of VRFs contributes to within-cohort differences in cortical thickness (CThk) among adults with mild cognitive impairment (MCI) and cognitively intact older controls from the AD Neuroimaging Initiative 1, GO, and 2 data sets. Multivariate partial least squares analysis was used to investigate the effect of VRF index on regional CThk measurements, which produced a significant latent variable and identified patterns of cortical thinning in the MCI group but not controls. Subsequent analyses tested the interaction effects between VRF index and cognitive grouping and examined 1-year follow-up data. There was evidence of a VRF index by cognitive group interaction. Partial least squares results were replicated at 1-year follow-up among MCI cohort in a subset of baseline CThk regions. This study provides evidence that a summative VRF index accounts for some of the variance in brain tissue loss in regions implicated in AD among MCI adults. PMID- 27459929 TI - Age-related changes in tonic activation of presynaptic versus extrasynaptic gamma amniobutyric acid type B receptors in rat medial prefrontal cortex. AB - The present study examined the effect of age on both glutamatergic and gamma aminobutyric acid mediated (GABAergic) signaling in the rodent medial prefrontal cortex (mPFC), with an emphasis on revealing novel changes contributing to increased inhibition in age. Whole-cell patch clamp recordings were obtained from layer 2/3 mPFC pyramidal neurons in acute cortical slices prepared from either young (4 months) or aged (20-24 months) male F344 rats. Results indicated that GABAB receptors on GABAergic, but not on glutamatergic, inputs to layer 2/3 pyramidal cells are tonically activated by ambient GABA in young animals and further demonstrated that this form of tonic inhibition is significantly attenuated in aged mPFC. Moreover, concurrent with loss of tonic presynaptic GABAB autoreceptor activation, layer 2/3 pyramidal cells in aged mPFC are subjected to increased tonic activation of extrasynaptic GABAA and GABAB receptors. These data demonstrate a shift in the site of GABAB receptor-mediated inhibitory tone in the aged mPFC that clearly promotes increased inhibition of pyramidal cells in aged animals, and that may plausibly contribute to impaired executive function. PMID- 27459931 TI - RAB39B gene mutations are not a common cause of Parkinson's disease or dementia with Lewy bodies. AB - Mutations in Ras-related protein Rab-39B (RAB39B) gene have been linked to X linked early-onset Parkinsonism with intellectual disabilities. The aim of this study was to address the genetic contribution of RAB39B to Parkinson's disease (PD), dementia with Lewy bodies (DLB), and pathologically confirmed Lewy body dementia (pLBD) cases. A cohort of 884 PD, 399 DLB, and 379 pLBD patients were screened for RAB39B mutations, but no coding variants were found, suggesting RAB39B mutations are not a common cause of PD, DLB, or pLBD in Caucasian population. PMID- 27459932 TI - New selective glucocorticoid receptor modulators reverse amyloid-beta peptide induced hippocampus toxicity. AB - In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-beta peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment. PMID- 27459933 TI - Perturbed cholesterol homeostasis in aging spinal cord. AB - The spinal cord is vital for the processing of sensorimotor information and for its propagation to and from both the brain and the periphery. Spinal cord function is affected by aging, however, the mechanisms involved are not well understood. To characterize molecular mechanisms of spinal cord aging, microarray analyses of gene expression were performed on cervical spinal cords of aging rats. Of the metabolic and signaling pathways affected, cholesterol-associated pathways were the most comprehensively altered, including significant downregulation of cholesterol synthesis-related genes and upregulation of cholesterol transport and metabolism genes. Paradoxically, a significant increase in total cholesterol content was observed-likely associated with cholesterol ester accumulation. To investigate potential mechanisms for the perturbed cholesterol homeostasis, we quantified the expression of myelin and neuroinflammation-associated genes and proteins. Although there was minimal change in myelin-related expression, there was an increase in phagocytic microglial and astrogliosis markers, particularly in the white matter. Together, these results suggest that perturbed cholesterol homeostasis, possibly as a result of increased inflammatory activation in spinal cord white matter, may contribute to impaired spinal cord function with aging. PMID- 27459934 TI - Age-related changes in the function and structure of the peripheral sensory pathway in mice. AB - This study is aimed at describing the changes occurring in the entire peripheral nervous system sensory pathway along a 2-year observation period in a cohort of C57BL/6 mice. The neurophysiological studies evidenced significant differences in the selected time points corresponding to childhood, young adulthood, adulthood, and aging (i.e., 1, 7, 15, and 25 months of age), with a parabolic course as function of time. The pathological assessment allowed to demonstrate signs of age related changes since the age of 7 months, with a remarkable increase in both peripheral nerves and dorsal root ganglia at the subsequent time points. These changes were mainly in the myelin sheaths, as also confirmed by the Rotating Polarization Coherent-Anti-stokes-Raman-scattering microscopy analysis. Evident changes were also present at the morphometric analysis performed on the peripheral nerves, dorsal root ganglia neurons, and skin biopsies. This extensive, multimodal characterization of the peripheral nervous system changes in aging provides the background for future mechanistic studies allowing the selection of the most appropriate time points and readouts according to the investigation aims. PMID- 27459935 TI - Attenuated anticorrelation between the default and dorsal attention networks with aging: evidence from task and rest. AB - Anticorrelation between the default and dorsal attention networks is a central feature of human functional brain organization. Hallmarks of aging include impaired default network modulation and declining medial temporal lobe (MTL) function. However, it remains unclear if this anticorrelation is preserved into older adulthood during task performance, or how this is related to the intrinsic architecture of the brain. We hypothesized that older adults would show reduced within- and increased between-network functional connectivity (FC) across the default and dorsal attention networks. To test this hypothesis, we examined the effects of aging on task-related and intrinsic FC using functional magnetic resonance imaging during an autobiographical planning task known to engage the default network and during rest, respectively, with young (n = 72) and older (n = 79) participants. The task-related FC analysis revealed reduced anticorrelation with aging. At rest, there was a robust double dissociation, with older adults showing a pattern of reduced within-network FC, but increased between-network FC, across both networks, relative to young adults. Moreover, older adults showed reduced intrinsic resting-state FC of the MTL with both networks suggesting a fractionation of the MTL memory system in healthy aging. These findings demonstrate age-related dedifferentiation among these competitive large-scale networks during both task and rest, consistent with the idea that age-related changes are associated with a breakdown in the intrinsic functional architecture within and among large-scale brain networks. PMID- 27459936 TI - Hippocampal network dynamics in response to alpha7 nACh receptors activation in amyloid-beta overproducing transgenic mice. AB - Amyloid-beta (Abeta) peptide overproduction is one of the pathomechanisms contributing to Alzheimer's disease (AD). Agonists of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that alpha7 nAChR agonists may improve cognitive functions in AD patients. However, interactions between Abeta and alpha7 nAChRs have been observed, implying that high levels of Abeta may modify the effects of alpha7 nAChR agonists. Therefore, we tested the alpha7 nAChR agonist FRM-17874, an analogue of encenicline, in 8-month-old Abeta overproducing 5xFAD mice in an in vivo neurophysiological assay with a high construct and predictive validity for testing procognitive drugs. By recording changes in brainstem-stimulation-elicited hippocampal oscillations, we identified previously undescribed neurophysiological impairments in 5xFAD mice, including significantly decreased power of theta and gamma oscillations and theta-phase gamma-amplitude coupling. Compared with their saline controls, systemically administered FRM-17874 significantly increased stimulation-induced theta power by 30% in both 5xFAD and wild-type mice. However, FRM-17874 did not impact gamma oscillation or theta-phase-gamma-amplitude coupling in either wild type or 5xFAD mice, and it did not eliminate the significant differences in these parameters between the 2 groups. PMID- 27459937 TI - Postmortem MRI: a novel window into the neurobiology of late life cognitive decline. AB - This study tested the hypothesis that indices of brain tissue integrity derived from postmortem magnetic resonance imaging (MRI) are associated with late life decline in cognitive function and dementia, over and above contributions from common age-related neuropathologies. Cerebral hemispheres were obtained from 425 deceased older adults who had undergone 2 or more annual cognitive assessments, which included clinical diagnosis of dementia. Specimens underwent MRI to produce maps of transverse relaxation rate, R2. Voxelwise regression revealed brain regions where R2 was associated with cognitive decline. We then used random effects models to quantify the extent to which R2 accounted for variation in decline, after adjustment for demographics and neuropathologic indices of the 3 most common causes of dementia: Alzheimer's disease, cerebrovascular disease, and Lewy body disease. We additionally tested whether R2 was tied to greater likelihood of clinical diagnosis of Alzheimer's dementia using logistic regression models. During an average of 8.1 years, the mean rate of decline in global cognitive function was 0.13 unit per year (p < 0.0001). The tissue alteration most commonly related to decline was R2 slowing in white matter. Each unit decrease in R2 was associated with an additional 0.053-unit per year steepening of the rate of global cognitive decline (p < 0.001). Furthermore, R2 accounted for 8.4% of the variance in rate of global cognitive decline, above and beyond the 26.5% accounted for by demographics and neuropathologic indices, and 7.1%-11.2% of the variance of the decline rates in episodic, semantic, and working memory and perceptual speed. Alterations in R2 were also related to an increased odds of clinical diagnosis of Alzheimer's dementia (odds ratio = 2.000, 95% confidence interval 1.600, 2.604). Therefore, postmortem MRI indices of brain tissue integrity, particularly in white matter, are useful for elucidating the basis of late life cognitive impairment in older adults and complement traditional indices of neuropathology derived using histopathologic methods. PMID- 27459939 TI - Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging. AB - The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimer's Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD. PMID- 27459938 TI - Emotional bias of sleep-dependent processing shifts from negative to positive with aging. AB - Age-related memory decline has been proposed to result partially from impairments in memory consolidation over sleep. However, such decline may reflect a shift toward selective processing of positive information with age rather than impaired sleep-related mechanisms. In the present study, young and older adults viewed negative and neutral pictures or positive and neutral pictures and underwent a recognition test after sleep or wake. Subjective emotional reactivity and affect were also measured. Compared with waking, sleep preserved valence ratings and memory for positive but not negative pictures in older adults and negative but not positive pictures in young adults. In older adults, memory for positive pictures was associated with slow wave sleep. Furthermore, slow wave sleep predicted positive affect in older adults but was inversely related to positive affect in young adults. These relationships were strongest for older adults with high memory for positive pictures and young adults with high memory for negative pictures. Collectively, these results indicate preserved but selective sleep dependent memory processing with healthy aging that may be biased to enhance emotional well-being. PMID- 27459940 TI - Resting-state fMRI evidence for early episodic memory consolidation: effects of age. AB - Aging-related episodic memory decline is often attributed to insufficient encoding of new information, although the underlying neural processes remain elusive. We here tested the hypothesis that impaired memory consolidation contributes to aging-related memory decline. To this end, we used resting state functional magnetic resonance imaging in healthy young and older adults and investigated neural network connectivity underlying episodic memory consolidation and the effects of aging thereon. During postencoding rest, connectivity increased in subregions of temporobasal and temporo-occipital networks but decreased in a precuneal network. These connectivity changes predicted subsequent memory performance thereby constituting functional correlates of early memory consolidation. Furthermore, these consolidation-related regional connectivity changes partially overlapped with encoding-related neural activity changes, suggesting a close relationship between encoding- and consolidation-related activity. Older when compared to young participants failed to increase connectivity in the right lingual gyrus as part of an extended default mode network during consolidation, thereby providing a functional correlate for spatial contextual memory deficits. In conclusion, results are consistent with previous reports of persistent activity in regions mediating memory encoding as a core mechanism underlying episodic memory consolidation. Our data extend previous findings suggesting that aging-related memory decline results from a reduction of consolidation processes. PMID- 27459941 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 27459942 TI - P-type transparent conducting oxides. AB - Transparent conducting oxides constitute a unique class of materials combining properties of electrical conductivity and optical transparency in a single material. They are needed for a wide range of applications including solar cells, flat panel displays, touch screens, light emitting diodes and transparent electronics. Most of the commercially available TCOs are n-type, such as Sn doped In2O3, Al doped ZnO, and F doped SnO2. However, the development of efficient p type TCOs remains an outstanding challenge. This challenge is thought to be due to the localized nature of the O 2p derived valence band which leads to difficulty in introducing shallow acceptors and large hole effective masses. In 1997 Hosono and co-workers (1997 Nature 389 939) proposed the concept of 'chemical modulation of the valence band' to mitigate this problem using hybridization of O 2p orbitals with close-shell Cu 3d (10) orbitals. This work has sparked tremendous interest in designing p-TCO materials together with deep understanding the underlying materials physics. In this article, we will provide a comprehensive review on traditional and recently emergent p-TCOs, including Cu(+)-based delafossites, layered oxychalcogenides, nd (6) spinel oxides, Cr(3+) based oxides (3d (3)) and post-transition metal oxides with lone pair state (ns (2)). We will focus our discussions on the basic materials physics of these materials in terms of electronic structures, doping and defect properties for p type conductivity and optical properties. Device applications based on p-TCOs for transparent p-n junctions will also be briefly discussed. PMID- 27459943 TI - Erratum. PMID- 27459944 TI - Anticoagulation in Elderly Patients With Chronic Kidney Disease: How Safe Is It? PMID- 27459947 TI - Working in partnership: the application of shared decision-making to health visitor practice. AB - AIMS AND OBJECTIVES: To explore the processes that support shared decision-making when health visitors and parents are creating plans to improve the well-being of babies and children. BACKGROUND: Worldwide, there is a focus on promoting children's well-being to enhance the population health. Within the United Kingdom, health visitors have a key responsibility for working in partnership with parents to support this agenda. Despite evidence that the application of 'shared decision-making' frameworks can increase patient participation, improve patient satisfaction and improve health outcomes, there is limited research linking shared decision-making with health visitor practice. DESIGN: A qualitative, descriptive study. METHODS: The study was undertaken in two phases: in Phase 1, data were collected by audio recording two health visitor-parent decision-making conversations, in the absence of the researcher, where decisions around planning for a baby or child were being made as part of usual care, and then the participants' experiences were sought through individual questionnaires. In Phase 2, semistructured interviews were conducted with nine health visitors and nine parents in relation to their recent experiences of planning care. RESULTS: Evidence of supportive processes included having a shared understanding around the issue needing to be addressed; being able to identify interventions that were accessible for the family; engaging in decision-making through deep, meaningful conversations using sensitive and responsive approaches; and establishing positive relationships between health visitors and parents, significant others within the family and other professionals. CONCLUSION: Despite evidence of strong, trusting relationships between parents and health visitors, there were times when shared decision-making was unable to take place due to the absence of supportive processes. RELEVANCE TO CLINICAL PRACTICE: Health visitors are aware that planning interventions with parents can be complex. These findings indicate the value of using a shared decision-making framework to structure planning, as application of a framework identified the processes that support a collaborative approach in practice. PMID- 27459945 TI - The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases. AB - Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor alpha, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1 phosphate receptor (S1PR)2. The ligand of S1PR2, sphingosine-1-phosphate (S1P), is a bioactive lipid mediator that regulates various physiological and pathophysiological cellular processes. We have recently reported that conjugated bile acids, via S1PR2, activate and upregulate nuclear sphingosine kinase 2, increase nuclear S1P, and induce genes encoding enzymes and transporters involved in lipid and sterol metabolism in the liver. Here, we discuss the role of bile acids and S1P signaling in the regulation of hepatic lipid metabolism and in hepatobiliary diseases. PMID- 27459948 TI - Signatures of a globally optimal searching strategy in the three-dimensional foraging flights of bumblebees. AB - Simulated annealing is a powerful stochastic search algorithm for locating a global maximum that is hidden among many poorer local maxima in a search space. It is frequently implemented in computers working on complex optimization problems but until now has not been directly observed in nature as a searching strategy adopted by foraging animals. We analysed high-speed video recordings of the three-dimensional searching flights of bumblebees (Bombus terrestris) made in the presence of large or small artificial flowers within a 0.5 m(3) enclosed arena. Analyses of the three-dimensional flight patterns in both conditions reveal signatures of simulated annealing searches. After leaving a flower, bees tend to scan back-and forth past that flower before making prospecting flights (loops), whose length increases over time. The search pattern becomes gradually more expansive and culminates when another rewarding flower is found. Bees then scan back and forth in the vicinity of the newly discovered flower and the process repeats. This looping search pattern, in which flight step lengths are typically power-law distributed, provides a relatively simple yet highly efficient strategy for pollinators such as bees to find best quality resources in complex environments made of multiple ephemeral feeding sites with nutritionally variable rewards. PMID- 27459949 TI - Early- and late-onset psoriasis: a cross-sectional clinical and immunocytochemical investigation. AB - BACKGROUND: There is accumulating evidence that early-onset psoriasis (EOP; presenting at or before 40 years of age) and late-onset psoriasis (LOP; presenting after 40 years of age) are different diseases. OBJECTIVES: We aimed to identify potential clinical and immunocytochemical differences between EOP and LOP. METHODS: We assessed immunocytochemistry in involved (PP) skin and uninvolved skin (n = 31) and demographics, psoriasis phenotype and psychological parameters (n = 340) in a cross-sectional study. RESULTS: Immunocytochemistry revealed (17 EOP, 14 LOP) a greater lymphocytic infiltrate in PP skin of EOP compared with LOP (P = 0.03), with a higher epidermal CD4+ : CD8+ ratio in LOP (1.3) compared with EOP (0.5) (P = 0.002). In 340 patients with psoriasis (278 EOP, 62 LOP), we found an association with a positive first or second degree family history of psoriasis [62.0% vs. 35.6%, adjusted odds ratio (OR) 8.32, 95% confidence interval (CI) 1.90-36.52] and a higher likelihood of having parents with EOP (adjusted OR 10.34, 95% CI 1.32-81.83) in the EOP group. Patients with EOP were more likely to have received biological therapy (13.3% EOP vs. 3.5% LOP, P = 0.042), while patients with LOP had a higher likelihood of having type 2 diabetes (adjusted OR 3.43, 95% CI 1.004-11.691) and autoimmune thyroiditis (adjusted OR 5.05, 95% CI 1.62-15.7). Patients with LOP also had greater anxiety than patients with EOP (mean Hospital Anxiety and Depression Scale-A score LOP 8 +/- 5, EOP 5 +/- 5; P = 0.006). CONCLUSIONS: Our findings provide further evidence for the difference between EOP and LOP. PMID- 27459950 TI - A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions. AB - STIM1 and Orai1 are the main components of a widely conserved Calcium influx pathway known as store-operated calcium entry (SOCE). STIM1 is a calcium sensor, which oligomerizes and activates Orai channels when calcium levels drop inside the endoplasmic reticulum (ER). The series of molecular rearrangements that STIM1 undergoes until final activation of Orai1 require the direct exposure of the STIM1 domain known as SOAR (Stim Orai Activating Region). In addition to these complex molecular rearrangements, other constituents like lipids at the plasma membrane, play critical roles orchestrating SOCE. PI(4,5)P2 and enriched cholesterol microdomains have been shown as important signaling platforms that recruit the SOCE machinery in steps previous to Orai1 activation. However, little is known about the molecular role of cholesterol once SOCE is activated. In this study we provide clear evidence that STIM1 has a cholesterol-binding domain located inside the SOAR region and modulates Orai1 channels. We demonstrate a functional association of STIM1 and SOAR to cholesterol, indicating a close proximity of SOAR to the inner layer of the plasma membrane. In contrast, the depletion of cholesterol induces the SOAR detachment from the plasma membrane and enhances its association to Orai1. These results are recapitulated with full length STIM1. PMID- 27459951 TI - Attitudes and attributes of pharmacists in relation to practice change - A scoping review and discussion. AB - BACKGROUND: Multiple barriers and facilitators to the uptake of cognitive services in pharmacy practice have been identified. Pharmacists' attitudes and attributes have been described as barriers and facilitators in relation to the uptake of extended pharmacy services, in addition to those of a more systemic nature. OBJECTIVES: To systematically scope and review the literature describing pharmacists' attitudes and attributes in relation to the implementation of cognitive services or role extension and to critically analyze and discuss their relevance as barriers or facilitators. METHOD: A scoping review of the literature on attitudes and attributes of pharmacists in relation to pharmacy practice was performed, including 47 articles on attitudes and 12 on attributes, forming the basis for a critical analysis within theoretical frameworks. RESULTS: Pharmacists' attitudes toward role extensions and new pharmacy service models are generally positive and their personal attributes and personality traits appear favorable for roles as health professionals. Pharmacists perceived a number of barriers to the uptake of extended roles. CONCLUSION: Pharmacists' attributes, including personality traits, and attitudes favor the implementation of cognitive and patient-focused health care services and should not be regarded as major barriers to the uptake of extended pharmacy practice roles. Framing their attitudes and attributes within the theories of planned behavior and personality trait theories indicates that individual motivation needs to be underscored by systemic support for pharmacy practice change to succeed on a wide scale. PMID- 27459952 TI - Role of the PKCalpha-c-Src tyrosine kinase pathway in the mediation of p120 catenin degradation in ventilator-induced lung injury. AB - BACKGROUND AND OBJECTIVE: Ventilator-induced lung injury (VILI) is commonly associated with respiratory barrier dysfunction; however, the mechanisms have not been fully elucidated. This study aimed to determine the order and components of the signalling pathway that mediates the degradation of adherin junction of p120 catenin in VILI. METHODS: For the in vivo study, C57BL/6 mice were pre-treated with inhibitors for 60 min prior to 4 h of mechanical ventilation. For the in vitro study, mouse lung epithelial 12 (MLE-12) cells were pre-treated with inhibitors for 60 min or small interfering RNA (siRNA) for 48 h prior to cyclic stretch at 20% for 4 h. The protein levels of protein kinase Calpha (PKCalpha), activated c-Src and p120-catenin were determined via western blot analysis. Lung injury was determined via HE staining, immunofluorescence, wet/dry ratio and lung injury scores. RESULTS: High tidal volume mechanical ventilation and 20% cyclic stretch resulted in the degradation of p120-catenin. Inhibitors of PKCalpha blocked c-Src kinase activation and p120-catenin degradation in VILI. Inhibitors of c-Src kinase or PP2 or siRNA blocked p120-catenin degradation but not PKCalpha activation. CONCLUSION: The current findings demonstrates that PKCalpha and c-Src kinase participate in VILI. PKCalpha activation phosphorylates c-Src kinase and further decreases p120-catenin in VILI. PMID- 27459953 TI - Use of intravenous immunoglobulin in neonates at a tertiary academic hospital: a retrospective 11-year study. AB - BACKGROUND: Intravenous immunoglobulin (IVIG) is used to treat a variety of diseases in the neonatal intensive care unit (NICU). Although audits have reported on the spectrum of IVIG use in adults, the indications and utilization in neonates has not been investigated. The objectives of this study were to describe the usage pattern of and indications for IVIG in a tertiary care NICU. STUDY DESIGN AND METHODS: A retrospective chart review was performed of all neonates who received IVIG in the NICU from January 2003 to December 2013. Data collected included patient demographic features, antenatal maternal details, neonatal laboratory results, treatment details, adverse events, and patient outcome. RESULTS: Thirty-seven neonates received IVIG over the 11-year period. Twenty-three (67%) were treated for hemolytic disease of the newborn (HDN); 13 treatments were ABO related, six were anti-D related, and four were for clinically significant antibodies. Fourteen (33%) were treated for non-HDN causes, including eight for septic neonates, two for neonates with necrotizing enterocolitis, two for neonates with a clinically significant antibody but without evidence of hemolysis, and two for neonates with glucose 6-phosphate dehydrogenase deficiency. A complete hemolytic workup was not performed consistently before the receipt of IVIG. CONCLUSIONS: This novel assessment of IVIG use in the NICU revealed the spectrum of disease for which IVIG is ordered. This study also found that key diagnostic tests needed to confirm an immune etiology for idiopathic jaundice are not performed routinely before IVIG receipt. Neonatal transfusion-related databases are needed to carry out pragmatic clinical trials to establish better evidence-based guidelines for IVIG therapy in the NICU. PMID- 27459954 TI - Opioids in Remote Ischemic Preconditioning-Induced Cardioprotection. AB - Remote ischemic preconditioning (RIPC) is an intriguing process whereby transient regional ischemia and reperfusion episodes to remote tissues including skeletal, renal, mesenteric provide protection to the heart against sustained ischemia reperfusion-induced injury. Clinically, this technique has been used in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention, and heart valve surgery. The endogenous opioid system is extensively expressed in the brain to modulate pain sensation. Besides the role of opioids in relieving pain, numerous researchers have found their critical involvement in evoking cardioprotective effects. Endogenous opioids including endorphins, enkephalins, and dynorphins are released during RIPC and are critically involved in mediating RIPC-induced cardioprotective effects. It has been suggested that during RIPC, the endogenous opioids may be released into the systemic circulation and may travel via bloodstream that act on the myocardial opioid receptors to induce cardioprotection. The present review describes the potential role of opioids in mediating RIPC-induced cardioprotection. PMID- 27459955 TI - Gabapentin for Perioperative Analgesia in Otorhinolaryngology-Head and Neck Surgery: Systematic Review. AB - OBJECTIVE: Recent research has investigated the role of gabapentin in perioperative pain relief in otorhinolaryngology-head and neck surgery. This review aims to identify whether sufficient evidence exists for the routine use of gabapentin in the perioperative setting. DATA SOURCES: MEDLINE, Cochrane CENTRAL, EMBASE, and Google Scholar. REVIEW METHODS: A comprehensive systematic search was performed with keywords for articles up to November 2015. The systematic review included all randomized, placebo-, and active-controlled trials investigating the role of perioperative gabapentin for pain in otorhinolaryngology-head and neck surgery. The studies were assessed for risk of bias and selected and reviewed by the main author. Selected trials were required to have data in the form of pain intensity scores, analgesic consumption, adverse effects, or return to normal function. RESULTS: A total of 14 randomized controlled trials were included, of which 4 had an active control. The placebo-controlled trials included 4 for tonsillectomy, 3 for rhinology, and 3 for thyroidectomy. These studies were not suitable for meta-analysis. Trial quality involving gabapentin in tonsillectomy surgery is variable. The higher-quality studies reported significantly reduced analgesic consumption in the gabapentin groups, with the effect on pain scores less clear. There was a significant benefit, within the first 24 hours, in pain and analgesic consumption as compared with placebo favoring the gabapentin groups following rhinologic and thyroid surgery. CONCLUSION: Overall, gabapentin appears to have a significant beneficial effect on perioperative pain relief and analgesic consumption in otorhinolaryngology-head and neck surgery procedures within the first 24 hours. PMID- 27459956 TI - Tumor Debulking in the Management of Laryngeal Cancer Airway Obstruction. AB - Patients presenting with advanced aerodigestive malignancy and respiratory compromise often undergo tracheotomy as initial airway management. Tumor debulking is a potential alternative. We present a case series with chart review to communicate our institutional experience with this technique. T3/4 glottic and supraglottic cancers treated between 2004 and 2014 underwent review, and 14 patients were identified for this study. Of these, 5 (35.7%) required subsequent tracheotomy, and 9 (64.3%) did not. Patients requiring subsequent tracheotomy had a delay in initiating definitive treatment when compared with those who did not (83.3 vs 31.3 days, P = .0025). No patient required a tracheotomy after initiation of definitive treatment. Our experience suggests that tumor debulking may be a viable option in select patients but that a delay in initiating treatment is associated with patients requiring tracheotomy subsequent to debulking. Further research is needed to better delineate patient scenarios in which tumor debulking alone is sufficient. PMID- 27459958 TI - Quality control in public participation assessments of water quality: the OPAL Water Survey. AB - BACKGROUND: Public participation in scientific data collection is a rapidly expanding field. In water quality surveys, the involvement of the public, usually as trained volunteers, generally includes the identification of aquatic invertebrates to a broad taxonomic level. However, quality assurance is often not addressed and remains a key concern for the acceptance of publicly-generated water quality data. The Open Air Laboratories (OPAL) Water Survey, launched in May 2010, aimed to encourage interest and participation in water science by developing a 'low-barrier-to-entry' water quality survey. During 2010, over 3000 participant-selected lakes and ponds were surveyed making this the largest public participation lake and pond survey undertaken to date in the UK. But the OPAL approach of using untrained volunteers and largely anonymous data submission exacerbates quality control concerns. A number of approaches were used in order to address data quality issues including: sensitivity analysis to determine differences due to operator, sampling effort and duration; direct comparisons of identification between participants and experienced scientists; the use of a self assessment identification quiz; the use of multiple participant surveys to assess data variability at single sites over short periods of time; comparison of survey techniques with other measurement variables and with other metrics generally considered more accurate. These quality control approaches were then used to screen the OPAL Water Survey data to generate a more robust dataset. RESULTS: The OPAL Water Survey results provide a regional and national assessment of water quality as well as a first national picture of water clarity (as suspended solids concentrations). Less than 10 % of lakes and ponds surveyed were 'poor' quality while 26.8 % were in the highest water quality band. CONCLUSIONS: It is likely that there will always be a question mark over untrained volunteer generated data simply because quality assurance is uncertain, regardless of any post hoc data analyses. Quality control at all stages, from survey design, identification tests, data submission and interpretation can all increase confidence such that useful data can be generated by public participants. PMID- 27378226 TI - The Membrane-Bound Form of IL-17A Promotes the Growth and Tumorigenicity of Colon Cancer Cells. AB - Interleukin-17A is a member of the IL-17 family, and is known as CTLA8 in the mouse. It is produced by T lymphocytes and NK cells and has proinflammatory roles, inducing cytokine and chemokine production. However, its role in tumor biology remains controversial. We investigated the effects of locally produced IL 17A by transferring the gene encoding it into CT26 colon cancer cells, either in a secretory or a membrane-bound form. Expression of the membrane-bound form on CT26 cells dramatically enhanced their proliferation in vitro. The enhanced growth was shown to be due to an increased rate of cell cycle progression: after synchronizing cells by adding and withdrawing colcemid, the rate of cell cycle progression in the cells expressing the membrane-bound form of IL-17A was much faster than that of the control cells. Both secretory and membrane-bound IL-17A induced the expression of Sca-1 in the cancer cells. When tumor clones were grafted into syngeneic BALB/c mice, the tumor clones expressing the membrane bound form IL-17A grew rapidly; those expressing the secretory form also grew faster than the wild type CT26 cells, but slower than the clones expressing the membrane-bound form. These results indicate that IL-17A promotes tumorigenicity by enhancing cell cycle progression. This finding should be considered in treating tumors and immune-related diseases. PMID- 27459959 TI - Placental transfer and mammary excretion of a novel angiotensin receptor blocker fimasartan in rats. AB - BACKGROUND: Fimasartan (FMS) is a potent angiotensin receptor blocker for the treatment of mild to moderate hypertension. This study aimed to evaluate the transfer of FMS to fetus and breast milk in rats. METHODS: In order to study the transfer to the fetus and nursing pup, pregnant and nursing maternal rats were administered with FMS by a constant intravenous infusion to reach target plasma concentrations of 200 ng/mL and 100 ng/mL. The concentrations of FMS in plasma, placenta, amniotic fluid, fetus, and milk were determined by a validated LC-MS/MS assay. RESULTS: Upon constant intravenous infusion, the plasma FMS concentration reached the target steady state concentrations (Css = 200 ng/mL and 100 ng/mL) in 24 h. The tissue-to-plasma partition coefficients (Kp) for placenta, amniotic fluid, and milk were obtained based on the observed FMS concentrations in the tissues and Css. The Kp values for all tissues were not different between high (Css = 200 ng/mL) and low (Css = 100 ng/mL) dose groups. While the mean Kp of the placenta was 44.6-59.0 %, the mean Kp was 1.3-1.7 % for the amniotic fluid and 14.9-17.0 % for fetus. The mean Kp of milk was 10.4-15.2 %. CONCLUSIONS: Placental transfer and milk excretion of FMS was relatively lower compared to other angiotensin receptor blockers. PMID- 27459961 TI - Equity in the use of public services for mother and newborn child health care in Pakistan: a utilization incidence analysis. AB - BACKGROUND: Poor maternal and infant health indicators are mostly concentrated among low income households in Pakistan and health care expenditures - especially on medical emergencies - are the most common income shocks experienced by the poor. Public investments in health are therefore considered as pro-poor interventions by the government of Pakistan. This study employs nationally representative household data for Pakistan for 2007-08 and 2010-11 to investigate whether benefits from publicly financed services on Mother and Newborn Child Health (MNCH) are effectively captured by the poor in terms of service utilization. METHODS: The study conducts a Utilization Incidence Analysis of the use of public health services for MNCH in Pakistan. For this purpose, the utilization shares of households, ranked by economic status, are computed. The concentration curves are plotted and their dominance is tested against an equal distribution and Lorenz curves to determine whether the distribution is pro-poor and progressive. RESULTS: Although the shares of bottom income groups in the utilization of most services for MNCH have increased between 2007 and 2011, the utilization of some services such as post-natal consultation; institutional maternal delivery; and Tetanus Toxoid injections for pregnant women remains pro rich in 2011. The utilization of pre-natal consultation, especially through lady health workers and visitors; the use of Family Panning Units; and immunization services is somewhat evenly distributed. The use of Basic Health Units (BHUs) is found to be pro-poor. The provincial analysis reveals that the province of Baluchistan depicts an unusually high level of inequity in the distribution of utilization benefits from almost all public health services. Finally, in terms of progressivity, public spending on all health services analyzed in the study is found to be progressive at the national level implying that investment in MNCH has the potential to redistribute income from rich to the poor. CONCLUSION: To target the poor effectively, the study recommends expanding the network of BHUs as well as basic reproductive and child health care services. The outreach of health facilities in Baluchistan need to be expanded while targeting the poor effectively by mitigating various access costs that prevent them from using public health services. PMID- 27459962 TI - Detecting epileptic seizures with electroencephalogram via a context-learning model. AB - BACKGROUND: Epileptic seizure is a serious health problem in the world and there is a huge population suffering from it every year. If an algorithm could automatically detect seizures and deliver the patient therapy or notify the hospital, that would be of great assistance. Analyzing the scalp electroencephalogram (EEG) is the most common way to detect the onset of a seizure. In this paper, we proposed the context-learning based EEG analysis for seizure detection (Context-EEG) algorithm. METHODS: The proposed method aims at extracting both the hidden inherent features within EEG fragments and the temporal features from EEG contexts. First, we segment the EEG signals into EEG fragments of fixed length. Second, we learn the hidden inherent features from each fragment with a sparse auto-encoder and thus the dimensionality of the original data is reduced. Third, we translate each EEG fragment to an EEG word so that a continuous EEG signal is converted to a sequence of EEG words. Fourth, by analyzing the context information of EEG words, we learn the temporal features for EEG signals. And finally, we concatenate the hidden features and the temporal features together to train a binary classifier which can be used to detect the onset of an epileptic sezure. RESULTS: 4302 EEG fragments from four different patients are used to train and test our model. An error rate of 22.93 % is achieved by our model as a general, non-patient specific seizure detector. The error rate of our model is averagely 16.7 % lower than the other baseline models. Receiver operating characteristics (ROC curve) and area under curve (AUC) confirm the effectiveness of our model. Furthermore, we discuss the extracted features and how to reconstruct the original data based on the extracted features, as well as the parameter sensitivity. CONCLUSIONS: Given a EEG fragment, by extracting high-quality features (the hidden inherent features and temporal features) from the EEG signals, our Context-EEG model is able to detect the onset of a seizure with high accuracy in real time. PMID- 27459964 TI - Goodpasture's syndrome with absence of circulating anti-glomerular basement membrane antibodies: a case report. AB - BACKGROUND: Goodpasture's syndrome, a rare disease, is an organ-specific autoimmune disease mediated by anti-glomerular basement membrane antibodies. Its pathology is characterized by crescentic glomerulonephritis with linear immunofluorescent staining for immunoglobulin G on the glomerular basement membrane. Although rare, a few cases with absence of circulating anti-glomerular membrane antibodies have been described. CASE PRESENTATION: The objective of this clinical case report is to describe and discuss a case of a 27-year-old white man who was hospitalized with a 1-year history of weight loss and a 1-month history of hemoptysis, with aggravation the day before, having developed dyspnea and cough in the previous 24 hours. An analytical study showed normocytic normochromic anemia with a hemoglobin level of 7.2 g/dL and leukocytosis with normal renal function and coagulation times. A blood transfusion was performed without complications. Chest computed tomography revealed a reticulonodular infiltrate of both lungs. Bronchoscopy showed no apparent lesions. Sputum cultures, rapid urine antigens for Legionella pneumophila and Streptococcus pneumoniae, studies for Influenza, virologic markers and serologic studies for autoimmunity were all negative. At the end of the tenth day his general state deteriorated with fatigue, hematuria, and in 3 days he developed aggravation of renal function with recurrent hemoptysis and anemia. Immunosuppression with daily prednisolone 1 g administered intravenously was initiated. An urgent bronchoscopy showed no lesions. A kidney biopsy showed fibrinoid necrosis and cellular crescents. Immunofluorescence revealed a linear immunoglobulin G deposition compatible with Goodpasture's syndrome. Immunosuppressive therapy with daily cyclophosphamide 120 mg orally was added. Subsequently he was transferred to a referral center at which 21 sessions of plasmapheresis and four sessions of hemodialysis were performed with good response; he currently has no need of hemodialysis. CONCLUSIONS: The absence of circulating anti-glomerular basement membrane antibodies in Goodpasture's syndrome adds complexity to the diagnosis creating an unusual setting in a rare disease. In our case a kidney biopsy was essential for diagnosis and clinical approach. Studies have shown that early aggressive therapy leads to an improved prognosis. Physicians should consider tissue diagnoses such as bronchoscopy and kidney biopsy in pulmonary renal syndrome. PMID- 27459960 TI - HIV integration and the establishment of latency in CCL19-treated resting CD4(+) T cells require activation of NF-kappaB. AB - BACKGROUND: Eradication of HIV cannot be achieved with combination antiretroviral therapy (cART) because of the persistence of long-lived latently infected resting memory CD4(+) T cells. We previously reported that HIV latency could be established in resting CD4(+) T cells in the presence of the chemokine CCL19. To define how CCL19 facilitated the establishment of latent HIV infection, the role of chemokine receptor signalling was explored. RESULTS: In resting CD4(+) T cells, CCL19 induced phosphorylation of RAC-alpha serine/threonine-protein kinase (Akt), nuclear factor kappa B (NF-kappaB), extracellular-signal-regulated kinase (ERK) and p38. Inhibition of the phosphoinositol-3-kinase (PI3K) and Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/ERK signalling pathways inhibited HIV integration, without significant reduction in HIV nuclear entry (measured by Alu-LTR and 2-LTR circle qPCR respectively). Inhibiting activation of MEK1/ERK1/2, c-Jun N-terminal kinase (JNK), activating protein-1 (AP-1) and NF kappaB, but not p38, also inhibited HIV integration. We also show that HIV integrases interact with Pin1 in CCL19-treated CD4(+) T cells and inhibition of JNK markedly reduced this interaction, suggesting that CCL19 treatment provided sufficient signals to protect HIV integrase from degradation via the proteasome pathway. Infection of CCL19-treated resting CD4(+) T cells with mutant strains of HIV, lacking NF-kappaB binding sites in the HIV long terminal repeat (LTR) compared to infection with wild type virus, led to a significant reduction in integration by up to 40-fold (range 1-115.4, p = 0.03). This was in contrast to only a modest reduction of 5-fold (range 1.7-11, p > 0.05) in fully activated CD4(+) T cells infected with the same mutants. Finally, we demonstrated significant differences in integration sites following HIV infection of unactivated, CCL19-treated, and fully activated CD4(+) T cells. CONCLUSIONS: HIV integration in CCL19-treated resting CD4(+) T cells depends on NF-kappaB signalling and increases the stability of HIV integrase, which allow subsequent integration and establishment of latency. These findings have implications for strategies needed to prevent the establishment, and potentially reverse, latent infection. PMID- 27459965 TI - Sarcoptic mange in the Scandinavian wolf Canis lupus population. AB - BACKGROUND: Sarcoptic mange, a parasitic disease caused by the mite Sarcoptes scabiei, is regularly reported on wolves Canis lupus in Scandinavia. We describe the distribution and transmission of this parasite within the small but recovering wolf population by analysing 269 necropsy reports and performing a serological survey on 198 serum samples collected from free-ranging wolves between 1998 and 2013. RESULTS: The serological survey among 145 individual captured Scandinavian wolves (53 recaptures) shows a consistent presence of antibodies against sarcoptic mange. Seropositivity among all captured wolves was 10.1 % (CI. 6.4 %-15.1 %). Sarcoptic mange-related mortality reported at necropsy was 5.6 % and due to secondary causes, predominantly starvation. In the southern range of the population, seroprevalence was higher, consistent with higher red fox densities. Female wolves had a lower probability of being seropositive than males, but for both sexes the probability increased with pack size. Recaptured individuals changing from seropositive to seronegative suggest recovery from sarcoptic mange. The lack of seropositive pups (8-10 months, N = 56) and the occurrence of seropositive and seronegative individuals in the same pack indicates interspecific transmission of S. scabiei into this wolf population. CONCLUSIONS: We consider sarcoptic mange to have little effect on the recovery of the Scandinavian wolf population. Heterogenic infection patterns on the pack level in combination with the importance of individual-based factors (sex, pack size) and the north-south gradient for seroprevalence suggests low probability of wolf-to-wolf transmission of S. scabiei in Scandinavia. PMID- 27459966 TI - The influence of postsynaptic structure on missing quanta at the Drosophila neuromuscular junction. AB - BACKGROUND: Synaptic transmission requires both pre- and post-synaptic elements for neural communication. The postsynaptic structure contributes to the ability of synaptic currents to induce voltage changes in postsynaptic cells. At the Drosophila neuromuscular junction (NMJ), the postsynaptic structure, known as the subsynaptic reticulum (SSR), consists of elaborate membrane folds that link the synaptic contacts to the muscle, but its role in synaptic physiology is poorly understood. RESULTS: In this study, we investigate the role of the SSR with simultaneous intra- and extra-cellular recordings that allow us to identify the origin of spontaneously occurring synaptic events. We compare data from Type 1b and 1s synaptic boutons, which have naturally occurring variations of the SSR, as well as from genetic mutants that up or down-regulate SSR complexity. We observed that some synaptic currents do not result in postsynaptic voltage changes, events we called 'missing quanta'. The frequency of missing quanta is positively correlated with SSR complexity in both natural and genetically-induced variants. Rise-time and amplitude data suggest that passive membrane properties contribute to the observed differences in synaptic effectiveness. CONCLUSION: We conclude that electrotonic decay within the postsynaptic structure contributes to the phenomenon of missing quanta. Further studies directed at understanding the role of the SSR in synaptic transmission and the potential for regulating 'missing quanta' will yield important information about synaptic transmission at the Drosophila NMJ. PMID- 27459967 TI - Opinions of maternity care professionals and other stakeholders about integration of maternity care: a qualitative study in the Netherlands. AB - BACKGROUND: This study aims to give insight into the opinions of maternity care professionals and other stakeholders on the integration of midwife-led care and obstetrician-led care and on the facilitating and inhibiting factors for integrating maternity care. METHODS: Qualitative study using interviews and focus groups from November 2012 to February 2013 in the Netherlands. Seventeen purposively selected stakeholder representatives participated in individual semi structured interviews and 21 in focus groups. One face-to-face focus group included a combined group of midwives, obstetricians and a paediatrician involved in maternity care. Two online focus groups included a group of primary care midwives and a group of clinical midwives respectively. Thematic analysis was performed using Atlas.ti. Two researchers independently coded the interview and focus group transcripts by means of a mind map and themes and relations between them were described. RESULTS: Three main themes were identified with regard to integrating maternity care: client-centred care, continuity of care and task shifting between professionals. Opinions differed regarding the optimal maternity care organisation model. Participants considered the current payment structure an inhibiting factor, whereas a new modified payment structure based on the actual amount of work performed was seen as a facilitating factor. Both midwives and obstetricians indicated that they were afraid to loose autonomy. CONCLUSIONS: An integrated maternity care system may improve client-centred care, provide continuity of care for women during labour and birth and include a shift of responsibilities between health care providers. However, differences of opinion among professionals and other stakeholders with regard to the optimal maternity care organisation model may complicate the implementation of integrated care. Important factors for a successful implementation of integrated maternity care are an appropriate payment structure and maintenance of the autonomy of professionals. PMID- 27459969 TI - Assessment of plasma B7-H3 levels in pediatric patients with different degrees of surgical stress. AB - BACKGROUND: Surgical stress initiates a series of host hormone, metabolism and immune responses, which predominantly affect the homeostatic mechanism of patients with major surgery. B7-H3 is a co-stimulatory molecule and has been shown to participate in both adaptive and innate immune responses. In this study we evaluated the clinical significance of plasma B7-H3 levels in pediatric patients with different types of operation and degrees of surgical stress. METHODS: A total of 48 children received pediatric general and cardiac surgery were recruited into this study. Based on the surgical stress scoring, children were divided into moderate stress (n = 14) and severe stress (n = 34) groups. Plasma B7-H3 levels were assessed at selected time points: before surgery, immediately after surgery, at day 1, day 3, and day 7 after surgery. Correlations between plasma B7-H3 levels and surgical stress scores were also examined. RESULTS: Plasma B7-H3 levels were significantly decreased in all 48 pediatric patients after surgery compared to the B7-H3 level before surgery (p < 0.01). Children with general surgery showed significant decreases in plasma B7-H3 immediately after surgery, and at day 3 and day 7 after surgery (p < 0.05, p < 0.01), whereas children with cardiac surgery showed reduced plasma B7-H3 immediately after surgery and at day 3 after surgery (p < 0.05). Plasma B7-H3 in cardiac surgery group was dropped much lower than that in general surgery group at day 1 (p < 0.05) and day 3 (p < 0.01) after surgery. Significantly reduced plasma B7-H3 was observed in the severe stress group, but not in the moderate stress group, immediately after surgery and at day 3 after surgery (p < 0.05), and severe stress group had significantly lower plasma B7-H3 levels than moderate stress group at day 1, day 3, and day 7 after surgery (p < 0.05). Furthermore, plasma B7-H3 levels at day 1 (p = 0.01) and day 3 (p = 0.025) after surgery correlated negatively with surgical stress scores. CONCLUSIONS: Plasma B7-H3 levels were decreased significantly in children subjected to pediatric general and cardiac surgery, which is closely associated with the severity of surgical stress. The negative correlation of plasma B7-H3 levels at day 1 and day 3 after surgery with surgical stress scoring implicates that the plasma B7-H3 level might be a useful biomarker for monitoring stress intensity during pediatric surgery. PMID- 27459968 TI - Identification of source and sink populations for the emergence and global spread of the East-Asia clone of community-associated MRSA. AB - BACKGROUND: Our understanding of the factors influencing the emergence, dissemination and global distribution of epidemic clones of bacteria is limited. ST59 is a major epidemic clone of community-associated MRSA in East Asia, responsible for extensive morbidity and mortality, but has a much lower prevalence in other parts of the world. The geographic origin of ST59 and its international routes of dissemination are unclear and disputed in the literature. RESULTS: To investigate the origin and spread of the ST59 clone, we obtained whole genome sequences of isolates from four continents, sampled over more than a decade, and carried out a time-scaled phylogeographic analysis. We discover that two distinct ST59 clades emerged concurrently, in East Asia and the USA, but underwent clonal expansion at different times. The East Asia clade was strongly enriched for gene determinants associated with antibiotic resistance, consistent with regional differences in antibiotic usage. Both clones spread independently to Australia and Europe, and we found evidence of the persistence of multi-drug resistance following export from East Asia. Direct transfer of strains between Taiwan and the USA was not observed in either direction, consistent with geographic niche exclusion. CONCLUSIONS: Our results resolve a longstanding controversy regarding the origin of the ST59 clone, revealing the major global source and sink populations and routes for the spread of multi-drug resistant clones. Additionally, our findings indicate that diversification of the accessory genome of epidemic clones partly reflects region-specific patterns of antibiotic usage, which may influence bacterial fitness after transmission to different geographic locations. PMID- 27459970 TI - Transcription factor c-jun regulates beta3Gn-T8 expression in gastric cancer cell line SGC-7901. AB - Aberrant glycosylation, a common feature of malignant alteration, is partly due to changes in the expression of glycosyltransferases, including beta1,3-N-acetyl glucosaminyltrans-ferase 8 (beta3Gn-T8), which synthesizes poly-N acetyllactosamine (poly-LacNAc) chains on beta1,6 branched N-glycans. Although the role of beta3Gn-T8 in tumors has been reported, the regulation of beta3Gn-T8 expression, however, is still poorly understood. In the present study, we used three online bioinformatic software tools to identify multiple c-jun binding sites in the promoter of the beta3Gn-T8 gene. Using luciferase reporter assay, chromatin immunoprecipitation (ChIP) analysis, RT-PCR and western blot analysis, we revealed that c-jun could bind to and activate the beta3Gn-T8 promoter, thus upregulating beta3Gn-T8 expression. This was also confirmed by changes in beta3Gn T8 activity as demonstrated by flow cytometry, immunofluorescence and lectin blot analysis using LEA lectin. Moreover, expression of glycoprotein HG-CD147, the substrate of beta3Gn-T8, was also regulated by c-jun. In addition, c-jun and beta3Gn-T8 were more highly expressed in the gastric cancer tissues when compared to these levels in the adjacent non-tumor gastric tissues, and beta3Gn-T8 expression was positively correlated with c-jun expression. These results suggest that c-jun plays a significant role in regulating the expression of beta3Gn-T8 in the SGC-7901 cell line and may be involved in the development of malignancy via the activity of beta3Gn-T8. PMID- 27459971 TI - Elevated STC-1 augments the invasiveness of triple-negative breast cancer cells through activation of the JNK/c-Jun signaling pathway. AB - Stanniocalcin-1 (STC-1), a secreted glycoprotein, is highly expressed in a variety of human malignancies. However, the role of STC-1 has not been fully elucidated in breast cancer cells. Here, we investigated whether STC-1 acts as a prognostic factor in triple-negative breast cancer (TNBC) patients, and we explored the cellular mechanism in breast cancer cells. The level of STC-1 expression was directly associated with the relapse-free and overall survival of basal-type breast cancer patients. Breast cancer patients with a high level of STC-1 had poor prognosis. In addition, our results showed that the level of STC-1 expression was markedly higher in TNBC than in non-TNBC cells. Invasiveness of the TNBC cells was also significantly increased in response to recombinant human STC-1 treatment. In contrast, the invaded cell numbers were completely decreased by STC-1 siRNA overexpression in the Hs578T and MDA-MB-231 TNBC cells. Our results showed that the phosphorylation of c-Jun N-terminal protein kinase (JNK) and c-Jun was increased after STC-1 treatment but not the phosphorylation of ERK and p38 MAPKs in the Hs578T and MDA-MB-231 TNBC cells. Furthermore, expression of one invasion-related gene MMP-9, was increased by STC-1 treatment. STC-1-induced MMP-9 expression was suppressed by SP600125 (a JNK inhibitor) in the Hs578T cells. STC-1-induced cell invasiveness was also inhibited by SP600125. Taken together, we demonstrated that aberrant STC-1 expression is associated with poor prognosis and stimulates the invasiveness of TNBC cells through the JNK/c-Jun dependent signaling pathway. PMID- 27459972 TI - The Mercedes-Benz sign. PMID- 27459973 TI - In vitro evaluation of osteoblast responses to carbon nanotube-coated titanium surfaces. AB - BACKGROUND: The effects of surface roughness and carboxyl functionalization of multi-walled carbon nanotubes (MWCNTs) mixed with collagen coated onto titanium (Ti) substrates on MC3T3-E1 osteoblasts were evaluated. METHODS: The proliferation, differentiation, and matrix mineralization were investigated using (1) smooth-surfaced Ti discs, (2) Ti discs coated with collagen and MWCNT (Ti MWCNT), and (3) Ti discs coated with collagen and MWCNT-COOH (Ti-MWCNT-COOH) for applications in orthodontic mini screw implants (MSIs). The coatings were uniform when analyzed using scanning electron microscopy (SEM), and surface roughness was evaluated by surface profilometry that demonstrated similar surface roughness (R a , mean +/- SD) in the MWCNT (0.83 +/- 0.02 MUm) and MWCNT-COOH (0.84 +/- 0.01 MUm) groups. MTT (3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide) assay was performed after days 1, 3, and 7 to assess proliferation. Alkaline phosphatase (ALP)-specific activity was assessed after day 7 to quantify differentiation. Alizarin red staining was measured after day 28 to quantify matrix mineralization. All data were analyzed with JMP Pro11 software (SAS, USA) with a statistical significance of p < 0.05. RESULTS: Surface profilometry demonstrated similar surface roughness (R a , mean +/- SD) in the MWCNT (0.83 +/- 0.02 MUm) and MWCNT-COOH (0.84 +/- 0.01 MUm) groups. On day 7, ALP assay showed that MWCNT-COOH (mean +/- SD 0.98 +/- 0.26 U/MUg of protein) enhanced cell differentiation when compared to the uncoated group (p = 0.05). Alizarin red staining after 28 days of cell culture revealed that MWCNT-COOH (mean +/- SD 1.5 +/- 0.2 OD405) increased (p = 0.03) matrix mineralization when compared to the uncoated group (0.9 +/- 0.09 OD405). CONCLUSIONS: This study showed that coatings containing MWCNT-COOH (increased hydrophilic surface chemistry) influence osteoblast proliferation, differentiation, and matrix mineralization and should be further studied for applications in orthodontic MSIs. PMID- 27459975 TI - [Redetection of tachycardia in severe ventricular undersensing]. AB - In a 50-year-old patient with arrhythmogenic right ventricular cardiomyopathy (ARVC) and implantable cardioverter defibrillator (ICD) two shock discharges occurred after several ineffective attempts with antitachycardia pacing. The analysis of the stored electrograms shows a peculiarity of shocks with low energy, a problem of ICD therapy in ARVC, and the impact of committed shocks as opposed to non-committed shocks. PMID- 27459974 TI - The effects of fixed and removable orthodontic retainers: a systematic review. AB - OBJECTIVE: In the view of the widespread acceptance of indefinite retention, it is important to determine the effects of fixed and removable orthodontic retainers on periodontal health, survival and failure rates of retainers, cost effectiveness, and impact of orthodontic retainers on patient-reported outcomes. METHODS: A comprehensive literature search was undertaken based on a defined electronic and gray literature search strategy ( PROSPERO: CRD42015029169). The following databases were searched (up to October 2015); MEDLINE via OVID, PubMed, the Cochrane Central Register of Controlled Trials, LILACS, BBO, ClinicalTrials.gov, the National Research Register, and ProQuest Dissertation and Thesis database. Randomized and non-randomized controlled clinical trials, prospective cohort studies, and case series (minimum sample size of 20) with minimum follow-up periods of 6 months reporting periodontal health, survival and failure rates of retainers, cost-effectiveness, and impact of orthodontic retainers on patient-reported outcomes were identified. The Cochrane Collaboration's Risk of Bias tool and Newcastle-Ottawa Scale were used to assess the quality of included trials. RESULTS: Twenty-four studies were identified, 18 randomized controlled trials and 6 prospective cohort studies. Of these, only 16 were deemed to be of high quality. Meta-analysis was unfeasible due to considerable clinical heterogeneity and variations in outcome measures. The mean failure risk for mandibular stainless steel fixed retainers bonded from canine to canine was 0.29 (95 % confidence interval [CI] 0.26, 0.33) and for those bonded to canines only was 0.25 (95 % CI: 0.16, 0.33). A meta-regression suggested that failure of fixed stainless steel mandibular retainers was not directly related to the period elapsed since placement (P = 0.938). CONCLUSION: Further well-designed prospective studies are needed to elucidate the benefits and potential harms associated with orthodontic retainers. PMID- 27459976 TI - Atrioventricular 1:1 tachycardia effectively terminated by antitachycardia pacing : What is your diagnosis? AB - This case describes a tachycardia with a 1:1 atrioventricular relationship that was effectively terminated with antitachycardia pacing by the implantable cardioverter defibrillator. The differential diagnosis and clues that allow the reader to establish the correct diagnosis are discussed. The case also serves to analyse technical features of Boston Scientific dual-chamber defibrillators. PMID- 27459977 TI - Single STE-MR Acquisition in MR-Based Attenuation Correction of Brain PET Imaging Employing a Fully Automated and Reproducible Level-Set Segmentation Approach. AB - PURPOSE: The aim of this study is to introduce a fully automatic and reproducible short echo-time (STE) magnetic resonance imaging (MRI) segmentation approach for MR-based attenuation correction of positron emission tomography (PET) data in head region. PROCEDURES: Single STE-MR imaging was followed by generating attenuation correction maps (MU-maps) through exploiting an automated clustering based level-set segmentation approach to classify head images into three regions of cortical bone, air, and soft tissue. Quantitative assessment was performed by comparing the STE-derived region classes with the corresponding regions extracted from X-ray computed tomography (CT) images. RESULTS: The proposed segmentation method returned accuracy and specificity values of over 90 % for cortical bone, air, and soft tissue regions. The MR- and CT-derived MU-maps were compared by quantitative histogram analysis. CONCLUSIONS: The results suggest that the proposed automated segmentation approach can reliably discriminate bony structures from the proximal air and soft tissue in single STE-MR images, which is suitable for generating MR-based MU-maps for attenuation correction of PET data. PMID- 27459978 TI - Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy for Patients with Axillary Metastases: Can We Avoid the Unavoidable? PMID- 27459979 TI - Impact of the Introduction of Calcimimetics on Timing of Parathyroidectomy in Secondary and Tertiary Hyperparathyroidism. AB - BACKGROUND: Hyperparathyroidism (HPT), both secondary and tertiary, is common in patients with end-stage renal disease, and is associated with severe bone disorders, cardiovascular complications, and increased mortality. Since the introduction of calcimimetics in 2004, treatment of HPT has shifted from surgery to predominantly medical therapy. OBJECTIVE: The aim of this study was to evaluate the impact of this change of management on the HPT patient population before undergoing (sub-)total parathyroidectomy (PTx). METHODS: Overall, 119 patients with secondary or tertiary HPT undergoing PTx were included in a retrospective, single-center cohort. Group A, who underwent PTx before January 2005, was compared with group B, who underwent PTx after January 2005. Patient characteristics, time interval between HPT diagnosis and PTx, and postoperative complications were compared. RESULTS: Group A comprised 70 (58.8 %) patients and group B comprised 49 (41.2 %) patients. The median interval between HPT diagnosis and PTx was 27 (interquartile range [IQR] 12.5-48.0) and 49 (IQR 21.0-75.0) months for group A and B, respectively (p = 0.007). Baseline characteristics were similar among both groups. The median preoperative serum parathyroid hormone (PTH) level was 936 pg/mL (IQR 600-1273) for group A versus 1091 pg/mL (IQR 482 1373) for group B (p = 0.38). PTx resulted in a dramatic PTH reduction (less than twofold the upper limit: A, 80.0 %; B, 85.4 %), and postoperative complication rates were low in both groups (A: 7.8 %; B: 10.2 %) [p = 0.66]. CONCLUSIONS: The introduction of calcimimetics in 2004 is associated with a significant 2-year delay of surgery with continuously elevated preoperative PTH levels, while parathyroid surgery, even in a fragile population, is considered a safe and effective procedure. PMID- 27459980 TI - Robotic Lymphadenectomy During Pancreatoduodenectomy with First Superior Mesenteric Artery Dissection. AB - BACKGROUND: An expert consensus meeting had defined the standard lymphadenectomy during pancreatoduodenectomy for an adenocarcinoma of the head of the pancreas. There is a controversy regarding the possibility to perform this optimal lymphadenectomy by minimally invasive approach. PATIENTS: The patient was a 68 year-old man with the diagnosis of an adenocarcinoma of the head of the pancreas. The 3D reconstructions evidenced the existence of a right hepatic artery. TECHNIQUE: The patient was positioned in the French position with the assistant between the legs and the robot at the head. Five trocars were used; the camera was introduced through the umbilicus trocar. The operation began with a peritoneal and liver exploration, and with an inter-aortico-caval picking. Because lymph nodes were noninvaded, pancreatoduodenectomy was decided with the first dissection of the superior mesenteric artery helped with a hanging maneuver. The right hepatic artery was dissected. Each structure of the hepatic pedicle was skeletonized. The camera was switched to the right side. The first jejunal loop was divided with a stapler. The specimen was totally mobilized en bloc, freed from the portal vascular axis with a dissection of the right border of the coeliac trunk. The pancreas was divided. At the end of the dissection, the different arterial and venous structures were skeletonized with a resection of the lymph node group 5-6-8a-12a,b,c-13a,b-14a,b-17a,b. Pathology confirmed R0 resection for a well-differentiated pancreatic adenocarcinoma graded pT3N1 (5/20). CONCLUSIONS: Robotic pancreatoduodenectomy could be performed with an optimal standard lymphadenectomy as recommended by the expert consensus. PMID- 27459981 TI - Pediatric Oncology Provider Views on Performing a Biopsy of Solid Tumors in Children with Relapsed or Refractory Disease for the Purpose of Genomic Profiling. AB - BACKGROUND: Patients with relapsed and refractory solid tumors have a poor prognosis. Recent advances in genomic technology have made it feasible to screen tumors for actionable mutations, with the anticipation that this may provide benefit to patients. METHODS: Pediatric oncologists were emailed an anonymous 34 question survey assessing their willingness to offer a rebiopsy to patients with relapsed disease for the purpose of tumor genomic profiling. They were presented with two scenarios evaluating morbidity and invasiveness of the procedures using the clinical examples of medulloblastoma and Ewing sarcoma. RESULTS: A total of 195 pediatric oncologists responded to the questionnaire. Morbidity and invasiveness of the procedure demonstrated significant differences in provider willingness to refer their patients for rebiopsy. The pretest probability was a major variable influencing provider willingness to offer a rebiopsy. Respondents were more likely to offer a rebiopsy if the likelihood was high that the results would have an impact on clinical management than if the biopsy was for histologic confirmation alone (mean 89 vs. 56 %; p = 0.017). Compared with the rate of a rebiopsy for histologic confirmation, significantly fewer providers were willing to offer a rebiopsy if they were led to believe the likelihood of finding an actionable mutation was low (mean 45 vs. 56 %; p = 0.021). CONCLUSION: The scenario showed that the pretest probability of finding an actionable mutation was influential in determining provider willingness to offer a rebiopsy for the purpose of tumor genomic profiling. Further research is warranted to evaluate the benefit of tumor genomic profiling in terms of patient outcomes. PMID- 27459982 TI - Timing of Adjuvant Chemotherapy and Impact on Survival for Resected Gastric Cancer. AB - BACKGROUND: Because postoperative convalescence often prolongs the interval between surgery and chemotherapy in patients undergoing treatment for advanced gastric cancer, this study assesses the survival impact of timing of adjuvant chemotherapy (AC) in patients undergoing curative resection for gastric cancer. METHODS: The 2003-2012 ACS NCDB was analyzed for patients treated with gastrectomy for stages 1-3 gastric cancer. Treatment groups were stratified by time to initiation of AC: initiation of chemotherapy within 8 weeks postoperatively, between 8 and 12 weeks postoperatively, after 12 weeks postoperatively, and no chemotherapy. Univariate and multivariate analyses were performed. RESULTS: Of 7942 patients undergoing gastrectomy, 29 % received AC. Of those who received AC, 58 % initiated AC within 8 weeks, 28 % initiated AC between 8 and 12 weeks, and 14 % received AC after 12 weeks. Among patients who received AC, median survival was not significantly different between time cohorts, even when stratified by pathologic stage. Median survival was longer for chemotherapy cohorts when compared with the no chemotherapy cohort, specifically in patients with pathologic stages 2 and 3 disease. In multivariable analysis, patients who received AC had a 27-29 % lower hazard of death (p < .0001), with administration of AC at any time, compared with patients who did not receive AC, but had no difference in hazard when comparing delayed AC to earlier administration of AC. CONCLUSIONS: Time to initiation of AC does not impact survival. With improved survival over patients who did not receive AC, even delayed initiation of chemotherapy should be offered, when appropriate. PMID- 27459983 TI - What's the Best Way to Treat GE Junction Tumors? Approach Like Gastric Cancer. AB - The debate as to the optimal classification, staging, and treatment of gastroesophageal junction (GEJ) tumors wages on, and one must acknowledge that there is no "one-size-fits-all" approach. However, in this review we are charged with defending the position that all GEJ tumors are best treated like gastric cancer. We submit that, as stated, this is not a defensible position and that a clear definition of terms is warranted. Given the rarity of squamous cell carcinoma and the dramatic rise in incidence of adenocarcinoma of the GEJ in the West, we define GEJ "tumors" to mean adenocarcinomas of the GEJ. Furthermore, on the basis of their location, pathogenesis, and biologic behavior, we submit that few would argue with the contention that Siewert type I GEJ tumors are best treated like distal esophageal cancer and that Siewert type III GEJ tumors are best treated like gastric cancer. The real debate concerns the management of Siewert type II GEJ tumors, which arise immediately at the esophagogastric junction. Thus, for the purposes of this review, we have taken the liberty of redefining the question as what's the best way to treat adenocarcinomas of the true GEJ (i.e., Siewert type II tumors), and we submit that these tumors are in fact best treated like gastric cancer. This approach ensures that patients receive those therapies needed for the locoregional and systemic control of their disease together with a surgical procedure that optimizes complete tumor and regional lymph node resection while limiting morbidity. PMID- 27459984 TI - Laparoscopic-Assisted Rectal Surgery for Rectal Cancer Using the Simple Rectum Catcher Device with an Intraoperative Colonoscopy: Results of Our Hospital Study in 203 Patients. AB - BACKGROUND: The gold standard of rectal surgery is TME and DST anastomosis.1 - 6 The division of mesorectum in tumor-specific mesorectal and total mesorectal excisions is one of the most difficult procedures of anterior dissection. We have developed a laparoscopic-assisted anterior dissection technique using the simple Rectum Catcher device (RC) with an intraoperative colonoscopy (CF).7 , 8 METHODS: Surgical and oncological outcomes were compared between 99 patients undergoing a laparoscopic approach with the RC and a CF (RCF) and 104 patients undergoing the laparoscopic approach without the RC and without a CF (NRCF). Our standardized procedure for RCF is shown in the video. RESULTS: BMI (p = .025) and tumor diameter (p = .002) were significantly higher in the RCF group. However, operation times (p = .005) and time to tolerate diet (p = .009) were significantly shorter. Estimated blood loss was significantly decreased (p = .005) and quality of TME or TSME was significantly better (p = .017) in the RCF group. When we further analyzed surgical and oncological outcomes by dividing 3 parts of the rectum, patients with rectosigmoid (Rs) cancer and patients with cancer in the rectum below the peritoneal reflection (Rb) had comparable results. Particularly, statistically significant differences in length of operation time (p = .018), estimated blood loss (p = .050), quality of TME or TSME (p = .017), time to tolerate diet (p = .010), and R0 resections (p = .050) were observed in the patients with cancer below the peritoneal reflection. CONCLUSIONS: Laparoscopic lower rectal surgery using the RC with a CF is feasible and provides acceptable surgical and oncological outcomes. PMID- 27459985 TI - The Disproportionate Effect of Perioperative Complications on Mortality within 1 Year After Colorectal Cancer Resection in Octogenarians. AB - PURPOSE: Risks and benefits of colorectal cancer resection in octogenarians are not clearly defined. This study aimed to assess the relationship between morbidity and mortality within 1 year after colorectal cancer resection in octogenarians compared with other age groups. METHODS: A single-institution, prospectively maintained database was queried to identify patients with sporadic, pathological stages I-III colorectal adenocarcinoma, electively undergoing radical resection with curative intent between 2000 and 2012. Patients were divided into three age groups: 'octogenarians' if >=80 years of age; 'intermediate' if >=65 and <80 years of age; and 'younger' if <65 years of age. RESULTS: Overall, 2485 patients fulfilled the inclusion criteria-326 in the octogenarian age group, 949 in the intermediate age group, and 1210 in the younger age group. Postoperative morbidity disproportionally increased 1-year mortality in octogenarians when compared with the younger age group (37 vs. 6.5 %; p < 0.001). Anastomotic leak, abdominopelvic abscess, reoperation, and readmission rates were comparable among different age groups, but were associated with a disproportionate risk of 1-year mortality in octogenarians (67, 43, 33, and 41 %, respectively). Multivariate analysis indicated that older age and postoperative complications were the only two independent variables associated with 30- and 90-day mortality. Besides these, American Society of Anesthesiologists (ASA) and pathological stage III were additional independent variables associated with 1-year mortality. An interaction test confirmed that age and postoperative complications were independent variables, with additive effect on 30-day, 90-day, and 1-year mortality. CONCLUSIONS: Age plays an important and independent role in affecting mortality when complications occur following surgery for colorectal cancer. The full magnitude of postoperative risks should be taken into consideration when discussing colorectal cancer surgery in octogenarians. PMID- 27459986 TI - Deviations from Expected Treatment of Pancreatic Cancer in Octogenarians: Analysis of Patient and Surgeon Factors. AB - BACKGROUND: Morbidity and mortality of pancreatectomy has improved and chemotherapeutic options for pancreatic cancer (PC) are growing, yet there is reluctance to treat octogenarians. This study examined the reasons for failure to treat and analyzes outcomes in octogenarians with PC. METHODS: Retrospective chart review 2005-2013. Demographics, tumor characteristics, treatment, reason for lack of treatment, Charlson comorbidity index (CCI), and survival were analyzed. Expected treatment for early-stage patients (I/II) included surgery +/- chemotherapy +/- radiation. Expected treatment for advanced stage patients (III/IV) was chemotherapy. RESULTS: A total of 431 octogenarians were analyzed. Mean age was 84.0 +/- 3.4, 59.6 % female, and 44.1 % received no treatment. Patients with operable tumors (I = 31 [7.2 %]/II = 214 [49.7 %]) had surgery 39.2 % of the time. Age was a predictor of not receiving surgery (odds ratio [OR] 0.78; 95 % confidence interval [CI] 0.70-0.86; p = 0.0001), whereas CCI was not. The most common reason for no surgery was contraindication despite similar CCI. Median overall survival for early-stage patients was better in the surgical group (15.8 vs. 5.5 months) than nonsurgical group (p < 0.0001). Advanced patients (III = 54 [12.5 %]/IV = 132 [30.6 %]) had similarly low treatment rates (n = 65 [34.9 %]). Survival for advanced disease was best for treated patients (6.9 vs. 1.8 months; p < 0.0001). CCI did not differ between those receiving chemotherapy and not, although age was significantly different (p < 0.0001). CONCLUSIONS: There is significant deviation from expected treatment for octogenarians with PC. While no correlation existed between CCI and treatment, age correlated with therapy for nearly all stages. Chronological age, not comorbidity, may drive recommendation for treatment in elderly patients. PMID- 27459987 TI - Early Recurrence and Omission of Adjuvant Therapy after Pancreaticoduodenectomy Argue against a Surgery-First Approach. AB - BACKGROUND: Sequencing therapy for patients with periampullary malignancy is controversial. Clinical trial data report high rates of adjuvant therapy completion, though contemporary, real-world rates remain incomplete. We sought to identify patients who failed to receive adjuvant therapy and those at risk for early recurrence (ER) who might benefit most from neoadjuvant therapy (NT). METHODS: We retrospectively reviewed medical records of 201 patients who underwent pancreaticoduodenectomy for periampullary malignancies between 1999 and 2015; patients receiving NT were excluded. Univariate and multivariate analyses were performed to identify predictors of failure to receive adjuvant therapy and ER (within 6 months) as the primary end points. RESULTS: The median age at the time of surgery was 65.5 years (interquartile range 57-74 years). The majority of tumors were pancreatic ductal adenocarcinoma (76.6 %), and 71.6 % of patients received adjuvant therapy after resection. Univariate predictors of failure to undergo adjuvant therapy were advanced age, age-adjusted Charlson comorbidity index, operative transfusion, reoperation, length of stay, and 30- to 90-day readmissions (all p < 0.05). Advanced age, specifically among patients >70 years, persisted as a significant preoperative predictor on multivariate analysis (p < 0.01). Patients who failed to receive adjuvant therapy and/or developed ER had significantly worse overall survival rates compared to all other patients (27.8 vs. 9.7 months; p < 0.01). CONCLUSIONS: Approximately one-third of surgery-first patients undergoing pancreaticoduodenectomy at our institution did not receive adjuvant therapy and/or demonstrated ER. This substantial subset of patients may particularly benefit from NT, ensuring completion of multimodal therapy and/or avoiding futile surgical intervention. PMID- 27459988 TI - [The register of activity at the Ebola treatment center in Forecariah (Guinea) from april 23 to june 5, 2015: analysis and thoughts]. AB - The register of activity at the Ebola Treatment Center (ETC) in Forecariah (Guinea), from April 23 to June 5, 2015 is presented for analysis. The viral load of each patient is evaluated by the cycle threshold (Ct). One hundred and thirty patients were seen in Triage at the ETC, of which 24 (18.5%) patients who failed to meet theWHO case criteria for viral hemorrhagic fever were excluded from admission to the ETC. Of the 106 patients admitted in the ETC, 72 (67.9%) were declared non-cases after the results of their two PCR (drawn 48 hours apart) tests were negative. Thirty-four patients were tested positive for Ebola virus disease (EVD): 19 women and 15 men (sex ratio: male/female = 0.78), mean age of 33.51 +/- 20.1 years (extremes of 42 days to 70 years), of which six children were aged below 8 years. The median initial Ct value was 21.6 +/- 6.3 cycles in this group. Enquiry into patient contacts was only able to identify actual contacts in 20 of these patients (58.8%). Thirteen patients were ultimately cured of EVD (six men and seven women) - with a median age of 31.8 years (extremes of 4 to 54 years). These patients presented on admission with a median Ct value of 21.88 +/- 6.2 cycles (extremes of 17.6 to 31.7). Of the six children aged below 8 years, only one survived. Twenty-one patients (61.76%) with EVD died (9 men and 12 women) - median age, 34 +/- 21 years (extremes of 42 days to 70 years). They presented on admission with a median Ct value of 18 +/- 7 cycles (extremes of 12 to 24). The single most important factor associated with lethality was the Ct value at the time of admission to the ETC (P = 0.0004), i.e., the lower the Ct value, the higher the lethality rate or simply stated, the higher the viral load, the greater the lethality. Age, sex, identification of contact, and delay between the onset of symptoms and admission did not prove to be predictive of death outcome in our series. PMID- 27459989 TI - Shear wave elastography using ultrasound: effects of anisotropy and stretch stress on a tissue phantom and in vivo reactive lymph nodes in the neck. AB - PURPOSE: The purpose of this study was to evaluate how the anisotropy and the static stretch stress of the cervical musculature influence the measured shear modulus in a tissue-mimicking phantom and in cervical lymph nodes in vivo by using shear wave elastography (SWE). METHODS: SWE was performed on a phantom using a pig muscle and on the middle jugular cervical lymph nodes in six volunteers. Tissue elasticity was quantified using the shear modulus and a supersonic shear wave imaging technique. For the phantom study, first, the optimal depth for measurement was determined, and then, SWE was performed in parallel and perpendicular to the muscle fiber orientation with and without strain stress. For the in vivo study, SWE was performed on the cervical lymph nodes in parallel and perpendicular to the sternocleidomastoid muscle fiber direction with and without neck stretching. The mean values of the shear modulus (meanSM) were then analyzed. RESULTS: In the phantom study, the measured depth significantly influenced the meanSM with a sharp decrease at the depth of 1.5 cm (P<0.001). Strain stress increased the meanSM, irrespective of the muscle fiber orientation (P<0.001). In the in vivo study, the meanSM values obtained in parallel to the muscle fiber orientation were greater than those obtained perpendicular to the fiber orientation, irrespective of the stretch stress (P<0.001). However, meanSM was affected significantly by the stretch stress parallel to the muscle fiber orientation (P<0.001). CONCLUSION: The anisotropic nature of the cervical musculature and the applied stretch stress explain the variability of the SWE measurements and should be identified before applying SWE for the interpretation of the measured shear modulus values. PMID- 27459990 TI - Differences between urban and rural hedges in England revealed by a citizen science project. AB - BACKGROUND: Hedges are both ecologically and culturally important and are a distinctive feature of the British landscape. However the overall length of hedges across Great Britain is decreasing. Current challenges in studying hedges relate to the dominance of research on rural, as opposed to urban, hedges, and their variability and geographical breadth. To help address these challenges and to educate the public on the importance of hedge habitats for wildlife, in 2010 the Open Air Laboratories (OPAL) programme coordinated a hedge-focused citizen science survey. RESULTS: Results from 2891 surveys were analysed. Woody plant species differed significantly between urban and rural areas. Beech, Holly, Ivy, Laurel, Privet and Yew were more commonly recorded in urban hedges whereas Blackthorn, Bramble, Dog Rose, Elder and Hawthorn were recorded more often in rural hedges. Urban and rural differences were shown for some groups of invertebrates. Ants, earwigs and shieldbugs were recorded more frequently in urban hedges whereas blowflies, caterpillars, harvestmen, other beetles, spiders and weevils were recorded more frequently in rural hedges. Spiders were the most frequently recorded invertebrate across all surveys. The presence of hard surfaces adjacent to the hedge was influential on hedge structure, number and diversity of plant species, amount of food available for wildlife and invertebrate number and diversity. In urban hedges with one adjacent hard surface, the food available for wildlife was significantly reduced and in rural hedges, one adjacent hard surface affected the diversity of invertebrates. CONCLUSIONS: This research highlights that urban hedges may be important habitats for wildlife and that hard surfaces may have an impact on both the number and diversity of plant species and the number and diversity of invertebrates. This study demonstrates that citizen science programmes that focus on hedge surveillance can work and have the added benefit of educating the public on the importance of hedgerow habitats. PMID- 27459992 TI - Medical security and catastrophic health expenditures among households containing persons with disabilities in Korea: a longitudinal population-based study. AB - BACKGROUND: Although persons with disabilities need access to comprehensive and consistent healthcare services, a significant number of the poor with disabilities do not receive Medical-Aid due to the conditions of eligibility. We aimed to compare the financial burden of healthcare services between two groups of poor persons with disabilities: those not enrolled in Medical-Aid and Medical Aid enrollees. METHODS: This study used the 1st-8th data (2008-2014 year) of Panel Survey of Employment for the Disabled (PSED) conducted by the Korea Employment Agency for the Disabled. We classified adults who did not exceed 100 % of the poverty level into two groups (N = 3,010). The first group consisted of enrollees in Medical-Aid (n = 1,259) and the second group comprised those not enrolled in Medical-Aid (n = 1,325). We applied generalized estimating equations (GEEs) to assess the independent effect of enrollment in Medical-Aid on catastrophic health expenditures (CHE). RESULTS: We found that about 4.2 % of the poor not enrolled in the Medical-Aid experienced CHE and the poor not enrolled in Medical-Aid were 2.1 times more likely to experience CHE than Medical-Aid enrollees after applying multivariate models adjusted for several covariates. CONCLUSIONS: Given the additional expenses for treatment and rehabilitation caused by disability-related health problems, persons with disabilities are more likely to face barriers to needed medical services. Thus, policy makers need to expand the number of people receiving Medical-Aid by loosening the strict criteria for those with disabilities. PMID- 27459991 TI - Galectin-8 promotes migration and proliferation and prevents apoptosis in U87 glioblastoma cells. AB - BACKGROUND: Glioblastoma is one of the most aggressive cancers of the brain. Malignant traits of glioblastoma cells include elevated migration, proliferation and survival capabilities. Galectins are unconventionally secreted glycan-binding proteins that modulate processes of cell adhesion, migration, proliferation and apoptosis by interacting with beta-galactosides of cell surface glycoproteins and the extracellular matrix. Galectin-8 is one of the galectins highly expressed in glioblastoma cells. It has a unique selectivity for terminally sialylated glycans recently found enhanced in these highly malignant cells. A previous study in glioblastoma cell lines reported that Gal-8 coating a plastic surface stimulates two-dimensional motility. Because in other cells Gal-8 arrests proliferation and induces apoptosis, here we extend its study by analyzing all of these processes in a U87 glioblastoma cell model. METHODS: We used immunoblot and RT-PCR for Gal 8 expression analysis, recombinant Gal-8 produced in a bacteria system for Gal-8 treatment of the cells, and shRNA in lentivirus transduction for Gal-8 silencing. Cell migration as assessed in transwell filters. Cell proliferation, cell cycle and apoptosis were analyzed by FACS. RESULTS: Gal-8 as a soluble stimulus triggered chemotactic migration of U87 cells across the polycarbonate filter of transwell chambers, almost as intensively as fetal bovine serum. Unexpectedly, Gal-8 also enhanced U87 cell growth. Co-incubation of Gal-8 with lactose, which blocks galectin-glycan interactions, abrogated both effects. Immunoblot showed Gal-8 in conditioned media reflecting its secretion. U87 cells transduced with silencing shRNA in a lentiviral vector expressed and secreted 30-40 % of their normal Gal-8 levels. These cells maintained their migratory capabilities, but decreased their proliferation rate and underwent higher levels of apoptosis, as revealed by flow cytometry analysis of cell cycle, CFSE and activated caspase-3 staining. Proliferation seemed to be more sensitive than migration to Gal-8 expression levels. CONCLUSIONS: Gal-8, either secreted or exogenously enriched in the media, and acting through extracellular glycan interactions, constitutes a strong stimulus of directional migration in glioblastoma U87 cells and for the first time emerges as a factor that promotes proliferation and prevents apoptosis in cancerous cells. These properties could potentially contribute to the exaggerated malignancy of glioblastoma cells. PMID- 27459993 TI - Learning temporal weights of clinical events using variable importance. AB - BACKGROUND: Longitudinal data sources, such as electronic health records (EHRs), are very valuable for monitoring adverse drug events (ADEs). However, ADEs are heavily under-reported in EHRs. Using machine learning algorithms to automatically detect patients that should have had ADEs reported in their health records is an efficient and effective solution. One of the challenges to that end is how to take into account the temporality of clinical events, which are time stamped in EHRs, and providing these as features for machine learning algorithms to exploit. Previous research on this topic suggests that representing EHR data as a bag of temporally weighted clinical events is promising; however, the weights were in that case pre-assigned according to their time stamps, which is limited and potentially less accurate. This study therefore focuses on how to learn weights that effectively take into account the temporality and importance of clinical events for ADE detection. METHODS: Variable importance obtained from the random forest learning algorithm is used for extracting temporal weights. Two strategies are proposed for applying the learned weights: weighted aggregation and weighted sampling. The first strategy aggregates the weighted clinical events from different time windows to form new features; the second strategy retains the original features but samples them by using their weights as probabilities when building each tree in the forest. The predictive performance of random forest models using the learned weights with the two strategies is compared to using pre assigned weights. In addition, to assess the sensitivity of the weight-learning procedure, weights from different granularity levels are evaluated and compared. RESULTS: In the weighted sampling strategy, using learned weights significantly improves the predictive performance, in comparison to using pre-assigned weights; however, there is no significant difference between them in the weighted aggregation strategy. Moreover, the granularity of the weight learning procedure has a significant impact on the former, but not on the latter. CONCLUSIONS: Learning temporal weights is significantly beneficial in terms of predictive performance with the weighted sampling strategy. Moreover, weighted aggregation generally diminishes the impact of temporal weighting of the clinical events, irrespective of whether the weights are pre-assigned or learned. PMID- 27459995 TI - Deletion 21q22.3 and duplication 7q35q36.3 in a Colombian girl: a case report. AB - BACKGROUND: Genetic disorders are a major cause in the etiology of cases with intellectual disability; however, analysis by a conventional technique such as cytogenetic karyotyping only allows the detection of chromosomal alterations in approximately 9.5 % of cases. The inclusion of new technologies such as high resolution microarray analysis has allowed the study of alterations in chromosomal segments that are less than 5 Mb in length; this has led to an increase in the diagnosis of these patients of up to 25 %. CASE PRESENTATION: We report the first case of an 8-year-old Colombian girl of mixed race ancestry (Mestizo), with clinical features that include: delayed psychomotor and language development, intellectual disability, upward slanting palpebral fissures, divergent strabismus, low-set and rotated ears, tall and broad nasal bridge, flat philtrum, bifid uvula, posterior cleft palate, increased anteroposterior diameter of her chest, congenital heart defect type interventricular communication, scoliosis, and umbilical hernia. Genetic analysis was performed using comparative genomic hybridization array, which evidenced the deletion of a region of approximately 3.608 Mb on chromosome 21q22.3, and a duplication of 12.326 Mb on chromosome 7q35q36.3, these alterations affect approximately 112 and 186 genes, respectively. CONCLUSIONS: To date, this is the first report of an associated terminal deletion of 21q and 7q duplication in a patient with delayed psychomotor development and intellectual disability. We consider that future implementation of exome and RNA sequencing techniques, and analysis of their proteomic expression in a clinical context could lead to better analysis and interpretation of the genotype-phenotype correlation in cases similar to that described. PMID- 27459996 TI - Has intravenous lidocaine improved the outcome in horses following surgical management of small intestinal lesions in a UK hospital population? AB - BACKGROUND: Perioperative lidocaine treatment is commonly used in horses that undergo surgical treatment of colic, to prevent or treat postoperative ileus and reduce the effects of intestinal ischaemia-reperfusion injury. However, its clinical efficacy has not been evaluated in a large population of horses undergoing small intestinal surgery. The aim of the current study was to evaluate whether systemic lidocaine administration reduced the prevalence, volume and duration of postoperative reflux and improved rates of survival following surgical treatment of small intestinal lesions. Data were collected as a part of two prospective studies investigating postoperative survival of surgical colic patients admitted to a UK equine referral hospital during the periods 2004-2006 and 2012-2014. Kaplan-Meier plots of cumulative probability of survival and the log-rank test were used to compare survival between horses that did or did not receive lidocaine. The Wilcoxon rank-sum test was used to compare the total reflux volume and duration of reflux between the groups. A multivariable Cox proportional hazards model was used to identify pre- and intraoperative risk factors for non-survival. RESULTS: Data from 318 horses were included in the final analysis. The overall prevalence of postoperative reflux was 24.5 %. This was significantly higher (34.8 %) in horses admitted in 2012-2014 compared to the 2004-2006 cohort (16.7). Perioperative lidocaine treatment had no effect on total reflux volume, duration of reflux or rates of postoperative survival nor was it a risk factor associated with altered postoperative survival. Variables identified to be associated with increased risk of postoperative mortality included packed cell volume on admission (hazard ratio [HR] 1.03 95 %, 95 % confidence interval [CI] 1.004-1.06, p = 0.024), heart rate on admission (HR 1.014, 95 % CI 1.004 1.024, p =0.008) and duration of surgery (HR 1.007, 95 % CI 1.002-1.01, p = 0.008). CONCLUSIONS: Lidocaine therapy had no effect on the prevalence of postoperative reflux, total reflux volume and duration of reflux nor did it have any effect on postoperative survival in horses undergoing surgical management of small intestinal disease for treatment of colic. There is a need for a well designed multicentre, prospective randomised controlled trial to fully investigate the efficacy of lidocaine across different hospital populations. PMID- 27459998 TI - Maternal and cord blood adiponectin levels in relation to post-natal body size in infants in the first year of life: a prospective study. AB - BACKGROUND: Adiponectin is an adipocyte hormone involved in energy homeostasis and metabolism. However, its role in early infancy is poorly understood. METHODS: We recruited a total of 443 pregnant women and their children in this prospective study. Cord blood samples were successfully obtained from 331 neonates. Maternal and umbilical blood serum adiponectin were measured. The weight-, height- and BMI for-age Z scores of infants at birth and at 3, 6 and 12 months of age were assessed. RESULTS: Multiple linear regression analysis indicated that cord blood but not maternal serum adiponectin was positively associated with all of the anthropometric measures at birth (P < 0.01). Using Generalized Estimating Equation model after adjustment for sex, time, maternal age, gestational age, prepregnancy BMI, weight gain during pregnancy, maternal education, parity, history of miscarriage and mode of delivery, for every 1-MUg/ml increment of maternal serum adiponectin, the height-for-age Z score during the first year of life increased by 0.026 (P =0.013) on average, and the height-for-age Z score of infants in the highest quartile of maternal serum adiponectin was 0.270 (95 % CI: 0.013-0.527) higher than those in the lowest quartile. The changes in weight-for age Z score from birth decreased by 0.67 * 10(-2) on average with every 1-MUg/ml additional increase of cord blood adiponectin (P = 0.047). The infants in the highest quartile of cord blood adiponectin showed a -0.368 (95 % CI, -0.701- 0.035) decrease in weight-for-age Z score change from birth compared with those in the lowest quartile. CONCLUSIONS: Cord blood adiponectin concentration is a determinant of infant birth size and weight gain in the first year of life. Circulating maternal adiponectin during pregnancy may predict postnatal height growth. PMID- 27459999 TI - A guide to translation of research results from model organisms to human. AB - A new study helps resolve a controversy about determinants of gene expression variability and might facilitate the effective translation of research results across species. PMID- 27459997 TI - Higher occurrence of nausea and vomiting after total hip arthroplasty using general versus spinal anesthesia: an observational study. AB - BACKGROUND: Under the assumption that postoperative nausea and vomiting (PONV) may occur after total hip arthroplasty (THA) regardless of the anesthetic technique used, it is not clear whether general (GA) or spinal (SA) anesthesia has higher causal effect on this occurrence. Conflicting results have been reported. METHODS: In this observational study, we selected all elective THA interventions performed in adults between 1999 and 2008 in a Swiss orthopedic clinic under general or spinal anesthesia. To assess the effect of anesthesia type on the occurrence of PONV, we used the propensity score and matching methods, which allowed us to emulate the design and results of an RCT. RESULTS: Among 3922 procedures, 1984 (51 %) patients underwent GA, of which 4.1 % experienced PONV, and 1938 underwent SA, of which 3.5 % experienced PONV. We found that the average treatment effect on the treated, i.e. the effect of anesthesia type for a sample of individuals that actually received spinal anesthesia compared to individuals who received GA, was ATET = 2.00 % [95 % CI, 0.78-3.19 %], which translated into an OR = 1.97 [95 % CI 1.35; 2.87]. CONCLUSION: This suggests that the type of anesthesia is not neutral regarding PONV, general anesthesia being more strongly associated with PONV than spinal anesthesia in orthopedic surgery. PMID- 27460001 TI - Brief Report: Self-Based and Mechanical-Based Future Thinking in Children with Autism Spectrum Disorder. AB - This brief report is a partial replication of the study by Jackson and Atance (J Dev Disabil 14:40-45, 2008) assessing nonverbal Self-based and Mechanical-based future thinking (FT) in children with Autism Spectrum Disorder (ASD). In a first step, these tasks were administered to 30 children with ASD. The two Self-based tasks were then modified as a verbal component could not be completely ruled out. Consequently, 77 children with ASD and 77 children with typical development received the modified Self-based FT tasks and the Mechanical-based FT tasks. We partially replicated the previous findings. Participants with ASD had impaired FT in both kinds of tasks and both groups performed better on tasks assessing Mechanical-based FT than Self-based FT. These results suggest that impairments of FT in ASD are not limited to Self-Projection. PMID- 27460002 TI - Parent-Reported Repetitive Behavior in Toddlers on the Autism Spectrum. AB - Toddlers with autism spectrum disorder (ASD) were assessed on the Repetitive Behavior Scale-Revised (RBS-R), which we found to have acceptable internal consistency. Stereotypical subscale scores showed a negligible association with cognitive level, but correlated more strongly with adaptive and social indicators. Relative to earlier reported RBS-R scores for older age groups, toddlers' scores trended toward higher stereotyped behavior and lower ritualistic/sameness behavior. Our findings on associations with developmental indicators align with those of researchers who used more resource-intensive repetitive behavior measures. The convergence of these findings with those derived from other measurement methods suggests that the RBS-R, a cost effective parent-report measure, is a viable means of assessing repetitive behavior in toddlers with autism. PMID- 27460003 TI - Two-Step Screening of the Modified Checklist for Autism in Toddlers in Thai Children with Language Delay and Typically Developing Children. AB - This study aimed to validate the use of two-step Modified Checklist for Autism in Toddlers (M-CHAT) screening adapted for a Thai population. Our participants included both high-risk children with language delay (N = 109) and low-risk children with typical development (N = 732). Compared with the critical scoring criteria, the total scoring method (failing >=3 items) yielded the highest sensitivity of 90.7 %; specificity was 99.7 %, positive predictive value 96.1 %, and negative predictive value 99.4 %. The two-step M-CHAT screening is a promising instrument that can be utilized to detect ASD in Thai children in both primary and clinical settings. Moreover, socio-cultural context should be considered when adopting the use and interpretation of the M-CHAT for each country. PMID- 27460004 TI - Meditation or Medication? Mindfulness training versus medication in the treatment of childhood ADHD: a randomized controlled trial. AB - BACKGROUND: Attention-Deficit-Hyperactivity-Disorder (ADHD) is, with a prevalence of 5 %, a highly common childhood disorder, and has severe impact on the lives of youngsters and their families. Medication is often the treatment of choice, as it currently is most effective. However, medication has only short-term effects, treatment adherence is often low and most importantly; medication has serious side effects. Therefore, there is a need for other interventions for youngsters with ADHD. Mindfulness training is emerging as a potentially effective training for children and adolescents with ADHD. The aim of this study is to compare the (cost) effectiveness of mindfulness training to the (cost) effectiveness of methylphenidate in children with ADHD on measures of attention and hyperactivity/impulsivity. METHODS/DESIGN: A multicenter randomized controlled trial with 2 follow-up measurements will be used to measure the effects of mindfulness training versus the effects of methylphenidate. Participants will be youngsters (aged 9 to 18) of both sexes diagnosed with ADHD, referred to urban and rural mental healthcare centers. We aim to include 120 families. The mindfulness training, using the MYmind protocol, will be conducted in small groups, and consists of 8 weekly 1.5-h sessions. Youngsters learn to focus and enhance their attention, awareness, and self-control by doing mindfulness exercises. Parents will follow a parallel mindful parenting training in which they learn to be fully present in the here and now with their child in a non judgmental way, to take care of themselves, and to respond rather than react to difficult behavior of their child. Short-acting methylphenidate will be administered individually and monitored by a child psychiatrist. Assessments will take place at pre-test, post-test, and at follow-up 1 and 2 (respectively 4 and 10 months after the start of treatment). Informants are parents, children, teachers, and researchers. DISCUSSION: This study will inform mental health care professionals and health insurance companies about the clinical and cost effectiveness of mindfulness training for children and adolescents with ADHD and their parents compared to the effectiveness of methylphenidate. Limitations and several types of bias that are anticipated for this study are discussed. TRIAL REGISTRATION: Dutch Trial Register: NTR4206 . Registered 11 October 2013. PMID- 27460000 TI - Roles and epigenetic regulation of epithelial-mesenchymal transition and its transcription factors in cancer initiation and progression. AB - The epithelial-mesenchymal transition (EMT) is a crucial developmental process by which epithelial cells undergo a mesenchymal phenotypic change. During EMT, epigenetic mechanisms including DNA methylation and histone modifications are involved in the regulation of EMT-related genes. The epigenetic gene silencing of the epithelial marker E-cadherin has been well characterized. In particular, three major transcriptional repressors of E-cadherin, Snail, ZEB, and Twist families, also known as EMT-inducing transcription factors (EMT-TFs), play a crucial role in this process by cooperating with multiple epigenetic modifiers. Furthermore, recent studies have identified the novel epigenetic modifiers that control the expression of EMT-TFs, and these modifiers have emerged as critical regulators of cancer development and as novel therapeutic targets for human cancer. In this review, the diverse functions of EMT-TFs in cancer progression, the cooperative mechanisms of EMT-TFs with epigenetic modifiers, and epigenetic regulatory roles for the expression of EMT-TFs will be discussed. PMID- 27460005 TI - Dopamine agonist therapy induces significant recovery of HPA axis function in prolactinomas independent of tumor size: a large single center experience. AB - Our objective was to compare prevalence and rates of recovery of hypothalamic pituitary-adrenal axis dysfunction in prolactinoma patients before and after dopamine agonist therapy with nonfunctioning pituitary adenoma patients pre transsphenoidal and post-transsphenoidal surgery. We retrospectively compared hypothalamic-pituitary-adrenal axis function in patients with prolactinomas naive to dopamine agonist therapy with a cohort of nonfunctioning pituitary adenoma patients matched for gender and tumor size by classification (n = 57; 30 male/27 female; 27 microadenoma/30 macroadenoma). Patients with <52 weeks follow up, previous medical therapy, surgery, or radiation therapy were excluded. At baseline, there was no difference between groups for age, mean tumor size, or prevalence of adrenal insufficiency. Recovery from baseline adrenal insufficiency was demonstrated in patients with microprolactinomas and macroprolactinomas at a 52 week follow up (p = 0.003 and p = 0.004). These rates were similar to nonfunctioning pituitary adenoma patients after surgery. We show, in a large uniform study, that adrenal insufficiency significantly recovered after dopamine agonist treatment, independent of tumor size and gender in patients with prolactinomas naive to therapy. PMID- 27460007 TI - Induced labour is not associated with risk of autism, say researchers. PMID- 27460006 TI - 8-Cl-cAMP and PKA I-selective cAMP analogs effectively inhibit undifferentiated thyroid cancer cell growth. AB - The main purpose of our work was to evaluate the effects of different cyclic adenosine monophosphate analogs on thyroid cancer-derived cell lines. In particular we studied 8-chloroadenosine-3',5'-cyclic monophosphate, the most powerful cyclic adenosine monophosphate analog, and the protein kinase A I selective combination of 8-hexylaminoadenosine-3',5'cyclic monophosphate and 8 piperidinoadenosine-3',5'-cyclic monophosphate. The cyclic adenosine monophosphate/protein kinase A pathway plays a fundamental role in the regulation of thyroid cells growth. Site-selective cyclic adenosine monophosphate analogs are a class of cyclic adenosine monophosphate-derivate molecules that has been synthesized to modulate protein kinase A activity. Although the cyclic adenosine monophosphate/protein kinase A pathway plays a fundamental role in the regulation of thyroid cells proliferation, there are currently no studies exploring the role of cyclic adenosine monophosphate analogs in thyroid cancer. We evaluated the effects on cell proliferation, apoptosis activation and alterations of different intracellular pathways using 3-(4,5-dimetylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytofluorimetry, western blotting, and kinase inhibitors. Our results show that both compounds have antiproliferative potential. Both treatments were able to modify protein kinase A RI/RII ratio, thus negatively influencing cancer cells growth. Moreover, the two treatments differentially modulated various signaling pathways that regulate cell proliferation and apoptosis. Both treatments demonstrated interesting characteristics that prompt further studies aiming to understand the intimate interaction between different intracellular pathways and possibly develop novel anticancer therapies for undifferentiated thyroid cancer. PMID- 27460008 TI - A taspine derivative supresses Caco-2 cell growth by competitively targeting EphrinB2 and regulating its pathway. AB - Colorectal cancer is a common gastrointestinal malignancy worldwide and it is a lethal and aggressive malignancy with a dismal prognosis. In the present study, we investigated the effect of taspine derivative 12k on human colorectal cancer targeted at EphrinB2 and its PDZ. The results indicated that 12k could bind to EphrinB2 and showed a higher suppressive effect on EphrinB2/HEK293 than on HEK293 cells. Caco-2 cells were screened for high expression of EphrinB2. We found that 12k not only significantly decreased Caco-2 cell viability and colony formation but impaired migration. Meanwhile, 12k effectively inhibited blood vessel formation in a tissue model of angiogenesis. Mechanistic studies revealed that 12k significantly reduced the phosphorylation of EphrinB2 and PDZ protein PICK1. Accordingly, it was associated with the downregulation by 12k of the PI3K/AKT/mTOR and MAPK signaling pathways which were downstream of VEGFR2, yet it had no effect on VEGFR3. Moreover, the expression of CD34, CD45 and HIF-1alpha were downregulated in the Caco-2 cells. In conclusion, our findings showed that 12k had an inhibitory effect on the growth of Caco-2 cells, and it functioned by interrupting the phosphorylation of EphrinB2 and its related signaling pathway. PMID- 27460009 TI - How Well Do Laboratories Adhere to Recommended Clinical Guidelines for the Management of Myocardial Infarction: The CARdiac MArker Guidelines Uptake in Europe Study (CARMAGUE). AB - BACKGROUND: We undertook an assessment of current use of evidence-based guidelines for the use of cardiac biomarkers in Europe (EU) and North America (NA). METHODS: In 2013-2014 a web-based questionnaire was distributed via NA and EU biochemical societies. Questions covered cardiac biomarkers measured, analytical methods used, decision thresholds, and use of decision-making protocols. Results were collated using a central database and analyzed using comparative and descriptive nonparametric statistics. RESULTS: In EU, returns were obtained from 442 hospitals, 50% central or university hospitals, and 39% from local hospitals from 35 countries with 395/442 (89%) provided an acute service. In NA there were 91 responses (63.7% central or university hospitals, 19.8% community hospitals) with 76/91 (83.5%) providing an acute service. Cardiac troponin was the preferred cardiac biomarker in 99.5% (EU) and 98.7% (NA), and the first line marker in 97.7% (EU) and 97.4% (NA). There were important differences in the choice of decision limits and their derivations. The origin of the information was also significantly different, with EU vs NA as follows: package insert, 61.9% vs 40%; publications, 17.1% vs 15.0%; local clinical or analytical validation choice, 21.0% vs 45.0%; P = 0.0003. CONCLUSIONS: There are significant differences between EU and NA use of cardiac biomarkers. This probably relates to different availability of assays between EU and NA (such as high-sensitivity troponin assays) and different laboratory practices on assay introduction (greater local evaluation of assay performance occurred in NA). PMID- 27460011 TI - Towards scanning probe lithography-based 4D nanoprinting by advancing surface chemistry, nanopatterning strategies, and characterization protocols. AB - Biointerfaces direct some of the most complex biological events, including cell differentiation, hierarchical organization, and disease progression, or are responsible for the remarkable optical, electronic, and biological behavior of natural materials. Chemical information encoded within the 4D nanostructure of biointerfaces - comprised of the three Cartesian coordinates (x, y, z), and chemical composition of each molecule within a given volume - dominates their interfacial properties. As such, there is a strong interest in creating printing platforms that can emulate the 4D nanostructure - including both the chemical composition and architectural complexity - of biointerfaces. Current nanolithography technologies are unable to recreate 4D nanostructures with the chemical or architectural complexity of their biological counterparts because of their inability to position organic molecules in three dimensions and with sub-1 micrometer resolution. Achieving this level of control over the interfacial structure requires transformational advances in three complementary research disciplines: (1) the scope of organic reactions that can be successfully carried out on surfaces must be increased, (2) lithography tools are needed that are capable of positioning soft organic and biologically active materials with sub-1 micrometer resolution over feature diameter, feature-to-feature spacing, and height, and (3) new techniques for characterizing the 4D structure of interfaces should be developed and validated. This review will discuss recent advances in these three areas, and how their convergence is leading to a revolution in 4D nanomanufacturing. PMID- 27460010 TI - Negative emotions and emotional eating: the mediating role of experiential avoidance. AB - PURPOSE: Emotional eating is a risk factor for eating pathology across the life- and weight-span. Research demonstrates that negative emotions are a precipitant of emotional eating, particularly among female college students. However, the underlying factors that explain this relationship are unclear. Experiential avoidance, a propensity toward being unwilling to remain in contact with aversive private experiences, may explain the association between negative emotions and emotional eating. The purpose of this study was to examine whether experiential avoidance would mediate the association between negative emotions and emotional eating. METHODS: A sample of 132 women (17.4 % African American, 59.8 % White) completed measures of mood, experiential avoidance and emotional eating. Bias corrected bootstrapping mediational analyses were conducted. RESULTS: Experiential avoidance mediated the relationship between negative emotions and emotional eating b = -0.21, 95 % BC CI [-0.43, -0.07]. The indirect effect through experiential avoidance accounted for 9 % of the variance, which represents a medium effect (k 2 = 0.09, 95 % BC CI [0.03, 0.18]). CONCLUSIONS: Results suggest that experiential avoidance is important for understanding the relationship between negative emotions and emotional eating and may inform potential strategies for prevention and treatment. PMID- 27460012 TI - Hemodynamics of Stent Implantation Procedures in Coronary Bifurcations: An In Vitro Study. AB - Stent implantation in coronary bifurcations presents unique challenges and currently there is no universally accepted stent deployment approach. Despite clinical and computational studies, the effect of each stent implantation method on the coronary artery hemodynamics is not well understood. In this study the hemodynamics of stented coronary bifurcations under pulsatile flow conditions were investigated experimentally. Three implantation methods, provisional side branch (PSB), culotte (CUL), and crush (CRU), were investigated using time resolved particle image velocimetry to measure the velocity fields. Subsequently, hemodynamic parameters including wall shear stress, oscillatory shear index (OSI), and relative residence time (RRT) were calculated. The pressure field through the vessel was non-invasively quantified and pressure wave speeds were computed. The effects of each stented case were evaluated and compared against an un-stented case. CRU provided the lowest compliance mismatch, but demonstrated detrimental stent interactions. PSB, the clinically preferred method, and CUL maintained many normal flow conditions. However, PSB provided about a 300% increase in both OSI and RRT. CUL yielded a 10 and 85% increase in OSI and RRT, respectively. The results of this study support the concept that different bifurcation stenting techniques result in hemodynamic environments that deviate from that of un-stented bifurcations, to varying degrees. PMID- 27460013 TI - Ultra-fast single-file transport of a simple liquid beyond the collective behavior zone. AB - We use molecular dynamics simulations to analyze the single-file transport behavior of a simple liquid through a narrow membrane channel. With the decrease of the liquid-channel interaction, the liquid flow exhibits a remarkable maximum behavior owing to the competition of liquid-liquid and liquid-channel interactions. Surprisingly, this maximum flow is coupled to a sudden reduce of the liquid occupancy, where the liquid particle is moving through the channel alone at nearly constant velocity, rather than in a collective motion mode. Further investigation on the encountered energy barrier suggests that this maximum flow should be induced by particles having large instant velocities (or thermal fluctuation) that overcome the liquid-liquid and liquid-channel interaction barriers. Further decreasing the liquid-channel interaction leads to the decrease and ultimate stabilization of the liquid flow, since the energy barrier will increase and becomes steady. These results suggest that the breakdown of collective behavior can be a new rule for achieving fast single-file transportation, especially for simple or nonpolar liquids with relatively weak liquid-liquid interactions, and is thus helpful for the design of high flux nanofluidic devices. PMID- 27460014 TI - A seeding-searching-ensemble method for gland segmentation in H&E-stained images. AB - BACKGROUND: Glands are vital structures found throughout the human body and their structure and function are affected by many diseases. The ability to segment and detect glands among other types of tissues is important for the study of normal and disease processes and helps their analysis and visualization by pathologists in microscopic detail. METHODS: In this paper, we develop a new approach for segmenting and detecting intestinal glands in H&E-stained histology images, which utilizes a set of advanced image processing techniques: graph search, ensemble, feature extraction, and classification. Our method is computationally fast, preserves gland boundaries robustly and detects glands accurately. RESULTS: We tested the performance of our gland detection and segmentation method by analyzing a dataset of over 1700 glands in digitized high resolution clinical histology images obtained from normal and diseased human intestines. The experimental results show that our method outperforms considerably the state-of the-art methods for gland segmentation and detection. CONCLUSIONS: Our method can produce high-quality segmentation and detection of non-overlapped glands that obey the natural property of glands in histology tissue images. With accurately detected and segmented glands, quantitative measurement and analysis can be developed for further studies of glands and computer-aided diagnosis. PMID- 27460015 TI - Safety, efficacy, and patient-perceived satisfaction of peripherally inserted central catheters in terminally ill cancer patients: a prospective multicenter observational study. AB - PURPOSE: The purpose of this study was to investigate the safety, efficacy, and subjective satisfaction of peripherally inserted central catheters (PICCs) in terminally ill cancer patients. METHODS: All PICCs were inserted by an interventional radiologist with radiological guidance. We monitored the occurrence of PICC-related complication and evaluated the patient-perceived satisfaction for PICC using semi-structured questionnaire. RESULTS: A total of 36 terminally ill cancer patients underwent PICC. Three patients had 2 PICC insertions; hence, finally 39 episodes during 829 PICC days were analyzed. All procedures were completed without any procedure-related complication. The median catheter life span was 19.0 days (95 % CI, 14.1-23.9). Thirty-four cases maintained the PICC until the intended time, while the other 5 cases (12.8 %; 6.1/1000 PICC days) were premature PICC removals. Totally 10 complications (25.6 %; 12.3/1000 PICC days) were reported including premature removals (n = 5), trivial bleedings (n = 3), and thrombophlebitis (n = 2). Patients reported that the procedure was not distressing (42 %), a little distressing (36 %), or distressing (21 %). Of 30 patients who had preserved cognitive function at fifth day, most patients (n = 25, 83 %) reported more comfort although the other 5 patients reported no change (n = 3) or less comfort (n = 2). CONCLUSIONS: PICCs were safely inserted and showed favorable maintenance rate with acceptable complications. Additionally, most of the patients felt that parenteral access became much comfortable after PICC insertion. When considering the characteristics of terminally ill cancer patients, poor general condition and a limited period of survival, PICC could be a safe and effective method for intravenous access. PMID- 27460016 TI - Quality of life amongst lymphoma survivors in a developing country. AB - PURPOSE: The survival for patients with lymphoma has improved over the past decades with the introduction of novel agents. Quality of life of these survivors is now being studied with focus on minimising the late effects of chemotherapy and improving psychosocial support. This study aims to determine the prevalence of anxiety and depression of lymphoma survivors and to investigate the possible association between these disorders and quality of life. METHODS: Patients with previous diagnosis of lymphoma who remained in remission were recruited from a major hospital in Malaysia. Quality of life of these patients was measured using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30). Anxiety and depression symptoms were assessed using Hospital Anxiety and Depression scale (HADS). RESULTS: A total of 156 patients participated in this study. Eighteen percent (18 %) of patients had symptoms of anxiety, and 10 % had symptoms of depression. Patients who had higher depression scores were older, of lower education level and had more than one comorbidity illness. Patients with anxiety were associated with lower overall quality of life (QOL) score, lower emotional and cognitive functioning and complained more of fatigue and insomnia (p < 0.05). Patients who had depression were associated with lower physical functioning and complained more of insomnia (p < 0.05). CONCLUSION: It is important for the treating physicians to ensure follow-up of lymphoma survivors for any psychological disorders in order early counseling and support can be provided. This may improve patients' quality of life. PMID- 27460017 TI - The pathogenic relevance of alphaM-integrin in Guillain-Barre syndrome. AB - The molecular determinants and mechanisms involved in leukocyte trafficking across the blood-nerve barrier (BNB) in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) variant of Guillain-Barre syndrome are incompletely understood. Prior work using a flow-dependent in vitro human BNB model demonstrated a crucial role for alphaM-integrin (CD11b)-intercellular adhesion molecule-1 interactions in AIDP patient leukocyte trafficking. The aim of this study is to directly investigate the biological relevance of CD11b in AIDP pathogenesis. Immunohistochemistry was performed on three AIDP patient sural nerve biopsies to evaluate endoneurial leukocyte CD11b expression. A severe murine experimental autoimmune neuritis (sm-EAN) model was utilized to determine the functional role of CD11b in leukocyte trafficking in vivo and determine its effect on neurobehavioral measures of disease severity, electrophysiological assessments of axonal integrity and myelination and histopathological measures of peripheral nerve inflammatory demyelination. Time-lapse video microscopy and electron microscopy were employed to observe structural alterations at the BNB during AIDP patient leukocyte trafficking in vitro and in situ, respectively. Large clusters of endoneurial CD11b+ leukocytes associated with demyelinating axons were observed in AIDP patient sural nerves. Leukocyte CD11b expression was upregulated during sm-EAN. 5 mg/kg of a function-neutralizing monoclonal rat anti mouse CD11b antibody administered after sm-EAN disease onset significantly ameliorated disease severity, as well as electrophysiological and histopathological parameters of inflammatory demyelination compared to vehicle- and isotype antibody-treated mice. Consistent with in vitro observations of leukocyte trafficking at the BNB, electron micrographs of AIDP patient sural nerves demonstrated intact electron-dense endoneurial microvascular intercellular junctions during paracellular mononuclear leukocyte transmigration. Our data support a crucial pathogenic role of CD11b in AIDP leukocyte trafficking, providing a potential therapeutic target for demyelinating variants of Guillain Barre syndrome. PMID- 27460018 TI - Variation in the human Achilles tendon moment arm during walking. AB - The Achilles tendon (AT) moment arm is an important determinant of ankle moment and power generation during locomotion. Load and depth-dependent variations in the AT moment arm are generally not considered, but may be relevant given the complex triceps surae architecture. We coupled motion analysis and ultrasound imaging to characterize AT moment arms during walking in 10 subjects. Muscle loading during push-off amplified the AT moment arm by 10% relative to heel strike. AT moment arms also varied by 14% over the tendon thickness. In walking, AT moment arms are not strictly dependent on kinematics, but exhibit important load and spatial dependencies. PMID- 27460019 TI - Evolution of gastric surgery techniques and outcomes. AB - Surgical management of gastric cancer improves survival. However, for some time, surgeons have had diverse opinions about the extent of gastrectomy. Researchers have conducted many clinical studies, making slow but steady progress in determining the optimal surgical approach. The extent of lymph node dissection has been one of the major issues in surgery for gastric cancer. Many trials demonstrated that D2 dissection resulted in greater morbidity and mortality than D1 dissection. However, long-term outcomes demonstrated that D2 dissection resulted in longer survival than D1 dissection. In 2004, the Japan Clinical Oncology Group reported a pivotal trial which was performed to determine whether para-aortic lymph node dissection combined with D2 dissection was superior to D2 dissection alone and found no benefit of the additional surgery. Gastrectomy with pancreatectomy, splenectomy, and bursectomy was initially recommended as part of the D2 dissection. Now, pancreas-preserving total gastrectomy with D2 dissection is standard, and ongoing trials are addressing the role of splenectomy. Furthermore, the feasibility and safety of laparoscopic gastrectomy are well established. Survival and quality of life are increasingly recognized as the most important endpoints. In this review, we present perspectives on surgical techniques and important trials of these techniques in gastric cancer patients. PMID- 27460020 TI - The effect of ball impact location on racket and forearm joint angle changes for one-handed tennis backhand groundstrokes. AB - Recreational tennis players tend to have higher incidence of tennis elbow, and this has been hypothesised to be related to one-handed backhand technique and off centre ball impacts on the racket face. This study aimed to investigate for a range of participants the effect of off-longitudinal axis and off-lateral axis ball-racket impact locations on racket and forearm joint angle changes immediately following impact in one-handed tennis backhand groundstrokes. Three dimensional racket and wrist angular kinematic data were recorded for 14 university tennis players each performing 30 "flat" one-handed backhand groundstrokes. Off-longitudinal axis ball-racket impact locations explained over 70% of the variation in racket rotation about the longitudinal axis and wrist flexion/extension angles during the 30 ms immediately following impact. Off lateral axis ball-racket impact locations had a less clear cut influence on racket and forearm rotations. Specifically off-longitudinal impacts below the longitudinal axis forced the wrist into flexion for all participants with there being between 11 degrees and 32 degrees of forced wrist flexion for an off longitudinal axis impact that was 1 ball diameter away from the midline. This study has confirmed that off-longitudinal impacts below the longitudinal axis contribute to forced wrist flexion and eccentric stretch of the wrist extensors and there can be large differences in the amount of forced wrist flexion from individual to individual and between strokes with different impact locations. PMID- 27460021 TI - Characteristics of daily life gait in fall and non fall-prone stroke survivors and controls. AB - BACKGROUND: Falls in stroke survivors can lead to serious injuries and medical costs. Fall risk in older adults can be predicted based on gait characteristics measured in daily life. Given the different gait patterns that stroke survivors exhibit it is unclear whether a similar fall-prediction model could be used in this group. Therefore the main purpose of this study was to examine whether fall prediction models that have been used in older adults can also be used in a population of stroke survivors, or if modifications are needed, either in the cut off values of such models, or in the gait characteristics of interest. METHODS: This study investigated gait characteristics by assessing accelerations of the lower back measured during seven consecutive days in 31 non fall-prone stroke survivors, 25 fall-prone stroke survivors, 20 neurologically intact fall-prone older adults and 30 non fall-prone older adults. We created a binary logistic regression model to assess the ability of predicting falls for each gait characteristic. We included health status and the interaction between health status (stroke survivors versus older adults) and gait characteristic in the model. RESULTS: We found four significant interactions between gait characteristics and health status. Furthermore we found another four gait characteristics that had similar predictive capacity in both stroke survivors and older adults. CONCLUSION: The interactions between gait characteristics and health status indicate that gait characteristics are differently associated with fall history between stroke survivors and older adults. Thus specific models are needed to predict fall risk in stroke survivors. PMID- 27460022 TI - A large-scale quantitative EM study on activation of olfactory glands shows no effect of cholinergic agents. AB - Little is known about olfactory glands' regulation despite their presumed importance for normal functioning of the cilia of olfactory neurons. The aim of this study was to establish an assay for olfactory gland activation by using large-scale quantitative electron microscopy (EM). In addition we wanted to test the hypothesis that cholinergic drugs activate the olfactory glands, by using our newly established EM assay. In total, over 70 000 secretory gland vesicles were quantified in over 3000 cells. Olfactory gland cell size (40.8 um2 +/- 2.0 SD), vesicle diameter (812 nm +/- 57 SD) and vesicles per cell (21.6 +/- 4.2 SD) were also quantified. The vesicle percentage of the cell area varied between 24% and 30%. In a blinded study we found no significant effects of cholinergic agents on parameters of vesicle number or vesicle diameter. Unexpectedly, pilocarpine treatment increased olfactory gland size, probably by inducing cell swelling. In conclusion, we have established a quantitative EM assay for olfactory gland activation and provided new data on basic olfactory gland cell characteristics. By using the EM assay, olfactory glands are shown not to be activated by cholinergic agents, which indicates an alternative regulation pathway or constitutive secretion from olfactory glands. PMID- 27460023 TI - Considerations on inhibition approaches for proinflammatory functions of ADAM proteases. AB - Proteases of the disintegrin and metalloproteinase (ADAM) family mediate the proteolytic shedding of various surface molecules including cytokine precursors, adhesion molecules, growth factors, and receptors. Within the vasculature ADAM10 and ADAM17 regulate endothelial permeability, transendothelial leukocyte migration, and the adhesion of leukocytes and platelets. In vivo studies show that both proteases are implicated in several inflammatory pathologies, for example, edema formation, leukocyte infiltration, and thrombosis. However, both proteases also contribute to developmental and regenerative processes. Thus, although ADAMs can be regarded as valuable drug targets in many aspects, the danger of severe side effects is clearly visible. To circumvent these side effects, traditional inhibition approaches have to be improved to target ADAMs at the right time in the right place. Moreover, the inhibitors need to be more selective for the target protease and if possible also for the substrate. Antibodies recognizing the active conformation of ADAMs or small molecules blocking exosites of ADAM proteases may represent inhibitors with the desired selectivities. PMID- 27460024 TI - The use of multilevel sampling techniques for determining shallow aquifer nitrate profiles. AB - Nitrate is a worldwide pollutant in aquifers. Shallow aquifer nitrate concentrations generally display vertical stratification, with a maximum concentration immediately below the water level. The concentration then gradually decreases with depth. Different techniques can be used to highlight this stratification. The paper aims at comparing the advantages and limitations of three open hole multilevel sampling techniques (packer system, dialysis membrane samplers and bailer), chosen on the base of a literary review, to highlight a nitrate vertical stratification under the assumption of (sub)horizontal flow in the aquifer. The sampling systems were employed at three different times of the year in a shallow aquifer piezometer in northern Italy. The optimal purge time, equilibration time and water volume losses during the time in the piezometer were evaluated. Multilevel techniques highlighted a similar vertical nitrate stratification, present throughout the year. Indeed, nitrate concentrations generally decreased with depth downwards, but with significantly different levels in the sampling campaigns. Moreover, the sampling techniques produced different degrees of accuracy. More specifically, the dialysis membrane samplers provided the most accurate hydrochemical profile of the shallow aquifer and they appear to be necessary when the objective is to detect the discontinuities in the nitrate profile. Bailer and packer system showed the same nitrate profile with little differences of concentration. However, the bailer resulted much more easier to use. PMID- 27460025 TI - Toward better understanding and feasibility of controlling greenhouse gas emissions from treatment of industrial wastewater with activated sludge. AB - Wastewater treatment plants (WWTPs) have been recognized as important sources for anthropogenic greenhouse gas (GHG) emission. The objective of the study was to thoroughly investigate a typical industrial WWTP in southern Taiwan in winter and summer which possesses the emission factors close to those reported values, with the analyses of emission factors, mass fluxes, fugacity, lab-scale in situ experiments, and impact assessment. The activated sludge was the important source in winter and summer, and nitrous oxide (N2O) was the main contributor (e.g., 57 to 91 % of total GHG emission in a unit of kg carbon dioxide-equivalent/kg chemical oxygen demand). Albeit important for the GHGs in the atmosphere, the fractional contribution of the GHG emission to the carbon or nitrogen removal in wastewater treatment was negligible (e.g., less than 1.5 %). In comparison with the sludge concentration or retention time, adjusting the aeration rate was more effective to diminish the GHG emission in the activated sludge without significantly affecting the treated water quality. When the aeration rate in the activated sludge simulation was reduced by 75 %, the mass flux of N2O could be diminished by up to 53 % (from 9.6 to 4.5 mg/m2-day). The total emission in the WWTP (including carbon dioxide, methane, and N2O) would decrease by 46 % (from 0.67 to 0.36 kg CO2-equiv/kg COD). However, the more important benefit of changing the aeration rate was lowering the energy consumption in operation of the WWTP, as the fractional contribution of pumping to the total emission from the WWTP ranged from 46 to 93 % within the range of the aeration rate tested. Under the circumstance in which reducing the burden of climate change is a global campaign, the findings provide insight regarding the GHG emission from treatment of industrial wastewater and the associated impact on the treatment performance and possible mitigation strategies by operational modifications. PMID- 27460026 TI - Levels, sources, and health risk assessment of polycyclic aromatic hydrocarbons in Brno, Czech Republic: a 5-year study. AB - This work aimed to determine the seasonal variations of polycyclic aromatic hydrocarbons (PAHs) in airborne PM10 at two background sites (Masna-MS, Lisen-LN) in Brno over a 5-year period (2009-2013). Samples were collected on quartz filters using a low-volume sampler by continual filtration. Concentrations of PAHs in collected PM10 samples were determined using a gas chromatography with a mass spectrometer as a detector. A different number of PAHs were determined to be at each site, i.e., 11 PAHs at the MS site and six PAHs at the LN site, and similarities between them were identified using non-parametric analysis of variance. Potential sources were identified using principal component analysis (PCA) and PAHs diagnostic ratios. The work also focused on health risk assessment. This was estimated using toxic equivalent factors to calculate individual lifetime cancer risk, which quantifies risk of exposure to PAHs for specific age groups. The average 11-PAH concentrations in M|S site annually ranged from 19.28 +/- 19.02 ng m-3 (2011) to 40.37 +/- 21.35 ng m-3 (2013). With regard to the LN site, the average six-PAH concentrations annually ranged from 3.64 +/- 3.87 ng m-3 (2009) and 5.27 +/- 6.19 ng m-3 (2012). PCA and diagnostic ratios indicate the main sources to be traffic emissions and coal combustion. Health risk assessment showed carcinogenic risk under limit value in all cases. PMID- 27460027 TI - Performance of mixed algae for treatment of slaughterhouse wastewater and microbial community analysis. AB - This study investigated organic matter (OM) and nutrient removal efficiency of mixed algal species from slaughterhouse wastewater (SWW) by using photo bioreactor. For this purpose, different dilution multiples of 10, 4, and 2 were applied to the SWW, and pure wastewater was finally used for algal cultivation. OM and nutrient removal performance in an algal photo-bioreactor were severely affected by the dilution ratio. After 7 days of cultivation, the highest removal percentages of total organic carbon (TOC), total nitrogen (TN), and total phosphorus (TP) were 89.6, 70.2, and 96.2 %, respectively. Furthermore, the changes in eukaryotic algae and cyanobacterial species in the algal photo bioreactors were investigated using polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE) techniques. The results indicated that cyanobacterial species were more efficient than eukaryotic species in removing nutrients from the SWW. This study suggests that mixed algal photo bioreactors could be used efficiently in the treatment of SWW. PMID- 27460028 TI - Role of exogenous salicylic acid in regulating physio-morphic and molecular changes under chromium toxicity in black- and yellow- seeded Brassica napus L. AB - Salicylic acid (SA) mediates tolerance mechanisms in plants against a wide spectrum of biotic and abiotic stresses. Therefore, the present study was carried out to determine how SA regulates the plant protection mechanisms in two cultivars of oilseed rape (Brassica napus L.) under chromium (Cr) stress. Exogenously applied SA enhanced plant growth, increased dry biomasses, and strengthened the reactive oxygen scavenging system by improving cell organelles that were severely damaged via Cr toxicity. The contents of Cr were significantly enhanced in both root and leaf of cultivar Zheda 622 (yellow color) compared with cultivar ZS 758 (black color). Exogenous application of SA significantly reduced the Cr contents in both plant organs as well as enhanced the SA contents under Cr stress. A dose-dependent increase was observed in reactive oxygen species (ROS) generation under Cr stress. To ease the inimical effects of ROS, plants' defense systems were induced under Cr stress, and SA further enhanced protection. Further, TEM micrographs results showed that Cr stress alone significantly ruptured the plant cell organelles of both cultivars by increasing the size of starch grain and the number of plastoglobuli, damaging the chloroplast and mitochondrion structures. However, exogenously applied SA significantly recovered these damages in the plant cells of both cultivars. It was also observed that cultivar ZS 758 was proved to be more tolerant under Cr toxicity. Gene expression analysis revealed that combined treatments of Cr and SA increased antioxidant related gene expression in both cultivars. Findings of the present study demonstrate that SA induces the enzymatic antioxidant activities and related gene expression, secondary metabolism, and improves the cell structural changes and the transcript level of specific stress-associated proteins in root and leaf of two oilseed rape cultivars under Cr toxicity. PMID- 27460029 TI - The effect of nutrients shortage on plant's efficiency to capture solar radiations under semi-arid environments. AB - Radiation use efficiency (RUE) is considered critical for calculation of crop yield. The crop productivity can be improved by increasing the interception of solar radiation and maintaining higher RUE for plants. Irrigation water and nitrogen (N) supply are the main limiting factors for RUE in maize (Zea mays L.) across the semi-arid environments. Field experiments were conducted during two consecutive growing seasons (2009-2010) to optimize RUE in relation to N application timings and rates with varying irrigation water management practices. In experiment 1, three N application timings were made, while in experiment 2, three possible water management practices were used. In both experiments, five N rates (100, 150, 200, 250, and 300 kg N ha-1) were applied to evaluate the effects of irrigation water and N on cumulative photosynthetic active radiation (PARi), dry matter RUE (RUEDM), and grain yield RUE (RUEGY). The results demonstrated that cumulative PARi and RUEs were not constant during the plant growth under varying the nutrients. The water and N significantly influenced cumulative PARi and RUEs during the both growing seasons. In experiment 1, the maximum cumulative PARi was observed by application of 250 kg N ha-1 in three splits (1/3 N at V2, 1/3 N at V16, and 1/3 N at R1 stage), and the highest RUEDM was achieved by the application of 300 kg N ha-1. However, the highest RUEGY was observed by application of 250 kg N ha-1. In experiment 2, the maximum cumulative PARi was attained at normal irrigation regime with 250 kg N ha-1, while the highest RUEDM and RUEGY were recorded at normal irrigation regime with the application of 300 kg N ha-1. The regression analysis showed significant and positive correlation of RUEGY with grain yield. Therefore, optimum water and N doses are important for attaining higher RUE, which may enhance maize grain yield semi-arid environment; this may be considered in formulating good agricultural practices for the environmental conditions resembling to those of this study. PMID- 27460030 TI - Endosulfan inhibiting the meiosis process via depressing expressions of regulatory factors and causing cell cycle arrest in spermatogenic cells. AB - Endosulfan is a persistent organic pollutant and widely used in agriculture as a pesticide. It is present in air, water, and soil worldwide; therefore, it is a health risk affecting especially the reproductive system. The aim of this study was to evaluate the toxicity of endosulfan in the reproductive system. To investigate the effect of endosulfan on meiosis process, 32 rats were divided into four groups, treated with 0, 1, 5, and 10 mg/kg/day endosulfan, respectively, and sacrificed after the 21 days of treatments. Results show that endosulfan caused the reductions in sperm concentration and motility rate, which resulted into an increased in sperm abnormality rate; further, endosulfan induced downregulation of spermatogenesis- and oogenesis-specific basic helix-loop-helix transcription factor (Sohlh1) which controls the switch on meiosis in mammals, as well cyclin A1, cyclin-dependent kinases 1 (CDK1), and cyclin-dependent kinases 2 (CDK2). In vitro, endosulfan induced G2/M phase arrest in the spermatogenic cell cycle and caused proliferation inhibition. Moreover, endosulfan induced oxidative stress and DNA damage in vivo and vitro. The results suggested that endosulfan could inhibit the start of meiosis by downregulating the expression of Sohlh1 and induce G2/M phase arrest of cell cycle by decreasing the expression of cyclin A1, CDK1, and CDK2 via oxidative damage, which inhibits the meiosis process, and therefore decrease the amount of sperm. PMID- 27460031 TI - Synthesis and antiproliferative activity of some N'-substituted 2,4 dihydroxybenzothiohydrazides. AB - The paper shows that new N'-substituted 2,4-dihydroxybenzocarbothiohydrazides are able to inhibit the in vitro proliferation of human tumor cell lines. The compounds were prepared by the reaction of sulfinylbis[(2,4 dihydroxyphenyl)methanethione] (STB) or its analogs with the hydrazines. The panel of N'-substitution included aryl, pyridinyl and pyrimidinyl rings. The highest antiproliferative activity for N'-(4-(4-chlorophenyl)-6 (trifluoromethyl)pyrimidin-2-yl)-5-ethyl-2,4-dihydroxybenzothiohydrazide (5b) was found. The antiproliferative potency of some compounds was similar to that of cisplatin. Analogs with the Et substituent on benzenediol moiety displayed higher potency than with the unsubstituted one. The influence of N'-substitution on antiproliferative activity of compounds was discussed. PMID- 27460032 TI - Cytomegalovirus Colitis and Subsequent New Diagnosis of Inflammatory Bowel Disease in an Immunocompetent Host: A Case Study and Literature Review. AB - BACKGROUND Infection with gastrointestinal cytomegalovirus in an immunocompetent host is a rather rare occurrence in the literature. There are a few reports of gastrointestinal infection in the immunocompetent who are then subsequently given a new diagnosis of inflammatory bowel disease. It is speculated that the initial cytomegalovirus colitis infection triggers the onset of inflammatory bowel disease. CASE REPORT Herein we report a case of cytomegalovirus colitis and new diagnosis of inflammatory bowel disease identified in a 40-year-old immunocompetent adult man who presented with gastrointestinal symptoms and disseminated cytomegalovirus infection requiring anti-viral therapy, which successfully treated the episode of cytomegalovirus infection. He then went on to have persistent symptomatic inflammatory bowel disease confirmed by pathology. CONCLUSIONS In this paper we will review the literature and explore the rare case of cytomegalovirus colitis in the immunocompetent host and discuss the pathology, physiology, diagnosis, and treatment of cytomegalovirus colitis. PMID- 27460033 TI - C3 mesangial proliferative glomerulonephritis initially presenting with atypical hemolytic uremic syndrome: a case report. AB - BACKGROUND: Hemolytic uremic syndrome is characterized by acute renal failure, thrombocytopenia, and Coombs-negative hemolytic anemia. In C3 mesangial proliferative glomerulonephritis, an increase in mesangial cell proliferation without thickening in the glomerular capillary wall can be seen under light microscopy, but the definitive diagnosis is made with the immunohistologic demonstration of isolated C3 deposits in the mesangium. C3 glomerulonephritis may be detected in childhood; however, in this case report we describe the first case of isolated C3 glomerulonephritis together with atypical hemolytic uremic syndrome in an adult patient. CASE PRESENTATION: Here we present a case of a 27 year-old white man with anuria who was hospitalized after being diagnosed as having hemolytic uremic syndrome accompanied by acute renal failure. Renal biopsy results revealed C3 glomerulonephritis. There was a complete recovery of renal function after hemodialysis, and prednisolone and plasma exchange treatment. CONCLUSIONS: C3 glomerulopathy is distinct from atypical hemolytic uremic syndrome although both diseases are due to abnormal control of the alternative complement pathway. In atypical hemolytic uremic syndrome activation of complement occurs on glomerular or microvascular endothelium causing a thrombotic microangiopathy; in most cases, no electron-dense deposits are seen on electron microscopy and glomerular C3 is not detected on immunofluorescence. PMID- 27460036 TI - Anisotropic optical and conductive properties of oriented 1D-nanoparticle thin films made by spray-assisted self-assembly. AB - We report on the fabrication of oriented anisotropic metal nanoparticle thin films made by Grazing Incidence Spraying (GIS) and on the anisotropic plasmonic properties of the resulting thin films. Gold nanorods of two different aspect ratios and silver nanowires were self-assembled as a uniaxially aligned monolayer with the GIS approach. In particular, we examine the influence of the nanowire/nanorod length and diameter on the degree of ordering determined by electron microscopy pictures. Furthermore, we show that the anisotropy of the optical properties (probed by polarized UV-visible-near infrared spectroscopy) strongly depend on the quality of alignment. The prepared monolayer thin films have an orientation order parameter of up to 0.83 for silver nanowires, which is reflected in an optical anisotropy of 0.57 in the UV-visible and 0.76 in the near infrared through the selective excitation of transverse and longitudinal surface plasmon resonance modes. The electronic transport in oriented silver nanowire monolayers is also shown to be highly directional, with the sheet resistance varying over almost an order of magnitude depending on the transport direction. Such anisotropic conductive plasmonic thin films may find applications in various fields like biochemical sensing, energy transport and harvesting or optoelectronic devices. PMID- 27460034 TI - Modelling with ANIMO: between fuzzy logic and differential equations. AB - BACKGROUND: Computational support is essential in order to reason on the dynamics of biological systems. We have developed the software tool ANIMO (Analysis of Networks with Interactive MOdeling) to provide such computational support and allow insight into the complex networks of signaling events occurring in living cells. ANIMO makes use of timed automata as an underlying model, thereby enabling analysis techniques from computer science like model checking. Biology experts are able to use ANIMO via a user interface specifically tailored for biological applications. In this paper we compare the use of ANIMO with some established formalisms on two case studies. RESULTS: ANIMO is a powerful and user-friendly tool that can compete with existing continuous and discrete paradigms. We show this by presenting ANIMO models for two case studies: Drosophila melanogaster circadian clock, and signal transduction events downstream of TNF alpha and EGF in HT-29 human colon carcinoma cells. The models were originally developed with ODEs and fuzzy logic, respectively. CONCLUSIONS: Two biological case studies that have been modeled with respectively ODE and fuzzy logic models can be conveniently modeled using ANIMO. The ANIMO models require less parameters than ODEs and are more precise than fuzzy logic. For this reason we position the modelling paradigm of ANIMO between ODEs and fuzzy logic. PMID- 27460037 TI - A polymer microgel at a liquid-liquid interface: theory vs. computer simulations. AB - We propose a mean-field theory and dissipative particle dynamics (DPD) simulations of swelling and collapse of a polymer microgel adsorbed at the interface of two immiscible liquids (A and B). The microgel reveals surface activity and lowers A-B interfacial tension. Attempting to occupy as large an interfacial area as possible, the microgel undergoes anisotropic deformation and adopts a flattened shape. Spreading over the interface is restricted by polymer subchain elasticity. The equilibrium shape of the microgel at the interface depends on its size. Small microgels are shown to be more oblate than the larger microgels. Increasing microgel cross-link density results in stronger reduction of the surface tension and weaker flattening. As the degree of immiscibility of A and B liquids increases, the microgel volume changes in a non-monotonous fashion: the microgel contraction at moderate immiscibility of A and B liquids is followed by its swelling at high incompatibility of the liquids. The segregation regime of the liquids within and outside the microgel is different. Being segregated outside the microgel, the liquids can be fully (homogeneously) mixed or weakly segregated within it. The density profiles of the liquids and the polymer were plotted under different conditions. The theoretical and the DPD simulation results are in good agreement. We hope that our findings will be useful for the design of stimuli responsive emulsions, which are stabilized by the microgel particles, as well as for their practical applications, for instance, in biocatalysis. PMID- 27460038 TI - Equitable access to integrated primary mental healthcare for people with severe mental disorders in Ethiopia: a formative study. AB - BACKGROUND: The provision of mental healthcare through integration into primary care is expected to improve access to care, but not all population groups may benefit equally. The aim of this study was to inform delivery of a new primary care-based mental health service in rural Ethiopia by identifying potential barriers to equitable access to mental healthcare and strategies to overcome them. METHODS: A qualitative study was conducted as formative work for the PRogramme for Improving Mental healthcarE (PRIME), a project supporting delivery of mental healthcare integrated into primary care in a rural district in south central Ethiopia. In-depth interviews (n = 21) were carried out with stakeholders selected purposively from mental health service users, caregivers, community leaders and healthcare administrators. A focus group discussion (n = 12) was conducted with community health extension workers. Framework analysis was employed using an adapted version of the access framework developed for use in contexts of livelihood insecurity, which considers (1) availability, (2) accessibility and affordability. and (3) acceptability and adequacy dimensions of access. RESULTS: Primary care-based mental healthcare was considered as a positive development, and would increase availability, accessibility and affordability of treatments. Low levels of community awareness, and general preference for traditional and religious healing were raised as potential challenges to the acceptability of integrated mental healthcare. Participants believed integrated mental healthcare would be comprehensive and of satisfactory quality. However, expectations about the effectiveness of treatment for mental disorders were generally low. Threats to equitable access to mental healthcare were identified for perinatal women, persons with physical disability, those living in extreme poverty and people with severe and persistent mental disability. CONCLUSION: Establishing an affordable service within reach, raising awareness and financial support to families from low socioeconomic backgrounds were suggested to improve equitable access to mental healthcare by vulnerable groups including perinatal women and people with disabilities. Innovative approaches, such as telephone consultations with psychiatric nurses based in nearby towns and home outreach need to be developed and evaluated. PMID- 27460039 TI - Exploring the kinetic and thermodynamic aspects of four-electron electrochemical reactions: electrocatalysis of oxygen evolution by metal oxides and biological systems. AB - Finding fundamental and general mechanisms for electrochemical reactions, such as the oxygen evolution reaction (OER) from water and reduction of CO2, plays vital roles in developing the desired electrocatalysts for facilitating solar fuel production. Recently, density functional theory (DFT) calculations have shown that there is a universal scaling relation of adsorption energy between key intermediate species, HO(ad) and HOO(ad), on the surface of metal oxides as OER electrocatalysts. In this paper, a kinetic and thermodynamic model for the four electron electrochemical reaction based on previous OER mechanisms proposed by DFT calculations is developed to further investigate the electrocatalytic properties over a wide range of metal oxides and photosystem II. The OER activity of metal oxides (i.e. electrocatalytic current) calculated from the DFT calculated equilibrium potentials with kinetic properties, such as the rate constants for interfacial electron transfer and catalytic turnover, can lead to a volcano-shaped trend that agrees with the results observed in experiments. In addition, the kinetic aspects of the impact on the electrocatalysts are evaluated. Finally, comparing the results of metal oxides and photosystem II, and fitting experimental voltammograms give further insights into kinetic and thermodynamic roles. Here, the general guidelines for designing OER electrocatalysts with unified kinetic and thermodynamic properties are presented. PMID- 27460040 TI - To have your citizen science cake and eat it? Delivering research and outreach through Open Air Laboratories (OPAL). AB - BACKGROUND: The vast array of citizen science projects which have blossomed over the last decade span a spectrum of objectives from research to outreach. While some focus primarily on the collection of rigorous scientific data and others are positioned towards the public engagement end of the gradient, the majority of initiatives attempt to balance the two. Although meeting multiple aims can be seen as a 'win-win' situation, it can also yield significant challenges as allocating resources to one element means that they may be diverted away from the other. Here we analyse one such programme which set out to find an effective equilibrium between these arguably polarised goals. Through the lens of the Open Air Laboratories (OPAL) programme we explore the inherent trade-offs encountered under four indicators derived from an independent citizen science evaluation framework. Assimilating experience from the OPAL network we investigate practical approaches taken to tackle arising tensions. RESULTS: Working backwards from project delivery to design, we found the following elements to be important: ensuring outputs are fit for purpose, developing strong internal and external collaborations, building a sufficiently diverse partnership and considering target audiences. We combine these 'operational indicators' with four pre existing 'outcome indicators' to create a model which can be used to shape the planning and delivery of a citizen science project. CONCLUSIONS: Our findings suggest that whether the proverb in the title rings true will largely depend on the identification of challenges along the way and the ability to address these conflicts throughout the citizen science project. PMID- 27460041 TI - Impact of continuing medical education in cancer diagnosis on GP knowledge, attitude and readiness to investigate - a before-after study. AB - BACKGROUND: Continuing medical education (CME) in earlier cancer diagnosis was launched in Denmark in 2012 as part of the Danish National Cancer Plan. The CME programme was introduced to improve the recognition among general practitioners (GPs) of symptoms suggestive of cancer and improve the selection of patients requiring urgent investigation. This study aims to explore the effect of CME on GP knowledge about cancer diagnosis, attitude towards own role in cancer detection, self-assessed readiness to investigate and cancer risk assessment of urgently referred patients. METHODS: We conducted a before-after study in the Central Denmark Region including 831 GPs assigned to one of eight geographical clusters. All GPs were invited to participate in the CME at three-week intervals between clusters. A questionnaire focusing on knowledge, attitude and clinical vignettes was sent to each GP one month before and seven months after the CME. The GPs were also asked to assess the risk of cancer in patients urgently referred to a fast-track cancer pathway during an eight-month period. CME participating GPs were compared with reference (non-participating) GPs by analysing before-after differences. RESULTS: One quarter of all GPs participated in the CME. 202 GPs (24.3 %) completed both the baseline and the follow-up questionnaires. 532 GPs (64.0 %) assessed the risk of cancer before the CME and 524 GPs (63.1 %) assessed the risk of cancer after the CME in urgently referred consecutive patients. Compared to the reference group, CME-participating GPs statistically significantly improved their understanding of a rational probability of diagnosing cancer among patients urgently referred for suspected cancer, increased their knowledge of cancer likelihood in a 50-year-old referred patient and lowered the assessed risk of cancer in urgently referred patients. CONCLUSIONS: The standardised CME lowered the GP-assessed cancer risk of urgently referred patients, whereas the effect on knowledge about cancer diagnosis and attitude towards own role in cancer detection was limited. No effect was found on the GPs' readiness to investigate. CME may be effective for optimising the interpretation of cancer symptoms and thereby improve the selection of patients for urgent cancer referral. TRIAL REGISTRATION: NCT02069470 on ClinicalTrials.gov. Retrospectively registered, 1/29/2014. PMID- 27460042 TI - The timing of antenatal care initiation and the content of care in Sindh, Pakistan. AB - BACKGROUND: Policymakers and program planners consider antenatal care (ANC) coverage to be a primary measure of improvements in maternal health. Yet, evidence from multiple countries indicates that ANC coverage has no necessary relationship with the content of services provided. This study examines the relationship between the timing of the first ANC check-up, a potential predictor of the content of services, and the provision of WHO recommended services to women during their pregnancy. METHODS: The study uses data from a representative household survey of Sindh with a sample comprising of 4,000 women aged 15-49 who had had a live birth in the two years before the survey. The survey obtained information about the elements of care provided during pregnancy, the timing of the first ANC check-up, the number of ANC visits made during the last pregnancy and women's socio-economic and demographic characteristics. Bivariate analysis was conducted to examine the relationship between the proportion of women who receive six WHO recommended services and the timing of their first ANC check-up. Multivariate analysis was conducted to identify predictors of the number of elements of care provided. RESULTS: While most women in Sindh (87 %) receive an ANC check-up, its timing varies by parity, education and household wealth. The median time to the first ANC check-up was 3 months for women in the richest and 7 months for women in the poorest wealth quintiles. In multivariate analysis, wealth, education, parity and age at marriage were significant predictors of the number of elements of care provided. Women who received an early ANC check-up were much more likely to receive WHO recommended services than other women, independent of a range of socio-economic and demographic variables and independent of the number of ANC visits made during pregnancy. CONCLUSIONS: In Sindh, the timing of the first ANC check-up has an independent effect on the content of care provided to pregnant women. While it is extremely important that providers are adequately trained and motivated to provide the WHO recommended standards of care, these findings suggest that motivating women to make an early first ANC check-up may be another mechanism through which the quality of care provided may be improved. Such a focus is most likely to benefit the poorest, least educated and highest parity women. Based on these findings, we recommend that routine data collected at health facilities in Pakistan should include the month of pregnancy at the time of the first ANC check-up. PMID- 27460043 TI - The impact of carbon and oxygen in alpha-titanium: ab initio study of solution enthalpies and grain boundary segregation. AB - The solution, grain boundary (GB) segregation, and co-segregation of carbon and oxygen atoms in alpha-titanium are studied using density functional theory. For five titanium tilt boundaries, including T1, T2, and C1 twin systems, we determine the GB structure, as well as GB energy and excess volume. The segregation energies and volumes of carbon and oxygen are calculated for 23 inequivalent interstitial voids, while for co-segregation 75 configurations are considered. It is obtained that depending on the type of the segregation void both a positive and a negative segregation process is possible. The physical reasons of segregation are explained in terms of the analysis of the void atomic geometry, excess volume and features of the electronic structure at the Fermi level. Although carbon and oxygen show qualitatively similar properties in alpha Ti, several distinctions are observed for their segregation behavior and mutual interactions. PMID- 27460045 TI - GATA binding protein 2 overexpression is associated with poor prognosis in KRAS mutant colorectal cancer. AB - Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Mutations in KRAS occur with the frequency of 30-50% in CRC leading to decreased therapeutic response to anti-epidermal growth factor receptor (EGFR) agents. Recently GATA2 was proven to be essential in the survival of KRAS mutant non-small cell lung cancer (NSCLC) cells. However, the association between KRAS mutation and GATA2 expression in CRC remains largely unknown. In the present study, dideoxy sequencing and immunohistochemistry were used to determine KRAS mutation and GATA2 expression, respectively, in a cohort of 236 patients. Cox proportional hazard regression and Kaplan-Meier survival analysis were performed to study the association between KRAS mutation or GATA2 expression and clinical outcomes. Kaplan-Meier analysis revealed that KRAS mutant patients with high expression of GATA2 had significantly worse long-term clinical outcomes than those with low expression of GATA2 (P<0.001). Further analysis showed that patients with both KRAS mutation and high GATA2 expression experienced significantly more unfavorable 5-year outcomes than patients with wild- type KRAS and low GATA2 expression (P=0.001). Univariate and multivariate Cox proportional hazard regression demonstrated the GATA2 expression level was an independent risk factor for overall survival of CRC patients (HR 1.645; 95% CI 1.004-2.696; P=0.048). In conclusion, the results of this study demonstrated that high expression of GATA2 is correlated with worse survival outcomes in KRAS mutant CRC patients, suggesting that GATA2 may serve as a novel biomarker for the survival of CRC patients harboring KRAS mutation. PMID- 27460044 TI - Vitamin D supplementation and its influence on muscle strength and mobility in community-dwelling older persons: a systematic review and meta-analysis. AB - BACKGROUND: It has been suggested that vitamin D status or supplementation is important for maintaining or improving muscle strength and mobility in older adults. The study results, however, do not provide consistent results. We therefore aimed to summarise the available evidence systematically, including only studies conducted in community-dwelling older persons. METHODS: A systematic search of the literature was performed in April of 2016. The systematic review includes studies that used vitamin D with or without calcium supplementation as the exposure variable and various measurements of muscle strength and mobility. The meta-analysis was limited to studies using hand grip strength (HGS) and timed up-and-go test as the outcome variables. RESULTS: A total of 15 studies out of 2408 articles from the literature search were included in the systematic review, providing 2866 participants above the age of 65 years. In the majority of studies, no improvement in muscle strength and mobility was observed after administration of vitamin D with or without calcium supplements. In the meta analysis, we observed a nonsignificant change in HGS [+0.2 kg (95% confidence interval = -0.25 to 0.7 kg; seven studies)] and a small, significant increase in the timed-up-and-go test [0.3 s (95% confidence interval = 0.1 to 0.5 s; five studies)] after vitamin D supplementation. The meta-analyses showed a high degree of heterogeneity between the studies. CONCLUSIONS: In conclusion, we observed no improvement in muscle strength after the administration of vitamin D with or without calcium supplements. We did find a small but significant deterioration of mobility. However, this is based on a limited number of studies and participants. PMID- 27460046 TI - The extended palliative phase of dementia - An integrative literature review. AB - This article presents an integrative literature review of the experience of dementia care associated with the extended palliative phase of dementia. The aim was to highlight how dementia is defined in the literature and describe what is known about the symptomatology and management of advanced dementia regarding the needs and preferences of the person with dementia and their family carer/s. There was no consistent definition of advanced dementia. The extended palliative phase was generally synonymous with end-of-life care. Advanced care planning is purported to enable professionals to work together with people with dementia and their families. A lack of understanding of palliative care among frontline practitioners was related to a dearth of educational opportunities in advanced dementia care. There are few robust concepts and theories that embrace living the best life possible during the later stages of dementia. These findings informed our subsequent work around the concept, 'Dementia Palliare'. PMID- 27460047 TI - Co-production and engagement of people with dementia: The issue of ethics and creative or intellectual copyright. PMID- 27460048 TI - Anatomical study of the auditory region of Arctotherium tarijense (Ursidae, Tremarctinae), an extinct short-faced bear from the Pleistocene of South America. AB - Here we present the most detailed morphological study of the auditory region of a tremarctinae bear, Arctotherium tarijense Ameghino. In addition, we provide new anatomical information of the Tremarctinae inner ear, such as coplanarity and deviation from orthogonality of the semicircular canals, as an approach to infer the head movements which encountered the extinct forms in locomotion. Based on morphological comparisons, A. tarijense exhibits the following particular features: the cavum tympani presents the highest relative volume compared with other ursids; the processus paraoccipitalis has a foramen that is absent in other tremarctines; there is only one (ventral) recess in the anterior region of the cavum tympani; and the recessus epytimpanicus is the smallest for all ursids studied. In relation to the inner ear, A. tarijense shows the lowest values of orthogonality deviation and highest scores of locomotor agility. Based on this, is possible to make a preliminary proposal that this species had a relative high vestibular sensibility and therefore a better ability to explore different kind of habitats. However, this hypothesis might be contrasted among bears taking into account the orientation of each semicircular canal in a phylogenetic framework. PMID- 27460049 TI - Development of a NanoString assay to detect leukemogenic fusion transcripts in acute myeloid leukemia. AB - INTRODUCTION: Detection of leukemogenic fusion transcripts in acute myeloid leukemia (AML) is critical for AML diagnosis. NanoString nCounter system is a novel probe-based gene expression platform capable of measuring up to 800 targets with advantages of reproducibility, accuracy, and sample type flexibility. To study the potential application of NanoString in leukemia at clinic, we used this technology to detect AML leukemogenic fusion transcripts and compared the performances with clinical molecular assays. METHODS: We developed a NanoString assay to detect seven leukemogenic fusion transcripts, namely RUNX1-RUNX1T1 (e5e12), PML-RARA (bcr1, bcr2, and bcr3), and CBFB-MYH11 (e5e12, e5e8, and e5e7). We set up the cut-off value for each fusion transcript and tested 42 de novo AML samples. We compared the results with reverse transcriptase-polymerase chain reaction (RT-PCR) and TaqMan reverse quantitative-polymerase chain reaction (RQ PCR), the molecular methods standardly used at clinic. RESULTS: We demonstrated that the NanoString and RT-PCR results correlate well (P < 0.0001) and are highly concordant (95.2%). Using TaqMan RQ-PCR as a validation method and gold standard, we demonstrated superior accuracy and sensitivity of NanoString compared to RT PCR and comparable specificity. Furthermore, we showed that NanoString is not as sensitive as TaqMan RQ-PCR in detecting very low level of fusion transcripts. CONCLUSIONS: NanoString can serve as a reliable and alternative molecular method to multiplexed RT-PCR for diagnosis of de novo AML with the perspective of screening/quantitation of a large number of leukemogenic fusion transcripts and prognostic genes. However, NanoString may not be an alternative method for monitoring minimal residual disease in AML. PMID- 27460050 TI - Influence of influenza vaccination on recurrent hospitalization in patients with heart failure. AB - BACKGROUND: The current study aimed to evaluate the influence of regular annual influenza vaccinations on cardiovascular (CV) death and heart failure-related hospitalizations (HFrH) in stable outpatients with heart failure with reduced ejection fraction. METHODS: The Turkish research team-HF (TREAT-HF) is a network undertaking multicenter, observational cohort studies in HF. This study is a subgroup analysis of TREAT-HF outpatient cohorts who completed a questionnaire on influenza vaccination status and for whom follow-up data were available. A total of 656 patients with available follow-up data for CV death and HFrH including recurrent hospitalization were included in the study. Patients were classified into two groups: those who received regular influenza vaccination (40 %) and those who did not receive vaccination. RESULTS: During a mean follow-up of 15 +/ 6 months, 113 (18 %) patients had CV death and 471 (72 %) patients had at least one HFrH. The CV death rate was similar in both groups of patients (16 vs. 19 %, p = 0.37), whereas, HFrH and recurrent HFrH were significantly less frequently encountered in patients who received regular influenza vaccination than in those who did not receive vaccination (43 vs. 92 % and 16 vs. 66 %, p < 0.001, respectively). In a multivariate Cox proportional hazards model - in addition to a few clinical factors - vaccination status (HR = 0.30, 95 % CI = 0.17-0.51, p < 0.001) and graduation from university (HR = 0.35, 95 % CI = 0.17-0.72, p = 0.004) remained independently associated with the risk of recurrent HFrH. CONCLUSION: Regular influenza vaccination does not influence CV deaths; however, it decreases HFrH including recurrent episodes of HFrH in outpatients with heart failure with reduced ejection fraction. PMID- 27460052 TI - Limits in Proton Nuclear Singlet-State Lifetimes Measured with para-Hydrogen Induced Polarization. AB - The synthesis of a hyperpolarized molecule was developed, where the polarization and the singlet state were preserved over two controlled chemical steps. Nuclear singlet-state lifetimes close to 6 min for protons are reported in dimethyl fumarate. Owing to the high symmetry (AA'X3 X3 ' and A2 systems), the singlet state readout requires either a chemical desymmetrization or a long and repeated spin lock. Using DFT calculations and relaxation models, we further determine nuclear spin singlet lifetime limiting factors, which include the intramolecular dipolar coupling mechanism (proton-proton and proton-deuterium), the chemical shift anisotropy mechanism (symmetric and antisymmetric), and the intermolecular dipolar coupling mechanism (to oxygen and deuterium). If the limit of paramagnetic relaxation caused by residual oxygen could be lifted, the intramolecular dipolar coupling to deuterium would become the limiting relaxation mechanism and proton lifetimes upwards of 26 min could become available in the molecules considered here (dimethyl maleate and dimethyl fumarate). PMID- 27460051 TI - [Interdisciplinary differential treatment of structural heart disease : When operation and when catheter-based intervention?]. AB - The demographic changes in society lead to an increasing number of patients with aortic valve stenosis and mitral regurgitation. Simultaneously the higher age of patients is associated with an increase in multimorbidity with a high surgical risk so that they cannot be referred to surgery. Besides the current gold standard of surgery, minimally invasive therapeutic options are increasingly becoming established for these patients. For the differentiated indications and therapeutic success, a multidisciplinary heart team assumes an important role. The next generation of transcatheter aortic valve implantation (TAVI) systems will lead to improvement in the results, lower complication rates and mortality and as a result there is a general trend towards expanding the indications. New innovative minimally invasive mitral valve devices are still undergoing clinical trials and will define future therapy options. PMID- 27460053 TI - Formation and decomplexation kinetics of copper(ii) complexes with cyclen derivatives having mixed carboxylate and phosphonate pendant arms. AB - The kinetic properties of Cu(ii) complexes of H4dota and its analogues with one (H5do3ap), two in the 1,7-position (trans-H6do2a2p), three (H7doa3p) and four (H8dotp) phosphonic acid pendant arms were investigated. The formation of a Cu(ii) complex with H4dota, trans-H6do2a2p and H8dotp at a slightly acidic pH is faster for the phosphonic acid derivatives than for H4dota, but with no simple dependence on the number of -CH2PO3H2 substituents (trans-H6do2a2p > H8dotp > H4dota; pH 4-6). Relative differences in the reactivity among the differently protonated species (HnL(x-)) of the same ligand are successively decreased with the more phosphonic acid groups in the ligand. The faster complexation is probably caused by the higher ability of phosphonates to bind the metal ion and/or to assist in the transfer of protons from the ring amine groups to the bulk water. The acid-assisted decomplexation kinetics of the complexes was followed in highly acidic solutions ([H(+)] = 0.01-5 M) and at different temperatures (15-70 degrees C) to determine the activation parameters of the reaction. The kinetic inertness of the Cu(ii) complexes follows the order: H4dota > H5do3ap > trans-H6do2a2p > H7doa3p > H8dotp. To obtain information on the influence of additional pendant arms, analogous data were obtained for trans H2do2a. The ligand is less reactive than H4dota, but the kinetic inertness of its Cu(ii) complex is similar to that of the H4dota complex. As it was considered that the published thermodynamics data on the Cu(ii)-H8dotp system are probably incorrect, the system was re-investigated. It showed a very high stability for the [Cu(dotp)](6-) species and the easy formation of several Cu2L species in the presence of an excess of the metal ion. Also, the structure of the (H6doa3p)(-) anion in the solid state was determined. These experimental data demonstrate that the substitution of acetic acid pendant arms by methylphosphonic acid ones in H4dota-like ligands increases the rate of complexation but significantly decreases the kinetic inertness of the Cu(ii) complexes. PMID- 27460054 TI - Mass mosquito trapping for malaria control in western Kenya: study protocol for a stepped wedge cluster-randomised trial. AB - BACKGROUND: Increasing levels of insecticide resistance as well as outdoor, residual transmission of malaria threaten the efficacy of existing vector control tools used against malaria mosquitoes. The development of odour-baited mosquito traps has led to the possibility of controlling malaria through mass trapping of malaria vectors. Through daily removal trapping against a background of continued bed net use it is anticipated that vector populations could be suppressed to a level where continued transmission of malaria will no longer be possible. METHODS/DESIGN: A stepped wedge cluster-randomised trial design was used for the implementation of mass mosquito trapping on Rusinga Island, western Kenya (the SolarMal project). Over the course of 2 years (2013-2015) all households on the island were provided with a solar-powered mosquito trapping system. A continuous health and demographic surveillance system combined with parasitological surveys three times a year, successive rounds of mosquito monitoring and regular sociological studies allowed measurement of intervention outcomes before, during and at completion of the rollout of traps. Data collection continued after achieving mass coverage with traps in order to estimate the longer term effectiveness of this novel intervention. Solar energy was exploited to provide electric light and mobile phone charging for each household, and the impacts of these immediate tangible benefits upon acceptability of and adherence to the use of the intervention are being measured. DISCUSSION: This study will be the first to evaluate whether the principle of solar-powered mass mosquito trapping could be an effective tool for elimination of malaria. If proven to be effective, this novel approach to malaria control would be a valuable addition to the existing strategies of long-lasting insecticide-treated nets and case management. Sociological studies provide a knowledge base for understanding the usage of this novel tool. TRIAL REGISTRATION: Trialregister.nl: NTR3496 - SolarMal. Registered on 20 June 2012. PMID- 27460055 TI - Development and psychometric properties of a measure of catheter burden with bladder drainage after pelvic reconstructive surgery. AB - AIMS: Catheter burden after pelvic reconstructive surgery is an important patient reported quality of life outcome in research and clinical practice. However, existing tools focus on long-term catheter users rather than short-term postoperative patients. The study aim was to evaluate the psychometric properties of a modified version of the intermittent self-catheterization questionnaire (ISC Q) in postoperative pelvic reconstructive patients. METHODS: After experts convened to discuss and modify the ISC-Q items based on their knowledge of women's experiences and clinical practices, 178 women (108 with transurethral and 70 with suprapubic catheters) completed the modified scale and other measures as part of a larger parent study designed to assess health-related quality of life (HRQoL) following pelvic reconstructive surgery requiring bladder drainage. RESULTS: During psychometric testing, the modified ISC-Q was reduced to six items encompassing two factors: a three-item difficulty of use factor and a 3-item embarrassment factor. The new scale was named the short-term catheter burden questionnaire (STCBQ). The two-factor model was robust in both subsamples. Only scores within and not between subsamples can be meaningfully compared due to a lack of scalar invariance. Correlations among STCBQ total scores, subscores, and a single satisfaction item indicated good construct validity. Correlations with patient demographics provided further information about the scale. CONCLUSIONS: The STCBQ is a short, efficient assessment of short-term catheter burden following pelvic reconstructive surgery. The scale can be used as an important patient reported outcome measure in clinical practice and research. Neurourol. Urodynam. 36:1140-1146, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27460056 TI - Spotlights on our sister journals: Chem. Eur. J. 32/2016. PMID- 27460057 TI - The relative efficacy of bona fide psychotherapies for post-traumatic stress disorder: a meta-analytical evaluation of randomized controlled trials. AB - BACKGROUND: In the treatment of PTSD, meta-analyses suggest comparable efficacy of cognitive behavioural therapies and various trauma focused treatments, but results for other treatments are inconsistent. One meta-analysis found no differences for bona fide therapies, but was critizised for overgeneralization and a biased study sample and relied on an omnibus test of overall effect size heterogeneity that is not widely used. METHODS: We present an updated meta analysis on bona fide psychotherapies for PTSD, contrasting an improved application of the omnibus test of overall effect size heterogeneity with conventional random-effects meta-analyses of specified treatment types against all others. Twenty-two studies were eligible, reporting 24 head-to-head comparisons in randomized controlled trials of 1694 patients. RESULTS: Head-to head comparison between trauma focused and non-trauma focused treatments revealed a small relative advantage for trauma focused treatments at post-treatment (Hedges' g = 0.14) and at two follow-ups (g = 0.17, g = 0.23) regarding PTSD symptom severity. Controlling and adjusting for influential studies and publication bias, prolonged exposure and exposure therapies (g = 0.19) were slightly more efficacious than other therapies regarding PTSD symptom severity at post-treatment; prolonged exposure had also higher recovery rates (RR = 1.26). Present-centered therapies were slightly less efficacious regarding symptom severity at post-treatment (g = -0.20) and at follow-up (g = -0.17), but equally efficacious as available comparison treatments with regards to secondary outcomes. The improved omnibus test confirmed overall effect size heterogeneity. CONCLUSIONS: Trauma focused treatments, prolonged exposure and exposure therapies were slightly more efficacious than other therapies in the treatment of PTSD. However, treatment differences were at most small and far below proposed thresholds of clinically meaningful differences. Previous null findings may have stemmed from not clearly differentiating primary and secondary outcomes, but also from a specific use of the omnibus test of overall effect size heterogeneity that appears to be prone to error. However, more high-quality studies using ITT analyses are still needed to draw firm conclusions. Moreover, the PTSD treatment field may need to move beyond a focus primarily on efficacy so as to address other important issues such as public health issues and the requirements of highly vulnerable populations. PMID- 27460058 TI - Prediction of cyclohexane-water distribution coefficients with COSMO-RS on the SAMPL5 data set. AB - The Conductor-Like-Screening-Model for Real Solvents (COSMO-RS) method has been used for the blind prediction of cyclohexane-water distribution coefficients logD within the SAMPL challenge. The partition coefficient logP of the neutral species was calculated first and then corrected for dissociation or protonation, as appropriate for acidic or basic solutes, to obtain the cyclohexane-water logD. Using the latest version of the COSMOtherm implementation, this approach in combination with a rigorous conformational sampling yielded a predictive accuracy of 2.11 log units (RMSD) for the 53 compounds of the blind prediction dataset. By that it was the most accurate of all contest submissions and it also achieved the best rank order. The RMSD mainly arises from a group of outliers in the negative logD range, which at least partly may arise from dimerization or other experimental problems coming up for very polar molecules in very non-polar solvents. PMID- 27460059 TI - Side chain flexibility and the pore dimensions in the GABAA receptor. AB - Permeation of ions through open channels and their accessibility to pore targeting drugs depend on the pore cross-sectional dimensions, which are known only for static X-ray and cryo-EM structures. Here, we have built homology models of the closed, open and desensitized alpha1beta2gamma2 GABAA receptor (GABAAR). The models are based, respectively, on the X-ray structure of alpha3 glycine receptor (alpha3 GlyR), cryo-EM structure of alpha1 GlyR and X-ray structure of beta3 GABAAR. We employed Monte Carlo energy minimizations to explore how the pore lumen may increase due to repulsions of flexible side chains from a variable diameter electroneutral atom (an expanding sphere) pulled through the pore. The expanding sphere computations predicted that the pore diameter averaged along the permeation pathway is larger by approximately 3 A than that computed for the models with fixed sidechains. Our models predict three major pore constrictions located at the levels of -2', 9' and 20' residues. Residues around the -2' and 9' rings are known to form the desensitization and activation gates of GABAAR. Our computations predict that the 20' ring may also serve as GABAAR gate whose physiological role is unclear. The side chain flexibility of residues -2', 9' and 20' and hence the dimensions of the constrictions depend on the GABAAR functional state. PMID- 27460060 TI - All-atom/coarse-grained hybrid predictions of distribution coefficients in SAMPL5. AB - We present blind predictions submitted to the SAMPL5 challenge on calculating distribution coefficients. The predictions were based on estimating the solvation free energies in water and cyclohexane of the 53 compounds in the challenge. These free energies were computed using alchemical free energy simulations based on a hybrid all-atom/coarse-grained model. The compounds were treated with the general Amber force field, whereas the solvent molecules were treated with the Elba coarse-grained model. Considering the simplicity of the solvent model and that we approximate the distribution coefficient with the partition coefficient of the neutral species, the predictions are of good accuracy. The correlation coefficient, R is 0.64, 82 % of the predictions have the correct sign and the mean absolute deviation is 1.8 log units. This is on a par with or better than the other simulation-based predictions in the challenge. We present an analysis of the deviations to experiments and compare the predictions to another submission that used all-atom solvent. PMID- 27460061 TI - Molecular and Statistical Analysis of Campylobacter spp. and Antimicrobial Resistant Campylobacter Carriage in Wildlife and Livestock from Ontario Farms. AB - The objectives of this study were to (i) compare the carriage of Campylobacter and antimicrobial-resistant Campylobacter among livestock and mammalian wildlife on Ontario farms, and (ii) investigate the potential sharing of Campylobacter subtypes between livestock and wildlife. Using data collected from a cross sectional study of 25 farms in 2010, we assessed associations, using mixed logistic regression models, between Campylobacter and antimicrobial-resistant Campylobacter carriage and the following explanatory variables: animal species (beef, dairy, swine, raccoon, other), farm type (swine, beef, dairy), type of sample (livestock or wildlife) and Campylobacter species (jejuni, coli, other). Models included a random effect to account for clustering by farm where samples were collected. Samples were subtyped using a Campylobacter-specific 40 gene comparative fingerprinting assay. A total of 92 livestock and 107 wildlife faecal samples were collected, and 72% and 27% tested positive for Campylobacter, respectively. Pooled faecal samples from livestock were significantly more likely to test positive for Campylobacter than wildlife samples. Relative to dairy cattle, pig samples were at significantly increased odds of testing positive for Campylobacter. The odds of isolating Campylobacter jejuni from beef cattle samples were significantly greater compared to dairy cattle and raccoon samples. Fifty unique subtypes of Campylobacter were identified, and only one subtype was found in both wildlife and livestock samples. Livestock Campylobacter isolates were significantly more likely to exhibit antimicrobial resistance (AMR) compared to wildlife Campylobacter isolates. Campylobacter jejuni was more likely to exhibit AMR when compared to C. coli. However, C. jejuni isolates were only resistant to tetracycline, and C. coli isolates exhibited multidrug resistance patterns. Based on differences in prevalence of Campylobacter spp. and resistant Campylobacter between livestock and wildlife samples, and the lack of similarity in molecular subtypes and AMR patterns, we concluded that the sharing of Campylobacter species between livestock and mammalian wildlife was uncommon. PMID- 27460062 TI - Pneumothorax as a Complication of Apnea Testing for Brain Death. AB - BACKGROUND: Pneumothorax is an under-recognized complication of apnea testing performed as part of the neurological determination of death. It may result in hemodynamic instability or even cardiac arrest, compromising ability to declare brain death (BD) and viability of organs for transplantation. We report three cases of pneumothorax with apnea testing (PAT) and review the available literature of this phenomenon. METHODS: Series of three cases supplemented with a systematic review of literature (including discussion of apnea testing in major brain death guidelines). RESULTS: Two patients were diagnosed with PAT due to immediate hemodynamic compromise, while the third was diagnosed many hours after BD. An additional nine cases of PAT were found in the literature. Information regarding oxygen cannula diameter was available for nine patients (range 2.3-5.3 mm), and flow rate was available for ten patients (mean 11 L/min). Pneumothorax was treated to resolution in the majority of patients (n = 8), although only six completed apnea testing following diagnosis/treatment of pneumothorax and only three patients became organ donors afterward. Review of major BD guidelines showed that although use of low oxygen flow rate (usually <= 6 L/min) during apnea testing is suggested, the risk of PAT was explicitly mentioned in just one. CONCLUSION: Development of PAT may adversely affect the process of BD determination and could limit the opportunity for organ donation. Each institution should have preventive measures in place. PMID- 27460063 TI - Development of a validated UPLC-MS/MS method for PK/PD analysis of SYL930 and its two major metabolites in dogs. AB - A sensitive and specific UPLC-MS/MS method was developed and validated for the simultaneous determination of 2-amino-2-(2-(4'-(2-propyloxazol-4-yl)-[1,1' biphenyl]-4-yl)ethyl)propane-1,3-diol (SYL930), phosphorylated metabolite (SYL930 P) and hydroxylated metabolite (SYL930-M) in dog blood using SYL927 and SYL927-P, analogues of SYL930, as the internal standards. Analytes were extracted with protein precipitation followed by chromatographic separation on a ZorbaxSB-C18 column (3.5 MUm, 2.1 * 100 mm) with a gradient elution of methanol-water containing 0.1% formic acid (v/v). A triple quadrupole tandem mass spectrometer operating in the positive electrospray ionization mode was used to detect SYL930, SYL930-P, SYL930-M and IS transitions of 381.2 -> 364.2, 461.2 -> 334.2, 397.3 -> 380.3, 367.1 -> 350.4 and 447.5 -> 320.2, respectively. The linear calibration curves for SYL930, SYL930-P and SYL930-M were 0.5-500, 0.2-100 and 0.5-100 ng/mL, respectively (r2 > 0.99). The intra-day and inter-day precisions (RSD, %) of analytes did not exceed 9.16% except for low QCs (<=16.22%), and the accuracy (RE, %) ranged from -14 to 11.4%. The mean recoveries for SYL930, SYL930-P and SYL930-M in dog blood were 85.13-107.94, 73.84-80.08 and 85.64-95.44%, respectively. The validated method was successfully applied to pharmacokinetic and PK/PD studies of SYL930 and its two major metabolites in dogs after an oral administration of SYL930. PMID- 27460064 TI - Concepts in glioma immunotherapy. AB - Immunotherapeutic concepts in neurooncology have been developed for many decades but have mainly been hampered by poor definition of relevant antigens and selective measures to target the central nervous system. Independent of the recent remarkable successes in clinical immunooncology with checkpoint inhibitors and vaccines, immunotherapy of brain tumors in general and gliomas in particular has evolved with novel neurooncology-specific concepts over the past years providing new phase 1 approaches of individualized immunotherapy to first phase three clinical trials. These concepts are driven by a high medical need in the absence of approved targeted therapies and refute the classic dogma that the central nervous system is immune-privileged and hence inaccessible to potent antitumor immunity. Instead, measures have been taken to improve the odds for successful immunotherapies, including rational targeting of relevant antigens and integration of immunotherapies into standard of care primary radiochemotherapy to increase the efficacy of antitumor immunity in a meaningful time window. This review highlights concepts and challenges associated with epitope discovery and selection and trial design. PMID- 27460065 TI - Development of a rapid stepping test to challenge rapid weight-shifting function in older adults. AB - BACKGROUND: The ability to step rapidly, shift weight from side-to-side, and maintain temporal rhythmicity are important functional elements for walking independently and preventing falls in seniors. AIMS: The purpose of this study was to develop a clinically feasible test of rapid stepping performance that challenges the ability to step rapidly, shift weight from side-to-side, and maintain temporal rhythmicity. METHODS: Participants were a volunteer sample of healthy, self-ambulating older adults aged 70-98 years. A Repeated Alternating Stair Touch Test was developed, which involved rapidly shifting weight in the medial-lateral direction by tapping each foot alternately onto a step. Performance on the test was assessed using trunk acceleration signals. Associations between the number of steps completed on the Repeated Alternating Stair Touch Test in 20 s and acceleration magnitude, variability, and stepping rhythmicity were assessed using Pearson correlations and linear regression. Repeatability was assessed during a 2-week follow-up period. RESULTS: The acceleration magnitude, variability, and stepping rhythmicity variables related moderately with the number of steps on the Repeated Alternating Stair Touch Test (r = 0.534-0.572, p < 0.05) and were independent predictors of the number of steps taken (R 2 adj. = 0.624, p < 0.001). Repeatability was mixed, though most acceleration variables and number of steps had moderate to high correlations between sessions (intraclass correlations: 0.486-0.828), but a learning effect was evident; performance improved between sessions. CONCLUSION: The Repeated Alternating Stair Touch Test has potential as a simple test of rapid, rhythmic weight-shifting function, but requires modification to improve repeatability. PMID- 27460066 TI - Intensive Glycemic Therapy in Patients With Type 2 Diabetes on beta-Blockers. AB - OBJECTIVE: Recent studies have suggested that beta-blockers may decrease the adverse influence of hypoglycemia and reduce hypoglycemia-associated cardiac arrhythmias and death. We evaluated whether intensive glycemic therapy in patients with diabetes receiving treatment with beta-blockers showed beneficial effects for the prevention of cardiovascular events without increased mortality compared with a standard glycemic therapy. RESEARCH DESIGN AND METHODS: We used Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial data to assess the risks of cardiovascular events, all-cause death, and cardiovascular death in patients with diabetes receiving treatment with beta-blockers (n = 3,079) and not receiving treatment with beta-blockers (n = 7,145) using Cox proportional hazard models. RESULTS: In patients receiving treatment with beta-blockers, the cumulative event rates for cardiovascular events were significantly lower in the intensive therapy group compared with the standard therapy group (hazard ratio [HR] 0.81; 95% CI 0.67-0.97; P = 0.02), whereas those rates in patients not receiving treatment with beta-blockers were not significantly different (HR 0.92; 95% CI 0.78-1.09; P = 0.36). Conversely, the cumulative event rates for all-cause and cardiovascular deaths in patients receiving treatment with beta-blockers were not significantly different between the standard therapy and intensive therapy groups (all-cause death: HR 1.08; 95% CI 0.83-1.42; P = 0.54; cardiovascular death: HR 1.05; 95% CI 0.72-1.51; P = 0.79), whereas in patients not receiving treatment with beta-blockers, the event rates were significantly higher in the intensive therapy group compared with the standard therapy group (all-cause death: HR 1.25; 95% CI 1.02-1.52; P = 0.02; cardiovascular death: HR 1.43; 95% CI 1.03-1.98; P = 0.03). CONCLUSIONS: Intensive glycemic therapy may be effective in patients with type 2 diabetes receiving treatment with beta-blockers. PMID- 27460067 TI - Kate Granger. PMID- 27460068 TI - Localization and identification of crustacean hyperglycemic hormone producing neurosecretory cells in the eyestalk of blue swimmer crab, Portunus pelagicus. AB - This study intensely focuses on to the localization and identification of crustacean hyperglycemic hormone (CHH) producing neurosecretory cells in the eyestalk of the blue swimmer crab Portunus pelagicus. Anti-Carcinus maenas-CHH was used to identify the location of CHH neurosecretory cells by immunohistochemistry. Ten pairs of eyestalks were collected from intact adult intermoult female crab and fixed in Bouin's fixative. Eyestalks were serially sectioned and stained with chrome-hematoxylin-phloxine stain. Histological studies show the presence of different types of neurosecretory cells namely A (multipolar), B (tripolar), C (bipolar), D (unipolar), E (oval), and F (spherical) in the medulla interna, externa, and terminalis regions based on their size, shape, and tinctorial properties. The neurohemal organ, sinus gland (SG) was observed laterally between medulla interna and terminalis regions. Immunohistochemical studies showed the presence of distinct CHH-like immunoreactivity in the optic ganglia. Divergent group of neurosecretory cells with varying degree of immunoreactivity with Anti-Carcinus maenas-CHH (low, moderate, and intense reactivity) were identified in medulla terminalis, medulla interna, medulla externa, and sinus gland. The present study maps the various types of neurosecretory cells in the optic ganglia and also shows the presence of CHH-like immunoreactivity in various regions of optic ganglia in P. pelagicus. The presence of these unique neurosecretory cell types with larger cell diameter in medulla terminalis, a region that bears the neurosecretory cell bodies, suggest high secretory activity. PMID- 27460069 TI - Influence of Structural Features on the Cellular Uptake Behavior of Non-Targeted Polyester-Based Nanocarriers. AB - The development of delivery systems efficiently uptaken by cells is of due importance since sites of drug action are generally localized in subcellular compartments. Herein, naked and core-shell polymeric nanoparticles (NPs) have been produced from poly(lactic-co-glycolic acid)-PLGA, poly(ethylene oxide)-b poly(epsilon-caprolactone)-PEO-b-PCL, and poly(ethylene oxide)-b-poly(lactic acid)-PEO-b-PLA. The nanostructures are characterized and the cellular uptake behavior is evaluated. The data evidence that cellular uptake is enhanced as the length of the hydrophilic PEO-stabilizing shell reduces and that high negative surface charge restricts cellular uptake. Furthermore, NPs of higher degree of hydrophobicity (PEO-b-PCL) are more efficiently internalized as compared to PEO-b PLA NPs. Accordingly, taking into account our recent published results and the findings of the current investigation, there should be a compromise regarding protein fouling and cellular uptake as resistance to nonspecific protein adsorption and enhanced cellular uptake are respectively directly and inversely related to the length of the PEO-stabilizing shell. PMID- 27460070 TI - Toward a hybrid brain-computer interface based on repetitive visual stimuli with missing events. AB - BACKGROUND: Steady-state visually evoked potentials (SSVEPs) can be elicited by repetitive stimuli and extracted in the frequency domain with satisfied performance. However, the temporal information of such stimulus is often ignored. In this study, we utilized repetitive visual stimuli with missing events to present a novel hybrid BCI paradigm based on SSVEP and omitted stimulus potential (OSP). METHODS: Four discs flickering from black to white with missing flickers served as visual stimulators to simultaneously elicit subject's SSVEPs and OSPs. Key parameters in the new paradigm, including flicker frequency, optimal electrodes, missing flicker duration and intervals of missing events were qualitatively discussed with offline data. Two omitted flicker patterns including missing black/white disc were proposed and compared. Averaging times were optimized with Information Transfer Rate (ITR) in online experiments, where SSVEPs and OSPs were identified using Canonical Correlation Analysis in the frequency domain and Support Vector Machine (SVM)-Bayes fusion in the time domain, respectively. RESULTS AND CONCLUSIONS: The online accuracy and ITR (mean +/- standard deviation) over nine healthy subjects were 79.29 +/- 18.14 % and 19.45 +/- 11.99 bits/min with missing black disc pattern, and 86.82 +/- 12.91 % and 24.06 +/- 10.95 bits/min with missing white disc pattern, respectively. The proposed BCI paradigm, for the first time, demonstrated that SSVEPs and OSPs can be simultaneously elicited in single visual stimulus pattern and recognized in real-time with satisfied performance. Besides the frequency features such as SSVEP elicited by repetitive stimuli, we found a new feature (OSP) in the time domain to design a novel hybrid BCI paradigm by adding missing events in repetitive stimuli. PMID- 27460071 TI - Automatic weighing attribute to retrieve similar lung cancer nodules. AB - BACKGROUND: Cancer is a disease characterized as an uncontrolled growth of abnormal cells that invades neighboring tissues and destroys them. Lung cancer is the primary cause of cancer-related deaths in the world, and it diagnosis is a complex task for specialists and it presents some big challenges as medical image interpretation process, pulmonary nodule detection and classification. In order to aid specialists in the early diagnosis of lung cancer, computer assistance must be integrated in the imaging interpretation and pulmonary nodule classification processes. Methods of Content-Based Image Retrieval (CBIR) have been described as one promising technique to computer-aided diagnosis and is expected to aid radiologists on image interpretation with a second opinion. However, CBIR presents some limitations: image feature extraction process and appropriate similarity measure. The efficiency of CBIR systems depends on calculating image features that may be relevant to the case similarity analysis. When specialists classify a nodule, they are supported by information from exams, images, etc. But each information has more or less weight over decision making about nodule malignancy. Thus, finding a way to measure the weight allows improvement of image retrieval process through the assignment of higher weights to that attributes that best characterize the nodules. METHODS: In this context, the aim of this work is to present a method to automatically calculate attribute weights based on local learning to reflect the interpretation on image retrieval process. The process consists of two stages that are performed sequentially and cyclically: Evaluation Stage and Training Stage. At each iteration the weights are adjusted according to retrieved nodules. After some iterations, it is possible reach a set of attribute weights that optimize the recovery of similar nodes. RESULTS: The results achieved by updated weights were promising because was possible increase precision by 10% to 6% on average to retrieve of benign and malignant nodules, respectively, with recall of 25% compared with tests without weights associated to attributes in similarity metric. The best result, we reaching values over 100% of precision average until thirtieth lung cancer nodule retrieved. CONCLUSIONS: Based on the results, WED applied to the three vectors used attributes (3D TA, 3D MSA and InV), with weights adjusted by the process, always achieved better results than those found with ED. With the weights, the Precision was increased on average by 17.3% compared with using ED. PMID- 27460072 TI - The Relationship Between Family Caregiving and the Mental Health of Emerging Young Adult Caregivers. AB - Caring for dependent relatives has become a normative challenge for families in the USA and throughout the world. The study objective was to examine the relationship of family caregiving responsibilities and the mental health and well being of individuals, ages 18-24 years, referred to as emerging young adults. It was hypothesized that young adult caregivers with past and present responsibilities would report significantly more symptoms of depression and anxiety, have lower self-esteem, and use less adaptive coping styles than non caregiving peers. The sample consisted of 353 undergraduates (81 past caregivers, 76 current/past caregivers, and 196 non-caregivers). Caregivers were also evaluated in terms of care recipients, duration of caregiving, tasks, and hours of effort. Caregivers had significantly higher levels of symptoms of depression and anxiety than non-caregivers. Research to clarify how caregiving interacts with other stressors in emerging young adults and influences behavioral health should be a priority. PMID- 27460073 TI - Long-term quality of life, satisfaction, pelvic floor symptoms and regret after colpocleisis. AB - PURPOSE: The aim of this study is to present long-term results including patients' satisfaction, pelvic floor symptoms, regret and change in body image in a long-term follow-up after colpocleisis. METHODS: All women who underwent colpocleisis between September 2001 and February 2014 were identified from the hospital operating lists. These women were contacted for a telephone survey up to 13 years after surgery and asked to complete a structured questionnaire to assess patients' satisfaction, Quality of Life (QoL) and pelvic floor symptoms. RESULTS: A total of 44 women underwent colpocleisis during the period from September 2001 to February 2014. Mean age was 78 years (range 65-91) years. Mean follow-up time was 41 months (range 10-120). Twenty women could be reached for the survey and were included in the analysis. 15 (75 %) reported a positive impact on QoL, 2 (10 %) a negative because of urinary problems, 2 (10 %) could not report any change in the QoL and 1 (5 %) could not answer this question. There was no recurrence of prolapse. The majority of patients (90 %) would undergo the same surgery again and no patient regretted the loss of her vaginal sexual function. CONCLUSIONS: Colpocleisis seems to be an effective treatment for pelvic organ prolapse. In the long term, impact on quality of life is positive, whilst urinary tract symptoms seem to be the most bothersome factor. PMID- 27460074 TI - IRES inhibition induces terminal differentiation and synchronized death in triple negative breast cancer and glioblastoma cells. AB - Internal ribosome entry site (IRES)-mediated translation is a specialized mode of protein synthesis which malignant cells depend on to survive adverse microenvironmental conditions. Our lab recently reported the identification of a group of compounds which selectively interfere with IRES-mediated translation, completely blocking de novo IGF1R synthesis, and differentially modulating synthesis of the two c-Myc isoforms. Here, we examine the phenotypic consequences of sustained IRES inhibition in human triple-negative breast carcinoma and glioblastoma cells. A sudden loss of viability affects the entire tumor cell population after ~72-h continuous exposure to the lead compound. The extraordinarily steep dose-response relationship (Hill-Slope coefficients -15 to 35) and extensive physical connections established between the cells indicate that the cells respond to IRES inhibition collectively as a population rather than as individual cells. Prior to death, the treated cells exhibit prominent features of terminal differentiation, with marked gains in cytoskeletal organization, planar polarity, and formation of tight junctions or neuronal processes. In addition to IGF1R and Myc, specific changes in connexin 43, BiP, CHOP, p21, and p27 also correlate with phenotypic outcome. This unusual mode of tumor cell death is absolutely dependent on exceeding a critical threshold in cell density, suggesting that a quorum-sensing mechanism may be operative. Death of putative tumor stem cells visualized in situ helps to explain the inability of tumor cells to recover and repopulate once the compound is removed. Together, these findings support the concept that IRES-mediated translation is of fundamental importance to maintenance of the undifferentiated phenotype and survival of undifferentiated malignant cells. PMID- 27460075 TI - Identification of a five-lncRNA signature for the diagnosis and prognosis of gastric cancer. AB - Gastric cancer (GC) is one of the most aggressive malignancies and has a poor prognosis. Identifying novel diagnostic and prognostic markers is of great importance for the management and treatment of GC. Long non-coding RNAs (lncRNAs), which are involved in multiple processes during the development and progression of cancer, may act as potential biomarkers of GC. Here, by performing data mining using four microarray data sets of GC downloaded from the Gene Expression Omnibus (GEO) database with different classifiers and risk score analyses, we identified a five-lncRNA signature (AK001094, AK024171, AK093735, BC003519 and NR_003573) displaying both diagnostic and prognostic values for GC. The results of the Kaplan-Meier survival analysis and log-rank test showed that the risk score based on this five-lncRNA signature was closely associated with overall survival time (p = 0.0001). Further analysis revealed that the risk score is an independent predictor of prognosis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of 30 pairs of GC tissue samples confirmed that the five lncRNAs were dysregulated in GC, and receiver operating characteristic (ROC) curves showed the high diagnostic ability of combining the five lncRNAs, with an area under the curve (AUC) of 0.95 +/- 0.025. The five lncRNAs involved in several cancer-related pathways were identified using gene set enrichment analysis (GSEA). These findings indicate that the five-lncRNA signature may have a good clinical applicability for determining the diagnosis and predicting the prognosis of GC. PMID- 27460076 TI - The inflammatory microenvironment in epithelial ovarian cancer: a role for TLR4 and MyD88 and related proteins. AB - The tumor-associated inflammatory microenvironment may play a pivotal role in epithelial ovarian cancer (EOC) carcinogenesis and outcomes, but a detailed profile in patient-derived tumors is needed. Here, we investigated the expression of TLR4- and MyD88-associated markers in tumors from over 500 EOC patients using immunohistochemical staining. We demonstrate that high expression of TLR4 and MyD88 predicts poorer overall survival in patients with EOC; most likely, this is due to their association with serous histology and features of high tumor burden and aggressiveness, including stage, grade, and ascites at surgery. Combined TLR4 and MyD88 expression appears to serve as an independent risk factor for shortened survival time, even after covariate adjustment (both moderate HR 1.1 [95 % CI 0.7 1.8], both strong HR 2.1 [95 % CI 1.1-3.8], both weak as referent; p = 0.027). We reveal that in EOC tissues with elevated expression of both TLR4 and MyD88 and activated NF-kappaB signaling pathway, expression of hsp60, hsp70, beta 2 defensin, and HMGB1 are also enriched. In total, these results suggest that activation of TLR4/MyD88/NF-kappaB signaling by endogenous ligands may contribute to an inflammatory microenvironment that drives a more aggressive phenotype with poorer clinical outcome in EOC patients. PMID- 27460077 TI - miR-326 reverses chemoresistance in human lung adenocarcinoma cells by targeting specificity protein 1. AB - Cisplatin resistance is a major obstacle in the treatment of lung adenocarcinoma (LAD), and its mechanism has not been fully elucidated. Here, we report that miR 326 is downregulated in cisplatin-resistant A549/CDDP cells compared with parental A549 cells. Overexpression of miR-326 reversed cisplatin chemoresistance of LAD cells in vitro and in vivo. Moreover, we identified the specificity protein 1 (SP1) gene as a novel direct target of miR-326. Knockdown of SP1 revealed similar effects as that of ectopic miR-326 expression. Decreased miR-326 expression was also detected in tumor tissues sampled from LAD patients treated with cisplatin-based chemotherapy and was proved to be correlated with high expression of SP1 and decreased sensitivity to cisplatin. Furthermore, we show that the long noncoding RNA HOTAIR repression reverses chemoresistance of LAD cells partially through modulation of miR-326/SP1 pathway. In summary, we unveil a branch of the HOTAIR/miR-326/SP1 pathway that regulates chemoresistance of LAD cells. PMID- 27460078 TI - VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway. AB - We previously developed (2-deoxyglucose)-(ABT-263) combination therapy (2DG-ABT), which induces apoptosis by activating Bak in the mitochondria of highly glycolytic cells with varied genetic backgrounds. However, the rates of apoptosis induced by 2DG-ABT were lower in von Hippel-Lindau (VHL)-deficient cancer cells. The re-expression of VHL protein in these cells lowered IGF1R expression in a manner independent of oxygen concentration. Lowering IGF1R expression via small interfering RNA (siRNA) sensitized the cells to 2DG-ABT, suggesting that IGF1R interfered with the activation of apoptosis by the mitochondria. To determine which of the two pathways activated by IGF1R, the Ras-ERK pathway or the PI3K-AKT pathway, was involved in the impairment of mitochondria activation, the cells were treated with a specific inhibitor of either PI3K or ERK, and 2DG-ABT was added to activate the mitochondria. The apoptotic rates resulting from 2DG-ABT treatment were higher in the cells treated with the PI3K inhibitor, while the rates remained approximately the same in the cells treated with the ERK inhibitor. In 2DG-ABT-sensitive cells, a 4-h 2DG treatment caused the dissociation of Mcl-1 from Bak, while ABT treatment alone caused the dissociation of Bcl-xL from Bak without substantially reducing Mcl-1 levels. In 2DG-ABT resistant cells, Mcl-1 dissociated from Bak only when AKT activity was inhibited during the 4-h 2DG treatment. Thus, in VHL-deficient cells, IGF1R activated AKT and stabilized the Bak-Mcl-1 complex, thereby conferring cell resistance to apoptosis. PMID- 27460079 TI - Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression. AB - During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment (TM) that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention. Graphical abstract Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment (TM), and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic cytomorphological variations, alterations in expression patterns of adhesion markers, redox homeostasis, and metabolic reprogramming that supports epithelial to mesenchymal transition and cancer progression. PMID- 27460080 TI - Systemic transcriptome analysis of hepatocellular carcinoma. AB - Liver cancer is one of the most common malignant tumors, and most of which is hepatocellular carcinoma (HCC). We aim to study the characteristic changes of numerous genes and their roles in HCC through systematical analysis of the characteristics of expression spectrum of HCC. Firstly, we made systematic clustering of the HCC samples according to the RNAseq data from TCGA (The Cancer Genome Atlas) and newly classified HCC. Then the characteristic genes in different molecular subtypes were found out and further analyzed combing with methylation and SNP 6.0 chip. Finally, these genes were subjected to do functional annotation and abnormal signaling pathways of HCC in various molecular subtypes and were screened out. There were 3843 differential genes screened; among which, 689 genes were enriched into 13 KEGG-related pathways, and the expression of 27 and 924 genes showed positive and negative correlation to methylation level, respectively, while the expression of 43 genes showed positive correlation to variation level of copy number. The methylation degree of ZSCAN18 may be considered as a marker for prognosis evaluation, and ABHD6 could be a potential anti-oncogene. PMID- 27460081 TI - G protein pathway suppressor 2 (GPS2) acts as a tumor suppressor in liposarcoma. AB - Liposarcoma(LPS) is the most common type of soft tissue sarcoma accounting for 20 % of all adult sarcomas. However, the molecular pathogenesis of this malignancy is still poorly understood. Here, we showed that GPS2 expression was downregulated in LPS and correlated with the prognosis of this disease. In vitro study showed that knockdown of GPS2 resulted in enhanced proliferation and migration of LPS cell line SW872, without significant influence of cell death. Conclusively, our results suggest that GPS2 may act as a tumor suppressor in LPS and serve as a potential prognosis marker for this disease. PMID- 27460082 TI - The anti-oncogenic influence of ellagic acid on colon cancer cells in leptin enriched microenvironment. AB - Ellagic acid (EA) has been proposed as a promising candidate for therapeutic use in colon cancer. Investigation of the effectiveness of EA in a leptin-enriched model might have been given a little interest. Here in, we investigated the anti tumor effect of EA in the presence of leptin to reflect on therapeutic use of EA in obesity-linked colon cancer. Proven effective in leptin-enriched microenvironment, EA inhibited cell proliferation of HCT-116 and CaCo-2 cell lines, modulated cell cycle, translocated Bax to the mitochondrial fraction of cells, activated caspase-8, and reduced PCNA expression. The current study findings cast a beam of light on the potential therapeutic use of EA in obesity related colon carcinogenesis. PMID- 27460083 TI - Neutral endopeptidase (NEP) is differentially involved in biological activities and cell signaling of colon cancer cell lines derived from various stages of tumor development. AB - The presented studies were aimed at exploring the role of neutral endopeptidase (NEP) in the function of colon cancer cell lines LS 180 and SW 620, derived from different grades and stages of tumor development. NEP silencing by siRNA resulted in decreased viability and proliferation accompanied by increased apoptosis in both cell lines. Additionally, cell cycle arrest at the G2/M phase was observed, but only in LS 180 cells. Opposite to these results, serum-stimulated migration was increased in both cell lines. Furthermore, NEP silencing influenced the invasive activity of LS 180 and SW 620 cells in an opposite manner: while LS 180 cells showed an enhanced invasiveness, SW 620 cells exerted a reduced activity. An exploration of the activity of signaling molecules responsible for the function of tumor cells-Akt, PTEN, and FAK-after NEP silencing indicated that the endopeptidase is involved in their regulation. The increased phosphorylation level of Akt was accompanied by a decrease in PTEN in the presence of a high concentration of serum. A reduced concentration of serum did not change the phosphorylation status of Akt. Enhanced autophosphorylation of FAK was observed in LS 180 and SW 620 cells cultivated in a medium with a high concentration of serum. Taken together, these results confirm that NEP is implicated in the regulation of the survival, growth, and motile activity of colon cancer. This is also the first report which shows that NEP mediates cancer cell migration and invasiveness, but not growth and survival, through Akt/FAK signaling pathways. PMID- 27460084 TI - Control of stress signaling in stem cells: crossroads of stem cells and cancer. AB - Tumorigenesis is a relatively rare event in the human body considering the enormous number of cells composing our body and the frequent occurrence of genetic mutations in each cell. Nevertheless, the cells that happen to meet the minimum requirements can be transformed when stressed by a variety of oncogenic stimulations, then progress to form tumors. The vigorous competition between oncogenic signaling and tumor-suppressor defense is a critical determinant of cellular fate, which can be either tumorigenic transformation or cellular senescence/apoptosis depending on "who wins the battle." Recently, a number of cancers have been reported to originate from stem cells, whose self-renewing properties are normally reduced by innate tumor suppressors. Therefore, exploring the innate mechanism by which stem cells modulate tumor suppressors to maintain their "stemness" may provide valuable clues to characterize the distinctive oncogenic susceptibility of stem cells. This review is focused on the recent advances in the field of tumorigenesis of stem cells and on the associated molecular mechanisms. PMID- 27460085 TI - Alternative splicing of S6K1 promotes non-small cell lung cancer survival. AB - Ribosomal S6 kinase 1 (S6K1) that acts downstream of the mammalian target of rapamycin (mTOR) plays an important role in cell proliferation, protein translation, and cell survival. The gene RPS6KB1 encoding for S6K1 had been found to be alternatively spliced to form different isoforms. In this study, we identified that short isoforms of S6K1 splice variant were overproduced in non small cell lung cancer (NSCLC). Moreover, suppression of S6K1 short isoforms inhibited NSCLC cell growth and induced apoptosis via upregulation of the BH3 only protein Bim in vitro and in vivo. Additionally, short isoforms of S6K1 activated mTORC1, leading to increased 4E-BP1 phosphorylation. Taken together, our findings suggested that S6K1 short isoforms were deregulated in NSCLC and promoted cell survival. Altogether, our study opens possibilities of new therapeutic approaches for NSCLC that selectively downregulate S6K1 shorter isoforms. PMID- 27460086 TI - Interleukin-6 receptor in spindle-shaped stromal cells, a prognostic determinant of early breast cancer. AB - Spindle-shaped stromal cells, like carcinoma-associated fibroblasts and mesenchymal stem cells, influence tumor behavior and can serve as parameters in the clinical diagnosis, therapy, and prognosis of early breast cancer. Therefore, the aim of this study is to explore the clinicopathological significance of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) receptors (Rs) 2 and 4 (TRAIL-R2 and R4), and interleukin-6 R (IL-6R) in spindle-shaped stromal cells, not associated with the vasculature, as prognostic determinants of early breast cancer patients. Receptors are able to trigger the migratory activity, among other functions, of these stromal cells. We conducted immunohistochemical analysis for the expression of these receptors in spindle-shaped stromal cells, not associated with the vasculature, of primary tumors from early invasive breast cancer patients, and analyzed their association with clinicopathological characteristics. Here, we demonstrate that the elevated levels of TRAIL-R2, TRAIL R4, and IL-6R in these stromal cells were significantly associated with a higher risk of metastatic occurrence (p = 0.034, 0.026, and 0.006; respectively). Moreover, high expression of TRAIL-R4 was associated with shorter disease-free survival and metastasis-free survival (p = 0.013 and 0.019; respectively). Also, high expression of IL-6R was associated with shorter disease-free survival, metastasis-free survival, and overall survival (p = 0.003, 0.001, and 0.003; respectively). Multivariate analysis showed that IL-6R expression was an independent prognostic factor for disease-free survival and metastasis-free survival (p = 0.035). This study is the first to demonstrate that high levels of IL-6R expression in spindle-shaped stromal cells, not associated with the vasculature, could be used to identify early breast cancer patients with poor outcomes. PMID- 27460088 TI - Overexpression of long non-coding RNA TUG1 predicts poor prognosis and promotes cancer cell proliferation and migration in high-grade muscle-invasive bladder cancer. AB - Long non-coding RNA TUG1 is involved in the development and progression of a variety of tumors. Little is known about TUG1 function in high-grade muscle invasive bladder cancer (MIBC). The aims of our study were to determine expression levels of long non-coding RNA TUG1 in tumor tissue, to evaluate its relationship with clinico-pathological features of high-grade MIBC, and to describe its function in MIBC cells in vitro. TUG1 expression levels were determined in paired tumor and adjacent non-tumor bladder tissues of 47 patients with high-grade MIBC using real-time PCR. Cell line T-24 and siRNA silencing were used to study the TUG1 function in vitro. We observed significantly increased levels of TUG1 in tumor tissue in comparison to adjacent non-tumor bladder tissue (P < 0.0001). TUG1 levels were significantly increased in metastatic tumors (P = 0.0147) and were associated with shorter overall survival of MIBC patients (P = 0.0241). TUG1 silencing in vitro led to 34 % decrease in cancer cell proliferation (P = 0.0004) and 23 % reduction in migration capacity of cancer cells (P < 0.0001). We did not observe any significant effects of TUG1 silencing on cell cycle distribution and number of apoptotic cells. Our study confirmed overexpression of TUG1 in MIBC tumor tissue and described its association with worse overall survival in high-grade MIBC patients. Together with in vitro observations, these data suggest an oncogenic role of TUG1 and its potential usage as biomarker or therapeutic target in MIBC. PMID- 27460087 TI - Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors. AB - Well-differentiated bronchial neuroendocrine tumors (B-NETs) are rare. They represent 1-5 % of all lung cancers. The incidence of these neoplasms has risen over the past 30 years and, especially for advanced or metastatic disease, management is complex and requires a multidisciplinary approach. Treatment with somatostatin analogs (SSAs) is the most important first-line therapy, in particular in well-differentiated NETs with high somatostatin type receptor (SSTR) expression. In these tumors, the role of mammalian target of rapamycin (m TOR) inhibitors and the potential utility of other target therapies remain unclear while chemotherapy represents the gold standard treatment only for aggressive forms with low SSTR expression. Peptide receptor radionuclide therapy (PRRT) is an emerging treatment modality for advanced NETs. There are many cumulative evidences about the effectiveness and tolerability of this therapeutic approach, especially in gastro-entero-pancreatic (GEP)-NETs. For B-NETs, scientific research is moving more slowly. Here, we performed a review in order to evaluate the efficacy and toxicity of PRRT with a focus on patients with inoperable or metastatic well-differentiated B-NETs. PMID- 27460089 TI - Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease. AB - The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 * per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML. PMID- 27460090 TI - Long noncoding RNA BCAR4 promotes osteosarcoma progression through activating GLI2-dependent gene transcription. AB - Despite great advances have been made in the understanding of biology of osteosarcoma, the molecular mechanisms involved in osteosarcoma tumorigenesis and progression are still largely unknown. Long noncoding RNA (lncRNA) is a new type of RNA molecule, which plays pivotal roles in many tumors. lncRNA BCAR4 has been identified as an oncogenetic lncRNA involved in the progression of breast cancer. However, the functions and clinical significances of BCAR4 in osteosarcoma are unknown now. In this study, we found that BCAR4 was significantly upregulated in osteosarcoma tissues. Increased expression of BCAR4 was significantly correlated with large tumor size, advanced Enneking stage, lung metastasis, and poor prognosis. Functional experiments demonstrated that knockdown of BCAR4 inhibits the proliferation and migration of osteosarcoma cell in vitro. Consistently, knockdown of BCAR4 inhibits osteosarcoma tumorigenesis and lung metastasis in vivo. Chromatin isolation by RNA purification assay showed that BCAR4 physically associates with the promoters of GLI2 target genes. The depletion of BCAR4 inhibits the expression of GLI2 target genes and GLI2 reporter luciferase activity in a dose-dependent manner. The expression of BCAR4 and GLI2 target genes is significantly correlated in osteosarcoma tissues. Depletion of DLI2 abolished the effects of BCAR4 on osteosarcoma. Taken together, these findings demonstrated that BCAR4 promotes osteosarcoma progression via activating GLI2 dependent gene transcription and serves as a potential prognostic biomarker and a therapeutic target of osteosarcoma. PMID- 27460091 TI - Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome. AB - DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST. PMID- 27460092 TI - Downregulation of CXCR7 inhibits proliferative capacity and stem cell-like properties in breast cancer stem cells. AB - Breast cancer stem cells (bCSCs) are considered an obstacle in breast cancer therapy because they exhibit long-term proliferative potential, phenotypic plasticity and high resistance to the current therapeutics. CXC chemokine receptor type 7 (CXCR7), which provides a growth advantage to breast cancer cells, has recently been demonstrated to play an important role in the maintenance of stem cell-like properties in the CSCs of glioblastoma and lung cancer, yet its role in bCSCs remains elusive. In this study, CD44+/CD24low bCSC enriched cells (bCSCs for short) were isolated from MCF-7 cells, and CXCR7 was stably knocked down in bCSCs via lentivirus-mediated transduction with CXCR7 short hairpin RNA (shRNA). Knockdown of CXCR7 in bCSCs decreased the proportion of CD44+/CD24low cells, and markedly reduced the clonogenicity of the cells. Moreover, silencing of CXCR7 downregulated the expression of stem cell markers, such as aldehyde dehydrogenase 1 (ALDH1), Oct4, and Nanog. In addition, CXCR7 silencing in bCSCs suppressed cell proliferation and G1/S transition in vitro, and delayed tumor growth in vivo in a xenograft mouse model. In situ immunohistochemical analysis revealed a reduction in Ki-67 expression and enhanced apoptosis in the xenograft tumors as a result of CXCR7 silencing. Furthermore, combined treatment with CXCR7 silencing and epirubicin displayed an outstanding anti-tumor effect compared with either single treatment. Our study demonstrates that CXCR7 plays a critical role in the maintenance of stem cell like properties and promotion of growth in bCSCs, and suggests that CXCR7 may be a candidate target for bCSCs in breast cancer therapy. PMID- 27460094 TI - HIV Serostatus Disclosure and Engagement in Medical Care Among Predominantly Low Income but Insured African American Adults with HIV. AB - More than half of persons living with HIV (PLWH) do not enter into or remain in continuous HIV medical care. Disclosure of HIV serostatus to social contacts may play an important role in successful engagement of PLWH with medical care. The effect of disclosure on medical care engagement was examined in a sample of African American PLWH (n = 262) recruited from community-based organizations as part of a peer community health worker initiative. At baseline assessment, many of the PLWH (46 %) reported they had not disclosed their serostatus to others. Engagement in medical care was assessed 45 and 90 days after enrollment. Participants who disclosed their HIV status were subsequently more likely to engage in HIV medical care (78 %) than persons who did not disclose their status (66 %), an effect that was confirmed in multiple logistic regression. The findings highlight disclosure as an important predictor of engagement in HIV medical care for PLWH. PMID- 27460095 TI - Inhibition of quorum-sensing-mediated biofilm formation in Cronobacter sakazakii strains. AB - The present study investigated plant extracts for their anti-quorum-sensing (QS) potential to inhibit the biofilm formation in Cronobacter sakazakii strains. The bioassay based on loss of pigment production by Chromobacterium violaceum 026 and Agrobacterium tumefaciens NTL4(pZLR4) was used for initial screening of the extracts. Further, the effect of extracts on the inhibition of QS-mediated biofilm in C. sakazakii isolates was evaluated using standard crystal violet assay. The effect on biofilm texture was studied using SYTO9 staining and light and scanning electron microscopy. Among the tested extracts, Piper nigrum and Cinnamomum verum at 100 ppm resulted in 78 and 68 % reduction in the production of violacein as well as blue-green colour in both biosensor strains. A higher inhibitory activity (>50 %) on biofilm formation in C. sakazakii was observed for Pip. nigrum and Cin. verum, whereas the other extracts possessed moderate (25-50 %) and minimal (<25 %) inhibitory activities. Further, the fluorescent and scanning electron microscopic images indicated a major disruption in the architecture of biofilms of tested strains by Pip. nigrum. This study points to the possibility of using Pip. nigrum and Cin. verum as inhibitor of QS-mediated biofilm formation by C. sakazakii that could be further explored for novel bioactive molecules to limit the emerging infections of C. sakazakii. PMID- 27460096 TI - Refrigerated storage of platelets initiates changes in platelet surface marker expression and localization of intracellular proteins. AB - BACKGROUND: Platelets (PLTs) are currently stored at room temperature (22 degrees C), which limits their shelf life, primarily due to the risk of bacterial growth. Alternatives to room temperature storage include PLT refrigeration (2-6 degrees C), which inhibits bacterial growth, thus potentially allowing an extension of shelf life. Additionally, refrigerated PLTs appear more hemostatically active than conventional PLTs, which may be beneficial in certain clinical situations. However, the mechanisms responsible for this hemostatic function are not well characterized. The aim of this study was to assess the protein profile of refrigerated PLTs in an effort to understand these functional consequences. STUDY DESIGN AND METHODS: Buffy coat PLTs were pooled, split, and stored either at room temperature (20-24 degrees C) or under refrigerated (2-6 degrees C) conditions (n = 8 in each group). PLTs were assessed for changes in external receptor expression and actin filamentation using flow cytometry. Intracellular proteomic changes were assessed using two-dimensional gel electrophoresis and Western blotting. RESULTS: PLT refrigeration significantly reduced the abundance of glycoproteins (GPIb, GPIX, GPIIb, and GPIV) on the external membrane. However, refrigeration resulted in the increased expression of high-affinity integrins (alphaIIbbeta3 and beta1) and activation and apoptosis markers (CD62P, CD63, and phosphatidylserine). PLT refrigeration substantially altered the abundance and localization of several cytoskeletal proteins and resulted in an increase in actin filamentation, as measured by phalloidin staining. CONCLUSION: Refrigerated storage of PLTs induces significant changes in the expression and localization of both surface-expressed and intracellular proteins. Understanding these proteomic changes may help to identify the mechanisms resulting in the refrigeration associated alterations in PLT function and clearance. PMID- 27460097 TI - Associations between microvascular function and short-term exposure to traffic related air pollution and particulate matter oxidative potential. AB - BACKGROUND: Short-term exposure to ambient air pollution has been associated with acute increases in cardiovascular hospitalization and mortality. However, causative chemical components and underlying pathophysiological mechanisms remain to be clarified. We hypothesized that endothelial dysfunction would be associated with mobile-source (traffic) air pollution and that pollutant components with higher oxidative potential to generate reactive oxygen species (ROS) would have stronger associations. METHODS: We carried out a cohort panel study in 93 elderly non-smoking adults living in the Los Angeles metropolitan area, during July 2012 February 2014. Microvascular function, represented by reactive hyperemia index (RHI), was measured weekly for up to 12 weeks (N = 845). Air pollutant data included daily data from regional air-monitoring stations, five-day average PM chemical components and oxidative potential in three PM size-fractions, and weekly personal nitrogen oxides (NOx). Linear mixed-effect models estimated adjusted changes in microvascular function with exposure. RESULTS: RHI was inversely associated with traffic-related pollutants such as ambient PM2.5 black carbon (BC), NOx, and carbon monoxide (CO). An interquartile range change increase (1.06 MUg/m(3)) in 5-day average BC was associated with decreased RHI, 0.093 (95 % CI: -0.151, -0.035). RHI was inversely associated with other mobile source components/tracers (polycyclic aromatic hydrocarbons, elemental carbon, and hopanes), and PM oxidative potential as quantified in two independent assays (dithiothreitol and in vitro macrophage ROS) in accumulation and ultrafine PM, and transition metals. CONCLUSIONS: Our findings suggest that short-term exposures to traffic-related air pollutants with high oxidative potential are major components contributing to microvascular dysfunction. PMID- 27460098 TI - Surveying the citizen science landscape: an exploration of the design, delivery and impact of citizen science through the lens of the Open Air Laboratories (OPAL) programme. AB - BACKGROUND: This paper provides a short introduction to the topic of citizen science (CS) identifying the shift from the knowledge deficit model to more inclusive, participatory science. It acknowledges the benefits of new technology and the opportunities it brings for mass participation and data manipulation. It focuses on the increase in interest in CS in recent years and draws on experience gained from the Open Air Laboratories (OPAL) programme launched in England in 2007. METHODS: The drivers and objectives for OPAL are presented together with background information on the partnership, methods and scales. The approaches used by researchers ranged from direct public participation in mass data collection through field surveys to research with minimal public engagement. The supporting services focused on education, particularly to support participants new to science, a media strategy and data services. RESULTS: Examples from OPAL are used to illustrate the different approaches to the design and delivery of CS that have emerged over recent years and the breadth of opportunities for public participation the current landscape provides. Qualitative and quantitative data from OPAL are used as evidence of the impact of CS. CONCLUSION: While OPAL was conceived ahead of the more recent formalisation of approaches to the design, delivery and analysis of CS projects and their impact, it nevertheless provides a range of examples against which to assess the various benefits and challenges emerging in this fast developing field. PMID- 27460099 TI - Novel and highly sensitive immunoassay for total hepatitis B surface antigen, including that complexed with hepatitis B surface antibody. AB - BACKGROUND: Hepatitis B surface antigen (HBsAg) is used as a clinical marker of hepatitis B virus (HBV) infection. However, conventional HBsAg assays have so far failed to accurately detect HBsAg in blood because of interference by patient derived antibodies against HBsAg (HBsAb). METHODS: We developed a novel, fully automated assay system that can detect total HBsAg in blood, including antigens complexed with HBsAb. The immunoassay inactivates HBsAb via a simple pretreatment step to dissociate the HBsAg molecule from HBsAg-HBsAb complexes and thereby estimate total HBsAg. Accordingly, the test has been termed the "immunoassay for total antigen including complex via pretreatment (iTACT)-HBsAg." RESULTS: The recovery rate of HBsAg in the presence of HBsAb was greater than 87 % at a cutoff value set at 5.0 mIU/mL on the basis of data from 545 healthy controls. Analyses using serial serum samples from 25 HBV carriers who became negative for HBsAg during follow-up showed that the iTACT-HBsAg could detect HBsAg over a period of years despite a loss in detection by conventional assays and was able to detect HBsAg in 39 (53 %) of 73 samples with HBsAb. CONCLUSIONS: The new iTACT-HBsAg assay appears to detect total HBsAg with high sensitivity, even in the presence of HBsAb, and may useful in identifying subclinical or occult HBV carriers. PMID- 27460101 TI - Impact of High-Flow Nasal Cannula Use on Neonatal Respiratory Support Patterns and Length of Stay. AB - BACKGROUND: Heated humidified high-flow nasal cannula (HFNC) is thought to be comparable with nasal CPAP. The effect of multimodality mid-level respiratory support use in the neonatal ICU is unknown. The objective of this work was to evaluate the effect of introducing HFNC on length of respiratory support and stay. METHODS: A chart review was conducted on subjects at 24-32 weeks gestation requiring mid-level support (HFNC/nasal CPAP) 1 y before and after HFNC implementation. The 2 groups were compared for clinical and demographic data using t test or chi-square analysis. Further, multivariate linear and logistic regression was done to determine significant risk factors for outcomes controlling for covariates. RESULTS: Eighty subjects were eligible in the pre HFNC group, and 83 were eligible in the post-HFNC group. Subjects were similar in their baseline characteristics. In clinical outcomes, the post-HFNC group had higher rates of retinopathy of prematurity (P = .02) and a trend toward higher bronchopulmonary dysplasia rates (P = .063). The post-HFNC subjects had longer duration of mid-level support and were older at the time they were weaned to stable low-flow nasal cannula (P < .05). Although the length of respiratory support and stay and corrected gestational age at discharge were similar, those in the pre-HFNC period were more likely to be receiving full oral feeds and be discharged home versus being transferred to an intermediate care facility (P < .05). CONCLUSIONS: HFNC introduction was significantly associated with a longer duration of mid-level respiratory support, decrease in oral feeding at discharge, increased retinopathy of prematurity rates, and higher use of intermediate care facilities, leading us to examine our noninvasive ventilation and weaning strategies. PMID- 27460100 TI - Comparison of sequential therapy and amoxicillin/tetracycline containing bismuth quadruple therapy for the first-line eradication of Helicobacter pylori: a prospective, multi-center, randomized clinical trial. AB - BACKGROUND: The <80 % Helicobacter pylori eradication rate with sequential therapy is unsatisfactory. Modified bismuth quadruple therapy, replacing metronidazole with amoxicillin, could be promising because H. pylori resistance to tetracycline or to amoxicillin is relatively low. A 14-day modified bismuth quadruple protocol as first-line H. pylori treatment was compared with 10-day sequential therapy. METHODS: In total, 390 H. pylori-infected subjects participated in the randomized clinical trial: 10-day sequential therapy (40 mg pantoprazole plus 1 g amoxicillin twice a day for 5 days, then 40 mg pantoprazole and 500 mg clarithromycin twice a day and 500 mg metronidazole three times a day for 5 days) or 14-day modified bismuth quadruple therapy (40 mg pantoprazole, 600 mg bismuth subcitrate, 1 g tetracycline, and 1 g amoxicillin, twice a day). (13)C urea breath test, rapid urease testing, or histology was performed to check for eradication. RESULTS: Intention-to-treat (ITT) eradication rates of 10-day sequential and 14-day quadruple therapy were 74.6 % and 68.7 %, respectively, and the per-protocol (PP) rates were 84.2 and 76.5 %, respectively. The eradication rate was higher in the sequential therapy group, but neither the ITT nor the PP analyses had a significant difference (P = 0.240 and P = 0.099, respectively). However, the adverse events were significantly lower in the modified bismuth quadruple therapy group than the sequential therapy group (36.9 vs. 47.7 %, P = 0.040). CONCLUSIONS: Ten-day sequential therapy appears to be more effective despite frequent adverse events. However, both 10-day SQT and 14-day PBAT did not reach the excellent eradication rates that exceed 90 %. Additional trials are needed to identify a more satisfactory first-line eradication therapy. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02159976 ); Registration date: 2014-06-03, CRIS ( KCT0001176 ); Registration date: 2014-07-23. PMID- 27460102 TI - Survey of Prolonged Mechanical Ventilation in Intensive Care Units in Mainland China. AB - INTRODUCTION: In mainland China, there are no special care centers (long-term acute care, weaning, chronic care facilities) for patients requiring prolonged mechanical ventilation (PMV). Our goal was to characterize the prevalence and outcome of patients undergoing PMV in Chinese intensive care units (ICUs). METHODS: A prospective 1-d prevalence study was performed at 55 ICUs, with 28-d follow-up. RESULTS: On the observation day, 622 adult patients occupied ICU beds. Enrollment criteria were met by 302 subjects receiving invasive mechanical ventilation, of which 109 (36.1%) had received ventilation for more than 21 d (median 51, 21-3,419), which was defined as PMV. During the following 28 d, another 45 subjects were classified as receiving PMV, but only 5% (3/58) of the subjects who were newly admitted to the ICU on the study day received PMV. Thirty six (22.9%) of the 157 subjects receiving PMV were weaned, and 81 (51.6%) continued ventilation in the ICU. In the logistic regression analysis, age >74 y (odds ratio = 2.78, 95% CI 1.05-7.40, P = .041) and chronic congestive heart failure (odds ratio =12.23, 95% CI 1.48-101.05, P = .020) were associated with failure to wean in 28 d, while acute respiratory distress syndrome (ARDS) as the reason for mechanical ventilation (odds ratio = 0.14, 95% CI 0.04-0.52, P = .003) was associated with successful weaning. CONCLUSION: The number of subjects receiving PMV was surprisingly high in this cross-section of Chinese ICUs. In the following 28 ICU days, only a small proportion of these subjects were weaned. Age and chronic heart dysfunction were high risk factors for weaning failure. PMID- 27460103 TI - Inter-Rater Agreement of Auscultation, Palpable Fremitus, and Ventilator Waveform Sawtooth Patterns Between Clinicians. AB - BACKGROUND: Clinicians often use numerous bedside assessments for secretion retention in participants who are receiving invasive mechanical ventilation. This study aimed to evaluate inter-rater agreement between clinicians when using standard clinical assessments of secretion retention and whether differences in clinician experience influenced inter-rater agreement. METHODS: Seventy-one mechanically ventilated participants were assessed by a research clinician and by one of 13 ICU clinicians. Each clinician conducted a standardized assessment of lung auscultation, palpation for chest-wall (rhonchal) fremitus, and ventilator inspiratory/expiratory flow-time waveforms for the sawtooth pattern. RESULTS: On the presence of breath sounds, agreement ranged from absolute to moderate in the upper zones and the lower zones, respectively. Kappa values for abnormal and adventitious lung sounds achieved moderate agreement in the upper zones, less than chance agreement to substantial agreement in the middle zones, and moderate agreement to almost perfect agreement in the lower zones. Moderate to almost perfect agreement was established for palpable fremitus in the upper zones, moderate to substantial agreement in the middle zones, and less than chance to moderate agreement in the lower zones. Inter-rater agreement on the presence of expiratory sawtooth pattern identification showed moderate agreement. The level of percentage agreement between the research and ICU clinicians for each respiratory assessment studied did not relate directly to level of clinical experience. CONCLUSIONS: Inter-rater agreement for all assessments showed variability between lung regions but maintained reasonable percentage agreement in mechanically ventilated participants. The level of percentage agreement achieved between clinicians did not directly relate to clinical experience for all respiratory assessments. Therefore, these respiratory assessments should not necessarily be viewed in isolation but interpreted within the context of a full clinical assessment. PMID- 27460104 TI - Endotracheal Tubes Cleaned With a Novel Mechanism for Secretion Removal: A Randomized Controlled Clinical Study. AB - INTRODUCTION: Intubation compromises mucus clearance, allowing secretions to accumulate inside the endotracheal tube (ETT). The purpose of this trial was to evaluate a novel device for ETT cleaning. We hypothesized that its routine use would reduce tube occlusion due to mucus accumulation, while decreasing airway bacterial colonization. METHODS: Subjects were randomized to either the use of the device every 8 h, or the institutional standard of care (blind tracheal suction) only. ETTs were collected at extubation and analyzed with high resolution computed tomography (HRCT) for quantification of mucus volume. Microbiological testing was performed on biofilm samples. Vital signs and ventilatory settings were collected at the bedside. In-hospital follow-up was conducted, and a final evaluation survey was completed by respiratory therapists. RESULTS: Seventy-four subjects expected to remain intubated for longer than 48 h were enrolled (77 ETTs, 37 treatment vs 40 controls). Treated tubes showed reduced mucus accumulation (0.56 +/- 0.12 vs 0.71 +/- 0.28 mL; P = .004) and reduced occlusion (6.3 +/- 1.7 vs 8.9 +/- 7.6%; P = .039). The HRCT slice showing the narrowest lumen within each ETT exhibited less occlusion in cleaned tubes (10.6 +/- 8.0 vs 17.7 +/- 13.4%, 95% CI: 2-12.1; P = .007). Data on microbial colonization showed a trend in the treatment group toward a reduced ETT-based biomass of bacteria known to cause ventilator-associated pneumonia. No adverse events were reported. The staff was satisfied by the overall safety and feasibility of the device. CONCLUSION: The endOclear is a safe and effective device. It prevents luminal occlusion, thereby better preserving ETT nominal function. PMID- 27460105 TI - Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases. AB - BACKGROUND: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function. METHODS: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types. RESULTS: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs. CONCLUSION: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism. TRIAL REGISTRATION: Trial registration number NCT01701869 . PMID- 27460106 TI - Factors associated with severe maternal morbidity in Kelantan, Malaysia: A comparative cross-sectional study. AB - BACKGROUND: Knowledge on the factors associated with severe maternal morbidity enables a better understanding of the problem and serves as a foundation for the development of an effective preventive strategy. However, various definitions of severe maternal morbidity have been applied, leading to inconsistencies between studies. The objective of this study was to identify the sociodemographic characteristics, medical and gynaecological history, past and present obstetric performance and the provision of health care services as associated factors for severe maternal morbidity in Kelantan, Malaysia. METHODS: A comparative cross sectional study was conducted in two tertiary referral hospitals in 2014. Postpartum women with severe morbidity and without severe morbidity who fulfilled the inclusion and exclusion criteria were eligible as cases and controls, respectively. The study population included all postpartum women regardless of their age. Pregnancy at less than 22 weeks of gestation, more than 42 days after the termination of pregnancy and non-Malaysian citizens were excluded. Consecutive sampling was applied for the selection of cases and for each case identified, one unmatched control from the same hospital was selected using computer-based simple random sampling. Simple and multiple logistic regressions were performed using Stata Intercooled version 11.0. RESULTS: A total of 23,422 pregnant women were admitted to these hospitals in 2014 and 395 women with severe maternal morbidity were identified, of which 353 were eligible as cases. An age of 35 or more years old [Adj. OR (95 % CI): 2.6 (1.67, 4.07)], women with past pregnancy complications [Adj. OR (95 % CI): 1.7 (1.00, 2.79)], underwent caesarean section deliveries [Adj. OR (95 % CI): 6.8 (4.68, 10.01)], preterm delivery [Adj. OR (95 % CI): 3.4 (1.87, 6.32)] and referral to tertiary centres [Adj. OR (95 % CI): 2.7 (1.87, 3.97)] were significant associated factors for severe maternal morbidity. CONCLUSIONS: Our study suggests the enhanced screening and monitoring of women of advanced maternal age, women with past pregnancy complications, those who underwent caesarean section deliveries, those who delivered preterm and the mothers referred to tertiary centres as they are at increased risk of severe maternal morbidity. Identifying these factors may contribute to specific and targeted strategies aimed at tackling the issues related to maternal morbidity. PMID- 27460107 TI - [The federal participation law : New requirements for needs assessment with special emphasis on medical rehabilitation services]. AB - The federal participation law (Bundesteilhabegesetz - BTHG) is one of the largest efforts in the last 15 years to reform the legal participation rights of people with disabilities. In particular, a number of enhancements are planned in the overall benefits law in Part 1 of Book IX in the Social Code (Sozialgesetzbuch - SGB), which applies to all rehabilitation carriers including general provisions and standards for needs assessment. This paper deals with the implications of these provisions and interacting standards, based on the draft bill of April 2016.The discussion takes place against the background of the regulatory objectives formulated in the ministerial draft itself, jurisprudential expertise on the effects of the current legal norms of the SGB IX as well as relevant professional political developments and statements by various stakeholders.The analysis shows a clear political commitment to increase the requirements for needs assessment in the overall law of the SGB IX and to express these more effectively. The draft bill seeks not only to modify procedures subsequent to the application for rehabilitation benefits, but also to precisely set out provisions on instruments for needs assessment in a new S 13. Common principles for these instruments of needs assessment should increase the cooperation, coordination and convergence among rehabilitation carriers.Nevertheless, with regard to the proposed regulatory texts, there is doubt that the objectives set by the draft bill itself will be achieved. For example, the required common principles for needs assessment are to be agreed upon based on the existing special legislation for the different rehabilitation carriers, without the SGB IX setting its own binding standards or framework principles. In addition, it lacks clear legal guidelines for the professional practice to make use of the bio-psycho-social model of the WHO and the ICF in the process of needs assessment. As a consequence the ICF cannot serve as a legally standardized reference point. PMID- 27460109 TI - Letters. PMID- 27460108 TI - Standardised Chinese herbal treatment delivered by GPs compared with individualised treatment administered by practitioners of Chinese herbal medicine for women with recurrent urinary tract infections (RUTI): study protocol for a randomised controlled trial. AB - BACKGROUND: In the UK, urinary tract infections (UTIs) are the most common bacterial infection presented by women in primary care. Recurrent urinary tract infections (RUTIs) are defined as three episodes of UTI in the last 12 months, or two episodes in the last 6 months. Between 20 and 30 % of women who have had one episode of UTI will have an RUTI, and approximately 25 % of these will develop subsequent recurrent episodes. RUTIs can have a significant negative effect on the quality of life, and have a high impact on health care costs as a result of outpatient visits, diagnostic tests and prescriptions. Chinese herbal medicine (CHM) has a recorded history of treatments for the symptoms of UTIs for more than 2000 years. More recent clinical research in China has provided some preliminary evidence that CHM can alleviate the symptoms of UTIs and reduce the rate of recurrence, but more rigorous investigation is required. METHODS/DESIGN: The RUTI trial is a double-blind, randomised, placebo-controlled, feasibility trial. A total of 80 women will be randomised to 'individualised' herbs prescribed by a Chinese herbal practitioner or to 'standardised' herbs provided by primary care clinicians. Both arms will have herbs for prevention of UTIs and treatment of acute episodes. Treatment duration is for 16 weeks. The primary outcomes are the number of episodes of recurrent UTIs during the trial period and in the 6 months of follow-up, and the number of days of symptoms rated moderately bad or worse based on patient diaries. Secondary outcomes will assess participant expectations and beliefs, adherence to the treatment, adverse events and health economics and provide quantitative and qualitative assessments of the impact of recurrent infections on the lives of women. DISCUSSION: The RUTI trial is the first instance of CHM delivered as a clinical trial of an investigatory medicinal product in the UK. This study provides important information regarding the feasibility and acceptability of researching and using CHM in Primary care. Once completed, it will provide provisional estimates of the variance of change in continuous outcomes to inform a power calculation for a larger, more definitive trial. TRIAL REGISTRATION: EudraCT, 2013-004657-24 . Registered on 5 September 2014. PMID- 27460110 TI - Scanning sports. PMID- 27460111 TI - Brief reports. PMID- 27460112 TI - A need to know. PMID- 27460115 TI - You Can't Trust a Doctor. PMID- 27460116 TI - The Ten Pains of Sportsmedicine. PMID- 27460117 TI - Predicting Exercise Capacity in Angina Patients on Propranolol. AB - The equations from this study provide measures that can be obtained with minimum risk and can predict the effects of treatment in angina pectoris patients. PMID- 27460118 TI - Runners' Injuries. AB - It's easier to prevent running injuries than to treat them. This article helps the physician pinpoint the problem and treat runners without taking them off their feet. PMID- 27460119 TI - Runners' Injuries. PMID- 27460120 TI - The Spokane Study: High School Football Injuries. AB - Until a uniform classification system is adopted, it will be hard to compare studies of football injuries. This author believes that the picture is not as grim as often reported. PMID- 27460121 TI - Kendo: A Safer Martial Art. AB - Kendo may be the answer for those interested in the martial arts but wary of karate blows and judo throws. PMID- 27460122 TI - Office Aerobics: Assessing Fitness Without Fuss. AB - The primary-care physician often leaves exercise prescription to sportsmedicine experts. Now some of those experts are urging GPs and family practitioners to bring aerobics into their offices. PMID- 27460124 TI - Ice: Friend or Foe? PMID- 27460126 TI - Post-traumatic stress disorder and its predictors among bereaved Tibetan adolescents four years after the Yushu earthquake: a cross-sectional survey in China. AB - AIMS AND OBJECTIVES: To examine the prevalence of post-traumatic stress disorder symptoms and to explore the predictive factors of post-traumatic stress disorder symptoms among bereaved adolescents four years after the Yushu earthquake. BACKGROUND: On 14 April 2010, the 7.1-magnitude Yushu earthquake occurred in the high-altitude, hypoxia-prone regions primarily inhabited by ethnic minorities. Many adolescents lost their parents during the earthquake. This study examined post-traumatic stress disorder and its predictors among bereaved Tibetan adolescents four years after the trauma in China. DESIGN: This was a cross sectional descriptive study. METHODS: This study used a cross-sectional design with 830 bereaved adolescents. Participant demographic data included gender, age and grade, and the earthquake exposure variables included the deceased relatives, whether they were buried, injured or amputated (non-life-threatening) and whether they witnessed a burial, injury or death. The post-traumatic stress disorder Checklist-Civilian version was used to assess the symptoms and prevalence of post traumatic stress disorder, and the Coping Style Scale assessed coping styles. RESULTS: The results indicated that the prevalence of post-traumatic stress disorder was 19.3%. Individuals who were buried, injured or amputated (non-life threatening), who witnessed a burial, injury or death, who suffered severe property loss during the earthquake and who had negative coping skills were the most likely individuals to have post-traumatic stress disorder symptoms. CONCLUSIONS: The presence of post-traumatic stress disorder was very prevalent among adolescents four years after the Yushu earthquake. Effective mental health services should be developed to facilitate postdisaster recovery for bereaved adolescents at high risk for post-traumatic stress disorder. RELEVANCE TO CLINICAL PRACTICE: The findings in this study improve our understanding of post traumatic stress disorder and related risk factors in bereaved adolescents in non Western communities, providing useful information for rebuilding and relief work. PMID- 27460127 TI - Environmental influence on the prevalence and pattern of airway dysfunction in elite athletes. AB - BACKGROUND AND OBJECTIVE: Elite swimming and boxing require athletes to achieve relatively high minute ventilation. The combination of a sustained high ventilation and provocative training environment may impact the susceptibility of athletes to exercise-induced bronchoconstriction (EIB). The purpose of this study was to evaluate the prevalence of EIB in elite Great British (GB) boxers and swimmers. METHODS: Boxers (n = 38, mean age: 22.1 +/- 3.1 years) and swimmers (n = 44, mean age: 21.1 +/- 2.6 years) volunteered for the study. Athletes completed an exercise-induced respiratory symptom questionnaire, baseline assessment of fraction of exhaled nitric oxide (FeNO), maximal spirometry manoeuvres and a eucapnic voluntary hyperpnoea (EVH) challenge. EIB was confirmed if forced expiratory volume in 1 s (FEV1 ) reduced by >=10% from baseline at two time points post-EVH challenge. RESULTS: The prevalence of EIB was greater in elite swimmers (30 of 44; 68%) than in boxers (3 of 38; 8%) (P < 0.001). Twenty-two out of the 33 (67%) EVH-positive athletes had no prior diagnosis of asthma/EIB. Moreover, 12% (6 of 49) of the EVH-negative athletes had a previous diagnosis of asthma/EIB. We found a correlation between FeNO and FEV1 change in lung function post-EVH challenge in swimmers (r = 0.32; P = 0.04) but not in boxers (r = 0.24; P = 0.15). CONCLUSION: The prevalence of EIB was ninefold greater in swimmers when compared with boxers. Athletes who train and compete in provocative environments at sustained high ventilation may have an increased susceptibility to EIB. It is not entirely clear whether increased susceptibility to EIB affects elite sporting performance and long-term airway health in elite athletes. PMID- 27460128 TI - Coronary revascularization strategies in diabetes after FREEDOM - is it already time for another trial? PMID- 27460129 TI - Using extra systoles to predict fluid responsiveness in cardiothoracic critical care patients. AB - Fluid responsiveness prediction is an unsettled matter for most critical care patients and new methods relying only on the continuous basic monitoring are desired. It was hypothesized that the post-ectopic beat, which is associated with increased preload, could be analyzed in relation to preceding sinus beats and that the change in cardiac performance (e.g. systolic blood pressure) at the post ectopic beat could predict fluid responsiveness. Cardiothoracic critical care patients scheduled for a 500 ml volume expansion were observed. In the 30 min prior to volume expansion, the ECG was analyzed for occurrence of extra systoles preceded by at least 10 sinus beats. Classification variables, were defined as the change in a variable (e.g. systolic blood pressure or pre-ejection period) from the median of 10 preceding sinus beats to extra systolic post-ectopic beat. A stroke volume increase >15 % following volume expansion defined fluid responsiveness. Thirty patients were included. The change in systolic blood pressure predicted fluid responsiveness in 24 patients correctly with 83 % specificity and 75 % sensitivity (optimal threshold: 5 % systolic blood pressure increase), receiver operating characteristic (ROC) area: 0.81 (CI [0.64;0.98]). The change in pre-ejection period predicted fluid responsiveness in 22 patients correctly with 67 % specificity and 83 % sensitivity (optimal threshold: 19 ms pre-ejection period decrease), ROC area: 0.81 (CI [0.66;0.96]). Pulse pressure variation had ROC area of 0.57 (CI [0.39;0.75]). Based on standard critical care monitoring, analysis of the extra systolic post-ectopic beat predicts fluid responsiveness in cardiothoracic critical care patients with good accuracy. PMID- 27460130 TI - Laparoscopic total pelvic exenteration using transanal minimal invasive surgery technique with en bloc bilateral lymph node dissection for advanced rectal cancer. AB - A 59-year-old man presenting with fecal occult blood visited our hospital. He was diagnosed with advanced lower rectal cancer, which was contiguous with the prostate and the left seminal vesicle. There were no metastatic lesions with lymph nodes or other organs. We performed laparoscopic total pelvic exenteration (LTPE) using transanal minimal invasive surgery technique with bilateral en bloc lateral lymph node dissection for advanced primary rectal cancer after neoadjuvant chemoradiotherapy. The total operative time was 760 min, and the estimated blood loss was 200 ml. LTPE is not well established technically, but it has many advantages including good visibility of the surgical field, less blood loss, and smaller wounds. A laparoscopic approach may be an appropriate choice for treating locally advanced lower rectal cancer, which requires TPE. PMID- 27460131 TI - Cognitive Decline and Recovery in Alcohol Abuse. AB - Alcohol consumption triggers a neuroinflammatory response which, if prolonged, can lead to substantial volume loss in both gray and white matter. This brain injury is associated with characteristic cognitive deficits, and, in extreme cases, with dementia. Even mild cognitive impairment creates a significant hurdle for alcohol rehabilitation, because the domains that are affected tend to be those important for sustaining abstinence. Thus, cognitive decline induced by alcohol contributes to the persistence of alcoholism. Here, I present converging data from animal and clinical studies that show how alcohol affects the brain and behavior. Although there is currently no targeted treatment for overcoming alcohol-induced cognitive decline, emerging evidence suggests that physical activity is both protective and restorative. This is a potential avenue for future programs targeted at treating alcohol abuse. PMID- 27460133 TI - Expression Pattern of Mouse Vasa Homologue (MVH) in the Ovaries of C57BL/6 Female Mice. AB - BACKGROUND Vasa (a DEAD-box helicase, also known as Ddx4) is an ATP-dependent RNA helicase highly conserved among all animals. Research on the presence and function of DDX4 in female mammals is limited. To gain greater insight into its distribution and role in female mice, we detected the expression of DDX4 protein in the ovaries and analyzed its expression pattern. MATERIAL AND METHODS MVH was detected in the cytoplasm of oocytes in all non-apoptotic follicles. RESULTS In the present study, we found that higher expression levels of ~55-60 kDa MVH isoform in the ovaries were followed by the accumulations of preovulatory follicles. CONCLUSIONS Higher levels of MVH protein in the ovaries might prepare oocytes for the competence to resume meiosis. PMID- 27460132 TI - Induced Pluripotent Stem Cell Differentiation and Three-Dimensional Tissue Formation Attenuate Clonal Epigenetic Differences in Trichohyalin. AB - The epigenetic background of pluripotent stem cells can influence transcriptional and functional behavior. Most of these data have been obtained in standard monolayer cell culture systems. In this study, we used exome sequencing, array comparative genomic hybridization (CGH), miRNA array, DNA methylation array, three-dimensional (3D) tissue engineering, and immunostaining to conduct a comparative analysis of two induced pluripotent stem cell (iPSC) lines used in engineering of 3D human epidermal equivalent (HEE), which more closely approximates epidermis. Exome sequencing and array CGH suggested that their genome was stable following 3 months of feeder-free culture. While the miRNAome was also not affected, ~7% of CpG sites were differently methylated between the two lines. Analysis of the epidermal differentiation complex, a region on chromosome 1 that contains multiple genes involved in skin barrier maturation (including trichohyalin, TCHH), found that in one of the iPSC clones (iKCL004), TCHH retained a DNA methylation signature characteristic of the original somatic cells, whereas in other iPSC line (iKCL011), the TCHH methylation signature matched that of the human embryonic stem cell line KCL034. The difference between the two iPSC clones in TCHH methylation did not have an obvious effect on its expression in 3D HEE, suggesting that differentiation and tissue formation may mitigate variations in the iPSC methylome. PMID- 27460134 TI - A novel micro-to-macro approach for cardiac tissue mechanics. AB - For studying cardiac mechanics, hyperelastic anisotropic computational models have been developed which require the tissue anisotropic and hyperelastic parameters. These parameters are obtained by tissue samples mechanically testing. The validity of such parameters are limited to the specific tissue sample only. They are not adaptable for pathological tissues commonly associated with tissue microstructure alterations. To investigate cardiac tissue mechanics, a novel approach is proposed to model hyperelasticity and anisotropy. This approach is adaptable to various tissue microstructural constituent's distributions in normal and pathological tissues. In this approach, the tissue is idealized as composite material consisting of cardiomyocytes distributed in extracellular matrix (ECM). The major myocardial tissue constituents are mitochondria and myofibrils while the main ECM's constituents are collagen fibers and fibroblasts. Accordingly, finite element simulations of uniaxial and equibiaxial tests of normal and infarcted tissue samples with known amounts of these constituents were conducted, leading to corresponding tissue stress-strain data that were fitted to anisotropic/hyperelastic models. The models were validated where they showed good agreement characterized by maximum average stress-strain errors of 16.17 and 10.01% for normal and infarcted cardiac tissue, respectively. This demonstrate the effectiveness of the proposed models in accurate characterization of healthy and pathological cardiac tissues. PMID- 27460135 TI - Oxidative stress in dairy cows naturally infected with the lungworm Dictyocaulus viviparus (Nematoda: Trichostrongyloidea). AB - The aim of this study was to analyse the oxidative and anti-oxidant status in serum samples from dairy cows naturally infected by Dictyocaulus viviparus and its relation with pathological analyses. The diagnosis of the disease was confirmed by necropsy of one dairy cow with heavy infection by the parasite in the lungs and bronchi. Later, blood and faeces were collected from another 22 cows from the same farm to measure reactive oxygen species (ROS) levels, thiobarbituric acid-reactive substances (TBARS), catalase (CAT) and superoxide dismutase (SOD) activities on day 0 (pre-treatment) and day 10 (post-treatment with eprinomectin). Faecal examination confirmed the infection in all lactating cows. However, the number of D. viviparus larvae per gram of faeces varied between animals. Cows showed different degrees of severity according to respiratory clinical signs of the disease (cough and nasal secretion). Further, they were classified and divided into two groups: those with mild (n = 10) and severe disease (n = 12). Increased levels of TBARS (P < 0.001), ROS (P = 0.002) and SOD activity (P < 0.001), as well as reduced CAT activity (P < 0.001) were observed in cows with severe clinical signs of the disease compared to those with mild clinical signs. Eprinomectin treatment (day 10) caused a reduction of ROS levels (P = 0.006) and SOD activity (P < 0.001), and an increase of CAT activity (P = 0.05) compared to day 0 (pre-treatment). TBARS levels did not differ with treatment (P = 0.11). In summary, increased ROS production and lipid peroxidation altered CAT and SOD activities, as an adaptive response against D. viviparus infection, contributing to the occurrence of oxidative stress and severity of the disease. Treatment with eprinomectin eliminated the infection, and thus minimized oxidative stress in dairy cows. PMID- 27460136 TI - Gallstones and Bariatric Surgery: To Treat or Not to Treat? PMID- 27460137 TI - MERCI for Improving Quality of Surgical Care at No Cost. PMID- 27460138 TI - Anastomosis Between Thoracic Duct and Azygos Vein During Esophagectomy: A Novel Technique with 3-year Follow-up. AB - BACKGROUND: Ligation of thoracic duct is the standard procedure currently used to prevent postoperative chylothorax for patients undergoing esophagectomy when thoracic duct is surgically injured or invaded by tumor. However, preservation of lymphovenous circulation is particularly important for a subset of patients, including individuals with liver cirrhosis, ascites, nephrotic syndrome, sclerosing mesenteritis, or some cardiac conditions. METHODS: We have developed a new technique of restoring lymphovenous circulation for patients undergoing esophagectomy. Intrathoracic lymphovenous anastomosis was performed for an esophageal cancer patient by intravenous catheter assisted end-to-side "insertion" technique. RESULTS: The time taken for lymphovenous anastomosis was 35 min. No massive bleeding or other adverse events occurred during operation, and the patient had an uneventful postoperative course. Lipid metabolisms, assessed by pre- and postoperative plasma concentrations of cholesterol, triglycerides, high-density and low-density lipoprotein, were not affected after lymphovenous anastomosis. Lymphangiography also indicated lymphovenous anastomosis remained patent 3 years after operation. No long-term surgery-related adverse events were observed during 3-year follow-up. CONCLUSION: Lymphovenous anastomosis was successfully implemented for the patient with esophagectomy, selected patients might benefit from this novel technique. PMID- 27460139 TI - Resolutions and Declarations in an Era of Global Surgery. PMID- 27460140 TI - The Reliability of the Pre-hospital Physical Examination of the Pelvis: A Retrospective, Multicenter Study. AB - INTRODUCTION: This study assesses the incidence of missed pelvic injuries in the pre-hospital setting. METHODS: All blunt trauma patients (ISS >= 9) with pre hospital suspicion of and/or radiologically proven pelvic fracture documented in the TraumaRegister DGU(r) (TR-DGU) of the German Trauma Society DGU (2002-2011) were identified and retrospectively analyzed. Patients with a missed pelvic injury in the pre-hospital period were compared with those who were correctly identified. RESULTS: Of the 11,062 patients included, 7201 patients (65.1 %) had a pelvic fracture diagnosed on hospital admission. In 44.1 % (n = 3178) of the patients with confirmed pelvic fracture, no pelvic injury was suspected pre clinically (overall sensitivity of the pre-hospital pelvic examination: 55.9 %). For type B and C pelvic fractures, 40.5 % and 32.3 %, respectively, were not suspected in the pre-hospital environment. Patients with a not-suspected pelvic injury were significantly more likely to have been involved in a motor vehicle accident, to have a GCS <= 8, to be intubated at the scene and to have an ISS of >=25 (all p < 0.05). Independent risk factors for missing a pelvic injury in the pre-hospital setting were an AIS head >=3, a GCS <= 8 and age above 60 years. The presence of hypotension (SBP <= 90 mmHg) as well as a high overall injury severity (ISS >= 25) decreased the risk of missing a pelvic injury. CONCLUSION: A significant proportion of severe pelvic fractures type B and C were not suspected in the pre-hospital setting. Therefore, in severely injured blunt trauma patients, a mechanical pelvic stabilization in the pre-hospital environment, irrespective of the findings of the physical examination of the pelvis, should be considered. PMID- 27460141 TI - Implementation of a Hospital Electronic Surgical Registry in a Lower-Middle Income Country. AB - BACKGROUND: While the benefits of using electronic health records (EHRs) in both developed and low- and middle-income countries are known, the barriers to implementing EHRs in lower-middle-income countries have not been fully characterized. We assessed organizational readiness for implementation of a mobile (tablet-based) EHR, to create a real-time electronic surgical registry, in a busy lower-middle-income country hospital. METHODS: Six semi-structured focus groups were conducted with hospital administrators, faculty surgeons, surgical residents, interns, nurses and medical students in a large urban hospital in Asuncion, Paraguay. Focus groups were conducted over the course of three weeks during the pre-implementation phase to identify barriers to implementation. Focus group data were coded using the Theoretical Domains Framework (TDF), which are 12 validated domains related to behavior change. RESULTS: Reinforcement, environmental context/resources and roles/responsibilities were the most relevant TDF domains that emerged. Residents and students were more uncertain than faculty and department heads about who would enforce the use of the tool in place of paper charting. Internet quality was a concern raised by all. The local, normative hierarchical structure within the surgical department, including piecemeal communication between the department heads and the residents about roles and responsibilities, was a major perceived barrier to implementation. CONCLUSIONS: Uncertainties about reinforcement, roles and responsibilities for using a novel EHR tool, and technology infrastructure are potential barriers to address in the pre-implementation phase of introducing an EHR to a lower-middle income country surgical service. Addressing these potential barriers with all stakeholders prior to implementation will be a critical next step in this effort. PMID- 27460142 TI - The Yield of Fever, Inflammatory Markers and Ultrasound in the Diagnosis of Acute Cholecystitis: A Validation of the 2013 Tokyo Guidelines. AB - BACKGROUND: Each year, 1-4 % of people with known gallstones become symptomatic, either presenting with biliary colic or as acute cholecystitis. The distinction between both diagnoses remains challenging. To aid the proper diagnosis, the revised 2013 Tokyo Guidelines (TG 2013) were proposed with a self-acclaimed diagnostic accuracy of over 90 %. However, this accuracy has not been verified by others so far. OBJECTIVE: To determine the accuracy of the TG 2013 guidelines in the diagnosis of acute cholecystitis both in its single components of fever, inflammatory markers and US features and of the combined application of the TG 2013 guidelines as a whole. METHODS: A 5-year retrospective analysis equal to the TG 2013 validation process of all emergency cholecystectomies for acute cholecystitis or persistent biliary pain with an ultrasound performed during the same admission. Acute cholecystitis at histology was the golden standard. RESULTS: Inclusion criteria were met by 169 patients with a prevalence of acute cholecystitis of 52.7 %. The individual features of fever, gallbladder wall thickening and probe tenderness were not significant in univariate analysis. In multivariate analysis only, neutrophil count was an independent predictor. The combined application of the TG 2013 guidelines led to a better sensitivity of 83.1 % at the cost a reduced specificity of 37.5 % compared to neutrophil count alone. The accuracy was therefore only 60.3 %, which was well below the TG 2013 report. CONCLUSION: The 2013 Tokyo Guidelines were slightly better in predicting acute cholecystitis but over diagnosed two-thirds of normal gallbladders compared to neutrophil count alone. PMID- 27460143 TI - Competition promotes the persistence of populations in ecosystems. AB - Competition is one of the most common form in ecological systems, which plays important roles in population dynamics. However, the influences of competition on persistence of populations remain unclear when space effect is included. In this paper, we investigated a predator-prey model with competition and spatial diffusion. Based on pattern formations and time series of populations, we found that competitions induce the persistence of populations, which denies competitive exclusion principle. Moreover, we testify the robustness of these effects. Our results also suggest that space may lead to the emergence of new phenomenon in ecosystems. PMID- 27460144 TI - Frontostriatal anatomical connections predict age- and difficulty-related differences in reinforcement learning. AB - Reinforcement learning (RL) is supported by a network of striatal and frontal cortical structures that are connected through white-matter fiber bundles. With age, the integrity of these white-matter connections declines. The role of structural frontostriatal connectivity in individual and age-related differences in RL is unclear, although local white-matter density and diffusivity have been linked to individual differences in RL. Here we show that frontostriatal tract counts in young human adults (aged 18-28), as assessed noninvasively with diffusion-weighted magnetic resonance imaging and probabilistic tractography, positively predicted individual differences in RL when learning was difficult (70% valid feedback). In older adults (aged 63-87), in contrast, learning under both easy (90% valid feedback) and difficult conditions was predicted by tract counts in the same frontostriatal network. Furthermore, network-level analyses showed a double dissociation between the task-relevant networks in young and older adults, suggesting that older adults relied on different frontostriatal networks than young adults to obtain the same task performance. These results highlight the importance of successful information integration across striatal and frontal regions during RL, especially with variable outcomes. PMID- 27460145 TI - Lynx1 and Abeta1-42 bind competitively to multiple nicotinic acetylcholine receptor subtypes. AB - Lynx1 regulates synaptic plasticity in the brain by regulating nicotinic acetylcholine receptors (nAChRs). It is not known to which extent Lynx1 can bind to endogenous nAChR subunits in the brain or how this interaction is affected by Alzheimer's disease pathology. We apply affinity purification to demonstrate that a water-soluble variant of human Lynx1 (Ws-Lynx1) isolates alpha3, alpha4, alpha5, alpha6, alpha7, beta2, and beta4 nAChR subunits from human and rat cortical extracts, and rat midbrain and olfactory bulb extracts, suggesting that Lynx1 forms complexes with multiple nAChR subtypes in the human and rodent brain. Incubation with Ws-Lynx1 decreases nicotine-mediated extracellular signal regulated kinase phosphorylation in PC12 cells and striatal neurons, indicating that binding of Ws-Lynx1 is sufficient to inhibit signaling downstream of nAChRs. The effect of nicotine in PC12 cells is independent of alpha7 or alpha4beta2 nAChRs, suggesting that Lynx1 can affect the function of native non-alpha7, non alpha4beta2 nAChR subtypes. We further show that Lynx1 and oligomeric beta amyloid1-42 compete for binding to several nAChR subunits, that Ws-Lynx1 prevents beta-amyloid1-42-induced cytotoxicity in cortical neurons, and that cortical Lynx1 levels are decreased in a transgenic mouse model with concomitant beta amyloid and tau pathology. Our data suggest that Lynx1 binds to multiple nAChR subtypes in the brain and that this interaction might have functional and pathophysiological implications in relation to Alzheimer's disease. PMID- 27460146 TI - VPS35 regulates cell surface recycling and signaling of dopamine receptor D1. AB - Vacuolar protein sorting 35 (VPS35) is a retromer complex component regulating membrane protein trafficking and retrieval. Mutations or dysfunction of VPS35 have been linked to Parkinson's disease (PD), which is pathologically characterized by the loss of dopamine neurons in brain substantia nigra region. Dopamine plays a key role in regulating various brain physiological functions by binding to its receptors and triggering their endocytosis and signaling pathways. However, it is unclear whether there is a link between VPS35 and dopamine signaling in PD. Herein, we found that VPS35 interacted with dopamine receptor D1 (DRD1). Notably, overexpression and downregulation of VPS35 increased and decreased steady-state cell surface levels of DRD1 and phosphorylation of cAMP response element binding protein (CREB) and extracellular regulated protein kinases (ERK) that are important dopamine signaling effectors, respectively. In addition, overexpression of VPS35 promoted cell surface recycling of endocytic DRD1. Furthermore, downregulation of VPS35 abolished dopamine-induced CREB/ERK phosphorylation. More importantly, although the PD-associated VPS35 mutant VPS35 (D620N) still interacted with DRD1, its expression did not affect cell surface recycling of DRD1 and phosphorylation of CREB/ERK nor rescue the reduction of CREB/ERK phosphorylation caused by VPS35 downregulation. These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. PMID- 27460148 TI - Increases of SET level and translocation are correlated with tau hyperphosphorylation at ser202/thr205 in CA1 of Ts65Dn mice. AB - SET is a multifunctional protein, but when present in the cytoplasm, acts as a powerful inhibitor of phosphatase 2A. We previously observed that in CA1 of Down syndrome (DS) patients, the level of SET is increased, and SET is translocated to the cytoplasm and associated with the hyperphosphorylation of tau at ser202/thr205. The presence of SET in the cytoplasm in DS brains may play a role in the progression of the disease. Here, we show that in CA1 of 3-month-old Ts65Dn mice modeling DS, SET level is increased, and SET is translocated to the cytoplasm and associated with tau hyperphosphorylations at ser202/thr205 and with amyloid precursor protein caspase cleaved as observed in Alzheimer disease brains. Tau hyperphosphorylation at ser356 and activation of other phosphatase 2A targets such as the mammalian target of rapamycin and adenosine monophosphate protein kinases were also observed, suggesting deleterious mechanisms. We propose Ts65Dn mice as a model for therapeutic approaches focused on SET overexpression and its cytoplasmic translocation to slow down disease progression. PMID- 27460147 TI - Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum. AB - The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated beta-amyloid, designated as "A+," and hippocampal volume and (18)fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration ("N+") at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1-6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio and gray matter volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG standardized uptake value ratio and gray matter volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway. PMID- 27460149 TI - Mean arterial pressure change associated with cerebral blood flow in healthy older adults. AB - We investigate over a 12-year period the association between regional cerebral blood flow (CBF) and cardiovascular risk factors in a prospective cohort of healthy older adults (81.96 +/- 3.82 year-old) from the Cognitive REServe and Clinical ENDOphenotype (CRESCENDO) study. Cardiovascular risk factors were measured over 12 years, and gray matter CBF was measured at the end of the study from high-resolution magnetic resonance imaging using arterial spin labeling. The association between cardiovascular risk factors, their long-term change, and CBF was assessed using multivariate linear regression models. Women were observed to have higher CBF than men (p < 0.05). Increased mean arterial pressure (MAP) over the 12-year period was correlated with a low cerebral blood flow (p < 0.05, R(2) = 0.21), whereas no association was detected between CBF and MAP at the time of imaging. High levels of glycemia tended to be associated with low cerebral blood flow values (p < 0.05). Age, alcohol consumption, smoking status, body mass index, history of cardiovascular disease, and hypertension were not associated with CBF. Our main result suggests that change in MAP is the most significant predictor of future CBF in older adults. PMID- 27460150 TI - Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging. AB - An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease. PMID- 27460151 TI - Discrepancies between fluid and crystallized ability in healthy adults: a behavioral marker of preclinical Alzheimer's disease. AB - Measures of core cognitive processes (fluid abilities) are highly correlated with measures of knowledge (crystallized abilities) in healthy adults. In early stages of Alzheimer's disease (AD), fluid abilities, however, decline more rapidly than crystallized abilities. We hypothesized that cognitively normal older adults who evidenced lower fluid ability compared with crystallized ability (an ability discrepancy) would show evidence of early AD neuropathology indexed via in vivo measures of amyloid-beta (Abeta) deposition and cortical thickness in AD vulnerable regions. A sample of older adults (n = 112) aged 65 to 89 underwent a cognitive battery, structural magnetic resonance imaging, and a subset (n = 75) also completed positron emission tomography scanning to measure Abeta deposition using F-18 Florbetapir. Of this sample, 60 older adults (43 with available positron emission tomography scans) evidenced a discrepancy where fluid ability was lower than crystallized ability. The magnitude of the ability discrepancy was independently associated with a greater Abeta deposition and thinner cortex in AD vulnerable regions, as well as age. The data suggest that such a discrepancy may be a marker of preclinical AD. PMID- 27460152 TI - Age differences in hippocampal activation during gist-based false recognition. AB - Age-related increases in reliance on gist-based processes can cause increased false recognition. Understanding the neural basis for this increase helps to elucidate a mechanism underlying this vulnerability in memory. We assessed age differences in gist-based false memory by increasing image set size at encoding, thereby increasing the rate of false alarms. False alarms during a recognition test elicited increased hippocampal activity for older adults as compared to younger adults for the small set sizes, whereas the age groups had similar hippocampal activation for items associated with larger set sizes. Interestingly, younger adults had stronger connectivity between the hippocampus and posterior temporal regions relative to older adults during false alarms for items associated with large versus small set sizes. With increased gist, younger adults might rely more on additional processes (e.g., semantic associations) during recognition than older adults. Parametric modulation revealed that younger adults had increased anterior cingulate activity than older adults with decreasing set size, perhaps indicating difficulty in using monitoring processes in error-prone situations. PMID- 27460154 TI - Contrasting neural effects of aging on proactive and reactive response inhibition. AB - Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition (anticipatory response slowing), which might be particularly evident with high information load. We used functional magnetic resonance imaging in young (n = 25, age range 18-32) and older adults (n = 23, 61-74) with a stop-signal task. Relative to young adults, older adults exhibited impaired reactive inhibition (i.e., longer stop-signal reaction time) and increased blood oxygen level-dependent (BOLD) signal for successful versus unsuccessful inhibition in the left frontal cortex and cerebellum. Furthermore, older adults also exhibited impaired proactive slowing, but only as a function of information load. This load-dependent behavioral deficit was accompanied by a failure to increase blood oxygen level-dependent (BOLD) signal under high information load in lateral frontal cortex, presupplementary motor area and striatum. Our findings suggest that inhibitory deficits in older adults are caused both by reduced stopping abilities and by diminished preparation capacity during information overload. PMID- 27460153 TI - Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer's disease: implications for neurometabolic regulation. AB - Age-dependent changes in nitric oxide ((*)NO) concentration dynamics may play a significant role in both decaying synaptic and metabolic functions in Alzheimer's disease (AD). This neuromodulator acts presynaptically to increase vesicle release and glutamatergic transmission and also regulates mitochondrial function. Under conditions of altered intracellular redox environment, (*)NO may react and produce reactive species such as peroxynitrite. Using the triple transgenic mouse model of AD (3xTgAD), we investigated age-dependent changes in the glutamate (*)NO axis in the hippocampus. Direct measurement of (*)NO concentration dynamics revealed a significant increase in N-methyl-D-aspartate type receptor-evoked peak (*)NO in the 3xTgAD model at an early age. Aging produced a decrease in peak (*)NO accompanied by significant decrease in production and decay rates in the transgenic model. Evaluation of energy metabolism revealed age-dependent decrease in basal oxygen consumption rate, a general decrease in mitochondrial oxidative phosphorylation parameters, and loss in mitochondrial sparing capacity in both genotypes. Finally, we observed age-dependent increase in 3-nitrotyrosine residues in the hippocampus, consistent with a putative shift in (*)NO bioactivity toward oxidative chemistry associated with neurotoxicity. PMID- 27460155 TI - A rate equation theory for the pore size distribution of calcined CaCO3 in calcium looping. AB - CaCO3 calcination is an important step in calcium looping, and the formed pore structure of porous CaO is critical for subsequent carbonation towards carbon dioxide. Therefore, it is necessary to investigate the evolution of the pore structure of the sorbent in the calcination step. A mathematical model describing the pore size distribution during the calcination of the CaCO3 particle was developed. CaCO3 calcination is calculated following a shrinking core model at the CaO-CaCO3 interface, and CO2 diffuses through the porous CaO layers. During the decomposition of CaCO3, after the departure of the CO2 molecule from its original lattice, a vacancy will be formed that will diffuse inside the solid, and the collision and coagulation of the vacancy results in pore formation. A rate equation theory was proposed to describe the vacancy coagulation and pore evolution inside the solid, with rate expressions derived for the pore size distribution function with time evolution. To validate the developed model, the evolution of the pore size distribution during CaCO3 calcination was experimentally measured in a high-temperature furnace combined with the nitrogen adsorption method. It was found that there is a characteristic bimodal distribution for the pore structure of calcined CaCO3, with average pore sizes of ~2.8 nm and ~50 nm. The calculated results agree well with the experimental data, and the relative importance of growth and coagulation was discussed. PMID- 27460156 TI - Spatial Clustering of Escherichia coli with Reduced Susceptibility to Cefotaxime and Ciprofloxacin among Dairy Cattle Farms Relative to European Starling Night Roosts. AB - European starlings (Sturnus vulgaris) have been implicated in the dispersal of zoonotic enteric pathogens. However, their role in disseminating antimicrobial resistant organisms through their home range has not been clearly established. The aim of this study was to determine whether starling night roosts served as foci for spreading organisms with reduced susceptibility to antimicrobials among dairy cattle farms. Bovine faecal pats were collected from 150 dairy farms in Ohio. Each farm was visited twice (in summer and fall) between 2007 and 2009. A total of 1490 samples (10 samples/farm over two visits) were tested for Escherichia coli with reduced susceptibility to cefotaxime and ciprofloxacin. Using a spatial scan statistic, focal scans were conducted to determine whether clusters of farms with a high prevalence of organisms with reduced susceptibility to cefotaxime and ciprofloxacin surrounded starling night roosts. Faecal pats 13.42% and 13.56% of samples carried Escherichia coli with reduced susceptibility to cefotaxime and ciprofloxacin, respectively. Statistically significant (P < 0.05) spatial clusters of faecal pats with high prevalence of Escherichia coli showing reduced susceptibility to cefotaxime and ciprofloxacin were identified around these night roosts. This finding suggests that the risk of carriage of organisms with reduced susceptibility to antimicrobials in cattle closer to starling night roosts was higher compared to cattle located on farms further from these sites. Starlings might have an important role in spreading antimicrobial resistant E. coli to livestock environments, thus posing a threat to animal and public health. PMID- 27460157 TI - A Zinc Morpholine Complex Prevents HCl/Ethanol-Induced Gastric Ulcers in a Rat Model. AB - Zinc is a naturally occurring element with roles in wound healing and rescuing tissue integrity, particularly in the gastrointestinal system, where it can be detected in the mucosal and submucosal layers. Zinc chelates are known to have beneficial effects on the gastrointestinal mucosa and in cases of gastric ulcer. We synthesized complexes of zinc featuring a heterocyclic amine binding amino acids then investigated their ability to enhance the gastric self-repair. Zinc morpholine complex, Zn(L)SCN, namely showed strong free-radical scavenging, promotion of the DNA and RNA polymerases reconstruction and suppression of cell damage. The complex's mode of action is proposed to involve hydrogen bond formation via its bis(thiocyanato-k)zinc moiety. Zn(L)SCN complex had potent effects on gastric enzymatic activity both in vitro and in vivo. The complex disrupted the ulcerative process as demonstrated by changes in the intermediate metabolites of the oxidative pathway - specifically, reduction in the MDA levels and elevation of reduced glutathione together with an attenuation of oxidative DNA damage. Additionally, Zn(L)SCN restored the gastric mucosa, inhibited the production of pro-inflammatory cytokines (IL-6, TNF and the caspases), and preserved the gastric mucous balance. Zn(L)SCN thus exhibited anti-oxidative, anti-inflammatory and anti-apoptotic activities, all of which have cytoprotective effects on the gastric lining. PMID- 27460159 TI - Juniors' "reduced" hours are more intense. PMID- 27460160 TI - Apatite Formation from Amorphous Calcium Phosphate and Mixed Amorphous Calcium Phosphate/Amorphous Calcium Carbonate. AB - Crystallization from amorphous phases is an emerging pathway for making advanced materials. Biology has made use of amorphous precursor phases for eons and used them to produce structures with remarkable properties. Herein, we show how the design of the amorphous phase greatly influences the nanocrystals formed therefrom. We investigate the transformation of mixed amorphous calcium phosphate/amorphous calcium carbonate phases into bone-like nanocrystalline apatite using in situ synchrotron X-ray diffraction and IR spectroscopy. The speciation of phosphate was controlled by pH to favor HPO4 (2-) . In a carbonate free system, the reaction produces anisotropic apatite crystallites with large aspect ratios. The first formed crystallites are highly calcium deficient and hydrogen phosphate rich, consistent with thin octacalcium phosphate (OCP)-like needles. During growth, the crystallites become increasingly stoichiometric, which indicates that the crystallites grow through addition of near stoichiometric apatite to the OCP-like initial crystals through a process that involves either crystallite fusion/aggregation or Ostwald ripening. The mixed amorphous phases were found to be more stable against phase transformations, hence, the crystallization was inhibited. The resulting crystallites were smaller and less anisotropic. This is rationalized by the idea that a local phosphate depletion zone formed around the growing crystal until it was surrounded by amorphous calcium carbonate, which stopped the crystallization. PMID- 27460158 TI - Surgical management of postpartum haemorrhage: survey of French obstetricians. AB - The aim of our study was to assess the theoretical and practical knowledge of French obstetricians about the surgical management of postpartum haemorrhage (PPH). Our study is a national anonymous self-administered survey. A total of 363 obstetricians responded to this questionnaire between December 2013 and April 2014. Questionnaire sent through email to all French obstetricians who are members of either of two federations of hospital-based obstetricians. Answers were collected until the end of June 2014. The main outcome measure was obstetricians' level of mastery of each surgical technique. The results were analysed descriptively (proportions). Only the 286 questionnaires fully completed were analysed; the complete response rate was 23% (286/1246). In all, 33% (95/286) of the responding obstetricians reported that they had not mastered sufficiently or even at all the technique for bilateral ligation of the uterine arteries, 37% (105/286) for uterine compression suture, 62% (178/286) for ligation of the internal iliac arteries, and 47% (134/286) for emergency peripartum hysterectomy. In all, 18% (52/286) of respondents stated that they had not mastered any of these techniques. Our study shows that a worrisome number of French obstetricians reported insufficient mastery of the surgical techniques for PPH management. PMID- 27460161 TI - Disaster Preparedness Among Older Japanese Adults With Long-Term Care Needs and Their Family Caregivers. AB - OBJECTIVE: In the 2011 Great East Japan Earthquake, as in Hurricanes Katrina and Rita in the United States, older individuals were at the greatest risk of mortality. Much concern has been raised about developing plans to reduce these risks, but little information has been provided about preparedness, and the key role played by caregivers has been largely unexplored. The aims of this study were thus to examine the preparedness of family caregivers of older adults with long-term care needs and to identify the characteristics of older adults and their caregivers that are associated with poor preparedness and greater concern about disasters. METHODS: Shortly after the Great East Japan Earthquake, the second wave of the Fukui Longitudinal Caregiver Study was administered to the family caregivers of older Japanese individuals with long-term care needs. The sample included 952 caregivers from 17 municipalities in Fukui prefecture. Logistic regression analyses were used to identify the factors associated with self-assessed preparedness, evacuation planning, and caregivers' concerns about preparedness. RESULTS: The majority (75%) of the caregivers had no concrete plans for evacuation in an emergency, and those caring for persons with dementia were 36% less likely to have any plan. In multivariate models, caregivers who were more experienced and wealthier and who reported more family and community support were more likely to feel well prepared. Caregivers with poor health or limited financial resources or who were responsible for older persons with mobility difficulties reported higher levels of anxiety about their disaster preparedness. CONCLUSIONS: This study indicates that most caregivers are ill prepared to respond in emergencies and that caregiver resources, community support, and the needs of older care recipients influence both preparedness and concern about disasters. Education for caregivers and the development of community support programs could provide important sources of assistance to this vulnerable group. (Disaster Med Public Health Preparedness. 2017;11:31-38). PMID- 27460162 TI - Shorter courses of antibiotic treatment for patients with pneumonia. PMID- 27460163 TI - Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. AB - BACKGROUND: Inhaled corticosteroids are important in the management of chronic obstructive pulmonary disease (COPD), but can slightly increase the risk of pneumonia in patients with moderate-to-severe COPD. Patients with circulating eosinophil counts of 2% or more of blood leucocytes respond better to inhaled corticosteroids than do those with counts of less than 2% and it was therefore postulated that blood eosinophil count might also have an effect on the risk of pneumonia in patients with COPD. In this post-hoc meta-analysis, we investigate whether a 2% threshold can identify patients who differ in their risk of pneumonia, irrespective of inhaled corticosteroid treatment. METHODS: From the GlaxoSmithKline trial registry, we selected randomised, double-blind, clinical trials of patients with COPD that had: inhaled corticosteroid arms (fluticasone propionate and salmeterol or fluticasone furoate and vilanterol); a control arm (not given inhaled fluticasone); and pre-randomisation measurements of blood eosinophil counts and were of at least 24 weeks in duration. With use of specified terms from the Medical Dictionary for Regulatory Activities we identified pneumonia adverse events in patient-level data. We calculated number of patients with pneumonia events, stratified by baseline blood eosinophil count (<2% vs >=2% of blood leucocytes) and whether or not patients had received inhaled corticosteroids. FINDINGS: We identified ten trials (conducted between 1998 and 2011), with eosinophil count data available for 10 861 patients with COPD. 4043 patients had baseline blood eosinophil counts of less than 2% and 6818 patients had baseline blood eosinophil counts of 2% or more. 149 (3.7%) patients with counts less than 2% had one or more pneumonia adverse events compared with 215 (3.2%) with counts of 2% or more (hazard ratio [HR] 1.31; 95% CI 1.06-1.62). In patients not treated with inhaled corticosteroids, 40 (3.8%) patients with less than 2% blood eosinophil counts had a pneumonia event versus 48 (2.4%) with 2% or more blood eosinophils (HR 1.53; 95% CI 1.01-2.31). In patients treated with inhaled corticosteroids, events occurred in 107 (4.5%) versus 164 (3.9%; HR 1.25; 95% CI 0.98-1.60), respectively. INTERPRETATION: Using 2% baseline eosinophil count as a threshold, patients with COPD with lower blood eosinophil counts had more pneumonia events than did those with higher counts. The magnitude of this increased risk was small and should be further explored in large, prospective studies. These data should be considered when making treatment decisions, alongside existing evidence that patients with COPD and baseline blood eosinophil counts less than 2% have a poorer response to inhaled corticosteroids. FUNDING: GlaxoSmithKline. PMID- 27460164 TI - Eosinophils in COPD: the Janus of phenotyping response to therapy? PMID- 27460166 TI - Nutritional status of Vietnamese outpatients with chronic obstructive pulmonary disease. AB - BACKGROUND: Nutritional screening and assessment is not currently part of routine clinical practice in Vietnam. Therefore, the present study aimed to investigate the utility of the commonly used methods for identifying malnutrition in outpatients with chronic obstructive pulmonary disease (COPD). METHODS: A cross sectional pilot study and a larger retrospective study were carried out in outpatients with COPD who were attending a respiratory clinic in Ho Chi Minh City, Vietnam. Routine clinical data were collected [body mass index (BMI), forced expiratory volume in 1 s (FEV1 )]. Nutritional screening and assessment were performed using the Malnutrition Screening Tool (MST) and Subjective Global Assessment (SGA) as the gold standard to diagnose malnutrition. RESULTS: In total, 393 outpatients had documented BMI and 29 were prospectively assessed using SGA: males, n = 25; females, n = 4; mean (SD) age 69.7 (9.6) years; mean (SD) BMI 21.0 (3.4) kg m-2 ; mean (SD) FEV1 percentage predicted 57.0% (19.7%). Malnutrition risk was identified in 20.7% (n = 6) of patients using the MST (38% sensitivity; 94% specificity). However, 45% (n = 13) were diagnosed as malnourished using the SGA (31% mild/moderate; 14% severe). All malnourished patients not identified by the MST had evidence of muscle wasting. BMI had a strong negative correlation with muscle wasting as assessed using the SGA (r = 0.857, n = 28; P < 0.001) and all malnourished patients had a BMI <21 kg m-2 (range 14.6-20.8 kg m-2 , nourished range 20.0-27.6 kg m-2 ). CONCLUSIONS: Malnutrition is common in Vietnamese outpatients with COPD. A BMI threshold of <21 kg m-2 appears to represent a useful and pragmatic cut-off point for identifying outpatients requiring comprehensive nutritional assessment and support. PMID- 27460165 TI - Maternal exposure to diluted diesel engine exhaust alters placental function and induces intergenerational effects in rabbits. AB - BACKGROUND: Airborne pollution is a rising concern in urban areas. Epidemiological studies in humans and animal experiments using rodent models indicate that gestational exposure to airborne pollution, in particular diesel engine exhaust (DE), reduces birth weight, but effects depend on exposure duration, gestational window and nanoparticle (NP) concentration. Our aim was to evaluate the effects of gestational exposure to diluted DE on feto-placental development in a rabbit model. Pregnant females were exposed to diluted (1 mg/m(3)), filtered DE (NP diameter ~ 69 nm) or clean air (controls) for 2 h/day, 5 days/week by nose-only exposure (total exposure: 20 days in a 31-day gestation). RESULTS: DE exposure induced early signs of growth retardation at mid gestation with decreased head length (p = 0.04) and umbilical pulse (p = 0.018). Near term, fetal head length (p = 0.029) and plasma insulin and IGF1 concentrations (p = 0.05 and p = 0.019) were reduced. Placental function was also affected, with reduced placental efficiency (fetal/placental weight) (p = 0.049), decreased placental blood flow (p = 0.009) and fetal vessel volume (p = 0.002). Non-aggregated and "fingerprint" NP were observed at various locations, in maternal blood space, in trophoblastic cells and in the fetal blood, demonstrating transplacental transfer. Adult female offspring were bred with control males. Although fetoplacental biometry was not affected near term, second generation fetal metabolism was modified by grand-dam exposure with decreased plasma cholesterol (p = 0.008) and increased triglyceride concentrations (p = 0.015). CONCLUSIONS: Repeated daily gestational exposure to DE at levels close to urban pollution can affect feto-placental development in the first and second generation. PMID- 27460167 TI - Antiviral activity of selected flavonoids against Chikungunya virus. AB - This study focuses on the antiviral activity of selected flavonoids against the Chikungunya virus (CHIKV), a mosquito-transmitted virus that can cause incapacitating arthritis in infected individuals. Based on the results of screening on Vero cells, the tested compounds were evaluated further with various assays, including cytotoxicity assay, virus yield assay by quantitative reverse transcription polymerase chain reaction (qRT-PCR), virus RNA replication assay with a CHIKV replicon cell line, Western blotting, and quantitative immunofluorescence assay. Baicalein, fisetin, and quercetagetin displayed potent inhibition of CHIKV infection, with 50% inhibitory concentrations [IC50] of 1.891 MUg/ml (6.997 MUM), 8.444 MUg/ml (29.5 MUM), and 13.85 MUg/ml (43.52 MUM), respectively, and with minimal cytotoxicity. The time-of-addition studies and various antiviral assays demonstrated that baicalein and quercetagetin mainly inhibited CHIKV binding to the Vero cells and displayed potent activity against extracellular CHIKV particles. The qRT-PCR, immunofluorescence assay, and Western blot analyses indicated that each of these flavonoids affects CHIKV RNA production and viral protein expression. These data provide the first evidence of the intracellular anti-CHIKV activity of baicalein, fisetin, and quercetagetin. PMID- 27460168 TI - Acetaminophen anaphylaxis diagnosed by skin prick test. PMID- 27460169 TI - How organic farming of wheat may affect the sourdough and the nutritional and technological features of leavened baked goods. AB - Organic farming is gaining broad recognition as a system that complies well with sustainability, an overarching principle that should drive agriculture now and in the coming year. Different cultivars and products can harbour different abundances of specific bacterial groups, farming system may influence the composition and abundances of microbial communities found on food product. Despite the growing interest towards organic foods, we still have a limited understanding of the diversity of food-associated microbial communities and the factors that influence the composition of these communities. Consumers in developed nations are commonly exposed to differences in farming practices through their choice between organic and conventionally farmed foods. Organic farming practices can differ from conventional farming practices in a variety of ways, including the types of fertilizer and pesticides that are used. This review aiming to gather current knowledge on chemical, technological, toxicological and functional properties and microbiota composition of wheat flours originating from organic and conventional farming systems and how the use of these may affect the sourdough fermentation and breadmaking. Sourdough fermentation is the most natural and best-performing process to ensure optimal sensory and functional characteristics. It fits perfectly into the processing chain that starts with the organic farming, especially for old wheat varieties with weaker technological properties. Recently, organic and sourdough microbiota diversity was investigated and in some case a comparison between organic and conventional microbial ecosystem was also carried out. Opposites evidences arise. Once a higher diversity of lactic acid bacteria species was found in conventional wheat sourdoughs, while when the diversity of Firmicutes was investigated, organic sourdoughs showed the highest complexity. When occurring, the differences between conventional and organic sourdough microbiota and their effects on bread properties are difficult to be identified and categorized due to the extremely large variability in baker's practices. Besides, this review would provide a critical view of this topic in order to avoid the speculation that in this field unavoidably arise. PMID- 27460170 TI - A Low-Symmetry Dysprosium Metallocene Single-Molecule Magnet with a High Anisotropy Barrier. AB - The single-molecule magnet (SMM) properties of the isocarbonyl-ligated dysprosium metallocene [Cp*2 Dy{MU-(OC)2 FeCp}]2 (1Dy ), which contains a rhombus-shaped Dy2 Fe2 core, are described. Combining a strong axial [Cp*](-) ligand field with a weak equatorial field consisting of the isocarbonyl ligands leads to an anisotropy barrier of 662 cm(-1) in zero applied field. The dominant thermal relaxation pathways in 1Dy involves at least the fourth-excited Kramers doublet, thus demonstrating that prominent SMM behavior can be observed for dysprosium in low-symmetry environments. PMID- 27460171 TI - Synthesis, biological evaluation and molecular modeling studies of psammaplin A and its analogs as potent histone deacetylases inhibitors and cytotoxic agents. AB - In this study, a concise synthetic method of psammaplin A was achieved from 3 bromo-4-hydroxybenzaldahyde and hydantoin through a four-step synthesis via Knoevenagel condensation, hydrolysis, oximation and amidation in 37% overall yield. A collection of novel psammaplin A analogs focused on the variations of substituents at the benzene ring and modifications at the oxime moiety were synthesized. Among all the synthesized compounds, 5d and 5e showed better HDAC inhibition than psammaplin A and comparable cytotoxicity against four cancer cell lines (PC-3, MCF-7, A549 and HL-60). Molecular docking and dynamics simulation revealed that (i) hydrogen atom of the oxime group interacts with Asp99 of HDAC1 through a water bridged hydrogen bond and (ii) a hydroxyl group is optimal attached on the para-position of benzene, interacting with Glu203 at the entrance to the active site tunnel. PMID- 27460172 TI - Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme. AB - Tricyclic, bicyclic, and monocyclic compounds containing cyanoenones induce various anti-inflammatory and cytoprotective enzymes through activation of the Keap1/Nrf2/ARE (antioxidant response element) pathway. The potency of these compounds as Nrf2 activators was determined using a prototypic cytoprotective enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The electron affinity (EA) of the compounds, expressed as the energy of their lowest unoccupied molecular orbital [E (LUMO)], was evaluated using two types of quantum mechanical calculations: the semiempirical (AM1) and the density functional theory (DFT) methods. We observed striking linear correlations [r=0.897 (AM1) and 0.936 (DFT)] between NQO1 inducer potency of these compounds and their E (LUMO) regardless of the molecule size. Importantly and interestingly, this finding demonstrates that the EA is the essentially important factor that determines the reactivity of the cyanoenones with Keap1. PMID- 27460177 TI - Phenamil enhances the adipogenic differentiation of hen preadipocytes. AB - A study was conducted to examine the effect of phenamil on adipogenic differentiation and expression of key adipogenic transcripts in hen preadipocytes. Preadipocytes were isolated from 20-week old Single Comb White Leghorn hens (Gallas gallus, Lohman strain). The experiment lasted for 48 h and had six treatments. Non-treated control (C) cells, cells treated with dexamethasone, 3-isobutyl-1-methylxanthine, insulin, and oleic acid (DMIOA) (T1), DMIOA + 15 MUM phenamil (T2), DMIOA + 30 MUM phenamil (T3), 15 MUM phenamil alone (T4), and 30 MUM phenamil alone (T5). Neutral lipid accumulation and the mRNA expression of key adipogenic transcripts were measured in all treatments and compared. Lipid accumulation was detected in T1, T2, and T3 only. Expression of peroxisome proliferator receptor-activator gamma 2 (PPARgamma2), the core enhancer binding protein alpha (C/EBPalpha), C/EBPbeta, fatty acid binding protein 4 (FABP4), and lipoprotein lipase (LPL) as well as ETS variant 4 (ETV4) and 5 was higher (P < 0.05) in T2, T3, T4, and T5 compared to C. Expression of these transcripts was higher (P < 0.05) in T2 and T3 compared to T4 and T5. The core enhancer binding protein alpha, C/EBPbeta, and FABP4 were highly expressed (P < 0.05) in T1 compared to C. However, the expression of PPARgamma2, LPL, and ETV4 and ETV5 was not significantly different. Expression of C/EBPalpha, C/EBPbeta, and FABP4 was higher (P < 0.05) in T2 and T3 compared to T1. Expression of sterol regulatory element binding protein 1 (SREBP1) and leptin receptor (LEPR) was not significantly different among the treatments. In conclusion, phenamil enhances DMIOA-induced adipogenic differentiation of hen preadipocytes but does not induce adipogenesis by itself. PMID- 27460179 TI - Clinicopathological features of histological transformation from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue to diffuse large B-cell lymphoma: an analysis of 467 patients. AB - This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation (HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) to diffuse large B cell lymphoma (DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases (n = 385) and 16% in advanced-stage diseases (n = 56) (P = 0.02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival (PFS) and overall survival (OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell (GCB)/non-GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 >= 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10(-) , BCL6(+) and MUM1(-) immunophenotypes; the remainder had CD10(+) immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS (P = 0.037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable. PMID- 27460178 TI - Legionella and risk management in hospitals-A bibliographic research methodology for people responsible for built environment and facility management. AB - An ongoing research project investigates the roles and duties of persons responsible for the built environment with respect to risk management of water systems and Legionella prevention from a facility management's perspective. Our literature review provides an approach for selecting and analysing abstracts of initially 177 journal articles, subjected to certain topic-specific inclusion and exclusion criteria. Different decision strategies of either logic 'yes/no', Boolean operators 'OR' or 'AND' and decisions for single counts or cumulative counts of the identified three principal keywords 'Legionella', 'hospital' and 'water', were completed. A final list of ten principal reference articles from 29 journals was compiled. It suggests that the interconnected perspective of water systems, Legionella and hospitals seems to be underrepresented in the field of the built environment and facility management. The term 'stakeholder', which would refer to decision-makers, was not found more than once. Our result is a useful summary of established sources of information on environmental Legionella research. The results can be helpful for those new to the topic. PMID- 27460180 TI - Hesperidin reverses cognitive and depressive disturbances induced by olfactory bulbectomy in mice by modulating hippocampal neurotrophins and cytokine levels and acetylcholinesterase activity. AB - Depression is a serious mental disorder that is becoming more common. To better treat patients suffering from this illness, elucidation of the underlying psychopathological and neurobiological mechanisms of depression is needed. Based on the evidence, we sought to investigate the effects of hesperidin in a model of depression induced by olfactory bulbectomy (OB). C57BL/6 mice were treated with hesperidin (50mg/kg) and imipramine (10mg/kg, positive control) after OB induction. The brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) levels and acetylcholinesterase activity were analyzed in the hippocampus of the mice. The behavioral parameters were also verified in the model of depression induced by OB. This study demonstrated that OB increased the pro-inflammatory cytokines levels and acetylcholinesterase activity in the hippocampus, exploratory activity in the open field test and immobility in the forced swimming test in mice. In addition, OB decreased the BDNF and NGF levels in the hippocampus, grooming time in the splash test and memory consolidation in the Morris water maze task. Treatment with hesperidin, similar to imipramine, was effective in preventing these behavioral and neurochemical alterations. We suggest that the main targets of hesperidin are pro-inflammatory cytokine modulation, helping to maintain brain plasticity and acetylcholinesterase activity regulation, which are closely linked with antidepressant-like action, as shown by behavior tests. This study demonstrated that there is a pharmacological effect of hesperidin in alterations induced by OB in mice, indicating that hesperidin could be useful as a treatment for depression. PMID- 27460181 TI - Genetically encoded protein photocrosslinker with a transferable mass spectrometry-identifiable label. AB - Coupling photocrosslinking reagents with mass spectrometry has become a powerful tool for studying protein-protein interactions in living systems, but it still suffers from high rates of false-positive identifications as well as the lack of information on interaction interface due to the challenges in deciphering crosslinking peptides. Here we develop a genetically encoded photo-affinity unnatural amino acid that introduces a mass spectrometry-identifiable label (MS label) to the captured prey proteins after photocrosslinking and prey-bait separation. This strategy, termed IMAPP (In-situ cleavage and MS-label transfer After Protein Photocrosslinking), enables direct identification of photo-captured substrate peptides that are difficult to uncover by conventional genetically encoded photocrosslinkers. Taking advantage of the MS-label, the IMAPP strategy significantly enhances the confidence for identifying protein-protein interactions and enables simultaneous mapping of the binding interface under living conditions. PMID- 27460182 TI - Workflow-driven clinical decision support for personalized oncology. AB - BACKGROUND: The adoption in oncology of Clinical Decision Support (CDS) may help clinical users to efficiently deal with the high complexity of the domain, lead to improved patient outcomes, and reduce the current knowledge gap between clinical research and practice. While significant effort has been invested in the implementation of CDS, the uptake in the clinic has been limited. The barriers to adoption have been extensively discussed in the literature. In oncology, current CDS solutions are not able to support the complex decisions required for stratification and personalized treatment of patients and to keep up with the high rate of change in therapeutic options and knowledge. RESULTS: To address these challenges, we propose a framework enabling efficient implementation of meaningful CDS that incorporates a large variety of clinical knowledge models to bring to the clinic comprehensive solutions leveraging the latest domain knowledge. We use both literature-based models and models built within the p medicine project using the rich datasets from clinical trials and care provided by the clinical partners. The framework is open to the biomedical community, enabling reuse of deployed models by third-party CDS implementations and supporting collaboration among modelers, CDS implementers, biomedical researchers and clinicians. To increase adoption and cope with the complexity of patient management in oncology, we also support and leverage the clinical processes adhered to by healthcare organizations. We design an architecture that extends the CDS framework with workflow functionality. The clinical models are embedded in the workflow models and executed at the right time, when and where the recommendations are needed in the clinical process. CONCLUSIONS: In this paper we present our CDS framework developed in p-medicine and the CDS implementation leveraging the framework. To support complex decisions, the framework relies on clinical models that encapsulate relevant clinical knowledge. Next to assisting the decisions, this solution supports by default (through modeling and implementation of workflows) the decision processes as well and exploits the knowledge embedded in those processes. PMID- 27460183 TI - Selective scanning tunneling microscope light emission from rutile phase of VO2. AB - We observed scanning tunneling microscope light emission (STM-LE) induced by a tunneling current at the gap between an Ag tip and a VO2 thin film, in parallel to scanning tunneling spectroscopy (STS) profiles. The 34 nm thick VO2 film grown on a rutile TiO2 (0 0 1) substrate consisted of both rutile (R)- and monoclinic (M)-structure phases of a few 10 nm-sized domains at room temperature. We found that STM-LE with a certain photon energy of 2.0 eV occurs selectively from R phase domains of VO2, while no STM-LE was observed from M-phase. The mechanism of STM-LE from R-phase VO2 was determined to be an interband transition process rather than inverse photoemission or inelastic tunneling processes. PMID- 27460184 TI - Anti-Ma and anti-Ma2-associated paraneoplastic neurological syndromes. AB - OBJECTIVE: Analyse the clinical profile, associated tumour types, and response to treatment of paraneoplastic neurological syndromes associated with antibodies against Ma proteins. METHODS: A retrospective study of patients with antibodies against Ma proteins identified in a neuroimmunology laboratory of reference. RESULTS: Of the 32 patients identified, 20 showed reactivity against Ma2 only (anti-Ma2 antibodies), 11 against Ma1 and Ma2 (anti-Ma antibodies), and 1 with reactivity against Ma1 only (anti-Ma1 antibodies). The most common clinical presentations were limbic encephalopathy, diencephalic dysfunction, or brainstem encephalopathy, frequently appearing as a combination of these features. Three patients had isolated cerebellar dysfunction with anti-Ma antibodies, and 2 exhibited peripheral nervous system syndrome with anti-Ma2 antibodies. Testicular tumours were the most common neoplasms (40%) in the anti-Ma2 cases. In the group associated with anti-Ma1 antibodies, the most common were lung tumours (36%), followed by testicular tumours. All idiopathic cases were reactive to Ma2. The clinical outcome was significantly better in the anti-Ma2 group. The patient with anti-Ma1 presented with limbic encephalitis and brainstem dysfunction associated with lymphoepithelioma of the bladder. CONCLUSIONS: Specifically determining the different reactivities of anti-Ma protein antibodies in order to differentiate between Ma1 and Ma2 antibodies is important because anti-Ma2-associated paraneoplastic syndromes have a better outcome. Lastly, this study is the first to confirm that there may be cases that react exclusively to antibodies against Ma1. PMID- 27460185 TI - Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia. AB - INTRODUCTION: Autosomal recessive spinocerebellar ataxia refers to a large group of diseases affecting the cerebellum and/or its connections, although they may also involve other regions of the nervous system. These diseases are accompanied by a wide range of systemic manifestations (cardiopathies, endocrinopathies, skeletal deformities, and skin abnormalities). DEVELOPMENT: This study reviews current knowledge of the most common forms of autosomal recessive spinocerebellar ataxia in order to provide tips that may facilitate diagnosis. CONCLUSIONS: A thorough assessment of clinical phenotype (pure cerebellar or cerebellar-plus syndrome, with or without systemic manifestations), laboratory tests (vitamin E, acanthocytosis, albumin, cholesterol, phytanic acid, lactic acid, creatine kinase, cholestanol, coenzyme Q10, alpha-fetoprotein, copper, ceruloplasmin, chitotriosidase), nerve conduction studies (presence and type of neuropathy), and an magnetic resonance imaging study (presence of cerebellar atrophy, presence and location of signal alterations) may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities (abetalipoproteinaemia, ataxia with vitamin E deficiency, Refsum disease, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, Wilson disease). Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible. PMID- 27460186 TI - Photoswitchable azobenzene-appended iridium(iii) complexes. AB - Iridium(iii) cyclometalated complexes have been used as models to study the effect that extended conjugation and substitution pattern has on the photochromic behavior of azobenzene-appended 2-phenylpyridyl (ppy) ligands. For this purpose four azobenzene-containing ppy ligands were synthesized. With these ligands, nine iridium(iii) complexes containing up to three appended azobenzenes were synthesized. Analysis of their photochromic behaviour by means of UV-vis and (1)H NMR spectroscopy permitted us to conclude that the light-induced trans-to-cis isomerization of the azobenzene was strongly inhibited upon coordination to the Ir(iii) cation when the electronic conjugation was extended along the whole ligand. The use of an aliphatic spacer unit (either -CH2- or -OCH2-) between the azobenzene and the ppy fragment of the ligand sufficed to disrupt the electronic communication, and obtain photochromic organometallic complexes. PMID- 27460187 TI - Congestive heart failure caused by transvenous pacemaker lead prolapse and associated right ventricular outflow tract obstruction in a dog. AB - A 16-year-old dog was presented for cough as well as increased respiratory rate and effort three years after implantation of a single-lead transvenous artificial pacemaker system. Thoracic radiographs and echocardiography disclosed prolapse of the pacemaker lead into the main pulmonary artery, causing severe pulmonary insufficiency and right-sided volume overload. Repositioning of the pacemaker lead led to improvement of pulmonary insufficiency and resolution of the dog's clinical signs and cavitary effusions. This case describes a late complication of pacemaker implantation that may be avoided by appropriate use of the manufacturer provided anchoring sleeve and avoidance of excessive lead redundancy. PMID- 27460190 TI - Orientational order and translational dynamics of magnetic particle assemblies in liquid crystals. AB - Implementing extensive molecular dynamics simulations we explore the organization of magnetic particle assemblies (clusters) in a uniaxial liquid crystalline matrix comprised of rodlike particles. The magnetic particles are modelled as soft dipolar spheres with diameter significantly smaller than the width of the rods. Depending on the dipolar strength coupling the magnetic particles arrange into head-to-tail configurations forming various types of clusters including rings (closed loops) and chains. In turn, the liquid crystalline matrix induces long range orientational ordering to these structures and promotes their diffusion along the director of the phase. Different translational dynamics are exhibited as the liquid crystalline matrix transforms either from isotropic to nematic or from nematic to smectic state. This is caused due to different collective motion of the magnetic particles into various clusters in the anisotropic environments. Our results offer a physical insight for understanding both the structure and dynamics of magnetic particle assemblies in liquid crystalline matrices. PMID- 27460189 TI - A novel approach for BCR-ABL1 standardization to improve International Scale estimation. AB - INTRODUCTION: Standardization of BCR-ABL1 messenger RNA quantification by real time PCR on the International Scale (IS) is critical for monitoring therapy response in chronic myelogenous leukaemia. Since 2006, BCR-ABL1 IS standardization is propagated along reference laboratories by calculating a laboratory-specific conversion factor (CF), co-ordinated in Europe through the European Treatment and Outcome Study project. Although this process has proven successful to some extent, it has not been achievable for all laboratories due to the complexity of the process and the stringent requirements in terms of numbers of samples to be exchanged. In addition, several BCR-ABL1 IS quantification methods and secondary reference materials became commercially available. However, it was observed that different IS methods generate consistently different results. METHODS: To overcome these difficulties, we have developed an alternative and simple approach of CF calculation, based on the retrospective analysis of existing external quality assessment (EQA) data. Our approach does not depend on the exchange of samples and is solely based on the mathematical CF calculation using EQA results. RESULTS AND CONCLUSION: We have demonstrated by thorough statistical validation that this approach performs well in converting BCR-ABL1 measurements to improve IS estimation. In expectation of a true golden standard method for BCR-ABL1 IS quantification, the proposed method is a valuable alternative. PMID- 27460188 TI - No relationship between prenatal androgen exposure and autistic traits: convergent evidence from studies of children with congenital adrenal hyperplasia and of amniotic testosterone concentrations in typically developing children. AB - BACKGROUND: There is a marked male preponderance in autism spectrum conditions. The extreme male brain theory and the fetal androgen theory of autism suggest that elevated prenatal testosterone exposure is a key contributor to autistic traits. The current paper reports findings from two separate studies that test this hypothesis. METHODS: A parent-report questionnaire, the Childhood Autism Spectrum Test (CAST), was employed to measure autistic traits in both studies. The first study examined autistic traits in young children with congenital adrenal hyperplasia (CAH), a condition causing unusually high concentrations of testosterone prenatally in girls. Eighty one children with CAH (43 girls) and 72 unaffected relatives (41 girls), aged 4-11 years, were assessed. The second study examined autistic traits in relation to amniotic testosterone in 92 typically developing children (48 girls), aged 3-5 years. RESULTS: Findings from neither study supported the association between prenatal androgen (testosterone) exposure and autistic traits. Specifically, young girls with and without CAH did not differ significantly in CAST scores and amniotic testosterone concentrations were not significantly associated with CAST scores in boys, girls, or the whole sample. CONCLUSIONS: These studies do not support a relationship between prenatal testosterone exposure and autistic traits. These findings augment prior research suggesting no consistent relationship between early androgen exposure and autistic traits. PMID- 27460192 TI - Evolution of RAG transposon unveiled. PMID- 27460191 TI - Acetylation modification regulates GRP78 secretion in colon cancer cells. AB - High glucose-regulated protein 78 (GRP78) expression contributes to the acquisition of a wide range of phenotypic cancer hallmarks, and the pleiotropic oncogenic functions of GRP78 may result from its diverse subcellular distribution. Interestingly, GRP78 has been reported to be secreted from solid tumour cells, participating in cell-cell communication in the tumour microenvironment. However, the mechanism underlying this secretion remains elusive. Here, we report that GRP78 is secreted from colon cancer cells via exosomes. Histone deacetylase (HDAC) inhibitors blocked GRP78 release by inducing its aggregation in the ER. Mechanistically, HDAC inhibitor treatment suppressed HDAC6 activity and led to increased GRP78 acetylation; acetylated GRP78 then bound to VPS34, a class III phosphoinositide-3 kinase, consequently preventing the sorting of GRP78 into multivesicular bodies (MVBs). Of note, we found that mimicking GRP78 acetylation by substituting the lysine at residue 633, one of the deacetylated sites of HDAC6, with a glutamine resulted in decreased GRP78 secretion and impaired tumour cell growth in vitro. Our study thus reveals a hitherto-unknown mechanism of GRP78 secretion and may also provide implications for the therapeutic use of HDAC inhibitors. PMID- 27460193 TI - Genomic landscape of gastric cancer: molecular classification and potential targets. AB - Gastric cancer imposes a considerable health burden worldwide, and its mortality ranks as the second highest for all types of cancers. The limited knowledge of the molecular mechanisms underlying gastric cancer tumorigenesis hinders the development of therapeutic strategies. However, ongoing collaborative sequencing efforts facilitate molecular classification and unveil the genomic landscape of gastric cancer. Several new drivers and tumorigenic pathways in gastric cancer, including chromatin remodeling genes, RhoA-related pathways, TP53 dysregulation, activation of receptor tyrosine kinases, stem cell pathways and abnormal DNA methylation, have been revealed. These newly identified genomic alterations await translation into clinical diagnosis and targeted therapies. Considering that loss of-function mutations are intractable, synthetic lethality could be employed when discussing feasible therapeutic strategies. Although many challenges remain to be tackled, we are optimistic regarding improvements in the prognosis and treatment of gastric cancer in the near future. PMID- 27460194 TI - Formation of membrane pores by gasdermin-N causes pyroptosis. PMID- 27460195 TI - Mid-term outcomes of a male retro-urethral, transobturator synthetic sling for treatment of post-prostatectomy incontinence: Impact of radiotherapy and storage dysfunction. AB - PURPOSE: To determine mid-term durability of the AdVance sling for post prostatectomy incontinence (PPI) and impact of prior radiotherapy and storage dysfunction. METHOD: Eighty men undergoing AdVance sling for PPI during 2008-2013 were reviewed. Pre-op urodynamics, pre and post-op pad usage, prior radiotherapy, and PGI-I scores were recorded. RESULT: Mean follow-up was 36 months (range 14 72). Twelve men had radiotherapy pre-op, 10 had detrusor overactivity (DO), and 20 reduced compliance. Pre-op mean 24-hr pad weight was 264 g and mean pads-per day (PPD) 2.60 +/- 0.29. In the early post-op period (3-6 months), mean PPD was 0.40 (SD 0.16); at mid-term follow-up mean PPD was 1.02 +/- 0.31. Radiotherapy and DO were independently predictive of poor mid-term outcome. Men with DO or radiotherapy were using 1.03 +/- 0.42 (P = 0.019) and 1.17 +/- 0.41 (P = 0.02) more PPD, respectively than men without these factors. At mid-term follow-up, men without radiotherapy or DO were using 1.98 +/- 0.28 less PPD compared to pre operatively (P < 0.0001); with radiotherapy or DO men were using 0.73 +/- 0.38 (P = 0.057) and 0.72 +/- 0.43 (P = 0.092) less PPD, respectively. PGI-I score for men without radiotherapy or DO was 1.98 +/- 0.40 ("much better"); with radiotherapy or DO PGI-I score was 3.80 +/- 0.49 ("no difference"). CONCLUSION: The AdVance sling provides mid-term improvement in men with PPI. However, men with radiotherapy or DO have significantly poorer outcomes with mid-term results indicating a return to baseline degree of incontinence. Caution should be taken when considering the AdVance sling in these men. Pre-op urodynamics in men with radiotherapy and/or overactive bladder may be important when considering men for AdVance sling. Neurourol. Urodynam. 36:1147-1150, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27460197 TI - In Reply to Drs Kounis, Kounis, Soufras, and Patsouras. PMID- 27460198 TI - Association of Cognitive Performance with Time at Altitude, Sleep Quality, and Acute Mountain Sickness Symptoms. AB - OBJECTIVE: It is well documented that cognitive performance may be altered with ascent to altitude, but the association of various cognitive performance tests with symptoms of acute mountain sickness (AMS) is not well understood. Our objective was to assess and compare cognitive performance during a high-altitude expedition using several tests and to report the association of each test with AMS, headache, and quality of sleep. METHODS: During an expedition to Mount Everest, 3 cognitive tests (Stroop, Trail Making, and the real-time cognitive assessment tool, an in-house developed motor accuracy test) were used along with a questionnaire to assess health and AMS. Eight team members were assessed pre expedition, postexpedition, and at several time points during the expedition. RESULTS: There were no significant differences (P >.05) found among scores taken at 3 time points at base camp and the postexpedition scores for all 3 tests. Changes in the Stroop test scores were significantly associated with the odds of AMS (P <.05). The logistic regression results show that the percent change from baseline for Stroop score (beta = -5.637; P = .032) and Stroop attempts (beta = 5.269; P = .049) are significantly associated with the odds of meeting the criteria for AMS. CONCLUSIONS: No significant changes were found in overall cognitive performance at altitude, but a significant relationship was found between symptoms of AMS and performance in certain cognitive tests. This research shows the need for more investigation of objective physiologic assessments to associate with self-perceived metrics of AMS to gauge effect on cognitive performance. PMID- 27460199 TI - The role of known variants of KCNQ1, KCNH2, KCNE1, SCN5A, and NOS1AP in water related deaths. AB - Drowning is one of the most frequent causes of accidental deaths worldwide, and still it remains a diagnosis of exclusion. Moreover, sudden cardiac deaths (SCD) or, if no actual cardiac alterations can be found, sudden unexplained deaths (SUD) represent a major group within mortality statistics as well. This leads to the assumption that there might be a general underlying cause for at least some cases of drowning, SCD, or SUD, for example, genetic aberrations in arrhythmia associated genes. In the present study, blood samples of 171 corpses found in water (drowning, death after almost drowning, and unclear deaths) were analyzed in 19 known variants of the genes KCNQ1, KCNH2, KCNE1, SCN5A, and NOS1AP by minisequencing. In three variants of NOS1AP, significant differences of allele and/or genotype frequencies could be demonstrated between victims of drowning and published controls as well as own controls. Moreover, similar differences were found comparing unexplained deaths in water and controls. Regarding the other genes, especially one single nucleotide polymorphism (SNP) of KCNQ1 could be associated with drowning. These results propose that performing a molecular autopsy analyzing known variants of arrhythmia-associated genes, in particular NOS1AP, may assist in establishing a cause of death for bodies found in water without clear drowning signs. PMID- 27460200 TI - Incidence of transfusion reactions: a multicenter study utilizing systematic active surveillance and expert adjudication. AB - BACKGROUND: Prevalence estimates of the serious hazards of transfusion vary widely. We hypothesized that the current reporting infrastructure in the United States fails to capture many transfusion reactions and undertook a multicenter study using active surveillance, data review, and adjudication to test this hypothesis. STUDY DESIGN AND METHODS: A retrospective record review was completed for a random sample of 17% of all inpatient transfusion episodes over 6 months at four academic tertiary care hospitals, with an episode defined as all blood products released to a patient in 6 hours. Data were recorded by trained clinical research nurses, and serious reactions were adjudicated by a panel of transfusion medicine experts. RESULTS: Of 4857 transfusion episodes investigated, 1.1% were associated with a serious reaction. Transfusion-associated circulatory overload was the most frequent serious reaction noted, being identified in 1% of transfusion episodes. Despite clinical notes describing a potential transfusion association in 59% of these cases, only 5.1% were reported to the transfusion service. Suspected transfusion-related acute lung injury/possible transfusion related acute lung injury, anaphylactic, and hypotensive reactions were noted in 0.08, 0.02, and 0.02% of transfusion episodes, respectively. Minor reactions, including febrile nonhemolytic and allergic, were noted in 0.62 and 0.29% of transfusion episodes, respectively, with 30 and 50% reported to the transfusion service. CONCLUSION: Underreporting of cardiopulmonary transfusion reactions is striking among academic, tertiary care hospitals. Complete and accurate reporting is essential to identify, define, establish pathogenesis, and mitigate/treat transfusion reactions. A better understanding of the failure to report may improve the accuracy of passive reporting systems. PMID- 27460201 TI - Efficacy of repetitive transcranial magnetic stimulation with quetiapine in treating bipolar II depression: a randomized, double-blinded, control study. AB - The clinical and cognitive responses to repetitive transcranial magnetic stimulation (rTMS) in bipolar II depressed patients remain unclear. In this study, thirty-eight bipolar II depressed patients were randomly assigned into three groups: (i) left high-frequency (n = 12), (ii) right low-frequency (n = 13), (iii) sham stimulation (n = 13), and underwent four-week rTMS with quetiapine concomitantly. Clinical efficacy was evaluated at baseline and weekly intervals using the 17-item Hamilton Depression Rating Scale (HDRS-17) and Montgomery-Asberg Depression Rating Scale (MADRS). Cognitive functioning was assessed before and after the study with the Wisconsin Card Sorting Test (WCST), Stroop Word-Color Interference Test (Stroop), and Trail Making Test (TMT). Thirty five patients were included in the final analysis. Overall, the mean scores of both the HDRS-17 and the MADRS significantly decreased over the 4-week trial, which did not differ among the three groups. Exploratory analyses revealed no differences in factor scores of HDRS-17s, or in response or remission rates. Scores of WCST, Stroop, or TMT did not differ across the three groups. These findings indicated active rTMS combined with quetiapine was not superior to quetiapine monotherapy in improving depressive symptoms or cognitive performance in patients with bipolar II depression. PMID- 27460203 TI - The Path From Hormone Abnormality to Hypoglycemia. PMID- 27460202 TI - RGDS- and SIKVAVS-Modified Superporous Poly(2-hydroxyethyl methacrylate) Scaffolds for Tissue Engineering Applications. AB - Three-dimensional hydrogel supports for mesenchymal and neural stem cells (NSCs) are promising materials for tissue engineering applications such as spinal cord repair. This study involves the preparation and characterization of superporous scaffolds based on a copolymer of 2-hydroxyethyl and 2-aminoethyl methacrylate (HEMA and AEMA) crosslinked with ethylene dimethacrylate. Ammonium oxalate is chosen as a suitable porogen because it consists of needle-like crystals, allowing their parallel arrangement in the polymerization mold. The amino group of AEMA is used to immobilize RGDS and SIKVAVS peptide sequences with an N-gamma maleimidobutyryloxy succinimide ester linker. The amount of the peptide on the scaffold is determined using 125 I radiolabeled SIKVAVS. Both RGDS- and SIKVAVS modified poly(2-hydroxyethyl methacrylate) scaffolds serve as supports for culturing human mesenchymal stem cells (MSCs) and human fetal NSCs. The RGDS sequence is found to be better for MSC and NSC proliferation and growth than SIKVAVS. PMID- 27460204 TI - Pseudomonas kribbensis sp. nov., isolated from garden soils in Daejeon, Korea. AB - Two bacterial strains, 46-1 and 46-2T, were isolated from garden soil. These strains were observed to be aerobic, Gram-stain negative, rod-shaped, non-spore forming, motile and catalase and oxidase positive. Phylogenetic analysis based on 16S rRNA gene sequences showed that the two strains shared 100 % sequence similarity with each other and belong to the genus Pseudomonas in the class Gammaproteobacteria. The concatenated 16S rRNA, gyrB, rpoB and rpoD gene sequences further confirmed that the isolates belong to the Pseudomonas koreensis subgroup (SG), with P. koreensis Ps 9-14T, Pseudomonas moraviensis 1B4T and Pseudomonas granadensis F-278,770T as their close relatives (>96 % pairwise similarity). DNA-DNA hybridization with the closely related type strain P. koreensis SG revealed a low level of relatedness (<50 %). A cladogram constructed using whole-cell matrix-assisted laser desorption/ionization time-of-flight (WC MALDI-TOF) MS analysis showed the isolates formed a completely separate monophyletic group. The isolates were negative for utilization of glycogen, D psicose, alpha-keto butyric acid, alpha-keto valeric acid, succinamic acid and D, L-alpha-glycerol phosphate. In contrast, all these reactions were positive in P. koreensis JCM 14769T and P. moraviensis DSM 16007T. The fatty acid C17:0 cyclo was detected as one of the major cellular fatty acids (>15 %) in the isolates but it was a minor component (<4 %) in both reference type strains. In contrast, the fatty acid, C12:0 was not observed in the isolates but was present in both reference strains. Based on differences such as phylogenetic position, low-level DNA-DNA hybridization, WC-MALDI-TOF MS analysis, fluorescence pigmentation, fatty acid profiles, and substrate utilization, we propose that the isolates 46-1 and 46-2T represent a novel species of the genus Pseudomonas, for which the name Pseudomonas kribbensis sp. nov. is proposed; the type strain is 46-2T (=KCTC 32541T = DSM 100278T). PMID- 27460205 TI - ALK ambiguous-positive non-small cell lung cancers are tumors challenged by diagnostic and therapeutic issues. AB - Searching for ALK rearrangements using the approved fluorescent in situ hybridization (FISH) test and complementary immunohistochemistry (IHC) has become the rule to treat patients with advanced non-small cell lung cancer (NSCLC) with anti-ALK targeted therapy. The concordance between the two techniques is reported to be strong but imperfect. We report our experience with cases of ALK-rearranged lung adenocarcinomas pointing out particularly ambiguous cases. FISH and IHC data on ALK but also c-MET IHC as well as EGFR and KRAS mutation screening are considered, together with response to crizotinib treatment. We classified the 55 FISH ALK-rearranged tumors into two groups according to the FISH and IHC results: a concordant FISH+IHC+ group (31 tumors) and an ambiguous group (24 tumors). These tumors were considered as 'ambiguous' ALK-positive due to negative (21 tumors) or non-contributive (3 tumors) IHC. In addition, the percentage of FISH positive nuclei was between 15 and 20% in 17 tumors belonging to one or the other group (now called borderline tumors). We discuss the accuracy of the different tests with intent to determine whether ambiguous and borderline tumors are real positive ALK-rearranged tumors. To conclude, ambiguous ALK-positive lung cancers are challenging tumors with diagnosis and therapeutic issues that can justify parallel FISH, IHC and molecular screening strategy. PMID- 27460206 TI - Therapeutic monoclonal antibodies and derivatives: Historical perspectives and future directions. AB - Biologics, both monoclonal antibodies (mAbs) and fusion proteins, have revolutionized the practice of medicine. This year marks the 30th anniversary of the Food and Drug Administration approval of the first mAb for human use. In this review, we examine the biotechnological breakthroughs that spurred the explosive development of the biopharmaceutical mAb industry, as well as how critical lessons learned about human immunology informed the development of improved biologics. We also discuss the most common mechanisms of action of currently approved biologics and the indications for which they have been approved to date. PMID- 27460208 TI - Extractive Atmospheric Pressure Photoionization (EAPPI) Mass Spectrometry: Rapid Analysis of Chemicals in Complex Matrices. AB - Extractive atmospheric pressure photoionization (EAPPI) mass spectrometry was designed for rapid qualitative and quantitative analysis of chemicals in complex matrices. In this method, an ultrasonic nebulization system was applied to sample extraction, nebulization, and vaporization. Mixed with a gaseous dopant, vaporized analytes were ionized through ambient photon-induced ion-molecule reactions, and were mass-analyzed by a high resolution time-of-flight mass spectrometer (TOF-MS). After careful optimization and testing with pure sample solution, EAPPI was successfully applied to the fast screening of capsules, soil, natural products, and viscous compounds. Analysis was completed within a few seconds without the need for preseparation. Moreover, the quantification capability of EAPPI for matrices was evaluated by analyzing six polycyclic aromatic hydrocarbons (PAHs) in soil. The correlation coefficients (R (2) ) for standard curves of all six PAHs were above 0.99, and the detection limits were in the range of 0.16-0.34 ng/mg. In addition, EAPPI could also be used to monitor organic chemical reactions in real time. Graphical Abstract ?. PMID- 27460209 TI - Design, synthesis and optimization of novel Alk5 (activin-like kinase 5) inhibitors. AB - Using SBDD, a series of 4-amino-7-azaindoles were discovered as a novel class of Alk5 inhibitors that are potent in both Alk5 enzymatic and cellular assays. Subsequently a ring cyclization strategy was utilized to improve ADME properties leading to the discovery of a series of 1H-imidazo[4,5-c]pyridin-2(3H)-one drug like Alk5 inhibitors. PMID- 27460210 TI - EPR and DFT analysis of biologically relevant chromium(V) complexes with d glucitol and d-glucose. AB - 1,2-diolato ligands, such as carbohydrates and glycoproteins, tend to stabilize chromium(V), thus forming important intermediates that have been implicated in the genotoxicity of Cr(VI). Since many years, room-temperature continuous-wave electron paramagnetic resonance (EPR) at X-band microwave frequencies has been used as a standard characterization tool to study chromium(V) intermediates formed during the reduction of Cr(VI) in the presence of biomolecules. In this work, the added value is tested of using a combination of pulsed and high-field EPR techniques with density functional theory computations to unravel the nature of Cr(V) complexes with biologically relevant chelators, such as carbohydrates. The study focuses on the oxidochromium(V) complexes formed during reduction of potassium dichromate with glutathione in the presence of the monosaccharide d glucose or the polyalcohol d-glucitol. It is shown that although the presence of a multitude of Cr(V) intermediates may hamper a complete structural determination, the combined EPR and DFT approach reveals unambiguously the effect of freezing on the location of the counterions, the gradual replacement of water ligands by the diols, and the preference of Cr(V) to bind certain conformers. PMID- 27460211 TI - Pharmacological regimens for eradication of Helicobacter pylori: an overview of systematic reviews and network meta-analysis. AB - BACKGROUND: Approximately half of the world's population is infected with Helicobacter pylori (H.pylori), a bacterium shown to be linked with a series of gastrointestinal diseases. A growing number of systematic reviews (SRs) have been published comparing the effectiveness of different treatments for H.pylori infection but have not reached a consistent conclusion. The objective of this study is to provide an overview of SRs of pharmacological therapies for the eradication of H.pylori. METHODS: Major electronic databases were searched to identify relevant SRs published between 2002 and February 2016. Studies were considered eligible if they included RCTs comparing different pharmacological regimens for treating patients diagnosed as H.pylori infected and pooled the eradication rates in a meta-analysis. A modified version of the 'A Measurement Tool to Assess Systematic Reviews' (AMSTAR) was used to assess the methodological quality. A Bayesian random effects network meta-analysis (NMA) was conducted to compare the different proton pump inhibitors (PPI) within triple therapy. RESULTS: 30 SRs with pairwise meta-analysis were included. In triple therapy, the NMA ranked the esomeprazole to be the most effective PPI, followed by rabeprazole, while no difference was observed among the three old generations of PPI for the eradication of H.pylori. When comparing triple and bismuth-based therapy, the relative effectiveness appeared to be dependent on the choice of antibiotics within the triple therapy; moxifloxacin or levofloxacin-based triple therapy were both associated with greater effectiveness than bismuth-based therapy as a second-line treatment, while bismuth-based therapy achieved similar or greater eradication rate compared to clarithromycin-based therapy. Inconsistent findings were reported regarding the use of levofloxacin/moxifloxacin in the first-line treatment; this could be due to the varied resistant rate to different antibiotics across regions and populations. Critical appraisal showed a low-moderate level of overall methodological quality of included studies. CONCLUSIONS: Our analysis suggests that the new generation of PPIs and use of moxifloxacin or levofloxacin within triple therapy as second line treatment were associated with greater effectiveness. Given the varied antibiotic resistant rate across regions, the appropriateness of pooling results together in meta-analysis should be carefully considered and the recommendation of the choice of antibiotics should be localized. PMID- 27460213 TI - Wastewater treatment aeration process optimization: A data mining approach. AB - Being water quality oriented, large-scale industries such as wastewater treatment plants tend to overlook potential savings in energy consumption. Wastewater treatment process includes energy intensive equipment such as pumps and blowers to move and treat wastewater. Presently, a data-driven approach has been applied for aeration process modeling and optimization of one large scale wastewater in Midwest. More specifically, aeration process optimization is carried out with an aim to minimize energy usage without sacrificing water quality. Models developed by data mining algorithms are useful in developing a clear and concise relationship among input and output variables. Results indicate that a great deal of saving in energy can be made while keeping the water quality within limit. Limitation of the work is also discussed. PMID- 27460212 TI - Recent exposure to ultrafine particles in school children alters miR-222 expression in the extracellular fraction of saliva. AB - BACKGROUND: Ultrafine particles (<100 nm) are ubiquitous present in the air and may contribute to adverse cardiovascular effects. Exposure to air pollutants can alter miRNA expression, which can affect downstream signaling pathways. miRNAs are present both in the intracellular and extracellular environment. In adults, miR-222 and miR-146a were identified as associated with particulate matter exposure. However, there is little evidence of molecular effects of ambient air pollution in children. This study examined whether exposure to fine and ultrafine particulate matter (PM) is associated with changes in the extracellular content of miR-222 and miR-146a of children. METHODS: Saliva was collected from 80 children at two different time points, circa 11 weeks apart and stabilized for RNA preservation. The extracellular fraction of saliva was obtained by means of differential centrifugation and ultracentrifugation. Expression levels of miR-222 and miR-146a were profiled by qPCR. We regressed the extracellular miRNA expression against recent exposure to ultrafine and fine particles measured at the school site using mixed models, while accounting for sex, age, BMI, passive smoking, maternal education, hours of television use, time of the day and day of the week. RESULTS: Exposure to ultrafine particles (UFP) at the school site was positively associated with miR-222 expression in the extracellular fraction in saliva. For each IQR increase in particles in the class room (+8504 particles/cm(3)) or playground (+28776 particles/cm(3)), miR-222 was, respectively 23.5 % (95 % CI: 3.5 %-41.1 %; p = 0.021) or 29.9 % (95 % CI:10.6 % 49.1 %; p = 0.0027) higher. No associations were found between miR-146a and recent exposure to fine and ultrafine particles. CONCLUSIONS: Our results suggest a possible epigenetic mechanism via which cells respond rapidly to small particles, as exemplified by miR-222 changes in the extracellular fraction of saliva. PMID- 27460214 TI - Technological change in revitalization - Phytoremediation and the role of nonknowledge. AB - In the 1990s, remediation methods that use plants to investigate and extract contaminations were developed. According to their proponents, these technologies have considerable potential for greening remediation and to develop a more sustainable trajectory for revitalization. Although a great deal of research has been conducted on these technologies they have, so far, rarely been applied in European countries. This article will contribute a perspective from social science to this debate. By taking an approach inspired by social science practice theories, attention will be drawn to a specific socio-cultural aspect: dealing with nonknowledge. The analysis of remediation practices reveals how the phenomenon of nonknowledge becomes relevant in the process of inventing and applying new technologies. This allows for a better understanding of technological innovation processes in remediation. Based on this understanding strategies are suggested which might increase the use of plant-based technologies in remediation and site management. PMID- 27460215 TI - Adaptive management for ecosystem services. AB - Management of natural resources for the production of ecosystem services, which are vital for human well-being, is necessary even when there is uncertainty regarding system response to management action. This uncertainty is the result of incomplete controllability, complex internal feedbacks, and non-linearity that often interferes with desired management outcomes, and insufficient understanding of nature and people. Adaptive management was developed to reduce such uncertainty. We present a framework for the application of adaptive management for ecosystem services that explicitly accounts for cross-scale tradeoffs in the production of ecosystem services. Our framework focuses on identifying key spatiotemporal scales (plot, patch, ecosystem, landscape, and region) that encompass dominant structures and processes in the system, and includes within- and cross-scale dynamics, ecosystem service tradeoffs, and management controllability within and across scales. Resilience theory recognizes that a limited set of ecological processes in a given system regulate ecosystem services, yet our understanding of these processes is poorly understood. If management actions erode or remove these processes, the system may shift into an alternative state unlikely to support the production of desired services. Adaptive management provides a process to assess the underlying within and cross scale tradeoffs associated with production of ecosystem services while proceeding with management designed to meet the demands of a growing human population. PMID- 27460216 TI - Monitoring of the degradation kinetics of diatrizoate sodium to its cytotoxic degradant using a stability-indicating high-performance liquid chromatographic method. AB - The X-ray diagnostic agent sodium diatrizoate (DTA) was studied for chemical degradation. The 3,5-diamino derivative was found to be the alkaline and acidic degradation product. The 3,5-diamino degradate is also the synthetic precursor of DTA and it is proved to have cytotoxic and mutagenic effects. A sensitive, selective and precise high-performance liquid chromatographic stability indicating method for the determination of DTA in the presence of its acidic degradation product and in pharmaceutical formulation was developed and validated. Owing to the high toxicity of the degradation product, the kinetics of the acidic degradation process was monitored by the developed RP-HPLC method. The reaction was found to follow pseudo-first order kinetics. The kinetic parameters such as rate constant (K) and half-life (t1/2 ) were calculated under different temperatures and acid concentrations; activation energy was estimated from the Arrhenius plot. The developed RP-HPLC method depends on isocratic elution of a mobile phase composed of methanol-water (25:75 v/v; pH adjusted with phosphoric acid), and UV detection at 238 nm. The method showed good linearity over a concentration range of 2-100 MUg/mL with mean percentage recovery of 100.04 +/- 1.07. The selectivity of the proposed method was tested using laboratory-prepared mixtures. The proposed method has been successfully applied to the analysis of DTA in pharmaceutical dosage forms without interference from other dosage form additives and the results were statistically compared with the official USP method. Validation of the proposed method was performed according to International Conference on Harmonization guidelines. PMID- 27460217 TI - Fine-scale genetic structure of natural Tuber aestivum sites in southern Germany. AB - Although the Burgundy truffle (Tuber aestivum) is an ectomycorrhizal fungus of important economic value, its subterranean life cycle and population biology are still poorly understood. Here, we determine mating type and simple sequence repeat (SSR) maternal genotypes of mapped fruiting bodies to assess their genetic structure within two naturally colonized forest sites in southern Germany. Forty one genotypes were identified from 112 fruiting bodies. According to their mating types, the maternal genotypes were aggregated only in one population. Genotypic diversity of individuals that mostly were small and occurred in 1 out of 2 years of sampling was high. Although these results suggested a ruderal colonization strategy, some genets spread several hundred meters. This result indicates that, besides sexual spore dispersal, vegetative growth or spreading by mycelial propagules contributes to dissemination. In one site, fewer individuals with a tendency to expand genets belonging to only one genetic group were observed. In the second site, numerous small individuals were found and were grouped into two clearly differentiated genetic groups that were spatially intermingled. Forest characteristics and disturbances are possible reasons for the observed genetic patterns. Our findings contribute to a better understanding of the biology of one of the most widespread and commercially important truffle species. This knowledge is critical for establishing and maintaining sustainable long-term truffle cultivations. PMID- 27460219 TI - Severe hyperkalemia following adrenalectomy for aldosteronoma: prediction, pathogenesis and approach to clinical management- a case series. AB - BACKGROUND: As the field of Primary Aldosteronism (PA) becomes ever expanded, diagnosis of PA is increasingly diagnosed by endocrinologists. With increased PA screening, many of the cases are now found in patients with complex co morbidities in addition to their hypertension. Post adrenalectomy renal impairment with hyperkalemia is now increasingly seen in these complex patients, as evidenced by the numerous reports on this issue that have appeared within the past 3 years. We present a small case series to illustrate the breadth of the problem, along with a discussion about how such CKD/hyperkalemic events may be predicted. CASE PRESENTATION: We present three cases of primary aldosteronism with long standing hypertension (more than 10 years) hypokalemia (2.0-3.0 mmol/l). Serum aldosterone was high with low renin activity leading to high aldosterone to renin ratio (ARR). They underwent abdominal CT scan revealing adrenal mass and adrenal vein sample confirmed lateralization. None of the patients had evidence of renal disease before surgery (as evident by normal eGFR and serum creatinine). Post adrenalectomy they had reduction in the blood pressure and became eukalemic. Serum aldosterone and renin activity were low leading to a low ARR. Case 1 developed hyperkalemia and increased serum creatinine 6 weeks post operatively which resolved with initiation of fludrocortisone and every attempt to discontinue fludrocortisone resulted in hyperkalemia and rising creatinine. Her hyperkalemia is under control with oral sodium bicarbonate. Case 2 developed hyperkalemia and increasing creatinine 2 months post operatively transiently requiring fludrocortisone and later on managed with furosemide for hyperkalemia. Case 3 developed renal impairment and hyperkalemia 2 weeks post operatively requiring fludrocortisone. CONCLUSION: Post APA resection severe hyperkalemia may be a common entity and screening should be actively considered in high risk patients. Older age, longer duration of hypertension, impaired pre-op and post-op GFR and higher levels of pre-op aldosterone and are all risk factors which predict the likelihood of developing post-operative hyperkalemia. Fludrocortisone, sodium bicarbonate, loop diuretics and potassium binders can be used for treatment. Treatment choice should be tailored to patient characteristics including fluid status, blood pressure and serum creatinine. Potassium binders should be avoided in patients with history of recent abdominal surgery, opioid use and constipation. Serum electrolytes and creatinine should be monitored every 1-2 weeks after starting treatment to ensure an adequate response. Prolonged management may be necessary in some cases and at risk patients should be counselled as to the meaning and importance of post operative changes in measured renal function and potassium. PMID- 27460218 TI - Silencing of hepatic fate-conversion factors induce tumorigenesis in reprogrammed hepatic progenitor-like cells. AB - BACKGROUND: Several studies have reported the direct conversion of mouse fibroblasts to hepatocyte-like cells with different degrees of maturation by expression of hepatic fate-conversion factors. METHODS: We have used a combination of lentiviral vectors expressing hepatic fate-conversion factors with Oct4, Sox2, Klf4, and Myc to convert mouse embryonic fibroblasts into hepatic cells. RESULTS: We have generated hepatic cells with progenitor-like features (iHepL cells). iHepL cells displayed basic hepatocyte functions but failed to perform functions characteristic of mature hepatocytes such as significant Cyp450 or urea cycle activities. iHepL cells expressed multiple hepatic-specific transcription factors and functional genes characteristic of immature hepatocytes and cholangiocytes, as well as high levels of Foxl1, Cd24a, and Lgr5, specific markers of hepatic progenitor cells. When transplanted into partial hepatectomized and hepatic irradiated mice, they differentiated into hepatocytes and cholangiocytes. However, iHepL cells formed malignant non-teratoma cell aggregations in one out of five engrafted livers and five out of five xenografts assays. All the cells in these tumors had silenced key hepatic fate-conversion factors, and lost hepatic features. CONCLUSIONS: This study highlights the dangers of using pluripotency factors in reprogramming strategies when fate conversion factors are silenced in vivo, and urges us to perform extensive tumorigenic tests in reprogrammed cells. PMID- 27460221 TI - Concordance between self-reported pre-pregnancy body mass index (BMI) and BMI measured at the first prenatal study contact. AB - BACKGROUND: The 2009 Institute of Medicine (IOM) gestational weight recommendations are tailored to women's pre-pregnancy body mass index (BMI). Limited evidence exists on methods for estimating women's pre-pregnancy BMI, particularly for women living in low and middle income countries. Using data from collected among Peruvian pregnant women, we compared the concordance between self reported pre-pregnancy BMI with BMI measured at the earliest prenatal study visit. METHODS: Data were from the Pregnancy Outcomes Maternal and Infant Study (PrOMIS), a cohort of pregnant women at the Instituto Nacional Materno Perinatal (INMP) in Lima, Peru. 2605 women aged 18 to 49 years (mean +/- SD gestational age = 10.9 +/- 3.3 weeks) were included in the study. Self-reported pre-pregnancy weight and height and measured weight and height were collected at the first prenatal study contact. We assessed the concordance between measured and self reported BMI; and, the agreement among indicators of nutritional status obtained using measured and self-reported BMI. RESULTS: On average, weight measured at the first prenatal study visit was 0.27 kg higher than self-reported pre-pregnancy weight (p < 0.05); and, measured height was 0.02 m lower than self-reported pre pregnancy height (p < 0.001). Correspondingly, measured BMI was 0.71 kg/m(2) higher than self-reported BMI (p < 0.001). Scatter and Bland-Altman plots indicated strong concordance between measured and self-reported BMI. The proportion of women in the normal BMI category tended to be higher when using self-reported BMI (59.6 %) than when using measured BMI (50.4 %). Conversely, the proportion of women in the overweight or obese BMI categories tended to be lower when using self-reported BMI (38.2 %) than when using measured BMI (47.7 %). CONCLUSION: Self-reported pre-pregnancy BMI was strongly correlated with BMI measured at the first prenatal study contact. The findings potentially suggest that, in this context, there is minimal change between pre-pregnancy BMI and BMI measured at the first prenatal study contact; or, that women in this study just recalled their most recent measured anthropometrics (including values obtained during the index pregnancy but before enrollment in the PrOMIS study). PMID- 27460220 TI - Cigarette smoke alters the ability of human dendritic cells to promote anti Streptococcus pneumoniae Th17 response. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation and impaired immune response to pathogens leading to bacteria-induced exacerbation of the disease. A defect in Th17 cytokines in response to Streptococcus pneumoniae, a bacteria associated with COPD exacerbations, has been recently reported. Dendritic cells (DC) are professional antigen presenting cells that drive T-cells differentiation and activation. In this study, we hypothesized that exposure to cigarette smoke, the main risk factor of COPD, might altered the pro-Th17 response to S. pneumoniae in COPD patients and human DC. METHODS: Pro-Th1 and -Th17 cytokine production by peripheral blood mononuclear cells (PBMC) from COPD patients was analyzed and compared to those from smokers and non-smokers healthy subjects. The effect of cigarette smoke extract (CSE) was analyzed on human monocyte-derived DC (MDDC) from controls exposed or not to S. pneumoniae. Bacteria endocytosis, maturation of MDDC and secretion of cytokines were assessed by flow cytometry and ELISA, respectively. Implication of the oxidative stress was analyzed by addition of antioxidants and mitochondria inhibitors. In parallel, MDDC were cocultured with autologous T-cells to analyze the consequence on Th1 and Th17 cytokine production. RESULTS: PBMC from COPD patients exhibited defective production of IL 1beta, IL-6, IL-12 and IL-23 to S. pneumoniae compared to healthy subjects and smokers. CSE significantly reduced S. pneumoniae-induced MDDC maturation, secretion of pro-Th1 and -Th17 cytokines and activation of Th1 and Th17 T-cell responses. CSE exposure was also associated with sustained CXCL8 secretion, bacteria endocytosis and mitochondrial oxidative stress. Antioxidants did not reverse these effects. Inhibitors of mitochondrial electron transport chain partly reproduced inhibition of S. pneumoniae-induced MDDC maturation but had no effect on cytokine secretion and T cell activation. CONCLUSIONS: We observed a defective pro-Th1 and -Th17 response to bacteria in COPD patients. CSE exposure was associated with an inhibition of DC capacity to activate antigen specific T cell response, an effect that seems to be not only related to oxidative stress. These results suggest that new therapeutics boosting this response in DC may be helpful to improve treatment of COPD exacerbations. PMID- 27460222 TI - Designing high-energy lithium-sulfur batteries. AB - Due to their high energy density and low material cost, lithium-sulfur batteries represent a promising energy storage system for a multitude of emerging applications, ranging from stationary grid storage to mobile electric vehicles. This review aims to summarize major developments in the field of lithium-sulfur batteries, starting from an overview of their electrochemistry, technical challenges and potential solutions, along with some theoretical calculation results to advance our understanding of the material interactions involved. Next, we examine the most extensively-used design strategy: encapsulation of sulfur cathodes in carbon host materials. Other emerging host materials, such as polymeric and inorganic materials, are discussed as well. This is followed by a survey of novel battery configurations, including the use of lithium sulfide cathodes and lithium polysulfide catholytes, as well as recent burgeoning efforts in the modification of separators and protection of lithium metal anodes. Finally, we conclude with an outlook section to offer some insight on the future directions and prospects of lithium-sulfur batteries. PMID- 27460224 TI - Implementation of protocolized tight control and biological dose optimization in daily clinical practice: results of a pilot study. AB - OBJECTIVES: To assess the effects of education, guideline development, and individualized treatment advice on rheumatologist adherence to tight control based treatment and biological dose optimization in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthropathy (SpA) patients. METHOD: This pilot study, among two rheumatologists and two specialized nurses in a general hospital, combined education, feedback, local guideline development, and individualized treatment advice. Outcomes (baseline and 1 year post-intervention) were the percentage of patients with a Disease Activity Score in 28 joints (DAS28) or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) measured during the visit, mean DAS28/BASDAI, and the percentage of patients using a reduced biological dose. DAS28 outcomes only applied to RA and PsA patients, BASDAI outcomes only applied to SpA patients whereas outcomes on biological dose applied to all patients. RESULTS: A total of 232 patients (67% RA, 15% PsA, 18% SpA; 58% female, mean age 56 +/- 15 years) were included in the study. The percentage of DAS28 and BASDAI measurements performed increased after the intervention [DAS28 15-51%, odds ratio (OR) 3.3, 95% confidence interval (CI) 2.1 5.5; BASDAI 23-50%, OR 2.2, 95% CI 1.0-5.5], with mean DAS28 and BASDAI scores remaining similar (DAS28: mean difference 0.1, 95% CI -0.3 to 0.5; BASDAI: mean difference 0.03, 95% CI -1.8 to 1.9). Use of a reduced biological dose increased from 10% to 61% (OR 3.9, 95% CI 2.4-6.5). CONCLUSIONS: A multicomponent intervention strategy aimed at rheumatologists can lead to improved adherence to tight control-based treatment and a reduction in the use of biologicals in RA, SpA, and PsA patients. PMID- 27460223 TI - Heterogeneity of incidence and outcome of acute exacerbation in idiopathic interstitial pneumonia. AB - BACKGROUND AND OBJECTIVE: Acute exacerbations (AEs) of idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonia (IIP) have a poor prognosis. This study aims to clarify the incidence and prognosis of AE in IPF and the other IIP. METHODS: A total of 229 patients were enrolled, of whom 92 had IPF and 137 had 'IIP other than IPF' based on the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) 2011 IPF Guidelines. IIP other than IPF included 11 patients with a surgical lung biopsy (SLB) and the remainder without such a biopsy. IIP other than IPF was further classified into IIP with a 'possible usual interstitial pneumonia (UIP)' pattern on HRCT (n = 75) and IIP with 'inconsistent with UIP' pattern (n = 62) based on published guidelines. Predictors of AE and the prognosis after AE were examined in these groups. RESULTS: The 1-year incidence of AE in IPF, IIP with possible UIP HRCT patterns and IIP with inconsistent with UIP HRCT patterns was 16.5%, 8.9% and 4.0%, respectively. AE occurred significantly more frequently in IPF than in IIP with possible UIP and inconsistent with UIP HRCT patterns after adjustment for BMI, modified Medical Research Council score and %forced vital capacity. Prognosis of AE-IIP with possible UIP HRCT pattern was significantly worse than that of AE IPF. CONCLUSION: Although AE occurred significantly less frequently in IIP with possible UIP and inconsistent with UIP HRCT patterns than in IPF, the prognosis of AE-IIP with possible UIP HRCT patterns might be worse than that of AE-IPF. PMID- 27460226 TI - [Robot-assisted surgeries in visceral surgery]. PMID- 27460225 TI - Cues and clues predicting presence of symptoms of depression in stroke survivors. AB - AIMS AND OBJECTIVES: To investigate to what extent self-reported cues about lack of treatment or concerns about inadequate health care from stroke survivors were associated with symptoms of depression. BACKGROUND: Stroke survivors are prone to depression, and thus, any easily available cues which may inform healthcare workers about patients' mental well-being are potentially important. This study investigates whether two such cues - Cue 1 the subjectively reported lack of access to rehabilitation, and more generally, Cue 2 an expressed concern that their healthcare needs may not be adequately met - may be clinically relevant to be on the outlook for. DESIGN: A cross-sectional survey of stroke survivors three months after discharge from a stroke unit. METHODS: Analysis of data on stroke survivors collected at three months after discharge from a hospital's stroke unit, by means of a mailed questionnaire. Descriptive statistics for the sample population were computed, and a binary logistic model fitted to estimate the impact of subjectively perceived lack of rehabilitation and subjectively reported low confidence in the healthcare system on symptoms of depression as measured by the Hospital Anxiety and Depression Scale. RESULTS: The percentage of patients reporting the presence of symptoms of depression three months postdischarge (22.6%) was consistent with the main body of literature on this subject. Both cues investigated had a significant (p < 0.05) and elevated odds ratio-Cue 1 odds ratio = 4.7 (1.3-18.4) and Cue 2 odds ratio = 2.8 (1.2-6.4), respectively - for showing symptoms of depression in our population. CONCLUSION: Healthcare workers who come in contact with stroke survivors who report having missed out on rehabilitation or express concern that their care needs may not be adequately met by their access to health care should ensure that the patients' mental well-being is being duly monitored and should consider further investigation for depression. RELEVANCE TO CLINICAL PRACTICE: Healthcare workers who come into contact with stroke survivors should pay attention to patients' remonstrance of access to rehabilitation, or concerns about adequacy of received care, as these might constitute cues for the presence of symptoms of depression. PMID- 27460227 TI - [Robotic technology for colorectal surgery : Procedures, current applications, and future innovative challenges - German version]. AB - BACKGROUND: Colorectal cancer is the third most common cancer worldwide. Current treatment approaches are multidisciplinary, including neoadjuvant chemoradiotherapy for rectal cancer. Several studies have reported an improvement in surgical techniques and in new devices facilitating better pre- and intraoperative staging. OBJECTIVES: Since its first application in 2002, robotic surgery has progressed steadily, offering good surgical results and better oncological outcomes. Currently, many studies and reviews have confirmed its safety and feasibility for colorectal cancer. MATERIAL AND METHODS: Robotic technology simplifies surgical maneuvers thanks to the three-dimensional magnification and stable vision, convenient mobility of the robotic arms, endowrist instruments with seven degrees of freedom, ambidextrous capability, tremor filtering and indocyanine green fluorescence imaging. RESULTS: Regarding the oncological outcome, the robotic technique is equivalent to the laparoscopic approach; however, a lower recurrence rate has been achieved with the robotic approach in extended lymphadenectomy as part of complete mesocolic excision for right colonic cancer and total mesorectal excision for low rectal tumors. CONCLUSION: Colorectal robotic surgery has progressively improved worldwide. Its advantages are related not only to better oncological outcomes, but also to improvements in terms of detection, accurate diagnosis and staging. PMID- 27460228 TI - Robotic technology for colorectal surgery : Procedures, current applications, and future innovative challenges. AB - BACKGROUND: Colorectal cancer is the third most common cancer worldwide. Current treatment approaches are multidisciplinary, including neoadjuvant chemoradiotherapy for rectal cancer. Several studies have reported an improvement in surgical techniques and in new devices facilitating better pre- and intraoperative staging. OBJECTIVES: Since its first application in 2002, robotic surgery has progressed steadily, offering good surgical results and better oncological outcomes. Currently, many studies and reviews have confirmed its safety and feasibility for colorectal cancer. MATERIALS AND METHODS: Robotic technology simplifies surgical maneuvers thanks to the three-dimensional magnification and stable vision, convenient mobility of the robotic arms, endowrist instruments with seven degrees of freedom, ambidextrous capability, tremor filtering, and indocyanine green fluorescence imaging. RESULTS: Regarding the oncological outcome, the robotic technique is equivalent to the laparoscopic approach; however, a lower recurrence rate has been achieved with the robotic approach in extended lymphadenectomy as part of complete mesocolic excision for right colonic cancer and total mesorectal excision for low rectal tumors. CONCLUSION: Colorectal robotic surgery has progressively improved worldwide. Its advantages are related not only to better oncological outcomes, but also to improvements in terms of detection, accurate diagnosis, and staging. PMID- 27460231 TI - Hypoglycaemia, thrombosis and vascular events in diabetes. PMID- 27460229 TI - Prophylactic meshes in the abdominal wall. AB - BACKGROUND: There is a high incidence of incisional hernias in specific high-risk patient populations. For these patients, the prophylactic placement of mesh during closure of the abdominal wall incision has been investigated in several prospective studies. OBJECTIVE: This article aims to summarize and synthetize the currently available evidence on prophylactic meshes in a narrative review. MATERIALS AND METHODS: Systematic reviews were performed on the use of prophylactic meshes in different indications: midline laparotomies, stoma reversal wounds, and permanent stoma. RESULTS: High-quality data from randomized trials shows that prophylactic synthetic non-absorbable mesh implantation is safe and effective, both in prevention of incisional hernias after midline laparotomies and during construction of an elective end colostomy. It should be considered in patients with a high risk for incisional hernia development, such as those receiving open abdominal aortic aneurysm, obesity, or colorectal cancer surgery. It is strongly recommended for construction of an elective permanent end colostomy. For midline laparotomies, both the retromuscular and onlay positions of a prophylactic mesh seem equally effective and safe. For parastomal hernia prevention, only the retromuscular prophylactic mesh and its use for end colostomies has been proven to be effective and safe. No data support the choice of a biological mesh or a synthetic absorbable mesh over a non-absorbable synthetic mesh, even in clean-contaminated surgical procedures. No data yet support the standard use of prophylactic mesh when closing the wound during closure of a temporary stoma. CONCLUSION: Prophylactic mesh implantation should be standard of care during construction of an elective end colostomy and will become standard of care for midline laparotomies in patients at a high risk of incisional hernias. PMID- 27460230 TI - [Selective internal radioembolization in nonresectable hepatocellular carcinoma]. AB - INTRODUCTION: The role of selective internal radioembolization (SIRT) in the treatment of hepatocellular carcinoma (HCC) is currently unclear. MATERIALS AND METHODS: We investigated 52 patients with nonresectable HCC in cirrhosis who underwent SIRT at the Department of General, Visceral and Vascular Surgery in co operation with the Department of Nuclear Medicine and the Institute of Diagnostic and Interventional Radiology between April 2011 and October 2015. RESULTS: In five patients, SIRT was employed for bridging to liver transplantation. In patients who had undergone pre-treatment with SIRT, histological examination of the explanted livers showed extensive tumor necrosis in the targeted areas with only minor remnant vital tissue at the margins. Four of the patients who underwent SIRT as local bridging treatment are tumor-free after transplantation. In the 47 palliatively treated patients, a total of 76 radioembolizations were performed. The observed 1- and 2-year survival rates in these patients were 58 and 29 %, respectively, after the first SIRT. In the multivariate analysis of the observed survival, AFP before the first SIRT >30ng/ml, time interval of <12 months between the initial diagnosis and the first SIRT, largest tumor diameter >5 cm and portal vein thrombosis were independent negative prognostic factors. In the multi-variate analysis, the time to progression was independently influenced only by the AFP level before the first SIRT. In addition to standard treatment with transarterial chemoembolization (TACE), SIRT is feasible in nonresectable HCC, in particular with portal vein thrombosis, with identical results, less interventions and few side effects. PMID- 27460232 TI - Erratum to: 'Chinese medicine combined with calcipotriol betamethasone and calcipotriol ointment for Psoriasis vulgaris (CMCBCOP): study protocol for a randomized controlled trial'. PMID- 27460233 TI - Does allopreening control avian ectoparasites? AB - For birds, the first line of defence against ectoparasites is preening. The effectiveness of self-preening for ectoparasite control is well known. By contrast, the ectoparasite control function of allopreening-in which one birds preens another-has not been rigorously tested. We infested captive pigeons with identical numbers of parasitic lice, and then compared rates of allopreening to the abundance of lice on the birds over time. We documented a negative relationship between rates of allopreening and the number of lice on birds. Moreover, we found that allopreening was a better predictor of louse abundance than self-preening. Our data suggest that allopreening may be a more important means of ectoparasite defence than self-preening when birds live in groups. Our results have important implications for the evolution of social behaviour. PMID- 27460235 TI - Principles of Amnis Imaging Flow Cytometry. AB - Over the last decade imaging flow cytometry (IFC) has become an established technique, as evidenced by its use in over 500 peer-reviewed scientific articles. Nevertheless, it is still an emerging technique with an installed base of less than 5 % that of conventional flow cytometers. In parallel with its adoption, the technology has evolved rapidly, increasing in speed, sensitivity, and real-time data analysis capacity by over an order of magnitude since its introduction. This chapter summarizes IFC's basic principles of operation and describes the current state of the art. PMID- 27460234 TI - Quantitative Functional Morphology by Imaging Flow Cytometry. AB - This chapter describes advantages and limitations of imaging flow cytometry (IFC) based on Imagestream instrumentation using a hybrid approach of morphometric measurement and quantitation of multiparametric fluorescent intensities' distribution in cells and particles. Brief comparison is given of IFC with conventional flow cytometry and fluorescent microscopy. Some future directions of the IFC technology are described and discussed. PMID- 27460236 TI - Ultrafast Microfluidic Cellular Imaging by Optical Time-Stretch. AB - There is an unmet need in biomedicine for measuring a multitude of parameters of individual cells (i.e., high content) in a large population efficiently (i.e., high throughput). This is particularly driven by the emerging interest in bringing Big-Data analysis into this arena, encompassing pathology, drug discovery, rare cancer cell detection, emulsion microdroplet assays, to name a few. This momentum is particularly evident in recent advancements in flow cytometry. They include scaling of the number of measurable colors from the labeled cells and incorporation of imaging capability to access the morphological information of the cells. However, an unspoken predicament appears in the current technologies: higher content comes at the expense of lower throughput, and vice versa. For example, accessing additional spatial information of individual cells, imaging flow cytometers only achieve an imaging throughput ~1000 cells/s, orders of magnitude slower than the non-imaging flow cytometers. In this chapter, we introduce an entirely new imaging platform, namely optical time-stretch microscopy, for ultrahigh speed and high contrast label-free single-cell (in a ultrafast microfluidic flow up to 10 m/s) imaging and analysis with an ultra-fast imaging line-scan rate as high as tens of MHz. Based on this technique, not only morphological information of the individual cells can be obtained in an ultrafast manner, quantitative evaluation of cellular information (e.g., cell volume, mass, refractive index, stiffness, membrane tension) at nanometer scale based on the optical phase is also possible. The technology can also be integrated with conventional fluorescence measurements widely adopted in the non-imaging flow cytometers. Therefore, these two combinatorial and complementary measurement capabilities in long run is an attractive platform for addressing the pressing need for expanding the "parameter space" in high-throughput single-cell analysis. This chapter provides the general guidelines of constructing the optical system for time stretch imaging, fabrication and design of the microfluidic chip for ultrafast fluidic flow, as well as the image acquisition and processing. PMID- 27460237 TI - Applications of Imaging Flow Cytometry for Microalgae. AB - The ability to image large numbers of cells at high resolution enhances flow cytometric analysis of cells and cell populations. In particular, the ability to image intracellular features adds a unique aspect to analyses, and can enable correlation between molecular phenomena resulting in alterations in cellular phenotype. Unicellular microalgae are amenable to high-throughput analysis to capture the diversity of cell types in natural samples, or diverse cellular responses in clonal populations, especially using imaging cytometry. Using examples from our laboratory, we review applications of imaging cytometry, specifically using an Amnis((r)) ImageStream((r))X instrument, to characterize photosynthetic microalgae. Some of these examples highlight advantages of imaging flow cytometry for certain research objectives, but we also include examples that would not necessarily require imaging and could be performed on a conventional cytometer to demonstrate other concepts in cytometric evaluation of microalgae. We demonstrate the value of these approaches for (1) analysis of populations, (2) documentation of cellular features, and (3) analysis of gene expression. PMID- 27460239 TI - Quantitation of Chromosome Damage by Imaging Flow Cytometry. AB - Biodosimetry is a method for measuring the dose of radiation to individuals using biological markers such as chromosome damage. Following mass casualty events, it is important to provide this information rapidly in order to assist with the medical management of potentially exposed casualties. Currently, the gold standard for biodosimetry is the dicentric chromosome assay, which accurately estimates the dose from the number of dicentric chromosomes in lymphocytes. To increase throughput of analysis following a large-scale mass casualty event, this assay has been adapted for use on the imaging flow cytometer. This chapter describes the methods for the identification and quantification of mono- and multicentric chromosomes using the imaging flow cytometer. PMID- 27460238 TI - The Analysis of Cell Cycle, Proliferation, and Asymmetric Cell Division by Imaging Flow Cytometry. AB - Measuring cellular DNA content by conventional flow cytometry (CFC) and fluorescent DNA-binding dyes is a highly robust method for analysing cell cycle distributions within heterogeneous populations. However, any conclusions drawn from single-parameter DNA analysis alone can often be confounded by the asynchronous nature of cell proliferation. We have shown that by combining fluorescent DNA stains with proliferation tracking dyes and antigenic staining for mitotic cells one can elucidate the division history and cell cycle position of any cell within an asynchronously dividing population. Furthermore if one applies this panel to an imaging flow cytometry (IFC) system then the spatial information allows resolution of the four main mitotic phases and the ability to study molecular distributions within these populations. We have employed such an approach to study the prevalence of asymmetric cell division (ACD) within activated immune cells by measuring the distribution of key fate determining molecules across the plane of cytokinesis in a high-throughput, objective, and internally controlled manner. Moreover the ability to perform high-resolution, temporal dissection of the cell division process lends itself perfectly to investigating the influence chemotherapeutic agents exert on the proliferative capacity of transformed cell lines. Here we describe the method in detail and its application to both ACD and general cell cycle analysis. PMID- 27460240 TI - Fluorescent In Situ Hybridization in Suspension by Imaging Flow Cytometry. AB - The emergence of imaging flow cytometry (IFC) has brought novel applications exploiting its advantages over conventional flow cytometry and microscopy. One of the new applications is fluorescence in situ hybridization in suspension (FISH IS). Conventional FISH is a slide-based approach in which the spotlike imagery resulting from hybridization with fluorescently tagged probes is evaluated by fluorescence microscopy. The FISH-IS approach evaluated by IFC enables the evaluation of tens to hundreds of thousands of cells in suspension and the analysis can be automated and standardized diminishing operator bias from the analysis. The high cell number throughput of FISH-IS improves the detection of rare events compared to conventional FISH. The applicability of FISH-IS is currently limited to detection of abnormal quantitative differences of hybridization targets such as occur in numerical chromosome abnormalities, deletions and amplifications.Here, we describe a protocol for FISH-IS using chromosome enumeration probes as an example. PMID- 27460241 TI - Analysis of Nucleocytoplasmic Protein Shuttling by Imaging Flow Cytometry. AB - Many intracellular signal transduction events involve the reversible shuttling of proteins between the cytoplasm and the nucleus. Study of these processes requires imaging information on the protein localization in a given cell and a large number of measurements to obtain sufficient statistics on the protein localization in the whole population. The protocol describes method for quantitative imaging flow cytometry analysis of intracellular distribution of NF kappaB in ARPE-19 cells stained with specific fluorochrome-conjugated antibodies. The described technique alone or in combination with standard flow cytometry methods can be applied to study any protein undergoing translocation from cytoplasm into the nucleus in a variety of cell lines as well as in heterogeneous primary cell populations. PMID- 27460242 TI - Using Image-Based Flow Cytometry with a FISH-Based FlowRNA Assay to Simultaneously Detect Intracellular TNF-alpha Protein and mRNA in Monocytes Following LPS Stimulation. AB - Existing methods of assessing monocyte inflammatory cytokine (IL-1beta, IL-6, IL 8, and TNF-alpha) response to in vitro lipopolysaccharide (LPS) stimulation lack the ability to simultaneously detect intracellular mRNA and protein. This procedure takes advantage of new methodologies and instrumentation to simultaneously measure intracellular TNF-alpha mRNA and protein in CD14(+) monocytes after 1, 3, and 6 h of LPS stimulation. By assessing multiple timepoints, we are able to discern how LPS stimulation affects the temporal relationship between TNF-alpha mRNA and protein. By using image-based flow cytometry it is possible to co-localize mRNA and protein signals to identify the length of incubation that is needed to initiate protein translation. PMID- 27460243 TI - Multiparametric Characterization of Human T-Cell Immune Synapses by InFlow Microscopy. AB - Immune cells need to communicate with each other via direct cell contact formation. The contact zone has similar functions as a neuronal synapse and is therefore named immune synapse. Supramolecular activation clusters consisting of a variety of surface receptors and cytoplasmic proteins are formed within the immune synapse, which are pivotal for T-cell activation. Thus, a malfunction of immune synapse formation has detrimental effects on the healthiness of the individual.Classical confocal microscopy to analyze the supramolecular cluster formation and maturation of the immune synapse between primary human T-cells and antigen-presenting cells is time consuming and the number of cells that can be analyzed is limited. Therefore, we have established an InFlow microscopy approach for the analysis of immune synapses. InFlow microscopy is a hybrid method combining fluorescence microscopy and flow cytometry. Our InFlow microscopy method allows quantifying protein distribution in immune synapses of several hundred or even thousand cell couples in one sample. Importantly, comparisons of different samples with a strong statistical power are possible with InFlow microcopy. PMID- 27460244 TI - Studying T Cells N-Glycosylation by Imaging Flow Cytometry. AB - Imaging flow cytometry is an emerging imaging technology that combines features of both conventional flow cytometry and fluorescence microscopy allowing quantification of the imaging parameters. The analysis of protein posttranslational modifications by glycosylation using imaging flow cytometry constitutes an important bioimaging tool in the glycobiology field. This technique allows quantification of the glycan fluorescence intensity, co localization with proteins, and evaluation of the membrane/cytoplasmic expression. In this chapter we provide the guidelines to analyze glycan expression, particularly the beta1,6 GlcNAc branched N-glycans, on the membrane of intestinal T cells from inflammatory bowel disease patients. PMID- 27460245 TI - Assessment of Granulocyte Subset Activation: New Information from Image-Based Flow Cytometry. AB - Analysis of granulocyte function can provide important information about the state of the body's innate immune system. Existing flow cytometry methods that lack image-based analysis capabilities fail to fully evaluate granulocyte function. In the present method, we combine simultaneous detection of phagocytosis and oxidative burst in granulocytes to identify unique subsets of activated granulocytes. This analysis method provides novel information about granulocytes that allows our lab and others to evaluate the effectiveness of nutritional and lifestyle countermeasures, designed to improve immunity. PMID- 27460246 TI - Using Image-Based Flow Cytometry to Assess Monocyte Oxidized LDL Phagocytosis Capacity. AB - The examination of monocyte phagocytosis of modified lipoproteins is important to the understanding of plaque deposition and the development of atherosclerosis. Current methods lack the high-throughput image-based analysis capabilities, which may yield novel information concerning monocyte activity in disease processes. Specifically, this method identifies monocyte phagocytosis of oxidized LDL along with a change in adhesion molecules and scavenger receptors. Our laboratory is currently implementing this method as a means to study how acute dietary modifications alter risk of developing atherosclerosis. PMID- 27460247 TI - Screening for Drugs Against the Plasmodium falciparum Digestive Vacuole by Imaging Flow Cytometry. AB - Phenotypic assays are increasingly employed to provide clues about drug mechanisms. In antimalarial drug screening, however, the majority of assays are designed to only measure parasite-killing activity. We describe here a high content assay to detect drug-mediated perturbation of the digestive vacuole integrity in the trophozoite stage of Plasmodium falciparum, using the ImageStream imaging flow cytometer. PMID- 27460248 TI - Accurate Assessment of Cell Death by Imaging Flow Cytometry. AB - The number of investigators using cell death analysis applications has greatly expanded since the introduction of flow cytometry. The Annexin V/propidium iodide (PI) method is among the most commonly used procedures and allows users to determine if cells are viable, apoptotic, or necrotic, based on changes in membrane lipid composition, integrity, and permeability. Unfortunately, PI can intercalate into RNA, in addition to DNA, which contributes to a large number of events showing PI staining within the cytoplasmic compartment. We show that this occurs across a broad range of animal primary cells and commonly used cell lines, and is most prevalent in large cells (nuclear:cytoplasmic ratio <0.5). Any cellular system where RNA levels change throughout an experiment will be particularly affected, such as those that utilize virally infected cells. As two examples, we highlight our recent work on cells infected with vesicular stomatitis virus (VSV), an RNA virus, and herpes simplex virus-1 (HSV-1), a DNA virus. Similarly, these issues are relevant to experimental systems where cells have increased RNA content such as during genotoxic stress, following exposure to cell cycle arrest drugs such as thymidine or hydroxyurea, or where developmental progression promotes discrete changes in cellular RNA synthesis. This chapter outlines a modified Annexin V/PI method that addresses cytoplasmic RNA staining issues to allow for accurate assessment of cell death. This protocol takes advantage of an additional cellular permeability caused by fixation to promote RNase A entry into the cell. Based on our observations, cell morphological parameters are well maintained and less than 5 % of total cellular events exhibit cytoplasmic PI staining under this protocol. PMID- 27460249 TI - Temporal Heterogeneity in Apoptosis Determined by Imaging Flow Cytometry. AB - Apoptotic process is highly heterogeneous, and a long-standing question is how many parameters define time and reversibility of the apoptotic response at a population and single-cell levels. Cell death analysis applications have greatly expanded since the introduction of flow cytometry. Classical approach for evaluation of apoptosis is en masse analysis of cells treated with different stimuli, but these methods cannot demonstrate heterogeneity in the population. Single-cell heterogeneity is now usually assessed by multicolor fluorescence microscopy; however obtaining reasonable statistics is time consuming and laborious. Therefore we combined flow cytometry, imaging flow cytometry, and fluorescent microscopy to characterize at a single-cell and population level sequence of apoptotic events induced by a variety of treatments (Vorobjev, Barteneva, J Histochem Cytochem 63:494-510, 2015). We show that simultaneous use of membrane potential dye TMRE, caspases 3/7 sensor, Annexin V and nuclear staining along with morphological parameters demonstrate heterogeneity of the whole process and is a valuable method for quantitative study of the apoptosis execution. Imaging flow cytometry allowed us to analyze correlation between TMRE, caspases 3/7, and Annexin V staining and morphological characteristics providing valuable information on the process of apoptotic execution. Importantly, comparisons of different data sets obtained by three methods allowed us to achieve temporal resolution of the whole process superior to that had been obtained by only one method. PMID- 27460250 TI - FlowCam: Quantification and Classification of Phytoplankton by Imaging Flow Cytometry. AB - The ability to enumerate, classify, and determine biomass of phytoplankton from environmental samples is essential for determining ecosystem function and their role in the aquatic community and microbial food web. Traditional micro phytoplankton quantification methods using microscopic techniques require preservation and are slow, tedious and very laborious. The availability of more automated imaging microscopy platforms has revolutionized the way particles and cells are detected within their natural environment. The ability to examine cells unaltered and without preservation is key to providing more accurate cell concentration estimates and overall phytoplankton biomass. The FlowCam((r)) is an imaging cytometry tool that was originally developed for use in aquatic sciences and provides a more rapid and unbiased method for enumerating and classifying phytoplankton within diverse aquatic environments. PMID- 27460251 TI - Detection and Characterization of Rare Circulating Endothelial Cells by Imaging Flow Cytometry. AB - Circulating endothelial cells (CECs) are angiogenic cells that appear in increased numbers in the peripheral circulation either as a result of vascular injury or in response to angiogenic stimuli. Elevated levels of CECs have been correlated with various disease states, indicating the use of CECs as a biomarker of disease. Flow cytometry is a widely accepted method for detecting and quantitating CECs. Flow cytometry provides statistical information on large numbers of cells but no information on morphological characteristics. Imaging flow cytometry combines traditional flow cytometry and microscopy, providing a streamlined, multiparameter approach to characterize the biological properties and morphology of large numbers of cells, and is particularly amenable for rare event analysis such as CECs. This approach for identifying and characterizing CECs allows the morphological characterization of large numbers of live, nucleated, single CECs, and alleviates the need for prior enrichment. PMID- 27460252 TI - Imaging Flow Cytometric Analysis of Primary Bone Marrow Megakaryocytes. AB - In light of the indispensible role of platelets in the maintenance of hemostasis, understanding the biology of platelet production from bone marrow megakaryocytes (MKs) may uncover new therapeutic strategies for thrombocytopenia. While there has been much recent interest in optimizing culture systems to facilitate the study of the morphologically unique MK lineage, these systems lack the intricacy of in vivo megakaryopoiesis. Given the limitations of many common techniques for the in vivo study of MKs, in this chapter we describe a method to quantify and analyze primary murine bone marrow megakaryocytes utilizing imaging flow cytometry. PMID- 27460253 TI - Sickle Cell Imaging Flow Cytometry Assay (SIFCA). AB - Hemoglobin S polymerization under hypoxic conditions in sickle cell disorders causes characteristic shape changes to human red blood cells. Previous sickling assays used to investigate the efficacy of novel agents to treat these disorders are laborious and observer dependent. Here, we describe a partially automated, high-throughput sickling assay using imaging flow cytometry. PMID- 27460254 TI - Drugs Delivery by Charities: A Possible Epidemiologic Indicator in Children of Undocumented Migrants. AB - Describing the health status of a population is difficult, especially in the case of irregular migrants who are now a growing population in western Countries. Data for children of these families are almost inexistent. In the absence of databases on this peculiar pediatric population, we analyzed drugs dispensation by a major Charity to have an insight into their health needs. This observational retrospective study was carried out during the entire 2015 and enrolled 628 undocumented children. A cohort of 8438 adult patients belonging to the same ethnic groups was used for comparison. Respiratory drugs were those most commonly prescribed, followed by those for skin and ocular diseases and by those for gastrointestinal disorders. Also in adults respiratory medications were the most dispensed, but almost in equal measure than cardiovascular drugs.To our knowledge this is the first study on the health needs of undocumented children residing in a western Country. The method we used seems to be a useful method for epidemiological analysis. As could be expected, respiratory and skin diseases ranked first, possibly owing to environmental factors. PMID- 27460255 TI - Erratum to: Black-White Health Inequalities in Canada. PMID- 27460256 TI - Percutaneous Transvesical Retrograde Ureteral Stent Insertion for Neoplastic Stricture. PMID- 27460257 TI - CT-Guided, Ethanol Sympatholysis for Primary Axillary-Palmar Hyperhidrosis. AB - PURPOSE: Primary hyperhidrosis is an excessive sweating due to an overactive sympathetic system. Our objective was to test the feasibility and provide early data on the safety/efficacy of CT-guided sympatholysis, for primary hyperhidrosis. MATERIALS AND METHODS: Nine consecutive patients with axillary palmar hyperhidrosis were treated between 2013 and 2015. CT-guided sympathetic block was performed in the outpatients at T-2, T-3, and T-4, bilaterally using alcohol under local anesthesia. Immediate postprocedure CT was obtained to assess the complications as per Common Terminology Criteria for Adverse Events, version 4. Technical success and clinical success were recorded. Primary and secondary efficacy were assessed by phone and clinical visits; mean follow-up was 12 months (6-26 months). Descriptive statistics was used to report the outcomes. RESULTS: One procedure was aborted due to eyelid ptosis after lidocaine injection. All other eight patients (5:3, F:M) (median age 32) had immediate cessation of sweating. Two major complications (pneumothorax, one requiring a chest tube) occurred. Two patients recurred with unilateral and one with bilateral symptoms. One of the unilateral recurrence and the bilateral recurrence patients was retreated successfully. Median follow-up was 1 year. No cases of Horner's or compensatory hyperhidrosis were observed. CONCLUSIONS: CT-guided EtOH sympatholysis for axillary/palmar primary hyperhidrosis is feasible. Technical failure rate was 11 %. Primary and secondary efficacy are 75 and 94 %, respectively, to a median follow-up of 1 year. Risk profile appears favorable. Despite a small sample size, results confirm feasibility and encourage a larger study. PMID- 27460258 TI - Range of generics will be withdrawn across Europe. PMID- 27460259 TI - Spatiotemporal distributions of intestinal helminths in female lesser scaup Aythya affinis during spring migration from the upper Midwest, USA. AB - We examined the associations between intestinal helminth infracommunity structure and infection parameters and the age, size, and year and region of collection of 130 female lesser scaup (Aythya affinis) during their 2014-2015 spring migrations through the upper Midwest, USA. We identified a total of 647,174 individual helminths from 40 taxa, including 20 trematodes, 14 cestodes, 4 nematodes and 2 acanthocephalans parasitizing lesser scaup within the study area. Lesser scaup were each infected with 2-23 helminth taxa. One digenean, Plenosoma minimum, is reported for the first time in lesser scaup and in the Midwest. Mean trematode abundance and total helminth abundance was significantly less in 2015 than 2014, and we suspect that colder weather late in 2015 impacted the intermediate host fauna and caused the observed differences. Brillouin's species diversity of helminths was greatest in the northernmost region of the study area, which coincides with the range of a non-indigenous snail that indirectly causes annual mortality events of lesser scaup. While host age and size were not determined to be influential factors of helminth infracommunity structure, non-parametric ordination and permutational analysis of co-variance revealed that year and region of collection explained differences in helminth infracommunities. Our results suggest that spatiotemporal variations play an important role in the structure of intestinal helminth infracommunities found in migrating lesser scaup hosts, and may therefore impact host ability to build endogenous reserves at certain stopover locations in the Midwest. PMID- 27460261 TI - Candle soot-based super-amphiphobic coatings resist protein adsorption. AB - Super nonfouling surfaces resist protein adhesion and have a broad field of possible applications in implant technology, drug delivery, blood compatible materials, biosensors, and marine coatings. A promising route toward nonfouling surfaces involves liquid repelling architectures. The authors here show that soot templated super-amphiphobic (SAP) surfaces prepared from fluorinated candle soot structures are super nonfouling. When exposed to bovine serum albumin or blood serum, x-ray photoelectron spectroscopy and time of flight secondary ion mass spectrometry analysis showed that less than 2 ng/cm(2) of protein was adsorbed onto the SAP surfaces. Since a broad variety of substrate shapes can be coated by soot-templated SAP surfaces, those are a promising route toward biocompatible materials design. PMID- 27460262 TI - Relative bioavailability of 13C5-folic acid in pectin-coated folate fortified rice in humans using stable isotope techniques. AB - BACKGROUND/OBJECTIVES: The aim of the study was to measure the relative bioavailability of labeled pteroylglutamic acid (13C5-PteGlu) from a pectin coated fortified rice in vivo to measure any effect of the edible coating on folic acid bioavailability. SUBJECTS/METHODS: Healthy volunteers (N=26) aged 18 39 years received three test meals in three randomized short-term cross-over trials: Trial 1: aqueous 400 MUg 13C5-PteGlu, Trial 2: 200 g cooked white rice+400 MUg 13C5-PteGlu,Trial 3: 200 g fortified cooked white rice with pectin coated premix containing 400 MUg 13C5-PteGlu. Blood samples were drawn at 0,1,2,5 and 8 h postprandial. The concentration of 13C5-5 methyl-tetrahydrofolate appearing in plasma was quantified using high performance liquid chromatography mass spectrometry (MS)/MS. For 24 h before baseline estimation and during the area under the curve (AUC) study, the subjects were placed on a low folate diet (~100 MUg/day). The relative bioavailability of the folic acid following Trial 3 was measured by comparing the 13C5-5 methyl-tetrahydrofuran (THF) AUC with Trials 1 and 2. RESULTS: The bioavailability of folic acid in a pectin-coated rice premix was 68.7% (range 47-105) and 86.5% (range 65-115) in uncoated fortified rice relative to aqueous folic acid. CONCLUSION: This study is the first demonstration of the bioavailability of folate in pectin-coated fortified rice in humans. PMID- 27460263 TI - Serum high-sensitivity C-reactive protein as a biomarker in patients with metabolic syndrome: evidence-based study with 7284 subjects. AB - BACKGROUND/OBJECTIVES: Metabolic syndrome (MetS) is characterized by abdominal obesity, dyslipidemia, hypertension and glucose intolerance, and is associated with an increased risk of developing cardiovascular disease (CVD), diabetes mellitus and related diseases. Circulating levels of inflammatory markers such as C-reactive-protein (CRP) have reported to be associated with CVD. Against this background, the prevalence of MetS is increasing globally, and thus predictive biomarkers are required for identification of MetS patients at an increased risk. Here we explored the value of CRP as a biomarker in 7284 subjects and also investigated which features of MetS have the greatest association with the hs-CRP level. SUBJECTS/METHODS: The subjects were recruited from the Mashhad stroke and heart atherosclerotic disorder study. Anthropometric factors and biochemical parameters (for example, high-sensitivity CRP (hs-CRP), high-density lipoprotein/low-density lipoprotein, triglycerides (TGs) and fasting blood glucose (FBG)) were determined. Univariate and multivariate analyses were conducted to evaluate the association of hs-CRP and MetS. RESULTS: Our results illustrated that the concentration of serum hs-CRP increased progressively with the number of MetS components, and subjects who fulfilled the criteria of MetS for waist circumference, TGs, blood pressure and FBG were found to have hs-CRP of 0.53, 0.38, 0.34 and 0.71 mg/l, respectively, higher than matched-subjects. Importantly, FBG had the greatest association with hs-CRP concentration. CONCLUSIONS: Our data demonstrate the significant association between MetS components with hs-CRP, indicating that this association was cumulative by increasing the number of the defining features of MetS, supporting further studies to explore the value of emerging marker as a novel method for detecting individuals at high risk of developing MetS. PMID- 27460264 TI - The influence of adjustment for energy misreporting on relations of cake and cookie intake with cardiometabolic disease risk factors. AB - BACKGROUND/OBJECTIVES: Previous cohort studies elucidated unexpected inverse relations of cake and cookie (CC) consumption with chronic disease risk. We assessed CC intake in relation to cardiometabolic disease risk factors in a well phenotyped population with emphasis on misreporting as the potential driving force behind inverse relations. SUBJECTS/METHODS: In a cross-sectional EPIC Potsdam sub-study individual usual CC intake was modeled by combining 24 h recall and food frequency questionnaire data. Cardiometabolic risk factors were anthropometry, blood lipids, blood pressure (BP), physical activity and fitness. Analysis of covariance models adjusted for (i) age/education/lifestyle and (ii) additionally for energy misreporting (ratio of energy intake over energy expenditure) were used to compute mean values of risk factors for quartiles of CC intake. RESULTS: Adjustment for misreporting had considerable impact on relations of CC intake. Initial inverse links with anthropometry were reversed to direct associations. Misreporting adjustment also nullified inverse relations with triglycerides and with total cholesterol in women. Negligible associations with high density lipoprotein cholesterol turned inverse (men: cross-quartile difference (DeltaQ4-Q1)=-1.7 mg/dl; women: DeltaQ4-Q1=-3.6 mg/dl), so did fitness (men: DeltaQ4-Q1=-1.2 ml/kg/min; women: DeltaQ4-Q1=-0.9 ml/kg/min). Direct relations with total/low density lipoprotein cholesterol in men were not changed by misreporting (DeltaQ4-Q1 max. 7.5 or 11.3 mg/dl). Reduced BP was observed in females with increased CC intake; only systolic BP remained relevant after misreporting adjustment (DeltaQ4-Q1=-4.6 mmHg). CONCLUSIONS: The strong impact of energy misreporting on relations of CC intake with risk factors emphasizes a careful analysis and interpretation of nutritional data. We showed that apparent favorable relations of CC intake changed with a different model specification, highlighting proper modeling considerations when analyzing diet-disease relations. PMID- 27460260 TI - Engineered Mesenchymal Stem Cells as an Anti-Cancer Trojan Horse. AB - Cell-based gene therapy holds a great promise for the treatment of human malignancy. Among different cells, mesenchymal stem cells (MSCs) are emerging as valuable anti-cancer agents that have the potential to be used to treat a number of different cancer types. They have inherent migratory properties, which allow them to serve as vehicles for delivering effective therapy to isolated tumors and metastases. MSCs have been engineered to express anti-proliferative, pro apoptotic, and anti-angiogenic agents that specifically target different cancers. Another field of interest is to modify MSCs with the cytokines that activate pro tumorigenic immunity or to use them as carriers for the traditional chemical compounds that possess the properties of anti-cancer drugs. Although there is still controversy about the exact function of MSCs in the tumor settings, the encouraging results from the preclinical studies of MSC-based gene therapy for a large number of tumors support the initiation of clinical trials. PMID- 27460267 TI - Gross and relative energy cost of domestic household activities in Asian men. AB - BACKGROUND/OBJECTIVES: Obesity is on the rise and participation in exercise has declined. Domestic household activities may help meet the recommended daily physical activity levels. This study aimed to measure the energy costs of household activities among Asian males. SUBJECTS/METHODS: This was a randomised cross-over study conducted in a whole-body calorimeter. The energy costs of 14 domestic household activities, divided into two studies, were measured in 10 healthy Asian males. Participants' weight, height, body composition and basal metabolic rate were measured on the first test visit. A standard breakfast was served and participants rested for an hour before the measurement of energy costs of domestic household activities. During the measurements, each activity was performed for 20 min, and participants rested for 30 min between activities. RESULTS: The mean energy costs of domestic household activities ranged from 5.92 to 11.97 kJ/min, which were significantly different between activities (repeated measures analysis of variance, P<0.001). When expressed as metabolic equivalents (METS), all domestic household activities were classified as low-intensity physical activities. Actual METS (METSactual) were significantly different to standard METS of eight activities, which may be partly explained by the universal assumption of 3.5 ml O2/kg/min made during the calculation of METS in the Asian population. CONCLUSIONS: The energy costs of a range of domestic household activities reported in this study may assist in the planning of physical activities among Asians to meet national physical activity guidelines. PMID- 27460266 TI - The impact of 1-year vitamin D supplementation on vitamin D status in athletes: a dose-response study. AB - BACKGROUND/OBJECTIVES: To assess the prevalence of vitamin D deficiency in Dutch athletes and to define the required dosage of vitamin D3 supplementation to prevent vitamin D deficiency over the course of a year. SUBJECTS/METHODS: Blood samples were collected from 128 highly trained athletes to assess total 25(OH)D concentration. Of these 128 athletes, 54 male and 48 female athletes (18-32 years) were included in a randomized, double blind, dose-response study. Athletes with either a deficient (<50 nmol/l) or an insufficient (50-75 nmol/l) 25(OH)D concentration were randomly assigned to take 400, 1100 or 2200 IU vitamin D3 per day orally for 1 year. Athletes who had a total 25(OH)D concentration above 75 nmol/l at baseline continued with the study protocol without receiving vitamin D supplements. Serum total 25(OH)D concentration was assessed every 3 months, as well as dietary vitamin D intake and sunlight exposure. RESULTS: Nearly 70% of all athletes showed an insufficient (50-75 nmol/l) or a deficient (<50 nmol/l) 25(OH)D concentration at baseline. After 12 months, serum 25(OH)D concentration had increased more in the 2200 IU/day group (+50+/-27 nmol/l) than the sufficient group receiving no supplements (+4+/-17 nmol/l; P<0.01) and the 1100 IU/day group (+25+/-23 nmol/l; P<0.05). Supplementation with 2200 IU/day vitamin D resulted in a sufficient 25(OH)D concentration in 80% of the athletes after 12 months. CONCLUSIONS: Vitamin D deficiency is highly prevalent in athletes. Athletes with a deficient or an insufficient 25(OH)D concentration can achieve a sufficient 25(OH)D concentration within 3 months by taking 2200 IU/day. PMID- 27460265 TI - Associations between CD36 gene polymorphisms, fat tolerance and oral fat preference in a young-adult population. AB - BACKGROUND/OBJECTIVES: CD36 is known to be an orosensory receptor for dietary long-chain fatty acids, as well as being involved in the chemosensory mechanisms within the human gut. Recent data have demonstrated an association between CD36 single-nucleotide polymorphisms (SNPs) and lipid consumption behaviours in humans. This study aimed to test for associations between CD36 SNPs and response to a high-fat meal in a young healthy Australian cohort. Secondary associations were tested between CD36 gene variants and fasting lipid parameters, body composition, cardiovascular disease (CVD) risk factors and measures of oral fat preference. SUBJECTS/METHODS: Two SNPs (rs1527479 and rs1984112) were assessed for associations with response to a 75 g saturated fat oral fat tolerance test (OFTT), whole-body substrate oxidation, fasting plasma lipids, CVD risk factors and self-reported habitual diet questionnaires. Genotyping was performed using real-time polymerase chain reaction. RESULTS: Cross-sectional data were collected on 56 individuals (28 m, 28 f; 24.9+/-3.3 years), with 42 completing participation in a high-fat OFTT. No genotypic associations were evident in anthropometric data or self-reported fat preference measures. AA SNP carriers at rs1984112 exhibited significantly elevated fasting triglyceride when compared with non-carriers (P=0.024). This group also tended to have an elevated response to a high-fat meal (P=0.078). CONCLUSIONS: Although these data show the potential pleiotropic influence of CD36 SNP rs1984112 on lipoprotein accumulation in a young healthy cohort, further assessment in a larger cohort is warranted. PMID- 27460268 TI - Exclusive breastfeeding duration and infant infection. AB - BACKGROUND/OBJECTIVES: We estimated the risk of infection associated with the duration of exclusive breastfeeding (EBF). SUBJECT/METHODS: We analysed the data on 15 809 term, singleton infants from the UK Millennium Cohort Study. Infants were grouped according to months of EBF: never, <2, 2-4, 4-6 and 6 (the latter being World Health Organisation (WHO) policy since 2001: 'post-2001 WHO policy'). Among those EBF for 4-6 months, we separated those who started solids, but not formula, before 6 months, and were still breastfeeding at 6 months (that is, WHO policy before 2001: 'pre-2001 WHO policy'), from other patterns. Outcomes were infection in infancy (chest, diarrhoeal and ear). RESULTS: EBF was not associated with the ear infection, but was associated with chest infection and diarrhoea. EBF for <4 months was associated with a significantly increased risk of chest infection (adjusted risk ratios (RR) 1.24-1.28) and diarrhoea (adjusted RRs 1.42 1.66) compared with the pre-2001 WHO policy. There was an excess risk of the chest infection (adjusted RR 1.19, 95% confidence interval (CI): 0.97-1.46) and diarrhoea (adjusted RR 1.66, 95% CI: 1.11, 2.47) among infants EBF for 4-6 months, but who stopped breastfeeding by 6 months, compared with the pre-2001 WHO policy. There was no significant difference in the risk of chest infection or diarrhoea in those fed according to the pre-2001 versus post-2001 WHO policy. CONCLUSIONS: There is an increased risk of infection in infants EBF for <4 months or EBF for 4-6 months who stop breastfeeding by 6 months. These results support current guidelines of EBF for either 4-6 or 6 months, with continued breastfeeding thereafter. PMID- 27460270 TI - When Perspective Taking Creates a Motivational Threat: The Case of Conservatism, Same-Sex Sexual Behavior, and Anti-Gay Attitudes. AB - Taking another person's perspective has generally been found to foster positive attitudes. We propose that perspective taking can lead to more negative attitudes when people imagine an experience that threatens their current motivations and goals. We test this idea by examining how taking the perspective of a male same sex couple influences political conservatives' attitudes. Across four studies, we demonstrate that (a) the extent to which conservatives (but not liberals) imagine same-sex sexual behavior predicts more anti-gay attitudes, (b) this effect is in part attributable to conservatives experiencing greater disgust, and (c) having conservatives reappraise disgust as not necessarily signaling the threat of disease eliminates this effect. These findings indicate that perspective taking can foster negative attitudes when the content of perspective taking threatens current motivations. The proposed ideas provide unique insights toward developing a more comprehensive framework of how perspective taking shapes attitudes. PMID- 27460269 TI - The association between the intake of specific dietary components and lifestyle factors and microscopic colitis. AB - BACKGROUND/OBJECTIVES: The incidence of microscopic colitis (MC) has increased over the previous decades. In addition to smoking and drugs, currently unidentified environmental factors may have a role. The aim of this study was to determine whether specific dietary or other lifestyle factors were associated with the development of MC. SUBJECT/METHODS: The population-based cohort Malmo Diet and Cancer Study of 28 095 individuals was examined. Information about dietary habits was collected by a modified diet history method. Data on anthropometry were measured, and socio-economic and lifestyle factors were collected by questionnaires. Cases of MC were identified in medical registers. Associations were estimated using Cox regression analysis. RESULTS: During a 22 year period, 135 patients were diagnosed with MC. Intakes of protein, carbohydrates, sucrose, saturated fat, monounsaturated fat, polyunsaturated fat, omega-3 or omega-6 fatty acids, fibre and zinc were not associated with MC. We could verify the previously reported association between MC and smoking (hazard ratio (HR): 2.29; 95% confidence interval (CI): 1.66-3.84) and the female gender (HR: 3.57; 95% CI: 2.22-5.74). High alcohol consumption was associated with an increased risk for MC (HR: 1.89 for the highest quartile; 95% CI: 0.82-4.33, P for trend=0.032). In a post hoc analysis, alcohol intake including all patients independently of consumption seemed to reduce the smoking-related risk. CONCLUSIONS: Despite a large cohort and a long follow-up period, we could not detect any dietary risk factors for MC. The aetiological mechanisms behind the positive impact of smoking and alcohol on MC risk should be investigated. PMID- 27460271 TI - Cultural Differences in Values as Self-Guides. AB - Three studies tested whether individualism-collectivism moderates the extent to which values are endorsed as ideal self-guides and ought self-guides, and the consequences for regulatory focus and emotion. Across Studies 1 and 2, individualists endorsed values that are relatively central to the self as stronger ideals than oughts, whereas collectivists endorsed them as ideals and oughts to a similar degree. Study 2 found that individualists justified central values using reasons that were more promotion focused than prevention focused, whereas collectivists used similar amount of prevention-focused and promotion focused reasons. In Study 3, individualists felt more dejected after violating a central (vs. peripheral) value and more agitated after violating a peripheral (vs. central) value. Collectivists felt a similar amount of dejection regardless of values centrality and more agitation after violating central (vs. peripheral) values. Overall, culture has important implications for how we regulate values that are central or peripheral to our self-concept. PMID- 27460272 TI - The Role of Affective and Cognitive Individual Differences in Social Perception. AB - Three studies explored the connection between social perception processes and individual differences in the use of affective and cognitive information in relation to attitudes. Study 1 revealed that individuals high in need for affect (NFA) accentuated differences in evaluations of warm and cold traits, whereas individuals high in need for cognition (NFC) accentuated differences in evaluations of competent and incompetent traits. Study 2 revealed that individual differences in NFA predicted liking of warm or cold targets, whereas individual differences in NFC predicted perceptions of competent or incompetent targets. Furthermore, the effects of NFA and NFC were independent of structural bases and meta-bases of attitudes. Study 3 revealed that differences in the evaluation of warm and cold traits mediated the effects of NFA and NFC on liking of targets. The implications for social perception processes and for individual differences in affect-cognition are discussed. PMID- 27460273 TI - Newcomers to Social Categories: Longitudinal Predictors and Consequences of Ingroup Identification. AB - In the present article, we propose a dynamic model of the longitudinal predictors and consequences of ingroup identification among newcomers to a social category. We hypothesize a shift in the relative importance of intragroup affiliation as compared with intergroup differentiation for ingroup identification. Two longitudinal studies confirm the theoretical model assessing cross-sectional and longitudinal relationships between ingroup identification and interpersonal attraction, self-prototypicality, and ingroup favoritism at three measurement points during the first 4 months of group membership in two different social categories. Results demonstrate that in the initial phases of group membership, ingroup identification is mainly determined by intragroup affiliation (interpersonal attraction) and that ingroup favoritism starts playing a relevant role later on, when category membership has been established. PMID- 27460274 TI - From the Immoral to the Incorruptible: How Prescriptive Expectations Turn the Powerful Into Paragons of Virtue. AB - Ample evidence documents that power increases unethical behavior. This article introduces a new theoretical framework for understanding when power leads to more versus less unethical behavior. Our key proposition is that people hold expectations about power that are both descriptive (how the powerful do behave) and prescriptive (how the powerful should behave). People hold descriptive beliefs that the powerful do behave more unethically than the powerless, but they hold prescriptive beliefs that the powerful should behave more ethically than the powerless. Whichever expectation-descriptive or prescriptive-is salient affects how power influences one's behavior. Three experiments demonstrate that activating descriptive expectations for power leads the powerful to cheat more than the powerless, whereas activating prescriptive expectations leads the powerful to cheat less than the powerless. The current work offers new ideas for curbing unethical behavior by those with power: focus their attention on prescriptive expectations for power. PMID- 27460275 TI - Cancer related gene alterations can be detected with next-generation sequencing analysis of bile in diffusely infiltrating type cholangiocarcinoma. AB - Genome-wide association study in diffusely infiltrating type cholangiocarcinoma (CC) can be limited due to the difficulty of obtaining tumor tissue. We aimed to evaluate the genomic alterations of diffusely infiltrating type CC using next generation sequencing (NGS) of bile and to compare the variations with those of mass-forming type CC. A total of 24 bile samples obtained during endoscopic retrograde cholangiopancreatography (ERCP) and 17 surgically obtained tumor tissue samples were evaluated. Buffy coat and normal tissue samples were used as controls for a somatic mutation analysis. After extraction of genomic DNA, NGS analysis was performed for 48 cancer related genes. There were 27 men and 14 women with a mean age of 65.0+/-11.8years. The amount of extracted genomic DNA from 3cm(3) of bile was 66.0+/-84.7MUg and revealed a high depth of sequencing coverage. All of the patients had genomic variations, with an average number of 19.4+/-2.8 and 22.3+/-3.3 alterations per patient from the bile and tumor tissue, respectively. After filtering process, damaging SNPs (8 sites for each type of CC) were predicted by analyzing tools, and their target genes showed relevant differences between the diffusely infiltrating and mass-forming type CC. Finally, in somatic mutation analysis, tumor-normal paired 14 tissue and 6 bile samples were analyzed, genomic alterations of EGFR, FGFR1, ABL1, PIK3CA, and CDKN2A gene were seen in the diffusely infiltrating type CC, and TP53, KRAS, APC, GNA11, ERBB4, ATM, SMAD4, BRAF, and IDH1 were altered in the mass-forming type CC group. STK11, GNAQ, RB1, KDR, and SMO genes were revealed in both groups. The NGS analysis was feasible with bile sample and diffusely infiltrating type CC revealed genetic differences compared with mass-forming type CC. Genome-wide association study could be performed using bile sample in the patients with CC undergoing ERCP and a different genetic approach for accurate diagnosis, pathogenesis study, and targeted therapy will be needed in diffusely infiltrating type CC. PMID- 27460276 TI - Depression and anxiety in patients with AL amyloidosis as assessed by the SF-36 questionnaire: experience in 1226 patients. AB - BACKGROUND: Our study examines depression and anxiety in patients with immunoglobulin light chain (AL) amyloidosis, and determines the associations between the mental health problems and patient characteristics (age, gender, race, marital status, alcohol consumption, smoking status and cardiac involvement). METHODS: Patients with AL amyloidosis who completed the 36-item Short Form General Health Survey (SF-36) during initial evaluation at a single center were studied. The SF-36 included assessments of depression, anxiety, role limitation due to emotional problems and the mental health subscale score. RESULTS: From 1226 patients with AL amyloidosis, 37.0% reported depression and 46.7% reported anxiety. Patients with cardiac amyloidosis reported more anxiety (odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.03-1.61) and role limitation due to emotional problems (OR = 1.32, 95%CI 1.05-1.65). No significant association between cardiac involvement and depression was found (OR = 1.22, 95%CI 0.97-1.54). Men reported less anxiety (OR = 0.72, 95%CI 0.57-0.91). Patients >=65 years experienced greater role limitation (OR = 1.36, 95%CI 1.08 1.71). Smokers (p = 0.019) and women (p = 0.006) scored lower on mental health subscales. CONCLUSIONS: Many patients with AL amyloidosis suffer from depression, anxiety and functional limitations. Psychiatric assessment and treatment is important, and further research is needed to clarify the long-term effects of depression and anxiety in AL amyloidosis. This current study was registered in ClinicalTrials.gov as NCT00898235. PMID- 27460278 TI - Imaging spectroscopic ellipsometry of MoS2. AB - Micromechanically exfoliated mono- and multilayers of molybdenum disulfide (MoS2) are investigated by spectroscopic imaging ellipsometry. In combination with knife edge illumination, MoS2 flakes can be detected and classified on arbitrary flat and also transparent substrates with a lateral resolution down to 1-2 um. The complex dielectric functions from mono- and trilayer MoS2 are presented. They are extracted from a multilayer model to fit the measured ellipsometric angles employing an anisotropic and an isotropic fit approach. We find that the energies of the critical points of the optical constants can be treated to be independent of the utilized model, whereas the magnitude of the optical constants varies with the used model. The anisotropic model suggests a maximum absorbance for a MoS2 sheet supported by sapphire of about 14% for monolayer and of 10% for trilayer MoS2. Furthermore, the lateral homogeneity of the complex dielectric function for monolayer MoS2 is investigated with a spatial resolution of 2 um. Only minor fluctuations are observed. No evidence for strain, for a significant amount of disorder or lattice defects can be found in the wrinkle-free regions of the MoS2 monolayer from complementary u-Raman spectroscopy measurements. We assume that the minor lateral variation in the optical constants are caused by lateral modification in the van der Waals interaction presumably caused by the preparation using micromechanical exfoliation and viscoelastic stamping. PMID- 27460277 TI - Cavity optomechanical spring sensing of single molecules. AB - Label-free bio-sensing is a critical functionality underlying a variety of health and security-related applications. Micro-/nano-photonic devices are well suited for this purpose and have emerged as promising platforms in recent years. Here we propose and demonstrate an approach that utilizes the optical spring effect in a high-Q coherent optomechanical oscillator to dramatically enhance the sensing resolution by orders of magnitude compared with conventional approaches, allowing us to detect single bovine serum albumin proteins with a molecular weight of 66 kDa at a signal-to-noise ratio of 16.8. The unique optical spring sensing approach opens up a distinctive avenue that not only enables biomolecule sensing and recognition at individual level, but is also of great promise for broad physical sensing applications that rely on sensitive detection of optical cavity resonance shift to probe external physical parameters. PMID- 27460279 TI - Duration of intraocular gases following vitreoretinal surgery. AB - BACKGROUND: Intraocular gas tamponades are an important tool in modern vitreoretinal surgery. However, there is considerable variation in their use and perceptions amongst clinicians regarding these agents. METHODS: An electronic survey of vitreoretinal surgeons in the UK was undertaken to establish the patterns of use and surgeons' estimates of the longevity and expansion timing of gas tamponades. In addition, data were prospectively collected on the longevity of gas tamponades in 114 patients from our unit. An analysis was performed to identify patient or surgery factors affecting gas longevity RESULTS: A wide variation in the patterns of use and estimates of longevity and expansion timing of intraocular tamponades was found in the survey of vitreoretinal surgeons. Data from our unit give informed estimates on the longevity of three commonly used tamponades. For 30 % sulphur hexafluoride (SF6), mean 18.0 days, standard deviation (SD) 2.6 days. For 20 % hexafluoroethane (C2F6), mean 34.5 days, SD 3.3 days. For 15 % perfluoropropane (C3F8), mean 67.7 days SD 5.5 days. In the C2F6 group there was correlation between longer duration of the gas bubble and longer axial length (r = 0.438, p = 0.02) and longer gas duration with male sex (p = 0.002). CONCLUSIONS: We present informed gas tamponade longevity figures in clinical practice and report statistically significant associations between longer gas longevity and increasing axial length and male sex. PMID- 27460282 TI - Two-Dimensional Boron Hydride Sheets: High Stability, Massless Dirac Fermions, and Excellent Mechanical Properties. AB - Two-dimensional (2D) boron sheets have been successfully synthesized in recent experiments, however, some important issues remain, including the dynamical instability, high energy, and the active surface of the sheets. In an attempt to stabilize 2D boron layers, we have used density functional theory and global minimum search with the particle-swarm optimization method to predict four stable 2D boron hydride layers, namely the C2/m, Pbcm, Cmmm, and Pmmn sheets. The vibrational normal mode calculations reveal all these structures are dynamically stable, indicating potential for successful experimental synthesis. The calculated Young's modulus indicates a high mechanical strength for the C2/m and Pbcm phases. Most importantly, the C2/m, Pbcm, and Pmmn structures exhibit Dirac cones with massless Dirac fermions and the Fermi velocities for the Pbcm and Cmmm structures are even higher than that of graphene. The Cmmm phase is reported as the first discovery of Dirac ring material among boron-based 2D structures. The unique electronic structure of the 2D boron hydride sheets makes them ideal for nanoelectronics applications. PMID- 27460281 TI - The influence of near work on myopic refractive change in urban students in Beijing: a three-year follow-up report. AB - PURPOSE: To investigate the influence of daily activities on myopic refractive change and myopic onset in Chinese urban students. METHODS: The Beijing Myopia Progression Study was a 3-year cohort study. Cycloplegic refraction and a daily activity questionnaire were assessed at baseline and at follow-up examinations. Refractive change was defined as the difference in cycloplegic spherical equivalent (SE) between the final follow-up and baseline. 386 students were initially enrolled in the baseline study. RESULTS: At the final follow-up, 222 students (57.5 %) with completed refractive error and daily activity data were analyzed. These students spent 0.32 +/- 2.33 h/day more on near work (p = 0.04), and 0.21 +/- 1.31 h/day less on outdoor leisure (p = 0.02), than they did at baseline. In the multivariate analysis, the younger among the secondary students (beta = 0.06, p < 0.001), and those with more near work hours at baseline (beta = -0.028, p = 0.033), exhibited more myopic refractive change. However, myopic refractive change was not found to be significantly associated with near work hours in the primary students, or with time spent outdoors, in either school level. After stratifying the activity hours into quartile groups, students with a greater near work load at baseline (trend P = 0.03) exhibited a greater myopic refractive change and had a higher risk to develop myopia (hazard ratio, 95 % confidence interval: 5.19, 1.49-18.13), after adjusting for the confounders. However, no significant association was found related to outdoor activity. CONCLUSIONS: In this cohort, children with a greater near work load at baseline exhibited more myopic refractive change and were also more likely to develop myopia. The protective effect of outdoor activity on myopic refractive change was not observed. PMID- 27460280 TI - Dexamethasone intravitreal implant in retinal vein occlusion: real-life data from a prospective, multicenter clinical trial. AB - PURPOSE: To evaluate the relationship between duration of macular edema associated with retinal vein occlusion (RVO) and the achievement of vision gain in patients receiving dexamethasone intravitreal implant (DEX implant) in real world clinical practice, and to define patterns of use of DEX implant and its efficacy and safety in the treatment of patients with RVO in clinical practice. METHODS: This prospective, open-label, multicenter, 6-month observational phase IV study conducted at 70 sites in Germany enrolled patients diagnosed with macular edema following branch or central RVO (BRVO, CRVO) who were given DEX implant. Follow-up visits and evaluations occurred in accordance with normal clinical practice. Re-treatment with DEX implant and use of other RVO therapies was at the discretion of the treating physician. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline at week 12. RESULTS: The analysis population consisted of 573 patients (64 % BRVO, 36 % CRVO). Patients received a mean of 1.17 DEX implant treatments during the study period; 84.3 % of patients received a single DEX implant and 19.9 % received adjunctive other RVO treatment. Among patients with analyzable BCVA data at baseline and week 12 (n = 351), mean change from baseline BCVA at week 12 was -0.16 (standard deviation, 0.30) logMAR (+7.8 approximate Early Treatment Diabetic Retinopathy Study [ETDRS] letters) (p < 0.001), and 33.9 % of patients had gained at least 3 lines in BCVA from baseline. Mean change from baseline BCVA at week 12 was +9.5, +7.3, and +5.4 approximate ETDRS letters in patients with macular edema duration < 90 days, from 90 to 180 days, and >180 days respectively. Improvement in BCVA through week 24 and decreases in central retinal thickness were seen in both BRVO and CRVO. The most common adverse drug reaction was increased intraocular pressure. No glaucoma incisional surgeries were required. CONCLUSIONS: DEX implant was effective in improving BCVA and central retinal thickness in patients with BRVO and CRVO in real-world clinical practice. The largest gains in BCVA over 6 months occurred in patients with recent onset macular edema, confirming the benefit of early treatment. DEX implant was well tolerated and had an acceptable safety profile. PMID- 27460283 TI - Cinical outcomes of Endurant II stent-graft for infrarenal aortic aneurysm repair: comparison of on-label versus off-label use. AB - PURPOSE: We aimed to compare the outcomes of the Endurant II (Medtronic) stent graft used under instructions for use versus off-label in high-risk patients considered unfit for conventional surgery. METHODS: Data from patients treated with the Endurant II stent-graft between December 2012 and March 2015 were retrospectively analyzed. Sixty-four patients were included. Patients were assigned to group A if treated under instructions for use (n=34, 53%) and to group B if treated off-label (n=30, 47%). Outcome measures included perioperative mortality and morbidity, survival, freedom from reintervention, endoleak incidence, in-hospital length of stay, and mean stent-graft component used. Mean follow-up was 22.61+/-12 months (median, 21.06 months; range, 0-43 months). RESULTS: One perioperative mortality (1.6%) and one perioperative complication (1.6%) occurred in group B. At two months follow-up, one iliac limb occlusion (1.6%) occurred in group A. No type I/III endoleaks were recorded. A type II endoleak was identified in three cases (4.7%). Overall survival at three years was 89% (97% for group A, 82% for group B; P = 0.428). Reintervention-free survival at three years was 97% for both groups (P = 0.991). A longer in-hospital stay was observed in group B (P = 0.012). CONCLUSION: The Endurant II (Medtronic) new generation device was safe in off-label setting at mid-term follow-up. The off-label use of the Endurant II (Medtronic) is justified in patients considered unfit for conventional surgery. Larger studies are required in this subgroup of patients. PMID- 27460285 TI - Multidetector CT of expected findings and complications after contemporary inguinal hernia repair surgery. AB - Inguinal hernia repair (IHR) with prosthetic mesh implantation is the most common procedure in general surgery, and may be performed using either an open or laparoscopic approach. This paper provides an overview of contemporary tension free IHR techniques and materials, and illustrates the expected postoperative imaging findings and iatrogenic injuries. Emphasis is placed on multidetector CT, which represents the ideal modality to comprehensively visualize the operated groin region and deeper intra-abdominal structures. CT consistently depicts seroma, mesh infections, hemorrhages, bowel complications and urinary bladder injuries, and thus generally provides a consistent basis for therapeutic choice. Since radiologists are increasingly requested to investigate suspected iatrogenic complications, this paper aims to provide an increased familiarity with early CT studies after IHR, including complications and normal postoperative appearances such as focal pseudolesions, in order to avoid misinterpretation and inappropriate management. PMID- 27460284 TI - Pleuroparenchymal fibroelastosis: the prevalence of secondary forms in hematopoietic stem cell and lung transplantation recipients. AB - PURPOSE: Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia, characterized by elastotic fibrosis involving the pleura and subpleural parenchyma, predominantly in the upper lobes. PPFE can be either idiopathic or secondary and mostly occurs as a late complication of lung or hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the prevalence of secondary forms in transplant recipients. METHODS: An expert thoracic radiologist retrospectively reviewed high-resolution computed tomography exams of 700 HSCT recipients and 53 lung transplant recipients from the database of the Radiology Department of S. Orsola-Malpighi Hospital dating back from 2007. For each case that radiologically fulfilled PPFE criteria, the following details were retrieved: clinical characteristics, laboratory and functional data, pathologic findings (obtained from one patient) and metabolic data (obtained from three patients). RESULTS: Six cases clinically and radiologically consistent with PPFE were identified: two HSCT recipients (0.28%) and four lung transplant recipients (7.54%). CONCLUSION: In this study, PPFE was strongly associated with lung transplants as a late complication, with a prevalence of 7.54%. PMID- 27460286 TI - Probing the interactions of structurally similar but chemically distinguishable organic solutes with 1-ethyl-3-methylimidazolium alkyl sulfate (alkyl = ethyl, hexyl and octyl) ionic liquids through fluorescence, NMR and fluorescence correlation spectroscopy (FCS) studies. AB - The rotational diffusion of two organic solutes, 4-(azitidine-1-yl)-7 nitrobenzo[1,2,5]oxadi-azole (ANBD) and 7-nitrobenzo[1,2,5]oxadiazole-4-amine (HNBD), has been examined in 1-ethyl-3-methylimidazolium alkyl sulfate (alkyl = ethyl, hexyl and octyl) ionic liquids with the aim of understanding intermolecular interactions among solute and solvent molecules. Solute-solvent interaction has also been investigated by employing fluorescence, NMR and fluorescence correlation spectroscopy (FCS). The ionic liquids (ILs) having a fixed cationic moiety are chosen to monitor the roles of the alkyl chain length as well as the solute-anion (sulfate) interactions in the rotational diffusion of the solutes in the given ILs. In the present study, two chemically distinguishable solutes with structural similarity in their fluorophore unit are employed so that the difference in the rotational behavior of the solutes, if any, can be correlated with the solute-solvent interactions, and not with other factors like the size of the solutes etc. The steady state absorption and emission data indicate that HNBD and ANBD exist in different microenvironments in both ILs. The rotational diffusion data for both the solutes have been analyzed in light of hydrodynamic and quasi hydrodynamic theories. Interestingly, the rotational dynamics of ANBD is observed to be relatively fast and shows slip hydrodynamics, whereas HNBD exhibits hindered rotation with superstick behavior. The hindered rotation of HNBD as compared to that of ANBD in both ILs has been explained by considering the strong hydrogen bonding interactions between the two N-H groups of HNBD and sulfate anions of ILs. The faster rotation of ANBD with the increasing anion chain length has been explained by invoking quasi hydrodynamic theory. The presence of a specific hydrogen bonding interaction between solute (HNBD) and solvent (ILs) molecules has been confirmed by (1)H-NMR experiments. FCS measurements have independently demonstrated the relatively strong association of HNBD with the present ILs as compared to that of ANBD. PMID- 27460288 TI - A multi-coordinating polymer ligand optimized for the functionalization of metallic nanocrystals and nanorods. AB - We report the design and use of a multi-coordinating polymer ligand that is ideally suited for functionalizing gold nanoparticles and nanorods, and promoting their steric stabilization in buffer media. The ligand is prepared via a one-step nucleophilic addition reaction between poly(isobutylene-alt-maleic anhydride) and amine-modified anchoring groups and hydrophilic moieties. Surface functionalization of gold nanoparticles and nanorods with this polymer yields nanocrystals that exhibit excellent long-term colloidal stability over a broad range of conditions, including pH changes and in growth media, as verified using dynamic light scattering measurements combined with agarose gel electrophoresis. This polymer coating can also prevent the formation of protein corona. These features bode well for use in biological applications where small size, reduced nonspecific interactions and colloidal stability are highly desired. Furthermore, this design can be easily expanded to functionalize a variety of other inorganic nanocrystals. PMID- 27460289 TI - Concatenation of 'alert' and 'identity' segments in dingoes' alarm calls. AB - Multicomponent signals can be formed by the uninterrupted concatenation of multiple call types. One such signal is found in dingoes, Canis familiaris dingo. This stereotyped, multicomponent 'bark-howl' vocalisation is formed by the concatenation of a noisy bark segment and a tonal howl segment. Both segments are structurally similar to bark and howl vocalisations produced independently in other contexts (e.g. intra- and inter-pack communication). Bark-howls are mainly uttered in response to human presence and were hypothesized to serve as alarm calls. We investigated the function of bark-howls and the respective roles of the bark and howl segments. We found that dingoes could discriminate between familiar and unfamiliar howl segments, after having only heard familiar howl vocalisations (i.e. different calls). We propose that howl segments could function as 'identity signals' and allow receivers to modulate their responses according to the caller's characteristics. The bark segment increased receivers' attention levels, providing support for earlier observational claims that barks have an 'alerting' function. Lastly, dingoes were more likely to display vigilance behaviours upon hearing bark-howl vocalisations, lending support to the alarm function hypothesis. Canid vocalisations, such as the dingo bark-howl, may provide a model system to investigate the selective pressures shaping complex communication systems. PMID- 27460287 TI - Chronic UVB-irradiation actuates perpetuated dermal matrix remodeling in female mice: Protective role of estrogen. AB - Chronic UVB-exposure and declined estradiol production after menopause represent important factors leading to extrinsic and intrinsic aging, respectively. Remodeling of the extracellular matrix (ECM) plays a crucial role in both responses. Whether the dermal ECM is able to recover after cessation of UVB irradiation in dependence of estradiol is not known, however of relevance when regarding possible treatment options. Therefore, the endogenous sex hormone production was depleted by ovariectomy in female mice. Half of the mice received estradiol substitution. Mice were UVB-irradiated for 20 weeks and afterwards kept for 10 weeks without irradiation. The collagen-, hyaluronan- and proteoglycan- (versican, biglycan, lumican) matrix, collagen cleavage products and functional skin parameters were analyzed. The intrinsic aging process was characterized by increased collagen fragmentation and accumulation of biglycan. Chronic UVB irradiation additionally augmented the lumican, versican and hyaluronan content of the dermis. In the absence of further UVB-irradiation the degradation of collagen and accumulation of biglycan in the extrinsically aged group was perpetuated in an excessive matter. Whereas estradiol increased the proteoglycan content, it reversed the effects of the perpetuated extrinsic response on collagen degradation. Suspension of the intrinsic pathway might therefore be sufficient to antagonize UVB-evoked long-term damage to the dermal ECM. PMID- 27460290 TI - Press-Printed Conductive Carbon Black Nanoparticle Films for Molecular Detection at the Microscale. AB - Carbon black nanoparticle (CBNP) press-transferred film-based transducers for the molecular detection at the microscale level were proposed for the first time. Current-sensing atomic force microscopy (CS-AFM) revealed that the CBNP films were effectively press-transferred, retaining their good conductivity. A significant correlation between the morphology and the resistance was observed. The highest resistance was localized at the top of the press-transferred film protrusions, whereas low values are usually obtained at the deep crevices or grooves. The amount of press-transferred CBNPs is the key parameter to obtain films with improved conductivity, which is in good agreement with the electrochemical response. In addition, the conductivity of such optimum films was not only Ohmic; in fact, tunneling/hopping contributions were observed, as assessed by CS-AFM. The CBNP films acted as exclusive electrochemical transducers as evidenced by using two classes of molecules, that is, neurotransmitters and environmental organic contaminants. These results revealed the potential of these CBNP press-transferred films for providing new options in microfluidics and other related micro- and nanochemistry applications. PMID- 27460291 TI - Sport activity in Charcot-Marie-Tooth disease: A case study of a Paralympic swimmer. AB - This study reports the positive physical, emotional and psychosocial changes induced by sport activity in a Paralympic swimmer with Charcot-Marie-Tooth (CMT) type 4A. When we compared evaluations before initiating sport activity with those after five years of competitive activity, we found: i) increased proximal muscles strength of upper limbs; ii) augmented ability to propel wheelchair independently; iii) improved quality of life; iv) reduced trait anxiety and striking improvement of depression; v) enhanced self-esteem. Longitudinal studies in large cohorts to evaluate the positive effects of sport activity are needed to support provision of evidence-based advice to patients and families. PMID- 27460292 TI - Opening the window: The case for carrier and perinatal screening for spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease that leads to infant mortality worldwide. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in a deficiency in SMN protein. For reasons that are still unclear, SMN protein deficiency predominantly affects alpha-motor neurons, resulting in their degeneration and subsequent paralysis of limb and trunk muscles, progressing to death in severe cases. Emerging evidence suggests that SMN protein deficiency also affects the heart, autonomic nervous system, skeletal muscle, liver, pancreas and perhaps many other organs. Currently, there is no cure for SMA. Patient treatment includes respiratory care, physiotherapy, and nutritional management, which can somewhat ameliorate disease symptoms and increase life span. Fortunately, several novel therapies have advanced to human clinical trials. However, data from studies in animal models of SMA indicate that the greatest therapeutic benefit is achieved through initiating treatment as early as possible, before widespread loss of motor neurons has occurred. In this review, we discuss the merit of carrier and perinatal patient screening for SMA considering the efficacy of emerging therapeutics and the physical, emotional and financial burden of the disease on affected families and society. PMID- 27460293 TI - Recent developments in the chromatographic bioanalysis of approved kinase inhibitor drugs in oncology. AB - In recent years (2010-present) there has been an increase in the number of publications reporting the development, validation and use of bioanalytical methods in the rapidly expanding drug class of small molecule protein kinase inhibitors. Most reports describe the technological set-up of the methods that have allowed for drug concentration measurements from various sample types. This includes plasma, dried blood-spot, and tissue-analysis. Also method development, exploration of various techniques, as well as measurement and identification of metabolites were addressed. For the bioanalysis, a variety of sample-pretreatment methods like protein-precipitation, liquid-liquid extraction, and solid-phase extraction have been employed, all varying in complexity, cleanliness and time consumption. Chromatographic separation, nowadays, is more focused on separating components from ion-suppressive effects, since for MS/MS detection, various components do not have to be baseline separated. For detection multiple types of detectors were used, ranging from state-of-the-art high resolution, and tandem mass spectrometry with low picogram per milliliter detection limits to the classical UV-detector with several nanograms per milliliter limits. As new bioanalytical methods have arisen that do rely on chromatographic separation, for example for high-throughput analysis, these are addressed in this review as well. PMID- 27460294 TI - Multiscale Cues Drive Collective Cell Migration. AB - To investigate complex biophysical relationships driving directed cell migration, we developed a biomimetic platform that allows perturbation of microscale geometric constraints with concomitant nanoscale contact guidance architectures. This permits us to elucidate the influence, and parse out the relative contribution, of multiscale features, and define how these physical inputs are jointly processed with oncogenic signaling. We demonstrate that collective cell migration is profoundly enhanced by the addition of contract guidance cues when not otherwise constrained. However, while nanoscale cues promoted migration in all cases, microscale directed migration cues are dominant as the geometric constraint narrows, a behavior that is well explained by stochastic diffusion anisotropy modeling. Further, oncogene activation (i.e. mutant PIK3CA) resulted in profoundly increased migration where extracellular multiscale directed migration cues and intrinsic signaling synergistically conspire to greatly outperform normal cells or any extracellular guidance cues in isolation. PMID- 27460296 TI - Differential Effect of Total Knee Arthroplasty on Valgus and Varus Knee Biomechanics During Gait. AB - BACKGROUND: Total knee arthroplasty and its relation to gait abduction or adduction moment has not been fully described. METHODS: Gait analysis was performed on 25 patients (27 knees) preoperatively, 6 months and 1 year after total knee arthroplasty. Reflective markers were placed on the lower extremity, and motion data were collected at 60 Hz using 6 infrared cameras. Ground reaction forces were recorded at 960 Hz with a force plate. Stance phase was divided into braking and propulsive phases. Coronal knee angles and moments were calculated. Repeated-measures analysis of variance was used to compare frontal plane knee impulse over time and between the braking and propulsive phases of stance. RESULTS: In varus knees, static alignment was corrected from 2.2 degrees varus to 3.3 degrees valgus and in valgus knees from 15.2 degrees valgus to 2.7 degrees valgus (P < .010). Braking phase adduction impulse decreased from 0.145 to 0.111 at 6 months but increased to 0.126 Nm/kg s (P > .05) at 1 year. Propulsive phase impulse changed from 0.129 to 0.085 and persisted at 1 year. Impulse changed from 0.01 (abduction) to 0.11 Nm/kg s (adduction) at 6 months and persisted (P = .01). CONCLUSION: Restoration of anatomic alignment and soft tissue balancing changes the lateral loading conditions of valgus knees. Both cases, between 6 months and 1 year, increased peak moment. PMID- 27460295 TI - Bacteremia due to Streptococcus tigurinus: A case report and literature review. AB - Gene sequence analysis methods, including 16S rRNA identification, allows accurate identification of Streptococcus species, which include phenotypically closely related species that are difficult to differentiate using conventional chemical methods. We report a case of bacteremia due to Streptococcus tigurinus, identified by 16S rRNA, in a 72-year-old woman with gastrointestinal cancer and ascites. She was hospitalized to undergo elective tumor-related surgery. Five days prior to undergoing surgery, she developed a fever with no obvious source of infection. Blood cultures identified gram-positive cocci. The patient's bacteremia was initially thought to be caused by an Enterococcus species, given her underlying gastrointestinal disease. However, alpha-hemolytic, mucoid, circular colonies were observed on sheep blood agar the following day. Although matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and biochemical testing suggested Streptococcus pneumoniae, we conducted further investigation to identify the bacterium, as the patient had no symptoms of infections usually related with S. pneumoniae such as pneumonia, meningitis, or sinusitis, and the bacteremia occurred 30 days after hospitalization. Finally, the gram-positive cocci were identified as S. tigurinus, assigned to the Streptococcus mitis group in 2012. Although the origin of infection was unclear, it was suspected that peritonitis or bacterial translocation from the gastrointestinal tract caused the bacteremia. This novel species was recently reported as being extremely pathogenic and different from other Streptococcus species. It has been reported to occur in cases of infectious endocarditis and bacteremia. In this article, we reviewed previous reports of S. tigurinus infection and summarized the clinical and pathogenetic features. PMID- 27460297 TI - A Comparison of the Medium-Term Results of Total Knee Arthroplasty Using Computer Assisted and Conventional Techniques to Treat Patients With Extraarticular Femoral Deformities. AB - BACKGROUND: We compared the medium-term results of total knee arthroplasty (TKA) performed using computer-assisted surgery (CAS) and conventional techniques in patients with extraarticular femoral deformities. METHODS: The clinical and radiographic data of 40 knees (34 patients) with extraarticular femoral deformities that underwent consecutive CAS-TKA were compared with those of a control group that underwent conventional TKA (80 knees, 63 patients). No demographic data (in particular, the causes of the extraarticular deformities) differed between the two groups. The follow-up periods of the CAS and conventional TKA groups were 6.0 and 6.3 years, respectively. RESULTS: In the CAS group, the average knee score increased from 48.2 to 89.6 at the final follow-up (P < .001); the average function score increased from 51.4 to 91.4. The range of motion averaged 105.5 degrees preoperatively and 123.3 degrees postoperatively. No significant differences were found in the knee score, function score, or range of motion after TKA between the 2 groups. The average preoperative mechanical axes were 18.1 degrees varus in both groups. The average postoperative mechanical axis was 1.4 degrees varus in the CAS group and 3.3 degrees varus in the conventional TKA group (P = .001). The proportion of postoperatively aligned knees was 77.5% in the CAS group and 32.5% in the conventional group (P < .001). CONCLUSION: Although the medium-term clinical results of TKA in extraarticular femoral deformities were satisfactory in both the CAS and conventional TKA groups, the former group exhibited more accurate postoperative coronal alignment. It was useful to employ navigation in patients with extraarticular deformities of various etiologies. PMID- 27460299 TI - Supplement to Proceedings-the 2015 AAHKS Annual Meeting. PMID- 27460298 TI - Does Taper Size Have an Effect on Taper Damage in Retrieved Metal-on-Polyethylene Total Hip Devices? AB - BACKGROUND: Taper design has been identified as a possible contributor to fretting corrosion damage at modular connections in total hip arthroplasty systems, but variations in as-manufactured taper interfaces may confound this analysis. This study characterized taper damage in retrievals with 2 different taper sizes but comparable taper surface finishes and investigated if fretting and corrosion damage is related to taper size in the context of a multivariable analysis for metal-on-polyethylene bearings. METHODS: A total of 252 cobalt chromium femoral heads were identified in a collection of retrievals: 77 with taper A and 175 with taper B. Implantation time averaged 5.4 +/- 6.0 years (range, 0-26 years). Explants were cleaned and analyzed using a 4-point semiquantitative method. Clinical and device factors related to head taper fretting corrosion damage were assessed using ordinal logistic regression with forward stepwise control. Components were then selected to create 2 balanced cohorts, matched on significant variables from the multivariable analysis. RESULTS: Increased head offset (P < .001), longer implantation time (P = .002), heavier patients (P < .001), and more flexible tapers (P < .001) were associated with increased taper fretting and corrosion damage. When damage scores were compared between the balanced groups, no significant differences were found. CONCLUSION: These results suggest that fretting and corrosion damage is insensitive to differences in taper size. The final model derived explains almost half of the fretting corrosion damage observed and identifies contributing factors that are consistent with other in vitro and retrieval studies. PMID- 27460300 TI - Influence of Medial Collateral Ligament Release for Internal Rotation of Tibia in Posterior-Stabilized Total Knee Arthroplasty: A Cadaveric Study. AB - BACKGROUND: Previous studies suggested that changes in kinematics in total knee arthroplasty (TKA) affected satisfaction level. The aim of this cadaveric study was to evaluate the effect of medial collateral ligament (MCL) release by multiple needle puncture on knee rotational kinematics in posterior-stabilized TKA. METHODS: Six fresh, frozen cadaveric knees were included in this study. All TKA procedures were performed with an image-free navigation system using a 10-mm polyethylene insert. Tibial internal rotation was assessed to evaluate intraoperative knee kinematics. Multiple needle puncturing was performed 5, 10, and 15 times for the hard portion of the MCL at 90 degrees knee flexion. Kinematic analysis was performed after every 5 punctures. After performing 15 punctures, a 14-mm polyethylene insert was inserted, and kinematic analysis was performed. RESULTS: The tibial internal rotation angle at maximum knee flexion without multiple needle puncturing was significantly larger (9.42 degrees ) than that after 15 punctures (3 degrees ). Negative correlation (Pearson r = -0.715, P < .001) between tibial internal rotation angle at maximum knee flexion and frequency of puncture was observed. The tibial internal rotation angle with a 14 mm insert was significantly larger (7.25 degrees ) compared with the angle after 15 punctures. CONCLUSION: Tibial internal rotation during knee flexion was reduced by extensive MCL release using multiple needle puncturing and was recovered by increasing of medial tightness. From the point of view of knee kinematics, medial tightness should be allowed to maintain the internal rotation angle of the tibia during knee flexion which might lead to patient satisfaction. PMID- 27460301 TI - Impact of Anterior vs Posterior Approach for Total Hip Arthroplasty on Post-Acute Care Service Utilization. AB - BACKGROUND: Controversy exists as to which surgical approach is best for total hip arthroplasty (THA). Previous studies suggested that the tissue-sparing anterior approach should result in a more rapid recovery requiring fewer postacute services, ultimately decreasing overall episodic cost. The purpose of this cross-sectional study was to determine if any significant differences exist between the anterior vs posterior approaches on postacute care service utilization, readmissions, or episodic cost. METHODS: Claims data from 26,773 Medicare fee-for-service beneficiaries receiving elective THAs (Medical Severity Diagnosis Related Groups (MS-DRGs) 469/470) were analyzed. Claims data were collected from the 2-year period, January 2013 through December 2014. The posterior surgical approach was performed on 23,653 patients while 3120 patients received the anterior approach. RESULTS: Data analysis showed negligible effect sizes in postacute care service utilization, readmission rate, and cost between the surgical approaches for elective THA (MS-DRG 469 and 470). Average THA total episode cost was negligibly higher for procedures using the anterior approach compared to the posterior approach ($22,517 and $22,068, respectively). Statistically significant differences were observed in inpatient rehab and home health cost and service utilization. However, the effect sizes of these comparisons are negligible when accounting for the large sample size. All other comparisons showed minimal and statistically insignificant variation. CONCLUSION: The results indicate that surgical approach alone is not the primary driver of postacute care service utilization, quality outcomes, or cost. Other factors such as physician-led patient-focused care pathways, care coordination, rapid rehabilitation protocols, perioperative pain management protocols, and patient education are integral for effective patient care. PMID- 27460302 TI - Impact of gender on long-term mortality in patients with unprotected left main disease: The Milan and New-Tokyo (MITO) Registry. AB - BACKGROUND: Although percutaneous intervention (PCI) for ULM is common, the impact of gender remains unclear. This study aimed to clarify the impact of gender in patients treated with drug-eluting stents (DES) for unprotected left main (ULM) disease. METHODS: Between April 2002 and August 2011, 1026 consecutive patients (212 women and 814 men) undergoing PCI using first or second generation DES for ULM stenosis were analyzed. Study endpoints included major adverse cardiac events (MACE) defined as composite of all-cause death, myocardial infarction (MI), and target lesion revascularization (TLR). Individual components of MACE and cardiac death were also evaluated. RESULTS: Women had greater comorbidity and more complex lesions, resulting in a higher incidence of cardiac death, TLR and MI {[HR, 1.94 (95% CI, 1.22-3.09, p=0.005)], [HR, 1.31 (95% CI 0.96-1.81), p=0.09] and [HR, 2.04 (95% CI, 0.98-4.25), p=0.06], respectively}. Propensity score matching identified 131 matched pairs. There were no differences in MACE [HR, 1.04 (95% CI, 0.68-1.61, p=0.85)], all-cause death [HR, 0.96 (95% CI, 0.52-1.77), p=0.89] or MI [HR, 0.84 (95% CI, 0.21-3.50, p=0.84)]. However, cardiac death [HR, 2.70 (95% CI, 0.98-7.49, p=0.056] and TLR [HR, 1.62 (95% CI, 0.93-2.84), p=0.09] showed a trend to being higher in women compared to men. CONCLUSIONS: In patients with ULM disease, women had greater comorbidity and more complex lesions, resulting in an increased risk of clinical events. However after propensity matching, there was no difference in the occurrence of MACE but cardiac death showed a trend to being higher in women compared to men. PMID- 27460303 TI - Incidence of Domestic Violence Against Pregnant Females After the Great East Japan Earthquake in Miyagi Prefecture: The Japan Environment and Children's Study. AB - OBJECTIVE: This study aimed to clarify the correlation between the 2011 Great East Japan Earthquake and domestic violence (DV) against pregnant females after the disaster in Miyagi Prefecture, an area damaged by the earthquake and tsunami. METHODS: We analyzed 7600 pregnant females from June to December 2011. The incidence of physical and mental DV and the proportions in the inland, north coastal, and south coastal areas of Miyagi Prefecture and nationwide were calculated, and a chi-square test was conducted for comparison. The risk factors for DV were estimated with multivariate logistic regression analyses on a prefecture-wide basis. RESULTS: The incidence levels for physical DV were found to be 5.9% in the north coastal area, which was significantly higher than in the inland area (1.3%, P=0.0007) and nationwide (1.5%, P<0.0001). There were no significant differences in the incidence of mental DV between the 3 areas in Miyagi Prefecture (inland 15.2%, north coast 15.7%, and south coast 18.8%) or nationwide (13.8%). Experiencing disease or injury in someone close and changes in the family structure were significantly associated with mental DV in Miyagi Prefecture. CONCLUSION: Continuous monitoring and support for pregnant females may be necessary to address this issue in disaster-affected areas. (Disaster Med Public Health Preparedness. 2017;11:216-226). PMID- 27460304 TI - The clinical significance and impact of interleukin 15 on keratinocyte cell growth and migration. AB - Chronic wounds represent a significant burden to health services and are associated with patient morbidity. Novel methods to diagnose and/or treat problematic wounds are needed. Interleukin (IL)-15 is a cytokine involved in a number of biological processes and disease states such as inflammation, healing and cancer progression. The current study explores the expression profile of IL 15 and IL-15 receptor alpha (IL-15Ralpha) in chronic wounds and its impact on keratinocytes. IL-15 and IL-15Ralpha expression were examined in healing and non healing chronic wounds using qPCR and immunohistochemical analysis. The impact of recombinant IL-15 (rhIL-15) on human adult low calcium temperature (HaCaT) keratinocyte growth and migratory potential was further examined. IL-15 transcript expression was slightly, though non-significantly elevated in healing chronic wounds compared with non-healing chronic wounds. IL-15 protein staining was minimal in both subtypes of chronic wounds. By contrast, IL-15Ralpha transcript and protein expression were both observed to be enhanced in non healing chronic wounds compared with healing chronic wounds. The treatment of HaCaT cells with rhIL-15 generally enhanced cell growth and promoted migration. Analysis with small molecule inhibitors suggested that the pro-migratory effect of rhIL-15 may be associated with ERK, AKT, PLCgamma and FAK signalling. IL-15 may promote healing traits in keratinocytes and the differential expression of IL 15Ralpha is observed in chronic wounds. Together, this may imply a complex role for this interleukin in wound healing. PMID- 27460305 TI - The organ preservation and enhancement of donation success ratio effect of extracorporeal membrane oxygenation in circulatory unstable brain death donor. AB - Between 2010 and 2013, we recorded 66 cases of failed organ donation after brain death (DBD) due to the excessive use of the vasoactive drugs resulting in impaired hepatic and/or renal function. To investigate the effect of extracorporeal membrane oxygenation (ECMO) in donor management, ECMO was used to provide support for DBD donors with circulatory and/or respiratory failure from 2013 to 2015. A retrospective cohort study between circulatory non-stable DBD with vasoactive drugs (DBD-drug) and circulatory non-stable DBD with ECMO (DBD ECMO) was designed to compare the transplant outcomes. A total of 19 brain death donors were supported by ECMO. The incidence rate of post-transplant liver primary non-function (PNF) was 10% (two of 20) in DBD-drug group and zero in DBD ECMO group. Kidney function indicators, including creatinine clearance and urine production, were significantly better in DBD-ECMO group, as well as the kidney delayed graft function (DGF) rate was found to be decreased by the use of ECMO in our study. Donation success rate increased steadily from 47.8% in 2011 to 84.6% in 2014 after the ECMO intervention. The use of ECMO in assisting circulatory and respiratory function of DBD can reduce liver and kidney injury from vasoactive drugs, thereby improving organ quality and reducing the organ discard rates. PMID- 27460306 TI - Young people have a new vision for essential medicines. PMID- 27460307 TI - Lipoprotein(a) and familial hypercholesterolaemia. PMID- 27460308 TI - Lipoprotein(a) and familial hypercholesterolaemia - Authors' reply. PMID- 27460309 TI - Collaborative funding for NCDs-a model of research funding. PMID- 27460310 TI - Organic nitrogen uptake is a significant contributor to nitrogen economy of subtropical epiphytic bryophytes. AB - Without any root contact with the soil, epiphytic bryophytes must experience and explore poor, patchy, and heterogeneous habitats; while, the nitrogen (N) uptake and use strategies of these organisms remain uncharacterized, which obscures their roles in the N cycle. To investigate the N sources, N preferences, and responses to enhanced N deposition in epiphytic bryophytes, we carried out an in situ manipulation experiment via the (15)N labelling technique in an Asian cloud forest. Epiphytic bryophytes obtained more N from air deposition than from the bark, but the contribution of N from the bark was non-negligible. Glycine accounted for 28.4% to 44.5% of the total N in bryophyte tissue, which implies that organic N might serve as an important N source. Increased N deposition increased the total N uptake, but did not alter the N preference of the epiphytic bryophytes. This study provides sound evidence that epiphytic bryophytes could take up N from the bark and wet deposition in both organic and inorganic N forms. It is thus important to consider organic N and bark N sources, which were usually neglected, when estimating the role of epiphytic bryophytes in N cycling and the impacts of N deposition on epiphytic bryophytes in cloud forests. PMID- 27460311 TI - Evaluation of the marginal and internal discrepancies of CAD-CAM endocrowns with different cavity depths: An in vitro study. AB - STATEMENT OF PROBLEM: The marginal and internal discrepancies of computer-aided design and computer-aided manufacturing (CAD-CAM) endocrowns are unknown. PURPOSE: The purpose of this in vitro study was to evaluate the marginal and internal discrepancies of endocrowns with different cavity depths by measuring them with microcomputed tomography (MUCT). MATERIAL AND METHODS: Endocrowns (n=48) of 2 different cavity depths (2 mm and 4 mm) were fabricated in 2 different chairside CAD-CAM systems (CEREC AC and E4D). A MUCT scan was made before and after cementation. For analysis of the marginal and internal discrepancies, reference points were selected in 2-dimensional views of 3 buccolingual cross-sections and 3 mesiodistal cross-sections. To calculate the total discrepancy volume, the MUCT sections were reconstructed 3-dimensional views, and changes in volume and surface area were examined. Statistical analysis was performed using 2-way ANOVA with Bonferroni correction (alpha=.05). RESULTS: An endocrown with a 4-mm cavity showed a larger marginal and internal volume than one with a 2-mm cavity. Cementation did not show significant differences in total discrepancy thickness. Discrepancies on the pulpal floor were largest in other sites. Both chairside CAD-CAM systems showed similar discrepancy in the endocrowns. CONCLUSIONS: Based on the present study, marginal and internal discrepancies increased depending on cavity depth. Cementation did not increase the dimension of the discrepancy between the restoration and the cavity wall. The discrepancy on the pulpal floor appeared to affect these results. PMID- 27460312 TI - Agreement of the International Classification of Sleep Disorders Criteria with polysomnography for sleep bruxism diagnosis: A preliminary study. AB - STATEMENT OF PROBLEM: Validated questionnaires and guidelines for assessing sleep bruxism (SB) that can be administered by dentists in clinical practice are still lacking. PURPOSE: The purpose of this preliminary study was to compare the third edition of the International Classification of Sleep Disorders (ICSD-3) criteria for diagnosing SB with the results of the gold standard polysomnography (PSG) examination. MATERIAL AND METHODS: Twenty consecutive postgraduate students and staff at Bauru School of Dentistry, University of Sao Paulo, Bauru, Brazil, participated. Each participant underwent interview, clinical assessment, and a PSG evaluation. Bruxers and nonbruxers were identified based only on the PSG analysis. The validity of the ICSD-3 criteria was assessed by receiver operating characteristics curve analysis, area under the curve (AUC), likelihood ratios (LR), and the diagnostic odds ratio (DOR). RESULTS: The ICSD-3 diagnostic criteria items for SB had fair to moderate concordance with the PSG diagnosis, with AUC ranging from 0.55 to 0.75. The best value of agreement was the association of SB more than once a week with transient morning jaw muscle pain or fatigue with a moderate but significant agreement with the PSG diagnosis of SB (AUC=0.75), with 90% specificity, positive LR=6, and DOR=13.5. When the frequency of self-reported SB increased to more than 4 times a week, the combination of this finding with tooth wear also had high values of agreement with the PSG diagnosis of SB (AUC= 0.75, +LR=6, DOR=13.6). CONCLUSIONS: The report of regular or frequent SB and the presence of (1) incident of abnormal tooth wear or (2) incidents of transient morning jaw muscle pain or fatigue were the best discriminatory items of ICSD-3 for SB diagnosis. PMID- 27460313 TI - Evaluation of metal-ceramic bond characteristics of three dental Co-Cr alloys prepared with different fabrication techniques. AB - STATEMENT OF PROBLEM: Limited information is available regarding the metal ceramic bond strength of dental Co-Cr alloys fabricated by casting (CAST), computer numerical control (CNC) milling, and selective laser melting (SLM). PURPOSE: The purpose of this in vitro study was to evaluate the metal-ceramic bond characteristics of 3 dental Co-Cr alloys fabricated by casting, computer numerical control milling, and selective laser melting techniques using the 3 point bend test (International Organization for Standardization [ISO] standard 9693). MATERIAL AND METHODS: Forty-five specimens (25*3*0.5 mm) made of dental Co Cr alloys were prepared by CAST, CNC milling, and SLM techniques. The morphology of the oxidation surface of metal specimens was evaluated by scanning electron microscopy (SEM). After porcelain application, the interfacial characterization was evaluated by SEM equipped with energy-dispersive spectrometry (EDS) analysis, and the metal-ceramic bond strength was assessed with the 3-point bend test. Failure type and elemental composition on the debonding interface were assessed by SEM/EDS. The bond strength was statistically analyzed by 1-way ANOVA and Tukey honest significant difference test (alpha=.05). RESULTS: The oxidation surfaces of the CAST, CNC, and SLM groups were different. They were porous in the CAST group but compact and irregular in the CNC and SLM groups. The metal-ceramic interfaces of the SLM and CNC groups showed excellent combination compared with those of the CAST group. The bond strength was 37.7 +/-6.5 MPa for CAST, 43.3 +/ 9.2 MPa for CNC, and 46.8 +/-5.1 MPa for the SLM group. Statistically significant differences were found among the 3 groups tested (P=.028). The debonding surfaces of all specimens exhibited cohesive failure mode. CONCLUSIONS: The oxidation surface morphologies and thicknesses of dental Co-Cr alloys are dependent on the different fabrication techniques used. The bond strength of all 3 groups exceed the minimum acceptable value of 25 MPa recommended by ISO 9693; hence, dental Co Cr alloy fabricated with the SLM techniques could be a promising alternative for metal ceramic restorations. PMID- 27460315 TI - Irradiated patients and survival rate of dental implants: A systematic review and meta-analysis. AB - STATEMENT OF PROBLEM: Radiotherapy has been considered a contraindication for rehabilitation with dental implants because it can change the survival rate of implants. Nevertheless, the installation of implants in irradiated patients has been used with varying success. PURPOSE: The purpose of this systematic review was to compare the success rate of implants placed in irradiated human bone tissue with that of implants placed in nonirradiated areas. MATERIAL AND METHODS: Searches were performed in the EMBASE, Cochrane, and PubMed/Medline databases up to December 2013 to identify clinical trials addressing the subject. This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The relative risks of implant failure and survival curves were calculated considering a confidence interval of 95%. Heterogeneity was analyzed by using a funnel chart. RESULTS: A total of 40 studies involving 2220 participants and 9231 dental implants were selected. The survival curve of the studies indicated a survival rate of 84.3% for implants installed in irradiated bone tissue. The meta-analysis indicated statistically significant differences (P<.001) between item success rates of implants placed in irradiated areas and those of implants placed in nonirradiated areas. CONCLUSIONS: Dental implants installed in the irradiated area of an oral cavity have a high survival rate, but strict monitoring is needed to prevent complications, thereby reducing possible failures. PMID- 27460314 TI - Effect of cement space on the marginal fit of CAD-CAM-fabricated monolithic zirconia crowns. AB - STATEMENT OF PROBLEM: Monolithic zirconia crowns fabricated with computer-aided design and computer-aided manufacturing (CAD-CAM) have recently become a common practice for the restoration of posterior teeth. The marginal fit of monolithic zirconia crowns may be affected by different cement space parameters set in the CAD software. Information is scarce regarding the effect of cement space on the marginal fit of monolithic zirconia crowns fabricated with CAD-CAM technology. PURPOSE: The purpose of this in vitro study was to evaluate the effect of cement space on the marginal fit of CAD-CAM-fabricated monolithic zirconia crowns before cementation. MATERIAL AND METHODS: Fifteen right maxillary first molar typodont teeth with standardized anatomic preparations for complete-coverage ceramic crowns were scanned with a 3-dimensional laboratory scanner. Crowns were designed 3-dimensionally using software and then milled from presintered monolithic zirconia blocks in a computer numerical control dental milling machine. The cement space was set at 25 MUm around the margins for all groups, and additional cement space starting 1 mm above the finish lines of the teeth was set at 30 MUm for group 25-30, 40 MUm for group 25-40, and 50 MUm for group 25-50 in the CAD software. A total of 120 images (3 groups, 5 crowns per group, 8 sites per crown) were measured for vertical marginal discrepancy under a stereoscopic zoom microscope and the data were statistically analyzed with 1-way analysis of variance, followed by the Tukey honestly significant difference test (alpha=.05). RESULTS: The results showed that different cement space values had statistically significant effect on the mean vertical marginal discrepancy value of tested crowns (P<.001). The mean marginal discrepancy was 85 MUm for group 25-30, 68 MUm for group 25-40, and 53 MUm for group 25-50. CONCLUSIONS: Within the limitations of this in vitro study, it was concluded that the cement space had a significant effect on the marginal fit of CAD-CAM-fabricated monolithic zirconia crowns. The marginal fit improved as the cement space decreased. PMID- 27460316 TI - An alternative conversion technique for fabricating an interim fixed implant supported complete arch prosthesis. AB - The conversion technique enables the immediate loading of implants using an existing or a new complete denture. Acrylic resin is generally used directly intraorally when the conventional conversion technique is used. The technique described suggests picking-up the interim copings and capturing the soft tissue contour with the conversion prosthesis with a polyether impression material when 4 implants are placed with an angled implant protocol. A polyether impression was made to complete an autopolymerized reline jig reline. Acrylic resin was applied on the cast generated from this impression outside the oral cavity. This technique may minimize chair time and maximize the ability of the technician/clinician to adapt the prosthesis to the soft tissue contour. PMID- 27460317 TI - A modified indirect method for fabricating silicone soft-lined complete dentures. AB - A method is described of polymerizing silicone soft lining materials with a hard acrylic resin base by using a photoactivated spacer. The use of a photoactivated spacer is convenient because of the ease in determining the correct location covering the attached mucosa but not extending to the border margins. By using this method, the optimum shape and thickness of the spacer can also be ensured. Thus, the long-term durability of soft lining dentures is achieved without invasion by microorganisms or peeling away from the denture margin. PMID- 27460318 TI - Effects of core-to-dentin thickness ratio on the biaxial flexural strength, reliability, and fracture mode of bilayered materials of zirconia core (Y-TZP) and veneer indirect composite resins. AB - STATEMENT OF PROBLEM: Indirect composite resins (ICR) are promising alternatives as veneering materials for zirconia frameworks. The effects of core-to-dentin thickness ratio (C/Dtr) on the mechanical property of bilayered veneer ICR/yttria tetragonal zirconia polycrystalline (Y-TZP) core disks have not been previously studied. PURPOSE: The purpose of this in vitro study was to assess the effects of C/Dtr on the biaxial flexural strength, reliability, and fracture mode of bilayered veneer ICR/ Y-TZP core disks. MATERIAL AND METHODS: A total of 180 bilayered 0.6-mm-thick composite resin disks in core material and C/Dtr of 2:1, 1:1, and 1:2 were tested with either core material placed up or placed down for piston-on-3-ball biaxial flexural strength. The mean biaxial flexural strength, Weibull modulus, and fracture mode were measured to evaluate the variation trend of the biaxial flexural strength, reliability, and fracture mode of the bilayered disks with various C/Dtr. One-way analysis of variance (ANOVA) and chi-square tests were used to evaluate the variation tendency of fracture mode with the C/Dtr or material placed down during testing (alpha=.05). Light microscopy was used to identify the fracture mode. RESULTS: The mean biaxial flexural strength and reliability improved with the increase in C/Dtr when specimens were tested with the core material either up and down, and depended on the materials that were placed down during testing. The rates of delamination, Hertzian cone cracks, subcritical radial cracks, and number of fracture fragments partially depended on the C/Dtr and the materials that were placed down during testing. CONCLUSION: The biaxial flexural strength, reliability, and fracture mode in bilayered structures of Y-TZP core and veneer ICR depend on both the C/Dtr and the material that was placed down during testing. PMID- 27460319 TI - Porosity of maxillofacial silicone elastomers and microleakage pattern of the commercially pure Ti-silicone elastomer interface after hydrothermal cycling. AB - STATEMENT OF PROBLEM: Delamination of the maxillofacial silicone elastomer away from the commercially pure titanium (cpTi)-encapsulated magnets affects the long term performance of the facial restoration. PURPOSE: The purposes of this in vitro study were to investigate the interfacial microleakage patterns of 2 maxillofacial silicone elastomers with cpTi when 3 different primers were used and to evaluate the porosity of the 2 elastomers tested. MATERIAL AND METHODS: To test the interfacial microleakage patterns of the 2 elastomers MDX4-4210 (EL1) and A-2006 (EL2) with cpTi when 3 metal primers, A-304 (PR1), A-320 bonding enhancer (PR2), Super-Bond C&B monomer (PR3), and ethyl-cyanoacrylate (Super Glue) were used, the bonded interfaces were observed using reflected light microscopy, and the percentage of the linear extent of leakage along the interface (%microleakage) was measured. High-resolution x-ray computed microtomography scanning was used to investigate the percentage of void volume fraction (%VF) for both silicone EL1 and EL2. The data were analyzed with 2-way ANOVA and post hoc tests (alpha=.05). RESULTS: No statistically significant differences were found among the percentages of PR1, PR2, and PR3 microleakage, whereas ethyl-cyanoacrylate showed a statistically significant higher percentage of microleakage than either of the silicone elastomers (P<.001). EL1 medical grade elastomer groups have always had a statistically significantly higher percentage of microleakage than the EL2 platinum silicone elastomer groups (P<.001). For both elastomers, no statistically significant differences were found in %VF (P=.056). CONCLUSIONS: Differences in mechanical properties, chemical composition, and manipulations during handling of the maxillofacial silicone elastomers can affect the linear microleakage along the cpTi-silicone elastomer bonding interface and the porosity of the silicone elastomer. PMID- 27460320 TI - Marginal and internal fit of metal copings fabricated with rapid prototyping and conventional waxing. AB - STATEMENT OF PROBLEM: Given the limitations of conventional waxing, computer aided design and computer-aided manufacturing (CAD-CAM) technologies have been developed as alternative methods of making patterns. PURPOSE: The purpose of this in vitro study was to compare the marginal and internal fit of metal copings derived from wax patterns fabricated by rapid prototyping (RP) to those created by the conventional handmade technique. MATERIAL AND METHODS: Twenty-four standardized brass dies were milled and divided into 2 groups (n=12) according to the wax pattern fabrication method. The CAD-RP group was assigned to the experimental group, and the conventional group to the control group. The cross sectional technique was used to assess the marginal and internal discrepancies at 15 points on the master die by using a digital microscope. An independent t test was used for statistical analysis (alpha=.01). RESULTS: The CAD-RP group had a total mean (+/-SD) for absolute marginal discrepancy of 117.1 (+/-11.5) MUm and a mean marginal discrepancy of 89.8 (+/-8.3) MUm. The conventional group had an absolute marginal discrepancy 88.1 (+/-10.7) MUm and a mean marginal discrepancy of 69.5 (+/-15.6) MUm. The overall mean (+/-SD) of the total internal discrepancy, separately calculated as the axial internal discrepancy and occlusal internal discrepancy, was 95.9 (+/-8.0) MUm for the CAD-RP group and 76.9 (+/ 10.2) MUm for the conventional group. The independent t test results showed significant differences between the 2 groups. The CAD-RP group had larger discrepancies at all measured areas than the conventional group, which was statistically significant (P<.01). CONCLUSIONS: Within the limitations of this in vitro study, the conventional method of wax pattern fabrication produced copings with better marginal and internal fit than the CAD-RP method. However, the marginal and internal fit for both groups were within clinically acceptable ranges. PMID- 27460321 TI - Randomized controlled within-subject evaluation of digital and conventional workflows for the fabrication of lithium disilicate single crowns. Part I: digital versus conventional unilateral impressions. AB - STATEMENT OF PROBLEM: Trials comparing the overall performance of fully digital and conventional workflows in reconstructive dentistry are needed. PURPOSE: The purpose of the first part of this randomized controlled clinical trial was to determine whether optical impressions produce different results from conventional impressions with respect to time efficiency and patient and operator perceptions of the clinical workflow. MATERIAL AND METHODS: Three digital impressions and 1 conventional impression were made in each of 10 participants according to a randomly generated sequence. The digital systems were Lava COS, iTero, and Cerec Bluecam. The conventional impression was made with the closed-mouth technique and polyvinyl siloxane material. The time needed for powdering, impressions, and interocclusal record was recorded. Patient and clinician perceptions of the procedures were rated by means of visual analog scales. The paired t test with Bonferroni correction was applied to detect differences (alpha=.05/6=.0083). RESULTS: The mean total working time +/-standard deviation amounted to 260 +/-66 seconds for the conventional impression, 493 +/-193 seconds for Lava, 372 +/-126 seconds for iTero, and 357 +/-55 seconds for Cerec. The total working time for the conventional impression was significantly lower than that for Lava and Cerec. With regard to the working time without powdering, the differences between the methods were not statistically significant. The patient rating (very uncomfortable=0; comfortable=100) measured 61 +/-34 for conventional impression, 71 +/-18 for Lava, 66 +/-20 for iTero, and 48 +/-18 for Cerec. The differences were not statistically significant. The clinician rating (simple=0; very difficult=100) was 13 +/-13 for the conventional impression, 54 +/-27 for Lava, 22 +/-11 for iTero, and 36 +/-23 for Cerec. The differences between the conventional impression and Lava and between iTero and Lava were statistically significant. CONCLUSIONS: The conventional impression was more time-effective than the digital impressions. In terms of patient comfort, no differences were found between the conventional and the digital techniques. With respect to the clinician perception of difficulty, the conventional impression and the digital impression with iTero revealed more favorable outcomes than the digital impression with Lava. PMID- 27460322 TI - Effects of antibacterial coating on monomer exudation and the mechanical properties of denture base resins. AB - STATEMENT OF PROBLEM: Denture base resin may be exposed to different conditions for long periods, resulting in the loss of monomer by exudation and a decrease in mechanical properties. PURPOSE: The purpose of this in vitro study was to evaluate monomer loss by exudation from denture base resins doped with antibacterial coatings and their mechanical properties after long-term water immersion. MATERIAL AND METHODS: Four kinds of dental base resin materials were used as experimental materials. The specimens of each resin were divided into an experimental group (coated) and a control group (uncoated). Monomer exudation was tested at 7 and 28 days by gas chromatography after materials were immersed in distilled water or a solution of 75% alcohol/distilled water. Flexural strength and elastic modulus were tested with a universal testing machine after immersion for 2 and 180 days. The surface morphology was characterized with atomic force microscopy. The data were analyzed using 3-way ANOVA followed by the Tukey-Kramer honest significant difference test (alpha=.05). RESULTS: In both of the immersion media, each of the 3 factors (materials, coating, and immersion time) significantly affected the monomer exudation (P<.05). In addition, the interaction between any 2 of those factors or among the 3 factors had a significant interaction effect on the monomer exudation of the denture base (P<.05). The mechanical properties of the tested materials were different, and the immersion time had a significant effect on the flexural properties (P<.05). For flexural strength, a significant interaction effect occurred among the 3 factors (material, coating, and immersion time) (P<.05). The coating has a significant effect on the elastic modulus of denture base resin (P<.05) and on the interaction between the material and immersion time (P<.05). CONCLUSIONS: The silver-loaded mesoporous silica antibacterial coating can effectively reduce monomer exudation and enhance the flexural properties of denture base resin after immersion. PMID- 27460323 TI - A technique for improving the fit of a vacuum-formed matrix. PMID- 27460324 TI - Influence of object translucency on the scanning accuracy of a powder-free intraoral scanner: A laboratory study. AB - STATEMENT OF PROBLEM: Limited information is available regarding the influence of object translucency on the scanning accuracy of a powder-free intraoral scanner. PURPOSE: The purpose of this in vitro study was to evaluate the scanning accuracy of a confocal microscopy principle powder-free intraoral scanner on ceramic copings and to analyze the relationship between scanning accuracy and object translucency. METHODS: Six slice specimens (12*10 mm) and 6 offset copings (1.00 mm thickness) were made from different translucent homogeneous ceramic blocks (CEREC Blocs, S0-M to S5-M, highest to lowest translucency). The primary sintered zirconia offset coping was produced in the same way as the control. Optical parameters related to the translucency of each slice were measured with a spectrophotometer. Three-dimensional (3D) datasets of the surface morphology of offset copings were obtained by using the intraoral scanner. The same white wax resin bases were used for registration. Quantitative parameters of scanning trueness and precision were measured. One-way ANOVA was used to analyze the values of each parameter among the 6 ceramic blocks. Bivariate correlation was used to analyze the relationships between each parameter of scanning accuracy and translucency (alpha=.05). RESULTS: Translucent copings showed a positive 3D bias (S0-M to S5-M: 0.149 +/-0.038 mm to 0.068 +/-0.020 mm), a narrower collar diameter (Dd=-0.067 mm), larger convergence angle (DeltaPhi=2.79 degrees), and larger curvature radius of the internal gingivoaxial corner (Deltarho=0.236 mm). The smaller the percentage sum of scattering and absorption, the greater was the occurrence of scanning bias (r=-0.918) and curvature (r=-0.935) decrease. CONCLUSIONS: Use of the tested powder-free intraoral scanner, higher translucency objects (greater translucency than S1-M/A1C) resulted in lower scanning accuracy and morphological changes. Therefore, more suitable methods of measurement are still required. PMID- 27460325 TI - Digital approach to assessing the 3-dimensional misfit of fixed dental prostheses. AB - The silicone replica technique has been used for determining the fit accuracy of fixed dental prostheses. Because this technique is performed manually with 2 dimensional evaluations, it is prone to methodological error and yields inadequate information. The application of computer-aided image analysis reduces errors and facilitates 3-dimensional discrepancy measurements. This article describes a method of visualizing and quantifying the fit discrepancy of fixed dental prostheses by digitizing a misfit space replica and using computer-aided spatial analysis. PMID- 27460326 TI - A selective laser sintering prototype guide used to fabricate immediate interim fixed complete arch prostheses in flapless dental implant surgery: Technique description and clinical results. AB - STATEMENT OF PROBLEM: Extensive occlusal adjustments and misfit of the prosthesis to prosthetic components are frequent problems related to fixed interim prosthesis fabrication with immediate dental implant loading. PURPOSE: The purpose of this clinical trial was to evaluate a prosthetic guide made with a rapid prototype model based on virtual surgical planning. This prosthetic guide was used to fabricate fixed interim prostheses that would allow immediate implant loading after computer-guided implant installation. MATERIAL AND METHODS: Nine interim prostheses were made for 9 participants with complete maxillary or mandibular edentulism. The virtual prosthetic guide was planned using computer assisted design (CAD) software and was fabricated with rapid prototyping equipment (selective laser sintering). The prosthetic guide had 3 portions: the occlusal portion, which had occlusal registration; the connection portion, which had the information of the position and angulation of the abutment/implant projection; and the mucosa portion, which had the registration of the alveolar mucosa architecture. The prosthetic guide was used by a dental technician to fabricate prostheses. A single trained examiner evaluated the passive fit of the interim prostheses, the average time required for installing the interim prosthesis and for occlusal adjustments, the satisfaction of the patient with the prosthesis; and the screws, torque, occlusion, and prosthesis status. RESULTS: Passive fit was achieved between the prosthetic components and prostheses in 7 participants. The average time required for installing the fixed interim prostheses was 64.44 minutes. All participants reported being more pleased with the fixed interim prosthesis than with the prosthesis worn before implant placement. Prosthesis fractures were observed in 3 participants (2 in the maxilla and 1 in the mandible); all fractures occurred 3 months or more after delivery. No further complication was observed during 6 months of follow-up. CONCLUSIONS: The prosthetic guide enabled fabrication of interim immediate prostheses that were easily seated and adjusted to accommodate any shifts in implant position occurring during computer-guided surgery. Immediate implant loading could be achieved in a reasonable operative time. PMID- 27460327 TI - A technique for retrieving cement-retained implant prostheses. AB - Lack of retrievability is one of the most important disadvantages of cement retained implant restorations. A straightforward and cost-effective technique for accessing the abutment screw channel and unscrewing the abutment and cement retained prosthesis as 1 unit is described. The technique does not jeopardize the integrity of the restoration, screw, abutment, or implant. A guiding acrylic resin index is fabricated for locating and guiding the access to the screw channel of the abutment, provided that the patient's cast with the implant analog is available. The procedure could be extrapolated to computer-aided designed and computer-aided manufactured (CAD-CAM) implant prostheses, whereby a CAD-CAM index could be fabricated on the digital model. PMID- 27460328 TI - A modified technique for preventing excess cement around implant supported restoration margins. AB - Different techniques have been proposed for cementing crown restorations to implant abutments without excess cement extruding beyond difficult-to-access restoration margins. In one approach, a copy abutment is fabricated onto which the cement-filled crown is fitted extraorally, allowing excess cement to be easily removed before intraoral transfer. This article presents a modification of this technique, wherein hot melt thermoplastic material is used for the copy abutment instead of polyvinyl siloxane. This simplifies the technique, making it faster and more reliable. It involves injecting hot melt thermoplastic material into the wetted intaglio surface of the crown, fitting a dowel pin to serve as a removal handle, filling the crown with cement, fitting it onto the copy abutment, and wiping the excess at the margins before intraoral transfer and definitive cementation. PMID- 27460329 TI - Survival of dental implants in patients with Down syndrome: A case series. AB - STATEMENT OF PROBLEM: The need for tooth replacement in individuals with Down syndrome (DS) is explained by the high prevalence of dental agenesis and by the premature loss of teeth through severe periodontal disease. Dental implants may be the dental procedure of choice in some of these patients. PURPOSE: The purpose of this clinical study was to analyze dental implant survival in a series of patients with DS. MATERIAL AND METHODS: This was a multicenter, retrospective, observational study. Information on patients was gathered using a standardized questionnaire designed specifically for this study, including personal details, oral health status, information on the surgical and prosthetic phases, and follow up visits. The questionnaire was sent to centers registered with the research network of the Spanish Society of Special Needs Dentistry (SEOENE). Patients with DS aged 18 years or older were included in the study if they had at least 1 dental implant and the corresponding prosthesis and had been followed up for at least a year. RESULTS: The study population was formed of 25 adult patients (13 men and 12 women) aged between 19 and 60 years. The interventions were performed by 5 different dental surgeons, usually under general anesthesia or deep sedation (n=17 patients). A total of 73 implants were inserted, 30 in the maxilla and 43 in the mandible, most commonly in the anterior region (n=51). The mean time to loading the implants was 4.1 +/-1.3 months after surgery (range, 1 to 7 months). All patients completed prosthetic rehabilitation; the most frequent design used was the single fixed prosthesis (n=13 patients). A total of 17 (23.2%) implants failed in 8 (32%) patients; the majority (n=14 implants) failed in the postsurgical period before implant loading. The distribution by patients was 1 implant failure in 6 patients, 3 failures in 1 patient, and 8 failures in 1 patient. CONCLUSIONS: Dental implant survival is lower in individuals with DS than in the general population. The reasons for early implant failure in these patients have still not been clearly identified. PMID- 27460330 TI - Effects of the type and thickness of ceramic, substrate, and cement on the optical color of a lithium disilicate ceramic. AB - STATEMENT OF PROBLEM: Reproducing the characteristics of natural teeth in ceramic crowns remains a complex and difficult process. PURPOSE: The purpose of this in vitro study was to evaluate the effect of the substrate, cement, type, and thickness of the ceramic on the resulting color of a lithium disilicate ceramic. MATERIAL AND METHODS: Forty ceramic disks were prepared from IPS e.max Press LT (low translucency) and HO (high opacity) in 2 different thicknesses (1.5 and 2 mm). The LT groups were composed of monolithic ceramic disks, and the HO groups were composed of disks fabricated with a 0.5-mm thickness combined with a 1- or 1.5-mm veneering ceramic thickness. Disks made of composite resin (R) and alloy (A) were used as substrate structures. The resin cement used was Variolink II. Color was measured with a spectrophotometer and expressed in CIELAB coordinates. Color differences (DeltaE) were calculated. The data were analyzed with ANOVA and the Tukey HSD test (alpha=.05). RESULTS: When the DeltaE of ceramic disks with both substrates, with and without cement, were compared, the lowest value (3) was obtained for ceramic HO with a 2-mm thickness/alloy substrate/without cement; the highest value (10) was obtained for ceramic LT with a1.5-mm thickness/alloy substrate/with cement. This difference was statistically significant. When the effect of cement on the DeltaE of ceramics in both substrates was compared, the lowest value (1.1) occurred with ceramic HO with a 1.5-mm thickness/resin substrate, and the highest was observed for ceramic LT with a 1.5-mm thickness/alloy substrate (6.4). This difference was statistically significant. CONCLUSIONS: The substrate color, type and thickness of ceramic, and presence of the cement significantly influenced the resulting optical color. The DeltaE values of cemented HO ceramics were lower than that of the LT ceramic. PMID- 27460331 TI - First-Principles Prediction of Ultralow Lattice Thermal Conductivity of Dumbbell Silicene: A Comparison with Low-Buckled Silicene. AB - The dumbbell structure of two-dimensional group IV material offers alternatives to grow thin films for diverse applications. Thermal properties are important for these applications. We obtain the lattice thermal conductivity of low-buckled (LB) and dumbbell (DB) silicene by using first-principles calculations and the Boltzmann transport equation for phonons. For LB silicene, the calculated lattice thermal conductivity with naturally occurring isotope concentrations is 27.72 W/mK. For DB silicene, the calculated value is 2.86 W/mK. The thermal conductivity for DB silicene is much lower than LB silicene due to stronger phonon scattering. Our results will induce further theoretical and experimental investigations on the thermoelectric (TE) properties of DB silicene. The size dependent thermal conductivity in both LB and DB silicene is investigated as well for designing TE devices. This work sheds light on the manipulation of phonon transport in two-dimensional group IV materials by dumbbell structure formed from the addition of adatoms. PMID- 27460332 TI - Kinetic Resolution of the Interactions between Agrochemical Products and Adjuvant Systems upon Mixing. AB - The addition of an adjuvant to a pesticide usually occurs in a mix-tank, before spray application to the crop. Their interaction is potentially crucial to overall efficacy but has received little attention from a physical-chemical perspective. Study was undertaken by laser diffraction, Raman spectroscopy, and small-angle X-ray scattering to resolve these physical processes. It was shown that migration of the pesticide into the adjuvant droplet occurred in all cases studied. The level of transfer was dependent upon adjuvant level, adjuvant solubility, and surfactant level. For suspension pesticides, dissolution of crystallites within the droplet occurred to a degree limited by solubility. The results directly demonstrate the transfer of the pesticide into the adjuvant carrier. This indicates that for emulsion-based pesticides, application to the target is likely as a homogeneously mixed droplet, whereas for suspension pesticides, solubility may limit transfer and dissolution, leading to heterogeneity in the applied particles. PMID- 27460333 TI - Maternal correlates of young children's physical activity across periods of the day. AB - OBJECTIVES: Associations between maternal correlates and young children's physical activity levels across the whole day and the segmented day were examined. DESIGN: Cross-sectional study METHODS: Participants were 136 mothers and their 1-3 year old children recruited between July 2013 and March 2014. Mothers reported time spent providing physical activity opportunities for their child, co-participating in and modelling physical activity and sedentary behaviours during the morning, afternoon and evening. Participants wore ActiGraph GT3X (mothers) and GT3X+ (children) accelerometers concurrently for seven consecutive days and the time spent in light- (LPA), moderate- to vigorous- (MVPA) and total (LMVPA) physical activity were assessed. Two-level (family; recruitment group) multivariate models examined associations between maternal correlates (including maternal objectively-assessed sedentary time [ST] and physical activity) and children's physical activity. RESULTS: Maternal self reported co-participation in sedentary behaviour and provision of child opportunities for physical activity were associated with children's physical activity; associations varied by period and physical activity intensity. During the morning period, mothers' objectively assessed ST was negatively associated with children's MVPA and LMVPA while her LPA was positively associated with children's LPA, MVPA and LMVPA. Mothers' MVPA was negatively associated with children's LPA and LMVPA during the evening period. CONCLUSIONS: Maternal correlates of young children's physical activity may be period- and intensity specific. Programmes promoting physical activity for families may need to consider incorporating strategies to reduce mother-child co-participation in sedentary behaviour, increase mothers' provision of opportunities to be active and increase mothers' own LPA over ST during certain periods of the day. PMID- 27460334 TI - Amyloid precursor protein cooperates with c-KIT mutation/overexpression to regulate cell apoptosis in AML1-ETO-positive leukemia via the PI3K/AKT signaling pathway. AB - It has been reported that amyloid precursor protein (APP) promotes cell proliferation and metastasis in various types of solid cancers. In our previous study, we showed that APP is highly expressed and regulates leukemia cell migration in AML1-ETO-positive (AE) leukemia. Whether APP is involved in the regulation of AE leukemia cell proliferation or apoptosis is unclear. In the present study we focused on the correlation of APP with c-KIT mutation/overexpression and cell proliferation and apoptosis in AE leukemia. APP and c-KIT expression detected by quantitative real-time (qPCR) method, and c-KIT mutations screened using PCR in bone marrow cells from 65 patients with AE leukemia before their first chemotherapy, were simultaneously assessed. Furthermore, the Kasumi-1 cell line was chosen as the cell model, and the APP gene was knocked down using siRNA technology. The correlation of cell cycle distribution and apoptosis and c-Kit expression with APP expression levels, as well as the regulation of the PI3K/AKT signaling pathway by APP were analyzed in the Kasumi-1 cell line. The results showed that peripheral white blood cell counts (P=0.008) and bone marrow cellularity (P=0.031), but not bone marrow blasts, were correlated with APP expression. Moreover, the patients with APP high expression had a significantly higher incidence of c-KIT mutations (P<0.001) and increased levels of c-KIT expression (P=0.001) and poorer disease outcome. In the Kasumi-1 cell line, as compared with the wild-type and negative control cells, cell apoptosis, both early (P<0.001) and late (P<0.001), was significantly increased when the APP gene was knocked down, concomitant with reduced levels of anti-apoptotic protein Bcl-2 and increased levels of caspase-3 and -9, however, no apparent change was observed in the cell cycle distribution (P>0.05). Moreover, the knockdown of APP markedly decreased c-KIT expression at both the transcription (as evidenced by qPCR analysis) and translation (as confirmed by CD117 assay and western blot analysis) levels, as well as p-AKT and its downstream targets including NF-kappaB, p53 and Bcl-2. In conclusion, APP may cooperate with c-KIT mutation/overexpression in the regulation of cell apoptosis but not proliferation in AE leukemia via the PI3K/AKT signaling pathway. PMID- 27460335 TI - Nitrous oxide emission related to ammonia-oxidizing bacteria and mitigation options from N fertilization in a tropical soil. AB - Nitrous oxide (N2O) from nitrogen fertilizers applied to sugarcane has high environmental impact on ethanol production. This study aimed to determine the main microbial processes responsible for the N2O emissions from soil fertilized with different N sources, to identify options to mitigate N2O emissions, and to determine the impacts of the N sources on the soil microbiome. In a field experiment, nitrogen was applied as calcium nitrate, urea, urea with dicyandiamide or 3,4 dimethylpyrazone phosphate nitrification inhibitors (NIs), and urea coated with polymer and sulfur (PSCU). Urea caused the highest N2O emissions (1.7% of N applied) and PSCU did not reduce cumulative N2O emissions compared to urea. NIs reduced N2O emissions (95%) compared to urea and had emissions comparable to those of the control (no N). Similarly, calcium nitrate resulted in very low N2O emissions. Interestingly, N2O emissions were significantly correlated only with bacterial amoA, but not with denitrification gene (nirK, nirS, nosZ) abundances, suggesting that ammonia-oxidizing bacteria, via the nitrification pathway, were the main contributors to N2O emissions. Moreover, the treatments had little effect on microbial composition or diversity. We suggest nitrate-based fertilizers or the addition of NIs in NH4(+)-N based fertilizers as viable options for reducing N2O emissions in tropical soils and lessening the environmental impact of biofuel produced from sugarcane. PMID- 27460336 TI - The course of early disinhibited social engagement among post-institutionalized adopted children. AB - BACKGROUND: Approximately 20% of post-institutionalized (PI) children exhibit disinhibited social engagement (DSE) or the propensity to approach and engage strangers. There is little longitudinal research examining changes in DSE after adoption, or methods of identifying children with persistent behaviors. METHODS: DSE was assessed observationally four times during the first 2 years postadoption in PI children 16-36 months at adoption (n = 68) relative to same-age nonadopted children (n = 52). At age 5, a validated interview determined which PI children met criteria for Disinhibited Social Engagement Disorder (DSED). RESULTS: DSE trajectories initially increased and then stabilized. PIs had higher DSE levels initially and a steeper increase rate than NAs. When separated into physical and nonphysical DSE components, group differences arose in initial physical DSE and the rate of change of nonphysical DSE. DSE rate of increase predicted DSED diagnosis, as did longer institutional duration and poorer institutional care. CONCLUSIONS: The rate of increase in DSE postadoption, rather than the level observed at adoption, is predictive of disordered social engagement by age 5 years. PMID- 27460337 TI - Comparison of a modified phenol/chloroform and commercial-kit methods for extracting DNA from horse fecal material. AB - There are many choices for methods of extracting bacterial DNA for Next Generation Sequencing (NGS) from fecal samples. Here, we compare our modifications of a phenol/chloroform extraction method plus an inhibitor removal solution (C3) (ph/Chl+C3) to the PowerFecal(r) DNA Isolation Kit (MoBio-K). DNA quality and quantity coupled to NGS results were used to assess differences in relative abundance, Shannon diversity index, unique species, and principle coordinate analysis (PCoA) between biological replicates. Six replicate samples, taken from a single ball of horse feces manually collected from the rectum, were subjected to each extraction method. The Ph/Chl+C3 method produced 100* higher DNA yields with less shearing than the MoBio-K method. To assess the methods, the two method samples were sent for sequencing of the bacterial V3-V4 region of 16S rRNA gene using the Illumina MiSeq platform. The relative abundance of Bacteroidetes was greater and there were more unique species assigned to this group in MoBio-K than in Ph/Chl+C3 (P<0.05). In contrast, Firmicutes had greater relative abundance and more unique species in Ph/Chl+C3 extracts than in MoBio-K (P<0.05). The other major bacterial phyla were equally abundant in samples using both extraction methods. Alpha diversity and Shannon Weaver indices showed greater evenness of bacterial distribution in Ph/Chl+C3 compared with MoBio-K (P<0.05), but there was no difference in the OTU richness. Principle coordinate analysis (PCoA) indicated a distinct separation between the two methods (P<0.05) and tighter clustering (less variability) in Ph/Chl+C3 than in MoBio-K. These results suggest that the Ph/Chl+C3 may be preferred for research to identify specific Firmicutes taxa such as Clostridium, and Bacillus. However; MoBio-K may be a better choice for projects focusing on Bacteroidetes abundance. The Ph/Chl+C3 method required less time, but has some safety concerns associated with exposure and disposal of phenol and chloroform. While the MoBio-K may be better choice for researchers with less access to safety equipment like a fume hood. PMID- 27460339 TI - [Lung cancer screening using low-dose computed tomography. In favour]. PMID- 27460338 TI - Phenotyping women with detrusor underactivity by presumed etiology: Is it plausible? AB - AIMS: Underactive bladder (UAB) is a symptom complex with poorly characterized causation. The aim of this study was to determine if clinical and UDS parameters differed between categories of presumed detrusor underactivity (DU) etiologies. METHODS: A retrospective review was performed at a single institution from 2011 to 2015 to identify patients with symptoms of UAB. Patients were excluded if they were male, had anti-incontinence, or pelvic organ prolapse (POP) surgery within 1 year, or the UDS did not demonstrate DU as defined within. Subjects were stratified by etiology into four cohorts: cardiovascular disease manifestations (CV), cardiac risk factors (CVR), neurologic (N), or idiopathic (I). Patient demographics, comorbidities, symptomatology, physical exam, and UDS parameters were compared. RESULTS: A total of 200 patients met inclusion criteria (CV: n = 53 [26.5%], CVR: n = 44 [22%] N: n = 81 [40.5%], I: n = 22 [11%]). Women in the CV cohort were significantly older and more likely to be post-menopausal (P < 0.001). There were no differences between cohorts for BMI (P = 0.48), recurrent UTI (P = 0.63), history of urinary retention (AUR) (P = 0.65), POP (0.49), American Urological Association Symptom Score (AUA-SS) (P = 0.06), presenting symptomatology [urgency, frequency, urgency urinary incontinence, AUR, incomplete emptying, hesitancy, UTI (P = 0.97)], or UDS parameters (first sensation [P = 0.25], normal desire [P = 0.80], strong desire [P = 0.58], capacity [P = 0.11], Qmax [P = 0.50], Pdet at Qmax [P = 0.22], post-void residual [P = 0.82]). CONCLUSIONS: Though differences were observed between cohorts for age and menopausal status, clinical or urodynamic parameters did not demonstrate distinct differences across presumed categories of etiology, suggesting that the etiology of DU may be multifactorial. Neurourol. Urodynam. 36:1151-1154, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27460340 TI - Building a Working Community: Staff Practices in a Clubhouse for People with Severe Mental Illness. AB - The trademark of mental health clubhouses is that members and staff work side-by side in partnership to enhance members' autonomy, competency, and recovery. To explore the intricacies of this unique approach, the author conducted 53 in-depth interviews and 262 h of participant observation in 41 visits over a five-month period in a clubhouse. Findings indicated that staff members built the clubhouse as a "working community" by skillfully integrating three practice domains: social relationships, unit work, and individuals' needs and pursuits. Distinctive skillsets helped to develop genuine relationships with members and facilitate community building, suggesting a model of generalist practice with specific intentionality. PMID- 27460341 TI - The place of hyperbaric oxygen therapy and ozone therapy in sudden hearing loss. AB - INTRODUCTION: It is difficult to evaluate the effect of drugs clinically used for idiopathic sudden sensorineural hearing loss, mainly because its underlying mechanism remains unknown. OBJECTIVE: This study assessed the efficacy of hyperbaric oxygen therapy or ozone therapy in the treatment of idiopathic sudden sensorineural hearing loss, when either therapy was included with steroid treatment. METHODS: A retrospective analysis examined 106 patients with idiopathic sudden sensorineural hearing loss seen between January 2010 and June 2012. Those with an identified etiology were excluded. The patients were divided into three treatment groups: oral steroid only (n=65), oral steroid+hyperbaric oxygen (n=26), and oral steroid+ozone (n=17). Treatment success was assessed using Siegel criteria and mean gains using pre- and post-treatment audiograms. RESULTS: The highest response rate to treatment was observed in the oral steroid+ozone therapy group (82.4%), followed by the oral steroid+hyperbaric oxygen (61.5%), and oral steroid groups (50.8%). There were no significant differences in the response to treatment between the oral steroid and oral steroid+hyperbaric oxygen groups (p<0.355). The oral steroid+ozone group showed a significantly higher response rate to treatment than the oral steroid group (p=0.019). There were no significant differences between the oral steroid+hyperbaric oxygen and oral steroid+ozone groups (p=0.146). CONCLUSION: The efficiency of steroid treatment in patients with severe hearing loss was low. It was statistically ascertained that adding hyperbaric oxygen or ozone therapy to the treatment contributed significantly to treatment success. PMID- 27460343 TI - Fecal thyroid hormones allow for the noninvasive monitoring of energy intake in capuchin monkeys. AB - Measuring energetic condition of wild animals is of major importance in ecological research, as it is profoundly linked to fitness. However, noninvasive monitoring of energetic condition in wild-living animals is methodologically challenging. Measuring urinary C-peptide levels is a suitable method to noninvasively assess energy balance in wild-living animals. As collecting urine is not always feasible in the wild, it is essential to establish alternative biomarkers for other sample types to assess energy balance. Thyroid hormones (TH) are potential candidates as they are involved in the regulation of metabolic processes. During periods of low energy intake, serum TH levels are reduced, leading to a decrease in metabolic activity. To investigate whether fecal TH can serve as a biomarker for energy balance, we validated a total T3 ELISA to measure immunoreactive T3 (iT3) in fecal samples of yellow-breasted capuchins. We restricted caloric intake of seven males, assessed daily group caloric intake and determined daily individual fecal iT3 levels. Analytical validation of the assay showed that fecal iT3 levels can be reliably measured; however, proper storage conditions must be implemented and possible degradation to be accounted for. IT3 levels were significantly higher on days with high group caloric intake. However, individual iT3 levels varied substantially, resulting in an overlap across individuals between conditions. Our results indicate that fecal iT3 levels can serve as a useful biomarker to detect changes in energy intake of yellow-breasted capuchins. Overall, measuring fecal iT3 levels may present a suitable method for monitoring energy balance when urine collection is impossible. PMID- 27460342 TI - Training the next generation of invasive cardiologists: Feasibility of implementing a trans-radial access program at an academic hospital. AB - BACKGROUND: Slow adoption of trans-radial access (TRA) for left heart catheterization (LHC) in the U.S. may be related to concerns about procedural complexity and a steep learning curve. However, TRA acceptance among novice operators remains poorly characterized. METHODS: We initiated a 1-year TRA learning period among lower-risk outpatients, followed by a "radial-first" policy for all LHC patients beginning year 2. By year 3, all fellows prospectively collected diagnostic LHC data as part of a quality improvement study. TRA procedural characteristics were compared with patients undergoing trans-femoral access for the 3months prior to the TRA program, and trends over time were evaluated. RESULTS: Between 7/2009 and 6/2012, we identified 960 patients undergoing LHC via TRA by 23 rotating cardiology fellows supervised by 5 interventional cardiologists. When evaluated against the 160 trans-femoral comparator patients, TRA patients had lower procedural success through the initial access site (88% vs. 99%, p<0.001) and longer fluoroscopy times (9.5 [5.8 15.9] vs. 6.5 [3.1-12.7] min, p<0.001), with similar contrast volumes and fewer catheters used. Despite tackling more complex patients during years 2-3, there were improvements in fluoroscopy times, catheter utilization, contrast volumes, and procedural success rates over time (all p<0.001). CONCLUSIONS: The dedicated adoption of TRA by an academic catheterization laboratory demonstrated improvements in efficiency and resource utilization over a relatively short period of time. Additional exposure to TRA during training may help facilitate acceptance of this approach among the next generation of invasive cardiologists. SHORT SUMMARY (FOR ANNOTATED TABLE OF CONTENTS): When initiating a trans-radial access program for cardiac catheterization at an academic training hospital, procedural success rates were lower and fluoroscopy times were higher than traditional trans-femoral access. Nonetheless, other procedural variables were similar between the 2 approaches, and improvements over time were consistent with the learning curves reported among experienced cardiologists in prior studies. Exposure to trans-radial access during training may help facilitate acceptance of this approach among the next generation of invasive cardiologists. PMID- 27460344 TI - Commonality amid diversity: Multi-study proteomic identification of conserved disease mechanisms in spinal muscular atrophy. AB - The neuromuscular disease spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting from low levels of full-length survival motor neuron (SMN) protein. Despite having a good understanding of the underlying genetics of SMA, the molecular pathways downstream of SMN that regulate disease pathogenesis remain unclear. The identification of molecular perturbations downstream of SMN is required in order to fully understand the fundamental biological role(s) for SMN in cells and tissues of the body, as well as to develop a range of therapeutic targets for developing novel treatments for SMA. Recent developments in proteomic screening technologies have facilitated proteome wide investigations of a range of SMA models and tissues, generating novel insights into disease mechanisms by highlighting conserved changes in a range of molecular pathways. Comparative analysis of distinct proteomic datasets reveals conserved changes in pathways converging on GAP43, GAPDH, NCAM, UBA1, LMNA, ANXA2 and COL6A3. Proteomic studies therefore represent a leading tool with which to dissect the molecular mechanisms of disease pathogenesis in SMA, serving to identify potentially attractive targets for the development of novel therapies. PMID- 27460345 TI - Normalization of sonographical multifocal nerve enlargements in a MADSAM patient following a good clinical response to intravenous immunoglobulin. AB - Focal nerve enlargements at sites of conduction blocks can be visualized sonographically in patients with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). However, little is known about association between nerve morphological changes and treatment responses. Here we present a 73-year old female MADSAM patient whose sonographical multifocal nerve enlargements normalized following a good treatment response. She was admitted to our department with progressive asymmetrical muscle weakness and sensory disturbances for 6 months. Ultrasonography revealed multifocal nerve enlargements at sites of electrophysiological demyelination. Intravenous immunoglobulin improved her symptoms and electrophysiological abnormalities. Six months later, ultrasonography revealed normalization of multifocal nerve enlargements. Contrary to our observations, one previous report described a MADSAM patient with persistent nerve enlargements at the sites of resolved conduction blocks. In this earlier patient, however, the time from onset to remission was approximately 30 months. Morphological changes of nerve enlargements in MADSAM may vary with treatment response. PMID- 27460346 TI - Japanese multiple epidermal growth factor 10 (MEGF10) myopathy with novel mutations: A phenotype-genotype correlation. AB - Mutations in the multiple epidermal growth factor-like domains 10 (MEGF10: NM_032446.2) gene are known to cause early-onset myopathy characterized by areflexia, respiratory distress, and dysphagia (EMARDD: OMIM 614399), and a milder phenotype of minicore myopathy. To date, there have been reports of six families with EMARDD and one with a milder disorder. Cysteine mutations in the extracellular EGF-like domain may be responsible for the milder phenotype, but the relationship is not conclusive because of the few reports of this disorder. We here present two Japanese patients with MEGF10 mutations: one with EMARDD phenotype who had a novel homozygous frameshift mutation, c.131_132del, and the other with the milder phenotype who harbored a compound heterozygous mutation, c.2981-2A > G, and a novel missense mutation, p.Cys810Tyr. This is the first report on East Asian patients with MEGF10 myopathy showing two phenotypes, indicating the genotype-phenotype correlation in MEGF10 myopathy. PMID- 27460347 TI - Multidisciplinary care allowing uneventful vaginal delivery in a woman with Pompe disease. AB - Pregnancy and delivery are challenging in women affected by Pompe disease with respiratory involvement. We describe a 28-year-old woman, who continued to receive enzyme replacement therapy during pregnancy and had an uneventful vaginal birth. Before pregnancy the patient's vital capacity was 52% in sitting position and 51% in supine position. At 32 weeks gestation her vital capacity in sitting position was 46% and 35% in supine position. Nocturnal non-invasive mechanical ventilation was introduced at this time. Labor was induced at 34 weeks following premature rupture of membranes, under epidural anesthesia. A 2590 g healthy baby was delivered by vacuum extraction. Assisted ventilation was continued throughout labor and post-partum. This observation suggests a successful pregnancy and a normal vaginal delivery can be achieved in patients with symptomatic Pompe Disease, provided multidisciplinary care is offered. PMID- 27460349 TI - A Cu(ii) MOF with a flexible bifunctionalised terpyridine as an efficient catalyst for the single-pot hydrocarboxylation of cyclohexane to carboxylic acid in water/ionic liquid medium. AB - The copper(ii) metal-organic framework (MOF) [Cu(eta-1kappaN,N',N'':2kappaO,O' L)(NO3)]n (1) [L = 4-((4-([2,2':6',2''-terpyridin]-4'-yl)benzyl)oxy)benzoate] has been synthesized from a flexible bifunctionalised terpyridine species (HL). It was characterized by elemental, FT-IR, powder and single crystal X-ray diffraction analyses. Single crystal X-ray crystallography of 1 shows a 1D polymeric architecture, whose topological analysis illustrates a uninodal (2) connected net having topological type 2C1. 1 shows good catalytic activity and selectivity towards the hydrocarboxylation of cyclohexane to cyclohexanecarboxylic acid in water/acetonitrile or water/ionic liquid [BMPyr][NTf2] [BMPyr = 1-butyl-1 methylpyrrolidinium; NTf2 = bis(trifluoromethanesulfonyl)imide] medium. It can be recycled and reused without any significant loss of catalytic efficiency. This study provides the first example of an efficient alkane hydrocarboxylation to carboxylic acid, in an ionic liquid and under mild conditions. PMID- 27460348 TI - Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III. AB - Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1.49, 1.10 and 0.70% of the predicted values (%pred), respectively. The MFM score and handgrip strength were also age sensitive but only in patients older than 29 and 37 years old with annual losses of 1.42 and 1.84%pred, respectively. Muscle strength assessed by MMT and elbow extension measured by HHD demonstrated an annual loss of less than 0.50%pred and are thus unlikely to be promising outcome measures for future clinical trials. In conclusion, our results identified age-sensitive outcomes from retrospective data and may serve for future longitudinal studies in which an estimation of the minimal number of subjects is provided. PMID- 27460350 TI - A New Way to Produce Cellobiose Carbonates Using Green Chemistry. AB - The preparation of cellulose derivatives using green (i.e., environmentally friendly) reagents would improve sustainability and reduce concerns arising from the use of non-green reagents. The objective of this work was to prepare cellobiose carbonate using a green reagent, dimethyl carbonate. The carbonation reaction was carried out in the presence of ethanolic potassium hydroxide solution and dimethyl carbonate for 6 h at a range of temperatures (25-70 degrees C). A cellobiose derivative was successfully prepared with a recovered yield of more than 70 % and characterized by FTIR and NMR spectroscopy techniques. The presence of a grafted disaccharide with a degree of substitution higher than 2 was determined by (13) C NMR analysis. The spectra of the prepared cellobiose carbonate exhibited peaks that were associated with cellulose molecules (C1 -C6 ) and corresponded to carbonate functions at around 159.4 ppm. PMID- 27460351 TI - Occupational therapy: An untapped resource for children and adolescents with type 1 diabetes. PMID- 27460352 TI - Multi-institutional Analysis Shows that Low PCAT-14 Expression Associates with Poor Outcomes in Prostate Cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are an emerging class of relatively underexplored oncogenic molecules with biological and clinical significance. Current inadequacies for stratifying patients with aggressive disease presents a strong rationale to systematically identify lncRNAs as clinical predictors in localized prostate cancer. OBJECTIVE: To identify RNA biomarkers associated with aggressive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Radical prostatectomy microarray and clinical data was obtained from 910 patients in three published institutional cohorts: Mayo Clinic I (N=545, median follow-up 13.8 yr), Mayo Clinic II (N=235, median follow-up 6.7 yr), and Thomas Jefferson University (N=130, median follow-up 9.6 yr). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary clinical endpoint was distant metastasis-free survival. Secondary endpoints include prostate cancer-specific survival and overall survival. Univariate and multivariate Cox regression were used to evaluate the association of lncRNA expression and these endpoints. RESULTS AND LIMITATIONS: An integrative analysis revealed Prostate Cancer Associated Transcript-14 (PCAT-14) as the most prevalent lncRNA that is aberrantly expressed in prostate cancer patients. Down-regulation of PCAT-14 expression significantly associated with Gleason score and a greater probability of metastatic progression, overall survival, and prostate cancer-specific mortality across multiple independent datasets and ethnicities. Low PCAT-14 expression was implicated with genes involved in biological processes promoting aggressive disease. In-vitro analysis confirmed that low PCAT-14 expression increased migration while overexpressing PCAT-14 reduced cellular growth, migration, and invasion. CONCLUSIONS: We discovered that androgen-regulated PCAT-14 is overexpressed in prostate cancer, suppresses invasive phenotypes, and lower expression is significantly prognostic for multiple clinical endpoints supporting its significance for predicting metastatic disease that could be used to improve patient management. PATIENT SUMMARY: We discovered that aberrant prostate cancer associated transcript-14 expression during prostate cancer progression is prevalent across cancer patients. Prostate cancer associated transcript-14 is also prognostic for metastatic disease and survival highlighting its importance for stratifying patients that could benefit from treatment intensification. PMID- 27460353 TI - Re: Anthony Zietman, Joseph Smith, Eric Klein, Michael Droller, Prokar Dasgupta, James Catto. Describing the Grade of Prostate Cancer: Consistent Use of Contemporary Terminology Is Now Required. Eur Urol 2016;70:1. PMID- 27460354 TI - Optimizing Active Surveillance. AB - Active surveillance is evolving as a management strategy for favorable-risk prostate cancer. Further study is needed to determine the safety of surveillance for specific subgroups of patients, and to clarify the role of genomic markers and image-guided biopsy. PMID- 27460355 TI - Comparative proteomics reveals the underlying toxicological mechanism of low sperm motility induced by iron ion radiation in mice. AB - The toxicological mechanism of low sperm motility induced by iron ion radiation (IIR) was investigated in mice. Reproductive organ indices were measured following whole-body irradiation with a 2Gy iron ion beam. Two-dimensional gel electrophoresis, immunoblotting and immunofluorescence were used to analyze protein expression, and real-time polymerase chain reaction was performed to confirm altered gene expression. Reproductive organ indices and sperm motility were lowest 2 weeks after IIR. Sperm function changes via testis and cauda epididymis function were also determined at this time point. Sixteen differentially expressed proteins were identified in sperm 2 weeks after IIR. Bioinformatics analysis indicated that alpha-enolase (Eno1) may be important in the regulation of glycolysis in sperm, and Eno1 expression was correlated with sperm motility. Eno1 may be a potential marker for low sperm motility induced by IIR, and these results may provide a useful reference for changes in astronaut fertility during long space missions. PMID- 27460357 TI - Gaze position lagging behind scene content in multiple object tracking: Evidence from forward and backward presentations. AB - In everyday life, people often need to track moving objects. Recently, a topic of discussion has been whether people rely solely on the locations of tracked objects, or take their directions into account in multiple object tracking (MOT). In the current paper, we pose a related question: do people utilise extrapolation in their gaze behaviour, or, in more practical terms, should the mathematical models of gaze behaviour in an MOT task be based on objects' current, past or anticipated positions? We used a data-driven approach with no a priori assumption about the underlying gaze model. We repeatedly presented the same MOT trials forward and backward and collected gaze data. After reversing the data from the backward trials, we gradually tested different time adjustments to find the local maximum of similarity. In a series of four experiments, we showed that the gaze position lagged by approximately 110 ms behind the scene content. We observed the lag in all subjects (Experiment 1). We further experimented to determine whether tracking workload or predictability of movements affect the size of the lag. Low workload led only to a small non-significant shortening of the lag (Experiment 2). Impairing the predictability of objects' trajectories increased the lag (Experiments 3a and 3b). We tested our observations with predictions of a centroid model: we observed a better fit for a model based on the locations of objects 110 ms earlier. We conclude that mathematical models of gaze behaviour in MOT should account for the lags. PMID- 27460359 TI - Prompt impact of first prospective statin mega-trials on postoperative lipid management of CABG patients: a 20-year follow-up in a single hospital. AB - BACKGROUND: The long-term success of coronary artery bypass grafting (CABG) depends on secondary prevention. Vast evidence provided by the results of cholesterol mega-trials over two decades has shown that effective reduction of LDL cholesterol improves the prognosis of patients with coronary heart disease. However, the implementation of these results into the clinical practice has turned out to be challenging. We analysed how the information derived from clinical statin trials and international recommendations affected the local treatment practices of dyslipidaemia of CABG patients during a 20-year time period. METHODS: The cohort includes all CABG patients (n = 953) treated in Kanta Hame Central Hospital during the time period 1990-2009. At the postoperative visits in the cardiology outpatient clinic, each patient's statin prescription was recorded, and blood lipids were determined. RESULTS: During 1990-1994, 12.0 % of patients were on statins and during the following 5-year time periods the proportion was 57.2, 82.2 and 96.8 %, respectively. During the 20-year observation period (1990-2009), the effective statin dose increased progressively during these 5-year periods up to 36-fold, while the mean concentration of LDL cholesterol decreased from 3.7 to 2.1 mmol/l and that of apolipoprotein B from 1.3 to 0.8 g/l. In the very last year of follow-up, the mean concentrations of LDL-C and apoB were 1.83 mmol/l and 0.78 g/l, respectively. The most prominent increase in statin use and dosage took place during 1994-1996 and 2003-2005, respectively. CONCLUSIONS: Among CABG patients the lipid-lowering efficacy of statin therapy improved dramatically since 1994. This progress was accompanied by significant and favourable changes of lipid and apolipoprotein-B values. This study shows that it is possible to effectively improve lipid treatment policy once the results of relevant trials are available, and that this may happen even before international or national guidelines have been updated. PMID- 27460360 TI - A new nail with a locking blade for complex proximal humeral fractures. AB - INTRODUCTION: The objective of this study was to assess the clinical outcome of displaced proximal humerus fracture treated with a new locking blade nail. MATERIALS AND METHODS: This prospective study included a series of 92 patients with acute fracture of the proximal humerus treated in one hospital level I trauma centre with locking blade nail between December 2010 and December 2013. According to the Neer classification, all fractures were two- to four-part fractures. Age adopted Constant score, DASH and visual analogue scores were used as outcome measures. RESULTS: A total of 92 patients were enrolled in the study. However, 29 patients were excluded due to loss to follow-up and death. Ultimately, 63 patients were available for final follow-up and data analysis. The mean duration of follow-up was 22 months (range 16-48 months). On average at 1 year, all fractures had united. The mean weighted Constant score was 84.2 % and the median disabilities of the arm, shoulder and hand (DASH) score was 26, the range of elevation was 115 and range of abduction was 97. The head shaft angle was 130, and pain visual analogue was 1.6. We found that 5 of the 63 patients (8 %) demonstrated complications. Two patients (3 %) displayed secondary displacement and require device removal. Two patients (3 %) had impingement due to prominent metal work, and one patient had a superficial wound infection which was treated with a course of antibiotics. CONCLUSION: Our study shows excellent results with new locking blade nail for displaced proximal humerus fractures. We think the locking blade nail offers stiff triangular fixation of the head fragment and support of the medial calcar region to prevent secondary varus collapse. LEVEL OF EVIDENCE: III. PMID- 27460361 TI - Proceedings of a workshop, held in Constanta, Romania on 22 May 2014, on Oral Health of Children in the Central and Eastern European Countries in the context of the current economic crisis. AB - This report presents the proceedings of a workshop held in Constanta, Romania on 22 May 2014. During the workshop, representatives from 18 Central and Eastern European countries gave oral presentations on the current oral health of children and young adults aged 16 years and younger. The aim of the workshop was to collect and present data relating to the oral health of children from Central and Eastern European countries and to discuss them in the context of the political changes that have taken place over the last two decades and the recent economic crisis.The presenters had previously completed a series of questions on oral epidemiological studies, prevention of oral disease, treatment and payment, dental personnel, uptake of oral health care and other considerations and structured their presentations on these topics plus the influence of the economic crisis on oral health. It should be remembered that this paper is a report of the proceedings of a workshop and not a study. Ethics approval is not required for workshops.After the 18 oral presentations a 90 min discussion took place during which further points were raised. The presentations, the discussion and the conclusions which were reached are reported in this manuscript. PMID- 27460362 TI - Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells. AB - BACKGROUND: Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. METHODS: We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. CONTROLS: To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. RESULTS: Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. CONCLUSIONS: BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression. PMID- 27460363 TI - Predicting who fails to meet the physical activity guideline in pregnancy: a prospective study of objectively recorded physical activity in a population-based multi-ethnic cohort. AB - BACKGROUND: A low physical activity (PA) level in pregnancy is associated with several adverse health outcomes. Early identification of pregnant women at risk of physical inactivity could inform strategies to promote PA, but no studies so far have presented attempts to develop prognostic models for low PA in pregnancy. Based on moderate-to-vigorous intensity PA (MVPA) objectively recorded in mid/late pregnancy, our objectives were to describe MVPA levels and compliance with the PA guideline (>=150 MVPA minutes/week), and to develop a prognostic model for non-compliance with the PA guideline. METHODS: From a multi-ethnic population-based cohort, we analysed data from 555 women with MVPA recorded in gestational week (GW) 28 with the monitor SenseWearTM Pro3 Armband. Predictor variables were collected in early pregnancy (GW 15). We organized the predictors within the domains health, culture, socioeconomic position, pregnancy, lifestyle, psychosocial factors, perceived preventive effect of PA and physical neighbourhood. The development of the prognostic model followed several steps, including univariate and multiple logistic regression analyses. RESULTS: Overall, 25 % complied with the PA guideline, but the proportion was lower in South Asians (14 %) and Middle Easterners (16 %) compared with Westerners (35 %). Among South Asians and Middle Easterners, 35 and 28 %, respectively, did not accumulate any MVPA minutes/week compared with 18 % among Westerners. The predictors retained in the prognostic model for PA guideline non-compliance were ethnic minority background, multiparity, high body fat percentage, and perception of few physically active friends. The prognostic model provided fair discrimination between women who did vs. did not comply with the PA guideline. CONCLUSION: Overall, the proportion who complied with the PA guideline in GW 28 was low, and women with ethnic minority background, multiparity, high body fat percentage and few physically active friends had increased probability of non-compliance. The prognostic model showed fair performance in discriminating between women who did comply and those who did not comply with the PA guideline. PMID- 27460365 TI - Using logic models to enhance the methodological quality of primary health-care interventions: guidance from an intervention to promote nutrition care by general practitioners and practice nurses. AB - The methodological designs underpinning many primary health-care interventions are not rigorous. Logic models can be used to support intervention planning, implementation and evaluation in the primary health-care setting. Logic models provide a systematic and visual way of facilitating shared understanding of the rationale for the intervention, the planned activities, expected outcomes, evaluation strategy and required resources. This article provides guidance for primary health-care practitioners and researchers on the use of logic models for enhancing methodological rigour of interventions. The article outlines the recommended steps in developing a logic model using the 'NutriCare' intervention as an example. The 'NutriCare' intervention is based in the Australian primary health-care setting and promotes nutrition care by general practitioners and practice nurses. The recommended approach involves canvassing the views of all stakeholders who have valuable and informed opinions about the planned project. The following four targeted, iterative steps are recommended: (1) confirm situation, intervention aim and target population; (2) document expected outcomes and outputs of the intervention; (3) identify and describe assumptions, external factors and inputs; and (4) confirm intervention components. Over a period of 2 months, three primary health-care researchers and one health-services consultant led the collaborative development of the 'NutriCare' logic model. Primary health care practitioners and researchers are encouraged to develop a logic model when planning interventions to maximise the methodological rigour of studies, confirm that data required to answer the question are captured and ensure that the intervention meets the project goals. PMID- 27460364 TI - Embryonic stem cell preconditioned microenvironment suppresses tumorigenic properties in breast cancer. AB - BACKGROUND: Microenvironment is being increasingly recognized as a critical determinant in tumor progression and metastasis. However, the appropriate regulatory mechanism to maintain the normal balance between differentiation and self-renewal of the cancer cell in microenvironment is not well known. METHODS: 4T1 breast cancer cells were treated with embryonic stem (ES) cell conditioned medium which was collected from mouse ES cells. Inhibition of tumor cell growth was based on the reduction of cell proliferation and viability, and inhibition of aggressive properties of tumor cells were examined using the wound-healing and mammosphere assays. The expression of stem cell-associated genes was detected by quantitative RT-PCR. RESULTS: We used a real-time imaging system to investigate the effect of the mouse ES cell microenvironment on aggressive breast cancer cells in vitro and in vivo. Exposure of breast cancer cells in mouse ES cell conditioned medium resulted in inhibition of growth, migration, metastasis, and angiogenesis of cancer cells. For many tumors, aggressive properties were tightly related to Stat3 signaling activation. We specifically discovered that the ES cell microenvironment sufficiently suppressed Stat3 signaling pathway activation in aggressive tumor cells, leading to a reduction in tumorigenesis and invasiveness. CONCLUSIONS: We identified important functions of Stat3 and their implications for antitumor effects of ES cell conditioned medium. Some factors secreted by ES cells could efficiently suppress Stat3 pathway activation in breast cancer cells, and were then involved in cancer cell growth, survival, invasion, and migration. This study may act as a platform to understand tumor cell plasticity and may offer new therapeutic strategies to inhibit breast cancer progression. PMID- 27460367 TI - Sampling of Riverine or Marine Bacterial Communities in Remote Locations: From Field to Publication. AB - This protocol describes how to sample and preserve microbial water column samples from rivers that can be used for 16S or 18S metabarcoding studies or shotgun sequencing. It further describes how to extract the DNA for sequencing and how to prepare raw Illumina MiSeq amplicon data and analyze it in the R environment. PMID- 27460366 TI - The association between graduated driver licensing laws and travel behaviors among adolescents: an analysis of US National Household Travel Surveys. AB - BACKGROUND: Young novice drivers have crash rates higher than any other age group. To address this problem, graduated driver licensing (GDL) laws have been implemented in the United States to require an extended learner permit phase, and create night time driving or passenger restrictions for adolescent drivers. GDL allows adolescents to gain experience driving under low-risk conditions with the aim of reducing crashes. The restricted driving might increase riding with parents or on buses, which might be safer, or walking or biking, which might be more dangerous. We examined whether GDL increases non-driver travels, and whether it reduces total travels combining drivers and non-drivers. METHODS: We used data from the US National Household Travel Survey for the years 1995-1996, 2001-2002, and 2008-2009 to estimate the adjusted ratio for the number of trips and trip kilometers made by persons exposed to a GDL law, compared with those not exposed. RESULTS: Adolescents aged 16 years had fewer trips and kilometers as drivers when exposed to a GDL law: ratio 0.84 (95 % confidence interval (CI) 0.71, 1.00) for trips; 0.79 (0.63, 0.98) for kilometers. For adolescents aged 17 years, the trip ratio was 0.94 (0.83, 1.07) and the kilometers ratio 0.80 (0.63, 1.03). There was little association between GDL laws and trips or kilometers traveled by other methods: ratio 1.03 for trips and 1.00 for kilometers for age 16 years, 0.94 for trips and 1.07 for kilometers for age 17. CONCLUSIONS: If these associations are causal, GDL laws reduced driving kilometers by about 20 % for 16 and 17 year olds, and reduced the number of driving trips by 16 % among 16 year olds. GDL laws showed little relationship with trips by other methods. PMID- 27460368 TI - DNA Extraction Protocols for Whole-Genome Sequencing in Marine Organisms. AB - The marine environment harbors a large proportion of the total biodiversity on this planet, including the majority of the earths' different phyla and classes. Studying the genomes of marine organisms can bring interesting insights into genome evolution. Today, almost all marine organismal groups are understudied with respect to their genomes. One potential reason is that extraction of high quality DNA in sufficient amounts is challenging for many marine species. This is due to high polysaccharide content, polyphenols and other secondary metabolites that will inhibit downstream DNA library preparations. Consequently, protocols developed for vertebrates and plants do not always perform well for invertebrates and algae. In addition, many marine species have large population sizes and, as a consequence, highly variable genomes. Thus, to facilitate the sequence read assembly process during genome sequencing, it is desirable to obtain enough DNA from a single individual, which is a challenge in many species of invertebrates and algae. Here, we present DNA extraction protocols for seven marine species (four invertebrates, two algae, and a marine yeast), optimized to provide sufficient DNA quality and yield for de novo genome sequencing projects. PMID- 27460369 TI - High-Throughput Sequencing of Complete Mitochondrial Genomes. AB - Next-generation sequencing has revolutionized mitogenomics, turning a cottage industry into a high throughput process. This chapter outlines methodologies used to sequence, assemble, and annotate mitogenomes of non-model organisms using Illumina sequencing technology, utilizing either long-range PCR amplicons or gDNA as starting template. Instructions are given on how to extract DNA, conduct long range PCR amplifications, generate short Sanger barcode tag sequences, prepare equimolar sample pools, construct and assess quality library preparations, assemble Illumina reads using either seeded reference mapping or de novo assembly, and annotate mitogenomes in the absence of an automated pipeline. Notes and recommendations, derived from our own experience, are given throughout this chapter. PMID- 27460370 TI - Phylogenomics Using Transcriptome Data. AB - This chapter presents a generalized protocol for conducting phylogenetic analyses using large-scale molecular datasets, specifically using transcriptome data from the Illumina sequencing platform. The general molecular lab bench protocol consists of RNA extraction, cDNA synthesis, and sequencing, in this case via Illumina. After sequences have been obtained, bioinformatics methods are used to assemble raw reads, identify coding regions, and categorize sequences from different species into groups of orthologous genes (OGs). The specific OGs to be used for phylogenetic inference are selected using a custom shell script. Finally, the selected orthologous groups are concatenated into a supermatrix. Generalized methods for phylogenomic inference using maximum likelihood and Bayesian inference software are presented. PMID- 27460371 TI - SNP Discovery Using Next Generation Transcriptomic Sequencing. AB - In this chapter, I will guide the user through methods to find new SNP markers from expressed sequence (RNA-Seq) data, focusing on the sample preparation and also on the bioinformatic analyses needed to sort through the immense flood of data from high-throughput sequencing machines. The general steps included are as follows: sample preparation, sequencing, quality control of data, assembly, mapping, SNP discovery, filtering, validation. The first few steps are traditional laboratory protocols, whereas steps following the sequencing are of bioinformatic nature. The bioinformatics described herein are by no means exhaustive, rather they serve as one example of a simple way of analyzing high throughput sequence data to find SNP markers. Ideally, one would like to run through this protocol several times with a new dataset, while varying software parameters slightly, in order to determine the robustness of the results. The final validation step, although not described in much detail here, is also quite critical as that will be the final test of the accuracy of the assumptions made in silico.There is a plethora of downstream applications of a SNP dataset, not covered in this chapter. For an example of a more thorough protocol also including differential gene expression and functional enrichment analyses, BLAST annotation and downstream applications of SNP markers, a good starting point could be the "Simple Fool's Guide to population genomics via RNA-Seq," which is available at http://sfg.stanford.edu . PMID- 27460372 TI - SNP Arrays for Species Identification in Salmonids. AB - The use of SNP genotyping microarrays, developed in one species to analyze a closely related species for which genomic sequence information is scarce, enables the rapid development of a genomic resource (SNP information) without the need to develop new species-specific markers. Using large numbers of microarray SNPs offers the best chance to detect informative markers in nontarget species, markers that can very often be assayed using a lower throughput platform as is described in this paper. PMID- 27460373 TI - The Next-Generation PCR-Based Quantification Method for Ambient Waters: Digital PCR. AB - Real-time quantitative PCR (qPCR) is increasingly being used for ambient water monitoring, but development of digital polymerase chain reaction (digital PCR) has the potential to further advance the use of molecular techniques in such applications. Digital PCR refines qPCR by partitioning the sample into thousands to millions of miniature reactions that are examined individually for binary endpoint results, with DNA density calculated from the fraction of positives using Poisson statistics. This direct quantification removes the need for standard curves, eliminating the labor and materials associated with creating and running standards with each batch, and removing biases associated with standard variability and mismatching amplification efficiency between standards and samples. Confining reactions and binary endpoint measurements to small partitions also leads to other performance advantages, including reduced susceptibility to inhibition, increased repeatability and reproducibility, and increased capacity to measure multiple targets in one analysis. As such, digital PCR is well suited for ambient water monitoring applications and is particularly advantageous as molecular methods move toward autonomous field application. PMID- 27460374 TI - Using Environmental DNA for Invasive Species Surveillance and Monitoring. AB - The method employed for environmental DNA (eDNA) surveillance for detection and monitoring of rare species in aquatic systems has evolved dramatically since its first large-scale applications. Both active (targeted) and passive (total diversity) surveillance methods provide helpful information for management groups, but each has a suite of techniques that necessitate proper equipment training and use. The protocols described in this chapter represent some of the latest iterations in eDNA surveillance being applied in aquatic and marine systems. PMID- 27460375 TI - Microarrays/DNA Chips for the Detection of Waterborne Pathogens. AB - DNA microarrays are useful for the simultaneous detection of microorganisms in water samples. Specific probes targeting waterborne pathogens are selected with bioinformatics tools, synthesized and spotted onto a DNA array. Here, the construction of a DNA chip for waterborne pathogen detection is described, including the processes of probe in silico selection, synthesis, validation, and data analysis. PMID- 27460376 TI - DNA Barcoding of Marine Metazoans. AB - The accumulation of DNA barcode sequences will provide an increasingly useful and comprehensive library for species identification and discovery of marine metazoans. Here we present a summary of protocols designed to obtain DNA barcodes of marine metazoans from diverse phyla. PMID- 27460377 TI - DNA Barcoding Marine Biodiversity: Steps from Mere Cataloguing to Giving Reasons for Biological Differences. AB - DNA barcoding has become a useful tool in many contexts and has opened up a completely new avenue for taxonomy. DNA barcoding has its widest application in biodiversity and ecological research to detect and describe diversity whenever morphological discrimination is difficult or impossible (e.g., in the case of species lacking diagnostic characters, early life stages, or cryptic species). In this chapter, we outline the utility of including physiological parameters as part of species description in publicly available databases that catalog taxonomic information resulting from barcoding projects. Cryptic species or different life stages of a species often differ in their physiological traits. Thus, if physiological aspects were included in species definitions, the presently cryptic species could be distinguished. We furthermore give suggestions for physiological information that should be included in a species description and describe potential applications of DNA barcoding for research with physiological components. PMID- 27460378 TI - Metabarcoding Marine Sediments: Preparation of Amplicon Libraries. AB - The accurate assessment of community composition and ultimately species identification is of utmost importance in any ecological and evolutionary study. Advances in sequencing technologies have allowed the unraveling of levels of biodiversity never imagined before when applied to large-scale environmental DNA studies (also termed metabarcoding/metagenetics/metasystematics/environmental barcoding). Here, we describe a detailed protocol to assess eukaryotic biodiversity in marine sediments, identifying key steps that should not be neglected when preparing Next-Generation Sequencing (NGS) amplicon libraries: DNA extraction, multiple PCR amplification of DNA barcode markers with index/ tag primers, and final Illumina MiSeq sequencing library preparation. PMID- 27460379 TI - Preparation of Amplicon Libraries for Metabarcoding of Marine Eukaryotes Using Illumina MiSeq: The Dual-PCR Method. AB - This protocol details the preparation of multiplexed amplicon libraries for metabarcoding (amplicon-based) studies of microscopic marine eukaryotes. Metabarcoding studies, based on the amplification of a taxonomically informative marker from a collection of organisms or an environmental sample, can be performed to analyze biodiversity patterns or predator-prey interactions. For Metazoa, we use the mitochondrial cytochrome oxidase 1 (CO1) or the small ribosomal subunit (SSU) markers. Here, we describe a strategy for the preparation of multiplexed Illumina MiSeq libraries using a dual-PCR approach for the addition of index and adaptor sequences. PMID- 27460380 TI - Preparation of Amplicon Libraries for Metabarcoding of Marine Eukaryotes Using Illumina MiSeq: The Adapter Ligation Method. AB - Amplicon-based studies of marine microscopic eukaryotes, also referred to as metabarcoding studies, can be performed to analyze patterns of biodiversity or predator-prey interactions targeting the mitochondrial cytochrome oxidase 1 (CO1) or the small ribosomal subunit (SSU) markers. Because high-throughput sequencing (HTS) Illumina platforms provide millions of reads per run, hundreds of samples may be sequenced simultaneously. This protocol details the preparation of multiplexed amplicon libraries for Illumina MiSeq sequencing. We describe a strategy for sample multiplexing using a combination of tailed PCR primers and ligation of indexed adapters. PMID- 27460381 TI - Visualizing Patterns of Marine Eukaryotic Diversity from Metabarcoding Data Using QIIME. AB - PCR amplification followed by deep sequencing of homologous gene regions is increasingly used to characterize the diversity and taxonomic composition of marine eukaryotic communities. This approach may generate millions of sequences for hundreds of samples simultaneously. Therefore, tools that researchers can use to visualize complex patterns of diversity for these massive datasets are essential. Efforts by microbiologists to understand the Earth and human microbiomes using high-throughput sequencing of the 16S rRNA gene has led to the development of several user-friendly, open-source software packages that can be similarly used to analyze eukaryotic datasets. Quantitative Insights Into Microbial Ecology (QIIME) offers some of the most helpful data visualization tools. Here, we describe functionalities to import OTU tables generated with any molecular marker (e.g., 18S, COI, ITS) and associated metadata into QIIME. We then present a range of analytical tools implemented within QIIME that can be used to obtain insights about patterns of alpha and beta diversity for marine eukaryotes. PMID- 27460382 TI - Analysis of Illumina MiSeq Metabarcoding Data: Application to Benthic Indices for Environmental Monitoring. AB - This protocol details the analysis of Illumina MiSeq amplicon libraries derived from marine benthic macroinvertebrate samples and based on two barcodes of the mitochondrial cytochrome oxidase 1 (CO1) gene: a "short region," covered by overlapping forward and reverse reads and a "long region" for which forward and reverse reads do not overlap. Aside from providing guidelines for analyzing both types of amplicons, we show how amplicon reads can be used for the calculation of benthic indices for environmental monitoring. PMID- 27460383 TI - The Status of Nursing Documentation in Slovenia: a Survey. AB - Health documentation is a prerequisite for good and sustainable health and social care. It is especially important for patient involvement and their empowerment. A transition from paper to e-documentation together with the electronic patient record should be based on thorough knowledge of the current state of documentation and its usages. The main objective of this paper was to analyse which documents and work methods of documenting processes within nursing are being used within different environments. Furthermore, what are the main reasons for their discrepancies from theoretical approaches and best practices. The analysis is based on a survey carried out on all three levels of healthcare. The survey questionnaire consisted of 12 questions to which responded 286 nursing teams from community health centres, hospitals and retirement homes in Slovenia. The results point to diversity in documenting as well as lack of interoperability. This is reflected in a great number of different documents. All phases of the nursing process were being documented in only 31.8 % of cases. The main reasons for this can be attributed to work organisation, different definitions of data-set requirements and inadequate knowledge by nurses. Survey results pointed out a need for the renewal of nursing documentation towards a more uniform system based on contemporary health technologies. PMID- 27460385 TI - [Not Available]. PMID- 27460384 TI - Epithelioid inflammatory myofibroblastic sarcoma: a clinicopathological, immunohistochemical and molecular cytogenetic analysis of five additional cases and review of the literature. AB - BACKGROUND: To explore the clinical characteristics and pathological features of epithelioid inflammatory myofibroblastic sarcoma (EIMS) with emphasis on the diagnostic spectrum. METHODS: The clinical data and histological features in 5 additional cases of EIMS were retrospectively reviewed. Immunohistochemical study and interphase fluorescence in situ hybridization (FISH) analysis were carried out. RESULTS: There were 2 males and 3 females with age at presentation ranging from 15 to 58 years (mean, 37 years). All 5 tumors were intra-abdominal with 2 arising in the mesentery and 1 each in the omentum, rectum and transverse colon. The tumor size ranged from 5 to 20 cm in maximum diameter (mean, 10.7 cm). Histologically, all 5 tumors were composed predominantly of large epithelioid cells possessing vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm. Mitotic figures were easily identified (mean, 20/10HPF). Tumor cells were arranged in clusters or sheets embedded in a myxoid stroma containing prominent neutrophils. A minor component of spindle cells was present in focal areas. By immunohistochemistry, all 5 cases were positive for anaplastic lymphoma kinase (ALK) with a nuclear membrane pattern in 4 and cytoplasmic staining with perinuclear accentuation in 1. Besides ALK, tumor cells stained variably for desmin (4/5), alpha smooth muscle actin (2/5), muscle-specific actin (1/2) and pan-cytokeratin (1/4). FISH analysis demonstrated the presence of ALK rearrangement in all 5 cases. Of 5 patients, 3 developed local recurrence, 1 died of disease 8 months after surgery. CONCLUSION: EIMS represents a highly aggressive variant of inflammatory myofibroblastic tumor characterized by epithelioid morphology, prominent neutrophilic infiltrate, and nuclear membrane staining of ALK with ALK rearrangement. As patients with ALK-rearrangement tumors may benefit from targeted therapy, accurate diagnosis of EIMS is very important. Familiar with the characteristic features of EIMS will help pathologists avoid misdiagnosing the tumor as other malignancies. PMID- 27460386 TI - NHS trust stands by doctors who set up clinic for private work. PMID- 27460387 TI - EUS-guided pancreatic drainage for pancreatic strictures after failed ERCP: a multicenter international collaborative study. AB - BACKGROUND AND AIMS: Endoscopic retrograde pancreatography (ERP) is considered first-line therapy for management of symptomatic pancreatic duct obstruction. Technical failure with ERP occurs when the main pancreatic duct cannot be cannulated. EUS-guided drainage of the pancreatic duct is a minimally invasive alternative to surgery for failed conventional ERP. We present an international, multicenter study on the safety and efficacy of EUS-guided pancreatic drainage (EUS-PD) for patients who fail conventional endoscopic therapy. METHODS: Between January 2006 and December 2015, 80 patients underwent EUS-PD at 4 academic centers in 3 countries. Patient demographics, medical history, procedure data, and follow-up clinical data were collected. Technical success was defined as successful pancreatic duct drainage with stent placement. Clinical success was defined as resolution or improvement of symptoms or improvement on postprocedure imaging. RESULTS: Eighty patients (62.5% men; mean age, 58.2 +/- 15.5 years) were included. All patients had attempted ERP and/or extracorporeal lithotripsy if needed before EUS-PD. Technical success was achieved in 89% of patients (n = 71). Clinical success was achieved in 81% of patients overall (65/80) and in 92% of patients who achieved technical success (65/71). Immediate adverse events occurred in 20% of patients (n = 16) and delayed adverse events occurred in 11% of patients (n = 9). CONCLUSIONS: With appropriate endoscopic expertise, EUS-PD offers a minimally invasive, more effective, and safer alternative to some surgical PD procedures. Prospective studies are needed to evaluate long-term outcomes. (Clinical trial registration number: NCT01522573.). PMID- 27460388 TI - Transoral incisionless endoscopic fundoplication guided by impedance planimetry to treat severe GERD symptoms after per-oral endoscopic myotomy. PMID- 27460389 TI - Survival benefit of additional surgery after noncurative endoscopic resection in patients with early gastric cancer. AB - BACKGROUND AND AIMS: Excellent long-term outcome is expected for early gastric cancers (EGCs) after endoscopic submucosal dissection (ESD). However, if ESD is considered noncurative at the pathologic evaluation, additional surgery is recommended. We evaluated whether long-term outcome is compromised if additional surgery is not performed for EGCs that are out-of-indication. METHODS: We retrospectively analyzed a cohort of patients with EGC not meeting ESD indications whose initial treatment was either ESD (n = 219) or surgery (n = 1799). Among them, 127 patients who underwent additional surgery after initial ESD and 67 patients who did not were matched using propensity scores to patients who initially underwent standard surgery, at a 1:1 ratio. Overall mortality and gastric cancer recurrence were compared. RESULTS: The overall mortality and gastric cancer recurrence rates were not significantly different between the 127 patients who underwent initial ESD with additional surgery and the corresponding initial standard surgery patients. However, the overall mortality of the 67 patients who underwent ESD without additional surgery (5-year mortality, 26.0%; 95% CI, 13.5%-49.9%) was higher than that of the matched initial standard surgery patients (5-year mortality, 14.5%; 95% CI, 6.3%-33.6%; P = .04). Gastric cancer recurrence was also higher in ESD patients without additional surgery (5-year recurrence, 17.0%; 95% CI, 7.6%-37.8%) than in the matched initial surgery group (0%; P = .002). In multivariate analyses, ESD without additional surgery was a significant risk factor for overall mortality and gastric cancer recurrence. CONCLUSIONS: Additional surgery should be encouraged after non-curative ESD to obtain long-term outcomes comparable with those of initial standard surgery. (Clinical trial registration number: NCC2015-0093.). PMID- 27460390 TI - An international multicenter study comparing EUS-guided pancreatic duct drainage with enteroscopy-assisted endoscopic retrograde pancreatography after Whipple surgery. AB - BACKGROUND AND AIMS: Endoscopic management of post-Whipple pancreatic adverse events (AEs) with enteroscopy-assisted endoscopic retrograde pancreatography (e ERP) is associated with high failure rates. EUS-guided pancreatic duct drainage (EUS-PDD) has shown promising results; however, no comparative data have been done for these 2 modalities. The goal of this study is to compare EUS-PDD with e ERP in terms of technical success (PDD through dilation/stent), clinical success (improvement/resolution of pancreatic-type symptoms), and AE rates in patients with post-Whipple anatomy. METHODS: This is an international multicenter comparative retrospective study at 7 tertiary centers (2 United States, 2 European, 2 Asian, and 1 South American). All consecutive patients who underwent EUS-PDD or e-ERP between January 2010 and August 2015 were included. RESULTS: In total, 66 patients (mean age, 57 years; 48% women) and 75 procedures were identified with 40 in EUS-PDD and 35 in e-ERP. Technical success was achieved in 92.5% of procedures in the EUS-PDD group compared with 20% of procedures in the e ERP group (OR, 49.3; P < .001). Clinical success (per patient) was attained in 87.5% of procedures in the EUS-PDD group compared with 23.1% in the e-ERP group (OR, 23.3; P < .001). AEs occurred more commonly in the EUS-PDD group (35% vs 2.9%, P < .001). However, all AEs were rated as mild or moderate. Procedure time and length of stay were not significantly different between the 2 groups. CONCLUSIONS: EUS-PDD is superior to e-ERP in post-Whipple anatomy in terms of efficacy with acceptable safety. As such, EUS-PDD should be considered as a potential first-line treatment in post-pancreaticoduodenectomy anatomy when necessary expertise is available. PMID- 27460391 TI - Clip retention rates and rates of residual polyp at the base of retained clips on colorectal EMR sites. AB - BACKGROUND AND AIMS: Prophylactic endoscopic clipping may be effective in preventing delayed post-polypectomy hemorrhage after EMR of large colorectal lesions. The rate of retention of hemoclips on EMR sites has not been fully described. The aim of this study was to evaluate the adherence rates of hemoclips placed after EMR of large colorectal lesions. METHODS: This was a retrospective review of a prospectively maintained database of large colorectal polyps (>=20 mm) referred to Indiana University Hospital between June 2006 and August 2015. Sites were closed with a mean of 4 clips. Patients were followed up for 3 to 6 months after EMR with a second follow-up 1 year later. Biopsy specimens of EMR scars were examined at follow-up, including the tissue at the base of retained clips. RESULTS: There were 479 EMR sites in 424 patients that had first follow-up at our center with high-quality photographs of the EMR sites taken immediately after clip placement and at follow-up. Of 1407 Boston Scientific Resolution clips placed, 59 (4.2%) were retained at follow-up. Of 532 Cook Instinct clips placed, 46 (8.6%) were retained at first follow-up (P = .0001). There was no difference in the follow-up interval for the 2 clips. No patient had residual polyp by biopsy at the base of a retained clip. CONCLUSIONS: Clip retention at first follow-up at 3 to 6 months after EMR was twice as high for the Cook Instinct clip compared with Boston Resolution clip but retention rates were low for both clips. Residual polyp at the base of retained clips was not a significant clinical problem. PMID- 27460392 TI - Clinical impact and characteristics of the narrow-band imaging magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team. AB - BACKGROUND AND AIMS: The Japan NBI Expert Team (JNET) was established in 2011 and has proposed a universal narrow-band imaging (NBI) magnifying endoscopic classification of colorectal tumors. The aim of this study was to evaluate the clinical usefulness of the JNET classification for colorectal lesions. METHODS: We analyzed 2933 colorectal lesions, which were diagnosed by NBI magnifying observation before endoscopic treatment or surgery. The colorectal lesions consisted of 136 hyperplastic polyps/sessile serrated polyps (HPs/SSPs), 1926 low grade dysplasia (LGD), 571 high-grade dysplasia (HGD), 87 superficial submucosal invasive (SM-s) carcinomas, and 213 deep submucosal invasive (SM-d) carcinomas. We evaluated the relationship between the JNET classification and the histologic findings of these lesions. RESULTS: The sensitivity, specificity, positive and negative predictive values, and accuracy of Type 1 lesions for the diagnosis of HP/SSP were, respectively, 87.5%, 99.9%, 97.5%, 99.4%, and 99.3%; of Type 2A lesions for the diagnosis of LGD were 74.3%, 92.7%, 98.3%, 38.7%, and 77.1%; of Type 2B lesions for the diagnosis of HGD/SM-s carcinoma were 61.9%, 82.8%, 50.9%, 88.2%, and 78.1%; for Type 3 lesions for the diagnosis of SM-d carcinoma were 55.4%, 99.8%, 95.2%, 96.6%, and 96.6%, respectively. CONCLUSIONS: Types 1, 2A, and 3 of the JNET classification were very reliable indicators for HP/SSP, LGD, and SM-d carcinoma, respectively. However, the specificity and positive predictive value of Type 2B were relatively lower than those of others. Therefore, an additional examination such as pit pattern diagnosis using chromoagents is necessary for accurate diagnosis of Type 2B lesions. PMID- 27460393 TI - An HPLC method for the determination of selected amino acids in human embryo culture medium. AB - A method for the determination of selected amino acids in culture medium using HPLC with fluorescence detection is described. Twenty hours after intra cytoplasmic sperm injection, one randomly selected zygote was transferred to the culture medium. After incubation (72 h after fertilization), the culture medium in which the embryo was incubated and blank medium was immediately stored at -80 degrees C. Filtered medium samples were derivatized with ortho-phthalaldehyde (naphthalene-2,3-dicarboxaldehyde), forming highly fluorescent amino acids derivatives. Reverse-phase columns (LichroCART, Purospher STAR RP18e or Ascentis Express C18 ) were used for the separation. The derivatives were analyzed by gradient elution with a mobile phase containing ethanol and sodium dihydrogen phosphate. The analytical performance of this method is satisfactory for all amino acids; the intra-assay coefficients of variation were <10% and quantitative recoveries were between 95.5 and 104.4%. Changes in the levels of selected amino acids before and after human embryo cultivation were observed. After embryo incubation, the levels of all amino acids in the medium were increased, apart from aspartate and asparagine. After the cultivation of some embryos, amino acids which were not part of the medium were detected. Low amino acids turnover was observed in some embryos. PMID- 27460394 TI - Carbon : nickel nanocomposite templates - predefined stable catalysts for diameter-controlled growth of single-walled carbon nanotubes. AB - Carbon : nickel (C : Ni) nanocomposite templates (NCTs) were used as catalyst precursors for diameter-controlled growth of single-walled carbon nanotubes (SWCNTs) by chemical vapor deposition (CVD). Two NCT types of 2 nm thickness were prepared by ion beam co-sputtering without (type I) or with assisting Ar(+) ion irradiation (type II). NCT type I comprised Ni-rich nanoparticles (NPs) with defined diameter in an amorphous carbon matrix, while NCT type II was a homogenous C : Ni film. Based on the Raman spectra of more than 600 individual SWCNTs, the diameter distribution obtained from both types of NCT was determined. SWCNTs with a selective, monomodal diameter distribution are obtained from NCT type I. About 50% of the SWCNTs have a diameter of (1.36 +/- 0.10) nm. In contrast to NCT type I, SWCNTs with a non-selective, relatively homogeneous diameter distribution from 0.80 to 1.40 nm covering 88% of all SWCNTs are obtained from NCT type II. From both catalyst templates predominantly separated as-grown SWCNTs are obtained. They are free of solvents or surfactants, exhibit a low degree of bundling and contain negligible amounts of MWCNTs. The study demonstrates the advantage of predefined catalysts for diameter-controlled SWCNT synthesis in comparison to in situ formed catalysts. PMID- 27460395 TI - Current perspectives in hypertrophic cardiomyopathy with the focus on patients in the Finnish population: a review. AB - Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, with the prevalence of about 1/500. During the last two decades, the knowledge of the etiology, pathogenesis, risk stratification and prevention of sudden death in HCM has substantially advanced. Most often, HCM is familial and caused by mutations in sarcomere genes, inherited in an autosomal dominant manner. In Finland, genetic background of HCM is unique, with a few founder mutations in cardiac sarcomere genes accounting for a considerable proportion of the disease. Pathogenic mechanisms induced by disease-causing mutations are still poorly understood, although alterations in intracellular calcium handling and inefficient generation of contractile force in myocytes are considered key features in triggering the hypertrophic response. Clinical features of the disease are highly variable from no symptoms to the spectrum of exertional dyspnea, angina, palpitations, syncope and sudden death. In the current patient care, implantable cardioverter defibrillators (ICDs) are successfully used to prevent sudden cardiac death in high risk subjects. Targeted genetic testing is recommended to confirm the diagnosis in patients with HCM and to identify family members with the disease. Future research is needed to elucidate key cellular mechanisms leading to HCM, which may allow specific prevention and treatment of the disease. Key messages Hypertrophic cardiomyopathy, most often caused by defects in sarcomere genes, is the most common inherited heart disease, and a common cause of sudden cardiac death (SCD) in athletes and young subjects. Cardiac imaging, ECG and genetic testing are pivotal in the diagnosis of the disease in patients and first-degree relatives. Implantable cardioverter defibrillators in patients with high risk for SCD and tailored pharmacotherapy are efficient tools in patient care, but so far, exact mechanisms leading to cardiac hypertrophy in HCM are only partially understood, and there is no curative treatment for the disease. PMID- 27460396 TI - Most of the genetic covariation between major depressive and alcohol use disorders is explained by trait measures of negative emotionality and behavioral control. AB - BACKGROUND: Mental health disorders commonly co-occur, even between conceptually distinct syndromes, such as internalizing and externalizing disorders. The current study investigated whether phenotypic, genetic, and environmental variance in negative emotionality and behavioral control account for the covariation between major depressive disorder (MDD) and alcohol use disorder (AUD). METHOD: A total of 3623 members of a national twin registry were administered structured diagnostic telephone interviews that included assessments of lifetime histories of MDD and AUD, and were mailed self-report personality questionnaires that assessed stress reactivity (SR) and behavioral control (CON). A series of biometric models were fitted to partition the proportion of covariance between MDD and AUD into SR and CON. RESULTS: A statistically significant proportion of the correlation between MDD and AUD was due to variance specific to SR (men = 0.31, women = 0.27) and CON (men = 0.20, women = 0.19). Further, genetic factors explained a large proportion of this correlation (0.63), with unique environmental factors explaining the rest. SR explained a significant proportion of the genetic (0.33) and environmental (0.23) overlap between MDD and AUD. In contrast, variance specific to CON accounted for genetic overlap (0.32), but not environmental overlap (0.004). In total, SR and CON accounted for approximately 70% of the genetic and 20% of the environmental covariation between MDD and AUD. CONCLUSIONS: This is the first study to demonstrate that negative emotionality and behavioral control confer risk for the co-occurrence of MDD and AUD via genetic factors. These findings are consistent with the aims of NIMH's RDoC proposal to elucidate how transdiagnostic risk factors drive psychopathology. PMID- 27460397 TI - Clinical guides for atypical hemolytic uremic syndrome in Japan. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In 2013, we developed diagnostic criteria to enable early diagnosis and timely initiation of appropriate treatment for aHUS. Recent clinical and molecular findings have resulted in several proposed classifications and definitions of thrombotic microangiopathy and aHUS. Based on recent advances in this field and the emerging international consensus to exclude secondary TMAs from the definition of aHUS, we have redefined aHUS and proposed diagnostic algorithms, differential diagnosis, and therapeutic strategies for aHUS. PMID- 27460398 TI - Intrapleural urokinase therapy in a neonate with pleural empyema. AB - Pleural empyema is rare in neonates, and treatment with systemic antibiotics and tube drainage may fail because of the thick viscous fluid, bacterial products with fibrin deposition, and multiple loculations. Intrapleural fibrinolytic therapy with urokinase is an effective and non-invasive treatment option that avoids surgical intervention, although its use in neonates has not been studied extensively. In this report, we describe the case of a 13-day-old male neonate with Escherichia coli sepsis and pneumonia, which rapidly progressed to parapneumonic effusion and pleural empyema. After inadequate response to i.v. antibiotics and chest tube drainage, the patient was successfully treated with intrapleural urokinase. PMID- 27460400 TI - Functional total anomalous pulmonary venous connection via levoatriocardinal vein. AB - We report a fetal case of double outlet right ventricle, mitral atresia, and intact atrial septum. Although the pulmonary veins were connected to the left atrium, pulmonary venous blood drained into the right superior vena cava via the stenotic levoatriocardinal vein (LACV), which resulted in a circulation resembling total anomalous pulmonary venous connection (TAPVC) with pulmonary venous obstruction. Since the pulmonary veins were connected to both the stenotic LACV and the "dead-end" left atrium, the pulmonary venous flow had a to-and-fro pattern along with atrial relaxation and contraction. Postnatal echocardiography and computed tomography confirmed the diagnosis of normally connected but anomalously draining pulmonary veins via the LACV. Surgical creation of an atrial septal defect on the day of birth successfully relieved pulmonary venous obstruction. Normally connected but anomalously draining pulmonary veins via the LACV should be considered for TAPVC differential diagnosis in fetuses with a left side heart obstruction. PMID- 27460399 TI - Cord blood transplantation in a young child with pyruvate kinase deficiency. AB - Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and frequent transfusion-dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase-liver and RBC (PK-LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity. PMID- 27460403 TI - Prevalence of abdominal migraine and recurrent abdominal pain in a Japanese clinic. AB - Prevalence of abdominal migraine (AM) and recurrent abdominal pain (RAP) was evaluated in patients who visited Hikita Pediatric Clinic between May 2010 and April 2015. Patient data were collected prospectively using a questionnaire. Out of a total of 3611 cases, observed prevalence was 2.44% for repeated abdominal pain over a period of >=3 months, 1.47% for RAP, and 0.19% for AM. Duration of abdominal pain was longer for AM than for non-AM RAP. Certain clinical features were significantly different between AM and non-AM RAP. No correlations were found among age at onset, frequency of attack, and duration of attack for various types of RAP. It was difficult to determine useful diagnostic criteria for distinguishing between AM and non-AM RAP. They did not appear to be separate disease entities but, instead, lie on a disease spectrum. The present prevalence of AM (0.19%) was lower than that in many previous studies from countries other than Japan. PMID- 27460401 TI - Response to propranolol in infantile hemangioma. AB - Propranolol, 2 mg/kg/day, is effective in the treatment of infantile hemangioma. We report the response to propranolol in infants with hemangioma at a dose of 1 mg/kg/day. Sixteen infants with newly diagnosed infantile hemangioma were given propranolol at a dose titrated from 0.5 mg/kg/day then increased to 1 or 2 mg/kg/day based on response to treatment until the lesions showed clinical stability for 3 consecutive months. Five out of 16 patients (31.2%) responded to propranolol at 1 mg/kg/day, while the remainder required 2 mg/kg/day for response. Vascular endothelial growth factor significantly decreased after treatment (median, 117.8 pg/mL; range, 35.3-468.7 pg/mL vs 59.2 pg/mL; range, 26.3-133.0 pg/mL; P = 0.016). Therefore, we recommend initiating treatment at 0.5 mg/kg/day for 2 days, then 1 mg/kg/day for 1 month. If the hemangioma has not decreased in size by 1 month follow up, the dose is subsequently increased to 2 mg/kg/day. PMID- 27460405 TI - Corrigendum. PMID- 27460406 TI - Cobalt-Catalyzed Oxidative C-H/C-H Cross-Coupling between Two Heteroarenes. AB - The first example of cobalt-catalyzed oxidative C-H/C-H cross-coupling between two heteroarenes is reported, which exhibits a broad substrate scope and a high tolerance level for sensitive functional groups. When the amount of Co(OAc)2 ?4 H2 O is reduced from 6.0 to 0.5 mol %, an excellent yield is still obtained at an elevated temperature with a prolonged reaction time. The method can be extended to the reaction between an arene and a heteroarene. It is worth noting that the Ag2 CO3 oxidant is renewable. Preliminary mechanistic studies by radical trapping experiments, hydrogen/deuterium exchange experiments, kinetic isotope effect, electron paramagnetic resonance (EPR), and high resolution mass spectrometry (HRMS) suggest that a single electron transfer (SET) pathway is operative, which is distinctly different from the dual C-H bond activation pathway that the well described oxidative C-H/C-H cross-coupling reactions between two heteroarenes typically undergo. PMID- 27460404 TI - Coexistence of congenital long QT syndrome and autonomic dysregulation in children. AB - Loss of consciousness (LOC) in long QT syndrome (LQTS) patients can be caused by torsade de pointes (TdP) or vasovagal syncope (VVS). On genetic testing and head up tilt testing (HUTT), we diagnosed three young patients with both genotyped LQTS and autonomic dysregulation. According to grade of prolongation of QT interval and LOC status, syncope episodes in two patients were classified as due to VVS, while those of the other patient were due to TdP. We also diagnosed one patient with postural orthostatic tachycardia syndrome. Syncope in LQTS patients should not automatically be labeled TdP. If there is a possibility of VVS, HUTT should be performed, but careful observation is required because TdP cannot be completely ruled out. PMID- 27460402 TI - Ultrasonography of the internal carotid artery during therapeutic hypothermia. AB - The purpose of this study was to determine the accuracy of mean blood flow velocity (mean V) in the internal carotid artery (ICA) for prediction of outcome in infants with hypoxic-ischemic encephalopathy (HIE) exposed to therapeutic hypothermia (TH). Five newborns with HIE who met the criteria for TH were enrolled. Ultrasonography of the right and left ICA was performed before, during, and after TH. Mean V of the sampling point in each ICA was measured. Mean V was suppressed during TH and increased after rewarming in four infants with normal neurological development. In one infant with neurological disability, however, mean V increased during TH and decreased after therapy. In conclusion, cervical ultrasonography for ICA in infants during TH may be useful for the prediction of neurodevelopmental outcome. PMID- 27460409 TI - Developing a tool to measure the factors influencing nurses' enjoyment of nursing. AB - AIMS AND OBJECTIVES: To develop a tool to measure the influencing nurses' enjoyment of nursing. BACKGROUND: Enjoyment in the workplace is an influential aspect found to boost work morale, job satisfaction leading to higher work retention which is important in nursing given the availability of nurses in the workforce. This study looks to refine the determinants of enjoyment from nurses in a large metropolitan hospital in western Sydney. DESIGN: Quantitative. METHODS: A 23-item survey questionnaire was used to ask nurses to rate the determinants that affect their enjoyment of nursing on a five-point Likert scale. The survey was distributed in a hard copy and online through a hospital-wide broadcast. Demographic items were also collected. RESULTS: A total of 124 responses were received, of which 54 were from online and 70 from hard copy surveys. The data analysis found 16 determinants of enjoyment. Of these, four were perceived by over 80% of the nurses to negatively impact their enjoyment. In contrast, nine items showed a positive effect on enjoyment with educating others, connecting with others, variety of work, doing and sharing with others, supporting others being the most positive (>=89% of responses). Three items were considered neutral: criticism, busy workload and changing policies. CONCLUSIONS: This study has added to the growing evidence on nurse enjoyment and its effects on job satisfaction. Nurses enjoy caring for patients and also find enjoyment and satisfaction in teaching others to care as well as socially connecting. RELEVANCE TO CLINICAL PRACTICE: Enjoyment seems to be one of the main reasons nurses continue to stay in nursing even though the system and people are not always supportive, encouraging or conducive to career development. PMID- 27460407 TI - Examination of Prepregnancy and Pregnancy Urinary Protein Levels in Healthy Nulliparous Women. AB - During pregnancy, abnormal proteinuria is defined as urine protein excretion greater than 300 mg/24 h. Although widely accepted, this definition is not based on clinical outcomes. Our study aimed to longitudinally examine proteinuria in healthy women prior to, and in late pregnancy and to compare inpatient and outpatient 24-hour urine collections. Nulliparous women planning to conceive were recruited and completed a 24-hour urinary collection. Those who subsequently conceived completed a second 24-hour urinary collection in late pregnancy. In the first 5 years of the study, urinary collections were completed during an inpatient admission; all collections during the latter part of the study were performed as outpatients. Urine protein was measured using the VITROS UPRO Slide kit. Wilcoxon signed rank tests were used for paired comparisons of prepregnancy and late pregnancy proteinuria and Wilcoxon rank sum tests were used to compare inpatient and outpatient collections. Among 134 women completing a prepregnancy collection, median urinary protein excretion was 188 mg/24 h (IQR 103-280). Sixty five women subsequently conceived and completed a late pregnancy collection. In healthy women, urinary protein increased to 254 mg/24 h during pregnancy (IQR 166 396). Forty-five percent of women exceeded the defined normal threshold of proteinuria in 24 hours in the absence of disease. Inpatient collections resulted in higher levels of urinary protein than outpatient at both time points. Our data suggest that significant proteinuria is present in healthy nonpregnant women. Even in the absence of disease, proteinuria increases during pregnancy. Outpatient collections may underestimate proteinuria, especially in late pregnancy. PMID- 27460410 TI - Biodegradation of high concentrations of formaldehyde by lyophilized cells of Methylobacterium sp. FD1. AB - In the present study, Methylobacterium sp. FD1 utilizing formaldehyde was isolated from soil. The resting cells of FD1 degraded high concentrations of formaldehyde (~2.7 M) and produced formic acid and methanol that were molar equivalents of one-half of the degraded formaldehyde. This result suggests that formaldehyde degradation by FD1 is caused by formaldehyde dismutase. The optimal temperature and pH for formaldehyde degradation by the resting cells of FD1 were 40 degrees C and 5-7, respectively. The lyophilized cells of FD1 also degraded high concentrations of formaldehyde. The formaldehyde degradation activity of the lyophilized cells was maintained as the initial activity at 25 degrees C for 287 days. These results suggest that the lyophilized cells of FD1 are useful as formaldehyde degradation materials. PMID- 27460408 TI - New approaches for fibrosis regression in alcoholic cirrhosis. AB - Liver fibrosis is a dynamic process of fibrinogenesis and fibrinolysis. It is sequelae of recurrent injury and inflammation to the liver. Only recently has there been significant progress in understanding the pathophysiology behind liver fibrosis. This has allowed for the development of identifiable targets for potential therapies. In this article we will discuss the underlying general cellular mechanisms that play a key role in the pathway of fibrinogenesis and fibrinolysis and then focus on the mechanisms that are key in alcohol-induced liver fibrosis. Challenges in formulating potential fibrosis therapies as well as current potential targets for liver fibrosis will be reviewed as well. PMID- 27460412 TI - No association between vitamin D levels around time of birth and later risk of developing oligo- and polyarticular juvenile idiopathic arthritis: a Danish case cohort study. AB - OBJECTIVES: Basic and epidemiological studies on rheumatic autoimmune diseases have suggested an association between vitamin D levels around time of birth and disease risk. The literature on vitamin D and juvenile idiopathic arthritis (JIA) is scarce. We hypothesized that low levels of 25-hydroxyvitamin D [25(OH)D] around time of birth would be associated with increased risk of oligo- or polyarticular JIA. METHOD: We conducted a case-cohort study of validated cases diagnosed with oligo- and polyarticular JIA (1993-2012) and controls matched on date of birth. Cases and controls were born in the period 1983-2010. Cases were diagnosed using international criteria. The concentration of 25(OH)D was assessed from neonatal dried blood spot (DBS) samples using high-sensitivity liquid chromatography tandem mass spectrometry (LC-MS/MS). Odds ratios (ORs) were calculated using conditional logistic regression and a two-way analysis of variance (ANOVA) was used to test for season and birth year 25(OH)D variations. A total of 300 matched pairs were included in the statistical analyses. RESULTS: No significant association was found between levels of 25(OH)D and JIA risk in the adjusted model [OR (per 25 nmol/L increase) 1.2, 95% confidence interval (CI) 0.9 1.6, p = 0.2]. 25(OH)D levels were found to fluctuate significantly with season (p < 0.0001) and year (p < 0.0001). The median level of 25(OH)D was 34.4 nmol/L in cases and 31.5 nmol/L in controls. CONCLUSIONS: Our study does not support the hypothesis that a window of vulnerability exists around time of birth with regard to 25(OH)D levels and later JIA risk. Further studies should explore whether 25(OH)D levels during early pregnancy or infancy may influence JIA risk. PMID- 27460414 TI - Guns, Doctors and Public Health. PMID- 27460411 TI - ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression. AB - Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4 deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation. PMID- 27460413 TI - Web-Based Interventions for Chronic Back Pain: A Systematic Review. AB - BACKGROUND: Chronic low back pain is one of the most common presenting complaints to a physician's office. Treatment is often challenging and recovery depends on various factors, often resulting in significant investments of time and resources. OBJECTIVE: The aim of this review is to determine which Web-based interventions aimed at chronic low back pain are of benefit to patients. METHODS: Randomized controlled trials (RCTs) studying Web-based interventions directed at adults with chronic low back pain were included. Retrospective studies, narrative reviews, nonrandomized trials, and observational studies were excluded. Electronic databases and bibliographies were searched. RESULTS: In total, nine unique RCTs were identified (total participants=1796). The number of patients randomized in each trial ranged from 51 to 580. Four trials studied online cognitive behavioral therapy (CBT) and five trials studied other Web-based interventions with interactive features. Empowerment/control was improved in six studies. Use of CBT was associated with reduced catastrophization among patients. Mixed results were reported with regards to reduction in pain levels and disability, although some studies showed promise in reducing disability in the short term. One study that measured health care utilization reported reduced utilization with the use of moderated email discussion. CONCLUSIONS: Limited data are available regarding effective Web-based interventions to improve outcomes for patients with chronic low back pain. Nine RCTs with small sample sizes were identified in this review. Online CBT appears to show some promise in terms of reducing catastrophization and improving patient attitudes. Further research in this area with larger-scale studies focusing on appropriate outcomes appears to be a priority. PMID- 27460415 TI - Vitamin D: Ten Beliefs. PMID- 27460417 TI - Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma. AB - The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (alpha-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce alpha-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of alpha-KG dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased alpha-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1(R314C), which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1(R314C) lacks isocitrate-to alpha-KG conversion activity due to reduced affinity for NADP(+), and differs from the IDH1(R132) mutants in that it does not produce D-2-HG. Because IDH1(R314C) is defective in producing alpha-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite. PMID- 27460419 TI - Unconventional quantum Hall effect in Floquet topological insulators. AB - We study an unconventional quantum Hall effect for the surface states of ultrathin Floquet topological insulators in a perpendicular magnetic field. The resulting band structure is modified by photon dressing and the topological property is governed by the low-energy dynamics of a single surface. An exchange of symmetric and antisymmetric surface states occurs by reversing the light's polarization. We find a novel quantum Hall state in which the zeroth Landau level undergoes a phase transition from a trivial insulator state, with Hall conductivity [Formula: see text] at zero Fermi energy, to a Hall insulator state with [Formula: see text]. These findings open new possibilities for experimentally realizing nontrivial quantum states and unusual quantum Hall plateaus at [Formula: see text]. PMID- 27460418 TI - Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues. AB - The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions. PMID- 27460421 TI - Whole-exome sequencing in pediatrics: parents' considerations toward return of unsolicited findings for their child. AB - Parents' preferences for unsolicited findings (UFs) from diagnostic whole-exome sequencing (WES) for their children remain largely unexplored. Our aim was to gain insight into parental considerations favoring acceptance/decline of UFs pertaining to their child. We conducted 20 qualitative, semistructured interviews with parents (n=34) of children with a developmental delay, aged <1 to 17 years, after consenting to WES, but before feedback of results. Key findings from our study were that all parents favored acceptance of UFs for medically actionable conditions in childhood, but that preferences and considerations diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier status. Sometimes non-medical utility considerations (considerations of usefulness of knowing UFs, not rooted in (preventive) medical treatment or controls) were given in favor of disclosure of UFs. Sometimes the child's future autonomy formed a reason to withhold UFs at present, despite an unfavorable prognosis concerning the child's cognitive capabilities. Some parents only preferred receiving UFs if these findings were directly related to their reasons for seeking a diagnosis. These findings are essential for developing morally responsible policy and for counseling. Further research should focus on whether considerations of non-medical utility alone can justify disclosure of UFs and whether reasons for seeking a diagnosis place further constraints on what UFs may be returned/withheld. How parents can be aided in contemplating different scenarios regarding their child's future development also deserves further inquiry. PMID- 27460422 TI - Near Full-Length Genomic Characterization of a Novel HIV-1 Unique Recombinant (CRF55_01B/CRF07_BC) from a Malaysian Immigrant Worker in Zhejiang, China. AB - Recombinant forms contribute substantially to the genetic diversity of human immunodeficiency virus type 1 (HIV-1). Here we report a novel HIV-1 recombinant detected from a comprehensive HIV-1 molecular epidemiologic study among cross border populations in China. Near full-length genome (NFLG) phylogenetic analysis showed that the novel HIV-1 recombinant ZJCIQ15005, which was isolated from a Malaysian immigrant worker in Zhejiang, China, clustered with CRF55_01B reference sequences but set up a distinct branch. Recombinant analysis showed that the NFLG of ZJCIQ15005 composed of CRF55_01B (as the backbone) and CRF07_BC, with 12 recombinant break points observed in the pol, vif, vpr, tat, rev, env, nef, and 3'LTR regions. This is the first detection of a novel HIV-1 recombinant (CRF55_01B/CRF07_BC) in immigrant workers in China. The emergence of this recombinant may increase the complexity of the HIV-1 epidemic in China and suggests the importance of continuous surveillance of the dynamic changes of HIV 1. PMID- 27460420 TI - An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. AB - Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods. PMID- 27460423 TI - Immunostimulatory activity of glycopeptides from Paecilomyces sinensis under normal and cyclophosphamide induced immunosuppressive conditions in mice models. AB - The present study was designed to evaluate immune-modulating effects of the glycopeptide from Paecilomyces sinensis (CPS-II) by using mouse peritoneal macrophage and cytoxan (CTX) induced immunosuppression models. Our results from phagocytotic and mononuclear phagocytic system function assays showed that CPS-II stimulated phagocytosis of the phagocytes. A splenocyte proliferation assay showed that CPS-II acted to combine Concanavalin A (ConA) or lipopolysaccharides (LPS) in splenocyte proliferation. The results demonstrated that CPS-II increased the indices of the thymus and spleen. Hematological and histopathological analysis revealed the protective effect of CPS-II against CTX induced immunosuppression. CPS-II also significantly increased the expression of CD4(+) and CD8(+) splenic T lymphocytes, which were suppressed by CTX in peripheral blood. The expressions of serum cytokines related to immune function, including TNF-alpha, IL-6, and IFN-gamma, were up-regulated in a dose-dependent manner. The expression of the transcription factor NF-kappaB in the spleen was enhanced after CPS-II-treatment. In conclusion, our results indicated that CPS-II was involved in immunostimulatory actions leading to its modulatory effects on immunosuppression, and one possible mechanism of action was to activate NF kappaB. PMID- 27460424 TI - The Involvement of Protease Nexin-1 (PN1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration. AB - Protease nexin-1 (PN-1) is a serine protease inhibitor belonging to the serpin superfamily. This study was undertaken to investigate the regulatory role of PN-1 in the pathogenesis of intervertebral disk (IVD) degeneration. Expression of PN-1 was detected in human IVD tissue of varying grades. Expression of both PN-1 mRNA and protein was significantly decreased in degenerated IVD, and the expression levels of PN-1 were correlated with the grade of disc degeneration. Moreover, a decrease in PN-1 expression in primary NP cells was confirmed. On induction by IL 1beta, the expression of PN-1 in NP cells was decreased at day 7, 14, and 21, as shown by western blot analysis and immunofluorescence staining. PN-1 administration decreased IL-1beta-induced MMPs and ADAMTS production and the loss of Agg and Col II in NP cell cultures through the ERK1/2/NF-kB signaling pathway. The changes in PN-1 expression are involved in the pathogenesis of IVD degeneration. Our findings indicate that PN-1 administration could antagonize IL 1beta-induced MMPs and ADAMTS, potentially preventing degeneration of IVD tissue. This study also revealed new insights into the regulation of PN-1 expression via the ERK1/2/NF-kB signaling pathway and the role of PN-1 in the pathogenesis of IVD degeneration. PMID- 27460425 TI - Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction. AB - Lymphedema following breast cancer surgery is considered to be mainly due to the mechanical injury from surgery. Recent research identified that inflammation infection and obesity may be the important predictors for lymphedema. The purpose of this exploratory research was to prospectively examine phenotype of arm lymphedema defined by limb volume and lymphedema symptoms in relation to inflammatory genes in women treated for breast cancer. A prospective, descriptive and repeated-measure design using candidate gene association method was used to enroll 140 women at pre-surgery and followed at 4-8 weeks and 12 months post surgery. Arm lymphedema was determined by a perometer measurement of >=5% limb volume increase from baseline of pre-surgery. Lymphedema symptom phenotype was evaluated using a reliable and valid instrument. Saliva samples were collected for DNA extraction. Genes known for inflammation were evaluated, including lymphatic specific growth factors (VEGF-C & VEGF-D), cytokines (IL1-a, IL-4, IL6, IL8, IL10, & IL13), and tumor necrosis factor-a (TNF-a). No significant associations were found between arm lymphedema phenotype and any inflammatory genetic variations. IL1-a rs17561 was marginally associated with symptom count phenotype of >=8 symptoms. IL-4 rs2070874 was significantly associated with phenotype of impaired limb mobility and fluid accumulation. Phenotype of fluid accumulation was significantly associated with IL6 rs1800795, IL4 rs2243250 and IL4 rs2070874. Phenotype of discomfort was significantly associated with VEGF-C rs3775203 and IL13 rs1800925. Precision assessment of heterogeneity of lymphedema phenotype and understanding the biological mechanism of each phenotype through the exploration of inherited genetic susceptibility is essential for finding a cure. Further exploration of investigative intervention in the context of genotype and gene expressions would advance our understanding of heterogeneity of lymphedema phenotype. PMID- 27460426 TI - Lack of doxycycline antimalarial prophylaxis impact on Staphylococcus aureus tetracycline resistance. AB - There is concern that susceptibility of Staphylococcus aureus to tetracyclines may decrease due to use of antimalarial prophylaxis (doxycycline). We examined characteristics related to tetracycline resistance, including doxycycline exposure, in S. aureus isolates collected via admission surveillance swabs and inpatient clinical cultures from United States military personnel injured during deployment (June 2009-January 2012). Tetracycline class resistance was determined using antimicrobial susceptibility testing. The first S. aureus isolate from 168 patients were analyzed, of which 38 (23%) isolates were resistant to tetracyclines (class). Tetracycline-resistant isolates had a higher proportion of resistance to clindamycin (P=0.019) compared to susceptible isolates. There was no significant difference in tetracycline resistance between isolates collected from patients with and without antimalarial prophylaxis; however, significantly more isolates had tet(M) resistance genes in the doxycycline exposure group (P=0.031). Despite 55% of the patients receiving doxycycline as antimalarial prophylaxis, there was no association with resistance to tetracyclines. PMID- 27460428 TI - LABAs (again), asthma exacerbations and anaphylaxis. PMID- 27460427 TI - A comparison of flocked swabs and traditional swabs, using multiplex real-time PCR for detection of common gastroenteritis pathogens in Botswana. AB - We compared the performance of flocked and matched traditional rectal swabs collected from 236 children admitted with gastroenteritis in Botswana. All samples were tested using real time multiplex-PCR assays for nine enteric pathogens. There was a 20% higher detection of Shigella from flocked swabs, but most other pathogens had similar detection rates. PMID- 27460430 TI - Grid-texture mechanisms in human vision: Contrast detection of regular sparse micro-patterns requires specialist templates. AB - Previous work has shown that human vision performs spatial integration of luminance contrast energy, where signals are squared and summed (with internal noise) over area at detection threshold. We tested that model here in an experiment using arrays of micro-pattern textures that varied in overall stimulus area and sparseness of their target elements, where the contrast of each element was normalised for sensitivity across the visual field. We found a power-law improvement in performance with stimulus area, and a decrease in sensitivity with sparseness. While the contrast integrator model performed well when target elements constituted 50-100% of the target area (replicating previous results), observers outperformed the model when texture elements were sparser than this. This result required the inclusion of further templates in our model, selective for grids of various regular texture densities. By assuming a MAX operation across these noisy mechanisms the model also accounted for the increase in the slope of the psychometric function that occurred as texture density decreased. Thus, for the first time, mechanisms that are selective for texture density have been revealed at contrast detection threshold. We suggest that these mechanisms have a role to play in the perception of visual textures. PMID- 27460431 TI - Response to the letter by Dr Sebastien Champion regarding the study "Can mortality due to circulatory failure in comatose out-of-hospital cardiac arrest patients be predicted on admission? A study in a retrospective derivation cohort validated in a prospective cohort". PMID- 27460432 TI - Effect of Metformin Use on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma. AB - INTRODUCTION: Observational studies have suggested that metformin use is associated with favorable outcomes in several cancers. For renal cell carcinoma (RCC), data have been limited. Therefore, we investigated the effect of metformin on survival in metastatic RCC (mRCC) using a large clinical trial database. PATIENTS AND METHODS: We conducted a retrospective analysis of patients with mRCC in phase II and III clinical trials. The overall survival (OS) in metformin users was compared with that of users of other antidiabetic agents and those not using antidiabetic agents. Progression-free survival, objective response rate, and adverse events were secondary endpoints. Subgroup analyses were conducted after stratifying by class of therapy, type of vascular endothelial growth factor tyrosine kinase inhibitors, and International Metastatic RCC Database Consortium (IMDC) risk groups. RESULTS: We identified 4736 patients with mRCC, including 486 with diabetes, of whom 218 (4.6%) were taking metformin. Metformin use did not affect OS when compared with users of other antidiabetic agents or those without diabetes. Furthermore, metformin use did not confer an OS advantage when stratified by class of therapy and IMDC risk group. However, in diabetic patients receiving sunitinib (n = 128), metformin use was associated with an improvement in OS compared with users of other antidiabetic agents (29.3 vs. 20.9 months, respectively; hazard ratio, 0.051; 95% confidence interval, 0.009-0.292; P = .0008). CONCLUSION: In the present study, we found a survival benefit for metformin use in mRCC patients treated with sunitinib. Clinical and preclinical studies are warranted to validate our results and guide the use of metformin in the clinic. PMID- 27460433 TI - Weight Loss Following Radical Cystectomy for Bladder Cancer: Characterization and Effect on Survival. AB - INTRODUCTION: The purpose of this study was to evaluate the prevalence of postoperative weight loss (WL) following radical cystectomy (RC) and its association with mortality. Nutritional status is recognized as a potential modifiable risk factor for postoperative complications following RC for bladder cancer. The American Society for Parenteral and Enteral Nutrition and the Academy of Nutrition and Dietetics recognize WL as a diagnostic measure for malnutrition. METHODS: Seventy-one patients underwent RC for bladder cancer between July 2008 and July 2013, in whom peri-operative weights were documented regularly. The primary predictor variable was substantial WL defined as >= 10% WL by postoperative month 1. Survival was estimated using Kaplan-Meier analysis; logistic regression was used for multivariate analyses. RESULTS: Mean postoperative WL at 2 weeks was 9.5 lbs (-5.2%), 14.3 lbs (-7.8%) at 1 month, 16.9 lbs (-9.0%) at 2 months, 12.6 lbs (-6.9%) at 3 months, and 8.9 lbs (-4.6%) at 4 months. Forty-two percent of patients met criteria for substantial WL. At 19 months median follow-up, the overall mortality rate was 31% (22 of 71), which rose to 64% (14 of 22) in patients who experienced substantial WL (P < .05). Substantial WL trended towards significance on multivariate analysis (P = .07). There was a significant decrease in 5-year survival in patients with >= 10% WL (log rank P < .05). CONCLUSIONS: Patients experience WL following RC, which may be indicative of malnutrition. Substantial WL may predict for poor overall survival. Prospective studies are needed to determine whether nutritional optimization can prevent significant WL and improve outcomes. PMID- 27460434 TI - Republic of Senegal Disaster Preparedness and Response Exercise: Lessons Learned and Progress Toward Key Goals. AB - OBJECTIVE: The Republic of Senegal Disaster Preparedness and Response Exercise was held from June 2-6, 2014, in Dakar, Senegal. The goal was to assist in familiarizing roles and responsibilities within 3 existing plans and to update the National Disaster Management Strategic Work Plan. METHODS: There were 60 participants in the exercise, which was driven by a series of evolving disaster scenarios. During the separate Disaster Management Strategic Work Plan review, participants refined a list of projects, including specific tasks to provide a "road map" for completing each project, project timelines, and estimated resource requirements. Project staff administered a survey to conference participants. RESULTS: A total of 86% of respondents had improved knowledge of Senegal disaster plans as a result of the exercise. A total of 89% of respondents had a better understanding of their ministry's role in disaster response, and 92% had a better understanding of the role of the military during a pandemic. Participants also generated ideas for disaster management system improvement in Senegal through a formal "gap analysis." CONCLUSIONS: Participants were in strong agreement that the exercise helped them to better understand the contents of their disaster response plans, build relationships across ministerial lines, and effectively enhance future disaster response efforts. (Disaster Med Public Health Preparedness. 2017;11:183-189). PMID- 27460435 TI - Effects of an intravitreal injection of interleukin-35-expressing plasmid on pro inflammatory and anti-inflammatory cytokines. AB - In order to explore the potential effects of interleukin (IL)-35 on IL-10, transforming growth factor-beta (TGF-beta), interferon-gamma (INF)-gamma, IL-12 and IL-17, a pcDNA3.1-IL-35 plasmid was injected into the vitreous cavity of BALB/c mice. Enzyme-linked immunosorbent assay, western blot analysis and quantitative PCR analysis were performed to confirm the successful expression of IL-35. Slit-lamp biomicroscopy, hematoxylin and eosin staining and immunofluorescence were employed to detect the status of eyes, and western blot analysis was performed to examine the expression of corneal graft rejection related cytokines. There were no abnormalities in the eyes pre-mydriasis or post mydriasis and no injuries to the cornea or retina following the injection of IL 35-expressing plasmid. An immunofluorescence assay detected the positive expression of IL-35 in corneal epithelial cells from IL-35-injected mice and negative staining in the control group. Further study revealed that IL-35 enhanced the expression of IL-10 and TGF-beta which reached their highest levels at 1 and 2 weeks after injection, respectively (p<0.01). Moreover, the expression of INF-gamma and IL-12 was decreased significantly at 2 weeks after the injection of IL-35-expressing plasmid (p<0.05), and the expression of IL-17 was suppressed notably at 4 weeks after the injection (p<0.05). The intravitreal injection of IL 35-expressing plasmid in mice downregulates the expression of pro-inflammatory cytokines and upregulates the expression of anti-inflammatory cytokines. Thus, IL 35 may further be assessed as a potential target for the treatment of corneal graft rejection. PMID- 27460436 TI - HIV DNA Set Point is Rapidly Established in Acute HIV Infection and Dramatically Reduced by Early ART. AB - HIV DNA is a marker of HIV persistence that predicts HIV progression and remission, but its kinetics in early acute HIV infection (AHI) is poorly understood. We longitudinally measured the frequency of peripheral blood mononuclear cells harboring total and integrated HIV DNA in 19 untreated and 71 treated AHI participants, for whom 50 were in the earliest Fiebig I/II (HIV IgM-) stage, that is <=2weeks from infection. Without antiretroviral therapy (ART), HIV DNA peaked at 2weeks after enrollment, reaching a set-point 2weeks later with little change thereafter. There was a marked divergence of HIV DNA values between the untreated and treated groups that occurred within the first 2weeks of ART and increased with time. ART reduced total HIV DNA levels by 20-fold after 2weeks and 316-fold after 3years. Therefore, very early ART offers the opportunity to significantly reduce the frequency of cells harboring HIV DNA. PMID- 27460438 TI - Salvaging patients with extracorporeal life support resuscitation. PMID- 27460437 TI - Rapid identification of intact bacterial resistance plasmids via optical mapping of single DNA molecules. AB - The rapid spread of antibiotic resistance - currently one of the greatest threats to human health according to WHO - is to a large extent enabled by plasmid mediated horizontal transfer of resistance genes. Rapid identification and characterization of plasmids is thus important both for individual clinical outcomes and for epidemiological monitoring of antibiotic resistance. Toward this aim, we have developed an optical DNA mapping procedure where individual intact plasmids are elongated within nanofluidic channels and visualized through fluorescence microscopy, yielding barcodes that reflect the underlying sequence. The assay rapidly identifies plasmids through statistical comparisons with barcodes based on publicly available sequence repositories and also enables detection of structural variations. Since the assay yields holistic sequence information for individual intact plasmids, it is an ideal complement to next generation sequencing efforts which involve reassembly of sequence reads from fragmented DNA molecules. The assay should be applicable in microbiology labs around the world in applications ranging from fundamental plasmid biology to clinical epidemiology and diagnostics. PMID- 27460440 TI - Parents in transition: Experiences of parents of young people with a liver transplant transferring to adult services. AB - Predictors of successful transition from pediatric to adult services include ability to self-manage and engage with healthcare services. Parents have a key role in healthcare management throughout childhood and adolescence including encouraging development of self-management skills in their children. Transition to adult services can be challenging for parents and young people, yet parents' views regarding transition remain largely unexplored. Nine parents of pediatric liver transplant recipients (15.2-25.1 yr) participated in semistructured interviews. Interviews were analyzed using IPA. Analysis revealed three key themes: "emotional impact of transplantation," "protection vs. independence," and "ending relationships and changing roles." Parents expressed the dichotomous nature of the desire to promote independence in their child while still maintaining control and protection, and discussed how changing roles and relationships were difficult to navigate. Parents are important facilitators of young people's development of self-management skills for successful transfer to adult services. Parents should be supported to move from a "managerial" to a "supervisory" role during transition to help young people engage independently with the healthcare team. Findings support the development of interventions for parents to emphasize their role in transition and guide the transfer of self management skills from parent to young person. PMID- 27460439 TI - Cu-Chitosan Nanoparticle Mediated Sustainable Approach To Enhance Seedling Growth in Maize by Mobilizing Reserved Food. AB - Food crop seedlings often have susceptibility to various abiotic and biotic stresses. Therefore, in the present study, we investigated the impact of Cu chitosan nanoparticles (NPs) on physiological and biochemical changes during maize seedling growth. Higher values of percent germination, shoot and root length, root number, seedling length, fresh and dry weight, and seed vigor index were obtained at 0.04-0.12% concentrations of Cu-chitosan NPs as compared to water, CuSO4, and bulk chitosan treatments. Cu-chitosan NPs at the same concentrations induced the activities of alpha-amylase and protease enzymes and also increased the total protein content in germinating seeds. The increased activities of alpha-amylase and protease enzymes corroborated with decreased content of starch and protein, respectively, in the germinating seeds. Cu chitosan NPs at 0.16% and CuSO4 at 0.01% concentrations showed inhibitory effect on seedling growth. The observed results on seedling growth could be explained by the toxicity of excess Cu and growth promotory effect of Cu-chitosan NPs. Physiological and biochemical studies suggest that Cu-chitosan NPs enhance the seedling growth of maize by mobilizing the reserved food, primarily starch, through the higher activity of alpha-amylase. PMID- 27460441 TI - Mutated BRAF and personalised medicine in differentiated thyroid cancer. PMID- 27460443 TI - Vitamin D and the characteristics associated with risk for knee pain among Korean older adults: Findings from a nationally representative survey. AB - AIM: To explore vitamin D and the risk factors associated with knee pain in a representative population of Korean older adults METHODS: Data were analyzed from the Korean National Health and Nutrition Examination Survey (2010-2013). A total of 3874 participants (1728 men, 2146 women) aged 65 years and older who had a measured serum 25-hydroxyvitamin D level were evaluated. Multivariate logistic regression was used to investigate the relationship between serum vitamin D and knee pain severity RESULTS: Sex, age, obesity, education, knee radiographic osteoarthritis, hip pain and back pain were associated with having knee pain. Also, the level of serum 25-hydroxyvitamin D was not significantly associated with knee pain severity. After controlling for confounding factors, the level of serum 25-hydroxyvitamin D was not significantly associated with knee pain, and severity levels of mild, moderate and severe. CONCLUSIONS: The results show that the serum vitamin D did not have a significant effect on knee pain in older adults in Korea. Geriatr Gerontol Int 2017; 17: 1278-1285. PMID- 27460444 TI - The biological role of epithelial-mesenchymal transition in lung cancer (Review). AB - Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells gradually transform into mesenchymal-like cells losing their epithelial functionality and characteristics. EMT is thought to be involved in the pathogenesis of numerous lung diseases ranging from developmental disorders and fibrotic tissue remodeling to lung cancer. Lung cancer is the most lethal form of cancer worldwide, and despite significant therapeutic improvements, the patient survival rate still remains low. Activation of EMT endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs. The present review provides a brief insight into the mechanism and biological assessment methods of EMT in lung cancer and summarizes the recent literature highlighting the controversial experimental data and conclusions. PMID- 27460442 TI - Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. AB - BACKGROUND: About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E) positive papillary thyroid cancer. METHODS: We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF(V600E) mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753. FINDINGS: Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18.8 months (IQR 14.2-26.0) in cohort 1 and 12.0 months (6.7-20.3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38.5%, 95% CI 20.2-59.4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased gamma-glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. INTERPRETATION: Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients. FUNDING: F Hoffmann-La Roche. PMID- 27460445 TI - Dynamics of mtDNA introgression during species range expansion: insights from an experimental longitudinal study. AB - Introgressive hybridization represents one of the long-lasting debated genetic consequences of species range expansion. Mitochondrial DNA has been shown to heavily introgress between interbreeding animal species that meet in new sympatric areas and, often, asymmetric introgression from local to the colonizing populations has been observed. Disentangling among the evolutionary and ecological processes that might shape this pattern remains difficult, because they continuously act across time and space. In this context, long-term studies can be of paramount importance. Here, we investigated the dynamics of mitochondrial introgression between two mosquito species (Aedes mariae and Ae. zammitii ) during a colonization event that started in 1986 after a translocation experiment. By analyzing 1,659 individuals across 25 years, we showed that introgression occurred earlier and at a higher frequency in the introduced than in the local species, showing a pattern of asymmetric introgression. Throughout time, introgression increased slowly in the local species, becoming reciprocal at most sites. The rare opportunity to investigate the pattern of introgression across time during a range expansion along with the characteristics of our study system allowed us to support a role of demographic dynamics in determining the observed introgression pattern. PMID- 27460446 TI - Plasticity in response to feed availability: Does feeding regime influence the relative growth performance of domesticated, wild and hybrid Atlantic salmon Salmo salar parr? AB - Growth of farmed, wild and F1 hybrid Atlantic salmon parr Salmo salar was investigated under three contrasting feeding regimes in order to understand how varying levels of food availability affects relative growth. Treatments consisted of standard hatchery feeding (ad libitum), access to feed for 4 h every day, and access to feed for 24 h on three alternate days weekly. Mortality was low in all treatments, and food availability had no effect on survival of all groups. The offspring of farmed S. salar significantly outgrew the wild S. salar, while hybrids displayed intermediate growth. Furthermore, the relative growth differences between the farmed and wild S. salar did not change across feeding treatments, indicating a similar plasticity in response to feed availability. Although undertaken in a hatchery setting, these results suggest that food availability may not be the sole driver behind the observed reduced growth differences found between farmed and wild fishes under natural conditions. PMID- 27460447 TI - Bioprospecting metagenomics of a microbial community on cotton degradation: Mining for new glycoside hydrolases. AB - Glycoside hydrolases (GHases) of higher performance are immediately needed for efficient degradation of plant biomass into fermentable sugars in industrial processes. The current study represents functional characterization of the enzymatic repertoire involved in crude cotton biomass degradation. Physical contact between cells and substrate is necessary for efficient hydrolysis of cellulose. Cytophagales, which plays a major role in cotton biomass decomposition, was identified as a prevalent community member by 16S rRNA analysis. From the metagenome data, 2058 GHase homologs were identified, of which sixteen were successfully expressed in E. coli. Four enzymes showed activities on p-nitrophenyl-beta-d-xylopyranoside, four showed activities on p-nitrophenyl-beta d-glucopyranoside, two had activities against p-nitrophenyl-beta-d-glucuronide, one showed activity on laminarin, three had activities against p-nitrophenyl-N acetyl-beta-d-glucosaminide, one had activity towards carboxymethyl cellulose, and one towards p-nitrophenyl-beta-d-mannopyranoside. Metagenomics provides a good resource for mining novel biomass degrading enzymes. The sixteen GHases that were cloned may have potential application for biomass conversion and bioproduct production. Functional characterization of the enzymatic repertoire in cotton biomass degradation and analysis of the GHases provide insight into the composition and interaction of enzymes and pathways of plant biomass degradation. PMID- 27460448 TI - Stress urinary incontinence surgery trends in academic female pelvic medicine and reconstructive surgery urology practice in the setting of the food and drug administration public health notifications. AB - AIMS: To investigate the possible effects of the Food and Drug Administration (FDA) Public Health Notifications in 2008 and 2011 regarding surgical trends in transvaginal mesh (TVM) placement for stress urinary incontinence (SUI) and related mesh revision surgery in Female Pelvic Medicine & Reconstructive Surgery (FPMRS) practice in tertiary care academic medical centers in the United States. METHODS: Surgical volume for procedures performed primarily by FPMRS surgeons at eight academic institutions across the US was collected using Current Procedural Terminology (CPT) codes for stress urinary incontinence repair and revision surgeries from 2007 to 2013. SAS statistical software was used to assess for trends in the data. RESULTS: There was a decrease in the use of synthetic mesh sling for the treatment of SUI at academic tertiary care centers over the past 7 years; however, this was not statistically significant. While the total number of surgical interventions for SUI remained stable, there was an increase in the utilization of autologous fascia pubovaginal slings (AFPVS). The number of mesh sling revision surgeries, including urethrolysis and removal or revision of slings, increased almost three-fold at these centers. CONCLUSIONS: These observed trends suggest a possible effect of the FDA Public Health Notifications regarding TVM on surgical practice for SUI in academic centers, even though they did not specifically warn against the use of synthetic mesh for this indication. Indications for surgery, complications, and outcomes were not evaluated during this retrospective study. However, such data may provide alternative insights into reasons for the observed trends. Neurourol. Urodynam. 36:1155-1160, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27460449 TI - Off-ladder alleles due to a single nucleotide polymorphism in the flanking region at DYS481 detected by the PowerPlex((r)) Y23 System. PMID- 27460450 TI - The characterization of anti-T. cruzi activity relationships between ferrocenyl, cyrhetrenyl complexes and ROS release. AB - Trypanosoma cruzi (T. cruzi) is the parasite that causes Chagas disease. Nifurtimox is the most used drug against the T. cruzi, this drug increases intermediaries nitro group, being mainly responsible for the high toxicity component, for this reason it is important to study new organic compounds and thus improve therapeutic strategies against Chagas disease. The electronic effects of ferrocenyl and cyrhetrenyl fragments were investigated by DFT calculation. A close correlation was found between HOMO-LUMO gap of nitro radical NO 2 (-) with the experimental reduction potential found for nitro group and IC50 of two forms the T. cruzi (epimastigote and trypomastigote). The IC50 on human hepatoma cells is higher for both compounds compared to IC50 demonstrated in the two forms the T. cruzi, and additionally show reactive oxygen species release. The information obtained in this paper could generate two new drugs with anti-T. cruzi activity, but additional studies are needed. PMID- 27460451 TI - Clinically important difference of Stroke-Specific Quality of Life Scale for aneurysmal subarachnoid hemorrhage. AB - Health-related quality of life measurements, are commonly used to quantify burden of disease, to evaluate treatment method, and to facilitate benchmarking. The aim of the current study was to determine the Clinically Important Difference (CID) for a Chinese version of Stroke-specific Quality of Life (SS-QOL) in an aneurysmal subarachnoid hemorrhage (SAH) patient cohort. The study recruited SAH patients in a neurosurgical unit in Hong Kong. SAH patients who completed both 3 month and 1-year assessments were included in the analysis. The study received ethical approvals from the joint CUHK-NTEC Clinical Ethics Committee and written informed consent was obtained from all participants or their next of kins. Over a 2-year period, 65 eligible patients were included in the study. Employing the anchor-based approach with global rating of change, the CID estimate of SS-QOL total score was 4.7 (95% confidence interval [CI]: 2.5-5.3), the CID estimate for SSQOL physical subscore was 2.1 (95% CI: 0.3-2.4), and the CID estimate for SS QOL psychosocial subscore change was 2.8 (95% CI: 1.8-3.7). In conclusion, our study defined the CID for SS-QOL applied to SAH patients and should be further validated in another SAH patient population. PMID- 27460452 TI - Risk factors for hyponatremia in aneurysmal subarachnoid hemorrhage. AB - Hyponatremia occurs commonly in patients with aneurysmal subarachnoid hemorrhage (aSAH). Our objective was to determine the time course of, and factors associated with, hyponatremia after aSAH. We performed a retrospective review of 259 patients with ruptured aneurysms at a single institution. Multivariate regression analysis was performed to determine the factors associated with hyponatremia. Increasing age was significantly associated with lower initial sodium (p=0.04) and incidence of delayed hyponatremia (p=0.01) while smoking was associated with longer duration of hyponatremia (p=0.02). Older patients should therefore be monitored closely for hyponatremia and patients who smoke should be treated more aggressively for hyponatremia given the greater frequency and longer duration of hyponatremia in these two groups, respectively. PMID- 27460453 TI - Pitfalls and uncertain prognosis in pathological diagnosis of psammomatous melanotic schwannoma. AB - A 20-year-old woman presenting with a pelvic mass identified as a psammomatous melanotic schwannoma (PMS) with atypical histological features was later found to have family history of cardiac myxomas consistent with Carney's complex. The BRAF V600E mutation was absent in the tumor. PMID- 27460454 TI - Low serum miR-320b expression as a novel indicator of carotid atherosclerosis. AB - We aimed to investigate correlation of carotid plaque with serum microRNA level and provide a potential mechanism for ischemic stroke prevention. Fasting serum was obtained from 177 patients with carotid plaques diagnosed using B ultrasound and 155 healthy subjects for RNA extraction and measurement of glucose, lipid and related biochemical indices. microRNAs level was assayed using microarray, validated using real-time PCR and statistically analyzed for their correlation with relevant clinical information. Statistical analyses showed significant differences between control and plaque groups in age, smoking history, and histories of cerebrovascular diseases, blood pressure, diabetes and coronary diseases. Patients in plaque group had significantly higher LDL-C level but significantly lower miR-320b level than healthy subjects. The P50 (P25-P75) of miR-320b was 2.38 (1.46-3.80) in control group and 1.20 (0.80-2.01) in plaque group (P=0.000), as well as 1.39 (0.83-2.08) in stable plaque group and 0.77 (0.590.99) in vulnerable plaque group (P=0.000). The area under the ROC curve of traditional factors, miR320b with traditional factors, traditional factors with plaque diameter, and traditional factors with IMT for patients with carotid plaques was 0.710, 0.834, 0.826 and 0.808, respectively. This study suggests that miR-320b is a specific serum marker of carotid atherosclerosis and vulnerable plaque, and its combination with traditional factors is the best means for diagnosis of cerebrovascular diseases. The carotid atherosclerosis complicated with vulnerable plaque is a high risk factor for cerebral infarction. B ultrasound examination combined with serum miR-320b expression and traditional indices could be used to predict subjects with high-risk for ischemic stroke. PMID- 27460455 TI - Surgical outcomes in patients with mild symptoms, but severely compressed spinal cord from cervical ossification of the posterior longitudinal ligament. AB - Surgical treatment is indicated in patients with moderate to severe myelopathy from cervical ossification of the posterior longitudinal ligaments (OPLL), but undertaking prophylactic surgery for asymptomatic or mildly symptomatic patients with a severely compressed spinal cord is debatable. Patients with <8mm space available in the spinal canal on CT scan, were divided into groups I (mild symptoms, Japanese Orthopedic Association (JOA) score range 15-16) and II (moderate to severe symptoms, JOA score <14). Medical charts including operative records were reviewed to obtain preoperative, perioperative, and final postoperative follow-up data. Group I included 24 patients (20 men, mean age 52.42years), and Group II included 46 patients (33 men, mean age 54.67years). Compared to Group II, Group I had a shorter preoperative symptom duration (19.21 vs. 38.23months, p=0.046) and a more favorable JOA score at final follow-up (p=0.007). The mean numbers of OPLL-involved segments were similar (Group I 2.96, Group II 3.09; p=0.773) as were the mean numbers of operated segments (Group I 2.71, Group II 3.35; p=0.076). Perioperative blood loss, operation duration, and hospital stay duration were significantly more favorable in Group I than in Group II. The numbers of surgery-related complications in the two groups were similar. Early surgical treatment for a favorable neurologic recovery with a low perioperative risk can be recommended in patients with severely compressed spinal cord from cervical OPLL who present with mild arm numbness. Surgery-related complications, however, should be carefully monitored regardless of symptom severity. PMID- 27460456 TI - Microsurgical treatment of large and giant paraclinoid carotid aneurysms using a revised endovascular suction decompression technique with Invatec Mo.Ma device. AB - Endovascular retrograde suction decompression (RSD) with balloon occlusion of the internal carotid artery is helpful to facilitate clipping large and giant paraclinoid carotid aneurysms. The authors reported a revised endovascular technique without internal carotid access using Mo.Ma device and analyzed its feasibility. In the series, 15 consecutive patients harboring 15 large and giant paraclinoid carotid aneurysms were clipped with assistance of this revised RSD technique. The technical feasibility of the procedure, procedure-related complications, angiographic results, and clinical outcome were evaluated. Technical success was achieved in 14 patients with aneurysm neck clipping and internal carotid artery (ICA) patent. No complication related to this endovascular technique occurred. At follow-up (mean time 15.3months), the modified Rankin Scale score was excellent in 11 patients, good in two patients and poor in one patient. Their preliminary experience indicates that revised retrograde suction decompression technique with Mo.Ma device seems effective and safe in the surgical treatment of large and giant paraclinoid ICA aneurysms. PMID- 27460457 TI - Long-term survival after chronic subdural haematoma. AB - Outcome after chronic subdural haematoma (CSDH) is invariably assumed favourable: however, little data regarding long term survival (LTS) exists. One study reported excess mortality restricted to year 1, but with expected actuarial rates thereafter. We aimed to determine LTS after CSDH in a retrospective analysis relative to actuarial data from age-matched controls. Data was obtained in n=155, (M:F 97:58, 69.3+/-2.3years). Follow-up maxima was 14.19years (mean: 4.02+/ 3.07years, median: 5.2years). Mortality in-hospital, at 6months, 1year, 2years and 5years was n=13 (8.39%), n=22 (14.19%), n=31 (20.35%), n=42 (27.1%) and n=54 (34.84%). LTS was significantly worse than controls (5.29+/-0.59years vs. 17.74+/ 1.8years, hazard ratio [HR]: 3.52, P<0.0001). Death most frequently related to pneumonia/sepsis and ischemic heart disease (IHD). Median modified Rankin score (mRS) in those discharged home (n=94, 60.65%) was 2 [IQR: 1-3]. Discharge mRS in those who died at 6months, 1year, 2years and 5years was 5 [IQR: 3-6], 5 [IQR: 4 6], 3 [IQR: 1-3], 4 [IQR: 2-5]. Discharge mRS was significantly worse with year 1 mortality (P=0.014). LTS related to discharge mRS (HR: 37.006, P<0.001), post operative motor-score (HR: 0.581, P=0.0026), IHD (HR: 5.186, P=0.005), warfarin use (HR: 5.93, P=0.036) and dementia (HR: 5.39, P=0.031). No long term recurrences (LTR) were recorded. Although most were discharged home with mRS=2, LTS was markedly less than previously reported: peers lived 12.4years longer. Although greater in year 1, excess mortality was not restricted to year 1, but continued throughout prolonged follow-up. LTS related to discharge disability and dependence, and co-morbid risk factors for cerebral atrophy. No LTR suggests that, once ultimately closed, the 'subdural space' remains closed. CSDH patients represent a vulnerable group who require continued long-term medical surveillance. PMID- 27460458 TI - Hydrolysis of thorium(iv) at variable temperatures. AB - Hydrolysis of Th(iv) was studied in tetraethylammonium perchlorate (0.10 mol kg( 1)) at variable temperatures (283-358 K) by potentiometry and microcalorimetry. Three hydrolysis reactions, mTh(4+) + nH2O = Thm(OH)n((4m-n)+) + nH(+), in which (n,m) = (2,2), (8,4), and (15,6), were invoked to describe the potentiometric and calorimetric data for solutions with the [hydroxide]/[Th(iv)] ratio <= 2. At higher ratios, the formation of (16,5) cannot be excluded. The hydrolysis constants, *beta2,2, *beta8,4, and *beta15,6, increased by 3, 7, and 11 orders of magnitude, respectively, as the temperature was increased from 283 to 358 K. The enhancement is mainly due to the significant increase of the degree of ionization of water as the temperature rises. All three hydrolysis reactions are endothermic at 298 K, with enthalpies of (118 +/- 4) kJ mol(-1), (236 +/- 7) kJ mol(-1), and (554 +/- 4) kJ mol(-1) for DeltaH2,2, DeltaH8,4, and DeltaH15,6 respectively. The hydrolysis constants at infinite dilution have been obtained with the specific ion interaction approach. The applicability of three approaches for estimating the equilibrium constants at different temperatures, including the constant enthalpy approach, the constant heat capacity approach and the DQUANT equation was evaluated with the data from this work. PMID- 27460459 TI - Coating Pt-Ni Octahedra with Ultrathin Pt Shells to Enhance the Durability without Compromising the Activity toward Oxygen Reduction. AB - We describe a new strategy to enhance the catalytic durability of Pt-Ni octahedral nanocrystals in the oxygen reduction reaction (ORR) by conformally depositing an ultrathin Pt shell on the surface. The Pt-Ni octahedra were synthesized according to a protocol reported previously and then employed directly as seeds for the conformal deposition of ultrathin Pt shells by introducing a Pt precursor dropwise at 200 degrees C. The amount of Pt precursor was adjusted relative to the number of Pt-Ni octahedra involved to obtain Pt Ni@Pt1.5L octahedra of 12 nm in edge length for the systematic evaluation of their chemical stability and catalytic durability compared to Pt-Ni octahedra. Specifically, we compared the elemental compositions of the octahedra before and after treatment with acetic and sulfuric acids. We also examined their electrocatalytic stability toward the ORR through an accelerated durability test by using a rotating disk electrode method. Even after treatment with sulfuric acid for 24 h, the Pt-Ni@Pt1.5L octahedra maintained their original Ni content, whereas 11 % of the Ni was lost from the Pt-Ni octahedra. After 10 000 cycles of ORR, the mass activity of the Pt-Ni octahedra decreased by 75 %, whereas the Pt Ni@Pt1.5L octahedra only showed a 25 % reduction. PMID- 27460460 TI - Influence of increasing body mass index on semen and reproductive hormonal parameters in a multi-institutional cohort of subfertile men. AB - OBJECTIVE: To determine whether obesity affects serum and seminal measures of male reproductive potential among a multi-institutional cohort. DESIGN: Retrospective multi-institutional cohort study. SETTING: Infertility clinics. PATIENT(S): All men referred for male infertility evaluation from 2002 to 2014 (n = 4,440). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Collected reproductive parameters included hormonal (gonadotropins, T, E2, PRL) and semen analysis (ejaculate volume, sperm concentration, motility, normal morphology) data. Body mass index (BMI) was calculated for all patients with comparisons to reproductive parameters using univariate and multiparametric models. RESULT(S): Based on World Health Organization definitions, 30.9% of the cohort was normal weight (BMI 18.5 24.9), 45.1% overweight (25-29.9), and 23.3% obese (>30). Neither FSH nor LH demonstrated significant correlations with BMI on multivariate analysis. Total T (r = -0.27) and the T:E2 ratio (r = -0.29) inversely varied with BMI, whereas E2 (r = 0.13) had a direct correlation. On univariate analyses, BMI had weak but significant negative correlations with ejaculate volume (r = -0.04), sperm concentration (r = -0.08), motility (r = -0.07), and morphology (r = -0.04). All parameters remained significant on multivariate modeling with the exception of sperm motility. Rates of azoospermia and oligospermia were also more prevalent among obese (12.7% and 31.7%, respectively) compared with normal weight men (9.8% and 24.5%). CONCLUSION(S): In one of the largest cohorts of male fertility and obesity, serum hormone and semen parameters demonstrated mild but significant relationships with BMI, possibly contributing to subfertility in this population. PMID- 27460461 TI - "That was the Last Time I Saw my House": The Importance of Place Attachment among Children and Youth in Disaster Contexts. AB - Place attachment is important for children and youth's disaster preparedness, experiences, recovery, and resilience, but most of the literature on place and disasters has focused on adults. Drawing on the community disaster risk reduction, recovery, and resilience literature as well as the literature on normative place attachment, children and youth's place-relevant disaster experiences are examined. Prior to a disaster, place attachments are postulated to enhance children and youth's disaster preparedness contributions and reinforce their pre-disaster resilience. During a disaster, damage of, and displacement from, places of importance can create significant emotional distress among children and youth. Following a disaster, pre-existing as well as new place ties can aid in their recovery and bolster their resilience moving forward. This framework enriches current theories of disaster recovery, resilience, and place attachment, and sets an agenda for future research. PMID- 27460462 TI - Financial competing interests were associated with favorable conclusions and greater author productivity in nonsystematic reviews of neuraminidase inhibitors. AB - OBJECTIVE: To characterize the conclusions and production of nonsystematic reviews about neuraminidase inhibitors relative to financial competing interests held by the authors. STUDY DESIGN AND SETTING: We searched for articles about neuraminidase inhibitors and influenza (January 2005 to April 2015), identifying nonsystematic reviews and grading them according to the favorable/nonfavorable presentation of evidence on safety and efficacy. We recorded financial competing interests disclosed in the reviews and from other articles written by their authors. We measured associations between competing interests, author productivity, and conclusions. RESULTS: Among 213 nonsystematic reviews, 138 (65%) presented favorable conclusions. Financial competing interests were identified for 26% (137/532) of authors; 51% (108/213) of reviews were associated with a financial competing interest. Reviews produced exclusively by authors with financial competing interests (33%; 71/213) were more likely to present favorable conclusions than reviews with no competing interests (risk ratio 1.27; 95% confidence interval 1.03-1.55). Authors with financial competing interests published more articles about neuraminidase inhibitors than their counterparts. CONCLUSION: Half of nonsystematic reviews about neuraminidase inhibitors included an author with a financial competing interest. Reviews produced exclusively by these authors were more likely to present favorable conclusions, and authors with financial competing interests published a greater number of reviews. PMID- 27460463 TI - Group size, vocal grooming and the origins of language. AB - I argue that speech and language evolved through a series of stages individually designed to break through successive glass ceilings on group size. Language was simply the last of these (and hence evolved late in hominin evolution), but its precursors (laughter and singing) each played a crucial role in preparing the way for speech production. PMID- 27460465 TI - Erratum to: 'Acceleration rate of mitral inflow E wave: a novel transmitral doppler index for assessing diastolic function'. PMID- 27460466 TI - [Induced pluripotent stem cells revolutionise research of neurodegenerative diseases]. AB - Research into the causes of neurodegenerative diseases like Parkinson's- and Alzheimer's disease has long been hampered by the lack of access to live disease afflicted neurons for in vitro studies. The introduction of induced pluripotent stem (iPS) cells has made such studies possible. iPS cells can be reprogrammed from somatic patient-derived cells (e.g. skin cells) and differentiated into any cell type of the body. This allows for the production of neurons, which have the genetic background of the patients and show disease-relevant phenotypes. PMID- 27460467 TI - [Sectio and Brugada syndrome]. AB - Brugada syndrome (BS) is an inherited cardiac disease with increased risk of ventricular tachyarrythmias, cardiac arrest and sudden death. BS is diagnosed on various criteria including specific electrocardiographic abnormalities in a structurally normal heart. Many drugs have been reported to induce fatal arrhythmias in patients with BS and in particular sodium channel blockers i.e. local anaesthetics such as bupivacaine. We report the anaesthetic management of two women with BS during caesarean section and provide a general discussion on the use of bupivacain for neuraxial blockade for patients with BS. PMID- 27460468 TI - [Diagnostics and treatment of trigeminal neuralgia]. AB - Trigeminal neuralgia (TN) is characterized by unilateral evoked short-lasting intense pain paroxysms in the face. A concomitant persistent background pain is frequently present. Neurovascular contact causing displacement or atrophy of the trigeminal nerve is important to TN aetiology. TN can also be secondary to a space-occupying lesion or multiple sclerosis. Early high-quality magnetic resonance imaging is mandatory as a part of the work-up. First-choice treatment is medical. Medically refractory patients are referred to neurosurgery. Nationwide in Denmark, there is a need for structured and uniform treatment of TN. PMID- 27460469 TI - [Akutte smerter og kraftnedsaettelse i underekstremitet]. PMID- 27460470 TI - Ultrastructural aspects of pollen ontogeny in an endangered plant species, Pancratium maritimum L. (Amaryllidaceae). AB - Pollen ontogeny in Pancratium maritimum L. was studied from the sporogenous cell to mature pollen grain stages using transmission electron, scanning electron, and light microscopy to determine whether the pollen development in P. maritimum follows the basic scheme in angiosperms or not. In the course of microsporogenesis and microgametogenesis, special attention was given to the considerable ultrastructural changes that are observed in the cytoplasm of microsporocytes, microspores, and mature pollen grains throughout the successive stages of pollen development. Microsporocyte differentiation concerning number and ultrastructure of organelles facilitates the transition of microsporocytes from the sporophytic phase to the gametophytic phase. However, cytoplasmic differentiation of generative and vegetative cells supports their functional distinctness and pollen maturation. Although microsporogenesis and microgametogenesis in P. maritimum generally follow the usual angiosperm pattern, abnormalities such as formation of unreduced gametes were observed. During normal microsporogenesis, meiocytes undergo meiosis and successive cytokinesis, resulting in the formation of isobilateral, decussate, and linear tetrads. Subsequent to the development of free and vacuolated microspores, the first mitotic division occurs and bicellular monosulcate pollen grains are produced. Pollen grains are shed from the anther at binucleate stage. During pollen ontogeny, three periods of vacuolization were observed: in meiocytes, in mononucleate free microspores, and in the generative cell. PMID- 27460471 TI - An oral health optimized diet can reduce gingival and periodontal inflammation in humans - a randomized controlled pilot study. AB - BACKGROUND: The aim of this pilot study was to investigate the effects of four weeks of an oral health optimized diet on periodontal clinical parameters in a randomized controlled trial. METHODS: The experimental group (n = 10) had to change to a diet low in carbohydrates, rich in Omega-3 fatty acids, and rich in vitamins C and D, antioxidants and fiber for four weeks. Participants of the control group (n = 5) did not change their dietary behavior. Plaque index, gingival bleeding, probing depths, and bleeding upon probing were assessed by a dentist with a pressure-sensitive periodontal probe. Measurements were performed after one and two weeks without a dietary change (baseline), followed by a two week transitional period, and finally performed weekly for four weeks. RESULTS: Despite constant plaque values in both groups, all inflammatory parameters decreased in the experimental group to approximately half that of the baseline values (GI: 1.10 +/- 0.51 to 0.54 +/- 0.30; BOP: 53.57 to 24.17 %; PISA: 638 mm(2) to 284 mm(2)). This reduction was significantly different compared to that of the control group. CONCLUSION: A diet low in carbohydrates, rich in Omega-3 fatty acids, rich in vitamins C and D, and rich in fibers can significantly reduce gingival and periodontal inflammation. TRIAL REGISTRATION: German Clinical Trials Register; https://www.germanctr.de (DRKS00006301). Registered on 2015-02 21. PMID- 27460472 TI - Pseudo-HE images derived from CARS/TPEF/SHG multimodal imaging in combination with Raman-spectroscopy as a pathological screening tool. AB - BACKGROUND: Due to the steadily increasing number of cancer patients worldwide the early diagnosis and treatment of cancer is a major field of research. The diagnosis of cancer is mostly performed by an experienced pathologist via the visual inspection of histo-pathological stained tissue sections. To save valuable time, low quality cryosections are frequently analyzed with diagnostic accuracies that are below those of high quality embedded tissue sections. Thus, alternative means have to be found that enable for fast and accurate diagnosis as the basis of following clinical decision making. METHODS: In this contribution we will show that the combination of the three label-free non-linear imaging modalities CARS (coherent anti-Stokes Raman-scattering), TPEF (two-photon excited autofluorescence) and SHG (second harmonic generation) yields information that can be translated into computational hematoxylin and eosin (HE) images by multivariate statistics. Thereby, a computational HE stain is generated resulting in pseudo-HE overview images that allow for identification of suspicious regions. The latter are analyzed further by Raman-spectroscopy retrieving the tissue's molecular fingerprint. RESULTS: The results suggest that the combination of non linear multimodal imaging and Raman-spectroscopy possesses the potential as a precise and fast tool in routine histopathology. CONCLUSIONS: As the key advantage, both optical methods are non-invasive enabling for further pathological investigations of the same tissue section, e.g. a direct comparison with the current pathological gold-standard. PMID- 27460473 TI - The effectiveness and safety of proton beam radiation therapy in children with malignant central nervous system (CNS) tumours: protocol for a systematic review. AB - BACKGROUND: The aim of this study is to use a systematic review framework to identify and synthesise the evidence on the use of proton beam therapy (PBT) for the treatment of children with CNS tumours and where possible compare this to the use of photon radiotherapy (RT). METHODS: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Twelve electronic databases have been searched, and further citation, hand searching and reference checking will be employed. Studies assessing the effects of PBT used either alone or as part of a multimodality treatment regimen in children with CNS tumours will be included. Relevant economic evaluations will also be identified. The outcomes are survival (overall, progression-free, event-free, disease-free), local and regional control rates, short- and long-term adverse events, functional status measures and quality of survival. Two reviewers will independently screen and select studies for inclusion in the review. All interventional study designs will be eligible for inclusion in the review. However, initial scoping searches indicate the evidence base is likely to be limited to case series studies, with no studies of a higher quality being identified. Quality assessment will be undertaken using pre specified criteria and tailored to study design if applicable. Studies will be combined using a narrative synthesis, with differences in results between studies highlighted and discussed in relation to the patient population, intervention and study quality. Where appropriate, if no studies of a comparative design are identified, outcomes will be compared against a range of estimates from the literature for similar populations and treatment regimens from the best available evidence from studies that include the use of advanced conventional photon therapy. DISCUSSION: The evidence base for the use of PBT in children with CNS tumours is likely to be relatively sparse, highly heterogeneous and potentially of a low quality with small sample sizes. Furthermore, selection and publication biases may limit the internal and external validity of studies. However, any tentative results from the review on potential treatment effects can be used to plan better quality research studies that are of a design appropriate for outcome comparison with conventional therapy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015029583. PMID- 27460474 TI - Genetic diversity of Plasmodium falciparum isolates from uncomplicated malaria cases in Ghana over a decade. AB - BACKGROUND: Genotyping malaria parasites to assess their diversity in different geographic settings have become necessary for the selection of antigenic epitopes for vaccine development and for antimalarial drug efficacy or resistance investigations. This study describes the genetic diversity of Plasmodium falciparum isolates from uncomplicated malaria cases over a ten year period (2003 2013) in Ghana using the polymorphic antigenic marker, merozoite surface protein 2 (msp2). METHODS: Archived filter paper blood blots from children aged nine years and below with uncomplicated malaria collected from nine sites in Ghana were typed for the presence of the markers. A total of 880 samples were genotyped for msp2 for the two major allelic families, FC27 and 3D7, using nested polymerase chain reaction (PCR). The allele frequencies and the multiplicity of infection were determined for the nine sites for five time points over a period of ten years, 2003-2004, 2005-2006, 2007-2008, 2010 and 2012-2013 malaria transmission seasons. RESULTS: The number of different alleles detected for the msp2 gene by resolving PCR products on agarose gels was 14. Both of the major allelic families, 3D7 and FC27 were common in all population samples. The highest multiplicity of infection (MOI) was observed in isolates from Begoro (forest zone, rural site): 3.31 for the time point 2007-2008. A significant variation was observed among the sites in the MOIs detected per infection (Fisher's exact test, P < 0.001) for the 2007 isolates and also at each of the three sites with data for three different years, Hohoe, P = 0.03; Navrongo, P < 0.001; Cape Coast, P < 0.001. Overall, there was no significant difference between the MOIs of the three ecological zones over the years (P = 0.37) and between the time points when data from all sites were pooled (P = 0.40). CONCLUSIONS: The diversity and variation between isolates detected using the msp2 gene in Ghanaian isolates were observed to be profound; however, there was homogeneity throughout the three ecological zones studied. This is indicative of gene flow between the parasite populations across the country probably due to human population movements (HPM). PMID- 27460475 TI - Threat appeals in health communication: messages that elicit fear and enhance perceived efficacy positively impact on young male drivers. AB - BACKGROUND: Health communications often present graphic, threat-based representations of the potential consequences of health-risk behaviours. These 'threat appeals' feature prominently in public health campaigns, but their use is controversial, with studies investigating their efficacy reporting inconsistent, and often negative, findings. This research examined the impact of a threat-based road safety advertisement on the driving behaviour of young male drivers. METHODS: To address limitations of previous research, we first identified a road safety advertisement that objectively and subjectively elicited fear using physiological and subjective measures. Study 1 (n = 62) examined the effect of this advertisement, combined with a manipulation designed to increase perceived efficacy, on speed choice. Study 2 (n = 81) investigated whether a state emotion, anger, impacts on the effectiveness of the advertisement in changing four distinct driving behaviours. Both studies examined short-term effects only. RESULTS: Study 1 findings indicated that a high threat message, when combined with high perceived efficacy, can lead to a decrease in speed choice. Study 2 results suggested that increased levels of state anger may counteract the potential value of combining fear-arousing threats and efficacy-building messages. CONCLUSIONS: Findings suggest that threat-based road safety communications that target affective (fear) and cognitive (perceived efficacy) mechanisms can positively affect driving behaviours. State emotions, such as anger, may negatively impact on the effectiveness of the message. Taken together, these findings provide additional support for the use of efficacy-building messages in threat-based communications, but highlight the need for further research into the complex array of affective influences on driving. PMID- 27460476 TI - Muscarinic type 3 receptor autoantibodies are associated with anti-SSA/Ro autoantibodies in Sjogren's syndrome. AB - Anti-muscarinic type 3 receptor autoantibodies (anti-M3R) are reported as potential inhibitors of saliva secretion in Sjogren's syndrome (SjS). However, despite extensive efforts to establish an anti-M3R detection method, there is no clinical test available for these autoantibodies. The purpose of this study was to propose inclusion of anti-M3R testing for SjS diagnosis through investigation of their prevalence using a modified In-Cell Western (ICW) assay. A stable cell line expressing human M3R tagged with GFP (M3R-GFP) was established to screen unadsorbed and adsorbed plasma from primary SjS (n=24), rheumatoid arthritis (RA, n=18), systemic lupus erythematosus (SLE, n=18), and healthy controls (HC, n=23). Anti-M3R abundance was determined by screening for the intensity of human IgG interacting with M3R-GFP cells by ICW assay, as detected by an anti-human IgG IRDye800-conjugated secondary antibody and normalized to GFP. Method comparisons and receiver-operating-characteristic (ROC)-curve analyses were performed to evaluate the diagnostic value of our current approaches. Furthermore, clinical parameters of SjS were also analyzed in association with anti-M3R. Anti-M3R was significantly elevated in SjS plasma in comparison with HC, SLE, or RA (P<0.01). SjS anti-M3R intensities were greater than two-standard deviations above the HC mean for both unadsorbed (16/24, 66.67%) and adsorbed (18/24, 75%) plasma samples. Furthermore, anti-M3R was associated with anti-SjS-related-antigen A/Ro positivity (P=0.0353). Linear associations for anti-M3R intensity indicated positive associations with focus score (R(2)=0.7186, P<0.01) and negative associations with saliva flow rate (R(2)=0.3052, P<0.05). Our study strongly supports our rationale to propose inclusion of anti-M3R for further testing as a non-invasive serological marker for SjS diagnosis. PMID- 27460478 TI - Rapid detection of Clostridium difficile via magnetic bead aggregation in cost effective polyester microdevices with cell phone image analysis. AB - Pathogen detection has traditionally been accomplished by utilizing methods such as cell culture, immunoassays, and nucleic acid amplification tests; however, these methods are not easily implemented in resource-limited settings because special equipment for detection and thermal cycling is often required. In this study, we present a magnetic bead aggregation assay coupled to an inexpensive microfluidic fabrication technique that allows for cell phone detection and analysis of a notable pathogen in less than one hour. Detection is achieved through the use of a custom-built system that allows for fluid flow control via centrifugal force, as well as manipulation of magnetic beads with an adjustable rotating magnetic field. Cell phone image capture and analysis is housed in a 3D printed case with LED backlighting and a lid-mounted Android phone. A custom written application (app.) is employed to interrogate images for the extent of aggregation present following loop-mediated isothermal amplification (LAMP) coupled to product-inhibited bead aggregation (PiBA) for detection of target sequences. Clostridium difficile is a pathogen of increasing interest due to its causative role in intestinal infections following antibiotic treatment, and was therefore chosen as the pathogen of interest in the present study to demonstrate the rapid, cost-effective, and sequence-specific detection capabilities of the microfluidic platform described herein. PMID- 27460477 TI - The Relationship Between Work-Disability Duration and Claimant's Expected Time to Return to Work as Recorded by Workers' Compensation Claims Managers. AB - Purpose This research sought to determine whether there is a relationship between claimants' expected time to return to work (RTW) as recorded by claims managers and compensated days of work disability. Methods We utilized workers' compensation data from a large, United States-based insurance company. RTW expectations were collected within 30 days of the claim being reported and these were compared with the termination of total temporary indemnity payments. Bivariate and hierarchical regression analyses were conducted. Results A significant relationship between expected time to RTW and compensated disability duration was observed. The unadjusted correlation between work-disability duration and expected time to RTW was .25 (p < .001). Our multivariate model explained 29.8 % of the variance, with expected time to RTW explaining an additional 9.5 % of the variance in work-disability duration beyond what was explained by the covariates. Conclusion The current study's findings support the hypothesis that claimant RTW estimates as recorded by claims managers are significantly related to compensated-disability duration, and the relationship is maintained after controlling for variance that can be explained by other variables available within workers' compensation databases. PMID- 27460479 TI - ALK-negative anaplastic large cell lymphoma with CNS involvement needs more than just brentuximab vedotin. PMID- 27460480 TI - Molecular diagnostic testing for primary biliary cholangitis. AB - INTRODUCTION: A reliable liver autoimmune serology for the diagnosis of primary biliary cholangitis (PBC) is of particular importance. Recognition of patients at early stages and prompt treatment initiation may alter the outcome, slow progression, delays liver failure, and improves survival. AREAS COVERED: In this review, we summarize and discuss the published data obtained from literature searches from PubMed and The National Library of Medicine (USA) and our own experience on the current and potential molecular based approaches to the diagnosis of PBC. Expert commentary: Standardization of liver diagnostic serology and clinical governance are two major points as antimitochondrial antibodies are the diagnostic hallmark of the disease and PBC-specific antinuclear antibodies could assist in the diagnosis and estimation of prognosis. New biomarkers such as novel autoantibodies, genetic polymorphisms, metabolomic profiling, micro-RNA and epigenetics may assist to the understanding, diagnosis and management of the disease. PMID- 27460481 TI - Erratum to: 'A modified theoretical framework to assess implementation fidelity of adaptive public health interventions'. PMID- 27460483 TI - [GnRH agonist in PCa patients with clinically significant pre-existing cardiovascular disease]. PMID- 27460482 TI - Reasons for drinking as predictors of alcohol involvement one year later among HIV-infected individuals with and without hepatitis C. AB - INTRODUCTION: Heavy drinking can be harmful for individuals with HIV, particularly those coinfected with hepatitis C virus (HCV). HIV patients' reasons for drinking predict short-term alcohol involvement, but whether they predict longer-term involvement is unknown. Also, it remains unknown whether these motives are differentially predictive for HIV monoinfected and HIV/HCV coinfected patients. METHOD: HIV-infected heavy drinkers (n = 254) participated in a randomized trial of brief alcohol interventions, 236 (92.9%) of whom reported on baseline motives and alcohol involvement 12 months later (77.1% male, 94.9% minority, 30.6% with HCV). RESULTS: Greater endorsement of baseline drinking to cope with negative affect predicted greater alcohol dependence symptoms at 12 months (incident rate ratio [IRR] = 1.80, p < 0.05), while greater endorsement of baseline drinking due to social pressure predicted fewer drinks consumed at 12 months (IRR = 0.67, p < 0.05). Coping and social reasons were both predictive for HIV monoinfected patients, whereas only coping reasons were predictive for HIV/HCV coinfected patients. DISCUSSION: Drinking for coping and social reasons predict alcohol involvement 12 months later; however, social reasons may only be important for HIV monoinfected patients. Understanding patient reasons for drinking may help predict patient risk up to a year later. KEY MESSAGES Among HIV patients, drinking motives predict alcohol involvement 12 months later. For HIV monoinfected patients, drinking to cope and drinking for social reasons predict 12-month alcohol involvement. For HIV/Hepatitis C coinfected patients, coping (but not social) motives predict 12-month alcohol involvement. PMID- 27460484 TI - A multidimensional approach to impulsivity in Parkinson's disease: measurement and structural invariance of the UPPS Impulsive Behaviour Scale. AB - BACKGROUND: Poor impulse control is a common feature in patients with Parkinson's disease (PD). However, before testing whether patients with PD and controls differ in impulsivity, one must assess whether impulsivity measures are invariant across groups. Consequently, we examined (a) the measurement and structural invariance of a scale assessing changes in four dimensions of impulsivity (urgency, lack of premeditation, lack of perseverance and sensation seeking) among patients with PD and controls; and (b) whether the four impulsivity traits relate differentially to risky decisions by patients. METHOD: Close relatives of 78 patients with idiopathic PD and 96 control participants were given the short Urgency-Premeditation-Perseverance-Sensation seeking Impulsive Behaviour Scale (UPPS), which assesses changes in four dimensions of impulsivity. Participants also completed the Game of Dice Task (GDT), a laboratory measure of risk taking. RESULTS: Multigroup confirmatory factor analyses supported measurement invariance across groups, whereas structural invariance was not confirmed. Patients with PD showed greater variability and higher impulsivity than controls. Furthermore, patients with impulse control disorders (ICDs) demonstrated even greater levels of sensation seeking than patients without ICDs. Finally, lower premeditation and greater perseverance were significantly associated with greater risk taking in patients with PD, and higher agonist dopaminergic doses with less risky choices on the GDT. CONCLUSIONS: The questionnaire appears to function comparably across patients and controls. Thus, group comparisons on the questionnaire can be considered valid. Mean differences between groups on the dimensions of impulsivity may reflect executive impairments and/or abnormal reward processing in patients with PD, which may lead to risky behaviours. PMID- 27460485 TI - Relapsed childhood acute myeloid leukemia patient with inversion of chromosome 16 harboring a low FLT3 internal tandem duplication allelic burden and KIT mutations. AB - Inversion of chromosome 16 [inv(16)] has a good prognosis in acute myeloid leukemia (AML), but additional genetic aberrations influence the outcome. We herein describe the case of a 15-year-old Japanese boy with inv(16) harboring a low-allelic burden internal tandem duplication of FLT3 (FLT3-ITD) and KIT mutations. Conventional chemotherapy eradicated a clone with a low-allelic burden FLT3-ITD mutation, although another clone with a KIT mutation occurred 17 months later. Further investigation is necessary to identify AML with inv(16) conferring poor prognosis, to facilitate appropriate treatment with additional drugs, such as dasatinib or gemtuzumab ozogamicin. PMID- 27460486 TI - Total Syntheses of Juglorescein and Juglocombins A and B. AB - Total syntheses of juglorescein and juglocombins A and B are reported. The highly oxygenated 6/6/5/6/6-fused pentacyclic ring system of these natural products was constructed through a bioinspired dimerization of 1,4-naphthoquinone. Notably, five new stereogenic centers were constructed in a single step by the dimerization reaction. The epoxide intermediate obtained from the dimerization was successfully converted into juglocombins A and B through photoinduced reduction of the epoxide, dehydration, and conversion of the resultant quinone into a hydroquinone derivative. The same epoxide intermediate was also converted into a dicarboxylic acid, which was transformed into juglorescein through intramolecular lactonization, hydrolysis of the resulting lactone, and removal of the protecting groups. Furthermore, the relative and absolute configurations of juglorescein and juglocombins A and B were determined. PMID- 27460487 TI - Neville Smith. PMID- 27460488 TI - Electrocardiographic Tremor as an Important Diagnostic Aid in Spinal Muscular Atrophy. PMID- 27460489 TI - Steven Johnson Syndrome: Drug or Bug? PMID- 27460490 TI - Inhibitory effect of the extract of Phellodendron amurense ruprecht root on collagen-induced arthritis in mice. AB - OBJECTIVE: To investigate whether the dried root of Phellodendron amurense Ruprecht (Phellodendri cortex; PC) extract improves arthritic symptoms through anti-inflammatory and immune-modulatory effects in collagen-induced arthritis in mice. METHODS: Rheumatoid arthritis (RA) was induced in male DBA/1 mice by immunization with type II collagen (ColII). CIA mice were divided into 5 groups (n=10 per a group) with normal, CIA control, PC extract (50 mg/kg and 100 mg/kg) treated, and meloxicam (50 mg/kg)-treated as the reference drug. The PC extract or meloxicam were administered orally in CIA mice once a day for 14 days after arthritis induction. Arthritic score, levels of anti-ColII IgG2a antibody, prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-alpha, and interleukin (IL) 17 in the sera of CIA mice were measured. Histopathological changes in the ankle joints of CIA mice were also analyzed by staining with hematoxylin and eosin (H and E), safranin-O and immunohistochemistry using anti-TNF-alpha and anti-IL-17 antibodies. RESULTS: The arthritic score was increased in CIA mice in a time dependent manner, as were the serum levels of anti-ColII IgG2a antibody, PGE2, TNF-alpha, and IL-17. However, the oral administration of PC extract at 50 and 100 mg/kg in CIA mice significantly decreased the arthritic scores, and the serum levels of anti-ColII IgG2a, PGE2, TNF-alpha, and IL-17 compared with those in the CIA group (P<0.05 or P<0.01). Furthermore, histopathological improvement of the joint architecture in CIA mice was observed after administration of PC extract. PC extract also significantly inhibited the expression of TNF-alpha and IL-17 in the joints of CIA mice by suppressing the expression of their mRNA and proteins. CONCLUSION: PC extract may improve the pathological progression of RA through the inhibition of joint destruction by synovial inflammation and immune-stimulation, therefore, it would be a potential anti-arthritic agent in RA. PMID- 27460491 TI - Influence of Musa sapientum L. on pharmacokinetic of metformin in diabetic gastroparesis. AB - OBJECTIVE: To investigate the effect of Musa sapientum L. (MS) bark juice in diabetic gastroparesis and its effect on pharmacokinetic of metformin (MET). METHODS: Diabetes was induced in rats by administering alloxan (120 mg/kg) saline solution and maintained for 8 week. All the 18 Sprague-Dawley rats were divided into three groups (n =6 in each group): normal control, diabetic control and MS bark juice. Assessment of diabetes was done by glucose oxidase-peroxidase method on the 3rd day of alloxan administration. The effects of MS bark juice (100 mL/kg) on gastric emptying time, intestinal transit time, contractility of fundus and pylorus as well as gastric acid secretion in chronic diabetic rats were observed after 8 weeks of alloxan administration. The effect of MS bark juice on the pharmacokinetic of orally administered single dose of MET (350 mg/kg) was evaluated on the 57th day of protocol. Any drugs that may reduce the blood glucose level or influence the fibrinolytic system were not used in this study. RESULTS: The MS bark juice significantly reduced the blood glucose level in the diabetic rats (P<0.01). There was significant decrease in the pylorus motility and increase in the gastric emptying time, intestinal transit time, contractility of fundus, gastric acid secretion in the MS bark juice treated group (P<0.01). There was significant decrease in the time at which drug at a maximum concentration, half life of drug and increase in the maximum concentration of drug in the plasma of MET in MS bark juice treated group as compared to diabetic control group (P<0.01). CONCLUSION: MS bark juice effectively manages diabetic gastroparesis and thereby improves the bioavailabilty of MET when administered with MS bark juice. PMID- 27460492 TI - Acupuncture points for treating Parkinson's disease based on animal studies. AB - Parkinson's disease (PD) is a well-known neurodegenerative disease caused by dopaminergic cell death in the nigrostriatal pathway. Recent studies have shown that acupuncture can be a potential therapy for the treatment of PD, but it is not clear which acupuncture points (acupoints) play major roles in reliving symptoms of PD. Yanglingquan (GB 34), Zusanli (ST 36), Fengfu (GV 16), Taichong (LR 3), Baihui (GV 20) and Dazhui (GV 14) acupoints have frequently been to investigate the effectiveness and action mechanism of acupuncture for treating PD, but it is not clear why they were selected. This review summarizes the current understanding of the acupoints for PD treatment based on Oriental medicine theories and on the accumulated findings from previous animal studies. The results of this study will be useful to development of a strategy for future research in this field. PMID- 27460493 TI - Recent highlights of Chinese herbs in treatment of allergic disease: Acting via mitogen-activated protein kinase signal pathway. AB - The histamine receptor antagonists in the treatment of allergic disease have limitations. The treatments of Chinese herbs have some curative effects on allergic skin lesions. Present research indicates that the mitogen-activated protein kinase (MAPK) signaling pathway might be equally important in allergic reactions. It was found that the inhibition of MAPK signaling pathways might relieve allergy symptoms, and some herbs can inhibit the MAPK pathway, which yields anti-allergy effects. Chinese medicines (CMs) have immense potential in the development of treatments for allergic disease. PMID- 27460494 TI - Patient-Reported Outcome Measures and Integration Into Electronic Health Records. PMID- 27460495 TI - What Is the Real Rate of Surgical Site Infection? AB - PURPOSE: Surgical site infections (SSIs) are associated with patient morbidity and increased health care costs. Although several national organizations including the University HealthSystem Consortium (UHC), the National Surgical Quality Improvement Program (NSQIP), and the National Healthcare Safety Network (NHSN) monitor SSI, there is no standard reporting methodology. METHODS: We queried the UHC, NSQIP, and NHSN databases from July 2012 to June 2014 for SSI after gynecologic surgery at our institution. Each organization uses different definitions and inclusion and exclusion criteria for SSI. The rate of SSI was also obtained from chart review from April 1 to June 30, 2014. SSI was classified as superficial, deep, or organ space infection. The rates reported by the agencies were compared with the rates obtained by chart review using Fisher's exact test. RESULTS: Overall SSI rates for the databases were as follows: UHC, 1.5%; NSQIP, 8.8%; and NHSN, 2.8% (P < .001). The individual databases had wide variation in the rate of deep infection (UHC, 0.7%; NSQIP, 4.7%; NHSN, 1.3%; P < .001) and organ space infection (UHC, 0.4%; NSQIP, 4.4%; NHSN, 1.4%; P < .001). In agreement with the variation in reporting methodology, only 19 cases (24.4%) were included in more than one database and only one case was included in all three databases (1.3%). CONCLUSION: There is discordance among national reporting agencies tracking SSI. Adopting standardized metrics across agencies could improve consistency and accuracy in assessing SSI rates. PMID- 27460496 TI - Trial Design and Efficacy Thresholds for Granting Breakthrough Therapy Designation in Oncology. AB - Breakthrough therapy designation (BTD) is a new approach created by the US Congress and the US Food and Drug Administration (FDA) as part of the FDA Innovation and Safety Act of 2012 to expedite the drug development process for serious illness, including cancer. By law, to qualify for BTD, a new molecular entity must demonstrate substantial clinical improvement over existing therapies. Although the administrative requirements for granting BTD have been made available by the FDA, the actual trial designs, end points, and quantitative therapeutic thresholds involved in the granting process have not been made public. This literature review evaluates nine oncology new molecular entities granted BTD involved in 10 accelerated approvals and summarizes the key factors in clinical trial design leading to successful BTD applications. This information can be used by oncology research teams to set goals for BTD when developing clinical trial designs and thresholds in expedited drug development programs. PMID- 27460498 TI - Population genetics from 1966 to 2016. AB - We describe the astonishing changes and progress that have occurred in the field of population genetics over the past 50 years, slightly longer than the time since the first Population Genetics Group (PGG) meeting in January 1968. We review the major questions and controversies that have preoccupied population geneticists during this time (and were often hotly debated at PGG meetings). We show how theoretical and empirical work has combined to generate a highly productive interaction involving successive developments in the ability to characterise variability at the molecular level, to apply mathematical models to the interpretation of the data and to use the results to answer biologically important questions, even in nonmodel organisms. We also describe the changes from a field that was largely dominated by UK and North American biologists to a much more international one (with the PGG meetings having made important contributions to the increased number of population geneticists in several European countries). Although we concentrate on the earlier history of the field, because developments in recent years are more familiar to most contemporary researchers, we end with a brief outline of topics in which new understanding is still actively developing. PMID- 27460499 TI - Origin of a cryptic lineage in a threatened reptile through isolation and historical hybridization. AB - Identifying phylogenetically distinct lineages and understanding the evolutionary processes by which they have arisen are important goals of phylogeography. This information can also help define conservation units in endangered species. Such analyses are being transformed by the availability of genomic-scale data sets and novel analytical approaches for statistically comparing different historical scenarios as causes of phylogeographic patterns. Here, we use genomic-scale restriction-site-associated DNA sequencing (RADseq) data to test for distinct lineages in the endangered Eastern Massasauga Rattlesnake (Sistrurus catenatus). We then use coalescent-based modeling techniques to identify the evolutionary mechanisms responsible for the origin of the lineages in this species. We find equivocal evidence for distinct phylogenetic lineages within S. catenatus east of the Mississippi River, but strong support for a previously unrecognized lineage on the western edge of the range of this snake, represented by populations from Iowa, USA. Snakes from these populations show patterns of genetic admixture with a nearby non-threatened sister species (Sistrurus tergeminus). Tests of historical demographic models support the hypothesis that the genetic distinctiveness of Iowa snakes is due to a combination of isolation and historical introgression between S. catenatus and S. tergeminus. Our work provides an example of how model-based analysis of genomic-scale data can help identify conservation units in rare species. PMID- 27460501 TI - Lower stress-reactive cortisol in female veterans associated with military status but not PTSD. AB - Female veterans are a growing yet understudied population. Currently, 14.6% of all troops deployed to Afghanistan and Iraq are female. Military service is associated with an increased risk for trauma exposure and subsequent development of posttraumatic stress disorder (PTSD). Dysregulation of the hypothalamic pituitary-adrenal axis is frequently associated with PTSD. Few studies have examined females diagnosed with PTSD and only one study, to our knowledge, has examined HPA-axis dysregulation in female veterans. This study examined salivary cortisol in 52 female veterans and civilians both with and without PTSD. We collected saliva samples at bedtime and awakening, as well as in response to the Trier social stress test (TSST). We found that female veterans had blunted cortisol concentrations at all time points during the TSST compared to female civilians, regardless of PTSD status. Even though all groups showed the expected diurnal decline in cortisol, the difference between awakening and bedtime samples were significant only in civilians without PTSD. The results of our study suggest that stressors specific to the military may lead to lower than normal cortisol, which may not be associated with the expressions of PTSD. PMID- 27460500 TI - CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. AB - Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL. PMID- 27460502 TI - Mobile Apps for Weight Management: A Scoping Review. AB - BACKGROUND: Obesity remains a major public health concern. Mobile apps for weight loss/management are found to be effective for improving health outcomes in adults and adolescents, and are pursued as a cost-effective and scalable intervention for combating overweight and obesity. In recent years, the commercial market for 'weight loss apps' has expanded at rapid pace, yet little is known regarding the evidence-based quality of these tools for weight control. OBJECTIVE: To characterize the inclusion of evidence-based strategies, health care expert involvement, and scientific evaluation of commercial mobile apps for weight loss/management. METHODS: An electronic search was conducted between July 2014 and July 2015 of the official app stores for four major mobile operating systems. Three raters independently identified apps with a stated goal of weight loss/management, as well as weight loss/management apps targeted to pediatric users. All discrepancies regarding selection were resolved through discussion with a fourth rater. Metadata from all included apps were abstracted into a standard assessment criteria form and the evidence-based strategies, health care expert involvement, and scientific evaluation of included apps was assessed. Evidence-based strategies included: self-monitoring, goal-setting, physical activity support, healthy eating support, weight and/or health assessment, personalized feedback, motivational strategies, and social support. RESULTS: A total of 393 apps were included in this review. Self-monitoring was most common (139/393, 35.3%), followed by physical activity support (108/393, 27.5%), weight assessment (100/393, 25.4%), healthy eating support (91/393, 23.2%), goal-setting (84/393, 21.4%), motivational strategies (28/393, 7.1%), social support (21/393, 5.3%), and personalized feedback (7/393, 1.8%). Of apps, 0.8% (3/393) underwent scientific evaluation and 0.3% (1/393) reported health care expert involvement. No apps were comprehensive in the assessment criteria, with the majority of apps meeting less than two criteria. CONCLUSIONS: Commercial mobile apps for weight loss/management lack important evidence-based features, do not involve health care experts in their development process, and have not undergone rigorous scientific testing. This calls into question the validity of apps' claims regarding their effectiveness and safety, at a time when the availability and growth in adoption of these tools is rapidly increasing. Collaborative efforts between developers, researchers, clinicians, and patients are needed to develop and test high-quality, evidence-based mobile apps for weight loss/management before they are widely disseminated in commercial markets. PMID- 27460503 TI - Characterizing Active Pharmaceutical Ingredient Binding to Human Serum Albumin by Spin-Labeling and EPR Spectroscopy. AB - Drug binding to human serum albumin (HSA) has been characterized by a spin labeling and continuous-wave (CW) EPR spectroscopic approach. Specifically, the contribution of functional groups (FGs) in a compound on its albumin-binding capabilities is quantitatively described. Molecules from different drug classes are labeled with EPR-active nitroxide radicals (spin-labeled pharmaceuticals (SLPs)) and in a screening approach CW-EPR spectroscopy is used to investigate HSA binding under physiological conditions and at varying ratios of SLP to protein. Spectral simulations of the CW-EPR spectra allow extraction of association constants (KA ) and the maximum number (n) of binding sites per protein. By comparison of data from 23 SLPs, the mechanisms of drug-protein association and the impact of chemical modifications at individual positions on drug uptake can be rationalized. Furthermore, new drug modifications with predictable protein binding tendency may be envisaged. PMID- 27460504 TI - Rapid real-time PCR and high resolution melt analysis in a self-filling thermoplastic chip. AB - A microfluidic platform designed for point-of-care PCR-based nucleic acid diagnostics is described. Compared to established microfluidic PCR technologies, the system is unique in its ability to achieve exceptionally rapid PCR amplification in a low cost thermoplastic format, together with high temperature accuracy enabling effective validation of reaction product by high resolution melt analysis performed in the same chamber as PCR. In addition, the system employs capillary pumping for automated loading of sample into the reaction chamber, combined with an integrated hydrophilic valve for precise self-metering of sample volumes into the device. Using the microfluidic system to target a mutation in the G6PC gene, efficient PCR from human genomic DNA template is achieved with cycle times as low as 14 s, full amplification in 8.5 min, and final melt analysis accurately identifying the desired amplicon. PMID- 27460505 TI - Interaction of Cr(3+) with valence and conduction bands in the long persistent phosphor ZnGa2O4:Cr(3+), studied by ENDOR spectroscopy. AB - Cr(3+)-doped zinc gallate ZnGa2O4 is a red-near infrared (IR) long persistent phosphor that can be excited by orange-red light, in the transparency window of living tissues. With this property, persistent luminescence nanoparticles were recently used for in vivo optical imaging of tumors in mice. In order to understand the origin of the excitability of persistent luminescence by visible light in this material, a Q-band ENDOR investigation of (71/69)Ga and (53)Cr nuclei was performed in ZnGa2O4:Cr(3+) to get information on the interaction of Cr(3+) with valence and conduction bands. The positive electron spin density at Ga nuclei revealed a dominant interaction of the (4)A2 ground state of Cr(3+) with the valence band, and a weaker interaction with the conduction band. The latter may occur only in the excited (2)E and (4)T2 states of Cr(3+). It is proposed that when these two interactions are present, pairs of electrons and holes can be generated from excited Cr(3+) in distorted sites undergoing local electric field produced by neighboring defects with opposite charges. PMID- 27460506 TI - An extract from pork bones containing osteocalcin improves glucose metabolism in mice by oral administration. AB - Osteocalcin (OC) is a bone-derived hormone that regulates energy metabolism. OC exists in two forms, carboxylated (GlaOC) and uncaboxylated (GluOC), but only the latter appears to have an endocrine function. In this study, we prepared an extract containing both Gla- and GluOC from boiled pork bone using 0.2 M carbonate buffer at pH 9.5, and tested whether the extract had beneficial effects on improving metabolic parameters in obese mice. The extract equivalent of 1.2 MUg of GluOC/mouse was orally administrated to C57BL/6 female mice fed a high fat, high-sucrose diet. Daily oral administration of the extract for four weeks decreased blood glucose levels and promoted glucose tolerance as well as insulin sensitivity. Our study shows for the first time that boiled pork bones are a source material for osteocalcin in the large-scale production of supplements designed to improve glucose metabolism. PMID- 27460508 TI - Physics of Majorana modes in interacting helical liquid. AB - As an attempt to understand and search for the existence of Majorana zero mode, we study the topological quantum phase transition and also the nature of this transition in helical liquid system, which appears in different physical systems. We present Majorana-Ising transition along with the phase boundary in the presence of interaction. We show the appearance of Majorana mode under the renormalization of the parameters of the system and also the topological protection of it. We present the length scale dependent condition for the appearance of Majorana edge state and also the absence of edge state for a certain regime of parameter space. PMID- 27460507 TI - The genetic architecture of resistance to virus infection in Drosophila. AB - Variation in susceptibility to infection has a substantial genetic component in natural populations, and it has been argued that selection by pathogens may result in it having a simpler genetic architecture than many other quantitative traits. This is important as models of host-pathogen co-evolution typically assume resistance is controlled by a small number of genes. Using the Drosophila melanogaster multiparent advanced intercross, we investigated the genetic architecture of resistance to two naturally occurring viruses, the sigma virus and DCV (Drosophila C virus). We found extensive genetic variation in resistance to both viruses. For DCV resistance, this variation is largely caused by two major-effect loci. Sigma virus resistance involves more genes - we mapped five loci, and together these explained less than half the genetic variance. Nonetheless, several of these had a large effect on resistance. Models of co evolution typically assume strong epistatic interactions between polymorphisms controlling resistance, but we were only able to detect one locus that altered the effect of the main effect loci we had mapped. Most of the loci we mapped were probably at an intermediate frequency in natural populations. Overall, our results are consistent with major-effect genes commonly affecting susceptibility to infectious diseases, with DCV resistance being a near-Mendelian trait. PMID- 27460509 TI - J'accuse! depression as a likely culprit in cases of AD. AB - Clinicians have long appreciated the links between depression, cognitive impairment, and development of Alzheimer's disease (AD) and other dementias. More recently, investigators in the fields of epidemiology, genetics, neuroimaging, and neuropathology have sought to quantify the risk and to understand the underlying neurobiology of the relationship between depression and AD. PMID- 27460510 TI - Discharge instruction delivery/modality and antibiotic retrieval: the author replies. PMID- 27460512 TI - Spatial temperature gradients guide axonal outgrowth. AB - Formation of neural networks during development and regeneration after injury depends on accuracy of axonal pathfinding, which is primarily believed to be influenced by chemical cues. Recently, there is growing evidence that physical cues can play crucial role in axonal guidance. However, detailed mechanism involved in such guidance cues is lacking. By using weakly-focused near-infrared continuous wave (CW) laser microbeam in the path of an advancing axon, we discovered that the beam acts as a repulsive guidance cue. Here, we report that this highly-effective at-a-distance guidance is the result of a temperature field produced by the near-infrared laser light absorption. Since light absorption by extracellular medium increases when the laser wavelength was red shifted, the threshold laser power for reliable guidance was significantly lower in the near infrared as compared to the visible spectrum. The spatial temperature gradient caused by the near-infrared laser beam at-a-distance was found to activate temperature-sensitive membrane receptors, resulting in an influx of calcium. The repulsive guidance effect was significantly reduced when extracellular calcium was depleted or in the presence of TRPV1-antagonist. Further, direct heating using micro-heater confirmed that the axonal guidance is caused by shallow temperature-gradient, eliminating the role of any non-photothermal effects. PMID- 27460513 TI - Elevated E2F7 expression predicts poor prognosis in human patients with gliomas. AB - E2F transcription factors have been studied extensively in a broad range of organisms as major regulators of cell cycle, apoptosis, and differentiation. The E2F family includes the atypical member E2F7, which has been rarely studied in gliomas. The aim of this study is to determine the expression status of E2F7 in gliomas, its relationship to clinicopathological features, and patients' outcome. The mRNA levels of E2F7 in the human brain and different grades of gliomas were analysed using datasets from the publically available Oncomine database. One of the most significant co-expression factors, CDK1, together with E2F7, was further validated by immunohistochemistry in 90 different grades of gliomas. Furthermore, univariate and multivariate analyses were performed to identify prognostic variables relative to patient and tumour characteristics and treatment modalities. E2F7 mRNA expression was found to be elevated in gliomas by Oncomine database analysis. Immunohistochemistry showed an increase in E2F7 labelling index in high- versus low-grade gliomas (62.1+/-11.8% vs. 18.9+/-10.2%, p<0.0001). There was a positive correlation between E2F7 and CDK1 immunoreactivity (Spearman r=0.446, p=0.037). Clinicopathological evaluation suggested that E2F7 expression was associated with tumour grade (p<0.0001) and recurrence (p=0.025). In Cox multivariate analysis, pathological classification and recurrence were independent prognostic factors of gliomas, and E2F7 was significantly related to progression-free survival (p=0.011), but not overall survival (p=0.062). Our findings suggested that E2F7 might act as an independent prognostic factor of gliomas and might constitute a potential therapeutic target for this disease. PMID- 27460511 TI - Recurrent violent injury: magnitude, risk factors, and opportunities for intervention from a statewide analysis. AB - INTRODUCTION: Although preventing recurrent violent injury is an important component of a public health approach to interpersonal violence and a common focus of violence intervention programs, the true incidence of recurrent violent injury is unknown. Prior studies have reported recurrence rates from 0.8% to 44%, and risk factors for recurrence are not well established. METHODS: We used a statewide, all-payer database to perform a retrospective cohort study of emergency department visits for injury due to interpersonal violence in Florida, following up patients injured in 2010 for recurrence through 2012. We assessed risk factors for recurrence with multivariable logistic regression and estimated time to recurrence with the Kaplan-Meier method. We tabulated hospital charges and costs for index and recurrent visits. RESULTS: Of 53 908 patients presenting for violent injury in 2010, 11.1% had a recurrent violent injury during the study period. Trauma centers treated 31.8%, including 55.9% of severe injuries. Among recurrers, 58.9% went to a different hospital for their second injury. Low income, homelessness, Medicaid or uninsurance, and black race were associated with increased odds of recurrence. Patients with visits for mental and behavioral health and unintentional injury also had increased odds of recurrence. Index injuries accounted for $105 million in costs, and recurrent injuries accounted for another $25.3 million. CONCLUSIONS: Recurrent violent injury is a common and costly phenomenon, and effective violence prevention programs are needed. Prevention must include the nontrauma centers where many patients seek care. PMID- 27460514 TI - Two cases of cystic enlargement of vestibular schwannoma as a late complication following gamma knife surgery. AB - Cyst formation is the most common long-term complication after gamma knife surgery (GKS) for cerebral arteriovenous malformations; however, this rarely occurs after GKS for vestibular schwannoma (VS). We describe two patients that developed aggressive, symptomatic large cysts at more than 4 and 12years after GKS for VS, although the tumor control for these patients had been acceptable at 3 and 11years, respectively. During the surgery, a reddish lesion, which was distinct from the surrounding tumor, was observed. The microscopic examination of the reddish lesion revealed dilated capillary vessels and hemorrhage, which was compatible with late radiation changes; these were usually seen in arteriovenous malformations following radiosurgery. The present patients indicated that cyst formation and enlargement may occur as a late complication following GKS even in extra-axial benign tumors such as VS. PMID- 27460515 TI - Efficacy of levetiracetam in primary hemifacial spasm. AB - Hemifacial spasm (HFS) is a peripherally-induced movement disorder characterized by the involuntary, unilateral, intermittent, irregular, tonic or clonic contractions of muscles innervated by the ipsilateral facial nerve. Kindling-like hyperactivity of the facial nucleus induced by constant stimulation of compressing artery is considered as the predominant mechanism underlying the pathogenesis of HFS. As a treatment for HFS, microsurgical decompression and botulinum toxin injection have been shown to be highly successful. Anticonvulsant drugs relieve HFS in some patients; however, the use of such drugs is limited owing to their side effects, predominantly in elderly patients. We experienced two elderly HFS patients who exhibited a marked response to levetiracetam (LEV) without side effects. Although the exact underlying pharmacological mechanism remains unknown, we assume anti-kindling effect as one of the important pharmacological mechanism underlying the effect of LEV against HFS. Moreover, LEV is considered to be suitable for use in elderly patients because of its good tolerability. In addition, the lack of hepatic induction or inhibition makes it an easy and safe drug when used in addition to other anticonvulsants. Although the long-term benefit remains unknown, LEV may represent an alternative treatment for elderly HFS patients who are unable to undergo or decline surgical intervention and/or botulinum toxin injections or are intolerant to other anticonvulsants. PMID- 27460516 TI - Human intersegmental reflexes from intercostal afferents to scalene muscles. AB - NEW FINDINGS: What is the central question of this study? The aim was to determine whether specific reflex connections operate between intercostal afferents and the scalene muscles in humans, and whether these connections operate after a clinically complete cervical spinal cord injury. What is the main finding and its importance? This is the first description of a short-latency inhibitory reflex connection between intercostal afferents from intercostal spaces to the scalene muscles in able-bodied participants. We suggest that this reflex is mediated by large-diameter afferents. This intercostal-to-scalene inhibitory reflex is absent after cervical spinal cord injury and may provide a way to monitor the progress of the injury. Short-latency intersegmental reflexes have been described for various respiratory muscles in animals. In humans, however, only short-latency reflex responses to phrenic nerve stimulation have been described. Here, we examined the reflex connections between intercostal afferents and scalene muscles in humans. Surface EMG recordings were made from scalene muscles bilaterally, in seven able-bodied participants and seven participants with motor- and sensory-complete cervical spinal cord injury (median 32 years postinjury, range 5 months to 44 years). We recorded the reflex responses produced by stimulation of the eighth or tenth left intercostal nerve. A short-latency (~38 ms) inhibitory reflex was evident in able-bodied participants, in ipsilateral and contralateral scalene muscles. This bilateral intersegmental inhibitory reflex occurred in 46% of recordings at low stimulus intensities (at three times motor threshold). It was more frequent (in 75-85% of recordings) at higher stimulus intensities (six and nine times motor threshold), but onset latency (38 +/- 9 ms, mean +/- SD) and the size of inhibition (23 +/- 10%) did not change with stimulus intensity. The reflex was absent in all participants with spinal cord injury. As the intercostal-to-scalene reflex did not increase with larger stimulus intensities, it is likely to be mediated by large-diameter intercostal muscle afferents. This is the first demonstration of an intercostal-to-scalene reflex. As the reflex requires intact spinal connections, it may be a useful marker for recovery of thoracic or cervical spinal injury. PMID- 27460517 TI - Parental smoking and children undergoing anesthesia: Is there a role for pediatric hospitals in smoking cessation? AB - PURPOSE: Pediatric hospitals within the Children's Hospital Association were surveyed to determine their tobacco cessation efforts for parents/patients. DESIGN AND METHODS: Electronic surveys were sent to 75 anesthesia providers and/or preoperative surgery specialists at 41 facilities. RESULTS: A total of 52 completed surveys were returned. The majority (97%) of facilities were smoke free, and 68% included preoperative questions about parental smoking and secondhand smoke (SHS) exposure. Few offered cessation assistance. PRACTICE IMPLICATIONS: Pediatric hospitals have a role in parental smoking cessation. This article provides recommendations for pediatric hospitals to assist parents to overcome their addiction to tobacco as they strive to provide the best possible healthcare services for children. PMID- 27460518 TI - Genomic portrait of ovarian follicle growth regulation in cattle. AB - The female reproductive cycle is characterized by cyclic patterns of growth of ovarian follicles destined to ovulate and the degeneration of those not chosen for ovulation. Apoptosis is the underlying mechanism of ovarian follicle degeneration during atresia. The fate of ovarian follicles is under the control of endocrine hormones (e.g. gonadotropins) and intra-ovarian regulators (e.g. growth factors and gonadal steroids), but the intra-cellular and molecular regulation of follicle fate (cellular proliferation or atresia) are still not fully understood. Studies using genomic tools which aim to determine the expression profiles of mRNAs and miRNAs in bovine dominant and subordinate ovarian follicles at different stages of the follicle wave have indicated that there are some novel molecular factors (e.g. FOXO1 and miR-183~96~182 cluster) associated with ovarian follicle development. Furthermore, bioinformatics tools have been used to identify the interactions between mRNAs and miRNAs leading to better understanding of ovarian follicle growth regulation in cattle. This review summarizes the recent findings about the complex intracellular communication networks involving miRNA, their target genes and signalling molecules which together may coordinate the fate of cattle ovarian follicles. PMID- 27460519 TI - Accumulation of HIV-1 Drug Resistance Mutations After First-Line Immunological Failure to Evaluate the Options of Recycling NRTI Drugs in Second-Line Treatment: A Study from South India. AB - Lack of HIV-1 viral load monitoring in resource-limited settings leads to the development of HIV drug resistance mutations, although WHO recommends viral load testing for monitoring as this helps in preserving future treatment options and also avoid unnecessary switching to more expensive drugs. A total of 101 patients attaining first-line treatment failure (FTF) were followed until second-line treatment failure (STF) to study the rate of accumulation of thymidine analogue mutations (TAMs), their future drug options, and genetic evolution. The result shows that predominant nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations were M184V/I (87.3% in FTF and 79% in STF) followed by TAMs (53.4% in FTF and 54.5% in STF). The rate of accumulation of TAMs was higher for a patient with TAMI [0.015 TAM per person-month (TPPM)], TAMII (0.042 TPPM), and 1 (0.005 TPPM) or 2 TAMs (0.008 TPPM) compared with a patient with both TAMs and 3 or >3 TAMs. Future ART options show that >50% of the patients can be considered for choices to recycle NRTIs in the second-line, and third-line therapy. We conclude that the patients who initiated thymidine analogue-based first-line before 2010 can be very well opted for AZT- and TDF-based second-line regimen in the future. PMID- 27460520 TI - [Hypertrophic obstructive cardiomyopathy and anemia: Cause and effect]. PMID- 27460521 TI - [SPRINT on clinical practice: It's time to change the management of arterial hypertension in Latin America?] AB - This paper analyzes the feasibility of the implementation of SPRINT trial results, the need to rethink the clinical practice guidelines(CPG) for the management of arterial hypertension and associated costs with daily practice applicability. SPRINT is a clinical trial comparing systolic blood pressure control <120mmHg and <140mmHg over cardiovascular complications, generating a great worldwide impact followed by publication of several studies that addressed relevance, usefulness, applicability and controversial aspects of SPRINT from different perspectives. Achieving blood pressure goals is one of the most discussed issue in widely used hypertension CPG around the world and in Latin American. SPRINT has generated and will generate a great impact on CPG, being necessary the reassessment of blood pressure goals and inclusion in future CPG, as has been considered in 2016 Canadian guideline and will be considered in NICE guideline update scheduled for June. The SPRINT trial raises new evidence for the management of hypertension, useful in people over 50 years, from urban populations, with defined cardiovascular risk without associated comorbidities. The applicability of SPRINT in Latin America is limited by increased costs associated with hypertensive patients' integrated health care, low care coverage, and lack of integrated care programs. PMID- 27460522 TI - The merry-go-round of approval, pricing and reimbursement of drugs against the Hepatitis C virus infection in Spain. AB - Given that drug innovation has been largely away from breakthroughs, arguing that a new drug recently approved and reaching the market is downright effective, safe and affordable is actually parlous. The soaring costs of an increasing number of new drugs (specially for cancer and rare diseases) threaten to supersede societal absorbing capacity, competing with other health and outside health sector resources. Some health systems are not making headways towards solving the current conundrum of keeping path with the state of the art regulatory mechanisms in delivering cost-effective, equitable and affordable treatments. The way pricing and reimbursement decisions have been made in Spain regarding the recent wave of new drugs against the hepatitis C virus could be one case in point. This paper analyses the path of decision-making and the positioning of the relevant actors in this case, that has set a cumbersome precedent (earmarked fund) for the Spanish National Health Service. It also stresses the need for current decision making mechanisms on approval, pricing, coverage and reimbursement in Spain to move to a transparent regulatory system, avoiding improvisation and incorporating the highest regulatory standards that other countries have in place. PMID- 27460523 TI - The correlation between regulatory conditions and antibiotic consumption within the WHO European Region. AB - BACKGROUND: In a global perspective, bacterial infections are still a major cause of morbidity and mortality; therefore, effective antibiotics are needed. However, the emergence of antibiotic resistance due to irrational use has now become a serious public health problem. Hence, the objective of this study was to analyse the association of regulatory aspects with antibiotic consumption. METHODS: A data set representing 20 countries throughout the WHO European Region was chosen based on data availability so as to analyse the correlation between specific regulatory conditions and antibiotic consumption, using total consumption data for 2011 and information about national provisions regarding rational use of medicines. Linear regression models were designed in order to evaluate individual aspects as well as the overall level of regulation. RESULTS: A high level of regulation, assessed by an overall index, was significantly correlated with lower antibiotic consumption; however, of all individual items analysed, only the presence of Standard Treatment Guidelines for hospital care as well as paediatric conditions, the non-availability of antibiotics without a prescription, and the existence of training modules for pharmacists covering rational use of medicines gave significant results, i.e. lower use of antibiotics, when regarded in isolation. CONCLUSION: Although national regulatory conditions intended to foster rational use of antibiotics seem to be correlated with antibiotic consumption, this association is potentially influenced by a wide range of contextual aspects. PMID- 27460524 TI - Indoor human thermal adaptation: dynamic processes and weighting factors. AB - In this study, we explore the correlations between indoor climate change and human thermal adaptation, especially with regard to the timescale and weighting factors of physiological adaptation. A comparative experiment was conducted in China where wintertime indoor climate in the southern region (devoid of space heating) is much colder than in the northern region (with pervasive district heating). Four subject groups with different indoor thermal experiences participated in this climate chamber experiment. The results indicate that previous indoor thermal exposure is an important contributor to occupants' physiological adaptation. More specifically, subjects acclimated to neutral-warm indoors tended to have stronger physiological responses and felt more uncomfortable in moderate cold exposures than those adapted to the cold. As for the driving force of thermal adaptation, physiological acclimation is an important aspect among all the supposed adaptive layers. However, the physiological adaptation speed lags behind changes in the overall subjective perception. PMID- 27460525 TI - The value of prognostic factors in Chinese patients with small cell lung cancer: A retrospective study of 999 patients. AB - INTRODUCTION: Little is known about the prognostic factors for small cell lung cancer (SCLC) in Chinese patients. OBJECTIVE: The aim of this retrospective study was to improve our understanding of overall survival (OS) and progression-free survival (PFS) prognostic factors in Chinese patients with SCLC. METHODS: A retrospective analysis of 999 SCLC cases was performed. Patient characteristics, treatments, and laboratory data, including platelet counts and serum lactate dehydrogenase (LDH) and serum sodium levels, were collected. Potential prognostic factors for OS and PFS were evaluated by univariate and multivariate analyses. RESULTS: The median OS and PFS were 10.6 and 7.0 months, respectively. The multivariate Cox proportional hazards model was used to identify stage, serum LDH, and several therapy-relevant factors, including the initial chemotherapy regimen, number of initial chemotherapy cycles, and combination therapy, as independent prognostic factors for OS. Furthermore, female sex, normal LDH levels, a response to therapy, receiving six cycles of initial chemotherapy, and receiving chemotherapy combined with radiotherapy and/or surgery were favorable prognostic factors for PFS. In addition, patients with hyponatremia had a worse OS; therefore, hyponatremia could not influence survival when a good response to therapy was achieved, and it failed to predict PFS. CONCLUSIONS: This study demonstrated that several factors, including patient, tumor, and treatment characteristics and serum LDH levels are independent prognostic factors for OS and PFS in Chinese patients with SCLC. The identification of such factors will help physicians compare different populations and to interpret the contribution of treatment to differences in survival among groups. PMID- 27460526 TI - Boron-Filled Hybrid Carbon Nanotubes. AB - A unique nanoheterostructure, a boron-filled hybrid carbon nanotube (BHCNT), has been synthesized using a one-step chemical vapor deposition process. The BHCNTs can be considered to be a novel form of boron carbide consisting of boron doped, distorted multiwalled carbon nanotubes (MWCNTs) encapsulating boron nanowires. These MWCNTs were found to be insulating in spite of their graphitic layered outer structures. While conventional MWCNTs have great axial strength, they have weak radial compressive strength, and do not bond well to one another or to other materials. In contrast, BHCNTs are shown to be up to 31% stiffer and 233% stronger than conventional MWCNTs in radial compression and have excellent mechanical properties at elevated temperatures. The corrugated surface of BHCNTs enables them to bond easily to themselves and other materials, in contrast to carbon nanotubes (CNTs). BHCNTs can, therefore, be used to make nanocomposites, nanopaper sheets, and bundles that are stronger than those made with CNTs. PMID- 27460527 TI - Mitochondrial Diseases: A Clinical and Molecular History. PMID- 27460528 TI - Pediatric Miller Fisher Syndrome Complicating an Epstein-Barr Virus Infection. AB - BACKGROUND: Miller Fisher syndrome, a variant of Guillain-Barre syndrome, is an acute inflammatory demyelinating polyradiculoneuropathy that may occur weeks after a bacterial or viral infection. Campylobacter jejuni and Haemophilus influenzae are frequently reported etiological agents. PATIENT DESCRIPTION: We describe a boy with Miller Fisher syndrome following Epstein-002DBarr virus primary infectious mononucleosis. He presented with bilateral dysfunction of several cranial nerves and hyporeflexia of the limbs but without ataxia. Miller Fisher syndrome was confirmed by the presence of anti-GQ1b antibodies in a blood sample. Epstein-Barr virus was identified by polymerase chain reaction and serology. CONCLUSION: Epstein-Barr virus should be considered as a Miller Fisher syndrome's causative agent. The physiopathology of this condition may involve cross-reactive T-cells against Epstein-Barr virus antigens and gangliosides. PMID- 27460530 TI - A potent bidirectional promoter from the monocot cereal Eleusine coracana. AB - Ragi bifunctional alpha-amylase-trypsin inhibitor (RBI) of Eleusine coracana (L.) Gaertn. (finger millet) simultaneously inhibits alpha-amylase and trypsin. In continuation of previous work on the cloning, expression and characterization of RBI, a bidirectional promoter from finger millet was explored on the basis of experimental observations. Two trypsin inhibitors were identified while purifying RBI from a trypsin-Sepharose column eluent. Using an FPLC gel filtration column, these three inhibitors were purified to homogeneity and subjected to MALDI-TOF TOF-MS/MS analysis and N-terminal sequencing. Both ragi trypsin inhibitors (RTIs) showed the same N-terminal sequence and considerable sequence similarity to RBI, indicating the presence of a multigene protease inhibitor family in finger millet. To gain insight into the evolution of these genes, the upstream region of RBI was explored by Genome Walking. Interestingly, on sequencing, a genome walking product of ~1 Kb showed presence of an N-terminal RBI specific primer sequence twice but in opposite directions and leaving an intervening region of ~0.9 Kb. The intervening region was presumed to represent an E. coracana bidirectional promoter (EcBDP), intuitively having a divergent RBI-RTI gene pair at two sides. For assaying the bidirectionality of promoter activity, a dual reporter GUS-GFP vector construct was made for plant expression containing the reporter genes at two ends of EcBDP, which was used to transform Agrobacterium tumefaciens LBA 4404. Transient plant transformation by recombinant Agrobacterium cells was carried out in onion scale epidermal cells and finger millet seedling leaves. Simultaneous expression of GUS and GFP under EcBDP established it as a potent natural bidirectional promoter from monocot origin, thereby potentially having vast application in cereal gene manipulations. In addition, inducibility of the EcBDP by either abscisic acid or cold treatment, as determined by transient transformation in onion, would substantiate more precise control of gene expression to mitigate the effects of adverse environmental conditions. PMID- 27460529 TI - Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family. AB - Colorectal cancer (CRC) is among the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for the development of new therapeutic approaches for the treatment of CRC. Accumulating evidence has revealed that niclosamide, an anthelminthic drug, exerts antitumor activity in several types of cancer, including colon cancer. However, the underlying molecular mechanisms responsible for the effects of this drug remain elusive. Previous studies have shown that the aberrant Notch signaling pathway contributes to the carcinogenesis of colon cancer. Herein, we examined the effects of niclosamide on the growth, migration and apoptosis of colon cancer cells, and the role of the Notch signaling pathway. By performing MTT, wound-healing and Transwell migration assays, we observed that niclosamide suppressed the growth and migration of colon cancer cells, and flow cytometry demonstrated that cell apoptosis was induced. This was associated with the decreased protein expression of Notch1, Notch2, Notch3 and Hey1, and the increased expression of the tumor suppressor microRNA (miR or miRNA)-200 family members (miR-200a, miR-200b, miR-200c, miR-141 and miR 429) that are typically downregulated in colon cancer. Collectively, these findings demonstrate that niclosamide potentially inhibits the progression of colon cancer by downregulating Notch signaling and by upregulating the miR-200 family members. PMID- 27460531 TI - Oleanane-type triterpenoid saponins from Silene armeria. AB - Twelve triterpenoid saponins, including seven compounds (i.e., armerosides A-G) hitherto unknown, were isolated from whole plants of Silene armeria. Their structures were established based on extensive spectroscopic analyses and chemical methods. From a biosynthetic perspective, C-23 oxidation of the sapogenin appears to be a key factor in the glycosylation pathway. PMID- 27460534 TI - Generation of Soluble Advanced Glycation End Products Receptor (sRAGE)-Binding Ligands during Extensive Heat Treatment of Whey Protein/Lactose Mixtures Is Dependent on Glycation and Aggregation. AB - Heating of protein- and sugar-containing materials is considered the primary factor affecting the formation of advanced glycation end products (AGEs). This study aimed to investigate the influence of heating conditions, digestion, and aggregation on the binding capacity of AGEs to the soluble AGE receptor (sRAGE). Samples consisting of mixtures of whey protein and lactose were heated at 130 degrees C. An in vitro infant digestion model was used to study the influence of heat treatment on the digestibility of whey proteins. The amount of sRAGE-binding ligands before and after digestion was measured by an ELISA-based sRAGE-binding assay. Water activity did not significantly affect the extent of digestibility of whey proteins dry heated at pH 5 (ranging from 3.3 +/- 0.2 to 3.6 +/- 0.1% for gastric digestion and from 53.5 +/- 1.5 to 64.7 +/- 1.1% for duodenal digestion), but there were differences in cleavage patterns of peptides among the samples heated at different pH values. Formation of sRAGE-binding ligands depended on the formation of aggregates and was limited in the samples heated at pH 5. Moreover, the sRAGE-binding activity of digested sample was changed by protease degradation and correlated with the digestibility of samples. In conclusion, generation of sRAGE-binding ligands during extensive heat treatment of whey protein/lactose mixtures is limited in acidic heating condition and dependent on glycation and aggregation. PMID- 27460532 TI - Temporal asynchrony and spatial perception. AB - Collinear facilitation is an enhancement in the visibility of a target by laterally placed iso-oriented flankers in a collinear (COL) configuration. Iso oriented flankers placed in a non-collinear configuration (side-by-side, SBS) produce less facilitation. Surprisingly, presentation of both configurations simultaneously (ISO-CROSS) abolishes the facilitation rather than increases it - a phenomenon that can't be fully explained by the spatial properties of the target and flankers. Based on our preliminary data and recent studies, we hypothesized that there might be a novel explanation based on the temporal properties of the excitation and inhibition, resulting in asynchrony between the lateral inputs received from COL and SBS, leading to cancelation of the facilitatory component in ISO-CROSS. We explored this effect using a detection task in humans. The results replicated the previous results showing that the preferred facilitation for COL and SBS was abolished for the ISO-CROSS configuration. However, presenting the SBS flankers, but not the COL flankers 20 msec before ISO-CROSS restored the facilitatory effect. We propose a novel explanation that the perceptual advantage of collinear facilitation may be cancelled by the delayed input from the sides; thus, the final perception is determined by the overall spatial-temporal integration of the lateral interactions. PMID- 27460535 TI - Role of race in kidney transplant outcomes in children with focal segmental glomerulosclerosis. AB - It is well established that racial differences exist in kidney transplant outcomes; however, there are no studies which focus on the role of race in transplant outcomes specifically in children diagnosed with FSGS. Associations between race and transplant outcomes in FSGS children were evaluated using the Organ Procurement and Transplantation Network database from 2000 to 2012. Recipients aged 2-21 years who received a kidney-only transplant were included. Multivariate regression models were used to evaluate transplant outcomes by race. Five hundred and thirty-six recipients (59.7% male, 15.6+/-3.9 years) were black and 1134 (55.7% male, 14.3+/-5.0 years) were non-black. Graft survival was significantly shorter in the black group (4.2+/-3.1 vs 4.6+/-3.3 years, P=.005). Black race was associated with significantly higher risk of graft failure (HR 1.34, 95% CI=1.21-1.49, P<.0001), acute rejection (OR 1.66 95% CI=1.39-1.97, P<.0001), and delayed graft function (OR 1.51, 95% CI=1.33-1.72, P<.001) compared to non-black race. There were no significant differences in mortality, prolonged hospitalization, or FSGS recurrence between groups. Race is a significant predictor for worse transplant outcomes in children with FSGS. PMID- 27460536 TI - Prof. Dr. Paul Hocker: Recipient, Cohn-de Laval Award, 2016. PMID- 27460537 TI - A review of statistical updating methods for clinical prediction models. AB - A clinical prediction model is a tool for predicting healthcare outcomes, usually within a specific population and context. A common approach is to develop a new clinical prediction model for each population and context; however, this wastes potentially useful historical information. A better approach is to update or incorporate the existing clinical prediction models already developed for use in similar contexts or populations. In addition, clinical prediction models commonly become miscalibrated over time, and need replacing or updating. In this article, we review a range of approaches for re-using and updating clinical prediction models; these fall in into three main categories: simple coefficient updating, combining multiple previous clinical prediction models in a meta-model and dynamic updating of models. We evaluated the performance (discrimination and calibration) of the different strategies using data on mortality following cardiac surgery in the United Kingdom: We found that no single strategy performed sufficiently well to be used to the exclusion of the others. In conclusion, useful tools exist for updating existing clinical prediction models to a new population or context, and these should be implemented rather than developing a new clinical prediction model from scratch, using a breadth of complementary statistical methods. PMID- 27460538 TI - Principal component of explained variance: An efficient and optimal data dimension reduction framework for association studies. AB - The genomics era has led to an increase in the dimensionality of data collected in the investigation of biological questions. In this context, dimension reduction techniques can be used to summarise high-dimensional signals into low dimensional ones, to further test for association with one or more covariates of interest. This paper revisits one such approach, previously known as principal component of heritability and renamed here as principal component of explained variance (PCEV). As its name suggests, the PCEV seeks a linear combination of outcomes in an optimal manner, by maximising the proportion of variance explained by one or several covariates of interest. By construction, this method optimises power; however, due to its computational complexity, it has unfortunately received little attention in the past. Here, we propose a general analytical PCEV framework that builds on the assets of the original method, i.e. conceptually simple and free of tuning parameters. Moreover, our framework extends the range of applications of the original procedure by providing a computationally simple strategy for high-dimensional outcomes, along with exact and asymptotic testing procedures that drastically reduce its computational cost. We investigate the merits of the PCEV using an extensive set of simulations. Furthermore, the use of the PCEV approach is illustrated using three examples taken from the fields of epigenetics and brain imaging. PMID- 27460539 TI - Propensity score matching and complex surveys. AB - Researchers are increasingly using complex population-based sample surveys to estimate the effects of treatments, exposures and interventions. In such analyses, statistical methods are essential to minimize the effect of confounding due to measured covariates, as treated subjects frequently differ from control subjects. Methods based on the propensity score are increasingly popular. Minimal research has been conducted on how to implement propensity score matching when using data from complex sample surveys. We used Monte Carlo simulations to examine two critical issues when implementing propensity score matching with such data. First, we examined how the propensity score model should be formulated. We considered three different formulations depending on whether or not a weighted regression model was used to estimate the propensity score and whether or not the survey weights were included in the propensity score model as an additional covariate. Second, we examined whether matched control subjects should retain their natural survey weight or whether they should inherit the survey weight of the treated subject to which they were matched. Our results were inconclusive with respect to which method of estimating the propensity score model was preferable. In general, greater balance in measured baseline covariates and decreased bias was observed when natural retained weights were used compared to when inherited weights were used. We also demonstrated that bootstrap-based methods performed well for estimating the variance of treatment effects when outcomes are binary. We illustrated the application of our methods by using the Canadian Community Health Survey to estimate the effect of educational attainment on lifetime prevalence of mood or anxiety disorders. PMID- 27460540 TI - Joint modeling of longitudinal zero-inflated count and time-to-event data: A Bayesian perspective. AB - Longitudinal zero-inflated count data are encountered frequently in substance-use research when assessing the effects of covariates and risk factors on outcomes. Often, both the time to a terminal event such as death or dropout and repeated measure count responses are collected for each subject. In this setting, the longitudinal counts are censored by the terminal event, and the time to the terminal event may depend on the longitudinal outcomes. In the study described herein, we expand the class of joint models for longitudinal and survival data to accommodate zero-inflated counts and time-to-event data by using a Cox proportional hazards model with piecewise constant baseline hazard. We use a Bayesian framework via Markov chain Monte Carlo simulations implemented in the BUGS programming language. Via an extensive simulation study, we apply the joint model and obtain estimates that are more accurate than those of the corresponding independence model. We apply the proposed method to an alpha-tocopherol, beta carotene lung cancer prevention study. PMID- 27460541 TI - Ezetimibe increases intestinal expression of the LDL receptor gene in dyslipidaemic men with insulin resistance. AB - AIM: To gain further insight into intestinal cholesterol homeostasis in dyslipidaemic men with insulin resistance (IR) by examining the impact of treatment with ezetimibe on the expression of key genes involved in cholesterol synthesis and LDL receptor (R)-mediated uptake of lipoproteins. METHODS: A total of 25 men with dyslipidaemia and IR were recruited to participate in this double blind, randomized, crossover, placebo-controlled trial. Participants received 10 mg/day ezetimibe or placebo for periods of 12 weeks each. Intestinal gene expression was measured by quantitative PCR in duodenal biopsy samples collected by gastroduodenoscopy at the end of each treatment. RESULTS: A total of 20 participants completed the protocol. Treatment with ezetimibe significantly increased intestinal LDLR (+16.2%; P = .01), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoAR; +14.0%; P = .04) and acetyl-Coenzyme A acetyltransferase 2 (ACAT-2) mRNA expression (+12.5%; P = .03). Changes in sterol regulatory element binding transcription factor 2 (SREBP-2) expression were significantly correlated with changes in HMG-CoAR (r = 0.55; P < .05), ACAT-2 (r = 0.69; P < .001) and proprotein convertase substilisin/kexin type 9 (PCSK9) expression (r = 0.45; P < .05). CONCLUSIONS: These results show that inhibition of intestinal cholesterol absorption by ezetimibe increases expression of the LDLR gene, supporting the concept that increased LDL clearance with ezetimibe treatment occurs not only in the liver but also in the small intestine. PMID- 27460542 TI - Low expression lncRNA RPLP0P2 is associated with poor prognosis and decreased cell proliferation and adhesion ability in lung adenocarcinoma. AB - We investigated the clinical roles and biological function of long non-coding (lncRNA) RPLP0P2 in lung adenocarcinoma (LAD). The expression level of RPLP0P2 was estimated by quantitative reverse transcription-polymerase chain reaction (qPCR) in 57 pairs of LAD and NT samples and the relation of RPLP0P2 to clinical data of LAD patients was analyzed. We overexpressed RPLP0P2 based on the human LAD cell line A549 by lentivirus-mediated technology, then oncological behavior change was observed of A549 cells and the change of mRNA level of LRRC10B and RPLP0P2 by qPCR. We found that RPLP0P2 expression was lower while LRRC10B mRNA level was higher in LAD than NT by qPCR. RPLP0P2 expression level was negative correlated to LRRC10B mRNA level (Pearson correlation =-0.754, P=0.0021). The expression of RPLP0P2 in lymph node metastasis of LAD group was significantly lower than LAD without lymph node metastasis group. Survival analysis showed that survival time of high expression of RPLP0P2 was significantly longer than low RPLP0P2 level in LAD patients. After RPLP0P2 was overexpressed, the proliferation rate, adhesion ability, S phase and G2/M phase cells and LRRC10B mRNA significantly reduced, while apoptosis and G0/G1 phase cells obviously increased, but migration ability and invasion did not significantly change. Our study ascertained that low expression of RPLP0P2 in LAD is associated with poor prognosis and decreased proliferation and adhesion ability of tumor cells. LRRC10B may be a downstream gene regulated by RPLP0P2. PMID- 27460543 TI - Transradial arterial access to the rescue? PMID- 27460544 TI - The regulation of thermal stress induced apoptosis in corals reveals high similarities in gene expression and function to higher animals. AB - Recent studies suggest that controlled apoptotic response provides an essential mechanism, enabling corals to respond to global warming and ocean acidification. However, the molecules involved and their functions are still unclear. To better characterize the apoptotic response in basal metazoans, we studied the expression profiles of selected genes that encode for putative pro- and anti-apoptotic mediators in the coral Stylophora pistillata under thermal stress and bleaching conditions. Upon thermal stress, as attested by the elevation of the heat-shock protein gene HSP70's mRNA levels, the expression of all studied genes, including caspase, Bcl-2, Bax, APAF-1 and BI-1, peaked at 6-24 h of thermal stress (hts) and declined at 72 hts. Adversely, the expression levels of the survivin gene showed a shifted pattern, with elevation at 48-72 hts and a return to basal levels at 168 hts. Overall, we show the quantitative anti-apoptotic traits of the coral Bcl-2 protein, which resemble those of its mammalian counterpart. Altogether, our results highlight the similarities between apoptotic networks operating in simple metazoans and in higher animals and clearly demonstrate the activation of pro-cell survival regulators at early stages of the apoptotic response, contributing to the decline of apoptosis and the acclimation to chronic stress. PMID- 27460545 TI - [Cardiovascular risk factors in users with severe mental disorder]. AB - OBJECTIVE: To identify the prevalence of the cardiovascular risk (RCV) in users with a Severe Mental Disorder (SMD) attended in mental health service in ParcTauli (Sabadell - Barcelona). METHOD: This is an observational, descriptive and transversal study of the factors of cardiovascular risk in 789 users with SMD. The instrument used was the scale of assessment of the Registre Gironi del Cor, which estimates the risk of cardiovascular disease. RESULTS: 26.6% of the sample has RCV (22.5% moderate, 3.8% high and 0.3% very high). The analysis of the modifiable risk factors shows that 16.5% of the patients are hypertensive, 55.2% are smokers, 19.77% have hyperglycaemia (8.2% of whom are diagnosed of diabetes mellitus), 40.2% have obesity, 36.2% overweight and 47.27% hypercholesterolemia. CONCLUSIONS: The study confirms that the prevalence of the RVC in SMD users is greater than the RCV in general population and it's associated to the presence of modifiable risk factors. Health education carried out by nurses is the best to prevent the RCV in SMD users. PMID- 27460546 TI - Observations on the biological traits of the rare shark Oxynotus centrina (Chondrichthyes: Oxynotidae) in the Hellenic Seas. AB - New records of the rare angular rough shark Oxynotus centrina from the Hellenic Seas are presented. Its occurrence is reported for the first time in the Corinthian Gulf. Some aspects of the species' biology are described and compared with previous studies. PMID- 27460547 TI - Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation. AB - HIV-1 Nef is necessary and may be sufficient for HIV-1-associated AIDS pathogenicity, in that knockout of Nef alone can protect HIV-infected patients from AIDS. We therefore investigated the feasibility of physical knockout of Nef, using the host ubiquitin proteasome system in HIV-1-infected cells. Our co immunoprecipitation analysis demonstrated that Nef interacted with ubiquitin specific protease 15 (USP15), and that USP15, which is known to stabilize cellular proteins, degraded Nef. Nef could also cause decay of USP15, although Nef-mediated degradation of USP15 was weaker than USP15-mediated Nef degradation. Direct interaction between Nef and USP15 was essential for the observed reciprocal decay of the proteins. Further, USP15 degraded not only Nef but also HIV-1 structural protein, Gag, thereby substantially inhibiting HIV-1 replication. However, Gag did not degrade USP15, indicating that the Nef and USP15 complex, in distinction to other viral proteins, play an integral role in coordinating viral protein degradation and hence HIV-1 replication. Moreover, Nef and USP15 globally suppressed ubiquitylation of cellular proteins, indicating that these proteins are major determinants for the stability of cellular as well as viral proteins. Taken together, these data indicate that Nef and USP15 are vital in regulating degradation of viral and cellular proteins and thus HIV-1 replication, and specific degradation of viral, not cellular proteins, by USP15 points to USP15 as a candidate therapeutic agent to combat AIDS by eliminating viral proteins from the infected cells via USP15-mediated proteosomal degradation. PMID- 27460548 TI - HIV-1 Vpr increases HCV replication through VprBP in cell culture. AB - Coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) occurs at a high frequency, in which HIV shows a promotion of HCV-derived liver diseases. However, the mechanism of how this occurs is not well understood. Our previous work has demonstrated that the HIV-1 accessory protein Vpr enhances HCV RNA replication in cell culture. Because Vpr performs most of its functions through host protein VprBP (DCAF1), the role of VprBP in the regulation of HCV by Vpr was investigated in this study. We found that the Vpr mutant Q65R, which is deficient in VprBP binding, could not enhance HCV replication. Furthermore, Vpr mediated enhancement of HCV replication was severely diminished in VprBP knockdown cells. In addition, an inhibitor of Cullin RING E3 ligases, MLN4924, impaired the function of Vpr during HCV replication. Together, these results suggest that Vpr promotes HCV replication in a VprBP-dependent manner, and that the activity of Cullin RING E3 ligases is essential to this process. In conclusion, our findings demonstrate that HIV-1 Vpr makes the cellular environment more suitable for HCV replication, which might relate with the host ubiquitination system. PMID- 27460549 TI - Rasch analysis of SF-Qualiveen in multiple sclerosis. AB - BACKGROUND: A 30-item Qualiveen questionnaire was developed to measure the impact of urinary problems on everyday living in spinal cord injury, and subsequently an 8-item SF-Qualiveen was developed for those with multiple sclerosis (MS). The validity of this short form has not been previously examined using modern psychometric techniques, such as the Rasch measurement model. OBJECTIVE: The aim of this study is to test if the short form meets the requirements of the Rasch model. METHODS: A total of 401 patients with clinically definite MS were given the questionnaire at three neuroscience centres in the UK. RESULTS: A total of 258 patients (64.3% response) completed the questionnaire. The original scale failed to meet the expectations of the Rasch model. A two-testlet solution was sought to account for local dependence, differential item functioning and disordered thresholds. After the modifications were made the scale fitted the model (chi2 = 5.93 P = 0.4305), had high internal consistency (alpha = 0.88) and was unidimensional. CONCLUSIONS: SF-Qualiveen is a simple and valid measure of the impact of urinary problems in multiple sclerosis, which meets the requirements of the Rasch measurement model. Summed ordinal scores can be converted to interval-level using the transformation table provided. PMID- 27460550 TI - Immunogenicity and safety of the inactivated Japanese encephalitis vaccine IXIARO(r) in elderly subjects: Open-label, uncontrolled, multi-center, phase 4 study. AB - BACKGROUND: IXIARO(r) is a Vero cell-derived, inactivated Japanese encephalitis (JE) vaccine licensed mainly in western countries for children and adults traveling to JE endemic areas. Limited immunogenicity and safety data in elderly travelers have been available. OBJECTIVES: To evaluate safety and immunogenicity of IXIARO in elderly subjects. METHODS: Open-label, single arm, multi-centered study. Two-hundred subjects with good general health, including adequately controlled chronic conditions, received two doses of IXIARO(r), 28days apart. Protective levels of antibodies were tested 42days after the second dose. Systemic and local adverse events (AEs) were solicited for 7days after each dose, unsolicited AEs were collected up to day 70 and in a phone call at month 7. SUMMARY OF RESULTS: Subjects were aged 64-83years (median 69.0years). Nineteen percent of subjects had serious or medically attended AEs up to Day 70 (primary endpoint), none of them causally linked to IXIARO. Solicited local AEs were reported by 33.5% (most common: local tenderness) and solicited systemic AEs by 27% (most common: headache) of subjects. The seroprotection rate was 65% with a geometric mean titre (GMT) of 37. Subjects with tick borne encephalitis (TBE) vaccinations in the past 5years (N=29) had a SCR of 90% and GMT of 65. CONCLUSIONS: IXIARO is generally well tolerated in the elderly, and the safety profile is largely comparable with younger adults. SCR and GMT are lower compared to younger adults, but SCR is in the range reported in elderly for other vaccines e.g. against TBE, hepatitis-A virus (HAV)/hepatitis-B virus (HBV), influenza. The differences in SCR and GMT from younger to elderly adults were in the range of other vaccines. Duration of protection is uncertain in older persons, therefore a booster dose (third dose) should be considered before any further exposure to JE virus. PMID- 27460551 TI - Simultaneously Photo-Cleavable and Activatable Prodrug-Backboned Block Copolymer Micelles for Precise Anticancer Drug Delivery. AB - A simultaneously photo-cleavable and activatable prodrug-backboned block copolymer (BCP) micelle strategy is demonstrated. Without light treatment, the micelles stay silent and inactivated, being biocompatible to normal tissues. Concurrent chain cleavage of BCP micelles and the activation of Pt(IV) prodrug could be temporally and spatially triggered by UV or even visible light for precise anticancer drug delivery. PMID- 27460552 TI - Prostate Cancer Predictive Simulation Modelling, Assessing the Risk Technique (PCP-SMART): Introduction and Initial Clinical Efficacy Evaluation Data Presentation of a Simple Novel Mathematical Simulation Modelling Method, Devised to Predict the Outcome of Prostate Biopsy on an Individual Basis. AB - INTRODUCTION: We developed a mathematical "prostate cancer (PCa) conditions simulating" predictive model (PCP-SMART), from which we derived a novel PCa predictor (prostate cancer risk determinator [PCRD] index) and a PCa risk equation. We used these to estimate the probability of finding PCa on prostate biopsy, on an individual basis. MATERIALS AND METHODS: A total of 371 men who had undergone transrectal ultrasound-guided prostate biopsy were enrolled in the present study. Given that PCa risk relates to the total prostate-specific antigen (tPSA) level, age, prostate volume, free PSA (fPSA), fPSA/tPSA ratio, and PSA density and that tPSA >= 50 ng/mL has a 98.5% positive predictive value for a PCa diagnosis, we hypothesized that correlating 2 variables composed of 3 ratios (1, tPSA/age; 2, tPSA/prostate volume; and 3, fPSA/tPSA; 1 variable including the patient's tPSA and the other, a tPSA value of 50 ng/mL) could operate as a PCa conditions imitating/simulating model. Linear regression analysis was used to derive the coefficient of determination (R2), termed the PCRD index. To estimate the PCRD index's predictive validity, we used the chi2 test, multiple logistic regression analysis with PCa risk equation formation, calculation of test performance characteristics, and area under the receiver operating characteristic curve analysis using SPSS, version 22 (P < .05). RESULTS: The biopsy findings were positive for PCa in 167 patients (45.1%) and negative in 164 (44.2%). The PCRD index was positively signed in 89.82% positive PCa cases and negative in 91.46% negative PCa cases (chi2 test; P < .001; relative risk, 8.98). The sensitivity was 89.8%, specificity was 91.5%, positive predictive value was 91.5%, negative predictive value was 89.8%, positive likelihood ratio was 10.5, negative likelihood ratio was 0.11, and accuracy was 90.6%. Multiple logistic regression revealed the PCRD index as an independent PCa predictor, and the formulated risk equation was 91% accurate in predicting the probability of finding PCa. On the receiver operating characteristic analysis, the PCRD index (area under the curve, 0.926) significantly (P < .001) outperformed other, established PCa predictors. CONCLUSION: The PCRD index effectively predicted the prostate biopsy outcome, correctly identifying 9 of 10 men who were eventually diagnosed with PCa and correctly ruling out PCa for 9 of 10 men who did not have PCa. Its predictive power significantly outperformed established PCa predictors, and the formulated risk equation accurately calculated the probability of finding cancer on biopsy, on an individual patient basis. PMID- 27460553 TI - Primary Adenocarcinoma of the Seminal Vesicles: A Very Rare Neoplasia Occurring in a 56-Year-Old Patient. PMID- 27460554 TI - External supports improve knee performance in anterior cruciate ligament reconstructed individuals with higher kinesiophobia levels. AB - BACKGROUND: The objectives of this study were to investigate the effects of knee brace (KB) and kinesiotaping (KT) on functional performance and self-reported function in individuals six months post-ACLR who desired to return to their pre injury activity levels but felt unable to do so due to kinesiophobia. METHODS: This was a cross-sectional study involving 30 individuals six months post-ACLR with Tampa Kinesiophobia Scores >37. Individuals were tested under three conditions: no intervention, KB and KT in a randomized order. Isokinetic concentric quadriceps and hamstring strength tests, one leg hop test, star excursion balance test and global rating scale were assessed under the three conditions. RESULTS: The involved side showed that KT and KB significantly increased the hop distance (P=0.01, P=0.04) and improved balance (P=0.01, P=0.04), respectively, but only KB was found to increase the quadriceps and hamstring peak torques compared to no intervention (P<0.05). Individuals reported having better knee function with KB when compared to no intervention (P<0.001) and KT (P=0.03). CONCLUSIONS: Both KB and KT have positive effects in individuals post-ACLR which may assist in reducing kinesiophobia when returning to their pre injury activity levels, with the KB appearing to offer the participants better knee function compared to KT. PMID- 27460555 TI - A novel in situ synthesis of SiBCN-Zr composites prepared by a sol-gel process and spark plasma sintering. AB - In the work reported here, SiBCN amorphous powders were first prepared by a mechanical alloying technique, employing cubic silicon, graphite and hexagonal boron nitride powders as raw materials. Zirconia was then introduced via sol-gel methods. The resulting powder composite was then consolidated via SPS sintering. The SPS sintering sample was evaluated using XRD, SEM and TEM. XRD reveals a chemical transformation wherein amorphous BN(C) and ZrO2 form the primary ZrC and ZrB2 phases after SPS processing along with SiC and BN(C). Thereafter ZrC reacts with BN(C) completely to form ZrB2. The reaction starts at the temperature of 1500 degrees C and is complete at the temperature of 1900 degrees C. The fracture toughness of the sintered composites reaches 4.9 +/- 0.2 MPa m(1/2) due to the presence of the laminated structure of the BN(C) phase. PMID- 27460556 TI - Enrichment of Pyrrolic Nitrogen by Hole Defects in Nitrogen and Sulfur Co-Doped Graphene Hydrogel for Flexible Supercapacitors. AB - The effect of the doping configuration and concentration of nitrogen (N) and sulfur (S) on the electrochemical performance of 3 D N and S co-doped hole defect graphene hydrogel (NS-HGH) electrodes is investigated. Surprisingly, by introducing a hole defect on the graphene surface, the difference in the doping concentrations of N and S can be used to effectively modulate the electrochemical behavior of the NS-HGH. The hole defects provide a rapid ion diffusion path. Finally, we showed that the intriguing specific capacitance (536 F g(-1) ) of the NS-HGH could enhance the overall performance of the pseudocapacitance and electric double layer capacitance. The rational design of the NS-HGH-based flexible solid state supercapacitor results in not only outstanding electrochemical performance with a maximum energy density of 14.8 Wh kg(-1) and power density of 5.2 KW kg(-1) but also in extraordinary mechanical flexibility and excellent cycle stability. PMID- 27460557 TI - Relationships between types of father breastfeeding support and breastfeeding outcomes. AB - Fathers' support can influence mothers' breastfeeding decisions and behavior. Potentially supportive behaviors have been reported in previous studies, but no studies have directly examined which, if any, of those actions are actually more likely to result in desired breastfeeding outcomes. The two studies reported in this paper address this gap by examining relationships between fathers' reported breastfeeding support and mothers' perceptions of received support and breastfeeding intentions, satisfaction, and duration. The Partner Breastfeeding Influence Scale (PBIS) was used in an online survey with 64 women and 41 men (34 couples) and a telephone survey with 80 mothers and 65 fathers (63 couples). Fathers' and mothers' reports of how often fathers engage in the types of support measured by the PBIS were used to predict breastfeeding intentions, satisfaction, and duration. In Study 1, responsiveness predicted breastfeeding success and satisfaction for men and satisfaction for women. However, mothers' intended breastfeeding duration was shorter when fathers both wanted them to breastfeed for a long time and were more appreciative and savvy about breastfeeding. In Study 2, when fathers reported being more appreciative and directly involved in breastfeeding, mothers reported shorter breastfeeding duration. In both studies, mothers' perceptions of their partners' responsiveness and fathers' reports of their own responsiveness predicted longer breastfeeding intentions and duration. These findings suggest that the most effective breastfeeding support is delivered using a sensitive, coordinated teamwork approach that is responsive to the mother's needs. PMID- 27460558 TI - Integrated Analysis of EEG and fMRI Using Sparsity of Spatial Maps. AB - Integration of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is an open problem, which has motivated many researches. The most important challenge in EEG-fMRI integration is the unknown relationship between these two modalities. In this paper, we extract the same features (spatial map of neural activity) from both modality. Therefore, the proposed integration method does not need any assumption about the relationship of EEG and fMRI. We present a source localization method from scalp EEG signal using jointly fMRI analysis results as prior spatial information and source separation for providing temporal courses of sources of interest. The performance of the proposed method is evaluated quantitatively along with multiple sparse priors method and sparse Bayesian learning with the fMRI results as prior information. Localization bias and source distribution index are used to measure the performance of different localization approaches with or without a variety of fMRI-EEG mismatches on simulated realistic data. The method is also applied to experimental data of face perception of 16 subjects. Simulation results show that the proposed method is significantly stable against the noise with low localization bias. Although the existence of an extra region in the fMRI data enlarges localization bias, the proposed method outperforms the other methods. Conversely, a missed region in the fMRI data does not affect the localization bias of the common sources in the EEG fMRI data. Results on experimental data are congruent with previous studies and produce clusters in the fusiform and occipital face areas (FFA and OFA, respectively). Moreover, it shows high stability in source localization against variations in different subjects. PMID- 27460559 TI - Reply to response to Wheatley et al., "Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation" Cancer Treatment Reviews April 2016;45:76. PMID- 27460560 TI - Regulation of the CCN genes by vitamin D: A possible adjuvant therapy in the treatment of cancer and fibrosis. AB - The CCN family is composed of six cysteine-rich, modular, and conserved proteins whose functions span a variety of tissues and include cell proliferation, adhesion, angiogenesis, and wound healing. Roles for the CCN proteins throughout the entire body including the skin, kidney, brain, blood vessels, hematopoietic compartment and others, are continuously being elucidated. Likewise, an understanding of the regulation of this important gene family is constantly becoming clearer, through identification of transcription factors that directly activate, repress, or respond to upstream cell signaling pathways, as well as other forms of gene expression control. Vitamin D (1,25-dihydroxyvitamin D3 or calcitriol), a vitamin essential for numerous biological processes, acts as a potent gene expression modulator. The regulation of the CCN gene family members by calcitriol has been described in many contexts. Here, we provide a concise and thorough overview of what is known about calcitriol and its regulation of the CCN genes, and argue that its regulation is of physiological importance in a wide breadth of tissues in which CCN genes function. In addition, we highlight the effects of vitamin D on CCN gene expression in the setting of two common pathologic conditions, fibrosis and cancer, and propose that the therapeutic effects of vitamin D3 described in these disease states may in part be attributable to CCN gene modulation. As vitamin D is perfectly safe in a wide range of doses and already showing promise as an adjuvant therapeutic agent, a deeper understanding of its control of CCN gene expression may have profound implications in clinical management of disease. PMID- 27460563 TI - Prodigiosin inhibits motility and activates bacterial cell death revealing molecular biomarkers of programmed cell death. AB - The antimicrobial activity of prodigiosin from Serratia nematodiphila darsh1, a bacterial pigment was tested against few food borne bacterial pathogens Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. The mode of action of prodigiosin was studied. Prodigiosin induced bactericidal activity indicating a stereotypical set of biochemical and morphological feature of Programmed cell death (PCD). PCD involves DNA fragmentation, generation of ROS, and expression of a protein with caspase-like substrate specificity in bacterial cells. Prodigiosin was observed to be internalized into bacterial cells and was localized predominantly in the membrane and the nuclear fraction, thus, facilitating intracellular trafficking and then binding of prodigiosin to the bacterial DNA. Corresponding to an increasing concentration of prodigiosin, the level of certain proteases were observed to increase in bacteria studied, thus initiating the onset of PCD. Prodigiosin at a sub-inhibitory concentration inhibits motility of pathogens. Our observations indicated that prodigiosin could be a promising antibacterial agent and could be used in the prevention of bacterial infections. PMID- 27460561 TI - How Do Meningeal Lymphatic Vessels Drain the CNS? AB - The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow. PMID- 27460564 TI - Association study of C-reactive protein associated gene HNF1A with ischemic stroke in Chinese population. AB - BACKGROUND: Ischemic stroke is a life-threatening condition due to obstructed blood supply of the brain. Elevation of plasma C-reactive protein, an important inflammatory marker, was known to associate with increased risk of ischemic stroke. Previous studies reported association between genetic variants of HNF1A and plasma level of C-reactive protein. The HNF1A gene encodes a hepatocyte transcription factor which might have regulatory effects on C-reactive protein synthesis in liver. Therefore, the C-reactive protein associated gene HNF1A seems to be a promising candidate gene for ischemic stroke. RESULTS: We used HNF1A as a candidate gene of ischemic stroke and evaluated seven common variants of HNF1A for their contribution to ischemic stroke. The association analysis of HNF1A variants with ischemic stroke was performed in a Chinese population with 918 cases and 979 controls. For total ischemic stroke and large vessel disease subtype, none of variants exceeded significant threshold. For small vessel disease subtype of ischemic stroke, the G allele of rs7953249 showed nominal association (OR = 0.82, p = 0.04) after data adjustment for conventional risk factors. However, our preliminary results did not survived bonferroni correction for multiple comparisons. CONCLUSIONS: Common genetic variants of HNF1A showed nominal association with small vessel disease subtype of ischemic stroke though not survived bonferroni correction for multiple comparisons. The association between HNF1A and ischemic stroke is limited by small effects of individual SNPs. Our study provided additional genetic evidences to understand the role of HNF1A gene and C-reactive protein underlying ischemic stroke. PMID- 27460565 TI - Cytocompatibility of calcium silicate-based sealers in a three-dimensional cell culture model. AB - OBJECTIVES: The aim of the present study was to evaluate cytotoxic effects and cytokine production of calcium silicate-based sealers (EndoSeal, EndoSequence BC Sealer, and MTA Fillapex) using an in vitro root canal filling model and three dimensional (3D) cell culture. AH Plus as a reference was compared to contemporary calcium silicate cements regarding cell viability and cytokine production. MATERIAL AND METHODS: Root canals of 30 human maxillary incisors were prepared using a single-file reciprocating technique. The samples were randomly distributed and canals filled with either AH Plus, EndoSeal, EndoSequence BC Sealer, and MTA Fillapex (n = 6). In the negative control group, the root canal remained unfilled. Sealers were placed into the canals along with a gutta-percha cone placed to working length. Balb/c 3T3 fibroblasts, cultured in a type I collagen 3D scaffold, were exposed to filling material and the respective root apex for 24 h. Cytocompatibility of the materials was evaluated using the methyl thiazoldiphenyl-tetrazolium (MTT) assay. The production of IL-1beta, IL-6, and IL 8 was analyzed using enzyme-linked immunosorbent assay (ELISA). One-way analysis of variance was performed, and when the F-ratios were significant, data were compared by Duncan's multiple-range test. The alpha-type error was set at 0.05. RESULTS: EndoSeal, Endosequence BC Sealer and AH Plus showed cell viability that was similar to the negative control group (P > 0.05), while MTA Fillapex sealer was cytotoxic (P < 0.05). Varying production of IL-1beta, IL-6, and IL-8 was detected in all samples. CONCLUSIONS: In an in vitro root canal filling model with 3D cell culture, AH Plus, EndoSeal, and EndoSequence BC Sealer were cytocompatible. CLINICAL RELEVANCE: These results may suggest that AH Plus, EndoSeal and EndoSequence BC Sealer may achieve better biological response when compared to MTA Fillapex. PMID- 27460566 TI - Complications of endodontically treated teeth restored with fiber posts and single crowns or fixed dental prostheses-a systematic review. AB - OBJECTIVE: The present systematic review aimed at assessing data from the literature on endodontic and prosthetic complications in endodontically treated teeth restored with fiber posts and single crowns (SCs) or fixed dental prostheses (FDPs). MATERIALS AND METHODS: Available randomized controlled clinical trials evaluating endodontic and prosthetic complications in the teeth treated with fiber posts and restored with different prosthetic restorations were reviewed. PubMed, Evidence-Based Dentistry, BMJ Clinical Evidence, Embase, DynaMed, and gray literature restricted to scientific literature were analyzed; also, manual researches were performed. English language and time filters (from 1990 to 2015) were used. RESULTS: The database search produced 4230 records, many of which were duplicates. The manual research did not produce any other relevant article. After duplications were removed, all the selected databases produced 3670 records. Reading titles and abstracts, two independent reviewers excluded 3664 reports. The full-texts of the remaining six reports were read. Only four studies met the inclusion criteria and were included in this systematic review. CONCLUSIONS: The most frequently reported failures in the available studies were as follows: fiber post debonding, loss of retention of single crowns, and marginal gaps. Less frequently, chippings and fractures were recorded in SCs. No studies about complications related to FDPs were found. CLINICAL RELEVANCE: A correlation between the failure rates of fiber posts and the type of prosthetic restorations just like SCs and FDPs cannot be found to date. Further randomized controlled clinical studies are required to achieve evidence-based conclusions, particularly about the use of fiber posts with FDPs. PMID- 27460567 TI - Effect of antiresorptive drugs in the alveolar bone healing. A histometric and immunohistochemical study in ovariectomized rats. AB - OBJECTIVES: The aim of this study is to evaluate the alendronate and raloxifene influence in the alveolar healing process of osteoporotic rats. MATERIALS AND METHODS: Sixty-four female rats were divided in four groups: sham rats (SHAM), ovariectomized rats and no medical treatment (OVX NT), ovariectomized rats and submitted to alendronate treatment (OVX ALE), and ovariectomized and submitted to raloxifene treatment (OVX RAL). The histomorphometrical and immunohistochemical analysis was performed. The quantitative data were analyzed through Kruskal Wallis and Dunn tests (alpha = 0.05). RESULTS: In the longest period, SHAM and OVX RAL groups showed the better bone formation responses (P < 0.05). The worst bone formation response was observed in the group OVX NT. OVX RAL group showed the better response at 42 days. OVX ALE group showed a favorable response at 14 days, in comparison with OVX RAL group, but a reduced response at 42 days. It was possible to observe a mature bone in SHAM group at 14 days and an immature bone in the OVX NT group. An intermediate quality bone was observed in the groups OVX ALE and OVX RAL. CONCLUSION: Alendronate and raloxifene treatment improved the alveolar healing process in osteoporotic rats, but not enough to achieve the histometrical and protein expression values that were observed in the SHAM group. CLINICAL RELEVANCE: Alendronate is largely used as a potent antiresorptive agent. Otherwise, considering the undesirable effects in relation to the alveolar healing, other antiosteoporosis medications should be studied. Raloxifene seems to be a good candidate once its action mechanism involves the activation of osteoblasts. PMID- 27460568 TI - Genetic testing and personalized ovarian cancer screening: a survey of public attitudes. AB - BACKGROUND: Advances in genetic technologies are expected to make population-wide genetic testing feasible. This could provide a basis for risk stratified cancer screening; but acceptability in the target populations has not been explored. METHODS: We assessed attitudes to risk-stratified ovarian cancer (OC) screening based on prior genetic risk assessment using a survey design. Home-based interviews were carried out by the UK Office of National Statistics in a population-based sample of 1095 women aged 18-74. Demographic and personal correlates of attitudes to risk-stratified OC screening based on prior genetic risk assessment were determined using univariate analyses and adjusted logistic regression models. RESULTS: Full data on the key analytic questions were available for 829 respondents (mean age 46 years; 27 % 'university educated'; 93 % 'White'). Relatively few respondents felt they were at 'higher' or 'much higher' risk of OC than other women of their age group (7.4 %, n = 61). Most women (85 %) said they would 'probably' or 'definitely' take up OC genetic testing; which increased to 88 % if the test also informed about breast cancer risk. Almost all women (92 %) thought they would 'probably' or 'definitely' participate in risk-stratified OC screening. In multivariate logistic regression models, university level education was associated with lower anticipated uptake of genetic testing (p = 0.009), but with more positive attitudes toward risk stratified screening (p <0.001). Perceived risk was not significantly associated with any of the outcome variables. CONCLUSIONS: These findings give confidence in taking forward research on integration of novel genomic technologies into mainstream healthcare. PMID- 27460569 TI - The effectiveness of mental health courts in reducing recidivism and police contact: a systematic review protocol. AB - BACKGROUND: Mental health courts were created to help criminal defendants who have a mental illness that significantly contributes to their criminal offense. Despite the increasing number of mental health courts around the world, data about their effectiveness have only begun to emerge in the past decade. The purpose of this systematic literature review is to assess the current evidence on the effectiveness of mental health courts. Specifically, this review will address the question, "How effective are mental health courts in reducing recidivism and police contact?" METHODS/DESIGN: Eight electronic databases will be searched, specifically PsycINFO, Medline, Medline In-Process, Embase, Web of Science, CINAHL, Social Work Abstracts, and Criminal Justice Abstracts. A multi-phase screening process will be used to identify relevant search hits. Articles that pass the three-stage screening process will then be assessed for risk of bias and have their reference lists hand searched. Full-text articles that are rated to have low to moderate risk of bias will be summarized into two tables, one containing a brief description of the study and the other reporting the results of relevant outcomes measured. DISCUSSION: By synthesizing the results of the studies, this systematic review will help illuminate gaps in the literature, direct future research, and inform policy makers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016036084. PMID- 27460570 TI - Taenia ovis: an emerging threat to the Chinese sheep industry? AB - BACKGROUND: Taenia ovis is a tapeworm that is mainly transmitted between dogs and sheep. Although T. ovis infection is not a public health issue, it causes a great financial loss due to condemnation of carcasses. The first outbreak of T. ovis infection in China occurred in 2015. Reassessment of adverse effects of T. ovis infection on Chinese sheep industry in future is necessary. DISCUSSION: The first T. ovis outbreak in China suggests that the epidemic situation across the country is underestimated. For the transmission of T. ovis, many factors, including eggs, dogs and wild canids, human behaviours and sheep trade, should be seriously considered. In blocking the transmission chain, regular treatments of the infected dogs using anthelmintics play a crucial step, but at the moment it is difficult to be fully executed in China, largely due to the behaviours, customs and faith of local farmers. Moreover, combined with no clinical symptoms in the infected adult sheep and goats, the lack of pre-mortem diagnostic tools makes it harder to practice a national wide surveillance as well as inspection and quarantine in increasingly frequent free sheep trade activities in China, leading to an inability to restrict T. ovis infection into small areas. Furthermore, the ongoing campaigns against Echinococcus granulosus may have an adverse effect on control of T. ovis infection because of no consideration of a role of dogs in the transmission of the parasite. CONCLUSION: Lack of national epidemic data, pre mortem diagnostic reagents and vaccines severely hampers the implementation of disease control campaigns and the restriction of T. ovis infection into small areas. Consequently, sheep and goats are at an increasing risk of T. ovis exposure and the possibility of large-scale outbreaks across China in future is possible, causing great adversity towards sheep industry. PMID- 27460572 TI - Obesity in British children with and without intellectual disability: cohort study. AB - BACKGROUND: Reducing the prevalence of and inequities in the distribution of child obesity will require developing interventions that are sensitive to the situation of 'high risk' groups of children. Children with intellectual disability appear to be one such group. We aimed to estimate the prevalence of obesity in children with and without intellectual disability in a longitudinal representative sample of British children and identify risk factors associated with obesity at age 11. METHODS: Information was collected on a nationally representative sample of over 18,000 at ages 9 months, 3, 5, 7 and 11 years. We used UK 1990 gender-specific growth reference charts and the LMS Growth programme to identify age and gender-specific overweight and obesity BMI thresholds for each child at ages 5, 7 and 11 years. RESULTS: Children with intellectual disabilities were significantly more likely than other children to be obese at ages five (OR = 1.32[1.03-1.68]), seven (OR = 1.39[1.05-1.83]) and eleven (OR = 1.68[1.39-2.03]). At ages five and seven increased risk of obesity among children with intellectual disabilities was only apparent among boys. Among children with intellectual disability risk of obesity at age eleven was associated with persistent maternal obesity, maternal education, child ethnicity and being bullied at age five. CONCLUSIONS: Children with intellectual disability are a high-risk group for the development of obesity, accounting for 5-6 % of all obese children. Interventions to reduce the prevalence and inequities in the distribution of child obesity will need to take account of the specific situation of this group of children. PMID- 27460573 TI - [Not Available]. PMID- 27460574 TI - [Not Available]. PMID- 27460571 TI - Rituximab plus chemotherapy as first-line treatment in Chinese patients with diffuse large B-cell lymphoma in routine practice: a prospective, multicentre, non-interventional study. AB - BACKGROUND: The efficacy and safety of rituximab-based chemotherapy (R-chemo), the standard regimen for patients with diffuse large B-cell lymphoma (DLBCL), which is more common in Asia than in Western countries, are well confirmed in randomized controlled trials (RCTs). However, the safety and effectiveness of R chemo in patients who are largely excluded from RCTs have not been well characterized. This real-world study investigated the safety and effectiveness of R-chemo as first-line treatment in Chinese patients with DLBCL. METHODS: Treatment-naive DLBCL patients who were CD20 positive and eligible to receive R chemo were enrolled with no specific exclusion criteria. Data collected at baseline included age, gender, disease stage, international prognostic index (IPI), B symptoms, extranodal involvement, performance status, and medical history. In the present study, data on safety, treatment effectiveness, and HBV infection management were collected 120 days after the last R-chemo administration. RESULTS: Overall, R-chemo was well tolerated. The safety profile of R-chemo in patients with a history of heart or liver disease was well described without any additional unexpected safety concerns. The overall response rate (ORR) in the Chinese patients from this study was 94.2 % (complete response [CR], 55.0 %; CR unconfirmed [CRu] 18.2 %; and partial response [PR], 20.9 %). Compared to patients with no history of disease, the CR and PR rates of patients with a history of heart or liver disease were lower and higher, respectively; this tendency could be in part explained by treatment interruptions in patients with heart or liver diseases. HBsAg positivity and a maximum tumor diameter of >=7.5 cm negatively correlated with CR + CRu, whereas age and HBsAg positivity negatively correlated with CR. CONCLUSIONS: This study further validated the safety and effectiveness of R-chemo in Chinese patients with DLBCL. Patients with a history of heart or liver disease may further benefit from R-chemo if preventive measures are taken to reduce hepatic and cardiovascular toxicity. In addition to IPI and tumor diameter, HBsAg positivity could also be a poor prognostic factor for CR in Chinese patients with DLBCL. TRIAL REGISTRATION: ClinicalTrials.gov # NCT01340443 , April 20, 2011. PMID- 27460575 TI - [Intubationskraevende facial erysipelas]. PMID- 27460576 TI - [Seizures caused by subarachnoid haemorrhage in a pregnant woman]. AB - This case report describes a pregnant woman of gestational week 37 + 2 days who was admitted to the hospital with first-time seizures. The patient was stabilized, and an acute caesarian section was performed due to the possible aetiology of eclampsia and the advanced gestational age. Because of the atypical clinical history and normal maternal blood samples a computed tomography of the cerebrum was performed demonstrating a subarachnoid haemorrhage. A computed tomography-angiography revealed an aneurism at the anterior communicating artery. The aneurism was coiled the following day to reduce the risk of rebleeding. PMID- 27460577 TI - [Development in abdominal hernia repair]. AB - Treatment of abdominal hernias has undergone considerable development over the last decades. Since the introduction of mesh-based methods the recurrence rate has dropped. Today there is considerable development regarding the meshes with resorbable meshes entering the market, but some patients might not need a mesh at all. This could lead to individualized choice of treatment for the patients. The treatment of hernias is thereby getting more specialized. This could argue for special hernia centres, so that development and training can be optimized. PMID- 27460578 TI - [Parenchymal splenic lesion after a water balloon shot]. AB - Acute splenic rupture can be a life-threatening condition which needs immediate attention. We report a case where parenchymal splenic lesions and subcapsular haematoma were developed after a patient was being hit with a water balloon from a slingshot. The patient was treated conservatively but developed an arteriovenous fistula which was treated with central arterial coiling. We discuss the need for acute computed tomography after relevant trauma as well as the evidence for follow-up scans and management of splenic pseudoaneurysms with splenic arterial embolization. PMID- 27460579 TI - Purification of Regucalcin from the Seminal Vesicular Fluid: A Calcium Binding Multi-Functional Protein. AB - Regucalcin is a multi-functional protein having roles in calcium homeostasis as well as in anti-apoptotic, anti-prolific and anti-oxidative functions. Recently, it has been reported from the male reproductive tract, but its role in male reproduction needs further investigation; for which the native regucalcin of reproductive origin will be more appropriate. The gel exclusion chromatography followed by diethyl aminoethane cellulose chromatography and two-dimentional cellulose acetate membrane electrophoresis used for its purification are time consuming and less specific. Here, the regucalcin gene from buffalo testis has been cloned, expressed and purified in recombinant form, and subsequently used for raising hyper-immune serum. The Western blot of seminal vesicular fluid probed with anti-regucalcin polyclonal and monoclonal antibodies showed the presence of 28 and 34 kDa bands specific to regucalcin. Further, an affinity matrix has been prepared using anti-regucalcin polyclonal antibodies. An immuno affinity chromatography method has been standardized to isolate regucalcin from seminal vesicular fluid. The initial complexity of the protein mixture in the seminal vesicular fluid has been reduced by a heat coagulation step. The purified protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a single band at 68 kDa that has been further confirmed as regucalcin by Liquid chromatography-mass spectrometry/mass spectrometry. The RGN purified from seminal vesicular fluid will be more appropriate for studying its possible role in male reproduction, especially sperm cell capacitation, hyperactivation, acrosome reaction and cryopreservation. The study can be applied in purifying regucalcin from different tissues or species with minor modifications in the methodology. PMID- 27460580 TI - Rufibacter soli sp. nov., a Bacterium Isolated from Soil. AB - A gram-negative bacterium, designated FJY1(T), was isolated from a soil sample obtained from a university campus in South Korea. Examination showed that FJY1(T) was red-pigmented, aerobic, motile, and composed of nonspore-forming rods. This strain grew in a temperature range of 15-37 degrees C and a pH range of 7-9. Based on 16S rRNA gene sequence similarity, strain FJY1(T) was most closely related to Rufibacter roseus H359(T) and Rufibacter tibetensis 1351(T), with sequence similarities of 95.98 and 95.46 %, respectively. Its major cellular fatty acids were iso-C15:0 (18.16 %) and summed feature 4 (C17:1 iso I and C17:1 anteiso B; 15.17 %). The DNA G+C content of FJY1(T) was 49.7 mol%; its predominant quinone was MK-7; and its major polar lipid was phosphatidylethanolamine. Phylogenetic analysis and analysis of its physiological and biochemical characteristics indicated that this isolate constituted a novel species, for which we propose the name Rufibacter soli sp. nov., with the type strain FJY1(T) (=KCTC 42815(T) = JCM 31024(T)). PMID- 27460581 TI - Oceanisphaera aquimarina sp. nov., Isolated from Oil-Contaminated Sediment of Ocean Coastal Area from South Korea. AB - Strain S33(T) was isolated from oil-contaminated sediment of Tae-an coastal region of South Korea. Cells are aerobic, motile, Gram staining-negative, and coccoid shaped. Strain S33(T) grew optimally at the temperature of 25 degrees C (range of 4-40 degrees C), pH 6.0 (range of pH 6.0-10.0), and in the presence of 1 % (w/v) NaCl (range of 0-10 %). Ubiquinone-8 was the predominant respiratory quinone. C16:0, summed feature 3 (comprising C16:1omega7c/C16:1omega6c) and C18:1omega7c were the major fatty acids. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, and diphosphatidylglycerol. Strain S33(T) showed the ability to degrade benzene, toluene, and ethylbenzene after 3 days incubation. 16S rRNA gene sequence analysis showed that the strain S33(T) was most closely related to Oceanisphaera sediminis TW92(T) (97.3 %), Oceanisphaera profunda SM1222(T) (97.2 %), and Oceanisphaera ostreae T-w6(T) (97.1 %) and <97 % with other members of the genus Oceanisphaera. The genomic DNA G+C mol% content of strain S33(T) was 51.0 mol%. Based on distinct phenotypic, genotypic, and phylogenetic analysis, strain S33(T) was proposed to represent a novel species in the genus Oceanisphaera as Oceanisphaera aquimarina sp. nov. (= KEMB 1002-058(T) = JCM 30 794(T)). PMID- 27460582 TI - Spermidine Synthase is Required for Growth of Synechococcus sp. PCC 7942 Under Osmotic Stress. AB - The Synechococcus sp. PCC 7942 spermidine synthase encoded by spds gene (Synpcc7942_0628) is responsible for spermidine biosynthesis. Two Synechococcus strains, the overexpressing spds (OX-spds) and the spds knockout (Deltaspds), were constructed and characterized for their growth and photosynthetic efficiency under osmotic stress imposed by sorbitol. The growth of Deltaspds was completely inhibited when cells were grown in the presence of 400 mM sorbitol. Under the same condition, the OX-spds showed a slightly higher growth than the wild type. The OX-spds under osmotic stress also had a significant increase of spermidine level in conjunction with the up-regulation of the genes involved in spermidine biosynthesis. A higher ratio of spermidine to putrescine, an index for stress tolerance, under osmotic stress was found in the OX-spds strain than in the wild type. Overall results indicated that the spermidine synthase enzyme plays an essential role in the survival of Synechococcus sp. PCC 7942 under osmotic stress. PMID- 27460583 TI - Characterization of Ciprofloxacin-Resistant and Ciprofloxacin-Susceptible Uropathogenic Escherichia coli Obtained from Patients with Gynecological Cancer. AB - The objective of this work was to assess the genetic characteristics of uropathogenic Escherichia coli, ciprofloxacin resistance or susceptibility, obtained from patients with gynecological cancer and urinary tract infection (UTI). Seventy-seven E. coli ciprofloxacin-resistant isolates and 38 ciprofloxacin-susceptible were analyzed by polymerase chain reaction (PCR) to determine the phylogenetic groups, virulence factors as iucC, fyuA, hlyC, cnf1 genes, and pks pathogenicity island. The presence of genes related to ciprofloxacin resistance such as qnrA, qnrB, qnrS, aac(6')-Ib-cr, and qepA, and the sequencing of DNA gyrase genes and topoisomerase IV were determined. The genetic profile of the isolates was determined by pulsed-field gel electrophoresis (PFGE). Statistical analysis was performed using Fisher's exact test and Chi-square test. Phylogenetic group B2 was the most prevalent although a great genetic diversity was observed by PFGE. Only genes associated to siderophores were found in ciprofloxacin-resistant isolates; however, in ciprofloxacin-susceptible isolates, genes related to siderophores and toxin, were detected. Additionally qnrB was detected in both populations, ciprofloxacin resistant and susceptible. DNA mutations in gyrA were Ser-83-Leu and Asp-87-Asn and in parC were Ser-80-Ile and Glu-84-Val, Glu-84-Lys. In conclusion, it was observed a high prevalence of qnrB in the population studied; in addition, it was the first time the pks island was observed only in ciprofloxacin-susceptible isolates. PMID- 27460584 TI - Purification and Evaluation of Polysaccharide Intercellular Adhesion (PIA) Antigen from Staphylococcus epidermidis. AB - The polysaccharide intercellular adhesin (PIA) confers major functional effects in biofilm formation, which bears an important role in the pathogenicity of Staphylococcus epidermidis. Following the identification of biofilm-forming strains by biochemical and molecular methods, isogenic strain was prepared and in vitro biofilm formation assay was performed consequently. By parallel analysis of both the PIA-positive and PIA-negative strains using size exclusion chromatography by Fast protein liquid chromatography (FPLC) method, the respective PIA was purified. Recovered PIA was examined using colorimetric and hemagglutination assays. Finally, the recovered PIA was analyzed using Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy methods. By the parallel purification process and comparison of the obtained graphs from the FPLC detector, fractions near the void volume were determined as PIA. The colorimetric and hemagglutination assays were applied and the content of carbohydrates (hexose = 620 ug/ml, hexosamine = 5700 ug/ml and ketoses = 170 ug/ml) and hemagglutination titer (1:128) in recovered polysaccharide were determined. This study shows that PIA has a significant role in the biofilm formation in S. epidermidis strains. The recovered polysaccharide and its molecular weight were analyzed within the near void volume of the utilized column. PMID- 27460585 TI - Methodology for analysis and reporting patterns of failure in the Era of IMRT: head and neck cancer applications. AB - BACKGROUND: The aim of this study is to develop a methodology to standardize the analysis and reporting of the patterns of loco-regional failure after IMRT of head and neck cancer. MATERIAL AND METHODS: Twenty-one patients with evidence of local and/or regional failure following IMRT for head-and-neck cancer were retrospectively reviewed under approved IRB protocol. Manually delineated recurrent gross disease (rGTV) on the diagnostic CT documenting recurrence (rCT) was co-registered with the original planning CT (pCT) using both deformable (DIR) and rigid (RIR) image registration software. Subsequently, mapped rGTVs were compared relative to original planning target volumes (TVs) and dose using a centroid-based approaches. Failures were then classified into five types based on combined spatial and dosimetric criteria; A (central high dose), B (peripheral high dose), C (central elective dose), D (peripheral elective dose), and E (extraneous dose). RESULTS: A total of 26 recurrences were identified. Using DIR, recurrences were assigned to more central TVs compared to RIR as detected using the spatial centroid-based method (p = 0.0002). rGTVs mapped using DIR had statistically significant higher mean doses when compared to rGTVs mapped rigidly (mean dose 70 vs. 69 Gy, p = 0.03). According to the proposed classification 22 out of 26 failures were of type A (central high dose) as assessed by DIR method compared to 18 out of 26 for the RIR because of the tendencey of RIR to assign failures more peripherally. CONCLUSIONS: RIR tends to assigns failures more peripherally. DIR-based methods showed that the vast majority of failures originated in the high dose target volumes and received full prescribed doses suggesting biological rather than technology-related causes of failure. Validated DIR-based registration is recommended for accurate failure characterization and a novel typology-indicative taxonomy is recommended for failure reporting in the IMRT era. PMID- 27460586 TI - Somatic Growth Dilution of a toxicant in a predator-prey model under stoichiometric constraints. AB - The development of aquatic food chain models that incorporate both the effects of nutrient availability, as well as, track toxicants through trophic levels will shed light on ecotoxicological processes and ultimately help improve risk assessment efforts. Here we develop a stoichiometric aquatic food chain model of two trophic levels that investigates concurrent nutrient and toxic stressors in order to improve our understanding of the processes governing the trophic transfer for nutrients, energy, and toxicants. Analytical analysis of positive invariance, local stability of boundary equilibria, numerical simulations, and bifurcation analysis are presented. The model captures and explores a phenomenon called the Somatic Growth Dilution (SGD) effect recently observed empirically, where organisms experience a greater than proportional gain in biomass relative to toxicant concentrations when consuming food with high nutritional content vs. low quality food. PMID- 27460587 TI - Locally dispersing populations in heterogeneous dynamic landscapes with spatiotemporal correlations. I. Block disturbance. AB - Locally dispersing populations are generally favorably affected by increasing the scale of habitat heterogeneity because they can exploit contiguous patches of suitable habitat. Increasing the spatial scale of landscape disturbances (such as by applying a pesticide to control an unwanted species) drives down population density because of reasons including dispersal-limited recolonization and the resulting increase in temporal variability. Here, we examine how population density changes as the spatial scale of landscape disturbance increases: does it increase due to increases in spatial correlations in landscape habitat type, or does it decrease due to the various spatial and temporal effects of larger-scale disturbances? We use simulations, mean field approximations, pair approximations, landscape-improved pair approximations (LIPA), and block probabilities to investigate a model of a locally dispersing species on a dynamic landscape with spatiotemporally structured heterogeneous habitat. Pesticide is applied at a given spatial scale, leaving habitat unsuitable for some time before dissipating and allowing the habitat to revert to a suitable state. We found that increasing the spatial scale of disturbances (while keeping the overall disturbance rate fixed) can increase population density, but generally only when landscape turnover is slow relative to population dynamics and when the population is somewhat close to its extinction threshold. Applying control measures at larger spatial scales may allow them to be more effective with the same overall treatment rate. The optimal spatial strategy for applying disturbances depends on both habitat availability as well as the turnover rate of the control measure being used. For the large-scale habitat dynamics in our model, it is possible to analytically calculate spatial correlations in habitat types over arbitrary scales. However, including exact habitat correlations at the triplet scale but approximating population correlations at that scale still neglects information needed to accurately predict simulation results, showing that larger-scale correlations in the population distribution have an important effect on dynamics. PMID- 27460588 TI - The dynamics of mobile promoters: Enhanced stability in promoter regions. AB - Mobile promoters are emerging as a new class of mobile genetic elements, first identified by examining prokaryote genome sequences, and more recently confirmed by experimental observations in bacteria. Recent datasets have identified over 40,000 putative mobile promoters in sequenced prokaryote genomes, however only one-third of these are in regions of the genome directly upstream from coding sequences, that is, in promoter regions. The presence of many promoter sequences in non-promoter regions is unexplained. Here we develop a general mathematical model for the dynamics of mobile promoters, extending previous work to capture the dynamics both within and outside promoter regions. From this general model, we apply rigorous model selection techniques to identify which parameters are statistically justified in describing the available mobile promoter data, and find best-fit values of these parameters. Our results suggest that high rates of horizontal gene transfer maintain the population of mobile promoters in promoter regions, and that once established at these sites, mobile promoters are rarely lost, but are commonly copied to other genomic regions. In contrast, mobile promoter copies in non-promoter regions are more numerous and more volatile, experiencing substantially higher rates of duplication, loss and diversification. PMID- 27460589 TI - Comparison of genomic data via statistical distribution. AB - Sequence comparison has become an essential tool in bioinformatics, because highly homologous sequences usually imply significant functional or structural similarity. Traditional sequence analysis techniques are based on preprocessing and alignment, which facilitate measuring and quantitative characterization of genetic differences, variability and complexity. However, recent developments of next generation and whole genome sequencing technologies give rise to new challenges that are related to measuring similarity and capturing rearrangements of large segments contained in the genome. This work is devoted to illustrating different methods recently introduced for quantifying sequence distances and variability. Most of the alignment-free methods rely on counting words, which are small contiguous fragments of the genome. Our approach considers the locations of nucleotides in the sequences and relies more on appropriate statistical distributions. The results of this technique for comparing sequences, by extracting information and comparing matching fidelity and location regularization information, are very encouraging, specifically to classify mutation sequences. PMID- 27460591 TI - Preoperative coronary calcium score is predictive of early postoperative cardiovascular complications in liver transplant recipients. PMID- 27460590 TI - A novel nitrogen-dependent gene associates with the lesion mimic trait in wheat. AB - KEY MESSAGE: Using bulk segregant analysis (BSA) coupling with RNA-seq and DNA markers identified a potentially novel nitrogen-dependent lesion mimic gene Ndhrl1 on 2BS in wheat. Lesion mimic (LM) refers to hypersensitive reaction-like (HRL) traits that appear on leaf tissue in the absence of plant pathogens. In a wheat line P7001, LM showed up on the leaves under the 0 g nitrogen (N) treatment, but disappeared when sufficient N was supplied, suggesting that LM is N-responsive and N dosage dependent. Using BSA strategy together with RNA-seq and DNA markers, we identified an N-dependent LM gene (Ndhrl1) and mapped it to the short arm of chromosome 2B using an F5 recombinant inbred population developed from the cross of P7001 * P216. The putative gene was delimited into an interval of 8.1 cM flanked by the CAPS/dCAPS markers 7hrC9 and 7hr2dc14, and co-segregated with the dCAPS marker 7hrdc2. This gene is most likely a novel gene for LM in wheat based on its chromosomal location. Further analysis of RNA-seq data showed that plant-pathogen interaction, nitrogen metabolism, zeatin biosynthesis and plant hormone signal transduction pathways were significantly differentially expressed between LM and non-LM lines. PMID- 27460592 TI - Colocalization coefficients evaluating the distribution of molecular targets in microscopy methods based on pointed patterns. AB - In biomedical studies, the colocalization is commonly understood as the overlap between distinctive labelings in images. This term is usually associated especially with quantitative evaluation of the immunostaining in fluorescence microscopy. On the other hand, the evaluation of the immunolabeling colocalization in the electron microscopy images is still under-investigated and biased by the subjective and non-quantitative interpretation of the image data. We introduce a novel computational technique for quantifying the level of colocalization in pointed patterns. Our approach follows the idea included in the widely used Manders' colocalization coefficients in fluorescence microscopy and represents its counterpart for electron microscopy. In presented methodology, colocalization is understood as the product of the spatial interactions at the single-particle (single-molecule) level. Our approach extends the current significance testing in the immunoelectron microscopy images and establishes the descriptive colocalization coefficients. To demonstrate the performance of the proposed coefficients, we investigated the level of spatial interactions of phosphatidylinositol 4,5-bisphosphate with fibrillarin in nucleoli. We compared the electron microscopy colocalization coefficients with Manders' colocalization coefficients for confocal microscopy and super-resolution structured illumination microscopy. The similar tendency of the values obtained using different colocalization approaches suggests the biological validity of the scientific conclusions. The presented methodology represents a good basis for further development of the quantitative analysis of immunoelectron microscopy data and can be used for studying molecular interactions at the ultrastructural level. Moreover, this methodology can be applied also to the other super-resolution microscopy techniques focused on characterization of discrete pointed structures. PMID- 27460593 TI - Zirconia-based catalyst for the one-pot synthesis of coumarin through Pechmann reaction. AB - Coumarins play an important role in drug development with diverse biological applications. Herein, we present the synthesis of coumarin through Pechmann reaction by using zirconia-based heterogeneous catalysts (ZrO2-TiO2, ZrO2-ZnO, and ZrO2/cellulose) in a solvent-free condition at room temperature. ZrO2-TiO2, ZrO2-ZnO, and ZrO2/cellulose were identified through spectroscopic techniques such as FESEM, X-ray, EDS, XPS, and FT-IR. ZrO2-TiO2 showed the best catalytic performance while ZrO2/cellulose was inactive. The kinetic parameters were observed in a solvent-free condition as well as in toluene and ethanol. The temperature effect was extensively studied which revealed that increasing the temperature will increase the rate of reaction. The rate of reaction in a solvent free condition, ethanol, and toluene were 1.7 * 10(-3), 1.7 * 10(-2), and 5.6 * 10(-3) g mol(-1) min(-1), respectively. PMID- 27460594 TI - Transition of Carrier Transport Behaviors with Temperature in Phosphorus-Doped Si Nanocrystals/SiO2 Multilayers. AB - High-conductive phosphorus-doped Si nanocrystals/SiO2(nc-Si/SiO2) multilayers are obtained, and the formation of Si nanocrystals with the average crystal size of 6 nm is confirmed by high-resolution transmission electron microscopy and Raman spectra. The temperature-dependent carrier transport behaviors of the nc-Si/SiO2 films are systematically studied by which we find the shift of Fermi level on account of the changing P doping concentration. By controlling the P doping concentration in the films, the room temperature conductivity can be enhanced by seven orders of magnitude than the un-doped sample, reaching values up to 110 S/cm for heavily doped sample. The changes from Mott variable-range hopping process to thermally activation conduction process with the temperature are identified and discussed. PMID- 27460595 TI - Hydrothermal Synthesis of ZnO Structures Formed by High-Aspect-Ratio Nanowires for Acetone Detection. AB - Snowflake-like ZnO structures originating from self-assembled nanowires were prepared by a low-temperature aqueous solution method. The as-grown hierarchical ZnO structures were investigated by X-ray diffraction (XRD) and field-emission scanning electron microscopy (FESEM). The results showed that the snowflake-like ZnO structures were composed of high-aspect-ratio nanowires. Furthermore, gas sensing properties to various testing gases of 10 and 50 ppm were measured, which confirms that the ZnO structures were of good selectivity and response to acetone and could serve for acetone sensor to detect low-concentration acetone. PMID- 27460596 TI - Small Molecule-Assisted Exfoliation of Layered Zirconium Phosphate Nanoplatelets by Ionic Liquids. AB - Exfoliation of layered inorganic nanomaterials into single-layered sheets has been widely interested in materials chemistry and composite fabrication. Here, we report the exfoliation of layered zirconium phosphate nanoplatelets by using small molecule intercalating agents in ionic liquids, which opens a new platform for fabricating single-layered inorganic materials from synthetic layered compounds. PMID- 27460597 TI - Self-forming TiBN Nanocomposite Multilayer Coating Prepared by Pulse Cathode Arc Method. AB - Novel multilayer structured TiBN coatings were deposited on Si (100) substrate using TiBN complex cathode plasma immersion ion implantation and deposition technique (PIIID). The coatings were characterized by X-ray diffraction (XRD), high-resolution transmission electron microcopy (HRTEM), energy-dispersive spectrometer (EDS) and ball-on-disk test. XRD results reveal that both samples of TiBN coatings have the main diffraction peak of TiN (200) and (220). Cross section TEM images reveal that these coatings have the character of self-forming multilayer and consists of face-centered cubic TiN and hexagonal BN nanocrystalline embedded in amorphous matrix. Because of the existence of hexagonal BN, the friction coefficient of the new TiBN coating in room temperature is obviously lower than that of the monolithic TiN nanocrystalline coating. PMID- 27460598 TI - Conflicting perspectives on neurobehavioral theories of the depressive disorders and drug actions. AB - OBJECTIVE: A prominent theory of depression focusses on neural plasticity and stress as central issues in seeking to develop a pattern of identifiable biological markers for the depressive disorders. Relative neglect, however, of clinical factors in that theory limits the uncovering of markers and opens to question their methodological approach. A conflicting theory, the 'opposed neurobehavioral states', based on dimensional analysis of monoamine neurotransmitter systems and behavioural factors is presented. This perspectives paper contrasts the two approaches viewing the biomarkers theory as premature at this point in the progress of depression research. METHOD: Studies developed to support the biomarkers theory and the opposed neurobehavioral states theory are examined for their strengths and limitations in explaining the nature of the disorder and the actions of therapeutic drugs. Reference is made to reviews of the many studies on biomarkers and the recent work that supports the opposed neurobehavioral states theory. Discussion Main issue: the biomarkers theory sets important goals, but despite the many advances in the neural investigations of factors underlying depression, is still not successful in specifying markers. Thus, it is believed to be applying the wrong methodologic approach and premature in its claims. PERSPECTIVE: the 'opposed neurobehavioral' theory is limited in its breadth of research. It applies, however, the dimensional approach to the clinical side of the problem, a methodological approach more likely to be effective in selecting the best clinical treatment and open to a more productive path to understanding of the nature of the disorder in future research. PMID- 27460599 TI - Epigenetic changes in cancer by Raman imaging, fluorescence imaging, AFM and scanning near-field optical microscopy (SNOM). Acetylation in normal and human cancer breast cells MCF10A, MCF7 and MDA-MB-231. AB - This paper examines epigenetic changes in breast cancer by Raman imaging, fluorescence imaging, AFM and SNOM and discusses how they contribute to different aspects of tumourigenesis in malignant human breast epithelial cell lines MCF7 and MDA-MB-231 compared with non-malignant MCF10A cell lines. The paper focuses on information that can be extracted from Raman microscopy and Raman imaging for the biological material of nucleoli contained within the cell nucleus and lipid droplets within the cell cytoplasm. The biochemical composition of the nuclei and lipid droplets in the non-malignant and malignant human breast epithelial cell lines has been monitored. The potential of Raman microspectroscopy to monitor acetylation processes and a prognostic value of Raman biomarkers in breast cancer have been discussed. PMID- 27460600 TI - Controlling the Localization of Liquid Droplets in Polymer Matrices by Evaporative Lithography. AB - Localized inclusions of liquids provide solid materials with many functions, such as self-healing, secretion, and tunable mechanical properties, in a spatially controlled mode. However, a strategy to control the distribution of liquid droplets in solid matrices directly obtained from a homogeneous solution has not been reported thus far. Herein, we describe an approach to selectively localize liquid droplets in a supramolecular gel directly obtained from its solution by using evaporative lithography. In this process, the formation of droplet-embedded domains occurs in regions of free evaporation where the non-volatile liquid is concentrated and undergoes a phase separation to create liquid droplets prior to gelation, while a homogeneous gel matrix is formed in the regions of hindered evaporation. The different regions of a coating with droplet embedment patterns display different secretion abilities, enabling the control of the directional movement of water droplets. PMID- 27460601 TI - Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome. AB - BACKGROUND/OBJECTIVES: Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-beta (TRbeta)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings. SUBJECTS/METHODS: Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and beta-cell area were assessed. RESULTS: GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TRbeta selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1a, Cidea, Dio2 and Cox5a showed significant upregulation in WAT in NMD-GC-1-treated mice, but decreased in BAT. Although mice treated by NMD GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in beta-cell area. CONCLUSIONS: Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance. PMID- 27460602 TI - Two-year changes in circulating adiponectin, ectopic fat distribution and body composition in response to weight-loss diets: the POUNDS Lost Trial. AB - BACKGROUND/OBJECTIVES: Adiponectin has a pivotal role in linking fat distribution with cardiometabolic disorders. We investigated the associations of long-term changes in circulating adiponectin with body composition and fat distribution at different abdominal depots in response to weight-loss dietary interventions, as well as the modification effect of sex. SUBJECTS/METHODS: In the 2-year Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial, 811 overweight or obese adults were randomly assigned to one of four diets varying in macronutrient intakes. Circulating concentrations of adiponectin were repeatedly measured at baseline, 6 months and 2 years. Body composition and fat distribution were repeatedly measured by dual-energy X-ray absorptiometry scan (n=424) and computed tomography (n=195). RESULTS: Over the 2-year intervention, after adjustment for age, sex, ethnicity, follow-up time, diet group, baseline body mass index and baseline level of respective outcome trait, increase of adiponectin was significantly associated with reduction of total fat mass (FM), total fat-free mass (FFM), whole body total percentage of fat mass (FM%), percentage of trunk fat (TF%), total adipose tissue (TAT), and adipose tissue mass at different depots including visceral (VAT), deep subcutaneous (DSAT) and superficial subcutaneous (SSAT; P<0.03 for each). The relations with FM, FM%, TF%, VAT and DSAT were significantly modified by sex (P for interaction=0.02, 0.005 and <0.001, 0.002, 0.03, respectively) with greater reductions associated with increase of adiponectin in men than in women. CONCLUSIONS: Long-term changes in circulating adiponectin were differentially associated with improvement of body composition and abdominal fat distribution in men and women. PMID- 27460603 TI - State-level estimates of childhood obesity prevalence in the United States corrected for report bias. AB - BACKGROUND/OBJECTIVES: State-specific obesity prevalence data are critical to public health efforts to address the childhood obesity epidemic. However, few states administer objectively measured body mass index (BMI) surveillance programs. This study reports state-specific childhood obesity prevalence by age and sex correcting for parent-reported child height and weight bias. SUBJECTS/METHODS: As part of the Childhood Obesity Intervention Cost Effectiveness Study (CHOICES), we developed childhood obesity prevalence estimates for states for the period 2005-2010 using data from the 2010 US Census and American Community Survey (ACS), 2003-2004 and 2007-2008 National Survey of Children's Health (NSCH) (n=133 213), and 2005-2010 National Health and Nutrition Examination Surveys (NHANES) (n=9377; ages 2-17). Measured height and weight data from NHANES were used to correct parent-report bias in NSCH using a non parametric statistical matching algorithm. Model estimates were validated against surveillance data from five states (AR, FL, MA, PA and TN) that conduct censuses of children across a range of grades. RESULTS: Parent-reported height and weight resulted in the largest overestimation of childhood obesity in males ages 2-5 years (NSCH: 42.36% vs NHANES: 11.44%). The CHOICES model estimates for this group (12.81%) and for all age and sex categories were not statistically different from NHANES. Our modeled obesity prevalence aligned closely with measured data from five validation states, with a 0.64 percentage point mean difference (range: 0.23-1.39) and a high correlation coefficient (r=0.96, P=0.009). Estimated state-specific childhood obesity prevalence ranged from 11.0 to 20.4%. CONCLUSION: Uncorrected estimates of childhood obesity prevalence from NSCH vary widely from measured national data, from a 278% overestimate among males aged 2-5 years to a 44% underestimate among females aged 14-17 years. This study demonstrates the validity of the CHOICES matching methods to correct the bias of parent-reported BMI data and highlights the need for public release of more recent data from the 2011 to 2012 NSCH. PMID- 27460604 TI - Novel genes on rat chromosome 10 are linked to body fat mass, preadipocyte number and adipocyte size. AB - BACKGROUND: The genetic architecture of obesity is multifactorial. We have previously identified a quantitative trait locus (QTL) on rat chromosome 10 in a F2 cross of Wistar Ottawa Karlsburg (WOKW) and Dark Agouti (DA) rats responsible for obesity-related traits. The QTL was confirmed in congenic DA.WOKW10 rats. To pinpoint the region carrying causal genes, we established two new subcongenic lines, L1 and L2, with smaller refined segments of chromosome 10 to identify novel candidate genes. METHODS: All lines were extensively characterized under different diet conditions. We employed transcriptome analysis in visceral adipose tissue (VAT) by RNA-Seq technology to identify potential underlying genes in the segregating regions. Three candidate genes were measured in human paired samples of VAT and subcutaneous (SC) AT (SAT) (N=304) individuals with a wide range of body weight and glucose homeostasis parameters. RESULTS: DA.WOKW and L1 subcongenic lines were protected against body fat gain under high-fat diet (HFD), whereas L2 and DA had significantly more body fat after high-fat feeding. Interestingly, adipocyte size distribution in SAT and epigonadal AT of L1 subcongenic rats did not undergo typical ballooning under HFD and the number of preadipocytes in AT was significantly elevated in L2 compared with L1 and parental rats. Transcriptome analysis identified three candidate genes in VAT on rat chromosome 10. In humans, these candidate genes were differentially expressed between SAT and VAT. Moreover, HID1 mRNA significantly correlates with parameters of obesity and glucose metabolism. CONCLUSIONS: Our data suggest novel candidate genes for obesity that map on rat chromosome 10 in an interval 102.2-104.7 Mb and are strongly associated with body fat mass regulation, preadipocyte number and adipocyte size in rats. Among those genes, AT head involution defective (HID1) mRNA expression may be relevant for human fat distribution and glucose homeostasis. PMID- 27460605 TI - Author's response: Dysfunction of small airways and prevalence, airway responsiveness and inflammation in asthma: much more than small particle size of pet animal allergens. PMID- 27460606 TI - SIDS-CDF hypothesis revisited: explaining hypoxia in SIDS. PMID- 27460608 TI - Oxygen exchange at gas/oxide interfaces: how the apparent activation energy of the surface exchange coefficient depends on the kinetic regime. AB - In the dedicated literature the oxygen surface exchange coefficient KO and the equilibrium oxygen exchange rate [Fraktur R] are considered to be directly proportional to each other regardless of the experimental circumstances. Recent experimental observations, however, contradict the consequences of this assumption. Most surprising is the finding that the apparent activation energy of KO depends dramatically on the kinetic regime in which it has been determined, i.e. surface exchange controlled vs. mixed or diffusion controlled. This work demonstrates how the diffusion boundary condition at the gas/solid interface inevitably entails a correlation between the oxygen surface exchange coefficient KO and the oxygen self-diffusion coefficient DO in the bulk ("on top" of the correlation between KO and [Fraktur R] for the pure surface exchange regime). The model can thus quantitatively explain the range of apparent activation energies measured in the different regimes: in the surface exchange regime the apparent activation energy only contains the contribution of the equilibrium exchange rate, whereas in the mixed or in the diffusion controlled regime the contribution of the oxygen self-diffusivity has also to be taken into account, which may yield significantly higher apparent activation energies and simultaneously quantifies the correlation KO ? DO(1/2) observed for a large number of oxides in the mixed or diffusion controlled regime, respectively. PMID- 27460607 TI - Multiple-component covalent organic frameworks. AB - Covalent organic frameworks are a class of crystalline porous polymers that integrate molecular building blocks into periodic structures and are usually synthesized using two-component [1+1] condensation systems comprised of one knot and one linker. Here we report a general strategy based on multiple-component [1+2] and [1+3] condensation systems that enable the use of one knot and two or three linker units for the synthesis of hexagonal and tetragonal multiple component covalent organic frameworks. Unlike two-component systems, multiple component covalent organic frameworks feature asymmetric tiling of organic units into anisotropic skeletons and unusually shaped pores. This strategy not only expands the structural complexity of skeletons and pores but also greatly enhances their structural diversity. This synthetic platform is also widely applicable to multiple-component electron donor-acceptor systems, which lead to electronic properties that are not simply linear summations of those of the conventional [1+1] counterparts. PMID- 27460613 TI - Special Supplement Introduction: The Fourth Kraepelin Symposium-Cognitive Dysfunction in Schizophrenia: Origins and Innovative Treatment. AB - This Special Supplement presents reports from working groups meeting at the Fourth Kraepelin Symposium in Munich, Germany, in September 2014. It covers the origins and therapy of cognitive dysfunction in schizophrenia. Cognitive deficits are core symptoms of schizophrenia being decisive for the long-term prognosis only improved moderately by antipsychotic treatment, however, showing more evidence for cognitive remediation. The authors refer to neurobiological and psychological underpinnings of cognitive deficits and to innovative treatment interventions aimed at improving cognitive dysfunction in order to improve outcome and to support coping with the illness. Therapeutic approaches include aerobic exercise, cognitive training, psychoeducation, cognitive therapy, noninvasive brain stimulation and pharmacotherapy in acute to post-acute patients. The supplement also presents novel diagnostic tools for early recognition, such as biomarkers, as well as cognitive training to prevent worsening of symptoms in individuals at clinical high risk for psychosis. In recent years there has been progress in basic science and outcomes research as well as psychopharmacological and psychological treatment options. Despite of this, treatment of cognitive deficits needs significant improvement and further research is needed. PMID- 27460614 TI - Classifying Schizophrenia Using Multimodal Multivariate Pattern Recognition Analysis: Evaluating the Impact of Individual Clinical Profiles on the Neurodiagnostic Performance. AB - Previous studies have shown that structural brain changes are among the best studied candidate markers for schizophrenia (SZ) along with functional connectivity (FC) alterations of resting-state (RS) patterns. This study aimed to investigate effects of clinical and sociodemographic variables on the classification by applying multivariate pattern analysis (MVPA) to both gray matter (GM) volume and FC measures in patients with SZ and healthy controls (HC). RS and structural magnetic resonance imaging data (sMRI) from 74 HC and 71 SZ patients were obtained from a Mind Research Network COBRE dataset available via COINS (http://coins.mrn.org/dx). We used a MVPA framework using support-vector machines embedded in a repeated, nested cross-validation to generate a multi modal diagnostic system and evaluate its generalizability. The dependence of neurodiagnostic performance on clinical and sociodemographic variables was evaluated. The RS classifier showed a slightly higher accuracy (70.5%) compared to the structural classifier (69.7%). The combination of sMRI and RS outperformed single MRI modalities classification by reaching 75% accuracy. The RS based moderator analysis revealed that the neurodiagnostic performance was driven by older SZ patients with an earlier illness onset and more pronounced negative symptoms. In contrast, there was no linear relationship between the clinical variables and neuroanatomically derived group membership measures. This study achieved higher accuracy distinguishing HC from SZ patients by fusing 2 imaging modalities. In addition the results of RS based moderator analysis showed that age of patients, as well as their age at the illness onset were the most important clinical features. PMID- 27460615 TI - Aberrant Functional Whole-Brain Network Architecture in Patients With Schizophrenia: A Meta-analysis. AB - Findings from multiple lines of research provide evidence of aberrant functional brain connectivity in schizophrenia. By using graph-analytical measures, recent studies indicate that patients with schizophrenia exhibit changes in the organizational principles of whole-brain networks and that these changes relate to cognitive symptoms. However, there has not been a systematic investigation of functional brain network changes in schizophrenia to test the consistency of these changes across multiple studies. A comprehensive literature search was conducted to identify all available functional graph-analytical studies in patients with schizophrenia. Effect size measures were derived from each study and entered in a random-effects meta-analytical model. All models were tested for effects of potential moderator variables as well as for the presence of publication bias. The results of a total of n = 13 functional neuroimaging studies indicated that brain networks in patients with schizophrenia exhibit significant decreases in measures of local organization (g = -0.56, P = .02) and significant decreases in small-worldness (g = -0.65, P = .01) whereas global short communication paths seemed to be preserved (g = 0.26, P = .32). There was no evidence for a publication bias or moderator effects. The present meta- analysis demonstrates significant changes in whole brain network architecture associated with schizophrenia across studies. PMID- 27460616 TI - Psychological Mechanisms Mediating Effects Between Trauma and Psychotic Symptoms: The Role of Affect Regulation, Intrusive Trauma Memory, Beliefs, and Depression. AB - Evidence suggests a causal role for trauma in psychosis, particularly for childhood victimization. However, the establishment of underlying trauma-related mechanisms would strengthen the causal argument. In a sample of people with relapsing psychosis (n = 228), we tested hypothesized mechanisms specifically related to impaired affect regulation, intrusive trauma memory, beliefs, and depression. The majority of participants (74.1%) reported victimization trauma, and a fifth (21.5%) met symptomatic criteria for Posttraumatic Stress Disorder. We found a specific link between childhood sexual abuse and auditory hallucinations (adjusted OR = 2.21, SE = 0.74, P = .018). This relationship was mediated by posttraumatic avoidance and numbing (OR = 1.48, SE = 0.19, P = .038) and hyperarousal (OR = 1.44, SE = 0.18, P = .045), but not intrusive trauma memory, negative beliefs or depression. In contrast, childhood emotional abuse was specifically associated with delusions, both persecutory (adjusted OR = 2.21, SE = 0.68, P = .009) and referential (adjusted OR = 2.43, SE = 0.74, P = .004). The link with persecutory delusions was mediated by negative-other beliefs (OR = 1.36, SE = 0.14, P = .024), but not posttraumatic stress symptoms, negative-self beliefs, or depression. There was no evidence of mediation for referential delusions. No relationships were identified between childhood physical abuse and psychosis. The findings underline the role of cognitive-affective processes in the relationship between trauma and symptoms, and the importance of assessing and treating victimization and its psychological consequences in people with psychosis. PMID- 27460617 TI - Decreased Oligodendrocyte and Neuron Number in Anterior Hippocampal Areas and the Entire Hippocampus in Schizophrenia: A Stereological Postmortem Study. AB - The hippocampus is involved in cognition as well as emotion, with deficits in both domains consistently described in schizophrenia. Moreover, the whole volumes of both the anterior and posterior region have been reported to be decreased in schizophrenia patients. While fewer oligodendrocyte numbers in the left and right cornu ammonis CA4 subregion of the posterior part of the hippocampus have been reported, the aim of this stereological study was to investigate cell numbers in either the dentate gyrus (DG) or subregions of the anterior hippocampus. In this design-based stereological study of the anterior part of the hippocampus comparing 10 patients with schizophrenia to 10 age- and gender-matched healthy controls were examined. Patients showed a decreased number of oligodendrocytes in the left CA4, fewer neurons in the left DG and smaller volumes in both the left CA4 and DG, which correlated with oligodendrocyte and neuron numbers, respectively. When exploring the total hippocampus, keeping previously published own results from the posterior part of the same brains in mind, both decreased oligodendrocyte numbers in the left CA4 and reduced volume remained significant. The decreased oligodendrocyte number speaks for a deficit in myelination and connectivity in schizophrenia which may originate from disturbed maturational processes. The reduced neuron number of the DG in the anterior hippocampus may well point to a reduced capacity of this region to produce new neurons up to adulthood. Both mechanisms may be involved in cognitive dysfunction in schizophrenia patients. PMID- 27460619 TI - Treatment of Cognition in the Schizophrenia Spectrum: The Context of Psychiatric Rehabilitation. AB - Evidence-based approaches and modalities for targeting and treating the cognitive impairments of schizophrenia have proliferated over the past 15 years. The impairments targeted are distributed across the cognitive spectrum, from elemental perception, attention, and memory, to complex executive and social cognitive functioning. Cognitive treatment is most beneficial when embedded in comprehensive programs of psychiatric rehabilitation. To personalize comprehensive treatment and rehabilitation of schizophrenia spectrum disorders, practitioners and participants must select from a rapidly expanding array of particular modalities and apply them in the broad context of the participant's overall recovery. At present, no particular treatment, cognitive or otherwise, can be considered more important or primary than the context in which it is applied. Persistent difficulty in dissemination of new technology for severe and disabling mental illness compounds the significance of the context created by a full treatment array. In this article, a case-study of a mental health service system is described, showing the broad-ranging effects of degrading the rehabilitative context of treatments, obviating the benefits of cognitive treatment and other modalities. To realize the promise of cognitive treatment, the problems that prevent dissemination and maintenance of complete psychiatric rehabilitation programs have to be addressed. PMID- 27460618 TI - Enhancing Cognitive Training Through Aerobic Exercise After a First Schizophrenia Episode: Theoretical Conception and Pilot Study. AB - Cognitive training (CT) and aerobic exercise have separately shown promise for improving cognitive deficits in schizophrenia. Aerobic exercise releases brain derived neurotrophic factor, which promotes synaptic plasticity and neurogenesis. Thus, aerobic exercise provides a neurotrophic platform for neuroplasticity-based CT. The combination of aerobic exercise and CT may yield more robust effects than CT alone, particularly in the initial course of schizophrenia. In a pilot study, 7 patients with a recent onset of schizophrenia were assigned to Cognitive Training & Exercise (CT&E) and 9 to CT alone for a 10-week period. Posit Science programs were used for CT. Neurocognitive training focused on tuning neural circuits related to perceptual processing and verbal learning and memory. Social cognitive training used the same learning principles with social and affective stimuli. Both groups participated in these training sessions 2d/wk, 2h/d. The CT&E group also participated in an aerobic conditioning program for 30 minutes at our clinic 2d/wk and at home 2d/wk. The effect size for improvement in the MATRICS Consensus Cognitive Battery Overall Composite score for CT&E patients relative to CT patients was large. Functional outcome, particularly independent living skills, also tended to improve more in the CT&E than in the CT group. Muscular endurance, cardiovascular fitness, and diastolic blood pressure also showed relative improvement in the CT&E compared to the CT group. These encouraging pilot study findings support the promise of combining CT and aerobic exercise to improve the early course of schizophrenia. PMID- 27460620 TI - A Randomized Controlled Trial of Group Coping-Oriented Therapy vs Supportive Therapy in Schizophrenia: Results of a 2-Year Follow-up. AB - OBJECTIVE: Over the past 30 years, illness management programs and cognitive behavioral therapy for psychosis have gained prominence in the treatment of schizophrenia. However, little is known about the long-term benefits of these types of programs when delivered during inpatient treatment following a symptom exacerbation. To evaluate this question, we conducted a randomized controlled trial comparing the long-term effects of a group-based coping-oriented program (COP) that combined the elements of illness management with cognitive behavioral therapy for psychosis, with an equally intensive supportive therapy (SUP) program. METHOD: 196 inpatients with DSM-IV schizophrenia were randomized to COP or SUP, each lasting 12 sessions provided over 6-8 weeks. Outcome measures were collected in the hospital at baseline and post-assessment, and following discharge into the community 1 and 2 years later. We compared the groups on rehospitalizations, symptoms, psychosocial functioning, and knowledge about psychosis. RESULTS: Intent-to-treat analyses indicated that patients in COP learned significantly more information about psychosis, and had greater reductions in overall symptoms and depression/anxiety over the treatment and follow-up period than patients in SUP. Patients in both groups improved significantly in other symptoms and psychosocial functioning. There were no differences between the groups in hospitalization rates, which were low. CONCLUSIONS: People with schizophrenia can benefit from short-term COPs delivered during the inpatient phase, with improvements sustaining for 2 years following discharge from the hospital. More research is needed to evaluate the long-term impact of coping-oriented and similar programs provided during inpatient treatment. PMID- 27460621 TI - Psychoeducational and Cognitive Behavioral Treatment Programs: Implementation and Evaluation From 1995 to 2015 in Kraepelin's Former Hospital. AB - OBJECTIVE: Programs that view individuals as capable of taking an active role in managing their illness have gained importance in Europe and the United States. This article describes the implementation and evaluation of group psychoeducational and cognitive behavioral treatment programs at the Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany, over the past 20 years. METHODS: Implementing psychoeducational programs was the first step to establish cognitive behavioral psychotherapy and dispel the myth of schizophrenia for patients. Programs are also provided for patients with mood disorders, substance use disorders, or both. These groups include topics such as psychoeducation about the illness, establishing rewarding activities, stress management, cognitive therapy, and relapse prevention. RESULTS: More than 1000 patients with schizophrenia or mood disorders (380 schizophrenia, 563 major depression, and 110 bipolar) have participated in illness management groups to learn about their illness and its treatment, and to learn skills to manage their illness. Patients have expressed satisfaction with the programs, and research has supported their effectiveness. CONCLUSIONS: Individuals with severe disorders can benefit from psychoeducational and cognitive treatment programs if the programs are adapted to the level of neuropsychological functioning and compensate for cognitive deficits and emotional overload. These findings suggest that providing information about the illness and coping skills for patients and relatives are important for treatment outcome. PMID- 27460622 TI - Dose Equivalents for Antipsychotic Drugs: The DDD Method. AB - BACKGROUND: Dose equivalents of antipsychotics are an important but difficult to define concept, because all methods have weaknesses and strongholds. METHODS: We calculated dose equivalents based on defined daily doses (DDDs) presented by the World Health Organisation's Collaborative Center for Drug Statistics Methodology. Doses equivalent to 1mg olanzapine, 1mg risperidone, 1mg haloperidol, and 100mg chlorpromazine were presented and compared with the results of 3 other methods to define dose equivalence (the "minimum effective dose method," the "classical mean dose method," and an international consensus statement). RESULTS: We presented dose equivalents for 57 first-generation and second-generation antipsychotic drugs, available as oral, parenteral, or depot formulations. Overall, the identified equivalent doses were comparable with those of the other methods, but there were also outliers. CONCLUSIONS: The major strength of this method to define dose response is that DDDs are available for most drugs, including old antipsychotics, that they are based on a variety of sources, and that DDDs are an internationally accepted measure. The major limitations are that the information used to estimate DDDS is likely to differ between the drugs. Moreover, this information is not publicly available, so that it cannot be reviewed. The WHO stresses that DDDs are mainly a standardized measure of drug consumption, and their use as a measure of dose equivalence can therefore be misleading. We, therefore, recommend that if alternative, more "scientific" dose equivalence methods are available for a drug they should be preferred to DDDs. Moreover, our summary can be a useful resource for pharmacovigilance studies. PMID- 27460624 TI - Now Is the Time for a Cybersecurity Standard for Connected Diabetes Devices. PMID- 27460623 TI - Repetitive Noninvasive Brain Stimulation to Modulate Cognitive Functions in Schizophrenia: A Systematic Review of Primary and Secondary Outcomes. AB - Despite many years of research, there is still an urgent need for new therapeutic options for the treatment of cognitive deficits in schizophrenia. Noninvasive brain stimulation (NIBS) has been proposed to be such a novel add-on treatment option. The main objective of this review was to systematically evaluate the cognitive effects of repetitive NIBS in schizophrenia. As most studies have not been specifically designed to investigate cognition as primary outcome, we have focused on both, primary and secondary outcomes. The PubMed/MEDLINE database (1985-2015) was systematically searched for interventional studies investigating the effects of repetitive NIBS on schizophrenia symptoms. All interventional clinical trials using repetitive transcranial stimulation, transcranial theta burst stimulation, and transcranial direct current stimulation for the treatment of schizophrenia were extracted and analyzed with regard to cognitive measures as primary or secondary outcomes. Seventy-six full-text articles were assessed for eligibility of which 33 studies were included in the qualitative synthesis. Of these 33 studies, only 4 studies included cognition as primary outcome, whereas 29 studies included cognitive measures as secondary outcomes. A beneficial effect of frontal NIBS could not be clearly established. No evidence for a cognitive disruptive effect of NIBS (temporal lobe) in schizophrenia could be detected. Finally, a large heterogeneity between studies in terms of inclusion criteria, stimulation parameters, applied cognitive measures, and follow-up intervals was observed. This review provides the first systematic overview regarding cognitive effects of repetitive NIBS in schizophrenia. PMID- 27460625 TI - DialBetics: Smartphone-Based Self-Management for Type 2 Diabetes Patients on Insulin Injections. PMID- 27460626 TI - Corrigendum. AB - dos Santos Silva M, Ramos LR, Tufik S, Togeiro SM, Lopes GS. Influence of Inspiratory Muscle Training on Changes in Fasting Hyperglycemia in the Older Adult: The Epidoso Project. J Diabetes Sci Technol. 2015;9:1352-1353.(Original DOI: 10.1177/1932296815599006)In the above article, published in Journal of Diabetes Science and Technology on July 2015, has incorrectly informed that professor Dr Guiomar Silva Lopes is related to the Preventine Medicine Department of Federal University of Sao Paulo. In fact, on the date of its submission and publication, the aforementioned professor was a member of Nursing Department of Federal University of Sao Paulo. PMID- 27460627 TI - The Prevalence of Sexual Behavior Stigma Affecting Gay Men and Other Men Who Have Sex with Men Across Sub-Saharan Africa and in the United States. AB - BACKGROUND: There has been increased attention for the need to reduce stigma related to sexual behaviors among gay men and other men who have sex with men (MSM) as part of comprehensive human immunodeficiency virus (HIV) prevention and treatment programming. However, most studies focused on measuring and mitigating stigma have been in high-income settings, challenging the ability to characterize the transferability of these findings because of lack of consistent metrics across settings. OBJECTIVE: The objective of these analyses is to describe the prevalence of sexual behavior stigma in the United States, and to compare the prevalence of sexual behavior stigma between MSM in Southern and Western Africa and in the United States using consistent metrics. METHODS: The same 13 sexual behavior stigma items were administered in face-to-face interviews to 4285 MSM recruited in multiple studies from 2013 to 2016 from 7 Sub-Saharan African countries and to 2590 MSM from the 2015 American Men's Internet Survey (AMIS), an anonymous Web-based behavioral survey. We limited the study sample to men who reported anal sex with a man at least once in the past 12 months and men who were aged 18 years and older. Unadjusted and adjusted prevalence ratios were used to compare the prevalence of stigma between groups. RESULTS: Within the United States, prevalence of sexual behavior stigma did not vary substantially by race/ethnicity or geographic region except in a few instances. Feeling afraid to seek health care, avoiding health care, feeling like police refused to protect, being blackmailed, and being raped were more commonly reported in rural versus urban settings in the United States (P<.05 for all). In the United States, West Africa, and Southern Africa, MSM reported verbal harassment as the most common form of stigma. Disclosure of same-sex practices to family members increased prevalence of reported stigma from family members within all geographic settings (P<.001 for all). After adjusting for potential confounders and nesting of participants within countries, AMIS-2015 participants reported a higher prevalence of family exclusion (P=.02) and poor health care treatment (P=.009) as compared with participants in West Africa. However, participants in both West Africa (P<.001) and Southern Africa (P<.001) reported a higher prevalence of blackmail. The prevalence of all other types of stigma was not found to be statistically significantly different across settings. CONCLUSIONS: The prevalence of sexual behavior stigma among MSM in the United States appears to have a high absolute burden and similar pattern as the same forms of stigma reported by MSM in Sub-Saharan Africa, although results may be influenced by differences in sampling methodology across regions. The disproportionate burden of HIV is consistent among MSM across Sub-Saharan Africa and the United States, suggesting the need in all contexts for stigma mitigation interventions to optimize existing evidence-based and human-rights affirming HIV prevention and treatment interventions. PMID- 27460628 TI - Assessment of quality of life in people living with HIV in Georgia. AB - The purpose of our study was to assess quality of life (QoL) among Georgian HIV infected individuals and to examine factors associated with QoL. Our cross sectional study sample consisted of 201 HIV-infected adult outpatients recruited at the National AIDS Center in Tbilisi, Georgia. WHOQOL-HIV-BREF was used to measure QoL. Data about other variables of interest were obtained from medical records. Modified Poisson regression with robust variance estimates was performed to create a predictive model of factors that influenced QoL. The study results showed the following factors as predictors of good general QoL: antiretroviral (ARV) treatment (prevalence ratio (PR)=2.87 (95% CI: 1.45, 5.67)); higher education level (PR = 1.51 (95% CI: 1.05, 2.17)); CD4 cells >=200 cells/mm3 (PR = 1.83 (95% CI: 1.13, 2.94)); and age >=40 years (PR = 1.60 (95% CI: 1.09, 2.36)). However, all factors examined were associated with at least one QoL domain. Our study suggests that HIV-infected individuals younger than 40 years and those with lower education level are more likely to have poorer QoL, while those receiving ARV treatment tend to have better QoL. This highlights the importance of educational interventions and ARV treatment in HIV patients. Future research should seek to implement additional evidence-based actions to improve QoL in this population. PMID- 27460629 TI - Biokinetics of 13C in the human body after oral administration of 13C-labeled glucose as an index for the biokinetics of 14C. AB - The retention of 13C in the human body after oral administration of 13C-labeled glucose was studied in three healthy volunteer subjects to estimate the 50 year cumulative body burden for 13C as an index of the committed dose of the radioisotope 14C. After administration of 13C-labeled glucose, the volunteers ingested controlled diets with a fixed number of calories for 112 d. Samples of breath and urine were collected up to 112 d after administration. Samples of feces were collected up to 14 d after administration. Hair samples were obtained at 119 d after administration and analyzed as a representative index of the rate of excretion of organic 13C via pathways such as skin cell exfoliation and mucus secretion. All samples were analyzed for 13C/12C atomic ratio to determine the rate of excretion via each pathway. We then constructed a metabolic model with a total of four pathways (breath, urine, feces, and other) comprising seven compartments. We determined the values of the biokinetic parameters in the model by using the obtained excretion data. From 74% to 94% of the 13C administered was excreted in breath, whereas <2% was excreted in urine and feces. In the other pathway, the excretion rate constant in the compartment with the longest residence time stretched to hundreds of days but the rate constant for each subject was not statistically significant (P value > 0.1). In addition, the dataset for one of the three subjects was markedly different from those of the other two. When we estimated the 50 year cumulative body burden for 13C by using our model and we included non-statistically significant parameters, a considerable cumulative body burden was found in the compartments excreting to the other pathway. Although our results on the cumulative body burden of 13C from orally administered carbon as glucose were inconclusive, we found that the compartments excreting to the other pathway had a markedly long residence time and therefore should be studied further to clarify the fate of carbon in the human body. In addition to excreta, data for serum and blood cell samples were also collected from the subjects to examine the metabolism of 13C in human body. PMID- 27460630 TI - Protective effects of miR-29a on diabetic glomerular dysfunction by modulation of DKK1/Wnt/beta-catenin signaling. AB - Dysregulation of specific microRNAs or Wnt/beta-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases. However, the relationship between microRNAs and Wnt/beta-catenin signaling in diabetes-induced glomerular sclerosis remains unknown. Here, we found that decreased miR-29a expression and attenuated Wnt/beta-catenin signaling were concomitantly detected in glomeruli of streptozotocin-induced diabetic mice. Gain of miR-29a function in diabetic mice substantially increased the expression of beta-catenin and blocked the expressions of profibrotic gene markers, including DKK1 (a Wnt antagonist), TGF-beta1 and fibronectin, in glomerular mesangium. Moreover, in the normal mice treated with miR-29a inhibitor, renal fibrosis was induced with an attenuated Wnt/beta-catenin signaling activity. Consistently, the constructed miR-29a transgenic mice that supported sustained Wnt/beta-catenin signaling had the ability to block the expressions of profibrotic genes after induction of diabetes. We also demonstrated that miR-29a acts as a positive regulator of Wnt/beta-catenin signaling in cultured mesangial cells and functions to protect cell apoptosis and fibrosis. Importantly, we showed that activation of Wnt/beta catenin signaling in cultured mesangial cells by transfecting the beta-catenin (Delta45) mutant or by a GSK-3beta inhibitor reversely upregulated miR29a. Our findings suggest that the reciprocal relationship between miR-29a and DKK1/Wnt/beta-catenin signaling may play an important part in protecting renal fibrogenesis. PMID- 27460631 TI - Developmental exposure to paraquat and maneb can impair cognition, learning and memory in Sprague-Dawley rats. AB - Paraquat and maneb are identified environmental pollutants. Combined exposure to paraquat and maneb is a latent risk factor for many diseases, particularly those of the central nervous system, including Parkinson's disease and Alzheimer's disease. Hippocampus is the key structure in memory formation and babies are more sensitive to environmental stimuli than adults, so we investigated the neurotoxicity of paraquat and maneb on the hippocampi of rat pups. Female and male Sprague-Dawley rats were mated (female : male = 2 : 1) every night for a week. The gravid rats were randomly divided into three groups (one control and two experimental groups). A mixed solution of paraquat-maneb was administered twice a week by lavage at a dose of 10 or 15 mg kg(-1) bodyweight (containing 30 or 45 mg kg(-1) bodyweight maneb, respectively) from day 6 after pregnancy till ablactation. Maternal weight gain and offspring bodyweights were not affected by the drugs. However, behavioral tests showed that reaction latency and mistake frequency increased after treatment. Intuitively, we found significant changes in the hippocampal neurons in the morphological observation. Taking into account the interaction of the related genes in the cAMP-PKA-CREB pathway, we used a variety of methods to detect the gene and protein levels. Reduced expression of cAMP and related genes and proteins in the hippocampus and serum was also observed. These results indicate that PQ-MB stimulates cAMP to reduce the production of PKA, thus reducing the phosphorylation of CREB and inhibiting the activation of other elements (BDNF, C-JUN, and C-FOS). These changes lead to hippocampal damage and impaired abilities (learning, cognition, and memory). Our results demonstrate that PQ-MB induces hippocampal toxicity in the early life of rats, and they thus provide a theoretical foundation for further investigation of the bathypelagic mechanism involved and measures that can be taken to avoid PQ-MB neurotoxicity. PMID- 27460632 TI - Importance of the Correlation between Width and Length in the Shape Analysis of Nanorods: Use of a 2D Size Plot To Probe Such a Correlation. AB - Analysis of nanoparticle size through a simple 2D plot is proposed in order to extract the correlation between length and width in a collection or a mixture of anisotropic particles. Compared to the usual statistics on the length associated with a second and independent statistical analysis of the width, this simple plot easily points out the various types of nanoparticles and their (an)isotropy. For each class of nano-objects, the relationship between width and length (i.e., the strong or weak correlations between these two parameters) may suggest information concerning the nucleation/growth processes. It allows one to follow the effect on the shape and size distribution of physical or chemical processes such as simple ripening. Various electron microscopy pictures from the literature or from the authors' own syntheses are used as examples to demonstrate the efficiency and simplicity of the proposed 2D plot combined with a multivariate analysis. PMID- 27460633 TI - Terror and bliss? Commonalities and distinctions between sleep paralysis, lucid dreaming, and their associations with waking life experiences. AB - Sleep paralysis and lucid dreaming are both dissociated experiences related to rapid eye movement (REM) sleep. Anecdotal evidence suggests that episodes of sleep paralysis and lucid dreaming are related but different experiences. In this study we test this claim systematically for the first time in an online survey with 1928 participants (age range: 18-82 years; 53% female). Confirming anecdotal evidence, sleep paralysis and lucid dreaming frequency were related positively and this association was most apparent between lucid dreaming and sleep paralysis episodes featuring vestibular-motor hallucinations. Dissociative experiences were the only common (positive) predictor of both sleep paralysis and lucid dreaming. Both experiences showed different associations with other key variables of interest: sleep paralysis was predicted by sleep quality, anxiety and life stress, whereas lucid dreaming was predicted by a positive constructive daydreaming style and vividness of sensory imagery. Overall, results suggest that dissociative experiences during wakefulness are reflected in dissociative experiences during REM sleep; while sleep paralysis is related primarily to issues of sleep quality and wellbeing, lucid dreaming may reflect a continuation of greater imaginative capacity and positive imagery in waking states. PMID- 27460634 TI - The anti-inflammatory effects of PGE2 on human lung macrophages are mediated by the EP4 receptor. AB - BACKGROUND AND PURPOSE: PGE2 inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti inflammatory effect of PGE2 has not been defined. The aim of this study was to identify the EP receptor by which PGE2 inhibits cytokine generation from human lung macrophages. This was determined by using recently developed EP receptor ligands. EXPERIMENTAL APPROACH: The effects of PGE2 and EP-selective agonists on LPS-induced generation of TNF-alpha and IL-6 from macrophages were evaluated. The effects of EP2 -selective (PF-04852946, PF-04418948) and EP4 -selective (L 161,982, CJ-042794) receptor antagonists on PGE2 responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT PCR. KEY RESULTS: PGE2 inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP2 and EP4 receptors. L-902,688 (EP4 receptor-selective agonist) was considerably more potent than butaprost (EP2 receptor-selective agonist) as an inhibitor of TNF-alpha generation from macrophages. EP2 receptor-selective antagonists had marginal effects on the PGE2 inhibition of TNF-alpha generation, whereas EP4 receptor-selective antagonists caused rightward shifts in the PGE2 concentration-response curves. CONCLUSIONS AND IMPLICATIONS: These studies demonstrate that the EP4 receptor is the principal receptor that mediates the anti-inflammatory effects of PGE2 on human lung macrophages. This suggests that EP4 receptor agonists could be effective anti-inflammatory agents in human lung disease. PMID- 27460635 TI - Alterations in autonomic cardiac modulation in response to normobaric hypoxia. AB - PURPOSE: The present study aimed to determine if autonomic cardiac modulation was influenced by acute exposure to normobaric hypoxia. METHOD: Ten healthy male lowland dwellers completed five block-randomised single-blinded, crossed-over acute exposures to a normobaric hypoxic environment, each separated by 24 hours' recovery (20.3%, 17.4%, 14.5%, 12.0% and 9.8% FIO2). Supine recordings were made of arterial oxygen saturation and electrocardiogram (ECG). RR intervals from the ECG trace were analysed for time (SDNN, lnrMSSD), frequency (lnVLF, lnLF, lnHF, lnTP, LFnu, and HFnu), and nonlinear (DFA-alpha1 and SampEn) heart rate variability components. RESULTS: A significant reduction in arterial SaO2 occurred with reduced FIO2, along with a rise in heart rate (Cohen's d = 1.16, 95% Confidence Interval [2.64-6.46]), significant at 9.8% FIO2. A decrease in autonomic cardiac modulation was also found as shown by a statistically significant (at 9.8% FIO2) decrease in lnTP (d = 1.84 [1.74-1.94]), and SampEn (d = 0.98 [0.83-1.12]) and an increase in DFA-alpha1 (d = 0.72 [0.60-0.84]) from normoxia at 9.8% FIO2. CONCLUSION: The decrease in variability indicated a reduction in autonomic cardiac modulation. There appears to be a threshold ~9.8% FIO2 (~6000 m equiv.), below which significant alterations in autonomic control occur. PMID- 27460636 TI - Near Full-Length Genomic Sequences of Two Novel HIV-1 Recombinant Forms Identified in Shenzhen, China. AB - Most HIV subtypes prevalent in China can be found in Shenzhen, including CRF07_BC, CRF01_AE, CRF08_BC, CRF55_01B, and subtype B. Multiple subtypes spreading in the same population always lead to the emergence of unique recombinant strains. Here, we report two unique recombinant forms (SZ44LS7251 and SZ95LS8027) of HIV-1 identified in a heterosexual population. Recombinant analyses were fulfilled based on the near full-length genomes. Both strains comprise subtypes B, C, and CRF01_AE. Phylogenetic analysis reveals that SZ44LS7251 is the second generation recombination originated from CRF55_01B andCRF07_BC, whereas SZ95LS8027 comprises CRF01_AE and CRF07_BC.The emergence of second generation recombination of HIV with complicated genomic structures supposed that high ratio of super infections or coinfections might happen in the Shenzhen area. PMID- 27460637 TI - Therapy modalities to reduce lymphoedema in female breast cancer patients: a systematic review and meta-analysis. AB - The aim of the present study was to evaluate the effects of compression bandages, sleeves, intermittent pneumatic compression (IPC) and active exercise on the reduction of breast cancer-related lymphoedema (BCRL). A systematic literature search up to the year January 2016 was performed in CINAHL, Cochrane Register of Controlled Trials, Embase, International Clinical Trials Registry Platform (WHO), PEDro and PubMed. Inclusion criteria were (1) RCTs, (2) reported adequate statistics for meta-analysis, (3) English or German language. Exclusion criteria were (1) effects of drugs, hormonal, radiation and surgical procedures, (2) studies with children, (3) non-breast cancers, lower extremity oedema, (4) impact on fatigue only, diets or sexually transmitted diseases, (5) cost-analysis only and (6) non-carcinogenic syndromes or (7) prevention of breast cancer. After scoring the methodological quality of the selected studies, data concerning volume reduction of the oedema swelling were extracted. Thirty-two studies were included in this systematic review. Nine studies were selected for the RCT-based studies and 19 studies were included in the pre-post studies-based random-effects meta-analyses. All conclusions should be taken with precautions because of the insufficient quality of the selected papers. Exercise seems beneficial in reducing oedema volume in BCRL. IPC seems beneficial in helping to reduce the oedema volume in the acute phase of treatment. Compression sleeves do not aid in the volume reduction in the acute phase; however, they do prevent additional swelling. PMID- 27460638 TI - Impact of body mass index (BMI) on the prognosis of high-risk early breast cancer (EBC) patients treated with adjuvant chemotherapy. AB - The association between obesity and prognosis in early breast cancer (EBC) is unclear, especially when aggressive phenotypes are considered. We evaluated the influence of BMI on the prognosis of women with high-risk EBC enrolled in a phase III trial of adjuvant chemotherapy (CT). The association was assessed in 1066 patients with rapidly proliferating tumors, randomized to receive adjuvant CT with or without anthracyclines. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier; multivariate analysis was performed according to age, tumor size, nodal, estrogen receptor (ER), and HER2 status and type of CT. Information on BMI was available for 959 women. Of these, 529 (55.2 %) were overweight or obese. Median age was 52 years. A total of 457 (47.7 %) patients had nodal involvement. Centralized pathology was performed in 850 cases: 522 (61.4 %) were ER positive, and 194 (22.8 %) were HER-2 positive. At a median follow-up of 103 months (range 1-188), 5-year DFS was 81 % (95 % CI 77-85), 82 % (95 % CI 77-86), and 76 % (95 % CI 70-83), in normal, overweight, and obese women, respectively (p = 0.44). Five-year OS was 92 % (95 % CI 89-95), 94 % (95 % CI 91-96), and 89 % (95 % CI 84-93), respectively (p = 0.60). BMI was not associated by multivariate analysis with differences in DFS or OS. Higher BMI had no influence on prognosis in high-risk EBC patients treated with CT. These data are consistent with prior observations and suggest that in aggressive biological subtypes, the impact of host factors on patient prognosis is minor. PMID- 27460639 TI - Novel HDAd/EBV Reprogramming Vector and Highly Efficient Ad/CRISPR-Cas Sickle Cell Disease Gene Correction. AB - CRISPR/Cas enhanced correction of the sickle cell disease (SCD) genetic defect in patient-specific induced Pluripotent Stem Cells (iPSCs) provides a potential gene therapy for this debilitating disease. An advantage of this approach is that corrected iPSCs that are free of off-target modifications can be identified before differentiating the cells into hematopoietic progenitors for transplantation. In order for this approach to be practical, iPSC generation must be rapid and efficient. Therefore, we developed a novel helper-dependent adenovirus/Epstein-Barr virus (HDAd/EBV) hybrid reprogramming vector, rCLAE-R6, that delivers six reprogramming factors episomally. HDAd/EBV transduction of keratinocytes from SCD patients resulted in footprint-free iPSCs with high efficiency. Subsequently, the sickle mutation was corrected by delivering CRISPR/Cas9 with adenovirus followed by nucleoporation with a 70 nt single stranded oligodeoxynucleotide (ssODN) correction template. Correction efficiencies of up to 67.9% (beta(A)/[beta(S)+beta(A)]) were obtained. Whole genome sequencing (WGS) of corrected iPSC lines demonstrated no CRISPR/Cas modifications in 1467 potential off-target sites and no modifications in tumor suppressor genes or other genes associated with pathologies. These results demonstrate that adenoviral delivery of reprogramming factors and CRISPR/Cas provides a rapid and efficient method of deriving gene-corrected, patient specific iPSCs for therapeutic applications. PMID- 27460640 TI - Characterisation of a New Fungal Immunomodulatory Protein from Tiger Milk mushroom, Lignosus rhinocerotis. AB - Lignosus rhinocerotis (Tiger milk mushroom) is an important folk medicine for indigenous peoples in Southeast Asia. We previously reported its de novo assembled 34.3 Mb genome encoding a repertoire of proteins including a putative bioactive fungal immunomodulatory protein. Here we report the cDNA of this new member (FIP-Lrh) with a homology range of 54-64% to FIPs from other mushroom species, the closest is with FIP-glu (LZ-8) (64%) from Ganoderma lucidum. The FIP Lrh of 112 amino acids (12.59 kDa) has a relatively hydrophobic N-terminal. Its predicted 3-dimensional model has identical folding patterns to FIP-fve and contains a partially conserved and more positively charged carbohydrates binding pocket. Docking predictions of FIP-Lrh on 14 glycans commonly found on cellular surfaces showed the best binding energy of -3.98 kcal/mol to N acetylgalactosamine and N-acetylglucosamine. Overexpression of a 14.9 kDa soluble 6xHisFIP-Lrh was achieved in pET-28a(+)/BL21 and the purified recombinant protein was sequence verified by LC-MS/MS (QTOF) analysis. The ability to haemagglutinate both mouse and human blood at concentration >=0.34 MUM, further demonstrated its lectin nature. In addition, the cytotoxic effect of 6xHisFIP-Lrh on MCF-7, HeLa and A549 cancer cell lines was detected at IC50 of 0.34 MUM, 0.58 MUM and 0.60 MUM, respectively. PMID- 27460641 TI - Knockdown of HMGN2 increases the internalization of Klebsiella pneumoniae by respiratory epithelial cells through the regulation of alpha5beta1 integrin expression. AB - Integrin receptors, a large family of adhesion receptors, are involved in the attachment of Klebsiella pneumoniae to respiratory epithelial cells, and subsequently cause the internalization of K. pneumoniae by host cells. Although a number of molecules have been reported to regulate the expression and activity of integrin receptors in respiratory epithelial cells, the specific underlying molecular mechanisms remain largely unknown. High mobility group nucleosomal binding domain 2 (HMGN2), a non-histone nuclear protein, is present in eukaryotic cells as a ubiquitous nuclear protein. Our previous studies have demonstrated that HMGN2 affects chromatin function and modulates the expression of antibacterial peptide in A549 cells exposed to lipopolysaccharide, which indicates the critical role of HMGN2 in innate immune responses. In addition, our cDNA microarray analysis suggested that HMGN2 knockdown induced the enhanced expression of alpha5beta1 integrin in A549 cells. Therefore, we hypothesized that intercellular HMGN2 may mediate the internalization of K. pneumoniae by altering the expression of alpha5beta1 integrin. Using the A549 cell line, we demonstrated that HMGN2 knockdown induced the increased expression of alpha5beta1 integrin on cell membranes, which resulted in a significant increase in K. pneumoniae internalization. Further results revealed that HMGN2 silencing induced the expression of talin and the activation of alpha5beta1 integrin, which led to actin polymerization following the phosphorylation of FAK and Src. This study suggests a possible therapeutic application for bacterial internalization by targeting HMGN2 in order to treat K. pneumoniae infection. PMID- 27460643 TI - Complementary and alternative medicine use and absenteeism among individuals with chronic disease. AB - BACKGROUND: It is estimated that over half of the adult U.S. population currently has one or more chronic conditions, resulting in up to an estimated $1,600 in productivity loss annually for each employee with chronic disease. Previous studies have suggested that integrating alternative or complementary health approaches with conventional medicine may be beneficial for managing the symptoms, lifestyle changes, treatment, physical and psychosocial consequences that result from chronic illness. METHODS: Using the 2012 National Health Interview Survey Data, we examined the associations between self-reported use of various forms of complementary and alternative medicine (CAM) therapies (dietary supplements, mind-body practices) and the number of days missed from job or business in the past 12 months due to illness or injury. Multivariable Poisson regression was used to determine the association between CAM use and absence from work among individuals with one or more chronic disease (n = 10,196). RESULTS: Over half (54 %) of the study population reported having one chronic disease, while 19 % had three or more conditions. The three most common chronic diseases were high cholesterol (48 %), arthritis (35 %) and hypertension (31 %). More participants used dietary supplements (72 %) while fewer individuals reported using mind-body practices (17 %) in the past twelve months. Over half of individuals reported missing any number of days from job or business due to illness or injury (53 %). Of those who had missed any days from work, 42 % missed one or two days, 36 % missed three to five days, and 23 % missed six days or more. The rate of missing days from job or business due to injury or illness increased among those who reported use of mind-body practices (Incidence Rate Ratio (IRR) = 1.55, 95 % CI: 1.09, 2.21). There was no association between use of dietary supplements and absenteeism (IRR = 1.13, 95 % CI: 0.85, 1.51). CONCLUSIONS: In a population of individuals with chronic disease, individuals who reported use of mind-body practices had higher rate of absenteeism due to injury or illness. Future studies should examine the effects CAM on symptoms associated with chronic disease and whether managing these symptoms can reduce absence from work, school, and other responsibilities. PMID- 27460642 TI - New congenital anomalies of the kidney and urinary tract and outcomes in Robo2 mutant mice with the inserted piggyBac transposon. AB - BACKGROUND: Disruption of ROBO2 in humans causes vesicoureteral reflux (VUR)/congenital anomalies of the kidney and urinary tract (CAKUT). PiggyBac (PB) is a DNA transposon, and its insertion often reduces-but does not eliminate-gene expression. The Robo2 insertion mutant exhibited non-dilating VUR, ureteropelvic junction obstruction (UPJO) not found in reported models. We studied the incidence and outcomes of VUR/CAKUT in this mutant and explored the relationship between Robo2 gene expression and the occurrence and severity of VUR/CAKUT. METHODS: The urinary systems of newborn mutants were evaluated via Vevo 770 micro ultrasound. Some of the normal animals-and all of the abnormal animals-were followed to adulthood and tested for VUR. Urinary obstruction experiments were performed on mice with hydronephrosis. The histology of the kidney and ureter was examined by light microscopy and transmission electron microscopy. Robo2 (PB/PB) mice were crossed with Hoxb7/myr-Venus mice to visualize the location of the ureters relative to the bladder. RESULTS: In Robo2 (PB/PB) mice, PB insertion led to an approximately 50 % decrease in Robo2 gene expression. The most common (27.07 %, 62/229) abnormality was non-dilating VUR, and no statistically significant differences were found between age groups. Approximately 6.97 % displayed ultrasound-detectable CAKUT, and these mice survived to adulthood without improvement. No severe CAKUT were found in Robo2 (PB/+) mice. The refluxing ureters showed disorganized smooth muscle fibers, reduced muscle cell populations, intercellular edema and intracytoplasmic vacuoles in smooth muscle cells. Both UPJ and UVJ muscle defects were noted in Robo2 (PB/PB) mice. CONCLUSIONS: Robo2 (PB/PB) mice is the first Robo2-deficient mouse model to survive to adulthood while displaying non-dilating VUR, UPJO, and multiple ureters with blind endings. The genetic background of these mutants may influence the penetrance and severity of the CAKUT phenotypes. VUR and other CAKUT found in this mutant had little chance of spontaneous resolution, and this requires careful follow-up. We reported for the first time that the non-dilated refluxing ureters showed disorganized smooth muscle fibers and altered smooth muscle cell structure, more accurately mimicking the characteristics of human cases. Future studies are required to test the role of Robo2 in the ureteric smooth muscle. PMID- 27460645 TI - Study of Regional Left Ventricular Longitudinal Function in Fetuses with Gestational Diabetes Mellitus by Velocity Vector Imaging. AB - OBJECTIVE: The purpose of this study was to investigate the clinical value of velocity vector imaging in the assessment of regional left ventricular longitudinal function in fetuses with gestational diabetes mellitus. METHODS: Digital dynamic four-chamber views of 98 fetuses with gestational diabetes mellitus and 135 normal fetuses were collected and analyzed using velocity vector imaging. The regional tissue velocity, strain, and strain rate of the interventricular septum and left lateral wall were separately measured in systole and diastole. RESULTS: A total of 207 of 233 cases were analyzed successfully. Vs (systolic velocity) and Vd (diastolic velocity) were age-dependent and gradually decreased from the basal segment to the apical segment in the left ventricle (P < 0.05). The Vs after 32(+0) weeks, Vd after 28(+0) weeks, and S (strain), SRs (systolic strain rate), and SRd (diastolic strain rate) after 24(+0) weeks in the left ventricle of fetuses with GDM were obviously lower than the corresponding parameters of normal fetuses (P < 0.05). CONCLUSION: VVI can evaluate the fetal regional left ventricular longitudinal function. PMID- 27460644 TI - Portuguese validation of the Cambridge pulmonary hypertension outcome review (CAMPHOR) questionnaire. AB - BACKGROUND: Patients with pulmonary arterial hypertension (PAH) and other forms of precapillary pulmonary hypertension (PH) have impaired quality of life (QoL). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is a PH-specific patient-reported outcome measure that assesses symptoms, activity limitations and QoL. It was originally developed in UK-English. The main objective of this study was to create an adaptation of the CAMPHOR suitable for a Portuguese-speaking population. METHODS: A multi-step approach was followed: bilingual and lay panel translation; cognitive debriefing interviews; and psychometric testing in repeated postal surveys (2 weeks apart) including assessment of internal consistency, reproducibility and validity. The Nottingham Health Profile (NHP) questionnaire was used as a comparator instrument to test convergent validity. RESULTS: The CAMPHOR was translated without difficulty by the two panels. Cognitive debriefing interviews showed the questionnaire was easily understood and considered relevant to patients' experience with their illness. Psychometric evaluation was performed with 50 PAH patients (47 +/- 14 years, 37 women). Cronbach's alpha coefficients showed good internal consistency for the three CAMPHOR scales [Symptoms = 0.95; Activities = 0.93 and QoL = 0.94]. Test-retest coefficients showed that all scales had excellent reliability (Symptoms = 0.94; Activities = 0.89 and QoL = 0.93), indicating low levels of random measurement error. The CAMPHOR correlated as expected with the NHP. The magnitude of correlations followed a similar pattern to those in the original development study. The CAMPHOR also exhibited evidence of known group validity in its ability to distinguish between self-reported severity and general health groups. CONCLUSIONS: A valid and reliable version of the CAMPHOR questionnaire for the European Portuguese-speaking population was developed and is recommended for use. PMID- 27460646 TI - A new approach for discriminative measurements of different components of external ionizing radiation. AB - For discriminative measurements of the different components of external ionizing radiation by passive dosimeters, a new monitoring post consisting of a 3-layer lead chamber and 4 sets of passive dosimeters was designed in this study. Based on the theoretical studies, the thicknesses of the lead layers were determined and the algorithm for quantifying the different components of external ionizing radiation was derived. To testify the design, in-situ measurements were carried out at two different sites throughout a year. The results indicated that the monitoring post could accurately measure the hard and soft components of secondary cosmic rays and the terrestrial gamma radiation. Furthermore, it was also confirmed that by adding a passive radon monitor in the monitoring site, the artificial gamma radiation around the monitoring site could also be quantified by the monitoring post. PMID- 27460647 TI - A systematic review protocol investigating tests for physical or physiological qualities and game-specific skills commonly used in rugby and related sports and their psychometric properties. AB - BACKGROUND: Scientific focus on rugby has increased over the recent years, providing evidence of the physical or physiological characteristics and game specific skills needed in the sport. Identification of tests commonly used to measure these characteristics is important for the development of test batteries, which in turn may be used for talent identification and injury prevention programmes. Although there are a number of tests available in the literature to measure physical or physiological variables and game-specific skills, there is limited information available on the psychometric properties of the tests. Therefore, the purpose of this study is to systematically review the literature for tests commonly used in rugby to measure physical or physiological characteristics and rugby-specific skills, documenting evidence of reliability and validity of the identified tests. METHODS/DESIGN: A systematic review will be conducted. Electronic databases such as Scopus, MEDLINE via EBSCOhost and PubMed, Academic Search Premier, CINAHL and Africa-Wide Information via EBSCOhost will be searched for original research articles published in English from January 1, 1995, to December 31, 2015, using a pre-defined search strategy. The principal investigator will select potentially relevant articles from titles and abstracts. To minimise bias, full text of titles and abstracts deemed potentially relevant will be retrieved and reviewed by two independent reviewers based on the inclusion criteria. Data extraction will be conducted by the principal investigator and verified by two independent reviewers. The Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist will be used to assess the methodological quality of the selected studies. DISCUSSION: Choosing an appropriate test to be included in the screening test battery should be based on sound psychometric properties of the test available. This systematic review will provide an overview of the tests commonly used in rugby union and other related high intermittent team sports characterised by skill executions using the hands and legs such as Rugby League and Australian Rules Football. In addition, the review will highlight the psychometric properties of the identified tests. This information is crucial in developing a sport-specific test battery which can be used for talent identification, especially among young adolescent players, and injury prevention programmes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015029747. PMID- 27460648 TI - Genes in Hiding. AB - Unrecognizable genes are an unsettling problem in genomics. Here, we survey the various types of cryptic genes and the corresponding deciphering strategies employed by cells. Encryption that renders genes substantially different from homologs in other species includes sequence substitution, insertion, deletion, fragmentation plus scrambling, and invasion by mobile genetic elements. Cells decode cryptic genes at the DNA, RNA or protein level. We will focus on a recently discovered case of unparalleled encryption involving massive gene fragmentation and nucleotide deletions and substitutions, occurring in the mitochondrial genome of a poorly understood protist group, the diplonemids. This example illustrates that comprehensive gene detection requires not only auxiliary sequence information - transcriptome and proteome data - but also knowledge about a cell's deciphering arsenal. PMID- 27460649 TI - Epigenetics ELSI: Darker Than You Think? AB - Emerging ethical, legal, and social implications (ELSI) scholarship in epigenetics has focused largely on hypothetical issues involving institutional racism, discrimination, and eugenics. To avoid an unwarranted backlash against this promising research field, we encourage a more balanced ELSI discussion conveying the full spectrum of issues faced by stakeholders. PMID- 27460650 TI - Transcultural validation of the Oxford Shoulder Score for the French-speaking population. AB - PURPOSE: Patient-reported outcome measures (PROMs) have been gaining in popularity over the last decade. The Oxford Shoulder Score (OSS) is a well established self-administered questionnaire for shoulder evaluation adapted for the English-speaking population. The aim of the present study was to develop a translation and a transcultural adaptation of the OSS and to assess its validity in native French-speaker patients with shoulder pain. METHODS: The translation process was carried out following a translation/back-translation methodology by two translators. All patients completed the French OSS, the Subjective Shoulder Value (SSV), and the Constant score. Internal consistency was tested using Cronbach's alpha coefficient. Validity was assessed by calculating the Pearson correlation coefficient between the OSS and the Constant score and the SSV. RESULTS: One hundred forty-four patients suffering from degenerative or inflammatory diseases of the shoulder were included in this study. The average time required to complete the French OSS was 2min and 45s. Seventy patients were asked to complete the questionnaire twice (test/retest reliability). Internal consistency was high with Cronbach's alpha coefficient=0.93. The intraclass correlation coefficient was 0.91 (95% CI: 0.88-0.94) for test/retest reliability. The French OSS score was significantly correlated with the Constant-Murley score (r=0.73 and P<0.0001) and with the SSV (r=0.68 and P<0.0001). CONCLUSIONS: The present study shows that the French version of the OSS is reliable, valid, and reproducible. The sensitivity to change now needs to be evaluated. This score was adapted to the French-speaking population for the self-assessment of patients with degenerative or inflammatory disorders of the shoulder. LEVEL OF EVIDENCE: Level 1, Test of previously developed criteria, diagnostic test study. PMID- 27460651 TI - [Experience in the first two years of rapid diagnostic unit in a local hospital]. PMID- 27460652 TI - [Reply to letter to the editor: "Terminology and communication between healthcare levels"]. PMID- 27460653 TI - [Withholding and whithdrawing treatment in patients admitted in an internal medicine ward]. PMID- 27460654 TI - The three 'S's of editing: story, structure, and style. PMID- 27460656 TI - Resilience and rejection sensitivity mediate long-term outcomes of parental divorce. AB - Increasing divorce rates leave more and more children to deal with the separation of their parents. Recent research suggests that children of divorced parents more often experience psychological and physical symptoms than children of non divorced parents. The processes that mediate the relationship between parental divorce and ill-health, however, are still elusive. This study investigated the mediating role of psychological factors such as resilience and rejection sensitivity on the long-term consequences of parental divorce in young adults. One hundred and ninety-nine participants (mean age 22.3 years) completed an online survey, including measures of mental health, childhood trauma, resilience, and rejection sensitivity. Participants with divorced parents (33 %) reported increased levels of psychological symptoms, childhood trauma, rejection sensitivity, and lower levels of resilience. The association between parental divorce and mental health was fully mediated by resilience, rejection sensitivity, and childhood trauma. The mediation model explained up to 44 % of the total variance in mental health symptoms. Resilience and rejection sensitivity are crucial factors for successful coping with the experience of parental separation. Prevention programs that help to boost children's resilience might help to reduce the long-term effects of parental divorce on their attachment style (e.g., rejection sensitivity), thereby improving their mental health on the long run. Furthermore, the results call for parental awareness and counseling to target and reduce the observed increased level of childhood trauma. Limitations concern the cross-sectional and retrospective design of the study. PMID- 27460655 TI - Galangin Induces Autophagy via Deacetylation of LC3 by SIRT1 in HepG2 Cells. AB - Galangin suppresses proliferation and induces apoptosis and autophagy in hepatocellular carcinoma (HCC) cells, but the precise mechanism is not clear. In this study, we demonstrated that galangin induced autophagy, enhanced the binding of SIRT1-LC3 and reduced the acetylation of endogenous LC3 in HepG2 cells. But this autophagy was inhibited by inactivation of SIRT1 meanwhile, galangin failed to reduce the acetylation of endogenous LC3 after SIRT1 was knocked-down. Collectively, these findings demonstrate a new mechanism by which galangin induces autophagy via the deacetylation of endogenous LC3 by SIRT1. PMID- 27460657 TI - The transcription factors MS188 and AMS form a complex to activate the expression of CYP703A2 for sporopollenin biosynthesis in Arabidopsis thaliana. AB - The sexine layer of pollen grain is mainly composed of sporopollenins. The sporophytic secretory tapetum is required for the biosynthesis of sporopollenin. Although several enzymes involved in sporopollenin biosynthesis have been reported, the regulatory mechanism of these enzymes in tapetal layer remains elusive. ABORTED MICROSPORES (AMS) and MALE STERILE 188/MYB103/MYB80 (MS188/MYB103/MYB80) are two tapetal cell-specific transcription factors required for pollen wall formation. AMS functions upstream of MS188. Here we report that AMS and MS188 target the CYP703A2 gene, which is involved in sporopollenin biosynthesis. We found that AMS and MS188 were localized in tapetum while CYP703A2 was localized in both tapetum and locule. Chromatin immunoprecipitation (ChIP) showed that MS188 directly bound to the promoter of CYP703A2 and luciferase-inducible assay showed that MS188 activated the expression of CYP703A2. Yeast two-hybrid and electrophoretic mobility shift assays (EMSAs) further demonstrated that MS188 complexed with AMS. The expression of CYP703A2 could be partially restored by the elevated levels of MS188 in the ams mutant. Therefore, our data reveal that MS188 coordinates with AMS to activate CYP703A2 in sporopollenin biosynthesis of plant tapetum. PMID- 27460661 TI - Severe Hypercalcemia in a Postpartum Patient. AB - BACKGROUND: There are multiple clinical manifestations of hypercalcemia and several causes of hypercalcemia. Hypercalcemia caused by milk-alkali syndrome is increasing in frequency. CASE REPORT: A 26-year-old woman presented after having undergone caesarian section. She complained of severe myalgias, arthralgias, an inability to ambulate, nausea, vomiting, abdominal pain, and marked depression. Each of these symptoms has a broad differential diagnosis, but when considered together the theme "stones, bones, moans, and groans," seen in patients with hypercalcemia, is evident. This patient was found to have hypercalcemia caused by milk-alkali syndrome related to the ingestion of calcium carbonate. Her symptoms and hypercalcemia resolved with treatment. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of the many different symptoms of hypercalcemia. This case emphasizes the need for a careful medication history for any patient presenting with hypercalcemia, including over the counter medications. Physicians should have a high level of suspicion for milk-alkali syndrome in patients with hypercalcemia because milk-alkali syndrome is no longer a rare etiology but rather one of the most common causes of hypercalcemia. PMID- 27460658 TI - Analysis of transcriptional profiles of Saccharomyces cerevisiae exposed to bisphenol A. AB - Bisphenol A (BPA), an endocrine disrupting chemical, is used as a monomer in the production of epoxy resins and polycarbonates, and as a plasticizer in polyvinyl chloride. As such, it is produced in large quantities worldwide and continuously leaches into the environment. To capture the genome reprogramming in eukaryotic cells under BPA exposure, here, we used Saccharomyces cerevisiae as model organism and analyzed the genome-wide transcriptional profiles of S. cerevisiae BY4742 in response to BPA, focusing on two exposure scenarios: (1) exposure to a low inhibition concentration (50 mg/L; resulting in <10 % inhibition in cell number) and (2) a high inhibition concentration (300 mg/L; resulting in >70 % inhibition in cell number). Based on the transcriptional profiling analyses, 81 genes were repressed and 104 genes were induced in response to 50 mg/L BPA. Meanwhile, 378 genes were downregulated and 606 genes were significantly upregulated upon exposure to 300 mg/L BPA. While similar processes were affected by exposure to distinct BPA concentrations, including mitochondrial processes, nucleobase-containing small molecule metabolic processes, transcription from the RNA polymerase II promoter, and mitosis and associated processes, the number and magnitude of differentially expressed genes differ between low and high inhibition concentration treatments. For example, exposure to 300 mg/L BPA resulted in severe changes in the expression levels of several genes involved in oxidative phosphorylation, the tricarboxylic acid cycle, ribosomal activity, replication, and chemical responses. Conversely, only slight changes were observed in the expression of genes involved in these processes in cells exposed to 50 mg/L BPA. These results demonstrate that yeast cells respond to BPA in a concentration-dependent manner at the transcriptional level via different genes and provide insight into the molecular mechanisms underlying the modes of action of BPA. PMID- 27460662 TI - Air in the Liver. PMID- 27460659 TI - Significance of glycolytic metabolism-related protein expression in colorectal cancer, lymph node and hepatic metastasis. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies and a leading cause of cancer death worldwide. Most cancer cells display high rates of glycolysis with production of lactic acid, which is then exported to the microenvironment by monocarboxylate transporters (MCTs). The main aim of this study was to evaluate the significance of MCT expression in a comprehensive series of primary CRC cases, lymph node and hepatic metastasis. METHODS: Expressions of MCT1, MCT4, CD147 and GLUT1 were studied in human samples of CRC, lymph node and hepatic metastasis, by immunohistochemistry. RESULTS: All proteins were overexpressed in primary CRC, lymph node and hepatic metastasis, when compared with non-neoplastic tissue, with exception of MCT1 in lymph node and hepatic metastasis. MCT1 and MCT4 expressions were associated with CD147 and GLUT1 in primary CRC. These markers were associated with clinical pathological features, reflecting the putative role of these metabolism-related proteins in the CRC setting. CONCLUSION: These findings provide additional evidence for the pivotal role of MCTs in CRC maintenance and progression, and support the use of MCTs as biomarkers and potential therapeutic targets in primary and metastatic CRC. PMID- 27460663 TI - Physician Risk Tolerance and Head Computed Tomography Use for Patients with Isolated Headaches. AB - BACKGROUND: Headaches are one of the most common afflictions in adults and reasons for emergency department (ED) visits. OBJECTIVE: We sought to determine the association between physician risk tolerance and head computed tomography (CT) use in patients with headaches in the ED. METHODS: We performed a retrospective study of patients with nontraumatic isolated headaches in the ED and then administered two instruments (Risk-Taking subscale [RTS] of the Jackson Personality Index and a Malpractice Fear Scale [MFS]) to attending physicians who had evaluated these patients and made decisions regarding head CT scans. Outcomes were head CT use during ED evaluation and hospital admission. A hierarchical logistic regression was used to determine the effect of risk scales on head CT use. RESULTS: Of the 1328 patients with headaches, 521 (39.2%) received brain CTs and 83 (6.9%) were admitted; 33 (2.5%) patients received a final diagnosis that the central nervous system was the origin of the disease. Among the 17 emergency physicians (EPs), the median of the MFS and RTS was 23 (interquartile range [IQR] 19-25) and 21 (IQR 20-23), respectively. EPs who were relatively risk-averse and those who possessed a higher level of malpractice fear were not more likely to order brain CTs for patients with isolated headaches. CONCLUSIONS: Individual EP risk tolerance, as measured by RTS, and malpractice concerns, measured by MFS, were not predictive of CT use in patients with isolated headaches. PMID- 27460664 TI - Prevalence of Retinal Hemorrhages in Infants Presenting with Isolated Long Bone Fractures and Evaluation for Abuse. AB - BACKGROUND: Fractures are a frequent reason for emergency department visits and evaluation for abusive head trauma is an associated concern in infants. Recent guidelines have suggested that retinal examination may not be necessary in the absence of intracranial injury, but there is a lack of empirical evidence in infants < 1 year of age. OBJECTIVE: Our aim was to evaluate the prevalence of retinal hemorrhages in infants with isolated long bone fractures. METHODS: Retrospective chart review of infants < 1 year of age who presented to an urban, tertiary care pediatric hospital between January 2004 and April 2014 with the diagnosis of an acute long bone fracture or retinal hemorrhages. Patients were excluded for head injury, altered mental status, injury mechanism of motor vehicle accident, multiple fractures or injuries outside the fracture area. Patients were identified through trauma registry data and International Classification of Diseases codes. RESULTS: One hundred and forty-six patients had isolated long bone fractures, of which 68 patients did not undergo a retinal examination and 78 patients had dilated eye examinations, with no patients identified as having retinal hemorrhages. There were 46 patients identified with retinal hemorrhages concerning for abuse. No patients with retinal hemorrhages had isolated long bone fractures. CONCLUSIONS: In infants < 1 year of age presenting with isolated long bone fractures, a dilated eye examination to evaluate for retinal hemorrhages is not likely to yield additional information. Our results support recent studies that a subset of children and infants may not require dilated eye examinations in the evaluation of possible abuse. PMID- 27460665 TI - Atypical Rash of the Hand. PMID- 27460666 TI - Sensitivity profile of the human EndoC-betaH1 beta cell line to proinflammatory cytokines. AB - AIMS/HYPOTHESIS: The aim of this study was to perform a detailed analysis of cytokine toxicity in the new human EndoC-betaH1 beta cell line. METHODS: The expression profile of the antioxidative enzymes in the new human EndoC-betaH1 beta cells was characterised and compared with that of primary beta cells in the human pancreas. The effects of proinflammatory cytokines on reactive oxygen species formation, insulin secretory responsiveness and apoptosis of EndoC-betaH1 beta cells were determined. RESULTS: EndoC-betaH1 beta cells were sensitive to the toxic action of proinflammatory cytokines. Glucose-dependent stimulation of insulin secretion and an increase in the ATP/ADP ratio was abolished by proinflammatory cytokines without induction of IL-1beta expression. Cytokine mediated caspase-3 activation was accompanied by reactive oxygen species formation and developed more slowly than in rodent beta cells. Cytokines transiently increased the expression of unfolded protein response genes, without inducing endoplasmic reticulum stress-marker genes. Cytokine-mediated NFkappaB activation was too weak to induce inducible nitric oxide synthase expression. The resultant lack of nitric oxide generation in EndoC-betaH1 cells, in contrast to rodent beta cells, makes these cells dependent on exogenously generated nitric oxide, which is released from infiltrating immune cells in human type 1 diabetes, for full expression of proinflammatory cytokine toxicity. CONCLUSIONS/INTERPRETATION: EndoC-betaH1 beta cells are characterised by an imbalance between H2O2-generating and -inactivating enzymes, and react to cytokine exposure in a similar manner to primary human beta cells. They are a suitable beta cell surrogate for cytokine-toxicity studies. PMID- 27460667 TI - Identification of LAMP2 Mutations in Early-Onset Danon Disease With Hypertrophic Cardiomyopathy by Targeted Next-Generation Sequencing. AB - Danon disease is an X-linked disorder with the clinical triad of cardiomyopathy, skeletal myopathy, and mental retardation. Early diagnosis of this disease remains a challenge, especially in the pediatric population. In this study, we developed a targeted panel-based next generation sequencing pipeline to identify mutations by sequencing of selected candidate genes in 136 pediatric patients with either hypertrophic cardiomyopathy (HC) or idiopathic dilated cardiomyopathy (IDC). This led to the identification of lysosome-associated membrane protein 2 (LAMP2) mutations in 4 of the 64 (6%) probands with HC, including 3 novel nonsense mutations (p.Q240X, p.S250X, and p.G22X). No LAMP2 mutation was detected in the other 72 probands with IDC. All 4 probands and one additional affected family member (2 men and 3 women) had an early-onset age and presented either HC alone or combined with Wolff-Parkinson-White syndrome and skeletal myopathy. Immunofluorescence staining and Western blot analysis revealed absent LAMP2 expression in both cardiac and skeletal muscle samples of the first proband and severely decreased LAMP2 expression in the skeletal muscle samples of the second proband. In conclusion, cardiomyopathy in the patients with Danon disease may occur during early childhood and tend to be HC rather than IDC in both affected men and women. Therefore, Danon disease should be considered as one of the leading causes of unexplained ventricular hypertrophy in pediatric patients. The inclusion of LAMP2 gene in cardiomyopathy genetic screening panels may contribute to early diagnosis of Danon disease. PMID- 27460668 TI - The discovery of novel and selective fatty acid binding protein 4 inhibitors by virtual screening and biological evaluation. AB - Adipocyte fatty acid binding protein (AFABP, FABP4) has been proven to be a potential therapeutic target for diabetes, atherosclerosis and inflammation related diseases. In this study, a series of new scaffolds of small molecule inhibitors of FABP4 were identified by virtual screening and were validated by a bioassay. Fifty selected compounds were tested, which led to the discovery of seven hits. Structural similarity-based searches were then performed based on the hits and led to the identification of one high affinity compound 33b (Ki=0.29+/ 0.07MUM, DeltaTm=8.5 degrees C). This compound's effective blockade of inflammatory response was further validated by its ability to suppress pro inflammatory cytokines induced by lipopolysaccharide (LPS) stimulation. Molecular dynamics simulation (MD) and mutagenesis studies validated key residues for its inhibitory potency and thus provide an important clue for the further development of drugs. PMID- 27460669 TI - Simple and accurate single base resolution analysis of 5-hydroxymethylcytosine by catalytic oxidative bisulfite sequencing using micelle incarcerated oxidants. AB - Oxidation of 5-methylcytosine (5mC) is catalyzed by ten-eleven translocation (TET) enzymes to produce 5-hydroxymethylcytosine (5hmC) and following oxidative products. The oxidized nucleotides were shown to be the intermediates for DNA demethylation, as the nucleotides are removed by base excision repair system initiated by thymine DNA glycosylase. A simple and accurate method to determine initial oxidation product 5hmC at single base resolution in genomic DNA is necessary to understand demethylation mechanism. Recently, we have developed a new catalytic oxidation reaction using micelle-incarcerated oxidants to oxidize 5hmC to form 5-formylcytosine (5fC), and subsequent bisulfite sequencing can determine the positions of 5hmC in DNA. In the present study, we described the optimization of the catalytic oxidative bisulfite sequencing (coBS-seq), and its application to the analysis of 5hmC in genomic DNA at single base resolution in a quantitative manner. As the oxidation step showed quite low damage on genomic DNA, the method allows us to down scale the sample to be analyzed. PMID- 27460670 TI - Improvement in glycemic control through changes in insulin regimens: findings from a Japanese cohort of children and adolescents with type 1 diabetes. AB - OBJECTIVE: Although insulin analogs have dramatically changed diabetes treatment, scarce evidence is available on those effects. We aimed to explore whether glycemic control had improved, the use of insulin analogs had been increased, and hypoglycemic events had decreased over time in Japanese pediatric patients with type 1 diabetes (T1D). METHODS: Glycated hemoglobin A1c (HbA1c) values, proportion of insulin regimens, incidence of severe hypoglycemic events, and pubertal increase in HbA1c were compared in three cohorts of childhood-onset Japanese T1D patients (567 subjects in the 1995 cohort, 754 subjects in the 2000 cohort, and 806 subjects in the 2008 cohort). RESULTS: Mean HbA1c values tended to decrease [78.5 mmol/mol (9.33%) in the 1995 cohort, 68.2 mmol/mol (8.39%) in the 2000 cohort, and 61.2 mmol/mol (7.75%) in the 2008 cohort; P < .0001]. The proportion of patients who received basal-bolus treatment tended to increase with statistical significance, as did the proportion on insulin analogs. The incidence of severe hypoglycemic events (events/100 patients/y) had decreased (19.1 in the 2000 cohort and 8.7 in the 2008 cohort; P = .02). The pubertal increase in HbA1c tended to decrease [males, 12.0 mmol/mol (1.10%) in 1995, 9.4 mmol/mol (0.85%) in 2008, and 9.4 mmol/mol (0.86%) in 2008; P = .55; females, 14.0 mmol/mol (1.28%) in 1995, 10.3 mmol/mol (0.94%) in 2000, and 4.2 mmol/mol (0.38%) in 2008; P = .0003]. CONCLUSIONS: Glycemic control and incidence of severe hypoglycemic events were chronologically improved, especially in female adolescents. PMID- 27460671 TI - Additive effect of knockdown resistance mutations, S989P, V1016G and F1534C, in a heterozygous genotype conferring pyrethroid resistance in Aedes aegypti in Thailand. AB - BACKGROUND: Mutation in the voltage-gated sodium channel gene that results in knockdown resistance (kdr), is a major mechanism of pyrethroid resistance in several mosquito species. In Aedes aegypti, V1016G (occurring with and without S989P) and F1534C mutations are common and widely distributed throughout Asia. The G1016 allele is known to be associated with resistance to type I and II pyrethroids. The C1534 allele is primarily associated with resistance to type I pyrethroids and is known to be a recessive allele in conferring kdr. METHODS: We performed crossing experiments using a P989 + G1016 homozygous mutant strain (UPK R), a C1534 homozygous mutant strain (PMD-R) and a pyrethroid susceptible strain (PMD) to determine the insecticide susceptibility of different genotypic hybrids. Allele-specific PCR methods were used to confirm the genotypes. Metabolic resistance caused by oxidative enzymes and esterase enzymes was ruled out by the addition of piperonyl butoxide (PBO) and bis(4-nitrophenyl)-phosphate, BNPP), respectively. RESULTS: The median lethal concentration (LC50) of deltamethrin susceptibility of a S/P989 + V/G1016 + F/F1534 double heterozygous hybrid from the UPK-R * PMD cross was 0.57 (95 % CI: 0.51-0.63) MUgl(-1), which was about 12 fold lower than for UPK-R, 6.98 (6.10-8.04) MUgl(-1), and only about 4-fold greater than the susceptible PMD, 0.13 (0.12-0.15) MUgl(-1). This resistance returned to 0.08 (0.07-0.09) MUgl(-1) on the addition of PBO suggesting that the P989 + G1016 kdr alleles are recessive. The LC50 of the S/P989 + V/G1016 + F/C1534 triple heterozygous hybrid was 3.58 (3.21-3.95) MUgl(-1), which was intermediate between that of the homozygous mutant genotypes, being 2-fold higher than the C1534 homozygote and 2-fold lower than the P989 + G1016 homozygote. These minor differences and the high LC50 values of the triple mutated heterozygote indicate there is some degree of functional equivalence of the P989 + G1016 and C1534 alleles in the heterozygote. Addition of PBO decreased the LC50 values by 2-fold, from 3.58 (3.21-3.95) to 1.52 (1.35-1.73) MUgl(-1), suggesting that oxidase enzymes play a partial role in resistance. The results are consistent with the median lethal time (LT50) of the triple mutated heterozygote against 0.05 % deltamethrin paper. An adult susceptibility test also revealed that the triple mutated heterozygote was resistant to deltamethrin and permethrin. CONCLUSIONS: The combination of the three kdr alleles in the triple mutated heterozygote, S/P989 + V/G1016 + F/C1534, confers high resistance to pyrethroids. This heterozygous form is common in Ae. aegypti populations throughout Thailand and may have an adverse effect on the efficacy of a mosquito control program using insecticide-based approaches. PMID- 27460672 TI - Matrix scaffolding for stem cell guidance toward skeletal muscle tissue engineering. AB - Extracellular matrix (ECM) is composed of many types of fibrous structural proteins and glycosaminoglycans. This important cell component not only provides a support for cells but is also actively involved in cell-cell interaction, proliferation, migration, and differentiation, representing, therefore, no longer only a mere static structural scaffold for cells but rather a dynamic and versatile compartment. This aspect leads to the need for investigating new bio inspired scaffolds or biomaterials, able to mimic ECM in tissue engineering. This new field of research finds particular employment in skeletal muscle tissue regeneration, due to the inability of this complex tissue to recover volumetric muscle loss (VML), after severe injury. Usually, this is the result of traumatic incidents, tumor ablations, or pathological states that lead to the destruction of a large amount of tissue, including connective tissue and basement membrane. Therefore, skeletal muscle tissue engineering represents a valid alternative to overcome this problem.Here, we described a series of natural and synthetic biomaterials employed as ECM mimics for their ability to recreate the correct muscle stem cell niche, by promoting myogenic stem cell differentiation and so, positively affecting muscle repair. PMID- 27460673 TI - A Positive Psychology Intervention in a Hindu Community: The Pilot Study of the Hero Lab Curriculum. AB - India has high rates of mental health issues among its youth and low-income communities experience a disproportionate amount of depression and suicide. Positive psychology, the act of promoting well-being, could be used as a tool to promote wellness and help improve the mental health of youth living in slum areas of India. A pilot positively psychology program, "The Hero Lab", was conducted in a migratory slum in Worli, Mumbai, with trained Hindu community leaders implementing the interventions toward at-risk Hindu youth. The curriculum's impact showed statistical improvement (p < 0.001) in happiness (General Happiness Scale from 11.24 +/- 1.56 to 19.08 +/- 3.32), grit (Grit Survey from 2.23 +/- 0.34 to 3.24 +/- 0.67), empathy (Toronto Empathy Questionnaire from 24.92 +/- 3.27 to 41.96 +/- 8.41), and gratitude (Gratitude Survey from 16.88 +/- 3.47 to 27.98 +/- 6.59). While a pilot study, the Hero Lab curriculum demonstrates that positive psychology interventions may be an important tool in improving mental health in at-risk children. PMID- 27460674 TI - The Association of Religious Affiliation with Overweight/Obesity Among South Asians: The Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study. AB - Religiosity has been associated with greater body weight. Less is known about South Asian religions and associations with weight. Cross-sectional analysis of the MASALA study (n = 906). We examined associations between religious affiliation and overweight/obesity after controlling for age, sex, years lived in the USA, marital status, education, insurance status, health status, and smoking. We determined whether traditional cultural beliefs, physical activity, and dietary pattern mediated this association. The mean BMI was 26 kg/m2. Religious affiliation was associated with overweight/obesity for Hindus (OR 2.12; 95 % CI: 1.16, 3.89), Sikhs (OR 4.23; 95 % CI: 1.72, 10.38), and Muslims (OR 2.79; 95 % CI: 1.14, 6.80) compared with no religious affiliation. Traditional cultural beliefs (7 %), dietary pattern (1 %), and physical activity (1 %) mediated 9 % of the relationship. Interventions designed to promote healthy lifestyle changes to reduce the burden of overweight/obesity among South Asians need to be culturally and religiously tailored. PMID- 27460675 TI - Behavioural intervention to increase physical activity in adults with coronary heart disease in Jordan. AB - BACKGROUND: Patients with coronary heart disease often do not follow prescribed physical activity recommendations. The aim of this study was to assess the efficacy of a behavioural intervention to increase physical activity in patients with coronary heart disease not attending structured cardiac rehabilitation programmes. METHODS: Parallel randomised controlled trial comparing 6-month multi component behavioural change intervention (n = 71) with usual care (n = 85) was conducted in two hospitals in Jordan, Middle East. Intervention included one face to-face individualised consultation, 6 telephone support calls (for goal-setting, feedback and self-monitoring) and 18 reminder text messages. Patients were randomly allocated to the two groups by opening opaque sealed sequence envelopes. The patients and the researcher who provided the intervention and assessed the outcomes were not blinded. Outcomes were assessed at baseline and 6 months. Primary outcome was physical activity level, secondary outcomes were blood pressure, body mass index, exercise self-efficacy for exercise and health-related quality of life. RESULTS: Intervention and control groups were comparable at baseline. Moderate physical activity significantly increased in the intervention group compared with control group (mean change (SD) of frequency: 0.23 (0.87) days/week versus -.06 (0.40); duration: 15.53 (90.15) minutes/week versus -3.67 (22.60) minutes/week; intensity: 31.05 (105.98) Metabolic equivalents (METs) versus 14.68 (90.40) METs). Effect size was 0.03 for moderate PA frequency, 0.02 for moderate PA duration and 0.01 for moderate PA intensity. Walking significantly increased in the intervention group compared with control group (mean change (SD) of frequency: 3.15 (2.75) days/week versus 0.37 (1.83) days/week; duration: 150.90 (124.47) minutes/week versus 24.05 (195.93) minutes/week; intensity: 495.12 (413.74) METs versus14.62 (265.06) METs). Effect size was 0.36 for walking frequency, 0.05 for walking duration, 0.32 for walking intensity and 0.29 for total PA intensity. Intervention participants had significantly lower blood pressure, lower body mass index, greater exercise self efficacy and better health-related quality of life at 6 months compared with controls. CONCLUSIONS: Multi-component behavioural intervention increases physical activity, and improves body composition, physiological and psychological outcomes in CHD patients not attending structured rehabilitation programmes. TRIAL REGISTRATION: Current Controlled Trials retrospectively registered in 21-03 2012. ISRCTN48570595 . PMID- 27460676 TI - Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. AB - Thalidomide was first developed as a sedative around 60 years ago, but exhibited teratogenicity, leading to serious defects such as limb deformities. Nevertheless, thalidomide is now recognized as a therapeutic drug for the treatment of Hansen's disease and myeloma. Immunomodulatory drugs (IMiDs), a new class of anti-cancer drug derived from thalidomide, have also been developed and exert potent anti-cancer effects. Although the molecular mechanism of thalidomide and IMiDs remained unclear for a long time, cereblon, a substrate receptor of the CRL4 E3 ubiquitin ligase was identified as a primary direct target by a new affinity technique. A growing body of evidence suggests that the effect of IMiDs on myeloma and other cancer cells is mediated by CRBN. Each IMiD binds to CRBN and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins such as Ikaros and Aiolos. Here we give an overview of the current understanding of mechanism of action of IMiDs via CRBN and prospects for the development of new drugs that degrade protein of interest. PMID- 27460677 TI - Phase I dose escalation study of high dose carfilzomib monotherapy for Japanese patients with relapsed or refractory multiple myeloma. AB - : We conducted a multicenter, open-label Phase I study of single-agent carfilzomib in Japanese patients with relapsed or refractory multiple myeloma. The primary endpoints were tolerability and safety. Carfilzomib was administrated for 30 min on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. In cycle 1, doses for days 1 and 2 were 20 mg/m2, followed by 45 or 56 mg/m2. Three and four subjects were enrolled in the 20/45 mg/m2 cohort and 20/56 mg/m2 cohort. No dose limiting toxicity was observed, and the tolerability of carfilzomib was confirmed. Pyrexia, hypertension, nausea and vomiting were considered as noteworthy adverse events (AE) when carfilzomib was administered at high doses. Moreover, pyrexia, blood creatinine increased, and body weight gain were observed as acute dose effects. These findings suggest that addition of dexamethasone is important to alleviate acute dose effect. The overall response rates of the 20/45 mg/m2 and 20/56 mg/m2 cohort were 66.7 % (two out of three) and 50 % (two out of four), respectively. Carfilzomib administrated at up to 20/56 mg/m2 was well tolerated and seemed active in Japanese patients with relapsed or refractory multiple myeloma. CLINICAL TRIAL REGISTRATION: JapicCTI-122020. PMID- 27460679 TI - Deviations of different systems for guided implant surgery. AB - OBJECTIVES: To compare the deviation of different systems for Guided Implant Surgery (GIS) related to the specific tolerance between drills and sleeves. MATERIAL AND METHODS: Four different systems for GIS and their appropriate sleeves were used: Camlog Guide (CG), Straumann Guided Surgery (SG), SIC Guide (SIG), and NobelGuide (NG). System-appropriate metal sleeves were inserted into plexiglass boxes, and guided drilling procedure was performed (i) holding the drills in the most centric position of the sleeves and (ii) applying forces eccentrically. Digital microscope images of the plexiglass boxes were taken and axial deviations were calculated based on the Pythagorean Theorem, whereas coronal and apical deviations were measured with a corresponding software-device and calculated by subtracting the measured deviations from the original diameter of the drills. Statistically significant differences between centric and eccentric drilling were determined applying the t-test for independent data. RESULTS: The axial deviation ranged from 0 degrees (SG) to 5.64 degrees (CG). The apical deviations varied between 0.01 mm (SIG) and 3.2 mm (NG) and the coronal deviations ranged from 0.01 mm (SIG) to 1.60 mm (NG). In terms of angular deviation, there were statistically significant differences between centric and eccentric drilling for all four systems. Coronal and apical deviations, showed no statistical significance between centric and eccentric drilling for SIG and NG, in contrast to CG and SG. CONCLUSIONS: The clinician may have considerable impact on the accuracy of GIS when applying eccentric forces. PMID- 27460678 TI - Changes from imatinib mesylate to second generation tyrosine kinase inhibitors improve renal impairment with imatinib mesylate in chronic myelogenous leukemia. AB - Understanding adverse events in long-term tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) is important. We investigated changes in renal function during TKI therapy for CML. We retrospectively analyzed levels of serum creatinine (sCrn) and values of estimated glomerular filtration rate (eGFR) from June 2001 to March 2015. Sixty patients initially treated with imatinib were enrolled in this study. Continuous variables of sCrn and eGFR were compared by paired student's t test. Median age or duration of treatment with imatinib was 49 years (range 19-81) or 101 months (range 8-165), respectively. Mean levels of sCrn or mean values of eGFR had increased or decreased 1 year later from start of imatinib throughout observation with statistical significance (p < 0.05), respectively. In 38 patients, the TKI used was changed from imatinib to a second generation TKI (nilotinib: 32; dasatinib: 6) for various reasons. We observed statistically significant (p < 0.05) amelioration in mean levels of sCrn and values of eGFR after only 1 month following the changes to second-generation TKIs. These results suggest that imatinib has adverse effects on renal function and that changes from imatinib to a second-generation TKI should be considered as a therapeutic option in cases of renal impairment due to imatinib. PMID- 27460681 TI - The Analytical Chemistry Advisory Boards. PMID- 27460680 TI - Low-dose computed tomography to diagnose fetal bone dysplasias. AB - We present a case of cleidocranial dysplasia diagnosed by low-dose fetal computed tomography (CT) in the 25th week of gestation. Severe bone dysplasia was suspected because of the fetus' low percentile in long bones length and the appearance of craniosynostosis on sonography. CT found no abnormalities incompatible with life. The effective dose was 5 mSv, within the recommended range for this type of examination. Low-dose fetal CT is a new technique that makes precision study of the bony structures possible from the second trimester of pregnancy. In Spain, abortion is legal even after the 22nd week of gestation in cases of severe fetal malformations. Therefore, in cases in which severe bone dysplasia is suspected, radiologists must know the strategies for reducing the dose of radiation while maintaining sufficient diagnostic quality, and they must also know which bony structures to evaluate. PMID- 27460682 TI - The influence of a specific ophthalmological electronic health record on ICD-10 coding. AB - BACKGROUND: A specific Electronic Health Record (EHR) for ophthalmology was introduced in an academic center in Germany. As diagnoses coding corresponding to the International Classification of Diseases Version 10 (ICD-10) is mandatory for billing reasons in Germany, we analyzed whether a change occurred in the diversity and number of diagnoses after the EHR introduction. The number of patients was also analyzed. Proper diagnoses coding is of the utmost importance for further data analysis or billing. METHODS: Graphical User Interfaces (GUIs) were created by using Advanced Business Application Programming language in EHR "i.s.h.med." Development of an EHR was conducted in close collaboration between physicians and software engineers. ICD-10 coding was implemented by using a "hit list" and a search engine for diagnoses. An observational analysis of a 6-month period prior to and after the introduction of an ophthalmological specific EHR was conducted by investigating the diversity and number of diagnoses in various ophthalmological disease categories and the number of patient consultations. RESULTS: During the introduction of a specific ophthalmological EHR, we observed a significant increase in the emergency department cases (323.9 vs. 359.9 cases per week), possibly related to documentation requirements. The number of scheduled outpatients didn't change significantly (355.12 vs. 360.24 cases per week). The variety of diagnoses also changed: on average, 156.2 different diagnoses were made per week throughout our hospital before the EHR launch, compared to 186.8 different diagnoses per week thereafter (p < 0.05). Additionally, a significantly higher number of diagnoses per case and per week were observed in both emergency and subspecialty outpatient clinics (1.15 vs. 1.22 and 1.10 vs. 1.47, respectively). CONCLUSIONS: An optimized EHR was created for ophthalmological needs and for simplified ICD-10 coding. The implementation of digital patient recording increased the diversity of the diagnoses used per case as well as the number of diagnoses coded per case. A general limitation to date is the suboptimal precision of ICD-10 coding in ophthalmology. Correct coding is of utmost importance for future data analysis. PMID- 27460683 TI - Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue. AB - Therapeutic nanoparticles (NPs) approved for clinical use in solid tumor therapy provide only modest improvements in patient survival, in part due to physiological barriers that limit delivery of the particles throughout the entire tumor. Here, we explore the thresholds for NP size and surface poly(ethylene glycol) (PEG) density for penetration within tumor tissue extracellular matrix (ECM). We found that NPs as large as 62nm, but less than 110nm in diameter, diffused rapidly within a tumor ECM preparation (Matrigel) and breast tumor xenograft slices ex vivo. Studies of PEG-density revealed that increasing PEG density enhanced NP diffusion and that PEG density below a critical value led to adhesion of NP to ECM. Non-specific binding of NPs to tumor ECM components was assessed by surface plasmon resonance (SPR), which revealed excellent correlation with the particle diffusion results. Intravital microscopy of NP spread in breast tumor tissue confirmed a significant difference in tumor tissue penetration between the 62 and 110nm PEG-coated NPs, as well as between PEG-coated and uncoated NPs. SPR assays also revealed that Abraxane, an FDA-approved non PEGylated NP formulation used for cancer therapy, binds to tumor ECM. Our results establish limitations on the size and surface PEG density parameters required to achieve uniform and broad dispersion within tumor tissue and highlight the utility of SPR as a high throughput method to screen NPs for tumor penetration. PMID- 27460684 TI - Nanomedicine approaches in acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the malignancy with the highest incidence amongst children (26% of all cancer cases), being surpassed only by the cancers of the brain and of the nervous system. The most recent research on ALL is focusing on new molecular therapies, like targeting specific biological structures in key points in the cell cycle, or using selective inhibitors for transmembranary proteins involved in cell signalling, and even aiming cell surface receptors with specifically designed antibodies for active targeting. Nanomedicine approaches, especially by the use of nanoparticle-based compounds for the delivery of drugs, cancer diagnosis or therapeutics may represent new and modern ways in the near future anti-cancer therapies. This review offers an overview on the recent role of nanomedicine in the detection and treatment of acute lymphoblastic leukemia as resulting from a thorough literature survey. A short introduction on the basics of ALL is presented followed by the description of the conventional methods used in the ALL detection and treatment. We follow our discussion by introducing some of the general nano-strategies used for cancer detection and treatment. The detailed role of organic and inorganic nanoparticles in ALL applications is further presented, with a special focus on gold nanoparticle-based nanocarriers of antileukemic drugs. PMID- 27460685 TI - Zika virus and the 2016 Olympic Games. PMID- 27460686 TI - Zika virus and the 2016 Olympic Games - Editors' reply. PMID- 27460687 TI - Quality control of house dust mite extracts by broad-spectrum profiling of allergen-related enzymatic activities. AB - BACKGROUND: Diagnosis and immunotherapy of allergy against mites is based on complex extracts from large-scale cultures. However, the analysis of their composition using specific antibodies is limited. By taking advantage of the prevailing enzymatic nature of mite allergens, we have developed a broad-spectrum biochemical method for the standardization of native mite products. METHODS: Microplate-based assays have been implemented for thirteen Dermatophagoides pteronyssinus enzymatic activities, associated with Der p 1, 3, 4, 6, 8, 9, 15 and 20 allergens. The dynamics of these activities along culture growth, and their profile in purified fractions (bodies and faeces) and international reference standards (WHO/IUIS, two CBER/FDA), have been characterized. The stability of enzymatic activities and major allergens under stress conditions (40 degrees C) has been assessed in the presence/absence of specific protease inhibitors. RESULTS: The analysis of enzymatic activities revealed distinct profiles along culture growth and between fractions (bodies and faeces). Remarkable differences were found when comparing international reference standards, being consistent with their source material (purified bodies or whole cultures). After 72 h at 40 degrees C, only trypsin and alpha-amylase maintained high activity. Notably, the prominent role of trypsins in the hydrolytic degradation of major allergens is demonstrated by the use of inhibitors. CONCLUSIONS: Our method offers a robust approach to assess the complexity of mite extracts and highlights the critical importance of source materials for the composition and stability of finished products. The implementation of this approach in industry-based quality control procedures would contribute to the standardization of allergenic extracts used for diagnosis and immunotherapy. PMID- 27460688 TI - Association between XPA gene rs1800975 polymorphism and susceptibility to lung cancer: a meta-analysis. AB - BACKGROUND: Xeroderma pigmentosum complementation group A (XPA) gene is a key member of nucleotide excision repair pathway. It was reported that XPA rs1800975 polymorphism was associated with susceptibility to lung cancer. However, the conclusions were controversial. METHODS: We conducted a computer retrieval of PubMed, EMbase, CNKI, CBM, and WanFang infrastructure platform from 1980 to 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength. Publication bias was detected by means of a funnel plot. RESULTS: A total of 11 articles (12 studies) involving 4257 cases and 5294 controls were included. Significant associations could be found between rs1800975 and lung cancer risk in these three models (codominant model AG vs. AA, overdominant genetic model AG vs. AA + GG, dominant model AG + GG vs. AA) in overall. In the stratified analysis by ethnicity, we found similar results as above in the Asian population. In the smoking population, the G allele carriers were associated with a significantly reduced risk of lung cancer (AG + GG vs. AA) compared with the AA carriers.Stratified analysis showed the AG genotype and G allele carriers (AG + GG) might be a protective factor compared with the AA gene for squamous carcinoma (AG vs. AA, AG + GG vs. AA). CONCLUSIONS: This meta analysis suggested that the XPA gene rs1800975 Polymorphism was associated with lung cancer susceptibility. By performing multiple separate pairwise comparisons, carriers with AG genotype under the codominant genetic model (AG vs. AA) might play actually the leading role in associating with lung cancer susceptibility in overall and in Asians. PMID- 27460689 TI - Repair-Gene Mutations Uncovered in Metastatic Prostate Cancer. AB - A new study finds that 11.8% of men with metastatic prostate cancer carry mutations in DNA repair genes. The mutations were more than five times as prevalent in men with metastatic disease as in men with localized prostate cancer. Although relatives of the men weren't more likely to have prostate cancer, they were more likely to have breast, ovarian, and other cancers. PMID- 27460690 TI - Analysis of pre- and post-pregnancy issues in women with hyperemesis gravidarum. AB - The purpose of this study is to determine the frequency of reporting of both pre pregnancy and post-pregnancy psychosocial and physical issues in women with hyperemesis gravidarum (HG). Conditions in 449 women with HG were compared to 459 unaffected women (controls). Binary responses were analyzed using either Chi squared or Fishers Exact test. Continuous responses were analyzed using a t-test. Among 60 pre-pregnancy conditions surveyed, 10 common (>5%) maternal pre pregnancy conditions were significantly more frequently reported by women with HG. Twenty rare (<5% controls) pre-pregnancy conditions with significantly increased reporting in the HG group were identified. Thirty (50%) pre-pregnancy conditions were similarly reported between cases and controls. Among 80 post pregnancy factors surveyed, women with HG also showed significantly higher reporting for 7 common and 50 rare post-pregnancy outcomes. Women with HG are significantly more likely to self-report physical and psychosocial issues both before and after pregnancy. PMID- 27460691 TI - Effect of endoscopic pyloric therapies for patients with nausea and vomiting and functional obstructive gastroparesis. AB - : Gastroparesis (GP) is associated with loss of interstitial cells of Cajal (ICCs) and gastric dysrhythmias such as tachygastria. We hypothesized that a subset of patients with GP, normal 3cycles per minute (cpm) gastric myoelectrical activity (GMA), and normal upper endoscopy may respond to pyloric therapies. AIMS: To determine the effect of botulinum toxin A (btA) injection or balloon dilation (BD) of the pylorus on symptoms and body weight in patients with GP and 3cpm GMA. METHODS: Patients were identified who had GP, normal 3cpm GMA, and normal endoscopy that excluded mechanical obstruction of the pylorus. Electrogastrograms (EGG) with water load tests (WLT) were recorded to determine GMA. Gastric emptying was measured with 4h scintigraphy. Each patient underwent up to three pyloric treatments with btA or BD. RESULTS: Thirty-three patients (29 women) with an average age of 42years were studied. Seventy-nine percent had idiopathic GP and 21% had diabetic GP. The average percent meal retained at 4h was 42% and each EGG test showed normal 3cpm GMA. Nausea was the major symptom in 76% of patients. Complete or partial symptom response occurred in 75%, 72%, and 88% of patients after the first, second, or third endoscopic pyloric treatment, respectively. Overall, 78% of the 33 patients reported improvement in symptoms and average weight gain was 1.54lb from baseline to final treatment (p<0.04). CONCLUSION: Pyloric therapies appear to be effective treatments in symptomatic patients with GP and 3cpm GMA and controlled trials are warranted. PMID- 27460692 TI - Metabolic responses to whole-body vibration: effect of frequency and amplitude. AB - PURPOSE: This study assessed the effect of whole-body vibration (WBV) of varying frequency and amplitude on metabolic responses during WBV treatment and subsequent aerobic exercise. METHODS: Eight men and eight women (21.0 +/- 1.9 years) underwent one no-WBV (NV) and six WBV at 30 Hz/low amplitude (30L), 30 Hz/high amplitude (30H), 40 Hz/low amplitude (40L), 40 Hz/high amplitude (40H), 50 Hz/low amplitude (50L), and 50 Hz/high amplitude (50H). During each protocol, subjects performed ten sets of ten body weight squats with 1-min rest period between sets on a vibration platform with a load that represented one of the six frequency-amplitude combinations. Each WBV treatment was immediately followed by 20 min of cycle exercise at 65 % VO2peak. Oxygen uptake (VO2) and rates of carbohydrate (COX) and fat oxidation (FOX) were measured during both the WBV session and subsequent exercise. RESULTS: During WBV, VO2 was higher (p < 0.05) in 40H, 50L and 50H than NV and in 50H than 30L, 30H and 40L. COX was higher (p < 0.05) in 40H, 50L, and 50H than NV, whereas FOX remained indifferent across all protocols. During subsequent exercise, VO2 was higher (p < 0.05) in 50L and 50H than NV and in 50H than 30L. No between-protocol differences were seen for COX or FOX. CONCLUSION: WBV combined with body weight squats can augment VO2 at 40 Hz of high amplitude and 50 Hz of both low and high amplitudes. This metabolic potentiation remains in effect during subsequent aerobic exercise. WBV did not affect fat oxidation across all vibratory loads. PMID- 27460693 TI - Predictors of vitamin D status in New Zealand preschool children. AB - Vitamin D deficiency has adverse health effects in young children. Our aims were to determine predictors of vitamin D status and then to use these factors to develop a practical tool to predict low 25(OH)D concentrations in preschool New Zealand children. A cross-sectional sample of 1329 children aged 2 to <5 years were enrolled from throughout New Zealand in late-winter to spring 2012. 25 Hydroxyvitamin D (25(OH)D) was measured on dried blood spot (DBS) samples collected using finger-prick sampling. Caregivers completed a questionnaire. Mean (SD) DBS 25(OH)D concentration was 52(19)nmol/L. 25(OH)D < 25 nmol/L was present in 86(7%), 25(OH)D < 50 nmol/L in 642(48%), 25(OH)D 50- < 75 nmol/L in 541(41%) and 25(OH)D > 75 nmol/L in 146(11%) of children. Factors independently associated with the risk of 25(OH)D < 25 nmol/L were female gender (OR 1.92,95%CI 1.17 3.14), other non-European ethnicities (not including Maori or Pacific) (3.51,1.89 6.50), had olive-dark skin colour (4.52,2.22-9.16), did not take vitamin D supplements (2.56,1.06-6.18), had mothers with less than secondary-school qualifications (5.00,2.44-10.21) and lived in more deprived households (1.27,1.06 1.53). Children who drank toddler milk (vitamin D fortified cow's milk formula marketed to young children) had a zero risk of 25(OH)D < 25 nmol/L. The predictive tool identified children at risk of 25(OH)D < 25 nmol/L with sensitivity 42%, specificity 97% and ROC area-under-curve 0.76(95%CI 0.67-0.86, p < 0.001). Predictors of low vitamin D status were consistent with those identified in previous studies of New Zealand children. The tool had insufficient predictive ability for use in clinical situations, and suggests a need to promote safe, inexpensive testing to determine vitamin D status in preschool children. PMID- 27460694 TI - Hiatal Hernia, GERD, and Sleeve Gastrectomy: a Complex Interplay. PMID- 27460695 TI - Vascular effects of linagliptin in non-obese diabetic mice are glucose independent and involve positive modulation of the endothelial nitric oxide synthase (eNOS)/caveolin-1 (CAV-1) pathway. AB - AIM: To test the effect of linagliptin in non-obese diabetic (NOD) mice, a murine model of type 1 diabetes, to unveil a possible direct cardiovascular action of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond glycaemia control. METHODS: NOD mice were grouped according to glycosuria levels as NODI: none; NODII: high; NODIII: severe. Linagliptin treatment was initiated once they reached NODII levels. Vascular reactivity was assessed ex vivo on aorta harvested from mice upon reaching NODIII level. In a separate set of experiments, the effect of linagliptin was tested directly in vitro on vessels harvested from untreated NODIII, glucagon-like peptide-1 (GLP-1) receptor knockout and soluble guanylyl cyclase-alpha1 knockout mice. Molecular and cellular studies were performed on endothelial and endothelial nitric oxide synthase (eNOS)-transfected cells. RESULTS: In this ex vivo vascular study, endothelium-dependent vasorelaxation was ameliorated and eNOS/nitric oxide (NO)/soluble guanylyl cyclase (sGC) signalling was enhanced. In the in vitro vascular study, linagliptin exerted a direct vasodilating activity on vessels harvested from both normo- or hyperglycaemic mice. The effect was independent from GLP-1/GLP-1 receptor (GLP-1R) interaction and required eNOS/NO/sGC pathway activation. Molecular studies performed on endothelial cells show that linagliptin rescues eNOS from caveolin-1 (CAV-1) binding in a calcium-independent manner. CONCLUSION: Linagliptin, by interfering with the protein-protein interaction CAV-1/eNOS, led to an increased eNOS availability, thus enhancing NO production. This mechanism accounts for the vascular effect of linagliptin that is independent from glucose control and GLP 1/GLP-1R interaction. PMID- 27460696 TI - Dynamic spatiotemporal trends of imported dengue fever in Australia. AB - Dengue fever (DF) epidemics in Australia are caused by infected international travellers and confined to Northern Queensland where competent vectors exist. Recent analyses suggest that global trade and climate change could lead to the re establishment of Ae. aegypti across the country and promote the spread of dengue nationally. This study aimed to describe the dynamic spatiotemporal trends of imported DF cases and their origins, identify the current and potential future high-risk regions and locate areas that might be at particular risk of dengue transmission should competent mosquito vectors expand their range. Our results showed that the geographical distribution of imported DF cases has significantly expanded in mainland Australia over the past decade. In recent years, the geographical distribution of source countries of DF has expanded from the Pacific region and Asia to include Africa and the Americas. Australia is now exposed to dengue importations from all of the regions involved in the current global pandemic. The public health implications of a range expansion of dengue mosquito vectors are severe. Enhanced mosquito surveillance in those areas that have high imported cases is called for to reduce emerging threats from this globally expanding pathogen. PMID- 27460698 TI - Chemistry and Chemical Biology of Therapeutically Important Compounds. PMID- 27460697 TI - Development of ethynyl-2'-deoxyuridine chemical probes for cell proliferation. AB - A common method of evaluating cellular proliferation is to label DNA with chemical probes. 5-Ethynyl-2'-deoxyuridine (EdU) is a widely utilized chemical probe for labeling DNA, and upon incorporation, EdU treatment of cells is followed by a reaction with a small molecule fluorescent azide to allow detection. The limitations when using EdU include cytotoxicity and a reliance on nucleoside active transport mechanisms for entry into cells. Here we have developed six novel EdU pro-labels that consist of EdU modified with variable lipophilic acyl ester moieties. This pro-label:chemical probe relationship parallels the prodrug:drug relationship that is employed widely in medicinal chemistry. EdU and EdU pro-labels were evaluated for their labeling efficacy and cytotoxicity. Several EdU pro-label analogues incorporate into DNA at a similar level to EdU, suggesting that nucleoside transporters can be bypassed by the pro labels. These EdU pro-labels also had reduced toxicity compared to EdU. PMID- 27460700 TI - beta2-adrenergic receptor activation promotes the proliferation of A549 lung cancer cells via the ERK1/2/CREB pathway. AB - Lung cancer is one of the most common cancers worldwide and accounts for 28% of all cancer-related deaths. The expression of the beta2-adrenergic receptor (beta2 AR), one of the stress-inducible receptors, has been reported to be closely correlated with malignant tumors. However, the role of beta2-AR activation in human lung epithelial-derived cancer A549 cells and the underlying mechanisms are not fully understood. In the present study, we found that activation of beta2-AR but not beta1-AR promoted the proliferation of A549 cells. Isoproterenol (ISO) stimulation of beta2-AR induced extracellular signal-regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Blocking the ERK1/2 pathway by U0126 inhibited CREB phosphorylation and also suppressed A549 cell proliferation. Moreover, ISO treatment enhanced the expression of matrix metalloproteinase (MMP) family proteins such as MMP-2, MMP-9, and also vascular endothelial growth factor (VEGF), which were able to be blocked by knockdown of CREB. In conclusion, our data revealed that beta2-AR induced ERK1/2 phosphorylation which in turn activated CREB to promote A549 cell proliferation. These findings elucidate potential therapeutic targets for lung cancer treatment. PMID- 27460699 TI - Synthesis and evaluation of multi-target-directed ligands for the treatment of Alzheimer's disease based on the fusion of donepezil and melatonin. AB - A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and beta-amyloid (Abeta) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Abeta aggregation (56.3% at 20MUM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment. PMID- 27460702 TI - Clinical Connections. PMID- 27460703 TI - Basement membrane protein ladinin-1 and the MIF-CD44-beta1 integrin signaling axis are implicated in laryngeal cancer metastasis. AB - Laryngeal squamous cell carcinoma (LSCC) is the most common form of malignant disease in the head and neck region characterized by frequent occurrence of metastases in the neck lymph nodes early in the disease onset. In the presented study, we performed quantitative proteomic profiling of patient-matched primary tumor and adjacent non-tumorous tissues derived from metastatic LSCC as to identify new protein candidates with potential diagnostic and therapeutic significance. Obtained results revealed for the first time involvement of the basement membrane protein ladinin-1 in laryngeal cancer metastases. Alterations in the cellular microenvironment that propel metastatic events in laryngeal cancer include activation of MIF-CD44-beta1 integrin signal transduction pathway and induction of downstream signaling mediated by NF-kappaB and Src tyrosine kinase, which ultimately impinge on cytoskeletal dynamics and architecture resulting in increased cellular motility and invasiveness. In this context, particularly interesting finding is upregulation of several actin-binding proteins novel to laryngeal cancer pathogenesis including coronin-1C and plastin 2, whose functional significance in laryngeal carcinogenesis has yet to be established. We also detected for the first time a complete loss of afamin in metastatic laryngeal cancer tissues, which warrants further studies into its use as a possible marker for monitoring disease progression and/or treatment outcome. PMID- 27460704 TI - Chronic venous disease - Part II: Proteolytic biomarkers in wound healing. AB - Venous leg ulcers (VLU) are characterized by sustained proteolytic microenvironment impairing the healing process. Wound fluid (WF) reflect the biomolecular activities occurring within the wound area; however, it is unclear if WF from different healing phases have different proteolytic profiles and how VLU microenvironment affects the wound healing mechanisms. We investigated the proteolytic network of WF from distinct VLU phases, and in WF- and LPS-stimulated THP-1 monocytes treated with glycosaminoglycan sulodexide, a well known therapeutic approach for VLU healing. WF were collected from patients with VLU during inflammatory (Infl) and granulating (Gran) phases. WF and THP-1 supernatants were analyzed for nine matrix metalloproteinases (MMP) and four tissue inhibitors of metalloproteinases (TIMP) by multiplex immunoassays. Our results demonstrated that: 1) WF from Infl VLU contained significantly increased concentrations of MMP-2, MMP-9, MMP-12, TIMP-1, and TIMP-2 compared to Gran WF; 2) WF from Gran VLU showed significantly increased levels of MMP-1, MMP-7, MMP 13, and TIMP-4 compared to Infl WF; 3) LPS- and WF-stimulation of THP-1 cells significantly increased the expression of several MMP compared to untreated cells; 4) Sulodexide treatment of both LPS- and WF-stimulated THP-1 significantly down-regulated the release of several MMPs. Our study provides evidence-based medicine during treatment of patients with VLU. WF from Infl and Gran VLU have different MMP and TIMP signatures, consistent with their clinical state. The modulation of proteolytic pathways in wound microenvironment by glycosaminoglycan sulodexide, provide insights for translating research into clinical practice during VLU therapy. PMID- 27460705 TI - Mitochondrial traffic jams in Alzheimer's disease - pinpointing the roadblocks. AB - The vigorous axonal transport of mitochondria, which serves to distribute these organelles in a dynamic and non-uniform fashion, is crucial to fulfill neuronal energetic requirements allowing the maintenance of neurons structure and function. Particularly, axonal transport of mitochondria and their spatial distribution among the synapses are directly correlated with synaptic activity and integrity. Despite the basis of Alzheimer's disease (AD) remains enigmatic, axonal pathology and synaptic dysfunction occur prior the occurrence of amyloid beta (Abeta) deposition and tau aggregation, the two classical hallmarks of this devastating neurodegenerative disease. Importantly, the early stages of AD are marked by defects on axonal transport of mitochondria as denoted by the abnormal accumulation of mitochondria within large swellings along dystrophic and degenerating neuritis. Within this scenario, this review is devoted to identify the molecular "roadblocks" underlying the abnormal axonal transport of mitochondria and consequent synaptic "starvation" and neuronal degeneration in AD. Understanding the molecular nature of defective mitochondrial transport may provide a new avenue to counteract AD pathology. PMID- 27460706 TI - Inhibition of IL-6 trans-signaling in the brain increases sociability in the BTBR mouse model of autism. AB - Autism is a severe neurodevelopmental disorder with a large population prevalence, characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. The BTBR T(+)Itpr3(tf) (BTBR) mice have emerged as strong candidates to serve as models of a range of autism-relevant behaviors. Increasing evidences suggest that interleukin (IL)-6, one of the most important neuroimmune factors, was involved in the pathophysiology of autism. It is of great importance to further investigate whether therapeutic interventions in autism can be achieved through the manipulation of IL-6. Our previous studies showed that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity. In this study, we evaluate whether inhibiting IL-6 signaling in the brain is sufficient to modulate the autism-like behaviors on the BTBR mice. The results showed that chronic infusion of an analog of the endogenous IL-6 trans-signaling blocker sgp130Fc protein increased the sociability in BTBR mice. Furthermore, no change was observed in the number of excitatory synapse, level of synaptic proteins, density of dentitic spine and postsynaptic density in BTBR cortices after inhibiting IL-6 trans-signaling. However, inhibition of IL-6 trans-signaling increased the evoked glutamate release in synaptoneurosomes from the cerebral cortex of BTBR mice. Our findings suggest that inhibition of excessive production of IL-6 may have selective therapeutic efficacy in treating abnormal social behaviors in autism. PMID- 27460708 TI - Energy expenditure and weight control: Is the biggest loser the best loser? PMID- 27460707 TI - Proteomic analysis of FUS interacting proteins provides insights into FUS function and its role in ALS. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Mutations in the Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) gene cause a subset of familial ALS cases and are also implicated in sporadic ALS. FUS is typically localized to the nucleus. The ALS-related FUS mutations cause cytoplasmic mis-localization and the formation of stress granule-like structures. Abnormal cytoplasmic FUS localization was also found in a subset of frontotemporal dementia (FTLD) cases without FUS mutations. To better understand the function of FUS, we performed wild-type and mutant FUS pull-downs followed by proteomic identification of the interacting proteins. The FUS interacting partners we identified are involved in multiple pathways, including chromosomal organization, transcription, RNA splicing, RNA transport, localized translation, and stress response. FUS interacted with hnRNPA1 and Matrin-3, RNA binding proteins whose mutations were also reported to cause familial ALS, suggesting that hnRNPA1 and Matrin-3 may play common pathogenic roles with FUS. The FUS interactions displayed varied RNA dependence. Numerous FUS interacting partners that we identified are components of exosomes. We found that FUS itself was present in exosomes, suggesting that the secretion of FUS might contribute to the cell-to-cell spreading of FUS pathology. FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. Our results provide insights into the physiological functions of FUS as well as important pathways where mutant FUS can interfere with cellular processes and potentially contribute to the pathogenesis of ALS. PMID- 27460709 TI - Metabolic adaptation: Here to stay? PMID- 27460710 TI - Adaptive thermogenesis: Do we need new thinking? PMID- 27460711 TI - Models of energy homeostasis in response to maintenance of reduced body weight. AB - OBJECTIVE: To test three proposed models for adaptive thermogenesis in compartments of energy expenditure following different degrees of weight loss. Specifically, (1) there is no adaptive thermogenesis [constant relationship of energy expenditure (EE) to metabolic mass]. (2) There is a fixed degree of adaptive thermogenesis once fat stores are below a "threshold." (3) The degree of adaptive thermogenesis is proportional to weight loss. METHODS: The relationship between weight loss and EE was examined in 17 inpatient subjects with stable weight and obesity studied at usual weight and again following a 10% and a 20% weight loss. RESULTS: Following initial weight loss (10%), resting (REE) and non resting (NREE) EE were significantly below those predicted on the basis of the amount and composition of weight lost. Further reductions below predicted values of NREE but not REE occurred following an additional 10% weight loss. Changes in body weight, composition, and/or energy stores were significantly correlated with changes in EE. CONCLUSIONS: All models are applicable to the decline in EE following weight loss. The disproportionate decline in REE is consistent with a threshold model (no change with further weight loss) while the disproportionate decline in NREE is largely reflective of the degree of weight loss. PMID- 27460713 TI - Resection of the large bowel suppresses hunger and food intake and modulates gastrointestinal fermentation. AB - OBJECTIVE: To assess appetite and gut hormone levels in patients following partial (PR) or total resection (TR) of the large bowel. METHODS: A comparative cross sectional study was carried out with healthy controls (n = 99) and patients who had undergone PR (n = 64) or TR (n = 12) of the large bowel. Participants consumed a standard (720 kcal) breakfast meal at 0830 (t = 0) h followed by lactulose (15 g) and a buffet lunch (t = 210 min). Participants rated the subjective feelings of hunger at t = -30, 0, 30, 60, 120, and 180 min. Breath hydrogen (BH) concentrations were also evaluated. In a matched subset (11 controls, 11 PR and 9 TR patients) PYY and GLP-1 concentrations were measured following breakfast. The primary outcome measure was appetite, as measured using visual analogue scales and the buffet lunch. The secondary outcome was BH concentrations following a test meal. RESULTS: PR and TR participants had lower hunger and energy intake at the buffet lunch meal compared to controls. PR subjects had higher BH concentrations compared to controls and TR subjects. BH levels correlated with circulating GLP-1 levels at specific time points. CONCLUSIONS: PR or TR of the large bowel reduced feelings of hunger and energy intake, and PR increased gastrointestinal fermentation. PMID- 27460712 TI - Body mass index: Has epidemiology started to break down causal contributions to health and disease? AB - OBJECTIVES: To review progress in understanding the methods and results concerning the causal contribution of body mass index (BMI) to health and disease. METHODS: In the context of conventional evidence focused on the relationship between BMI and health, this review considers current literature on the common, population-based, genetic contribution to BMI and how this has fed into the developing field of applied epidemiology. RESULTS: Technological and analytical developments have driven considerable success in identifying genetic variants relevant to BMI. This has enabled the implementation of Mendelian randomization to address questions of causality. The product of this work has been the implication of BMI as a causal agent in a host of health outcomes. Further breakdown of causal pathways by integration with other "omics" technologies promises to deliver additional benefit. CONCLUSIONS: Gaps remain in our understanding of BMI as a risk factor for health and disease, and while promising, applied genetic epidemiology should be considered alongside alternative methods for assessing the impact of BMI on health. Potential limitations, relating to inappropriate or nonspecific measures of obesity and the improper use of genetic instruments, will need to be explored and incorporated into future research aiming to dissect BMI as a risk factor. PMID- 27460715 TI - Corrigendum: Carnosine: Potential aid for diabetes and cardiovascular disease. PMID- 27460714 TI - Inverse association between carbohydrate consumption and plasma adropin concentrations in humans. AB - OBJECTIVE: The role of metabolic condition and diet in regulating circulating levels of adropin, a peptide hormone linked to cardiometabolic control, is not well understood. In this study, weight loss and diet effects on plasma adropin concentrations were examined. METHODS: This report includes data from (1) a weight loss trial, (2) an evaluation of acute exercise effects on mixed-meal (60% kcal from carbohydrates) tolerance test responses, and (3) a meta-analysis to determine normal fasting adropin concentrations. RESULTS: Distribution of plasma adropin concentrations exhibited positive skew and kurtosis. The effect of weight loss on plasma adropin concentrations was dependent on baseline plasma adropin concentrations, with an inverse association between baseline and a decline in concentrations after weight loss (Spearman's rho = -0.575; P < 0.001). When ranked by baseline plasma adropin concentrations, only values in the upper quartile declined with weight loss. Plasma adropin concentrations under the main area of the bell curve correlated negatively with habitual carbohydrate intake and plasma lipids. There was a negative correlation between baseline values and a transient decline in plasma adropin during the mixed-meal tolerance test. CONCLUSIONS: Plasma adropin concentrations in humans are sensitive to dietary macronutrients, perhaps due to habitual consumption of carbohydrate-rich diets suppressing circulating levels. Very high adropin levels may indicate cardiometabolic conditions sensitive to weight loss. PMID- 27460716 TI - Erratum: Postprandial metabolism in adults with prader-willi syndrome. PMID- 27460717 TI - Erratum: The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. PMID- 27460719 TI - Inhibition of the JNK signaling pathway increases sensitivity of hepatocellular carcinoma cells to cisplatin by down-regulating expression of P-glycoprotein. PMID- 27460718 TI - Policosanol as a new inhibitor candidate for vascular calcification in diabetic hyperlipidemic rats. AB - This work mainly aimed to investigate the probable changes of aortic calcification by policosanol, omega-3 fatty acids in comparison with atorvastatin and subsequent progression of atherosclerosis in diabetic hyperlipemic rat model. Adult male albino rats of wistar strain (30) were divided into five groups (n = 6/group); one was fed normal diet and was used as a normal group, the other groups received alloxan, atherogenic diet (CCT - rat chow diet supplemented with 4% cholesterol, 1% cholic acid, and 0.5% thiouracil) and categorized as follows: the second group received no treatment and kept as control (diabetic hyperlipidemic control group (DHC)). The other groups received daily oral doses of atorvastatin, policosanol (10 mg/kg body weight) and omega-3 (50 mg/kg body weight), respectively, for eight weeks. Different biomarkers were used for the evaluation that included inflammatory (C reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha)), oxidative stress (glutathione (GSH), malondialdehyde (MDA)) bone calcification markers (alkaline phosphatase (ALP), Vitamin D, parathyroid hormone (PTH)), lipogram pattern in addition to histochemical demonstration of calcium in the aorta. Diabetic hyperlipemic group demonstrated significant hyperglycemia, hyperlipidemia, and increased inflammation, oxidative stress, calcification, and finally atherogenesis progression. Treatment of diabetic hyperlipemic rats with, policosanol, omega-3 fatty acids (natural products) and atorvastatin for eight weeks significantly increased high-density lipoprotein cholesterol (HDL-C), Vitamin D, decreased aortic vacuoles number, and inhibited calcification process. Policosanol induced more remarkable reduction in the density and number of foam cells and improved the intimal lesions of the aorta as compared to atorvastatin. Drugs under study exerted hypoglycemic effect along with an inhibition of inflammation, oxidative stress, and calcium deposition with certain variations but policosanol effect was remarkable in comparison with other drugs. PMID- 27460720 TI - Comparative study of oncoplastic versus non-oncoplastic breast conserving surgery in a group of 211 breast cancer patients. AB - OBJECTIVE: Breast conserving surgery (BCS) followed by radiotherapy is the standard of care for most patients with early breast cancers; however, the aesthetic outcomes of this procedure is not always desirable. Oncoplastic breast surgery is an innovative approach that aims at the safe and effective treatment of the cancerous lesion while achieving the best possible aesthetic outcome. The aim of this study was to evaluate and compare oncoplastic and non-oncoplastic procedures. PATIENTS AND METHODS: A retrospective observational study was conducted on a group of patients who underwent oncoplastic or non-oncoplastic breast surgery at the Breast Unit of the University of Rome Tor Vergata. RESULTS: Out of 211 patients, 154 (73%) underwent non-oncoplastic surgery, while 61 (27%) underwent an oncoplastic procedure. The percentage of patients requiring re excision was twice greater for women in the non-oncoplastic group: 12.9% vs. 6.5% in the oncoplastic group. The rate of complications was higher in the oncoplastic group compared to the non-oncoplastic one (4.9% vs. 1.3%). The size of the tumor, the number of the patients receiving post-operative radiation, the interval between surgery and radiotherapy and follow-up were similar between the two groups. CONCLUSIONS: Oncoplastic surgery represents a valid alternative to breast conserving surgery for patients with breast cancer, with only minimal differences in long-term complications and similar results in terms of local recurrence and number of metastasis. PMID- 27460721 TI - When alarm bells ring: emergency tinnitus. AB - OBJECTIVE: The aim of this study is to develop a diagnostic-therapeutic algorithm for those suffering from tinnitus who seek emergency aid. MATERIALS AND METHODS: A literature review has been performed on articles from the last 30 years. RESULTS: It is important to activate medical or surgical diagnostic and therapeutic strategies, in order to safeguard and rehabilitate the various functions affected. Psychiatric comorbidity is the most frequent pathological condition of those with serious or catastrophic tinnitus. In these cases, mortality risk is linked to suicide, morbidity to tinnitus-correlated distress. CONCLUSIONS: Tinnitus, mainly linked to loss of hearing, is a frequent symptom among the population at large. About 7% of those affected by tinnitus turn to their doctor to solve their problem, while between 0.5 and 2% request urgent medical assistance. Their cry for help may be the result of an acute onset of tinnitus or the rapid impairment of an already chronic condition. Tinnitus is not considered an urgent ear, nose and throat (ENT) condition by the Associazione Otorinolaringologi Ospedalieri Italiani (AOOI) [Italian Association of Hospital ENT], even though there are many pathological conditions, sometimes serious, associated with tinnitus and emergency action is necessary to reduce the risk of morbidity and mortality. PMID- 27460722 TI - Clinical significance of maternal serum vascular endothelial growth factor (VEGF) level in idiopathic recurrent pregnancy loss. AB - OBJECTIVE: The aim of this study was to determine whether maternal serum vascular endothelial growth factor (VEGF) levels are associated with unexplained recurrent pregnancy losses (RPLs). PATIENTS AND METHODS: Twenty-one pregnant women with idiopathic RPLs who were selected from 47 cases with RPLs were compared with age matched 24 control participants. Transvaginal obstetric ultrasonographies were performed and maternal serum samples were collected between 5th and 10th gestational weeks to evaluate serum VEGF and progesterone (P4) concentrations. Enzyme-linked immunosorbent assay technique was used in measurements of VEGF and P4. RESULTS: Prevalence of idiopathic cases among all RPLs was 44.7%. Median serum VEGF value was found statistically higher in RPL group when compared to control group (210.33 +/- 108.23 pg/ml vs. 123.91 +/- 18.8 pg/ml, respectively). There was no statistical difference between the median values of serum P4 levels in idiopathic RPL group and the control group (19.53 +/- 5.79 ng/ml and 20.08 +/- 7.85 ng/ml, respectively). Serum VEGF levels did not differ significantly with regard to gestational age within the RPL and control groups (p = 0.72 and p = 0.89, respectively). A positive correlation was found between VEGF levels and the patients' age within RPL group (r = 0.515). CONCLUSIONS: Serum VEGF levels are independent by the gestational age. Serum VEGF concentrations correlate positively with maternal age. Increased maternal age, especially maternal age over 35 years, is related to elevated serum VEGF concentration. Increased maternal serum VEGF concentration is related to recurrent pregnancy loss. PMID- 27460723 TI - The association between mean platelet volume and infants with meconium stained amniotic fluid. AB - OBJECTIVE: The exact pathophysiology of meconium passage into the amniotic fluid is unknown, but it is frequently associated with fetal hypoxia. The mean platelet volume (MPV) seems to be a marker of platelet production and consumption and may be related to the severity of some diseases associated with bone marrow, hypoxia, and perinatal infections. We aimed to investigate the association between MPV levels and meconium-stained amniotic fluid (MSAF) in infants. PATIENTS AND METHODS: MPV, serum-reactive protein and hemoglobin levels, and leukocyte and thrombocyte counts were measured in 106 infants with MSAF and a comparison group of 78 healthy control infants. RESULTS: The mean MPV values of the infants with MSAF were statistically significantly lower than those of the control group (p < 0.001). There was no statistically significant difference in the hemoglobin levels or leukocyte and thrombocyte counts in the study group compared to the control group (p > 0.05). There was also no statistically significant difference in the MPV levels of the infants with meconium aspiration syndrome (MAS) compared to the infants with MSAF without MAS (p = 0.107). The optimal cut-off value for the MPV was 9.90 fl (area under the curve [AUC: 0.788]) in the infants with MSAF, with a sensitivity of 78.1% and specificity of 74.3%. CONCLUSIONS: Our data suggest that the MPV levels of infants with MSAF were significantly lower than those of healthy infants. This might be associated with a hypoxic process. However, the MPV levels of infants with MSAF and MAS were statistically similar. Thus, the MPV level could not be used to detect patients with or without severe disease. PMID- 27460724 TI - Comparison of the VISX wavescan and OPD-scan III with the subjective refraction. AB - OBJECTIVE: To compare the refractive errors measured by the VISX WaveScan, OPD Scan III and the subjective refraction. The optometry accuracy of computer operated aberrometer used before refractive surgery has been debatable. Hence, a clear study on the role of such automated equipment in optometry is the need of the hour as compared to subjective refraction. PATIENTS AND METHODS: Seventy-six patients (152 eyes) were recruited from January 2013 to December 2013. All patients were measured with subjective refraction by the phoropter (NIDEK, RT 5100), objective refraction by the WaveScan (AMO Company, USA), OPD-Scan III (Nidek Technologies, Japan). The sphere, cylinder, axis of the three methods were compared and analyzed. RESULTS: The diopter of sphere power measured by WaveScan was lower than that of the subjective refraction and the difference was 0.13 +/- 0. 30D (t = 3. 753, p <0. 001). While the diopter of cylinder power was higher and the difference was 0.13 +/-0.43D (t = 3. 664, p <0. 001). There was no significance for sphere, cylinder and spherical equivalent between OPD-Scan III and subjective refraction (p >0. 05). The value of the difference between WaveScan and subjective refraction was 5.87 degrees +/-6.19 degrees on average, while the difference between OPD-Scan III and subjective refraction was 3.82 degrees +/-3.95 degrees on average. The differences between the two were statistically significant (t =2. 817, p =0. 006). CONCLUSIONS: The results of sphere and cylinder measured by WaveScan and subjective refraction were different. As the latest integrated equipment, the Nidek OPD-Scan III gives a more accurate measurement of objective refraction when compared with subjective refraction. The latest Nidek OPD-Scan III may prove to be an useful tool for preoperative optometry deviation based on objective refraction. PMID- 27460725 TI - The use of optical coherence tomography (OCT) to evaluate the efficacy of different photo-coagulations in diabetic macular edema treatment. AB - OBJECTIVE: To evaluate the therapeutic effects of the early application of photocoagulation for treating the macular edema in non-proliferative diabetic retinopathy (NPDR). We also wanted to evaluate the potential of optical coherence tomography (OCT) to make a quantitative detection in patients suffering from this condition. PATIENTS AND METHODS: From October 2010 to October 2014, a total of 132 patients, all diagnosed with NPDR combined with clinically significant macular edema (CSME) in our hospital, were enrolled in this study. After obtaining the approval of the hospital Ethics Committee and the informed consents of patients and families, we divided the cases into two groups: PRP group (n=63) and macular edema group (n=69). Clinical effects and complications associated with the used methods were compared and analyzed in two groups. RESULTS: We analyzed the panretinal photocoagulation (PRP), and macular grid photocoagulation curative effects. The difference in successful surgery rate, between the two groups, was not statistically significant (p > 0.05). When we examined patients 1 month, 3 months, and 6 months after the surgery, average retinal thickness and volume in macular region in both groups were reduced. In the group, the comparison was statistically significant (p < 0.05) while between the groups, the comparison was not statistically significant (p > 0.05). Visions in both groups were improved after treatment and difference on the post-operative 6-month vision improvement degree between the two groups was not statistically significant (p > 0.05). CONCLUSIONS: We concluded that the early photocoagulation could significantly improve the vision. However, the clinical effects and complications associated with the use of PRP and macular grid photocoagulation had no significant differences. PMID- 27460726 TI - Effects of light on the development of melanoposin containing retinal ganglion cells in rats. AB - OBJECTIVE: The present study was planned to evaluate the effect of light on the development of light-sensitive retinal ganglion cells. MATERIALS AND METHODS: The Sprague-Dawley (SD) rats were segregated into 3 groups (n=18) which included routine feeding 10-day group 1, routine feeding 14-day group 2 and light deprivation feeding 14-day group 3. The group 1 animals were routinely fed for 10 days in normal light conditions and were sacrificed for analyses on day 10. Similarly, group 2 animals were routinely fed for 14 days in normal light conditions and were sacrificed for analyses on day 14. The group 3 animals were kept were routinely fed for 7 days which was followed by their feeding in a light deprived conditions and were sacrificed on day 14. RESULTS: The expression of the opsin gene determined by real-time PCR in retinal tissues showed a significant decline in the light-deprived group 3 when compared to other two groups. Furthermore, the melanopsin protein also showed a significant decline in its protein expression in light-deprived group 3 as observed by immune-blot analyses. The immuno-fluorescence analyses also showed the similar trend confirming the effect of light on the development of retinal ganglion cells. CONCLUSIONS: Light is essential for the proper development process of retinal ganglion cells as light directly affects regulatory opsin gene expression. PMID- 27460727 TI - Surgical treatment of acetabular metastasis. AB - Breast cancer is the most common malignancy in women. Bone represents the first site of metastasis in more than 50% of patients who relapse systematically. The pelvis in the most common localization after spine in bone metastasis due to breast cancer. The peri-acetabular localization is a greater concern rather than another part of the pelvis. Bone destruction in this anatomical localization lead to pain and mechanical instability, resulting in a great reduction of autonomy and deterioration of patient's quality of life. In the current report, the Authors review the literature about the surgical treatment, the indications and complications of each surgical technique underling the importance of tailoring each surgical procedure on life span and quality of life in order to minimize peri-operative complications and maximize functional results for the patients. PMID- 27460728 TI - HIFs-MiR-33a-Twsit1 axis can regulate invasiveness of hepatocellular cancer cells. AB - OBJECTIVE: In this study, we investigated whether miR-33a downregulation in HCC is a result of hypoxia-inducible factors (HIFs) overexpression. Then, we further studied the regulative effects of miR-33a on Twist1 and their regulation in HCC cell invasiveness. MATERIALS AND METHODS: Human hepatocellular cancer (HCC) cell lines (HepG2 and BEL-7402) were transfected with miR-33a mimics, HIFs siRNA or Twist1 siRNA. MiR-33a level was measured using QRT-PCR. The binding between miR 33a and Twist1 3'UTR was verified using Western blot analysis and dual luciferase assay. E-cadherin and N-cadherin expression levels were detected by western blot analysis. Tumor cell invasion was assessed using transwell assay. RESULTS: MiR 33a downregulation in HCC cells is hypoxia-induced and is a result of HIFs upregulation. HIF-1alpha and HIF-2alpha suppression partly rescued miR-33a expression under hypoxia. Both HepG2 and BEL-7402 cells with miR-33a overexpression had significantly decreased E-cadherin expression and increased N cadherin level. Transwell analysis confirmed that miR-33a overexpression significantly suppressed the tumor cell invasion capability. Twist1 is a direct target of miR-33a in HCC. HepG2 cells with Twist1 knockdown had significantly increased E-cadherin, decreased N-cadherin and suppressed invasion capability. CONCLUSIONS: MiR-33a downregulation in HCC cells is hypoxia-induced and is a result of HIFs upregulation. MiR-33a can modulate EMT and invasion of hepatocellular cancer cells at least partly via downregulating Twist1. PMID- 27460729 TI - Bioinformatic analysis of RNA-seq data unveiled critical genes in rectal adenocarcinoma. AB - OBJECTIVE: RNA-seq data of rectal adenocarcinoma (READ) were analyzed with bioinformatics tools to unveil potential biomarkers in the disease. MATERIALS AND METHODS: RNA-seq data of READ were downloaded from The Cancer Genome Atlas (TCGA) database. Differential analysis was performed with package edgeR. False discovery rate (FDR) < 0.05 and |log2 (fold change)|>1 were set as cut-off values to screen out differentially expressed genes (DEGs). Gene coexpression network was constructed with package Ebcoexpress. Gene Ontology enrichment analysis was performed for the DEGs in the gene coexpression network with DAVID online tool. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was also performed for the genes with KOBASS 2.0. RESULTS: A total of 620 DEGs, 389 up regulated genes, and 231 down-regulated genes, were identified from 163 READ samples and 9 normal controls. A gene coexpression network consisting of 71 DEGs and 253 edges were constructed. Genes were associated with ribosome and focal adhesion functions. Three modules were identified, in which genes were involved in muscle contraction, negative regulation of glial cell proliferation and extracellular matrix organization functions, respectively. Several critical hub genes were disclosed, such as RPS2, MMP1, MMP11 and FAM83H. Thirteen relevant small molecule drugs were identified, such as scriptaid and spaglumic acid. A total of 8 TFs and 5 miRNAs were acquired, such as MYC, NFY, STAT5A, miR-29, miR 200 and miR-19. CONCLUSIONS: Several critical genes and relevant drugs, TFs and miRNAs were revealed in READ. These findings could advance the understanding about the disease and benefit therapy development. PMID- 27460730 TI - Downregulation of miR-145-5p correlates with poor prognosis in gastric cancer. AB - OBJECTIVE: The aim of this study was to explore the clinical significance of miR 145-5p expression in gastric cancer (GC). PATIENTS AND METHODS: Expression of miR 145-5p was evaluated by qRT- PCR in tumor and normal gastric tissues in 145 GC patients. The correlation between the miR-145-5p expression and clinicopathological parameters was investigated. Finally, the survival was assessed by the Kaplan-Meier method and proportional hazards model. RESULTS: Expression levels of miR-145-5p in GC tissues were significantly lower than those in adjacent normal tissues (p < 0.001). MiR-145-5p expression was significantly associated with lymph node metastasis, metastasis stage, and distant metastasis (all p < 0.05). Furthermore, Patients with low miR-145-5p expression had poorer overall survival time than those with high miR-145-5p expression (p = 0.014). Moreover, univariate and multivariate Cox analysis showed that miR-145-5p was an independent prognostic indicator for OS (p = 0.011). CONCLUSIONS: MiR-145-5p is down-expressed in GC, and can be used as a marker of poor prognosis in GC patients. PMID- 27460731 TI - Over-expression of lncRNA SBF2-AS1 is associated with advanced tumor progression and poor prognosis in patients with non-small cell lung cancer. AB - OBJECTIVE: Emerging evidence suggest that long non-coding RNAs (lncRNAs) may play important roles in human cancers. The aim of this study was to investigate the expression of SBF2-AS1 in non small cell lung cancer (NSCLC) and its correlation with clinicopathological features and prognosis in NSCLC. PATIENTS AND METHODS: The expression of lncRNA SBF2-AS1 was measured in 174 NSCLC samples and their matched non-tumor tissues by using RT-PCR. Association of SBF2-AS1 expression with clinicopathological features was analyzed in NSCLC. Kaplan-Meier analysis was performed to evaluate the overall survival of NSCLC patients. RESULTS: The expression of SBF2-AS1 was higher in NSCLC tissues compared with adjacent non tumor tissues (p < 0.01). Additionally, high expression level of SBF2-AS1 was significantly associated with NSCLC histological grade, and lymph node metastasis. Furthermore, a higher SBF2-AS1 expression was demonstrated to be associated with poor overall survival times in NSCLC patients (p < 0.001). Multivariate analysis suggested that SBF2-AS1 expression was an independent prognostic factor for overall survival of patients with NSCLC (p = 0.013). CONCLUSIONS: Our data suggest that SBF2-AS1 could represent a novel prognostic marker and potential therapeutic target in patients with NSCLC. PMID- 27460732 TI - Long noncoding RNA SPRY4-IT1 is a prognostic factor for poor overall survival and has an oncogenic role in glioma. AB - OBJECTIVE: Long non-coding RNAs (lncRNAs) are emerging as biomarkers and as important regulators of the biological processes and tumorigenesis in cancer. The purpose of this study is to investigate the clinical significance of lncRNA SPRY4 IT1 in glioma. PATIENTS AND METHODS: The expression level of SPRY4-IT1 was examined by the quantitative Real-time PCR (qRT-PCR) in glioma tissues and control tissues and its association with overall survival of patients was analyzed by statistical analysis. Survival curves were made using the Kaplan Meier method, and the log-rank test was used to analyze the differences between clinicopathological characteristics and survival in glioma patients. RESULTS: The expression level of SPRY4-IT1 was significantly higher in glioma in comparison to normal matched tissue (p < 0.01). Furthermore, lncRNA SPRY4-IT1 was associated significantly with WHO grade (p = 0.009) and tumor size (p = 0.003). A significant difference was found that glioma patients with high SPRY4-IT1 expression level had distinctly shorter OS than patients with low SPRY4-IT1 expression level. Furthermore, Multivariate analysis indicated SPRY4-IT1 as an independent prognostic indicator for glioma patients (p = 0.003), CONCLUSIONS: The lncRNA SPRY4-IT1 may be a potential prognostic bio!marker of glioma. PMID- 27460733 TI - Role of microRNA in prostate cancer stem/progenitor cells regulation. AB - Most of the human tumors contain a population of cells with stem cell properties, called cancer stem cells (CSCs), which are believed to be responsible for tumor establishment, metastasis, and resistance to clinical therapy. It's crucial to understand the regulatory mechanisms unique to CSCs, in order to design CSC specific therapeutics. Recent discoveries of microRNA (miRNA) have provided a new avenue for understanding the regulatory mechanisms of cancer. The present review article will discuss important milestones associated with mircroRNA regulation during prostate carcinogenesis. PMID- 27460734 TI - Neutrophil/lymphocyte ratio and mean platelet volume in Behcet's disease. AB - OBJECTIVE: With this retrospective study, we researched the effects of mean platelet volume (MPV) and neutrophil/lymphocyte ratio (NLR) on the activity of Behcet's disease and susceptibility to thrombosis. PATIENTS AND METHODS: One hundred eighty-six patients with Behcet's disease, who met the inclusion criteria, were separated into two groups: 120 patients had active Behcet's disease (Group I) and 66 patients with inactive Behcet's disease (Group II). 79 healthy subjects as controls were included in the study. RESULTS: MPV was similar between all three groups. CRP (C reactive protein) was statistically higher in the active BD group when compared to the inactive BD group and the control group. CRP of the inactive BD and the healthy control group were similar. In addition, erythrocyte sedimentation rate (ESR) was found higher than the control group in both active and inactive BD groups, whereas ESR of the active BD group was higher than the inactive BD group. N/L ratio was found statistically higher in the active BD group when compared to inactive BD and healthy control groups, while the N/L ratio of inactive BD and healthy control groups were found similar to each other. While MPV, CRP, and NLR didn't statistically differ between active BD subgroups with and without thrombosis, ESR was statistically and significantly higher in the active BD group with thrombosis when compared to the active BD group without thrombosis. CONCLUSIONS: The data obtained from the present study showed that the patients with BD are exposed to chronic inflammation. And the N/L ratio may be a simple, inexpensive, and convenient diagnostic marker of active BD. PMID- 27460735 TI - Hypoxia-induced miR-17-5p ameliorates the viability reduction of astrocytes via targeting p21. AB - OBJECTIVE: Glial scars are widely seen as a mechanical barrier to central nervous system regeneration. Up to now, several studies have addressed and clarified how different lesion microenvironment properties affect astrogliosis. In particular, hypoxia induces the astrocyte astrogliosis, and thus promotes the formation of glial scars. However, little is known about the mechanism underlining such process. In the present study, we investigated the regulation by the miR-17-5p on the hypoxia-induced viability via targeting p21. MATERIALS AND METHODS: We examined the expression of miR-15a, miR-16, miR-17-5p, hypoxia inducible factor 1alpha (HIF-1alpha) and p21 in the astrocytes under hypoxia, with quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) methods. Then investigated the regulatory role of miR-17-5p on the level of HIF-1alpha and p21, with qRT-PCR, WB and luciferase reporting assay, and examined the activity of astrocytes under normoxia or hypoxia. RESULTS: Results demonstrated that miR 15a, miR-16, miR-17-5p were significantly upregulated, while HIF-1alpha and p21 were markedly downregulated in the hypoxia-treated astrocytes. And the transfection with miR-17-5p mimics significantly downregulated the expression of HIF-1alpha and p21 in such cells. And the luciferase reporter assay confirmed the targeting inhibiting of p21 by miR-17-5p in astrocytes. Moreover, the viability of astrocytes was significantly upregulated by the miR-17-5p mimics transfection under the hypoxia condition. CONCLUSIONS: Our novel data suggest that the upregulated miR-17-5p contributes to the proliferation of astrocytes, in response to hypoxia, implying the potential role of miR-17-5p in the formation of glial scars. PMID- 27460736 TI - Immune related factors in pathogenesis of autism spectrum disorders. AB - OBJECTIVE: Etiology of Autism Spectrum Disorders (ASD) is insufficiently known. It is suggested that genes play a crucial role in ASD but additional environmental factors to exacerbate the syndrome are needed. Recently, the inflammatory factors in ASD that may predispose to the disorder attract a great attention. Therefore, the aim of this article was to review the literature on the possible association of the immune system malfunctions with the risk of developing ASD. MATERIALS AND METHODS: Available articles from PubMed and Google Scholar were analyzed using time descriptors: 1996-2015 and key words: autism spectrum disorder, cytokines and immune system. RESULTS: Individuals with ASD demonstrate aberrant immune response in central nervous system, peripheral blood and gastrointestinal tract. CONCLUSIONS: Immune malfunctions may play a role in developing ASD. PMID- 27460737 TI - Neurological, otolaryngological and ophthalmological implications of Susac syndrome - a case report. AB - Susac syndrome is an endotheliopathy affecting the arterioles of the brain, retina, and inner ear. Many cases of Susac syndrome are underdiagnosed, mainly at the early stages of the disease, while prompt diagnosis enables a speedy recovery. Immediate treatment can halt disease progression and even prevent future disability. We report a case of Susac syndrome, describe the difficulties in the diagnosis of this case, and include a detailed history of a 35-year-old man via the presentation of extensive laboratory work-up and imaging studies. Audiometry showed sensorineural hearing loss of about 75 dB in the left ear. Ovoid lesions of the corpus callosum in magnetic resonance (MR) were present as were advanced binocular ophthalmological changes in fluorescent angiography. Methylprednisolone with acetylsalicylic acid and intravenous immunoglobulin (IVIG) were implemented with a positive outcome (clinical and audiometric improvement). PMID- 27460738 TI - Comparison of imaging value for diabetic lower extremity arterial disease between FBI and CE-MRA. AB - OBJECTIVE: This study adopted self-control study method to assess the efficacy of fresh blood imaging (FBI) and contrast-enhanced MR angiography (CE-MRA) for patients with diabetic lower extremity arterial disease (DLEAD) (Fontaine stage I to IV), and to evaluate the imaging of lower extremity peripheral arterial disease (PAD) in different stages of diabetes mellitus (DM). PATIENTS AND METHODS: 1. This study recruited 44 diabetic patients with suspected lower extremity PAD to take both FBI and CE-MRA. 2. Two experienced cardiovascular radiologists assessed the image quality, the detection of lower extremity arterial branches, and tissue contamination (veins, arteries, and soft tissues) of FBI and CE-MRA, as well as the presence and severity of stenotic lesions. 3. Statistical differences of the quality of FBI and CE-MRA were determined using paired t-test. 4. Correlation analysis was adopted for determining the direction and strength of the relationship between the changes of the indexes of FBI and the different Fontaine stages. RESULTS: 1. The quality evaluation results of the image of lower extremity arteries from the 44 diabetic patients indicated no statistically significant difference between FBI and CE-MRA in the patients with Fontaine stage I-III (p >0.05). However, a statistically significant difference was observed in the patients with Fontaine stage IV (p <0.05), and the quality of FBI was slightly worse. 2. Arterial branches that observed from FBI and CE-MRA were 885 and 904, respectively. There was no statistically significant difference for the arterial branches between FBI and CE-MRA in the patients with Fontaine stage I-III (p >0.05). However, a statistically significant difference was observed in the patients with Fontaine stage IV (p <0.05), and CE-MRA indicated more artery branches than FBI. 3. There was a statistically significant difference for the evaluation of venous contamination between FBI and CE-MRA (p <0.05), and there was less venous contamination using FBI. 4. The study results indicated that with Fontaine stages going on the FBI's image quality and arterial branches reduced gradually, and the degree of tissue interference and arteriostenosis was rising gradually. CONCLUSIONS: The results of this study indicated that using FBI in lower extremity PAD of diabetics had good quality and high diagnostic accurancy, and the tissue contamination (veins and soft tissues of calf) was effectively avoided. Especially in Fontaine stage I-III, FBI can be used as an alternative technique of CE-MRA, and it also can be used in diabetic patients with renal impairment in Fontaine IV. PMID- 27460739 TI - Biological interaction between sleep quality and depression in type 2 diabetes. AB - OBJECTIVE: To explore the interaction of sleep quality and depression among patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: With multistage cluster sampling, the living quality of all participants was investigated. The indicator of interaction was calculated according to the delta method and non-conditional logistic regression model. RESULTS: There were 944 residents involved in the final analysis including 365 males and 579 females. The average age was (64 +/- 10.2) years. The rate of poor sleep quality and poor sleep quality combined depression were 33.6% and 40.1%, respectively. Due to poor sleep quality and depression in patients with T2DM, the combined interaction index was 2.48 (95% CI 1.44-4.29), the relative excess risk was 3.42 (95% CI 2.16 4.67), and the attributable proportion was 0.51 (95% CI 0.32-0.70). CONCLUSIONS: An additive interaction rather than a multiplicative interaction of poor sleep quality and depression in affecting the quality of life was found in T2DM patients. When both factors existed at the same time, the interaction effect of these 2 factors was greater than the sum of the two factors. PMID- 27460740 TI - microRNA-181a is upregulated in human atherosclerosis plaques and involves in the oxidative stress-induced endothelial cell dysfunction through direct targeting Bcl-2. AB - OBJECTIVE: Atherosclerosis is featured as artery wall thickness as a result of invasion and accumulation of white blood cells and proliferation of intimal smooth muscle cells. Endothelial dysfunction has been linked to a variety of vascular diseases, including atherosclerosis. MicroRNAs play essential roles during the atherosclerotic plaques formation. In this study, we investigate the roles of miR-181a in the oxidative stress-induced endothelial cells dysfunction. MATERIALS AND METHODS: The expressions of miR-181a were compared between human atherosclerotic plaques and normal blood vessels. The Bcl-2 protein expression was measured by Western blot and mRNA expression was measured by qRT-PCR. HUVECs were transiently transfected with pre-miR-181a or control microRNAs by Lipofectamine 2000. The viability of HUVECs in response to H2O2 was measured by MTT assay. RESULTS: We report miR-181a is upregulated in human atherosclerotic plaques compared with the normal blood vessel. The miR-181a is induced by H2O2 treatments. The exogenous overexpression of miR-181a accelerates the apoptosis rates of HUVECs in response to H2O2. We identify Bcl-2 as a direct target of miR 181a. Also, we observed H2O2 treatments inhibited Bcl-2 expressions at both protein and mRNA levels. Inhibition of miR-181a restores Bcl-2 expressions, leading to increased resistance to H2O2. Moreover, restoration of Bcl-2 in miR 181a-overexpressing HUVECs renders cells tolerate higher concentrations of H2O2. Finally, a reverse correlation between miR-181a and Bcl-2 expression in human atherosclerosis plaques is illustrated. CONCLUSIONS: Our results revealed an essential role of miR-181a in the development of atherosclerosis through the regulation of the endothelial dysfunction, providing mechanisms for the development of new antioxidant drugs for the treatment of atherosclerosis. PMID- 27460741 TI - The influence of HOXA5-specific siRNA on the expression of Livin and Smac proteins. AB - OBJECTIVE: To Knockdown Homeobox A5 (HOXA5) expression by HOXA5-specific siRNA and evaluate the effects on Livin and Smac proteins expression in acute T cell leukemia Jurkat cells. MATERIALS AND METHODS: We designed and constructed HOXA5 specific siRNA, and using liposomes we transfected Jurkat cells with this siRNA. The experiment was designed for three groups: (i) experimental group with Jurkat cells transfected with HOXA5-specific siRNA (siRNA transfection group), (ii) negative control group (irrelevant siRNA transfection) with Jurkat cells transfected with pRNAT-U6.1-siD and (iii) normal control group (untransfected Jurkat cells, only with equivalent amounts of cells and medium). We used FQ-PCR and Western blot to detect the relative expression levels of HOXA5 mRNA and protein in each group separately. The Western blot was also used to detect Livin and Smac protein levels in Jurkat cells. RESULTS: Expression levels of HOXA5 mRNA and protein were significantly reduced in the group with Jurkat cells transfected with HOXA5 siRNA (p<0.05). The expression of Livin protein was significantly down regulated (p<0.05) while the expression of Smac protein was significantly up regulated (p <0.05). CONCLUSIONS: HOXA5-specific siRNA effectively silenced the HOXA5 gene expression and down-regulation of HOXA5 induced the down-regulation of Livin protein expression and up-regulation of Smac protein. We suggest the HOXA5 gene to be considered as the new target for acute leukemia gene therapy. PMID- 27460742 TI - The effect of smoking on neutrophil/lymphocyte and platelet/lymphocyte ratio and platelet indices: a retrospective study. AB - OBJECTIVE: Smoking commonly leads to death. Although the neutrophil/lymphocyte Ratio, platelet/lymphocyte ratio and platelet indices have been shown to be important for the diagnosis, prognosis and severity of some diseases, the smoking status of patients in these studies has not been well defined. In this study, we compared ratios derived from complete blood count and platelet indices to smoking status and length in smokers and non-smokers. PATIENTS AND METHODS: The data of healthy males and females aged between 18-60 years who presented to our institute for a routine check-up were collected, and subjects were divided in two groups - smokers and non-smokers. The presence of medical history or laboratory results which could affect inflammatory response, formed our exclusion criteria. All complete blood count results were noted and persons' smoking habits were calculated as pack/years. RESULTS: White blood cell, neutrophil, basophil and eosinophil counts; mean corpuscular volume, red cell distribution width and neutrophil/lymphocyte ratio were significantly higher in smokers when compared to non-smokers (p<0.05). When smokers were grouped according to smoking habits; positive linear correlations were detected between pack/year and Neutrophil/lymphocyte ratio and also pack/year and plateletcrit in smokers (p<0.05). CONCLUSIONS: Neutrophil/lymphocyte ratio increases in correlation with pack/year while platelet/lymphocyte ratio is not affected and platelet distribution width is increased in smokers. If smokers are not excluded from studies evaluating neutrophil/lymphocyte ratio and platelet distribution width, the relationship between smoking status as well as pack/year must be determined and reported. PMID- 27460743 TI - Tiapride is more effective and causes fewer adverse effects than risperidone in the treatment of senile dementia. AB - OBJECTIVE: We wanted to compare the effects of tiapride and risperidone in treating behavioral and psychological symptoms of senile dementia. PATIENTS AND METHODS: 108 patients with senile dementia received respective treatments (54 patients per treatment, either with 100 mg/day risperidone or 2.0 mg tiapride/day) for 2 months. Outcomes included the positive and negative syndrome scale (PANSS) scores, the curative rate of senile dementia, and prevalence of adverse effects (somnolence, headache, loss of weight, extrapyramidal system response, irritation and insomnia). RESULTS: PANSS scores before treatment were comparable between treatment groups. On days 7, 15, 30, and 60 of the treatment, the differences between two treatment groups became evident. Thus, curative rates in patients treated with risperidone were 74.1% and in those treated with tiapride 88.9% (p < 0.05). Prevalence of adverse reactions was significantly lower in the latter group (9.3% vs. 25.9% in patients treated with risperidone; p < 0.05). CONCLUSIONS: Tiapride is more effective in improving clinical symptoms of senile dementia and causes fewer adverse effects. PMID- 27460744 TI - Anticonvulsant activities of Sambucus nigra. AB - OBJECTIVE: Sambucus (S) spp. is reported to possess a variety of activities and has been used in traditional medicine for many years. In spite of CNS activity of this genus, nothing is known about the anticonvulsant activity of S. nigra. MATERIALS AND METHODS: Anticonvulsant activities of methanolic extracts of bark, fruit and leaf of S. nigra at doses of 250, 500 and 1000 mg kg-1 were determined by pentylenetetrazole (PTZ) induced and maximal electroshock (MES) induced convulsions in mice. RESULTS: Normal saline treated mice showed tonic hind limb extension for a duration of 6.58 +/- 1.24 s in MES model. Administration of extracts significantly and dose-dependently increased the delay of the onset of seizures and decreased significantly the duration of tonic hind limb extension. Bark extract at 500 and leaf extract at 1000 mg kg-1 gave 100% protection against seizures. They inhibited induction of convulsion and gave 100% protections against mortality. PTZ (100 mg kg-1) induced tonic seizures in all of the control mice. Pretreatment with leaf extract at 500 and 1000 mg kg-1 significantly decreased duration of tonic hind limb extension (p < 0.05 and p < 0.001). CONCLUSIONS: GABA receptors were involved in epilepsy. Reduction of mortality and increase the onset of convulsion in MES model was comparable with that of diazepam. Extracts might possibly be producing an antiepileptic action by increasing the level of GABA. PMID- 27460745 TI - Should we care about sativex-induced neurobehavioral effects? A 6-month follow-up study. AB - OBJECTIVE: Sativex(r) is an exclusive cannabinoid-based drug approved for the treatment of spasticity due to Multiple Sclerosis (MS). The most common side effects include dizziness, nausea, and somnolence. However, it is still under debate whether the drug could cause negative cognitive effects. The aim of our study was to investigate the effect of Sativex(r) on functional and psychological status in cannabis-naive MS patients. PATIENTS AND METHODS: All the study participants (i.e. 40 patients affected by MS) underwent a specific clinical and neuropsychological assessment to investigate spasticity and associated symptoms, besides the cognitive and psychiatric domains commonly impaired in MS, before and after 1 and 6 months of Sativex(r) administration. RESULTS: After the treatment, we did not observe any significant neurobehavioral impairment in all the patients, but one. CONCLUSIONS: Our findings suggest that Sativex(r) treatment does not significantly affect the cognitive and neurobehavioral functions. However, the study supports the relevance of an extensive neuropsychological evaluation in MS patients selected for the drug administration, in an attempt to early detect the uncommon but important neurobehavioral side effects. PMID- 27460746 TI - Effect of different doses of dexmedetomidine on median effective concentration of propofol for anesthesia induction: a randomized controlled trial. AB - OBJECTIVE: Dexmedetomidine, a highly selective alpha2-adrenergic receptor agonist with sedative and analgesic properties, is used as an anesthetic adjunct. We determined the effects of different dexmedetomidine doses on the median effective concentration (EC50) of propofol and bispectral index (BIS) values during anesthesia induction. PATIENTS AND METHODS: This randomized, prospective, case control clinical trial involved 120 patients (56 women; physical status, American Society of Anesthesiologists grades I or II) scheduled to undergo surgery requiring general anesthesia from July 15th, 2014 to June 15th, 2015. The patients were divided into groups of 30 and received dexmedetomidine (0.5 ug/kg, group L; 0.75 ug/kg, group M; 1 ug/kg, group H) with propofol for loss of consciousness or propofol only (control group, group C). EC50, BIS, hemodynamics, and side effects were assessed. RESULTS: The EC50 of propofol was significantly lower in the dexmedetomidine groups than in group C, and decreased with increasing dexmedetomidine dose (p < 0.05). BIS values significantly decreased after 2 min of dexmedetomidine infusion in all dexmedetomidine groups; the values at 8 and 10 min were lower in the dexmedetomidine groups than in group C. The heart rate was lower in the dexmedetomidine groups than in group C. The incidence of bradycardia at loss of consciousness increased with increasing dexmedetomidine dose. CONCLUSIONS: Dexmedetomidine significantly and dose-dependently reduced the EC50 of propofol and BIS values during anesthesia induction. A loading dexmedetomidine dose of 0.5 ug/kg significantly reduced the EC50 of propofol and BIS value, and was associated with a lower incidence of bradycardia than higher doses. PMID- 27460747 TI - The petrosal bone and bony labyrinth of early to middle Miocene European deer (Mammalia, Cervidae) reveal their phylogeny. AB - Deer (Cervidae) have a long evolutionary history dating back to the Early Miocene, around 19 million years ago. The best known fossils to document this history belong to European taxa, which all bear cranial appendages more or less similar to today's deer antlers. Despite the good fossil record, relationships of the earliest stem deer and earliest crown deer are much debated. This hampers precise calibration against the independent evidence of the fossil record in molecular clock analyses. While much has been written on the Early and Middle Miocene deer, only two phylogenetic analyses have been performed on these taxa to date mostly based on cranial appendage characters. Because the petrosal bone and bony labyrinth have been shown to be relevant for phylogeny in ruminants, we describe for the first time these elements for four iconic early cervids from Europe (Procervulus dichotomus, Heteroprox larteti, Dicrocerus elegans and Euprox furcatus) and include them in a phylogenetic analysis based on the ear region exclusively. The analysis recovered E. furcatus in a sister position to the living red deer (Cervus elaphus). Further, it placed D. elegans in a sister position to Euprox + Cervus and a clade Procervulinae that includes P. dichotomus and H. larteti, in sister position to all other deer. The inclusion of E. furcatus in crown Cervidae, which was previously suggested based on antler morphology, cannot be ruled out here but needs a more comprehensive comparison to other crown deer to be confirmed. J. Morphol. 277:1329-1338, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27460748 TI - Prevalence odds ratio versus prevalence ratio: choice comes with consequences. AB - Odds ratio, risk ratio, and prevalence ratio are some of the measures of association which are often reported in research studies quantifying the relationship between an independent variable and the outcome of interest. There has been much debate on the issue of which measure is appropriate to report depending on the study design. However, the literature on selecting a particular category of the outcome to be modeled and/or change in reference group for categorical independent variables and the effect on statistical significance, although known, is scantly discussed nor published with examples. In this article, we provide an example of a cross-sectional study wherein prevalence ratio was chosen over (Prevalence) odds ratio and demonstrate the analytic implications of the choice of category to be modeled and choice of reference level for independent variables. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27460749 TI - Evolving Practice Patterns in Imaging Pregnant Patients With Acute Abdominal and Pelvic Conditions. AB - OBJECTIVE: The purpose of our study was to determine the current practice patterns of U.S. radiologists in imaging pregnant or potentially pregnant patients with acute abdominal and pelvic conditions. MATERIALS AND METHODS: After obtaining an Institutional Review Board waiver, all members of the Association of University Radiologists, the Association of Program Directors in Radiology, and the Society of Radiologists in Ultrasound were invited via e-mail to take a 23 question online survey on radiology practices and clinical scenarios about acute abdominal and pelvic imaging of pregnant patients. RESULTS: Comparisons were made with previously published surveys. A total of 225 responses were received. Areas of high consensus included pregnancy assessment (97%) and obtaining informed consent (87%) before imaging, having a written policy on imaging pregnant patients (79%), modification of computed tomography (CT) protocols (74%), avoiding gadolinium contrast in magnetic resonance imaging (MRI) (74%), using ultrasound for initial imaging in some scenarios, and using CT in trauma cases after inconclusive ultrasound. Areas of emerging consensus compared to 2007 included the use of serum or urine testing to confirm pregnancy status (59.4%; previously 14%) and the use of MRI in suspected appendicitis after an inconclusive ultrasound (73% in first trimester and 67% in third trimester; previously 46% and 29%, respectively). Areas without clear consensus included policy development, additional modifications to MRI protocols, choice of imaging modality, radiation dose, and the use of contrast agents in some scenarios. CONCLUSION: In conclusion, high or increasing consensus exists in some areas of imaging pregnant patients with acute abdominal and pelvic conditions, but has yet to emerge in other areas. PMID- 27460751 TI - Cellular identity at the single-cell level. AB - A single cell creates surprising heterogeneity in a multicellular organism. While every organismal cell shares almost an identical genome, molecular interactions in cells alter the use of DNA sequences to modulate the gene of interest for specialization of cellular functions. Each cell gains a unique identity through molecular coding across the DNA, RNA, and protein conversions. On the other hand, loss of cellular identity leads to critical diseases such as cancer. Most cell identity dissection studies are based on bulk molecular assays that mask differences in individual cells. To probe cell-to-cell variability in a population, we discuss single cell approaches to decode the genetic, epigenetic, transcriptional, and translational mechanisms for cell identity formation. In combination with molecular instructions, the physical principles behind cell identity determination are examined. Deciphering and reprogramming cellular types impact biology and medicine. PMID- 27460752 TI - Information gaps in medication communication during clinical handover calls for a different approach. PMID- 27460750 TI - Warfarin treatment and risk of stroke among primary care patients with atrial fibrillation. AB - OBJECTIVE: Our aim was to study the risk of a first ischaemic stroke (IS) in patients with atrial fibrillation (AF) treated in primary healthcare. DESIGN: The study population included all adults (n = 11,517), 45 years and older diagnosed with AF, from 75 primary care centres in Sweden between 2001 and 2007. IS was defined as a hospital care event of stroke between 2001 and 2010. Association between incident stroke and warfarin treatment was explored using Cox regression analysis, with hazard ratios (HRs), and 95% confidence intervals (95%CIs). Adjustment was made for age, socioeconomic factors and co-morbidity. RESULTS: Persistent treatment with warfarin was present among 33.7% of women and 40.0% among men. Persistent warfarin treatment, compared to no persistent treatment, was associated with a stroke preventing effect with fully adjusted HRs of 0.25 (95%CI 0.18-0.36) in women, and 0.25 (95%CI 0.19-0.32) in men. A CHA2DS2-VASc score of at least two among women, and three among men, was associated with a stroke risk exceeding 18% during a mean follow-up of 5.4 years. Risk of haemorrhagic stroke was not increased. CONCLUSIONS: Warfarin is effective in preventing stroke in AF patients in primary healthcare. PMID- 27460753 TI - Financial Barriers to Health Care Among Mexican Americans With Chronic Disease and Depression or Anxiety in El Paso, Texas. AB - PURPOSE: To determine the barriers to health care access by chronic disease and depression/anxiety diagnosis in Mexican Americans living in El Paso, TX. DESIGN: A secondary analysis was conducted using data for 1,002 Hispanics from El Paso, TX (2009-2010). Logistic regression was conducted for financial barriers by number of chronic conditions and depression/anxiety diagnosis. Interaction models were conducted between number of chronic conditions and depression or anxiety. RESULTS: Depressed/anxious individuals reported more financial barriers than those with chronic conditions alone. There were significant interactions between number of chronic conditions and depression/anxiety for cost, denied treatment because of an inability to pay, and an inability to pay $25 for health care. CONCLUSION: Financial barriers should be considered to maintain optimal care for both mental and physical health in this population. IMPLICATIONS FOR PRACTICE: There should be more focus on the impact of depression or anxiety as financial barriers to compliance. PMID- 27460754 TI - Metallogel formation in aqueous DMSO by perfluoroalkyl decorated terpyridine ligands. AB - Terpyridine based ligands 1 and 2, decorated with a C8F17 perfluorinated tag, are able to form stable thermoreversible gels in the presence of several d-block metal chloride salts. The gel systems obtained have been characterized by NMR, X ray diffraction, electron microscopies and Tgel experiments in order to gain insights into the observed different behaviour of the two similar ligands, also in terms of the effect of additional common anionic species. PMID- 27460755 TI - Temporal stability and rates of post-depositional change in geochemical signatures of brown trout Salmo trutta scales. AB - This study investigates temporal stability in the scale microchemistry of brown trout Salmo trutta in feeder streams of a large heterogeneous lake catchment and rates of change after migration into the lake. Laser-ablation inductively coupled plasma mass spectrometry was used to quantify the elemental concentrations of Na, Mg, Mn, Cu, Zn, Ba and Sr in archived (1997-2002) scales of juvenile S. trutta collected from six major feeder streams of Lough Mask, County Mayo, Ireland. Water-element Ca ratios within these streams were determined for the fish sampling period and for a later period (2013-2015). Salmo trutta scale Sr and Ba concentrations were significantly (P < 0.05) correlated with stream water sample Sr:Ca and Ba:Ca ratios respectively from both periods, indicating multi-annual stability in scale and water-elemental signatures. Discriminant analysis of scale chemistries correctly classified 91% of sampled juvenile S. trutta to their stream of origin using a cross-validated classification model. This model was used to test whether assumed post-depositional change in scale element concentrations reduced correct natal stream classification of S. trutta in successive years after migration into Lough Mask. Fish residing in the lake for 1 3 years could be reliably classified to their most likely natal stream, but the probability of correct classification diminished strongly with longer lake residence. Use of scale chemistry to identify natal streams of lake S. trutta should focus on recent migrants, but may not require contemporary water chemistry data. PMID- 27460756 TI - Quantifying Nonindex Hospital Readmissions and Care Fragmentation after Major Urological Oncology Surgeries in a Nationally Representative Sample. AB - PURPOSE: We quantified the underestimation of hospital readmission rates that can occur with institutional databases and the incidence of care fragmentation among patients undergoing urological oncology procedures in a nationally representative database. MATERIALS AND METHODS: The 2013 Nationwide Readmissions Database was queried for patients undergoing prostatectomy, cystectomy, nephroureterectomy, nephrectomy, partial nephrectomy and retroperitoneal lymph node dissection for urological malignancies. Nationally representative 30 and 90-day readmission and care fragmentation rates were calculated for all procedures. Readmission rates with and without nonindex hospital readmissions were compared with Pearson's chi square test. Multivariable logistic regression models were used to identify predictors of care fragmentation at 90-day followup. RESULTS: For all surgical procedures readmission rates were consistently underestimated by 17% to 29% at 90 day followup. The rates of care fragmentation among readmitted patients were similar for all procedures, ranging from 24% to 34% at 90-day followup. Overall 1 in 4 readmitted patients would not be captured in institutional databases and 1 in 3 readmitted patients experienced care fragmentation. Multivariable models did not identify a predictor of care fragmentation that was consistent across all procedures. CONCLUSIONS: The high rate of underestimation of readmission rates across all urological oncology procedures highlights the importance of linking institutional and payer claims databases to provide more accurate estimates of perioperative outcomes and health care utilization. The high rate of care fragmentation across all procedures emphasizes the need for future efforts to understand the clinical relevance of care fragmentation in patients with urological malignancies, and to identify patients at risk along with potentially modifiable risk factors for care fragmentation. PMID- 27460757 TI - Immunotherapy for the Treatment of Urothelial Carcinoma. AB - PURPOSE: We review the biological mechanisms of action, clinical safety and efficacy of immunotherapies for urothelial carcinoma. We also describe current areas of research in immunotherapy, and highlight ongoing trials and promising and novel investigational agents. MATERIALS AND METHODS: Data were obtained by a search of PubMed(r), ClinicalTrials.gov and Cochrane databases for English language articles published through February 2016. Applicable abstracts from recent Society of Urologic Oncology, European Association of Urology, American Urological Association and ASCO(r) meetings were used. RESULTS: Bacillus Calmette Guerin is one of the most successful immunotherapies in cancer treatment and remains the gold standard of care for patients with high risk, nonmuscle invasive bladder cancer, with initial response rates of approximately 70%. However, with the exception of valrubicin and standard chemotherapeutics there is a paucity of available treatment options for patients with recurrence or progression to more advanced disease. Recently there has been significant interest in novel immunotherapeutic agents in the management of cases where bacillus Calmette Guerin fails, as well as cases of more advanced cancer. These investigational therapies can generally be classified into several broad categories, including recombinant bacillus Calmette-Guerin and cell wall derived therapies, cytokines, gene therapy, cancer vaccines, immune checkpoint inhibitors, oncolytic viruses, adoptive immunotherapies and immune agonists, as well as several additional immunomodulatory agents. The majority of these agents are currently under investigation in phase I or II clinical trials. Recently investigators reported evidence that inhibition of the PD-1/PD-L1 pathway has clinical activity in patients with advanced bladder cancer. These findings, along with successful phase III trials and U.S. Food and Drug Administration approvals of other checkpoint inhibitors in melanoma, nonsmall cell lung cancer and renal cell carcinoma, ultimately led to Food and Drug Administration approval of atezolizumab for advanced disease, the first new treatment approved for advanced urothelial carcinoma in 20 years. CONCLUSIONS: While bacillus Calmette-Guerin has demonstrated significant clinical efficacy in the treatment of patients with bladder cancer, additional therapies are needed for those in whom bacillus Calmette-Guerin fails, as well as for those with advanced disease. Immunotherapy for urothelial carcinoma remains a promising and active area of research, and numerous agents, particularly the monoclonal antibodies targeting checkpoint inhibition pathways, are showing encouraging signs of clinical activity. PMID- 27460758 TI - A unified strategy in selection of the best allometric scaling methods to predict human clearance based on drug disposition pathway. AB - 1. It is critical to develop a unified strategy to select the best allometric scaling (AS) method for a given group of drugs. 2. A total of 446 drugs with known human CLiv, clear disposition pathway and animal (rat, dog, monkey) CLiv were analyzed. All drugs were stratified based on their disposition pathway, liver extraction ratio (ERH) and ratios of unbound clearance to renal glomerular filtration rate (RGFR). Up to 22 AS methods were applied and compared in prediction of human CLiv to each group of drugs. 3. AS methods that give the best prediction of human CLiv, were identified for drugs primarily eliminated through liver with a fraction of renal elimination (frenal) within 0.3-0.5 or ERH > 0.3, where human CLiv of more than 80% or 90% drugs could be accurately (within 2- or 3-fold error) predicted. For drugs with ERH < 0.3, acceptable accuracy could be achieved by a two species method TSR,D resulting more than 60% or 75% drugs were predicted within 2- or 3-fold error. 4. By stratified analysis of drugs, according to their disposition pathway and organ extraction ratio, a unified strategy was developed to select the best AS method in prediction of human CLiv. PMID- 27460759 TI - Clicking the Arsenic-Carbon Triple Bond: An Entry into a New Class of Arsenic Heterocycles. AB - Arsaalkynes can undergo regioselective and quantitative [3+2] cycloaddition reactions with organic azides to give hitherto unknown 3H-1,2,3,4-triazaarsole derivatives. The reaction product was obtained as a white, air- and moisture stable solid, and the presence of a planar, five-membered arsenic heterocycle was unambiguously verified by means of X-ray crystallography. DFT calculations gave insight into the electronic structure of these novel compounds compared to tetrazoles and triazaphospholes. The coordination chemistry towards Re(I) was investigated and compared with the structurally related phosphorus-containing ligand. These preliminary investigations pave the way for a new class of arsenic heterocycles and fill the gap between the azaarsoles already known. PMID- 27460760 TI - Genome-wide transcriptomic analysis uncovers the molecular basis underlying early flowering and apetalous characteristic in Brassica napus L. AB - Floral transition and petal onset, as two main aspects of flower development, are crucial to rapeseed evolutionary success and yield formation. Currently, very little is known regarding the genetic architecture that regulates flowering time and petal morphogenesis in Brassica napus. In the present study, a genome-wide transcriptomic analysis was performed with an absolutely apetalous and early flowering line, APL01, and a normally petalled line, PL01, using high-throughput RNA sequencing. In total, 13,205 differential expressed genes were detected, of which 6111 genes were significantly down-regulated, while 7094 genes were significantly up-regulated in the young inflorescences of APL01 compared with PL01. The expression levels of a vast number of genes involved in protein biosynthesis were altered in response to the early flowering and apetalous character. Based on the putative rapeseed flowering genes, an early flowering network, mainly comprised of vernalization and photoperiod pathways, was built. Additionally, 36 putative upstream genes possibly governing the apetalous character of line APL01 were identified, and six genes potentially regulating petal origination were obtained by combining with three petal-related quantitative trait loci. These findings will facilitate understanding of the molecular mechanisms underlying floral transition and petal initiation in B. napus. PMID- 27460761 TI - Versicones E-H and arugosin K produced by the mangrove-derived fungus Aspergillus versicolor HDN11-84. AB - Four new xanthonoids, versicones E-H (1-4), and a biogenetically related new derivative arugosin K (5), were isolated from a culture extract of the mangrove derived fungus Aspergillus versicolor HDN11-84. Their structures were elucidated on the basis of extensive NMR spectroscopic data analysis. Versicone E (1) represents the first example of naturally occurring xanthonoids containing a 2 butenamide moiety. Among them, 5 showed the best cytotoxicity against Hela cell line with an IC50 value of 9.2 MUm. PMID- 27460762 TI - New aliphatic acid amides from Streptomyces maoxianensis sp. nov. PMID- 27460763 TI - Identification of a prodigiosin cyclization gene in the roseophilin producer and production of a new cyclized prodigiosin in a heterologous host. PMID- 27460764 TI - In vitro activity of tigecycline in combination with rifampin, doripenem or ceftazidime against carbapenem-resistant Klebsiella pneumoniae bloodstream isolates. PMID- 27460765 TI - Far-field nanoscale infrared spectroscopy of vibrational fingerprints of molecules with graphene plasmons. AB - Infrared spectroscopy, especially for molecular vibrations in the fingerprint region between 600 and 1,500 cm(-1), is a powerful characterization method for bulk materials. However, molecular fingerprinting at the nanoscale level still remains a significant challenge, due to weak light-matter interaction between micron-wavelengthed infrared light and nano-sized molecules. Here we demonstrate molecular fingerprinting at the nanoscale level using our specially designed graphene plasmonic structure on CaF2 nanofilm. This structure not only avoids the plasmon-phonon hybridization, but also provides in situ electrically-tunable graphene plasmon covering the entire molecular fingerprint region, which was previously unattainable. In addition, undisturbed and highly confined graphene plasmon offers simultaneous detection of in-plane and out-of-plane vibrational modes with ultrahigh detection sensitivity down to the sub-monolayer level, significantly pushing the current detection limit of far-field mid-infrared spectroscopies. Our results provide a platform, fulfilling the long-awaited expectation of high sensitivity and selectivity far-field fingerprint detection of nano-scale molecules for numerous applications. PMID- 27460766 TI - Association of NKAPL, TSPAN18, and MPC2 gene variants with schizophrenia based on new data and a meta-analysis in Han Chinese. AB - BACKGROUND: Schizophrenia (SZ) is suggested to be a complex polygenetic disorder with high heritability. Genome-wide association studies have found that the rs1635, rs11038167, and rs10489202 polymorphisms are associated with SZ in Han Chinese. However, results of validation studies are inconsistent. This study aimed to test the association between the NKAPL rs1635, TSPAN18 rs11038167, and MPC2 rs10489202 polymorphisms and SZ in a Chinese population. METHODS: This study contained 700 unrelated SZ patients (300 Zhuang and 400 Han) and 700 gender- and age-matched controls (300 Zhuang and 400 Han). The polymorphisms in TSPAN18 (rs11038167), NKAPL (rs1635), and MPC2 (rs10489202) were genotyped using the Sequenom MassARRAY method. Statistical analyses were performed with PLINK program and SPSS l6.0 for Windows. STATA11.1 was used for meta-analysis. RESULTS: No statistically significant difference was found in different allele and genotype frequencies of rs1635, rs11038167, and rs10489202 between SZ cases and controls of Zhuang and Han ethnicities and the total samples (all p>0.05). Further meta analysis suggested that single-nucleotide polymorphism rs10489202 was significantly associated with SZ in a Han Chinese population (p OR=0.002). CONCLUSIONS: Our case-control study failed to validate the significant association of NKAPL rs1635, TSPAN18 rs11038167, and MPC2 rs10489202 polymorphisms with SZ susceptibility in the southern Zhuang or Han Chinese population. However, meta-analysis showed a significant association between MPC2 variant rs10489202 and SZ susceptibility in Han Chinese. PMID- 27460768 TI - Highly Emissive Far Red/Near-IR Fluorophores Based on Borylated Fluorene Benzothiadiazole Donor-Acceptor Materials. AB - Stille, Suzuki-Miyaura and Negishi cross-coupling reactions of bromine functionalised borylated precursors enable the facile, high yielding, synthesis of borylated donor-acceptor materials that contain electron-rich aromatic units and/or extended effective conjugation lengths. These materials have large Stokes shifts, low LUMO energies, small band-gaps and significant fluorescence emission >700 nm in solution and when dispersed in a host polymer. PMID- 27460767 TI - Prognostic value of T1-mapping in TAVR patients: extra-cellular volume as a possible predictor for peri- and post-TAVR adverse events. AB - The benefit of a transcatheter aortic valve replacement (TAVR) can differ in patients, and therapy bears severe risks. High-degree aortic stenosis can lead to cardiac damage such as diffuse myocardial fibrosis, evaluable by extra-cellular volume (ECV) in CMR. Therefore, fibrosis might be a possible risk factor for unfavorable outcome after TAVR. We sought to assess the prognostic value of T1 mapping and ECV to predict adverse events during and after TAVR. The study population consisted of patients undergoing clinically indicated TAVR by performing additional CMR with native and contrast-enhanced T1-mapping sequences for additional evaluation of ECV. Study endpoints were congestive heart failure (CHF) and TAVR-associated conduction abnormalities defined as new onset of left bundle branch block (LBBB), AV-Block or implantation of a pacemaker. 94 patients were examined and followed. Median follow up time was 187 days (IQR 79-357 days). ECV was increased (>30 %) in 38 patients (40 %). There was no significant correlation between ECV and death, Hazard ratio (HR) 0.847 (95 % CI 0.335; 2.14), p = 0.72. ECV in patients with subsequent CHF was higher than in those without an event (33.5 +/- 4.6 and 29.1 +/- 4.1 %, respectively), but the difference just did not reach the level of significance HR 2.16 (95 % CI 0.969; 4.84), p = 0.06. Patients with post-TAVR conduction abnormality (LBBB, AV-block or pacemaker implantation) had statistically relevant lower ECV values compared to those without an event. Patients with an event had a mean ECV of 28.1 +/- 3.16 %; patients without an event had a mean ECV of 29.8 +/- 4.53, HR 0.56 (95 % CI 0.32; 0.96), p = 0.036. In this study, elevated myocardial ECV is a predictor of CHF by trend; CMR may be helpful in identifying patients with a high risk for post-TAVR cardiac decompensation benefitting from an intensified post-interventional surveillance. Patients with post-TAVR conductions abnormalities have a significantly decreased ECV. Nevertheless, it remains unclear which precise molecular tissue alteration is the protective factor or risk factor in this case. PMID- 27460769 TI - Patterns and trends of computed tomography usage in outpatients of the Brazilian public healthcare system, 2001-2011. AB - While the patterns and trends of computed tomography (CT) are well documented in developed countries, relatively little is known about CT usage in developing countries, including Brazil. We evaluated CT usage among outpatients from the public healthcare system in Brazil (SUS), which is the unique healthcare provider to about 75% of the Brazilian population. We collected the annual number of CT procedures and type of CT examinations performed in SUS for the period 2001-2011. Age at examination was evaluated for 2008-2011. CT usage in Brazil has more than tripled during the study period, but the most striking annual increase (17.5%) was observed over the years 2008-2011. Head was the most frequently examined region for all age groups, but a decreasing trend of proportional contribution of head CT, with a simultaneous increase of abdomen/pelvis and chest CT over time was observed. CT examination for pediatric and young adult patients was about 13% of all CTs (9% if we considered age-standardized CT rates). CT usage has grown rapidly in Brazil and may still be increasing. Increased CT usage may certainly be associated with improved patient care. However, given the high frequency of pediatric and young adult CT procedures and the suggested associated cancer risk, efforts need to be undertaken to reduce unwarranted CT scans in Brazil. PMID- 27460770 TI - Investigation of the chemical origin and evidential value of differences in the SERS spectra of blue gel inks. AB - Highly swellable polymer films doped with Ag nanoparticle aggregates (poly-SERS films) have been used to record very high signal : noise ratio, reproducible surface-enhanced (resonance) Raman (SER(R)S) spectra of in situ dried ink lines and their constituent dyes using both 633 and 785 nm excitation. These allowed the chemical origins of differences in the SERRS spectra of different inks to be determined. Initial investigation of pure samples of the 10 most common blue dyes showed that the dyes which had very similar chemical structures such as Patent Blue V and Patent Blue VF (which differ only by a single OH group) gave SERRS spectra in which the only indications that the dye structure had been changed were small differences in peak positions or relative intensities of the bands. SERRS studies of 13 gel pen inks were consistent with this observation. In some cases inks from different types of pens could be distinguished even though they were dominated by a single dye such as Victoria Blue B (Zebra Surari) or Victoria Blue BO (Pilot Acroball) because their predominant dye did not appear in other inks. Conversely, identical spectra were also recorded from different types of pens (Pilot G7, Zebra Z-grip) because they all had the same dominant Brilliant Blue G dye. Finally, some of the inks contained mixtures of dyes which could be separated by TLC and removed from the plate before being analysed with the same poly-SERS films. For example, the Pentel EnerGel ink pen was found to give TLC spots corresponding to Erioglaucine and Brilliant Blue G. Overall, this study has shown that the spectral differences between different inks which are based on chemically similar, but nonetheless distinct dyes, are extremely small, so very close matches between SERRS spectra are required for confident identification. Poly-SERS substrates can routinely provide the very stringent reproducibility and sensitivity levels required. This, coupled with the awareness of the reasons underlying the observed differences between similarly coloured inks allows a more confident assessment of the evidential value of inks SERS and should underpin adoption of this approach as a routine method for the forensic examination of inks. PMID- 27460771 TI - Voice-Message-Based mHealth Intervention to Reduce Postoperative Penetrative Sex in Recipients of Voluntary Medical Male Circumcision in the Western Cape, South Africa: Protocol of a Randomized Controlled Trial. AB - BACKGROUND: There is an increased risk of transmission of sexually transmitted infections (STIs), including HIV, in the postoperative period after receiving voluntary medical male circumcision (VMMC). In South Africa, over 4 million men are being targeted with VMMC services but the health system is not able to offer quality counseling. More innovative strategies for communicating with and altering behavior in men and their partners in the postoperative period after VMMC are needed. OBJECTIVE: This paper presents a study protocol to test the effectiveness of an mHealth intervention designed to task-shift behavior change communication from health care personnel to an automated phone message system, encouraging self-care. METHODS: A single-blind, randomized controlled trial will be used. A total of 1188 participants will be recruited by nurses or clinicians at clinics in the study districts that have a high turnover of VMMC clients. The population will consist of men aged 18 years and older who indicate at the precounseling session that they possess a mobile phone and consent to participating in the study. Consenting participants will be randomized into either the control or intervention arm before undergoing VMMC. The control arm will receive the standard of care (pre- and postcounseling). The intervention arm will received standard of care and will be sent 38 messages over the 6-week recovery period. Patients will be followed up after 42 days. The primary outcome is self-reported sexual intercourse during the recovery period. Secondary outcomes include nonpenetrative sexual activity, STI symptoms, and perceived risk of acquiring HIV. Analysis will be by intention-to-treat. RESULTS: Enrollment is completed. Follow-up is ongoing. Loss to follow-up is under 10%. No interim analyses have been conducted. CONCLUSIONS: The intervention has the potential of reducing risky sexual behavior after VMMC. The platform itself can be used for many other areas of health that require task shifting to patients for better efficiency and access. TRIAL REGISTRATION: Pan-African Clinical Trial Registry: PACTR201506001182385. PMID- 27460772 TI - Oral abstracts of the 21st International AIDS Conference 18-22 July 2016, Durban, South Africa. PMID- 27460773 TI - Deep sequencing reveals global patterns of mRNA recruitment during translation initiation. AB - In this work, we developed a method to systematically study the sequence preference of mRNAs during translation initiation. Traditionally, the dynamic process of translation initiation has been studied at the single molecule level with limited sequencing possibility. Using deep sequencing techniques, we identified the sequence preference at different stages of the initiation complexes. Our results provide a comprehensive and dynamic view of the initiation elements in the translation initiation region (TIR), including the S1 binding sequence, the Shine-Dalgarno (SD)/anti-SD interaction and the second codon, at the equilibrium of different initiation complexes. Moreover, our experiments reveal the conformational changes and regional dynamics throughout the dynamic process of mRNA recruitment. PMID- 27460774 TI - beta-Boswellic acid, a bioactive substance used in food supplements, inhibits protein synthesis by targeting the ribosomal machinery. AB - The Boswellia gum resin extracts have been used in traditional medicines because of their remarkable anti-inflammatory properties. Nowadays, these extracts are on the market as food supplements. beta-Boswellic acid (betaBA) is one of the main pentacyclic triterpene components, among the family of BAs, of the Boswellia gum resins. BAs have been broadly studied and are well known for their wide anti inflammatory and potential anticancer properties. In this paper, a mass spectrometry-based chemoproteomic approach has been applied to characterize the whole betaBA interacting profile. Among the large numbers of proteins fished out, proteasome, 14-3-3 and some ribosomal proteins were considered the most interesting targets strictly connected to the modulation of the cancer progression. In particular, because of their recent assessment as innovative chemotherapeutic targets, the ribosomal proteins were considered the most attractive betaBA partners, and the biological role of their interaction with the natural compound has been evaluated. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27460775 TI - Breast reconstruction after mastectomy. PMID- 27460776 TI - Screening for Gram-negative bacteria: Impact of preanalytical parameters. AB - Screening recommendations for multidrug-resistant Gram-negative bacteria comprise microbiological analyses from rectal swabs. However, essential specifications of the preanalytic steps of such screenings, i.e. the sampling technique, sampling devices and sampling site, are lacking. For standardized and optimum screening conditions these parameters are indispensable. Here, the optimum parameters were examined irrespective of the antibiotic resistance patterns of the target bacteria in order to establish a general basis for this type of screening. Swabs with rayon, polyurethane-cellular-foam and nylon-flocked tips were tested. Different sampling locations were evaluated, i.e. perianal, intraanal and deep intraanal. Subjects were swabbed and quantities of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii were assessed. Overall prevalences of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii were 94%, 16%, 12%, and 2%, respectively. Bacterial recovery rates were independent from the sampling timepoint during hospital stay. Polyurethane-cellular-foam or nylon-flocked swabs recovered significantly more bacteria as compared to rayon swabs. Intraanal swabbing resulted in significantly higher bacterial quantities as compared to perianal swabbing. In contrast, for the detection of A. baumannii, perianal swabbing seems more suitable than intraanal swabbing. Gender-related differences in bacterial recovery could be detected from perianal but not from intraanal swabs. PMID- 27460778 TI - Structure and dynamics of European sports science textual contents: Analysis of ECSS abstracts (1996-2014). AB - The article discusses general structure and dynamics of the sports science research content as obtained from the analysis of 21998 European College of Sport Science abstracts belonging to 12 science topics. The structural analysis showed intertwined multidisciplinary and unifying tendencies structured along horizontal (scope) and vertical (level) axes. Methodological (instrumental and mode of inquiry) integrative tendencies are dominant. Theoretical integrative tendencies are much less detectable along both horizontal and vertical axes. The dynamic analysis of written abstracts text content over the 19 years reveals the contextualizing and guiding role of thematic skeletons of each sports science topic in forming more detailed contingent research ideas and the role of the latter in stabilizing and procreating the former. This circular causality between both hierarchical levels and functioning on separate characteristic time scales is crucial for understanding how stable research traditions self-maintain and self-procreate through innovative contingencies. The structure of sports science continuously rebuilds itself through use and re-use of contingent research ideas. The thematic skeleton ensures its identity and the contingent conceptual sets its flexibility and adaptability to different research or applicative problems. PMID- 27460777 TI - Loss of NAD-Dependent Protein Deacetylase Sirtuin-2 Alters Mitochondrial Protein Acetylation and Dysregulates Mitophagy. AB - AIMS: Sirtuins connect energy generation and metabolic stress to the cellular acetylome. Currently, only the mitochondrial sirtuins (SIRT3-5) and SIRT1 have been shown to direct mitochondrial function; however, Aims: NAD-dependent protein deacetylase sirtuin-2 (SIRT2), the primary cytoplasmic sirtuin, is not yet reported to associate with mitochondria. RESULTS: This study revealed a novel physiological function of SIRT2: the regulation of mitochondrial function. First, the acetylation of several metabolic mitochondrial proteins was found to be altered in Sirt2-deficient mice, which was, subsequently, validated by immunoprecipitation experiments in which the acetylated mitochondrial proteins directly interacted with SIRT2. Moreover, immuno-gold electron microscopic images of mouse brains showed that SIRT2 associates with the inner mitochondrial membrane in central nervous system cells. The loss of Sirt2 increased oxidative stress, decreased adenosine triphosphate levels, and altered mitochondrial morphology at the cellular and tissue (i.e., brain) level. Furthermore, the autophagic/mitophagic processes were dysregulated in Sirt2-deficient neurons and mouse embryonic fibroblasts. INNOVATION: For the first time it is shown that SIRT2 directs mitochondrial metabolism. CONCLUSION: Together, these findings support that SIRT2 functions as a mitochondrial sirtuin, as well as a regulator of autophagy/mitophagy to maintain mitochondrial biology, thus facilitating cell survival. Antioxid. Redox Signal. 26, 849-863. PMID- 27460779 TI - Cross-sectional survey in CKD patients across Europe describing the association between quality of life and anaemia. AB - BACKGROUND: Deteriorating renal function in chronic kidney disease (CKD) patients is commonly associated with reduced haemoglobin levels, adding to the already considerable humanistic burden of CKD. This analysis evaluated the impact of anaemia on disease burden in patients with CKD stages 3-4, and in those on dialysis. METHODS: This was a descriptive, cross-sectional analysis of European data from an Adelphi CKD Disease-Specific Programme. This programme collected data from patients and their treating nephrologists/endocrinologists; patient- and physician-reported data were matched for each patient. Health-related quality of life (HRQoL) data were obtained through patient completion of the EQ-5D, SF-12 and KDQOL-36. Additional information was obtained via physician reporting of patient symptoms, and patients' reports of impaired activity. Anaemia was defined by haemoglobin level and/or current use of erythropoiesis stimulating agents. RESULTS: Significant, but modest Spearman's rank correlations were observed between haemoglobin levels and extent of HRQoL impairment, regardless of instrument used (range 0.19-0.23; all P-values < 0.0001). When stratified by anaemia status, impairment was consistently lower for anaemic than non-anaemic CKD patients across measurement scales (e.g. EQ-5D index value [standard deviation {SD}] 0.72 [0.31] vs 0.83 [0.23], respectively; P < 0.0001). Physician reported patient tiredness was associated with increased disease burden at all levels of CKD studied (total EQ-5D index value [SD] in patients reporting no tiredness vs tiredness 0.81 [0.26] vs 0.70 [0.30] respectively; P < 0.0001) with P < 0.0001 for no tiredness vs tiredness at all stages of CKD. The presence of anaemia was associated with impaired activity levels at CKD stages 3 (37.5 % vs 28.4 %, respectively; P = 0.0044) and 4 (48.1 % vs 39.9 %, respectively; P = 0.0292), and in patients on dialysis (52.0 % vs 45.0 %, respectively; P = 0.0732). CONCLUSIONS: The analysis found that CKD patients with anaemia typically had a lower HRQoL than those without anaemia. The impairment correlated with anaemia was more apparent in non-dialysis patients with CKD stages 3 or 4 than in those receiving dialysis. Coexisting CKD and anaemia may have an impact on patient HRQoL similar to other chronic conditions such as diabetes, epilepsy or certain forms of cancer. PMID- 27460780 TI - Effects of Tangshen Formula on urinary and plasma liver-type fatty acid binding protein levels in patients with type 2 diabetic kidney disease: post-hoc findings from a multi-center, randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Tangshen Formula in patients with type 2 diabetic kidney disease. AB - BACKGROUND: Tangshen Formula (TSF) is a traditional Chinese medicine for the treatment of diabetic kidney disease (DKD). Liver-type fatty acid binding protein (L-FABP) is expressed in various tissues, including the kidney, where it is known as urinary L-FABP. Other studies demonstrated that urinary L-FABP may be a useful biomarker for monitoring DKD. This post-hoc analysis and cross-sectional study evaluated the changes in urinary L-FABP in DKD patients treated with TSF and conventional medicine. METHODS: Post-hoc analysis was conducted on a multicenter, randomized, double-blind, placebo-controlled trial. A total of 180 participants with DKD including 98 with microalbuminuria and 82 with macroalbuminuria were enrolled in the original study. In addition to conventional treatment, 122 participants were randomly assigned to receive TSF and 58 to receive placebo. After 24-weeks of treatment, the intention-to-treat population in microalbuminuria stage was 56 in the TSF group and 25 in the placebo group, and in the macroalbuminuria stage 42 and 19, respectively. The primary outcome in the original trial was urinary protein level. In the current study, urinary and plasma L-FABP levels were measured in 30 microalbuminuria patients (15 in the TSF group and 15 in the placebo group) and 30 macroalbuminuria patients (15 in the TSF group and 15 in the placebo group). In addition, another 30 patients with normoalbuminuria (urinary albumin excretion rate (UAER) < 20 MUg/min) were recruited for the cross-sectional study. RESULTS: (1) In microalbuminuria patients, UAER in the TSF group displayed a significant decrease after 24 weeks of treatment (P = 0.045). Levels of urinary L-FABP in the TSF group were markedly lower than in the placebo group after 12 and 24 weeks (P = 0.004 and P = 0.047, respectively). (2) In macroalbuminuria patients, 24-h urinary protein levels decreased significantly compared with baseline in the TSF group at week 12 (P = 0.042) and week 24 (P = 0.041). The TSF group showed a significant decrease in urinary L-FABP after 12 and 24 weeks (P = 0.036 and P = 0.046, respectively). (3) Levels of urinary L-FABP increased markedly, correlating with severity of DKD. L FABP in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria were 5.9 (5.2, 7.8) MUg/ml, 11.4 (6.8, 13.4) MUg/ml and 18.5 (10.9, 23.4) MUg/ml, respectively (P = 0.000). CONCLUSIONS: TSF combined with conventional therapy appeared to be effective in reducing urinary protein and urinary L-FABP. Urinary L-FABP levels appear to be associated with the severity of DKD. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-10000843 . Registered 15 April 2010. PMID- 27460781 TI - Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation. AB - Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS-2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-kappaB (NF-kappaB), cyclo oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-alpha (IFN-alpha) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-kappaB, COX-2, MAPK and Stat3, which orchestrate pro-inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection validated these results. Treatment with HDACis alleviated airway inflammation and reduced in vivo RSV replication. Our data demonstrated that RSV reduced histone acetylation by enhancing HDAC2 expression. Treatment with HDACis (TSA/SAHA) significantly inhibited RSV replication and decreased RSV-induced airway inflammation and oxidative stress. Therefore, the inhibition of HDACs represents a novel therapeutic approach in modulating RSV-induced lung disease. PMID- 27460782 TI - Left Ventricular Function in Patients with Pulmonary Arterial Hypertension: The Role of Two-Dimensional Speckle Tracking Strain. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by elevated mean pulmonary arterial pressure with abnormal right ventricular (RV) pressure overload that may alter left ventricular (LV) function. The aim of this study was to assess the impact of RV pressure overload on LV function in PAH patients using two-dimensional (2D) speckle tracking strain. METHODS: The study enrolled 37 group 1 PAH patients and 38 age- and gender-matched healthy controls. LV longitudinal and radial 2D strains were measured with and without including the ventricular septum. Six-minute walk test (6MWT) and brain natriuretic peptide (BNP) levels were also obtained in patients with PAH. RESULTS: The mean age of patients was 46.4 +/- 14.8 years, 76% women, and 16 patients (43%) had schistosomiasis. Sixteen patients (43%) were in WHO class III or IV under specific treatment for PAH. The overall 6MWT distance was 441 meters, and the BNP levels were 80 pg/mL. Patients with PAH more commonly presented with LV diastolic dysfunction and impairment of RV function when compared to controls. LV global longitudinal and radial strains were lower in patients than in controls (-17.9 +/ 2.8 vs. -20.5 +/- 1.9; P < 0.001 and 30.8 +/- 10.5 vs. 49.8 +/- 15.4; P < 0.001, respectively). After excluding septal values, LV longitudinal and radial strains remained lower in patients than in controls. The independent factors associated with global LV longitudinal strain were LV ejection fraction, RV fractional area change, and tricuspid annular systolic motion. CONCLUSIONS: This study showed impaired LV contractility in patients with PAH assessed by speckle tracking strain, irrespective of ventricular septal involvement. Global LV longitudinal strain was associated independently with RV fractional area change and tricuspid annular systolic motion, after adjustment for LV ejection fraction. PMID- 27460783 TI - Evolution of the management of ranulas: change in a single surgeon's practice 2001-14. AB - Excision of the sublingual gland is the traditional cure for ranulas, but is invasive with considerable morbidity. We report techniques that have been developed to minimise this by targeting their specific pathophysiology, which include an intraoral approach to plunging ranulas, and gland-preserving selective excision with a highly conservative suture technique for simple ranulas. Fifty four ranulas in 53 (20 male and 33 female, mean age 29 (range 7-57) years) consecutive patients were treated by a single surgeon between 2001-14 and their records reviewed retrospectively. Their personal details, operations, types of ranula, and outcomes were recorded. Follow up was for a minimum of six months without recurrent disease before discharge. Of the 54 ranulas treated, 26 had standard traditional sublingual gland excision (17 simple and 9 plunging), nine simple ranulas were selectively excised, 10 were treated with the new suture technique, and nine plunging ranulas were aspirated, after which they were ligated and the sublingual gland excised. Two of the 10 treated by the new suture technique had residual ranulas. The procedure was repeated in both cases, and one had a small residual ranula for which further intervention was declined. One complication developed after excision of a plunging ranula using the traditional intraoral and extraoral approaches, and two developed after aspiration of the sac, ligation, and excision of the gland. Traditional excision of simple ranulas was followed by three complications, but none were reported after simple ranulas had been treated with selective excision or suture. Minimally invasive techniques offer cure, with a lower risk of morbidity. PMID- 27460784 TI - The fractions of cancer attributable to modifiable factors: A global review. AB - Worldwide, the burden of cancer is rising, stimulating efforts to develop strategies to control these diseases. Primary prevention, a key control strategy, aims to reduce cancer incidence through programs directed towards reducing population exposure to known causal factors. Before enacting such strategies, it is necessary to estimate the likely effect on cancer incidence if exposures to known causal factors were reduced or eliminated. The population attributable fraction (PAF) is the epidemiological measure which quantifies this potential reduction in incidence. We surveyed the literature to document and summarise the proportions of cancers across the globe attributable to modifiable causes, specifically tobacco smoke, alcohol, overweight/obesity, insufficient physical activity, solar ultraviolet (UV) radiation and dietary factors (insufficient fruit, non-starchy vegetables and fibre; red/processed meat; salt). In total, we identified 55 articles that presented PAF estimates for one or more causes. Information coverage was not uniform, with many articles reporting cancer PAFs due to overweight/obesity, alcohol and tobacco, but fewer reporting PAFs for dietary factors or solar UV radiation. At all cancer sites attributable to tobacco and alcohol, median PAFs were markedly lower for women than men. Smoking contributed to very high median PAFs (>50%) for cancers of the lung and larynx. Median PAFs for men, attributable to alcohol, were high (25-50%) for cancers of the oesophagus, oral cavity/pharynx, larynx and liver. For cancers causally associated with overweight/obesity, high median PAFs were reported for oesophageal adenocarcinoma (men 29%, women 37%), gallbladder (men 11%, women 42%) and endometrium (36%). The cancer PAF literature is growing rapidly. Repeating this survey in the future should lead to more precise estimates of the potentially preventable fractions of cancer. PMID- 27460785 TI - Cadmium and lead exposure and risk of cataract surgery in U.S. adults. AB - Cataract is a major cause of visual dysfunction and the leading cause of blindness. Elevated levels of cadmium and lead have been found in the lenses of cataract patients, suggesting these metals may play a role in cataract risk. This study aimed to examine the associations of blood lead, blood cadmium and urinary cadmium with cataract risk. We identified 9763 individuals aged 50 years and older with blood lead and cadmium levels, and a randomly selected subgroup of 3175 individuals with available urinary cadmium levels, from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2008 (mean age=63years). Participants were considered to have cataract if they self-reported prior cataract surgery in NHANES's vision examination. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using survey logistic regression models. We identified 1737 cataract surgery cases (the weighted prevalence=14.1%). With adjustment for age, race/ethnicity, gender, education, diabetes mellitus, body mass index, cigarette smoking (serum cotinine and pack-years) and urine hydration, every 2-fold increase in urinary cadmium was associated with a 23% higher risk of cataract surgery (OR=1.23, 95% CI: 1.04, 1.46, p=0.021). We found no associations of cataract surgery with blood cadmium (OR=0.97, 95% CI: 0.89, 1.07) and blood lead (OR=0.97, 95% CI: 0.88, 1.06). Mediation analysis showed that for the smoking-cadmium-cataract pathway, the ratio of smoking's indirect effect to the total effect through cadmium was more than 50%. These results suggest that cumulative cadmium exposure may be an important under-recognized risk factor for cataract. However, these findings should be interpreted with a caution because of inconsistent results between urinary cadmium and blood cadmium. PMID- 27460786 TI - Percutaneous radiofrequency ablation with contrast-enhanced ultrasonography for solitary and sporadic renal cell carcinoma in patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND: The aim of this study was to assess the functional and oncologic outcomes of percutaneous radiofrequency ablation (RFA) with contrast-enhanced ultrasonography (CEUS) for renal cell carcinoma in patient with autosomal dominant polycystic kidney. METHODS: We performed a retrospective review of five patients with renal cell carcinoma (RCC) in autosomal dominant polycystic kidney disease (ADPKD) from January 2009 to December 2014 with a media follow-up of 33 months. The tumors were ablated with Cool-tip RFA system under the guidance of CEUS. Routine follow-up included contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) and renal function tests. RESULTS: Media diameter of the treated renal tumors was 3.1 cm (range 1.7-5.2 cm). Initial ablation success rate was 4/5. After over 6 months contrast-enhanced CT/MRI follow-up after RFA, no patients experienced local tumor recurrence. No patients required dialysis in the periprocedural period. Minor complications only developed in two cases. There was no significant difference in estimated glomerular filtration rate (eGFR) between pre- and post-RFA. CONCLUSIONS: Our initial experience of this technique for RCC in ADPKD was favorable with good renal function preservation and oncologic outcomes. It may be a good choice for RCC in ADPKD. PMID- 27460787 TI - [Radical cystectomy with orthotopic neobladder replacement: Comparison of robotic assisted and open surgical route]. AB - INTRODUCTION: Radical cystectomy remains the referent treatment of non-metastatic muscle-invasive bladder cancer (MIBC). The fast development of robotic surgery has led some teams to use it for the surgical treatment of the MIBC, in the hope of reducing postoperative morbidity. Urinary diversion by bladder substitution is a bypass option. The aim of our study was to compare the robot-assisted cystectomy with open cystectomy, with urinary diversion by bladder substitution. PATIENTS AND METHODS: Over a two-year period, all the patients who underwent a robot-assisted laparoscopic or open cystectomy with urinary diversion by bladder substitution have been included. The urinary diversion performed was extra corporeal. RESULTS: The study concerned were 26 men, 15 of them underwent robot assisted cystectomy, and 11 open cystectomy. There was no significant difference in the median operating time or duration of stay (300 vs 314min and 14 vs 18 days). However, there were less blood loss and more lymph nodes collected in the cystectomies robot-assisted group (median: 400 vs 800mL, P=0.016; 15 vs 10, P=0.01). Three grade III complications of the Clavien-Dindo classification have been described in the robot-assisted group, and none in the open group. No robot assisted procedure required a conversion to laparotomy. Within 90 postoperative days, complications are basically low grades and results are consistent with the literature. CONCLUSION: In our series, robot-assisted cystectomies with extracorporeal bladder substitution is technically feasible, with best results on blood loss and the number of lymph nodes removed, without impact on the length of stay. LEVEL OF EVIDENCE: 4. PMID- 27460788 TI - Internalized Tau sensitizes cells to stress by promoting formation and stability of stress granules. AB - Stress granules are membrane-less RNA- and RNA-binding protein-containing complexes that are transiently assembled in stressful conditions to promote cell survival. Several stress granule-associated RNA-binding proteins have been associated with neurodegenerative diseases. In addition, a close link was recently identified between the stress granule core-nucleating protein TIA-1 and Tau. Tau is a central pathological protein in Alzheimer's disease and other tauopathies, and misfolded, aggregated Tau is capable of propagating pathology via cell-to-cell transmission. Here we show that following internalization hyperphosphorylated extracellular Tau associates with stress granules in a TIA-1 dependent manner. Cytosolic Tau normally only weakly interacts with TIA-1 but mutations mimicking abnormal phosphorylation promote this interaction. We show that internalized Tau significantly delays normal clearance of stress granules in the recipient cells sensitizing them to secondary stress. These results suggest that secreted Tau species may have properties, likely related to its hyperphosphorylation and oligomerization, which promote pathological association of internalized Tau with stress granules altering their dynamics and reducing cell viability. We suggest that stress granules and TIA-1 play a central role in the cell-to-cell transmission of Tau pathology. PMID- 27460790 TI - Early changes of gene activity in developing seedlings of Arabidopsis hybrids relative to parents may contribute to hybrid vigour. AB - Hybrid vigour (heterosis) has been used for decades in crop industries, especially in the production of maize and rice. Hybrid varieties usually exceed their parents in plant biomass and seed yield. But the molecular basis of hybrid vigour is not fully understood. In this project, we studied heterosis at early stages of seedling development in Arabidopsis hybrids derived from crossing Ler and C24 accessions. We found that early heterosis is associated with non-additive gene expression that resulted from earlier changes in gene expression in the hybrids relative to the parents. The non-additively expressed genes are involved in metabolic pathways, including photosynthesis, critical for plant growth. The early increased expression levels of genes involved in energy production in hybrids is associated with heterosis in the young seedlings that could be essential for biomass heterosis at later developmental stages of the plant. PMID- 27460789 TI - An evidence map of the effect of Tai Chi on health outcomes. AB - BACKGROUND: This evidence map describes the volume and focus of Tai Chi research reporting health outcomes. Originally developed as a martial art, Tai Chi is typically taught as a series of slow, low-impact movements that integrate the breath, mind, and physical activity to achieve greater awareness and a sense of well-being. METHODS: The evidence map is based on a systematic review of systematic reviews. We searched 11 electronic databases from inception to February 2014, screened reviews of reviews, and consulted with topic experts. We used a bubble plot to graphically display clinical topics, literature size, number of reviews, and a broad estimate of effectiveness. RESULTS: The map is based on 107 systematic reviews. Two thirds of the reviews were published in the last five years. The topics with the largest number of published randomized controlled trials (RCTs) were general health benefits (51 RCTs), psychological well-being (37 RCTs), interventions for older adults (31 RCTs), balance (27 RCTs), hypertension (18 RCTs), fall prevention (15 RCTs), and cognitive performance (11 RCTs). The map identified a number of areas with evidence of a potentially positive treatment effect on patient outcomes, including Tai Chi for hypertension, fall prevention outside of institutions, cognitive performance, osteoarthritis, depression, chronic obstructive pulmonary disease, pain, balance confidence, and muscle strength. However, identified reviews cautioned that firm conclusions cannot be drawn due to methodological limitations in the original studies and/or an insufficient number of existing research studies. CONCLUSIONS: Tai Chi has been applied in diverse clinical areas, and for a number of these, systematic reviews have indicated promising results. The evidence map provides a visual overview of Tai Chi research volume and content. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009907. PMID- 27460791 TI - Does cefuroxime alter fracture healing in vivo? A micro-computertomographic, biomechanical, and histomorphometric evaluation using a rat fracture model. AB - Cefuroxime is widely used for antibiotic prophylaxis in orthopedic surgery. However, a recent study indicated a dose-dependent reduction in osteoblast function in vitro. Nevertheless, cell culture might not sufficiently imitate the complex process of bone remodeling. As data concerning possible in vivo interactions of cefuroxime on fracture healing are completely missing, we investigated the following hypothesis: Does Cefuroxime impair bone healing in vivo? Therefore, 34 male Wistar rats were randomised to cefuroxime-treated or control groups, a Kirschner wire was inserted into right femora and closed transverse fractures were produced. Twenty-one days later, the structural properties of the fracture callus in the early fracture healing phase were evaluated via a combination of micro-CT (MUCT), biomechanics and histology. uCT demonstrated similar values in the cefuroxime and control group (e.g., callus volume: 67.19 +/- 14.90 mm3 vs. 55.35 +/- 6.74 mm3 , p = 0.12; density: 635.48 +/ 14.81 mg HA/cm3 vs. 647.87 +/- 13.01 mg HA/cm3 , p = 0.16). Biomechanically, similar values were again determined between the groups, in terms of both maximum load (77.65 +/- 41.82 vs. 78.54 +/- 20.52, p = 0.95) and stiffness (122.44 +/- 81.16 vs. 123.74 +/- 60.08, p = 0.97). Histological findings were consistent with the radiographic results. Thus, no relevant differences between the cefuroxime and control groups could be found and the reported negative effects on osteoblasts in vitro were not confirmed in vivo by using standard concentrations of cefuroxime. In conclusion, cefuroxime can reasonably be recommended in a clinical setting as an antibiotic therapy when fracture healing is involved. However, supraphysiological doses were not evaluated, which may be present when cefuroxime is used as an additive to bone cement and released over time. Therefore, future studies should evaluate the in vivo effects of prolonged high cefuroxime doses on implant incorporation. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2282-2291, 2017. PMID- 27460792 TI - The Microbial Signature Provides Insight into the Mechanistic Basis of Coral Success across Reef Habitats. AB - For ecosystems vulnerable to environmental change, understanding the spatiotemporal stability of functionally crucial symbioses is fundamental to determining the mechanisms by which these ecosystems may persist. The coral Pachyseris speciosa is a successful environmental generalist that succeeds in diverse reef habitats. The generalist nature of this coral suggests it may have the capacity to form functionally significant microbial partnerships to facilitate access to a range of nutritional sources within different habitats. Here, we propose that coral is a metaorganism hosting three functionally distinct microbial interactions: a ubiquitous core microbiome of very few symbiotic host selected bacteria, a microbiome of spatially and/or regionally explicit core microbes filling functional niches (<100 phylotypes), and a highly variable bacterial community that is responsive to biotic and abiotic processes across spatial and temporal scales (>100,000 phylotypes). We find that this coral hosts upwards of 170,000 distinct phylotypes and provide evidence for the persistence of a select group of bacteria in corals across environmental habitats of the Great Barrier Reef and Coral Sea. We further show that a higher number of bacteria are consistently associated with corals on mesophotic reefs than on shallow reefs. An increase in microbial diversity with depth suggests reliance by this coral on bacteria for nutrient acquisition on reefs exposed to nutrient upwelling. Understanding the complex microbial communities of host organisms across broad biotic and abiotic environments as functionally distinct microbiomes can provide insight into those interactions that are ubiquitous niche symbioses and those that provide competitive advantage within the hosts' environment. IMPORTANCE: Corals have been proposed as the most diverse microbial biosphere. The high variability of microbial communities has hampered the identification of bacteria playing key functional roles that contribute to coral survival. Exploring the bacterial community in a coral with a broad environmental distribution, we found a group of bacteria present across all environments and a higher number of bacteria consistently associated with mesophotic corals (60 to 80 m). These results provide evidence of consistent and ubiquitous coral bacterial partnerships and support the consideration of corals as metaorganisms hosting three functionally distinct microbiomes: a ubiquitous core microbiome, a microbiome filling functional niches, and a highly variable bacterial community. PMID- 27460794 TI - Erratum for Bergstrand et al., Delineation of Steroid-Degrading Microorganisms through Comparative Genomic Analysis. PMID- 27460793 TI - Genomes of Abundant and Widespread Viruses from the Deep Ocean. AB - The deep sea is a massive, largely oligotrophic ecosystem, stretched over nearly 65% of the planet's surface. Deep-sea planktonic communities are almost completely dependent upon organic carbon sinking from the productive surface, forming a vital component of global biogeochemical cycles. However, despite their importance, viruses from the deep ocean remain largely unknown. Here, we describe the first complete genomes of deep-sea viruses assembled from metagenomic fosmid libraries. "Candidatus Pelagibacter" (SAR11) phage HTVC010P and Puniceispirillum phage HMO-2011 are considered the most abundant cultured marine viruses known to date. Remarkably, some of the viruses described here recruited as many reads from deep waters as these viruses do in the photic zone, and, considering the gigantic scale of the bathypelagic habitat, these genomes provide information about what could be some of the most abundant viruses in the world at large. Their role in the viral shunt in the global ocean could be very significant. Despite the challenges encountered in inferring the identity of their hosts, we identified one virus predicted to infect members of the globally distributed SAR11 cluster. We also identified a number of putative proviruses from diverse taxa, including deltaproteobacteria, bacteroidetes, SAR11, and gammaproteobacteria. Moreover, our findings also indicate that lysogeny is the preferred mode of existence for deep sea viruses inhabiting an energy-limited environment, in sharp contrast to the predominantly lytic lifestyle of their photic-zone counterparts. Some of the viruses show a widespread distribution, supporting the tenet "everything is everywhere" for the deep-ocean virome. IMPORTANCE: The deep sea is among the largest known habitats and a critical cog in biogeochemical cycling but remains underexplored in its microbiology. Even more than is the case for its prokaryotic community, our knowledge of its viral component has remained limited by the paucity of information provided by studies dependent upon short sequence fragments. In this work, we attempt to fill this existing gap by using a combination of classical fosmid libraries with next-generation sequencing and assembly to recover long viral genomic fragments. We have sequenced ca. 6,000 fosmids from two metagenomics libraries made from prokaryotic biomass from the deep Mediterranean Sea and recovered twenty-eight complete viral genomes, all of them novel and quite distinct from all previously described viral genomes. They are preferentially found in deeper waters and are widely distributed all over the oceans. To our knowledge, this is the first report on complete and cosmopolitan viral genomes from the bathypelagic habitat. PMID- 27460795 TI - Novel Picornavirus Associated with Avian Keratin Disorder in Alaskan Birds. AB - Avian keratin disorder (AKD), characterized by debilitating overgrowth of the avian beak, was first documented in black-capped chickadees (Poecile atricapillus) in Alaska. Subsequently, similar deformities have appeared in numerous species across continents. Despite the widespread distribution of this emerging pathology, the cause of AKD remains elusive. As a result, it is unknown whether suspected cases of AKD in the afflicted species are causally linked, and the impacts of this pathology at the population and community levels are difficult to evaluate. We applied unbiased, metagenomic next-generation sequencing to search for candidate pathogens in birds affected with AKD. We identified and sequenced the complete coding region of a novel picornavirus, which we are calling poecivirus. Subsequent screening of 19 AKD-affected black capped chickadees and 9 control individuals for the presence of poecivirus revealed that 19/19 (100%) AKD-affected individuals were positive, while only 2/9 (22%) control individuals were infected with poecivirus. Two northwestern crows (Corvus caurinus) and two red-breasted nuthatches (Sitta canadensis) with AKD consistent pathology also tested positive for poecivirus. We suggest that poecivirus is a candidate etiological agent of AKD. IMPORTANCE: Avian keratin disorder (AKD) is an increasingly common disease of wild birds. This disease, characterized by beak overgrowth, was first described in the late 1990s and has been spreading rapidly both geographically and in terms of host species affected. AKD decreases host fitness and can be fatal. However, the cause of the disease has remained elusive, and its impact on host populations is poorly understood. We found a novel and divergent picornavirus in 19/19 AKD-affected black-capped chickadees that we examined but in only 2/9 control cases. We also found this virus in 4 individuals of 2 other passerine species that exhibited symptoms consistent with AKD. Our data suggest that this novel picornavirus warrants further investigation as the causative agent of AKD. PMID- 27460796 TI - Cell Division by Longitudinal Scission in the Insect Endosymbiont Spiroplasma poulsonii. AB - Spiroplasma bacteria are highly motile bacteria with no cell wall and a helical morphology. This clade includes many vertically transmitted insect endosymbionts, including Spiroplasma poulsonii, a natural endosymbiont of Drosophila melanogaster S. poulsonii bacteria are mainly found in the hemolymph of infected female flies and exhibit efficient vertical transmission from mother to offspring. As is the case for many facultative endosymbionts, S. poulsonii can manipulate the reproduction of its host; in particular, S. poulsonii induces male killing in Drosophila melanogaster Here, we analyze the morphology of S. poulsonii obtained from the hemolymph of infected Drosophila This endosymbiont was not only found as long helical filaments, as previously described, but was also found in a Y-shaped form. The use of electron microscopy, immunogold staining of the FtsZ protein, and antibiotic treatment unambiguously linked the Y shape of S. poulsonii to cell division. Observation of the Y shape in another Spiroplasma, S. citri, and anecdotic observations from the literature suggest that cell division by longitudinal scission might be prevalent in the Spiroplasma clade. Our study is the first to report the Y-shape mode of cell division in an endosymbiotic bacterium and adds Spiroplasma to the so far limited group of bacteria known to utilize this cell division mode. IMPORTANCE: Most bacteria rely on binary fission, which involves elongation of the bacteria and DNA replication, followed by splitting into two parts. Examples of bacteria with a Y-shape longitudinal scission remain scarce. Here, we report that Spiroplasma poulsonii, an endosymbiotic bacterium living inside the fruit fly Drosophila melanogaster, divide with the longitudinal mode of cell division. Observations of the Y shape in another Spiroplasma, S. citri, suggest that this mode of scission might be prevalent in the Spiroplasma clade. Spiroplasma bacteria are wall-less bacteria with a distinctive helical shape, and these bacteria are always associated with arthropods, notably insects. Our study raises the hypothesis that this mode of cell division by longitudinal scission could be linked to the symbiotic mode of life of these bacteria. PMID- 27460797 TI - Polyamines and Hypusination Are Required for Ebolavirus Gene Expression and Replication. AB - Ebolavirus (EBOV) is an RNA virus that is known to cause severe hemorrhagic fever in humans and other primates : EBOV successfully enters and replicates in many cell types. This replication is dependent on the virus successfully coopting a number of cellular factors. Many of these factors are currently unidentified but represent potential targets for antiviral therapeutics. Here we show that cellular polyamines are critical for EBOV replication. We found that small molecule inhibitors of polyamine synthesis block gene expression driven by the viral RNA-dependent RNA polymerase. Short hairpin RNA (shRNA) knockdown of the polyamine pathway enzyme spermidine synthase also resulted in reduced EBOV replication. These findings led us to further investigate spermidine, a polyamine that is essential for the hypusination of eukaryotic initiation factor 5A (eIF5A). Blocking the hypusination of eIF5A (and thereby inhibiting its function) inhibited both EBOV gene expression and viral replication. The mechanism appears to be due to the importance of hypusinated eIF5A for the accumulation of VP30, an essential component of the viral polymerase. The same reduction in hypusinated eIF5A did not alter the accumulation of other viral polymerase components. This action makes eIF5A function an important gate for proper EBOV polymerase assembly and function through the control of a single virus protein. IMPORTANCE: Ebolavirus (EBOV) is one of the most lethal human pathogens known. EBOV requires host factors for replication due to its small RNA genome. Here we show that the host protein eIF5A in its activated form is necessary for EBOV replication. We further show that the mechanism is through the accumulation of a single EBOV protein, VP30. To date, no other host proteins have been shown to interfere with the translation or stability of an EBOV protein. Activated eIF5A is the only protein in the cell known to contain the specific modification of hypusine; therefore, this pathway is a target for drug development. Further investigation into the mechanism of eIF5A interaction with VP30 could provide insight into therapeutics to combat EBOV. PMID- 27460799 TI - Helicopter Journals. PMID- 27460798 TI - Unlocking the Constraints of Cyanobacterial Productivity: Acclimations Enabling Ultrafast Growth. AB - Harnessing the metabolic potential of photosynthetic microbes for next-generation biotechnology objectives requires detailed scientific understanding of the physiological constraints and regulatory controls affecting carbon partitioning between biomass, metabolite storage pools, and bioproduct synthesis. We dissected the cellular mechanisms underlying the remarkable physiological robustness of the euryhaline unicellular cyanobacterium Synechococcus sp. strain PCC 7002 (Synechococcus 7002) and identify key mechanisms that allow cyanobacteria to achieve unprecedented photoautotrophic productivities (~2.5-h doubling time). Ultrafast growth of Synechococcus 7002 was supported by high rates of photosynthetic electron transfer and linked to significantly elevated transcription of precursor biosynthesis and protein translation machinery. Notably, no growth or photosynthesis inhibition signatures were observed under any of the tested experimental conditions. Finally, the ultrafast growth in Synechococcus 7002 was also linked to a 300% expansion of average cell volume. We hypothesize that this cellular adaptation is required at high irradiances to support higher cell division rates and reduce deleterious effects, corresponding to high light, through increased carbon and reductant sequestration. IMPORTANCE: Efficient coupling between photosynthesis and productivity is central to the development of biotechnology based on solar energy. Therefore, understanding the factors constraining maximum rates of carbon processing is necessary to identify regulatory mechanisms and devise strategies to overcome productivity constraints. Here, we interrogate the molecular mechanisms that operate at a systems level to allow cyanobacteria to achieve ultrafast growth. This was done by considering growth and photosynthetic kinetics with global transcription patterns. We have delineated putative biological principles that allow unicellular cyanobacteria to achieve ultrahigh growth rates through photophysiological acclimation and effective management of cellular resource under different growth regimes. PMID- 27460800 TI - Proteomics Analysis Reveals Previously Uncharacterized Virulence Factors in Vibrio proteolyticus. AB - Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals. We found that V. proteolyticus causes actin cytoskeleton rearrangements followed by cell lysis in HeLa cells in a contact-independent manner. In search of the responsible virulence factor involved, we determined the V. proteolyticus secretome. This proteomics approach revealed various putative virulence factors, including active type VI secretion systems and effectors with virulence toxin domains; however, these type VI secretion systems were not responsible for the observed cytotoxic effects. Further examination of the V. proteolyticus secretome led us to hypothesize and subsequently demonstrate that a secreted hemolysin, belonging to a previously uncharacterized clan of the leukocidin superfamily, was the toxin responsible for the V. proteolyticus mediated cytotoxicity in both HeLa cells and macrophages. Clearly, there remains an armory of yet-to-be-discovered virulence factors in the Vibrio pan-genome that will undoubtedly provide a wealth of knowledge on how a pathogen can manipulate host cells. IMPORTANCE: The pan-genome of the genus Vibrio is a potential reservoir of unidentified toxins that can provide insight into how members of this genus have successfully risen as emerging pathogens worldwide. We focused on Vibrio proteolyticus, a marine bacterium that was previously implicated in virulence toward marine animals, and characterized its interaction with eukaryotic cells. We found that this bacterium causes actin cytoskeleton rearrangements and leads to cell death. Using a proteomics approach, we identified a previously unstudied member of the leukocidin family of pore-forming toxins as the virulence factor responsible for the observed cytotoxicity in eukaryotic cells, as well as a plethora of additional putative virulence factors secreted by this bacterium. Our findings reveal a functional new clan of the leukocidin toxin superfamily and establish this pathogen as a reservoir of potential toxins that can be used for biomedical applications. PMID- 27460801 TI - Shared decision-making as an existential journey: Aiming for restored autonomous capacity. AB - OBJECTIVE: We describe the different ways in which illness represents an existential problem, and its implications for shared decision-making. METHODS: We explore core concepts of shared decision-making in medical encounters (uncertainty, vulnerability, dependency, autonomy, power, trust, responsibility) to interpret and explain existing results and propose a broader understanding of shared-decision making for future studies. RESULTS: Existential aspects of being are physical, social, psychological, and spiritual. Uncertainty and vulnerability caused by illness expose these aspects and may lead to dependency on the provider, which underscores that autonomy is not just an individual status, but also a varying capacity, relational of nature. In shared decision-making, power and trust are important factors that may increase as well as decrease the patient's dependency, particularly as information overload may increase uncertainty. CONCLUSION: The fundamental uncertainty, state of vulnerability, and lack of power of the ill patient, imbue shared decision-making with a deeper existential significance and call for greater attention to the emotional and relational dimensions of care. Hence, we propose that the aim of shared decision making should be restoration of the patient's autonomous capacity. PRACTICE IMPLICATIONS: In doing shared decision-making, care is needed to encompass existential aspects; informing and exploring preferences is not enough. PMID- 27460802 TI - General Strategies in Inflammasome Biology. AB - The complementary actions of the innate and adaptive immune systems often provide effective host defense against microbial pathogens and harmful environmental agents. Germline-encoded pattern recognition receptors (PRRs) endow the innate immune system with the ability to detect and mount a rapid response against a given threat. Members of several intracellular PRR families, including the nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs), the AIM2-like receptors (ALRs), and the tripartite motif-containing (TRIM) protein Pyrin/TRIM20, nucleate the formation of inflammasomes. These cytosolic scaffolds serve to recruit and oligomerize the cysteine protease caspase-1 in filaments that promote its proximity-induced autoactivation. This oligomerization occurs either directly or indirectly through intervention of the bipartite adaptor protein ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD), which is needed for the domain interaction. Caspase-1 cleaves the precursors of the inflammatory cytokines interleukin (IL)-1beta and IL-18 and triggers their release into the extracellular space, where they act on effector cells to promote both local and systemic immune responses. Additionally, inflammasome activation gives rise to a lytic mode of cell death, named pyroptosis, which is thought to contribute to initial host defense against infection by eliminating replication niches of intracellular pathogens and exposing them to the immune system. Inflammasome-induced host defense responses are the subject of intense investigation, and understanding their physiological roles during infection and the regulatory circuits that are involved is becoming increasingly detailed. Here, we discuss current understanding of the activation mechanisms and biological outcomes of inflammasome activation. PMID- 27460803 TI - Structural Mechanisms in NLR Inflammasome Assembly and Signaling. AB - Inflammasomes are multimeric protein complexes that mediate the activation of inflammatory caspases. One central component of inflammasomes is nucleotide binding domain (NBD)- and leucine-rich repeat (LRR)-containing proteins (NLRs) that can function as pattern recognition receptors (PRRs). In resting cells, NLR proteins exist in an auto-inhibited, monomeric, and ADP-bound state. Perception of microbial or damage-associated signals results in NLR oligomerization, thus recruiting inflammatory caspases directly or through the adaptor molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). The assembled NLR inflammasomes serve as dedicated machinery to facilitate the activation of the inflammatory caspases. Here, we review current understanding of the structures of NLR inflammasomes with an emphasis on the molecular mechanisms of their assembly and activation. We also discuss implications of the self-propagation model derived from the NAIP-NLRC4 inflammasomes for the activation of other NLR inflammasomes and a potential role of the C-terminal LRR domain in the activation of an NLR protein. PMID- 27460804 TI - Salmonella and the Inflammasome: Battle for Intracellular Dominance. AB - Inflammasomes are macromolecular cytoplasmic complexes that act as signaling platforms for the activation of inflammatory caspases. Their activation triggers the processing and secretion of the pro-inflammatory cytokines IL-1beta and IL 18, as well as the induction of a specialized form of inflammatory cell death termed pyroptosis. Here, we review the mechanisms of inflammasome activation triggered by the intracellular pathogen Salmonella enterica serovar Typhimurium. We highlight the different inflammasome subfamilies utilized by macrophages, neutrophils, dendritic cells, and intestinal epithelial cells response to a Salmonella infection as well as the Salmonella ligands that trigger each inflammasome's formation. We also discuss the evasion strategies utilized by Salmonella to avoid inflammasome detection. Overall, inflammasomes play a key and multilayered role at distinct stages of host cell defense against Salmonella infection. PMID- 27460805 TI - Activation and Evasion of Inflammasomes by Yersinia. AB - The innate immune system plays an essential role in initiating the early response against microbial infection, as well as instructing and shaping subsequent responses. Microbial pathogens are enormously diverse in terms of the niches they occupy, their metabolic properties and requirements, and the cellular pathways that they target. Nevertheless, innate sensing of pathogens triggers a relatively stereotyped set of responses that involve transcriptional induction of key inflammatory mediators, as well as post-translational assembly and activation of a multiprotein inflammatory complex termed 'the inflammasome.' Along with classical Pattern Recognition Receptors, the inflammasome activation pathway has emerged as a key regulator of tissue homeostasis and immune defense. Components of the inflammasome generally exist within the cell in a soluble, monomeric state, and oligomerize in response to diverse enzymatic activities associated with infection or cellular stress. Inflammasome assembly triggers activation of the pro-enzyme caspase-1, resulting in the cleavage of caspase-1 targets. The most extensively studied targets are the cytokines of the IL-1 family, but the recent discovery of Gasdermin D as a novel target of caspase-1 and the related inflammatory caspase, caspase-11, has begun to mechanistically define the links between caspase-1 activation and cell death. Cell death is a hallmark of macrophage infection by many pathogens, including the gram-negative bacterial pathogens of the genus Yersinia. Intriguingly, the activities of the Yersinia secreted effector proteins and the type III secretion system (T3SS) itself have been linked to both inflammasome activation and evasion during infection. The balance between these activating and inhibitory activities shapes the outcome of Yersinia infection. Here, we describe the current state of knowledge on interactions between Yersinia and the inflammasome system, with the goal of integrating these findings within the general framework of inflammasome responses to microbial pathogens. PMID- 27460806 TI - The Orchestra and Its Maestro: Shigella's Fine-Tuning of the Inflammasome Platforms. AB - Shigella spp. are the causative agents of bacillary dysentery, leading to extensive mortality and morbidity worldwide. These facultative intracellular bacteria invade the epithelium of the colon and the rectum, inducing a severe inflammatory response from which the symptoms of the disease originate. Shigella are human pathogens able to manipulate and subvert the innate immune system surveillance. Shigella dampens inflammasome activation in epithelial cells. In infected macrophages, inflammasome activation and IL-1beta and IL-18 release lead to massive neutrophil recruitment and greatly contribute to inflammation. Here, we describe how Shigella hijacks and finely tunes inflammasome activation in the different cell populations involved in pathogenesis: epithelial cells, macrophages, neutrophils, DCs, and B and T lymphocytes. Shigella emerges as a "sly" pathogen that switches on/off the inflammasome mechanisms in order to optimize the interaction with the host and establish a successful infection. PMID- 27460807 TI - Inflammasome Activation by Helicobacter pylori and Its Implications for Persistence and Immunity. AB - Infection with the Gram-negative pathogen Helicobacter pylori is the most prevalent chronic bacterial infection affecting about 50 % of the human world population and is the main risk factor for gastric cancer development. The pro inflammatory cytokine IL-1beta plays a crucial role in the development of gastric tumors, and polymorphisms in the IL-1 gene cluster resulting in increased IL 1beta production have been associated with increased risk for gastric cancer. Recently, Helicobacter pylori was postulated to activate the inflammasome in human and mouse immune cells, and the molecular mechanisms and the bacterial virulence factors activating the inflammasome were elucidated in cell culture as well as animal models. It appears that H. pylori-induced IL-1beta secretion is mediated by activation of toll-like receptor 2 (TLR-2), Nod-like receptor family member NLRP3 and caspase-1. The cag pathogenicity island-encoded type IV secretion system, lipopolysaccharide, vacuolating cytotoxin, and urease B subunit appear to play a role in inflammasome activation. In addition, recent results indicate that the TLR-2 -> NLRP3 -> caspase-1 -> IL-18 axis is critical to H. pylori-specific immune regulation conferring protection against allergen-induced asthma and inflammatory bowel disease in murine models. The present chapter will review the proposed mechanisms of NLRP3 inflammasome activation during H. pylori infection and discuss the recent progress in this important research field. PMID- 27460809 TI - Inflammasome Recognition and Regulation of the Legionella Flagellum. AB - The Gram-negative bacterium Legionella pneumophila colonizes extracellular environmental niches and infects free-living protozoa. Upon inhalation into the human lung, the opportunistic pathogen grows in macrophages and causes a fulminant pneumonia termed Legionnaires' disease. L. pneumophila employs a biphasic life cycle, comprising a replicative, non-virulent, and a stationary, virulent form. In the latter phase, the pathogen produces a plethora of so-called effector proteins, which are injected into host cells, where they subvert pivotal processes and promote the formation of a distinct membrane-bound compartment, the Legionella-containing vacuole. In the stationary phase, the bacteria also produce a single monopolar flagellum and become motile. L. pneumophila flagellin is recognized by and triggers the host's NAIP5 (Birc1e)/NLRC4 (Ipaf) inflammasome, which leads to caspase-1 activation, pore formation, and pyroptosis. The production of L. pneumophila flagellin and pathogen-host interactions are controlled by a complex stationary phase regulatory network, detecting nutrient availability as well as the Legionella quorum sensing (Lqs) signaling compound LAI-1 (3-hydroxypentadecane-4-one). Thus, the small molecule LAI-1 coordinates L. pneumophila flagellin production and motility, inflammasome activation, and virulence. PMID- 27460810 TI - Inflammasome Activation and Function During Infection with Mycobacterium Tuberculosis. AB - Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb) and represents one of the most relevant bacterial diseases worldwide. Recent advances have yielded new insights into the molecular basis of the immune response required for restriction of the pathogen and also highlighted determinants of immunopathology in TB. Several innate immune mediators including soluble proteins as well as lipid molecules participate in both processes, and their mechanisms of action during TB have been extensively studies over the past years. Among those mediators, inflammasomes are essential signaling platforms that execute crucial functions in several areas of immunology and beyond. This chapter aims to summarize what is known about the roles of the inflammasome during infection with Mtb from both in vitro studies as well as from in vivo work. A better understanding of the complex interactions between Mtb and the host immune system could reveal novel therapeutic approaches and improve current vaccination protocols in TB. PMID- 27460808 TI - Listeria monocytogenes and the Inflammasome: From Cytosolic Bacteriolysis to Tumor Immunotherapy. AB - Inflammasomes are cytosolic innate immune surveillance systems that recognize a variety of danger signals, including those from pathogens. Listeria monocytogenes is a Gram-positive intracellular bacterium evolved to live within the harsh environment of the host cytosol. Further, L. monocytogenes can activate a robust cell-mediated immune response that is being harnessed as an immunotherapeutic platform. Access to the cytosol is critical for both causing disease and inducing a protective immune response, and it is hypothesized that the cytosolic innate immune system, including the inflammasome, is critical for both host protection and induction of long-term immunity. L. monocytogenes can activate a variety of inflammasomes via its pore-forming toxin listeriolysin-O, flagellin, or DNA released through bacteriolysis; however, inflammasome activation attenuates L. monocytogenes, and as such, L. monocytogenes has evolved a variety of ways to limit inflammasome activation. Surprisingly, inflammasome activation also impairs the host cell-mediated immune response. Thus, understanding how L. monocytogenes activates or avoids detection by the inflammasome is critical to understand the pathogenesis of L. monocytogenes and improve the cell-mediated immune response generated to L. monocytogenes for more effective immunotherapies. PMID- 27460811 TI - Role of Canonical and Non-canonical Inflammasomes During Burkholderia Infection. AB - Burkholderia pseudomallei is a Gram-negative flagellate bacterium that causes melioidosis, a disease endemic to Southeast Asia and other tropical regions. Following infection of macrophages and other non-phagocytic cell types, B. pseudomallei or B. thailandensis (a related species that causes disease in mice but not humans) are able to escape the phagosome and replicate in the host cell cytoplasm. Resistance to infection with Burkholderia is dependent on the Nlrp3 and Nlrc4 inflammasomes and the non-canonical caspase-11 inflammasome. Nlrc4 mediates protection through induction of pyroptosis in the early phase of infection. As the infection progresses and as IL-18-dependent IFNgamma production increases, caspase-11-dependent pyroptosis acquires a preponderant protective role. Production of IL-1beta and IL-18 during infection is primarily mediated by Nlrp3. IL-18 is essential for survival because of its ability to induce IFNgamma production, which in turn activates macrophage microbicidal functions and primes for caspase-11 expression. In contrast, during melioidosis, IL-1beta has deleterious effects due to excessive recruitment of neutrophils to the lung and consequent tissue damage. PMID- 27460812 TI - Inflammasomes in Pneumococcal Infection: Innate Immune Sensing and Bacterial Evasion Strategies. AB - Streptococcus pneumoniae frequently colonizes the upper respiratory tract of healthy individuals, but also commonly causes severe invasive infections such as community-acquired pneumonia and meningitis. One of the key virulence factors of pneumococci is the pore-forming toxin pneumolysin which stimulates cell death and is involved in the evasion of some defense mechanisms. The immune system, however, employs different inflammasomes to sense pneumolysin-induced pore formation, cellular membrane damage, and/or subsequent leakage of bacterial nucleic acid into the host cell cytosol. Canonical inflammasomes are cytosolic multiprotein complexes consisting of a receptor molecule such as NLRP3 or AIM2, the adapter ASC, and caspase-1. NLRP3 and AIM2 inflammasomes mediate cell death and production of important IL-1 family cytokines to recruit leukocytes and defend against S. pneumoniae. Here, we review recent evidence that highlights inflammasomes as critical sensors of S. pneumoniae-induced cellular perturbations, summarize their role in pneumococcal infections, and discuss potential evasion strategies of some emerging pneumococcal strains. PMID- 27460813 TI - Francisella Inflammasomes: Integrated Responses to a Cytosolic Stealth Bacterium. AB - Francisella tularensis is a facultative intracellular bacterium causing tularemia, a zoonotic disease. Francisella replicates in the macrophage cytosol and eventually triggers cytosolic immune responses. In murine macrophages, Francisella novicida and Francisella tularensis live vaccine strain lyse in the host cytosol and activate the cytosolic DNA receptor Aim2. Here, we review the mechanisms leading or contributing to Aim2 inflammasome activation, including the role of TLRs and of IFN signaling and the implication of the guanylate-binding proteins 2 and 5 in triggering cytosolic bacteriolysis. Furthermore, we present how this cytosolic Gram-negative bacterium escapes recognition by caspase-11 but can trigger a non-canonical caspase-8 inflammasome. In addition, we highlight the differences in inflammasome activation in murine and human cells with pyrin, NLRP3, and AIM2 involved in sensing Francisella in human phagocytes. From a bacterial prospective, we describe the hiding strategy of Francisella to escape recognition by innate sensors and to resist to bacteriolysis in the host cytosol. Finally, we discuss the inability of the inflammasome sensors to detect F. tularensis subspecies tularensis strains, making them highly pathogenic stealth microbes. PMID- 27460815 TI - Reply. PMID- 27460814 TI - Inflammasome Activation Can Mediate Tissue-Specific Pathogenesis or Protection in Staphylococcus aureus Infection. AB - Staphylococcus aureus is a Gram-positive coccus that interacts with human hosts on a spectrum from quiet commensal to deadly pathogen. S. aureus is capable of infecting nearly every tissue in the body resulting in cellulitis, pneumonia, osteomyelitis, endocarditis, brain abscesses, bacteremia, and more. S. aureus has a wide range of factors that promote infection, and each site of infection triggers a different response in the human host. In particular, the different patterns of inflammasome activation mediate tissue-specific pathogenesis or protection in S. aureus infection. Although still a nascent field, understanding the unique host-pathogen interactions in each infection and the role of inflammasomes in mediating pathogenesis may lead to novel strategies for treating S. aureus infections. Reviews addressing S. aureus virulence and pathogenesis (Thammavongsa et al. 2015), as well as epidemiology and pathophysiology (Tong et al. 2015), have recently been published. This review will focus on S. aureus factors that activate inflammasomes and their impact on innate immune signaling and bacterial survival. PMID- 27460816 TI - Pars Plana Vitrectomy Combined With Either Secondary Scleral Fixated or Anterior Chamber Intraocular Lens Implantation. PMID- 27460817 TI - Pharmacognostic, physicochemical and chromatographic characterization of Samasharkara Churna. AB - BACKGROUND: Samasharkara Churna, a polyherbal Ayurvedic formulation, is prescribed for treating various conditions such as asthma and cough. Literature review suggested that characterization parameters of Samasharkara Churna are not reported. OBJECTIVE: To report characteristic parameters of Samasharkara Churna to conform its identity, quality and purity. MATERIALS AND METHODS: Samasharkara Churna was evaluated for pharmacognostic, physicochemical, microbiological, and chromatographic parameters. RESULTS: The chromatographic analysis was able to showed presence of all ingredients in Samasharkara Churna. CONCLUSION: The characterization parameters presented in this paper may serve as standard reference for the quality control analysis of Samasharkara Churna. PMID- 27460818 TI - Health-selective migration among patients with rheumatoid arthritis in Quebec: a cohort study using administrative data. AB - Little is known about how rheumatoid arthritis (RA) affects an individual's ability to relocate. The current literature suggests the relationship between health and migration is often disease-specific. We sought to estimate the impact of RA diagnosis on migration within a Canadian province, comparing migration rates in residents before and after RA diagnosis. We identified a cohort of 81,181 individuals diagnosed with RA between 1998 and 2009 using Quebec administrative databases. A migration was defined as a change in the first three characters of the postal code. We categorized migrations as urban or rural depending upon an individual's origin and destination. We estimated the association between RA diagnosis and migration by fitting marginal models using a generalized estimating equations approach, adjusting for age, sex, and population level socioeconomic status indicators. The vast majority of moves after RA diagnosis were within urban areas. RA diagnosis was associated with increased migration except for people around age 50 moving within urban areas. Although RA was associated with increased inter-urban migration in many demographic groups, the net result did not translate to higher rates of rural-to-urban migration after RA diagnosis. Our results suggest fairly complex associations between RA diagnosis and migration. Both age and location (urban or rural) modify this effect. Overall, we did not see a greater movement from rural-to-urban areas after RA diagnosis. This is of interest for studies of regional environmental effects on chronic disease patterns. PMID- 27460819 TI - Andersson lesions of whole spine magnetic resonance imaging compared with plain radiography in ankylosing spondylitis. AB - The objective of this study was to identify the characteristics of Andersson lesions using whole spine magnetic resonance imaging (MRI) compared with plain radiography in ankylosing spondylitis (AS). A total of 62 patients with AS who had undergone whole spine MRI and plain radiography were retrospectively enrolled in this study. We compared the number of discovertebral units (DVUs) with Andersson lesions with clinical and radiographic indices such as erythrocyte sediment rate (ESR), C-reactive protein (CRP), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Fifty three patients (85.5 %) by whole spine MRI and 23 patients (37.1 %) by plain radiography had at least one Andersson lesion. We found 129 DVUs with Andersson lesions (11.1 %) by MRI and 35 DVUs by plain radiography over all the spine levels. Andersson lesions by MRI were most commonly detected at the lower thoracic spine (from T7-8 to T12-L1). Among the 151 total Andersson lesions by whole spine MRI, 41 were identified as central disc type, 26 as anterior peripheral disc type, 44 as posterior peripheral disc type, and 40 as diffuse disc type. However, the number of Andersson lesions did not correlate with ESR, CRP, BASDAI, BASFI, or mSASSS (p > 0.05 for all). Our study indicates that the presence of Andersson lesions in patients with AS is clearly underestimated. MRI is a superior technique for detecting early Andersson lesions compared with plain radiography. PMID- 27460822 TI - Arsenic Uptake by Muskmelon (Cucumis melo) Plants from Contaminated Water. AB - Arsenic is a carcinogenic element that occurs naturally in the environment. High levels of arsenic are found in water in some parts of the world, including Texas. The aims of this study were to determine the distribution of arsenic in muskmelon (Cucumis melo) plants accumulated from arsenic spiked water and to observe effects on plant biomass. Plants were grown and irrigated using water spiked with variable concentrations of arsenic. Inductively coupled plasma mass spectrometry was used to quantify arsenic in different parts of the plant and fruit. Under all conditions tested in this study, the highest concentrations of arsenic were found in the leaves, soil, and roots. Arsenic in the water had no significant effect on plant biomass. Fruits analyzed in this study had arsenic concentrations of 101 MUg/kg or less. Consuming these fruits would result in less arsenic exposure than drinking water at recommended levels. PMID- 27460820 TI - Vascular disruptive agent OXi4503 and anti-angiogenic agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis. AB - BACKGROUND: Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model. METHODS: CBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study. RESULTS: Combination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance. CONCLUSIONS: Combination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment. PMID- 27460823 TI - Tracking Metal Pollution in Lake Chapala: Concentrations in Water, Sediments, and Fish. AB - We measured concentrations of selected metals (Al, Ba, Cu, Mn, Hg, Sr, V, and Zn) in water, sediments, and fish from Lake Chapala and a reference site to evaluate potential negative effects on wildlife, particularly fish-eating birds. Fish metal concentrations ranged from 0.05 ug/g wet weight (ww) for Al and Cu to 64.70 ug/g ww for Sr. There was a positive and significant correlation between fish length and metals particularly for Ba, Cu, Mn, and Zn in Lake Chapala (p < 0.05). However, there were no significant correlations between metal concentrations and delta(15)N values in fish indicating no biomagnification through the food web. Overall, metal concentrations in water, sediments, and fish were similar to and in some cases below those reported for Lake Chapala over the last 20 years. Also, metal concentrations were below those that could be of concern for negative effects on fish and wildlife of Lake Chapala. PMID- 27460825 TI - ZNStress: a high-throughput drug screening protocol for identification of compounds modulating neuronal stress in the transgenic mutant sod1G93R zebrafish model of amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease with death on average within 2-3 years of symptom onset. Mutations in superoxide dismutase 1 (SOD1) have been identified to cause ALS. Riluzole, the only neuroprotective drug for ALS provides life extension of only 3 months on average. Thishighlights the need for compound screening in disease models to identify new neuroprotective therapies for this disease. Zebrafish is an emerging model system that is well suited for the study of diseasepathophysiology and also for high throughput (HT) drug screening. The mutant sod1 zebrafish model of ALS mimics the hallmark features of ALS. Using a fluorescence based readout of neuronal stress, we developed a high throughput (HT) screen to identify neuroprotective compounds. RESULTS: Here we show that the zebrafish screen is a robust system that can be used to rapidly screen thousands ofcompounds and also demonstrate that riluzole is capable of reducing neuronal stress in this model system. The screen shows optimal quality control, maintaining a high sensitivity and specificity withoutcompromising throughput. Most importantly, we demonstrate that many compounds previously failed in human clinical trials, showed no stress reducing activity in the zebrafish assay. CONCLUSION: We conclude that HT drug screening using a mutant sod1 zebrafish is a reliable model system which supplemented with secondary assays would be useful in identifying drugs with potential for neuroprotective efficacy in ALS. PMID- 27460824 TI - The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. AB - BACKGROUND: The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries. METHODS: We modeled common tumor profiling modalities-large (n = 300 genes), medium (n = 48 genes), and small (n = 15 genes) panels-using clinical whole exomes (WES) from 157 patients with lung or colon adenocarcinoma. We created a tumor-only analysis algorithm to assess germline false positive rates, the impact of patient ancestry on tumor-only results, and neoantigen detection. RESULTS: After optimizing a germline filtering strategy, the germline false positive rate with tumor-only large panel sequencing was 14 % (144/1012 variants). For patients whose tumor-only results underwent molecular pathologist review (n = 91), 50/54 (93 %) false positives were correctly interpreted as uncertain variants. Increased germline false positives were observed in tumor-only sequencing of non-European compared with European ancestry patients (p < 0.001; Fisher's exact) when basic germline filtering approaches were used; however, the ExAC database (60,706 germline exomes) mitigated this disparity (p = 0.53). Matched and unmatched large panel mutational load correlated with WES mutational load (r(2) = 0.99 and 0.93, respectively; p < 0.001). Neoantigen load also correlated (r(2) = 0.80; p < 0.001), though WES identified a broader spectrum of neoantigens. Small panels did not predict mutational or neoantigen load. CONCLUSIONS: Large tumor-only targeted panels are sufficient for most somatic variant identification and mutational load prediction if paired with expanded germline analysis strategies and molecular pathologist review. Paired germline sequencing reduced overall false positive mutation calls and WES provided the most neoantigens. Without patient-matched germline data, large germline databases are needed to minimize false positive mutation calling and mitigate ethnic disparities. PMID- 27460826 TI - Carbon-Based Metal-Free Catalysts for Electrocatalysis beyond the ORR. AB - Besides their use in fuel cells for energy conversion through the oxygen reduction reaction (ORR), carbon-based metal-free catalysts have also been demonstrated to be promising alternatives to noble-metal/metal oxide catalysts for the oxygen evolution reaction (OER) in metal-air batteries for energy storage and for the splitting of water to produce hydrogen fuels through the hydrogen evolution reaction (HER). This Review focuses on recent progress in the development of carbon-based metal-free catalysts for the OER and HER, along with challenges and perspectives in the emerging field of metal-free electrocatalysis. PMID- 27460827 TI - Family Financial Stress and Adolescent Sexual Risk-Taking: The Role of Self Regulation. AB - The ability to control one's emotions, thoughts, and behaviors is known as self regulation. Family stress and low adolescent self-regulation have been linked with increased engagement in risky sexual behaviors, which peak in late adolescence and early adulthood. The purpose of this study was to assess whether adolescent self-regulation, measured by parent and adolescent self-report and respiratory sinus arrhythmia, mediates or moderates the relationship between family financial stress and risky sexual behaviors. We assessed these relationships in a 4-year longitudinal sample of 450 adolescents (52 % female; 70 % white) and their parents using structural equation modeling. Results indicated that high family financial stress predicts engagement in risky sexual behaviors as mediated, but not moderated, by adolescent self-regulation. The results suggest that adolescent self-regulatory capacities are a mechanism through which proximal external forces influence adolescent risk-taking. Promoting adolescent self-regulation, especially in the face of external stressors, may be an important method to reduce risk-taking behaviors as adolescents transition to adulthood. PMID- 27460829 TI - Bifrontal brain abscesses secondary to orbital cellulitis and sinusitis extension. AB - BACKGROUND: Intracranial abscesses are rare and life-threatening conditions that typically originate from direct extension from nearby structures, hematogenous dissemination or following penetrating cerebral trauma or neurosurgery. FINDINGS: A 36-year-old male presented to our emergency department with complaints of left eye swelling, headache and drowsiness. On physical exam, the patient was febrile and his left upper eyelid was markedly swollen with fluctuance and drainage. Maxillofacial computed tomography was obtained to evaluate for orbital pathology but revealed bifrontal brain abscesses. CONCLUSIONS: Brain abscesses should be considered in the differential diagnosis for patients who present with the classic triad of headache, fever and neurological deficit. PMID- 27460828 TI - Medical costs and quality-adjusted life years associated with smoking: a systematic review. AB - BACKGROUND: Estimated medical costs ("T") and QALYs ("Q") associated with smoking are frequently used in cost-utility analyses of tobacco control interventions. The goal of this study was to understand how researchers have addressed the methodological challenges involved in estimating these parameters. METHODS: Data were collected as part of a systematic review of tobacco modeling studies. We searched five electronic databases on July 1, 2013 with no date restrictions and synthesized studies qualitatively. Studies were eligible for the current analysis if they were U.S.-based, provided an estimate for Q, and used a societal perspective and lifetime analytic horizon to estimate T. We identified common methods and frequently cited sources used to obtain these estimates. RESULTS: Across all 18 studies included in this review, 50 % cited a 1992 source to estimate the medical costs associated with smoking and 56 % cited a 1996 study to derive the estimate for QALYs saved by quitting or preventing smoking. Approaches for estimating T varied dramatically among the studies included in this review. T was valued as a positive number, negative number and $0; five studies did not include estimates for T in their analyses. The most commonly cited source for Q based its estimate on the Health Utilities Index (HUI). Several papers also cited sources that based their estimates for Q on the Quality of Well-Being Scale and the EuroQol five dimensions questionnaire (EQ-5D). CONCLUSIONS: Current estimates of the lifetime medical care costs and the QALYs associated with smoking are dated and do not reflect the latest evidence on the health effects of smoking, nor the current costs and benefits of smoking cessation and prevention. Given these limitations, we recommend that researchers conducting economic evaluations of tobacco control interventions perform extensive sensitivity analyses around these parameter estimates. PMID- 27460830 TI - Identifying seasonal and temporal trends in the pressures experienced by hospitals related to unscheduled care. AB - BACKGROUND: As part of an electronic dashboard operated by Public Health Wales, senior managers at hospitals in Wales report daily "escalation" scores which reflect management opinion on the pressure a hospital is experiencing and ability to meet ongoing demand with respect to unscheduled care. An analysis was undertaken of escalation scores returned for 18 hospitals in Wales between the years 2006 and 2014 inclusive, with a view to identifying systematic temporal patterns in pressure experienced by hospitals in relation to unscheduled care. METHODS: Exploratory data analysis indicated the presence of within-year cyclicity in average daily scores over all hospitals. In order to quantify this cyclicity, a Generalised Linear Mixed Model was fitted which incorporated a trigonometric function (sine and cosine) to capture within-year change in escalation. In addition, a 7-level categorical day of the week effect was fitted as well as a 3-level categorical Christmas holiday variable based on patterns observed in exploration of the raw data. RESULTS: All of the main effects investigated were found to be statistically significant. Firstly, significant differences emerged in terms of overall pressure reported by individual hospitals. Furthermore, escalation scores were found to vary systematically within-year in a wave-like fashion for all hospitals (but not between hospitals) with the period of highest pressure consistently observed to occur in winter and lowest pressure in summer. In addition to this annual variation, pressure reported by hospitals was also found to be influenced by day of the week (low at weekends, high early in the working week) and especially low over the Christmas period but high immediately afterwards. CONCLUSIONS: Whilst unpredictable to a degree, quantifiable pressure experienced by hospitals can be anticipated according to models incorporating systematic temporal patterns. In the context of finite resources for healthcare services, these findings could optimise staffing schedules and inform resource utilisation. PMID- 27460831 TI - Effects of drop height and surface instability on neuromuscular activation during drop jumps. AB - The purpose of this study was to examine whether drop height-induced changes in leg muscle activity during drop jumps (DJ) are additionally modulated by surface condition. Twenty-four healthy participants (23.7 +/- 1.8 years) performed DJs on a force plate on stable, unstable, and highly unstable surfaces using different drop heights (i.e., 20 cm, 40 cm, 60 cm). Electromyographic (EMG) activity of soleus (SOL), gastrocnemius (GM), tibialis anterior (TA) muscles and coactivation of TA/SOL and TA/GM were analyzed for time intervals 100 ms prior to ground contact (preactivation) and 30-60 ms after ground contact [short latency response (SLR)]. Increasing drop heights resulted in progressively increased SOL and GM activity during preactivation and SLR (P < 0.01; 1.01 <= d <= 5.34) while TA/SOL coactivation decreased (P < 0.05; 0.51 <= d <= 3.01). Increasing surface instability produced decreased activities during preactivation (GM) and SLR (GM, SOL) (P < 0.05; 1.36 <= d <= 4.30). Coactivation increased during SLR (P < 0.05; 1.50 <= d <= 2.58). A significant drop height * surface interaction was observed for SOL during SLR. Lower SOL activity was found on unstable compared to stable surfaces for drop heights >=40 cm (P < 0.05; 1.25 <= d <= 2.12). Findings revealed that instability-related changes in activity of selected leg muscles are minimally affected by drop height. PMID- 27460832 TI - The dispositions of things: the non-human dimension of power and ethics in patient-centred medicine. AB - This article explores power relations between clinicians, patients and families as clinicians engage in patient-centred ethical work. Specifically, we draw on actor-network theory to interrogate the role of non-human elements in distributing power relations in clinical settings, as clinicians attempt to manage the expectations of patients and families. Using the activities of a multidisciplinary team providing deep brain stimulation to children with severe movement disorders as an example, we illustrate how a patient-centred tool is implicated in establishing relations that constitute four modes of power: 'power over', 'power to', "power storage" and "power/discretion". We argue that understanding the role of non-human elements in structuring power relations can guide and inform bioethical discussions on the suitability of patient-centred approaches in clinical settings. PMID- 27460833 TI - Reply to: "HCV RNA kinetics on-treatment do not predict sustained virologic response in HCV genotype 3 patients receiving sofosbuvir and ribavirin". PMID- 27460834 TI - Reply to: "Therapeutic drug monitoring for sofosbuvir and daclatasvir in transplant recipients with chronic hepatitis C and advanced renal disease". PMID- 27460835 TI - HCV-RNA kinetics on-treatment do not predict sustained virologic response in HCV genotype 3 patients receiving sofosbuvir and ribavirin. PMID- 27460836 TI - Hunting for help in South America. PMID- 27460837 TI - Radiologic computed tomography features of Mycobacterium abscessus in cystic fibrosis. AB - INTRODUCTION: Mycobacterium abscessus infection in cystic fibrosis (CF) patients can lead to poor outcomes. Early diagnosis is important, but there are no studies outlining specific imaging features of M. abscessus in CF. OBJECTIVES: To describe the computed tomography (CT) findings of early M. abscessus infection in our CF population. METHODS: Thirteen CF patients with sputum cultures positive for M. abscessus from 2006 to 2013 were identified at our institution. Clinical characteristics including culture dates and lung function were reviewed. Positive cultures were classified as "disease" versus "colonization" based on published criteria. Chest CT scans were reviewed at times closest to initial infection, and features including bronchiectasis, mucous plugging, consolidation, ground glass opacities, nodules, and cavitation were evaluated. Brody scores were calculated to evaluate extent of CF lung disease. RESULTS: All patients had bronchiectasis and mucous plugging, with 10 of 13 (76.9%) in an upper lobe distribution. Consolidation was seen in 12 of 13 (92.3%) patients, 8 (61.5%) patients had nodules, and 5 (38.5%) with cavitation. The average Brody score was 59.5, which was no different than previously described CF cohorts without M. abscessus. There were no significant differences between subjects with disease versus colonization. CONCLUSION: The most common CT features of early M. abscessus in our CF population include bronchiectasis, mucus plugging, and consolidation, but the findings did not reveal a unique radiologic signature. CT at this initial time point may not distinguish early M. abscessus infection from background lung disease or mycobacterial colonization in CF patients. PMID- 27460838 TI - Corrigendum to ''Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2'' [Free Radic. Biol. Med. 89 (2015) 431-42]. PMID- 27460839 TI - High-Throughput Detection of Thiamine Using Periplasmic Binding Protein-Based Biorecognition. AB - Although antibodies and aptamers are commonly used bioaffinity recognition elements, they are not available for many important analytes. As an alternative, we demonstrate use of a periplasmic binding protein (PBP) to provide high affinity recognition for thiamine (vitamin B1), an analyte of great importance to human and environmental health for which, like so many other small molecules, no suitable biorecognition element is available. We demonstrate that with an appropriate competitive strategy, a highly sensitive (limit of detection of 0.5 nM) and specific bioassay for thiamine and its phosphorylated derivatives can be designed. The high-throughput method relies upon the thiamine periplasmic binding protein (TBP) from Escherichia coli for thiamine biorecognition and dye encapsulating liposomes for signal-enhancement. A thiamine monosuccinate-PEG biotin derivative was synthesized to serve as an immobilized competitor that overcame constraints imposed by the deep binding cleft and structural recognition requirements of PBPs. The assay was applied to ambient environmental samples with high reproducibility. These findings demonstrate that PBPs can serve as highly specific and sensitive affinity recognition elements in bioanalytical assay formats, thereby opening up the field of affinity sensors to a new range of analytes. PMID- 27460840 TI - Predictive factors for recurrence in T2N0 and T3N0 gastric cancer patients. AB - PURPOSE: Adjuvant chemotherapy is an indispensable component of treatment for preventing recurrence in advanced gastric cancer patients after macroscopically complete tumor resection (R0). However, the efficacy of this treatment for patients with T2N0 and T3N0 gastric cancer is not well characterized. METHODS: This study examined 1019 T1, 126 T2N0, and 67 T3N0 gastric adenocarcinoma patients who underwent gastrectomies at our institution between 1975 and 2005 to determine the predictive factors for recurrence in T2N0 and T3N0 gastric cancer patients. RESULTS: Among 193 T2N0 and T3N0 patients, 14 patients (7.3 %) have recurred. The prevalence of ly2/3 and v2/3 was significantly higher in patients with recurrence compared with those without recurrence. The prognosis for either T2N0 or T3N0 gastric cancer patients was significantly worse than that for T1 gastric cancer patients. Multivariate analysis indicated that lymphatic and blood vessel invasion were independent prognostic indicators in T2N0 and T3N0 gastric cancer patients. Ten-year survival rates for T2N0 and T3N0 gastric cancer patients with both ly2/3 and v2/3, with either ly2/3 or v2/3, and without ly2/3 and v2/3 were 42.9, 86.1, and 96.7 %, respectively. T2N0 and T3N0 gastric cancer patients with both ly2/3 and v2/3 had a significantly worse prognosis than that of patients with either ly2/3 or v2/3 and those without ly2/3 and v2/3. CONCLUSIONS: Our data indicate that T2N0 and T3N0 patients with both ly2/3 and v2/3 have a high risk of recurrence. Therefore, adjuvant chemotherapy should be administered to these patients. PMID- 27460842 TI - Hagfish slime and mucin flow properties and their implications for defense. AB - When hagfish (Myxinidae) are attacked by predators, they form a dilute, elastic, and cohesive defensive slime made of mucins and protein threads. In this study we propose a link between flow behavior and defense mechanism of hagfish slime. Oscillatory rheological measurements reveal that hagfish slime forms viscoelastic networks at low concentrations. Mucins alone did not contribute viscoelasticity, however in shear flow, viscosity was observed. The unidirectional flow, experienced by hagfish slime during suction feeding by predators, was mimicked with extensional rheology. Elongational stresses were found to increase mucin viscosity. The resulting higher resistance to flow could support clogging of the attacker's gills. Shear flow in contrast decreases the slime viscosity by mucin aggregation and leads to a collapse of the slime network. Hagfish may benefit from this collapse when trapped in their own slime and facing suffocation by tying a sliding knot with their body to shear off the slime. This removal could be facilitated by the apparent shear thinning behavior of the slime. Therefore hagfish slime, thickening in elongation and thinning in shear, presents a sophisticated natural high water content gel with flow properties that may be beneficial for both, defense and escape. PMID- 27460841 TI - A novel small molecule liver X receptor transcriptional regulator, nagilactone B, suppresses atherosclerosis in apoE-deficient mice. AB - AIMS: Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. We hypothesized that nagilactone B (NLB), a small molecule extracted from the root bark of Podocarpus nagi (Podocarpaceae), suppresses atherosclerosis in an atherosclerotic mouse model. METHODS AND RESULTS: Male apoE-deficient mice on C57BL/6J background received NLB (10 and 30 mg/kg) for 12 weeks. Compared with the model group, NLB treatment (10 and 30 mg/kg) significantly reduced en face lesions of total aorta areas. In RAW264.7 cells, NLB significantly ameliorated cholesterol accumulation in macrophages via enhancing apolipoprotein A-I and HDL-mediated cholesterol efflux. Mechanistically, NLB induced messenger RNA and protein expression of the ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 and THP-1 cells. Liver X receptor (LXR) site mutations in the mouse ABCA1 promoter abrogated NLB-mediated luciferase reporter activity. LXRalpha and LXRbeta small interfering RNA suppressed NLB-mediated induction of ABCA1 expression. Consistent with in vitro results, NLB induced ABCA1 expression and suppressed macrophage areas in the aortic sinus. Moreover, NLB treatment did not induce the protein expression of LXR in liver. Hepatic and intestinal cholesterol accumulation was significantly alleviated on NLB treatment. Besides, NLB significantly improved plasma lipid profiles in apoE-deficient mice. CONCLUSION: Selective LXR activation in macrophages with NLB induces ABCA1- and ABCG1-mediated cholesterol efflux while exerting minimal effects on lipogenesis and lipid accumulation in liver, resulting in regression of atherosclerosis, and therefore might be a promising strategy for therapeutics. PMID- 27460843 TI - Cost analysis of minimally invasive hysterectomy vs open approach performed by a single surgeon in an Italian center. AB - Despite the rapid uptake of robotic surgery, the effectiveness of robotically assisted hysterectomy (RAH) remains uncertain, due to the costs widely variable. Observed the different related costs of robotic procedures, in different countries, we performed a detailed economic analysis of the cost of RAH compared with total laparoscopic (TLH) and open hysterectomy (OH). The three surgical routes were matched according to age, BMI, and comorbidities. Hysterectomy costs were collected prospectively from September 2014 to September 2015. Direct costs were determined by examining the overall medical pathway for each type of intervention. Surgical procedure cost for RAH was ?3598 compared with ?912 for TLH and ?1094 for OH. The cost of the robot-specific supplies was ?2705 per intervention. When considering overall medical surgical care, the patient treatment average cost of a RAH was ?4695 with a hospital stay (HS) of 2 days (range 2-4) compared with ?2053 for TLH and ?2846 for OH. The main driver of additional costs is disposable instruments of the robot, which is not compensated by the hospital room costs and by an experienced team staff. Implementation of strategies to reduce the cost of robotic instrumentation is due. No significant cost difference among the three procedures was observed; however, despite the optimal operative time, the experienced, surgeon and the lower HS, RAH resulted 2, 3 times and 1, 6 times more expensive in our institution than TLH and OH, respectively. PMID- 27460844 TI - Post-chemotherapy robotic bilateral retroperitoneal lymph node dissection using a novel single-dock technique. AB - There have been no previous reports of post-chemotherapy robotic bilateral retroperitoneal lymph node dissection (RPLND) using a single-dock technique. One deterrent of robotic RPLND is that accessing bilateral retroperitoneal spaces requires patient reposition and surgical robot redocking, therefore increasing operative time. Herein we provide the first step-by-step description of a single dock technique for robotic bilateral RPLND in the post-chemotherapy setting. We describe port placement and technique for robot positioning to optimize access to bilateral retroperitoneal spaces with a single dock. We also demonstrate the feasibility of sparing the inferior mesenteric artery when utilizing this approach. This single-dock approach was used on two patients at our institution who had residual paracaval masses following chemotherapy for metastatic testicular cancer. Mean operative time was 6 h, and neither patient had significant blood loss or suffered from any peri-operative complications. PMID- 27460845 TI - ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC. AB - Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. We previously reported that ACE2 overexpression may inhibit cell growth and vascular endothelial growth factor (VEGF) production in vitro and in vivo. In the present study, we investigated the effect of ACE2 on tumor-associated angiogen-esis after the development of acquired platinum resistance in non-small cell lung cancer (NSCLC). Four NSCLC cell lines, A549, LLC, A549-DDP and LLC-DDP, were used in vitro, while A549 and A549-DDP cells were used in vivo. A549-DDP and LLC-DDP cells were newly established at our institution as acquired platinum-resistant sublines by culturing the former parent cells in cisplatin (CDDP)-containing conditioned medium for 6 months. These platinum-resistant cells showed significantly higher angiotensin II type 1 receptor (AT1R), ACE and VEGF production and lower ACE2 expression than their corresponding parent cells. We showed that ACE2 overexpression inhibited the production of VEGF in vitro and in vivo compared to their corresponding parent cells. We also found that ACE2 overexpression reduced the expression of AT1R and ACE. Additionally, we confirmed that ACE2 overexpres-sion inhibited cell growth and VEGF production while simultaneously suppressing ACE and AT1R expression in human lung cancer xenografts. Our findings indicate that ACE2 overexpression may potentially suppress angiogenesis in NSCLC after the development of acquired platinum resistance. PMID- 27460846 TI - Taylor Dispersion Analysis as a promising tool for assessment of peptide-peptide interactions. AB - Protein-protein and peptide-peptide (self-)interactions are of key importance in understanding the physiochemical behavior of proteins and peptides in solution. However, due to the small size of peptide molecules, characterization of these interactions is more challenging than for proteins. In this work, we show that protein-protein and peptide-peptide interactions can advantageously be investigated by measurement of the diffusion coefficient using Taylor Dispersion Analysis. Through comparison to Dynamic Light Scattering it was shown that Taylor Dispersion Analysis is well suited for the characterization of protein-protein interactions of solutions of alpha-lactalbumin and human serum albumin. The peptide-peptide interactions of three selected peptides were then investigated in a concentration range spanning from 0.5mg/ml up to 80mg/ml using Taylor Dispersion Analysis. The peptide-peptide interactions determination indicated that multibody interactions significantly affect the PPIs at concentration levels above 25mg/ml for the two charged peptides. Relative viscosity measurements, performed using the capillary based setup applied for Taylor Dispersion Analysis, showed that the viscosity of the peptide solutions increased with concentration. Our results indicate that a viscosity difference between run buffer and sample in Taylor Dispersion Analysis may result in overestimation of the measured diffusion coefficient. Thus, Taylor Dispersion Analysis provides a practical, but as yet primarily qualitative, approach to assessment of the colloidal stability of both peptide and protein formulations. PMID- 27460847 TI - John Stuart Garrow, MD, PhD, FRCP(E), FRCP (London) (1929-2016). PMID- 27460848 TI - Effect of uterine contractions on fetal heart rate in pregnancy: a prospective observational study. AB - INTRODUCTION: The new Holter monitoring technology enables long-term electrocardiographic recording of the fetal heart rate without discomfort for the mother. The aim of the study was to assess the feasibility of a fetal Holter monitor. This technology was further used to study fetal heart rate outside the hospital setting during normal daily activities and to test the hypothesis that uterine activity during pregnancy influences fetal heart rate. MATERIAL AND METHODS: Prospective observational study including 12 healthy pregnant women at 20-40 weeks of gestation. Data were collected using the Monica AN24 system. Outcome measures were fetal heart rate, maternal heart rate, and uterine activity categorized according to the strength of the electrohysterographic signal. RESULTS: The recordings had a median length of 18.8 h, and fetal heart rate and maternal heart rate were obtained with success rates of 73.1 and 99.9%, respectively. Uterine activity was found to affect fetal heart rate in all participants. Compared with the basal tone and mild levels of uterine activity, moderate and strong levels of uterine activity were associated with increases in fetal heart rate of 4.0 and 5.7 beats/min, respectively. At night, the corresponding increases were 4.9 and 7.6 beats/min. Linear correlations were found between maternal heart rate and fetal heart rate in 11 of the 12 cases, with a mean coefficient beta of 0.189. Both maternal heart rate and fetal heart rate exhibited a diurnal pattern, with lower heart rates being recorded at night. CONCLUSIONS: Uterine activity during pregnancy is associated with a graded response in fetal heart rate and may represent a physiological challenge for the development and adaptation of the fetal cardiovascular system. PMID- 27460849 TI - Fat-Derived Stromal Vascular Fraction Cells Enhance the Bone-Forming Capacity of Devitalized Engineered Hypertrophic Cartilage Matrix. AB - : : Engineered and devitalized hypertrophic cartilage (HC) has been proposed as bone substitute material, potentially combining the features of osteoinductivity, resistance to hypoxia, capacity to attract blood vessels, and customization potential for specific indications. However, in comparison with vital tissues, devitalized HC grafts have reduced efficiency of bone formation and longer remodeling times. We tested the hypothesis that freshly harvested stromal vascular fraction (SVF) cells from human adipose tissue-which include mesenchymal, endothelial, and osteoclastic progenitors-enhance devitalized HC remodeling into bone tissue. Human SVF cells isolated from abdominal lipoaspirates were characterized cytofluorimetrically. HC pellets, previously generated by human bone marrow-derived stromal cells and devitalized by freeze/thaw, were embedded in fibrin gel with or without different amounts of SVF cells and implanted either ectopically in nude mice or in 4-mm-diameter calvarial defects in nude rats. In the ectopic model, SVF cells added to devitalized HC directly contributed to endothelial, osteoblastic, and osteoclastic populations. After 12 weeks, the extent of graft vascularization and amount of bone formation increased in a cell-number-dependent fashion (up to, respectively, 2.0-fold and 2.9-fold using 12 million cells per milliliter of gel). Mineralized tissue volume correlated with the number of implanted, SVF-derived endothelial cells (CD31+ CD34+ CD146+). In the calvarial model, SVF activation of HC using 12 million cells per milliliter of gel induced efficient merging among implanted pellets and strongly enhanced (7.3-fold) de novo bone tissue formation within the defects. Our findings outline a bone augmentation strategy based on off-the-shelf devitalized allogeneic HC, intraoperatively activated with autologous SVF cells. SIGNIFICANCE: This study validates an innovative bone substitute material based on allogeneic hypertrophic cartilage that is engineered, devitalized, stored, and clinically used, together with autologous cells, intraoperatively derived from a lipoaspirate. The strategy was tested using human cells in an ectopic model and an orthotopic implantation model, in immunocompromised animals. PMID- 27460850 TI - Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. AB - : : Paracrine signaling by bone-marrow-derived mesenchymal stem cells (MSCs) plays a major role in tissue repair. Although the production of regulatory cytokines by MSC transplantation is a critical modulator of tissue regeneration, we focused on exosomes, which are extracellular vesicles that contain proteins and nucleic acids, as a novel additional modulator of cell-to-cell communication and tissue regeneration. To address this, we used radiologic imaging, histological examination, and immunohistochemical analysis to evaluate the role of exosomes isolated from MSC-conditioned medium (CM) in the healing process in a femur fracture model of CD9-/- mice, a strain that is known to produce reduced levels of exosomes. We found that the bone union rate in CD9-/- mice was significantly lower than wild-type mice because of the retardation of callus formation. The retardation of fracture healing in CD9-/- mice was rescued by the injection of exosomes, but this was not the case after the injection of exosomes free conditioned medium (CM-Exo). The levels of the bone repair-related cytokines, monocyte chemotactic protein-1 (MCP-1), MCP-3, and stromal cell derived factor-1 in exosomes were low compared with levels in CM and CM-Exo, suggesting that bone repair may be in part mediated by other exosome components, such as microRNAs. These results suggest that exosomes in CM facilitate the acceleration of fracture healing, and we conclude that exosomes are a novel factor of MSC paracrine signaling with an important role in the tissue repair process. SIGNIFICANCE: This work focuses on exosomes, which are extracellular vesicles, as a novel additional modulator of cell-to-cell communication. This study evaluated the role of exosomes isolated from mesenchymal stem cell (MSC) conditioned medium (MSC-CM) in the fracture-healing process of CD9-/- mice, a strain that is known to produce reduced levels of exosomes. Retardation of fracture healing in CD9-/- mice was rescued by the injection of MSC exosomes, but this was not the case after the injection of exosome-free CM. This study finds that MSC exosomes are a novel factor of MSC paracrine signaling, with an important role in the tissue repair process. PMID- 27460851 TI - miR-145 Regulates Diabetes-Bone Marrow Stromal Cell-Induced Neurorestorative Effects in Diabetes Stroke Rats. AB - : : In rats with type 1 diabetes (T1DM), the therapeutic effects and underlying mechanisms of action of stroke treatment were compared between bone-marrow stromal cells (BMSCs) derived from T1DM rats (DM-BMSCs) and BMSCs derived from normal rats (Nor-BMSCs). The novel role of microRNA-145 (miR-145) in mediating DM BMSC treatment-induced benefits was also investigated. T1DM rats (n = 8 per group) underwent 2 hours of middle cerebral artery occlusion (MCAo) and were treated 24 hours later with the one of the following (5 * 106 cells administered i.v.): (a) phosphate-buffered saline (PBS); (b) Nor-BMSCs; (c) DM-BMSCs; (d) DM BMSCs with miR-145 overexpression (miR-145+/+DM-BMSCs); or (e) Nor-BMSCs with miR 145 knockdown. Evaluation of functional outcome, vascular and white-matter remodeling and microRNA expression was made, and in vitro studies were performed. In vitro, DM-BMSCs exhibited decreased miR-145 expression and increased survival compared with Nor-BMSCs. Capillary tube formation and axonal outgrowth in cultured primary cortical neurons were significantly increased by DM-BMSC conditioned medium compared with Nor-BMSCs, and significantly decreased by miR 145+/+DM-BMSC-conditioned medium compared with DM-BMSCs. In T1DM rats in which stroke had been induced (T1DM stroke rats), DM-BMSC treatment significantly improved functional outcome, increased vascular and white matter remodeling, decreased serum miR-145 expression, and increased expression of the miR-145 target genes adenosine triphosphate-binding cassette transporter 1 (ABCA1) and insulin-like growth factor 1 receptor (IGFR1), compared with Nor-BMSCs or PBS treatment. However, miR-145+/+DM-BMSCs significantly increased serum miR-145 expression and decreased brain ABCA1 and IGFR1 expression, as well as attenuated DM-BMSC-induced neurorestorative effects in T1DM-MCAo rats. DM-BMSCs exhibited decreased miR-145 expression. In T1DM-MCAo rats, DM-BMSC treatment improved functional outcome and promoted neurorestorative effects. The miR-145/ABCA1/IGFR1 pathway may contribute to the enhanced DM-BMSCs' functional and neurorestorative effects in T1DM stroke rats. SIGNIFICANCE: In rats with type 1 diabetes (T1DM), the therapeutic effects and underlying mechanisms of action of stroke treatment were compared between bone-marrow stromal cells (BMSCs) derived from T1DM rats (DM-BMSCs) and BMSCs derived from normal rats (Nor-BMSCs). In vitro, DM-BMSCs and derived exosomes decreased miR-145 expression and increased DM-BMSC survival, capillary tube formation, and axonal outgrowth, compared with Nor-BMSCs; these effects were decreased by DM-BMSCs in which miR-145 was overexpressed. In vivo, compared with Nor-BMSC or phosphate-buffered saline treatment, DM-BMSC treatment improved functional outcome and vascular and white matter remodeling, decreased serum miR-145 expression, and increased expression of the miR-145 target genes ABCA1 and IGFR1. microRNA-145 mediated the benefits induced by DM-BMSC treatment. PMID- 27460852 TI - Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling. AB - : : Chondrogenic differentiation of bone marrow-derived mesenchymal stromal/stem cells (MSCs) can be induced by presenting morphogenetic factors or soluble signals but typically suffers from limited efficiency, reproducibility across primary batches, and maintenance of phenotypic stability. Considering the avascular and hypoxic milieu of articular cartilage, we hypothesized that sole inhibition of angiogenesis can provide physiological cues to direct in vivo differentiation of uncommitted MSCs to stable cartilage formation. Human MSCs were retrovirally transduced to express a decoy soluble vascular endothelial growth factor (VEGF) receptor-2 (sFlk1), which efficiently sequesters endogenous VEGF in vivo, seeded on collagen sponges and immediately implanted ectopically in nude mice. Although naive cells formed vascularized fibrous tissue, sFlk1-MSCs abolished vascular ingrowth into engineered constructs, which efficiently and reproducibly developed into hyaline cartilage. The generated cartilage was phenotypically stable and showed no sign of hypertrophic evolution up to 12 weeks. In vitro analyses indicated that spontaneous chondrogenic differentiation by blockade of angiogenesis was related to the generation of a hypoxic environment, in turn activating the transforming growth factor-beta pathway. These findings suggest that VEGF blockade is a robust strategy to enhance cartilage repair by endogenous or grafted mesenchymal progenitors. This article outlines the general paradigm of controlling the fate of implanted stem/progenitor cells by engineering their ability to establish specific microenvironmental conditions rather than directly providing individual morphogenic cues. SIGNIFICANCE: Chondrogenic differentiation of mesenchymal stromal/stem cells (MSCs) is typically targeted by morphogen delivery, which is often associated with limited efficiency, stability, and robustness. This article proposes a strategy to engineer MSCs with the capacity to establish specific microenvironmental conditions, supporting their own targeted differentiation program. Sole blockade of angiogenesis mediated by transduction for sFlk-1, without delivery of additional morphogens, is sufficient for inducing MSC chondrogenic differentiation. The findings represent a relevant step forward in the field because the method allowed reducing interdonor variability in MSC differentiation efficiency and, importantly, onset of a stable, nonhypertrophic chondrocyte phenotype. PMID- 27460853 TI - Human Endomyocardial Biopsy Specimen-Derived Stromal Cells Modulate Angiotensin II-Induced Cardiac Remodeling. AB - : : Cardiac-derived adherent proliferating cells (CardAPs) are cells derived from human endomyocardial biopsy specimens; they share several properties with mesenchymal stromal cells. The aims of this study were to evaluate whether intramyocardial injection of CardAPs modulates cardiac fibrosis and hypertrophy in a mouse model of angiotensin II (Ang II)-induced systolic heart failure and to analyze underlying mechanisms. Intramyocardial application of 200,000 CardAPs improved left ventricular function. This was paralleled by a decline in left ventricular remodeling, as indicated by a reduction in cardiac fibrosis and hypertrophy. CardAPs reduced the ratio of the left ventricle to body weight and cardiac myosin expression (heavy chain), and decreased the Ang II-induced phosphorylation state of the cardiomyocyte hypertrophy mediators Akt, extracellular-signal regulated kinase (ERK) 1, and ERK2. In accordance with the antifibrotic and antihypertrophic effects of CardAPs shown in vivo, CardAP supplementation with cardiac fibroblasts decreased the Ang II-induced reactive oxygen species production, alpha-SMA expression, fibroblast proliferation, and collagen production. Coculture of CardAPs with HL-1 cardiomyocytes downregulated the Ang II-induced expression of myosin in HL-1. All antifibrotic and antihypertrophic features of CardAPs were mediated in a nitric oxide- and interleukin (IL)-10-dependent manner. Moreover, CardAPs induced a systemic immunomodulation, as indicated by a decrease in the activity of splenic mononuclear cells and an increase in splenic CD4CD25FoxP3, CD4-IL-10, and CD8-IL 10 T-regulatory cells in Ang II mice. Concomitantly, splenocytes from Ang II CardAPs mice induced less collagen in fibroblasts compared with splenocytes from Ang II mice. We conclude that CardAPs improve Ang II-induced cardiac remodeling involving antifibrotic and antihypertrophic effects via paracrine actions and immunomodulatory properties. SIGNIFICANCE: Despite effective pharmacological treatment with angiotensin II type I receptor antagonists or angiotensin II converting enzyme inhibitors, morbidity and mortality associated with heart failure are still substantial, prompting the search of novel therapeutic strategies. There is accumulating evidence supporting the use of cell therapy for cardiac repair. This study demonstrates that cells derived from human endomyocardial biopsies, cardiac-derived adherent proliferating cells (CardAPs), have the potential to reduce angiotensin II-induced cardiac remodeling and improve left ventricular function in angiotensin II mice. The mechanism involves antifibrotic and antihypertrophic effects via paracrine actions and immunomodulatory properties. These findings support the potential of CardAPs for the treatment of heart failure. PMID- 27460854 TI - Smooth Muscle Progenitor Cells Derived From Human Pluripotent Stem Cells Induce Histologic Changes in Injured Urethral Sphincter. AB - : : Data suggest that myoblasts from various sources, including bone marrow, skeletal muscle, and adipose tissue, can restore muscle function in patients with urinary incontinence. Animal data have indicated that these progenitor cells exert mostly a paracrine effect on the native tissues rather than cell regeneration. Limited knowledge is available on the in vivo effect of human stem cells or muscle progenitors on injured muscles. We examined in vivo integration of smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs). pSMCs were derived from a human embryonic stem cell line (H9-ESCs) and two induced pluripotent stem cell (iPSC) lines. pSMCs were injected periurethrally into urethral injury rat models (2 * 106 cells per rat) or intramuscularly into severe combined immunodeficiency mice. Histologic and quantitative image analysis revealed that the urethras in pSMC-treated rats contained abundant elastic fibers and thicker muscle layers compared with the control rats. Western blot confirmed increased elastin/collagen III content in the urethra and bladder of the H9-pSMC-treated rats compared with controls. iPSC pSMC treatment also showed similar trends in elastin and collagen III. Human elastin gene expression was not detectable in rodent tissues, suggesting that the extracellular matrix synthesis resulted from the native rodent tissues rather than from the implanted human cells. Immunofluorescence staining and in vivo bioluminescence imaging confirmed long-term engraftment of pSMCs into the host urethra and the persistence of the smooth muscle phenotype. Taken together, the data suggest that hPSC-derived pSMCs facilitate restoration of urethral sphincter function by direct smooth muscle cell regeneration and by inducing native tissue elastin/collagen III remodeling. SIGNIFICANCE: The present study provides evidence that a pure population of human smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs) (human embryonic stem cells and patient induced pluripotent stem cells) restores urethral sphincter function by two mechanisms: modulation of extracellular matrix protein metabolism in vivo and pSMC proliferation and differentiation into smooth muscle cells to regenerate the muscle layer in the lower urinary tract. These findings on the in vivo effects of human pSMCs should aid in optimizing regenerative therapies using human myoblasts. PMID- 27460856 TI - Hydrogen isotope exchange with highly active iridium(I) NHC/phosphine complexes: a comparative counterion study. AB - Herein, we present a range of substrates that undergo hydrogen isotope exchange with an iridium(I) N-heterocyclic carbene/phosphine complex bearing the less coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate counterion and compare these with labelling using the equivalent, more established hexafluorophosphate complex. The changes in reactivity and selectivity of these complexes in a series of solvents are examined. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27460855 TI - Biodistribution and Clearance of Human Mesenchymal Stem Cells by Quantitative Three-Dimensional Cryo-Imaging After Intravenous Infusion in a Rat Lung Injury Model. AB - : : Cell tracking is a critical component of the safety and efficacy evaluation of therapeutic cell products. To date, cell-tracking modalities have been hampered by poor resolution, low sensitivity, and inability to track cells beyond the shortterm. Three-dimensional (3D) cryo-imaging coregisters fluorescent and bright-field microcopy images and allows for single-cell quantification within a 3D organ volume. We hypothesized that 3D cryo-imaging could be used to measure cell biodistribution and clearance after intravenous infusion in a rat lung injury model compared with normal rats. A bleomycin lung injury model was established in Sprague-Dawley rats (n = 12). Human mesenchymal stem cells (hMSCs) labeled with QTracker655 were infused via jugular vein. After 2, 4, or 8 days, a second dose of hMSCs labeled with QTracker605 was infused, and animals were euthanized after 60, 120, or 240 minutes. Lungs, liver, spleen, heart, kidney, testis, and intestine were cryopreserved, followed by 3D cryo-imaging of each organ. At 60 minutes, 82% +/- 9.7% of cells were detected; detection decreased to 60% +/- 17% and 66% +/- 22% at 120 and 240 minutes, respectively. At day 2, 0.06% of cells were detected, and this level remained constant at days 4 and 8 postinfusion. At 60, 120, and 240 minutes, 99.7% of detected cells were found in the liver, lungs, and spleen, with cells primarily retained in the liver. This is the first study using 3D cryo-imaging to track hMSCs in a rat lung injury model. hMSCs were retained primarily in the liver, with fewer detected in lungs and spleen. SIGNIFICANCE: Effective bench-to-bedside clinical translation of cellular therapies requires careful understanding of cell fate through tracking. Tracking cells is important to measure cell retention so that delivery methods and cell dose can be optimized and so that biodistribution and clearance can be defined to better understand potential off-target toxicity and redosing strategies. This article demonstrates, for the first time, the use of three-dimensional cryo imaging for single-cell quantitative tracking of intravenous infused clinical grade mesenchymal stem cells in a clinically relevant model of lung injury. The important information learned in this study will help guide future clinical and translational stem cell therapies for lung injuries. PMID- 27460857 TI - Robust estimation of partially linear models for longitudinal data with dropouts and measurement error. AB - Outliers, measurement error, and missing data are commonly seen in longitudinal data because of its data collection process. However, no method can address all three of these issues simultaneously. This paper focuses on the robust estimation of partially linear models for longitudinal data with dropouts and measurement error. A new robust estimating equation, simultaneously tackling outliers, measurement error, and missingness, is proposed. The asymptotic properties of the proposed estimator are established under some regularity conditions. The proposed method is easy to implement in practice by utilizing the existing standard generalized estimating equations algorithms. The comprehensive simulation studies show the strength of the proposed method in dealing with longitudinal data with all three features. Finally, the proposed method is applied to data from the Lifestyle Education for Activity and Nutrition study and confirms the effectiveness of the intervention in producing weight loss at month 9. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27460858 TI - Comparison of placental elasticity in normal and pre-eclamptic pregnant women by acoustic radiation force impulse elastosonography. AB - AIM: The aim of this research was to study and compare placental elasticity with acoustic radiation force impulse (ARFI) elastography in pre-eclamptic and normal pregnancies. METHODS: A total of 107 singleton pregnancies in the third trimester (38 healthy control subjects, 34 patients with gestational hypertension, and 35 pre-eclampsia patients) were included in the study. ARFI elastography was used to determine the placental elasticity in the three predetermined regions of the placenta (the fetal edge, maternal edge, and central part of the placenta). The obstetrical data regarding grayscale and Doppler ultrasonography and perinatal outcomes were reviewed. A mean placental shear wave velocity cut-off value that predicts the presence of pre-eclampsia was determined. RESULTS: The shear wave elasticity values in the pre-eclampsia group in all three regions were significantly higher than in the gestational hypertension and healthy control groups (P = 0.001). The most significant difference was found in the peripheral edge of the placenta from the fetal surface in the pre-eclampsia group (P = 0.001). CONCLUSION: The stiffness of the placenta determined by the ARFI technique is significantly higher in pre-eclampsia patients. ARFI elastography of the placenta might be used as a non-invasive and easy method in the diagnosis and evaluation of pre-eclampsia as a supplement to the already existing methods. PMID- 27460859 TI - Medical marijuana legalization and cigarette and marijuana co-use in adolescents and adults. AB - BACKGROUND: Medical marijuana legalization is associated with a higher prevalence of marijuana use which may affect cigarette use and nicotine dependence in co users. In the present study, we examined relationships between statewide legalization of medical marijuana and prevalence of cigarette and marijuana co use and nicotine dependence in co-using adolescents and adults. METHODS: Data were analyzed from the 2013 National Survey on Drug Use and Health. We compared cigarette and marijuana co-use in the past 30days across age categories (12-64 years) by statewide medical marijuana legalization. Logistic regression models were used to estimate the odds of having nicotine dependence among current cigarette smokers who also reported past 30-day marijuana use and "ever but not current" marijuana use (vs. "never" use) adjusting for covariates including statewide legalization of medical marijuana. RESULTS: Overall, 5.1% of the sample reported past 30-day cigarette and marijuana co-use and a higher proportion of co users resided in states where medical marijuana was legal compared to illegal (5.8% vs. 4.8%; p=0.0011). Co-use was associated with greater odds of having nicotine dependence compared to cigarette-only use across age categories. Odds were highest and up to 3-times higher in adolescents aged 12-17 years (OR=3.54; 95%CI: 1.81-6.92) and adults aged 50-64 years (OR=3.08; CI: 1.45-6.55). CONCLUSION: Marijuana policy could inadvertently affect cigarette and marijuana co-use and pose challenges to tobacco cessation. PMID- 27460860 TI - Reasons for using flavored liquids among electronic cigarette users: A concept mapping study. AB - BACKGROUND: Electronic cigarettes (ECIGs) aerosolize liquids often containing flavorants for inhalation. Few studies have examined the role of flavors in ECIG use. This study's purpose was to examine reasons for flavored ECIG use using a mixed-method approach, concept mapping (CM). METHODS: Forty-six past 30-day adult ECIG users recruited from vape forums/conferences completed three online CM tasks. Participants brainstormed responses to a prompt: "A specific reason I use flavored e-liquid in my electronic cigarette product is...". The final 107 brainstormed statements were sorted by participants into groups of similar content. Participants rated each statement on a 7-point scale (1-Definitely NOT a reason to 7-Definitely a reason) based on a prompt: "This is a specific reason why I used flavored e-liquid in my electronic cigarette product in the past month." A cluster map was generated from participants' sorting and ratings using CM statistical software. Cluster mean ratings were compared. RESULTS: Analysis revealed five clusters of reasons for flavored ECIG use including Increased Satisfaction/Enjoyment, Better Feel/Taste than Cigarettes, Variety/Customization, Food Craving Suppression, and Social Impacts. Statements in the Increased Satisfaction/Enjoyment and Better Feel/Taste than Cigarettes clusters were rated significantly higher than statements from other clusters (ps<0.05). Some statements indicated flavors were perceived as masking agents for nicotine or other bad tastes associated with cigarette smoking making ECIG use more palatable. CONCLUSIONS: Flavored ECIGs are used for many reasons. Some statements suggested flavors may increase the rewarding and possible addictive effects of ECIGs. These results support continued examination of the role of flavors and ECIG use behaviors. PMID- 27460862 TI - Comparison of KP1019 and NAMI-A in tumour-mimetic environments. AB - NAMI-A and KP1019 are Ru(III)-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru(II). The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic and necrotic tumour tissues were modelled by multicellular spheroids of SH-SY5Y human neuroblastoma cells of various diameters (50-800 MUm). The variation in spheroid environment was confirmed with pimonidazole staining. Laser-ablation inductively coupled plasma mass spectrometry showed KP1019 and NAMI-A penetration into the spheroid hypoxic region. XANES showed that the speciation of NAMI-A biotransformation products did not change significantly as hypoxia levels increased. KP1019 metabolites showed a correlation between the degree of spheroid hypoxia and the Ru K-edge energy consistent with either partial reduction of Ru(III) to Ru(II) in tumour microenvironments, increased S/Cl coordination or a reduced fraction of polynuclear Ru species. EXAFS spectroscopy was undertaken in an attempt to distinguish between these scenarios but was inconclusive. PMID- 27460861 TI - A case of bullous pemphigoid induced by vildagliptin. AB - Bullous pemfigoid (BP), an autoimmune disorder, can also be induced by some medications. Vildagliptin is a new drug used to treat diabetes mellitus (DM). Recently, a few cases of vildagliptin-induced BP have been described in the literature. We report a patient with BP in which vildagliptin was thought to be as a possible causative agent. The awareness of BP development risk during gliptin therapy can prevent unnecessary usage of systemic drugs with serious side effects. PMID- 27460863 TI - Goblet-shaped pentanuclear lanthanide clusters assembled with a cyclen derivative ligand exhibiting slow magnetic relaxation. AB - Two coordination compounds with the formula Ln5(H2O)(OH)4(NO3)3(BZA)4L (Ln = Tb(3+) (1), Dy(3+) (2)) have been assembled in a one-pot synthesis from the tetrasubstituted cyclen derivative ligand N,N',N'',N'''-tetra(2-hydroxy-3-methoxy 5-methylbenzyl)-1,4,7,10-tetraazacyclododecane (H4L), Ln(NO3)3.xH2O (Ln = Tb(3+) (x = 6), Dy(3+) (x = 5)) and the auxiliary ligand benzoic acid (HBZA). Single crystal X-ray diffraction studies reveal that both compounds feature a novel homometallic appended cubane geometry. The magnetic study on 1 suggests the presence of anti-ferromagnetic interactions, whereas 2 exhibits weak ferromagnetic coupling. Under an applied dc field, 1 shows no out-of-phase alternating current (ac) signal whereas 2 shows slow-relaxation processes that correspond to an energy gap (Ea/kB) of 4.11 K and a pre-exponential factor (tau0) of 3.45 * 10(-5) s. PMID- 27460864 TI - Observations of newborn blue sharks Prionace glauca in shallow inshore waters of the north-east Atlantic Ocean. AB - The anomalous presence of numerous blue shark Prionace glauca neonates and juveniles in shallow inshore waters of Galicia, north-west Spain, during the summers of 2014 and 2015 is reported. Changes in oceanographic conditions, high recruitment events or changes in the pupping area are discussed as possible causes of this unusual behaviour. PMID- 27460865 TI - Hypolipidemic, antiobesity and cardioprotective effects of sardinelle meat flour and its hydrolysates in high-fat and fructose diet fed Wistar rats. AB - AIMS: The present study aims to evaluate the antiobesity, hypolipidemic and cardioprotective effects of fermented sardinelle (Sardinella aurita) protein hydrolysates (FSPHs) produced with two proteolytic bacteria, Bacillus subtilis A26 (FSPH-A26) and Bacillus amyloliquefaciens An6 (FSPH-An6). MAIN METHODS: Wistar rats were fed during 10weeks a standard laboratory diet, a high caloric diet (HCD) and a HCD coupled with the oral administration of sardinelle meat flour (SMF) or FSPHs. KEY FINDINGS: HCD caused hyperlipidemia and increased body weight (BW). The daily oral administration of FSPHs or SMF reduced the total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL c) serum levels, and increased the level of high-density lipoprotein cholesterol (HDL-c). Nevertheless, FSPHs were found to be more efficient than SMF. FSPHs also lowered hepatic TC and TG content and decreased the pancreatic lipase activity. Further, the administration of FSPHs or SMF decreased the BW gain, the food intake and the relative epididymal adipose tissue weight. FSPHs exhibited a potent cardioprotective effect against heart attack, which was demonstrated by returning atherogenic indexes to their normal levels and the conservation of standard histological structure of the heart and aorta. SIGNIFICANCE: The overall results indicate that FSPHs contained bioactive peptides which significantly attenuated hyperlipidemia, and might reduce the risk of cardiovascular disease (CVD) in rats fed HCD. PMID- 27460866 TI - An open-label, single-dose, phase 1 study of the absorption, metabolism and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia. AB - 1. Quizartinib absorption, metabolism and excretion were characterized in six healthy men receiving a single oral dose of 60 mg (~100 MUCi) of [14C] quizartinib. Blood, plasma, urine and faeces were collected <=336 h postdose. 2. Four hours postdose, maximum mean +/- SD blood radioactivity concentrations were 296 +/- 67.4 ng equivalents/g. A mean +/- SD of 1.64 +/- 0.482% and 76.3 +/- 6.23% of the dose was recovered in urine and faeces, respectively, within 336 h postdose. 3. Radio-detector high-performance liquid chromatography (radio-HPLC) and liquid chromatography-mass spectrometry (LC-MS) showed two main radioactive peaks in plasma, unchanged quizartinib and mono-oxidative metabolite, AC886. Five additional metabolites in plasma were identified by LC-MS, but low levels prevented radio-HPLC detection. Although unchanged quizartinib was the main radioactive component in faeces (mean, 4.0% of administered dose), 15 metabolites representing a mean of 1.0-3.5% of administered dose were found. Quizartinib was predominantly metabolized by phase I biotransformations (oxidation, reduction, dealkylation, deamination, hydrolysis and combinations thereof). 4. This study indicated that quizartinib was rapidly and orally bioavailable, extensively metabolized, with AC886 as the major circulating metabolite, and predominantly eliminated in faeces. Quizartinib was well tolerated in the subjects. PMID- 27460867 TI - The Molecular Mechanism of P2Y1 Receptor Activation. AB - Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1 R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 MUs all-atom long-timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1 R activation. PMID- 27460868 TI - Efficient double-quenching of electrochemiluminescence from CdS:Eu QDs by hemin graphene-Au nanorods ternary composite for ultrasensitive immunoassay. AB - A novel ternary composite of hemin-graphene-Au nanorods (H-RGO-Au NRs) with high electrocatalytic activity was synthesized by a simple method. And this ternary composite was firstly used in construction of electrochemiluminescence (ECL) immunosensor due to its double-quenching effect of quantum dots (QDs). Based on the high electrocatalytic activity of ternary complexes for the reduction of H2O2 which acted as the coreactant of QDs-based ECL, as a result, the ECL intensity of QDs decreased. Besides, due to the ECL resonance energy transfer (ECL-RET) strategy between the large amount of Au nanorods (Au NRs) on the ternary composite surface and the CdS:Eu QDs, the ECL intensity of QDs was further quenched. Based on the double-quenching effect, a novel ultrasensitive ECL immunoassay method for detection of carcinoembryonic antigen (CEA) which is used as a model biomarker analyte was proposed. The designed immunoassay method showed a linear range from 0.01 pg mL(-1) to 1.0 ng mL(-1) with a detection limit of 0.01 pg mL(-1). The method showing low detection limit, good stability and acceptable fabrication reproducibility, provided a new approach for ECL immunoassay sensing and significant prospect for practical application. PMID- 27460869 TI - Exploring the diversification mechanism of skeletal construction in representative natural product families. PMID- 27460870 TI - Nature as organic chemist. PMID- 27460871 TI - Selecting Appropriate Tests to Assess the Benefits of Bilateral Amplification With Hearing Aids. AB - The aim of this study was to investigate the effect of bilateral hearing aids (HA) in subjects with mild and moderate-to-severe hearing loss. This study was designed as a within-subject feasibility study. Bilateral HA use was assessed using different laboratory tests on speech reception, listening effort, noise tolerance, and localization. All data were evaluated with bilateral and unilateral HA fittings. Forty experienced bilateral HA users were included with hearing impairment ranging from mild to moderate-to-severe. Subjects were stratified into two groups based on the degree of hearing loss. Speech reception in noise, listening effort, and localization tests showed a bilateral benefit for the moderate-to-severely hearing-impaired subjects. A bilateral benefit was also observed for listening effort in the mildly hearing-impaired group. The assessment of listening effort shows promise as a measure of bilateral HA benefit for mild hearing impairment. Localization and speech reception in noise tests provide additional value for larger losses. The next step is to compare experienced unilateral with bilateral HA users. PMID- 27460872 TI - Structural and compositional dependence of the CdTexSe1-x alloy layer photoactivity in CdTe-based solar cells. AB - The published external quantum efficiency data of the world-record CdTe solar cell suggests that the device uses bandgap engineering, most likely with a CdTexSe1-x alloy layer to increase the short-circuit current and overall device efficiency. Here atom probe tomography, transmission electron microscopy and electron beam-induced current are used to clarify the dependence of Se content on the photoactive properties of CdTexSe1-x alloy layers in bandgap-graded CdTe solar cells. Four solar cells were prepared with 50, 100, 200 and 400 nm-thick CdSe layers to reveal the formation, growth, composition, structure and photoactivity of the CdTexSe1-x alloy with respect to the degree of Se diffusion. The results show that the CdTexSe1-x layer photoactivity is highly dependent on the crystalline structure of the alloy (zincblende versus wurtzite), which is also dependent on the Se and Te concentrations. PMID- 27460873 TI - The Healthy Children, Strong Families intervention promotes improvements in nutrition, activity, and body weight in American Indian families with young children - ERRATUM. PMID- 27460874 TI - The US as an example of how not to legalize marijuana? PMID- 27460875 TI - Base-Promoted Tandem Reaction Involving Insertion into Carbon-Carbon sigma-Bonds: Synthesis of Xanthone and Chromone Derivatives. AB - Tandem reactions using base-promoted processes have been developed for the synthesis of xanthone and chromone derivatives. The first examples of base promoted insertion reactions of isolated carbon-carbon triple bonds into carbon carbon sigma-bonds have been reported. Using these approaches, polycyclic structures can be prepared. This reaction has the potential to become a general synthetic protocol for the preparation of multi-substituted xanthones and chromones due to the abundance of easily accessible starting materials possessing diverse substituent groups. PMID- 27460876 TI - InterCardioRisk: a novel online tool for estimating doses of ionising radiation to occupationally-exposed medical staff and their associated health risks. AB - Those working in interventional cardiology and related medical procedures are potentially subject to considerable exposure to x-rays. Two types of tissue of particular concern that may receive considerable doses during such procedures are the lens of the eye and the brain. Ocular radiation exposure results in lens changes that, with time, may progress to partial or total lens opacification (cataracts). In the early stages, such opacities do not result in visual disability; the severity of such changes tends to increase progressively with dose and time until vision is impaired and cataract surgery is required. Scattered radiation doses to the eye lens of an interventional cardiologist in typical working conditions can exceed 34 MUGy min-1 in high-dose fluoroscopy modes and 3 MUGy per image during image acquisition (instantaneous rate values) when radiation protection tools are not used. A causal relation between exposure to ionising radiation and increased risk of brain and central nervous system tumours has been shown in a number of studies. Although absorbed doses to the brain in interventional cardiology procedures are lower than those to the eye lens by a factor between 3.40 and 8.08 according to our simulations, doses to both tissues are among the highest occupational radiation doses documented for medical staff whose work involves exposures to x-rays. We present InterCardioRisk, a tool featuring an easy-to-use web interface that provides a general estimation of both cumulated absorbed doses experienced by medical staff exposed in the interventional cardiology setting and their estimated associated health risks. The tool is available at http://intercardiorisk.creal.cat. PMID- 27460877 TI - Dynamic pH junction preconcentration in capillary electrophoresis- electrospray ionization-mass spectrometry for proteomics analysis. AB - Capillary zone electrophoresis (CZE)-electrospray ionization (ESI)-mass spectrometry (MS) is an interesting complimentary technique to reversed phase liquid chromatography (RPLC)-ESI-MS for proteomics research. However, the low sample loading capacity of CZE (typically a few nL) can limit its application for large-scale proteomics. A number of on-line sample preconcentration methods have been developed to increase sample loading volumes. This review considers the dynamic pH junction as a simple on-line sample preconcentration method; this method is well suited for amphiprotic analytes. In the pH junction, these analytes are suspended in a basic buffer, injected by pressure into the capillary, and separated in an acidic background electrolyte, with no changes in either CZE-MS operations or instrumentation. We have demonstrated that the dynamic pH junction method can improve the sample loading volume to sub-MUL volumes without significant loss of separation capacity for bottom-up proteomic analysis. The dynamic pH junction based CZE-ESI-MS system has been applied for a number of complex biological samples, including the E. coli proteome, impurities in recombinant antibody therapeutics, and the characterization of the phosphoproteome from a human cell line. PMID- 27460878 TI - Report of the clinical donor case workshop of the European Association of Tissue Banks annual meeting 2014. AB - The European Association of Tissue Banks (EATB) donor case workshop is a forum held within the program of the EATB annual congress. The workshop offers an opportunity to discuss and evaluate possible approaches taken to challenging situations regarding donor selection. Donor case workshops actively engage participants with diverging background and experience in an informal, secure and enjoyable setting. The resulting discussion with peers promotes consensus development in deciding tissue donor acceptability, especially when donor health issues are not conclusively addressed in standards and regulations. Finally the workshop serves to strengthen the professional tissue banking networks across Europe and beyond. This report reflects some of the discussion at the workshop during the annual congress in Lund, Sweden, in 2014. The cases presented demonstrate that the implications of various donor illnesses, physical findings and behaviours on the safety of tissue transplantation, may be interpreted in a different way by medical directors and other professionals of different tissue facilities. This will also result in diverging preventive measures and decisions taken by the tissue facilities. Some of the donor cases illustrate varied responses from participants and demonstrate that operating procedures, regulations and standards cannot comprehensively cover all tissue donor illnesses, medical histories and circumstances surrounding the cause of death. For many of the issues raised, there is a lack of published scientific evidence. In those cases, tissue bank medical director judgement is critical to guarantee transplantation safety. This judgement should be based on a proper and documented risk assessment case by case. Conditions or parameters taken into account for risk assessment are amongst others, the type of tissue, the type of processing, the characteristics of the final product, and the availability of an adequate sterilisation methodology. By publishing these difficult donor suitability cases, and the resulting discussions, we provide information for future similar cases and we identify needs for future literature review and scientific research. In this way the donor case workshops play a role in optimizing the quality and security of tissue donation. PMID- 27460879 TI - Collection and characterization of amniotic fluid from scheduled C-section deliveries. AB - Amniotic fluid (AF) possesses anti-inflammatory, anti-microbial and regenerative properties that make it attractive for use in clinical applications. The goals of this study were to assess the feasibility of collecting AF from full-term pregnancies and to evaluate non-cellular and cellular properties of AF for clinical applications. Donor informed consent and medical histories were obtained from pregnant women scheduled for C-sections and infectious disease testing was performed the day of collection. AFs were evaluated for total volume, fluid chemistries, total protein, and hyaluronic acid (HA) levels. AF was also assessed with quantitative antibody arrays, cellular content and for an ability to support angiogenesis. Thirty-six pregnant women consented and passed donor screening to give birth tissue. AF was successfully collected from 17 individuals. Median AF volumes were 70 mL (range 10-815 mL; n = 17). Fluid chemistries were similar, but some differences were noted in HA levels and cytokine profiles. Cytokine arrays revealed that an average of 304 +/- 20 of 400 proteins tested were present in AF with a majority of cytokines associated with host defense. AF supported angiogenesis. Epithelioid cells were the major cell type in AF with only a minor population of lymphoid cells. Cultures revealed a highly proliferative population of adherent cells capable of producing therapeutic doses of mesenchymal stromal cells (MSCs). These findings showed that significant volumes of AF were routinely collected from full-term births. AF contained a number of bioactive proteins and only a rare population of MSCs. Variations noted in components present in different AFs, warrant further investigations to determine their relevance for specific clinical applications. PMID- 27460880 TI - Methodological Credibility: An Empirical Investigation of the Public's Perception of Evaluation Findings and Methods. AB - BACKGROUND: When evaluations are broadly disseminated, the public can use them to support a program or to advocate for change. METHODS: To explore how evaluations are perceived and used by the public, individuals in a sample of 425 people in the United States were recruited through an online crowdsourcing service called Mechanical Turk (www.mturk.com). Participants were randomly assigned to receive different versions of a press release describing a summative evaluation of a program. Each condition contained a unique combination of methods (e.g., randomized controlled design) and findings (positive or negative) to describe the evaluation and its findings. Participants in each condition responded to questions about their trust in the content of the evaluation findings and their attitudes toward the program. RESULTS: Results indicated that the type of evaluation methods and the direction of the findings both influenced the credibility of the findings and that the credibility of the findings moderated the relationship between the direction of the evaluation findings and attitudes toward the evaluated program. Additional evaluation factors to explore in future research with the public are recommended. PMID- 27460881 TI - Prevalence of Enterobius vermicularis among preschool children in 2003 and 2013 in Xinxiang city, Henan province, Central China. AB - The present study was performed to assess the prevalence of Enterobius vermicularis infection among preschool children in Xinxiang city, Henan province, China and the changes in the egg positive rate for E. vermicularis over a 10 year period. A total of 510 preschool children in 17 kindergartens were examined using the cellophane-tape perianal swab method in 2003, while 1734 preschool children in 10 kindergartens were examined in 2013 using the same method. The overall egg positive rate for E. vermicularis was 12.75% (65 out of 510) in 2003 and 5.13% (89 out of 1734) in 2013; the former was significantly higher than the latter (p < 0.05). In both 2003 and 2013, the egg positive rate for 5 to 6-year-old children was significantly higher than that of 2 to 4-year-old children (p < 0.05). However, positive rates were not significantly dependent on gender or area. Among selected personal hygiene factors, no hand washing before eating, sucking fingers or toys, and scratching around the anus were all associated with enterobiasis. The present study confirmed that the prevalence of E. vermicularis infection among preschool children decreased significantly over the 10 year period in Xinxiang city, but infection was still prevalent. Improving sanitation and personal hygiene practices, especially hand washing, could help prevent the transmission of E. vermicularis. PMID- 27460882 TI - Gastrointestinal Spatiotemporal mRNA Expression of Ghrelin vs Growth Hormone Receptor and New Growth Yield Machine Learning Model Based on Perturbation Theory. AB - The management of ruminant growth yield has economic importance. The current work presents a study of the spatiotemporal dynamic expression of Ghrelin and GHR at mRNA levels throughout the gastrointestinal tract (GIT) of kid goats under housing and grazing systems. The experiments show that the feeding system and age affected the expression of either Ghrelin or GHR with different mechanisms. Furthermore, the experimental data are used to build new Machine Learning models based on the Perturbation Theory, which can predict the effects of perturbations of Ghrelin and GHR mRNA expression on the growth yield. The models consider eight longitudinal GIT segments (rumen, abomasum, duodenum, jejunum, ileum, cecum, colon and rectum), seven time points (0, 7, 14, 28, 42, 56 and 70 d) and two feeding systems (Supplemental and Grazing feeding) as perturbations from the expected values of the growth yield. The best regression model was obtained using Random Forest, with the coefficient of determination R(2) of 0.781 for the test subset. The current results indicate that the non-linear regression model can accurately predict the growth yield and the key nodes during gastrointestinal development, which is helpful to optimize the feeding management strategies in ruminant production system. PMID- 27460883 TI - Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model. AB - Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model. Liposomes accumulate in the post-anastomotic area of the venous outflow tract in which the vascular pathology is most prominent in failed AVFs. On a histological level, we observed a reduction of lymphocytes and granulocytes in the vascular wall. In addition, a strong anti-inflammatory effect of liposomal prednisolone on macrophages was demonstrated in vitro. Therefore, treatment with liposomal prednisolone might be a valuable strategy to improve AVF maturation. PMID- 27460885 TI - Rapid discrimination of bergamot essential oil by paper spray mass spectrometry and chemometric analysis. AB - A novel approach for the rapid discrimination of bergamot essential oil from other citrus fruits oils is presented. The method was developed using paper spray mass spectrometry (PS-MS) allowing for a rapid molecular profiling coupled with a statistic tool for a precise and reliable discrimination between the bergamot complex matrix and other similar matrices, commonly used for its reconstitution. Ambient mass spectrometry possesses the ability to record mass spectra of ordinary samples, in their native environment, without sample preparation or pre separation by creating ions outside the instrument. The present study reports a PS-MS method for the determination of oxygen heterocyclic compounds such as furocoumarins, psoralens and flavonoids present in the non-volatile fraction of citrus fruits essential oils followed by chemometric analysis. The volatile fraction of Bergamot is one of the most known and fashionable natural products, which found applications in flavoring industry as ingredient in beverages and flavored foodstuff. The development of the presented method employed bergamot, sweet orange, orange, cedar, grapefruit and mandarin essential oils. PS-MS measurements were carried out in full scan mode for a total run time of 2 min. The capability of PS-MS profiling to act as marker for the classification of bergamot essential oils was evaluated by using multivariate statistical analysis. Two pattern recognition techniques, linear discriminant analysis and soft independent modeling of class analogy, were applied to MS data. The cross validation procedure has shown excellent results in terms of the prediction ability because both models have correctly classified all samples for each category. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27460884 TI - Latency for cytomegalovirus impacts T cell ageing significantly in elderly end stage renal disease patients. AB - The number of elderly patients with end-stage renal disease (ESRD) has increased significantly during the last decade. Elderly ESRD patients are vulnerable to infectious complications because of an aged immune system. Additional immunological ageing effects may be derived from the uraemic environment and cytomegalovirus (CMV) latency. Elderly patients may be affected by these factors in particular, but data in this age group are limited. To assess the degree of immunological ageing and proliferative capacity of T lymphocytes, 49 elderly ESRD patients (defined as aged >= 65 years) on the renal transplantation waiting list were recruited and compared to 44 elderly healthy individuals (HI), matched for age and CMV serostatus. CMV latency was associated with more highly differentiated CD4+ and CD8+ T cells in both elderly HI and patients. Elderly CMV seropositive ESRD patients showed a substantial reduction in the number of naive CD4+ and CD8+ T cells compared with age- and CMV serostatus-matched HI. Elderly ESRD patients also showed significantly decreased numbers of central memory CD4+ and CD8+ T cells compared with HI, independently of CMV serostatus. In addition, thymic output and relative telomere length of both CD4+ and CD8+ T cells were decreased in CMV seropositive ESRD patients compared with HI. The proliferative capacity of T cells was similar for patients and HI. Elderly ESRD patients have an advanced aged T cell compartment when compared to age-matched healthy controls, which is driven mainly by CMV latency. PMID- 27460886 TI - The Arab American experience with diabetes: Perceptions, myths and implications for culturally-specific interventions. AB - AIMS: Culturally-specific lifestyle diabetes prevention programs require an assessment of population disease perceptions and cultural influences on health beliefs and behaviors. The primary objectives were to assess Arab Americans' knowledge and perceptions of diabetes and their preferences for a lifestyle intervention. METHODS: Sixty-nine self-identified Arab or Arab Americans >=30 years of age and without diabetes participated in 8 focus groups. RESULTS: Emerging themes from the data included myths about diabetes etiology, folk remedies, and social stigma. The main barrier to healthcare was lack of health insurance and/or cost of care. Intervention preferences included gender-specific exercise, group-delivered education featuring religious ideology, inclusion of the family, and utilization of community facilities. CONCLUSION: Lifestyle interventions for Arab Americans need to address cultural preferences, diabetes myths, and folk remedies. Interventions should incorporate Arabic cultural content and gender-specific group education and exercise. Utilization of family support and religious centers will enable culturally-acceptable and cost effective interventions. PMID- 27460887 TI - Psoriasis risk in patients with type 2 diabetes in German primary care practices. AB - AIM: To analyze psoriasis risk in type 2 diabetes mellitus (T2DM) patients treated in German primary care practices. METHODS: The study included 87,964 T2DM patients aged 40 years or over who received their initial diabetes diagnosis between 2004 and 2013. Patients were excluded if they had been diagnosed with psoriasis prior to diabetes diagnosis or if the observation period prior to the index date was less than 365 days. After applying these exclusion criteria, 72,148 T2DM patients were included. A total of 72,148 non-diabetic controls were matched (1:1) to T2DM cases based on age, gender, type of health insurance (private or statutory), number of medical visits, and index date. The primary outcome was the diagnosis of psoriasis. Skin infections, dermatitis/eczema, hyperlipidemia, and medications associated with psoriasis (beta blockers, angiotensin-converting enzyme (ACE) inhibitors, lithium, antimalarials, nonsteroidal anti-inflammatory drugs, and benzodiazepines) were included as potential confounders. RESULTS: The mean age was 68.7 years (SD=12.7 years) and 48.6% of subjects were men. Hyperlipidemia, dermatitis/eczema, and skin infections were more frequent in T2DM patients than in controls. Beta blockers, ACE inhibitors, and nonsteroidal anti-inflammatory drugs were also more commonly used in people with T2DM than in controls. A total of 3.4% of T2DM patients and 2.8% of matched controls developed psoriasis within ten years of follow-up (p value <0.001). T2DM patients were at a higher risk of developing psoriasis than controls (HR=1.18, 95% CI: 1.08-1.29). CONCLUSION: T2DM was positively associated with psoriasis in patients treated in German primary care practices. PMID- 27460888 TI - The SLC2A14 gene: genomic locus, tissue expression, splice variants, and subcellular localization of the protein. AB - The SLC2A14 gene encodes for GLUT14, an orphan member of the facilitated membrane glucose transporter family, which was originally described to be exclusively expressed in human testis. However, genetic variations in SLC2A14 are associated with chronic diseases such as Alzheimer's disease and Inflammatory Bowel Disease, which cannot be explained by a strictly testicular expression. Therefore we analyzed available information on the SLC2A14 gene to update knowledge of the locus and its encoded products. This report presents an expanded SLC2A14 gene locus and a more diverse tissue expression, concurring with the existing evidence for disease associations. The exon utilization is tissue specific, with major expression in testis. When the 2 major testicular protein isoforms were expressed in mammalian cells, they located to the plasmalemma membrane, providing early evidence that GLUT14 could function as a membrane transporter. PMID- 27460889 TI - Comparison of coagulation pretreatment of produced water from natural gas well by polyaluminium chloride and polyferric sulphate coagulants. AB - This study aimed to optimise coagulation pretreatment of the produced water (PW) collected from a natural gas field. Two coagulants, polyferric sulphate (PFS) and polyaluminium chloride (PACl), were applied separately for the organics, suspended solids (SS), and colour removal. Treatment performance at different coagulant dosages, initial pH values, stirring patterns, and the addition of cationic polyacrylamide (PAM) was investigated in jar tests. The optimal coagulation conditions were dosage of PACl 25 g/L or PFS 20 g/L with that of PAM 30 mg/L, initial pH of 11, and fast mixing of 1.5 min (for PACl) or 2 min (for PFS) at 250 rpm followed by slow mixing of 15 min at 50 rpm for both coagulants. PACl performed better than PFS to remove chemical oxygen demand (COD), total organic carbon (TOC), SS, and colour, and achieved a removal efficiency of 90.1%, 89.4%, 99.0%, and 99.9%, respectively, under the optimal condition; while PFS efficiency was 86.1%, 86.1%, 99.0%, and 98.2%, respectively. However, oil removal was higher in PFS coagulation compared to PACl and showed 98.9% and 95.3%, respectively. Biodegradability, ratio of the biological oxygen demand (five-day) (BOD5)/COD, of the PW after pretreatment increased from 0.08 to 0.32 for PFS and 0.43 for PACl. Zeta potential (Z-potential) analysis at the optimum coagulant dosage of PACl and PFS suggests that charge neutralisation was the predominant mechanism during coagulation. Better efficiency was observed at higher pH. The addition of PAM and starring pattern had a minor influence on the removal performance of both coagulants. The results suggest that PACl or PFS can be applied for the pretreatment of PW, which can provide substantial removal of carbon, oil, and colour, a necessary first step for subsequent main treatment units such as chemical oxidation or biological treatment. PMID- 27460890 TI - No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. AB - AIMS: Statins have modest adverse effects on glycaemic control. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers low-density lipoprotein cholesterol. This study assessed the effects of alirocumab on new onset diabetes and pre-diabetes incidence in individuals without diabetes at baseline. METHODS AND RESULTS: Pooled analysis of 10 ODYSSEY Phase 3 trials (n = 4974) of 24-104 weeks duration. Six trials (n = 4211) were >=52 weeks in length. Most patients received background maximally tolerated statin. Alirocumab effect on the rate of diabetes-related treatment-emergent adverse events (TEAEs), and/or fasting plasma glucose (FPG) and glycated haemoglobin A1C (HbA1C) was measured at baseline and every 12-24 weeks. Transition to diabetes analysis combined TEAE and FPG/HbA1C laboratory data. At baseline, 30.7% of individuals had diabetes and were excluded from the current analysis. The remaining 3448 individuals without diabetes had pre-diabetes (39.6%) or were normoglycaemic (29.7%). The hazard ratio (HR; 95% confidence interval) for diabetes-related TEAEs in alirocumab was 0.64 (0.36-1.14) vs. placebo and 0.55 (0.22-1.41) vs. ezetimibe. The HR associated for transition from pre-diabetes to new-onset diabetes for alirocumab was 0.90 (0.63-1.29) vs. placebo and 1.10 (0.57-2.12) vs. ezetimibe. Mean change in FPG/HbA1C over time showed no difference between treatment groups in patients without diabetes. CONCLUSIONS: There was no evidence of an effect of alirocumab on transition to new-onset diabetes in 3448 individuals without diabetes at baseline with a follow-up period of 6-18 months, compared to either placebo or ezetimibe. Longer follow-up with larger number of individuals is needed to conclusively rule out an effect. PMID- 27460892 TI - Environmental stressors and cardio-metabolic disease: part I-epidemiologic evidence supporting a role for noise and air pollution and effects of mitigation strategies. AB - Traffic noise and air pollution together represent the two most important environmental risk factors in urbanized societies. The first of this two-part review discusses the epidemiologic evidence in support of the existence of an association between these risk factors with cardiovascular and metabolic disease. While independent effects of these risk factors have now clearly been shown, recent studies also suggest that the two exposures may interact with each other and with traditional risk factors such as hypertension and type 2 diabetes. From a societal and policy perspective, the health effects of both air pollution and traffic noise are observed for exposures well below the thresholds currently accepted as being safe. Current gaps in knowledge, effects of intervention and their impact on cardiovascular disease, will be discussed in the last section of this review. Increased awareness of the societal burden posed by these novel risk factors and acknowledgement in traditional risk factor guidelines may intensify the efforts required for effective legislation to reduce air pollution and noise. PMID- 27460891 TI - Environmental stressors and cardio-metabolic disease: part II-mechanistic insights. AB - Environmental factors can act as facilitators of chronic non-communicable diseases. Ambient noise and air pollution collectively outrank all other environmental risk factors in importance, contributing to over 75% of the disease and disability burden associated with known environmental risk factors. In the first part of this review, we discussed the global burden and epidemiologic evidence supporting the importance of these novel risk factors as facilitators of cardiometabolic disease. In this part, we will discuss pathophysiological mechanisms responsible for noise and air pollution-mediated effects. Akin to traditional cardiovascular risk factors, a considerable body of evidence suggests that these environmental agents induce low-grade inflammation, oxidative stress, vascular dysfunction, and autonomic nervous system imbalance, thereby facilitating the development of diseases such as hypertension and diabetes. Through their impact on traditional risk factors and via additional novel mechanisms, environmental risk factors may have much larger impact on cardiovascular events than currently appreciated. In the second part of this review, we discuss deficiencies and gaps in knowledge and opportunities for new research. PMID- 27460893 TI - Temperature and parasite life-history are important modulators of the outcome of Trypanosoma rangeli-Rhodnius prolixus interactions. AB - Trypanosoma rangeli is a protozoan parasite, which does not cause disease in humans, although it can produce different levels of pathogenicity to triatomines, their invertebrate hosts. We tested whether infection imposed a temperature dependent cost on triatomine fitness using T. rangeli with different life histories. Parasites cultured only in liver infusion tryptose medium (cultured) and parasites exposed to cyclical passages through mice and triatomines (passaged) were used. We held infected insects at four temperatures between 21 and 30 degrees C and measured T. rangeli growth in vitro at the same temperatures in parallel. Overall, T. rangeli infection induced negative effects on insect fitness. In the case of cultured infection, parasite effects were temperature-dependent. Intermoult period, mortality rates and ecdysis success were affected in those insects exposed to lower temperatures (21 and 24 degrees C). For passaged-infected insects, the effects were independent of temperature, intermoult period being prolonged in all infected groups. Trypanosoma rangeli seem to be less tolerant to higher temperatures since cultured-infected insects showed a reduction in the infection rates and passaged-infected insects decreased the salivary gland infection rates in those insects submitted to 30 degrees C. In vitro growth of T. rangeli was consistent with these results. PMID- 27460894 TI - Ultrastructure observation on the cells at different life history stages of Cryptocaryon irritans (Ciliophora: Prostomatea), a parasitic ciliate of marine fishes. AB - Cells of Cryptocaryon irritans at different life history stages were studied using both light and electron microscopy. The characteristics of several organelles were revealed for the first time at the ultrastructural level. It was confirmed that the cytostome of trophonts, protomonts and theronts was surrounded by cilium-palp triplets rather than ciliary triplets. The nematodesmata underlying the circumoral dikinetids were single bundles, whereas these were always paired in Prorodontids. Toxicysts were present in late-stage tomonts and theronts, but were absent in trophonts and protomonts. We posited that toxicysts might play a role in infection and invasion of host-fish tissue by theronts. The adoral brosse was unlike that of any other family of the class Prostomatea based on its location and morphology. Membranous folds were present in trophonts, protomonts and theronts. These folds were longer and more highly developed in C. irritans than in exclusively free-living prostome ciliates suggesting that they might be linked to parasitism in C. irritans. Trophonts, protomonts and theronts had multiple contractile vacuoles. The basic ultrastructure of the contractile vacuole of C. irritans was similar to that of other kinetofragminophoran ciliates. They might play different roles in different stages of the life cycle since their ultrastructure varied among trophonts, protomonts and theronts. PMID- 27460895 TI - Ultrastructure observation on the cells at different life history stages of Cryptocaryon irritans (Ciliophora: Prostomatea), a parasitic ciliate of marine fishes - CORRIGENDUM. PMID- 27460897 TI - Targeted blockade of JAK/STAT3 signaling inhibits proliferation, migration and collagen production as well as inducing the apoptosis of hepatic stellate cells. AB - Protein tyrosine kinases belonging to the Janus kinase (JAK) family are associated with many cytokine receptors, which, on ligand binding, regulate important cellular functions such as proliferation, apoptosis and differentiation. The protective effects of JAK inhibitors on fibrotic diseases such as myelofibrosis and bone marrow fibrosis have been demonstrated in previous studies. The JAK inhibitor SHR0302 is a synthetic molecule that potently inhibits all members of the JAK family, particularly JAK1. However, its effect on hepatic fibrosis has not been investigated to date, to the best of our knowledge. In the present study, the effects of SHR0302 on the activation, proliferation, migration and apoptosis of hepatic stellate cells (HSCs) as well as HSC collagen production were investigated. Our data demonstrated that treatment with SHR0302 (10-9-10-5 mol/l) exerted an inhibitory effect on the activation, proliferation and migration of HSCs. In addition, the expression of collagen I and collagen III were significantly decreased following treatment with SHR0302. Furthermore, SHR0302 induced the apoptosis of HSCs, which was demonstrated by Annexin V/PI staining. SHR0302 significantly increased the activation of caspase-3 and Bax in HSCs whereas it decreased the expression of Bcl-2. SHR0302 also inhibited the activation of Akt signaling pathway. The pharmacological inhibition of the JAK1/signal transducer and activator of transcription (STAT)3 pathway led to the disruption of functions essential for HSC growth. Taken together, these findings provide evidence that SHR0302 may have the potential to alleviate hepatic fibrosis by targeting HSC functions. PMID- 27460896 TI - Are low birth weight neonates at risk for suboptimal renal growth and function during infancy? AB - BACKGROUND: To assess the renal growth and function of neonates during infancy in relation to birth weight and gestational age. METHODS: A longitudinal study was conducted at a tertiary hospital in South India from June 2010 to August 2014. Low birth weight neonates (LBW) were further sub-classified based on gestational age and compared with normal birth weight (NBW) full term neonates at birth, 6 months and 18-24months of age. The renal volume was measured by ultrasound and renal function by Cystatin C- derived glomerular filtration rate (CysGFR) at the three time points during the dynamic phase of renal maturation in infancy. RESULTS: We recruited 100 LBW and 66 NBW term neonates. Thirty five percent of the LBW neonates were SGA. Among the AGA neonates, 39 % were LBW neonates. The mean height and weight of the LBW neonates were significantly lower compared to NBW neonates throughout infancy. The increment in kidney volume was in accordance with the change in body size, being lower in LBW compared to NBW infants. The combined kidney volume was significantly lower in LBW and SGA neonates across all three time points (p < 0.001). CysGFR in the LBW and SGA infants, despite having low kidney volumes, were comparable to the GFRs of NBW and AGA neonates at the end of infancy. CONCLUSION: This study highlights the fact that both birth weight and gestational age influence kidney growth and function in infancy. At the end of infancy, despite a significant difference in kidney volumes and age at last follow up, the glomerular filtration rate was comparable between LBW and NBW infants. Though not statistically significant, there was a trend towards higher urine microalbumin in LBW compared to NBW in infancy. PMID- 27460898 TI - Connective tissue growth factor is critical for proper beta-cell function and pregnancy-induced beta-cell hyperplasia in adult mice. AB - During pregnancy, maternal beta-cells undergo compensatory changes, including increased beta-cell mass and enhanced glucose-stimulated insulin secretion. Failure of these adaptations to occur results in gestational diabetes mellitus. The secreted protein connective tissue growth factor (CTGF) is critical for normal beta-cell development and promotes regeneration after partial beta-cell ablation. During embryogenesis, CTGF is expressed in pancreatic ducts, vasculature, and beta-cells. In adult pancreas, CTGF is expressed only in the vasculature. Here we show that pregnant mice with global Ctgf haploinsufficiency (Ctgf(LacZ/+)) have an impairment in maternal beta-cell proliferation; no difference was observed in virgin Ctgf(LacZ/+) females. Using a conditional CTGF allele, we found that mice with a specific inactivation of CTGF in endocrine cells (Ctgf(DeltaEndo)) develop gestational diabetes during pregnancy, but this is due to a reduction in glucose-stimulated insulin secretion rather than impaired maternal beta-cell proliferation. Moreover, virgin Ctgf(DeltaEndo) females also display impaired GSIS with glucose intolerance, indicating that underlying beta-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for CTGF in beta-cell function has been reported. PMID- 27460899 TI - Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. AB - Glucocorticoid excess is a major cause of low bone mass and fractures. Glucocorticoid administration decreases cortical thickness and increases cortical porosity in mice, and these changes are associated with increased osteoclast number at the endocortical surface. Receptor activator of NF-kappaB ligand (RANKL) produced by osteocytes is required for osteoclast formation in cancellous bone as well as the increase in cortical bone resorption caused by mechanical unloading or dietary calcium deficiency. However, whether osteocyte-derived RANKL also participates in the increase in bone resorption caused by glucocorticoid excess is unknown. To address this question, we examined the effects of prednisolone on cortical bone of mice lacking RANKL production in osteocytes. Prednisolone administration increased osteoclast number at the endocortical surface, increased cortical porosity, and reduced cortical thickness in control mice, but none of these effects occurred in mice lacking RANKL in osteocytes. Prednisolone administration did not alter RANKL mRNA abundance but did reduce osteoprotegerin (OPG) mRNA abundance in osteocyte-enriched cortical bone. Similarly, dexamethasone suppressed OPG but did not increase RANKL production in cortical bone organ cultures and primary osteoblasts. These results demonstrate that RANKL produced by osteocytes is required for the cortical bone loss caused by glucocorticoid excess but suggest that the changes in endocortical resorption are driven by reduced OPG rather than elevated RANKL expression. PMID- 27460900 TI - Effects of biochars on the availability of heavy metals to ryegrass in an alkaline contaminated soil. AB - A pot experiment was conducted to investigate the effects of biochars on the availability of heavy metals (Cd, Cu, Mn, Ni, Pb, and Zn) to ryegrass in an alkaline contaminated soil. Biochars only slightly decreased or even increased the availability of heavy metals assesses by chemical extractant (a mixture of 0.05 mol L-1 ethylenediaminetetraacetic acid disodium, 0.01 mol L-1 CaCl2, and 0.1 mol L-1 triethanolamine). The significantly positive correlation between most chemical-extractable heavy metals and the ash content in biochars indicated the positive role of ash in this extraction. Biochars significantly reduced the plant uptake of heavy metals, excluding Mn. The absence of a positive correlation between the chemical-extractable heavy metals and the plant uptake counterparts (except for Mn) indicates that chemical extractability is probably not a reliable indicator to predict the phytoavailability of most heavy metals in alkaline soils treated with biochars. The obviously negative correlation between the plant uptake of heavy metals (except for Mn) and the (O + N)/C and H/C indicates that biochars with more polar groups, which were produced at lower temperatures, had higher efficiency for reducing the phytoavailability of heavy metals. The significantly negative correlations between the plant uptake of Mn and ryegrass biomass indicated the "dilution effect" caused by the improvement of biomass. These observations will be helpful for designing biochars as soil amendments to reduce the availability of heavy metals to plants in soils, especially in alkaline soils. PMID- 27460901 TI - Simultaneous sorption of four ionizable pharmaceuticals in different horizons of three soil types. AB - Soils may be contaminated by human or veterinary pharmaceuticals. Their behaviour in soil environment is largely controlled by sorption of different compounds in a soil solution onto soil constituents. Here we studied the sorption affinities of 4 pharmaceuticals (atenolol, trimethoprim, carbamazepine and sulfamethoxazole) applied in solute mixtures to soils taken from different horizons of 3 soil types (Greyic Phaeozem on loess, Haplic Luvisol on loess and Haplic Cambisol on gneiss). In the case of the carbamazepine (neutral form) and sulfamethoxazole (partly negatively charged and neutral), sorption affinity of compounds decreased with soil depth, i.e. decreased with soil organic matter content. On the other hand, in the case of atenolol (positively charged) and trimethoprim (partly positively charged and neutral) compound sorption affinity was not depth dependent. Compound sorption affinities in the four-solute systems were compared with those experimentally assessed in topsoils, and were estimated using the pedotransfer rules proposed in our previous study for single-solute systems. While sorption affinities of trimethoprim and carbamazepine in topsoils decreased slightly, sorption affinity of sulfamethoxazole increased. Decreases in sorption of the two compounds could be attributed to their competition between each other and competition with atenolol. Differences between carbamazepine and atenolol behaviour in the one- and four-solute systems could also be explained by the slightly different soil properties in this and our previous study. A great increase of sulfamethoxazole sorption in the Greyic Phaeozem and Haplic Luvisol was observed, which was attributed to elimination of repulsion between negatively charged molecules and particle surfaces due to cation sorption (atenolol and trimethoprim) on soil particles. Thus, our results proved not only an antagonistic but also a synergic affect of differently charged organic molecules on their sorption to soil constituents. PMID- 27460902 TI - A snapshot of the microbiome of Amblyomma tuberculatum ticks infesting the gopher tortoise, an endangered species. AB - The gopher tortoise tick, Amblyomma tuberculatum, has a unique relationship with the gopher tortoise, Gopherus polyphemus, found in sandy habitats across the southeastern United States. We aimed to understand the overall bacterial community associated with A. tuberculatum while also focusing on spotted fever group Rickettsia. These tortoises in the Southern Mississippi region are a federally threatened species; therefore, we have carefully trapped the tortoises and removed the species-specific ticks attached to them. Genomic DNA was extracted from individual ticks and used to explore overall bacterial load using pyrosequencing of bacterial 16S rRNA on 454-sequencing platform. The spotted fever group of Rickettsia was explored by amplifying rickettsial outer membrane protein A (rompA) gene by nested PCR. Sequencing results revealed 330 bacterial operational taxonomic units (OTUs) after all the necessary curation of sequences. Four whole A. tuberculatum ticks showed Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes as the most dominant phyla with a total of 74 different bacterial genera detected. Together Rickettsiae and Francisella showed >85% abundance, thus dominating the bacterial community structure. Partial sequences obtained from ompA amplicons revealed the presence of an uncharacterized Rickettsia similar to the Rickettsial endosymbiont of A. tuberculatum. This is the first preliminary profile of a complete bacterial community from gopher tortoise ticks and warrants further investigation regarding the functional role of Rickettsial and Francisella-like endosymbionts in tick physiology. PMID- 27460903 TI - The first molecular evidence of severe fever with thrombocytopenia syndrome virus in ticks in Jilin, Northeastern China. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonosis. The aim of this study was to investigate SFTS virus (SFTSV) infections in ticks in Northeastern China. A total of 6427 ticks, including 5450 Haemaphysalis longicornis, 463 Dermacentor silvarum, 351 Dermacentor nuttalli, and 163 Ixodes persulcatus, were sampled in the Liaoning, Jilin, and Heilongjiang Provinces of Northeastern China. Viral megagenomic analysis of the ticks revealed 25 contigs targeting the M and L segments of the SFTSV genome. H. longicornis collected from Jinxing, Jilin Province, were analyzed by RT-PCR, which showed positive results for SFTSV, with a minimum prevalence of 3.0%. The full-length sequence of the S, M, and L segments of the SFTSV were obtained, and phylogenetic analysis showed that the virus strain found in Jilin formed a monophyletic cluster with the SFTSV strains from Jiangsu, suggesting that SFTSV in the Jilin Province may have spread from the Jiangsu Province. These findings are the first to demonstrate molecular evidence of SFTSV in ticks in the Jilin Province of Northeastern China and indicate the need for measures to prevent and control SFTS. PMID- 27460904 TI - Acute and chronic toxicities of Bacopa monnieri extract in Sprague-Dawley rats. AB - BACKGROUND: Bacopa monnieri is a medicinal plant which has long been used in Ayurvedic medicines to augment brain function and to improve memory. The purpose of our study was to identify and evaluate possible toxic effects of B. monnieri extract in rats by assessing hematological, biochemical, and histopathological parameters. METHODS: Acute oral toxicity of Bacopa monnieri extract was studied in female rats by giving a single orally administered dose at a level of 5,000 mg/kg. The rats were monitored for toxic signs for 14 days. In the chronic toxicity test, groups of both female and male rats were given daily oral doses of B. monnieri extract at dose levels of either 30, 60, 300 or 1,500 mg/kg for 270 days. The behavior and health of the animals was then monitored. At the end of the observation period, the body and organ weights of the rats in each group were measured. Blood was collected and necropsy was performed to evaluate their hematology, blood clinical chemistry, and microanatomy. RESULTS: The acute toxicity test found no significant differences between the experimental and the control group rats. In the chronic toxicity test, animal behavior and health of the experimental groups were normal, just as in the control rats. All values of other parameters assessed remained within the normal range. CONCLUSION: A single oral administration of B. monnieri extract at the dose of 5,000 mg/kg did not cause any serious undesirable effects. B. monnieri extract at doses of 30, 60, 300 and 1,500 mg/kg given for 270 days did not produce any toxicity in rats. PMID- 27460905 TI - Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine The POKER Study: A Randomized Double-Blind Clinical Trial. AB - STUDY OBJECTIVE: We determine whether emergency physician-provided deep sedation with 1:1 ketofol versus propofol results in fewer adverse respiratory events requiring physician intervention when used for procedural sedation and analgesia. METHODS: Consenting patients requiring deep sedation were randomized to receive either ketofol or propofol in a double-blind fashion according to a weight-based dosing schedule. The primary outcome was the occurrence of a respiratory adverse event (desaturation, apnea, or hypoventilation) requiring an intervention by the sedating physician. Secondary outcomes included hypotension and patient satisfaction. RESULTS: Five hundred seventy-three patients were enrolled and randomized, 292 in the propofol group and 281 in the ketofol group. Five percent in the propofol group and 3% in the ketofol group met the primary outcome, an absolute difference of 2% (95% confidence interval [CI] -2% to 5%). Patients receiving propofol were more likely to become hypotensive (8 versus 1%; difference 7%; 95% CI 4% to 10%). Patient satisfaction was very high in both groups (10/10; interquartile range 10 to 10/10), and although the ketofol group was more likely to experience severe emergence delirium (5% versus 2%; difference 3%; 95% CI 0.4% to 6%), they had lower pain scores at 30 minutes postprocedure. Other secondary outcomes were similar between groups. CONCLUSION: Ketofol and propofol resulted in a similar incidence of adverse respiratory events requiring the intervention of the sedating physician. Although propofol resulted in more hypotension, the clinical relevance of this is questionable, and both agents are associated with high levels of patient satisfaction. PMID- 27460906 TI - ECM1 promotes migration and invasion of hepatocellular carcinoma by inducing epithelial-mesenchymal transition. AB - BACKGROUND: Extracellular matrix protein 1 (ECM1) is a glycoprotein involved in many biologic processes. To determine the expression of ECM1 in hepatocellular carcinoma (HCC), and to study the role of ECM1 in inducing epithelia-mesenchymal transition (EMT) to analyze the effect of ECM1 on the migration and invasion of HCC cells. METHODS: The expression of ECM1 in HCC specimens was examined by immunohistochemistry staining, and the correlations were analyzed between the expression of ECM1 and the clinicopathological data. The ECM1 expression plasmid was transfected into Bel-7402 cells to induce exogenous overexpression of ECM1 protein. The changes of the expression of ECM1, EMT-related protein (E-cadherin, Vimentin), in Bel-7402 cells were detected by Western blot after transfection of ECM1; the wound healing and invasion assay in vitro were used to determine the role of ECM1 gene transfection on the ability of migration and invasive potential of Bel-7402 cells. RESULTS: Immumohistochemistry staining method displayed the ECM1 expression was positively associated with vascular invasion, TNM stage, and poor prognosis. A significant positive correlation was found between the expressions of ECM1 and Vimentin. After ECM1 overexpression, Western blot exhibited that the expression of E-cadherin was down-regulated and Vimentin expression was up-regulated in Bel-7402 cells; the wound healing and invasion assay showed that the migration and invasion potentials of Bel-7402 cells were significantly enhanced. CONCLUSIONS: ECM1, which displayed a high expression in HCC specimens, was closely associated with clinicopathologic data and may promote migration and invasion of HCC cells by inducing EMT. PMID- 27460907 TI - Food groups and risk of chronic disease: a protocol for a systematic review and network meta-analysis of cohort studies. AB - BACKGROUND: There is a lack of systematic and comprehensive evaluations whether food intakes lower or increase risk of chronic diseases. In this network meta analysis of prospective cohort studies, we aim to evaluate the effects of different foods on risk of chronic diseases. METHODS/DESIGN: We will search PubMed and EMBASE. This will be supplemented by a hand search and author contacts. Citations, abstracts, and relevant papers will be screened for eligibility by two reviewers independently. Prospective cohort studies will be included if they meet the following criteria: (1) evaluate the association of single food or food groups with all-cause mortality, cardiovascular diseases (incidence and mortality), cancer (incidence and mortality) or risk of type 2 diabetes. The following food groups will be evaluated: whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy products, fish, red meat, processed meat and sugar-sweetened beverages; (2) include participants >=18 years of age; and (3) study population were free of outcome(s) of interest at the onset of the study. To assess study quality, we will extract the following characteristics: study size, duration of follow-up, dietary assessment method, assessment of outcome and adjustment factors. If the identified studies appear sufficiently similar within and across the different comparisons between pairs of food groups, we will estimate summary-relative effects using random effects network meta-analysis. Subgroup and meta-regression analyses will be performed stratified by different follow-up cut-points, geographical region and sex. DISCUSSION: This is a presentation of the study protocol only. Results and conclusions are pending completion of this study. Our systematic review will be of great value to national and international authorities for evidence-based nutritional recommendation/guidelines, regarding the implementation of food-based dietary guidelines for prevention of chronic diseases. Moreover, our results can be implemented to develop new diet quality indices/scores. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037069. PMID- 27460908 TI - Functional status as a predictor of outcomes in open and endovascular abdominal aortic aneurysm repair. AB - BACKGROUND: Functional status is a simple and rapidly assessable metric that may be used as a predictor for surgical outcomes. This study examined the association of functional status with short-term mortality after abdominal aortic aneurysm (AAA) repair in octogenarians to characterize the utility of functional status as a means of preoperative risk assessment. METHODS: All patients who underwent endovascular and open AAA repair from 2002 to 2010 within the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database were identified. Functional status, defined as an ordinal scale from 1 to 3 (1, independent; 2, partially dependent; 3, totally dependent), was examined using multivariate regression models with 30-day mortality as the primary outcome. For the purpose of analysis, this 3-point scale was converted into a binomial scale of function, with "normal" including 1 (completely independent) and "abnormal" including 2 or 3 (partially to totally dependent). RESULTS: We identified 9030 patients who underwent AAA repair (46.6% open and 53.4% endovascular). Mortality at 30 days was 2.8% for the entire cohort (4.2% open, 1.7% endovascular; P < .001). There were 1340 patients aged >=80 years, of which 67.3% underwent endovascular AAA repair. Among all age groups, functional status was a significant predictor of 30 day mortality (<80 years, P < .001; >=80 years, P < .001). The >=80 cohort with abnormal function status also demonstrated increased operative mortality (P = .002), length of stay (P = .001), and incidence of pulmonary complications (P = .025) compared with the cohort with normal functional status. Multivariate logistic regression demonstrated that within the >=80-year-old cohort, only functional status remained a significant predictor of mortality (P < .001). In addition, the strength of the association between functional status and mortality was greater in the older cohort than in the younger one (Cox regression hazard ratio: 3.13 vs 2.18). CONCLUSIONS: Functional status is a simple and rapidly applicable predictor of mortality within AAA patients and may be a useful tool to help preoperatively risk-stratify elderly patients presenting with AAA in need of repair. Further studies are needed to understand how best to apply these data to the clinical setting to guide preoperative decision making. PMID- 27460909 TI - Low-dose aspirin and rupture of abdominal aortic aneurysm. AB - OBJECTIVE: The use of low-dose aspirin (acetylsalicylic acid [ASA]) has been suggested to attenuate growth of abdominal aortic aneurysms (AAAs), yet solid clinical evidence of this hypothesis is still missing. This study aimed to investigate whether preadmission ASA use influenced the risk of presenting with rupture of AAA (rAAA) on hospital admission and subsequent 30-day case fatality. METHODS: There were 4010 patients with an incident diagnosis of rAAA and 4010 age and sex-matched AAA patients identified in the Danish National Registry of Patients. Data on comorbidity, concomitant drug use, primary health care utilization, socioeconomic status, and vital status were obtained from nationwide health care and administrative registries. RESULTS: Preadmission ASA use was identified for 1815 (45.3%) rAAA patients and 2111 (52.6%) AAA patients, corresponding to a crude odds ratio for rAAA in ASA users of 0.72 (95% confidence interval [CI], 0.66-0.79) compared with nonusers. However, after adjustment for possible confounders, no association between ASA use and the risk of rAAA was found (adjusted odds ratio, 0.97; 95% CI, 0.86-1.08). The aggregated 30-day rAAA case-fatality rate for users of ASA was 66.0% compared with 56.9% for nonusers, corresponding to an adjusted mortality rate ratio of 1.16 (95% CI, 1.06-1.27). CONCLUSIONS: Preadmission ASA use is not associated with an altered risk of AAA rupture but seems to be associated with a worse prognosis after rupture of AAA. PMID- 27460910 TI - European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection. AB - In 2009 the first European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline for diagnosing Clostridium difficile infection (CDI) was launched. Since then newer tests for diagnosing CDI have become available, especially nucleic acid amplification tests. The main objectives of this update of the guidance document are to summarize the currently available evidence concerning laboratory diagnosis of CDI and to formulate and revise recommendations to optimize CDI testing. This update is essential to improve the diagnosis of CDI and to improve uniformity in CDI diagnosis for surveillance purposes among Europe. An electronic search for literature concerning the laboratory diagnosis of CDI was performed. Studies evaluating a commercial laboratory test compared to a reference test were also included in a meta analysis. The commercial tests that were evaluated included enzyme immunoassays (EIAs) detecting glutamate dehydrogenase, EIAs detecting toxins A and B and nucleic acid amplification tests. Recommendations were formulated by an executive committee, and the strength of recommendations and quality of evidence were graded using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. No single commercial test can be used as a stand-alone test for diagnosing CDI as a result of inadequate positive predictive values at low CDI prevalence. Therefore, the use of a two-step algorithm is recommended. Samples without free toxin detected by toxins A and B EIA but with positive glutamate dehydrogenase EIA, nucleic acid amplification test or toxigenic culture results need clinical evaluation to discern CDI from asymptomatic carriage. PMID- 27460911 TI - Practice patterns, counseling and promotion of physical activity by sports medicine physicians. AB - OBJECTIVES: This study examined sports medicine physicians with an established interest in physical activity to investigate attitudes surrounding exercise, physical activity and patient-counseling behavior. The degree to which physicians' personal knowledge of physical activity and related resources, involvement with common activities, and perceived barriers were assessed. DESIGN: An internet survey was designed in four domains: (1) counseling behavior, (2) tools and resources, (3) appropriateness of common physical activities for patients and (4) barriers. METHODS: The survey was sent to 3570 members of two electronic mailing lists - Institute of Lifestyle Medicine, Boston, MA and The American College of Sports Medicine. Surveys were emailed during 2011-2012 and analyzed in 2013-2014. Each survey contained 39 questions. RESULTS: The response rate of the surveys was 16%. Of 412 physicians, 74% regularly recommended physical activity, 66% talked about exercise with patients, and 49% included as a vital sign. Only 26% of physicians provided a written exercise prescription. ACSM's Exercise is Medicine(r) (37%) was the most popular resource. Walking, followed by aerobic activity, strength training and cycling were the most recommended forms of activity and were associated with physicians' personal experiences. The most potent inhibitor was time. CONCLUSIONS: Physicians with an interest in exercise and physical activity recognize the importance of recommending and counseling patients on exercise and physical activity. Physician counseling was associated with personal familiarity with physical activity. Increasing knowledge and experience with exercise, physical activity and counseling behavior is an important component to encourage physical activity assessment and promotion by sports medicine physicians. PMID- 27460912 TI - Current and Emerging Therapies for Itch Management in Psoriasis. AB - Pruritus is a common and significant symptom among patients with psoriasis. Pruritus is often present beyond the borders of psoriatic plaques, and frequently affects the scalp and genital regions. Psoriatic itch may be severe and can profoundly affect quality of life and sleep, even in the context of mild-to moderate disease. These features often make the treatment of psoriatic pruritus challenging. However, there are a variety of effective topical and systemic treatment modalities available to address this symptom. While there remains a need for treatments that specifically target psoriatic itch, newly licensed therapies including secukinumab, ixekizumab and apremilast have been shown to rapidly and effectively mediate itch reduction. PMID- 27460913 TI - Sitagliptin and risk of heart failure hospitalization in patients with type 2 diabetes on dialysis: A population-based cohort study. AB - The incidence of heart failure hospitalization (HHF) after taking sitagliptin in type 2 diabetes (T2DM) patients with end stage renal disease (ESRD) on dialysis is unclear. In this population-based cohort study, we identified individuals with T2DM and ESRD on dialysis who were treated with sitagliptin between 2009 and 2011 and randomly selected a control cohort matched by age, sex, duration of T2DM, hypertension medications, use of statin and aspirin, sulfonylureas, glinides, and insulin usage, atherosclerotic heart disease, congestive heart failure and chronic obstructive pulmonary disease at a 1:4 ratio. Multivariable Cox proportional hazards regression analysis was used to evaluate HHF risk. The overall incidence of HHF was higher in the sitagliptin cohort than in the control cohort (1130 vs. 754 per 10000 person-years; adjusted hazard ratio (HR): 1.52, 95% CI = 1.21-1.90). There was a significant trend towards increased HHF risk associated with increased sitagliptin dose (p for trend < 0.01). Subjects at greater risk of HHF after taking sitagliptin were those without severe hypoglycemia, without ACE inhibitors treatment, with history of heart failure or receiving hemodialysis rather than peritoneal dialysis. In conclusion, use of sitagliptin was associated with an increased risk of HHF in patients with T2DM on dialysis. PMID- 27460914 TI - Early and Late Outcomes of Operation for Acute Type A Aortic Dissection in Patients Aged 80 Years and Older. AB - BACKGROUND: The number of elderly patients undergoing emergency operation for acute type A aortic dissection is increasing in the aging society. We examined the early and late outcomes of operation for acute type A aortic dissection in elderly patients (>=80 years old). METHODS: From January 2001 to December 2015, 345 consecutive patients underwent surgical treatment for acute type A aortic dissection at our institution. Of these, 63 elderly patients (>=80 years old; 28 men; mean age, 83.7 +/- 3.0 years) were reviewed and compared with nonelderly patients (<=79 years old). RESULTS: The hospital death was 9/63 (14.3%) and 25/282 (8.9%) in patients 80 years and older but 79 years or younger, respectively (p = 0.28). Multivariate analysis showed age 80 years or older was a significant risk factor for hospital mortality (odds ratio 3.27, 95% confidence interval: 1.22 to 8.76, p = 0.02). During follow-up period (mean, 51.3 +/- 40.9 months; range, 1 to 162 months), the 5-year survival of the elderly patients discharged from the hospital was 58.6% +/- 8.7%. At postoperative 6 months and the latest follow-up (mean, 44.3 +/- 25.6 months) of the elderly patients excluding late death, 90.2% (46/51) and 88% (22/25) of elderly patients had totally or almost independent daily life, respectively. CONCLUSIONS: Although age 80 years or older was the risk factor for hospital mortality in operation for acute type A aortic dissection, the long-term survival of the hospital survivors and the level of activity of daily life were acceptable. Aggressive surgical treatment could be a reasonable option for selected elderly patients. PMID- 27460915 TI - Resident Identification of Significant Learning Experiences: A Qualitative Analysis. AB - BACKGROUND: Practice-based learning is a core competency that is required of residency programs. This study uses a simple written system to encourage structured reflection and describes the experiences residents identify as significant for learning. METHODS: Thoracic surgery residents were asked to submit a brief monthly written reflection, highlighting something they learned from a clinical experience. Qualitative analysis of these reflections was performed with grounded theory to generate categories of learning topics. These categories were then combined into themes used to develop theories about how residents learn from their experiences. The frequency of responses within each category was compared between senior and junior residents to examine differences in their approach to learning. RESULTS: Seven residents submitted 56 learning experiences (19 by seniors, 37 by juniors) over a 1-year period. Open coding revealed 113 learning points in 12 unique categories. Procedure choice was the most common category reported. Senior residents were more likely to report learning points that involved procedure choice (31% versus 18%, p = 0.01) and procedure timing (8% versus 2%, p = 0.04) than junior residents. The 12 categories were combined into four themes: evaluation and management; technical skills; complication identification and management; and teamwork and communication. Seniors were more likely to report learning points in the preoperative phase (46% versus 32%, p = 0.01). CONCLUSIONS: Brief written reflection is a feasible approach to encourage thoughtful reflection and practice based learning. Faculty members should explicitly help residents improve their practice by using individualized guidance and can influence resident learning by asking targeted questions, clarifying decisions, and modeling behavior. PMID- 27460916 TI - Protective Effects of Imatinib on Ischemia/Reperfusion Injury in Rat Lung. AB - BACKGROUND: Ischemia/reperfusion injury (IRI) remains a significant complication after lung transplantation. Endothelial damage and inflammation contribute to its development. Imatinib has been reported to regulate vascular permeability by maintaining endothelial junctions and showing antiinflammatory effects through inhibition of the Abl kinases. We hypothesized that imatinib could have a protective effect against IRI. METHODS: Male Lewis rats were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes followed by reperfusion for 120 minutes. Imatinib mesylate (50 mg/kg) and a solvent were administered intraperitoneally 20 minutes before ischemia in the imatinib group and the vehicle group, respectively (n = 7 in each group). After reperfusion, lung function, lung wet to dry weight (W/D) ratio, and histologic findings were obtained. The expression of vascular endothelial cadherin (VEC), the phosphorylation level of CrkL (pCrkL) (an exclusive target of Abl kinases), and the cytokine level were evaluated using lung tissue lysate. The imatinib concentrations of plasma and lungs after reperfusion were measured in this hilar clamp model (n = 7). RESULTS: In the imatinib group, lung function was improved with a lower W/D ratio. Perivascular edema and neutrophil infiltration were ameliorated. The imatinib group demonstrated maintained expression of VEC, inhibition of pCrkL, and a significantly higher level of interleukin (IL)-10. The imatinib concentration in both lungs showed a strong correlation with plasma concentration. CONCLUSIONS: In a rat IRI model, imatinib attenuated lung injury by an antipermeability and antiinflammatory effect. The delivery and function of imatinib in the lung was also confirmed in this model. PMID- 27460917 TI - Raising Awareness: The Need to Promote Allocation of Pancreata From Rare Nondiabetic Donors With Pancreatic Islet Autoimmunity to Type 1 Diabetes Research. PMID- 27460918 TI - Incidence and frequency of nondental incidental findings on cone-beam computed tomography. AB - PURPOSE: The purpose of the present study was to determine the frequency of relevant nondental related incidental findings in cone-beam computed tomography (CBCT) of the head and neck. MATERIAL AND METHODS: Nine hundred ninety-nine images were retrospectively reviewed for incidental findings. Those were defined as carotid artery calcification (CAC), paranasal sinus findings (PSF), sialolithiasis of the parotid gland (SP) or submandibular gland (SSub), calcification of the ligamentum stylohyoideum (CLS), and Stafne bone cavity (SBC). All datasets obtained between 2010 and 2014 at a university-based school of dental medicine in Switzerland were reviewed. Demographic data such as age and sex were also recorded. RESULTS: A total of 350 incidental findings within the 999 CBCT scans were identified. The most frequent finding was PSF (27.8%), followed by CLS (11.6%), CAC (5.3%), and SSub (0.8%). No SP or SBC was found. Incidental findings were most frequent between 61 and 70 years of age. Males had a higher prevalence in CAC, PSF, and SSub than females. CONCLUSIONS: These results underscore the need for a complete examination of every CBCT image beyond the region of interest. PMID- 27460919 TI - Emerging trends on drug use globally. PMID- 27460920 TI - Building research capacity: the value of conferences. PMID- 27460921 TI - TD-DFT calculations and thermal effects on conformers of calmagite in protic solvents varying the degree of protonation. AB - The main absorption peaks were obtained for 1-(1-hydroxy-4-methyl-2-phenylazo)-2 naphthol-4-sulfonic acid. Generalized gradient approximation, hybrid, semi empirical, and Coulomb attenuating methods were utilized to compare theoretical electronic transitions and experimental absorption spectra at different pH. The main peaks and shoulders observed in experimental spectra were assigned to its correct conformer. In order to find the most populated conformer, thermal effects on stability calculations were investigated to obtain molar fractions of possible isomers present at room and higher temperature. Theoretical electronic transitions at distinct pH could be obtained varying the protonation a deprotonation degree. It was found that generalized gradient approximation performs very well the first transition peak at neutral pH. For higher pH, all methodologies got a bathochromic shift in agreement with experiment and finally, from these theoretical results, it was obtained that this azo dye is hardly protonated in experiments since results presented here, predict a variation of absorption spectra for all proposed methodologies when the molecule is protonated, which is different to experimental results. Graphical Abstract Calculated electronic transitions of azo and hydrazone tautomers in water implicit solvent (BLYP/6-311G(2d,p) methodology). PMID- 27460923 TI - Modeling, Simulation, and Implementation of Solar-Driven Water-Splitting Devices. AB - An integrated cell for the solar-driven splitting of water consists of multiple functional components and couples various photoelectrochemical (PEC) processes at different length and time scales. The overall solar-to-hydrogen (STH) conversion efficiency of such a system depends on the performance and materials properties of the individual components as well as on the component integration, overall device architecture, and system operating conditions. This Review focuses on the modeling- and simulation-guided development and implementation of solar-driven water-splitting prototypes from a holistic viewpoint that explores the various interplays between the components. The underlying physics and interactions at the cell level is are reviewed and discussed, followed by an overview of the use of the cell model to provide target properties of materials and guide the design of a range of traditional and unique device architectures. PMID- 27460922 TI - Atypical ubiquitin ligase RNF31: the nuclear factor modulator in breast cancer progression. AB - Breast cancer causes the No.1 women cancer prevalence and the No.2 women cancer mortality worldwide. Nuclear receptor/transcriptional factor signaling is aberrant and plays important roles in breast cancer pathogenesis and evolution, such as estrogen receptor alpha (ERalpha/ESR1), tumor protein p53 (p53/TP53) and Nuclear factor kappa B (NFkappaB). About 60-70 % of breast tumors are ERalpha positive, while approximate 70 % of breast tumors are P53 wild type. Recent studies indicate that nuclear receptors/transcriptional factors could be tightly controlled through protein post-translational modification.The nuclear receptors/transcriptional factors could endure several types of modifications, including phosphorylation, acetylation and ubiquitination. Compared with the other two types of modifications, ubiquitination was mostly linked to protein degradation process, while few researches focused on the functional changes of the target proteins. Until recent years, ubiquitination process is no longer regarded as merely a protein degradation process, but aslo treated as one kind of modification signal.As an atypical E3 ubiquitin ligase, RNF31 was previously found to facilitate NFkappaB signaling transduction through linear ubiquitination on IKKgamma(IkappaB kinase gamma). Our previous studies showed important regulatory functions of RNF31 in controlling important oncogenic pathways in breast cancer, such as ERalpha and p53. This review highlights recent discoveries on RNF31 functions in nuclear factor modifications, breast cancer progression and possible therapeutic inhibitors targeting RNF31. PMID- 27460925 TI - Alignment in total knee arthroplasty. PMID- 27460926 TI - Single-cell TCRseq: paired recovery of entire T-cell alpha and beta chain transcripts in T-cell receptors from single-cell RNAseq. AB - Accurate characterization of the repertoire of the T-cell receptor (TCR) alpha and beta chains is critical to understanding adaptive immunity. Such characterization has many applications across such fields as vaccine development and response, clone-tracking in cancer, and immunotherapy. Here we present a new methodology called single-cell TCRseq (scTCRseq) for the identification and assembly of full-length rearranged V(D)J T-cell receptor sequences from paired end single-cell RNA sequencing reads. The method allows accurate identification of the V(D)J rearrangements for each individual T-cell and has the novel ability to recover paired alpha and beta segments. Source code is available at https://github.com/ElementoLab/scTCRseq . PMID- 27460927 TI - Hippocampus-based contextual memory alters the morphological characteristics of astrocytes in the dentate gyrus. AB - Astrocytes have been reported to exist in two states, the resting and the reactive states. Morphological changes in the reactive state of astrocytes include an increase in thickness and number of processes, and an increase in the size of the cell body. Molecular changes also occur, such as an increase in the expression of glial fibrillary acidic protein (GFAP). However, the morphological and molecular changes during the process of learning and memory have not been elucidated. In the current study, we subjected Fvb/n mice to contextual fear conditioning, and checked for morphological and molecular changes in astrocytes. 1 h after fear conditioning, type II and type III astrocytes exhibited a unique status with an increased number of processes and decreased GFAP expression which differed from the typical resting or reactive state. In addition, the protein level of excitatory excitatory amino acid transporter 2 (EAAT2) was increased 1 h to 24 h after contextual fear conditioning while EAAT1 did not show any alterations. Connexin 43 (Cx43) protein was found to be increased at 24 h after fear conditioning. These data suggest that hippocampus-based contextual memory process induces changes in the status of astrocytes towards a novel status different from typical resting or reactive states. These morphological and molecular changes may be in line with functional changes. PMID- 27460930 TI - Editors' note on future series of papers in INNOVATION. PMID- 27460929 TI - Muscle fiber types composition and type identified endplate morphology of forepaw intrinsic muscles in the rat. AB - The failure to accept reinnervation is considered to be one of the reasons for the poor motor functional recovery of intrinsic hand muscles (IHMs) after nerve injury. Rat could be a suitable model to be used in simulating motor function recovery of the IHMs after nerve injury as to the similarities in function and anatomy of the muscles between human and rat. However, few studies have reported the muscle fiber types composition and endplate morphologic characteristics of intrinsic forepaw muscles (IFMs) in the rat. In this study, the myosin heavy chain isoforms and acetylcholine receptors were stained by immunofluorescence to show the muscle fiber types composition and endplates on type-identified fibers of the lumbrical muscles (LMs), interosseus muscles (IMs), abductor digiti minimi (AM) and flexor pollicis brevis (FM) in rat forepaw. The majority of IFMs fibers were labeled positively for fast-switch fiber. However, the IMs were composed of only slow-switch fiber. With the exception of the IMs, the other IFMs had a part of hybrid fibers. Two-dimensional morphological characteristics of endplates on I and IIa muscle fiber had no significant differences among the IFMs. The LMs is the most suitable IFMs of rat to stimulate reinnervation of the IHMs after nerve injury. Gaining greater insight into the muscle fiber types composition and endplate morphology in the IFMs of rat may help understand the pathological and functional changes of IFMs in rat model stimulating reinnervation of IHMs after peripheral nerve injury. PMID- 27460931 TI - Real-time ultrasonography for placement of central venous catheters in children: A multi-institutional study. AB - BACKGROUND: Recommendations for the use of real-time ultrasonography for placement of central venous catheters in children are based on studies involving adults treated by nonsurgeons. Our purpose was to determine the frequency of use of real-time ultrasonography use by pediatric surgeons during central venous catheter placement, patient and procedure factors associated with real-time ultrasonography use, and adverse event rates. METHODS: Using data gathered from 14 institutions, we performed a retrospective cohort study of patients <18 years old who underwent central venous catheter placement. Patient demographics and operative details were collected. We used a logistic regression model to evaluate factors associated with real-time ultrasonography use. RESULTS: Real-time ultrasonography was used in 33% of attempts (N = 1,146). The subclavian vein (64%) was accessed preferentially for first site insertion. Real-time ultrasonography was less likely to be used for subclavian vein (odds ratio = 0.002; P < .0001) and more likely to be used when coagulopathy (international normalized ratio >1.5) was present (odds ratio = 11.1; P = .03). The rate of mechanical complications was 3.5%. Real-time ultrasonography use was associated with greater procedural success rates on first-site attempt, but also with a greater risk of hemothorax. CONCLUSION: Pediatric surgeons access preferentially the subclavian vein for central venous access, yet are less likely to use real time ultrasonography at this site. Real-time ultrasonography was superior to the landmark techniques for the first-site procedure success, yet was associated with greater rates of hemothorax. Prospective trials involving children treated by pediatric surgeons are needed to generate more definitive data. PMID- 27460932 TI - Discussion. PMID- 27460933 TI - A problem-oriented approach to resident performance ratings. AB - BACKGROUND: Global, end-of-rotation evaluations are often difficult to interpret due to their high level of abstraction (eg, excellent, good, poor) and the bias toward high ratings. This study documents the utility of and measurement characteristics of serious problem items, an alternative item format. METHODS: This report is based on 4,234 faculty performance ratings for 105 general surgery residents. Faculty members reported whether each resident had a serious problem for each of 8 areas of clinical performance and 6 areas of professional behavior. RESULTS: A total of 263 serious problems were reported. The performance category with the most total serious problems noted was knowledge and that with the least problems noted was relations with patients and family members. Seven residents accounted for 86.9% of all serious problem reports. Each resident had serious problems in multiple performance areas. Problems were reported most frequently in knowledge, management, technical/procedural skills, ability to assume responsibility within level of competence, and problem identification. Citations of these serious problems were most common in year 3. Traditional ratings of global performance were not an adequate means for identifying residents with serious performance problems. CONCLUSION: Serious problem ratings can communicate faculty concerns about residents more directly and can be used as a complement to conventional global rating scales without substantially increasing faculty workload. PMID- 27460934 TI - Factors associated with self-reported health: implications for screening level community-based health and environmental studies. AB - BACKGROUND: Advocates for environmental justice, local, state, and national public health officials, exposure scientists, need broad-based health indices to identify vulnerable communities. Longitudinal studies show that perception of current health status predicts subsequent mortality, suggesting that self reported health (SRH) may be useful in screening-level community assessments. This paper evaluates whether SRH is an appropriate surrogate indicator of health status by evaluating relationships between SRH and sociodemographic, lifestyle, and health care factors as well as serological indicators of nutrition, health risk, and environmental exposures. METHODS: Data were combined from the 2003-2006 National Health and Nutrition Examination Surveys for 1372 nonsmoking 20-50 year olds. Ordinal and binary logistic regression was used to estimate odds ratios and 95 % confidence intervals of reporting poorer health based on measures of nutrition, health condition, environmental contaminants, and sociodemographic, health care, and lifestyle factors. RESULTS: Poorer SRH was associated with several serological measures of nutrition, health condition, and biomarkers of toluene, cadmium, lead, and mercury exposure. Race/ethnicity, income, education, access to health care, food security, exercise, poor mental and physical health, prescription drug use, and multiple health outcome measures (e.g., diabetes, thyroid problems, asthma) were also associated with poorer SRH. CONCLUSION: Based on the many significant associations between SRH and serological assays of health risk, sociodemographic measures, health care access and utilization, and lifestyle factors, SRH appears to be a useful health indicator with potential relevance for screening level community-based health and environmental studies. PMID- 27460935 TI - Stratified, precision or personalised medicine? Cancer services in the 'real world' of a London hospital. AB - We conducted ethnographic research in collaboration with a large, research intensive London breast cancer service in 2013-2014 so as to understand the practices and potential effects of stratified medicine. Stratified medicine is often seen as a synonym for both personalised and precision medicine but these three terms, we found, also related to distinct facets of treatment and care. Personalised medicine is the term adopted for the developing 2016 NHS England Strategy, in which breast cancer care is considered a prime example of improved biological precision and better patient outcomes. We asked how this biologically stratified medicine affected wider relations of care and treatment. We interviewed formally 33 patients and 23 of their carers, including healthcare workers; attended meetings associated with service improvements, medical decision making, public engagement, and scientific developments as well as following patients through waiting rooms, clinical consultations and other settings. We found that the translation of new protocols based on biological research introduced further complications into an already-complex patient pathway. Combinations of new and historic forms of stratification had an impact on almost all patients, carers and staff, resulting in care that often felt less rather than more personal. PMID- 27460936 TI - Quality by Design Empowered Development and Optimisation of Time-Controlled Pulsatile Release Platform Formulation Employing Compression Coating Technology. AB - The research was envisaged for development of time-controlled pulsatile release (PR) platform formulation to facilitate management of early morning chronological attacks. The development was started using prednisone as a model drug wherein core tablets were prepared using direct compression method and subsequently compression-coated with ethylcellulose (EC)-hydroxypropyl methylcellulose (HPMC) excipient blend. Initially, quality target product profile was established and risk assessment was performed using failure mode and effect analysis. In an endeavour to accomplish the objective, central composite design was employed as a design of experiment (DoE) tool. Optimised compression-coated tablet (CCT) exhibited 4-6 h lag time followed by burst release profile under variegated dissolution conditions viz. multi-media, change in apparatus/agitation and biorelevant media. Afterwards, five different drugs, i.e. methylprednisolone, diclofenac sodium, diltiazem hydrochloride, nifedipine and lornoxicam, were one by-one incorporated into the optimised prednisone formula with replacement of former drug. Change in drug precipitated the issues like poor solubility and flow property which were respectively resolved through formulation of solid dispersion and preparation of active pharmaceutical ingredient (API) granules. Albeit, all drug CCTs exhibited desired release profile similar to prednisone CCTs. In nutshell, tour de force of research epitomised the objective of incorporating diverse drug molecules and penultimately obtaining robust release profile at varying dissolution conditions. PMID- 27460937 TI - Short-term cross-sensitizion of need-free sugar intake by combining sodium depletion and hypertonic NaCl intake. AB - History of sodium depletion cross-sensitizes the effects of drugs of abuse. The objective of the present study was to find out if history of sodium depletion also cross-sensitizes a natural reward such as sugar intake in the rat. Sodium depletion was induced by furosemide combined with removal of ambient sodium for 24 h; it was repeated seven days later. The depletion was immediately followed by 0.3 M NaCl intake in a sodium appetite test (active sodium repletion). Seven days after the last depletion, hydrated and fed (need-free) sucrose-naive animals were offered 10% sucrose in a first 2-h sucrose test. The sucrose test was repeated once a day in a series of five consecutive days. History of sodium depletion enhanced sucrose intake in the first and second tests; it had no effect from the third to fifth sucrose test. The effect on the initial sucrose intake tests disappeared if the rats did not ingest 0.3 M NaCl in the sodium appetite test. Prior experience with sucrose intake in need-free conditions had no effect on sodium appetite. History of intracellular dehydration transiently influenced sucrose intake in the first sucrose test. We found no evidence for thirst sensitization. We conclude that history of dehydration, particularly that resulting from sodium depletion, combined to active sodium repletion, produced short-term cross-sensitization of sucrose intake in sucrose-naive rats. The results suggest that the cross-sensitization of sucrose intake related with acquisition of sugar as a novel nutrient rather than production of lasting effects on sugar rewarding properties. PMID- 27460938 TI - Economic crisis, austerity and unmet healthcare needs: the case of Greece. AB - BACKGROUND: The programme for fiscal consolidation in Greece has led to income decrease and several changes in health policy. In this context, this study aims to assess how economic crisis affected unmet healthcare needs in Greece. METHODS: Time series analysis was performed for the years 2004 through 2011 using the EU SILC database. The dependent variable was the percentage of people who had medical needs but did not use healthcare services. Median income, unemployment and time period were used as independent variables. We also compared self reported unmet healthcare needs drawn from a national survey conducted in pre crisis 2006 with a similar survey from 2011 (after the onset of the crisis). A common questionnaire was used in both years to assess unmet healthcare needs, including year of survey, gender, age, health status, chronic disease, educational level, income, employment, health insurance status, and prefecture. The outcome of interest was unmet healthcare needs due to financial reasons. Ordinary least squares, as well as logistic regression analysis were conducted to analyze the results. RESULTS: Unmet healthcare needs increased after the enactment of austerity measures, while the year of participation in the survey was significantly associated with unmet healthcare needs. Income, educational level, employment status, and having insurance, private or public, were also significant determinants of unmet healthcare needs due to financial reasons. CONCLUSIONS: The adverse economic environment has significantly affected unmet health needs. Therefore health policy actions and social policy measures are essential in order to mitigate the negative impact on access to healthcare services and health status. PMID- 27460939 TI - Comparing nationwide prevalences of hypertension and depression based on claims data and survey data: An example from Germany. AB - INTRODUCTION: Coded diagnoses in claims data offer a comprehensive basis for health sciences and health policy decisions. For example, morbidity-based risk adjustment schemes use coded diagnoses to allocate resources. Therefore a routinely performed validation is important. Data reconciliation with medical records would be first best, but is not possible here. This paper validates population-based prevalences of hypertension and depression based on claims data by comparing them with prevalences stem from two different epidemiological survey data. METHOD: Data sources accessible are a nationwide sample based on outpatient claims data (GSPR), a nationwide health interview and examination survey (DEGS1) and a nationwide telephone interview survey (GEDA). The analysis includes SHI insured aged 18-79 who live in 2010 in Germany. RESULTS: There was high agreement for hypertension prevalences between GSPR (28.98% [28.95-29.02]) and DEGS1 (28.0% [26.5-29.5]) but not with GEDA (22.9% [22.1-23.7]). The agreement for depression prevalences was high between the two surveys (DEGS1: 7.6% [6.7-8.5] and GEDA: 6.7% [6.3-7.2]) and moderate compared to GSPR (12.23% [12.21-12.26]). CONCLUSION: For an objectifiable disease, such as hypertension, diagnostic coding with claims data seems to be valid to be used for risk adjustment in German outpatient health care. Even though depression prevalences differ between claims data and survey data, more effort is required to understand the magnitude of a reference systems impact on prevalence estimates. PMID- 27460940 TI - Measuring and improving quality in university hospitals in Canada: The Collaborative for Excellence in Healthcare Quality. AB - Measuring and monitoring overall health system performance is complex and challenging but is crucial to improving quality of care. Today's health care organizations are increasingly being held accountable to develop and implement actions aimed at improving the quality of care, reducing costs, and achieving better patient-centered care. This paper describes the development of the Collaborative for Excellence in Healthcare Quality (CEHQ), a 5-year initiative to achieve higher quality of patient care in university hospitals across Canada. This bottom-up initiative took place between 2010 and 2015, and was successful in engaging health care leaders in the development of a common framework and set of performance measures for reporting and benchmarking, as well as working on initiatives to improve performance. Despite its successes, future efforts are needed to provide clear national leadership on standards for measuring performance. PMID- 27460941 TI - Dabigatran can cause eosinophilic pleural and pericardial effusion with blood eosinophilia. AB - Eosinophilic pleural effusions (EPE) account for 5%-8% of all exudative pleural effusions. A pleural effusion is defined as eosinophilic if it contains 10% or more eosinophils. We present the case of a 70-year-old man with EPE, blood eosinophilia and pericardial effusion due to dabigatran, a novel anti-thrombin agent. PMID- 27460942 TI - Influence of body mass index on the prevalence and progression of dysplasia in Barrett's esophagus: a retrospective analysis (.). AB - OBJECTIVE: High body mass index (BMI) is a risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Our aim was to determine if prevalence of dysplasia in BE varies by BMI and study the effect of BMI on progression to high-grade dysplasia (HGD) or EAC. MATERIALS AND METHODS: This is a retrospective review of patients with endoscopic evidence of BE confirmed by presence of intestinal metaplasia on histology from January 2000 to December 2012 at Cleveland Clinic. Patient demographics, BMI and endoscopic findings such as length of BE, dysplasia in BE and size of hiatal hernia were reviewed. Dysplasia was classified as no dysplasia (NDBE), low-grade dysplasia (LGD), HGD and EAC. RESULTS: In this cohort of 1239 patients, average BMI was 29.8 +/- 6 kg/m(2). There were 228 (18.4%) in group with BMI <25, 236 (19%) in BMI group 25-27.4, 262 (21.1%) in BMI 27.5-29.9, 303 (24.5%) in BMI 30-34.9, 126 (10.2%) in BMI 35-39.9 and 86 (6.8%) in BMI >=40. Lower BMI groups had lower prevalence of dysplasia while higher BMI groups had higher prevalence of dysplasia (p = 0.002). During mean follow up of 31.6 +/- 26 months, there were 14 cases of HGD/EAC in NDBE group and 29 cases of HGD/EAC in LGD group. BMI or BMI change was not associated with progression to HGD/EAC in NDBE. CONCLUSIONS: High BMI was associated with higher prevalence of dysplasia in BE. But once in a surveillance program, higher BMI is not associated with progression of dysplasia in NDBE. PMID- 27460943 TI - Wound management for the 21st century: combining effectiveness and efficiency. AB - Treatment of wounds of different aetiologies constitutes a major part of the total health care budget. It is estimated that 1.5-2 million people in Europe suffer from acute or chronic wounds. These wounds are managed both in hospitals and in community care. The patients suffering from these wounds report physical, mental and social consequences of their wounds and the care of them. It is often believed that the use of wound dressings per se is the major cost driver in wound management, whereas in fact, nursing time and hospital costs are together responsible for around 80-85% of the total cost. Healing time, frequency of dressing change and complications are three important cost drivers. However, with the use of modern, advanced technology for more rapid wound healing, all these cost drivers can be substantially reduced. A basic understanding of the terminology and principles of Health Economics in relation to wound management might therefore be of interest. PMID- 27460944 TI - A novel roseobacter phage possesses features of podoviruses, siphoviruses, prophages and gene transfer agents. AB - Bacteria in the Roseobacter lineage have been studied extensively due to their significant biogeochemical roles in the marine ecosystem. However, our knowledge on bacteriophage which infects the Roseobacter clade is still very limited. Here, we report a new bacteriophage, phage DSS3Phi8, which infects marine roseobacter Ruegeria pomeroyi DSS-3. DSS3Phi8 is a lytic siphovirus. Genomic analysis showed that DSS3Phi8 is most closely related to a group of siphoviruses, CbK-like phages, which infect freshwater bacterium Caulobacter crescentus. DSS3Phi8 contains a smaller capsid and has a reduced genome size (146 kb) compared to the CbK-like phages (205-279 kb). DSS3Phi8 contains the DNA polymerase gene which is closely related to T7-like podoviruses. DSS3Phi8 also contains the integrase and repressor genes, indicating its potential to involve in lysogenic cycle. In addition, four GTA (gene transfer agent) genes were identified in the DSS3Phi8 genome. Genomic analysis suggests that DSS3Phi8 is a highly mosaic phage that inherits the genetic features from siphoviruses, podoviruses, prophages and GTAs. This is the first report of CbK-like phages infecting marine bacteria. We believe phage isolation is still a powerful tool that can lead to discovery of new phages and help interpret the overwhelming unknown sequences in the viral metagenomics. PMID- 27460946 TI - Spontaneity of smile after facial paralysis rehabilitation when using a non facial donor nerve. AB - INTRODUCTION: The current focus in dynamic reanimation of facial paralysis lies not only in restoring movement but also regaining smile spontaneity. It has been argued that a spontaneous smile can only be achieved using the contralateral facial nerve as donor via cross-face nerve grafting. Techniques based on the motor nerve to the masseter, however, have shown good rates of spontaneity as well. PATIENTS AND METHODS: Patients with complete facial paralysis reanimated using free gracilis to masseteric nerve or masseteric-to-facial nerve transfer were included. Patients were grouped according to gender comparing the rates of spontaneous smile. RESULTS: Thirty-six patients (17 women and 19 men) underwent gracilis innervated by the masseteric nerve whereas masseteric-to-facial nerve transfer was performed in 30 cases (14 women and 16 men). For both techniques, women showed significantly higher rates of spontaneity. Additionally, women recovered spontaneity earlier than men. CONCLUSIONS: Along with providing a strong and reliable commissural pull, the motor nerve to the masseter is able to restore spontaneity as well. Women seem more prone to achieving it. Brain plasticity and the close relationship between the cortical areas of the masseteric and facial nerves are most likely the mechanisms underlying smile spontaneity. PMID- 27460945 TI - Spatio-temporal diversification of the cell wall matrix materials in the developing stomatal complexes of Zea mays. AB - MAIN CONCLUSION: The matrix cell wall materials, in developing Zea mays stomatal complexes are asymmetrically distributed, a phenomenon appearing related to the local cell wall expansion and deformation, the establishment of cell polarity, and determination of the cell division plane. In cells of developing Zea mays stomatal complexes, definite cell wall regions expand determinately and become locally deformed. This differential cell wall behavior is obvious in the guard cell mother cells (GMCs) and the subsidiary cell mother cells (SMCs) that locally protrude towards the adjacent GMCs. The latter, emitting a morphogenetic stimulus, induce polarization/asymmetrical division in SMCs. Examination of immunolabeled specimens revealed that homogalacturonans (HGAs) with a high degree of de-esterification (2F4- and JIM5-HGA epitopes) and arabinogalactan proteins are selectively distributed in the extending and deformed cell wall regions, while their margins are enriched with rhamnogalacturonans (RGAs) containing highly branched arabinans (LM6-RGA epitope). In SMCs, the local cell wall matrix differentiation constitutes the first structural event, indicating the establishment of cell polarity. Moreover, in the premitotic GMCs and SMCs, non esterified HGAs (2F4-HGA epitope) are preferentially localized in the cell wall areas outlining the cytoplasm where the preprophase band is formed. In these areas, the forthcoming cell plate fuses with the parent cell walls. These data suggest that the described heterogeneity in matrix cell wall materials is probably involved in: (a) local cell wall expansion and deformation, (b) the transduction of the inductive GMC stimulus, and PMID- 27460947 TI - Comparison of two treatment protocols in children with unilateral complete cleft lip and palate: Tridimensional evaluation of the maxillary dental arch. AB - OBJECTIVE: The aim of this study was to evaluate the dimensional alterations of the maxillary dental arches after lip repair in children with unilateral complete cleft lip and palate of two different protocols. MATERIAL AND METHODS: The sample was composed of 94 digital models and divided in two groups: Group I - 23 children, (protocol 1) - with presurgical orthopedic intervention: Hotz plate; Group II - 24 children, (protocol 2) - without presurgical orthopedic intervention. The three dimensional images of the maxillary arch were obtained before lip repair (stage 1) and at approximately 1 year of age (stage 2). Interstages changes for each group were evaluated using dependent t test and Wilcoxon test, and in the intergroup were used independent t test, and Mann Whitney test. RESULTS: The comparison of the dimensional alterations of dental arches between the two protocols exhibited differences: in the stage 1, the intercanine was smaller in Group II; in the stage 2, the anterior cleft width, the intercanine and the anteroposterior cleft were smaller in Group II. CONCLUSION: The results reported here suggest that the use of infant orthopedic plate as applied in protocol 1 may favor correct arch form establishment in infants with unilateral complete cleft lip and palate. PMID- 27460948 TI - Abnormal appearance of the umbilicus: an indicator of urachal anomalies. AB - The urachus is an intra-abdominal fibrous remnant of the allantois. The non involution of the allantois can result in urachal anomalies. The abnormal appearance of the umbilicus may be a sign of such anomalies. We have observed 3 cases of term neonates with atypical appearance of the umbilical stump, all of which manifested urachal anomalies, as documented by ultrasound scan. These appearances are rarely described in the literature, and seem to regress at around 2 months. Therefore, it is important that healthcare professionals should be aware of the possible implications of atypical umbilical stumps, evaluate each case accordingly and, if an urachal anomaly is diagnosed, refer the patient to a paediatric surgery centre, as such malformations carry an underlying risk of infection or malignancy. PMID- 27460949 TI - Effect of saracatinib on pulmonary metastases from hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Src is involved in multiple processes of cancer metastasis; however, its significance in HCC is not well defined. In the present study, overexpression of Src phosphorylation (Y416) was observed in the highly metastatic MHCC97H cell line; additionally, through inhibition of Src kinase activation, HCC cell proliferation, migration, invasion and colony formation were significantly reduced in vitro. Tumour growth was not affected in the orthotopic xenograft HCC model, but the metastasic potential was inhibited as revealed by reduced lung metastasic foci after administration of saracatinib. Phosphorylation level of Src pathway signalling molecules, such as Src, FAK and Stat3, were also reduced in vitro and in vivo, as a result of the anti-metastasic effects caused by saracatinib treatment. In conclusion, we demonstrated the pro-metastasic role of Src in HCC, and further experiments suggest the use of the Src inhibitor in combination with cytotoxic agents and other anticancer treatments to improve HCC prognosis. PMID- 27460950 TI - Usefulness of procalcitonin level as an outcome predictor of adult bacterial meningitis. AB - Acute bacterial meningitis is rare, but can be fulminant unless rapidly evaluated and treated. The aim of this study was to evaluate whether serum procalcitonin (PCT) levels could predict unfavorable outcomes of bacterial meningitis. We retrospectively reviewed the medical records of 604 meningitis patients from the emergency department (ED) of our tertiary care, university-affiliated hospital over a five-year period. We analyzed the ability of blood PCT levels on admission to predict the outcome at discharge (defined as Glasgow Outcome Scale scores of 1 4). Of 71 patients with acute bacterial meningitis, 28 (39 %) experienced an unfavorable outcome at discharge (overall mortality: 5 %). The serum PCT level at admission was a predictive indicator of an unfavorable outcome [adjusted odds ratio: 1.04, 95 % confidence interval (CI) 1.01-1.09, p = 0.05]. As assessed using receiver operating characteristic curves for an unfavorable outcome, the area under the PCT curve was 0.708 (95 % CI 0.58-0.84, p < 0.01). When the PCT cutoff value was >=1.10 ng/mL, the sensitivity, specificity, positive predictive value and negative predictive value for an unfavorable outcome were 75, 70, 62, and 81 %, respectively. An association between the serum PCT level and an unfavorable outcome is observed. PMID- 27460951 TI - Duran Madonna (c. 1435-1438) by Rogier van der Weyden: a case of congenital goiter. PMID- 27460952 TI - Topical application of superoxide dismutase mediated by HIV-TAT peptide attenuates UVB-induced damages in human skin. AB - The purpose of this study was to evaluate whether topical application of superoxide dismutase with cell penetrating peptide (HIV-TAT) could protect against skin damage induced by UVB irradiation in humans. The permeability through stratum corneum of large proteins linked to TAT peptide was firstly confirmed by confocal microscopy and tape stripping. Ten healthy volunteers with either Fitzpatrick skin type II or III were recruited in this clinical study. TAT SOD (300units/cm(2)) and vehicle cream were applied on two symmetric areas of both inner upper arms 1h prior to UVB irradiation. After one hour of pretreatment, subjects received 10 incremental doses of UVB on pretreated areas. 24h later, erythema, blood flow and apoptotic cells were measured. Pretreatment with TAT-SOD 1h prior to UVB radiation promoted a mean minimal erythema dose (MED) increase of 36.6+/-18.4% (p=0.013<0.05. n=10) compared to vehicle control. The median blood flow values of all subjects following 2 and 3-MED of UVB were 107.8+/-51.0units and 239.5+/-88.0units respectively, which account for 26% and 25% decrease with respect to vehicle groups. These data suggest that TAT-SOD significantly suppresses UVB induced erythema formation and blood flow rise. Furthermore, pretreatment with TAT-SOD 1h prior to 2-MED of UVB irradiation reduced the apoptotic sunburn cell formation by 47.6+/-8.6% (p<0.0001) in all subjects. Evaluating results generated from all measurements, we conclude that topical application of TAT-SOD significantly attenuates UVB-induced skin damage in man. These biological effects of TAT-SOD are probably mediated via its free radical scavenging properties, clearly differentiating it from other physical sunscreen agents. PMID- 27460953 TI - Frog Foam Nest Protein Diversity and Synthesis. AB - Some amphibian species have developed a breeding strategy in which they deposit their eggs in stable foam nests to protect their eggs and larvae. The frog foam nests are rich in proteins (ranaspumin), especially surfactant proteins, involved in the production of the foam nest. Despite the ecological importance of the foam nests for evolution and species conservation, the biochemical composition, the long-term stability and even the origin of the components are still not completely understood. Recently we showed that Lv-RSN-1, a 23.5-kDa surfactant protein isolated from the nest of the frog Leptodacylus vastus, presents a structural conformation distinct from any protein structures yet reported. So, in the current study we aimed to reveal the protein composition of the foam nest of L. vastus and further characterize the Lv-RSN-1. Proteomic analysis showed the foam nest contains more than 100 of proteins, and that Lv-RSN-1 comprises 45% of the total proteins, suggesting a key role in the nest construction and stability. We demonstrated by Western blotting that Lv-RSN-1 is mainly produced only by the female in the pars convoluta dilata, which highlights the importance of the female preservation for conservation of species that depend on the production of foam nests in the early stages of development. Overall, our results showed the foam nest of L. vastus is composed of a great diversity of proteins and that besides Lv-RSN-1, the main protein in the foam, other proteins must have a coadjuvant role in building and stability of the nest. PMID- 27460954 TI - The synthesis and analysis of [phenyl-14 C(U)]BMS-770767 and [13 C6 ]BMS-770767 for use in discovery biotransformation, human ADME and bioanalytical studies. AB - Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-770767 as an inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) for type 2 diabetes was required the synthesis of carbon-14 labelled material for use in metabolic profiling and for the human adsorption, distribution, metabolism and excretion (ADME) study. Initially, [phenyl-14 C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [14 C(U)]2-chlorophenol to give the desired final product in 18% yield. Later, the synthesis was completed for the human ADME clinical study using a combination of the discovery and process chemistry routes under cGMP to prepare [phenyl-14 C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl-14 C(U)]BMS 770767 after dilution with unlabelled clinical grade BMS-770767 was 99.1% having a specific activity of 1.61 MUCi/mg. In addition, to support the quantification of BMS-770767 in LC/MS analyses, [13 C6 ]BMT-770767 was prepared in two steps from a late-stage intermediate and [13 C6 ]2-chlorophenol. PMID- 27460955 TI - Increasing incidence of postpartum hemorrhage: the Dutch piece of the puzzle. AB - INTRODUCTION: An increase of postpartum hemorrhage (PPH) has been reported in many high-income countries. In addition to this data, this study reports on trends in the incidence of PPH in the Netherlands in 2000-2013, and examines the extent to which temporal changes in risk indicators could explain a possible change in incidence of PPH. MATERIAL AND METHODS: We used data from the Dutch Perinatal Registry, which contains prospectively collected antenatal, peripartum and neonatal data of 95-99% of all women and neonates in the Netherlands. We selected births >=22 weeks of gestation from January 2000 until December 2013. Changes in the incidence of PPH and its risk indicators were studied over time. Main outcome measure was PPH, defined as blood loss >1000 mL within 24 h following delivery. RESULTS: The data comprised 2 406 784 women. The incidence of PPH rose significantly from 4.1% in 2000 to 6.4% in 2013 (p < 0.0001). The incidence of previously identified risk indicators for PPH increased over time. Manual removal of placenta was strongly associated with PPH (OR 29.3, CI 28.8 29.8). The incidence of PPH-related blood transfusion decreased remarkably. CONCLUSIONS: In line with international observations, Dutch data suggest a considerable increase in the incidence of PPH which can only partly be explained by the studied risk indicators. The decreasing incidence of obstetric blood transfusion suggests an increased incidence of blood loss of 1000-1500 mL. PMID- 27460956 TI - Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1. AB - OBJECTIVE: Individuals with neurofibromatosis type 1 (NF1) are at an increased risk of developing a pheochromocytoma or paraganglioma (PHEO/PGL). However, the best case detection strategy is unknown. Our objectives were to describe the prevalence, clinical presentation and outcomes of PHEO/PGL associated with NF1 and formulate case detection testing recommendations for PHEO/PGL. DESIGN: A retrospective cohort study from 1959 to 2015, Tertiary medical centre. PATIENTS AND MEASUREMENTS: We studied 41 patients with NF1 and PHEO/PGL who were identified using the PHEO/PGL and NF1 databases: 3289 and 1415 patients, respectively. Our main outcome measures were prevalence of PHEO/PGL in NF1 and occurrence of bilateral, recurrent, or metastatic disease and method of PHEO/PGL detection (symptoms vs incidental vs biochemical case detection testing). RESULTS: The prevalence of PHEO/PGL in patients with NF1 was 2.9%. The 41 patients included 23 men (56%) and 18 women. The median age at diagnosis was 41.0 years (range 14-67). The median tumour size was 3.4 cm (range 0.8-9.5). Bilateral PHEO was identified in 17% (n = 7) of patients, all women. Metastatic or recurrent disease occurred in 7.3% (n = 3). In the last 25 years, PHEO/PGL was diagnosed after incidental finding on computed imaging in 31% of patients (n = 11). Only three patients (7.3%) had PHEO/PGL discovered because of biochemical case detection testing. CONCLUSION: We recommend patients with NF1 have biochemical case detection testing for PHEO/PGL every 3 years starting at age 10 to 14 years. Biochemical case detection testing should also be carried out prior to elective surgical procedures and conception. PMID- 27460957 TI - Effects of travel distance and season of the year on transport-related mortality in cattle. AB - The number of animals that die during transport to a slaughterhouse or shortly after being delivered to a slaughterhouse may serve as an indicator of animal welfare during transport. The aim of this study was to determine the mortality rate in cattle resulting from transport to slaughter in the Czech Republic in the period from 2009 to 2014, and to investigate the effect of travel distance and season of the year. Transport-related mortality rates were recorded for all categories of cattle for the following travel distances: up to 50 km, 51-100 km, 101-200 km and over 200 km. Higher mortality rates occurred with shorter travel distances (<50 km and 51-100 km) when compared to longer travel distances (101 200 km and > 200 km), with a significant difference (P < 0.01) between short and long travel distances being found in feeders and dairy cows. Also, the season of the year had a significant impact on the mortality rate among transported cattle. The highest mortality rate in all categories was observed in spring months. The lowest mortality rate was found in autumn months for fat cattle and dairy cows and in winter months for feeders and calves. PMID- 27460958 TI - Genotoxicity assessment and oxidative stress responses in freshwater African catfish Clarias gariepinus exposed to fenthion formulations. AB - Fenthion is one of the most widely used organophosphate insecticides for the control of many varieties of pests in Nigeria. The genotoxic effect of the pesticide was evaluated in the blood erythrocytes of Clarias gariepinus using the micronucleus (MN) test. The oxidative stress parameters were also studied in the liver and gill tissues. Fish were exposed to 2.0, 4.0, and 8.0 mgL-1 of fenthion and sampling was done on days 1, 7, 14, 21 and after 7-day recovery. Micronuclei induction was highest (7.55) on day 14 at all concentrations in the peripheral blood cells. Oxidative stress was evidenced by increased lipid peroxidation (LPO). Maximum LPO values of 62.47% and 71.17% were observed in the gill and liver tissues respectively in C. gariepinus exposed to 8.0 mgL-1 concentration of fenthion. There were alterations in the values of reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) during the exposure and recovery periods. The 7-day recovery period was not adequate to eliminate fenthion-induced changes as LPO, CAT, and GR activity remain elevated. However, MN frequency and activity of SOD, GSH, and GPx (except at 8.0 mgL-1) recovered. The present findings give further credence on the integrated use of MN test and oxidative stress parameters in risk assessment of pollutants in aquatic ecosystem. PMID- 27460960 TI - Metal-ligand cooperation at tethered pi-ligands. AB - Metal-ligand cooperativity in homogeneous catalysis is emerging as a powerful tool for the design of efficient transition-metal catalysts. This perspective highlights recent advances in the use of neutral pi-coordinating ligands, tethered to a transition-metal center by other donor ligands, as cooperative reaction centers. The state-of-the-art organometallic complexes, including pi coordinating ligands originating from C[double bond, length as m-dash]C, C[double bond, length as m-dash]E (E = O, N) and boron containing moieties, are described here, with special attention on their specific reactivity. Geometric and electronic aspects of ligand design and their influence on the coordination mode and reactivity of the pi-system are discussed. PMID- 27460959 TI - Investigation of mechanism of bone regeneration in a porous biodegradable calcium phosphate (CaP) scaffold by a combination of a multi-scale agent-based model and experimental optimization/validation. AB - Herein, we have developed a novel approach to investigate the mechanism of bone regeneration in a porous biodegradable calcium phosphate (CaP) scaffold by a combination of a multi-scale agent-based model, experimental optimization of key parameters and experimental data validation of the predictive power of the model. The advantages of this study are that the impact of mechanical stimulation on bone regeneration in a porous biodegradable CaP scaffold is considered, experimental design is used to investigate the optimal combination of growth factors loaded on the porous biodegradable CaP scaffold to promote bone regeneration and the training, testing and analysis of the model are carried out by using experimental data, a data-mining algorithm and related sensitivity analysis. The results reveal that mechanical stimulation has a great impact on bone regeneration in a porous biodegradable CaP scaffold and the optimal combination of growth factors that are encapsulated in nanospheres and loaded into porous biodegradable CaP scaffolds layer-by-layer can effectively promote bone regeneration. Furthermore, the model is robust and able to predict the development of bone regeneration under specified conditions. PMID- 27460961 TI - Osteology of the crescent gunnel Pholis laeta and the phylogeny of the family Pholidae (Cottiformes, Zoarcoidei). AB - This study provides a complete description of the osteology of the crescent gunnel Pholis laeta based on cleared-and-stained specimens and X-rays to help provide sufficient morphological data to generate a robust phylogeny for the family Pholidae. Pholis laeta exhibits high variation in the structure of its caudal skeleton. The length of the preural (pu)2 neural spine is variably reduced (most common) or elongated (i.e. of similar length to that of pu3). Additionally, the neural spine of pu3 is either bifurcated or single. These results document and describe characters useful for phylogenetic inference of the family, including the insertion pattern of anal-fin pterygiophores between haemal spines. Pholidae was recovered as monophyletic (synapomorphies: ribs absent, haemonephropophyses present, gill membranes broadly joined, first neural arch fused to centrum, first anal-fin spine very robust, the dorsal fin comprises only spines and the presence of five branchiostegals), with monophyletic genera Pholis and Apodichthys (Rhodymenichthys is monotypic) and Apodichthys and Rhodymenichthys as sister taxa. The elongation of its pu2 neural spine defines Pholis and synapomorphies for Apodichthys include five infraorbital bones, no pelvic fin, a hypertrophied first anal-fin spine, the presence of two or three empty interhaemal spaces after the anteriormost anal-fin spine and having 35-46 abdominal vertebrae. Apodichthys and Rhodymenichthys are sister taxa based on the continuity of the caudal fin with the dorsal and anal fins and uniform colouration. Future study is needed to more fully resolve the interrelationships of species within Pholidae (especially the genus Pholis) and solidify the position of Pholidae within the Zoarcoidei. PMID- 27460962 TI - Downregulation of ClC-3 in dorsal root ganglia neurons contributes to mechanical hypersensitivity following peripheral nerve injury. AB - ClC-3 chloride channel/antiporter has been demonstrated to play an important role in synaptic transmission in central nervous system. However, its expression and function in sensory neurons is poorly understood. In present work, we found that ClC-3 is expressed at high levels in dorsal root ganglia (DRG). Co immunofluorescent data showed that ClC-3 is mainly distributed in A- and C-type nociceptive neurons. ClC-3 expression in DRG is decreased in the spared nerve injury (SNI) model of neuropathic pain. Knockdown of local ClC-3 in DRG neurons with siRNA increased mechanical sensitivity in naive rats, while overexpression of ClC-3 reversed the hypersensitivity to mechanical stimuli after peripheral nerve injury. In addition, genetic deletion of ClC-3 enhances mouse mechanical sensitivity but did not affect thermal and cold threshold. Restoration of ClC-3 expression in ClC-3 deficient mice reversed the mechanical sensitivity. Mechanistically, loss of ClC-3 enhanced mechanical sensitivity through increasing the excitability of DRG neurons. These data indicate that ClC-3 is an endogenous inhibitor of neuropathic pain development. Downregulation of ClC-3 by peripheral nerve injury is critical for mechanical hypersensitivity. Our findings suggest that ClC-3 is a novel therapeutic target for treating neuropathic pain. PMID- 27460963 TI - Severe stress hormone conditions cause an extended window of excitability in the mouse basolateral amygdala. AB - Shortly after stress, basolateral amygdala neurons are exposed to sequential yet partly overlapping waves of hormones. We examined how these hormonal waves can change activity of basolateral amygdala neurons such that emotional aspects of stress become so deeply ingrained. To this end, spontaneous glutamatergic transmission was recorded during and up to several hours after combined adrenergic and corticosteroid waves, targeting the time-window relevant for encoding of stress-related information. Hormonal waves mimicking moderately stressful conditions cause a transient enhancement followed by later suppression of glutamatergic transmission. However, this late phase flips from suppressed to enhanced glutamatergic transmission with conditions mimicking severe stress. Such a prolonged window of enhanced excitability may contribute to the excessively strong encoding seen after the experience of highly stressful or traumatic events. PMID- 27460964 TI - Exercise and Strength Training in Postmenopausal Women at Risk for Cardiovascular Disease: Need for Strategies to Improve Adherence. PMID- 27460965 TI - Diverse N-Heterocyclic Ring Systems via Aza-Heck Cyclizations of N (Pentafluorobenzoyloxy)sulfonamides. AB - Aza-Heck cyclizations initiated by oxidative addition of Pd(0) -catalysts into the N-O bond of N-(pentafluoro-benzoyloxy)sulfonamides are described. These studies, which encompass only the second class of aza-Heck reaction developed to date, provide direct access to diverse N-heterocyclic ring systems. PMID- 27460966 TI - Ediacaran discs from South America: probable soft-bodied macrofossils unlock the paleogeography of the Clymene Ocean. AB - The origin, affinity and paleoecology of macrofossils of soft-bodied organisms of the terminal Ediacaran Period have been highly debated. Previous discoveries in South America are restricted to small shelly metazoans of the Nama Assemblage. Here we report for the first time the occurrence of discoidal structures from the Upper Ediacaran Cerro Negro Formation, La Providencia Group, Argentina. Specimens are preserved in tabular sandstones with microbially-induced sedimentary structures. Flute marks and linear scours at the base of the sandstone layers indicate deposition under high energy, episodic flows. Stratigraphic, sedimentologic, petrographic and taphonomic analyses indicate that the origin of these structures is not related to abiotic process. Preservational and morphological features, as invagination and the presence of radial grooves, indicate that they resemble typical morphs of the Aspidella plexus. The large number of small-sized individuals and the wide range of size classes with skewed distribution suggest that they lived in high-density communities. The presence of Aspidella in the Cerro Negro Formation would represent the first reliable record of Ediacaran soft-bodied organisms in South America. It also supports the paleogeographic scenario of the Clymene Ocean, in which a shallow sea covered part of the southwest Gondwana at the end of the Ediacaran. PMID- 27460967 TI - Predictions of the affordable care act's impact on neonatal practice. PMID- 27460968 TI - Palliative care for terminally ill patients in the intensive care unit: Systematic review and metaanalysis. AB - OBJECTIVE: The purpose of our systematic review was to determine whether the introduction of palliative care (PC) teams reduces length of stay and/or mortality for terminally ill patients (TIPs) in an intensive care unit (ICU). METHOD: We hoped to examine studies that compared TIPs in an ICU who received end of-life care following implementation of a PC team (intervention group) to those who received care where PC teams had not yet been introduced (control group). We searched MEDLINE via PubMed, LILACS, Scopus, Embase, and Cochrane CENTRAL (search conducted in December of 2015) without language restrictions. Our outcome measures were length of stay in an ICU, presented as an average difference with a corresponding 95% confidence interval (CI 95%), and mortality in the ICU, presented as a risk ratio with a corresponding CI 95%. Two of our authors independently extracted all of the data. RESULTS: Of the 399 publications identified, 27 were selected for full-text analysis and 19 were excluded, leaving 8 articles for inclusion, which involved a total of 7,846 patients. A metaanalysis of mortality in the ICU was conducted with four studies. Lower mortality was found in the intervention group: risk ratio = 0.78 (CI 95% = 0.70 0.87), p < 0.00001, I 2 = 18%. Length of stay in the ICU was presented as a mean and standard deviation in four studies, and the result was a reduction of ~2.5 days in the length of stay with application of the intervention: mean = -2.44 days (CI 95% = -4.41 to -0.48), p = 0.01, I 2 = 86%. SIGNIFICANCE OF RESULTS: Introduction of palliative care teams can reduce mortality rates in the ICU, and perhaps shorten length of stay in the ICU for terminally ill patients. PMID- 27460969 TI - Electrochemical detection of PCR amplicons of Escherichia coli genome based on DNA nanostructural probes and polyHRP enzyme. AB - Fast, portable and sensitive analysis of E. coli is becoming an important challenge in many critical fields (e.g., food safety, environmental monitoring and clinical diagnosis). Thus, electrochemical biosensing of PCR amplicons from the bacterial genome has attracted reasonable research attention. In this work, we utilized a 3D DNA tetrahedral probe to establish a "sandwich-type" electrochemical DNA biosensor for sensitive and specific analysis of a 250 bp unpurified PCR amplicon from the uidA gene of the E. coli genome. Asymmetric PCR was used to produce single-stranded PCR products. Streptavidin-polyHRP80 was employed to improve the signal gain during electrochemical detection. We optimized important experimental conditions for DNA sensing, including the streptavidin-polyHRP, the signal probe and the ion strength. Finally, we achieved a remarkable sensitivity of 10 fM synthetic DNA target, and successfully performed the analysis of PCR amplicons from as low as 0.2 pg MUL(-1) of E. coli genome. Compared with traditional single stranded DNA (ssDNA) probe based detection, our present work demonstrated 3 orders of magnitude improvement in sensitivity. In addition, our electrochemical DNA biosensor was 4 orders of magnitude more sensitive than normal electrophoretic analysis of PCR products. Our work made important progress in DNA nanostructured probe-based biosensors toward application in real applications. PMID- 27460970 TI - Building protection- and building shielding-factors for environmental exposure to radionuclides and monoenergetic photon emissions. AB - We describe a simplified method for calculating both building protection- and shielding-factors for generic one- and two-story housing-unit models that are source-term dependent. Typically, radionuclide-independent factors are applied generically to external dose coefficients to account for the radiation shielding effects of indoor residences. In reality, the shielding effectiveness of each housing-unit would change over time as the radionuclide mixture and gamma-ray energy spectrum change due to physical effects such as deposition, radioactive decay, weathering effects, and decontamination efforts. Thus, it is necessary to develop factors designed for multiple photon energy spectrums to generate a more realistic estimate of the shielding effectiveness of a particular building. It is impractical to develop factors specific to a spectrum of photons emitted by each radionuclide of interest. Therefore, Monte Carlo simulations have been performed for sixteen monoenergetic photon energies from 0.10 to 3.0 MeV to characterize the 3D radiation fluence through each housing-unit produced by two idealized, yet realistic, environmental exposure scenarios. Results of these simulations were then used to develop fitted logarithmic functions (extrapolated to 0.0 MeV) to correlate an estimated factor to any monoenergetic photon energy up to 3.0 MeV. To verify these functions, another series of Monte Carlo simulations were performed for a select set of radionuclides to develop radionuclide-specific building protection- and shielding-factors. Good agreement is achieved between factors estimated using the presented functions and those calculated directly using Monte Carlo methods. Factors predicted by these functions are found to be in general agreement with other study results reported on similar structures which applied various computational methods and source-terms. This study only focuses on generic one- and two-story homes to provide a practical application that can contribute to improve the preparedness for and the response to a nuclear or radiological emergency. PMID- 27460971 TI - Donor-Appended N,C-Chelate Organoboron Compounds: Influence of Donor Strength on Photochromic Behaviour. AB - Recently, four-coordinated N,C-chelate organoboron compounds have been found to show many interesting photochemical transformations depending on the nature of their chelating framework. As such, the effect of substitution on the chelate ligand has been well-established and understood, but the impact of the aryl groups attached to the boron atom remains less clear. To investigate the effect of enhanced charge-transfer character, a series of new N,C-chelate organoboron compounds with donor-functionalized aryl groups have been synthesized and characterized using NMR, UV/Vis, and electrochemical methods. These compounds were found to possess bright and tunable charge-transfer luminescence which is dependent on the donor strength of the amino substituent. In addition, some of these compounds undergo photochromic switching, producing dark isomers of various colors. This work establishes that donor-functionalization of the aryl groups in N,C-chelate boron compounds is an effective strategy for tuning both the photophysical and photochemical properties of such systems. The new findings also help elucidate the influence of electronic structure on the photoreactivity of N,C-chelate organoboron compounds which appears to be as important as steric crowding around the boron atom. PMID- 27460972 TI - Corrigendum: Quantification of topological features in cell meshes to explore E cadherin dysfunction. PMID- 27460973 TI - Tuning the MYC response. AB - Altering the ability of the MYC transcription factor to bind to individual genes can customize the global gene expression output of cells. PMID- 27460975 TI - Enhanced Information Exclusion Relations. AB - In Hall's reformulation of the uncertainty principle, the entropic uncertainty relation occupies a core position and provides the first nontrivial bound for the information exclusion principle. Based upon recent developments on the uncertainty relation, we present new bounds for the information exclusion relation using majorization theory and combinatoric techniques, which reveal further characteristic properties of the overlap matrix between the measurements. PMID- 27460974 TI - Different promoter affinities account for specificity in MYC-dependent gene regulation. AB - Enhanced expression of the MYC transcription factor is observed in the majority of tumors. Two seemingly conflicting models have been proposed for its function: one proposes that MYC enhances expression of all genes, while the other model suggests gene-specific regulation. Here, we have explored the hypothesis that specific gene expression profiles arise since promoters differ in affinity for MYC and high-affinity promoters are fully occupied by physiological levels of MYC. We determined cellular MYC levels and used RNA- and ChIP-sequencing to correlate promoter occupancy with gene expression at different concentrations of MYC. Mathematical modeling showed that binding affinities for interactions of MYC with DNA and with core promoter-bound factors, such as WDR5, are sufficient to explain promoter occupancies observed in vivo. Importantly, promoter affinity stratifies different biological processes that are regulated by MYC, explaining why tumor-specific MYC levels induce specific gene expression programs and alter defined biological properties of cells. PMID- 27460976 TI - DJ-1 modulates mitochondrial response to oxidative stress: clues from a novel diagnosis of PARK7. AB - DJ-1 mutations are associated to early-onset Parkinson's disease and accounts for about 1-2% of the genetic forms. The protein is involved in many biological processes and its role in mitochondrial regulation is gaining great interest, even if its function in mitochondria is still unclear. We describe a 47-year-old woman affected by a multisystem disorder characterized by progressive, early onset parkinsonism plus distal spinal amyotrophy, cataracts and sensory-neural deafness associated with a novel homozygous c.461C>A [p.T154K] mutation in DJ-1. Patient's cultured fibroblasts showed low ATP synthesis, high ROS levels and reduced amount of some subunits of mitochondrial complex I; biomarkers of oxidative stress also resulted abnormal in patient's blood. The clinical pattern of multisystem involvement and the biochemical findings in our patient highlight the role for DJ-1 in modulating mitochondrial response against oxidative stress. PMID- 27460977 TI - Do Place and Time Make a Difference? Examining Quality of Life Among Homeless Persons in Northwest Arkansas and Birmingham. AB - This study examines the role that life chances and choices play in determining quality of life among homeless people. Given the prominent negative impact of homelessness, this paper specifically examines the impact of length of time homeless and location on adverse quality of life. OLS regression examined quality of life among 264 homeless adults living in Northwest Arkansas and Birmingham, Alabama. Analysis shows no significant impact of life choices on quality of life but a significant impact of life chances including strong social ties and mastery of fate, on adverse quality of life. Length of time homeless was related to adverse quality of life, but location was not, indicating that the homeless experience with regards to subjective quality of life did not vary significantly between Birmingham and Northwest Arkansas. PMID- 27460978 TI - Sense of Coherence in Religious Christian Orthodox Women in Greece. AB - Investigation of correlation between the way of life of women-secular and devoted (belonging to a Christian Orthodox fraternity)-and their stress management skills. Sample population consisted of 200 women, 100 belonging to an Orthodox Christian fraternity and 100 secular women, 18 years of age and older from the wider Thessaloniki area (North Greece). Antonovsky's Scale Sense of Coherence (SOC) was used for stress management skills evaluation. The mean SOC score was 138 (95 % CI 133.9-142.1) for secular and 149.9 (95 % CI 144.9-154.9) for devoted women. The presence of a strong sense of coherence for those women belonging to the fraternity (p = 0.004) and older age (p = 0.019) correlate with higher SOC scores. Religiousness appears to enhance stress management skills in women although additional evidence needs in support of the findings of this research. PMID- 27460979 TI - Glucose solution is more effective in relieving pain in neonates than non nutritive sucking: A randomized clinical trial. AB - BACKGROUND: Few studies have compared the analgesic effect of 25% glucose and non nutritive sucking. We compared the analgesic effect of 25% glucose and non nutritive sucking in newborns undergoing hepatitis B vaccination. Our hypothesis is that 25% glucose is more effective in relieving pain than non-nutritive sucking. METHODS: A randomized clinical trial with 78 healthy newborns was performed. Neonates were assigned randomly to receive 25% glucose (G25) and non nutritive sucking (NNS). Pain was assessed using the Neonatal Infant Pain Scale (NIPS) before and during the immunization procedure. In addition, we evaluated various physiological parameters and crying time. RESULTS: Neonates who received 25% glucose registered lower NIPS scores than those from the NNS group [mean (SD), 3.3 (2.1) vs. 5.6 (1.6), p < 0.001]. The crying time was shorter among newborns in the G25 group than in the NNS and control groups. CONCLUSION: The use of 25% glucose before the vaccination procedure was more effective in relieving acute pain, with newborns in the G25 group registering scores two times lower on the NIPS scale. The clinical practice of administering 25% glucose is therefore a suggested nondrug measure for pain relief during painful procedures. SIGNIFICANCE: Neonates who received 25% glucose registered lower NIPS scores than those from the NNS group; the crying time was shorter among newborns in the G25 group than in the NNS and control groups; the use of 25% glucose before the vaccination procedure was more effective in relieving acute pain. PMID- 27460980 TI - An accelerated background subtraction algorithm for processing high-resolution MS data and its application to metabolite identification. AB - BACKGROUND: Metabolite identification without radiolabeled compound is often challenging because of interference of matrix-related components. RESULTS: A novel and an effective background subtraction algorithm (A-BgS) has been developed to process high-resolution mass spectral data that can selectively remove matrix-related components. The use of a graphics processing unit with a multicore central processing unit enhanced processing speed several 1000-fold compared with a single central processing unit. A-BgS algorithm effectively removes background peaks from the mass spectra of biological matrices as demonstrated by the identification of metabolites of delavirdine and metoclopramide. CONCLUSION: The A-BgS algorithm is fast, user friendly and provides reliable removal of matrix-related ions from biological samples, and thus can be very helpful in detection and identification of in vivo and in vitro metabolites. PMID- 27460981 TI - Advances in high-resolution MS and hepatocyte models solve a long-standing metabolism challenge: the loratadine story. AB - BACKGROUND: Loratadine (LOR, Claritin((r))) is a long-acting antihistamine used to treat allergic rhinitis. The major active human metabolite, desloratadine (DL, Clarinex((r))), is extensively metabolized to 3-hydroxydesloratadine (3-OH-DL) (M40) and subsequently glucuronidated before elimination. This study revealed the ability of a novel, long-term hepatocyte micropatterned co-culture (MPCC) model to generate in vivo metabolites. Metabolites were detected and characterized using non-targeted MS/MS(ALL) with SWATHTM acquisition by a UHPLC-Q-TOF system. Results & methodology: Human MPCCs extensively metabolized LOR and formed 3-OH-DL glucuronide (M13). Cross-species comparisons revealed monkey- and rat-specific metabolites with gender-specific DL-pyridine-N-oxide formation in male rats. These results demonstrate a first for an in vitro hepatocyte model to generate circulating metabolites of LOR and detect species-specific differences. Early focus on human metabolites could have spared characterization of nonhuman metabolites in preclinical species. PMID- 27460982 TI - HRMS using a Q-Exactive series mass spectrometer for regulated quantitative bioanalysis: how, when, and why to implement. AB - High-resolution MS (HRMS) has seen an uptake in use for discovery qual/quan workflows, however, its utilization in late discovery/development has been slow. Past reports comparing HRMS to triple quadrupole (QQQ) instrumentation to date have indicated that HRMS instruments are capable of producing data acceptable for regulated bioanalysis, however lack the sensitivity required for sub ng/ml LLOQ assays. Recent advances in HRMS instrumentation have closed the sensitivity gap with QQQ and have even provided improved selectivity and sensitivity over QQQ SRM assays. Herein, the authors will describe how, when, and why HRMS (specifically Q Exactive series mass spectrometers) should be considered for implementation in regulated quantitative bioanalysis assays. PMID- 27460983 TI - SWATH acquisition mode for drug metabolism and metabolomics investigations. AB - AIM: Sequential window acquisition of all theoretical fragment-ion spectra (SWATH) has recently emerged as a powerful high resolution mass spectrometric data independent acquisition technique. In the present work, the potential and challenges of an integrated strategy based on LC-SWATH/MS for simultaneous drug metabolism and metabolomics studies was investigated. METHODOLOGY: The richness of SWATH data allows numerous data analysis approaches, including: detection of metabolites by prediction; metabolite detection by mass defect filtering; quantification from high-resolution MS precursor chromatograms or fragment chromatograms. Multivariate analysis can be applied to the data from the full scan or SWATH windows and allows changes in endogenous metabolites as well as xenobiotic metabolites, to be detected. Principal component variable grouping detects intersample variable correlation and groups variables with similar profiles which simplifies interpretation and highlights related ions and fragments. Principal component variable grouping can extract product ion spectra from the data collected by fragmenting a wide precursor ion window. CONCLUSION: It was possible to characterize 28 vinpocetine metabolites in urine, mostly mono- and di-hydroxylated forms, and detect endogenous metabolite expression changes in urine after the administration of a single dose of a model drug (vinpocetine) to rats. PMID- 27460984 TI - Comprehensive Reviews. PMID- 27460985 TI - How patients and clinicians make meaning of physical suffering in mental health evaluations. AB - Clinicians in community mental health settings frequently evaluate individuals suffering from physical health problems. How patients make meaning of such "comorbidity" can affect mental health in ways that may be influenced by cultural expectations and by the responses of clinicians, with implications for delivering culturally sensitive care. A sample of 30 adult mental health intakes exemplifying physical illness assessment was identified from a larger study of patient-provider communication. The recordings of patient-provider interactions were coded using an information checklist containing 21 physical illness items. Intakes were analyzed for themes of meaning making by patients and responses by clinicians. Post-diagnostic interviews with these patients and clinicians were analyzed in similar fashion. Clinicians facilitated disclosures of physical suffering to varying degrees and formulated them in the context of the culture of mental health services. Patients discussed their perceptions of what was at stake in their experience of physical illness: existential loss, embodiment, and limits on the capacity to work and on their sense of agency. The experiences of physical illness, mental health difficulties, and social stressors were described as mutually reinforcing. In mental health intakes, patients attributed meaning to the negative effects of physical health problems in relation to mental health functioning and social stressors. Decreased capacity to work was a particularly salient concern. The complexity of these patient-provider interactions may best be captured by a sociosomatic formulation that addresses the meaning of physical and mental illness in relation to social stressors. PMID- 27460986 TI - Pathways to mental healthcare in south-eastern Nigeria. AB - In sub-Saharan Africa, traditional and faith healers provide competing services alongside biomedical professionals. This may be associated with delays in reaching specialised mental health services, and hence with longer duration of untreated illness. As first line care constitutes a crucial stage in accessing of psychiatric care, investigating pathways to mental healthcare can highlight help seeking choices. This study explored the pathways to care for mental illness preferred by a non-clinical sample of the population in south-eastern Nigeria. Multistage sampling was used to select participants (N = 706) who completed questionnaires on help-seeking. Results showed a significant preference for biomedical (90.8%) compared to spiritual (57.8%) and traditional (33.2%) pathways. Higher education predicted preference for the biomedical model, while low education was associated with traditional and spiritual pathways. Protestants preferred the spiritual pathway more than did Catholics. The use of biomedical care is potentially undermined by poor mental health infrastructure, a lack of fit between the culture of biomedical care and the deep-seated cultural/religious worldviews of the people, stigma surrounding mental illness, and the likelihood of a social desirability bias in responses. A complementary model of care is proposed. PMID- 27460987 TI - GLIPR1 inhibits the proliferation and induces the differentiation of cancer initiating cells by regulating miR-16 in osteosarcoma. AB - Osteosarcoma is a common, highly malignant and metastatic bone cancer. Elucidation of the molecular mechanisms of osteosarcoma may further help us to understand the pathogenesis of the disease, and offer novel targets for effective therapies. Human glioma pathogenesis-related protein 1 (GLIPR1) has been found to be downregulated in human cancers. However, its roles have not been reported in osteosarcoma. In the present study, we demonstrated that GLIPR1 protein was downregulated in osteosarcoma. Its overexpression inhibited the proliferation, migration and invasion and induced the differentiation of cancer-initiating cells (CICs) in osteosarcoma. Moreover, GLIPR1 overexpression upregulated miR-16 in osteosarcoma cells. The upregulation suppressed proliferation, migration and invasion as well as induced differentiation of CICs in osteosarcoma. Thus, we conclude that GLIPR1 inhibited the proliferation, migration and invasion and induced the differentiation of CICs by regulating miR-16 in osteosarcoma. The present study provides direct evidence that GLIPR1 is a bona fide tumor suppressor and identified GLIPR1 and miR-16 as key components for regulating the proliferation, migration, invasion and CICs in osteosarcoma. PMID- 27460988 TI - Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration. AB - Photoreceptor cell degeneration leads to visual impairment and blindness in several types of retinal disease. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor cell protection remains challenging. Targeting distinct cellular pathways with low doses of different drugs that produce a functionally synergistic effect could provide a strategy for preventing or treating retinal dystrophies. We took a systems pharmacology approach to identify potential combination therapies using a mouse model of light induced retinal degeneration. We showed that a combination of U.S. Food and Drug Administration-approved drugs that act on different G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) exhibited synergistic activity that protected retinas from light-induced degeneration even when each drug was administered at a low dose. In functional assays, the combined effects of these drugs were stimulation of Gi/o signaling by activating the dopamine receptors D2R and D4R, as well as inhibition of Gs and Gq signaling by antagonizing D1R and the alpha1A-adrenergic receptor ADRA1A, respectively. Moreover, transcriptome analyses demonstrated that such combined GPCR-targeted treatments preserved patterns of retinal gene expression that were more similar to those of the normal retina than did higher-dose monotherapy. Our study thus supports a systems pharmacology approach to identify treatments for retinopathies, an approach that could extend to other complex disorders. PMID- 27460989 TI - Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling. AB - The T cell costimulatory receptor CD28 is required for the full activation of naive T cells and for the development and maintenance of Foxp3(+) regulatory T (Treg) cells. We showed that the cytoplasmic domain of CD28 was bound to the plasma membrane in resting cells and that ligand binding to CD28 resulted in its release. Membrane binding by the CD28 cytoplasmic domain required two clusters of basic amino acid residues, which interacted with the negatively charged inner leaflet of the plasma membrane. These same clusters of basic residues also served as interaction sites for Lck, a Src family kinase critical for CD28 function. This signaling complex was further stabilized by the Lck-mediated phosphorylation of CD28 Tyr(207) and the subsequent binding of the Src homology 2 (SH2) domain of Lck to this phosphorylated tyrosine. Mutation of the basic clusters in the CD28 cytoplasmic domain reduced the recruitment to the CD28-Lck complex of protein kinase Ctheta (PKCtheta), which serves as a key effector kinase in the CD28 signaling pathway. Consequently, mutation of either a basic cluster or Tyr(207) impaired CD28 function in mice as shown by the reduced thymic differentiation of FoxP3(+) Treg cells. On the basis of these results, we propose a previously undescribed model for the initiation of CD28 signaling. PMID- 27460992 TI - Off-pump midline repair of coarctation of aorta when associated with intracardiac defects: an alternate approach for single-stage correction. AB - OBJECTIVES: Strategies for the optimal surgical management of coarctation of aorta with associated intracardiac defects continue to be debated upon. We describe a previously unreported surgical technique for the management of this combination of defects and present our early results. METHODS: Thirty-one patients (median age: 73 days and median weight: 3.9 kg) underwent repair of coarctation of aorta with associated cardiac defects, in a single-stage, through a midline sternotomy. Twenty-eight patients had associated distal arch hypoplasia and 1 had a type I interruption. The coarctation and when necessary, the distal arch, was repaired prior to the institution of cardiopulmonary bypass. Cardiopulmonary bypass was subsequently instituted for the repair of the associated intracardiac defects. RESULTS: All patients had successful repair of coarctation and distal arch hypoplasia without the need for rescue cardiopulmonary bypass. In addition, 29 patients had closure of one or more ventricular septal defects, 3 patients had an arterial switch procedure and 1 had repair of double outlet right ventricle. Repair of supramitral ring and subaortic membrane was performed in another 3 patients. One patient underwent concomitant mitral valve repair. There was one in-hospital mortality (3.22%) due to fulminant sepsis. The median follow-up was 29.5 months (range: 1-58 months). There was no late mortality. Two patients required balloon dilatation for recurrent coarctation. Overall event-free survival rate was 88.5% at both 2 and 3 years of follow-up after surgery. However, intervention-free survival at 2 and 3 years of follow-up was 91.7% among the survivors. CONCLUSION: Repair of coarctation and distal arch hypoplasia or type I arch interruption is feasible prior to the institution of cardiopulmonary bypass without the use of hypothermic circulatory arrest or regional cerebral perfusion, with acceptable and reproducible results. PMID- 27460990 TI - RhoA inhibits neural differentiation in murine stem cells through multiple mechanisms. AB - Spontaneous neural differentiation of embryonic stem cells is induced by Noggin mediated inhibition of bone morphogenetic protein 4 (BMP4) signaling. RhoA is a guanosine triphosphatase (GTPase) that regulates cytoskeletal dynamics and gene expression, both of which control stem cell fate. We found that disruption of Syx, a gene encoding a RhoA-specific guanine nucleotide exchange factor, accelerated retinoic acid-induced neural differentiation in murine embryonic stem cells aggregated into embryoid bodies. Cells from Syx(+/+) and Syx(-/-) embryoid bodies had different abundances of proteins implicated in stem cell pluripotency. The differentiation-promoting proteins Noggin and RARgamma (a retinoic acid receptor) were more abundant in cells of Syx(-/-) embryoid bodies, whereas the differentiation-suppressing proteins SIRT1 (a protein deacetylase) and the phosphorylated form of SMAD1 (the active form of this transcription factor) were more abundant in cells of Syx(+/+) embryoid bodies. These differences were blocked by the overexpression of constitutively active RhoA, indicating that the abundance of these proteins was maintained, at least in part, by RhoA activity. The peripheral stress fibers in cells from Syx(-/-) embryoid bodies were thinner than those in Syx(+/+) cells. Furthermore, less Noggin and fewer vesicles containing Rab3d, a GTPase that mediates Noggin trafficking, were detected in cells from Syx(-/-) embryoid bodies, which could result from increased Noggin exocytosis. These results suggested that, in addition to inhibiting Noggin transcription, RhoA activity in wild-type murine embryonic stem cells also prevented neural differentiation by limiting Noggin secretion. PMID- 27460993 TI - Feeding: an important, complex skill that impacts nutritional, social, motor and sensory experiences. PMID- 27460991 TI - Assessment of the RIFLE criteria for the diagnosis of Acute Kidney Injury; a retrospective study in South-Western Ghana. AB - BACKGROUND: Acute kidney injury (AKI) affects 3-7 % of patients admitted to the hospital and approximately 25-30 % of patients in the intensive care unit. RIFLE, a newly developed international consensus classification for AKI, defines three grades of severity-class R (risk), I (injury) and F (failure). The aim of this study was to evaluate whether the RIFLE system of classification can detect the incidence of AKI using retrospective data of in-patients at the Effia-Nkwanta Regional Hospital. METHODS: A total of 1070 in-patients' records spanning a period of 6 months, from July 2014 to December 2014, was used. Demographic data and hospital admission serum creatinine of each participant were used for the calculation of estimated glomerular filtration rate (eGFR) using the 4-variable modification of diet in renal disease (MDRD) equation. Also, the baseline serum creatinine was estimated assuming a standard GFR of 75 ml/min/1.73 m(2) using the simplified MDRD equation. RESULTS: Males had higher serum creatinine, eGFR, and baseline serum creatinine than females (P < 0.0001). However, the level of increase in baseline serum creatinine was higher in females than males (P = 0.0212). The percentage ratios of the various classes from the SCr/ePCr (hospital admission serum creatinine/estimated plasma creatinine) criteria (R-1.45, I-1.53 and F-3.26) were higher than that of the eGFR criteria (R-0.34, I-0.11, F-0.12). The SCr/ePCr criteria gave more risk (89.7 %) than that of the eGFR criteria (23.1 %). The number of Injury and normal patients from the eGFR criteria was higher than the SCr/ePCr criteria. CONCLUSION: AKI was common in the ICU population with SCr/ePCr detecting more AKI than the eGFR criteria. Males had more injury and failure than females using the eGFR criteria whereas the SCr/ePCr gave females more risk and injury than males. A prospective cohort study must be employed in subsequent studies using the RIFLE criteria to assess the incidence of AKI in hospitalized patients with known diseases or medical conditions. PMID- 27460994 TI - Recent trends in surgical research of cancer treatment in the elderly, with a primary focus on lung cancer: Presentation at the 2015 annual meeting of SIOG. AB - Surgical research concentrating on cancer in the elderly has changed from small single institution outcome studies of carefully selected patients to larger studies that test specific aspects of surgical selection, treatment, and outcome. The purpose of this paper is to review major new trends in surgical geriatric oncology research within the last decade. Reviewing PubMed listings of the last 10years reveals several identifiable areas of particular concentration. Although we use specific studies primarily from lung cancer treatment, the generalizations can be seen across the spectrum of geriatric cancers. These trends include screening for disease that can be successfully treated, integration of operative and non-operative therapies that are changing the indications for surgery, the use of prehabilitation to allow more borderline frail patients to be treated surgically, the use of rehabilitation to facilitate rapid and complete recovery, prevention and treatment of common morbidities, with a special recent focus on delirium and cognitive impairment. New areas of surgical research include research on team building in the OR and ICU. Recent surgical research is becoming quantitative and multi-institutionally based. Overall surgical mortality has dropped over the past 25years in both academic and community hospitals. Prevention of morbidity and loss of functional status is a major focus of research. Funding for new Quality Assurance Projects for elderly patients has been awarded to the American College of Surgeons, and should provide multi institutional quality outcome data within 5years. PMID- 27460995 TI - Hantavirus Pulmonary Syndrome: High-resolution Computed Tomography Findings. PMID- 27460996 TI - Hering-Breuer reflex and non-invasive mechanical ventilation. Does it also occur during expiration? PMID- 27460998 TI - [Ethics in blood transfusion: A passion for teachers and students]. PMID- 27460999 TI - Repetitive Stresses Generate Osteochondral Lesions in Skeletally Immature Rabbits. AB - BACKGROUND: The origin of juvenile osteochondritis dissecans (OCD) is unknown. Existing experimental animal models of OCD most frequently involve surgically created lesions but do not examine repetitive stress as a possible cause of OCD. HYPOTHESIS: Repetitive stresses can cause OCD-like lesions in immature animals. STUDY DESIGN: Controlled laboratory study. METHODS: Six juvenile rabbits were subjected to repetitive loading forces of approximately 160% body weight to the right hindlimb during five 45-minute sessions per week for 5 weeks. The contralateral limb was the unloaded control. After 5 weeks, rabbits were euthanized and examined with radiographs, micro-computed tomography, and gross and histopathologic analysis. RESULTS: All 6 rabbits developed osteochondral lesions in loaded limbs on the medial and lateral femoral condyles, while contralateral unloaded limbs did not demonstrate lesions. Loaded limbs developed relative osteopenia in the femoral epiphysis and tibial metaphysis with associated decreased trabecular density. Loaded limbs also demonstrated increased femoral subchondral bone thickness near the lesions. Lesions did not have grossly apparent extensive articular cartilage damage; however, cartilage thickness increased on histology with reduced ossification. Loaded knees demonstrated abundant chondrocyte cloning, limited cartilage fissuring, and a focal loss of cellularity at the articular surface. CONCLUSION: Low-grade lesions in human OCD have little gross articular cartilage involvement despite substantial changes to the subchondral bone as shown on magnetic resonance imaging and radiographs. Histopathology findings in this study included cartilage thickening and chondrocyte cloning resembling those of recently published human OCD biopsy studies. Our animal model supports the hypothesis that repetitive stress to immature knees may contribute to the development of human OCD. This model may be useful in understanding the pathophysiology and healing of human OCD. CLINICAL RELEVANCE: Repetitive physiologic stress generated changes to the subchondral bone in immature animals without causing extensive articular damage. The similarities of these lesions in gross and histologic appearance with human OCD support repetitive stress as the likely the cause for human OCD. PMID- 27460997 TI - Preliminary assessment of free radical scavenging, thrombolytic and membrane stabilizing capabilities of organic fractions of Callistemon citrinus (Curtis.) skeels leaves. AB - BACKGROUND: Callistemon citrinus (Curtis.) (Family- Myrtaceae) is a popular evergreen shrub in Bangladesh. In the present study, the leaves of this plant have been assessed comprehensively for free radical scavenging, thrombolytic and membrane stabilizing activities. METHODS: The leaves were collected, powdered and extracted with methanol. The extract was then concentrated and successively fractionated into petroleum ether, carbon tetrachloride, chloroform and aqueous soluble fractions. The extractives were investigated for free radical scavenging, thrombolytic and membrane stabilizing activities. RESULTS: In case of 1,1 diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide radical scavenging assays, the crude methanol extract of the leaves showed the highest free radical scavenging activity among the tested materials including standard ascorbic acid (p = 0.0000). Besides, this extract was also found significantly rich (p = 0.0000) in phenolics and flavonoids compared to other organic fractions. In thrombolytic study, the petroleum ether fraction exhibited significantly stronger thrombolysis (p = 0.024) than other leaf extractives but was weaker than the standard streptokinase. In membrane stabilizing assay, the activity of chloroform fraction was similar to that of standard acetylsalicylic acid (p = 1.000) in hypotonic solution induced hemolysis. However, membrane stabilization activity of this chloroform fraction was found significantly stronger than that of the standard (p = 0.0000) in heat induced hemolysis. CONCLUSION: This study has revealed the medicinal capabilities of different organic fractions of C. citrinus displaying free radical scavenging, thrombolysis and membrane stabilizing antiinflammatory potentials. Further bioactivity guided isolation is required to obtain pharmacologically secondary metabolites. PMID- 27461000 TI - Immune Response Signaling: Combinatorial and Dynamic Control. AB - Macrophages mount complex responses to pathogens. Although several key signaling pathways have been identified, it remains unclear how they work together to provide specificity. In a recent paper, Gottschalk et al. report that differential dose-response behaviors of the NFkappaB and MAPK pathways allow dose specific gene expression programs. PMID- 27461001 TI - Retroperitoneal paravertebral ganglioneuroma: a multidisciplinary approach facilitates less radical surgery. AB - BACKGROUND: Ganglioneuroma (GN) of the adult is a rare benign tumour originating from neural crest-derived cells. In most cases, GN is found in the mediastinum or retroperitoneum incidentally and may present with unspecific symptoms caused by space-occupying effects. The correct diagnosis of a retroperitoneal mass is still a challenge. Nevertheless, a preoperatively confirmed diagnosis of GN may support the concept of a less radical approach and may help to prevent unnecessary morbidity or loss of function. CASE PRESENTATION: We report a case of a symptomatic retroperitoneal paravertebral GN in a 33-year-old woman. She has been referred with abdominal discomfort, lancinating pain in the right leg, headache and nausea. Magnetic resonance imaging revealed a solid paravertebral tumour adjacent to the psoas muscle. Computed tomography-guided core needle biopsy yielded the diagnosis of GN. The tumour was resected completely via a laparotomy. Immunohistopathological examinations confirmed a benign GN. CONCLUSIONS: Diagnostic studies and therapeutic interventions of retroperitoneal GN are discussed. In our case, a core needle biopsy preceding complete resection was helpful to prevent too extensive surgical approach. PMID- 27461003 TI - Anxiety-linked attentional bias and its modification: Illustrating the importance of distinguishing processes and procedures in experimental psychopathology research. AB - In this review of research concerning anxiety-linked attentional bias, we seek to illustrate a general principle that we contend applies across the breadth of experimental psychopathology. Specifically, we highlight how maintenance of a clear distinction between process and procedure serves to enhance the advancement of knowledge and understanding, while failure to maintain this distinction can foster confusion and misconception. We show how such clear differentiation has permitted the continuous refinement of assessment procedures, in ways that have led to growing confidence in the existence of the putative attentional bias process of interest, and also increasing understanding of its nature. In contrast, we show how a failure to consistently differentiate between process and procedure has contributed to confusion concerning whether or not attentional bias modification reliably alters anxiety vulnerability and dysfunction. As we demonstrate, such confusion can be avoided by distinguishing the process of attentional bias modification from the procedures that have been employed with the intention of evoking this target process. Such an approach reveals that procedures adopted with the intention of eliciting the attentional bias modification process do not always do so, but that successful evocation of the attentional bias modification process quite reliably alters anxiety symptomatology. We consider some of the specific implications for future research concerning attentional bias modification, while also pointing to the broader implications for experimental psychopathology research in general. PMID- 27461002 TI - Vitamin E delta-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells. AB - Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of delta-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. delta-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, delta-TT exerted its antitumor effect through activation of the PERK/p eIF2alpha/ATF4/CHOP, IRE1alpha and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of delta-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that delta-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by delta-TT treatment. In conclusion, delta TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. delta-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma. PMID- 27461005 TI - Sleep Control, GPCRs, and Glucose Metabolism. AB - Modern lifestyles prolong daily activities into the nighttime, disrupting circadian rhythms, which may cause sleep disturbances. Sleep disturbances have been implicated in the dysregulation of blood glucose levels and reported to increase the risk of type 2 diabetes (T2D) and diabetic complications. Sleep disorders are treated using anti-insomnia drugs that target ionotropic and G protein-coupled receptors (GPCRs), including gamma-aminobutyric acid (GABA) agonists, melatonin agonists, and orexin receptor antagonists. A deeper understanding of the effects of these medications on glucose metabolism and their underlying mechanisms of action is crucial for the treatment of diabetic patients with sleep disorders. In this review we focus on the beneficial impact of sleep on glucose metabolism and suggest a possible strategy for therapeutic intervention against sleep-related metabolic disorders. PMID- 27461004 TI - Association of six CpG-SNPs in the inflammation-related genes with coronary heart disease. AB - BACKGROUND: Chronic inflammation has been widely considered to be the major risk factor of coronary heart disease (CHD). The goal of our study was to explore the possible association with CHD for inflammation-related single nucleotide polymorphisms (SNPs) involved in cytosine-phosphate-guanine (CpG) dinucleotides. A total of 784 CHD patients and 739 non-CHD controls were recruited from Zhejiang Province, China. Using the Sequenom MassARRAY platform, we measured the genotypes of six inflammation-related CpG-SNPs, including IL1B rs16944, IL1R2 rs2071008, PLA2G7 rs9395208, FAM5C rs12732361, CD40 rs1800686, and CD36 rs2065666). Allele and genotype frequencies were compared between CHD and non-CHD individuals using the CLUMP22 software with 10,000 Monte Carlo simulations. RESULTS: Allelic tests showed that PLA2G7 rs9395208 and CD40 rs1800686 were significantly associated with CHD. Moreover, IL1B rs16944, PLA2G7 rs9395208, and CD40 rs1800686 were shown to be associated with CHD under the dominant model. Further gender-based subgroup tests showed that one SNP (CD40 rs1800686) and two SNPs (FAM5C rs12732361 and CD36 rs2065666) were associated with CHD in females and males, respectively. And the age-based subgroup tests indicated that PLA2G7 rs9395208, IL1B rs16944, and CD40 rs1800686 were associated with CHD among individuals younger than 55, younger than 65, and over 65, respectively. CONCLUSIONS: In conclusion, all the six inflammation-related CpG-SNPs (rs16944, rs2071008, rs12732361, rs2065666, rs9395208, and rs1800686) were associated with CHD in the combined or subgroup tests, suggesting an important role of inflammation in the risk of CHD. PMID- 27461006 TI - Sirtuins in Cardiovascular Health and Diseases. PMID- 27461007 TI - Economic Crisis, Austerity Policies, Health and Fairness: Lessons Learned in Spain. AB - This paper reviews economic and medical research publications to determine the extent to which the measures applied in Spain to control public health spending following the economic and financial crisis that began in 2008 have affected healthcare utilization, health and fairness within the public healthcare system. The majority of the studies examined focus on the most controversial cutbacks that came into force in mid-2012. The conclusions drawn, in general, are inconclusive. The consequences of this new policy of healthcare austerity are apparent in terms of access to the system, but no systematic effects on the health of the general population are reported. Studies based on indicators of premature mortality, avoidable mortality or self-perceived health have not found clear negative effects of the crisis on public health. The increased demands for co-payment provoked a short-term cutback in the consumption of medicines, but this effect faded after 12-18 months. No deterioration in the health of immigrants after the onset of the crisis was unambiguously detected. The impact of the recession on the general population in terms of diseases associated with mental health is well documented; however, the high levels of unemployment are identified as direct causes. Therefore, social policies rather than measures affecting the healthcare system would be primarily responsible. In addition, some health problems have a clear social dimension, which seems to have become more acute during the crisis, affecting in particular the most vulnerable population groups and the most disadvantaged social classes, thus widening the inequality gap. PMID- 27461008 TI - No impairment of pulmonary function in children with Henoch-Schonlein purpura after 4-year follow-up. AB - Henoch-Schonlein purpura (HSP) is a generalized form of IgA-mediated vasculitis that usually spares pulmonary circulation. Nevertheless, it is conceivable that subclinical changes at the HSP onset may lead to lung impairment in the long term. Therefore, we decided to follow a group of HSP patients for 4 years to monitor changes in pulmonary function. A group of 11 children and adolescents diagnosed with HSP without apparent pulmonary involvement was subjected to pulmonary function tests (PFTs), i.e., spirometry, body plethysmography, and diffusing capacity for CO (DLCO); these tests were repeated after 48 months. No significant impairment was observed in variables of spirometry, body plethysmography, and DLCO expressed as % of predicted values (% predicted) after 4 years. Specifically, no significant change in DLCO, corrected for blood hemoglobin concentration was noted, i.e., 79.3 +/- 10.1 vs. 81.6 +/- 14.7 % predicted at the beginning and the end of the study, respectively. IgA vasculitis seems to spare pulmonary circulation as we found no impairment in PFTs within the study time frame and a median of almost 6 years from the first episode of the disease. PMID- 27461009 TI - Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics. AB - Tuberculosis (TB) is an intractable chronic infection. Disease treatment with anti-TB drugs remains challenging due to drug-induced hepatotoxicity. The toxicity of the anti-TB drugs rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) either alone or in combination was investigated in HepG2 cells. Assays of intracellular adenosine triphosphate (ATP) levels at 4-, 24- and 48-h post exposure to gradient concentrations of RIF, INH and PZA were conducted. Drug induced effects on mitochondrial membrane potential (MMP), mitochondrial complex I and complex III activity, nicotinamide adenine dinucleotide (NAD+) levels and cellular lactate production were assessed. Decreased ATP levels were dose dependent and correlated with drug exposure duration. Approximate 24-h IC50s were 0.5 mM, 70 mM and 84 mM for RIF, INH and PZA, respectively. Twenty-four hours post-drug treatment, reductions of MMP ( p = 0.0005), mitochondrial complex I and III activities ( p = 0.0001 and p = 0.0003, respectively), NAD+ levels ( p = 0.0057) and increased lactate production ( p < 0.0001) were observed. Drug combinations used to mimic cumulative drug treatments induced a synergistic inhibition of mitochondrial complex I activity. An assessment of cellular ultrastructure using transmission electron microscopy indicated drug-induced mitophagy. Collectively, our study suggests that hepatotoxicity of commonly employed anti-TB drugs is mediated by their curtailment of mitochondrial function. PMID- 27461010 TI - Serum paraoxonase activity and oxidative stress levels in patients with cutaneous anthrax. AB - INTRODUCTION: Anthrax is a bacterial disease caused by the aerobic sporeforming bacterium Bacillus anthracis. It has been suggested that oxidative stress plays an important role in the pathogenesis of B. anthracis. The aim of this study was to investigate serum paraoxonase 1 (PON1) activity, catalase activity, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) levels in patients with cutaneous anthrax. MATERIALS AND METHODS: Fifteen patients with cutaneous anthrax and 15 healthy controls were enrolled in this study. The serum MDA levels, SOD levels, paraoxonase, arylesterase, and catalase activities were measured using a spectrophotometer. RESULTS: The serum SOD levels, paraoxonase, arylesterase, and catalase activities were significantly lower in patients with cutaneous anthrax than in controls (for all, p < 0.001), whereas MDA levels were significantly higher ( p < 0.001). No significant correlation was found between serum paraoxonase activity, arylesterase activity, SOD levels, and MDA levels (all, p > 0.05) in patients with cutaneous anthrax. CONCLUSIONS: The current study was the first to show decreased antioxidant levels and increased oxidant levels in patients with cutaneous anthrax. Therefore, decreased PON1 activity may play a role in the pathogenesis of cutaneous anthrax. PMID- 27461011 TI - Ameliorative effect of vitamin C against hepatotoxicity induced by emamectin benzoate in rats. AB - In the present study, we aimed to assess the potential protective effect of ascorbic acid (AA) against emamectin benzoate (EMB)-induced hepatotoxicity. For this purpose, biochemical, histopathological and analytical investigations were performed. Male Wistar rats were distributed into three groups, that is, a control group, an EMB group given 10 mg EMB/kg body weight (BW) by gavage and an EMB + AA group given 10 mg EMB/kg BW and vitamin C intraperitoneally (200 mg/kg). The duration of the treatment was 28 days and the duration of the study was 42 days. There was a statistically significant increase of all hepatic biomarkers, that is, aspartate aminotransferase, alanine aminotransferase and gamma glutamyltransferase activities, and glycemia, in EMB-treated group when compared with the control group. Light microscopic observations revealed variable signs of hepatotoxicity in the EMB group, which were represented by alteration of normal hepatic architecture, inflammatory cell infiltration, hepatocellular steatosis and foci of necrosis at 28 and 42 days post-treatment. However, co-treatment with vitamin C reduced EMB-related liver toxicity and diminished the abnormal biochemical and architectural damage. Emamectin B1a and B1b residues were detectable in all plasma samples of treated rats at 14, 21 and 28 days of treatment. The drug liver tissue concentration was significantly lower in EMB + AA group compared with EMB group at 28 and 42 days. In conclusion, the findings of the present study clearly indicate a significant protective action of vitamin C against EMB hepatotoxicity. PMID- 27461012 TI - Transcriptome analysis of paired primary colorectal carcinoma and liver metastases reveals fusion transcripts and similar gene expression profiles in primary carcinoma and liver metastases. AB - BACKGROUND: Despite the clinical significance of liver metastases, the difference between molecular and cellular changes in primary colorectal cancers (CRC) and matched liver metastases is poorly understood. METHODS: In order to compare gene expression patterns and identify fusion genes in these two types of tumors, we performed high-throughput transcriptome sequencing of five sets of quadruple matched tissues (primary CRC, liver metastases, normal colon, and liver). RESULTS: The gene expression patterns in normal colon and liver were successfully distinguished from those in CRCs; however, RNA sequencing revealed that the gene expression between primary CRCs and their matched liver metastases is highly similar. We identified 1895 genes that were differentially expressed in the primary carcinoma and liver metastases, than that in the normal colon tissues. A major proportion of the transcripts, identified by gene expression profiling as significantly enriched in the primary carcinoma and metastases, belonged to gene ontology categories involved in the cell cycle, mitosis, and cell division. Furthermore, we identified gene fusion events in primary carcinoma and metastases, and the fusion transcripts were experimentally confirmed. Among these, a chimeric transcript resulting from the fusion of RNF43 and SUPT4H1 was found to occur frequently in primary colorectal carcinoma. In addition, knockdown of the expression of this RNF43-SUPT4H1 chimeric transcript was found to have a growth-inhibitory effect in colorectal cancer cells. CONCLUSIONS: The present study reports a high concordance of gene expression in the primary carcinoma and liver metastases, and reveals potential new targets, such as fusion genes, against primary and metastatic colorectal carcinoma. PMID- 27461013 TI - [Surgical removal of Salzmann's nodules using intraoperative mitomycin C]. AB - Salzmann's nodules comprise a heterogeneous group of greyish superficial corneal opacities. A substantial percentage is most likely caused by dystrophies. This could explain the recurrences after surgical removal. The Eye Center of the University Hospital Freiburg has been using mitomycin C intraoperatively during surgical removal of Salzmann's nodules since 2007 to prevent recurrences. We recently performed an uncontrolled prospective trial to evaluate this approach and also reviewed the literature. Worldwide, a total of 38 eyes have been treated with mitomycin C during surgery for Salzmann's nodules. No recurrences have been reported so far with follow-up exceeding at least 2 years in almost all eyes. No severe side effects have been observed to date. We therefore think that mitomycin C during surgery for Salzmann's nodules is advisable despite the lack of evidence from a randomized clinical trial. However, all patients must consent to the off label use of mitomycin C. PMID- 27461014 TI - [Atypical acute syphilitic posterior placoid chorioretinitis]. AB - Syphilis is an infectious disease that can cause a wide variety of ocular signs. One of the rarest manifestations of ocular syphilis is acute syphilitic posterior placoid chorioretinitis (ASPPC). We report the case of an immunocompetent 38-year old woman diagnosed with unilateral, atypical, acute syphilitic posterior placoid chorioretinitis. Fundoscopic examination revealed a yellow-white, subretinal, placoid lesion at the posterior pole, which is typical sign of ASPPC. In the periphery of the retina, multifocal choroiditis was also found. Fundus and angiographic changes in ASPPC may mimic other chorioretinal diseases. Accurate diagnosis of ASPPC as a presenting sign of syphilis is important for the prompt initiation of systemic antibiotic treatment. PMID- 27461015 TI - [Impact of timing of surgery on outcome in children with bilateral congenital cataract]. AB - BACKGROUND: The optimal time for surgical intervention in bilateral congenital cataract is still a matter of controversy. OBJECTIVES: Herein, we evaluated clinical and functional results after bilateral congenital cataract surgery and performed subgroup analysis based on the age at the time of surgery. MATERIALS AND METHODS: We retrospectively reviewed the records of 52 eyes of 26 children who underwent surgery for bilateral congenital cataract without intraocular lens implantation within the first 12 months of life; 16 eyes underwent phacoaspiration within the first 10 weeks of life (group A) and 26 eyes had cataract extraction at an age of >10 weeks (group B). We defined the primary outcome measure to be the prevalence of mild, moderate, and severe amblyopia in relationship to age-dependent visual acuity norms after a mean follow-up of 59.7 +/- 43.2 months. Secondary outcome measures were interocular difference of visual acuity and the presence of strabismus, nystagmus, posterior capsule opacification, and aphakic glaucoma. RESULTS: The prevalence of amblyopia was not statistically different between the two age groups. Of all children, 62.5 % (A) and 61.1 % (B) developed age-dependent normal visual acuity or mild amblyopia. However, the younger cohort developed significantly less strabismus than the older cohort (P = 0.03). There was a strong relationship between cataract surgery within the first 14 weeks of life and the development of aphakic glaucoma. All children developing secondary cataract formation underwent cataract surgery in the first 20 weeks of life. CONCLUSIONS: Our results suggest that long-term prevalence of mild, moderate, and severe amblyopia is similar between the two cohorts of bilateral congenital cataract eyes based on the age <= or >10 weeks at the time of surgery. Because there is a strong relationship between postoperative complications and a young age at the time of cataract surgery, close postoperative follow-up is essential. Strabismus is less likely to develop in infants after bilateral cataract surgery within the first 10 weeks of life. PMID- 27461017 TI - The impact of depot medroxyprogesterone acetate on fracture risk: a case-control study from the UK. AB - : There has been concerning about women receiving depot medroxyprogesterone acetate (DMPA) contraception because of the prolonged hypoestrogenemic state regarding the potential negative effects on bone health. This study showed that DMPA exposure is associated with increased fracture risk and that fracture risk increases with longer DMPA exposure. INTRODUCTION: DMPA has been associated with impaired bone mineral acquisition during adolescence and accelerated bone loss in later life. We performed this large population-based study to assess the association between use of DMPA or combined oral contraceptives and the incident risk of fracture. METHODS: We identified 4189 women between 20 and 44 years of age with a first-time fracture diagnosis, matched them with 4189 random controls using the Disease Analyzer database and investigated the relation with DMPA exposure. RESULTS: Overall, 11 % of the fracture cases and 7.7 % of the controls had DMPA use recorded. The adjusted OR for developing a fracture in patients with current use of DMPA compared to non-users was 0.97 (95 % CI 0.51-1.86), 2.41 (95 % CI 1.42-4.08), and 1.46 (95 % CI 0.96-2.23) for 1-2, 3-9, and >=10 prescriptions, respectively. The adjusted OR for developing a fracture in patients with past use of DMPA compared to non-users was 0.96 (95 % CI 0.73 1.26), 1.14 (95 % CI 0.86-1.51), and 1.55 (95 % CI 1.07-2.27) for 1-2, 3-9, and >=10 prescriptions, respectively. The highest fracture risk was identified in young patients less than 30 years with longer DMPA exposure (>=10 prescriptions; OR 3.04, 95 % CI 1.36-6.81), as well as in patients in the late reproductive years with past use of DMPA (OR 1.72, 95 % CI 1.13-2.63). CONCLUSIONS: Our results indicate that DMPA exposure is associated with increased fracture risk and may have negative effects on bone metabolism, resulting in impaired bone mineral acquisition during adolescence and accelerated bone loss in adult life. PMID- 27461018 TI - Influential Factors of Puerto Rican Mother-Child Communication About Sexual Health Topics. AB - Introduction Latina mothers play a central role in raising and socializing their children; however, few studies have examined the cultural, socio-cognitive and neighborhood-related variables influencing the level of communication between Puerto Rican mothers and their children about sexuality and sexual health. This cross-sectional study sought to examine these influences. Methods Puerto Rican mothers with children aged 10-19 years (n = 193) were selected randomly for an ethnographic interview as part of a community participatory action research project in a U.S. urban northeastern community. Results Bivariate analyses found statistically significant associations between the child's age (p = 0.002), the mother's past communication about traditional gender role norms of women (marianismo) (p < 0.001), her positive outcome expectations for communications with her child (p < 0.025), and her perceptions of the physical condition (p < 0.001) and sexual health problems (p = 0.047) in the neighborhood. In a multivariate model, all of these variables remained significant except sexual health problems, and mother's attitudes toward the obligations of children to parents (familismo) emerged as a factor associated with a decrease in the number of sexual health topics that mothers raised with their children. No significant effects were found for mother's spiritual and religious experience (religiosidad). Discussion Our study highlights the importance of marianismo as a framework within which Puerto Rican mothers communicate sexual health information as well as the need to improve mothers' confidence discussing sexual health issues with their children. Future public health interventions to promote communication about sexuality and sexual health among Puerto Rican mothers should consider addressing this issue as a part of comprehensive neighborhood improvement projects. PMID- 27461019 TI - Response to an Online Version of a PRAMS-like Survey in South Dakota. AB - Objectives Increasing response rates for research surveys is challenging, especially in minority populations. A unique minority group in South Dakota is the American Indian (AI) representing about 9 % of the state's population and 15 % of the births. The purpose of this study was to determine race differences among White, AI, and Other Races (OR) in contact, participation, and response rates in the South Dakota Pregnancy Risk Assessment Monitoring System (SDPRAMS). We determined response rates of an online version and evaluated demographic characteristics associated with online response. Methods The SDPRAMS was sent to 1814 mothers randomly sampled from 2014 birth certificate files. Results The weighted response rate was 71.3 %, and varied significantly among the three races: 79.1 % for White race, 48.6 % for AI race, and 60.6 % for OR (p < 0.01). A higher percent of White mothers responded online than AI and OR (35, 25 and 26 %, respectively; p = 0.001); no difference between AI and OR. Online responders were more likely to be married, educated beyond high school and having annual incomes >=$25,000 (p <= 0.01 for all), but only education (p < 0.001) and income (p = 0.05) remained significant in the logistic models. 26 % of White, 43 % of AI, and 46 % of OR online respondents used a smartphone to respond (p = 0.01). Conclusions Response rates differed among races. An online version of the PRAMS is a viable method of response to offer participants. Response to the online version via smartphone may increase response from minority populations, emphasizing the importance of mobile friendly formats. PMID- 27461020 TI - Obesity, Diabetes, and Birth Outcomes Among American Indians and Alaska Natives. AB - Objectives To examine the relationships between prepregnancy diabetes mellitus (DM), gestational diabetes mellitus (GDM), and prepregnancy body mass index, with several adverse birth outcomes: preterm delivery (PTB), low birthweight (LBW), and macrosomia, comparing American Indians and Alaska Natives (AI/AN) with other race/ethnic groups. Methods The sample includes 5,193,386 singleton US first births from 2009-2013. Logistic regression is used to calculate adjusted odds ratios controlling for calendar year, maternal age, education, marital status, Kotelchuck prenatal care index, and child's sex. Results AI/AN have higher rates of diabetes than all other groups, and higher rates of overweight and obesity than whites or Hispanics. Neither overweight nor obesity predict PTB for AI/AN, in contrast to other groups, while diabetes predicts increased odds of PTB for all groups. Being overweight predicts reduced odds of LBW for all groups, but obesity is not predictive of LBW for AI/AN. Diabetes status also does not predict LBW for AI/AN; for other groups, LBW is more likely for women with DM or GDM. Overweight, obesity, DM, and GDM all predict higher odds of macrosomia for all race/ethnic groups. Conclusions for Practice Controlling diabetes in pregnancy, as well as prepregnancy weight gain, may help decrease preterm birth and macrosomia among AI/AN. PMID- 27461021 TI - A Preconception Nomogram to Predict Preterm Delivery. AB - Objective Preterm birth is a leading cause of perinatal morbidity and mortality. Prevention strategies rarely focus on preconception care. We sought to create a preconception nomogram that identifies nonpregnant women at highest risk for preterm birth using the Pregnancy Risk Assessment Monitoring System (PRAMS) surveillance data. Methods We used PRAMS data from 2004 to 2009. The odds ratios (ORs) of preterm birth for each preconception variable was estimated and adjusted analyses were conducted. We created a validated nomogram predicting the probability of preterm birth using multivariate logistic regression coefficients. Results 192,208 cases met inclusion criteria. Demographic/maternal health characteristics and associations with preterm birth and ORs are reported. After validation, we identified the following significant predictors of preterm birth: prior history of preterm birth or low birth weight baby, prior spontaneous or elective abortion, maternal diabetes prior to conception, maternal race (e.g., non-Hispanic black), intention to get pregnant prior to conception (i.e., did not want or wanted it sooner), and smoking prior to conception (p < 0.05). Overall, our preconception preterm risk model correctly classified 76.1 % of preterm cases with a negative predictive value (NPV) of 76.7 %. A nomogram using a 0-100 scale illustrates our final preconception model for predicting preterm birth. Conclusion This preconception nomogram can be used by clinicians in multiple settings as a tool to help predict a woman's individual preterm birth risk and to triage high-risk non-pregnant women to preconception care. Future studies are needed to validate the nomogram in a clinical setting. PMID- 27461022 TI - Use of Antidepressants During Pregnancy?: What to Consider when Weighing Treatment with Antidepressants Against Untreated Depression. AB - Introduction Mood disorders impact many pregnant women, particularly those who have experienced symptoms prior to conception, and there are significant barriers, including stigma and access, to seeking and receiving appropriate treatments. Antidepressants are a helpful option in treating perinatal depression, but research on risks and benefits of antidepressant use in pregnancy is difficult given lack of "gold standard" comparative trials. Methods This paper summarizes current state of knowledge on the safety of antidepressants during pregnancy by providing a summary of the literature published in the past 3 years (January 2013-October 2015). We identified 21 reviews and meta-analyses that were included in this summary report. This report is meant to provide a user-friendly, yet comprehensive guide summarizing the abundant, and in part contradicting, literature on risks and benefits of antidepressants during pregnancy, in order to assist busy primary care prescribers in educating their patients. Our goal is also to contrast the risks/benefits of untreated depression in pregnancy versus treatment with antidepressant medication in pregnancy, and in such support prescribers in their decision-making. Results The past 3 years have yielded an abundance of publications on the topic, in part, with conflicting findings adding to confusion and concern among providers, patients, and their families. Many reported studies have methodological problems limiting their impact. Data on adverse effects of medications on pregnancy and fetal outcomes have to be weighed against the impact of untreated illness and poor health habits associated with untreated illness on the same outcomes. Discussion Medical-decision making is often complex and seldom free of risks. Obviously, as providers we cannot guarantee that fetal exposure to antidepressants is totally free of risk, yet this is true for any medicine taken in pregnancy. However, to date, perinatal psychiatry has collected enough evidence to suggest that, if the clinical picture warrants it, the use of many antidepressants, especially the SSRIs, is favorable compared to exposing mother and child to untreated depressive illness. PMID- 27461023 TI - Community-Academic Partnership to Investigate Low Birth Weight Deliveries and Improve Maternal and Infant Outcomes at a Baltimore City Hospital. AB - Purpose Mercy Medical Center (MMC), a community hospital in Baltimore Maryland, has undertaken a community initiative to reduce low birth weight (LBW) deliveries by 10 % in 3 years. MMC partnered with a School of Public Health to evaluate characteristics associated with LBW deliveries and formulate collaborations with obstetricians and community services to improve birth outcomes. Description As part of the initiative, a case control study of LBW was undertaken of all newborns weighing <2500 grams during June 2010-June 2011 matched 2:1 with newborns >=2500 grams (n = 862). Assessment Logistic regression models including maternal characteristics prior to and during pregnancy showed an increased odds of LBW among women with a previous preterm birth (aOR 2.48; 95 % CI: 1.49-4.13), chronic hypertension (aOR: 2.53; 95 % CI: 1.25-5.10), hospitalization during pregnancy (aOR: 2.27; 95 % CI:1.52-3.40), multiple gestation (aOR:12.33; 95 % CI:5.49-27.73) and gestational hypertension (aOR: 2.81; 95 % CI: 1.79-4.41). Given that both maternal pre-existing conditions and those occurring during pregnancy were found to be associated with LBW, one strategy to address pregnant women at risk of LBW infants is to improve the intake and referral system to better triage women to appropriate services in the community. Meetings were held with community organizations and feedback was operationalized into collaboration strategies which can be jointly implemented. Conclusion Education sessions with providers about the referral system are one ongoing strategy to improve birth outcomes in Baltimore City, as well as provision of timely home visits by nurses to high-risk women. PMID- 27461025 TI - The use of dronedarone for recurrent ventricular tachycardia: a case report and review of the literature. AB - BACKGROUND: Dronedarone is a benzofuran derivative resembling amiodarone that was intended to reduce the iodine-associated tissue deposition and organ toxicity seen with the latter. The utility of dronedarone for patients with ventricular arrhythmias has not been thoroughly evaluated. We present our experience with its use to treat refractory ventricular tachycardia storm and review the literature. CASE PRESENTATION: An 85 year-old gentleman with multiple medical comorbidities including ischemic and non-ischemic cardiomyopathy with severe biventricular systolic dysfunction presented with ventricular tachycardia storm. Therapeutic options were limited given his frail medical status, failures of sotalol, mexilitine, and catheter ablation therapies along with drug-toxicities from amiodarone. Dronedarone was thus considered as off-label use following informed consent. The patient unfortunately developed fatal multisystem organ failure including acute severe hepatotoxicity from dronedarone. CONCLUSION: Novel therapies for drug-refractory ventricular arrhythmias are long overdue given the limitations of available pharmacologic and non-pharmacologic options. Off-label use of antiarrhythmic agents such as dronedarone is considered a treatment of last-resort in patients who otherwise have no therapeutic options. Given the paucity of reported cases regarding dronedarone for the treatment of ventricular tachyarrhythmias, no conclusive recommendations can be made at this time aside from words of caution. Despite the potential ventricular antiarrhythmic effects of dronedarone, careful patient evaluation is required to identify those at greatest risk of drug-related adverse events particularly in those patients with significant comorbidities such as advanced hepatic, renal, and cardiovascular disease. PMID- 27461024 TI - Pre-eclampsia in American Indians/Alaska Natives and Whites: The Significance of Body Mass Index. AB - Introduction The prevalence of pre-eclampsia, a major cause of maternal morbidity, varies by race, being greater in African Americans, and lower in Asians and Hispanics than in White women. Little is known about its prevalence in American Indians/Alaska Natives (AI/ANs). We estimated pre-eclampsia risk in AI/ANs compared to Whites, with consideration of the potential effect of obesity, a major risk factor for pre-eclampsia, and a condition disproportionately affecting AI/AN women. Methods This retrospective cohort study of linked birth hospital discharge data from Washington State (2003-2013) included all AI/AN women and a sample of White first-time mothers with singleton deliveries. Logistic regression was used to estimate odds ratio (OR) and 95 % confidence intervals (CI) for pre-eclampsia risk in AI/ANs compared to Whites, first controlling for several important risk factors, and subsequently with additional adjustment for pre-pregnancy body mass index (BMI). Results AI/ANs had an increased risk of pre-eclampsia compared to Whites after controlling for all covariates except BMI (OR 1.17, 95 % CI 1.06-1.29). After further adjustment for BMI, the racial disparity in pre-eclampsia risk was greatly attenuated (OR 1.05, 95 % CI 0.95-1.16). Discussion This population-based study suggests that any increased risk in AI/ANs relative to Whites may be at least partly due to differences in BMI. PMID- 27461026 TI - Risk of venous thromboembolism in hospitalised cancer patients in England-a cohort study. AB - BACKGROUND: Venous thromboembolism (VTE) is a well-recognised and life threatening complication in patients with cancer. However, the precise risk of VTE in hospitalised cancer patients in England has not been previously reported. METHODS: We conducted a cohort study using linked Hospital Episodes Statistics and Office for National Statistics mortality data. We determined the risk of VTE separately for 24 cancer sites following first hospitalisation for cancer (index date) and how this varied by age, proximity from hospital admission, administration of chemotherapy and calendar time. RESULTS: Between 1998 and 2012, 3,558,660 patients were hospitalised for cancer. The cancer sites with the highest risk of VTE during initial hospitalisation for cancer were pancreatic (4.9 %), ovarian (4 %) and liver (3.8 %). The three cancer sites with the highest risk of first VTE event within 6 months from discharge were pancreatic (3.7 %), oesophagus (3 %) and stomach (2.8 %). For most cancers, the risk of VTE within 6 months from discharge was higher amongst patients who underwent chemotherapy compared to those who did not. The impact of age on risk of VTE varied considerably between cancer sites. CONCLUSIONS: The risk of VTE amongst patients hospitalised for cancer varies greatly by cancer site, age, proximity from hospital admission, and chemotherapy administration. PMID- 27461028 TI - Ceanothane-type triterpenoids from Cyphostemma adenocaule. AB - Phytochemical investigation of the methanol extract of Cyphostemma adenocaule liana (bark and wood) led to the isolation of two new ceanothane-type triterpenoids, cyphostemmic acid A 1 and cyphostemmic acid B 2, together with the known triterpenoids 3-7, beta-sitosterol and its glucoside. The structures of the isolated compounds were established by 1D- and 2D-NMR spectroscopy. Ozonolysis of cyphostemmic acid A 1, epigouanic acid A 3 and betulin 6 yielded semisynthetic derivatives, cyphostemmic acid C 8, cyphostemmic acid D 9, and 3beta,28-dihydroxy 30-norlupan-20-one 10 respectively. Compounds 1-4, 6, 8-10 were tested in vitro, for their antiplasmodial activity against Plasmodium falciparum 3D7 strain and showed weak activity. PMID- 27461027 TI - Nutritional health attitudes and behaviors and their associations with the risk of overweight/obesity among child care providers in Michigan Migrant and Seasonal Head Start centers. AB - BACKGROUND: Children enrolled in Migrant and Seasonal Head Start (MSHS) programs are at high risks of health problems. Although non-family child care providers play important roles on children's health status as role models, educators, program deliverers, and information mediators, little is known about their nutritional health attitudes and behaviors, and weight status. Therefore, we investigated nutritional health attitudes and behaviors and their associations with overweight/obesity among child care providers in Michigan MSHS centers. METHODS: A total of 307 child care providers aged >= 18 years working in 17 Michigan MSHS centers were included in this cross-sectional study conducted in 2013. An online survey questionnaire was used to collect data on nutritional health attitudes and behaviors of child care providers. Weight status was categorized into normal weight (18.5 <= BMI < 25 kg/m(2)), overweight (25 <= BMI < 30 kg/m(2)), and obese (BMI >= 30 kg/m(2)) based on child care providers' self reported height and weight. Factor analysis was performed to investigate patterns of nutritional health attitudes and behaviors. Multivariate logistic regression was conducted to estimate the odds ratios (ORs) and 95 % confidence intervals (CIs) of overweight/obesity across tertiles of pattern scores taking the lowest tertile group as the reference group after adjustment for potential confounding variables. RESULTS: Three patterns of nutritional health attitudes and behaviors were identified: pattern 1) "weight loss practices with weight dissatisfaction", pattern 2) "healthy eating behaviors", and pattern 3) "better knowledge of nutrition and health". The pattern 1 scores were positively associated with overweight/obesity (Tertile 2 vs. Tertile 1: OR = 5.81, 95 % CI = 2.81-12.05; Tertile 3 vs. Tertile 1: OR = 14.89, 95 % CI = 6.18-35.92). Within the pattern 2, the OR for overweight/obesity in individuals with the highest scores was 0.37 (95 % CI = 0.19-0.75) compared with those with the lowest scores. However, the pattern 3 was not associated with the risk of overweight/obesity. CONCLUSIONS: Our findings support that nutrition education or health interventions targeting MSHS child care providers are urgently necessary. These efforts might be an efficient and effective approach for improving the nutritional health status of young children enrolled in MSHS programs. PMID- 27461029 TI - Preparation and activity evaluation of chrysin-beta-D-galactopyranoside. AB - Chrysin-beta-D-galactopyranoside was efficiently synthesized, evaluated for its inhibitory activities against H22 cell lines compared with chrysin, the scavenging of hydroxyl radical, DPPH radical and superoxide anion, inhibitory effect against bacteria and fungi. The structures of all compounds were fully characterized by spectroscopic data (NMR, MS). The anti-tumor, antioxidant and antimicrobial activities of chrysin-beta-D-galactopyranoside were proved to be enhanced significantly compared with chrysin. PMID- 27461030 TI - Is the Job Satisfaction Survey a good tool to measure job satisfaction amongst health workers in Nepal? Results of a validation analysis. AB - BACKGROUND: Job satisfaction is an important predictor of an individual's intention to leave the workplace. It is increasingly being used to consider the retention of health workers in low-income countries. However, the determinants of job satisfaction vary in different contexts, and it is important to use measurement methods that are contextually appropriate. We identified a measurement tool developed by Paul Spector, and used mixed methods to assess its validity and reliability in measuring job satisfaction among maternal and newborn health workers (MNHWs) in government facilities in rural Nepal. METHODS: We administered the tool to 137 MNHWs and collected qualitative data from 78 MNHWs, and district and central level stakeholders to explore definitions of job satisfaction and factors that affected it. We calculated a job satisfaction index for all MNHWs using quantitative data and tested for validity, reliability and sensitivity. We conducted qualitative content analysis and compared the job satisfaction indices with qualitative data. RESULTS: Results from the internal consistency tests offer encouraging evidence of the validity, reliability and sensitivity of the tool. Overall, the job satisfaction indices reflected the qualitative data. The tool was able to distinguish levels of job satisfaction among MNHWs. However, the work environment and promotion dimensions of the tool did not adequately reflect local conditions. Further, community fit was found to impact job satisfaction but was not captured by the tool. The relatively high incidence of missing responses may suggest that responding to some statements was perceived as risky. CONCLUSION: Our findings indicate that the adapted job satisfaction survey was able to measure job satisfaction in Nepal. However, it did not include key contextual factors affecting job satisfaction of MNHWs, and as such may have been less sensitive than a more inclusive measure. The findings suggest that this tool can be used in similar settings and populations, with the addition of statements reflecting the nature of the work environment and structure of the local health system. Qualitative data on job satisfaction should be collected before using the tool in a new context, to highlight any locally relevant dimensions of job satisfaction not already captured in the standard survey. PMID- 27461031 TI - Diagnostic Detection of Allelic Losses and Imbalances by Next-Generation Sequencing: 1p/19q Co-Deletion Analysis of Gliomas. AB - Cancer cells are genomically unstable and accumulate tumor type-specific molecular aberrations, which may represent hallmarks for predicting prognosis and targets for therapy. Co-deletion of chromosomes 1p and 19q marks gliomas with an oligodendroglioma component and predicts a better prognosis and response to chemotherapy. In the current study, we present a novel method to detect chromosome 1p/19q co-deletion or loss of heterozygosity (LOH) in a diagnostic setting, based on single-nucleotide polymorphism (SNP) analysis and next generation sequencing (NGS). We selected highly polymorphic SNPs distributed evenly over both chromosome arms. To experimentally determine the sensitivity and specificity of targeted SNP analysis, we used DNAs extracted from 49 routine formalin-fixed, paraffin-embedded glioma tissues and compared the outcome with diagnostic microsatellite-based LOH analysis and calculated estimates. We show that targeted SNP analysis by NGS allows reliable detection of 1p and/or 19q deletion in a background of 70% of normal cells according to calculated outcomes, is more sensitive than microsatellite-based LOH analysis, and requires much less DNA. This specific and sensitive SNP assay is broadly applicable for simultaneous allelic imbalance analysis of multiple genomic regions and can be incorporated easily into NGS mutation analyses. The combined mutation and chromosomal imbalance analysis in a single NGS assay is suited perfectly for routine glioma diagnostics and other diagnostic molecular pathology applications. PMID- 27461032 TI - ADAP-GC 3.0: Improved Peak Detection and Deconvolution of Co-eluting Metabolites from GC/TOF-MS Data for Metabolomics Studies. AB - ADAP-GC is an automated computational pipeline for untargeted, GC/MS-based metabolomics studies. It takes raw mass spectrometry data as input and carries out a sequence of data processing steps including construction of extracted ion chromatograms, detection of chromatographic peak features, deconvolution of coeluting compounds, and alignment of compounds across samples. Despite the increased accuracy from the original version to version 2.0 in terms of extracting metabolite information for identification and quantitation, ADAP-GC 2.0 requires appropriate specification of a number of parameters and has difficulty in extracting information on compounds that are in low concentration. To overcome these two limitations, ADAP-GC 3.0 was developed to improve both the robustness and sensitivity of compound detection. In this paper, we report how these goals were achieved and compare ADAP-GC 3.0 against three other software tools including ChromaTOF, AnalyzerPro, and AMDIS that are widely used in the metabolomics community. PMID- 27461033 TI - Major ontogenetic transitions during Volvox (Chlorophyta) evolution: when and where might they have occurred? AB - This paper represents an attempt to unify data from various lines of Volvox research: developmental biology, biogeography, and evolution. Several species (such as Volvox carteri and Volvox spermatosphaera) are characterized by rapid divisions of asexual reproductive cells, which may proceed in darkness. By contrast, several other species (such as Volvox aureus, Volvox globator, and Volvox tertius) exhibit slow and light/dependent divisions. The transition from the former pattern of asexual life cycle to the latter one has occurred in three lineages of the genus Volvox. Since V. aureus (unlike V. carteri) is able to complete the life cycle at a short photoperiod (8 h light/16 h dark regime), it is reasonable to suggest that the abovementioned evolutionary transitions might have occurred as adaptations to short winter days in high latitudes under warm climate conditions in the deep past. In the case of the lineage leading to V. tertius + Volvox dissipatrix, the crucial reorganizations of asexual life cycle might have occurred between about 45 and 60 million years ago in relatively high latitudes of Southern Hemisphere. PMID- 27461034 TI - Stronger enhancer II/core promoter activities of hepatitis B virus isolates of B2 subgenotype than those of C2 subgenotype. AB - Hepatitis B virus (HBV) genotype C causes prolonged chronic infection and increased risk for liver cancer than genotype B. Our previous work revealed lower replication capacity of wild-type genotype C2 than B2 isolates. HBV DNA replication is driven by pregenomic RNA, which is controlled by core promoter (CP) and further augmented by enhancer I (ENI) and enhancer II (ENII). DNA fragments covering these regulatory elements were amplified from B2 and C2 isolates to generate luciferase reporter constructs. As ENII is fully embedded in CP, we inserted HBV DNA fragments in the sense orientation to determine their combined activities, and in the antisense orientation to measure enhancer activities alone. Genotype B2 isolates displayed higher ENI+ENII+CP, ENII+CP, and ENII activities, but not ENI or ENI+ENII activity, than C2 isolates. The higher ENII+CP activity was partly attributable to 4 positions displaying genotype specific variability. Exchanging CP region was sufficient to revert the replication phenotypes of several B2 and C2 clones tested. These results suggest that a weaker ENII and/or CP at least partly accounts for the lower replication capacities of wild-type C2 isolates, which could drive the subsequent acquisition of CP mutations. Such mutations increase genome replication and are implicated in liver cancer development. PMID- 27461035 TI - Breast-cancer-isation explored: Social experiences of gynaecological cancer in a Norwegian context. AB - This article's point of departure is recent claims that breast cancer survivorship displaying positivity and self-growth represents the gold standard for all forms of cancer survivorship in English-speaking Western cultures. An interview study of Norwegian women regarding gynaecological cancer followed by hysterectomy is used to explore whether this process is taking place beyond this setting. Results show that the women's experiences of having to display survivorship in this manner are not as notable as found in English-speaking Western countries, neither is their experience of social othering. Reasons for this may be strong norms of social egalitarianism marking Norwegian culture and breast cancer informational campaigns that have not yet totally defined Norwegian norms for how to survive cancer. At the clinic and in the public sphere, however, the women experience gynaecological cancer as clearly having lower status than breast cancer, leading to a strong sense that the bodily site of their disease is taboo. Hence, as found in English-speaking cultures, the complex embodied nature of having gynaecological cancer and life beyond treatment seems to be silenced by the media and medical institutions. Finally, implications for future research and health care related to cancer survivorship are also discussed. PMID- 27461036 TI - Circulating Tumor DNA to Monitor Therapy for Aggressive B-Cell Lymphomas. AB - OPINION STATEMENT: The goal of therapy for aggressive B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is to achieve cure. Combination chemotherapy with rituximab cures most patients, but those with recurrent disease have a poor prognosis. Medical imaging scans such as computed tomography (CT) and positron emission tomography (PET) are the principal methods to assess response and monitor for disease relapse after therapy but are fundamentally limited by risks of radiation, cost, and a lack of tumor specificity. Novel sequencing-based DNA monitoring methods are capable of quantifying small amounts of circulating tumor DNA (ctDNA) before, during, and after therapy for mature B-cell lymphomas. Detection of ctDNA encoding clonal rearranged variable-diversity-joining (VDJ) receptor gene sequences has demonstrated improved analytical sensitivity and enhanced tumor specificity compared to imaging scans in DLBCL, offering broad clinical applicability across a range of aggressive B-cell lymphomas. Molecular monitoring of ctDNA has vaulted into the spotlight as a promising non-invasive tool with immediate clinical impact on monitoring for recurrence after therapy prior to clinical symptoms. As these clinical observations are validated, ctDNA monitoring needs to be investigated as a tool for response-adapted therapy and as a marker of minimal residual disease upon completion of therapy in aggressive B-cell lymphomas. Molecular monitoring of ctDNA holds tremendous promise that may ultimately transform our ability to monitor disease in aggressive B-cell lymphomas. PMID- 27461037 TI - The Promise of Molecularly Targeted and Immunotherapy for Advanced Melanoma. AB - OPINION STATEMENT: Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations. Mutational oncogenic "drivers" may be targeted with chronically administered, oral kinase inhibitors, currently consisting of the mitogen-activated protein kinase (MAPK) inhibitor combinations of BRAF plus MEK-targeted drugs. These agents work quickly to relieve symptoms and induce remissions but generally have limited durations of disease control. Immunotherapies include the immune checkpoint inhibitors that block CTLA4 or PD-1 negative immune signaling as well as interleukin-2, a cytokine that stimulates T lymphocytes and natural killer cells. A combination of CTLA4 plus PD-1 blockade has the highest activity ever reported for metastatic melanoma, at the cost of high autoimmune-like toxicities. However, immunotherapies of this type may provide durable responses and even cure a subset of patients. Thus, these immunotherapeutic agents are recommended as first-line therapy for most patients with advanced melanoma. Patients with rapidly progressive, symptomatic melanoma whose tumor carries a BRAF mutation may benefit more from initial therapy with combined MAPK inhibitors. PMID- 27461038 TI - Relapsed Glioblastoma: Treatment Strategies for Initial and Subsequent Recurrences. AB - OPINION STATEMENT: At the time of glioblastoma (GBM) recurrence, a sharp analysis of prognostic factors, disease characteristics, response to adjuvant treatment, and clinical conditions should be performed. A prognostic assessment could allow a careful selection between patients that could be proposed to intensified approaches or palliative setting. Participation in clinical trials aims to improve outcome, and should be encouraged due to dismal prognosis of GBM patients after recurrence. Reoperation should be proposed if the tumor is amenable to a complete resection and if prognostic factors suggest that patient could benefit from a second surgery. Second-line chemotherapy should be chosen based on MGMT status, time to disease recurrence, and toxicity profile. If enrollment into a clinical trial is not possible, a nitrosourea-based regimen is the preferred choice, carefully evaluating any previous temozolomide (TMZ)-related toxicity. In MGMT-methylated patients relapsing after TMZ completion, a rechallenge could be proposed. After second progression, the clinical advantage of subsequent lines of chemotherapy still needs to be clarified. However, based on performance status, patients' preference, and disease behavior, a third-line treatment could be considered. Available treatments include nitrosoureas, bevacizumab, or carboplatin plus etoposide. However, more effective therapeutic options are needed. PMID- 27461039 TI - The acute lethal dose 50 (LD50) of caffeine in albino rats. AB - An acute LD50 is a statistically derived amount of a substance that can be expected to cause death in 50% of the animals when given by a specified route as a single dose and the animals observed for a specified time period. Although conducting routine acute toxicity testing in rodents has been criticized, it can serve useful functions and also have practical implications. Material safety data sheets (MSDS) will reflect the acute toxicity of a substance and may require workers to wear protective gear, if appropriate, based on the LD50. There is no information in the scientific published literature which calculates a mean LD50 and standard deviation for caffeine administered orally to rats, using studies performed under good laboratory practice (GLP) or equivalent. This report does that and should be useful to manufacturers, packagers, transporters and regulators of this material. Using data from studies that are reproducible and reliable, the most accurate estimate of the acute LD50 of caffeine administered orally in male albino rats is hereby reported to be 367/mg/kg. PMID- 27461040 TI - Optimizing the design of a reproduction toxicity test with the pond snail Lymnaea stagnalis. AB - This paper presents the results from two ring-tests addressing the feasibility, robustness and reproducibility of a reproduction toxicity test with the freshwater gastropod Lymnaea stagnalis (RENILYS strain). Sixteen laboratories (from inexperienced to expert laboratories in mollusc testing) from nine countries participated in these ring-tests. Survival and reproduction were evaluated in L. stagnalis exposed to cadmium, tributyltin, prochloraz and trenbolone according to an OECD draft Test Guideline. In total, 49 datasets were analysed to assess the practicability of the proposed experimental protocol, and to estimate the between-laboratory reproducibility of toxicity endpoint values. The statistical analysis of count data (number of clutches or eggs per individual day) leading to ECx estimation was specifically developed and automated through a free web-interface. Based on a complementary statistical analysis, the optimal test duration was established and the most sensitive and cost-effective reproduction toxicity endpoint was identified, to be used as the core endpoint. This validation process and the resulting optimized protocol were used to consolidate the OECD Test Guideline for the evaluation of reproductive effects of chemicals in L. stagnalis. PMID- 27461041 TI - Transparency in Ecology and Evolution: Real Problems, Real Solutions. AB - To make progress scientists need to know what other researchers have found and how they found it. However, transparency is often insufficient across much of ecology and evolution. Researchers often fail to report results and methods in detail sufficient to permit interpretation and meta-analysis, and many results go entirely unreported. Further, these unreported results are often a biased subset. Thus the conclusions we can draw from the published literature are themselves often biased and sometimes might be entirely incorrect. Fortunately there is a movement across empirical disciplines, and now within ecology and evolution, to shape editorial policies to better promote transparency. This can be done by either requiring more disclosure by scientists or by developing incentives to encourage disclosure. PMID- 27461043 TI - Huaier aqueous extract inhibits proliferation and metastasis of tuberous sclerosis complex cell models through downregulation of JAK2/STAT3 and MAPK signaling pathways. AB - Tuberous sclerosis complex (TSC) is a genetic disorder with formation of benign tumors in many different organs. It has attracted increasing attention from researchers to search for therapeutic drugs for TSC patients. Traditional Chinese medicine (TCM) has become an important source for finding antitumor drugs. Trametes robiniophila MUurr. (Huaier) is a kind of officinal fungi in China and has been applied in TCM for approximately 1,600 years. A large number of clinical applications have revealed that Huaier has good antitumor effect. In this study, we have investigated the effects of Huaier aqueous extract on two TSC cell models, including inhibition of proliferation, induction of apoptosis, cell cycle arrest, and anti-metastasis. We demonstrated that Huaier aqueous extract inhibited JAK2/STAT3 and MAPK signaling pathways in a dose-dependent manner. Therefore, based on the low toxicity and the multi-targets of Huaier treatment, Huaier may be a promising therapeutic drug for TSC. PMID- 27461042 TI - Leveraging Mechanisms Governing Pancreatic Tumorigenesis To Reduce Pancreatic Cancer Mortality. AB - Pancreatic ductal adenocarcinoma (PDA) is a devastating malignancy with limited and modest clinical treatments. High-throughput technologies and accurate disease models now provide a comprehensive picture of the diverse molecular signaling pathways and cellular processes governing PDA tumorigenesis. Central among these is oncogenic KRAS, a mediator of cellular plasticity, metabolic reprogramming, and inflammatory and paracrine signaling required for tumor development and maintenance. Biological aggressiveness is further conferred by a highly fibrotic and immunosuppressive PDA microenvironment that also acts as a barrier to effective drug delivery. The regulation of these mechanisms and their implications for early cancer detection, chemoprevention and therapy are discussed. PMID- 27461044 TI - Clinicophysiological outcomes after total pancreatectomy. AB - PURPOSE: Total pancreatectomy (TP) for pancreatic neoplasms is associated with high morbidity and mortality rates. However, with recent advances in surgical techniques and improved postoperative management, the number of cases with clinical indications for TP is increasing. Here, we evaluated the clinical outcomes post-TP. MATERIALS AND METHODS: Patients (n = 41) who underwent TP between 2004 and 2011 at Tokyo Women's Medical University were retrospectively examined. Pre- and postoperative clinicophysiological data were collected up to 12 months post-TP and then analyzed. RESULTS: Only glycated hemoglobin (HbA1c), percentage of lymphocytes and hepatic Hounsfield unit level on computed tomography (CT) were significantly different between the preoperative state and at 12 months post-TP, while other clinicophysiological parameters remained unchanged. The quantity of the pancreatic enzyme administered significantly influenced glycemic control at 12 months post-TP (p < 0.05). CONCLUSIONS: All clinicophysiological parameters except for HbA1c were temporarily decreased after TP but normalized by 12 months. Thus, TP is a feasible surgical approach to treating pancreatic neoplasms with the potential to spread across the entire pancreas when adequately supplemented by synthetic insulin and pancreatic enzymes. PMID- 27461045 TI - The diagnosis and management of the haematologic manifestations of lupus. AB - Haematological manifestations in systemic lupus erythematosus (SLE) are frequently observed. They are diverse and range from mild to severe. Therefore, different treatment approaches are needed from simply keeping vigilant to significant immunosuppression. Most treatment evidence is based on case-reports or small retrospective studies, as few randomized controlled trials have been performed. The development of biological therapy has opened new possible ways to treat the most severe cases but further clinical trials are necessary. In this review we consider the most common and characteristic haematological manifestations of SLE patients, focusing on their pathogenesis and management. PMID- 27461046 TI - Endoscopic treatment of idiopathic subglottic stenosis with digital AcuBlade robotic microsurgery system. AB - Herein, we described a novel method as the use of AcuBlade robotic microsurgery system to manage idiopathic subglottic stenosis in a 73-y-old lady. Compared to traditional CO2 lasers, AcuBlade facilitated the scar resection by the generation of different shape of beams (straight, curved, or disk). The same setting used for phonomicrosurgery (1-mm beam length, power of 10 W and pulse duration of 0.05 s) allowed to obtain fast, long, and uniform cuts. In addition, the reduction of the number of laser passes over the same area prevented injury of adjacent tissue and thus reduced the risk of recurrence. PMID- 27461047 TI - Ethnic inequalities in periodontal disease among British adults. AB - AIM: To explore ethnic inequalities in periodontal disease among British adults, and the role of socioeconomic position (SEP) in those inequalities. METHODS: We analysed data on 1925 adults aged 16-65 years, from the East London Oral Health Inequality (ELOHI) Study, which included a random sample of adults living in an ethnically diverse and socially deprived area. Participants completed a questionnaire and were clinically examined for the number of teeth with periodontal pocket depth (PPD)>=4 mm and loss of attachment (LOA)>=4 mm. Ethnic inequalities in periodontal measures were assessed in negative binomial regression models before and after adjustment for demographic (gender and age groups) and SEP indicators (education and socioeconomic classification). RESULTS: Compared to White British, Pakistani, Indian, Bangladeshi and Asian Others had more teeth with PPD>=4 mm whereas White East European, Black African and Bangladeshi had more teeth with LOA>=4 mm, after adjustments for demographic and SEP measures. The association of ethnicity with periodontal disease was moderated by education, but not by socioeconomic classification. Stratified analysis showed that ethnic disparities in the two periodontal measures were limited to more educated groups. CONCLUSION: This study showed considerable ethnic disparities in periodontal disease between and within the major ethnic categories. PMID- 27461048 TI - Postmenopausal Hormone Therapy and Breast Cancer Prognostic Characteristics: A Linkage between Nationwide Registries. AB - BACKGROUND: The effects of use of different types of hormone therapy on breast cancer risk according to prognostic factors are largely unknown. METHODS: We linked data from the Norwegian Prescription Database and the Cancer Registry of Norway during 2004 to 2009 on all women ages 45 to 79 years (N = 686,614). We estimated rate ratios and 95% confidence intervals for breast cancer in relation to hormone therapy using Poisson regression. RESULTS: During an average 4.8 years of follow-up, 7,910 invasive breast cancers were diagnosed. Compared with nonusers of hormone therapy, users of estradiol and tibolone were more likely to be diagnosed with grade I, lymph node-negative, and estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) tumors. However, compared with nonusers, users of the most common estrogen and progestin combinations [estradiol norethisterone acetate (NETA) preparations (Kliogest, Activelle or Trisekvens)] were at a 4- to 5-fold elevated risk of grade I tumors, 3-fold elevated risk of lymph node-negative tumors, and 3- to 4-fold elevated risk of ER+/PR+ tumors. Importantly, estradiol-NETA users were also at a 2- to 3-fold increased risk of medium differentiated (grade II) tumors and tumors with lymph node involvement. CONCLUSIONS: Use of oral estradiol, tibolone, and estradiol-NETA predominantly increases the risk of breast cancer with favorable prognosis characteristics. However, use of estradiol-NETA preparations also increases the risk of breast cancers with less favorable characteristics. IMPACT: The hormone therapy preparations most commonly used in the Nordic countries are associated with both breast cancers with good and less favorable prognosis characteristics. Cancer Epidemiol Biomarkers Prev; 25(11); 1464-73. (c)2016 AACR. PMID- 27461050 TI - Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. AB - Neuropeptide Y (NPY) and NPY receptors are widely expressed in the mammalian central nervous system. Studies in both humans and rodent models revealed that brain NPY levels are altered in some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease. In this review, we will focus on the roles of NPY in the pathological mechanisms of these disorders, highlighting NPY as a neuroprotective agent, as a neural stem cell proliferative agent, as an agent that increases trophic support, as a stimulator of autophagy and as an inhibitor of excitotoxicity and neuroinflammation. Moreover, the effect of NPY in some clinical manifestations commonly observed in Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease, such as depressive symptoms and body weight loss, are also discussed. In conclusion, this review highlights NPY system as a potential therapeutic target in neurodegenerative diseases. PMID- 27461049 TI - Long-term Diet and Biomarker Changes after a Short-term Intervention among Hispanic Breast Cancer Survivors: The !Cocinar Para Su Salud! Randomized Controlled Trial. AB - BACKGROUND: Among Hispanic breast cancer survivors, we examined the long-term effects of a short-term culturally based dietary intervention on increasing fruits/vegetables (F/V), decreasing fat, and changing biomarkers associated with breast cancer recurrence risk. METHODS: Spanish-speaking women (n = 70) with a history of stage 0-III breast cancer who completed treatment were randomized to !Cocinar Para Su Salud! (n = 34), a culturally based 9-session program (24 hours over 12 weeks, including nutrition education, cooking classes, and food-shopping field trips), or a control group (n = 36, written dietary recommendations for breast cancer survivors). Diet recalls, fasting blood, and anthropometric measures were collected at baseline, 6, and 12 months. We report changes between groups at 12 months in dietary intake and biomarkers using 2-sample Wilcoxon t tests and generalized estimating equation (GEE) models. RESULTS: At 12 months, the intervention group compared with the control group reported higher increases in mean daily F/V servings (total: +2.0 vs. -0.4; P < 0.01), and nonsignificant decreases in the percentage of calories from fat (-2.2% vs. -1.1%; P = 0.69) and weight (-2.6 kg vs. -1.5 kg; P = 0.56). Compared with controls, participants in the intervention group had higher increases in plasma lutein (+20.4% vs. -11.5%; P < 0.01), and borderline significant increases in global DNA methylation (+0.8% vs. -0.5%; P = 0.06). CONCLUSIONS: The short-term !Cocinar Para Su Salud! program was effective at increasing long-term F/V intake in Hispanic breast cancer survivors and changed biomarkers associated with breast cancer recurrence risk. IMPACT: It is possible for short-term behavioral interventions to have long-term effects on behaviors and biomarkers in minority cancer patient populations. Results can inform future study designs. Cancer Epidemiol Biomarkers Prev; 25(11); 1491-502. (c)2016 AACR. PMID- 27461051 TI - Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1(G93A) ALS mice and after partial muscle denervation. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motoneurons, which is preceded by loss of neuromuscular connections in a "dying back" process. Neuregulin-1 (Nrg1) is a neurotrophic factor essential for the development and maintenance of neuromuscular junctions, and Nrg1 receptor ErbB4 loss-of-function mutations have been reported as causative for ALS. Our main goal was to investigate the role of Nrg1 type I (Nrg1-I) in SOD1(G93A) mice muscles. We overexpressed Nrg1-I by means of an adeno-associated viral (AAV) vector, and investigated its effect by means of neurophysiological techniques assessing neuromuscular function, as well as molecular approaches (RT-PCR, western blot, immunohistochemistry, ELISA) to determine the mechanisms underlying Nrg1-I action. AAV-Nrg1-I intramuscular administration promoted motor axon collateral sprouting by acting on terminal Schwann cells, preventing denervation of the injected muscles through Akt and ERK1/2 pathways. We further used a model of muscle partial denervation by transecting the L4 spinal nerve. AAV-Nrg1-I intramuscular injection enhanced muscle reinnervation by collateral sprouting, whereas administration of lapatinib (ErbB receptor inhibitor) completely blocked it. We demonstrated that Nrg1-I plays a crucial role in the collateral reinnervation process, opening a new window for developing novel ALS therapies for functional recovery rather than preservation. PMID- 27461052 TI - Novel synthetic lethality screening method identifies TIP60-dependent radiation sensitivity in the absence of BAF180. AB - In recent years, research into synthetic lethality and how it can be exploited in cancer treatments has emerged as major focus in cancer research. However, the lack of a simple to use, sensitive and standardised assay to test for synthetic interactions has been slowing the efforts. Here we present a novel approach to synthetic lethality screening based on co-culturing two syngeneic cell lines containing individual fluorescent tags. By associating shRNAs for a target gene or control to individual fluorescence labels, we can easily follow individual cell fates upon siRNA treatment and high content imaging. We have demonstrated that the system can recapitulate the functional defects of the target gene depletion and is capable of discovering novel synthetic interactors and phenotypes. In a trial screen, we show that TIP60 exhibits synthetic lethality interaction with BAF180, and that in the absence of TIP60, there is an increase micronuclei dependent on the level of BAF180 loss, significantly above levels seen with BAF180 present. Moreover, the severity of the interactions correlates with proxy measurements of BAF180 knockdown efficacy, which may expand its usefulness to addressing synthetic interactions through titratable hypomorphic gene expression. PMID- 27461053 TI - A Role of Suppressor of Cytokine Signaling 2 in the Regulation of Ecdysteroid Signaling Pathway in Procambarus clarkii. AB - A suppressor of cytokine signaling 2 (SOCS-2) homolog was identified from the red crayfish Procambarus clarkii. Phylogenic analysis showed that P. clarkii SOCS-2 (Pc-SOCS-2) was very similar to that of invertebrates. The sequence contains a central SH2 domain, a conserved SOCS box, and a variable N-terminal domain. Real time polymerase chain reaction showed that Pc-SOCS-2 mRNA level was higher in muscle and heart than in the other tissues examined. A 40-kDa recombinant protein was successfully expressed and purified from Escherichia coli cells as confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Pc-SOCS-2 was significantly downregulated in the hepatopancreas after 20-hydroxyecdysone injection. Knockdown of Pc-SOCS-2 gene by small interfering RNA transfection in the hepatopancreas increased the expression levels of 20-hydroxyecdysone-responsive genes at 48 hr. Taken together, these results suggest that Pc-SOCS-2 is a negative regulator of ecdysteroid signaling transduction. PMID- 27461054 TI - Synthesis of 3-Aminoimidazo[1,2-a]pyridines from alpha-Aminopyridinyl Amides. AB - 3-Aminoimidazo[1,2-a]pyridines are rapidly synthesized via a facile and mild cyclodehydration-aromatization reaction starting from readily available amides. The cyclodehydration step is mediated by the activation of N-Boc-protected 2 aminopyridine-containing amides by triflic anhydride (Tf2O) in the presence of 2 methoxypyridine (2-MeO-Py). Subsequently, the addition of K2CO3 in THF ensured a clean deprotection-aromatization sequence to afford the desired heterocycle. A wide variety of functional groups and substitution patterns were tolerated under the optimized procedure, and good to excellent yields were obtained for the fused bicyclic 3-aza-heterocycles. In addition, the reaction was found to be scalable to gram-scale and could be performed with unprotected acyclic amide precursors. We also found that the resulting products were valuable intermediates for both Pd and Ru-catalyzed C-H arylation reactions, allowing for the elaboration to diversely functionalized building blocks. PMID- 27461055 TI - Gastrointestinal stromal tumors in kidney transplant recipients: Report of two cases and literature review. AB - Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal gastrointestinal neoplasms. However, GISTs occurring in kidney transplant recipients, including their treatment and outcome, are rarely described in literature. We hereby report two kidney transplant recipients with GISTs. Our first patient was diagnosed with high-risk epithelioid gastric GIST 2 years after kidney transplant. He received everolimus after resection and remained disease free for 2 years before liver metastasis was confirmed. Imatinib therapy was planned but he died of fulminant pneumonia shortly. Our second patient was diagnosed with spindle cell GISTs in the mesentery 1 year after kidney transplant. Only partial response was obtained with imatinib as new lesions continued to develop. Withdrawal of cyclosporine and introduction of sirolimus resulted in complete shrinkage of existing tumors and no new lesions. He remained disease-free for more than 10 years. Combination therapy consisting of imatinib and inhibitors of mammalian target of rapamycin (mTORi) seems to be safe and effective in kidney transplant recipients. However, therapeutic drug monitoring of mTORi is essential to avoid nephrotoxicity. Further trials addressing the optimal dosage of imatinib and mTORi in kidney transplant recipients are recommended. PMID- 27461057 TI - Potential carcinogenicity predicted by computational toxicity evaluation of thiophosphate pesticides using QSTR/QSCarciAR model. AB - This study presents in silico prediction of toxic activities and carcinogenicity, represented by the potential carcinogenicity DSSTox/DBS, based on vector regression with a new Kernel activity, and correlating the predicted toxicity values through a QSAR model, namely: QSTR/QSCarciAR (quantitative structure toxicity relationship/quantitative structure carcinogenicity-activity relationship) described by 2D, 3D descriptors and biological descriptors. The results showed a connection between carcinogenicity (compared to the structure of a compound) and toxicity, as a basis for future studies on this subject, but each prediction is based on structurally similar compounds and the reactivation of the substructures of these compounds. PMID- 27461056 TI - Impact of increased risk for fetal aneuploidy on maternal mood: a prospective longitudinal study. AB - INTRODUCTION: Our goal was to prospectively compare the trajectories of depression symptoms through pregnancy and postpartum between women who received normal prenatal screening results and those whose results indicated an increased risk for fetal aneuploidy. MATERIAL AND METHODS: Women completed the Edinburgh Postnatal Depression Scale (EPDS) at 4-week intervals between <26 weeks' gestation and 3 months postpartum. We categorized women into four groups: (i) negative serum screening and ultrasound results (SS(-) /US(-) , n = 103), (ii) positive serum screening/negative ultrasound results (SS(+) /US(-) , n = 42), (iii) negative serum screening/positive ultrasound results (SS(-) /US(+) , n = 19), or (iv) positive serum screening and ultrasound results (SS(+) /US(+) , n = 13), and compared EPDS scores between groups using Poisson regression. RESULTS: Women who received any positive prenatal screening result had significantly higher EPDS scores during pregnancy than SS(-) /US(-) women (p = 0.002), with SS( ) /US(+) women having the highest scores. During the postpartum, any positive screening test result was only marginally significantly associated with EPDS scores (p = 0.06), but women in the SS(-) /US(+) group had significantly higher scores than women in the SS(-) /US(-) group (p = 0.05). CONCLUSIONS: Our data suggest that different types of prenatal screening tests may have different effects on women's moods, and that depression symptoms persist for women who have soft markers identified on ultrasound. PMID- 27461058 TI - Ballistic heat transport in laser generated nano-bubbles. AB - Nanobubbles generated by laser heated plasmonic nanoparticles are of interest for biomedical and energy harvesting applications. Of utmost importance is the maximal size of these transient bubbles. Here, we report hydrodynamic phase field simulations of the dynamics of laser induced nanobubbles, with the aim to understand which physical processes govern their maximal size. We show that the nanobubble maximal size and lifetime are to a large extent controlled by the ballistic thermal flux which is present inside the bubble. Taking into account this thermal flux, we can reproduce the fluence dependence of the maximal nanobubble radius as reported experimentally. We also discuss the influence of the laser pulse duration on the number of nanobubbles generated and their maximal size. These studies represent a significant step toward the optimization of the nanobubble size, which is of crucial importance for photothermal cancer therapy applications. PMID- 27461059 TI - Alteration of Esophageal Microbiome by Antibiotic Treatment Does Not Affect Incidence of Rat Esophageal Adenocarcinoma. AB - BACKGROUND: Recent studies suggest that chronic inflammation-associated cancer is relevant to microbiome. Esophageal adenocarcinoma arises from an inflammatory condition called Barrett's esophagus, which is caused by gastroesophageal reflux. We hypothesized that esophageal microbiome plays a role in carcinogenesis of esophageal adenocarcinoma. AIM: We investigated whether alteration of microbiome using antibiotics affects the development of esophageal adenocarcinoma in a rat model. METHODS: Seven-week-old male Wistar rats which had undergone esophagojejunostomy were divided into control (n = 21) and antibiotic groups (n = 22) at 21 weeks after surgery. Control animals were given drinking water, while the other group was given penicillin G and streptomycin in drinking water until rats were killed at 40 weeks after operation. Incidence rates of Barrett's esophagus and adenocarcinoma in each group were evaluated by histological analysis. DNA was extracted from a portion of the distal esophagus, and the microbiome was investigated using terminal restriction fragment length polymorphism (T-RFLP) analysis. RESULTS: All rats in both groups developed Barrett's esophagus. Incidence of esophageal adenocarcinoma was similar between both groups with a trend to reduced incidence in the antibiotics group (89 % in the control group, 71 % in the antibiotics group, P = 0.365). T-RFLP analysis showed that esophageal microbiome was different between two groups such as the proportion of Lactobacillales was lower in the antibiotics group and Clostridium cluster XIVa and XVIII was higher in the antibiotics group. CONCLUSIONS: Alteration of microbiome does not affect the incidence of esophageal adenocarcinoma. Microbiome may not contribute to the development of esophageal adenocarcinoma. PMID- 27461061 TI - Syntheses of a radiolabelled CXCR2 antagonist AZD5069 and its major human metabolite. AB - The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14 labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group. PMID- 27461060 TI - Exposure to Ambient Air Pollution and the Risk of Inflammatory Bowel Disease: A European Nested Case-Control Study. AB - BACKGROUND: Industrialization has been linked to the etiology of inflammatory bowel disease (IBD). AIM: We investigated the association between air pollution exposure and IBD. METHODS: The European Prospective Investigation into Cancer and Nutrition cohort was used to identify cases with Crohn's disease (CD) (n = 38) and ulcerative colitis (UC) (n = 104) and controls (n = 568) from Denmark, France, the Netherlands, and the UK, matched for center, gender, age, and date of recruitment. Air pollution data were obtained from the European Study of Cohorts for Air Pollution Effects. Residential exposure was assessed with land-use regression models for particulate matter with diameters of <10 MUm (PM10), <2.5 MUm (PM2.5), and between 2.5 and 10 MUm (PMcoarse), soot (PM2.5 absorbance), nitrogen oxides, and two traffic indicators. Conditional logistic regression analyses were performed to calculate odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: Although air pollution was not significantly associated with CD or UC separately, the associations were mostly similar. Individuals with IBD were less likely to have higher exposure levels of PM2.5 and PM10, with ORs of 0.24 (95 % CI 0.07-0.81) per 5 MUg/m(3) and 0.25 (95 % CI 0.08-0.78) per 10 MUg/m(3), respectively. There was an inverse but nonsignificant association for PMcoarse. A higher nearby traffic load was positively associated with IBD [OR 1.60 (95 % CI 1.04-2.46) per 4,000,000 motor vehicles * m per day]. Other air pollutants were positively but not significantly associated with IBD. CONCLUSION: Exposure to air pollution was not found to be consistently associated with IBD. PMID- 27461062 TI - Therapeutic potential of targeting sphingosine kinases and sphingosine 1 phosphate in hematological malignancies. AB - Sphingolipids, such as ceramide, sphingosine and sphingosine 1-phosphate (S1P) are bioactive molecules that have important functions in a variety of cellular processes, which include proliferation, survival, differentiation and cellular responses to stress. Sphingolipids have a major impact on the determination of cell fate by contributing to either cell survival or death. Although ceramide and sphingosine are usually considered to induce cell death, S1P promotes survival of cells. Sphingosine kinases (SPHKs) are the enzymes that catalyze the conversion of sphingosine to S1P. There are two isoforms, SPHK1 and SPHK2, which are encoded by different genes. SPHK1 has recently been implicated in contributing to cell transformation, tumor angiogenesis and metastatic spread, as well as cancer cell multidrug-resistance. More recent findings suggest that SPHK2 also has a role in cancer progression. This review is an overview of our understanding of the role of SPHKs and S1P in hematopoietic malignancies and provides information on the current status of SPHK inhibitors with respect to their therapeutic potential in the treatment of hematological cancers. PMID- 27461063 TI - Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3 PBX1 acute lymphoblastic leukemia. AB - TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression. By drug-sensitivity testing of leukemic blasts from the index patient, control samples and TCF3-PBX1 positive and negative BCP-ALL cell lines, we identified the phosphatidylinositide 3-kinase delta (p110delta) inhibitor idelalisib as an effective treatment for TCF3-PBX1 BCP-ALL. This was further supported by evidence showing TCF3-PBX1 directly regulates expression of PIK3CD, the gene encoding p110delta. Other somatic mutations to TP53 and MTOR, as well as aberrant expression of CXCR4, may influence additional drug sensitivities specific to the index patient and accompanied progression of the disease. Our results suggest that idelalisib is a promising treatment option for patients with TCF3-PBX1 BCP-ALL, whereas other drugs could be useful depending on the genetic context of individual patients. PMID- 27461064 TI - HLA polymorphism and risk of multiple myeloma. PMID- 27461065 TI - Search for an index for the taste of Japanese Black cattle beef by panel testing and chemical composition analysis. AB - To search for an index for chemical composition related to superior taste in Japanese Black beef, we conducted panel tests and analyzed the chemical composition of seven beef brands. Thirty-five sirloin beefs from five heifers were used in this study, sold under seven beef brands graded as more than A4 on the Japanese Meat Grade scale. The chemical composition analyses assessed both raw and roasted meat, the latter of which was roasted under the same conditions as those used for the panel test. Results of the panel test and chemical composition analyses revealed that fatty acid composition, sugar content, adenosine triphosphage (ATP)-related compounds, amino acid composition and odor composition in the sirloin meat differed among beef brands. Furthermore, the correlations of chemical compositions between roasted and raw meat were significantly high. Sugar content and ATP-related compounds in roasted meat were significantly correlated with the item 'overall evaluation' of the panel test. ATP-related compounds, such as inosinic acid, carnosine and taurine, in roasted and raw meat were correlated significantly with the item 'umami intensity' of the panel test. These results suggest that the composition of these components is important for an index related to the overall evaluation of beef. PMID- 27461066 TI - Predicting Glucose Effectiveness in Chinese Participants Using Routine Measurements. AB - BACKGROUND: Glucose effectiveness (GE) is the capacity of glucose to increase its own uptake and to maintain endogenous hepatic glucose output under basal insulin levels. In addition to decreased insulin sensitivity (IS) and impaired insulin secretion, GE plays a critical role in glucose balance in patients with type 2 diabetes (T2DM). In the study, we developed an equation for predicting GE. METHODS: We enrolled 227 participants with glucose tolerances ranging from normal glucose tolerance to diabetes. Of the participants, 75% (171) participants were randomly assigned to the study group, whose data were used to construct the equation for estimating GE. The remaining 56 participants comprised the validation group. All participants underwent a frequently sampled intravenous glucose tolerance test; IS, GE, and the acute insulin response after the glucose load were determined. RESULTS: Age, triglyceride (TG), and fasting plasma glucose (FPG) were independently correlated with GE and selected for inclusion in multiple linear regression analysis. We constructed the following equation: GE = (29.196 - 0.103 * age - 2.722 * TG - 0.592 * FPG) * 10-3. Using this same equation, we also calculated the GE of the validation group. The calculated GE was significantly correlated with the measured GE (r = 0.430, P = 0.001). CONCLUSIONS: Using the equation based on routine measurements enabled the GE to be predicted with acceptable accuracy (r = 0.430). This method of predicting GE may aid clinicians in further understanding the underlying pathological mechanisms of T2DM. PMID- 27461067 TI - Sturgeon and paddlefish (Acipenseridae) sagittal otoliths are composed of the calcium carbonate polymorphs vaterite and calcite. AB - This study sought to resolve whether sturgeon (Acipenseridae) sagittae (otoliths) contain a non-vaterite fraction and to quantify how large a non-vaterite fraction is using neutron diffraction analysis. This study found that all otoliths examined had a calcite fraction that ranged from 18 +/- 6 to 36 +/- 3% by mass. This calcite fraction is most probably due to biological variation during otolith formation rather than an artefact of polymorph transformation during preparation. PMID- 27461068 TI - Comparing the performance of trained radiographers against experienced radiologists in the UK lung cancer screening (UKLS) trial. AB - OBJECTIVE: To compare the performance of radiographers against that of radiologists for CT lung nodule detection in the UK Lung Cancer Screening (UKLS) pilot trial. METHODS: Four radiographers, trained in CT nodule detection, and three radiologists were prospectively evaluated. 290 CTs performed for the UKLS were independently read by 2 radiologists and 2 radiographers. The reference standard comprised all radiologist-identified positive nodules after arbitration of discrepancies. For each radiographer and radiologist, relative sensitivity and average false positives (FPs) per case were compared for all cases read, as well as for subsets of cases read by each radiographer-radiologist combination (10 combinations). RESULTS: 599 nodules in 209/290 (72.1%) CT studies comprised the reference standard. The relative mean (+/-standard deviation) sensitivity of the four radiographers was 71.6 +/- 8.5% compared with 83.3 +/- 8.1% for the three radiologists. Radiographers were less sensitive and detected more FPs per case than radiologists in 7/10 and 8/10 radiographer-radiologist combinations, respectively (ranges of difference 11.2-33.8% and 0.4-2.6; p < 0.05). In 3/10 and 2/10 combinations, there was no difference in sensitivity and FPs per case between radiographers and radiologists. For nodules >=100 mm(3) in volume or >=5 mm in maximum diameter, radiographers were relatively less sensitive than radiologists in only 5/10 radiographer-radiologist combinations (range of difference 16.1-30.6%; p < 0.05) and not significantly different in the remaining 5/10 combinations. CONCLUSION: Although overall radiographer performance was lower than that of experienced radiologists in this study, some radiographer performances were comparable with that of radiologists. ADVANCES IN KNOWLEDGE: Overall, radiographers were less sensitive than radiologists reading the same CTs and also displayed higher average FP detections per case when compared with a reference standard derived from radiologist readings. However, some radiographers compared favourably with radiologists, especially when considering larger potentially clinically relevant nodules. Thus, while probably not sensitive enough to function as first readers, radiographers may still be able to fulfil the role of an assistant reader-that is, as a first or concurrent reader, who presents detected nodules for verification to a reading radiologist. PMID- 27461069 TI - Automated algorithm for CBCT-based dose calculations of prostate radiotherapy with bilateral hip prostheses. AB - OBJECTIVE: Cone beam CT (CBCT) images contain more scatter than a conventional CT image and therefore provide inaccurate Hounsfield units (HUs). Consequently, CBCT images cannot be used directly for radiotherapy dose calculation. The aim of this study is to enable dose calculations to be performed with the use of CBCT images taken during radiotherapy and evaluate the necessity of replanning. METHODS: A patient with prostate cancer with bilateral metallic prosthetic hip replacements was imaged using both CT and CBCT. The multilevel threshold (MLT) algorithm was used to categorize pixel values in the CBCT images into segments of homogeneous HU. The variation in HU with position in the CBCT images was taken into consideration. This segmentation method relies on the operator dividing the CBCT data into a set of volumes where the variation in the relationship between pixel values and HUs is small. An automated MLT algorithm was developed to reduce the operator time associated with the process. An intensity-modulated radiation therapy plan was generated from CT images of the patient. The plan was then copied to the segmented CBCT (sCBCT) data sets with identical settings, and the doses were recalculated and compared. RESULTS: Gamma evaluation showed that the percentage of points in the rectum with gamma < 1 (3%/3 mm) were 98.7% and 97.7% in the sCBCT using MLT and the automated MLT algorithms, respectively. Compared with the planning CT (pCT) plan, the MLT algorithm showed -0.46% dose difference with 8 h operator time while the automated MLT algorithm showed -1.3%, which are both considered to be clinically acceptable, when using collapsed cone algorithm. CONCLUSION: The segmentation of CBCT images using the method in this study can be used for dose calculation. For a patient with prostate cancer with bilateral hip prostheses and the associated issues with CT imaging, the MLT algorithms achieved a sufficient dose calculation accuracy that is clinically acceptable. The automated MLT algorithm reduced the operator time associated with implementing the MLT algorithm to achieve clinically acceptable accuracy. This saved time makes the automated MLT algorithm superior and easier to implement in the clinical setting. ADVANCES IN KNOWLEDGE: The MLT algorithm has been extended to the complex example of a patient with bilateral hip prostheses, which with the introduction of automation is feasible for use in adaptive radiotherapy, as an alternative to obtaining a new pCT and reoutlining the structures. PMID- 27461071 TI - A homoleptic, all-alkynyl-stabilized highly luminescent Au8Ag8 cluster with a single crystal X-ray structure. AB - A homoleptic, all-alkynyl-stabilized [Au8Ag8(ArC[triple bond, length as m dash]C)16] (1, Ar = 3,5-di-tert-butylphenyl) cluster was synthesized and characterized with a single crystal X-ray structure. Reactions of 3,5-di-tert butyl-phenylacetylene with Ag(i) and Au(i) gave [Ag(ArC[triple bond, length as m dash]C)]n and Au(PPh3)(ArC[triple bond, length as m-dash]C), respectively, where both have unusually high solubility in nonpolar organic solvents. In addition to drastically increased solubility, the two bulky tert-butyl substituents on the phenyl ring can confine the metal core to a certain size by preventing infinite aggregation of d(10) metals. This feature makes the isolation of an all-alkynyl stabilized Au-Ag cluster possible. Complex 1 is intensely luminescent with a very high quantum yield of 0.67 in solution at room temperature. Theoretical studies offered valuable insights into the intriguing photophysical properties, and revealed the significant role of metal-alkynyl bond interactions and enhanced molecular rigidity provided by tert-butyl groups. PMID- 27461070 TI - Comparison and Interpretation of Taxonomical Structure of Bacterial Communities in Two Types of Lakes on Yun-Gui plateau of China. AB - Bacterial communities from freshwater lakes are shaped by various factors such as nutrients, pH value, temperature, etc. Their compositions and relative abundances would undergo changes to adapt the changing environments, and in turn could affect the environments of freshwater lakes. Analyses of the freshwater lake's bacterial communities under different environments would be of pivotal importance to monitor the condition of waterbody. In this study, we have collected freshwater samples from two lakes on Yun-Gui plateau of China, Lake Dianchi and Lake Haixihai, and analyzed the bacterial community structures from these samples based on 16S rRNA sequencing. Results have shown that: Firstly, the bacterial community of these samples have very different taxonomical structures, not only between two lakes but also among the intra-groups for samples collected from Dianchi. Secondly, the differences between samples from two lakes are highly associated with the chemical-geographical properties of the two lakes. Thirdly, for samples of Dianchi and Haixihai, analytical results of physicochemical, taxonomical structure and relative abundance of community revealed that extreme physicochemical factors caused by human activities have strongly affected the bacterial ecosystem in Dianchi. These results have clearly indicated the importance of combining biological profiling and chemical-geographical properties for monitoring Chinese plateau freshwater bacterial ecosystem, which could provide clues for Chinese freshwater ecosystem remediation on plateau. PMID- 27461072 TI - Investigating social cognition in epilepsy using a naturalistic task. AB - OBJECTIVE: The primary objective for this study was to assess social cognition in patients with focal epilepsy using a naturalistic task, which accurately models complex real-world social interaction. METHODS: We conducted an observational study of social cognition in 43 patients with focal epilepsy and in 22 controls. Patients and controls completed The Awareness of Social Inference Test, which measures both basic and advanced social cognition in a realistic video-based format. Patient and controls also completed standard measures of cognitive functioning and measures of depression. RESULTS: Compared to controls, we found that patients with epilepsy (PWEs) had no difficulty identifying positively valenced emotional states (happiness) yet had difficulty identifying most negatively valenced emotional states (anger, fear, and disgust). In addition, PWEs were able to identify sincere exchanges correctly but could not identify sarcastic and insincere exchanges. We found that basic social cognition significantly correlated with standard generalized cognitive measures, whereas advanced social cognition did not. Finally, age at onset had significant impact on social cognition, whereas other epilepsy characteristics did not. SIGNIFICANCE: PWEs have deficits in social cognition when measured using a naturalistic video-based task. Advanced social cognition may be an independent cognitive domain in PWEs that is not adequately measured using standard psychometric instruments. Problems with social cognition may arise as a consequence of epilepsy during the periods of robust social development in childhood and adolescence. PMID- 27461073 TI - Formation of Coaxial Nanocables with Amplified Supramolecular Chirality through an Interaction between Carbon Nanotubes and a Chiral pi-Gelator. AB - In an attempt to gather experimental evidence for the influence of carbon allotropes on supramolecular chirality, we found that carbon nanotubes (CNTs) facilitate amplification of the molecular chirality of a pi-gelator (MC-OPV) to supramolecular helicity at a concentration much lower than that required for intermolecular interaction. For example, at a concentration 1.8*10(-4) m, MC-OPV did not exhibit a CD signal; however, the addition of 0-0.6 mg of SWNTs resulted in amplified chirality as evident from the CD spectrum. Surprisingly, AFM analysis revealed the formation of thick helical fibers with a width of more than 100 nm. High-resolution TEM analysis and solid-state UV/Vis/NIR spectroscopy revealed that the thick helical fibers were cylindrical cables composed of individually wrapped and coaxially aligned SWNTs. Such an impressive effect of CNTs on supramolecular chirality and cylindrical-cable formation has not been reported previously. PMID- 27461075 TI - Uncovering the neural magnitude and spatio-temporal dynamics of natural image categorization in a fast visual stream. AB - Perceptual categorization occurs rapidly under natural viewing conditions. Yet, the neural spatio-temporal dynamics of category-selective processes to single glanced, natural (i.e., unsegmented) images in a rapidly changing presentation stream remain unknown. We presented human observers with natural images of objects at a fast periodic rate of 12.5Hz, i.e., every 80ms. Images of faces were inserted every 3, 5, 7, 9, or 11 stimuli, defining stimulus-onset-asynchronies (SOAs) between 240-880ms, i.e., presentation frequencies (Fs) between 4.17 1.14Hz. Robust face-selective responses were objectively identified and quantified at F and its harmonics (2F, 3F, etc.) for every condition in the electroencephalogram (EEG). The summed-harmonic face-selective response was significantly reduced by 25% at the lowest face SOA, i.e. 240ms between two faces, but remained stable from 400ms SOA onward. This high-level, right lateralized face-selective response emerged at about 100ms post-stimulus onset and progressed spatially throughout four successive time-windows (i.e., P1-face, N1-face, P2-face, P3-face) from posterior to anterior occipito-temporal electrode sites. The total duration of a category-selective response to a briefly presented face stimulus in a rapid sequence of objects was estimated to be 420ms. Uncovering the neural spatio-temporal dynamics of category-selectivity in a rapid stream of natural images goes well beyond previous evidence obtained from spatially and temporally isolated stimuli, opening an avenue for understanding human vision and its relationship to categorization behavior. PMID- 27461074 TI - Human DNA-Damage-Inducible 2 Protein Is Structurally and Functionally Distinct from Its Yeast Ortholog. AB - Although Ddi1-like proteins are conserved among eukaryotes, their biological functions remain poorly characterized. Yeast Ddi1 has been implicated in cell cycle regulation, DNA-damage response, and exocytosis. By virtue of its ubiquitin like (UBL) and ubiquitin-associated (UBA) domains, it has been proposed to serve as a proteasomal shuttle factor. All Ddi1-like family members also contain a highly conserved retroviral protease-like (RVP) domain with unknown substrate specificity. While the structure and biological function of yeast Ddi1 have been investigated, no such analysis is available for the human homologs. To address this, we solved the 3D structures of the human Ddi2 UBL and RVP domains and identified a new helical domain that extends on either side of the RVP dimer. While Ddi1-like proteins from all vertebrates lack a UBA domain, we identify a novel ubiquitin-interacting motif (UIM) located at the C-terminus of the protein. The UIM showed a weak yet specific affinity towards ubiquitin, as did the Ddi2 UBL domain. However, the full-length Ddi2 protein is unable to bind to di ubiquitin chains. While proteomic analysis revealed no activity, implying that the protease requires other factors for activation, our structural characterization of all domains of human Ddi2 sets the stage for further characterization. PMID- 27461076 TI - Morphology, orthography, and the two hemispheres: A divided visual field study with Hindi/Urdu biliterates. AB - Although identical on the spoken level, Hindi and Urdu differ markedly on the written level in terms of reading/writing direction and orthographic depth, with discernible processing consequences. The present study used a divided field paradigm to study the impact of writing system characteristics of Hindi and Urdu on word naming latencies in skilled biliterate users of these languages. Hindi (read/written from left to right) was hypothesized to show a larger right field advantage than Urdu (read/written from right to left); Hindi words sharing form overlap with primes were expected to show a significant priming effect in the left visual field, but a significant right field effect for morphologically primed naming. Both these expectations were confirmed. An overall right field advantage was obtained for one syllable Hindi and Urdu words; two syllable Urdu words showed either no visual field differences or a left field advantage, and the right field advantage for Hindi was significantly greater for two syllable than one syllable words. Further, Hindi words showed significant form priming (relative to control stimuli) in the left visual field and significant morphological priming (relative to form priming) in the right visual field. By contrast, Urdu words showed no significant form priming in either visual field, and significantly greater morphological than form priming in the left visual field. These results are taken to suggest that visual field asymmetries in word naming are sensitive to differences in reading habit-related scanning biases and to orthographic depth-related differences in word recognition processes. PMID- 27461077 TI - fMRI evidence of equivalent neural suppression by repetition and prior knowledge. AB - Stimulus repetition speeds behavioral responding (behavioral priming) and is accompanied by suppressed neural responses (repetition suppression; RS) that have been observed up to three days after initial exposure. While some proposals have suggested the two phenomena are linked, behavioral priming has been observed many years after initial exposure, whereas RS is widely considered a transitory phenomenon. This raises the question: what is the true upper limit of RS persistence? To answer this question, we scanned healthy, English-native adults with fMRI as they viewed novel (Asian) proverbs, recently repeated (Asian) proverbs, and previously known (English) proverbs that were matched on various dimensions. We then estimated RS by comparing repeated or previously known proverbs against novel ones. Multivariate analyses linked previously known and repeated proverbs with statistically indistinguishable RS in a broad visual linguistic network. In each suppressed region, prior knowledge and repetition also induced a common shift in functional connectivity, further underscoring the similarity of the RS phenomenon induced by these conditions. By contrast, activated regions readily distinguished prior knowledge and repetition conditions in a manner consistent with engagement of semantic and episodic memory systems, respectively. Our results illustrate that regardless of whether RS is understood in terms of its magnitude, spatial extent or functional connectivity profile, typical RS effects can be elicited even under conditions where recently triggered biological processes or episodic memory are unlikely to play a prominent role. These results provide important new evidence that RS (of the kind observed after an interval of at least several minutes) reflects the facilitation of perceptual and comprehension processes by any type of information retrieved from long-term memory. PMID- 27461078 TI - A Water-Based Chitosan-Maleimide Precursor for Bioconjugation: An Example of a Rapid Pathway for an In Situ Injectable Adhesive Gel. AB - Chitosan conjugated with maleimide (CS-Mal) as a potential precursor for bioconjugation and the example of the application in in situ injectable adhesive gel is proposed. The homogeneous reaction in water/dimethyl sulfoxide (DMSO) (1:1) followed by dialysis in HCl (10 * 10-3 m) is a good condition to obtain CS Mal. When SH-PEG-SH is applied as the crosslinker, the gel can be obtained in a few seconds without any by-products at room temperature. The gel formation and properties are controllable by simply varying the concentration and the molecular weight of CS, the Mal substitution degree, and the temperature. The gel is injectable and shows adhesive property for soft tissue. Moreover, the gel shows not only biocompatibility to SAOS2 cells but also antimicrobial activity against both gram-negative and gram-positive bacteria. CS-Mal is useful not only for bioconjugation of CS but also for development of biomaterials. PMID- 27461079 TI - Supersizing pyrrole-modified porphyrins by reversal of the 'breaking and mending' strategy. AB - While the 'breaking and mending of porphyrin strategy' proved versatile in the generation of a range of pyrrole-modified porphyrins containing 4-, 5-, and 6 membered heterocycles, it failed to access systems incorporating larger rings. A reversal of the strategy - first mending, then breaking - now allowed the formation of a pyrrole-modified porphyrin containing an 8-membered 1,3,6 triazocine-2,4,8-trione heterocycle. PMID- 27461080 TI - Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling. AB - Opioid tolerance and the potential for addiction is a significant burden associated with pain management, yet its precise underlying mechanism and prevention remain elusive. Immune signaling contributes to the decreased efficacy of opioids, and we recently demonstrated that Toll-like receptor 4 (TLR4) mediated neuroinflammation in the periaqueductal gray (PAG) drives tolerance. Tumor necrosis factor (TNF), a product of TLR4 signaling, promotes inflammation and facilitates glutamatergic signaling, key components of opioid tolerance. Therefore, we hypothesize that TLR4-mediated opioid tolerance requires TNF signaling. By expression of a dominant-negative TNF peptide via lentiviral vector injection in rat PAG to sequester soluble TNF (solTNF), we demonstrate that solTNF mediates morphine tolerance induced by TLR4 signaling, stimulates neuroinflammation (increased IL-1beta and TLR4 mRNA), and disrupts glutamate reuptake (decreased GLT-1 and GLAST mRNA). We further demonstrate the efficacy of the brain-permeant PEGylated version of the anti-solTNF peptide, XPro1595, injected systemically, to normalize morphine-induced CNS neuroinflammation and morphine- and endotoxin-induced changes in glutamate transport, effectively preserving the efficacy of morphine analgesia and eliminating tolerance. Our findings provide a novel pharmacological target for the prevention of opioid induced immune signaling, tolerance, and addiction. PMID- 27461081 TI - Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal. AB - Dysregulated catecholamine signaling has long been implicated in drug abuse. Although much is known about adaptations following chronic drug administration, little work has investigated how a single drug exposure paired with withdrawal influences catecholamine signaling in vivo. We used fast-scan cyclic voltammetry in freely moving rats to measure real-time catecholamine overflow during acute morphine exposure and naloxone-precipitated withdrawal in two regions associated with the addiction cycle: the dopamine-dense nucleus accumbens (NAc) and norepinephrine-rich ventral bed nucleus of the stria terminalis (vBNST). We compared dopamine transients in the NAc with norepinephrine concentration changes in the vBNST, and correlated release with specific withdrawal-related behaviors. Morphine increased dopamine transients in the NAc, but did not elicit norepinephrine responses in the vBNST. Conversely, dopamine output was decreased during withdrawal, while norepinephrine was released in the vBNST during specific withdrawal symptoms. Both norepinephrine and withdrawal symptoms could be elicited in the absence of morphine by administering naloxone with an alpha2 antagonist. The data support reciprocal roles for dopamine and norepinephrine signaling during drug exposure and withdrawal. The data also support the allostasis model and show that negative-reinforcement may begin working after a single exposure/withdrawal episode. PMID- 27461082 TI - Characterization of Glutamatergic and GABAA-Mediated Neurotransmission in Motor and Dorsolateral Prefrontal Cortex Using Paired-Pulse TMS-EEG. AB - Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are noninvasive transcranial magnetic stimulation (TMS) measures of GABAA receptor-mediated inhibition and glutamatergic excitatory transmission, respectively. Conventionally these measures have been restricted to the motor cortex. We investigated whether SICI and ICF could be recorded from the dorsolateral prefrontal cortex (DLPFC) using combined TMS and electroencephalography (TMS-EEG). We first characterized the neural signature of SICI and ICF in M1 in terms of TMS-evoked potentials (TEPs) and spectral power modulation. Subsequently, these paradigms were applied in the DLPFC to determine whether similar neural signatures were evident. With TMS at M1, SICI and ICF led to bidirectional modulation (inhibition and facilitation, respectively) of P30 and P60 TEP amplitude, which correlated with MEP amplitude changes. With DLPFC stimulation, P60 was bidirectionally modulated by SICI and ICF in the same manner as for M1 stimulation, whereas P30 was absent. The sole modulation of early TEP components is in contradistinction to other measures such as long-interval intracortical inhibition and may reflect modulation of short latency excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Overall, the data suggest that SICI and ICF can be recorded using TMS-EEG in DLPFC providing noninvasive measures of glutamatergic and GABAA receptor-mediated neurotransmission. This may facilitate future research attempting to ascertain the role of these neurotransmitters in the pathophysiology and treatment of neurological and psychiatric disorders. PMID- 27461083 TI - Recovery from Posttraumatic Stress Requires Dynamic and Sequential Shifts in Amygdalar Connectivities. AB - The neural mechanisms underlying the development and maintenance of posttraumatic stress disorder (PTSD) have long been studied. However, little is known about the neural correlates of the recovery process from PTSD. A 5-year longitudinal study was conducted to investigate the trajectory of structural connectivities of the amygdala in disaster survivors with PTSD. Thirty disaster survivors, who were diagnosed with PTSD, and 29 healthy individuals, who were not exposed to trauma, underwent three waves of assessments including neuroimaging scanning over a 5 year period from the time of the disaster at approximately 1.3-year intervals. All disaster survivors showed significant improvements in PTSD symptoms over time. Using diffusion tensor imaging analysis, a 5-year trajectory of amygdalar structural connectivities with key brain regions was assessed. The amygdala insula connection was initially strengthened and then normalized during recovery, while the amygdala-prefrontal cortex (PFC) connection was at first unaffected, then strengthened, and eventually normalized. The lower tract strength of the amygdala-thalamus connection normalized during recovery, while that of amygdala hippocampus connection remained low. The greater amygdala-PFC connectivity was associated with less PTSD symptom severity. The present longitudinal study revealed that recovery from PTSD parallels dynamic and sequential shifts in amygdalar connectivities with multiple brain regions, suggesting the expanded view of fear circuitry including the insula and thalamus, beyond the traditional model which primarily involves the amygdala, PFC, and hippocampus. PMID- 27461085 TI - A combinatorial Bayesian and Dirichlet model for prostate MR image segmentation using probabilistic image features. AB - Blurred boundaries and heterogeneous intensities make accurate prostate MR image segmentation problematic. To improve prostate MR image segmentation we suggest an approach that includes: (a) an image patch division method to partition the prostate into homogeneous segments for feature extraction; (b) an image feature formulation and classification method, using the relevance vector machine, to provide probabilistic prior knowledge for graph energy construction; (c) a graph energy formulation scheme with Bayesian priors and Dirichlet graph energy and (d) a non-iterative graph energy minimization scheme, based on matrix differentiation, to perform the probabilistic pixel membership optimization. The segmentation output was obtained by assigning pixels with foreground and background labels based on derived membership probabilities. We evaluated our approach on the PROMISE-12 dataset with 50 prostate MR image volumes. Our approach achieved a mean dice similarity coefficient (DSC) of 0.90 +/- 0.02, which surpassed the five best prior-based methods in the PROMISE-12 segmentation challenge. PMID- 27461084 TI - Constitutive and Acquired Serotonin Deficiency Alters Memory and Hippocampal Synaptic Plasticity. AB - Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo transmission and memory and underlying mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning, or fear memory. Viral delivery of designer receptors exclusively activated by designer drugs was used to selectively silence the activity of 5-HT neurons in the raphe. Inhibition of 5-HT neurons in the median raphe, but not the dorsal raphe, was sufficient to impair object recognition in adult mice. In vivo electrophysiology in behaving mice showed that long-term potentiation in the hippocampus of 5-HT-deficient mice was altered, and administration of the 5-HT1A agonist 8-OHDPAT rescued the memory deficits. Our data suggest that hyposerotonergia selectively affects declarative hippocampal dependent memory. Serotonergic projections from the median raphe are necessary to regulate object memory and hippocampal synaptic plasticity processes, through an inhibitory control mediated by 5-HT1A receptors. PMID- 27461087 TI - Implant-supported removable partial dentures in the mandible: A 3-16 year retrospective study. AB - PURPOSE: The purpose of this retrospective study was to assess performance, together with biological and technical complications, of implant-supported removable partial dentures (ISRPD) in mandibular Kennedy class I situations with implants placed in the anterior or posterior position. METHODS: 23 subjects with two endosseous implants to support a bilateral-free-ending mandibular removable denture were examined. Eight subjects had implants in the premolar (anterior) region and 15 subjects implants in the molar (posterior) region. Biological and technical complications were recorded from the patients' medical record. Patients filled out a validated questionnaire regarding their appreciation of oral health related quality of life (OHIP-NL49) and a VAS score on overall satisfaction. RESULTS: Over a mean follow-up period of 8 years (median 8 years, range 3-16 years) the cumulative implant survival rate was 91.7% (SE 0.05). Mean peri implant bone loss was 0.9mm (SD 1.0mm). Scores for bleeding on probing, plaque and mucosal health were generally low, but significantly worse for posteriorly placed implants. Significantly more biological complications occurred in the posterior group (X2(1)=3.9; p=0.048). In 65% of the cases no technical complications were registered. Mean overall OHIP score was 16.1 (SD 18.4) and patients were highly satisfied (VAS: 8.4; SD 2.1). CONCLUSIONS: Within the limitations of this retrospective study, in case of a Kennedy class I situation in the mandible, an ISRPD is a viable treatment option with a high implant survival rate and satisfied patients after a maximum of 16 years. Technical and biological complications should be anticipated. Anteriorly placed implants performed slightly better. PMID- 27461086 TI - Long-term outcomes in antineutrophil cytoplasmic autoantibody-positive eosinophilic granulomatosis with polyangiitis patients with renal involvement: a retrospective study of 14 Chinese patients. AB - BACKGROUND: The clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied. METHODS: Fourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed. RESULTS: The most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti PR3 in 2). Elevated eosinophils (median 15 %, range 10-45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200-1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47-11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5 7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6-83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR. CONCLUSIONS: Renal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival. PMID- 27461089 TI - From entanglement witness to generalized Catalan numbers. AB - Being extremely important resources in quantum information and computation, it is vital to efficiently detect and properly characterize entangled states. We analyze in this work the problem of entanglement detection for arbitrary spin systems. It is demonstrated how a single measurement of the squared total spin can probabilistically discern separable from entangled many-particle states. For achieving this goal, we construct a tripartite analogy between the degeneracy of entanglement witness eigenstates, tensor products of SO(3) representations and classical lattice walks with special constraints. Within this framework, degeneracies are naturally given by generalized Catalan numbers and determine the fraction of states that are decidedly entangled and also known to be somewhat protected against decoherence. In addition, we introduce the concept of a "sterile entanglement witness", which for large enough systems detects entanglement without affecting much the system's state. We discuss when our proposed entanglement witness can be regarded as a sterile one. PMID- 27461088 TI - Comparison of the accuracy of direct and indirect three-dimensional digitizing processes for CAD/CAM systems - An in vitro study. AB - PURPOSE: To compare the accuracy (trueness, precision) of direct and indirect scanning CAD/CAM methods. METHODS: A master cast with prepared abutments and edentulous parts was created from polymethyl methacrylate (PMMA). A high resolution industrial scanner was used to create a reference model. Polyvinyl siloxane (PVS) impressions and digital impressions with three intraoral scanners (iTero, Cerec, Trios) were made (n=10 for each) from the PMMA model. A laboratory scanner (Scan CS2) was used to digitize the sectioned cast made from the PVS impressions. The stereolithographic (STL) files of the impressions (n=40) were exported. Each file was compared to the reference using Geomagic Verify software. Six points were assigned to enable virtual calliper measurement of three distances of varying size within the arch. Methods were compared using interquartile range regression and equality-of-variance tests for precision, and mixed-effects linear regression for trueness. RESULTS: The mean (SD) deviation of short distance measurements from the reference value was -40.3 (79.7) MUm using the indirect, and 22.3 (40.0) MUm using the direct method. For the medium distance, indirect measurements deviated by 5.2 (SD: 111.3) MUm, and direct measurements by 115.8 (SD: 50.7) MUm, on average; for the long distance, the corresponding estimates were -325.8 (SD: 134.1) MUm with the indirect, and -163.5 (SD: 145.5) MUm with the direct method. Significant differences were found between the two methods (p<0.05). CONCLUSIONS: With both methods, the shorter the distance, the more accurate results were achieved. Virtual models obtained by digital impressions can be more accurate than their conventional counterparts. PMID- 27461091 TI - Effects of different drying treatments on fungal population and ochratoxin A occurrence in sultana type grapes. AB - This study aimed to determine the changes in mould and ochratoxin A (OTA) occurrence in sultanas under three different conventional drying conditions. Five different vineyards were chosen, and the three different treatments were applied to these grapes while drying. At the end of the drying process, total mould and black aspergilli (BA) populations in the samples varied from 2.45 to 5.61 log colony-forming units (CFU) g(-)(1) and from 0 to 4.92 log CFU g(-)(1), respectively. Significant increases (p < 0.05) occurred in mould loads depending on the extending drying period. However, independent of vineyard location, all the samples treated with cold dipping solution showed the lowest fungal loads. These results indicate that dipping solution treatment was the most effective drying method to minimise fungal infection of grapes. The expected results could not be achieved by drying grapes artificially contaminated with ochratoxigenic Aspergillus carbonarius spores. Seventy-one of 96 isolates (73.95%) obtained during drying were Aspergillus spp., and the remaining (n = 25, 26.05%) belonged to other genera, such as Penicillium, Trichoderma and Cladosporium. Grape juice based agar medium was used to determine the realistic OTA production capacities of the isolated mould strains. The highest OTA production capacities were 809.70 +/- 9.19, 87.58 +/- 16.89 and 45.44 +/- 18.78 ng g(-1) in 50% grape juice agar (GJ50), all five of which were from A. niger isolates. OTA was not present in any sample during the drying period; however, OTA was detected in two samples at 0.32 +/- 0.15 and 0.52 +/- 0.36 ug kg(-)(1) after the end of the drying process. The limit of detection (LOD) and limit of quantitation (LOQ) of the method used for detecting OTA in samples were 0.1 and 0.3 ug kg(-)(1), respectively. PMID- 27461090 TI - Validation of the new Vancouver Chest Pain Rule in Asian chest pain patients presenting at the emergency department. AB - OBJECTIVES: The new Vancouver Chest Pain (VCP) Rule recommends early discharge for chest pain patients who are at low risk of developing acute coronary syndrome (ACS), and thus can be discharged within 2 hours of arrival at the emergency department (ED). This study aimed to assess the performance of the new VCP Rule for Asian patients presenting with chest pain at the ED. METHODS: This prospective cohort study involved patients attended to at the ED of a large urban centre. Patients of at least 25 years old, presenting with stable chest pain and a non-diagnostic ECG, and with no history of active coronary artery disease were included in the study. The main outcome measures were cardiac events, angioplasty, or coronary artery bypass within 30 days of enrolment. RESULTS: The study included 1690 patients from 27 August 2000 to 1 May 2002, with 661 patients fulfilling the VCP criteria. Of those for early discharge, 24 had cardiac events and 13 had angioplasty or bypass at 30 days, compared to 91 and 41, respectively, for those unsuitable for discharge. This gave the rule a sensitivity of 78.1% for cardiac events, including angioplasty and bypass. Specificity was 41.0%, and negative predictive value (NPV) was 94.4%. CONCLUSION: We found the new VCP Rule to have moderate sensitivity and poor specificity for adverse cardiac events in our population. With an NPV of less than 100%, this means that a small proportion of patients sent home with early discharge would still have adverse cardiac events. PMID- 27461092 TI - Audiovisual distraction for pain relief in paediatric inpatients: A crossover study. AB - BACKGROUND: Pain is a stressful experience that can have a negative impact on child development. The aim of this crossover study was to examine the efficacy of audiovisual distraction for acute pain relief in paediatric inpatients. METHOD: The sample comprised 40 inpatients (6-11 years) who underwent painful puncture procedures. The participants were randomized into two groups, and all children received the intervention and served as their own controls. Stress and pain catastrophizing assessments were initially performed using the Child Stress Scale and Pain Catastrophizing Scale for Children, with the aim of controlling these variables. The pain assessment was performed using a Visual Analog Scale and the Faces Pain Scale-Revised after the painful procedures. Group 1 received audiovisual distraction before and during the puncture procedure, which was performed again without intervention on another day. The procedure was reversed in Group 2. Audiovisual distraction used animated short films. A 2 * 2 * 2 analysis of variance for 2 * 2 crossover study was performed, with a 5% level of statistical significance. RESULTS: The two groups had similar baseline measures of stress and pain catastrophizing. A significant difference was found between periods with and without distraction in both groups, in which scores on both pain scales were lower during distraction compared with no intervention. The sequence of exposure to the distraction intervention in both groups and first versus second painful procedure during which the distraction was performed also significantly influenced the efficacy of the distraction intervention. CONCLUSION: Audiovisual distraction effectively reduced the intensity of pain perception in paediatric inpatients. SIGNIFICANCE: The crossover study design provides a better understanding of the power effects of distraction for acute pain management. Audiovisual distraction was a powerful and effective non pharmacological intervention for pain relief in paediatric inpatients. The effects were detected in subsequent acute painful procedures. PMID- 27461093 TI - Intermediates Formed in the Reactions of Organocuprates with alpha,beta Unsaturated Nitriles. AB - Conjugate additions of organocuprates are of outstanding importance for organic synthesis. To improve our mechanistic understanding of these reactions, we have used electrospray ionization mass spectrometry for the identification of the ionic intermediates formed upon the treatment of LiCuR2 ?LiCN (R=Me, Bu, Ph) with a series of alpha,beta-unsaturated nitriles. Acrylonitrile, the weakest Michael acceptor included, did not afford any detectable intermediates. Fumaronitrile (FN) yielded adducts of the type Lin-1 Cun R2n (FN)n (-) , n=1-3. When subjected to fragmentation in the gas phase, these adducts were not converted into the conjugate addition products, but re-dissociated into the reactants. In contrast, the reaction with 1,1-dicyanoethylene furnished the products of the conjugate addition without any observable intermediates. Tri- and tetracyanoethylene proved to be quite reactive as well. The presence of several cyano groups in these substrates opened up reaction pathways different from simple conjugate additions, however, and led to dimerization and substitution reactions. Moreover, the gas phase fragmentation behavior of the species formed from these substrates indicated the occurrence of single-electron transfer processes. Additional quantum-chemical calculations provided insight into the structures and stabilities of the observed intermediates and their consecutive reactions. PMID- 27461094 TI - Polyvictimization Among Children and Adolescents in Low- and Lower-Middle-Income Countries: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Most of the world's children and adolescents live in low- and lower middle-income countries (LALMIC), but there is limited evidence about polyvictimization (experiences of multiple forms of victimization) among them. The aims of this article were to systematically review the evidence from LALMIC about the overall prevalence of polyvictimization and to identify the associations between polyvictimization and health and well-being among children and adolescents. METHOD: A systematic search of the English-language peer reviewed literature to identify empirical, quantitative studies conducted in LALMIC between 2005 and 2015, assessing at least four forms of victimization among young people aged up to 19 years. Where prevalence of any victimization and of polyvictimization were reported, meta-analyses were performed. RESULTS: A total of 30/8,496 articles were included in the review. Evidence was available from 16/84 LALMIC and methodology and quality varied. Pooled prevalence of experiences of any victimization was 76.8% (95% confidence interval (CI) [64.8%, 88.9%]). Prevalence of polyvictimization ranged from 0.3% to 74.7% with an overall estimate of 38.1% (95% CI [18.3%, 57.8%]). None of the studies examined the associations between polyvictimization and physical or reproductive health or quality of life. Polyvictimization was associated with increased likelihood of mental health problems and involvement in health risk behaviors. CONCLUSIONS: Experiences of polyvictimization among children and adolescents in LALMIC are more prevalent than in high- and upper-middle-income countries and contribute to the burden of poor health among children and adolescents. Most LALMIC lack local data, and research is required to address this knowledge gap. PMID- 27461095 TI - Vegetation with a lizard-tail appearance in the left atrium. PMID- 27461096 TI - Usefulness of ethomidate in patients with Cushing syndrome with severe arterial hypertension and hypopotassemia. PMID- 27461097 TI - An unusual cause of cardiogenic shock. PMID- 27461098 TI - Author's reply: Education and awareness in the diabetic patient with ST-segment elevation acute coronary syndrome. PMID- 27461099 TI - Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function. AB - AIM: There have been few studies on long-term electroretinographic findings in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). This study correlated long-term electroretinographic findings with age, metabolic control and clinical symptoms. METHODS: We examined 12 Swedish patients with LCHADD. Visual acuity testing, fundus examinations, optical coherence tomography and electroretinography were performed. The results were correlated to age, the levels of 3-hydroxyacylcarnitine and acylcarnitine and clinical metabolic control. RESULTS: Blindness or moderate visual impairment was found in two patients. Retinal pigmentation, atrophy and fibrosis were present in 11, seven and one of the patients, respectively, and optical coherence tomography showed retinal thinning in three of the six patients examined. Electroretinography was performed on 11 of the 12 patients. It was pathological, with reduced rod and cone responses, in five patients, subnormal in four and was related to poor clinical metabolic control and severe neonatal symptoms. Repeated electroretinographies revealed reduced function with increasing age. CONCLUSION: More than 80% of the LCHADD patients developed pathological or subnormal retinal function. This was more pronounced in patients with neonatal symptoms, but ameliorated by strict dietary treatment. Annual ophthalmological follow-ups, with electroretinography every second or third year, are recommended. PMID- 27461100 TI - Plumbagin reduces chronic lymphocytic leukemia cell survival by downregulation of Bcl-2 but upregulation of the Bax protein level. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and mainly originates from an accumulation of abnormal B cells caused by the dysregulation of cell proliferation and apoptosis rates. The aberration of apoptosis-related genes in CLL cells results in defective apoptosis of CLL cells in response to traditional therapeutic medicine. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), a natural compound from Plumbago zeylinica, has been shown to exhibit pro-apoptotic activities in tumor cells. In the present study, we report that plumbagin effectively inhibited CLL cell viability with a lower dose compared to fludarabine, and inhibited cell proliferation in a dose-dependent manner. In addition, plumbagin promoted accumulation of MEC-1 cells in the S phase, and blocked cell cycle transition of HG3 cells from G0/G1 to S phase. Molecularly, plumbagin markedly induced CLL cell apoptosis through reduction of Bcl-2, but through an increase in the Bax protein level. These results suggest that plumbagin may be considered as a potential anticancer agent for CLL therapy. PMID- 27461101 TI - A long-living case of carotid aneurysm caused by inflammatory leiomyosarcoma. AB - We report here on a long-surviving patient with a vascular leiomyosarcoma arising in the right common carotid artery, and some possible reasons for the long-term survival. The patient was a 40-year-old woman who was diagnosed with a right common carotid aneurysm and underwent aneurysmectomy with graft replacement. Two years and nine months after her surgery, she developed a cerebral infarction and left hemiparesis due to graft occlusion, but later achieved functional recovery through physical rehabilitation. She has been alive for 20 years since her surgery. PMID- 27461102 TI - Transcatheter heart valve crimping and the protecting effects of a polyester cuff. AB - INTRODUCTION: Prior to deployment, the percutaneous heart valves must be crimped and loaded into sheaths of diameters that can be as low as 6mm for a 23mm diameter valve. However, as the valve leaflets are fragile, any damage caused during this crimping process may contribute to reducing its long-term durability in vivo. MATERIAL AND METHOD: Bovine pericardium percutaneous valves were manufactured as follows. The leaflets were sutured on a nitinol frame. A polyester cuff fabric served as a buffer between the pericardium and the stent. Two valves were crimped and one valve was used as control. The valves were examined in gross observation and micro-CT scan and then the leaflets were processed for histology and analyzed in scanning electron microscopy, light microscopy and transmission electron microscopy. RESULT: Crimping of the valves resulted in the increase thickness of the leaflets and there was no evidence of additional delamination. The heavy prints of the stents were irregularly distributed on the outflow surface in the crimped devices and were shallow and did not penetrate throughout the thickness of the leaflets. However, the wavy microscopy of collagen fiber bundles was well preserved. They were found to remain individualized without any agglutination as shown by the regular banding appearance. CONCLUSION: Crimping of self-deployable valves per se caused only minor damages to the leaflets. However, the procedure could be refined in order to minimize areas of high pressure and swelling of the tissue that can be accompanied with flow surface disruption and increase of the hydraulic conductance. The incorporation of a polyester buffer serves to prevent the deleterious effects that may be caused if the pericardium tissue were in direct contact with the nitinol stent. PMID- 27461104 TI - Extraction and purification of total flavonoids from pine needles of Cedrus deodara contribute to anti-tumor in vitro. AB - BACKGROUND: Cedrus deodara is one of the traditional Chinese medicinal herbs that exhibits a line of biological activities. The current study extracted the total flavonoids from the pine needles of Cedrus deodara (TFPNCD), and investigated its anti-cancer effects in tumor cell lines. METHODS: The total flavonoids was extracted from pine needles of Cedrus deodara by ethanol hot refluxing and purified by HPD722 macroporous resin. The contents of total flavonoids and the active ingredients of TFPNCD were analyzed through UV and HPLC. MTT assay was used to investigate its inhibitory effect on tumor cell lines. The flow cytometry was employed to determine the apoptosis and cell cycle distribution after treated TFPNCD on HepG2 cells. RESULTS: The TFPNCD, in which the contents of total flavonoid reached up to 54.28 %, and the major ingredients of myricetin, quercetin, kaempferol and isorhamnetin in TFPNCD were 1.89, 2.01, 2.94 and 1.22 mg/g, respectively. The MTT assays demonstrated that TFPNCD inhibited the growth of HepG2 cells in a dose-dependent manner, with the IC50 values of 114.12 MUg/mL. By comparison, TFPNCD inhibited the proliferation to a less extent in human cervical carcinoma HeLa, gastric cancer MKN28 cells, glioma SHG-44 cells and lung carcinoma A549 than HepG2 cells. We found that even at the lower doses, the total flavonoids effectively inhibited the proliferation of HepG2 cells. Comparison of IC50 values implicated that HepG2 cells might be more sensitive to the treatment with total flavonoids. TFPNCD was able to increase the population of HepG2 cells in G0 /G1 phase. Meanwhile, TFPNCD treatment increased the percentage of apoptotic HepG2 cells. CONCLUSION: These data suggested that TFPNCD might have therapeutic potential in cancer through the regulation of cell cycle and apoptosis. PMID- 27461103 TI - Empowering Regulatory T Cells in Autoimmunity. AB - Regulatory T cells (Tregs) are capable of dampening immune-mediated inflammation and avert the destructive effects of uncontrolled inflammation. Distinct molecules and pathways, including various transcription factors, phosphatases, and kinases, impact the ability of Tregs to function as negative regulators of the immune response, and are presumably amenable to therapeutic manipulation. Here, we discuss recently identified molecular networks and the therapeutic potential for treating autoimmune diseases. PMID- 27461105 TI - An assessment of health research impact in Iran. AB - BACKGROUND: In recent years, Iran has made significant developments in the field of health sciences. However, the question is whether this considerable increase has affected public health. The research budget has always been negligible and unsustainable in developing countries. Hence, using the Payback Framework, we conducted this study to evaluate the impact of health research in Iran. METHODS: By using a cross-sectional method and two-stage stratified cluster sampling, the projects were randomly selected from six medical universities. A questionnaire was designed according to the Payback Framework and completed by the principle investigators of the randomly selected projects. RESULTS: The response rate was 70.4%. Ten point twenty-four percent (10.24%) of the studies had been ordered by a knowledge user organization. The average number of articles published in journals per project was 0.96, and half of the studies had no articles published in Scopus. The results of 12% of the studies had been used in systematic review articles and the same proportion had been utilized in clinical or public health guidelines. The results of 5.3% of the studies had been implemented in the Health Ministry's policymaking. 62% of the studies were expected to affect health directly, 38% of them had been implemented, and among the latter 60% had achieved the expected results. Concerning the economic impacts, the most common expected impact was the reduction of 'days of work missed because of illness or disability' and impact on personal and health system costs. About 36% of these studies had been implemented, and 61% had achieved the expected impact. CONCLUSION: In most aspects, the status of research impact needs improvement. A comparison of Iran's ranking of knowledge creation and knowledge impact in the Global Innovation Index confirms these findings. The most important problems identified were, not conducting research based on national needs, and the lack of implementation of research results. PMID- 27461106 TI - A comparative study of k-spectrum-based error correction methods for next generation sequencing data analysis. AB - BACKGROUND: Innumerable opportunities for new genomic research have been stimulated by advancement in high-throughput next-generation sequencing (NGS). However, the pitfall of NGS data abundance is the complication of distinction between true biological variants and sequence error alterations during downstream analysis. Many error correction methods have been developed to correct erroneous NGS reads before further analysis, but independent evaluation of the impact of such dataset features as read length, genome size, and coverage depth on their performance is lacking. This comparative study aims to investigate the strength and weakness as well as limitations of some newest k-spectrum-based methods and to provide recommendations for users in selecting suitable methods with respect to specific NGS datasets. METHODS: Six k-spectrum-based methods, i.e., Reptile, Musket, Bless, Bloocoo, Lighter, and Trowel, were compared using six simulated sets of paired-end Illumina sequencing data. These NGS datasets varied in coverage depth (10* to 120*), read length (36 to 100 bp), and genome size (4.6 to 143 MB). Error Correction Evaluation Toolkit (ECET) was employed to derive a suite of metrics (i.e., true positives, false positive, false negative, recall, precision, gain, and F-score) for assessing the correction quality of each method. RESULTS: Results from computational experiments indicate that Musket had the best overall performance across the spectra of examined variants reflected in the six datasets. The lowest accuracy of Musket (F-score = 0.81) occurred to a dataset with a medium read length (56 bp), a medium coverage (50*), and a small sized genome (5.4 MB). The other five methods underperformed (F-score < 0.80) and/or failed to process one or more datasets. CONCLUSIONS: This study demonstrates that various factors such as coverage depth, read length, and genome size may influence performance of individual k-spectrum-based error correction methods. Thus, efforts have to be paid in choosing appropriate methods for error correction of specific NGS datasets. Based on our comparative study, we recommend Musket as the top choice because of its consistently superior performance across all six testing datasets. Further extensive studies are warranted to assess these methods using experimental datasets generated by NGS platforms (e.g., 454, SOLiD, and Ion Torrent) under more diversified parameter settings (k-mer values and edit distances) and to compare them against other non-k-spectrum-based classes of error correction methods. PMID- 27461107 TI - Assessing Analytical Similarity of Proposed Amgen Biosimilar ABP 501 to Adalimumab. AB - BACKGROUND: ABP 501 is being developed as a biosimilar to adalimumab. Comprehensive comparative analytical characterization studies have been conducted and completed. OBJECTIVE: The objective of this study was to assess analytical similarity between ABP 501 and two adalimumab reference products (RPs), licensed by the United States Food and Drug Administration (adalimumab [US]) and authorized by the European Union (adalimumab [EU]), using state-of-the-art analytical methods. METHODS: Comprehensive analytical characterization incorporating orthogonal analytical techniques was used to compare products. Physicochemical property comparisons comprised the primary structure related to amino acid sequence and post-translational modifications including glycans; higher-order structure; primary biological properties mediated by target and receptor binding; product-related substances and impurities; host-cell impurities; general properties of the finished drug product, including strength and formulation; subvisible and submicron particles and aggregates; and forced thermal degradation. RESULTS: ABP 501 had the same amino acid sequence and similar post-translational modification profiles compared with adalimumab RPs. Primary structure, higher-order structure, and biological activities were similar for the three products. Product-related size and charge variants and aggregate and particle levels were also similar. ABP 501 had very low residual host-cell protein and DNA. The finished ABP 501 drug product has the same strength with regard to protein concentration and fill volume as adalimumab RPs. ABP 501 and the RPs had a similar stability profile both in normal storage and thermal stress conditions. CONCLUSION: Based on the comprehensive analytical similarity assessment, ABP 501 was found to be similar to adalimumab with respect to physicochemical and biological properties. PMID- 27461109 TI - The Psychological Cost of Making Control Responses in the Nonstereotype Direction. AB - OBJECTIVE: The aim of this study was to develop a scale for the "psychological cost" of making control responses in the nonstereotype direction. BACKGROUND: Wickens, Keller, and Small suggested values for the psychological cost arising from having control/display relationships that were not in the common stereotype directions. We provide values of such costs specifically for these situations. METHOD: Working from data of Chan and Hoffmann for 168 combinations of display location, control type, and display movement direction, we define values for the cost and compare these with the suggested values of Wickens et al.'s Frame of Reference Transformation Tool (FORT) model. RESULTS: We found marked differences between the values of the FORT model and the data of our experiments. The differences arise largely from the effects of the Worringham and Beringer visual field principle not being adequately considered in the previous research. CONCLUSION: A better indication of the psychological cost for use of incorrect control/display stereotypes is given. It is noted that these costs are applicable only to the factor of stereotype strength and not other factors considered in the FORT model. APPLICATION: Effects of having controls and displays that are not arranged to operate with population expectancies can be readily determined from the data in this paper. PMID- 27461108 TI - Saikosaponin d induces cell death through caspase-3-dependent, caspase-3 independent and mitochondrial pathways in mammalian hepatic stellate cells. AB - BACKGROUND: Saikosaponin d (SSd) is one of the main active triterpene saponins in Bupleurum falcatum. It has a steroid-like structure, and is reported to have pharmacological activities, including liver protection in rat, cell cycle arrest and apoptosis induction in several cancer cell lines. However, the biological functions and molecular mechanisms of mammalian cells under SSd treatment are still unclear. METHODS: The cytotoxicity and apoptosis of hepatic stellate cells (HSCs) upon SSd treatment were discovered by MTT assay, colony formation assay and flow cytometry. The collage I/III, caspase activity and apoptotic related genes were examined by quantitative PCR, Western blotting, immunofluorescence and ELISA. The mitochondrial functions were monitored by flow cytometry, MitoTracker staining, ATP production and XF24 bioenergetic assay. RESULTS: This study found that SSd triggers cell death via an apoptosis path. An example of this path might be typical apoptotic morphology, increased sub-G1 phase cell population, inhibition of cell proliferation and activation of caspase-3 and caspase-9. However, the apoptotic effects induced by SSd are partially blocked by the caspase-3 inhibitor, Z-DEVD-FMK, suggesting that SSd may trigger both HSC-T6 and LX-2 cell apoptosis through caspase-3-dependent and independent pathways. We also found that SSd can trigger BAX and BAK translocation from the cytosol to the mitochondria, resulting in mitochondrial function inhibition, membrane potential disruption. Finally, SSd also increases the release of apoptotic factors. CONCLUSIONS: The overall analytical data indicate that SSd-elicited cell death may occur through caspase-3-dependent, caspase-3-independent and mitochondrial pathways in mammalian HSCs, and thus can delay the formation of liver fibrosis by reducing the level of HSCs. PMID- 27461110 TI - Representational pseudoneglect for detecting changes to Rey-Osterrieth figures. AB - When dividing attention between the left and right sides of physical space, most individuals pay slightly more attention to the left side. This phenomenon, known as pseudoneglect, may also occur for the left and right sides of mental representations of stimuli. Representational pseudoneglect has been shown for the recall of real-world scenes and for simple, briefly presented stimuli. The current study sought to investigate the effect of exposure duration and complexity using adaptations of the Rey-Osterrieth figures. Undergraduates (n = 97) were shown a stimulus for 20 s and asked to remember it. Participants were then shown a probe and indicated whether it was the same or different. Results showed that, irrespective of whether an element was added or subtracted, changes on the left side of the remembered image were better detected. These results are consistent with representational pseudoneglect and demonstrate that this effect occurs for complex stimuli when presented for an extended period of time. Representation neglect is therefore unlikely to be the result of an initial saccade to the left-but could be related to the formation or recall of the representation. PMID- 27461111 TI - Diagnosis of minimal hepatic encephalopathy in a tertiary care center from eastern Romania: validation of the psychometric hepatic encephalopathy score (PHES). AB - The psychometric hepatic encephalopathy score (PHES) is frequently used as a "gold standard" for the diagnosis of minimal hepatic encephalopathy (MHE). In Romania, there are currently no widely available tests for the detection of MHE. In this study we aimed to standardize the PHES in a healthy Romanian population and to estimate the prevalence of MHE in a group of Romanian patients with liver cirrhosis. A total of 260 healthy volunteers and 106 patients with liver cirrhosis were included in the study. The five neuropsychological tests comprising the PHES were administered to all enroled subjects. Blood samples for routine tests and serum ammonia were collected. In the healthy volunteer group age and education years were found to be predictors of all tests and gender only in two tests: digit symbol test and serial dotting test. The PHES of the healthy volunteer group was 0,43 +/- 1,37 and the cut-off between normal and pathological values was set at -3 points. In the liver cirrhosis group the mean PHES was -2,44 +/- 3,41, significantly lower than in the control group (p = 0,001). The estimated prevalence of MHE was 34,7 % (37 patients). In patients with cirrhosis there was a significant correlation between PHES and the severity of the liver disease according to Child-Pugh classification (r = 0,529, p = 0,001) and MELD score (r = -0,525, p = 0,001). According to our results, accurate Romanian PHES norms for the diagnosis of MHE have been developed. MHE was diagnosed in a significant proportion of Romanian patients with liver cirrhosis. PMID- 27461112 TI - Carotid duplex ultrasound and transcranial Doppler findings in commercial divers and pilots. AB - The risky working environments of divers and pilots, and the possible role of extreme ambient pressure in carotid stenosis, make ischemic stroke an important occupational concern among these professionals. In this study, we aimed to evaluate the association of being exposed to hyperbaric or hypobaric conditions with carotid artery stenosis by comparing common carotid intima-media thickness (CCIMT) and blood flow velocities of cerebral arteries in divers and pilots using carotid duplex ultrasound (CDUS) and transcranial Doppler (TCD). CDUS and transtemporal TCD were performed in 29 divers, 36 pilots and 30 control participants. Medical history, blood pressure, lipid profile and blood sugar were recorded to control the previously well-known risk factors of atherosclerosis. Findings of the CDUS and TCD [including: CCIMT and blood flow velocities of internal carotid artery (ICA), common carotid artery (CCA), and middle cerebral artery (MCA)] of divers and pilots were compared with those of the control group using regression analysis models. Both right and left side CCIMT were significantly higher in divers (P < 0.05) and pilots (P < 0.05) in comparison with the control group. Carotid index [peak systolic velocity (PSV) of ICA/PSV of CCA) of divers and pilots were also higher than the control group. TCD findings were not significantly different between divers, pilots, and the control group. Increased CCIMT and carotid index in diver and pilot groups appear to be suggestive of accelerated atherosclerosis of carotid artery in these occupational groups. PMID- 27461113 TI - Detection of the bacterial endosymbiont Neorickettsia in a New Zealand digenean. AB - Neorickettsia are endosymbiotic bacteria that infect digeneans (Trematoda). These bacteria are of interest worldwide because of their ability to move from the parasite to its host, where they can cause serious diseases of humans and animals. While several disease-forming species of Neorickettsia have been well studied, and numerous Neorickettsia types have been identified in regions such as North America and parts of Asia, records from other locations are sparse. To date, there have been no reports of Neorickettsia from New Zealand. We screened ten species of digeneans infecting seven native gastropod species (both marine and freshwater) found near Dunedin, New Zealand, for the presence of neorickettsial infections. A >1300 bp long section of 16S rRNA belonging to a Neorickettsia bacterium was isolated from opecoelid digeneans of two individuals of the mudflat topshell snail Diloma subrostrata. These sequences represent the first evidence of neorickettsial infection in native New Zealand animals and are also the first Neorickettsia found in digeneans of the family Opecoelidae. PMID- 27461114 TI - Assessment of the effect of treatment and assistance program on advanced patients with schistosomiasis japonica in China from 2009 to 2014. AB - Schistosomiasis is one of the most important zoonoses, threatening approximately 800 million people in 78 countries with a loss of 70 million disability-adjusted life years. Over the past six decades, China has made remarkable achievements in morbidity control, but disability and mortality control remains much to desire; thus, advanced schistosomiasis is a growing problem when on the road to schistosomiasis elimination. Since 2005, China has initiated a national treatment and assistance program to advanced patients, aiming to improve patients' symptoms and quality of life. Here, we conducted a two-phase study to evaluate the program's implementation and effect on advanced patients from 2009 to 2014 in Jiangxi Province, China. A total of 6425 advanced schistosomiasis cases were included in this study. For those having been treated and assisted (90.7 %), the cure or improvement rate was over 99.9 %, with 668 (11.5 %) cases having reached clinical cure and 5152 (88.4 %) cases' condition having improved, which can be partially reflected in the significant decline of the proportion of hepatomegaly (splenomegaly), the degree of liver fibrosis, ascites-related indicators (abdominal girth and frequency of shifting dullness), and portal hypertension related indices (inner diameter of portal vein and frequency of subcutaneous varicose vein of abdominal wall). Besides, it was estimated to have saved 2004 years of life lost at total. Therefore, the government should continue support and increase input of treatment and assistance program so that this project can reach more patients, leading to consolidation of achievements of schistosomiasis control and contribution to schistosomiasis elimination. PMID- 27461115 TI - Vibration transmission through sheet webs of hobo spiders (Eratigena agrestis) and tangle webs of western black widow spiders (Latrodectus hesperus). AB - Web-building spiders construct their own vibratory signaling environments. Web architecture should affect signal design, and vice versa, such that vibratory signals are transmitted with a minimum of attenuation and degradation. However, the web is the medium through which a spider senses both vibratory signals from courting males and cues produced by captured prey. Moreover, webs function not only in vibration transmission, but also in defense from predators and the elements. These multiple functions may impose conflicting selection pressures on web design. We investigated vibration transmission efficiency and accuracy through two web types with contrasting architectures: sheet webs of Eratigena agrestis (Agelenidae) and tangle webs of Latrodectus hesperus (Theridiidae). We measured vibration transmission efficiencies by playing frequency sweeps through webs with a piezoelectric vibrator and a loudspeaker, recording the resulting web vibrations at several locations on each web using a laser Doppler vibrometer. Transmission efficiencies through both web types were highly variable, with within-web variation greater than among-web variation. There was little difference in transmission efficiencies of longitudinal and transverse vibrations. The inconsistent transmission of specific frequencies through webs suggests that parameters other than frequency are most important in allowing these spiders to distinguish between vibrations of prey and courting males. PMID- 27461117 TI - DNA methylation of claudin-6 promotes breast cancer cell migration and invasion by recruiting MeCP2 and deacetylating H3Ac and H4Ac. AB - BACKGROUND: Claudin-6 (CLDN6), a member of claudin transmembrane protein family, has recently been reported to be undetectable or at low levels in human breast cancer cell lines and tissues and plays a role in suppression of migration and invasion in breast cancer cells. In addition, it is reported that CLDN6 expression is regulated by DNA methylation in various human cancers and cell lines. However, it is unclear how DNA methylation regulates CLDN6 expression. Here we show the mechanism by which DNA methylation regulates CLDN6 expression in human breast cancer cell line MCF-7. METHODS: RT-PCR, Western blot and immunofluorescent staining were utilized to investigate CLDN6 expression in breast cancer tissues and MCF-7 cells. Methylation-Specific PCR (MSP) was applied to determine DNA methylation status in CLDN6 gene promoter region. Wound-healing assay and invasion assay were utilized to test mobility of MCF-7 cells treated with 5-aza-dC (DNA methyltransferase inhibitor). MeCP2 binding, H3Ac and H4Ac in CLDN6 promoter region were analyzed by ChIP assay. Nuclease accessibility assay was performed for analysis of the chromatin conformation of CLDN6 gene. To study the role of CLDN6 in malignant progression, we used RNAi to knockdown CLDN6 expression in MCF-7 cells treated with 5-aza-dC, and examined the mobility of MCF 7 cells by wound-healing assay and invasion assay. RESULTS: 5-aza-dC and TSA (histone deacetylase inhibitor) application induced CLDN6 expression in MCF-7 cells respectively and synergistically. 5-aza-dC treatment induced CLDN6 demethylation, inhibited MeCP2 binding to CLDN6 promoter and increased H3Ac and H4Ac in the promoter. In addition, TSA increased H4Ac, not H3Ac in the promoter. The chromatin structure of CLDN6 gene became looser than the control group after treating with 5-aza-dC in MCF-7 cells. 5-aza-dC up-regulated CLDN6 expression and suppressed migration and invasion in MCF-7 cells, whereas CLDN6 silence restored tumor malignance in MCF-7 cells. CONCLUSIONS: DNA methylation down-regulates CLDN6 expression through MeCP2 binding to the CLDN6 promoter, deacetylating H3 and H4, and altering chromatin structure, consequently promoting migratory and invasive phenotype in MCF-7 cells. PMID- 27461118 TI - Use of propensity score methods to address adverse events associated with the storage time of blood in an obstetric population: a comparison of methods. AB - BACKGROUND: A recent topic of interest in the blood transfusion literature is the existence of adverse effects of transfusing red cells towards the end of their storage life. This interest has been sparked by conflicting results in observational studies, however a number of methodological difficulties with these studies have been noted. One potential strategy to address these difficulties is the use of propensity scores, of which there are a number of possible methods. This study aims to compare the traditional methods for binary exposures with more recently developed generalised propensity score methods. METHODS: Data were obtained from probabilistically linked hospital, births and blood bank databases for all women giving birth from 23 weeks gestation in New South Wales, Australia, between July 2006 and December 2010 with complete information on the birth admission and blood issued. Analysis was restricted to women who received 1-4 units of red cells. Three different propensity score methods (for binary, ordinal and continuous exposures) were compared, using each of four different approaches to estimating the effect (matching, stratifying, weighting and adjusting by the propensity score). Each method was used to determine the effect of blood storage time on rates of severe morbidity and readmission or transfer. RESULTS: Data were available for 2990 deliveries to women receiving 1-4 units of red cells. The rate of severe maternal morbidity was 3.7 %, and of readmission or transfer was 14.4 %. There was no association between blood storage time and rates of severe morbidity or readmission irrespective of the approach used. There was no single optimal propensity score method; the approaches differed in their ease of implementation and interpretation. CONCLUSIONS: Within an obstetric population, there was no evidence of an increase in adverse events following transfusion of older blood. Propensity score methods provide a useful tool for addressing the question of adverse events with increasing storage time of blood, as these methods avoid many of the pitfalls of previous studies. In particular, generalised propensity scores can be used in situations where the exposure is not binary. PMID- 27461119 TI - Factors associated with overweight: are the conclusions influenced by choice of the regression method? AB - BACKGROUND: Different analytical techniques have been used to study the determinants of overweight. However, certain commonly used techniques may be limited by the continuous nature and skewed distribution of body mass index (BMI) data. In this article, different regression models are compared to identify the best approach for analysing predictors of BMI. METHODS: Data collected on 2270 nurses at 18 public hospitals in Rio de Janeiro, RJ (2010-2011) were analysed (80.6 % of the respondents). The explanatory variables considered were age, marital status, race/colour, mother's schooling, domestic overload, years worked at night, consumption of fried food, physical inactivity, self-rated health and BMI at age 20 years. In addition to gamma regression, regarded as the reference method for selecting the set of explanatory variables described here, other modelling strategies - including linear, quantile (for the 0.25, 0.50 and 0.75 quantiles), binary and multinomial logistic regression - were compared in terms of final results and measures of fit. RESULTS: The variables age, marital status, race/colour, domestic overload, self-rated health, physical inactivity and BMI at age 20 years were significantly associated with BMI, independently of the method used. In the same way, consumption of fried food was significant in all the models, but a dose-response pattern was identified only in the gamma and normal models and the quantile model for the 0.75 quantile. Years worked at night was also associated with BMI in these three models only. The variable mother's schooling returned significant results only for the category 12 or more years of schooling, except for overweight in the multinomial model and for the 0.50 quantile in the quantile model, in which the two categories were not significant. The results of the quantile regression showed that, generally, the effects of the variables investigated were greater in the upper quantiles of the BMI distribution. Of the models using BMI in its continuous form, the gamma model showed best fit, followed by the quantile models (0.25 and 0.5 quantiles). CONCLUSIONS: The different strategies used produced similar results for the factors associated with BMI, but differed in the magnitude of the associations and goodness of fit. We recommend using the different approaches in combination, because they furnish complementary information on the problem studied. PMID- 27461121 TI - Register study of migrants' hospitalization in Norway: world region origin, reason for migration, and length of stay. AB - BACKGROUND: The proportion of migrants and refugees increase in many populations. Health planners have to consider how migration will influence demand for health care. This study explores how migrants' geographical origin, reason for migration, and duration of residence are associated with admission rates to somatic hospitals in Norway. METHODS: Sociodemographic information on all individuals residing in Norway at the start of 2008 was linked to data on all admissions to somatic hospitals during 2008-2011. Migrants, age 30-69, who had come to Norway during 1970-2007 (N = 217,907), were classified into seven world region origins and compared with native Norwegians of the same age (N = 2,181,948). Any somatic hospital stay 2008-2011 and number of hospital admissions 2008-2011 per 1000 personyears for a set of somatic diagnoses were analyzed by age and gender standardized rates, linear probability models, and Poisson regression. RESULTS: In the native Norwegian sample, 28.7 % had at least one admission 2008-2011, and there were 116 admissions per 1000 personyears. Corresponding age and gender adjusted figures for the migrant sample were 27.0 % and 103 admissions. Admission rates varied with migrants' geographical origin, with relatively many admissions among migrants from West and South Asia and relatively few admissions among migrants from Western, East European, and Other Asian countries. Hospitalization varied strongly with reason for migration, with low admission rates for recent work migrants and high admission rates for recent refugees. Admission rates tended to move towards the level among native Norwegians with increasing length of stay. Among longstanding migrants (arrival period 1970-1989), admission rates were close to the levels of native Norwegians for most analyzed migrant categories. CONCLUSION: Both world region origin, reason for migration, and duration of residence are important sources for variations in migrants' utilization of somatic hospitals. Forecasts about migrants' use of hospital services have to take into account how the migrant population is composed as to these three determinants. High admission rates among recently arrived refugees should be a health policy concern. PMID- 27461120 TI - The Role of the Pharmacist in the Treatment of Patients with Infantile Hemangioma Using Propranolol. AB - INTRODUCTION: Infantile hemangiomas (IH) are the most common benign vascular tumors of childhood, with an incidence of 5-10% during the first year of age. Propranolol is considered the first-line treatment for this condition. Potentially there is a high probability of negative results to therapy, because in many countries there are no treatment protocols or propranolol formulations appropriate for the pediatric population. The objective of the present study was to evaluate the impact of pharmacist interventions such as detecting, analyzing, and solving problems presented during treatment with propranolol in patients with IH. METHODS: An open observational prospective study was performed over 25 months in a group of pediatric patients diagnosed with infantile hemangioma treated with propranolol. Pharmacist participation consisted of development of an extemporaneous formulation and counseling the child's parents. At each visit to the pharmacy service, family members were interviewed, detecting and classifying problems related to treatment. RESULTS: Sixty-three children with IH were treated during the period under review. Patient ages ranged from 3 to 11 months old; 64% were female and 36% were male. Forty-nine problems in 30 patients were detected, principally inadequate dose (18.4%), non-adherence to treatment (16.3%), side effects (14.3%), and wrong administration (14.3%). Of the problems detected, 81.6% were resolved. Interventions by the pharmacist in 27 patients were intensive counseling on adherence to therapy (20%), detection of adverse effects (11.4%), and adjustment of the dose (22.9%). In 95.2% of patients a good response to treatment was obtained compared with 77.2% reported in European studies without pharmacist intervention. CONCLUSION: It seems that pharmacist participation increases adherence to treatment and reduces the likelihood of adverse effects, allowing for safe and effective therapy in patients with IH. PMID- 27461123 TI - The Left, The Better: White-Matter Brain Integrity Predicts Foreign Language Imitation Ability. AB - Speech imitation is crucial for language acquisition and second-language learning. Interestingly, large individual differences regarding the ability in imitating foreign-language sounds have been observed. The origin of this interindividual diversity remains unknown, although it might be partially explained by structural predispositions. Here we correlated white-matter structural properties of the arcuate fasciculus (AF) with the performance of 52 German-speakers in a Hindi sentence- and word-imitation task. First, a manual reconstruction was performed, permitting us to extract the mean values along the three branches of the AF. We found that a larger lateralization of the AF volume toward the left hemisphere predicted the performance of our participants in the imitation task. Second, an automatic reconstruction was carried out, allowing us to localize the specific region within the AF that exhibited the largest correlation with foreign language imitation. Results of this reconstruction also showed a left lateralization trend: greater fractional anisotropy values in the anterior half of the left AF correlated with the performance in the Hindi imitation task. From the best of our knowledge, this is the first time that foreign language imitation aptitude is tested using a more ecological imitation task and correlated with DTI tractography, using both a manual and an automatic method. PMID- 27461124 TI - The body's tailored suit: Skin as a mechanical interface. AB - Skin, by nature, is very similar to the Rouquayrol-Denayrouze suit mentioned by Jules Verne in Twenty Thousand Leagues Under the Sea: it allows "to risk (...) new physiological conditions without suffering any organic disorder". Mechanical cues, to the same extent as other environmental parameters, are such "new physiological conditions". Indeed, skin's primary function is to form a protective barrier to shield inner tissues from the external environment. This requires unique mechanical properties as well as the ability to sense mechanical cues from the environment in order to prevent or repair mechanical damages as well as to function as the primary mechanosensory interface of the whole body. PMID- 27461122 TI - Rostro-caudal Architecture of the Frontal Lobes in Humans. AB - The nature of the inputs and outputs of a brain region defines its functional specialization. The frontal portion of the brain is essential for goal-directed behaviors, however, the biological basis for its functional organization is unknown. Here, exploring structural connectomic properties, we delineated 12 frontal areas, defined by the pattern of their white matter connections. This result was highly reproducible across neuroimaging centers, acquisition parameters, and participants. These areas corresponded to regions functionally engaged in specific tasks, organized along a rostro-caudal axis from the most complex high-order association areas to the simplest idiotopic areas. The rostro caudal axis along which the 12 regions were organized also reflected a gradient of cortical thickness, myelination, and cell body density. Importantly, across the identified regions, this gradient of microstructural features was strongly associated with the varying degree of information processing complexity. These new anatomical signatures shed light onto the structural organization of the frontal lobes and could help strengthen the prediction or diagnosis of neurodevelopmental and neurodegenerative disorders. PMID- 27461125 TI - Establishment of an equine tetanus antitoxin reference standard for veterinary use in Japan. AB - To establish the first National Veterinary Assay Laboratory (NVAL) equine tetanus antitoxin reference standard for veterinary use, we manufactured vials of a candidate antitoxin. These were quality tested for moisture content, vacuum, colour, clarity, and the presence of foreign objects. Ultimately, 115 quality controlled vials were prepared. To estimate the antitoxin potency of the candidate standard, three different laboratories conducted parallel line assays alongside the existing antitoxin standard. These potency estimates ranged from 38 to 42 IU. This activity was maintained for two years after manufacture, as compared with a fresh vial. No statistically significant non-linearity or non parallelism of the regression lines was observed (p > 0.05). Statistical assessment of inter- and intra-laboratory variability revealed acceptable coefficients of variation of 3.2% and 2.4-3.1%, respectively. Based on these results, the potency of the potential reference standard was calculated at 40 units of antitoxin activity per 1-mL vial. Vials of this preparation were distributed for use as the first equine tetanus antitoxin reference standard for veterinary use in September 2015. PMID- 27461126 TI - High-risk human papilloma virus genotypes in cervical carcinoma of Serbian women: Distribution and association with pathohistological findings. AB - A significant role of high-risk Human papilloma viruses (HR HPV) in the development of cervical carcinoma is well known. HR HPV 16 and 18 account for approximately 70% of all cases of cervical cancer worldwide. The incidence of cervical cancer in Serbia, is one of the highest in Europe. The aim of our study was to investigate the distribution of HR HPV types in cervical carcinoma of Serbian women, as well as association between the HPV types and pathohistological findings. The study included 80 archival cervical cancer tissues from the same number of patients. The presence of HPV DNA was determined using MY09/MY11 primers for L1 gene and GP1/GP2 primers for E1 gene. HPV was detected in 78.75% tissues. HR HPV genotypes found in the decreasing order of frequency were: HPV16 (80.39%), HPV33 (7.84%), HPV58 (5.88%), HPV18 (1.96%), HPV45 (1.96%) and HPV53 (1.96%). The examined tissues were 91.25% squamous cell carcinomas and 8.75% adenocarcinoma. The high frequency of HPV 16 was observed in both types of carcinoma (80.8% and 75%, respectively) while the prevalence of HPV18 was low. These results may contribute to the implementation of cervical carcinoma prevention program in Serbia, including the selection of the most appropriate vaccine and immunization program. PMID- 27461127 TI - Integration of QbD risk assessment tools and overall risk management. AB - Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody. This chapter describes how the risk assessments, logic and interactions of the tools are designed to connect the set of QbD tools and elements into an overarching risk management system. The tools allow comparisons of options based on elective decisions that the sponsor could take and reflect relative values of these options. The overall risk management strategy assures product quality from this enhanced set of assessments and employs a science and risk based approach resulting in a consistent and transparent set of process and product controls and a rational monitoring system. PMID- 27461128 TI - A collaborative study to establish the 1st WHO International Standard for Epstein Barr virus for nucleic acid amplification techniques. AB - Variability in viral load measurements using nucleic acid amplification techniques (NAT) has a significant impact on the management of Epstein-Barr virus (EBV)-associated diseases, and has highlighted a need for standardisation of these measurements. The aim of this collaborative study was to evaluate the suitability of a range of candidate reference materials to harmonise EBV viral load measurements in a wide range of NAT assays. Candidate materials included lyophilised and liquid whole virus preparations of the EBV B95-8 strain, and preparations of Namalwa and Raji cells. Variability between the individual laboratory mean estimates for each candidate was 2.5 log10 copies/mL. The agreement between laboratories was improved when the potency of each candidate was expressed relative to the lyophilised B95-8 preparation. The results of the study indicate the suitability of this candidate as the 1st WHO International Standard for EBV for NAT. It was established in October 2011 by the WHO's Expert Committee on Biological Standardisation with an assigned potency of 5 * 10(6) International Units (IU) (NIBSC code 09/260). It is intended to be used for the calibration of secondary reference materials, used in EBV NAT assays, in IU, thereby improving the comparability of patient viral load measurements. PMID- 27461129 TI - Report of the International Regulatory Forum on Human Cell Therapy and Gene Therapy Products. AB - The development of human cell therapy and gene therapy products has progressed internationally. Efforts have been made to address regulatory challenges in the evaluation of quality, efficacy, and safety of the products. In this forum, updates on the specific challenges in quality, efficacy, and safety of products in the view of international development were shared through the exchange of information and opinions among experts from regulatory authorities, academic institutions, and industry practitioners. Sessions identified specific/critical points to consider for the evaluation of human cell therapy and gene therapy products that are different from conventional biological products; common approaches and practices among regulatory regions were also shared. Certain elements of current international guidelines might not be appropriate to be applied to these products. Further, international discussion on the concept of potency and in vivo tumorigenicity studies, among others, is needed. This forum concluded that the continued collective actions are expected to promote international convergence of regulatory approaches of the products. The Pharmaceuticals and Medical Devices Agency and Japanese Society for Regenerative Medicine jointly convened the forum with support from the National Institutes of Biomedical Innovation, Health and Nutrition. Participants at the forum include 300 experts in and outside of Japan. PMID- 27461130 TI - Three Distinct Glutamate Decarboxylase Genes in Vertebrates. AB - Gamma-aminobutyric acid (GABA) is a widely conserved signaling molecule that in animals has been adapted as a neurotransmitter. GABA is synthesized from the amino acid glutamate by the action of glutamate decarboxylases (GADs). Two vertebrate genes, GAD1 and GAD2, encode distinct GAD proteins: GAD67 and GAD65, respectively. We have identified a third vertebrate GAD gene, GAD3. This gene is conserved in fishes as well as tetrapods. We analyzed protein sequence, gene structure, synteny, and phylogenetics to identify GAD3 as a homolog of GAD1 and GAD2. Interestingly, we found that GAD3 was lost in the hominid lineage. Because of the importance of GABA as a neurotransmitter, GAD3 may play important roles in vertebrate nervous systems. PMID- 27461131 TI - Neutropenia and eosinophilia among Ethiopian immigrants to Israel: Familial or environmental? AB - BACKGROUND: Due to trends of population movements, Israeli family physicians are treating increasing numbers of African immigrants from Ethiopia. These immigrants were found to have complete blood counts (CBC) that are different from other ethnic groups, with a higher prevalence of eosinophilia and neutropenia. OBJECTIVES: To evaluate haematological findings in an attempt to define whether they behave as familial (genetic) or environmental. METHODS: Retrospective chart review of 300 patients from a primary care clinic: 100 individuals of Ethiopian heritage born in Ethiopia (EE); 100 individuals of Ethiopian heritage born in Israel, whose parents were born in Ethiopia (EI), and a control group of 100 patients who were not of Ethiopian heritage (C). RESULTS: Absolute eosinophilia (greater than 500/dl) was found in 13% of the EE study group significantly higher than the two other groups (P < 0.05), with no difference between EI and C. neutropenia (defined as less than 1500/dl) was found in 32% of EE group, 20% of EI, and 1% of C (P < 0.01). CONCLUSION: On the one hand, findings point to a marked environmental influence on the eosinophilic response (most probably due to intestinal parasites present in immigrants from Ethiopia). On the other hand, a familial-genetic nature is probably the reason for the higher prevalence of neutropenia in this population, although some environmental influence may play a role. The knowledge of these findings may be useful for physicians treating people migrating from Africa. PMID- 27461132 TI - CCY-1a-E2 induces G2/M phase arrest and apoptotic cell death in HL-60 leukemia cells through cyclin-dependent kinase 1 signaling and the mitochondria-dependent caspase pathway. AB - Our previous study demonstrated that 2-[(3-methoxybenzyl)oxy]benzaldehyde (CCY-1a E2) is a potent compound that acts against multiple human leukemia cell lines. CCY-1a-E2 was also shown to have efficacious anti-leukemic activity in vivo. However, the molecular mechanism of action of CCY-1a-E2 attributed to its anticancer effect remains poorly understood. In the present study, CCY-1a-E2 suppressed cell viability in multiple leukemia cell lines (HL-60, K562, KG-1 and KG-1a) via inhibition of cell proliferation, cell cycle arrest and induction of apoptosis. CCY-1a-E2 exhibited a marked toxic effect on HL-60 cells and displayed low cytotoxicity in normal human peripheral blood mononuclear cells (PBMCs). Results from flow cytometric analysis indicated that CCY-1a-E2 promoted G2/M phase arrest and promoted apoptosis in the HL-60 cells. CCY-1a-E2 treatment upregulated cyclin B, cyclin-dependent kinase 1 (CDK1), cell division cycle 25C (cdc25C) and p21 protein expression. CCY-1a-E2 caused apoptotic cell death and DNA fragmentation as determined by 4',6-diamidino-2-phenylindole (DAPI) staining and DNA gel electrophoresis. Elevated activities of caspase-8, -9 and -3 were observed during CCY-1a-E2-induced cell apoptosis; their specific inhibitors were found to block CCY-1a-E2-induced apoptosis, respectively. Moreover, CCY-1a-E2 time-dependently disrupted the mitochondrial membrane potential (DeltaPsim), and it enhanced the protein levels of Fas/CD95, cytochrome c, Bax, cleaved PARP, as well as attenuated Bcl-2 expression in the HL-60 cells. Our results provide direct evidence that supports the future potential therapeutic application of CCY 1a-E2 in leukemia. PMID- 27461133 TI - Regular consumption of Lactobacillus reuteri-containing lozenges reduces pregnancy gingivitis: an RCT. AB - AIM: This randomized controlled trial assessed the impact of Lactobacillus reuteri on pregnancy gingivitis in healthy women. MATERIALS AND METHODS: Forty five healthy women (24 test/21 placebo) with pregnancy gingivitis in the third trimester of pregnancy were enrolled. At baseline Gingival Index (GI) and Plaque Index (PlI) were assessed at the Ramfjord teeth and venous blood taken for TNF alpha analysis. Subsequently participants were randomly provided with lozenges to be consumed 2 * daily until birth (approx. 7 weeks) containing >=108 CFU L. reuteri ATCC PTA 5289 and >=108 CFU L. reuteri DSM 17938 (test) or being devoid of L. reuteri (placebo). Within 2 days after birth recording of GI, PlI and blood sampling were repeated. RESULTS: At baseline, mean GI and mean PlI did not differ significantly between both groups. In the test group mean TNF-alpha serum level was significantly (p < 0.02) lower than in the placebo group. At reevaluation, mean GI and mean PlI of the test group were both significantly (p < 0.0001) lower than in the placebo group. Mean TNF-alpha serum level did no longer differ significantly between the groups. CONCLUSIONS: The consumption of L. reuteri lozenges may be a useful adjunct in the control of pregnancy gingivitis. PMID- 27461134 TI - Mucosal-associated invariant T cells are reduced and functionally immature in the peripheral blood of primary Sjogren's syndrome patients. AB - The frequencies, immunophenotype, and function of mucosal-associated invariant T (MAIT) cells were studied in patients with primary Sjogren syndrome (pSS) and healthy controls. MAIT cells were significantly decreased in the peripheral blood (PB) of patients with pSS. Valpha7.2+ MAIT cells were detected in the salivary gland tissue from pSS patients, but not in controls, indicating that the reduction of MAIT cells in PB might be due to migration into the target tissue. Furthermore, the residual peripheral blood MAIT cells in pSS patients showed altered immunophenotype and function. While MAIT cells from controls were almost exclusively CD8+ and expressed an effector memory immunophenotype, in pSS patients they were enriched in CD4+ and naive subpopulations. Consistently, the functional studies demonstrated that MAIT cells from pSS showed a lower level of activation with reduced expression of CD69 and CD154 (CD40L), and a lower production of TNF and IFN-gamma. In summary, our findings demonstrate that MAIT cells were reduced and phenotypically and functionally altered in PB of pSS patients. The altered function of MAIT cells in target tissues from pSS patients may result in dysregulation of mucosal immunity leading to microbial damage of mucosal surfaces and subsequent initiation of autoimmune response. PMID- 27461135 TI - Giant Pressure-Driven Lattice Collapse Coupled with Intermetallic Bonding and Spin-State Transition in Manganese Chalcogenides. AB - Materials with an abrupt volume collapse of more than 20 % during a pressure induced phase transition are rarely reported. In such an intriguing phenomenon, the lattice may be coupled with dramatic changes of orbital and/or the spin-state of the transition metal. A combined in situ crystallography and electron spin state study to probe the mechanism of the pressure-driven lattice collapse in MnS and MnSe is presented. Both materials exhibit a rocksalt-to-MnP phase transition under compression with ca. 22 % unit-cell volume changes, which was found to be coupled with the Mn(2+) (d(5) ) spin-state transition from S=5/2 to S=1/2 and the formation of Mn-Mn intermetallic bonds as supported by the metallic transport behavior of their high-pressure phases. Our results reveal the mutual relationship between pressure-driven lattice collapse and the orbital/spin-state of Mn(2+) in manganese chalcogenides and also provide deeper insights toward the exploration of new metastable phases with exceptional functionalities. PMID- 27461136 TI - Botulinum Toxin for Rhinitis. AB - PURPOSE OF REVIEW: Rhinitis is a common clinical entity. Besides nasal obstruction, itching, and sneezing, one of the most important symptoms of rhinitis is nasal hypersecretion produced by nasal glands and exudate from the nasal vascular bed. Allergic rhinitis is an IgE-mediated inflammatory reaction of nasal mucosa after exposure to environmental allergens. Idiopathic rhinitis describes rhinitis symptoms that occur after non-allergic, noninfectious irritants. Specific allergen avoidance, topical nasal decongestants, nasal corticosteroids, immunotherapy, and sinonasal surgery are the main treatment options. Because the current treatment modalities are not enough for reducing rhinorrhea in some patients, novel treatment options are required to solve this problem. RECENT FINDINGS: Botulinum toxin is an exotoxin generated by Clostridium botulinum. It disturbs the signal transmission at the neuromuscular and neuroglandular junction by inhibiting the acetylcholine release from the presynaptic nerve terminal. It has been widely used in neuromuscular, hypersecretory, and autonomic nerve system disorders. There have been a lot of published articles concerning the effect of this toxin on rhinitis symptoms. Based on the results of these reports, intranasal botulinum toxin A administration appears to be a safe and effective treatment method for decreasing rhinitis symptoms in rhinitis patients with a long-lasting effect. Botulinum toxin type A will be a good treatment option for the chronic rhinitis patients who are resistant to other treatment methods. PMID- 27461137 TI - The role of epsilon PKC in acute and chronic diseases: Possible pharmacological implications of its modulators. AB - Epsilon Protein kinase C (epsilonPCK) is a particular kinase that, when activated, is able to protect against different stress injuries and therefore has been proposed to be a potential molecular target against acute and chronic diseases. Particular attention has been focused on epsilonPCK for its involvement in the protective mechanism of Ischemic Preconditioning (IPC), a powerful endogenous mechanism characterized by subthreshold ischemic insults able to protect organs against ischemic injury. Therefore, in the past decades several epsilonPCK modulators have been tested with the object to emulate epsilonPCK mediate protection. Among these the most promising, so far, has been the PsiepsilonRACK peptide, a homologous of RACK receptor for epsilonPKC, that when administrated can mimic its effect in the cells. However, results from studies on epsilonPCK indicate controversial role of this kinase in different organs and diseases, such as myocardial infarct, stroke, diabetes and cancer. Therefore, in this review we provide a discussion on the function of epsilonPCK in acute and chronic diseases and how the different activators and inhibitors have been used to modulate its activity. A better understanding of its function is still needed to definitively target epsilonPCK as novel therapeutic strategy. PMID- 27461138 TI - Novel targets for paclitaxel nano formulations: Hopes and hypes in triple negative breast cancer. AB - Triple negative breast cancer is defined as one of the utmost prevailing breast cancers worldwide, possessing an inadequate prognosis and treatment option limited to chemotherapy and radiotherapy, creating a challenge for researchers as far as developing a specific targeted therapy is concerned. The past research era has shown several promising outcomes for TNBC such as nano-formulations of the chemotherapeutic agents already used for the management of the malignant tumor. Taking a glance at paclitaxel nano formulations, it has been proven beneficial in several researches in the past decade; nevertheless its solubility is often a challenge to scientists in achieving success. We have henceforth discussed the basic heterogeneity of triple negative breast cancer along with the current management options as well as a brief outlook on pros and cons of paclitaxel, known as the most widely used chemotherapeutic agent for the treatment of the disease. We further analyzed the need of nanotechnology pertaining to the problems encountered with the current paclitaxel formulations available discussing the strategic progress in various nano-formulations till date taking into account the basic research strategies required in terms of solubility, permeability, physicochemical properties, active and passive targeting. A thorough review in recent advances in active targeting for TNBC was carried out whereby the various ligands which are at present finding its way into TNBC research such as hyaluronic acid, folic acid, transferrin, etc. were discussed. These ligands have specific receptor affinity to TNBC tumor cells hence can be beneficial for novel drug targeting approaches. Conversely, there are currently several novel strategies in the research pipeline whose targeting ligands have not yet been studied. Therefore, we reviewed upon the numerous novel receptor targets along with the respective nano-formulation aspects which have not yet been fully researched upon and could be exemplified as outstanding target strategies for TNBC which is currently an urgent requirement. PMID- 27461139 TI - Stress-induced and epigenetic-mediated maize transcriptome regulation study by means of transcriptome reannotation and differential expression analysis. AB - Plant's response and adaptation to abiotic stresses involve sophisticated genetic and epigenetic regulatory systems. To obtain a global view of molecular response to osmotic stresses, including the non-coding portion of genome, we conducted a total leaf transcriptome analysis on maize plants subjected to prolonged drought and salt stresses. Stress application to both B73 wild type and the epiregulator mutant rpd1-1/rmr6 allowed dissection of the epigenetic component of stress response. Coupling total RNA-Seq and transcriptome re-assembly we annotated thousands of new maize transcripts, together with 13,387 lncRNAs that may play critical roles in regulating gene expression. Differential expression analysis revealed hundreds of genes modulated by long-term stress application, including also many lncRNAs and transposons specifically induced by stresses. The amplitude and dynamic of the stress-modulated gene sets are very different between B73 and rpd1-1/rmr6 mutant plants, as result of stress-like effect on genome regulation caused by the mutation itself, which activates many stress-related genes even in control condition. The analyzed extensive set of total RNA-Seq data, together with the improvement of the transcriptome and the identification of the non coding portion of the transcriptome give a revealing insight into the genetic and epigenetic mechanism responsible for maize molecular response to abiotic stresses. PMID- 27461140 TI - A product of immunoreactive trypsinogen and pancreatitis-associated protein as second-tier strategy in cystic fibrosis newborn screening. AB - BACKGROUND: In cystic fibrosis newborn screening (CFNBS), immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) can be used as screening parameters. We evaluated the IRT*PAP product as second-tier parameter in CFNBS in newborns with elevated IRT. METHODS: Data on 410,111 screened newborns including 78 patients with classical cystic fibrosis (CF) from two European centers were retrospectively analyzed by discrimination analysis to identify a screening protocol with optimal cutoffs. We also studied differences in PAP measurement methods and the association of IRT and PAP with age. RESULTS: PAP values differed systematically between fluorometric and photometric assays. The IRT*PAP product showed better discrimination for classical CF than PAP only as second-tier screening parameter (p<0.001). In CF patients, IRT decreased while PAP values remained high over years. In newborns without CF, IRT decreased after birth over weeks while PAP increased within days. CONCLUSIONS: The IRT*PAP product performs well as second-tier cutoff parameter for CFNBS. Screening quality parameters depend on the analytic method and on age at blood collection. PMID- 27461141 TI - Ode to the exocrine pancreas. PMID- 27461143 TI - Enzymatically Crosslinked Emulsion Gels Using Star-Polymer Stabilizers. AB - A novel type of emulsion gel based on star-polymer-stabilized emulsions is highlighted, which contains discrete hydrophobic oil and hydrophilic aqueous solution domains. Well-defined phenol-functionalized core-crosslinked star polymers are synthesized via reversible addition-fragmentation chain transfer (RAFT)-mediated dispersion polymerization and are used as stabilizers for oil-in water emulsions. Horseradish-peroxidase-catalyzed polymerization of the phenol moieties in the presence of H2 O2 enables rapid formation of crosslinked emulsion gels under mild conditions. The crosslinked emulsion gels exhibit enhanced mechanical strength, as well as widely tunable composition. PMID- 27461144 TI - Can hair re-growth be considered an early clinical marker of treatment resistance to Hedgehog inhibitors in patients with advanced basal cell carcinoma? A report of two cases. AB - INTRODUCTION: Basal cell carcinomas (BCCs) are the most common skin cancers in the Caucasian population. BCCs are in the majority of cases adequately managed with surgical excision, however a small subset of these tumours exhibit resistance to conventional therapies and progress to become locally advanced or even metastatic. Although Hedgehog inhibitors have been successfully used during the last few years in the treatment of locally advanced or metastatic BCCs, resistance to treatment remains an issue. Until this point, no biomarkers or clinical markers of drug resistance for Hedgehog inhibitors have been identified. METHODS AND RESULTS: We report two patients, a female patient with Gorlin syndrome and a male patient with locally advanced BCC, which received treatment with the Hedgehog inhibitor Vismodegib. These patients responded adequately to treatment and they both developed Hedgehog inhibitor-induced alopecia as an adverse event. However, after 2.5 and 1.5 years of treatment, respectively, the patients exhibited progressive disease that was accompanied by reversal of the Hedgehog inhibitor-induced alopecia, although still under treatment with Vismodegib. CONCLUSION: Although alopecia is a well-known adverse event associated with the administration of Hh inhibitors, data associated with the appearance and/or clinical severity of alopecia and the treatment efficacy of Hedgehog inhibitors are limited. The Hedgehog pathway plays an important role in the normal cycling of the hair follicles in adults and, therefore, the pathomechanism of Hedgehog inhibitor-induced alopecia is considered unique for this drug class. Based on the fact that Hh inhibitor resistance is associated with partial reactivation of the Hh pathway, it would not be illogical to suggest that reversal of Hh inhibitor-induced alopecia in patients under treatment with Hh inhibitors could serve as a clinical marker of drug resistance. However, this observation, as reported in this paper, is only limited in two patients and therefore more information is needed in order to assess its actual clinical importance. PMID- 27461142 TI - Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide mediated impairment of macrophage innate immune functions. AB - Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4(+/+) wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4(+/-) heterozygous mice. To confirm these observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca(++) homeostasis. ATO induces Ca(++)-dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca(++) homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic. PMID- 27461145 TI - Ultrastable Hydroxyapatite/Titanium-Dioxide-Supported Gold Nanocatalyst with Strong Metal-Support Interaction for Carbon Monoxide Oxidation. AB - Supported Au nanocatalysts have attracted intensive interest because of their unique catalytic properties. Their poor thermal stability, however, presents a major barrier to the practical applications. Here we report an ultrastable Au nanocatalyst by localizing the Au nanoparticles (NPs) in the interfacial regions between the TiO2 and hydroxyapatite. This unique configuration makes the Au NP surface partially encapsulated due to the strong metal-support interaction and partially exposed and accessible by the reaction molecules. The strong interaction helps stabilizing the Au NPs while the partially exposed Au NP surface provides the active sites for reactions. Such a catalyst not only demonstrated excellent sintering resistance with high activity after calcination at 800 degrees C but also showed excellent durability that outperforms a commercial three-way catalyst in a simulated practical testing, suggesting great potential for practical applications. PMID- 27461146 TI - Rapid protein immobilization for thin film continuous flow biocatalysis. AB - A versatile enzyme immobilization strategy for thin film continuous flow processing is reported. Here, non-covalent and glutaraldehyde bioconjugation are used to immobilize enzymes on the surfaces of borosilicate reactors. This approach requires only ng of protein per reactor tube, with the stock protein solution readily recycled to sequentially coat >10 reactors. Confining reagents to thin films during immobilization reduced the amount of protein, piranha cleaning solution, and other reagents by ~96%. Through this technique, there was no loss of catalytic activity over 10 h processing. The results reported here combines the benefits of thin film flow processing with the mild conditions of biocatalysis. PMID- 27461147 TI - Kenneth R. Silk (May 1944-April 2016). AB - Ken was a founding editor of Personality and Mental Health. He thoroughly enjoyed this role and played a major part in getting the journal off to a flying start, so that it was well received in the area of personality disorder and had an impact factor within 2 years of publication. Editorial strategy was mainly carried out by international teleconference, not easy to time with editors in Scotland, New Zealand and the United States, but these, well-organised with Eddie Kane's help, were good-natured, jolly and remarkably productive, with Ken's wit and wisdom adding to their value. Ken maintained his enthusiasm for the journal to the end of his life and despite his illness was able to complete the overview of the 2016 special issue published in May, accompanied by a short and pithy editorial pointing to the importance of empirical studies in a subject where opinion alone has ruled for far too long. PMID- 27461148 TI - Infectious diseases: Two-pronged attack on HIV. PMID- 27461149 TI - Neuroimmunology: Social support from the immune system. PMID- 27461150 TI - Mucosal immunology: Glial cells support ILC3s and gut defence. PMID- 27461151 TI - The antioxidant, cytotoxic, and antigenotoxic effects of galangin, puerarin, and ursolic acid in mammalian cells. AB - Phenolic compounds not only contribute to the sensory qualities of fruits and vegetables but also exhibit several health protective properties. Galangin, puerarin, and ursolic acid are commonly used plant phenolics in folk medicine. In this study, the antioxidant capacities of galangin, puerarin, and ursolic acid by the trolox equivalent antioxidant capacity (TEAC) assay and the cytotoxic effects by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in V79 cells were investigated. The genotoxic potentials of galangin, puerarin, and ursolic acid were evaluated by micronucleus (MN) and alkaline COMET assays in human lymphocytes and in V79 cells. Galangin, puerarin, and ursolic acid (10, 100, 500, 1000, 2000, 5000, 10 000, and 20 000 MUM) were found to have antioxidant activities at the studied concentrations. IC50 values of galangin, puerarin, and ursolic acid in V79 cells were found to be 275.48 MUM, 2503.712 MUM, and 224.85 MUM, respectively. Galangin, puerarin, and ursolic acid, at the all concentrations, have not exerted genotoxic effects and galangin, puerarin, and ursolic acid revealed a reduction in the frequency of MN and DNA damage induced by H2O2. PMID- 27461152 TI - Pineal calcification is associated with pediatric primary brain tumor. AB - AIM: Melatonin has been associated with various tumors, including brain tumor, and shown to inhibit growth of neuroblastoma cells and gliomas in animal models. Likewise, patients with glioblastoma receiving melatonin reported better survival than controls. Pineal calcification may lead to a decreased production of melatonin by calcified glands. This study assessed association between pineal calcification and primary brain tumor in pediatric/adolescent patients. METHODS: Medical chart review was conducted in 181 patients <15 years old who had undergone brain computed tomography (CT) during 2008-2012. Pineal calcification was identified using brain CT scan by an experienced neurosurgeon. Primary brain tumor was confirmed by CT scan and histology, and association with pineal calcification was estimated using multiple logistic regression, adjusted for age and gender. RESULTS: Primary brain tumor was detected in 51 patients (mean age 9.0, standard deviation 4.0 years), with medulloblastoma being the most common (11 patients). Pineal calcification was detected in 12 patients (23.5%) with primary brain tumor, while only 11 patients (8.5%) without tumor had pineal calcification. Adjusted for patients' ages and genders, pineal calcification was associated with an increase in primary brain tumor of 2.82-fold (odds ratio 2.82; 95% confidence interval 1.12-7.08, P = 0.027). CONCLUSION: Pineal calcification appears to be associated with primary brain tumor. Further studies to explore this link are discussed and warranted. PMID- 27461153 TI - Variants in 9p21 Predicts Severity of Coronary Artery Disease in a Chinese Han Population. AB - Recent genome-wide association studies identified the common genetic variants in 9p21 were associated with the coronary artery disease (CAD). However, whether this locus could predict the severity of CAD in Chinese Han population is unclear. 499 CAD patients who underwent coronary angiography (CAG) have been enrolled for this study. The single-nucleotide polymorphisms rs2383207 and rs2383206 in 9p21 were genotyped in 499 CAG cases and 1519 controls in Chinese Han population. The gene dosage of 9p21 was stratified by the degree of vascular lesions and tested for association with the severity of CAD. Rs2383207 and rs2383206 demonstrated significant associations with 2-vessel and 3-vessel disease (P = 2.0*10(-3) and 1.9*10(-4) , respectively). GG genotypes of rs2383206 occurred higher proportion of left main trunk (LM) disease (P = 6.0*10(-3) ). GG genotypes of rs2383207 occurred higher proportion of left anterior descending artery disease (LAD) and right CAD (RCA) (P = 2.7*10(-6) and 1.6*10(-4) , respectively). The risk allele G of rs2383207 was associated with severity of CAD estimated by the Gensini score (P = 3.6*10(-5) ). Rs2383207 may strongly influence the development of CAD in Chinese Han population. The gene dosage in 9p21 could predict the severity of CAD. PMID- 27461155 TI - Chemotaxonomic Screening of Seed Oils from the Family Saxifragaceae and Comparison with Data on Seed Oils from Grossulariaceae Obtained from Literature. AB - Seeds of 25 members of the family Saxifragaceae, 1 * Astilbe, 1 * Darmera, 1 * Leptarrhena, 1 * Tellima, 3 * Mitella, and 18 * Saxifraga were investigated regarding oil content, as well as composition and content of fatty acids and vitamin E active compounds. The results were compared with results obtained from literature for members of the genus Ribes belonging to the closely related family Grossulariaceae to find chemometric differences between the different genera and between members of the family Saxifragaceae and Grossulariaceae, respectively. Members of the family Saxifragaceae are dominated by high amounts of linoleic and alpha-linolenic acid which together account for about 80% of the total fatty acids. While alpha-linolenic acid is characteristic for members of the genus Saxifraga, in other genera, linoleic acid is predominant. In comparison to members of the family Saxifragaceae members of the family Grossulariaceae also contain gamma-linolenic acid and stearidonic acid which allow a significant differentiation between both families. By principle component analysis, members of both families were divided into three distinct groups, i) species with a high content of alpha-linolenic acid (genus Saxifraga), ii) species with high amounts of gamma-linolenic acid and stearidonic acid (genus Ribes), and iii) species with higher amounts of linoleic acid (other members of the family Saxifragaceae). The composition of the vitamin E active compounds was characterized by a high content of gamma-tocopherol in most members of the family Saxifragaceae, but no chemotaxonomic relevance. PMID- 27461154 TI - Using machine learning to predict radiation pneumonitis in patients with stage I non-small cell lung cancer treated with stereotactic body radiation therapy. AB - To develop a patient-specific 'big data' clinical decision tool to predict pneumonitis in stage I non-small cell lung cancer (NSCLC) patients after stereotactic body radiation therapy (SBRT). 61 features were recorded for 201 consecutive patients with stage I NSCLC treated with SBRT, in whom 8 (4.0%) developed radiation pneumonitis. Pneumonitis thresholds were found for each feature individually using decision stumps. The performance of three different algorithms (Decision Trees, Random Forests, RUSBoost) was evaluated. Learning curves were developed and the training error analyzed and compared to the testing error in order to evaluate the factors needed to obtain a cross-validated error smaller than 0.1. These included the addition of new features, increasing the complexity of the algorithm and enlarging the sample size and number of events. In the univariate analysis, the most important feature selected was the diffusion capacity of the lung for carbon monoxide (DLCO adj%). On multivariate analysis, the three most important features selected were the dose to 15 cc of the heart, dose to 4 cc of the trachea or bronchus, and race. Higher accuracy could be achieved if the RUSBoost algorithm was used with regularization. To predict radiation pneumonitis within an error smaller than 10%, we estimate that a sample size of 800 patients is required. Clinically relevant thresholds that put patients at risk of developing radiation pneumonitis were determined in a cohort of 201 stage I NSCLC patients treated with SBRT. The consistency of these thresholds can provide radiation oncologists with an estimate of their reliability and may inform treatment planning and patient counseling. The accuracy of the classification is limited by the number of patients in the study and not by the features gathered or the complexity of the algorithm. PMID- 27461156 TI - Isocyanates and isothiocyanates as versatile platforms for accessing (thio)amide type compounds. AB - The addition of carbon (Grignard and organolithium reagents) and hydride nucleophiles (Schwartz reagent) to isocyanates and isothiocyanates constitutes a versatile, direct and high yielding approach to the synthesis of functionalized (thio)amide derivatives including haloamides and formamides. The chemoselective delivery of a nucleophilic (eventually configurationally stable) organometallic species to a given iso(thio)cyanate is the crucial parameter for the success of the strategy. Thus, the influence of the factors governing classical methodologies (e.g. dehydrative condensation) such as steric hindrance and electronic properties of the reactants become practically negligible. PMID- 27461157 TI - Structural Heart Disease in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Prevalence and Clinical Profile in a Spanish Sample. PMID- 27461158 TI - A Living Eukaryotic Autocementation Kit from Surface Display of Silica Binding Peptides on Yarrowia lipolytica. AB - With the development of civil engineering, the demand for suitable cementation materials is increasing rapidly. However, traditional cementation methods are not eco-friendly enough and more sustainable approach such as biobased cementation is required. To meet such demand, Euk.cement, a living eukaryotic cell-based biological autocementation kit, was created in this work. Through the surface display of different silica binding peptides on the fungus Yarrowia lipolytica, Euk.cement cells can immobilize onto any particles with a silica containing surface with variable binding intensity. Meanwhile, recombinant MCFP3 released from the cells will slowly consolidate this binding of cells to particles. The metabolism of immobilized living cells will finally complete the carbonate sedimentation and tightly stick the particles together. The system is designed to be initiated by blue light, making it controllable. This autocementation kit can be utilized for industrial and environmental applications that fit our concerns on making the cementation process eco-friendly. PMID- 27461159 TI - Dermoscopic changes in malignant melanoma after successful treatment with nivolumab: A case report. PMID- 27461160 TI - Global maternal health and newborn health: Looking backwards to learn from history. AB - The late appearance of the 'M' on the international health agenda - in its own right and not just as a carrier of the intrauterine passenger - is thought provoking. The 'M' was absent for decades in textbooks of 'tropical medicine' until the rhetoric question was formulated: 'Where is the "M" in MCH?' The selective antenatal 'high-risk approach' gained momentum but had to give way to the fact that all pregnant women are at risk due to unforeseeable complications. In order to provide trained staff to master such complications in impoverished rural areas (with no doctors), some countries have embarked on training of non physician clinicians/associate clinicians for major surgery with excellent results in 'task-shifting' practice. The alleged but non-existent 'human right' to survive birth demonstrates that there have been no concrete accountability and no 'legal teeth' to make a failing accountability legally actionable to guarantee such a right. PMID- 27461161 TI - Mitigation of the processing contaminant acrylamide in bread by reducing asparagine in the bread dough. AB - Over the past few years there has been an increasing awareness regarding acrylamide (AAM) content of various foods. Although there are several relevant articles on AAM mitigation in industrially prepared products, the literature regarding homemade preparations is rather scarce. The objective of this study is to mitigate the AAM formation in baked buns made with 1:1 sifted wheat/wholegrain flour through the depletion of asparagine (ASN) in the bread dough. Using a full factorial design, the effect of four factors (yeast amount, fermentation time, fermentation temperature and yeast types) was tested. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used for AAM and its main precursor, ASN, determination. The resulting ASN depletion in the dough (68-89%) is significantly affected by fermentation time and yeast type, while AAM mitigation levels in the baked buns are significantly influenced by yeast amount, fermentation time and yeast type. The mean concentrations for each combination range between 5 and 15 ug kg(-)(1). PMID- 27461162 TI - Evaluation of potential human health effects associated with the agricultural uses of 1,3-D: Spatial and temporal stochastic risk analysis. AB - Dow AgroSciences (DAS) markets and sells 1,3-Dichloropropene (1,3-D), the active ingredient in Telone(r), which is used as a pre-plant soil fumigant nematicide in economically important crops in California. 1,3-D has been regulated as a "probable human carcinogen" and the California Department of Pesticide Regulation limits use of 1,3-D based on human health risk assessments for bystanders. This paper presents a risk characterization for bystanders based on advances in the assessment of both exposure and hazard. The revised bystander risk assessment incorporates significant advances: 1) new data on residency duration and mobility in communities where 1,3-D is in high demand; 2) new information on spatial and temporal concentrations of 1,3-D in air based on multi-year modeling using a validated model; and 3) a new stochastic spatial and temporal model of long-term exposures. Predicted distributions of long-term, chronic exposures indicate that current, and anticipated uses of 1,3-D would result in lifetime average daily doses lower than 0.002mg/kg/d, a dose associated with theoretical lifetime excess cancer risk of <10(-5) to >95% of the local population based on a non-threshold risk assessment approach. Additionally, examination of 1,3-D toxicity studies including new chronic toxicity data and mechanism of action supports the use of a non-linear, threshold based risk assessment approach. The estimated maximum annual average daily dose of <0.0016mg/kg/d derived from the updated exposure assessment was then compared with a threshold point of departure. The calculated margin of exposure is >1000-fold, a clear indication of acceptable risk for human health. In summary, the best available science supports 1,3-D's threshold nature of hazard and the revised exposure assessment supports that current agricultural uses of 1,3-D are associated with reasonable certainty of no harm, i.e., estimated long-term exposures pose insignificant health risks to bystanders even when the non-threshold approach is assumed. PMID- 27461163 TI - Reproductive strategy of the Patagonian catfish Hatcheria macraei. AB - This study describes the reproductive strategy of the stream-dwelling catfish Hatcheria macraei in the Pichileufu River, Argentina. Gonad maturity phases, classified on the basis of histological analysis, stages of gamete development and the frequency distribution of oocyte size, were correlated with macroscopic features of the gonads. Hatcheria macraei has a cystovarian ovary, asynchronous oocyte development and lobular testes. Five oocyte and four spermatogenic stages were identified and related to macroscopic gonad characteristics, making it possible to divide gonad development into five phases for females and males. Mature oocyte diameter ranged from 922 to 1935 um. Absolute fecundity in mature females varied from 115 to 480 oocytes. Hatcheria macraei has multiple spawning during a protracted reproductive season that extends from December to April. This, together with its small size, is characteristic of an opportunistic reproductive strategy, commonly found in species that inhabit adverse and unpredictable environments, such as the low-order rivers of Patagonia. PMID- 27461164 TI - Predictors for future clinically significant pain in patients with temporomandibular disorder: A prospective cohort study. AB - BACKGROUND: Up to 30% of patients with temporomandibular disorder (TMD) run the risk of progressing to chronic pain with significant disability. This prospective cohort study assessed the effects of baseline pain and general health and psychosocial factors on the presence of clinically significant pain in patients with TMD pain at 1 year after initial consultation. METHODS: 263 primary care patients with TMD pain were included. At the baseline, patients completed a pain questionnaire including a wide range of putative prognostic factors, which were assessed using validated self-report scales. The outcome, clinically significant pain at 1 year was defined as grades IV and III and grades II and I with any disability points on the Graded Chronic Pain Scale (GCPS). Multivariable logistic regression was used to study the association between the outcome and each predictor variable. RESULTS: At 1 year, 26.9% of the patients reported clinically significant pain. The number of previous healthcare visits (OR 1.19, 95% CI 1.02 1.39), pain intensity/dysfunction of other pain conditions (OR 1.35, 95% CI 1.07 1.69), the number of other pain conditions (OR 1.31, 95% CI 0.98-1.74), the number of disability days (OR 1.05, 95% CI 1.00-1.12), and perceived ability to control pain (OR 0.79, 95% CI 0.61-1.01) were associated with the outcome. The area under the curve (AUC) for the whole model indicated acceptable discriminative ability (0.74, 95% CI 0.66-0.82). CONCLUSIONS: Reporting several previous healthcare visits and comorbid pains with high pain intensity and disability signal increased risk for poor prognosis of TMD pain. SIGNIFICANCE: About 27% of primary care TMD pain patients reported clinically significant pain at 1 year after initial consultation. Reporting several previous healthcare visits and comorbid pains with high pain intensity and disability were associated with poor prognosis of TMD pain. PMID- 27461165 TI - Magnetic Resonance Imaging of Glucose Uptake and Metabolism in Patients with Head and Neck Cancer. AB - Imaging metabolic dysfunction, a hallmark of solid tumors, usually requires radioactive tracers. Chemical exchange saturation transfer (CEST) imaging can potentially detect and visualize glucose uptake and metabolism, without the need for radioisotopes. Here, we tested the feasibility of using glucose CEST (glucoCEST) to image unlabeled glucose uptake in head and neck cancer by using a clinical 3T magnetic resonance imaging (MRI) scanner. The average CEST contrast between tumors and normal tissue in 17 patients was 7.58% (P = 0.006) in the 3-4 ppm offset frequency range and 5.06% (P = 0.02) in 1-5 ppm range. In a subgroup of eight patients, glucoCEST signal enhancement was higher in tumors than in normal muscle (4.98% vs. 1.28%, P < 0.021). We conclude that glucoCEST images of head and neck cancer can be obtained with a clinical 3T MRI scanner. PMID- 27461166 TI - Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3 year results from the SELECTED open-label extension study. AB - BACKGROUND: Daclizumab is a humanized monoclonal antibody against CD25 that modulates interleukin 2 signaling. The SELECT TRILOGY of clinical studies (SELECT/SELECTION/SELECTED) evaluated the safety and efficacy of daclizumab in patients with relapsing-remitting multiple sclerosis (RRMS). We report the long term safety and efficacy of daclizumab 150 mg subcutaneous every 4 weeks in patients with RRMS in the SELECTED open-label extension study. METHODS: An interim intent-to-treat analysis of all enrolled patients was performed in January 2014 for this ongoing study. RESULTS: The SELECTED study enrolled 90% of patients who completed SELECTION. In the safety and efficacy analysis (N = 410), median treatment time in SELECTED was 25 months (range, <1-45). Adverse events (AEs) were reported in 76% of patients, serious AEs (SAEs) excluding MS relapse in 16%, and treatment discontinuation due to AEs including multiple sclerosis (MS) relapse in 12%. AEs were primarily of mild to moderate severity, and common AEs (>=10%), excluding MS relapse, were nasopharyngitis (12%) and upper respiratory tract infection (12%). Most commonly reported SAEs (in >=3 patients), excluding MS relapses, were increased serum hepatic enzymes, pneumonia, ulcerative colitis, and urinary tract infection (<1% each). Incidences of AE groups of interest include cutaneous events (28%), cutaneous SAEs (2%), gastrointestinal SAEs (2%), hepatic SAEs, (1%) and malignancies (1%). The incidence of AEs, SAEs, and treatment-related study discontinuations did not increase over time and no deaths were reported. The adjusted annualized relapse rate (95% confidence interval (CI)) analyzed at 6-month intervals was 0.15 (0.10 0.22) for weeks 97-120 and 0.15 (0.10-0.21) for weeks 121-144. In year 3, the adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions was 1.26 (0.93-1.72) and the mean (median) annualized change in brain volume was 0.32% (-0.34%). CONCLUSIONS: The AE incidence did not increase with extension of therapy into year 3 in SELECTED; the safety profile was similar to that previously observed. The clinical efficacy of daclizumab was sustained over the 3 years comprising the SELECT TRILOGY, although potential selection bias cannot be excluded. TRIAL REGISTRATION: Clinicaltrials.gov NCT01051349; first registered January 15, 2010. PMID- 27461167 TI - Late-night overeating is associated with smaller breakfast, breakfast skipping, and obesity in children: The Healthy Growth Study. AB - OBJECTIVE: Excessive energy intake during evening hours is associated with several health problems. The aim of this study was to investigate for the first time the possible association of late-night overeating with breakfast habits and obesity in a large sample of Greek children ages 9 to 13 y. METHODS: In all, 2655 schoolchildren (9-13 y) participated in the Healthy Growth Study, a cross sectional epidemiologic study conducted in 77 primary schools in four large regions in Greece. The present study presents results on 1912 children having full data regarding anthropometric, dietary, physical activity, and physical examination indices. RESULTS: High-energy intake at dinner and evening snack was associated with higher likelihood of skipping breakfast (odds ratio, 1.85; 95% confidence interval 1.42-2.39) and with lower caloric intake at breakfast (beta = 0.14; P < 0.001). Children at the lowest quartile of physical activity levels were found to have a positive association between the calories consumed at dinner and their body mass index (beta = 0.11; P = 0.019). This association was inverse for children at the highest quartile of physical activity levels (beta = -0.10; P = 0.033). CONCLUSIONS: Late-night overeating is associated with skipping and/or consuming a smaller breakfast. In children with low levels of physical activity, it is associated with increased body mass index. Future relevant studies are essential to further explore and confirm the findings of the present study. PMID- 27461168 TI - An open-label, randomized, parallel-group comparative study of the efficacy of sorghum bicolor extract in preoperative anemia. AB - OBJECTIVE: Anemia in patients presenting for elective surgery is associated with increased morbidity, allogeneic blood transfusion, and delay of surgery. Extract of sorghum bicolor has been shown to have hemopoietic, immune-stimulating, and antioxidant effects in rats and in patients with HIV. The aim of this study was to determine the effect of the extract in patients with preoperative anemia booked for myomectomy. METHODS: Consenting patients (N = 66) were randomly assigned to two groups. The test group (n = 34) was given folic acid 5 mg/d, 200 mg iron tablet three times daily, and 500 mg/d of the extract. The control group (n = 32) was given the same doses of folic acid and iron for a period of 3 wk. Blood samples were taken at baseline and weekly for full blood cell count and liver and kidney function tests. Participants were screened for tuberculosis, HIV, hepatitis, and sickle cell anemia. RESULTS: Increases in red blood cell count, hematocrit, and hemoglobin concentration in participants in the test group were highly significant (P < 0.0002, P < 0.0001, and P < 0.0001, respectively). Participants in the control group had a significant increase in the hemoglobin concentration (P > 0.04). The changes in liver enzymes, urea, and creatinine for participants in the test group were within the normal ranges. CONCLUSION: The addition of the extract of sorghum bicolor to routine hematinics is superior to the use of routine hematinics alone. Although the difference is not statistically significant, the extract will correct preoperative anemia in an additional 15% of the patients. PMID- 27461169 TI - Summer holidays as break-point in shaping a tannery sludge microbial community around a stable core microbiota. AB - Recently, several investigations focused on the discovery of a bacterial consortium shared among different wastewater treatment plants (WWTPs). Nevertheless, the definition of a core microbiota over time represents the necessary counterpart in order to unravel the dynamics of bacterial communities in these environments. Here we performed a monthly survey on the bacterial community of a consortial industrial plant. Objectives of this study were: (1) to identify a core microbiota constant over time; (2) to evaluate the temporal dynamics of the community during one year. A conspicuous and diversified core microbiota is constituted by operational taxonomic units which are present throughout the year in the plant. Community composition data confirm that the presence and abundance of bacteria in WWTPs is highly consistent at high taxonomic level. Our results indicate however a difference in microbial community structure between two groups of samples, identifying the summer holiday period as the break-point. Changes in the structure of the microbial community occur otherwise gradually, one month after another. Further studies will clarify how the size and diversity of the core microbiota could affect the observed dynamics. PMID- 27461170 TI - Health law and policy: The scope and bounds of liberty? PMID- 27461171 TI - Faith, Hope And (No) Clarity. PMID- 27461172 TI - Assisted dying. PMID- 27461173 TI - Functional Connectivity of Resting Hemodynamic Signals in Submillimeter Orientation Columns of the Visual Cortex. AB - Resting-state functional magnetic resonance imaging has been increasingly used for examining connectivity across brain regions. The spatial scale by which hemodynamic imaging can resolve functional connections at rest remains unknown. To examine this issue, deoxyhemoglobin-weighted intrinsic optical imaging data were acquired from the visual cortex of lightly anesthetized ferrets. The neural activity of orientation domains, which span a distance of 0.7-0.8 mm, has been shown to be correlated during evoked activity and at rest. We performed separate analyses to assess the degree to which the spatial and temporal characteristics of spontaneous hemodynamic signals depend on the known functional organization of orientation columns. As a control, artificial orientation column maps were generated. Spatially, resting hemodynamic patterns showed a higher spatial resemblance to iso-orientation maps than artificially generated maps. Temporally, a correlation analysis was used to establish whether iso-orientation domains are more correlated than orthogonal orientation domains. After accounting for a significant decrease in correlation as a function of distance, a small but significant temporal correlation between iso-orientation domains was found, which decreased with increasing difference in orientation preference. This dependence was abolished when using artificially synthetized orientation maps. Finally, the temporal correlation coefficient as a function of orientation difference at rest showed a correspondence with that calculated during visual stimulation suggesting that the strength of resting connectivity is related to the strength of the visual stimulation response. Our results suggest that temporal coherence of hemodynamic signals measured by optical imaging of intrinsic signals exists at a submillimeter columnar scale in resting state. PMID- 27461174 TI - Difference of Type 3 secretion system (T3SS) effector gene genotypes (exoU and exoS) and its implication to antibiotics resistances in isolates of Pseudomonas aeruginosa from chronic otitis media. AB - OBJECTIVE: Type 3 secretion system (T3SS) is the most important virulence factor in Pseudomonas aeruginosa infection. Of the various T3SS effector genes, exoS and exoU showed mutually exclusive distributions, and these two genes showed varied virulence. In many pseudomonal infections, the distribution of these genes showed different pattern and it influenced severity of infection. This study was aimed to evaluate differences of virulence factors and antibiotics resistance between chronic otitis media and other body infection caused by P. aeruginosa. METHODS: To estimate the prevalence of effector genes of T3SS, especially the distributions of exoS and exoU genes and their association with antibiotic resistance in COM, we compared the prevalence of T3SS genes in isolates from COM with those from lower respiratory infection and bacteremia. Other virulence genes, including groEL, pilA, ndvB, lasB, rhlI, and apr, were also studied to evaluate prevalence. These isolates were tested for antibiotic susceptibility, and we examined the association between antibiotic susceptibility and the prevalence of T3SS effector genes. RESULTS: The COM group showed a significantly higher exoU-positive rate than the control group (70.6% vs. 6.7%; P<0.01). Furthermore, COM patients with exoU showed significant antibiotic resistance to ciprofloxacin and tobramycin (P=0.035), whereas there was no significant difference in the control group. CONCLUSIONS: The high incidence of exoU-positive P. aeruginosa and ciprofloxacin resistance can explain the chronicity and intractability of infection in COM. Elucidation of this pathogenicity will facilitate the development of new treatment options for COM patients. PMID- 27461175 TI - Endoscopic versus microscopic stapes surgery. AB - OBJECTIVE: The aim of this study to compare the outcomes and complications of endoscopic stapes surgery versus microscopic stapes surgery. METHODS: This study involved patients who underwent stapedotomy at the Department of Otorhinolaryngology, Faculty of Medicine, Cukurova University between January 2012 and July 2014. The patients were divided into two groups. Patients in group I were operated with endoscope and patients in group II were operated with microscope. Pure tone audiometry was carried out in all patients preoperatively. Peroperative surgical findings, complications, and duration of surgery were noted and compared between the two groups. Air conduction and bone conduction thresholds were measured at frequencies of 500, 1000, 2000, and 4000Hz, and the mean (+/-SD) air-bone gap was noted. RESULTS: Mean preoperative air-bone gap was 36.9+/-6.8dB (23.3-50dB) in group I and 35.1+/-6dB (26.6-50dB) in group II. Mean postoperative air-bone gap was 9.3+/-7.1dB (0-30dB) in group I and 13.5+/-9.7dB (1.6-35dB) in group II. The difference in preoperative and postoperative air-bone gap between the two groups was statistically significant (p=0.023). Patients in group I did not complain of postoperative pain but this was felt in four patients in group II. The difference was statistically significant (p=0.045). CONCLUSION: Endoscopic stapes surgery has many benefits such as good visualization, and easy accessibility to the stapes, oval window niche, and facial nerve. Removal of the scutum and manipulation of the chorda tympani nerve are less frequent with the endoscopic technique. PMID- 27461176 TI - Fecal microbiota transplantation in inflammatory bowel disease: the quest for the holy grail. AB - Inflammatory bowel disease (IBD) is due to an aberrant immune response toward luminal antigens, probably commensal bacteria, in genetically susceptible subjects and is also influenced by environmental factors. An imbalanced intestinal microbiota known as "dysbiosis," characterized by an increased proportion of pro-inflammatory microorganisms and a decreased proportion of anti inflammatory microorganisms, has been repeatedly observed in IBD and is now recognized as a key factor in the gut inflammatory process. Fecal microbiota transplantation (FMT) has gained interest as a novel treatment option in IBD. The goal of FMT in IBD is not only to correct the dysbiosis, but also to restore a normal dialog between the host immune system and the microbiota. Data are still scarce, but the results of the first studies suggest that FMT could be a promising therapy in IBD. More studies are needed to define the best indications, optimal timing, frequency, mode of delivery, and the optimal donor for each patient. PMID- 27461179 TI - Impact of cone beam computed tomography (CBCT) on diagnostic thinking in endodontics of posterior teeth: A before- after study. AB - OBJECTIVES: The aim of this study was to evaluate the impact of limited volume CBCT upon diagnosis as part of endodontic management of posterior teeth. The null hypothesis that CBCT does not make any difference in endodontic diagnosis was tested. METHODS: A single-centre "before-after" study was conducted in a secondary healthcare establishment. Eligible patients were all adults aged 18 years or over who were referred to a specialist endodontic unit. Further inclusion criteria were that the cases were either re-treatment or de novo root canal treatment where the anatomy was judged to be complex. Exclusion criteria included vulnerable groups and de novo endodontic treatment with uncomplicated root canal anatomy. As well as a full history and clinical examination, a high quality colour photographic intraoral image, two paralleling technique periapical radiographs and limited volume CBCT examination were carried out for each patient. All components, except the CBCT dataset, were combined into a Powerpoint presentation and assessed by 4 observers. A questionnaire was designed for the observers as part of the study. RESULTS: CBCT information only changed the radiological findings and the final diagnosis in a minority of cases. There was no clear evidence that CBCT increases the confidence of observers or that CBCT was helpful in making a diagnosis. CONCLUSIONS: Routine use of CBCT cannot not be justified on the basis of a change in diagnosis and carefully selected use is appropriate. CLINICAL SIGNIFICANCE: CBCT is being increasingly used in the field of endodontics. The benefits gained from the use of CBCT must be carefully balanced against the increased radiation dosage. Determination of selection criteria for the use of CBCT in endodontics is, therefore, essential. PMID- 27461177 TI - The human intestinal B-cell response. AB - The intestinal immune system is chronically challenged by a huge plethora of antigens derived from the lumen. B-cell responses in organized gut-associated lymphoid tissues and regional lymph nodes that are driven chronically by gut antigens generate the largest population of antibody-producing cells in the body: the gut lamina propria plasma cells. Although animal studies have provided insights into mechanisms that underpin this dynamic process, some very fundamental differences in this system appear to exist between species. Importantly, this prevents extrapolation from mice to humans to inform translational research questions. Therefore, in this review we will describe the structures and mechanisms involved in the propagation, dissemination, and regulation of this immense plasma cell population in man. Uniquely, we will seek our evidence exclusively from studies of human cells and tissues. PMID- 27461180 TI - Haberland syndrome: Clinical and neuroimaging findings leading to diagnosis. PMID- 27461178 TI - Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection. AB - Mucosal antigen-specific CD4 T-cell responses to intestinal pathogens remain incompletely understood. Here we examined the CD4 T-cell response after oral infection with an internalin A 'murinized' Listeria monocytogenes (Lm). Oral Lm infection induced a robust endogenous listeriolysin O (LLO)-specific CD4 T-cell response with distinct phenotypic and functional characteristics in the intestine. Circulating LLO-specific CD4 T cells transiently expressed the 'gut homing' integrin alpha4beta7 and accumulated in the intestinal lamina propria and epithelium where they were maintained independent of interleukin (IL)-15. The majority of intestinal LLO-specific CD4 T cells were CD27- Ly6C- and CD69+ CD103- while the lymphoid LLO-specific CD4 T cells were heterogeneous based on CD27 and Ly6C expression and predominately CD69-. LLO-specific effector CD4 T cells transitioned into a long-lived memory population that phenotypically resembled their parent effectors and displayed hallmarks of residency. In addition, intestinal effector and memory CD4 T cells showed a predominant polyfunctional Th1 profile producing IFNgamma, TNFalpha, and IL-2 at high levels with minimal but detectable levels of IL-17A. Depletion of CD4 T cells in immunized mice led to elevated bacterial burden after challenge infection highlighting a critical role for memory CD4 T cells in controlling intestinal intracellular pathogens. PMID- 27461181 TI - Conservative treatment in patients with mild to moderate carpal tunnel syndrome: A systematic review. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy. It is characterised by the compression of the median nerve in the carpal tunnel. CTS presents a high prevalence and it is a disabling condition from the earliest stages. Severe cases are usually treated surgically, while conservative treatment is recommended in mild to moderate cases. The aim of this systematic review is to present the conservative treatments and determine their effectiveness in mild-to-moderate cases of CTS over the last 15 years. METHODS: A systematic review was performed according to PRISMA criteria. We used the Medline, PEDro, and Cochrane databases to find and select randomised controlled clinical trials evaluating the effects of conservative treatment on the symptoms and functional ability of patients with mild to moderate CTS; 32 clinical trials were included. There is evidence supporting the effectiveness of oral drugs, although injections appear to be more effective. Splinting has been shown to be effective, and it is also associated with use of other non-pharmacological techniques. Assessments of the use of electrotherapy techniques alone have shown no conclusive results about their effectiveness. Other soft tissue techniques have also shown good results but evidence on this topic is limited. Various treatment combinations (drug and non-pharmacological treatments) have been proposed without conclusive results. CONCLUSIONS: Several conservative treatments are able to relieve symptoms and improve functional ability of patients with mild to-moderate CTS. These include splinting, oral drugs, injections, electrotherapy, specific manual techniques, and neural gliding exercises as well as different combinations of the above. We have been unable to describe the best technique or combination of techniques due to the limitations of the studies; therefore, further studies of better methodological quality are needed. PMID- 27461182 TI - Patterns of anaesthetic pericranial nerve block in headache patients. AB - : Anaesthetic blocks, whether used alone or combined with other treatments, are a therapeutic resource for many patients with headaches. However, usage patterns by different professionals show significant heterogeneity. MATERIAL AND METHODS: The Headache Study Group of the Spanish Society of Neurology (GECSEN) designed a self administered cross-sectional survey and sent it to all group members through the SEN's scientific area web platform in February 2016. The objective was to ascertain the main technical and formal aspects of this procedure and compare them with data obtained in a similar survey conducted in 2012. RESULTS: A total of 39 neurologists (mean age 41.74 years; SD: 9.73), 23 men (43.7 years; SD: 9.92) and 16 women (38.94 years; SD: 9.01) participated in this survey. Of these respondents, 76.9% used anaesthetic block in their clinical practice (79.16% in a tertiary-care hospital). The main indications were diagnosis and treatment of neuralgia (100%), prevention of chronic migraine (61.7%), episodic cluster headache (51.3%), and chronic cluster headache (66.7%). AB was used by 31% of the respondents to block only the lateral occipital complex, 13% also infiltrated the supraorbital nerve, and another 13% infiltrated the auriculotemporal nerve as well. CONCLUSIONS: The indications for anaesthetic blocks and the territories most frequently infiltrated are similar to those cited in the earlier survey. However, we observed increased participation in this latest survey and a higher percentage of young neurologists (35.89% aged 35 or younger), indicating that use of this technique has entered mainstream clinical practice. PMID- 27461183 TI - Emery-Dreifuss muscular dystrophy type 2: New de novo mutation in the lamin A/C gene. PMID- 27461184 TI - Muscle atrophy and fasciculations as a manifestation of sporadic Creutzfeldt Jakob disease: A case report. PMID- 27461185 TI - Varicella-zoster virus meningitis in an immunocompetent paediatric patient. PMID- 27461187 TI - Electrochemically reduced graphene oxide on silicon nanowire arrays for enhanced photoelectrochemical hydrogen evolution. AB - Photoelectrochemical (PEC) water splitting into hydrogen and oxygen by sunlight is a promising approach to solve energy and environmental problems. In this work, silicon nanowire arrays (SiNWs) photocathodes decorated with reduced graphene oxide (rGO) for PEC water splitting were successfully prepared by a flexible and scalable electrochemical reduction method. The SiNWs photocathode with the optimized rGO decoration (SiNWs/rGO20) shows an enhanced activity with a much higher photocurrent density and significantly positive shift of onset potential compared to the bare SiNWs arrays for the hydrogen evolution reaction (HER). The enhanced PEC activity is ascribed to the high electrical conductivity of rGO and improved separation of the photogenerated charge carriers. This work not only demonstrates a facile, rapid and tunable electrochemical reduction method to produce rGO, but also exhibits an efficient protocol to enhance the PEC water splitting of silicon-based materials. PMID- 27461186 TI - Cost-effectiveness of hemodialysis and peritoneal dialysis: A national cohort study with 14 years follow-up and matched for comorbidities and propensity score. AB - Although treatment for the dialysis population is resource intensive, a cost effectiveness analysis comparing hemodialysis (HD) and peritoneal dialysis (PD) by matched pairs is still lacking. After matching for clinical characteristics and propensity scores, we identified 4,285 pairs of incident HD and PD patients from a Taiwanese national cohort during 1998-2010. Survival and healthcare expenditure were calculated by data of 14-year follow-up and subsequently extrapolated to lifetime estimates under the assumption of constant excess hazard. We performed a cross-sectional EQ-5D survey on 179 matched pairs of prevalent HD and PD patients of varying dialysis vintages from 12 dialysis units. The product of survival probability and the mean utility value at each time point (dialysis vintage) were summed up throughout lifetime to obtain the quality adjusted life expectancy (QALE). The results revealed the estimated life expectancy between HD and PD were nearly equal (19.11 versus 19.08 years). The QALE's were also similar, whereas average lifetime healthcare costs were higher in HD than PD (237,795 versus 204,442 USD) and the cost-effectiveness ratios for PD and HD were 13,681 and 16,643 USD per quality-adjusted life year, respectively. In conclusion, PD is more cost-effective than HD, of which the major determinants were the costs for the dialysis modality and its associated complications. PMID- 27461188 TI - Evaluation of cardiac output by bioreactance technique in patients undergoing liver transplantation. AB - BACKGROUND: This study compared the cardiac output (CO) obtained from PiCCO with that obtained from the noninvasive NICOM method. METHODS: Twenty-one cirrhotic patients receiving liver transplantation were enrolled. During the operation, their CO was measured by the PiCCO system via the thermodilution method as the standard and by the NICOM method. Two parameters including cardiac index (CI) and stroke volume index (SVI) were collected simultaneously at three phases during the surgery including the dissection phase (T1), the anhepatic phase (T2), and the reperfusion phase (T3). Correlation, Bland and Altman methods, and linear mixed model were used to evaluate the monitoring ability of both systems. RESULTS: Poor correlation was noted between the data measured by NICOM and PiCCO; the correlation coefficients for CI and SVI measured between the two systems were 0.32 and 0.39, respectively. Bland and Altman analysis showed the percentage error of CI as 63.7%, and that of SVI as 66.6% for NICOM compared to PiCCO. Using the linear mixed model, the CI and SVI measured using NICOM were significantly higher than those using PiCCO (estimated regression coefficient 0.92 and 10.77, both p < 0.001). Mixed model analysis showed no differences between the trends of CI and SVI measured by the two methods. CONCLUSIONS: NICOM provided a comparable CI and SVI trend when compared to the gold standard PiCCO, but it raises concerns as an effective CO monitor because of its tendency to overestimate CI and SVI especially during the state of high cardiac output. PMID- 27461189 TI - Development of measures to evaluate youth advocacy for obesity prevention. AB - BACKGROUND: Youth advocacy has been successfully used in substance use prevention but is a novel strategy in obesity prevention. As a precondition for building an evidence base for youth advocacy for obesity prevention, the present study aimed to develop and evaluate measures of youth advocacy mediator, process, and outcome variables. METHODS: The Youth Engagement and Action for Health (YEAH!) program (San Diego County, CA) engaged youth and adult group leaders in advocacy for school and neighborhood improvements to nutrition and physical activity environments. Based on a model of youth advocacy, scales were developed to assess mediators, intervention processes, and proximal outcomes of youth advocacy for obesity prevention. Youth (baseline n = 136) and adult group leaders (baseline n = 47) completed surveys before and after advocacy projects. With baseline data, we created youth advocacy and adult leadership subscales using confirmatory factor analysis (CFA) and described their psychometric properties. RESULTS: Youth came from 21 groups, were ages 9-22, and most were female. Most youth were non White, and the largest ethnic group was Hispanic/Latino (35.6%). The proposed factor structure held for most (14/20 youth and 1/2 adult) subscales. Modifications were necessary for 6 of the originally proposed 20 youth and 1 of the 2 adult multi-item subscales, which involved splitting larger subscales into two components and dropping low-performing items. CONCLUSIONS: Internally consistent scales to assess mediators, intervention processes, and proximal outcomes of youth advocacy for obesity prevention were developed. The resulting scales can be used in future studies to evaluate youth advocacy programs. PMID- 27461190 TI - Epidemiologic studies and novel clinical research approaches that impact TB vaccine development. AB - The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Developing TB Vaccines for Prevention of Disease, Prevention of Infection, and Immunotherapy Indications; Concepts and Approaches in Clinical Research & Development; and Epidemiological Research. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. PMID- 27461191 TI - Analgesia for acute gingivostomatitis: a national survey of pediatric emergency physicians. AB - OBJECTIVES: Gingivostomatitis is a common, painful pediatric presentation, and yet, few studies are available to guide management. We aimed to describe pediatric emergency physicians' current practice patterns, with respect to analgesic use in children with acute gingivostomatitis, in order to inform future studies. METHODS: A national survey was conducted at all 15 national academic pediatric centres. Electronic surveys were distributed to pediatric emergency physicians using a modified Dillman protocol; non-respondents received paper surveys via post. Data were collected regarding demographic characteristics, clinical behaviour, factors that may influence practice, and future directions. RESULTS: Response rate was 74% (150/202). Most physicians (72%) preferred the combination of acetaminophen and ibuprofen to either agent alone (ibuprofen 19%, acetaminophen 7%). The preferred second-line analgesics were oral morphine (48%, 72/150) and compounded topical formulas (42%, 64/150). The most commonly cited compounded agent was Benadryl plus Maalox (23%, 35/150). Clinical experience with a medication had the greatest influence on practice pattern, with 52% (78/149) strongly agreeing. The most commonly cited barrier to adequate analgesia was difficulty in the administration of topical or oral medication to children. CONCLUSIONS: As with many other painful conditions, the combination of acetaminophen and ibuprofen was preferred, followed by either agent alone. Oral morphine and topical compounded agents were also frequently prescribed. Regardless of patient age, physicians preferred oral morphine as a second-line agent to treat pain from severe gingivostomatitis. Future research will focus on determining which analgesic and route (oral or topical) is the most effective and best-tolerated choice. PMID- 27461192 TI - Metabolite profiles of synovial fluid change with the radiographic severity of knee osteoarthritis. AB - OBJECTIVES: To investigate potential pathogenic pathways in the synovial fluid of osteoarthritis (OA) patients at different disease stages [early vs. late, determined based on the Kellgren-Lawrence (KL) grading scale], through metabolite profiles that were performed by using gas-chromatography/time-of-flight mass spectrometry (GC/TOF MS). METHODS: Synovial fluid samples were obtained from 15 patients with knee OA, divided into early- (KL grade: 1 and 2) and late-stage OA (KL grade: 3 and 4). Metabolite profiles of OA based on KL grading scale were performed using GC/TOF MS, with multivariate statistical analyses conducted by orthogonal partial least squares discriminant analysis (OPLS-DA) and hierarchical clustering analysis (HCA). RESULTS: A total of 114 metabolites were identified and classified into various classes, such as amino acids, sugars and sugar alcohols, fatty acids, and organic acids. Significant discrimination of metabolite profiles between the early- and late-stage OA groups was shown by OPLS DA and HCA. Twenty-eight metabolites, including malate, ethanolamine, squalene, glycerol, myristic acid, oleic acid, lanosterol, heptadecanoic acid, and capric acid, were identified as critical metabolites for discriminating between the early- and late-OA groups by using Student's t-test, as they showed significant differences in abundance between the two OA groups. These metabolites were related to fatty acid metabolism, glycerolipid metabolism, and the tricarboxylic acid cycle. CONCLUSIONS: These results revealed that metabolite profiles are robustly altered along the radiographic stage of knee OA. Metabolomic approaches based on GC/TOF MS could provide valuable information on the underlying pathogenic mechanisms of OA progression. PMID- 27461193 TI - Identification of protein complexes from multi-relationship protein interaction networks. AB - BACKGROUND: Protein complexes play an important role in biological processes. Recent developments in experiments have resulted in the publication of many high quality, large-scale protein-protein interaction (PPI) datasets, which provide abundant data for computational approaches to the prediction of protein complexes. However, the precision of protein complex prediction still needs to be improved due to the incompletion and noise in PPI networks. RESULTS: There exist complex and diverse relationships among proteins after integrating multiple sources of biological information. Considering that the influences of different types of interactions are not the same weight for protein complex prediction, we construct a multi-relationship protein interaction network (MPIN) by integrating PPI network topology with gene ontology annotation information. Then, we design a novel algorithm named MINE (identifying protein complexes based on Multi relationship protein Interaction NEtwork) to predict protein complexes with high cohesion and low coupling from MPIN. CONCLUSIONS: The experiments on yeast data show that MINE outperforms the current methods in terms of both accuracy and statistical significance. PMID- 27461194 TI - Developing a bioethics curriculum for medical students from divergent geo political regions. AB - BACKGROUND: The World Health Organization calls for stronger cross-cultural emphasis in medical training. Bioethics education can build such competencies as it involves the conscious exploration and application of values and principles. The International Pediatric Emergency Medicine Elective (IPEME), a novel global health elective, brings together 12 medical students from Canada and the Middle East for a 4-week, living and studying experience. It is based at a Canadian children's hospital and, since its creation in 2004, ethics has informally been part of its curriculum. Our study sought to determine the content and format of an ideal bioethics curriculum for a culturally diverse group of medical students. METHODS: We conducted semi-structured interviews with students and focus groups with faculty to examine the cultural context and ethical issues of the elective. Three areas were explored: 1) Needs Analysis - students' current understanding of bioethics, prior bioethics education and desire for a formal ethics curriculum, 2) Teaching formats - students' and faculty's preferred teaching formats, and 3) Curriculum Content - students' and faculty's preferred subjects for a curriculum. RESULTS: While only some students had received formal ethics training prior to this program, all understood that it was a necessary and desirable subject for formal training. Interactive teaching formats were the most preferred and truth telling was considered the most important subject. CONCLUSIONS: This study helps inform good practices for ethics education. Although undertaken with a specific cohort of students engaging in a health-for-peace elective, it may be applicable to many medical education settings since diversity of student bodies is increasing world-wide. PMID- 27461195 TI - Editorial. PMID- 27461196 TI - NRP 7th Edition: Are You Prepared? AB - The seventh edition of the American Academy of Pediatrics/American Heart Association Neonatal Resuscitation Program (NRP) materials must be in use by January 1, 2017. As in previous editions, changes in resuscitation science are based on an international review and consensus of current resuscitation science. The seventh edition NRP materials also include enhancements to training materials aimed at improving the quality of NRP instruction and providing the opportunity for ongoing education. A standardized approach to instructor training, an online Instructor Toolkit, eSim cases, and a new learning management system are among the new resources. PMID- 27461198 TI - Integrated Evaluation of Neonatal Hemodynamics, Part 2: Systematic Bedside Assessment. AB - Intact hemodynamics results when there is adequate oxygen uptake by the respiratory system, normal cardiac output, sufficient oxygen-carrying capacity of blood, and intact autoregulatory mechanisms to maintain enough oxygenation for normal end-organ function. The current routine monitoring of cardiovascular dynamics in sick preterm and term infants has been based on incomplete evaluation and relies on nonspecific and sometimes misleading clinical markers such as blood pressure. A thorough understanding of perinatal and neonatal cardiovascular, respiratory, oxygen, and other specific end-organ physiology is also mandatory for proper targeted interpretation. PMID- 27461199 TI - An Integrated Review of Intestinal Microbiota in the Very Premature Infant. AB - BACKGROUND: The intestinal microbiota is important for optimal intestinal function and protection against infection. Disruption of the intestinal microbiota has been linked to necrotizing enterocolitis (NEC) and late-onset sepsis (LOS). OBJECTIVES: To determine what is known about the intestinal microbiota of very premature infants. We describe the relationship of the intestinal microbiota to NEC and LOS and provide an overview of the effect of environmental factors. METHODS: A review was conducted using PubMed/MEDLINE from 2008 to 2015 to examine what is currently known about the intestinal microbiota of very premature infants. DISCUSSION: The intestinal bacteria are low in diversity and generally contain a predominance of potentially pathogenic bacteria. Evidence suggests that these bacteria play a role in NEC as well as LOS through translocation. Environmental factors such as mode of delivery, use of antibiotics, and type of feeding may also contribute to the development of the intestinal microbiota. PMID- 27461200 TI - Eating in "SINC": Safe Individualized Nipple-Feeding Competence, a Quality Improvement Project to Explore Infant-Driven Oral Feeding for Very Premature Infants Requiring Noninvasive Respiratory Support. AB - Oral feeding is a developmental task for all premature infants. often, independent nipple feeding is the last barrier to discharge home from the NICU. A relationship exists between consistent, infant-driven feeding management practices and improved feeding performance. Conversely, a random approach to feeding may contribute to poor short-term and long-term clinical outcomes. We report a quality improvement project that was undertaken across five NICUs in an urban setting. our aim was to safely initiate and advance nipple feeding for very preterm neonates (born at <32 weeks gestation) who had a respiratory morbidity requiring nasal continuous positive airway pressure therapy. A novel algorithm entitled "eating in SINC: Safe individualized nipple-Feeding Competence" was developed. Safe individualized nipple-feeding competence involves the baby, the parents, and the health care team by using infant-driven strategies, common language, and developmentally appropriate goals while supporting fragile neonates to be skilled feeders. PMID- 27461201 TI - NeoSeal to Prevent Nasal Injury in Preterm Infants Receiving Oxygen Therapy. AB - PURPOSE: To determine if a foam septum protector prevents nasal injury in preterm infants receiving nasal heated humidified oxygen. DESIGN: A retrospective before and after comparative design was used. SAMPLE: Medical records of 101 preterm infants receiving either nasal continuous positive airway pressure (NCPAP) or nasal intermittent positive pressure ventilation (NIPPV) were reviewed; 50 were in the control group and 51 were in the intervention group that had the NeoSeal septum protector applied. The groups were not different in terms of gender, birth weight, gestational age, days intubated, or on days on NCPAP/NIPPV. Skin condition of nares was scored daily using the Neonatal Skin Risk Assessment Scale (NSRAS). RESULTS: Infants who had the NeoSeal applied had significantly less nasal injuries, OR = 4.08; 95% confidence interval (CI), 1.22-9.59; p = .01. The best predictors of nasal injury were gestational age and whether the NeoSeal was applied or not. PMID- 27461202 TI - Systemic Corticosteroids for the Prevention of Bronchopulmonary Dysplasia: Picking the Right Drug for the Right Baby. AB - Bronchopulmonary dysplasia is a morbidity of prematurity with implications into adulthood on respiratory and neurologic health. Multiple risk factors contribute to the development of bronchopulmonary dysplasia leading to examination of various strategies of prevention. Systemic corticosteroids are one prevention strategy with a large body of data, creating an ongoing controversy regarding the risks and benefits of therapy. Careful consideration of the available data along with the clinical characteristics of the individual infant is required before using this powerful therapy. PMID- 27461204 TI - Continuing Education Course. PMID- 27461203 TI - Postpartum Mood Disorders Screening in the NICU. AB - Maternal depression is increasingly recognized as the leading complication of childbearing. A mother's mental health impacts the well-being and long-term outcomes of her children. This column will discuss a systematic approach to screening for maternal postpartum mood disorders (PPMDs) and referring women to resources according to an established algorithm. This work was undertaken in a tertiary referral NICU and performed by dedicated NICU personnel with the goals of optimizing NICU infants' outcomes and supporting maternal and family health and well-being. PMID- 27461205 TI - News of the Academy of Neonatal Nursing. PMID- 27461206 TI - In vivo assessment of aortic root geometry in normal controls using 3D analysis of computed tomography. AB - Aims: Understanding normal asymmetry in the aortic root could aid in the development of new surgical repair techniques or devices with improved haemodynamic performance. The purpose of this study was to assess geometric asymmetry and age-related changes in the normal aortic root using 3D computed tomography. Methods and Results: The institutional review board approved this retrospective study of 130 normal subjects (mean age, 51.4 years; 58 men). Specialized 3D software measured individual cusp sinus volumes (CSVs), cusp surface areas (CSAs), and intercommissural distances (ICDs). Age-related aortic root changes were evaluated with simple correlation, ANOVA test among age groups, and multivariable linear regression analyses. The CSV and CSA of left coronary cusp (LCC) were significantly smaller than those of right coronary cusp (RCC) and non-coronary cusp (NCC) (both, P < 0.001) in all age groups. The mean ratios of RCC or NCC-to-LCC were 1.38 and 1.36 for CSV, 1.19 and 1.20 for CSA, and 1.21 and 1.06 for ICD, respectively. The CSV and ICD increased in older age with weak-to moderate correlation coefficients in both men and women. By multivariable linear regression, CSVs and ICDs of all cusps showed a positive correlation with age (P < 0.05), and the female gender was associated with a smaller size of the CSV and CSA. Conclusions: The LCC was significantly smaller than the other two cusps, and the aortic root size increased with age. PMID- 27461207 TI - Impact of age and sex on left ventricular function determined by coronary computed tomographic angiography: results from the prospective multicentre CONFIRM study. AB - Background: Left ventricular (LV) volumetric and functional parameters measured with cardiac computed tomography (cardiac CT) augment risk prediction and discrimination for future mortality. Gender- and age-specific standard values for LV dimensions and systolic function obtained by 64-slice cardiac CT are lacking. Methods and results: 1155 patients from the Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry (54.5% males, mean age 53.1 +/- 12.4 years, range: 18-92 years) without known coronary artery disease (CAD), structural heart disease, diabetes, or hypertension who underwent cardiac CT for various indications were categorized according to age and sex. A cardiac CT data acquisition protocol was used that allowed volumetric measuring of LV function. Image interpretation was performed at each site. Patients with significant CAD (>50% stenosis) on cardiac CT were excluded from the analysis. Overall, mean left ventricular ejection fraction (LVEF) was higher in women when compared with men (66.6 +/- 7.7% vs. 64.6 +/- 8.1%, P < 0.001). This gender difference in overall LVEF was caused by a significantly higher LVEF in women >=70 years when compared with men >=70 years (69.95 +/- 8.89% vs. 65.50 +/- 9.42%, P = 0.004). Accordingly, a significant increase in LVEF was observed with age (P = 0.005 for males and P < 0.001 for females), which was more pronounced in females (5.21%) than in males (2.6%). LV end-diastolic volume decreased in females from 122.48 +/- 27.87 (<40 years) to 95.56 +/- 23.17 (>70 years; P < 0.001) and in males from 155.22 +/- 35.07 (<40 years) to 130.26 +/- 27.18 (>70 years; P < 0.001). Conclusion: Our findings indicate that the LV undergoes a lifelong remodelling and highlight the need for age and gender adjusted reference values. PMID- 27461208 TI - Altered aortic shape in bicuspid aortic valve relatives influences blood flow patterns. AB - AIMS: Bicuspid aortic valve (BAV) is known to exhibit familial inheritance and is associated with aortopathy and altered aortic haemodynamics. However, it remains unclear whether BAV-related aortopathy can be inherited independently of valve morphology. METHODS AND RESULTS: Four-dimensional flow magnetic resonance imaging for the in vivo assessment of thoracic aortic 3D blood flow was performed in 24 BAV relatives with trileaflet aortic valves (age = 40 +/- 14 years) and 15 healthy controls (age = 37 +/- 10 years). Data analysis included aortic dimensions, shape (round/gothic/cubic), and 3D blood flow characteristics (semi quantitative vortex/helix grading and peak velocities). Cubic and gothic aortic shapes were markedly more prevalent in BAV relatives compared with controls (38 vs. 7%). Ascending aorta (AAo) vortex flow in BAV relatives was significantly increased compared with controls (grading = 1.5 +/- 1.0 vs. 0.6 +/- 0.9, P = 0.015). Aortic haemodynamics were influenced by aortic shape: peak velocities were reduced for gothic aortas vs. round aortas (P = 0.003); vortex flow was increased for cubic aortas in the AAo (P < 0.001) and aortic arch (P = 0.004); vortex and helix flows were elevated for gothic aortas in the AAo and descending aorta (P = 0.003, P = 0.029). Logistic regression demonstrated significant associations of shape with severity of vortex flow in AAo (P < 0.001) and aortic arch (P = 0.016) in BAV relatives. CONCLUSION: BAV relatives expressed altered aortic shape and increased vortex flow despite the absence of valvular disease or aortic dilatation. These data suggest a heritable component of BAV-related aortopathy affecting aortic shape and aberrant blood flow, independent of valve morphology. PMID- 27461209 TI - Prediction of fluoroscopic angulations for transcatheter aortic valve implantation by CT angiography: influence on procedural parameters. AB - Aims: Repeated angiograms to achieve an exactly orthogonal visualization of the aortic valve plane can substantially contribute to the total contrast amount required for transcatheter aortic valve implantation (TAVI). We investigated whether pre-procedural identification of an optimal fluoroscopic projection by cardiac computed tomography (CT) can significantly reduce the amount of a procedure-related contrast agent compared with angiographic determination of suitable angulations. Methods and results: Eighty consecutive patients (81 +/- 5 years, 55% male) with symptomatic severe aortic valve stenosis and normal renal function who underwent cardiac CT prior to TAVI were prospectively randomized. In 40 patients, a CT-predicted suitable angulation was used for the first aortic angiogram (CT cohort); in the other 40 patients, the first aortogram was acquired at LAO 10 degrees /cranial 10 (angiography cohort). Additional aortograms were performed if no satisfactory view of the aortic valve plane was obtained. The number of aortograms needed to achieve a satisfactory fluoroscopic projection (1.2 +/- 0.6 vs. 3.2 +/- 1.7; P < 0.001) and the total amount of contrast agent per TAVI procedure were significantly lower in the CT cohort (95 +/- 21 vs. 125 +/- 36 mL; P < 0.001). Incidence of acute kidney injury was not significantly different. There was no significant difference regarding radiation dose, time of procedure, degree of post-procedural aortic regurgitation, complications and 30 day mortality between the cohorts. Conclusion: Pre-procedural identification of a suitable fluoroscopic projection by cardiac CT significantly reduces a procedural contrast agent volume required for TAVI. PMID- 27461210 TI - Utility of adenosine stress perfusion CMR to assess paediatric coronary artery disease. AB - Aims: Cardiovascular magnetic resonance (CMR), using adenosine stress perfusion and late-gadolinium enhancement (LGE), is becoming the 'gold standard' non invasive imaging modality in the assessment of adults with coronary artery disease (CAD). However, despite its proved feasibility in paediatric patients, clinical utility has not been demonstrated. Therefore, this study aims to establish the role of adenosine stress perfusion CMR as a screening test in paediatric patients with acquired or congenital CAD. Methods and results: A total of 58 paediatric patients underwent 61 consecutive clinically indicated coronary artery assessments for diagnostic and clinical decision-making purposes. The diagnosis was based on X-ray or computed tomography coronary angiography for anatomy, adenosine stress CMR imaging for myocardial perfusion and LGE for tissue characterization. Two studies were aborted because of unwanted side effects of adenosine stress, thus 59 studies were completed in 56 patients [median age 14.1 years (interquartile range 10.9-16.2)]. When compared with coronary anatomical imaging, adenosine stress perfusion CMR performed as follows: sensitivity 100% (95% confidence interval, CI: 71.6-100%), specificity 98% (95% CI: 86.7-99.9%), positive predictive value (PPV) 92.9% (95% CI: 64.2-99.6%), and negative predictive value 100% (95% CI: 89.9-100%). Conclusion: In paediatric CAD, adenosine stress perfusion CMR imaging is adequate as an initial, non-invasive screening test for the identification of significant coronary artery lesions, with anatomical imaging used to confirm the extent of the culprit lesion. PMID- 27461211 TI - Association of global and local low endothelial shear stress with high-risk plaque using intracoronary 3D optical coherence tomography: Introduction of 'shear stress score'. AB - Aims: The association of low endothelial shear stress (ESS) with high-risk plaque (HRP) has not been thoroughly investigated in humans. We investigated the local ESS and lumen remodelling patterns in HRPs using optical coherence tomography (OCT), developed the shear stress score, and explored its association with the prevalence of HRPs and clinical outcomes. Methods and results: A total of 35 coronary arteries from 30 patients with stable angina or acute coronary syndrome (ACS) were reconstructed with three dimensional (3D) OCT. ESS was calculated using computational fluid dynamics and classified into low, moderate, and high in 3-mm-long subsegments. In each subsegment, (i) fibroatheromas (FAs) were classified into HRPs and non-HRPs based on fibrous cap (FC) thickness and lipid pool size, and (ii) lumen remodelling was classified into constrictive, compensatory, and expansive. In each artery the shear stress score was calculated as metric of the extent and severity of low ESS. FAs in low ESS subsegments had thinner FC compared with high ESS (89 +/- 84 vs.138 +/- 83 um, P < 0.05). Low ESS subsegments predominantly co-localized with HRPs vs. non-HRPs (29 vs. 9%, P < 0.05) and high ESS subsegments predominantly with non-HRPs (9 vs. 24%, P < 0.05). Compensatory and expansive lumen remodelling were the predominant responses within subsegments with low ESS and HRPs. In non-stenotic FAs, low ESS was associated with HRPs vs. non-HRPs (29 vs. 3%, P < 0.05). Arteries with increased shear stress score had increased frequency of HRPs and were associated with ACS vs. stable angina. Conclusion: Local low ESS and expansive lumen remodelling are associated with HRP. Arteries with increased shear stress score have increased frequency of HRPs and propensity to present with ACS. PMID- 27461212 TI - Non-invasive assessment of the haemodynamic significance of coronary stenosis using fusion of cardiac computed tomography and 3D echocardiography. AB - Aims: Abnormal computed tomography coronary angiography (CTCA) often leads to stress testing to determine haemodynamic significance of stenosis. We hypothesized that instead, this could be achieved by fusion imaging of the coronary anatomy with 3D echocardiography (3DE)-derived resting myocardial deformation. Methods and results: We developed fusion software that creates combined 3D displays of the coronary arteries with colour maps of longitudinal strain and tested it in 28 patients with chest pain, referred for CTCA (256 Philips scanner) who underwent 3DE (Philips iE33) and regadenoson stress CT. To obtain a reference for stenosis significance, coronaries were also fused with colour maps of stress myocardial perfusion. 3D displays were used to detect stress perfusion defect (SPD) and/or resting strain abnormality (RSA) in each territory. CTCA showed 56 normal arteries, stenosis <50% in 17, and >50% in 8 arteries. Of the 81 coronary territories, SPDs were noted in 20 and RSAs in 29. Of the 59 arteries with no stenosis >50% and no SPDs, considered as normal, 12 (20%) had RSAs. Conversely, with stenosis >50% and SPDs (haemodynamically significant), RSAs were considerably more frequent (5/6 = 83%). Overall, resting strain and stress perfusion findings were concordant in 64/81 arteries (79% agreement). Conclusions: Fusion of CTCA and 3DE-derived data allows direct visualization of each coronary artery and strain in its territory. In this feasibility study, resting strain showed good agreement with stress perfusion, indicating that it may be potentially used to assess haemodynamic impact of coronary stenosis, as an alternative to stress testing that entails additional radiation exposure. PMID- 27461213 TI - Hypersensitivity Events, Including Potentially Hypersensitivity-Related Skin Events, with Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis. AB - BACKGROUND: In patients with type 2 diabetes mellitus (T2DM), dapagliflozin improves glycemic control and has a safety profile typically related to its mechanism of action. Hypersensitivity adverse events (AEs) have been reported in some patients with sodium-glucose cotransporter 2 (SGLT2) inhibitors, including a recent report of dermatological AEs in Japan. METHODS: We investigated the frequency and characteristics of hypersensitivity AEs, including potentially hypersensitivity-related skin AEs, across 21 phase IIb/III trials of dapagliflozin (N = 5936) versus active or placebo comparators (N = 3403), including the subpopulation of Asian patients (N = 1563). RESULTS: Overall, AEs and serious AEs (SAEs) of hypersensitivity were infrequent and were reported in a similar proportion of patients with dapagliflozin versus active or placebo comparators (AEs: 4.5 vs. 4.3 %; SAEs: 0.2 vs. 0.1 %, respectively). The most common events affected the skin or subcutaneous tissue: rash (dapagliflozin: 1.1 %, comparator: 1.1 %), eczema (0.6, 0.8 %), dermatitis (0.5, 0.4 %), and urticaria (0.5, 0.2 %). Few patients discontinued as a result of hypersensitivity AEs (<=0.2 %). In patients of Asian descent, a lower frequency of hypersensitivity AEs was observed with dapagliflozin versus comparators (2.0 vs. 4.5 %). In the subset of placebo-controlled trials, hypersensitivity AEs were slightly more frequent with dapagliflozin than with placebo across the overall population (4.7 vs. 3.8 %), and less frequent with dapagliflozin in Asian patients (1.5 vs. 5.0 %). CONCLUSIONS: The findings of this post hoc analysis indicate that dapagliflozin does not lead to an increased risk of serious hypersensitivity reactions or potentially hypersensitivity-related skin events among patients with T2DM, including Asian patients. Long-term outcome studies and postmarketing surveillance will provide further information on hypersensitivity reactions with SGLT2 inhibitors. CLINICALTRIALS. GOV IDENTIFIERS: NCT01042977, NCT01031680, NCT00855166, NCT00984867, NCT01294423, NCT00673231, NCT00972244, NCT00680745, NCT00660907, NCT01095653, NCT00831779, NCT00976495, NCT00859898, NCT00736879, NCT00683878, NCT00663260, NCT00643851, NCT00528879, NCT00528372, NCT00357370, NCT00263276. PMID- 27461214 TI - Cytotoxicity of Manganese (III) Complex in Human Breast Adenocarcinoma Cell Line Is Mediated by the Generation of Reactive Oxygen Species Followed by Mitochondrial Damage. AB - Manganese (Mn) complexes are widely studied because of their important catalytic properties in synthetic and biochemical reactions. A Mn (III) complex of an amidoamine ligand was synthesized using a tetradentate amidoamine ligand. In this study, the Mn (III) complex was evaluated for its biological activity by measuring its cytotoxicity in human breast adenocarcinoma cell line (MCF-7). Cytotoxic effects of the Mn (III) complex were determined using established biomarkers in an attempt to delineate the mechanism of action and the utility of the complex as a potential anticancer drug. The Mn (III) complex induces cell death in a dose- and time-dependent manner as shown by microculture tetrazolium assay, a measure of cytotoxic cell death. Our results demonstrated that cytotoxic effects were significantly increased at higher concentrations of Mn (III) complex and with longer time of treatment. The IC50 (Inhibitor concentration that results in 50% cell death) value of Mn (III) complex in MCF-7 cells was determined to be 2.5 mmol/L for 24 hours of treatment. In additional experiments, we determined the Mn (III) complex-mediated cell death was due to both apoptotic and nonspecific necrotic cell death mechanisms. This was assessed by ethidium bromide/acridine orange staining and flow cytometry techniques. The Mn (III) complex produced reactive oxygen species (ROS) triggering the expression of manganese superoxide dismutase 1 and ultimately damaging the mitochondrial function as is evident by a decline in mitochondrial membrane potential. Treatment of the cells with free radical scavenger, N, N-dimethylthiourea decreased Mn (III) complex-mediated generation of ROS and attenuated apoptosis. Together, these results suggest that the Mn (III) complex-mediated MCF-7 cell death utilizes combined mechanism involving apoptosis and necrosis perhaps due to the generation of ROS. PMID- 27461215 TI - Can Intestinal Phosphate Binding or Inhibition of Hydroxyapatite Growth in the Vascular Wall Halt the Progression of Established Aortic Calcification in Chronic Kidney Disease? AB - Vascular calcification significantly contributes to mortality in chronic kidney disease (CKD) patients. Sevelamer and pyrophosphate (PPi) have proven to be effective in preventing vascular calcification, the former by controlling intestinal phosphate absorption, the latter by directly interfering with the hydroxyapatite crystal formation. Since most patients present with established vascular calcification, it is important to evaluate whether these compounds may also halt or reverse the progression of preexisting vascular calcification. CKD and vascular calcification were induced in male Wistar rats by a 0.75 % adenine low protein diet for 4 weeks. Treatment with PPi (30 or 120 umol/kg/day), sevelamer carbonate (1500 mg/kg/day) or vehicle was started at the time point at which vascular calcification was present and continued for 3 weeks. Hyperphosphatemia and vascular calcification developed prior to treatment. A significant progression of aortic calcification in vehicle-treated rats with CKD was observed over the final 3-week period. Sevelamer treatment significantly reduced further progression of aortic calcification as compared to the vehicle control. No such an effect was seen for either PPi dose. Sevelamer but not PPi treatment resulted in an increase in both osteoblast and osteoid perimeter. Our study shows that sevelamer was able to reduce the progression of moderate to severe preexisting aortic calcification in a CKD rat model. Higher doses of PPi may be required to induce a similar reduction of severe established arterial calcification in this CKD model. PMID- 27461216 TI - Efficacy of Osteoporosis Therapies in Diabetic Patients. AB - Diabetes is characterized by increased fracture risk and by reduced bone strength for a given density. Contributing factors may include lower bone turnover and accumulation of advanced glycation endproducts. There are concerns that the pharmacological therapies for osteoporosis, particularly anti-resorptive therapies that suppress bone turnover, may not be as effective in the setting of diabetes. This review considers clinical trials and observational studies that have assessed the efficacy of anti-resorptive and anabolic therapies in diabetic patients. Post hoc analyses of randomized trials indicate that raloxifene has similar efficacy for prevention of vertebral fractures in diabetic compared with non-diabetic patients. Evidence from randomized clinical trials is lacking for anti-fracture efficacy of other osteoporosis therapies in diabetes. However, observational studies suggest that bisphosphonates are effective in preventing fractures in diabetic patients. The great majority of diabetic patients in studies to date have been type 2, and efficacy of osteoporosis therapies in type 1 diabetic patients remains to be addressed. Further evaluation of the efficacy of osteoporosis therapies in the setting of diabetes is needed to provide optimal fracture prevention for this population. PMID- 27461217 TI - A multifaceted computational report on the variants effect on KIR2DL3 and IFNL3 candidate gene in HCV clearance. AB - HCV infection causes acute and chronic liver diseases including, cirrhosis and hepatocellular carcinoma. Following HCV infection, spontaneous clearance occurs in approximately 20 % of the population dependant upon HCV genotype. In this study, functional and non-functional variant analysis was executed for the classical and the latest HCV clearance candidate genes namely, KIR2DL3 and IFNL3. Initially, the functional effects of non-synonymous SNPs were assigned on exposing to homology based tools, SIFT, PolyPhen-2 and PROVEAN. Further, UTR and splice sites variants were scanned for the gene expression and regulation changes. Subsequently, the haplotype and CNV were also identified. The mutation H77Y of KIR2DL3 and R157Q, H156Y, S63L, R157W, F179V, H128R, T101M, R180C, and F176I of IFNL3 results in conservation, RMSD, total energy, stability, and secondary structures revealed a negative impact on the structural fitness. UTRscan and the splice site result indicate functional change, which may affect gene regulation and expression. The graphical display of selected population shows alleles like rs270779, rs2296370, rs10423751, rs12982559, rs9797797, and rs35987710 of KIR2DL3 and rs12972991, rs12980275, rs4803217, rs8109886, and rs8099917 of IFNL3 are in high LD with a measure of [Formula: see text] broadcasting its protective effect in HCV clearance. Similarly, CNV report suggests major DNA fragment loss that could have a profound impact on the gene expression affecting the overall phenotype. This roundup report specifies the effect of NK cell receptor, KIR2DL3 and IFNL3 variants that can have a better prospect in GWAS and immunogenetic studies leading to better understanding of HCV clearance and progression. PMID- 27461218 TI - Pro-survival responses to the dual inhibition of anti-apoptotic Bcl-2 family proteins and mTOR-mediated signaling in hypoxic colorectal carcinoma cells. AB - BACKGROUND: The use of targeted agents to impel dual inhibition of anti-apoptotic mechanisms and mTOR-mediated pro-survival signaling in colorectal carcinoma (CRC) cell lines with KRAS or BRAF mutation has been shown to induce apoptosis, a timely result given CRC entities harboring such mutations are in need of new therapies. Since CRC comprises heterogeneous tumors with predominant hypoxic components, we investigated effects of an inhibitor of anti-apoptotic Bcl-2 family proteins (ABT-737) in combination with an mTOR inhibitor (AZD8055) collectively referred to as combo-Rx, in hypoxic CRC cell lines. METHODS: Cell viability measures, expression of proteins implicated in apoptosis and MAPK/PI3K AKT/mTOR pathway signaling, and profiling of composite kinase activities were undertaken in a panel of 14 cell lines. RESULTS: In hypoxic conditions, combo-Rx suppressed viability of 13 of the cell lines, albeit ABT-737 did not significantly potentiate the inhibitory effect of single-agent AZD8055 in six of the models. Hypoxic KRAS/PIK3CA-mutant HCT-116 and HCT-15 cell lines (both with low endogenous expression of the anti-apoptotic Mcl-1 protein and showing augmented inhibition of viability following the addition of ABT-737 to AZD8055) responded to combo-Rx by induction of apoptosis but with the simultaneous strong Mcl-1 up-regulation and activation of MAPK/PI3K-conducted signaling. In contrast, in hypoxic KRAS-mutant LoVo (devoid of PIK3CA mutation), BRAF/PIK3CA-mutant RKO, and wild-type Colo320DM cell lines (all with high endogenous Mcl-1 expression and being resistant to the additional effect of ABT-737 to AZD8055), combo-Rx did not elicit apoptotic or pro-survival responses. CONCLUSIONS: The concurrent inhibition of anti-apoptotic proteins and mTOR-mediated signaling in hypoxic KRAS/PIK3CA-mutant CRC cell lines resulted in pro-survival responses in parallel with the intended anti-proliferative effects, a finding that should be of note if considering combinatory targeting of multiple pathways in this CRC entity. PMID- 27461220 TI - The evidence for applying Streptococcus salivarius 24SMB by nasal spray for preventing recurrent acute otitis media. PMID- 27461219 TI - Association of kidney structure-related gene variants with type 2 diabetes attributed end-stage kidney disease in African Americans. AB - African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D) attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P corr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P corr < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D attributed ESKD in the AA population. PMID- 27461221 TI - Impact of malignancy on Clostridium difficile infection. AB - PURPOSE: The purpose of this study was to investigate the impact of malignancy and chemotherapy on the clinical and microbiological characteristics of Clostridium difficile infections (CDI). METHODS: CDI patients with a history of malignancy within 5 years were defined as the cancer group. The characteristics of the patients were compared according to the presence of malignancy. RESULTS: Of 580 patients with CDI, 159 (27.4 %) belonged to the cancer group and 421 (72.6 %) to the non-cancer group. More of the patients in the cancer group than those in the non-cancer group had been hospitalized within the prior 2 months (P < 0.001). Leukocytosis was more common in the non-cancer group (P = 0.034), while infection by PCR ribotype 017 strains was more common in the cancer group, with marginal significance (P = 0.07). Recurrence was more frequent in the cancer group (20.4 % vs. 9.5 %, P =0.005) and cancer was an independent risk factor for recurrence of CDI (OR = 2.66, 95 % CI 1.34-5.29, P =0.005). Age also contributed to the recurrence of CDI (OR = 1.03, 95 % CI 1.00-1.06, P =0.026). CONCLUSIONS: Malignancy and age are independent risk factors for recurrence of CDI. Cancer patients require careful observation for recurrence after treatment of CDI. PMID- 27461223 TI - Ultrasonography features of medullary thyroid cancer as predictors of its biological behavior. AB - Background Although there are many well-known prognostic predictors of medullary thyroid carcinoma (MTC), the ultrasonography (US) findings of MTC have not been sufficiently validated in this regard. Purpose To investigate the US findings of MTC and their relationship with the biological behavior of MTC. Material and Methods The US findings and clinical and pathology records of 123 MTC nodules from 108 patients were retrospectively analyzed at two tertiary referral hospitals. MTCs were classified according to US findings, i.e. MTC with benign (B MTC) and malignant US findings (M-MTC). We then compared the clinical and pathology findings between the two groups. Results Eighty-two M-MTCs (66.7%) and 41 B-MTCs (33.3%) were identified. M-MTCs showed a significantly higher prevalence of lateral lymph node metastases as well as extrathyroidal and extranodal extension (all P < 0.05). M-MTCs larger than 1 cm showed a significantly higher prevalence of multifocality, recurrence, extrathyroidal and extranodal extension than B-MTCs larger than 1 cm in the largest dimension (all P < 0.05). Tumors > 1 cm were more likely to be B-MTC and one-third of all MTCs had benign US features. The common findings of B-MTC included a solid, ovoid to round shape, with a smooth margin, hypoechogenicity, and without calcification. Conclusion The biological behavior of M-MTCs results in poorer outcomes than that of B-MTCs. PMID- 27461224 TI - Contrast-enhanced ultrasound (CEUS) in assessing early response among patients with invasive breast cancer undergoing neoadjuvant chemotherapy. AB - Background One of the big challenges in onco-radiology is to find a reliable imaging method that may predict early response during the first cycles of any neoadjuvant chemotherapy. Purpose To evaluate the use of real-time harmonic contrast-enhanced ultrasound (CEUS) in predicting early response in breast cancer tumors under neoadjuvant chemotherapy (NAC) treatment. Material and Methods Nineteen consecutive patients with invasive breast cancer were evaluated with a bolus dose of 2.4 mL contrast agent using CEUS, before and after two cycles of epirubicin and docetaxel. The lognormal function was used for quantitative analysis of kinetic data to evaluate early response. Results There was statistically significant difference in time-to-peak ( tp) between responders and non-responders (two sample t-test, P = 0.027) where tp was significantly longer at the week 5 than at the baseline scan among responders when compared to non responders. Conclusion In-flow of intravascular contrast agent in tumors is significantly slower in responders at real-time harmonic CEUS, and might be effectively used for the evaluation of early response to chemotherapy in invasive breast cancer. However, further investigations in a larger and more heterogeneous population should be performed to corroborate the reliability of the method. PMID- 27461225 TI - The role of PAQR3 gene promoter hypermethylation in breast cancer and prognosis. AB - PAQR3 is a tumor suppressor in breast cancer and its expression regulation mechanism has not been well elucidated. In this study, we found that PAQR3 expression was downregulated in breast cancer tissues, and the downregulation of PAQR3 expression was found to be significantly associated with aberrant methylation of the gene promoter. Methylation-specific PCR showed that hypermethylation of the PAQR3 gene was observed in 71.8% of the breast cancers, whereas it was found in only 28.2% of the corresponding non-tumor tissues. Moreover, we found that the PAQR3 promoter methylation status was related to lymph node metastasis (P=0.01). In addition, overexpression of PAQR3 inhibited breast cancer cell invasion and growth. Furthermore, PAQR3 expression was restored in MCF-7 cells after treatment with the demethylating agent, 5-aza-2' deoxycytidine, and the effect of demethylation induced invasion and proliferation suppression of MCF-7 cells. Collectively, our results suggested that the aberrant methylation of PAQR3 underlies its downregulation in breast cancer and our data indicated that epigenetic silencing of PAQR3 gene expression by promoter hypermethylation may play an important role in breast cancer. PMID- 27461226 TI - The B-cell compartment in antibody-deficient infants and young children - developing common variable immunodeficiency or transient immune maturation? AB - BACKGROUND: Hypogammaglobulinemia in early childhood is a common feature characterized by distinct intrinsic and extrinsic factors leading to disturbed peripheral blood lymphocyte homeostasis. Detailed flow cytometric immunophenotyping of the peripheral blood B cell compartment is an informative tool for delineating disturbed generation of B cell subpopulations crucial for the diagnosis of hypogammaglobulinemia in young children. METHODS: We analyzed by flow cytometry the proportions and absolute values of total, naive, memory - non switched and switched, transitional and immature B lymph cells as well as plasmablasts in the peripheral blood of 50 hypogammaglobulinemic children aged from 3 to 50 months. RESULTS: Beyond physiological, age-related changes within the B cell pool, a proportion of children manifested defective differentiation into switched memory and accumulation of CD21lo immature B cells. CONCLUSIONS: Dynamic shifts within B cell subpopulations of the immature immune system being most prominent during the first two years of life contribute to the age-related developmental abnormalities of the B cell compartment. Therefore, a reliable diagnosis of common variable immunodeficiency (CVID) in young hypogammaglobulinemic children cannot yet be established despite their clinical and immunological phenotypes sharing common features with this primary immunodeficiency. PMID- 27461227 TI - Air breathing and aquatic gas exchange during hypoxia in armoured catfish. AB - Air breathing in fish is commonly believed to have arisen as an adaptation to aquatic hypoxia. The effectiveness of air breathing for tissue O2 supply depends on the ability to avoid O2 loss as oxygenated blood from the air-breathing organ passes through the gills. Here, we evaluated whether the armoured catfish (Hypostomus aff. pyreneusi)-a facultative air breather-can avoid branchial O2 loss while air breathing in aquatic hypoxia, and we measured various other respiratory and metabolic traits important for O2 supply and utilization. Fish were instrumented with opercular catheters to measure the O2 tension (PO2) of expired water, and air breathing and aquatic respiration were measured during progressive stepwise hypoxia in the water. Armoured catfish exhibited relatively low rates of O2 consumption and gill ventilation, and gill ventilation increased in hypoxia due primarily to increases in ventilatory stroke volume. Armoured catfish began air breathing at a water PO2 of 2.5 kPa, and both air-breathing frequency and hypoxia tolerance (as reflected by PO2 at loss of equilibrium, LOE) was greater in individuals with a larger body mass. Branchial O2 loss, as reflected by higher PO2 in expired than in inspired water, was observed in a minority (4/11) of individuals as water PO2 approached that at LOE. Armoured catfish also exhibited a gill morphology characterized by short filaments bearing short fused lamellae, large interlamellar cell masses, low surface area, and a thick epithelium that increased water-to-blood diffusion distance. Armoured catfish had a relatively low blood-O2 binding affinity when sampled in normoxia (P50 of 3.1 kPa at pH 7.4), but were able to rapidly increase binding affinity during progressive hypoxia exposure (to a P50 of 1.8 kPa). Armoured catfish also had low activities of several metabolic enzymes in white muscle, liver, and brain. Therefore, low rates of metabolism and gill ventilation, and a reduction in branchial gas-exchange capacity, may help minimize branchial O2 loss in armoured catfish while air breathing in aquatic hypoxia. PMID- 27461228 TI - Pyosalpinx causing acute appendicitis in a 32-year-old Cameroonian female: a case report. AB - BACKGROUND: Pyosalpinx as a cause of acute appendicitis is very rare. We report the first case of a right pyosalpinx causing an extrinsic compression of the appendiceal lumen and consequently an acute appendicitis following an obstruction. CASE PRESENTATION: A 32 year old female from the North west region of Cameroon, presented with an acute exacerbation of a mild chronic right iliac fossa pain over a 2 day duration. She underwent exploratory laparotomy and intraoperative findings were a bilateral pyosalpinx, with the right fallopian tube adhering to the caecum and the terminal ileum, and obstructing the lumen of an inflammed appendix. A classical appendectomy and a right salpingectomy were done. The post-operative period was uneventful and she returned after 2 weeks for a follow-up visit with no further complaints. CONCLUSION: We describe to the best of our knowledge, the first case of an acute appendicitis caused by an extrinsic obstruction of the appendiceal lumen by a pyosalpinx. The close proximity of the caecum to the right fallopian tube most likely accounted for this occurrence. Although a rare entity, physicians should always keep in mind very rare causes of an acute appendicitis to guide management. This case highlights the shortcomings of pelvic ultrasonography in the diagnosis this condition. A pelvic computed tomography scanning should therefore be sought in case of a doubtful pelvic ultrasonography result. Finally, there is an urgent need to improve the awareness on sexually transmitted infections in our setting. PMID- 27461229 TI - Incidence of tuberculosis among school-going adolescents in South India. AB - BACKGROUND: Tuberculosis (TB) incidence data in vaccine target populations, particularly adolescents, are important for designing and powering vaccine clinical trials. Little is known about the incidence of tuberculosis among adolescents in India. The objective of current study is to estimate the incidence of pulmonary tuberculosis (PTB) disease among adolescents attending school in South India using two different surveillance methods (active and passive) and to compare the incidence between the two groups. METHODS: The study was a prospective cohort study with a 2-year follow-up period. The study was conducted in Palamaner, Chittoor District of Andhra Pradesh, South India from February 2007 to July 2010. A random sampling procedure was used to select a subset of schools to enable approximately 8000 subjects to be available for randomization in the study. A stratified randomization procedure was used to assign the selected schools to either active or passive surveillance. Participants who met the criteria for being exposed to TB were referred to the diagnostic ward for pulmonary tuberculosis confirmation. A total number of 3441 males and 3202 females between the ages 11 and less than 18 years were enrolled into the study. RESULTS: Of the 3102 participants in the active surveillance group, four subjects were diagnosed with definite tuberculosis, four subjects with probable tuberculosis, and 71 subjects had non-tuberculous Mycobacteria (NTM) isolated from their sputum. Of the 3541 participants in the passive surveillance group, four subjects were diagnosed with definite tuberculosis, two subjects with probable tuberculosis, and 48 subjects had non-tuberculosis Mycobacteria isolated from their sputum. The incidence of definite + probable TB was 147.60 / 100,000 person years in the active surveillance group and 87 / 100,000 person years in the passive surveillance group. CONCLUSION: The incidence of pulmonary tuberculosis among adolescents in our study is lower than similar studies conducted in South Africa and Eastern Uganda - countries with a higher incidence of tuberculosis and human immunodeficiency virus (HIV) than India. The study data will inform sample design for vaccine efficacy trials among adolescents in India. PMID- 27461230 TI - From the Medical Board of the National Psoriasis Foundation: Perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis. AB - Treatment with systemic immunomodulatory agents is indicated for patients with moderate to severe plaque psoriasis and psoriatic arthritis. In these patients, surgery may confer an increased risk of infectious or surgical complications. We conducted a literature review to examine studies addressing the use of methotrexate, cyclosporine, and targeted immunomodulatory agents (tumor necrosis factor-alfa inhibitors, interleukin [IL]-12/23 inhibitors, IL-17 inhibitors) in patients undergoing surgery. We examined 46 total studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. One study in patients with psoriasis and psoriatic arthritis reviewed 77 procedures and did not find an elevated risk of postoperative complications with tumor necrosis factor-alfa and IL-12/23 inhibitors even with major surgeries. Based on level III evidence, infliximab, adalimumab, etanercept, methotrexate, and cyclosporine can be safely continued through low-risk operations in patients with psoriasis and psoriatic arthritis. For moderate- and high-risk surgeries, a case-by-case approach should be taken based on the patient's individual risk factors and comorbidities. PMID- 27461231 TI - Recommendations of "not-to-do": Proposals of the Spanish Association of Surgeons to the project "Commitment to quality of scientific societies". AB - INTRODUCTION: The initiative of the Spanish Ministry of Health "Commitment to quality of scientific societies", aims to reduce unnecessary interventions of healthcare professionals. METHODS: The Spanish Association of Surgeons has selected 22 experts from the different sections that have participated in the identification of 26 proposals "do not do" to be ordered by the expected impact its implementation would have according to the GRADE methodology. From these proposals, the Delphi technique was used to select 5 recommendations presented in more detail in this article. RESULTS: The 5 selected recommendations are: Do not perform cholecystectomy in patients with asymptomatic cholelithiasis; do not keep bladder catheterization more than 48hours; do not extend antibiotic prophylaxis treatments more than 24hours after a surgical procedure; do not perform routine antibiotic prophylaxis for uncomplicated clean and no prosthetic surgery; and do not use antibiotics postoperatively after uncomplicated appendicitis. CONCLUSION: The Spanish Association of Surgeons's participation in this campaign has allowed a reflection on those activities that do not add value in the field of surgery and it is expected that the spread of this process serves to reduce its performance. PMID- 27461232 TI - Response to treatment and interval to surgery after preoperative short-course radiotherapy in rectal cancer. AB - INTRODUCTION: Preoperative short-course radiotherapy with immediate surgery improves local control in patients with rectal cancer. Tumor responses are smaller than those described with radiochemotherapy. Preliminary data associate this lower response to the short period until surgery. The aim of this study is to analyze the response to preoperative short-course radiotherapy and its correlation with the interval to surgery especially analyzing patients with mesorectal fascia involvement. METHODS: A total of 155 patients with locally advanced rectal cancer treated with preoperative radiotherapy (5*5Gy) were retrospectively analyzed. Tumor response in terms of rates of complete pathological response, downstaging, tumor regression grading and status of the circumferential resection margin were quantified. RESULTS: The mean interval from radiotherapy to surgery was 23 days. The rate of complete pathological response was 2.2% and 28% experienced downstaging (stage decreased). No differences between these rates and interval to surgery were detected. Eighty-eight patients had magnetic resonance imaging for staging (in 31 patients the mesorectal fascia was involved).The mean time to surgery in patients with involvement of the fascia and R0 surgery was 27 days and 16 days if R1 (P=.016). The cutoff of 20 days reached the highest probability of achieving a free circumferential resection margin between patients with mesorectal fascia involvement, with no statistically significant differences: RR 3.036 95% CI=(0.691-13.328), P=.06. CONCLUSIONS: After preoperative short-course radiotherapy, an interval>20 days enhances the likelihood of achieving a free circumferential resection margin in patients with mesorectal fascia involvement. PMID- 27461233 TI - What to do with an intraductal papilary mucinous pancreatic neoplasm? Our experience. AB - INTRODUCTION: Cystic pancreatic neoplasms are a heterogeneous group of pathology, and intraductal papillary mucinous neoplasia is becoming more common. The aim of this study is to review our series of cystic pancreatic neoplasms that underwent surgery and to evaluate the similarities with Fukuoka recommendations. METHODS: Retrospective review of our experience analyzing clinical and radiological data, indication for surgery and pathology study of 11 patients operated on in our centre from july 2011 to july 2015, aiming to evaluate the degree of agreement with the current consensus. RESULTS: In our series the majority of cases (7/11) had symptoms at diagnosis. Preoperative diagnosis was achieved in 10 patients using radiology and/or endoscopy. Indications for surgery were the presence of symptoms, radiological data suspicious of malignancy, and secondary branch neoplasia over 30mm. Pathological findings were malignancy in 6/11 cases (2 invasive neoplasia, 4 high grade dysplasia), moderate dysplasia in 2/11, low grade dysplasia in 2/11 and no dysplasia in one patient. CONCLUSIONS: Surgical indication of intraductal mucinous pancreatic neoplasms depends on the associated symptoms, size, location, risk and suspicion of malignancy. PMID- 27461234 TI - Questioning glucose measurements used in the International Diabetes Federation (IDF) Atlas. PMID- 27461235 TI - Platelet activation risk index as a prognostic thrombosis indicator. AB - Platelet activation in blood flow under high, overcritical shear rates is initiated by Von Willebrand factor. Despite the large amount of experimental data that have been obtained, the value of the critical shear rate, above which von Willebrand factor starts to activate platelets, is still controversial. Here, we recommend a theoretical approach to elucidate how the critical blood shear rate is dependent on von Willebrand factor size. We derived a diagram of platelet activation according to the shear rate and von Willebrand factor multimer size. We succeeded in deriving an explicit formula for the dependence of the critical shear rate on von Willebrand factor molecule size. The platelet activation risk index was introduced. This index is dependent on the flow conditions, number of monomers in von Willebrand factor, and platelet sensitivity. Probable medical applications of the platelet activation risk index as a universal prognostic index are discussed. PMID- 27461236 TI - A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14. AB - OBJECTIVE: More than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA. METHODS: 906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations. RESULTS: 43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1*10-4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5*10-7). Such association appeared to be independent of HLA-B27. CONCLUSIONS: We report here for the first time a family based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association. PMID- 27461237 TI - Emergency Department and Inpatient Healthcare utilization due to Hypertension. AB - BACKGROUND: Hypertension is one of the commonest chronic diseases, yet limited data are available for related health care utilization. Our study objective was to describe the emergency department (ED) and subsequent hospitalization related health care utilization and charges due to hypertension in the U.S. METHODS: We used the National ED sample (NEDS) to study hypertension-related utilization and charges. Multivariable-adjusted linear or logistic regression was used to assess hypertension-associated ED and hospitalization outcomes (disposition, length of stay, charges), adjusted for patient demographic, comorbidity and hospital characteristics. RESULTS: There were 0.92, 0.97 and 1.04 million ED visits (0.71 0.77 % of all ED visits) with hypertension as the primary diagnosis in 2009, 2010 and 2012, respectively; 23 % resulted in hospitalization. ED charges were $2.00, $2.27 and $2.86 billion, and for those hospitalized, total charges (ED plus inpatient) were $6.62, $7.09 and $7.94 billion, in 2009, 2010 and 2012, respectively. Older age (50 to 65 years), female sex, metropolitan area residence, South or West U.S. hospital location, private insurance and the presence of congestive heart failure were each associated with higher charges for an ED visit with hypertension as the primary diagnosis. Younger age, metropolitan residence, Medicaid insurance, hospital location in the Northeast and co-existing diabetes, gout, coronary heart disease, chronic obstructive pulmonary disease, hyperlipidemia and osteoarthritis were associated with higher risk, whereas male sex was associated with lower risk of hospitalization after ED visit for hypertension. In 2012, 71.6 % of all patients hospitalized with hypertension as the primary diagnosis were discharged home. Older age, metropolitan residence and most comorbidities were associated with lower odds, whereas male sex, payer other than Medicare, South or West U.S. hospital location were associated with higher odds of discharge to home. CONCLUSIONS: Hypertension is associated with significant healthcare burden in the U.S. Future studies should assess strategies to reduce hypertension-associated cost and health care burden. PMID- 27461238 TI - Study of the ambient air metallic elements Cr, Cu, Zn, Cd and Pb at HAF sampling sites. AB - This study characterized diurnal variations in the compositions of total suspended particulates (TSP) and dry deposits of particulates from ambient air, and the metallic elements that are contained in them at harbor, airport and farmland (HAF) sampling sites from August, 2013 to July, 2014. Two-way ANOVA of the amounts of metallic elements in the TSP and dry deposits was carried out in all four seasons at the HAF sampling sites. The metallic elements Cr and Cu originated in local emission sources at the airport. Metallic elements Zn and Pb originated in local emission sources at the harbor. Finally, metallic element Cd originated in local emissions form farmland. The following results were also obtained. (1) The metallic composition of the TSP differed significantly from that of the dry deposits in all four seasons at the harbor and farmland sampling sites, but not at the airport sampling site. (2) High correlations coefficients were found between the amounts of metallic elements Cr and Cu in the TSP and those in the dry deposits at the airport sampling site. (3) Pb was present in the TSP and the dry deposits at the harbor sampling site. PMID- 27461239 TI - Determination of critical quality attributes for monoclonal antibodies using quality by design principles. AB - Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody. This chapter describes the identification of critical quality attributes (CQAs) as an important first step for QbD development of biopharmaceuticals. A systematic scientific based risk ranking and filtering approach allows a thorough understanding of quality attributes and an assignment of criticality for their impact on drug safety and efficacy. To illustrate the application of the approach and tools, a few examples from monoclonal antibodies are shown. The identification of CQAs is a continuous process and will further drive the structure and function characterization of therapeutic proteins. PMID- 27461240 TI - Use of flagellin and cholera toxin as adjuvants in intranasal vaccination of mice to enhance protective immune responses against uropathogenic Escherichia coli antigens. AB - Urinary tract infections (UTIs) caused by Uropathogenic Escherichia coli (UPEC) are among the most common infections in human. Antibiotics are common therapy for UTIs, but increase in antibiotic resistance will complicate future treatment of the infections, making the development of an efficacious UTI vaccine more urgent. In this study, we have evaluated intranasally the efficacy of FliC and FimH antigens of UPEC in different vaccine formulations with and without cholera toxin (CT) adjuvant. Immunization of mice with FliC in fusion form or admixed with FimH elicited higher levels of serum, mucosal and cell-mediated responses than FimH alone. Furthermore, the use of CT in synergism with FliC resulted in the stimulation of a mixed Th1 and Th2 responses against FimH and FliC as antigen and maintained the antibody responses for at least 24 weeks following the last vaccine dose. Of the vaccine preparations, Fusion, Fusion + CT, and FimH admixed with FliC and CT showed the best protection against UPEC. These data indicated that intranasal administration of a FliC and CT adjuvant-based vaccine has the potential to provide protective responses against UPEC strains. PMID- 27461241 TI - Probe-free and sensitive detection of diarrhea-causing pathogens using RT-PCR combined high resolution melting analysis. AB - Rapid and sensitive diagnostic methods are needed to help physicians make faster and better treatment decision for patients suffered from diarrhea. In the present study, a probe-free and sensitive RT-PCR combined high resolution melting analysis (HRMA) assay was established successfully for the detection of four major diarrhea-causing pathogens. The lower limit of detection of the assay were 10(0), 10(2), 10(0) and 10(3) copies/reaction for rotaviruses group A, astroviruses serotype 1, noroviruses genogroup II, and sapoviruses genegroup I, respectively, which were 1000-fold, 10-fold, 1000-fold and 10-fold more sensitive than conventional RT-PCR assay developed in parallel and comparable to or higher than commercially available real-time RT-PCR assay. Blinded sample evaluation showed that the assay was 100% concordant to both conventional RT-PCR and commercial real-time RT-PCR, indicating high reliability of the new assay. Therefore, the assay could provide a valuable platform for the probe-free and sensitive diagnosis of these pathogens. PMID- 27461242 TI - Hepatitis E virus derived from different sources exhibits different behaviour in virus inactivation and/or removal studies with plasma derivatives. AB - Hepatitis E virus (HEV) causes viral hepatitis, and is considered a risk factor for blood products. Although some HEV inactivation/removal studies have been reported, detailed investigations of different manufacturing steps as heat treatment, partitioning during cold ethanol fractionation, low pH treatment, and virus filtration have yet to be reported for plasma-derived medicinal products. In this study, human serum- and swine faeces-derived HEVs, with and without detergent treatment, were used. The kinetic patterns of inactivation, log reduction value, or partitioning during the process were evaluated. In addition, the mouse encephalomyocarditis virus (EMCV) and canine and porcine parvoviruses (CPV/PPV) were also evaluated as model viruses for HEV. Small pore size (19 or 15 nm) virus filtration demonstrated effective removal of HEV. Middle pore size (35 nm) virus filtration and 60 degrees C liquid heating demonstrated moderate inactivation/removal. Ethanol fractionation steps demonstrated limited removal of HEV. Unpurified HEV exhibited different properties than the detergent-treated HEV, and both forms displayed differences when compared with EMCV, CPV, and PPV. Limited or no inactivation of HEV was observed during low pH treatment. Untreated plasma-derived HEV from humans showed different properties compared to that of HEV treated with detergent or derived from swine faeces. Therefore, HEV spike preparation requires more attention. PMID- 27461243 TI - Statistical approaches for identifying heavy users of inpatient mental health services. AB - BACKGROUND: A lack of consensus exists concerning how to identify "heavy users" of inpatient mental health services. AIM: To identify a statistical approach that captures, in a clinically meaningful way, "heavy" users of inpatient services using number of admissions and total time spent in hospital. METHODS: "Simple" statistical methods (e.g. top 2%) and data driven methods (e.g. the Poisson mixture distribution) were applied to admissions made to adult acute services of a London mental health trust. RESULTS: The Poisson mixture distribution distinguished "frequent users" of inpatient services, defined as having 4 + admissions in the study period. It also distinguished "high users" of inpatient services, defined as having 52 + occupied bed days. Together "frequent" and "high" users were classified as "heavy users". CONCLUSIONS: Data driven criteria such as the Poisson mixture distribution can identify "heavy" users of inpatient services. The needs of this group require particular attention. PMID- 27461244 TI - miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway. AB - Hepatocellular carcinoma (HCC) is a highly vascularized tumor and the third ranking contributor of tumor-associated death. Our previous study corroborated the inhibitory roles of miRNA-451 (miR-451) in HCC cell growth and invasion. However, its effect on angiogenesis in HCC remains poorly elucidated. In this study, overexpression of miR-451 clearly attenuated the promoting effects of HCC cells on cell proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, ectopic expression of miR-451 also attenuated tumor growth and angiogenesis in nude mice. In vitro, the expression of IL-6 receptor (IL-6R) was reduced and identified as a direct target of miR-451 by bioinformatics and a dual-firefly luciferase reporter assay. Moreover, upregulation of IL-6R strikingly ameliorated the inhibitory function of conditioned medium from miR-451-transfected HCC cells in HUVEC proliferation, migration and tube formation. Further mechanistic assay substantiated that miR 451 restrained vascular endothelial growth factor (VEGF) production of HCC cells by targeting IL-6R-STAT3 signaling as evidenced that IL-6R upregulation induced the increase in VEGF levels and interrupting signal transducer and activator of transcription 3 (STAT3) signaling with ectopic expression of dominant-negative STAT3 (STAT3D) markedly decreased VEGF expression. Additionally, conditioned medium of miR-451-overexpressed HCC also impaired the VEGF receptor 2 (VEGFR2) signaling in HUVECs. Accordingly, miR-451 may function as a potential suppressor of tumor angiogenesis in HCC by targeting IL-6R-STAT3-VEGF signaling, suggesting a promising therapeutic avenue for managing HCC. PMID- 27461245 TI - Predictors for vascular cognitive impairment in stroke patients. AB - BACKGROUND: Around two thirds stroke patients may suffer from vascular cognitive impairment (VCI). Our previous study has validated the NINDS-CSN harmonization standard for VCI diagnosis in Chinese. In this study, we aimed to investigate the predictors for VCI in Chinese post-stroke patients. METHODS: We compared epidemiological, clinical, and neuroimaging data (number, size and location of acute infarcts and lacunes, severities of white matter hyperintensities and brain atrophy) between stroke patients with and without VCI. Univariate and logistic regression analyses were utilized to determine VCI predictors. RESULTS: Fifty-six consecutive patients (age, 63.8 +/- 8.3 years; female, 37.5%) were recruited at a mean interval of 7.1 months after stroke onset, and 31 (55.4%) patients were diagnosed with VCI based on a validated 60-min neuropsychological battery. VCI patients were older (p = 0.023), less educated (p = 0.001), more likely to be female (p < 0.001), had a recurrent stroke (p = 0.028), and described higher apathy (p = 0.022) and worse pre-stroke cognition (p = 0.048) than cognitively normal patients. Lower educational level (adjusted odds ratio [OR] 0.750, 95% confidence interval [CI], 0.573-0.981; p = 0.035), female sex (adjusted OR 8.288, 95% CI, 1.522-45.113; p = 0.014), recurrent stroke (adjusted OR 11.327, 95% CI, 1.335-96.130, p = 0.026), and global cortical atrophy (adjusted OR 5.730, 95% CI, 1.128-29.101, p = 0.035) were independently associated with VCI in post-stroke patients. CONCLUSIONS: Lower education, female sex, recurrent stroke and global cortical atrophy were associated with VCI in Chinese stroke patients. PMID- 27461246 TI - Rice Varieties in Archaic East Asia: Reduction of Its Diversity from Past to Present Times. AB - The Asian cultivated rice, Oryza sativa, is one of the most important crops feeding more than a third of global population. In spite of the studies for several decades, the origin and domestication history of rice varietal groups, japonica and indica, have not been fully unveiled. Genetic information of ancient rice remains is essential for direct and exclusive insight into the domestication history of rice. We performed ancient DNA analysis of 950- to 2,800-year-old rice remains excavated from Japan and Korea. We found the presence of both japonica- and indica-type varieties in the Yayoi period and the middle ages of Japan and the middle part of Korea Peninsula 2,000 years ago. It is popularly considered that japonica has been exclusively cultivated in northern part of East Asia including Japan and Korea. Our result disclosed unexpectedly wide diversity of rice varieties in archaic East Asia. The present results from ancient rice DNA reveal an exclusive insight for the domestication history of rice which is not provided as far as contemporary rice. PMID- 27461247 TI - The clinical significance of snail protein expression in gastric cancer: a meta analysis. AB - BACKGROUND: Snail is a typical transcription factor that could induce epithelial mesenchymal transition (EMT) and cancer progression. There are some related reports about the clinical significance of snail protein expression in gastric cancer. However, the published results were not completely consistent. This study was aimed to investigate snail expression and clinical significance in gastric cancer. RESULTS: A systematic review of PubMed, CNKI, Weipu, and Wanfang database before March 2015 was conducted. We established an inclusion criterion according to subjects, method of detection, and results evaluation of snail protein. Meta analysis was conducted using RevMan4.2 software. And merged odds ratio (OR) and 95 % CI (95 % confidence interval) were calculated. Also, forest plots and funnel plot were used to assess the potential of publication bias. A total of 10 studies were recruited. The meta-analysis was conducted to evaluate the positive rate of snail protein expression. OR and 95 % CI for different groups were listed below: (1) gastric cancer and para-carcinoma tissue [OR = 6.15, 95 % CI (4.70, 8.05)]; (2) gastric cancer and normal gastric tissue [OR = 17.00, 95 % CI (10.08, 28.67)]; (3) non-lymph node metastasis and lymph node metastasis [OR = 0.40, 95 % CI (0.18, 0.93)]; (4) poor differentiated cancer, highly differentiated cancer, and moderate cancer [OR = 3.34, 95 % CI (2.22, 5.03)]; (5) clinical stage TI + TII and stage TIII + TIV [OR = 0.38, 95 % CI (0.23, 0.60)]; (6) superficial muscularis and deep muscularis [OR = 0.18, 95 % CI (0.11, 0.31)]. CONCLUSIONS: Our results indicated that the increase of snail protein expression may play an important role in the carcinogenesis, progression, and metastasis of gastric cancer. And this result might provide instruction for the diagnosis, therapy, and prognosis of gastric cancer. PMID- 27461248 TI - ADAMTSL5 is upregulated in melanoma tissues in patients with idiopathic psoriasis vulgaris induced by nivolumab. PMID- 27461249 TI - Validity of a new assessment rubric for a short-answer test of clinical reasoning. AB - BACKGROUND: The validity of high-stakes decisions derived from assessment results is of primary concern to candidates and certifying institutions in the health professions. In the field of orthopaedic manual physical therapy (OMPT), there is a dearth of documented validity evidence to support the certification process particularly for short-answer tests. To address this need, we examined the internal structure of the Case History Assessment Tool (CHAT); this is a new assessment rubric developed to appraise written responses to a short-answer test of clinical reasoning in post-graduate OMPT certification in Canada. METHODS: Fourteen physical therapy students (novices) and 16 physical therapists (PT) with minimal and substantial OMPT training respectively completed a mock examination. Four pairs of examiners (n = 8) participated in appraising written responses using the CHAT. We conducted separate generalizability studies (G studies) for all participants and also by level of OMPT training. Internal consistency was calculated for test questions with more than 2 assessment items. Decision studies were also conducted to determine optimal application of the CHAT for OMPT certification. RESULTS: The overall reliability of CHAT scores was found to be moderate; however, reliability estimates for the novice group suggest that the scale was incapable of accommodating for scores of novices. Internal consistency estimates indicate item redundancies for several test questions which will require further investigation. CONCLUSION: Future validity studies should consider discriminating the clinical reasoning competence of OMPT trainees strictly at the post-graduate level. Although rater variance was low, the large variance attributed to error sources not incorporated in our G studies warrant further investigations into other threats to validity. Future examination of examiner stringency is also warranted. PMID- 27461250 TI - Prospective Analysis in GIST Patients on the Role of Alpha-1 Acid Glycoprotein in Imatinib Exposure. AB - BACKGROUND: For imatinib, a relationship between systemic exposure and clinical outcome has been suggested. Importantly, imatinib concentrations are not stable and decrease over time, for which several mechanisms have been suggested. In this study, we investigated if a decrease in alpha-1 acid glycoprotein (AGP) is the main cause of the lowering in imatinib exposure over time. METHODS: We prospectively measured imatinib trough concentration (C min) values in 28 patients with gastrointestinal stromal tumours, at 1, 3 and 12 months after the start of imatinib treatment. At the same time points, AGP levels were measured. RESULTS: Overall, imatinib C min and AGP levels were correlated (r 2 = 0.656; P < 0.001). However, AGP levels did not fluctuate significantly over time, nor did the change in AGP levels correlate with the change in the imatinib C min. CONCLUSION: We showed that systemic AGP levels are not likely to be a key player in the decrease in systemic imatinib exposure over time. As long as intra individual changes in imatinib exposure remain unexplained, researchers should standardize the sampling times for imatinib in order to be able to assess the clinical applicability of therapeutic drug monitoring. PMID- 27461251 TI - Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products: Similarities and Differences Between Japan, USA, and the European Union. AB - In Japan, the development of generic oral dry powder inhaler (DPI) drug products for marketing approval has recently increased. The Pharmaceuticals and Medical Devices Agency (PMDA) considers the required data for each drug product in the consultation meeting. However, guidelines for DPI drug products have been published by the US Food and Drug Administration and the European Medicines Agency. Recently, the basic principles of bioequivalence evaluations of generic DPI drug products were published in March 2016 by the Ministry of Health, Labour and Welfare. The document mainly outlines the current understanding regarding the bioequivalence evaluations of generic DPI drug products based on knowledge from PMDA consultation meetings. In this review, we compared the bioequivalence evaluations of DPI drug products among Japan, USA, and the European Union and discuss future development of generic DPI drug products in Japan. PMID- 27461252 TI - Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition. AB - Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci. PMID- 27461254 TI - Assessment of the Forward Contamination Risk of Mars by Clean Room Isolates from Space-Craft Assembly Facilities through Aeolian Transport - a Model Study. AB - The increasing number of missions to Mars also increases the risk of forward contamination. Consequently there is a need for effective protocols to ensure efficient protection of the Martian environment against terrestrial microbiota. Despite the fact of constructing sophisticated clean rooms for spacecraft assembly a 100 % avoidance of contamination appears to be impossible. Recent surveys of these facilities have identified a significant number of microbes belonging to a variety of taxonomic groups that survive the harsh conditions of clean rooms. These microbes may have a strong contamination potential, which needs to be investigate to apply efficient decontamination treatments. In this study we propose a series of tests to evaluate the potential of clean room contaminants to survive the different steps involved in forward contamination. We used Staphylococcus xylosus as model organism to illustrate the different types of stress that potential contaminants will be subjected to on their way from the spacecraft onto the surface of Mars. Staphylococcus xylosus is associated with human skin and commonly found in clean rooms and could therefore contaminate the spacecraft as a result of human activity during the assembling process. The path the cell will take from the surface of the spacecraft onto the surface of Mars was split into steps representing different stresses that include desiccation, freezing, aeolian transport in a Martian-like atmosphere at Martian atmospheric pressure, and UV radiation climate. We assessed the surviving fraction of the cellular population after each step by determining the integrated metabolic activity of the survivor population by measuring their oxygen consumption rate. The largest fraction of the starting culture (around 70 %) was killed during desiccation, while freezing, Martian vacuum and short-term UV radiation only had a minor additional effect on the survivability of Staphylococcus xylosus. The study also included a simulation of atmospheric transport on Martian dust, which did not significantly alter the metabolic potential of the cells. The high survival potential of skin microbes, which are not among the most robust isolates, clearly underlines the necessity for efficient decontamination protocols and of adequate planetary protection measures. Thus we propose a series of tests to be included into the description of isolates from spacecraft assembly clean rooms in order to assess the forward contamination potential of the specific isolate and to categorize the risk level according to the organisms survival potential. We are aware that the tests that we propose do not exhaust the types of challenges that the microbes would meet on their way and therefore the series of tests is open to being extended. PMID- 27461253 TI - Evidence for an Opportunistic and Endophytic Lifestyle of the Bursaphelenchus xylophilus-Associated Bacteria Serratia marcescens PWN146 Isolated from Wilting Pinus pinaster. AB - Pine wilt disease (PWD) results from the interaction of three elements: the pathogenic nematode, Bursaphelenchus xylophilus; the insect-vector, Monochamus sp.; and the host tree, mostly Pinus species. Bacteria isolated from B. xylophilus may be a fourth element in this complex disease. However, the precise role of bacteria in this interaction is unclear as both plant-beneficial and as plant-pathogenic bacteria may be associated with PWD. Using whole genome sequencing and phenotypic characterization, we were able to investigate in more detail the genetic repertoire of Serratia marcescens PWN146, a bacterium associated with B. xylophilus. We show clear evidence that S. marcescens PWN146 is able to withstand and colonize the plant environment, without having any deleterious effects towards a susceptible host (Pinus thunbergii), B. xylophilus nor to the nematode model C. elegans. This bacterium is able to tolerate growth in presence of xenobiotic/organic compounds, and use phenylacetic acid as carbon source. Furthermore, we present a detailed list of S. marcescens PWN146 potentials to interfere with plant metabolism via hormonal pathways and/or nutritional acquisition, and to be competitive against other bacteria and/or fungi in terms of resource acquisition or production of antimicrobial compounds. Further investigation is required to understand the role of bacteria in PWD. We have now reinforced the theory that B. xylophilus-associated bacteria may have a plant origin. PMID- 27461255 TI - Circulating proteins in response to combined-modality therapy in rectal cancer identified by antibody array screening. AB - BACKGROUND: The increasingly complex programs of contemporary cancer therapy emphasize the need for biological indicators of both therapeutic response and adverse effects. One example is combined-modality treatment aimed at improving long-term outcome in patients with locally advanced rectal cancer, which commonly comes at the price of extended limits of patient tolerance. METHODS: In a prospective study with intensified neoadjuvant treatment of rectal cancer patients, using an antibody array, the profiling of approximately 500 proteins was performed in serial serum samples collected at different stages of the treatment course. RESULTS: The small number of proteins whose levels significantly changed after induction neoadjuvant chemotherapy (NACT) expanded substantially following the sequential chemoradiotherapy (CRT) and persisted four weeks later at treatment evaluation before pelvic surgery. Serum levels of proteins selected for validation of the experimental design, lipocalin-2 and matrix metalloproteinase-9, declined after NACT and gradually reverted to baseline values during the remaining neoadjuvant course. Of note, the greater the decline in post-NACT and post-CRT matrix metalloproteinase-9 levels, the more favorable progression-free survival. No correlation was found, however, with diarrhea scores, the clinical correlate of adverse therapeutic effects. CONCLUSIONS: Even though the findings were indicative of only tumor and not normal tissue effects, multiplex immunoassay analysis of circulating proteins in patients undergoing combined-modality therapy may in principle dissect the contribution of the individual modalities to overall systemic responses in patient outcome and tolerance. TRIAL REGISTRATION: ClinicalTrials.gov NCT00278694 ; registration date: January 16, 2006, retrospective to enrollment of the first 10 patients of the current report. PMID- 27461256 TI - Masks in imaging flow cytometry. AB - Data analysis in imaging flow cytometry incorporates elements of flow cytometry together with other aspects of morphological analysis of images. A crucial early step in this analysis is the creation of a mask to distinguish the portion of the image upon which further examination of specified features can be performed. Default masks are provided by the manufacturer of the imaging flow cytometer but additional custom masks can be created by the individual user for specific applications. Flawed or inaccurate masks can have a substantial negative impact on the overall analysis of a sample, thus great care must be taken to ensure the accuracy of masks. Here we discuss various types of masks and cite examples of their use. Furthermore we provide our insight for how to approach selecting and assessing the optimal mask for a specific analysis. PMID- 27461259 TI - Upper gastrointestinal endoscopy: expected post-procedural findings and adverse events. AB - Complications related to endoscopy are commonly encountered in the emergency department (ED) due to an increased use of outpatient diagnostic and therapeutic upper gastrointestinal endoscopic procedures. A majority of these procedures are performed on an outpatient basis, and patients with post-procedural symptoms may return to the ED. Since these patients often undergo computed tomography (CT) for diagnosis of post-procedure complications, the emergency radiologist should be familiar with the spectrum of expected post-procedural findings, as well as common and rare complications. We present a pictorial review of post-endoscopy complications and review imaging protocols in different clinical scenarios. PMID- 27461260 TI - High-Resolution NMR Determination of the Dynamic Structure of Membrane Proteins. AB - (15) N spin-relaxation rates are demonstrated to provide critical information about the long-range structure and internal motions of membrane proteins. Combined with an improved calculation method, the relaxation-rate-derived structure of the 283-residue human voltage-dependent anion channel revealed an anisotropically shaped barrel with a rigidly attached N-terminal helix. Our study thus establishes an NMR spectroscopic approach to determine the structure and dynamics of mammalian membrane proteins at high accuracy and resolution. PMID- 27461257 TI - Epithelial-mesenchymal transition in tissue repair and fibrosis. AB - The epithelial-mesenchymal transition (EMT) describes the global process by which stationary epithelial cells undergo phenotypic changes, including the loss of cell-cell adhesion and apical-basal polarity, and acquire mesenchymal characteristics that confer migratory capacity. EMT and its converse, MET (mesenchymal-epithelial transition), are integral stages of many physiologic processes and, as such, are tightly coordinated by a host of molecular regulators. Converging lines of evidence have identified EMT as a component of cutaneous wound healing, during which otherwise stationary keratinocytes (the resident skin epithelial cells) migrate across the wound bed to restore the epidermal barrier. Moreover, EMT plays a role in the development of scarring and fibrosis, as the matrix-producing myofibroblasts arise from cells of the epithelial lineage in response to injury but are pathologically sustained instead of undergoing MET or apoptosis. In this review, we summarize the role of EMT in physiologic repair and pathologic fibrosis of tissues and organs. We conclude that further investigation into the contribution of EMT to the faulty repair of fibrotic wounds might identify components of EMT signaling as common therapeutic targets for impaired healing in many tissues. Graphical Abstract Model for injury triggered EMT activation in physiologic wound repair (left) and fibrotic wound healing (right). PMID- 27461261 TI - Fluoride incorporation in high phosphate containing bioactive glasses and in vitro osteogenic, angiogenic and antibacterial effects. AB - OBJECTIVES: To manufacture and assess bioactivity of low fluoride/high phosphate (low F(-)/high P2O5) bioglasses (BGs). Then the effects of BG-conditioned medium on osteoblast-like cell behavior and BG particles on bactericidal activity were investigated. METHODS: BGs (0-7% F(-) content, constant 6.33% P2O5 in mol%) were designed and produced. BG particles was immersed in Tris Buffer solution or alpha MEM to determine apatite formation and ion (Ca, P, Si and F) release. Osteoblast like cells MC3T3-E1 were treated with BG-conditioned medium and assessed for cytotoxicity, pre-osteogenic and pro-angiogenic responses. Antibacterial ability was explored by incubating sub-gingival bacteria with BG particulates. RESULTS: Rapid apatite formation was observed in F(-) containing BGs after only 2-8h immersion in Tris buffer solution. In the F(-) free group, apatite was not detectable until 72h. Peak Ca, P and F release into Tris buffer was at 2h immersion, and then the levels decreased. In alpha-MEM, apatite formation in all the BGs was undetectable until 72h immersion. Alkaline phosphatase activity, cell number, collagen formation, bone-like mineral nodules and osteogenic gene expression of MC3T3-E1 cells were significantly promoted in low F(-) BG (P6.33F1) conditioned medium. MC3T3-E1 VEGF gene expression was increased, and protein production was dose-dependently promoted with F(-) BG-conditioned medium. After incubation with BG particulates, the growth of sub-gingival bacteria, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, was significantly inhibited; the antibacterial activity being dependent on the F(-) content of the BGs. SIGNIFICANCE: These results show that low F(-)/high P2O5 BGs significantly accelerated apatite formation and promoted both pre-osteogenic and pro-angiogenic responses of MC3T3-E1 osteoblast-like cells and inhibited the growth of periodontal pathogens in vitro. These BGs may prove useful as bone graft substitutes. PMID- 27461262 TI - Longitudinal Relationships Between Productive Activities and Functional Health in Later Years: A Multivariate Latent Growth Curve Modeling Approach. AB - This study examined the longitudinal relationships between functional health in later years and three types of productive activities: volunteering, full-time, and part-time work. Using the data from five waves (2000-2008) of the Health and Retirement Study, we applied multivariate latent growth curve modeling to examine the longitudinal relationships among individuals 50 or over. Functional health was measured by limitations in activities of daily living. Individuals who volunteered, worked either full time or part time exhibited a slower decline in functional health than nonparticipants. Significant associations were also found between initial functional health and longitudinal changes in productive activity participation. This study provides additional support for the benefits of productive activities later in life; engagement in volunteering and employment are indeed associated with better functional health in middle and old age. PMID- 27461263 TI - Concurrent hyperthyroidism and papillary thyroid cancer: a fortuitous and ambiguous case report from a resource-poor setting. AB - BACKGROUND: Concurrent thyroid cancer (TC) and hyperthyroidism (HT) is rare though increasingly being reported. HT due to TC is much rarer and more challenging especially in Africa where TC and HT have significant case fatality rates. CASE PRESENTATION: We present a 37-year-old Cameroonian female who had been on irregular regimens of propranolol and digoxin as treatment for worsening palpitations for 12 months. She came to our district hospital for her propranolol medication refill. We fortuitously identified features of HT and found a left uninodular goiter with no cervical lymphadenopathy. She was referred for thyroid assessment which suggested primary HT and an enlarged heterogeneous left lobe with a well-defined homogenous solid mass. We restarted her on propranolol and referred her for a course of methimazole. At the referral hospital, she also underwent a left thyroid lobectomy. The resected lobe was sent for histopathology which revealed a neoplastic nodule with features suggestive of a papillary thyroid cancer (PTC) causing HT. The patient's clinical progress postoperatively was good and there was regression of hyperthyroid symptoms. CONCLUSIONS: The historical, clinical, and laboratory findings were suggestive of HT due to PTC. A high index of suspicion, prompt referral and counter-referral lead to a positive outcome of such a rare case in a resource poor setting. We advocate for systematic and careful evaluation of all thyroid nodules. PMID- 27461264 TI - Variable course of disease of rheumatoid arthritis-associated usual interstitial pneumonia compared to other subtypes. AB - BACKGROUND: In rheumatoid arthritis-associated interstitial lung disease (RA ILD), occurring in 10 % of patients with patients with RA, usual interstitial pattern (UIP) has shown to associate with poor prognosis but more detailed data about the course of the disease in different subtypes is limited. Our aim was to compare the disease course of patients with RA-ILD categorized into either UIP or other types of ILDs. METHODS: Clinical and radiological information of 59 patients with RA-ILD were re-assessed and re-classified into UIP or non-UIP groups, followed by a between-group comparison of demographic data, lung function, survival, cause of death and comorbidities. RESULTS: The majority of patients (n = 35/59.3 %) showed a radiological UIP-like pattern in high resolution computed tomography. The median survival was 92 months (95 % CI 62.8 121.2) in the UIP-group and 137 months (95 % CI 31.0-243.0) in the non-UIP-group (p = 0.417). Differences in course of disease were found in the number of hospitalizations for respiratory reasons (mean 1.9 +/- 2.6 in UIP vs. 0.5 +/- 0.9 in non-UIP group, p = 0.004), the use of oxygen therapy (8/22.9 % UIP patients vs. 0 non-UIP patients, p = 0.016), number of deaths (23/65.7 % vs. 10/41.7 %, p = 0.046) and decline in diffusion capacity (56 +/- 20.6 vs. 69 +/- 20.2, p = 0.021). Dyspnea and inspiratory crackles were detected more often in the UIP group. RA-ILD was the most common primary cause of death (39.4 % of cases). Hypertension, coronary artery disease, chronic obstructive pulmonary disease, heart insufficiency, diabetes and asthma were common comorbidities. ILD preceded RA diagnosis in 13.6 % of patients. CONCLUSIONS: The course of the disease in RA UIP patients is different from the other RA-ILD subtypes. Several comorbidities associated commonly with RA-ILD, although ILD was the predominant primary cause of death. PMID- 27461265 TI - Newborn screening and prophylactic interventions for sickle cell disease in 47 countries in sub-Saharan Africa: a cost-effectiveness analysis. AB - BACKGROUND: Sickle cell disease (SCD) constitutes a major public health problem in sub-Saharan Africa (SSA). Newborn screening and early subsequent clinical intervention can reduce early mortality and increase life expectancy, but have not been widely implemented in SSA. This analysis assesses the cost-effectiveness of a newborn screening and prophylactic intervention (NSPI) package for SCD in 47 SSA countries. METHODS: A lifetime Markov model with annual cycles was built with infants either being screened using isoelectric focusing (IEF) or not screened. Confirmed positive cases received interventions including insecticide-treated mosquito bed nets, folic acid supplementation, prophylactic antimalarial and penicillin therapy, and vaccinations against bacterial infections. Estimates for the local incidence of SCD, the life expectancy of untreated children, the SCD disability weight, and the cost of screening laboratory tests were based on published sources. Among treated infants, the annual probability of mortality until 30 years of age was derived from a pediatric hospital-based cohort. The outcome of interest included a country-specific cost per Disability Adjusted Life Year (DALY) averted. RESULTS: Of 47 modeled countries in SSA, NSPI is almost certainly highly cost-effective in 24 countries (average cost per DALY averted: US$184); in 10 countries, it is cost-effective in the base case (average cost per DALY averted: US$285), but the results are subject to uncertainty; in the remaining 13, it is most likely not cost-effective. We observe a strong inverse relationship between the incidence rate of SCD and the cost per DALY averted. Newborn screening is estimated to be cost-effective as long as the incidence rate exceeds 0.2-0.3 %, although in some countries NSPI is cost-effective at incidence rates below this range. In total, NSPI could avert over 2.4 million disability adjusted life years (DALYs) annually across SSA. CONCLUSIONS: Using IEF to screen all newborns for SCD plus administration of prophylactic interventions to affected children is cost-effective in the majority of countries in SSA. PMID- 27461266 TI - Psychometric properties of the Chinese version of the Problem Areas in Diabetes scale (SG-PAID-C) among high-risk polypharmacy patients with uncontrolled type 2 diabetes in Singapore. AB - AIMS/INTRODUCTION: Undetected diabetes distress is a cause of concern. However, the lack of a validated questionnaire is a barrier to screening for diabetes distress. The aim of the present study was to examine the validity and reliability of the Chinese version of the Problem Areas in Diabetes scale (SG PAID-C), and its association with sociodemographic and clinical parameters in patients with type 2 diabetes. MATERIALS AND METHODS: This cross-sectional study was carried out in four outpatient healthcare institutions in Singapore. Chinese speaking patients with uncontrolled type 2 diabetes, polypharmacy, and multiple comorbidities were administered the SG-PAID-C and European Quality of Life-5 Dimensions questionnaires as quality of life measures. The factorial construct, convergent validity and internal consistency of SG-PAID-C were evaluated. RESULTS: The exploratory factor analysis resulted in a three-factor structure of SG-PAID-C with subscales on emotional- and management-related problem (11 items), ability to cope with diabetes problem (3 items) and support-related problem (2 items). The findings also showed good model fit in the confirmatory factor analysis, and provided support for the construct and convergent validity of SG PAID-C. Overall, the internal consistency of SG-PAID-C was good (Cronbach's alpha = 0.900). Sex and duration of diabetes were positively associated with the 16 item SG-PAID-C, whereas age and type of antidiabetic agents were inversely associated with the 16-item SG-PAID-C. CONCLUSIONS: The 16-item SG-PAID-C is a valid and reliable instrument for use among patients with uncontrolled type 2 diabetes in Singapore. Future studies on its clinical utility should be carried out. PMID- 27461267 TI - Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype. AB - The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how-through continuous dialogue between bench and bedside-immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL-1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin-18 are already used daily in clinic as markers for active sJIA. For non-sJIA subtypes, HLA-B27, antinuclear-antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA. PMID- 27461268 TI - The prevalence and predictors of subsyndromal anxiety and depression in adult Asian cancer patients across the first year of diagnosis. AB - AIM: There is an increased prevalence of anxiety and depression in Asian patients diagnosed with cancers; these are known to interfere with treatment, treatment adherence and mortality. This study sought to investigate the prevalence and predictors of subsyndromal anxiety and depression in first-year Asian cancer patients. METHODS: A total of 206 patients newly diagnosed with cancer in Singapore completed the Hospital Anxiety and Depression Scale (HADS) at T1 (baseline; on average 2 months post-diagnosis), T2 (3 months post-baseline) and T3 (6 months post-baseline). Subsyndromal anxiety and depression were identified using locally validated cut-offs (HADS-A >=5 and HADS-D >=7). Adjusted odds ratios were calculated using baseline predictors. RESULTS: Across the three time points, 68-69% of participants were identified as having subsyndromal anxiety and close to 27-38% participants were identified as having subsyndromal depression. Multivariate logistic regressions revealed a lack of predictors for T1 subsyndromal anxiety and depression. Participants with late/metastatic stages of cancer were almost four times as likely to suffer from subsyndromal anxiety at T2. Single participants had a 75% lowered odds, but those living in three to four room public housing were close to four times as likely to suffer from subsyndromal depression at T2. Older patients and those who had undergone surgery were found to significantly suffer from subsyndromal depression at T3. CONCLUSION: The significant levels of depression and anxiety coupled with the lack of consistent predictors across the first year following cancer diagnosis further underscore the importance of careful assessment and clinician-vigilance in recognizing and identifying Asian patients who may express these emotional sequelae following the cancer diagnosis. A better understanding of patients' pathophysiological and psychological responses and individual strengths and coping skills are thus essential. PMID- 27461269 TI - Society and health of migrants. PMID- 27461271 TI - Understanding the true significance of a P value. PMID- 27461272 TI - Atypical teratoid/rhabdoid tumour following craniopharyngioma radiotherapy during childhood. PMID- 27461270 TI - Differences in mortality by immigrant status in Italy. Results of the Italian Network of Longitudinal Metropolitan Studies. AB - Despite a rapid increase in immigration from low-income countries, studies on immigrants' mortality in Italy are scarce. We aimed to describe differences in all and cause-specific mortality among immigrants and Italians residing in Turin and Reggio Emilia (Northern Italy), two cities participating in the Italian Network of Longitudinal Metropolitan Studies (IN-LiMeS). We used individual data from the municipal population registers linked to the cause of death registers. All people aged 1-64 years residing between 2001 and 2010 were enrolled (open cohort) and followed up until 2013. The mortality of citizens from high migratory pressure countries (as a whole, and for each macro-area group) was compared with that of Italians; differences were estimated by Poisson regression adjusted by age and calendar year mortality rate ratios (MRRs), and by age-standardized mortality ratios for the analysis of cause-specific mortality. Compared with Italians, immigrants had lower overall mortality (MRR for men: 0.82, 95 % CI: 0.75-0.90; for women: 0.71, 95 % CI: 0.63-0.81). Sub-Saharan Africans experienced a significant higher mortality than Italians (MRR for men 1.29, 95 % CI: 1.03 1.61; for women: 1.70, 95 % CI: 1.22-2.36). Higher mortality for immigrants compared to Italians was observed for infectious diseases, congenital anomalies, some site-specific tumours and homicide mortality. Our study showed heterogeneity in mortality across the macro-areas of origin, and in particular Sub-Saharan Africans seemed to be a vulnerable population. The extension to other cohorts of IN-LiMeS will allow the health status of immigrants and vulnerable groups to be studied and monitored in more depth. PMID- 27461273 TI - Atretic cephaloceles: a comprehensive analysis of historical cohort. AB - PURPOSE: This study aims to analyze the historical cohort of patients with atretic cephaloceles (ACs) comprehensively, since the literature regarding ACs is limited by small case series or case reports and to report a new venous anomaly concomitant with a parietal AC in our exemplary case. METHODS: After a PubMed/Medline search with "atretic cephalocele" in April 2016, we retrieved 42 articles, 41 of which were relevant with the topic. Full texts of accessible articles and abstracts of inaccessible articles were read comprehensively. References of retrieved articles were manually searched. Additional 29 articles reporting the cases of atretic, rudimentary, occult, or sequestered cephaloceles were accessed, since these terms have been used interchangeably in the literature. RESULTS: Median age and mean age of the patients were 1 and 6.69 years, respectively. Female/male ratio was 1.03:1. Atretic cephaloceles were located in different regions, in decreasing order of frequency: parietal (55 %; n = 105), occipital (37 %; n = 71), parieto-occipital (n = 8), frontal (n = 4), asterion (n = 1), and sincipital (n = 1). Concomitant central nervous system (CNS) anomalies were present in 73.3 % of patients with parietal atretic cephaloceles and in 32.4 % of patients with occipital atretic cephaloceles (p < 0.0001). We realized that all patients with worse outcomes had concomitant CNS anomalies (100 %), whereas only 48 % of those with good clinical outcomes had concomitant anomalies (p = 0.0248). CONCLUSIONS: Atretic cephaloceles present as nodular extrusions on the parietal and occipital regions. Concomitant CNS anomalies, which impair the clinical outcomes, are more common in patients with parietal ACs. Observation-only approach is enough in patients with asymptomatic ACs. However, life-long follow-ups are required, because of recurrence after the surgery. PMID- 27461274 TI - Next-Generation Therapeutics for Inflammatory Bowel Disease. AB - Tumor necrosis factor (TNF) antagonists are the cornerstone of therapy for moderately to severely active inflammatory bowel disease (IBD). Although our understanding of pharmacokinetics, pharmacodynamics, and treatment optimization for these agents has evolved considerably over the past decade, a substantial majority of individuals fail to respond or lose response to TNF-antagonists over time. A need therefore remains for efficacious treatment options in these patients. Alternative immunological targets have now been identified, and several novel therapeutic agents are in development for IBD. In this review article, we discuss these novel therapeutic agents, with a particular focus on those demonstrated to be efficacious in phase 2 and 3 clinical trials. We further discuss considerations to be made when integrating these agents into routine practice over the next decade. PMID- 27461275 TI - Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015. PMID- 27461277 TI - Superficial leiomyosarcoma histopathologically mimicking dermatofibroma: Pitfall in the diagnosis. PMID- 27461276 TI - Patient Preferences for Oral Anticoagulation Therapy in Atrial Fibrillation: A Systematic Literature Review. AB - OBJECTIVES: Since the introduction of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs), an additional treatment option, apart from VKAs, has become available for stroke prevention in patients with atrial fibrillation (AF). For various reasons, it is important to consider patients' preferences regarding type of medication, particularly in view of the established relationship between preferences towards treatment, associated burden of treatment, and treatment adherence. This review aimed to systematically analyse the scientific literature assessing the preferences of AF patients with regard to long-term oral anticoagulant (OAC) treatment. METHODS: We searched the MEDLINE, Scopus and EMBASE databases (from 1980 to 2015), added records from reference lists of publications found, and conducted a systematic review based on all identified publications. Outcomes of interest included any quantitative information regarding the opinions or preferences of AF patients towards OAC treatment, ideally specified according to different clinical or convenience attributes describing different OAC treatment options. RESULTS: Overall, 27 publications describing the results of studies conducted in 12 different countries were included in our review. Among these, 16 studies analysed patient preferences towards OACs in general. These studies predominantly assessed which benefits (mainly lower stroke risk) AF patients would require to tolerate harms (mainly higher bleeding risk) associated with an OAC. Most studies showed that patients were willing to accept higher bleeding risks if a certain threshold in stroke risk reduction could be reached. Nevertheless, most of the publications also showed that the preferences of AF patients towards OACs may differ from the perspective of clinical guidelines or the perspective of physicians. The remaining 11 studies included in our review assessed the preferences of AF patients towards specific OAC medication options, namely NOACs versus VKAs. Our review showed that AF patients prefer easy-to-administer treatments, such as treatments that are applied once daily without any food/drug interactions and without the need for bridging and frequent blood controls. CONCLUSION: Stroke risk reduction and a moderate increase in the risk of bleeding are the most important attributes for an AF patient when deciding whether they are for or against OAC treatment. If different anticoagulation options have similar clinical characteristics, convenience attributes matter to patients. In this review, AF patients favour attribute levels that describe NOAC treatment. PMID- 27461278 TI - Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin. AB - The cell-adhesion glycoprotein PODXL is associated with an aggressive tumor phenotype in several forms of cancer. Here, we report that high PODXL expression was an independent predictor of worse overall survival of pancreatic cancer patients, and that PODXL promoted pancreatic cancer cell motility and invasion by physically binding to the cytoskeletal protein gelsolin. Suppression of PODXL or gelsolin decreased membrane protrusions with abundant peripheral actin structures, and in turn inhibited cell motility and invasion. Transfection of a PODXL-rescue construct renewed the expression of gelsolin bound to peripheral actin structures in cell protrusions, and abrogated the decreased cell protrusions caused by the knockdown of PODXL. Furthermore, transfection of a PODXL-rescue construct into pancreatic cancer cells in which both PODXL and gelsolin were suppressed failed to increase the formation of the protrusions. Thus, PODXL enhances motility and invasiveness through an increase in gelsolin actin interactions in cell protrusions. PMID- 27461279 TI - Prescribing in obese children: how good are paediatricians? AB - Childhood obesity is increasing nationally and worldwide. Using the child's total body weight to calculate drug doses for certain medications could result in incorrect dosing. The aim of this study was to assess whether paediatric doctors have knowledge about prescribing correct doses of medications for obese children by using methods to calculate the 'ideal body weight' (IBW). A questionnaire was sent to paediatric doctors asking whether they understand IBW and how to calculate it using the McLaren method. The results suggested that most paediatric doctors did not determine whether a child was obese when calculating drug doses. There was relatively poor understanding about the concept of IBW and only 9% of paediatricians in this study knew how to calculate it. There should be more training and guidance about calculating IBW in obese children to avoid potentially toxic errors. PMID- 27461280 TI - Restoration of visual performance by d-serine in models of inner and outer retinal dysfunction assessed using sweep VEP measurements in the conscious rat and rabbit. AB - The NMDA subtype of glutamate receptor and its co-agonist d-serine play a key role in synaptic function in the central nervous system (CNS), including visual cortex and retina. In retinal diseases such as glaucoma and macular degeneration, a loss of vision arises from malfunction of retinal cells, resulting in a glutamate hypofunctional state along the visual pathway in the affected parts of the visual field. An effective strategy to remedy this loss of function might be to increase extracellular levels of d-serine and thereby boost synaptic NMDA receptor-mediated visual transmission and/or plasticity to compensate for the impairment. We tested this idea in brain slices of visual cortex exhibiting long term potentiation, and in rodent models of visual dysfunction caused by retinal insults at a time when the injury had stabilized to look for neuroenhancement effects. An essential aspect of the in vivo studies involved adapting sweep VEP technology to conscious rats and rabbits and combining it with intracortical recording while the animals were actively attending to visual information. Using this technology allowed us to establish complete contrast sensitivity function curves. We found that systemic d-serine dose-dependently rescued the contrast sensitivity impairment in rats with blue light-induced visual dysfunction. In rabbits with inner retinal dysfunction, both systemic and intravitreal routes of d-serine provided a rescue of visual function. In sum, we show that co-agonist stimulation of the NMDA receptor via administration of exogenous d-serine might be an effective therapeutic strategy to enhance visual performance and compensate for the loss of vision resulting from retinal disease. PMID- 27461281 TI - High-Throughput Mutational Analysis of a Twister Ribozyme. AB - Recent discoveries of new classes of self-cleaving ribozymes in diverse organisms have triggered renewed interest in the chemistry and biology of ribozymes. Functional analysis and engineering of ribozymes often involve performing biochemical assays on multiple ribozyme mutants. However, because each ribozyme mutant must be individually prepared and assayed, the number and variety of mutants that can be studied are severely limited. All of the single and double mutants of a twister ribozyme (a total of 10 296 mutants) were generated and assayed for their self-cleaving activity by exploiting deep sequencing to count the numbers of cleaved and uncleaved sequences for every mutant. Interestingly, we found that the ribozyme is highly robust against mutations such that 71 % and 30 % of all single and double mutants, respectively, retain detectable activity under the assay conditions. It was also observed that the structural elements that comprise the ribozyme exhibit distinct sensitivity to mutations. PMID- 27461283 TI - Bone health and disease in cystic fibrosis. AB - Low bone mineral density is common in children and adults with CF. It has a multifactorial aetiology that includes direct effects of CFTR dysfunction on bone cell activity, as well as the secondary effects of CFTR dysfunction including pancreatic insufficiency (leading to malnutrition/malabsorption of fat soluble vitamins) and pulmonary infection (leading to systemic inflammation and increased bone resorption). Strategies to improve bone health in CF include optimising general CF nutritional and pulmonary care and the judicious use of bisphosphonates in selected patients. CFTR correctors/potentiators may have positive impact on bone metabolism in people with CF. PMID- 27461284 TI - Scrapping nursing student bursaries makes no sense. AB - I'm a nursing student and have just worked 85 hours in the last 8 days. I've had 1 day off in that period of time. I've not seen my daughter in days and I can't get a paid part time job as, let's face it, I have to actually sleep.' PMID- 27461285 TI - Scrapping of student bursaries confirmed. AB - Student bursaries for nurses will be scrapped from next year, the government has confirmed. Undergraduate nursing and midwifery students in England will now face tuition fees and student loans from August 2017. PMID- 27461282 TI - Increased dynamics in the 40-57 Omega-loop of the G41S variant of human cytochrome c promote its pro-apoptotic conformation. AB - Thrombocytopenia 4 is an inherited autosomal dominant thrombocytopenia, which occurs due to mutations in the human gene for cytochrome c that results in enhanced mitochondrial apoptotic activity. The Gly41Ser mutation was the first to be reported. Here we report stopped-flow kinetic studies of azide binding to human ferricytochrome c and its Gly41Ser variant, together with backbone amide H/D exchange and (15)N-relaxation dynamics using NMR spectroscopy, to show that alternative conformations are kinetically and thermodynamically more readily accessible for the Gly41Ser variant than for the wild-type protein. Our work reveals a direct conformational link between the 40-57 Omega-loop in which residue 41 resides and the dynamical properties of the axial ligand to the heme iron, Met80, such that the replacement of glycine by serine promotes the dissociation of the Met80 ligand, thereby increasing the population of a peroxidase active state, which is a key non-native conformational state in apoptosis. PMID- 27461287 TI - Nurses pay tribute to Kate Granger. AB - Tributes have been paid to a campaigning doctor who inspired legions of nurses to change their practice with her influential #Hellomynameis campaign. PMID- 27461286 TI - Honorary degree. AB - A British nurse who survived the Ebola virus has received an honorary degree from the University of Essex. PMID- 27461288 TI - Staff try their hand at wedding planning. AB - Kind-hearted hospital staff pulled out all the stops for a nurse bride and her groom on their big day. PMID- 27461290 TI - NHS reveals level of attacks on staff by over 75s. AB - Almost 300,000 healthcare staff have been subject to 'unacceptable' physical assaults in the last five years, new figures reveal. PMID- 27461293 TI - nursing.standard.com. AB - 1 Nurses and other healthcare professionals must treat signs of sepsis with the same urgency as symptoms of a possible heart attack, the National Institute of Health and Care Excellence said in new guidance. Read more rcni.com/sepsis guidance. PMID- 27461292 TI - Hundreds of students disciplined for cheating. AB - Hundreds of UK nursing students have been disciplined for cheating in their university studies, new figures have revealed. PMID- 27461294 TI - Bereaved actor stars in educational film about the dangers of sepsis. AB - An actor whose three-year-old daughter died from undiagnosed sepsis has described his family's experience to raise awareness among healthcare staff. PMID- 27461295 TI - Concern over plans to remove 'ghost patients' from GP lists. AB - Nursing leaders have criticised plans to axe patients from GP lists in England if they have not visited their surgery for five years. PMID- 27461296 TI - PM May sets out her NHS moves. AB - Will a new Conservative government mean change for nurses, the NHS and the people who use it? PMID- 27461299 TI - Haematological cancers. AB - Essential facts Haematological malignancies are a diverse group of cancers that affect the blood, bone marrow and lymphatic systems. The main categories are lymphoma, leukaemia, myeloma, myelodysplastic syndromes and myeloproliferative neoplasms. In addition, there are subtypes of lymphoma and leukaemia, as well as more rare haematological cancers that have their own categories. There are also borderline conditions such as aplastic anaemia and other non-malignant bone marrow failure syndromes. The charity Bloodwise says 38,000 people in Britain are diagnosed every year with blood cancer or a related disorder, making it the country's fifth most common cancer. PMID- 27461300 TI - Too many older people take medications inappropriately. AB - Many older people in the community are taking prescription medications inappropriately, increasing the risk of mortality and hospitalisation, suggest results in a new study. PMID- 27461301 TI - Prostate cancer gene test aids treatment precision. AB - A simple test for men with advanced prostate cancer could identify those with an inherited gene mutation who would most benefit from precision treatments, new research suggests. PMID- 27461302 TI - List cigarette chemicals on packets, say smokers. AB - With the exception of nicotine, most smokers do not know what chemicals are in cigarettes, but would welcome this information being on packs, say researchers from the University of North Carolina in the US. PMID- 27461303 TI - Pregnancy vitamins are a 'needless expense'. AB - Pregnant women should focus on improving their overall diet rather than going to the needless expense of buying multivitamins and mineral supplements, say researchers. PMID- 27461305 TI - Nursing on the Zika front line. AB - Paediatric nurse Roberta Seabra quickly and quietly takes control when the mother of baby Graziella breaks down. Ushering visitors from the room, she reassures Inabela Souza about her six-month-old daughter, who has been born with an abnormally small head and brain - one of 5,000 babies thought to be affected by microcephaly in Brazil. PMID- 27461306 TI - Seacole an inspiration for all nurses. AB - After more than 12 long years of fundraising a memorial statue to Jamaican Scottish Crimean War nurse and businesswoman Mary Seacole was unveiled on 30 June. The sun shone brightly and it was one of my proudest days. PMID- 27461307 TI - Innovation improves care. AB - The three nurses featured here work in very different settings but have in common their 'inspirational approach', according to RCN eastern region director Karen Webb. 'These nurses, who work in the vital areas of child mental health, emergency care and patient records, demonstrate how - by taking an inspirational approach - nurses are improving patient experience,' she says. PMID- 27461308 TI - Our philosophy of care. AB - We work in a multiprofessional and multifaceted health and social care environment. Confidence in dealing with the concepts of research, enquiry, abstraction and unpredictability has seldom been so important. PMID- 27461310 TI - Let's hope for a fresh start with Jeremy Hunt. AB - Working in the health service prepares you for dealing with the unexpected. But even the most experienced nurse would be taken aback by the amount of uncertainty facing the country at the moment. PMID- 27461309 TI - Think about your ink. AB - During my nursing career, I did what you do - blue or black for day shifts and red ink for night shifts. This allowed us to quickly find an entry as the night shifts stood out from the day entries. PMID- 27461311 TI - Pioneering spirit. AB - For many patients, clinical research nurses are the face of clinical studies. It can be hard work bridging the gap between patients and other healthcare professionals, but it is well worth the effort. PMID- 27461314 TI - Prioritising mental health. AB - My hospital's children, women and diagnostic division has created a new post of clinical lead nurse for mental health to offer mental health support to staff, patients and parents. PMID- 27461312 TI - Barriers to writing. AB - How can we encourage our colleagues to become involved in writing for publication. PMID- 27461316 TI - Invest in better staffing levels. AB - NHS Improvement chief executive Jim Mackey says: 'I've met with providers who even went above the 1:8 ratio.' He talks as if one nurse to eight patients is a ceiling when in fact it is the level at which harm to patients starts. PMID- 27461317 TI - A visionary eye expert worthy of celebration. AB - A gracious thank you came my way from a patient who had just undergone a cataract operation. My role in the procedure had been minuscule, but I was intrigued by her vote of thanks. PMID- 27461318 TI - Readers' panel - Can Jeremy Hunt improve his standing with NHS staff? AB - Our experts consider a hot topic of the day. PMID- 27461320 TI - NICE Guidance. AB - Nurses and health professionals will now be able to access guidance from the National Institute for Health and Care Excellence (NICE) while on the move. PMID- 27461322 TI - Student life - Helping nurses to speak up. AB - How we respond to students who raise concerns is important because the experience will shape their future practice. Students often worry about what they might experience when they return to the practice environment, so need to be reassured they are doing the right thing. PMID- 27461323 TI - Commit to communication. AB - While working on an intensive care unit, I helped care for a man who had sustained a severe right-sided brain injury aft er falling down the stairs. PMID- 27461324 TI - Providing helpful feedback. AB - It can be easy to get into the habit of filtering the truth to avoid having difficult conversations. But you can enhance your skills so you are confident your feedback is constructive and will contribute to your colleague's professional growth and development. PMID- 27461325 TI - Nursing in the world's most challenging places. AB - Josie Gilday has worked in some of the world's most challenging places, including Haiti after the devastating earthquake and civil war-plagued Ivory Coast. PMID- 27461326 TI - A passion for improving care. AB - Jim Bethel has worked in emergency nursing for 30 years. Married with two children and two grandchildren, he is a senior lecturer in emergency care at the University of Wolverhampton and an advanced practitioner in the emergency directorate of Sandwell and West Birmingham Hospitals NHS Trust. PMID- 27461327 TI - How to obtain confirmation for revalidation. AB - Rationale and key points This is the seventh in a series of eight articles providing information about the Nursing and Midwifery Council revalidation process. This article focuses on obtaining confirmation for revalidation. " Revalidation is a mandatory process for nurses and midwives, enabling them to demonstrate their ability to practise safely and effectively. " Confirmation provides assurance that nurses and midwives have met the requirements of revalidation. " Confirmation does not involve making judgements about whether a nurse or midwife is fit to practise. Reflective activity 'How to' revalidate articles can help to update your practice and provide information about the revalidation process, including how you can obtain confirmation for revalidation. Reflect on and write a short account of: 1. The information that nurses and midwives are required to collect to meet the revalidation requirements. 2. How you could use this article to educate your colleagues. Subscribers can upload their reflective accounts at: rcni.com/portfolio. PMID- 27461328 TI - Supporting assistant practitioners during their training. AB - Assistant practitioners, also known as associate practitioners, provide support to the registered healthcare workforce, practising with advanced knowledge and skills. Assistant practitioners require substantial training to obtain the skills and knowledge required for the role. This article identifies the challenges trainee assistant practitioners may encounter, and makes recommendations for how they can be best supported. The core areas where trainee assistant practitioners require support from their colleagues and mentors are workload, role clarity, mentoring, academic challenge and recognition as learners. PMID- 27461329 TI - Falls risk assessment in older patients in hospital. AB - Falls are the most frequent adverse event reported in hospitals, usually affecting older patients. All hospitals in NHS organisations develop risk prevention policies that include falls risk assessment. Falls risk assessment involves the use of risk screening tools, aimed at identifying patients at increased risk of falls, and risk assessment tools, which identify a patient's risk factors for falls. Various risk screening tools have been used in clinical practice, but no single tool is able to identify all patients at risk of falls or to accurately exclude all those who are not at risk of falls. Guidelines recommend that patients aged 65 years and over who are admitted to hospital should be considered at high risk of falls and that a multifactorial falls risk assessment should be performed. Therefore, falls risk assessment tools should be used to identify the risk factors for each inpatient aged 65 years or over, in order to determine the most appropriate care plan for falls prevention and to maximise patient mobility and independence. PMID- 27461331 TI - A force for good. AB - In the first year of my marriage, my husband was medically discharged from the army with post-traumatic stress disorder (PTSD). Neither of us knew who to turn to or how this would affect our lives. PMID- 27461330 TI - Polypharmacy. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article was about polypharmacy, which is defined as the prescribing of many medicines for one individual. The article was of particular interest to me as I work in renal care, where patients are often prescribed several different medicines. PMID- 27461332 TI - Perils of the green-eyed monster. AB - Can preoccupation with the academic success of others be detrimental for nurse academics' own career progression? Michelle Cleary and colleagues, writing in Nurse Researcher, examine envy and jealousy in nursing academia. PMID- 27461333 TI - Big picture. AB - A visit to a memory clinic proved interesting when a patient passed her dementia test - even pointing out a flawed Shakespeare quotation to a doctor. PMID- 27461334 TI - Online. AB - 'I realised continuing to be a nurse is a privilege, not a right, and how much public trust there is in me every time I say I am a nurse'. PMID- 27461335 TI - How to retain staff right from the start. AB - Constance McIntosh and Cynthia Thomas write in Nursing Management about the benefits of creating a welcoming culture to retain staff. PMID- 27461336 TI - Benefit of joint response in a mental health crisis. AB - Andrew Lancaster writes in Mental Health Practice about the critical role mobile crisis teams (MCTs) can play in delivering a joint response from the police and mental health services to people in a mental health crisis. PMID- 27461337 TI - Automated quantification of Ki67/MART1 stains may prevent false-negative melanoma diagnoses. AB - BACKGROUND: Inability to distinguish melanomas from benign nevi is the most frequent reason for malpractice lawsuits in surgical pathology. Reliable diagnostic tools to support hematoxylin and eosin (H&E) stains and induce diagnostic vigilance are thus highly needed. Because high diagnostic performance recently was showed using automated image analysis, the immunohistochemical proliferation marker Ki67 seems a potential candidate. This study aimed to investigate if this previously presented automated algorithm could have prevented 10 false-negative melanoma diagnoses. In addition, diagnostic utility of another, but narrower, immunohistochemical proliferation marker, phosphohistone H3 (PHH3), was explored. METHODS: A total of 10 formalin-fixed paraffin-embedded melanocytic tumors, initially classified as benign or dysplastic but revised as melanomas at metastatic debut, were dual-stained for Ki67/MART1 and PHH3/MART1. A Ki67 index was automatically calculated in epidermis, dermis, a combination of such, and a dermal hot spot. Dermal PHH3/MART1 scores were established semi-automatically. RESULTS: The dermal Ki67 index identified all 10 melanomas, the hot-spot index 8 and the epidermal and combined indices only 2 and 5, respectively. Nine melanomas were PHH3 positive and scores correlated with Ki67. CONCLUSIONS: PHH3 added limited information, but supplemental automated Ki67 assessment could possibly have prevented the misdiagnosis of most melanomas had the algorithm been available at the time of diagnosis. PMID- 27461338 TI - Home Enteral Nutrition therapy: Difficulties, satisfactions and support needs of caregivers assisting older patients. AB - BACKGROUND & AIMS: The purpose of this study was to comprehend and describe the views, experiences and adaptations of caregivers who assist older patients treated with Home Enteral Nutrition. The objective was to gather empirical evidence to improve the delivery of Home Enteral Nutrition for old patients taking into account the caregivers' support needs. METHODS: A qualitative methodology with focus groups as data collection method was used to collect the testimonies of 30 informal and formal caregivers of older patients treated with Home Enteral Nutrition by the Clinical Nutrition Service of INRCA (Ancona) during 2014. Quantitative methodology was used to collect socio-demographic data. Partially modified Silver's "Home Enteral Nutrition Caregiver Task Checklist" was used to identify training needs. The constant comparison method was used to code and categorize data and to develop themes of focus groups. Simple descriptive statistics were used to summarize questionnaires. RESULTS: Five main themes were identified from focus groups: acceptance of the therapy, skill acquisition process, need for psychological and practical support at home from healthcare professionals, lifestyle adaptation, affirmation of life and family. All caregivers testified the initial fear and refusal to manage the nutrition pump and the therapy. They expressed the need to be trained gradually, starting during a patient's hospitalization, and continuing in the community. With reference to their overall QoL, it emerged that informal caregivers suffered mostly from the reduction of their free time while formal caregivers suffered social isolation and psychological burden. For both groups the monthly home visit was the most important element of the HEN service. Informal caregivers highlighted the importance of having their loved ones at home. Unsatisfied training needs were identified by the modified Silver's "Home Enteral Nutrition Caregiver Task Checklist". CONCLUSIONS: This qualitative study underlined the challenges and adaptations of caregivers who assist older patients treated with Home Enteral Nutrition, which should be considered when defining clinical protocols and supporting caregivers. PMID- 27461339 TI - Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with lateral medullary syndrome: case report and literature review. AB - BACKGROUND: Only one case of syndrome of inappropriate secretion of antidiuretic hormone with lateral medullary syndrome has been reported so far. We report a case of lateral medullary syndrome showing syndrome of inappropriate secretion of antidiuretic hormone and analyze the pathomechanism underlying its clinical features. CASE PRESENTATION: A 67-year-old man was admitted to our hospital for dizziness, dysarthria, and dysphagia. He was diagnosed with lateral medullary syndrome based on the neurological examination and brain magnetic resonance imaging. Horner syndrome was absent. Asymptomatic hyponatremia appeared 9 days after admission and the patient was diagnosed with syndrome of inappropriate secretion of antidiuretic hormone. Fluid restriction and intravenous furosemide injection improved the hyponatremia. CONCLUSION: Lateral medullary syndrome could be associated with syndrome of inappropriate secretion of antidiuretic hormone. PMID- 27461341 TI - Application of Targeted Molecular and Material Property Optimization to Bacterial Attachment-Resistant (Meth)acrylate Polymers. AB - Developing medical devices that resist bacterial attachment and subsequent biofilm formation is highly desirable. In this paper, we report the optimization of the molecular structure and thus material properties of a range of (meth)acrylate copolymers which contain monomers reported to deliver bacterial resistance to surfaces. This optimization allows such monomers to be employed within novel coatings to reduce bacterial attachment to silicone urinary catheters. We show that the flexibility of copolymers can be tuned to match that of the silicone catheter substrate, by copolymerizing these polymers with a lower Tg monomer such that it passes the flexing fatigue tests as coatings upon catheters, that the homopolymers failed. Furthermore, the Tg values of the copolymers are shown to be readily estimated by the Fox equation. The bacterial resistance performance of these copolymers were typically found to be better than the neat silicone or a commercial silver containing hydrogel surface, when the monomer feed contained only 25 v% of the "hit" monomer. The method of initiation (either photo or thermal) was shown not to affect the bacterial resistance of the copolymers. Optimized synthesis conditions to ensure that the correct copolymer composition and to prevent the onset of gelation are detailed. PMID- 27461340 TI - Dying well with reduced agency: a scoping review and thematic synthesis of the decision-making process in dementia, traumatic brain injury and frailty. AB - BACKGROUND: In most Anglophone nations, policy and law increasingly foster an autonomy-based model, raising issues for large numbers of people who fail to fit the paradigm, and indicating problems in translating practical and theoretical understandings of 'good death' to policy. Three exemplar populations are frail older people, people with dementia and people with severe traumatic brain injury. We hypothesise that these groups face some over-lapping challenges in securing good end-of-life care linked to their limited agency. To better understand these challenges, we conducted a scoping review and thematic synthesis. METHODS: To capture a range of literature, we followed established scoping review methods. We then used thematic synthesis to describe the broad themes emerging from this literature. RESULTS: Initial searches generated 22,375 references, and screening yielded 49, highly heterogeneous, studies that met inclusion criteria, encompassing 12 countries and a variety of settings. The thematic synthesis identified three themes: the first concerned the processes of end-of-life decision-making, highlighting the ambiguity of the dominant shared decision making process, wherein decisions are determined by families or doctors, sometimes explicitly marginalising the antecedent decisions of patients. Despite this marginalisation, however, the patient does play a role both as a social presence and as an active agent, by whose actions the decisions of those with authority are influenced. The second theme examined the tension between predominant notions of a good death as 'natural' and the drive to medicalise death through the lens of the experiences and actions of those faced with the actuality of death. The final theme considered the concept of antecedent end-of life decision-making (in all its forms), its influence on policy and decision making, and some caveats that arise from the studies. CONCLUSIONS: Together these three themes indicate a number of directions for future research, which are likely to be applicable to other conditions that result in reduced agency. Above all, this review emphasises the need for new concepts and fresh approaches to end of life decision-making that address the needs of the growing population of frail older people, people with dementia and those with severe traumatic brain injury. PMID- 27461343 TI - Molecular Mechanisms of Action of M5 Muscarinic Acetylcholine Receptor Allosteric Modulators. AB - Recently, the first subtype-selective allosteric modulators of the M5 muscarinic acetylcholine receptor (mAChR) have been described, but their molecular mechanisms of action remain unknown. Using radioligand-binding and functional assays of inositol phosphate (IP) accumulation and Ca(2+) mobilization in a recombinant cell line stably expressing the human M5 mAChR, we investigated the effects of the positive allosteric modulator (PAM), ML380, and negative allosteric modulator, ML375. In functional assays, ML380 caused robust enhancements in the potency of the full agonists, acetylcholine (ACh), carbachol, and oxotremorine-M, while significantly increasing the maximal response to the partial agonist, pilocarpine. ML380 also demonstrated direct allosteric agonist activity. In contrast, ML375 displayed negative cooperativity with each of the agonists in a manner that varied with the pathway investigated and progressively reduced the maximal pilocarpine response. Radioligand-binding affinity cooperativity estimates were consistent with values derived from functional assays in some instances but not others, suggesting additional allosteric effects on orthosteric ligand efficacy. For ML375 this was confirmed in IP assays performed after reduction of receptor reserve by the alkylating agent, phenoxybenzamine, as it reduced the maximal ACh response. In contrast, ML380 enhanced only ACh potency after receptor alkylation, with no effect on maximal response, consistent with studies of the M1 mAChR with the prototypical PAM, BQZ12. Interaction studies between ML380 and ML375 also indicated that they most likely used an overlapping allosteric site. Our findings indicate that novel small-molecule modulators of the M5 mAChR display mixed mechanisms of action compared with previously characterized modulators of other mAChRs. PMID- 27461342 TI - Hypomethylation coordinates antagonistically with hypermethylation in cancer development: a case study of leukemia. AB - BACKGROUND: Methylation changes are frequent in cancers, but understanding how hyper- and hypomethylated region changes coordinate, associate with genomic features, and affect gene expression is needed to better understand their biological significance. The functional significance of hypermethylation is well studied, but that of hypomethylation remains limited. Here, with paired expression and methylation samples gathered from a patient/control cohort, we attempt to better characterize the gene expression and methylation changes that take place in cancer from B cell chronic lymphocyte leukemia (B-CLL) samples. RESULTS: Across the dataset, we found that consistent differentially hypomethylated regions (C-DMRs) across samples were relatively few compared to the many poorly consistent hypo- and highly conserved hyper-DMRs. However, genes in the hypo-C-DMRs tended to be associated with functions antagonistic to those in the hyper-C-DMRs, like differentiation, cell-cycle regulation and proliferation, suggesting coordinated regulation of methylation changes. Hypo-C DMRs in B-CLL were found enriched in key signaling pathways like B cell receptor and p53 pathways and genes/motifs essential for B lymphopoiesis. Hypo-C-DMRs tended to be proximal to genes with elevated expression in contrast to the transcription silencing-mechanism imposed by hypermethylation. Hypo-C-DMRs tended to be enriched in the regions of activating H4K4me1/2/3, H3K79me2, and H3K27ac histone modifications. In comparison, the polycomb repressive complex 2 (PRC2) signature, marked by EZH2, SUZ12, CTCF binding-sites, repressive H3K27me3 marks, and "repressed/poised promoter" states were associated with hyper-C-DMRs. Most hypo-C-DMRs were found in introns (36 %), 3' untranslated regions (29 %), and intergenic regions (24 %). Many of these genic regions also overlapped with enhancers. The methylation of CpGs from 3'UTR exons was found to have weak but positive correlation with gene expression. In contrast, methylation in the 5'UTR was negatively correlated with expression. To better characterize the overlap between methylation and expression changes, we identified correlation modules that associate with "apoptosis" and "leukocyte activation". CONCLUSIONS: Despite clinical heterogeneity in disease presentation, a number of methylation changes, both hypo and hyper, appear to be common in B-CLL. Hypomethylation appears to play an active, targeted, and complementary role in cancer progression, and it interplays with hypermethylation in a coordinated fashion in the cancer process. PMID- 27461344 TI - First contact: acute stress reactions and experiences of emergency department consultations following an incident of intimate partner violence. AB - AIMS AND OBJECTIVES: The aim of this research was to explore women's emotional and affective responses following an incident of intimate partner violence experienced during emergency department attendances. BACKGROUND: A growing body of research has explored women's experiences of emergency departments following intimate partner violence still little remains known about the experience and impact of emotional and affective responses during these attendances. DESIGN: A descriptive qualitative design was used, underpinned theoretically by critical realism and postmodern complexity theory to attend to multiple, intersecting mechanisms that lie behind events and experiences. METHODS: Semistructured interviews with six women who had attended an emergency department directly following an incident of intimate partner violence. Interview data were transcribed and thematically analysed in nvivo9 using a coding framework. RESULTS: There were three interconnected key findings. First, was the commonality of acute stress experiences among women attending an emergency department following partner violence, second was that these acute stress reactions negatively impacted women's consultations, and third was the need for specialist domestic violence services at the point of first contact to assist service users navigate an effective consultation. CONCLUSIONS: Acute stress reactions were an important feature of women's experiences of emergency department consultations following intimate partner violence. Attending to psychological first aid; providing a safe and quiet space; and affording access to specialist violence advocacy services at the point of first contact will limit harm and improve health consultation outcomes for this population. RELEVANCE TO CLINICAL PRACTICE: This research provides an account of emotional and affective responses experienced by women attending emergency departments following intimate partner violence and explicates how these acute stress reactions impacted their consultation. This research has relevance for practitioners in many first contact health services, such as urgent and emergency care, general practice, community public health and mental health. PMID- 27461345 TI - In this issue August 2016: Preventive health care of Pony Club horses . Treatment of subclinical Streptococcus equi in Thoroughbreds . Cardiac biomarker concentrations in canine tick paralysis . Lead toxicity diagnosis in two dogs . Feline leprosy syndrome (FLS) in a cat . Skin blistering in a dog exposed to Plumbago auriculata . Postpartum anoestrus in seasonally-calving dairy farms in Victoria . Plasmodium infection in a Leadbeater's possum. PMID- 27461346 TI - Anthony William English AM RFD BVSc(Hons) PhD FACVs 1943 - 2015. PMID- 27461347 TI - Preventive health care of Pony Club horses in rural New South Wales, Australia. AB - OBJECTIVE: To describe preventive health care provided to a cohort of Pony Club horses in rural New South Wales, Australia, and the associated veterinary involvement. DESIGN: Prospective longitudinal study METHODS: Observational data collected for 48 Pony Club horses using daily owner-kept diaries and monthly veterinary visits for 9-12 months. RESULTS: Frequency of healthcare events varied markedly between the horses; 54% of horses received 5 or more foot-care treatments, 69% received 1-3 anthelmintic treatments, 40% received dental care, 21% received chiropractic care; only 8% were vaccinated. Farriers and owners administered most of the health care. Veterinarians were infrequently involved, administering 2 of the 111 anthelmintic administrations and 2 of the 244 foot care treatments. No annual health checks or prepurchase examinations were recorded. All dental care was provided by non-veterinary dentists. Horse turnover appeared quick, with 54% of horses acquired within the previous 12 months. CONCLUSION: The majority of preventive health care was provided by farriers and the owners themselves. The type and frequency of healthcare events varied markedly and most commonly involved foot care and anthelmintic administration. The reasons for the lack of veterinary involvement are unclear. Veterinarians engaging with Pony Club families in a preventive context would likely bring health benefits to this population of horses. This may require adaptation of existing veterinary services to meet the demands of this unique population of horses and young riders. Furthermore, epidemiological studies are required to describe the effects of various preventive healthcare interventions on subsequent and long-term horse health. PMID- 27461349 TI - Erratum. PMID- 27461348 TI - Preliminary study of tissue concentrations of penicillin after local administration into the guttural pouches in four healthy horses. AB - BACKGROUND: Treatment of subclinical carriers of Streptococcus equi subsp. equi with a gelatine-penicillin formulation deposited in the guttural pouch has been empirically proposed, but data on local tissue penicillin concentrations after treatment are lacking. METHODS: We analysed tissue levels of penicillin after administration into the guttural pouches of four healthy horses. Two horses received local treatment with gelatine-penicillin and two horses received local treatment with an intramammary formulation of penicillin. Tissues were harvested for analysis either 12 or 24 h later. CONCLUSION: Results indicate that local treatment may be effective, but more research on optimal drug formulations in a larger sample size is warranted. PMID- 27461351 TI - Erratum. PMID- 27461350 TI - NT-proBNP and cardiac troponin I concentrations in dogs with tick paralysis caused by Ixodes holocyclus. AB - OBJECTIVE: The purpose of this study was to determine through measurement of cardiac biomarkers whether there was cardiac involvement in dogs infested with Ixodes holocyclus. METHODS: Dogs with tick paralysis and no-mild (group 1; n = 44) or moderate-severe respiratory compromise (group 2; n = 36) and a control group of dogs (n = 31) were enrolled. Plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), serum cardiac troponin I (cTnI) and serum creatinine concentrations were determined. For most of the affected dogs SpO2 was determined. RESULTS: SpO2 readings did not differ between groups 1 and 2. Three animals in group 2 had an SpO2 reading <90%. NT-proBNP concentrations were lower in both groups 1 and 2 compared with the control group. There was no difference in cTnI concentrations among groups, although they were elevated in four dogs, including the three dogs in group 2 with SpO2 readings <90%. Creatinine concentrations were within the reference interval for all dogs, but did differ among the groups, with control dogs having the highest values, followed by group 1 and then group 2. CONCLUSION: This study did not detect significant cardiac involvement in dogs with tick paralysis induced by I. holocyclus. Evidence for reduced preload in dogs with tick paralysis was provided by lower NT-proBNP concentrations compared with control dogs. Severe hypoxaemia may not be a significant component of the clinical picture in many of the dogs presenting with tick paralysis. Dogs with severe hypoxaemia may have loss of cardiomyocyte integrity, reflected by elevated cTnI concentrations. PMID- 27461352 TI - Proximal tubular nephropathy in two dogs diagnosed with lead toxicity. AB - CASE REPORT: Lead toxicity was diagnosed in two dogs presenting with vague clinical symptoms. Complete blood count, biochemical testing and imaging changes showed a metarubricytosis in dog 1, but were largely normal in dog 2. Both dogs had glucosuria and proteinuria on urinalysis consistent with damage to the proximal renal tubules. Both animals returned elevated blood lead levels. A history of ingestion of lead was reported by the owner in one dog and elucidated from the second owner once the animal had recorded elevated blood lead levels. CONCLUSION: Lead toxicity is rarely reported in the human literature as a cause of proximal tubular dysfunction. To the author's knowledge this is the first case report specifically examining this in the dog. The clinical awareness that lead is a potential cause of proximal renal tubular dysfunction offers another tool to assist the clinician in the diagnostic process. This is particularly important given that the clinical signs and minimum database findings in animals with lead toxicosis are highly variable. Evidence of proximal tubular dysfunction should trigger the clinician to closely examine the history for a potential source of lead exposure and consider submitting samples to test blood lead levels. PMID- 27461353 TI - Autochthonous feline leprosy caused by Mycobacterium sp. strain Tarwin affecting a cat from the Central Coast of New South Wales. AB - CASE REPORT: A 5-year-old Domestic Shorthair-cross was presented with a raised, alopecic skin nodule affecting the external surface of the right upper lip with an adjacent second smaller satellite lesion. Fine needle aspiration cytology revealed numerous intracellular and extracellular negatively stained bacilli. Histopathology confirmed granulomatous inflammation with multinucleate giant cell formation and abundant intracellular acid-fast bacilli, consistent with a mycobacterial aetiology. PCR testing of the fresh tissue from the satellite lesion and subsequent sequence analysis identified Mycobacterium sp. strain Tarwin. The skin lesion was surgically excised and clarithromycin 62.5 mg twice daily was administered to the cat for 25 days. CONCLUSION: There was no recurrence of the lesion at the time of writing, 16 months after the surgery. This is the second autochthonous case of feline leprosy caused by M. sp. strain Tarwin originating in New South Wales, Australia. PMID- 27461354 TI - A vesicular (blistering) skin condition in a dog following putative contact exposure to Plumbago auriculata. AB - CASE REPORT: A 2-year-old male Airedale Terrier was presented with an acute and painful, predominantly ventral, vesicular skin eruption following putative dermal contact with Plumbago auriculata (Sky Flower, Leadwort). Prompt dermal decontamination and supportive therapy brought about a rapid recovery in the patient. CONCLUSION: Contact with botanical triggers is an important consideration for causes of acute vesicular skin conditions in dogs. PMID- 27461355 TI - Postpartum anoestrus in five seasonally-calving dairy farms in Victoria, Australia. AB - OBJECTIVE: A cross-sectional study of seasonally-calving dairy cows in south western Victoria to quantify the prevalence of anoestrus and to assess the effect of body condition score (BCS), days in milk (DIM) at mating start date (MSD) and age on the likelihood of being diagnosed as anoestrus. METHODS: Age, DIM and BCS details were collected from 1795 cycling and 1399 cows diagnosed as anoestrus in five seasonally-calving dairy herds in Victoria. Multivariable logistic regression was used to quantify the association between BCS, DIM and age and the probability of being diagnosed as anoestrus. RESULTS: The apparent prevalence of anoestrus in cows that took part in the study was 44% (95% confidence interval (CI) 42-46%). The risk of anoestrus increased with decreases in DIM and BCS. There was a significant interaction between BCS and DIM. For cows >90 DIM at MSD (the reference category) the odds of anoestrus in cows with BCS <4.00 was 8.05 fold (95% CI 3.2-20.2) that of cows of BCS >=4.50. The risk of anoestrus decreased with increases in cow age. Cows aged 2 and 3-5 years had 2.4-fold (95% CI 1.79-3.22) and 1.4 (95% CI 1.11-1.77) odds of anoestrus, respectively, compared with cows aged >=6 years. CONCLUSION: Reproductive management to maximise the number of days calved at MSD and nutritional management to ensure cows are in BCS >4.5 at mating will reduce the prevalence of anoestrus in Victorian dairy herds. PMID- 27461356 TI - Plasmodium infection in a Leadbeater's possum (Gymnobelideus leadbeateri). AB - CASE REPORT: A wild-caught, adult female Leadbeater's possum (Gymnobelideus leadbeateri) died while in captivity after suffering from chronic ill-thrift that progressed to acute respiratory distress. On histopathological examination of tissues, the cause of death was determined to be severe acute pneumonia with pulmonary oedema associated with an intracellular protozoan parasite present within erythrocytes. Transmission electron microscopy was performed on lung tissues and organisms consistent for Plasmodium sp. were identified within numerous erythrocytes. Molecular characterisation of the parasite from DNA extracted from tissue blocks of fixed lung determined the organism to belong to the genus Plasmodium (100% similarity to Plasmodium species when a BLAST analysis was performed); however, speciation of the organism was not possible. CONCLUSION: This is the first report of Plasmodium sp. infection and subsequent disease in a native Australian mammal. The lifecycle of this parasite remains unknown. It is also unknown what effects haemoparasitism may have on the population dynamics of this endangered possum species. PMID- 27461358 TI - MALDI imaging mass spectrometry analysis-A new approach for protein mapping in multiple sclerosis brain lesions. AB - Multiple sclerosis is a disease of the central nervous system characterized by recurrent inflammatory demyelinating lesions in the early disease stage. Lesion formation and mechanisms leading to lesion remyelination are not fully understood. Matrix Assisted Laser Desorption Ionisation Mass Spectrometry imaging (MALDI-IMS) is a technology which analyses proteins and peptides in tissue, preserves their spatial localization, and generates molecular maps within the tissue section. In a pilot study we employed MALDI imaging mass spectrometry to profile and identify peptides and proteins expressed in normal-appearing white matter, grey matter and multiple sclerosis brain lesions with different extents of remyelination. The unsupervised clustering analysis of the mass spectra generated images which reflected the tissue section morphology in luxol fast blue stain and in myelin basic protein immunohistochemistry. Lesions with low remyelination extent were defined by compounds with molecular weight smaller than 5300Da, while more completely remyelinated lesions showed compounds with molecular weights greater than 15,200Da. An in-depth analysis of the mass spectra enabled the detection of cortical lesions which were not seen by routine luxol fast blue histology. An ion mass, mainly distributed at the rim of multiple sclerosis lesions, was identified by liquid chromatography and tandem mass spectrometry as thymosin beta-4, a protein known to be involved in cell migration and in restorative processes. The ion mass of thymosin beta-4 was profiled by MALDI imaging mass spectrometry in brain slides of 12 multiple sclerosis patients and validated by immunohistochemical analysis. In summary, our results demonstrate the ability of the MALDI-IMS technology to map proteins within the brain parenchyma and multiple sclerosis lesions and to identify potential markers involved in multiple sclerosis pathogenesis and/or remyelination. PMID- 27461359 TI - Simultaneous pentafluorobenzyl derivatization and GC-ECNICI-MS measurement of nitrite and malondialdehyde in human urine: Close positive correlation between these disparate oxidative stress biomarkers. AB - Urinary nitrite and malondialdehyde (MDA) are biomarkers of nitrosative and oxidative stress, respectively. At physiological pH values of urine and plasma, nitrite and MDA exist almost entirely in their dissociated forms, i.e., as ONO- (ONOH, pKa=3.4) and -CH(CHO)2 (CH2(CHO)2, pKa=4.5). Previously, we reported that nitrite and MDA react with pentafluorobenzyl (PFB) bromide (PFB-Br) in aqueous acetone. Here, we report on the simultaneous derivatization of nitrite and MDA and their stable-isotope labeled analogs O15NO- (4MUM) and CH2(CDO)2 (1MUM or 10MUM) with PFB-Br (10MUL) to PFBNO2, PFB15NO2, C(PFB)2(CHO)2), C(PFB)2(CDO)2 by heating acetonic urine (urine-acetone, 100:400MUL) for 60min at 50 degrees C. After acetone evaporation under a stream of nitrogen, derivatives were extracted with ethyl acetate (1mL). A 1-MUL aliquot of the ethyl acetate phase dried over anhydrous Na2SO4 was injected in the splitless mode for simultaneous GC-MS analysis in the electron capture negative-ion chemical ionization mode. Quantification was performed by selected-ion monitoring (SIM) the anions [M-PFB] m/z 46 for ONO-, m/z 47 for O15NO-, m/z 251 for -C(PFB)(CHO)2, and m/z 253 for C(PFB)(CDO)2. The retention times were 3.18min for PFB-ONO2/PFB-O15NO2, and 7.13min for -C(PFB)(CHO)2/-C(PFB)(CDO)2. Use of CH2(CDO)2 at 1MUM but not at 10MUM was associated with an unknown interference with the C(PFB)2(CDO)2 peak. Endogenous MDA can be quantified using O15NO- (4MUM) and CH2(CDO)2 (10MUM) as the internal standards. The method is also useful for the measurement of nitrate and creatinine in addition to nitrite and MDA. Nitrite and MDA were measured by this method in urine of elderly healthy subjects (10 females, 9 males; age, 60-70 years; BMI, 25-30kg/m2). Creatinine-corrected excretion rates did not differ between males and females for MDA (62.6 [24-137] vs 80.2 [52-118]nmol/mmol, P=0.448) and for nitrite (102 [71-174] vs. 278 [110-721]nmol/mmol P=0.053). We report for the first time a close correlation (r=0.819, P<0.0001) between MDA and nitrite in human urine. This correlation is assumed to be due to involvement of myeloperoxidase which catalyzes the formation of hypochlorite (-OCl) from chloride and hydrogen peroxide. In turn, hypochlorite reacts both with nitrite and with polyunsaturated fatty acids such as arachidonic acid, with the later reaction generating MDA. The proposed mechanisms are supported by the literature but remain to be fully explored. PMID- 27461360 TI - Cyclin E as a potential therapeutic target in high grade serous ovarian cancer. AB - Cyclin E1 (CCNE1) gene amplification occurs in approximately 20% of ovarian high grade serous carcinoma (HGSC) and is associated with chemotherapy resistance and, in some studies, overall poor prognosis. The role of cyclin E1 in inducing S phase entry relies upon its interactions with cyclin dependent kinases (CDK), specifically CDK2. Therapies to target cyclin E1-related functions have centered on CDK inhibitors and proteasome inhibitors. While many studies have helped elucidate the functions and regulatory mechanisms of cyclin E1, further research utilizing cyclin E1 as a therapeutic target in ovarian cancer is warranted. This review serves to present the scientific background describing the role and function of cyclin E1 in cancer development and progression, to distinguish cyclin E1-amplified HGSC as a unique subset of ovarian cancer deserving of further therapeutic investigation, and to provide an updated overview on the studies which have utilized cyclin E1 as a target for therapy in ovarian cancer. PMID- 27461361 TI - Tracking of plus-ends reveals microtubule functional diversity in different cell types. AB - Many cellular processes are tightly connected to the dynamics of microtubules (MTs). While in neuronal axons MTs mainly regulate intracellular trafficking, they participate in cytoskeleton reorganization in many other eukaryotic cells, enabling the cell to efficiently adapt to changes in the environment. We show that the functional differences of MTs in different cell types and regions is reflected in the dynamic properties of MT tips. Using plus-end tracking proteins EB1 to monitor growing MT plus-ends, we show that MT dynamics and life cycle in axons of human neurons significantly differ from that of fibroblast cells. The density of plus-ends, as well as the rescue and catastrophe frequencies increase while the growth rate decreases toward the fibroblast cell margin. This results in a rather stable filamentous network structure and maintains the connection between nucleus and membrane. In contrast, plus-ends are uniformly distributed along the axons and exhibit diverse polymerization run times and spatially homogeneous rescue and catastrophe frequencies, leading to MT segments of various lengths. The probability distributions of the excursion length of polymerization and the MT length both follow nearly exponential tails, in agreement with the analytical predictions of a two-state model of MT dynamics. PMID- 27461362 TI - Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice. AB - Acute pancreatitis (AP) is a common and devastating gastrointestinal disorder that causes significant morbidity. The disease starts as local inflammation in the pancreas that may progress to systemic inflammation and complications. Protein tyrosine phosphatase 1B (PTP1B) is implicated in inflammatory signaling, but its significance in AP remains unclear. To investigate whether PTP1B may have a role in AP, we used pancreas PTP1B knockout (panc-PTP1B KO) mice and determined the effects of pancreatic PTP1B deficiency on cerulein- and arginine-induced acute pancreatitis. We report that PTP1B protein expression was increased in the early phase of AP in mice and rats. In addition, histological analyses of pancreas samples revealed enhanced features of AP in cerulein-treated panc-PTP1B KO mice compared with controls. Moreover, cerulein- and arginine-induced serum amylase and lipase were significantly higher in panc-PTP1B KO mice compared with controls. Similarly, pancreatic mRNA and serum concentrations of the inflammatory cytokines IL-1B, IL-6, and tumor necrosis factor-alpha were increased in panc PTP1B KO mice compared with controls. Furthermore, panc-PTP1B KO mice exhibited enhanced cerulein- and arginine-induced NF-kappaB inflammatory response accompanied with increased mitogen-activated protein kinases activation and elevated endoplasmic reticulum stress. Notably, these effects were recapitulated in acinar cells treated with a pharmacological inhibitor of PTP1B. These findings reveal a novel role for pancreatic PTP1B in cerulein- and arginine-induced acute pancreatitis. PMID- 27461363 TI - Lung Epithelial Cell-Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa(-/-) Mice. AB - Lysosomal acid lipase (LAL), a key enzyme in the metabolic pathway of neutral lipids, has a close connection with inflammation and tumor progression. One major manifestation in LAL-deficient (Lipa(-/-)) mice is an increase of tumor growth and metastasis associated with expansion of myeloid-derived suppressor cells. In the lung, LAL is highly expressed in alveolar type II epithelial cells. To assess how LAL in lung epithelial cells plays a role in this inflammation-related pathogenic process, lung alveolar type II epithelial cell-specific expression of human LAL (hLAL) in Lipa(-/-) mice was established by crossbreeding of CCSP driven rtTA transgene and (TetO)7-CMV-hLAL transgene into Lipa(-/-) mice (CCSP Tg/KO). hLAL expression in lung epithelial cells not only reduced tumor-promoting myeloid-derived suppressor cells in the lung, but also down-regulated the synthesis and secretion of tumor-promoting cytokines and chemokines into the bronchoalveolar lavage fluid of Lipa(-/-) mice. hLAL expression reduced the immunosuppressive functions of bronchoalveolar lavage fluid cells, inhibited bone marrow cell transendothelial migration, and inhibited endothelial cell proliferation and migration in Lipa(-/-) mice. As a result, hLAL expression in CCSP-Tg/KO mice corrected pulmonary damage, and inhibited tumor cell proliferation and migration in vitro, and tumor metastasis to the lung in vivo. These results support a concept that LAL is a critical metabolic enzyme in lung epithelial cells that regulates lung homeostasis, immune response, and tumor metastasis. PMID- 27461364 TI - Galectin-3, Cardiac Function, and Fibrosis. AB - This Correspondence relates to the article by Frunza et al (Myocardial Galectin-3 Expression Is Associated with Remodeling of the Pressure-Overloaded Heart and May Delay the Hypertrophic Response without Affecting Survival, Dysfunction, and Cardiac Fibrosis. Am J Pathol 2016, 186:1114-1127). PMID- 27461365 TI - Authors' Reply. AB - This correspondence is a reply to Galectin-3, Cardiac Function, and Fibrosis by Wouter C. Meijers et al. PMID- 27461366 TI - Corrections. PMID- 27461367 TI - Modelling the cost-effectiveness of pharmacist-managed anticoagulation service for older adults with atrial fibrillation in Singapore. AB - Background Oral anticoagulation with warfarin is the cornerstone therapy in atrial fibrillation (AF) for stroke prevention. Multi-disciplinary anticoagulation management services have been shown to be cost-effective in the United States, Hong Kong and Thailand, but the findings are not readily generalizable to Singapore's healthcare system. Objective This study aimed to evaluate the cost-effectiveness of pharmacist-managed anticoagulation clinic (ACC) compared with usual care (UC) for the management of older adults with AF receiving oral anticoagulation with warfarin. Setting Pharmacist-managed ACC in an academic medical centre. Method A Markov model with 3-month cycle length and 30-year time horizon compared costs and quality-adjusted life-years (QALYs) of ACC and UC from the patient's and healthcare provider's perspectives. Four pathways based on time in therapeutic range (TTR) were: ACC TTR < 70 %, ACC TTR >= 70 %, UC TTR < 70 % and UC TTR >= 70 %. A hypothetical cohort of 70-year-old Singaporean AF patients receiving warfarin was utilised. Local data from national disease registries, patient surveys and hospital databases were used. When local data was not available, published studies on Asian populations were utilized when available. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to account for uncertainties. Costs and QALYs were discounted annually by 3 %. Main outcome measure Costs and QALYs of ACC and UC. Results Pharmacist-managed ACC was found to dominate UC in all comparisons. It improved effectiveness by 0.19 and 0.13 QALYs at TTR < 70 % and TTR >= 70 % respectively compared with UC. From the patient's perspective, ACC reduced costs by SG$1222.67 (?1110.24) for TTR < 70 % and SG$1008.16 (?915.46) for TTR >= 70 %. Similar trends were observed from the healthcare provider's perspective, with ACC reducing costs by SG$1444.79 (?1311.94) for TTR < 70 % and SG$1269.17 (?1152.46) for TTR >= 70 % compared with UC. The results were robust to variations of the parameters over their plausible ranges in one-way sensitivity analyses. Probabilistic sensitivity analyses demonstrated that ACC was cost-effective more than 79 % of the time from both perspectives at a willingness-to-pay threshold of SG$69,050 (?62,701) per QALY. Conclusion Pharmacist-managed ACC is more effective and less costly compared with UC regardless of the quality of anticoagulation therapy. The findings support the current body of evidence demonstrating the cost effectiveness of ACC. PMID- 27461368 TI - How Variable Is Our Delivery of Information? Approaches to Patient Education About Oral Chemotherapy in the Pediatric Oncology Clinic. AB - In pediatric patients with acute lymphoblastic leukemia, adherence to oral chemotherapy relies largely on a parent's comprehension of the drug's indication and administration guidelines. We assessed how pediatric oncology providers educate families about oral chemotherapy. We conducted a cross-sectional survey of 68 physicians and nurses from 9 institutions in the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium. The inter-individual approach to patient education is variable and may consist of handouts, treatment calendars, and discussions. The extent of teaching often varies depending on a provider's subjective assessment of a family's needs. Twenty-five percent of providers suggested standardizing patient teaching. When developing educational models, care teams should consider approaches that (a) objectively identify families in need of extensive teaching, (b) designate allotted teaching time by nursing staff during clinic visits, and (c) maintain the variation and dynamism that informs a successful provider-patient relationship. PMID- 27461369 TI - Theory for nonlinear dynamic force spectroscopy. AB - Dynamic force spectroscopy (DFS) is an experimental technique that is commonly used to assess information on the strength, energy landscape, and lifetime of noncovalent bio-molecular interactions. DFS traditionally requires an applied force that increases linearly with time so that the bio-complex under investigation is exposed to a constant loading rate. However, tethers or polymers can modulate the applied force in a nonlinear manner. For example, bacterial adhesion pili and polymers with worm-like chain properties are structures that show nonlinear force responses. In these situations, the theory for traditional DFS cannot be readily applied. In this work, we expand the theory for DFS to also include nonlinear external forces while still maintaining compatibility with the linear DFS theory. To validate the theory, we modeled a bio-complex expressed on a stiff, an elastic, and a worm-like chain polymer, using Monte Carlo methods, and assessed the corresponding rupture force spectra. It was found that the nonlinear DFS (NLDFS) theory correctly predicted the numerical results. We also present a protocol suggesting an experimental approach and analysis method of the data to estimate the bond length and the thermal off-rate. PMID- 27461370 TI - Chronic postsurgical pain in patients 5 years after cardiac surgery: A prospective cohort study. AB - BACKGROUND: Chronic postsurgical pain (CPSP) is a common complication after many surgical procedures, including cardiac surgery. The prevalence of CPSP after cardiac surgery ranges from 9.5% to 56%. Most studies on CPSP after cardiac surgery are retrospective and long-term prospective studies are scarce. The aim of this study was to follow CPSP and health-related quality of life (HRQOL) prospectively in a cohort of patients, emphasizing the prevalence from 12 months to 5 years. METHODS: A total of 534 patients (23% >=75 years, 67% men) were consecutively included before surgery. Study-specific questionnaires and the Brief Pain Inventory (BPI) were used to measure CPSP at baseline, 12 months and 5 year follow-up. Short-Form Health Survey (SF-36) was used to measure HRQOL. RESULTS: Among 458 patients who were alive after 5 years, 82% responded (n = 373). The majority, 89.8% (335/373), did not report CPSP, neither 12 months nor 5 years after surgery. Among the 38 patients who reported CPSP after 12 months, 24 (63%) patients did not report CPSP after 5 years. The overall prevalence of CPSP after 5 years was 3.8% (14/373). Patients reporting CPSP and resolved CPSP had lower scores on HRQOL and more pain preoperatively than patients who did not report CPSP. CONCLUSIONS: The prevalence of CPSP was lower in this study than previously reported. Among the patients reporting CPSP at 12 months, 63% did not report CPSP after 5 years. Hence, the observed decline in CPSP is in line with studies evaluating CPSP in noncardiac surgery. SIGNIFICANCE: The prevalence of chronic postsurgical pain (CPSP) at 5 years after surgery of 3.8% is lower than previously reported. The majority of patients reporting CPSP after 12 months did not report CPSP after 5 years. PMID- 27461371 TI - Endocannabinoids control vesicle release mode at midbrain periaqueductal grey inhibitory synapses. AB - KEY POINTS: The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices. Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular. Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode. Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release. These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition. ABSTRACT: The midbrain periaqueductal grey (PAG) has a crucial role in coordinating endogenous analgesic responses to physiological and psychological stressors. Endocannabinoids are thought to mediate a form of stress induced analgesia within the PAG by relieving GABAergic inhibition of output neurons, a process known as disinhibition. This disinhibition is thought to be achieved by a presynaptic reduction in GABA release probability. We examined whether other mechanisms have a role in endocannabinoid modulation of GABAergic synaptic transmission within the rat PAG. The group I mGluR agonist DHPG ((R,S) 3,5-dihydroxyphenylglycine) inhibited evoked IPSCs and increased their paired pulse ratio in normal external Ca2+ , and when release probability was reduced by lowering Ca2+ . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca2+ . Lowering external Ca2+ had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca2+ . The low affinity GABAA receptor antagonist TPMPA ((1,2,5,6 tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca2+ . Together these findings indicate that the normal mode of GABA release is multivesicular within the PAG, and that DHPG and lowering external Ca2+ switch this to a univesicular mode. The effects of DHPG were mediated by mGlu5 receptor engagement of the retrograde endocannabinoid system. Blockade of endocannabinoid breakdown produced a similar shift in the mode of release. We conclude that endocannabinoids control both the mode and the probability of GABA release within the PAG. PMID- 27461372 TI - [Corynebacterium striatum meningitis]. PMID- 27461373 TI - Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus. AB - Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3beta (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID- 27461374 TI - Bioconjugation - using selective chemistry to enhance the properties of proteins and peptides as therapeutics and carriers. AB - The pharmaceutical market has largely been dominated by small molecule drugs; however, larger biomolecules have recently become important contenders. Of these biomolecules, protein and peptide therapeutics are proving useful due to their often improved pharmacokinetic properties. In many circumstances, functionalisation of the protein or peptide therapeutics results in performance enhancement, and various methodologies are applied. In addition, introducing unnatural amino acids for structural reinforcement via chemical modification is also common. These strategies are discussed in this review. PMID- 27461375 TI - Underlying Mechanisms of Pituitary-Thyroid Axis Function Disruption by Chronic Iodine Excess in Rats. AB - BACKGROUND: Iodine is essential for thyroid hormone synthesis and is an important regulator of thyroid function. Chronic iodine deficiency leads to hypothyroidism, but iodine excess also impairs thyroid function causing hyperthyroidism, hypothyroidism, and/or thyroiditis. This study aimed to investigate the underlying mechanisms by which exposure to chronic iodine excess impairs pituitary-thyroid axis function. METHODS: Male Wistar rats were treated for two months with NaI (0.05% and 0.005%) or NaI+NaClO4 (0.05%) dissolved in drinking water. Hormone levels, gene expression, and thyroid morphology were analyzed later. RESULTS: NaI-treated rats presented high levels of iodine in urine, increased serum thyrotropin levels, slightly decreased serum thyroxine/triiodothyronine levels, and a decreased expression of the sodium iodide symporter, thyrotropin receptor, and thyroperoxidase mRNA and protein, suggesting a primary thyroid dysfunction. In contrast, thyroglobulin and pendrin mRNA and protein content were increased. Kidney and liver deiodinase type 1 mRNA expression was decreased in iodine-treated rats. Morphological studies showed larger thyroid follicles with higher amounts of colloid and increased amounts of connective tissue in the thyroid of iodine-treated animals. All these effects were prevented when perchlorate treatment was combined with iodine excess. CONCLUSIONS: The present data reinforce and add novel findings about the disruption of thyroid gland function and the compensatory action of increased thyrotropin levels in iodine-exposed animals. Moreover, they draw attention to the fact that iodine intake should be carefully monitored, since both deficient and excessive ingestion of this trace element may induce pituitary-thyroid axis dysfunction. PMID- 27461376 TI - The relative importance of vertical soil nutrient heterogeneity, and mean and depth-specific soil nutrient availabilities for tree species richness in tropical forests and woodlands. AB - The relative importance of resource heterogeneity and quantity on plant diversity is an ongoing debate among ecologists, but we have limited knowledge on relationships between tree diversity and heterogeneity in soil nutrient availability in tropical forests. We expected tree species richness to be: (1) positively related to vertical soil nutrient heterogeneity; (2) negatively related to mean soil nutrient availability; and (3) more influenced by nutrient availability in the upper than lower soil horizons. Using a data set from 60, 20 * 40-m plots in a moist forest, and 126 plots in miombo woodlands in Tanzania, we regressed tree species richness against vertical soil nutrient heterogeneity, both depth-specific (0-15, 15-30, and 30-60 cm) and mean soil nutrient availability, and soil physical properties, with elevation and measures of anthropogenic disturbance as co-variables. Overall, vertical soil nutrient heterogeneity was the best predictor of tree species richness in miombo but, contrary to our prediction, the relationships between tree species richness and soil nutrient heterogeneity were negative. In the moist forest, mean soil nutrient availability explained considerable variations in tree species richness, and in line with our expectations, these relationships were mainly negative. Soil nutrient availability in the top soil layer explained more of the variation in tree species richness than that in the middle and lower layers in both vegetation types. Our study shows that vertical soil nutrient heterogeneity and mean availability can influence tree species richness at different magnitudes in intensively utilized tropical vegetation types. PMID- 27461378 TI - Commentary to "Hypospadias: Are we as good as we think when we correct proximal hypospadias?". PMID- 27461377 TI - Flexibility in metabolic rate and activity level determines individual variation in overwinter performance. AB - Energy stores are essential for the overwinter survival of many temperate and polar animals, but individuals within a species often differ in how quickly they deplete their reserves. These disparities in overwinter performance may be explained by differences in their physiological and behavioral flexibility in response to food scarcity. However, little is known about whether individuals exhibit correlated or independent changes in these traits, and how these phenotypic changes collectively affect their winter energy use. We examined individual flexibility in both standard metabolic rate and activity level in response to food scarcity and their combined consequences for depletion of lipid stores among overwintering brown trout (Salmo trutta). Metabolism and activity tended to decrease, yet individuals exhibited striking differences in their physiological and behavioral flexibility. The rate of lipid depletion was negatively related to decreases in both metabolic and activity rates, with the smallest lipid loss over the simulated winter period occurring in individuals that had the greatest reductions in metabolism and/or activity. However, changes in metabolism and activity were negatively correlated; those individuals that decreased their SMR to a greater extent tended to increase their activity rates, and vice versa, suggesting among-individual variation in strategies for coping with food scarcity. PMID- 27461379 TI - ExPRESS miniature glaucoma shunt for intractable secondary glaucoma in superior vena cava syndrome - a case report. AB - BACKGROUND: The aim of this study was to clarify the pathogenic mechanism and to evaluate an intervention for intractable secondary glaucoma in superior vena cava (SVC) syndrome. CASE PRESENTATION: A 66-year-old female with underlying hypertension, diabetes mellitus, ischaemic heart disease and end-stage renal disease complained of bilateral puffy eyelids for 3 months. Over three years, the patient experienced a progressive, marked face and neck swelling, which was accompanied by dyspnoea and nocturnal coughing. The patient has been under haemodialysis for the past 5 years; there were several occurrences of vascular access re-establishment for susceptibility to vascular thrombosis, and she was also diagnosed with SVC syndrome 2 years after haemodialysis. The patient's best corrected visual acuity (BCVA) was 20/60 in the right eye and 20/400 in the left eye. Pneumatic tonometry revealed a gradual increase in the intraocular pressure (IOP), even with the use of three types of anti-glaucoma agents. The ratio was 0.7 and bilaterally symmetric; optical coherence tomography indicated a thinning of the superior and inferior retina nerve fibre layers, and standard automated perimetry showed partial to generalized depression in both eyes. Filtering surgery for the left eye was performed, but postoperatively, the IOP increased gradually over three months. The subsequent placement of the ExPRESS miniature glaucoma device p200 effectively lowered the IOP. Postoperatively, the IOP of the left eye remained under 20 mmHg without a further decrease in visual acuity, while the right eye, which was controlled with only medication, had an IOP of greater than 30 mmHg. Because this patient refused cardiovascular intervention, conventional trabeculectomy was used to redirect the aqueous humour to the subconjunctival space to form a bleb, but failed. Fortunately, the subsequent ExPRESS implant effectively facilitated aqueous outflow through the intrascleral space, resulting in the maintenance of a normal IOP at 6 months, postoperatively. CONCLUSION: Sustained high IOP may occur after conventional filtration surgery for secondary glaucoma in SVC syndrome. To facilitate aqueous outflow, an ExPRESS glaucoma implant can be used to effectively control the IOP. PMID- 27461381 TI - Women in Transition: Experiences of Health and Health Care for Recently Incarcerated Women Living in Community Corrections Facilities. AB - Health priorities of women after incarceration remain poorly understood, constraining development of interventions targeted at their health during that time. We explored the experience of health and health care after incarceration in a focused ethnography of 28 women who had been released from prison or jail within the past year and were living in community corrections facilities. The women's outlook on health was rooted in a newfound core optimism, but this was constrained by their pressing health-related issues; stress and uncertainty; and the pressures of the criminal justice system. These external forces threatened to cause collapse of women's core optimism. Findings support interventions that capitalize on women's optimism and address barriers specific to criminal justice contexts. (c) 2016 Wiley Periodicals, Inc. PMID- 27461382 TI - Unusual kappa1 coordination of a beta-diketiminate ligand in niobium complexes. AB - Reaction of (BDI)Nb(N(t)Bu)Cl2py with NaCp results in the kappa(1)-coordination of the BDI ligand in the complex (kappa(1)-N,BDI)CpNb(N(t)Bu)Cl (2). Via chloride abstraction from 2, we develop synthetic routes to structurally analogous cationic and Nb(IV) pseudo-four coordinate complexes where the BDI ligand returns to the kappa(2)-coordination mode. We compare these to our previously reported tetrahedral niobium bis(imido) complexes to investigate the effects of the Cp ligand on the properties of Nb-BDI-imido systems. Substitution of the chloride in 2 with a hydride also causes return to bidentate binding of the BDI ligand. The X ray crystal structures of these complexes have been determined, and the structural parameters reflecting the consequences of the electronic differences are discussed. PMID- 27461380 TI - Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides. AB - Gapmer antisense oligonucleotides cleave target RNA effectively in vivo, and is considered as promising therapeutics. Especially, gapmers modified with locked nucleic acid (LNA) shows potent knockdown activity; however, they also cause hepatotoxic side effects. For developing safe and effective gapmer drugs, a deeper understanding of the mechanisms of hepatotoxicity is required. Here, we investigated the cause of hepatotoxicity derived from LNA-modified gapmers. Chemical modification of gapmer's gap region completely suppressed both knockdown activity and hepatotoxicity, indicating that the root cause of hepatotoxicity is related to intracellular gapmer activity. Gene silencing of hepatic ribonuclease H1 (RNaseH1), which catalyses gapmer-mediated RNA knockdown, strongly supressed hepatotoxic effects. Small interfering RNA (siRNA)-mediated knockdown of a target mRNA did not result in any hepatotoxic effects, while the gapmer targeting the same position on mRNA as does the siRNA showed acute toxicity. Microarray analysis revealed that several pre-mRNAs containing a sequence similar to the gapmer target were also knocked down. These results suggest that hepatotoxicity of LNA gapmer is caused by RNAseH1 activity, presumably because of off-target cleavage of RNAs inside nuclei. PMID- 27461383 TI - Radiation dose in fluoroscopy: Experience does matter. PMID- 27461384 TI - SPECT-CT/VQ versus CTPA for diagnosing pulmonary embolus and other lung pathology: Pre-existing lung disease should not be a contraindication. AB - INTRODUCTION: Single Photon Emission Computed Tomography-Ventilation-Perfusion (SPECT-VQ) with low-dose CT (SPECT-CT/VQ) has equivalent diagnostic accuracy to CTPA for diagnosing pulmonary embolus (PE) while using lower radiation doses, but is underutilized owing to perceived inaccuracy of scintigraphy in the setting of pre-existing lung disease. This study assesses the accuracy of SPECT-CT/VQ compared with CTPA for the diagnosis of PE, including in patients with pre existing lung disease. METHODS: Retrospective non-inferiority cohort study of all patients who underwent SPECT-CT/VQ scanning at St Vincent's Hospital, NSW, from June 2012 to November 2013, who also had a CTPA within the same admission and <72 h apart (n = 102). RESULTS: SPECT-CT/VQ had 100% sensitivity and 94.4% specificity when compared with CTPA. Of the 102 patients, 14 were lung transplant patients, and 27 had other pre-existing lung disease (41/102, 40.2%), with SPECT CT/VQ having a sensitivity of 100% and specificity of 97.2% in this patient group. Non-inferiority of SPECT-CT/VQ was demonstrated at a significance level of 0.005. CONCLUSION: SPECT-CT/VQ has high sensitivity and specificity for diagnosing PE compared with CTPA, even among patients with pre-existing lung disease, with lower radiation doses. PMID- 27461386 TI - Prostate brachytherapy: Why do we ignore the evidence? PMID- 27461385 TI - Non-invasive prenatal testing: Women's post-test opinions and raising awareness amongst radiologists. PMID- 27461387 TI - Efficient TALEN-mediated myostatin gene editing in goats. AB - BACKGROUND: Myostatin (MSTN) encodes a negative regulator of skeletal muscle mass that might have applications for promoting muscle growth in livestock. In this study, we aimed to test whether targeted MSTN editing, mediated by transcription activator-like effector nucleases (TALENs), is a viable approach to create myostatin-modified goats (Capra hircus). RESULTS: We obtained a pair of TALENs (MTAL-2) that could recognize and cut the targeted MSTN site in the goat genome. Fibroblasts from pedigreed goats were co-transfected with MTAL-2, and 272 monoclonal cell strains were confirmed to have mono- or bi-allelic mutations in MSTN. Ten cell strains with different genotypes were used as donor cells for somatic cell nuclear transfer, which produced three cloned kids (K179/MSTN(-/-), K52-2/MSTN (+/-), and K52-1/MSTN (+/+)). CONCLUSIONS: The results suggested that the MTAL-2 could disrupt MSTN efficiently in the goat genome. The mutated somatic cells could be used to produce MSTN-site mutated goats without developmental disruption. Thus, TALENs is an effective method for accurate genome editing to produce site-modified goats. PMID- 27461389 TI - Intermolecular iodofunctionalization of allenamides with indoles, pyrroles, and furans: synthesis of iodine-substituted Z-enamides. AB - A new method was developed to synthesize iodine-substituted Z-enamides through N iodosuccinimide-mediated intermolecular iodofunctionalization of allenamides with indoles, pyrroles, and furans. These reactions proceed rapidly and tolerate a broad scope of substrates. The conjugated sulfimide ion species probably acts as the key intermediate. PMID- 27461388 TI - Medical management of secretory syndromes related to gastroenteropancreatic neuroendocrine tumours. AB - Although recent epidemiological evidence indicates that the prevalence of non functioning gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) is rising, a significant number of GEP-NETs still present with symptoms related to the secretion of biologically active substances leading to the development of distinct clinical syndromes. In the past, these syndromes were associated with substantial morbidity and mortality due to the lack of specific therapies; however, since the introduction of long-acting somatostatin analogues and medications such as proton pump inhibitors, their control has been greatly improved. As a result, nowadays, the main cause of morbidity and mortality in GEP NETs is mostly directly related to tumour growth and the extent of metastatic disease. However, in some patients with functioning tumours and extensive disease, control of the secretory syndrome still remains problematic, necessitating the employment of several cytoreductive techniques, which may not always be sufficient. Recently, new agents directed against tumour growth, or exerting increased binding activity to receptors expressed in these tumours, or interfering with the synthetic pathway of some of the compounds secreted by these tumours, have been developed. Since there are no specific guidelines addressing the totality of the management of the secretory syndromes related to GEP-NETs, this review aims at critically analysing the medical management of previously recognised secretory syndromes; it also addresses areas of uncertainty, assesses the newer therapeutic developments and also addresses recently described but poorly characterised secretory syndromes related to GEP-NETs. PMID- 27461390 TI - [How I do... the ultrasound examination of fetal semicircular canals]. PMID- 27461392 TI - Actin assembly: never forget rate constants. PMID- 27461393 TI - Mechanotransduction: May the force be with you. PMID- 27461396 TI - Adaptive moment closure for parameter inference of biochemical reaction networks. AB - Continuous-time Markov chain (CTMC) models have become a central tool for understanding the dynamics of complex reaction networks and the importance of stochasticity in the underlying biochemical processes. When such models are employed to answer questions in applications, in order to ensure that the model provides a sufficiently accurate representation of the real system, it is of vital importance that the model parameters are inferred from real measured data. This, however, is often a formidable task and all of the existing methods fail in one case or the other, usually because the underlying CTMC model is high dimensional and computationally difficult to analyze. The parameter inference methods that tend to scale best in the dimension of the CTMC are based on so called moment closure approximations. However, there exists a large number of different moment closure approximations and it is typically hard to say a priori which of the approximations is the most suitable for the inference procedure. Here, we propose a moment-based parameter inference method that automatically chooses the most appropriate moment closure method. Accordingly, contrary to existing methods, the user is not required to be experienced in moment closure techniques. In addition to that, our method adaptively changes the approximation during the parameter inference to ensure that always the best approximation is used, even in cases where different approximations are best in different regions of the parameter space. PMID- 27461395 TI - A longitudinal magnetic resonance elastography study of murine brain tumors following radiation therapy. AB - An accurate and noninvasive method for assessing treatment response following radiotherapy is needed for both treatment monitoring and planning. Measurement of solid tumor volume alone is not sufficient for reliable early detection of therapeutic response, since changes in physiological and/or biomechanical properties can precede tumor volume change following therapy. In this study, we use magnetic resonance elastography to evaluate the treatment effect after radiotherapy in a murine brain tumor model. Shear modulus was calculated and compared between the delineated tumor region of interest (ROI) and its contralateral, mirrored counterpart. We also compared the shear modulus from both the irradiated and non-irradiated tumor and mirror ROIs longitudinally, sampling four time points spanning 9-19 d post tumor implant. Results showed that the tumor ROI had a lower shear modulus than that of the mirror ROI, independent of radiation. The shear modulus of the tumor ROI decreased over time for both the treated and untreated groups. By contrast, the shear modulus of the mirror ROI appeared to be relatively constant for the treated group, while an increasing trend was observed for the untreated group. The results provide insights into the tumor properties after radiation treatment and demonstrate the potential of using the mechanical properties of the tumor as a biomarker. In future studies, more closely spaced time points will be employed for detailed analysis of the radiation effect. PMID- 27461391 TI - Mechanisms and regulation of endothelial VEGF receptor signalling. AB - Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth. PMID- 27461394 TI - Cluster headache attack remission with sphenopalatine ganglion stimulation: experiences in chronic cluster headache patients through 24 months. AB - BACKGROUND: Cluster headache (CH) is a debilitating headache disorder with severe consequences for patient quality of life. On-demand neuromodulation targeting the sphenopalatine ganglion (SPG) is effective in treating the acute pain and a subgroup of patients experience a decreased frequency of CH attacks. METHODS: We monitored self-reported attack frequency, headache disability, and medication intake in 33 patients with medically refractory, chronic CH (CCH) in an open label follow-up study of the original Pathway CH-1 study. Patients were followed for at least 24 months (average 750 +/- 34 days, range 699-847) after insertion of an SPG microstimulator. Remission periods (attack-free periods exceeding one month, per the ICHD 3 (beta) definition) occurring during the 24-month study period were characterized. Attack frequency, acute effectiveness, medication usage, and questionnaire data were collected at regular clinic visits. The time point "after remission" was defined as the first visit after the end of the remission period. RESULTS: Thirty percent (10/33) of enrolled patients experienced at least one period of complete attack remission. All remission periods followed the start of SPG stimulation, with the first period beginning 134 +/- 86 (range 21-272) days after initiation of stimulation. On average, each patient's longest remission period lasted 149 +/- 97 (range 62-322) days. The ability to treat acute attacks before and after remission was similar (37 % +/- 25 % before, 49 % +/- 32 % after; p = 0.2188). Post-remission headache disability (HIT-6) was significantly improved versus baseline (67.7 +/- 6.0 before, 55.2 +/- 11.4 after; p = 0.0118). Six of the 10 remission patients experienced clinical improvements in their preventive medication use. At 24 months post insertion headache disability improvements remained and patient satisfaction measures were positive in 100 % (10/10). CONCLUSIONS: In this population of 33 refractory CCH patients, in addition to providing the ability to treat acute attacks, neuromodulation of the SPG induced periods of remission from cluster attacks in a subset of these. Some patients experiencing remission were also able to reduce or stop their preventive medication and remissions were accompanied by an improvement in headache disability. PMID- 27461397 TI - Prevalence of electrocardiographic abnormalities based on hypertension severity and blood pressure levels: the Reasons for Geographic and Racial Differences in Stroke study. AB - We evaluated the prevalence of major and minor electrocardiographic (ECG) abnormalities based on blood pressure (BP) control and hypertension (HTN) treatment resistance. We analyzed data from the Reasons for Geographic and Racial Differences in Stroke study of 20,932 participants who were divided into presence of major (n = 3782), only minor (n = 8944), or no (n = 8206) ECG abnormalities. The cohort was stratified into normotension (n = 3373), pre-HTN (n = 4142), controlled HTN (n = 8619), uncontrolled HTN (n = 3544), controlled apparent treatment-resistant HTN (aTRH, n = 400), and uncontrolled aTRH (n = 854) groups, and the prevalence ratios (PRs) of major and minor ECG abnormalities were assessed separately for each BP group. The full multivariable adjustment included demographics, risk factors, and HTN duration. Compared with normotension, the PRs of major ECG abnormalities for pre-HTN, controlled HTN, uncontrolled HTN, controlled aTRH, and uncontrolled aTRH groups were 1.01 (0.90-1.14), 1.30 (1.16 1.45), 1.37 (1.23-1.54), 1.42 (1.22-1.64), and 1.44 (1.26-1.65), respectively (P < .001), whereas the PRs of minor ECG abnormalities among each of the above BP groups were similar. Detection of major ECG abnormalities among hypertensive persons with poor control and treatment resistance may help improve their cardiovascular risk stratification and early intervention. PMID- 27461398 TI - Does masked hypertension impact left ventricular deformation? AB - Our aim was to compare left ventricular (LV) deformation in subjects with masked hypertension (MH) to normotensive and sustained hypertensive patients. This cross sectional study included 185 untreated subjects who underwent 24-hour ambulatory blood pressure (BP) monitoring and complete two-dimensional echocardiographic (2DE) examination including multilayer strain analysis. MH was diagnosed if clinic BP was normal (<140/90 mm Hg), and 24-hour BP was increased (>=130/80 mm Hg). 2DE LV longitudinal and circumferential strains gradually and significantly decreased from normotensive controls across MH individuals to sustained hypertensive patients. 2DE radial strain was not different between groups. 2DE longitudinal and circumferential endocardial and midmyocardial layer strains progressively decreased from normotensive control to sustained hypertensive individuals. Longitudinal and circumferential epicardial layer strains were lower in sustained hypertensive patients than in normotensive controls. Clinic and 24 hour systolic BP were associated with 2DE LV longitudinal endocardial strain, midmyocardial strain, and 2DE circumferential endocardial strain in the whole study population independent of LV structure and diastolic function. MH significantly affect LV deformation assessed by 2DE traditional strain and 2DE multilayer strain. Clinic and 24-hour systolic BP were associated with LV mechanics evaluated with comprehensive 2DE strain analysis independent of LV structure and diastolic function. PMID- 27461399 TI - Intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia: A pragmatic double-blind randomized trial. AB - OBJECTIVE: To evaluate and compare the effectiveness and adverse effects of intramuscular (IM) olanzapine and IM aripiprazole for the treatment of agitated patients with schizophrenia in clinical practice. METHODS: A 24-hour randomized double-blind study carried out at a psychiatric hospital in Thailand enrolled adult patients (18-65years old) with schizophrenia experiencing agitation. Patients received one dose of IM olanzapine or IM aripiprazole followed by routine oral psychotropic medications. Efficacy was primarily measured using the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC). RESULTS: A total of 80 patients with a PANSS-EC score range of 22-35 entered the study, of whom 13% had a medical comorbidity and 40% a history of active substance abuse. The 40 patients receiving IM olanzapine showed greater improvement than the 40 patients receiving IM aripiprazole in PANSS-EC scores at 2h after the injection (p=0.002) but not at 24h. The two treatments were well tolerated. Patients receiving IM olanzapine experienced greater somnolence than those receiving IM aripiprazole. There were no clinically relevant changes in vital signs in either group. CONCLUSION: The results indicate that IM olanzapine and aripiprazole are similarly effective and well tolerated in the real-world treatment of agitation associated with schizophrenia over the first 24h. However, in the early hours, IM olanzapine may produce more sedation and reductions in agitation. PMID- 27461400 TI - Interrater reliability of schizoaffective disorder compared with schizophrenia, bipolar disorder, and unipolar depression - A systematic review and meta analysis. AB - Schizoaffective disorder is a common diagnosis in clinical practice but its nosological status has been subject to debate ever since it was conceptualized. Although it is key that diagnostic reliability is sufficient, schizoaffective disorder has been reported to have low interrater reliability. Evidence based on systematic review and meta-analysis methods, however, is lacking. Using a highly sensitive literature search in Medline, Embase, and PsycInfo we identified studies measuring the interrater reliability of schizoaffective disorder in comparison to schizophrenia, bipolar disorder, and unipolar disorder. Out of 4126 records screened we included 25 studies reporting on 7912 patients diagnosed by different raters. The interrater reliability of schizoaffective disorder was moderate (meta-analytic estimate of Cohen's kappa 0.57 [95% CI: 0.41-0.73]), and substantially lower than that of its main differential diagnoses (difference in kappa between 0.22 and 0.19). Although there was considerable heterogeneity, analyses revealed that the interrater reliability of schizoaffective disorder was consistently lower in the overwhelming majority of studies. The results remained robust in subgroup and sensitivity analyses (e.g., diagnostic manual used) as well as in meta-regressions (e.g., publication year) and analyses of publication bias. Clinically, the results highlight the particular importance of diagnostic re-evaluation in patients diagnosed with schizoaffective disorder. They also quantify a widely held clinical impression of lower interrater reliability and agree with earlier meta-analysis reporting low test-retest reliability. PMID- 27461401 TI - Synthesis of Degradable Poly[(Ethylene Glycol)-co-(Glycolic Acid)] via the Post Polymerization Oxyfunctionalization of Poly(Ethylene Glycol). AB - To enhance the limited degradability of poly(ethylene glycol) (PEG), a straightforward method of synthesizing poly[(ethylene glycol)-co-(glycolic acid)] (P(EG-co-GA)) via a ruthenium-catalyzed, post-polymerization oxyfunctionalization of various PEGs is developed. Using this method, a set of copolymers with GA compositions of up to 8 mol% are prepared with minimal reduction in molecular weight (<10%) when compared to their commercially available starting materials. The P(EG-co-GA) copolymers are shown to undergo hydrolysis under mild conditions. PMID- 27461403 TI - Reply to Lu Yang, Shi Qiu and Qiang Wei's Letter to the Editor re: Christopher E. Bayne, Stephen B. Williams, Matthew R. Cooperberg, et al. Treatment of the Primary Tumor in Metastatic Prostate Cancer: Current Concepts and Future Perspectives. Eur Urol 2016;69:775-87. PMID- 27461402 TI - Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3. AB - Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Here we show that Lkb1 controls BAT expansion and UCP1 expression in mice. We generate adipocyte-specific Lkb1 knockout mice and show that, compared with wild-type littermates, these mice exhibit elevated UCP1 expression in BAT and subcutaneous white adipose tissue, have increased BAT mass and higher energy expenditure. Consequently, KO mice have improved glucose tolerance and insulin sensitivity, and are more resistant to high-fat diet (HFD)-induced obesity. Deletion of Lkb1 results in a cytoplasm to nuclear translocation of CRTC3 in brown adipocytes, where it recruits C/EBPbeta to enhance Ucp1 transcription. In parallel, the absence of Lkb1 also suppresses AMPK activity, leading to activation of the mTOR signalling pathway and subsequent BAT expansion. These data suggest that inhibition of Lkb1 or its downstream signalling in adipocytes could be a novel strategy to increase energy expenditure in the context of obesity, diabetes and other metabolic diseases. PMID- 27461404 TI - MicroRNA-1207-5p inhibits hepatocellular carcinoma cell growth and invasion through the fatty acid synthase-mediated Akt/mTOR signalling pathway. AB - Fatty acid synthase (FASN) has emerged as a unique oncologic target for the treatment of cancers, including hepatocellular carcinoma (HCC). However, effective inhibitors of FASN for cancer treatment are lacking. MicroRNAs (miRNAs) have emerged as novel and endogenic inhibitors of gene expression. In the present study, we aimed to investigate the role of miR-1207-5p in HCC and the regulation of FASN through miR-1207-5p. The expression of miR-1207-5p was markedly reduced in HCC tissues and cell lines as detected with real-time quantitative polymerase chain reaction (qPCR). Overexpression of miR-1207-5p significantly suppressed the cell growth and invasion of HCC cells. By contrast, inhibition of miR-1207-5p exhibited an opposite effect. Bioinformatics analysis showed that FASN is a predicted target of miR-1207-5p which was validated by dual-luciferase reporter assay, qPCR and western blot analysis. Overexpression of miR-1207-5p inhibited the Akt/mTOR signalling pathway, and promotion of this pathway was noted following inhibition of miR-1207-5p. Rescue experiments showed that the restoration of FASN expression partially reversed the inhibitory effect of miR 1207-5p on cell growth, invasion and Akt phosphorylation. In conclusion, our study suggests that miR-1207-5p/FASN plays an important role in HCC, and provides novel insight into developing new inhibitors for FASN for therapeutic interventions for HCC. PMID- 27461406 TI - A 1 + 1' resonance-enhanced multiphoton ionization scheme for rotationally state selective detection of formaldehyde via the A (1)A2 <- X[combining tilde] (1)A1 transition. AB - The formaldehyde molecule is an important model system for understanding dynamical processes in small polyatomic molecules. However, prior to this work, there have been no reports of a resonance-enhanced multiphoton ionization (REMPI) detection scheme for formaldehyde suitable for rovibrationally state-selective detection in molecular beam scattering experiments. Previously reported tunable REMPI schemes are either non-rotationally resolved, involve multiple resonant steps, or involve many-photon ionization steps. In the current work, we present a new 1 + 1' REMPI scheme for formaldehyde. The first photon is tunable and provides rotational resolution via the vibronically allowed A (1)A2 <- X[combining tilde] (1)A1 transition. Molecules are then directly ionized from the A state by one photon of 157 nm. The results indicate that the ionization cross section from the 4(1) vibrational level of the A state is independent of the rotational level used as intermediate, to within experimental uncertainty. The 1 + 1' REMPI intensities are therefore directly proportional to the A <- X[combining tilde] absorption intensities and can be used for quantitative measurement of X[combining tilde]-state population distributions. PMID- 27461405 TI - Levodopa modulates small-world architecture of functional brain networks in Parkinson's disease. AB - BACKGROUND: PD is associated with disrupted connectivity to a large number of distributed brain regions. How the disease alters the functional topological organization of the brain, however, remains poorly understood. Furthermore, how levodopa modulates network topology in PD is largely unknown. The objective of this study was to use resting-state functional MRI and graph theory to determine how small-world architecture is altered in PD and affected by levodopa administration. METHODS: Twenty-one PD patients and 20 controls underwent functional MRI scanning. PD patients were scanned off medication and 1 hour after 200 mg levodopa. Imaging data were analyzed using 226 nodes comprising 10 intrinsic brain networks. Correlation matrices were generated for each subject and converted into cost-thresholded, binarized adjacency matrices. Cost integrated whole-brain global and local efficiencies were compared across groups and tested for relationships with disease duration and severity. RESULTS: Data from 2 patients and 4 controls were excluded because of excess motion. Patients off medication showed no significant changes in global efficiency and overall local efficiency, but in a subnetwork analysis did show increased local efficiency in executive (P = 0.006) and salience (P = 0.018) networks. Levodopa significantly decreased local efficiency (P = 0.039) in patients except within the subcortical network, in which it significantly increased local efficiency (P = 0.007). CONCLUSIONS: Levodopa modulates global and local efficiency measures of small-world topology in PD, suggesting that degeneration of nigrostriatal neurons in PD may be associated with a large-scale network reorganization and that levodopa tends to normalize the disrupted network topology in PD. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27461407 TI - Poor retention in early care increases risk of mortality in a Brazilian HIV infected clinical cohort. AB - Retention in early HIV care has been associated with decreased mortality and improved viral suppression, however the consequences of poor retention in early care in Brazil remain unknown. We assessed the effect of poor retention on mortality in a Brazilian HIV-infected clinical cohort. The analysis included ART naive, HIV-infected adults linked to care at the Instituto Nacional de Infectologia Evandro Chagas, Fundacao Oswaldo Cruz between 2000 and 2010, who did not become pregnant nor participate in a clinical trial during the first two years in care (early care). Poor retention in early care was defined as less than 3 out of 4 six-month intervals with a CD4 or HIV-1 RNA laboratory result during early care. Cox proportional hazards models were used to identify factors associated with mortality, and Kaplan-Meier plots were used to describe the survival probability for participants with poor retention versus good retention. Among 1054 participants with a median (interquartile range) follow-up time of 4.2 years (2.6, 6.3), 20% had poor retention in early care and 8% died. Poor retention in early care [adjusted hazard ratio (aHR) 3.09; 95% CI 1.65-5.79], AIDS defining illness (aHR 1.95; 95% CI 1.20-3.18) and lower education (aHR 2.33; 95% CI 1.45-3.75) were associated with increased mortality risk. Our findings highlight the importance of adopting strategies to improve retention in early HIV care. PMID- 27461408 TI - Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats. AB - In cats with chronic kidney disease (CKD), the most common histopathologic finding is tubulointerstitial inflammation and fibrosis. However, these changes reflect a nonspecific response of the kidney to any inciting injury. The risk of developing CKD is likely to reflect the composite effects of genetic predisposition, aging, and environmental and individual factors that affect renal function over the course of a cat's life. However, there is still little information available to determine exactly which individual risk factors predispose a cat to develop CKD. Although many cats diagnosed with CKD have stable disease for years, some cats show overtly progressive disease. PMID- 27461409 TI - Spectroscopic and computational investigations on the origin of charge transfer between included neutral guest molecules and a functionalized anionic layered host. AB - Layered double hydroxides (LDHs) or anionic clays are an important class of ion exchange materials, well known for drug and gene delivery and several other applications including catalysis, bioactive nanocomposite, electroactive and photoactive materials. Their structure is based on positively charged brucite like inorganic sheets with the interlamellar space being occupied by charge compensating exchangeable anions. In spite of having a vast scope many of the applications of LDHs are restricted as their host-guest chemistry is limited to ion-exchange reactions. Recently we have shown for the first time that charge transfer interactions can be used as a driving force for the insertion of neutral guest molecules (ortho- and para-chloranil) within the galleries of an Mg-Al LDH by forming a charge-transfer complex with aniline pre-intercalated as p aminobenzoate anion. Here, we have performed quantum chemical calculations in combination with molecular dynamics simulations to elucidate the nature of interactions, arrangement and the evaluation of electronic and Raman spectral signatures of the chloranil charge-transfer complex included within the galleries of the Mg-Al LDH. The natural bond orbital (NBO) analysis has been used to understand the nature and origin of the unidirectional charge-transfer that lead to the unusual insertion of chloranil in the galleries of the Mg-Al LDH. The NBO analysis reveals that a considerable amount of electronic charge redistribution occurs from the p-aminobenzoate to the chloranil during latter's insertion within the LDH galleries with a very negligible amount of back donation. This work is expected to pave the way for understanding the host-guest chemistry and targeted and controlled delivery of poorly soluble drugs. PMID- 27461411 TI - Assessment of genotoxicity of pyrethrin in cultured human lymphocytes. AB - Pyrethrin is an insecticide that is obtained from the Chrysanthemum flower (Pyrethrum). In this study, we examined the genotoxic effects of pyrethrin on cultured human lymphocytes using sister chromatid exchanges (SCEs) and 8-hydroxy deoxyguanosine (8-OHdG) assays. Cultures were treated with different concentrations of pyrethrin (25, 50, and 100 MUg/mL), which was dissolved in in dimethyl sulfoxide (DMSO). The results showed that treatment of cultured lymphocytes with pyrethrin at 50 MUg/mL and 100 MUg/mL induced significant elevation in SCEs (p < 0.05). In addition, the 100 MUg/mL concentration significantly affected both mitotic and proliferative indices (p < 0.05). Finally, pyrethrin induced significant elevation in the oxidative stress marker 8 OHdG in a dose-dependent manner (p < 0.001). In conclusion, the results suggest that pyrethrin is genotoxic as measured by two independent assays on genetic toxicity. PMID- 27461412 TI - In situ investigation of energy transfer in hybrid organic/colloidal quantum dot light-emitting diodes via magneto-electroluminescence. AB - Energy transfer (ET) and charge injection (CI) in the hybrid organic/colloidal quantum dot light-emitting diodes (QD-LEDs) have been investigated by using magneto-electroluminescence (MEL) as an in situ tool. The feasibility and availability of MEL as an in situ tool were systematically demonstrated in the typical QD-LEDs based on CdSe-ZnS core-shell QDs. Our results suggest that the ET and CI processes can be well discerned by MEL measurements since these two processes exhibit distinct responses to the applied magnetic field. Through measurement of the MEL and current efficiency, we indicated that ET would be the main mechanism for light emission in the present hybrid QD-LEDs. This study strongly suggests that MEL could be a highly sensitive fingerprint for ET, which provides a facile and efficient method for the in situ investigation of fundamental processes in hybrid organic/colloidal QD-LEDs and other organic/inorganic composites. PMID- 27461410 TI - Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson's disease etiology. AB - Recent genome-wide association studies (GWAS) of Parkinson's disease (PD) revealed at least 26 risk loci, with associated single nucleotide polymorphisms (SNPs) located in non-coding DNA having unknown functions in risk. In order to explore in which cell types these SNPs (and their correlated surrogates at r(2) >= 0.8) could alter cellular function, we assessed their location overlap with histone modification regions that indicate transcription regulation in 77 diverse cell types. We found statistically significant enrichment of risk SNPs at 12 loci in active enhancers or promoters. We investigated 4 risk loci in depth that were most significantly enriched (-logeP > 14) and contained 8 putative enhancers in the different cell types. These enriched loci, along with eQTL associations, were unexpectedly present in non-neuronal cell types. These included lymphocytes, mesendoderm, liver- and fat-cells, indicating that cell types outside the brain are involved in the genetic predisposition to PD. Annotating regulatory risk regions within specific cell types may unravel new putative risk mechanisms and molecular pathways that contribute to PD development. PMID- 27461413 TI - Changing public stigma with continuum beliefs. AB - BACKGROUND: Given the egregious effect of public stigma on the lives of people with mental illness, researchers have sought to unpack and identify effective components of anti-stigma programs. AIM: We expect to show that continuum messages have more positive effect on stigma and affirming attitudes (beliefs that people with mental illness recover and should be personally empowered) than categorical perspectives. The effect of continuum beliefs will interact with contact strategies. METHOD: A total of 598 research participants were randomly assigned to online presentations representing one of the six conditions: three messages (continuum, categorical, or neutral control) by two processes (education or contact). Participants completed measures of continuum beliefs (as a manipulation check), stigma and affirming attitudes after viewing the condition. RESULTS: Continuum messages had significantly better effect on views that people with mental illness are "different," a finding that interacted with contact. Continuum messages also had better effects on recovery beliefs, once again an effect that interacted significantly with contact. CONCLUSIONS: Implications of these findings for improving anti-stigma programs are discussed. PMID- 27461414 TI - Conservation priorities for the different lines of Dutch Red and White Friesian cattle change when relationships with other breeds are taken into account. AB - From a genetic point of view, the selection of breeds and animals within breeds for conservation in a national gene pool can be based on a maximum diversity strategy. This implies that priority is given to conservation of breeds and animals that diverge most and overlap of conserved diversity is minimized. This study investigated the genetic diversity in the Dutch Red and White Friesian (DFR) cattle breed and its contribution to the total genetic diversity in the pool of the Dutch dairy breeds. All Dutch cattle breeds are clearly distinct, except for Dutch Friesian breed (DF) and DFR and have their own specific genetic identity. DFR has a small but unique contribution to the total genetic diversity of Dutch cattle breeds and is closely related to the Dutch Friesian breed. Seven different lines are distinguished within the DFR breed and all contribute to the diversity of the DFR breed. Two lines show the largest contributions to the genetic diversity in DFR. One of these lines comprises unique diversity both within the breed and across all cattle breeds. The other line comprises unique diversity for the DFR but overlaps with the Holstein Friesian breed. There seems to be no necessity to conserve the other five lines separately, because their level of differentiation is very low. This study illustrates that, when taking conservation decisions for a breed, it is worthwhile to take into account the population structure of the breed itself and the relationships with other breeds. PMID- 27461415 TI - A blueprint for improving undergraduate education in intensive care medicine. PMID- 27461416 TI - Pancytopenia during tyrosine kinase inhibitor treatment - coexistence of chronic myeloid leukemia and visceral leishmaniasis: a case report. AB - BACKGROUND: Visceral leishmaniasis is a zoonosis characterized by chronic evolution of symptoms; it usually appears 2 to 4 months after the initial infection, with multiple cutaneous lesions and systemic involvement, which if left untreated results in death in 90 % of cases. CASE PRESENTATION: We present a case of 29-year-old white male farmer, with chronic myeloid leukemia treated with imatinib who developed significant pancytopenia, leading to discontinuation of treatment. His neutrophil count fell to 0.5 * 10(9)/L, his platelets dropped to 85 * 10(9)/MUL, and his hemoglobin was 6.4 g/dL. A bone marrow study was performed, showing complete remission of chronic myeloid leukemia and numerous Leishmania amastigotes within the macrophages. He used pentavalent antimonials replaced by amphotericin B due to acute cardiac toxicity. After 3 months, imatinib was restarted, and he again showed adequate control of the disease. The last polymerase chain reaction assessment showed a deep molecular response. CONCLUSION: The hypothesis of an adverse event or secondary resistance to tyrosine kinase inhibitors, with subsequent progression to advanced disease, was initially raised, although a detailed evaluation has shown that it was an associated infectious disease. PMID- 27461417 TI - STC-1 expression is upregulated through an Akt/NF-kappaB-dependent pathway in triple-negative breast cancer cells. AB - Stanniocalcin-1 (STC-1) is a secreted glycoprotein and its expression is strongly correlated with cancer development. However, regulatory mechanism of STC-1 expression in breast cancer cells is not clear. In the present study, we investigated whether STC-1 acts as a prognostic factor in TNBC patients and the regulation of STC-1 expression in breast cancer cells. Basal levels of STC-1 were significantly higher in TNBC cells than in non-TNBC cells. Induction of STC-1 expression was also associated with poor relapse-free survival of TNBC patients. In addition, we verified the correlation between the invasiveness of TNBC cells and the STC-1 expression. We found that recombinant human STC-1 treatment increased the invasiveness of TNBC cells. In contrast, STC-1-induced cell invasiveness was completely inhibited by anti-STC-1 monoclonal antibody treatment. We found that the basal levels of STC-1 expression in TNBC cells were decreased by treatment with LY294002 or Bay11-7085, but not SB203580. In contrast, transcript levels of STC-1 and protein secretion were increased by constitutively active Akt (CA-Akt) or NF-kappaB overexpression in TNBC cells. Finally, we observed that phosphorylation of NF-kappaB was significantly increased by CA-Akt overexpression in TNBC cells. Taken together, elevated STC-1 expression is associated with poor clinical outcome in TNBC patients, and STC-1 is directly involved in the invasiveness of TNBC cells. STC-1 expression is upregulated through a PI-3K/Akt/NF-kappaB-dependent signaling pathway in TNBC cells. PMID- 27461418 TI - "Quality of life of patients after surgical treatment of cervical spine metastases". AB - BACKGROUND: Metastases of malignant neoplasms to the cervical spine are relatively rare. The most common symptom of metastatic disease is pain. Symptoms associated with roots damage or spinal cord compression indicate locally advanced disease. In a large number of patients, surgical treatment brings benefits such as pain reduction and improvement of the quality of life. Pain intensity, neurological status, and quality of patients' lives are measured with the VAS, Frankel, and Karnofsky scales. METHODS: Symptoms of the disease, morphology of the metastasis and treatment outcomes were evaluated in 57 patients treated surgically because of metastases to the cervical spine over the period 2010-2014 in Brzozow. The morphology of the metastases was assessed on the basis of CT and MR examinations. Pre- and postoperative functional status of the patients was evaluated using Karnofsky scale. The intensity of pain was assessed with VAS and the neurological status was evaluated by using Frankel's grades. Anterior approach was employed in 16 patients, posterior approach in 30 patients, and postero-anterior approach in 11 patients. The inter-group differences were evaluated using the U Mann-Whitney and Wilcoxon Matched Pairs test. All statistical analyses were performed by using Statistica 10. A value of P < 0.05 was considered statistically significant. RESULTS: The majority of patients suffered from pain associated with instability of the spine. Multi-level metastases were noted in 40 patients, while in 17 patients 1 vertebra was involved. In 51 patients the metastases caused pathological fractures of the vertebrae. The most common neurological complications was observed in patients with multi-level tumors and with pedicles involvement. After surgery patients functional status improved and pain intensity decreased. The best results (statistically significant) were observed in patients operated with anterolateral approach. Complications were scarce. Two patients required reoperation due to infection. CONCLUSIONS: Surgical treatment of metastases to the cervical spine gives good outcomes and it ought to be a treatment of choice. Proper and multifaceted qualification of the patients for different treatments is of vital importance. PMID- 27461419 TI - Advancing scoping study methodology: a web-based survey and consultation of perceptions on terminology, definition and methodological steps. AB - BACKGROUND: Scoping studies (or reviews) are a method used to comprehensively map evidence across a range of study designs in an area, with the aim of informing future research practice, programs and policy. However, no universal agreement exists on terminology, definition or methodological steps. Our aim was to understand the experiences of, and considerations for conducting scoping studies from the perspective of academic and community partners. Primary objectives were to 1) describe experiences conducting scoping studies including strengths and challenges; and 2) describe perspectives on terminology, definition, and methodological steps. METHODS: We conducted a cross-sectional web-based survey with clinicians, educators, researchers, knowledge users, representatives from community-based organizations, graduate students, and policy stakeholders with experience and/or interest in conducting scoping studies to gain an understanding of experiences and perspectives on the conduct and reporting of scoping studies. We administered an electronic self-reported questionnaire comprised of 22 items related to experiences with scoping studies, strengths and challenges, opinions on terminology, and methodological steps. We analyzed questionnaire data using descriptive statistics and content analytical techniques. Survey results were discussed during a multi-stakeholder consultation to identify key considerations in the conduct and reporting of scoping studies. RESULTS: Of the 83 invitations, 54 individuals (65 %) completed the scoping questionnaire, and 48 (58 %) attended the scoping study meeting from Canada, the United Kingdom and United States. Many scoping study strengths were dually identified as challenges including breadth of scope, and iterative process. No consensus on terminology emerged, however key defining features that comprised a working definition of scoping studies included the exploratory mapping of literature in a field; iterative process, inclusion of grey literature; no quality assessment of included studies, and an optional consultation phase. We offer considerations for the conduct and reporting of scoping studies for researchers, clinicians and knowledge users engaging in this methodology. CONCLUSIONS: Lack of consensus on scoping terminology, definition and methodological steps persists. Reasons for this may be attributed to diversity of disciplines adopting this methodology for differing purposes. Further work is needed to establish guidelines on the reporting and methodological quality assessment of scoping studies. PMID- 27461420 TI - Herpes Zoster Overlying Recently Placed Central Venous Access Site: A Case Report. AB - Herpes zoster, commonly called shingles, is a disease that results from the reactivation of varicella zoster virus. Local trauma has been reported as a precipitant for reactivation, but this condition is rarely seen localized to a fresh surgical incision. We present the case of a patient who developed shingles overlying the incision site of a recently buried central venous access port, illustrating the need to consider this diagnosis as a unique imposter of localized infection or reaction at sites of recent procedural trauma. PMID- 27461421 TI - Cardiac disease and depression; a direct association? PMID- 27461422 TI - Characterization and expression analysis of a peptidoglycan recognition protein gene, SmPGRP2 in mucosal tissues of turbot (Scophthalmus maximus L.) following bacterial challenge. AB - Peptidoglycan recognition receptor proteins (PGRPs), a group of pattern recognition receptors (PRRs), can recognize peptidoglycan (PGN) of the bacteria cell wall and play an important role in host immune defense against pathogen infection. They are highly structurally conserved through evolution, but with different function in innate immunity between invertebrates and vertebrates. In teleost fish, several PGRPs have been characterized recently. They have both amidase activity and bactericidal activity and are involved in indirectly killing bacteria and regulating multiple signaling pathways. However, the knowledge of PGRPs in mucosal immunity of teleost fish is still limited. In this study, we identified a PGRPs gene (SmPGRP2) of turbot and investigated its expression patterns in mucosal tissues after challenge with Gram-positive bacteria Streptococcus iniae and Gram-negative bacteria Vibrio anguillarum. Phylogenetic analysis showed the strongest relationship of turbot PGRP to halibut, which was consistent with their phylogenetic relationships. In addition, SmPGRP2 was ubiquitously expressed in turbot tissues, and constitutive expression levels were higher in classical immune tissues (including liver, spleen, and head-kidney) than mucosal tissues (intestine, gill and skin). After bacterial challenge, the expression of SmPGRP2 was induced and showed a general trend of up-regulation in mucosal tissues, except in intestine following V. anguillarum infection. These different expression patterns varied depending on both pathogen and tissue type, suggesting its distinct roles in the host immune response to bacterial pathogen. PMID- 27461423 TI - Biochemical studies on the effect of different water resources in Hail region on liver and kidney functions of rats. AB - Low concentration of a heavy metal is toxic and can be classified as one of the pollution sources. Industrial and human waste can pollute water with heavy metals and soils breaking down under the effect of acidic rain, which release heavy metals into river, streams, lakes, and ground water. Bioaccumulation of heavy metals in vital organs of the human body damages these organs, including the liver and kidney, which are the main organs for metabolism, detoxification, and excretion. The present study aims to investigate into concentrations of such heavy metals (Fe, Cu, Zn, and Pb) in both ground and tap water samples collected from different areas in Hail region, KSA. Then, this study moves forward to examine the effects of such concentrations on the biochemistry of serum in rats. In this regard, the results demonstrate the presence of significant differences (p < 0.05) in the liver function parameters, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total proteins, albumin, and globulin between all the studied groups that were exposed to heavy-metals-polluted water, when compared with the control group. In addition, there were significant differences (p < 0.05) in the kidney function parameters, uric acid, urea, and creatinine, when compared with the control group. Thence, and as this study indicates, heavy-metals-polluted water can cause disturbance in the liver and kidney function parameters, which highlights health risks of the water polluted with heavy metals. In this sense, the concerned authorities should regularly carry out survey and should monitor underground water, and people have to be aware of such risks. PMID- 27461424 TI - Dietary exposure to pesticide residues from foods of plant origin and drinks in Lebanon. AB - This study assesses the dietary exposure of Lebanese adults to 47 pesticide residues from both foods of plant origin and drinks. The study was conducted using the Total Diet Study protocol in two different areas of Lebanon: Greater Beirut (urban) and Keserwan (semi-rural). A total of 1860 individual foods were collected, prepared, and cooked prior to analysis. Composite samples of similar foods were analyzed, following the QuEChERS Multiresidue method. Eighteen residues were detected/quantified on at least one composite sample, with 66.7 % of the results being quantifiable and 33.3 % detectable. Quantifiable levels ranged between 10.3 and 208 MUg/kg. For the composite samples where residues were detected, 55 % had one residue, while 45 % had 2-4 residues. The most frequently detected/quantified pesticide residues included Chlorpyrifos, Procymidone, Primiphos methyl, Dimethoate, and Dieldrin. The dietary exposure assessment was conducted using the deterministic approach with two scenarios: (1) the lower bound (LB) approach and (2) the upper bound (UB) approach. Using the LB approach, mean estimated daily exposures were far below the acceptable daily intakes (ADIs) for all investigated residues. Using the UB approach, which tends to overestimate exposure, mean estimated daily exposures were below the ADIs for all residues except for Dieldrin (semi-rural: 128.7 % ADI; urban: 100.7 % ADI). Estimates of mean exposure to Diazinon reached 50.3 % of ADI in the urban diet and 61.9 % in the semi-rural diet. Findings of this study identify specific pesticide residues as monitoring priorities for which more comprehensive and sensitive analyses are needed in order to refine exposure assessment. PMID- 27461425 TI - Accuracy of land use change detection using support vector machine and maximum likelihood techniques for open-cast coal mining areas. AB - One objective of the present study was to evaluate the performance of support vector machine (SVM)-based image classification technique with the maximum likelihood classification (MLC) technique for a rapidly changing landscape of an open-cast mine. The other objective was to assess the change in land use pattern due to coal mining from 2006 to 2016. Assessing the change in land use pattern accurately is important for the development and monitoring of coalfields in conjunction with sustainable development. For the present study, Landsat 5 Thematic Mapper (TM) data of 2006 and Landsat 8 Operational Land Imager (OLI)/Thermal Infrared Sensor (TIRS) data of 2016 of a part of Jharia Coalfield, Dhanbad, India, were used. The SVM classification technique provided greater overall classification accuracy when compared to the MLC technique in classifying heterogeneous landscape with limited training dataset. SVM exceeded MLC in handling a difficult challenge of classifying features having near similar reflectance on the mean signature plot, an improvement of over 11 % was observed in classification of built-up area, and an improvement of 24 % was observed in classification of surface water using SVM; similarly, the SVM technique improved the overall land use classification accuracy by almost 6 and 3 % for Landsat 5 and Landsat 8 images, respectively. Results indicated that land degradation increased significantly from 2006 to 2016 in the study area. This study will help in quantifying the changes and can also serve as a basis for further decision support system studies aiding a variety of purposes such as planning and management of mines and environmental impact assessment. PMID- 27461426 TI - Long-term Safety of Asenapine in Pediatric Patients Diagnosed With Bipolar I Disorder: A 50-Week Open-Label, Flexible-Dose Trial. AB - BACKGROUND: Sublingually administered asenapine was approved in March 2015 by the United States Food and Drug Administration for patients aged 10-17 years with an acute manic or mixed episode associated with bipolar I disorder (BP-1). This is the first long-term safety and tolerability study of asenapine in this population. METHODS: Following the 3-week randomized, double-blind, placebo controlled trial of patients aged 10-17 years with an acute manic or mixed episode associated with BP-1, patients could enroll in this flexible-dose (2.5-10 mg twice daily) open-label extension (OLE) study for an additional 50 weeks, conducted from August 2011 to September 2014 in the United States and Russia. Treatment-emergent adverse events (TEAEs) were assessed and predefined TEAEs of interest reported in addition to metabolic and anthropometric parameters. The Young Mania Rating Scale (YMRS) and Clinical Global Impressions scale in bipolar illness (CGI-BP) were used to assess effectiveness. RESULTS: A total of 321 patients (lead-in study treatment: placebo, n = 80; asenapine, n = 241) were included; 267 (83.2 %) reported one or more TEAE and 181 (56.4 %) discontinued early, 48 (15.0 %) due to TEAEs. Of the predefined TEAEs of interest, combined somnolence/sedation/hypersomnia occurred most frequently (42.4 %) followed by oral hypoesthesia/dysgeusia (7.5 %). In total, 109 (34.8 %) patients experienced clinically significant weight gain (>=7 % increase). No clinically meaningful changes were noted for laboratory parameters measured. Eighteen patients met the criteria for new-onset metabolic syndrome (MBS) post-baseline during the extension study, whereas 10 patients who met MBS criteria at baseline did not meet MBS criteria at endpoint. A total of 12 patients met MBS at baseline and endpoint. Mean change in YMRS total score from OLE baseline was -9.2 points at week 50, and change in CGI-BP severity overall score was similar among all treatment groups (those who initially received asenapine and those who initially received placebo). After 26 weeks of treatment in the OLE, 79.2 % of patients were classified as YMRS 50 % responders relative to acute trial baseline. CONCLUSIONS: Asenapine was generally well tolerated in pediatric patients with BP 1 during <=50 weeks of open-label treatment; among predefined TEAEs of interest, the combination of somnolence/sedation/hypersomnia was the most common. Trial registration ClinicalTrials.gov: NCT01349907. PMID- 27461427 TI - An Update on the Therapeutic Approach to Vernal Keratoconjunctivitis. AB - Vernal keratoconjunctivitis (VKC) is an inflammatory disease of the ocular surface. It commonly occurs in the first decade of life, has a wide geographical distribution, and usually occurs in warm, dry areas. The pathogenesis of VKC seems to have an immune, nervous, and endocrine basis. The most common eye symptoms are itching, discharge, tearing, eye irritation, redness of the eyes, and photophobia. Although VKC generally has a good prognosis, the lack of clarity regarding the origin of the disease makes treatment a challenge for pediatricians and ophthalmologists. The purpose of this review is to discuss the pathogenesis, clinical features, and diagnostic criteria in VKC, with a focus on its therapeutic management. The selection of a therapeutic scheme from the many available options is based on clinical features and the personal preferences of both physicians and patients. Due to the lack of uniform grading of disease severity, there is no worldwide consensus on first-line and second-line therapeutic approaches. The choice of treatment for long-term moderate to severe VKC includes topical cyclosporine or tacrolimus. Further data are needed to define the minimal effective concentration and the safety of these drugs in eye drops and to clarify the diagnosis of VKC in patients who require these drugs. Finally, while promising newly discovered drugs are expected to enter into clinical practice, further studies on their efficacy and safety are required. PMID- 27461429 TI - Perinatal features of congenital cystic lung diseases: results of a nationwide multicentric study in Japan. AB - PURPOSE: The current study aimed to assess the perinatal risk and clinical features of congenital cystic lung diseases (CCLD). MATERIALS AND METHODS: Of the 874 CCLD patients identified in a nationwide survey, 428 patients born between 1992 and 2012 and treated at 10 high-volume centers, were retrospectively reviewed. RESULTS: Fetal hydrops was visualized using MRI in 9.2 % of the patients. Prenatal interventions were described for 221 of the 428 patients, including the maternal administration of steroid and pleuro-amniotic shunting. Postnatally, a right-to-left shunt flow through a persistent ductus arteriosus was observed in 7.8 % of the patients. The fetal lung lesion volume ratio (LVR) was significantly higher among these symptomatic patients (2.04 +/- 1.71 vs. 0.98 +/- 0.50, P < 0.00071), and decreased to a greater degree in non-CCAM patients compared with CCAM patients during the late gestational period (from 1.37 +/- 1.28 to 1.14 +/- 0.84 in CCAM and from 1.08 +/- 0.47 to 0.46 +/- 0.64 in non CCAM). CONCLUSIONS: An estimated 8-9 % of prenatally diagnosed patients carry the highest risk of perinatal respiratory distress. Fetal LVR remaining at a high level during the late gestational period seems to predict a high risk. PMID- 27461428 TI - Improved enteral tolerance following step procedure: systematic literature review and meta-analysis. AB - Surgical management of children with short bowel syndrome (SBS) changed with the introduction of the serial transverse enteroplasty procedure (STEP). We conducted a systematic review and meta-analysis using MEDLINE and SCOPUS to determine if children with SBS had improved enteral tolerance following STEP. Studies were included if information about a child's pre- and post-STEP enteral tolerance was provided. A random effects meta-analysis provided a summary estimate of the proportion of children with enteral tolerance increase following STEP. From 766 abstracts, seven case series involving 86 children were included. Mean percent tolerance of enteral nutrition improved from 35.1 to 69.5. Sixteen children had no enteral improvement following STEP. A summary estimate showed that 87 % (95 % CI 77-95 %) of children who underwent STEP had an increase in enteral tolerance. Compilation of the literature supports the belief that SBS subjects' enteral tolerance improves following STEP. Enteral nutritional tolerance is a measure of efficacy of STEP and should be presented as a primary or secondary outcome. By standardizing data collection on children undergoing STEP procedure, better determination of nutritional benefit from STEP can be ascertained. PMID- 27461430 TI - Evaluation of the intraoperative risk factors for esophageal anastomotic complications after primary repair of esophageal atresia with tracheoesophageal fistula. AB - PURPOSE: The aim of this study is to identify the risk factors for esophageal anastomotic stricture (EAS) and/or anastomotic leakage (EAL) after primary repair of esophageal atresia with tracheoesophageal fistula (EA/TEF) in infants. METHODS: A retrospective chart review of 52 patients with congenital EA/TEF between January 2000 and December 2015 was conducted. Univariate and multivariate analyses were performed to identify the risk factors for anastomotic complications. RESULTS: Twenty-four patients were excluded from the analysis because they had insufficient data, trisomy 18 syndrome, delayed anastomosis, or multi-staged operations; the remaining 28 were included. Twelve patients (42.9 %) had anastomotic complications. EAS occurred in 12 patients (42.9 %), and one of them had EAL (3.57 %). There was no correlation between anastomotic complications and birth weight, gestational weeks, sex, the presence of an associated anomaly, age at the time of repair, gap between the upper pouch and lower pouch of the esophagus, number of sutures, blood loss, and gastroesophageal reflux. Anastomosis under tension and tracheomalacia were identified as risk factors for anastomotic complications (odds ratio 15, 95 % confidence interval (CI) 1.53 390.0 and odds ratio 8, 95 % CI 1.33-71.2, respectively). CONCLUSION: Surgeons should carefully perform anastomosis under less tension to prevent anastomotic complications in the primary repair of EA/TEF. PMID- 27461431 TI - Effective treatment for infantile hemangioma with long-pulsed dye laser with oral propranolol medication: a preliminary report. AB - PURPOSE: To investigate the efficacy of our treatment of infantile hemangioma (IH)s retrospectively presenting as disfiguring or functionally threatening lesions. MATERIALS AND METHODS: 25 infants with IH treated with long-pulsed dye laser or laser with or without propranolol. Tumor fading after treatment was evaluated using both color and size rating scales, before, during and after treatment. RESULTS: 6 infants were treated by laser, 11, oral propranolol and 8 using both treatments. Each treatment was effective for most IH with a median treatment duration of 7.7 months for laser, and 13.3 months for the latter two. Combination therapy was the most effective in both color-fading and size reduction by the 3rd month. Laser alone was most effective in color-fading with almost complete disappearance of most tumors. Oral propranolol to the three site specific IHs was effective with disappearance of tumors. There were no apparent side effects related to laser treatment, but one infant suffered from allergy and another from bronchial asthma due to propranolol medication. CONCLUSIONS: Most IHs discolored and regressed considerably with these treatments, including complete disappearance of the three functionally threatening lesions. This combined approach is quite useful for accelerating tumor regression. PMID- 27461432 TI - Impact of botulinum toxin A injection on esophageal anastomosis in a rabbit model. AB - PURPOSE: The management of esophageal atresia is established, but the rate of postoperative complications remains high. We focused on a new, recently reported method of esophageal elongation using botulinum toxin type A (BTX-A) and evaluated the efficacy of BTX-A injection around esophageal anastomoses with tension in a rabbit model. METHODS: Twenty rabbits aged 8-10 weeks and weighing 1.27-1.72 kg underwent resections of the esophagus measuring 1.5 cm long using an anterior cervical approach. Esophagoesophagostomies were performed after intramural administration of XeominTM (3 U/body) in the BTX-A group and saline in the control group. Morphological and histological evaluations were examined on postoperative day 14. RESULTS: Six rabbits in each group survived. The BTX-A group showed significantly less postoperative anastomotic stricture and less fibrosis than the control group. Changes in wall thickness on both sides of the anastomotic areas were equivalent between the two groups, and no muscle fracturing was observed. CONCLUSION: Local administration of BTX-A for esophagoesophagostomy significantly reduced postoperative anastomotic stricture with less fibrosis than that observed in the control group. Reduced anastomotic tension with BTX-A presumably contributed to better anastomotic healing. Determining the optimum dose of BTX-A is necessary for clinical application. PMID- 27461433 TI - Efficacy of ethanol locks to reduce the incidence of catheter-related bloodstream infections for home parenteral nutrition pediatric patients: comparison of therapeutic treatment with prophylactic treatment. AB - PURPOSE: Children with intestinal failure (IF) requiring central venous catheters (CVCs) often experience frequent catheter-related bloodstream infections (CRBSIs), which is a serious and life-threatening complication. To reduce the incidence of CRBSI, prophylactic ethanol lock therapy (ELT) was initiated. METHODS: Patients with IF received home parenteral nutrition via a silicone tunneled CVC. All of them had received therapeutic ELT from January 2009 (first period) and prophylactic ELT from December 2012 (second period). Prophylactic ELT refers to ethanol lock for 2 h during the monthly hospital visit. We compared the CRBSI rate and number of CVC replacements between both periods. RESULTS: Four patients received 19 CVCs for a total of 5623 catheter days. In the first period, there were 12 CRBSIs in 1823 catheter days (rate 6.77 per 1000 catheter days). In the second period, there were 9 CRBSIs in 3800 catheter days (rate 3.13 per 1000 catheter days). Overall, the rate of CVC replacement decreased from 4.92 to 1.72 per 1000 catheter days (p = 0.04). No adverse reactions were experienced during ethanol instillation. CONCLUSION: Monthly prophylactic ELT for IF patients is considered to be a safe and effective modality for reducing the replacement of CVCs due to CRBSIs. PMID- 27461434 TI - Risk factors and prevention for surgical intestinal disorders in extremely low birth weight infants. AB - PURPOSE: Surgical intestinal disorders (SID), such as necrotizing enterocolitis (NEC), focal intestinal perforation (FIP), and meconium-related ileus (MRI), are serious morbidities in extremely low birth weight (ELBW, birth weight <1000 g) infants. From 2010, we performed enteral antifungal prophylaxis (EAP) in ELBWI to prevent for SID. The aim of this study was to identify disease-specific risk factors and to evaluate the efficacy of prevention for SID in ELBW infants. METHODS: A retrospective chart review of all consecutive patients between January 2006 and March 2015, which included 323 ELBW infants who were admitted to Shizuoka Children's Hospital, was conducted. RESULTS: The number of infants with NEC, FIP, and MRI was 9, 12, and 13, respectively; 28 in 323 ELBW infants died. The control group defined the cases were not SID. In-hospital mortality was higher in infants with NEC relative to those in the control group. On logistic regression analysis, low gestational age and cardiac malformations were associated with increased risk of NEC. IUGR were associated with increased risk of MRI. EAP decreased risk of NEC and FIP. Low gestational weight and NEC were associated with increased risk of death. CONCLUSION: Survival to hospital discharge after operation for NEC in ELBW infants remains poor. EAP decreased risk of NEC and FIP in ELBW infants. PMID- 27461435 TI - Contraindications and image-defined risk factors in laparoscopic resection of abdominal neuroblastoma. AB - PURPOSE: Minimally invasive surgery (MIS) has become widely accepted as a technique for abdominal neuroblastoma resection. However, the indications for MIS are still controversial. The aim of this study was to evaluate image-defined risk factors (IDRFs), complications, and oncologic outcomes in patients with abdominal neuroblastomas treated with MIS. METHODS: Between August 1998 and February 2016, MIS was planned for 20 children with abdominal neuroblastomas. Clinical data were retrospectively reviewed and compared between the IDRF-negative and IDRF-positive patients. RESULTS: On the basis of the latest IDRF guidelines, five patients were classified as IDRF-positive and four of them had operative complications; namely, partial infarction of the ipsilateral kidney or open conversion. Concerning the two patients who needed open conversion, the primary reason for open conversion was difficulty in dissection of the tumor from the vena cava. Preoperative images of these cases showed either deformation or subtotal encasement of the vena cava. Relapse occurred in three high-risk patients and in none of the low/intermediate risk patients. No complication occurred in the IDRF-negative cases. CONCLUSIONS: IDRF-negative might be a good indication for MIS for abdominal neuroblastoma. However, deformation or subtotal encasement of the vena cava should be considered as IDRF-positive for MIS. PMID- 27461437 TI - Elemental Bromine Production by TiO2 Photocatalysis and/or Ozonation. AB - Significant production of elemental bromine (Br2 ) was observed for the first time when treating bromide containing solutions at acidic pH, with TiO2 photocatalyst, ozone, or a combination thereof. Br2 selectivities up to approximately 85 % were obtained and the corresponding bromine mass balance values satisfied. The process is general and may be applied at a laboratory scale for green bromination reactions, or industrially as a cheap, safe, and environmentally sustainable alternative to the currently applied bromine production methods. PMID- 27461436 TI - Echocardiography and Alternative Cardiac Imaging Strategies for Long-Term Cardiotoxicity Surveillance of Cancer Survivors Treated with Chemotherapy and/or Radiation Exposure. AB - Cardiotoxicity from chemotherapy is a leading cause of morbidity and mortality in cancer survivors. Cardiotoxic effects include left ventricular systolic dysfunction, coronary artery disease, hypertension, bradycardia, arrhythmias, pericardial disease, valvular disease, and radiation-induced restrictive cardiomyopathy. Noninvasive cardiac imaging has been at the forefront of detecting cardiotoxicity in patients receiving chemotherapeutic agents known to adversely affect cardiac structure and function. Regimens for cardiotoxicity surveillance prior to and during chemotherapy administration have been proposed; however, optimal screening for and treatment of long-term cancer survivors have yet to be clarified. This review focuses on the most common imaging modalities for assessing cardiac dysfunction along with newer imaging technologies, and reviews suggested long-term surveillance strategies in cancer survivors following chemotherapy and radiation therapy. PMID- 27461438 TI - Global dissemination and implementation of behavioural activation. PMID- 27461439 TI - Polonium-210 poisoning: a first-hand account. AB - BACKGROUND: Polonium-210 ((210)Po) gained widespread notoriety after the poisoning and subsequent death of Mr Alexander Litvinenko in London, UK, in 2006. Exposure to (210)Po resulted initially in a clinical course that was indistinguishable from infection or exposure to chemical toxins, such as thallium. METHODS: A 43-year-old man presented to his local hospital with acute abdominal pain, diarrhoea, and vomiting, and was admitted to the hospital because of dehydration and persistent gastrointestinal symptoms. He was initially diagnosed with gastroenteritis and treated with antibiotics. Clostridium difficile toxin was subsequently detected in his stools, which is when he first raised the possibility of being poisoned and revealed his background and former identity, having been admitted under a new identity with which he had been provided on being granted asylum in the UK. Within 6 days, the patient had developed thrombocytopenia and neutropenia, which was initially thought to be drug induced. By 2 weeks, in addition to bone marrow failure, he had evidence of alopecia and mucositis. Thallium poisoning was suspected and investigated but ultimately dismissed because blood levels of thallium, although raised, were lower than toxic concentrations. The patient continued to deteriorate and within 3 weeks had developed multiple organ failure requiring ventilation, haemofiltration, and cardiac support, associated with a drop in consciousness. On the 23rd day after he first became ill, he suffered a pulseless electrical activity cardiorespiratory arrest from which he could not be resuscitated and was pronounced dead. FINDINGS: Urine analysis using gamma-ray spectroscopy on day 22 showed a characteristic 803 keV photon emission, raising the possibility of (210)Po poisoning. Results of confirmatory analysis that became available after the patient's death established the presence of (210)Po at concentrations about 10(9)-times higher than normal background levels. Post-mortem tissue analyses showed autolysis and retention of (210)Po at lethal doses in several organs. On the basis of the measured amounts and tissue distribution of (210)Po, it was estimated that the patient had ingested several 1000 million becquerels (a few GBq), probably as a soluble salt (eg, chloride), which delivered very high and fatal radiation doses over a period of a few days. INTERPRETATION: Early symptoms of (210)Po poisoning are indistinguishable from those of a wide range of chemical toxins. Hence, the diagnosis can be delayed and even missed without a high degree of suspicion. Although body surface scanning with a standard Geiger counter was unable to detect the radiation emitted by (210)Po, an atypical clinical course prompted active consideration of poisoning with radioactive material, with the diagnosis ultimately being made with gamma-ray spectroscopy of a urine sample. FUNDING: UK NHS, Public Health England, and the UK Department of Health. PMID- 27461441 TI - Distilling the essence-a guide to short but complete reports. PMID- 27461440 TI - Cost and Outcome of Behavioural Activation versus Cognitive Behavioural Therapy for Depression (COBRA): a randomised, controlled, non-inferiority trial. AB - BACKGROUND: Depression is a common, debilitating, and costly disorder. Many patients request psychological therapy, but the best-evidenced therapy-cognitive behavioural therapy (CBT)-is complex and costly. A simpler therapy-behavioural activation (BA)-might be as effective and cheaper than is CBT. We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression. METHODS: In this randomised, controlled, non inferiority trial, we recruited adults aged 18 years or older meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for major depressive disorder from primary care and psychological therapy services in Devon, Durham, and Leeds (UK). We excluded people who were receiving psychological therapy, were alcohol or drug dependent, were acutely suicidal or had attempted suicide in the previous 2 months, or were cognitively impaired, or who had bipolar disorder or psychosis or psychotic symptoms. We randomly assigned participants (1:1) remotely using computer-generated allocation (minimisation used; stratified by depression severity [Patient Health Questionnaire 9 (PHQ-9) score of <19 vs >=19], antidepressant use, and recruitment site) to BA from junior mental health workers or CBT from psychological therapists. Randomisation done at the Peninsula Clinical Trials Unit was concealed from investigators. Treatment was given open label, but outcome assessors were masked. The primary outcome was depression symptoms according to the PHQ-9 at 12 months. We analysed all those who were randomly allocated and had complete data (modified intention to treat [mITT]) and also all those who were randomly allocated, had complete data, and received at least eight treatment sessions (per protocol [PP]). We analysed safety in the mITT population. The non-inferiority margin was 1.9 PHQ-9 points. This trial is registered with the ISCRTN registry, number ISRCTN27473954. FINDINGS: Between Sept 26, 2012, and April 3, 2014, we randomly allocated 221 (50%) participants to BA and 219 (50%) to CBT. 175 (79%) participants were assessable for the primary outcome in the mITT population in the BA group compared with 189 (86%) in the CBT group, whereas 135 (61%) were assessable in the PP population in the BA group compared with 151 (69%) in the CBT group. BA was non-inferior to CBT (mITT: CBT 8.4 PHQ-9 points [SD 7.5], BA 8.4 PHQ-9 points [7.0], mean difference 0.1 PHQ-9 points [95% CI -1.3 to 1.5], p=0.89; PP: CBT 7.9 PHQ-9 points [7.3]; BA 7.8 [6.5], mean difference 0.0 PHQ-9 points [-1.5 to 1.6], p=0.99). Two (1%) non trial-related deaths (one [1%] multidrug toxicity in the BA group and one [1%] cancer in the CBT group) and 15 depression-related, but not treatment-related, serious adverse events (three in the BA group and 12 in the CBT group) occurred in three [2%] participants in the BA group (two [1%] patients who overdosed and one [1%] who self-harmed) and eight (4%) participants in the CBT group (seven [4%] who overdosed and one [1%] who self-harmed). INTERPRETATION: We found that BA, a simpler psychological treatment than CBT, can be delivered by junior mental health workers with less intensive and costly training, with no lesser effect than CBT. Effective psychological therapy for depression can be delivered without the need for costly and highly trained professionals. FUNDING: National Institute for Health Research. PMID- 27461442 TI - JNK1 inhibits transcriptional and pro-apoptotic activity of TAp63gamma. PMID- 27461443 TI - The closed conformation of the LDL receptor is destabilized by the low Ca(++) concentration but favored by the high Mg(++) concentration in the endosome. PMID- 27461444 TI - Prostate-specific antigen kinetics following hypofractionated stereotactic body radiotherapy versus conventionally fractionated external beam radiotherapy for low- and intermediate-risk prostate cancer. AB - AIM: The purpose of this study was to compare the prostate-specific antigen (PSA) kinetics between stereotactic body radiotherapy (SBRT) using Cyberknife and conventionally fractionated external beam radiotherapy (CF-EBRT) in low- and intermediate-risk prostate cancer. METHODS: A total of 69 patients with low- and intermediate-risk prostate cancer were enrolled. Thirty-four patients were treated with SBRT (36.25 Gy in five fractions) using Cyberknife and 35 patients treated with CF-EBRT (70.2-75.6 Gy in 39-42 fractions). PSA nadir, rate of PSA decline and biochemical failure (BCF) free survival were calculated and compared. RESULTS: With a median follow-up of 53.6 months (range, 14-74), the median slopes for SBRT were -0.430, -0.199, -0.127 and -0.094 ng/mL/month, respectively, for durations of 1, 2, 3 and 4 years following radiotherapy. Similarly, for CF-EBRT, the median slopes were -0.529, -0.138, -0.109 and -0.056 ng/mL/month, respectively. The slope of CF-EBRT was significantly different with a greater median rate of change for 1 year than SBRT (P = 0.018). Conversely, the slopes of SBRT for duration for 2, 3 and 4 year tended to be continuously greater than CF EBRT (P = 0.028, P = 0.058 and P = 0.128, respectively). The significantly lower PSA nadir was observed in SBRT (nadir 0.23 ng/mL) compared with CF-EBRT (nadir 0.37 ng/mL) (P = 0.011). Five-year BCF free survivals were 100% for SBRT and 80.8% for CF-EBRT (P = 0.031). CONCLUSIONS: Patients treated with SBRT experienced a lower PSA nadir and tended to a continuously greater rate of decline of PSA for duration 2, 3 and 4 years than CF-EBRT. The improved PSA kinetics of SBRT leaded to favorable BCF-free survival. PMID- 27461445 TI - Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. AB - Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF 04449913 (PF-913) is a selective, small-molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof-of-concept and mechanism of action of PF-913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF-913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34+ cells than CD34- cells. In vitro treatment with PF-913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF-913 attenuated the leukemia-initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF-913 modulated self-renewal signatures and cell cycle progression. Furthermore, PF-913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS 5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia-initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment. PMID- 27461446 TI - miR-34C Disrupts the Stemness of Purified CD133+ Prostatic Cancer Stem Cells. AB - OBJECTIVE: To find the potential micro-RNA (miRNA) that could determine the fate of prostate cancer stem cells. MATERIALS AND METHODS: We compared miRNA expression between our purified CD133+ prostatic cancer stem cells (PCSCs) and CD133- cells. Sphere formation assay and matrigel-based cell invasion assay were applied to determine the stemness of CD133+ PCSCs after our manipulation of miRNA using miRNA mimic or miRNA inhibitor. RESULTS: In this study, we identified that miR-34C was under-expressed in the purified CD133+ PCSCs and enforced introduction of miR-34C attenuated the stemness of CD133+ PCSCs. Clinically, we also observed a negative correlation between miR-34C and CD133. CONCLUSION: Our data strongly suggest that miR-34C may play essential role in conferring castration resistance by equilibrating PSCS population. PMID- 27461447 TI - Remarkable Points for Urodynamic Studies in Neurogenic Bladder Management. PMID- 27461449 TI - Histopathological aspects and differential diagnosis of CD8 positive lymphomatoid papulosis. AB - Lymphomatoid papulosis (LyP) belongs to CD30+ lymphoproliferative disorders with indolent clinical course. Classic histological subtypes, A, B and C are characterized by the CD4+ phenotype, while CD8+ variants, most commonly classified as type D, were reported in recent years. We present 14 cases of CD8+ LyP. In all patients, self-resolving or treatment-sensitive papules were observed. Of 14 cases 7 produced results with typical microscopic features of LyP type D mimicking primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. The infiltration pattern in 4 of 14 cases were consistent with classic LyP type B, without CD30 expression in two cases, resembling mycosis fungoides (MF). The morphology of 2 of 14 cases shared a certain consistency with classic type A and C, lacking eosinophils and neutrophils. Extensive folliculotropism characteristic to type F was observed in 1 of 14 case. Significant MUM1 and PD1 expression were detected in 2 of 14 and 3 of 14 cases, respectively. We concluded that CD8+ LyP may present with different histopathological features compared with type D, similar to CD4+ LyP variants. Differential diagnoses include CD8+ papular MF, folliculotropic MF and anaplastic large cell lymphoma in addition to primary cutaneous aggressive epidermotropic T-cell lymphoma. We emphasise that rare CD8+ LyP cases may exist with CD30-negativity. PMID- 27461448 TI - Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development. AB - GluA2-containing AMPA receptors (AMPARs) play a critical role in various aspects of neurodevelopment. However, the molecular mechanisms underlying these processes are largely unknown. We report here that the interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is necessary for neuron and cortical development. Using an interfering peptide (GluA2-G-Gpep) that specifically disrupts this interaction, we found that primary neuron cultures with peptide treatment displayed growth cone development deficits, impairment of axon formation, less dendritic arborization and lower spine protrusion density. Consistently, in vivo data with mouse brains from pregnant dams injected with GluA2-G-Gpep daily during embryonic day 8 to 19 revealed a reduction of cortical tract axon integrity and neuronal density in post-natal day 1 offspring. Disruption of GluA2-GAPDH interaction also impairs the GluA2-Plexin A4 interaction and reduces p53 acetylation in mice, both of which are possible mechanisms leading to the observed neurodevelopmental abnormalities. Furthermore, electrophysiological experiments indicate altered long-term potentiation (LTP) in hippocampal slices of offspring mice. Our results provide novel evidence that AMPARs, specifically the GluA2 subunit via its interaction with GAPDH, play a critical role in cortical neurodevelopment. PMID- 27461451 TI - Pelvic floor muscle exercise for fecal incontinence quality of life after coloanal anastomosis. AB - AIMS AND OBJECTIVES: To assess the efficacy of pelvic floor muscle exercise for enhancing fecal incontinence quality of life after coloanal anastomosis in colorectal cancer patients. BACKGROUND: Methods of improving incontinence have been evaluated in many countries, but never in a Taiwan population. DESIGN: A longitudinal experimental study. METHODS: Fifty-two colorectal cancer patients who had received colostomy closure and coloanal anastomosis surgery were recruited from a general hospital in southern Taiwan and randomly assigned to an experimental group (n = 26) or a control group (n = 26). Both groups received routine postoperative care. However, the experimental group received private consultations, educational DVDs and pamphlets to instruct them in performing pelvic flow muscle exercise. In all participants, the Fecal Incontinence Quality of Life Scale was used to measure quality of life before discharge and at one, two, three, six and nine months after discharge. Generalised estimating equations were used to compare longitudinal effects between the two groups. RESULTS: The generalised estimating equations revealed that all participants had significantly improved Fecal Incontinence Quality of Life Scale scores at two, three, six and nine months after discharge. Compared to the controls, however, the experimental group had significantly higher scores at two, three, and six months after discharge. CONCLUSIONS: Patient education in pelvic floor muscle exercise positively affects Fecal Incontinence Quality of Life Scale scores in patients who have received coloanal anastomosis. RELEVANCE TO CLINICAL PRACTICE: Early education in pelvic floor muscle exercise can improve management of fecal incontinence symptoms after coloanal anastomosis and can improve quality of life. PMID- 27461450 TI - Five-Year Oncologic Outcomes of Volume Displacement Procedures After Partial Mastectomy for Breast Cancer. AB - BACKGROUND: Volume displacement techniques that use remnant breast tissue are useful in reconstructive procedures after partial mastectomy. The authors analyzed the oncologic results of volume displacement surgery after partial mastectomy and their associations with various clinicopathologic factors. PATIENTS AND METHODS: One hundred fifty-eight eligible patients with breast cancer who underwent volume displacement procedures after partial mastectomy were included in this prospective study, in which associations between clinicopathologic factors and locoregional recurrence, distant metastasis, and death were analyzed. RESULTS: During a mean follow-up of 60.8 months, locoregional recurrence occurred in 3 cases (1.9%) and distant metastasis in 4 (2.5%). According to multivariate analysis, bilaterality of breast cancer (P = .035) and adjuvant chemotherapy (P = .042) were associated with distant metastasis. CONCLUSION: Volume displacement procedures after partial mastectomy have good oncologic results and are acceptable procedures for patients with breast cancer. PMID- 27461452 TI - A Molybdenum(0) Isocyanide Analogue of Ru(2,2'-Bipyridine)3 (2+) : A Strong Reductant for Photoredox Catalysis. AB - We report the first homoleptic Mo(0) complex with bidentate isocyanide ligands, which exhibits metal-to-ligand charge transfer ((3) MLCT) luminescence with quantum yields and lifetimes similar to Ru(bpy)3 (2+) (bpy=2,2'-bipyridine). This Mo(0) complex is a very strong photoreductant, which manifests in its capability to reduce acetophenone with essentially diffusion-limited kinetics as shown by time-resolved laser spectroscopy. The application potential of this complex for photoredox catalysis was demonstrated by the rearrangement of an acyl cyclopropane to a 2,3-dihydrofuran, which is a reaction that requires a reduction potential so negative that even the well-known and strongly reducing Ir(2 phenylpyridine)3 photosensitizer cannot catalyze it. Our study thus provides the proof-of-concept for the use of chelating isocyanides to obtain Mo(0) complexes with long-lived (3) MLCT excited states that are applicable to unusually challenging photoredox chemistry. PMID- 27461453 TI - Design of Controllable Bio-Inspired Chiroptic Self-Assemblies. AB - Modulation of chiroptics, chiral phenomena of the optical properties, is pivotal in a variety of advanced applications, including chirality-specific biosensing and photonic switches. One of the most effective methods for achieving this control is assembly of the optical moieties into chiral nanostructures. Lipopeptide self-assemblies have been extensively employed as soft templates to organize composites into low-dimensional superstructures due to their rigidity and ease of functionalization. Therefore, an appealing approach is to provide chiroptical control by using lipopeptide self-assemblies as templates to assemble chromophores. Herein, two lipopeptidic molecules, namely, C14-FFK and C14-FK, composed of phenylalanine and lysine residues conjugated to a myristic acid chain, were custom-designed. Spectroscopic and microscopic characterizations indicated that C14-FFK self-assembled to wide, slightly left-handed nanoribbons, while C14-FK formed narrow, intensely right-handed nanofibers. The different chirality was derived from the distinct self-assembly driving forces, especially the molecular bending dimensions. These superstructures presented an ideal capability to serve as soft templates to assemble porphyrin (ZnTPyP) through noncovalent electrostatic attractive interactions, or assemble the phenolic groups through covalent conjugation to peptide backbones. The distinct exciton coupling of the chromophores allowed their achiral optics to become chiral, showing negative Cotton effect when templated by nanoribbons and positive Cotton effect with nanofibers as templates. Following replacement of the lipopeptides with their d-type enantiomers, the handedness of the superstructures and the associated chiroptics were reversed and presented "mirror" symmetric CD signals to their l-type counterparts. These findings may pave the way to the formation of morphologically and chioptically controllable nanomaterials. PMID- 27461454 TI - Complex models of white and gray matter integration following training. AB - For many tasks, an increase in competence is associated with faster response time. Voelker et al (this issue) explore the possible role of white matter reorganization as a mechanism underlying this relationship. With such a strong focus on this possible interpretation and the limits of current neuroimaging methods, the authors constrained their options to the point of only considering simplified models of how training might result in faster responses. PMID- 27461455 TI - Biosimilars in psoriasis: Clinical practice and regulatory perspectives in Latin America. AB - Latin American countries view biosimilar agents as an effective approach to curtail health-care expenditures while maintaining the safety and efficacy profile of their branded innovator comparators. To understand the complexities of the regulatory landscape and key therapeutic issues for use of biosimilars to treat moderate to severe psoriasis in Latin America, the International Psoriasis Council convened dermatology experts from Argentina, Brazil, Chile, Colombia and Mexico in October 2015 to review the definition, approval, marketing and future of biosimilars in each country and develop a consensus statement. The regulatory framework for marketing approval of biosimilars in Latin America is currently a mosaic of disparate, country-specific, regulatory review processes, rules and standards, with considerable heterogeneity in clarity and specificity. Regulations in Argentina, Brazil, Chile and Mexico have undergone multiple refinements whereas Colombia is finalizing draft guidelines. Verification of the similarity in quality, safety and efficacy of biosimilars to the innovator biologic remains a key challenge for policy makers and regulatory authorities. Other key regulatory challenges include: naming of agents and traceability, pharmacovigilance, extrapolation of indications, and interchangeability and substitution. An urgent need exists for more Latin American countries to establish national psoriasis registries and to integrate their common components into a multinational psoriasis network, thereby enhancing their interpretative power and impact. A Latin American psoriasis network similar to PSONET in Europe would assist health-care providers, pharmaceutical companies, regulators and patients to fully comprehend specific products being prescribed and dispensed and to identify potential regional trends or differences in safety or outcomes. PMID- 27461456 TI - Corrigendum to "Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines" [Vaccine 34 (2016) 757-761]. PMID- 27461457 TI - Assessing dengue vaccination impact: Model challenges and future directions. AB - In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia(r) (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making. PMID- 27461458 TI - Assessment of outer membrane vesicles of periodontopathic bacterium Porphyromonas gingivalis as possible mucosal immunogen. AB - Periodontitis is the most prevalent infectious disease and related to oral and systemic health, therefore novel prophylaxis to prevent the disease is highly desirable. Here, we assessed the outer membrane vesicles (OMVs) of a keystone periodontal pathogen, Porphyromonas gingivalis, as a candidate mucosal immunogen and adjuvant for a periodontitis vaccine. The structural and functional stability of OMVs, demonstrated by proteinase K resistance and ability to withstand long term storage, are considered advantageous for carrying the OMV components into the host immune system. Intranasal vaccination of OMVs in mice elicited production of P. gingivalis-specific antibodies in blood and saliva by OMVs in a dose-dependent manner, which was dramatically enhanced by addition of a TLR3 agonist, Poly(I:C). Serum samples from mice immunized with OMVs plus Poly(I:C) adjuvant [OMV+Poly(I:C)] showed significant inhibition of gingipain proteolytic activity of not only the vaccine strain, but also heterologous strains. The viability of P. gingivalis was also decreased by preincubation with OMV+Poly(I:C) immunized sera, while the killing effect was partially blocked by heat inactivation of the sera. Saliva samples from mice immunized with OMV+Poly(I:C) enhanced bacterial agglutination of both the vaccine and heterologous strains. In an oral infection mouse model, the numbers of P. gingivalis in the oral cavity were significantly decreased in mice intranasally immunized with OMV+Poly(I:C) as compared to mock (only Poly[I:C])-immunized mice. The high levels of serum IgG (including IgG1 and IgG2a) and salivary S-IgA were elicited in mice intranasally immunized with OMV+Poly(I:C), which were maintained for at least 28 and 18weeks, respectively, after immunization. An experiment examining the accumulation of OMVs after intranasal immunization in proximal organs and an intracerebral injection experiment confirmed the safety of OMVs. Based on our results, we propose that intranasal immunization with OMV+Poly(I:C) is a feasible vaccine strategy in the context of bacterial clearance and safety. PMID- 27461460 TI - Dynamic models for estimating the effect of HAART on CD4 in observational studies: Application to the Aquitaine Cohort and the Swiss HIV Cohort Study. AB - Highly active antiretroviral therapy (HAART) has proved efficient in increasing CD4 counts in many randomized clinical trials. Because randomized trials have some limitations (e.g., short duration, highly selected subjects), it is interesting to assess the effect of treatments using observational studies. This is challenging because treatment is started preferentially in subjects with severe conditions. This general problem had been treated using Marginal Structural Models (MSM) relying on the counterfactual formulation. Another approach to causality is based on dynamical models. We present three discrete time dynamic models based on linear increments models (LIM): the first one based on one difference equation for CD4 counts, the second with an equilibrium point, and the third based on a system of two difference equations, which allows jointly modeling CD4 counts and viral load. We also consider continuous-time models based on ordinary differential equations with non-linear mixed effects (ODE-NLME). These mechanistic models allow incorporating biological knowledge when available, which leads to increased statistical evidence for detecting treatment effect. Because inference in ODE-NLME is numerically challenging and requires specific methods and softwares, LIM are a valuable intermediary option in terms of consistency, precision, and complexity. We compare the different approaches in simulation and in illustration on the ANRS CO3 Aquitaine Cohort and the Swiss HIV Cohort Study. PMID- 27461459 TI - Non-reassuring fetal status: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. PMID- 27461461 TI - Elemental Detection of Cerium and Gadolinium in Aqueous Aerosol via Laser-Induced Breakdown Spectroscopy. AB - Laser-induced breakdown spectroscopy (LIBS) was used to detect and measure the concentrations of Ce and Gd in aqueous aerosol solutions. A total of 36 standards, with concentrations of Ce and Gd ranging from 100 parts per million (ppm) to 10 000 ppm, were made to explore the relationship between them. In this study, a Collison nebulizer with an argon carrier gas was used to generate the aerosol droplets. For each liquid sample, ten repetitions of 200 laser shots each were recorded. The percent relative standard deviations (%RSD) were on an average of 7.5% between the ten different sample repetitions. Due to the close proximity of the Ce and Gd lines, it was challenging to identify peaks with low interferences. However, several lines were identified, calibration curves were constructed, and the best curves were generated using the 457.228 nm line for Ce and the 409.861 nm line for Gd. The LODs for these curves were calculated to be 209.7 ppm and 216.4 ppm for the Ce line and Gd line, respectively. PMID- 27461462 TI - In Situ Identification of Pigment Composition and Particle Size on Wall Paintings Using Visible Spectroscopy as a Noninvasive Measurement Method. AB - Noninvasive examination methods of chemical composition and particle size are presented here based on visible spectroscopy to achieve the identification and recording of mineral pigments used on ancient wall paintings. The normalized spectral curve, slope and curvature extracted from visible spectral reflectance are combined with adjustable weighting coefficients to construct the identification feature space, and Euclid distances between spectral reflectance from wall paintings and a reference database are calculated in the feature space as the discriminant criterion to identify the chemical composition of mineral pigments. A parametric relationship between the integral quantity of spectral reflectance and logarithm of mean particle size is established using a quadratic polynomial to accomplish the noninvasive prediction of mineral pigment particle size used on ancient wall paintings. The feasibility of the proposed methods is validated by the in situ nondestructive identification of the wall paintings in the Mogao Grottoes at Dunhuang. Chinese painting styles and historical evolution are then analyzed according to the identification results of 16 different grottoes constructed from the Sixteen Kingdoms to the Yuan Dynasty. PMID- 27461463 TI - Further steps in the modeling of behavioural crowd dynamics, good news for safe handling: Comment on "Human behaviours in evacuation crowd dynamics: From modelling to "big data" toward crisis management" by Nicola Bellomo et al. PMID- 27461464 TI - Modeling social crowds: Comment on "Human behaviours in evacuation crowd dynamics: From modelling to "big data" toward crisis management" by Nicola Bellomo et al. PMID- 27461465 TI - Association between vertebral artery hypoplasia and posterior circulation stroke. AB - BACKGROUND: The clinical significance of vertebral artery (VA) hypoplasia is under discussion. The aim of this retrospective study is to evaluate a hypothesis of a possible causal link between VA hypoplasia (VAH) and the incidence of posterior circulation stroke (PCS) or TIA depending on the degree of VAH and vascular risk factors. METHODS: A total of 367 symptomatic (PCS or TIA) and 742 asymptomatic subjects, were selected to participate in the study. The extracranial arteries were examined by ultrasound. VAH was defined as VA diameter in entire course <3 mm, although different degrees of VAH were examined. All the symptomatic patients underwent MRI or CT and MRA or CTA. The study assessed all the subjects in terms of their age, gender, co-risk factors (hypertension, hyperlipidemia, diabetes mellitus, peripheral arterial diseases, atrial fibrillation, myocardial infarction), as well as height of 180 healthy volunteers. RESULTS: VAH, regardless of the degree of severity, was more frequent in patients with non-cardioembolic PCS or TIA rather than in asymptomatic patients. The increasing degree of hypoplasia in patients under 65 years of age was a predictor of PCS/TIA, OR = 1.8, 95% CI: 1.3-2.5; p < 0.001. In subjects older than 65 years of age, this association failed. Only in patients aged under 50, VAH was significantly more frequent in the TIA group rather than in the PCS group (68.2% and 50%, respectively; p = 0.047). The optimal VA diameter cutoff point separating PCS/TIA and asymptomatic group was 2.7 mm. This value may vary in different populations, because VA diameter showed a significant dependence on sex as well as anthropometric parameters (height). With the increasing degree of VAH, the likelihood of the occurrence of the distal VA part stenosis/occlusion was growing (OR = 1.6, 95% CI: 1.2-2.1; p = 0.002). The distal VA stenosis/occlusion was likely to occur where the VA diameter was <2.2 mm. CONCLUSIONS: The impact of the VAH on PCS/TIA and its pathogenetic mechanism was significantly influenced by age. The cutoff point of VA diameter, affecting the occurrence of PCS in different populations may vary because VA diameter depends on gender and anthropometric parameters (especially height). PMID- 27461466 TI - Disturbed canonical nuclear factor of kappa light chain signaling in B cells of patients with common variable immunodeficiency. AB - BACKGROUND: Most patients with common variable immunodeficiency (CVID) present with severely reduced switched memory B-cell counts, and some display an increase of CD21low B-cell counts (CVID 21low), whereas others do not (CVID 21norm). Altered B-cell receptor (BCR) signaling might contribute to the defective memory formation observed in patients with CVID. OBJECTIVE: We sought to investigate canonical nuclear factor of kappa light chain (NF-kappaB) signaling in B cells from patients with CVID as a central pathway in B-cell differentiation. METHODS: Degradation of inhibitor of kappaBalpha (IkappaBalpha) and p65 phosphorylation, nuclear translocation of p65, and regulation of target genes and cell function were investigated after different modes of B-cell stimulation. RESULTS: BCR mediated canonical NF-kappaB signaling was impaired in all mature naive CVID derived B cells. This impairment was more profound in naive B cells from CVID 21low patients than CVID 21norm patients and most pronounced in CD21low B cells. The signaling defect translated into reduced induction of Bcl-xL and IkappaBalpha, 2 bona fide target genes of the canonical NF-kappaB pathway. CD40 ligand- and Toll-like receptor 9-mediated signaling were less strongly altered. Signaling in CD21low B cells but not CD21+ B cells of patients with HIV was similarly affected. CONCLUSION: Combined with the previous description of disturbed Ca2+ signaling, the discovery of NF-kappaB signaling defects, especially in CVID 21low patients, suggests a broad underlying signaling defect affecting especially BCR-derived signals. Given the immune phenotype of monogenic defects affecting Ca2+ and NF-kappaB signaling, the latter is more likely to contribute to the humoral deficiency. The strongly disturbed BCR signaling of CD21low B cells is characteristic for this cell type and independent of the underlying disease. PMID- 27461467 TI - Improving the recognition of grips and movements of the hand using myoelectric signals. AB - BACKGROUND: People want to live independently, but too often disabilities or advanced age robs them of the ability to do the necessary activities of daily living (ADLs). Finding relationships between electromyograms measured in the arm and movements of the hand and wrist needed to perform ADLs can help address performance deficits and be exploited in designing myoelectrical control systems for prosthetics and computer interfaces. METHODS: This paper reports on several machine learning techniques employed to discover the electromyogram patterns present when performing 24 typical fine motor functional activities of the hand and the rest position used to accomplish ADLs. Accelerometer data is collected from the hand as an aid in identifying the start and end of movements and to help in labeling the signal data. Techniques employed include classification of 100 ms individual signal instances, using a symbolic representation to approximate signal streams, and the use of nearest neighbor in two specific situations: creation of an affinity matrix to model learning instances and classify based on multiple adjacent signal values, and using Dynamic Time Warping (DTW) as a distance measure to classify entire activity segments. RESULTS: Results show the patterns can be learned to an accuracy of 76.64 % for a 25 class problem when classifying 100 ms instances, 83.63 % with the affinity matrix approach with symbolic representation, and 85.22 % with Dynamic Time Warping. Classification errors are, with a few exceptions, concentrated within particular grip action groups. CONCLUSION: The findings reported here support the view that grips and movements of the hand can be distinguished by combining electrical and mechanical properties of the task to an accuracy of 85.22 % for a 25 class problem. Converting the signals to a symbolic representation and classifying based on larger portions of the signal stream improve classification accuracy. This is both clinically useful and opens the way for an approach to help simulate hand functional activities. With improvements it may also prove useful in real time control applications. PMID- 27461468 TI - The up-regulation of Myb may help mediate EGCG inhibition effect on mouse lung adenocarcinoma. AB - BACKGROUND: Green tea polyphenol epigallocatechin-3-gallate (EGCG) has been demonstrated to inhibit cancer in experimental studies through its antioxidant activity and modulations on cellular functions by binding specific proteins. By means of computational analysis and functional genomic approaches, we previously identified a set of protein coding genes and microRNAs whose expressions were significantly modulated in response to the EGCG treatment in tobacco carcinogen induced lung adenocarcinoma in A/J mice. However, to what degree these genes are involved in the cancer inhibition of EGCG remains unclear. RESULTS: In this study, we further employed statistical methods and literature research to analyze these data in combination with The Cancer Genome Atlas (TCGA) lung adenocarcinoma datasets for additional data mining. Under the assumption that, if a gene mediates EGCG's cancer inhibition, its expression level change caused by EGCG should be opposite to what occurred in the carcinogenesis, we identified Myb and Peg3 as the primary putative genes involved in the cancer inhibitory activity. Further analysis suggested that the regulation of Myb could be mediated through an EGCG-upregulated microRNA, miR-449c-5p. CONCLUSIONS: Although the actions of EGCG involve multiple targets/pathways, further analysis by mining the existing genomic datasets revealed that the upregulations of Myb and Peg3 are likely the key anti-cancer events of EGCG in vivo. PMID- 27461469 TI - Detecting early signs of the 2007-2008 crisis in the world trade. AB - Since 2007, several contributions have tried to identify early-warning signals of the financial crisis. However, the vast majority of analyses has focused on financial systems and little theoretical work has been done on the economic counterpart. In the present paper we fill this gap and employ the theoretical tools of network theory to shed light on the response of world trade to the financial crisis of 2007 and the economic recession of 2008-2009. We have explored the evolution of the bipartite World Trade Web (WTW) across the years 1995-2010, monitoring the behavior of the system both before and after 2007. Our analysis shows early structural changes in the WTW topology: since 2003, the WTW becomes increasingly compatible with the picture of a network where correlations between countries and products are progressively lost. Moreover, the WTW structural modification can be considered as concluded in 2010, after a seemingly stationary phase of three years. We have also refined our analysis by considering specific subsets of countries and products: the most statistically significant early-warning signals are provided by the most volatile macrosectors, especially when measured on developing countries, suggesting the emerging economies as being the most sensitive ones to the global economic cycles. PMID- 27461470 TI - Pro-inflammatory cytokines enhance ERAD and ATF6alpha pathway activity in salivary glands of Sjogren's syndrome patients. AB - Salivary gland (SG) acinar-cells are susceptible to endoplasmic reticulum (ER) stress related to their secretory activity and the complexity of synthesized secretory products. SGs of Sjogren's syndrome patients (SS)-patients show signs of inflammation and altered proteostasis, associated with low IRE1alpha/XBP-1 pathway activity without avert increases in apoptosis. Acinar-cells may avoid apoptosis by activation of the ATF6alpha pathway and ER-associated protein degradation (ERAD). The aim of this study was to evaluate the role of pro inflammatory cytokines in ATF6alpha pathway/ERAD activation and cell viability in labial salivary glands (LSG) of SS-patients. In biopsies from SS-patients increased ATF6alpha signaling pathway activity, as evidenced by generation of the ATF6f cleavage fragment, and increased expression of ERAD machinery components, such as EDEM1, p97, SEL1L, gp78, UBE2J1, UBE2G2, HERP and DERLIN1, were observed compared to controls. Alternatively, for pro- (active-caspase-3) and anti apoptotic (cIAP2) markers no significant difference between the two experimental groups was detected. Increased presence of ATF6f and ERAD molecules correlated significantly with increased expression of pro-inflammatory cytokines. These observations were corroborated in vitro in 3D-acini treated with TNF-alpha and/or IFN-gamma, where an increase in the expression and activation of the ATF6alpha sensor and ERAD machinery components was detected under ER stress conditions, while changes in cell viability and caspase-3 activation were not observed. Cytokine stimulation protected cells from death when co-incubated with an ERAD machinery inhibitor. Alternatively, when cytokines were eliminated from the medium prior to ERAD inhibition, cell death increased, suggesting that the presence of pro-inflammatory cytokines in the medium is essential to maintain cell viability. In conclusion, the ATF6alpha pathway and the ERAD machinery are active in LSG of SS-patients. Both were also activated by TNF-alpha and IFN-gamma in vitro in 3D-acini and aided in preventing apoptosis. IFN-gamma levels were elevated in SS-patients and UPR responses triggered in vitro by this cytokine closely matched those observed in LSG from SS-patients, suggesting that cytokines may induce ER stress. PMID- 27461472 TI - Activation of ephrinB-EphB receptor signalling in rat spinal cord contributes to maintenance of diabetic neuropathic pain. AB - BACKGROUND: Diabetic neuropathic pain (DNP) is severe and intractable in clinic. The specific cellular and molecular mechanisms underlying DNP remain elusive and its treatment are limited. We investigated roles of EphB1 receptor in the development of DNP. METHODS: Diabetic neuropathic pain was produced in male, adult, Sprague-Dawley rats by a single i.p. streptozotocin (STZ) or alloxan. Western blot analysis and immunohistochemistry were used to analyse expression of EphB1 receptor as well as the activation of the glial cells and the pro inflammatory cytokines in the spinal cord. DNP manifested as mechanical allodynia, which was determined by measuring incidence of foot withdrawal in response to mechanical indentation of the hind paw by an electro von Frey filament. RESULTS: Diabetic neuropathic pain and high blood glucose were exhibited simultaneously in around 70% of animals that received i.p. STZ or alloxan. Phosphorylation of EphB1, activation of the astrocytes and microglial cells, and level of tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta in the spinal cord were significantly increased in rats with DNP. Spinal blocking EphB1 receptor activation in the late phase after STZ injection significantly suppressed the established mechanical allodynia as well as activation of the astrocytes and microglial cells and activity of TNF-alpha and IL-1beta. However, spinal treatment of EphB1-Fc in the early phase after STZ injection did not prevent the induction of DNP. CONCLUSIONS: EphB1 receptor activation in the spinal cord is critical to the maintenance, but not induction of diabetic pain. EphB1 receptor may be a potential target for relieving the established diabetic pain. SIGNIFICANCE: Activation of EphB1 receptor in the spinal cord is critical to maintaining the established diabetic neuropathic pain, but not to diabetic pain induction. Spinal blocking EphB1 receptor activation suppresses ongoing diabetic neuropathic pain. PMID- 27461471 TI - Loss of Cdk5 function in the nucleus accumbens decreases wheel running and may mediate age-related declines in voluntary physical activity. AB - KEY POINTS: Physical inactivity, which drastically increases with advancing age, is associated with numerous chronic diseases. The nucleus accumbens (the pleasure and reward 'hub' in the brain) influences wheel running behaviour in rodents. RNA sequencing and subsequent bioinformatics analysis led us to hypothesize a potential relationship between the regulation of dendritic spine density, the molecules involved in synaptic transmission, and age-related reductions in wheel running. Upon completion of follow-up studies, we developed the working model that synaptic plasticity in the nucleus accumbens is central to age-related changes in voluntary running. Testing this hypothesis, inhibition of Cdk5 (comprising a molecule central to the processes described above) in the nucleus accumbens reduced wheel running. The results of the present study show that reductions in synaptic transmission and Cdk5 function are related to decreases in voluntary running behaviour and provide guidance for understanding the neural mechanisms that underlie age-dependent reductions in the motivation to be physically active. ABSTRACT: Increases in age are often associated with reduced levels of physical activity, which, in turn, associates with the development of numerous chronic diseases. We aimed to assess molecular differences in the nucleus accumbens (NAc) (a specific brain nucleus postulated to influence rewarding behaviour) with respect to wheel running and sedentary female Wistar rats at 8 and 14 weeks of age. RNA-sequencing was used to interrogate transcriptomic changes between 8- and 14-week-old wheel running rats, and select transcripts were later analysed by quantitative RT-PCR in age-matched sedentary rats. Voluntary wheel running was greatest at 8 weeks and had significantly decreased by 12 weeks. From 619 differentially expressed mRNAs, bioinformatics suggested that cAMP-mediated signalling, dopamine- and cAMP-regulated neuronal phosphoprotein of 32 kDa feedback, and synaptic plasticity were greater in 8- vs. 14-week-old rats. In depth analysis of these networks showed significant (~20 30%; P < 0.05) decreases in cell adhesion molecule (Cadm)4 and p39 mRNAs, as well as their proteins from 8 to 14 weeks of age in running and sedentary rats. Furthermore, Cadm4, cyclin-dependent kinase 5 (Cdk5) and p39 mRNAs were significantly correlated with voluntary running distance. Analysis of dendritic spine density in the NAc showed that wheel access increased spine density (P < 0.001), whereas spine density was lower in 14- vs. 8-week-old sedentary rats (P = 0.03). Intriguingly, intra-NAc injection of the Cdk5 inhibitor roscovitine, dose dependently decreased wheel running. Collectively, these experiments suggest that an age-dependent loss in synaptic function and Cdk5/p39 activity in the NAc may be partially responsible for age-related declines in voluntary running behaviour. PMID- 27461474 TI - Improved thrombin binding aptamer analogues containing inversion of polarity sites: structural effects of extra-residues at the ends. AB - In this paper, we report the investigations, based on NMR, molecular modelling, CD measurements and electrophoresis, of thrombin binding aptamer (TBA) analogues containing an extra-residue at the 3'-end or at both the ends of the original TBA sequence, linked through 3'-3' or 5'-5' phosphodiester bonds. The data indicate that most of the modified aptamers investigated adopt chair-like G-quadruplex structures very similar to that of the TBA and that stacking interactions occur between the 3'-3' or 5'-5' extra residues and the deoxyguanosines of the upper G tetrad. A comparison of the thermodynamic data of TBA-A and TBA-T containing a 3' 3' extra residue and their canonical versions clearly indicates that the 3'-3' phosphodiester bond is fundamental in endowing the modified aptamers with remarkably higher thermal stabilities than the original TBA. PMID- 27461475 TI - Effect of partial replacement of alfalfa hay with Moringa species leaves on milk yield and composition of Najdi ewes. AB - The present study was carried out to investigate changes in milk yield and composition of Najdi ewes fed 25 % Moringa oleifera (MOD) or Moringa peregrina (MPD) leaf diets as a supplement to alfalfa hay diet (AHD). Thirty ewes (average 55 kg, 2 years old) were randomly sorted into three experimental groups with 10 animals each and were fed for a 6-week period with these diets (AHD, MOD, or MPD). Diets dry matter, crude protein, and crude fiber were comparable, while fat, nitrogen-free extract (NFE), neutral detergent fiber (NDF), acid detergent fiber (ADF), metabolizable energy (ME), total phenolic, and antioxidant activity varied (p <= 0.05) between the diets. Feeding ewes with MOD increased (p <= 0.05) the milk yield compared to those fed AHD while milk composition was similar (p <= 0.05) between treatments. The concentration of malondialdehyde (MDA) in the ewes' milk and serum was lower (p <= 0.05) for MOD, while the total antioxidant capacity, catalase activity, and vitamin C contents were increased (p <= 0.05). The serum cholesterol and glucose of the ewes were lower (p <= 0.05) for those fed MOD. Moringa diets increased (p <= 0.05) average daily weight gain of lambs compared to those fed alfalfa diets. The results obtained showed that the inclusion of Moringa, especially M. oleifera, in the diet of Najdi ewes can improve milk yield and quality. PMID- 27461476 TI - Effect of replacing marine fish meal with catfish (Pangasius hypophthalmus) by product protein hydrolyzate on the growth performance and diarrhoea incidence in weaned piglets. AB - The present study consists of two experiments. In experiment 1, a total of 120 weaned piglets (Yorkshire * Landrace) (7.3 +/- 1.9 kg) were allocated to five treatments, and four replications (pens) with six piglets/pen. In experiment 2, 40 male pigs (23.0 +/- 2.2 kg) were allocated to five treatments and eight replications (individual pens). In both experiments, the control diet contained fish meal (FM) as the sole protein supplement (CPH0), while the experimental diets consisted of four different diets in which crude protein (CP) from FM in CPH0 was replaced by the CP from catfish (Pangasius hypophthalmus) by-product protein hydrolyzate (CPH) at four different levels: 100 % (CPH100), 75 % (CPH75), 50 % (CPH50) and 25 % (CPH25). The results in experiment 1 showed that the highest average daily gain (ADG) over the 5-week period after weaning was recorded for piglets on CPH100 (307 g/day), and the lowest for piglets fed CPH0 (287 g/day) (P < 0.01). Feed conversion ratio (FCR) was lower in CPH100 (1.43 kg feed/kg gain) than in CPH0 (1.51 kg feed/kg gain) (P < 0.01). The piglets fed CPH100 were less affected by diarrhoea (6.55 %) than piglets fed the control diet CPH0 (17.3 %) after weaning, and faecal scores were also lower. In experiment 2, ADG was lowest in CPH0, and the cost/gain in pigs fed CPH100 was lowest in both weaning and growing pigs. In conclusion, it is possible to replace up to 100 % of the FM by CPH in diets for weaning and growing pigs, resulting in improved ADG and FCR, lower feed cost/gain as well as reduced diarrhoea incidence and improved faecal score. PMID- 27461477 TI - Significance of positive selection and gene duplication in adaptive evolution: in memory of Austin L. Hughes. AB - In this minireview, we highlight the contributions of the late Austin L. Hughes to two areas of molecular evolution: the role of positive (Darwinian) selection, and the impact of gene duplications during genome evolution. PMID- 27461478 TI - DNA fingerprinting and antimicrobial susceptibility pattern of clinical and environmental Acinetobacter baumannii isolates: a multicentre study. AB - BACKGROUND AND AIM: The aims of this study were to establish antibiotic profile and the molecular epidemiology of Acinetobacter baumannii isolates, with considering the effectiveness of control infection measures across three hospitals in the Kurdistan, west part of Iran. METHODS: Fifty-four A. baumannii isolates were collected from patients and environmental specimens. Antibiotic susceptibility patterns (Antibio-type) were evaluated for 17 different antibiotics and MIC for imipenem was done. Isolates were assessed for the presence of metallo-beta-lactamases (MBLs), class 1 and 2 integrons, and integrated gene cassettes and blaOXA-likefamilies genes. Repetitive-sequence based PCR (REP-PCR) was done for analysing clonality and relativeness of isolates (REP-type). RESULTS: Antibiotic susceptibility patterns distinguished 11 distinct Antibio-types and REP-PCR showed three clusters with 20 subclusters, mostly belonged to two clonal subgroups, A1 and B1. blaOXA-51 and blaOXA-23 were detected in 100% (54/54) and 52% (28/54), respectively, while blaOXA-24-like and blaOXA-58 were not present in isolates. MBLs were not detected, but, however, high rate of imipenem resistance was observed (52%). MIC90 of imipenem was 16 mg/ml. Class 1 integrons were detected in 11% (6/54) of isolates followed by 24% (13/54) of class 2. Both classes of integron genes were detected in 15% (8/54) of isolates. Integrated gene cassettes were in low level (11% of class 1 harboring isolates). Two arrays of gene cassettes were revealed, dfrA5-like and dfrA17 aadA5. CONCLUSION: Infection control surveillance should be considered as a serious manner, even the superficial eradication of hospital acquired pathogens. MBL genes were not induced carbapenem resistance in studied hospital settings, but blaOXA-51 & 23 contributed in imipenem resistant. Integrons had a little share in resistance of A. baumannii isolates. PMID- 27461479 TI - Determination of synergy between sulbactam, meropenem and colistin in carbapenem resistant Klebsiella pneumoniae and Acinetobacter baumannii isolates and correlation with the molecular mechanism of resistance. AB - Treatment of infections with carbapenem-resistant Gram negative organism is a major challenge especially among intensive care patients. Combinations of sulbactam, meropenem and colistin was studied for its synergistic activity against 100 invasive isolates of carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii-calcoaceticus complex by checkerboard assay and time kill assay (TKA). In addition, presence of carbapenemase production was determined by multiplex PCR. Time kill assay detected more synergy than checkerboard assay. Good bactericidal activity of 70-100% was noted with the combinations tested. Among K. pneumoniae, isolates producing NDM carbapenemase alone showed significantly more synergy than isolates producing OXA-48-like carbapenemases. In treatment of infection with carbapenem-resistant organisms, the site of infection and the type of carbapenemase produced may help to determine the most effective combination of antimicrobials. PMID- 27461480 TI - A Pilot Study of the Head Extension Swallowing Exercise: New Method for Strengthening Swallowing-Related Muscle Activity. AB - This pilot study examined the effect of a new head extension swallowing exercise (HESE) on submental muscle activity and tongue strength in healthy volunteers. Fifteen young adults (10 females and 5 males) were instructed to extend their head backwards as much as possible, and while watching the ceiling, swallowed their saliva every 10 s for a duration of 20 min. Twenty-four treatments were performed over 8 weeks. The outcome variables evaluated at baseline, 4 and 8 weeks of training, and 12-week follow-up included mean and peak submental muscle activation amplitudes during normal and effortful swallowing measured via surface electromyography, and anterior and posterior isometric tongue pressures were measured with the Iowa Oral Performance Instrument. Results indicated that the muscle activation amplitudes during effortful swallowing increased significantly at 4 and 8 weeks compared to baseline (p < 0.025). However, the increases in amplitudes during normal swallowing were minor (nonsignificant) after 8 weeks compared to baseline. The isometric pressures of the tongue tip and the posterior part of the oral tongue were significantly higher at 8 weeks compared to baseline (p < 0.025). Thus, the 8-week HESE protocol significantly improved suprahyoid muscle activity during effortful swallowing as well as the isometric tongue pressures. The HESE appears effective in exercising and strengthening the suprahyoid muscles and tongue muscles in healthy participants. Although encouraging, these results need to be replicated in clinical trials for testing the therapeutic effects of the HESE in older adults and patients with dysphagia who present with decreased hyolaryngeal elevation. PMID- 27461481 TI - Reflex Cough and Disease Duration as Predictors of Swallowing Dysfunction in Parkinson's Disease. AB - Patients with Parkinson's disease (PD) have progressive and pervasive disorders of airway protection. Recent work has highlighted the relationship between reflex and voluntary cough and swallowing safety. The goal of this study was to test the sensitivity and specificity of several airway protective and disease-specific factors for predicting swallowing safety outcomes in PD. Sixty-four participants (44 males) completed measures of voluntary and reflex cough, and swallowing safety. Clinical predictors included disease severity and duration, and cough airflow and sensitivity measures. ROC and Chi-square analyses identified predictors of swallowing safety (penetration-aspiration score) in PD. Disease duration significantly discriminated between patients with normal and abnormal swallowing safety (p = 0.027, sensitivity: 71 %, specificity: 55.4 %). Cough reflex sensitivity significantly discriminated between patients who penetrated above the level of the vocal folds and those with more severe penetration/aspiration (p = 0.021, sensitivity: 71.0 %, specificity 57.6 %). Urge to-cough sensitivity (log-log linear slope) was the only variable which significantly discriminated between patients with penetration versus aspiration (p = 0.017, sensitivity: 85.7 %, specificity 73.2 %). It is important to identify the factors which influence airway protective outcomes in PD especially given that aspiration pneumonia is a leading cause of death. Results from this study highlight the ecological validity of reflex cough in the study of airway protection and this study further identifies important factors to consider in the screening of airway protective deficits in PD. PMID- 27461482 TI - Cervical Osteophytes Increase the Risk for Foreign Body Impaction: A 171-Patient Case-Control Study. AB - The aim of this study is to define the relationship between anatomical and pathological cervical structures and the impaction of ingested foreign bodies (FBs). The effects of such structures on deglutition have been previously discussed, however their contribution to FB impaction has not yet been examined. This was a retrospective case-control study of 171 patients who underwent computed tomography (CT) scans over the period 2008-2014: 57 patients with an esophageal or hypopharyngeal FB; the other 114 comprised the control group, selected using the 'neighbor control' method. CT scans were reviewed for measurements of cervical structures. The mean age was 63 +/- 13 years and 55 +/- 17 years in the case and control groups, respectively (p-value = 0.003). Age was the only demographic or clinical characteristic which demonstrated a significant difference. Overall, 24 patients had cervical osteophytes: 28 %(16) with an impacted FB, compared with 7 %(8) from the control group (p-value < 0.001). Of the patients with osteophytes and impacted FBs, 62.5 % had the FB lodged at a vertebral level corresponding to their osteophytes, while another 18.75 % had the FB within three vertebral levels above the osteophytes. Stepwise logistic regression revealed that osteophytes were a significant factor, independent of older age (p-value = 0.004). Adjusted odds ratio for FB impaction in the presence of osteophytes was 4.04. Ventral cervical osteophytes increase the risk for FB impaction in the upper digestive tract. This risk is independent of older age. These findings can be of value in preventive medicine, and emphasize the importance of looking for spinal changes in patients with recurrent FB impaction. PMID- 27461483 TI - Direct injection of HILIC fractions on the reversed-phase trap column improves protein identification rates for salivary proteins. AB - Online combination of hydrophilic interaction chromatography (HILIC) and RP chromatography for separation of tryptic peptides is a challenging approach due to the incompatibility of direct loading HILIC fractions on the RP trapping column. High amounts of organic modifiers in loading solvents decrease the binding efficiency of tryptic peptides on C18 phases and lower the number of identifications. A 500 MUL loop upfront of the trapping column filled with aqueous mobile phase was employed as a mixing chamber and enabled direct injections and improved saliva protein identification rates of HILIC fractions. PMID- 27461485 TI - Comments on "A Four-Layer Wound Closure Technique with Barbed Sutures for Stable Reset of the Inframammary Fold in Breast Augmentation". PMID- 27461486 TI - Commentary on: Autologous Fat Grafting in Cosmetic Breast Augmentation: A Systematic Review on Radiological Safety, Complications, Volume Retention, and Patient/Surgeon Satisfaction. PMID- 27461484 TI - Hypotonic fluid reduce serum sodium compared to isotonic fluids during anesthesia induction in pediatric patients undergoing maxillofacial surgery-type of infusion affects blood electrolytes and glucose: an observational study. AB - BACKGROUND: Reportedly, administration of hypotonic fluids containing 30.8-74 mEq/L sodium with 5 % glucose may lead to serious hyponatremia or hyperglycemia. In Japan, hypotonic fluids containing 90 mEq/L sodium with 2.6 % glucose are commonly used. We compared blood electrolyte balance and blood glucose concentration with the use of isotonic (140 mEq/L sodium with 1 % glucose) versus hypotonic fluids in pediatric patients. METHODS: We studied 77 children aged 5 months to 2 years who underwent oro-maxillofacial surgery and dental treatment under general anesthesia. Patients were categorized according to the fluids infused (hypotonic or isotonic). Blood samples were obtained from the dorsalis pedis artery between the conclusion of anesthesia induction and commencement of surgery. We compared blood sodium, potassium and glucose concentrations in the two fluid groups during the pre-anesthesia and post-anesthesia-induction periods. RESULTS: There were no significant differences in pre-anesthesia values between isotonic (n = 35) and hypotonic groups (n = 42). There were significant differences between isotonic and hypotonic groups in post-anesthesia-induction concentrations of sodium (isotonic, 138.7 +/- 1.4 mEq/L; hypotonic, 137.5 +/- 1.3 mEq/L; p = 0.0003) and glucose (isotonic, 88.0 +/- 9.4 mg/dL; hypotonic, 109.9 +/ 18.4 mg/dL; p < 0.0001), while potassium concentrations were not significantly different (isotonic, 4.0 +/- 0.3 mEq/L; hypotonic, 4.0 +/- 0.2 mEq/L; p = 0.6615) between the two groups. CONCLUSION: Isotonic solution administration enables avoidance of serum sodium reduction and serum glucose elevation in infants, and may therefore enhance patient safety in comparison with hypotonic solutions. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry ( UMIN000014648 ), registration 25 July 2014. PMID- 27461487 TI - Response to "Comments on 'A Four-Layer Wound Closure Technique with Barbed Sutures for Stable Reset of the Inframammary Fold in Breast Augmentation'". PMID- 27461488 TI - From ligands to binding motifs and beyond; the enhanced versatility of nanocrystal surfaces. AB - Surface chemistry bridges the gap between nanocrystal synthesis and their applications. In this respect, the discovery of complex ligand binding motifs on semiconductor quantum dots and metal oxide nanocrystals opens a gateway to new areas of research. The implications are far-reaching, from catalytic model systems to the performance of solar cells. PMID- 27461491 TI - Development and validation of a new instrument measuring guideline adherence in clinical practice. AB - BACKGROUND: Education in evidence-based medicine (EBM) is an important part of the postgraduate training of GPs. Evaluation of its effect on EBM behaviour in daily clinical practice is difficult and instruments are scarce. Working in accordance with guidelines is considered as one of the key indicators of EBM behaviour. OBJECTIVE: To develop and validate an instrument assessing guideline adherence of GP trainees in clinical practice. METHODS: We developed an instrument that assesses guideline adherence, taking conscious deviation into account. The instrument assesses guideline adherence on 59 different management decisions (diagnosis N = 17, therapy N = 20, referral N = 22) for 23 conditions as described in 27 different clinical practice guidelines. We validated this instrument using performance data as collected by third-year GP trainees on three important properties: validity, reliability and feasibility. RESULTS: Performance data were collected by 76 GP trainees on 12106 patient consultations with 12587 different reasons for encounter. Overall, guideline adherence was 82% (95% confidence interval 77-88%). The significant correlation with the national GP knowledge test (r 0.33, P 0.004) showed the instrument to be a valid instrument. Interrater reliabilities (intraclass correlation coefficient) varied between moderate and excellent (0.64-1.00, P < 0.001). The instrument proved feasible with coverage of 24% (N = 3082) of reasons for encounter presented to GP trainees and a mean and median time of 1 minute to score a patient consultation. CONCLUSION: This instrument proved valid, reliable and feasible to assess guideline adherence among trainees in the clinical primary care setting. PMID- 27461492 TI - Rh(iii)-catalyzed C-H activation reactions forming 1H-isoindoles containing a quaternary carbon center from aryl ketones or benzylamines. AB - Rh(iii)/Cu(OAc)2 catalyzed, one-pot reactions of aryl ketones, acrylate esters and ammonium acetate or alpha-substituted benzylamines under microwave irradiation conditions produce 1H-isoindoles bearing a quarternary carbon center. PMID- 27461489 TI - Transcriptomic changes in relation to early-life events in the gilthead sea bream (Sparus aurata). AB - BACKGROUND: Teleosts are exposed to a broad range of external stimuli, which may be either of acute or chronic nature. The larval phase of certain fish species offer a unique opportunity to study the interactions between genes and environmental factors during early life. The present study investigates the effects of early-life events, applied at different time points of early ontogeny (first feeding, flexion and development of all fins; Phase 1) as well as on the subsequent juvenile stage after the application of an additional acute stressor (Phase 2) in the gilthead sea bream (Sparus aurata), a commercially important European aquaculture species. Animal performance, the cortisol response and gene expression patterns during early development as well as on the subsequent phases (juveniles) after the application of additional acute stressors were investigated. RESULTS: Significant differences on fish performance were found only for juveniles exposed to early-life events at the phase of the formation of all fins. On the transcriptome level distinct expression patterns were obtained for larvae as well as for juveniles with the most divergent expression pattern found to be again at the phase of the development of all fins, which showed to have also an impact later on in the acute stress response of juveniles. CONCLUSIONS: The present study showed that applying an early-life protocol, characterized by the unpredictable, variable and moderate intensity of the applied stimuli provides a relative realistic model to evaluate the impact of daily aquaculture practices on fish performance. In addition, the power of investigating global gene expression patterns is shown, providing significant insights regarding the response of early-life events during development and as juveniles after the application of extra acute stressors. PMID- 27461490 TI - Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness. AB - INTRODUCTION: The Mediterranean diet (MeDi) is associated with reduced risk of cognitive impairment, but it is unclear whether it is associated with better brain imaging biomarkers. METHODS: Among 672 cognitively normal participants (mean age, 79.8 years, 52.5% men), we investigated associations of MeDi score and MeDi components with magnetic resonance imaging measures of cortical thickness for the four lobes separately and averaged (average lobar). RESULTS: Higher MeDi score was associated with larger frontal, parietal, occipital, and average lobar cortical thickness. Higher legume and fish intakes were associated with larger cortical thickness: legumes with larger superior parietal, inferior parietal, precuneus, parietal, occipital, lingual, and fish with larger precuneus, superior parietal, posterior cingulate, parietal, and inferior parietal. Higher carbohydrate and sugar intakes were associated with lower entorhinal cortical thickness. DISCUSSION: In this sample of elderly persons, higher adherence to MeDi was associated with larger cortical thickness. These cross-sectional findings require validation in prospective studies. PMID- 27461493 TI - [Osteocytes and osteonetwork]. AB - Osteocytes are the most abundant osteolineage cells in the bone tissue, and they control the balance of activity between osteoblasts and osteoclasts in bone metabolism. Recent studies have revealed that the bone equipped with osteocytes controls not only bone marrow hematopoiesis but also regulates the functions of remote organs/tissues such as thymus and fat. Communications of bone cells with hematopoiesis, immunity and energy metabolism are overviewed. PMID- 27461494 TI - [Interaction between bone and artery]. AB - Both osteoporosis and vascular calcification are highly prevalent in aged subjects and patients with diabetes and chronic kidney disease(CKD). Although it has long been thought that vascular calcification is a consequence of degeneration of vessel walls, recent studies unveiled the molecular mechanism of vascular calcification and identified the vascular calcification as a process similar to bone formation. With the advent of the understanding of the basis for bone remodeling, several hypotheses have been proposed for the underlying mechanism of the interaction between osteoporosis and vascular calcification. Briefly,(1)impaired bone remodeling may perturb serum calcium/phosphate, thus contributing to increased vascular calcification,(2)vascular calcification may precede osteoporosis, and(3)molecules responsible for bone remodeling, including estrogen, parathyroid hormone and vitamin D, RANK(receptor activator of nuclear factor kB), RANK ligand(RANKL), and osteoprotegerin(OPG), Wnt signaling, and loss of calcification inhibitors(matrix Gla protein)may promote vascular calcification. This review discusses the emerging role of bone remodeling factors in vascular calcification. PMID- 27461495 TI - ["Osteo-neural" related factors - bridge over bone homeostasis]. AB - Bone tissues including bone marrow are comprised of various cells. A growing body of evidence suggests that nerve cells which exist in and around bone such as periosteal and bone marrow build a close relationship with bone cells. Namely, it was revealed that central nervous system governs bone tissues via peripheral nervous system and neurotransmitters or cytokines play a role for the communication between bone and nerve in the last decade. In this paper, I would like to review "osteo-neural" related factors which has been well-documented so far. PMID- 27461496 TI - [RANKL Biology ~Beyond the bone biology~]. AB - Receptor activator of nuclear factor-kappaB ligand(RANKL),a transmembrane protein of the tumor necrosis factor(TNF) superfamily cytokine, currently provides a paradigm that enables the molecular understanding of the linkage among bone metabolism, organization of lymphoid tissues, establishment of the thymic microenviroment, thermoregulation, metabolic regulation, mammary gland development and tumorigenesis. Here we summarize the recent progress in the understanding of RANKL biology by focusing on the investigation of RANKL expressing cells/organs, signaling and related diseases in the context of the newly established interdisciplinary field of osteonetwork. The elucidation of both physiological and pathological RANKL function will provide a scientific basis for future therapeutic approaches to several RANKL-related diseases. PMID- 27461497 TI - [FGF23 and osteonetwork]. AB - Fibroblast growth factor 23(FGF23)is produced mainly by osteocytes and works as a hormone that reduces serum phosphate level in a Klotho-dependent manner. The identification of FGF23 revealed that bone works as an endocrine organ. On the other hand, FGF23 has been shown to be high in patients with chronic kidney disease and suggested to cause several adverse events including left ventricular hypertrophy and impaired immune function in a Klotho-independent manner. However, it is not known how FGF23 can work without Klotho. PMID- 27461498 TI - [Osteocalcin and osteonetwork]. AB - Nearly nine years ago, new mechanism that bone secretes a hormone called osteocalcin and regulates glucose/energy metabolism was discovered. To date the study of osteocalcin as the bone hormone was progressed well, and the new roles in various tissues, such as glucose metabolism, male fertility, and development of the brain, are demonstrated. On the other hand, signaling pathway of osteocalcin has not yet been fully understood, though its receptor was reported. This review focuses on the diverse roles of osteocalcin and also on the future task that should be solved. PMID- 27461499 TI - [Klotho and vascular calcification]. AB - The link between chronic kidney disease(CKD)and cardiovascular diseases has recently been attracting attention as cardiorenal connection. Vascular calcification due to down-regulation of klotho is partly involved in the pathogenesis of cardiorenal connection. Klotho protein which is mainly expressed in the distal convoluted tubule, is directly correlated with renal function. Of note, its expression has already been decreased in patients with estimated glomerula filtration rate(eGFR)of 60~90 mL/min/1.73 m2 compared with those with eGFR of more than 90 mL/min/1.73 m2. In early CKD, compensatory mechanisms mediated by fibroblast growth factor 23(FGF23)maintain phosphaturia at a sufficient level;however, in end-staging kidney disease, impaired compensatory mechanisms by further down-regulation of klotho promotes osteochondrocytic differentiation of vascular smooth muscle cells(VSMCs)through phosphate hoarding and increased transcription factors. On the other hands, Klotho protein expressed in VSMCs, suppresses osteochondrocytic differentiation with inhibition of phosphate uptake. Both renal and vascular Klotho protect VSMCs against vascular calcification. PMID- 27461500 TI - [Regulation of bone homeostasis by glucose]. AB - Synthesis of type I collagen, a major component of the bone matrix, precedes the expression of Runt-related transcription factor 2(Runx2), a master regulator in osteoblast differentiation. Thus, a direct link between osteoblast differentiation and bone formation is seemingly absent, and how these are maintained in a coordinated matter remains unclear. It was recently demonstrated that osteoblasts depend on glucose, which glucose transporter type 1(GLUT1)takes up as an energy source, and it was found that glucose uptake promotes osteoblast differentiation and bone formation via AMP-activated protein kinase. It was also shown that Runx2 upregulates GLUT1 expression, and this Runx2-GLUT1 feedforward regulation integrates and coordinates osteoblast differentiation and bone formation throughout life. These previous findings revealed that the energy metabolism balance in osteoblasts integrates the differentiation and function of osteoblasts, and re-emphasized the importance of crosstalk between bone and sugar metabolism. PMID- 27461501 TI - [Sarcopenia and bone mineral property with age]. AB - In order to maintain functional activities in the elderly, promotion of musculoskeletal care is important toward successful aging and healthy longevity. In practice, reduction of falls and fall-related injuries together with treatment of osteoporosis is important to keep activities of daily living. Recent findings suggest the possibility that there is a relationship between skeletal muscle and bone mineral property, represented by pathophysiological linkage between sarcopenia and osteoporosis. PMID- 27461502 TI - [Anti-osteoporotic drugs and their interactions with multiple organs]. AB - Anti-osteoporotic drugs directly control bone metabolism. Then, they are possibly involved in interactions between bone and many other tissues. It is not, however, clear how they influence several organs other than bone, or what clinical significance they have. Recently, accumulating evidence suggests that osteocalcin as a humoral factor from bone is actively involved in glucose metabolism. Since interaction between osteoporosis and diabetes mellitus is an emerging clinical issue, there are several clinical questions under vigorous investigations. PMID- 27461503 TI - [Diabetes mellitus and bone]. AB - It has been shown that diabetic patients have bone fragility independent of bone mineral density. Recently, diabetes-related bone disease is recognized as one of diabetic complications. It is reported that advanced glycation end products(AGEs)collagen cross-links, low bone turnover with osteoblastic dysfunction, and abnormality of microarchitectures such as cortical porosity and deterioration of trabecular bone structure are involved in diabetes-related bone disease. AGEs and homocysteine directly and negatively affect osteoblasts and osteocytes. Moreover, anti-diabetic drugs also affect bone metabolism. Therefore, the underlying mechanisms are very complex. In this review, we describe the effects of diabetes on bone metabolism based on the recent evidence. PMID- 27461504 TI - [COPD and bone]. AB - Chronic obstructive pulmonary disease(COPD)is a chronic inflammatory airway disease associated with various systemic comorbidities including osteoporosis. Osteoporosis is extremely common in COPD patients;up to 80%prevalence of vertebral fracture has been reported. However, its low awareness has left many patients untreated. Although pathophysiology of COPD-associated osteoporosis is largely unknown, multiple risk factors for osteoporosis are present, such as smoking, low body weight, systemic inflammation, vitamin D insufficiency, hypoxia. Further research to elucidate its pathophysiology is needed. But, more importantly, increased awareness of its significance is urgently called upon. PMID- 27461505 TI - [Chronic Kidney Disease and Bone]. AB - Both bone and kidney are members of the physiological network sharing a purpose of systemic mineral metabolism. In patients with chronic kidney disease whose kidney function is lost, the organ functions of other mineral metabolism network member including bone fail into uncontrollable due to dysregulated feedback system. This is the concept of Chronic Kidney Disease(related)- Mineral and Bone Disorder(CKD-MBD). However, the bone metabolic abnormalities in patients with chronic kidney disease cannot be explained merely by the framework of this mineral metabolism network. Although dialysis patients show several times higher hip fracture risk than general population, the main pathogenesis seems not to be their disordered mineral metabolism. We need to consider "uremic osteoporosis" characterized by deteriorated bone material properties due to uremic condition. PMID- 27461506 TI - Exploring the relationship between exposure to technological and gastrointestinal stress and probiotic functional properties of lactobacilli and bifidobacteria. AB - Strains of Lactobacillus and Bifidobacterium are considered probiotic because of their associated potential health benefits. Probiotics are commonly administered orally via incorporation into food products. Microorganisms for use as probiotics encounter stress conditions, which include acid, bile, osmotic, oxidative, heat and cold stresses. These can occur during processing and storage and during passage through the gastrointestinal tract, and can affect viability. Probiotic bacteria have to remain viable to confer any health benefits. Therefore, the ability to withstand technological and gastrointestinal stresses is crucial probiotic selection criteria. While the stress tolerance mechanisms of lactobacilli and bifidobacteria are largely understood, the impact of exposure to stressful conditions on the functional properties of surviving probiotic microorganisms is not clear. This review explores the potentially positive and negative relationships between exposure to stress conditions and probiotic functional properties, such as resistance to gastric acid and bile, adhesion and colonization potential, and tolerance to antibiotics. Protective strategies can be employed to combat negative effects of stress on functional properties. However, further research is needed to ascertain synergistic relationships between exposure to stress and probiotic properties. PMID- 27461507 TI - Integrative pharmacokinetic-pharmacodynamic modeling and simulation of amenamevir (ASP2151) for treatment of recurrent genital herpes. AB - Amenamevir is a novel drug that targets the viral helicase-primase complex. While dose-dependent efficacy had been observed in non-clinical studies, no clear dose dependence has been observed in humans. We therefore developed a pharmacokinetic/pharmacodynamic (PK/PD) model to explain this inconsistency between species and to clarify the immune-related healing of amenamevir in humans. The model consisted of a non-linear kinetic model for a virtual number of virus plaques as a built-in biomarker. Lesion score was defined as an endpoint of antiviral efficacy, and logit model analysis was applied to the ordered categorical lesion score. The modeling results suggested the time course profiles of lesion score could be explained with the efficacy terms in the logit model, using change in number of virus plaques as an indicator of the effects of amenamevir and time elapsed as an indicator of the healing of the immune response. In humans, the PD effect was almost dose-independent, and immune related healing may have been the driving force behind the reduction in lesion scores. Drug efficacy is occasionally masked in diseases healed by the immune response, such as genital herpes. The PK/PD model proposed in the present study must be useful for explanation the PK/PD relationship of such drugs. PMID- 27461508 TI - Linking genomics and population genetics with R. AB - Population genetics and genomics have developed and been treated as independent fields of study despite having common roots. The continuous progress of sequencing technologies is contributing to (re-)connect these two disciplines. We review the challenges faced by data analysts and software developers when handling very big genetic data sets collected on many individuals. We then expose how r, as a computing language and development environment, proposes some solutions to meet these challenges. We focus on some specific issues that are often encountered in practice: handling and analysing single-nucleotide polymorphism data, handling and reading variant call format files, analysing haplotypes and linkage disequilibrium and performing multivariate analyses. We illustrate these implementations with some analyses of three recently published data sets that contain between 60 000 and 1 000 000 loci. We conclude with some perspectives on future developments of r software for population genomics. PMID- 27461510 TI - Physical analysis of the shielding capacity for a lightweight apron designed for shielding low intensity scattering X-rays. AB - The purpose of this paper is to develop a lightweight apron that will be used for shielding low intensity radiation in medical imaging radiography room and to apply it to a custom-made effective shielding. The quality of existing aprons made for protecting our bodies from direct radiation are improved so that they are suitable for scattered X-rays. Textiles that prevent bodies from radiation are made by combining barium sulfate and liquid silicon. These materials have the function of shielding radiation in a manner like lead. Three kinds of textiles are produced. The thicknesses of each textile are 0.15 mm, 0.21 mm, and 0.29 mm and the corresponding lead equivalents are 0.039 mmPb, 0.095 mmPb, 0.22 mmPb for each. The rate of shielding space scattering rays are 80% from the distance of 0.5 m, 86% from 1.0 m, and 97% from 1.5 m. If we intend to approach with the purpose of shielding scattering X-rays and low intensity radiations, it is possible to reduce the weight of the apron to be 1/5 compared to that of the existing lead aprons whose weight is typically more than 4 kg. We confirm, therefore, that it is possible to produce lightweight aprons that are used for the purpose of shielding low dose radiations. PMID- 27461509 TI - Genomic epidemiology and global diversity of the emerging bacterial pathogen Elizabethkingia anophelis. AB - Elizabethkingia anophelis is an emerging pathogen involved in human infections and outbreaks in distinct world regions. We investigated the phylogenetic relationships and pathogenesis-associated genomic features of two neonatal meningitis isolates isolated 5 years apart from one hospital in Central African Republic and compared them with Elizabethkingia from other regions and sources. Average nucleotide identity firmly confirmed that E. anophelis, E. meningoseptica and E. miricola represent demarcated genomic species. A core genome multilocus sequence typing scheme, broadly applicable to Elizabethkingia species, was developed and made publicly available (http://bigsdb.pasteur.fr/elizabethkingia). Phylogenetic analysis revealed distinct E. anophelis sublineages and demonstrated high genetic relatedness between the African isolates, compatible with persistence of the strain in the hospital environment. CRISPR spacer variation between the African isolates was mirrored by the presence of a large mobile genetic element. The pan-genome of E. anophelis comprised 6,880 gene families, underlining genomic heterogeneity of this species. African isolates carried unique resistance genes acquired by horizontal transfer. We demonstrated the presence of extensive variation of the capsular polysaccharide synthesis gene cluster in E. anophelis. Our results demonstrate the dynamic evolution of this emerging pathogen and the power of genomic approaches for Elizabethkingia identification, population biology and epidemiology. PMID- 27461512 TI - Field-induced exciton condensation in LaCoO3. AB - Motivated by recent observation of magnetic field induced transition in LaCoO3 we study the effect of external field in systems close to instabilities towards spin state ordering and exciton condensation. We show that, while in both cases the transition can be induced by an external field, temperature dependencies of the critical field have opposite slopes. Based on this result we argue that the experimental observations select the exciton condensation scenario. We show that such condensation is possible due to high mobility of the intermediate spin excitations. The estimated width of the corresponding dispersion is large enough to overrule the order of atomic multiplets and to make the intermediate spin excitation propagating with a specific wave vector the lowest excitation of the system. PMID- 27461513 TI - Confabulation: What is associated with its rise and fall? A study in brain injury. AB - The aim of this study was to investigate cognitive and emotional factors associated with the presence and clinical course of confabulation. 24 confabulating participants were compared with 11 brain injured and 6 healthy controls on measures of temporal context confusions (TCC), mood state (elation, depression) and lack of insight. Measures of autobiographical memory and executive function were also available. Changes in confabulation and these other measures were monitored over 9 months in the confabulating group. We found that TCC were more common in confabulating patients than in healthy controls, and that the decline in these errors paralleled the recovery from confabulation. However, TCC were not specific to the presence of confabulation in brain injury; and their decline was not correlated with change in confabulation scores over 9 months. We found that elated mood and lack of insight discriminated between confabulating and non-confabulating patients, but these measures did not correlate with either the severity of confabulation or change in confabulation scores through time. What seems to have been most strongly associated with the severity of confabulation scores at 'baseline' and changes through time (over 9 months) were the severity of memory impairment (especially on autobiographical memory) and errors on executive tests (particularly in making cognitive estimates). Greater autobiographical memory and executive impairment were associated with more severe confabulation. The findings were consistent with the view that confabulation results from executive dysfunction where autobiographical memory is also impaired; and that it resolves as these impairments subside. PMID- 27461514 TI - Overexpression of CRF in the BNST diminishes dysphoria but not anxiety-like behavior in nicotine withdrawing rats. AB - Smoking cessation leads to dysphoria and anxiety, which both increase the risk for relapse. This negative affective state is partly mediated by an increase in activity in brain stress systems. Recent studies indicate that prolonged viral vector-mediated overexpression of stress peptides diminishes stress sensitivity. Here we investigated whether the overexpression of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST) diminishes nicotine withdrawal symptoms in rats. The effect of nicotine withdrawal on brain reward function was investigated with an intracranial self-stimulation (ICSS) procedure. Anxiety-like behavior was investigated in the elevated plus maze test and a large open field. An adeno-associated virus (AAV) pseudotype 2/5 vector was used to overexpress CRF in the lateral BNST and nicotine dependence was induced using minipumps. Administration of the nicotinic receptor antagonist mecamylamine and cessation of nicotine administration led to a dysphoria-like state, which was prevented by the overexpression of CRF in the BNST. Nicotine withdrawal also increased anxiety-like behavior in the elevated plus maze test and large open field test and slightly decreased locomotor activity in the open field. The overexpression of CRF in the BNST did not prevent the increase in anxiety-like behavior or decrease in locomotor activity. The overexpression of CRF increased CRF1 and CRF2 receptor gene expression and increased the CRF2/CRF1 receptor ratio. In conclusion, the overexpression of CRF in the BNST prevents the dysphoria-like state associated with nicotine withdrawal and increases the CRF2/CRF1 receptor ratio, which may diminish the negative effects of CRF on mood. PMID- 27461515 TI - Whole-genome expression analysis reveals genes associated with treatment response to escitalopram in major depression. AB - The reasons for variability in treatment response in major depressive disorder (MDD) are not fully understood, but there is accumulating evidence suggesting that therapeutic outcomes of antidepressants can be influenced by genetic factors. In the present study we applied the microarray Illumina platform for whole genome expression profiling in depressive patients treated with escitalopram medication in order to identify genes underlying response to antidepressant treatment. The initial study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1+/-11.6 years, 68% females) treated with escitalopram 10-20mg/day for 12 weeks, from which 87 patients (55 females) were included in gene expression analyzing. The gene expression profiles were measured on peripheral blood cells at baseline, at week 4 and at the end of treatment (week 12) using BeadChips Illumina. The fold change was used to demonstrate rate of changes in average gene expressions between studied groups. Statistical analyses were performed using the false discovery rate (FDR). The most interesting gene, which showed the predictive effect on treatment outcome by delineating low dose responders and treatment-resistant patients at the beginning of medication, was NLGN2, belonging to a family of neuronal cell surface proteins and involving in synapse formation. In addition, the several gene clusters, related to immune response, signal transduction and neurotrophin pathway, have distinguished responders from non-responders at the week 4 of treatment. After 4 weeks of escitalopram treatment (10mg/day), the YWHAZ gene has showed the highest transcriptional change in responders as compared with non-responders. Finally, at the end of the treatment we noticed that at least three genes (NR2C2, ZNF641, FKBP1A) have been strongly associated with resistance to escitalopram. Thus the results of this study support that exploration of peripheral gene expression is a useful tool in the further identification of novel genetic biomarkers for antidepressant treatment response. PMID- 27461516 TI - Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis. AB - Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large-scale genetic profiling was performed on paired PT-MLN samples obtained from 10 OTSCC patients using high-density single-nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy-neutral loss-of heterozygosity (CN-LOH). Unsupervised hierarchical clustering analysis indicated that 8 of the 10 PT-MLN sample pairs formed clusters, indicating that the primary and metastatic tumors were composed of predominantly genetically similar tumor cells. In 6 of the 10 pairs, 8q11.21, 8q12.2-3, and 8q21.3 gains, and 22q11.23 loss were detected in both the PT and MLN. In addition, 16p11.2 CN-LOH was identified in 9 of the 10 pairs. Conversely, 20q11.2 gain was only observed in the MLNs of 5 of the 10 sample pairs, indicating that genes in this chromosomal region may play a significant role in OTSCC lymph node metastasis. To confirm this, we investigated the expression of two candidate 20q11.2 genes in a separate patient cohort. The expression of one of these genes, E2F1, was significantly increased during the process of metastasis. This study indicates that additional genetic changes, such as 20q11.2 gain, which encodes the E2F1 gene, can be acquired through clonal evolution, and may be required for the metastatic process. (c) 2016 Wiley Periodicals, Inc. PMID- 27461517 TI - Intramedullary nailing for correction of post-traumatic deformity in late diagnosed distal radius fractures. AB - BACKGROUND: Post-traumatic deformity of the distal radius may lead to multiple sequelae and severe functional impairment. Intramedullary fixation is a novel technique for treatment of distal radius fractures. The present study aimed to evaluate the functional and radiographic outcomes of intramedullary nailing for correction of post-traumatic deformity in late-diagnosed fractures of the distal radius. MATERIALS AND METHODS: From July 2009 to February 2011, 16 patients with late-diagnosed displaced fractures of the distal radius were included. Eligible inclusion was extra-articular fracture for more than 4 weeks. Surgical correction and internal fixation with intramedullary nailing was performed for treatment of ten AO type A2 and six AO type A3 fractures. All patients were followed up radiographically and clinically for an average of 20.3 months. RESULTS: All fractures achieved bone union without major complications. Functional status and radiographic alignment significantly improved postoperatively. There was no significantly secondary displacement comparing early postoperative and final radiographic parameters. The functional results according to the Mayo wrist scoring system were good or excellent in 94 % of patients. The mean score was 83.8. CONCLUSION: Surgical correction and internal fixation with the intramedullary nail is a feasible and less invasive technique with few complications in the treatment of post-traumatic deformity of the distal radius. LEVEL OF EVIDENCE: IV. PMID- 27461518 TI - Chromosomal aberrations, sister chromatid exchanges, and micronuclei in lymphocytes of oncology department personnel handling anti-neoplastic drugs. AB - OBJECTIVE: Concern exists regarding the possible hazards to the personnel handling anti-neoplastic drugs. The purpose of the present study was to assess the genotoxicity induced by anti-neoplastic agents in oncology department personnel. MATERIALS AND METHODS: To do this, the frequency of chromosomal aberrations (CAs) induced in peripheral blood lymphocytes was assessed at G0 phase of the cell cycle using metaphase analysis, cytokinesis block-micronucleus (MN) assay and sister chromatid exchange (SCE) assay. These cytogenetic end points were measured among 71 nurses in oncology department and 10 drugstore personnel handling and preparing anti-neoplastic drugs. The results were compared to those of 74 matched nurses for age and sex not exposed to any anti-neoplastic agents. RESULTS: There was no significant difference between the age of study subjects and control group (p > 0.05). The results showed that the mean frequency of cytogenetic damages in terms of CAs [chromatid breaks (p = 0.01), chromosome breaks (p = 0.005), total CAs (p = 0.001)], MN formation (p = 0.001), and SCE (p = 0.004) in lymphocytes of personnel handling anti-neoplastic drugs were significantly higher than those in control unexposed group. CONCLUSION: Results of the present study demonstrate the cytogenetic damage in peripheral blood lymphocytes of oncology department personnel. Suitable training and proper knowledge when handling anti-neoplastic drugs are emphasized to avoid potential health hazards caused by cytostatic agents. PMID- 27461519 TI - Corrigendum to "Neuropathic pain induced by spinal cord injury: Role of endothelin ETA and ETB receptors" [Neurosci. Lett. 617 (2016) 14-21]. PMID- 27461520 TI - MyoRing treatment of myopia. AB - INTRODUCTION: Laser Vision Correction is not always possible for the treatment of myopia. The aim of this paper is to present results after MyoRing implantation in myopic eyes who in their majority were not eligible for LVC. Safety, effectivity and patient selection is discussed. The aim of the treatment was to be spectacle independent in everyday-life. MATERIALS AND METHODS: 19 myopic eyes of 12 patients ranging from -2.25 to -16.5 dioptres (D) in sphere and from 0 to -4D in cylinder were analyzed. RESULTS: After treatment, 84% of the eyes reached uncorrected distance visual acuity (UDVA) of 0.5 or better, 42% reached UDVA of 0.8 or better and 16% reached UDVA of 1.0 or better. Before treatment, no eye reached UDVA of 0.5 or better. Corrected distance visual acuity (CDVA) preoperatively and postoperatively did not differ. The treatment changed the average spherical equivalent from -10.27D to -0.93D. Efficacy index was 0.76 and safety index was 1.02. CONCLUSION: MyoRing implantation for myopia is safe and effective with highly satisfied patents in a particular subgroup of myopic patients. Patient selection is important. PMID- 27461521 TI - CXCR3A contributes to the invasion and metastasis of gastric cancer cells. AB - CXCR3, belonging to CXC chemokine receptors, has been identified to be overexpressed in various kinds of tumors. There are three mRNA variants of CXCR3 (CXCR3A, CXCR3B and CXCR3alt) in human cells. The functions of major CXCR3 isoforms (CXCR3A, CXCR3B) have been reported in some tumors including prostate and breast cancer. However, the effects of CXCR3A and CXCR3B on gastric cancer cell progression remain unknown. The present investigation found that CXCR3A mRNA level was upregulated but CXCR3B mRNA level was downregulated in gastric cancer cells and tissues. In vitro growth analysis showed that CXCR3A acted as a positive mediator in regulating cell growth, whereas CXCR3B exerted the opposite effect. In vitro invasion and migration assays showed that CXCL10 promoted gastric cancer cell invasion and migration via CXCR3A, but not CXCR3B. Moreover, knockdown of CXCR3A inhibited cell growth and metastasis in vivo. Additionally, CXCR3A knockdown attenuated matrix metalloproteinase (MMP)-13 and IL-6 expression, and reduced ERK1/2 activation. Together, these data suggest that CXCR3A contributes to the growth, invasion and metastasis of gastric cancer cells in vitro and in vivo, and thus may be a key mediator of gastric cancer progression. PMID- 27461522 TI - Synergistic inhibition of characteristics of liver cancer stem-like cells with a combination of sorafenib and 8-bromo-7-methoxychrysin in SMMC-7721 cell line. AB - Sorafenib, a multi-kinase inhibitor, has shown its promising antitumor effect in a series of clinical trials, and has been approved as the current standard treatment for advanced hepatocellular carcinoma (HCC). 8-Bromo-7-methoxychrysin (BrMC) is a novel chrysin synthetic analogue that has been reported to inhibit the growth of various tumor cells and possess properties for targeting liver cancer stem cells (LCSCs) . The present study investigated the synergistic targeting effects on the properties of liver cancer stem-like cells (LCSLCs) by a combination of sorafenib and BrMC in SMMC-7721 cell line. We also investigated whether this effect involves regulation of HIF-1alpha, Twist and NF-kappaB protein. We found that the sphere-forming cells (SFCs) from the SMMC-7721 cells possessed the properties of LCSLCs. Sorafenib diminished the self-renewal capacity and downregulated the expression of stem cell biomarkers (CD133, CD44 and ALDH1) in a dose-dependent manner, while BrMC cooperated with sorafenib to strengthen this inhibition. Moreover, the combination of sorafenib and BrMC led to a remarkable decrease in the cellular migration and invasion, the downregulation of N-cadherin protein and upregulation of E-cadherin protein, and increase of cell apoptosis in LCSLCs. BrMC has a remarkable antagonistic effect on the upregulation of protein expression and DNA binding activity of NF-kappaB (p65) induced by sorafenib. In addition, our results indicated that the synergistic inhibition of sorafenib and BrMC on the characteristics of LCSLCs involves the downregulated expression of HIF-1alpha and EMT regulator Twist1. Collectively, the combination therapy of sorafenib and BrMC could be a new and promising therapeutic approach in the treatment of HCC. PMID- 27461524 TI - Enantioselective and Regiodivergent Functionalization of N-Allylcarbamates by Mechanistically Divergent Multicatalysis. AB - A pair of mechanistically divergent multicatalytic reaction sequences has been developed consisting of nickel-catalyzed isomerization of N-allylcarbamates and subsequent phosphoric-acid-catalyzed enantioselective functionalization of the resulting intermediates. By appropriate selection of reaction partners, in situ generated imines and ene-carbamates are mechanistically partitioned to yield opposing functionalized products. Formal alpha-functionalization to give protected alpha-arylamines is achieved upon enantioselective Friedel-Crafts reaction with arene nucleophiles, whereas formal beta-functionalization is achieved upon reaction with diarylimine electrophiles in an enantioselective Povarov-[4+2] cycloaddition. PMID- 27461523 TI - Dietary supplementation with rice bran or navy bean alters gut bacterial metabolism in colorectal cancer survivors. AB - SCOPE: Heat-stabilized rice bran (SRB) and cooked navy bean powder (NBP) contain a variety of phytochemicals that are fermented by colonic microbiota and may influence intestinal health. Dietary interventions with these foods should be explored for modulating colorectal cancer risk. METHODS AND RESULTS: A randomized controlled pilot clinical trial investigated the effects of eating SRB (30 g/day) or cooked navy bean powder (35 g/day) on gut microbiota and metabolites (NCT01929122). Twenty-nine overweight/obese volunteers with a prior history of colorectal cancer consumed a study-provided meal and snack daily for 28 days. Volunteers receiving SRB or NBP showed increased gut bacterial diversity and altered gut microbial composition at 28 days compared to baseline. Supplementation with SRB or NBP increased total dietary fiber intake similarly, yet only rice bran intake led to a decreased Firmicutes:Bacteroidetes ratio and increased SCFA (propionate and acetate) in stool after 14 days but not at 28 days. CONCLUSION: These findings support modulation of gut microbiota and fermentation byproducts by SRB and suggest that foods with similar ability to increase dietary fiber intake may not have equal effects on gut microbiota and microbial metabolism. PMID- 27461526 TI - Use of fractional flow reserve in patients with coronary artery disease: The right choice for the right outcome. AB - Despite advances in therapy, coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide. Over the past years, the utilization of revascularization procedures has been refined, and in the best interest of the patient and to reduce the healthcare burden of CAD, it is paramount that patients are appropriately selected for therapies aiming at improving their symptoms and prognosis. Fractional flow reserve (FFR) is the current invasive standard test to identify hemodynamically significant coronary artery stenoses with resultant implications for revascularization and clinical outcomes. In this review, we discuss the current evidence behind the use of FFR as well as new trends in the application of this technique to help guide clinicians in making the best management decisions for patients with CAD. PMID- 27461525 TI - Adipocyte-secreted chemerin is processed to a variety of isoforms and influences MMP3 and chemokine secretion through an NFkB-dependent mechanism. AB - Obesity is associated with white adipose tissue (WAT) remodelling characterized by changes in cellular composition, size, and adipokine secretion. Levels of the adipokine chemerin are positively associated with obesity; however, the biological function of chemerin in WAT is poorly understood. We identified factors involved in WAT remodelling, including matrix metalloproteinase (Mmp)3 and chemokines (Ccl2, 3, 5, 7), as novel targets of chemerin signalling in mature adipocytes. Inhibition of chemerin signalling increased MMP activity and the recruitment of macrophages towards adipocyte-conditioned media. These effects were mediated through increases in NFkB signalling, suggesting that chemerin exerts an anti-inflammatory influence. We also demonstrate that multiple chemerin isoforms are present in adipocyte-conditioned media and that adipocyte-secreted chemerin, but not synthetic chemerin, recapitulates the activity of endogenous chemerin. Considered altogether, this suggests that endogenously secreted chemerin plays an autocrine/paracrine role in WAT, identifying chemerin as a therapeutic target to modulate adipose remodelling. PMID- 27461527 TI - Reproducibility of semi-automatic coronary plaque quantification in coronary CT angiography with sub-mSv radiation dose; common mistakes. AB - Reliability (repeatability or reproducibility) is being assessed by different statistical tests including Pearson r or Spearman rho which is one of the common mistakes in reliability analysis. Briefly, for quantitative variable Intra Class Correlation Coefficient (ICCC) single measure should be used. Reporting inter- and intra-observer mean percentage differences is another mistake in reliability analysis because individual approach should be considered instead of global average. As a take home message, for reliability analysis, appropriate tests should be applied by researchers. Otherwise, misdiagnosis and mismanagement of the patients cannot be avoided. PMID- 27461528 TI - Influence of the coronary calcium score on the ability to rule out coronary artery stenoses by coronary CT angiography in patients with suspected coronary artery disease. AB - BACKGROUND: Recent guidelines for the workup of patients with chest pain and suspected coronary artery disease include coronary computed tomography angiography (CTA). However, its diagnostic value may be limited in patients with severe coronary calcification. OBJECTIVE: We investigated the relationship between the extent of coronary calcium and the ability of coronary CTA to rule out significant stenoses in a series of consecutive patients with suspected coronary artery disease. METHODS: 2614 consecutive patients with suspected coronary artery disease in whom coronary calcium scoring and coronary CTA had been performed by Dual Source CT were analyzed. The ability of coronary CTA to rule out coronary artery stenoses (fully evaluable coronary arteries and absence of any luminal stenosis >75%) was analyzed relative to the coronary calcium score. RESULTS: The median coronary calcium score was 12, with calcium present in 60.5% of all patients. Coronary CTA ruled out stenoses in 82% of patients, while in 18% of patients at least one stenosis was found or could not be excluded. The threshold above which coronary CTA permitted to rule out stenoses in less than 50% of patients was an "Agatston Score" of 287. This threshold was significantly lower for male patients (213 vs. 330), for patients with a heart rate >65 beats/min (157 vs. 317) and for patients with a body mass index >=25 kg/m(2) (208 vs. 392). The evaluability of coronary arteries decreased with increasing amounts of calcium and differed significantly between heart rates <=65 beats/min and >65 beats/min (p < 0.0001). CONCLUSION: In the largest patient series evaluated so far, we identified an "Agatston Score" of 287 to represent a threshold above which coronary CTA permits to rule out coronary artery stenoses in less than 50% of cases. PMID- 27461530 TI - Community treatment orders - what are the views of decision makers? AB - BACKGROUND: Community treatment orders (CTOs) are being increasingly used in Western countries. The scheme implies that mental health patients can live outside a hospital, but still be subject to coercive care to ensure compliance with their treatment. There is limited knowledge of how the scheme is practised. AIMS: To gain knowledge of how decision makers weigh and evaluate various considerations when making decisions on CTOs. METHOD: Qualitative in-depth interviews with decision makers responsible for CTOs in Norway. RESULTS: Decision makers viewed CTOs as a useful scheme to ensure control, continuity and follow-up care in the treatment of outpatients with a history of poor treatment motivation. They had varied interest in and knowledge of the patient's life situation and how the scheme affects the patient's everyday life. Little attention was devoted to patient experiences of formal and informal coercion. CONCLUSION: When deciding on CTOs, decision makers should pay more attention to the negative consequences that patients may experience. In many cases, decision makers are probably not aware of these coercive factors. PMID- 27461531 TI - In Heart Failure, You Can Embrace Your Inner Provocateur. PMID- 27461529 TI - A single-molecule view of transcription reveals convoys of RNA polymerases and multi-scale bursting. AB - Live-cell imaging has revealed unexpected features of gene expression. Here using improved single-molecule RNA microscopy, we show that synthesis of HIV-1 RNA is achieved by groups of closely spaced polymerases, termed convoys, as opposed to single isolated enzymes. Convoys arise by a Mediator-dependent reinitiation mechanism, which generates a transient but rapid succession of polymerases initiating and escaping the promoter. During elongation, polymerases are spaced by few hundred nucleotides, and physical modelling suggests that DNA torsional stress may maintain polymerase spacing. We additionally observe that the HIV-1 promoter displays stochastic fluctuations on two time scales, which we refer to as multi-scale bursting. Each time scale is regulated independently: Mediator controls minute-scale fluctuation (convoys), while TBP-TATA-box interaction controls sub-hour fluctuations (long permissive/non-permissive periods). A cellular promoter also produces polymerase convoys and displays multi-scale bursting. We propose that slow, TBP-dependent fluctuations are important for phenotypic variability of single cells. PMID- 27461532 TI - CEO Update. PMID- 27461533 TI - Molecular epidemiology reveals genetic diversity among 363 isolates of the Cryptococcus neoformans and Cryptococcus gattii species complex in 61 Ivorian HIV positive patients. AB - Cryptococcal meningitis is a severe opportunistic infection in HIV-infected patients. In Ivory Coast, despite the availability of antiretroviral treatment (ART), this infection is still prevalent. The study investigates the genetic diversity of 363 clinical isolates of Cryptococcus from 61 Ivorian HIV-positive patients, the occurrence of mixed infections and the in vitro antifungal susceptibility of the isolates. Serotyping was performed via LAC1 and CAP64 gene amplification. Genotyping was performed using the phage M13 core (GACA)4 and (GTG)5 primers and restriction fragment length polymorphism analysis of the URA5 gene. By PCR fingerprinting, the presence of the three serotypes were demonstrated among the 363 isolates in the population studied: A (n=318; 87.6%), AD (n=40; 11%) and B (n=4; 1.1%). Using PCR fingerprinting with primers M13 (GACA)4 and (GTG)5 , we grouped the isolates into 56 molecular subtypes. We observed a high frequency (39.3%) of mixed infections, with up to two different genotypes per sample. None of the isolates were resistant to amphotericin B. Only 0.3% and 1.1% of the isolates were resistant to fluconazole and flucytosine respectively. This study revealed the high genetic diversity among Cryptococcus isolates, the occurrence of mixed infections and a high antifungal susceptibility for the majority of Ivorian cryptococcal isolates. PMID- 27461534 TI - Unusual gastric mucosal infiltration by a medullary thyroid carcinoma: a case report. AB - BACKGROUND: Medullary thyroid carcinoma accounts for approximately 1 to 2 % of all thyroid carcinoma cases. The most common route of dissemination is to locoregional lymph nodes. Distant metastases commonly affect bones, lungs, and liver. We present a case of a white woman with a 25-year history of medullary thyroid carcinoma on multiple medications including tyrosine kinase inhibitor therapy for the last 11 months, who exhibited unusual diffuse infiltration of advanced stage medullary thyroid carcinoma to her gastric mucosa. CASE PRESENTATION: A 53-year-old white woman presented with increasing fatigue, loss of appetite, and severe epigastric pain radiating to her back. She had a history of medullary thyroid carcinoma (pT2pN1b), diagnosed 25 years ago and treated by complete thyroidectomy and repeated bilateral cervical lymph node dissection. Medical therapy included octreotide 20 mg every 4 weeks, which was switched to the tyrosine kinase inhibitor vandetanib 300 mg/day 11 months ago when computed tomography scanning revealed progressive mediastinal lymph node and diffuse and symptomatic pulmonary metastases. Of note, she demonstrated macroscopically stable pulmonary and mediastinal lymph node metastases; however, her calcitonin serum levels dramatically increased. Computed tomography scanning revealed a single new intrahepatic lesion (4 mm) as well as multiple (>10) new supraclavicular lesions suggestive of medullary thyroid carcinoma progress. As proven by gastric biopsy and immunohistochemical evaluation, her epigastric pain was explained by a diffuse infiltration of her gastric mucosa by metastatic medullary thyroid carcinoma. Subsequently, she rapidly deteriorated and died. CONCLUSIONS: The current case report shows for the first time an unusual metastatic infiltration of the gastric mucosa by medullary thyroid carcinoma. When treating these patients, it is important to include this differential diagnosis during follow-up. PMID- 27461535 TI - Prevalence and its risk factors for low back pain among operation and maintenance personnel in wind farms. AB - BACKGROUND: With the increasingly severe energy shortage and climate change problems, developing wind power has become a key energy development strategy and an inevitable choice to protect the ecological environment worldwide. The purpose of this study was to investigate the prevalence of low back pain (LBP) and analyze its risk factors among operation and maintenance personnel in wind farms (OMPWF). METHODS: A cross-sectional survey of 151 OMPWF was performed, and a comprehensive questionnaire, which was modified and combined from Nordic Musculoskeletal Questionnaires (NMQ), Washington State Ergonomics Tool (WSET) and Syndrome Checklist-90(SCL-90) was used to assess the prevalence and risk factors of LBP among OMPWF. RESULTS: The prevalence of LBP was 88.74 % (134/151) among OMPWF. The multivariable model highlighted four related factors: backrest, somatization, squatting and lifting objects weighing more than 10 lb more than twice per minute. CONCLUSIONS: The prevalence of LBP among OMPWF appears to be high and highlights a major occupational health concern. PMID- 27461537 TI - Special Issue of Health Care Analysis: Translational Bodies-Ethical Aspects of Uses of Human Biomaterials. PMID- 27461536 TI - Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats. AB - 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, 'foxy') is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeO-DIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5 MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeO-DIPT. PMID- 27461538 TI - Assessing the Value of Treatment to Address Various Symptoms Associated with Multiple Sclerosis: Results from a Contingent Valuation Study. AB - BACKGROUND: Although it is well recognized that people with multiple sclerosis (MS) may experience impairments in addition to limited mobility, there has been little effort to study their relative importance to patients with the condition. The objective of this study was to assess patient preferences for addressing various MS symptoms. METHODS: This study was conducted at Tufts Medical Center, Boston, Massachusetts. We developed a national online survey of MS patients and neurologists to estimate the value each group places on treating specific MS symptoms. Each respondent was presented with two randomly selected scenarios with different symptoms and treatments. MS patients were asked about their own preferences, whereas neurologists were asked to consider what a patient of theirs would do or think in each scenario. We used a bidding game approach to elicit respondents' willingness to pay (WTP) for the treatments. RESULTS: To treat mobility alone, WTP for MS patients averaged US$410-US$520 per month, depending on the scenario. For paired symptoms, MS patients would pay most to treat mobility and upper limb function (US$525/month) or mobility and cognition (US$514/month), somewhat less to treat mobility and eyesight (US$445/month), and least to treat mobility and fatigue (US$371/month). Patient WTP values increased with income and education. Neurologists believed their patients would be willing to pay US$216-US$249 per month to treat mobility alone, depending on the scenario. For paired symptoms, neurologists believed patients would pay most to treat mobility and fatigue (US$263/month) and least to treat mobility and upper limb function (US$177/month). CONCLUSION: Our findings suggest MS patients may value one outcome (e.g., improved arm and hand coordination) over another (e.g., less fatigue). Further, MS patients and neurologists may rank the importance of treating various symptoms differently. Given this potential mismatch, it is crucial for MS patients and their clinicians to discuss treatment priorities that take into account patient preferences. PMID- 27461539 TI - Evaluation of the vascular anatomy of the right-sided colon using three dimensional computed tomography angiography: a single-center study of 536 patients and a review of the literature. AB - PURPOSE: The requisite for a rigorous preoperative understanding of vascular branching continues to grow in parallel with the implementation of laparoscopic surgery. Three-dimensional (3D)-computed tomography (CT) angiography is a less invasive modality than traditional angiographic examination. Therefore, we aimed to evaluate branching patterns of the superior mesenteric artery (SMA). METHODS: In the present study, 536 consecutive patients who underwent preoperative 3D-CT angiography from April 2012 to March 2014 were prospectively enrolled. The branching pattern of the right colic artery (RCA) and the intersectional patterns of the RCA, ileocolic artery (ICA), and superior mesenteric vein (SMV) were evaluated. RESULTS: The RCA existed in only 179 cases (33.4 %); the remaining 357 patients (66.6 %) lacked evidence of the RCA. The ICA was detected in all cases. The RCA ran ventral to the SMV in the majority of cases (89.4 %). Conversely, the ICA ran ventral to the SMV in only half of the cases (50.6 %). When the RCA was observed to pass dorsal to the SMV, the ICA also ran dorsal to SMV in all cases. CONCLUSIONS: 3D-CT angiography can aid surgeons in identifying and understanding the anatomical vascular variations and intersectional patterns of the RCA, ICA, and SMV. Developing awareness of these variations can aid in the prevention of unexpected vascular injury during laparoscopic right-sided colon surgery. PMID- 27461540 TI - ACE-Inhibitory and Antioxidant Activities of Peptide Fragments Obtained from Tomato Processing By-Products Fermented Using Bacillus subtilis: Effect of Amino Acid Composition and Peptides Molecular Mass Distribution. AB - The effects of amino acid composition and peptide molecular mass on ACE inhibitory and antioxidant activities of protein fragments obtained from tomato waste fermented using Bacillus subtilis were evaluated. The addition of B. subtilis increased the relative amounts of aromatic and positively-charged amino acids which have been described to influence the biological activities of peptide fragments. IC50 values of hydrolysates for ACE-inhibitory and 2, 2'-diphenyl-1 picrylhydrazyl (DPPH) scavenging activities were found to be 1.5 and 8.2 mg/mL, respectively. Size-exclusion chromatography (SEC) pattern of the hydrolysate indicated the breakdown of parent proteins to smaller peptides with molecular weights mainly below 1400 Da. MALDI-TOF mass spectrometry analysis revealed that the highest ACE-inhibitory activity was due to peptides showing molecular mass range 500-800 Da, while the most active antioxidant peptides were found to be mainly at the two different peptide weight ranges 500-800 Da and 1200-1500 Da. PMID- 27461541 TI - Effects of Melatonin on Colchicine-Treated PLBs of Dendrobium sonia-28 Orchid. AB - Dendrobium hybrid orchid is popular in orchid commercial industry due to its short life cycle and ability to produce various types of flower colours. This study was conducted to identify the morphological, biochemical and scanning electron microscopy (SEM) analysis in the Dendrobium sonia-28 orchid plants. In this study, 0.05 and 0.075 % of colchicine-treated Dendrobium sonia-28 (4-week old culture) protocorm-like bodies (PLBs) were treated in different concentrations of melatonin (MEL) posttreatments (0, 0.05, 0.1, 0.5, 1, 5 and 10 MUM). Morphological parameters such as number of shoots, growth index and number of PLBs were determined. In the 0.05 and 0.075 % of colchicine-treated PLBs which were posttreated with 0.05 MUM MEL resulted in the highest value of the morphological parameters tested based on the number of shoots (84.5 and 96.67), growth index (16.94 and 12.15) and number of PLBs (126.5 and 162.33), respectively. SEM analysis of the 0.05 MUM MEL posttreatment on both the colchicine-treated regenerated PLBs showed irregular cell lineages, and some damages occurred on the stomata. This condition might be due to the effect of plasmolyzing occurred in the cell causing irregular cell lineages. PMID- 27461542 TI - Farmer views on calving difficulty consequences on dairy and beef farms. AB - Calving difficulty (CD) is a key functional trait with significant influence on herd profitability and animal welfare. Breeding plays an important role in managing CD both at farm and industry level. An alternative to the economic value approach to determine the CD penalty is to complement the economic models with the analysis of farmer perceived on-farm impacts of CD. The aim of this study was to explore dairy and beef farmer views and perceptions on the economic and non economic on-farm consequences of CD, to ultimately inform future genetic selection tools for the beef and dairy industries in Ireland. A standardised quantitative online survey was released to all farmers with e-mail addresses on the Irish Cattle Breeding Federation database. In total, 271 farmers completed the survey (173 beef farmers and 98 dairy farmers). Both dairy and beef farmers considered CD a very important issue with economic and non-economic components. However, CD was seen as more problematic by dairy farmers, who mostly preferred to slightly reduce its incidence, than by beef farmers, who tended to support increases in calf value even though it would imply a slight increase in CD incidence. Farm size was found to be related to dairy farmer views of CD with farmers from larger farms considering CD as more problematic than farmers from smaller farms. CD breeding value was reported to be critical for selecting beef sires to mate with either beef or dairy cows, whereas when selecting dairy sires, CD had lower importance than breeding values for other traits. There was considerable variability in the importance farmers give to CD breeding values that could not be explained by the farm type or the type of sire used, which might be related to the farmer non-economic motives. Farmer perceived economic value associated with incremental increases in CD increases substantially as the CD level considered increases. This non-linear relationship cannot be reflected in a standard linear index weighting. The results of this paper provide key underpinning support to the development of non-linear index weightings for CD in Irish national indexes. PMID- 27461543 TI - Re: Abkhezr M and Dryer SE (2014) Angiotensin II and Canonical Transient Receptor Potential-6 Activation Stimulate Release of a Signal Transducer and Activator of Transcription 3-Activating Factor from Mouse Podocytes Mol Pharmacol August 2014 86:150-158; doi:10.1124/mol.114.092536. PMID- 27461544 TI - Re: Abkhezr M and Dryer SE (2015) STAT3 Regulates Steady-State Expression of Synaptopodin in Cultured Mouse Podocytes Mol Pharmacol February 2015 87:231-239; doi:10.1124/mol.114.094508. PMID- 27461545 TI - Erratum to: Amelioration of autoimmune arthritis by adoptive transfer of Foxp3 expressing regulatory B cells is associated with the Treg/Th17 cell balance. PMID- 27461546 TI - Activational action of testosterone on androgen receptors protects males preventing temporomandibular joint pain. AB - BACKGROUND: Testosterone protects male rats from Temporomandibular Joint (TMJ) pain. This study investigated whether this protective effect is mediated by an organizational action of testosterone during nervous system development, by central estrogen and androgen receptors and by the 5alpha-reduced metabolite of testosterone, dihydrotestosterone. METHODS: A pharmacological approach was used to assess the ability of the androgen receptor antagonist flutamide, the estrogen receptor antagonist ICI 182 780 and the 5-alpha reductase inhibitor dutasteride to block the protective effect of testosterone, evaluated through the behavioral response induced by a TMJ injection of 0.5% formalin. Flutamide and ICI 182 780 were injected into the medullary subarachnoid space, and dutasteride and testosterone were systemically administered. RESULTS: The TMJ injection of 0.5% formalin induced a significant nociceptive behavioral response in gonadectomized male and naive female, but not in sham gonadectomized male rats, confirming that endogenous testosterone prevents TMJ nociception in males. Testosterone administration prevented formalin-induced TMJ nociception in males gonadectomized either in the neonatal (at the day of birth) or adult period and in naive female rats, suggesting that the protective effect of testosterone on TMJ nociception does not depend on its organizational actions during critical periods of development. The administration of flutamide and dutasteride but not of ICI 182 780 blocked the protective effect of testosterone. CONCLUSIONS: We conclude that the protective effect of testosterone on TMJ nociception depends on activational actions of dihydrotestosterone on androgen receptors rather than on organizational androgenic actions during central nervous system development or estrogenic actions. PMID- 27461548 TI - Gravitational mass of positron from LEP synchrotron losses. AB - General relativity(GR) is the current description of gravity in modern physics. One of the cornerstones of GR, as well as Newton's theory of gravity, is the weak equivalence principle (WEP), stating that the trajectory of a freely falling test body is independent of its internal structure and composition. WEP is known to be valid for the normal matter with a high precision. However, due to the rarity of antimatter and weakness of the gravitational forces, the WEP has never been confirmed for antimatter. The current direct bounds on the ratio between the gravitational and inertial masses of the antihydrogen do not rule out a repulsive nature for the antimatter gravity. Here we establish an indirect bound of 0.13% on the difference between the gravitational and inertial masses of the positron (antielectron) from the analysis of synchrotron losses at the Large Electron Positron collider (LEP). This serves as a confirmation of the conventional gravitational properties of antimatter without common assumptions such as, e.g., coupling of gravity to virtual particles, dynamics of distant astrophysical sources and the nature of absolute gravitational potentials. PMID- 27461547 TI - Moderation of nicotine effects on covert orienting of attention tasks by poor placebo performance and cue validity. AB - INTRODUCTION AND RATIONALE: Given baseline-dependent effects of nicotine on other forms of attention, there is reason to believe that inconsistent findings for the effects of nicotine on attentional orienting may be partly due to individual differences in baseline (abstinence state) functioning. Individuals with low baseline attention may benefit more from nicotine replacement. METHOD: The effects of nicotine as a function of baseline performance (bottom, middle, and top third of mean reaction times during placebo) were assessed in 52 habitual abstinent smokers (26 females/26 males) utilizing an arrow-cued covert orienting of attention task. RESULTS: Compared to a placebo patch, a 14mg nicotine patch produced faster overall reaction times (RTs). In addition, individuals with slower RTs during the placebo condition benefitted more from nicotine on cued trials than did those who had shorter (faster) RTs during placebo. Nicotine also enhanced the validity effect (shorter RTs to validly vs. invalidly cued targets), but this nicotine benefit did not differ as a function of overall placebo baseline performance. CONCLUSIONS: These findings support the view that nicotine enhances cued spatial attentional orienting in individuals who have slower RTs during placebo (nicotine-free) conditions; however, baseline-dependent effects may not generalize to all aspects of spatial attention. These findings are consistent with findings indicating that nicotine's effects vary as a function of task parameters rather than simple RT speeding or cognitive enhancement. PMID- 27461549 TI - Design of Highly Stable Echogenic Microbubbles through Controlled Assembly of Their Hydrophobin Shell. AB - Dispersing hydrophobin HFBII under air saturated with perfluorohexane gas limits HFBII aggregation to nanometer-sizes. Critical basic findings include an unusual co-adsorption effect caused by the fluorocarbon gas, a strong acceleration of HFBII adsorption at the air/water interface, the incorporation of perfluorohexane into the interfacial film, the suppression of the fluid-to-solid 2D phase transition exhibited by HFBII monolayers under air, and a drastic change in film elasticity of both Gibbs and Langmuir films. As a result, perfluorohexane allows the formation of homogenous populations of spherical, narrowly dispersed, exceptionally stable, and echogenic microbubbles. PMID- 27461550 TI - The societal cost of Huntington's disease: are we underestimating the burden? AB - BACKGROUND AND PURPOSE: Approximately 9000 people in the UK are affected by Huntington's disease (HD). People with HD require ongoing health and social care support. There is a knowledge gap about costs of health and social care use associated with HD in the UK. This paper estimates the economic cost in the UK. METHODS: Data on UK patients for the year 2013 were extracted from the European Huntington's Disease Network REGISTRY study, a full clinical dataset, including the full medical history and medication history for patients with HD. National unit costs for the price year 2013 were applied to health and social care services. RESULTS: Data were available for 131 people. The mean annual cost per person with HD was L21 605. The largest proportion of this cost (65%) was due to informal care (L14 085). CONCLUSIONS: Informal care was the largest driver of costs across all stages of HD; thus there is a need to also consider the needs of carers when planning services for people with HD. PMID- 27461551 TI - In Vitro Antihepatoma Activity of Novel 3D-Copper Cyanide Supramolecular Coordination Polymers. AB - This study aimed to investigate the inhibitory effect of novel 3D-organocopper supramolecular coordination polymers (SCPs) on the invasive potential of HepG2 cells. Chemoprevention could represent an important means to inhibit the process of hepatocarcinogenesis. The inhibitory effect of an SCP compound on the proliferation of HepG2 hepatoma cells was evaluated by cell vibility assay. DNA ladder bands were observed by DNA agarose gel electrophoresis. The influence of the SCP compound on phosphorylated ERK1/2, Bcl-2, and beta-catenin protein expression of HepG2 cells was analyzed by Western blot. The SCP compound exerted an inhibitory effect on HepG2 cell proliferation in a dose-dependent manner. This inhibitory effect was confirmed by examination of cell morphology and DNA fragmentation. Furthermore, Western blot analysis revealed that phosphorylated ERK1/2 and beta-catenin protein expression was inhibited after 24 h of treatment with the SCP compound, and that this event was associated with decreased Bcl-2 expression. We concluded that SCP can effectively inhibit the invasive potential of the ERK signaling pathway in HepG2 cells by altering apoptosis and by inhibiting Bcl-2 and beta-catenin, which may play a significant role in this process. PMID- 27461552 TI - Incidental corticobasal degeneration. PMID- 27461553 TI - The association between ocular dominance and physiological palpebral fissure asymmetry. AB - Physiological palpebral fissure asymmetry is a common observation in a physician's everyday practice. The goal of this study was to examine the relationship between palpebral fissure height (PFH) and ocular dominance. Sixty nine healthy volunteers (42 female, 27 male) were included in this research, and ocular dominance was determined using hole-in-the-card and pointing-a-finger tests. Those volunteers with inconsistent test results were excluded. Standard photographs were taken of all of the subjects in the primary position with a consistent background and photographic equipment. The PFHs were measured using an ImageJ analyser, and a mixed ANOVA was used for the statistical analysis. Overall, 87% of the participants showed small differences in their PFHs, with their dominant eyes being significantly wider than their non-dominant eyes (10.51 +/- 0.97 vs. 10.32 +/- 1.03; p = .001). This study revealed that ocular dominance has a significant effect on the PFH. Further research is required to understand the importance of this association in daily practice. PMID- 27461554 TI - Enhanced Performance of a Lithium-Sulfur Battery Using a Carbonate-Based Electrolyte. AB - The lithium-sulfur battery is regarded as one of the most promising candidates for lithium-metal batteries with high energy density. However, dendrite Li formation and low cycle efficiency of the Li anode as well as unstable sulfur based cathode still hinder its practical application. Herein a novel electrolyte (1 m LiODFB/EC-DMC-FEC) is designed not only to address the above problems of Li anode but also to match sulfur cathode perfectly, leading to extraordinary electrochemical performances. Using this electrolyte, lithium|lithium cells can cycle stably for above 2000 hours and the average Coulumbic efficiency reaches 98.8 %. Moreover, the Li-S battery delivers a reversible capacity of about 1400 mAh g(-1) sulfur with retention of 89 % for 1100 cycles at 1 C, and a capacity above 1100 mAh g(-1) sulfur at 10 C. The more advantages of this cell system are its outstanding cycle stability at 60 degrees C and no self-discharge phenomena. PMID- 27461555 TI - Registered nurses' experience of delegating the administration of medicine to unlicensed personnel in residential care homes. AB - AIMS AND OBJECTIVE: The aim was to describe registered nurses' experience in the context of delegating the administration of medication to unlicensed personnel in residential care homes. BACKGROUND: The residents in residential care homes have a need for extensive care and nursing, and large amounts of medicines are common practice. Registered nurses' workload and difficulties in fulfilling their duties, such as administration of medicines, have led to frequent delegation of this task between the registered nurses and unlicensed assisting personnel. It is, of course, a great responsibility to ensure that the care of the older people remains safe while maintaining quality in the prevailing situation. DESIGN: A qualitative inductive descriptive study. METHODS: Data were collected using audio recorded semistructured interviews with a purposive sample of 18 registered nurses and interpreted using manifest content analysis. The study was approved by the ethical research committee. RESULTS: Registered nurses found the organisation unsupportive with regard to nursing interventions. The delegation context was experienced as a grey zone; the rules and regulations were not in line with the unspoken expectation to delegate the administration of medicine to unlicensed personnel, in order to be able to manage their daily work. CONCLUSIONS: The slimmed organisation of residential care homes relies upon registered nurses' use of delegation of medicine administration to unlicensed assistant personnel. It becomes an inevitable assignment entailing a challenging responsibility for patient safety and the quality of care. RELEVANCE TO CLINICAL PRACTICE: The results of this study may contribute to a better understanding of the complexity of caring for older people in residential care homes and to improving the work environment of all healthcare personnel. PMID- 27461556 TI - Subcutaneous hyalohyphomycosis due to Purpureocillium lilacinum in an immunocompromised patient after renal transplantation. PMID- 27461557 TI - Effects on primary stability of three different techniques for implant site preparation in synthetic bone models of different densities. AB - Preparation of implant sites affect the primary stability of implants that is necessary for osseointegration. We have investigated the effect on the primary stability of implants of three techniques used to prepare the site for implants in synthetic bone models of different densities. A total of 540 implants of varying diameters (3.3 (narrow), 4.1 (standard), and 4.8 (wide) mm) and lengths (8 or 12mm) were inserted into three artificial bone blocks (the density of which decreased from D2, D3, to D4), and we compared conventional, fully-guided, and condensing preparation of the site. After insertion, primary stability was measured using resonance frequency analysis. There were significant differences between conventional and condensing procedures (p <0.0001 in all cases) and between fully-guided and condensing procedures (p<0.01 in all cases), but there were no differences between fully-guided and conventional procedures when short implants were used, with a standard or wide diameter in low-density bone blocks (D3 and D4). In low-density bone blocks (D3 and D4) wide implants (4.8mm) compared with narrow (3.3mm) resulted in significantly better primary stability (p<0.0001 in all cases). Fully-guided preparation of the implant site is associated with increased primary stability, but is not an alternative to bone condensing. Use of longer or wider implants can increase primary stability, but the effect is less pronounced after bone condensing. PMID- 27461558 TI - The geographical pattern of distribution of the genus Tityobuthus Pocock, 1890, a typical Ananterinae element endemic to Madagascar (Scorpiones: Buthidae). AB - New comments are proposed for the Ananterinae (sensu Pocock) or the 'Ananteris Group'. The worldwide pattern of distribution of the elements associated with the Ananterinae, as well as aspects of their ecology, is discussed. The biogeographic patterns presented by extant and fossil elements of this group confirm not only the characteristics of a lineage representing a typical Gondwanian distribution, but correspond also to older Pangean patterns. One new species is described in the genus Tityobuthus Pocock. This new species is also a possible endemic element to the Island of Nosy-Be or at least to the Sambirano region. Generally, the Madagascar pattern of Tityobuthus is following the Neogrosphus rule, showing typical high species richness with low dispersal when the ancestral population had a large niche breadth. PMID- 27461560 TI - High chance that current atmospheric greenhouse concentrations commit to warmings greater than 1.5 degrees C over land. AB - The recent Paris UNFCCC climate meeting discussed the possibility of limiting global warming to 2 degrees C since pre-industrial times, or possibly even 1.5 degrees C, which would require major future emissions reductions. However, even if climate is stabilised at current atmospheric greenhouse gas (GHG) concentrations, those warming targets would almost certainly be surpassed in the context of mean temperature increases over land only. The reason for this is two fold. First, current transient warming lags significantly below equilibrium or "committed" warming. Second, almost all climate models indicate warming rates over land are much higher than those for the oceans. We demonstrate this potential for high eventual temperatures over land, even for contemporary GHG levels, using a large set of climate models and for which climate sensitivities are known. Such additional land warming has implications for impacts on terrestrial ecosystems and human well-being. This suggests that even if massive and near-immediate emissions reductions occur such that atmospheric GHGs increase further by only small amounts, careful planning is needed by society to prepare for higher land temperatures in an eventual equilibrium climatic state. PMID- 27461559 TI - Genetic variation and phylogenetic relationship analysis of Jatropha curcas L. inferred from nrDNA ITS sequences. AB - Genetic variation and phylogenetic relationships among 102 Jatropha curcas accessions from Asia, Africa, and the Americas were assessed using the internal transcribed spacer region of nuclear ribosomal DNA (nrDNA ITS). The average G+C content (65.04%) was considerably higher than the A+T (34.96%) content. The estimated genetic diversity revealed moderate genetic variation. The pairwise genetic divergences (GD) between haplotypes were evaluated and ranged from 0.000 to 0.017, suggesting a higher level of genetic differentiation in Mexican accessions than those of other regions. Phylogenetic relationships and intraspecific divergence were inferred by Bayesian inference (BI), maximum parsimony (MP), and median joining (MJ) network analysis and were generally resolved. The J. curcas accessions were consistently divided into three lineages, groups A, B, and C, which demonstrated distant geographical isolation and genetic divergence between American accessions and those from other regions. The MJ network analysis confirmed that Central America was the possible center of origin. The putative migration route suggested that J. curcas was distributed from Mexico or Brazil, via Cape Verde and then split into two routes. One route was dispersed to Spain, then migrated to China, eventually spreading to southeastern Asia, while the other route was dispersed to Africa, via Madagascar and migrated to China, later spreading to southeastern Asia. PMID- 27461562 TI - Diacetoxyiodobenzene assisted C-O bond formation via sequential acylation and deacylation process: synthesis of benzoxazole amides and their mechanistic study by DFT. AB - An efficient method for the transformation of N-substituted-N'-benzoylthioureas to substituted N-benzoxazol-2-yl-amides using diacetoxyiodobenzene (DIB) is described in this work. The transformation follows the C-O bond formation leading to the benzoxazole derivative, due to oxidative dehydrogenation by DIB, instead of the expected C-S bond formation of the benzothiazole moiety. The C-O bond formation leading to benzoxazole is due to consecutive acylation and deacylation in conjunction with the reduction of two moles of DIB. A plausible mechanism was proposed for the reaction and density functional calculations were also performed to study the reaction mechanism. PMID- 27461561 TI - Lipolysis and thermogenesis in adipose tissues as new potential mechanisms for metabolic benefits of dietary fiber. AB - OBJECTIVE: Dietary fiber consumption is associated with reduced risk for the development of noncommunicable diseases. The aim of the present study was to evaluate the effects of cereal dietary fiber on the levels of proteins involved in lipolysis and thermogenesis in white adipose tissue (WAT) and brown adipose tissue (BAT) of C57 BL/6 J mice fed a high-fat diet (HFD). METHODS: Male C57BL/6 J mice were fed normal chow diet (Chow), HFD, HFD plus oat fiber (H-oat), or HFD plus wheat bran fiber (H-wheat) for 24 wk. Body weight and food intake were recorded weekly. Serum adiponectin was assayed by an enzyme-linked immunosorbent assay kit. Western blotting was used to assess the protein expressions of adipose triacylglycerol lipase (ATGL), cAMP protein kinase catalytic subunit (cAMP), protein kinase A (PKA), perilipin A, hormone-sensitive lipase (HSL), uncoupling protein 1 (UCP1), fibroblast growth factor 21 (FGF-21), beta3-adrenergic receptor (beta3AR), and proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) in the WAT and BAT. RESULTS: At the end of the feeding period, body and adipose tissues weight in both H-oat and H-wheat groups were lower than in the HFD group. Mice in the H-oat and H-wheat groups showed an increasing trend in serum adiponectin level. Compared with the HFD group, cereal dietary fiber increased protein expressions involved in the lipolysis and browning process. Compared with the H-wheat group, H-oat was more effective in protein expressions of PKA, PGC-1 alpha, and UCP1 of the WAT samples. Compared with the H-oat group, H-wheat was more effective in protein expressions of PKA, ATGL, UCP1, beta3AR, and FGF-21 of the BAT samples. CONCLUSIONS: Taken together, our results suggested that cereal dietary fiber enhanced adipocyte lipolysis by the cAMP-PKA-HSL pathway and promoted WAT browning by activation of UCP1, and consequently reduced visceral fat mass in response to HFD feeding. PMID- 27461563 TI - Short-stay hospital admission after free tissue transfer for head and neck reconstruction. AB - OBJECTIVES/HYPOTHESIS: To show that, for patients with few medical comorbidities and at low risk for airway compromise or fistula formation, early discharge after free tissue transfer for head and neck reconstruction is a safe and viable option. STUDY DESIGN: Retrospective chart review. METHODS: A cohort of patients who underwent free tissue transfer for head and neck reconstruction between February 2010 and December 2014 and who were discharged from the hospital by postoperative day 3 were reviewed. RESULTS: Fifty patients undergoing 51 free tissue transfer surgeries were discharged by postoperative day 3. The surgeries performed included anterolateral thigh free flaps (ALT) (n = 46), radial forearm free flaps (n = 2), latissimus myogenous and myocutaneous free flaps (n = 1), supraclavicular free flap (n = 1), and serratus free flap (n = 1). All ALT flaps were harvested exclusively as perforator free flaps; and the vast majority used superficial temporal, angular, or facial vessels. All free flaps were viable without evidence of vascular compromise at discharge and the initial follow-up appointment. One patient required take-back for successful flap salvage. One patient experienced late flap failure (between 2-3 weeks postoperatively), requiring another surgery. This resulted in an overall success rate of 98% in this cohort. No other postoperative complications related to early discharge were identified. CONCLUSION: In a carefully selected subset of patients undergoing free tissue transfer, early discharge has been shown to be possible without compromising patient safety or surgery success rates. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2679-2683, 2016. PMID- 27461564 TI - Antiplatelet and Anticoagulant Therapies for Prevention of Ischemic Stroke. AB - Ischemic stroke represents one of the leading causes of death and disability in both the United States and abroad, particularly for patients with prior ischemic stroke or transient ischemic attack (TIA). A quintessential aspect of secondary stroke prevention is the use of different pharmacological agents, mainly antiplatelets and anticoagulants. Antiplatelets and anticoagulants exhibit their effect by blocking the activation pathways of platelets and the coagulation cascade, respectively. Clinical trials have demonstrated the safety and efficacy of antiplatelets for noncardioembolic stroke prevention, while anticoagulants are more often used for cardioembolic stroke prevention. Commonly used antiplatelets include aspirin, clopidogrel, and aggrenox (aspirin plus extended-release dipyridamole). Furthermore, commonly used anticoagulants include warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. Each of these drugs has a unique mechanism of action, and they share some common adverse events such as gastrointestinal bleeding and intracranial hemorrhage in more serious cases. Consequently, physicians should carefully assess the benefits and risks of using different antiplatelet or anticoagulant therapies when managing patients with previous ischemic stroke or TIA. This review discuses the published literature on major clinical trials assessing the efficacy of different antiplatelet and anticoagulant drugs under varying circumstances and the subsequent guidelines that have been developed by the American Heart Association/American Stroke Association. Additionally, the role of imaging in stroke prevention is discussed. PMID- 27461567 TI - Dual gold photoredox C(sp(2))-C(sp(2)) cross couplings - development and mechanistic studies. AB - A dual visible light photoredox and gold-catalysed C(sp(2))-C(sp(2)) cross coupling is described. The success of this mild, oxidant- and base-free cross coupling is highly dependent on the amount of water added. Mechanistic studies show two distinct pathways depending on the gold catalyst employed: transmetallation of the arylboronic acid with gold(i) occurs prior to oxidation of gold(i) to gold(iii) using cationic gold(i) catalysts, whereas oxidation of gold(i) to gold(iii) precedes transmetallation using neutral gold(i) catalysts. PMID- 27461566 TI - Combined treatment, based on lysomustine administration with mesenchymal stem cells expressing cytosine deaminase therapy, leads to pronounced murine Lewis lung carcinoma growth inhibition. AB - BACKGROUND: The combination of stem cell-based gene therapy with chemotherapy comprises an advantageous strategy that results in a reduction of system toxicity effects and an improvement in the general efficacy of treatment. In the present study, we estimated the efficacy of adipose tissue-derived mesenchymal stem cells (AT-MSCs) expressing cytosine deaminase (CDA) combined with lysomustine chemotherapy in mice bearing late stage Lewis lung carcinoma (LLC). METHODS: Adipose tissue-derived mesenchymal stem cells were transfected with non-insert plasmid construct transiently expressing fused cytosine deaminase-uracil phosphoribosyltransferase protein (CDA/UPRT) or the same construct fused with Herpes Simplex Virus Type1 tegument protein VP22 (CDA/UPRT/VP22). Systemic administration of 5-fluorocytosine (5FC) and lysomustine was implemented after a single intratumoral injection of transfected AT-MSCs. RESULTS: We demonstrated that direct intratumoral transplantation of AT-MSCs expressing CDA/UPRT or CDA/UPRT/VP22 followed by systemic administration of 5FC resulted in a significant tumor growth inhibition. There was a 56% reduction in tumor volume in mice treated by AT-MSCs-CDA/UPRT + 5FC or with AT-MSCs-CDA/UPRT/VP22 + 5FC compared to control animals grafted with lung carcinoma alone. Transplantation of AT-MSCs-CDA/UPRT + 5FC and AT-MSCs-CDA/UPRT/VP22 + 5FC prolonged the life span of mice bearing LLC by 27% and 31%, respectively. Co-administration of lysomustine and AT-MSCs-CDA/UPRT + 5FC led to tumor growth inhibition (by 86%) and life span extension (by 60%) compared to the control group. CONCLUSIONS: Our data indicate that a combination CDA/UPRT-expressing AT-MSCs with lysomustine has a superior antitumor effect in the murine lung carcinoma model compared to monotherapies with transfected AT-MSCs or lysomustine alone, possibly because of a synergistic effect of the combination therapy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27461565 TI - Divergent shifts in lipid mediator profile following supplementation with n-3 docosapentaenoic acid and eicosapentaenoic acid. AB - In contrast to the well-characterized effects of specialized proresolving lipid mediators (SPMs) derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), little is known about the metabolic fate of the intermediary long chain (LC) n-3 polyunsaturated fatty acid (PUFA) docosapentaenoic acid (DPA). In this double blind crossover study, shifts in circulating levels of n-3 and n-6 PUFA-derived bioactive lipid mediators were quantified by an unbiased liquid chromatography-tandem mass spectrometry lipidomic approach. Plasma was obtained from human subjects before and after 7 d of supplementation with pure n-3 DPA, n 3 EPA or placebo (olive oil). DPA supplementation increased the SPM resolvin D5n 3DPA (RvD5n-3DPA) and maresin (MaR)-1, the DHA vicinal diol 19,20-dihydroxy-DPA and n-6 PUFA derived 15-keto-PG E2 (15-keto-PGE2). EPA supplementation had no effect on any plasma DPA or DHA derived mediators, but markedly elevated monohydroxy-eicosapentaenoic acids (HEPEs), including the e-series resolvin (RvE) precursor 18-HEPE; effects not observed with DPA supplementation. These data show that dietary n-3 DPA and EPA have highly divergent effects on human lipid mediator profile, with no overlap in PUFA metabolites formed. The recently uncovered biologic activity of n-3 DPA docosanoids and their marked modulation by dietary DPA intake reveals a unique and specific role of n-3 DPA in human physiology.-Markworth, J. F., Kaur, G., Miller, E. G., Larsen, A. E., Sinclair, A. J., Maddipati, K. R., Cameron-Smith, D. Divergent shifts in lipid mediator profile following supplementation with n-3 docosapentaenoic acid and eicosapentaenoic acid. PMID- 27461568 TI - On the use of a Euclidean norm function for the estimation of local dynamic stability from 3D kinematics using time-delayed Lyapunov analyses. AB - Several different state-space reconstruction methods have been employed to assess the local dynamic stability (LDS) of a 3D kinematic system. One common method is to use a Euclidean norm (N) transformation of three orthogonal x, y, and z time series' followed by the calculation of the maximum finite-time Lyapunov exponent (lambdamax) from the resultant N waveform (using a time-delayed state space reconstruction technique). By essentially acting as a weighted average, N has been suggested to account for simultaneous expansion and contraction along separate degrees of freedom within a 3D system (e.g. the coupling of dynamic movements between orthogonal planes). However, when estimating LDS using N, non linear transformations inherent within the calculation of N should be accounted for. Results demonstrate that the use of N on 3D time-series data with arbitrary magnitudes of relative bias and zero-crossings cause the introduction of error in estimates of lambdamax obtained through N. To develop a standard for the analysis of 3D dynamic kinematic waveforms, we suggest that all dimensions of a 3D signal be independently shifted to avoid the incidence of zero-crossings prior to the calculation of N and subsequent estimation of LDS through the use of lambdamax. PMID- 27461569 TI - Impact of anomalous transport kinetics on the progress of wound healing. AB - This work focuses on the transport kinetics of chemical and cellular species during wound healing. Anomalous transport kinetics, coupling sub- and superdiffusion with chemotaxis, and fractional viscoelasticity of soft tissues are analyzed from a modeling point of view. The paper presents a generalization of well stablished mechano-chemical models of wound contraction (Murphy et al., 2012; Valero et al., 2014) to include the previously mentioned anomalous effects by means of partial differential equations of fractional order. Results show the effect that anomalous dynamics have on the contraction rate and extension and on the distribution of biological species, and indicators of fibroproliferative disorders are identified. PMID- 27461570 TI - Liquid chromatography coupled to molecular fluorescence with postcolumn UV sensitization for thimerosal and derivative compounds monitoring in environmental samples. AB - A HPLC coupled with molecular fluorescence (MF) spectrometry method for determination of thimerosal (THM, sodium ethylmercurythiosalicylate, C9 H9 HgNaO2 S), and derivatives is proposed. A sensitization of MF was provoked by UV irradiation of analytes in a home-made photoreactor that served as interface between the LC column and MF spectrometer. This method is applied to determination of THM, ethyl mercury, and thiosalicylic acid in samples of pharmaceutical industry effluents, and waters of La Carolina and Jachal rivers situated in the center-west side of San Luis city and in the east of San Juan city (Middle West, Argentine) where the effluents are dumped. The LODs calculated on basis of 3sigma criterion were 1.8, 5, and 0.05 MUmol/L for THM, ethyl mercury, and for thiosalicylic acid, respectively. PMID- 27461571 TI - Memorial address for Dr. Hideyuki Yamada, distinguished professor. PMID- 27461572 TI - Pentoxifylline abrogates cardiotoxicity induced by the administration of a single high dose or multiple low doses of doxorubicin in rats. AB - Doxorubicin (DOX) possesses a broad-spectrum antineoplastic activity; however, its clinical application is impeded by cardiotoxicity. This study aimed to investigate the protective effect of pentoxifylline (PXF), which possesses antioxidant and anti-inflammatory properties against cardiotoxicity induced by a single high dose (15 mg/kg, i.p.) or multiple low doses (2.5 mg/kg, i.p., three times per week for 2 weeks) of DOX. At the end of the experimental period, the serum creatine kinase (CK)-MB and lactate dehydrogenase (LDH) activities were measured. The hearts were then removed for evaluating TNF-alpha, NO, malondialdehyde (MDA), and reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and the expression of iNOS, NF-kappaB, Fas ligand (FasL), and caspase-3. The administration of DOX in both dose regimens caused increases in serum CK-MB and LDH activities, in cardiac TNF-alpha, NO and MDA levels, as well as in the cardiac expression of iNOS, NF-kappaB, FasL and caspase-3, whereas it significantly reduced the cardiac GSH level, as well as SOD and CAT activities (P < 0.05). Prophylactic treatment of rats with PXF diminished DOX-induced alterations in theses parameters. Our results warrant the clinical use of PXF as an adjuvant therapy to abrogate cardiotoxicity of DOX and extend its clinical applications. PMID- 27461573 TI - Corrigendum: The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity. AB - [This corrects the article DOI: 10.3389/fphys.2016.00245.]. PMID- 27461574 TI - Postoperative chylothorax after pulmonary wedge resection in two patients who underwent radical neck dissection: A case report. AB - Postoperative chylothorax after wedge resection without mediastinal lymph node dissection is extremely rare. Herein, we report two cases: one case of postoperative chylothorax that developed after wedge resection and another of expanded collaterals detected during thoracoscopic surgery. We believe the cause of this complication to be the history of neck and pulmonary ligament dissections during pulmonary surgery. PMID- 27461575 TI - Isoalantolactone inhibits the migration and invasion of human breast cancer MDA MB-231 cells via suppression of the p38 MAPK/NF-kappaB signaling pathway. AB - Isoalantolactone is a bioactive sesquiterpene lactone isolated from the flowering plant Inula helenium L. This study was conducted to assess the anti-migratory and anti-invasive activities of isoalantolactone in MDA-MB-231 cells, and to explore the underlying mechanisms. Wound-healing and Transwell chambers assays demonstrated that isoalantolactone inhibited the adhesion, migration and invasion of MDA-MB-231 cells. The activity and expression of MMP-2 and MMP-9 were downregulated by isoalantolactone in a dose-dependent manner. Additionally, isoalantolactone markedly decreased the p-p38 MAPK level, whereas no significant change in p-ERK1/2 and p-JNK1/2 was noted. The downregulation of MMP-2 and MMP-9 protein expression and suppression of in vitro invasion might be associated with the blockade of p38 MAPK activation. Furthermore, isoalantolactone blocked the translocation of NF-kappaB p65 from the cytoplasm into the nucleus. These results revealed that isoalantolactone inhibited the adhesion, migration and invasion of MDA-MB-231 cells via suppression of the p38 MAPK/NF-kappaB signaling pathway, and isoalantolactone might be an alternative treatment for breast cancer. PMID- 27461576 TI - Persistent Atrial Fibrillation Ablation in Females: Insight from the MAGIC-AF Trial. AB - INTRODUCTION: Atrial fibrillation (AF) ablation is less frequently performed in women when compared to men. There are conflicting data on the safety and efficacy of AF ablation in women. The objective of this study was to compare the clinical characteristics and outcomes in a contemporary cohort of men and women undergoing persistent AF ablation procedures. METHODS AND RESULTS: A total of 182 men and 53 women undergoing a first-ever persistent AF catheter ablation procedure in The Modified Ablation Guided by Ibutilide Use in Chronic Atrial Fibrillation (MAGIC AF) trial were evaluated. Clinical and procedural characteristics were compared between each gender. The primary efficacy endpoint was the 1-year single procedure freedom from atrial arrhythmia off anti-arrhythmic drugs. Women undergoing catheter ablation procedures were older than men (P < 0.001). The duration of AF and associated co-morbidities were similar between both genders. Single procedure drug-free atrial arrhythmia recurrence occurred in 53% of the cohort with no difference based on gender (men = 54%, women = 53%; P = 1.0). Procedural (P = 0.04), fluoroscopic (P = 0.02), and ablation times (P = 0.003) were shorter in women compared to men. Periprocedural complications and postablation improvement in quality of life were similar between men and women. CONCLUSION: Women undergoing a first-ever persistent AF ablation procedure were older but had similar clinical outcomes and complications when compared with men. PMID- 27461577 TI - Field studies of Pan troglodytes reviewed and comprehensively mapped, focussing on Japan's contribution to cultural primatology. AB - Field studies done over decades of wild chimpanzees in East, Central and West Africa have yielded impressive, cumulative findings in cultural primatology. Japanese primatologists have been involved in this advance from the outset, over a wide variety of topics. Here I review the origins and development of field studies of Pan troglodytes, then assess their progress based on analogy between cultural primatology and cultural anthropology, through four stages: natural history, ethnography, ethnology, and intuition. Then, I focus on six topics that continue to yield informative debate: technology, universals, nuanced variation, archaeology, applied primatology, and ecology. Finally, I offer a map of sites of field study of wild chimpanzees. It is clear that Japanese primatologists have made a significant contribution to East-West scientific exchange, especially at the field sites of Bossou and Mahale. PMID- 27461579 TI - Current landscape of protein glycosylation analysis and recent progress toward a novel paradigm of glycoscience research. AB - This review covers the basics and some applications of methodologies for the analysis of glycoprotein glycans. Analytical techniques used for glycoprotein glycans, including liquid chromatography (LC), capillary electrophoresis (CE), mass spectrometry (MS), and high-throughput analytical methods based on microfluidics, were described to supply the essentials about biopharmaceutical and biomarker glycoproteins. We will also describe the MS analysis of glycoproteins and glycopeptides as well as the chemical and enzymatic releasing methods of glycans from glycoproteins and the chemical reactions used for the derivatization of glycans. We hope the techniques have accommodated most of the requests from glycoproteomics researchers. PMID- 27461580 TI - The presence of small ruminant lentiviruses in Mexican Pelibuey sheep. AB - The transmission frequency of small ruminant lentiviruses (SRLVs) through the placenta is controversial and may be associated with breed susceptibility. In Mexico, SRLV infections in sheep have been poorly studied. This work explores the presence of antibodies and proviral DNA in Mexican Pelibuey sheep. Enzyme-linked immunosorbent assays (ELISAs; three commercial kits and two on the basis of synthetic peptides) and polymerase chain reaction (PCR; amplifying the long terminal repeat and gag segments) were performed to diagnose SRLV infection in 25 adult Pelibuey ewes with an average age of 2.5 years and 32 fetuses with gestational ages ranging from 40 to 90 days without clinical signs of SRLV. Two of the three commercial ELISAs and the synthetic peptide-based ones were positive for SRLV antibody detection in 28% and 24% of the ewes, respectively, whereas none of the fetuses were positive by any of the ELISAs. By PCR, 31% of the ewes and, interestingly, two fetuses were positive. Characteristic SRLV lesions were not found in the fetal and/or ewe tissues, including those with positive PCR results. These findings demonstrate the susceptibility of Pelibuey sheep to SRLV infection and the low transmission frequency through the placenta. PMID- 27461578 TI - Mn-, Fe-, and Co-Catalyzed Radical Hydrofunctionalizations of Olefins. AB - Cofactor-mimetic aerobic oxidation has conceptually merged with catalysis of syngas reactions to form a wide range of Markovnikov-selective olefin radical hydrofunctionalizations. We cover the development of the field and review contributions to reaction invention, mechanism, and application to complex molecule synthesis. We also provide a mechanistic framework for understanding this compendium of radical reactions. PMID- 27461582 TI - Modifiable and non-modifiable risk factors for pancreatic cancer: A review. AB - Pancreatic ductal adenocarcinoma is associated with a poor prognosis and a high case-fatality rate. The reasons for poor prognosis are low rates of curative resection due to local infiltration and distant metastasis. To increase survival rates of patients with pancreatic cancer, early detection through surveillance and screening is important. However, screening could only be cost-effective in high-risk populations. Identification of significant risk factors therefore assumes significance. Risk factors could be non-modifiable or modifiable. Non modifiable risk factors include increasing age, familial cancer syndromes, Afro American race, hereditary and other forms of chronic pancreatitis, diabetes, and non-O blood group. Important modifiable risk factors include smoking, obesity, dietary factors such as non-vegetarian diet, and toxins. Preventive strategies at the population level and an effective screening program targeted at high-risk people may help in prevention and early detection of pancreatic ductal adenocarcinoma. PMID- 27461581 TI - ANRIL lncRNA triggers efficient therapeutic efficacy by reprogramming the aberrant INK4-hub in melanoma. AB - Melanoma is an extremely aggressive disease with rapid progression, high metastatic potential and recurrence. Simultaneous correction of multiple tumor specific gene abnormalities has become an attractive approach for developing therapeutics to treat melanoma. To potentiate anti-melanoma activity, we tested a "domino effect-like" therapeutic approach by uniquely targeting one defect and automatically triggering the endogenous corrections of other defects. Using this strategy, in a suspicious INK4b-ARF-INK4a gene cluster at chromosome 9p21, aberrant INK4a and INK4b defects were simultaneously endogenously auto-corrected after targeting the suppression of abnormal ANRIL lncRNA. In cell culture, this treatment significantly reduced the tumor metastatic capacity and tumor formation compared with absence of treatment. In animals harboring tumor xenografts, this therapeutic approach significantly inhibited tumor growth and reduced the tumor weight. Our results reveal a novel therapeutic strategy that significantly potentiates anti-melanoma efficiency by reprogramming the aberrant INK4-hub. PMID- 27461585 TI - Equilibration and Aging of Liquids of Non-Spherically Interacting Particles. AB - The nonequilibrium self-consistent generalized Langevin equation theory of irreversible processes in liquids is extended to describe the positional and orientational thermal fluctuations of the instantaneous local concentration profile n(r,Omega,t) of a suddenly quenched colloidal liquid of particles interacting through nonspherically symmetric pairwise interactions, whose mean value n(r,Omega,t) is constrained to remain uniform and isotropic, n (r,Omega, t) = n (t). Such self-consistent theory is cast in terms of the time-evolution equation of the covariance [Formula: see text] of the fluctuations [Formula: see text] of the spherical harmonics projections nlm(k;t) of the Fourier transform of n(r,Omega,t). The resulting theory describes the nonequilibrium evolution after a sudden temperature quench of both, the static structure factor projections Slm(k,t) and the two-time correlation function [Formula: see text], where tau is the correlation delay time and t is the evolution or waiting time after the quench. As a concrete and illustrative application we use the resulting self consistent equations to describe the irreversible processes of equilibration or aging of the orientational degrees of freedom of a system of strongly interacting classical dipoles with quenched positional disorder. PMID- 27461583 TI - A novel combinatorial strategy using Seliciclib((r)) and Belinostat((r)) for eradication of non-small cell lung cancer via apoptosis induction and BID activation. AB - With conventional anticancer agents for non-small cell lung cancer (NSCLC) reaching therapeutic ceiling, the novel combination using histone deacetylase inhibitor, PXD101 (Belinostat((r))), and CDK inhibitor, CYC202 (Seliciclib((r))), was investigated as an alternative anticancer strategy. At clinically achievable concentration of CYC202 (15 uM), combination therapy resulted in significant reduction in cell proliferation (IC50 = 3.67 +/- 0.80 uM, p < 0.05) compared with PXD101 alone (IC50 = 6.56 +/- 0.42 uM) in p53 wild-type A549 cells. Significant increase in apoptosis that occurred independently of cell cycle arrest was observed after concurrent treatment. This result was corroborated by greater formation of cleaved caspase-8, caspase-3 and PARP. Up-regulation of p53 and truncated BID protein levels was seen while Mcl-1 and XIAP protein levels were down-regulated upon combined treatment. Further analysis of apoptotic pathways revealed that caspase inhibitors, but not p53 silencing, significantly abrogated the cytotoxic enhancement. Moreover, the enhanced efficacy of this combination was additionally confirmed in p53 null H2444 cells, suggesting the potential of this combination for treatment of NSCLC that are not amenable to effects of conventional p53-inducing agents. PMID- 27461584 TI - Peri-prosthetic femoral fractures of hip or knee arthroplasty. Analysis of 34 cases and a review of Spanish series in the last 20 years. AB - PURPOSE: To evaluate peri-prosthetic femoral fractures by analysing type of patient, treatment and outcomes, and to compare them with Spanish series published in the last 20 years. MATERIAL AND METHODS: A retrospective review of the medical records of patients with peri-prosthetic femoral fractures treated in our hospital from 2010 to 2014, and telephone survey on the current status. RESULTS: A total of 34 peri-prosthetic femoral fractures were analysed, 20 in hip arthroplasty and 14 in knee arthroplasty. The mean age of the patients was 79.9 years, and 91% had previous comorbidity, with up to 36% having at least 3 prior systemic diseases. Mean hospital stay was 8.7 days, and was higher in surgically treated than in conservative-treated patients. The majority (60.6%) of patients had complications, and mortality was 18%. Functional status was not regained in 61.5% of patients, and pain was higher in hip than in knee arthroplasty. DISCUSSION: Peri-prosthetic femoral fractures are increasing in frequency. This is due to the increasing number of arthroplasties performed and also to the increasing age of these patients. Treatment of these fractures is complex because of the presence of an arthroplasty component, low bone quality, and comorbidity of the patients. CONCLUSION: Peri-prosthetic femoral fractures impair quality of life. They need individualised treatment, and have frequent complications and mortality. PMID- 27461586 TI - Prospective Randomized Trial for Image-Guided Biopsy Using Cone-Beam CT Navigation Compared with Conventional CT. AB - PURPOSE: To compare cone-beam computed tomography (CT) navigation vs conventional CT image guidance during biopsies. MATERIALS AND METHODS: Patients scheduled for image-guided biopsies were prospectively and randomly assigned to conventional CT guidance vs cone-beam CT navigation. Radiation dose, accuracy of final needle position, rate of histopathologic diagnosis, and number of needle repositions to reach the target (defined as pullback to adjust position) were compared. RESULTS: A total of 58 patients (mean age, 57 y; 62.1% men) were randomized: 29 patients underwent 33 biopsies with CT guidance and 29 patients with 33 lesions underwent biopsy with cone-beam CT navigation. The average body mass index (BMI) was similar between groups, at 28.8 kg/m(2) +/- 6.55 (P = .18). There was no difference between groups in terms of patient and lesion characteristics (eg, size, depth). The average lesion size was 29.1 +/- 12.7mm for CT group vs 32.1mm +/-16.8mm for cone-beam CT group (P < 0.59). Location of lesions was equally divided between the 2 groups, 20 lung lesions, 18 renal lesions and 20 other abdominal lesions. Mean number of needle repositions in the cone-beam CT group was 0.3 +/- 0.5, compared with 1.9 +/- 2.3 with conventional CT (P < .001). The average skin entry dose was 29% lower with cone-beam CT than with conventional CT (P < .04 accounting for BMI). The average estimated effective dose for the planning scan from phantom data was 49% lower with cone-beam CT vs conventional CT (P = .018). Accuracy, defined as the difference between planned and final needle positions, was 4.9 mm +/- 4.1 for the cone-beam CT group, compared with 12.2 mm +/- 8.1 for conventional CT (P < .001). Histopathologic diagnosis rates were similar between groups, at 90.9% for conventional CT and 93.9% for cone-beam CT (P = .67). CONCLUSIONS: Cone-beam CT navigation for biopsies improved targeting accuracy with fewer needle repositions, lower skin entry dose, and lower effective dose for planning scan, and a comparable histopathologic diagnosis rate. PMID- 27461587 TI - Medicare Utilization of CT Angiography from 2001 through 2014: Continued Growth by Radiologists. AB - PURPOSE: To examine changes in utilization of computed tomography (CT) angiography nationally and changing relative specialty roles in examination interpretation. MATERIALS AND METHODS: Service-specific claims data for region specific CT angiography examinations were identified using Medicare Physician Supplier Procedure Summary Master Files from 2001 through 2014. Longitudinal national utilization rates were calculated using annual Medicare enrollment data for 2001-2013. Procedure volumes by specialty group and site of service were analyzed. RESULTS: Total annual claims for CT angiography for Medicare fee for service beneficiaries increased from 64,846 to 1,709,088 (compound annual growth rate [CAGR] 29%) between 2001 and 2014. Per 1,000 beneficiaries, overall CT angiography utilization increased annually from 2.1 in 2001 to 47.6 in 2013. Overall interpretation market share increased 4% (91%-95%) for radiology. Cardiology increased from 1% in 2001 to 6% in 2007 but decreased annually to 2% in 2014. Vascular surgery market share remained < 1% throughout the study period. Growth of CT angiography in the emergency department (ED) outpaced all other sites of service, increasing from 11% to 28% (CAGR 38%). The chest was the dominant body region imaged with CT angiography, increasing from 36,984 to 914,086 (CAGR 28%). CONCLUSIONS: Utilization of CT angiography in the Medicare population increased markedly for 2001-2014, particularly in the ED, with radiologists remaining dominant providers. The chest is the most common body region imaged with CT angiography. PMID- 27461588 TI - Yttrium-90 Radioembolization of Advanced, Unresectable Breast Cancer Liver Metastases-A Single-Center Experience. AB - PURPOSE: To determine value of transarterial radioembolization (TARE) for palliative treatment of unresectable liver-dominant breast metastases (LdBM) and to determine prognostic parameters. MATERIALS AND METHODS: Records of patients undergoing TARE for progressing LdBM between June 2006 and March 2015 were retrospectively reviewed; 44 female patients (mean age 56.1 y; range, 34.9-85.3 y) underwent 69 TAREs (56 resin-based, 13 glass-based). Of 44 patients, 42 had bilobar disease. Mean administered activity was 1.35 GBq +/- 0.71. Median clinical and imaging follow-up times were 121 days (range, 26-870 d; n = 42 patients) and 93 days (range, 26-2,037 d; n = 38 patients). Clinical and biochemical toxicities, imaging response (according to Response Evaluation Criteria In Solid Tumors), time to progression, and overall survival (OS) were evaluated. Data were analyzed with stratification according to clinical and procedural parameters. RESULTS: Toxicities included 1 cholecystitis (grade 2) and 1 duodenal ulceration (grade 3); no grade >= 4 clinical toxicities were noted. Objective response rate (complete + partial response) was 28.9% (11/38); disease control rate (response + stable disease) was 71.1% (27/38). Median time to progression of treated liver lobe was 101 days (range, 30-2,037 d). During follow up, 34/42 patients died (median OS after first TARE: 184 d [range 29-2,331 d]). On multivariate analysis, baseline Eastern Cooperative Oncology Group (ECOG) status of 0 (P < .0001, hazard ratio [HR] = 0.146) and low baseline gamma glutamyltransferase (GGT) levels (P = .0146, HR = 0.999) were predictors of longer OS. CONCLUSIONS: TARE can successfully delay progression of therapy refractory LdBM with low complication rate. Nonelevated baseline ECOG status and low GGT levels were identified as prognostic factors. PMID- 27461589 TI - Long-Term Survival after Radiofrequency Ablation of Lung Oligometastases from Five Types of Primary Lesions: A Retrospective Evaluation. AB - PURPOSE: To conduct a retrospective evaluation of long-term survival after radiofrequency (RF) ablation for lung oligometastases from 5 types of primary lesions. MATERIALS AND METHODS: The study population consisted of 123 patients with lung oligometastases from colorectal cancer (CRC), non-small-cell lung cancer, hepatocellular carcinoma, esophageal cancer, and renal-cell carcinoma treated with RF ablation. Lung oligometastases were defined as 1-5 metastases confined to the lung while the primary cancer and other metastases were eradicated. Overall survival (OS) and recurrence-free survival (RFS) were estimated for the overall study population and for patients with each type of primary lesion. The OS and RFS rates were compared with those of the patients with any of the other four primary lesion types. Finally, various variables were analyzed to determine what factors influenced OS and RFS. RESULTS: The median follow-up was 45.7 months, and the 5-year OS and RFS rates for all 123 patients were 62% and 25%, respectively. The OS time for patients with metastases from CRC was significantly longer (P = .042); it was significantly shorter (P = .022) in patients with metastases from esophageal cancer. Longer disease-free interval was significantly (P = .015) associated with better OS. There was no variable significantly associated with OS and RFS on multivariate analyses. CONCLUSIONS: Data from this single-center study appear promising in terms of long-term survival after RF ablation of lung oligometastases from 5 primary lesions. PMID- 27461590 TI - Lessons from the wild. PMID- 27461591 TI - Oxidative stress marker in oral cancer: A review. AB - Oxygen derived species such as hydrogen peroxide, superoxide anion radical, hydroxyl radical (OH-), and singlet oxygen are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer. Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS) during their metabolism. Oxidative damage to cellular DNA can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. ROS influences central cellular processes such as proliferation, apoptosis, and senescence which are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention. PMID- 27461592 TI - Clinical significance of inflammatory mediators in the pathogenesis of oral cancer. AB - Oral cancer has become a grave problem in many parts of the globe with two.thirds of the cases occurring in developing countries. Chronic inflammation plays a prominent role in the development of oral cancer. The rationale for molecular targeted prevention of oral cancer is promising. Therefore, there are continued improvements to our understanding of the molecular connections between inflammation and oral cancer. The inflammatory mediators including nuclear factor kappa B, vascular endothelial growth factor, inflammatory cytokines, prostaglandin pathways, p53, reactive oxygen and nitrogen species, and microRNAs are major key players in the pathogenesis of oral cancer. Currently, visual cytology.based techniques and biopsy are used to detect dysplasia and early stage of oral squamous cell carcinoma. These approaches are limited in their ability to judge the severities of oral lesions and are useful only after the appearance of visual changes. Thus, traditional cytological and biopsy assays combined with testing of inflammatory biomarkers would be beneficial for the efficient early detection of oral dysplastic lesions and early stages of oral squamous cell carcinoma. PMID- 27461593 TI - Oral cancer: Etiology and risk factors: A review. AB - Oral cancer is the sixth most common malignancy in the world. Oral cancer is of major concern in Southeast Asia primarily because of the prevalent oral habits of betel quid chewing, smoking, and alcohol consumption. Despite recent advances in cancer diagnoses and therapies, the 5.year survival rate of oral cancer patients has remained at a dismal 50% in the last few decades. This paper is an overview of the various etiological agents and risk factors implicated in the development of oral cancer. PMID- 27461594 TI - Anesthetics impact on cancer recurrence: What do we know? AB - Surgery is an important component of treatment in cancer patients. However, surgical stress, anesthesia, and perioperative analgesia interfere with the host immune defense mechanisms and may contribute to metastatic dissemination of malignant tumors and cancer progression. Little is known about the effects of anesthesia on tumor recurrence. In vivo studies and clinical data show some evidence that regional anesthesia is beneficial for cancer patients as it may decrease the risk of metastasis. This short review summarizes the clinical data on the possible association between anesthesia, perioperative analgesia, and the risk of cancer recurrence. Most of the clinical reports are based on retrospective studies, and properly designed prospective trials including a sufficient number of patients is required to reveal the interaction of various anesthetic drugs and methods and cancer progression. PMID- 27461595 TI - Proliferative verrucous leukoplakia: An update. AB - Proliferative verrucous leukoplakia (PVL) is a rare form of oral leukoplakia, which was first described in 1985 by Hansen et al. Since then, various published case series have presented PVL as a disease with aggressive biological behavior due to its high probability of recurrence and a high rate of malignant transformation, usually higher than 70%. PVL is a long-term progressive condition, which is observed more frequently in elderly women, over 60 years at the time of diagnosis. The buccal mucosa and tongue are the most frequently involved sites. It develops initially as a white plaque of hyperkeratosis that eventually becomes a multifocal disease with confluent, exophytic and proliferative features with a progressive deterioration of the lesions, making it more and more difficult to control. Tobacco use does not seem to have a significant influence on the appearance or progression of PVL and may occur both in smokers and nonsmokers. Prognosis is poor for this seemingly harmless appearing white lesion of the oral mucosa. At present, the etiology of PVL remains unclear as well as its management and diagnosis, which is still retrospective, late and poorly defined, lacking consensus criteria. This short review discusses the clinical and histopathological features, diagnosis, traditional treatment and the current management of the disease. PMID- 27461596 TI - Electronic game: A key effective technology to promote behavioral change in cancer patients. AB - Cancer diagnosis is a very unpleasant and unbelievable experience. Appropriate management and treatment of these diseases require a high degree of patient engagement. Interactive health electronic games are engaging, fun, challenging, and experiential and have the potential to change the attitude and behavior, which can improve the player's health. The use of these digital tools, as one of the most attractive and entertaining modern technologies, canem power patients, provide suitable palliative care, promote health behavior change strategies, increase patient engagement, enhance healthy lifestyle habits, improve self.management, and finally improve the quality of life of the patients. Finally, the aim of this article was to describe electronic games and their effects on the promotion of behavior change in cancer patients. In addition, this article describes categories, characteristic features, and benefits of this digital media in the lifestyle modification of cancer patients. PMID- 27461597 TI - Tele-cytology: An innovative approach for cervical cancer screening in resource poor settings. AB - Carcinoma cervix remains a leading cause of cancer mortality among women in countries lacking any screening program. The existing screening policy and approach via conventional cytology centered mainly in Tertiary Care Center, is totally unaffordable to Indian women, especially in the remote areas. This suggests the need of depolarizing the resources via generating the near real time modalities which could be used at the door step of the needy ones. For any screening modality to be effective it should be adequately sensitive, specific, reproducible, cheap, simple, affordable, and the most important is should be real time to ensure wide coverage and curtail loss to follow-up. Incorporating telecytology as a screening tool could make the dream come true. Telecytology is the interpretation of cytology material at a distance using digital images. Use of mobile telecytology unit housed in a van carrying satellite equipment and the automated image capturing systems is the central theme behind this idea. The imaging equipment would be carrying out the imaging of Papanicolaou smears prepared at the screening site and sending the images to the central laboratories situated at some tertiary care level. This concept could overcome the hindrance of trained cytology infrastructure in the resource poor settings and could provide an efficient and economical way of screening patients. There is possibility that the designed approach may not detect the entire women positive for the disease but if the desired objective was to diagnose as many cases as possible in resource poor setting, then this process offers an advantage over no screening at all. PMID- 27461598 TI - A review on oral cancer biomarkers: Understanding the past and learning from the present. AB - Biomarkers are broadly classified as genomic, proteomic, or metabolomic. Molecular biology and oncology research studies on oral cancer biomarkers focus on identifying key biological molecules or markers that could be linked to cancer development, risk assessment, screening, recurrence prediction, indicating prognosis, indicating invasion/metastasis and monitoring therapeutic responses of cancer. Cluster of differentiation factor 34 is a salivary biomarker that can identify recurrence potential of oral squamous cell carcinoma (OSCC). Integrin alpha3 and integrin beta4 are genomic biomarkers that are helpful in estimating the risk of regional and hematogenous dissemination of malignant oral squamous cells. Other examples are vascular endothelial growth factor, B-cell lymphoma-2, claudin 4, yes-associated protein 1 and MET proto-oncogene, and receptor tyrosine kinase, which are genomic biomarkers that are used to predict radio-resistance in OSCC tissue. The present article reviews the clinical application, methodologies and steps in developing candidate biomarkers, protocols in reporting, evaluating candidate biomarkers, and challenges in biomarker research with a focus OSCC. PMID- 27461599 TI - Exploring the role of dietary factors in the development of breast cancer. AB - The aim of the current review is to assess the magnitude of the breast cancer, and to explore the contribution of different dietary constituents in both the causation and the prevention of the disease. An exhaustive search for all materials related to the topic was made in different search engines, including PubMed, World Health Organization Web site, and Google scholar, for a duration of 30 days (June 2014). Relevant documents, systematic reviews, technical publication series, research articles, books, and guidelines focusing on the association of dietary factors and breast cancer, published in 1998-2014 were included in the review. Overall, 56 articles were selected based on the suitability with the current review objectives and analyzed. Although specific foods and nutrients have been attributed to the causation of breast cancer, the association of the same with overall diet is still inconsistent and unexplored. As the etiology of breast cancer is multifactorial and because contribution of each factor in the development of the disease is still unclear, early detection of the disease remains the crucial factor in breast cancer control. To conclude, a definite direct or inverse association has been observed in the development of breast cancer with the dietary nutrients, and thus there is an urgent need to develop cost-effective and readily available approach for the early detection and treatment of breast cancer, especially among women from low-resource settings. PMID- 27461600 TI - SiRNA and epigenetic aberrations in ovarian cancer. AB - Ovarian cancer has the most noteworthy lethal rate around gynecologic malignancies, and it is also considered as the fourth most frequent cancer in the woman in world. Two most critical barriers to treatment of ovarian malignancy are absence of early diagnostic markers and advancement of drug resistance after therapy, especially in advanced stages. Various epigenetic changes have been recognized in ovarian cancer. Recent progresses in our understanding of molecular pathogenesis of ovarian malignancy have dramatically provided potential new targets for molecularly targeted therapies. In very recent years, small interfering RNA (siRNA)-mediated gene silencing has been emerging as a novel treatment modality in preclinical studies in the light of its strong gene specific silencing. Gene suppression mediated by RNA interference (RNAi) significantly suppressed gene expression at the messenger RNA (mRNA) and protein levels. SiRNAs have therapeutic potential for ovarian cancer through various mechanisms. In this review, we not only provide an overview of siRNA designing for epigenetic silencing of genes aberrantly expressed in ovarian cancer but also we will highlight that the epigenetically silenced genes offer new targets for therapeutic approaches based on re-expression of tumor suppressor genes via demethylating and deacetylating drugs. PMID- 27461601 TI - Oxaliplatin-induced acute thrombocytopenia. AB - Oxaliplatin (1, 2-diamminocyclohexaneoxalato-platinum) is a novel platin analog, which is widely used in gastrointestinal malignancies. Platinum analogs damage cellular deoxyribonucleic acid (DNA) by leading covalent bifunctional DNA adducts with cellular DNA. Major side effects of oxaliplatin are neurotoxicity (peripheral neuropathy), myelosuppression with moderate thrombocytopenia and gastrointestinal toxicity (diarrhea). Thrombocytopenia might be related to myelosuppression and/or drug-induced immune thrombocytopenia (DIIT). In here, oxaliplatin-induced thrombocytopenia is discussed with review of the literature. PMID- 27461602 TI - Superior vena cava syndrome: A radiation oncologist's perspective. AB - Superior vena cava syndrome is referred to as a constellation of symptoms and signs caused by obstruction of superior vena cava. It can occur due to both benign and malignant causes with the latter being the predominant. There is a paradigm shift in the approach to manage this condition. It is no longer considered a medical emergency and histological diagnosis is necessary before treatment. This article reviews the causes, symptoms, pathophysiology, and overall management policy which have changed over decades. PMID- 27461603 TI - Boron neutron capture therapy: Moving toward targeted cancer therapy. AB - Boron neutron capture therapy (BNCT) occurs when a stable isotope, boton-10, is irradiated with low-energy thermal neutrons to yield stripped down helium-4 nuclei and lithium-7 nuclei. It is a binary therapy in the treatment of cancer in which a cytotoxic event is triggered when an atom placed in a cancer cell. Here, we provide an overview on the application of BNCT in cancer therapy as well as current preclinical and clinical evidence on the efficacy of BNCT in the treatment of melanoma, brain tumors, head and neck cancer, and thyroid cancer. Several studies have shown that BNCT is effective in patients who had been treated with a full dose of conventional radiotherapy, because of its selectivity. In addition, BNCT is dependent on the normal/tumor tissue ratio of boron distribution. Increasing evidence has shown that BNCT can be combined with different drug delivery systems to enhance the delivery of boron to cancer cells. The flexibility of BNCT to be used in combination with different tumor-targeting approaches has made this strategy a promising option for cancer therapy. This review aims to provide a state-of-the-art overview of the recent advances in the use of BNCT for targeted therapy of cancer. PMID- 27461604 TI - Mythology and evidence-based oncology: An indivisible link. AB - Religion has an important role in the birth of medicine and shares a long history. Contradiction has separated spirituality and medicine. For so many years, the spiritual dimension of medicine was seen as unnecessary and inappropriate. However times are changing again and since the last few decades, recent literature and various ongoing studies have focused on unmet spiritual needs of physician and patient. This article focuses on the rejuvenating link between medicine and spirituality. PMID- 27461605 TI - Chemotherapy for advanced non-small cell lung cancer with a focus on squamous cell carcinoma. AB - Lung cancers are broadly divided into small-cell lung cancer (SCLC) and non-SCLC (NSCLC), and the treatments for each differ. NSCLC includes squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and others. However, because there is little difference in treatment efficacy between these histological types, they have collectively been treated as a single entity. Cytotoxic anti cancer agents, mainly platinum-based drugs, are the first-line treatment for unresectable advanced NSCLC, and the standard therapy is combination chemotherapy with two drugs, usually involving one platinum-based and one unrelated cytotoxic drug. Such regimens have been used for all the different histological types. In recent years, however, genetic abnormalities in NSCLCs known as driver mutations have been identified. These include epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocations, which are responsible for both carcinogenesis and cancer growth and survival. The advent of molecular targeted therapies that target these mutations has clearly improved the prognosis for NSCLC. However, effective molecular targeted drugs or novel anti-cancer agents that greatly prolong survival have not yet been developed to treat squamous cell carcinoma or 30% of adenocarcinomas. For patients with these types of cancers, it is important to use existing cytotoxic anti-cancer agents appropriately in their treatment. In this paper, we review the treatment options for unresectable advanced NSCLC on the basis of recent findings, with a particular focus on squamous cell carcinoma, for which groundbreaking drugs have yet to be discovered. PMID- 27461606 TI - Acupuncture for hot flashes in women with breast cancer: A systematic review. AB - BACKGROUND: Acupuncture is applied worldwide in treating hot flashes (HFs), which may be a common complication experienced by women with breast cancer (BC). Although researches associated with the effect of acupuncture for HFs have been done by many people, there is a lack of comprehensive evaluation of the effect of this therapy. OBJECTIVE: The aim of this systematic review is to assess the effectiveness of acupuncture for HFs in women with BC. METHODS: Seven databases (Cochrane Central Register of Controlled Trials, Embase, PubMed, Web of Science, Chinese National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, and Wan Fang Database) were searched from their inceptions to June 2015 without language restrictions. Randomized controlled trials (RCTs) were aggregated to evaluate the therapeutic effect of acupuncture for HFs in women with BC. RESULTS: Twelve RCTs were identified at last, and all of the studies agreed on the potential therapeutic effect of acupuncture for HFs in women with BC. However, three trials showed significant difference compared with the controls. One research demonstrated an encouraging trend, and six did not find any difference between acupuncture and controls. Another two trials got a negative result compared with hormone therapy. The meta-analysis indicated a difference in the number of HFs after treatment and during follow-up compared with the controls. Three trials reported Kupperman index scores, and meta analysis showed significant difference between acupuncture and controls after treatment and during follow-up. CONCLUSION: Acupuncture seems to be an effective therapy for HFs in women with BC; however, there was insufficient evidence to support the efficacy of acupuncture. However, the results should be interpreted cautiously, because of the poor quality and small number of included studies. PMID- 27461607 TI - Association between fibroblast growth factor receptor-2 gene polymorphism and risk of breast cancer in Chinese populations: A HuGE review and meta-analysis. AB - AIM OF STUDY: To evaluate the effect of fibroblast growth factor receptor.2. (FGFR2) on genetic susceptibility for breast cancer. (BC) in Chinese populations. MATERIALS AND METHODS: A computerized literature search was carried out in PubMed, Chinese Biomedical Database. (CBM), and Chinese National Knowledge Infrastructure. (CNKI) to collect relevant articles. Pooled odds ratio. (OR) and 95% confidence interval. (CI) were used to assess the strength of the associations. RESULTS: A total of 21 articles involving a total of 15 polymorphisms of the FGFR2 gene were included in the meta-analysis. Due to the limited studies for rs17102287, rs2981578, rs3135718, rs3803662, rs3750817, rsl0510097, rsl7542768, rs13387042, and rs1982073; we only pooled the six polymorphisms. (rs11200014, rs1219648, rs2420946, rs2912778, rs2981579, and rs2981582) into this meta. ANALYSIS: Overall, significantly increased BC risk was associated with five polymorphisms. (rs2981579, rs2981582, rs1219648, rs2420946, and rs2912778) when all studies were pooled into the meta. ANALYSIS: When stratified by ethnicity and source of controls, similar results were also detected. However, for rs2981579 no significant association was found among Chinese Han in all genetic models. CONCLUSION: Our meta-analysis suggests that FGFR2 is likely an important genetic marker contributing to susceptibility of BC. We recommend that these single nucleotide polymorphisms to be included in future association studies and functional assays. PMID- 27461608 TI - Comparison between endoscopic thyroidectomy and conventional open thyroidectomy for papillary thyroid microcarcinoma: A meta-analysis. AB - BACKGROUND: Endoscopic thyroidectomy (ET) has gained acceptance among surgeons as its feasibility has been well-documented. The aim of this systematic review with meta-analysis has been to assess and validate the safety and feasibility of ET when compared to conventional open thyroidectomy (COT) for papillary thyroid microcarcinoma (PTMC) and to verify other potential benefits and drawbacks. MATERIALS AND METHODS: PubMed, Web of Knowledge are searched for studies concerning treatment for papillary thyroid microcarcinoma between 2000 and 2013, the method of meta-analysis is performed to compare the effect of different treatment. RESULT: Six studies with a total of 1081 patients were included. Primary outcomes include transient recurrent laryngeal nerve (RLN) palsy, permanent PLN palsy, transient hypocalcemia, permanent hypocalcemia, and overall recurrence. ET experienced a higher incidence of transient RLN palsy than COT. There were no statistically significant differences for the presence of permanent PLN palsy, transient hypocalcemia, and permanent hypocalcemia. Tumor recurrence was detected in the both group, but the difference was not statistically significant. Secondary outcomes include operative time, length of hospitalization, and cosmetic results. Patient satisfactory score significantly favored ET (mean difference [MD] = -1.64, 95% confidence interval [CI] [-1.85, 1.43], P < 0.00001). Operative time was significantly longer in ET (MD = 38.18, 95% CI [22.24, 54.11], P < 0.00001). The length of hospitalization was not significantly different in both groups (MD = -0.46, 95% CI = [-1.40, 0.47], P = 0.33). CONCLUSION: For PTMC, ET is a feasible, practical, and safe alternative with better cosmetic benefits, and it can be performed with an ease of manipulation that is similar to that of COT. PMID- 27461609 TI - Antileukemic effects of piperlongumine and alpha lipoic acid combination on Jurkat, MEC1 and NB4 cells in vitro. AB - AIM OF STUDY: This research indicated to evaluate the effects of piperlongumine (PL), a biologically active alkaloid, and alpha lipoic acid (ALA), a naturally occurring cofactor existed in multienzyme complexes regulating metabolism on leukemia cells. Excessive production of reactive oxygen species (ROS) can lead to oxidative stress, a state that has been observed in several hematopoietic malignancies, including acute and chronic myeloid leukemias. The importance of the association between oxidative stress and malignancy is not currently clear; however, there is evidence that tumor.derived ROS may promote cell survival, migration and metastasis, proliferation and even drug.resistance depending on the origin of the cancer. Increased oxidative stress in leukemic cells may represent a potential therapeutic target, although there are differing opinions on whether therapeutic strategies should aim to antagonize or further promote oxidative stress in leukemic cells. MATERIALS AND METHODS: The effects of PL alone (5, 15, 30 MUM) and in combination (30 MU M) with ALA (200 MU M) on Jurkat, NB4 and MEC1 leukemia cell lines were investigated through MTT, caspase-3 and cyclooxygenase-2 (COX-2) activities. RESULTS: Inhibition of COX-2 and the induction of caspase.3 cleavage in Nb4 (acute promyelocytic leukemia) cells were found to be significant following PL application and synergistic effects with combination of ALA (inhibition of COX-2 as 23.74% and 3.55-fold increase of caspase-3). CONCLUSION: PL and ALA may have a potential value as a therapeutic agent for patients with acute promyelocytic leukemia. PMID- 27461610 TI - Protective effect of ayurvedic formulations against doxorubicin-induced cardiotoxicity: Preliminary studies on Brahma Rasayana and Chyavanaprash. AB - AIM OF STUDY: The present work aimed to examine the efficacy of two ayurvedic formulations, Brahma Rasayana (BRM) and Chyavanaprash (CHM) to alleviate doxorubicin (DOX) induced acute cardiotoxicity. MATERIALS AND METHODS: Swiss albino mice were administered with DOX (25 mg/kg, i.p.) and two doses of BRM or CHM (1 and 2 g/kg). Cardiotoxicity was assessed by measuring the levels of various antioxidant parameters in the heart as well as release of marker enzymes in the serum was assayed. Histology of the heart was also performed to check for DOX-induced damages. RESULTS: Administration of either BRM or CHM (1 and 2 g/kg) maintained the antioxidant status in the heart thereby preventing tissue damage as well as the release of marker enzymes. DOX-induced variation of cardiac architecture was also prevented by BRM and CHM administration. CONCLUSION: BRM and CHM administration could prevent DOX-induced acute cardiotoxicity. PMID- 27461611 TI - Antibiotic protocol for the prevention of osteoradionecrosis following dental extractions in irradiated head and neck cancer patients: A 10 years prospective study. AB - AIMS OF STUDY: The aim of the study was to establish the long term efficacy of a perioperative antibiotic protocol combined with antibacterial mouthwashes in preventing osteoradionecrosis (ORN). MATERIALS AND METHODS: Irradiated head and neck cancer patients reporting for dental extractions were prospectively enrolled to the study between January 2002 and December 2009. Selection criteria for the patients included the presence of nonrestorable tooth/teeth in the field of radiation, latency period of 6 months since completion of radiotherapy, radiation dosages >60 Gy, and availability for follow-up. Starting from 10 days preextraction, the patients were prescribed 8th hourly oral amoxicillin 500 mg along with 12th hourly mouthwashes using 10 ml of undiluted chlorhexidine gluconate 0.2% solution. The same prescription was continued for 7 days postextraction. All patients were followed-up at regular intervals until December 2013. RESULTS: A total of 89 patients (55 male and 34 female) underwent extractions of teeth which were present in the radiation field. Mean age of the patients was 41.8 years (range 36-54 years) and extractions were done between 12 and 33 months (mean - 15 months) postradiation therapy. Altogether, 232 teeth were extracted (maxilla - 78/mandible - 154) at an average of 2.6 teeth per patients. After a mean follow-up period of 63 months (range 48-123 months) there were no reported cases of ORN. CONCLUSION: Based on the results of this study, perioperative oral antibiotics in combination with antibacterial mouthwashes are effective in preventing ORN following dental extractions in irradiated patients. PMID- 27461612 TI - The role of angiogenesis inhibitors in the treatment of elderly patients with advanced non-small-cell lung cancer: A meta-analysis of eleven randomized controlled trials. AB - PURPOSE: Data on the role of angiogenesis inhibitors (AIs) in the treatment of elderly patients with advanced non-small-cell lung cancer (NSCLC) remains limited. We aimed to assess the overall efficacy of AIs-containing regimens in the treatment of advanced NSCLC in this setting. MATERIALS AND METHODS: Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) meeting up to October 31, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating therapies with or without AIs in elderly patients with advanced NSCLC. The endpoints were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted by using random effects models and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 3,709 elderly patients with advanced NSCLC from 11 RCTs were identified for analysis. The pooled results demonstrated that there was a clinical benefit in PFS for AIs-containing regimens (hazard ratio (HR) 0.88, 95%CI: 0.78-1.00, P = 0.053) when compared to non-AIs-containing regimens, but not for OS (HR 0.99, 95%CI: 0.90-1.10, P = 0.89). On subgroup analysis, similar results were found based on treatment line. No publication bias was detected by Begg's and Egger's tests for OS. CONCLUSIONS: In elderly patients with advanced NSCLC, AIs containing therapies offer a clinical benefit in PFS but for OS. With present available data from RCTs, we are still unable to clearly set the role of specific AIs in the treatment of advanced NSCLC in this setting. PMID- 27461613 TI - Cancer incidence and all-cause mortality in HIV-positive patients in Northeastern Algeria before and during the era of highly active antiretroviral therapy. AB - AIMS: To assess cancer incidence and all-cause mortality trends in HIV-positive patients in Algeria before and during the highly active antiretroviral therapy (HAART) era. SETTINGS AND DESIGN: Cross-sectional study. SUBJECTS AND METHODS: We used hospital-based data of patients with HIV/AIDS between January 1988 and December 2010. STATISTICAL ANALYSIS USED: Cancer incidence, standardized mortality ratios (SMRs), risk of death, and proportion of HIV-positive patients treated before and during the HAART era were calculated. The joinpoint model was used to assess the magnitude of changes in SMRs. RESULTS: In 1988-2010, 156 patients were diagnosed as HIV-positive. During pre-HAART era, Kaposi sarcoma (KS) incidence was 5%. After the introduction of HAART, KS incidence decreased to 2%. No other AIDS-related cancer was diagnosed during the study. One-third died (52/156), of which 83.6% died in the same year as or in the year after HIV diagnosis; median age at death (interquartile range) was 34.5 (11.8) years. Yearly risk of death declined from 100% in 1998 to 8% in 2010; percentage of patients treated with HAART increased from 13% in 1998 to >80% after 2002. Overall SMR decreased from 200.2 (95% confidence interval [95% CI], 123.2-325.2) before the HAART era to 91.4 (95% CI, 66.0-126.6) thereafter. From 2003, yearly SMRs decreased significantly by 66.1% (P < 0.05) until 2006 but not thereafter. CONCLUSIONS: Since 1998, the proportion of HIV-positive patients treated with HAART increased, reaching 84% in 2010, all-cause mortality decreased, and cancer remained rare. However, almost all patients who died during the study seemed to be diagnosed at a late stage of the disease, emphasizing the need for earlier diagnosis of HIV in Algeria. PMID- 27461614 TI - Neutrophil-lymphocyte ratio and CEA level as prognostic and predictive factors in colorectal cancer: A systematic review and meta-analysis. AB - INTRODUCTION: There is a growing body of evidence showing the functional relationship between inflammation index like netrophil.lymphocyte ratio. (NLR) and colorectal cancer. (CRC) in both experimental and clinical situations. The serum carcinoembryonic antigen. (CEA) level is the most widely used marker and associate with poor prognosis in most studies. For these factors to be clinically useful, they should be routinely available, well standardized, and validated in different patient cohorts. AIMS: There is a growing body of evidence showing the functional relationship between inflammation index like netrophil-lymphocyte ratio. (NLR) and colorectal cancer. (CRC) in both experimental and clinical situations. The serum carcinoembryonic antigen. (CEA) level is the most widely used marker and associate with poor prognosis in most studies. For these factors to be clinically useful, they should be routinely available, well standardized, and validated in different patient cohorts. MATERIALS AND METHODS: We systemically searched PubMed, Embase, and SciVerse Scopus databases, and performed a meta.analysis by Review Manager 5.2 software. (The Cochrane Collaboration, Software Update, Oxford). Two reviewers selected studies, assessed risk of bias, and extracted data independently. Newcastle.Ottawa Scale was applied to assess the quality of included studies. RESULTS: Fifteen studies involving 7741 patients with CRC were analyzed. Patients with an NLR < 5 before treatment were significantly more likely to have 5-year overall survival (odds ratio [OR] = 2.03; 95% confidence interval [CI] = 1.56-2.63) and 5-year disease free survival (OR = 1.67; 95% CI = 1.19-2.35). Pretreatment CEA level < 5 were significantly associated with complete tumor response and tumor downstaging after neoadjuvant treatment. The result also showed that patients with NLR > 5 were expected to have a larger tumor, poorer tumor differentiation, and higher CEA level. CONCLUSION: NLR and CEA are valuable tools for the prediction of prognosis in CRC and adjusting the treatment strategy. PMID- 27461615 TI - Expression of complement C5a receptor and the viability of 4T1 tumor cells following agonist-antagonist treatment. AB - BACKGROUND: Complement system is theoretically believed to halt the progression of tumor by the activity of C5a/CD88. Protein C5a is a potent pro.inflammatory mediator that activates the complement system by binding to its receptor. OBJECTIVES: The purpose of this study is to determine the expression of the anaphylatoxin C5a receptor on 4T1 cell line and to study the viability of the cells after being treated with the C5a peptides. MATERIALS AND METHODS: The cells 4T1 had undergone immunofluorescence staining, conventional polymerase chain reaction (PCR) and real-time PCR for the expression of determination part. Whereas Alamar Blue and MTT assays were conducted for the viability study of the cells. RESULTS: The cells showed positive result in expressing the receptor of the C5a through immunostaining and PCR. The CT value recorded at initial dilution was 22.24. In cell viability assay, the cell was treated with C5a peptides, PMX205 and EP54. The purpose of this treatment was to see whether C5a had a direct effect on the cell itself using both assays. The result showed that PMX205, which is an antagonist, gave more effects towards the cell as compared with the treatment of EP54. CONCLUSION: This experiment shows the presence of C5a receptor on 4T1 cell line. We believe that the antagonist peptide is eligible to be used widely in cancer immunotherapy field; but in vivo studies need to be carried out first in the future, as it will determine how these drugs affect the tumor cell growth. PMID- 27461616 TI - Correlations between gastric cancer family history and ROBO2 and RASSF2A gene methylations. AB - OBJECTIVE: To explore the correlation between ROBO2 and RASSF2A gene methylations and gastric cancer family history. MATERIALS AND METHODS: ROBO2 and RASSF2A gene methylations in gastric cancer tissues and peri.cancerous tissues were detected with methylation.specific PCR in 36. patients with gastric cancer family history and 33 without gastric cancer family history. The correlations of ROBO2 and RASSF2A gene methylations with family history, and clinical and pathological characteristics were analyzed. RESULTS: ROBO2 and RASSF2A gene methylations were all significantly higher in gastric cancer tissues (30% and 26%) than in peri cancerous tissues (0% and 0%) (all P < 0.05). ROBO2 gene methylation was significantly lower in the patients with gastric cancer family history (17%, 6/36) than in the patients without gastric cancer family history (41%, 15/33) (P < 0.05). CONCLUSION: ROBO2 and RASSF2A gene methylations may be related to gastric tumorigenesis, and ROBO2 gene methylation is associated with sporadic gastric cancer. PMID- 27461617 TI - Association of ABO blood types and clinicopathological features of ureteral transitional cell carcinoma in a single-center in China. AB - PURPOSE: The purpose of this study was to evaluate the correlation of ABO blood types and clinicopathological characteristics of patients with ureteral transitional cell carcinoma. MATERIALS AND METHODS: In our study, an entire cohort of 239 patients who were pathological diagnosed as ureteral transitional cell carcinoma (TCC) between February 2002 and March 2010 were reviewed retrospectively. Variables including demographic features, tumor grades, tumor stages, type of surgery and number of tumors as well as ABO blood types status were evaluated. The relationship between the ABO blood group and clinicopathological variables was assessed by Chi-squared analysis. RESULTS: The ratio of male to female was 1: 1.12. The median age at diagnosis was 68.5 years. A total of 111 neoplasms located in the right ureter. A total of 218 patients had radical nephroureterectomy (RNU). Multifocality was observed in 32 patients. The pathology was as follow: Grade 1 (seven cases), Grade 2 (110 cases) and Grade 3 (122 cases); Ta and T1 (83 cases), T2-T4 (156 cases). The distribution of ABO blood types was A, B, O and AB in 70 (29.3%), 76 (31.8%), 66 (27.6%) and 27 (11.3%), respectively. There were no significant differences in the clinicopathological variables among individuals with different ABO blood types. In a subgroup analysis, B and O group showed a worse tumor stage compared with A and AB groups (P = 0.01). CONCLUSION: B and O blood types are at higher risk of muscle invasive ureteral TCC as compared with A and AB blood types. We suggest ABO blood types to be taken into consideration when urologists select therapeutic schemes for individuals with ureteral TCC. PMID- 27461618 TI - Abnormal vascular endothelial growth factor protein expression may be correlated with poor prognosis in diffuse large B-cell lymphoma: A meta-analysis. AB - OBJECTIVE: We conducted the present meta-analysis with relevant cohort studies to determine whether expression levels of vascular endothelial growth factor. (VEGF) could predict the prognosis of diffuse large B.cell lymphoma. (DLBCL). MATERIALS AND METHODS: The MEDLINE (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982--2013), Web of Science (1945-2013), and the Chinese Biomedical Database (1982-2013) were searched without any language restrictions. Meta-analysis was conducted using STATA software (Version 12.0, Stata Corporation, College Station, Texas USA). Hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. RESULTS: Eight clinical cohort studies, which recruited a total 670 DLBCL patients, were included in the meta-analysis. The results of this meta-analysis indicate that DLBCL patients with positive VEGF expression had a shorter overall survival than those with negative VEGF expression. (HR = 1.58, 95% CI = 0.80-2.36, P < 0.001). Ethnicity-stratified analysis illustrates that high expression levels of VEGF may be significantly correlated with poor DLBCL prognosis among both Caucasian and Asian populations. (Caucasian: HR = 1.73, 95% CI = 0.56-2.90, P = 0.004; Asian: HR = 1.45, 95% CI = 0.41-2.50, P = 0.006). CONCLUSION: The major findings of our meta-analysis reveal that the aberrant expression of VEGF may correspond to shorter overall survival of patients with DLBCL, revealing that VEGF expression could be an unbiased prognostic determinant in the management of DLBCL patients. PMID- 27461619 TI - Majority of the most-cited articles on cutaneous malignant melanoma are published in non-dermatology/melanoma specialized journals. AB - BACKGROUND: The most-cited articles. (MCAs) are likely those that impressed other researchers and had profound influence on clinical practice or future developments in the related scientific field. AIM: This study was conducted to explore a bibliometric approach to assess in where the cutaneous malignant melanoma. (CMM) related MCAs have been published. MATERIALS AND METHODS: We identified journals for publications with the word "melanoma" in the title by using the ISI Web of Knowledge Database between 2000 and 2010. The term MCAs arbitrarily defined as equal or more than 100 citations. RESULTS: A total of 425 MCAs were published in 93 journals, led by the Cancer Research. (n = 58) and Journal of Clinical Oncology. (n = 53). Journal categories with the MCAs were the Oncology with 232 articles, followed by the Medicine with 138. articles. The median number of citations was 147. The total numbers of citations were most prominent for the journal Nature and the New England Journal of Medicine. (NEJM) (median 385 and 354, respectively). Total number of citations was the highest for the Science.categorized journals. (median 211). Articles categorized as Dermatology and Melanoma was the least (median 132.5). The median number of citations per year was 14.91. The most valuable cited articles of per year were also published in the journal Nature. (median 59.67) and the NEJM. (median 48.67). The number of citation was the highest for the Science-categorized journals. (median 25.92). CONCLUSION: Majority of the MCAs on CMM were published in non-dermatology/melanoma specialized journals. PMID- 27461620 TI - Frequency of epidermal growth factor receptor mutations in Jordanian lung adenocarcinoma patients at diagnosis. AB - BACKGROUND: Somatic mutations of the epidermal growth factor receptor (EGFR) gene have been associated with tumor response to tyrosine kinase inhibitors (TKIs) and favorable outcome in patients with non-small-cell lung cancer (NSCLC). The activating mutations that confer sensitivity to EGFR TKIs are present in the TK domain of the EGFR gene. This study aims to report on the prevalence of EGFR mutations in NSCLC and non-squamous lung cancer patients at diagnosis, using genomic deoxyribonucleic acid (DNA) obtained from paraffin-embedded tissue samples. MATERIALS AND METHODS: We collected formalin.fixed, paraffin.embedded. (FFPE) tissue samples from 166. cases of lungadenocarcinomas referring to Jordan University Hospital and King Hussein Cancer Center between 2007 and first half of 2013. None of the patients met the definition of never smoker defined as those who smoked less than 100 cigarettes in their lifetime. We evaluated EGFR mutations by nested polymerase chain reaction. (PCR) followed by direct sequencing of the EGFR kinase domain from exon 18 to 21. RESULTS: Six different point mutations were detected in 24 patients (14.46%) of the study population. The resultant mutations were as follows: Ten patients have deletion in exon 19, sevenpatients have L858R, two patients have L861P, and one of each of the following: A735T, D770_N771 insY, L858P, L861Q, and G917C. CONCLUSION: The present study revealed that the EGFR mutations rate in Jordanian patients with adenocarcinoma of the lung was higher than in African-American, and some white Caucasian patients, and was lower than in patients in East Asia, and other countries of South Asia. PMID- 27461621 TI - Characterization of immunophenotypic aberrancies in adult and childhood acute lymphoblastic leukemia: A study from Northern India. AB - BACKGROUND: Identification of aberrant antigen expression is important in characterizing neoplastic population among non.neoplastic bone marrow counterparts and further in the detection of minimal residual disease. (MRD). Flow cytometry (FCM) is an important tool in identifying aberrant phenotypes. Incidence of aberrant phenotypes varies considerably in independent studies and its association with prognostic factors is still debatable. AIM: To identify the prevalence of aberrant phenotypes on immunophenotyping in a large series of de novo acute lymphoblastic leukemia (ALL) and to evaluate any association with initial clinical and hematological features. MATERIALS AND METHODS: In the current study, 303 patients of de novo ALL were included from the Department of Hematology, PGIMER, Chandigarh during the time period (July 2010 to June 2012). The immunophenotype of all cases of ALL was studied using FCM. RESULTS: Aberrant myeloid antigen expression was seen in 42.5% cases. Most frequent aberrant myeloid antigen was CD13 (32.2% cases), followed by CD33 (27.2% cases) and CD117 (18.5% cases). The expression of CD117 was relatively frequent in comparison to earlier reports which describe its rare expression. Adult T- ALL showed higher expression of CD33 and CD117 than pediatric T-ALL (P = 0.032 and 0.043, respectively). Myeloid antigen expression in ALL was associated with lower WBC count (P < 0.05) and lower number of peripheral blasts (P < 0.05). Expression of CD34 was higher in My + ALL group (P < 0.05) than My- ALL group. CONCLUSION: In summary, CD117 is a relatively frequently expressed myeloid marker contrary to earlier reports which describes its rare expression. Pediatric and adult ALL cases with low blast count and CD34 positivity are more likely to express aberrant myeloid markers. Current study also supports that myeloid antigen expression in both adult and pediatric ALL is not associated with adverse presenting clinical and biological features. PMID- 27461622 TI - Prognostic value of Prominin-1 Expression in Egyptian children with Acute Lymphoblastic Leukemia: Two centers Egyptian study. AB - OBJECTIVES: Acute lymphoblasstic leukemia (ALL) is the most common childhood malignancy. Prominin-1 is a cell-surface trans-membrane glycoprotein expressed on the stem cell surface and has potential role in diagnostic and prognostic work-up of several stem cell cancers. Aim of this Work: To assess the prognostic value of Prominin-1 expression in Egyptian children with ALL. SUBJECTS AND METHODS: This study was conducted on 80 Egyptian children with newly diagnosed ALL and 30 healthy children of matched age and sex as a control group. Patient history, and clinical and laboratory examination results were taken, including complete blood count, serum LDH, bone marrow aspiration with cytochemistry, immunophenotyping, Fluorescent In Situ Hybridization technique for detection of t(9;22) and Flow cytometery for estimation of Prominin-1 expression on blast cells. RESULTS: No statistically significant differences were observed between Prominin-1 positive and negative patients regarding age, sex and clinical presentation at diagnosis. No statistically significant differences between Prominin-1 positive and negative patients were observed regarding white blood cells and platelet counts, peripheral blood and bone marrow blast cells percentage while there were significantly higher hemoglobin and LDH levels in Prominin-1 positive patients. There were no significant differences between Prominin-1 positive and negative patients regarding immunophenotyping and t(9;22). There were statistically significant differences in disease outcome between Prominin-1 positive and negative expression with higher rate of relapse and death and lower rate of complete remission in patients with Prominin-1 positive expression (14 cases with Prominin-1 positive relapsed versus 2 cases with Prominin-1 negative, 12 cases with Prominin-1 positive died versus 2 cases with Prominin-1 negative and complete remission occurred in 20 cases with Prominin-1 positive versus 30 cases with Prominin-1 negative) (P =0.017). There was statistically significant difference in disease-free survival (P = 0.0072) and overall survival (P = 0.0424) between ALL patients with Prominin-1 positive and Prominin--1 negative expression. CONCLUSION: Prominin-1 is a helpful prognostic marker in patients with ALL; therefore, it should be routinely assessed at diagnosis in ALL patients for better prognostic assessment and should be taken in consideration in designing future therapeutic strategies based on patient-specific risk factors. PMID- 27461623 TI - A non-invasive study to estimate and compare salivary sialic acid level as tumor marker in patients with pre-cancer and oral cancer. AB - INTRODUCTION: Sialic acids are important terminal sugars of the carbohydrate chains of cell membrane glycoproteins and glycolipids. The progressive rise in total sialic acid (TSA) levels has been significantly associated with tumor progression and metastasis. MATERIALS AND METHODS: Samples of 2 ml of unstimulated whole saliva were collected from 20 healthy patients, and 20 cases of histopathologically confirmed oral pre-cancer patients and 20 cases of histopathologically confirmed oral squamous cell carcinoma (OSCC) patients, using the method of Navazesh. Estimation of total sialic acid was done by the histochemical method of Yao et al. RESULTS: The study revealed significantly elevated total sialic acid (TSA) levels in the saliva of oral precancer and OSCC patients, yielding a mean value of 59.75 +/- 7.29 mg/dl and 204.85 +/- 60.38 mg/dl, respectively, against the mean value of 21.65 +/- 5.71 mg/dl of the healthy controls. Also, high total sialic acid (TSA) levels in the well differentiated squamous cell carcinoma cases were appreciable to those of moderately differentiated ones. DISCUSSION AND CONCLUSION: The result suggests the correlation of elevated salivary TSA levels with the progression of OSCC. In conclusion, the study indicates that the glycoprotein metabolism is significantly altered in the saliva of patients, with both oral pre-cancer and OSCC. PMID- 27461624 TI - Involvement of syk and VEGF-C in invasion of lung adenocarcinoma A549 cells. AB - BACKGROUND AND AIMS: Lung cancer has become one of the most dangerous malignant tumors in the world nowadays, whose pathogenesis is complex involving multi-genes and multi-elements. This study aims to investigate the values of spleen tyrosine kinase (Syk) and vascular endothelial growth factor-C (VEGF-C) in lymphangiogenesis and metastasis of lung adenocarcinoma A549 cells. MATERIALS AND METHODS: The pcDNA3.1-VEGF-C and pLNCX-syk were constructed and transfected into A549 cells. After cells with stable expression were sorted, the level of VEGF-C was tested by RT-PCR and immunohistochemistry and the mRNA of syk was tested by RT-PCR. The cell invasion assay was investigated by transwell chamber in vitro. Restriction enzyme digestion and gel electrophoresis demonstrated successful construction of the pcDNA3.1-VEGF-C. RESULTS: RT-PCR and immunohistochemistry revealed higher expression of VEGF-C in VEGFC-construct-transfected A549 cells than that in controls (P < 0.05). Successful construction of the pLNCX-syk was demonstrated by restriction enzyme electrophoresis and sequencing. RT-PCR revealed Syk expression higher in syk-construct-transfected cells than in controls (P < 0.05). CONCLUSIONS: The results indicate a potential link between the upregulation of Syk and VEGF-C expression and lung adenocarcinoma. PMID- 27461625 TI - Combinatorial effect of zoledronic acid and irradiation on the prevention of DMBA induced precancerogenic changes in the mammary tissues of rats. AB - BACKGROUND: At present, the rates of breast cancer are continuously increasing, with over a million new cases being diagnosed worldwide each year. Hence, the development of new breast cancer chemopreventive drugs with acceptable efficacy and toxicity that are suitable for use for a protracted period of time is urgently needed. The present study investigated the potential preventive effects of zoledronic acid [ZOL] and radiotherapy [RT], both alone and in combination, on precancerogenic changes on the breast tissues of females. MATERIALS AND METHODS: Wistar rats were treated with 7,12-dimethylbenz [a] anthracene [DMBA] at the acute phase. Fifty female rats were divided into seven groups: Control group [I]; ZOL, group [II]; RT, group [III]; DMBA, group [IV]; DMBA + RT, group [V]; DMBA + ZOL, group [VI]; and DMBA + ZOL + RT, group [VII]. RESULTS: The treatment of DMBA exposed rats with ZOL and RT, both alone and in combination, successfully upregulates the transcriptional levels of Bax, caspase-3, caspase-9, p21, and BRCA 1 in mammary tissues, which may account for the elevated apoptotic activities observed and the eventual inhibition of tumor growth. The administration of RT and ZOL both alone and in combination was found to be effective for inhibiting the DMBA-induced precancerogenic changes on breast tissues and modulating the expression of apoptosis-associated proteins in the acute phase. CONCLUSIONS: The combination of RT and ZOL was more effective than either agent alone. Our results suggest that the administration of ZOL and irradiation in combination can offer maximal protection against DMBA-induced mammary precancerogenic changes. PMID- 27461626 TI - Application of intelligent algorithm in the optimization of novel protein regulatory pathway: Mechanism of action of gastric carcinoma protein p42.3. AB - AIMS: This purpose of the study was to optimize the regulatory mechanism of p42.3 novel protein molecule in gastric cancer and also verified it by the use of intelligent algorithms. SUBJECTS AND METHODS: Threading method was employed to analyze structural domain characteristics of p42.3 protein. Referential proteins were gathered and formed by domain homology and function similarity. Afterwards, the possible regulatory network of p42.3 was established by analyzing the acting pathways of the referential proteins. Spherical polar coordinates stratification and stratified multi-parameter weight were used for calculation of the similarity between the referential proteins and p42.3 protein, the result of which was taken as the prior probability of the initial node in Bayes network, thus the probability of occurrence of each pathway was figured out by using conditional probability formula, and the one with the biggest probability was considered as the possible pathway of p42.3. At last, molecular biological experiments were conducted to verify it. RESULTS: The acting pathway with the maximum probability predicted by Bayesian probability optimizing calculation was "S100A11" - RAGE - P38 - MAPK - Microtubule-associated protein - Spindle protein-Centromere protein Cell proliferation" which was the most likely acting pathway participated by p42.3, and has been validated by biological experiments. CONCLUSIONS: By the theoretical analysis and experimental verification, this study confirmed that assumptions that p42.3 protein was related to the occurrence and development of gastric carcinoma, predicted and verified the acting pathways of p42.3, which will provide a new research direction of the relationship between p42.3 and gastric cancer, as well as the target therapy of gastric cancer. The algorithm in predicting the acting pathway of the protein also offers a new thought in studying new functional proteins. PMID- 27461627 TI - Octreotide reverses the resistance of A2780/Pacliaxel ovarian cancer cell line to paclitaxel chemotherapy in vitro. AB - OBJECTIVE: To study the anti-tumor effects of octreotide on A2780/Taxol ovarian cancer cells in vitro, and further explore its potential molecular mechanism. MATERIALS AND METHODS: Immunocytochemistry was performed to determine the expression of SSTR2 on A2780/Taxol cells. Octreotide at different concentrations (0, 1.25, 2.5, 5.0, 10.0, and 20.0 nmol/ml) were administrated to A2780/Taxol cells in vitro. CCK-8 assay was used to measure the effects on cell proliferation, and the cytometry of octreotide determined the cell apoptosis. The expressions of SSTR2 MDR1, and vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) were investigated by quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay and the expressions of the above protein were investigated after A2780/Taxol was treated with octreotide for 48 hours by western blot in vitro. RESULTS: Positive expression of SSTR2 was observed on the membrane of A2780/Taxol cells. The proliferation of A2780/Taxol cells was gradually inhibited with increasing octreotide concentration in a concentration-dependent and time-dependent manner. Meanwhile, flow cytometry data demonstrated the octreotide-induced cell apoptosis. The results of SSTR2 mRNA suggested that there was no significant difference between each concentration group of octreotide (P > 0.05). Compared with the control group, both the MDR1 and VEGF mRNA decreased in a dose-dependent manner following 48 hours of treatment of octreotide (P < 0.05). The results of western blot showed that octreotide decreased the expressions of SSTR2, MDR1, and VEGF protein in a dose dependent manner (P < 0.05). CONCLUSIONS: Octreotide significantly inhibits ovarian cancer's proliferation and promotes its apoptosis via the cell surface expression of SSTR2. It could be used as a new targeted drug for treatment of ovarian cancer. PMID- 27461628 TI - Syk expression in non-small-cell lung cancer and its relation with angiogenesis. AB - OBJECTIVE: To study the expression of spleentyrosine kinase (Syk) gene in non- small--cell lung cancer and the relationship between Syk mRNA and microvessel density (MVD) in the tumor cells. MATERIALS AND METHODS: The expression of Syk gene in 70 cases of lung tumor tissues, adjacent tissues, and normal lung tissues were examined with reverse transcription polymerase chain reaction (RT--PCR). The expression of MVD was examined with immunohistochemical streptavidin--biotin complex (SABC). The relation between them was analyzed. RESULTS: Syk mRNA expression rates were 5.7, 95.7, and 100% in tumor, adjacent lung cells, and normal lung cells, respectively. The expression rate in tumor cells was significantly lower compared with those in normal lung tissue and adjacent lung tissue (P < 0.05), expression rate among different pathologic types, differentiation and clinical stages did not reveal any statistically significant differences (P > 0.05). The positive rate of CD34 in tumor was higher than that in adjacent tissues and normal lung tissues. The expression of Syk mRNA and MVD were negatively correlated. CONCLUSIONS: The lack of Syk mRNA expression in lung cancer play an important role in angiogenesis. PMID- 27461629 TI - Critical appraisal of stromal CD10 staining in fibroepithelial lesions of breast with a special emphasis on expression patterns and correlation with WHO grading. AB - BACKGROUND: Fibroepithelial lesions of the breast are classified into fibroadenoma and phyllodes tumor (PT). Although WHO has established a well defined grading system for PT, dilemma of discriminating borderline from malignant PT still exists. Stromal CD10 is a known poor prognostic factor in invasive breast cancer, its expression in fibroepithelial lesions of the breast is not well-documented. Till date, only one study has correlated the CD10 staining score with tumor grade in PT. OBJECTIVE: To evaluate whether the differences in expression patterns of CD10 and staining intensity correlate with the degree of malignancy in fibroepithelial tumors of the breast. MATERIALS AND METHODS: This is a retrospective study in which stromal CD10 expression was studied in 75 cases of fibroepithelial lesions of the breast using immunohistochemistry. Statistical analysis was performed using Chi-square test. RESULTS: There was a statistically significant trend of increasing stromal expression of CD10 with increasing degree of malignancy (P = 0.001). CONCLUSIONS: CD10 staining pattern and its scoring can assist the pathologist to accurately grade the PT of the breast for adequate treatment and can also be used as a target for the development of novel therapies. PMID- 27461630 TI - Down-expression of circulating micro ribonucleic acid (miRNA)-148/152 family in plasma samples of non-small cell lung cancer patients. AB - AIMS: Circulating extracellular micro ribonucleic acids (miRNAs) are considered as potential biomarkers for malignancy detection and diagnosis. The aim of this study was to determine whether circulating miRNA-148/152 family (miR-148a, miR 148b, and miR-152) expression in plasma could be used as potential biomarkers for non-small cell lung cancer (NSCLC) patients and healthy individuals. SUBJECTS AND METHODS: The levels of miRNA-148/152 family were detected by TaqMan quantitative polymerase chain reaction (qPCR) assay in plasma of 20 NSCLC patients and 10 healthy individuals. The miRNA expression level of each sample was normalized to that of miR-16 and expressed as relative expression (2-DeltaDeltaCt). RESULTS: The circulating level of all three members of miRNA-148/152 family were significantly lower in plasma samples of NSCLC patients compared with those of healthy controls (P = 0.007, P = 0.003, and P = 0.000, respectively). The expression levels of miR-148a, miR-148b, and miR-152 in the late-stage NSCLC group were all lower than the early-stage NSCLC group (all P < 0.05). CONCLUSIONS: The present study suggests that the expression levels of miR-148/152 family in plasma might be useful biomarkers for NSCLC patients samples in the early diagnosis of NSCLC and monitoring of tumour development. PMID- 27461631 TI - Meta-analysis of the relationship between microRNA-499 rs3746444 polymorphism and hepatocellular carcinoma risk in Asians. AB - OBJECTIVE: Numerous studies have reported the role of microRNA-499 rs3746444 polymorphism with hepatocellular carcinoma. (HCC) risk in Asians, but the specific association is still controversial. MATERIALS AND METHODS: To derive a more precise estimation of the relationship, a meta-analysis was performed. An electronic search of PubMed database was conducted to select relevant studies. Odds ratios. (ORs) with 95% confidence intervals. (CIs) were estimated to assess the relationship between microRNA-499 rs3746444 polymorphism and HCC risk in Asians. RESULTS: Eight relevant studies including 2196 cases and 2701 controls were included in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, no significant association of HCC risk with microRNA-499 rs3746444 polymorphism was found in Asians (TT vs. CC: OR = 1.00 95% CI = 0.54 1.83; TT vs. TC: OR = 0.89, 95% CI = 0.66-1.20; dominant model: OR = 1.13, 95% CI = 0.81-1.58; recessive model: OR = 0.99, 95% CI = 0.56-1.76). CONCLUSION: This meta-analysis suggests that the microRNA-499 rs3746444 polymorphism is not contributed to the risk of HCC in Asians. However, more studies should be performed in the future to confirm this association. PMID- 27461632 TI - Diagnostic accuracy of endoscopic brush cytology in malignancies of upper gastrointestinal tract: A prospective study of 251 patients in North India. AB - AIM: To find the spectrum and frequency of upper gastrointestinal malignancies and diagnostic accuracy of endoscopic brush cytology in their diagnosis. MATERIALS AND METHODS: This study was a prospective study carried out on 251 patients over 1-year in the Department of Pathology. Brushing material was smeared directly on to at least two clean glass slides and was stained with May Grunwald-Giemsa stain. The endoscopic biopsies were examined grossly and were fixed in 10% formalin, processed, and stained with hematoxylin and eosin stain. OBSERVATION AND RESULTS: The age range of the patients varied from 8 to 90 years, with the mean being 56 years. Male to female ratio was 2.5:1. On brush cytology, out of 251 cases, 110 had benign lesions and 97 had malignant lesions. Forty-four samples were considered suspicious of malignancy. On histopathology, benign lesions were present in 105 patients while malignant lesions were seen in 139 patients. In seven cases, results were inconclusive due to inadequate/superficial biopsy. STATISTICAL ANALYSIS: Statistical analysis revealed the overall sensitivity of upper gastrointestinal brush cytology as 83.45% and specificity 80.95%. The accuracy of brush cytology came out to be 82.37% in upper gastrointestinal tract. CONCLUSION: Brush cytology is a reliable, safe, inexpensive, and rapid method of diagnosing upper gastrointestinal lesions. Although endoscopic biopsies are established gold standard for diagnosing gastrointestinal malignancy, use of both biopsy and brushing together increases the diagnostic accuracy. PMID- 27461633 TI - Trismus in head and neck cancer patients treated by telecobalt and effect of early rehabilitation measures. AB - CONTEXT: Trismus is one of the common late side effects of radiotherapy (RT) of head and neck cancers. It occurs in about 30% of patients treated by telecobalt. It, in turn, leads to significant morbidity, including malnutrition, difficulty in speaking, and compromised oral hygiene with severe psychosocial, and economic impacts. AIMS: To determine the prevalence of trismus and its progression in patients who have received radical concurrent chemoradiation for head and neck cancer by telecobalt at our institution. To note the effect of early rehabilitative measures on the severity of trismus and to assess its impact on the quality of life (QOL). SUBJECTS AND METHODS: A total of 47 evaluable patients of head and neck cancer patients treated by telecobalt with radical intent between January 2012 and December 2013 were analyzed and baseline maximal inter incisal opening (MIO) and MIO at the completion of RT, after 3 months, 6 months, and 1 year, after completion of RT were noted. Grading of trismus was done using Modified Common Toxicity Criteria (CTCAE Version 3.0). QOL assessment was done using European Organization for Research and Treatment of Cancer QLQ-HN35. The time when the rehabilitative measures were started were also noted. STATISTICAL ANALYSIS USED: Chi-square test with Fisher exact probability test and Students t test. RESULTS: Radiation-induced trismus (RIT) was seen in 31.9%, 34.04%, and 38.39% of cases at 3, 6, and 12 months after completion of RT. Grade II and III trismus accounted for 17.02% and 6.38% at the end of 1 year. Patients who started regular rehabilitative exercises soon, after completion of RT had a better mean MIO as compared to those who were not compliant (32 mm vs. 24 mm at 1 year), and there was a trend toward delayed progression in them. Trismus was also seen to adversely affect QOL of the patients. CONCLUSIONS: RIT is a major cause for late morbidity in patients treated with conventional RT leading to poor QOL. Early rehabilitative measures are useful in preventing progression of trismus. PMID- 27461634 TI - Influencing factors and interventional strategies for early enteral nutrition after gastric carcinoma surgery. AB - OBJECTIVE: The aim of this study is to investigate the factors influencing early enteral nutrition (EN) to develop guidelines after gastric carcinoma (GC) surgery, and to propose appropriate interventions. MATERIALS AND METHODS: A total of 118 GC patients have administrated EN 24 h after surgery and were divided into standard-achieving and nonstandard-achieving groups based on meeting 60% of energy needs. The clinical data of these two groups were retrospectively analyzed and compared. RESULTS: The intraoperative blood loss, proportion of those with body mass <=60 kg, and those cases tolerating EN in the standard-achieving group were significantly greater than in the nonstandard-achieving group, and the differences were statistically significant (P < 0.05). Gender, age, operative time, catheter length, American Society of Anesthesiologists risk class, and postoperative exhaust time showed no statistically significant differences (P > 0.05). However, logistic regression analysis revealed that intraoperative blood loss, body mass, and EN tolerance were independent risk factors influencing achievement of standards for early postoperative EN in GC patients (P < 0.05). CONCLUSIONS: Individual differences should be considered when performing EN, and individualized nutritional support should be provided to improve the standard achieving rate. PMID- 27461635 TI - Increased expression of microRNA-301a in nonsmall-cell lung cancer and its clinical significance. AB - AIMS: Recently, accumulating evidence indicates that dysregulation of microRNAs is associated with the initiation and progression of cancer. Oncogenic miR-301a has been reported upregulation and associated with tumorigenesis and progression in various types of cancer. The aim of this study was to investigate the expression of miR-301a in nonsmall-cell lung cancer. (NSCLC), and to assess its association with malignancy, metastasis and prognosis. SUBJECTS AND METHODS: total of 88 NSCLC patients (females = 21 and males = 67), aged 15-81 years were included in the study. miR-301a expression in tumor tissue was estimated by real time quantitative reverse transcription polymerase chain reaction. RESULTS: miR 301a was significantly upregulated in NSCLC tissues compared with their paired adjacent nontumor tissues. (P < 0.001). Increased expression of miR-301a was detected in tumors with lymph node metastases. (P =0.003). In addition, high miR 301a expression was significantly associated with poorly differentiation. (P =0.015), lymph node metastasis. (P =0.013) and advanced tumor-node-metastasis. (TNM) stage. (P =0.018). A. comparison of survival curves of low versus high expressers of miR-301a revealed a highly significant difference in NSCLC, which suggests that overexpression of miR-301a is associated with a poorer disease-free survival (DFS) (P =0.002). Moreover, multivariate Cox proportional hazard regression analyses revealed that the miR-301a overexpression was an unfavorable prognostic factor for disease-free survival in addition to TNM stage. CONCLUSIONS: miR-301a may represent a novel prognostic indicator, a biomarker for the early detection of lymph node metastasis and a therapeutic target in NSCLC. PMID- 27461636 TI - rs61764370 polymorphism of Kras and risk of cancer in Caucasian population: A meta-analysis. AB - BACKGROUND: Kras is an important oncogene that plays a pivotal role in carcinogenesis. Rs61764370 polymorphism in Kras 3'-untranslated region is a candidate factor for contributing susceptibility to cancer. However, the results of emerging studies concerning association between rs61764370 and cancer risk remain elusive. MATERIALS AND METHODS: The association between rs61764370 and risk of cancer was evaluated in 30 studies including 14936. cases and 15168 controls. RESULTS: Meta-analysis result showed that genotype. GT/GG of rs61764370 was not associated with cancer in Caucasian population. After stratifying the overall population into cancer type subgroups, no significant association was observed between genotype. GT/GG and ovarian, breast, colorectal, non.-small cell lung cancer or head-neck carcinoma in Caucasian population, respectively. CONCLUSION: These results indicated that genotype. GT/GG of rs61764370 was not a genetic susceptible risk factor for cancer, and rs61764370 could not be used as a biomarker for estimating cancer risk in Caucasian population. PMID- 27461637 TI - Quantification of oral palatine Langerhans cells in HIV/AIDS associated oral Kaposi sarcoma with and without oral candidiasis. AB - CONTEXT: Langerhans cells (LCs) are effective antigen-presenting cells that function as "custodians" of mucosa, modifying the immune system to pathogen entry, and tolerance to self-antigen and commensal microbes. A reduction in number of LCs in human immunodeficiency virus (HIV)-positive individuals may predispose to local mucosal infections. AIMS: To quantitatively determine the number of oral mucosal LCs in HIV/acquired immunodeficiency syndrome HIV/acquired immunodeficiency syndrome (AIDS) associated oral Kaposi sarcoma (KS) with/without oral candidiasis (OC) and to define in situ interrelationships between the cells, OC, and HIV infection. MATERIALS AND METHODS: Thirty-two periodic acid-Schiff. (PAS) stained histologic sections of palatal HIV/AIDS associated KS with intact oral epithelium were examined for Candida and divided into two groups: . (1) KS coinfected with Candida and. (2) KS noninfected with Candida. Sections were immunohistochemically stained with CD1a. The standard length of surface epithelium was measured and number of positively stained LCs counted per unit length. Control cases included non-Candida infected palatal mucosa overlying pleomorphic adenoma. (PA) and oral mucosa infected with Candida in otherwise healthy individuals. RESULTS: LC number per unit length of surface epithelium was statistically significantly greatest in uninfected PA mucosa and lowest in KS coinfected with Candida (P = 0.0001). A statistically significant difference was also noted between uninfected PA mucosa and non-Candida infected KS (P = 0.0014), in KS coinfected with Candida and non-infected KS (P = 0.0035), between OC and PA (P = 0.0001), and OC and KS coinfected with Candida (P = 0.0247). CONCLUSION: LC numbers are significantly reduced in oral tissues of HIV/AIDS infected patients by Candida infection when compared to oral tissues without. PMID- 27461638 TI - GSTM1 null genotype and susceptibility to cervical cancer in the Chinese population: An updated meta-analysis. AB - AIM OF STUDY: To clarify the effects of glutathione S-transferases mu-1. (GSTM1) null genotype on the risk of CC, an updated meta-analysis. was performed in Chinese populations. MATERIALS AND METHODS: An extensive literature search for relevant studies was conducted on Pub Med, Springer Link, Ovid SP, Chinese Biomedical (CBM), Chinese National Knowledge Infrastructure (CNKI), VIP, and Wan fang Database from their inception through 22 October, 2014. This meta-analysis was performed using the STATA 10.0 software. The crude odds ratio (OR) with 95% confidence interval (CI) was calculated. RESULTS: A total of four studies including 364 cervical cancer cases and 378 controls were involved in this meta analysis. Overall, significant association was found between GSTM1 null genotype and CC risk when all studies in the Chinese population pooled into the meta- analysis. In subgroup analyses stratified by geographical location, ethnicity, and source of controls; the same results were observed. CONCLUSION: This meta analysis provides the evidence that GSTM1 null genotype may contribute to the CC development in Chinese and studies with large sample size and wider spectrum of population are warranted to verify this finding. PMID- 27461639 TI - Relation between kidney cancer and Soil leads in Isfahan Province, Iran between 2007 and 2009. AB - INTRODUCTION: The present study sets out to investigate the correlation between kidney cancer and the concentration of lead in Isfahan Province, Iran. All cases of kidney cancer recorded between 2007 and 2009 were utilized. In order to calculate the lead concentrations associated with the poll frequency of kidney cancer, the concentrations of lead in province (case study) were examined. MATERIALS AND METHODS: In this study, the first challenge was to collect some relevant information. In this connection, the authors managed to gain access to data concerning kidney cancer in Isfahan province. The data, which had been collected by Isfahan Province Health Centre, provided information from 2007-2009. Besides, Map of Lead Distribution in soil, which had been drawn by the Mineral Exploration Organization. Using GIS (Geographic Information System Software such Arc Gis), the researchers drew the map of the spatial distribution of kidney cancer in the province. In this research, we applied target detection algorithms on MODIS images to detect leads contamination in soil. RESULTS: The results indicated a significantly positive correlation approximately 88% between kidney cancer and the distribution of lead in soil. CONCLUSIONS: The findings of the current study emphasized not only the importance of preventing exposure to lead but also the importance of controlling lead-producing industries. PMID- 27461640 TI - Systemic lupus erythematous increased lung cancer risk: Evidence from a meta analysis. AB - AIMS: Several studies suggested that systemic lupus erythematosus (SLE) were associated with the risk of lung cancer. However, other studies did not confirm the result. Therefore, we conducted a meta-analysis to investigate this association. MATERIALS AND METHODS: A systematic literature search was conducted using the PubMed, Cochrane Library, EMBASE, Chinese National Knowledge Infrastructure, and WANFANG databases for relevant published articles. The strength of the associations between SLE and lung cancer risk was measured by odds ratio (ORs) and 95% confidence interval (CIs). RESULTS: All 12 studies, involving a total of 57,890 SLE patients were included in the meta-analysis. A statistically significant association between SLE and lung cancer risk was found. The data showed that SLE patients had an increased lung cancer risk (OR = 1.60; 95% CI: 1.44-1.77; P < 0.00001). In the subgroup analysis of study design, population and hospital based studies also showed an increased lung cancer risks (OR = 1.68; 95% CI: 1.49-1.89; P < 0.00001; OR = 1.38; 95% CI: 1.12-1.69; P = 0.002). In the subgroup analysis of follow-up duration, significant results were observed in the study with more than 10 years (OR = 1.72; 95% CI: 1.08-2.73; P = 0.02) and < 10 years (OR = 1.59; 95% CI: 1.43-1.77; P < 0.00001), respectively. In addition, studies with large and small sample size also showed an increased lung cancer risk (OR = 1.58; 95% CI: 1.42-1.76; P < 0.00001; OR = 1.76; 95% CI: 1.16-2.67; P = 0.007). CONCLUSION: This meta-analysis suggested that SLE was associated with an increased lung cancer risk. PMID- 27461641 TI - Investigation of simvastatin-induced apoptosis and cell cycle arrest in cancer stem cells of MCF-7. AB - CONTEXT: Recent studies have shown the association between statins use and cancer risk reduction. Furthermore the importance of cancer stem cells (CSCs) in tumor initiation, progression and migration has been firmly established in a variety of solid tumors. Hence, the effective targeting of breast CSCs has a potential to improve cancer treatment outcome significantly. AIMS: This study has been designed to investigation the anticancer effects of simvastatin on breast CSCs. SETTINGS AND DESIGN: In this study, MCF-7 CSCs were isolated from parent cells and cytotoxic effects of simvastatin were evaluated and compared in both cells. SUBJECTS AND METHODS: Stem cell isolation was done by flow cytometry technique and the effects of simvastatin on the stem cell viability, apoptosis and cell cycle were evaluated and compared with parent cells. STATISTICAL ANALYSIS USED: The results were analyzed using one.way ANOVA, followed by Tukey.Kramer posttest. The P < 0.05 was considered as significant. RESULTS: Based on the result, simvastatin shows dose-dependent cytotoxic effects on both CSCs and parent MCF-7 cells, whereas the apoptosis induction and the elimination of nonapoptotic programmed death were increased in CSC compared with parent cells. In addition, simvastatin showed the reduction in DNA synthesis and induced cell cycle arrest in the G1 phase in MCF-7 CSCs. CONCLUSIONS: This finding indicates that simvastatin with specific apoptotic effect on MCF-7 CSC may provide supporting reasons for future in vivo and in vitro statin trials. PMID- 27461642 TI - Association of GSTM1 and GSTT1 deletion with lung cancer development in Pakistani population. AB - AIM: Lung cancer has increased rapidly in the past few decades. Environmental and genetic factors are contributing toward its incidence. Several studies have been reported with conflicting results regarding polymorphism of GSTM1 and GSTT1 genes and their contribution in development of lung cancer. It has been observed that these genetic polymorphisms show geographical variations. Therefore, we conducted a case control study to find the association of various environmental factors as well as GSTM1 and GSTT1 deletion with susceptibility of lung cancer. PATIENTS AND METHODS: DNA of pathologically confirmed lung cancer patients and cancer-free controls were amplified using multiplex PCR to check the deletion of GSTM1 and GSTT1 genes. RESULTS: Demographic factors like age, gender, smoking, passive smoking, smoking duration, smoking dose and other addictions were found to be significantly related (P = 0.05) with incidence of lung cancer. Deletion of GSTM1 and GSTT1 showed non--significant results (P = 0.05) when comparing with development of lung cancer. CONCLUSION: Results revealed that certain environmental factors may be considered as a risk factor but deletion of GSTM1 and GSTT1 are not associated with the development of lung cancer; however, studies including >500 patient samples is suggested. PMID- 27461643 TI - Injectable Chinese herbal formula Kang'ai for nonsmall cell lung cancer: Trial sequential analysis of 2,259 participants from 31 randomized controlled trials. AB - OBJECTIVE: The aim was to evaluate the efficacy and safety of Kang' ai (KA) injection for patients with nonsmall cell lung cancer (NSCLC). Furthermore, to identify if more trials are needed before reliable conclusions could be drawn with regard to these outcomes. MATERIALS AND METHODS: We searched the Cochrane library, PubMed, EMBASE, VIP, CBMdisc, and CNKI in September 2012, and then an additional updated search was conducted in January 2013. Only relevant randomized controlled trials (RCTs) on KA injection plus first-line cisplatin-based chemotherapy in the treatment of NSCLC were identified. Trials' data was reviewed and extracted by two reviewers independently. The quality of included studies was assessed according to a statement from Cochrane Handbook. RevMan 5 Software and Trial sequential analysis (TSA) software were applied for data analyses. RESULTS: A total of 31 RCTs involving 2259 patients were included. The results of meta analysis showed that compared with chemotherapy alone, the combination of KA injection plus chemotherapy had a statistically significant benefit in improving clinical response rate (relative risk [RR] =1.29, 95% confidence interval [CI]: 1.17-1.41, P < 0.00001), clinical benefit rate (RR = 1.19, 95% CI: 1.14-1.25, P < 0.00001) and quality of life (RR = 1.79, 95% CI: 1.63-1.98, P < 0.00001); hematological toxicity (white blood cell) (RR = 0.71, 95% CI: 0.66-0.76, P < 0.00001) and nonhematological toxicity (nausea and vomiting) (RR = 0.73, 95% CI: 0.65-0.83, P < 0.00001) were improved as well. TSA showed that all cumulative Z score crossed their monitoring boundaries, demonstrating that no more trials are needed before reliable conclusions could be drawn. CONCLUSION: Current evidence presented that KA injection might improve the therapeutic effect when combined with chemotherapy. Moreover, no more trials are needed in future according to TSA. Nevertheless, additional randomized studies investigating KA injection are needed to be further evaluated. PMID- 27461644 TI - Apparent diffusion coefficient value of diffusion-weighted imaging for differential diagnosis of ductal carcinoma in situ and infiltrating ductal carcinoma. AB - PURPOSE: The present meta-analysis investigated the clinical value of apparent diffusion coefficient (ADC) values in diffusion-weighted imaging (DWI) for differential diagnosis of ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC). MATERIALS AND METHODS: Electronic databases searches were employed to identify relevant scientific literature, and the search results were screened to selected high-quality studies for this meta-analysis. Methodological quality of the enrolled studies was evaluated by quality evaluation of diagnostic accuracy studies (QUADAS). Summary odds ratios (ORs) and its corresponding 95% confidence interval (95% CI) were calculated for DCIS versus IDC category of ADC value using Z test. RESULTS: Our meta-analysis contained a combined total of 1,097 subjects (928 patients with IDC and 169 patients with DCIS) from 9 relevant high-quality cohort studies. Pooled ORs demonstrated that ADC value in IDC patients was significantly lower than DCIS patients. Subgroup analysis stratified by ethnicity indicated a higher ADC value in DCIS patients compared to IDC, in Asian population, but not in Caucasians. Magnetic resonance imaging (MRI) machine type-stratified analysis revealed that the ADC value of DWI obtained from both non- General Electric Company (GE) 1.5T and GE 1.5T machines were highly reliable in the differential diagnosis of DCIS and IDC. CONCLUSION: Our meta-analysis provides evidence that ADC values in DWI accurately conveys the differences in tumor architecture between IDC and DCIS, which has high clinical value in differentiatal diagnosis of IDC and DCIS. This may lead to improved BC prediction and treatment. PMID- 27461645 TI - A clinicoepidemiological study of young age bladder tumors: An eastern Indian scenario. AB - INTRODUCTION: Though, bladder cancer is one of the most common urological malignancies, studies addressing the young age group bladder tumors are rare. Present study was done to determine the clinicoepidemiological aspects of bladder tumor diagnosed in young age patients and to compare these aspects with elderly patients. PATIENTS AND METHODS: Patients with urinary bladder tumor were selectively divided into two groups; young (<40 years) and elderly (>60 years). Groups were compared on various parameters and statistically analyzed using Fisher's exact two-tailed test. RESULTS: Smoking, tea and coffee intake and exposure of dye were found significantly associated with development of bladder tumor. Most of the tumors in young age were small, solitary, and papillomatous. Transitional cell carcinoma (TCC) was the most common histological subtype, though most were of low grade and were non-muscle invasive in comparison to the tumors in elderly group. CONCLUSION: The incidence of bladder cancer is common in younger age group. Active and passive cigarette smoking, tea, coffee intake, and exposure to organic dyes are major risk factor for younger age group bladder tumor in this part of world. TCC is most common histological subtype and most of them are in low grade without muscle invasion. PMID- 27461646 TI - Chemopreventive effect of carvacrol on 1,2-dimethylhydrazine induced experimental colon carcinogenesis. AB - PURPOSE: Colorectal cancer (CRC) is a leading cause for cancer-related death and its prevention is of great importance throughout the world. Chemoprevention offers a novel approach to control the incidence of colon cancer. The present study was performed to evaluate the efficacy of carvacrol supplementation on colonic aberrant crypt foci (ACF), lipid peroxidation, and antioxidant defense system in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. MATERIALS AND METHODS: The rats were randomly divided into six groups. Group 1, control rats received modified pellet diet; Group 2 rats received modified pellet diet along with carvacrol (80 mg/kg b.wt/day); Groups 3-6 received subcutaneous injection of DMH (20 mg/kg b.wt), once a week for the first 4 weeks; in addition Groups 4-6 received carvacrol at three different doses of 20, 40, and 80 mg/kg b.wt/day for 16 weeks. RESULTS: Our result suggest that increased tumor incidence and increased number of ACF, increased bacterial enzymes accompanied by a decrease in the colonic lipid peroxidation, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities were observed in DMH-treated rats. Administration of carvacrol to DMH-treated rats significantly decreased the tumor incidence and the number of ACF and bacterial enzymes with enhancement of colonic lipid peroxidation, GPx, SOD, and CAT activities. CONCLUSION: The results of this study suggest that carvacrol at a dose of 40 mg/kg b.wt showed a significant beneficial effect against chemically induced colon carcinogenesis in rats. PMID- 27461647 TI - An analysis of autopsy cases of non-Hodgkin lymphoma-with special reference to those masquerading as acute febrile illness. AB - CONTEXT: As in any medical disorder, in non-Hodgkin lymphomas (NHLs) also, precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality. AIMS: The aim of this study was to review the clinical presentation, mode of death and the immunophenotype of the autopsy cases of NHL. SETTINGS AND DESIGN: Autopsy cases wherein NHL was diagnosed, were selected for study. SUBJECTS AND METHODS: Autopsy cases which were diagnosed as NHL, either antemortem or after autopsy during a 7 years period at a tertiary care referral centre were studied and reviewed. STATISTICAL ANALYSIS USED: Descriptive statistical analysis used. RESULTS: The autopsy findings seen in eight cases of NHL were reviewed. Except one, all cases were above 40 years age. Infective etiology (62%) followed by cardiorespiratory failure (38%) was the cause of death observed in these patients. In three cases, the antemortem diagnosis of NHL was missed as the patients were being treated for acute febrile illness and were referred late to the Tertiary Care Centre. One of these was a case of extra-nodal primary splenic lymphoma. CONCLUSION: As NHL present with nonspecific symptoms, these tumours may not be detected in early stages and hence may not be treated appropriately. These patients have weakened immunity and hence are prone to infection and sepsis which can be a major cause of mortality. This autopsy study experience has shown that NHL can masquerade as acute febrile illness which if not detected early and treated adequately can turn fatal. PMID- 27461648 TI - Missed opportunities for breast awareness information among women attending the maternal and child health services of an urban tertiary hospital in Northern Nigeria. AB - BACKGROUND: Breast cancer is the most common cancer that affects women worldwide. Many women, however, are not exposed to information that will promote awareness and early detection of this disease. We undertook this study to determine the missed opportunities to breast awareness information at the maternal and child health (MCH) services of our hospital. MATERIALS AND METHODS: Between July and September 2011, we conducted a cross-sectional survey of women attending the postnatal and immunization clinics (ICs) of our hospital. Data were collected using a structured interviewer-administered questionnaire. A total of 492 respondents were randomly selected. Data were analyzed using SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: The mean age of the respondents was 27.67 years (standard deviation 5.92 years). Only 56.1% (276/492) had a postsecondary education, and 58.7% (289/492) were multiparous. Among the respondents, 81.7% had been exposed to breast awareness information at the antenatal clinic, 6.55% at the postnatal clinic, and 5.24% at the IC. There was a statistically significant association (P < 0.05) between missed opportunity for breast awareness information and family income (P = 0.019) and also with the level of education (P = 0.007). CONCLUSION: Most of the opportunities to educate women on breast awareness were missed at the postnatal and ICs of our hospital. Integrating breast health education into MCH care programs in developing countries will assist in the early detection of breast pathologies. PMID- 27461649 TI - Whole brain radiotherapy and stereotactic radiosurgery for patients with recursive partitioning analysis I and lesions <5 cm(3): A matched pair analysis. AB - OBJECTIVE: The intention of this study is to compare whole brain radiotherapy and stereotactic radiosurgery (WBRT + SRS) with WBRT in patients with 1-4 brain metastases to find a subgroup of patients that have a great benefit with aggressive treatment. MATERIALS AND METHODS: Between December 2002 and December 2013, 60 patients with 1-4 brain metastases were treated by WBRT + SRS. In this period, 60 patients treated with WBRT were matched with patients treated with WBRT + SRS. RESULTS: The median survival for the entire cohort was 8.3 months. In the univariate analysis, WBRT + SRS (0.031), the presence of extracranial disease (P = 0.02), Karnofsky performance score <70 (P = 0.0001), and age >65 (P = 0.001) years were significant factors for survival. In the entire cohort, the median survival for recursive partitioning analysis (RPA) classes I, II, and III was 11, 7, and 3 months, respectively (P = 0.0001). In a stratified analysis, only RPA class I achieved statistical significance for 1-year survival between the groups (WBRT + SRS = 51% and WBRT = 23%, P = 0.03). Cox regression analysis revealed WBRT + SRS, age >65 years, and extracranial disease as independent prognostic factors. In the univariate analysis, lesion volume <=5 cm 3 (P = 0.002) and WBRT + SRS (P = 0.003) were the significant factors associated with better brain control. CONCLUSION: WBRT plus SRS was an independent prognostic factor for survival. However, the combined treatment appears to be justified only in patients with RPA I and lesion volume <=5 cm 3, independently of the number of lesions. PMID- 27461650 TI - Incidence and risk of hypertension associated with ramucirumab in cancer patients: A systematic review and meta-analysis. AB - BACKGROUND: Ramucirumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has been approved for the treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma. Hypertension has been described as a common adverse event with ramucirumab, but the incidence and risk have not been well determined. We conduct this meta-analysis to investigate the overall incidence and risk of developing hypertension associated with use of ramucirumab. MATERIALS AND METHODS: Databases from PubMed, Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) meeting up to May 31, 2014, were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating ramucirumab in cancer patients with adequate data on hypertension. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% confidence intervals (CIs) by using either random--effect or fixed--effect models according to the heterogeneity of included studies. RESULTS: A total of 2,649 patients with a variety of solid tumors from eight prospective clinical trials were included in our analysis. The incidence of all--grade and high-grade hypertension associated with ramucirumab was 16.4% (95%CI: 11.9-22.3%) and 9.8% (95%CI: 7.2-13.0%), respectively. Patients treated with ramucirumab had a significantly increased risk of developing all-grade (RR: 2.28, 95%CI: 1.61-3.24, P < 0.001) and high grade (RR: 3.59, 95%CI: 2.32-5.53, P < 0.001) hypertension compared with patients treated with control medication. No evidence of publication bias was observed. CONCLUSIONS: The use of ramucirumab is associated with a significantly increased risk of developing hypertension when compared with controls. Close monitoring and appropriate managements are recommended during the therapy. PMID- 27461651 TI - DPYD*2A/*5A/*9A and UGT1A1*6/*28 polymorphisms in Chinese colorectal cancer patients. AB - AIM OF STUDY: Fluorouracil drugs and irinotecan are commonly used in the treatment of colorectal cancer (CRC), but some patients have severe toxic side effects in the conventional dose. DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 polymorphisms are related to the toxicity of fluorouracil drugs and irinotecan, respectively. Herein, we investigated the frequencies of DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 genotypes in Chinese CRC patients. MATERIALS AND METHODS: For this study, 117 CRC patients' tumor tissues were examined through sequencing technology of the first generation to explore the distribution of DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 genotypes. RESULTS: DPYD*2A G/G genotype accounted for 100%. DPYD*5A A/A, A/G, and G/G genotypes accounted for 48.2, 37.5, and 14.3%, respectively. DPYD*9A T/T and T/C genotypes accounted for 85.7 and 14.3%, respectively. UGT1A1 * 6 G/G, G/A, and A/A genotypes accounted for 74.6, 21.8, and 3.6%, respectively. UGT1A1 * 28 TA6/TA6, TA6/TA7, and TA7/TA7 genotypes accounted for 71.8, 27.3, and 0.9%, respectively. The genotypes of DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 were not associated with patient's sex, age, and primary tumor sites. Our findings showed that: (i) almost 57.1% of Chinese CRC patients had at least one variant of DPYD*5A and DPYD*9A; (ii) nearly 37.3% of Chinese CRC patients had at least one variant of UGT1A1 * 6 and UGT1A1 * 28. CONCLUSION: It suggests that it is necessary for Chinese CRC patients to detect the genotypes of DPYD*5A/*9A and UGT1A1 * 6/*28 before treating with fluorouracil drugs and irinotecan. PMID- 27461652 TI - CADBOSS: A computer-aided diagnosis system for whole-body bone scintigraphy scans. AB - AIMS: The aim of this study is to develop a computer-aided diagnosis system for bone scintigraphy scans. (CADBOSS). CADBOSS can detect metastases with a high success rates. The primary purpose of CADBOSS is as supplementary software to facilitate physician's decision making. MATERIALS AND METHODS: CADBOSS consists of various elements, such as hotspot segmentation, feature extraction/selection and classification. A level set active contour segmentation algorithm was used for the detection of hotspots. Moreover, a novel image gridding method was proposed for feature extraction of metastatic regions. An artificial neural network classifier was used to determine whether metastases were present. Performance evaluation of CADBOSS was performed with the help of an image database which included 130 images. (30 non-metastases and 100 metastases) collected from 60 volunteers. All images were obtained within approximately 3 hours after injecting a small amount of radioactive material 99mTc-MDP into the patients and then carrying out scanning with a gamma camera. The 10-fold cross validation technique was used for all tests. RESULTS: CADBOSS could correctly identify in 120 out of 130 images. Thus, the accuracy, sensitivity, and specificity of CADBOSS were 92.30%, 94%, and 86.67%, respectively. Moreover, CADBOSS increased physician's success in detecting metastases from 95.38% to 96.9%. CONCLUSIONS: Detailed experiments showed that CADBOSS outperforms state-of the-art computer-aided diagnosis. (CAD) systems and reasonably improves physician' diagnostic success. PMID- 27461653 TI - Immunohistochemical expression of chemokine receptor CXCR3 and its ligand CXCL10 in low-grade astrocytomas and glioblastoma multiforme: A tissue microarray-based comparison. AB - Glioblastoma multiforme (GBM) and diffuse astrocytoma (DA) are the most frequently encountered gliomas. Due to poor prognosis and limited success of the currently available treatment modalities there is a need to identify new therapeutic targets. Chemokines (CKs) regulate cellular functions like chemotaxis, angiogenesis, apoptosis, and cell cycle progression that play role in tumor growth. OBJECTIVE: To study comparative immunoexpression of CXCR3 and CXCL10 in DA and GBM using a high-throughput tissue microarray (TMA). MATERIALS AND METHODS: A TMA of 1.0 mm core diameter was made from formalin-fixed, paraffin embedded donor blocks of 25 pilocytic astrocytomas (PA), 45 DA, and 75 GBM. Immunohistochemical staining for CXCR3 and CXCL10 was performed. RESULTS: Out of 145, 129 cores were suitable for immunohistochemical evaluation after processing and immunohistochemistry. Strong CXCR3 immunoexpression was observed in 72.7% cases of GBM as compared to 31.8% cases of DA. 50.7% of GBM and 24.5% of DA showed strong immunoexpression of CXCL10. Overall comparisons between DA and GBM for CXCR3 and CXCL10 showed statistically significant correlation between the two with P < 0.001 and P = 0.02, respectively. A positive correlation was observed between CXCR3 and MIB-1. Pearson's correlation coefficient r = 0.548 and 0.330 for DA and GBM, respectively with P < 0.01. CONCLUSION: GBM shows overexpression of CXCR3 and CXCL10 in comparison to DA, indicating that they play an important role in tumor growth and progression. Inhibition of this receptor-ligand axis may be a potential therapeutic target for arresting tumor growth and development of a glioblastoma. PMID- 27461654 TI - Treatment of undifferentiated colorectal cancer cells with fish-oil derived docosahexaenoic acid triggers caspase-3 activation and apoptosis. AB - BACKGROUND: The effectiveness of chemotherapy is often limited by the side effects on normal tissues. Consequently, the search for new therapeutic agents with minimal toxicity is of particular interest in cancer management. Many studies have shown that docosahexaenoic acid (DHA) have cytotoxic effects against different kinds of cancer cells. However, little attention has been paid to explore the effect of DHA on undifferentiated colorectal cancer cells. In this study, the effects of DHA on LS174T cells as an early stage of tumor initiation were investigated. MATERIALS AND METHODS: Tumor cells were treated to various concentrations of DHA and proliferation, survivin expression, caspase-3 activation, and apoptosis were evaluated by different cellular and molecular techniques. RESULTS: Following 48 h treatment, proliferation was measured to be 73 +/- 4.5% (P = 0.000), 53 +/- 5.7% (P = 0.000) and 26.3 +/- 3.5% (P = 0.000) for 50, 100, and 150 uM DHA, respectively compared to untreated cells. This molecule induced 63% (P = 0.001) and 46% (P = 0.000) decrease in survivin messenger ribonucleic acid (mRNA) level as well as 1.8 (P = 0.001) and three-fold (P = 0.000) increase in caspase-3 activation for 50 and 100 uM DHA, respectively compared to untreated cells. Our evidence showed that survivin mRNA is expressed at the early stage of colorectal cancer cells and DHA-treated cells expressed markedly a lower survivin mRNA compared to untreated cells. CONCLUSIONS: DHA is an attractive repressor of survivin expression, increases caspase-3 and apoptosis in colorectal cancer cells and may provide a novel approach to the treatment of colorectal cancer at the early stage of tumor initiation. PMID- 27461655 TI - Retroperitoneoscopic versus open surgical radical nephrectomy for 152 Chinese patients with large renal cell carcinoma in clinical stage cT2 or cT3a: A long term retrospective comparison. AB - INTRODUCTION: To evaluate the feasibility, safety, and long-term efficacy of retroperitoneal laparoscopic radical nephrectomy for Chinese patients with a mean body mass index (BMI) of <=24 and large renal cell carcinoma (RCC). MATERIALS AND METHODS: A long-term retrospective analysis of clinical data of 152 Chinese patients with a mean BMI of <=24 and large RCC. Totally, 84 patients who underwent retroperitoneal laparoscopic radical nephrectomy (RPNx) for tumor size >7 cm (group 1) were compared with 68 patients, who underwent open radical nephrectomy (group 2) for tumor with similar size characteristics. Moreover, their 10 years outcomes (or the number of patients) were divided into segments (e.g., the first 5 and last 5 years, the first 30 and last 30 patients, etc.) looking for the differences of learning curve. RESULTS: RPNx patients experienced significantly shorter hospital stay, less blood loss, and had a decreased analgesic requirement and more rapid convalescence. The incidence of intra- and post-operative complications was 6% and 13%, 7.2% and 16.1% in the two groups, respectively. The 5-year survival rates of the two groups were 86% and 82%, respectively. CONCLUSION: Retroperitoneal laparoscopic radical nephrectomy for patients with a mean BMI of <=24 and large RCC is safe, feasible, and the efficacious procedure produced good long-term results. PMID- 27461656 TI - Flavopiridol's antiproliferative effects in glioblastoma multiforme. AB - AIM OF STUDY: Glioblastoma multiforme (GBM) is largely refractory to surgical operation, radiotherapy, and chemotherapy in use today. Remaining lifetime accounting for the GBM-affected patients varies between 12 and 16 months generally. The most frequently altered genes in GBM are p53, epidermal growth factor receptor, PTEN, and cyclin-dependent kinase inhibitor 2A. Our aim is to investigate the antiproliferative and apoptotic effects of flavopiridol, a cyclin dependent kinases and specific phosphokinase inhibitor, on glioblastoma cell lines having different genetic profiles: U87MG, U118MG, and T98G. MATERIALS AND METHODS: Cell viability and IC50 values were detected by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay, protein expressions were determined by Western blot and caspase activities were analyzed by activity kit. RESULTS: Western blot analysis showed down-regulation of the cyclin D1, c-Myc, and p53 protein activities, and up-regulation of p27KIP1 activity after flavopiridol treatment. Additionally, flavopiridol diminished p-Akt protein levels generally which induces inhibition of proliferation. CONCLUSION: The present study demonstrated that flavopiridol did not induce caspase-3/7 activation, BIM, and BAX pro-apoptotic proteins but it leads to the expression changes of various proteins that inhibit proliferation and eternity in glioblastoma cell lines which have different genetic alterations. PMID- 27461658 TI - Measurement of in-phantom neutron flux and gamma dose in Tehran research reactor boron neutron capture therapy beam line. AB - AIM: Determination of in-phantom quality factors of Tehran research reactor (TRR) boron neutron capture therapy (BNCT) beam. MATERIALS AND METHODS: The doses from thermal neutron reactions with 14N and 10B are calculated by kinetic energy released per unit mass approach, after measuring thermal neutron flux using neutron activation technique. Gamma dose is measured using TLD-700 dosimeter. RESULTS: Different dose components have been measured in a head phantom which has been designed and constructed for BNCT purpose in TRR. Different in-phantom beam quality factors have also been determined. CONCLUSIONS: This study demonstrates that the TRR BNCT beam line has potential for treatment of superficial tumors. PMID- 27461657 TI - Classifying prostate cancer patients based on total prostate-specific antigen and free prostate-specific antigen features by support vector machine. AB - AIMS OF STUDY: In this work, we enhanced the role of prostate-specific antigen (PSA) test by examining the relation between free PSA (fPSA) and total PSA (tPSA) value and other biological information such as age and volume of prostate. Our primary goal is to find an approach that improves the sensitivity but still give a reasonable specificity. SUBJECTS AND METHODS: We proposed a new approach to predict the prostate cancer (PCa) based on tPSA, fPSA, age, and prostate volume by using combination of statistical techniques and support vector machine (SVM). Our approach detected PCa based on following two steps: Classifying patients into normal or abnormal group by means of SVM method and then predicting which patients in abnormal group with PCa. RESULTS: The sensitivity of our system was 95.1%, whereas the specificity was acceptable (84.6%). The positive biopsy rate was 58% while the unnecessary biopsy rate was 15.4%. We further developed a program to assist clinicians in predicting PCa. CONCLUSIONS: Applying SVM not only improved the performance of PSA test in screening and detecting PCa but also explored some molecular information. Based on the information, we can discover more knowledge about cancer disease. PMID- 27461659 TI - Treatment of the early-stage glottic cancer using low-temperature radiofrequency coblation. AB - OBJECTIVE: Radiofrequency (RF) coblation operates at low temperatures (40-70 degrees C) and allows for ablation, hemostasis, and aspiration, in addition to the lesion excision; thermal damage to the surrounding tissues is thus minimized. Herein, we evaluated the benefit of low-temperature RF coblation treatment of the early-stage glottic cancer. The main aim of the study was to evaluate the feasibility, complications, and efficacy of low-temperature RF coblation as a treatment modality for the early-stage glottic cancer. MATERIALS AND METHODS: The data obtained from a 1-year study of six T1 glottic cancer patients treated at our department are presented. Six early-stage glottic cancer (Tla = 5; Tlb = 1) patients (male; mean age 60.1 years) treated using low-temperature RF coblation were enrolled in this study. RESULTS: The outcomes of the surgical technique were analyzed. STATISTICAL ANALYSIS USED: Study outcomes were analyzed (noted and/or photographed). All patients were able to eat on the next day after the surgery. No gastric tube or tracheotomy was required. No postoperative cough, discomfort or difficult breathing was noted. No complications, such as recurrence or cervical lymph node metastasis, occurred over the 6-12 months follow-up. All patients regained satisfactory voice 2 months after the surgery. CONCLUSIONS: Although the current probe design has limitations for the resection of certain tumors, low-temperature RF coblation appears to be a potentially effective method for the endoscopic resection of selected glottic cancers. PMID- 27461660 TI - Characterization and localization of c-kit and epidermal growth factor receptor in different patterns of adenoid cystic carcinoma. AB - INTRODUCTION: Adenoid cystic carcinoma (ACC) is malignant neoplasm of the salivary glands. It accounts for most cases of minor salivary gland malignancies and a substantial proportion of parotid and submandibular gland malignancies. ACC is associated with a high mortality rate, and it often recurs after prolonged periods of time, and this occurs even when radical excision has been performed. AIMS: The present study was aimed to determine the localization of dual cell population and to analyze the potency of using a system of dual markers (c-kit and epidermal growth factor receptor [EGFR]) in enhancing the characterization of ACC. SUBJECT AND METHOD: Three micrometer thin sections of adenoid cystic carcinoma were obtained. One set of slides was stained by hematoxylin and eosin for reconfirmation of histological diagnosis while the other two sets were stained for c-kit and EGFR using immunohistochemical method. Statistical Analysis Used and Results: Show c-kit expression to be limited to the inner ductal epithelial cells and the EGFR expression mainly to the outer myoepithelial cells in the majority of tubular and cribriform patterns. In solid ACC, c-kit was uniformly positive while EGFR was consistently negative. CONCLUSIONS: C-kit and EGFR biomarkers can be used to enhance the characterization of ACC and to determine the localization of dual cell population which could suggest the dual origin of ACC and provides evidence for the new therapeutic strategy in ACC. PMID- 27461661 TI - Sentinel lymph node status affects long-term survival in patients with intermediate-thickness melanoma. AB - OBJECTIVE: The aim of this study was to examine the role of sentinel lymph node biopsy (SLNB) on long-term disease outcome in patients with intermediate thickness primary cutaneous melanomas. MATERIALS AND METHODS: Forty patients with intermediate-thickness melanomas, defined as 1.0-4.0 mm, underwent SLNB between 1998 and 2011. The disease-free survival (DFS), overall survival (OS) and prognostic factors were analyzed. RESULTS: Median age was 53 years (range: 24-74 years). Median Breslow thickness was 2.8 mm (range: 1.0-4.0 mm) and 27.5% were ulcerated melanomas. Median follow-up time was 70 months (range: 23-168 months). The number of patients with sentinel lymph node (SLN)-positive was 9 (22.5%) and completion lymph node dissection was performed in all of these patients. Ten patients (25%) developed distant and locoregional recurrence; 4 in the SLN positive group (4/9; 45%) and 6 in the SLN-negative group (6/31; 19%), P < 0.042. In the SLN-negative group, one patient developed regional node recurrence; false negative rate was 10%. SLN positivity and ulceration were independent prognostic factors for DFS in multivariate analysis (hazard ratio [HR] of 4.6, and 10.5, respectively; P < 0.011). For OS SLN positivity, ulceration and Breslow thickness were found to be the significant prognostic factors (HR of 5.4, 8.5 and 5.0, respectively; P < 0.024). Ten-year DFS and OS for SLN-negative and SLN-positive patients were 71%, 47% (P < 0.003), and 80%, 55% (P < 0.005), respectively. CONCLUSION: This study shows that survival rates are worse in the SLN-positive patients according to the long-term follow-up data. Ulceration and Breslow thickness also have significant effects on long-term survival in patients with intermediate-thickness primary cutaneous melanomas. PMID- 27461662 TI - Radiation dose to dysphagia aspiration-related structures and its effect on swallowing: Comparison of three-dimensional conformal radiotherapy and intensity modulated radiation therapy plans. AB - CONTEXT: Radiotherapy techniques have improved over years but have also raised concerns over subsequent acute and late effects. One such complication, dysphagia, has led to much interest and optimization in treatment delivery. AIMS: The aim of this study was to compare radiation dose to dysphagia aspiration related structures (DARS) in intensity modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT), and assess its relation to post treatment swallowing status, in patients of carcinoma of the anterior two thirds of tongue. MATERIALS AND METHODS: Treatment plans of patients treated with IMRT and 3DCRT, from November 2011 to December 2012, were retrieved. Swallowing structures were contoured. Dose volume histograms were generated. Constraint doses were considered based on the statistical derivations. Swallowing status was evaluated based on University of Washington Head- and Neck-related Quality-of Life questions addressing swallowing. STATISTICAL ANALYSIS USED: IBM SPSS Statistics 20 Windows (SPSS Inc., Chicago, IL, USA) was used. Mann-Whitney U test, Spearman's rho correlation coefficient, and receiver operating curves were used. RESULTS: Definitive statistical and subjective correlations were found to exist between doses of swallowing structures, especially the constrictor muscles, the base of the tongue and larynx. Probable mean dose constraints derived statistically clinically corroborates with the swallowing status of patients. IMRT had statistically significant advantage over 3DCRT, in terms of V30 (P - 0.051), V50 (P - 0.002), V60 (P - 0.002), and D80 (P - 0.023) for swallowing structures taken together. CONCLUSION: Our study is probably one of the few studies predicting possible mean dose constraints for superior constrictor, the base of the tongue and larynx. Further prospective studies are required to confirm these and to improve the swallowing quality. PMID- 27461663 TI - Dosimetric comparison of intensity modulated radiosurgery with dynamic conformal arc radiosurgery for small cranial lesions. AB - AIMS: To dosimetrically compare the fixed gantry intensity modulated radiosurgery (IMRS) with dynamic conformal arc radiosurgery (DCARS) for cranial lesions. This study investigates whether IMRS can be an adequate dosimetric alternative to DCARS for cranial stereotactic radiosurgery (SRS). SUBJECTS AND METHODS: Forty five SRS procedures for solitary brain metastasis (range: 0.44-29.18 cm 3) performed at our institution were selected for this study. Two plans were generated per patient: One IMRS plan using a multileaf collimation (MLC) of 5 mm, and one DCARS plan designed with a 3 mm micro-MLC. Dosimetric comparison metrics include the target coverage (Cov), conformity index (CI), homogeneity index (HI), gradient index (GI), and volume of the normal brain tissue receiving >=12 Gy (V12). In addition, maximum doses to organs at risk (OAR) (brainstem, optic apparatus and cochlea) were compared for both techniques. RESULTS: Compared to DCARS, IMRS improved mean CI (IMRS: 0.81 vs. DCARS: 0.63, P < 0.001), with no significant difference in target Cov (IMRS: 0.99 vs. DCARS: 0.99, P > 0.05), HI (IMRS: 1.22 vs. DCARS: 1.24, P > 0.05), GI (IMRS: 5.44 vs. DACRS: 5.44, P > 0.05). A weak significant difference in V12 (IMRS: 4.6 cm 3 vs. 5.2 cm 3, P = 0.033) was obtained. Subgroup analysis per target volume (small: <1 cm 3, intermediate: <=1 cm 3 and <5 cm 3 and large: >=5 cm 3) only revealed the statistically difference for CI metric (P < 0.001). No significant differences were found for maximum dose to the OAR. CONCLUSIONS: We have shown that IMRS provides the dosimetric advantages compared with DCARS. Based on the dosimetric findings in this study, fixed gantry IMRS technique can be adopted as a standard procedure for cranial SRS when micro-MLC technology is not available on the linear accelerator. PMID- 27461664 TI - Radiation dose measurements during kilovoltage-cone beam computed tomography imaging in radiotherapy. AB - OBJECTIVE: The use of image guidance during radiotherapy for accurate localization and setup has become the standard care of practice in radiotherapy. This mostly involves the use of kilovoltage-cone beam computed tomography (kV CBCT) for verification of patient setup on the first few days and on a weekly basis. Some protocols require this to be performed daily and also before and after the treatment. Though the radiation due to this kV-CBCT is small, the repeated use could deliver a dose that could increase the probability of the stochastic effect. The main purpose of this work is to measure radiation dose during image guidance with kV-CBCT. MATERIALS AND METHODS: In this work, we have attempted to measure the dose during kV-CBCT for different sites both on a humanoid phantom and on patients undergoing image-guided radiotherapy with MOSFETs calibrated against an ion chamber. RESULTS: The dose measurement on patients during kV-CBCT resulted in mean doses of 0.19 and 0.3 cGy to the ipsilateral and contralateral eyes, 0.625 and 1.097 cGy to the surface of the ipsilateral and contralateral breasts, and 3.01 cGy to the surface of the pelvis. CONCLUSION: Radiation dose to the eye, breast, and the surface of the pelvis have been arrived at during CBCT. The doses measured on patients agreed closely with those measured on humanoid phantom and with published values. PMID- 27461665 TI - Apparent diffusion coefficient measurements with diffusion-weighted imaging for differential diagnosis of soft-tissue tumor. AB - OBJECTIVES: To evaluate the diagnostic potential of apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI) in distinguishing malignant and benign soft-tissue tumors. MATERIALS AND METHODS: Published studies were retrieved through comprehensive search in various computerized databases. High-quality studies relevant to ADC values of DWI in differential diagnosis of soft-tissue tumors were screened using our stringent inclusion and exclusion criteria for this meta-analysis. The standard mean difference with 95% confidence interval (95% CI) was estimated. Statistical analyses were performed using the STATA statistical software (Stata Co., College Station, TX, USA). RESULTS: Thirteen cohort studies were finally included, and these studies provided the required information on the diagnostic value of diffusion magnetic resonance imaging in soft-tissue tumors. The 13 studies contained a combined total of 344 malignant soft tumors and 315 benign soft tumors. The results of our meta analysis revealed that mean ADC value in patients with malignant soft-tissue tumor decreased significantly in comparison with the ADC values obtained in patients with benign soft-tissue tumor (P < 0.001). Country-stratified analysis suggested that ADC value might play a predictive role in the differential diagnosis of soft-tissue tumors in China (P = 0.007), Egypt (P < 0.001), Germany (P = 0.001), Japan (P = 0.049), and The Netherlands (P < 0.001). CONCLUSION: Our results provide strong evidence that patients diagnosed with malignant soft tissue tumors have low ADC values of DWI compared to those with benign soft tissue tumors. Therefore, ADC measurements with DWI may be reliable in differential diagnosis of soft-tissue tumors. PMID- 27461666 TI - Detection of human papilloma virus in patients with squamous cell carcinoma of the esophagus planned for definitive chemo-radiotherapy, and a study of their clinical characteristics. AB - CONTEXT: To identify the incidence of human papilloma virus (HPV) infection in squamous esophageal cancer. AIMS: To identify high-risk (HR) HPV positivity rates in patients with squamous carcinoma esophagus and to compare their characteristics with HPV negative counterparts. SETTINGS AND DESIGN: A prospective study, in which tumor biopsies of 18 consecutive patients with squamous carcinoma of the esophagus treated with definitive chemo-radiotherapy (CT-RT) were evaluated for the presence of HPV. SUBJECTS AND METHODS: Tumor biopsies of 18 consecutive patients with squamous carcinoma esophagus treated with definitive CT-RT were assessed for presence of HR HPV DNA by hybrid DNA capture technique (Digene-HC2). The clinical characteristics and treatment outcomes of the two groups were then compared. STATISTICAL ANALYSIS USED: Pearson's Chi-squared test, Kaplan-Mier survival curve/log rank test. RESULTS: Nine patients (50%) tested positive for HR HPV. The clinical features including age, gender, grade, location, and tumor extent were similar between the two groups. All the three patients with residual disease at the end of treatment tested positive for HPV (P = 0.058). At a mean follow-up of 52 weeks, the estimated median recurrence free survival was 37 weeks (95% confidence interval (CI): 13.6-60.4) among HPV positive patients compared to 53 weeks (95% CI: 29.6 76.4 weeks) for the HPV negative (P = 0.93). CONCLUSIONS: There appears to be a high incidence of HPV among patients with squamous oesophageal cancer in coastal Karnataka. Further studies are required to evaluate its causative role and prognostic implications. PMID- 27461667 TI - The effect of diabetes with pharmacotherapy for breast cancer on care resource use. AB - INTRODUCTION: The aim of this study was to quantify the effects of diabetes with pharmacotherapy-treated breast cancer on care resource use. MATERIALS AND METHODS: The study was designed as a single institutional retrospective cohort study using hospital administrative data. The subjects were 152 patients admitted to a hospital from 2008 to 2012 diagnosed with breast cancer, and who underwent pharmacotherapy. We identified diabetes group and nondiabetes group in addition to other variables and quantified the effects of diabetes with breast cancer patients undergoing pharmacotherapy on care resource use, using a multilevel linear regression model. RESULTS: Diabetes was significantly correlated to both longer length of stay (coefficient standard error: 0.75 [0.19], P < 0.001) and higher total hospital charge (0.72 [0.18], P < 0.001), controlled for age, pharmacotherapeutic agent, steroid use, admission route, procedures, and postpharmacotherapy events. CONCLUSION: This study showed that diabetes itself is a risk factor for greater care resource use after controlling for confounding factors. Pharmacotherapy for breast cancer may influence poor glycemic control, thus leading to greater care resource use. Early detection and careful monitoring of diabetes are essential in malignancy to eliminate this burden on the health care system. PMID- 27461668 TI - Irinotecan compared with etoposide in combination with platinum in previously untreated extensive stage small cell lung cancer: An updated systemic review. AB - OBJECTIVE: To compare the therapeutic effect of irinotecan/platinum (IP) and etoposide/platinum (EP) in treatment-naive extensive small cell lung cancer patients. METHODS: Systematic computerized searches of PubMed database and Chinese National Knowledge Infrastructure were performed. Summary odds ratio (OR) or hazard ratio (HR), and 95% confidence intervals (95% CI) were used to compare IP with EP in previously untreated small cell lung cancer patients. RESULTS: A total of 10 randomized trials were included in the analyses. The result showed the patients treated with irinotecan combinations experienced longer overall survival than epotoside, the pooled HR was 0.85 (95% CI = 0.78-0.92). The pooled OR revealed that IP stated better objective overall response than EP regimens (OR = 1.10, 95% CI = 0.92-1.32). Treatment-related deaths were similar between the two groups. CONCLUSION: IP regimens could be used as first-line treatment for extensive stage small cell lung cancer patients. PMID- 27461669 TI - Reconstruction of full-thickness cheek defects with a folded extended supraclavicular fasciocutaneous island flap following ablation of advanced oral cancer. AB - PURPOSE: The aim of the present clinical study was to evaluate the feasibility of a folded extended supraclavicular fasciocutaneous island flap (SFIF) for full thickness cheek defect reconstruction following ablative oral cancer surgery. PATIENTS AND METHODS: The nine patients with advanced squamous cell carcinoma of the buccal mucosa were six men and three women, with a mean age of 60.8 years. All patients were treated with surgery including ipsilateral radical neck dissection. A folded extended SFIF with a skin paddle ranging between 6 * (6 + 5) cm and 7 * (10 + 9) cm were used to reconstruct the full-thickness cheek defects. RESULTS: One minor flap failure and one wound dehiscence in donor site occurred, but all flaps survived, and there was no major complication in any patient. All patients were able to receive all of their nutrition orally and had normal speech. The patients were followed-up for 9-28 months; six patients were living with no evidence of disease, two was living with disease, and one died of local recurrence. CONCLUSION: The folded extended SFIF to reconstruct full-thickness cheek defects is reliable and an excellent alternative to other options for patients who have full-thickness defect of the cheek. PMID- 27461670 TI - CLIC1 overexpression is associated with poor prognosis in pancreatic ductal adenocarcinomas. AB - BACKGROUND: Clinical significance of chloride intracellular channel 1 (CLIC1) in pancreatic ductal adenocarcinomas (PDAC) remains largely unknown. This study was performed to assess the expression of CLIC1 in benign and malignant pancreatic lesions, and to assess its clinicopathological significance. MATERIALS AND METHODS: Tissue samples from resected PDAC (n = 70) and their matched normal pairs were evaluated for CLIC1 expression by immunohistochemical staining. Their expression was correlated with different clinicopathological parameters. RESULTS: CLIC1 expression was significantly higher (67.1%) in PDAC than in adjacent control tissues (25.7%, P < 0.001). High CLIC1 levels were associated with the histological grade (P < 0.001) and tumor size (P < 0.001); but not with sex, age, tumor-node-metastasis (TNM) stage, tumor location, or lymph node metastasis (P < 0.05). Univariate Kaplan-Meier analysis showed that a positive CLIC1 expression was associated with a decreased overall survival (P < 0.01). Multivariate cox regression analysis showed that CLIC1 expression and lymph node metastasis were independent risk factors for disease-free survival. CONCLUSION: The expression of CLIC1 might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of pancreatic ductal adenocarcinomas. PMID- 27461671 TI - Serum adiponectin levels are inversely correlated with leukemia: A meta-analysis. AB - OBJECT: This study is aimed at exploring the correlation between serum adiponectin (ADPN) levels and leukemia. MATERIALS AND METHODS: Eligible studies were retrieved using both computerized and manual searches. Relevant case-control studies were enrolled in strict accordance to our inclusion and exclusion criteria. RESULT: We searched 130 published studies and included 11 eligible studies for our meta-analysis according to our rigorous inclusion and exclusion criteria. The selected studies included 637 leukemia patients and 524 healthy controls. Our meta-analysis showed: (1) Serum ADPN levels of patients with leukemia were lower than healthy controls; (2) a subgroup analysis based on sample size verified that serum ADPN levels in patients with leukemia were significantly lower than that in healthy controls irrespective of a large sample size (n >= 80) or a small sample size (n < 80). CONCLUSION: Our meta-analysis suggested that serum ADPN levels may be inversely correlated with leukemia, and ADPN levels can be used as an effective biologic marker in early diagnosis and therapeutic monitoring of leukemia. PMID- 27461672 TI - Novel diagnostic biomarker for patients with Non-Hodgkin's Lymphoma by IgH gene rearrangement. AB - AIM OF STUDY: Novel biomarkers for improving accuracy could be beneficial for disease monitoring and surveillance of Non-Hodgkin's lymphomas (NHL). So we explored the viability of analytical methods for identifying the rearranged immunoglobulin (Ig) H genes sequence. MATERIALS AND METHODS: Next-generation sequencing (NGS) was used to sequence deoxyribonucleic acid (DNA) extracted directly from the tumor tissues of patients with NHL, and then specific rearranged DNA fragments from plasma was detected by polymerase chain reaction (PCR). RESULTS: By parallel DNA capturing and sequencing of IgH genomic regions (IgCap), the sequence of rearranged IgH loci could be detected and precisely determined in tumor tissues of 12 patients with NHL. The circulating rearranged DNA fragments had been identified in the plasma of one patient. CONCLUSION: IgCap may be the favorable diagnostic method for patients with NHL in clinical. PMID- 27461673 TI - Prognostic significance of residual or recurrent lymph nodes in the neck for patients with nasopharyngeal carcinoma after radiotherapy. AB - BACKGROUND: Nasopharyngeal carcinoma is the most frequently diagnosed primary tumor originating from the nasopharynx, and the preferred treatment modality is radiotherapy. AIMS: To identify nasopharyngeal carcinoma prognostic factors in patients with residual or recurrent cervical lymph node metastases after radiotherapy. PATIENTS AND METHODS: The clinicopathologic characteristics and prognoses of 67 nasopharyngeal carcinoma patients with residual or recurrent cervical lymph node metastases who were diagnosed and treated were analyzed retrospectively. The Chi-squared test and Cox proportional hazard regression model were used to investigate associations between survival and clinicopathological features. Cumulative survival plots were obtained using the Kaplan-Meier method. RESULTS: Data analysis using the Cox proportional hazard regression model revealed that the size of residual or recurrent lymph node metastases, level V lymph node involvement, number of involved levels, surgical procedure performed, and distant metastases were significantly associated with overall survival. Chi-squared analysis only determined a significant correlation between distant metastases and patient survival. Furthermore, the Kaplan-Meier analysis demonstrated that the 1-, 3-, and 5-year survival rates for patients were 86.6%, 52.2%, and 38.6%, respectively. Radical neck dissection resulted in substantially longer overall survival than modified neck dissection. CONCLUSION: The size of residual or recurrent lymph node metastases, level V lymph node involvement, number of involved levels, surgical procedure performed, and presence of distant metastases were prognostic factors for nasopharyngeal carcinoma patients with residual or recurrent cervical lymph node metastases after radiotherapy, with distant metastases being the most important determinant. Classical radical neck dissection is recommended for treating recurrent nodal disease in nasopharyngeal carcinoma. PMID- 27461674 TI - Iranian women's attitude toward prophylactic mastectomy for breast cancer. AB - AIM: Breast cancer is the most common cancer among women worldwide. Science has already proved that some breast cancer genes are inherited from parents. It is generally believed that the probability of cancer diagnosis in carriers of those genes is considerably higher than the normal population. It is in the same direction that modern medicine has introduced prophylactic mastectomy - one of the key preventive methods which is the focus of the present research. Nevertheless, whether women that have been diagnosed with breast cancer would take this approach depends on their local culture and their set of beliefs. In this regard, the present research was meant to evaluate the acceptability rate of prophylactic mastectomy among women in Iran after they are informed of the positive genetic test results. METHODS: Six hundred and five healthy women, who had no history of breast cancer, were selected by nonprobability sampling method. A predesigned questionnaire was filled out by the interviewer. RESULTS: Results showed that about 15% of respondents were willing to pick the prophylactic mastectomy in case they are identified as carriers of breast cancer genes. Twenty two percent of participants with positive family history was agreed with prophylactic mastectomy while in the negative family history group it was about 14%. CONCLUSION: Preventive mastectomy has a higher rate of acceptability among women who have had a family history of breast cancer. Therefore, it may be concluded that raising public awareness about the advantages of prophylactic mastectomy could help better address breast cancer in Iran. PMID- 27461675 TI - Comparison of outcome and toxicity of two different regimes of neoadjuvant chemotherapy followed by external beam radiotherapy in stages III and IV larynx and laryngopharyngeal malignancies in years 2013-2014. AB - INTRODUCTION: Both induction chemotherapy (ICT) followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx/hypopharynx cancer. MATERIALS AND METHODS: Of the 60 enrolled patients, randomly assigned into two groups (30 in each group) previously untreated patients with stages III to IV larynx/hypopharynx squamous cell carcinoma were assigned to received two cycles of ICT with interval of 3 weeks (a) Group A paclitaxel 175 mg/m 2 on day 1 and carboplatin 450 mg on day 2 (PC), (b) Group B docetaxel and cisplatin 75 mg/m 2 each on day 1 and ifosfamide 2 g/m 2 on day 1-3 along with mesna (docetaxel ifosfamide-cisplatin). Both groups were followed by conventional radiotherapy (60 70 Gy/5#/week). Primary end point was a response after ICT. Secondary endpoints included acute toxicities and overall response. RESULTS: Baseline patient and tumor characteristics were well balanced between both groups, the response after ICT seen was 80% in Group A complete response (CR) 36.6% and partial response (PR) 43.3% and in Group B 79% response, CR 33% and PR 46%; whereas toxicities in Group B grade 3/4 neutropenia and grade 2/3 vomiting more severe than Group A. Radiation therapy was well tolerable to both groups with mild side effects. CONCLUSIONS: Definite role of neoadjuvant chemotherapy in locally advanced larynx/laryngopharyngeal cancer as organ preservation therapy. The efficacy found was quite similar and improved response in both groups except toxicity profile of Group B more severe, requiring the use of colony stimulating factors and supportive care along with. PMID- 27461676 TI - Comparison of clinical outcomes after thoracoscopic sublobectomy versus lobectomy for Stage I nonsmall cell lung cancer: A meta-analysis. AB - BACKGROUND: Although lobectomy has long been considered the standard procedure for Stage I nonsmall cell lung cancer (NSCLC), the selection of sublobectomy for Stage I NSCLC remains controversial. Amidst growing enthusiasm for minimally invasive surgery, the comparison of clinical outcomes after thoracoscopic sublobectomy versus thoracoscopic lobectomy may be of immense value. OBJECTIVE: The present study aimed to compare the overall survival (OS) and disease-free survival (DFS) outcomes of patients who underwent thoracoscopic sublobectomy with those who underwent thoracoscopic lobectomy for Stage I NSCLC. METHODS: An electronic search was conducted using five online databases from their dates of inception to February 2014. Hazard ratio (HR) was used in this meta-analysis, calculated from the published survival data. RESULTS: Eight studies met the selection criteria, including a total of 1613 patients (463 patients underwent thoracoscopic sublobectomy, and 1150 patients underwent thoracoscopic lobectomy). From the available data, compared with thoracoscopic sublobectomy, there was a significant benefit of thoracoscopic lobectomy on OS (HR: 1.45; 95% confidence interval [CI]: 1.11-1.90; P = 0.007). However, in subgroup analysis of thoracoscopic segmentectomy and thoracoscopic lobectomy, there was no significant difference in OS (HR: 1.03; 95% CI: 0.76-1.39; P = 0.85) or DFS (HR: 1.19; 95% CI: 0.67-2.10; P = 0.56) between the two groups. In addition, compared with thoracoscopic wedge resection, there was a significant benefit of thoracoscopic lobectomy on OS (HR: 4.19; 95% CI: 2.19-8.03, P < 0.0001). CONCLUSION: For Stage I patients, thoracoscopic segmentectomy leads to survival rates comparable to thoracoscopic lobectomy. However, the overall several of thoracoscopic lobectomy is superior to that of wedge resection. PMID- 27461677 TI - Acute toxicities of adjuvant treatment in patients of oral squamous cell carcinoma with and without submucous fibrosis: A retrospective audit. AB - OBJECTIVE: To assess the severity of acute toxicities of postoperative adjuvant therapy on oral squamous cell carcinoma (OSCC) patients with and without submucous fibrosis (SMF). MATERIALS AND METHODS: The study population comprised treatment naive OSCC patients who underwent curative intent surgical resection from June 2010 to April 2011 followed by adjuvant treatment. Patients whose treatment details including toxicity profile were available were included in the study. One-hundred nine patients met the inclusion criteria of whom 36 had associated SMF and 73 no SMF. Overall, 35 patients received chemotherapy (CT) with radiotherapy (RT) and the rest only RT. Forty-two patients had centralized and 67 lateralized lesions. All patients with centralized lesions and 3 with lateralized lesion received radiation to bilateral face and neck. All others received ipsilateral radiation. The severity of mucositis, xerostomia, and skin toxicity (as per radiation therapy oncology group scale of acute toxicity) was compared between the SMF and non-SMF groups and patients with centralized and lateralized lesions. RESULTS: CT in addition to RT did not add significant to the assessed toxicities. Severe mucositis as well as treatment breaks were more in SMF group as compared to non-SMF group (P = 0.001 and <0.001 respectively). Severe mucositis and xerostomia were more in centralized than in lateralized lesions (P = 0.002 and 0.00 respectively). In subgroups of lateralized as well as centralized lesions, severe mucositis was more common in SMF patients than those without SMF (P = 0.01 and 0.02 respectively). CONCLUSION: OSCC patients with SMF have worse toxicity with adjuvant therapy and require good supportive care. PMID- 27461678 TI - Survey of cervical cancer survivors regarding quality of life and sexual function. AB - OBJECTIVE: To investigate the quality of life (QOL) of cervical cancer survivors in China. METHODS: Cervical cancer survivors were selected from 4 Tertiary Provincial Hospitals in Changsha, Hunan Province. Enrolled were 140 patients who received cancer treatments in these hospitals from 2007 to 2010. The Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) Questionnaire was used to assess the QOL of the participants. Spiritual well-being was evaluated with the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being (FACIT-Sp). Sexual function was measured with the Female Sexual Functioning Index. RESULTS: The average total FACT-Cx score was 124.45 (70-157). The average FACT-general score was 112.39 (49-150), and the average FACIT-Sp score was 13.9 (2-33.6). The prevalence of sexual dysfunction in our participants was 78%. Factors that were associated with QOL in cervical cancer survivors included gastrointestinal symptoms, health insurance, age, sleep disorders, and the number of complications. Sexual function was affected by radiotherapy, age, type of surgery, sleep disorders, and occupation. CONCLUSION: The QOL and sexual function of cervical cancer survivors were lower than the general population. Treatment related complications and sexual dysfunction significantly affected patients' QOL. Having health insurance was associated with better QOL. Sexual function was adversely affected by radiotherapy and radical hysterectomy. PMID- 27461679 TI - Prognostic impact of the high-sensitivity modified Glasgow prognostic score in patients with resectable non-small cell lung cancer. AB - OBJECTIVE: The present study compared the prognostic value of the Glasgow prognostic score (GPS), modified GPS (mGPS), high-sensitivity mGPS (HS-mGPS), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI) in patients with resectable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective study included 327 consecutive patients with resectable NSCLC with a follow.-up period. >5. years. Initially, the HS-mGPS was directly compared with the GPS and mGPS in terms of their ability to predict survival in patients with resectable NSCLC. Second, inflammation.-based scores, including the HS-mGPS, NLR, PLR, PI, and PNI, were analyzed preoperatively using multivariate Cox analysis. Clinical characteristics reflecting cancer progression were also analyzed. RESULTS: Elevated GPS (P < 0.001), mGPS (P < 0.001), and HS-mGPS (P < 0.001) levels were associated with reduced overall survival. The HS-mGPS (P < 0.001) was superior to the GPS and mGPS (P = 0.884) as a prognostic marker of postoperative outcomes. On multivariate Cox analysis, age (P = 0.026), p-T status (P < 0.001), p-N status (P < 0.001), lymphatic vessel invasion (P = 0.008), and the HS-mGPS (P = 0.016) were independent prognostic factors for survival. CONCLUSION: These results suggest that the HS-mGPS might have a greater prognostic impact than the GPS, mGPS, NLR, PLR, PI, or PNI in patients with resectable NSCLC. PMID- 27461680 TI - Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival. AB - BACKGROUND: We seek to investigate whether carboplatin-based induction chemotherapy before modern day concurrent chemoradiotherapy (CCRT) improves survival in patients with bulky, locally advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 105 patients with Stage II and III NSCLC treated with definitive CCRT from 2003 to 2013. All patients underwent definitive treatment with weekly platinum-based doublet chemotherapy delivered concurrently with 60-66 Gy of thoracic radiotherapy. Thirty patients who received induction chemotherapy before CCRT had T4 disease, N3 disease, or gross tumor volume (GTV) of >150 cm 3. These patients were compared to those with unresectable disease who received CCRT alone without induction chemotherapy. Statistical analysis included univariate and multivariate methods. RESULTS: Mean follow-up time was 15.6 months. Patients treated with carboplatin based induction chemotherapy demonstrated prolonged overall survival (28.2 vs. 14.2 months, P = 0.04), progression free survival (12.6 vs. 9.0 months, P = 0.02), and distant metastasis free survival (15.8 vs. 10.1months, P = 0.05) compared to those who received CCRT alone without induction chemotherapy. Univariate analysis revealed older age, larger GTV, and squamous pathology as negative prognostic factors. When controlling for these factors, Cox regression analysis indicated a trend toward significantly improved overall survival in the induction cohort (P = 0.10). CONCLUSION: In patients with large tumors or bulky nodal NSCLC, carboplatin-based induction chemotherapy may be an important addition to definitive CCRT in the modern era. Our findings strongly support further investigation induction chemotherapy in this population. PMID- 27461681 TI - Epidermal growth factor receptor expression in carcinoma gallbladder: A prospective study in Indian scenario. AB - AIM: Gallbladder cancer (GBC) is an aggressive disease with poor prognosis and complete surgical resection offering the only cure. Increased epidermal growth factor receptor (EGFR) expression has been noted in various cancers including GBC. Several studies across the world have examined the expression of EGFR in GBC. This study has been done to see the EGFR expression in GBC in Indian context. MATERIALS AND METHODS: Fifty cases of GBC were evaluated histopathologically using hematoxylin and eosin stained sections. Immunohistochemical assessment of EGFR expression was done, and scoring was done as per Kaufman et al. Data were collected, tabulated, and analyzed statistically by SPSS 16.0 version (Chicago, Inc., USA) software. RESULTS: Of 50 cases, 44 revealed EGFR over-expression while 6 were negative. Of the 44 cases, 10 had weak EGFR immunostaining intensity (1+), 26 had moderate (2+), and 8 showed strong EGFR immunostaining (3+). We found that most of the cases showing weak EGFR immunostaining intensity (1+) were well-differentiated tumor (70%) and cases with a strong EGFR immunostaining intensity (3+) were poorly differentiated cases of adenocarcinoma (75%). Moderately differentiated adenocarcinoma showed moderate EGFR immunostaining intensity (2+) in most of the cases (53.8%). CONCLUSION: EGFR is expressed in most of the cases of GBC. In well-differentiated adenocarcinoma, the EGFR expression is less compared to EGFR expression in poorly differentiated tumor, leading to the conclusion that the differentiation of the tumor and EGFR expression is inversely related. Thus, intensity of EGFR expression may correlate with aggressiveness of disease. PMID- 27461682 TI - Chemotherapy effectively suppresses interleukin-20, receptor activator of nuclear factor kappa-B ligand, and osteoprotegerin levels in patients with lung adenocarcinoma and bone metastasis. AB - BACKGROUND: Bone metastasis (BM) is common in patients with lung cancer. Osteolysis is caused by increased osteoclast activity. Interleukin-20 (IL-20) and receptor activator of nuclear factor kappa-B ligand (RANKL) are crucial for osteoclast formation. Osteoprotegerin (OPG) inhibits a receptor activator of RANKL/RANK signaling. The aims of this study were to analyze the serum levels of IL-20, OPG, and RANKL in patients with and without BM and to observe the effect of chemotherapy on these cytokines. PATIENTS AND METHODS: A total 54 cases of pathologically confirmed lung adenocarcinoma (ADC) and 18 healthy individuals (Control) were enrolled in this study. Eligible patients were divided into three groups (18 patients per group): ADC without BM (ADC), ADC with BM (ADC + BM), and ADC with BM treated with chemotherapy (ADC + BM + Chemo). Serum IL-20, RANKL, and OPG levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Serum IL 20, RANKL, and OPG levels in ADC + BM patients were significantly elevated compared with that in the Control or ADC groups (both P < 0.001). The serum cytokine levels were significantly lower following chemotherapy compared with that in patients who did not receive chemotherapy (P < 0.001). CONCLUSIONS: Serum IL-20, RANKL, and OPG levels increase in patients with lung cancer and BMs. Chemotherapy suppresses the elevation of these cytokines. PMID- 27461683 TI - Systematic meta-analysis on association of human papilloma virus and oral cancer. AB - BACKGROUND: Oral cancer is a disease with complex etiology. There is a strong evidence for the role of smoking, alcohol, genetic susceptibility, and indications that DNA viruses could also be involved in oral cancer. Recognized initially as sexually transmitted agent, human papilloma virus (HPV) is now considered a human carcinogen. Papilloma viruses are epitheliotropic viruses. A strong association of cervical cancer has been implicated with high-risk HPV16 and HPV18 infections, establishing the viral pathogenesis of the carcinoma. The etiopathogenesis is still unclear referring mainly to conflicting evidences in the detection of such viruses in oral carcinoma in spite of few studies suggesting their positive correlation. AIM OF THE STUDY: This systematic meta analysis aimed to provide evidence-based analysis of literature relating oral cancer and HPV, along with identification of reliable diagnostic methodology for identifying HPV in oral and oropharyngeal cancer. MATERIALS AND METHODS: A systematic review was performed using PubMed (from the year 1995 to 2015), Medline, Cochrane, ScienceDirect, and the Internet search. Reviewed literature included randomized control trials, cross sectional and cohort studies. Pooled data were analyzed by calculating relative risk and odds ratios (ORs), using a binary random-effects model. RESULTS: Out of 1497 cases, 588 patients were positive for HPV DNA, detected by various methods. About 39.27% of case samples were positive for HPV DNA. The calculated OR was 2.82 and 95% confidence interval, which showed significantly an increased risk of HPV among case group when compared to that of controls. CONCLUSION: The present meta-analysis suggests a potentially significant casual relation between HPV and oral and oropharyngeal cancers. PMID- 27461684 TI - Dosimetric comparison of different treatment planning techniques with International Commission on Radiation Units and Measurements Report-83 recommendations in adjuvant pelvic radiotherapy of gynecological malignancies. AB - AIM: The study evaluates the different treatment planning techniques according to three recommendation levels of the International Commission on Radiation Units and Measurements Report-83 in gynecologic cancer patients treated with adjuvant pelvic radiotherapy (APR). MATERIALS AND METHODS: Computerized tomography images of ten endometrial and cervical cancer patients who were treated with APR were assessed. For each patient, five different treatment plans were created. One homogeneity index and four different conformity indexes (CIs) were calculated for three-dimensional conformal radiotherapy (3D-CRT), field-in-field (FIF), seven field intensity modulated radiotherapy (7-IMRT) with two different degrees beginning (7A-IMRT, 7B-IMRT) and 9-IMRT treatment plans. Dose volume histogram parameters and normal tissue complication probability (NTCP) were compared for organs at risk (OAR). RESULTS: The CI values of the IMRT were closer to 1 with respect to other plans (P < 0.05). The rectum and the bladder volumes which received more than 40 Gy were decreased with IMRT compared to 3D-CRT (P < 0.05). Doses received by the 195 cc volume of the small intestine and NTCP values were significantly decreased with IMRT (P < 0.05). CONCLUSION: IMRT provided more protection than FIF plans at high dose volumes of the OAR; however, it did not show any superiority at low-dose volumes. The NTCP results supported IMRT for only small intestine protection. Because IMRT is increasingly used clinically, the comparison of NTCP will become more common in the near future. Therefore, new prospective studies with sufficient number of patients and appropriate NTCP models are needed for this treatment modality. PMID- 27461685 TI - Insights into significant pathways and gene interaction networks in peripheral blood mononuclear cells for early diagnosis of hepatocellular carcinoma. AB - BACKGROUND: Early diagnosis of hepatocellular cancer (HCC) significantly helps improve patient survival. However, high specific and sensitive tests for screening patients with early stage of HCC are not yet available. Novel HCC biomarkers based on gene expression profiles of peripheral blood mononuclear cells (PBMCs) might change the situation. Recently, a three gene-based signature for the non-invasive detection of early HCC was reported. OBJECTIVE: To compare the differences in global gene expression profiles in PBMCs of healthy individuals and HCC patients, with a specific aim to uncover the significantly altered biological pathways and important hub genes. MATERIALS AND METHODS: Two groups of data were extracted from Affymetrix microarray expression dataset GSE49515. One group had 10 PBMCs samples from healthy control individuals, and the other had 10 PBMCs samples from patients with HCC. Gene expression profiles of both groups were analyzed and compared. Furthermore, ribonucleic acid (RNA) levels of seven of the identified differentially expressed genes (DEGs) were further confirmed by quantitative reverse transcription polymerase chain reaction (QRT-PCR). RESULTS: Significant differences were uncovered in gene expression profiles in PBMCs of healthy individuals and HCC patients. Three hundred and seventy-five up-regulated and 169 down-regulated DEGs were identified. Three hundred and eighty-seven gene ontology (GO) biological processes and 15 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were over-represented by the identified DEGs. CONCLUSIONS: Using identified DEGs, significantly changed biological processes such as nucleic acid metabolic process and KEGG pathways such as cytokine-cytokine receptor interaction in PBMCs of HCC patients were identified. In addition, several important hub genes, for example, CUL4A, and interleukin (IL) 8 were also uncovered. PMID- 27461686 TI - Evaluation of the radioprotective effect of Turkish propolis on foreskin fibroblast cells. AB - AIM OF STUDY: Propolis is a resinous bee product, rich of polyphenolic compounds and flavonoids. It is known that in different geographic zones its chemical composition varies due to the different plant sources. Many biological properties including antimicrobial, antioxidative, anti-inflammatory, antitumoral, antigenotoxic, antimutagenic, cytostatic activities have been ascribed to propolis. These biological effects are predominantly attributed to its content of polyphenols. In this study, we aimed to evaluate the radioprotective effect of ethanolic extract of Turkish propolis. (EETP) against gamma-ray-induced DNA damage on fibroblast cells using comet assay for the first time. MATERIALS AND METHODS: Fibroblast cells were pretreated 15 and 30 min with concentrations of 100, 200 and 300 MUg/mL EETP then they were exposed to 3 Gy gamma-rays. Amifostine (synthetic aminothiol compound) was used as a positive control. RESULTS: The results showed a significant decrease in gamma-ray-induced DNA damage on cells treated with EETP and amifostine when compared to only irradiated cells. (P < 001). CONCLUSION: It was concluded that EETP prevent gamma-ray induced DNA damage in fibroblast cells and might have radioprotective activity. PMID- 27461687 TI - Predictive factors for positive surgical margins in the treatment of breast ductal carcinoma in situ. AB - CONTEXT: Surgery is the main form of treatment for ductal carcinoma in situ (DCIS) of the breast. Among other factors, treatment success requires that the surgical margins are free of disease, to reduce the risk of recurrence. AIMS: The purpose of this study was to analyze factors that might be associated with positive margins in patients diagnosed with DCIS. SETTINGS AND DESIGN: A retrospective analysis was performed of hospital databases from the year 2006 to 2014, to identify patients with an initial diagnosis of DCIS made by percutaneous biopsy. SUBJECTS AND METHODS: Age, the presence of disease symptoms, lesion size on mammogram, and the presence of estrogen receptors, and their relationship to the surgical margins were evaluated in 249 patients. STATISTICAL ANALYSIS USED: Shapiro and Wilcoxon-Mann-Whitney tests were used to verify that the data were normally distributed. Chi-squared test was used to verify the independence of the variables. RESULTS: Lesions measuring 1.55 cm or greater had a relative risk of positive margins after conservative surgery of 1.39 (95% confidence interval [95% CI]: 1.02-1.90). The presence of symptoms had a relative risk of positive margins after conservative surgery of 1.54 (95% CI: 1.17-2.02). CONCLUSION: Lesions measuring 1.55 cm or greater and the presence of symptoms are risk factors for positive margins in the treatment of ductal carcinoma in situ. Therefore, these patients need a better surgical planning in order to reduce the risk of positive margins. There is a clear need for large prospective studies to validate our findings and define other factors that might contribute to the success of surgical resection for ductal carcinoma in situ. PMID- 27461688 TI - Maternal smoking during pregnancy and risk of childhood neuroblastoma: Systematic review and meta-analysis. AB - BACKGROUND: Prior epidemiological studies suggest a possible association between maternal smoking during pregnancy and risk of childhood neuroblastoma. A meta analysis was performed statistically surmising all available observational studies on this topic in order to evaluate the potential correlation of maternal smoking during pregnancy and risk of childhood neuroblastoma. METHODS: Published literature was obtained from PubMed, Embase, ISI Web of Science, and Cochrane library, and all studies were inclusive until July 2014. Data from epidemiological studies were combined using a general variance-based meta analytic method employing 95% confidence intervals. The outcome of interest was shown as odds ratio (OR) reflecting the risk of neuroblastoma development associated with smoking while pregnant. Newcastle-Ottawa Scale was used to assess the quality of studies. RESULTS: Seven case-control studies meeting protocol specified inclusion criteria were obtained through a comprehensive literature search. These studies enrolled a total of 1909 patients and 15,683 controls. Analysis for homogeneity demonstrated that the data were heterogeneous (P < 0.05) and could be statistically combined with randomized effect model. Combining all seven reports yielded an OR of 1.28 (1.01-1.62), a statistically significant result suggesting possible association between maternal smoking during pregnancy and risk of childhood neuroblastoma development (P = 0.005). There was no association between the dosage of maternal smoking during pregnancy and risk of neuroblastoma. CONCLUSION: The available epidemiological data support a possible association between maternal smoking during pregnancy and pediatric neuroblastoma development. PMID- 27461689 TI - The significance of enlarged cervical lymph nodes in diagnosing thyroid cancer. AB - INTRODUCTION: We aim to investigate the significance of enlarged cervical lymph nodes (ECLN) identified by initial surgeon-performed ultrasound (US) as a tool for determining the risk of malignancy in the patients presenting with suspicious thyroid nodules. METHODS: Radiological and surgical reports were retrospectively reviewed for the patients with suspicious thyroid nodules who underwent thyroidectomy and preoperative comprehensive neck US. Ultrasonographic features of the identified cervical lymph nodes were correlated with the final pathology report. Patients with malignancy other than papillary thyroid cancer (PTC) were excluded. RESULTS: The study consisted of 440 patients. On final pathology, PTC was found in 142 patients (32.3%), the remaining 298 (67.7%) exhibited benign findings. ECLN (>1 cm) were found in 66 (46.5%) patient with PTC compared to only 53 (17.8%) patients with benign nodules (P < 0.001). Of the 119 patients with ECLN, 54.6% had benign appearing ECLN with no suspicious features, 26.1% had one suspicious feature, and 19.3% had more than one suspicious features. Benign appearing ECLN had a positive predictive value (PPV) of 41.54%, negative predictive value (NPV) of 59.02%, sensitivity of 51.92%, and specificity of 48.65% in predicting malignancy as opposed to the absence of ECLN. While as opposed to benign looking ECLN, ECLN with only one suspicious feature had a PPV of 70.97%, NPV of 50.00%, sensitivity of 33.33%, and specificity of 83.02%, and ECLN with two or more suspicious feature had a PPV of 73.91%, NPV of 48.96%, sensitivity of 25.76%, and specificity of 88.68%. CONCLUSION: ECLN are associated with an increased likelihood of thyroid malignancy in the patients undergoing evaluation of a suspicious nodule. The risk of malignancy in thyroid nodules increases with the presence of suspicious ultrasonographic features on cervical lymph nodes. PMID- 27461690 TI - What is the role of florine-18 fluorodeoxyglucose/positron emission tomography/computed tomography imaging in well-differentiated thyroid cancers with negative iodine-131 scan high thyroglobulin and normal anti-thyroglobulin levels. AB - PURPOSE: This retrospective study aims to assess the cut-off value of thyroglobulin (Tg) levels in nux or metastatic well-differentiated thyroid cancers (DTCs) with normal anti-Tg levels using with fluorodeoxyglucose/positron emission tomography/computed tomography (FDG PET/CT). MATERIALS AND METHODS: We reviewed FDG PET/CT images of 104 patients with well DTC (28 men, 76 women) whose: Iodine-131 (131 I) whole-body scanning was negative but had elevated Tg with normal anti-Tg levels. RESULTS: The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of florine-18-FDG PET/CT findings were found to be 95.92%, 87.27%, 87.04%, 96.00%, and 91.35%, respectively. The best Tg cut-off value was found to be 10.4 ng/ml. In the Tg level <10.4 ng/ml group, the sensitivity, specificity, PPV, NPV, and accuracy of FDG PET/CT were found to be 94.1%, 91.30%, 88.8%, 95.4%, and 92.5%, respectively. In the other group, which Tg level >=10.4 ng/ml, sensitivity, specificity, PPV, NPV, and accuracy of FDG PET/CT exams were found to be 96.8%, 84.3%, 86.1%, 96.4%, and 90.6%, respectively. CONCLUSION: FDG PET/CT imaging is a valuable imaging method in the evaluation of patients with elevated serum Tg levels and normal anti-Tg levels. Furthermore, it has potential utility in the dedifferentiation of active foci that are present, and in assessing optimal decision making during follow-up. PMID- 27461691 TI - Predicting genitourinary toxicity in three-dimensional conformal radiotherapy for localized prostate cancer: A dose-volume parameters analysis of the bladder. AB - PURPOSE: In prostate cancer radiotherapy, the relationship between genitourinary (GU) toxicity and clinical-dosimetric parameters is debated. We report our analysis of the parameters associated with GU toxicity. MATERIALS AND METHODS: Eighty-six consecutive patients treated with conformal radiotherapy for localized prostate cancer were retrospectively analyzed; the bladder was delineated both as "whole bladder" (WB: Defined in its entirety as a solid organ) and "inferior bladder" (IB: Corresponding to the distal part of the bladder). GU toxicity and dose-volume parameters were correlated using the point biserial correlation coefficient. The normal tissue complication probability (NTCP) cut-off volume model was fitted to toxicity data; univariate analysis between GU toxicity and clinical parameters was done. RESULTS: Acute GU toxicity was correlated to doses higher than 80 Gy (P < 0.05) while late GU was correlated to doses higher than 77 Gy for WB and from 77.5 Gy for IB. The NTCP cut-off volume model identified for both WB and IB a bladder volume of 6 cc receiving a dose >=77 Gy corresponding to a 50% probability of GU toxicity. At univariate analysis, acute GU toxicity was correlated with smoke (P < 0.001). CONCLUSION: Bladder maximal doses quantified as hotspots show a correlation to GU toxicity. PMID- 27461692 TI - The effect of curcumin on low-passage glioblastoma cells in vitro. AB - BACKGROUND: Plant extract therapy has been the cornerstone of cancer treatment for many years. The natural component curcumin demonstrated antineoplastic effects on different type of tumor cells. In this study, we explored the effectiveness of curcumin against low-passage human primary glioblastoma (GB) cell cultures. MATERIALS AND METHODS: Early passage GB cell cultures (GB3B, GB4B, and GB5B) were established from fresh samples tissue obtained from GB patients. Growth rate (GR) and doubling time (DT) was determined for each cell line. The cytotoxic effect of curcumin was quantified by hemocytometer cell counting, using trypan blue. To study the changes in cell shape, GB cells exposed to a concentration corresponding to inhibitory concentration 50 (IC50) of curcumin were studied by phase-contrast microscopy by capturing images during the treatment. RESULTS: Our results showed that GB cells proliferate with a GR of 0.2872 and a DT of 2.41 days for GB3B, a GR of 0.2787 and a DT of 2.49 days for GB4B, and a GR of 0.2787 and a DT of 2.49 days for GB5B. Curcumin induced cell death in GB cells in a time- and dose-dependent manner. The IC50 for GB3B was 46.4 uM, for GB4B was 78,3 uM, and for GB5B was 47.7 uM. Phase contrast microscopy showed that cultures treated with curcumin in a concentration corresponding to IC50 contained rounded cells and cell fragments, 72 h after the treatment. CONCLUSIONS: The results of the present investigation proved that curcumin is a natural compound potentially useful in the fight against GB. PMID- 27461693 TI - Lac dye as a potential anti-neoplastic agent. AB - OBJECTIVE: Certain anthraquinone compounds are effectively used for treatment of cancer. The present study describes the inhibitory activity of lac dye, a mixture of polyhydroxy anthraquinone compounds (Laccaic acid A, B, C, D and E), produced by the Indian lac insect, Kerria lacca (Kerr). MATERIALS AND METHODS: In vitro testing for anticancer activity of lac dye was done at four concentrations (10, 20, 40, 80 MUg/ml) on ten human malignant cell lines including six human leukemia cell lines, U973, Raji, K562, Jurkat, MOLT 4 and HL60 using SRB assay. RESULTS AND CONCLUSION: Both crimson and yellow lac dye inhibits proliferation of Human leukemia cell lines, Raji, U937, K562, HL60 and Jurkat, therefore can be considered as a potential anticancer agent for leukemia. PMID- 27461694 TI - Expression analysis of human epidermal growth factor receptor type 2 transcripts in breast cancer cohort and its association with clinical features. AB - AIM OF STUDY: Increased expression of human epidermal growth factor receptor type 2 (HER2) is significantly associated with poor prognosis in breast cancer patients. However, data on HER2 at transcript levels in Pakistani mammary tumor affected females is still limited. In the current study, HER2 transcripts were explored in breast cancer cohort and correlated with various clinical parameters. MATERIALS AND METHODS: Freshly excised tumors along with adjacent normal background tissues of 94 patients were collected at the time of surgery and immediately stored in RNAlater (r) solution. Clinical data for these samples (disease stage, grade, age, and menopausal status) was also retrieved after a subsequent follow-up. Isolation of RNA and cDNA synthesis was done using an already established protocol. HER2 expression was evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR) technique while beta actin was used as an internal control. RESULTS: In the given cohort, 31 (33%) patients were found positive for HER2. These tumors showed a pronounced increase in HER2 as compared to controls (P = 0.0004). Interestingly, the significant relevance of high HER2 mRNA among moderately differentiated tumor tissues in comparison to controls was also observed (P = 0.02). A significant association of HER2 levels with premenopausal status was also reported. CONCLUSION: Based on these findings, early screening of HER2 using qRT-PCR should be incorporated for breast cancer patients of Pakistani population diagnosis. PMID- 27461695 TI - Polymorphisms in the telomerase reverse transcriptase promoter are associated with risk of breast cancer: A meta-analysis. AB - AIMS: Recently, the relationship between telomerase reverse transcriptase (TERT) polymorphisms and breast cancer risk has been investigated in several publications. However, the results were inconclusive. In this study, we examined the association between TERT polymorphisms and breast cancer risk by meta analysis. MATERIALS AND METHODS: The PubMed, Cochrane Library, and EMBASE databases were searched independently by two investigators to retrieve relevant studies published to March 21, 2015. The strength of the association was calculated with the odds ratio (OR) and 95% confidence interval (CI). All statistical tests were used by the RevMan 5.1 software (Nordic Cochrane Center, Copenhagen, Denmark). RESULTS: We observed a statistically significant association between rs2736109 polymorphism and breast cancer risk (OR = 1.13; 95% CI: 1.00-1.28; P = 0.04). In addition, rs2736109 polymorphism was associated with breast cancer risk in Caucasian population (OR = 1.18; 95% CI: 1.00-1.38; P = 0.04). We also found rs2853669 and rs2736098 polymorphisms were significantly associated with breast cancer risk (OR = 0.76; 95% CI: 0.63-0.90; P = 0.002 and OR = 0.79; 95% CI: 0.72-0.87; P < 0.00001), respectively. Furthermore, rs10069690 polymorphism was showed to be associated with breast cancer risk (OR = 1.16; 95% CI: 1.11-1.22; P < 0.00001). In the subgroup analysis, this polymorphism might be associated with estrogen receptor-negative breast cancer risk (OR = 1.16; 95% CI: 1.12-1.21; P < 0.00001) and breast cancer risk in Caucasian population (OR = 1.18; 95% CI: 1.14-1.23; P < 0.00001). One single nucleotide polymorphism, rs2735940, was not significantly associated with breast cancer risk (OR = 0.85; 95% CI: 0.66-1.11; P = 0.24). CONCLUSION: This meta-analysis suggested that TERT rs2736109, rs2853669, rs2736098, and rs10069690 polymorphisms were associated with increased risk of developing breast cancer. PMID- 27461696 TI - Dosimetric study of beam angle optimization in intensity-modulated radiation therapy planning. AB - PURPOSE: The quality of intensity-modulated radiotherapy (IMRT) highly depends on the choice of beam orientations and optimization algorithms used in the treatment planning. The present work reports dosimetric study of IMRT plans generated using preselected equiangular beam orientations (PSBO) and beam angle optimization (BAO) for the patients of prostate, head and neck, and esophagus carcinoma. MATERIALS AND METHODS: The computed tomography (CT) datasets of 30 patients treated with IMRT for prostate, head and neck, and esophagus carcinoma were selected. Two IMRT plans were made for each patient. First plan was prepared for seven to nine fields PSBO in coplanar arrangement. The second plan was made using the BAO by a computerized algorithm compatible treatment planning system (TPS). The dose-volume histograms (DVHs) of PSBO and BAO plans were compared for all the patients. The treatment plans were compared using the parameters delivered monitor units (MUs), doses delivered to organs at risk (OARs), target coverage (conformity index (CI)), homogeneity index (HI), and quality index (QI). RESULTS: DVHs generated showed that OARs receive almost identical or slightly better doses in case of BAO as compared to PSBO. CI, HI, and QI values were almost same for two plans. However, we have noticed significant reduction in MUs for all the plans generated using BAO. CONCLUSIONS: It is concluded that BAO provides superior plan with respect to MUs and should be used whenever possible in IMRT planning. PMID- 27461697 TI - Response of primary culture of human ovarian cancer cells to chemotherapy: In vitro individualized therapy. AB - OBJECTIVE: This study focused on whether primary cultures of ovarian cancer (OC) cells established from ascites can be used to evaluate response to chemotherapeutic agents and if curcumin could enhance the efficacy of these agents. MATERIALS AND METHODS: We established five primary cultures of ascitic cells from OC patients and treated them with curcumin, carboplatin, and paclitaxel singly and in combinations. The percentage of apoptotic cells was determined by flow cytometry. RESULTS: There was a wide variation in the response of individual primary cultures to treatment with the chemotherapeutic agents. Curcumin by itself was as good as carboplatin or paclitaxel in inducing apoptosis in the primary OC cells. Curcumin was not able to affect the carboplatin mediated cell killing. However, a combination of curcumin and paclitaxel was additive and was equally effective as a combination of carboplatin and paclitaxel. A combination of curcumin carboplatin, and paclitaxel was also found to be additive and, in fact, turned out to be the best combination that gave the highest percentage of apoptosis in vitro. CONCLUSION: This study highlights the fact that primary cultures of OC cells can be used to detect response to chemotherapeutic agents and help to individualize the treatment offered to OC patients. PMID- 27461698 TI - Radiological safety features of indigenously developed radiotherapy simulator. AB - OBJECTIVE: To study the radiological safety feature of indigenously developed radiotherapy simulator. MATERIALS AND METHODS: A comprehensive study for radiological safety features of the unit were carried out as per the standard protocol/guidelines. NERO mAx X-ray test device was used for KVp, mA, mAs, and X rays output related test of the units along with other required test device. RESULTS: All the measurement results indicate that all the tested parameters of this simulator are well within the prescribed tolerance limit. CONCLUSION: The simulator is safe for routine clinical use. PMID- 27461699 TI - Study on the measurement of photo-neutron for15 MV photon beam from medical linear accelerator under different irradiation geometries using passive detectors. AB - AIM OF STUDY: The photo-neutron dose equivalents of 15 MV Elekta precise accelerators were measured for different depths in phantom, for various field sizes, at different distances from the isocenter in the patient plane and for various wedged fields. MATERIALS AND METHODS: Fast and thermal neutrons are measured using passive detectors such as Columbia Resin-39 and pair of thermoluminescent dosimetry (TLD) 600 and TLD 700 detector from Elekta medical linear accelerator. RESULTS: It is found that fast photo-neutron dose rate decreases as the depth increases, with a maximum of 0.57 +/- 0.08 mSv/Gy photon dose at surface and minimum of 0.09 +/- 0.02 mSv/Gy photon dose at 15 cm depth of water equivalent phantom with 10 cm backscatter. Photo neutrons decreases from 1.28 +/- 0.03 mSv/Gy to 0.063 +/- 0.032 when measured at isocenter and at 100 cm far from the field edge along the longitudinal direction in the patient plane. Fast and thermal neutron doses increases from 0.65 +/- 0.05 mSv/Gy to 1.08 +/- 0.07 mSv/Gy as the field size increases; from 5 cm * 5 cm to 30 cm * 30 cm for fast neutrons. With increase in wedge field angle from 0 degrees to 60 degrees , it is observed that the fast neutron dose increases from 0.42 +/- 0.03 mSv/Gy to 0.95 +/- 0.05 mSv/Gy.s CONCLUSIONS: Measurements indicate the photo-neutrons at few field sizes are slightly higher than the International Electrotechnical Commission standard specifications. Photo-neutrons from Omni wedged fields are studied in details. These studies of the photo-neutron energy response will enlighten the neutron dose to radiation therapy patients and are expected to further improve radiation protection guidelines. PMID- 27461700 TI - Evaluation of anaplastic lymphoma kinase expression in nonsmall cell lung cancer;a tissue microarray analysis. AB - INTRODUCTION: The oncogenic form of anaplastic lymphoma kinase (ALK) gene is an attractive candidate marker for diagnostic and therapeutic purposes in several malignancies, including nonsmall cell lung cancer (NSCLC). This study aimed to examine the expression levels and clinical significance of ALK in a series of NSCLC tumors. MATERIAL AND METHODS: We retrospectively reviewed 140 samples of NSCLC, including 64 (46%) squamous cell carcinoma (SCC), 62 (44%) adenocarcinoma (ADC), and 14 (10%) large cell carcinoma (LCC) for expression of ALK using immunohistochemistry; and immunostaining patterns were correlated with clinicopathological parameters. RESULTS: Expression of ALK was significantly different between SCC with ADC (P < 0.001) and LCC samples (P < 0.001). The highest level of ALK expression was found in ADC cases with poor differentiation and high nuclear grade (P = 0.005 and P = 0.005, respectively). Furthermore, high level of ALK expression was more often observed in ADC cases with poor prognosis features (P = 0.013). CONCLUSIONS: These findings suggested that ALK can be considered as a promising target in the targeted therapy in patients with lung ADC. PMID- 27461701 TI - The role low microRNA-335 expression in prognosis prediction of human cancers. AB - INTRODUCTION: MicroRNA-335 (miR-335) serves as one of the known miRs in human cancers, however, its prognostic role has yet been settled down. The present research is formed to discuss whether or not miR-335 could be identified as a prognostic biomarker of human cancers. MATERIALS AND METHODS: All eligible references from four main databases were included in this study based on the inclusion/exclusion criteria. Moreover, we performed a meta-analysis to explore the prognostic role of miR-335 in human cancers. RESULTS: Finally, we found eight articles which met the inclusion/exclusion criteria, involving 1098 subjects. miR 335 is deregulated in human cancer tissues compared to noncancerous tissues. We found that the pooled hazard ratios with 95% confidence interval were 1.35 (1.00, 1.83) for overall survival and 1.54 (0.36, 6.68) for relapse-free survival. CONCLUSION: The prognostic value of the low miR-335 expression cannot be completely decided based on the present evidences. More related clinical research should be implemented to further study the prognostic role of miR-335 in human cancers. PMID- 27461702 TI - Is the Wnt/beta catenin signalling pathway activated in Seminoma?: An immunohistochemical study. AB - BACKGROUND: The loss of reduction of some adhesion molecules is associated with the invasive phenotype of carcinomas. The aim of this paper was to study the expression of some proteins related to the Wnt/beta catenin signalling pathway in seminomas by immunohistochemical techniques in order to assess the contribution of this pathway to the tumoral development. MATERIALS AND METHODS: Immunohistochemistry for E-cadherin, beta-catenin, vimentin, C-Myc, cyclin D1 (CD1) and placental alkaline phosphatase. (PALP) was carried out in 24 archival tissue blocks of seminomas. Two cellular lines were used as E-cadherin and beta catenin controls. (JKT-1 and TCam-2). RESULTS: E-cadherin was positive in two seminomas and in one carcinoma in situ. (CIS), showing a membranous pattern. betacatenin was principally expressed in Sertoli cells, in some malignant gonocytes of CIS and in the membranes of seminomatous cells. No beta-catenin immunostaining was detectable in the cytoplasm and the nuclei of neoplastic cells. Seminomas were weakly possitive for vimentin in 11/24 cases. None of the tumors displayed expression of C-Myc or CD1. CONCLUSIONS: The results does not indicate the activation of the Wnt pathway, due to the lack of vimentin expression in 13/24 seminomas, the low expression in the rest of the cases, the lack of beta-catenin in nuclei and the absence of CD1 and C-Myc expression. Further work is needed to confirm these observations and to test other signaling pathways in seminomas. PMID- 27461703 TI - Need of collaborative radiology-radiation oncology workshops in decision making for head and neck cancer (HNC) management in India: Perspectives of the radiation oncologists. AB - BACKGROUND: In India, head and neck cancer (HNC) has always been a challenge to treatment due to its various disease., treatment., and patient.related factors. Recent developments in the field of both radiology and radiation oncology brings us to a stage where combined collaborative efforts are required for proper management of HNC. The article identifies the potential areas of such need through online survey. MATERIALS AND METHODS: This anonymous online survey with specific questions and their responses from radiation oncology community identifies potential areas of radiology expertise as perceived by a radiation oncologist. The questions were simple Likert-type and the best possible response was sought for. RESULTS: There were 57 email responses and majority (37) agreed upon the extreme importance of such collaborative efforts. The major areas where a radiation oncologist would seek help are target volume delineation and response evaluation posttreatment in HNC, though other areas are also important albeit to a lesser degree. CONCLUSION: There is urgent need of radiology.radiation oncology workshops in managing HNC in the modern era of image.based and image-guided treatment. Future larger hospital.based survey would determine need on a large scale basis at resolving these issues. PMID- 27461704 TI - Off-label use of Sorafenib in patients with advanced thyroid carcinoma: Retrospective analysis of five cases. AB - We present results obtained in five patients with advanced thyroid cancer, derived from the follicular epithelium, treated with Sorafenib used off-label. The median age at the time Sorafenib was started was 61 years. Only one patient tolerated the standard dose of 400 mg twice daily. The most severe adverse events were. PMID- 27461705 TI - Thai waste landfill site fire crisis, particular matter 10, and risk of lung cancer. AB - In March 2014, a big waste pollution occurs in Thailand. A big fire occurs at a big industrial waste landfill site, Phraeksa, Samut Prakan Province, Bangkok Metropolitan Region. This fire generates several pollutants, including particular matter 10 (PM10). According to the official report of the Bangkok Metropolis, the PM10 in the nearby area (5 km from the crisis area) is equal to 0.575 mg/m 3. The concern is on chronic health effect of PM10 exposure. Recently, the possible carcinogenic property of PM10 is mentioned. To estimate the cancer risk due to this crisis in Thailand, the author calculates the risk based on the ratio by Raaschou-Nielsen et al.; the risk is equal to 70.15 times. Based on the present study, a closed following up and monitoring on the problem of lung cancer in the future among the people living near the crisis area are needed. PMID- 27461706 TI - ALK positivity on pleuroscopic pleural biopsy in lung adenocarcinoma. AB - Lung cancer is the leading cause of cancer deaths worldwide, and around 75% to 80% of lung cancers are detected in advanced stage. Multiple genetic mutations are identified and reported in adenocarcinoma of the lung. Various pulmonary samples can be tested for molecular mutations in lung cancer. However, feasibility of molecular profiling of pleuroscopic pleural biopsies in lung adenocarcinoma is not reported. We describe a case of advanced adenocarcinoma of lung with positive anaplastic lymphoma tyrosine kinase mutation on pleuroscopic pleural biopsy and improved with oral crizotinib. The current case highlights the feasibility of pleuroscopy.-guided pleural biopsies in molecular profiling of lung adenocarcinoma. PMID- 27461707 TI - Bronchoscopic and surgical management of rare endobronchial tumors. AB - Pure endobronchial neoplasms are a rare entity, and they may present with diverse pathological findings. Malignant diseases are more common than benign ones, and they mostly originate from the surface epithelium. Endobronchial tumors usually present with symptoms such as cough, hemoptysis, recurrent pneumonia, wheezing, and chest pain. Flexible bronchoscopy is necessary for diagnosis and evaluation of these endobronchial tumors. Advance bronchoscopy or definitive surgery is the modality of treatment for these tumors based on the presentation. We present a case series of patients suffering from different rare endobronchial tumors and their management along with the review of literature. PMID- 27461708 TI - Multimodality management of primary diaphragmatic synovial sarcoma: First report. AB - Synovial cell sarcoma is an extremely rare tumor of mesenchymal origin. It commonly affects the soft tissues of the extremities but could possibly origin from the head and neck, heart, lung, pleura, mediastinum, esophagus, abdominal wall and the mesentery, and retroperitoneum. Primary synovial sarcoma of pleura, mediastinum, and lung have been reported. Primary synovial sarcoma of the diaphragm has not been reported to the best of our knowledge. We report a case of primary synovial cell sarcoma of the diaphragm presenting as a recurrent pleural effusion and pain in the left hypochondrium managed with multimodality approach. PMID- 27461709 TI - Cerrobend shielding stents for buccal carcinoma patients. AB - Buccal carcinoma is one of the most common oral malignant neoplasms, especially in the South Asian region. Radiotherapy, which plays a significant role in the treatment of this carcinoma, has severe adverse effects. Different types of prosthesis may be constructed to protect healthy tissues from the adverse effects of treatment and concentrate radiation in the region of the tumor mass. However, the technique for fabrication of shielding stent with Lipowitz's alloy (cerrobend/Wood's alloy) has not been well documented. This article describes detailed technique for fabrication of such a stent for unilateral buccal carcinoma patients to spare the unaffected oral cavity from potential harmful effects associated with radiotherapy. PMID- 27461710 TI - Erratum: Human worth in the era of market forces. AB - [This corrects the article DOI: 10.4103/0973-1482.180080.]. PMID- 27461716 TI - Corrigendum: Transcriptional repression of SIRT1 by protein inhibitor of activated STAT 4 (PIAS4) in hepatic stellate cells contributes to liver fibrosis. PMID- 27461717 TI - Establishment and characterization of a novel human cholangiocarcinoma cell line with high metastatic activity. AB - Cholangiocarcinoma (CCA) is a highly metastatic tumor, and the lung is a common site of metastasis. A greater understanding of the biology of metastases is needed to improve treatment outcomes. Herein, a highly metastatic human CCA subline, KKU-213L5 from an original cell line, KKU-213 that has marginally metastatic ability, was established and characterized. KKU-213L5 was selected in vivo through the fifth serial passage of pulmonary metastasized tissues via tail vein injection in NOD/scid/Jak3 mice. The metastatic abilities of the KKU-213L5 cells were compared with the parental line in vitro and in vivo. The expression profile of this metastatic cell line was determined using real-time PCR. KKU 213L5 cells were found to possess higher metastatic phenotypes, i.e., growth rates, stem cell surface markers (CD133), migration and invasion characteristics when compared with the parental cells. Compared to the KKU-213 cells, KKU-213L5 cells formed larger tumors in subcutaneous xenografted mice and had a >10-fold increase in lung metastases in the tail-vein injected metastatic mouse model. Mice injected intravenously with KKU-213L5 cells had a significantly shorter survival. Analysis of the expressed genes related to progression of cancer revealed significant upregulation of anterior gradient protein-2 (AGR2) and suppression of KiSS-1 in the KKU-213L5 cells. The association of these two genes with metastasis was affirmed in CCA patient tissues since increased AGR2 expression and decreased KiSS-1 expression were found in higher stage patient tumors. In conclusion, a highly metastatic human CCA cell line was established and characterized. It is plausible that the differential expression between the parental KKU-213 and highly metastatic KKU-213L5 cells may be beneficial to classify novel genes associated with metastasis. The KKU-213L5 cell line should serve as a valued device for discovering the molecular mechanisms of CCA metastasis and enabling the search for an effective therapy for the unmet clinical need in CCA. PMID- 27461718 TI - Mono- and dimeric complexes of an asymmetric heterotopic P,CNHC,pyr ligand. AB - An asymmetric heterotopic ligand (S-N(Me)CP) containing a central bicyclic, expanded-ring NHC with one pyridyl and one phosphine exo-substituent has been synthesised and its coordination chemistry with selected late transition metals investigated. The amidinium precursor [S-N(Me)CHP]PF6 shows variable coordination modes with Ag(i), Cu(i) and Au(i) depending on the L : M ratio. The reaction of two mols of [S-N(Me)CHP]PF6 with [Cu(MeCN)4]BF4, AgBF4 or Au(THT)Cl gives the bis ligand complexes [Cu(kappa-P-N(Me)CHP)2(CH3CN)2]BF4.(PF6)2, 1, and [M(kappa-P N(Me)CHP)2]X.(PF6)2 (3: M = Ag, X = BF4; 6: M = Au, X = Cl) respectively. The 1 : 1 reaction of [S-N(Me)CHP]PF6 with AgOTf gave the head-to-tail dimer H,T-[Ag2(MU N,P-N(Me)CHP)2(MU-OTf)2](PF6)2, 2, whereas the analogous reaction with Au(THT)Cl gave monomeric [Au(kappa-P-N(Me)CHP)Cl]PF6, 5. Complex 2 was converted to H,T [Ag2(MU-C,P-N(Me)CP)2](PF6)2, 4, upon addition of base, while 6 gave [Au(kappa-C N(Me)CP)2]Cl, 8, when treated likewise. Reaction of [S-N(Me)CHP]PF6 with Ni(1,5 COD)2 gave the oxidative addition/insertion product [Ni(kappa(3)-N,C,P N(Me)CP)(eta(3)-C8H13)]PF6, 9, which converted to [Ni(kappa(3)-N,C,P N(Me)CP)Cl]PF6, 10, upon exposure of a CHCl3 solution to air. Complex 10 showed conformational isomerism that was also present in [Rh(kappa(3)-N,C,P N(Me)CP)(CO)]PF6, 14, prepared from the precursor complex [Rh(kappa-P N(Me)CHP)(acac)(CO)]PF6, 13, upon heating in C6H5Cl. [Pt(kappa(3)-N,C,P N(Me)CP)(Cl)]PF6, 12, derived from trans-[Pt(kappa-P-N(Me)CHP)2(Cl)2](PF6)2, 11, was isolated as a single conformer. PMID- 27461719 TI - Towards a structural biology of the hydrophobic effect in protein folding. AB - The hydrophobic effect is a major driving force in protein folding. A complete understanding of this effect requires the description of the conformational states of water and protein molecules at different temperatures. Towards this goal, we characterise the cold and hot denatured states of a protein by modelling NMR chemical shifts using restrained molecular dynamics simulations. A detailed analysis of the resulting structures reveals that water molecules in the bulk and at the protein interface form on average the same number of hydrogen bonds. Thus, even if proteins are 'large' particles (in terms of the hydrophobic effect, i.e. larger than 1 nm), because of the presence of complex surface patterns of polar and non-polar residues their behaviour can be compared to that of 'small' particles (i.e. smaller than 1 nm). We thus find that the hot denatured state is more compact and richer in secondary structure than the cold denatured state, since water at lower temperatures can form more hydrogen bonds than at high temperatures. Then, using Phi-value analysis we show that the structural differences between the hot and cold denatured states result in two alternative folding mechanisms. These findings thus illustrate how the analysis of water protein hydrogen bonds can reveal the molecular origins of protein behaviours associated with the hydrophobic effect. PMID- 27461722 TI - Evaluation of Cystatin C for the Detection of Chronic Kidney Disease in Cats. AB - BACKGROUND: Serum cystatin C (sCysC) and urinary cystatin C (uCysC) are potential biomarkers for early detection of chronic kidney disease (CKD) in cats. An in depth clinical validation is required. OBJECTIVES: To evaluate CysC as a marker for CKD in cats and to compare assay performance of the turbidimetric assay (PETIA) with the previously validated nephelometric assay (PENIA). ANIMALS: Ninety cats were included: 49 CKD and 41 healthy cats. METHODS: Serum CysC and uCysC concentrations were prospectively evaluated in cats with CKD and healthy cats. Based on plasma exo-iohexol clearance test (PexICT), sCysC was evaluated to distinguish normal, borderline, and low GFR. Sensitivity and specificity to detect PexICT < 1.7 mL/min/kg were calculated. Serum CysC results of PENIA and PETIA were correlated with GFR. Statistical analysis was performed using general linear modeling. RESULTS: Cats with CKD had significantly higher mean +/- SD sCysC (1.4 +/- 0.5 mg/L) (P < .001) and uCysC/urinary creatinine (uCr) (291 +/- 411 mg/mol) (P < .001) compared to healthy cats (sCysC 1.0 +/- 0.3 and uCysC/uCr 0.32 +/- 0.97). UCysC was detected in 35/49 CKD cats. R(2) values between GFR and sCysC or sCr were 0.39 and 0.71, respectively (sCysC or sCr = MU + GFR + epsilon). Sensitivity and specificity were 22 and 100% for sCysC and 83 and 93% for sCr. Serum CysC could not distinguish healthy from CKD cats, nor normal from borderline or low GFR, in contrast with sCr. CONCLUSION: Serum CysC is not a reliable marker of reduced GFR in cats and uCysC could not be detected in all CKD cats. PMID- 27461721 TI - What's in a Name? Classification of Diabetes Mellitus in Veterinary Medicine and Why It Matters. AB - Diabetes Mellitus (DM) is a syndrome caused by various etiologies. The clinical manifestations of DM are not indicative of the cause of the disease, but might be indicative of the stage and severity of the disease process. Accurately diagnosing and classifying diabetic dogs and cats by the underlying disease process is essential for current and future studies on early detection, prevention, and treatment of underlying disease. Here, we review the current etiology-based classification of DM and definitions of DM types in human medicine and discuss key points on the pathogenesis of each DM type and prediabetes. We then review current evidence for application of this etiology-based classification scheme in dogs and cats. In dogs, we emphasize the lack of consistent evidence for autoimmune DM (Type 1) and the possible importance of other DM types such as DM associated with exocrine pancreatic disease. While most dogs are first examined because of DM in an insulin-dependent state, early and accurate diagnosis of the underlying disease process could change the long-term outcome and allow some degree of insulin independence. In cats, we review the appropriateness of using the umbrella term of Type 2 DM and differentiating it from DM secondary to other endocrine disease like hypersomatotropism. This differentiation could have crucial implications on treatment and prognosis. We also discuss the challenges in defining and diagnosing prediabetes in cats. PMID- 27461723 TI - Quantitative PCR and Cytology of Bronchoalveolar Lavage Fluid in Dogs with Bordetella bronchiseptica Infection. AB - BACKGROUND: The use of quantitative PCR (qPCR) for detection of Bordetella bronchiseptica in bronchoalveolar lavage fluid (BALF) and demonstration of bacteria adhering to ciliated epithelial cells in BALF or bronchial brushing fluid (BBF) has not been assessed in a series of affected dogs. Coinfections can worsen the clinical severity in bordetellosis, but the specific association with Mycoplasma cynos has not been evaluated. OBJECTIVES: To assess the utility of culture, qPCR and cytologic examination of cytospin preparations in the diagnosis of bordetellosis in dogs and the influence of coinfection by M. cynos on disease severity. ANIMALS: Twenty-four referred dogs with B. bronchiseptica infection and 10 healthy dogs. METHODS: Retrospective case series. qPCR (B. bronchiseptica and M. cynos) and culture results from BALF were recorded. Cytospin preparations from BALF and BBF were reviewed. qPCR on BALF from 10 healthy dogs were used as negative control. RESULTS: The BALF culture and qPCR detected B. bronchiseptica in 14/24 and 18/18 dogs, respectively. Coccobacilli were found adhering to ciliated epithelial cells in 20 of the 21 BALF cytologic preparations where epithelial cells were found, and 2/3 BBF cytologic preparations. Quantitative PCR detected a low level of B. bronchiseptica in one healthy dog. The frequency of detection of M. cynos was not significantly different in B. bronchiseptica (9/17 dogs) compared with healthy dogs (2/10 dogs) (P = .09). CONCLUSION AND CLINICAL IMPORTANCE: Quantitative PCR detection of B. bronchiseptica in BALF appears to be a useful diagnostic tool. Cytologic examination of BALF or BBF, when positive, allows a rapid and reliable diagnosis. PMID- 27461725 TI - Erratum. PMID- 27461726 TI - Erratum. PMID- 27461724 TI - Risk Factors for Equine Gastric Glandular Disease: A Case-Control Study in a Finnish Referral Hospital Population. AB - BACKGROUND: Equine gastric glandular disease (EGGD) is a term used to classify erosive and ulcerative diseases of the glandular mucosa of the equine stomach. Epidemiologic studies of risk factors for EGGD have not been reported. OBJECTIVE: To determine risk factors for EGGD. ANIMALS: Cases (n = 83) had endoscopic evidence of EGGD; controls (n = 34) included healthy horses and horses with equine squamous gastric disease (ESGD) without EGGD. METHODS: Retrospective case control study. The data were analyzed by multivariable logistic regression modeling. Analysis was performed on the full dataset. An additional analysis compared horses with glandular lesions (n = 43) against healthy horses (n = 22). RESULTS: On first analysis, Warmblood breed (OR = 13.9, 95% CI 2.2-90.9, P = .005) and an increasing number of caretakers (OR = 7.3, 95% CI 0.98-55.6, P = .053) were associated with an increased risk of EGGD. On analysis of the subset of data, Warmblood breed (OR = 28.6, 95% CI 2.96-250.0, P = .004) and increasing number of riders (OR = 12.99, 95% CI 0.94-166.7, P = .056) were risk factors. The presence of sand in the colon appeared to have a protective effect against EGGD (OR = 0.195, 95% CI 0.04-1.0, P = .051 for sand versus not having sand). CONCLUSIONS AND CLINICAL IMPORTANCE: This study suggests that Warmbloods are predisposed to EGGD and multiple handlers/riders might increase the risk of EGGD. Identification of risk factors allows speculation on potential pathophysiological mechanisms of EGGD. PMID- 27461727 TI - Adults aging 'with' and 'into' paralysis: Epidemiological analyses of demography and health. AB - BACKGROUND: Survival for many individuals with paralysis is increasing, making this population a larger subset of the aging population (Molton, & Jensen, 2010). Yet little is known about the demographics and health of this population (Freedman, 2014). OBJECTIVE: This study is one of the first evaluations of the differences in etiology, sociodemographic and health characteristics (i.e., health status, chronic, and secondary and medical conditions) of adults aging with versus into disability. METHODS: A cross sectional epidemiological study was performed using secondary data from a nationally representative sample of adults with paralysis. The National Paralysis Survey is a random digit-dial survey of over 70,000 households. Weighted descriptive and regression analyses were conducted. RESULTS: Eighty percent of those aging with paralysis had disabilities for 40+ years. They showed significantly better self-reported health status, and a trend for more secondary and medical conditions. Those aging into paralysis had more chronic diseases. CONCLUSIONS: Differences are evident between those aging with vs. into paralysis. These findings suggest that differentiating subgroups of older adults with disabilities by onset of disability makes disability and health information more actionable for programs and policies. Additional studies to explore the intersection of aging and disability onset across adulthood could increase our understanding of the dynamics of aging in persons with early and later onset disabilities. PMID- 27461728 TI - Females With ADHD Report More Severe Symptoms Than Males on the Adult ADHD Self Report Scale. AB - OBJECTIVE: To investigate gender differences in self-reported ADHD symptoms in a group of adults with ADHD and a control group. METHODS: A total of 682 adults with ADHD (49.9% females) and 882 controls (59.2% females) completed the Adult ADHD Self-Report Scale (ASRS), listing the 18 symptoms included in the diagnostic criteria of ADHD. RESULTS: Within the ADHD group, females reported more severe symptoms of inattention and hyperactivity/impulsivity than males. This higher symptom report of females was not found in the control group, where the number of severe inattention symptoms rather was higher in males. CONCLUSION: The results suggest that childhood symptoms of ADHD may have gone unnoticed in girls, emphasizing the need for longitudinal studies of ADHD symptoms across the life span. PMID- 27461730 TI - Validation of a global scale to assess the quality of interprofessional teamwork in mental health settings. AB - BACKGROUND: Few scales currently exist to assess the quality of interprofessional teamwork through team members' perceptions of working together in mental health settings. AIMS: The purpose of this study was to revise and validate an interprofessional scale to assess the quality of teamwork in inpatient psychiatric units and to use it multi-nationally. METHODS: A literature review was undertaken to identify evaluative teamwork tools and develop an additional 12 items to ensure a broad global focus. Focus group discussions considered adaptation to different care systems using subjective judgements from 11 participants in a pre-test of items. Data quality, construct validity, reproducibility, and internal consistency were investigated in the survey using an international comparative design. RESULTS: Exploratory factor analysis yielded five factors with 21 items: 'patient/community centred care', 'collaborative communication', 'interprofessional conflict', 'role clarification', and 'environment'. High overall internal consistency, reproducibility, adequate face validity, and reasonable construct validity were shown in the USA and Japan. CONCLUSIONS: The revised Collaborative Practice Assessment Tool (CPAT) is a valid measure to assess the quality of interprofessional teamwork in psychiatry and identifies the best strategies to improve team performance. Furthermore, the revised scale will generate more rigorous evidence for collaborative practice in psychiatry internationally. PMID- 27461729 TI - Systematic identification of protein combinations mediating chromatin looping. AB - Chromatin looping plays a pivotal role in gene expression and other biological processes through bringing distal regulatory elements into spatial proximity. The formation of chromatin loops is mainly mediated by DNA-binding proteins (DBPs) that bind to the interacting sites and form complexes in three-dimensional (3D) space. Previously, identification of DBP cooperation has been limited to those binding to neighbouring regions in the proximal linear genome (1D cooperation). Here we present the first study that integrates protein ChIP-seq and Hi-C data to systematically identify both the 1D- and 3D-cooperation between DBPs. We develop a new network model that allows identification of cooperation between multiple DBPs and reveals cell-type-specific and -independent regulations. Using this framework, we retrieve many known and previously unknown 3D-cooperations between DBPs in chromosomal loops that may be a key factor in influencing the 3D organization of chromatin. PMID- 27461731 TI - Haplotyping the human leukocyte antigen system from single chromosomes. AB - We describe a method for determining the parental HLA haplotypes of a single individual without recourse to conventional segregation genetics. Blood samples were cultured to identify and sort chromosome 6 by bivariate flow cytometry. Single chromosome 6 amplification products were confirmed with a single nucleotide polymorphism (SNP) array and verified by deep sequencing to enable assignment of both alleles at the HLA loci, defining the two haplotypes. This study exemplifies a rapid and efficient method of haplotyping that can be applied to any chromosome pair, or indeed all chromosome pairs, using a single sorting operation. The method represents a cost-effective approach to complete phasing of SNPs, which will facilitate a deeper understanding of the links between SNPs, gene regulation and protein function. PMID- 27461732 TI - Quality of Radiation Therapy Referral and Utilisation Post-prostatectomy: A Population-based Study of Time Trends. AB - AIMS: Adjuvant radiotherapy post-prostatectomy has been shown to benefit patients with adverse pathology. It remains unclear whether salvage radiotherapy confers equivalent outcomes. Practice guidelines recommend referral to radiation oncology within 6 months after prostatectomy to discuss adjuvant and salvage radiotherapy. The study objectives were to assess, at a population level: (i) post prostatectomy referral patterns for radiotherapy; (ii) adjuvant and salvage radiotherapy utilisation; and (iii) time trends in relation to clinical trials and guidelines. These findings provide indications of access to quality care. MATERIALS AND METHODS: This was a retrospective cohort study. Electronic radiotherapy consultation and treatment records were linked to the population based Ontario Cancer Registry. The population included prostate cancer cases treated with prostatectomy in Ontario between 2003 and 2012. Radiotherapy referral and treatment rates over time were analysed using the chi-squared trend test. RESULTS: Over the study period, 30 447 prostate cancer patients received prostatectomy. The proportion seen by radiation oncology within 6 months after prostatectomy doubled from 10.7% in 2003-2004 to 21.7% in 2011-2012 (P < 0.0001 for trend), with the largest annual percentage difference in 2009-2011 (3.4%). Among 4641 patients seen within 6 months, adjuvant radiotherapy rates remained at 51.0% +/- 3.0%. Contemporaneous with radiation oncology referral trends, overall adjuvant radiotherapy use increased from 6.2% in 2003-2004 to 11.0% in 2011-2012 (P < 0.001), while salvage radiotherapy remained at 8.4% +/- 0.4%. Consequently, the total proportion receiving radiotherapy within 24 months increased from 14.1% in 2003-2004 to 17.7% in 2009-2010 (P < 0.0001). CONCLUSIONS: There was an increase in access to early radiation oncology referral post-prostatectomy and adjuvant radiotherapy in Ontario between 2003 and 2012, following guideline publication. PMID- 27461734 TI - Asymmetric MoS2 /Graphene/Metal Sandwiches: Preparation, Characterization, and Application. AB - The polarizable organic/water interface is used to construct MoS2 /graphene nanocomposites, and various asymmetrically dual-decorated graphene sandwiches are synthesized. High-resolution transmission electron microscopy and 3D electron tomography confirm their structure. These dual-decorated graphene-based hybrids show excellent hydrogen evolution activity and promising capacitance performance. PMID- 27461735 TI - The role of fluid intelligence and learning in analogical reasoning: How to become neurally efficient? AB - This study on analogical reasoning evaluates the impact of fluid intelligence on adaptive changes in neural efficiency over the course of an experiment and specifies the underlying cognitive processes. Grade 10 students (N=80) solved unfamiliar geometric analogy tasks of varying difficulty. Neural efficiency was measured by the event-related desynchronization (ERD) in the alpha band, an indicator of cortical activity. Neural efficiency was defined as a low amount of cortical activity accompanying high performance during problem-solving. Students solved the tasks faster and more accurately the higher their FI was. Moreover, while high FI led to greater cortical activity in the first half of the experiment, high FI was associated with a neurally more efficient processing (i.e., better performance but same amount of cortical activity) in the second half of the experiment. Performance in difficult tasks improved over the course of the experiment for all students while neural efficiency increased for students with higher but decreased for students with lower fluid intelligence. Based on analyses of the alpha sub-bands, we argue that high fluid intelligence was associated with a stronger investment of attentional resource in the integration of information and the encoding of relations in this unfamiliar task in the first half of the experiment (lower-2 alpha band). Students with lower fluid intelligence seem to adapt their applied strategies over the course of the experiment (i.e., focusing on task-relevant information; lower-1 alpha band). Thus, the initially lower cortical activity and its increase in students with lower fluid intelligence might reflect the overcoming of mental overload that was present in the first half of the experiment. PMID- 27461736 TI - Individual differences in conditioned fear expression are associated with enduring differences in endogenous Fibroblast Growth Factor-2 and hippocampal mediated memory performance. AB - Rodent studies of individual differences in fear expression following Pavlovian fear conditioning are thought to provide useful means by which to examine the factors associated with vulnerability and resilience to anxiety and trauma- and stressor-related disorders in humans. We have recently demonstrated that rats that naturally exhibit low levels of conditioned fear have greater hippocampal expression of the neurotrophic factor Fibroblast Growth Factor-2 (FGF2), relative to rats that naturally exhibit high levels of conditioned fear. In the present study we determined whether individual variance in conditioned fear expression is associated with distinct behavioral profiles across a range of tasks designed to assess expression of trait anxiety and non-emotional memory performance, and whether the differences in hippocampal FGF2 are relatively stable across time. Results indicated that, relative to rats naturally exhibiting low levels of fear, rats naturally exhibiting high levels of fear in the presence of a previously conditioned cue and context also showed heightened levels of trait anxiety, reduced ability to discriminate between a previously conditioned context and a safe context, and impaired performance on the hippocampal-mediated place recognition task, but not on the non-hippocampal-mediated object recognition task. Moreover, differences in hippocampal FGF2 expression were evident between high and low fear rats even three months following the tests for conditioned fear expression. Together, these results suggest that individual differences in conditioned fear expression may be mediated partly by enduring differences in hippocampal functioning. PMID- 27461738 TI - Influence of previous treatment of oral squamous cell carcinoma on the geographic distribution of recurrent neck metastases: A case series of unusual level 4 metastases. AB - BACKGROUND: Cervical node management is vital for the successful treatment of oral squamous cell carcinoma (OSCC). Lymphatic spread from intra-oral malignancies usually follows a predictable path. We report on two patients with isolated level 4 recurrence following previous treatment for OSCC. METHODS: Single institutional case series. RESULTS: Two patients, initially N0, treated by surgery and ipsilateral neck dissection, presented with recurrent OSCC. One patient received adjuvant radiotherapy. Both patients developed recurrent/new disease at 7years and and 22months, respectively, and had salvage surgery, one had adjuvant radiation therapy. Both, subsequently, presented again at 3 and 12months with isolated, ipsilateral level 4 metastases. CONCLUSION: These two patients presented with delayed skip metastases which defies normal drainage patterns. The experience with these patients and a review of the literature raises the question of addressing the treatment of level 4 lymph nodes in recurrent OSCC due to altered drainage. PMID- 27461739 TI - Body traits, carcass characteristics and price of cull cows as affected by farm type, breed, age and calving to culling interval. AB - Beef production from cull cows is an additional source of income for dairy farms and greatly contributes to red meat production, but the sources of variation of live animal characteristics and the carcass traits of cull cows have rarely been examined. This study investigated the effects of the farm type, breed, age at slaughter (AGE) and calving to culling interval (Calv_Cull) on the body traits and carcass characteristics of dairy and dual-purpose cull cows. Data from 555 cull cows from 182 herds belonging to five farm types, characterised by a combination of housing and feeding systems, were recorded and analysed. Dairy breeds, such as Holstein Friesian and Brown Swiss, and dual-purpose breeds (Simmental, Rendena) were included in the trait assessments. The day before slaughter, the cows were weighed and scored for body condition (BCS) and fleshiness, and then, their heart girth and wither height were measured. At the slaughterhouse, the carcass weight (CW), dressing percentage (DP), carcass conformation and fatness scores, carcass price per kg and carcass total value were obtained. On average, the cows were slaughtered at nearly 71+/-27 months of age, 285+/-187 days after the last calving; 615+/-95 kg BW; and provided a 257+/ 51 kg CW. Nearly 50% of the cows fell within the BCS range of 2.75 to 3.50, and the carcasses were mostly graded in the lowest class of conformation and fatness scores. Cull cows from free-stall farms had a higher DP, carcass conformation score and price than those from traditional tie-stall farms. The breed influenced the AGE, live animal characteristics and carcass traits. Cows from dairy breeds were younger at slaughter, had a lower BCS and fleshiness, and greater body measurements, but a lower DP and carcass price than those from dual-purpose breeds, although differences between the breeds were found within both groups. The age of the cows at slaughter influenced the Calv_Cull and increased the BW, body measurements and CW, but not the fleshiness and fatness appreciation (both in vivo and postmortem) or carcass price. The increasing Calv_Cull improved the BW, BCS, fleshiness, CW and carcass conformation and fatness. In conclusion, the decision to cull dairy cows should also take into account the factors that affect their carcass value in regards to improving the carcass price of cows. PMID- 27461737 TI - The rich somatic life of Wolbachia. AB - Wolbachia is an intracellular endosymbiont infecting most arthropod and some filarial nematode species that is vertically transmitted through the maternal lineage. Due to this primary mechanism of transmission, most studies have focused on Wolbachia interactions with the host germline. However, over the last decade many studies have emerged highlighting the prominence of Wolbachia in somatic tissues, implicating somatic tissue tropism as an important aspect of the life history of this endosymbiont. Here, we review our current understanding of Wolbachia-host interactions at both the cellular and organismal level, with a focus on Wolbachia in somatic tissues. PMID- 27461740 TI - Sequence-specific DNA binding by AT-hook motifs in MeCP2. AB - MeCP2 is a chromatin-associated protein that is mutated in Rett syndrome. Its methyl-CpG-binding domain interacts with DNA containing methylated cytosine, but other modes of recruitment to the genome have also been proposed. Here, we use in vitro and in vivo assays to investigate the DNA binding specificity of two AT hook motifs in MeCP2. One exhibits robust sequence-specific DNA binding, whereas the other is a much weaker AT-hook. Our data indicate that these motifs are secondary contributors to DNA binding by MeCP2, and this view is supported by the absence of disease-causing missense mutations at these sites. PMID- 27461741 TI - Wrinkling Non-Spherical Particles and Its Application in Cell Attachment Promotion. AB - Surface wrinkled particles are ubiquitous in nature and present in different sizes and shapes, such as plant pollens and peppercorn seeds. These natural wrinkles provide the particles with advanced functions to survive and thrive in nature. In this work, by combining flow lithography and plasma treatment, we have developed a simple method that can rapidly create wrinkled non-spherical particles, mimicking the surface textures in nature. Due to the oxygen inhibition in flow lithography, the non-spherical particles synthesized in a microfluidic channel are covered by a partially cured polymer (PCP) layer. When exposed to plasma treatment, this PCP layer rapidly buckles, forming surface-wrinkled particles. We designed and fabricated various particles with desired shapes and sizes. The surfaces of these shapes were tuned to created wrinkle morphologies by controlling UV exposure time and the washing process. We further demonstrated that wrinkles on the particles significantly promoted cell attachment without any chemical modification, potentially providing a new route for cell attachment for various biomedical applications. PMID- 27461743 TI - Development and validation of a shared decision-making instrument for health related quality of life one year after total hip replacement based on quality registries data. AB - RATIONALE, AIMS AND OBJECTIVES: Clinicians considering improvements in health related quality of life (HRQoL) after total hip replacement (THR) must account for multiple pieces of information. Evidence-based decisions are important to best assess the effect of THR on HRQoL. This work aims at constructing a shared decision-making tool that helps clinicians assessing the future benefits of THR by offering predictions of 1-year postoperative HRQoL of THR patients. METHODS: We used data from the Swedish Hip Arthroplasty Register. Data from 2008 were used as training set and data from 2009 to 2012 as validation set. We adopted two approaches. First, we assumed a continuous distribution for the EQ-5D index and modelled the postoperative EQ-5D index with regression models. Second, we modelled the five dimensions of the EQ-5D and weighted together the predictions using the UK Time Trade-Off value set. As predictors, we used preoperative EQ-5D dimensions and the EQ-5D index, EQ visual analogue scale, visual analogue scale pain, Charnley classification, age, gender, body mass index, American Society of Anesthesiologists, surgical approach and prosthesis type. Additionally, the tested algorithms were combined in a single predictive tool by stacking. RESULTS: Best predictive power was obtained by the multivariate adaptive regression splines (R2 = 0.158). However, this was not significantly better than the predictive power of linear regressions (R2 = 0.157). The stacked model had a predictive power of 17%. CONCLUSIONS: Successful implementation of a shared decision-making tool that can aid clinicians and patients in understanding expected improvement in HRQoL following THR would require higher predictive power than we achieved. For a shared decision-making tool to succeed, further variables, such as socioeconomics, need to be considered. PMID- 27461742 TI - Simultaneous Identification of Spectral Properties and Sizes of Multiple Particles in Solution with Subnanometer Resolution. AB - We report an unsurpassed solution characterization technique based on analytical ultracentrifugation, which demonstrates exceptional potential for resolving particle sizes in solution with sub-nm resolution. We achieve this improvement in resolution by simultaneously measuring UV/Vis spectra while hydrodynamically separating individual components in the mixture. By equipping an analytical ultracentrifuge with a novel multi-wavelength detector, we are adding a new spectral discovery dimension to traditional hydrodynamic characterization, and amplify the information obtained by orders of magnitude. We demonstrate the power of this technique by characterizing unpurified CdTe nanoparticle samples, avoiding tedious and often impossible purification and fractionation of nanoparticles into apparently monodisperse fractions. With this approach, we have for the first time identified the pure spectral properties and band-gap positions of discrete species present in the CdTe mixture. PMID- 27461745 TI - The pressing need for real-time risk assessment of hospital-acquired acute kidney injury. AB - Acute Kidney Injury (AKI) is associated with short- and long-term outcomes that reflect the severity of the injury. Recent studies have suggested that 'early' initiation of renal replacement therapy may alter the course of AKI and improve short-term outcomes like inpatient mortality. The current Kidney Disease Improving Global Outcomes (KDIGO) consensus definition of AKI has been criticized for misclassification bias, lack of sensitivity and the static manner in which AKI stages are defined. This editorial reviews various approaches to improving the specificity and sensitivity of the KDIGO AKI criteria, and also concludes that a staging system based on creatinine trajectories would be better suited for developing a prognostic index for real-time, dynamic risk assessment that the current KDIGO staging criteria. PMID- 27461744 TI - Back-calculating baseline creatinine overestimates prevalence of acute kidney injury with poor sensitivity. AB - AIM: Acute kidney injury (AKI) is diagnosed by a 50% increase in creatinine. For patients without a baseline creatinine measurement, guidelines suggest estimating baseline creatinine by back-calculation. The aim of this study was to evaluate different glomerular filtration rate (GFR) equations and different GFR assumptions for back-calculating baseline creatinine as well as the effect on the diagnosis of AKI. METHODS: The Modification of Diet in Renal Disease, the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Mayo quadratic (MQ) equation were evaluated to estimate baseline creatinine, each under the assumption of either a fixed GFR of 75 mL min-1 1.73 m-2 or an age-adjusted GFR. Estimated baseline creatinine, diagnoses and severity stages of AKI based on estimated baseline creatinine were compared to measured baseline creatinine and corresponding diagnoses and severity stages of AKI. RESULTS: The data of 34 690 surgical patients were analysed. Estimating baseline creatinine overestimated baseline creatinine. Diagnosing AKI based on estimated baseline creatinine had only substantial agreement with AKI diagnoses based on measured baseline creatinine [Cohen's kappa ranging from 0.66 (95% CI 0.65-0.68) to 0.77 (95% CI 0.76-0.79)] and overestimated AKI prevalence with fair sensitivity [ranging from 74.3% (95% CI 72.3-76.2) to 90.1% (95% CI 88.6-92.1)]. Staging AKI severity based on estimated baseline creatinine had moderate agreement with AKI severity based on measured baseline creatinine [Cohen's kappa ranging from 0.43 (95% CI 0.42-0.44) to 0.53 (95% CI 0.51-0.55)]. CONCLUSION: Diagnosing AKI and staging AKI severity on the basis of estimated baseline creatinine in surgical patients is not feasible. Patients at risk for post-operative AKI should have a pre-operative creatinine measurement to adequately assess post-operative AKI. PMID- 27461746 TI - Effect of amylose, particle size & morphology on the functionality of starches of traditional rice cultivars. AB - The research was carried out to investigate the effect of starch powder particle size, morphology, amylose content and varietal effect on physicochemical, X-ray diffraction pattern, thermal and pasting characteristics. The results indicated that starches isolated from seven traditional rice cultivars of temperate region of India have possessed higher yield (82.47-86.83%) with lower degree of granule damage and higher level of starch crystallinity (36.55-39.15%). The water and oil binding capacities were observed to correlate positively with amylose content. The bulk density and color parameters of starches were found to have linked with starch powder particle size coupled with arrangement and morphology of the starch granules. The rice cultivars having smaller starch powder particle size indicated lowest degree of crystallinity. Morphological studies revealed that the starches with tightly packed granules had greater mean granular width, while granules with openly spaced granular morphology depicted the higher values for mean granular length. The peak height index (PHI) among different starches ranged from 1.01 to 2.57 whereas the gelatinization range varied from 10.66 to 10.88. Concluding, the differences in distributional pattern of starch granule size and shape and powder particle size indicated a significant effect on the functional properties of starch. PMID- 27461747 TI - Case of desmoplastic melanoma with lung metastasis maintaining complete response after cessation of nivolumab. PMID- 27461748 TI - Biomimetic Total Synthesis of Hyperjapones A-E and Hyperjaponols A and C. AB - Hyperjapones A-E and hyperjaponols A-C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A-E using a biomimetic, oxidative hetero-Diels-Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid-catalyzed epoxide ring-opening; and 3) a concerted, asynchronous alkene cyclization and 1,2-alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponol C to be completed in which six carbon-carbon bonds, six stereocenters, and three rings were constructed in just four steps. PMID- 27461749 TI - Prior task experience and comparable stimulus exposure nullify focal and nonfocal prospective memory retrieval differences. AB - We explored the nature of focal versus nonfocal event-based prospective memory retrieval. In the context of a lexical decision task, people received an intention to respond to a single word (focal) in one condition and to a category label (nonfocal) for the other condition. Participants experienced both conditions, and their order was manipulated. The focal instruction condition was a single word presented multiple times. In Experiment 1, the stimuli in the nonfocal condition were different exemplars from a category, each presented once. In the nonfocal condition retrieval was poorer and reaction times were slower during the ongoing task as compared to the focal condition, replicating prior findings. In Experiment 2, the stimulus in the nonfocal condition was a single category exemplar repeated multiple times. When this single-exemplar nonfocal condition followed in time the single-item focal condition, focal versus nonfocal performance was virtually indistinguishable. These results demonstrate that people can modify their stimulus processing and expectations in event-based prospective memory tasks based on experience with the nature of prospective cues and with the ongoing task. PMID- 27461750 TI - Addition of biochar to sewage sludge decreases freely dissolved PAHs content and toxicity of sewage sludge-amended soil. AB - Due to an increased content of polycyclic aromatic hydrocarbons (PAHs) frequently found in sewage sludges, it is necessary to find solutions that will reduce the environmental hazard associated with their presence. The aim of this study was to determine changes of total and freely dissolved concentration of PAHs in sewage sludge-biochar-amended soil. Two different sewage sludges and biochars with varying properties were tested. Biochars (BC) were produced from biogas residues at 400 degrees C or 600 degrees C and from willow at 600 degrees C. The freely dissolved PAH concentration was determined by means of passive sampling using polyoxymethylene (POM). Total and freely dissolved PAH concentration was monitored at the beginning of the experiment and after 90 days of aging of the sewage sludge with the biochar and soil. Apart from chemical evaluation, the effect of biochar addition on the toxicity of the tested materials on bacteria - Vibrio fischeri (Microtox(r)), plants - Lepidium sativum (Phytotestkit F, Phytotoxkit F), and Collembola - Folsomia candida (Collembolan test) was evaluated. The addition of biochar to the sewage sludges decreased the content of Cfree PAHs. A reduction from 11 to 43% of sewage sludge toxicity or positive effects on plants expressed by root growth stimulation from 6 to 25% to the control was also found. The range of reduction of Cfree PAHs and toxicity was dependent on the type of biochar. After 90 days of incubation of the biochars with the sewage sludge in the soil, Cfree PAHs and toxicity were found to further decrease compared to the soil with sewage sludge alone. The obtained results show that the addition of biochar to sewage sludges may significantly reduce the risk associated with their environmental use both in terms of PAH content and toxicity of the materials tested. PMID- 27461751 TI - Airborne fine particulate matter alters the expression of endothelin receptors in rat coronary arteries. AB - Exposure to airborne fine particulate matter (PM2.5) is associated with cardiovascular diseases. However, a comprehensive understanding of the underlying mechanisms by which PM2.5 induces or aggravates these diseases is still insufficiently clear. The present study investigated whether PM2.5 alters the expression of the endothelin subtype B (ETB) and endothelin subtype A (ETA) receptors in the coronary artery and examined the underlying mechanisms. Rat coronary artery segments were cultured with PM2.5 in the presence or absence of MEK/ERK1/2, JNK, and p38 pathway inhibitors. Contractile reactivity was measured by myography. ETB and ETA receptor expression was evaluated using RT-PCR, western blot and immunohistochemistry. Compared with fresh arteries, the cultured coronary arteries showed a significantly enhanced contraction mediated by the ETB receptor and an unaltered contraction mediated by the ETA receptor. Culture with PM2.5 significantly enhanced the contraction and the mRNA and protein expression levels of the ETB and ETA receptors in the coronary arteries, suggesting that PM2.5 induces an upregulation of ETA and ETB receptors. In addition, the PM2.5 induced increases in ETB- and ETA-mediated vasoconstriction and receptor expressions could be notably decreased by MEK1/2 inhibitor, U0126 and Raf inhibitor, SB386023, suggesting that the upregulation of ETB and ETA receptors is related with MEK/ERK1/2 pathway. In conclusion, PM2.5 induces the ETB and ETA receptor upregulation in rat coronary arteries, and the MEK/ERK1/2 pathway may be involved in this process. PMID- 27461753 TI - Nurses' representations of caring for intellectually disabled patients and perceived needs to ensure quality care. AB - AIMS AND OBJECTIVES: To explore nurses' representations of caring for people with an intellectual disability, intervention strategies they currently use, and to identify needs to ensure quality care. BACKGROUND: Nurses work in many environments and with diverse clienteles. Certain clienteles have needs that require specific approaches, such as persons who have an intellectual disability. The care offered to these patients can be influenced by the representations held by the nurses caring for them. DESIGN: Qualitative descriptive study. METHODS: Semi-structured interviews using thematic analysis were conducted with 18 nurses working in hospital and community settings. RESULTS: Nurses are concerned with their ability to recognise the specific nature and complex needs associated with patients' intellectual disabilities, promoting quality care by managing the behavioural and communication challenges, as well as coping with the perceived lack of time and organisation within the work environment. Current strategies involve trying to promote the continuity of care. Participants also identified their learning needs, which are relational and informational in nature. CONCLUSIONS: Nurses appear typically mindful of wanting to provide quality care to patients who have an intellectual disability, while recognising that there are many contextual and practical elements that require improvement to ensure the security of these patients. RELEVANCE TO CLINICAL PRACTICE: Nurses must be educated to adapt to findings emerging from current research showing that people with an intellectual disability want to be part of their local communities and encourage these persons to do so. This can be facilitated through the adoption of specific guidelines, protocols and care programmes. Further research is needed to develop a better understanding of the expectations of these patients and their caregivers, focusing on self-advocacy as well as health promotion techniques, with the goal of enhancing personalised practice standards and reducing health education inequalities for these patients. PMID- 27461752 TI - A quantitative assessment of source contributions to fine particulate matter (PM2.5)-bound polycyclic aromatic hydrocarbons (PAHs) and their nitrated and hydroxylated derivatives in Hong Kong. AB - Atmospheric polycyclic aromatic hydrocarbons (PAHs) and their derivatives are of great concern due to their adverse health effects. However, source identification and apportionment of these compounds, particularly their nitrated and hydroxylated derivatives (i.e., NPAHs and OHPAHs), in fine particulate matter (PM2.5) in Hong Kong are still lacking. In this study, we conducted a 1-year observation at an urban site in Hong Kong. PM2.5-bound PAHs and their derivatives were measured, with median concentrations of 4590, 44.4 and 31.6 pg m-3 for ?21PAHs, ?13NPAHs, and ?12OHPAHs, respectively. Higher levels were observed on regional pollution days than on long regional transport (LRT) or local emission days. Based on positive matrix factorization analysis, four sources were determined: marine vessels, vehicle emissions, biomass burning, and a mixed source of coal combustion and NPAHs secondary formation. Coal combustion and biomass burning were the major sources of PAHs, contributing over 85% of PAHs on regional and LRT days. Biomass burning was the predominant source of OHPAHs throughout the year, while NPAHs mainly originated from secondary formation and fuel combustion. For benzo[a]pyrene (BaP)-based PM2.5 toxicity, the mixed source of coal combustion and NPAHs secondary formation was the major contributor, followed by biomass burning and vehicle emissions. PMID- 27461755 TI - Analysis of Vitamin D2 and Vitamin D3 in Fortified Milk Powders and Infant and Nutritional Formulas by Liquid Chromatography-Tandem Mass Spectrometry: Single Laboratory Validation, First Action 2016.05. AB - A method for the determination of vitamin D2 and vitamin D3 in fortified milk powders and infant and adult nutritional formulas is described. Samples are saponified at high temperature and lipid-soluble components are extracted into isooctane. A portion of the isooctane layer is transferred and washed, and an aliquot of 4-phenyl-1,2,4-triazoline-3,5-dione is added to derivatize the vitamin D to form a high-molecular-mass, easily ionizable adduct. The vitamin D adduct is then re-extracted into a small volume of acetonitrile and analyzed by RPLC. Detection is by tandem MS, using multiple reaction monitoring. Stable isotope labeled vitamin D2 and vitamin D3 internal standards are used for quantitation to correct for losses in extraction and any variation in derivatization and ionization efficiencies. A single-laboratory validation of the method using AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) kit samples was performed and compared with parameters defined according to the vitamin D Standard Method Performance Requirements (SMPR((r))). Linearity was demonstrated over the range specified in the SMPR, with the LOD being estimated at below that required. Method spike recovery (vitamin D2, 97.0-99.2%; and vitamin D3, 96.0 101.0%) and RSDr (vitamin D3, 1.5-5.2%) were evaluated and compared favorably with limits in the vitamin D SMPR. Acceptable bias for vitamin D3 was demonstrated against both the certified value for National Institute of Standards and Technology 1849a Standard Reference material (P(alpha = 0.05) = 0.25) and AOAC INTERNATIONAL reference method 2002.05 (P(alpha = 0.05) = 0.09). The method was demonstrated to meet the requirements of the vitamin D SMPR as defined by SPIFAN, and was recently approved for Official First Action status by the AOAC Expert Review Panel on SPIFAN Nutrient Methods. PMID- 27461754 TI - Npy deletion in an alcohol non-preferring rat model elicits differential effects on alcohol consumption and body weight. AB - Neuropeptide Y (NPY) is widely expressed in the central nervous system and influences many physiological processes. It is located within the rat quantitative trait locus (QTL) for alcohol preference on chromosome 4. Alcohol nonpreferring (NP) rats consume very little alcohol, but have significantly higher NPY expression in the brain than alcohol-preferring (P) rats. We capitalized on this phenotypic difference by creating an Npy knockout (KO) rat using the inbred NP background to evaluate NPY effects on alcohol consumption. Zinc finger nuclease (ZNF) technology was applied, resulting in a 26-bp deletion in the Npy gene. RT-PCR, Western blotting and immunohistochemistry confirmed the absence of Npy mRNA and protein in KO rats. Alcohol consumption was increased in Npy(+/-) but not Npy(-/-) rats, while Npy(-/-) rats displayed significantly lower body weight when compared to Npy(+/+) rats. In whole brain tissue, expression levels of Npy-related and other alcohol-associated genes, Npy1r, Npy2r, Npy5r, Agrp, Mc3r, Mc4r, Crh and Crh1r, were significantly greater in Npy(-/-) rats, whereas Pomc and Crhr2 expressions were highest in Npy(+/-) rats. These findings suggest that the NPY-system works in close coordination with the melanocortin (MC) and corticotropin-releasing hormone (CRH) systems to modulate alcohol intake and body weight. PMID- 27461756 TI - Vocal fold control beyond the species-specific repertoire in an orang-utan. AB - Vocal fold control was critical to the evolution of spoken language, much as it today allows us to learn vowel systems. It has, however, never been demonstrated directly in a non-human primate, leading to the suggestion that it evolved in the human lineage after divergence from great apes. Here, we provide the first evidence for real-time, dynamic and interactive vocal fold control in a great ape during an imitation "do-as-I-do" game with a human demonstrator. Notably, the orang-utan subject skilfully produced "wookies" - an idiosyncratic vocalization exhibiting a unique spectral profile among the orang-utan vocal repertoire. The subject instantaneously matched human-produced wookies as they were randomly modulated in pitch, adjusting his voice frequency up or down when the human demonstrator did so, readily generating distinct low vs. high frequency sub variants. These sub-variants were significantly different from spontaneous ones (not produced in matching trials). Results indicate a latent capacity for vocal fold exercise in a great ape (i) in real-time, (ii) up and down the frequency spectrum, (iii) across a register range beyond the species-repertoire and, (iv) in a co-operative turn-taking social setup. Such ancestral capacity likely provided the neuro-behavioural basis of the more fine-tuned vocal fold control that is a human hallmark. PMID- 27461757 TI - High-glucose environment disturbs the physiologic functions of keratinocytes: Focusing on diabetic wound healing. AB - Impaired wound healing is a common and potentially serious complication in patients with diabetes. In recent years, disturbed physiologic functions of epidermal keratinocytes have been found to play a central role in the poor healing ability of diabetic wounds. Factors involving keratinocytes that may contribute to the dysfunctional wound healing process in diabetes include impaired keratinocyte migration and proliferation, gap junction abnormalities, chronic inflammation, chronic infections associated with defective innate immunity, impaired angiogenesis, increased oxidative stress, and abnormal expression of matrix metalloproteinases (MMPs). In this review article, we provide evidence from the scientific literature for the molecular mechanisms of delayed wound healing in diabetes, with particular emphasis on keratinocytes. Elucidating the spectrum of molecular and functional abnormalities in keratinocytes induced by high-glucose environment may lead to more effective and individualized therapeutic strategies for the prevention and management of chronic diabetic wounds. PMID- 27461758 TI - Atopic dermatitis, naevi count and skin cancer risk: A meta-analysis. AB - BACKGROUND: The risk of skin malignancy among atopic dermatitis (AD) patients is not well established. OBJECTIVE: We reviewed the epidemiological evidence on the association between AD, naevi count, and the risk of cutaneous melanoma and keratinocyte skin cancer (KSC). METHODS: We included all studies that compared the naevi count and the risk of skin cancer (melanoma and/or KSC) between AD patients and unaffected individuals. We calculated summary relative risks (SRRs) and 95% confidence intervals (CI) through random effects models; explored correlates of between-studies heterogeneity using sub-group and sensitivity analysis; and assessed publication bias using a funnel-plot-based approach. RESULTS: The number of common naevi larger >=2mm on the whole body was consistently lower among AD patients vs. unaffected individuals when measured by trained health professionals. The risk of melanoma was not increased among AD patients (SRR=0.77, 95%CI 0.44-1.35, I2=85%). We found a significantly increased risk of basal cell cancer (BCC) (SRR=1.34, 95%CI 1.03-1.75, I2=24.0%) but not for squamous cell cancer (SRR=1.91, 95% CI 0.74-4.91, I2=0.0%); however, only a few papers adjusted for phenotypic characteristics and/or sunlight exposure. We found no evidence of publication bias. CONCLUSIONS: AD patients may be at increased BCC risk; however, methodological limitations prevented from drawing definitive conclusions. Despite the lack of strong scientific evidence, AD patients should avoid excessive sun exposure, regularly perform skin self examination, and consult a doctor in case of a suspicious skin lesion. PMID- 27461759 TI - Palladium-catalyzed beta-(hetero)arylation of alpha,beta-unsaturated valerolactams. AB - A method for the palladium-catalyzed arylation of alpha,beta-unsaturated valerolactams is reported. This new protocol provides arylation products in yields up to 95% and is applicable to a wide array of aryl and heteroaryl bromides. The optimization, scope and limitations are described. PMID- 27461760 TI - Resilience to Cumulative Stressors: A Prediction Study of Schoolchildren Living With Maternal Depression. AB - PURPOSE: To identify the predictive effect of multiple variables of risk and resilience on the behavior of school-age children living with maternal depression. DESIGN AND METHODS: In a cross-sectional predictive study, the influence of maternal depression, cumulative stressors, and resilience on the behavior of children was analyzed. FINDINGS: In the univariate analysis, maternal depression and cumulative stressors were considered as risks, and resilience as protection for the children. In the multivariate analysis, resilience was a predictor of fewer problems in the presence of maternal depression and risks. PRACTICE IMPLICATIONS: The degree of resilience was an indicator for the relevance of developmental actions involving effective coping skills for cumulative stressors, including maternal depression. PMID- 27461761 TI - Spring-action Apparatus for Fixation of Eyeball (SAFE): a novel, cost-effective yet simple device for ophthalmic wet-lab training. AB - Achieving a formed and firm eyeball which is stably fixed in a holding device is a major challenge of surgical wet-lab training. Our innovation, the 'Spring action Apparatus for Fixation of Eyeball (SAFE)' is a robust, simple and economical device to solve this problem. It consists of a hollow iron cylinder to which a spring-action syringe is attached. The spring-action syringe generates vacuum and enables reliable fixation of a human or animal cadaveric eye on the iron cylinder. The rise in intraocular pressure due to vacuum fixation can be varied as per need or nature of surgery being practised. A mask-fixed version of this device is also designed to train surgeons for appropriate hand positioning. An experienced surgeon performed various surgeries including manual small incision cataract surgery (MSICS), phacoemulsification, laser in situ keratomileusis (LASIK), femtosecond LASIK docking, Descemet's stripping endothelial keratoplasty, deep anterior lamellar keratoplasty, penetrating keratoplasty and trabeculectomy on this device, while a trainee surgeon practised MSICS and wound suturing. Skill-appropriate comfort level was much higher with SAFE than with conventional globe holders for both surgeons. Due to its stability, pressure adjustability, portability, cost-efficiency and simplicity, we recommend SAFE as the basic equipment for every wet lab. PMID- 27461762 TI - Challenges to Adolescent Confidentiality in a Children's Hospital. AB - OBJECTIVES: Protecting confidentiality for hospitalized adolescents can be challenging and may interfere with optimal adolescent-friendly care. The goal of this study was to explore physician trainees' experience with adolescent confidentiality at an academic children's hospital. METHODS: A total of 175 trainees were invited to complete an online survey about knowledge, attitudes, and experiences with confidential adolescent concerns in the inpatient setting. A total of 133 (76%) responded: 78% female; 65% pediatric or family medicine residents; and 35% medical students. RESULTS: In the past year, 56 (42%) of 133 trainees cared for a hospitalized adolescent whose confidentiality had been breached. Barriers to ensuring confidentiality included: patient/family not knowledgeable about minor consent law (50%); trainees not knowledgeable about minor consent law (47%); and hospital discharge summary requiring parental signature (47%). On patient- and family-centered rounds (PFCR), respondents reported that minor adolescents (aged <18 years) compared with young adults (aged >=18 years) were more likely to have social history discussed away from the bedside (91% vs 84%; P < .001) and less likely to have confidential time with the medical team (28% vs 47%; P < .001). Barriers to participation in PFCR included the following: patient was sleeping (61%), patient declined to participate (51%), and confidentiality concerns (32%). CONCLUSIONS: Breaches in confidentiality for hospitalized adolescents are a common trainee experience. On PFCR, adolescents are less likely to have confidential time with the medical team than young adults. In trainees' experience, hospital systems such as PFCR and discharge procedures pose inherent challenges to confidentiality for minor adolescent patients, as do lack of knowledge of minor consent laws by both clinicians and families. PMID- 27461763 TI - In this issue September 2016. PMID- 27461764 TI - The big research question: who decides? PMID- 27461765 TI - The translational value of chart reviews and the need for trials. PMID- 27461766 TI - Current practice of acute pain management in children-a national follow-up survey in Germany. AB - OBJECTIVES: This study aimed to summarize the current standard practices for acute pain management in children in Germany and the implementation of these procedures. The last survey on acute pain management in children was performed in 1999, highlighting the need for an up to date review. METHODS: A questionnaire was mailed to German departments of anesthesiology (n = 885), asking for structures and processes of acute pain management in children. Results were compared between hospitals with and without an acute pain service and with and without a pediatric department. RESULTS: Of the 407 responding hospitals (response rate of 46%), 342 treated children younger than 14 years. These were considered for analysis. Of the 342 hospitals, 42% contained either a general pediatric department or a department of pediatric surgery, and the majority of the responding hospitals had an acute pain service (83%). Pain intensities were measured at least once per shift in 40% of the institutions, and at least once or twice a day in 27%. Of the institutions, 31% did not document pain scores regularly, without any difference between hospitals with or without a pediatric department. Standard operating procedures for acute pain management existed in 68% of the hospitals, with large differences in content and length. Opioids were administered to children in 85% of the hospitals. Nonopioid analgesics were the first choice baseline analgesics in most hospitals. Peripheral regional and epidural analgesia were performed in children in 18% and 8% of the hospitals, respectively (21%/16% with a paediatric department, 16%/1% without; P < 0.001). CONCLUSION: Current practice of pediatric pain management varied widely and the recommendations of guidelines, like regular pain management, were frequently not met. However, improvements could be observed since 1999, for example, an increase in regular pain measurements (4% vs 67%). Furthermore, pain management in hospitals running a pediatric department had a higher degree of organization, and more sophisticated analgesic techniques. PMID- 27461767 TI - Bispectral index under propofol anesthesia in children: a comparative randomized study between TIVA and TCI. AB - BACKGROUND: In children, only a few studies have compared different modes of propofol infusion during a total intravenous anesthesia (TIVA) with propofol and remifentanil. The aim of this study was to compare Bispectral Index (BIS) profiles (percentage of time spent at adequate BIS values) between four modes of propofol infusion: titration of the infusion rate on clinical signs (TIVA0 ), titration of the infusion rate on the BIS (TIVABIS ), target controlled infusion (TCI) guided by the BIS either with the Kataria model (TCI KBIS ) or the Schnider model (TCI SBIS ). METHODS: Sixty-six children (aged from 4 to 14 years) were prospectively randomized into one of the four groups. In the TIVA0 group, the anesthesiologist was blinded to the BIS. In each group, the percentage of time with adequate BIS values (45-55), the bias, and imprecision were calculated. RESULTS: The propofol consumption was similar in the four groups. During the maintenance phase, the percentage of time spent in the targeted BIS range was significantly lower in the TIVA0 group compared to the three other groups (TIVA0 : 31% +/- 22, TIVABIS : 59% +/- 17, TCI KBIS : 53% +/- 12, TCI SBIS : 56% +/- 17). The bias was not statistically different between the four groups, but the imprecision was larger for the TIVA0 group. Compared to the Kataria model, the Schnider model was associated with shorter time delay to reach the desired BIS, to eyes opening, and to tracheal extubation. CONCLUSIONS: Propofol administration using manual infusion guided by clinical signs was associated with higher risks of over- or underdosage when compared to BIS-guided administrations. When propofol infusion was guided by the BIS, no major difference was found between TIVA and TCI (either with the Kataria or the Schnider model). This study highlights the need of a pharmacodynamic feedback during propofol anesthesia in children. PMID- 27461768 TI - The vanishing neck mass: how using a laryngeal mask airway during magnetic resonance imaging of a child can cause misdiagnosis. PMID- 27461769 TI - An unusual airway obstruction caused by partial detachment of inner layer of reinforced endotracheal tube. PMID- 27461770 TI - Single-shot thoracic epidural: an aid to earlier discharge for pediatric laparoscopic cholecystectomy. PMID- 27461771 TI - Chelation competition induced polymerization (CCIP): construction of integrated hollow polydopamine nanocontainers with tailorable functionalities. AB - A novel 'chelation competition induced polymerization' route was developed to construct hollow polydopamine nanocontainers with tailorable functionalities. The mechanism is systematically investigated and the nanocontainers constructed through this method show excellent chemo-thermo performance in vitro. This strategy is facile and is expected to be used for the construction of a series of hollow polymer nanostructures. PMID- 27461772 TI - Consequences of Late-Stage Non-Small-Cell Lung Cancer Cachexia on Muscle Metabolic Processes. AB - INTRODUCTION: The loss of muscle is common in patients with advanced non-small cell lung cancer (NSCLC) and contributes to the high morbidity and mortality of this group. The exact mechanisms behind the muscle loss are unclear. PATIENTS AND METHODS: To investigate this, 4 patients with stage IV NSCLC who met the clinical definitions for sarcopenia and cachexia were recruited, along with 4 age-matched healthy volunteers. After an overnight fast, biopsy specimens were obtained from the vastus lateralis, and the key components associated with inflammation and the control of muscle protein, carbohydrate, and fat metabolism were assessed. RESULTS: Compared with the healthy volunteers, significant increases in mRNA levels for interleukin-6 and NF-kappaB signaling and lower intramyocellular lipid content in slow-twitch fibers were observed in NSCLC patients. Although a significant decrease in phosphorylation of the mechanistic target of rapamycin (mTOR) signaling protein 4E-BP1 (Ser65) was observed, along with a trend toward reduced p70 S6K (Thr389) phosphorylation (P = .06), no difference was found between groups for the mRNA levels of MAFbx (muscle atrophy F box) and MuRF1 (muscle ring finger protein 1), chymotrypsin-like activity of the proteasome, or protein levels of multiple proteasome subunits. Moreover, despite decreases in intramyocellular lipid content, no robust changes in mRNA levels for key proteins involved in insulin signaling, glycolysis, oxidative metabolism, or fat metabolism were observed. CONCLUSION: These findings suggest that examining the contribution of suppressed mTOR signaling in the loss of muscle mass in late stage NSCLC patients is warranted and reinforces our need to understand the potential contribution of impaired fat metabolism and muscle protein synthesis in the etiology of cancer cachexia. PMID- 27461773 TI - Efficacy and Safety Results From a Phase II, Placebo-Controlled Study of Onartuzumab Plus First-Line Platinum-Doublet Chemotherapy for Advanced Squamous Cell Non-Small-Cell Lung Cancer. AB - INTRODUCTION: The treatment options for squamous cell non-small-cell lung cancer (NSCLC) are limited. We assessed the efficacy and safety of onartuzumab plus platinum-doublet chemotherapy in previously untreated advanced squamous cell NSCLC. PATIENTS AND METHODS: The patients were randomized to receive onartuzumab plus paclitaxel plus carboplatin/cisplatin (n = 55) or placebo plus paclitaxel plus carboplatin/cisplatin (n = 54). Randomization was stratified by MET diagnostic status: MET immunohistochemistry (IHC)-positive (MET IHC 3+/2+) or MET IHC-negative (MET IHC 1+/0). The co-primary endpoints were investigator-assessed progression-free survival in the intent-to-treat and the MET IHC+ populations. RESULTS: The risk of disease progression or death was similar between the 2 treatment arms in both the intent-to-treat (stratified hazard ratio, 0.95; 95% confidence interval, 0.63-1.43) and MET IHC+ populations (unstratified hazard ratio, 1.27; 95% confidence interval, 0.69-2.32). Comparable results were obtained for overall survival and the objective response rate. In all safety evaluable patients, the grade 3 to 5 adverse events occurring at a > 5% greater incidence in the onartuzumab-containing versus the placebo-containing arm were neutropenia (14.8% vs. 5.8%) and pulmonary embolism (5.6% vs. 0%). Eight patients died as a result of adverse events: 1 case each of pneumonitis, pneumonia, cardiac failure, and unexplained death in the onartuzumab arm and 1 case each of hemorrhage, cardiac arrest, hemoptysis, and febrile neutropenia in the placebo arm. CONCLUSION: Studies using alternative assays of MET activation might help to clarify the role of onartuzumab. However, with the lack of clinical activity seen in the present study, the development of onartuzumab for squamous cell NSCLC will not be pursued further. PMID- 27461774 TI - Soluble c-Met Levels Correlated With Tissue c-Met Protein Expression in Patients With Advanced Non-Small-Cell Lung Cancer. AB - BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridization are reliable methods for identifying c-Met protein expression or c-Met gene amplification. However, each technique requires a high-quality tissue sample, which might not be available. The aim of the present study was to investigate the correlation between the soluble c-Met level and tissue c-Met protein expression and the relationship between these markers and patient prognosis. MATERIALS AND METHODS: In 198 patients with advanced non-small-cell lung cancer, tumor tissue c Met expression was determined using IHC according to the H score criteria. Positivity was defined as >= 50% of cells with strong staining (IHC 3+). The concentration of c-Met protein in paired plasma samples was measured using a human soluble c-Met quantitative enzyme-linked immunosorbent assay kit, and the predictive value was determined using receiver operating characteristic curve analysis. RESULTS: Of the 198 patients, 140 (70.7%) had tissue c-Met- findings and 58 (29.3%) tissue c-Met+ findings. Receiver operating characteristic curve analysis showed 67.2% specificity and 65.0% sensitivity for predicting tissue c Met positivity at a plasma c-Met cutoff of 766 ng/mL. The correlation between the soluble c-Met level and tissue c-Met protein expression was significant (Pearson's r = 0.309; P < .001). Patients with high soluble c-Met levels (> 766 ng/mL) had poorer overall survival than patients with low soluble c-Met levels (9.5 vs. 22.2 months; P < .001). Multivariate analyses demonstrated the same result (hazard ratio, 2.15; 95% confidence interval, 1.334-3.446; P = .002). CONCLUSION: A significant correlation was found between the plasma soluble c-Met levels and tissue c-Met protein expression in patients with advanced non-small cell lung cancer. A high level of soluble c-Met was associated with a poor prognosis. PMID- 27461775 TI - Effect of Accurate Staging Using Positron Emission Tomography on the Outcomes of Prophylactic Cranial Irradiation in Patients With Limited Stage Small-Cell Lung Cancer. AB - BACKGROUND: Prophylactic cranial irradiation (PCI) was reported to offer survival benefits in patients with limited stage small-cell lung cancer (LS-SCLC). However, earlier studies did not routinely use positron emission tomography (PET) as part of the initial evaluation, thereby reducing the accuracy of tumor staging. We examined the effect of more accurate staging with PET on the role of PCI in patients with LS-SCLC. PATIENTS AND METHODS: We retrospectively collected data from 280 patients with LS-SCLC who had objective responses after combined chemoradiotherapy between 2001 and 2013. The outcomes of PCI were analyzed after stratifying the patients according to whether or not the initial staging included PET imaging. RESULTS: The risk of brain metastasis as the first site of relapse was lower in patients who received PCI than in those who did not, only in patients without initial PET imaging (13.3% vs. 37.0%; P = .020), but not in patients with initial PET imaging (34.3% vs. 41.1%; P = .243). There was no survival difference between subgroups who received PCI or not (5-year survival rates, 34.8% vs. 34.1%; P = .938). Patients who had initial staging evaluation with PET achieved long-term survival even without PCI (5-year survival rates, 38.3% with PCI, 38.6% without PCI). CONCLUSION: The role of PCI needs to be critically reassessed in LS-SCLC patients whose initial staging evaluation included PET because the benefit of PCI was not apparent for them. PMID- 27461776 TI - Immunotherapy Comes of Age in Lung Cancer. AB - Lung carcinoma is the leading cause of death by cancer worldwide. When possible, surgery is the best treatment strategy for patients with non-small-cell lung cancer. However, even with curative-intent therapy, most patients will develop local or systemic recurrence and, ultimately, succumb to their disease. In recent years, evidence on the role of the antitumor activity of the immune system and the understanding of tumor immunosurveillance have resulted in the emergence of immunotherapy as a promising therapeutic approach in lung cancer. The main approaches are immune checkpoint inhibition, such as blockade of the cytotoxic T lymphocyte antigen-4 and programmed cell death-1 receptors and the programmed cell death-1 ligand, and vaccine therapy, which elicits specific antitumor immunity against relevant tumor-associated antigens. We have reviewed recently reported results from clinical trials and the possible future role of vaccine therapy and immune checkpoint inhibition in the treatment of small cell lung cancer and non-small-cell lung cancer. PMID- 27461777 TI - Comparison between suprapatellar and parapatellar approaches for intramedullary nailing of the tibia. Cadaveric study. AB - : Intramedullary nailing is one viable option for treating fractures of the tibia with a short, proximal segment. For a procedure being carried out with the knee in a semi-extended position, either a suprapatellar or parapatellar approach may be used. The objective of this study is to demonstrate whether the entry point for tibia nails is obtainable through suprapatellar or parapatellar approaches and to evaluate the most frequent injuries of the knee with these two approaches. MATERIALS AND METHODS: Paired legs from 10 fresh frozen cadavers were used. An arthroscopy was performed in each knee, documenting the status of the knee prior to the insertion of the tibia nail. In a random manner, the left or right leg underwent nailing with a suprapatellar or parapatellar approach in a semi extended position. Fluoroscopy was utilized in each case to localize the entry point, and a tibia nail was inserted in all cases. A knee arthrotomy was then performed and the status of the following structures was assessed: patella and trochlea cartilage, tibia plateau cartilage, inter-meniscal ligament, lateral and medial meniscus, and the ACL. RESULTS: The correct fluoroscopy entry point was achieved in all of the specimens (20). Three legs (3/10) with parapatellar approach had intra-articular disruption. In legs with a suprapatellar approach, patellar cartilage and trochlea cartilage damage was found in two of the specimens, respectively. There was one specimen with cartilage damage in the parapatellar approach. There were no meniscal injuries. Partial laceration of the intermeniscal ligament was found in three of the knees for each approach. One ACL injury was found in the suprapatellar group. Mean distance from the entry point to major structures is not significantly different with either approach. (p=0.45). CONCLUSIONS: A good fluoroscopic entry point can be achieved using either the parapatellar or suprapatellar approach. The parapatellar approach for tibia nailing has similar rate of soft tissue damage compared to the suprapatellar approach. The suprapatellar approach damaged the cartilage in one third of the cases and if cartilage injury occurs with the parapatellar approach, this is located in a low risk area. PMID- 27461778 TI - Negligence claims following non-union and malunion of long bone fractures: An analysis of 15 years of data. AB - INTRODUCTION: Non-unions and malunions are recognised to be complications of the treatment of long bone fractures. No previous work has looked at the implications of these complications from a medicolegal perspective. METHODS: A complete database of litigation claims in Trauma and Orthopaedic Surgery was obtained from the NHS Litigation Authority. Two separate modalities of the treatment of long bone fractures were examined i) non-union and ii) acquired deformity. The type of complaint, whether defended or not, and costs were analysed. RESULTS: There were claims of which 97 related to non-union and 32 related to postoperative limb deformity. The total cost was L8.2 million over a 15-year period in England and Wales. Femoral and tibial non-unions were more expensive particularly if they resulted in amputation. Rotational deformity cost nearly twice as much as angulation deformities. CONCLUSIONS: The cosmetic appearances of rotational malalignment and amputation results in higher compensation; this reinforces an outward perception of outcome as being more important than harmful effects. Notwithstanding the limitations of this database, there are clinical lessons to be gained from these litigation claims. PMID- 27461779 TI - Augmentation by cerclage wire improves fixation of vertical shear femoral neck fractures-A biomechanical analysis. AB - BACKGROUND: Femoral neck fractures in young individuals are typically vertical shear fractures. These injuries are difficult to stabilize due to a significant varus displacement force across the hip with weight bearing. The purpose of this study was to evaluate the biomechanical stability offered by the addition of an augmented wire to conventional inverted triangle triple screw fixation for stabilizing vertical shear femoral neck fracture. METHODS: Sixteen medium 4th generation synthetic composite femurs (Sawbones Pacific Research Laboratories, Vashon, WA) were divided into two groups. Vertical osteotomy was performed to mimic Pauwels III femoral neck fracture. Group A (n=8) was fixed with three parallel 6.5-mm cannulated screws (Stryker) with washer in inverted triangle configuration. In group B (n=8), all the screws were set using methods identical to group A, with the addition of the cerclage wire. Both groups were tested with nondestructive axial compression test at 7 and 25 degrees of valgus stress, respectively. Then axial cyclic loading test with 1000N was applied for 1000 cycles, and interfragmentary displacement was measured with Fastrak magnetic tracking system (Polhemus, Colchester, VT, USA). Finally, destructive axial compression test was conducted at 7 degrees of valgus stress. RESULTS: Axial stiffness showed that group B had a 66% increase (879N/mm vs. 1461N/mm, P<0.01) at 7 degrees valgus and a 46% increase (1611N/mm vs. 2349N/mm, P<0.01) at 25 degrees valgus in comparison with group A. Interfragmentary fracture displacement after cyclic loading was significantly less for group B compared with group A (0.34 vs 0.13mm, P=0.0016). For axial failure load, there was 42% increase in group B compared with group A (2602N/mm vs. 3686N/mm, P=0.0023). CONCLUSIONS: Our study demonstrates that the addition of a cerclage wire to inverted triangle triple screws provides substantial improvement in mechanical performance regarding fixation of vertically oriented femoral neck fractures when compared with the conventional construct. Our study provides support from a mechanical analysis perspective for the reported clinical usefulness of the cerclage wire. PMID- 27461780 TI - Can applied external fixators be sterilized for surgery? A prospective cohort study of orthopaedic trauma patients. AB - BACKGROUND: Temporary external fixators are often used to stabilize fractures when definitive fracture surgery must be delayed. Sometimes, external fixators are left in place during repeat operations, including definitive internal fixation of tibial pilon and tibial plateau fractures. It is unknown how well current surgical preparation sterilizes these devices, which become part of the surgical field. Our hypothesis was that our institution's standard surgical preparation creates a low rate of culture-positive environments on external fixators at the time of surgical skin incision. METHODS: We prospectively consented and enrolled patients to obtain cultures (48 patients, 55 external fixators, 165 sets of culture data). After standard preparation and immediately before incision, cultures were obtained from three sites on each external fixator: 1) most distal pin 1cm from pin-skin interface, 2) most distal bar at midpoint between pin and clamp connectors, and 3) most distal clamp at bar-clamp interface. Our standard preparation for patients with external fixation in place is to don sterile gloves and wipe down all components of the external fixator with 70% alcohol-soaked sterile 4*4in gauze sponges before skin preparation. The skin and external fixator are then prepped in the usual fashion with ChloraPrep for closed wounds or with povidone iodine scrub and paint for open wounds. Swabs were processed and organisms from cultures identified. Clinicians were blinded to study results until study completion. RESULTS: Two of 165 cultures (1.2%; 95% confidence interval [CI]: 0-2.9%) were positive for common pathogens sometimes observed in surgical site infection. Four cultures (2.4%; 95% CI: 0-4.8%) had pathogens that are rarely associated with surgical site infection, and four (2.4%; 95% CI: 0-4.8%) had nonpathogenic organisms. CONCLUSION: Using 70% alcohol on external fixators plus either ChloraPrep for closed wounds or povidone iodine for open wounds seems to result in a low rate of positive cultures. Most species that were isolated are infrequently identified as sources of surgical site infections. This preparation protocol might be effective at producing a relatively clean environment at the time of surgery for patients with external fixators already in place. PMID- 27461781 TI - Total hip replacement for neck of femur fracture: Comparing outcomes with matched elective cohort. AB - INTRODUCTION: Current literature suggests that total hip replacement (THR) is superior to hemiarthroplasty (HA) for neck of femur fracture in selected group of patients. The outcomes of THR undertaken for trauma setting remain unclear when comparing with elective THR. We compared the outcomes of THR trauma cohort with best-matched elective cohort. METHODS: We retrospectively reviewed 102 patients that underwent THR due to trauma from 2011 to 2013. We had access to 90 cases with complete records. Another 90 matched elective cases were obtained from local arthroplasty database. The elective cases were matched for gender, surgical approaches, surgeon's grade, types of implant, patient's age at operation date of +/-5 years and operation date of +/-60days. Subsequently, the selection criteria were relaxed to patient's age at operation date of +/-10 years and operation date of +/-60days. Unmatched cases were excluded. Complications and death rate were compared. RESULTS: The average age for both cohorts was 70 years. The trauma cohort had statistically significant lower BMI and longer hospital stay (p=0.001). The Functional Comorbidity Index (FCI) and Charlson Age Comorbidity Index (CACI) were the same for both cohorts, reflecting an active patient selection for THR in our centre. The trauma cohort had higher surgical complication rate (9% vs 4%), particularly higher dislocation rate (7% vs 1%); and higher medical complication rate (32% vs 6%). These were consistent with the literature. Contrary to literature, the trauma cohort had six dislocations that five of them were done via anterolateral approach. Among the eight trauma cases with surgical complications, six cases were performed by trainees. The cause of surgical complications remains unclear due to the nature of retrospective study. The trauma cohort had higher death rate than the elective cohort (14% vs 4%), with one post-operative cardiac arrest in the trauma cohort. The rest were non orthopaedic related deaths, ranging between four months to four years. CONCLUSION: A more robust way of selecting trauma patients for THR is warranted to reduce morbidity and mortality. Follow-up for the trauma cohort is warranted, as the patients are likely to outlive the implants. PMID- 27461782 TI - Development of an in vivo anti-androgenic activity detection assay using fenitrothion in Japanese medaka (Oryzias latipes). AB - The effects of endocrine disruptors, including anti-androgenic chemicals, on aquatic environments have received increased attention in recent years. Currently, the method used to screen chemicals for anti-androgenic activity is called the androgenized female stickleback screen, and it was established by the Organization of Economic Cooperation and Development in 2011 using the three spined stickleback. However, screening chemicals for anti-androgenic activity has yet to be established using Japanese medaka. Thus, the purpose of this study was to establish a screening method for anti-androgenic activity utilizing the number of papillary processes in Japanese medaka (Oryzias latipes) as an indicator of the chemical's anti-androgenic activity. Thus, at 35 days post-fertilization, medaka were exposed to fenitrothion, an anti-androgenic compound, for 28 days. In the control group, the formation of papillary processes was observed in XY medaka, but not in XX medaka. However, after fenitrothion exposure, the number of papillary processes was significantly decreased in a dose-dependent manner in XY medaka; in the 300 MUg l-1 concentration group, four of 11 XY medaka showed no papillary processes even if there were no significant effects on total length and wet body weight compared with the control group. Our results indicate that the number of papillary processes in Japanese medaka can be used as an indicator of anti-androgenic activity and that this model may prove useful as a chemical screening method. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27461784 TI - Dose reduction potential of iterative reconstruction algorithms in neck CTA-a simulation study. AB - OBJECTIVES: This study aimed to determine the degree of radiation dose reduction in neck CT angiography (CTA) achievable with Sinogram-affirmed iterative reconstruction (SAFIRE) algorithms. METHODS: 10 consecutive patients scheduled for neck CTA were included in this study. CTA images of the external carotid arteries either were reconstructed with filtered back projection (FBP) at full radiation dose level or underwent simulated dose reduction by proprietary reconstruction software. The dose-reduced images were reconstructed using either SAFIRE 3 or SAFIRE 5 and compared with full-dose FBP images in terms of vessel definition. 5 observers performed a total of 3000 pairwise comparisons. RESULTS: SAFIRE allowed substantial radiation dose reductions in neck CTA while maintaining vessel definition. The possible levels of radiation dose reduction ranged from approximately 34 to approximately 90% and depended on the SAFIRE algorithm strength and the size of the vessel of interest. In general, larger vessels permitted higher degrees of radiation dose reduction, especially with higher SAFIRE strength levels. With small vessels, the superiority of SAFIRE 5 over SAFIRE 3 was lost. CONCLUSIONS: Neck CTA can be performed with substantially less radiation dose when SAFIRE is applied. The exact degree of radiation dose reduction should be adapted to the clinical question, in particular to the smallest vessel needing excellent definition. PMID- 27461785 TI - Electrocardiographic Abnormalities, Malignant Ventricular Arrhythmias, and Cardiomyopathy Associated With Loperamide Abuse. AB - A 20-year-old man presented with recurrent syncope and abnormal electrocardiogram (ECG). His evaluation revealed a prolonged QT interval >600 milliseconds, witnessed torsades de pointes (TdP), and dilated cardiomyopathy. At his initial admission, an ICD was implanted and atrial pacing at 80 beats per minute suppressed ventricular arrhythmias. The patient was readmitted with device infection and recurrent TdP leading to intubation. This led to the discovery of a hitherto unrevealed loperamide abuse and his cardiac arrhythmias and LV dysfunction were determined to be related to large doses of loperamide. Following abstinence, his ejection fraction and ECG returned to normal. PMID- 27461783 TI - Pharmacological treatment in Parkinson's disease: Effects on gait. AB - Gait impairments are a hallmark of Parkinson's disease (PD), both as early symptom and an important cause of disability later in the disease course. Although levodopa has been shown to improve gait speed and step length, the effect of dopamine replacement therapy on other aspects of gait is less well understood. In fact, falls are not reduced and some aspects of postural instability during gait are unresponsive to dopaminergic treatment. Moreover, many medications other than dopaminergic agents, can benefit or impair gait in people with PD. We review the effects of pharmacological interventions used in PD on gait, discriminating, whenever possible, among effects on four components of everyday mobility: straight walking, gait initiation, turning, gait adaptability. Additionally, we summarize the effects on freezing of gait. There is substantial evidence for improvement of spatial characteristics of simple, straight-ahead gait with levodopa and levodopa-enhancing drugs. Recent work suggests that drugs aiming to enhance the acetylcholine system might improve gait stability measures. There is a lack of well-designed studies to evaluate effects on more complex, but highly relevant walking abilities such as turning and making flexible adjustments to gait. Finally, paucity in the literature exists on detrimental effects of drugs used in PD that are known to worsen gait and postural stability in the elderly population. PMID- 27461786 TI - Downregulation of nucleolar and spindle-associated protein 1 expression suppresses cell migration, proliferation and invasion in renal cell carcinoma. AB - Nucleolar and spindle-associated protein 1 (NUSAP1) is a microtubule-binding protein that plays an essential role in mitosis and cancer. Previous studies have demonstrated that NUSAP1 expression is relatively elevated in several malignancies. However, the biological roles of NUSAP1 in renal cell carcinoma (RCC) remain unknown. In the present study, we firstly performed reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis to reveal that the expression of NUSAP1 was relatively elevated in clear cell RCC (ccRCC) tissue specimens and RCC cell lines. Immunohistochemical analysis showed that upregulation of NUSAP1 was significantly correlated with Fuhrman grade (P<0.001), tumor size (P=0.016), clinical stage (P<0.001) and distant metastasis (P=0.023). Additionally, high expression of NUSAP1 was closely associated with a shorter overall survival time of the ccRCC patients (P=0.006). Furthermore, we investigated the biological behaviors of RCC cells in vitro, and we identified that NUSAP1 depletion inhibited RCC cell migration, proliferation and invasion, and apoptosis was induced and the cell cycle was arrested. On the basis of our studies, NUSAP1 was identified as a potential prognostic indicator and a novel therapeutic target for RCC patients. PMID- 27461787 TI - Does Liposomal Bupivacaine (Exparel) Significantly Reduce Postoperative Pain/Numbness in Symptomatic Teeth with a Diagnosis of Necrosis? A Prospective, Randomized, Double-blind Trial. AB - INTRODUCTION: Medical studies have shown some potential for infiltrations of liposomal bupivacaine (Exparel; Pacira Pharmaceuticals, San Diego, CA), a slow release bupivacaine solution, to extend postoperative benefits of numbness/pain relief for up to several days. Because the Food and Drug Administration has approved Exparel only for infiltrations, we wanted to evaluate if it would be effective as an infiltration to control postoperative pain. The purpose of this study was to compare an infiltration of bupivacaine with liposomal bupivacaine for postoperative numbness and pain in symptomatic patients diagnosed with pulpal necrosis experiencing moderate to severe preoperative pain. METHODS: One hundred patients randomly received a 4.0-mL buccal infiltration of either bupivacaine or liposomal bupivacaine after endodontic debridement. For postoperative pain, patients were given ibuprofen/acetaminophen, and they could receive narcotic pain medication as an escape. Patients recorded their level of numbness, pain, and medication use the night of the appointment and over the next 5 days. Success was defined as no or mild postoperative pain and no narcotic use. RESULTS: The success rate was 29% for the liposomal group and 22% for the bupivacaine group, with no significant difference (P = .4684) between the groups. Liposomal bupivacaine had some effect on soft tissue numbness, pain, and use of non narcotic medications, but it was not clinically significant. There was no significant difference in the need for escape medication. CONCLUSIONS: For symptomatic patients diagnosed with pulpal necrosis experiencing moderate to severe preoperative pain, a 4.0-mL infiltration of liposomal bupivacaine did not result in a statistically significant increase in postoperative success compared with an infiltration of 4.0 mL bupivacaine. PMID- 27461788 TI - These lemons are sour: Investigating the influence of demonstrative determiners on the N400 complex. AB - Demonstrative determiners create a joint focus of attention of speaker and hearer on a particular set of entities in a given context. Despite their omnipresence, very little is known with regard to the online integration of demonstrative determiners during comprehension. Here we investigated whether the N400 reflects meaning differences introduced by determiners. We analyzed whether previously established differences - between correct, contingent, world-knowledge and semantic violations in bare plural generic sentences - were modified by the addition of demonstrative determiners. Off-line ratings suggested that the correct sentences in the generic version (e.g. Zebras are stripy) become less sensible when adding a demonstrative determiner (e.g. These zebras are stripy). In contrast, contingent sentences - that is, sentences with predicates that are true for a subgroup of exemplars but not for all - become more sensible than correct sentences if a demonstrative determiner is added (e.g. These trousers are stripy). Both semantic and world-knowledge violations slightly improve in sensibility if demonstrative determiners are added (These ladybirds/journeys are stripy). None of these differences was reflected in the N400 amplitude. Instead, the previous findings using the bare plural generic sentences were fully replicated, showing largest N400 amplitudes for semantic violations, followed by contingent and world-knowledge violations and finally the correct sentences. This suggests that demonstrative determiners are not automatically integrated during meaning comprehension. Implications with respect to the processes that are reflected in the N400 will be discussed. PMID- 27461789 TI - Amyloid binding properties of curcumin analogues in Alzheimer's disease postmortem brain tissue. AB - The presence of beta-amyloid (Abeta) containing plaques in the brain is a hallmark of Alzheimer's disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Early diagnosis is of great importance for optimal treatment and for monitoring disease progression in the brain. Highly specific and sensitive biomarkers are thus greatly needed to assess therapeutic efficacy, not only clinically, but also in terms of clearance of histopathological lesions and decelerated neurodegeneration. The objective of the present study was to give more insight into the binding of curcumin analogues, curcuminoids, to Abeta containing plaques in postmortem tissue from AD patients. In vitro autoradiography was utilized to explore affinity and displacement of the curcuminoids; curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and dimethoxycurcumin (DIMC). We found that BDMC had the highest affinity for Abeta containing plaques in cortical AD brain tissue in comparison to other curcuminoids. Subsequently, [(3)H]BDMC showed significantly higher specific binding in cortical AD brain tissue compared to control subjects. These findings suggest that curcumin analogues, especially BDMC, may serve as a potential radioligands for Abeta plaque neuroimaging. PMID- 27461790 TI - Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus. AB - Cannabinoid CB1 receptor (CB1R) is highly expressed in the mesocorticolimbic system and associated with drug craving and relapse. Clinical trials suggest that CB1R antagonists may represent new therapies for drug addiction. However, the downstream signaling of CB1R is not fully elucidated. In the present study, we investigated the relationship between CB1R and the extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF) signaling in the nucleus accumbens (NAc) and hippocampus in morphine-induced conditioned place preference (CPP), which is used to assess the morphine-induced reward memory. The protein level of CB1R, ERK, CREB, and BDNF were detected by western blotting. Additionally, a CB1R antagonist, AM251, was used to study whether blockade of CB1R altered the CPP and above-mentioned molecules. We found an increase of CB1R expression in the NAc and hippocampus of the mice following morphine CPP, but not those after repeated morphine in home cage without context exposure (NO-CPP). Both morphine CPP and NO CPP induced an upregulation of ERK, CREB phosphorylation and BDNF expression. Furthermore, pretreatment with AM251 before morphine attenuated the CPP acquisition and CB1R expression as well as the activation of ERK-CREB-BDNF cascade. Collectively, these findings demonstrate that (1) Repeated morphine with context exposures but not merely the pharmacological effects of morphine increased CB1R expression both in the NAc and hippocampus. (2) CB1R antagonist mediated blockade of ERK-CREB-BDNF signaling activation in the NAc and hippocampus may be an important mechanism underlying the attenuation of morphine CPP. PMID- 27461791 TI - Altered topological organization of high-level visual networks in Alzheimer's disease and mild cognitive impairment patients. AB - Altered regional activation of high-level visual (HLV) cortices in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) has been well documented in previous fMRI studies, which led us to investigate the underlying alteration of the HLV networks in the terms of intrinsic interaction and topological organization. First, the activation likelihood estimation, a coordinate-based meta-analysis approach, was used to define the cortical regions/nodes included in HLV networks of "what" and "where" visions. Secondly, the acquired HLV regions were used as seeds to calculate their interregional resting-state functional connectivities (RSFCs) based on the temporal correlation of rs-functional MRI (rs-fMRI) time series. Here, the rs-fMRI data of AD (n=30), late MCI (n=35), early MCI (n=52) and matched healthy controls (n=44) were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset. Finally, based on the calculated pair-wise RSFCs, the "what" and "where" HLV networks were respectively constructed, and their topological properties were calculated and analyzed among groups using the graph theory method. The results demonstrated increased clustering coefficient combined with a prolonged characteristic path length of the "where" visual network in AD patients. No significant alternation of the "what" visual network was found among the groups. These results suggest that the abnormality of the HLV networks could be a late-stage outcome in AD and that the "where" visual network may be more susceptible to the AD-related neuropathological changes than the "what" visual network. In addition, the dysfunction of the "where" network is found to be characterized by a decreased integration combined with an increased local segregation. PMID- 27461792 TI - Tongluo Xingnao Effervescent Tablet preserves mitochondrial energy metabolism and attenuates cognition deficits in APPswe/PS1De9 mice. AB - Tongluo Xingnao Effervescent Tablet (TXET), a traditional Chinese herbal formula composed of Ligusticum chuanxiong hor, Scutellaria baicalensis Georgi and Angelica sinensis, has been widely used to treat Alzheimer's disease (AD) and related dementias for decades in China. In the present study, we investigated the effects of TXET on mitochondrial function, energy metabolism and cognitive amelioration in the APPswe/PS1De9 transgenetic mouse model of AD. The energy charge and phosphocreatine, activity of the mitochondrial electron transport chain complexes, mitochondrial membrane potential, activity of Na(+)-K(+) ATPase and the expression levels of Bcl-2 and Bax in the brains were measured, respectively. TXET exhibits significant protection on mitochondrial function and energy supply in addition to ameliorating cognitive decline in APPswe/PS1De9 mice. TXET rescues mitochondrial function by increasing the mitochondrial membrane potential, energy charge levels, activity of respiratory chain complexes and Na(+)-K(+) ATPase activity. These findings suggest that TXET may attenuate cognition impairment through the restoration of mitochondrial function and energy metabolism in the brains in APPswe/PS1De9 mice. PMID- 27461793 TI - Microinjection of the melanin-concentrating hormone into the sublaterodorsal tegmental nucleus inhibits REM sleep in the rat. AB - A study was performed on the effects of local microinjection of melanin concentrating hormone (MCH) into the right sublaterodorsal tegmental nucleus (SLD) on sleep and wakefulness in rats prepared for chronic sleep recordings. MCH 200ng significantly decreased rapid-eye-movement sleep (REMS) time during the first and second 2-h of the recording period which was related to the reduction of the number of REMS periods and the increase of REMS latency. It is proposed that REMS inhibition was related to the direct deactivation of SLD glutamatergic neurons by the peptide. PMID- 27461794 TI - Impact of Body Mass Index on Outcomes in Cardiac Surgery. AB - OBJECTIVES: Body mass index (BMI) commonly is used in obesity classification as a surrogate measure, and obesity is associated with a cluster of risk factors for cardiovascular disease. The aim of this study was to investigate the impact of BMI on short-term outcomes after cardiac surgery. DESIGN: A retrospective cohort study. SETTING: University teaching hospital, 2 centers. PARTICIPANTS: The study comprised 4,740 patients who underwent cardiac surgery at 2 hospitals-from July 1, 2001, to June 30, 2013, in 1 hospital and from September 1, 2003, to August 31, 2014, in a second hospital. INTERVENTIONS: No changes to standard practice were required. MEASUREMENTS AND MAIN RESULTS: Patients were assigned into 6 BMI groups as follows: underweight (BMI<18.5 kg/m(2)), normal weight (>=18.5 to<25 kg/m(2)), overweight (>=25 to<30 kg/m(2)), class I obese (>=30 to<35 kg/m(2)), class II obese (>=35 to<40 kg/m(2)), and class III obese (BMI>=40 kg/m(2)). Short term major postoperative complications (postoperative stroke, cardiac arrest, new atrial fibrillation/flutter, permanent rhythm device insertion, deep sternal infection, sepsis, prolonged ventilation, pneumonia, renal dialysis, renal failure, intensive care unit readmission, total intensive care unit hours, and readmission in 30 days, and mortalities (in-hospital mortality, 30-day mortality, surgical mortality) were compared among various BMI groups after cardiac surgery. Age, sex, surgery type, family history of coronary artery disease, diabetes, hypertension, heart failure, and lipid-lowering medication were the risk factors for early outcomes. Multiple logistic regression analysis indicated that the underweight and class III obese BMI groups demonstrated significant, adverse differences in some short-term outcomes, including deep sternal infection, prolonged ventilation, new atrial fibrillation/flutter, and renal failure. However, being in the overweight or class I obese group demonstrated a positive effect on discharge and surgical mortality. CONCLUSIONS: The results of this study demonstrated that extreme obesity and underweight were significantly associated with early major adverse clinical outcomes. However, there was an "obese paradox" in short-term mortality after cardiac surgery. PMID- 27461795 TI - Heparin Reversal After Cardiopulmonary Bypass: Are Point-of-Care Coagulation Tests Interchangeable? AB - OBJECTIVE: Protamine is used to neutralize heparin after patient separation from cardiopulmonary bypass (CPB). Different bedside tests are used to monitor the adequacy of heparin neutralization. For this study, the interchangeability of the activated coagulation time (ACT) and thromboelastometry (ROTEM; Tem Innovations GmbH, Basel, Switzerland) clotting time (CT) ratios in children undergoing cardiac surgery was assessed. DESIGN: Single-center, retrospective, cohort study between September 2010 and January 2012. SETTING: University children's hospital. PARTICIPANTS: The study comprised children 0 to 16 years old undergoing elective cardiac surgery with CPB. Exclusion criteria were preoperative coagulopathy, Jehovah's witnesses, and children in a moribund condition (American Society of Anesthesiologists score 5). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After heparin neutralization with protamine, the ratio between ACT, with and without heparinase, and the CT measured with INTEM/HEPTEM (intrinsic test activated with ellagic acid was performed without heparinase [INTEM] and with heparinase [HEPTEM]) using tests of ROTEM were calculated. Agreement was evaluated using Cohen's kappa statistics, Passing-Bablok regression, and Bland Altman analysis. Among the 173 patients included for analysis, agreement between both tests showed a Cohen's kappa statistic of 0.06 (95% CI: -0.02 to 0.14; p = 0.22). Bland-Altman analysis showed a bias of 0.01, with a standard deviation of 0.13, and limits of agreement between -0.24 and 0.26. Passing-Bablok regression showed a systematic difference of 0.40 (95% CI: 0.16-0.59) and a proportional difference of 0.61 (95% CI: 0.42-0.86). The residual standard deviation was 0.11 (95% CI: -0.22 to 0.22), and the test for linearity showed p = 0.10. CONCLUSION: ACT, with or without heparinase, and the INTEM/HEPTEM CT ratios are not interchangeable to evaluate heparin reversal after pediatric patient separation from CPB. Therefore, the results of these tests should be corroborated with the absence/presence of bleeding and integrated into center-specific treatment algorithms. PMID- 27461796 TI - Incidental Finding of a Right Atrial Appendage Thrombus During Cardiac Surgery. PMID- 27461797 TI - An Echodensity in the Sinus of Valsalva. PMID- 27461798 TI - In vitro activity of Ceftaroline against bacterial pathogens isolated from patients with skin and soft tissue and respiratory tract infections in African and Middle Eastern countries: AWARE global surveillance program 2012-2014. AB - The objective of this report was to document antimicrobial susceptibility testing surveillance data for ceftaroline and comparative agents from the AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) global surveillance program for bacterial pathogens causing skin and soft tissue and respiratory tract infections in African and Middle Eastern countries from 2012 through 2014. Pathogen identities were confirmed by MALDI-TOF and antimicrobial susceptibility testing performed by CLSI broth microdilution methodology in a central laboratory. All methicillin-susceptible Staphylococcus aureus (MSSA) (n= 923; MIC90, 0.25 MUg/mL) and 91.8% of methicillin-resistant S. aureus (MRSA) (n= 1161; MIC90, 1 MUg/mL) tested were susceptible to ceftaroline. The maximum ceftaroline MIC observed for isolates of MRSA was 2 MUg/mL. All Streptococcus pyogenes (n= 174; MIC90, 0.008 MUg/mL), Streptococcus agalactiae (n= 44; MIC90, 0.015 MUg/mL), Streptococcus pneumoniae (n= 351; MIC90, 0.25 MUg/mL), and Haemophilus influenzae (n= 84; MIC90, <=0.015 MUg/mL) were susceptible to ceftaroline. Rates of susceptibility to ceftaroline among ESBL-negative Escherichia coli (n= 338), Klebsiella pneumoniae (n= 241), and Klebsiella oxytoca (n= 97) were 89.1% (MIC90, 1 MUg/mL), 94.2% (MIC90, 0.5 MUg/mL), and 99.0% (MIC90, 0.5 MUg/mL), respectively. PMID- 27461799 TI - MEDLINE, pubmed, and pubmed central ((r)): Analogous or dissimilar. PMID- 27461800 TI - Management of grossly decayed primary anteriors using various intracanal post systems: A clinical study. AB - PURPOSE: The aim of the present study was to clinically evaluate and compare the efficacy and retention of various types of intracanal posts in the restoration of grossly decayed deciduous anterior teeth. The various posts used were polyethylene post, glass post, and composite post. MATERIALS AND METHODS: A total number of 16 patients with 45 grossly decayed primary anterior teeth were selected. After biomechanical preparation and obturation, patients were randomly divided on the basis of posts to be used into three groups (Group I: Polyethylene post; Group II: Glass post, and Group III: Composite post). Then, space was created in the obturated canal and posts were placed, followed by core build up. RESULTS: After an interval of 12 months, 86.67% of the teeth exhibited complete retention of the post restored with polyethylene post (P > 0.005) and 93.3% of the teeth exhibited complete retention of the post that were restored with glass post (P > 0.005) whereas only 60% of the teeth exhibited complete retention of the post that were restored with composite post (P< 0.005). Only 20% of the teeth exhibited marginal discoloration in both Groups I and III and 13.33% in Group II and this was nonsignificant. CONCLUSION: Both glass post and polyethylene post proved to be effective. Glass post showed the maximum retention and marginal adaptation followed by polyethylene post. Thus, it appears to be of potential interest for use especially in clinical pediatric dentistry. PMID- 27461801 TI - Predicting the mesiodistal width of unerupted canine and premolars by using width of the permanent mandibular incisors and first molar in the Himachal population. AB - INTRODUCTION: The determination of tooth size to arch length discrepancy in mixed dentition requires an accurate prediction of mesiodistal width of unerupted permanent teeth. Presently available methods use only the mesiodistal width of mandibular incisors. Melgaco (2007) introduced a new method of estimating width of unerupted canine and premolars by using mesiodistal width of incisors and first permanent molar. AIM: The aim of this study is to determine linear regression equation for estimating the widths of mandibular permanent canines and premolars using mesiodistal width of mandibular incisors and first molars in the Himachal population. MATERIALS AND METHODS: Dental casts of 250 subjects were selected from the Himachal population who had fully erupted mandibular permanent incisors, canine, premolar, and first molar. Actual mesiodistal width of all fully erupted teeth were measured with digital vernier caliper and the values obtained were subjected to statistical and regression analysis. RESULTS: High values of correlation (0.957) were found while considering Melgaco's method. CONCLUSION: From this study, it can be evaluated that Melgaco's method gives better prediction of unerupted permanent canines and premolars, and the equation Y = 13.48 + 0.614X can be suggested for the present population. PMID- 27461802 TI - Evaluation of antimicrobial effect of azadirachtin plant extract (Soluneem (TM)) on commonly found root canal pathogenic microorganisms (viz. Enterococcus faecalis) in primary teeth: A microbiological study. AB - AIM: The aim of this study is to evaluate the antimicrobial activity of Soluneem TM when used as an irrigating solution along with other commonly used irrigating solution sodium hypochlorite (NaOCl) against Enterococcus faecalis. MATERIALS AND METHODS: Microorganism used in this study was E. faecalis (Microbial Type Culture Collection 439). Test substance used was Soluneem TM, which was obtained from Vittal Mallya Scientific Research Foundation (VMSRF), Bengaluru. This study was conducted in a microbiology laboratory (Biocare Research India Pvt., Ltd. Laboratory, Ahmedabad, Gujarat) to evaluate the antimicrobial effect of Soluneem TM (Azadirachtin) on E. faecalis. Antimicrobial activity testing was performed using the macrobroth dilution method according to the Clinical Laboratory Standards Institute guidelines. All determinations were performed thrice. RESULTS: Minimum bactericidal concentration (MBC) was seen as 2.6% for Soluneem TM while the same was seen at 0.1% for NaOCl. Independent sample t-test was carried out to compare the MBC of Soluneem TM and NaOCl, which showed that there was no statistically significant difference between them, i.e., 2.6% Soluneem TM was as effective as 0.1% NaOCl. CONCLUSION: Soluneem TM showed antimicrobial activity against E. faecalis at various concentrations. It was also found that the efficacy of Soluneem TM at 2.6% concentration and above was relatively similar to that of gold standard irrigating solution (NaOCl) on inhibition of E. faecalis. PMID- 27461803 TI - Comparative evaluation of diffusion hypoxia and psychomotor skills with or without postsedation oxygenation following administration of nitrous oxide in children undergoing dental procedures: A clinical study. AB - BACKGROUND: Diffusion hypoxia is the most serious potential complication associated with nitrous oxide. It occurs during the recovery period. Hence, administration of 100% oxygen is mandatory as suggested by many authors. AIM: The aim of this study is to evaluate the occurrence/nonoccurrence of diffusion hypoxia in two groups of patients undergoing routine dental treatment under nitrous oxide sedation when one group is subjected to 7 min of postsedation oxygenation and the second group of the patients is made to breathe room air for the similar period. MATERIALS AND METHODS: A total of sixty patients within the age group of 7-10 years requiring invasive dental procedures were randomly divided into two groups of 30 each using chit method. In the control group, patients were administered 100% oxygen postsedation, whereas, in the study group, patients were made to breathe room air postsedation. Various parameters (pulse rate, respiratory rate, blood pressure, and oxygen saturation [SpO2]) were recorded pre- and post-operatively. Data were collected and then sent for statistical analysis. RESULTS: The mean postoperative SpO2 at measurement times 1, 3, 5, and 7 min in both the groups was higher than the mean preoperative SpO2. This increase was statistically significant. No significant difference was found between the Trieger test scores. CONCLUSION: This study proves that clinical occurrence of diffusion hypoxia is not possible while following the routine procedure of nitrous oxide sedation. PMID- 27461804 TI - Health camps in schools and content analysis of the school textbooks: A cross sectional study in Tamil Nadu. AB - BACKGROUND: School textbooks have been considered as an effective platform for promoting oral health. The information on oral health in the Indian school textbooks has not been evaluated. AIM: The aim of this study was to evaluate the contents of school textbooks on oral health and to quantitatively analyze the school health camps and guest lectures/demonstrations conducted in the schools of three districts in Tamil Nadu. METHODOLOGY: Twenty schools which participated in the study followed the Central Board of Secondary Education, matriculation, or the state board syllabus. A questionnaire was designed to collect information about the medical camps, dental camps, guest lectures, and demonstrations conducted in the last academic year from the schools. The questionnaires were distributed among the school teachers of grades I-V. They were asked to provide photocopies of the topics on oral health which were included in the syllabus. Content analysis of the information on oral health-related topics in the school textbooks was done. Descriptive statistics of the details of the camps and lectures was done using Pearson's Chi-square test (SPSS version 17) (SPSS Inc. Chicago, Illinois, USA). RESULTS: There was no significant difference in the number of medical camps (P = 0.445), dental camps (P = 0.055), and guest lectures (P = 0.069) organized among the three boards of schools. Basic information on the parts and type of teeth, tooth decay, and brushing were present in the textbooks of all three boards of schools. CONCLUSION: The school textbooks of all the three boards contained basic and adequate information on oral health. Periodic revisions of the content and quality of information in the school textbooks are essential. To make the information sticky for long-term, reinforcements in the form of school health education is needed. PMID- 27461805 TI - Evaluation of total antioxidant level of saliva in modulation of caries occurrence and progression in children. AB - CONTEXT: Recent studies have implicated a direct relation between dental caries and salivary total antioxidant level (TAL), which can be suggested as an indicator (either harmful or protective) for susceptibility of individuals for dental caries. AIM: To evaluate the total antioxidant level (TAL) in unstimulated saliva of children, and to correlate the TAL with caries experience and BMI (body mass index). SETTINGS AND DESIGN: 60 children, aged 6-12 yrs, were randomly selected for the study. Two groups were made (study group n=30 and control group n=30), and subdivisions based on gender were made out of both groups [male (n=15) and female (n=15)]. In control group, subjects with no dental caries and study group, subjects having decayed teeth score >=4 were included. STATISTICAL ANALYSIS: Data analysis was done using Statistical Package for Social Sciences (SPSS V. 21). Shapiro - Wilks test showed that TAL (absorbance) did not follow normal distribution. Hence, for comparison between cases and control for TAL non parametric test namely Mann- Whitney U test was applied. RESULTS: Statistically significant strong positive correlation was seen between age and TAL (P< 0.05). PMID- 27461806 TI - Color stability of esthetic restorative materials used in pediatric dentistry: An in vitro study. AB - BACKGROUND: Children consume foods that are colorful which contain food additives that stain not only the tooth structure but also the restorations. As esthetics is of prime concern for both parents and children nowadays, long-term color stability of restorative materials is of utmost importance. AIM: To evaluate the color stability of two tooth-colored restorative materials (conventional glass ionomer cement [GIC] and giomer) when immersed in various consumable drinks and food (aerated beverage, ice candy, and health drink) at different immersion periods (low, moderate, and high). MATERIALS AND METHODS: A total of 100 specimens were made with each restorative material. Ten were used as a control and remaining (n = 90) as experimental. The experimental specimens were divided into three groups based on media of immersion (n = 30 each) and were further divided into three subgroups based on immersion time (n = 10 each). The color changes (DeltaE values) were measured using spectrophotometer. RESULTS: Both the tested materials showed color change; however, conventional GIC showed greater DeltaE values when compared to giomer and the samples exposed to aerated beverage resulted in highest color change. It is also noticed that greater the exposure time, higher are the DeltaE values. CONCLUSION: Giomer showed more resistance to color change than conventional GIC with all the tested media and immersion regimes. PMID- 27461807 TI - Awareness and prevention of patient gag reflex among pedodontists in India: A web based survey. AB - AIM: The aim of this study is to devise a reliable and valid web-based survey to predict the awareness level and prevention of patient's gag reflex among Indian pedodontists. MATERIALS AND METHODS: An 11-question predictive gagging survey was created, refined, and tested on 377 pedodontists. The questions focused on age group, common procedure associated with gag reflex and the most common technique adapted by dentists in their clinics to prevent gag. RESULTS: There was no statistically significant difference in gagging reflex among age groups with 53.5% of patients reported anxiety and fear as a main cause of gag; behavioral modification technique was considered as the most reliable method for gagging prevention in 68.5% of patients and there was no statistically significant difference in gagging severity index among patients irrespective of age, causes, and methods used to prevent it. CONCLUSION: The web-based gagging survey established that level of awareness regarding management of patient's gag is significantly low among pedodontists in India and hence is a major hindrance in the clinical practice. PMID- 27461808 TI - Caries risk assessment among 12-13 year old school-going children of government and private schools of Tirupur district, Tamil Nadu. AB - BACKGROUND: Dental caries is as ancient as humankind and has the longest association with the dental profession, an association that is punctuated with agony and ecstasy. The agonizing fact is that despite several efforts toward total eradication, this disease is still prevalent. Nevertheless, an ecstatic success of the profession is the global decline in the incidence compared to the yesteryears' epidemics. Hence, predicting dental caries earlier is a boon. One such model to predict is cariogram developed by Bratthall in 1996. AIM: The aim of this study was to assess the caries risk among 12-13 year old school-going children of government and private schools of Tirupur district in Tamil Nadu using cariogram computer model. METHODS: A cross-sectional survey was carried out among 136 study subjects of 12-13 year of age, who fulfilled the inclusion and exclusion criteria. Data were collected using a predesigned questionnaire and scored according to a standardized protocol. The Chi-square test was used to find differences between caries-related factors and cariogram group. The correlation was acquired using Spearman's correlation. RESULTS: Government school study subjects had 56% of chance of avoiding caries whereas the private school study subjects had 66% of chance of avoiding caries in future and the differences were statistically significant (P = 0.001). A negative correlation was observed between the chance to avoid dental caries and cariogram sectors. CONCLUSION: The majority of the study subjects from government school belonged to medium-risk category and private school subjects belonged to low-risk category which inferred that private school students have high chance to avoid dental caries compared to government study subjects. PMID- 27461809 TI - Caries prevalence of school-going boys and girls according to cleaning methods and soft drink-taking frequency in different localities, in and around Guwahati City. AB - BACKGROUND: Dental caries is a multifactorial disease, causes of which are mostly understood nowadays. This disease is not only treatable but also preventable, if detected in its initial stage. In a developing country like India, facility of dental treatment is available mostly for urban population, whereas a very common approach of dental disease treatment is still traditional for the rural people. OBJECTIVE: The objective of this study was to find out the prevalence of dental caries, teeth cleaning methods, and sweet and soft drink-taking frequency among boys and girls of Guwahati City and its nearby semi-urban and rural areas. MATERIALS AND METHODS: Cross sectional study was carried out among school going boys and girls of 3-17 years group, using the modified WHO oral health survey form. The number of population was 2396 from urban locality, 2370 from semi urban, and 2467 from rural. RESULTS: Caries prevalence is much higher in urban (62.77%), contrary to rural where 76% of the sample is caries free. Those who take sweet occasionally suffered less or almost caries free (7.93% in urban and 0% in rural) than among those who consume it more than five times a day (90.75% in urban, 100% in semi-urban, and 99.33% in rural). DISCUSSION AND CONCLUSION: Urban localities are two times and semi-urban areas are 1.64 times more at risk of dental caries than rural areas. The odds ratio for cleaning frequency shows that the effect of cleaning by brush on caries is less (78%, not significant) than chewing stick while the risk associated with finger and charcoal use is about 19.63 times and 7.11 times, respectively. PMID- 27461810 TI - Assessment of salivary and plaque pH and oral health status among children with and without intellectual disabilities. AB - BACKGROUND: This study explores the association of disabilities and oral health. The aim of the study was to assess the salivary and plaque pH and oral health status of children with and without disabilities. MATERIALS AND METHODS: A total of 100 schoolchildren (50 with disabilities and 50 without disabilities) were examined from 9 to 15 years age group. Saliva and plaque pH analysis were done to both the groups. Clinical data were collected on periodontal status, dental caries using WHO criteria. pH values of different groups, difference between the means were calculated using independent t-test, and frequency distribution was analyzed using Chi-square test. Statistical significance, P value was set at 0.05. RESULTS: Mean plaque and salivary pH scores were lesser (5.73 and 5.67) in children with intellectual disabilities (IDs) (P< 0.001). Subjects with disabilities had also statistically significant higher CPI scores and decayed, missing, and filled scores than their healthy counterparts (P< 0.001). CONCLUSION: There is a statistically significant difference in plaque and salivary pH among children with and without ID with lower plaque and salivary pH among children with ID. In addition to this, the oral health was also more compromised in children with ID, which confirms a need for preventive treatment for these children. PMID- 27461811 TI - Determination of physical height from crown dimensions of deciduous tooth: A dental morphometric study. AB - BACKGROUND: Dental morphometrics is a subject of great significance in forensic odontology in identification of an individual. Use of teeth to represent a physical profile is valuable for identification of an individual. AIMS AND OBJECTIVES: The present study aims to assess the clinical crown length (CL) of erupted deciduous teeth and height of the child. A correlation of these parameters was attempted to arrive at a mathematical equation which would formulate a ratio of tooth CL to individual height that would support in estimating the probable height of the child. MATERIALS AND METHODS: About 60 children (30 males and 30 females) of age ranged from 3-6 years were included in this study. Clinical vertical CLs of the deciduous dentition (tooth numbers 51, 52, 53, 54, and 55) were calculated using digital Vernier calipers (Aerospace Ltd., Bengaluru, Karnataka, India) on the cast models. Child height was measured using a standard measuring tape. Ratios of deciduous CL to height of the child were recorded. Linear stepwise forward regression analysis was applied to predict the probability of CL of a tooth most likely to support in prediction of physical height of the child. RESULTS: Tabulated results showed a probable correlation between tooth CL and height of the child. Tooth CLs of deciduous upper right second molar (55) among the males, lateral incisor (52) among females, and canine (53) using the combined male and female data were statistically significant, and they approximately predicted the child height with minimal variations. Mathematically derived equations based on linear stepwise forward regression analysis using sixty children data are height prediction (derived from combined data of male and female children) = 400.558 + 90.264 (53 CL), male child height prediction (derived from data of male children) = 660.290 + 72.970 (55 CL), and female child height prediction (derived from data of female children) = -187.942 + 194.818 (52 CL). CONCLUSION: In conclusion, clinical vertical CL is an important parameter in prediction of individual height and possible identification of the individual. An extension of the similar technique to all the deciduous dentition using a larger group of children would probably give us the best options available among vertical CLs for prediction of the child height. PMID- 27461812 TI - An in vitro evaluation of cytotoxicity of curcumin against human dental pulp fibroblasts. AB - OBJECTIVE: The objective of this study was to evaluate the cytotoxicity of curcumin to primary dental pulp fibroblasts in vitro. MATERIALS AND METHODS: Dental pulp fibroblasts from primary maxillary central incisors were cultured and used for cytotoxicity tests after the fourth passage. Ninety-five percent curcumin was diluted with dimethylsulfoxide to prepare 100%, 50%, and 25% concentrations. Each concentration of curcumin was added in triplicate into 96 well microtiter plate containing the fibroblast culture at 104/well. Cells without treatment served as a control group. The number of viable cells after 48 hrs incubation at 37 degrees C in a humidified atmosphere of 5 % CO2 and 95 % air was determined by the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. The relative viability of pulp cells was expressed as color intensity of the number in the experimental wells relative to that of the control group. Absorbances were read at 492 nm on a microplate reader with a background subtraction at 620 nm. RESULTS: Cell viability of primary dental pulp fibroblasts to 25%, 50%, and 100% curcumin concentration was 174%, 310%, and 317%, respectively. CONCLUSIONS: Curcumin promotes cell viability and induces proliferation of primary dental pulp fibroblasts and has the potential to be developed into an economical and reliable medicament for vital pulp therapy. PMID- 27461813 TI - Evaluation of chemokines in gingival crevicular fluid in children with dental caries and stainless steel crowns: A clinico-biochemical study. AB - AIMS AND OBJECTIVES: The study was conducted to detect the presence of macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta and estimate their levels in gingival crevicular fluid (GCF) in children with dental caries and stainless steel crowns. MATERIALS AND METHODS: A total of 80 children with primary dentition were selected and categorized into four groups with twenty in each group; Group 1 - healthy subjects, Group 2 - dental caries, Group 3 - dental caries involving the pulp, and Group 4 - stainless steel crowns. GCF samples were collected by an extra-crevicular method with microcapillary pipettes. The GCF samples were quantified by ELISA and the levels of MIP-1alpha and MIP-1beta were determined. RESULTS: MIP-1alpha and MIP-1beta were detected in all the samples. Highest mean concentration in GCF was obtained for Group 3 followed by Groups 2 and 4 while the lowest concentration was seen in Group 1. This suggests that MIP 1alpha and MIP-1beta levels in GCF increased proportionately with the inflammation. CONCLUSIONS: GCF serves as a noninvasive diagnostic fluid to measure biomarkers released during dental caries initiation and progression. MIP 1alpha and MIP-1beta chemokines can be considered as novel biomarkers, in biological mechanism underlying the pathogenesis and inflammation in children with dental caries and stainless steel crowns. PMID- 27461814 TI - A comparative evaluation of microleakage and compressive strength of Ketac Molar, Giomer, Zirconomer, and Ceram-x: An in vitro study. AB - BACKGROUND: Microleakage around dental restorative material and strength to withstand the masticatory forces is major problem in dentistry. Instead, many new materials available, very few actually bond to tooth surface and bear masticatory load. AIM: The aim of this study is to evaluate and compare the microleakage and compressive strength of Ketac Molar, Giomer, Zirconomer, and Ceram-x. MATERIALS AND METHODS: For the evaluation of microleakage, Class V cavities were prepared on sixty human premolar teeth and divided into four study groups (n = 15): Group I (Ketac Molar), Group II (Giomer), Group III (Zirconomer), and Group IV (Ceram x). The samples were thermocycled and subjected to dye penetration test. The sections were made and evaluated under stereomicroscope at * 40 magnification. For the compressive strength evaluation, sixty cylindrical specimens were fabricated measuring 5 mm * 6 mm and grouped into four study groups (n = 15): Group I (Ketac Molar), Group II (Giomer), Group III (Zirconomer), and Group IV (Ceram-x). All were then subjected to the Universal Testing Machine at crosshead speed of 1 mm/s. STATISTICAL ANALYSIS USED: The data were analyzed using paired t test and ANOVA. RESULTS: The microleakage was found insignificant (P > 0.05) for all study groups, with Giomer showing maximum followed by Zirconomer, Ceram-x, and Ketac Molar. The compressive strength was found to be highly significant (P < 0.01) with the maximum score for Giomer followed by Ceram-x, Zirconomer, and Ketac Molar. CONCLUSION: The sealing ability was maximum in Ketac Molar, Zirconomer, Ceram-x, and Giomer whereas the compressive strength was maximum for Giomer followed by Ceram-x, Zirconomer, and Ketac Molar. PMID- 27461815 TI - Impact of various extra-oral factors on caries experience among mentally disabled children residing in Bhopal city, central India: A cross-sectional study. AB - BACKGROUND: Dental caries is the most common dental problem among the mentally challenged children. There are various extra-oral factors responsible for high caries experience among such children. AIM: The aim of the present investigation was to study the impact of various extra-oral factors on dental caries experience among mentally challenged children residing in Bhopal city, Central India. MATERIALS AND METHODS: One hundred and fifty-two children between the age group 5 and 15 years were included in this descriptive cross-sectional study. A pretested pro forma was used to record information about socioeconomic status, demographic data, mental retardation (MR) type, and intelligent quotient. The clinical examination was performed to evaluate dental caries and treatment needs using the World Health Organization dentition status and treatment needs index. RESULTS: The mean decayed, missing, and filled teeth (DMFT and dmft) were 2.32 and 2.21, respectively. Age, parent occupation, income, and intelligent quotient were significant predictors of both DMFT and dmft. In addition, socio-economic status and type of MR were significant predictors of only DMFT. CONCLUSION: Dental health professionals should, therefore, be aware of the various extra-oral factors responsible for high caries experience of mentally challenged children. They should understand and provide basic treatment needs to such children. PMID- 27461816 TI - An adenomatoid odontogenic tumor in disguise. AB - Adenomatoid odontogenic tumor (AOT) is a slowly growing benign tumor of the oral cavity. It accounts of 3-7% of all odontogenic tumors. It is seen to occur commonly in the anterior maxilla. The tumor is usually associated with an impacted tooth with maxillary canine being the most common tooth. AOT is seen in a younger group, especially below 20 years with a female preponderance. AOT occurs in two main variants: Central or intraosseous which is more common and second is peripheral which is rare. Radiologically, it represents as a radiolucent lesion with radiopaque foci usually an impacted or a supernumerary tooth. With a close clinical and radiographic resemblance to dentigerous cyst correct diagnosis and treatment is necessary. AOT being benign in nature requires a conservative management with enucleation. This is a case report of a 13-year old girl with an AOT occurring in the anterior maxillary region. PMID- 27461818 TI - Diagnosing endometriosis: CA125 rules in, but not out. PMID- 27461817 TI - New electronic habit reminder for the management of thumb-sucking habit. AB - Methods for intervention of nonnutritive sucking habits include counseling, positive reinforcement, calendar with rewards, adhesive bandage, bitter nail polish, long sleeves, and appliance therapy. All these methods have been reported in the literature with variable success rates. We present a case of an 8-year-old child with thumb-sucking habit successfully managed in a short period of 5 months by a new electronic habit reminder, an extraoral appliance which was designed to overcome the disadvantages associated with intraoral appliances. PMID- 27461819 TI - Efficient high repetition rate electro-optic Q-switched laser with an optically active langasite crystal. AB - With an optically active langasite (LGS) crystal as the electro-optic Q-switch, we demonstrate an efficient Q-switched laser with a repetition rate of 200 kHz. Based on the theoretical analysis of the interaction between optical activity and electro-optic property, the optical activity of the crystal has no influence on the birefringence during Q-switching if the quarter wave plate used was rotated to align with the polarization direction. With a Nd:LuVO4 crystal possessing a large emission cross-section and a short fluorescence lifetime as the gain medium, a stable LGS Q-switched laser was designed with average output power of 4.39 W, corresponding to a slope efficiency of 29.4% and with a minimum pulse width of 5.1 ns. This work represents the highest repetition rate achieved so far in a LGS Q-switched laser and it can provide a practical Q-switched laser with a tunable high repetition rates for many applications, such as materials processing, laser ranging, medicine, military applications, biomacromolecule materials, remote sensing, etc. PMID- 27461820 TI - MicroRNA-520a attenuates proliferation of Raji cells through inhibition of AKT1/NF-kappaB and PERK/eIF2alpha signaling pathway. AB - Burkitt's lymphoma (BL) is a fast growing cancer of the human lymphatic system, and an extremely invasive B-cell non-Hodgkin's lymphoma. We explored the mechanism of apoptosis in Raji cells associated with the post-transcriptional regulation factors. To confirm that the predicted microRNA-520a (miR-520a) is matched with AKT1, 3' untranslated region (UTR) luciferase activity of AKT1 was used in the assessment. In the presence of the mimics or inhibitors of miR-520a, cell function of Raji, such as proliferation, growth and apoptosis were analyzed. The expression of endoplasmic reticulum (ER) stress-related proteins were examined. Luciferase reporter analysis showed that miR-520a leads to decreased activity of luciferase gene fused with AKT1 3'UTR. Therefore, AKT1 is a direct target of miR-520a. Our data indicated that the mimics of miR-520a inhibited growth, proliferation of Raji cells and promoted its apoptosis, which was related to downregulation of AKT1, NF-kappaB and ER stress response mediated by PERK/eIF2alpha pathway. On the contrary, the inhibitors of miR-520a promoted growth, proliferation of Raji cells and inhibited its apoptosis, which was related to AKT1/NF-kappaB and PERK/eIF2alpha pathway. We identified miR-520a, which specifically binds to AKT1 mRNA 3'UTR. miR-520a is a crucial mediator for proliferation and ER stress in Raji cells through regulating the AKT1/NF-kappaB or PERK/eIF2alpha signaling pathway. Our findings suggest that targeting miR-520a is a promising therapeutic strategy in BL. PMID- 27461821 TI - Anchoring of Ag6Si2O7 nanoparticles on alpha-Fe2O3 short nanotubes as a Z-scheme photocatalyst for improving their photocatalytic performances. AB - Coupling two different semiconductors to form composite photocatalysts is the most significant method for environmental remediation. In this regard, tube-like alpha-Fe2O3/Ag6Si2O7 heterostructures are synthesized via anchoring p-type Ag6Si2O7 nanoparticles (NPs) on the surface of n-type alpha-Fe2O3 short nanotubes (SNTs) by conventional wet-chemical routes. alpha-Fe2O3 SNTs are firstly fabricated by a hydrothermal method with the assistance of dihydrogen phosphate and sulphate. Then, Ag6Si2O7 NPs are anchored on alpha-Fe2O3 SNTs by an in situ deposition method, and the alpha-Fe2O3/Ag6Si2O7 p-n heterostructures are finally obtained. The morphologies, crystal structure, photocatalytic performance and photocurrent properties of as-synthesized alpha-Fe2O3/Ag6Si2O7 heterostructures are investigated. Six organic dyes are used for determining the high-efficiency Z scheme photocatalytic activities of the as-obtained photocatalysts under ultraviolet and visible light (mercury lamp, 300 W). Compared with pure alpha Fe2O3 SNTs, the photocurrent intensity of the alpha-Fe2O3/Ag6Si2O7 heterostructures is improved 62 times. The enhanced significant photocatalytic performance of alpha-Fe2O3/Ag6Si2O7 heterostructures could be attributed to charge transfer between Ag6Si2O7 NPs and the charge separation between Ag6Si2O7 NPs and alpha-Fe2O3 SNTs. These composite heterostructures are proposed to be an example for the preparation of other composite silicate photocatalysts for practical application in environmental remediation issues. PMID- 27461823 TI - The role of pathologic evaluation of endometrial ablation resections in predicting ablation failure and adenomyosis in hysterectomy. AB - Endometrial ablation is commonly performed to manage heavy menstrual bleeding. However, failure in symptom control eventually requiring hysterectomy is frequent. Adenomyosis is common in such failure cases. Ablations using a resectoscope will produce an Endo-Myometrial Resection (EMR) specimen. The value of histopathologic examination of EMRs in predicting treatment failure and adenomyosis has not been addressed. We retrieved histologic material from subjects with failed ablation (persistent symptoms requiring hysterectomy) and subjects with ablation followed by clinical improvement and no hysterectomy (control group). Material was evaluated for features of an abnormal endometrial distribution suggestive of adenomyosis: myometrial fragments with endometrium on opposite edges, myometrium with endometrium in >=3 edges and areas of endometrium completely surrounded by myometrium (endometrial islands). Hysterectomy specimens from the study group were evaluated for the presence of adenomyosis and its distribution (superficial/deep). Both study and control groups consisted of 18 patients each. The number of fragments with endometrium on opposite sides was significantly higher in the study group: 2.11 vs 0.94 in the control group (p=0.005). Conversely, maximum aggregate dimension (2.3cm vs 2.79cm), number of fragments with endometrium on three sides (4.5 vs 2.78) and number of fragments with endometrial islands (4.5 vs 4.11) did not significantly differ between groups. Adenomyosis was seen in 72.2% hysterectomies from the study group; 27.8% involved deep myometrium. None of the EMR features were statistically associated with adenomyosis. Certain endomyometrial distribution patterns in EMR specimens correlate with future ablation failure and need for definitive surgery. This may be explained by residual endometrial tissue not resected due to a markedly irregular endomyometrial interface. Adenomyosis is frequent in cases of ablation failure. However, a significant association between EMR patterns studied and adenomyosis was not observed. PMID- 27461822 TI - EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review. AB - For the last two decades, evolution in molecular biology has expanded our knowledge in decoding a broad spectrum of genomic imbalances that progressively lead normal cells to a neoplastic state and finally to complete malignant transformation. Concerning oncogenes and signaling transduction pathways mediated by them, identification of specific gene alterations remains a critical process for handling patients by applying targeted therapeutic regimens. The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating cell proliferation, differentiation and apoptosis in normal cells. EGFR mutations and amplification represent the gene's main deregulation mechanisms in cancers of different histo-genetic origin. Furthermore, intra cancer molecular heterogeneity due to clonal rise and expansion mainly explains the variable resistance to novel anti-EGFR monoclonal antibody (mAb), and also tyrosine kinase inhibitors (TKIs). According to recently published 2015 WHO new classification, lung cancer is the leading cause of death related to cancer and its incidence is still on the increase worldwide. The majority of patients suffering from lung cancer are diagnosed with epithelial tumors (adenocarcinoma predominantly and squamous cell carcinoma represent ~85% of all pathologically defined lung cancer cases). In those patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify patients' sensitivity (i.e. exon 21 L858R, exon 19 LREA deletion) or resistance (ie exon 20 T790M and/or insertion) to TKI mediated targeted therapeutic strategies. Additionally, the role of specific micro-RNAs that affect EGFR regulation is under investigation. In the current review, we focused on EGFR gene/protein structural and functional aspects and the corresponding alterations that occur mainly in lung adenocarcinoma to critically modify its molecular landscape. PMID- 27461824 TI - Chondroma arising from the spinal dura mater at the thoracic level: A case report with molecular analysis. AB - Chondromas are benign tumors that can be found at several sites in the body, while those arising from the dura mater are extremely rare. Among them, although chondromas arising from the cranial dura mater have been reported, those arising from the spinal dura mater have not been reported in the literature to date. A 66 year-old woman presented with right-sided continuous backache which she had developed recently. After detailed examinations, an epidural tumor at the thoracic level was detected. The patient underwent surgery and a total en-bloc resection was accomplished. From the clinical and pathological findings, the tumor was revealed as chondroma arising from the spinal dura mater. A recent comprehensive study has identified the isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations in conventional central and periosteal cartilaginous tumors, and it has subsequently been analyzed in intracranial chondrosarcoma and chondroma, including chondroma of the convexity dura mater. Herein, we describe a novel case of chondroma arising from the spinal dura mater, with mutation analysis of IDH1 and IDH2 both of which revealed wild-type. PMID- 27461825 TI - Validation of a low-cost modified technique for constructing tissue microarrays for canine mammary tumor analysis. AB - Compared with conventional histological paraffin blocks, tissue microarray (TMA) represents a "high-throughput tool" that provides rapid results, a time- and cost effective approach and simultaneous investigation of several tissue samples under the same conditions. Given the large number of cases of dogs affected with mammary tumors, the complexity of these tumors and their similarity with breast cancer in women, this study aimed to validate a low-cost modified method to construct TMAs for canine mammary tumor analysis using immunomarkers. Carcinoma cases were selected from canine mammary carcinomas in mixed tumors (CMT) because this tumor type is the most heterogeneous among the histopathological types of mammary tumors observed in female dogs. Through a histopathological examination, tumor representativity was compared between conventional sections and histological sections obtained from the TMA block; both were stained with hematoxylin and eosin. An immunohistochemistry analysis was performed to compare the percentages of immunoreactive cells obtained in whole tissue sections versus those obtained from sections from the TMA block. Streptavidin-biotin peroxidase complex and anti-PCNA, anti-vimentin and anti-pancytokeratin antibodies were used. Statistical analysis consisted of the nonparametric Friedman's test (p<=0.05) and descriptive statistical analysis. Histopathological analysis showed tumor representativity in all TMA cores selected for the study. There was no difference between the immunohistochemical analysis of mammary tumors using conventional histological sections or sections obtained from a single 1-mm diameter TMA core, regardless of the marker used: PCNA (p=0.279), pancytokeratin (p=0.243) and vimentin (p=0.967). The results did not change even when the means of any number of cores were compared among each other and with the conventional histological section: PCNA (p=0.413), pancytokeratin (p=0.177) and vimentin (p=1.0). Therefore, this study validates the use of a low-cost and modified TMA construction technique proposed by Pires et al. for canine mammary tumor analysis. PMID- 27461826 TI - Assessment of HER2 amplification status in breast cancer using a new automated HER2 IQFISH pharmDxTM (Dako Omnis) assay. AB - In breast cancer the human epidermal growth factor receptor 2 (HER2) is an important target for a number of different HER2 inhibitors. Different slide-based assays are available for assessment of treatment eligibility, which include fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods for assessment of the HER2 gene status. Here we report a summary of the validation data on HER2 IQFISH pharmDxTM (Dako Omnis), a newly developed assay for the automated staining platform Dako Omnis. The assay uses a non-toxic buffer that significantly reduces the hybridization time, which results in a total turnaround time of 31/2 to 4h from deparaffinization to counting of the gene and centromere signals. The data reported in the current summary covers method comparison, assessment of staining quality, observer-to-observer reproducibility as well as reproducibility within and between laboratories. Based on data from the different studies it was concluded that HER2 IQFISH pharmDx (Dako Omnis) is a reliable and robust assay with a high precision that is at least comparable to the manual HER2 IQFISH pharmDxTM assay and the PathVysion((r))HER-2 DNA Probe Kit. PMID- 27461827 TI - Prognostic significance of human papillomavirus viral load in correlation with different therapeutic modalities in cervical cancer patients. AB - PURPOSE: High-risk human papillomavirus (HR-HPV) infections were the causal factor in the development of cervical cancer, but the significance of HPV viral load in the prediction of the response to current therapeutic approaches had not reached consensus. The present study was performed to assess the high risk HPV viral load of cervical cancer patients who underwent radiotherapy alone or in combination with chemotherapy or hyperthermotherapy or both in correlation to long-term survival. METHODS: 116 cervical cancer patients were recruited and assigned into four groups of different therapeutic modalities. The prevalent high risk types of HPV 16, 18, 58 were detected by type specific in situ hybridization (ISH), and HPV mRNA was detected by RNA scope assay using RNA scope 2.0 FFPE Reagent Kit. Semi-quantification of the HR-HPV viral load was measured based on the intensity of ISH signal captured from the tumor nests in the grey scale. RESULTS: The HR-HPV viral load had a significant negative correlation with survival (rs=-0.368, P=0.001). The 15-year survival rate of low viral load group was 68.18%, moderate viral load group was 52.17%, and high viral load group was 34.69% (P=0.001). HPV mRNA expression was strongly consistent with HPV viral load. The 15-year survival rates of different therapeutic groups were 39.29%, 58.62%, 50.00%, 55.17%, respectively (P=0.545). Combinatorial treatment modalities improved the actual survival, which demonstrated no significant difference among 5, 10 and 15 years comparison. Cox regression analysis showed that the relative risk of death was obviously higher in the HPV 18 single positive group and high HPV viral load group. CONCLUSIONS: The semi-quantitive viral load assessment in situ is a feasible approach in clinical practice. The more the HPV viral load was, the worse the survival of patients would be. The combinational treatments were in favor of the disease-stabilization. PMID- 27461828 TI - Upregulation of long noncoding RNA ZFAS1 predicts poor prognosis and prompts invasion and metastasis in colorectal cancer. AB - PURPOSE: ZFAS1 is a newly identified long non-coding RNA. The present study investigated the relationships of ZFAS1 expression with clinicalpathologic parameters and the prognosis of patients with colorectal cancer (CRC). The effects of ZFAS1 on cell migration, invasion and metastasis were also been evaluated in CRC cell lines. METHODS: A total of 159 paired primary CRC tissues and adjacent noncancerous tissues (NCTs) were collected and were tested for the expression of ZFAS1. Cell migration and invasion were measured by wound-healing and Transwell assays, respectively. Tumor metastasis was assessed using a lung metastasis model of nude mouse. RESULTS: The ZFAS1 expression was significantly upregulated in 47.8% (76 of 159) of cancerous tissues compared with NCTs(p<0.0001), and was higher in metastatic tumors than in corresponding primary CRC tumors (p=0.010). ZFAS1 expression in CRC was positively correlated with lymphatic invasion (p=0.045) and TNM stage (p=0.003). Patients with increased ZFAS1 expression showed shorter relapse-free survival and overall survival (p<0.05). Cox multivariate analyses confirmed that ZFAS1 expression is an independent prognostic factor in CRC (p<0.05). The knockdown of ZFAS1 decreased cell migration and invasive ability of LoVo and HCT116 cells in vitro (p<0.05). Moreover, silencing ZFAS1 expression inhibited the in vivo metastasis of CRC cells (p<0.05). CONCLUSIONS: The expression of ZFAS1 is positively correlated with TNM stage and appears to be a new prognostic factor in CRC. ZFAS1 promptes cell migration, invasive and metastasis ability of CRC cells. PMID- 27461829 TI - Nuclear aldehyde dehydrogenase 1A1 (ALDH1A1) expression is a favorable prognostic indicator in colorectal carcinoma. AB - AIM: To assess the expression pattern of aldehyde dehydrogenase 1A1 (ALDH1A1) in the normal-adenoma-primary carcinoma-liver metastasis sequence, and investigate its association with clinicopathological features and outcomes. METHODS: Immunohistochemistry for ALDH1A1 was performed on two cohorts. One used tissue microarrays (TMAs) of 395 primary colorectal carcinomas, and the other used whole tissue sections from 217 adenomas, 265 primary carcinomas, and 72 liver metastatic carcinomas. Both the epithelial and stromal expression of ALDH1A1 were evaluated. Both cytoplasmic and nuclear expression were assessed in epithelial cells. RESULTS: In the TMA and whole-tissue cohorts, univariate analysis indicated that the cytoplasmic expression of ALDH1A1 cannot be considered as a prognosis marker of CRCs. In the whole-tissue cohort, nuclear expression was found in a small subgroup of CRC patients. Here, both univariate and multivariate analysis showed that nuclear expression was significantly associated with longer disease-specific survival. In addition, we found that nuclear expression in low grade adenoma was predominant over high-grade adenoma, primary CRC and the correpsonding liver metastasis. CONCLUSIONS: Whole-tissue is better than TMA for the detection of ALDH1A1 nuclear staining in CRC patients, and nuclear expression is associated with a better outcome. Cytoplasmic expression is not a suitable prognostic marker of CRC. PMID- 27461830 TI - The spectrum of gastric pathology in portal hypertension-An endoscopic and pathologic study of 550 cases. AB - One of the main tasks for pathologists when evaluating gastric biopsies from patients with portal hypertensive gastropathy (PHG) is to examine whether there is increased mucosal vasculature as suggested by endoscopy. However, the full spectrum of pathology findings in patients with portal hypertension (pHTN) is largely unknown. We systematically characterized the endoscopic and pathologic features in gastric biopsies from pHTN patients (study group) and compared with those from patients without pHTN (control group). The study group consisted of 550 consecutive surveillance esophagogastroduodenoscopic (EGD) biopsies, whereas the control group included 281 consecutive EGD biopsies for a variety of indications. As expected, the endoscopic prevalence of PHG was 28%, among which two-thirds showed corresponding histopathologic evidence of increased vasculature. However, non-Helicobacter pylori gastritis was the most common finding in pHTN patients on histology (40%). In addition, hyperplastic polyp was also more common in pHTN patients than in controls (6% vs 3%; P=0.0314). In contrast, pathology findings of nonspecific reactive changes (29% vs 51%; P<0.0001), proton pump inhibitor-related changes (16% vs 30%; P<0.0001), and malignancy (1% vs 3%; P=0.0138) were less common in pHTN patients. Our results show a spectrum of gastric endoscopic and pathologic findings in pHTN patients. The predominant gastric pathology in pHTN patients may be associated with pHTN induced gastric microcirculation impairment. PMID- 27461832 TI - Urinary bladder carcinoma with divergent differentiation featuring small cell carcinoma, sarcomatoid carcinoma, and liposarcomatous component. AB - Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary. PMID- 27461831 TI - San Huang Decoction downregulates Aurora kinase A to inhibit breast cancer cell growth and enhance chemosenstivity to anti-tumor drugs. AB - Our study aimed to explore whether San Huang Decoction (SHD) inhibited the development of breast cancer by regulating Aurora A. Human breast cancer cell lines MCF-7 and MDA-MB-231 were cultured and SHD extract was prepared. Cell growth assay and apoptosis analysis were respectively performed to detect the effects of SHD on breast cancer cells. In addition, the effects of SHD on the expression of Aurora A and p53 were determined by RT-PCR and western blot. Besides, we used Aurora A siRNA to knock down Aurora A. We then co-administrated SHD and tamoxifen or epirubicin to detect the effect of SHD on chemosensitivity to tamoxifen or epirubicin. SHD treatment significantly inhibited cell growth in a dose-dependent manner. Moreover, SHD treatment resulted in a marked decrease in Aurora A expression and obvious increase in p53 expression. In addition, knockdown of Aurora A induced cell growth inhibition, which was similar to the effect of SHD treatment. Besides, SHD exerted an additive effect on cell growth inhibition and apoptosis induction when breast cancer cells were co administration of SHD with tamoxifen or epirubicin. Our study indicates that SHD treatment may inhibit cell growth and enhance chemosenstivity to other anti-tumor drugs in breast cancer via down-regulation of Aurora A. PMID- 27461833 TI - Poly (C)-binding protein 2 (PCBP2) promotes the progression of esophageal squamous cell carcinoma (ESCC) through regulating cellular proliferation and apoptosis. AB - PCBP2 (Poly(C)-binding protein 2) is a member of PCBP family, which has many functions including mRNA stabilization, translational silence and translational enhancement performed by their poly(C)-binding ability. The abnormal expression of PCBP2 was correlated with various carcinomas. However, the significance and mechanism of PCBP2 in esophageal squamous cell carcinoma (ESCC) progression remain unclear. In this study, Western Blot and immunohistochemistry (IHC) analysis revealed that PCBP2 was overexpressed in ESCC tissues and cell lines. Statistical results also indicated that PCBP2 expression level was significantly positively correlated with ESCC clinicopathological parameters such as tumor grade and tumor size. Furthermore, PCBP2 expression level could also be recognized as an independent prognostic factor for ESCC patients' overall survival. Serum starvation and refeeding assay along with PCBP2-shRNA transfection demonstrated that PCBP2 expression promoted proliferation of ESCC cells. The results above are partly due to growth arrest of cell cycle at G1/S phase. We also found that reduced PCBP2 expression might induce ESCC cell apoptosis with increased cleaved caspase3 expression. Overall, our findings indicated that PCBP2 might be involved in the ESCC progression and be considered as a new treatment target in ESCC. PMID- 27461835 TI - Development of a High-Throughput Gene Expression Screen for Modulators of RAS MAPK Signaling in a Mutant RAS Cellular Context. AB - The RAS-MAPK pathway controls many cellular programs, including cell proliferation, differentiation, and apoptosis. In colorectal cancers, recurrent mutations in this pathway often lead to increased cell signaling that may contribute to the development of neoplasms, thereby making this pathway attractive for therapeutic intervention. To this end, we developed a 26-member gene signature of RAS-MAPK pathway activity utilizing the Affymetrix QuantiGene Plex 2.0 reagent system and performed both primary and confirmatory gene expression-based high-throughput screens (GE-HTSs) using KRAS mutant colon cancer cells (SW837) and leveraging a highly annotated chemical library. The screen achieved a hit rate of 1.4% and was able to enrich for hit compounds that target RAS-MAPK pathway members such as MEK and EGFR. Sensitivity and selectivity performance measurements were 0.84 and 1.00, respectively, indicating high true positive and true-negative rates. Active compounds from the primary screen were confirmed in a dose-response GE-HTS assay, a GE-HTS assay using 14 additional cancer cell lines, and an in vitro colony formation assay. Altogether, our data suggest that this GE-HTS assay will be useful for larger unbiased chemical screens to identify novel compounds and mechanisms that may modulate the RAS-MAPK pathway. PMID- 27461836 TI - What Are the Newer Applications for Therapeutic Apheresis in Nephrology?: What Is on the Horizon for Therapeutic Apheresis Medicine in Nephrology? PMID- 27461834 TI - P53 overexpression and Ki67-index are associated with outcome in ductal pancreatic adenocarcinoma with adjuvant gemcitabine treatment. AB - In pancreatic cancer there is a need for prognostic risk stratification and subsequent therapy strategies. Molecular analysis has shown in different cancers that variation in clinical behavior can be associated with specific alterations. The cell cycle regulators p16 and p53 belong to the most often alterated genes in pancreatic ductal adenocarcinoma (PDAC). We analyzed protein expression of p16, p53 and Ki67 by immunohistochemistry in 162 tumours of the CONKO-001 trial that investigated the role of adjuvant gemcitabine in pancreatic cancer patients. We could show that high proliferation of tumours and strong and consistent nuclear p53 expression by tumour cells is associated with a worse disease-free survival and overall survival in the overall study population. However, stratified analysis according to treatment arm revealed that the effect of deregulated p53 expression and high Ki67 expression was restricted to the disease free survival of patients treated with adjuvant gemcitabine. In multivariable survival analysis, p53 did not retain its prognostic status. Our study supports the important role of p53 and Ki67 expression in PDAC. They provide prognostic information in patients with adjuvant gemcitabine treatment and may contribute to treatment decision. However, these results should be validated in further studies. PMID- 27461837 TI - Prevalence of sleep disorders and their relationship with core symptoms of inattention and hyperactivity in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVES: To determine the prevalence of sleep disorders in children with attention-deficit/hyperactivity disorder (ADHD) and in a control population. To examine the relationship between sleep disorders and symptoms of inattention, hyperactivity/impulsiveness and executive dysfunction. MATERIALS AND METHODS: We studied 126 children with ADHD and 1036 control children aged between 5 and 18 years old. Caregivers completed the Pediatric Sleep Questionnaire and the ADHD Rating Scale (ADHD-RS). Children with ADHD were subsequently assessed for executive function with the Conner's Continuous Performance Test (CPT) or with AULA Nesplora. RESULTS: Children with ADHD slept less at night and were more likely to display sleep-related rhythmic movements. Children in the ADHD group who were under 12 years old and who had total ADHD-RS scores over the 90th percentile had more difficulty falling asleep than other children; there was also a relationship between total ADHD-RS scores over the 90th percentile and certain parasomnias in the control population. There was a correlation between shorter duration of night-time sleep and omission errors in children who were 12 or older and who were under pharmacological treatment for ADHD. Bedtime resistance and difficulty falling sleep were more frequent in children with ADHD whose symptoms were not treated pharmacologically, than in children receiving treatment. INTERPRETATION: Symptoms of inattention and hyperactivity are correlated with impaired sleep duration and quality; specifically, there is an association between ADHD symptoms and problems falling asleep and parasomnias, however, the current study does not address the nature and direction of causality. Children with ADHD and receiving methylphenidate had fewer sleep disorders, suggesting that, at least in some children, stimulant treatment is associated with improvement of some aspects of sleep. Shorter sleep duration in adolescents under pharmacological treatment for ADHD tended to result in more errors of omission, suggesting that it is important to promote good sleep habits in this population. PMID- 27461839 TI - Characterization of the novel HLA-C*16:97 allele in an Italian bone marrow donor. AB - The HLA-C*16:97 allele differs from HLA-C*16:01:01:01 at position 666 of exon 4. PMID- 27461840 TI - Pentlandite rocks as sustainable and stable efficient electrocatalysts for hydrogen generation. AB - The need for sustainable catalysts for an efficient hydrogen evolution reaction is of significant interest for modern society. Inspired by comparable structural properties of [FeNi]-hydrogenase, here we present the natural ore pentlandite (Fe4.5Ni4.5S8) as a direct 'rock' electrode material for hydrogen evolution under acidic conditions with an overpotential of 280 mV at 10 mA cm(-2). Furthermore, it reaches a value as low as 190 mV after 96 h of electrolysis due to surface sulfur depletion, which may change the electronic structure of the catalytically active nickel-iron centres. The 'rock' material shows an unexpected catalytic activity with comparable overpotential and Tafel slope to some well-developed metallic or nanostructured catalysts. Notably, the 'rock' material offers high current densities (<=650 mA cm(-2)) without any loss in activity for approximately 170 h. The superior hydrogen evolution performance of pentlandites as 'rock' electrode labels this ore as a promising electrocatalyst for future hydrogen-based economy. PMID- 27461841 TI - Ligubenzocycloheptanone A, a Novel Tricyclic Butenolide with a 6/7/5 Skeleton from Ligusticum chuanxiong. AB - Ligubenzocycloheptanone A (1), a novel tricyclic butenolide with a 6/7/5-membered ring skeleton, was isolated from the rhizome of Ligusticum chuanxiong. Its unusual structure was determined using UV, IR, HRESIMS, 1D and 2D NMR data, X-ray diffraction crystallography and by the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. 1 possessed a benzocycloheptanone core featuring butyrolactone, which is rarely observed in nature. A possible biosynthetic pathway was proposed. Ligubenzocycloheptanone A showed strong radical scavenging activity with an IC50 value of 2.3 MUM. PMID- 27461842 TI - Determination of sulfonate ester genotoxic impurities in imatinib mesylate by gas chromatography with mass spectrometry. AB - Methyl methanesulfonate and ethyl methanesulfonate are potential genotoxic impurities in imatinib mesylate. In this work, a simple, sensitive, reliable, and fast gas chromatography with mass spectrometry method for the simultaneous determination of methyl methanesulfonate and ethyl methanesulfonate was developed and validated. Total analysis time was only 7 min. An n-hexane/water solution was used to dissolve samples, and then extracted-ion-chromatogram mode was used to quantify methyl methanesulfonate and ethyl methanesulfonate. Calibration curves showed good linearity over the studied range for methyl methanesulfonate and ethyl methanesulfonate. The correlation coefficient of fit exceeded 0.999 for each impurity. The LOD and LOQ of methyl methanesulfonate and ethyl methanesulfonate were as low as 0.001 and 0.005 MUg/mL, respectively, with RSDs of the peak area within 1.06-1.96%. Method accuracy was within 97.2-99.8% for methyl methanesulfonate and ethyl methanesulfonate. Therefore, this method can be used to quantify methyl methanesulfonate and ethyl methanesulfonate impurities at extremely low levels in imatinib mesylate. PMID- 27461843 TI - Evaluation of an International Disaster Relief Team After Participation in an ASEAN Regional Forum Disaster Relief Exercise. AB - OBJECTIVE: Devastating disasters around the world directly contribute to significant increases in human mortality and economic costs. The objective of this study was to examine the current state of the Korea Disaster Relief Team that participated in an international training module. METHODS: The whole training period was videotaped in order to observe and evaluate the respondents. The survey was carried out after completion of the 3-day training, and the scores were reported by use of a 5-point Likert scale. RESULTS: A total of 43 respondents were interviewed for the survey, and the results showed that the overall preparedness score for international disasters was 3.4+/-1.6 (mean+/-SD). The awareness of the Incident Command System for international disasters was shown to be low (3.5+/-1.1). Higher scores were given to personnel who took on leadership roles in the team and who answered "I knew my duty" (4.4+/-0.6) in the survey, as well as to the training participants who answered "I clearly knew my duty" (4.5+/-0.5). CONCLUSION: The preparedness level of the Korea Disaster Relief Team was shown to be insufficient, whereas understanding of the roles of leaders and training participants in the rescue team was found to be high. It is assumed that the preparedness level for disaster relief must be improved through continued training. (Disaster Med Public Health Preparedness. 2016;1-5). PMID- 27461844 TI - Mental health professional experiences of the flexible assertive community treatment model: a grounded theory study. AB - BACKGROUND: Despite the lack of evidence for effectiveness of the Flexible Assertive Community Treatment (Flexible ACT), the model is considered feasible and is well received by mental health professionals. No current studies have adequately examined mental health professional experiences of working with Flexible ACT. AIMS: The aim of this study was to explore mental health professional experiences of working with the Flexible ACT model compared with standard care. METHOD: The study was guided by grounded theory and based on the interviews with 19 theoretically chosen mental health professionals in Swedish urban areas primarily working with consumers with psychosis, who had worked with the Flexible ACT model for at least 6 months. RESULTS: The analysis resulted in the core category: "Flexible ACT and the shared caseload create a common action space" and three main categories: (1) "Flexible ACT fills the need for a systematic approach to crisis intervention"; (2) "Flexible ACT has advantages in the psychosocial working environment"; and (3) "Flexible ACT increases the quality of care". CONCLUSIONS: Mental health professionals may benefit from working with the Flexible ACT model through decreased job-strain and stress, increased feeling of being in control over their work situation, and experiences of providing higher quality of care. PMID- 27461845 TI - The challenges and opportunities in researching intimacy and sexuality in care homes accommodating older people: a feasibility study. AB - AIM: To explore the challenges of conducting research on sexuality and intimacy among older care home residents. BACKGROUND: Sexuality and intimacy are neglected in care policies and practices. DESIGN: Qualitative analytical study drawing on poststructuralist theorizing. METHODS: Semi-structured interviews were conducted with residents and spouses (n = 6) and care staff (n = 16) in two care homes in Northwest England in 2014. The sample was obtained through a network of 'research ready' care homes. Thematic analysis was used to make sense of narratives with the aid of NVivo10. RESULTS: Participant responses highlight the workings of ageist erotophobic discourse that undergirds the assumption of residents (and old people generally) as postsexual. This materialized in reservations about the research ranging from opposition on moral grounds to doubts about its feasibility given the age-group concerned. However, residents and care home staff can also draw on counter-discourses that resist/challenge ageist erotophobic thinking, which materialized in methodological and ethical recommendations. CONCLUSION: Participants generally agreed with the principle of the research and made recommendations that could counter/resist ageist erotophobic governance and guide researchers on sampling, style of questioning and communicating with (prospective) study participants on a sensitive subject. PMID- 27461846 TI - Pharmacokinetics and Safety of Tedizolid after Single and Multiple Intravenous/Oral Sequential Administrations in Healthy Chinese Subjects. AB - PURPOSE: Tedizolid phosphate is a new antibacterial agent under investigation for the treatment of Gram-positive infections in China. This study was conducted to assess the pharmacokinetic (PK) properties, oral bioavailability, and safety of once daily tedizolid phosphate 200 mg in Chinese subjects to support its further clinical development in China. METHODS: This Phase I single-center study, conducted in 16 healthy Chinese male subjects, consisted of a single-dose administration, 1:1 randomized, two-way, intravenous (IV)/oral (PO) crossover of tedizolid phosphate 200 mg (Part 1) and, after a 7-day washout, a nonrandomized, multiple-dose, 7-day tedizolid phosphate 200 mg once daily administration (IV for 3 days, PO for 4 days; Part 2). Blood samples were collected for up to 72 hours after single dosing and for up to 2 hours on Day 3 and 72 hours on Day 7 of multiple dosing to determine PK parameters. Adverse events (AEs) were recorded throughout the entire study. FINDINGS: The Cmax and AUC of tedizolid (the active moiety of tedizolid phosphate) were 3.02 ug/mL and 30.50 ug * h/mL after single IV dosing of tedizolid phosphate, and 2.25 ug/mL and 26.10 ug * h/mL after single PO dosing, respectively, and the mean half-life was 10.1 hours for both administration routes. The oral bioavailability of tedizolid was 85.5%. PK parameters of tedizolid were similar after single and multiple dosing of tedizolid phosphate, indicating no time dependency. Only minor accumulation of tedizolid was observed after multiple dosing (expressed as accumulation ratios RAAUC: 1.18 for PO dosing, and RACmax: 1.16 and 1.05 for IV and PO dosing, respectively). Steady state of tedizolid was reached after about 3 days, and trough concentrations remained constant when switching from IV to PO dosing. Tedizolid phosphate was well tolerated with 6 subjects (37.5%) in Part 1 and 5 subjects (31.3%) in Part 2 experiencing an AE; all AEs but one were related to the study drug assessed by the investigator. All AEs were of mild intensity and had recovered or resolved by the end of the study. No serious AEs were observed, and no subjects prematurely discontinued the study due to an AE. IMPLICATIONS: The results of this Phase I study conducted in Chinese male subjects indicate that no dosage adjustment of tedizolid phosphate 200 mg would be required when switching administration routes in this population. Tedizolid phosphate was well tolerated in healthy Chinese subjects. China Food and Drug Administration clinical trial permission numbers 2014L00360 and 2014L00361. PMID- 27461847 TI - Mitochondrial transit peptide exhibits cell penetration ability and efficiently delivers macromolecules to mitochondria. AB - Mitochondrial malfunction under various circumstances can lead to a variety of disorders. Effective targeting of macromolecules (drugs) is important for restoration of mitochondrial function and treatment of related disorders. We have designed a novel cell-penetrating mitochondrial transit peptide (CpMTP) for delivery of macromolecules to mitochondria. Comparison between properties of cell penetrating peptides (CPPs) and mitochondrial signal sequences enabled prediction of peptides with dual ability for cellular translocation and mitochondrial localization. Among the predicted peptides, CpMTP translocates across HeLa cells and shows successful delivery of noncovalently conjugated cargo molecules to mitochondria. CpMTP may have applications in transduction and transfection of mitochondria for therapeutics. PMID- 27461848 TI - In silico synchronization reveals regulators of nuclear ruptures in lamin A/C deficient model cells. AB - The nuclear lamina is a critical regulator of nuclear structure and function. Nuclei from laminopathy patient cells experience repetitive disruptions of the nuclear envelope, causing transient intermingling of nuclear and cytoplasmic components. The exact causes and consequences of these events are not fully understood, but their stochastic occurrence complicates in-depth analyses. To resolve this, we have established a method that enables quantitative investigation of spontaneous nuclear ruptures, based on co-expression of a firmly bound nuclear reference marker and a fluorescent protein that shuttles between the nucleus and cytoplasm during ruptures. Minimally invasive imaging of both reporters, combined with automated tracking and in silico synchronization of individual rupture events, allowed extracting information on rupture frequency and recovery kinetics. Using this approach, we found that rupture frequency correlates inversely with lamin A/C levels, and can be reduced in genome-edited LMNA knockout cells by blocking actomyosin contractility or inhibiting the acetyl transferase protein NAT10. Nuclear signal recovery followed a kinetic that is co determined by the severity of the rupture event, and could be prolonged by knockdown of the ESCRT-III complex component CHMP4B. In conclusion, our approach reveals regulators of nuclear rupture induction and repair, which may have critical roles in disease development. PMID- 27461849 TI - Dose-Dependent Suppression of Cytokine production from T cells by a Novel Phosphoinositide 3-Kinase Delta Inhibitor. AB - There remains a significant need for development of effective small molecules that can inhibit cytokine-mediated inflammation. Phosphoinositide 3 kinase (PI3K) is a direct upstream activator of AKT, and plays a critical role in multiple cell signaling pathways, cell cycle progression, and cell growth, and PI3K inhibitors have been approved or are in clinical development. We examined novel PI3Kdelta inhibitors, which are highly selective for the p110delta isoform of in CD3/CD28 stimulated T-cell cytokine production. In vitro generated CD4+ T effector cells stimulated in the presence of a PI3Kdelta inhibitor demonstrated a dose-dependent suppression of cytokines produced by Th1, Th2, and Th17 cells. This effect was T cell intrinsic, and we observed similar effects on human PBMCs. Th17 cells expressing a constitutively activated form of AKT were resistant to PI3Kdelta inhibition, suggesting that the inhibitor is acting through AKT signaling pathways. Additionally, PI3Kdelta inhibition decreased IL-17 production in vivo and decreased neutrophil recruitment to the lung in a murine model of acute pulmonary inflammation. These experiments show that targeting PI3Kdelta activity can modulate T-cell cytokine production and reduce inflammation in vivo, suggesting that PI3Kdelta inhibition could have therapeutic potential in treating inflammatory diseases. PMID- 27461850 TI - Renal cell carcinoma with vascular invasion: Mortality and prognostic factors. AB - OBJECTIVE: Analysis of the results of patients who had been operated of renal cell carcinoma with vascular invasion in our institution, evaluation of prognostic factors and complications. METHODS: Retrospective observational study of 37 patients diagnosed of renal cell carcinoma with vascular invasion operated between May 1999 and July 2013. We used the method of Kaplan-Meier survival analysis and the Mantel-Haenszel's test (log rank) and the Cox's proportional hazards analysis test to analyse the risk factors of mortality. RESULTS: The median age was 60 years. Mean follow-up period was 42.1 months. The median overall survival and disease-free survival were 53.8and 36.3 months, respectively. There was statistical association between overall survival and ASA (p=0.047), tumor stage (p=0.003), lymph node involvement (p=0.024), presence of metastases (p=0.013), level of tumor thrombus (p=0, 05) and histological type (p=0.001). 14 patients had grade IIIb complications or higher according to the Clavien Dindo classification, the most frequent was bleeding. CONCLUSIONS: Renal cell carcinoma with vascular invasion is a disease with high rate of mortality. Surgery is a therapeutic option that can be curative. The number of complications is important. Survival is conditioned by the ASA, tumor stage, the level of tumor thrombus, lymph node involvement, metastasis and histological type. PMID- 27461851 TI - Phosphate-Binding Agents in Adults With CKD: A Network Meta-analysis of Randomized Trials. AB - BACKGROUND: Guidelines preferentially recommend noncalcium phosphate binders in adults with chronic kidney disease (CKD). We compare and rank phosphate-binder strategies for CKD. STUDY DESIGN: Network meta-analysis. SETTING & POPULATION: Adults with CKD. SELECTION CRITERIA FOR STUDIES: Randomized trials with allocation to phosphate binders. INTERVENTIONS: Sevelamer, lanthanum, iron, calcium, colestilan, bixalomer, nicotinic acid, and magnesium. OUTCOMES: The primary outcome was all-cause mortality. Additional outcomes were cardiovascular mortality, myocardial infarction, stroke, adverse events, serum phosphorus and calcium levels, and coronary artery calcification. RESULTS: 77 trials (12,562 participants) were included. Most (62 trials in 11,009 patients) studies were performed in a dialysis population. Trials were generally of short duration (median, 6 months) and had high risks of bias. All-cause mortality was ascertained in 20 studies during 86,744 patient-months of follow-up. There was no evidence that any drug class lowered mortality or cardiovascular events when compared to placebo. Compared to calcium, sevelamer reduced all-cause mortality (OR, 0.39; 95% CI, 0.21-0.74), whereas treatment effects of lanthanum, iron, and colestilan were not significant (ORs of 0.78 [95% CI, 0.16-3.72], 0.37 [95% CI, 0.09-1.60], and 0.55 [95% CI, 0.07-4.43], respectively). Lanthanum caused nausea, whereas sevelamer posed the highest risk for constipation and iron caused diarrhea. All phosphate binders lowered serum phosphorus levels to a greater extent than placebo, with iron ranked as the best treatment. Sevelamer and lanthanum posed substantially lower risks for hypercalcemia than calcium. LIMITATIONS: Limited testing of consistency; short follow-up. CONCLUSIONS: There is currently no evidence that phosphate-binder treatment reduces mortality compared to placebo in adults with CKD. It is not clear whether the higher mortality with calcium versus sevelamer reflects whether there is net harm associated with calcium, net benefit with sevelamer, both, or neither. Iron-based binders show evidence of greater phosphate lowering that warrants further examination in randomized trials. PMID- 27461852 TI - Falsely Elevated Plasma Creatinine Due to an Immunoglobulin M Paraprotein. AB - The most common method for measuring plasma creatinine is based on its reaction with picric acid. However, enzymatic methods are becoming more popular due to improved specificity. We present a case of falsely elevated plasma creatinine values obtained by an enzymatic method that turned out to be due to a monoclonal immunoglobulin M (IgM) paraprotein. A 63-year-old woman evaluated for lung transplantation had falsely increased plasma creatinine levels (1.54-1.71mg/dL; corresponding to estimated glomerular filtration rates of 32-36 mL/min/1.73m2) as measured by the Roche Creatinine plus enzymatic assay when compared with the picric acid-based procedure and several other enzymatic methods, which gave plasma creatinine values of 0.7 to 0.8mg/dL. Serum protein electrophoresis revealed an IgM kappa light chain paraprotein. Removal of high-molecular-weight (>30kDa) proteins by ultrafiltration reduced the patient's plasma creatinine level by the Roche enzymatic method to 0.7mg/dL. Addition of the patient's immunoglobulin fraction to plasma from other patients with normal plasma creatinine levels resulted in values that were increased by 0.58 to 0.62mg/dL. Furthermore, removal of non-IgM immunoglobulins with protein G-coupled beads did not eliminate the interference from the patient's plasma. Taken together, these studies demonstrate that falsely elevated plasma creatinine values by the Roche enzymatic method can be due to an IgM paraprotein. PMID- 27461853 TI - Identification of three cytochrome P450 genes in the Chagas' disease vector Triatoma infestans: Expression analysis in deltamethrin susceptible and resistant populations. AB - Cytochrome P450 monooxygenases play a predominant role in the metabolism of insecticides. Many insect P450 genes have frequently been associated with detoxification processes allowing the insect to become tolerant or resistant to insecticides. The increases of expression of P450 genes at transcriptional level are often consider responsible for increasing the metabolism of insecticides and seems to be a common phenomenon in the evolution of resistance development in insects. As pyrethroid resistance has been detected in Triatoma infestans, it was of interest to analyze genes associated with resistance to insecticides such as those encoding for cytochromes P450. With this purpose, the cDNA sequences of three cytochrome P450 genes (CYP4EM7, CYP3085B1, and CYP3092A6) were identified in this species. Primers and specific Taqman probes were designed from these sequences to determine their expression by quantitative PCR. The mRNA levels of the cytochrome P450 genes identified were determined from total RNA extracted from pools of fat body collected from individuals of different resistant and susceptible strains of T. infestans, and at different interval times after the topical application of the lethal doses 50% (LD50) of deltamethrin on the ventral abdomen of insects belonging to the different populations analyzed. It was detected overexpression of the CYP4EM7 gene in the most resistant strain of T. infestans and the expression of the three cytochrome P450 genes isolated was induced by deltamethrin in the susceptible and resistant populations included in this study. These results suggest that these genes would be involved in the detoxification of deltamethrin and support the hypothesis that considers to the cytochrome P450 genes of importance in the development of pyrethroid resistance. PMID- 27461854 TI - Targeting cellular and microenvironmental multidrug resistance. PMID- 27461856 TI - Science in Focus - Oncolytic Viruses: New Multifunctional Immunotherapeutics. PMID- 27461858 TI - Trypsin differentially modulates the surface expression and function of channel catfish leukocyte immune-type receptors. AB - Channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) are immunoregulatory proteins that control innate immune cellular responses. Previously, we demonstrated that two representative IpLITR forms, IpLITR 2.6b and IpLITR 1.1b, engage distinct components of the phagocytic machinery resulting in unique target capture and engulfment phenotypes. IpLITR-induced phagocytic mechanisms were also differentially susceptible to temperature and pharmacological inhibitors of canonical signaling mediators. In the present study, we examined the sensitivity of IpLITR-mediated phagocytosis to the endogenous serine-protease trypsin, a well-known mediator of immunoregulatory receptor functions. Trypsin selectively reduced IpLITR 1.1b cell surface expression and phagocytic activity in a dose-dependent manner. We also observed a significant alteration of the IpLITR 1.1b phagocytic phenotype post-trypsin exposure; whereas, the IpLITR 2.6b-mediated target engulfment phenotype was unchanged. Recovery experiments suggested that trypsin-induced inhibition of IpLITR 1.1b-dependent phagocytosis was reversible and that the re-establishment of phagocytic function was associated with a recovery of receptor surface expression. Cell-surface biotinylation and immunoprecipitation studies demonstrated that IpLITR 1.1b normally exists as a mature (~70 kDa) protein on the cell surface. However, trypsin treatment reduced expression of the mature receptor and processed IpLITR 1.1b into an ~60 kDa form. The trypsin-generated and putative immature IpLITR 1.1b form was not present on the cell surface; suggesting that the cleaved receptor may have been internalized, post-processing, by regulated endocytosis. Taken together, these results reveal a unique role for trypsin as a selective modulator of IpLITR-mediated phagocytosis and highlight a conserved role for serine proteases as potent immunomodulatory factors. PMID- 27461857 TI - Racial/ethnic differences in unmet needs for mental health and substance use treatment in a community-based sample of sexual minority women. AB - AIMS AND OBJECTIVES: To examine the unmet needs for mental health and substance use treatment among a diverse sample of sexual minority women (lesbian, bisexual). BACKGROUND: Sexual minority women are more likely than heterosexual women to report depression and hazardous drinking. However, relatively little is known about sexual minority women's use of mental health or substance use treatment services, particularly about whether use varies by race/ethnicity. DESIGN: Cross-sectional analysis of existing data. METHODS: Analyses included data from 699 Latina, African American and white sexual minority women interviewed in wave 3 of the 17-year Chicago Health and Life Experiences of Women study. Using logistic regression, we examined the associations among sexual identity, race/ethnicity, use of mental health and substance use treatment, as well as potential unmet need for treatment. RESULTS: Overall, women in the study reported high levels of depression and alcohol dependence, and these varied by sexual identity and race/ethnicity. Use of mental health and substance use treatment also varied by race/ethnicity, as did potential unmet need for both mental health and substance use treatment. CONCLUSIONS: Our findings that suggest although use of treatment among sexual minority women is high overall, there is a potentially sizable unmet need for mental health and substance use treatment that varies by race/ethnicity, with Latina women showing the greatest unmet need for treatment. RELEVANCE TO CLINICAL PRACTICE: Nurses and other healthcare providers should be aware of the high rates of depression and hazardous drinking among sexual minority women, understand the factors that may increase the risk of these conditions among sexual minority women, the potentially high unmet need for mental health and substance use treatment - perhaps particularly among Latina women and be equipped to provide culturally sensitive care or refer to appropriate treatment services as needed. PMID- 27461859 TI - The location of the Trait Emotional Intelligence in the Zuckerman's Personality Model space and the role of General Intelligence and social status. AB - The aim of this study was to investigate the relationships between Emotional Intelligence (EI) measured by the Trait Emotional Intelligence Questionnaire (TEIQue) and personality measured by the Zuckerman-Kuhlman-Aluja Personality Questionnaire (ZKA-PQ) with the purpose of analyzing similarities and differences of both psychological constructs. Additionally, we studied the relationship among EI, personality, General Intelligence (GI) and a social position index (SPI). Results showed that the ZKA-PQ predicts the 66% (facets) and the 64% (factors) of the TEIQue. High scores in EI correlated negatively with Neuroticism (r: -0.66) and Aggressiveness (r: -0.27); and positively with Extraversion (r: 0.62). Oblique factorial analyses demonstrated that TEIQue scales were located basically in the Neuroticism and Extraversion factors. The SPI and GI no loaded in any factor. These findings showed that EI is a not a distinct construct of personality and it cannot be isolated in the ZKA-PQ personality space. GI is related with the SPI (r: 0.26), and EI correlated with GI (r: 0.18) and SPI (r: 0.16). Nevertheless, we found differences between GI high groups and the TEIQue and ZKA-PQ factors when controlling age and sex. These findings are discussed in the individual differences context. PMID- 27461855 TI - Glycosaminoglycan-Based Biohybrid Hydrogels: A Sweet and Smart Choice for Multifunctional Biomaterials. AB - Glycosaminoglycans (GAGs) govern important functional characteristics of the extracellular matrix (ECM) in living tissues. Incorporation of GAGs into biomaterials opens up new routes for the presentation of signaling molecules, providing control over development, homeostasis, inflammation, and tumor formation and progression. Recent approaches to GAG-based materials are reviewed, highlighting the formation of modular, tunable biohybrid hydrogels by covalent and non-covalent conjugation schemes, including both theory-driven design concepts and advanced processing technologies. Examples of the application of the resulting materials in biomedical studies are provided. For perspective, solid phase and chemoenzymatic oligosaccharide synthesis methods for GAG-derived motifs, rational and high-throughput design strategies for GAG-based materials, and the utilization of the factor-scavenging characteristics of GAGs are highlighted. PMID- 27461860 TI - Insights into Population Health Management Through Disease Diagnoses Networks. AB - The increasing availability of electronic health care records has provided remarkable progress in the field of population health. In particular the identification of disease risk factors has flourished under the surge of available data. Researchers can now access patient data across a broad range of demographics and geographic locations. Utilizing this Big healthcare data researchers have been able to empirically identify specific high-risk conditions found within differing populations. However to date the majority of studies approached the issue from the top down, focusing on the prevalence of specific diseases within a population. Through our work we demonstrate the power of addressing this issue bottom-up by identifying specifically which diseases are higher-risk for a specific population. In this work we demonstrate that network based analysis can present a foundation to identify pairs of diagnoses that differentiate across population segments. We provide a case study highlighting differences between high and low income individuals in the United States. This work is particularly valuable when addressing population health management within resource-constrained environments such as community health programs where it can be used to provide insight and resource planning into targeted care for the population served. PMID- 27461861 TI - The role of prenatal exposures on body fat patterns at 7 years: Intrauterine programming or birthweight effects? AB - BACKGROUND AND AIMS: It remains unknown whether the effects of prenatal exposures on child's adiposity reflect entirely intrauterine programming. We aimed to assess the effects of maternal gestational weight gain, diabetes and smoking on the child's body fat patterns, disentangling the direct (through intrauterine programming) and indirect (through birthweight) effects. METHODS AND RESULTS: We included 4747 singleton 7-year-old children from the Generation XXI birth cohort (Porto, Portugal). At birth, maternal and newborn's characteristics were obtained. Anthropometrics were measured at age 7 years and body fat patterns were identified by principal component analysis. Path analysis was used to quantify direct, indirect and total effects of gestational weight gain, diabetes and smoking on body fat patterns. Pattern 1 was characterized by strong factor loadings with body mass index, fat mass index and waist-to-height ratio (fat quantity) and pattern 2 with waist-to-hip ratio, waist-to-thigh ratio, and waist to-weight ratio (fat distribution). The positive total effect of maternal gestational weight gain and diabetes on the child's fat quantity was mainly through a direct pathway, responsible for 91.7% and 83.7% of total effects, respectively (beta = 0.022; 95% Confidence Interval (CI): 0.017, 0.027; beta = 0.041; 95% CI: -0.011, 0.093). No effects on fat distribution were found. Maternal prenatal smoking had a positive direct effect on patterns 1 and 2, explaining 94.9% and 76.1% of total effects, respectively. CONCLUSION: The effects of maternal gestational weight gain, diabetes and smoking on a child's fat quantity seem to be mainly through intrauterine programming. Maternal smoking also showed a positive direct effect on child's fat distribution. PMID- 27461862 TI - Serum 25-hydroxyvitamin D predicts early recurrent stroke in ischemic stroke patients. AB - BACKGROUND AND AIM: This study was conducted to determine 25-hydroxyvitamin D [25(OH) D] levels in serum, and to investigate their associations with stroke recurrence events in a 3-month follow-up study in Chinese patients with first ever ischemic stroke. METHODS AND RESULTS: From February 2014 to September 2015, consecutive first-ever ischemic stroke patients admitted to the Department of Emergency of our hospital were identified. Serum 25(OH) D levels were measured at admission. We followed the participants for a median of 3 months (range, 2.5-3.5 months) using a standard questionnaire. We used logistic regression models to assess the relationship between 25(OH) levels and risk of recurrent stroke. In this study, 349 ischemic stroke patients were included and completed follow-up. Thirty-seven patients (10.6%) had a stroke recurrence. Serum 25(OH) D levels in patients with recurrent stroke were significantly lower as compared with those in patients without recurrent stroke [9.9 (IQR, 7.9-14.8) ng/mL vs. 17.9 (IQR, 13.4 23.4) ng/mL; P < 0.001). After adjusting for traditional risk factors, serum 25(OH) D levels were negatively associated with the stroke recurrence (OR, 0.897; 95% CI, 0.848-0.950; P < 0.001). Compared with the first quartile of serum 25(OH) D levels, the second quartile OR for recurrent stroke was 0.466 (95% CI, 0.308 707; P = 0.006). For the third and fourth quartiles, it was 0.248 (95% CI, 0.100 0.618; P = 0.001) and 0.173 (95% CI, 0.062-0.482; P < 0.001), respectively. CONCLUSIONS: Our findings suggest that reduced serum levels of 25(OH) D can predict the risk of early stroke recurrence in patients with first-ever ischemic stroke. PMID- 27461863 TI - Case of Japanese carpenter bee (Xylocopa appendiculata circumvolans) stings. PMID- 27461864 TI - Cellular perception and misperception: Internal models for decision-making shaped by evolutionary experience. AB - Cells live in dynamic environments that necessitate perpetual adaptation. Since cells have limited resources to monitor external inputs, they are required to maximize the information content of perceived signals. This challenge is not unique to microscopic life: Animals use senses to perceive inputs and adequately respond. Research showed that sensory-perception is actively shaped by learning and expectation allowing internal cognitive models to "fill in the blanks" in face of limited information. We propose that cells employ analogous strategies and use internal models shaped through the long process of evolutionary adaptation. Given this perspective, we postulate that cells are prone to "misperceptions," analogous to visual illusions, leading them to incorrectly decode patterns of inputs that lie outside of their evolutionary experience. Mapping cellular misperception can serve as a fundamental approach for dissecting regulatory networks and could be harnessed to modulate cell behavior, a potentially new avenue for therapy. PMID- 27461865 TI - Active Vaccines for Alzheimer Disease Treatment. AB - INTRODUCTION: Vaccination against peptides specific to Alzheimer disease may generate an immune response that could help inhibit disease and symptom progression. METHODS: PubMed and Scopus were searched for clinical trial articles, review articles, and preclinical studies relevant to the field of active Alzheimer disease vaccines and raw searches yielded articles ranging from 2016 to 1973. ClinicalTrials.gov was searched for active Alzheimer disease vaccine trials. Manual research and cross-referencing from reviews and original articles was performed. RESULTS: First generation Abeta42 phase 2a trial in patients with mild to moderate Alzheimer disease resulted in cases of meningoencephalitis in 6% of patients, so next generation vaccines are working to target more specific epitopes to induce a more controlled immune response. Difficulty in developing these vaccines resides in striking a balance between providing a vaccine that induces enough of an immune response to actually clear protein sustainably but not so much of a response that results in excess immune activation and possibly adverse effects such as meningoencephalitis. CONCLUSIONS: Although much work still needs to be done in the field to make this a practical possibility, the enticing allure of being able to treat or even prevent the extraordinarily impactful disease that is Alzheimer disease makes the idea of active vaccination for Alzheimer disease very appealing and something worth striving toward. PMID- 27461866 TI - The Utility of Brief Cognitive Tests for Patients With Type 2 Diabetes Mellitus: A Systematic Review. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk for mild cognitive impairment and dementia in both middle-aged and older individuals. Brief cognitive tests can potentially serve as a reliable and cost effective approach to detect for cognitive decrements in clinical practice. OBJECTIVE: This systematic review examined the utility of brief cognitive tests in studies with patients with T2DM. METHOD: This systematic review was conducted according to guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. "PubMed," "PsychINFO," "ScienceDirect," and "ProQuest" electronic databases were searched to identify articles published from January 1, 2005 to December 31, 2015. RESULTS: The search yielded 22 studies, with only 8 using brief tests as a cognitive screening tool, whereas the majority using these tests as a measure of global cognitive functions. In regard to cognitive screening studies, most had failed to fulfil the standard reporting of diagnostic test accuracy criteria such as Standards for Reporting of Diagnostic Accuracy for dementia and cognitive impairment. Moreover, few studies reported discriminant indices such as sensitivity, specificity, and positive and negative predictive values of brief cognitive tests in detecting cognitive impairment in patients with T2DM. Among studies which used brief cognitive tests as a measure of global cognitive function, patients with diabetes tended to perform worse than patients without diabetes. Processing speed appeared to be particularly impaired among patients with diabetes, therefore, measures of processing speed such as the Digit Symbol Substitution Test may add value to brief cognitive tests such as the Montreal Cognitive Assessment. CONCLUSIONS: The Montreal Cognitive Assessment supplemented by the Digit Symbol Substitution Test indicate initial promise in screening for cognitive impairment in T2DM. PMID- 27461867 TI - Geographic Variation in Hip Fracture Among United States Long-Stay Nursing Home Residents. AB - INTRODUCTION: Despite high rates of hip fracture among United States (US) nursing home (NH) residents, little is known about geographic variation in hip fracture incidence. We used nationally representative data to identify geographic variation in hip fracture among US NH residents. DESIGN AND SETTING: Retrospective cohort study using Part A claims for a 100% of Medicare enrollees in 15,289 NHs linked to NH minimum data set and Online Survey, Certification, and Reporting databases. PARTICIPANTS: A total of 891,085 long-stay (continuous residence of >=100 days) NH residents >=65 years old. MEASUREMENTS: Medicare Part A claims documenting a hip fracture. Mean incidence rates of hip fracture for long-stay NH residents were calculated for each state and US Census Division from 2007 to 2010. RESULTS: The age-, sex-, and race-adjusted incidence rate of hip fracture ranged from 1.49 hip fractures/100 person-years (Hawaii) to 3.60 hip fractures/100 person-years (New Mexico), with a mean of 2.38 (standard deviation 0.43) hip fractures/100 person-years. The mean incidence of hip fracture was 1.7 fold greater in the highest quintile than the lowest. CONCLUSIONS: We observed modest US state and regional variation in hip fracture incidence among long-stay NH residents. Future studies should assess whether state policies or NH characteristics explain the variation. PMID- 27461868 TI - [Bedside ultrasound in the critically ill paediatric patient]. PMID- 27461869 TI - [Persistent Mullerian duct syndrome due to a mutation in the anti-Mullerian hormone receptor gene (AMHR2)]. PMID- 27461870 TI - Emissions from Electronic Cigarettes: Key Parameters Affecting the Release of Harmful Chemicals. AB - Use of electronic cigarettes has grown exponentially over the past few years, raising concerns about harmful emissions. This study quantified potentially toxic compounds in the vapor and identified key parameters affecting emissions. Six principal constituents in three different refill "e-liquids" were propylene glycol (PG), glycerin, nicotine, ethanol, acetol, and propylene oxide. The latter, with mass concentrations of 0.4-0.6%, is a possible carcinogen and respiratory irritant. Aerosols generated with vaporizers contained up to 31 compounds, including nicotine, nicotyrine, formaldehyde, acetaldehyde, glycidol, acrolein, acetol, and diacetyl. Glycidol is a probable carcinogen not previously identified in the vapor, and acrolein is a powerful irritant. Emission rates ranged from tens to thousands of nanograms of toxicants per milligram of e-liquid vaporized, and they were significantly higher for a single-coil vs a double-coil vaporizer (by up to an order of magnitude for aldehydes). By increasing the voltage applied to a single-coil device from 3.3 to 4.8 V, the mass of e-liquid consumed doubled from 3.7 to 7.5 mg puff(-1) and the total aldehyde emission rates tripled from 53 to 165 MUg puff(-1), with acrolein rates growing by a factor of 10. Aldehyde emissions increased by more than 60% after the device was reused several times, likely due to the buildup of polymerization byproducts that degraded upon heating. These findings suggest that thermal degradation byproducts are formed during vapor generation. Glycidol and acrolein were primarily produced by glycerin degradation. Acetol and 2-propen-1-ol were produced mostly from PG, while other compounds (e.g., formaldehyde) originated from both. Because emissions originate from reaction of the most common e-liquid constituents (solvents), harmful emissions are expected to be ubiquitous when e-cigarette vapor is present. PMID- 27461871 TI - Endocytic regulation of cytokine receptor signaling. AB - Signaling of plasma membrane receptors can be regulated by endocytosis at different levels, including receptor internalization, endocytic sorting towards degradation or recycling, and using endosomes as mobile signaling platforms. Increasing number of reports underscore the importance of endocytic mechanisms for signaling of cytokine receptors. In this short review we present both consistent and conflicting data regarding endocytosis and its role in signaling of receptors from the tumor necrosis factor receptor superfamily (TNFRSF) and those for interleukins (ILRs) and interferons (IFNRs). These receptors can be internalized through various endocytic routes and most of them are able to activate downstream pathways from endosomal compartments. Moreover, some of the cytokine receptors clearly require endocytosis for proper signal transduction. Still, the data describing internalization mechanisms and fate of cytokine receptors are often fragmentary and barely address the relation between their endocytosis and signaling. In the light of growing knowledge regarding different mechanisms of endocytosis, extending it to the regulation of cytokine receptor signaling may improve our understanding of the complex and pleiotropic functions of these molecules. PMID- 27461872 TI - Structural stability of flagellin subunit affects the rate of flagellin export in the absence of FliS chaperone. AB - FliS chaperone binds to flagellin FliC in the cytoplasm and transfers FliC to a sorting platform of the flagellar type III export apparatus through the interaction between FliS and FlhA for rapid and efficient protein export during flagellar filament assembly. FliS also suppresses the secretion of an anti-sigma factor, FlgM. Loss of FliS results in a short filament phenotype although the expression levels of FliC are increased considerably due to an increase in the secretion level of FlgM. Here to clarify the rate limiting step of FliC export in the absence of FliS, we isolated bypass mutants from a Salmonella DeltafliS mutant. All the bypass mutations were identified in FliC. These bypass mutations increased the export rate of FliC by ca. twofold, allowing the bypass mutant cells to produce longer filaments than the parental DeltafliS cells. Both far-UV CD measurements and limited proteolysis revealed that the bypass mutations significantly destabilize the folded structure of FliC monomer. These results suggest that an unfolding step of FliC limits the export rate of FliC in the DeltafliS mutant, thereby producing short filaments. We propose that FliS promotes FliC docking at the FlhA platform to facilitate subsequent unfolding of FliC. PMID- 27461873 TI - Expression of the complement system's activation factors in plasma of patients with early/late-onset severe pre-eclampsia. AB - PROBLEM: To investigate the expression of complement activation factors in plasma of patients with early/late-onset severe pre-eclampsia. METHODS: A case-control study was performed. The study group consisted of 30 cases of early-onset severe pre-eclampsia (EOSPE) and 30 cases of late-onset severe pre-eclampsia (LOSPE). Thirty cases were selected as the early-onset control group (E-control) and 30 as the late-onset control group (L-control). ELISA was used to test C1q, C4d, MBL, Bb, C3a, C5a, and MAC in the maternal peripheral circulation. RESULTS: The complement activation factors Bb, C3a, C5a, and MAC were increased significantly in EOSPE (all P<.01) and LOSPE (P value: .027, <.001, .001, and <.001, respectively) compared with E/L-control. C1q and C4d were increased significantly in LOSPE (P value: .003 and .014, respectively) compared with L-control. CONCLUSION: Abnormal activation of the complement system exists in the maternal circulation of patients with early- and late-onset severe pre-eclampsia. In patients complicated with LOSPE, the complement system was activated through both the classical and alternative pathways, while in EOSPE, the complement system was activated mainly through the alternative pathway. PMID- 27461874 TI - Clinical and histological features of lupus nephritis in Japan: A cross-sectional analysis of the Japan Renal Biopsy Registry (J-RBR). AB - AIM: The clinical and histological features of lupus nephritis (LN) are highly variable, depending on race and ethnicity. The Japan Renal Biopsy Registry (J RBR) is a nationwide registry of renal biopsies. Here, we report a cross sectional analysis of Japanese LN using the J-RBR database. METHODS: Out of 18 463 patients registered in the J-RBR, 331 LN patients, who received renal biopsy for the first time, were extracted and their clinical features were analyzed according to the ISN/RPS 2003 classification. RESULTS: The median age of the 331 LN patients was 37 years (women, 81.3%). The frequencies of each of the ISN/RPS Classes were as follows: I, 1.2%; II, 7.9%; III (+/-V), 25.1%; IV-S (+/-V), 13.0%; IV-G (+/-V), 31.1%; V, 20.8%; and VI, 0.9%. The level of proteinuria and the prevalence of nephrotic syndrome were highest for Class IV-G (+/-V). When Classes I, II, and VI were excluded from the analysis, Class IV-G (+/-V) was significantly associated with a lower eGFR and severer haematuria than the other classes. CONCLUSION: This nationwide study revealed that Class IV-G (+/-V) was the most prevalent form of LN in Japan and was associated with a severe clinical renal presentation. PMID- 27461875 TI - Convergent synthesis of oligosaccharides on the gram-scale using cetyl thioglycoside based on a hydrophobically assisted switching phase method. AB - A hydrophobically assisted switching phase (HASP) method is an efficient strategy for the synthesis of carrier-loaded oligosaccharides. We improved this method by using cetyl thioglycoside as the carrier, which made it possible to use the synthetic oligosaccharide block directly as the donor. We applied this improved HASP method in the successful assembly of a gp120-associated nona-mannoside. Our results indicated that the HASP method is an efficient strategy for the synthesis of complex oligosaccharides and glycoconjugates. PMID- 27461876 TI - Breast cancer-associated high-order SNP-SNP interaction of CXCL12/CXCR4-related genes by an improved multifactor dimensionality reduction (MDR-ER). AB - In association studies, the combined effects of single nucleotide polymorphism (SNP)-SNP interactions and the problem of imbalanced data between cases and controls are frequently ignored. In the present study, we used an improved multifactor dimensionality reduction (MDR) approach namely MDR-ER to detect the high order SNP-SNP interaction in an imbalanced breast cancer data set containing seven SNPs of chemokine CXCL12/CXCR4 pathway genes. Most individual SNPs were not significantly associated with breast cancer. After MDR-ER analysis, six significant SNP-SNP interaction models with seven genes (highest cross-validation consistency, 10; classification error rates, 41.3-21.0; and prediction error rates, 47.4-55.3) were identified. CD4 and VEGFA genes were associated in a 2 loci interaction model (classification error rate, 41.3; prediction error rate, 47.5; odds ratio (OR), 2.069; 95% bootstrap CI, 1.40-2.90; P=1.71E-04) and it also appeared in all the best 2-7-loci models. When the loci number increased, the classification error rates and P-values decreased. The powers in 2-7-loci in all models were >0.9. The minimum classification error rate of the MDR-ER generated model was shown with the 7-loci interaction model (classification error rate, 21.0; OR=15.282; 95% bootstrap CI, 9.54-23.87; P=4.03E-31). In the epistasis network analysis, the overall effect with breast cancer susceptibility was identified and the SNP order of impact on breast cancer was identified as follows: CD4 = VEGFA > KITLG > CXCL12 > CCR7 = MMP2 > CXCR4. In conclusion, the MDR-ER can effectively and correctly identify the best SNP-SNP interaction models in an imbalanced data set for breast cancer cases. PMID- 27461877 TI - Expectation to feel more pain disrupts the habituation of laser-pain rating and laser-evoked potential amplitudes. AB - Increased pain perception due to the expectation to feel more pain is called nocebo effect. The present study aimed at investigating whether: (1) the mere expectation to feel more pain after the administration of an inert drug can affect the laser-pain rating and the laser-evoked potential (LEP) amplitude, and (2) the learning potentiates the nocebo effect. Eighteen healthy volunteers were told that an inert cream, applied on the right hand, would increase the laser pain and LEP amplitude to right hand stimulation. They were randomly assigned to either "verbal session" or "conditioning session". In the "verbal session", LEPs to both right and left hand stimulation were recorded at the same intensity before (baseline) and after cream application. In the "conditioning session", after an initial cream application the laser stimulus intensity was increased surreptitiously to make the subjects believe that the treatment really increased the pain sensation. Then, the cream was reapplied, and LEPs were recorded at the same stimulus intensity as at the baseline. It was found that the verbal suggestion to feel more pain disrupted the physiological habituation of the laser pain rating and LEP amplitude to treated (right) hand stimulation. Unlike previously demonstrated for the placebo effect, the learning did not potentiate the nocebo effect. PMID- 27461878 TI - Changes in serum lipid profile in the acute and convalescent Plasmodium vivax malaria: A cohort study. AB - Although serum lipids are known to be altered in Plasmodium falciparum-induced malaria, little is known about such changes due to Plasmodium vivax infection. This cohort study assessed serum concentrations of triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in 164 patients in the acute phase of malaria caused by P. vivax and characterized these changes in the convalescent phase after treatment with chloroquine and primaquine. Compared to reference values, serum total cholesterol, LDL, and HDL levels were lower and triglyceride levels were higher in the acute phase. Moreover, the parasite density was negatively correlated with LDL (r=-0,189; p=0.027) and HDL (r=-0,256; p=0.001) serum levels. Eighty patients returned for clinical and laboratory revaluation 7-12days after treatment initiation. All patients showed parasite clearance and the absence of symptoms during the convalescent phase. Analysis of the serum lipids of these 80 patients showed significant increases in the serum levels of total cholesterol (p<0.0001), LDL (p<0.0001), and HDL (p<0.0001) as well as a significant reduction in triglycerides (p=0.004), indicating a trend towards a return to normal levels. This transient change in lipid profile between the acute and convalescent stages may be useful for the clinical monitoring of patients treated for vivax malaria. PMID- 27461879 TI - The association between fructosamine-3 kinase 900C/G polymorphism, transferrin polymorphism and human herpesvirus-8 infection in diabetics living in South Kivu. AB - Prevalences of human herpesvirus-8 (HHV-8) infection and diabetes mellitus are very common in certain parts of Africa, containing iron-rich soils. We hypothesized that some genetic factors could have a link with susceptibility to HHV-8 infection. We focused on ferroportin Q248H mutation (rs11568350), transferrin (TF) polymorphism and fructosamine-3 kinase (FN3K) 900C/G polymorphism (rs1056534). The study population consisted of 210 type 2 diabetic adults and 125 healthy controls recruited in Bukavu (South Kivu). In the whole study population (diabetics+healthy controls), ferroportin Q248H mutation was detected in 47 subjects (14.0%) with 43 heterozygotes and 4 homozygotes. TF phenotype frequencies were 88.1% (CC), 10.4% (CD) and 1.5% (BC). Genotype frequencies of FN3K 900C/G polymorphism were respectively 9,3% (CC), 43.3% (GC) and 47.4% (GG). Prevalence of HHV8-infection in the study population was 77.3%. HHV-8 infection rate and HHV-8 IgG antibody titer were significantly higher in diabetics then in controls (p<0.0001). Significant differences were observed in HHV-8 infection rate and in HHV-8 IgG antibody titer according to FN3K rs1056534 (p<0.05 and p<0.05, respectively) and TF polymorphism (p<0.05 and p=0.005, respectively). No significant differences in HHV-8 infection rate and in HHV-8 IgG antibody titer were observed in the ferroportin Q248H mutation carriers (rs11568350) in comparison with ferroportin wild type. In a multiple regression analysis, FN3K rs1056534, TF polymorphism and presence of diabetes mellitus were predictors for HHV-8 infection. In contrast to these findings, ferroportin Q248H mutation (rs11568350) did not influence the susceptibility for an HHV-8 infection in sub-Saharan Africans. PMID- 27461880 TI - Effectiveness and stability of silane coupling agent incorporated in 'universal' adhesives. AB - OBJECTIVE: For bonding indirect restorations, some 'universal' adhesives incorporate a silane coupling agent to chemically bond to glass-rich ceramics so that a separate ceramic primer is claimed to be no longer needed. With this work, we investigated the effectiveness/stability of the silane coupling function of the silanecontaining experimentally prepared adhesives and Scotchbond Universal (3MESPE). METHODS AND MATERIALS: Experimental adhesives consisted of Scotchbond Universal and the silane-free Clearfil S3 ND Quick (Kuraray Noritake) mixed with Clearfil Porcelain Bond Activator (Kuraray Noritake) and the two adhesives to which gamma-methacryloxypropyltrimethoxysilane (gamma-MPTS) was added. Shear bond strength was measured onto silica-glass plates; the adhesive formulations were analyzed using fourier transform infrared spectroscopy (FTIR) and 13C nuclear magnetic resonance (NMR). In addition, shear bond strength onto CAD-CAM composite blocks was measured without and after thermo-cycling ageing. RESULTS: A significantly higher bond strength was recorded when Clearfil Porcelain Bond Activator was freshly mixed with the adhesive. Likewise, the experimental adhesives, to which gamma-MPTS was added, revealed a significantly higher bond strength, but only when the adhesive was applied immediately after mixing; delayed application resulted in a significantly lower bond strength. FTIR and (13)C NMR revealed hydrolysis and dehydration condensation to progress with the time after gamma-MPTS was mixed with the two adhesives. After thermo-cycling, the bond strength onto CAD-CAM composite blocks remained stable only for the two adhesives with which Clearfil Porcelain Bond Activator was mixed. SIGNIFICANCE: Only the silane coupling effect of freshly prepared silanecontaining adhesives was effective. Clinically, the use of a separate silane primer or silane freshly mixed with the adhesive remains recommended to bond glass-rich ceramics. PMID- 27461881 TI - (17)O NMR and Raman Spectroscopies of Green Tea Infusion with Nanomaterial to Investigate Their Properties. AB - (17)O NMR and Raman spectrograms of green tea infusions with nanomaterial were investigated. Different green tea infusions were prepared by steeping tea powder with different concentrations of nanomaterial aqueous solution. The tea infusions were tested with (17)O NMR and Raman spectroscopies. The (17)O NMR results showed that line width increased to 90 in the tea infusions after nanomaterial was added as a result of the effects of the self-association of Ca(2+) and tea polyphenol. The results of Raman spectroscopy showed that, in tea infusions, the enhancement of C?C and C?O stretching vibrations suggest an increase in the number of effective components in water. PMID- 27461882 TI - Rugby World Cup 2015: World Rugby injury surveillance study. AB - OBJECTIVE: To determine the incidence, severity and nature of injuries sustained during the Rugby World Cup (RWC) 2015 together with the inciting events leading to the injuries. DESIGN: A prospective, whole population study. POPULATION: 639 international rugby players representing 20 countries. METHOD: The study protocol followed the definitions and procedures recommended in the consensus statement for epidemiological studies in rugby union; output measures included players' age (years), stature (cm), body mass (kg) and playing position, and the group-level incidence (injuries/1000 player-hours), mean and median severity (days-absence), location (%), type (%) and inciting event (%) for match and training injuries. RESULTS: Incidence of injury was 90.1 match injuries/1000 player-match-hours (backs: 100.4; forwards: 81.1) and 1.0 training injuries/1000 player-training hours (backs: 0.9; forwards: 1.2). The mean severity of injuries was 29.8 days absence (backs: 30.4; forwards: 29.1) during matches and 14.4 days-absence (backs: 6.3; forwards: 19.8) during training. During matches, head/face (22.0%), knee (16.2%), muscle-strain (23.1%) and ligament-sprain (23.1%) and, during training, lower limb (80.0%) and muscle-strain (60.0%) injuries were the most common locations and types of injury. Being-tackled (24.7%) was the most common inciting event for injury during matches and rugby-skills-contact activities (70.0%) the most common during training. CONCLUSIONS: While the incidence, nature and inciting events associated with match injuries at RWC 2015 were similar to those reported previously for RWCs 2007 and 2011, there were increasing trends in the mean severity and total days-absence through injury. PMID- 27461883 TI - Terbutaline: level the playing field for inhaled beta2-agonists by introducing a dosing and urine threshold. AB - Terbutaline, a short-acting beta2-agonist similar to salbutamol, is widely used in Europe in the treatment of asthma and exercise-induced bronchoconstriction. Unlike salbutamol, terbutaline requires therapeutic use exemption (TUE) for therapeutic inhaled use in competitive sport. There is now compelling evidence that supratherapeutic use of terbutaline is performance enhancing, via oral dosing and inhalation. It is likely that the ergogenic effects of terbutaline are class specific for all beta2-agonists. The World Anti-Doping Agency (WADA) has introduced dosing and urine threshold and decision limits for other common beta2 agonists. This allows athletes to use these drugs for therapeutic purposes while minimising the potential for doping and administrative burden of TUEs. However, no such threshold limits currently exist for terbutaline. For terbutaline, athletes can be granted a TUE, then administer the drug via inhalation at supratherapeutic doses with impunity. The introduction of threshold dosing and urine limits for terbutaline should be a high priority, given the drug's demonstrated ergogenic effects. PMID- 27461884 TI - Relationship between markers of plaque vulnerability in optical coherence tomography and atherosclerotic progression in adult patients with heart transplantation. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease, and optical coherence tomography (OCT) provides detailed microstructural information. The current study was designed to test the hypothesis that markers of plaque vulnerability derived from OCT could predict CAV progression after heart transplantation (HTx). METHODS: In 34 consecutive patients (median 3.1 years from HTx), intravascular ultrasound (IVUS) and OCT were performed in the left anterior descending artery (LAD) during routine annual coronary angiography. The presence of vulnerability markers, such as lipid pools, thin-cap fibroatheroma, macrophages and microchannels, was assessed in 100 consecutive frames of OCT in 20-mm segments of proximal LAD. The total number of appearances of vulnerable markers was defined as the vulnerability score (VS). Plaque volume (PV) was measured in the same study segment using IVUS at baseline and at 1-year follow-up, and the association between the baseline VS and the subsequent change in percent PV (PV / vessel volume * 100 [%PV]) was evaluated. RESULTS: Follow-up IVUS study was conducted after 12.5 +/- 1.3 months. The mean VS was 59.9 +/- 44.6. Compared with the initial %PV, the follow-up %PV increased in the study segment (25.6 +/- 13.7% to 31.8 +/- 17.5%, p < 0.001). The correlations between baseline VS and Delta%PV were significant in the study segment (r = 0.757, p < 0.001). On multivariable analysis, only the VS correlated significantly with Delta%PV. CONCLUSIONS: Our results demonstrate that the markers of plaque vulnerability in OCT can predict the progression of CAV. Therefore, in patients with HTx, OCT may aid in determining prognosis and guiding therapy related to CAV. PMID- 27461885 TI - Ultrasound-guided forearm nerve blocks for hand blast injuries: case series and multidisciplinary protocol. PMID- 27461886 TI - The efficacy of transcutaneous cardiac pacing in ED. AB - INTRODUCTION: Transcutaneous cardiac pacing (TCP) is a rapid, time-saving, and noninvasive ventricular stimulation that is tolerated by conscious patients despite the painful intervention for treatment of symptomatic bradycardias. The goal of this study was to determine the efficacy of TCP in unstable bradycardia patients in emergency department (ED). METHODS: This single-central, observational clinical study was conducted on patients older than 18 years who presented with acute unstable bradycardia to the tertiary care university ED. Primary outcome measure was to determine the efficacy of TCP in unstable bradycardia patients in the emergency settings. Efficacy of TCP was to determine changes of clinically significant vital signs and electrocardiography. RESULTS: Of 349 patients who visited the ED presenting with bradycardia, 89 patients who met the criteria were included in the study. There was a statistically significant difference between before and after the first administration TCP in mean systolic (71.2 [64.8-77.6] and 105.3 [97.6-112.9 mm Hg]) and diastolic blood pressure (42.9 [38.8-47.0] and 61.0 [56.4-65.5] mm Hg) and median heart rate (40 [39-42] and 74 [71-78] beats/min, P< .0001). CONCLUSION: Transcutaneous cardiac pacing is a clinically effective treatment modality in patients with atropine resistant unstable bradycardia. PMID- 27461887 TI - Shock index, modified shock index, and age shock index for prediction of mortality in Emergency Severity Index level 3. AB - OBJECTIVES: To elucidate the predictive capability of shock index (SI), modified SI (MSI), and age SI for mortality in patients assigned to Emergency Severity Index (ESI) level 3 patients. METHODS: This was a retrospective medical record review performed in an academic internal medicine emergency department in Kerman, Iran. All patients older than 14 years triaged to ESI level 3 were enrolled in the study. Triage time vital signs were used to calculate SI, MSI, and age SI. The primary outcome was in-hospital mortality. RESULTS: A total number of 3375 patients were enrolled in the study, in which 84 (2.5%) died during hospital stay. In the adjusted multivariate analysis, age SI, systolic blood pressure (SBP), and sex were independently associated with mortality, with P values (odds ratio [95% confidence interval]) of <.001 (1.03 [1.01-1.04]), .003 (0.97 [0.96 0.99]), and .04 (1.61 [1.01-2.59]), respectively. Receiver operating characteristic curve showed an area under curve of 0.717 for the 3-variable final model and an area under curve of 0.678 for age SI in mortality prediction. CONCLUSIONS: In ESI level 3 patients, age SI and SBP showed to be better than SI or MSI in predicting mortality. However, because their predictive capability was modest, age SI or SBP should be considered adjuncts to sort actions in favor of patients with higher risk for mortality. PMID- 27461888 TI - Seventy-two-hour antibiotic retrieval from the ED: reporting the strength of association. PMID- 27461889 TI - Ultrahard stitching of nanotwinned diamond and cubic boron nitride in C2-BN composite. AB - Materials combining the hardness and strength of diamond with the higher thermal stability of cubic boron nitride (cBN) have broad potential value in science and engineering. Reacting nanodiamond with cBN at moderate pressures and high temperatures provides a pathway to such materials. Here we report the fabrication of Cx-BN nanocomposites, measuring up to 10 mm in longest dimension, by reacting nanodiamond with pre-synthesized cBN in a large-volume press. The nanocomposites consist of randomly-oriented diamond and cBN domains stitched together by sp(3) hybridized C-B and C-N bonds, leading to p-type semiconductivity. Dislocations near the sutures accommodate lattice mismatch between diamond and cBN. Nanotwinning within both diamond and cBN domains further contributes to a bulk hardness ~50% higher than sintered cBN. The nanocomposite of C2-BN exhibits p type semiconductivity with low activation energy and high thermal stability, making it a functional, ultrahard substance. PMID- 27461890 TI - Supramolecular adducts based on weak interactions between the trimeric Lewis acid complex (perfluoro-ortho-phenylene)mercury and polypnictogen complexes. AB - Reactions of the trinuclear Lewis acid perfluoro-ortho-phenylene)mercury [(o HgC6F4)3] (1) with the polypnictogen complex [CpMo(CO)2(eta(3)-P3)] (2) containing a cyclo-P3 ligand and the series of E2 complexes [{CpMo(CO)2}2(MU,eta(2):eta(2)-E2)] (E = P(3a), As(3b), Sb(3c), Bi(3d)) are reported. In all cases, the reaction products show very weak interactions between the En ligand complexes and the Lewis acid 1, as evidenced by their highly dynamic behaviour in solution and the formation of adducts in the solid state showing HgE contacts below the respective sum of the van der Waals radii. The complexes 2 (P3), 3a (P2) and 3b (As2) show interactions of only one pnictogen atom with all three Hg atoms of 1. The complex 3c (Sb2) forms two adducts with 1 showing either a side-on coordination of the Sb2 dumbbell towards Hg or an end-on coordination of both Sb atoms towards two independent molecules of 1. The Bi2 complex 3d shows an almost parallel alignment of the Bi2 dumbbell situated above the center of the planar Lewis acid 1. The arrangements of the E2 complex series towards 1 are rationalized with the help of electrostatic potential maps obtained by DFT calculations. Finally the structural characterizations of a new modification of the free Sb2 complex 3c, the Bi2 complex 3d, the starting material of its preparation [Bi{CpMo(CO)3}3] (4) and an unprecedented 'Cr4As5' cluster 5 are presented. PMID- 27461892 TI - What Are the Newer Applications for Therapeutic Apheresis in Nephrology?: Novel Uses and Techniques of Therapeutic Apheresis. PMID- 27461891 TI - Oroesophageal Fish Bone Foreign Body. AB - Fish bone foreign body (FFB) is the most frequent food-associated foreign body (FB) in adults, especially in Asia, versus meat in Western countries. The esophageal sphincter is the most common lodging site. Esophageal FB disease tends to occur more frequently in men than in women. The first diagnostic method is laryngoscopic examination. Because simple radiography of the neck has low sensitivity, if perforation or severe complications requiring surgery are expected, computed tomography should be used. The risk factors associated with poor prognosis are long time lapse after FB involvement, bone type, and longer FB (>3 cm). Bleeding and perforation are more common in FFB disease than in other FB diseases. Esophageal FB disease requires urgent treatment within 24 hours. However, FFB disease needs emergent treatment, preferably within 2 hours, and definitely within 6 hours. Esophageal FFB disease usually occurs at the physiological stricture of the esophagus. The aortic arch eminence is the second physiological stricture. If the FB penetrates the esophageal wall, a life threatening aortoesophageal fistula can develop. Therefore, it is better to consult a thoracic surgeon prior to endoscopic removal. PMID- 27461894 TI - Persistent Genital Arousal Disorder: A Review of Its Conceptualizations, Potential Origins, Impact, and Treatment. AB - INTRODUCTION: Persistent genital arousal disorder (PGAD) is a condition characterized by symptoms of physiologic (typically genital) sexual arousal in the absence of perceived subjective sexual arousal. The physiologic arousal can last hours or days, or it can occur constantly, and it does not typically remit after orgasm(s). The symptoms are usually described as distressing, intrusive, and unwanted. AIM: To review the available literature on PGAD. METHODS: A literature review through April 2016 was undertaken using terms persistent genital arousal disorder, persistent sexual arousal syndrome, and restless genital syndrome. MAIN OUTCOME MEASURES: The main outcome is a review of the conceptualization of PGAD, its prevalence, proposed etiologies and treatments, and its impact on psychosocial and sexual functioning. RESULTS: Much of the research on the potential etiologies and treatments of PGAD is published in the form of case studies. Several etiologies of PGAD have been proposed; however, a cause or causes have not been confirmed. A range of treatments has been explored primarily in case studies, from electroconvulsive therapy to oral medication, with variable success rates. Psychologically based treatments have been suggested but have yet to be evaluated. Online surveys have found initial evidence supporting the negative impact of PGAD on mental health and sexual functioning; however, more research is needed in this area. CONCLUSION: Although PGAD was first conceptualized 15 years ago, it remains a very under-researched condition. Currently, little is known about its biopsychosocial correlates, etiologies, or successful treatments. Future research directions are identified. PMID- 27461896 TI - How to Effectively Implement a Peer Review Process for Interventional Radiology Procedures. PMID- 27461895 TI - Deciphering and modulating G protein signalling in C. elegans using the DREADD technology. AB - G-protein signalling is an evolutionary conserved concept highlighting its fundamental impact on developmental and functional processes. Studies on the effects of G protein signals on tissues as well as an entire organism are often conducted in Caenorhabditis elegans. To understand and control dynamics and kinetics of the processes involved, pharmacological modulation of specific G protein pathways would be advantageous, but is difficult due to a lack in accessibility and regulation. To provide this option, we designed G protein coupled receptor-based designer receptors (DREADDs) for C. elegans. Initially described in mammalian systems, these modified muscarinic acetylcholine receptors are activated by the inert drug clozapine-N-oxide, but not by their endogenous agonists. We report a novel C. elegans-specific DREADD, functionally expressed and specifically activating Gq-protein signalling in vitro and in vivo which we used for modulating mating behaviour. Therefore, this novel designer receptor demonstrates the possibility to pharmacologically control physiological functions in C. elegans. PMID- 27461897 TI - Multi-component determination and chemometric analysis of Paris polyphylla by ultra high performance liquid chromatography with photodiode array detection. AB - Multi-source analysis of traditional Chinese medicine is key to ensuring its safety and efficacy. Compared with traditional experimental differentiation, chemometric analysis is a simpler strategy to identify traditional Chinese medicines. Multi-component analysis plays an increasingly vital role in the quality control of traditional Chinese medicines. A novel strategy, based on chemometric analysis and quantitative analysis of multiple components, was proposed to easily and effectively control the quality of traditional Chinese medicines such as Chonglou. Ultra high performance liquid chromatography was more convenient and efficient. Five species of Chonglou were distinguished by chemometric analysis and nine saponins, including Chonglou saponins I, II, V, VI, VII, D, and H, as well as dioscin and gracillin, were determined in 18 min. The method is feasible and credible, and enables to improve quality control of traditional Chinese medicines and natural products. PMID- 27461898 TI - The impact of individual and organizational resources on nurse outcomes and intent to quit. AB - AIM: To examine the impact of an individual resource factor (psychological capital) and an organizational resource (management support) on nurses' intentions to quit. BACKGROUND: Nursing work can be stressful and as a consequence, nurses suffer greater stress and stress-related sickness, including depression, than the general population. Stress can be mitigated in the workplace depending on the availability of resources in the workplace. Resources can come from the organization or the individual themselves. DESIGN: The study is quantitative using a cross-sectional design. METHODS: The study analysed data from 242 nurses working in five Australian hospitals in the one regional network during 2013. FINDINGS: The predictors explained almost half of the variance of nurses' intent to quit. Psychological capital had the dual benefits of reducing nurses' perceptions of psychological distress and simultaneously increasing their job satisfaction. CONCLUSION: Psychological capital is an example of the personal resources a nurse brings to work. Nurse managers can now understand the impact of a new form of protective resources that influence the levels of strain felt by nurses. If nurses present with low psychological capital, then up-skilling nurses with these personal attributes will positively impact on their health and well being and, in turn, enhance the care of patients. PMID- 27461899 TI - Water droplet impact on elastic superhydrophobic surfaces. AB - Water droplet impact on surfaces is a ubiquitous phenomenon in nature and industry, where the time of contact between droplet and surface influences the transfer of mass, momentum and energy. To manipulate and reduce the contact time of impacting droplets, previous publications report tailoring of surface microstructures that influence the droplet - surface interface. Here we show that surface elasticity also affects droplet impact, where a droplet impacting an elastic superhydrophobic surface can lead to a two-fold reduction in contact time compared to equivalent rigid surfaces. Using high speed imaging, we investigated the impact dynamics on elastic nanostructured superhydrophobic substrates having membrane and cantilever designs with stiffness 0.5-7630 N/m. Upon impact, the droplet excites the substrate to oscillate, while during liquid retraction, the substrate imparts vertical momentum back to the droplet with a springboard effect, causing early droplet lift-off with reduced contact time. Through detailed experimental and theoretical analysis, we show that this novel springboarding phenomenon is achieved for a specific range of Weber numbers (We >40) and droplet Froude numbers during spreading (Fr >1). The observation of the substrate elasticity-mediated droplet springboard effect provides new insight into droplet impact physics. PMID- 27461900 TI - High-contrast X-ray micro-radiography and micro-CT of ex-vivo soft tissue murine organs utilizing ethanol fixation and large area photon-counting detector. AB - Using dedicated contrast agents high-quality X-ray imaging of soft tissue structures with isotropic micrometre resolution has become feasible. This technique is frequently titled as virtual histology as it allows production of slices of tissue without destroying the sample. The use of contrast agents is, however, often an irreversible time-consuming procedure and despite the non destructive principle of X-ray imaging, the sample is usually no longer usable for other research methods. In this work we present the application of recently developed large-area photon counting detector for high resolution X-ray micro radiography and micro-tomography of whole ex-vivo ethanol-preserved mouse organs. The photon counting detectors provide dark-current-free quantum-counting operation enabling acquisition of data with virtually unlimited contrast-to-noise ratio (CNR). Thanks to the very high CNR even ethanol-only preserved soft-tissue samples without addition of any contrast agent can be visualized in great detail. As ethanol preservation is one of the standard steps of tissue fixation for histology, the presented method can open a way for widespread use of micro-CT with all its advantages for routine 3D non-destructive soft-tissue visualisation. PMID- 27461901 TI - Author's reply: Accessibility to healthcare of diabetic patients with acute coronary syndrome with ST-segment elevation. PMID- 27461902 TI - Increased Interleukin-6 (IL-6) in Exhaled Breath Condensate of Asthmatic Children. PMID- 27461903 TI - Quantifying reperfusion of the ischemic region on whole-brain computed tomography perfusion. AB - To derive the reperfusion index best predicting clinical outcome of ischemic stroke patients, we retrospectively analysed the acute and 24-h computed tomography perfusion data of 116 patients, collected from two centres equipped with whole-brain computed tomography perfusion. Reperfusion index was defined by the percentage of the ischemic region reperfused from acute to 24-h computed tomography perfusion. Recanalization was graded by arterial occlusive lesion system. Receiver operator characteristic analysis was performed to assess the prognostic value of reperfusion and recanalization in predicting good clinical outcome, defined as modified Rankin Score of 0-2 at 90 days. Among previous reported reperfusion measurements, reperfusion of the Tmax>6 s region resulted in higher prognostic value than recanalization at predicting good clinical outcome (area under the curve = 0.88 and 0.74, respectively, p = 0.002). Successful reperfusion of the Tmax>6 s region (>=60%) had 89% sensitivity and 78% specificity in predicting good clinical outcome. A reperfusion index defined by Tmax>2 s or by mean transit time>145% had much lower area under the curve in comparison to Tmax>6 s measurement (p < 0.001 and p = 0.003, respectively), and had no significant difference to recanalization at predicting clinical outcome (p = 0.58 and 0.63, respectively). In conclusion, reperfusion index calculated by Tmax>6 s is a stronger predictor of clinical outcome than recanalization or other reperfusion measures. PMID- 27461905 TI - Observation of Charge Separation and Space-Charge Region in Single-Crystal P3HT/C60 Heterojunction Nanowires. AB - We directly observed charge separation and a space-charge region in an organic single-crystal p-n heterojunction nanowire, by means of scanning photocurrent microscopy. The axial p-n heterojunction nanowire had a well-defined planar junction, consisted of P3HT (p-type) and C60 (n-type) single crystals and was fabricated by means of the recently developed inkjet-assisted nanotransfer printing technique. The depletion region formed at the p-n junction was directly observed by exploring the spatial distribution of photogenerated carriers along the heterojunction nanowire under various applied bias voltages. Our study provides a facile approach toward the precise characterization of charge transport in organic heterojunction systems as well as the design of efficient nanoscale organic optoelectronic devices. PMID- 27461904 TI - MRI of cerebral micro-vascular flow patterns: A multi-direction diffusion weighted ASL approach. AB - The study and clinical assessment of brain disease is currently hindered by a lack of non-invasive methods for the detailed and accurate evaluation of cerebral vascular pathology. Angiography can detect aberrant flow in larger feeding arteries/arterioles but cannot resolve the micro-vascular network. Small vessels are a key site of vascular pathology that can lead to haemorrhage and infarction, which may in turn trigger or exacerbate neurodegenerative processes. In this study, we describe a method to investigate microvascular flow anisotropy using a hybrid arterial spin labelling and multi-direction diffusion-weighted MRI sequence. We present evidence that the technique is sensitive to the mean/predominant direction of microvascular flow in localised regions of the rat cortex. The data provide proof of principle for a novel and non-invasive imaging tool to investigate cerebral micro-vascular flow patterns in healthy and disease states. PMID- 27461906 TI - Development of a cost-effective 'duplexed' real-time PCR assay for minimal residual disease monitoring of chronic myeloid leukemia using locked nucleic acid probes. PMID- 27461908 TI - Do we really need herbal medicine in LUTS/BPH treatment in the 21st century? PMID- 27461907 TI - Can gallbladder polyps predict colorectal adenoma or even neoplasia? A systematic review. AB - OBJECTIVE: The purpose of the present systematic review is to identify whether an association between gallbladder polyps and colorectal adenoma or neoplasia exists. DATA SOURCES: We conducted a systematic review searching the Medline (1966-2016), Scopus (2004-2016), ClinicalTrials.gov (2008-2016) and Cochrane Central Register of Controlled Trials CENTRAL (1999-2016) databases together with reference lists from included studies. STUDY ELIGIBILITY CRITERIA: All prospective and retrospective observational cohort studies were included. RESULTS: Four studies were finally included which included 17,437 patients. The association between gallbladder polyps and colorectal adenoma or even neoplasia is not unanimously supported. However, a possible association is clearly depicted. According to one study it seems that this correlation seems to become significant only when the gallbladder polyps exceed the size of 5 mm. However, the impact of size of gallbladder polyps was not investigated in the remaining studies. CONCLUSION: According to the results of our systematic review there is some evidence to support the hypothesis that gallbladder polyps might adequately predict future risk of colorectal neoplasia. At present, however, current knowledge is very limited and the available data scarce. In this context further studies are necessary to be carried out, before the presence of gallbladder polyps on ultrasound can be recommended as an indication to perform a screening colonoscopy on the same patient. PMID- 27461909 TI - Structural-Engineering Rationales of Gold Nanoparticles for Cancer Theranostics. AB - Personalized theranostics of cancer is increasingly desired, and can be realized by virtue of multifunctional nanomaterials with possible high performances. Gold nanoparticles (GNPs) are a type of especially promising candidate for cancer theranostics, because their synthesis and modification are facile, their structures and physicochemical properties are flexibly controlled, and they are also biocompatible. Especially, the localized surface plasmon resonance and multivalent coordination effects on the surface endow them with NIR light triggered photothermal imaging and therapy, controlled drug release, and targeted drug delivery. Although the structure, properties, and theranostic application of GNPs are considerably plentiful, no expert review systematically explains the relationships among their structure, property. and application and induces the engineering rationales of GNPs for cancer theranostics. Hence, there are no clear rules to guide the facile construction of optimal GNP structures aiming at a specific theranostic application. A series of structural-engineering rationales of GNPs for cancer theranostics is proposed through digging out the deep relationships between the structure and properties of GNPs. These rationales will be inspiring for guiding the engineering of specific and advanced GNPs for personalized cancer theranostics. PMID- 27461910 TI - Deep-water feeding and behavioral plasticity in Manta birostris revealed by archival tags and submersible observations. AB - Foraging drives many fundamental aspects of ecology, and an understanding of foraging behavior aids in the conservation of threatened species by identifying critical habitats and spatial patterns relevant to management. The world's largest ray, the oceanic manta (Manta birostris) is poorly studied and threatened globally by targeted fisheries and incidental capture. Very little information is available on the natural history, ecology and behavior of the species, complicating management efforts. This study provides the first data on the diving behavior of the species based on data returned from six tagged individuals, and an opportunistic observation from a submersible of a manta foraging at depth. Pop off archival satellite tags deployed on mantas at the Revillagigedo Archipelago, Mexico recorded seasonal shifts in diving behavior, likely related to changes in the location and availability of zooplankton prey. Across seasons, mantas spent a large proportion of their time centered around the upper limit of the thermocline, where zooplankton often aggregate. Tag data reveal a gradual activity shift from surface waters to 100-150m across the tagging period, possibly indicating a change in foraging behavior from targeting surface associated zooplankton to vertical migrators. The depth ranges accessed by mantas in this study carry variable bycatch risks from different fishing gear types. Consequently, region-specific data on diving behavior can help inform local management strategies that reduce or mitigate bycatch of this vulnerable species. PMID- 27461911 TI - Working with complexity: experiences of caring for mothers seeking residential parenting services in New South Wales, Australia. AB - AIM AND OBJECTIVES: To investigate staff perception of the changing complexity of mothers and infants admitted to two residential parenting services in New South Wales in the decade from 2005-2015. BACKGROUND: For many mothers with a young child, parenting is difficult and stressful. If parenting occurs within the context of anxiety, mental illness or abuse it often becomes a high-risk situation for the primary caregiver. Residential parenting services provide early nursing intervention before parenting problems escalate and require physical or mental health focused care. DESIGN: A qualitative descriptive design using semi structured interview questions was used as phase three of a larger study. Data were gathered from 35 child and family health nurses and ten physicians during eight focus groups. RESULTS: Three main themes emerged: (1) dealing with complexity; (2) changing practice; and (3) appropriate knowledge and skills to handle greater complexity. CONCLUSIONS: There was a mix of participant opinions about the increasing complexity of the mothers presenting at residential parenting services during the past decade. Some of the nurses and physicians confirmed an increase in complexity of the mothers while several participants proposed that it was linked to their increased psychosocial assessment knowledge and skill. All participants recognised their work had grown in complexity regardless of their perception about the increased complexity of the mothers. RELEVANCE TO CLINICAL PRACTICE: Australian residential parenting services have a significant role in supporting mothers and their families who are experiencing parenting difficulties. It frequently provides early intervention that helps minimise later emotional and physical problems. Nurses are well placed to work with and support mothers with complex histories. Acknowledgement is required that this work is stressful and nurses need to be adequately supported and educated to manage the complex presentations of many families. PMID- 27461912 TI - The centrality of fear extinction in linking risk factors to PTSD: A narrative review. AB - Recent prospective studies in emergency services have identified impaired fear extinction learning and memory to be a significant predictor of Posttraumatic Stress Disorder (PTSD), complementing a wealth of cross-sectional evidence of extinction deficits associated with the disorder. Additional fields of research show specific risk factors and biomarkers of the disorder, including candidate genotypes, stress and sex hormones, cognitive factors, and sleep disturbances. Studies in mostly nonclinical populations also reveal that the aforementioned factors are involved in fear extinction learning and memory. Here, we provide a comprehensive narrative review of the literature linking PTSD to these risk factors, and linking these risk factors to impaired fear extinction. On balance, the evidence suggests that fear extinction may play a role in the relationship between risk factors and PTSD. Should this notion hold true, this review carries important implications for the improvement of exposure-based treatments, as well as strategies for the implementation of treatment. PMID- 27461913 TI - Eye movements in the wild: Oculomotor control, gaze behavior & frames of reference. AB - Understanding the brain's capacity to encode complex visual information from a scene and to transform it into a coherent perception of 3D space and into well coordinated motor commands are among the outstanding questions in the study of integrative brain function. Eye movement methodologies have allowed us to begin addressing these questions in increasingly naturalistic tasks, where eye and body movements are ubiquitous and, therefore, the applicability of most traditional neuroscience methods restricted. This review explores foundational issues in (1) how oculomotor and motor control in lab experiments extrapolates into more complex settings and (2) how real-world gaze behavior in turn decomposes into more elementary eye movement patterns. We review the received typology of oculomotor patterns in laboratory tasks, and how they map onto naturalistic gaze behavior (or not). We discuss the multiple coordinate systems needed to represent visual gaze strategies, how the choice of reference frame affects the description of eye movements, and the related but conceptually distinct issue of coordinate transformations between internal representations within the brain. PMID- 27461915 TI - Depression and cardiovascular disease: Epidemiological evidence on their linking mechanisms. AB - Depression's burden of disease goes beyond functioning and quality of life and extends to somatic health. Results from longitudinal cohort studies converge in illustrating that major depressive disorder (MDD) subsequently increases the risk of cardiovascular morbidity and mortality with about 80%. The impact of MDD on cardiovascular health may be partly explained by mediating mechanisms such as unhealthy lifestyle (smoking, excessive alcohol use, physical inactivity, unhealthy diet, therapy non-compliance) and unfavorable pathophysiological disturbances (autonomic, HPA-axis, metabolic and immuno-inflammatory dysregulations). A summary of the literature findings as well as relevant results from the large-scale Netherlands Study of Depression and Anxiety (N=2981) are presented. Persons with MDD have significantly worse lifestyles as well as more pathophysiological disturbances as compared to healthy controls. Some of these differences seem to be specific for (typical versus 'atypical', or antidepressant treated versus drug-naive) subgroups of MDD patients. Alternative explanations are also present, namely undetected confounding, iatrogenic effects or 'third factors' such as genetics. PMID- 27461916 TI - The perception of self in birds. AB - The perception of self is an important topic in several disciplines such as ethology, behavioral ecology, psychology, developmental and cognitive neuroscience. Self-perception is investigated by experimentally exposing different species of animals to self-stimuli such as their own image, smell or vocalizations. Here we review more than one hundred studies using these methods in birds, a taxonomic group that exhibits a rich diversity regarding ecology and behavior. Exposure to self-image is the main method for studying self recognition, while exposing birds to their own smell is generally used for the investigation of homing or odor-based kin discrimination. Self-produced vocalizations - especially in oscine songbirds - are used as stimuli for understanding the mechanisms of vocal coding/decoding both at the neural and at the behavioral levels. With this review, we highlight the necessity to study the perception of self in animals cross-modally and to consider the role of experience and development, aspects that can be easily monitored in captive populations of birds. PMID- 27461914 TI - Adolescent brain development and depression: A case for the importance of connectivity of the anterior cingulate cortex. AB - We propose that structural and functional connectivity of the anterior cingulate cortex (ACC) represents a critical component of adolescent developmental psychopathology. We hypothesize that connectivity of the ACC, a hub for integrating cognitive, affective, and social information to guide self-regulation across domains, supports adaptive development of self-regulation during adolescence and that, conversely, disrupted maturation of ACC connectivity contributes to the development of depression. To integrate findings on typical development, we report results of a meta-analysis of diffusion imaging findings of typical adolescent development of the cingulum and anterior thalamic radiations, the tracts most relevant to ACC connectivity, and provide a critical review of the literature on ACC functional connectivity. Finally, we review the evidence for altered structural and functional connectivity in adolescents with depression. Although the evidence for our claim is persuasive, a more comprehensive understanding of the ACC's role depends upon future investigations with sophisticated modeling of networks, prospective and longitudinal designs, and examination of structure-function associations. PMID- 27461917 TI - Psychometric properties of the Affect Phobia Test. AB - The aim of this study was to make the first evaluation of the psychometric properties of the Affect Phobia Test, using the Swedish translation - a test developed to screen the ability to experience, express and regulate emotions. Data was collected from a clinical sample (N = 82) of patients with depression and/or anxiety participating in randomized controlled trial of Internet-based affect-focused treatment, and a university student sample (N = 197). The internal consistency for the total score was satisfactory (Clinical sample alpha = 0.88/Student sample alpha = 0.84) as well as for all the affective domains, except Anger/Assertion (alpha = 0.44/0.36), Sadness/Grief (alpha = 0.24/0.46) and Attachment/Closeness (alpha = 0.67/0.69). Test retest reliability was satisfactory (ICC > 0.77) for the total score and for all the affective domains except for Sadness/Grief (ICC = 0.04). The exploratory factor analysis resulted in a six-factor solution and did only moderately match the test's original affective domains. An empirical cut-off between the clinical and the university student sample were calculated and yielded a cut-off of 72 points. As expected, the Affect Phobia test showed negative significant correlations in the clinical group with measures on depression (rxy = -0.229; p < 0.01) and anxiety (rxy = 0.315; p < 0.05). The conclusion is that the psychometric properties are satisfactory for the total score of the Affect Phobia Test but not for some of the test's affective domains. Consequently the domains should not be used as subscales. The test can discriminate between individuals who seek help for psychological problems and those who do not. PMID- 27461918 TI - Problems encountered when defining Arctic amplification as a ratio. AB - In climate change science the term 'Arctic amplification' has become synonymous with an estimation of the ratio of a change in Arctic temperatures compared with a broader reference change under the same period, usually in global temperatures. Here, it is shown that this definition of Arctic amplification comes with a suite of difficulties related to the statistical properties of the ratio estimator itself. Most problematic is the complexity of categorizing uncertainty in Arctic amplification when the global, or reference, change in temperature is close to 0 over a period of interest, in which case it may be impossible to set bounds on this uncertainty. An important conceptual distinction is made between the 'Ratio of Means' and 'Mean Ratio' approaches to defining a ratio estimate of Arctic amplification, as they do not only possess different uncertainty properties regarding the amplification factor, but are also demonstrated to ask different scientific questions. Uncertainty in the estimated range of the Arctic amplification factor using the latest global climate models and climate forcing scenarios is expanded upon and shown to be greater than previously demonstrated for future climate projections, particularly using forcing scenarios with lower concentrations of greenhouse gases. PMID- 27461919 TI - Artemisinin Resistance and the Blame Game. PMID- 27461921 TI - 3-(Phenyl-4-oxy)-5-phenyl-4,5-dihydro-(1H)-pyrazole: A fascinating molecular framework to study the enantioseparation ability of the amylose (3,5 dimethylphenylcarbamate) chiral stationary phase. Part I. Structure enantioselectivity relationships. AB - Chiral stationary phases (CSPs) based on amylose (3,5-dimethylphenylcarbamate) (ADMPC) exhibit a wide-range of enantioselectivity in high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC). Although this class of CSPs has been extensively used, chiral discriminations at receptorial level, which are useful to develop predictive molecular models, have been rarely reported in the literature. Herein, we describe the results obtained in the enantioselective HPLC of a set of six C5-chiral 4,5-dihydro-(1H)-pyrazole derivatives on the ADMPC-based Chiralpak AD-3 CSP (CSP) under normal-phase and polar organic conditions. Using pure methanol as a mobile phase the exceptional enantioseparation factor value of 50 at 25 degrees C was found for one of the investigated analytes. To the best of our knowledge, the enantiomeric bias represents the most outstanding enantioseparation ever recorded on ADMPC-based CSPs. Systematic variations in chemical groups in specific positions of the 3 (phenyl-4-oxy)-5-phenyl-4,5-dihydro-(1H)-pyrazole molecular framework resulted in peculiar changes in retention and enantioselectivity. A careful analysis of the chromatographic data permitted to advance some hypotheses concerning the role played by the individual chemical groups in determining the exceptional enantioseparation. In particular, under methanol-rich mode, the prenyl moiety of the second eluted enantiomer of the better resolved analyte was recognized as a critical structural element to establish direct and favorable solvophobic interactions with apolar portions of selector. PMID- 27461920 TI - Adherence to Antiretroviral Therapy During and After Pregnancy: Cohort Study on Women Receiving Care in Malawi's Option B+ Program. AB - BACKGROUND: Adherence to antiretroviral therapy (ART) is crucial to preventing mother-to-child transmission of human immunodeficiency virus (HIV) and ensuring the long-term effectiveness of ART, yet data are sparse from African routine care programs on maternal adherence to triple ART. METHODS: We analyzed data from women who started ART at 13 large health facilities in Malawi between September 2011 and October 2013. We defined adherence as the percentage of days "covered" by pharmacy claims. Adherence of >=90% was deemed adequate. We calculated inverse probability of censoring weights to adjust adherence estimates for informative censoring. We used descriptive statistics, survival analysis, and pooled logistic regression to compare adherence between pregnant and breastfeeding women eligible for ART under Option B+, and nonpregnant and nonbreastfeeding women who started ART with low CD4 cell counts or World Health Organization clinical stage 3/4 disease. RESULTS: Adherence was adequate for 73% of the women during pregnancy, for 66% in the first 3 months post partum, and for about 75% during months 4-21 post partum. About 70% of women who started ART during pregnancy and breastfeeding adhered adequately during the first 2 years of ART, but only about 30% of them had maintained adequate adherence at every visit. Risk factors for inadequate adherence included starting ART with an Option B+ indication, at a younger age, or at a district hospital or health center. CONCLUSIONS: One-third of women retained in the Option B+ program adhered inadequately during pregnancy and breastfeeding, especially soon after delivery. Effective interventions to improve adherence among women in this program should be implemented. PMID- 27461922 TI - Enantioseparations in open-tubular capillary electrochromatography: Recent advances and applications. AB - This review highlights recent advances and applications in open-tubular capillary electrochromatography (OT-CEC) for enantioseparations during the last decade. Although extensive research has been conducted in the area of separations by use of CEC, and a big number of reviews have been published, there is not a review on exclusively the use of chiral stationary phases (CSPs) in OT-CEC for enantioseparations. Therefore, in this review, the design and synthesis of different CSPs are presented, and their potential applications in OT-CEC for enantioseparations are discussed. The different approaches to CSP development include chiral nanomaterials, porous layers, molecular imprinting, sol-gel technique, polyelectrolyte multilayer coating, polymeric coating and others. PMID- 27461923 TI - Advances in high-throughput and high-efficiency chiral liquid chromatographic separations. AB - The need for improved liquid chromatographic chiral separations has led to the advancement of chiral screening techniques as well as the development of new, high efficiency chiral separation methods and stationary phases. This review covers these advancements, which primarily occurred over the last 15 years. High throughput techniques include multi-column screening units, multiple injection sequences, and fast gradient SFC screening. New separation methods and column technologies that aim at high efficiency chiral separations include the use of achiral UHPLC (i.e. sub-2MUm) columns for separating derivatized chiral analytes or using chiral additives in the run buffer, UHPLC chiral stationary phases, and superficially porous particle based chiral stationary phases. Finally, the enhancement of chiral separations through these new technologies requires that certain instrumental considerations be made. Future directions in continuing to improve chiral separations are also discussed. PMID- 27461924 TI - Transtrochanteric rotational osteotomy for avascular necrosis of the femoral head after unstable slipped capital femoral epiphysis: 10-year clinical results. AB - BACKGROUND: Avascular necrosis of the femoral head (AVN) is the most serious complication after unstable slipped capital femoral epiphysis (SCFE), and is often unsalvageable. We report a minimum 10 years of clinical results for transtrochanteric rotational osteotomy of the femoral head (TRO) for AVN. METHODS: This study included 7 patients (7 hips) with a mean age at surgery of 13.3 years, and the follow-up period was 15.8 years. All patients had prior treatment via closed reduction and pinning of the unstable SCFE, and showed severely collapsed femoral heads. The direction of rotation was anterior in 3 hips and posterior in 4. The Merle d'Aubigne-Postel score (MDPS) was used for clinical assessment, and joint degeneration was assessed with the Kellgren and Lawrence classification (KL-grade). RESULTS: The spherical intact area of the femoral head was moved to the weight-bearing portion, and subluxation was corrected via rotation combined with intentional varus positioning. The mean MDPS improved from 10.3 points to 15.6 points at 5 years, and it was maintained at 15.0 points by 10 years; 3 hips were excellent, 1 was good, 2 were fair, and 1 showed poor outcomes. No patient experienced re-collapse after TRO or required conversion to hip replacement or arthrodesis. After 10 years, degenerative changes became evident over time, and 2 hips progressed to KL-4 with a decreased MDPS. CONCLUSIONS: Although some joint degeneration is inevitable in the long term, TRO is an effective salvage procedure for treating AVN after unstable SCFE. PMID- 27461926 TI - Get social with SVM. PMID- 27461925 TI - The importance and challenge of recruitment for peripheral artery disease randomized clinical trials. PMID- 27461927 TI - A practical synthesis of chiral tricyclic cyclopenta[b]benzofuran, a key intermediate of Beraprost. AB - A novel formal synthesis of Beraprost (1) is described. The tricyclic cyclopent[b]benzofuran core is efficiently prepared from (-)-Corey lactone diol in 12 steps with an overall yield of 37.4%. Key features of the strategy include a ring-closing metathesis reaction and aromatization to form the tricyclic cyclopenta[b]benzofuran framework, and selective halogenation/formylation to install the butyrate side-chain. PMID- 27461928 TI - Sulfate reduction in microorganisms-recent advances and biotechnological applications. AB - Sulfur, the least common of the five macroelements, plays an important role in biochemistry due to its ability to be easily reduced or oxidized, leading to a great amount of research concerning sulfur bioconversion. Interestingly, new studies concerning microbial sulfate reduction pathways in the last half decade have become increasingly sparse, indicating that most of the pathways involved have been discovered and studied. Despite this, systems biology approaches to model these pathways are often missing or not used. As the products of microbial sulfate reduction play important roles in the environment, biotechnology, and industry, modeling sulfur bioconversion remains an untapped research space for future work. PMID- 27461929 TI - Genome-wide genetic variation discovery in Chinese Taihu pig breeds using next generation sequencing. AB - The Chinese Taihu pig breeds are an invaluable component of the world's pig genetic resources, and they are the most prolific breeds of swine in the world. In this study, the genomes of 252 pigs of the six indigenous breeds in the Taihu Lake region were sequenced using the genotyping by genome reducing and sequencing approach. A total of 950 million good reads were obtained using an Illumina Hiseq2000 at an average depth of 13* (for SNP calling) and an average coverage of 2.3%. In total, 122 632 indels, 31 444 insertions, 44 056 deletions and 455 CNVs (copy number variants) were identified in the genomes of the pigs. Approximately 2.3% of these genetic markers were mapped to gene exon regions, and 25% were in QTL regions related to economically important traits. The KEGG pathway or GO enrichment analyses revealed that genetic variants assumed to be large-effect mutations were significantly overrepresented in 22 SNP, 56 indel, 26 insertion, 28 deletion and three CNV gene sets. A total of 343 breed-specific SNPs were also identified in the six Chinese indigenous pigs. The findings from this study can contribute to future investigations of the genetic diversity, population structure, positive selection signals and molecular evolutionary history of these pigs at the genome level and can serve as a valuable reference for improving the breeding and cultivation of these pigs. PMID- 27461931 TI - Critical renal adverse event induced by nivolumab therapy in a stage IV melanoma patient. PMID- 27461932 TI - Why who we are makes a difference. PMID- 27461930 TI - Fecal microbiota transplantation for patients with steroid-resistant acute graft versus-host disease of the gut. AB - Increasing evidence indicates that the gut microbiota is closely associated with acute graft-versus-host disease (aGVHD) in stem cell transplantation (SCT). Fecal microbiota transplantation (FMT) could represent an alternative treatment option for aGVHD. However, FMT for SCT patients carries a potential risk of infection by infused microbiota because of the severely immunosuppressed status. We therefore conducted a pilot study to evaluate the safety of FMT in SCT. A total of 4 patients with steroid-resistant (n = 3) or steroid-dependent gut aGVHD (n = 1) received FMT. No severe adverse events attributed to FMT were observed. All patients responded to FMT, with 3 complete responses and 1 partial response. Temporal dynamics of microbiota seemed to be linked to the gut condition of patients and peripheral effector regulatory T cells also increased during response to FMT. FMT was safely performed in our patients and might offer a novel therapeutic option for aGVHD. This trial was registered at the University Hospital Medical Information Network (https://upload.umin.ac.jp/cgi-open bin/icdr_e/ctr_view.cgi?recptno=R000017575) as #UMIN000015115. PMID- 27461933 TI - Fear of faith: A reflection on 'Family therapy and fundamentalism'. AB - This short essay explores some of the assumptions enbedded within 'Family therapy and fundamentalism' from the perspective of a person of faith. It questions the usefulness of the term 'fundamentalist families' and highlights the systemic interaction between the secular and religious worlds. PMID- 27461934 TI - Triptolide induces the cell apoptosis of osteosarcoma cells through the TRAIL pathway. AB - Research on triptolide, a diterpenoid epoxide found in the Thunder God Vine Tripterygium wilfordii, has increased our knowledge of the pharmacology, pharmacokinetics, toxicology and clinical application of this agent. In the present study, we aimed to identify the effects of triptolide on the apoptosis of osteosarcoma cells and to evaluate the anti-proliferative action of this agent. MG-63 cells were treated either with various doses of triptolide (50, 100 or 200 nM) or DMSO for 6, 12 and 24 h. Treatment with triptolide effectively suppressed the cell viability and induced the apoptosis of osteosarcoma MG-63 cells as detected by MTT assay and flow cytometry, respectively. In addition, by using caspase-3, caspase-8 and caspase-9 activity assays and western blot analysis, the anticancer effects of triptolide against osteosarcoma growth were found to involve activation of the DR-5/p53/Bax/caspase-9/ caspase-3 signaling pathway and the DR-5/FADD/caspase-8/lysosomal/cathepsin B/caspase-3 signaling pathway in the MG-63 cells. An important factor in the anticancer effects of triptolide against osteosarcoma was TRAIL-DR-5. The data suggest that triptolide may be a potential novel chemotherapeutic agent for osteosarcoma and acts through the TRAIL-DR-5 signaling pathway. PMID- 27461935 TI - N-Doped Sub-3 nm Co Nanoparticles as Highly Efficient and Durable Aerobic Oxidative Coupling Catalysts. AB - A nano-coating associated with sulfuric acid leaching protocol was developed to prepare N-doped sub-3 nm Co-based nanoparticle catalyst (Co-N/C) using melamine formaldehyde resin as the N-containing precursor, active carbon as the support, and Co(NO3 )2 as the Co-containing precursor. By thermal treatment under nitrogen atmosphere at 800 degrees C and leached with sulfuric acid solution, a stable and highly dispersive Co-N coordination structure was uniformly dispersed on the formed Co-N/C catalyst with a Co loading of 0.47 wt % and Co nanoparticle size of 2.55 nm. The Co-N/C catalyst was characterized with XRD, XPS, Raman, SEM, TEM, ICP, and elemental analysis. The Co-N/C catalyst showed extremely high catalytic efficiency with a TON of 257 for the aerobic oxidative coupling of aldehydes with methanol to directly synthesize methyl esters with molecular oxygen as the final oxidant. The Co-N/C catalyst also showed broad substrate range and stable recyclability. After recycling for 7 times, no obvious deactivation was detected. It was confirmed that the sub-3 nm Co-N coordination structure formed between metallic Co nanoparticles and pyridinic nitrogen doping into graphitic layers functions as the active site to activate molecular oxygen for the beta-H elimination from generated hemiacetal intermediates to produce methyl esters. The nano-coating associated with acid leaching protocol provides a novel strategy to prepare highly efficient non-precious metal-based catalysts. PMID- 27461936 TI - The Effect of Antiplatelet Agents on Bleeding-Related Complications After Ureteroscopy. AB - INTRODUCTION: The American Urological Association (AUA) guidelines state that continuing anticoagulation and antiplatelet agents in routine ureteroscopy (URS) is safe and without increased risk of complications. However, these recommendations are based on small case series; thus, we sought to analyze bleeding-related complications among patients on antiplatelet therapy (APT). MATERIALS AND METHODS: Overall, 4799 URS procedures performed at our institution between June 2009 and February 2016 were identified. Records were then retrospectively reviewed to confirm APT use and to identify periprocedural complications. Antiplatelet agents evaluated included aspirin (low dose and full dose) and P2Y12 receptor antagonists (clopidogrel, prasugugrel, ticagrelor). Patients were excluded if they were taking a concurrent anticoagulant agent or if additional non-URS procedures were performed. RESULTS: Of 4799 URS procedures, 314 (6.5%) were performed on patients taking APT, of which 234 (74.5%) held APT, 63 (20.1%) continued APT, and 17 (5.4%) continued dual APT. The mean age was 70.1 years, and the majority of patients (69.6%) underwent a stone procedure with a stone-free rate of 80.2%. The overall bleeding-related complication rate was 1.9%, whereas the significant bleeding-related event rate was 1.6% and this did not differ among the groups (p = 0.3). The power to detect a 3% difference in bleeding between the groups was 0.95. CONCLUSIONS: Continuing APT in patients on chronic therapy does not appear to pose an increased risk of bleeding-related complications. Our findings support the current AUA guidelines as they relate to APT. PMID- 27461937 TI - Labelled microbial culture as a calibration medium for (13) C-isotope measurement of derivatized compounds: application to tert-butyldimethylsilyl amino acids. AB - RATIONALE: Compound-specific stable carbon isotope analysis by gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) is widely used in studies of environmental or biological functioning. In the case of derivatized molecules, a calibration might be required due to added non-analyte carbon and in some cases non-stoichiometric recovery by the mass spectrometer. METHODS: Two biological materials of known isotopic composition were produced by microbial cell cultures on either (13) C-labelled glucose or non-labelled glucose as sole source of carbon. Subsequent hydrolyzed amino acids were derivatized as tert-butyldimethylsilyl (tBDMSi) derivatives and analyzed by GC/C/IRMS. The (13) C-enrichment measurements were used as a direct calibration to calculate the original (13) C/(12) C ratios of individual amino acids. We tested this calibration on both known and unknown samples. RESULTS: For the main proteinogenic amino acids we could determine the number of non-analyte added carbon atoms and assess the non-stoichiometrical recovery of tBDMSi carbon atoms, due to their incomplete oxidation in the combustion step of GC/C/IRMS. The calibration enabled the determination of the natural abundances (delta(13) C values) of amino acids with an average accuracy of +/-1.1 0/00. We illustrate the application of the calibration to determine the (13) C/(12) C ratios of amino acids, and the associated uncertainty, in biological and plant materials. CONCLUSIONS: The analysis of a labelled microbial cell culture offers a straightforward, rapid and reliable estimate of non-analyte carbon contribution to stable isotope composition. We recommend this method as a calibration or a control in artificial or natural (13) C-tracing experiments. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27461938 TI - Methyl Mercury Formation in Hillslope Soils of Boreal Forests: The Role of Forest Harvest and Anaerobic Microbes. AB - Final harvest (clear-cutting) of coniferous boreal forests has been shown to increase streamwater concentrations and export of the neurotoxin methyl mercury (MeHg) to freshwater ecosystems. Here, the spatial distribution of inorganic Hg and MeHg in soil as a consequence of clear-cutting is reported. A comparison of soils at similar positions along hillslopes in four 80 years old Norway spruce (Picea abies) stands (REFs) with those in four similar stands subjected to clear cutting (CCs) revealed significantly (p < 0.05) enhanced MeHg concentrations (ng g(-1)), MeHg areal masses (g ha(-1)), and percent MeHg of HgTOT in O horizons of CCs located between 1 and 41 m from streams. Inorganic Hg measures did not differ between REFs and CCs at any position. The O horizon thickness did not differ between CCs and REFs, but the groundwater table and soil water content were significantly higher at CCs than at REFs. The largest difference in percent MeHg of HgTOT (12 times higher at CCs compared to REFs, p = 0.003) was observed in concert with a significant enhancement in soil water content (p = 0.0003) at intermediate hillslope positions (20-38 m from stream), outside the stream riparian zone. Incubation experiments demonstrated that soils having significantly enhanced soil pools of MeHg after clear-cutting also showed significantly enhanced methylation potential as compared with similarly positioned soils in mature reference stands. The addition of inhibitors demonstrated that sulfate-reducing bacteria (SRB) and methanogens were key methylators. Rates of demethylation did not differ between CCs and REFs. Our results suggest that enhanced water saturation of organic soils providing readily available electron donors stimulate Hg-methylating microbes to net formation and buildup of MeHg in O horizons after forest harvest. PMID- 27461939 TI - Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration. AB - RATIONALE: Catecholamines increase cardiac contractility, but exposure to high concentrations or prolonged exposures can cause cardiac injury. A recent study demonstrated that a single subcutaneous injection of isoproterenol (ISO; 200 mg/kg) in mice causes acute myocyte death (8%-10%) with complete cardiac repair within a month. Cardiac regeneration was via endogenous cKit(+) cardiac stem cell mediated new myocyte formation. OBJECTIVE: Our goal was to validate this simple injury/regeneration system and use it to study the biology of newly forming adult cardiac myocytes. METHODS AND RESULTS: C57BL/6 mice (n=173) were treated with single injections of vehicle, 200 or 300 mg/kg ISO, or 2 daily doses of 200 mg/kg ISO for 6 days. Echocardiography revealed transiently increased systolic function and unaltered diastolic function 1 day after single ISO injection. Single ISO injections also caused membrane injury in ~10% of myocytes, but few of these myocytes appeared to be necrotic. Circulating troponin I levels after ISO were elevated, further documenting myocyte damage. However, myocyte apoptosis was not increased after ISO injury. Heart weight to body weight ratio and fibrosis were also not altered 28 days after ISO injection. Single- or multiple-dose ISO injury was not associated with an increase in the percentage of 5-ethynyl-2' deoxyuridine-labeled myocytes. Furthermore, ISO injections did not increase new myocytes in cKit(+/Cre)*R-GFP transgenic mice. CONCLUSIONS: A single dose of ISO causes injury in ~10% of the cardiomyocytes. However, most of these myocytes seem to recover and do not elicit cKit(+) cardiac stem cell-derived myocyte regeneration. PMID- 27461941 TI - Homebound status among middle-aged and older adults with disabilities in ADLs and its associations with clinical, functional, and environmental factors. AB - BACKGROUND: Homebound status is associated with poor health, comorbidity, and mortality and represents a major challenge for health systems. However, its prevalence among people with disabilities in the basic activities of daily living (ADLs) is unknown. OBJECTIVES: The objectives were to: (1) examine the prevalence of the homebound status among middle-aged and older adults with disabilities in ADLs, and (2) identify its clinical, functional, and environmental determinants. METHODS: This study included 221 community-dwelling subjects, aged >=50 years, who applied for long-term care services at the Office for Legal Certification of Long-term Care Need of Coruna (Spain). Each subject had a disability in ADLs and was interviewed by a trained examiner in the subject's home. The participants were considered homebound if they remained inside their home during the previous week. MEASURES: Demographic, clinical, functional, and environmental factors. Multiple logistic regression was used to determine the factors associated with homebound status. RESULTS: The prevalence of homebound status was 39.8%. A multivariate analysis revealed that the presence of architectural barriers at the home entrance (stairs [OR: 6.67, p < 0.001] or a heavy door [OR: 2.83, p = 0.023]), walking ability limitations (OR: 3.26, p = 0.006), and higher age (OR: 1.05, p = 0.04) were associated with homebound status. CONCLUSIONS: Homebound status is a highly prevalent problem among middle-aged and older adults with disabilities in ADLs. Architectural factors in the home and walking ability limitations seem to be important predictors, suggesting that health care interventions should target home adaptations and mobility skills as a means to preventing or decreasing homebound status. PMID- 27461940 TI - Divergence of helper, cytotoxic, and regulatory T cells in the decidua from miscarriage. AB - PROBLEM: The aim of this prospective study was to evaluate phenotypic differences of helper T (Th), cytotoxic T (Tc), and regulatory T (Treg) cells in the deciduae of missed miscarriage with a normal chromosome karyotype of a fetus (MN) and missed miscarriage with an abnormal chromosome karyotype of a fetus (MA). METHODS OF STUDY: The decidua of 19 MN and 28 MA was obtained. Additionally, the decidua of 15 induced abortion (IA) and the endometrium of 19 non-pregnant women (EM) were obtained. IFN-gamma(+) , IL-17(+) , CD25(high) Foxp3(+) cells in CD4(+) (Th) cells, and IFN-gamma(+) cells in CD8(+) (Tc) cells were evaluated by flow cytometry. RESULTS: The percentages of IFN-gamma(+) Tc and CD4(+) CD25(high) Foxp3(+) (Treg) cells in MN were significantly increased as compared with MA and IA. The percentage of IFN-gamma(+) Th in MN was increased as compared with IA. CONCLUSION: Activation of IFN-gamma(+) Tc and Treg cells in the decidua might be associated with the pathophysiology underlying MN. PMID- 27461942 TI - Recent advances in renal cell carcinoma from a pathological point of view. AB - The purpose of this article is to review the recent advances in renal cell carcinoma (RCC) from a pathological point of view. Because the genetic features and morphological characteristics have become major criteria for the classification of RCC, special techniques, such as immunohistochemistry, are essential to the differential diagnosis of renal tumors. Metastasis is frequently observed among the RCC patients with curative nephrectomy, and extracellular matrix-degrading enzymes, such as matrix metalloproteinases (MMP) and heparanase, play a key role in invasion and metastasis of RCC. Snail and Slug, transcription factors of epithelial-mesenchymal transition (EMT), accelerate cancer cell invasion through downregulation of E-cadherin and up-regulation of MMP. Therapies targeted at the vascular endothelial growth factor pathway have become the standard treatment of metastatic RCC. Although they lead to tumor shrinkage mainly by inhibiting angiogenesis, they have typically been associated with drug resistance. The mechanism of the resistance remains largely unknown, but complex events including re-activation of angiogenesis, EMT and cancer stem cells, and immune escape are implicated in the refractory response to the therapy. Recent advances of the research on RCC have caused the changes of classification and therapy, and pathologists should take overall view of these as integrated pathology. PMID- 27461943 TI - Cultural challenges to engaging patients in shared decision making. AB - OBJECTIVE: Engaging patients in their health care through shared decision-making is a priority embraced by several national and international groups. Missing from these initiatives is an understanding of the challenges involved in engaging patients from diverse backgrounds in shared decision-making. In this commentary, we summarize some of the challenges and pose points for consideration regarding how to move toward more culturally appropriate shared decision-making. DISCUSSION: The past decade has seen repeated calls for health policies, research projects and interventions that more actively include patients in decision making. Yet research has shown that patients from different racial/ethnic and cultural backgrounds appraise their decision making process less positively than do white, U.S.-born patients who are the current demographic majority. CONCLUSION: While preliminary conceptual frameworks have been proposed for considering the role of race/ethnicity and culture in healthcare utilization, we maintain that more foundational and empirical work is necessary. We offer recommendations for how to best involve patients early in treatment and how to maximize decision making in the way most meaningful to patients. Innovative and sustained efforts are needed to educate and train providers to communicate effectively in engaging patients in informed, shared decision-making and to provide culturally competent health care. PMID- 27461944 TI - A scoping review of the literature on benefits and challenges of participating in patient education programs aimed at promoting self-management for people living with chronic illness. AB - OBJECTIVE: To give a comprehensive overview of benefits and challenges from participating in group based patient education programs that are carried out by health care professionals and lay participants, aimed at promoting self management for people living with chronic illness. METHODS: We searched 8 literature databases. Full text articles meeting the inclusion criteria were retrieved and reviewed. Arksey and O'Malley's framework for scoping studies guided the review process and thematic analysis was undertaken to synthesize extracted data. RESULTS: Of the 5935 titles identified, 47 articles were included in this review. The participants experienced the programs as beneficial according to less symptom distress and greater awareness of their own health, improved self management strategies, peer support, learning and hope. CONCLUSION: A substantial evidence base supports the conclusion that group based self-management patient education programs in different ways have been experienced as beneficial, but more research is needed. PRACTICE IMPLICATIONS: The insights gained from this review can enable researchers, health care professionals, and participants to understand the complexity in evaluating self-management patient education programs, and constitute a basis for a more standardized and systematic evaluation. The results may also encourage health care professionals in planning and carrying out programs in cooperation with lay participants. PMID- 27461945 TI - Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p. AB - Long non-coding RNA (lncRNA) X inactivate-specific transcript (XIST) has been verified as an oncogenic gene in several human malignant tumors, and its dysregulation was closed associated with tumor initiation, development and progression. Nevertheless, whether the aberrant expression of XIST in human nasopharyngeal carcinoma (NPC) is corrected with malignancy, metastasis or prognosis has not been elaborated. Here, we discovered that XIST was up-regulated in NPC tissues and higher expression of XIST contributed to a markedly poorer survival time. In addition, multivariate analysis demonstrated XIST was an independent risk factor for prognosis. XIST over-expression enhanced, while XIST silencing hampered the cell growth in NPC. Additionally, mechanistic analysis revealed that XIST up-regulated the expression of miR-34a-5p targeted gene E2F3 through acting as a competitive 'sponge' of miR-34a-5p. Taking all into account, we concluded that XIST functioned as an oncogene in NPC through up-regulating E2F3 in part through 'spongeing' miR-34a-5p. PMID- 27461946 TI - Comparison of apoptosis between adult worms of Schistosoma japonicum from susceptible (BALB/c mice) and less-susceptible (Wistar rats) hosts. AB - Schistosomiasis remains a serious public health concern in China. BALB/c mice are susceptible to Schistosoma japonicum infection, whereas the Wistar rats are less susceptible. Apoptosis phenomenon was observed in 42d adult worms of S. japonicum from both rats and mice at the morphologic, DNA, cellular, and gene levels by transmission electron microscopy (TEM), fluorometric terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) analysis, fluorescein isothiocyanate-annexin-V/propidium iodide staining flow cytometry (FCM) analysis, and real-time PCR. The results showed that the apoptotic state in worms from two different susceptible hosts was diverse. Several classical hallmarks of apoptosis, including cell shrinkage, chromatin condensation and lunate marginalization, splitting of the nucleoli, nuclear shrinkage and apoptotic body formation were observed by TEM. TUNEL analysis showed that there were much more apoptosis spots in adult worms from rats than those from mice. Statistical analysis revealed that the degree of apoptosis and percentage of necrotic cells in adult worms from Wistar rats were significantly greater (P<0.01) than those from BALB/c mice by flow cytometry. A total of 15 apoptosis-associated genes including the major components of an intrinsic cell-death pathway were identified from S. japonicum in this study, suggested that a similar apoptosis pathway might occur in S. japonicum. Real-time PCR analyses revealed that the expression levels of most of the tested apoptosis-associated genes, except CASP7, were significantly higher or at the similar level in adult worms from Wistar rats, as compared to those from BALB/c mice. The results obtained in this study collectively demonstrated that differential development of adult S. japonicum in less-susceptible rats and susceptible mice was significantly associated with apoptosis in the worm, and provided valuable information to guide further investigations of the mechanisms governing apoptosis and host interactions in schistosome infection. PMID- 27461947 TI - Differentiation-inducing and anti-proliferative activities of isoliquiritigenin and all-trans-retinoic acid on B16F0 melanoma cells: Mechanisms profiling by RNA seq. AB - Melanoma is a cancer that arises from melanocytes, specialized pigmented cells that are found predominantly in the skin. The incidence of malignant melanoma has significantly increased over the last decade. With the development of therapy, the survival rate of some kind of cancer has been improved greatly. But the treatment of melanoma remains unsatisfactory. Much of melanoma's resistance to traditional chemotherapy is believed to arise intrinsically, by virtue of potent growth and cell survival-promoting genetic alteration. Therefore, significant attention has recently been focused on differentiation therapy, as well as differentiation inducer compounds. In previous study, we found isoliquiritigenin (ISL), a natural product extracted from licorice, could induce B16F0 melanoma cell differentiation. Here we investigated the transcriptional response of melanoma differentiation process induced by ISL and all-trans-retinoic acid (RA). Results showed that 390 genes involves in 201 biochemical pathways were differentially expressed in ISL treatment and 304 genes in 193 pathways in RA treatment. Differential expressed genes (DGEs, fold-change (FC)>=10) with the function of anti-proliferative and differentiation inducing indicated a loss of grade malignancy characteristic. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated glutathione metabolism, glycolysis/gluconeogenesis and pentose phosphate pathway were the top three relative pathway perturbed by ISL, and mitogen-activated protein kinase (MAPK) signaling pathway was the most important pathway in RA treatment. In the analysis of hierarchical clustering of DEGs, we discovered 72 DEGs involved in the process of drug action. We thought Cited1, Tgm2, Xaf1, Cd59a, Fbxo2, Adh7 may have critical role in the differentiation of melanoma. The evidence displayed herein confirms the critical role of reactive oxygen species (ROS) in melanoma pathobiology and provides evidence for future targets in the development of next-generation biomarkers and therapeutics. PMID- 27461948 TI - Role of miR-181a-5p and endoplasmic reticulum stress in the regulation of myogenic differentiation. AB - Accumulating evidence has indicated that microRNAs (miRNAs) and endoplasmic reticulum (ER) stress play critical roles in myoblast differentiation. However, the regulation roles of miRNAs and ER stress in myogenic differentiation have not been fully revealed and need to be further studied. Here, we discovered that the expression levels of miR-181a-5p were strongly upregulated during C2C12 cell differentiation. miR-181a-5p overexpression promoted ER stress and differentiation of C2C12 cells, which was accompanied by increasing expression levels of marker genes related to ER stress-mediated apoptosis and myogenic differentiation. Opposite results were observed after inhibition of the miR-181a 5p expression. The gain- and loss-of-function experiments on C2C12 cells showed that miR-181a-5p affected the development of muscle fiber type, but had no significant influence on C2C12 cell proliferation. In the ER-stressed C2C12 cells induced by thapsigargin (Tg), the expression levels of both miR-181a-5p and marker genes related to ER stress and myogenesis were upregulated. In the ER stressed C2C12 cells and porcine muscle fibroblast (PMF) cells pretreated with Tg, we found that miR-181a-5p targeted glucose-regulated protein, 78kDa/binding immunoglobulin protein (GRP78/BIP), and influenced cell apoptosis. In conclusion, these results indicate that miR-181a-5p and ER stress have positive synergistic effects on myogenic differentiation by increasing the expression levels of myogenic differentiation key genes and activating the ER stress-mediated apoptosis signaling pathway. PMID- 27461949 TI - Vertical transmission of hepatitis C virus-like non-primate hepacivirus in horses. AB - Non-primate hepacivirus (NPHV), a recently discovered hepatotropic virus infecting horses, is phylogenetically the closest known homologue of hepatitis C virus (HCV). The main route for acquiring HCV infection in childhood is vertical transmission. However, nothing is known about the natural mode of transmission for NPHV. To investigate the possibility of vertically transmitted NPHV infection in horses, 20 Thoroughbred broodmares and their foals were monitored during foaling season 2015 until 6 months post-partum. Prepartal serum was taken from the mares, and during foaling umbilical cord blood and colostrum samples were collected. Postnatal serum samples were taken from the foals after delivery. In addition, serum was taken at 3 and 6 months after foaling from all mares and foals. Samples were analysed for the presence of NPHV RNA by quantitative real time PCR and for the presence of anti-NPHV NS3 antibodies by luciferase immunoprecipitation system. Identified NPHV isolates were sequenced and phylogenetic analysis of the viral glycoproteins was used to track the course of naturally occurring infections and the circulation of distinct isolates within the herd. At parturition, 16 mares were seropositive, including four viraemic mares. Vertical transmission occurred in one of these four mare-foal pairs. Interestingly, NPHV isolates of newly infected foals and mares after 3 and 6 months cluster in their respective pasture herds suggesting another horizontal route of transmission. PMID- 27461950 TI - The Benefits of Supporting the Autonomy of Individuals with Mild Intellectual Disabilities: An Experimental Study. AB - BACKGROUND: The benefits of autonomy support with the general population have been demonstrated numerous times. However, little research has been conducted to verify if these benefits apply to people with special needs. METHODS: The goal of the study was to examine whether autonomy support (AS) can foster the sense of autonomy of people with a mild intellectual disabilities (MIDs) and improve their experience while engaging in an important but unpleasant learning activity. This experiment compares the effects of two contexts: with and without AS. All participants (N = 51) had a mild intellectual disability and were recruited from rehabilitation centres. RESULTS: Compared to participants in the control group, participants in the AS group tended to experience greater autonomy satisfaction and tended to perceive more value to the activity. They were also significantly more engaged in it, and they experienced a steeper decrease in anxiety over time. CONCLUSIONS: This study suggests that the benefits of AS extend to individuals with mild intellectual disability. PMID- 27461951 TI - Peptides NAP and SAL attenuate human tau granular-shaped oligomers in vitro and in SH-SY5Y cells. PMID- 27461952 TI - Potential Reuse of Oncology Drugs in the Treatment of Rare Diseases. AB - Cancer research has made remarkable progress with the help of advancing genomics techniques, resulting in more precise clinical application and many new anticancer drugs on the market. By contrast, very few treatment options are available for rare diseases that are often progressive, severe, and life threatening. In this opinion we elaborate on the possible association between cancers and rare diseases across three different levels including clinical observation, crosstalk between germline mutation and somatic mutation, and shared biological pathways. Consequently, by utilizing systematic drug-repositioning approaches, and taking safety issues into consideration, we suggest that oncology drugs have great potential for reuse in the treatment of rare diseases. PMID- 27461953 TI - Evaluation of the breeding behavior of Brazilian Pony stallions. AB - The aim of this study was to evaluate the breeding behavior of Brazilian Pony stallions during semen collection to examine the effect of age category (AC) and month of evaluation on the characteristics of breeding behavior. Nine stallions were evaluated during the breeding and non-breeding season, 5-8 (AC1) and 9-13 years (AC2) of age. The variables evaluated were reaction time (RT), mount time one (MT1) and two (MT2), mount and ejaculation time (MEjT), mounting without erection (MWEr), mounting without ejaculation (MWEj), flehmen, kicks, bites, smells, vocalizations and serum testosterone concentration. Analyses of variance and correlation were performed. The average scores were RT: 56.2+/-92.9s, MT1: 115.0+/-122.4s, MT2: 196.4+/-160.7s, MEjT: 21.8+/-3.2s, MWEr: 0.8+/-1.3s, MWEj: 2.1+/-3.5s, flehmen: 3.8+/-3.0s, kicks: 0.3+/-1.2s, bites: 1.0+/-2.0s, smells: 5.7+/-3.5s, vocalizations: 6.4+/-6.3s and testosterone: 0.89+/-0.52ng/mL. The AC affected the RT (P<0.05) but not the other traits. Month of evaluation did not affect most variables (P>0.05). The correlations between age and RT and between age and MT1 and MT2 were significant. The correlation between testosterone and MEjT was moderate and negative. The breeding behavior of Brazilian Pony stallions was similar across different months of evaluation and different age categories. The month of evaluation and age category also did not affect testosterone concentrations, meaning that semen collection is feasible throughout the year. PMID- 27461954 TI - Differences in the geographic distribution of lymphoma subtypes in Golden retrievers in the USA. AB - The purpose of this cross-sectional study was to examine differences in the geographic distribution of two distinct subtypes of canine lymphoma (CL), B-cell lymphoma (BCL) and T-zone lymphoma (TZL), in the USA while accounting for heritable risks associated with the outcome of disease through inclusion of only one breed of dog. This study included 454 Golden retrievers and associations between geographic areas of the USA and the phenotypic variant of lymphoma were examined using multivariable logistic regression. There was a detectable difference in the geographic distribution of BCL and TZL with dogs in the Northeast [odds ratio (OR) = 3.4, 95% confidence interval (CI) = 1.6-7.0] and East North Central regions (OR = 12.1, 95%CI = 3.6-40.5) being more likely to be diagnosed with TZL as compared to dogs in the Mountain region of the USA. The finding of non-random geographic distribution of lymphoma subtypes suggest that environmental risk factors may contribute to the development of different types of CL. PMID- 27461955 TI - BATCH-GE: Batch analysis of Next-Generation Sequencing data for genome editing assessment. AB - Targeted mutagenesis by the CRISPR/Cas9 system is currently revolutionizing genetics. The ease of this technique has enabled genome engineering in-vitro and in a range of model organisms and has pushed experimental dimensions to unprecedented proportions. Due to its tremendous progress in terms of speed, read length, throughput and cost, Next-Generation Sequencing (NGS) has been increasingly used for the analysis of CRISPR/Cas9 genome editing experiments. However, the current tools for genome editing assessment lack flexibility and fall short in the analysis of large amounts of NGS data. Therefore, we designed BATCH-GE, an easy-to-use bioinformatics tool for batch analysis of NGS-generated genome editing data, available from https://github.com/WouterSteyaert/BATCH GE.git. BATCH-GE detects and reports indel mutations and other precise genome editing events and calculates the corresponding mutagenesis efficiencies for a large number of samples in parallel. Furthermore, this new tool provides flexibility by allowing the user to adapt a number of input variables. The performance of BATCH-GE was evaluated in two genome editing experiments, aiming to generate knock-out and knock-in zebrafish mutants. This tool will not only contribute to the evaluation of CRISPR/Cas9-based experiments, but will be of use in any genome editing experiment and has the ability to analyze data from every organism with a sequenced genome. PMID- 27461957 TI - Intracranial evaluation and laser ablation for epilepsy with periventricular nodular heterotopia. AB - Surgical treatment of focal epilepsy in the presence of periventricular nodular heterotopia (PVNH) poses a challenge, as the relative roles of the nodular tissue and the overlying cortex in the generation of seizures can be complex and variable. Here, we review the literature on chronic invasive EEG recordings in humans with this substrate and present two illustrative cases from our practice. We found that while inter-ictal spiking from nodules is common, clinical seizures rarely arise solely from nodular tissue. More typically, ictal onset is simultaneous with overlying neocortex or mesial temporal structures. Surgical outcome is more favorable in cases with unilateral (as opposed to bilateral) PVNH, and when a substantial or complete ablation of PVNH is performed. In rare cases, nodular ablation alone may be sufficient, as may be completed by MRI guided laser interstitial thermal therapy. The mechanism(s) by which PNVH interacts with overlying cortex are not fully understood, but we suggest that PVNH either orchestrates or amplifies local network epileptogenicity. At present, invasive recordings with penetrating depth electrodes are required prior to surgical therapy, as illustrated in our cases. PMID- 27461956 TI - The mouse receptor transporting protein RTP1S and the fly SNMP1 support the functional expression of the Drosophila odorant coreceptor Orco in mammalian culture cells. AB - BACKGROUND: Functional expression of vertebrate and insect odorant receptors (ORs) in mammalian culture cells is hampered by an incorrect trafficking of these proteins to the plasma membrane. Receptor transporting proteins (RTPs) have been found to enhance the activity of transfected mammalian ORs in several heterologous systems. NEW METHODS: We co-transfected the Drosophila olfactory coreceptor (Orco) in HEK293 cells with a truncated form of the mouse RTP1 (RTP1S) or with the Drosophila sensory neuron membrane protein 1 (SNMP1), which is required for the detection of the pheromone cis-vaccenyl acetate and was shown to be apposed to Orco within the functional receptor unit. RESULTS: Co-transfection of Orco with either of the two constructs led to an enhanced response to stimulations with the synthetic Orco agonist VUAA1, as compared to transfection with Orco alone. COMPARISON WITH EXISTING METHODS: This method enhances the functional expression of Orco in HEK293 cells in comparison to conventional transfection with Orco alone and enables the use of a lower amount of Orco DNA for transfection. CONCLUSION: Mammalian RTPs can enhance the expression of insect ORs. Moreover, the ability of SNMP1 to mimic the RTP1S effect may indicate possible new roles of this protein apart from being involved in pheromone detection. These results provide researchers with a fast and inexpensive way to optimize the functional expression of insect ORs in heterologous systems and open the search for insect proteins analogous to mammalian RTPs. PMID- 27461958 TI - Recent developments in liquid chromatography-mass spectrometry analyses of ghrelin and related peptides. AB - Profiling and monitoring concentrations of key hormones in body have long been critical aims in clinical therapy. As a crucial hormone, identification and quantification of ghrelin is a fundamental, often key, step in understanding human physiological mechanisms. Through the advances and improvements of different analytical techniques, ghrelin measurement is generally feasible, and the number of successful reports is progressively being increased with new aspects of selectivity, sensitivity and ease of use in various circumstances. Herein we discuss current chromatographic methods for sample collection, separation and a mass spectrometry method for detection and measurement of ghrelin and other proghrelin-derived peptides in biological metrics. We describe the most commonly applied analytical LC-MS procedures for determination of proghrelin-derived peptides and provide illustrative instances representing the state of the art. This review is intended for bioanalytical chemists or clinical researchers who are interested in this field of research. PMID- 27461959 TI - Role of active site loop in coenzyme binding and flavin reduction in cytochrome P450 reductase. AB - Cytochrome P450 reductase (CPR) contains a loop within the active site (comprising Asp(634), Ala(635), Arg(636) and Asn(637); human CPR numbering) that relocates upon NADPH binding. Repositioning of the loop triggers the reorientation of an FAD-shielding tryptophan (Trp(679)) to a partially stacked conformer, reducing the energy barrier for displacement of the residue by the NADPH nicotinamide ring: an essential step for hydride transfer. We used site directed mutagenesis and kinetic analysis to investigate if the amino acid composition of the loop influences the catalytic properties of CPR. The D634A and D634N variants elicited a modest increase in coenzyme binding affinity coupled with a 36- and 10-fold reduction in cytochrome c(3+) turnover and a 17- and 3 fold decrease in the pre-steady state rate of flavin reduction. These results, in combination with a reduction in the kinetic isotope effect for hydride transfer, suggest that diminished activity is due to destabilization of the partially stacked conformer of Trp(677) and slower release of NADP(+). In contrast, R636A, R636S and an A635G/R636S double mutant led to a modest increase in cytochrome c(3+) reduction, which is linked to weaker coenzyme binding and faster interflavin electron transfer. A potential mechanism by which Arg(636) influences catalysis is discussed. PMID- 27461960 TI - The occurrence of endocrine disrupting compounds in off-shore sediments from the southern Baltic Sea. AB - This paper presents the study on the occurrence and spatial distribution of polybrominated diphenyl ethers (PBDEs), butyltin compounds (BTCs), bisphenol A (BPA), and alkylphenols (APs) in sediments. The study focused mainly on off-shore surface sediments collected from the southern Baltic Sea. The pollutant concentrations were as follows: C) (HBB:c.92 + 5G->C) with HbA2 of 1% showing the presence of delta-globin gene variant HbA2 St. George CD 81 (C->T) (HBD:c.244C->T). A similar observation was reported in another unrelated patient who showed near absence of HbA2 level in HPLC. He showed a presence of delta globin gene mutation HbA2 Saurashtra CD 100(C->T) (HBD: c.301C->T) and a single 3.7 kb deletion in the alpha-globin gene. CONCLUSION: In the countries, where beta-thalassaemia is prevalent, an awareness and detection of different delta globin gene mutations is important, as complex interactions between these haemoglobinopathies can lead to the misdiagnosis of beta-thalassaemia carriers. PMID- 27461963 TI - Penile Girth Enhancement With Polymethylmethacrylate-Based Soft Tissue Fillers. AB - INTRODUCTION: An unknown percentage of men will take every risk to develop a larger penis. Thus far, most injectables have caused serious problems. Polymethylmethacrylate (PMMA) microspheres have been injected as a wrinkle filler and volumizer with increasing safety since 1989. AIM: To report on a safe and permanently effective method to enhance penile girth and length with an approved dermal filler (ie, PMMA). METHODS: Since 2007, the senior author has performed penile augmentation in 752 men mainly with Metacrill, a suspension of PMMA microspheres in carboxymethyl-cellulose. MAIN OUTCOME MEASURES: The data of 729 patients and 203 completed questionnaires were evaluated statistically. RESULTS: The overall satisfaction rate was 8.7 on a scale of 1 to 10. After one to three injection sessions, average girth increased by 3.5 cm, or 134% (10.2 to 13.7 cm = 134.31%). Penile length also increased by weight and stretching force of the implant from an average of 9.8 to 10.5 cm. Approximately half the patients perceived some irregularities of the implant, which caused no problems. Complications occurred in 0.4%, when PMMA nodules had to be surgically removed in three of the 24% of patients who had a non-circumcised penis. CONCLUSION: After 5 years of development, penile augmentation with PMMA microspheres appears to be a natural, safe, and permanently effective method. The only complication of nodule formation and other irregularities can be overcome by an improved injection technique and better postimplantation care. PMID- 27461964 TI - Impact of Contraceptive Type on Sexual Desire of Women and of Men Partnered to Contraceptive Users. AB - INTRODUCTION: Research investigating the impact of contraceptive use on sexual desire has produced mixed results. This scholarship also has had inconsistent methodology, with some studies not separating contraceptive types and others lacking non-hormonal comparison groups. Relationship context of contraceptive use and sexual behavior also have not been well represented. AIMS: To investigate the impact of contraceptive type on sexual desire in women and in men who are partnered to contraceptive-using women. METHODS: In two separate studies we examined the impact of contraceptives on the sexual desire of women currently using contraceptives and men partnered to women using contraceptives. The first study examined the impact of contraceptive type on sexual desire in women and in men partnered to contraceptive users in relationships of different lengths. The second study examined this impact in heterosexual couples in long-term relationships. MAIN OUTCOME MEASURES: Solitary and dyadic sexual desire as measured by the Sexual Desire Inventory and contraceptive type as categorized into three types: oral hormonal contraceptive, other hormonal contraceptive, and non-hormonal contraceptive. RESULTS: Contraceptive type significantly affected solitary and dyadic desire. Women on non-hormonal contraceptives reported higher solitary sexual desire than women on other hormonal contraceptives. Women on oral hormonal contraceptives reported significantly higher dyadic sexual desire than women on non-hormonal contraceptives. In male partners of female contraceptive users, solitary and dyadic sexual desires were not affected by partner contraceptive type. In the multivariate model, relationship length and age were stronger predictors of contraceptive type than was solitary or dyadic sexual desire. At the couple level, contraceptive type also was not related to solitary or dyadic sexual desire in men and women. CONCLUSION: Contraceptive type can affect solitary and dyadic sexual desire in women; however, contextual factors seem to be stronger predictors of sexual desire for long-term coupled women and men than contraception type. PMID- 27461965 TI - Discovery of the Pt-Based Superconductor LaPt5As. AB - A novel superconductor, LaPt5As, which exhibits a new crystal structure was discovered by high-pressure synthesis using a Kawai-type apparatus. A superconducting transition temperature was observed at 2.6 K. Depending on the sintering pressure, LaPt5As has superconducting and non-superconducting phases with different crystal structures. A sintering pressure of around 10 GPa is effective to form single-phase superconducting LaPt5As. This material has a very unique crystal structure with an extremely long c lattice parameter of over 60 A and corner-sharing tetrahedrons composed of network-like Pt layers. Density functional theory calculations have suggested that the superconducting current flows through these Pt layers. Also, this unique layered structure characteristic of LaPt5As is thought to play a key role in the emergence of superconductivity. Furthermore, due to a stacking structure which makes up layers, various structural modifications for the LaPt5As family are conceivable. Since such a high-pressure synthesis using a Kawai-type apparatus is not common in the field of materials science, there is large room for further exploration of unknown phases which are induced by high pressure in various materials. PMID- 27461966 TI - A Dual-Phase Ceramic Membrane with Extremely High H2 Permeation Flux Prepared by Autoseparation of a Ceramic Precursor. AB - A novel concept for the preparation of multiphase composite ceramics based on demixing of a single ceramic precursor has been developed and used for the synthesis of a dual-phase H2 -permeable ceramic membrane. The precursor BaCe0.5 Fe0.5 O3-delta decomposes on calcination at 1370 degrees C for 10 h into two thermodynamically stable oxides with perovskite structures: the cerium-rich oxide BaCe0.85 Fe0.15 O3-delta (BCF8515) and the iron-rich oxide BaCe0.15 Fe0.85 O3 delta (BCF1585), 50 mol % each. In the resulting dual-phase material, the orthorhombic perovskite BCF8515 acts as the main proton conductor and the cubic perovskite BCF1585 as the main electron conductor. The dual-phase membrane shows an extremely high H2 permeation flux of 0.76 mL min(-1) cm(-2) at 950 degrees C with 1.0 mm thickness. This auto-demixing concept should be applicable to the synthesis of other ionic-electronic conducting ceramics. PMID- 27461967 TI - What are the Newer Applications for Therapeutic Apheresis in Nephrology?: Clinical Application of Therapeutic Apheresis in Nephrology in Japan. PMID- 27461968 TI - Optical Relaxation Time Enhancement in Graphene-Passivated Metal Films. AB - Due to the small skin depth in metals at optical frequencies, their plasmonic response is strongly dictated by their surface properties. Copper (Cu) is one of the standard materials of choice for plasmonic applications, because of its high conductivity and CMOS compatibility. However, being a chemically active material, it gets easily oxidized when left in ambient environment, causing an inevitable degradation in its plasmonic resonance. Here, for the first time, we report a strong enhancement in the optical relaxation time in Cu by direct growth of few layer graphene that is shown to act as an excellent passivation layer protecting Cu surface from any deterioration. Spectroscopic ellipsometry measurements reveal a 40-50% reduction in the total scattering rate in Cu itself, which is attributed to an improvement in its surface properties. We also study the impact of graphene quality and show that high quality graphene leads to an even larger improvement in electron scattering rate. These findings are expected to provide a big push towards graphene-protected Cu plasmonics. PMID- 27461969 TI - A review of radiofrequency ablation: Large target tissue necrosis and mathematical modelling. AB - Radiofrequency ablation (RFA) is an effective clinical method for tumour ablation with minimum intrusiveness. However, the use of RFA is mostly restricted to small tumours, especially those <3cm in diameter. This paper discusses the state-of-the art of RFA, drawn from experimental and clinical results, for large tumours (i.e. ?3cm in diameter). In particular, the paper analyses clinical results related to target tissue necrosis (TTN) and mathematical modelling of the RFA procedure to understand the mechanism whereby the TTN is limited to under 3cm with RFA. This paper also discusses a strategy of controlling of the temperature of target tissue in the RFA procedure with the state-of-art device, which has the potential to increase the size of TTN. This paper ends with a discussion of some future ideas to solve the so-called 3-cm problem with RFA. PMID- 27461970 TI - Quantitative study on exact reconstruction sampling condition by verifying solution uniqueness in limited-view CT. AB - In limited-view computed tomography reconstruction, iterative image reconstruction with sparsity-exploiting methods, such as total variation (TV) minimization, inspired by compressive sensing, potentially claims large reductions in sampling requirements. However, a quantitative notion of this claim is non-trivial because of the ill-defined reduction in sampling achieved by the sparsity-exploiting method. In this paper, exact reconstruction sampling condition for limited-view problem is studied by verifying the uniqueness of solution in TV minimization model. Uniqueness is tested by solving a convex optimization problem derived from the sufficient and necessary condition of solution uniqueness. Through this method, the sufficient sampling number of exact reconstruction is quantified for any fixed phantom and settled geometrical parameter in the limited-view problem. This paper provides a reference to quantify the sampling condition. Three phantoms are tested to study the sampling condition of limited view exact reconstruction in this paper. The experiment results show the quantified sampling number and indicate that an object would be accurately reconstructed as the scanning range becomes narrower by increasing sampling number. The increased samplings compensate for the deficiency of the projection angle. However, the lower bound of the scanning range corresponding to three different phantoms are presented, in which an exact reconstruction cannot be obtained once the projection angular is narrowed to this extent no matter how to increase sampling. PMID- 27461971 TI - A novel cell therapy for stress urinary incontinence, midterm out come. PMID- 27461972 TI - Getting along or ahead: Effects of gender identity threat on communal and agentic self-presentations. AB - When faced with a threat to gender identity, people may try to restore their gender status by acting in a more gender-typical manner. The present research investigated effects of gender identity threat on self-presentations of agentic and communal traits in a Swedish and an Argentine sample (N = 242). Under threat (vs. affirmation), Swedish women deemphasized agentic traits (d [95% CI] = -0.41 [-0.93, 0.11]), Argentine women increased their emphasis on communal traits (d = 0.44 [-0.08, 0.97]), and Argentine men increased their emphasis on agentic traits (d = 0.49 [-0.03, 1.01]). However, Swedish men did not appear to be affected by the threat regarding agentic (d = 0.04 [-0.47, 0.55]) or communal traits (d = 0.23 [-0.29, 0.74]). The findings are to be considered tentative. Implications for identity threat research are discussed. PMID- 27461974 TI - All-Trans Retinoic Acid Increases Aquaporin 3 Expression in Human Vaginal Epithelial Cells. AB - INTRODUCTION: Water channel aquaporin 3 (AQP3) is an aquaglyceroporin that transports small neutral solutes and water. All-trans retinoic acid (ATRA), a member of the retinoid drug class, acts as a regulator in several biological processes. AIM: To investigate the effect of ATRA on the expression of AQP3 in human vaginal epithelial cells. METHODS: Human vaginal mucosal epithelial cells (CRL2616) were treated with ATRA 0, 0.01, 0.1, and 1 MUmol/L for 24 hours to examine the dose-dependent effects of ATRA and with ATRA 1 MUmol/L for 0, 3, 6, 12, and 24 hours. MAIN OUTCOME MEASURES: The expression of AQP3 and retinoic acid receptor (RAR) was determined by western blot analysis and reverse transcription polymerase chain reaction. RESULTS: AQP3 was detected in the cell membrane of human vaginal epithelial cells. ATRA increased the protein expression and mRNA levels of AQP3 in a dose-dependent manner (P < .05). ATRA also increased the protein expression of RARalpha (P < .05). Treatment of CRL2616 cells with an RAR antagonist (Ro 41-5253) significantly decreased AQP3 protein expression (P < .05). CONCLUSION: ATRA mediated by RARalpha increased AQP3 gene and protein expression in human vaginal mucosal epithelial cells. These results imply that AQP3 regulated by ATRA could play an important role in the mechanism of vaginal lubrication. PMID- 27461976 TI - Methodological exemplar of integrating quantitative and qualitative evidence - supportive care for men with prostate cancer: what are the most important components? AB - AIMS: To present a methodological exemplar of integrating findings from a quantitative and qualitative review on the same topic to provide insight into components of care that contribute to supportive care that is acceptable to men with prostate cancer. BACKGROUND: Men with prostate cancer are likely to live a long time with the disease, experience side effects from treatment and therefore have ongoing supportive care needs. Quantitative and qualitative reviews have been published but the findings have yet to be integrated. DESIGN: Integration of quantitative and qualitative synthesized evidence. DATA SOURCE: Two previously published systematic reviews. REVIEW METHODS: Synthesized evidence on supportive care for men with prostate cancer was integrated from two previously published systematic reviews: a narrative quantitative review and a qualitative review with thematic synthesis. These two streams of synthesized evidence were synthesized using concurrent narrative summary. Data from both reviews were used to develop a set of propositions from which a summary of components of care that likely to contribute to supportive care acceptable to men with prostate cancer were identified. RESULTS: Nine propositions were developed which covered men's supportive care focusing on the role of health professionals. These propositions were used to compose nine components of care likely to lead to supportive care that is acceptable to men with prostate cancer. Some of these components are no/low cost such as developing a more empathic personalized approach, but more specific approaches need further investigation in randomized controlled trials, for example, online support. CONCLUSION: This methodological exemplar demonstrates the integration of quantitative and qualitative synthesized data to determine components of care likely to lead to provision of supportive care acceptable to men with prostate cancer. PMID- 27461975 TI - Smoking, pregnancy and the subgingival microbiome. AB - The periodontal microbiome is known to be altered during pregnancy as well as by smoking. However, despite the fact that 2.1 million women in the United States smoke during their pregnancy, the potentially synergistic effects of smoking and pregnancy on the subgingival microbiome have never been studied. Subgingival plaque was collected from 44 systemically and periodontally healthy non-pregnant nonsmokers (control), non-pregnant smokers, pregnant nonsmokers and pregnant smokers and sequenced using 16S-pyrotag sequencing. 331601 classifiable sequences were compared against HOMD. Community ordination methods and co-occurrence networks were used along with non-parametric tests to identify differences between groups. Linear Discriminant Analysis revealed significant clustering based on pregnancy and smoking status. Alpha diversity was similar between groups, however, pregnant women (smokers and nonsmokers) demonstrated higher levels of gram-positive and gram-negative facultatives, and lower levels of gram negative anaerobes when compared to smokers. Each environmental perturbation induced distinctive co-occurrence patterns between species, with unique network anchors in each group. Our study thus suggests that the impact of each environmental perturbation on the periodontal microbiome is unique, and that when they are superimposed, the sum is greater than its parts. The persistence of these effects following cessation of the environmental disruption warrants further investigation. PMID- 27461977 TI - Bilingualism in children with developmental disorders: A narrative review. AB - Children with developmental disabilities (DD) often need and sometimes opt to become bilingual. The context for bilingual acquisition varies considerably and can impact outcomes. In this first article of the special issue, we review research on the timing and amount of bilingual exposure and outcomes of either direct language intervention or educational placements in three groups of children with DD: Specific Language Impairment (SLI), Autism Spectrum Disorders (ASD), and Down syndrome (DS). Children with SLI have been studied more than the other two groups. Findings showed that, on the one hand, the communication skills of simultaneous bilinguals and matched monolinguals with DD were similar for all groups when the stronger language or both languages of the bilingual children were considered. On the other hand, similar to typically developing children, sequential bilinguals and matched monolinguals with SLI (other groups not studied) differed on some but not all second language (L2) measures; even after an extended period of exposure, differences in L2 outcomes were not completely resolved. There is emerging evidence that the typological similarity of the languages being learned influences L2 development in sequential bilinguals, at least in children with SLI. Increasing the frequency of exposure seems to be more related to development of the weaker language in bilinguals with DD than their stronger language. Language intervention studies show the efficacy of interventions but provide little evidence for transfer across languages. In addition, only one (unpublished) study has compared the language and academic outcomes of children with DD in different language education programs. Research on bilingual children with DD in different educational settings/programs is limited, probably as a result of restricted inclusion of these children in some educational settings. We argue for the implementation of full inclusion policies that provide increased access to dual language programs for children with DD and access to a complete range of support services. PMID- 27461978 TI - Meaningful Use of the Indian Health Service Electronic Health Record. AB - OBJECTIVE: To understand the use of electronic health record (EHR) functionalities by physicians practicing in an underserved setting. DATA SOURCE/STUDY SETTING: A total of 333 Indian Health Service physicians (55 percent response rate) in August 2012. STUDY DESIGN: Cross-sectional. DATA COLLECTION: The survey assessed routine use of EHR functionalities, perceived usefulness, and barriers to adoption. PRINCIPAL FINDINGS: Physicians routinely used a median 7 of 10 EHR functionalities targeted by the Meaningful Use program, but only 5 percent used all 10. Most (63 percent) felt the EHR improved quality of care. Many (76 percent) reported increased documentation time and poorer quality patient physician interactions (45 percent). Primary care specialty and time using the EHR were positively associated with use of EHR functionalities, while perceived productivity loss was negatively associated. CONCLUSIONS: Significant opportunities exist to increase use of EHR functionalities and preserve physician patient interactions and productivity in a resource-limited environment. PMID- 27461980 TI - Combined proteomics and transcriptomics identifies sting-related toxins of jellyfish Cyanea nozakii. AB - Jellyfish sting has become a worldwide issue of critical concern to human health and safety in coastal areas in recent decades. Cyanea nozakii is one of the dominant blooming species and dangerous stingers in China. However, it remains unclear how many and what types of toxins are present in the venom. So, we used a combined transcriptomics and proteomics approach to investigate the venom composition of jellyfish C. nozakii. In total 4,608,524 Illumina valid reads were obtained to de novo assemble to 40,434 unigenes in the transcriptomics analysis. And, a total of 311,635 MS/MS spectra with 12,247 unique MS/MS spectra were generated to 1556 homologous proteins in the proteomics analysis. 174 potential toxin proteins were identified, with 27 proteins homology to the toxins from venomous animals, including phospholipase A2, zinc metalloproteinase-disintegrin agkistin, serine protease inhibitor, plancitoxin-1, alpha-latrocrustotoxin-Lt1a, etc. This study described the transcriptomics and venom proteomics of jellyfish C. nozakii for the first time. Our findings provide a comprehensive understanding of the venom composition of C. nozakii. Furthermore, the results may also be very helpful for the discovery of novel bioactive proteins, as well as the development of effective treatments for jellyfish sting in the future. BIOLOGICAL SIGNIFICANCE: Jellyfish Cyanea nozakii is one of the most dangerous stingers in the coast of china. Hundreds of thousands of people would be stung every year and victims suffered a severe pain, itch, swelling, inflammation, wheal and even more serious consequence. However, it remains unclear how many and what types of toxins are present as well as the relationship between the clinical symptoms and toxins. Our combined transcriptomics and proteomics findings can provide a comprehensive understanding of the venom composition of C. nozakii and will also be helpful for the development of effective treatments for jellyfish sting in the future. PMID- 27461979 TI - Integrative proteomic analysis reveals reprograming tumor necrosis factor signaling in epithelial mesenchymal transition. AB - The airway epithelium is a semi-impermeable barrier whose disruption by growth factor reprogramming is associated with chronic airway diseases of humans. Transforming growth factor beta (TGFbeta)-induced epithelial mesenchymal transition (EMT) plays important roles in airway remodeling characteristic of idiopathic lung fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Inflammation of the airways leads to airway injury and tumor necrosis factor alpha (TNFalpha) plays an important pro-inflammatory role. Little systematic information about the effects of EMT on TNFalpha signaling is available. Using an in vitro model of TGFbeta-induced EMT in primary human small airway epithelial cells (hSAECs), we applied quantitative proteomics and phosphoprotein profiling to understand the molecular mechanism of EMT and the impact of EMT on innate inflammatory responses. We quantified 7925 proteins and 1348 phosphorylation sites by stable isotope labeling with iTRAQ technology. We found that cellular response to TNFalpha is cell state dependent and the relative TNFalpha response in mesenchymal state is highly compressed. Combined bioinformatics analyses of proteome and phosphoproteome indicate that the EMT state is associated with reprogramming of kinome, signaling cascade of upstream transcription regulators, phosphor-networks, and NF-kappaB dependent cell signaling. BIOLOGICAL SIGNIFICANCE: Epithelial mesenchymal transition and inflammation have important implications for clinical and physiologic manifestations of chronic airway diseases such as severe asthma, COPD, and lung fibrosis. Little systematic information on the interplay between EMT and innate inflammation is available. This study combined quantitative proteomics and phosphorproteomics approach to obtain systems-level insight into the upstream transcription regulators involved in the TGFbeta-induced EMT in primary human small airway epithelial cells and to elucidate how EMT impacts on the TNFalpha signaling pathways. The proteomics and phosphoproteomics analysis indicates that many signaling pathways involved in TGFbeta-induced EMT and EMT has profound reprogramming effects on innate inflammation response. PMID- 27461981 TI - Australian primary health care nurses most and least satisfying aspects of work. AB - AIMS AND OBJECTIVES: To identify the aspects of working in Australian primary health care that nurses rate as the most and least satisfying. BACKGROUND: The nursing workforce in Australian primary health care has grown exponentially to meet the growing demand for health care. To maintain and further growth requires the recruitment and retention of nurses to this setting. Understanding the factors that nurses' rate as the most and least satisfying about their job will inform strategies to enhance nurse retention. DESIGN: A cross-sectional online survey. METHOD: Nurses employed in primary health care settings across Australia were recruited (n = 1166) to participate in a survey which combined items related to the respondent, their job, type of work, clinical activities, job satisfaction and future intention, with two open-ended items about the most and least satisfying aspects of their work. RESULTS: Patient interactions, respect, teamwork, collegiality and autonomy were identified as the most satisfying professional aspects of their role. Personal considerations such as family friendly work arrangements and a satisfactory work-life balance were also important, overriding negative components of the role. The least satisfying aspects were poor financial support and remuneration, lack of a career path, physical work environment and time constraints. National restructuring of the primary health care environment was seen as a barrier to role stability and ability to work to a full scope of practice. CONCLUSIONS: This study has identified a range of positive and negative professional and personal aspects of the primary health care nursing role, which may impact on staff recruitment and retention. Findings from the study should be considered by employers seeking to retain and maximise the skills of their primary health care workforce. RELEVANCE TO CLINICAL PRACTICE: Understanding the factors that nurses perceive as being the most and least satisfying aspects of the work is can open up dialogue about how to improve the working experience of nurses in primary health care. PMID- 27461982 TI - [Partial anomalous pulmonary venous connection in children, a challenging diagnose in pediatric cardiology]. PMID- 27461983 TI - Successful transradial antegrade recanalization of a chronic total occlusion of an anomalous circumflex artery arising from the right sinus of Valsalva. PMID- 27461984 TI - [Assessment of body composition and prognosis in chronic heart failure. Beyond the "obesity paradox"]. AB - OBJECTIVE: It is unknown the influence of body composition in the inverse relationship of mortality with overweight and obesity in heart failure patients. METHODS: 234 patients with chronic heart failure were evaluated. Body mass index, tricipital skinfold thickness, brachial muscle circumference and body fat percentage determined by bioelectrical impedance analysis were measured. The influence of previous anthropometric variables on total mortality was analyzed. RESULTS: Mean follow-up was 21+/-10.7 months. We observed an inverse relationship of total mortality with body mass index (hazard ratio=0.91, 95% confidence interval, 0.87-0.96; P<.001), with body fat estimated by the tricipital skinfold thickness (hazard ratio=0.95, 95% confidence interval, 0.92-0.99; P=.013) and the fat percentage obtained by bioelectrical impedance analysis (hazard ratio=0.96; 95% confidence interval, 0.93-0.99; P=.007) and with muscle mass estimated by the brachial muscle circumference (hazard ratio=0.87; 95% confidence interval,0.81 0.94; P=.001). Only brachial muscle circumference maintained its prognostic significance in multivariate analysis that included different anthropometric measurements (hazard ratio=0.88, 95% confidence interval 0.77-0.99; P=.035). Finally we found a positive linear correlation between the values of body mass index with tricipital skinfold thickness, fat percentage and brachial muscle circumference. CONCLUSIONS: The muscle mass of patients with heart failure, estimated by the brachial muscle circumference, is associated inversely with overall mortality. The correlation between values of brachial muscle circumference with the body mass index would explain the "obesity paradox" observed. PMID- 27461985 TI - Intensified Springtime Deep Convection over the South China Sea and the Philippine Sea Dries Southern China. AB - Springtime rainfall, accounting for 25-40% of the annual rainfall in southern China, exerts great agricultural and socioeconomic impacts on the region. In the recent decades, southern China has experienced a significant declining trend of precipitation in boreal spring. Meanwhile, precipitation has increased over the South China Sea and the Philippine Sea (SCS-PhS). This paper presents observational and modeling evidences suggesting that the intensified latent heating released by the convection over SCS-PhS leads to suppressed springtime rainfall over southern China. Moisture budget analysis indicates that the drying trend over southern China is due mainly to weakened convergence of moisture flux, which is controlled by a heat-induced anomalous overturning circulation reinforced by the convection over SCS-PhS. Further idealized simulations support the feature that the heat-induced overturning circulation and its corresponding anomalous cyclone can be well established in several days under the spring mean flow condition. Thus, this rapid dynamic process is associated with both the intraseasonal-to-interannual variations and the long-term change of the springtime rainfall over southern China. PMID- 27461986 TI - Qualitative research in Spanish cannabis social clubs: "The moment you enter the door, you are minimising the risks". AB - BACKGROUND: Cannabis social clubs (CSCs) in Spain are non-profit organisations that connect regular adult cannabis users. One of their functions is to supply cannabis to the closed circuit of members. The CSCs do not breach any international treaties. The aim of the paper is to present the findings of a qualitative study among Spanish CSCs in order to assess their potential for minimising the harm resulting from cannabis use (such as respiratory and mental health risks, the risk of dependence, and social risks). METHOD: A convenience sample of 11 CSCs was selected from four regions of Spain - the Basque country, Catalonia, the Balearic Islands, and Galicia. 94 respondents took part in 14 focus groups (FGs). The number of participants in a FG ranged from two to 12. A semi-structured interview guide and a structured questionnaire were used in the FG. FINDINGS: Members described a variety of risk minimising features of the CSCs: the availability of a quality product and mechanisms for its control, availability of different strains of cannabis and knowledge about their different psychoactive effects, increased control over personal cannabis use, informal information sharing and interaction, reduced stigma, and reduced criminal risks. CONCLUSIONS: The fact that the CSCs have no incentive to increase members' consumption means that they should be considered to be feasible spaces for the implementation of public health policies. Policy objectives could include a requirement that CSC members have control over the quality of cannabis, that different strains of cannabis are available together with information on their effects, that quantity of cannabis at intake is restricted and planned for each member, and that harm minimisation activities are both formally and informally implemented in the clubs. PMID- 27461987 TI - Metal-Organic-Framework-Derived Mesoporous Carbon Nanospheres Containing Porphyrin-Like Metal Centers for Conformal Phototherapy. AB - Mesoporous carbon nanospheres containing porphyrin-like metal centers (denoted as "PMCS") are successfully synthesized by the pyrolysis of an imidazolate framework using a mesoporous-silica protection strategy. The PMCS allow infrared and photoacoustic imaging and synergetic photothermal therapy/photodynamic therapy derived from the porphyrin-like moieties, offering the possibility of real-time monitoring of therapeutic processes and image-guided precise conformal phototherapy. PMCS thus represent a novel multifunctional theranostic platform for improved treatment efficiencies. PMID- 27461988 TI - A survey among hospital specialists and pharmacists about biosimilars. PMID- 27461989 TI - Are we really tackling the "evidence-based medicine issue" in Alzheimer's disease? PMID- 27461990 TI - [Talk to them: Narrative care within a person-centered care framework]. AB - The aim of this paper is to highlight the importance of narrative care in the attention of older people who receive care in institutions, underlining how its use provides a better understanding of the Person Centered Care (PCC) model and valuable strategies to put it into practice. To achieve this goal, firstly, we describe the relevance of a narrative approach for understanding the experience of the old person who receive care in institutions, with regards to individual aspects as well as to her/his relationships with professionals and the institutional discourse which contextualize these relationships. Secondly, we specify different ways in which the use of narratives could have an impact on the improvement of the quality of attention and well-being of older people receiving care in institutions. PMID- 27461991 TI - Quantity and quality in medicine: lessons from the humble Pap. PMID- 27461992 TI - Barriers and facilitators to evaluation of health policies and programs: Policymaker and researcher perspectives. AB - Our research sought to identify the barriers and facilitators experienced by policymakers and evaluation researchers in the critical early stages of establishing an evaluation of a policy or program. We sought to determine the immediate barriers experienced at the point of initiating or commissioning evaluations and how these relate to broader system factors previously identified in the literature. We undertook 17 semi-structured interviews with a purposive sample of senior policymakers (n=9) and senior evaluation researchers (n=8) in Australia. Six themes were consistently raised by participants: political influence, funding, timeframes, a 'culture of evaluation', caution over anticipated results, and skills of policy agency staff. Participants also reflected on the dynamics of policy-researcher relationships including different motivations, physical and conceptual separation of the policy and researcher worlds, intellectual property concerns, and trust. We found that political and system factors act as macro level barriers to good evaluation practice that are manifested as time and funding constraints and contribute to organisational cultures that can come to fear evaluation. These factors then fed into meso and micro level factors. The dynamics of policy-researcher relationship provide a further challenge to evaluating government policies and programs. PMID- 27461993 TI - Composition dependence of charge and magnetic length scales in mixed valence manganite thin films. AB - Mixed-valence manganese oxides present striking properties like the colossal magnetoresistance, metal-insulator transition (MIT) that may result from coexistence of ferromagnetic, metallic and insulating phases. Percolation of such phase coexistence in the vicinity of MIT leads to first-order transition in these manganites. However the length scales over which the electronic and magnetic phases are separated across MIT which appears compelling for bulk systems has been elusive in (La1-yPry)1-xCaxMnO3 films. Here we show the in-plane length scale over which charge and magnetism are correlated in (La0.4Pr0.6)1-xCaxMnO3 films with x = 0.33 and 0.375, across the MIT temperature. We combine electrical transport (resistance) measurements, x-ray absorption spectroscopy (XAS), x-ray magnetic circular dichroism (XMCD), and specular/off-specular x-ray resonant magnetic scattering (XRMS) measurements as a function of temperature to elucidate relationships between electronic, magnetic and morphological structure of the thin films. Using off-specular XRMS we obtained the charge-charge and charge magnetic correlation length of these LPCMO films across the MIT. We observed different charge-magnetic correlation length for two films which increases below the MIT. The different correlation length shown by two films may be responsible for different macroscopic (transport and magnetic) properties. PMID- 27461994 TI - Biofabrication: a secret weapon to advance manufacturing, economies, and healthcare. PMID- 27461995 TI - Membrane-bound electron transport systems of an anammox bacterium: A complexome analysis. AB - Electron transport, or oxidative phosphorylation, is one of the hallmarks of life. To this end, prokaryotes evolved a vast variety of protein complexes, only a small part of which have been discovered and studied. These protein complexes allow them to occupy virtually every ecological niche on Earth. Here, we applied the method of proteomics-based complexome profiling to get a better understanding of the electron transport systems of the anaerobic ammonium-oxidizing (anammox) bacteria, the N2-producing key players of the global nitrogen cycle. By this method nearly all respiratory complexes that were previously predicted from genome analysis to be involved in energy and cell carbon fixation were validated. More importantly, new and unexpected ones were discovered. We believe that complexome profiling in concert with (meta)genomics offers great opportunities to expand our knowledge on bacterial respiratory processes at a rapid and massive pace, in particular in new and thus far poorly investigated non-model and environmentally-relevant species. PMID- 27461996 TI - The Science of Salt: A Regularly Updated Systematic Review of Salt and Health Outcomes (August to November 2015). AB - The purpose of this review was to systematically identify, summarize, and critically appraise studies on dietary salt relating to health outcomes that were published from August to November 2015. The search strategy was adapted from a previous systematic review on dietary salt and health. Overall, 15 studies were included in the review: one study assessed cardiovascular events, five studies assessed blood pressure or hypertension incidence, six studies assessed surrogate outcomes for cardiovascular or kidney diseases, and three studies assessed other outcomes (age-related cataracts, rheumatoid arthritis, and bone mineral density, respectively). Four studies were selected for detailed appraisal and commentary. PMID- 27461997 TI - Multiple testing corrections in quantitative proteomics: A useful but blunt tool. AB - Multiple testing corrections are a useful tool for restricting the FDR, but can be blunt in the context of low power, as we demonstrate by a series of simple simulations. Unfortunately, in proteomics experiments low power can be common, driven by proteomics-specific issues like small effects due to ratio compression, and few replicates due to reagent high cost, instrument time availability and other issues; in such situations, most multiple testing corrections methods, if used with conventional thresholds, will fail to detect any true positives even when many exist. In this low power, medium scale situation, other methods such as effect size considerations or peptide-level calculations may be a more effective option, even if they do not offer the same theoretical guarantee of a low FDR. Thus, we aim to highlight in this article that proteomics presents some specific challenges to the standard multiple testing corrections methods, which should be employed as a useful tool but not be regarded as a required rubber stamp. PMID- 27461998 TI - New record of Scedosporium dehoogii from Chile: Phylogeny and susceptibility profiles to classic and novel putative antifungal agents. AB - BACKGROUND: Scedosporium species are considered emerging agents causing illness in immunocompromised patients. In Chile, only Scedosporium apiospermum, Scedosporium boydii and Lomentospora prolificans haven been reported previously. AIMS: The study aimed to characterize genetically Scedosporium dehoogii strains from Chilean soil samples, and assessed the antifungal susceptibility profile to classic and novel putative antifungal molecules. METHODS: In 2014, several samples were obtained during a survey of soil fungi in urban areas from Chile. Morphological and phylogenetic analyses of the internal transcribed spacer region (ITS), tubulin (TUB), and calmodulin (CAL) sequences were performed. In addition, the susceptibility profiles to classic antifungal and new putative antifungal molecules were determined. RESULTS: Four strains of Scedosporium dehoogii were isolated from soil samples. The methodology confirmed the species (reported here as a new record for Chile). Antifungal susceptibility testing demonstrates the low activity of terpenes (alpha-pinene and geraniol) against this species. Voriconazole (VRC), posaconazole (PSC), and the hydroxyquinolines (clioquinol, and 5,7-dibromo-8-hydroxyquinoline) showed the best antifungal activity. CONCLUSIONS: Our results demonstrate that Scedosporium dehoogii is present in soil samples from Chile. This study shows also that hydroxyquinolines have potential as putative antifungal molecules. PMID- 27461999 TI - Nonoperative management of grade III blunt thoracic aortic injuries. AB - OBJECTIVE: Blunt thoracic aortic injuries (BTAIs) have historically been treated with open surgery; thoracic endovascular aortic repair (TEVAR), however, is rapidly becoming the standard of care for all grades of injury. Previous studies have shown successful, conservative management of low-grade (I and II) BTAI, but limited literature exists regarding nonoperative management (NOM) for high-grade BTAI. The purpose of this study was to evaluate NOM for grade III BTAI compared with TEVAR. METHODS: There were 75 patients diagnosed with BTAI between January 2004 and June 2015. Of these, 40 were excluded for different grades of BTAI (17), death before any treatment (6), and need for urgent open repair (17). The remaining 35 patients were divided into two groups by treatment approach: NOM (n = 18) and TEVAR (n = 17). Primary end points were complications and mortality. The secondary end point was difference in pseudoaneurysm and aortic diameter measurements between groups. RESULTS: The groups of patients were similar in age, gender, Injury Severity Score, length of stay, in-hospital mortality, and hospital-associated complications. There were four TEVAR-related complications: graft involutions (2), type I endoleak (1), and distal embolization (1). All TEVAR-related complications required either an adjunctive procedure at the time of the primary procedure or an additional procedure. No patients from the NOM group required operative intervention. There were seven in-hospital mortalities: two in the TEVAR group (11.8%) and five in the NOM group (27.8%; P = .402). One death in the NOM group was related to aortic disease. Follow-up computed tomography imaging revealed similar aortic-related outcomes between groups, with a high proportion showing resolved or improved aortic injury (NOM, 87.5%; TEVAR, 92.9%; P = .674). Initial computed tomography imaging showed similar aortic diameters between groups. The average diameter of the aorta distal to the subclavian artery was 22.6 mm in the NOM group vs 22.8 mm in the TEVAR group (P = .85). The average maximum diameter of the pseudoaneurysm was 30.1 mm in the TEVAR group and 29.9 mm in the NOM group (P = .90). The average ratio of diameter of the pseudoaneurysm to diameter of the aorta distal to the subclavian artery was 1.32 for the TEVAR group and 1.33 for the NOM group (P = .85). CONCLUSIONS: The natural history of grade III BTAIs is not well described. This study suggests that observation and NOM of grade III BTAI may be a reasonable therapeutic option in selected patients. It also speaks to the need for further delineation of the natural history of this injury. Serial imaging and long-term follow-up are necessary to monitor the progression of the pseudoaneurysm. PMID- 27462000 TI - Contemporary comparison of aortofemoral bypass to alternative inflow procedures in the Veteran population. AB - OBJECTIVE: Multiple vascular inflow reconstruction options exist for claudication, including aortofemoral bypass (AFB) and alternative inflow procedures (AIPs) such as femoral reconstruction with iliac stents, and femoral femoral, iliofemoral, and axillofemoral bypass. Contemporary multi-institution comparison of these techniques is lacking. METHODS: The Veterans Affairs Surgical Quality Improvement Project (VASQIP) national database (2005-2013) was used to compare AFB vs AIP in a propensity-matched analysis. Primary outcome was mortality at 30 and 90 days. Secondary outcomes included rates of postoperative complications. Multivariable regression assessed the adjusted effect of inflow procedure type on mortality. RESULTS: A matched cohort of 748 claudicant patients (373 AFB, 375 AIP) was identified. The AFB and AIP groups had similar mean age (59.9 vs 60.8 years; P = .30), gender (P = .51), race (P = .52), recent smoking (79.1% vs 76.5%; P = .43), history of coronary artery disease (14.8% vs 14.7%; P > .99), chronic obstructive pulmonary disease (18.8% vs 18.4%; P = .92), renal insufficiency (5.9% vs 6.1%; P > .99), and diabetes (22% vs 20%; P = .53), and American Society of Anesthesiologists Physical Status Classification (P = .41). The AFB group had longer mean operative time (4.9 vs 3.5 hours; P < .0001), more senior resident assistants (72.4% vs 61.1%; P < .0001), and greater mean red blood cell transfusion (1.1 vs 0.12 units; P < .0001). AFB and AIP had similar rates of outflow bypass (1.9% vs 1.3%; P = .58) and outflow endovascular interventions (0.54% vs 1.6%; P = .29). AFB trended toward a higher rate of mortality at 30 days postoperatively (2.7% vs 0.8%; P = .06), but by 90 days, the crude mortality rates were similar for the two (2.9% vs 2.1%; P = .5). AFB had higher rates of pneumonia (5.9% vs 0.8%; P < .001), deep vein thrombosis/pulmonary embolism (1.3% vs 0%; P = .03), postoperative transfusion (2.7% vs 0.53%; P = .02), and urinary tract infection (3.5% vs 0.8%; P = .01), but similar rates of myocardial infarction (1.6% vs 0.8%; P = .34), stroke (0.8% vs 0%; P = .12), wound complications (13.1% vs 12.8%; P = .91), renal failure (1.1% vs 0.3%; P = .22), graft failure (1.3% vs 1.1%; P = .75), and return to the operating room (12.9% vs 9.6%; P = .17). Multivariable analysis showed AFB was not independently associated with mortality (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.1-3.0). Significant factors included age (OR, 1.2; 95% CI, 1.1-1.4), postoperative renal insufficiency (OR, 2.5; 95% CI, 1.6-4.0), and unplanned reintubation (OR, 35.5; 95% CI, 3.1-399). CONCLUSIONS: For claudicant patients with inflow disease, AFB has higher rates of 30-day complications and a trend toward higher mortality; however by 90 days postoperatively, the two procedure types have similar rates of mortality. PMID- 27462001 TI - Effectiveness and outcome of endovascular therapy for late-onset postpancreatectomy hemorrhage using covered stents and embolization. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical and long-term outcome of patients who underwent covered stent treatment because of late-onset postpancreatectomy hemorrhage in a greater number of patients. A secondary study goal was to compare embolization techniques with covered stents regarding differences in early and late clinical outcome, rebleeding, and vessel patency. METHODS: Between December 2008 and June 2015, 27 consecutive patients suffering from major hemorrhage after pancreatic surgery underwent either covered stent placement or embolization of the affected visceral artery. The patients' medical reports and radiologic images were retrospectively reviewed. The main study end point was technical and clinical success, including survival and complications; the secondary end points were perfusion distal to the target vessel and, for covered stent placement, patency of the affected artery. RESULTS: Covered stent placement was successful in 14 of 16 patients (88%); embolization was successful in 10 of 11 (91%) patients. For the embolization group, the overall 30-day and 1 year survival rate was 70%, and the 1- and 2-year survival rate was 56%; for the covered stent group, these rates were 81% and 74%, respectively. The 30-day patency of the covered stent was 84%, and 1-year patency was 42%; clinically relevant ischemia was observed in two patients. Infarction distal to the embolized vessel occurred in 6 of 11 patients (55%). CONCLUSIONS: Endovascular treatment using either covered stents or embolization techniques is an effective and safe emergency therapy for life-threatening postpancreatectomy hemorrhage with good clinical success rates and long-term results. Covered stent placement preserving vessel patency in the early postoperative phase should be preferred to embolization if it is technically feasible. PMID- 27462002 TI - Treatment of the femoropopliteal artery with the bioresorbable REMEDY stent. AB - OBJECTIVE: Bioresorbable stents are an emerging technology in the endovascular treatment of femoropopliteal lesions. They address the issue of leaving permanent stents in the treated arterial segment that are only temporarily needed to treat dissection or recoil. The REMEDY stent (Kyoto Medical Planning Co, Kyoto, Japan) was the first commercially available biodegradable scaffold for peripheral use. We evaluated its performance and safety in the treatment of short femoropopliteal stenosis or occlusion. METHODS: A prospective, multicenter, observational registry was set up of patients in Rutherford-Becker categories 2 to 5 with femoropopliteal lesions that could be treated with one REMEDY stent. Clinical examination and duplex ultrasound imaging were performed at 1, 6, and 12 months. The primary end point was absence of clinically driven target lesion revascularization at 12 months. Secondary end points were technical and clinical success, primary and secondary patency rate, clinically driven target vessel revascularization, major complications, and Rutherford-Becker classification at 6 and 12 months. RESULTS: The registry enrolled 99 patients between January 2011 and July 2013 in 12 centers in Belgium. Most lesions were determined as TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) A (n = 80) and located in the superficial femoral artery (n = 91). There were 19 total occlusions (mean length, 41.3 mm) and 80 stenoses (mean length, 37.5 mm). Technical success was achieved in 96 patients, and clinical success was obtained in 95. Target lesion revascularization, which equalled target vessel revascularization, was 19% at 6 months and rose to 33% at 12 months. Primary patency was 68% at 6 months and 58% at 12 months. Secondary patency was 85% at 6 months and 86% at 12 months. After 12 months, two patients had undergone an amputation. CONCLUSIONS: The 1-year follow-up results of the REMEDY stent do not meet current standards set by nitinol stents. Given the significant issues concerning bioresorbable stents in femoropopliteal arteries, their use outside clinical trials should be withheld until improvements are made and better data are available. PMID- 27462003 TI - Percutaneous intervention for carotid in-stent restenosis does not improve outcomes compared with nonoperative management. AB - BACKGROUND: The appropriateness of percutaneous intervention for moderate to severe carotid in-stent restenosis (C-ISR) is unclear. We therefore sought to compare stroke/death/myocardial infarction (MI) rates between percutaneous interventions and nonoperative management for >=50% C-ISR. METHODS: We performed a single-center retrospective review of consecutive patients presenting with >=50% C-ISR to the vascular surgery service. Demographics, comorbidities, and intraoperative and postoperative variables were obtained. The degree of stenosis was verified by review of digital subtraction or computed tomography angiograms. The primary outcome was stroke/death/MI after the diagnosis of >=50% C-ISR. chi2, Kruskal-Wallis, and Kaplan-Meier analysis was used to quantify outcomes of the patients treated percutaneously vs nonoperatively. RESULTS: During a 13-year period, 59 patients (75 C-ISRs) presented with >=50% C-ISRs (n = 58 male [98%]; n = 57 C-ISRs asymptomatic [76%]) with a median age of 67.5 years (62.8-74.6). The initial pathologic process underlying the original stent was atherosclerosis in 33 (70%), radiation induced in 10 (21%), prior carotid endarterectomy in 4 (9%), and unknown in 28 (37%). Forty C-ISRs underwent a percutaneous intervention (19 percutaneous angioplasty only [48%]; 21 repeated stent and percutaneous angioplasty [52%]). Median follow-up for the entire cohort was 948 days (283 2322) and similar between the intervention and nonintervention arms. There were no significant differences between the arms with respect to age (P = .16), medical comorbidities (P > .05), original stent type (P = .46), or clopidogrel use (P = .74). At 30 days, there was one stroke and subsequent death in the intervention arm and none in the nonintervention arm. During the follow-up period, a median of 1.0 procedure was required to maintain patency. By Kaplan Meier analysis, there were no statistically significant differences between the intervention and nonintervention arms with respect to stroke/death/MI as a composite or any of the individual components at last follow-up (P = .82). Kaplan Meier estimated patency was not significantly superior in the intervention vs the nonintervention arm (8.0 years +/- 1.1 vs 5.3 years +/- 0.7; P = .14). CONCLUSIONS: Over 13 years, percutaneous interventions for >=50% C-ISR were safe and durable. However, interventions fail to improve long-term stroke/death/MI or patency rates relative to nonintervention. Intervention for C-ISR may not be necessary, although future appropriately powered, prospective trials will be necessary to confirm these findings and to determine the appropriateness of interventions for C-ISR. PMID- 27462004 TI - Patient selection and perioperative outcomes are similar between targeted and nontargeted hospitals (in the National Surgical Quality Improvement Program) for abdominal aortic aneurysm repair. AB - OBJECTIVE: The targeted vascular module in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) consists of self-selected hospitals that choose to collect extra clinical details for better risk adjustment and improved procedure-specific outcomes. The purpose of this study was to compare patient selection and outcomes between targeted and nontargeted hospitals in the NSQIP regarding the operative management of abdominal aortic aneurysm (AAA). METHODS: We identified all patients who underwent endovascular aneurysm repair (EVAR) or open AAA repair from 2011 to 2013 and compared cases by whether the operation took place in a targeted or nontargeted hospital. EVAR and open repair as well as intact and ruptured aneurysms were evaluated separately. Only variables contained in both modules were used to evaluate rupture status and operation type. All thoracoabdominal aneurysms were excluded. Univariate analysis was performed for intact and ruptured EVAR and open repair grouped by complexity, defined as visceral involvement in open repair and a compilation of concomitant procedures for EVAR. Multivariable models were developed to identify effect of hospital type on mortality. RESULTS: There were 17,651 AAA repairs identified. After exclusion of aneurysms involving the thoracic aorta (n = 352), there were 1600 open AAA repairs at targeted hospitals (21% ruptured) and 2725 at nontargeted hospitals (19% ruptured) and 4986 EVARs performed at targeted hospitals (6.7% ruptured) and 7988 at nontargeted hospitals (5.2% ruptured). There was no significant difference in 30-day mortality rates between targeted and nontargeted hospitals for intact aneurysms (EVAR noncomplex, 1.8% vs 1.4% [P = .07]; open repair noncomplex, 4.2% vs 4.5% [P = .7]; EVAR complex, 5.0% vs 3.2% [P = .3]; open repair complex, 8.0% vs 6.0% [P = .2]). For ruptured aneurysms, again there was no difference in mortality between the targeted and nontargeted hospitals (EVAR noncomplex, 23% vs 25% [P = .4]; open repair noncomplex, 38% vs 34% [P = .2]; EVAR complex, 29% vs 33% [P = 1.0]; open repair complex, 27% vs 41% [P = .09]). Multivariable analysis further demonstrated that having an operation at a targeted vs nontargeted hospital had no impact on mortality for both intact and ruptured aneurysms (odds ratio, 1.1 [0.9-1.4] and 1.0 [0.8-1.3], respectively). CONCLUSIONS: This analysis highlights the similarities between targeted and nontargeted hospitals within the NSQIP for AAA operative management and suggests that data from the targeted NSQIP, in terms of AAA management, are generalizable to all NSQIP hospitals. PMID- 27462005 TI - Stable preparations of tyrosine hydroxylase provide the solution structure of the full-length enzyme. AB - Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of catecholamine neurotransmitters. TH is a highly complex enzyme at mechanistic, structural, and regulatory levels, and the preparation of kinetically and conformationally stable enzyme for structural characterization has been challenging. Here, we report on improved protocols for purification of recombinant human TH isoform 1 (TH1), which provide large amounts of pure, stable, active TH1 with an intact N-terminus. TH1 purified through fusion with a His-tagged maltose-binding protein on amylose resin was representative of the iron-bound functional enzyme, showing high activity and stabilization by the natural feedback inhibitor dopamine. TH1 purified through fusion with a His tagged ZZ domain on TALON is remarkably stable, as it was partially inhibited by resin-derived cobalt. This more stable enzyme preparation provided high-quality small-angle X-ray scattering (SAXS) data and reliable structural models of full length tetrameric TH1. The SAXS-derived model reveals an elongated conformation (Dmax = 20 nm) for TH1, different arrangement of the catalytic domains compared with the crystal structure of truncated forms, and an N-terminal region with an unstructured tail that hosts the phosphorylation sites and a separated Ala-rich helical motif that may have a role in regulation of TH by interacting with binding partners. PMID- 27462006 TI - In vitro stereoselective inhibition of ginsenosides toward UDP glucuronosyltransferase (UGT) isoforms. AB - We evaluated in vitro, the potential of the six pairs of ginsenoside isomers, stereoisomers at the chiral carbon on position 20, to inhibit the enzymatic activity of several UDP-glucuronosyltransferase (UGT) isoenzymes, major players in the human phase II drug metabolism. The results show that the tested six pairs of ginsenoside isomers exhibited stereoselective inhibitory effects of varying degrees on the ten UGT isoenzymes explored. Of the tested twelve stereoselective ginsenosides, 20(R)-Rg3 had the strongest inhibitory effect on the UGT1A8 isoform with the lowest IC50 value of 5.66+/-1.04MUM. On the other hand, the (S)-isomers of Rg3 and Rh2 also exerted remarkable inhibition on UGT1A8, with IC50 values of 6.89+/-0.812MUM and 5.85+/-0.821MUM, respectively. Although the inhibitory effect was low, both 20(R)-PPT and 20(S)-PPT also inhibited UGT1A8 activity. Considering 1) that the relative contents of 20(R)-Rg3 in processed ginseng are high, 2) that higher exposure to (R)-isomers of ginsenosides occur in the intestine compared to that in the liver, and 3) the inhibitory effects of other ginsenosides on enzymatic activity [20(S)-Rg3, 20(S)-Rh2, 20(R)- and 20(S)-PPT], there may be a potential for herb-drug interactions between processed ginseng and UGT1A8 substrates when concomitantly administered. PMID- 27462007 TI - Pathway Complexity in the Enantioselective Self-Assembly of Functional Carbonyl Bridged Triarylamine Trisamides. AB - Functional supramolecular systems like carbonyl-bridged triarylamine (CBT) trisamides are known for their long-range energy transport at room temperature. Understanding the complex self-assembly processes of this system allows for control over generated structures using controlled supramolecular polymerization. Here, we present two novel CBT trisamides with (S)- or (R)-chiral side chains which show a two-pathway self-assembly behavior in solution. Depending on the thermal profile during the self-assembly process, two different stable states are obtained under otherwise identical conditions. A kinetically trapped state A is reached upon cooling to 7 degrees C, via a proposed isodesmic process. In addition, there is a thermodynamically stable state B at 7 degrees C that is induced by first undercooling to -5 degrees C, via a nucleation-elongation mechanism. In both cases, helical supramolecular aggregates comprising H aggregated CBTs are formed. Additionally, controlled supramolecular polymerization was achieved by mixing the two different states (A and B) from the same enantiomer, leading to a conversion of the kinetically trapped state to the thermodynamically stable state. This process is highly enantioselective, as no conversion is observed if the two states consist of opposite enantiomers. We thus show the importance and opportunities emerging from understanding the pathway complexity of functional supramolecular systems. PMID- 27462008 TI - Underdamped scaled Brownian motion: (non-)existence of the overdamped limit in anomalous diffusion. AB - It is quite generally assumed that the overdamped Langevin equation provides a quantitative description of the dynamics of a classical Brownian particle in the long time limit. We establish and investigate a paradigm anomalous diffusion process governed by an underdamped Langevin equation with an explicit time dependence of the system temperature and thus the diffusion and damping coefficients. We show that for this underdamped scaled Brownian motion (UDSBM) the overdamped limit fails to describe the long time behaviour of the system and may practically even not exist at all for a certain range of the parameter values. Thus persistent inertial effects play a non-negligible role even at significantly long times. From this study a general questions on the applicability of the overdamped limit to describe the long time motion of an anomalously diffusing particle arises, with profound consequences for the relevance of overdamped anomalous diffusion models. We elucidate our results in view of analytical and simulations results for the anomalous diffusion of particles in free cooling granular gases. PMID- 27462010 TI - Textiloma: A forgotten diagnosis. PMID- 27462009 TI - A randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy and safety of oral salmon calcitonin in the treatment of osteoporosis in postmenopausal women taking calcium and vitamin D. AB - This randomized, double-blind, placebo-controlled phase III study was conducted to assess the efficacy and safety of oral calcitonin (SMC021) for the treatment of postmenopausal osteoporosis. A total of 4665 postmenopausal women with osteoporosis were randomized 1:1 to receive calcium and vitamin D plus either SMC021 tablets (0.8mg/d) or placebo for 36months. The primary endpoint was the proportion of patients with a new vertebral fracture. The two groups were well balanced at baseline with regards to demographic and clinical data. No effect of SMC021 on preventing new vertebral fractures was observed, nor was any effect seen on new hip or non-vertebral fractures. Women receiving SMC021 had a mean 1.02% (+/-0.12%) increase in lumbar spine bone mineral density (BMD) compared with a mean 0.18% (+/-0.12%) increase in the placebo group by the end of the study (p<0.0001). Similarly, small increases in BMD were observed at the femoral neck and hip in both groups. Levels of the biomarkers of bone turnover, urinary CTX-I and CTX-II, were 15% lower in the SMC021 group than in the placebo arm at 12 and 24months, but not at 36months. No change in quality of life between groups, assessed by the Qualeffo-14 questionnaire, was observed in either group between baseline and month 36. Pharmacokinetics analysis confirmed exposure to SMC021, but the drug levels were markedly lower than expected. Approximately 92% of subjects in each treatment group experienced an adverse event (AE), the majority of which were mild or moderate in intensity. AEs associated with SMC021 were primarily of gastrointestinal origin and included nausea, vomiting and abdominal pain, as well as hot flushes which were the reason for the slightly higher drop-out rate in the active treatment arm compared to placebo. The number of severe AEs was low in both groups. Thirty-five deaths were reported but none were considered treatment-related. Due to the lack of efficacy in preventing fractures, the development of the orally formulated calcitonin was terminated despite the promising results in earlier studies. PMID- 27462012 TI - Functional fun: Legitimising adult recreational drug use. AB - BACKGROUND: Recent statistics from the Crime Survey for England and Wales report a slight increase in past year drug use for the over thirty-age range (Home Office, 2014). This paper explores how adult 'recreational' drug takers account for their illicit consumption alongside otherwise conforming lives. METHODS: Twenty-six in-depth interviews were conducted with individuals between the ages of 30 and 59. Each participant had taken drugs in the past year, their main source of income was not a result of criminal activity and they were not currently receiving drug treatment. Discursive Psychology was used to analyse how the participants describe, reason and justify their use. RESULTS: The analysis resulted in the development of three discursive frameworks that demonstrate the different ways in which illicit drug use can be legitimised. The 'drug cultures' framework achieves this through highlighting the accommodation of drugs within social networks. The 'planned celebration' framework outlines the occasional frequency of drug use to legitimise consumption. The 'situational opportunity' framework positions the wide access and availability of drugs as the influence of their behaviour. CONCLUSION: If drug takers can articulate their ability to control their use and maintain functionality within their lives, then both drug taker and drug use may be legitimated. In order to better understand the conceptualisation of drug use and the acceptable boundaries of behaviour, this research has demonstrated that it is more appropriate to conceptualise drug use on a spectrum that runs from control through to dysfunction, rather than either recreational or problematic. PMID- 27462013 TI - Electric-Field-Induced Degradation of Methylammonium Lead Iodide Perovskite Solar Cells. AB - Perovskite solar cells have great potential for high efficiency generation but are subject to the impact of external environmental conditions such as humidity, UV and sun light, temperature, and electric fields. The long-term stability of perovskite solar cells is an important issue for their commercialization. Various studies on the stability of perovskite solar cells are currently being performed; however, the stability related to electric fields is rarely discussed. Here the electrical stability of perovskite solar cells is studied. Ion migration is confirmed using the temperature-dependent dark current decay. Changes in the power conversion efficiency according to the amount of the external bias are measured in the dark, and a significant drop is observed only at an applied voltage greater than 0.8 V. We demonstrate that perovskite solar cells are stable under an electric field up to the operating voltage. PMID- 27462015 TI - Brains and Beyond: The Unfolding Vision of Health and Healing. PMID- 27462014 TI - Bloodstain pattern analysis as optimisation problem. AB - Bloodstain pattern analysis (BPA) is an approach to support forensic investigators in reconstructing the dynamics of bloody crimes. This forensic technique has been successfully applied in solving heinous and complex murder cases around the world and, recently, computer-based BPA approaches have been designed to better support investigators both in terms of speed and quality of analysis. However, despite its widespread use, current automatic techniques for BPA try to define some algorithmic steps to replicate a sequence of subjective investigators' tasks without relying on any mathematical formalism to compute an objective reconstruction of the crime. The lack of an objective mathematical foundation is a critical issue in a scenario where the quality of evidences can strongly affect a court trial and the life of people involved in that trial. This paper introduces the very first formal representation of BPA by means of an optimisation problem, on which to base the next generation of crime reconstruction techniques. As an example of the benefits provided by the proposed formal representation of BPA, a case study based on a genetic algorithm shows how the BPA optimisation problem can support investigators in performing a fast, precise, automatic and objective analysis. PMID- 27462016 TI - Therapeutic application of extracellular vesicles in acute and chronic renal injury. AB - A new cell-to-cell communication system was discovered in the 1990s, which involves the release of vesicles into the extracellular space. These vesicles shuttle bioactive particles, including proteins, mRNA, miRNA, metabolites, etc. This particular communication has been conserved throughout evolution, which explains why most cell types are capable of producing vesicles. Extracellular vesicles (EVs) are involved in the regulation of different physiological processes, as well as in the development and progression of several diseases. EVs have been widely studied over recent years, especially those produced by embryonic and adult stem cells, blood cells, immune system and nervous system cells, as well as tumour cells. EV analysis from bodily fluids has been used as a diagnostic tool for cancer and recently for different renal diseases. However, this review analyses the importance of EVs generated by stem cells, their function and possible clinical application in renal diseases and kidney transplantation. PMID- 27462017 TI - Practical application of stereological methods in experimental kidney animal models. AB - The kidneys are vital organs responsible for excretion, fluid and electrolyte balance and hormone production. The nephrons are the kidney's functional and structural units. The number, size and distribution of the nephron components contain relevant information on renal function. Stereology is a branch of morphometry that applies mathematical principles to obtain three-dimensional information from serial, parallel and equidistant two-dimensional microscopic sections. Because of the complexity of stereological studies and the lack of scientific literature on the subject, the aim of this paper is to clearly explain, through animal models, the basic concepts of stereology and how to calculate the main kidney stereological parameters that can be applied in future experimental studies. PMID- 27462018 TI - Effects of different ligands on epidermal growth factor receptor (EGFR) nuclear translocation. AB - The epidermal growth factor receptor (EGFR) is activated through binding to specific ligands and generates signals for proliferation, differentiation, migration, and cell survival. Recent data show the role of nuclear EGFR in tumors. Although many EGFR ligands are upregulated in cancers, little is known about their effects on EGFR nuclear translocation. We have compared the effects of six EGFR ligands (EGF, HB-EGF, TGF-alpha, beta-Cellulin, amphiregulin, and epiregulin) on nuclear translocation of EGFR, receptor phosphorylation, migration, and proliferation. Cell fractionation and confocal immunofluorescence detected EGFR in the nucleus after EGF, HB-EGF, TGF-alpha and beta-Cellulin stimulation in a dose-dependent manner. In contrast, amphiregulin and epiregulin did not generate nuclear translocation of EGFR. EGF, HB-EGF, TGF-alpha and beta Cellulin showed correlations between a higher rate of wound closure and increased phosphorylation of residues in the carboxy-terminus of EGFR, compared to amphiregulin and epiregulin. The data indicate that EGFR is translocated to the nucleus after stimulation with EGF, HB-EGF, TGF-alpha and beta-Cellulin, and that these ligands are related to increased phosphorylation of EGFR tyrosine residues, inducing migration of SkHep-1 cells. PMID- 27462019 TI - Elevated expression of WWP2 in human lung adenocarcinoma and its effect on migration and invasion. AB - Lung cancer has been a hot area of research because of its high incidence and mortality. In this study, WWP2, an E3 ubiquitin ligase, is proposed to be an oncoprotein contributing to lung tumorigenesis. We attempted to determine if WWP2 gene expression is correlated with the development of human lung adenocarcinoma. Real-time PCR and western blotting were used to detect the expression of WWP2 in 65 paired lung adenocarcinoma and adjacent normal lung tissues. We found that WWP2 expression was elevated in lung adenocarcinoma tissues and was correlated with the tumor differentiation stage, TNM stage and presence of lymph node metastasis. We performed CCK-8 and colony formation assays and found that down regulation of WWP2 inhibited proliferation in A549 and SPC-A-1 cells. A wound healing assay and trans-well invasion assays showed that down-regulation of WWP2 inhibited the migration and invasion of lung adenocarcinoma cells. It could be predicted from these data that elevated expression of WWP2 may play a role in facilitating the development of lung adenocarcinoma. PMID- 27462020 TI - Glycyrrhizic acid prevents astrocyte death by neuromyelitis optica-specific IgG via inhibition of C1q binding. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system and is mediated by complement-dependent cytotoxicity (CDC) of NMO-specific immunoglobulin G (IgG) antibodies (NMO-IgG). Glycyrrhizic acid (GA) has numerous pharmacological effects including inhibition of the complement pathway. We aimed to study the influence of GA on NMO-IgG-induced CDC. NMO-IgG samples from 7 patients with NMO, together with human complement, induced CDC in an aquaporin 4 M23-overexpressing glial cell line, an in vitro NMO model. GA attenuated NMO-IgG-induced CDC in a dose-dependent manner. The mechanism of the GA-related CDC inhibition was sequentially dissected and found to involve inhibition of C1q binding to NMO-IgG. Consequently, GA attenuates NMO-IgG-induced CDC and may be a promising novel therapeutic agent against NMO. PMID- 27462021 TI - Designer interface peptide grafts target estrogen receptor alpha dimerization. AB - The nuclear transcription factor estrogen receptor alpha (ERalpha), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERalpha is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERalpha dimerization is therefore a complementary and alternative strategy to combat anti estrogen resistance. Dimer interface peptide "I-box" derived from ER residues 503 518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERalpha LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERalpha residues 479-485), LQQQHQRLAQ (residues 497-506), and LSHIRHMSNK (residues 511-520) and reported the suitability of using LQQQHQRLAQ (ER 497-506) as a template to design inhibitors of ERalpha dimerization. Stability and self aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERalpha mediated activity in silico and in vitro. The Grafted peptides blocked ERalpha mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. PMID- 27462022 TI - ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells. AB - Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, we examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co regulators that may determine the final outcome of AR function. PMID- 27462023 TI - Methylene blue intra-arterial staining of resected colorectal cancer specimens improves accuracy of nodal staging: A randomized controlled trial. AB - INTRODUCTION: Metastatic involvement of regional lymph nodes is a major prognostic factor of colorectal cancer, which influences also its treatment strategy. International consensus foresees retrieval of >=12 lymph nodes from colorectal specimens. The aim of the study was to assess the effect of intra arterial staining of colorectal specimens with methylene blue on lymph node harvest. MATERIALS AND METHODS: A total of 266 radically operated colorectal cancer patients were randomized into the methylene blue staining and non-staining groups. In the staining group, methylene blue solution was injected into the colorectal specimen's artery after its removal. The specimens were analysed for lymph node count, diameter and metastatic involvement. RESULTS: The median number of lymph nodes was higher in the staining group, 27 (95% CI 23-31%), compared with the control group, 16 (95% CI 14-19, p < 0.001). The number of examined lymph-nodes was >=12 in 86% of the cases in the staining group and in 69% of the cases in the control group (p = 0.001). In the staining group more small-diameter (<=4 mm) lymph nodes were examined (median number 20.5 vs. 10, p < 0.001). The proportion of patients with metatatic lymph nodes was 42% in the staining group and 43% in the control group (NS). CONCLUSIONS: Methylene blue staining improves significantly staging accuracy through finding more small-diameter lymph nodes. It enables to detect >=12 lymph nodes in the majority of cases. We recommend routine use of this technique in all colorectal resections with curative intent. PMID- 27462024 TI - Prognosis of patients with esophageal squamous cell carcinoma who achieve major histopathological response after neoadjuvant chemoradiotherapy. AB - BACKGROUND: The purpose of this study was to investigate the prognosis and its predictors in patients with esophageal squamous cell carcinoma (ESCC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT). METHODS: We examined a total of 187 ESCC patients who achieved MaHR following nCRT and survived the perioperative period. MaHR was defined as either absence or <10% vital residual tumor cells (VRTC) in the resected esophagus without nodal involvement. Univariate and multivariate analyses were used to identify factors significantly associated with overall survival (OS). RESULTS: At the time of analysis, 113 patients (60.4%) were dead (5-year OS = 48%; median survival time = 54.8 months). The amount of VRTC (1-10% versus 0% VRTC; hazard ratio [HR] = 1.9, P < 0.001) and the thoroughness of histopathological examination (standard [<= 4 tumor blocks] versus thorough [> 4 tumor blocks], HR = 1.57; P = 0.013) were independent predictors of OS in multivariate analysis. A stepwise increase in OS was observed in the following groups: patients with 1-10% VRTC identified by the standard protocol, patients with 1-10% VRTC identified by the thorough protocol, patients with 0% VRTC identified by the standard protocol, and patients with 0% VRTC identified by the thorough protocol (5-year OS rates = 20%, 40%, 50%, and 62%, respectively, P < 0.001). CONCLUSIONS: In ESCC patients who achieve MaHR after nCRT, the presence of microscopical residual disease and the thoroughness of histopathological examination are associated with survival. PMID- 27462025 TI - Spontaneous formation of spiral-like patterns with distinct periodic physical properties by confined electrodeposition of Co-In disks. AB - Spatio-temporal patterns are ubiquitous in different areas of materials science and biological systems. However, typically the motifs in these types of systems present a random distribution with many possible different structures. Herein, we demonstrate that controlled spatio-temporal patterns, with reproducible spiral like shapes, can be obtained by electrodeposition of Co-In alloys inside a confined circular geometry (i.e., in disks that are commensurate with the typical size of the spatio-temporal features). These patterns are mainly of compositional nature, i.e., with virtually no topographic features. Interestingly, the local changes in composition lead to a periodic modulation of the physical (electric, magnetic and mechanical) properties. Namely, the Co-rich areas show higher saturation magnetization and electrical conductivity and are mechanically harder than the In-rich ones. Thus, this work reveals that confined electrodeposition of this binary system constitutes an effective procedure to attain template-free magnetic, electric and mechanical surface patterning with specific and reproducible shapes. PMID- 27462026 TI - Evaluation of preclinical formulations for a poorly water-soluble compound. AB - One central aim of the present work was to find a robust oral formulation approach for Compound A, both to achieve reliable pharmacodynamic read outs but also for long time safety assessment studies. The compound has low aqueous solubility (0.4MUM at 37 degrees C), is highly lipophilic and has high Caco-2 permeability, i.e. a typical BCS II compound. A nanocrystal formulation, some oil approaches and a fat diet approach were evaluated in vivo in rats. The two latter strategies resulted in significantly higher in vivo exposures after oral administration compared to the nanocrystal approach. For simplicity, and due to the project development program, a food pellet formulation was selected. In addition, tentative data from a subcutaneous study in mice using nanocrystals of the compound are presented, showing extended profiles on the cost of Cmax. Exposure data in monkeys after administration of nanocrystals both intravenously and per oral are presented. When switched from nanocrystals to an oil formulation, the observed oral exposure behavior was similar as observed in rats. PMID- 27462027 TI - Lung cancer risk assessment at receptor site of a waste-to-energy plant. AB - The toxicity of particulate matter emitted from waste-to-energy plants, is associated to the compounds attached to the particles, several of which have been classified by the International Agency for Research on Cancer (IARC) in the Group 1 carcinogens. In this paper a modified risk-assessment model, deriving from an existing one, was applied to estimate the lung cancer risk related to both ultrafine and coarse particles emitted from an incinerator whose people living nearby are exposed to. To this end, the measured values of Polycyclic Aromatic Hydrocarbons (PAHs), heavy metals (As, Cd, Ni) and PCDD/Fs (Polychlorinated dibenzodioxins/furans) emitted from an incinerator placed in Italy were used to calculate the Excess Lifetime Cancer Risk (ELCR) at the stack of the plant. The estimated ELCR was then used as input data in a numerical CFD (Computational Fluid Dynamics) model that solves the mass, momentum, turbulence and species transport equations to study the influence of wind speed and chimney height on the ELCR at receptor sites. Furthermore, combining meteorological data (wind speed and direction), and hypothesizing different exposure scenarios on the basis of time-activity patterns of people living nearby the plant, specific risk maps were obtained by evaluating ELCR around the incinerator. Results show that with the increasing of wind speed, the ELCR value downwind at the plant decreases and its point of maximum risk becomes closer to the stack. On the other hand, increasing the stack height decreases the ELCR, moving away from the stack the point of maximum risk. Finally, the risk maps for people living or working nearby the plant have highlighted that the excess risk of lung cancer due to the presence of the incinerator is below the WHO target (1*10(-5)). PMID- 27462028 TI - Heat management strategies for MSW landfills. AB - Heat is a primary byproduct of landfilling of municipal solid waste. Long-term elevated temperatures have been reported for MSW landfills under different operational conditions and climatic regions around the world. A conceptual framework is presented for management of the heat generated in MSW landfills. Three main strategies are outlined: extraction, regulation, and supplementation. Heat extraction allows for beneficial use of the excess landfill heat as an alternative energy source. Two approaches are provided for the extraction strategy: extracting all of the excess heat above baseline equilibrium conditions in a landfill and extracting only a part of the excess heat above equilibrium conditions to obtain target optimum waste temperatures for maximum gas generation. Heat regulation allows for controlling the waste temperatures to achieve uniform distribution at target levels at a landfill facility. Two approaches are provided for the regulation strategy: redistributing the excess heat across a landfill to obtain uniform target optimum waste temperatures for maximum gas generation and redistributing the excess heat across a landfill to obtain specific target temperatures. Heat supplementation allows for controlling heat generation using external thermal energy sources to achieve target waste temperatures. Two approaches are provided for the supplementation strategy: adding heat to the waste mass using an external energy source to increase waste temperatures and cooling the waste mass using an external energy source to decrease waste temperatures. For all strategies, available landfill heat energy is determined based on the difference between the waste temperatures and the target temperatures. Example analyses using data from landfill facilities with relatively low and high heat generation indicated thermal energy in the range of 48.4 to 72.4MJ/m(3) available for heat management. Further modeling and experimental analyses are needed to verify the effectiveness and feasibility of design, installation, and operation of heat management systems in MSW landfills. PMID- 27462029 TI - Prevalence of Respiratory Protective Devices in U.S. Health Care Facilities: Implications for Emergency Preparedness. AB - An online questionnaire was developed to explore respiratory protective device (RPD) prevalence in U.S. health care facilities. The survey was distributed to professional nursing society members in 2014 and again in 2015 receiving 322 and 232 participant responses, respectively. The purpose of this study was to explore if the emergency preparedness climate associated with Ebola virus disease changed the landscape of RPD use and awareness. Comparing response percentages from the two sampling time frames using bivariate analysis, no significant changes were found in types of RPDs used in health care settings. N95 filtering facepiece respirators continue to be the most prevalent RPD used in health care facilities, but powered air-purifying respirators are also popular, with regional use highest in the West and Midwest. Understanding RPD use prevalence could ensure that health care workers receive appropriate device trainings as well as improve supply matching for emergency RPD stockpiling. PMID- 27462030 TI - Occupational Functionality: A Concept Analysis. AB - Occupational health nursing has evolved since the late 19th century and, with the inclusion of advanced practice nursing, has become essential to the health and safety of workers. A key component of the knowledge required of advanced practice occupational health nurses is an understanding of what it means for workers to be fit for duty The definition or concept of being fit for duty varies depending on the point-of-view of the health care provider. Health care providers across all professions must have a consistent understanding of what it means to be fit for duty Literature shows that professions and specialties that often collaborate have varying ideas about what it means to be fit for duty These differences highlight the need for a consistent concept that can be used across professions, is holistic, and incorporates other concepts critical to all points of view. To better understand fit for duty, a concept analysis, using the Walker and Avant framework, focused on the concept of occupational functionality (OF). Occupational functionality is best defined as the qualities of being suited to serve an occupational purpose efficiently and effectively within the physical, occupational, environmental, and psychological demands of a unique work setting. This concept analysis offers an initial step in understanding fit for duty and gives health care providers a concept that can be used across disciplines. PMID- 27462031 TI - Occupational Functionality: A Concept Analysis. PMID- 27462033 TI - Evolutionary Endocrinology: Hormones as Mediators of Evolutionary Phenomena: An Introduction to the Symposium. PMID- 27462034 TI - Are Migratory Animals Superspreaders of Infection? AB - Migratory animals are simultaneously challenged by the physiological demands of long-distance movements and the need to avoid natural enemies including parasites and pathogens. The potential for animal migrations to disperse pathogens across large geographic areas has prompted a growing body of research investigating the interactions between migration and infection. However, the phenomenon of animal migration is yet to be incorporated into broader theories in disease ecology. Because migrations may expose animals to a greater number and diversity of pathogens, increase contact rates between hosts, and render them more susceptible to infection via changes to immune function, migration has the potential to generate both "superspreader species" and infection "hotspots". However, migration has also been shown to reduce transmission in some species, by facilitating parasite avoidance ("migratory escape") and weeding out infected individuals ("migratory culling"). This symposium was convened in an effort to characterize more broadly the role that animal migrations play in the dynamics of infectious disease, by integrating a range of approaches and scales across host taxa. We began with questions related to within-host processes, focusing on the consequences of nutritional constraints and strenuous movement for individual immune capability, and of parasite infection for movement capacity. We then scaled-up to between-host processes to identify what types, distances, or patterns of host movements are associated with the spread of infectious agents. Finally, we discussed landscape-scale relationships between migration and infectious disease, and how these may be altered as a result of anthropogenic changes to climate and land use. We are just beginning to scratch the surface of the interactions between infection and animal migrations; yet, with so many migrations now under threat, there is an urgent need to develop a holistic understanding of the potential for migrations to both increase and reduce infection risk. PMID- 27462035 TI - Baseline Functioning and Stress Reactivity in Maltreating Parents and At-Risk Adults: Review and Meta-Analyses of Autonomic Nervous System Studies. AB - We reviewed and meta-analyzed 10 studies ( N = 492) that examined the association between (risk for) child maltreatment perpetration and basal autonomic activity, and 10 studies ( N = 471) that examined the association between (risk for) child maltreatment and autonomic stress reactivity. We hypothesized that maltreating parents/at-risk adults would show higher basal levels of heart rate (HR) and skin conductance (SC) and lower levels of HR variability (HRV) and would show greater HR and SC stress reactivity, but blunted HRV reactivity. A narrative review showed that evidence from significance testing within and across studies was mixed. The first set of meta-analyses revealed that (risk for) child maltreatment was associated with higher HR baseline activity ( g = 0.24), a possible indication of allostatic load. The second set of meta-analyses yielded no differences in autonomic stress reactivity between maltreating/at-risk participants and nonmaltreating/low-risk comparison groups. Cumulative meta analyses showed that positive effects for sympathetic stress reactivity as a risk factor for child maltreatment were found in a few early studies, whereas each subsequently aggregated study reduced the combined effect size to a null effect, an indication of the winner's curse. Most studies were underpowered. Future directions for research are suggested. PMID- 27462037 TI - Marked enlargement of neck circumference from nerve hypertrophy in CIDP. PMID- 27462036 TI - Meta-analysis of the Interval between the Onset and Management of Bipolar Disorder. AB - OBJECTIVE: To evaluate the length of the interval between the onset and the initial management of bipolar disorder (BD). METHOD: We conducted a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Systematic searches located studies reporting estimates of the age of onset (AOO) and indicators of the age at initial management of BD. We calculated a pooled estimate of the interval between AOO and age at management. Factors influencing between-study heterogeneity were investigated using sensitivity analyses, meta-regression, and multiple meta-regression. RESULTS: Twenty-seven studies, reporting 51 samples and a total of 9415 patients, met the inclusion criteria. The pooled estimate for the interval between the onset of BD and its management was 5.8 years (standardized difference, .53; 95% confidence interval, .45 to .62). There was very high between-sample heterogeneity ( I2 = 92.6; Q = 672). A longer interval was found in studies that defined the onset according to the first episode (compared to onset of symptoms or illness) and defined management as age at diagnosis (rather than first treatment or first hospitalization). A longer interval was reported among more recently published studies, among studies that used a systematic method to establish the chronology of illness, among studies with a smaller proportion of bipolar I patients, and among studies with an earlier mean AOO. CONCLUSIONS: There is currently little consistency in the way researchers report the AOO and initial management of BD. However, the large interval between onset and management of BD presents an opportunity for earlier intervention. PMID- 27462038 TI - Serial arterial spin labeling MRI in autonomic status epilepticus due to anti LGI1 encephalitis. PMID- 27462039 TI - Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. PMID- 27462040 TI - Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. PMID- 27462041 TI - Assessing bioequivalence of generic modified-release antiepileptic drugs. PMID- 27462042 TI - Mystery Case: Brown-Sequard syndrome caused by idiopathic spinal cord herniation. PMID- 27462043 TI - Pearls & Oy-sters: Vascular EDS presenting with acute proptosis: Always revisit the history. PMID- 27462044 TI - Teaching NeuroImages: Coats disease revealing facioscapulohumeral muscular dystrophy. PMID- 27462045 TI - Teaching NeuroImages: Intracranial hypotension in a patient with Marfan syndrome. PMID- 27462046 TI - Using stem cells to treat ALS. PMID- 27462047 TI - Increasing Pediatricians' Smoking Cessation Promotion and Knowledge of the Smoking Cessation Trust. AB - The link between second hand smoke exposure (SHSe) and health issues in children has been well established. The objective of this study was to determine if a short intervention implemented among pediatricians promotes improvement in the promotion of smoking cessation to caregivers and increase pediatricians' awareness of the Smoking Cessation Trust (SCT). Pediatricians from 6 clinics were randomly assigned to the control or intervention group. All pediatricians received a survey to assess baseline knowledge, confidence and behaviors in smoking cessation promotion and utilization of the SCT. Pediatricians in intervention group received an educational lecture delivered by a physician. Two months post intervention, pediatricians in the control and intervention group received a survey to assess changes from baseline. Out of 36 general pediatricians, 27 completed the surveys for use in the analysis of this study (75%). Intervention group made more referrals to the SCT, compared to controls (p=0.048) and to baseline (p=0.0065). Pediatricians in the intervention group were more confident in recommending the use of NRT (0.040) and schedule a follow up to discuss smoking cessation (p=0.029) after the intervention. The intervention group was more likely to refer caregivers to smoking cessation programs (p=0.027), discuss a child's health risk from SHSe (0.031) and recommending the use of NRT to help quit (p=0.047) post intervention. The results from this study indicate that a short intervention can increase confidence and behavior in various parameters of smoking cessation promotion and significantly improve the rate in which pediatricians refer smoking caregivers to the SCT. PMID- 27462048 TI - Orbital Myositis. PMID- 27462049 TI - Low aerobic capacity in middle-aged men associated with increased mortality rates during 45 years of follow-up. AB - BACKGROUND: Low aerobic capacity has been associated with increased mortality in short-term studies. The aim of this study was to evaluate the predictive power of aerobic capacity for mortality in middle-aged men during 45-years of follow-up. DESIGN: The study design was a population-based prospective cohort study. METHODS: A representative sample from Gothenburg of men born in 1913 was followed from 50-99 years of age, with periodic medical examinations and data from the National Hospital Discharge and Cause of Death registers. At 54 years of age, 792 men performed an ergometer exercise test, with 656 (83%) performing the maximum exercise test. RESULTS: In Cox regression analysis, low predicted peak oxygen uptake ([Formula: see text]), smoking, high serum cholesterol and high mean arterial blood pressure at rest were significantly associated with mortality. In multivariable analysis, an association was found between predicted [Formula: see text] tertiles and mortality, independent of established risk factors. Hazard ratios were 0.79 (95% confidence interval (CI) 0.71-0.89; p < 0.0001) for predicted [Formula: see text], 1.01 (1.002-1.02; p < 0.01) for mean arterial blood pressure, 1.13 (1.04-1.22; p < 0.005) for cholesterol, and 1.58 (1.34-1.85; p < 0.0001) for smoking. The variable impact (Wald's chi(2)) of predicted [Formula: see text] tertiles (15.3) on mortality was secondary only to smoking (31.4). The risk associated with low predicted [Formula: see text] was evident throughout four decades of follow-up. CONCLUSION: In this representative population sample of middle-aged men, low aerobic capacity was associated with increased mortality rates, independent of traditional risk factors, including smoking, blood pressure and serum cholesterol, during more than 40 years of follow-up. PMID- 27462050 TI - Failing Heart and Starving Brain: Ketone Bodies to the Rescue. PMID- 27462051 TI - Ruminations About Renal Denervation. PMID- 27462052 TI - Frequency, Type, and Volume of Leisure-Time Physical Activity and Risk of Coronary Heart Disease in Young Women. AB - BACKGROUND: The inverse association between physical activity and coronary heart disease (CHD) risk has primarily been shown in studies of middle-aged and older adults. Evidence for the benefits of frequency, type, and volume of leisure-time physical activity in young women is limited. METHODS: We conducted a prospective analysis among 97 230 women aged 27 to 44 years at baseline in 1991. Leisure-time physical activity was assessed biennially by questionnaire. Cox proportional hazards models were used to examine the associations between physical activity frequency, type, and volume, and CHD risk. RESULTS: During 20 years of follow-up, we documented 544 incident CHD cases. In multivariable-adjusted models, the hazard ratio (95% confidence interval) of CHD comparing >=30 with <1 metabolic equivalent of task-hours/wk of physical activity was 0.75 (0.57-0.99) (P, trend=0.01). Brisk walking alone was also associated with significantly lower CHD risk. Physical activity frequency was not associated with CHD risk when models also included overall activity volume. Finally, the association was not modified by body mass index (kg/m(2)) (P, interaction=0.70). Active women (>=30 metabolic equivalent of task-hours/wk) with body mass index<25 kg/m(2) had 0.52 (95% confidence interval, 0.35-0.78) times the rate of CHD in comparison with women who were obese (body mass index>=30 kg/m(2)) and inactive (physical activity <1 metabolic equivalent of task-hours/wk). CONCLUSIONS: These prospective data suggest that total volume of leisure-time physical activity is associated with lower risk of incident CHD among young women. In addition, this association was not modified by weight, emphasizing that it is important for normal weight, overweight, and obese women to be physically active. PMID- 27462053 TI - Encouraging Young Women to Move More: Linking Physical Activity in Young Adulthood to Coronary Risk in Women. PMID- 27462054 TI - Ablation of Atrial Fibrillation: Patient Selection, Periprocedural Anticoagulation, Techniques, and Preventive Measures After Ablation. AB - Atrial fibrillation (AF) is the most common arrhythmia encountered by cardiologists and is a major cause of morbidity and mortality. Risk factors for AF include age, male sex, genetic predisposition, hypertension, diabetes mellitus, sleep apnea, obesity, excessive alcohol, smoking, hyperthyroidism, pulmonary disease, air pollution, heart failure, and possibly excessive exercise. The management of AF involves decisions about rate versus rhythm control. Asymptomatic patients are generally managed with rate control and anticoagulation. Symptomatic patients will desire rhythm control. Rhythm control options are either antiarrhythmic agents or ablation, with each having its own risks and benefits. Ablation of AF has evolved from a rare and complex procedure to a common electrophysiological technique. Selection of patients to undergo ablation is an important aspect of AF care. Patients with the highest success rates of ablation are those with normal structural hearts and paroxysmal AF, although those with congestive heart failure have the greatest potential benefit of the procedure. Although pulmonary vein isolation of any means/energy source is the approach generally agreed on for those with paroxysmal AF, optimal techniques for the ablation of nonparoxysmal AF are not yet clear. Anticoagulation reduces thromboembolic complications; the newer anticoagulants have eased management for both the patient and the cardiologist. Aggressive management of modifiable risk factors (hypertension, diabetes mellitus, sleep apnea, obesity, excessive alcohol, smoking, hyperthyroidism, pulmonary disease, air pollution, and possibly excessive exercise) after ablation reduces the odds of recurrent AF and is an important element of care. PMID- 27462055 TI - Cardio-Oncology Programs Strive to Balance Cancer Care With Heart Health. PMID- 27462056 TI - Watching Television and Risk of Mortality From Pulmonary Embolism Among Japanese Men and Women: The JACC Study (Japan Collaborative Cohort). PMID- 27462057 TI - Letter by McGorrian et al Regarding Article, "A Shocking Development in a Young Male Athlete With Chest Pain". PMID- 27462058 TI - Letter by Bairey Merz et al Regarding Article, "A Shocking Development in a Young Male Athlete With Chest Pain". PMID- 27462059 TI - Response by Alexander et al to Letters Regarding Article, "A Shocking Development in a Young Male Athlete With Chest Pain". PMID- 27462060 TI - Letter by Mezue et al Regarding Article, "Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial". PMID- 27462061 TI - Response by Peralta et al to Letter Regarding Article, "Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial". PMID- 27462062 TI - Parental Physical Force and Alcohol Use in Emerging Adults: Mediation by Psychological Problems. AB - Research has indicated that negative parenting practices, such as physical punishment, are associated with negative outcomes in children. These negative outcomes can present during childhood and during emerging adulthood. One negative consequence can be excessive alcohol use, a problematic outcome with its own myriad consequences. The goal of the current study was to examine the effects of parental physical force on emerging adult functioning, specifically alcohol and psychological problems. A sample of 488 young adults completed questionnaires on current perceptions related to alcohol-related problems, physical and psychological aggression by their parents experienced during the previous year, and current emotional and behavioral functioning. Results showed full mediation between paternal physical force and emerging adult alcohol problems by emerging adult psychological problems. Emerging adult psychological problems partially mediated the effect of maternal physical force on emerging adult alcohol problem. Gender did not moderate these effects. The results support existing literature suggesting that the use of parental physical force may lead to a chain reaction of problems, even during emerging adulthood. These results also reveal that emerging adults report currently receiving physical force from their parents, which brings to light a concerning lack of literature on the use of parental physical force on emerging adult children. These results advocate for positive parenting practives and efforts to teach them, even for emerging adult children. The results may also clinically suggest that paying attention to parental force in emerging adult clients could yield a better understanding of their current functioning, especially including excessive alcohol use. PMID- 27462063 TI - Relations Among Victimization, Witnessing, and Perpetration of Aggression: Impact of Gender Among Youth Offenders. AB - The participants included 251 (158 males; 93 females) youth offenders who were arrested and incarcerated in a juvenile facility in the Midwest United States. The aims were to assess (a) how often they were a victim, a witness, and/or a perpetrator of social aggression, simple assault, and aggravated assault during the past year; (b) to examine whether exposure (either witness or victim or both) predicted committing three types of aggressive behaviors; and (c) to assess the impact of gender among the youth offenders. Differential predictability models were utilized to assess gender differences. The findings revealed that gender was an important predictor. For example, females reported higher rates of being a witness, a victim, and a perpetrator of social aggression than did males. Moreover, female offenders committed simple assault more often than males and males committed aggravated assault more often than females. The general results suggest that it is important to examine the various forms of aggression, and exposure, as well as how gender affects these relationships. PMID- 27462064 TI - Psychopathy Traits and Violent Assault Among Men With and Without History of Arrest. AB - Although research suggests that the antisocial behavior (ASB) facet of psychopathy generally carries the greatest predictive power for future violence, these findings are drawn primarily from forensic samples and may reflect criterion contamination between historical violence and future violence perpetration. Likewise, these findings do not negate the association of other psychopathy facets to violence or their role in the development of violence, nor do they offer practical utility in the primary prevention of violence. There are a number of empirical and theoretical reasons to suspect that the callous affect (CA) facet of psychopathy may demonstrate stronger statistical association to violence in nonforensic populations. We tested the association of CA to severe acts of violence (e.g., assault with intent to harm, injure, rape, or kill) among men with and without history of arrest ( N = 600) using both the three- and four facet models of psychopathy. CA was robustly associated with violence outcomes across the two groups in the three-facet model. When testing the four-facet model, CA was strongly associated with violence outcomes among men with no history of arrest, but only moderately associated with assaults causing injury among men with history of arrest. These results are consistent with data from youth populations that implicate early emotional deficits in later aggressive behavior and suggest CA may help to identify individuals at risk for violence before they become violent. Implications for the public health system and the primary prevention of violence are discussed. PMID- 27462066 TI - Two Case Reports of FGF23-Induced Hypophosphatemia in Childhood Biliary Atresia. AB - Cholestatic liver disease has long been associated with childhood rickets, secondary to impaired absorption of fat-soluble vitamin D. Elevated serum levels of fibroblast growth factor 23 (FGF23), secondary to genetic defects or tumor induced osteomalacia, causes hypophosphatemic rickets in childhood. We present 2 infants with end-stage liver disease due to biliary atresia (BA) who developed hypophosphatemia with renal phosphate wasting. Serum FGF23 levels were elevated more than 8 times the upper limit of normal, and the older infant showed radiographic evidence of rickets. Both infants required large supplements of phosphate in addition to calcitriol. Following liver transplantation, FGF23 normalized in both patients and phosphate and calcitriol supplementation were discontinued. Immunohistochemistry revealed ectopic overexpression of FGF23 by hepatocytes in the BA liver. These observations highlight a unique cause of hypophosphatemic rickets in childhood and suggest the need for further investigation into the relationship between BA and other cholestatic disorders, and bone metabolism. PMID- 27462065 TI - Impact of a Web-Portal Intervention on Community ADHD Care and Outcomes. AB - BACKGROUND: The quality of care for children with attention-deficit/hyperactivity disorder (ADHD) delivered in community-based pediatric settings is often poor. Interventions have been developed to improve community-based ADHD care but have not demonstrated that better care results in improved patient outcomes. The objective of this study was to determine whether an ADHD quality improvement (QI) intervention for community-based pediatric practices improves patient outcomes. METHODS: A cluster randomized controlled trial was conducted in which 50 community-based pediatric primary care practices (213 providers) were randomized either to receive a technology-assisted QI intervention or to a control condition. The intervention consisted of 4 training sessions, office flow modification, guided QI, and an ADHD Internet portal to assist with treatment monitoring. ADHD treatment processes and parent- and teacher-rated ADHD symptoms over the first year of treatment were collected for 577 patients. RESULTS: Intent to-treat analyses examining outcomes of all children assessed for ADHD were not significant (b = -1.97, P = .08). However, among the 373 children prescribed ADHD medication, there was a significant intervention effect (b = -2.42, P = .04) indicating greater reductions in parent ratings of ADHD symptoms after treatment among patients treated by intervention physicians compared with patients treated at control practices. There were no group differences on teacher ratings of ADHD symptoms. ADHD treatment care around medication was significantly better at intervention practices compared with control practices. CONCLUSIONS: A technology assisted QI intervention improved some ADHD care quality and resulted in additional reductions in parent-rated ADHD symptoms among patients prescribed ADHD medications. PMID- 27462067 TI - Biofeedback as Prophylaxis for Pediatric Migraine: A Meta-analysis. AB - CONTEXT: Migraine is a common problem in children and adolescents, but few satisfactory prophylactic treatments exist. OBJECTIVE: Our goal was to investigate the pooled evidence for the effectiveness of using biofeedback to reduce childhood migraine. DATA SOURCES: A systematic search was conducted across the databases Medline, Embase, CENTRAL, CINAHL, and PsychINFO. STUDY SELECTION: Prospective, randomized controlled trials of biofeedback for migraine among children and adolescents were located in the search. DATA EXTRACTION: Data on reduction of mean attack frequency and a series of secondary outcomes, including adverse events, were extracted. Risk of bias was also assessed. RESULTS: Forest plots were created by using a fixed effects model, and mean differences were reported. Five studies with a total of 137 participants met the inclusion criteria. Biofeedback reduced migraine frequency (mean difference, -1.97 [95% confidence interval (CI), -2.72 to -1.21]; P < .00001), attack duration (mean difference, -3.94 [95% CI, -5.57 to -2.31]; P < .00001), and headache intensity (mean difference, -1.77 [95% CI, -2.42 to -1.11]; P < .00001) compared with a waiting-list control. Biofeedback demonstrated no adjuvant effect when combined with other behavioral treatment; neither did it have significant advantages over active treatment. Only 40% of bias judgments were deemed as "low" risk. LIMITATIONS: Methodologic issues hampered the meta-analyses. Only a few studies were possible to include, and they suffered from incomplete reporting of data and risk of bias. CONCLUSIONS: Biofeedback seems to be an effective intervention for pediatric migraine, but in light of the limitations, further investigation is needed to increase our confidence in the estimate. PMID- 27462068 TI - Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes. AB - BACKGROUND: Patients with heterozygous familial hypercholesterolemia (FH) and coronary heart disease have high mortality rates. However, in an era of high-dose statin prescription after acute coronary syndrome (ACS), the risk of recurrent coronary and cardiovascular events associated with FH might be mitigated. We compared coronary event rates between patients with and without FH after ACS. METHODS: We studied 4534 patients with ACS enrolled in a multicenter, prospective cohort study in Switzerland between 2009 and 2013 who were individually screened for FH on the basis of clinical criteria according to 3 definitions: the American Heart Association definition, the Simon Broome definition, and the Dutch Lipid Clinic definition. We used Cox proportional models to assess the 1-year risk of first recurrent coronary events defined as coronary death or myocardial infarction and adjusted for age, sex, body mass index, smoking, hypertension, diabetes mellitus, existing cardiovascular disease, high-dose statin at discharge, attendance at cardiac rehabilitation, and the GRACE (Global Registry of Acute Coronary Events) risk score for severity of ACS. RESULTS: At the 1-year follow-up, 153 patients (3.4%) had died, including 104 (2.3%) of fatal myocardial infarction. A further 113 patients (2.5%) experienced nonfatal myocardial infarction. The prevalence of FH was 2.5% with the American Heart Association definition, 5.5% with the Simon Broome definition, and 1.6% with the Dutch Lipid Clinic definition. Compared with patients without FH, the risk of coronary event recurrence after ACS was similar in patients with FH in unadjusted analyses, although patients with FH were >10 years younger. However, after multivariable adjustment including age, the risk was greater in patients with FH than without, with an adjusted hazard ratio of 2.46 (95% confidence interval, 1.07-5.65; P=0.034) for the American Heart Association definition, 2.73 (95% confidence interval, 1.46-5.11; P=0.002) for the Simon Broome definition, and 3.53 (95% confidence interval, 1.26-9.94; P=0.017) for the Dutch Lipid Clinic definition. Depending on which clinical definition of FH was used, between 94.5% and 99.1% of patients with FH were discharged on statins and between 74.0% and 82.3% on high dose statins. CONCLUSIONS: Patients with FH and ACS have a >2-fold adjusted risk of coronary event recurrence within the first year after discharge than patients without FH despite the widespread use of high-intensity statins. PMID- 27462069 TI - Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart. AB - BACKGROUND: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (IK,Ado). METHODS: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). RESULTS: Optical mapping of coronary perfused atria (n=24) revealed that adenosine perfusion (10-100 umol/L) produced more significant shortening of action potential durations in RA (from 290+/-45 to 239+/-41 ms, 17.3+/-10.4%; P<0.01) than LA (from 307+/-24 to 286+/-23 ms, 6.7+/ 6.6%; P<0.01). In 10 hearts, adenosine induced AF (317+/-116 s) that, when sustained (>=2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10-100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7+/-1.7-fold; P<0.01) and GIRK4 (1.7+/-0.8-fold; P<0.05) protein expression than lateral/posterior LA. CONCLUSIONS: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine. PMID- 27462070 TI - The role of Cx36 and Cx43 in 4-aminopyridine-induced rhythmic activity in the spinal nociceptive dorsal horn: an electrophysiological study in vitro. AB - Connexin (Cx) proteins and gap junctions support the formation of neuronal and glial syncytia that are linked to different forms of rhythmic firing and oscillatory activity in the CNS. In this study, quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to profile developmental expression of two specific Cx proteins, namely glial Cx43 and neuronal Cx36, in postnatal lumbar spinal cord aged 4, 7, and 14 days. Extracellular electrophysiology was used to determine the contribution of Cx36 and Cx43 to a previously described form of 4-aminopyridine (4-AP)-induced 4-12 Hz rhythmic activity within substantia gelatinosa (SG) of rat neonatal dorsal horn (DH) in vitro. The involvement of Cx36 and Cx43 was probed pharmacologically using quinine, a specific uncoupler of Cx36 and the mimetic peptide blocker Gap 26 which targets Cx43. After establishment of 4-12 Hz rhythmic activity by 4-AP (25 MUmol/L), coapplication of quinine (250 MUmol/L) reduced 4-AP-induced 4-12 Hz rhythmic activity (P < 0.05). Preincubation of spinal cord slices with Gap 26 (100 MUmol/L), compromised the level of 4-AP-induced 4-12 Hz rhythmic activity in comparison with control slices preincubated in ACSF alone (P < 0.05). Conversely, the nonselective gap junction "opener" trimethylamine (TMA) enhanced 4-12 Hz rhythmic behavior (P < 0.05), further supporting a role for Cx proteins and gap junctions. These data have defined a physiological role for Cx36 and Cx43 in rhythmic firing in SG, a key nociceptive processing area of DH. The significance of these data in the context of pain and Cx proteins as a future analgesic drug target requires further study. PMID- 27462071 TI - Limited effects of preterm birth and the first enteral nutrition on cerebellum morphology and gene expression in piglets. AB - Preterm pigs show many signs of immaturity that are characteristic of preterm infants. In preterm infants, the cerebellum grows particularly rapid and hypoplasia and cellular lesions are associated with motor dysfunction and cognitive deficits. We hypothesized that functional brain delays observed in preterm pigs would be paralleled by both structural and molecular differences in the cerebellum relative to term born piglets. Cerebella were collected from term (n = 56) and preterm (90% gestation, n = 112) pigs at 0, 5, and 26 days after birth for stereological volume estimations, large-scale qPCR gene expression analyses (selected neurodevelopmental genes) and western blot protein expression analysis (Sonic Hedgehog pathway). Memory and learning was tested using a T-maze, documenting that preterm pigs showed delayed learning. Preterm pigs also showed reduced volume of both white and gray matter at all three ages but the proportion of white matter increased postnatally, relative to term pigs. Early initiation of enteral nutrition had limited structural or molecular effects. The Sonic Hedgehog pathway was unaffected by preterm birth. Few differences in expression of the selected genes were found, except consistently higher mRNA levels of Midkine, p75, and Neurotrophic factor 3 in the preterm cerebellum postnatally, probably reflecting an adaptive response to preterm birth. Pig cerebellar development appears more affected by postconceptional age than by environmental factors at birth or postnatally. Compensatory mechanisms following preterm birth may include faster white matter growth and increased expression of selected genes for neurotrophic factors and regulation of angiogenesis. While the pig cerebellum is immature in 90% gestation preterm pigs, it appears relatively mature and resilient toward environmental factors. PMID- 27462072 TI - Family-specific Kinesin Structures Reveal Neck-linker Length Based on Initiation of the Coiled-coil. AB - Kinesin-1, -2, -5, and -7 generate processive hand-over-hand 8-nm steps to transport intracellular cargoes toward the microtubule plus end. This processive motility requires gating mechanisms to coordinate the mechanochemical cycles of the two motor heads to sustain the processive run. A key structural element believed to regulate the degree of processivity is the neck-linker, a short peptide of 12-18 residues, which connects the motor domain to its coiled-coil stalk. Although a shorter neck-linker has been correlated with longer run lengths, the structural data to support this hypothesis have been lacking. To test this hypothesis, seven kinesin structures were determined by x-ray crystallography. Each included the neck-linker motif, followed by helix alpha7 that constitutes the start of the coiled-coil stalk. In the majority of the structures, the neck-linker length differed from predictions because helix alpha7, which initiates the coiled-coil, started earlier in the sequence than predicted. A further examination of structures in the Protein Data Bank reveals that there is a great disparity between the predicted and observed starting residues. This suggests that an accurate prediction of the start of a coiled-coil is currently difficult to achieve. These results are significant because they now exclude simple comparisons between members of the kinesin superfamily and add a further layer of complexity when interpreting the results of mutagenesis or protein fusion. They also re-emphasize the need to consider factors beyond the kinesin neck-linker motif when attempting to understand how inter-head communication is tuned to achieve the degree of processivity required for cellular function. PMID- 27462073 TI - Cell Damage in Light Chain Amyloidosis: FIBRIL INTERNALIZATION, TOXICITY AND CELL MEDIATED SEEDING. AB - Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis. PMID- 27462074 TI - Nuclear Mitotic Apparatus (NuMA) Interacts with and Regulates Astrin at the Mitotic Spindle. AB - The large nuclear mitotic apparatus (NuMA) protein is an essential player in mitotic spindle assembly and maintenance. We report here the identification of Astrin, a spindle- and kinetochore-associated protein, as a novel interactor of NuMA. We show that the C-terminal tail of NuMA can directly bind to the C terminus of Astrin and that this interaction helps to recruit Astrin to microtubules. Knockdown of NuMA by RNA interference dramatically impaired Astrin recruitment to the mitotic spindle. Overexpression of the N terminus of mammalian homologue of Drosophila Pins (LGN), which blocks the microtubule binding of NuMA and competes with Astrin for NuMA binding, also led to similar results. Furthermore, we found that cytoplasmic dynein is required for the spindle pole accumulation of Astrin, and dynein-mediated transport is important for balanced distribution of Astrin between spindle poles and kinetochores. On the other hand, if Astrin levels are reduced, then NuMA could not efficiently concentrate at the spindle poles. Our findings reveal a direct physical link between two important regulators of mitotic progression and demonstrate the critical role of the NuMA Astrin interaction for accurate cell division. PMID- 27462075 TI - Transforming Growth Factor-beta (TGF-beta) Inhibits the Expression of Factor VII activating Protease (FSAP) in Hepatocytes. AB - Deletion of the Habp2 gene encoding Factor VII-activating protease (FSAP) increases liver fibrosis in mice. A single nucleotide polymorphism (G534E) in HABP2 leads to lower enzymatic activity and is associated with enhanced liver fibrosis in humans. Liver fibrosis is associated with a decrease in FSAP expression but, to date, nothing is known about how this might be regulated. Primary mouse hepatocytes or the hepatocyte cell line, AML12, were treated with different factors, and expression of FSAP was determined. Of the various regulatory factors tested, only transforming growth factor-beta (TGF-beta) demonstrated a concentration- and time-dependent inhibition of FSAP expression at the mRNA and protein level. The TGF-beta-Type I receptor (ALK-5) antagonist SB431542 and Smad2 siRNA, but neither SIS3, which inhibits SMAD3, nor siRNA against Smad3 could block this effect. Various regions of the HABP2 promoter region were cloned into reporter constructs, and the promoter activity was determined. Accordingly, the promoter activity, which could phenocopy changes in Habp2 mRNA in response to TGF-beta, was found to be located in the 177-bp region upstream of the transcription start site, and this region did not contain any SMAD binding sites. Mutation analysis of the promoter and chromatin immunoprecipitation assays were performed to identify an important role for the ATF3 binding element. Thus, TGF-beta is the most likely mediator responsible for the decrease in FSAP expression in liver fibrosis. PMID- 27462076 TI - A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of gamma Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes. AB - Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternative targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized, and characterized a chemically active alkylphenol anesthetic (2 ((prop-2-yn-1-yloxy)methyl)-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenol, AziPm click (1)), for affinity-based protein profiling (ABPP) of propofol-binding proteins in their native state within mouse synaptosomes. The ABPP strategy captured ~4% of the synaptosomal proteome, including the unbiased capture of five alpha or beta GABAA receptor subunits. Lack of gamma2 subunit capture was not due to low abundance. Consistent with this, independent molecular dynamics simulations with alchemical free energy perturbation calculations predicted selective propofol binding to interfacial sites, with higher affinities for alpha/beta than gamma-containing interfaces. The simulations indicated hydrogen bonding is a key component leading to propofol-selective binding within GABAA receptor subunit interfaces, with stable hydrogen bonds observed between propofol and alpha/beta cavity residues but not gamma cavity residues. We confirmed this by introducing a hydrogen bond-null propofol analogue as a protecting ligand for targeted-ABPP and observed a lack of GABAA receptor subunit protection. This investigation demonstrates striking interfacial GABAA receptor subunit selectivity in the native milieu, suggesting that asymmetric occupancy of heteropentameric ion channels by alkylphenol-based anesthetics is sufficient to induce modulation of activity. PMID- 27462077 TI - Why Calcium? How Calcium Became the Best Communicator. AB - Calcium carries messages to virtually all important functions of cells. Although it was already active in unicellular organisms, its role became universally important after the transition to multicellular life. In this Minireview, we explore how calcium ended up in this privileged position. Most likely its unique coordination chemistry was a decisive factor as it makes its binding by complex molecules particularly easy even in the presence of large excesses of other cations, e.g. magnesium. Its free concentration within cells can thus be maintained at the very low levels demanded by the signaling function. A large cadre of proteins has evolved to bind or transport calcium. They all contribute to buffer it within cells, but a number of them also decode its message for the benefit of the target. The most important of these "calcium sensors" are the EF hand proteins. Calcium is an ambivalent messenger. Although essential to the correct functioning of cell processes, if not carefully controlled spatially and temporally within cells, it generates variously severe cell dysfunctions, and even cell death. PMID- 27462079 TI - Metals in Biology 2016: Molecular Basis of Selection of Metals by Enzymes. AB - This ninth Metals in Biology Thematic Series deals with the fundamental issue of why certain enzymes prefer individual metals. Why do some prefer sodium and some prefer potassium? Is it just the size? Why does calcium have so many regulatory functions? Why do some proteins have an affinity for zinc? How is the homeostasis of calcium and zinc achieved? How do enzymes discriminate between the similar metals magnesium and manganese? Four Minireviews address these and related questions about metal ion preferences in biological systems. PMID- 27462078 TI - Molecular Mechanisms of Enzyme Activation by Monovalent Cations. AB - Regulation of enzymes through metal ion complexation is widespread in biology and underscores a physiological need for stability and high catalytic activity that likely predated proteins in the RNA world. In addition to divalent metals such as Ca2+, Mg2+, and Zn2+, monovalent cations often function as efficient and selective promoters of catalysis. Advances in structural biology unravel a rich repertoire of molecular mechanisms for enzyme activation by Na+ and K+ Strategies range from short-range effects mediated by direct participation in substrate binding, to more distributed effects that propagate long-range to catalytic residues. This review addresses general considerations and examples. PMID- 27462080 TI - Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface. AB - Among the biologically required first row, late d-block metals from MnII to ZnII, the catalytic and structural reach of ZnII ensures that this essential micronutrient touches nearly every major metabolic process or pathway in the cell. Zn is also toxic in excess, primarily because it is a highly competitive divalent metal and will displace more weakly bound transition metals in the active sites of metalloenzymes if left unregulated. The vertebrate innate immune system uses several strategies to exploit this "Achilles heel" of microbial physiology, but bacterial evolution has responded in kind. This review highlights recent insights into transcriptional, transport, and trafficking mechanisms that pathogens use to "win the fight" over zinc and thrive in an otherwise hostile environment. PMID- 27462081 TI - Different Divalent Cations Alter the Kinetics and Fidelity of DNA Polymerases. AB - Divalent metal ions are essential components of DNA polymerases both for catalysis of the nucleotidyl transfer reaction and for base excision. They occupy two sites, A and B, for DNA synthesis. Recently, a third metal ion was shown to be essential for phosphoryl transfer reaction. The metal ion in the A site is coordinated by the carboxylate of two highly conserved acidic residues, water molecules, and the 3'-hydroxyl group of the primer so that the A metal is in an octahedral complex. Its catalytic function is to lower the pKa of the hydroxyl group, making it a highly effective nucleophile that can attack the alpha phosphorous atom of the incoming dNTP. The metal ion in the B site is coordinated by the same two carboxylates that are affixed to the A metal ion as well as the non-bridging oxygen atoms of the incoming dNTP. The carboxyl oxygen of an adjacent peptide bond serves as the sixth ligand that completes the octahedral coordination geometry of the B metal ion. Similarly, two metal ions are required for proofreading; one helps to lower the pKa of the attacking water molecule, and the other helps to stabilize the transition state for nucleotide excision. The role of different divalent cations are discussed in relation to these two activities as well as their influence on base selectivity and misincorporation by DNA polymerases. Some, but not all, of the effects of these different metal ions can be rationalized based on their intrinsic properties, which are tabulated in this review. PMID- 27462082 TI - A Conserved Hydrophobic Core in Galphai1 Regulates G Protein Activation and Release from Activated Receptor. AB - G protein-coupled receptor-mediated heterotrimeric G protein activation is a major mode of signal transduction in the cell. Previously, we and other groups reported that the alpha5 helix of Galphai1, especially the hydrophobic interactions in this region, plays a key role during nucleotide release and G protein activation. To further investigate the effect of this hydrophobic core, we disrupted it in Galphai1 by inserting 4 alanine amino acids into the alpha5 helix between residues Gln(333) and Phe(334) (Ins4A). This extends the length of the alpha5 helix without disturbing the beta6-alpha5 loop interactions. This mutant has high basal nucleotide exchange activity yet no receptor-mediated activation of nucleotide exchange. By using structural approaches, we show that this mutant loses critical hydrophobic interactions, leading to significant rearrangements of side chain residues His(57), Phe(189), Phe(191), and Phe(336); it also disturbs the rotation of the alpha5 helix and the pi-pi interaction between His(57) and Phe(189) In addition, the insertion mutant abolishes G protein release from the activated receptor after nucleotide binding. Our biochemical and computational data indicate that the interactions between alpha5, alpha1, and beta2-beta3 are not only vital for GDP release during G protein activation, but they are also necessary for proper GTP binding (or GDP rebinding). Thus, our studies suggest that this hydrophobic interface is critical for accurate rearrangement of the alpha5 helix for G protein release from the receptor after GTP binding. PMID- 27462083 TI - ACYL-ACYL CARRIER PROTEIN DESATURASE2 and 3 Are Responsible for Making Omega-7 Fatty Acids in the Arabidopsis Aleurone. AB - Omega-7 monounsaturated fatty acids (omega-7s) are specifically enriched in the aleurone of Arabidopsis (Arabidopsis thaliana) seeds. We found significant natural variation in seed omega-7 content and used a Multiparent Advanced Generation Inter-Cross population to fine-map a major quantitative trait loci to a region containing ACYL-ACYL CARRIER PROTEIN DESATURASE1 (AAD1) and AAD3 We found that AAD3 expression is localized to the aleurone where mutants show an approximately 50% reduction in omega-7 content. By contrast, AAD1 is localized to the embryo where mutants show a small reduction in omega-9 content. Enzymatic analysis has previously shown that AAD family members possess both stearoyl- and palmitoyl-ACP Delta(9) desaturase activity, including the predominant isoform SUPPRESSOR OF SALICYLIC ACID INSENSITIVE2. However, aad3 ssi2 aleurone contained the same amount of omega-7s as aad3 Within the AAD family, AAD3 shares the highest degree of sequence similarity with AAD2 and AAD4. Mutant analysis showed that AAD2 also contributes to omega-7 production in the aleurone, and aad3 aad2 exhibits an approximately 85% reduction in omega-7s Mutant analysis also showed that FATTY ACID ELONGASE1 is required for the production of very long chain omega 7s in the aleurone. Together, these data provide genetic evidence that the omega 7 pathway proceeds via Delta(9) desaturation of palmitoyl-ACP followed by elongation of the product. Interestingly, significant variation was also identified in the omega-7 content of Brassica napus aleurone, with the highest level detected being approximately 47% of total fatty acids. PMID- 27462084 TI - Cell Wall Invertase Promotes Fruit Set under Heat Stress by Suppressing ROS Independent Cell Death. AB - Reduced cell wall invertase (CWIN) activity has been shown to be associated with poor seed and fruit set under abiotic stress. Here, we examined whether genetically increasing native CWIN activity would sustain fruit set under long term moderate heat stress (LMHS), an important factor limiting crop production, by using transgenic tomato (Solanum lycopersicum) with its CWIN inhibitor gene silenced and focusing on ovaries and fruits at 2 d before and after pollination, respectively. We found that the increase of CWIN activity suppressed LMHS-induced programmed cell death in fruits. Surprisingly, measurement of the contents of H2O2 and malondialdehyde and the activities of a cohort of antioxidant enzymes revealed that the CWIN-mediated inhibition on programmed cell death is exerted in a reactive oxygen species-independent manner. Elevation of CWIN activity sustained Suc import into fruits and increased activities of hexokinase and fructokinase in the ovaries in response to LMHS Compared to the wild type, the CWIN-elevated transgenic plants exhibited higher transcript levels of heat shock protein genes Hsp90 and Hsp100 in ovaries and HspII17.6 in fruits under LMHS, which corresponded to a lower transcript level of a negative auxin responsive factor IAA9 but a higher expression of the auxin biosynthesis gene ToFZY6 in fruits at 2 d after pollination. Collectively, the data indicate that CWIN enhances fruit set under LMHS through suppression of programmed cell death in a reactive oxygen species-independent manner that could involve enhanced Suc import and catabolism, HSP expression, and auxin response and biosynthesis. PMID- 27462086 TI - Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression: 20 years on. AB - In 1997, neuropsychological and neuroimaging evidence supported the involvement of the frontal lobes and indeed the brain in depression. This was a challenge to conventional phenomenology and linked with the imperative to use neuroscience to understand major mental illness. Since that time, we are seeing ever more convincing evidence for the genetic basis of mental illness (including depression), relevant abnormality in grey and white matter and neuropsychological analysis of brain function. It has proved more difficult to pin down structural abnormality in major depression at the cellular level, but a focus on glial cells is increasingly justified by the evidence. Neuroscience continues to be a buttress against anti-scientific impulses in psychiatry and can help attract young people to enter it as a profession. PMID- 27462085 TI - Cytokinins Are Initial Targets of Light in the Control of Bud Outgrowth. AB - Bud outgrowth is controlled by environmental and endogenous factors. Through the use of the photosynthesis inhibitor norflurazon and of masking experiments, evidence is given here that light acts mainly as a morphogenic signal in the triggering of bud outgrowth and that initial steps in the light signaling pathway involve cytokinins (CKs). Indeed, in rose (Rosa hybrida), inhibition of bud outgrowth by darkness is suppressed solely by the application of CKs. In contrast, application of sugars has a limited effect. Exposure of plants to white light (WL) induces a rapid (after 3-6 h of WL exposure) up-regulation of CK synthesis (RhIPT3 and RhIPT5), of CK activation (RhLOG8), and of CK putative transporter RhPUP5 genes and to the repression of the CK degradation RhCKX1 gene in the node. This leads to the accumulation of CKs in the node within 6 h and in the bud at 24 h and to the triggering of bud outgrowth. Molecular analysis of genes involved in major mechanisms of bud outgrowth (strigolactone signaling [RwMAX2], metabolism and transport of auxin [RhPIN1, RhYUC1, and RhTAR1], regulation of sugar sink strength [RhVI, RhSUSY, RhSUC2, and RhSWEET10], and cell division and expansion [RhEXP and RhPCNA]) reveal that, when supplied in darkness, CKs up-regulate their expression as rapidly and as intensely as WL Additionally, up-regulation of CKs by WL promotes xylem flux toward the bud, as evidenced by Methylene Blue accumulation in the bud after CK treatment in the dark. Altogether, these results suggest that CKs are initial components of the light signaling pathway that controls the initiation of bud outgrowth. PMID- 27462089 TI - Stroke: So much to do, still so poorly resourced! PMID- 27462088 TI - Psychiatric comorbidity associated with synthetic cannabinoid use compared to cannabis. AB - BACKGROUND: Synthetic cannabinoids (SC) use has had a dramatic increase in recent years, but data regarding their adverse effects on mental health is limited. In this study, we compared clinical presentations of SC users with cannabis users in a psychiatric inpatient setting. METHODS: Digital charts of all patients who were admitted to a dual diagnosis psychiatric unit in one year were reviewed. Patients who had any current substance use disorder were categorized in four groups: (1) SC use and cannabis use (SC+MJ+), (2) SC use without cannabis use (SC+MJ-), (3) cannabis use without SC use (SC-MJ+), and (4) No SC or cannabis use (SC-MJ-). RESULTS: A total of 594 charts were included. SC+MJ- patients had significantly more psychotic symptoms (OR: 4.44, 95% CI: 1.98-9.94), followed by SC+MJ+ (OR: 3.61, 95% CI: 1.87-6.97) and SC-MJ+ (OR: 1.87, 95%CI: 1.33-2.64) patients. The SC+MJ- group also had more agitation and aggression was most prominent in SC+MJ+ subjects. Multivariate analyses showed that the psychiatric associations of SC and cannabis use remained significant even after controlling for potential confounds such as other substance use. CONCLUSIONS: The prominent psychiatric features of SC users as compared to cannabis users in an inpatient setting are psychotic presentations and agitation, which have important treatment implications. PMID- 27462087 TI - The NK1R-/- mouse phenotype suggests that small body size, with a sex- and diet dependent excess in body mass and fat, are physical biomarkers for a human endophenotype with vulnerability to attention deficit hyperactivity disorder. AB - The abnormal behaviour of NK1R-/- mice (locomotor hyperactivity, inattentiveness and impulsivity in the 5-Choice Serial Reaction-Time Test) is arguably analogous to that of patients with attention deficit hyperactivity disorder (ADHD). Evidence suggests that small body size and increased body weight are risk factors for ADHD. Here, we compared the body size, body mass and body composition of male and female NK1R-/- mice and their wildtypes that had been fed either standard laboratory chow or a high-fat (45%: 'Western') diet. Male NK1R-/- mice from both cohorts were approximately 7% shorter than wildtypes. A similar trend was evident in females. Male NK1R-/- mice fed the normal diet weighed less than wildtypes but the 'body mass index' ('mBMI': weight (mg)/length (cm)(2)) of female NK1R-/- mice was higher than wildtypes. When given the high-fat diet, the mBMI of both male and female NK1R-/- mice was higher than wildtypes. There were no consistent genotype or sex differences in protein, ash or water content of mice from the two cohorts. However, the fat content of male NK1R-/- mice on the Western diet was considerably (35%) higher than wildtypes and resembled that of females from both genotypes. We conclude that a lack of functional NK1R is associated with small body size but increases vulnerability to an increase in mBMI and fat content, especially in males. This phenotype could also be evident in ADHD patients with polymorphism(s) of the TACR1 gene (the human equivalent of Nk1r). PMID- 27462090 TI - European Recommendations on Organisation of Interventional Care in Acute Stroke (EROICAS). PMID- 27462091 TI - Granulomatous Responses in HIV and Mycobacterium tuberculosis Coinfection. PMID- 27462092 TI - Relationship Between HIV Coinfection, Interleukin 10 Production, and Mycobacterium tuberculosis in Human Lymph Node Granulomas. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis than HIV-uninfected persons. Low peripheral CD4+ T cell count is not the sole cause of higher susceptibility, because HIV-infected persons with a high peripheral CD4+ T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis-associated granulomas. METHODS: We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4+ T cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas. RESULTS: HIV increased M. tuberculosis numbers and reduced CD4+ T cell counts within granulomas. Peripheral CD4+ T-cell depletion correlated with granulomas that contained fewer CD4+ and CD8+ T cells, less interferon gamma, more neutrophils, more interleukin 10 (IL-10), and increased M. tuberculosis numbers. M. tuberculosis numbers correlated positively with IL-10 and interferon alpha levels and fewer CD4+ and CD8+ T cells. ART reduced IL-10 production. CONCLUSIONS: Peripheral CD4+ T-cell depletion correlated with increased M. tuberculosis presence, increased IL-10 production, and other phenotypic changes within granulomas, demonstrating the HIV infection progressively changes these granulomas. PMID- 27462093 TI - Hormonal Contraceptive Use Among HIV-Positive Women and HIV Transmission Risk to Male Partners, Zambia, 1994-2012. AB - BACKGROUND: Evidence on the association between female-to-male human immunodeficiency virus (HIV) transmission risk and hormonal contraception is sparse and conflicting. METHODS: Heterosexual HIV-discordant couples from Lusaka, Zambia, were followed longitudinally at 3 month-intervals from 1994 to 2012. The impact of hormonal contraception on time to HIV transmission from HIV-positive women to their HIV-negative male partners (M-F+) was evaluated. RESULTS: Among 1601 M-F+ couples, 171 genetically linked HIV transmissions occurred in men over 3216 couple-years (5.3 transmissions/100 couple-years; 95% confidence interval [CI], 4.5-6.2). In multivariable Cox models, neither injectable (adjusted hazard ratio [aHR], 0.6; 95% CI, .4-1.2), oral contraceptive pill (aHR, 0.8; 95% CI, .3 2.1), nor implant (aHR, 0.8; 95% CI, .5-1.4) use was associated with HIV transmission, relative to nonhormonal methods, after controlling for the man's age at baseline and time-varying measures of pregnancy, self-reported unprotected sex with the study partner, sperm present on a vaginal swab wet mount, genital inflammation of either partner, genital ulceration of the man, and first follow up interval. Sensitivity analyses, including marginal structural modeling and controlling for viral load and fertility intentions available in a subset of couples, led to similar conclusions. CONCLUSIONS: Our findings suggest null associations between hormonal contraception and risk of female-to-male HIV transmission. We support efforts to increase the contraceptive method mix for all women, regardless of HIV serostatus, along with reinforced condom counseling for HIV-serodiscordant couples. PMID- 27462094 TI - Development of an Immunochromatography Assay (QuickNavi-Ebola) to Detect Multiple Species of Ebolaviruses. AB - The latest outbreak of Ebola virus disease (EVD) in West Africa has highlighted the urgent need for the development of rapid and reliable diagnostic assays. We used monoclonal antibodies specific to the ebolavirus nucleoprotein to develop an immunochromatography (IC) assay (QuickNavi-Ebola) for rapid diagnosis of EVD. The IC assay was first evaluated with tissue culture supernatants of infected Vero E6 cells and found to be capable of detecting 103-104 focus-forming units/mL of ebolaviruses. Using serum samples from experimentally infected nonhuman primates, we confirmed that the assay could detect the viral antigen shortly after disease onset. It was also noted that multiple species of ebolaviruses could be detected by the IC assay. Owing to the simplicity of the assay procedure and absence of requirements for special equipment and training, QuickNavi-Ebola is expected to be a useful tool for rapid diagnosis of EVD. PMID- 27462095 TI - Blood pressure burden and outcome in warfarin-related intracerebral hemorrhage. AB - Background and purpose Blood pressure reduction is a promising intervention for acute intracerebral hemorrhage, but clinical trials of this treatment often exclude those with anticoagulant-associated intracerebral hemorrhage, leaving it unclear whether this population might benefit. We examined whether persistently elevated blood pressure values (blood pressure burden) over the first 24 h are associated with hematoma expansion and mortality in anticoagulant-associated intracerebral hemorrhage. Methods We retrospectively identified consecutive patients with primary anticoagulant-associated intracerebral hemorrhage (warfarin anticoagulation) who presented within 6 h after symptom onset and a matched set of non-anticoagulant-associated intracerebral hemorrhage patients. Associations between 24 h blood pressure burden, hematoma expansion, and mortality were evaluated using univariable and multivariable logistic regression. Results Sixty nine anticoagulant-associated intracerebral hemorrhage and 69 matched non anticoagulant-associated intracerebral hemorrhage patients were included. Hematoma expansion occurred in 25 anticoagulant-associated intracerebral hemorrhage patients (36%) and 15 control patients (22 %; p = 0.091). Twenty-four hour blood pressure burden was in fact lower in anticoagulant-associated intracerebral hemorrhage than in non-anticoagulant-associated intracerebral hemorrhage patients (p = 0.033). No association was found in anticoagulant associated intracerebral hemorrhage and non-anticoagulant-associated intracerebral hemorrhage between BP burden, hematoma expansion, and 30-day mortality. Conclusion We found no evidence that higher 24 h blood pressure burden is associated with hematoma expansion or mortality in anticoagulant-associated intracerebral hemorrhage. PMID- 27462096 TI - A randomized controlled trial on rehabilitation through caregiver-delivered nurse organized service programs for disabled stroke patients in rural china (the RECOVER trial): design and rationale. AB - RATIONALE: Stroke is the leading cause of death and disability in rural China. For stroke patients residing in resource-limited rural areas, secondary prevention and rehabilitation are largely unavailable, and where present, are far below evidence-based standards. AIM: This study aims to develop and implement a simplified stroke rehabilitation program that utilizes nurses and family caregivers for service delivery, and evaluate its feasibility and effectiveness in rural China. METHODS AND DESIGN: This 2-year randomized controlled trial is being conducted in 2-3 county hospitals located in northwest, northeast, and southwest China. Eligible and consenting stroke inpatients (200 in total) have been recruited and randomized into either a control or intervention group. Nurses in the county hospital are trained by rehabilitation specialists and in turn train the family caregivers in the intervention group. They also provide telephone follow-up care three times post discharge. The recruitment, baseline, intervention, follow-up care, and evaluation are guided by the RECOVER mobile phone app specifically designed for this study. STUDY OUTCOME: The primary outcome is patients' Barthel Index (activities of daily living: mobility, self care, and toileting) at 6 months. Process and economic evaluation will also be conducted. DISCUSSION: The results of our study will generate initial high quality evidence to improve stroke care in resource-scarce settings. If proven effective, this innovative care delivery model has the potential to improve the health and function of stroke patients, relieve caregiver burden, guide policy making, and advance translational research in the field of stroke care. PMID- 27462097 TI - Homocysteine lowering for stroke prevention: Unravelling the complexity of the evidence. AB - Elevated levels of total homocysteine impair endothelial dysfunction and increase thrombosis. Homocysteine is causal in animal models, and in human studies, elevated total homocysteine is significantly associated with carotid atherosclerosis, lacunar infarction, and markedly increased risk of stroke in atrial fibrillation. Because two of the early large trials of B vitamin therapy (Vitamin Intervention for Stroke Prevention and the Norwegian Vitamin Study) did not show any reduction of stroke, and the Heart Outcomes Prevention Evaluation 2 trial was mistakenly interpreted as not showing a reduction of stroke (because the authors could not think of a biological difference between stroke and myocardial infarction), there has been widespread pessimism regarding treatment to lower total homocysteine for stroke prevention. However, the Heart Outcomes Prevention Evaluation 2 trial, the French trial of folic acid and omega three oils, the Vitamins to Prevent Stroke subgroup excluding antiplatelet therapy all showed a significant reduction of stroke. Reasons why the Vitamin Intervention for Stroke Prevention trial were negative included folate fortification in North America, provision of injections of B12 to patients with low baseline serum B12, and as it turns out, harm from cyanide in cyanocobalamin among participants with impaired renal function. In the Diabetic Intervention with Vitamins in Nephropathy trial, B vitamins including cyanocobalamin were harmful, and in a Vitamin Intervention for Stroke Prevention subgroup excluding participants who received B12 injections and those with impaired renal function, there was a statistically significant reduction of stroke/myocardial infarction/vascular death. In 2015, the China Stroke Primary Prevention Trial (CSPPT), in over 20,000 participants followed for 5 years, showed a significant reduction of stroke with folic acid in a setting where folate fortification has not been implemented. In the setting of folate fortification, the main causes of elevated total homocysteine are renal failure and metabolic B12 deficiency; the latter is very common among stroke patients (30% over age 71), and frequently missed. Serum B12 and total homocysteine should be checked routinely in stroke patients and elevated total homocysteine should be treated. PMID- 27462098 TI - Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease. AB - BACKGROUND: Moyamoya disease is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for Moyamoya disease in East Asian countries. However, the pathogenesis of Moyamoya disease remains unclear. METHODS: We prospectively analyzed clinical data for 139 patients with Moyamoya disease (108 bilateral Moyamoya disease, 31 unilateral Moyamoya disease), 61 patients with intracranial atherosclerotic stroke, and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor (VEGF) and receptor (VEGFR2), and antagonizing cytokine (endostatin)) and endothelial dysfunction (asymmetric dimethylarginine (ADMA), and nitric oxide and its metabolites (nitrite and nitrate)) between patients with Moyamoya disease and intracranial atherosclerotic stroke. We then performed path analysis to evaluate whether a certain protein biomarker mediates the association between genes and Moyamoya disease. RESULTS: Caveolin-1 level was decreased in patients with Moyamoya disease and markedly decreased in RNF213 variant carriers. Circulating factors such as VEGF and VEGFR2 did not differ among the groups. Markers for endothelial dysfunction were significantly higher in patients with intracranial atherosclerotic stroke but normal in those with Moyamoya disease. Path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 levels that could lead to Moyamoya disease. The level of combined marker of Moyamoya disease (caveolin-1) and intracranial atherosclerotic stroke (ADMA, an endothelial dysfunction marker) predicted Moyamoya disease with good sensitivity and specificity. CONCLUSION: Our results suggest that Moyamoya disease is a caveolae disorder but is not related to endothelial dysfunction or dysregulation of circulating cytokines. PMID- 27462099 TI - Hemodynamic correlates of transient cognitive impairment after transient ischemic attack and minor stroke: A transcranial Doppler study. AB - BACKGROUND AND AIMS: Transient cognitive impairment (TCI) on the Mini Mental State Evaluation score is common after transient ischemic attack/minor stroke and might identify patients at increased risk of dementia. We aimed to replicate TCI using the Montreal Cognitive Assessment (MoCA), compare it with persistent Mild Cognitive Impairment (PMCI), and to determine whether global cerebral hemodynamic changes could explain transient impairment. METHODS: Consecutive patients with transient ischemic attack/minor stroke (NIHSS <= 3) were assessed with the MoCA and transcranial Doppler ultrasound acutely and at 1 month. We compared patients with TCI (baseline MoCA < 26 with >= 2 points increase at 1 month), PMCI (MoCA < 26 with < 2 points increase), and no cognitive impairment (NCI; MoCA >= 26). RESULTS: Of 326 patients, 46 (14.1%) had PMCI, 98 (30.1%) TCI, and 182 (55.8%) NCI. At baseline, TCI patients had higher systolic blood pressure (150.95 +/- 21.52 vs 144.86 +/- 22.44 mmHg, p = 0.02) and lower cerebral blood flow velocities, particularly end-diastolic velocity (30.16 +/- 9.63 vs 35.02 +/- 9.01 cm/s, p < 0.001) and mean flow velocity (48.95 +/- 12.72 vs 54 +/- 12.46 cm/s, p = 0.001) than those with NCI, but similar clinical and hemodynamic profiles to those with PMCI. Systolic BP fell between baseline and 1 month (mean reduction = 14.01 +/- 21.26 mmHg) and end-diastolic velocity and mean flow velocity increased (mean increase = + 2.42 +/- 6.41 and 1.89 +/- 8.77 cm/s, respectively), but these changes did not differ between patients with TCI, PMCI, and NCI. CONCLUSIONS: TCI is detectable with the MoCA after transient ischemic attack and minor stroke and has similar clinical and hemodynamic profile to PMCI. However, TCI does not appear to be due to exaggerated acute reversible global hemodynamic changes. PMID- 27462101 TI - mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1alpha-dependent glycolytic pathway. AB - The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct innate and adaptive immune responses. Myeloid-derived suppressive cells (MDSCs) are a heterogeneous cell population that plays a crucial regulatory effect in immune-related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unexplored. Here, we show that mTOR signaling is a pivotal, negative determinant of MDSC function in immune-mediated hepatic injury (IMH) diseases. In the context of IMH, the blocking of mTOR with rapamycin or mTOR deficient CD11b+Gr1+ MDSCs mediates the protection against IMH; mTOR with rapamycin and mTOR-deficient CD11b+Gr1+ MDSCs are suppressive immune modulators that result in less IFN-gamma-producing TH1 cells and more Foxp3+ Tregs Mechanistically, mTOR activity down-regulation in MDSCs induced iNOS expressions and NO productions. Pharmacologic inhibitions of iNOS completely eliminate MDSC suppressive function and lose their inducible effects on T cell differentiation. Importantly, HIF1alpha-dependent glycolytic activity is responsible for mTOR deficient, increased MDSC functional changes in IMH inflammation. Thus, these data demonstrate that mTOR acts as a fundamental "rheostat" in MDSCs to link immunologic signals to glycolytic pathways and functional fitness and highlights a central role of metabolic programming of MDSC-suppressive activity in protecting against immune hepatic injuries. PMID- 27462102 TI - Reply to Davis-Stober et al.: Violations of rationality in a psychophysical task are not aggregation artifacts. PMID- 27462100 TI - Inflammatory responses to alcohol in the CNS: nuclear receptors as potential therapeutics for alcohol-induced neuropathologies. AB - Fetal alcohol spectrum disorder (FASD), which results from ethanol exposure during pregnancy, and alcohol use disorder (AUD), which includes both binge and chronic alcohol abuse, are strikingly common and costly at personal and societal levels. These disorders are associated with significant pathology, including that observed in the CNS. It is now appreciated in both humans and animal models that ethanol can induce inflammation in the CNS. Neuroinflammation is hypothesized to contribute to the neuropathologic and behavioral consequences in FASD and AUD. In this review, we: 1) summarize the evidence of alcohol-induced CNS inflammation, 2) outline cellular and molecular mechanisms that may underlie alcohol induction of CNS inflammation, and 3) discuss the potential of nuclear receptor agonists for prevention or treatment of neuropathologies associated with FASD and AUD. PMID- 27462103 TI - Reported violations of rationality may be aggregation artifacts. PMID- 27462104 TI - Reply to Varma: Elucidation of the signal origin for label-free, free-solution interactions. PMID- 27462105 TI - AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity. AB - Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1beta. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity. PMID- 27462106 TI - Structures of mammalian ER alpha-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals. AB - The biosynthesis of enveloped viruses depends heavily on the host cell endoplasmic reticulum (ER) glycoprotein quality control (QC) machinery. This dependency exceeds the dependency of host glycoproteins, offering a window for the targeting of ERQC for the development of broad-spectrum antivirals. We determined small-angle X-ray scattering (SAXS) and crystal structures of the main ERQC enzyme, ER alpha-glucosidase II (alpha-GluII; from mouse), alone and in complex with key ligands of its catalytic cycle and antiviral iminosugars, including two that are in clinical trials for the treatment of dengue fever. The SAXS data capture the enzyme's quaternary structure and suggest a conformational rearrangement is needed for the simultaneous binding of a monoglucosylated glycan to both subunits. The X-ray structures with key catalytic cycle intermediates highlight that an insertion between the +1 and +2 subsites contributes to the enzyme's activity and substrate specificity, and reveal that the presence of d mannose at the +1 subsite renders the acid catalyst less efficient during the cleavage of the monoglucosylated substrate. The complexes with iminosugar antivirals suggest that inhibitors targeting a conserved ring of aromatic residues between the alpha-GluII +1 and +2 subsites would have increased potency and selectivity, thus providing a template for further rational drug design. PMID- 27462107 TI - Hair cells use active zones with different voltage dependence of Ca2+ influx to decompose sounds into complementary neural codes. AB - For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca(2+) influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca(2+) influx ranged over ~20 mV. Ca(2+) influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca(2+) channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca(2+) influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca(2+) influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca(2+) influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca(2+) channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs. PMID- 27462109 TI - Stacked charge stripes in the quasi-2D trilayer nickelate La4Ni3O8. AB - The quasi-2D nickelate La4Ni3O8 (La-438), consisting of trilayer networks of square planar Ni ions, is a member of the so-called T' family, which is derived from the Ruddlesden-Popper (R-P) parent compound La4Ni3O10-x by removing two oxygen atoms and rearranging the rock salt layers to fluorite-type layers. Although previous studies on polycrystalline samples have identified a 105-K phase transition with a pronounced electronic and magnetic response but weak lattice character, no consensus on the origin of this transition has been reached. Here, we show using synchrotron X-ray diffraction on high-pO2 floating zone-grown single crystals that this transition is associated with a real space ordering of charge into a quasi-2D charge stripe ground state. The charge stripe superlattice propagation vector, q = (2/3, 0, 1), corresponds with that found in the related 1/3-hole doped single-layer R-P nickelate, La5/3Sr1/3NiO4 (LSNO-1/3; Ni(2.33+)), with orientation at 45 degrees to the Ni-O bonds. The charge stripes in La-438 are weakly correlated along c to form a staggered ABAB stacking that reduces the Coulomb repulsion among the stripes. Surprisingly, however, we find that the charge stripes within each trilayer of La-438 are stacked in phase from one layer to the next, at odds with any simple Coulomb repulsion argument. PMID- 27462108 TI - Impact of a homing intein on recombination frequency and organismal fitness. AB - Inteins are parasitic genetic elements that excise themselves at the protein level by self-splicing, allowing the formation of functional, nondisrupted proteins. Many inteins contain a homing endonuclease (HEN) domain and rely on its activity for horizontal propagation. However, successful invasion of an entire population will make this activity redundant, and the HEN domain is expected to degenerate quickly under these conditions. Several theories have been proposed for the continued existence of the both active HEN and noninvaded alleles within a population. However, to date, these models were not directly tested experimentally. Using the natural cell fusion ability of the halophilic archaeon Haloferax volcanii we were able to examine this question in vivo, by mating polB intein-positive [insertion site c in the gene encoding DNA polymerase B (polB-c)] and intein-negative cells and examining the dispersal efficiency of this intein in a natural, polyploid population. Through competition between otherwise isogenic intein-positive and intein-negative strains we determined a surprisingly high fitness cost of over 7% for the polB-c intein. Our laboratory culture experiments and samples taken from Israel's Mediterranean coastline show that the polB-c inteins do not efficiently take over an inteinless population through mating, even under ideal conditions. The presence of the HEN/intein promoted recombination when intein-positive and intein-negative cells were mated. Increased recombination due to HEN activity contributes not only to intein dissemination but also to variation at the population level because recombination tracts during repair extend substantially from the homing site. PMID- 27462110 TI - Peripheral tolerance can be modified by altering KLF2-regulated Treg migration. AB - Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels. PMID- 27462112 TI - Article does not explain the origin of free-solution protein interaction signals. PMID- 27462111 TI - Dimerization of visual pigments in vivo. AB - It is a deeply engrained notion that the visual pigment rhodopsin signals light as a monomer, even though many G protein-coupled receptors are now known to exist and function as dimers. Nonetheless, recent studies (albeit all in vitro) have suggested that rhodopsin and its chromophore-free apoprotein, R-opsin, may indeed exist as a homodimer in rod disk membranes. Given the overwhelmingly strong historical context, the crucial remaining question, therefore, is whether pigment dimerization truly exists naturally and what function this dimerization may serve. We addressed this question in vivo with a unique mouse line (S opsin(+)Lrat(-/-)) expressing, transgenically, short-wavelength-sensitive cone opsin (S-opsin) in rods and also lacking chromophore to exploit the fact that cone opsins, but not R-opsin, require chromophore for proper folding and trafficking to the photoreceptor's outer segment. In R-opsin's absence, S-opsin in these transgenic rods without chromophore was mislocalized; in R-opsin's presence, however, S-opsin trafficked normally to the rod outer segment and produced functional S-pigment upon subsequent chromophore restoration. Introducing a competing R-opsin transmembrane helix H1 or helix H8 peptide, but not helix H4 or helix H5 peptide, into these transgenic rods caused mislocalization of R-opsin and S-opsin to the perinuclear endoplasmic reticulum. Importantly, a similar peptide-competition effect was observed even in WT rods. Our work provides convincing evidence for visual pigment dimerization in vivo under physiological conditions and for its role in pigment maturation and targeting. Our work raises new questions regarding a potential mechanistic role of dimerization in rhodopsin signaling. PMID- 27462113 TI - Reply to Westaway and Lyman: Emus, dingoes, and archaeology's role in conservation biology. PMID- 27462114 TI - The need to overcome risks associated with combining inadequate paleozoological records and conservation biology. PMID- 27462115 TI - Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia. AB - BACKGROUND AND PURPOSE: Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption. METHODS: Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression. RESULTS: Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013). CONCLUSIONS: This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator. PMID- 27462116 TI - Multiple Infarcts Are Associated With Long-Term Stroke Recurrence and All-Cause Mortality in Cryptogenic Stroke Patients. AB - BACKGROUND AND PURPOSE: Brain infarct patterns that are observed via diffusion weighted imaging are useful for classifying stroke subtypes. However, it is unclear whether infarct patterns can predict long-term outcomes in cryptogenic stroke patients. Herein, we investigated the association between acute brain infarct patterns and long-term stroke outcomes in cryptogenic stroke patients. METHODS: Acute cryptogenic stroke patients were consecutively enrolled between April 2008 and March 2012. Diffusion-weighted imaging ischemic lesion patterns were classified as single lesions, scattered lesions in one vascular territory, or multiple lesions in multiple vascular territories. Survivors (at discharge) were followed up for 3 years after stroke onset. RESULTS: A total of 272 cryptogenic stroke patients (132 women; aged 72+/-13 years) were enrolled. Among these patients, 169 (62.1%) had a single lesion, 38 (14.0%) had scattered lesions, and 65 (23.9%) had multiple lesions. Next, 261 patients (96.0%) were evaluated to assess right-to-left shunting, and 61 patients (23.4%) exhibited right-to-left shunting. On patient admission, right-to-left shunting and increased D-dimer levels were independently associated with multiple lesions but not single or scattered lesions. During the follow-up period (median, 1093 days), 30 patients (11.0%) developed recurrent stroke and 35 patients (12.9%) died. Multivariate Cox proportional hazard analyses showed that multiple infarcts were independently associated with recurrent stroke and all-cause mortality (hazard ratio, 3.79; 95% confidence interval, 2.24-6.37; P<0.001). CONCLUSIONS: Multiple brain infarcts on diffusion-weighted imaging were independently associated with long-term stroke outcomes in cryptogenic stroke patients. PMID- 27462117 TI - Incidence and Predictors of Early Recanalization After Intravenous Thrombolysis: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: After the demonstration of efficacy of bridging therapy, reliably predicting early recanalization (ER; <=3 hours after start of intravenous thrombolysis) would be essential to limit futile, resource-consuming, interhospital transfers. We present the first systematic review on the incidence and predictors of ER after intravenous thrombolysis alone. METHODS: We systematically searched for studies including patients solely treated by intravenous thrombolysis that reported incidence of ER and its association with baseline variables. Using meta-analyses, we estimated pooled incidence of ER, including according to occlusion site, and summarized the available evidence regarding predictors of no-ER. RESULTS: We identified 26 studies that together included 2063 patients. The overall incidence of partial or complete ER was 33% (95% confidence interval, 27-40). It varied according to occlusion site: 52% (39 64) for distal middle cerebral artery, 35% (28-42) for proximal middle cerebral artery, 13% (6-22) for intracranial carotid artery, and 13% (0-35) for basilar occlusion. Corresponding rates for complete ER were 38% (22-54), 21% (15-29), 4% (1-8), and 4% (0-22), respectively. Proximal occlusion and higher National Institute of Health Stroke Scale were the most consistent no-ER predictors. Other factors, such as long or totally occlusive thrombus and poor collateral circulation, emerged as potential predictors but will need confirmation. CONCLUSION: The overall incidence of ER after intravenous thrombolysis is substantial, highlighting the importance of reliably predicting ER to limit futile, interhospital transfers. Incidence of no-ER is particularly high for proximal occlusion and severe strokes. Given the scarcity of published data, further studies are needed to improve no-ER prediction accuracy. PMID- 27462118 TI - ALIAS (Albumin in Acute Ischemic Stroke) Trials: Analysis of the Combined Data From Parts 1 and 2. AB - BACKGROUND AND PURPOSE: The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size. METHODS: The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). RESULTS: The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87-15.57). CONCLUSIONS: Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00235495. PMID- 27462119 TI - Postmortem Study of Validation of Low Signal on Fat-Suppressed T1-Weighted Magnetic Resonance Imaging as Marker of Lipid Core in Middle Cerebral Artery Atherosclerosis. AB - BACKGROUND AND PURPOSE: High signal on T1-weighted fat-suppressed images in middle cerebral artery plaques on ex vivo magnetic resonance imaging was verified to be intraplaque hemorrhage histologically. However, the underlying plaque component of low signal on T1-weighted fat-suppressed images (LST1) has never been explored. Based on our experience, we hypothesized that LST1 might indicate the presence of lipid core within intracranial plaques. METHODS: 1.5 T magnetic resonance imaging was performed in the postmortem brains to scan the cross sections of bilateral middle cerebral arteries. Then middle cerebral artery specimens were removed for histology processing. LST1 presence was identified on magnetic resonance images, and lipid core areas were measured on the corresponding histology sections. RESULTS: Total 76 middle cerebral artery locations were included for analysis. LST1 showed a high specificity (96.9%; 95% confidence interval, 82.0%-99.8%) but a low sensitivity (38.6%; 95% confidence interval, 24.7%-54.5%) for detecting lipid core of all areas. However, the sensitivity increased markedly (81.2%; 95% confidence interval, 53.7%-95.0%) when only lipid cores of area >=0.80 mm(2) were included. Mean lipid core area was 5* larger in those with presence of LST1 than in those without (1.63+/-1.18 mm(2) versus 0.32+/-0.31 mm(2); P=0.003). CONCLUSIONS: LST1 is a promising imaging biomarker of identifying intraplaque lipid core, which may be useful to distinguish intracranial atherosclerotic disease from other intracranial vasculopathies and to assess plaque vulnerability for risk stratification of patients with intracranial atherosclerotic disease. In vivo clinical studies are required to explore the correlation between LST1 and clinical outcomes of patients with intracranial atherosclerotic disease. PMID- 27462121 TI - The combination of sequence-specific and nonspecific DNA-binding modes of transcription factor SATB1. AB - Transcription factor SATB1 (special AT-rich sequence binding protein 1) contains multiple DNA-binding domains (DBDs), i.e. two CUT-domain repeats (CUTr1 and CUTr2 from the N-terminus) and a homeodomain, and binds to the matrix attachment region (MAR) of DNA. Although CUTr1 and the homeodomain, but not CUTr2, are known to contribute to DNA binding, different research groups have not reached a consensus on which DBD is responsible for recognition of the target sequence in MAR, 5' TAATA-3'. Here, we used isothermal titration calorimetry to demonstrate that CUTr1 has binding specificity to this motif, whereas the homeodomain shows affinity for a variety of DNAs without specificity. In line with nonspecific DNA binding properties of the homeodomain, a mutation of the invariant Asn at position 51 of the homeodomain (typically in contact with the A base in a sequence-specific binding mode) did not affect the binding affinity significantly. The NMR analyses and computational modeling of the homeodomain, however, revealed the tertiary structure and DNA-binding mode that are typical of homeodomains capable of sequence-specific binding. We believe that the lack of highly conserved basic residues in the helix relevant to the base recognition loosens its fitting into the DNA groove and impairs the specific binding. The two DBDs, when fused in tandem, showed strong binding to DNA containing the 5'-TAATA 3' motif with an affinity constant >10(8) M(-1) and retained nonspecific binding activity. The combination of the sequence-specific and nonspecific DNA-binding modes of SATB1 should be advantageous in a search for target loci during transcriptional regulation. PMID- 27462122 TI - Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum. AB - Malaria is one of the world's most prevalent parasitic diseases, with over 200 million cases annually. Alarmingly, the spread of drug-resistant parasites threatens the effectiveness of current antimalarials and has made the development of novel therapeutic strategies a global health priority. Malaria parasites have a complicated lifecycle, involving an asymptomatic 'liver stage' and a symptomatic 'blood stage'. During the blood stage, the parasites utilise a proteolytic cascade to digest host hemoglobin, which produces free amino acids absolutely necessary for parasite growth and reproduction. The enzymes required for hemoglobin digestion are therefore attractive therapeutic targets. The final step of the cascade is catalyzed by several metalloaminopeptidases, including aminopeptidase P (APP). We developed a novel platform to examine the substrate fingerprint of APP from Plasmodium falciparum (PfAPP) and to show that it can catalyze the removal of any residue immediately prior to a proline. Further, we have determined the crystal structure of PfAPP and present the first examination of the 3D structure of this essential malarial enzyme. Together, these analyses provide insights into potential mechanisms of inhibition that could be used to develop novel antimalarial therapeutics. PMID- 27462120 TI - Persistence of circulating endothelial microparticles in COPD despite smoking cessation. AB - INTRODUCTION: Increasing evidence links COPD pathogenesis with pulmonary capillary apoptosis. We previously demonstrated that plasma levels of circulating microparticles released from endothelial cells (EMPs) due to apoptosis are elevated in smokers with normal spirometry but low diffusion capacity, that is, with early evidence of lung destruction. We hypothesised that pulmonary capillary apoptosis persists with the development of COPD and assessed its reversibility in healthy smokers and COPD smokers following smoking cessation. METHODS: Pulmonary function and high-resolution CT (HRCT) were assessed in 28 non-smokers, 61 healthy smokers and 49 COPD smokers; 17 healthy smokers and 18 COPD smokers quit smoking for 12 months following the baseline visit. Total EMP (CD42b-CD31+), pulmonary capillary EMP (CD42b-CD31+ACE+) and apoptotic EMP (CD42b-CD62E+/CD42b CD31+) levels were quantified by flow cytometry. RESULTS: Compared with non smokers, healthy smokers and COPD smokers had elevated levels of circulating EMPs due to active pulmonary capillary endothelial apoptosis. Levels remained elevated over 12 months in healthy smokers and COPD smokers who continued smoking, but returned to non-smoker levels in healthy smokers who quit. In contrast, levels remained significantly abnormal in COPD smokers who quit. CONCLUSIONS: Pulmonary capillary apoptosis is reversible in healthy smokers who quit, but continues to play a role in COPD pathogenesis in smokers who progressed to airflow obstruction despite smoking cessation. TRIAL REGISTRATION NUMBER: NCT00974064; NCT01776398. PMID- 27462124 TI - From the Editor's Desk, Editor's Highlights, Letters to the Editor. PMID- 27462125 TI - Three Years After. PMID- 27462123 TI - CD133-positive dermal papilla-derived Wnt ligands regulate postnatal hair growth. AB - Active Wnt/beta-catenin signaling in the dermal papilla (DP) is required for postnatal hair cycling. In addition, maintenance of the hair-inducing ability of DP cells in vitro requires external addition of Wnt molecules. However, whether DP cells are a critical source of Wnt ligands and induce both autocrine and paracrine signaling cascades to promote adult hair follicle growth and regeneration remains elusive. To address this question, we generated an animal model that allows inducible ablation of Wntless (Wls), a transmembrane Wnt exporter protein, in CD133-positive (CD133+) DP cells. CD133+ cells have been shown to be a specific subpopulation of cells in the DP, which possesses the hair inducing capability. Here, we show that ablation of Wls expression in CD133+ DP cells results in a shortened period of postnatal hair growth. Mutant hair follicles were unable to enter full anagen (hair growth stage) and progressed toward a rapid regression. Notably, reduced size of the DP and decreased expression of anagen DP marker, versican, were observed in hair follicles when CD133+ DP cells lost Wls expression. Further analysis showed that Wls-deficient CD133+ DP cells led to reduced proliferation and differentiation in matrix keratinocytes and melanocytes that are needed for the generation of the hair follicle structure and a pigmented hair shaft. These findings clearly demonstrate that Wnt ligands produced by CD133+ DP cells play an important role in postnatal hair growth by maintaining the inductivity of DP cells and mediating the signaling cross-talk between the mesenchyme and the epithelial compartment. PMID- 27462126 TI - MicroRNA Biomarkers of Toxicity in Biological Matrices. AB - Biomarker measurements that reliably correlate with tissue injury and that can be measured within accessible biofluids offer benefits in terms of cost, time, and convenience when assessing chemical and drug-induced toxicity in model systems or human cohorts. MicroRNAs (miRNAs) have emerged in recent years as a promising new class of biomarker for monitoring toxicity. Recent enthusiasm for miRNA biomarker research has been fueled by evidence that certain miRNAs are cell-type specific and are released during injury, thus raising the possibility of using biofluid based miRNAs as a "liquid biopsy" that may be obtained by sampling extracellular fluids. As biomarkers, miRNAs demonstrate improved stability as compared with many protein markers and sequences are largely conserved across species, simplifying analytical techniques. Recent efforts have sought to identify miRNAs that are released into accessible biofluids following xenobiotic exposure, using compounds that target specific organs. Whereas still early in the discovery phase, miRNA biomarkers will have an increasingly important role in the assessment of adverse effects of both environmental chemicals and pharmaceutical drugs. Here, we review the current findings of biofluid-based miRNAs, as well as highlight technical challenges in assessing toxicologic pathology using these biomarkers. PMID- 27462127 TI - Extensive Myocardial Infarction in a Fetus With Cystic Fibrosis and Meconium Peritonitis. PMID- 27462128 TI - Hip Gout Arthritis Revealed by Sonography. PMID- 27462129 TI - Dealing With the Processus Vaginalis: Last 25 Years' Data on Histology and Embryology Are Missing From a Series of Publications in the Imaging Literature. PMID- 27462130 TI - Reply. PMID- 27462131 TI - Comment on "Fetal Cardiac Screening: What Are We (and Our Guidelines) Doing Wrong?". PMID- 27462132 TI - Reply. PMID- 27462133 TI - Ultrastructural Localization of Endogenous Exchange Factor for ARF6 in Adrenocortical Cells In Situ of Mice. AB - EFA6 (exchange factor for ARF6) activates Arf6 (ADP ribosylation factor 6) by exchanging ADP to ATP, and the resulting activated form of Arf6 is involved in the membrane dynamics and actin re-organization of cells. The present study was attempted to localize EFA6 type D (EFA6D) in mouse adrenocortical cells in situ whose steroid hormone secretion is generally considered not to depend on the vesicle-involved regulatory mechanism. In immunoblotting, an immunoreactive band with the same size as brain EFA6D was detected in homogenates of adrenal cortical tissues almost free of adrenal capsules and medulla. In immuno-light microscopy, EFA6D-immunoreactivity was positive in adrenocortical cells and it was often distinct along the plasmalemma, especially along portions of the cell columns facing the interstitium. In immuno-electron microscopy, the gold-labeling was more dense in the peripheral intracellular domains than the central domain of the immunopositive cells. The labeling was deposited on the plasma membranes in a discontinuous pattern and in cytoplasmic domains rich in filaments. It was also associated with some, but not all, of pleiomorphic vesicles and coated pits/vesicles. No labeling was seen in association with lipid droplets or smooth endoplasmic reticulum. The present finding is in support of the importance of EFA6D for activation of Arf6 in adrenocortical cells. PMID- 27462134 TI - Aquaporin-4 Protein Is Stably Maintained in the Hypertrophied Muscles by Functional Overload. AB - Aquaporin-4 (AQP4) is a selective water channel that is located on the plasma membrane of myofibers in skeletal muscle and is bound to alpha1-syntrophin. It is considered that AQP4 is involved in the modulation of homeostasis in myofibers through the regulation of water transport and osmotic pressure. However, it remains unclear whether AQP4 expression is altered by skeletal muscle hypertrophy to modulate water homeostasis in myofibers. The present study investigated the effect of muscle hypertrophy on the changes in AQP4 and alpha1-syntrophin expression patterns in myofibers. Novel findings indicated in the present study were as follows: 1) Expression levels of AQP4 and alpha1-syntrophin were stably maintained in hypertrophied muscles, and 2) AQP4 was not expressed in the myofibers containing the slow-type myosin heavy chain isoform (MHC) with or without the presence of fast-type MHC. The present study suggests that AQP4 may regulate the efficiency of water transport in hypertrophied myofibers through its interaction with alpha1-syntrophin. In addition, this study suggests that AQP4 expression may be inhibited by a regulatory mechanism activated under physiological conditions that induces the expression of slow-type MHC in skeletal muscles. PMID- 27462135 TI - Regulation and Biological Significance of Formation of Osteoclasts and Foreign Body Giant Cells in an Extraskeletal Implantation Model. AB - The implantation of biomaterials induces a granulomatous reaction accompanied by foreign body giant cells (FBGCs). The characterization of multinucleated giant cells (MNGCs) around bone substitutes implanted in bone defects is more complicated because of healing with bone admixed with residual bone substitutes and their hybrid, and the appearance of two kinds of MNGCs, osteoclasts and FBGCs. Furthermore, the clinical significance of osteoclasts and FBGCs in the healing of implanted regions remains unclear. The aim of the present study was to characterize MNGCs around bone substitutes using an extraskeletal implantation model and evaluate the clinical significance of osteoclasts and FBGCs. Beta tricalcium phosphate (beta-TCP) granules were implanted into rat subcutaneous tissue with or without bone marrow mesenchymal cells (BMMCs), which include osteogenic progenitor cells. We also compared the biological significance of plasma and purified fibrin, which were used as binders for implants. Twelve weeks after implantation, osteogenesis was only detected in specimens implanted with BMMCs. The expression of two typical osteoclast markers, tartrate-resistant acid phosphatase (TRAP) and cathepsin-K (CTSK), was analyzed, and TRAP-positive and CTSK-positive osteoclasts were only detected beside bone. In contrast, most of the MNGCs in specimens without the implantation of BMMCs were FBGCs that were negative for TRAP, whereas the degradation of beta-TCP was detected. In the region implanted with beta-TCP granules with plasma, FBGCs tested positive for CTSK, and when beta-TCP granules were implanted with purified fibrin, FBGCs tested negative for CTSK. These results showed that osteogenesis was essential to osteoclastogenesis, two kinds of FBGCs, CTSK-positive and CTSK-negative, were induced, and the expression of CTSK was plasma-dependent. In addition, the implantation of BMMCs was suggested to contribute to osteogenesis and the replacement of implanted beta-TCP granules to bone. PMID- 27462136 TI - The Effect of Chronic Alprazolam Intake on Memory, Attention, and Psychomotor Performance in Healthy Human Male Volunteers. AB - Alprazolam is used as an anxiolytic drug for generalized anxiety disorder and it has been reported to produce sedation and anterograde amnesia. In the current study, we randomly divided 26 healthy male volunteers into two groups: one group taking alprazolam 0.5 mg and the other taking placebo daily for two weeks. We utilized the Cambridge Neuropsychological Test Automated Battery (CANTAB) software to assess the chronic effect of alprazolam. We selected Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) tests for memory, Rapid Visual Information Processing (RVP) for attention, and Choice Reaction Time (CRT) for psychomotor performance twice: before starting the treatment and after the completion of the treatment. We found statistically significant impairment of visual memory in one parameter of PAL and three parameters of DMS in alprazolam group. The PAL mean trial to success and total correct matching in 0-second delay, 4-second delay, and all delay situation of DMS were impaired in alprazolam group. RVP total hits after two weeks of alprazolam treatment were improved in alprazolam group. But such differences were not observed in placebo group. In our study, we found that chronic administration of alprazolam affects memory but attentive and psychomotor performance remained unaffected. PMID- 27462137 TI - Entire lacrimal sac within the ethmoid sinus: outcomes of powered endoscopic dacryocystorhinostomy. AB - BACKGROUND: The aim of this study was to report the outcomes of powered endoscopic dacryocystorhinostomy (PEnDCR) in patients with lacrimal sac within the sinus. MATERIALS AND METHODS: Retrospective analysis was performed on all patients who underwent PEnDCR and were intraoperatively documented to have complete lacrimal sac in sinus. Data collected included demographics, clinical presentations, associated lacrimal and nasal anomalies, intraoperative findings, intraoperative guidance, complications, postoperative ostium behavior, and anatomical and functional success. A minimum follow-up of 6 months postsurgery was considered for final analysis. RESULTS: A total of 17 eyes of 15 patients underwent PEnDCR using standard protocols, but with additional intraoperative guidance where required and careful maneuvering in the ethmoid sinus. The mean age of the patients was 37.2 (range 17-60) years. Of the unilateral cases, 69% (nine of 13) showed left-side predisposition; 80% of patients showed regurgitation on pressure over the lacrimal sac area. Associated lacrimal and nasal anomalies were observed in 13.3% (two of 15) and 40% (six of 15), respectively. At a mean follow-up of 6.6 months, anatomical and functional success were observed in 93.3% (14 of 15). One patient showed failure secondary to cicatricial closure of the ostium. CONCLUSION: An entire sac within an ethmoid sinus poses a surgical challenge. Good sinus-surgery training, thorough knowledge of endoscopic anatomy, careful maneuvering, and use of intraoperative navigation guidance result in good outcomes with PEnDCR. PMID- 27462138 TI - Age-dependent vitreous separation from the macula in a clinic population. AB - BACKGROUND: Vitreous degeneration begins soon after birth and accelerates throughout life. Vitreous liquefaction with a slowly progressive separation of the posterior hyaloid from the peripheral macula usually leads to complete posterior vitreous detachment. The purpose of this study is to measure the age related prevalence of partial vitreous separation and the length of residual vitreous adhesion in an ophthalmology clinic population. METHODS: Patients examined by the senior author (MWS) during a 6-month period were included in a retrospective chart review. Demographic data and spectral domain optical coherence tomography scan results were gathered. Data analysis with descriptive statistics focused on the prevalence and extent of partial vitreous separation. RESULTS: The mean age of the study patients was 69.9 years, and 62% were phakic. The highest prevalence of partial posterior hyaloid separation from the internal limiting membrane (71.2%) was seen in the 50- to 54-year age group. This prevalence rate steadily decreased to 5.6% in the 95- to 99-year age group. The prevalence of complete vitreous detachment as determined by slit-lamp biomicroscopy increased from 1.7% in the <50-year age group to a maximum of 29.2% in the 75- to 79-year group. The length of vitreomacular adhesion averaged 4.6 mm in the 50- to 54-year age group and steadily decreased to 2.1 mm in the 90- to 95 year group. CONCLUSION: Vitreomacular separation affects the majority of eyes in the sixth decade of life. The prevalence of partial vitreous separation decreases with advancing age, probably because an increasing number of these patients progress to complete posterior vitreous detachment. PMID- 27462139 TI - Guanine nucleotide exchange factor H1 can be a new biomarker of melanoma. AB - Guanine nucleotide exchange factor H1 (GEF-H1), which couples microtubule dynamics to RhoA activation, is a microtubule-regulated exchange factor. Studies have shown that GEF-H1 can be involved in various cancer pathways; however, the clinical significance of GEF-H1 expression and functions in melanoma has not been established. In this study, we investigated the relationship between clinical outcomes and GEF-H1 functions in melanoma. A total of 60 cases of different grades of melanoma samples were used to detect the expression of GEF-H1. Results showed that both messenger RNA and protein levels of GEF-H1 were significantly higher in high-grade melanomas. Furthermore, patients with high GEF-H1 expression had a shorter overall survival (22 months) than patients with low level of GEF-H1 expression (33.38 months). We also found that GEF-H1 can promote the proliferation and metastasis of melanoma cells. In summary, these results suggested that GEF-H1 may be a valuable biomarker for assessing the degree and prognosis of melanoma following surgery. PMID- 27462140 TI - Neutralizing activities of human immunoglobulin derived from donors in Japan against mosquito-borne flaviviruses, Japanese encephalitis virus, West Nile virus, and dengue virus. AB - Japanese encephalitis virus (JEV), West Nile virus (WNV), and dengue virus (DenV) are causal agents of Japanese encephalitis, West Nile fever, and dengue fever, respectively. JEV is considered to be indigenized and widespread in Japan, whereas WNV and DenV are not indigenized in Japan. Globulin products seem to reflect the status of the donor population according to antivirus neutralization activity. However, the anti-JEV, -WNV, and -DenV neutralization activities of globulin products derived from donors in Japan have not been clarified. Furthermore, potential candidates for the development of an effective immunotherapeutic drug for encephalitis caused by JEV, WNV, or DenV have also not been identified. Therefore, the aim of this study was to determine the overall status of the donor population in Japan based on globulin products by evaluating anti-JEV, -WNV, and -DenV neutralizing activities of intravenous immunoglobulin. Overall, intravenous immunoglobulin products showed stable neutralizing activity against JEV but showed no or only weak activity against WNV or DenV. These results suggest that the epidemiological level against WNV and DenV in the donor population of Japan is still low, suggesting that these viruses are not yet indigenized. In addition, JEV vaccinations and/or infections in the donor population do not induce a cross-reactive antibody against WNV. PMID- 27462141 TI - Cabozantinib in the treatment of advanced renal cell carcinoma: design, development, and potential place in the therapy. AB - The treatment of metastatic renal cell carcinoma (mRCC) has markedly improved over the last few years with the introduction of several targeted agents in clinical practice. Nevertheless, either primary or secondary resistance to inhibition of VEGF and mTOR pathways has limited the clinical benefit of these systemic treatments. Recently, a better understanding of the involvement of MET and its ligand HGF in many biological processes made this signaling pathway an attractive therapeutic target in oncology, particularly in mRCC. Herein, we review the development of cabozantinib, a recently approved inhibitor of multiple tyrosine kinase receptors, including MET, VEGFRs, and AXL, which has proven to increase progression-free survival and overall survival when compared to everolimus in mRCC patients who had progressed after VEGFR-targeted therapy. Finally, we discuss the potential role of cabozantinib within the current treatment landscape for mRCC. PMID- 27462142 TI - The effects of ferulic acid on the pharmacokinetics of warfarin in rats after biliary drainage. AB - According to previous research studies, warfarin can be detected in human bile after oral administration. Ferulic acid (FA) is the main bioactive component of many Chinese herbs for the treatment of cardiovascular disease. To elucidate the effects of FA on the pharmacokinetics of warfarin in rats after biliary drainage is necessary. Twenty rats were randomly divided into four groups: Group 1 (WN): healthy rats after the administration of warfarin sodium, Group 2 (WO): a rat model of biliary drainage after the administration of warfarin sodium, Group 3 (WFN): healthy rats after the administration of warfarin sodium and FA, and Group 4 (WFO): a rat model of biliary drainage after the administration of warfarin sodium and FA. Blood samples were collected at different time points after administration. The concentrations of blood samples were determined by ultraperformance liquid chromatography-tandem mass spectrometry. Comparisons between groups were performed according to the main pharmacokinetic parameters calculated by the DAS 2.1.1 software. The pharmacokinetic parameters showed a significant difference between the WN and WO groups, the WO group showed a decrease of 51% and 41.6% in area under the curve from 0 to time (AUC0- t ) and peak plasma concentration (C max), respectively, whereas time to C max (T max) was delayed 3.27 folds. There were significant differences between the WFO and WFN groups, the WFO group showed a decrease of 63.8% and 70% in AUC0- t and C max, respectively; the delay in T max between the WN and WFN groups (mean, from 132-432 minutes) was significantly different; the mean retention time from 0 to time (MRT0- t ) between the WO and WFO groups (mean, from 718.31-606.13 minutes) also showed a significant difference. Enterohepatic circulation markedly influences the disposition of warfarin in rats, and FA significantly affected the warfarin disposition in rat plasma. PMID- 27462143 TI - Effect of N-methyl deuteration on metabolism and pharmacokinetics of enzalutamide. AB - BACKGROUND: The replacement of hydrogen with deuterium invokes a kinetic isotope effect. Thus, this method is an attractive way to slow down the metabolic rate and modulate pharmacokinetics. PURPOSE: Enzalutamide (ENT) acts as a competitive inhibitor of the androgen receptor and has been approved for the treatment of metastatic castration-resistant prostate cancer by the US Food and Drug Administration in 2012. To attenuate the N-demethylation pathway, hydrogen atoms of the N-CH3 moiety were replaced by the relatively stable isotope deuterium, which showed similar pharmacological activities but exhibited favorable pharmacokinetic properties. METHODS: We estimated in vitro and in vivo pharmacokinetic parameters for ENT and its deuterated analog (d3-ENT). For in vitro studies, intrinsic primary isotope effects (K H/K D) were determined by the ratio of intrinsic clearance (CLint) obtained for ENT and d3-ENT. The CLint values were obtained by the substrate depletion method. For in vivo studies, ENT and d3-ENT were orally given to male Sprague Dawley rats separately and simultaneously to assess the disposition and metabolism of them. We also investigated the main metabolic pathway of ENT by comparing the rate of oxidation and hydrolysis in vitro. RESULTS: The in vitro CLint (maximum velocity/Michaelis constant [V max/K m]) of d3-ENT in rat and human liver microsomes were 49.7% and 72.9% lower than those of the non-deuterated compound, corresponding to the K H/K D value of ~2. The maximum observed plasma concentration, C max, and area under the plasma concentration -time curve from time zero to the last measurable sampling time point (AUC0-t) were 35% and 102% higher than those of ENT when orally administered to rats (10 mg/kg). The exposure of the N-demethyl metabolite M2 was eightfold lower, whereas that of the amide hydrolysis metabolite M1 and other minor metabolites was unchanged. The observed hydrolysis rate of M2 was at least ten times higher than that of ENT and d3-ENT in rat plasma. CONCLUSION: ENT was mainly metabolized through the "parent->M2->M1" pathway based on in vitro and in vivo elimination behavior. The observed in vitro deuterium isotope effect translated into increased exposure of the deuterated analog in rats. Once the carbon-hydrogen was replaced with carbon-deuterium (C-D) bonds, the major metabolic pathway was retarded because of the relatively stable C-D bonds. The systemic exposure to d3-ENT can increase in humans, so the dose requirements can be reduced appropriately. PMID- 27462144 TI - Rosmarinic acid ameliorates hyperglycemia and insulin sensitivity in diabetic rats, potentially by modulating the expression of PEPCK and GLUT4. AB - BACKGROUND: Rosmarinic acid (RA) is a natural substance that may be useful for treating diabetes mellitus. The present study investigated the effects of RA on glucose homeostasis and insulin regulation in rats with streptozocin (STZ) induced type 1 diabetes or high-fat diet (HFD)-induced type 2 diabetes. METHODS: Glucose homeostasis was determined using oral glucose tolerance tests and postprandial glucose tests, and insulin activity was evaluated using insulin tolerance tests and the homeostatic model assessment for insulin resistance. Additionally, the protein expression levels of PEPCK and GLUT4 were determined using Western blot analysis. RESULTS: RA administration exerted a marked hypoglycemic effect on STZ-induced diabetic rats and enhanced glucose utilization and insulin sensitivity in HFD-fed diabetic rats. These effects of RA were dose dependent. Meanwhile, RA administration reversed the STZ- and HFD-induced increase in PEPCK expression in the liver and the STZ- and HFD-induced decrease in GLUT4 expression in skeletal muscle. CONCLUSION: RA reduces hyperglycemia and ameliorates insulin sensitivity by decreasing PEPCK expression and increasing GLUT4 expression. PMID- 27462145 TI - A renewed Medication Adherence Alliance call to action: harnessing momentum to address medication nonadherence in the United States. AB - THE PROBLEM: Nonadherence to prescription medications is a common and costly problem with multiple contributing factors, spanning the dimensions of individual behavior change, psychology, medicine, and health policy, among others. Addressing the problem of medication nonadherence requires strategic input from key experts in a number of fields. MEETING OF EXPERTS: The Medication Adherence Alliance is a group of key experts, predominately from the US, in the field of medication nonadherence. Members include representatives from consumer advocacy groups, community health providers, nonprofit groups, the academic community, decision-making government officials, and industry. In 2015, the Medication Adherence Alliance convened to review the current landscape of medication adherence. The group then established three working groups that will develop recommendations for shifting toward solutions-oriented science. COMMENTARY OF EXPERT OPINION: From the perspective of the Medication Adherence Alliance, the objective of this commentary is to describe changes in the US landscape of medication adherence, framing the evolving field in the context of a recent think tank meeting of experts in the field of medication adherence. PMID- 27462146 TI - Electroencephalography-driven approach to prodromal Alzheimer's disease diagnosis: from biomarker integration to network-level comprehension. AB - Decay of the temporoparietal cortex is associated with prodromal Alzheimer's disease (AD). Additionally, shrinkage of the temporoparietal cerebral area has been connected with an increase in alpha3/alpha2 electroencephalogram (EEG) power ratio in prodromal AD. Furthermore, a lower regional blood perfusion has been exhibited in patients with a higher alpha3/alpha2 proportion when contrasted with low alpha3/alpha2 proportion. Furthermore, a lower regional blood perfusion and reduced hippocampal volume has been exhibited in patients with higher alpha3/alpha2 when contrasted with lower alpha3/alpha2 EEG power ratio. Neuropsychological evaluation, EEG recording, and magnetic resonance imaging were conducted in 74 patients with mild cognitive impairment (MCI). Estimation of cortical thickness and alpha3/alpha2 frequency power ratio was conducted for each patient. A subgroup of 27 patients also underwent single-photon emission computed tomography evaluation. In view of alpha3/alpha2 power ratio, the patients were divided into three groups. The connections among cortical decay, cerebral perfusion, and memory loss were evaluated by Pearson's r coefficient. Results demonstrated that higher alpha3/alpha2 frequency power ratio group was identified with brain shrinkage and cutdown perfusion inside the temporoparietal projections. In addition, decay and cutdown perfusion rate were connected with memory shortfalls in patients with MCI. MCI subgroup with higher alpha3/alpha2 EEG power ratio are at a greater risk to develop AD dementia. PMID- 27462148 TI - Successful device closure of a post-infarction ventricular septal defect. AB - Ventricular septal defect (VSD) is a lethal complication of myocardial infarction. The event occurs 2-8 days after an infarction and patients should undergo emergency surgical treatment. We report on successful device closure of post-infarction VSD. A previously healthy 66-year-old male was admitted with aggravated dyspnea. Echocardiography showed moderate left ventricular (LV) systolic dysfunction with akinesia of the left anterior descending (LAD) territory and muscular VSD size approximately 2 cm. Coronary angiography showed mid-LAD total occlusion without collaterals. Without percutaneous coronary intervention due to time delay, VSD repair was performed. However, a murmur was heard again and pulmonary edema was not controlled 3 days after the operation. Echocardiography showed remnant VSD, and medical treatment failed. Percutaneous treatment using a septal occluder device was decided on. After the procedure, heart failure was controlled and the patient was discharged without complications. This is the first report on device closure of post-infarction VSD in Korea. PMID- 27462147 TI - Safety and effectiveness of daily teriparatide in a prospective observational study in patients with osteoporosis at high risk of fracture in Japan: final report. AB - This postmarketing surveillance study assessed the safety and effectiveness of teriparatide in patients with osteoporosis at high risk of fracture in Japan. The patients received teriparatide 20 MUg daily by subcutaneous injection, for a maximum of 24 months. Safety and effectiveness analyses were based on data from 1,847 patients who were predominantly female (92.6%) with a mean age of 75.4 years. A total of 157 adverse drug reactions (ADRs) were reported in 140 (7.58%) patients; the most common ADRs were hyperuricemia, nausea, and dizziness. Only six (0.32%) patients reported serious ADRs, the most common being nausea (two patients; 0.1%). Persistence with teriparatide treatment was 60.8% and 39.1% at 18 and 24 months, respectively. There were significant increases in biomarkers for bone formation (procollagen type I N-terminal propeptide and bone-specific alkaline phosphatase) and bone resorption (collagen type I cross-linked C telopeptide and tartrate-resistant acid phosphatase 5b) throughout the study. These were accompanied by significant increases in bone mineral density and low incidences of new vertebral and nonvertebral fractures. Patient-reported measurements for health-related quality of life revealed significant improvements from baseline in back pain and overall health-related quality of life (Short Form 8TM health survey). The results of this 24-month postmarketing surveillance study imply that teriparatide has a favorable safety profile and is effective in the treatment of patients with osteoporosis at high risk of fracture in Japan. Teriparatide may also be a useful treatment for osteoporosis in other societies with aging populations. PMID- 27462149 TI - Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension. AB - INTRODUCTION: Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT) based functional respiratory imaging (FRI). METHODS: Six patients with secondary PH due to COPD received "pulsed" iNO in combination with oxygen for 20 minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings. RESULTS: Pulmonary blood vessel volume increased by 7.06%+/-5.37% after iNO. A strong correlation (Omega(2) 0=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation. CONCLUSION: Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted. PMID- 27462150 TI - The COPD assessment test and St George's Respiratory Questionnaire: are they equivalent in subjects with COPD? AB - BACKGROUND: The chronic obstructive pulmonary disease (COPD) assessment test (CAT) is a short questionnaire that has facilitated health status measurements in subjects with COPD. However, it remains controversial as to whether the CAT can be used as a suitable substitute for the St George's Respiratory Questionnaire (SGRQ). This study investigated the reliability and score distributions of the CAT and SGRQ and evaluated which factors contributed to health status for each questionnaire. METHODS: A total of 109 consecutive subjects with stable COPD from a single center were enrolled in this study. Each subject completed pulmonary function tests, exercise tests, and the following self-administered questionnaires: the Baseline Dyspnea Index, the Hospital Anxiety and Depression Scale, the CAT, and SGRQ. RESULTS: Internal consistencies of CAT and SGRQ total scores were both excellent (Cronbach's alpha coefficients =0.890 and 0.933). Statistically significant correlations were observed between CAT and SGRQ total scores (R=0.668, P<0.001). Correlations of CAT scores with parameters related to pulmonary function, dyspnea, exercise performance, and psychological factors were inferior to correlations with those parameters with SGRQ total scores. Both multiple regression analyses and principal component analyses revealed that there were slight differences between SGRQ total scores and CAT scores. CONCLUSION: The CAT is similar to SGRQ in terms of discriminating health status. However, we demonstrated that what is assessed by the CAT may differ slightly from what is measured by SGRQ. PMID- 27462151 TI - Multifunctional selenium nanoparticles as carriers of HSP70 siRNA to induce apoptosis of HepG2 cells. AB - Small interfering RNA (siRNA) as a new therapeutic modality holds promise for cancer treatment, but it is unable to cross cell membrane. To overcome this limitation, nanotechnology has been proposed for mediation of siRNA transfection. Selenium (Se) is a vital dietary trace element for mammalian life and plays an essential role in the growth and functioning of humans. As a novel Se species, Se nanoparticles have attracted more and more attention for their higher anticancer efficacy. In the present study, siRNAs with polyethylenimine (PEI)-modified Se nanoparticles (Se@PEI@siRNA) have been demonstrated to enhance the apoptosis of HepG2 cells. Heat shock protein (HSP)-70 is overexpressed in many types of human cancer and plays a significant role in several biological processes including the regulation of apoptosis. The objective of this study was to silence inducible HSP70 and promote the apoptosis of Se-induced HepG2 cells. Se@PEI@siRNA were successfully prepared and characterized by various microscopic methods. Se@PEI@siRNA showed satisfactory size distribution, high stability, and selectivity between cancer and normal cells. The cytotoxicity of Se@PEI@siRNA was lower for normal cells than tumor cells, indicating that these compounds may have fewer side effects. The gene-silencing efficiency of Se@PEI@siRNA was significantly much higher than Lipofectamine 2000@siRNA and resulted in a significantly reduced HSP70 mRNA and protein expression in cancer cells. When the expression of HSP70 was diminished, the function of cell protection was also removed and cancer cells became more sensitive to Se@PEI@siRNA. Moreover, Se@PEI@siRNA exhibited enhanced cytotoxic effects on cancer cells and triggered intracellular reactive oxygen species, and the signaling pathways of p53 and AKT were activated to advance cell apoptosis. Taken together, this study provides a strategy for the design of an anticancer nanosystem as a carrier of HSP70 siRNA to achieve synergistic cancer therapy. PMID- 27462152 TI - Lipid nanoparticles for targeted siRNA delivery - going from bench to bedside. AB - This review covers the basic aspects of small interfering RNA delivery by lipid nano-particles (LNPs) and elaborates on the current status of clinical trials for these systems. We briefly describe the roles of all LNP components and possible strategies for their improvement. We also focus on the current clinical trials using LNP-formulated RNA and the possible outcomes for therapy in the near future. Also, we present a critical analysis of selected clinical trials that reveals the common logic behind target selection. We address this review to a wide audience, especially to medical doctors who are interested in the application of RNA interference-based treatment platforms. We anticipate that this review may spark interest in this particular audience and generate new ideas in target selection for the disorders they are dealing with. PMID- 27462153 TI - Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer. AB - Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein)-coated magnetic iron oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF) of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP) were engineered on this nanoplatform. High drug loading (~25 wt%) and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T2-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO CDDP. Overall, our results suggest that ATF-CNIO-CDDP can be an effective theranostic platform for active targeting-enhanced and image-guided cancer treatment while simultaneously reducing the systemic toxicity. PMID- 27462154 TI - Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage. AB - Apatinib, a novel and selective inhibitor of vascular endothelial growth factor (VEGF) receptor 2, has been demonstrated recently to exhibit anticancer efficacy by inhibiting the VEGF signaling pathway. Given the importance of VEGF in retinal vascular leakage, the present study was designed to investigate whether apatinib loaded polymeric nanoparticles inhibit VEGF-mediated retinal vascular hyperpermeability and block diabetes-induced retinal vascular leakage. For the delivery of water-insoluble apatinib, the drug was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro paracellular permeability and transendothelial electric resistance assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles significantly inhibited VEGF-induced endothelial hyperpermeability in human retinal microvascular endothelial cells. In addition, they substantially reduced the VEGF induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes. In vivo intravitreal injection of Apa-HSA-PEG nanoparticles in mice blocked VEGF-induced retinal vascular leakage. These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood-retinal barrier. In vivo experiments with streptozotocin-induced diabetic mice showed that an intravitreal injection of Apa-HSA-PEG nanoparticles substantially inhibited diabetes-induced retinal vascular leakage. These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders. PMID- 27462155 TI - Risk-factor differences for nonsuicidal self-injury and suicide attempts in Mexican psychiatric patients. AB - BACKGROUND: The present study compared sociodemographic characteristics, comorbidities with substance use, and impulsivity features in three groups of psychiatric patients - suicide attempters, nonsuicidal self-injury, and nonsuicidal without self-injury - to determine the predictive factors for nonsuicidal self-injury or suicide behavior. PATIENTS AND METHODS: Demographic features and self-reported substance use were assessed in 384 Mexican psychiatric patients. Impulsivity features were evaluated using the Plutchik Impulsivity Scale. Comparison analyses between groups were performed and a logistic regression model used to determine the factors associated with nonsuicidal with self-injury behavior and suicidal behavior. RESULTS: Different predictive factors were observed for nonsuicidal self-injury and suicidal behavior. Females were more likely to present nonsuicidal self-injury behaviors (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.18-0.93; P=0.03). For suicide attempters, the factors associated were younger age (OR 0.89, 95% CI 0.85-0.93; P<0.001), less than 6 years of schooling (OR 0.2, 95% CI 0.06-0.6; P=0.004), and higher impulsivity traits, such as self-control (OR 1.19, 95% CI 1.03-1.36; P=0.01), planning of future actions (OR 0.79, 95% CI 0.66-0.95; P=0.01), and physiological behavior (OR 1.34, 95% CI 1.01-1.78; P=0.03). CONCLUSION: Our results show that in a Mexican population, impulsivity features are predictors for suicide attempts, but not for self-injury. Other factors related to sociocultural background and individual features (such as personality) may be involved in this behavioral distinction, and should be studied in future research aimed at better understanding of both self-harmful behaviors. PMID- 27462156 TI - Age at diagnosis of autism spectrum disorders: is there an association with socioeconomic status and family self-education about autism? AB - BACKGROUND: The marked increase in autism spectrum disorders (ASD) prevalence has stimulated worldwide interest in exploring broader circumstances of care of autistic children, including the role of socioeconomic status (SES) and family information on autism. METHODS: Our sample comprised of 160 children who participated in a diagnostic examination focused on autism, and their parents who completed a simple descriptive questionnaire focusing on the family situation as well as family self-education about autism. The diagnosis of ASD was confirmed in 120 children (75% of the sample; 94 boys, 26 girls) with mean age 6.2+/-2.7 years (median 5.3, range 2.2-17.2 years). In 71 autistic patients (59.2%), a diagnosis of mental retardation was also established. RESULTS: The age at diagnosis of ASD correlated negatively with maternal (P=0.014) and paternal (P=0.002) ages at the time of birth of the ASD child as well as with paternal (P=0.002) and maternal (P=0.050) education. The age at diagnosis of ASD did not correlate with family SES. Mothers were significantly more active in seeking information on autism than fathers or both parents equally (80 vs 9 vs 28 cases, respectively; P<0.001). The mean number of information sources on autism was 3.5+/-1.8 with a range 0-9. The mean number of resources did not differ among the three SES groups (3.50 vs 3.49 vs 4.25, respectively; P=0.704). The mean number of sources did not correlate with the age at diagnosis of ASD. The most often used sources were the Internet (81.7%), followed by psychologists (48.3%), books (46.7%), and child and adolescent psychiatrists (43.3%). CONCLUSION: An earlier diagnosis of ASD is associated with higher parental age at birth and higher parental education but not with family SES or number of family information sources. PMID- 27462157 TI - Decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor, tacrolimus, for leukemia. AB - BACKGROUND: The calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain. CASE: A 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN immunoreactive neurons in layers III-VI of the BA46 and the putamen tended to be lower in the tacrolimus case. CONCLUSION: Tacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia. PMID- 27462158 TI - Historical evolution of the concept of anorexia nervosa and relationships with orthorexia nervosa, autism, and obsessive-compulsive spectrum. AB - Eating disorders have been defined as "characterized by persistence disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food and that significantly impairs health or psychosocial functioning". The psychopathology of eating disorders changed across time under the influence of environmental factors, determining the emergence of new phenotypes. Some of these conditions are still under investigation and are not clearly identified as independent diagnostic entities. In this review, the historic evolution of the eating disorder concept up to the recent Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, has been evaluated. We also examined literature supporting the inclusion of new emergent eating behaviors within the eating disorder spectrum, and their relationship with anorexia, autism, and obsessive-compulsive disorder. In particular, we focused on what is known about the symptoms, epidemiology, assessment, and diagnostic boundaries of a new problematic eating pattern called orthorexia nervosa that could be accepted as a new psychological syndrome, as emphasized by an increasing number of scientific articles in the last few years. PMID- 27462159 TI - Relationship of attention-deficit/hyperactivity disorder symptom severity with severity of alcohol-related problems in a sample of inpatients with alcohol use disorder. AB - PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) has been shown to be related to a higher risk of developing psychiatric problems such as depressive disorders, substance use disorder, and impulsivity. Adults who have comorbid ADHD and alcohol use disorder (AUD) are at greater risk of negative outcomes. Thus, it is important to evaluate the relationship of ADHD symptoms and the severity of alcohol-related problems among patients with AUD. The aim of the present study was to evaluate the effect of ADHD symptoms on severity of alcohol-related problems, while controlling the effects of depression and impulsivity in a sample of inpatients with AUD. PATIENTS AND METHODS: Participants (n=190) were evaluated with the Beck Depression Inventory, the Short Form Barratt Impulsiveness Scale, the Michigan Alcohol Screening Test, and the Adult ADHD Self-Report Scale. RESULTS: Severity of the scale scores was positively correlated with each other. Although severity of depression and impulsivity (particularly non-planning impulsivity) predicted the severity of alcohol-related problems in a linear regression model, when severity of ADHD symptoms was included in the analysis, the inattentive subscale score, in particular, predicted the severity of alcohol related problems together with non-planning impulsivity, whereas depression was no longer a predictor. CONCLUSION: These findings suggest that, together with non planning impulsivity, symptoms of ADHD (particularly inattentive factor) are an important factor that predict alcohol-related problems, while controlling the severity of depressive symptoms among inpatients with AUD. PMID- 27462161 TI - Erratum: Profile of eliglustat tartrate in the management of Gaucher disease [Corrigendum]. AB - [This corrects the article on p. 53 in vol. 12, PMID: 26811686.]. PMID- 27462162 TI - Relationship between the iceA gene of Helicobacter pylori and clinical outcomes. AB - BACKGROUND: The complex pathogenesis of Helicobacter pylori (H. pylori) and the features of the host influence the diverse clinical outcomes. A mass of studies about virulence genes have accelerated the exploration of pathogenesis of H. pylori infection. Induced by contact with epithelium gene A (iceA) is one of the biggest concerned virulence genes. In this study, we explored the relationship between iceA and the magnitude of the risk for clinical outcomes and the prevalence of iceA-positive H. pylori in People's Republic of China and other countries. METHODS: We searched the electronic databases of PubMed, Embase, CNKI, VIP, and Wanfang by literature search strategy. The studies conforming to the inclusion criteria were assessed. With these data, we systematically analyzed the relationship between the iceA gene of H. pylori and clinical outcomes. RESULTS: Nineteen articles with 22 studies, a total of 2,657 cases, were involved in the study. The iceA1 gene was significantly associated with peptic ulcer disease (odds ratio =1.28, 95% confidence interval =1.03-1.60; P=0.03), especially in People's Republic of China (odds ratio =1.40, 95% confidence interval =1.07-1.83; P=0.01). Moreover, the prevalence of iceA1 was significantly higher than iceA2 in People's Republic of China (P<0.0001). The prevalence of both iceA1 and iceA2 was significantly different (P<0.0001) in People's Republic of China and in other countries. CONCLUSION: The system analysis showed that infection with the iceA1 positive H. pylori significantly increased the overall risk for peptic ulcer disease, especially in People's Republic of China. The iceA2 gene status and clinical outcome of H. pylori infection have no significant correlation. H. pylori iceA1 genotype is the major epidemic strain in People's Republic of China. PMID- 27462160 TI - Autism spectrum disorder in adults: diagnosis, management, and health services development. AB - Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by pervasive difficulties since early childhood across reciprocal social communication and restricted, repetitive interests and behaviors. Although early ASD research focused primarily on children, there is increasing recognition that ASD is a lifelong neurodevelopmental disorder. However, although health and education services for children with ASD are relatively well established, service provision for adults with ASD is in its infancy. There is a lack of health services research for adults with ASD, including identification of comorbid health difficulties, rigorous treatment trials (pharmacological and psychological), development of new pharmacotherapies, investigation of transition and aging across the lifespan, and consideration of sex differences and the views of people with ASD. This article reviews available evidence regarding the etiology, legislation, diagnosis, management, and service provision for adults with ASD and considers what is needed to support adults with ASD as they age. We conclude that health services research for adults with ASD is urgently warranted. In particular, research is required to better understand the needs of adults with ASD, including health, aging, service development, transition, treatment options across the lifespan, sex, and the views of people with ASD. Additionally, the outcomes of recent international legislative efforts to raise awareness of ASD and service provision for adults with ASD are to be determined. Future research is required to identify high-quality, evidence-based, and cost-effective models of care. Furthermore, future health services research is also required at the beginning and end of adulthood, including improved transition from youth to adult health care and increased understanding of aging and health in older adults with ASD. PMID- 27462163 TI - The value of intravoxel incoherent motion model-based diffusion-weighted imaging for outcome prediction in resin-based radioembolization of breast cancer liver metastases. AB - PURPOSE: To evaluate prognostic values of clinical and diffusion-weighted magnetic resonance imaging-derived intravoxel incoherent motion (IVIM) parameters in patients undergoing primary radioembolization for metastatic breast cancer liver metastases. SUBJECTS AND METHODS: A total of 21 females (mean age 54 years, range 43-72 years) with liver-dominant metastatic breast cancer underwent standard liver magnetic resonance imaging (1.5 T, diffusion-weighted imaging with b-values of 0, 50, and 800 s/mm(2)) before and 4-6 weeks after radioembolization. The IVIM model-derived estimated diffusion coefficient D' and the perfusion fraction f' were evaluated by averaging the values of the two largest treated metastases in each patient. Kaplan-Meier and Cox regression analyses for overall survival (OS) were performed. Investigated parameters were changes in f'- and D' values after therapy, age, sex, Eastern Cooperative Oncology Group (ECOG) status, grading of primary tumor, hepatic tumor burden, presence of extrahepatic disease, baseline bilirubin, previous bevacizumab therapy, early stasis during radioembolization, chemotherapy after radioembolization, repeated radioembolization and Response Evaluation Criteria in Solid Tumors (RECIST) response at 6-week follow-up. RESULTS: Median OS after radioembolization was 6 (range 1.5-54.9) months. In patients with therapy-induced decreasing or stable f' values, median OS was significantly longer than in those with increased f'-values (7.6 [range 2.6-54.9] vs 2.6 [range 1.5-17.4] months, P<0.0001). Longer median OS was also seen in patients with increased D'-values (6 [range 1.6-54.9] vs 2.8 [range 1.5-17.4] months, P=0.008). Patients with remission or stable disease (responders) according to RECIST survived longer than nonresponders (7.2 [range 2.6-54.9] vs 2.6 [range 1.5-17.4] months, P<0.0001). An ECOG status <=1 resulted in longer median OS than >1 (7.6 [range 2.6-54.9] vs 1.7 [range 1.5-4.5] months, P<0.0001). Pretreatment IVIM parameters and the other clinical characteristics were not associated with OS. Classification by f'-value changes and ECOG status remained as independent predictors of OS on multivariate analysis, while RECIST response and D'-value changes did not predict survival. CONCLUSION: Following radioembolization of breast cancer liver metastases, early changes in the IVIM model-derived perfusion fraction f' and baseline ECOG score were predictive of patient outcome, and may thus help to guide treatment strategy. PMID- 27462164 TI - Targeted therapy for localized non-small-cell lung cancer: a review. AB - Targeted therapies have markedly improved the management of patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy in localized NSCLC is less well established. The aim of this review is to analyze trials of targeted therapies in localized NSCLC. In patients with wild-type EGFR, tyrosine kinase inhibitors have shown no efficacy in Phase III trials. Few data are available for EGFR-mutated localized NSCLC, as routine biological profiling is not recommended. Available studies are small, often retrospectives, and/or conducted in a single-center making it difficult to draw firm conclusions. Ongoing prospective Phase III trials are comparing adjuvant tyrosine kinase inhibitor administration versus adjuvant chemotherapy. By analogy with the indication of bevacizumab in advanced NSCLC, use of antiangiogenic agents in the perioperative setting is currently restricted to nonsquamous NSCLC. Several trials of adjuvant or neoadjuvant bevacizumab are planned or ongoing, but for the moment there is no evidence of efficacy. Data on perioperative use of biomarkers in early-stage NSCLC come mainly from small, retrospective, uncontrolled studies. Assessment of customized adjuvant or neoadjuvant therapy in localized NSCLC (with or without oncogenic driver mutations) is a major challenge. PMID- 27462165 TI - Expression of G protein-coupled receptor 56 is associated with tumor progression in non-small-cell lung carcinoma patients. AB - BACKGROUND: G protein-coupled receptor 56 (GPR56) is an adhesion G protein coupled receptor with essential functions for cell physiology and survival, and its expression correlates with prognosis in a number of malignancies. The aim of this study is to determine the relationship of GPR56 expression with clinicopathological parameters and prognosis in non-small-cell lung carcinoma (NSCLC). METHODS: The levels of GPR56 were evaluated by immunohistochemistry in 157 NSCLC tissue samples. The association between GPR56 and clinicopathological parameters was evaluated by chi (2) test. Univariate and multivariate analyses were performed to demonstrate the prognosis role of GPR56. The function of GPR56 in NSCLC cell lines was also explored through overexpression and knockdown studies. RESULTS: The expression level of GPR56 in tumor tissues was significantly correlated with the TNM stage of NSCLC (P=0.005). Univariate and multivariate analyses revealed that GPR56 can act as an independent prognostic factor for overall survival. Furthermore, through overexpression and knockdown experiments, we confirmed that GPR56 can promote the proliferation and invasion of NSCLC cells. CONCLUSION: GPR56 plays an important role in tumor development and may serve as a promising target for prognostic prediction in NSCLC. PMID- 27462166 TI - Effect of evodiamine and berberine on miR-429 as an oncogene in human colorectal cancer. AB - Loss of epithelial organization and deregulated microRNAs are hallmarks of malignant carcinomas, but the relationship between them has been poorly understood. This study was designed to investigate the changes in the expression of E-cadherin, Par3, and miR-429 during the development of human colorectal cancer (CRC). E-cadherin and Par3 levels were quantitatively detected by immunohistochemistry and Western blotting. An in vitro culture of colorectal tissue was established to analyze the effect of berberine (BER) and evodiamine (EVO) on the level of miR-429. Our results suggested that E-cadherin and Par3 were remarkably decreased in tumor tissues compared with those in normal tissues, and miR-429 was upregulated in tumor tissues. After treatment of BER and EVO, the level of miR-429 was lower in tumor tissues than in normal tissues. This study investigated the potential relationship between miR-429, E-cadherin, and Par3 in CRC. The data suggested that BER and EVO can be potential therapeutic agents for CRC, as they downregulated the expression level of miR-429. PMID- 27462167 TI - Long-term survival and prognosis for primary clear cell carcinoma of the liver after hepatectomy. AB - BACKGROUND: The aim of this study was to investigate the long-term survival and prognosis for primary clear cell carcinoma of the liver (PCCCL) of the liver after hepatectomy. METHODS: Our study retrospectively analyzed the clinicopathological data of 64 patients with PCCCL (PCCCL group) and 247 with nonclear cell hepatocellular carcinoma (NHCC group) after hepatectomy between January 1996 and December 2006. The overall survival (OS) and disease-free survival of the two groups was compared using the Kaplan-Meier method. Prognostic factors of survival were identified by multivariate analysis. RESULTS: The 1-, 3 , and 5-year OS (P=0.016) and disease-free survival (P<0.001) of the PCCCL group were significantly higher than that of the NHCC group. In mutivariate analysis, tumor size >5 cm, presence of portal vein tumor thrombosis and proportion of clear cells <=70% were risk factors for OS of the PCCCL group. The prognosis of a subgroup with higher proportion of clear cells was markedly better than that of the subgroup with a lower proportion of clear cells. CONCLUSION: Our results suggested that the prognosis of patients with PCCCL was better than that of the patients with NHCC. The higher the proportion of clear cells, the better the prognosis. PMID- 27462168 TI - Fundamental effects of PD-1 antibody on the body: a brief report. AB - We report the case of a 61-year-old man with squamous cell carcinoma of the left lung and mediastinal lymph node metastases who received nivolumab and experienced a better antitumor effect than expected but died soon afterward. A clinical analysis showed that the grades of the treatment-related events did not cause death. The immunological impact of this treatment on his body, especially at his age and with concurrent infection, possibly augmented by the blockade of the PD 1/PD-L1 signaling pathway, is proposed to be one of the key factors for his death. Consequently, we suggest that the cellular immune status and the clinical characteristics of patients, especially the symptoms like concurrent infection, should be considered in the design of clinical protocol of such a kind of therapy. PMID- 27462169 TI - Blood oxygenation level-dependent magnetic resonance imaging during carbogen breathing: differentiation between prostate cancer and benign prostate hyperplasia and correlation with vessel maturity. AB - OBJECTIVE: The aim of this study was to investigate whether the blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) can evaluate tumor maturity and preoperatively differentiate prostate cancer (PCa) from benign prostate hyperplasia (BPH). PATIENTS AND METHODS: BOLD MRI based on transverse relaxation time*-weighted echo planar imaging was performed to assess PCa (19) and BPH (22) responses to carbogen (95% O2 and 5% CO2). The average signal values of PCa and BPH before and after carbogen breathing and the relative increased signal values were computed, respectively. The endothelial-cell marker, CD31, and the pericyte marker, alpha-smooth muscle actin (mature vessels), were detected with immunofluorescence, and were assessed by microvessel density (MVD) and microvessel pericyte density (MPD). The microvessel pericyte coverage index (MPI) was used to evaluate the degree of vascular maturity. The changed signal from BOLD MRI was correlated with MVD, MPD, and MPI. RESULTS: After inhaling carbogen, both PCa and BPH showed an increased signal, but a lower slope was found in PCa than that in BPH (P<0.05). PCa had a higher MPD and MVD but a lower MPI than BPH. The increased signal intensity was positively correlated with MPI in PCa and that in BPH (r=0.616, P=0.011; r=0.658, P=0.002); however, there was no correlation between the increased signal intensity and MPD or MVD in PCa than that in BPH (P>0.05). CONCLUSION: Our results confirmed that the increased signal values induced by BOLD MRI well differentiated PCa from BPH and had a positive correlation with vessel maturity in both of them. BOLD MRI can be utilized as a surrogate marker for the noninvasive assessment of the degree of vessel maturity. PMID- 27462170 TI - Prognostic significance of circulating laminin gamma2 for early-stage non-small cell lung cancer. AB - BACKGROUND: Laminin gamma2 (Ln-gamma2) chain, a distinctive subunit of heterotrimeric laminin-332, is frequently upregulated in carcinomas and is of great importance in cell migration and invasion. Despite this, the status of circulating Ln-gamma2 in lung cancer patients is still uncertain. PATIENTS AND METHODS: In this retrospective study, serum samples from 538 all-stage (stages I IV) patients with non-small-cell lung cancer (NSCLC) and 94 age-matched healthy volunteers were investigated by enzyme-linked immunosorbent assay. Data were statistically analyzed in combination with clinicopathological information. RESULTS: Circulating Ln-gamma2 was markedly increased in NSCLC, even in stage I cases (P<0.01), reflecting the progression of lung cancer. Survival analysis on 370 eligible patients indicated that serum Ln-gamma2-negative patients survived much longer compared with Ln-gamma2-positive individuals (P=0.028), and it was especially the case for stage I (P<0.001), stage T1 (P=0.001), and stage N0 patients (P=0.038), all of whom represented early-stage cases. For the advanced patients, however, overall survivals were not significantly different among stages II-IV (P=0.830), stages T2-T4 (P=0.575), stages N1-N3 (P=0.669), and stage M1 (P=0.849). Cox analysis subsequently defined serum Ln-gamma2 as an independent prognostic indicator of NSCLC, particularly for early-stage patients. Furthermore, we demonstrated the association of serum Ln-gamma2 with smoking behavior, but its association with tumor progression and early prognostic significance were not altered in the nonsmoking cohort. CONCLUSION: Our study demonstrated that elevation of circulating Ln-gamma2 was an early-emerging event in NSCLC and was significantly associated with poor prognosis in NSCLC, especially for early-stage cases. PMID- 27462172 TI - Erratum: Ignoring the sacroiliac joint in chronic low back pain is costly [Corrigendum]. AB - [This corrects the article on p. 23 in vol. 8, PMID: 26855595.]. PMID- 27462171 TI - Polymorphism in IGFBP3 gene is associated with prostate cancer risk: an updated meta-analysis. AB - OBJECTIVE: Insulin-like growth factor-binding protein-3 (IGFBP3) is the major protein that binds with insulin-like growth factor-1 (IGF-1) and is considered to be involved in the development and progression of various cancers. We aimed to examine the association between prostate cancer (PCa) and the IGFBP3 gene-202A/C polymorphism. METHODS: A comprehensive search within PubMed, EMBASE, and Cochrane Library was conducted to identify all case-control studies up to October 30, 2015, for a meta-analysis. Pooled odds ratios (ORs) and the 95% confidence intervals (CIs) were calculated using the fixed or random effects model. RESULTS: Eighteen studies including 10,538 cases and 10,078 controls were identified. Overall, the CC genotype of IGFBP3-202A/C polymorphism was associated with increased risk of PCa in homozygote comparison (CC vs AA - OR =1.16, 95% CI: 1.08 1.25) and in recessive model (CC vs AA+AC - OR =1.11, 95% CI: 1.04-1.17). In dominant model, the CC/AC genotypes also implicated an increased risk of PCa (CC+AC vs AA - OR =1.11, 95% CI: 1.05-1.19). The C allele of IGFBP3-202A/C polymorphism was the risk allele for PCa relative to the A allele (OR =1.09, 95% CI: 1.05-1.14). Further stratification analysis revealed that the association between -202A/C polymorphism and PCa risk among Caucasians, but not in other ethnicities, was statistically significant (recessive model, OR =1.10, 95% CI: 1.02-1.19). In addition, the IGFBP3-202A/C polymorphism was associated with PCa risk in both population-based and hospital-based studies in homozygote comparison, recessive model, and allele model. CONCLUSION: Our meta-analysis indicates that the IGFBP3-202A/C polymorphism is associated with the risk of PCa, particularly in Caucasians, with the C allele being the risk allele for PCa. PMID- 27462173 TI - Clinical, patient-related, and economic outcomes of home-based high-dose hemodialysis versus conventional in-center hemodialysis. AB - Despite technological advances in renal replacement therapy, the preservation of health and quality of life for individuals on dialysis still remains a challenge. The high morbidity and mortality in dialysis warrant further research and insight into the clinical domains of the technique and practice of this therapy. In the last 20 years, the focus of development in the field of hemodialysis (HD) has centered around adequate removal of urea and other associated toxins. High-dose HD offers an opportunity to improve mortality, morbidity, and quality of life of patients with end-stage kidney disease. However, the uptake of this modality is low, and the risk associated with the therapy is not fully understood. Recent studies have highlighted the evidence base and improved our understanding of this technique of dialysis. This article provides a review of high-dose and home HD, its clinical impact on patient outcome, and the controversies that exist. PMID- 27462176 TI - First molar health status in different craniofacial relationships. AB - OBJECTIVE: To investigate the association between the health status of permanent first molars and different craniofacial relationships among adolescents. STUDY DESIGN: This is a retrospective study on patients' records aged 11-15 years. Sex, skeletal relationship, vertical growth pattern, malocclusion, overjet, and overbite were assessed. The health status of permanent first molars was recorded from the orthopantomograms and intraoral photographs as "sound" and "not sound". Chi-square, Mann-Whitney U and Kruskal-Wallis tests, and Pearson's correlation coefficient were used to analyze and correlate the assessed variables. Significance level was set at P<0.05. RESULTS: A total of 210 records were evaluated; 81 were male, 68 had Class I and 91 had Class II skeletal relationships. More than half of the subjects had normal (n=67) to moderate deep bite (n=72); normal (n=91), moderately increased (n=54), to severely increased (n=50) overjet; and Class I (n=106) and Class II division 1 (n=75) malocclusion. Significant differences were found in the health status of the permanent first molars with respect to sex (P=0.034), vertical growth pattern (P=0.01), and overbite (P=0.047). Strong correlations were only found between the health status of the permanent first molars and the following variables: sex (P=0.036) and vertical growth pattern (P=0.004). Significant correlation was further found between the upper left first molar health status and sex (P=0.019) and the lower right first molar health status and the vertical growth pattern (P=0.001). No significant association was found with the anteroposterior craniofacial relationships (P>0.05). CONCLUSION: Sex difference and vertical growth patterns were found to be potential predictors of the health status of the permanent first molars. No significant association was found with the anteroposterior craniofacial relationships. PMID- 27462174 TI - Preoperative physical therapy treatment did not influence postoperative pain and disability outcomes in patients undergoing shoulder arthroscopy: a prospective study. AB - BACKGROUND: There is limited literature investigating preoperative physical therapy (pre-op PT) treatment on pain intensity and disability after musculoskeletal surgery. The purposes of the present cohort study were to describe patient characteristics for those who had and did not have pre-op PT treatment and determine whether pre-op PT influenced the length of postoperative physical therapy (post-op PT) treatment (number of sessions) and 3-month and 6 month postsurgical outcomes, such as pain intensity and disability. PATIENTS AND METHODS: A total of 124 patients (mean age =43 years, 81 males) with shoulder pain were observed before and after shoulder arthroscopic surgery. Demographic data, medical history, and validated self-report questionnaires were collected preoperatively and at 3 months and 6 months after surgery. Analysis of variance models were performed to identify differences across measures for patients who had pre-op PT treatment and those who did not and to examine outcome differences at 3 months and 6 months. Alpha was set at the 0.05 level for statistical significance. RESULTS: Males had less participation in pre-op PT than females (P=0.01). In contrast, age, pain intensity, disability, and pain-associated psychological factors did not differ between pre-op PT treatment groups (P>0.05). Subacromial bursectomies were more commonly performed in patients having pre-op PT treatment (P<0.05). Pre-op PT treatment did not influence length of post-op PT treatment and did not affect 3-month and 6-month pain intensity and disability outcomes. Differences in distribution of pre-op PT for males and females and subacromial bursectomy did not influence 3-month or 6-month postsurgical outcomes. CONCLUSION: Receiving pre-op PT treatment did not influence post-op PT treatment or pain and disability outcomes at 3 months and 6 months. This prospective cohort study provides no evidence of benefit for pre-op PT on post-op PT treatment or postsurgical outcomes. Females or patients receiving certain surgical procedures are more likely to undergo pre-op PT treatment. However, these differences did not influence postoperative outcomes in this cohort. PMID- 27462175 TI - Effects of low-dose ketamine on succinylcholine-induced postoperative myalgia in outpatient surgeries: a randomized, double-blind study. AB - OBJECTIVE: Despite the many complications of succinylcholine, it is still widely used as a superior muscle relaxant for rapid sequence induction. One of these complications is postoperative myalgia (POM). The aim of this study was to investigate the prophylactic effect of low-dose ketamine on the incidence and severity of POM. MATERIALS AND METHODS: In this double-blind clinical study, a total of 148 patients scheduled for general anesthesia were randomly divided into two equal groups. Initially, in Group K, 0.5 mg/kg of ketamine was injected intravenously, whereas in Group N, the same volume (5 mL) of normal saline was injected. Thereafter, anesthesia was induced in all patients, by injecting 1.5 mg/kg of fentanyl and 2 mg/kg of propofol intravenously. Following the loss of eyelid reflex, 1.5 mg/kg of succinylcholine was injected intravenously as a muscle relaxant and then the patients were intubated. POM was defined as a pain with no surgical interferences, and its intensity was graded based on a four point scale. The incidence and severity of myalgia were assessed by a blinded observer 24 hours after surgery. RESULTS: In terms of demographic data, the results of this study showed that there is no significant difference between patients in both groups (P>0.05). Overall, the incidence of POM in Group K was significantly less, when compared with Group N (P<0.05), but both groups were comparable based on the grade 2 of POM. After the induction of anesthesia, the systolic and diastolic blood pressure values were found to reduce in both groups (P<0.05). However, the changes were somehow similar, and repeated measures of variance analysis showed no significant difference in the two study groups (P>0.05). CONCLUSION: The addition of 0.5 mg/kg of ketamine to propofol for the induction of anesthesia can be effective in reducing the incidence of low-grade POM. PMID- 27462177 TI - Decreases in human immunodeficiency virus infection rates in Kombolcha, Ethiopia: a 10-year data review. AB - INTRODUCTION: Acquired immunodeficiency syndrome is one of the most serious public health and development challenges in sub-Saharan Africa, including Ethiopia. A particular challenge for prevention strategies has been the emergence of hotspot areas. Therefore, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome programs should not be based on national level statistics, but need to be more focused geographically. Kombolcha is one of the high spot areas with different projects and development corridors. Hence, the aim of this study is to assess the trend of HIV infection rates among patients who visited Africa Service Committee clinic from 2005 to 2014. METHODS: An institutional-based cross-sectional study was conducted from January 1 to January 30, 2016. All records of new patients enrolled from February 8, 2005 to December 31, 2014 were reviewed. Data on sociodemographic information, risky sexual behavior, and HIV test result were collected from each study participant using data collection format. Data were analyzed using SPSS version 20.0. A multivariate logistic regression model was used to identify risk factors of HIV infection. RESULTS: The overall HIV infection was 10.8% (2,233/20,674). The rate of infection varied from 13.3% in 2005 to 4.5% in 2014, and its trend had significantly declined from 2008 to 2014. Urban residence (adjusted odds ratio [AOR]: 2.53; 95% confidence interval [CI]: 1.22-5.25), patients who ever had intercourse with penetration (AOR: 5.62; 95% CI: 1.11-28.57), and those who had marriage experience (AOR: 11.65; 95% CI: 4.2-32.3) were more infected with HIV. CONCLUSION: The trend of HIV infection significantly reduced in the last 10 years in Kombolcha area. However, the HIV infection still remains high (4.5%) that needs intervention of those who had marriage experience, risky sexual behavior, and urban dwellers. PMID- 27462178 TI - Evaluation of cotrimoxazole use as a preventive therapy among patients living with HIV/AIDS in Gondar University Referral Hospital, northwestern Ethiopia: a retrospective cross-sectional study. AB - PURPOSE: Cotrimoxazole preventive therapy (CPT) is a feasible, inexpensive, and well-tolerated way of using cotrimoxazole intervention for patients living with HIV/AIDS to reduce HIV/AIDS-related morbidities and mortalities caused by various bacteria, fungi, and protozoa. The aim of this study was to evaluate the use of cotrimoxazole as a prophylaxis therapy among patients living with HIV/AIDS at Gondar University Referral Hospital (GURH), northwestern Ethiopia. MATERIALS AND METHODS: A retrospective cross-sectional study was used to evaluate the use of cotrimoxazole as a prophylaxis therapy among people living with HIV/AIDS at GURH, northwestern Ethiopia from September 2013 to October 2015. Medical records of 264 patients were selected by using systematic random sampling technique from the sampling frame list of all patients' medical records. Data were collected from patients' medical records using the structured checklist and evaluated against World Health Organization (WHO) guidelines on the use of cotrimoxazole prophylaxis. The quantitative data were analyzed using the statistical packages for social sciences Version 20. Descriptive and binary logistic regression analyses were used to describe and assess the association between different variables. RESULTS: Approximately 95 (36.0%) patients were at WHO clinical stage III at the start of CPT. The use of CPT was consistent with the guidelines in the rationale for indication 200 (75.75%) and dose 263 (99.62%), despite the presence of contraindications in 24 (9.90%) patients. The occurrence of cotrimoxazole associated side effects was higher in the first month of therapy. Problems regarding drug-drug interactions were identified in 63 (23.86%) patients, and 92 (34.84%) patients discontinued CPT due to different reasons. CONCLUSION: Although the practice of discontinuation of CPT and follow-up for adverse drug effects were not consistent with WHO guidelines on the rational use of cotrimoxazole prophylaxis, the use of CPT among people living with HIV/AIDS at GURH was appropriate. Health professionals who were working in the antiretroviral therapy units should update themselves and adhere to the available updated guidelines to reduce the occurrence of adverse effects and prophylaxis failure. PMID- 27462179 TI - Uterine cancer presenting as obstructive jaundice. AB - Obstructive jaundice as an initial manifestation of uterine cancer is extremely rare. We present a case of a 72-year-old female who presented with obstructive jaundice, supposedly for pancreatic cancer. After detailed diagnostic investigation, the cause of the jaundice was attributed to a metastatic compression of the common bile duct, from the primary neoplasm of the uterus. This case highlights the importance of including uterine cancer in the differential diagnosis of woman presenting with obstructive jaundice, even though it is very rare. PMID- 27462180 TI - The tongue after whiplash: case report and osteopathic treatment. AB - The tongue plays a fundamental role in several bodily functions; in the case of a dysfunction, an exhaustive knowledge of manual techniques to treat the tongue is useful in order to help patients on their path toward recovery. A 30-year-old male patient with a recent history of whiplash, with increasing cervical pain during swallowing and reduced ability to open the mouth, was treated with osteopathic techniques addressed to the tongue. The osteopathic techniques led to a disappearance of pain and the complete recovery of the normal functions of the tongue, such as swallowing and mouth opening. The manual osteopathic approach consists of applying a low load, in order to produce a long-lasting stretching of the myofascial complex, with the aim of restoring the optimal length of this continuum, decreasing pain, and improving functionality. According to the authors' knowledge, this is the first article reporting a case of resolution of a post whiplash disorder through osteopathic treatment of the tongue. PMID- 27462181 TI - Pupil-occluding organized hyphema anterior to the intraocular lens treated by neodymium: yttrium-aluminum-garnet laser: a case report. AB - We report, to our best knowledge, the first case of treatment of pupil-occluding postoperative organized hyphema anterior to the intraocular lens (IOL) using neodymium: yttrium-aluminum-garnet (Nd:YAG) laser. A 78-year-old Asian female underwent uneventful cataract operation. She had been taking aspirin, which she discontinued 1 week before surgery. Iris prolapse occurred at the end of the surgery, which led to intracameral bleeding. Two weeks later, her best-corrected visual acuity was hand motion. Although hyphema had decreased, pupil-occluding organized hematoma had formed anterior to the IOL. The blood clot anterior to the IOL was removed using Nd:YAG laser. One week later, although the hematoma anterior to the IOL resolved, endocapsular hematoma was observed, which was dispersed with Nd:YAG laser posterior capsulotomy. Two weeks later, her best corrected visual acuity improved to 20/60. There was no complication associated with Nd:YAG laser. In conclusion, pupil-occluding organized hyphema anterior to the IOL can occur as a complication of cataract surgery, in which Nd:YAG laser can be a useful treatment option. PMID- 27462184 TI - Learning approach among health sciences students in a medical college in Nepal: a cross-sectional study. PMID- 27462183 TI - Characterizing neuropathic pain profiles: enriching interpretation of painDETECT. AB - PURPOSE: To psychometrically evaluate painDETECT, a patient-reported screening questionnaire for neuropathic pain (NeP), for discriminating among sensory pain symptoms (burning, tingling/prickling, light touching, sudden pain attacks/electric shock-type pain, cold/heat, numbness, and slight pressure). METHODS: The seven-item version of painDETECT provides an overall score that targets only sensory symptoms, while the nine-item version adds responses on two items to the overall score, covering pain course pattern and pain radiation. Both versions have relevance in terms of characterizing broad NeP. The nine- and seven item versions of painDETECT were administered to subjects with confirmed NeP across six conditions identified during office visits to US community-based physicians. Responses on the sensory symptom items were dichotomized into "at least moderate" (ie, moderate, strongly, very strongly) relative to the combined other responses (never, hardly noticed, slightly). Logistic regression of dichotomized variables on the total painDETECT score provided probabilities of experiencing each symptom across the range of painDETECT scores. RESULTS: Both painDETECT versions discriminated among the symptoms with similar probabilities across the score ranges. Using these data, the probability of moderately experiencing each pain sensory item was estimated for a particular score, providing a pain profile. Additionally, the likelihood of experiencing each sensation was determined for a discrete increase in score, ie, the odds of at least a moderate sensation of burning (versus less than a moderate sensation) was 1.29 for a 1-point increase, 3.52 for a 5-point increase, and 12.42 for every 10 point increase in the nine-item painDETECT score. CONCLUSION: painDETECT differentiates pain profiles across the range of scores such that, for a particular score, the probability of experiencing at least a moderate sensation of each symptom was determined and compared. These results can help characterize NeP symptomatology, enrich interpretation of painDETECT scores, and provide a basis for individualizing NeP management. PMID- 27462182 TI - Multimorbidity in chronic disease: impact on health care resources and costs. AB - Effective and resource-efficient long-term management of multimorbidity is one of the greatest health-related challenges facing patients, health professionals, and society more broadly. The purpose of this review was to provide a synthesis of literature examining multimorbidity and resource utilization, including implications for cost-effectiveness estimates and resource allocation decision making. In summary, previous literature has reported substantially greater, near exponential, increases in health care costs and resource utilization when additional chronic comorbid conditions are present. Increased health care costs have been linked to elevated rates of primary care and specialist physician occasions of service, medication use, emergency department presentations, and hospital admissions (both frequency of admissions and bed days occupied). There is currently a paucity of cost-effectiveness information for chronic disease interventions originating from patient samples with multimorbidity. The scarcity of robust economic evaluations in the field represents a considerable challenge for resource allocation decision making intended to reduce the burden of multimorbidity in resource-constrained health care systems. Nonetheless, the few cost-effectiveness studies that are available provide valuable insight into the potential positive and cost-effective impact that interventions may have among patients with multiple comorbidities. These studies also highlight some of the pragmatic and methodological challenges underlying the conduct of economic evaluations among people who may have advanced age, frailty, and disadvantageous socioeconomic circumstances, and where long-term follow-up may be required to directly observe sustained and measurable health and quality of life benefits. Research in the field has indicated that the impact of multimorbidity on health care costs and resources will likely differ across health systems, regions, disease combinations, and person-specific factors (including social disadvantage and age), which represent important considerations for health service planning. Important priorities for research include economic evaluations of interventions, services, or health system approaches that can remediate the burden of multimorbidity in safe and cost-effective ways. PMID- 27462185 TI - Applicability of the 5S management method for quality improvement in health-care facilities: a review. AB - BACKGROUND: The 5S management method (where 5S stands for sort, set in order, shine, standardize, and sustain) was originally implemented by manufacturing enterprises in Japan. It was then introduced to the manufacturing sector in the West and eventually applied to the health sector for organizing and standardizing the workplace. 5S has recently received attention as a potential solution for improving government health-care services in low- and middle-income countries. We conducted a narrative literature review to explore its applicability to health care facilities globally, with a focus on three aspects: (a) the context of its application, (b) its impacts, and (c) its adoption as part of government initiatives. METHODS: To identify relevant research articles, we researched public health databases in English, including CINAHL, PubMed, ScienceDirect, and Web of Science. We found 15 of the 114 articles obtained from the search results to be relevant for full-text analysis of the context and impacts of the 5S application. To identify additional information particularly on its adoption as part of government initiatives, we also examined other types of resources including reference books, reports, didactic materials, government documents, and websites. RESULTS: The 15 empirical studies highlighted its application in primary health-care facilities and a wide range of hospital areas in Brazil, India, Jordan, Senegal, Sri Lanka, Tanzania, the UK, and the USA. The review also found that 5S was considered to be the starting point for health-care quality improvement. Ten studies presented its impacts on quality improvements; the changes resulting from the 5S application were classified into the three dimensions of safety, efficiency, and patient-centeredness. Furthermore, 5S was adopted as part of government quality improvement strategies in India, Senegal, Sri Lanka, and Tanzania. CONCLUSIONS: 5S could be applied to health-care facilities regardless of locations. It could be not only a tool for health workers and facility managers but also a strategic option for policymakers. They could consider 5S as the starting point of a government-led quality improvement initiative for improving safety, efficiency, or patient-centeredness aspects particularly in low- and middle-income countries. However, the evidence base, particularly in resource-poor settings, must be expanded. PMID- 27462186 TI - Topoisomerase IIbeta mediates the resistance of glioblastoma stem cells to replication stress-inducing drugs. AB - BACKGROUND: Glioblastoma stem cells (GSC) have been extensively recognized as a plausible cause of glioblastoma resistance to therapy and recurrence resulting in high glioblastoma mortality. Abnormalities in the DNA repair pathways might be responsible for the inability of the currently used chemotherapeutics to eliminate the (GSC) subpopulation. METHODS: In this work, we compared the expression of sixty DNA repair related genes between primary glioblastoma cell cultures and the glioblastoma enriched stem cell primary cultures. MTT test was used to analyze the effect of selected drugs and immunofluorescence to evaluate the load of DNA damage. RESULTS: We found several differentially expressed genes and we identified topoisomerase IIbeta (Top2beta) as the gene with highest up regulation in GSC. Also among the tested cell lines the expression of Top2beta was the highest in NCH421k cells, a well-characterized glioblastoma cell line with all the stemness characteristics. On the other hand, Top2beta expression markedly decreased upon the induction of differentiation by all trans-retinoic acid. Depletion of Top2beta increased the sensitivity of NCH421k cells to replication stress inducing drugs, such as cisplatin, methyl-methanesulfonate, hydrogen peroxide, and temozolomide. Consistently, we found an increased load of DNA damage and increased Chk1 activation upon Top2beta depletion in NCH421k cells. CONCLUSION: We suggest that Top2beta may represent a new target for gene therapy in glioblastoma. In addition, the other genes that we found to be up regulated in GSC versus glioblastoma primary cells should be further investigated as glioblastoma theranostics. PMID- 27462187 TI - Pulmonary Crohn's Disease in Down Syndrome: A Link or Linkage Problem. AB - Crohn's disease (CD) is an autoimmune inflammatory disorder that primarily affects the gastrointestinal tract. It may have pulmonary involvement, which has been rarely reported in pediatric patients. Down syndrome (DS) has been associated with increased frequency of autoimmune diseases. However, associations between CD and DS have been rarely reported. We present the case of a 5-year-old girl with known DS and a history of chronic intermittent abdominal pain who presented with persistent pneumonia. Her workup included a chest computed tomography (CT) scan that showed multiple noncalcified pulmonary nodules. An extensive infectious workup was done that was negative. CT-guided needle biopsy of the lung nodules showed necrotizing granulomas. This raised concern for primary CD with extraintestinal pulmonary manifestation. An esophagogastroduodenoscopy and colonoscopy were performed, and colon biopsies showed scattered epithelioid granulomas. Based on this information, there was consensus that her lung nodules were secondary to CD. She was started on standard therapy for CD, and her abdominal and respiratory symptoms gradually improved. However, she continues to have mild residual lung calcification and fibrosis. To our knowledge, this is the first reported case of pulmonary CD in a child with DS. The natural history of pulmonary CD in the pediatric population is not very well studied. Furthermore, since DS has been well known to be associated with increased frequency of malignancies and autoimmune conditions due to immune dysregulation, it is difficult to predict the severity and possible complications in this patient. PMID- 27462188 TI - Traumatic Gallbladder Rupture Treated by Laparoscopic Cholecystectomy. AB - Gallbladder rupture due to blunt abdominal injury is rare. There are few reports of traumatic gallbladder injury, and it is commonly associated with other concomitant visceral injuries. Therefore, it is difficult to diagnose traumatic gallbladder rupture preoperatively when it is caused by blunt abdominal injury. We report a patient who underwent laparoscopic cholecystectomy after an exact preoperative diagnosis of traumatic gallbladder rupture. A 43-year-old man was admitted to our hospital due to blunt abdominal trauma. The day after admission, abdominal pain and ascites increased and a muscular defense sign appeared. Percutaneous drainage of the ascites was performed, and the aspirated fluid was bloody and almost pure bile. He was diagnosed with gallbladder rupture by the cholangiography using the endoscopic retrograde cholangiopancreatography technique. Laparoscopic cholecystectomy was performed safely, and he promptly recovered. If accumulated fluids contain bile, endoscopic cholangiography is useful not only to diagnose gallbladder injury but also to determine the therapeutic strategy. PMID- 27462189 TI - Unintentional Long-Term Esophageal Stenting due to a Complete Response in a Patient with Stage UICC IV Adenocarcinoma of the Gastroesophageal Junction. AB - Endoscopic stent implantation is a common short-treatment option in palliative settings in patients with esophageal cancer. Advanced disease is associated with low survival rates; therefore, data on the long-term outcome are limited. So far, cases of long-term remission or even cure of metastasized adenocarcinoma of the gastroesophageal junction or stomach (AGS) have only been reported from Asia. A 51-year-old male patient primarily diagnosed with metastasized adenocarcinoma of the gastroesophageal junction (GEJ) [type I, cT3cN+cM1 (hep), CEA positive, UICC stage IV] received palliative esophageal stenting with a self-expandable metal stent. As disease progressed after four cycles with epirubicin, oxaliplatin, and capecitabin, treatment was changed to 5-FU and Irinotecan. The patient did not return after 5 cycles of FOLFIRI, but presented 4 years later with mild dysphagia. Endoscopy surprisingly revealed no relevant stenosis or stent migration. Repeated histological analyses of a residual mass at the GEJ did not detect malignancy. Since the initially diagnosed hepatic metastases were no longer detectable by computed tomography, cure from esophageal cancer was assumed. Dysphagia was ascribed to esophageal motility disorder by a narrowed esophageal lumen after long-term stenting. Thus, endoscopic stent implantation is an important method in palliative treatment of dysphagia related to AGS. New systemic treatment strategies like trastuzumab in Her2neu positive cases or new VEGF-inhibitors like ramucirumab will lead to more long-time survivors with AGS. In conclusion, future endoscopic treatment strategies in AGS represent a challenge for the development of new stent techniques in either extraction or programmed complete dissolution. PMID- 27462190 TI - The Challenging Buried Bumper Syndrome after Percutaneous Endoscopic Gastrostomy. AB - Buried bumper syndrome (BBS) is a rare complication developed after percutaneous endoscopic gastrostomy (PEG). We report a case of a 38-year-old male patient who sustained severe traumatic brain injury that was complicated with early BBS after PEG tube insertion. On admission, bedside PEG was performed, and 7 days later the patient developed signs of sepsis with rapid progression to septic shock and acute kidney injury. Abdominal CT scan revealed no collection or leakage of the contrast, but showed malpositioning of the tube bumper at the edge of the stomach and not inside of it. Diagnostic endoscopy revealed that the bumper was hidden in the posterolateral part of the stomach wall forming a tract inside of it, which confirmed the diagnosis of BBS. The patient underwent laparotomy with a repair of the stomach wall perforation, and the early postoperative course was uneventful. Acute BBS is a rare complication of PEG tube insertion which could be manifested with severe complications such as pressure necrosis, peritonitis and septic shock. Early identification is the mainstay to prevent such complications. Treatment selection is primarily guided by the presenting complications, ranging from simple endoscopic replacement to surgical laparotomy. PMID- 27462191 TI - Pleomorphic Carcinoma of the Colon: Morphological and Immunohistochemical Findings. AB - Pleomorphic carcinoma is an aggressive neoplasm defined by the World Health Organization (WHO) as a poorly differentiated (squamous cell carcinoma or adenocarcinoma) or undifferentiated carcinoma in which at least 10% spindle and/or giant cells are identified, or as a carcinoma constituted purely of spindle and giant cells. Although this entity has initially been shown in the lung, it has been described also in extrapulmonary locations, with only one report for a colonic site. A 65-year-old woman developed a caecal tumour. Gross examination revealed an endophytic/ulcerative mass 7 cm in length. Microscopically, the tumour was a poorly differentiated adenocarcinoma with a pleomorphic component that occupied more than 10% of the specimen. The tumour shared these histopathological findings with pulmonary giant cell carcinoma but differed in other clinicopathological features such as a pushing growth pattern, stage pT3N1, and an uneventful outcome 24 months after operation. The pleomorphic component showed morphological and immunohistochemical features compatible with mitotic catastrophe, a non-apoptotic cell death occurring in cycling cells after aberrant mitosis. These features included multinucleation, micronucleation, atypical mitoses, foci of geographic necrosis, as well as immunohistochemical overexpression of p53 and Ki-67. The interpretation of the pleomorphic component as morphological expression of mitotic catastrophe may be useful in comprehending the pathogenesis of this rare neoplasm, and it may have practical implications as a potential cancer therapeutic target. PMID- 27462192 TI - Synchronous Upper and Lower Gastrointestinal Mucosa-Associated Lymphoid Tissue Lymphomas. AB - Mucosa-associated lymphoid tissue lymphoma (MALToma) is a subtype of B-cell non Hodgkin's lymphoma, comprising ~17% of all gastrointestinal (GI) tract lymphomas. It is associated with chronic inflammation and autoimmunity, for example Helicobacter pylori gastritis and Sjogren's syndrome, respectively. Approximately 50% of GI MALTomas occur in the stomach, with small bowel and colonic lesions being less frequent. Synchronous upper and lower GI MALTomas occur rarely, with few cases reported. We present the case of a 73-year-old patient who presented with change in bowel habit and was found to have synchronous multifocal upper and lower GI MALTomas, which did not respond to H. pylori cure or to rituximab therapy, but did respond to a combination of surgery and chemotherapy with rituximab and bendamustine. PMID- 27462193 TI - Successful Eradication of Hepatitis C Virus by Interferon-Free Regimens in Two Patients with Advanced Liver Fibrosis following Kidney Transplantation. AB - Hepatitis C virus (HCV) infection leads to acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Following kidney transplantation, HCV increases the risk of graft loss and patient mortality compared with uninfected patients. The achievement of a sustained virological response with antiviral therapy improves survival and diminishes the risk of hepatic decompensation in HCV patients after a kidney transplant. It has been reported that direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of HCV in patients who are liver transplant recipients. In the present study, we investigated HCV eradication via interferon-free therapies with DAAs in two HCV patients with advanced liver fibrosis following renal transplantation. In both cases, the interferon-free regimens with DAAs were effective in eradicating HCV in the patients after kidney transplantation. No adverse events caused by interferon were identified with the exception of anemia. Interferon-free regimens with DAAs for recurrent HCV in patients following kidney transplantation are relatively safe and effective. However, attention should be focused on anemia during these treatments. PMID- 27462194 TI - Slow-Growing Early Adenocarcinoma Arising from Traditional Serrated Adenoma in the Duodenum. AB - Serrated polyps are classified into 3 distinct types: hyperplastic polyp, sessile serrated adenoma, or transitional serrated adenoma. A serrated adenoma is a precursor lesion for colorectal carcinoma. Serrated polyps are commonly found in the colorectum but have rarely been described in other parts of the gastrointestinal tract. Serrated adenomas in the small intestine may represent aggressive lesions with high malignant potential, according to some reports. A 66 year-old man with no significant medical history underwent esophagogastroduodenoscopy (EGD) for general examination. He had a 1-cm sized, Yamada type IV polyp, with focal white patch in the second portion of the duodenum. The biopsy result revealed gastric metaplasia and chronic inflammation. He wanted regular follow -up examinations. The follow-up EGDs were done every year. There were no changes in the shape and size of the polyp. The pathologic findings were unchanged. Then, he underwent EGD for general medical check-up again 5 years after the first detection. The size of the polyp was slightly increased. The biopsy result revealed serrated polyp, unclassified. Endoscopic mucosal resection was done. The pathologic result revealed a 0.8 * 0.5-cm sized, well differentiated tubular adenocarcinoma. Carcinomas are multifocally spread on the traditional serrated adenoma, and the proportion of the adenocarcinoma component is approximately 50%. The tumor had invaded the lamina propria but confined to the mucosa. The resection margins were negative, and no lymphovascular invasion or perineural invasion was seen. Abdominal pelvic computed tomography and positron emission tomography showed no other solid organ involvement or metastasis. Surveillance follow-up EGDs were done after 3 months and 1 year. There was no evidence of recurrence. PMID- 27462195 TI - Superior Mesenteric Vein Thrombosis Associated with Hormonal Contraceptive Use. AB - A 44-year-old woman was admitted with a 7-day history of lower abdominal pain and nausea. Physical examination demonstrated tenderness in the lower abdomen without signs of peritonitis. There were no specific findings in the laboratory evaluation. She had a history of dysmenorrhea for 15 years and was taking a combined hormonal contraceptive containing 0.02 mg ethinyl estradiol and 3 mg drospirenone for 19 months. Contrast-enhanced computed tomography showed superior mesenteric vein thrombosis (SMVT). Systemic anticoagulant infusion was immediately administered and the symptoms disappeared within 2 days. The thrombus disappeared after 3 months. This case report suggests that early diagnosis of SMVT and immediate systemic anticoagulant therapy may reduce the rate of intestinal infarction. PMID- 27462196 TI - Infected Urachal Cyst in an Adult: A Laparoscopic Approach. AB - Urachal cysts occur infrequently in adults and are rarely reported in the literature. Laparoscopic excision or robot-assisted laparoscopic excision of urachal cysts has widely been applied in recent years. We present a case of urachal cyst infection treated with antibiotics and two-staged operation. The laparoscopic procedure was performed without any complications. Strong suspicion is the key for early diagnosis. PMID- 27462197 TI - Unusual False-Positive Mesenteric Lymph Nodes Detected by PET/CT in a Metastatic Survey of Lung Cancer. AB - Positron emission tomography/computed tomography (PET/CT) is a credible diagnostic modality for detecting primary and metastatic malignancy. PET/CT sometimes shows false positives and negatives, which make clinical diagnosis difficult. A 42-year-old man who had undergone right upper lobectomy for lung cancer 1 year previously had PET/CT for a metastatic survey of the lung. The lung cancer was stage IB (pT2N0M0) bronchioloalveolar carcinoma. PET/CT showed massive (18)F-fluorodeoxyglucose (FDG) uptake in the mesenteric lymph nodes. Because the mesentery is an unusual site of metastasis, the patient was under watchful observation. Another PET/CT after 6 months still showed FDG uptake in the same location, with a slightly increased standard uptake value. A systemic survey was performed, but it did not reveal any malignancies or inflammatory diseases. Eventually, the patient underwent probing laparoscopic surgery. For complete resection of the lymph nodes, laparoscopic ileocecal resection was performed. Histologically, the resected lymph nodes showed reactive lymphadenitis. Glucose transporter 1 immunostainings of the lung cancer and the lymph node were positive and partially positive, respectively. Although PET/CT is a powerful diagnostic modality, clinical interpretation of unusual results is difficult. PMID- 27462198 TI - Long-Term Clinical Remission in Biologically Naive Crohn's Disease Patients with Adalimumab Therapy, Including Analyses of Switch from Adalimumab to Infliximab. AB - There is little evidence regarding the maintenance of long-term clinical remission by adalimumab (ADA) therapy in Crohn's disease (CD) patients naive to anti-tumor necrosis factor treatment (naive CD patients), since most CD patients are treated with ADA after infliximab (IFX) therapy. The long-term clinical response to ADA was retrospectively analyzed in 17 naive CD patients for at least 24 months, and the serum trough IFX levels were evaluated in patients switching from ADA to IFX. Of the 17 naive CD patients, 14 (82.4%) maintained long-term clinical remission with ADA therapy for at least 24 months, without serious adverse events. The clinical condition of 7 patients was observed for more than 36 months, and 3, 1, 1, and 2 cases maintained remission at months 42, 48, 54, and 60 after ADA therapy, respectively. Three patients (17.6%) switched from ADA to IFX less than 24 months after the start of ADA therapy, and they had remission, retaining trough levels of IFX higher than 1 MUg/ml, occasionally by dose escalation. In conclusion, maintenance ADA therapy achieves long-term clinical remission in naive CD patients. Switching from ADA to IFX is an important therapeutic option in CD patients showing loss of response to ADA, occasionally with dose escalation, based on the analysis of serum IFX trough levels. PMID- 27462199 TI - Concurrent Gastric Adenocarcinoma of Fundic Gland Type and Carcinoma with Lymphoid Stroma: A Rare Case Report. AB - Both gastric adenocarcinoma of fundic gland type (ADC-FG) and carcinoma with lymphoid stroma (lymphoepithelioma-like carcinoma, LELC) are relatively rare. Epstein-Barr virus (EBV) has been implicated in the pathogenesis of LELC. However, the pathogenesis of ADC-FG, as well as the role of EBV in the carcinogenesis of LELC, remain unclear and under debate. The current study presents a case of concurrent ADC-FG and LELC in the stomach in a 69-year-old man. Total gastrectomy was performed, and two separate masses were identified. Upon histological and immunohistochemical examination, the mass located in the lower body was determined to be LELC and the mass in the upper body was diagnosed as ADC-FG. The lesions were characterized by different mucin phenotypes and EBV in situ results. In the lower-body mass, EBV in situ hybridization expression was diffusely strongly positive, but MUC2, MUC5AC, MUC6, and CD10 were all negative. On the other hand, in the upper-body mass, the results were positive for MUC6 but negative for MUC2, MUC5AC, CD10, and EBV by in situ hybridization. The remaining gastric tissue was unremarkable, and perigastric lymph node metastases were absent. Seven months after the gastrectomy, a postoperative computed tomography scan revealed no recurrence or metastasis. PMID- 27462200 TI - Laparoscopic and Endoscopic Cooperative Surgery for Plexiform Angiomyxoid Myofibroblastic Tumor. AB - Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a recently described distinctive gastric mesenchymal entity with a peculiar plexiform pattern, bland spindle cells and a myxoid stroma rich in arborizing blood vessels. In this study, we report a new case of this rare gastric tumor resected by laparoscopic and endoscopic cooperative surgery (LECS). A 39-year-old Japanese man was admitted with a gastric mass. Gastroscopy showed an elevated mass in the anterior wall of the gastric antrum. Endoscopic ultrasound examination revealed a focal hypoechoic lesion protruding into the lumen. A partial gastrectomy by LECS was performed, and the patient made an uneventful recovery and remains well 9 months later. The tumor in this case depicted all the typical histopathologic and immunochemical features of gastric PAMT (c-kit negative and smooth muscle actin positive). Especially, it was characterized by multiple nodules protruding outward within the serosa. Therefore, it is important that the resection line is determined on the serosa to ensure the complete resection of these nodules together. PMID- 27462203 TI - Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia. AB - Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFalpha (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFalpha and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult. PMID- 27462202 TI - A Review of Control Strategies in Closed-Loop Neuroprosthetic Systems. AB - It has been widely recognized that closed-loop neuroprosthetic systems achieve more favorable outcomes for users then equivalent open-loop devices. Improved performance of tasks, better usability, and greater embodiment have all been reported in systems utilizing some form of feedback. However, the interdisciplinary work on neuroprosthetic systems can lead to miscommunication due to similarities in well-established nomenclature in different fields. Here we present a review of control strategies in existing experimental, investigational and clinical neuroprosthetic systems in order to establish a baseline and promote a common understanding of different feedback modes and closed-loop controllers. The first section provides a brief discussion of feedback control and control theory. The second section reviews the control strategies of recent Brain Machine Interfaces, neuromodulatory implants, neuroprosthetic systems, and assistive neurorobotic devices. The final section examines the different approaches to feedback in current neuroprosthetic and neurorobotic systems. PMID- 27462201 TI - From Genetics to Epigenetics: New Perspectives in Tourette Syndrome Research. AB - Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome. This review provides a summary of the recent findings in genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS. PMID- 27462205 TI - Transgenic Mouse Expressing Optical MicroRNA Reporter for Monitoring MicroRNA-124 Action during Development. AB - MicroRNAs (miRNAs) fine-tune target protein synthesis by suppressing gene expression, temporally changing along development and possibly in pathological conditions. A method to monitor the action of miRNAs in vivo shall help understand their dynamic behavior during development. In this study, we established a transgenic mouse harboring miR-124 responsive element in their luciferase-eGFP reporter transgenes which enabled monitoring the action of miR 124 in the brain and other organs in vivo by the bioluminescence imaging. The mouse model was produced and verified by imaging ex vivo so that luminescence by luciferase shone and then reduced during development with miR-124 expression. Bioluminescence dramatically decreased in the brain between embryonic day 13 and 16 as endogenous miR-124 expression increased, which sustained into adulthood. The inverse relationship of miR-124 expression was observed with luciferase bioluminescence and activity ex vivo as well as in vivo. Taken together, one can use this microRNA-transgenic mouse to investigate the temporal changes of microRNA action in vivo in the brain as well as in other organs. PMID- 27462204 TI - The Interaction between the Immune System and Epigenetics in the Etiology of Autism Spectrum Disorders. AB - Recent studies have firmly established that the etiology of autism includes both genetic and environmental components. However, we are only just beginning to elucidate the environmental factors that might be involved in the development of autism, as well as the molecular mechanisms through which they function. Mounting epidemiological and biological evidence suggest that prenatal factors that induce a more activated immune state in the mother are involved in the development of autism. In parallel, molecular studies have highlighted the role of epigenetics in brain development as a process susceptible to environmental influences and potentially causative of autism spectrum disorders (ASD). In this review, we will discuss converging evidence for a multidirectional interaction between immune system activation in the mother during pregnancy and epigenetic regulation in the brain of the fetus that may cooperate to produce an autistic phenotype. This interaction includes immune factor-induced changes in epigenetic signatures in the brain, dysregulation of epigenetic modifications specifically in genomic regions that encode immune functions, and aberrant epigenetic regulation of microglia. Overall, the interaction between immune system activation in the mother and the subsequent epigenetic dysregulation in the developing fetal brain may be a main consideration for the environmental factors that cause autism. PMID- 27462206 TI - Caveats in Transneuronal Tracing with Unmodified Rabies Virus: An Evaluation of Aberrant Results Using a Nearly Perfect Tracing Technique. AB - Apart from the genetically engineered, modified, strains of rabies virus (RABV), unmodified 'fixed' virus strains of RABV, such as the 'French' subtype of CVS11, are used to examine synaptically connected networks in the brain. This technique has been shown to have all the prerequisite characteristics for ideal tracing as it does not metabolically affect infected neurons within the time span of the experiment, it is transferred transneuronally in one direction only and to all types of neurons presynaptic to the infected neuron, number of transneuronal steps can be precisely controlled by survival time and it is easily detectable with a sensitive technique. Here, using the 'French' CVS 11 subtype of RABV in Wistar rats, we show that some of these characteristics may not be as perfect as previously indicated. Using injection of RABV in hind limb muscles, we show that RABV-infected spinal motoneurons may already show lysis 1 or 2 days after infection. Using longer survival times we were able to establish that Purkinje cells may succumb approximately 3 days after infection. In addition, some neurons seem to resist infection, as we noted that the number of RABV-infected inferior olivary neurons did not progress in the same rate as other infected neurons. Furthermore, in our hands, we noted that infection of Purkinje cells did not result in expected transneuronal labeling of cell types that are presynaptic to Purkinje cells such as molecular layer interneurons and granule cells. However, these cell types were readily infected when RABV was injected directly in the cerebellar cortex. Conversely, neurons in the cerebellar nuclei that project to the inferior olive did not take up RABV when this was injected in the inferior olive, whereas these cells could be infected with RABV via a transneuronal route. These results suggest that viral entry from the extracellular space depends on other factors or mechanisms than those used for retrograde transneuronal transfer. We conclude that transneuronal tracing with RABV may result in unexpected results, as not all properties of RABV seem to be ubiquitously valid. PMID- 27462207 TI - Feasibility of Diffusion Tractography for the Reconstruction of Intra-Thalamic and Cerebello-Thalamic Targets for Functional Neurosurgery: A Multi-Vendor Pilot Study in Four Subjects. AB - Functional stereotactic neurosurgery by means of deep brain stimulation or ablation provides an effective treatment for movement disorders, but the outcome of surgical interventions depends on the accuracy by which the target structures are reached. The purpose of this pilot study was to evaluate the feasibility of diffusion tensor imaging (DTI) based probabilistic tractography of deep brain structures that are commonly used for pre- and perioperative targeting for functional neurosurgery. Three targets were reconstructed based on their significance as intervention sites or as a no-go area to avoid adverse side effects: the connections propagating from the thalamus to (1) primary and supplementary motor areas, (2) to somatosensory areas and the cerebello-thalamic tract (CTT). We evaluated the overlap of the reconstructed connectivity based targets with corresponding atlas based data, and tested the inter-subject and inter-scanner variability by acquiring repeated DTI from four volunteers, and on three MRI scanners with similar sequence parameters. Compared to a 3D histological atlas of the human thalamus, moderate overlaps of 35-50% were measured between connectivity- and atlas based volumes, while the minimal distance between the centerpoints of atlas and connectivity targets was 2.5 mm. The variability caused by the MRI scanner was similar to the inter-subject variability, except for connections with the postcentral gyrus where it was higher. While CTT resolved the anatomically correct trajectory of the tract individually, high volumetric variability was found across subjects and between scanners. DTI can be applied in the clinical, preoperative setting to reconstruct the CTT and to localize subdivisions within the lateral thalamus. In our pilot study, such subdivisions moderately matched the borders of the ventrolateral posteroventral (VLpv) nucleus and the ventral-posterolateral (VPL) nucleus. Limitations of the currently used standard DTI protocols were exacerbated by large scanner-to-scanner variability of the connectivity-based targets. PMID- 27462208 TI - Evolutionary Basis of Human Running and Its Impact on Neural Function. AB - Running is not unique to humans, but it is seemingly a basic human capacity. This article addresses the evolutionary origins of humans running long distances, the basic physical capability of running, and the neurogenesis of aerobic fitness. This article more specifically speaks to the conditions that set the stage for the act of running, and then looks at brain expression, and longer-term consequences of running within a context of specific morphological features and diverse information molecules that participate in our capacity for running and sport. While causal factors are not known, we do know that physiological factors are involved in running and underlie neural function. Multiple themes about running are discussed in this article, including neurogenesis, neural plasticity, and memory enhancement. Aerobic exercise increases anterior hippocampus size. This expansion is linked to the improvement of memory, which reflects the improvement of learning as a function of running activity in animal studies. Higher fitness is associated with greater expansion, not only of the hippocampus, but of several other brain regions. PMID- 27462209 TI - Prenatal Stress, Fearfulness, and the Epigenome: Exploratory Analysis of Sex Differences in DNA Methylation of the Glucocorticoid Receptor Gene. AB - Exposure to stress in utero is a risk factor for the development of problem behavior in the offspring, though precise pathways are unknown. We examined whether DNA methylation of the glucocorticoid receptor gene, NR3C1, was associated with experiences of stress by an expectant mother and fearfulness in her infant. Mothers reported on prenatal stress and infant temperament when infants were 5 months old (n = 68). Buccal cells for methylation analysis were collected from each infant. Prenatal stress was not related to infant fearfulness or NR3C1 methylation in the sample as a whole. Exploratory sex-specific analysis revealed a trend-level association between prenatal stress and increased methylation of NR3C1 exon 1F for female, but not male, infants. In addition, increased methylation was significantly associated with greater fearfulness for females. Results suggest an experience-dependent pathway to fearfulness for female infants via epigenetic modification of the glucocorticoid receptor gene. Future studies should examine prenatal stress in a comprehensive fashion while considering sex differences in epigenetic processes underlying infant temperament. PMID- 27462211 TI - Transcranial Direct Current Stimulation (tDCS) of the Right Inferior Frontal Gyrus Attenuates Skin Conductance Responses to Unpredictable Threat Conditions. AB - Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition * tDCS for the SCR (F (2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t (24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders. PMID- 27462212 TI - Epileptic Electroencephalography Profile Associates with Attention Problems in Children with Fragile X Syndrome: Review and Case Series. AB - Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and a variant of autism spectrum disorder (ASD). The FXS population is quite heterogeneous with respect to comorbidities, which implies the need for a personalized medicine approach, relying on biomarkers or endophenotypes to guide treatment. There is evidence that quantitative electroencephalography (EEG) endophenotype-guided treatments can support increased clinical benefit by considering the patient's neurophysiological profile. We describe a case series of 11 children diagnosed with FXS, aged one to 14 years, mean 4.6 years. Case data are based on longitudinal clinically-observed reports by attending physicians for comorbid symptoms including awake and asleep EEG profiles. We tabulate the comorbid EEG symptoms in this case series, and relate them to the literature on EEG endophenotypes and associated treatment options. The two most common endophenotypes in the data were diffuse slow oscillations and epileptiform EEG, which have been associated with attention and epilepsy respectively. This observation agrees with reported prevalence of comorbid behavioral symptoms for FXS. In this sample of FXS children, attention problems were found in 37% (4 of 11), and epileptic seizures in 45% (5 of 11). Attention problems were found to associate with the epilepsy endophenotype. From the synthesis of this case series and literature review, we argue that the evidence-based personalized treatment approach, exemplified by neurofeedback, could benefit FXS children by focusing on observable, specific characteristics of comorbid disease symptoms. PMID- 27462210 TI - Distinct Brain and Behavioral Benefits from Cognitive vs. Physical Training: A Randomized Trial in Aging Adults. AB - Insidious declines in normal aging are well-established. Emerging evidence suggests that non-pharmacological interventions, specifically cognitive and physical training, may counter diminishing age-related cognitive and brain functions. This randomized trial compared effects of two training protocols: cognitive training (CT) vs. physical training (PT) on cognition and brain function in adults 56-75 years. Sedentary participants (N = 36) were randomized to either CT or PT group for 3 h/week over 12 weeks. They were assessed at baseline-, mid-, and post-training using neurocognitive, MRI, and physiological measures. The CT group improved on executive function whereas PT group's memory was enhanced. Uniquely deploying cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) MRI, the CT cohort showed increased CBF within the prefrontal and middle/posterior cingulate cortex (PCC) without change to CVR compared to PT group. Improvements in complex abstraction were positively associated with increased resting CBF in dorsal anterior cingulate cortex (dACC). Exercisers with higher CBF in hippocampi bilaterally showed better immediate memory. The preliminary evidence indicates that increased cognitive and physical activity improves brain health in distinct ways. Reasoning training enhanced frontal networks shown to be integral to top-down cognitive control and brain resilience. Evidence of increased resting CBF without changes to CVR implicates increased neural health rather than improved vascular response. Exercise did not improve cerebrovascular response, although CBF increased in hippocampi of those with memory gains. Distinct benefits incentivize testing effectiveness of combined protocols to strengthen brain health. PMID- 27462213 TI - Cathodal Transcranial Direct Current Stimulation on the Right Temporo-Parietal Junction Modulates the Use of Mitigating Circumstances during Moral Judgments. AB - Recently, a few transcranial magnetic stimulation or transcranial direct current stimulation (tDCS) studies have shown that the right temporo-parietal junction (rTPJ) plays a causal role in moral reasoning especially in cases of accidental harms or attempted harms. The profile of results across studies is, however, not entirely consistent: sometimes the stimulation affects predominantly attempted harms while sometimes the stimulation affects predominantly accidental harms. We argue that such discrepancy could reflect different functional contributions of the rTPJ in moral judgments and that the chosen design parameters or stimulation method may differentially bring to light one or the other functional role of the rTPJ. In the current study, we found that tDCS specifically affected accidental harms but not attempted harms. Low cathodal stimulation of the rTPJ led to a marginally significant increase in the severity of judgments of accidental harms (Experiment 1) while higher cathodal current density led to a highly significant decrease in the severity of judgments of accidental harms (Experiment 2). Our pattern of results in the context of our experimental design can best be explained by a causal role of the rTPJ in processing the mitigating circumstances which reduce a protagonist's moral responsibility. We discuss these results in relation to the idea that the rTPJ may play multiple roles in moral cognition and in relation to methodological aspects related to the use of tDCS. PMID- 27462214 TI - Subcortical Volumes Differ in Parkinson's Disease Motor Subtypes: New Insights into the Pathophysiology of Disparate Symptoms. AB - OBJECTIVES: Patients with Parkinson's disease (PD) can be classified, based on their motor symptoms into the Postural Instability Gait Difficulty (PIGD) subtype or the Tremor Dominant (TD) subtype. Gray matter changes between the subtypes have been reported using whole brain Voxel-Based Morphometry (VBM), however, the evaluation of subcortical gray matter volumetric differences between these subtypes using automated volumetric analysis has only been studied in relatively small sample sizes and needs further study to confirm that the negative findings were not due to the sample size. Therefore, we aimed to evaluate volumetric changes in subcortical regions and their association with PD motor subtypes. METHODS: Automated volumetric magnetic resonance imaging (MRI) analysis quantified the subcortical gray matter volumes of patients with PD in the PIGD subtype (n = 30), in the TD subtype (n = 30), and in 28 healthy controls (HCs). RESULTS: Significantly lower amygdala and globus pallidus gray matter volume was detected in the PIGD, as compared to the TD subtype, with a trend for an association between globus pallidus degeneration and higher (worse) PIGD scores. Furthermore, among all the patients with PD, higher hippocampal volumes were correlated with a higher (better) dual tasking gait speed (r = 0.30, p < 0.002) and with a higher global cognitive score (r = 0.36, p < 0.0001). Lower putamen volume was correlated with a higher (worse) freezing of gait score (r = -0.28, p < 0.004), an episodic symptom which is common among the PIGD subtype. As expected, differences detected between HCs and patients in the PD subgroups included regions within the amygdala and the dorsal striatum but not the ventral striatum, a brain region that is generally considered to be more preserved in PD. CONCLUSIONS: The disparate patterns of subcortical degeneration can explain some of the differences in symptoms between the PD subtypes such as gait disturbances and cognitive functions. These findings may, in the future, help to inform a personalized therapeutic approach. PMID- 27462215 TI - Uncontrolled Manifold Reference Feedback Control of Multi-Joint Robot Arms. AB - The brain must coordinate with redundant bodies to perform motion tasks. The aim of the present study is to propose a novel control model that predicts the characteristics of human joint coordination at a behavioral level. To evaluate the joint coordination, an uncontrolled manifold (UCM) analysis that focuses on the trial-to-trial variance of joints has been proposed. The UCM is a nonlinear manifold associated with redundant kinematics. In this study, we directly applied the notion of the UCM to our proposed control model called the "UCM reference feedback control." To simplify the problem, the present study considered how the redundant joints were controlled to regulate a given target hand position. We considered a conventional method that pre-determined a unique target joint trajectory by inverse kinematics or any other optimization method. In contrast, our proposed control method generates a UCM as a control target at each time step. The target UCM is a subspace of joint angles whose variability does not affect the hand position. The joint combination in the target UCM is then selected so as to minimize the cost function, which consisted of the joint torque and torque change. To examine whether the proposed method could reproduce human like joint coordination, we conducted simulation and measurement experiments. In the simulation experiments, a three-link arm with a shoulder, elbow, and wrist regulates a one-dimensional target of a hand through proposed method. In the measurement experiments, subjects performed a one-dimensional target-tracking task. The kinematics, dynamics, and joint coordination were quantitatively compared with the simulation data of the proposed method. As a result, the UCM reference feedback control could quantitatively reproduce the difference of the mean value for the end hand position between the initial postures, the peaks of the bell-shape tangential hand velocity, the sum of the squared torque, the mean value for the torque change, the variance components, and the index of synergy as well as the human subjects. We concluded that UCM reference feedback control can reproduce human-like joint coordination. The inference for motor control of the human central nervous system based on the proposed method was discussed. PMID- 27462216 TI - Affective Interaction with a Virtual Character Through an fNIRS Brain-Computer Interface. AB - Affective brain-computer interfaces (BCI) harness Neuroscience knowledge to develop affective interaction from first principles. In this article, we explore affective engagement with a virtual agent through Neurofeedback (NF). We report an experiment where subjects engage with a virtual agent by expressing positive attitudes towards her under a NF paradigm. We use for affective input the asymmetric activity in the dorsolateral prefrontal cortex (DL-PFC), which has been previously found to be related to the high-level affective-motivational dimension of approach/avoidance. The magnitude of left-asymmetric DL-PFC activity, measured using functional near infrared spectroscopy (fNIRS) and treated as a proxy for approach, is mapped onto a control mechanism for the virtual agent's facial expressions, in which action units (AUs) are activated through a neural network. We carried out an experiment with 18 subjects, which demonstrated that subjects are able to successfully engage with the virtual agent by controlling their mental disposition through NF, and that they perceived the agent's responses as realistic and consistent with their projected mental disposition. This interaction paradigm is particularly relevant in the case of affective BCI as it facilitates the volitional activation of specific areas normally not under conscious control. Overall, our contribution reconciles a model of affect derived from brain metabolic data with an ecologically valid, yet computationally controllable, virtual affective communication environment. PMID- 27462217 TI - A Patient with Giant Rippled-Pattern Sebaceoma in the Occipital Region. AB - A 72-year-old male visited a nearby hospital with a large tumor in his occipital region, which had existed since 20 years. Since malignant tumor was suspected, he was referred to our department. At the initial consultation, an elastic-hard, yellow-brown, sessile tumor, measuring 8 * 7 * 5 cm and with a flat surface, was observed in the occipital region. The tumor was resected and covered with artificial dermis. Histopathologically, the lesion was composed of basal-cell like cells with nest formation in the dermis. A rippled pattern, or the single line arrangement of tumor cells involving the stroma, was present. In addition, some tumor clusters revealed the differentiation to sebaceous glands, and these cells were positive for cytokeratin (AE1/AE3) and epithelial membrane antigen, which is consistent with the staining of sebaceous glands. On the contrary, tumor cells were negative for epithelial antigen (Ber-EP4), and Ki67 (MIB1) index was 5% or lower. Therefore, we diagnosed the tumor as rippled-pattern sebaceoma and not as basal cell carcinoma. Although this case was quite unique in its large size, immunostaining was useful for the definite diagnosis. PMID- 27462218 TI - Verrucous Hemangioma Treated with Electrocautery. AB - Verrucous hemangioma is a rare vascular malformation consisting of a proliferation of dilated blood vessels of different sizes that occupy the dermis and hypodermis. The epidermis of the affected area shows a strong proliferative reaction that presents as a warty appearance. Here, we report the case of a 17 year-old male who presented with an asymptomatic warty growth above the lateral malleolus on the right leg, which healed after electrocautery. PMID- 27462219 TI - Localized Eruptive Blue Nevi after Herpes Zoster. AB - A 52-year-old White man presented with a dozen small, well-restricted, punctiform, asymptomatic, blue-gray macules on the left shoulder. A few months earlier, he had been treated with oral acyclovir for herpes zoster (HZ) affecting the left C7-C8 dermatomes. All the blue macules appeared over a short period of time and then remained stable. The patient had not experienced any previous trauma or had tattooing in this anatomical region. The clinical diagnosis suggested blue nevi. Dermatoscopy revealed small, well-limited, dark-blue, compact, homogeneous areas evoking dermal blue nevi. An excisional biopsy was performed and the histological examination confirmed a blue nevus. As far as we are aware of, this is the first report of eruptive blue nevi following HZ, and it should be included in the differential diagnosis of zosteriform dermatoses responding to an isotopic pathway. In addition, a brief review concerning eruptive nevi is presented. PMID- 27462220 TI - Reactive Eccrine Syringofibroadenoma Associated with Neuropathy, Venous Stasis, and Diabetic Foot Ulcer. AB - Eccrine syringofibroadenoma (ESFA) is an uncommon benign adnexal neoplasm which derives from cells of the acrosyringium of eccrine sweat glands. The clinical appearance is nonspecific but the histological features are typical. Five clinical subtypes of ESFA exist: (1) solitary ESFA; (2) multiple ESFA associated with ectodermal dysplasia; (3) multiple ESFA without cutaneous features; (4) unilateral linear ESFA (nevoid), and (5) reactive ESFA associated with inflammatory or neoplastic dermatoses. We report the case of a 42-year-old man with long-standing diabetes and neuropathy, presenting with a 4-year history of asymptomatic erythematous plaques on a background of brown hyperpigmentation on the left foot. The clinical presentation and histopathological findings are compatible with reactive ESFA. PMID- 27462221 TI - RANKL-Expressing Ectopic Extramammary Paget's Disease on the Lower Abdomen. AB - Ectopic extramammary Paget's disease (EMPD) is a rare variant of EMPD that develops in nonapocrine regions. Since reports about ectopic EMPD are limited, little is known about the biological and immunological background of ectopic EMPD. In this report, we present a case of ectopic EMPD on the lower abdomen that expressed RANKL but lacked the expression of MMP7. As we previously reported, Paget's cells express RANKL and MMP7, release soluble RANKL in the tumor microenvironment, and stimulate tumor-associated macrophages to produce tumor loading factors in conventional EMPD. In our present case, both CCL5-expressing cells and MMP25-bearing cells were lacking, whereas substantial numbers of CCL5 expressing cells and MMP25-bearing cells were found in conventional EMPD. Our case suggested that the lack of MMP7 on Paget's cells might be one of the possible explanations for the biology of ectopic EMPD. PMID- 27462222 TI - A Patient with Refractory Psoriasis Who Developed Sebaceous Carcinoma on the Neck during Cyclosporine Therapy and Showed Rapid Progression. AB - We report a patient who developed sebaceous carcinoma on the neck during therapy with immunosuppressive agents (cyclosporine, corticosteroid, methotrexate) for refractory psoriasis vulgaris, which showed rapid enlargement, leading to a fatal outcome. Multiple-organ metastases were detected. Weekly carboplatin + paclitaxel therapy resulted in the disappearance of tumor cells, but the patient died of febrile neutropenia. The development of sebaceous carcinoma is rare among psoriasis patients receiving immunosuppressive agents including cyclosporine. PMID- 27462223 TI - Ulcers as a Sign of Skin Infection with Mycobacterium wolinskyi: Report of a Case and Review of the Literature. AB - Infection with Mycobacterium wolinskyi, if not detected, may cause severe skin and soft tissue infection with prolonged healing process and is therefore associated with high morbidity. Only about 20 cases of M. wolinskyi infections in humans have been described in the literature until now, none of them in Switzerland. We report a case of an infection in a 72-year-old male patient with recurrent subcutaneous abdominal wall abscesses and ulcer formation after insulin injection in the underbelly. A culture of skin biopsy tissue showed rapid growth of non-tuberculous mycobacteria (NTM), which were identified by 16S rRNA gene sequencing as M. wolinskyi. Surgical excision and primary closure of all abdominal ulcers in combination with antibiotic therapy, based on the antimicrobiotic susceptibility test results, were performed and resulted in complete resolution of the clinical symptoms and no recurrence of infection at a 6-month follow-up. The present case emphasizes the importance of accurate diagnosis and treatment of chronic infection with ulcer formation. In such cases, it is crucial to consider the presence of NTM, such as M. wolinskyi, in order to obtain rapid diagnosis, specific treatment and improved patient care. PMID- 27462224 TI - Keloidal Atypical Fibroxanthoma: Case and Review of the Literature. AB - Keloidal atypical fibroxanthoma (KAF) has recently been categorized as a variant of atypical fibroxanthoma. This paper will emphasize the importance of including KAF in both clinical and histological differential diagnosis of benign and malignant lesions which exhibit keloidal collagen and will also review the current literature on epidemiology, pathogenesis, histology, immunochemistry and treatments. PMID- 27462225 TI - Effects of Intravenous Ketamine Infusions in a Neuropathic Pain Patient with Lichen Sclerosus et Atrophicus. AB - A patient reported to the Florida Spine Institute (Clearwater, Fla., USA) with severe lichen sclerosus of the anogenital region and legs. The patient's pain presentation was neuropathic with hypersensitivity, allodynia, swelling, and weakness. The patient had failed multiple pain management modalities including opioid therapy, anticonvulsants, and antidepressants. The patient completed a standard intravenous ketamine infusion regimen developed at the Florida Spine Institute and reported complete abolishment of her pain syndrome. For the first time, we report that ketamine infusions also dramatically improved a patient's lichen sclerosus. That ketamine is known to have immunomodulatory properties, and given the clinical observations described in this case report, suggests that ketamine should be explored as a possible new therapeutic option for managing lichen sclerosus, especially in cases that are refractory to conventional therapies. PMID- 27462226 TI - A Pediatric Case of Acute Generalized Pustular Eruption without Streptococcal Infection. AB - Generalized pustular lesions characterized by acute onset with fever occur in pustulosis acuta generalisata, acute generalized exanthematous pustulosis, and generalized pustular psoriasis. In the present report, we describe a pediatric case of generalized pustular eruption that was not completely consistent with clinical features. Our patient had no evidence of a post-streptococcal infection. We observed scattered symmetric eruption of discrete pustules with an inflammatory halo on normal skin. The eruption was absent on her palms and soles of the feet. To the best of our knowledge, there are no reports in the English literature of cases with clinical features similar to those of our patient. PMID- 27462227 TI - Primary Effusion Lymphoma: Is Dose-Adjusted-EPOCH Worthwhile Therapy? AB - Primary effusion lymphoma (PEL) is a rare condition, which accounts for approximately 4% of all human immunodeficiency virus (HIV)-associated non-Hodgkin lymphomas. PEL has a predilection for body cavities and occurs in the pleural space, pericardium, and peritoneum. Without treatment, the median survival is approximately 2-3 months, and with chemotherapy, the median survival is approximately 6 months. We describe the case of a 47-year-old male with HIV and Kaposi's sarcoma who presented with complaints of abdominal pain and distension and was subsequently diagnosed with PEL. Despite limited clinical data being available, chemotherapy with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) has proven to increase survival rates in patients with this condition. PMID- 27462228 TI - Spinal Cord Compression Secondary to Extramedullary Hematopoiesis: Case Report and Review of the Literature. AB - Extramedullary hematopoiesis (EMH) is a rare cause of spinal cord compression (SCC). EMH represents the growth of blood cells outside of the bone marrow and occurs in a variety of hematologic illnesses, including various types of anemia and myeloproliferative disorders. Although EMH usually occurs in the liver, spleen, and lymph nodes, it may also occur within the spinal canal. When this occurs, the mass effect can compress the spinal cord, potentially leading to the development of neurological deficits. We present a case of SCC secondary to EMH. This report illustrates the importance of considering EMH in the differential diagnosis of SCC, even in the absence of signs of its most common etiologies. PMID- 27462229 TI - Small Cell Carcinoma of the Ovary (Hypercalcemic Type): Malignant Rhabdoid Tumor. AB - We present a rare case of malignant rhabdoid tumor (ovarian small cell carcinoma of hypercalcemic type) in a 24-year-old female with fulminant course. Clinically, hypercalcemia was not found at the time of primary diagnosis. However, it appeared later during the course of tumor progression. Histologically, the tumor showed classical features of small cell carcinoma of hypercalcemic type. Therapy included radical surgery with adjuvant chemotherapy. Despite this intensive therapy, the disease recurred and the patient died 10 months after the diagnosis. We discuss the diagnosis and therapy of this tumor, as well as its recent classification as malignant rhabdoid tumor. PMID- 27462230 TI - A Unique Hairy Cell Leukemia Variant. AB - A 65-year-old woman presented with easy bruising, left upper quadrant pain, decreased appetite, and weight loss. She had splenomegaly and lymphocytosis (lymphocyte count of 11.6 * 10(9)/l), with remarkably abnormal appearing morphology. Her hemoglobin and platelet counts were normal. Peripheral blood flow cytometry revealed a monoclonal B-cell population expressing CD11c, CD25, CD19, CD20, and CD103. An initial diagnosis of hairy cell leukemia (HCL) was made, and the patient was treated with a standard 5-day course of cladribine. However, her lymphocytosis improved transiently, with a relapse 4 months later. There was no improvement in her splenomegaly. An HCL variant (HCL-v) was considered based on her resistance to treatment with a purine nucleoside analog. A subsequent splenectomy improved symptoms. Two years after, the patient suffered a relapse and underwent 6 cycles of CHOP-R (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone, and rituximab), achieving partial remission. While under observation, she progressed with lymphocytosis 6 months later and was treated with pentostatin. There was no significant improvement in her disease, and she died 8 weeks following treatment initiation. HCL-v is a clinically more aggressive mature B-cell lymphoma than HCL with worse splenomegaly, higher lymphocyte counts, and resistance to typical HCL therapy with purine nucleoside analogs. Early recognition of HCL-v in the history, physical examination, and investigations with morphology and flow cytometry is key to patient management. Further, as in our case of HCL-v, cell morphology can be distinctly atypical, with large nucleoli and extremely convoluted nuclei. The distinction between HCL and HCL-v is important as HCL-v patients require more aggressive therapy and closer follow-up. PMID- 27462231 TI - A Case Report of Ischemic Stroke in a Patient with Metastatic Gastric Cancer Secondary to Treatment with the Vascular Endothelial Growth Factor Receptor-2 Inhibitor Ramucirumab. AB - Ramucirumab is an antiangiogenesis agent targeting the vascular endothelial growth factor receptor-2 (VEGFR-2), approved to treat advanced gastric and colon cancer. In clinical trials, it was shown to cause a small increase in arterial thromboembolism compared to placebo, including cerebral and myocardial ischemia, which was not statistically significant. Detailed case reports are lacking and we here present one of the first case reports of stroke secondary to ramucirumab induced in situ thrombosis. PMID- 27462232 TI - Spontaneous Hepatic Infarction in a Patient with Gallbladder Cancer. AB - Hepatic infarction is known as a rare disease entity in nontransplant patients. Although a few cases of hepatic infarction have been reported to be linked with invasive procedures, trauma, and hypercoagulability, a case of spontaneous hepatic infarction in a nontransplanted patient has hardly ever been reported. However, many clinical situations of patients with cancer, in particular biliary cancer, can predispose nontransplant patients to hepatic infarction. Besides, the clinical outcome of hepatic infarction in patients with cancer can be worse than in patients with other etiologies. As for treatment, anticoagulation treatment is usually recommended. However, because of its multifactorial etiology and combined complications, treatment of hepatic infarction is difficult and not simple. Herein, we report a case of fatal hepatic infarction that occurred spontaneously during the course of treatment in a patient with gallbladder cancer. Hepatic infarction should be considered as a possible fatal complication in patients during treatment of biliary malignancies. PMID- 27462233 TI - Understanding the Significance of Mutations in Tumor Suppressor Genes Identified Using Next-Generation Sequencing: A Case Report. AB - Next-generation sequencing (NGS) of tumors has been heralded as a promising tool to identify 'actionable' abnormalities susceptible to therapies targeting these mutated genes. Inhibiting the oncoprotein expressed from a single dominant mutated gene (oncogene) forms the basis for the success of most of the targeted gene therapies approved in the last several years. The well over 20 FDA-approved kinase inhibitors for cancer treatment are examples [Janne et al.: Nat Rev Drug Discov 2009;8: 709-723]. These and other similar agents in development might prove effective therapies for tumors originating from tissues other than those for which these drugs are currently approved. Finding such mutations in tumors of patients through NGS is being aggressively pursued by patients and their oncologists. For identified mutated tumor suppressor genes (TSG) the challenge is really the opposite. Rather than inhibiting the action of an oncoprotein, targeting would involve restoring the activity of the wild-type (WT) TSG function [Knudson: Proc Natl Acad Sci USA 1971;249: 912-915]. Here, a case is reported that illustrates the implications of a mutated TSG (BRIP1) identified by NGS as potentially actionable. In such cases, measuring allelic mutation frequency potentially allows for the identification of tumors where the loss of heterozygosity of a TSG exists. Without substantial loss of expression of the WT TSG product, it would seem very unlikely that 'replacing' a WT TSG product that is not a lost product would be a useful therapy. PMID- 27462234 TI - Advanced Mucinous Adenocarcinoma Arising from a Mature Cystic Teratoma: A Case Report and Literature Review. AB - PURPOSE: To describe the postoperative progressive course of advanced-stage adenocarcinoma arising from a mature cystic teratoma (MCT) and review the literature regarding this disease. METHODS: A 59-year-old woman visited our hospital with an abdominal mass. Laparotomy showed enlargement of the left ovary and dissemination throughout the abdominal and pelvic cavities. The diagnosis was FIGO stage IIIB adenocarcinoma arising from a MCT. We report this case in detail with a review of the literature. RESULTS: A literature search yielded 9 cases of stage III adenocarcinoma with malignant transformation. Six of these 9 patients died within 12 months after diagnosis. Of the 8 patients who underwent postoperative chemotherapy, 3 survived for over 39 months. The review indicates that prognosis of adenocarcinoma is as poor as that for squamous cell carcinoma arising from a MCT. CONCLUSIONS: In general, as with this case, prognosis of advanced adenocarcinoma associated with a MCT is poor. However, we should be aware that not all patients are resistant to chemotherapy. PMID- 27462235 TI - Plasma Cell Leukemia Presenting as a Chest Wall Mass: A Case Report. AB - Plasma cell leukemia (PCL) is an uncommon neoplasm of plasma cells, with an aggressive clinical course and poor outcome, even with current standard of care. It can occur either de novo (primary PCL) or as a progression of multiple myeloma (MM). This disease has unique diagnostic criteria but certain genetic markers and clinical features may overlap with MM. Due to the low prevalence of PCL, guidelines on its management are extrapolated from the management of MM and based on small retrospective studies and cases reports/series. We present an interesting case of PCL in a middle-aged African-American male, who was diagnosed incidentally after chest wall imaging for an unrelated complaint. The diagnostic approach, management and outcomes of PCL are discussed. PMID- 27462236 TI - A Case of Malignant Gastrointestinal Stromal Tumor Initially Misdiagnosed as Malignant B-Cell Lymphoma. AB - Errors that occur in anatomic pathology influence the treatment strategy of patients with malignancy. There are four general types of error with three subtypes in the category of defective interpretation. The first subtype is a false-negative diagnosis or undercall of the extent or severity of the lesion, the second is a false-positive diagnosis, and the third is misclassification. We herein report a 65-year-old female patient with malignant gastrointestinal stromal tumor that was diagnosed after reevaluation of the lesion at our hospital - and treated with proximal gastrectomy - after initial diagnosis as malignant B cell lymphoma on esophagogastroduodenoscopy biopsy of a small gastric fundic mass and subsequent treatment with six cycles of CHOP chemotherapy with aggravation of the mass at another hospital. PMID- 27462237 TI - Postictal Magnetic Resonance Imaging Changes Masquerading as Brain Tumor Progression: A Case Series. AB - Seizures are common among patients with brain tumors. Transient, postictal magnetic resonance imaging abnormalities are a long recognized phenomenon. However, these radiographic changes are not as well studied in the brain tumor population. Moreover, reversible neuroimaging abnormalities following seizure activity may be misinterpreted for tumor progression and could consequently result in unnecessary tumor-directed treatment. Here, we describe two cases of patients with brain tumors who developed peri-ictal pseudoprogression and review the relevant literature. PMID- 27462238 TI - Pazopanib in Primary Cardiac Angiosarcoma of the Right Atrium: A Case Report. AB - Primary heart tumors are an extremely rare oncological entity with primary cardiac sarcomas usually representing 20% of all primary cardiac tumorous lesions [Shanmugam: Eur J Cardiothorac Surg 2006;29: 925-932; Orlandi et al.: J Thorac Oncol 2010;5: 1483-1489]. Angiosarcoma is the most prevalent histology and despite a multidisciplinary approach tends to have a dismal prognosis [Shanmugam: Eur J Cardiothorac Surg 2006;29: 925-932; Fury et al.: Cancer J 2005;11: 241 247]. Based on the prevailing literature, we report a 48-year-old woman diagnosed with primary metastatic cardiac angiosarcoma who showed a severe hypersensitivity reaction to conventional chemotherapy with taxanes but an excellent response to treatment with the multitargeted receptor tyrosine kinase inhibitor pazopanib. PMID- 27462239 TI - A Giant Retroperitoneal Liposarcoma Encasing the Entire Left Kidney and Adherent to Adjacent Structures: A Case Report. AB - Retroperitoneal liposarcoma is a rare tumor. The dimension and weight of liposarcoma are variable; those over 20 kg are called 'giant liposarcoma'. Herein, we report giant retroperitoneal liposarcoma measuring 45 cm in diameter and 25 kg in weight encasing the entire left kidney and adherent to adjacent structures. A 71-year-old woman presented for a regular checkup. Image study revealed a huge mass probably indicative of retroperitoneal liposarcoma encasing the entire left kidney and adherent to adjacent structures. We performed an organ preserving surgical removal. The pathologic report was liposarcoma. At postoperative month 16, a follow-up CT revealed a locally recurrent tumor. The patient underwent surgical removal of the newly discovered mass. After the second surgery, the patient underwent regular follow-up CT for approximately 12 months, and to date, there has been no evidence of tumor recurrence. High-grade liposarcoma shows sensitivity to radiation therapy. However, the toxic effect of radiation therapy limits this option by treatment modality. The use of chemotherapy is also controversial. As a result, complete resection is the gold standard treatment. Here, we report a giant retroperitoneal liposarcoma encasing the entire left kidney and adherent to adjacent structures, describe successful organ-preserving surgical removal and discuss prognosis. PMID- 27462240 TI - Development of Hemolytic Anemia in a Nivolumab-Treated Patient with Refractory Metastatic Squamous Cell Skin Cancer and Chronic Lymphatic Leukemia. AB - Management of patients with metastatic squamous cell skin cancer, refractory to initial therapy with standard chemotherapy and radiation protocols, remains difficult with poor overall prognosis and limited therapeutic options. Recently, promising response rates with nivolumab, a programmed death receptor-1-blocking antibody, in squamous cancer of the head and neck have been demonstrated. Considering the similar histological patterns of squamous cell cancer of the skin and squamous cell cancer of the head and neck, we assumed that nivolumab could also be effective in our patients with refractory metastatic squamous cell cancer of the skin. So far, there have been no clinical data on the therapeutic efficacy of nivolumab in squamous cell skin cancer. We here present a case of a patient with metastatic squamous cell skin cancer refractory to previous therapies, who showed a good response to nivolumab over a period of 5 months, but developed a serious hemolytic crisis under nivolumab treatment after eight applications. PMID- 27462241 TI - Reversible Valproate Induced Pisa Syndrome and Parkinsonism in a Neuro-Oncology Patient with Depression and Epilepsy. AB - Neurological and psychiatric conditions frequently overlap in neuro-oncology. This overlapping negatively affects patients' quality of life and decreases the ability of providers to manage specific symptoms by therapy modulation, especially when psychopharmacotherapy needs to be prescribed. We describe here a patient with recurrent brain tumor, symptomatic epilepsy and depression who developed Pisa syndrome and parkinsonism after several months of valproic acid use. An accurate recognition of symptoms and treatment side effect allowed an appropriate clinical approach so as to rapidly improve both movement disorder and depression without increasing the risk of developing seizure. This has improved the autonomy and quality of life in a patient with poor prognosis. PMID- 27462242 TI - Factors Affecting Phenotype Variability in a Family with CMT2B: Gender and LRSAM1 Genotype. AB - Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified. In this family, none of the individuals had ulceromutilating features, and there was a marked variability in the age of onset. We discuss the possible etiology of the observed phenotypic variability including the role of gender and possible RAB7A/LRSAM1 gene interactions. PMID- 27462243 TI - New-Onset Refractory Status Epilepticus: More Investigations, More Questions. AB - A 27-year-old previously healthy woman was admitted to the hospital with recurrent seizures. Status epilepticus developed that became refractory to third line therapy with propofol and barbiturates. The patient had a very extensive diagnostic workup including autoimmune, viral and genetic investigations. A tentative immune therapy was proposed with high doses of steroids and plasma exchanges. Our patient had an inherited heterozygous single nucleotide variant in the sequence c.1280A>G [p.Lys427Arg] of the SMC3 gene that was insufficient to explain the seizures. Surprisingly, IgM antibodies against Japanese encephalitis virus were positive on the serum drawn 11 days after symptom onset, as detected by ELISA and the immunofluorescence antibody (IFA) technique. IgG antibodies were also positive using the IFA technique, but not with ELISA. The same investigations as well as the detection of the viral genome by the q-RT-PCR technique were negative on cerebrospinal fluid. Despite the suspicion of a viral infection, we concluded that our patient had a new-onset refractory status epilepticus of cryptogenic origin. Termination of the status epilepticus was obtained after 47 days, with a possible benefit from the introduction of ketamine. PMID- 27462244 TI - Hyperpigmented Torpedo Maculopathy with Pseudo-Lacuna: A 5-Year Follow-Up. AB - PURPOSE: The aim of the study was to describe a case of globally hyperpigmented torpedo maculopathy that also contained a novel central lesion resembling a 'pseudo-lacuna'. We compare the morphology of the lesion after 5 years of follow up. CASE PRESENTATION: An asymptomatic 10-year-old Caucasian male was referred by his optometrist after having found a hyperpigmented lesion on routine dilated examination in 2010. Color fundus photography OS from October 2015 showed a 1.74 * 0.67 mm hyperpigmented oval-shaped lesion temporal to the macula. Since June 2010, the hyperpigmented torpedo lesion appeared to have assumed a more ovoid shape and increased in size in the vertical axis. Centrally, there was a small pearlescent-colored pseudo-lacuna lesion that seemed to also have significantly increased in size since June 2010. Enhanced depth imaging optical coherence tomography of this pseudo-lacuna showed retinal pigment epithelium clumping and migration. Fundus autofluorescence revealed reduced autofluorescence of the torpedo lesion and marked hyperautofluorescence of the pseudo-lacuna. Fluorescein angiography shows no neovascular disease or leakage. CONCLUSION: Torpedo maculopathy has been described previously as a hypopigmented, nonprogressive lesion of unknown etiology. The findings of global hyperpigmentation, pseudo lacuna formation, and morphologic changes over time in this lesion challenge these classically held descriptions, and necessitate long-term follow-up with multimodal imaging. PMID- 27462245 TI - Patch Grafting Using a Cryopreserved Descemet Stripping Automated Endothelial Keratoplasty Flap for Treating Corneal Perforation. AB - A 73-year-old woman with a corneal perforation of undetermined etiology was treated with corneal patch grafting. A residual partial-thickness corneal button obtained during a previous Descemet stripping automated endothelial keratoplasty (DSAEK) surgery and stored at -80 degrees C in Optisol GS for 3 months was used as a patch graft. Five days postoperatively, the anterior chamber was reformed and the perforation was masked by the donor cornea. During the next several weeks, gradual displacement of the anterior edge of the donor cornea in the limbal direction occurred. Seven weeks postoperatively, further displacement of the donor cornea resulted in unmasking of the perforated area. At this time, the corneal defect was closed by stromal scar tissue and corneal epithelium. Five months postoperatively, best corrected visual acuity was 1.0 without marked astigmatism and intraocular pressure was 9 mm Hg in the left eye. From this case, we learned that cryopreserved DSAEK flaps stored longer than reported previously can be used as patch grafts to treat emergency conditions. Scar tissue can fill a corneal stromal defect 1 mm in diameter during temporary patch grafting for less than 2 months. PMID- 27462246 TI - Chronic Inflammation in an Anophthalmic Socket due to a Room Temperature Vulcanized Silicone Implant. AB - Two case reports are used to illustrate the signs and symptoms, complications and treatments of chronic socket inflammation due to intraorbital implants. The ophthalmic examination, surgeries and treatments are documented. Two anophthalmic cases that underwent enucleation and multiple orbital surgeries to enhance the anophthalmic socket volume developed pain, intense discharge and contracted cavities with chronic inflammation in the socket which was nonresponsive to medical therapy. Computed tomography indicated a hypodense foreign body in both cases causing an intense inflammatory reaction. The implants were removed by excisional surgery and a room temperature vulcanized silicone implant was retrieved in both cases. Socket inflammation resolved in both cases after implant removal. An intraorbital inflammatory reaction against an intraorbital implant can cause chronic socket inflammation in patients with a history of multiple surgeries. Diagnosis requires imaging and the definitive treatment is implant removal. PMID- 27462247 TI - Subretinal Fluid Drainage and Vitrectomy Are Helpful in Diagnosing and Treating Eyes with Advanced Coats' Disease. AB - Severe forms of Coats' disease are often associated with total retinal detachment, and a differential diagnosis from retinoblastoma is critically important. In such eyes, laser- and/or cryoablation is often ineffective or sometimes impossible to perform. We report a case of advanced Coats' disease in which a rapid pathological examination of subretinal fluid was effective for the diagnosis, and external subretinal drainage combined with vitrectomy was effective in preserving the eye. PMID- 27462248 TI - A Case of Sustained Intraocular Pressure Elevation after Multiple Intravitreal Injection of Ranibizumab and Aflibercept for Neovascular Age-Related Macular Degeneration. AB - Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are widely used to treat neovascular age-related macular degeneration (nAMD). Although these treatments are effective, multiple injections have recently been recommended to ensure that there is a good long-term prognosis. However, sustained intraocular pressure (IOP) elevations have been reported to develop after multiple injections of anti-VEGF agents. We present our findings of a case of uncontrolled and persistent IOP elevation after switching from intravitreal ranibizumab injections to intravitreal aflibercept injections. A 74-year-old Japanese man without a history of glaucoma underwent 22 ranibizumab injections for nAMD and suddenly developed an elevated IOP after the 22nd injection. Although the subsequent medical treatment led to normalization of his IOP, the subretinal fluid under the central fovea remained even after the 25th injection of ranibizumab. Thus, ranibizumab treatment was switched to bimonthly intravitreal aflibercept injections in conjunction with glaucoma medications. His IOP recovered to within the normal range; however, after the 11th aflibercept injection, there was a sudden elevation of his IOP in spite of the continued glaucoma medications. Due to this sustained IOP elevation, his aflibercept injections were suspended for 16 weeks. Because his IOP could not be normalized by a full glaucoma medication regimen, the patient underwent trabeculotomy, which resulted in a lowering of the IOP to normal levels. We conclude that patients who receive serial intravitreal injections of anti-VEGF agents need to be closely monitored because severe and sustained ocular hypertension can develop. PMID- 27462249 TI - Therapeutical Management for Ocular Rosacea. AB - PURPOSE: The purpose of this study is to describe a case of ocular rosacea with a very complex evolution. Rosacea is a chronic dermatological disease that may affect the ocular structures up to 6-72% of all cases. This form is often misdiagnosed, which may lead to long inflammatory processes with important visual consequences for affected patients. Therefore, an early diagnosis and an adequate treatment are important. METHODS: We report the case of a 43-year-old patient who had several relapses of what seemed an episode of acute bacterial conjunctivitis. Two weeks later, he developed a corneal ulcer with a torpid evolution including abundant intrastromal infiltrators and calcium deposits. He was diagnosed with ocular rosacea and treated with systemic doxycycline and topical protopic. RESULTS: A coating with amniotic membrane was placed in order to heal the ulcer, but a deep anterior lamellar keratoplasty to restore the patient's vision because of the corneal transparency loss was necessary. CONCLUSIONS: Ocular rosacea includes multiple ophthalmic manifestations ranging from inflammation of the eyelid margin and blepharitis to serious corneal affectations. A delayed diagnosis can result in chronic inflammatory conditions including keratinization and loss of corneal transparency, which lead to important visual sequelae for affected patients. PMID- 27462250 TI - Long-Term Follow-Up Case of Multiple Retinal Arterial Macroaneurysms Developing Branch Retinal Vein Occlusion following Ruptured Macroaneurysm. AB - PURPOSE: Retinal arterial macroaneurysm (RAM) has been reported in association with branch retinal vein occlusion (BRVO), and usually BRVO precedes RAM. We present a long-term follow-up case report of unilateral multiple RAMs that developed BRVO following ruptured RAM in the same retinal quadrant. CASE PRESENTATION: An 80-year-old woman presented with floaters in her right eye in June 2012. Visual acuity (VA) was 20/25 in her right eye with posterior capsular opacity. Her fundus showed the first ruptured RAM at the superotemporal vascular arcade with subinternal limiting membrane and subretinal hemorrhages not involving the macula. These were absorbed gradually with a VA of 20/20. After 2 years, the second RAM at the proximal superotemporal vascular arcade developed and impending BRVO occurred with macular edema at the distal site of the RAM. With the RAM located close to the arteriovenous crossing, her VA was dropped to 20/60. Intravitreal injection of ranibizumab was performed and macular edema was resolved with improved vision of 20/30. Three months later, she realized a sudden vision loss of 2/200. Her posterior pole showed massive pre- and subretinal hemorrhages, and vitrectomy was performed. The source of bleeding was the third RAM's rupture in a different artery. Her vision improved to 20/30. The unaffected eye showed no RAMs. CONCLUSION: We experienced a long-term follow-up case of multiple RAMs showing different courses. We should cautiously note that BRVO can occur following RAM at the arteriovenous crossing. PMID- 27462251 TI - Spontaneous Scleral Perforation of an Anterior Chamber Intraocular Lens. AB - A routine eye examination of a 69-year-old man revealed a scleral perforation of one of the haptics of the anterior chamber intraocular lens (AC IOL) which had been implanted many years ago. The patient was asymptomatic with good visual acuity. His history was negative for any trauma, eye rubbing, topical corticosteroid use, or autoimmune disease. The horizontal and vertical white-to white diameters of the cornea in the right eye were 11.5 and 10.5 mm, respectively. Anterior segment optical coherence tomography showed the anterior chamber length to be 12.28 mm horizontally and 10.63 mm vertically. The patient underwent an IOL exchange, and the length of the explanted AC IOL was measured to be 12 mm. We speculate that the AC IOL, which was vertically aligned, was oversized. This case demonstrates the need for proper sizing and positioning of an AC IOL. In complex cases where AC IOL may be used, measuring the horizontal and vertical lengths of the anterior chamber by anterior segment optical coherence tomography prior to surgery may be useful. PMID- 27462252 TI - Cytopathological Features of a Severe Type of Corneal Intraepithelial Neoplasia. AB - PURPOSE: To report the cytopathological features of corneal intraepithelial neoplasia (CIN) through the investigation of cytokeratin expression pattern, keratinization, cell proliferation, apoptosis, and epithelial mesenchymal transition. PATIENT AND METHODS: Corneal tissue excised from a CIN patient was examined in this study. Cryosections of the excised CIN epithelial tissue were examined by immunostaining analysis using antibodies against cytokeratins, keratinization-related proteins, Ki-67, human telomerase reverse transcriptase (hTERT), and epithelial mesenchymal transition (EMT)-related proteins. Subcellular localization of F-actin was also analyzed using phalloidin. For the detection of apoptotic cells, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed. Real-time polymerase chain reaction was performed to quantify the expression level of hTERT in the CIN epithelium. RESULTS: The CIN epithelium exhibited a significantly altered cytokeratin expression pattern compared to normal corneas with an upregulated expression of keratinization-related proteins. The CIN epithelium also demonstrated an increased number of Ki-67-positive cells with an upregulated expression of hTERT, while exhibiting an increased number of apoptotic cells. EMT did not occur in the CIN epithelium. CONCLUSION: CIN epithelium seems to be slightly dedifferentiated from the corneal epithelial lineage. The status of cell proliferation and apoptosis in the CIN epithelium was significantly altered from that of normal corneal epithelium, but its malignancy level does not appear to be as high as that of metastasis-competent malignant cancers. PMID- 27462253 TI - Epibulbar Nodular Fasciitis. AB - PURPOSE: To report a case of epibulbar nodular fasciitis in a 32-year-old female and provide context by reviewing the current literature. RESULTS: Using excisional biopsy, the patient was successfully diagnosed and treated for epibulbar nodular fasciitis. Upon follow-up, there has been no recurrence, consistent with the typical course for nodular fasciitis. CONCLUSIONS: Epibulbar nodular fasciitis is a rare process that can be successfully treated by surgical resection. While two cases of trauma-associated epibulbar nodular fasciitis have been present in the literature, our case did not have such a history. The etiology of nodular fasciitis remains unclear. PMID- 27462254 TI - A Case of a Newborn with Agenesis of the Corpus Callosum Complicated with Ocular Albinism. AB - PURPOSE: To report a case of ocular albinism found in a newborn infant in whom agenesis of the corpus callosum (ACC) was indicated in utero. CASE REPORT: This study involved a female newborn who was delivered after a gestational period of 41 weeks. The patient was referred to the Obstetrics Department at Takatsuki Hospital, Takatsuki City, Japan, after the indication of ACC by magnetic resonance imaging (MRI) at a nearby clinic during the fetal period. At birth, the baby's weight was 2,590 g, and ACC and ventricular enlargement were found by cranial sonography and cranial MRI. While initial ophthalmic findings noted partial loss of pigmentation of the iris and hypopigmentation of broad areas of the fundus in both eyes, nystagmus was not observed. The patient's hair pigment was slightly diluted, and the color of her skin was slightly off-white. At 2 years after birth, obvious mental retardation was observed. With regard to other systemic findings, no apparent heart, kidney, or immune system abnormalities were found. CONCLUSION: Although the patient in question is presently growing without any major systemic problems, it will be necessary in the future to pay attention to any changes in systemic and ophthalmic findings. PMID- 27462255 TI - Lacrimal Sac Mucoepidermoid Carcinoma with Metastases to the Cavernous Sinus Following Dacryocystorhinostomy Treated with Stereotactic Radiotherapy. AB - PURPOSE: We report a very good outcome in a 44-year-old woman in whom cancer was missed as the cause of nasolacrimal duct obstruction and dacryocystitis and which was deemed inoperable after spreading to the cavernous sinus. CASE REPORT: The patient was referred to our unit 12 months following uneventful right dacryocystorhinostomy for nasolacrimal duct obstruction. This had been complicated by the formation of a significant canthal swelling 6 months later, which had been excised at that time. The symptom of nasolacrimal duct obstruction and scar recurrence prompted the referral to our unit. Examination and biopsy confirmed a malignancy. Despite extensive surgery, including concurrent radical neck dissection and parotidectomy, within 6 months, her mucoepidermoid carcinoma was found to have spread to the cavernous sinus, restricting blood flow from the carotid and causing an abducens nerve palsy. Though deemed inoperable at first, Gamma Knife stereotactic radiosurgery was sought as treatment for her disease, resulting in a good outcome 4 years after surgery. CONCLUSION: Experience from this case suggests the importance of considering malignancy as a cause in young patients when presenting with nasolacrimal duct obstruction. In such cases, and perhaps for all patients, biopsy specimens should be submitted as many tumours are found incidentally at the time of dacryocystorhinostomy. Whilst the external approach to dacryocystorhinostomy may identify abnormal anatomy intraoperatively, prompting biopsy, this is less likely with an endonasal approach where osteotomy precedes sac visualisation. The endonasal approach may therefore be less appropriate in such cases where malignancy is suspected as osteotomy may aid in the spread. PMID- 27462256 TI - Non-Descemet Stripping Automated Endothelial Keratoplasty for Bullous Keratopathy in Buphthalmic Eye. AB - PURPOSE: To report the 2-year follow-up findings in a patient with buphthalmic bullous keratopathy (BK) who was successfully treated with non-Descemet stripping automated endothelial keratoplasty (nDSAEK). METHODS: A 39-year-old man had an endothelial graft of 8.0 mm diameter placed uneventfully using the nDSAEK method for phakic BK with buphthalmos of the left eye. He had had a penetrating keratoplasty in the right eye due to aphakic BK 5 years earlier, which, however, resulted in the invasion of blood vessels and graft failure. Since the left eye was phakic, Descemetorhexis was not performed because the instruments might touch the crystalline lens. The best-corrected visual acuity (BCVA), intraocular pressure (IOP), and endothelial cell density (ECD) were determined at 2 weeks, and at 1, 3, 6, 12, 18 and 24 months after nDSAEK. RESULTS: Twenty-four months after nDSAEK, his left cornea and lens remained clear, and the decimal BCVA was 0.8. However, the ECD of the graft had decreased from 2,274 cells/mm(2) before nDSAEK to 539 cells/mm(2) 24 months after the surgery, and the rate of decrease appeared to be slightly faster than that of former reports. An IOP of $1003e;30 mm Hg was recorded at around 2 months after the surgery, but was well controlled by tapering the topical steroids and the addition of topical brinzolamide and latanoprost. CONCLUSION: Our findings show that nDSAEK can be successfully used to treat buphthalmic BK. We recommend that nDSAEK be considered especially in phakic eyes with a smooth posterior surface around the pupillary area. PMID- 27462257 TI - Tram-Track Suture Technique for Pupillary Capture of a Scleral Fixated Intraocular Lens. AB - PURPOSE: To report a new technique using tram-track suture for pupillary capture of a scleral fixated posterior chamber intraocular lens (PC-IOL) to reposition the tilted IOL. METHODS: In this prospective interventional case series, we describe a tram-track suture for pupillary capture of a scleral fixated PC-IOL. A long straight needle with double-armed 10-0 polypropylene is passed behind the iris and just above the optic portion (tilted forward) of the IOL. The other straight needle with double-armed 10-0 polypropylene is passed just below the optic portion (tilted backward) of the IOL. After the IOL is repositioned properly, the polypropylene sutures are gently pulled and tied. RESULTS: Four eyes of 4 patients underwent tram-track suture for pupillary capture of a scleral fixated PC-IOL. No intra- or postoperative complications were noted, and no pupillary captures were detected during the follow-up period. CONCLUSIONS: The tram-track suture technique provides good centration and stability of a PC-IOL. This technique is an easy and effective way to reposition pupillary capture of an IOL. Further, it is also minimally invasive as it maintains a closed system. PMID- 27462258 TI - Glaucoma Management in Carotid Cavernous Fistula. AB - Carotid cavernous fistulas (CCF) are vascular communications between the carotid artery and the cavernous sinus. Ophthalmologists are called to diagnose and manage the condition in cases that present with ocular features. A 73-year-old female was referred to our glaucoma center clinic. Eight years before, she had started receiving medication for glaucoma and had undergone laser iridotomy, but a satisfactory management of intraocular pressure (IOP) had not been achieved. The patient was complaining of intermittent diplopia, bilateral proptosis, and conjunctival chemosis over the past 6 months. Best-corrected visual acuity in the right (OD) and left eye (OS) was 9/10 and 10/10, respectively. Visual field testing showed slight paracentral field defects mostly in OS. IOP was 20 mm Hg in OD and 34 mm Hg in OS. We referred the patient to neuroradiology, and MRI angiography revealed a CCF with angiographic classification of Cognard grade 2. Closure of the CCF by transarterial embolization was performed in the neuroradiology department. One week following the procedure, the clinical signs of diplopia, proptosis, and conjunctival chemosis had greatly improved, and IOP was reduced to 12 mm Hg OD and 19 mm Hg in OS. Glaucoma treatment was maintained with topical brimatoprost, brinzolamide, and timolol. Owing to the risk of vision loss associated with vascular stasis, retinal ischemia, and high IOP, ophthalmologists must be aware of the clinical features of CCF and should request appropriate imaging studies such as MRI angiography in order to confirm the diagnosis and plan multidisciplinary treatment. PMID- 27462259 TI - Bilateral Cytomegalovirus Retinitis in a Patient with Systemic Lupus Erythematosus. AB - PURPOSE: The purpose of this study was to report the case of a patient who underwent vitrectomy for bilateral rhegmatogenous retinal detachment caused by cytomegalovirus (CMV) retinitis while undergoing steroid and immunosuppressant therapy for systemic lupus erythematosus (SLE). CASE REPORT: We report on a 29 year-old female who was undergoing steroids and immunosuppressants treatment for SLE at Osaka Medical College Hospital, Takatsuki City, Japan. Examination of the patient due to prolonged and worsening diarrhea revealed positive test results for C7-HRP, and she was diagnosed with CMV colitis. She was subsequently admitted to the hospital and started on intravenous ganciclovir for treatment. Approximately 1.5 months later, her primary complaint was deterioration of the upper visual field in her left eye, and she was then referred to the Department of Ophthalmology. Numerous granular exudative spots were found around the lower retinal area of her left eye with retinal breaks that had developed in an area of retinal necrosis that resulted in retinal detachment. After time was allowed for the patient's general condition to improve, a vitrectomy was performed on that eye. The patient subsequently developed a similar retinal detachment in her right eye, for which she underwent a vitrectomy. Although the patient required multiple surgeries on both eyes, her retinas currently remain reattached and the inflammation has subsided. CONCLUSION: The findings of this study show that strict attention must be paid to SLE patients on immunosuppressive therapy due to the possible association of CMV retinitis. PMID- 27462260 TI - Is Spectral-Domain Optical Coherence Tomography Always Able to Detect the Anti Vascular Endothelial Growth Factor Action on Neovascular Membrane? AB - PURPOSE: To show the presence of an active neovascular membrane in age-related macular degeneration even if optical coherence tomography (OCT) does not detect intra- or subretinal edema. METHODS: This is a retrospective case report. During the follow-up after the intravitreal injection, 3 patients showed no intraretinal or subretinal edema by OCT; however, there was a progressive reduction in their visual acuity; thus, a fluorangiography (FA) examination was performed. RESULTS: In these 3 cases, FA showed an active neovascular network. CONCLUSION: OCT could show a real reduction in the edema, but it is not always able to detect neovessel presence. Intravitreal injection could improve the vessel permeability without care and delete the neovascular network. PMID- 27462261 TI - Bilateral Rhegmatogenous Retinal Detachment during External Beam Radiotherapy. AB - Herein, we report a case of nontraumatic bilateral rhegmatogenous retinal detachment (RRD) during external beam radiotherapy for nonocular tumor, presented as an observational case study in conjunction with a review of the relevant literature. A 65-year-old male was referred to our hospital due to bilateral RRD. He underwent a biopsy for a tumor of the left frontal lobe 4 months prior to presentation, and the tumor had been diagnosed as primary central nerve system B cell type lymphoma. He received chemotherapy and external beam radiotherapy for 1 month. There were no traumatic episodes. Bilateral retinal detachment occurred during a series of radiotherapies. Simultaneous nontraumatic bilateral retinal detachment is rare. The effects of radiotherapy on ocular functionality, particularly in cases involving retinal adhesion and vitreous contraction, may include RRD. Thus, it is necessary to closely monitor the eyes of patients undergoing radiotherapy, particularly those undergoing surgery for retinal detachment and those with a history of photocoagulation for retinal tears, a relevant family history, or risk factors known to be associated with RRD. PMID- 27462262 TI - The Effect of a Diving Mask on Intraocular Pressure in a Healthy Population. AB - PURPOSE: Swimming goggles increase the intraocular pressure (IOP) via the periorbital frame pressure and suction effect. In comparison, diving masks have a larger frame rim and incorporate the nose. The exact effect(s) of diving masks on IOP is unknown. This study evaluates the influence of diving masks on IOP in normal, healthy subjects. METHODS: Tonometry was performed in both eyes of all subjects with an AVIA((r))Tono-Pen by a single investigator. Measurements were taken at baseline without the diving mask and with the subjects wearing a small volume, double-window diving mask, but with the mask lenses removed. Two IOP readings in each eye were measured, and an additional reading was measured if the difference between the initial 2 was >=2 mm Hg. Central corneal thickness (CCT) was also measured in each eye, using a contact pachymeter (OcuScan((r))Alcon). RESULTS: Forty eyes of 20 healthy volunteers (age 29.7 +/- 9.3 years; range 21 52) were included. The mean CCT was 544.4 +/- 43.5 um. The mean IOP before the diving mask was worn had been 17.23 +/- 2.18 mm Hg (n = 40). The IOP decreased by 0.43 mm Hg (p $1003c; 0.05) to 16.80 +/- 2.57 mm Hg after the diving mask had been put on. There was no correlation between IOP change and age (r = 0.143, p = 0.337), gender (r = -0.174, p = 0.283) or CCT (r = -0.123, p = 0.445). CONCLUSION: There was no increase in IOP after the diving mask had been worn. A small but statistically significant decrease in IOP was observed. This study demonstrates that unlike swimming goggles, the strap tension and frame pressure on the periorbital tissue from a diving mask does not increase IOP. Diving masks may be a suitable alternative to swimming goggles for patients with advanced glaucoma or glaucoma filtration surgery. PMID- 27462263 TI - Vitrectomy for Tractional Retinal Detachment with Twin Retinal Capillary Hemangiomas in a Patient with Von Hippel-Lindau Disease: A Case Report. AB - PURPOSE: The purpose of this study was to report a case of Von Hippel-Lindau disease (VHL) with twin retinal capillary hemangiomas that was successfully treated by vitreous surgery for tractional retinal detachment following laser photocoagulation. CASE: A 44-year-old male presented at our university hospital after noticing decreased visual acuity in his right eye. The patient had previously undergone multiple operations for cerebellar, thoracic, and lumbar spine hemangioblastomas when he was approximately 19 years old. Upon initial examination, ocular findings revealed twin connected retinal capillary hemangiomas around the temporal upper area of the patient's right eye. The patient was subsequently diagnosed with VHL based on his medical history and current observations of the ocular fundus. Tractional retinal detachment had occurred as the result of the formation of proliferative membranes following laser photocoagulation. The patient underwent vitreous surgery to treat the tractional retinal detachment, resulting in a successful postoperative outcome. CONCLUSION: The findings of this study show the possibility that proliferative changes and tractional retinal detachment can arise following photocoagulation for retinal capillary hemangiomas in patients with VHL. PMID- 27462264 TI - Bilateral Simultaneous Rhegmatogenous Retinal Detachment following Laser in situ Keratomileusis. AB - A 21-year-old woman developed simultaneous rhegmatogenous retinal detachment after laser in situ keratomileusis (LASIK) in both eyes. She underwent pars plana vitrectomy surgery combined with endolaser photocoagulation and silicone oil tamponade in the right eye. A week later, pneumatic retinopexy was done in the left eye. As the retinal tear did not seal, 360 degrees scleral buckling surgery was performed and retina was attached. Bilateral simultaneous rhegmatogenous retinal detachment after LASIK for correction of myopia can be a serious complication. Patients should be informed about the possibility of this complication. PMID- 27462265 TI - Different Alterations of Cerebral Regional Homogeneity in Early-Onset and Late Onset Parkinson's Disease. AB - HIGHLIGHTS Eighteen EOPD, 21 LOPD and 37 age-matched normal control subjects participated in the resting state fMRI scans.Age at onset of PD modulates the distribution of cerebral regional homogeneity during resting state.Disproportionate putamen alterations are more prominent in PD patients with a younger age of onset. OBJECTIVE: Early-onset Parkinson's disease (EOPD) is distinct from late-onset PD (LOPD) as it relates to the clinical profile and response to medication. The objective of current paper is to investigate whether characteristics of spontaneous brain activity in the resting state are associated with the age of disease onset. METHODS: We assessed the correlation between neural activity and age-at-onset in a sample of 39 PD patients (18 EOPD and 21 LOPD) and 37 age-matched normal control subjects. Regional homogeneity (ReHo) approaches were employed using ANOVA with two factors: PD and age. RESULTS: In the comparisons between LOPD and EOPD, EOPD revealed lower ReHo values in the right putamen and higher ReHo values in the left superior frontal gyrus. Compared with age-matched control subjects, EOPD exhibited lower ReHo values in the right putamen and higher ReHo values in the left inferior temporal gyrus; However, LOPD showed lower ReHo values in the right putamen and left insula. The ReHo values were negatively correlated with the UPDRS total scores in the right putamen in LOPD, but a correlation between the ReHo value and UPDRS score was not detected in EOPD. CONCLUSIONS: Our findings support the notion that age at onset is associated with the distribution of cerebral regional homogeneity in the resting state and suggest that disproportionate putamen alterations are more prominent in patients with a younger age of onset. PMID- 27462266 TI - Effects of Age and Task Load on Drivers' Response Accuracy and Reaction Time When Responding to Traffic Lights. AB - Due to population aging, elderly drivers represent an increasing proportion of car drivers. Yet, how aging alters sensorimotor functions and impacts driving safety remains poorly understood. This paper aimed at assessing to which extent elderly drivers are sensitive to various task loads and how this affects the reaction time (RT) in a driving context. Old and middle-aged people completed RT tasks which reproduced cognitive demands encountered while driving. Participants had to detect and respond to traffic lights or traffic light arrows as quickly as possible, under three experimental conditions of incremental difficulty. In both groups, we hypothesized that decision-making would be impacted by the number of cues to be processed. The first test was a simple measure of RT. The second and third tests were choice RT tasks requiring the processing of 3 and 5 cues, respectively. Responses were collected within a 2 s time-window. Otherwise, the trial was considered a no-response. In both groups, the data revealed that RT, error rate (incorrect answers), and no-response rate increased along with task difficulty. However, the middle-aged group outperformed the elderly group. The RT difference between the two groups increased drastically along with task difficulty. In the third test, the rate of no-response suggested that elderly drivers needed more than 2 s to process complex information and respond accurately. Both prolonged RT and increased no-response rate, especially for difficult tasks, might attest an impairment of cognitive abilities in relation to aging. Accordingly, casual driving conditions for young drivers may be particularly complex and stressful for elderly people who should thus be informed about the effects of normal aging upon driving. PMID- 27462267 TI - A Systems View of the Differences between APOE epsilon4 Carriers and Non-carriers in Alzheimer's Disease. AB - APOE epsilon4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and accounts for 50-65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE epsilon4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE epsilon4 stratification. Two specific modules were identified in AD APOE epsilon4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE epsilon4 carriers were ISOC1, ENO3, GDF10, GNB3, XPO4, ACLY and MATN2. The other module of AD APOE epsilon4 carriers consisted of 10 hub genes including ANO3, ARPP21, HPCA, RASD2, PCP4 and ADORA2A. The module of AD APOE epsilon4 non carriers consisted of 16 hub genes including DUSP5, TNFRSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE epsilon4 carriers including ISOC1 and ENO3 and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the ISOC1 and ENO3 module of carriers was shown to be correlated in a time-dependent manner under APOE epsilon4 treatment but not under APOE epsilon3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers' module was correlated under APOE epsilon3 treatment but not under APOE epsilon4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson's disease. These data demonstrate that AD in APOE epsilon4 carriers involves more genetic factors and particular biological processes, whereas AD in APOE epsilon4 non-carriers shares more common pathways with other types of diseases. The study reveals differential genetic bases and pathogenic and pathological processes between carriers and non-carriers, providing new insight into the mechanisms of the differences between APOE epsilon4 carriers and non-carriers in AD. PMID- 27462268 TI - Involvement of Cyclic Guanosine Monophosphate-Dependent Protein Kinase I in Renal Antifibrotic Effects of Serelaxin. AB - INTRODUCTION: Kidney fibrosis has shown to be ameliorated through the involvement of cyclic guanosine monophosphate (cGMP) and its dependent protein kinase I (cGKI). Serelaxin, the recombinant form of human relaxin-II, increases cGMP levels and has shown beneficial effects on kidney function in acute heart failure patients. Antifibrotic properties of serelaxin are supposed to be mediated via relaxin family peptide receptor 1 and subsequently enhanced nitric oxide/cGMP to inhibit transforming growth factor-beta (TGF-beta) signaling. This study examines the involvement of cGKI in the antifibrotic signaling of serelaxin. METHODS AND RESULTS: Kidney fibrosis was induced by unilateral ureteral obstruction in wildtype (WT) and cGKI knock-out (KO) mice. After 7 days, renal antifibrotic effects of serelaxin were assessed. Serelaxin treatment for 7 days significantly increased cGMP in the kidney of WT and cGKI-KO. In WT, renal fibrosis was reduced through decreased accumulation of collagen1A1, total collagen, and fibronectin. The profibrotic connective tissue growth factor as well as myofibroblast differentiation were reduced and matrix metalloproteinases-2 and -9 were positively modulated after treatment. Moreover, Smad2 as well as extracellular signal-regulated kinase 1 (ERK1) phosphorylation were decreased, whereas phosphodiesterase (PDE) 5a phosphorylation was increased. However, these effects were not observed in cGKI-KO. CONCLUSION: Antifibrotic renal effects of serelaxin are mediated via cGMP/cGKI to inhibit Smad2- and ERK1-dependent TGF-beta signaling and increased PDE5a phosphorylation. PMID- 27462269 TI - Synergistic Effects of Chinese Herbal Medicine: A Comprehensive Review of Methodology and Current Research. AB - Traditional Chinese medicine (TCM) is an important part of primary health care in Asian countries that has utilized complex herbal formulations (consisting 2 or more medicinal herbs) for treating diseases over thousands of years. There seems to be a general assumption that the synergistic therapeutic effects of Chinese herbal medicine (CHM) derive from the complex interactions between the multiple bioactive components within the herbs and/or herbal formulations. However, evidence to support these synergistic effects remains weak and controversial due to several reasons, including the very complex nature of CHM, misconceptions about synergy and methodological challenges to study design. In this review, we clarify the definition of synergy, identify common errors in synergy research and describe current methodological approaches to test for synergistic interaction. We discuss the strengths and weaknesses of these models in the context of CHM and summarize the current status of synergy research in CHM. Despite the availability of some scientific data to support the synergistic effects of multi-herbal and/or herb-drug combinations, the level of evidence remains low, and the clinical relevancy of most of these findings is undetermined. There remain significant challenges in the development of suitable methods for synergistic studies of complex herbal combinations. PMID- 27462270 TI - Strong and Long-Lasting Antinociceptive and Anti-inflammatory Conjugate of Naturally Occurring Oleanolic Acid and Aspirin. AB - The conjugate 8 was obtained as a result of condensation of 3 hydroxyiminooleanolic acid morfolide (7) and aspirin in dioxane. Analgesic effect of OAO-ASA (8) for the range of doses 0.3-300.0 mg/kg (p.o.) was performed in mice using a hot-plate test. Anti-inflammatory activity was assessed on carrageenan-induced paw edema in rats for the same range of doses. The conjugate OAO-ASA (8) did not significantly change locomotor activity of mice, therefore sedative properties of the compound should be excluded. The compound 8 proved a simple, proportional, dose-dependent analgesic action and expressed strong anti inflammatory activity showing a reversed U-shaped, dose-dependent relation with its maximum at 30.0 mg/kg. After its combined administration with morphine (MF, 5.0 mg/kg, s.c.) the lowering of antinociceptive activity was found; however, the interaction with naloxone (NL, 3.0 mg/kg, s.c.) did not affect the antinociceptive effect of OAO-ASA (8), therefore its opioid mechanism of action should be rather excluded. After combined administration with acetylsalicylic acid (ASA, 300.0 mg/kg, p.o.) in hot-plate test, the examined compound 8 enhanced the antinociceptive activity in significant way. It also shows that rather the whole molecule is responsible for the antinociceptive and anti-inflammatory effect of the tested compound 8, however, it cannot be excluded that the summarizing effect is produced by ASA released from the compound 8 and the rest of triterpene derivative. The occurrence of tolerance for triterpenic derivative 8 was not observed, since the analgesic and anti-inflammatory effects after chronic administration of the conjugate OAO-ASA (8) was on the same level as after its single treatment. It seemed that the anti-inflammatory mechanism of action of OAO-ASA (8) is not simple, even its chronic administration lowered both blood concentration of IL-6 and mRNA IL-6 expression. However, the effects of the conjugate OAO-ASA (8) on TNF-alpha level and mRNA expression were opposite. Moreover, compound 8 did not change unequivocally mRNA TLR1, and TLR3 expression. Concluding, the obtained results regarding the antinociceptive and anti inflammatory activity of new conjugate of oleanolic acid oxime and acetylsalicylic acid (OAO-ASA 8) are very interesting, but for explanation of its mechanism of action, more detailed studies are necessary. PMID- 27462271 TI - In vitro Models to Evaluate Drug-Induced Hypersensitivity: Potential Test Based on Activation of Dendritic Cells. AB - Hypersensitivity drug reactions (HDRs) are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug induced adverse effects, and include immune-mediated ("allergic") and non-immune mediated ("pseudo allergic") reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon. We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells. PMID- 27462273 TI - Increased Hepatic Fatty Acids Uptake and Oxidation by LRPPRC-Driven Oxidative Phosphorylation Reduces Blood Lipid Levels. AB - Hyperlipidemia is one of the major risk factors of atherosclerosis and other cardiovascular diseases. This study aimed to investigate the impact of leucine rich pentatricopeptide repeat containing protein (LRPPRC)-driven hepatic oxidative phoshorylation on blood lipid levels. The hepatic LRPPRC level was modulated by liver-specific transgenic or adeno-associated virus 8 carried shRNA targeting Lrpprc (aav-shLrpprc). Mice were fed with a high fat diet to induce obesity. Gene expression was analyzed by quantitative real-time PCR and / or western blot. The hepatic ATP level, hepatic and serum lipids contents, and mitochondria oxidative phosphorylation (OxPhos) complex activities were measured using specific assay kits. The uptake and oxidation of fatty acid by hepatocytes were assessed using (14)C-palmitate. LRPPRC regulated the expression of genes encoded by mitochondrial genome but not those by nuclear genome involved in mitochondria biogenesis, OxPhos, and lipid metabolism. Increased OxPhos in liver mediated by LRPPRC resulted in the increase of hepatic ATP level. Lrpprc promoted palmitate uptake and oxidation by hypatocytes. The hepatic and serum triglyceride and total cholesterol levels were inversely associated with the hepatic LRPPRC level. These data demonstrated that LRPPRC-driven hepatic OxPhos could promote fatty acids uptake and oxidation by hepatocytes and reduce both hepatic and circulating triglyceride and cholesterol levels. PMID- 27462272 TI - Activation of Sterol Regulatory Element Binding Factors by Fenofibrate and Gemfibrozil Stimulates Myelination in Zebrafish. AB - Oligodendrocytes are major myelin-producing cells and play essential roles in the function of a healthy nervous system. However, they are also one of the most vulnerable neural cell types in the central nervous system (CNS), and myelin abnormalities in the CNS are found in a wide variety of neurological disorders, including multiple sclerosis, adrenoleukodystrophy, and schizophrenia. There is an urgent need to identify small molecular weight compounds that can stimulate myelination. In this study, we performed comparative transcriptome analysis to identify pharmacodynamic effects common to miconazole and clobetasol, which have been shown to stimulate myelination by mouse oligodendrocyte progenitor cells (OPCs). Of the genes differentially expressed in both miconazole- and clobetasol treated mouse OPCs compared with untreated cells, we identified differentially expressed genes (DEGs) common to both drug treatments. Gene ontology analysis revealed that these DEGs are significantly associated with the sterol biosynthetic pathway, and further bioinformatics analysis suggested that sterol regulatory element binding factors (SREBFs) might be key upstream regulators of the DEGs. In silico screening of a public database for chemicals associated with SREBF activation identified fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, as a drug that increases the expression of known SREBF targets, raising the possibility that fenofibrate may also stimulate myelination. To test this, we performed in vivo imaging of zebrafish expressing a fluorescent reporter protein under the control of the myelin basic protein (mbp) promoter. Treatment of zebrafish with fenofibrate significantly increased expression of the fluorescent reporter compared with untreated zebrafish. This increase was attenuated by co-treatment with fatostatin, a specific inhibitor of SREBFs, confirming that the fenofibrate effect was mediated via SREBFs. Furthermore, incubation of zebrafish with another PPARalpha agonist, gemfibrozil, also increased expression of the mbp promoter-driven fluorescent reporter in an SREBF-dependent manner. These results suggest that activation of SREBFs by small molecular weight compounds may be a feasible therapeutic approach to stimulate myelination. PMID- 27462274 TI - Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat. AB - Alterations to the supply of oxygen during early life presents a profound stressor to physiological systems with aberrant remodeling that is often long lasting. Chronic intermittent hypoxia (CIH) is a feature of apnea of prematurity, chronic lung disease, and sleep apnea. CIH affects respiratory control but there is a dearth of information concerning the effects of CIH on respiratory muscles, including the diaphragm-the major pump muscle of breathing. We investigated the effects of exposure to gestational CIH (gCIH) and postnatal CIH (pCIH) on diaphragm muscle function in male and female rats. CIH consisted of exposure in environmental chambers to 90 s of hypoxia reaching 5% O2 at nadir, once every 5 min, 8 h a day. Exposure to gCIH started within 24 h of identification of a copulation plug and continued until day 20 of gestation; animals were studied on postnatal day 22 or 42. For pCIH, pups were born in normoxia and within 24 h of delivery were exposed with dams to CIH for 3 weeks; animals were studied on postnatal day 22 or 42. Sham groups were exposed to normoxia in parallel. Following gas exposures, diaphragm muscle contractile, and endurance properties were examined ex vivo. Neither gCIH nor pCIH exposure had effects on diaphragm muscle force-generating capacity or endurance in either sex. Similarly, early life exposure to CIH did not affect muscle tolerance of severe hypoxic stress determined ex vivo. The findings contrast with our recent observation of upper airway dilator muscle weakness following exposure to pCIH. Thus, the present study suggests a relative resilience to hypoxic stress in diaphragm muscle. Co ordinated activity of thoracic pump and upper airway dilator muscles is required for optimal control of upper airway caliber. A mismatch in the force-generating capacity of the complementary muscle groups could have adverse consequences for the control of airway patency and respiratory homeostasis. PMID- 27462275 TI - Mechanical Forces Accelerate Collagen Digestion by Bacterial Collagenase in Lung Tissue Strips. AB - Most tissues in the body are under mechanical tension, and while enzymes mediate many cellular and extracellular processes, the effects of mechanical forces on enzyme reactions in the native extracellular matrix (ECM) are not fully understood. We hypothesized that physiological levels of mechanical forces are capable of modifying the activity of collagenase, a key remodeling enzyme of the ECM. To test this, lung tissue Young's modulus and a nonlinearity index characterizing the shape of the stress-strain curve were measured in the presence of bacterial collagenase under static uniaxial strain of 0, 20, 40, and 80%, as well as during cyclic mechanical loading with strain amplitudes of +/-10 or +/ 20% superimposed on 40% static strain, and frequencies of 0.1 or 1 Hz. Confocal and electron microscopy was used to determine and quantify changes in ECM structure. Generally, mechanical loading increased the effects of enzyme activity characterized by an irreversible decline in stiffness and tissue deterioration seen on both confocal and electron microscopic images. However, a static strain of 20% provided protection against digestion compared to both higher and lower strains. The decline in stiffness during digestion positively correlated with the increase in equivalent alveolar diameters and negatively correlated with the nonlinearity index. These results suggest that the decline in stiffness results from rupture of collagen followed by load transfer and subsequent rupture of alveolar walls. This study may provide new understanding of the role of collagen degradation in general tissue remodeling and disease progression. PMID- 27462276 TI - Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure. AB - Circulating dipeptidyl peptidase IV (DPPIV) activity is associated with worse cardiovascular outcomes in humans and experimental heart failure (HF) models, suggesting that DPPIV may play a role in the pathophysiology of this syndrome. Renal dysfunction is one of the key features of HF, but it remains to be determined whether DPPIV inhibitors are capable of improving cardiorenal function after the onset of HF. Therefore, the present study aimed to test the hypothesis that DPPIV inhibition by vildagliptin improves renal water and salt handling and exerts anti-proteinuric effects in rats with established HF. To this end, male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were randomly divided into two groups and treated for 4 weeks with vildagliptin (120 mg/kg/day) or vehicle by oral gavage. Echocardiography was performed before (pretreatment) and at the end of treatment (post-treatment) to evaluate cardiac function. The fractional area change (FAC) increased (34 +/- 5 vs. 45 +/- 3%, p < 0.05), and the isovolumic relaxation time decreased (33 +/- 2 vs. 27 +/- 1 ms; p < 0.05) in HF rats treated with vildagliptin (post-treatment vs. pretreatment). On the other hand, cardiac dysfunction deteriorated further in vehicle-treated HF rats. Renal function was impaired in vehicle-treated HF rats as evidenced by fluid retention, low glomerular filtration rate (GFR) and high levels of urinary protein excretion. Vildagliptin treatment restored urinary flow, GFR, urinary sodium and urinary protein excretion to sham levels. Restoration of renal function in HF rats by DPPIV inhibition was associated with increased active glucagon-like peptide-1 (GLP-1) serum concentration, reduced DPPIV activity and increased activity of protein kinase A in the renal cortex. Furthermore, the anti proteinuric effect of vildagliptin treatment in rats with established HF was associated with upregulation of the apical proximal tubule endocytic receptor megalin and of the podocyte main slit diaphragm proteins nephrin and podocin. Collectively, these findings demonstrate that DPPIV inhibition exerts renoprotective effects and ameliorates cardiorenal function in rats with established HF. Long-term studies with DPPIV inhibitors are needed to ascertain whether these effects ultimately translate into improved clinical outcomes. PMID- 27462277 TI - Different Anti-Contractile Function and Nitric Oxide Production of Thoracic and Abdominal Perivascular Adipose Tissues. AB - Divergent phenotypes between the perivascular adipose tissue (PVAT) surrounding the abdominal and the thoracic aorta might be implicated in regional aortic differences, such as susceptibility to atherosclerosis. Although PVAT of the thoracic aorta exhibits anti-contractile function, the role of PVAT in the regulation of the vascular tone of the abdominal aorta is not well defined. In the present study, we compared the anti-contractile function, nitric oxide (NO) availability, and reactive oxygen species (ROS) formation in PVAT and vessel walls of abdominal and thoracic aorta. Abdominal and thoracic aortic tissue from male Wistar rats were used to perform functional and molecular experiments. PVAT reduced the contraction evoked by phenylephrine in the absence and presence of endothelium in the thoracic aorta, whereas this anti-contractile effect was not observed in the abdominal aorta. Abdominal PVAT exhibited a reduction in endothelial NO synthase (eNOS) expression compared with thoracic PVAT, without differences in eNOS expression in the vessel walls. In agreement with this result, NO production evaluated in situ using 4,5-diaminofluorescein was less pronounced in abdominal compared with thoracic aortic PVAT, whereas no significant difference was observed for endothelial NO production. Moreover, NOS inhibition with L-NAME enhanced the phenylephrine-induced contraction in endothelial-denuded rings with PVAT from thoracic but not abdominal aorta. ROS formation and lipid peroxidation products evaluated through the quantification of hydroethidine fluorescence and 4-hydroxynonenal adducts, respectively, were similar between PVAT and vessel walls from the abdominal and thoracic aorta. Extracellular superoxide dismutase (SOD) expression was similar between the vessel walls and PVAT of the abdominal and thoracic aorta. However, Mn-SOD levels were reduced, while CuZn-SOD levels were increased in abdominal PVAT compared with thoracic aortic PVAT. In conclusion, our results demonstrate that the anti contractile function of PVAT is lost in the abdominal portion of the aorta through a reduction in eNOS-derived NO production compared with the thoracic aorta. Although relative SOD isoforms are different along the aorta, ROS formation, and lipid peroxidation seem to be similar. These findings highlight the specific regional roles of PVAT depots in the control of vascular function that can drive differences in susceptibility to vascular injury. PMID- 27462279 TI - Aliskiren Administration during Early Postnatal Life Sex-Specifically Alleviates Hypertension Programmed by Maternal High Fructose Consumption. AB - Key points summary Maternal high-fructose (HF) induces programmed hypertension in adult offspring.Early aliskiren administration prevents HF-induced hypertension in both sexes of adult offspring.HF regulates RAS components in the offspring kidney in a sex-specific manner.HF alters renal transcriptome, with female offspring being more sensitive.Deprogramming strategy to prevent hypertension might be sex-specific. BACKGROUND: Maternal high fructose (HF) intake induced renal programming and hypertension in male adult offspring. We examined whether maternal HF intake causes programmed hypertension and whether aliskiren administration confers protection against the process in a sex-specific manner, with a focus on the transcriptome changes in the kidney using next-generation RNA sequencing (NGS) technology and renin-angiotensin system (RAS). METHODS: Pregnant Sprague-Dawley rats received regular chow or chow supplemented with 60% fructose throughout pregnancy and lactation. Offspring were assigned to six groups: male control, male HF (MHF), MHF+Aliskiren, female control, female HF (FHF), and FHF+Aliskiren. Oral aliskiren 10 mg/kg/day was administered via gastric gavage between 2 and 4 weeks of age. Rats were sacrificed at 12 weeks of age. RESULTS: Maternal HF intake induced programmed hypertension in 12-week-old offspring of both sexes. HF regulated renal transcriptome and RAS components in the offspring kidney in a sex-specific manner. Aliskiren administration prevented HF-induced programmed hypertension in both sexes of adult offspring. Aliskiren administration increased ACE2 and MAS protein levels in female kidneys exposed to maternal HF intake. CONCLUSION: Maternal HF induced programmed hypertension in both sexes of adult offspring, which was sex-specifically mitigated by early aliskiren administration. Better understanding of the sex-dependent mechanisms that underlie maternal HF-induced renal programming will help develop a novel sex specific strategy to prevent programmed hypertension. PMID- 27462278 TI - Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. AB - 1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis ((epid) Vdr (-/-) and (epid) Casr (-/-)). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and beta-catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr (-/-) mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the (epid) Vdr (-/-) or (epid) Casr (-/-). But in mice with epidermal specific deletion of both Vdr and Casr ((epid) Vdr (-/ )/(epid) Casr (-/-) [DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the beta-catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed. PMID- 27462280 TI - Corrigendum: Extending decision making competence to special populations: a pilot study of persons on the autism spectrum. AB - [This corrects the article on p. 539 in vol. 6, PMID: 25972831.]. PMID- 27462281 TI - The More (Social Group Memberships), the Merrier: Is This the Case for Asians? AB - While previous studies have consistently shown that belonging to multiple groups enhances well-being, the current research proposes that for Asians, multiple group memberships (MGM) may confer fewer well-being benefits. We suggest that this is due, in part, to Asian norms about relationships and support seeking, making Asians more reluctant to enlist social support due to concerns about burdening others. Overall, MGM was associated with enhanced well-being in Westerners (Study 2), but not Asians (Studies 1-3). Study 2 showed that social support mediated the relationship between MGM and well-being for Westerners only. In Study 3, among Asians, MGM benefited the well-being of those who were least reluctant to enlist support. Finally, reviewing the MGM evidence-base to date, relative to Westerners, MGM was less beneficial for the well-being of Asians. The evidence underscores the importance of culture in influencing how likely individuals utilize their group memberships as psychological resources. PMID- 27462282 TI - Cross-Validation of the Spanish HP-Version of the Jefferson Scale of Empathy Confirmed with Some Cross-Cultural Differences. AB - CONTEXT: Medical educators agree that empathy is essential for physicians' professionalism. The Health Professional Version of the Jefferson Scale of Empathy (JSE-HP) was developed in response to a need for a psychometrically sound instrument to measure empathy in the context of patient care. Although extensive support for its validity and reliability is available, the authors recognize the necessity to examine psychometrics of the JSE-HP in different socio-cultural contexts to assure the psychometric soundness of this instrument. The first aim of this study was to confirm its psychometric properties in the cross-cultural context of Spain and Latin American countries. The second aim was to measure the influence of social and cultural factors on the development of medical empathy in health practitioners. METHODS: The original English version of the JSE-HP was translated into International Spanish using back-translation procedures. The Spanish version of the JSE-HP was administered to 896 physicians from Spain and 13 Latin American countries. Data were subjected to exploratory factor analysis using principal component analysis (PCA) with oblique rotation (promax) to allow for correlation among the resulting factors, followed by a second analysis, using confirmatory factor analysis (CFA). Two theoretical models, one based on the English JSE-HP and another on the first Spanish student version of the JSE (JSE S), were tested. Demographic variables were compared using group comparisons. RESULTS: A total of 715 (80%) surveys were returned fully completed. Cronbach's alpha coefficient of the JSE for the entire sample was 0.84. The psychometric properties of the Spanish JSE-HP matched those of the original English JSE-HP. However, the Spanish JSE-S model proved more appropriate than the original English model for the sample in this study. Group comparisons among physicians classified by gender, medical specialties, cultural and cross-cultural backgrounds yielded statistically significant differences (p < 0.001). CONCLUSIONS: The findings support the underlying factor structure of the Jefferson Scale of Empathy (JSE). The results reveal the importance of culture in the development of medical empathy. The cross-cultural differences described could open gates for further lines of medical education research. PMID- 27462283 TI - Disorganization, COMT, and Children's Social Behavior: The Norwegian Hypothesis of Legacy of Disorganized Attachment. AB - Why is disorganized attachment associated with punitive-controlling behavior in some, but caregiving-controlling in others? Hygen et al. (2014) proposed that variation in the Catechol-O-methyl transferase(COMT) Val158Met genotype explains this variation, providing preliminary data to this effect. We offer a conceptual replication, analyzing data on 560 children (males: 275) drawn from the NICHD Study of Early Child Care and Youth Development. As predicted, competitive model fitting indicated that disorganized infants carrying Met alleles engage in more positive behavior and less negative behavior than other children at age 5 and 11, with the reverse true of Val/Val homozygotes, seemingly consistent with caregiving-controlling and punitive-controlling styles, respectively, but only in the case of maternal and not teacher reports, thereby confirmating a relationship specific hypothesis. PMID- 27462284 TI - The Semantic Associative Ability in Preschoolers with Different Language Onset Time. AB - Aim of the study is to verify the semantic associative abilities in children with different language onset times: early, typical, and delayed talkers. The study was conducted on the sample of 74 preschool children who performed a Perceptual Associative Task, in order to evaluate the ability to link concepts by four associative strategies (function, part/whole, contiguity, and superordinate strategies). The results evidenced that the children with delayed language onset performed significantly better than the children with early language production. No difference was found between typical and delayed language groups. Our results showed that the children with early language onset presented weakness in the flexibility of elaboration of the concepts. The typical and delayed language onset groups overlapped performance in the associative abilities. The time of language onset appeared to be a predictive factor in the use of semantic associative strategies; the early talkers might present a slow pattern of conceptual processing, whereas the typical and late talkers may have protective factors. PMID- 27462286 TI - Editorial: Linguistic Influences on Mathematics. PMID- 27462285 TI - No Interrelation of Motor Planning and Executive Functions across Young Ages. AB - The present study examined the developmental trajectories of motor planning and executive functioning in children. To this end, we tested 217 participants with three motor tasks, measuring anticipatory planning abilities (i.e., the bar transport-task, the sword-rotation-task and the grasp-height-task), and three cognitive tasks, measuring executive functions (i.e., the Tower-of-Hanoi-task, the Mosaic-task, and the D2-attention-endurance-task). Children were aged between 3 and 10 years and were separated into age groups by 1-year bins, resulting in a total of eight groups of children and an additional group of adults. Results suggested (1) a positive developmental trajectory for each of the sub-tests, with better task performance as children get older; (2) that the performance in the separate tasks was not correlated across participants in the different age groups; and (3) that there was no relationship between performance in the motor tasks and in the cognitive tasks used in the present study when controlling for age. These results suggest that both, motor planning and executive functions are rather heterogeneous domains of cognitive functioning with fewer interdependencies than often suggested. PMID- 27462287 TI - Cognitive Effects of Mindfulness Training: Results of a Pilot Study Based on a Theory Driven Approach. AB - The present paper reports a pilot study which tested cognitive effects of mindfulness practice in a theory-driven approach. Thirty-four fifth graders received either a mindfulness training which was based on the mindfulness-based stress reduction approach (experimental group), a concentration training (active control group), or no treatment (passive control group). Based on the operational definition of mindfulness by Bishop et al. (2004), effects on sustained attention, cognitive flexibility, cognitive inhibition, and data-driven as opposed to schema-based information processing were predicted. These abilities were assessed in a pre-post design by means of a vigilance test, a reversible figures test, the Wisconsin Card Sorting Test, a Stroop test, a visual search task, and a recognition task of prototypical faces. Results suggest that the mindfulness training specifically improved cognitive inhibition and data-driven information processing. PMID- 27462288 TI - Electrophysiological Correlates of Emotional Source Memory in High-Trait-Anxiety Individuals. AB - The interaction between recognition memory and emotion has become a research hotspot in recent years. Dual process theory posits that familiarity and recollection are two separate processes contributing to recognition memory, but further experimental evidence is needed. The present study explored the emotional context effects on successful and unsuccessful source retrieval amongst 15 high trait-anxiety college students by using event-related potentials (ERPs) measurement. During study, a happy, fearful, or neutral face picture first was displayed, then a Chinese word was superimposed centrally on the picture and subjects were asked to remember the word and the corresponding type of picture. During the test participants were instructed to press one of four buttons to indicate whether the displayed word was an old or new word. And then, for the old word, indicate whether it had been shown with a fearful, happy, or neutral face during the study. ERPs were generally more positive for remembered words than for new words and the ERP difference was termed as an old/new effect. It was found that, for successful source retrieval (it meant both the item and the source were remembered accurately) between 500 and 700 ms (corresponding to a late positive component, LPC), there were significant old/new effects in all contexts. However, for unsuccessful source retrieval (it meant the correct recognition of old items matched with incorrect source attribution), there were no significant old/new effects in happy and neutral contexts, though significant old/new effects were observed in the fearful context. Between 700 and 1200 ms (corresponding to a late slow wave, LSW), there were significant old/new effects for successful source retrieval in happy and neutral contexts. However, in the fearful context, the old/new effects were reversed, ERPs were more negative for successful source retrieval compared to correct rejections. Moreover, there were significant emotion effects for successful source retrieval at this time window. Further analysis showed ERPs of old items were more negative in fearful context than in neutral context. The results showed that early unsuccessful fearful source retrieval processes (related to familiarity) were enhanced, but late successful fearful source retrieval processes during source retrieval monitoring (related to recollection) were weakened. This provided preliminary evidence for the dual processing theory. PMID- 27462289 TI - Positive Affect Is Inversely Associated with Mortality in Individuals without Depression. AB - BACKGROUND: Some studies have analyzed the relation between well-being and mortality but none of them have attempted to disentangle the differential influence that positive affect, negative affect, and evaluative well-being might have on mortality using a longitudinal design in the general population and measuring independently and accurately each component of well-being. The aim of the present study is to assess the association of these well-being components with mortality after adjusting for health and other lifestyle factors and to analyze whether this association is different in people with and without depression. METHODS: A nationally representative sample of 4753 people from Spain was followed up after 3 years. Analyses were performed with Cox regression models among the total sample and separately in people with and without depression. RESULTS: In the analyses adjusted for age, sex, and years of education, all three well-being variables showed separately a statistically significant association with mortality. However, after adjustment for health status and other confounders including the other well-being components, only positive affect remained as marginally associated with a decreased risk of mortality in the overall sample [HR = 0.87; 95% CI = 0.73-1.03], in particular among individuals without depression [HR = 0.82; 95% CI = 0.68-0.99]. CONCLUSION: Positive affect is inversely associated with mortality in individuals without depression. Future research should focus on assessing interventions associated with a higher level of positive affect. PMID- 27462290 TI - Experimental But Not Sex Differences of a Mental Rotation Training Program on Adolescents. AB - Given the importance of visuospatial processing in areas related to the STEM (Science, Technology, Engineering, and Mathematics) disciplines, where there is still a considerable gap in the area of sex differences, the interest in the effects of visuospatial skills training continues to grow. Therefore, we have evaluated the visuospatial improvement of adolescents after performing a computerized mental rotation training program, as well as the relationship of this visuospatial ability with other cognitive, emotional factors and those factors based on the experience with videogames. The study, which was performed on students aged 14 and 15 years old, showed a significant improvement in this visuospatial skill for a training group (n = 21) compared to a control group (n = 24). Furthermore, no significant sex differences were obtained for spatial ability or for any of the other tasks evaluated, either before or after training. Regarding the relationship between skills, a significant correlation between experience with video games and spatial ability was found, as well as between mathematical reasoning and intelligence and with spatial ability in the initial phase for the total sample. These findings are discussed from a cognitive point of view and within the current sociocultural context, where the equal use of new technologies could help reduce the visuospatial gap between sexes. PMID- 27462291 TI - New Evidence on Causal Relationship between Approximate Number System (ANS) Acuity and Arithmetic Ability in Elementary-School Students: A Longitudinal Cross Lagged Analysis. AB - Approximate number system (ANS) acuity and mathematical ability have been found to be closely associated in recent studies. However, whether and how these two measures are causally related still remain less addressed. There are two hypotheses about the possible causal relationship: ANS acuity influences mathematical performances, or access to math education sharpens ANS acuity. Evidences in support of both hypotheses have been reported, but these two hypotheses have never been tested simultaneously. Therefore, questions still remain whether only one-direction or reciprocal causal relationships existed in the association. In this work, we provided a new evidence on the causal relationship between ANS acuity and arithmetic ability. ANS acuity and mathematical ability of elementary-school students were measured sequentially at three time points within one year, and all possible causal directions were evaluated simultaneously using cross-lagged regression analysis. The results show that ANS acuity influences later arithmetic ability while the reverse causal direction was not supported. Our finding adds a strong evidence to the causal association between ANS acuity and mathematical ability, and also has important implications for educational intervention designed to train ANS acuity and thereby promote mathematical ability. PMID- 27462293 TI - Music Undergraduates' Usefulness and Importance Expectations: The Bologna Process from an Australian University Perspective. AB - The Bologna Process model of higher education has been introduced into some Australian universities since 2008. This model promoted university study through a liberal arts philosophy that advanced a worldview approach at the undergraduate level. The model generalized the student experience and eliminated undergraduate specialization. An interesting situation for music undergraduate study thus arose. Expertise and expert performance research has argued an opposing educational approach, namely: Extensive long-term commitment through focused practical engagement and specialized tuition as prerequisites to achieving musical mastery, especially in performance. Motivation research has shown that the majority of this specialized development in pre-university years would be accessed and reinforced predominantly through private music tuition. Drawing on this contextual literature, commencing university music undergraduates would have expectations of their prospective study founded from two historical influences. The first: How undergraduates had accessed pre-university music tuition. The second: How and in what ways undergraduates' pre-university musical activities were experienced and reinforced. Using usefulness and importance measures, the study observed the expectations of students about to commence music undergraduate studies at three representative Australian university music schools. One of these universities operated the Bologna styled model. No other known Australian study has investigated this implementation for any effects upon music undergraduate expectations. How much commencing music undergraduates would draw on their pre university music instruction and experiences to predict their usefulness and importance expectations formed the basis for this investigation. Strong relationships between usefulness and importance were found across all units of study. Despite strong correlations across all units of study between usefulness and importance, there was a reluctance to be outwardly positive toward units of study that were not practical and performance-related, such as Music History. The educational model did not appear to affect music undergraduate expectations. PMID- 27462292 TI - Cognitive, Emotional, and Psychosocial Functioning of Girls Treated with Pharmacological Puberty Blockage for Idiopathic Central Precocious Puberty. AB - Central precocious puberty (CPP) develops due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in early pubertal changes and rapid bone maturation. CPP is associated with lower adult height and increased risk for development of psychological problems. Standard treatment of CPP is based on postponement of pubertal development by blockade of the HPG axis with gonadotropin releasing hormone analogs (GnRHa) leading to abolition of gonadal sex hormones synthesis. Whereas the hormonal and auxological effects of GnRHa are well-researched, there is a lack of knowledge whether GnRHa treatment influences psychological functioning of treated children, despite the fact that prevention of psychological problems is used as one of the main reasons for treatment initiation. In the present study we seek to address this issue by exploring differences in cognitive function, behavior, emotional reactivity, and psychosocial problems between GnRHa treated CPP girls and age-matched controls. Fifteen girls with idiopathic CPP; median age 10.4 years, treated with slow release GnRHa (triptorelin acetate-Decapeptyl SR(r) 11.25) and 15 age-matched controls, were assessed with a comprehensive test battery consisting of paper and pencil tests, computerized tasks, behavioral paradigms, heart rate variability, and questionnaires filled in by the children's parents. Both groups showed very similar scores with regard to cognitive performance, behavioral and psychosocial problems. Compared to controls, treated girls displayed significantly higher emotional reactivity (p = 0.016; Cohen's d = 1.04) on one of the two emotional reactivity task conditions. Unexpectedly, the CPP group showed significantly lower resting heart rates than the controls (p = 0.004; Cohen's d = 1.03); lower heart rate was associated with longer treatment duration (r = -0.582, p = 0.037). The results suggest that GnRHa treated CPP girls do not differ in their cognitive or psychosocial functioning from age matched controls. However, they might process emotional stimuli differently. The unexpected finding of lower heart rate that was associated with longer duration of the treatment should be further explored by methods appropriate for assessment of cardiac health. PMID- 27462294 TI - Perceived Threat Associated with Police Officers and Black Men Predicts Support for Policing Policy Reform. AB - Racial disparities in policing and recent high-profile incidents resulting in the deaths of Black men have ignited a national debate on policing policies. Given evidence that both police officers and Black men may be associated with threat, we examined the impact of perceived threat on support for reformed policing policies. Across three studies we found correlational evidence that perceiving police officers as threatening predicts increased support for reformed policing practices (e.g., limiting the use of lethal force and matching police force demographics to those of the community). In contrast, perceiving Black men as threatening predicted reduced support for policing policy reform. Perceived threat also predicted willingness to sign a petition calling for police reform. Experimental evidence indicated that priming participants to associate Black men with threat could also reduce support for policing policy reform, and this effect was moderated by internal motivation to respond without prejudice. Priming participants to associate police officers with threat did not increase support for policing policy reform. Results indicate that resistance to policing policy reform is associated with perceiving Black men as threatening. Moreover, findings suggest that publicizing racially charged police encounters, which may conjure associations between Black men and threat, could reduce support for policing policy reform. PMID- 27462295 TI - Joint Perception of a Shared Object: A Minimalist Perceptual Crossing Experiment. AB - The minimalist perceptual crossing paradigm has emphasized the essential role of interpersonal dynamics on social understanding. Within the particular case of minimalist interaction, it has been argued that interpersonal processes can constitute social cognition, at least partially, which calls for a paradigm shift in social cognition studies. In this paper, we review several perceptual crossing experiments and their theoretical implications, and propose an original experiment to go beyond strictly dyadic interactions. Whereas past experiments have used objects as distracters of dyadic interaction, our experiment aims at integrating objects themselves as the goal of interpersonal coordination. We asked 24 subjects to participate in a minimalist perceptual crossing experiment where they had to decide, based on their on-line interaction in a one-dimensional digital space, which of the objects they perceived was also perceptible by their partner. The main results suggest that the mutual awareness of a shared object (SO) arises from the quality of sensorimotor coordination between the partners. Indeed, the presence of a SO acts as a simultaneous affordance that attracts and structures individual perceptive activities, giving both partners the opportunity to co-construct a shared world where their respective actions make sense. We discuss our results by way of an enactive account of social cognition, taking the joint perception of a SO as a first step to account for joint attention. PMID- 27462296 TI - Geometric Constraints on Human Speech Sound Inventories. AB - We investigate the idea that the languages of the world have developed coherent sound systems in which having one sound increases or decreases the chances of having certain other sounds, depending on shared properties of those sounds. We investigate the geometries of sound systems that are defined by the inherent properties of sounds. We document three typological tendencies in sound system geometries: economy, a tendency for the differences between sounds in a system to be definable on a relatively small number of independent dimensions; local symmetry, a tendency for sound systems to have relatively large numbers of pairs of sounds that differ only on one dimension; and global symmetry, a tendency for sound systems to be relatively balanced. The finding of economy corroborates previous results; the two symmetry properties have not been previously documented. We also investigate the relation between the typology of inventory geometries and the typology of individual sounds, showing that the frequency distribution with which individual sounds occur across languages works in favor of both local and global symmetry. PMID- 27462297 TI - The Effect of Self-Esteem on Corrupt Intention: The Mediating Role of Materialism. AB - The present set of studies aimed to explore the effect of self-esteem on corrupt intention and the mediating role of materialism in generating this effect. In Study 1, we used questionnaires to investigate the correlation among self-esteem, materialism, and corrupt intention. In Study 2, we manipulated self-esteem to explore the causal effect of self-esteem on materialism and corrupt intention. In Study 3, we manipulated materialism to examine whether inducing materialism can reduce the relationship between self-esteem and corrupt intention. The three studies converged to show that increased self-esteem caused a low level of materialism, which in turn decreased corrupt intention. The theoretical and practical implications of the results are discussed. PMID- 27462298 TI - Phosphatidylinositol 3-Kinase-Associated Protein (PI3KAP)/XB130 Crosslinks Actin Filaments through Its Actin Binding and Multimerization Properties In Vitro and Enhances Endocytosis in HEK293 Cells. AB - Actin-crosslinking proteins control actin filament networks and bundles and contribute to various cellular functions including regulation of cell migration, cell morphology, and endocytosis. Phosphatidylinositol 3-kinase-associated protein (PI3KAP)/XB130 has been reported to be localized to actin filaments (F actin) and required for cell migration in thyroid carcinoma cells. Here, we show a role for PI3KAP/XB130 as an actin-crosslinking protein. First, we found that the carboxyl terminal region of PI3KAP/XB130 containing amino acid residues 830 840 was required and sufficient for localization to F-actin in NIH3T3 cells, and this region is directly bound to F-actin in vitro. Moreover, actin-crosslinking assay revealed that recombinant PI3KAP/XB130 crosslinked F-actin. In general, actin-crosslinking proteins often multimerize to assemble multiple actin-binding sites. We then investigated whether PI3KAP/XB130 could form a multimer. Blue native-PAGE analysis showed that recombinant PI3KAP/XB130 was detected at 250 1200 kDa although the molecular mass was approximately 125 kDa, suggesting that PI3KAP/XB130 formed multimers. Furthermore, we found that the amino terminal 40 amino acids were required for this multimerization by co-immunoprecipitation assay in HEK293T cells. Deletion mutants of PI3KAP/XB130 lacking the actin binding region or the multimerizing region did not crosslink actin filaments, indicating that actin binding and multimerization of PI3KAP/XB130 were necessary to crosslink F-actin. Finally, we examined roles of PI3KAP/XB130 on endocytosis, an actin-related biological process. Overexpression of PI3KAP/XB130 enhanced dextran uptake in HEK 293 cells. However, most of the cells transfected with the deletion mutant lacking the actin-binding region incorporated dextran to a similar extent as control cells. Taken together, these results demonstrate that PI3KAP/XB130 crosslinks F-actin through both its actin-binding region and multimerizing region and plays an important role in endocytosis. PMID- 27462299 TI - Endozoicomonas Are Specific, Facultative Symbionts of Sea Squirts. AB - Ascidians are marine filter feeders and harbor diverse microbiota that can exhibit a high degree of host-specificity. Pharyngeal samples of Scandinavian and Mediterranean ascidians were screened for consistently associated bacteria by culture-dependent and -independent approaches. Representatives of the Endozoicomonas (Gammaproteobacteria, Hahellaceae) clade were detected in the ascidian species Ascidiella aspersa, Ascidiella scabra, Botryllus schlosseri, Ciona intestinalis, Styela clava, and multiple Ascidia/Ascidiella spp. In total, Endozoicomonas was detected in more than half of all specimens screened, and in 25-100% of the specimens for each species. The retrieved Endozoicomonas 16S rRNA gene sequences formed an ascidian-specific subclade, whose members were detected by fluorescence in situ hybridization (FISH) as extracellular microcolonies in the pharynx. Two strains of the ascidian-specific Endozoicomonas subclade were isolated in pure culture and characterized. Both strains are chemoorganoheterotrophs and grow on mucin (a mucus glycoprotein). The strains tested negative for cytotoxic or antibacterial activity. Based on these observations, we propose ascidian-associated Endozoicomonas to be commensals, living off the mucus continuously secreted into the pharynx. Members of the ascidian-specific Endozoicomonas subclade were also detected in seawater from the Scandinavian sampling site, which suggests acquisition of the symbionts by horizontal transmission. The combined results indicate a host-specific, yet facultative symbiosis between ascidians and Endozoicomonas. PMID- 27462300 TI - Populations of Stored Product Mite Tyrophagus putrescentiae Differ in Their Bacterial Communities. AB - BACKGROUND: Tyrophagus putrescentiae colonizes different human-related habitats and feeds on various post-harvest foods. The microbiota acquired by these mites can influence the nutritional plasticity in different populations. We compared the bacterial communities of five populations of T. putrescentiae and one mixed population of T. putrescentiae and T. fanetzhangorum collected from different habitats. MATERIAL: The bacterial communities of the six mite populations from different habitats and diets were compared by Sanger sequencing of cloned 16S rRNA obtained from amplification with universal eubacterial primers and using bacterial taxon-specific primers on the samples of adults/juveniles or eggs. Microscopic techniques were used to localize bacteria in food boli and mite bodies. The morphological determination of the mite populations was confirmed by analyses of CO1 and ITS fragment genes. RESULTS: The following symbiotic bacteria were found in compared mite populations: Wolbachia (two populations), Cardinium (five populations), Bartonella-like (five populations), Blattabacterium-like symbiont (three populations), and Solitalea-like (six populations). From 35 identified OTUs97, only Solitalea was identified in all populations. The next most frequent and abundant sequences were Bacillus, Moraxella, Staphylococcus, Kocuria, and Microbacterium. We suggest that some bacterial species may occasionally be ingested with food. The bacteriocytes were observed in some individuals in all mite populations. Bacteria were not visualized in food boli by staining, but bacteria were found by histological means in ovaria of Wolbachia infested populations. CONCLUSION: The presence of Blattabacterium-like, Cardinium, Wolbachia, and Solitalea-like in the eggs of T. putrescentiae indicates mother to offspring (vertical) transmission. RESULTS of this study indicate that diet and habitats influence not only the ingested bacteria but also the symbiotic bacteria of T. putrescentiae. PMID- 27462301 TI - Occurrence of OXA-48 Carbapenemase and Other beta-Lactamase Genes in ESBL Producing Multidrug Resistant Escherichia coli from Dogs and Cats in the United States, 2009-2013. AB - OBJECTIVE: The aim of this study was to explore the occurrence and molecular characterization of extended-spectrum beta-lactamases (ESBL), plasmid-mediated AmpC beta-lactamase (pAmpC) and carbapenemases among ESBL-producing multidrug resistant (MDR) Escherichia coli from dogs and cats in the United States. METHODS: Of 2443 E.coli isolated from dogs and cats collected between August 2009 and January 2013, 68 isolates were confirmed as ESBL-producing MDR ones. PCR and sequencing were performed to identify beta-lactamases and plasmid-mediated quinolone resistance (PMQR) genes, and shed light on the virulence gene profiles, phylogenetic groups and ST types. RESULTS: Phylogenic group D and B2 accounted for 69.1% of the isolates. 50 (73.5%) isolates carried CTX-M ESBL gene, and the most predominant specific CTX-M subtype identified was bla CTX-M-15 (n = 33), followed by bla CTX-M-1 (n = 32), bla CTX-M-123 (n = 27), bla CTX-M-9 (n = 19) and bla CTX-M-14 (n = 19), and bla CTX-M-123 was firstly reported in E. coli isolates in the United States alone or in association. Other beta-lactamase genes bla TEM, bla SHV, bla OXA-48, and bla CMY-2 were detected in 41.2, 29.4, 19.1, and 17.6% of 68 ESBL-producing MDR isolates, respectively. The bla TEM and bla SHV genes were classfied as ESBLs with the exception of the bla TEM-1 gene. Additionally, 42.6% (29/68) of isolates co-expressed bla CTX-M-15 and PMQR gene aac(6')-Ib-c. The overall occurrence of virulence genes ranged from 11.8 (ireA) to 88.2% (malX), and most of virulence genes were less frequent among CTX-M producing isolates than non-CTX-M isolates with the exception of malX and iutA. The 68 isolates analyzed were assigned to 31 STs with six being novel. Three pandemic clonal lineages ST131 (n = 10), ST648 (n = 9), and ST405 (n = 9) accounted for more than 41% of the investigated isolates, and ST648 and ST405 of phylogenetic D were firstly reported in E. coli from dogs and cats in the United States. CONCLUSION: bla CTX-M-123 of ESBLs and carbapenemase bla OXA-48 were firstly reported in ESBL-producing MDR E.coli from dogs and cats in the United States, and ST131, ST648, and ST405 were the predominant clonal groups. PMID- 27462302 TI - Variations in the Post-weaning Human Gut Metagenome Profile As Result of Bifidobacterium Acquisition in the Western Microbiome. AB - Studies of the gut microbiome variation among human populations revealed the existence of robust compositional and functional layouts matching the three subsistence strategies that describe a trajectory of changes across our recent evolutionary history: hunting and gathering, rural agriculture, and urban post industrialized agriculture. In particular, beside the overall reduction of ecosystem diversity, the gut microbiome of Western industrial populations is typically characterized by the loss of Treponema and the acquisition of Bifidobacterium as an abundant inhabitant of the post-weaning gut microbial ecosystem. In order to advance the hypothesis about the possible adaptive nature of this exchange, here we explore specific functional attributes that correspond to the mutually exclusive presence of Treponema and Bifidobacterium using publically available gut metagenomic data from Hadza hunter-gatherers and urban industrial Italians. According to our findings, Bifidobacterium provides the enteric ecosystem with a diverse panel of saccharolytic functions, well suited to the array of gluco- and galacto-based saccharides that abound in the Western diet. On the other hand, the metagenomic functions assigned to Treponema are more predictive of a capacity to incorporate complex polysaccharides, such as those found in unrefined plant foods, which are consistently incorporated in the Hadza diet. Finally, unlike Treponema, the Bifidobacterium metagenome functions include genes that permit the establishment of microbe-host immunological cross-talk, suggesting recent co-evolutionary events between the human immune system and Bifidobacterium that are adaptive in the context of agricultural subsistence and sedentary societies. PMID- 27462303 TI - Pathophysiological Mechanisms of Staphylococcus Non-aureus Bone and Joint Infection: Interspecies Homogeneity and Specific Behavior of S. pseudintermedius. AB - Implicated in more than 60% of bone and joint infections (BJIs), Staphylococci have a particular tropism for osteoarticular tissue and lead to difficult-to treat clinical infections. To date, Staphylococcus aureus internalization in non professional phagocytic cells (NPPCs) is a well-explored virulence mechanism involved in BJI chronicity. Conversely, the pathophysiological pathways associated with Staphylococcus non-aureus (SNA) BJIs have scarcely been studied despite their high prevalence. In this study, 15 reference strains from 15 different SNA species were compared in terms of (i) adhesion to human fibronectin based on adhesion microplate assays and (ii) internalization ability, intracellular persistence and cytotoxicity based on an in vitro infection model using human osteoblasts. Compared to S. aureus, S. pseudintermedius was the only species that significantly adhered to human fibronectin. This species was also associated with high (even superior to S. aureus) internalization ability, intracellular persistence and cytotoxicity. These findings were confirmed using a panel of 17 different S. pseudintermedius isolates. Additionally, S. pseudintermedius internalization by osteoblasts was completely abolished in beta1 integrin-deficient murine osteoblasts. These results suggest the involvement of beta1 integrin in the invasion process, although this mechanism was previously restricted to S. aureus. In summary, our results suggest that internalization into NPPCs is not a classical pathophysiologic mechanism of SNA BJIs. S. pseudintermedius appears to be an exception, and its ability to invade and subsequently induce cytotoxicity in NPPCs could explain its severe and necrotic forms of infection, notably in dogs, which exhibit a high prevalence of S. pseudintermedius infection. PMID- 27462304 TI - Improvement of Ethanol Production in Saccharomyces cerevisiae by High-Efficient Disruption of the ADH2 Gene Using a Novel Recombinant TALEN Vector. AB - Bioethanol is becoming increasingly important in energy supply and economic development. However, the low yield of bioethanol and the insufficiency of high efficient genetic manipulation approaches limit its application. In this study, a novel transcription activator-like effector nuclease (TALEN) vector containing the left and right arms of TALEN was electroporated into Saccharomyces cerevisiae strain As2.4 to sequence the alcohol dehydrogenase gene ADH2 and the hygromycin resistant gene hyg. Western blot analysis using anti-FLAG monoclonal antibody proved the successful expression of TALE proteins in As2.4 strains. qPCR and sequencing demonstrated the accurate knockout of the 17 bp target gene with 80% efficiency. The TALEN vector and ADH2 PCR product were electroporated into DeltaADH2 to complement the ADH2 gene (ADH2 (+) As2.4). LC-MS and GC were employed to detect ethanol yields in the native As2.4, DeltaADH2 As2.4, and ADH2 (+) As2.4 strains. Results showed that ethanol production was improved by 52.4 +/ 5.3% through the disruption of ADH2 in As2.4. The bioethanol yield of ADH2 (+) As2.4 was nearly the same as that of native As2.4. This study is the first to report on the disruption of a target gene in S. cerevisiae by employing Fast TALEN technology to improve bioethanol yield. This work provides a novel approach for the disruption of a target gene in S. cerevisiae with high efficiency and specificity, thereby promoting the improvement of bioethanol production in S. cerevisiae by metabolic engineering. PMID- 27462305 TI - Polyclonal Intestinal Colonization with Extended-Spectrum Cephalosporin-Resistant Enterobacteriaceae upon Traveling to India. AB - We aimed to assess the intestinal colonization dynamics by multiple extended spectrum cephalosporin-resistant Enterobacteriaceae (ESC-R-Ent) clones in Swiss travelers to India, a country with high prevalence of these multidrug-resistant pathogens. Fifteen healthy volunteers (HVs) colonized with ESC-R-Ent after traveling to India who provided stools before, after, and at 3- and 6-month follow-up are presented in this study. Stools were enriched in a LB broth containing 3 mg/L cefuroxime and plated in standard selective media (BLSE, ChromID ESBL, Supercarba) to detect carbapenem- and/or ESC-R-Ent. At least 5 Enterobacteriaceae colonies were analyzed for each stool provided. All strains underwent phenotypic tests (MICs in microdilution) and molecular typing to define bla genes (microarray, PCR/sequencing), clonality (MLST, rep-PCR), and plasmid content. While only three HVs were colonized before the trip, all participants had positive stools after returning, but the colonization rate decreased during the follow-up period (i.e., six HVs were still colonized at both 3 and 6 months). More importantly, polyclonal acquisition (median of 2 clones, range 1-5) was identified at return in all HVs. The majority of the Escherichia coli isolates belonged to phylogenetic groups A and B1 and to high diverse non-epidemic sequence types (STs); however, 15% of them belonged to clonal complex 10 and mainly possessed bla CTX-M-15 genes. F family plasmids were constantly found (~80%) in the recovered ESC-R-Ent. Our results indicate a possible polyclonal acquisition of the ESC-R-Ent via food-chain and/or through an environmental exposure. For some HVs, prolonged colonization in the follow-up period was observed due to clonal persistence or presence of the same plasmid replicon types in a new bacterial host. Travel medicine practitioners, clinicians, and clinical microbiologists who are facing the returning travelers and their samples for different reasons should be aware of this important phenomenon, so that better infection control measures, treatment strategies, and diagnostic tests can be adopted. PMID- 27462306 TI - Outbreak of Extended-Spectrum Beta-Lactamase Producing Enterobacter cloacae with High MICs of Quaternary Ammonium Compounds in a Hematology Ward Associated with Contaminated Sinks. AB - OBJECTIVE: To investigate an outbreak of extended-spectrum beta-lactamase (ESBL) producing Enterobacter cloacae that occurred in the Hematology ward (24-bed unit) of the Francois Mitterrand University Hospital (Dijon, France) between January 2011 and December 2013. The outbreak involved 43 patients (10 infected and 33 colonized). DESIGN: We performed environmental analysis to detect multiresistant E. cloacae for comparison with clinical isolates (genotyping by pulsed-field gel electrophoresis and MLST as well as ESBL-typing) and determined the MICs of the quaternary ammonium compounds (QACs) alkyldimethylbenzylammonium chloride (ADBAC) and didecyldimethylammonium chloride (DDAC). A bleach-based cleaning-disinfection program was implemented in December 2012 after mechanical removal of the biofilm in all sinks. RESULTS: We have detected 17 ESBL-producing E. cloacae in patients sink drains, shower drains and medical sink drains. Sequencing of the bla genes performed on 60 strains recovered from patients and environment (n = 43 clinical and n = 17 environmental) revealed that bla CTX-M15 was predominant (37 isolates) followed by bla CTX-M9 plus bla SHV-12 (20 isolates). We observed a great diversity among the isolates: 14 pulsotypes (11 STs) in clinical isolates and 9 pulsotypes (7 STs) in environmental isolates. Six pulsotypes were identical between clinical and environmental isolates. MICs of the quaternary ammonium compounds widely used for disinfection were very high in clinical and environmental isolates. Immediately after the implementation of the disinfection program we noticed a substantial fall in cases number. Our findings demonstrate the role of drains as important reservoir of ESBL-producing E. cloacae and highlight the necessity to settle drains accessible to achieve correct cleaning as well as to use disinfectant with proved activity against nosocomial pathogens. PMID- 27462307 TI - A Novel Electrophototrophic Bacterium Rhodopseudomonas palustris Strain RP2, Exhibits Hydrocarbonoclastic Potential in Anaerobic Environments. AB - An electrophototrophic, hydrocarbonoclastic bacterium Rhodopseudomonas palustris stain RP2 was isolated from the anodic biofilms of hydrocarbon fed microbial electrochemical remediation systems (MERS). Salient properties of the strain RP2 were direct electrode respiration, dissimilatory metal oxide reduction, spore formation, anaerobic nitrate reduction, free living diazotrophy and the ability to degrade n-alkane components of petroleum hydrocarbons (PH) in anoxic, photic environments. In acetate fed microbial electrochemical cells, a maximum current density of 305 +/- 10 mA/m(2) (1000Omega) was generated (power density 131.65 +/- 10 mW/m(2)) by strain RP2 with a coulombic efficiency of 46.7 +/- 1.3%. Cyclic voltammetry studies showed that anaerobically grown cells of strain RP2 is electrochemically active and likely to transfer electrons extracellularly to solid electron acceptors through membrane bound compounds, however, aerobically grown cells lacked the electrochemical activity. The ability of strain RP2 to produce current (maximum current density 21 +/- 3 mA/m(2); power density 720 +/- 7 MUW/m(2), 1000 Omega) using PH as a sole energy source was also examined using an initial concentration of 800 mg l(-1) of diesel range hydrocarbons (C9-C36) with a concomitant removal of 47.4 +/- 2.7% hydrocarbons in MERS. Here, we also report the first study that shows an initial evidence for the existence of a hydrocarbonoclastic behavior in the strain RP2 when grown in different electron accepting and illuminated conditions (anaerobic and MERS degradation). Such observations reveal the importance of photoorganotrophic growth in the utilization of hydrocarbons from contaminated environments. Identification of such novel petrochemical hydrocarbon degrading electricigens, not only expands the knowledge on the range of bacteria known for the hydrocarbon bioremediation but also shows a biotechnological potential that goes well beyond its applications to MERS. PMID- 27462308 TI - Antimicrobial Activities of Bacteria Associated with the Brown Alga Padina pavonica. AB - Macroalgae belonging to the genus Padina are known to produce antibacterial compounds that may inhibit growth of human- and animal pathogens. Hitherto, it was unclear whether this antibacterial activity is produced by the macroalga itself or by secondary metabolite producing epiphytic bacteria. Here we report antibacterial activities of epiphytic bacteria isolated from Padina pavonica (Peacocks tail) located on northern coast of Tunisia. Eighteen isolates were obtained in pure culture and tested for antimicrobial activities. Based on the 16S rRNA gene sequences the isolates were closely related to Proteobacteria (12 isolates; 2 Alpha- and 10 Gammaproteobacteria), Firmicutes (4 isolates) and Actinobacteria (2 isolates). The antimicrobial activity was assessed as inhibition of growth of 12 species of pathogenic bacteria (Aeromonas salmonicida, A. hydrophila, Enterobacter xiangfangensis, Enterococcus faecium, Escherichia coli, Micrococcus sp., Salmonella typhimurium, Staphylococcus aureus, Streptococcus sp., Vibrio alginoliticus, V. proteolyticus, V. vulnificus) and one pathogenic yeast (Candida albicans). Among the Firmicutes, isolate P8, which is closely related to Bacillus pumilus, displayed the largest spectrum of growth inhibition of the pathogenic bacteria tested. The results emphasize the potential use of P. pavonica associated antagonistic bacteria as producers of novel antibacterial compounds. PMID- 27462310 TI - Plasma Membrane Profiling Reveals Upregulation of ABCA1 by Infected Macrophages Leading to Restriction of Mycobacterial Growth. AB - The plasma membrane represents a critical interface between the internal and extracellular environments, and harbors multiple proteins key receptors and transporters that play important roles in restriction of intracellular infection. We applied plasma membrane profiling, a technique that combines quantitative mass spectrometry with selective cell surface aminooxy-biotinylation, to Bacille Calmette-Guerin (BCG)-infected THP-1 macrophages. We quantified 559 PM proteins in BCG-infected THP-1 cells. One significantly upregulated cell-surface protein was the cholesterol transporter ABCA1. We showed that ABCA1 was upregulated on the macrophage cell-surface following infection with pathogenic mycobacteria and knockdown of ABCA1 resulted in increased mycobacterial survival within macrophages, suggesting that it may be a novel mycobacterial host-restriction factor. PMID- 27462309 TI - The Gut Microbiota in Immune-Mediated Inflammatory Diseases. AB - The collection of microbes and their genes that exist within and on the human body, collectively known as the microbiome has emerged as a principal factor in human health and disease. Humans and microbes have established a symbiotic association over time, and perturbations in this association have been linked to several immune-mediated inflammatory diseases (IMID) including inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. IMID is a term used to describe a group of chronic, highly disabling diseases that affect different organ systems. Though a cornerstone commonality between IMID is the idiopathic nature of disease, a considerable portion of their pathobiology overlaps including epidemiological co-occurrence, genetic susceptibility loci and environmental risk factors. At present, it is clear that persons with an IMID are at an increased risk for developing comorbidities, including additional IMID. Advancements in sequencing technologies and a parallel explosion of 16S rDNA and metagenomics community profiling studies have allowed for the characterization of microbiomes throughout the human body including the gut, in a myriad of human diseases and in health. The main challenge now is to determine if alterations of gut flora are common between IMID or, if particular changes in the gut community are in fact specific to a single disease. Herein, we review and discuss the relationships between the gut microbiota and IMID. PMID- 27462311 TI - Whole-Transcriptome Analysis of Verocytotoxigenic Escherichia coli O157:H7 (Sakai) Suggests Plant-Species-Specific Metabolic Responses on Exposure to Spinach and Lettuce Extracts. AB - Verocytotoxigenic Escherichia coli (VTEC) can contaminate crop plants, potentially using them as secondary hosts, which can lead to food-borne infection. Currently, little is known about the influence of the specific plant species on the success of bacterial colonization. As such, we compared the ability of the VTEC strain, E. coli O157:H7 'Sakai,' to colonize the roots and leaves of four leafy vegetables: spinach (Spinacia oleracea), lettuce (Lactuca sativa), vining green pea (Pisum sativum), and prickly lettuce (Lactuca serriola), a wild relative of domesticated lettuce. Also, to determine the drivers of the initial response on interaction with plant tissue, the whole transcriptome of E. coli O157:H7 Sakai was analyzed following exposure to plant extracts of varying complexity (spinach leaf lysates or root exudates, and leaf cell wall polysaccharides from spinach or lettuce). Plant extracts were used to reduce heterogeneity inherent in plant-microbe interactions and remove the effect of plant immunity. This dual approach provided information on the initial adaptive response of E. coli O157:H7 Sakai to the plant environment together with the influence of the living plant during bacterial establishment and colonization. Results showed that both the plant tissue type and the plant species strongly influence the short-term (1 h) transcriptional response to extracts as well as longer-term (10 days) plant colonization or persistence. We show that propagation temperature (37 vs. 18 degrees C) has a major impact on the expression profile and therefore pre-adaptation of bacteria to a plant-relevant temperature is necessary to avoid misleading temperature-dependent wholescale gene-expression changes in response to plant material. For each of the plant extracts tested, the largest group of (annotated) differentially regulated genes were associated with metabolism. However, large-scale differences in the metabolic and biosynthetic pathways between treatment types indicate specificity in substrate utilization. Induction of stress-response genes reflected the apparent physiological status of the bacterial genes in each extract, as a result of glutamate-dependent acid resistance, nutrient stress, or translational stalling. A large proportion of differentially regulated genes are uncharacterized (annotated as hypothetical), which could indicate yet to be described functional roles associated with plant interaction for E. coli O157:H7 Sakai. PMID- 27462312 TI - Comparison of Nitrogen Oxide Metabolism among Diverse Ammonia-Oxidizing Bacteria. AB - Ammonia-oxidizing bacteria (AOB) have well characterized genes that encode and express nitrite reductases (NIR) and nitric oxide reductases (NOR). However, the connection between presence or absence of these and other genes for nitrogen transformations with the physiological production of nitric oxide (NO) and nitrous oxide (N2O) has not been tested across AOB isolated from various trophic states, with diverse phylogeny, and with closed genomes. It is therefore unclear if genomic content for nitrogen oxide metabolism is predictive of net N2O production. Instantaneous microrespirometry experiments were utilized to measure NO and N2O emitted by AOB during active oxidation of ammonia (NH3) or hydroxylamine (NH2OH) and through a period of anoxia. This data was used in concert with genomic content and phylogeny to assess whether taxonomic factors were predictive of nitrogen oxide metabolism. Results showed that two oligotrophic AOB strains lacking annotated NOR-encoding genes released large quantities of NO and produced N2O abiologically at the onset of anoxia following NH3-oxidation. Furthermore, high concentrations of N2O were measured during active O2-dependent NH2OH oxidation by the two oligotrophic AOB in contrast to non-oligotrophic strains that only produced N2O at the onset of anoxia. Therefore, complete nitrifier denitrification did not occur in the two oligotrophic strains, but did occur in meso- and eutrophic strains, even in Nitrosomonas communis Nm2 that lacks an annotated NIR-encoding gene. Regardless of mechanism, all AOB strains produced measureable N2O under tested conditions. This work further confirms that AOB require NOR activity to enzymatically reduce NO to N2O in the nitrifier denitrification pathway, and also that abiotic reactions play an important role in N2O formation, in oligotrophic AOB lacking NOR activity. PMID- 27462313 TI - Sublethal Concentrations of Antibiotics Cause Shift to Anaerobic Metabolism in Listeria monocytogenes and Induce Phenotypes Linked to Antibiotic Tolerance. AB - The human pathogenic bacterium Listeria monocytogenes is exposed to antibiotics both during clinical treatment and in its saprophytic lifestyle. As one of the keys to successful treatment is continued antibiotic sensitivity, the purpose of this study was to determine if exposure to sublethal antibiotic concentrations would affect the bacterial physiology and induce antibiotic tolerance. Transcriptomic analyses demonstrated that each of the four antibiotics tested caused an antibiotic-specific gene expression pattern related to mode-of-action of the particular antibiotic. All four antibiotics caused the same changes in expression of several metabolic genes indicating a shift from aerobic to anaerobic metabolism and higher ethanol production. A mutant in the bifunctional acetaldehyde-CoA/alcohol dehydrogenase encoded by lmo1634 did not have altered antibiotic tolerance. However, a mutant in lmo1179 (eutE) encoding an aldehyde oxidoreductase where rerouting caused increased ethanol production was tolerant to three of four antibiotics tested. This shift in metabolism could be a survival strategy in response to antibiotics to avoid generation of ROS production from respiration by oxidation of NADH through ethanol production. The monocin locus encoding a cryptic prophage was induced by co-trimoxazole and repressed by ampicillin and gentamicin, and this correlated with an observed antibiotic dependent biofilm formation. A monocin mutant (DeltalmaDCBA) had increased biofilm formation when exposed to increasing concentration of co-trimoxazole similar to the wild type, but was more tolerant to killing by co-trimoxazole and ampicillin. Thus, sublethal concentrations of antibiotics caused metabolic and physiological changes indicating that the organism is preparing to withstand lethal antibiotic concentrations. PMID- 27462314 TI - Evaluation of the Antioxidant Activity of Aqueous and Methanol Extracts of Pleurotus ostreatus in Different Growth Stages. AB - Total polyphenols and flavonoids contents, as well as ferric reducing antioxidant power (FRAP), metal ions chelating activity, reducing power assay and scavenging activity of DPPH and ABTS radicals in aqueous and methanolic extracts obtained from mycelium, primordium, and fruiting body of Pleurotus ostreatus in both fresh as dry, were evaluated. The total polyphenol content of dried samples was higher in aqueous extracts obtained both in room temperature and boiling. The total polyphenol content of the fresh samples obtained at room temperature and boiling was higher in aqueous extract of mycelium and in the methanolic extract of the fruiting body. In general, flavonoids represented a very small percentage of the total polyphenol content. The antioxidant activity measured by the FRAP method of extracts from fresh samples were higher with respect to the dried samples. The results of the metal ion chelating activity indicate that all extracts tested had acted. The reducing power of all samples was concentration dependent. In general, the extracts of dried samples showed higher reducing power than the extracts of fresh samples and tend to show greater reducing power by aqueous than methanolic extracts. It was observed that the DPPH and ABTS radical scavenging activities were positively correlated to the concentration of the extract. The results suggested that antioxidant activity could be due to polyphenols, but mainly by different molecules or substances present in the extracts. Overall, the fruiting body of P. ostreatus showed the best results and the possibility of continuing to investigate its functional properties of this fungus is opened. This is the first report where the antioxidant activity of P. ostreatus in different growth stage was reported. PMID- 27462315 TI - Is the Antitumor Property of Trypanosoma cruzi Infection Mediated by Its Calreticulin? AB - Eight to 10 million people in 21 endemic countries are infected with Trypanosoma cruzi. However, only 30% of those infected develop symptoms of Chagas' disease, a chronic, neglected tropical disease worldwide. Similar to other pathogens, T. cruzi has evolved to resist the host immune response. Studies, performed 80 years ago in the Soviet Union, proposed that T. cruzi infects tumor cells with similar capacity to that displayed for target tissues such as cardiac, aortic, or digestive. An antagonistic relationship between T. cruzi infection and cancer development was also proposed, but the molecular mechanisms involved have remained largely unknown. Probably, a variety of T. cruzi molecules is involved. This review focuses on how T. cruzi calreticulin (TcCRT), exteriorized from the endoplasmic reticulum, targets the first classical complement component C1 and negatively regulates the classical complement activation cascade, promoting parasite infectivity. We propose that this C1-dependent TcCRT-mediated virulence is critical to explain, at least an important part, of the parasite capacity to inhibit tumor development. We will discuss how TcCRT, by directly interacting with venous and arterial endothelial cells, inhibits angiogenesis and tumor growth. Thus, these TcCRT functions not only illustrate T. cruzi interactions with the host immune defensive strategies, but also illustrate a possible co evolutionary adaptation to privilege a prolonged interaction with its host. PMID- 27462316 TI - Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells. AB - Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), gammadelta T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli derived factors could modulate their activation. PBMC were cultured with S. aureus 161:2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-gamma and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation. PMID- 27462317 TI - Association Study for 26 Candidate Loci in Idiopathic Pulmonary Fibrosis Patients from Four European Populations. AB - Idiopathic pulmonary fibrosis (IPF) affects lung parenchyma with progressing fibrosis. In this study, we aimed to replicate MUC5B rs35705950 variants and determine new plausible candidate variants for IPF among four different European populations. We genotyped 26 IPF candidate loci in 165 IPF patients from four European countries, such as Czech Republic (n = 41), Germany (n = 33), Greece (n = 40), France (n = 51), and performed association study comparing observed variant distribution with that obtained in a genetically similar Czech healthy control population (n = 96) described in our earlier data report. A highly significant association for a promoter variant (rs35705950) of mucin encoding MUC5B gene was observed in all IPF populations, individually and combined [odds ratio (95% confidence interval); p-value as 5.23 (8.94-3.06); 1.80 * 10(-11)]. Another non-coding variant, rs7934606 in MUC2 was significant among German patients [2.85 (5.05-1.60); 4.03 * 10(-4)] and combined European IPF cases [2.18 (3.16-1.50); 3.73 * 10(-5)]. The network analysis for these variants indicated gene-gene and gene-phenotype interactions in IPF and lung biology. With replication of MUC5B rs35705950 previously reported in U.S. populations of European descent and indicating other plausible polymorphic variants relevant for IPF, we provide additional reference information for future extended functional and population studies aimed, ideally with inclusion of clinical parameters, at identification of IPF genetic markers. PMID- 27462318 TI - A De Novo-Assembly Based Data Analysis Pipeline for Plant Obligate Parasite Metatranscriptomic Studies. AB - Current and emerging plant diseases caused by obligate parasitic microbes such as rusts, downy mildews, and powdery mildews threaten worldwide crop production and food safety. These obligate parasites are typically unculturable in the laboratory, posing technical challenges to characterize them at the genetic and genomic level. Here we have developed a data analysis pipeline integrating several bioinformatic software programs. This pipeline facilitates rapid gene discovery and expression analysis of a plant host and its obligate parasite simultaneously by next generation sequencing of mixed host and pathogen RNA (i.e., metatranscriptomics). We applied this pipeline to metatranscriptomic sequencing data of sweet basil (Ocimum basilicum) and its obligate downy mildew parasite Peronospora belbahrii, both lacking a sequenced genome. Even with a single data point, we were able to identify both candidate host defense genes and pathogen virulence genes that are highly expressed during infection. This demonstrates the power of this pipeline for identifying genes important in host pathogen interactions without prior genomic information for either the plant host or the obligate biotrophic pathogen. The simplicity of this pipeline makes it accessible to researchers with limited computational skills and applicable to metatranscriptomic data analysis in a wide range of plant-obligate-parasite systems. PMID- 27462319 TI - Non-targeted Metabolomics in Diverse Sorghum Breeding Lines Indicates Primary and Secondary Metabolite Profiles Are Associated with Plant Biomass Accumulation and Photosynthesis. AB - Metabolomics is an emerging method to improve our understanding of how genetic diversity affects phenotypic variation in plants. Recent studies have demonstrated that genotype has a major influence on biochemical variation in several types of plant tissues, however, the association between metabolic variation and variation in morphological and physiological traits is largely unknown. Sorghum bicolor (L.) is an important food and fuel crop with extensive genetic and phenotypic variation. Sorghum lines have been bred for differing phenotypes beneficial for production of grain (food), stem sugar (food, fuel), and cellulosic biomass (forage, fuel), and these varying phenotypes are the end products of innate metabolic programming which determines how carbon is allocated during plant growth and development. Further, sorghum has been adapted among highly diverse environments. Because of this geographic and phenotypic variation, the sorghum metabolome is expected to be highly divergent; however, metabolite variation in sorghum has not been characterized. Here, we utilize a phenotypically diverse panel of sorghum breeding lines to identify associations between leaf metabolites and morpho-physiological traits. The panel (11 lines) exhibited significant variation for 21 morpho-physiological traits, as well as broader trends in variation by sorghum type (grain vs. biomass types). Variation was also observed for cell wall constituents (glucan, xylan, lignin, ash). Non targeted metabolomics analysis of leaf tissue showed that 956 of 1181 metabolites varied among the lines (81%, ANOVA, FDR adjusted p < 0.05). Both univariate and multivariate analyses determined relationships between metabolites and morpho physiological traits, and 384 metabolites correlated with at least one trait (32%, p < 0.05), including many secondary metabolites such as glycosylated flavonoids and chlorogenic acids. The use of metabolomics to explain relationships between two or more morpho-physiological traits was explored and showed chlorogenic and shikimic acid to be associated with photosynthesis, early plant growth and final biomass measures in sorghum. Taken together, this study demonstrates the integration of metabolomics with morpho-physiological datasets to elucidate links between plant metabolism, growth, and architecture. PMID- 27462320 TI - Plasticity of the Berry Ripening Program in a White Grape Variety. AB - Grapevine (Vitis vinifera L.) is considered one of the most environmentally sensitive crops and is characterized by broad phenotypic plasticity, offering important advantages such as the large range of different wines that can be produced from the same cultivar, and the adaptation of existing cultivars to diverse growing regions. The uniqueness of berry quality traits reflects complex interactions between the grapevine plant and the combination of natural factors and human cultural practices which leads to the expression of wine typicity. Despite the scientific and commercial importance of genotype interactions with growing conditions, few studies have characterized the genes and metabolites directly involved in this phenomenon. Here, we used two large-scale analytical approaches to explore the metabolomic and transcriptomic basis of the broad phenotypic plasticity of Garganega, a white berry variety grown at four sites characterized by different pedoclimatic conditions (altitudes, soil texture, and composition). These conditions determine berry ripening dynamics in terms of sugar accumulation and the abundance of phenolic compounds. Multivariate analysis unraveled a highly plastic metabolomic response to different environments, especially the accumulation of hydroxycinnamic and hydroxybenzoic acids and flavonols. Principal component analysis (PCA) revealed that the four sites strongly affected the berry transcriptome allowing the identification of environmentally-modulated genes and the plasticity of commonly-modulated transcripts at different sites. Many genes that control transcription, translation, transport, and carbohydrate metabolism showed different expression depending on the environmental conditions, indicating a key role in the observed transcriptomic plasticity of Garganega berries. Interestingly, genes representing the phenylpropanoid/flavonoid pathway showed plastic responses to the environment mirroring the accumulation of the corresponding metabolites. The comparison of Garganega and Corvina berries showed that the metabolism of phenolic compounds is more plastic in ripening Garganega berries under different pedoclimatic conditions. PMID- 27462321 TI - Genotypic Variation in a Breeding Population of Yellow Sweet Clover (Melilotus officinalis). AB - Yellow sweet clover is a widely spread legume species that has potential to be used as a forage crop in Western China. However, limited information is available on the genetic variation for herbage yield, key morphological traits, and coumarin content. In this study, 40 half sib (HS) families of M. officinalis were evaluated for genotypic variation and phenotypic and genotypic correlation for the traits: LS (leaf to stem ratio), SV (spring vigor), LA (leaf area), PH (plant height), DW (herbage dry weight), SD (stem diameter), SN (stem number), Cou (coumarin content), SY (seed yield), across two locations, Yuzhong and Linze, in Western China. There was significant (P < 0.05) genotypic variation among the HS families for all traits. There was also significant (P < 0.05) genotype-by environment interaction for the traits DW, PH, SD, SN, and SV. The estimates of HS family mean repeatability across two locations ranged from 0.32 for SN to 0.89 for LA. Pattern analysis generated four HS family groups where group 3 consisted of families with above average expression for DW and below average expression for Cou. The breeding population developed by polycrossing the selected HS families within group 3 will provide a significant breeding pool for M. officinalis cultivar development in China. PMID- 27462322 TI - Stem Rust Resistance in a Geographically Diverse Collection of Spring Wheat Lines Collected from Across Africa. AB - Following the emergence of the Ug99 lineage of Puccinia graminis f. sp. tritici (Pgt) a collective international effort has been undertaken to identify new sources of wheat stem rust resistance effective against these races. Analyses were undertaken in a collection of wheat genotypes gathered from across Africa to identify stem rust resistance effective against the Pgt races found in Eastern and Southern Africa. The African wheat collection consisted of historic genotypes collected in Kenya, South Africa, Ethiopia, Sudan, Zambia, Morocco, and Tunisia, and current South African breeding lines. Both Bayesian cluster and principal coordinate analyses placed the wheat lines from Sudan in a distinct group, but indicated a degree of genetic relatedness among the other wheat lines despite originating from countries across Africa. Seedling screens with Pgt race PTKST, pedigree information and marker haplotype analysis confirmed the presence of Sr2, Sr36, Sr24, Sr31, and Lr34/Yr18/Sr57 in a number of the lines. A genome-wide association study (GWAS) undertaken with Diversiry Arrays Technology (DArT) and stem rust (Sr) gene associated markers and Stem Area Infected (SAI) and Reaction Type (RT) field phenotypes, collected from trials carried out across two seasons in Kenya in 2009 and in South Africa in 2011, identified 29 marker-trait associations (MTA). Three MTA were in common between SAI and RT, with the biggest effect MTA being found on chromosome 6AS. Two wheat lines, W1406 and W6979 that exhibited high levels of adult plant stem rust resistance were selected to generate bi-parental mapping populations. Only the MTA on chromosomes 6AS and 3BS, and the locus Lr34/Yr18/Sr57 were confirmed following QTL mapping. Additional stem rust resistance QTL, not detected by the GWAS, were found on chromosomes 2BS, 2DL, 3DL, and 4D. PMID- 27462323 TI - Identification and Characterization of Switchgrass Histone H3 and CENH3 Genes. AB - Switchgrass is one of the most promising energy crops and only recently has been employed for biofuel production. The draft genome of switchgrass was recently released; however, relatively few switchgrass genes have been functionally characterized. CENH3, the major histone protein found in centromeres, along with canonical H3 and other histones, plays an important role in maintaining genome stability and integrity. Despite their importance, the histone H3 genes of switchgrass have remained largely uninvestigated. In this study, we identified 17 putative switchgrass histone H3 genes in silico. Of these genes, 15 showed strong homology to histone H3 genes including six H3.1 genes, three H3.3 genes, four H3.3-like genes and two H3.1-like genes. The remaining two genes were found to be homologous to CENH3. RNA-seq data derived from lowland cultivar Alamo and upland cultivar Dacotah allowed us to identify SNPs in the histone H3 genes and compare their differential gene expression. Interestingly, we also found that overexpression of switchgrass histone H3 and CENH3 genes in N. benthamiana could trigger cell death of the transformed plant cells. Localization and deletion analyses of the histone H3 and CENH3 genes revealed that nuclear localization of the N-terminal tail is essential and sufficient for triggering the cell death phenotype. Our results deliver insight into the mechanisms underlying the histone triggered cell death phenotype and provide a foundation for further studying the variations of the histone H3 and CENH3 genes in switchgrass. PMID- 27462324 TI - A Clade-Specific Arabidopsis Gene Connects Primary Metabolism and Senescence. AB - Nearly immobile, plants have evolved new components to be able to respond to changing environments. One example is Qua Quine Starch (QQS, AT3G30720), an Arabidopsis thaliana-specific orphan gene that integrates primary metabolism with adaptation to environment changes. SAQR (Senescence-Associated and QQS-Related, AT1G64360), is unique to a clade within the family Brassicaceae; as such, the gene may have arisen about 20 million years ago. SAQR is up-regulated in QQS RNAi mutant and in the apx1 mutant under light-induced oxidative stress. SAQR plays a role in carbon allocation: overexpression lines of SAQR have significantly decreased starch content; conversely, in a saqr T-DNA knockout (KO) line, starch accumulation is increased. Meta-analysis of public microarray data indicates that SAQR expression is correlated with expression of a subset of genes involved in senescence, defense, and stress responses. SAQR promoter::GUS expression analysis reveals that SAQR expression increases after leaf expansion and photosynthetic capacity have peaked, just prior to visible natural senescence. SAQR is expressed predominantly within leaf and cotyledon vasculature, increasing in intensity as natural senescence continues, and then decreasing prior to death. In contrast, under experimentally induced senescence, SAQR expression increases in vasculature of cotyledons but not in true leaves. In SAQR KO line, the transcript level of the dirigent-like disease resistance gene (AT1G22900) is increased, while that of the Early Light Induced Protein 1 gene (ELIP1, AT3G22840) is decreased. Taken together, these data indicate that SAQR may function in the QQS network, playing a role in integration of primary metabolism with adaptation to internal and environmental changes, specifically those that affect the process of senescence. PMID- 27462325 TI - Identification of Putative RuBisCo Activase (TaRca1)-The Catalytic Chaperone Regulating Carbon Assimilatory Pathway in Wheat (Triticum aestivum) under the Heat Stress. AB - RuBisCo activase (Rca) is a catalytic chaperone involved in modulating the activity of RuBisCo (key enzyme of photosynthetic pathway). Here, we identified eight novel transcripts from wheat through data mining predicted to be Rca and cloned a transcript of 1.4 kb from cv. HD2985, named as TaRca1 (GenBank acc. no. KC776912). Single copy number of TaRca1 was observed in wheat genome. Expression analysis in diverse wheat genotypes (HD2985, Halna, PBW621, and HD2329) showed very high relative expression of TaRca1 in Halna under control and HS-treated, as compared to other cultivars at different stages of growth. TaRca1 protein was predicted to be chloroplast-localized with numerous potential phosphorylation sites. Northern blot analysis showed maximum accumulation of TaRca1 transcript in thermotolerant cv. during mealy-ripe stage, as compared to thermosusceptible. Decrease in the photosynthetic parameters was observed in all the cultivars, except PBW621 in response to HS. We observed significant increase in the Rca activity in all the cultivars under HS at different stages of growth. HS causes decrease in the RuBisCo activity; maximum reduction was observed during pollination stage in thermosusceptible cvs. as validated through immunoblotting. We observed uniform carbon distribution in different tissues of thermotolerant cvs., as compared to thermosusceptible. Similarly, tolerance level of leaf was observed maximum in Halna having high Rca activity under HS. A positive correlation was observed between the transcript and activity of TaRca1 in HS treated Halna. Similarly, TaRca1 enzyme showed positive correlation with the activity of RuBisCo. There is, however, need to manipulate the thermal stability of TaRca1 enzyme through protein engineering for sustaining the photosynthetic rate under HS-a novel approach toward development of "climate-smart" crop. PMID- 27462326 TI - Response of Soil Properties and Microbial Communities to Agriculture: Implications for Primary Productivity and Soil Health Indicators. AB - Agricultural intensification is placing tremendous pressure on the soil's capacity to maintain its functions leading to large-scale ecosystem degradation and loss of productivity in the long term. Therefore, there is an urgent need to find early indicators of soil health degradation in response to agricultural management. In recent years, major advances in soil meta-genomic and spatial studies on microbial communities and community-level molecular characteristics can now be exploited as 'biomarker' indicators of ecosystem processes for monitoring and managing sustainable soil health under global change. However, a continental scale, cross biome approach assessing soil microbial communities and their functional potential to identify the unifying principles governing the susceptibility of soil biodiversity to land conversion is lacking. We conducted a meta-analysis from a dataset generated from 102 peer-reviewed publications as well as unpublished data to explore how properties directly linked to soil nutritional health (total C and N; C:N ratio), primary productivity (NPP) and microbial diversity and composition (relative abundance of major bacterial phyla determined by next generation sequencing techniques) are affected in response to agricultural management across the main biomes of Earth (arid, continental, temperate and tropical). In our analysis, we found strong statistical trends in the relative abundance of several bacterial phyla in agricultural (e.g., Actinobacteria and Chloroflexi) and natural (Acidobacteria, Proteobacteria, and Cyanobacteria) systems across all regions and these trends correlated well with many soil properties. However, main effects of agriculture on soil properties and productivity were biome-dependent. Our meta-analysis provides evidence on the predictable nature of the microbial community responses to vegetation type. This knowledge can be exploited in future for developing a new set of indicators for primary productivity and soil health. PMID- 27462327 TI - Transcription of TIR1-Controlled Genes Can be Regulated within 10 Min by an Auxin Induced Process. Can TIR1 be the Receptor? AB - ABP1 and TIR1/AFBs are known as auxin receptors. ABP1 is linked to auxin responses several of which are faster than 10 min. TIR1 regulates auxin-induced transcription of early auxin genes also within minutes. We use transcription of such TIR1-dependent genes as indicator of TIR1 activity to show the rapid regulation of TIR1 by exogenous auxin. To this end, we used quantification of transcription of a set of fifteen early auxin-induced reporter genes at t = 10 and t = 30 min to measure this as a TIR1-dependent auxin response. We conducted this study in 22 mutants of auxin transporters (pin5, abcb1, abcb19, and aux1/lax3), protein kinases and phosphatases (ibr5, npr1, cpk3, CPK3-OX, d6pk1, d6pkl1-1, d6pkl3-2, d6pkl1-1/d6pkl2-2, and d6pkl1-1/d6pkl3-2), of fatty acid metabolism (fad2-1, fad6-1, ssi2, lacs4, lacs9, and lacs4/lacs9) and receptors (tir1, tir1/afb2, and tir1/afb3) and compared them to the wild type. After 10 min auxin application, in 18 out of 22 mutants mis-regulated expression of at least one reporter was found, and in 15 mutants transcription of two-to-three out of five selected auxin reporter genes was mis-regulated. After 30 min of auxin application to mutant plants, mis-regulation of reporter genes ranged from one to 13 out of 15 tested reporter genes. Those genes chosen as mutants were themselves not regulated in their expression by auxin for at least 1 h, excluding an influence of TIR1/AFBs on their transcription. The expression of TIR1/AFB genes was also not modulated by auxin for up to 3 h. Together, this excludes a feedback or feedforward of these mutant genes/proteins on TIR1/AFBs output of transcription in this auxin-induced response. However, an auxin-induced response needed an as yet unknown auxin receptor. We suggest that the auxin receptor necessary for the fast auxin-induced transcription modulation could be, instead, ABP1. The alternative hypothesis would be that auxin-induced expression of a protein, initiated by TIR1/AFBs receptors, could initiate these responses and that this unknown protein regulated TIR1/AFB activities within 10 min. PMID- 27462328 TI - The Rosa chinensis cv. Viridiflora Phyllody Phenotype Is Associated with Misexpression of Flower Organ Identity Genes. AB - Phyllody is a flower abnormality in which leaf-like structures replace flower organs in all whorls. Here, we investigated the origin and the molecular mechanism of phyllody phenotype in Rosa chinensis cv. Viridiflora, an ancient naturally occurring Chinese mutant cultivar. Reciprocal grafting experiments and microscopy analyses, demonstrated that the phyllody phenotype in Viridiflora is not associated with phytoplasmas infection. Transcriptome comparisons by the mean of RNA-Seq identified 672 up-regulated and 666 down-regulated genes in Viridiflora compared to its closely related genotype R. chinensis cv. Old Blush. A fraction of these genes are putative homologs of genes known to be involved in flower initiation and development. We show that in flower whorl 2 of Viridiflora, a down-regulation of the floral organ identity genes RcPISTILLATA (RcPI), RcAPETALA3 (RcAP3) and RcSEPALLATA3 (RcSEP3), together with an up-regulation of the putative homolog of the gene SUPPRESSOR of OVEREXPRESSION of CONSTANS1 (RcSOC1) are likely at the origin of the loss of petal identity and leaf-like structures formation. In whorl 3 of Viridiflora, ectopic expression of RcAPETALA2 (RcAP2) along with the down regulation of RcPI, RcAP3, and RcSEP3 is associated with loss of stamens identity and leaf-like structures formation. In whorl 4, the ectopic expression of RcAP2 associated with a down-regulation of RcSEP3 and of the C-class gene RcAGAMOUS correlate with loss of pistil identity. The latter also suggested the antagonist effect between the A and C class genes in the rose. Together, these data suggest that modified expression of the ABCE flower organ identity genes is associated with the phyllody phenotype in the rose Viridiflora and that these genes are important for normal flower organs development. PMID- 27462329 TI - Mini Review: Potential Applications of Non-host Resistance for Crop Improvement. AB - Plant breeding for disease resistance is crucial to sustain global crop production. For decades, plant breeders and researchers have extensively used host plant resistance genes (R-genes) to develop disease resistant cultivars. However, the general instability of R-genes in crop cultivars when challenged with diverse pathogen populations emphasizes the need for more stable means of resistance. Alternatively, non-host resistance is recognized as the most durable, broad-spectrum form of resistance against the majority of potential pathogens in plants and has gained great attention as an alternative target for managing resistance. While transgenic approaches have been utilized to transfer non-host resistance to host species, conventional breeding applications have been more elusive. Nevertheless, avenues for discovery and deployment of genetic loci for non-host resistance via hybridization are increasingly abundant, particularly when transferring genes among closely related species. In this mini review, we discuss current and developing applications of non-host resistance for crop improvement with a focus on the overlap between host and non-host mechanisms and the potential impacts of new technology. PMID- 27462330 TI - Micrasterias as a Model System in Plant Cell Biology. AB - The unicellular freshwater alga Micrasterias denticulata is an exceptional organism due to its complex star-shaped, highly symmetric morphology and has thus attracted the interest of researchers for many decades. As a member of the Streptophyta, Micrasterias is not only genetically closely related to higher land plants but shares common features with them in many physiological and cell biological aspects. These facts, together with its considerable cell size of about 200 MUm, its modest cultivation conditions and the uncomplicated accessibility particularly to any microscopic techniques, make Micrasterias a very well suited cell biological plant model system. The review focuses particularly on cell wall formation and composition, dictyosomal structure and function, cytoskeleton control of growth and morphogenesis as well as on ionic regulation and signal transduction. It has been also shown in the recent years that Micrasterias is a highly sensitive indicator for environmental stress impact such as heavy metals, high salinity, oxidative stress or starvation. Stress induced organelle degradation, autophagy, adaption and detoxification mechanisms have moved in the center of interest and have been investigated with modern microscopic techniques such as 3-D- and analytical electron microscopy as well as with biochemical, physiological and molecular approaches. This review is intended to summarize and discuss the most important results obtained in Micrasterias in the last 20 years and to compare the results to similar processes in higher plant cells. PMID- 27462331 TI - QTL Mapping by SLAF-seq and Expression Analysis of Candidate Genes for Aphid Resistance in Cucumber. AB - Cucumber, a very important vegetable crop worldwide, is easily damaged by pests. Aphid is one of the most serious cucumber pests and frequently cause severe damage to commercially produced crops. Understanding the genetic mechanisms underlying pest resistance is important for aphid-resistant cucumber varieties breeding. In this study, two parental cucumber lines, JY30 (aphid susceptible) and EP6392 (aphid resistant), and pools of resistant and susceptible (n = 50 each) plants from 1000 F2 individuals derived from crossing JY30 with EP6392, were used to detect genomic regions associated with aphid resistance in cucumbers. The analysis was performed using specific length amplified fragment sequencing (SLAF-seq), bulked segregant analysis (BSA), and single nucleotide polymorphism index (SNP-index) methods. A main effect QTL (quantitative trait locus) of 0.31 Mb on Chr5, including 43 genes, was identified by association analysis. Sixteen of the 43 genes were identified as potentially associated with aphid resistance through gene annotation analysis. The effect of aphid infestation on the expression of these candidate genes screened by SLAF-seq was investigated in EP6392 plants by qRT-PCR. The results indicated that seven genes including encoding transcription factor MYB59-like (Csa5M641610.1), auxin transport protein BIG-like (Csa5M642140.1), F-box/kelch-repeat protein At5g15710 like (Csa5M642160.1), transcription factor HBP-1a-like (Csa5M642710.1), beta glucan-binding protein (Csa5M643380.1), endo-1,3(4)-beta-glucanase 1-like (Csa5M643880.1), and proline-rich receptor-like protein kinase PERK10-like (Csa5M643900.1), out of the 16 genes were down regulated after aphid infestation, whereas 5 genes including encoding probable leucine-rich repeat (LRR) receptor like serine/threonine-protein kinase At5g15730-like (Csa5M642150.1), Stress induced protein KIN2 (Csa5M643240.1 and Csa5M643260.1), F-box family protein (Csa5M643280.1), F-box/kelch-repeat protein (Csa5M643290.1), were up-regulated after aphid infestation. The gene Csa5M642150.1, encoding probable LRR receptor like serine/threonine-protein kinase At5g15730-like, was most likely a key candidate gene in cucumber plants in response to infestation. This study provides a certain theoretical basis of molecular biology for genetic improvement of cucumber aphid resistance and aphid resistant variety breeding. PMID- 27462332 TI - The Role of DNA Methylation in Xylogenesis in Different Tissues of Poplar. AB - In trees, xylem tissues play a key role in the formation of woody tissues, which have important uses for pulp and timber production; also DNA methylation plays an important part in gene regulation during xylogenesis in trees. In our study, methylation-sensitive amplified polymorphism (MSAP) analysis was used to analyze the role cytosine methylation plays in wood formation in the commercially important tree species Populus tomentosa. This analysis compared the methylation patterns between xylem tissues (developing xylem and mature xylem) and non-xylem tissues (cambium, shoot apex, young leaf, mature leaf, phloem, root, male catkin, and female catkin) and found 10,316 polymorphic methylation sites. MSAP identified 132 candidate genes with the same methylation patterns in xylem tissues, including seven wood-related genes. The expression of these genes differed significantly between xylem and non-xylem tissue types (P < 0.01). This indicated that the difference of expression of specific genes with unique methylation patterns, rather than relative methylation levels between the two tissue types plays a critical role in wood biosynthesis. However, 46.2% of candidate genes with the same methylation pattern in vascular tissues (cambium, phloem, and developing xylem) did not have distinct expression patterns in xylem and non-xylem tissue. Also, bisulfite sequencing and transcriptome sequencing of MYB, NAC and FASCICLIN-LIKE AGP 13 revealed that the location of cytosine methylation in the gene might affect the expression of different transcripts from the corresponding gene. The expression of different transcripts that produce distinct proteins from a single gene might play an important role in the regulation of xylogenesis. PMID- 27462334 TI - G1/ELE Functions in the Development of Rice Lemmas in Addition to Determining Identities of Empty Glumes. AB - Rice empty glumes, also named sterile lemmas or rudimentary lemmas according to different interpretations, are distinct from lemmas in morphology and cellular pattern. Consistently, the molecular mechanism to control the development of lemmas is different from that of empty glumes. Rice LEAFY HULL STERILE1(OsLHS1) and DROOPING LEAF(DL) regulate the cellular pattern and the number of vascular bundles of lemmas respectively, while LONG STERILE LEMMA1 (G1)/ELONGATED EMPTY GLUME (ELE) and PANICLE PHYTOMER2 (PAP2)/OsMADS34 determine identities of empty glumes. Though some progress has been made, identities of empty glumes remain unclear, and genetic interactions between lemma genes and glume genes have been rarely elucidated. In this research, a new G1/ELE mutant g1-6 was identified and the phenotype was analyzed. Similar to previously reported mutant lines of G1/ELE, empty glumes of g1-6 plants transform into lemma-like organs. Furthermore, Phenotypes of single and double mutant plants suggest that, in addition to their previously described gene-specific functions, G1/ELE and OsLHS1 play redundant roles in controlling vascular bundle number, cell volume, and cell layer number of empty glumes and lemmas. Meanwhile, expression patterns of G1/ELE in osmads1-z flowers and OsLHS1 in g1-6 flowers indicate they do not regulate each other at the level of transcription. Finally, down-regulation of the empty glume gene OsMADS34/PAP2 and ectopic expression of the lemma gene DL, in the g1-6 plants provide further evidence that empty glumes are sterile lemmas. Generally, our findings provided valuable information for better understanding functions of G1 and OsLHS1 in flower development and identities of empty glumes. PMID- 27462333 TI - Neuroprotective Activity of Hypericum perforatum and Its Major Components. AB - Hypericum perforatum is a perennial plant, with worldwide distribution, commonly known as St. John's wort. It has been used for centuries in traditional medicine for the treatment of several disorders, such as minor burns, anxiety, and mild to moderate depression. In the past years, its antidepressant properties have been extensively studied. Despite that, other H. perforatum biological activities, as its neuroprotective properties have also been evaluated. The present review aims to provide a comprehensive summary of the main biologically active compounds of H. perforatum, as for its chemistry, pharmacological activities, drug interactions and adverse reactions and gather scattered information about its neuroprotective abilities. As for this, it has been demonstrated that H. perforatum extracts and several of its major molecular components have the ability to protect against toxic insults, either directly, through neuroprotective mechanisms, or indirectly, through is antioxidant properties. H. perforatum has therefore the potential to become an effective neuroprotective therapeutic agent, despite further studies that need to be carried out. PMID- 27462336 TI - Identification of Genomic Insertion and Flanking Sequence of G2-EPSPS and GAT Transgenes in Soybean Using Whole Genome Sequencing Method. AB - Molecular characterization of sequence flanking exogenous fragment insertion is essential for safety assessment and labeling of genetically modified organism (GMO). In this study, the T-DNA insertion sites and flanking sequences were identified in two newly developed transgenic glyphosate-tolerant soybeans GE-J16 and ZH10-6 based on whole genome sequencing (WGS) method. More than 22.4 Gb sequence data (~21 * coverage) for each line was generated on Illumina HiSeq 2500 platform. The junction reads mapped to boundaries of T-DNA and flanking sequences in these two events were identified by comparing all sequencing reads with soybean reference genome and sequence of transgenic vector. The putative insertion loci and flanking sequences were further confirmed by PCR amplification, Sanger sequencing, and co-segregation analysis. All these analyses supported that exogenous T-DNA fragments were integrated in positions of Chr19: 50543767-50543792 and Chr17: 7980527-7980541 in these two transgenic lines. Identification of genomic insertion sites of G2-EPSPS and GAT transgenes will facilitate the utilization of their glyphosate-tolerant traits in soybean breeding program. These results also demonstrated that WGS was a cost-effective and rapid method for identifying sites of T-DNA insertions and flanking sequences in soybean. PMID- 27462335 TI - Circadian Profiling of the Arabidopsis Proteome Using 2D-DIGE. AB - Clock-generated biological rhythms provide an adaptive advantage to an organism, resulting in increased fitness and survival. To better elucidate the plant response to the circadian system, we surveyed protein oscillations in Arabidopsis seedlings under constant light. Using large-scale two-dimensional difference in gel electrophoresis (2D-DIGE) the abundance of more than 1000 proteins spots was reproducibly resolved quantified and profiled across a circadian time series. A comparison between phenol-extracted samples and RuBisCO-depleted extracts identified 71 and 40 rhythmically-expressed proteins, respectively, and between 30 and 40% of these derive from non-rhythmic transcripts. These included proteins influencing transcriptional regulation, translation, metabolism, photosynthesis, protein chaperones, and stress-mediated responses. The phasing of maximum expression for the cyclic proteins was similar for both datasets, with a nearly even distribution of peak phases across the time series. STRING clustering analysis identified two interaction networks with a notable number of oscillating proteins: plastid-based and cytosolic chaperones and 10 proteins involved in photosynthesis. The oscillation of the ABA receptor, PYR1/RCAR11, with peak expression near dusk adds to a growing body of evidence that intimately ties ABA signaling to the circadian system. Taken together, this study provides new insights into the importance of post-transcriptional circadian control of plant physiology and metabolism. PMID- 27462337 TI - Genome Wide Association Mapping in Arabidopsis thaliana Identifies Novel Genes Involved in Linking Allyl Glucosinolate to Altered Biomass and Defense. AB - A key limitation in modern biology is the ability to rapidly identify genes underlying newly identified complex phenotypes. Genome wide association studies (GWAS) have become an increasingly important approach for dissecting natural variation by associating phenotypes with genotypes at a genome wide level. Recent work is showing that the Arabidopsis thaliana defense metabolite, allyl glucosinolate (GSL), may provide direct feedback regulation, linking defense metabolism outputs to the growth, and defense responses of the plant. However, there is still a need to identify genes that underlie this process. To start developing a deeper understanding of the mechanism(s) that modulate the ability of exogenous allyl GSL to alter growth and defense, we measured changes in plant biomass and defense metabolites in a collection of natural 96 A. thaliana accessions fed with 50 MUM of allyl GSL. Exogenous allyl GSL was introduced exclusively to the roots and the compound transported to the leaf leading to a wide range of heritable effects upon plant biomass and endogenous GSL accumulation. Using natural variation we conducted GWAS to identify a number of new genes which potentially control allyl responses in various plant processes. This is one of the first instances in which this approach has been successfully utilized to begin dissecting a novel phenotype to the underlying molecular/polygenic basis. PMID- 27462338 TI - Shotgun Label-free Proteomic Analysis of Clubroot (Plasmodiophora brassicae) Resistance Conferred by the Gene Rcr1 in Brassica rapa. AB - Clubroot, caused by the plasmodiophorid pathogen Plasmodiophora brassicae, is one of the most serious diseases on Brassica crops worldwide and a major threat to canola production in western Canada. Host resistance is the key strategy for clubroot management on canola. Several clubroot resistance (CR) genes have been identified, but the mechanisms associated with these CR genes are poorly understood. In the current study, a label-free shotgun proteomic approach was used to profile and compare the proteomes of Brassica rapa carrying and not carrying the CR gene Rcr1 in response to P. brassicae infection. A total of 527 differentially accumulated proteins (DAPs) were identified between the resistant (with Rcr1) and susceptible (without Rcr1) samples, and functional annotation of these DAPs indicates that the perception of P. brassicae and activation of defense responses are triggered via an unique signaling pathway distinct from common modes of recognition receptors reported with many other plant-pathogen interactions; this pathway appears to act in a calcium-independent manner through a not-well-defined cascade of mitogen-activated protein kinases and may require the ubiquitin-26S proteasome found to be related to abiotic stresses, especially the cold-stress tolerance in other studies. Both up-regulation of defense-related and down-regulation of pathogenicity-related metabolism was observed in plants carrying Rcr1, and these functions may all contribute to the CR mediated by Rcr1. These results, combined with those of transcriptomic analysis reported earlier, improved our understanding of molecular mechanisms associated with Rcr1 and CR at large, and identified candidate metabolites or pathways related to specific resistance mechanisms. Deploying CR genes with different modes of action may help improve the durability of CR. PMID- 27462340 TI - Long Term Sugarcane Crop Residue Retention Offers Limited Potential to Reduce Nitrogen Fertilizer Rates in Australian Wet Tropical Environments. AB - The warming of world climate systems is driving interest in the mitigation of greenhouse gas (GHG) emissions. In the agricultural sector, practices that mitigate GHG emissions include those that (1) reduce emissions [e.g., those that reduce nitrous oxide (N2O) emissions by avoiding excess nitrogen (N) fertilizer application], and (2) increase soil organic carbon (SOC) stocks (e.g., by retaining instead of burning crop residues). Sugarcane is a globally important crop that can have substantial inputs of N fertilizer and which produces large amounts of crop residues ('trash'). Management of N fertilizer and trash affects soil carbon and nitrogen cycling, and hence GHG emissions. Trash has historically been burned at harvest, but increasingly is being retained on the soil surface as a 'trash blanket' in many countries. The potential for trash retention to alter N fertilizer requirements and sequester SOC was investigated in this study. The APSIM model was calibrated with data from field and laboratory studies of trash decomposition in the wet tropics of northern Australia. APSIM was then validated against four independent data sets, before simulating location * soil * fertilizer * trash management scenarios. Soil carbon increased in trash blanketed soils relative to SOC in soils with burnt trash. However, further increases in SOC for the study region may be limited because the SOC in trash blanketed soils could be approaching equilibrium; future GHG mitigation efforts in this region should therefore focus on N fertilizer management. Simulated N fertilizer rates were able to be reduced from conventional rates regardless of trash management, because of low yield potential in the wet tropics. For crops subjected to continuous trash blanketing, there was substantial immobilization of N in decomposing trash so conventional N fertilizer rates were required for up to 24 years after trash blanketing commenced. After this period, there was potential to reduce N fertilizer rates for crops when trash was retained (<=20 kg N ha(-1) per plant or ratoon crop) while maintaining >=95% of maximum yields. While these savings in N fertilizer use were modest at the field scale, they were potentially important when aggregated at the regional level. PMID- 27462339 TI - Drought Stress Responses in Soybean Roots and Nodules. AB - Drought is considered to be a major threat to soybean production worldwide and yet our current understanding of the effects of drought on soybean productively is largely based on studies on above-ground traits. Although the roots and root nodules are important sensors of drought, the responses of these crucial organs and their drought tolerance features remain poorly characterized. The symbiotic interaction between soybean and rhizobia facilitates atmospheric nitrogen fixation, a process that provides essential nitrogen to support plant growth and development. Symbiotic nitrogen fixation is important for sustainable agriculture, as it sustains plant growth on nitrogen-poor soils and limits fertilizer use for crop nitrogen nutrition. Recent developments have been made in our understanding of the drought impact on soybean root architecture and nodule traits, as well as underpinning transcriptome, proteome and also emerging metabolome information, with a view to improve the selection of more drought tolerant soybean cultivars and rhizobia in the future. We conclude that the direct screening of root and nodule traits in the field as well as identification of genes, proteins and also metabolites involved in such traits will be essential in order to gain a better understanding of the regulation of root architecture, bacteroid development and lifespan in relation to drought tolerance in soybean. PMID- 27462342 TI - The Banana Transcriptional Repressor MaDEAR1 Negatively Regulates Cell Wall Modifying Genes Involved in Fruit Ripening. AB - Ethylene plays an essential role in many biological processes including fruit ripening via modulation of ethylene signaling pathway. Ethylene Response Factors (ERFs) are key transcription factors (TFs) involved in ethylene perception and are divided into AP2, RAV, ERF, and DREB sub-families. Although a number of studies have implicated the involvement of DREB sub-family genes in stress responses, little is known about their roles in fruit ripening. In this study, we identified a DREB TF with a EAR motif, designated as MaDEAR1, which is a nucleus localized transcriptional repressor. Expression analysis indicated that MaDEAR1 expression was repressed by ethylene, with reduced levels of histone H3 and H4 acetylation at its regulatory regions during fruit ripening. In addition, MaDEAR1 promoter activity was also suppressed in response to ethylene treatment. More importantly, MaDEAR1 directly binds to the DRE/CRT motifs in promoters of several cell wall-modifying genes including MaEXP1/3, MaPG1, MaXTH10, MaPL3, and MaPME3 associated with fruit softening during ripening and represses their activities. These data suggest that MaDEAR1 acts as a transcriptional repressor of cell wall modifying genes, and may be negatively involved in ethylene-mediated ripening of banana fruit. Our findings provide new insights into the involvement of DREB TFs in the regulation of fruit ripening. PMID- 27462341 TI - Multi-Substrate Terpene Synthases: Their Occurrence and Physiological Significance. AB - Terpene synthases are responsible for synthesis of a large number of terpenes in plants using substrates provided by two distinct metabolic pathways, the mevalonate-dependent pathway that is located in cytosol and has been suggested to be responsible for synthesis of sesquiterpenes (C15), and 2-C-methyl-D-erythritol 4-phosphate pathway located in plastids and suggested to be responsible for the synthesis of hemi- (C5), mono- (C10), and diterpenes (C20). Recent advances in characterization of genes and enzymes responsible for substrate and end product biosynthesis as well as efforts in metabolic engineering have demonstrated existence of a number of multi-substrate terpene synthases. This review summarizes the progress in the characterization of such multi-substrate terpene synthases and suggests that the presence of multi-substrate use might have been significantly underestimated. Multi-substrate use could lead to important changes in terpene product profiles upon substrate profile changes under perturbation of metabolism in stressed plants as well as under certain developmental stages. We therefore argue that multi-substrate use can be significant under physiological conditions and can result in complicate modifications in terpene profiles. PMID- 27462343 TI - Correlation-Based Network Analysis of Metabolite and Enzyme Profiles Reveals a Role of Citrate Biosynthesis in Modulating N and C Metabolism in Zea mays. AB - To investigate the natural variability of leaf metabolism and enzymatic activity in a maize inbred population, statistical and network analyses were employed on metabolite and enzyme profiles. The test of coefficient of variation showed that sugars and amino acids displayed opposite trends in their variance within the population, consistently with their related enzymes. The overall higher CV values for metabolites as compared to the tested enzymes are indicative for their greater phenotypic plasticity. H(2) tests revealed galactinol (1) and asparagine (0.91) as the highest scorers among metabolites and nitrate reductase (0.73), NAD glutamate dehydrogenase (0.52), and phosphoglucomutase (0.51) among enzymes. The overall low H(2) scores for metabolites and enzymes are suggestive for a great environmental impact or gene-environment interaction. Correlation-based network generation followed by community detection analysis, partitioned the network into three main communities and one dyad, (i) reflecting the different levels of phenotypic plasticity of the two molecular classes as observed for the CV values and (ii) highlighting the concerted changes between classes of chemically related metabolites. Community 1 is composed mainly of enzymes and specialized metabolites, community 2' is enriched in N-containing compounds and phosphorylated-intermediates. The third community contains mainly organic acids and sugars. Cross-community linkages are supported by aspartate, by the photorespiration amino acids glycine and serine, by the metabolically related GABA and putrescine, and by citrate. The latter displayed the strongest node betweenness value (185.25) of all nodes highlighting its fundamental structural role in the connectivity of the network by linking between different communities and to the also strongly connected enzyme aldolase. PMID- 27462345 TI - Corrigendum: Overexpression of Rice Glutaredoxin OsGrx_C7 and OsGrx_C2.1 Reduces Intracellular Arsenic Accumulation and Increases Tolerance in Arabidopsis thaliana. AB - [This corrects the article on p. 740 in vol. 7, PMID: 27313586.]. PMID- 27462344 TI - Assessing Fungal Population in Soil Planted with Cry1Ac and CPTI Transgenic Cotton and Its Conventional Parental Line Using 18S and ITS rDNA Sequences over Four Seasons. AB - Long-term growth of genetically modified plants (GMPs) has raised concerns regarding their ecological effects. Here, FLX-pyrosequencing of region I (18S) and region II (ITS1, 5.8S, and ITS2) rDNA was used to characterize fungal communities in soil samples after 10-year monoculture of one representative transgenic cotton line (TC-10) and 15-year plantation of various transgenic cotton cultivars (TC-15mix) over four seasons. Soil fungal communities in the rhizosphere of non-transgenic control (CC) were also compared. No notable differences were observed in soil fertility variables among CC, TC-10, and TC 15mix. Within seasons, the different estimations were statistically indistinguishable. There were 411 and 2 067 fungal operational taxonomic units in the two regions, respectively. More than 75% of fungal taxa were stable in both CC and TC except for individual taxa with significantly different abundance between TC and CC. Statistical analysis revealed no significant differences between CC and TC-10, while discrimination of separating TC-15mix from CC and TC 10 with 37.86% explained variance in PCoA and a significant difference of Shannon indexes between TC-10 and TC-15mix were observed in region II. As TC-15mix planted with a mixture of transgenic cottons (Zhongmian-29, 30, and 33B) for over 5 years, different genetic modifications may introduce variations in fungal diversity. Further clarification is necessary by detecting the fungal dynamic changes in sites planted in monoculture of various transgenic cottons. Overall, we conclude that monoculture of one representative transgenic cotton cultivar may have no effect on fungal diversity compared with conventional cotton. Furthermore, the choice of amplified region and methodology has potential to affect the outcome of the comparison between GM-crop and its parental line. PMID- 27462346 TI - Design Space Toolbox V2: Automated Software Enabling a Novel Phenotype-Centric Modeling Strategy for Natural and Synthetic Biological Systems. AB - Mathematical models of biochemical systems provide a means to elucidate the link between the genotype, environment, and phenotype. A subclass of mathematical models, known as mechanistic models, quantitatively describe the complex non linear mechanisms that capture the intricate interactions between biochemical components. However, the study of mechanistic models is challenging because most are analytically intractable and involve large numbers of system parameters. Conventional methods to analyze them rely on local analyses about a nominal parameter set and they do not reveal the vast majority of potential phenotypes possible for a given system design. We have recently developed a new modeling approach that does not require estimated values for the parameters initially and inverts the typical steps of the conventional modeling strategy. Instead, this approach relies on architectural features of the model to identify the phenotypic repertoire and then predict values for the parameters that yield specific instances of the system that realize desired phenotypic characteristics. Here, we present a collection of software tools, the Design Space Toolbox V2 based on the System Design Space method, that automates (1) enumeration of the repertoire of model phenotypes, (2) prediction of values for the parameters for any model phenotype, and (3) analysis of model phenotypes through analytical and numerical methods. The result is an enabling technology that facilitates this radically new, phenotype-centric, modeling approach. We illustrate the power of these new tools by applying them to a synthetic gene circuit that can exhibit multi stability. We then predict values for the system parameters such that the design exhibits 2, 3, and 4 stable steady states. In one example, inspection of the basins of attraction reveals that the circuit can count between three stable states by transient stimulation through one of two input channels: a positive channel that increases the count, and a negative channel that decreases the count. This example shows the power of these new automated methods to rapidly identify behaviors of interest and efficiently predict parameter values for their realization. These tools may be applied to understand complex natural circuitry and to aid in the rational design of synthetic circuits. PMID- 27462347 TI - Palindrome-Mediated Translocations in Humans: A New Mechanistic Model for Gross Chromosomal Rearrangements. AB - Palindromic DNA sequences, which can form secondary structures, are widely distributed in the human genome. Although the nature of the secondary structure single-stranded "hairpin" or double-stranded "cruciform"-has been extensively investigated in vitro, the existence of such unusual non-B DNA in vivo remains controversial. Here, we review palindrome-mediated gross chromosomal rearrangements possibly induced by non-B DNA in humans. Recent advances in next generation sequencing have not yet overcome the difficulty of palindromic sequence analysis. However, a dozen palindromic AT-rich repeat (PATRR) sequences have been identified at the breakpoints of recurrent or non-recurrent chromosomal translocations in humans. The breakages always occur at the center of the palindrome. Analyses of polymorphisms within the palindromes indicate that the symmetry and length of the palindrome affect the frequency of the de novo occurrence of these palindrome-mediated translocations, suggesting the involvement of non-B DNA. Indeed, experiments using a plasmid-based model system showed that the formation of non-B DNA is likely the key to palindrome-mediated genomic rearrangements. Some evidence implies a new mechanism that cruciform DNAs may come close together first in nucleus and illegitimately joined. Analysis of PATRR-mediated translocations in humans will provide further understanding of gross chromosomal rearrangements in many organisms. PMID- 27462348 TI - Endoscopic Hands-Off Technique versus Conventional Technique for Conversion from an Orobiliary to a Nasobiliary Tube. AB - Background. The aim of this study was to compare the outcomes of the endoscopic hands-off technique and the conventional technique when repositioning an endoscopic nasobiliary drainage (ENBD) tube from the mouth to the nose. Methods. We conducted a retrospective cohort study of all endoscopic retrograde cholangiopancreatographies (ERCPs) performed between July 2013 and May 2015 at a single tertiary referral center. A total of 1187 ERCPs were performed during the study period. Among them, 114 patients who underwent ENBD were enrolled in this study. In those patients, we used the endoscopic hands-off technique between July 2013 and May 2014 (endoscopy group) and the conventional technique between June 2014 and May 2015 (conventional group). Results. Technical success was achieved in 100% (58/58) of the endoscopy group and 94.6% (53/56) of the conventional group (P = 0.115). In the 3 cases of failed conventional technique, the endoscopic hands-off technique was then performed, and conversion of the ENBD tube was successful in all of these patients. The procedure time was significantly shorter in the endoscopy group than in the conventional group (124 s versus 149 s, P = 0.001). Conclusion. The endoscopic hands-off technique was feasible and effective for oral-nasal conversion of an ENBD tube. PMID- 27462349 TI - NK Cell Subtypes as Regulators of Autoimmune Liver Disease. AB - As major components of innate immunity, NK cells not only exert cell-mediated cytotoxicity to destroy tumors or infected cells, but also act to regulate the functions of other cells in the immune system by secreting cytokines and chemokines. Thus, NK cells provide surveillance in the early defense against viruses, intracellular bacteria, and cancer cells. However, the effecter function of NK cells must be exquisitely controlled to prevent inadvertent attack against normal "self" cells. In an organ such as the liver, where the distinction between immunotolerance and immune defense against routinely processed pathogens is critical, the plethora of NK cells has a unique role in the maintenance of homeostasis. Once self-tolerance is broken, autoimmune liver disease resulted. NK cells act as a "two-edged weapon" and even play opposite roles with both regulatory and inducer activities in the hepatic environment. That is, NK cells act not only to produce inflammatory cytokines and chemokines, but also to alter the proliferation and activation of associated lymphocytes. However, the precise regulatory mechanisms at work in autoimmune liver diseases remain to be identified. In this review, we focus on recent research with NK cells and their potential role in the development of autoimmune liver disease. PMID- 27462350 TI - Incidental Findings on Cone Beam Computed Tomography Studies outside of the Maxillofacial Skeleton. AB - Objective. To define the presence and prevalence of incidental findings in and around the base of skull from large field-of-view CBCT of the maxillofacial region and to determine their clinical importance. Methods. Four hundred consecutive large fields of view CBCT scans viewed from January 1, 2007, to January 1, 2014, were retrospectively evaluated for incidental findings of the cervical vertebrae and surrounding structures. Findings were categorized into cervical vertebrae, intracranial, soft tissue, airway, carotid artery, lymph node, and skull base findings. Results. A total of 653 incidental findings were identified in 309 of the 400 CBCT scans. The most prevalent incidental findings were soft tissue calcifications (29.71%), followed by intracranial calcifications (27.11%), cervical vertebrae (20.06%), airway (11.49%), external carotid artery calcification (10.41%), lymph node calcification (0.77%), subcutaneous tissue calcification and calcified tendonitis of the longus colli muscle (0.3%), and skull base finding (0.15%). A significant portion of the incidental findings (31.24%) required referral, 17.76% required monitoring, and 51% did not require either. Conclusion. A comprehensive review of the CBCT images beyond the region of interest, especially incidental findings in the base of skull, cervical vertebrae, pharyngeal airway, and soft tissue, is necessary to avoid overlooking clinically significant lesions. PMID- 27462351 TI - Filaggrin gene mutations and new SNPs in asthmatic patients: a cross-sectional study in a Spanish population. AB - BACKGROUND: Several null-mutations in the FLG gene that produce a decrease or absence of filaggrin in the skin and predispose to atopic dermatitis and ichthyosis vulgaris have been described. The relationship with asthma is less clear and may be due to the influence of atopy in patients with associated asthma. METHODS: Four hundred individuals were included, 300 patients diagnosed with asthma divided into two groups according to their phenotype (allergic and non-allergic asthma) and 100 strictly characterized controls. The coding region and flanking regions of the FLG gene were amplified by PCR. We proceeded to the characterization of potential gene variants in that region by RFLP and sequencing and analysed their association with lung function parameters, asthma control and severity, and quality of life. RESULTS: We identified two null-mutations (R501X and 2282del4), seven SNPs previously described in databases and three SNPs that had not been previously described. One of the SNP identified in this study (1741A > T) was more frequently detected in patients with non-allergic asthma, worse FVC, FEV1 and PEF values and a higher treatment step. In addition, lowered spirometric values were observed in the non-allergic group carrying any of the nonsynonymous SNPs. CONCLUSIONS: In the association study of genetic variants of the FLG gene in our population the 1741A > T polymorphism seems to be associated with non-allergic asthma. PMID- 27462352 TI - Nutritional concerns in pediatric inflammatory bowel disease. AB - The pathophysiology and fundamental etiologic mechanism of inflammatory bowel disease (IBD) is not well understood even though therapeutic regimens and drugs are rapidly evolutionary. IBD has complicated connections with genetic, immunologic, gut microbial, environmental, and nutritional factors. It is not clearly well known to the physicians how to feed, what nutrients are more helpful, and what food to be avoided. This review discusses the issues of growth and important nutritional concerns in the management of IBD in childhood. PMID- 27462353 TI - Pneumocystis jirovecii pneumonia in pediatric patients: an analysis of 15 confirmed consecutive cases during 14 years. AB - PURPOSE: Pneumocystis jirovecii pneumonia occurs in various immunocompromised patients. Despite the prophylaxis strategies in clinical practice, certain patients develop P. jirovecii pneumonia. This study was performed to investigate pediatric cases with P. jirovecii pneumonia in a single center. METHODS: We identified pediatric patients younger than 19 years with microbiologically confirmed P. jirovecii pneumonia from January 2000 to February 2014. A retrospective chart review was performed. RESULTS: Fifteen episodes of P. jirovecii pneumonia in 14 patients were identified with median age of 8.3 years (range, 0.4-18.6 years). Among these patients, 11 patients had hematology oncology diseases, 2 had primary immunodeficiency disorders (one with severe combined immunodeficiency and the other with Wiskott Aldrich syndrome), 1 had systemic lupus erythematosus and 1 received kidney transplant. Four patients were transplant recipients; 1 allogeneic and 2 autologous hematopoietic cell transplant and 1 with kidney transplant. The median absolute lymphocyte count at the diagnosis of P. jirovecii pneumonia was 5,156 cells/mm(3) (range, 20-5,111 cells/mm(3)). In 13 episodes (13 of 15, 86.7%), patients were not receiving prophylaxis at the onset of P. jirovecii pneumonia. For treatment, trimethoprim/sulfamethoxazole was given as a main therapeutic agent in all 15 episodes. Steroid was given in 9 episodes (60%). Median treatment duration was 15 days (range, 4-33 days). Overall mortality at 60 days was 35.7% (5 of 14). CONCLUSION: Majority of our patients developed P. jirovecii pneumonia while not on prophylaxis. Continuous efforts and more data are needed to identify high risk patients who may get benefit from P. jirovecii pneumonia prophylaxis. PMID- 27462354 TI - Usefulness of interferon-gamma release assay for the diagnosis of latent tuberculosis infection in young children. AB - PURPOSE: Latent tuberculosis infection (LTBI) in young children may progress to severe active tuberculosis (TB) disease and serve as a reservoir for future transmission of TB disease. There are limited data on interferon-gamma release assay (IGRA) performance in young children, which our research aims to address by investigating the usefulness of IGRA for the diagnosis of LTBI. METHODS: We performed a tuberculin skin test (TST) and IGRA on children who were younger than 18 years and were admitted to Chung-Ang University Hospital during May 2011-June 2015. Blood samples for IGRA were collected, processed, and interpreted according to manufacturer protocol. RESULTS: Among 149 children, 31 (20.8%) and 10 (6.7%) were diagnosed with LTBI and active pulmonary TB, respectively. In subjects lacking contact history with active TB patients, TST and IGRA results were positive in 41.4% (29 of 70) and 12.9% (9 of 70) subjects, respectively. The agreement (kappa) of TST and IGRA was 0.123. The control group, consisting of non TB-infected subjects, showed no correlation between age and changes in interferon gamma concentration after nil antigen, TB-specific antigen, or mitogen stimulation in IGRAs (P=0.384, P=0.176, and P=0.077, respectively). In serial IGRAs, interferon-gamma response to TB antigen increased in IGRA-positive LTBI subjects, but did not change considerably in initially IGRA-negative LTBI or control subjects. CONCLUSION: The lack of decrease in interferon-gamma response in young children indicates that IGRA could be considered for this age group. Serial IGRA tests might accurately diagnose LTBI in children lacking contact history with active TB patients. PMID- 27462355 TI - The effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline-induced right ventricular failure. AB - PURPOSE: Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. METHODS: The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. RESULTS: The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-alpha, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. CONCLUSION: Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function. PMID- 27462356 TI - Clinical importance of F-waves as a prognostic factor in Guillain-Barre syndrome in children. AB - PURPOSE: A limited number of studies have examined the link between F-wave abnormalities and clinical presentation in pediatric Guillain-Barre syndrome (GBS). Therefore, this study examined the importance of F-wave abnormalities as a prognostic factor in pediatric GBS patients. METHODS: The records and electrodiagnostic studies (EDS) of 70 GBS patients were retrospectively evaluated, and divided into 2 groups according to the results of EDS. Group A (n=33) presented with F-wave abnormalities, and group B (n=26) exhibited normal findings. We compared laboratory reports, clinical features, response to treatment, and prognosis between the 2 groups. RESULTS: Motor weakness was the most frequently observed symptom for either group. Clinically, the incidence of fever and upper respiratory symptoms differed between the 2 groups, while the prevalence of abnormal deep tendon reflex (DTR) was significantly higher in group A than B (P<0.05). Patients diagnosed with GBS had received intravenous immunoglobulin treatment: 94% in group A and 58% in group B. Furthermore, significantly greater numbers of patients in group A showed H-reflex abnormalities and poor prognosis compared with group B (P<0.05). CONCLUSION: This study demonstrated that F-waves are a clinically important prognostic factor in GBS. F-wave abnormalities were associated with abnormal DTR and poor prognosis in patients. Limited studies have examined the link between F-wave abnormalities and clinical results; therefore, further randomized controlled studies are needed to confirm the clinical characteristics and efficacy of treatments. PMID- 27462357 TI - A rare case of Sjogren-Larsson syndrome with recurrent pneumonia and asthma. AB - Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder with worldwide incidence of 0.4 per 100,000 people. It is characterized by the triad of congenital ichthyosis, spastic diplegia or quadriplegia, and mental retardation. Herein we report a 2-year-old male child with SLS, asthma, and recurrent pneumonia. SLS was confirmed by a molecular genetics study that revealed a deletion mutation in the ALDH3A2 gene. An ALDH3A2 gene mutation results in dysfunction of the microsomal enzyme fatty aldehyde dehydrogenase and impaired metabolism and accumulation of leukotriene B4, which is a key molecule and a pro-inflammatory mediator in developing allergic diseases, especially asthma. An increased level of leukotriene B4 has been reported in SLS patients. As far as we are aware, this is the first report of SLS associated with asthma and recurrent pneumonia. In conclusion, pediatricians should be aware of and evaluate patients with SLS for possible associated asthma and allergic disorders. PMID- 27462358 TI - Two cases of familial cerebral cavernous malformation caused by mutations in the CCM1 gene. AB - Cerebral cavernous malformation (CCM) is a vascular malformation characterized by abnormally enlarged capillary cavities without any intervening neural tissue. We report 2 cases of familial CCMs diagnosed with the CCM1 mutation by using a genetic assay. A 5-year-old boy presented with headache, vomiting, and seizure like movements. Brain magnetic resonance imaging (MRI) revealed multiple CCM lesions in the cerebral hemispheres. Subsequent mutation analysis of his father and other family members revealed c.940_943 del (p.Val314 Asn315delinsThrfsX3) mutations of the CCM1 gene. A 10-month-old boy who presented with seizure-like movements was reported to have had no perinatal event. His aunt was diagnosed with cerebral angioma. Brain and spine MRI revealed multiple angiomas in the cerebral hemisphere and thoracic spinal cord. Mutation analysis of his father was normal, although that of the patient and his mother revealed c.535C>T (p.Arg179X) mutations of the CCM1 gene. Based on these studies, we suggest that when a child with a familial history of CCMs exhibits neurological symptoms, the physician should suspect familial CCMs and consider brain imaging or a genetic assay. PMID- 27462359 TI - Corrigendum to "Zingiber zerumbet (L.) Smith: A Review of Its Ethnomedicinal, Chemical, and Pharmacological Uses". AB - [This corrects the article DOI: 10.1155/2011/543216.]. PMID- 27462361 TI - Antiretroviral treatment regardless of CD4 count: the universal answer to a contextual question. AB - After a period where it was recommended to start antiretroviral therapy (ART) early, the CD4 threshold for treating asymptomatic adults dropped to 200/mm(3) at the beginning of the 2000s. This was mostly due to a great prudence with regards to drug toxicity. The ART-start CD4 threshold in most international guidelines was then raised to 350/mm(3) in 2006-2009 and to 500/mm(3) in 2009-2013. Between 2012 and 2015, international guidelines went the last step further and recommended treating all HIV-infected adults regardless of their CD4 count. This ultimate step was justified by the results of three randomized controlled trials, HPTN 052, Temprano ANRS 12136 and START. These three trials assessed the benefits and risks of starting ART immediately upon inclusion ("early ART") versus deferring ART until the current starting criteria were met ("deferred ART"). Taken together, they recruited 8427 HIV-infected adults in 37 countries. The primary outcome was severe morbidity, a composite outcome that included all-cause deaths, AIDS diseases, and non-AIDS cancers in the three trials. The trial results were mutually consistent and reinforcing. The overall risk of severe morbidity was significantly 44-57 % lower in patients randomized to early ART as compared to deferred ART. Early ART also decreased the risk of AIDS, tuberculosis, invasive bacterial diseases and Kaposi's sarcoma considered separately. The incidence of severe morbidity was 3.2 and 3.5 times as high in HPTN052 and Temprano as in START, respectively. This difference is mostly due to the geographical context of morbidity. The evidence is now strong that initiating ART at high CD4 counts entails individual benefits worldwide, and that this is all the more true in low resource contexts where tuberculosis and other bacterial diseases are highly prevalent. These benefits in addition to population benefits consisting of preventing HIV transmission demonstrated in HPTN052, justify the recommendation that HIV-infected persons should initiate ART regardless of CD4 count. This recommendation faces many challenges, including the fact that switching from "treat at 500 CD4/mm(3)" to "treat everyone" not only requires more tests and more drugs, but also more people to support patients and help them remain in care. PMID- 27462360 TI - Plasma HIV-1 RNA viral load rebound among people who inject drugs receiving antiretroviral therapy (ART) in a Canadian setting: an ethno-epidemiological study. AB - BACKGROUND: People who inject drugs (PWID) living with HIV often experience sub optimal antiretroviral therapy (ART) treatment outcomes, including HIV plasma viral load (PVL) rebound. While previous studies have identified risk factors for PVL rebound among PWID, no study has examined the perspectives of PWID who have experienced PVL rebound episodes. We conducted an ethno-epidemiological study to investigate the circumstances surrounding the emergence of rebound episodes among PWID in Vancouver, BC, Canada. METHODS: Comprehensive clinical records linked to a community-based prospective observational cohort of HIV-positive drug users were used to identify PWID who had recently experienced viral rebound. In-depth qualitative interviews with 16 male and 11 female participants explored participant perspectives regarding the emergence of viral rebound. A timeline depicting each participant's HIV viral load and adherence to ART was used to elicit discussion of circumstances surrounding viral rebound. FINDINGS: Viral rebound episodes were shaped by interplay between various individual, social, and environmental factors that disrupted routines facilitating adherence. Structural environmental influences resulting in non-adherence included housing transitions, changes in drug use patterns and intense drug scene involvement, and inadequate care for co-morbid health conditions. Social-environmental influences on ART adherence included poor interactions between care providers and patients producing non-adherence, and understandings of HIV treatment that fostered intentional treatment discontinuation. CONCLUSIONS: This study describes key pathways which led to rebound episodes among PWID receiving ART and illustrates how environmental forces may increase vulnerability for non-adherence leading to treatment failure. Our findings have potential to help inform interventions and supports that address social-structural forces that foster non-adherence among PWID. PMID- 27462362 TI - Malignant mesothelioma incidence by nation-wide cancer registry: a population based study. AB - BACKGROUND: Malignant mesothelioma caused by asbestos exposure has a long latency period. A ban on asbestos use may not be apparent in decreased incidence in the population until after several decades. The aim was to evaluate changes in the incidence of malignant mesothelioma, and the possible impact of the asbestos ban implemented in Iceland in 1983. METHODS: This is a population study on aggregate level; the source of data was the Icelandic Cancer Registry, the National Cause of-Death Registry, and the National Register. Volume of asbestos import was obtained from Customs Tariff. The import figures reflect fairly accurately the amount used, as there are no mines in the country. RESULTS: Asbestos import peaked in 1980 at 15.0 kg/capita/year, diminishing to 0.3 kg/capita/year ten years after the ban in 1983, and to zero in the most recent years. Seventy-nine per cent of the cases of malignant mesothelioma were men, and 72 % were of pleural origin. Mesothelioma incidence increased steadily from 1965 to 2014, when it reached 21.4 per million among men, and 5.6 among women. Mortality in 2014 was 22.2 per million among men, and 4.8 among women. CONCLUSION: Malignant mesothelioma incidence and mortality increased in the population during the period, despite the ban on asbestos use from 1983. This is in agreement with the long latency time for malignant mesothelioma. In line with the previously high per capita volume of asbestos import, many buildings, equipment, and structures contain asbestos, so there is an on-going risk of asbestos exposure during maintenance, renovations and replacements. It is thus difficult to predict when the incidence of malignant mesothelioma will decrease in the future. During the last ten-year period, the incidence in Iceland was higher than the recently reported incidence in neighbouring countries. PMID- 27462363 TI - A Canonical Correlation Analysis of AIDS Restriction Genes and Metabolic Pathways Identifies Purine Metabolism as a Key Cooperator. AB - Human immunodeficiency virus causes a severe disease in humans, referred to as immune deficiency syndrome. Studies on the interaction between host genetic factors and the virus have revealed dozens of genes that impact diverse processes in the AIDS disease. To resolve more genetic factors related to AIDS, a canonical correlation analysis was used to determine the correlation between AIDS restriction and metabolic pathway gene expression. The results show that HIV-1 postentry cellular viral cofactors from AIDS restriction genes are coexpressed in human transcriptome microarray datasets. Further, the purine metabolism pathway comprises novel host factors that are coexpressed with AIDS restriction genes. Using a canonical correlation analysis for expression is a reliable approach to exploring the mechanism underlying AIDS. PMID- 27462364 TI - A Run-Length Encoding Approach for Path Analysis of C. elegans Search Behavior. AB - The nematode Caenorhabditis elegans explores the environment using a combination of different movement patterns, which include straight movement, reversal, and turns. We propose to quantify C. elegans movement behavior using a computer vision approach based on run-length encoding of step-length data. In this approach, the path of C. elegans is encoded as a string of characters, where each character represents a path segment of a specific type of movement. With these encoded string data, we perform k-means cluster analysis to distinguish movement behaviors resulting from different genotypes and food availability. We found that shallow and sharp turns are the most critical factors in distinguishing the differences among the movement behaviors. To validate our approach, we examined the movement behavior of tph-1 mutants that lack an enzyme responsible for serotonin biosynthesis. A k-means cluster analysis with the path string-encoded data showed that tph-1 movement behavior on food is similar to that of wild-type animals off food. We suggest that this run-length encoding approach is applicable to trajectory data in animal or human mobility data. PMID- 27462365 TI - Human herpesvirus multiplex ddPCR detection in brain tissue from low- and high grade astrocytoma cases and controls. AB - BACKGROUND: Glioblastoma (GBM) is a fatal CNS malignancy, representing 50 % of all gliomas with approximately 12-18 months survival time after initial diagnosis. Recently, the human herpesvirus cytomegalovirus (CMV) has been suggested to have an oncogenic role, yet this association remains controversial. In addition, human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have also been associated with low-grade gliomas, but few studies have examined HHV-6 and EBV in glioblastomas. Droplet digital PCR (ddPCR) is a highly precise diagnostic tool that enables the absolute quantification of target DNA. This study examines the association between multiple human herpesviruses and astrocytomas. METHODS: This study analyzed 112 brain tissue specimens, including 45 glioblastoma, 12 astrocytoma grade III, 2 astrocytoma grade II, 4 astrocytoma grade I, and 49 controls. All brain tissue samples were de-identified and pathologically confirmed. Each tissue block was sectioned for DNA extraction and CMV, EBV, HHV 6A and HHV-6B, and a cellular housekeeping gene were amplified by ddPCR. RESULTS: Neither CMV nor HHV-6A were detected in any of the astrocytoma samples. However, HHV-6B (p = 0.147) and EBV (p = 0.049) had a higher positivity frequency in the GBM compared to the controls. CONCLUSION: The undetectable CMV DNA in the astrocytoma cohort does not support the observation of an increased prevalence of CMV DNA in GBM, as reported in other studies. EBV has a significantly higher positivity in the GBM cohort compared to the controls, while HHV-6B has a higher but not statistically significant positivity in the case cohort. Whether these viruses play an oncogenic role in GBM remains to be further investigated. PMID- 27462366 TI - Proteotyping of biogas plant microbiomes separates biogas plants according to process temperature and reactor type. AB - BACKGROUND: Methane yield and biogas productivity of biogas plants (BGPs) depend on microbial community structure and function, substrate supply, and general biogas process parameters. So far, however, relatively little is known about correlations between microbial community function and process parameters. To close this knowledge gap, microbial communities of 40 samples from 35 different industrial biogas plants were evaluated by a metaproteomics approach in this study. RESULTS: Liquid chromatography coupled to tandem mass spectrometry (Orbitrap EliteTM Hybrid Ion Trap-Orbitrap Mass Spectrometer) of all 40 samples as triplicate enabled the identification of 3138 different metaproteins belonging to 162 biological processes and 75 different taxonomic orders. The respective database searches were performed against UniProtKB/Swiss-Prot and seven metagenome databases. Subsequent clustering and principal component analysis of these data allowed for the identification of four main clusters associated with mesophile and thermophile process conditions, the use of upflow anaerobic sludge blanket reactors and BGP feeding with sewage sludge. Observations confirm a previous phylogenetic study of the same BGP samples that was based on 16S rRNA gene sequencing by De Vrieze et al. (Water Res 75:312-323, 2015). In particular, we identified similar microbial key players of biogas processes, namely Bacillales, Enterobacteriales, Bacteriodales, Clostridiales, Rhizobiales and Thermoanaerobacteriales as well as Methanobacteriales, Methanosarcinales and Methanococcales. For the elucidation of the main biomass degradation pathways, the most abundant 1 % of metaproteins was assigned to the KEGG map 1200 representing the central carbon metabolism. Additionally, the effect of the process parameters (i) temperature, (ii) organic loading rate (OLR), (iii) total ammonia nitrogen (TAN), and (iv) sludge retention time (SRT) on these pathways was investigated. For example, high TAN correlated with hydrogenotrophic methanogens and bacterial one-carbon metabolism, indicating syntrophic acetate oxidation. CONCLUSIONS: This is the first large-scale metaproteome study of BGPs. Proteotyping of BGPs reveals general correlations between the microbial community structure and its function with process parameters. The monitoring of changes on the level of microbial key functions or even of the microbial community represents a well-directed tool for the identification of process problems and disturbances.Graphical abstractCorrelation between the different orders and process parameter, as well as principle component analysis of all investigated biogas plants based on the identified metaproteins. PMID- 27462368 TI - Cellulolytic enzyme expression and simultaneous conversion of lignocellulosic sugars into ethanol and xylitol by a new Candida tropicalis strain. AB - BACKGROUND: Lignocellulosic ethanol production involves major steps such as thermochemical pretreatment of biomass, enzymatic hydrolysis of pre-treated biomass and the fermentation of released sugars into ethanol. At least two different organisms are conventionally utilized for producing cellulolytic enzymes and for ethanol production through fermentation, whereas in the present study a single yeast isolate with the capacity to simultaneously produce cellulases and xylanases and ferment the released sugars into ethanol and xylitol has been described. RESULTS: A yeast strain isolated from soil samples and identified as Candida tropicalis MTCC 25057 expressed cellulases and xylanases over a wide range of temperatures (32 and 42 degrees C) and in the presence of different cellulosic substrates [carboxymethylcellulose and wheat straw (WS)]. The studies indicated that the cultivation of yeast at 42 degrees C in pre treated hydrolysate containing 0.5 % WS resulted in proportional expression of cellulases (exoglucanases and endoglucanases) at concentrations of 114.1 and 97.8 U g(-1) ds, respectively. A high xylanase activity (689.3 U g(-1) ds) was also exhibited by the yeast under similar growth conditions. Maximum expression of cellulolytic enzymes by the yeast occurred within 24 h of incubation. Of the sugars released from biomass after pretreatment, 49 g L(-1) xylose was aerobically converted into 15.8 g L(-1) of xylitol. In addition, 25.4 g L(-1) glucose released after the enzymatic hydrolysis of biomass was fermented by the same yeast to obtain an ethanol titer of 7.3 g L(-1). CONCLUSIONS: During the present study, a new strain of C. tropicalis was isolated and found to have potential for consolidated bioprocessing (CBP) applications. The strain could grow in a wide range of process conditions (temperature, pH) and in the presence of lignocellulosic inhibitors such as furfural, HMF and acetic acid. The new yeast produced cellulolytic enzymes over a wide temperature range and in the presence of various cellulosic substrates. The cellulolytic enzymes produced by the yeast were effectively used for the hydrolysis of pretreated biomass. The released sugars, xylose and glucose were, respectively, converted into xylitol and ethanol. The potential shown by the new inhibitor tolerant cellulolytic C. tropicalis to produce ethanol or xylitol is of great industrial significance. PMID- 27462367 TI - Identification and genome reconstruction of abundant distinct taxa in microbiomes from one thermophilic and three mesophilic production-scale biogas plants. AB - BACKGROUND: Biofuel production from conversion of biomass is indispensable in the portfolio of renewable energies. Complex microbial communities are involved in the anaerobic digestion process of plant material, agricultural residual products and food wastes. Analysis of the genetic potential and microbiology of communities degrading biomass to biofuels is considered to be the key to develop process optimisation strategies. Hence, due to the still incomplete taxonomic and functional characterisation of corresponding communities, new and unknown species are of special interest. RESULTS: Three mesophilic and one thermophilic production-scale biogas plants (BGPs) were taxonomically profiled using high throughput 16S rRNA gene amplicon sequencing. All BGPs shared a core microbiome with the thermophilic BGP featuring the lowest diversity. However, the phyla Cloacimonetes and Spirochaetes were unique to BGPs 2 and 3, Fusobacteria were only found in BGP3 and members of the phylum Thermotogae were present only in the thermophilic BGP4. Taxonomic analyses revealed that these distinctive taxa mostly represent so far unknown species. The only exception is the dominant Thermotogae OTU featuring 16S rRNA gene sequence identity to Defluviitoga tunisiensis L3, a sequenced and characterised strain. To further investigate the genetic potential of the biogas communities, corresponding metagenomes were sequenced in a deepness of 347.5 Gbp in total. A combined assembly comprised 80.3 % of all reads and resulted in the prediction of 1.59 million genes on assembled contigs. Genome binning yielded genome bins comprising the prevalent distinctive phyla Cloacimonetes, Spirochaetes, Fusobacteria and Thermotogae. Comparative genome analyses between the most dominant Thermotogae bin and the very closely related Defluviitoga tunisiensis L3 genome originating from the same BGP revealed high genetic similarity. This finding confirmed applicability and reliability of the binning approach. The four highly covered genome bins of the other three distinct phyla showed low or very low genetic similarities to their closest phylogenetic relatives, and therefore indicated their novelty. CONCLUSIONS: In this study, the 16S rRNA gene sequencing approach and a combined metagenome assembly and binning approach were used for the first time on different production-scale biogas plants and revealed insights into the genetic potential and functional role of so far unknown species. PMID- 27462370 TI - A de novo duplication of chromosome 9q34.13-qter in a fetus with Tetralogy of Fallot Syndrome. AB - BACKGROUND: Partial duplications of the distal 9q have been rarely reported in literatures. The key features included characteristic facial appearance, long fingers and toes, slight psychomotor retardation, heart murmur et al. But rare severe congenital heart defects (CHD) such as TOF were reported to be associated with 9qter duplications. CASE PRESENTATION: A 23-year-old woman was referred for genetic counseling and prenatal diagnosis at 25(3/7) weeks of gestation due to her male fetus, diagnosed as Tetralogy of Fallot Syndrome (TOF) by prenatal ultrasound. SNP (Single nucleotide polymorphism) array revealed that the male fetus had a de novo 5.47 Mb duplication at 9q34.13-qter. Meanwhile, non-invasive prenatal testing (NIPT) using low coverage whole genome massively parallel sequencing of circulating cell-free fetal DNA (cffDNA) showed consistent results. Multiplex ligation-dependent probe amplification (MLPA) also confirmed the duplication at 9qter. CONCLUSION: In this paper, we present an Asian fetus with TOF caused by a de novo 5.47 Mb duplication at 9q34.13-qter. Duplication of 9q34.13-qter should be considered as an etiological diagnosis in the case of TOF. Our prenatal diagnostic findings provide important information for genetic counseling on the male fetus and future pregnancies in this family. Chromosomal microarray analysis (CMA) remains the first-tier clinical diagnostic test for prenatal fetus with suspicious syndromes. We also highlight the high potential application of NIPT in the screening of sub-chromosomal rearrangement. PMID- 27462369 TI - The dangers of lithotomy positioning in the operating room: case report of bilateral lower extremity compartment syndrome after a 90-minutes surgical procedure. AB - BACKGROUND: Lower extremity acute compartment syndrome after gynecologic surgery in the lithotomy position is a rare, yet potentially devastating complication. A high level of suspicion is paramount for early recognition and mitigation of acute compartment syndrome originating from prolonged surgery in lithotomy position. CASE PRESENTATION: A 23-year-old female, gravida 1, para 0, underwent a laparoscopic salpingectomy for a ruptured ectopic pregnancy. Surgical time was 90 min. Postoperatively, the patient developed acute compartment syndrome of both legs necessitating emergent bilateral four-compartment fasciotomies, with repeated returns to the operating room for 2nd look procedures and delayed wound closures. The patient regained full function within 3 months and returned to an unrestricted baseline activity level. CONCLUSION: Technical diligence in applying a lithotomy position is paramount for preventing postoperative lower extremity compartment syndrome. A high level of suspicion for this severe complication in conjunction with early recognition and immediate surgical management can mitigate long-term adverse sequelae and improve postoperative outcomes. PMID- 27462371 TI - Representing and querying disease networks using graph databases. AB - BACKGROUND: Systems biology experiments generate large volumes of data of multiple modalities and this information presents a challenge for integration due to a mix of complexity together with rich semantics. Here, we describe how graph databases provide a powerful framework for storage, querying and envisioning of biological data. RESULTS: We show how graph databases are well suited for the representation of biological information, which is typically highly connected, semi-structured and unpredictable. We outline an application case that uses the Neo4j graph database for building and querying a prototype network to provide biological context to asthma related genes. CONCLUSIONS: Our study suggests that graph databases provide a flexible solution for the integration of multiple types of biological data and facilitate exploratory data mining to support hypothesis generation. PMID- 27462372 TI - Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non alcoholic steatohepatitis and diabetes. AB - BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are new oral antidiabetic drugs that reduce hyperglycemia by promoting urinary glucose excretion. Glycosuria produced by SGLT2 inhibitors is associated with weight loss, mainly due to reduced fat volume. We investigated the effects of empagliflozin (selective SGLT2 inhibitor) and linagliptin (DPP-4 inhibitor) on steatohepatitis and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH) with diabetes. METHODS: A novel NASH model was generated by administration of streptozotocin to C57BL/6J mice at 2 days old, with a high-fat diet from 4 weeks. NASH mice aged 6 weeks were divided into four groups of 6 animals: vehicle, linagliptin (10 mg/kg), empagliflozin (10 mg/kg), and linagliptin + empagliflozin. The histological non-alcoholic fatty liver disease activity score was significantly lower in the empagliflozin and linagliptin + empagliflozin groups than in the vehicle or linagliptin groups. Hepatic expression of inflammatory genes (tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1) was decreased in the empagliflozin and linagliptin + empagliflozin groups compared with the vehicle group. The collagen deposition with Sirius red staining was significantly reduced in the linagliptin + empagliflozin group compared with the linagliptin or the empagliflozin group. Immunohistochemistry showed that expression of alpha-smooth muscle actin, a marker of myofibroblasts (fibrosis), was reduced in the linagliptin + empagliflozin group compared with the vehicle group, as was expression of type 1 and 3 collagen mRNA. Linagliptin + empagliflozin decreased expression of mRNAs for genes related to fatty acid synthesis, but did not increase mRNAs for beta oxidation-related genes. CONCLUSIONS: While empagliflozin alone attenuates development of NASH showing anti-steatotic and anti-inflammatory effects, combined administration of empagliflozin and linagliptin can synergistically ameliorates NASH with stronger anti-fibrotic effects. PMID- 27462373 TI - Is vaspin related to cardio-metabolic status and autonomic function in early stages of glucose intolerance and in metabolic syndrome? AB - BACKGROUND: This study aims to assess serum vaspin in early stages of glucose intolerance and in the presence of metabolic syndrome (MetS); and to evaluate vaspin correlation to different cardio-metabolic parameters and autonomic tone in these subjects. METHODS: 185 subjects (80 males and 105 females) of mean age 45.8 +/- 11.6 years and mean BMI 31.2 +/- 6.3 kg/m(2), divided into groups according to: glucose tolerance, presence of MetS and cardio-vascular autonomic dysfunction (CAD), were enrolled. Glucose tolerance was studied during OGTT. Anthropometric indices, blood pressure, HbA1c, serum lipids, hsCRP, fasting immunoreactive insulin and serum vaspin were measured. Body composition was estimated by impedance analysis. AGEs were assessed by skin fluorescence. CAD was assessed by ANX-3.0. RESULTS: There was no difference in vaspin levels between the groups according to glucose tolerance, presence of MetS, and CAD. Regression analysis revealed independent association between serum vaspin and total body fat in newly diagnosed type 2 diabetes (NDT2D) group, and between serum vaspin and age and total body fat in MetS group. Vaspin negatively correlated with both sympathetic and parasympathetic activity in normal glucose tolerance (NGT) and just with parasympathetic tone in NGT without MetS. CONCLUSION: Our results demonstrate no overt fluctuations in vaspin levels in the early stages of glucose intolerance and in MetS. Total body fat seems to be related to vaspin levels in MetS and NDT2D. Our data show negative correlation between vaspin and autonomic function in NGT, as vaspin is associated with parasympathetic activity even in the absence of MetS. PMID- 27462374 TI - Obesity, maternal smoking and SHBG in neonates. AB - BACKGROUND: Sex hormone binding globulin (SHBG), a glycoprotein produced by hepatocytes that transports testosterone and other steroids in plasma, is a marker for developing metabolic syndrome and T2DM. SHBG is present in umbilical cord blood where it may be epigenetically regulated. This study was conducted to investigate whether the fetal environment, based on maternal pre-pregnancy weight, pregnancy weight gain or smoking during pregnancy, influence SHBG in newborns. METHODS: Maternal and newborn characteristics and SHBG levels and other variables were measured in cord and day 2 heel-stick blood samples in 60 healthy full-term singleton babies (31 F, 29 M). RESULTS: SHBG levels varied nearly fivefold among male and female newborns and were unrelated to sex, neonatal adiposity, determined by the Ponderal index and skinfold thickness, nor TNF? in cord blood. There were also no statistically significant associations between pre pregnancy weight or pregnancy weight gain and newborn SHBG levels. However, cord blood SHBG was higher and insulin levels were lower when mothers were smokers, but normalized by day 2. DISCUSSION: While SHBG levels are low in obese children and adults, and portend the development of metabolic syndrome and T2DM, our study of healthy babies born to normal women, found no connection between maternal obesity or newborn adiposity and SHBG levels in newborns. Insofar as women who smoked during pregnancy were thinner and had lower cord blood insulin levels than nonsmokers, higher SHBG in their newborns at birth might have been due to insulin sensitivity, or perhaps to an effect of smoking on placental gene expression. CONCLUSIONS: Factors other than maternal weight and pregnancy weight gain appear to be the major determinants of SHBG in newborns. Higher SHBG levels when mothers smoke during pregnancy may contribute to overweight beginning later in childhood. Whether newborn SHBG levels predict the development of overweight and metabolic syndrome remains to be determined. PMID- 27462375 TI - Genome-wide DNA methylation profiling with MeDIP-seq using archived dried blood spots. AB - BACKGROUND: In utero and early-life experienced environmental exposures are suggested to play an important role in many multifactorial diseases potentially mediated through lasting effects on the epigenome. As the epigenome in addition remains modifiable throughout life, identifying specific disease-relevant biomarkers may prove challenging. This has led to an increased interest in epigenome-wide association studies using dried blood spots (DBS) routinely collected in perinatal screening programs. Such programs are in place in numerous countries around the world producing large and unique biobanks. However, availability of this biological material is highly limited as each DBS is made only from a few droplets of blood and storage conditions may be suboptimal for epigenetic studies. Furthermore, as relevant markers may reside outside gene bodies, epigenome-wide interrogation is needed. RESULTS: Here we demonstrate, as a proof of principle, that genome-wide interrogation of the methylome based on methylated DNA immunoprecipitation coupled with next-generation sequencing (MeDIP seq) is feasible using a single 3.2 mm DBS punch (60 ng DNA) from filter cards archived for up to 16 years. The enrichment profile, sequence quality and distribution of reads across genetic regions were comparable between samples archived 16 years, 4 years and a freshly prepared control sample. CONCLUSIONS: In summary, we show that high-quality MeDIP-seq data is achievable from neonatal screening filter cards stored at room temperature, thereby providing information on annotated as well as on non-RefSeq genes and repetitive elements. Moreover, the quantity of DNA from one DBS punch proved sufficient allowing for multiple epigenome studies using one single DBS. PMID- 27462377 TI - Fifty years of dielectrophoretic cell separation technology. AB - In 1966, Pohl and Hawk [Science 152, 647-649 (1966)] published the first demonstration of dielectrophoresis of living and dead yeast cells; their paper described how the different ways in which the cells responded to an applied nonuniform electric field could form the basis of a cell separation method. Fifty years later, the field of dielectrophoretic (DEP) cell separation has expanded, with myriad demonstrations of its ability to sort cells on the basis of differences in electrical properties without the need for chemical labelling. As DEP separation enters its second half-century, new approaches are being found to move the technique from laboratory prototypes to functional commercial devices; to gain widespread acceptance beyond the DEP community, it will be necessary to develop ways of separating cells with throughputs, purities, and cell recovery comparable to gold-standard techniques in life sciences, such as fluorescence- and magnetically activated cell sorting. In this paper, the history of DEP separation is charted, from a description of the work leading up to the first paper, to the current dual approaches of electrode-based and electrodeless DEP separation, and the path to future acceptance outside the DEP mainstream is considered. PMID- 27462376 TI - Increased global placental DNA methylation levels are associated with gestational diabetes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. METHODS: Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single center birth cohort study. RESULTS: Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 +/- 0.63 vs. 3.00 +/- 0.46 %; p = 0.013; +/-SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1-4 (2.9 5.3 %), whereas the frequency in the fifth quintile was significantly higher (10.7 %; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. CONCLUSIONS: This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors. PMID- 27462378 TI - Nanoslit design for ion conductivity gradient enhanced dielectrophoresis for ultrafast biomarker enrichment in physiological media. AB - Selective and rapid enrichment of biomolecules is of great interest for biomarker discovery, protein crystallization, and in biosensing for speeding assay kinetics and reducing signal interferences. The current state of the art is based on DC electrokinetics, wherein localized ion depletion at the microchannel to nanochannel interface is used to enhance electric fields, and the resulting biomarker electromigration is balanced against electro-osmosis in the microchannel to cause high degrees of biomarker enrichment. However, biomarker enrichment is not selective, and the levels fall off within physiological media of high conductivity, due to a reduction in ion concentration polarization and electro-osmosis effects. Herein, we present a methodology for coupling AC electrokinetics with ion concentration polarization effects in nanoslits under DC fields, for enabling ultrafast biomarker enrichment in physiological media. Using AC fields at the critical frequency necessary for negative dielectrophoresis of the biomarker of interest, along with a critical offset DC field to create proximal ion accumulation and depletion regions along the perm-selective region inside a nanoslit, we enhance the localized field and field gradient to enable biomarker enrichment over a wide spatial extent along the nanoslit length. While enrichment under DC electrokinetics relies solely on ion depletion to enhance fields, this AC electrokinetic mechanism utilizes ion depletion as well as ion accumulation regions to enhance the field and its gradient. Hence, biomarker enrichment continues to be substantial in spite of the steady drop in nanostructure perm-selectivity within physiological media. PMID- 27462379 TI - Paper-based diagnostic devices for clinical paraquat poisoning diagnosis. AB - This article unveils the development of a paper-based analytical device designed to rapidly detect and clinically diagnose paraquat (PQ) poisoning. Using wax printing technology, we fabricated a PQ detection device by pattering hydrophobic boundaries on paper. This PQ detection device employs a colorimetric sodium dithionite assay or an ascorbic acid assay to indicate the PQ level in a buffer system or in a human serum system in 10 min. In this test, colorimetric changes, blue in color, were observable with the naked eye. By curve fitting models of sodium dithionite and ascorbic acid assays in normal human serum, we evaluated serum PQ levels for five PQ-poisoned patients before hemoperfusion (HP) treatment and one PQ-poisoned patient after HP treatment. As evidenced by similar detection outcomes, the analytical performance of our device can compete with that of the highest clinical standard, i.e., spectrophotometry, with less complicated sample preparation and with more rapid results. Accordingly, we believe that our rapid PQ detection can benefit physicians determining timely treatment strategies for PQ-poisoned patients once they are taken to hospitals, and that this approach will increase survival rates. PMID- 27462380 TI - Acoustofluidic harvesting of microalgae on a single chip. AB - We present an on-chip acoustofluidic platform for harvesting a target microalgal species from a heterogeneous population of cells and particles based on their size, density, and compressibility in a rapid, non-invasive, energy-efficient, continuously running, and automated manner. For our proof-of-principle demonstration, we use Euglena gracilis as a target species. Specifically, we show the simultaneous separation and enrichment of E. gracilis from a mixed population of E. gracilis in pond water (consisting of other microalgae and various kinds of particles as contaminants) on a single acoustofluidic chip with a recovery ratio of 92.6%, a target separation ratio of 90.1%, a concentration factor of 3.43, an enrichment factor of 12.76, and a cell viability rate of 98.3% at a high volume rate of 500 MUl/min. Our results indicate that the on-chip acoustofluidic platform is an effective tool for harvesting target microalgae from mixed populations of microalgae and other contaminants. PMID- 27462381 TI - Spatial selective manipulation of microbubbles by tunable surface acoustic waves. AB - A microfluidic device based on a pair of slant-finger interdigital transducers (SFITs) is developed to achieve a selective and flexible manipulation of microbubbles (MBs) by surface acoustic waves (SAWs). The resonance frequency of SAWs generated by the SFITs depends on the location of its parallel pathway; the particles at different locations of the SAWs' pathway can be controlled selectively by choosing the frequency of the excitation signal applied on the SFITs. By adjusting the input signal continuously, MBs can be transported along the acoustic aperture precisely. The displacement of MBs has a linear relationship with the frequency shift. The resolution of transportation is 15.19 +/- 2.65 MUm when the shift of input signal frequency is at a step of 10 kHz. In addition, the MBs can be controlled in a two-dimensional plane by combining variations of the frequency and the relative phase of the excitation signal applied on the SFITs simultaneously. This technology may open up the possibility of selectively and flexibly manipulating MBs using a simple one-dimensional device. PMID- 27462382 TI - Simple microfluidic stagnation point flow geometries. AB - A geometrically simple flow cell is proposed to generate different types of stagnation flows, using a separation flow and small variations of the geometric parameters. Flows with high local deformation rates can be changed from purely rotational, over simple shear flow, to extensional flow in a region surrounding a stagnation point. Computational fluid dynamic calculations are used to analyse how variations of the geometrical parameters affect the flow field. These numerical calculations are compared to the experimentally obtained streamlines of different designs, which have been determined by high speed confocal microscopy. As the flow type is dictated predominantly by the geometrical parameters, such simple separating flow devices may alleviate the requirements for flow control, while offering good stability for a wide variety of flow types. PMID- 27462383 TI - Evaluation of a Prototype Hybrid Vacuum Pump to Provide Vacuum-Assisted Suspension for Above-Knee Prostheses. AB - Vacuum-assisted suspension (VAS) of prosthetic sockets utilizes a pump to evacuate air from between the prosthetic liner and socket, and are available as mechanical or electric systems. This technical note describes a hybrid pump that benefits from the advantages of mechanical and electric systems, and evaluates a prototype as proof-of-concept. Cyclical bench testing of the hybrid pump mechanical system was performed using a materials testing system to assess the relationship between compression cycles and vacuum pressure. Phase 1 in vivo testing of the hybrid pump was performed by an able-bodied individual using prosthesis simulator boots walking on a treadmill, and phase 2 involved an above knee prosthesis user walking with the hybrid pump and a commercial electric pump for comparison. Bench testing of 300 compression cycles produced a maximum vacuum of 24 in-Hg. In vivo testing demonstrated that the hybrid pump continued to pull vacuum during walking, and as opposed to the commercial electric pump, did not require reactivation of the electric system during phase 2 testing. The novelty of the hybrid pump is that while the electric system provides rapid, initial vacuum suspension, the mechanical system provides continuous air evacuation while walking to maintain suspension without reactivation of the electric system, thereby allowing battery power to be reserved for monitoring vacuum levels. PMID- 27462384 TI - Status Report from the Scientific Panel on Antibiotic Use in Dermatology of the American Acne and Rosacea Society: Part 1: Antibiotic Prescribing Patterns, Sources of Antibiotic Exposure, Antibiotic Consumption and Emergence of Antibiotic Resistance, Impact of Alterations in Antibiotic Prescribing, and Clinical Sequelae of Antibiotic Use. AB - Oral and topical antibiotics are commonly prescribed in dermatologie practice, often for noninfectious disorders, such as acne vulgaris and rosacea. Concerns related to antibiotic exposure from both medical and nonmedical sources require that clinicians consider in each case why and how antibiotics are being used and to make appropriate adjustments to limit antibiotic exposure whenever possible. This first article of a three-part series discusses prescribing patterns in dermatology, provides an overview of sources of antibiotic exposure, reviews the relative correlations between the magnitude of antibiotic consumption and emergence of antibiotic resistance patterns, evaluates the impact of alterations in antibiotic prescribing, and discusses the potential relevance and clinical sequelae of antibiotic use, with emphasis on how antibiotics are used in dermatology. PMID- 27462385 TI - A Randomized, Double-blind, Placebo-controlled Clinical Trial Evaluating an Oral Anti-aging Skin Care Supplement for Treating Photodamaged Skin. AB - OBJECTIVE: Evaluate an anti-aging skin care supplement on the appearance of photodamaged skin. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. Following a one-month washout period, subjects received two anti-aging skin care formula tablets (total daily dose: marine complex 210mg, vitamin C 54mg, zinc 4mg) or placebo daily for 16 weeks. Subjects were restricted from products/procedures that may affect the condition/appearance of skin, including direct facial sun or tanning bed exposure. PARTICIPANTS utilized a standardized facial cleanser and SPF15 moisturizer. SETTING: Single study center (Texas, United States; June-November 2007). PARTICIPANTS: Healthy women aged 35 to 60 years (mean, 50 years), Fitzpatrick skin type I-IV, modified Glogau type II-III. MEASUREMENTS: Subjects were assessed at Weeks 6, 12, and 16 on clinical grading (0-10 VAS), bioinstrumentation, digital photography, and self-assessments. Analysis of variance with treatment in the model was used for between-group comparisons (alpha P<=0.05). RESULTS: Eighty-two anti-aging skin care formula subjects and 70 placebo subjects completed the study. Significant differences in change from baseline to Week 16 scores were observed for clinical grading of overall facial appearance (0.26; P<0.0001), radiant complexion (0.59; P<0.0001), periocular wrinkles (0.08; P<0.05), visual (0.56; P<0.0001) and tactile (0.48; P<0.0001) roughness, and mottled hyperpigmentation (0.15; P<0.001) favoring the subjects in the anti-aging skin care supplement group. Ultrasound skin density (Week 16) was significantly reduced for placebo versus anti-aging skin care supplement group (-1.4% vs. 0%; P<0.01). Other outcomes were not significant. Mild gastrointestinal symptoms possibly related to the anti-aging skin care supplement (n=1) and placebo (n=2) were observed. CONCLUSION: Women with photodamaged skin receiving anti-aging skin care supplement showed significant improvements in the appearance of facial photodamage. TRIAL REGISTRY: Not applicable. Study precedes FDAAA 801 clinical trial registration and results submission requirements. PMID- 27462386 TI - A Preliminary, Open Label, Single-arm Study of Calcipotriene/Betamethasone Topical Suspension as a Supplement to Non-biologic Systemic Therapy for Psoriasis. AB - BACKGROUND: Calcipotriene/betamethasone topical suspension is a topical therapy that is often used as monotherapy as a first-line treatment for plaque psoriasis. The objective of this preliminary, open label, single arm study was to determine the efficacy of adding a topical suspension to a traditional systemic therapy for psoriasis, either methotrexate or acitretin. METHODS: In this exploratory study, eight patients with chronic plaque psoriasis who were on stable methotrexate or acitretin treatment without clearance were treated with once-daily calcipotriene/betamethasone topical suspension. Subjects completed five study visits over 12 weeks. Primary outcome measure was improvement of two or more points in Investigator Global Assessment. Secondary endpoints included change in Body Surface Area, Dermatology Life Quality Index, and Patient's Global Assessment from baseline to Week 12. RESULTS: Overall, the median decrease in Investigator Global Assessment over 12 weeks was 1.5 points, with 50 percent of subjects experiencing a drop of two or more points in Investigator Global Assessment. All eight subjects had a reduction in Body Surface Area and Patient's Global Assessment. There was a mean decrease in Dermatology Life Quality Index score of 78.9 percent, showing improved patient quality of life. In addition, all patients tolerated the treatment well and 6 of 8 patients had improved satisfaction level with their treatment by the end of the study. CONCLUSION: The topical suspension was effective and well-tolerated in conjunction with stable methotrexate or acitretin treatment in all eight patients in this study. These results support the feasibility of a larger scale study to further investigate the efficacy of these treatment combinations. The trial is registered at ClinicalTrials.gov, number NCT01761019. PMID- 27462387 TI - Cosmetically Induced Disorders of the Nail with Update on Contemporary Nail Manicures. AB - The nail carries a significant cosmetic impact and plays an integral role in the multi-billion dollar salon industry. This review focuses on nail disorders that are induced by nail cosmetics via procedures, equipment, or materials that are intended to beautify or adorn the nail. The authors give specific attention to clinical presentations that are common, novel, and underreported, but may be misdiagnosed easily by the competent dermatologist. They also provide an update on the controversies surrounding contemporary nail cosmetic procedures, such as acrylic and gel manicures. PMID- 27462388 TI - Psoriasiform Sarcoidosis: Collision of Two Entities or Expression of One Common Pathogenesis? AB - BACKGROUND: Psoriasiform lesions are an established, but rare, manifestation of sarcoidosis. Only 0.9 percent of patients with cutaneous sarcoidosis develop this form of the disease. OBSERVATION: The authors present a case of a 61-year-old woman with a history of pulmonary sarcoidosis who presented to their dermatology clinic with thick plaques resembling psoriasis. Biopsy of one of the lesions revealed sarcoidal granulomas in association with psoriasiform changes. CONCLUSION: Psoriasiform lesions are a rare manifestation of sarcoidosis. The authors theorize that the co-expression of TNF-alpha in both entities is a possible explanation of the psoriasiform expression of sarcoidosis. PMID- 27462389 TI - Umbilical hernia in patients with liver cirrhosis: A surgical challenge. AB - Umbilical hernia occurs in 20% of the patients with liver cirrhosis complicated with ascites. Due to the enormous intraabdominal pressure secondary to the ascites, umbilical hernia in these patients has a tendency to enlarge rapidly and to complicate. The treatment of umbilical hernia in these patients is a surgical challenge. Ascites control is the mainstay to reduce hernia recurrence and postoperative complications, such as wound infection, evisceration, ascites drainage, and peritonitis. Intermittent paracentesis, temporary peritoneal dialysis catheter or transjugular intrahepatic portosystemic shunt may be necessary to control ascites. Hernia repair is indicated in patients in whom medical treatment is effective in controlling ascites. Patients who have a good perspective to be transplanted within 3-6 mo, herniorrhaphy should be performed during transplantation. Hernia repair with mesh is associated with lower recurrence rate, but with higher surgical site infection when compared to hernia correction with conventional fascial suture. There is no consensus on the best abdominal wall layer in which the mesh should be placed: Onlay, sublay, or underlay. Many studies have demonstrated several advantages of the laparoscopic umbilical herniorrhaphy in cirrhotic patients compared with open surgical treatment. PMID- 27462390 TI - Chronic haemorrhagic radiation proctitis: A review. AB - Chronic haemorrhagic radiation proctitis (CHRP) is a difficult problem faced by the patients following radiation for pelvic malignancy. There is no standard treatment for this condition, but many methods of treatment are available. The aim of this study was to review the literature to see whether there is an improvement in the available evidence in comparison with previously published systematic reviews in treating patients with CHRP. The PubMed/Medline database and Google Scholar search was selectively searched. Studies, which treated patients with rectal bleeding due to chronic radiation proctitis or CHRP, were included. Seventy studies were finally selected out of which 14 were randomized controlled clinical trials. Though these studies could not be compared, it could be seen that there was an improvement in the methodology of the studies. There was an objective assessment of symptoms, signs and an objective assessment of outcomes. But, still, there were only a few studies that looked into the quality of life following treatment of CHRP. To increase recruitment to trials, a national registry of cases with established late radiation toxicity would facilitate the further improvement of such studies. Some of the conclusions that could be reached based on the available evidence are 4% formalin should be the first line treatment for patients with CHRP. Formalin and argon plasma coagulation (APC) are equally effective, but formalin is better for severe disease. Refractory patients, not responding to formalin or APC, need to be referred for hyperbaric oxygen therapy or surgery. Radio-frequency ablation is a promising modality that needs to be studied further in randomized trials. PMID- 27462391 TI - Early surgery in Crohn's disease a benefit in selected cases. AB - AIM: To compare the outcomes of a cohort of Crohn's disease (CD) patients undergoing early surgery (ES) to those undergoing initial medical therapy (IMT). METHODS: We performed a review of a prospective database CD patients managed at a single tertiary institution. Inclusion criteria were all patients with ileal or ileocolonic CD between 1995-2014. Patients with incomplete data, isolated colonic or perianal CD were excluded. Primary endpoints included the need for, and time to subsequent surgery. Secondary endpoints included the number and duration of hospital admissions, and medical therapy. RESULTS: Forty-two patients underwent ES and 115 underwent IMT. The operative intervention rate at 5 years in the ES group was 14.2% vs IMT 31.3% (HR = 0.41, 95%CI: 0.23-0.72, P = 0.041). The ES group had fewer hospital admissions per patient [median 1 vs 3 (P = 0.012)] and fewer patients required anti-TNF therapy than IMT (33.3% vs 57%, P = 0.003). A subgroup analysis of 62 IMT patients who had undergone surgery were compared to ES patients, and showed similar 5 year (from index surgery) re-operation rates 16.1% vs 14.3%. In this subset, a significant difference was still found in median number of hospital admissions favouring ES, 1 vs 2 (P = 0.002). CONCLUSION: Our data supports other recent studies suggesting that patients with ileocolonic CD may have a more benign disease course if undergoing early surgical intervention, with fewer admissions to hospital and a trend to reduced overall operation rates. PMID- 27462392 TI - Aspirin use for primary prophylaxis: Adverse outcomes in non-variceal upper gastrointestinal bleeding. AB - AIM: To compare outcomes of patients with non-variceal upper gastrointestinal bleeding (NVUGIB) taking aspirin for primary prophylaxis to those not taking it. METHODS: Patients not known to have any vascular disease (coronary artery or cerebrovascular disease) who were admitted to the American University of Beirut Medical Center between 1993 and 2010 with NVUGIB were included. The frequencies of in-hospital mortality, re-bleeding, severe bleeding, need for surgery or embolization, and of a composite outcome defined as the occurrence of any of the 4 bleeding related adverse outcomes were compared between patients receiving aspirin and those on no antithrombotics. We also compared frequency of in hospital complications and length of hospital stay between the two groups. RESULTS: Of 357 eligible patients, 94 were on aspirin and 263 patients were on no antithrombotics (control group). Patients in the aspirin group were older, the mean age was 58 years in controls and 67 years in the aspirin group (P < 0.001). Patients in the aspirin group had significantly more co-morbidities, including diabetes mellitus and hypertension [25 (27%) vs 31 (112%) and 44 (47%) vs 74 (28%) respectively, (P = 0.001)], as well as dyslipidemia [21 (22%) vs 16 (6%), P < 0.0001). Smoking was more frequent in the aspirin group [34 (41%) vs 60 (27%), P = 0.02)]. The frequencies of endoscopic therapy and surgery were similar in both groups. Patients who were on aspirin had lower in-hospital mortality rates (2.1% vs 13.7%, P = 0.002), shorter hospital stay (4.9 d vs 7 d, P = 0.01), and fewer composite outcomes (10.6% vs 24%, P = 0.01). The frequencies of in-hospital complications and re-bleeding were similar in the two groups. CONCLUSION: Patients who present with NVUGIB while receiving aspirin for primary prophylaxis had fewer adverse outcomes. Thus aspirin may have a protective effect beyond its cardiovascular benefits. PMID- 27462393 TI - What operation for recurrent rectal prolapse after previous Delorme's procedure? A practical reality. AB - AIM: To report our experience with perineal repair (Delorme's procedure) of rectal prolapse with particular focus on treatment of the recurrence. METHODS: Clinical records of 40 patients who underwent Delorme's procedure between 2003 and 2014 were reviewed to obtain the following data: Gender; duration of symptoms, length of prolapse, operation time, ASA grade, length of post-operative stay, procedure-related complications, development and treatment of recurrent prolapse. Analysis of post-operative complications, rate and time of recurrence and factors influencing the choice of the procedure for recurrent disease was conducted. Continuous variables were expressed as the median with interquartile range (IQR). Statistical analysis was carried out using the Fisher exact test. RESULTS: Median age at the time of surgery was 76 years (IQR: 71-81.5) and there were 38 females and 2 males. The median duration of symptoms was 6 mo (IQR: 3.5 12) and majority of patients presented electively whereas four patients presented in the emergency department with irreducible rectal prolapse. The median length of prolapse was 5 cm (IQR: 5-7), median operative time was 100 min (IQR: 85-120) and median post-operative stay was 4 d (IQR: 3-6). Approximately 16% of the patients suffered minor complications such as - urinary retention, delayed defaecation and infected haematoma. One patient died constituting post-operative mortality of 2.5%. Median follow-up was 6.5 mo (IQR: 2.15-16). Overall recurrence rate was 28% (n = 12). Recurrence rate for patients undergoing an urgent Delorme's procedure who presented as an emergency was higher (75.0%) compared to those treated electively (20.5%), P value 0.034. Median time interval from surgery to the development of recurrence was 16 mo (IQR: 5-30). There were three patients who developed an early recurrence, within two weeks of the initial procedure. The management of the recurrent prolapse was as follows: No further intervention (n = 1), repeat Delorme's procedure (n = 3), Altemeier's procedure (n = 5) and rectopexy with faecal diversion (n = 3). One patient was lost during follow up. CONCLUSION: Delorme's procedure is a suitable treatment for rectal prolapse due to low morbidity and mortality and acceptable rate of recurrence. The management of the recurrent rectal prolapse is often restricted to the pelvic approach by the same patient-related factors that influenced the choice of the initial operation, i.e., Delorme's procedure. Early recurrence developing within days or weeks often represents a technical failure and may require abdominal rectopexy with faecal diversion. PMID- 27462394 TI - Three-dimensional endoanal ultrasound for diagnosis of perianal fistulas: Reliable and objective technique. AB - AIM: To evaluate accuracy of three-dimensional endoanal ultrasound (3D-EAUS) as compared to 2D-EAUS and physical examination (PE) in diagnosis of perianal fistulas and correlate with intraoperative findings. METHODS: A prospective observational consecutive study was performed with patients included over a two years period. All patients were studied and operated on by the Colorectal Unit surgeons. The inclusion criteria were patients over 18, diagnosed with a criptoglandular perianal fistula. The PE, 2D-EAUS and 3D-EAUS was performed preoperatively by the same colorectal surgeon at the outpatient clinic prior to surgery and the fistula anatomy was defined and they were classified in intersphincteric, high or low transsphincteric, suprasphincteric and extrasphincteric. Special attention was paid to the presence of a secondary tract, the location of the internal opening (IO) and the site of external opening. The results of these different examinations were compared to the intraoperative findings. Data regarding location of the IO, primary tract, secondary tract, and the presence of abscesses or cavities was analysed. RESULTS: Seventy patients with a mean age of 47 years (range 21-77), 51 male were included. Low transsphincteric fistulas were the most frequent type found (33, 47.1%) followed by high transsphincteric (24, 34.3%) and intersphincteric fistulas (13, 18.6%). There are no significant differences between the number of IO diagnosed by the different techniques employed and surgery (P > 0.05) and, there is a good concordance between intraoperative findings and the 2D-EAUS (k = 0.67) and 3D-EAUS (k = 0.75) for the diagnosis of the primary tract. The ROC curves for the diagnosis of transsphincteric fistulas show that both ultrasound techniques are adequate for the diagnosis of low transsphincteric fistulas, 3D EAUS is superior for the diagnosis of high transsphincteric fistulas and PE is weak for the diagnosis of both types. CONCLUSION: 3D-EAUS shows a higher accuracy than 2D-EAUS for assessing height of primary tract in transsphincteric fistulas. Both techniques show a good concordance with intraoperative finding for diagnosis of primary tracts. PMID- 27462395 TI - Benefits of post-operative oral protein supplementation in gastrointestinal surgery patients: A systematic review of clinical trials. AB - AIM: To evaluate published trials examining oral post-operative protein supplementation in patients having undergone gastrointestinal surgery and assessment of reported results. METHODS: Database searches (MEDLINE, BIOSIS, EMBASE, Cochrane Trials, Cinahl, and CAB), searches of reference lists of relevant papers, and expert referral were used to identify prospective randomized controlled clinical trials. The following terms were used to locate articles: "oral'' or "enteral'' and "postoperative care'' or "post-surgical'' and "proteins'' or "milk proteins'' or "dietary proteins'' or "dietary supplements'' or "nutritional supplements''. In databases that allowed added limitations, results were limited to clinical trials that studied humans, and publications between 1990 and 2014. Quality of collated studies was evaluated using a qualitative assessment tool and the collective results interpreted. RESULTS: Searches identified 629 papers of which, following review, 7 were deemed eligible for qualitative evaluation. Protein supplementation does not appear to affect mortality but does reduce weight loss, and improve nutritional status. Reduction in grip strength deterioration was observed in a majority of studies, and approximately half of the studies described reduced complication rates. No changes in duration of hospital stay or plasma protein levels were reported. There is evidence to suggest that protein supplementation should be routinely provided post-operatively to this population. However, despite comprehensive searches, clinical trials that varied only the amount of protein provided via oral nutritional supplements (discrete from other nutritional components) were not found. At present, there is some evidence to support routinely prescribed oral nutritional supplements that contain protein for gastrointestinal surgery patients in the immediate post-operative stage. CONCLUSION: The optimal level of protein supplementation required to maximise recovery in gastrointestinal surgery patients is effectively unknown, and may warrant further study. PMID- 27462396 TI - Short-term outcomes after laparoscopic colorectal surgery in patients with previous abdominal surgery: A systematic review. AB - AIM: To perform a systematic review focusing on short-term outcomes after colorectal surgery in patients with previous abdominal open surgery (PAOS). METHODS: A broad literature search was performed with the terms "colorectal", "colectomy", "PAOS", "previous surgery" and "PAOS". Studies were included if their topic was laparoscopic colorectal surgery in patients with PAOS, whether descriptive or comparative. Endpoints of interest were conversion rates, inadvertent enterotomy and morbidity. Analysis of articles was made according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: From a total of 394 citations, 13 full-texts achieved selection criteria to be included in the study. Twelve of them compared patients with and without PAOS. All studies were retrospective and comparative and two were case-matched. The selected studies comprised a total of 5005 patients, 1865 with PAOS. Among the later, only 294 (16%) had history of a midline incision for previous gastrointestinal surgery. Conversion rates were significantly higher in 3 of 12 studies and inadvertent enterotomy during laparoscopy was more prevalent in 3 of 5 studies that disclosed this event. Morbidity was similar in the majority of studies. A quantitative analysis (meta-analysis) could not be performed due to heterogeneity of the studies. CONCLUSION: Conversion rates were slightly higher in PAOS groups, although not statistical significant in most studies. History of PAOS did not implicate in higher morbidity rates. PMID- 27462397 TI - Erratum: Health Blief Model-based intervention to improve nutritional behavior among elderly women. AB - [This corrects the article on p. 352 in vol. 10, PMID: 27247733.]. PMID- 27462399 TI - Erratum to: Neurocritical care update. AB - [This corrects the article DOI: 10.1186/s40560-016-0141-8.]. PMID- 27462398 TI - ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments. AB - BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti cancer agents has not been elucidated yet. METHODS: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. RESULTS: Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression. CONCLUSIONS: Anti-ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients. PMID- 27462400 TI - Ferumoxytol versus iron sucrose treatment: a post-hoc analysis of randomized controlled trials in patients with varying renal function and iron deficiency anemia. AB - BACKGROUND: Iron deficiency anemia is highly prevalent in patients with chronic kidney disease and is often treated with intravenous iron. There are few trials directly comparing the safety and efficacy of different intravenous iron products. METHODS: This post-hoc analysis pooled data from 767 patients enrolled in two randomized, controlled, open-label trials of similar design comparing the treatment of iron deficiency anemia with ferumoxytol and iron sucrose across patients with all stages of renal function. One trial was conducted in adults with CKD either on or not on dialysis and the second in adults with IDA of any underlying cause and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used who had normal to no worse than moderately impaired renal function. Patients were categorized by chronic kidney disease stage (i.e., estimated glomerular filtration rate), and the primary efficacy endpoint was the mean change in hemoglobin from Baseline to Week 5. RESULTS: The overall incidence of adverse events was numerically lower in ferumoxytol-treated patients compared to those treated with iron sucrose (42.4 vs. 50.2 %, respectively); the incidence of treatment-related adverse events was generally similar between the two treatment groups (13.6 vs. 16.0 %, respectively). Adverse events of Special Interest (i.e., hypotension, hypersensitivity) occurred at lower rates in those treated with ferumoxytol compared to those treated with iron sucrose (2.5 vs. 5.3 %, respectively). Overall, mean hemoglobin increased in both treatment groups, regardless of degree of renal insufficiency, although greater increases were seen among those with less severe kidney damage. Mean increases in hemoglobin from Baseline to Week 5 were significantly greater with ferumoxytol than with iron sucrose treatment in the subgroup with an estimated glomerular filtration rate >=90 mL/min (Least Squares mean difference = 0.53 g/dL; p < 0.001). There were no other consistent, significant differences in hemoglobin levels between treatment groups for the other chronic kidney disease categories except for isolated instances favoring ferumoxytol. CONCLUSIONS: The efficacy and safety of ferumoxytol is at least comparable to iron sucrose in patients with varying degrees of renal function. TRIAL REGISTRATION: (CKD-201; ClinicalTrials.gov identifier: NCT01052779; registered 15 January, 2010), (IDA-302; ClinicalTrials.gov identifier: NCT01114204; registered 29 April, 2010). PMID- 27462401 TI - Bovine colostrum supplementation and upper respiratory symptoms during exercise training: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: Bovine colostrum is proposed as a nutritional countermeasure to the risk of upper respiratory symptoms (URS) during exercise training. The aim of this systematic review and meta-analysis was to estimate the size of the effect of bovine colostrum supplementation on URS. METHODS: Databases (CDSR, CENTRAL, Cinahl, ClinicalTrials.gov, Current Controlled Trials, DARE, EMBASE, Medline, PROSPERO and Web of Science) of published, unpublished and ongoing studies were searched for randomised controlled trials of healthy adults (>=18 years), evaluating the effect of oral bovine colostrum supplementation compared to a concurrent control group on URS. RESULTS: Five trials (152 participants) met the inclusion criteria, all of which involved individuals involved in regular exercise training. Over an 8-12 week follow-up period, bovine colostrum supplementation when compared to placebo significantly reduced the incidence rate of URS days (rate ratio 0.56, 95 % confidence intervals 0.43 to 0.72, P value < 0.001) and URS episodes (0.62, 0.40 to 0.99, P value = 0.04) by 44 and 38 % respectively. There were limited data and considerable variation in results of included studies for duration of URS episodes hence a meta-analysis of this outcome was deemed inappropriate. The risk of bias assessment in this review was hindered by poor reporting practices of included studies. Due to incomplete reporting of study methods, four of the five studies were judged to have a moderate or high risk of overall bias. Our findings must be interpreted in relation to quantity and quality of the available evidence. CONCLUSIONS: The present systematic review and meta-analysis provides evidence that bovine colostrum supplementation may be effective in preventing the incidence of URS days and episodes in adults engaged in exercise training. The fact that the majority of included studies did not report significant effects on URS outcomes mitigates concerns about publication bias. The point estimates of the random effects meta-analyses are greater than the smallest clinically important difference, but the low precision of the individual study estimates means the evidence presented in this review needs to be followed up with an appropriately designed and adequately powered, randomised control trial. TRIAL REGISTRATION: Protocol was registered (CRD42015014925) on the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO/). PMID- 27462402 TI - One-Pot synthesis, characterization and adsorption studies of amine functionalized magnetite nanoparticles for removal of Cr (VI) and Ni (II) ions from aqueous solution: kinetic, isotherm and thermodynamic studies. AB - BACKGROUND: Discharge of heavy metals such as hexavalent chromium (Cr (VI)) and nickel (Ni (II)) into aquatic ecosystems is a matter of concern in wastewater treatment due to their harmful effects on humans. In this paper, removal of Cr (VI) and Ni (II) ions from aqueous solution was investigated using an amino functionalized magnetic Nano-adsorbent (Fe3O4-NH2). METHODS: An amino functionalized magnetic Nano-adsorbent (Fe3O4-NH2) was synthesized by compositing Fe3O4 with 1, 6-hexanediamine for removal of Cr (VI) and Ni (II) ions from aqueous solution. The adsorbent was characterized by Scanning Electron Microscope (SEM), Transmission Electron Microscopy (TEM), powder X-Ray Diffraction (XRD), and Vibrating Sample Magnetometry (VSM). Also, the effects of various operational parameters were studied. RESULTS: According to our finding, Fe3O4-NH2 could be simply separated from aqueous solution with an external magnetic field at 30 s. The experimental data for the adsorption of Cr (VI) and Ni (II) ions revealed that the process followed the Langmuir isotherm and the maximum adsorption capacity was 232.51 mg g(-1) for Cr (VI) at pH = 3 and 222.12 mg g(-1) and for Ni(II) at pH = 6 at 298 degrees K. Besides, the kinetic data indicated that the results fitted with the pseudo-second-order model (R(2): 0.9871 and 0.9947 % for Cr (VI) and Ni (II), respectively. The results of thermodynamic study indicated that: standard free energy changes (DeltaG(o)), standard enthalpy change (DeltaH(o)), and standard entropy change (DeltaS(o)) were respectively -3.28, 137.1, and 26.91 kJ mol(-1) for Cr (VI) and -6.8433, 116.7, and 31.02 kJ mol(-1) for Ni (II). The adsorption/desorption cycles of Fe3O4-NH2 indicated that it could be used for five times. CONCLUSIONS: The selected metals' sorption was achieved mainly via electrostatic attraction and coordination interactions. In fact, Fe3O4-NH2 could be removed more than 96 % for both Cr (VI) and Ni (II) ions from aqueous solution and actual wastewater. PMID- 27462403 TI - Adipocyte nuclei captured from VAT and SAT. AB - BACKGROUND: Obesity-related comorbidities are thought to result from the reprogramming of the epigenome in numerous tissues and cell types, and in particular, mature adipocytes within visceral and subcutaneous adipose tissue, VAT and SAT. The cell-type specific chromatin remodeling of mature adipocytes within VAT and SAT is poorly understood, in part, because of the difficulties of isolating and manipulating large fragile mature adipocyte cells from adipose tissues. METHODS: We constructed MA-INTACT (Mature Adipocyte-Isolation of Nuclei TAgged in specific Cell Types) mice using the adiponectin (ADIPOQ) promoter (ADNp) to tag the surface of mature adipocyte nuclei with a reporter protein. The SUN1mRFP1Flag reporter is comprised of a fragment of the nuclear transmembrane protein SUN1, the fluorescent protein mRFP1, and three copies of the Flag epitope tag. RESULTS: Mature adipocyte nuclei were rapidly and efficiently immuno captured from VAT and SAT (MVA and MSA nuclei, respectively), of MA-INTACT mice. MVA and MSA nuclei contained 1,000 to 10,000-fold higher levels of adipocyte specific transcripts, ADIPOQ, PPARg2, EDNRB, and LEP, relative to uncaptured nuclei, while the latter expressed higher levels of leukocyte and endothelial cell markers IKZF1, RETN, SERPINF1, SERPINE1, ILF3, and TNFA. MVA and MSA nuclei differentially expressed several factors linked to adipogenesis or obesity related health risks including CEBPA, KLF2, RETN, SERPINE1, and TNFA. The various nuclear populations dramatically differentially expressed transcripts encoding chromatin remodeler proteins regulating DNA cytosine methylation and hydroxymethylation (TETs, DNMTs, TDG, GADD45s) and nucleosomal histone modification (ARID1A, KAT2B, KDM4A, PRMT1, PRMT5, PAXIP1). Remarkably, MSA and MVA nuclei expressed 200 to 1000-fold higher levels of thermogenic marker transcripts PRDM16 and UCP1. CONCLUSIONS: The MA-INTACT mouse enables a simple way to perform cell-type specific analysis of highly purified mature adipocyte nuclei from VAT and SAT and increases the statistical significance of data collected on adipocytes. Isolated VAT and SAT adipocyte nuclei expressed distinct patterns of transcripts encoding chromatin remodeling factors and proteins relevant to diabetes, cardiovascular disease, and thermogenesis. The MA-INTACT mouse is an useful model to test the impact of caloric intake, dietary nutrients, exercise, and pharmaceuticals on the epigenome-induced health risks of obesity. PMID- 27462404 TI - A novel role for synaptic acetylcholinesterase as an apoptotic deoxyribonuclease. AB - In addition to terminating neurotransmission by hydrolyzing acetylcholine, synaptic acetylcholinesterase (AChES) has been found to have a pro-apoptotic role. However, the underlying mechanism has rarely been investigated. Here, we report a nuclear translocation-dependent role for AChES as an apoptotic deoxyribonuclease (DNase). AChES polypeptide binds to and cleaves naked DNA at physiological pH in a Ca(2+)-Mg(2+)-dependent manner. It also cleaves chromosomal DNA both in pre-fixed and in apoptotic cells. In the presence of a pan-caspase inhibitor, the cleavage still occurred after nuclear translocation of AChES, implying that AChES-DNase acts in a CAD- and EndoG-independent manner. AChE gene knockout impairs apoptotic DNA cleavage; this impairment is rescued by overexpression of the wild-type but not (aa 32-138)-deleted AChES. Furthermore, in comparison with the nuclear-localized wild-type AChES, (aa 32-138)-deleted AChES loses the capacity to initiate apoptosis. These observations confirm that AChES mediates apoptosis via its DNase activity. PMID- 27462405 TI - High-yield production of extracellular type-I cellulose by the cyanobacterium Synechococcus sp. PCC 7002. AB - Cellulose synthase, encoded by the cesA gene, is responsible for the synthesis of cellulose in nature. We show that the cell wall of the cyanobacterium Synechococcus sp. PCC 7002 naturally contains cellulose. Cellulose occurs as a possibly laminated layer between the inner and outer membrane, as well as being an important component of the extracellular glycocalyx in this cyanobacterium. Overexpression of six genes, cmc-ccp-cesAB-cesC-cesD-bgl, from Gluconacetobacter xylinus in Synechococcus sp. PCC 7002 resulted in very high-yield production of extracellular type-I cellulose. High-level cellulose production only occurred when the native cesA gene was inactivated and when cells were grown at low salinity. This system provides a method for the production of lignin-free cellulose from sunlight and CO2 for biofuel production and other biotechnological applications. PMID- 27462406 TI - Modulation of tumorigenesis by the pro-inflammatory microRNA miR-301a in mouse models of lung cancer and colorectal cancer. AB - Lung cancer and colorectal cancer account for over one-third of all cancer deaths in the United States. MicroRNA-301a (miR-301a) is an activator of both nuclear factor-kappaB (NF-kappaB) and Stat3, and is overexpressed in both deadly malignancies. In this work, we show that genetic ablation of miR-301a reduces Kras-driven lung tumorigenesis in mice. And miR-301a deficiency protects animals from dextran sodium sulfate-induced colon inflammation and colitis-associated colon carcinogenesis. We also demonstrate that miR-301a deletion in bone marrow derived cells attenuates tumor growth in the colon carcinogenesis model. Our findings ascertain that one microRNA-miR-301a-activates two major inflammatory pathways (NF-kappaB and Stat3) in vivo, generating a pro-inflammatory microenvironment that facilitates tumorigenesis. PMID- 27462407 TI - Gut-neuron interaction via Hh signaling regulates intestinal progenitor cell differentiation in Drosophila. AB - Intestinal homeostasis is maintained by intestinal stem cells (ISCs) and their progenies. A complex autonomic nervous system spreads over posterior intestine. However, whether and how neurons regulate posterior intestinal homeostasis is largely unknown. Here we report that neurons regulate Drosophila posterior intestinal homeostasis. Specifically, downregulation of neuronal Hedgehog (Hh) signaling inhibits the differentiation of ISCs toward enterocytes (ECs), whereas upregulated neuronal Hh signaling promotes such process. We demonstrate that, among multiple sources of Hh ligand, those secreted by ECs induces similar phenotypes as does neuronal Hh. In addition, intestinal JAK/STAT signaling responds to activated neuronal Hh signaling, suggesting that JAK/STAT signaling acts downstream of neuronal Hh signaling in intestine. Collectively, our results indicate that neuronal Hh signaling is essential for the determination of ISC fate. PMID- 27462408 TI - Efficient genome editing in filamentous fungus Trichoderma reesei using the CRISPR/Cas9 system. AB - Filamentous fungi have wide applications in biotechnology. The CRISPR/Cas9 system is a powerful genome-editing method that facilitates genetic alterations of genomes in a variety of organisms. However, a genome-editing approach has not been reported in filamentous fungi. Here, we demonstrated the establishment of a CRISPR/Cas9 system in the filamentous fungus Trichoderma reesei by specific codon optimization and in vitro RNA transcription. It was shown that the CRISPR/Cas9 system was controllable and conditional through inducible Cas9 expression. This system generated site-specific mutations in target genes through efficient homologous recombination, even using short homology arms. This system also provided an applicable and promising approach to targeting multiple genes simultaneously. Our results illustrate that the CRISPR/Cas9 system is a powerful genome-manipulating tool for T. reesei and most likely for other filamentous fungal species, which may accelerate studies on functional genomics and strain improvement in these filamentous fungi. PMID- 27462410 TI - Cell Discovery: A new publishing experience. PMID- 27462409 TI - The PRC2-associated factor C17orf96 is a novel CpG island regulator in mouse ES cells. AB - CpG islands (CGIs) are key DNA regulatory elements in the vertebrate genome and are often found at gene promoters. In mammalian embryonic stem (ES) cells, CGIs are decorated by either the active or repressive histone marks, H3K4me3 and H3K27me3, respectively, or by both modifications ('bivalent domains'), but their precise regulation is incompletely understood. Remarkably, we find that the polycomb repressive complex 2 (PRC2)-associated protein C17orf96 (a.k.a. esPRC2p48 and E130012A19Rik) is present at most CGIs in mouse ES cells. At PRC2 rich CGIs, loss of C17orf96 results in an increased chromatin binding of Suz12 and elevated H3K27me3 levels concomitant with gene repression. In contrast, at PRC2-poor CGIs, located at actively transcribed genes, C17orf96 colocalizes with RNA polymerase II and its depletion leads to a focusing of H3K4me3 in the core of CGIs. Our findings thus identify C17orf96 as a novel context-dependent CGI regulator. PMID- 27462411 TI - Cytosine methylation of tRNA-Asp by DNMT2 has a role in translation of proteins containing poly-Asp sequences. AB - The Dnmt2 RNA methyltransferase catalyses the methylation of C38 in the anticodon loop of tRNA-Asp, but the molecular role of this methylation is unknown. Here, we report that mouse aspartyl-tRNA synthetase shows a four to fivefold preference for C38-methylated tRNA-Asp. Consistently, a 30% reduced charging level of tRNA Asp was observed in Dnmt2 knockout (KO) murine embryonic fibroblast cells. Gene expression analysis with fluorescent reporter proteins fused to an N-terminal poly-Asp sequence showed that protein synthesis of poly-Asp-tagged reporter proteins was reduced in Dnmt2 KO cells as well. The same effect was observed with endogenous proteins containing poly-Asp sequences, indicating that Dnmt2-mediated C38 methylation of tRNA-Asp regulates the translation of proteins containing poly Asp sequences. Gene ontology searches for proteins containing poly-Asp sequences in the human proteome showed that a significant number of these proteins have roles in transcriptional regulation and gene expression. Hence, the Dnmt2 mediated methylation of tRNA-Asp exhibits a post-transcriptional regulatory role by controlling the synthesis of a group of target proteins containing poly-Asp sequences. PMID- 27462412 TI - Autologous iPSC-derived dopamine neuron transplantation in a nonhuman primate Parkinson's disease model. AB - Autologous dopamine (DA) neurons are a new cell source for replacement therapy of Parkinson's disease (PD). In this study, we tested the safety and efficacy of autologous induced pluripotent stem cell (iPSC)-derived DA cells for treatment of a cynomolgus monkey PD model. Monkey bone marrow mesenchymal cells were isolated and induced to iPSCs, followed by differentiation into DA cells using a method with high efficiency. Autologous DA cells were introduced into the brain of a cynomolgus monkey PD model without immunosuppression; three PD monkeys that had received no grafts served as controls. The PD monkey that had received autologous grafts experienced behavioral improvement compared with that of controls. Histological analysis revealed no overgrowth of grafts and a significant number of surviving A9 region-specific graft-derived DA neurons. The study provided a proof-of-principle to employ iPSC-derived autologous DA cells for PD treatment using a nonhuman primate PD model. PMID- 27462413 TI - Pyridoxamine is a substrate of the energy-coupling factor transporter HmpT. AB - Energy-coupling factor (ECF) transporters belong to a novel family of proteins that forms a subset within the ATP-binding cassette (ABC) transporter family. These proteins are responsible for the uptake of micronutrients in bacteria. ECF transporters are composed of four proteins: the A- and A'-components, the T component and the S-component. One of the ECF transporters, named HmpT, was crystallized in the apo form with all four components. It is currently unknown whether HmpT serves as a transporter for hydroxymethyl pyrimidine or the different forms of vitamin B6 (pyridoxine, pyridoxal or pyridoxamine). Using a combination of molecular dynamics (MD) simulations and mass spectrometry, we have identified pyridoxamine to be the preferred substrate of HmpT. Mass spectra show that the mass of the substrate from the HmpT-substrate complex matches that of pyridoxamine. MD simulations likewise indicate that pyridoxamine interacts most strongly with most of the conserved residues of the S-component (Glu 41, His 84 and Gln 43) compared with the other vitamin B6 forms. Furthermore, the simulations have implied that loops 1 and 5 of the S-component can participate in the gating action for HmpT. PMID- 27462414 TI - Immunogenicity and functional evaluation of iPSC-derived organs for transplantation. AB - Whether physiologically induced pluripotent stem cell (iPSC)-derived organs are immunogenic and can be used for transplantation is unclear. Here, we generated iPSC-derived skin, islet, and heart representing three germ layers of the body through 4n complementation and evaluated their immunogenicity and therapeutic efficacy. Upon transplantation into recipient mice, iPSC-derived skin successfully survived and repaired local tissue wounds. In diabetic mouse models, explanted iPSC-derived islets effectively produced insulin and lowered blood glucose to basal levels. iPSC-derived heart grafts maintained normal beating for more than 3 months in syngeneic recipients. Importantly, no obvious immune rejection responses against iPSC-derived organs were detected long after transplantation. Our study not only demonstrates the fundamental immunogenicity and function of iPSC derivatives, but also provides preclinical evidence to support the feasibility of using iPSC-derived skin, islet, and heart for therapeutic use. PMID- 27462415 TI - Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners. AB - The tumor suppressor APC employs its conserved armadillo repeat (ARM) domain to recognize many of its binding partners, including Amer1/WTX, which is mutated in Wilms' tumor and bone overgrowth syndrome. The APC-Amer1 complex has important roles in regulating Wnt signaling and cell adhesion. Three sites A1, A2, and A3 of Amer1 have been reported to mediate its interaction with APC-ARM. In this study, crystal structures of APC-ARM in complexes with Amer1-A1, -A2, and -A4, which is newly identified in this work, were determined. Combined with our GST pull-down, yeast two-hybrid, and isothermal titration calorimetry (ITC) assay results using mutants of APC and Amer1 interface residues, our structures demonstrate that Amer1-A1, -A2, and -A4, as well as other APC-binding proteins such as Asef and Sam68, all employ a common recognition pattern to associate with APC-ARM. In contrast, Amer1-A3 binds to the C-terminal side of APC-ARM through a bipartite interaction mode. Composite mutations on either APC or Amer1 disrupting all four interfaces abrogated their association in cultured cells and impaired the membrane recruitment of APC by Amer1. Our study thus comprehensively elucidated the recognition mechanism between APC and Amer1, and revealed a consensus recognition sequence employed by various APC-ARM binding partners. PMID- 27462416 TI - AF9 promotes hESC neural differentiation through recruiting TET2 to neurodevelopmental gene loci for methylcytosine hydroxylation. AB - AF9 mutations have been implicated in human neurodevelopmental diseases and murine Af9 mediates histone methylation during cortical neuron generation. However, AF9 function and related mechanisms in human neurodevelopment remain unknown. Here we show that AF9 is necessary and sufficient for human embryonic stem cell (hESC) neural differentiation and neurodevelopmental gene activation. The 5-methylcytosine (5mC) dioxygenase TET2, which was identified in an AF9 associated protein complex, physically interacted with AF9. Both AF9 and TET2 co localized in 5-hydroxymethylcytosine (5hmC)-positive hESC-derived neurons and were required for appropriate hESC neural differentiation. Upon binding to AAC containing motifs, AF9 recruited TET2 to occupy the common neurodevelopmental gene loci to direct 5mC-to-5hmC conversion, which was followed by sequential activation of neural target genes and hESC neural commitment. These findings define an AF9-TET2 regulatory complex for modulating human neural development and reveal a novel mechanism by which the AF9 recognition specificity and TET2 hydroxylation activity cooperate to control neurodevelopmental gene activation. PMID- 27462417 TI - ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction. AB - The modular adaptor protein ALIX is critically involved in endosomal sorting complexes required for transport (ESCRT)-mediated multivesicular body (MVB) sorting of activated epidermal growth factor receptor (EGFR); however, ALIX contains a default intramolecular interaction that renders ALIX unable to perform this ESCRT function. The ALIX partner protein ALG-2 is a calcium-binding protein that belongs to the calmodulin superfamily. Prompted by a defined biological function of calmodulin, we determined the role of ALG-2 in regulating ALIX involvement in MVB sorting of activated EGFR. Our results show that calcium dependent ALG-2 interaction with ALIX completely relieves the intramolecular interaction of ALIX and promotes CHMP4-dependent ALIX association with the membrane. EGFR activation induces increased ALG-2 interaction with ALIX, and this increased interaction is responsible for increased ALIX association with the membrane. Functionally, inhibition of ALIX activation by ALG-2 inhibits MVB sorting of activated EGFR as effectively as inhibition of ALIX interaction with CHMP4 does; however, inhibition of ALIX activation by ALG-2 does not affect cytokinetic abscission or equine infectious anemia virus (EIAV) budding. These findings indicate that calcium-dependent ALG-2 interaction with ALIX is specifically responsible for generating functional ALIX that supports MVB sorting of ubiquitinated membrane receptors. PMID- 27462418 TI - Cell cycle-dependent inhibition of 53BP1 signaling by BRCA1. AB - DNA damage response mediator protein 53BP1 is a key regulator of non-homologous end-joining (NHEJ) repair. 53BP1 protects DNA broken ends from resection by recruiting two downstream factors, RIF1 (RAP1-interacting factor 1) and PTIP (Pax transactivation domain-interacting protein), to double-stranded breaks (DSBs) via ATM (ataxia telangiectasia mutated)-mediated 53BP1 phosphorylation, and competes with BRCA1-mediated homologous recombination (HR) repair in G1 phase. In contrast, BRCA1 antagonizes 53BP1-direct NHEJ repair in S/G2 phases. We and others have found that BRCA1 prevents the translocation of RIF1 to DSBs in S/G2 phases; however, the underlying mechanism remains unclear. Here we show that efficient ATM-dependent 53BP1 phosphorylation is restricted to the G1 phase of the cell cycle, as a consequence RIF1 and PTIP accumulation at DSB sites only occur in G1 phase. Mechanistically, both BRCT and RING domains of BRCA1 are required for the inhibition of 53BP1 phosphorylation in S and G2 phases. Thus, our findings reveal how BRCA1 antagonizes 53BP1 signaling to ensure that HR repair is the dominant repair pathway in S/G2 phases. PMID- 27462419 TI - eIF2 interactions with initiator tRNA and eIF2B are regulated by post translational modifications and conformational dynamics. AB - Translation of messenger RNA (mRNA) into proteins is key to eukaryotic gene expression and begins when initiation factor-2 (eIF2) delivers methionyl initiator tRNA (Met-tRNAi (Met)) to ribosomes. This first step is controlled by eIF2B mediating guanine nucleotide exchange on eIF2. We isolated eIF2 from yeast and used mass spectrometry to study the intact complex, and found that eIF2beta is the most labile of the three subunits (eIF2alpha/beta/gamma). We then compared conformational dynamics of the ternary complex eIF2:GTP:Met-tRNAi (Met) with apo eIF2 using comparative chemical cross-linking. Results revealed high conformational dynamics for eIF2alpha in apo eIF2 while in the ternary complex all three subunits are constrained. Novel post-translational modifications identified here in both eIF2 and eIF2B were combined with established sites, and located within protein sequences and homology models. We found clustering at subunit interfaces and highly phosphorylated unstructured regions, at the N terminus of eIF2beta, and also between the eIF2Bepsilon core and catalytic domains. We propose that modifications of these unstructured regions have a key role in regulating interactions between eIF2 and eIF2B, as well as other eIFs. PMID- 27462420 TI - Targeting the gamma-/beta-secretase interaction reduces beta-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis. AB - Despite decades of intense global effort, no disease-modifying drugs for Alzheimer's disease have emerged. Molecules targeting catalytic activities of gamma-secretase or beta-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and gamma-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress Abeta generation. Through high-throughput screening, we discovered that 3-alpha-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces Abeta production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce Abeta production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and Abeta-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer's disease therapeutics. PMID- 27462421 TI - Uniparental disomy of the entire X chromosome in Turner syndrome patient-specific induced pluripotent stem cells. AB - The human induced pluripotent stem cell (iPSC) technique promises to provide an unlimited, reliable source of genetically matched pluripotent cells for personalized therapy and disease modeling. Recently, it is observed that cells with ring chromosomes 13 or 17 autonomously correct the defects via compensatory uniparental disomy during cellular reprogramming to iPSCs. This breakthrough finding suggests a potential therapeutic approach to repair large-scale chromosomal aberrations. However, due to the scarceness of ring chromosome samples, the reproducibility of this approach in different individuals is not carefully evaluated yet. Moreover, the underlying mechanism and the applicability to other types of chromosomal aberrations remain unknown. Here we generated iPSCs from four 45,X chorionic villous fibroblast lines and found that only one reprogrammed line acquired 46,XX karyotype via uniparental disomy of the entire X chromosome. The karyotype correction was reproducible in the same cell line by either retroviral or episomal reprogramming. The karyotype-corrected iPSCs were subject to X chromosome inactivation and obtained better colony morphology and higher proliferation rate than other uncorrected ones. Further transcriptomic comparison among the fibroblast lines identified a distinct expression pattern of cell cycle regulators in the uncorrectable ones. These findings demonstrate that the iPSC technique holds the potential to correct X monosomy, but the correction rate is very low, probably due to differential regulation of cell cycle genes between individuals. Our data strongly suggest that more systematic investigations are needed before defining the iPSC technique as a novel means of chromosome therapy. PMID- 27462422 TI - Selected SNARE proteins are essential for the polarized membrane insertion of igf 1 receptor and the regulation of initial axonal outgrowth in neurons. AB - The establishment of polarity necessitates initial axonal outgrowth and, therefore, the addition of new membrane to the axon's plasmalemma. Axolemmal expansion occurs by exocytosis of plasmalemmal precursor vesicles (PPVs) primarily at the neuronal growth cone. Little is known about the SNAREs family proteins involved in the regulation of PPV fusion with the neuronal plasmalemma at early stages of differentiation. We show here that five SNARE proteins (VAMP2, VAMP4, VAMP7, Syntaxin6 and SNAP23) were expressed by hippocampal pyramidal neurons before polarization. Expression silencing of three of these proteins (VAMP4, Syntaxin6 and SNAP23) repressed axonal outgrowth and the establishment of neuronal polarity, by inhibiting IGF-1 receptor exocytotic polarized insertion, necessary for neuronal polarization. In addition, stimulation with IGF-1 triggered the association of VAMP4, Syntaxin6 and SNAP23 to vesicular structures carrying the IGF-1 receptor and overexpression of a negative dominant form of Syntaxin6 significantly inhibited exocytosis of IGF-1 receptor containing vesicles at the neuronal growth cone. Taken together, our results indicated that VAMP4, Syntaxin6 and SNAP23 functions are essential for regulation of PPV exocytosis and the polarized insertion of IGF-1 receptor and, therefore, required for initial axonal elongation and the establishment of neuronal polarity. PMID- 27462423 TI - A novel ER-microtubule-binding protein, ERLIN2, stabilizes Cyclin B1 and regulates cell cycle progression. AB - The gene encoding endoplasmic reticulum (ER) lipid raft-associated protein 2 (ERLIN2) is amplified in human breast cancers. ERLIN2 gene mutations were also found to be associated with human childhood progressive motor neuron diseases. Yet, an understanding of the physiological function and mechanism for ERLIN2 remains elusive. In this study, we reveal that ERLIN2 is a spatially and temporally regulated ER-microtubule-binding protein that has an important role in cell cycle progression by interacting with and stabilizing the mitosis-promoting factors. Whereas ERLIN2 is highly expressed in aggressive human breast cancers, during normal development ERLIN2 is expressed at the postnatal stage and becomes undetectable in adulthood. ERLIN2 interacts with the microtubule component alpha tubulin, and this interaction is maximal during the cell cycle G2/M phase where ERLIN2 simultaneously interacts with the mitosis-promoting complex Cyclin B1/Cdk1. ERLIN2 facilitates K63-linked ubiquitination and stabilization of Cyclin B1 protein in G2/M phase. Downregulation of ERLIN2 results in cell cycle arrest, represses breast cancer proliferation and malignancy and increases sensitivity of breast cancer cells to anticancer drugs. In summary, our study revealed a novel ER-microtubule-binding protein, ERLIN2, which interacts with and stabilizes mitosis-promoting factors to regulate cell cycle progression associated with human breast cancer malignancy. PMID- 27462424 TI - Senataxin controls meiotic silencing through ATR activation and chromatin remodeling. AB - Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA-DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3 related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx (-/-) pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration. PMID- 27462425 TI - EZH2 promotes progression of small cell lung cancer by suppressing the TGF-beta Smad-ASCL1 pathway. AB - Transforming growth factor-beta (TGF-beta) induces apoptosis in many types of cancer cells and acts as a tumor suppressor. We performed a functional analysis of TGF-beta signaling to identify a molecular mechanism that regulated survival in small cell lung cancer cells. Here, we found low expression of TGF-beta type II receptor (TbetaRII) in most small cell lung cancer cells and tissues compared to normal lung epithelial cells and normal lung tissues, respectively. When wild type TbetaRII was overexpressed in small cell lung cancer cells, TGF-beta suppressed cell growth in vitro and tumor formation in vivo through induction of apoptosis. Components of polycomb repressive complex 2, including enhancer of zeste 2 (EZH2), were highly expressed in small cell lung cancer cells; this led to epigenetic silencing of TbetaRII expression and suppression of TGF-beta mediated apoptosis. Achaete-scute family bHLH transcription factor 1 (ASCL1; also known as ASH1), a Smad-dependent target of TGF-beta, was found to induce survival in small cell lung cancer cells. Thus, EZH2 promoted small cell lung cancer progression by suppressing the TGF-beta-Smad-ASCL1 pathway. PMID- 27462426 TI - Direct regulation of p53 by miR-142a-3p mediates the survival of hematopoietic stem and progenitor cells in zebrafish. AB - Hematopoietic stem and progenitor cells have the capacity to self-renew and differentiate into all blood cell lineages, and thus sustain life-long homeostasis of the hematopoietic system. Although intensive studies have focused on the orchestrated genetic network of hematopoietic stem and progenitor cell specification and expansion, relatively little is known on the regulation of hematopoietic stem and progenitor cell survival during embryogenesis. Here, we generated two types of miR-142a-3p genetic mutants in zebrafish and showed that the loss-of-function mutants displayed severe reduction of hematopoietic stem and progenitor cells. Further analysis showed that the diminished proliferation and excessive apoptosis in miR-142a-3p mutants were attributed to the increased p53 signaling. Mechanistically, we demonstrated that miR-142a-3p directly targets p53 during hematopoietic stem and progenitor cell development, and the hematopoietic stem and progenitor cell survival defect in miR-142a-3p mutants could be rescued by loss of p53. Therefore, our work reveals the significance of the miR-142a-3p p53 pathway in controlling hematopoietic stem and progenitor cell survival, and thus advances our understanding of the role of p53 in vertebrate hematopoiesis. PMID- 27462427 TI - RNAi pathway participates in chromosome segregation in mammalian cells. AB - The RNAi machinery is a mighty regulator in a myriad of life events. Despite lines of evidence that small RNAs and components of the RNAi pathway may be associated with structure and behavior of mitotic chromosomes in diverse organisms, a direct role of the RNAi pathway in mammalian mitotic chromosome segregation remains elusive. Here we report that Dicer and AGO2, two central components of the mammalian RNAi pathway, participate in the chromosome segregation. Knockdown of Dicer or AGO2 results in a higher incidence of chromosome lagging, and this effect is independent from microRNAs as examined with DGCR8 knockout cells. Further investigation has revealed that alpha satellite RNA, a noncoding RNA derived from centromeric repeat region, is managed by AGO2 under the guidance of endogenous small interference RNAs (ASAT siRNAs) generated by Dicer. Furthermore, the slicer activity of AGO2 is essential for the chromosome segregation. Level and distribution of chromosome-associated alpha satellite RNA have crucial regulatory effect on the localization of centromeric proteins such as centromere protein C1 (CENPC1). With these results, we also provide a paradigm in which the RNAi pathway participates in vital cellular events through the maintenance of level and distribution of noncoding RNAs in cells. PMID- 27462428 TI - Increased CD271 expression by the NF-kB pathway promotes melanoma cell survival and drives acquired resistance to BRAF inhibitor vemurafenib. AB - Specific BRAFV600E inhibitors (BRAFi) are highly effective in the treatment of melanoma. However, acquired drug resistances invariably develop after the initial response. Therefore, the identification of new mechanisms of acquired resistance gives important clues towards the development of therapies that could elicit long lasting responses. Here we report that CD271 confers resistance to BRAFi in melanoma cells. The expression of CD271 is increased by BRAFi through a stimulation of tumor necrosis factor-alpha (TNFalpha) secretion that leads to NF kappaB signaling pathway activation. CD271 is upregulated in a subset of BRAFi resistant melanoma cells. The inhibition of TNFalpha/NF-kappaB pathway and CD271 silencing restore the BRAFi sensitivity of resistant melanoma cells. Finally, increase of CD271 expression is validated in BRAFi-resistant xenografts tumors and also in tumors from the patients who relapsed under BRAFi. In summary, these results reveal a novel TNFalpha/NF-kappaB/CD271 axis whose activation contributes to the acquisition of resistance to BRAFi and therefore may represent a novel therapeutic target to improve the efficacy of therapy in melanoma. PMID- 27462429 TI - Rapidly generating knockout mice from H19-Igf2 engineered androgenetic haploid embryonic stem cells. AB - Haploid mammalian embryonic stem cells (ESCs) hold great promise for functional genetic studies and assisted reproduction. Recently, rodent androgenetic haploid ESCs (AG-haESCs) were generated from androgenetic blastocysts and functioned like sperm to produce viable offspring via the intracytoplasmic AG-haESCs injection into oocytes. However, the efficiency of this reproduction was very low. Most pups were growth-retarded and died shortly after birth, which is not practical for producing knockout animals. Further investigation suggested a possible link between the low birthrate and aberrant expression of imprinted genes. Here, we report the high-frequency generation of healthy, fertile mice from H19-Igf2 imprinting-locus modified AG-haESCs, which maintained normal paternal imprinting and pluripotency. Moreover, it is feasible to perform further genetic manipulations in these AG-haESCs. Our study provides a reliable and efficient tool to rapidly produce gene-modified mouse models and will benefit reproductive medicine in the future. PMID- 27462430 TI - Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation. AB - Genetic variations in the human dysbindin-1 gene (DTNBP1) have been associated with schizophrenia. As a result of alternative splicing, the human DTNBP1 gene generates at least three distinct protein isoforms, dysbindin-1A, -1B and -1C. Significant effort has focused on dysbindin-1A, an important player in multiple steps of neurodevelopment. However, the other isoforms, dysbindin-1B and dysbindin-1C have not been well characterized. Nor have been associated with human diseases. Here we report an increase in expression of DTNBP1b mRNA in patients with paranoid schizophrenia as compared with healthy controls. A single nucleotide polymorphism located in intron 9, rs117610176, has been identified and associated with paranoid schizophrenia, and its C allele leads to an increase of DTNBP1b mRNA splicing. Our data show that different dysbindin splicing isoforms exhibit distinct subcellular distribution, suggesting their distinct functional activities. Dysbindin-1B forms aggresomes at the perinuclear region, whereas dysbindin-1A and -1C proteins exhibit diffused patterns in the cytoplasm. Dysbindin-1A interacts with dysbindin-1B, getting recruited to the aggresome structure when co-expressed with dysbindin-1B. Moreover, cortical neurons over expressing dysbindin-1B show reduction in neurite outgrowth, suggesting that dysbindin-1B may interfere with dysbindin-1A function in a dominant-negative manner. Taken together, our study uncovers a previously unknown association of DTNBP1b expression with schizophrenia in addition to its distinct biochemical and functional properties. PMID- 27462431 TI - ER network homeostasis is critical for plant endosome streaming and endocytosis. AB - Eukaryotic cells internalize cargo at the plasma membrane via endocytosis, a vital process that is accomplished through a complex network of endosomal organelles. In mammalian cells, the ER is in close association with endosomes and regulates their fission. Nonetheless, the physiological role of such interaction on endocytosis is yet unexplored. Here, we probed the existence of ER-endosome association in plant cells and assayed its physiological role in endocytosis. Through live-cell imaging and electron microscopy studies, we established that endosomes are extensively associated with the plant ER, supporting conservation of interaction between heterotypic organelles in evolutionarily distant kingdoms. Furthermore, by analyzing ER-endosome dynamics in genetic backgrounds with defects in ER structure and movement, we also established that the ER network integrity is necessary for homeostasis of the distribution and streaming of various endosome populations as well as for efficient endocytosis. These results support a novel model that endocytosis homeostasis depends on a spatiotemporal control of the endosome dynamics dictated by the ER membrane network. PMID- 27462432 TI - A genome-wide IR-induced RAD51 foci RNAi screen identifies CDC73 involved in chromatin remodeling for DNA repair. AB - To identify new regulators of homologous recombination repair, we carried out a genome-wide short-interfering RNA screen combined with ionizing irradiation using RAD51 foci formation as readout. All candidates were confirmed by independent short-interfering RNAs and validated in secondary assays like recombination repair activity and RPA foci formation. Network analysis of the top modifiers identified gene clusters involved in recombination repair as well as components of the ribosome, the proteasome and the spliceosome, which are known to be required for effective DNA repair. We identified and characterized the RNA polymerase II-associated protein CDC73/Parafibromin as a new player in recombination repair and show that it is critical for genomic stability. CDC73 interacts with components of the SCF/Cullin and INO80/NuA4 chromatin-remodeling complexes to promote Histone ubiquitination. Our findings indicate that CDC73 is involved in local chromatin decondensation at sites of DNA damage to promote DNA repair. This function of CDC73 is related to but independent of its role in transcriptional elongation. PMID- 27462433 TI - Identification of putative novel O-glycosylations in the NK killer receptor Ncr1 essential for its activity. AB - Natural killer (NK) cells kill tumor and virus-infected cells using activating NK cell receptors. One of the major NK-activating receptors is NKp46 and its mouse ortholog Ncr1. NKp46/Ncr1 is expressed exclusively on NK cells and on a subset of innate lymphoid cells. NKp46/Ncr1 was shown to be involved in a myriad of pathologies and immunological settings. Specifically, NKp46/Ncr1 was shown to interact with the viral hemagglutinin (HA) protein and with an unknown tumor/cellular ligand. NKp46 and Ncr1 are structurally similar; however, they are substantially different in their glycosylation patterns. Although the human NKp46 carries both O- and N-glycosylations that are essential for its activity, the mouse Ncr1 was predicted to have N-linked glycosylations only. Here we discovered using prediction algorithms and high-performance liquid chromatography analysis that Ncr1 carries two putative novel O-glycosylations, one of which (Thr 225) is conserved in NKp46. We next used surface plasmon resonance, biochemical, mutational and functional in vitro and in vivo assays to demonstrate that the putative O-glycosylations of Ncr1 are critical for its function. PMID- 27462434 TI - Structural basis for Sfm1 functioning as a protein arginine methyltransferase. AB - SPOUT proteins constitute one class of methyltransferases, which so far are found to exert activity mainly towards RNAs. Previously, yeast Sfm1 was predicted to contain a SPOUT domain but can methylate ribosomal protein S3. Here we report the crystal structure of Sfm1, which comprises of a typical SPOUT domain and a small C-terminal domain. The active site is similar to that of protein arginine methyltransferases but different from that of RNA methyltransferases. In addition, Sfm1 exhibits a negatively charged surface surrounding the active site unsuitable for RNA binding. Our biochemical data show that Sfm1 exists as a monomer and has high activity towards ribosomal protein S3 but no activity towards RNA. It can specifically catalyze the methylation of Arg146 of S3 and the C-terminal domain is critical for substrate binding and activity. These results together provide the structural basis for Sfm1 functioning as a PRMT for ribosomal protein S3. PMID- 27462435 TI - Overlapping functions of the MAP4K family kinases Hppy and Msn in Hippo signaling. AB - The Hippo (Hpo) tumor suppressor pathway is an evolutionarily conserved signaling pathway that controls tissue growth and organ size in species ranging from Drosophila to human, and its malfunction has been implicated in many types of human cancer. In this study, we conducted a kinome screen and identified Happyhour (Hppy)/MAP4K3 as a novel player in the Hpo pathway. Our biochemical study showed that Hppy binds and phosphorylates Wts. Our genetic experiments suggest that Hppy acts in parallel and partial redundantly with Misshapen (Msn)/MAP4K4 to regulate Yki nuclear localization and Hpo target gene expression in Drosophila wing imaginal discs. Furthermore, we showed that cytoskeleton stress restricts Yki nuclear localization through Hppy and Msn when Hpo activity is compromised, thus providing an explanation for the Wts-dependent but Hpo independent regulation of Yki in certain contexts. Our study has unraveled an additional layer of complexity in the Hpo signaling pathway and laid down a foundation for exploring how different upstream regulators feed into the core Hpo pathway. PMID- 27462436 TI - Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA. AB - Chimeric antigen receptor T cell immunotherapy is a promising therapeutic strategy for treating tumors, demonstrating its efficiency in eliminating several hematological malignancies in recent years. However, a major obstacle associated with current chimeric antigen receptor T cell immunotherapy is that the limited replicative lifespan of chimeric antigen receptor T cells prohibits the long-term persistence and expansion of these cells in vivo, potentially hindering the long term therapeutic effects of chimeric antigen receptor T cell immunotherapy. Here we showed that the transient delivery of modified mRNA encoding telomerase reverse transcriptase to human chimeric antigen receptor T cells targeting the CD19 antigen (CD19 chimeric antigen receptor T cells) would transiently elevate the telomerase activity in these cells, leading to increased proliferation and delayed replicative senescence without risk of insertion mutagenesis or immortalization. Importantly, compared to conventional CD19 chimeric antigen receptor T cells, after the transient delivery of telomerase reverse transcriptase mRNA, these CD19 chimeric antigen receptor T cells showed improved persistence and proliferation in mouse xenograft tumor models of human B-cell malignancies. Furthermore, the transfer of CD19 chimeric antigen receptor T cells after the transient delivery of telomerase reverse transcriptase mRNA enhanced long-term antitumor effects in mouse xenograft tumor models compared with conventional CD19 chimeric antigen receptor T cell transfer. The results of the present study provide an effective and safe method to improve the therapeutic potential of chimeric antigen receptor T cells, which might be beneficial for treating other types of cancer, particularly solid tumors. PMID- 27462437 TI - A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/beta-catenin signalling pathway. AB - Nitrilase1 was classified as a tumour suppressor in association with the fragile histidine-triad protein Fhit. However, knowledge about nitrilase1 and its tumour suppressor function is still limited. Whereas nitrilase1 and Fhit are discrete proteins in mammals, they are merged in Drosophila melanogaster and Caenorhabditis elegans. According to the Rosetta-Stone hypothesis, proteins encoded as fusion proteins in one organism and as separate proteins in another organism may act in the same signalling pathway. Although a direct interaction of human nitrilase1 and Fhit has not been shown, our previous finding that Fhit interacts with beta-catenin and represses its transcriptional activity in the canonical Wnt pathway suggested that human nitrilase1 also modulates Wnt signalling. In fact, human nitrilase1 forms a complex with beta-catenin and LEF 1/TCF-4, represses beta-catenin-mediated transcription and shows an additive effect together with Fhit. Knockdown of human nitrilase1 enhances Wnt target gene expression. Moreover, our experiments show that beta-catenin competes away human nitrilase1 from LEF-1/TCF and thereby contributes to the activation of Wnt-target gene transcription. Inhibitory activity of human nitrilase1 on vertebrate Wnt signalling was confirmed by repression of Wnt-induced double axis formation in Xenopus embryogenesis. In line with this finding, the Drosophila fusion protein Drosophila NitFhit directly binds to Armadillo and represses the Wingless pathway in reporter gene assays. Genetic experiments confirmed the repressive activity of Drosophila NitFhit on Wingless signalling in the Drosophila wing imaginal disc. In addition, colorectal tumour microarray analysis revealed a significantly reduced expression of human nitrilase1 in poorly differentiated tumours. Taken together, repression of the canonical Wnt pathway represents a new mechanism for the human nitrilase1 tumour suppressor function. PMID- 27462438 TI - Temporal activation of XRCC1-mediated DNA repair is essential for muscle differentiation. AB - Transient DNA strand break formation has been identified as an effective means to enhance gene expression in living cells. In the muscle lineage, cell differentiation is contingent upon the induction of caspase-mediated DNA strand breaks, which act to establish the terminal gene expression program. This coordinated DNA nicking is rapidly resolved, suggesting that myoblasts may deploy DNA repair machinery to stabilize the genome and entrench the differentiated phenotype. Here, we identify the base excision repair pathway component XRCC1 as an indispensable mediator of muscle differentiation. Caspase-triggered XRCC1 repair foci form rapidly within differentiating myonuclei, and then dissipate as the maturation program proceeds. Skeletal myoblast deletion of Xrcc1 does not have an impact on cell growth, yet leads to perinatal lethality, with sustained DNA damage and impaired myofiber development. Together, these results demonstrate that XRCC1 manages a temporally responsive DNA repair process to advance the muscle differentiation program. PMID- 27462439 TI - SMG7 is a critical regulator of p53 stability and function in DNA damage stress response. AB - The p53 tumor suppressor functions as a transcription factor and plays a pivotal role in regulation of cellular response to DNA damage by activating various genes including those involved in cell cycle arrest. p53 stability is essential for its function during stress response; however, the molecular mechanism for DNA damage induced stabilization of p53 is not fully understood. In our present study, we have identified SMG7 (suppressor with morphological defects in genitalia 7), also known as EST1C, as a novel p53-binding protein. SMG7 is an mRNA surveillance factor implicated in degradation of p53 mRNA-containing nonsense mutations, yet it is completely unknown whether SMG7 regulates p53 function. Here, we show that SMG7 has a crucial role in p53-mediated response to genotoxic stress by regulating p53 stability. Using somatic gene knockout, we found that deletion of SMG7 abrogates DNA damage-induced p53 stabilization, although it exhibits minimal effect on the basal levels of p53. Importantly, loss of SMG7 impairs p53-mediated activation of p21 and cell cycle arrest following DNA damage. Pharmacological inhibition of Mdm2, a major E3 ubiquitin ligase for p53, restored p53 stability in gamma-irradiated SMG7-deficient cells. Furthermore, SMG7 physically interacts with Mdm2 and promotes ATM-mediated inhibitory phosphorylation of Mdm2 following ionizing radiation. Therefore, our present data demonstrate that SMG7 is critical for p53 function in DNA damage response, and reveal the SMG7-mediated phosphorylation of Mdm2 as a previously unknown mechanism for p53 regulation. PMID- 27462440 TI - A novel miR-200b-3p/p38IP pair regulates monocyte/macrophage differentiation. AB - Monocyte/macrophage differentiation represents a major branch of hematopoiesis and is a central event in the immune response, but the molecular mechanisms underlying are not fully delineated. Here we show that p38 mitogen-activated protein kinase (MAPK) interacting protein (p38IP) is downregulated during monocyte/macrophage differentiation in vitro. Overexpression of p38IP halted monocyte/macrophage differentiation, whereas forward knockdown of p38IP by RNA interference induced G1/S arrest and promoted monocyte differentiation into macrophages and the maturation of macrophages as well. Moreover, we found that miR-200b-3p was upregulated during monocyte/macrophage differentiation and mediated the downregulation of p38IP by binding to the 3' untranslated terminal region of p38IP mRNA. Overexpression of a miR-200b-3p mimic resembled the effect of p38IP knockdown, whereas a miR-200b-3p inhibitor blocked monocyte/macrophage differentiation by enhancing p38IP expression. Further western blotting analysis revealed that p38IP downregulation enhanced the activity of p38 MAPK and the subsequent accumulation of cyclin-dependent kinase inhibitor p21, thus promoting G1/S arrest and monocyte/macrophage differentiation. Moreover, the decline of GCN5 acetyltransferase caused by p38IP downregulation was required but was not sufficient for monocyte/macrophage differentiation. This study demonstrated a new role for p38IP and a novel miR-200b-3p/p38IP pair in the regulation of monocyte/macrophage differentiation. PMID- 27462441 TI - Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner. AB - Anaphase-promoting complex/cyclosome/Cdh1 is a multi-subunit ubiquitin E3 ligase that drives M to G1 cell cycle progression through primarily earmarking various substrates for ubiquitination and subsequent degradation by the 26S proteasome. Notably, emerging evidence suggested that Cdh1 could also function in various cellular processes independent of anaphase-promoting complex/cyclosome. To this end, we recently identified an anaphase-promoting complex/cyclosome-independent function of Cdh1 in modulating osteoblast differentiation through activating Smurf1, one of the NEDD4 family of HECT domain-containing E3 ligases. However, it remains largely unknown whether Cdh1 could exert its tumor suppressor role through similarly modulating the E3 ligase activities of other NEDD4 family members, most of which have characterized important roles in tumorigenesis. Here we report that in various tumor cells, Cdh1, conversely, suppresses the E3 ligase activity of WWP2, another NEDD4 family protein, in an anaphase-promoting complex/cyclosome-independent manner. As such, loss of Cdh1 activates WWP2, leading to reduced abundance of WWP2 substrates including PTEN, which subsequently activates PI3K/Akt oncogenic signaling to facilitate tumorigenesis. This study expands the non-anaphase-promoting complex/cyclosome function of Cdh1 in regulating the NEDD4 family E3 ligases, and further suggested that enhancing Cdh1 to inhibit the E3 ligase activity of WWP2 could be a promising strategy for treating human cancers. PMID- 27462442 TI - Mapping gene regulatory circuitry of Pax6 during neurogenesis. AB - Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system development. However, the gene regulatory circuitry of Pax6 underlying these functions remains elusive. We find that Pax6 targets a large number of promoters in neural progenitors cells. Intriguingly, many of these sites are also bound by another progenitor factor, Sox2, which cooperates with Pax6 in gene regulation. A combinatorial analysis of Pax6-binding data set with transcriptome changes in Pax6-deficient neural progenitors reveals a dual role for Pax6, in which it activates the neuronal (ectodermal) genes while concurrently represses the mesodermal and endodermal genes, thereby ensuring the unidirectionality of lineage commitment towards neuronal differentiation. Furthermore, Pax6 is critical for inducing activity of transcription factors that elicit neurogenesis and repress others that promote non-neuronal lineages. In addition to many established downstream effectors, Pax6 directly binds and activates a number of genes that are specifically expressed in neural progenitors but have not been previously implicated in neurogenesis. The in utero knockdown of one such gene, Ift74, during brain development impairs polarity and migration of newborn neurons. These findings demonstrate new aspects of the gene regulatory circuitry of Pax6, revealing how it functions to control neuronal development at multiple levels to ensure unidirectionality and proper execution of the neurogenic program. PMID- 27462443 TI - Involvement of PARP1 in the regulation of alternative splicing. AB - Specialized chromatin structures such as nucleosomes with specific histone modifications decorate exons in eukaryotic genomes, suggesting a functional connection between chromatin organization and the regulation of pre-mRNA splicing. Through profiling the functional location of Poly (ADP) ribose polymerase, we observed that it is associated with the nucleosomes at exon/intron boundaries of specific genes, suggestive of a role for this enzyme in alternative splicing. Poly (ADP) ribose polymerase has previously been implicated in the PARylation of splicing factors as well as regulation of the histone modification H3K4me3, a mark critical for co-transcriptional splicing. In light of these studies, we hypothesized that interaction of the chromatin-modifying factor, Poly (ADP) ribose polymerase with nucleosomal structures at exon-intron boundaries, might regulate pre-mRNA splicing. Using genome-wide approaches validated by gene specific assays, we show that depletion of PARP1 or inhibition of its PARylation activity results in changes in alternative splicing of a specific subset of genes. Furthermore, we observed that PARP1 bound to RNA, splicing factors and chromatin, suggesting that Poly (ADP) ribose polymerase serves as a gene regulatory hub to facilitate co-transcriptional splicing. These studies add another function to the multi-functional protein, Poly (ADP) ribose polymerase, and provide a platform for further investigation of this protein's function in organizing chromatin during gene regulatory processes. PMID- 27462444 TI - Ack promotes tissue growth via phosphorylation and suppression of the Hippo pathway component Expanded. AB - Non-receptor tyrosine kinase activated cdc42 kinase was reported to participate in several types of cancers in mammals. It is also believed to have an anti apoptotic function in Drosophila. Here, we report the identification of Drosophila activated cdc42 kinase as a growth promoter and a novel Hippo signaling pathway regulator. We find that activated cdc42 kinase promotes tissue growth through modulating Yorkie activity. Furthermore, we demonstrate that activated cdc42 kinase interacts with Expanded and induces tyrosine phosphorylation of Expanded on multiple sites. We propose a model that activated cdc42 kinase negatively regulates Expanded by changing its phosphorylation status to promote tissue growth. Moreover, we show that ack genetically interacts with merlin and expanded. Thus, we identify Drosophila activated cdc42 kinase as a Hippo pathway regulator. PMID- 27462445 TI - Conserved regulators of Rag GTPases orchestrate amino acid-dependent TORC1 signaling. AB - The highly conserved target of rapamycin complex 1 (TORC1) is the central component of a signaling network that couples a vast range of internal and external stimuli to cell growth, proliferation and metabolism. TORC1 deregulation is associated with a number of human pathologies, including many cancers and metabolic disorders, underscoring its importance in cellular and organismal growth control. The activity of TORC1 is modulated by multiple inputs; however, the presence of amino acids is a stimulus that is essential for its activation. Amino acid sufficiency is communicated to TORC1 via the highly conserved family of Rag GTPases, which assemble as heterodimeric complexes on lysosomal/vacuolar membranes and are regulated by their guanine nucleotide loading status. Studies in yeast, fly and mammalian model systems have revealed a multitude of conserved Rag GTPase modulators, which have greatly expanded our understanding of amino acid sensing by TORC1. Here we review the major known modulators of the Rag GTPases, focusing on recent mechanistic insights that highlight the evolutionary conservation and divergence of amino acid signaling to TORC1. PMID- 27462446 TI - TRIB2 regulates normal and stress-induced thymocyte proliferation. AB - TRIB2, a serine/threonine pseudokinase identified as an oncogene, is expressed at high levels in the T-cell compartment of hematopoiesis. The proliferation of developing thymocytes is tightly controlled to prevent leukemic transformation of T cells. Here we examine Trib2 loss in murine hematopoiesis under steady state and proliferative stress conditions, including genotoxic and oncogenic stress. Trib2 (-/-) developing thymocytes show increased proliferation, and Trib2 (-/-) mice have significantly higher thymic cellularity at steady state. During stress hematopoiesis, Trib2 (-/-) developing thymocytes undergo accelerated proliferation and demonstrate hypersensitivity to 5-fluorouracil (5-FU)-induced cell death. Despite the increased cell death post 5-FU-induced proliferative stress, Trib2 (-/-) mice exhibit accelerated thymopoietic recovery post treatment due to increased cell division kinetics of developing thymocytes. The increased proliferation in Trib2 (-/-) thymocytes was exacerbated under oncogenic stress. In an experimental murine T-cell acute lymphoblastic leukemia (T-ALL) model, Trib2 (-/-) mice had reduced latency in vivo, which associated with impaired MAP kinase (MAPK) activation. High and low expression levels of Trib2 correlate with immature and mature subtypes of human T-ALL, respectively, and associate with MAPK. Thus, TRIB2 emerges as a novel regulator of thymocyte cellular proliferation, important for the thymopoietic response to genotoxic and oncogenic stress, and possessing tumor suppressor function. PMID- 27462447 TI - Erratum: Discovery of a highly potent glucocorticoid for asthma treatment. AB - [This corrects the article DOI: 10.1038/celldisc.2015.35.]. PMID- 27462448 TI - Deubiquitylating enzyme USP9x regulates hippo pathway activity by controlling angiomotin protein turnover. AB - The Hippo pathway has been identified as a key barrier for tumorigenesis, acting through downregulation of YAP/TAZ activity. Elevated YAP/TAZ activity has been documented in many human cancers. Ubiquitylation has been shown to play a key role in regulating YAP/TAZ activity through downregulation of a number of Hippo pathway components. Several ubiquitin ligase complexes have been implicated in this process, however, little is known about the deubiquitylating enzymes that counteract these activities to regulate YAP/TAZ. Here we identify the deubiquitylating enzyme USP9x as a regulator of YAP/TAZ activity. We demonstrate that USPx regulates ubiquitin-mediated turnover of the YAP inhibitor, Angiomotin. USP9x acts to deubiquitylate Angiomotin at lysine 496, resulting in stabilization of Angiomotin and lower YAP/TAZ activity. USP9x mRNA levels were reduced in several cancers. Clinically, USP9x mRNA levels were reduced in several cancers with low USPx expression correlating with poor prognosis in renal clear cell carcinoma. Our data indicate that USP9x may be a useful biomarker for renal clear cell carcinoma. PMID- 27462449 TI - The interchange of immunophilins leads to parallel pathways and different intermediates in the assembly of Hsp90 glucocorticoid receptor complexes. AB - Hormone receptors require participation of the chaperones Hsp40/Hsp70 to form client-transfer complexes with Hsp90/Hop. Interaction with the co-chaperone p23 releases Hop and Hsp70, and the immunophilin FKBP52 mediates transfer of the Hsp90-receptor complex to the nucleus. Inhibition of glucocorticoid receptor (GR) transport by FKBP51, but not by FKBP52, has been observed at the cellular level, but the subunit composition of the intermediates involved has not been deduced. Here we use mass spectrometry to show that FKBP51/52 form analogous complexes with GR/Hsp90/Hop/Hsp70/ATP, but differences emerge upon addition of p23 to client-transfer complexes. When FKBP51 is present, a stable intermediate is formed (FKBP51)1(GR)1(Hsp90)2(p23)2 by expulsion of Hsp70 and Hop. By contrast, in the presence of FKBP52, ejection of p23 also takes place to form the nuclear transfer complex (FKBP52)1(GR)1(Hsp90)2. Our results are therefore consistent with pathways in which FKBP51/52 are interchangeable during the early assembly reactions. Following interaction with p23, however, the pathways diverge with FKBP51 sequestering GR in a stable intermediate complex with p23. By contrast, binding of FKBP52 occurs almost concomitantly with release of p23 to form a highly dynamic transfer complex, primed for interaction with the dynactin transport machinery. PMID- 27462450 TI - PBR1 selectively controls biogenesis of photosynthetic complexes by modulating translation of the large chloroplast gene Ycf1 in Arabidopsis. AB - The biogenesis of photosystem I (PSI), cytochrome b 6 f (Cytb 6 f) and NADH dehydrogenase (NDH) complexes relies on the spatially and temporally coordinated expression and translation of both nuclear and chloroplast genes. Here we report the identification of photosystem biogenesis regulator 1 (PBR1), a nuclear encoded chloroplast RNA-binding protein that regulates the concerted biogenesis of NDH, PSI and Cytb 6 f complexes. We identified Ycf1, one of the two largest chloroplast genome-encoded open reading frames as the direct downstream target protein of PBR1. Biochemical and molecular analyses reveal that PBR1 regulates Ycf1 translation by directly binding to its mRNA. Surprisingly, we further demonstrate that relocation of the chloroplast gene Ycf1 fused with a plastid transit sequence to the nucleus bypasses the requirement of PBR1 for Ycf1 translation, which sufficiently complements the defects in biogenesis of NDH, PSI and Cytb 6 f complexes in PBR1-deficient plants. Remarkably, the nuclear-encoded PBR1 tightly controls the expression of the chloroplast gene Ycf1 at the translational level, which is sufficient to sustain the coordinated biogenesis of NDH, PSI and Cytb 6 f complexes as a whole. Our findings provide deep insights into better understanding of how a predominant nuclear-encoded factor can act as a migratory mediator and undergoes selective translational regulation of the target plastid gene in controlling biogenesis of photosynthetic complexes. PMID- 27462451 TI - The Chp1 chromodomain binds the H3K9me tail and the nucleosome core to assemble heterochromatin. AB - To maintain genome stability, cells pack large portions of their genome into silent chromatin or heterochromatin. Histone H3 lysine 9 methylation, a hallmark of heterochromatin, is recognized by conserved readers called chromodomains. But how chromodomains interact with their actual binding partner, the H3K9 methylated nucleosome, remains elusive. We have determined the structure of a nucleosome trimethylated at lysine 9 of histone H3 (H3K9me3 Nucleosome) in a complex with the chromodomain of Chp1, a protein required for RNA interference-dependent heterochromatin formation in fission yeast. The cryo-electron microscopy structure reveals that the chromodomain of Chp1 binds the histone H3 lysine 9 methylated tail and the core of the nucleosome, primarily histones H3 and H2B. Mutations in chromodomain of Chp1 loops, which interact with the nucleosome core, abolished this interaction in vitro. Moreover, fission yeast cells with Chp1 loop mutations have a defect in Chp1 recruitment and heterochromatin formation. This study reveals the structural basis for heterochromatic silencing and suggests that chromodomains could read histone code in the H3 tail and the nucleosome core, which would provide an additional layer of regulation. PMID- 27462452 TI - Hypertension-associated C825T polymorphism impairs the function of Gbeta3 to target GRK2 ubiquitination. AB - Population-based and case-control studies in different ethnicities have linked a polymorphism, C825T, in exon 10 of GNB3 gene to hypertension and several additional diseases. The 825T allele is associated with alternative splicing and results in a shortened Gbeta3 protein, referred to as Gbeta3s, which loses 41 amino acids encompassing one WD40 repeat domain. The mechanism of how Gbeta3 C825T polymorphism is associated with hypertension has remained unclear, but an impairment of its canonical function in G-protein-coupled receptor signaling has been ruled out. Here, we report that Gbeta3, like other Gbeta proteins, binds to DDB1 and assembles a DDB1-CUL4A-ROC1 E3 ubiquitin ligase (CRL4A(Gbeta3)) to target GRK2 ubiquitination. The loss of the 41 amino-acid residues disrupts the Gbeta3-DDB1 binding and impairs the function of Gbeta3s to ubiquitinate GRK2. GRK2 ubiquitination levels were decreased and protein levels were accumulated in the blood samples of Gbeta3 825T allele carriers. Deletion of Cul4a in mice resulted in systolic pressure increased and weakened heart function in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a mechanism explaining the link between Gbeta3 C825T polymorphism and hypertension. PMID- 27462453 TI - Taiman acts as a coactivator of Yorkie in the Hippo pathway to promote tissue growth and intestinal regeneration. AB - The Hippo signaling pathway regulates tissue growth and organ size through controlling cell growth, proliferation and apoptosis. During these processes, the coactivator Yorkie partners with the transcription factor Scalloped to mediate Hippo pathway-regulated cellular functions. Here, we demonstrate that Taiman facilitates the activity of Yorkie. First, Taiman overexpression upregulates Hippo pathway-responsive genes and induces tissue overgrowth. Second, the loss of tai downregulates the expression of Hippo pathway target genes and reduces organ size as well as tissue overgrowth caused by Yorkie overexpression. Furthermore, we provide evidence that Taiman binds to Yorkie and facilitates the activity of Yorkie-Scalloped to activate the transcription of several Hippo pathway target genes. Moreover, we found that the C-terminus of Taiman is indispensable for the function of Taiman in Hippo signaling. Finally, we demonstrate that Taiman is also required in intestinal stem cell proliferation. Our findings suggest Taiman is an essential coactivator of Yorkie. PMID- 27462454 TI - Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer. AB - Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation. Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth. We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A. PMID- 27462455 TI - MLL1 and MLL1 fusion proteins have distinct functions in regulating leukemic transcription program. AB - Mixed lineage leukemia protein-1 (MLL1) has a critical role in human MLL1 rearranged leukemia (MLLr) and is a validated therapeutic target. However, its role in regulating global gene expression in MLLr cells, as well as its interplay with MLL1 fusion proteins remains unclear. Here we show that despite shared DNA binding and cofactor interacting domains at the N terminus, MLL1 and MLL-AF9 are recruited to distinct chromatin regions and have divergent functions in regulating the leukemic transcription program. We demonstrate that MLL1, probably through C-terminal interaction with WDR5, is recruited to regulatory enhancers that are enriched for binding sites of E-twenty-six (ETS) family transcription factors, whereas MLL-AF9 binds to chromatin regions that have no H3K4me1 enrichment. Transcriptome-wide changes induced by different small molecule inhibitors also highlight the distinct functions of MLL1 and MLL-AF9. Taken together, our studies provide novel insights on how MLL1 and MLL fusion proteins contribute to leukemic gene expression, which have implications for developing effective therapies in the future. PMID- 27462456 TI - A CRISPR-based approach for targeted DNA demethylation. AB - In mammalian cells, DNA methylation critically regulates gene expression and thus has pivotal roles in myriad of physiological and pathological processes. Here we report a novel method for targeted DNA demethylation using the widely used clustered regularly interspaced short palindromic repeat (CRISPR)-Cas system. Initially, modified single guide RNAs (sgRNAs) (sgRNA2.0) were constructed by inserting two copies of bacteriophage MS2 RNA elements into the conventional sgRNAs, which would facilitate the tethering of the Tet1 catalytic domain (Tet CD), in fusion with dCas9 or MS2 coat proteins, to the targeted gene loci. Subsequently, such system was shown to significantly upregulate transcription of the target genes, including RANKL, MAGEB2 or MMP2, which was in close correlation to DNA demethylation of their neighboring CpGs in the promoters. In addition, the dCas9/sgRNA2.0-directed demethylation system appeared to afford efficient demethylation of the target genes with tenuous off-target effects. Applications of this system would not only help us understand mechanistically how DNA methylation might regulate gene expression in specific contexts, but also enable control of gene expression and functionality with potential clinical benefits. PMID- 27462458 TI - Regulation of the divalent metal ion transporter via membrane budding. AB - The release of extracellular vesicles (EVs) is important for both normal physiology and disease. However, a basic understanding of the targeting of EV cargoes, composition and mechanism of release is lacking. Here we present evidence that the divalent metal ion transporter (DMT1) is unexpectedly regulated through release in EVs. This process involves the Nedd4-2 ubiquitin ligase, and the adaptor proteins Arrdc1 and Arrdc4 via different budding mechanisms. We show that mouse gut explants release endogenous DMT1 in EVs. Although we observed no change in the relative amount of DMT1 released in EVs from gut explants in Arrdc1 or Arrdc4 deficient mice, the extent of EVs released was significantly reduced indicating an adaptor role in biogenesis. Furthermore, using Arrdc1 or Arrdc4 knockout mouse embryonic fibroblasts, we show that both Arrdc1 and Arrdc4 are non redundant positive regulators of EV release. Our results suggest that DMT1 release from the plasma membrane into EVs may represent a novel mechanism for the maintenance of iron homeostasis, which may also be important for the regulation of other membrane proteins. PMID- 27462457 TI - Identification of key factors conquering developmental arrest of somatic cell cloned embryos by combining embryo biopsy and single-cell sequencing. AB - Differentiated somatic cells can be reprogrammed into totipotent embryos through somatic cell nuclear transfer. However, most cloned embryos arrest at early stages and the underlying molecular mechanism remains largely unexplored. Here, we first developed a somatic cell nuclear transfer embryo biopsy system at two- or four-cell stage, which allows us to trace the developmental fate of the biopsied embryos precisely. Then, through single-cell transcriptome sequencing of somatic cell nuclear transfer embryos with different developmental fates, we identified that inactivation of Kdm4b, a histone H3 lysine 9 trimethylation demethylase, functions as a barrier for two-cell arrest of cloned embryos. Moreover, we discovered that inactivation of another histone demethylase Kdm5b accounts for the arrest of cloned embryos at the four-cell stage through single cell analysis. Co-injection of Kdm4b and Kdm5b can restore transcriptional profiles of somatic cell nuclear transfer embryos and greatly improve the blastocyst development (over 95%) as well as the production of cloned mice. Our study therefore provides an effective approach to identify key factors responsible for the developmental arrest of somatic cell cloned embryos. PMID- 27462459 TI - An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology. AB - G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein-protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class. PMID- 27462460 TI - Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA. AB - The DNA damage response involves coordinated control of gene expression and DNA repair. Using deep sequencing, we found widespread changes of alternative cleavage and polyadenylation site usage on ultraviolet-treatment in mammalian cells. Alternative cleavage and polyadenylation regulation in the 3' untranslated region is substantial, leading to both shortening and lengthening of 3' untranslated regions of genes. Interestingly, a strong activation of intronic alternative cleavage and polyadenylation sites is detected, resulting in widespread expression of truncated transcripts. Intronic alternative cleavage and polyadenylation events are biased to the 5' end of genes and affect gene groups with important functions in DNA damage response and cancer. Moreover, intronic alternative cleavage and polyadenylation site activation during DNA damage response correlates with a decrease in U1 snRNA levels, and is reversible by U1 snRNA overexpression. Importantly, U1 snRNA overexpression mitigates ultraviolet induced apoptosis. Together, these data reveal a significant gene regulatory scheme in DNA damage response where U1 snRNA impacts gene expression via the U1 alternative cleavage and polyadenylation axis. PMID- 27462461 TI - A genome-scale CRISPR-Cas9 screening method for protein stability reveals novel regulators of Cdc25A. AB - The regulation of stability is particularly crucial for unstable proteins in cells. However, a convenient and unbiased method of identifying regulators of protein stability remains to be developed. Recently, a genome-scale CRISPR-Cas9 library has been established as a genetic tool to mediate loss-of-function screening. Here, we developed a protein stability regulators screening assay (Pro SRSA) by combining the whole-genome CRISPR-Cas9 library with a dual-fluorescence based protein stability reporter and high-throughput sequencing to screen for regulators of protein stability. Using Cdc25A as an example, Cul4B-DDB1(DCAF8) was identified as a new E3 ligase for Cdc25A. Moreover, the acetylation of Cdc25A at lysine 150, which was acetylated by p300/CBP and deacetylated by HDAC3, prevented the ubiquitin-mediated degradation of Cdc25A by the proteasome. This is the first study to report that acetylation, as a novel posttranslational modification, modulates Cdc25A stability, and we suggest that this unbiased CRISPR-Cas9 screening method at the genome scale may be widely used to globally identify regulators of protein stability. PMID- 27462462 TI - Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity. AB - MicroRNAs have an important role in bone homeostasis. However, the detailed mechanism of microRNA-mediated intercellular communication between bone cells remains elusive. Here, we report that osteoclasts secrete microRNA-enriched exosomes, by which miR-214 is transferred into osteoblasts to inhibit their function. In a coculture system, inhibition of exosome formation and secretion prevented miR-214 transportation. Exosomes specifically recognized osteoblasts through the interaction between ephrinA2 and EphA2. In osteoclast-specific miR 214 transgenic mice, exosomes were secreted into the serum, and miR-214 and ephrinA2 levels were elevated. Therefore, these exosomes have an inhibitory role in osteoblast activity. miR-214 and ephrinA2 levels in serum exosomes from osteoporotic patients and mice were upregulated substantially. These exosomes may significantly inhibit osteoblast activity. Inhibition of exosome secretion via Rab27a small interfering RNA prevented ovariectomized-induced osteoblast dysfunction in vivo. Taken together, these findings suggest that exosome-mediated transfer of microRNA plays an important role in the regulation of osteoblast activity. Circulating miR-214 in exosomes not only represents a biomarker for bone loss but could selectively regulate osteoblast function. PMID- 27462463 TI - TRAIP regulates replication fork recovery and progression via PCNA. AB - PCNA is a central scaffold that coordinately assembles replication and repair machineries at DNA replication forks for faithful genome duplication. Here, we describe TRAIP (RNF206) as a novel PCNA-interacting factor that has important roles during mammalian replicative stress responses. We show that TRAIP encodes a nucleolar protein that migrates to stalled replication forks, and that this is accomplished by its targeting of PCNA via an evolutionarily conserved PIP box on its C terminus. Accordingly, inactivation of TRAIP or its interaction with the PCNA clamp compromised replication fork recovery and progression, and leads to chromosome instability. Together, our findings establish TRAIP as a component of the mammalian replicative stress response network, and implicate the TRAIP-PCNA axis in recovery of stalled replication forks. PMID- 27462464 TI - Nuclear localization of platelet-activating factor receptor controls retinal neovascularization. AB - Platelet-activating factor (PAF) is a pleiotropic phospholipid with proinflammatory, procoagulant and angiogenic actions on the vasculature. We and others have reported the presence of PAF receptor (Ptafr) at intracellular sites such as the nucleus. However, mechanisms of localization and physiologic functions of intracellular Ptafr remain poorly understood. We hereby identify the importance of C-terminal motif of the receptor and uncover novel roles of Rab11a GTPase and importin-5 in nuclear translocation of Ptafr in primary human retinal microvascular endothelial cells. Nuclear localization of Ptafr is independent of exogenous PAF stimulation as well as intracellular PAF biosynthesis. Moreover, nuclear Ptafr is responsible for the upregulation of unique set of growth factors, including vascular endothelial growth factor, in vitro and ex vivo. We further corroborate the intracrine PAF signaling, resulting in angiogenesis in vivo, using Ptafr antagonists with distinct plasma membrane permeability. Collectively, our findings show that nuclear Ptafr translocates in an agonist independent manner, and distinctive functions of Ptafr based on its cellular localization point to another dimension needed for pharmacologic selectivity of drugs. PMID- 27462465 TI - Cellular mechanisms for cargo delivery and polarity maintenance at different polar domains in plant cells. AB - The asymmetric localization of proteins in the plasma membrane domains of eukaryotic cells is a fundamental manifestation of cell polarity that is central to multicellular organization and developmental patterning. In plants, the mechanisms underlying the polar localization of cargo proteins are still largely unknown and appear to be fundamentally distinct from those operating in mammals. Here, we present a systematic, quantitative comparative analysis of the polar delivery and subcellular localization of proteins that characterize distinct polar plasma membrane domains in plant cells. The combination of microscopic analyses and computational modeling revealed a mechanistic framework common to diverse polar cargos and underlying the establishment and maintenance of apical, basal, and lateral polar domains in plant cells. This mechanism depends on the polar secretion, constitutive endocytic recycling, and restricted lateral diffusion of cargos within the plasma membrane. Moreover, our observations suggest that polar cargo distribution involves the individual protein potential to form clusters within the plasma membrane and interact with the extracellular matrix. Our observations provide insights into the shared cellular mechanisms of polar cargo delivery and polarity maintenance in plant cells. PMID- 27462466 TI - The ERK signaling target RNF126 regulates anoikis resistance in cancer cells by changing the mitochondrial metabolic flux. AB - Loss of anchorage to the extracellular matrix leads to apoptosis (anoikis) in normal cells, but cancerous cells are usually resistant to such stress. Here we report the pivotal role of an E3 ubiquitin ligase, ring-finger protein 126 (RNF126), in the resistance of cancer cells to the stress associated with non adherent conditions. Non-adherent cancer cells exhibited increased flux through the tricarboxylic acid cycle via increased conversion of pyruvate to acetyl-CoA. RNF126 was found to act as a ubiquitin ligase for pyruvate dehydrogenase kinases (PDKs), resulting in their proteasomal degradation. This decrease in PDK levels allowed pyruvate dehydrogenases to catalyze the conversion of pyruvate to acetyl CoA. Moreover, depletion of RNF126 or increased expression of PDK1 in cancer cells suppressed colony formation in soft agar as well as tumorigenicity in mice. RNF126 expression in cancer cells was found to be under the control of the extracellular signal-regulated kinase signaling pathway, which is essential for anoikis resistance. Thus, RNF126 is an attractive molecule for treating cancer by selectively targeting anchorage-independent growth. PMID- 27462467 TI - Dual function of partitioning-defective 3 in the regulation of YAP phosphorylation and activation. AB - Partitioning-defective 3 (Par3), a key component of the evolutionarily conserved polarity PAR complex (Par3/Par6/aPKC), controls cell polarity and contributes to cell migration, proliferation and tumor development. Emerging evidence indicates that cell polarity proteins function as upstream modulators that regulate the Hippo pathway. However, little is known about Par3's involvement in the Hippo pathway. Here, we find Par3 and YAP dynamically co-localize in different subcellular compartments; that is, the membrane, cytoplasm and nucleus, in a cell density-dependent manner. Interestingly, Par3 knockdown promotes YAP phosphorylation, leading to a significant impairment of YAP nuclear translocation at low cell density, but not at high density, in MDCK cells. Furthermore, via its third PDZ domain, Par3 directly binds to the PDZ-binding motif of YAP. The interaction is required for regulating YAP phosphorylation and nuclear localization. Mechanistically, Par3, as a scaffold protein, associates with LATS1 and protein phosphatase 1, alpha subunit (PP1A) in the cytoplasm and nucleus. Par3 promotes the dephosphorylation of LATS1 and YAP, thus enhancing YAP activation and cell proliferation. Strikingly, we also find that under the condition of PP1A knockdown, Par3 expression promotes YAP hyperphosphorylation, leading to the suppression of YAP activity and its downstream targets. Par3 expression results in differential effects on YAP phosphorylation and activation in different tumor cell lines. These findings indicate that Par3 may have a dual role in regulating the activation of the Hippo pathway, in a manner possibly dependent on cellular context or cell type in response to cell-cell contact and cell polarity signals. PMID- 27462469 TI - A Focus Group on Dental Pain Complaints with General Medical Practitioners: Developing a Treatment Algorithm. AB - Objective. The differential diagnosis of pain in the mouth can be challenging for general medical practitioners (GMPs) as many different dental problems can present with similar signs and symptoms. This study aimed to create a treatment algorithm for GMPs to effectively and appropriately refer the patients and prescribe antibiotics. Design. The study design is comprised of qualitative focus group discussions. Setting and Subjects. Groups of GMPs within the Gold Coast and Brisbane urban and city regions. Outcome Measures. Content thematically analysed and treatment algorithm developed. Results. There were 5 focus groups with 8-9 participants per group. Addressing whether antibiotics should be given to patients with dental pain was considered very important to GMPs to prevent overtreatment and creating antibiotic resistance. Many practitioners were unsure of what the different forms of dental pains represent. 90% of the practitioners involved agreed that the treatment algorithm was useful to daily practice. Conclusion. Common dental complaints and infections are seldom surgical emergencies but can result in prolonged appointments for those GMPs who do not regularly deal with these issues. The treatment algorithm for referral processes and prescriptions was deemed easily downloadable and simple to interpret and detailed but succinct enough for clinical use by GMPs. PMID- 27462468 TI - Let's Wiggle with 5-2-1-0: Curriculum Development for Training Childcare Providers to Promote Activity in Childcare Settings. AB - Overweight and obesity are increasing in preschool children in the US. Policy, systems, and environmental change interventions in childcare settings can improve obesity-related behaviors. The aim of this study was to develop and pilot an intervention to train childcare providers to promote physical activity (PA) in childcare classrooms. An evidence scan, key informant (n = 34) and focus group (n = 20) interviews with childcare directors and staff, and environmental self assessment of childcare facilities (n = 22) informed the design of the training curriculum. Feedback from the interviews indicated that childcare providers believed in the importance of teaching children about PA and were supportive of training teachers to incorporate PA into classroom settings. The Promoting Physical Activity in Childcare Setting Curriculum was developed and training was implemented with 16 teachers. Participants reported a positive experience with the hands-on training and reported acquiring new knowledge that they intended to implement in their childcare settings. Our findings highlight the feasibility of working with childcare staff to develop PA training and curriculum. Next steps include evaluating the curriculum in additional childcare settings and childcare staff implementation of the curriculum to understand the effectiveness of the training on PA levels of children. PMID- 27462470 TI - Ten-Year Trends in the Morbidity of Diabetes Mellitus and Antidiabetic Drug Utilization in Croatia: A Study Based on Routinely Collected Data. AB - Objectives. To investigate trends of diabetes mellitus (DM) morbidity and antidiabetic drug utilization in Croatian primary health care (PHC) from 2005 to 2014. Method. Routinely collected morbidity data from all PHC units, presented in Croatian health-statistics yearbooks, were retrieved. Data on drug utilization were retrieved from the Annual Reports of the Croatian Agency for Medicinal Products and Medical Devices (ATC/DDD, antidiabetic, A10). Results. Total morbidity increased by 33.3% and DM increased by 65.6%, mostly in patients over age 65 (from 50% to 57%). Estimated DM prevalence in adults increased from 3.9% to 6.4%. Increased morbidity was followed by an even higher increase in drug utilization (120%). Metformin was first, with a constant increase (from 18% to 39%), followed by glimepiride, while glibenclamide use decreased. Total utilization of insulin increased even more, mostly for aspart (600%) and newly introduced glargine and detemir, while human insulin usage sharply decreased. Spending also increased, mostly for aspart (from 21% to 61% of total). Conclusions. Increased DM is followed by a higher increase in antidiabetic drug utilization; this trend will continue in the future. In Croatian PHC, metformin has primacy along with insulin analogues. PMID- 27462471 TI - Arthroscopic Repair of Articular Surface Partial-Thickness Rotator Cuff Tears: Transtendon Technique versus Repair after Completion of the Tear-A Meta-Analysis. AB - Articular surface partial-thickness rotator cuff tears (PTRCTs) are commonly repaired using two different surgical techniques: transtendon repair or repair after completion of the tear. Although a number of studies have demonstrated excellent clinical outcomes, it is unclear which technique may provide superior clinical outcomes and tendon healing. The purpose was to evaluate and compare the clinical outcomes following arthroscopic repair of articular surface PTRCT using a transtendon technique or completion of the tear. A systematic review of the literature was performed following PRISMA guidelines and checklist. The objective outcome measures evaluated in this study were the Constant Score, American Shoulder and Elbow Surgeons score, Visual Analogue Scale, physical examination, and complications. Three studies met our criteria. All were prospective randomized comparative studies with level II evidence and published from 2012 to 2013. A total of 182 shoulders (mean age 53.7 years; mean follow-up 40.5 months) were analyzed as part of this study. Both procedures provided excellent clinical outcomes with no significant difference in Constant Score and other measures between the procedures. Both procedures demonstrated improved clinical outcomes. However, there were no significant differences between each technique. Further studies are required to determine the long-term outcome of each technique. PMID- 27462472 TI - Dengue Deaths: Associated Factors and Length of Hospital Stay. AB - Background. Dengue continues to pose a public health problem globally. Objective. To review factors associated with patients who died from dengue in Trinidad. Methods. A retrospective case note review of hospitalized patients who died during 2001 to 2010. Results. A total of 23 cases were identified: 13 males, 10 females-12 East Indians, 9 Africans, and 2 unknown. More than half (n = 17) were over 40 years of age with 10 being over 60 years of age; three were children. A falling platelet count was observed in 16 while 18 patients had a low normal haematocrit. There was a significant association of ethnicity, hypertension, and diabetes with length of hospital stay. Conclusions. The study sample included 10 patients over 60 years of age. Patients with diabetes and hypertension and patients of East Indian origin appeared to have a shorter hospital stay prior to death. PMID- 27462473 TI - Corrigendum to "Cutaneous Plasmacytosis with Perineural Involvement". AB - [This corrects the article DOI: 10.1155/2014/840845.]. PMID- 27462474 TI - Hepatotoxicity due to Clindamycin in Combination with Acetaminophen in a 62-Year Old African American Female: A Case Report and Review of the Literature. AB - Clindamycin is a bacteriostatic lincosamide antibiotic with a broad spectrum. Side effects include nausea, vomiting, diarrhea, and metallic taste; however, hepatotoxicity is rare. The incidence is unknown. It is characterized by increases in aspartate and alanine transaminases. There may be no symptoms and the treatment is to stop the administration of clindamycin. We have described a 62-year-old African American female medicated with acetaminophen and clindamycin who had initially presented to the dental clinic for the evaluation of gum pain following tooth extraction. She had significantly increased levels of liver transaminases, which trended downwards on quitting the medication. PMID- 27462475 TI - Appendagitis following Diagnostic Laparoscopy and Laparoscopic Appendicectomy. AB - Appendagitis is an uncommon clinical entity, often not recognised, and mistaken for more serious infective conditions. We describe a proven case of appendagitis which occurred after confirmed appendicitis. We postulate that this condition can coexist with appendicitis and indeed may be the result of coinflammation. This has several implications. Firstly, clinicians must retain an index of suspicion for this condition in a patient with localised abdominal pain which occurs after appendicitis. Secondly, it would be reasonable to suggest careful examination of colocated appendages in a patient with an otherwise normal-appearing appendix. Treatment might require laparoscopic resection, as performed in this case. PMID- 27462476 TI - The Invention and Early History of the N-Localizer for Stereotactic Neurosurgery. AB - Nearly four decades after the invention of the N-localizer, its origin and history remain misunderstood. Some are unaware that a third-year medical student invented this technology. The following conspectus accurately chronicles the origin of the N-localizer, presents recently discovered evidence that documents its history, and corrects misconceptions related to its origin and early history. PMID- 27462477 TI - Assessment of Simple Gait Related Dual and Triple Tests in Predicting the Risk of Fall in Adults Above Age of 50 years. AB - Timed UP and Go Test (TUG) is conventionally used as predictor of falls in adults. Routine daily activities include multiple tasks performed concurrently. When two or more tasks (Dual/Triple test) needed to be carried out concurrently, task performance declined at least in one of them. Our study aimed to find temporal and demographic variations in the performance after adding a cognitive, motor or both tasks, while performing TUG, compared to performance during conventional TUG. Sixty randomly selected healthy adults, with age ranging from 53 to 90 years, consented to participate in the study. Each participant underwent six tests (Conventional TUG, Motor TUG, Cognitive TUG, Motor and Cognitive TUG, Visuospatial TUG, Motor and Visuospatial TUG), with time measured in seconds. 6 (10%) had a previous history of fall. Triple test identified the highest number of participants at risk of fall (16.67%). One way ANOVA test showed significant temporal variation with the addition of task (p value< 0.0002). There was moderate positive correlation of age with the time taken to perform each test with addition of task. Conventional TUG in itself was found to be most sensitive and specific test to identify fallers. Though dual and triple task tests were also comparable, addition of task to TUG is not a sensitive indicator to identify fallers as compared to TUG. PMID- 27462478 TI - Biologics and Pediatric Generalized Pustular Psoriasis: An Emerging Therapeutic Trend. AB - Generalized pustular psoriasis (GPP) is a rare form of childhood psoriasis, often requiring systemic therapy, which is challenging as there is a paucity of randomized controlled trials and standardized guidelines. Biologic agents have been used in adults and in pediatric plaque psoriasis, but evidence regarding their efficacy in pediatric GPP has slowly become available. The objective of this study is to summarize and compare the efficacy and safety of biologic agents, such as etanercept, infliximab, and adalimumab, in the treatment of pediatric GPP. A PubMed literature review was conducted and 12 studies met the inclusion criteria for analysis. After reviewing the efficacy of these drugs in pediatric GPP patients and their safety in the use of other pediatric conditions, etanercept was identified as a possible first-line biologic agent for pediatric psoriasis, including GPP, followed by infliximab and adalimumab. In conclusion, several case reports have documented the successful use of biologic agents in refractory cases of pediatric GPP, but clinical trials are needed to gain a better understanding of the efficacy and side effect profile in this population. PMID- 27462480 TI - A Series of Cerebral Venous Sinus Thromboses Treated with Intra-Arterial tPA infused over Ten Hours with a 0.027-inch Catheter and Literature Review. AB - Cerebral venous sinus thrombosis (CVST) can have devastating results, with mortality reported in 44% of cases. No randomized trials exist in order to define what qualifies as failure of conservative therapy, and there is no specific intervention to date which is considered safe and effective. Case series suggest that thrombolysis infusion is safer than thrombectomy, but methods of administration, dose, and duration of therapy tend to vary widely. We present three consecutive CVST patients treated with heparin who suffered both clinical and radiographic deterioration, and went on to have endovascular therapy. Each patient was successfully recanalized by placing a 0.027-inch microcatheter at the proximal portion of the thrombus and infusing 20 mg of alteplase dissolved in 1 liter of normal saline infused at 100 ml per hour for an infusion of 2 mg of alteplase per hour for ten hours. PMID- 27462479 TI - Focal Correction of Severe Fixed Kyphosis with Single Level Posterior Ponte Osteotomy and Interbody Fusion. AB - OBJECTIVE: To report the successful correction of a severe, fixed kyphotic deformity utilizing a combination posterior lumbar interbody fusion (PLIF) and Ponte osteotomy at the site of acute kyphosis. SUMMARY OF BACKGROUND DATA: There have been no reports on the experience and surgical strategy of combined one level focal PLIF and Ponte osteotomy for fixed severe kyphotic deformity. Typically, these corrections would need a pedicle subtraction osteotomy or a vertebrectomy. METHODS: A 24-year-old man presented with progressive back pain and a fixed severe thoracolumbar kyphosis centered at the L2-L3 disc space seven years after removal of instrumentation for intractable infection following correction of Scheuermann's Kyphosis. The patient also demonstrated pseudoarthrosis of the posterior thoracolumbar fusion bed. The original operative plan was to perform a vertebral column resection (VCR) of L2 to correct his severe kyphosis. During preparation for the VCR, the patient's deformity corrected completely after insertion of blunt distraction paddles for the interbody fusion after the Ponte osteotomy at L2-L3. A VCR was avoided, and the construct was able to be completed with simple rod insertion and posterolateral fusion. RESULTS: The described technique achieved 69 degrees of correction at the L2-L3 disc space without any remodeling of the surrounding vertebrae. The C7 plumb line was normalized, and the patient was able to stand upright with horizontal gaze and without pre-existing discomfort. At the six-month follow-up, the patient reported a significant improvement in pain and was able to resume normal activities. PMID- 27462481 TI - Effects of wall suction/blowing on two-dimensional flow past a confined square cylinder. AB - A numerical simulation is conducted to study the laminar flow past a square cylinder confined in a channel (the ratio of side length of the square to channel width is fixed at 1/4) subjected to a locally uniform blowing/suction speed placed at the top and bottom channel walls. Governing equations with boundary conditions are resolved using a finite volume method in pressure-velocity formulation. The flow patterns relevant to the critical spacing values are investigated. Numerical results show that wall blowing has a stabilizing effect on the flow, and the corresponding critical Reynolds number increases monotonically with increasing blowing velocity. Remarkably, steady asymmetric solutions and hysteretic mode transitions exist in a certain range of parameters (Reynolds number and suction speed) in the case of suction. PMID- 27462482 TI - Global [Formula: see text] stabilization of fractional-order memristive neural networks with time delays. AB - This article is concerned with the global [Formula: see text] stabilization for a class of fractional-order memristive neural networks with time delays (FMDNNs). Two kinds of control scheme (i.e., state feedback control law and output feedback control law) are employed to stabilize a class of FMDNNs. Several stabilization conditions in form of algebraic criteria are presented based on a new fractional order Lyapunov function method and Leibniz rule. Some examples are given to substantiate the effectiveness of the presented theoretical results. PMID- 27462483 TI - Genetic characterization of commensal Escherichia coli isolated from laboratory rodents. AB - BACKGROUND: Escherichia coli, a commensal in the intestines of vertebrates, is capable of colonizing many different hosts and the environment. Commensal E. coli strains are believed to be the precursor of pathogenic strains by means of acquisition of antimicrobial resistant and virulence genes. Laboratory rodents are inherently susceptible to numerous known infectious agents, which could transfer virulence determinants to commensal E. coli. Hence, in this study, the genetic structure of commensal E. coli found in laboratory rodents and their antimicrobial resistance profiles were investigated. RESULTS: E. coli strains belonging to phylogroup A were the predominant strain obtained from the animals used in the study. Four novel sequence types (ST746, ST747, ST748 and ST749) were discovered using the multi locus sequence typing, together with one common ST357 in the gastrointestinal tract, liver and, the trachea and lung. Serotyping demonstrated that these commensal E. coli strains were non-Shiga toxin-producers. Phenotypic and genotypic analyses of extended spectrum beta lactamases were also negative. CONCLUSIONS: These findings implied that the E. coli strains recovered from the laboratory rodents were truly commensal in nature. Further study is required to investigate the possible influence of gender on the susceptibility of hosts to E. coli colonization in laboratory rodents. PMID- 27462484 TI - Evaluation of different time domain peak models using extreme learning machine based peak detection for EEG signal. AB - Various peak models have been introduced to detect and analyze peaks in the time domain analysis of electroencephalogram (EEG) signals. In general, peak model in the time domain analysis consists of a set of signal parameters, such as amplitude, width, and slope. Models including those proposed by Dumpala, Acir, Liu, and Dingle are routinely used to detect peaks in EEG signals acquired in clinical studies of epilepsy or eye blink. The optimal peak model is the most reliable peak detection performance in a particular application. A fair measure of performance of different models requires a common and unbiased platform. In this study, we evaluate the performance of the four different peak models using the extreme learning machine (ELM)-based peak detection algorithm. We found that the Dingle model gave the best performance, with 72 % accuracy in the analysis of real EEG data. Statistical analysis conferred that the Dingle model afforded significantly better mean testing accuracy than did the Acir and Liu models, which were in the range 37-52 %. Meanwhile, the Dingle model has no significant difference compared to Dumpala model. PMID- 27462485 TI - Delineation of attenuation of oxidative stress and mutagenic stress by Murraya exotica L. leaves. AB - BACKGROUND: Murraya exotica L., a member of family Rutaceae is rich in biologically active secondary metabolites and also known for its ethnobotanical importance. With this in mind, the plant was chosen and leaves were extracted sequentially to obtain ethanol, hexane, chloroform, ethyl acetate, n-butanol and aqueous fractions. The extract/fractions were evaluated for total phenolic and flavonoid content by spectrophotometric methods. The UHPLC technique was employed for profiling the different polyphenolic compounds present in the extract/fractions. Furthermore, the extract/fractions were analysed for the antioxidant and antimutagenic activities using different in vitro assays. RESULTS: It was observed that, among the different extract/fractions, ethyl acetate fraction exhibited maximum total phenolic content i.e. 119.6 mg of GAE/g whereas chloroform fraction showed maximum total flavonoid content i.e. 323.5 mg of RE/g. Likewise, UHPLC method also showed maximum number as well as amount of polyphenolic compounds in ethyl acetate fraction. It was further analyzed that the same fraction exhibited the maximum radical scavenging activity in all antioxidant assays. In Ames assay, ethyl acetate fraction again showed maximum antimutagenic activity of 97.70 % against the 2-aminofluorene mutagen in TA100 tester strain of Salmonella typhimurium. CONCLUSION: Overall, among all the extract/fractions, ethyl acetate fraction was observed to be highly effective in scavenging the free radical as well as reducing the mutagenic effect of the mutagen. The maximum bioactivities of the ethyl acetate fraction may be linked to the presence of high number of polyphenolic compounds as shown by spectrophotometric as well as UHPLC methods. PMID- 27462486 TI - CO2-storage assessment and effective capacity in Algeria. AB - Deep saline aquifers widely distributed deep in the earth offer the greatest CO2 storage potential in all current geological CO2 storage approaches. The western region of the Saharan platform in Algeria includes several sedimentary basins characterized by a large production of dry gas with high CO2 rates sometimes exceeding 9 %. To reduce CO2 emissions, these basins were analyzed to identify those with the largest potential for the geological sequestration of CO2 (GSC). The evaluation methodology applied to determine the basin potential is based on qualitative geological and practical criteria to which we have assigned normalized numerical values. This evaluation method allows us to quantitatively compare and evaluate the basins in Algeria. Estimations of the CO2 storage capacities of several structures in the sedimentary Ahnet-Gourara Basin, which has the greatest potential for GSC, vary from 1 Gt to over 5 Gt. Based on cautious estimations, these geologic structures should be able to contain the entire volume of the CO2 emitted over the next three decades at least. PMID- 27462487 TI - Determinants for the success of regional ICT ventures: a close examination of South Korea. AB - BACKGROUND: This study identifies the key motivational factors in enhancing economic performance and increasing new job opportunities for information and communication technology ventures (ICTVs) in South Korea and examines their potential causal relationships through structural equation modeling analysis on data collected from over 200 ICTVs located in Daedeok Innopolis. RESULTS: The results indicate that the economic performance of ICTVs is determined mainly by government support, innovation effort, and private equity and support. Government support and innovation effort are also positively associated with new job opportunities. CONCLUSIONS: The theoretical, industrial implications of the key findings, and recommendations for the Korean government are discussed. PMID- 27462488 TI - Enhanced xylose fermentation and hydrolysate inhibitor tolerance of Scheffersomyces shehatae for efficient ethanol production from non-detoxified lignocellulosic hydrolysate. AB - Effective conversion of xylose into ethanol is important for lignocellulosic ethanol production. In the present study, UV-C mutagenesis was used to improve the efficiency of xylose fermentation. The mutated Scheffersomyces shehatae strain TTC79 fermented glucose as efficiently and xylose more efficiently, producing a higher ethanol concentration than the wild-type. A maximum ethanol concentration of 29.04 g/L was produced from 71.31 g/L xylose, which was 58.95 % higher than that of the wild-type. This mutant also displayed significantly improved hydrolysate inhibitors tolerance and increased ethanol production from non-detoxified lignocellulosic hydrolysates. The ethanol yield, productivity and theoretical yield by TTC79 from sugarcane bagasse hydrolysate were 0.46 g/g, 0.20 g/L/h and 90.61 %, respectively, while the corresponding values for the wild-type were 0.20 g/g, 0.04 g/L/h and 39.20 %, respectively. These results demonstrate that S. shehatae TTC79 is a useful non-recombinant strain, combining efficient xylose consumption and high inhibitor tolerance, with potential for application in ethanol production from lignocellulose hydrolysates. PMID- 27462489 TI - Inhibition of astrocyte metabolism is not the primary mechanism for anaesthetic hypnosis. AB - Astrocytes have been promoted as a possible mechanistic target for anaesthetic hypnosis. The aim of this study was to explore this using the neocortical brain slice preparation. The methods were in two parts. Firstly, multiple general anaesthetic compounds demonstrating varying in vivo hypnotic potency were analysed for their effect on "zero-magnesium" seizure-like event (SLE) activity in mouse neocortical slices. Subsequently, the effect of astrocyte metabolic inhibition was investigated in neocortical slices, and compared with that of the anaesthetic drugs. The rationale was that, if suppression of astrocytes was both necessary and sufficient to cause hypnosis in vivo, then inhibition of astrocytic metabolism in slices should mimic the anaesthetic effect. In vivo anaesthetic potency correlated strongly with the magnitude of reduction in SLE frequency in neocortical slices (R(2) 37.7 %, p = 0.002). Conversely, SLE frequency and length were significantly enhanced during exposure to both fluoroacetate (23 and 20 % increase, respectively, p < 0.01) and aminoadipate (12 and 38 % increase, respectively, p < 0.01 and p < 0.05). The capacity of an anaesthetic agent to reduce SLE frequency in the neocortical slice is a good indicator of its in vivo hypnotic potency. The results do not support the hypothesis that astrocytic metabolic inhibition is a mechanism of anaesthetic hypnosis. PMID- 27462490 TI - An improved generalized Newton method for absolute value equations. AB - In this paper, we suggest and analyze an improved generalized Newton method for solving the NP-hard absolute value equations [Formula: see text] when the singular values of A exceed 1. We show that the global and local quadratic convergence of the proposed method. Numerical experiments show the efficiency of the method and the high accuracy of calculation. PMID- 27462491 TI - Calciphylaxis following acute renal injury: a case and literature review. AB - BACKGROUND: Calciphylaxis following acute renal failure is rare. FINDINGS: We report A 57-year-old male with an acute renal failure associated with necrotizing fasciitis. We also review the cases of calciphylaxis due to acute renal disorder further. CONCLUSIONS: It should be kept in mind that calciphylaxis is observed in patient with not only chronic renal disease but also acute renal failure. PMID- 27462492 TI - The delta high-density lipoprotein cholesterol ratio: a novel parameter for gram negative sepsis. AB - OBJECTIVE: To study changes in blood lipid metabolism in sepsis patients, especially high-density lipoprotein cholesterol (HDL-C) changes in the diagnosis of sepsis and the type of bacteria involved. METHODS: Two-hundred-twenty cases of patients with febrile infections were divided into local infection, systemic inflammatory response syndrome or sepsis (sepsis) group. For controls, 81 cases of patients with a healthy check-up were used. Lipid levels and inflammatory state were supervised, and a comparative analysis of patients admitted to the hospital after 1, 5, 10 days was performed. RESULTS: In patients with sepsis, total cholesterol, HDL-C, and apolipoprotein A 1 (apoA 1) were significantly decreased in this group. Particularly HDL-C was decreased 1 day after admission. Compared with the patients with gram-positive sepsis, HDL-C and apoA1 were significantly reduced in the patients with gram-negative sepsis at admission. The 24-h change ratio of HDL-C was different between the gram-negative and gram positive sepsis patients with a 70.5 % specificity and 76.5 % sensitivity. The area under the curve was 0.744, and the critical value was -21.1 %. CONCLUSIONS: The sepsis patients had lower HDL-C than the other groups. The 24-h change ratio of HDL-C can be used as a sepsis diagnosis maker and to distinguish between the bacteria involved in sepsis. PMID- 27462493 TI - Biometrics based authentication scheme for session initiation protocol. AB - Many two-factor challenge-response based session initiation protocol (SIP) has been proposed, but most of them are vulnerable to smart card stolen attacks and password guessing attacks. In this paper, we propose a novel three-factor SIP authentication scheme using biometrics, password and smart card, and utilize the pi calculus-based formal verification tool ProVerif to prove that the proposed protocol achieves security and authentication. Furthermore, our protocol is highly efficient when compared to other related protocols. PMID- 27462494 TI - Quantification of protein Z expression in lung adenocarcinoma tissues and cells. AB - As a regulator of coagulation, abnormal Protein Z (PZ) expression may lead to the formation of blood clots in humans. While previous studies have shown that PZ protein is altered in several types of cancer, however, additional observations are needed to understand the complex biology involved. Herein, we investigated local alterations in PZ expression in lung adenocarcinomas by measuring gene and protein expression in both cancerous and normal lung tissues. Twenty-two (22) specimens of lung adenocarcinoma and 22 specimens of normal lung tissues from human patients were compared for the expression of PZ. In addition, A549 adenocarcinoma cells were compared to a normal epithelial cell line, 16-HBE, for in vitro PZ expression. In tissues and cells, PZ protein and gene expression were determined using western blot, immunohistochemistry and PCR. Lung adenocarcinoma tissues showed elevated expression of both PZ mRNA and protein compared with healthy tissue. Only protein expression was increased in cultured cell lines, which holds implications for the dominant source of PZ in tissues, as well as protein modifications necessary for PZ function. Protein Z appears to be associated with the presence of lung adenocarcinoma and may be a viable prognostic biomarker for lung cancer. PMID- 27462495 TI - Effects of compression clothing on speed-power performance of elite Paralympic sprinters: a pilot study. AB - BACKGROUND: Compression garments are thought to aid performance in some selected speed-power activities owing to improved sensory feedback and proprioception. The aim of this study was to test the effects of using compression garments on speed and power-related performances in elite sprinters with visual impairment, who rely more on proprioception to perform than their Olympic peers. Eight top-level Paralympic sprinters competing in 100- and 200-m races performed, in the following order: unloaded squat jump (SJ), loaded jump squat (JS) and sprint tests over 20- and 70-m distances; using or not the compression garment. The maximum mean propulsive power value obtained during the JS attempts (starting at 40 % of their body mass, after which a load of 10 % of body mass was progressively added) was considered for data analysis purposes. The athletes executed the SJ and JS attempts without any help from their guides. Magnitude based inference was used to analyze the results. FINDINGS: The unloaded SJ was possibly higher in the compression than the placebo condition (41.19 +/- 5.09 vs. 39.49 +/- 5.75 cm). Performance differences in the loaded JS and sprint tests were all rated as unclear. CONCLUSIONS: It was concluded that the acute enhancement in vertical jump ability should be explored in the preparation of Paralympic sprinters during power-related training sessions. However, chronic effects in Paralympic athletes wearing compression garments need to be further tested, in order to support its use as a specific training aid. PMID- 27462496 TI - Health-related quality of life and depression among medical sales representatives in Pakistan. AB - Pharmaceutical companies have been known to pose stress and mental harassment on medical sales representatives (MSRs) in-order to increase pharmaceutical sales. This cross sectional descriptive study, conducted during November and December 2014 in the Lahore and Bahawalpur districts of Punjab, Pakistan, evaluates the Health-Related Quality of Life (HRQoL) and extent of depression among MSRs in Pakistan. The significant predictors of HRQoL and depression among the MSRs were also determined. Using a convenience sampling technique, all consenting MSRs (N = 318) of pharmaceutical companies were asked to self-complete the Short Form-36 (SF-36v2) Health Survey and Stanford Personal Health Questionnaire (PHQ-8). The standard scoring scheme for the SF36v2 and PHQ-8 questionnaires was used. The PHQ 8 scores showed that 16.4 % (n = 52) and 2.5 % of respondents were suffering from major depression and severe major depression, respectively. Being depressed and having difficulty in achieving sales targets were the factors independently associated with lower physical health. Similarly, depression, insufficient time for the family and monthly income less than 36,000 Pakistan Rupees were significant predictors of lower mental health. The factors associated with depression included insufficient time for the family and unsatisfactory behavior of the managers. Compromised mental health and the prevalence of depression among the MSRs suggest pharmaceutical companies need to devise health management strategies and interventions to ensure effective prevention and management of mental health problems among Pakistani MSRs. PMID- 27462497 TI - Existence detection and embedding rate estimation of blended speech in covert speech communications. AB - Covert speech communications may be used by terrorists to commit crimes through Internet. Steganalysis aims to detect secret information in covert communications to prevent crimes. Herein, based on the average zero crossing rate of the odd even difference (AZCR-OED), a steganalysis algorithm for blended speech is proposed; it can detect the existence and estimate the embedding rate of blended speech. First, the odd-even difference (OED) of the speech signal is calculated and divided into frames. The average zero crossing rate (ZCR) is calculated for each OED frame, and the minimum average ZCR and AZCR-OED of the entire speech signal are extracted as features. Then, a support vector machine classifier is used to determine whether the speech signal is blended. Finally, a voice activity detection algorithm is applied to determine the hidden location of the secret speech and estimate the embedding rate. The results demonstrate that without attack, the detection accuracy can reach 80 % or more when the embedding rate is greater than 10 %, and the estimated embedding rate is similar to the real value. And when some attacks occur, it can also reach relatively high detection accuracy. The algorithm has high performance in terms of accuracy, effectiveness and robustness. PMID- 27462498 TI - Elastic-plastic model identification for rock surrounding an underground excavation based on immunized genetic algorithm. AB - To compute the stability of underground engineering, a constitutive model of surrounding rock must be identified. Many constitutive models for rock mass have been proposed. In this model identification study, a generalized constitutive law for an elastic-plastic constitutive model is applied. Using the generalized constitutive law, the problem of model identification is transformed to a problem of parameter identification, which is a typical and complicated optimization. To improve the efficiency of the traditional optimization method, an immunized genetic algorithm that is proposed by the author is applied in this study. In this new algorithm, the principle of artificial immune algorithm is combined with the genetic algorithm. Therefore, the entire computation efficiency of model identification will be improved. Using this new model identification method, a numerical example and an engineering example are used to verify the computing ability of the algorithm. The results show that this new model identification algorithm can significantly improve the computation efficiency and the computation effect. PMID- 27462499 TI - Prediction of in-hospital stroke mortality in critical care unit. AB - BACKGROUND: Critical stroke causes high morbidity and mortality. We examined if variables in the early stage of critical stroke could predict in-hospital mortality. METHODS: We recruited 611 ischemic and 805 hemorrhagic stroke patients who were admitted within 24 h after the symptom onset. Data were analyzed with independent t test and Chi square test, and then with multivariate logistic regression analysis. RESULTS: In ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score (OR 1.08; 95 % CI 1.06-1.11; P < 0.01), white blood cell count (OR 1.11; 95 % CI 1.05-1.18; P < 0.01), systolic blood pressure (BP) (OR 0.49; 95 % CI 0.26-0.90; P = 0.02) and age (OR 1.03; 95 % CI 1.00-1.05; P = 0.03) were associated with in-hospital mortality. In hemorrhagic stroke, NIHSS score (OR 1.12; 95 % CI 1.09-1.14; P < 0.01), systolic BP (OR 0.25; 95 % CI 0.15 0.41; P < 0.01), heart disease (OR 1.94; 95 % CI 1.11-3.39; P = 0.02) and creatinine (OR 1.16; 95 % CI 1.01-1.34; P = 0.04) were related to in-hospital mortality. Nomograms using these significant predictors were constructed for easy and quick evaluation of in-hospital mortality. CONCLUSION: Variables in acute stroke can predict in-hospital mortality and help decision-making in clinical practice using nomogram. PMID- 27462500 TI - Prediction of ovarian function in premenopausal breast cancer patients with amenorrhoea after chemotherapy: a simple clinical score. AB - We evaluated a non-invasive method for predicting the ovarian function of premenopausal breast cancer patients with amenorrhoea after chemotherapy. A total of 34 patients had ovarian function, whereas 56 had no ovarian function. Logistic regression analysis indicated that age (P = 0.034; hazards ratio [HR], 0.29; confidence interval [CI], 0.091-0.910), follicle-stimulating hormone (P = 0.032; HR 0.97; CI 0.944-0.997) and oestradiol (P = 0.047; HR 1.01; CI 1.000-1.015) were independent influencing factors that determine ovarian function. The ovarian function score (OFS) (P < 0.001; HR 48.00; CI 10.174-226.452) was obtained through a comprehensive analysis of these three variables, and it could more effectively predict ovarian function. According to receiver operating characteristic curve analysis, the OFS had the highest values compared with the other three variables (sensitivity, 94.6 %; specificity, 79.3 %). The OFS is simple and easy to use; thus, it is expected to become a new method for determining drug-induced amenorrhoea in women with breast cancer. Ovarian function likely still exists if the OFS is <=1. PMID- 27462501 TI - A semi-active Hinfinity control strategy with application to the vibration suppression of nonlinear high-rise building under earthquake excitations. AB - Different from previous researches which mostly focused on linear response control of seismically excited high-rise buildings, this study aims to control nonlinear seismic response of high-rise buildings. To this end, a semi-active control strategy, in which Hinfinity control algorithm is used and magneto rheological dampers are employed for an actuator, is presented to suppress the nonlinear vibration. In this strategy, a modified Kalman-Bucy observer which is suitable for the proposed semi-active strategy is developed to obtain the state vector from the measured semi-active control force and acceleration feedback, taking into account of the effects of nonlinearity, disturbance and uncertainty of controlled system parameters by the observed nonlinear accelerations. Then, the proposed semi-active Hinfinity control strategy is applied to the ASCE 20 story benchmark building when subjected to earthquake excitation and compared with the other control approaches by some control criteria. It is indicated that the proposed semi-active Hinfinity control strategy provides much better control performances by comparison with the semi-active MPC and Clipped-LQG control approaches, and can reduce nonlinear seismic response and minimize the damage in the buildings. Besides, it enhances the reliability of the control performance when compared with the active control strategy. Thus, the proposed semi-active Hinfinity control strategy is suitable for suppressing the nonlinear vibration of high-rise buildings. PMID- 27462502 TI - Dormant micro arteriovenous malformations lead to recurrent cerebral haemorrhage. AB - INTRODUCTION: Some micro arteriovenous malformations (AVMs) located in deep brain are undetectable. How to choose a proper timing to detect these AVMs remains unclear. CASE DESCRIPTION: A 21-year-old male patient was admitted to our center for intraventricular haematoma. Digital subtraction angiographies (DSAs) were performed one week and one month respectively after his haemorrhage, but no positive results were obtained. The patient was hospitalized for re-haemorrhage six years later. A micro AVM with two diffused niduses was detected and embolised three months after his re-haemorrhage. The patient recovered without any neurological deficit. DISCUSSION AND EVALUATION: Compressive effects of haematoma and spontaneous obliteration of AVMs might play pivotal roles in negative DSA results. CONCLUSIONS: Strategic and timely use of DSA could identify some dormant re-haemorrhagic AVMs. PMID- 27462503 TI - Mathematical analysis of a nutrient-plankton system with delay. AB - A mathematical model describing the interaction of nutrient-plankton is investigated in this paper. In order to account for the time needed by the phytoplankton to mature after which they can release toxins, a discrete time delay is incorporated into the system. Moreover, it is also taken into account discrete time delays which indicates the partially recycled nutrient decomposed by bacteria after the death of biomass. In the first part of our analysis the sufficient conditions ensuring local and global asymptotic stability of the model are obtained. Next, the existence of the Hopf bifurcation as time delay crosses a threshold value is established and, meanwhile, the phenomenon of stability switches is found under certain conditions. Numerical simulations are presented to illustrate the analytical results. PMID- 27462505 TI - Erratum to: Level of habitual physical activity in children and adolescents from the Region of Murcia (Spain). AB - [This corrects the article DOI: 10.1186/s40064-016-2033-8.]. PMID- 27462504 TI - Once-weekly teriparatide improves glucocorticoid-induced osteoporosis in patients with inadequate response to bisphosphonates. AB - BACKGROUND: Patients with glucocorticoid-induced osteoporosis (GIOP) are at very high risk of fracture, and patients with severe GIOP often experience fractures during treatment with bisphosphonates. Teriparatide (TPTD) is the only currently available anabolic agent expected to be effective for GIOP. Once-weekly TPTD decreased bone resorption marker with primary osteoporosis different from daily TPTD, but it has not yet been tested with GIOP. OBJECTIVES: To evaluate the efficacy of once-weekly TPTD for patients with GIOP and inadequate response to bisphosphonates. METHODS: Patients with GIOP and collagen diseases treated with prednisolone for at least 6 months with inadequate responses to bisphosphonates were administered once-weekly TPTD. Bone density of the lumbar spine and femoral neck, measured as percent young adult mean (YAM); serum concentrations of cross linked N-terminal telopeptides of type I collagen (NTx), bone alkaline phosphatase (BAP), and calcium; and FRAX were measured at baseline and 6, 12 and 18 months after starting TPTD. RESULTS: Of the 12 GIOP patients with collagen diseases enrolled, nine (seven females, two males; mean age 57.4 +/- 11.1 years) completed treatment, including six with systemic lupus erythematosus, two with rheumatoid arthritis, and one with adult onset still disease. Only one new fracture event, a lumbar compression fracture, occurred during the study period, although seven patients experienced eight fracture events within 18 months before starting TPTD (p = 0.04). Lumbar spine YAM significantly improved at 18 months (p = 0.04), whereas femoral neck YAM did not (p = 0.477). Serum NTx, BAP, Ca, and FRAX were not significantly affected by TPTD treatment. CONCLUSIONS: Once-weekly TPTD reduces fracture events and increases bone density of the lumbar spine of GIOP patients with inadequate response to bisphosphonates. PMID- 27462506 TI - Sucrose and KF quenching system for solution phase parallel synthesis. AB - The KF, sucrose (table sugar) exploited as quenching system in solution phase parallel synthesis. Excess of electrophiles were covalently trapped with hydroxyl functionality of sucrose and due to polar nature of sucrose derivative was solubilize in water. Potassium fluoride used to convert various excess electrophilic reagents such as acid chlorides, sulfonyl chlorides, isocyanates to corresponding fluorides, which are less susceptible for hydrolysis and subsequently sucrose traps these fluorides and dissolves them in water thus removing them from reaction mixture. Various excess electrophilic reagents such as acid chlorides, sulfonyl chlorides, and isocyanates were quenched successfully to give pure products in excellent yields. PMID- 27462507 TI - Doping offences in male professional tennis: how does sanction affect players' career? AB - BACKGROUND: The use of performance enhancing drugs is still a major problem in competitive sports. Even though tennis is not affected by systematic doping, there is lack of scientific evidence on the effect of sanctions on players' career. The aim of this study was to analyze male tennis players' career after a doping sanction. METHODS: All doping offences committed by male professional tennis players during 2003-2014 were registered from the International Tennis Federation records and analyzed considering three ranking positions: at sanction date, the peak career position, and the highest position after doping violation. RESULTS: Forty-six players (aged 26.04 +/- 3.48 years) committed 47 doping offences in a 14-year period with an average ineligibility time of 11.13 +/- 9.90 months. Ranking position at sanction date averaged 409.53 +/- 437.53 (median 266); the highest career position averaged 201.12 +/- 293.96 (median 83) and the highest career position after doping violation was 350.85 +/- 441.38 (median 156). Elite players committed less doping offences than players beyond the 100 degrees ranking position (29.78 and 70.21 %, respectively; p < 0.01). Most players (72.34 %) reached their career highest position before the doping sanction (p = 0.01). The average time to retirement was 35.76 +/- 31.03 months, while 12 % did not return to professional tennis competition after the doping offence. CONCLUSIONS: Most suspended tennis players were not elite players. Doping sanction seems to significantly affect male tennis players' career. Only a minority of sanctioned players could reach their peak ranking position after the doping offence and suspension may accelerate the retirement process. PMID- 27462508 TI - Characterization of antimicrobial substance from Lactobacillus salivarius KL-D4 and its application as biopreservative for creamy filling. AB - Lactobacillus salivarius KL-D4 isolated from duck intestine produced bacteriocin which was stable at high temperature and a wide pH range of 3-10. Its cell free supernatant at pH 5.5 exhibited wide inhibitory spectrum against both G+ and G- bacteria. The highest bacteriocin production was obtained in MRS broth supplemented with 0.5 % (w/v) CaCO3 at 6 h by gentle shaking. PCR walking using specific primers at the conserved region of class-II bacteriocin resulted in 4 known genes of kld1, kld2, kld3 and kld4 with 100 % similarity to genes encoding for salivaricin alpha, beta, induction peptide and histidine protein kinase of Lb. salivarius GJ-24 which did not previously report for bacteriocin characterization, while showing 94, 93, 59 and 62 % to other salivaricin gene cluster, respectively. The high activities of 25,600 AU/ml indicated a strong induction peptide expressed by kld3 which has low similarity to previous inducer reported. Based on operon analysis, only kld1, kld3 and kld4 could be expressed and subsequently elucidated that only salivaricin alpha like bacteriocin was produced and secreted out of the cells. Using protein purification, only a single peptide band obtained showed that this strain produced one bacteriocin which could be salivaricin alpha namely salivaricin KLD showing about 4.3 kDa on SDS PAGE. Partial purification by 20 % ammonium sulfate precipitation of the product was tested on the artificial contamination of creamy filling by Bacillus cereus, Enterococcus faecalis, Pseudomonas stutzeri, Staphylococcus sp. and Stenotrophomonas sp. resulting the growth inhibitory efficiency of 4.45-66.9, 11.5-100, 100, 0-28.1 and 5-100 % respectively. Therefore, salivaricin KLD can be a tentative biopreservative for food industry in the future. PMID- 27462509 TI - Flow and heat transfer in a Maxwell liquid film over an unsteady stretching sheet in a porous medium with radiation. AB - A problem of flow and heat transfer in a non-Newtonian Maxwell liquid film over an unsteady stretching sheet embedded in a porous medium in the presence of a thermal radiation is investigated. The unsteady boundary layer equations describing the problem are transformed to a system of non-linear ordinary differential equations which is solved numerically using the shooting method. The effects of various parameters like the Darcy parameter, the radiation parameter, the Deborah number and the Prandtl number on the flow and temperature profiles as well as on the local skin-friction coefficient and the local Nusselt number are presented and discussed. It is observed that increasing values of the Darcy parameter and the Deborah number cause an increase of the local skin-friction coefficient values and decrease in the values of the local Nusselt number. Also, it is noticed that the local Nusselt number increases as the Prandtl number increases and it decreases with increasing the radiation parameter. However, it is found that the free surface temperature increases by increasing the Darcy parameter, the radiation parameter and the Deborah number whereas it decreases by increasing the Prandtl number. PMID- 27462510 TI - Chemometric investigation of light-shade effects on essential oil yield and morphology of Moroccan Myrtus communis L. AB - BACKGROUND: To investigate the effect of environmental factors such as light and shade on essential oil yield and morphological traits of Moroccan Myrtus communis, a chemometric study was conducted on 20 individuals growing under two contrasting light environments. RESULTS: The study of individual's parameters by principal component analysis has shown that essential oil yield, altitude, and leaves thickness were positively correlated between them and negatively correlated with plants height, leaves length and leaves width. Principal component analysis and hierarchical cluster analysis have also shown that the individuals of each sampling site were grouped separately. The one-way ANOVA test has confirmed the effect of light and shade on essential oil yield and morphological parameters by showing a statistically significant difference between them from the shaded side to the sunny one. Finally, the multiple linear model containing main, interaction and quadratic terms was chosen for the modeling of essential oil yield in terms of morphological parameters. CONCLUSIONS: Sun plants have a small height, small leaves length and width, but they are thicker and richer in essential oil than shade plants which have shown almost the opposite. The highlighted multiple linear model can be used to predict essential oil yield in the studied area. PMID- 27462511 TI - Effects of modified electroconvulsive therapy on the electroencephalogram of schizophrenia patients. AB - BACKGROUND: This study aimed to investigate the modified electroconvulsive therapy (MECT) on the electroencephalogram (EEG) of schizophrenia patients. A total of 26 schizophrenia patients who received MECT were recruited. EEG recording was initiated at 30 min before 1st and 6th MECT and terminated on the 2nd day. Images without artifacts were selected for the analysis of delta, theta, alpha1, alpha2 and beta bands. The wave energy at each frequency, index of waves at different bands from the same lead, index of waves at the same band from different leads, time of epileptic discharge, time of resting state, and time to the stable EEG were determined and compared. RESULTS: The energy of slow waves increased. alpha waves reduced, but theta waves increased in the frontotemporal area. The index of theta waves increased. After resting state, brainwaves first occurred in the frontal area. Significant difference was observed in the time to waves returning to normal (P = 0.05). CONCLUSIONS: After MECT, the theta waves in the same lead increases, and its energy also elevates; alpha wave in the frontotemporal area reduces; there is transient reduction in cerebral function during MECT. After electric resting state, brainwaves mainly occur in the frontal area, and the time to brainwaves returning to normal reduces over time after MECT. PMID- 27462512 TI - A range division and contraction approach for nonconvex quadratic program with quadratic constraints. AB - This paper presents a novel range division and contraction approach for globally solving nonconvex quadratic program with quadratic constraints. By constructing new underestimating linear relaxation functions, we can transform the initial nonconvex quadratic program problem into a linear program relaxation problem. By employing a branch and bound scheme with a range contraction approach, we describe a novel global optimization algorithm for effectively solving nonconvex quadratic program with quadratic constraints. Finally, the global convergence of the proposed algorithm is proved and numerical experimental results demonstrate the effectiveness of the proposed approach. PMID- 27462513 TI - Contamination of Ethiopian paper currency notes from various food handlers with E. coli. AB - Contamination rate of Ethiopian paper currency notes handled by various food handlers with Escherichia coli and antimicrobial susceptibility of the isolates was assessed. A total of 384 Ethiopian Birr (ETB) notes were randomly sampled from meat handlers at butchers, bread and the related food handlers at cafeteria, fruit and vegetables handlers at supermarket, and milk sellers both at open market and dairy station. Fifty control new currencies were also sampled from Commercial Bank of Ethiopia. Both surfaces of the currency were swabbed using wet sterile cotton. The swab was overnight incubated in buffered peptone water. A loop full was streaked on eosin methylene blue agar and followed by biochemical test on presumptive E. coli colonies. Randomly selected isolates were exposed to chloramphenicol (C-30 ug), neomycin (N-30 ug), oxytetracycline (OT-30 ug), polymyxin-B (PB-300 IU) and trimethoprim-sulfamethoxazole (SXT-1.25/23.75/ug) susceptibility using disc diffusion techniques. E. coli was not isolated from currency used as control. A total of 288 (75 %) currency notes were found carrying E. coli. E. coli prevalence was ranges from 67.2 % at open market milk sellers to 87.2 % at dairy station milk sellers; from 64.8 % on ETB 100 to 82.9 % on ETB 1. Differences were not observed in E. coli prevalence on currency notes from among almost all food handlers (P > 0.05). Susceptibility of tested isolates to each chloramphenicol, oxytetracycline and trimethoprim-sulfamethoxazole was 100 %, and to polymyxin-B was 97.3 %. High resistance (83.7 %) was observed to neomycin. The finding indicates, contaminated food can be a source of E. coli for further contamination of currency which again transfer through various foods ready for consumption. PMID- 27462514 TI - An effective numerical method to solve a class of nonlinear singular boundary value problems using improved differential transform method. AB - In this work, an effective numerical method is developed to solve a class of singular boundary value problems arising in various physical models by using the improved differential transform method (IDTM). The IDTM applies the Adomian polynomials to handle the differential transforms of the nonlinearities arising in the given differential equation. The relation between the Adomian polynomials of those nonlinear functions and the coefficients of unknown truncated series solution is given by a simple formula, through which one can easily deduce the approximate solution which takes the form of a convergent series. An upper bound for the estimation of approximate error is presented. Several physical problems are discussed as illustrative examples to testify the validity and applicability of the proposed method. Comparisons are made between the present method and the other existing methods. PMID- 27462515 TI - Correlation between Al grain size, grain boundary grooves and local variations in oxide barrier thickness of Al/AlOx/Al tunnel junctions by transmission electron microscopy. AB - A thickness variation of only one Angstrom makes a significant difference in the current through a tunnel junction due to the exponential thickness dependence of the current. It is thus important to achieve a uniform thickness along the barrier to enhance, for example, the sensitivity and speed of single electron transistors based on the tunnel junctions. Here, we have observed that grooves at Al grain boundaries are associated with a local increase of tunnel barrier thickness. The uniformity of the barrier thickness along the tunnel junction thus increases with increasing Al grain size. We have studied the effect of oxidation time, partial oxygen pressure and also temperature during film growth on the grain size. The implications are that the uniformity improves with higher temperature during film growth. PMID- 27462516 TI - Abietane and nor-abitane diterpenoids from the roots of Salvia rhytidea. AB - BACKGROUND: The genus Salvia is a rich source of structurally diverse terpenoids. Different species of the Salvia have been used in folk medicine of Iran and therefore attracted the attention of researchers for exploring their chemical constituents. In a project directed at structurally interesting bioactive metabolites from Iranian Lamiaceae, we studied Salvia rhytidea. RESULTS: Fractionation of the petroleum ether extract of the root of S. rhytidea led to the isolation of a new 20-nor-abietane diterpenoid (1), together with seven known compounds, comprising five abietane diterpenoids (2-6), and two rearranged abietanes (7, 8). Their structures were established by a combination of 1D and 2D NMR. CONCLUSIONS: Our results showed that the root of S. rhytidea could be considered as a new and rich source of different types of abietane and rearranged abietane diterpenoids. PMID- 27462517 TI - An exploratory investigation of changes in gait parameters with age in elderly Japanese women. AB - BACKGROUND: The aim of the present study was to identify gait parameters in elderly Japanese women. 30 elderly women (65-74.9 years old) and 19 very elderly women (>=75 years old) participated in this study. A 3-dimensional (3D) motion analysis system was used to collect kinematic data, and a total of 70 gait parameters were analysed. Gait parameters included basic gait parameters, gait cycle parameters, and joints angle parameters, as well as angular velocity parameters, such as peak velocity and timing at the hip, knee, and ankle joints. RESULTS: Our results indicated that basic gait parameters, such as the gait cycle, peak joint angle timing, and angular velocity parameters, significantly differ between elderly and very elderly women. Delayed peak joint angle timing and angular velocity parameters occurred during critical phases throughout the gait cycle: pre-swing, initial swing, and terminal swing phases. CONCLUSIONS: Several gait parameters exhibited significant differences between elderly and very elderly women. The timing of the peak joint angle and angular velocity parameters are primary characteristics defining gait changes in the elderly. PMID- 27462518 TI - Fampridine and quality of life in individuals with multiple sclerosis. AB - BACKGROUND: Fampridine improves walking in patients with multiple sclerosis (pwMS). However, little is known about its impact on the quality of life (QoL) of pwMS. OBJECTIVES: This study aimed to evaluate the contribution of fampridine on the QoL of pwMS and to determine if improvements in QoL are best associated with walk respondents. METHODS: Fifty pwMS were included in this study. The PERSEPP scale and the GaitRite system were used to evaluate QoL and gait respectively. QoL was evaluated 7 days before fampridine (Pre1), on the day the fampridine treatment was initiated (Pre2), and 14 and 21 days after fampridine (Post1 and Post2 respectively). Gait was assessed at Pre-1, Pre-2 and Post-1. RESULTS: For all patients, fampridine had significant effects (p = 0.05-10(-4), d = 0.25-0.45) on the Overall, Relationship difficulties, Fatigue, Time perspective and Symptoms QoL indices and for gait parameters (p = 0.05-10(-4), d = 0.17-0.38). Non respondents scored significant effects (p < 0.05-0.01, d = 0.32-0.41) for Overall, Time perspective and Symptoms QoL indices, whereas respondents scored significant effects (p < 0.05-0.01, d = 0.51-0.8) for Overall, Relationship difficulties, Fatigue and Symptoms. CONCLUSION: The QoL of pwMS improved after fampridine, suggesting a real benefit in their lives. However, the contributions to the overall QoL index seem different between groups. PMID- 27462519 TI - Non-invasive evaluation of pulmonary arterial blood flow and wall shear stress in pulmonary arterial hypertension with 3D phase contrast magnetic resonance imaging. AB - BACKGROUND: Recently, time-resolved 3D phase contrast magnetic resonance imaging (4D-flow) allows flow dynamics in patients with pulmonary arterial hypertension to be measured. Abnormal flow dynamics, such as vortex blood flow pattern in the pulmonary artery (PA), may reflect progression of pulmonary arterial hypertension (PAH). Some reports suggested that abnormal blood flow parameters including wall shear stress (WSS) could be markers of PAH. However, it was not fully assessed clinical usefulness of these variables. We aimed to assess whether these flow dynamic parameters, such as vortex formation time (VFT) and WSS, were associated with right ventricular (RV) function. RESULTS: Fifteen subjects, nine with PAH and six healthy volunteers, underwent 4D-flow. Differences of Blood flow patterns, blood flow velocities and WSS between PAH patients and healthy volunteers were evaluated. We also assessed the association between VFT, WSS and RV function in PAH patients. Both vortex blood flow patterns and early systolic retrograde flow in the main PA were observed in all patients with PAH. The PA flow velocities and WSS in patients with PAH were lower than those in healthy volunteers, but that blood flow volumes in the MPA, RPA and LPA and SV in the MPA were broadly comparable between the groups. The mean VFT was 35.0 +/- 16.6 % of the cardiac cycle. The VFT significantly correlated with RV ejection fraction, RV end systolic volume, and RV end systolic volume index (RVEF = 75.1 + (-85.7).VFT, p = 0.003, RVESV = 12.4 + 181.8.VFT, p = 0.037 and RVESVI = 10.6 + 114.8.VFT, p = 0.038, respectively) in PAH patients, whereas WSS did not correlate with RV function. CONCLUSIONS: We confirmed that abnormal blood flow dynamics, including the vortex formation and the early onset of retrograde flow, low WSS in the PA were characteristics of PAH. The VFT may be associated with right ventricular dysfunction, whereas WSS was not. Our results suggest that 4D-flow is an effective means of detecting right heart failure as well as diagnosing PAH. CLINICAL TRIAL REGISTRATION URL: https://upload.umin.ac.jp/cgi-open bin/ctr/ctr.cgi. Unique identifier: UMIN000011128. PMID- 27462520 TI - Elevated level of nerve growth factor in the bladder pain syndrome/interstitial cystitis: a meta-analysis. AB - OBJECTIVES: To elucidate the association between nerve growth factor (NGF) level and bladder pain syndrome/interstitial cystitis (BPS/IC) by conducting a meta analysis. METHODS: We conducted a systematic literature search to identify original studies of NGF level in BPS/IC before November 2015. Eligible studies were retrieved via both computer searches and manual review of references. The summary difference estimates between controlled group and BPS/IC group were calculated based on the weighted mean difference (WMD) with its 95 % confidence interval (CI). Sensitivity and publication analyses were performed after the pooled analysis. RESULTS: Meta-analysis of 10 original studies involving 295 cases and 290 normal controls showed an increased level of urinary NGF in BPS/IC patients (z = 3.08, P = 0.002). The combined WMD was 36.39 (95 % CI 13.27-59.51). There was significant difference between controlled group and BPS/IC patients in the term of NGF/Cr level (WMD = 0.96, 95 % CI 0.58-1.35; z = 4.89, P < 0.01). There was no significant publication bias in the included studies (P for Begg's test = 0.73, P for egger's test = 0.13). CONCLUSIONS: Our results demonstrated that there was an increased level of NGF in the BPS/IC patients. PMID- 27462521 TI - Insights into the interactions between tetracycline, its degradation products and bovine serum albumin. AB - Tetracyclines (TCs) are the most widely used antibiotics in the world. Because antibiotics have low bioavailability and are difficult to completely remove using current sewage treatment facilities, residual TCs and their degradation products in the environment, animal and plant foodstuffs and personal care products may enter the body through the food chain, thus causing unpredictable effects on human health. We studied bovine serum albumin (BSA) (a functional protein) as a target of tetracycline-induced toxicity by examining its interactions with TC, anhydrotetracycline (ATC) and epitetracycline (ETC), based on a fluorescence spectroscopy and molecular docking method under simulated physiological conditions. The interaction mechanism was elucidated at the molecular level. The results show that TC, ATC and ETC bind at site II of BSA and interact mainly through hydrogen bonding interactions and van der Waals interactions. The binding affinities can be ranked in the order ATC > TC > ETC. PMID- 27462522 TI - Compressive cryotherapy versus cryotherapy alone in patients undergoing knee surgery: a meta-analysis. AB - AIM: This study aims to conduct a meta-analysis to identify and compare the effectiveness of compressive cryotherapy and cryotherapy alone for patients undergoing knee surgery. BACKGROUND: Postoperative management is an important guarantee for the success of surgery. Cryotherapy and compression are two common nursing techniques after knee surgery, and are considered to be effective for postoperative clinical symptoms such as local pain and swelling. However, no previous meta-analyses have compared the effectiveness of compressive cryotherapy and cryotherapy alone in patients undergoing knee surgery. DESIGN: A meta analysis of randomized controlled trials (RCTs). METHODS: We conducted a search in MEDLINE (via Pubmed, 1990-2014), EMBASE (via Elsevier, 1990-2014), Cochrane Central Register of Controlled Trials (The Cochrane Library, 1990-2014), CINAHL (1990-2014) and China National Knowledge Infrastructure (1990-2014) databases for RCTs published in English and Chinese. The primary outcome measure of interest was visual analog scale and girth measure. Finally, a meta-analysis was carried out using RevMan 5.3. RESULTS: Among the 593 RCTs, 10 RCTs were selected and included into this study. These studies included 522 patients who underwent knee surgery. Patients who underwent compressive cryotherapy tended to have less pain than patients who underwent cryotherapy alone at POD2 and POD3, while compressive cryotherapy had a strong tendency towards less swelling over cryotherapy alone at POD1 and POD2. However, there was no significant difference between compressive cryotherapy and cryotherapy alone at the intermediate stage of rehabilitation after knee surgery. All adverse reactions were recorded in all included RCTs. CONCLUSION: Current evidence suggests that compressive cryotherapy is beneficial to patients undergoing knee surgery at the early rehabilitation stage. At the last stage, the effectiveness of compressive cryotherapy and cryotherapy alone were found to be similar. PMID- 27462523 TI - Experimental analysis and numerical simulation of bed elevation change in mountain rivers. AB - Studies of sediment transport problems in mountainous rivers with steep slopes are difficult due to rapid variations in flow regimes, abrupt changes in topography, etc. Sediment transport in mountainous rivers with steep slopes is a complicated subject because bed materials in mountainous rivers are often heterogeneous and contain a wide range of bed material sizes, such as gravel, cobbles, boulders, etc. This paper presents a numerical model that was developed to simulate the river morphology in mountainous rivers where the maximum bed material size is in the range of cobbles. The governing equations were discretized using a finite difference method. In addition, an empirical bed load formula was established to calculate the bed load transport rate. The flow and sediment transport modules were constructed in a decoupled manner. The developed model was tested to simulate the river morphology in an artificial channel and in the Asungjun River section of the mountainous Yangyang Namdae River (South Korea). The simulation results exhibited good agreement with field data. PMID- 27462524 TI - Reliability analysis using an exponential power model with bathtub-shaped failure rate function: a Bayes study. AB - Models with bathtub-shaped hazard function have been widely accepted in the field of reliability and medicine and are particularly useful in reliability related decision making and cost analysis. In this paper, the exponential power model capable of assuming increasing as well as bathtub-shape, is studied. This article makes a Bayesian study of the same model and simultaneously shows how posterior simulations based on Markov chain Monte Carlo algorithms can be straightforward and routine in R. The study is carried out for complete as well as censored data, under the assumption of weakly-informative priors for the parameters. In addition to this, inference interest focuses on the posterior distribution of non-linear functions of the parameters. Also, the model has been extended to include continuous explanatory variables and R-codes are well illustrated. Two real data sets are considered for illustrative purposes. PMID- 27462525 TI - Headache in Behcet's disease: types and characteristics. AB - BACKGROUND: Behcet's disease involves several systems in the body. Neurological involvement is identified by different symptoms. Headache is one of the common complaints of patients with Behcet's disease. It might be a part of neurological involvement or may arise independently in the course of disease. Studies with small sample size have resulted in various findings in this field. Since the prevalence of Behcet's disease is relatively high in Iran, this study was carried out to compare the features of headache between an acceptable number of patients with this rare disease and a control group. METHODS: The current case-control study was performed to compare the features of headache between 312 patients with definite Behcet's disease who referred to a Behcet's clinic and healthy individuals. Patients with Behcet's disease were randomly selected. Controls were matched for age and sex. They were personally examined and interviewed meticulously using a questionnaire that met the standards of the International Headache Society classification for different types of headache. RESULTS: The incidence of headache in the case and control groups was 28.3 % (n = 120) and 18.6 % (n = 59), respectively (p < 0.05; OR 2.73). Tension-type headache was observed in 12.2 % (n = 38) of cases which was significantly higher than control group (n = 6.3 %) (p = 0.011; OR 2.05). The most frequent type of headache in the case group was tension-type headache (12.2 %). In the control group, however, migraine without aura was the most common type (9.1 %). A correlation between ophthalmological involvement and headache was observed in 11 patients in the case group. In addition, a significantly higher systolic blood pressure was found in the case group compared to the controls (125.1 vs. 121.7 mmHg; p = 0.007). There was no major correlation between prednisolone consumption in patients with Behcet's disease and the type and frequency of headache. CONCLUSIONS: Headache, especially tension-type headache, is more common in patients with Behcet's disease. This might be the result of specific types of uveitis-related and non structural headaches seen in Behcet's disease. PMID- 27462526 TI - Erratum to: Efficient reference-free adaptive artifact cancellers for impedance cardiography based remote health care monitoring systems. AB - [This corrects the article DOI: 10.1186/s40064-016-2461-5.]. PMID- 27462527 TI - Electrocardiography versus photoplethysmography in assessment of maternal heart rate variability during labor. AB - PURPOSE: Evaluation of maternal heart rate (MHR) variability provides useful information on the maternal-fetal clinical state. Electrocardiography (ECG) is the most accurate method to monitor MHR but it may not always be available, and pulse oximetry using photoplethysmography (PPG) can be an alternative. In this study we compared ECG and PPG signals, obtained with conventional fetal monitors, to evaluate signal loss, MHR variability indices, and the ability of the latter to predict fetal acidemia and operative delivery. METHODS: Both signals were simultaneously acquired in 51 term pregnancies during the last 2 h of labor (H1 and H2). Linear time- and frequency-domain, and nonlinear MHR variability indices were estimated, and the dataset was divided into normal and acidemic cases, as well as into normal and operative deliveries. Differences between ECG and PPG signals were assessed using non-parametric confidence intervals, hypothesis testing, correlation coefficient and a measure of disagreement. Prediction of fetal acidemia and operative delivery was assessed using areas under the receiver operating characteristic curve (auROC). RESULTS: Signal loss was higher with ECG during the first segments of H1, and higher with PPG in the last segment of H2, and it increased in both signals with labour progression. MHR variability indices were significantly different when acquired with ECG and PPG signals, with low correlation coefficients and high disagreement for entropy and fast oscillation based indices, and low disagreement for the mean MHR and slow oscillation-based indices. However, both acquisition modes evidenced significant differences between H1 and H2 and comparable auROC values were obtained in the detection of fetal acidemia and operative vaginal delivery. CONCLUSION: Although PPG captures the faster oscillations of the MHR signal less well than ECG and is prone to have higher signal loss in the last 10-min preceding delivery, it can be considered an alternative for MHR monitoring during labor, with adaptation of cut-off values for MHR variability indices. PMID- 27462528 TI - Publicly-funded biobanks and networks in East Asia. AB - With the enactment of the Nagoya Protocol, international competitions to secure biological resources are intensifying. Biobanking is one of the many attempts to preserve biological resources and their information for the use in future research and development. Asian countries, especially China, Japan, and Korea are very active in biobanking activities under the strategic plans coordinated by their governments. They also proactively established networks for biobanks of Asia to facilitate resource and expertise sharing. Biobanks of these countries should furthermore standardize operating procedures and diversify funding sources for establishing stable operation systems. PMID- 27462529 TI - Primary care-public health linkages: Older primary care patients with prediabetes & type 2 diabetes encouraged to attend community-based senior centers. AB - The Institute of Medicine (IOM) suggests that primary care-public health integration can improve health outcomes for vulnerable patients, but the extent to which formal linkages may enhance patients' use of community resources, or the factors that may influence providers to encourage their patients to use these resources, remain unclear. We conducted baseline assessments in 2014-2015 with 149 older adults with prediabetes or diabetes who had recently joined three senior centers linked to a network of primary care clinics in San Antonio, Texas. In addition to collecting sociodemographic and clinical characteristics, we asked members to identify their source of primary care and whether a health care provider had encouraged them to go to the senior center. We also asked members why they had joined the senior centers and which programs interested them the most. Members' source of primary care was not associated with being encouraged to attend the senior centers by a health care professional. Multivariable analysis indicated that participants with total annual household incomes of $20,000 or less [OR = 2.78; 95% CI = (1.05, 7.14)] and those reporting 12 years of education or less [OR = 3.57; 95% CI = (1.11, 11.11)] were significantly more likely to report being encouraged to attend the senior center by a health care provider. Providers who are aware of community-based resources to support patient self management may be just as likely to encourage their socioeconomically vulnerable patients with prediabetes or diabetes to use them as providers who have a more formal partnership with the senior centers. PMID- 27462530 TI - Auxiliary measures to assess factors related to food insecurity: Preliminary testing and baseline characteristics of newly designed hunger-coping scales. AB - The objective of this paper is to describe the development and preliminary testing of new scales to assess hunger-coping behaviors in a very low-income population. Very low-income adults (>= 19 years), caregivers to at least one child (n = 306) completed a survey in a community setting (e.g., libraries). The survey included novel items assessing hunger-coping behaviors (e.g., trade-offs to purchase food, strategies to stretch and obtain food), food insecurity status, and physiological hunger. Internal consistency of hunger-coping scales, one-way ANOVAs, post-hoc analyses, Spearman's correlations among variables. Respondents were 75% female, 51% African American, 34% White, and 15% Hispanic, and 73% earned <$20,000/year. Four scales emerged: hunger-coping trade-offs, financial coping strategies, rationing coping strategies, and physiological adult hunger symptoms. All scales demonstrated acceptable internal consistency (alpha/KR-20 = 0.70-0.90). Predictive, construct, and content validity were demonstrated by correlations between hunger-coping scales and food insecurity (FI), measured with the USDA 6-item HFSSM (rs = 0.42-0.68, ps < 0.001). Higher levels of hunger coping trade-offs (F(2,297) = 42.54, p < 0.001), financial coping strategies (F(2,287) = 70.77, p < 0.001), and rationing coping strategies (F(2,284) = 69.19, p < 0.001), corresponded with increasing levels of FI. These preliminary results support use of newly developed hunger-coping scales in a very low-income population and can compliment traditional food security measures to inform hunger prevention policy and programming. PMID- 27462531 TI - The search for healthy schools: A multilevel latent class analysis of schools and their students. AB - The objective of this study was to establish and investigate a taxonomy of school health among high school students in Ontario, Canada. Data analyzed were based on 3358 9th-12th graders attending 103 high schools who participated in the 2011 Ontario Student Drug Use and Health Survey. Based on 10 health-related indicators, multilevel latent class analysis was used to extract 4 student-level latent classes and 3 school-level latent classes. Unhealthy schools (19% of schools) had the lowest proportion of healthy students (39%) and the highest proportion of substance-using (31%) and unhealthy (18%) students. Healthy schools (66%) contained the highest proportion of healthy students (56%) and smaller proportions of substance-using (22%) and unhealthy students (8%). Distressed schools (15%) were similar to healthy schools in terms of the proportions of healthy and unhealthy students. Distressed schools, however, were characterized by having the largest proportion of distressed students (35%) and the lowest proportion of substance-using students (4%). Meaningful categories of schools with respect to healthy environments can be identified and these categories could be used for focusing interventions and evaluating school health programs. PMID- 27462532 TI - Arthroscopic Removal of Symptomatic Proximal Humerus Locking Plates With Bone Void Filler Augmentation. AB - Open reduction internal fixation of proximal humerus fractures is often accomplished with proximal humerus locking plates. While these plates have a good track record, they can become symptomatic and require removal once the fracture has healed. Open hardware removal is associated with a number of additional risks to the patient, including infection, scarring, nerve damage, and blood loss. In addition, the recovery time after open hardware removal may be prolonged, thereby predisposing the patient to postoperative stiffness. The purpose of this article is to describe a technique for removing proximal humerus locking plates arthroscopically. Although technically demanding, the benefits of this technique include smaller incisions, quicker recovery time, decreased risk of infection, and reduced blood loss. Arthroscopy also provides the surgeon with the ability to address concomitant intra-articular pathology at the time of surgery. Additionally, we use a bone-void filler to reduce the risk of fracture through stress caused by previous screw holes. PMID- 27462533 TI - Arthroscopically Assisted Ligamentoplasty for Axial and Dorsal Reconstruction of the Scapholunate Ligament. AB - Scapholunate (SL) ligament injury is among the most common injuries of the intrinsic ligaments of the carpus. Arthroscopic treatment in complete and nonacute injuries has had poor results. These cases have typically been treated using open surgical techniques that require a broad dorsal approach and produce soft tissue impairment, which leads to reduced wrist mobility. The development of wrist arthroscopy techniques has allowed the treatment of complete and nonacute injuries of the SL ligament, without the disadvantages of open surgery, respecting the soft tissues and avoiding injury of the posterior interosseous nerve, in an attempt to preserve the proprioception of the wrist and the secondary dorsal stabilizers. This arthroscopically assisted technique reconstructs the SL ligament using a tendon graft placed between the scaphoid and lunate and complemented by the reconstruction of the dorsal portion of the SL ligament, with the aim of creating an axial and dorsal tendinous ligamentoplasty between both bones. PMID- 27462534 TI - Arthroscopic Labrum Reconstruction in the Hip Using the Indirect Head of Rectus Femoris as a Local Graft: Surgical Technique. AB - The importance of the acetabular labrum has been well documented for the health and function of the hip joint. Labral reconstruction has proven effective but often requires the use of a cadaveric allograft or auto graft from the fascia lata or gracilis. The indirect head of the rectus femoris is in close proximity with the anterior superior acetabulum, which is the most common site of labral tears. Using the indirect head of the rectus femoris as a local graft minimizes surgical invasiveness by mitigating the need to harvest the graft from a different location, in case of an autograft, and by minimizing donor site morbidity and damage to local tissues. The graft is harvested and fixed to the acetabular rim through the same arthroscopic portals. Hip labral reconstruction using the reflected head of the rectus femoris tendon is a minimally invasive surgical procedure that restores stability to the hip joint, is applicable in all patients undergoing hip labral reconstruction, and offers decreased tissue morbidity compared with other grafting techniques. PMID- 27462535 TI - Hip Capsular Reconstruction Using Dermal Allograft. AB - Because hip arthroscopic procedures are increasing in number, complications related to the operation itself are starting to emerge. Whereas the capsule has been recognized as an important static stabilizer for the hip, it has not been until recently that surgeons have realized the importance of its preservation and restoration. Disruption of the capsule during arthroscopic procedures is a potential contributor to postoperative iatrogenic hip instability. In cases of a symptomatic deficient capsule, a capsular reconstruction is mandatory because instability may lead to detrimental chondral and labral changes. The purpose of this report was to describe our technique for arthroscopic hip capsular reconstruction using dermal allograft. PMID- 27462536 TI - Lateral Meniscal Allograft Transplantation: The Bone Trough Technique. AB - The lateral meniscus plays a critical role in the stability and health of the knee. Treating patients who have undergone a total lateral meniscectomy or functional equivalent is challenging, especially young and active patients. Current literature regarding meniscal tears supports that repair should be the first surgical option. Moreover, it is recommended to preserve as much meniscal tissue as possible. In cases in which a total or functional meniscectomy is a pre existing condition, a lateral meniscal allograft transplantation is a possible option. The purpose of this surgical technique description was to detail the method of lateral meniscal allograft transplantation using a bone trough. PMID- 27462537 TI - Arthroscopic Fixation of Glenoid Rim Fractures After Reduction by Labral Repair. AB - Surgical fixation of displaced, intra-articular glenoid fractures represents a clinical challenge. These fractures have traditionally been treated through open approaches to the glenohumeral joint; however, the morbidity associated with open surgery may be reduced with arthroscopic techniques. Previously described arthroscopic methods commonly use clamps and/or Kirschner wires to obtain and maintain provisional fixation. We describe our technique for minimally invasive, arthroscopic fixation of glenoid rim fractures using labral repair as an indirect reduction maneuver, followed by final fixation with an extra-articular screw. This method is safe, efficient, and reliable, and it can be used to approach a variety of intra-articular glenoid fractures. PMID- 27462538 TI - Transosseous-Equivalent Repair for Distal Patellar Tendon Avulsion. AB - Extensor mechanism disruptions are relatively uncommon injuries involving injury to the quadriceps tendon, patella, or patellar tendon. Patellar tendon avulsions from the tibial tubercle in adults are rare; as such, little technical information has been written regarding surgical management of this injury in the adult. Transosseous-equivalent repairs have been described in the management of several types of tendon ruptures, including rotator cuff and distal triceps tendon ruptures, but not previously in patellar injuries. We present a technique for repairing an avulsion injury of the patellar tendon from the tibial tubercle using suture anchors in a transosseous-equivalent manner. This technique for treating distal patellar tendon avulsion injuries likely increases contact area at the repair site while potentially improving fixation strength. PMID- 27462539 TI - Self-flip Technique of the TightRope RT Button for Soft-Tissue Anterior Cruciate Ligament Reconstruction. AB - The TightRope RT (Arthrex, Naples, FL) is a suspensory device for anterior cruciate ligament reconstruction. However, there is a potential risk of the button being pulled too far off the lateral femoral cortex into the soft tissue because the adjustable loop is long. The purpose of this article is to present an easy and safe technique for self-flip. As to the preparation of the graft, we draw the first line in the loop of the TightRope RT at the same length as the femoral tunnel, and we draw the second line 7 mm longer than the length of the femoral tunnel as a self-flip line. Concerning passing of the graft, the side sutures are pulled from the lateral side. We stop pulling the sutures just at the self-flip line by holding the graft at the tibial end. The side suture is inclined to the medial side with strong pulling of the suture at full extension of the knee. Then the surgeon pulls the tibial end of the graft to feel a secure positioning of the button on the lateral femoral cortex. Although it has limitations, the present technique is easy and certainly helps surgeons achieve appropriate positioning of the button. PMID- 27462540 TI - All-Arthroscopic Implantation of Minced Juvenile Chondral Allograft for an Isolated, Full-Thickness Chondral Lesion in the Trochlea of an Adult Knee. AB - Current use of juvenile chondral allograft (DeNovo; Zimmer, Warsaw, IN) within the knee is an emerging treatment option for full-thickness, isolated chondral lesions. Its implantation traditionally involves a formal arthrotomy for exposure. Arthroscopic implantation minimizes the morbidity associated with this treatment option yet retains the promising functional results already established in the literature. We present a technique for all-arthroscopic implantation of juvenile chondral allograft (DeNovo) for a symptomatic, isolated chondral lesion within the trochlea of an adult knee. PMID- 27462541 TI - Reverse Flipping Technique: An Alternate Approach to Tie Reversing Half-Hitches on Alternating Posts. AB - Arthroscopic knot tying requires practice and attention to detail, especially tying the 3 reversing half-hitches on alternating posts (RHAPs) in a knot. Mistakes can occur that result in an unintentional tension (>10 N) applied to the wrapping suture limb, and by placing tension in the wrong limb, the previously "flipped" half-hitch is converted from a series of RHAPs into a series of identical half-hitches on the same post, thereby producing insecure knots or suture loops. This was hypothesized to be a source of knot failure by knot slippage. This error can be avoided by using a technique we describe as "reverse flipping," which purposely "flips" the half-hitch down at the main knot while tying the 3 RHAPs in a knot, and then the half-hitch is retightened using either a past-pointing or over-pointing technique. This way the surgeon can be absolutely sure that the half-hitch is tightened in the direction that it was intended to be placed, and can also prevent the unintentional tension applied to the wrapping suture limb that causes the half-hitch to "flip." However, caution should be used when tensioning the half-hitches; overtensioning (>40 N) during past-pointing or over-pointing could also potentially "flip" the previous half hitch that has already been tightened and cause potential knot failure. PMID- 27462542 TI - Arthroscopically Assisted Open Reduction-Internal Fixation of Ankle Fractures: Significance of the Arthroscopic Ankle Drive-through Sign. AB - Standalone open reduction-internal fixation (ORIF) of unstable ankle fractures is the current standard of care. Intraoperative stress radiographs are useful for assessing the extent of ligamentous disruption, but arthroscopic visualization has been shown to be more accurate. Concomitant arthroscopy at the time of ankle fracture ORIF is useful for accurately diagnosing and managing syndesmotic and deltoid ligament injuries. The arthroscopic ankle drive-through sign is characterized by the ability to pass a 2.9-mm shaver (Smith & Nephew, Andover, MA) easily through the medial ankle gutter during arthroscopy, which is not usually possible with both an intact deltoid ligament and syndesmosis. This arthroscopic maneuver indicates instability after ankle reduction and fixation and is predictive of the need for further stabilization. Furthermore, when this sign remains positive after fracture fixation, it may guide the surgeon to further evaluate the adequacy of fixation for the possible need for further fixation of the syndesmosis or deltoid. We present the case of an ankle fracture managed with arthroscopy-assisted ORIF and describe the clinical utility of the arthroscopic ankle drive-through sign. PMID- 27462543 TI - Arthroscopic Debridement of Pediatric Accessory Anterolateral Talar Facet Causing Impingement. AB - Symptomatic subfibular and/or lateral talocalcaneal impingement in pediatric patients may result from an accessory anterolateral talar facet (AALTF). This impingement may cause pain and disability and may limit athletic performance in high-level athletes. We report the case of a 12-year-old female competitive gymnast who had refractory, lateral-sided right ankle pain for 4 months and underwent right ankle arthroscopic resection of the AALTF causing impingement. Standard medial and anterolateral portals with the addition of an accessory anterolateral-distal portal were used in conjunction with a 30 degrees 2.7-mm diameter arthroscope. The AALTF was resected with a combination of a shaver and a motorized rasp. Intraoperative fluoroscopy was used to verify successful debridement of the bony facet. This case illustrates that arthroscopic debridement is a technique to treat subfibular and/or talocalcaneal impingement associated with an AALTF. PMID- 27462544 TI - Endoscopic Distal Tibiofibular Syndesmosis Arthrodesis. AB - Chronic distal tibiofibular syndesmosis disruption can be managed by endoscopic arthrodesis of the syndesmosis. This is performed through the proximal anterolateral and posterolateral portals. The scar tissue and bone block are resected to facilitate the subsequent reduction of the syndesmosis. The reduction of the syndesmosis can be guided either arthroscopically or endoscopically. The tibial and fibular surfaces of the tibiofibular overlap can be microfractured to facilitate subsequent fusion. PMID- 27462545 TI - Abdominal Compartment Syndrome and Necrotizing Pancreatitis Following Extracorporeal Shock Wave Lithotripsy. AB - Extracorporeal shock wave lithotripsy (ESWL) is a common procedure in the treatment of renal calculi. There have been major complications reported with ESWL such as acute pancreatitis, bower perforation, venous thrombosis, and biliary obstruction. There are few reports in the literature of necrotizing pancreatitis secondary to ESWL. We have a case report of a 29-year-old female that developed an abdominal compartment syndrome with an acute necrotizing pancreatitis hours after extracorporeal shock wave lithotripsy. PMID- 27462546 TI - Urinary Bladder Xanthoma - Is Immunohistochemistry Necessary? AB - Urinary Bladder Xanthomas (UBX) are non-neoplastic reactive tumor like process. Isolated UBX is rare with only around 15 cases reported (Yu, Patel, & Bonert, 2015). UBX are reported in older patients who present with non specific symptoms like UTI or hematuria. Patients often have associated lipid anomalies. UBX have been vaguely described as yellowish white plaques or patches. Also, recent reports have stressed on the role of Immunohistochemistry in the diagnosis (Al Daraji, Varghese, & Husain, 2007; Vimal, Masih, Manipadam, & Chacko, 2012). The objective of this report is to provide a cystoscopic view of the tumor which will enable easier identification and also to debate on the role of IHC in diagnosis. PMID- 27462547 TI - Operative Management of Crossover Femoral-femoral Graft Erosion into Bladder: A Case Report. AB - Erosion of vascular grafts is not uncommon as seen in the recent literature. There have been many case reports documenting the work up and management of erosion of these grafts into bowel. We report a case of a crossover femoral femoral graft that eroded into the anterior bladder wall and was incidentally found as an adherent bladder stone during cystoscopy. We demonstrate the importance of having a high level of clinical suspicion for eroding vascular grafts when preoperative imaging shows close proximity of graft to bladder. PMID- 27462548 TI - The effect of celery (Apium graveolens) on reproductive parameters in male wistar rat. PMID- 27462549 TI - Phytochemical and pharmacological aspects of Descurainia sophia Webb ex Prantl: modern and traditional applications. AB - Seed of Descurainia sophia Webb ex Prantl has been traditionally prescribed as treatment for palpitation, varicose vein, varicocele, constipation, hemorrhoid, skin eruptions, and impotence. To outline a view for further approaches, current work compiled a survey on all relevant clinical properties of this medicament in addition to the traditional reports. To do this, databases as PubMed, Scopus, EMBASE, IranMedex and Science information databases (SID) were searched by keywords, i.e., "Descurainia sophia", "Khaksheer", and "Flixweed" as well as "pharmacology" and "phytochemistry". According to the findings, scant experimental evaluation and clinical assessment have been performed on this medicament. Of those, only anti-inflammatory, analgesic, and antipyretic effects as well as antioxidant and anthelmintic activities were assessed and confirmed in experimental studies. Despite broad administration of this herb in folk and traditional medicine, only two human clinical trials in bowel discomfort and pregnant subjects were conducted. Taken as a whole, more comprehensive clinical evaluations should be conducted on respective applications to support those traditional and folk uses. PMID- 27462550 TI - Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women: a systematic review and meta analysis. AB - OBJECTIVE: In this study, we aimed at evaluation of the efficacy of Hypericum perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women. MATERIALS AND METHODS: We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (RCT) to explore trials that assessed the effectiveness of H. perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers. In this regard, the following terms were used "menopause AND H. perforatum OR flaxseed OR Linum usitatissimum. Only randomized controlled trials were included in the study. RESULTS: Nine RCTs were included in this systematic review. Based on the literature, flaxseed showed beneficial effect on hot flash frequency and intensity, which was not statistically significant. According to two trials, flaxseed showed estrogenic effects; however, no conclusion regarding cancer promoting or protecting effects can be made. The evidence of the efficacy of the flaxseed on alleviating vaginal atrophy was also limited due to inconsistent findings in this regard. One trial declared that Vitex agnus-castus and H. perforatum showed comparable decrease in the frequency of hot flashes. CONCLUSION: The results of our systematic review suggest beneficial effect on vasomotor symptom with both of flaxseed and H. perforatum. Consistent conclusion regarding estrogen-dependent cancers and maturation value is limited due to small number of trials related to flaxseed. Further trials are still needed to confirm the results of our systematic review. PMID- 27462551 TI - Anti-inflammatory and antinociceptive activities of Solenostemon monostachyus aerial part extract in mice. AB - OBJECTIVE: Solenostemon monostachyus is used in traditional medicine for the treatment of various ailments such as ulcer, hypertension, pains and inflammatory diseases. Evaluation of anti-inflammatory and analgesic activities of S. monostachyus aerial parts was carried out to ascertain its uses in traditional medicine. MATERIALS AND METHODS: The aerial parts of S. monostachyus was cold extracted by soaking the dried powdered material in ethanol. The aerial parts crude extract (75 -225 mg/kg) of S. monostachyus was investigated for analgesic and anti-inflammatory activities using various experimental models; acetic acid, formalin and thermal- induced pains models for analgesic study and carrageenin, egg albumin and xylene - induced edema models for anti-inflammatory investigation. RESULTS: The extract caused a significant (p<0.05 - 0.001) dose dependent reduction of inflammation and pains induced by different phlogistic agents used. These effects were comparable to those of the standard drug, (ASA, 100 mg/kg) used in some models. CONCLUSION: The anti-inflammatory and analgesic effects of this plant may in part be mediated through the chemical constituents of the plant and the results of the analgesic action suggest central and peripheral mechanisms. The findings of this work confirm the ethno medical use of this plant to treat inflammatory conditions. PMID- 27462552 TI - Evaluation of wound healing, antioxidant and antimicrobial efficacy of Jasminum auriculatum Vahl. leaves. AB - OBJECTIVE: To validate the ethno-therapeutic claim of the traditionally used plant Jasminum auriculatum (J. auriculatum) in skin diseases, by evaluating its wound healing potential along with its antioxidant and antimicrobial properties; so as to understand their role in wound healing. MATERIALS AND METHODS: Excision and incision wound models were used to evaluate the wound healing activity on albino rats. The wound healing potential was assessed by measuring rate of wound contraction, epithelialization period, hydroxyproline content, skin breaking strength and histopathological parameters. Reference standard drug was Nitrofurazone ointment. The antioxidant activity was determined using 2, 2 diphenyl-1-picrylhydrazyl (DPPH) method. The antimicrobial activity was determined by agar well diffusion method and minimum inhibitory concentration by serial dilution method. RESULTS: Higher rate of wound contraction (83.66+/-0.50% on 15th day), decrease in the period of epithelialization (17.83+/-1.6days), higher skin breaking strength (170.71+/-1.52g), higher collagen content and favourable histopathological changes revealed that topical application of ointment containing successive ethanolic extract (S.E.E) of J. auriculatum leaves has the most potent wound healing ability compared to control group in both the models studied. The DPPH radical scavenging activity of successive ethanolic extract was found to be 33.39ug/ml. Successive ethanolic extract was found to be most effective against Pseudomonas auregenosa having a zone of inhibition 16.65+/ 0.6mm and the minimum inhibitory concentration was 0.78mg/ml. CONCLUSION: The data of this study indicate that successive ethanolic extract of the leaves exhibit potent wound healing, antioxidant and antimicrobial properties. This justifies the ethno-medicinal use of plant for the treatment of wound and microbial infections. PMID- 27462553 TI - Anticonvulsant effect of Satureja hortensis aerial parts extracts in mice. AB - OBJECTIVE: Regarding the anticonvulsant effects of Satureja hortensis (S . hortensis) in Avicenna's book: canon of medicine; the present study was undertaken to evaluate the anti- eplileptic effects of S . hortensis aqueous and ethanolic aerial part extracts. Furthermore, the mechanisms of their anticonvulsant activities were also evaluated. MATERIALS AND METHODS: Seizure was induced by Pentylentetrazol (PTZ) and MES (maximal electroshock) models. Mice were randomly divided into 8 groups; negative control (normal saline, 10ml/Kg), positive control (diazepam, 2 mg/kg), S. hortensis aqueous and ethanolic extracts (200, 400 and 600 mg/kg). In PTZ test, latency to the first minimal clonic seizure (MCS), latency to the first generalized tonic-clonic seizures (GTCS), the total duration of seizures and protection against mortality were evaluated. In MES test, the stretching length of extremities and protection against mortality were recorded. RESULTS: Aqueous and ethanolic extracts (400 and 600 mg/kg) significantly increased MCS and GTCS latencies in PTZ model. Three doses of the extracts decreased the total duration of seizure. These extracts did not show any protective effects on seizure induced by MES model. In PTZ model, flumazenil, an antagonist of benzodiazepine (BZD) site in the GABAA-BZD receptor complex and 7- nitroindazole (7- NI), a selective nNOS (neuronal nitric oxide synthase) inhibitor, reduced the prolongation of seizure latency. CONCLUSION: S. hortensis showed anticonvulsant activity in PTZ model and this effect may be mediated, at least partly, through interacting with nitric oxide and GABAA-BZD receptor complex. PMID- 27462554 TI - Effect of different brewing times on antioxidant activity and polyphenol content of loosely packed and bagged black teas (Camellia sinensis L.). AB - OBJECTIVE: Determination and comparison of the effect of infusion time on the antioxidant activity and total polyphenol contents of bagged and loosely packed black teas. MATERIALS AND METHODS: For twenty loosely packed and eleven bagged tea samples, the antioxidant activity and total polyphenol content were analyzed using FRAP and Folin-Ciocalteau methods, respectively. The ANOVA with Tukey post hoc test and independent t-test were used for statistical analysis. RESULTS: The antioxidant activity and polyphenol content of various brands of tea samples were significantly different. There were significant differences in the antioxidant activity of loosely packed teas between 5, 15(p=0.03), 30(p=0.02) and 60(p=0.007) minutes of brewing times. Besides, there was a significant difference in antioxidant activity of bagged samples infused for 1 minute with four other infusion time points (p<0.001). In the case of polyphenol content, in loosely packed tea samples, there were not significant differences between different brewing times (p=0.15). However, in bagged samples, the polyphenol contents of samples that were brewed for 1 minute were significantly lower than samples brewed for 3, 4, and 5 minutes (p<0.05). The antioxidant activity and polyphenol content of tea bags were significantly higher than those ofloosely-packed forms of the same brands at 5-min of brewing time (p<0.001). CONCLUSION: The infusion time and the form of tea (loosely packed or bagged) were shown to be important determinants of the antioxidant activity and polyphenol content of black tea infusions in addition to the variety, growing environment and manufacturing conditions. PMID- 27462555 TI - Evaluation of antidepressant-like effects of aqueous and ethanolic extracts of Pimpinella anisum fruit in mice. AB - OBJECTIVE: Pimpinella anisum (P. anisum ) has different pharmacological properties such as anticonvulsant, analgesic, tranquilizer, antidepressant and anti-anxiety effects. In this study the antidepressant-like effect of aqueous and ethanolic extracts of P. anisum fruit in mice was investigated. MATERIALS AND METHODS: Forced swimming test (FST) and tail suspension test (TST) were used to determine the antidepressant effects of P. anisum (50, 100 and 200 mg/kg, i.p.) fruit extracts. Fluoxetine (20 mg/kg, i.p.) and imipramine (30 mg/kg, i.p.) were used as standard drugs. RESULTS: All the three doses of aqueous and ethanolic extracts (except 50 mg/kg of aqueous extract in FST) significantly and dose dependently reduced the immobility times in both FST and TST. All doses of extracts increased the swimming time dose-dependently, without any significant change in climbing time. In addition, all doses of ethanolic extract reduced immobility times and increased swimming time insignificantly higher than aqueous extract. But, the two extracts decreased the duration of climbing time similarly. Fluoxetine and imipramine decreased immobility time in both tests. Fluoxetine increased the swimming time without modifying climbing time. In contrast, imipramine increased climbing time without any significant change in swimming time. CONCLUSION: The results of this study suggest that P. anisum possesses an antidepressant-like activity similar to that of fluoxetine, which has a potential clinical value for application in the management of depression. PMID- 27462556 TI - Protective role of Lactobacillus plantarum A7 against irinotecan-induced genotoxicity. AB - OBJECTIVE: Irinotecan is a botanical derivative and an anti-cancer drug with cytotoxic and genotoxic effects. The present study evaluated the effect of Lactobacillus plantarum A7 on the genotoxic activity of irinotecan in a hepatocellular carcinoma cell line (HepG2) by comet assay. MATERIALS AND METHODS: HepG2 were incubated with irinotecan (100 uM), heat-killed cells (0.025 ug/ml) + irinotecan (100 uM), and cell-free supernatants (0.5 and 1 ug/ml) of L. plantarum A7 + irinotecan (100 uM). Phosphate buffered saline (PBS) was used as negative control. RESULTS: Irinotecan was shown to induce DNA damage in HepG2 cells. The results showed that heat-killed cells (0.025 ug/ml) and cell-free supernatants (0.5 and 1 ug/ml) of L. plantarum significantly reduce irinotecan- induced DNA damage. CONCLUSION: Our results indicate that L. plantarum A7 can decrease the genotoxic effects of irinotecan in HepG2 cells, in vitro. This finding may be supportive for the optimization of therapeutic efficacy in irinotecan treatment. PMID- 27462557 TI - Evaluation of antibacterial effects of Zataria multiflora Boiss extracts against ESBL-producing Klebsiella pneumoniae strains. AB - OBJECTIVE: There are few therapeutic options for treatment of multidrug resistant Klebsiella pneumoniae isolates as a hospital infectious agent (nosocomial infection). The aim of this study was to evaluate the antibacterial activity of Zataria multiflora Boiss extracts against ESBL-producing Klebsiella pneumoniae strains. MATERIALS AND METHODS: This study was conducted on 100 K. pneumoniae isolates from two hospitals in Tehran, Iran. Antibiotic susceptibility tests were performed by Kirby-Bauer disc diffusion and microdilution broth methods and detection of ESBL was carried out according to CLSI guidelines. The blaCTX-M-15 plasmid gene was detected by PCR and sequencing methods. Extracts susceptibility test was performed by broth microdilution method. RESULTS: Among 100 K. pneumoniae strains, 48 (48%) were ESBL positive. In this study, fosfomycin, colistin and tigecycline were more active than other antibiotics. The existence of blaCTX-M-15 was detected in 30 (62.5%) of 48 ESBL-producing isolates. The chloroformic extract showed potent activity against ESBL-producing K. pneumoniae strains (MIC50 = 1.56 mg/ml and MIC90=3.12mg/ml). The MIC50 and MIC90 (The MIC50 represents the MIC value at which >=50% of the isolates in a test population are inhibited and the MIC90 represents the MIC value at which >=90% of the strains within a test population are inhibited) were 3.12 and 6.25 mg/ml and 6.25 and 12.5 mg/ml for methanolic and acetonic extracts, respectively. CONCLUSION: The incidence of ESBL-producing K. pneumoniae is very high. Therefore, detection of ESBL-producing K. pneumoniae isolates is of great importance in identifying drug resistance patterns in K. pneumoniae isolates and in control of infections. Zataria multiflora may have the potential to be used against multidrug resistant organisms such as clinical isolates of ESBL-producing K. pneumoniae. PMID- 27462558 TI - Evaluation of anxiolytic-like activity of Vitis vinifera juice in mice. AB - OBJECTIVE: Scientific studies have shown that Vitis vinifera (V. vinifera) contains flavonoids and stillbenoids. Flavonoids are well known to possess anxiolytic activities. In view of the idea that flavonoids present in V. vinifera could be useful in anxiety, we evaluated anxiolytic-like activity of V. vinifera juice (VVJ). MATERIALS AND METHODS: Light/dark box and the open field test were used to assess the anxiolytic potential of V. vinifera juice (VVJ). The juice was given orally by gavage at the dose of 4 and 8 mL/kg body weight. Diazepam (1 mg/kg i.p.) was used as the standard drug. RESULTS: It was observed that the juice produced significant and dose dependent increase in the time spent in light cubicle (p<0.001), transfer latency from the light to dark cubicle (p<0.001) and the number of transitions between the two cubicles (p<0.001) as compared with the control group. V. vinifera also demonstrated significant and dose dependent increase in ambulation (P<0.001) and rearing (p<0.001) in open field test as compared to the control group. CONCLUSION: In conclusion, the present study establishes the anxiolytic-like activity of VVJ in animal models of anxiety. PMID- 27462559 TI - Safety assessment of rice bran oil in a chicken embryo model. AB - OBJECTIVE: Rice Bran Oil (RBO) is extracted from the outer layer of rice. Little information is available regarding its safety. The present study was conducted to assess its safety in chicken embryo model. MATERIALS AND METHODS: RBO was injected on day 4 of incubation of chickens. The tissues and serum samples were collected. Oxidative stress parameters in the liver, kidney and brain and biochemical parameters of serum were measured. The deformities were also investigated. RESULTS: The changes in the liver enzymes activity were not statistically significant. There was significant decrease and increase in lipid peroxidation and glutathione level, respectively. It is suggested that RBO is a natural antioxidant source. Low-density lipoprotein cholesterol (LDL) also decreased. No abnormal findings were observed in the chickens. CONCLUSION: No toxic effect was observed following RBO administration in chicken embryos. This study showed that RBO is not a safety concern. PMID- 27462560 TI - Chemical composition and antibacterial properties of essential oil and fatty acids of different parts of Ligularia persica Boiss. AB - OBJECTIVE: The objective of this research was to investigate the chemical composition and antibacterial activities of the fatty acids and essential oil from various parts of Ligularia persica Boiss (L. persica) growing wild in north of Iran. MATERIALS AND METHODS: Essential oils were extracted by using Clevenger type apparatus. Antibacterial activity was tested on two Gram-positive and two Gram-negative bacteria by using micro dilution method. RESULTS: GC and GC/MS analysis of the oils resulted in detection of 94%, 96%, 93%, 99% of the total essential oil of flowers, stems, roots and leaves, respectively. The main components of flowers oil were cis-ocimene (15.4%), beta-myrcene (4.4%), beta ocimene (3.9%), and gamma-terpinene (5.0%). The major constituents of stems oil were beta-phellandrene (5.4%), beta-cymene (7.0%), valencene (3.9%). The main compounds of root oil were fukinanolid (17.0%), alpha-phellandrene (11.5%) and Beta-selinene (5.0%) and in the case of leaves oil were cis-ocimene (4.8%), beta ocimene (4.9%), and linolenic acid methyl ester (4.7%). An analysis by GC-FID and GC-MS on the fatty-acid composition of the different parts of L. persica showed that major components were linoleic acid (11.3-31.6%), linolenic acid (4.7-21.8%) and palmitic acid (7.2-23.2%). Saturated fatty acids were found in lower amounts than unsaturated ones. The least minimum inhibition concentration (MIC) of the L. persica was 7.16 MUg/ml against Pseudomonas aeruginosa. CONCLUSION: Our study indicated that the essential oil from L. persica stems and flowers showed high inhibitory effect on the Gram negative bacteria. The results also showed that fatty acids from the stems and leaves contained a high amount of poly-unsaturated fatty acids (PUFAs). PMID- 27462561 TI - Ghost Surgeries Must Be Eradicated. PMID- 27462562 TI - Effective Lateral Canthal Lengthening with Triangular Rotation Flap. AB - In Korea, lateral canthoplasty, along with medial epicanthoplasty, has become popular over the past years to widen the horizontal length of the palpebral fissure. However, the effect of the surgery differs greatly depending on the shape and structure of the eyes. If over-widened, complications such as eversion, scarring, and conjunctival exposure may occur. Thus, the author of this study suggests a more effective and safe method for lateral canthal lengthening that causes minimal complications. A total of 236 patients underwent lateral canthoplasty between July 2007 and December 2015. For each patient, a triangular flap 4-5 mm away from the lateral canthus was elevated and rotated 45 degrees laterally while the continuity of the lower eyelid gray line was maintained. A new lateral canthus was created by fixating the rotation flap to the lateral orbital rim with minimal skin trimming and tension-free sutures, preventing relapse and maintaining a triangular shape. In more than 95% of cases, effective and satisfactory extension was achieved. On average, a 3 mm extension of the lateral canthus was achieved. There were minor complications such as wound dehiscence, webbing, and scarring, which were easily corrected. The author not only extended the lateral canthus 3-4 mm laterally but also maintained the continuity of the gray line on the lower lid as a more natural-looking triangular shape, while minimizing complications such as webbing and conjunctival exposure. PMID- 27462563 TI - Cosmetic Lateral Canthoplasty: Preserving the Lateral Canthal Angle. AB - Cosmetic lateral canthoplasty, in which the size of the eye is increased by extending the palpebral fissure and decreasing the degree of the eye slant, has become a prevalent procedure for East Asians. However, it is not uncommon for there to be complications or unfavorable results after the surgery. With this in mind, the authors have designed a surgical method to reduce complications in cosmetic lateral canthoplasty by preserving the lateral canthal angle. We discuss here the anatomy required for surgery, the surgical methods, and methods for reducing complications during cosmetic lateral canthoplasty. PMID- 27462564 TI - Cosmetic Lateral Canthoplasty: Lateral Canthoplasty to Lengthen the Lateral Canthal Angle and Correct the Outer Tail of the Eye. AB - There are many women who want larger and brighter eyes that will give a favorable impression. Surgical methods that make the eye larger and brighter include double eyelidplasty, epicanthoplasty, as well as lateral canthoplasty. Double eyelidplasty produces changes in the vertical dimension of the eyes, whereas epicanthoplasty and lateral canthoplasty create changes in the horizontal dimension of the eyes. Epicanthoplasty, a surgical procedure which enlarges the eye horizontally, is performed at the inner corner of the eye, whereas lateral canthoplasty enlarges the outer edge of the eye. In particular, if the slant of the palpebral fissure is raised and the horizontal dimension of the palpebral fissure is short, adjusting the slant of the palpebral fissure through lateral canthoplasty can achieve an enlargement of eye width and smoother features. Depending on the patient's condition, even better results can be achieved if this procedure is performed in conjunction with other procedures, such as double eyelidplasty, epicanthoplasty, eye roll formation surgery, fat graft, and facial bone contouring surgery. In this paper, the authors will introduce in detail their surgical method for a cosmetic lateral canthoplasty that lengthens the lateral canthal angle and corrects the outer tail of the eyes, in order to ease the unfavorable impression. PMID- 27462566 TI - A Revision Restoring Projection after Nipple Reconstruction by Burying Four Triangular Dermal Flaps. AB - BACKGROUND: Numerous techniques have been used to achieve long-term projection of the nipple following nipple-areola reconstruction. However, the reconstructed nipple loses projection over time. We describe a technique that uses local flaps to improve the lost projection of reconstructed nipples. METHODS: Between November 2013 and March 2015, nine patients (11 nipples) underwent revisional nipple reconstruction for lost projection. Only C-H nipple reconstructions were included in this study. The medical history of each patient was reviewed and photographs were taken in front and lateral views. All patients attended routine follow-up visits. Deepithelialized triangular flaps were made on all four sides of the nipple and buried in the opposite corners in order to augment the volume of the nipple. Anchoring sutures were used to attach each triangular flap on the side opposite their point of origin, and the resulting defects were closed directly. RESULTS: This procedure was used successfully in nine patients (11 nipples). Adequate projection was achieved in all patients and no complications occurred. The average nipple height was 3 mm before operation, 7 mm one day after operation, 5 mm at the six-month follow-up, and 5 mm at the 12-month follow-up. The average nipple-areolar angle was 164 degrees before the operation, 111 degrees one day after the operation, 130 degrees at the six-month follow-up, and 133 degrees at the 12-month follow-up. CONCLUSIONS: The method described provides a solution to the loss of projection in reconstructed nipples. We recommend this technique because it leads to better projection, greater volume, and a more natural shape. PMID- 27462565 TI - The Oncological Safety of Nipple-Sparing Mastectomy: A Systematic Review of the Literature with a Pooled Analysis of 12,358 Procedures. AB - Nipple-sparing mastectomy (NSM) is increasingly popular as a procedure for the treatment of breast cancer and as a prophylactic procedure for those at high risk of developing the disease. However, it remains a controversial option due to questions regarding its oncological safety and concerns regarding locoregional recurrence. This systematic review with a pooled analysis examines the current literature regarding NSM, including locoregional recurrence and complication rates. Systematic electronic searches were conducted using the PubMed database and the Ovid database for studies reporting the indications for NSM and the subsequent outcomes. Studies between January 1970 and January 2015 (inclusive) were analysed if they met the inclusion criteria. Pooled descriptive statistics were performed. Seventy-three studies that met the inclusion criteria were included in the analysis, yielding 12,358 procedures. After a mean follow up of 38 months (range, 7.4-156 months), the overall pooled locoregional recurrence rate was 2.38%, the overall complication rate was 22.3%, and the overall incidence of nipple necrosis, either partial or total, was 5.9%. Significant heterogeneity was found among the published studies and patient selection was affected by tumour characteristics. We concluded that NSM appears to be an oncologically safe option for appropriately selected patients, with low rates of locoregional recurrence. For NSM to be performed, tumours should be peripherally located, smaller than 5 cm in diameter, located more than 2 cm away from the nipple margin, and human epidermal growth factor 2-negative. A separate histopathological examination of the subareolar tissue and exclusion of malignancy at this site is essential for safe oncological practice. Long-term follow-up studies and prospective cohort studies are required in order to determine the best reconstructive methods. PMID- 27462567 TI - Technical Aspects and Difficulties in the Management of Head and Neck Cutaneous Malignancies in Xeroderma Pigmentosum. AB - BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by xerosis, ultraviolet light sensitivity, and cutaneous dyspigmentation. Due to defects in their DNA repair mechanism, genetic mutations and carcinogenesis inevitably occurs in almost all patients. In these patients, reconstruction of cutaneous malignancies in the head and neck area is associated with some challenges such as likelihood of recurrence and an aggressive clinical course. The aim of this study is to discuss the therapeutic options and challenges commonly seen during the course of treatment. METHODS: Between 2005 and 2015, 11 XP patients with head and neck cutaneous malignancies were included in this study. Demographic data and treatment options of the patients were evaluated. RESULTS: The mean age of the patients was 32 years (range, 10-43) (4 males, 7 females). The most common tumor type and location were squamous cell carcinoma (6 patients) and the orbital region (4 patients), respectively. Free tissue transfer was the most commonly performed surgical intervention (4 patients). The average number of surgical procedures was 5.5 (range, 1-25). Six patients were siblings with each other, 5 patients had local recurrences, and one patient was lost to follow-up. CONCLUSIONS: Although genetic components of the disease have been elucidated, there is no definitive treatment algorithm. Early surgical intervention and close follow-up are the gold standard modalities due to the tendency toward rapid tumor growth and possible recurrence. Treatment must be individualized for each patient. In addition, the psychological aspect of the disease is an important issue for both patients and families. PMID- 27462568 TI - Deep-Plane Lipoabdominoplasty in East Asians. AB - BACKGROUND: The objective of this study was to develop a new surgical technique by combining traditional abdominoplasty with liposuction. This combination of operations permits simpler and more accurate management of various abdominal deformities. In lipoabdominoplasty, the combination of techniques is of paramount concern. Herein, we introduce a new combination of liposuction and abdominoplasty using deep-plane flap sliding to maximize the benefits of both techniques. METHODS: Deep-plane lipoabdominoplasty was performed in 143 patients between January 2007 and May 2014. We applied extensive liposuction on the entire abdomen followed by a sliding flap through the deep plane after repairing the diastasis recti. The abdominal wound closure was completed with repair of Scarpa's fascia. RESULTS: The average amount of liposuction aspirate was 1,400 mL (700-3,100 mL), and the size of the average excised skin ellipse was 21.78*12.81 cm (from 15*10 to 25*15 cm). There were no major complications such as deep-vein thrombosis or pulmonary embolism. We encountered 22 cases of minor complications: one wound infection, one case of skin necrosis, two cases of undercorrection, nine hypertrophic scars, and nine seromas. These complications were solved by conservative management or simple revision. CONCLUSIONS: The use of deep-plane lipoabdominoplasty can correct abdominal deformities more effectively and with fewer complications than traditional abdominoplasty. PMID- 27462569 TI - Thromboprophylaxis in Abdominoplasty: Efficacy and Safety of a Complete Perioperative Protocol. AB - BACKGROUND: Venous thromboembolism, a spectrum of diseases ranging from deep venous thrombosis to pulmonary embolism, is a major source of morbidity and mortality. The majority of cases described in plastic surgery involve abdominoplasty. Risk assessment and prophylaxis are paramount in such patients. General recommendations were recently developed, but the evidence in the literature was insufficient to prepare exhaustive guidelines regarding the medication, dosage, timing, or length of the prophylaxis. METHODS: A thromboprophylaxis protocol was developed for patients undergoing abdominoplasty. The protocol consisted of preoperative, intraoperative, and postoperative measures. Enoxaparin was administered as chemoprophylaxis in selected patients. The study involved 253 patients. The patients were analyzed for age, body mass index, enoxaparin dosage, risk factors, and complications. RESULTS: Deep venous thrombosis was documented in two cases (0.8%). No pulmonary embolism occurred. Three patients (1.2%) presented mild subcutaneous abdominal hematoma within the first postoperative week that spontaneously resorbed with neither aesthetic nor functional complications. Two patients (0.8%) presented severe hematoma requiring surgical re-intervention for drainage and hemostasis revision. Statistical analysis showed no significant correlation between enoxaparin dosage and hematoma (P=0.18) or deep venous thrombosis (P=0.61). CONCLUSIONS: The described thromboprophylaxis protocol proved to be effective in the prevention of thrombotic events, with an acceptable risk of hemorrhagic complications. Furthermore, it provides new evidence regarding the currently debated variables of chemoprophylaxis, namely type, dosage, timing, and length. PMID- 27462570 TI - Development and Validation of the Expectations of Aesthetic Rhinoplasty Scale. AB - BACKGROUND: There is a growing concern in the field of aesthetic surgery about the need to measure patients' expectations preoperatively. The present study was designed to develop and validate the Expectations of Aesthetic Rhinoplasty Scale (EARS), and to compare expectations between rhinoplasty patients with and without body dysmorphic disorder (BDD). METHODS: In total, 162 college students and 20 rhinoplasty candidates were recruited. The measures included the newly developed EARS, a measure of psychopathology, and demographics. The DSM-IV structured clinical interview for BDD was used to confirm the diagnosis in rhinoplasty patients. RESULTS: The EARS was constructed of six items based on their significant content validity. In the scale development phase, Cronbach's alpha was 0.87. The test-retest reliability coefficient of the scale was satisfactory (intraclass correlation coefficient, 0.94; 95% confidence interval, 0.82-0.98) over a four-week period. Scores on the EARS were significantly positively correlated with psychopathological symptoms (r=0.16; P<0.05). Moreover, comparison of EARS scores between BDD (M=25.90, standard deviation [SD]=6.91) and non-BDD rhinoplastic patients (M=15.70, SD=5.27) suggested that BDD patients held significantly higher expectations (P<0.01). CONCLUSIONS: The expectations of aesthetic rhinoplasty patients toward surgery may play a crucial role in their postoperative satisfaction. While the value of patients' expectations is clinically recognized, no empirical study has measured these expectations in a psychometrically sound manner. The current study developed and validated the EARS. It may be easily used as a valid and reliable instrument in clinical and research settings. PMID- 27462571 TI - Intraneural Venous Malformations of the Median Nerve. AB - Venous malformations arising from the peripheral nerve are a rare type of vascular malformation. We present the first case of an intraneural venous malformation of the median nerve to be reported in a child and review the previous two cases of median nerve compression due to a venous malformation that have been reported. These cases presented with painless masses in the volar aspect of the wrist or with symptoms suggestive of carpal tunnel syndrome. Clinical suspicion should lead to the use of Doppler ultrasonography as the first line diagnostic tool. Magnetic resonance imaging and histopathology can confirm the diagnosis, as phleboliths are pathognomonic of venous malformations. Surgical treatment appears to be the only modality capable of successfully controlling the growth of an intraneural malformation. Sclerotherapy and radiotherapy have never been used to treat this type of malformation. PMID- 27462572 TI - A Novel Approach to Submandibular Gland Ptosis: Creation of a Platysma Muscle and Hyoid Bone Cradle. AB - Submandibular gland ptosis is a common impediment to obtaining superior surgical aesthetic results in neck lift surgery. Techniques for suspending the submandibular gland have been proposed, but these procedures have the drawbacks of disturbing the floor of the mouth mucosa and periosteum. We present an approach of submandibular gland suspension for the treatment of gland ptosis by employing a platysma and hyoid bone fascia cradle. Our technique was performed on cadaveric models. The platysma muscle and hyoid bone cradle for submandibular gland ptosis was created on the left side of the neck in two cadavers. A submental incision with sharp dissection was performed to raise a supraplatysmal flap. A subplatysmal plane was developed until the submandibular gland was identified. Sutures were used to pexy the platysma to the hyoid bone periosteum and deep cervical fascia, tightening the overlying muscle and in turn elevating the submandibular gland. Submandibular gland ptosis must be corrected in order to achieve exemplary aesthetic results. Our approach of creating a cradle with the platysma and hyoid bone avoids the potential complications of previously described sling procedures, while still maintaining the integrity of the gland and surrounding tissues. PMID- 27462573 TI - Split-Rib Cranioplasty Using a Patient-Specific Three-Dimensional Printing Model. PMID- 27462574 TI - Post-Traumatic Cutaneous Meningioma. PMID- 27462575 TI - Cross-Leg Flap-Sharing Technique Using an Anterolateral Thigh Perforator Flap. PMID- 27462576 TI - A Rare Case of Bilateral Upper Extremity Hypercalcinosis in Systemic Sclerosis Requiring Multiple Radical Debridements. PMID- 27462577 TI - Wrist Pain due to Abnormal Extensor Carpi Ulnaris Tendon. PMID- 27462578 TI - Editorial: Human Tumor-Derived p53 Mutants: A Growing Family of Oncoproteins. PMID- 27462579 TI - Prevalence of Class D Carbapenemases among Extended-Spectrum beta-Lactamases Producing Escherichia coli Isolates from Educational Hospitals in Shahrekord. AB - INTRODUCTION: Extended-spectrum beta-lactamases (ESBLs) are a set of plasmid borne, various and quickly evolving enzymes that are a main therapeutic issue now a-days for inpatient and outpatient treatment. AIM: The aim of this study was to determine multi-drug resistance (MDR) and ESBLs producing E. coli strains, prevalence of class D Carbapenemases among ESBLs producing Escherichia coli isolates from educational hospitals in Shahrekord, Iran. MATERIALS AND METHODS: Uropathogenic Escherichia coli strains were isolated from patients with Urinary Tract Infections (UTIs). The agar disc diffusion test was used to characterize the antimicrobial sensitivity of the E. coli isolates. The ESBL positive strains were identified by phenotypic double-disk synergy test, by third-generation cephalosporin in combination with or without clavulanic acid. Multiplex PCR was carried out for detection of the three families of OXA-type carbapenamases including OXA-23, OXA-24, and OXA-48 in E. coli strains. RESULTS: All bacterial isolates were susceptible to meropenem. Ninety isolates produced ESBL, 55 E. coli isolates from inpatients, and 35 isolates from outpatients, with a significant association (p< 0.05). The prevalence of OXA-23, OXA-24, and OXA-48 in the ESBLs producing isolates was respectively 21%, 18%, and 11% for inpatients, and 10%, 8%, and 6% for outpatients. CONCLUSION: ESBL-producing E. coli isolates are also a major threat in the clinical setting. The findings of this study indicated the high occurrence of ESBLs and multiple antibiotic resistance in E. coli isolates. PMID- 27462580 TI - Regulation of exercise-stimulated glucose uptake in skeletal muscle. AB - AMP-activated protein kinase (AMPK) is a Ser/Thr kinase that has been thought to be an important mediator for exercise-stimulated glucose uptake in skeletal muscle. Liver kinase B1 (LKB1) is an upstream kinase for AMPK and AMPK-related protein kinases, of which the function in skeletal muscle has not been well documented. Our group and others have generated mice lacking AMPK activity in skeletal muscle, as well as muscle-specific LKB1 knockout mice. In this review, we discuss the potential role of AMPK and LKB1 in regulating exercise-stimulated glucose uptake in skeletal muscle. We also discuss our recent study, demonstrating the molecular mechanism of obesity-induced development of skeletal muscle insulin resistance. PMID- 27462581 TI - An update on the genetic causes of central precocious puberty. AB - Central precocious puberty (CPP) is caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, nutritional, and environmental factors play a crucial role in determining pubertal timing. Recently mutations in kisspeptin (KISS1), kisspeptin receptor (KISS1R), and makorin RING finger protein 3 (MKRN3) genes have been identified as genetic causes of CPP. In particular, the MKRN3 gene is known to affect pubertal initiation. The MKRN3 gene is located on chromosome 15q11-q13 in the Prader-Willi syndrome (PWS) critical region. MKRN3 deficiency, due to a loss of function mutation, leads to the withdrawal of hypothalamic inhibition and prompts pulsatile gonadotropin-releasing hormone secretion, resulting in precocious puberty. The exact functions of these genes associated with CPP are still not well understood. Larger studies are required to discover the mechanisms involved in pubertal development. PMID- 27462582 TI - Predictive factors for early response to methimazole in children and adolescents with Graves disease: a single-institute study between 1993 and 2013. AB - PURPOSE: We aimed to investigate the predictive factors for early response to methimazole (MMI) in pediatric patients with Graves disease (GD). METHODS: Our study included 44 pediatric patients who were diagnosed with GD between January 1, 1993, and December 31, 2013, and were available for follow-up, achieving a normalization of thyroid functions (TFs) at the Chonbuk National University Hospital Pediatric Department. We retrospectively analyzed TFs such as tri iodothyronine (T3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), and thyroid antibody levels at diagnosis. We also examined their family history of thyroid disease, symptoms at presentation, and normalization time for TF after treatment. We divided our clinical series of patients into the following 4 age groups: <7 years old, 7-12 years old, 13-15 years old, and 16-18 years old. RESULTS: At diagnosis, the time of normalization of T3 was significantly shorter in the higher antimicrosomal antibody (AMA) group compared with the lower AMA group (2.53 months vs. 6.18 months) (P<0.05). However, the time of normalization of T3/fT4/TSH had no significant correlations with other variables such as age, sex, a family history of thyroid diseases, thyroglobulin, thyroid-stimulating immunoglobulin, or antithyroglobulin antibody (ATA). CONCLUSION: Higher serological titers of AMA at diagnosis may have prognostic value in the response to initial MMI treatment in pediatric hyperthyroid GD patients. PMID- 27462583 TI - Ultrasound measurement of pediatric visceral fat thickness: correlations with metabolic and liver profiles. AB - PURPOSE: Abdominal obesity is a fundamental factor underlying the development of metabolic syndrome. Because of radiation exposure and cost, computed tomography or dual-energy X-ray absorptiometry to evaluate abdominal adiposity are not appropriate in children. Authors evaluated whether ultrasound results could be an indicator of insulin resistance and nonalcoholic fatty liver disease (NAFLD). METHODS: We enrolled 73 subjects (aged 6-16 years) who were evaluated abdominal adiposity by ultrasound. Subcutaneous fat thickness was defined as the measurement from the skin-fat interface to the linea alba, and visceral fat thickness (VFT) was defined as the thickness from the linea alba to the aorta. Anthropometric and biochemical metabolic parameters were also collected and compared. The subjects who met 2 criteria, radiologic confirmed fatty liver and alanine aminotransferase >40, were diagnosed with NAFLD. RESULTS: There was a strong positive correlation between VFT and obesity. VFT was highly correlated with the homeostasis model assessment for insulin resistance score (r=0.403, P<0.001). The area under the curve for VFT as a predictor of NAFLD was 0.875 (95% confidence interval [CI], 0.787-0.964). VFT of 34.3 mm was found to be the discriminating cutoff for NAFLD (sensitivity, 84.6%; specificity, 71.2%, respectively). CONCLUSION: Ultrasound could be useful in measuring VFT and assessing abdominal adiposity in children. Moreover, increased VFT might be an appropriate prognostic factor for insulin resistance and NAFLD. PMID- 27462584 TI - The changes of subtypes in pediatric diabetes and their clinical and laboratory characteristics over the last 20 years. AB - PURPOSE: We studied the changes in subtypes of diabetes mellitus (DM) in children and evaluated the characteristics of each group over the past 20 years. In addition, we also examined the correlation between the glycated hemoglobin (HbA1c) values at the time of diagnosis and lipid profiles. METHODS: The patients were divided into 2 groups: there were a total of 190 patients under 20 years of age firstly diagnosed with DM in Ajou University Hospital. The patients in groups I and II were diagnosed from September 1995 to December 2004 and from January 2005 to April 2014, respectively. RESULTS: The characteristics were compared between the 2 groups of patients. The result showed an increase in percentage of type 2 diabetes and maturity onset diabetes of the young (MODY) patients between the 2 groups. HbA1c and total cholesterol level had statistical significances to explain increasing the low-density lipoprotein cholesterol level among age, HbA1c, total cholesterol level, and z-scores of weight and body mass index (BMI) in type 2 diabetes. R-square was 0.074. However, z-score of BMI and total cholesterol level, not HbA1c, had statistical significances in type 1 diabetic patients. R-square was 0.323. CONCLUSION: The increase in the proportions of both type 2 diabetes and MODY in the last 10 years needed to be reminded when diagnosing the subtypes of DM, and the dyslipidemia should be attended more as a common problem of pediatric diabetic patients. PMID- 27462585 TI - Insulin and glucagon levels of umbilical cord blood in appropriate for gestational age - preterm infants with or without postnatal hypoglycemia. AB - PURPOSE: To determine whether serum insulin and glucagon levels of umbilical cord blood correlate with subsequent postnatal hypoglycemia in appropriate for gestational age (AGA) - preterm infants at different gestational ages (GAs). METHODS: The serum insulin and glucagon levels of umbilical cord blood were measured using magnetic bead based multiplex immunoassay in 69 AGA - premature infants, stratified according to GA: GA 23-30 weeks, early preterm (EP, n=31); GA 31-34 weeks, late preterm (LP, n=38). Postnatal hypoglycemia was defined as a capillary glucose level <40 mg/dL within the first 60 minutes of life, regardless of GA. RESULTS: The capillary glucose concentration in EP infants (65.5+/-21.2 mg/dL) was significantly higher than that of LP infants (55.9+/-17.3 mg/dL) (P=0.043). The serum glucagon level in EP infants (44.3+/-28.7 pg/mL) was significantly higher than that in LP infants (28.1+/-13.6 pg/mL) (P=0.006). There was not a significant difference in serum insulin level between EP and LP infants (372.7+/-254.2 pg/mL vs. 372.4+/-209.1 pg/mL, P=0.996). There was a significant difference in the serum glucagon level between infants with and without hypoglycemia (27.7+/-8.9 mg/dL vs. 36.8+/-24.6 mg/dL, P=0.036), but not in the serum insulin level (451.9+/-256.9 pg/mL vs. 357.4+/-222.2 pg/mL, P=0.211). Postnatal glucose concentration within the first 60 minutes of life had a significant positive correlation with serum glucagon levels (r=0.256, P=0.034), but not with serum insulin levels (r=-0.020, P=0.867). CONCLUSION: Lower glucagon levels of cord blood were seen in premature infants with higher GA, which might contribute to the occurrence of postnatal hypoglycemia. PMID- 27462586 TI - Dilated cardiomyopathy with Graves disease in a young child. AB - Graves disease (GD) can lead to complications such as cardiac arrhythmia and heart failure. Although dilated cardiomyopathy (DCMP) has been occasionally reported in adults with GD, it is rare in children. We present the case of a 32 month-old boy with DCMP due to GD. He presented with irritability, vomiting, and diarrhea. He also had a history of weight loss over the past few months. On physical examination, he had tachycardia without fever, a mild diffuse goiter, and hepatomegaly. The chest radiograph showed cardiomegaly with pulmonary edema, while the echocardiography revealed a dilated left ventricle with an ejection fraction (EF) of 28%. The thyroid function test (TFT) showed elevated serum T3 and decreased thyroid stimulating hormone (TSH) levels. The TSH receptor autoantibody titer was elevated. He was diagnosed with DCMP with GD; treatment with methylprednisolone, diuretics, inotropics, and methimazole was initiated. The EF improved after the TFT normalized. At follow-up several months later, although the TFT results again showed evidence of hyperthyroidism, his EF had not deteriorated. His cardiac function continues to remain normal 1.5 months after treatment was started, although he still has elevated T3 and high TSH receptor antibody titer levels due to poor compliance with drug therapy. To summarize, we report a young child with GD-induced DCMP who recovered completely with medical therapy and, even though the hyperthyroidism recurred several months later, there was no relapse of the DCMP. PMID- 27462587 TI - Multiple daily injection of insulin regimen for a 10-month-old infant with type 1 diabetes mellitus and diabetic ketoacidosis. AB - The incidence of type 1 diabetes is increasing worldwide, and the greatest increase has been observed in very young children under 4 years of age. A case of infantile diabetic ketoacidosis in a 10-month-old male infant was encountered by these authors. The infant's fasting glucose level was 490 mg/dL, his PH was 7.13, his pCO2 was 15 mmHg, and his bicarbonate level was 5.0 mmol/L. The glycosylated hemoglobin level had increased to 9.4%. Ketonuria and glucosuria were detected in the urinalysis. The fasting C-peptide and insulin levels had decreased. The infant was positive for anti-insulin and antiglutamic acid decarboxylase antibodies. Immediately after the infant's admission, fluid therapy and intravenous insulin infusion therapy were started. On the second day of the infant's hospitalization and after fluid therapy, he recovered from his lethargic condition, and his general condition improved. Feeding was started on the third day, and he was fed a formula 5 to 7 times a day and ate rice, vegetables, and lean meat. Due to the frequent feeding, the frequency of rapid-acting insulin injection was increased from 3 times before feeding to 5 times, adjusted according to the feeding frequency. The total dose of insulin that was injected was 0.8-1.1 IU/kg/day, and the infant was discharged on the 12th day of his hospitalization. The case is presented herein with a brief review of the relevant literature. PMID- 27462588 TI - A successful treatment of hypercalcemia with zoledronic acid in a 15-year-old boy with acute lymphoblastic leukemia. AB - Severe hypercalcemia in children is a rare medical emergency. We present a case of a 15-year-old boy with hypercalcemia (total calcium level, 14.2 mg/dL) with a normal complete blood count, no circulating blasts in the peripheral blood film, and no other signs of acute lymphoblastic leukemia (ALL), including no signs of lymphadenopathy or hepatosplenomegaly. The hypercalcemia was successfully treated with zoledronic acid. As hypercalcemia can be the only presenting symptom of ALL in children, the diagnosis is often delayed. In children presenting with hypercalcemia, malignancies must be considered in the differential diagnosis. PMID- 27462589 TI - Thyroxine binding globulin excess detected by neonatal screening. AB - Inherited thyroxine binding globulin (TBG) disorder can be identified incidentally or through neonatal screening test. TBG excess is characterized by high levels of thyroxine (T4) but normal level of free T4 (fT4), while TBG deficiency presents with low T4 levels and normal fT4 levels. A 27-day-old newborn was brought to the hospital because of hyperthyroxinemia detected by neonatal screening. His T4 level was 18.83 ug/dL (normal range, 5.9-16.0 ug/dL). His mother had no history of any thyroid disease. His fT4 and thyroid stimulating hormone (TSH) levels were 1.99 ng/dL (normal range, 0.8-2.1 ng/dL) and 4.54 mIU/L (normal range, 0.5-6.5 mIU/L), respectively. His serum total triiodothyronine (T3) level was 322.5 ng/dL (normal range, 105.0-245.0 ng/dL). His TBG level was 68.27 mg/L (normal range, 16.0-36.0 mg/L) at the age of 3 months. At 6 months and 12 months of age, his TBG levels were 48.77 mg/L (normal range, 16.0-36.0 mg/L) and 50.20 mg/L (normal range, 14.0-28.0 mg/L), respectively, which were 2 to 3 times higher than normal values. Hormonal studies showed consistently elevated T3 and T4 levels and upper normal levels of fT4 and free T3 with normal TSH levels. His growth and development were normal. TBG excess should be considered as a potential differential diagnosis for hyperthyroxinemia and especially high T3 levels with normal TSH concentration. PMID- 27462590 TI - The Author Reply: Endocrine and metabolic emergencies in children: hypocalcemia, hypoglycemia, adrenal insufficiency, and metabolic acidosis including diabetic ketoacidosis. PMID- 27462591 TI - Surgical treatments for vaginal apical prolapse. AB - Pelvic organ prolapse is a common condition, occurring in up to 11% of women in the United States. Often, pelvic organ prolapse recurs after surgery; when it recurs after hysterectomy, it frequently presents as vaginal apical prolapse. There are many different surgical treatments for vaginal apical prolapse; among them, abdominal sacral colpopexy is considered the gold standard. However, recent data reveal that other surgical procedures also result in good outcome. This review discusses the various surgical treatments for vaginal apical prolapse including their risks and benefits. PMID- 27462592 TI - The effect of salinomycin on ovarian cancer stem-like cells. AB - OBJECTIVE: The identification of cancer stem-like cells is a recent development in ovarian cancer. Compared to other cancer cells, cancer stem-like cells present more chemo-resistance and more aggressive characteristics. They play an important role in the recurrence and drug resistance of cancer. Therefore, the target therapy of cancer stem-like cell may become a promising and effective approach for ovarian cancer treatment. It may also help to provide novel diagnostic and therapeutic strategies. METHODS: The OVCAR3 cell line was cultured under serum free conditions to produce floating spheres. The CD44(+)CD117(+) cell line was isolated from the human ovarian cancer cell line OVCAR3 by using immune magnetic activated cell sorting system. The expression of stemness genes such as OCT3/4, NANOG and SOX2 mRNA were determined by reverse transcription polymerase chain reaction. OVCAR3 parental and OVCAR3 CD44(+)CD117(+) cells were grown in different doses of paclitaxel and salinomycin to evaluate the effect of salinomycin. And growth inhibition of OVCAR3 CD44(+)CD117(+) cells by paclitaxel combined with salinomycin was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-2H-tetrazolium bromide (MTT) assay. RESULTS: Tumor spheroids generated from the OVCAR3 cell line are shown to have highly enriched CD44 and CD117 expression. Treatment with a combination of paclitaxel and salinomycin demonstrated growth inhibition of OVCAR3 CD44(+)CD117(+) cells. CONCLUSION: The present study is a detailed investigation on the expression of CD44 and CD117 in cancer stem cells and evaluates their specific tumorigenic characteristics in ovarian cancer. This study also demonstrates significant growth inhibition of cancer stem-like cells by paclitaxel combined with salinomycin. Identification of these cancer stem-like cell markers and growth inhibition effect of salinomycin may be the next step to the development of novel target therapy in ovarian cancer. PMID- 27462593 TI - Clinical value of routine serum squamous cell carcinoma antigen in follow-up of patients with locally advanced cervical cancer treated with radiation or chemoradiation. AB - OBJECTIVE: The objective of this study was to evaluate the clinical benefits of routine squamous cell carcinoma antigen (SCC-Ag) monitoring of patients with locally advanced cervical squamous cell carcinoma treated with radiation or chemoradiation. METHODS: A total of 53 patients with recurrent cervical squamous cell carcinoma treated with radiotherapy or chemoradiation were enrolled in this study. A retrospective review of medical records was conducted. The role of routine monitoring of serum SCC-Ag was evaluated in terms of cost effectiveness and effect on survival after diagnosis of recurrence. RESULTS: Serum SCC-Ag abnormality (>=2.5 ng/mL) was observed in 62.3% of patients when recurrent disease was diagnosed. The first indicator of relapse was abnormal serum SCC-Ag level in 21 patients (39.6%), 10 of whom had asymptomatic recurrent disease amenable to salvage therapy. Adding SCC-Ag measurement to the basic follow up protocol improved the sensitivity for detecting recurrence (The sensitivity of the basic protocol vs. addition of SCC-Ag: 49.1% vs. 88.7%, P<0.001). Twenty three patients who were candidates for salvage therapy with curative intent showed better survival compared with those who were not candidates for therapy (5 year survival: 36.6% vs. 0%, P=0.012). CONCLUSION: Surveillance with routine serum SCC-Ag monitoring can better detect asymptomatic recurrent disease that is potentially amenable to salvage therapy with curative intent. Early diagnosis of recurrent disease that can be treated with salvage therapy may lead to better survival. PMID- 27462594 TI - Association of plasma adiponectin and leptin levels with the development and progression of ovarian cancer. AB - OBJECTIVE: Decreased adiponectin and increased leptin plasma concentrations are believed to be associated with the occurrence and progression of cancers such as endometrial cancer and breast cancer. The aim of this study was to explore the association of plasma adiponectin and leptin levels with the development and progression of ovarian cancer. METHODS: For patients with ovarian cancer and the control group, adiponectin and leptin levels were measured; anthropometric data were obtained during a chart review. Statistical comparisons between groups were analyzed using the Student's t-test; correlations were confirmed using the Pearson correlation. RESULTS: The mean adiponectin and leptin concentrations in patients with ovarian cancer were lower than those of the control group (8.25 vs. 11.44 ug/mL, respectively; P=0.026) (7.09 vs. 15.4 ng/mL, respectively; P=0.001). However, there was no significant difference in adiponectin and leptin levels between early-stage (I/II) and advanced-stage (III/IV) disease (P=0.078). CONCLUSION: Compared with other gynecological cancers, the level of adiponectin and leptin were decreased in ovarian cancer that may have some diagnostic value; additional study to elucidate the function of these two hormones in the development of ovarian carcinogenesis is necessitated. PMID- 27462595 TI - Preoperative risk factors in recurrent endometrioma after primary conservative surgery. AB - OBJECTIVE: Endometriosis is a common gynecological disorder caused by ectopic implantation of endometrial glandular and stromal cells outside the uterine cavity. Among several types of endometriosis, endometrioma is the only subtype that could be determined preoperatively using pelvic ultrasonography, and guidelines recommend pathologic confirmation of endometrioma greater than 3 cm in diameter. However, although surgery is performed in cases of endometrioma, endometrioma has a high cumulative rate of recurrence. Therefore, because determining the possibility of recurrence before performance of initial surgery is important, we examined preoperative factors associated with recurrent endometrioma. METHODS: This was a retrospective, comparative study including 236 patients who visited the outpatient clinic between January 2009 and December 2011. Patients who were pathologically diagnosed with endometrioma were included in this study. They were followed up postoperatively and were divided into two groups according to presence of recurrent endometrioma. RESULTS: We examined associations between baseline factors and recurrent endometrioma. In multivariate analysis, dysmenorrhea and cyst septation were statistically significant after adjusting with age, parity, surgical staging and postoperative management. We examined cumulative recurrence free survival within cases of recurrent endometriosis, based on the presence of inner cyst septation. The cumulative recurrence free survival was lower in cases with septation. CONCLUSION: Our study found that recurrent endometrioma is more likely in patients with inner cyst septation and the recurrence occurred within a shorter duration of time than in patients without inner cyst septation on preoperative ultrasonography. Therefore intensive caution and postoperative long term medical therapy would be appropriate in patients with inner cyst septation on preoperative ultrasonography before undergoing primary surgery for endometrioma. PMID- 27462596 TI - Analysis of falsely elevated risk of ovarian malignancy algorithm in women with ovarian endometrioma. AB - OBJECTIVE: To estimate the incidence of falsely elevated risk of ovarian malignancy algorithm (ROMA) in a group of women with pathologically confirmed endometrioma and to investigate the associated factors. METHODS: One hundred premenopausal women surgically diagnosed with ovarian endometrioma were selected. Preoperative clinical, laboratory, and surgical characteristics were compared between the elevated-risk group (ROMA-premenopausal value, >=7.4%) and normal risk group (ROMA-premenopausal value, <7.4%). RESULTS: Elevated ROMA was observed in 15 women (false positive rate, 15%). Excluding one woman with known chronic renal failure, we compared the characteristics of 99 women between the elevated risk group (n=14) and the normalrisk group (n=85). None of the clinical and surgical variables distinguished the two groups. Serum level of CA 125 >82.3 U/mL and serum level of human epididymis protein 4 (HE4) >46 pmol/L could predict an elevated ROMA test with a statistical significance. When serum level of HE4 <=46 pmol/L, none of the women showed an elevated ROMA test, regardless of serum level of CA 125; however, 55.6% of the women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 <=82.3 U/mL and all women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL. CONCLUSION: The incidence of falsely elevated ROMA was 15% in the group of women with pathologically confirmed endometrioma. Interpretation of the ROMA results should be cautious when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL in women with suspicious ovarian endometrioma. PMID- 27462597 TI - Reference values for the cervical length measurement in the second trimester of pregnancy using the transvaginal ultrasound in a large Brazilian population. AB - To establish reference values for the cervical length (CL) measurement by transvaginal ultrasound between 20 and 24+6 weeks of gestation in a large Brazilian population. A retrospective cross-sectional study was performed with 996 singleton pregnancies. The CL measurement (mm) using the transvaginal ultrasound was obtained in a sagittal view and the calipers positioned to measure the linear distance between the triangular area of echodensity at the external os and the internal os. The median+/-standard deviation and ranges for the CL measurement (mm) was 37.0+/-10.7 (range, 8 to 51). CL measurement did not modify significantly with gestational age. The observed percentiles for the CL measurement (mm) considering all number case were the following: 5th, 28 mm; 50th, 37 mm; and 95th, 45 mm. Reference values for the CL measurement by transvaginal ultrasound between 20 and 24+6 weeks of gestation in a large heterogeneous Brazilian population were established. PMID- 27462598 TI - Embryonic development after exposure of mouse oocyte to various amount of ovarian endometriotic fluid. AB - This study assesses the fertilization and blastocyst-forming rate in mice cumulus oocyte complexes (COCs) after the exposure of human ovarian endometriotic fluid. Endometriotic fluid was obtained from a single patient by aspiration at the time of a laparoscopic cystectomy and serially diluted. COCs were obtained from 46 week-old female BDF1 mice. After exposure to ovarian endometriotic fluid for five minutes, the COCs were washed three times and the oocytes were then fertilized by mice sperm. The fertilization and blastocyst formation rate and the proportion of hatching/hatched blastocyst in the four treatment groups were not inferior to those in non-exposure group. PMID- 27462599 TI - Monochorionic twin delivery after conservative surgical treatment of a patient with severe diffuse uterine adenomyosis without uterine rupture. AB - A 31-year-old nulliparous woman with severe diffuse uterine adenomyosis, which replaced nearly the whole uterine myometrium, visited our hospital due to severe dysmenorrhea, menorrhagia, and a desire to have a baby. The patient had a history of two spontaneous abortions. Laparotomic adenomyomectomy with transient occlusion of uterine arteries (TOUA) was performed safely and the patient tried in vitro fertilization and achieved a intrauterine twin pregnancy after recovery time of the operation. At 31+6 weeks of gestation, a male neonate baby weighing 1,620 g and a male neonate baby weighing 1,480 g were born by transverse lower segment cesarean delivery. There was no complication after the operation. The babies were discharged after receiving routine neonatal intensive care for neonatal respiratory distress syndrome. Adenomyomectomy with TOUA technique would be an option for conservative surgical treatment in patients with severe diffuse whole uterine adenomyosis. This is the first report of twin pregnancy after diffuse whole uterine adenomyomectomy with TOUA. PMID- 27462600 TI - Heterotopic pregnancy after a single embryo transfer. AB - Heterotopic pregnancy is a rare and life-threatening condition which is defined as coexistent intrauterine and ectopic gestation. The risk of ectopic and heterotopic pregnancy is increasing due to the increased risk of multiple pregnancies with the aid of assisted reproductive technologies. However, it hardly happens in the setting of single embryo transfer, since single embryo transfer significantly reduces the incidence of multiple pregnancies. Surprisingly, we experienced a case of heterotopic pregnancy after a single embryo transfer caused by coincidental natural pregnancy during assisted reproductive technologies. An infertile woman who underwent, during her natural cycle, transfer of a single embryo that had been cryopreserved for 3 years was found to be heterotopically pregnant. After an early and successful management with laparoscopic right salpingectomy, she finally reached at full-term vaginal delivery. PMID- 27462601 TI - Successful term delivery cases of trans-abdominal cervicoisthmic cerclage performed at more than 18 weeks of gestation. AB - A 38-year-old nulliparous woman was referred to our clinic because of cervical incompetence at 19 weeks of gestation. Trans-abdominal cervicoisthmic cerclage was performed after failure of modified Shirodkar cerclage operation in the patient at 21 weeks of gestation via a laparotomic approach. Another 38-year-old patient, who underwent loop electrosurgical excision procedure conization for treatment of cervical dysplasia 4 years ago, presented for cervical incompetence. At 18 weeks of gestation, we performed trans-abdominal laparotomic cervicoisthmic cerclage without any post-operative complications. During antenatal follow-up, there were no obstetrical co-morbidities and finally she gave birth to a healthy infant at full term by cesarean section. We report two cases of women who underwent trans-abdominal cervicoisthmic cerclage surgery because of cervical incompetence as they were not suitable for transvaginal cervical cerclage. Both patients successfully maintained their pregnancy until full term after undergoing transabdominal cervicoisthmic cerclage at more than 18 weeks of gestation. PMID- 27462602 TI - A case of advanced-stage endometrial stromal sarcoma of the ovary arising from endometriosis. AB - Endometrial stromal sarcoma (ESS) is a rare malignancy. Development of extrauterine ESS form endometriosis is particularly rare. The majority of extrauterine ESS occurs in areas with preexisting endometriosis. The most common site is the ovary. We experienced a case of ESS of the ovary that arose from endometriosis with multiple disseminated lesions. This disease was managed by total abdominal hysterectomy, bilateral salpingo-oophorectomy, both pelvic lymph nodes dissection, omentectomy, and appendectomy followed by postoperative high dose progesterone therapy. Here, we report this case with literature review. PMID- 27462603 TI - A female adnexal tumor of probable Wolffian origin showing positive O-6 methylguanine-DNA methyltransferase methylation. AB - Female adnexal tumor of probable Wolffian origin (FATWO) is a rare disease entity that arises from the mesonephric duct system. FATWO is different than other gynecological cancers in terms of embryology. Here, we describe the case of a 52 year-old woman with malignant FATWO. The patient underwent explorative laparotomy and surgical staging after a frozen section revealed malignancy. Detailed examination of the pathologic findings were consistent with FATWO. Counseling and further testing were provided to the patient to assess the risk of germline mutation and epigenetic change. An O-6-methylguanine-DNA methyltransferase gene methylation test was positive, and all other tests were normal. This is the first study to report a case of O-6-methylguanine-DNA methyltransferase methylation with FATWO in Korea. PMID- 27462604 TI - A case report of a young girl with mucinous borderline tumor of the ovary. AB - Ovarian tumors are relatively rare in children and adolescent. The incidence of malignancies in these groups is 1% to 1.5%. The common histologic type is non epithelial type such as germ cell tumors or sex cord-stromal tumors and only 10% to 17% of those are epithelial tumors. It is important to accurately diagnose in the early these rare tumors for proper staging and treatment to save the patient's life and fertility. We present a case of a 13-year-old girl with a giant ovarian mucinous borderline tumor. PMID- 27462605 TI - Combined hysteroscopy-laparoscopy approach for excision of pelvic nitinol fragment from Essure contraceptive device: Role of intraoperative fluoroscopy for uterine conservation. AB - We describe the successful removal of a pelvic contraceptive coil in a symptomatic 46-year-old patient who had Essure devices for four years, using a combined hysteroscopy-laparoscopy-fluoroscopy approach. Following normal hysteroscopy, at laparoscopy the right Essure implant was disrupted and its outer nitinol coil had perforated the fallopian tube. However, the inner rod (containing polyethylene terephthalate) had migrated to an extrapelvic location, near the proximal colon. In contrast, the left implant was situated within the corresponding tube. Intraoperative fluoroscopy was used to confirm complete removal of the device, which was further verified by postoperative computed tomography. The patient's condition improved after surgery and she continues to do well. This is the first report to describe this technique in managing Essure complications remote from time of insertion. Our case highlights the value and limitations of preoperative and intraoperative imaging to map Essure fragment location before surgery. PMID- 27462606 TI - A successful laparoscopic neovaginoplasty using peritoneum in Mullerian agenesis with inguinal ovaries accompanied by primary ovarian insufficiency. AB - The combination of Mullerian agenesis with inguinal ovaries accompanied by primary ovarian insufficiency is extremely rare. A 21-year-old Korean woman was referred to our center with primary amenorrhea. The patient was diagnosed with Mullerian agenesis with inguinal ovaries. Her hormonal profile showed hypergonadotrophic hypogonadism suggesting primary ovarian insufficiency. We performed laparoscopic neovaginoplasty using modified Davydov's procedure and reposition inguinal ovaries in the pelvic cavity. Oral estrogen replacement was applied for the treatment of primary ovarian insufficiency. This is a rare case report on Mayer-Rokitansky-Kuster-Hauser syndrome accompanied not only by inguinal ovaries but also with primary ovarian insufficiency. We present our first experience on the laparoscopic neovaginoplasty performed on the patient with mullerian agenesis accompanied by inguinal ovaries and primary ovarian insufficiency. PMID- 27462607 TI - Corrigendum to "A Versatile Orthotopic Nude Mouse Model for Study of Esophageal Squamous Cell Carcinoma". AB - [This corrects the article DOI: 10.1155/2015/910715.]. PMID- 27462608 TI - Effect of Regular Resistance Training on Motivation, Self-Perceived Health, and Quality of Life in Previously Inactive Overweight Women: A Randomized, Controlled Trial. AB - Objectives. The aim was to investigate the effects of three different types of resistance training implementation. Design. Randomized controlled trial. Methods. Inactive, overweight women (n = 143), mean BMI 31.3 +/- 5.2 kg/m(2), mean age 39.9 +/- 10.5 years, were randomized to one of the following groups: A (BodyPump group training), B (individual follow-up by a personal trainer), C (nonsupervised exercise), or D (controls). The intervention included 12 weeks of 45-60 minutes' full-body resistance training three sessions per week. The outcomes in this paper are all secondary outcome measures: exercise motivation, self-perceived health, and quality of life. Results. Adherence averaged 26.1 +/- 10.3 of 36 prescribed sessions. After the intervention period, all three training groups (A-C) had better scores on exercise motivation (A = 43.9 +/- 19.8, B = 47.6 +/- 15.4, C = 48.4 +/- 17.8) compared to the control group (D) (26.5 +/- 18.2) (p < 0.001). Groups B and C scored better on self-perceived health (B = 1.9 +/- 0.8, C = 2.3 +/- 0.8), compared to group D (3.0 +/- 0.6) (p < 0.001). For quality of life measurement, there was no statistically significant difference between either intervention groups or the control. Conclusions. Resistance training contributed to higher scores in important variables related to exercise motivation and self perceived health. Low adherence showed that it was difficult to motivate previously inactive, overweight women to participate in regular strength training. PMID- 27462609 TI - Combination of Intra-Articular and Intraosseous Injections of Platelet Rich Plasma for Severe Knee Osteoarthritis: A Pilot Study. AB - The aim of this study was to assess a novel approach to treating severe knee osteoarthritis by targeting synovial membrane, superficial articular cartilage, synovial fluid, and subchondral bone by combining intra-articular injections and intraosseous infiltrations of platelet rich plasma. We explored a new strategy consisting of intraosseous infiltrations of platelet rich plasma into the subchondral bone in combination with the conventional intra-articular injection in order to tackle several knee joint tissues simultaneously. We assessed the clinical outcomes through osteoarthritis outcome score (KOOS) and the inflammatory response by quantifying mesenchymal stem cells in synovial fluid. There was a significant pain reduction in the KOOS from baseline (61.55 +/- 14.11) to week 24 (74.60 +/- 19.19), after treatment (p = 0.008), in the secondary outcomes (symptoms, p = 0.004; ADL, p = 0.022; sport/rec., p = 0.017; QOL, p = 0.012), as well as VAS score (p < 0.001) and Lequesne Index (p = 0.008). The presence of mesenchymal stem cells in synovial fluid and colony-forming cells one week after treatment decreased substantially from 7.98 +/- 8.21 MSC/MUL to 4.04 +/- 5.36 MSC/MUL (p = 0.019) and from 601.75 +/- 312.30 to 139.19 +/- 123.61 (p = 0.012), respectively. Intra-articular injections combined with intraosseous infiltrations of platelet rich plasma reduce pain and mesenchymal stem cells in synovial fluid, besides significantly improving knee joint function in patients with severe knee osteoarthritis. This trial is registered on EudraCT with the number 2013-003982-32. PMID- 27462610 TI - Prognostic Value of Osteopontin Splice Variant-c Expression in Breast Cancers: A Meta-Analysis. AB - Objectives. Osteopontin (OPN) is overexpressed in breast cancers, while its clinical and prognostic significance remained unclear. This study aimed to assess the prognostic value of OPN, especially its splice variants, in breast cancers. Methods. Data were extracted from eligible studies concerning the OPN and OPN-c expression in breast cancer patients and were used to calculate the association between OPN/OPN-c and survival. Two reviewer teams independently screened the literatures according to the inclusion and exclusion criteria based on quality evaluation. Following the processes of data extraction, assessment, and transformation, meta-analysis was carried out via RevMan 5.3 software. Results. A total of ten studies involving 1,567 patients were included. The results demonstrated that high level OPN indicated a poor outcome in the OS (HR = 2.22, 95% CI: 1.23-4.00, and P = 0.008; random-effects model) with heterogeneity (I (2) = 62%) of breast cancer patients. High level OPN-c appeared to be more significantly associated with poor survival (HR = 2.14, 95% CI: 1.51-3.04, and P < 0.0001; fixed-effects model) with undetected heterogeneity (I (2) = 0%). Conclusions. Our analyses indicated that both OPN and OPN-c could be considered as prognostic markers for breast cancers. The high level of OPN-c was suggested to be more reliably associated with poor survival in breast cancer patients. PMID- 27462611 TI - Laser Application in Dentistry: Irradiation Effects of Nd:YAG 1064 nm and Diode 810 nm and 980 nm in Infected Root Canals-A Literature Overview. AB - Objective. In endodontics, Nd:YAG laser (1064 nm) and diode laser (810 nm and 980 nm) devices are used to remove bacteria in infected teeth. A literature review was elaborated to compare and evaluate the advantages and disadvantages of using these lasers. Methods. Using combined search terms, eligible articles were retrieved from PubMed and printed journals. The initial search yielded 40 titles and 27 articles were assigned to full-text analysis. The studies were classified based upon laser source, laser energy level, duration/similarity of application, and initial and final bacterial count at a minimum of 20 prepared root canals. Part of the analysis was only reduced microorganisms and mechanically treated root canals upon preparation size of ISO 30. All studies were compared to evaluate the most favorable laser device for best results in endodontic therapy. Results. A total of 22 eligible studies were found regarding Nd:YAG laser 1064 nm. Four studies fulfilled all demanded criteria. Seven studies referring to the diode laser 980 nm were examined, although only one fulfilled all criteria. Eleven studies were found regarding the diode laser 810 nm, although only one study fulfilled all necessary criteria. Conclusions. Laser therapy is effective in endodontics, although a comparison of efficiency between the laser devices is not possible at present due to different study designs, materials, and equipment. PMID- 27462612 TI - Effect of self-care education on the quality of life in patients with breast cancer. AB - CONTEXT: Breast cancer is the most common cancer among Iranian women. Although survival rate of breast cancer patients has been increased some distresses affect the patients' quality of life negatively. the effectiveness of self-care education, particularly in the sociocultural context of Iran, has not been adequately investigated. AIMS: This study aims at evaluating the effectiveness of nurse-led self-care education program on quality of life in this patients. SETTINGS AND DESIGN: A controlled trial as pretest and posttest design was conducted in Sayyed-Al-Shohada Hospital in Isfahan in 2012. MATERIALS AND METHODS: Sixty patients with breast cancer were assigned to either the nurse-led self-care education program (n = 30), or to routine care (n = 30). Quality of life was measured at the time of recruitment and also 3 months after the intervention by the instrument of the National Medical Center and Beckman Research Institute. STATISTICAL ANALYSIS USED: Data were analyzed by SPSS (version 16) software using T-independent, T-paired and chi(2), and Fisher's exact tests. RESULTS: The intervention group had significantly greater improvements in quality of life status (P < 0.05). Furthermore, self-care education caused a significant increase in the quality of life score related to physical (P = 0.00), psychological (P = 0.00), social (P = 0.00), and emotional (P = 0.00) dimensions. CONCLUSIONS: Quality of life in patients with breast cancer can be improved by participating in a nurse-led self-care education program. It is suggested that self-care education to be added to the routine nursing care delivered to these patients. PMID- 27462613 TI - Routine programs of health care systems as an opportunity toward communication skills training for family physicians: A randomized field trial. AB - BACKGROUND: To have high-quality primary health care services, an adequate doctor patient communication is necessary. Because of time restrictions and limited budget in health system, an effective, feasible, and continuous training approach is important. The aim of this study is to assess the appropriateness of a communication skills training program simultaneously with routine programs of health care system. MATERIALS AND METHODS: It was a randomized field trial in two health network settings during 2013. Twenty-eight family physicians through simple random sampling and 140 patients through convenience sampling participated as intervention and control group. The physicians in the intervention group (n = 14) attended six educational sessions, simultaneous organization meeting, with case discussion and peer education method. In both the groups, physicians completed communication skills knowledge and attitude questionnaires, and patients completed patient satisfaction of medical interview questionnaire at baseline, immediately after intervention, and four months postintervention. Physicians and health network administrators (stakeholders), completed a set of program evaluation forms. Descriptive statistics and Chi-square test, t-test, and repeated measure analysis of variance were used to analyze the data. RESULTS: Use of routine program as a strategy of training was rated by stakeholders highly on "feasibility" (80.5%), "acceptability" (93.5%), "educational content and method appropriateness" (80.75%), and "ability to integrating in the health system programs" (approximate 60%). Significant improvements were found in physicians' knowledge (P < 0.001), attitude (P < 0.001), and patients' satisfaction (P = 0.002) in intervention group. CONCLUSIONS: Communication skills training program, simultaneous organization meeting was successfully implemented and well received by stakeholders, without considering extra time and manpower. Therefore it can be a valuable opportunity toward communication skills training. PMID- 27462614 TI - Fluoride exposure and its health risk assessment in drinking water and staple food in the population of Dayyer, Iran, in 2013. AB - AIMS: The aims of this study were to determine fluoride concentration in drinking water and staple foods consumed by residents of Dayyer port (Bushehr province, south of Iran) and to assess its health risk via human intake in 2013. MATERIALS AND METHODS: Health risk assessment due to fluoride exposure via consumption of drinking water, date, vegetables and fish was conducted in spring and summer of 2013 using the US-EPA (United States-Environmental Protection Agency) method, which considers hazard quotient (HQ) as a ratio of the estimated dose of a contaminant to the reference dose. A fluoride ion-selective electrode (ISE) measured the fluoride contents of food samples. The sodium-2-(parasulfophenyl largo)-1,8-dihydroxy-3,6-naphtnalene disulfonate colorimetric method (SPADNS) was used to determine fluoride concentration in water samples. RESULTS: The total estimated oral intake of fluoride for children in summer and spring were 120.6 and 145.6 ug/kg/day, respectively. These values for adults were 99.2 and 112 ug/kg/day. This survey demonstrated that drinking water was the most important contributor of dietary fluoride intake in the study area. CONCLUSION: HQ values for adults and children were >1 which approves that a potential health risk of fluorosis can exist. The recommendations for the study area are supplying drinking water from alternative sources and defluoridation of drinking water by an adsorption technique and membrane filtration, respectively. Furthermore, people are suggested to have a good nutrition (especially rich of vitamin C) to reduce the risk of fluorosis. PMID- 27462615 TI - Health and healthy human being in Islamic thought: Reflection on application for the nursing concept - A philosophical inquiry. AB - INTRODUCTION: Health and healthy human being as a core concept of nursing have attracted considerable attention in the Western literature but have received less attention in the context of Eastern philosophy contexts. METHODS: This study was done based on philosophical inquiry; this method could be accomplished by means of different approaches like philosophical analysis through concept analysis. There are different methods for concept analysis. Mors's method was employed to analyze the concept of health and healthy human being, we sought to clarify them according to ideas deriving from the Islamic thought. To achieve the research objective, Islamic texts were studied and analyzed based on the criteria of concept analysis (definition, attributes/characteristics, and beaneries). RESULTS: Our analysis revealed in the Islamic thought human being is an integrated entity. Therefore, his health not only consists of each single dimension, but also the full health together with the health of society gets meaning in a balanced and coordinated set. CONCLUSION: Based on the results, in this study, there are a series of similarities and differences with the perspectives of health in Islamic thought and holism paradigm available in nursing. PMID- 27462616 TI - The effect of implementation of family-centered empowerment model on the self esteem of the old people with hypertension. AB - INTRODUCTION: Noncommunicable diseases are recognized as the major cause of old people's death. One of the models concerning the family health level is the family-centered empowerment model (FCEM) which has been designed with the aim of promoting the health level and self-esteem of the patients and their family members. PURPOSE: This study was carried out to investigate about the effect of implementation of FCEM on the self-esteem of old people with high blood pressure. SETTINGS AND DESIGN: This was a clinical trial study which focused on 62 old adults with high blood pressure in 1392. After cluster sampling, samples were divided randomly into test group and control group. METHODS: FCEM was used for the test group; whereas, for the control group, common health cares and one educational session were performed. Study materials were checklist of demographic information, and a researcher-made questioner to evaluate the level of self esteem. Posttest was given 1-weak after the intervention and was followed-up 1(1/2) months later. STATISTICAL TESTS: T-test, analysis of variance, and SPSS 20 were used to analyze the date. FINDING: Before the intervention, the mean scores of self-esteem in both the test group and the control group were the same (t = 0.55) (P > 0.05). However, 1-week after the intervention (t = 6.38) and 1(1/2) months later, meaningful differences were observed in the test group (P < 0.001). CONCLUSION: Implementation of FCEM has a positive effect on the high self-esteem of the old people with high blood pressure. PMID- 27462617 TI - Evaluating the clinical quality of departments as viewed by juniors and seniors of Shiraz dental school. AB - INTRODUCTION: Assessment of students' perspective is an essential element in effective educational quality evaluation. By identifying strengths and weaknesses, it leads to improvement in future performance. METHODS: This cross sectional study was performed through a questionnaire comprising 23 questions. Reliability was assessed using alpha-Chronbach (alpha =0.87), and validity was confirmed by a group of five experts. Tukey test, Pearson correlation coefficient, and two sample t-tests were used for data analysis. METHODS: This cross-sectional study was performed through a questionnaire comprising 23 questions. Reliability was assessed using alpha-Chronbach (alpha =0.87), and validity was confirmed by a group of five experts. Tukey test, Pearson correlation coefficient, and two sample t-tests were used for data analysis. RESULTS: A total of 168 answered questionnaires were entered in our study. Maximum satisfaction in most items was shown in removable prosthodontics and orthodontics departments whereas oral surgery and comprehensive treatment departments acquired the least scores. In all departments, personnels' respectful attitude had the highest score whereas minimum grade was given to stressful workload and overall satisfaction in each department. In comparison with a similar study, conducted 3 years ago, level of satisfaction was raised for orthodontics and removable prosthodontics departments though it was declined for the pediatrics department. CONCLUSION: The special cadre of clinical instructors comprising both experienced and young members is considered as an important factor leading to high student satisfaction in the orthodontics department. Promotion of a removable prosthodontics department is related to the high relevance between the implemented educational program and the curriculum. The moderate performance of oral surgery and restorative departments is indicative of the need for more attention from ministry authorities to major dental departments such as oral surgery, endodontic, restorative and periodontics, in order to increase the students' scientific capability in these fields. PMID- 27462618 TI - Effect of information literacy training course on information literacy skills of undergraduate students of Isfahan University of Medical Sciences based on ACRL standards. AB - BACKGROUND: Information literacy is the basis for lifelong learning. Information literacy skills, especially for student in an environment that is full of information from multiple technologies are being developed is equally important. Information literacy is a set of cognitive and practical skills and like any other science, proper training is needed, and standard-based education is definitely better and evaluation would be easier. This study aimed to determine the impact of information literacy training course on information literacy skills of Isfahan University of Medical Sciences students based on ACRL standard in 2012. MATERIALS AND METHODS: The study method is semi-experience with two group design (with pre-test and post-test) and applied. The data collection toll was a questionnaire assessing student's information literacy that developed by Davarpanah and Siamak and validity was confirmed by professional librarians and reliability as measured by Cronbach's alpha, was 0.83. The sample consisted of 50 undergraduate students from Isfahan University of Medical Sciences that by random sampling method was perch in both case and control groups. Before and after the training (once a week), a questionnaire was distributed between the two groups. This training was held in a classroom equipped with computers with internet access and in addition to training using brochures and librarian presentation, interactive methods such as discussion and exercises were used. The data were analyzed using SPSS version 20 software and two level of descriptive (mean and SD) and inferential statistics (t-test and t-paired). RESULTS: The results showed that the students' information literacy scores before the training was lower than average, so that in the control group was 32.96 and in the case group was 33.24; while information literacy scores in the case group significantly increased after the training (46.68). Also, the effect of education, respectively had a greater impact on the ability to access information (the second standard), ethics and legal use of information (the third standard), effective use of information (the fourth standard), critically evaluate information and its sources (the fifth standard). CONCLUSION: This study showed that the training was effective on enhancing students' information literacy skills as the greatest impact was on increasing the ability to access information. Due to low mean score information literacy in the context of object recognition, there is a need for more training in this area. PMID- 27462619 TI - Messages to promote physical activity: Are descriptors of required duration and intensity related to intentions to be more active? AB - INTRODUCTION: Mass-media campaigns such as, "Change4Life' in the UK and "get active America" in the US, promote physical activity (PA) recommendations of at least 150 min/week of moderate-to-vigorous PA (MVPA). We investigated whether different messages used in MVPA campaigns were associated with intention to engage in more MVPA. MATERIALS AND METHODS: Theory of planned behavior (TPB) constructs; subjective norms, affective attitudes, instrumental attitudes and perceived behavioral control (PBC) were applied to explain the associations between campaign messages and intentions to engage in more MVPA. RESULTS: A total of 1412 UK adults completed an online survey on MVPA and TPB. The sample was 70% female and 93% white with 23% reporting meeting PA guidelines. Participants received one of three messages: A walking message either with or without the 150 min/week threshold (WalkT; WalkNT); a physiological description of MVPA with the 150 min/week threshold (PhysT). ANCOVA examined group differences in intention. Path analysis evaluated mediation by TPB variables. ANCOVA identified lower intentions to increase MVPA in group PhysT relative to WalkT and WalkNT (P < 0.001). PBC mediated this relationship in WalkT (beta = 0.014, 95% confidence interval [CI] = 0.004-0.028) whereas affective attitudes mediated this relationship in WalkNT (beta = 0.059, 95% CI = 0.006-0.113). CONCLUSIONS: Campaigns promoting MVPA guidelines need to choose their messages carefully. Messages which exemplified MVPA through walking were associated with higher intentions to increase MVPA than messages using a physiological description. Further, PBC was enhanced when the 150 min/week threshold was promoted alongside the walking exemplar. Future exemplars should be investigated to inform adults how to meet MVPA guidelines. PMID- 27462620 TI - Effect of peer education in school on sexual health knowledge and attitude in girl adolescents. AB - BACKGROUND: Adolescence is associated with so many changes, and to provide sexual health it is necessary for teenagers to learn enough knowledge about the changes and appropriate health behaviors. The attraction of sexual issues in teenagers is associated with more conversations related to sexual matters. Therefore, this study has evaluated the effect of organizing these interactions using peer education in schools on the knowledge and attitude toward sexual health. MATERIALS AND METHODS: This was an interventional study conducted on 282 girl teenagers from high schools of Isfahan that were divided into two groups of intervention and control. Peer education in the intervention group was done through 35 trained teenagers during normal communications in school. Before the training knowledge and attitude of students in both groups were evaluated; then peer education was conducted during 6 weeks through normal communications on the intervention group and then afterward the knowledge and attitude of the students were evaluated again. To analysis of data independent t-test and paired t-test were used. RESULTS: The results showed that the mean score of knowledge and attitudetoward all sexual health dimensions during puberty in the intervention group was significantly higher after the intervention (P < 0.05). In addition, there was a significant difference between the mean score of knowledge and approach toward all the aspects of sexual health of both the studied groups. CONCLUSIONS: The results showed that using peer education in schools informally could enhance the knowledge and approach toward aspects of physical health, sexual behaviors, and social and mental changes among female adolescences and could be applied in schools. PMID- 27462621 TI - The relationship between social capital and the way of spending leisure time, based on physical activities. AB - BACKGROUND: Today, social capital is a need in the society. Also, leisure time and physical activities are among the most important productive sources of social capital, which have been realized recently. This study aims to find the relationship between social capital and physical leisure time of the faculty members of Isfahan University of Medical Sciences. MATERIALS AND METHODS: A descriptive correlation method was used in this study. Two questionnaires were used for data collection. Social capital questionnaire is based on SCAT Model. Also, leisure time questionnaire was made by the researcher for which face and content validity was verified by experts. Reliability coefficients by using Cronbach's alpha coefficients were calculated as 0.92 and 0.82, respectively. Sample population was calculated by Cochran's formula, and 150 people were selected as the sample using multiple cluster sampling by taking the sex and college into consideration as the variables. FINDINGS: According to the findings, there was a direct relationship between a combination of social capital parameters (including commitment, attitude, trust, participation, mutual relationship, social norm, and unity) and the way of spending physical leisure time (R = 0.659, P = 0.000). Among the parameters, "commitment" was significant with a beta coefficient B = 0.293 and P = 0.044 and social norms was significant with a beta coefficient B = 0.196 and P = 0.047, but the rest of the factors were not significant. CONCLUSION: Playing sport and doing physical activities in the leisure time and also taking part in group activities and their membership provide a situation for people to respect the group interests through communication. Such activities can cause the level of social capital and its factors to be increased. PMID- 27462622 TI - Pathology of Isfahan University of Medical Sciences based on Weisbord six box model and its relation with mental health. AB - BACKGROUND: The aim of this research was to study the pathology of Isfahan University of Medical Sciences based on Weisbord six box model and to find its relation with mental health. MATERIALS AND METHODS: The research method followed was a descriptive survey. The statistical society consisted of all staffs of the Isfahan University of Medical Sciences consisting of professors in the year 2012 (personnel of deputy of treatment, deputy of training, cultural-student deputy, supporting deputy, deputy of food and drugs, health deputy, and deputy of research). The number of subjects in the mentioned society was 1647, sample size was 332 Based on Cochrane's formula. They were selected by random sampling method in proportion with the statistical society. The measurement instruments included organizational pathology questionnaire (ODQ) with 35 questions and the questionnaire of mental health standard [General Health Questionnaire (GHQ)] with 28 questions. The validity of the questionnaires obtained from reviews by faculties and experts, and the reliability of the questionnaire assessed through Cronbach's coefficient were 0.86, 0.85, and 0.76, respectively. To analyze data, the statistical methods such as single-variance t-test, regression analysis, correlation coefficient, Kolmogorov-Smirnov test, and Multivariate Analysis of Variance (MANOVA) were used. FINDINGS: The findings of research demonstrated that the organizational damage based on six box model was seen only in the reward component at the Isfahan University of Medical Sciences. Mental health of persons in the sample group of Isfahan University of Medical Sciences was in the suitable status. There was a meaningful and positive interrelation between mental health and attitude toward the organizational damages in the dimensions of communications, useful merchandises, and attitude to change. However, no meaningful interrelation was seen between aims, structure, leadership, and reward and mental health. There was no meaningful difference between the averages of staffs' attitude about their mental health per the demographic properties. CONCLUSIONS: The results show that there was a meaningful and positive interrelation between mental health and attitude toward the organizational damages in the dimensions of communications, useful merchandises, and attitude to change. Therefore, managers should focus on all parts of the organization and the pathology strengths and weaknesses in these areas. PMID- 27462623 TI - Physical activity among employee women based on transtheoretical model. AB - INTRODUCTION: Today, many jobs are associated with the inactivity or sedentary lifestyle. Employees' health will be affected by their depriving of the benefits of physical activity (PA). Therefore, the present study was undertaken to determine the PA among employee women in Isfahan University of Medical Sciences based on the transtheoretical model. MATERIALS AND METHODS: This is a cross sectional study has been performed in Isfahan University of Medical Sciences employee women (2013). A convenience sample of 100 women was selected. Data were collected by validated and reliable questionnaire in three parts (demographics information, PA scale, and TTM constructs). Data were analyzed by SPSS SPSS (version 16.0; SPSS, IBM, Inc, Chicago, IL, USA) and descriptive and analytical statistics such as ANOVA and independent t-test were used. A two-tailed P < 0.05 was considered statistically significant. RESULTS: The mean of PA was 21.17 +/- 27.30 min in a day. Weekly heavy, moderate, and light exercise mean was 0.72 +/- 1.81, 0.89 +/- 1.87 and 0.57 +/- 1.57 days, respectively. In this study, 26% of women were in contemplation, 22% in contemplation, 20% in preparation, 13% in action, and 19% in the maintenance stage. Furthermore, there were significant differences between consciousness raising, dramatic relief, counter-conditioning, stimulus control, helping relationships, reinforcement management, and self liberation with stages of change constructs. CONCLUSION: Because of a significant relationship between cognitive and behavioral processes and PA in this group, designing and implementing an educational program based on the transtheoretical model may be useful in promoting PA of a female employee. PMID- 27462624 TI - South African rural community understanding of fermented foods preparation and usage. AB - BACKGROUND: The benefits of fermented foods consumption have been demonstrated in a number of research reports. These qualities have been demonstrated, for example, to reduce childhood diseases such as diarrhea and malnutrition. Thus, fermented foods may be recommended for improving the health and nutritional quality of traditional African foods and regular inclusion of fermented foods as part of the daily diet would be desirable. AIMS: Lack of knowledge and understanding toward fermented food preparation may limit their usage. This study explores the South African community's understanding of fermented foods preparation and usage. MATERIALS AND METHODS: This was a qualitative study using focus group interviews to determine the community's understanding and their perception of fermented foods preparation in the rural villages of Odi, in Gauteng Province between May and June 2012. The target population was the caregivers of children under 5 years, attending the hospital's antenatal clinic at the time of study. The information was transcribed, coded, and analyzed using NVivo software. RESULTS: Most caregivers were aware of food fermentation process, and some of them could not clearly differentiate between fermented and unfermented foods. Although most participants knew what fermented foods were, there were misconceptions on how they were made. This was exemplified by the undesirable artifacts, labeled as ingredients, in the fermentation process. CONCLUSION: Caregivers demonstrated a fair knowledge of fermented foods but lack a standard preparation procedure for these foods. There is an urgent need to educate communities and conduct a health promotion campaign on the fermented foods and probiotics. PMID- 27462625 TI - The challenges of healthcare delivery to people with multiple sclerosis in Iran. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic disease prevalent in young and middle-aged people. Patients with MS often have numerous complicated needs and, consequently, require a broad range of health services. Results of a number of studies indicate that patients' needs are only partially met. AIMS: This study was conducted to explore the challenges of healthcare delivery to patients with MS in Iran. MATERIALS AND METHODS: In this qualitative case study, 43 participants selected through purposeful sampling were interviewed using semi structured method in the cities of Isfahan and Tehran in 2012-2013. Besides the interview, documentations relevant to healthcare delivery were collected from different sources, including websites of all Iranian universities of medical sciences, insurance organizations, patients' weblogs, news agencies, the MS Center forum for MS patients, and MS Payam bimonthly. The data were analyzed through the constant comparative analysis. RESULTS: The data were categorized into four main categories, including functional challenges (diagnosis problems, failure to pay attention to patient needs, failure to follow-up, and miscommunication), administrative challenges (resource allocation and supervision), policy-making challenges (lack of comprehensive services, bureaucracy, and problems in provision of medications), and structural challenges (difficult access to services, lack of comprehensive centers, space limit, and long wait). CONCLUSION: Despite all attempts of governmental and nongovernmental organizations for healthcare delivery to MS patients, these services cannot satisfy all needs of the patients. In this regard, service providers and administrators should pay more attention to the needs and expectations of patients and their families. PMID- 27462626 TI - The relationship between weight gain during pregnancy and urinary tract infections in pregnant women of Shahrekord, by using the "Nested case-control study", in 2013. AB - BACKGROUND AND OBJECTIVES: Pregnancy is one of the most important and risky periods in mothers and the fetus life, which plays a key role in health and social activity of the person, family and community. This study is trying to see if there is a relation between increasing weight and urinary tract infection (UTI) in pregnancy by using the open nested case-control study in the city of Shahrekord. MATERIALS AND METHODS: In a nested case-control study, one cohort including 832 patients was examined until week 26 to 30 of pregnancy and their UTIs were studied. The required information was collected by examining the health records of pregnant women and completion of the data registration forms. Data collection was controlled by using SPSS and analyzed by using an independent t test, Chi-square test, Pearson correlation and logistic regression. RESULTS: According to the results of the cohort study with 832 individuals, average weight gain of the group with a UTI was 11.13 +/- 3.9 kg and it was 10.63 +/- 3.9 kg in the group without UTI, showing no statistically significant difference (P = 0.245). According to the results, genitourinary problems had the highest predictive value for UTIs and the numbers of infertility and the childbirth variables were in the second and third positions, respectively. CONCLUSION: According to the results study we can conclude that screening and treatment of UTIs have been on time and appropriate in health systems of the city of Shahrekord which have lead to the reduction of infant and maternal diseases even with the condition in having no UTI, and continuing this process for screening and treatment is recommended. PMID- 27462627 TI - The impact of group training about parenting styles on maternal attitudes toward parenting styles. AB - BACKGROUND: Parenting style is one of the most important and effective factors in training and growth of children and adolescents and the method that parents communicate with their children is an effective factor on family contact models. OBJECTIVES: The aim of this study was to determine the impact of group training about parenting styles on maternal attitudes that were admitted to Isfahan Imam Ali (AS) health care center in 2013. MATERIALS AND METHODS: This was an experimental study, which was conducted on a random sample of 25 mothers referred to this health care center. They were divided into two groups (experimental and control). The experimental group received five sessions of group training, and the control group received a booklet about parenting styles. The used tool in this study was the Bamerind Parenting Style Questionnaire that was completed by the mothers before and after the intervention and finally, their obtained scores were compared with each other. RESULTS: The results of the present study showed that the mean score of attitude toward easy-going style in test group was less than the control group after intervention (P = 0.045). The mean score of attitude toward authoritative style in the experimental group was less than control group after intervention (P = 0.037) and the mean score of attitude toward authoritative style in the experimental group was more than the control group after intervention (P = 0.011). CONCLUSIONS: Group training can be an appropriate method in changing maternal attitudes toward parenting styles. PMID- 27462628 TI - Role of soap and water in the treatment of wound dehiscence compared to normal saline plus povidone-iodine: A randomized clinical trial. AB - BACKGROUND: The incidence of cesarean section is increased. About 3-30% of the women who undergo cesarean experience surgical site infections (SSIs). Many methods, have been used to decrease the incidence of SSIs, but despite much effort, no definite efficacious method has been suggested. MATERIALS AND METHODS: In this parallel, single-blinded, randomized control trial, 56 women with post surgical superficial wound dehiscence were divided into two groups in a 1:1 ratio. One group was irrigated with normal saline for irrigation and Firooz(r) baby soapand the other with normal saline for irrigation and povidone-iodine. Formation of granulation tissue was monitored in both groups. Also, the reason for surgery, length of wound dehiscence, and duration of hospitalization and wound union after were compared in both group's. RESULTS: The soap group patients were irrigated for 4.18 +/- 1.96 days compared to 5.36 +/- 2.83 days for the patients in povidone-iodine group (P = 0.414). The granulation tissue was formed after 3.88 +/- 1.94 days in the soap group compared to 4.48 +/- 2.92 days in the other group (P = 0.391), and the duration of hospitalization was 5.48 +/- 2.04 days in the soap group compared to 6.3 +/- 2.95 days in the other group (P = 0.423). So, no differences were observed between the two groups. CONCLUSION: It can be concluded since there is no difference between the results of two groups, irrigation with normal saline and soap is safe, easy and causes no harm or allergy compared with povidone iodine and normal saline. PMID- 27462629 TI - Reproductive health care seeking behavior among urban slum women of Delhi. AB - BACKGROUND: The study tries to understand what are the dimensions of Reproductive Health care seeking behavior among the urban slum women in Delhi, their level of awareness and treatment seeking patterns? MATERIALS AND METHODS: The study was carried out in one of the slum in south district of Delhi. 253 women of reproductive age group were selected by systematic random sampling. Interpersonal interview was conducted to seek information on the selected parameter. RESULTS: Around three/fourth women had undergone for blood pressure check up, weight recording and stomach/abdomen check up during pregnancy. Only 39.9% received advice on avoiding intake of medicine during pregnancy. About 14.6% mentioned that at least 40 days rest were required for resuming daily routine activities after delivery. Thus majority of these slum women are ignorant about the importance of post natal care which was necessary for post delivery care of the women and her infant. CONCLUSION: The correct knowledge on the importance of ANC and PNC and various checkups need to be carried out during pregnancy and postnatal period needs to be imparted to these women. Thus, health education and health promotion campaigns are needed for bring changes in the existing health seeking behaviors among urban slum women. PMID- 27462630 TI - Effect of public health nurses' educational intervention on self-care of the patients with type 2 diabetes. AB - BACKGROUND: Diabetes is the most common metabolic disease and the sixth cause of mortality in the world. Most of the conducted studies show that the only way to control this disease and prevent its disabling complications is constant administration of self-care. AIM: This study was conducted with the goal of determining the effect of public health nurses' educational intervention on the self-care of the patients with type 2 diabetes who referred to Hazrat Ali clinic in Isfahan. MATERIALS AND METHODS: This is a two-group two-step clinical trial with a before-after intervention design in which 50 patients with type 2 diabetes and with a mean age of 40-70 years were selected and assigned to study (n = 25) and control (n = 25) groups by allotting them even and add numbers. Educational intervention was conducted in the study group through seven educational sessions. Mean scores of self-care before and after interventions were compared by Toobert and Glasgow brief self-care activities questionnaire. RESULTS: Results showed no significant difference in the self-care scores before intervention in the two groups (P = 0.67, z = 0.43), but the mean score of self-care showed a significant increase after intervention in the study group, compared to the control group (P = 0.002, z = 3.14). CONCLUSION: Based on the obtained results, it is suggested to provide constant education of self-care for diabetic patients in health care centers, with more emphasis on a change in self-care skills and behavior. PMID- 27462631 TI - Relationship between the components of on-site training and emotional intelligence in the librarians of Isfahan University of Medical Sciences and Isfahan University with moderating role of personality characteristics. AB - INTRODUCTION: Training the man power is an inevitable necessity that the organizations need in order to survive and develop in today changing world. AIMS: The aim of the present study is to identify the relationship between the components of on-site training and emotional intelligence in librarians of Isfahan University of Medical Sciences and Isfahan University with moderating role of personality characteristics. SETTINGS AND DESIGN: Descriptive correlation method was used in the present study. The statistical population of the study was all of the 157 librarians of Isfahan University of Medical Sciences and Isfahan University from whom the appointed individuals were selected through random sampling method. SUBJECTS AND METHODS: The research tools included the researcher made questionnaire of investigating the effectiveness of on-site training system and two other standard questionnaires of Shrink emotional intelligence, and NEO personality questionnaire, which all of them had the needed reliability and validity. STATISTICAL ANALYSIS: The descriptive indices (distribution and mean) and also the inferential methods (Pearson correlation, regression analysis and analysis of variance) were used through applying version 20 of SPSS software to analyze the obtained data. RESULTS: There was a significant relationship with certainty level of 95% between the components of on-site training with emotional intelligence in those who obtained low grades in the features of being extrovert and between the individual aspects of on-site training with emotional intelligence in those who got higher grades in the characteristic of being extrovert. CONCLUSION: The emotional intelligence is a promotable skill and considering the existence of a significant relationship between some components of emotional intelligence and on-site training, these skills can be institutionalized through conducting mentioned educational courses. PMID- 27462632 TI - Effect of educational intervention on knowledge, perceived benefits, barriers and self-efficacy regarding AIDS preventive behaviors among drug addicts. AB - BACKGROUND AND OBJECTIVES: Addicts account for approximately 68.15% of AIDS cases in Iran and injection drug users are considered as a major factor in the spread of AIDS in Iran. The purpose of this study was to determine the effect of an educational intervention on the perceived self-efficacy, benefits, and barriers concerning AIDS preventive behaviors among drug addicts in Khorramabad, Iran. METHODS: This is a quasi-experimental study carried out in 2013 on 88 addicts kept in rehabilitations center in Khorramabad. The data collection instruments included a questionnaire on self-efficacy, perceived benefits, perceived barriers, knowledge and preventive behaviors regarding HIV. Data were analyzed by paired t-test, independent t-test, Chi-square and analysis of covariance. RESULTS: Paired t-test showed that the mean scores for perceived benefits and barriers, knowledge and preventive behaviors significantly increased in the intervention group after the intervention than before the intervention. But the increase in self-efficacy score was not statistically significant. CONCLUSIONS: The results of this study showed that training and education based on the health belief model led to an increase in knowledge, self-efficacy, perceived benefits, performance and reduction in perceived barriers in addicts. It is recommended that future studies should include strategies for enhancing self-efficacy and perceived benefits as well as strategies for reducing barriers to the adoption of preventive behaviors. PMID- 27462633 TI - Health literacy among adults in Yazd, Iran. AB - The purpose of this survey was to assess the health literacy levels and determine the relationship between health literacy with demographic variables and the socioeconomic status Three hundred and eighty adults, 18 years and older, were randomly selected and assessed by the Test of Functional Health Literacy in Adults (TOFHLA) instrument in two sections of reading comprehension and numeracy. The second instrument used to detect the relationship between the demographic variables and socio-economic status and the level of health literacy of the subjects of adults in Yazd district. Three hundred and eighty adults, 18 years and older, were randomly selected and assessed by the Test of Functional Health Literacy in Adults (TOFHLA) instrument in two sections of reading comprehension and numeracy. The second instrument used to detect the relationship between the demographic variables and socio-economic status and the level of health literacy of the subjects. The mean score of a participant's health literacy was 73.33 +/- 1.29. Fifty-four percent of the individuals had adequate health literacy and the rest of them had limited health literacy. The mean score of functional health literacy was significantly different by socio-economic status (p0.05) and the years of schooling (P = 0.00). On the basis of linear regression, in this research, the years of schooling (B0.28, p0.01) and marital status (B = 3.08, p0.05) were two predictors of health literacy. PMID- 27462634 TI - Study of the relationship between quality of life and socioeconomic status in Isfahan at 2011. AB - BACKGROUND: Quality of life (QOL) is one of the health indexes for which many efforts have been made to define and measure during the last four decades of the 20(th) century in many countries. This paper is aimed at studying the QOL in relation to socioeconomic status of the general population of Isfahan in 1390. MATERIALS AND METHODS: We applied a descriptive-analytical and sectional method. In this research, 385 women and men over 15 years of age from 14 regions of Isfahan's municipality were studied using multi-stage quota sampling. We examined QOL using the SF-36 standard questionnaire, along with two domains of mental and physical health and eight subscales within the validity domain of 65-90%. Social (81%) and economical (70%) status was also measured by the questionnaire instrument in both objective and subjective domains after confirming the validity and reliability of the instruments. The given data were analyzed by SPSS 17 software and using descriptive and statistical tests. RESULTS: The indicators of QOL showed that a score deviation of the SF-36 questionnaire in physical health (SD = 2.31) and mental health (SD = 3.22) domains was obtained from the population. Of the eight subscales, bodily pains and limitations on functioning as physical and mental had an inverse relationship with socioeconomic status. However, physical health, mental health, social activities, public health, and vitality had a significant positive relationship, including different strengths and weaknesses, with socioeconomic status. Also, sexuality and housing status had no relationship with QOL. CONCLUSION: There is a direct and significant relationship between quality of life and socioeconomic status variables in Isfahan. PMID- 27462635 TI - Knowledge, risk perception, and behavioral intention about hepatitis C, among university students. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is a major complex public health problem. Different resources have proved that healthcare workers more than the general population are at a risk of infection. Therefore, medical field students, due to the future occupational hazards, are included in the risk group. AIM: The purpose of the study was to evaluate the level of knowledge, public and individual risk perception, and behavioral intention about HCV, among medical sciences students of the Isfahan University of Medical Sciences. SETTINGS AND DESIGN: This is a descriptive-analytical study that was conducted among 457 students of the Medical Sciences in the Isfahan University of Medical Sciences. MATERIALS AND METHODS: The data was collected using a questionnaire. Sampling was done randomly. STATISTICAL ANALYSIS USED: The data was analyzed using the SPSS18 software and statistical tests of Pearson, Spearman, T- test, and the analysis of variance (ANOVA); P < 0.05 was considered significant. RESULTS: Four hundred and fifty-seven students (41.8% male and 58.2% female) in 29 fields of study (six categories) participated in this research. The mean age was 21.55 +/- 2.6 years. The mean and standard deviations of the students' knowledge was 3.71 +/- 2.9 (out of 8), and the behavioral intention to accruing information and performance of preventive actions related to HCV was 11.52 +/- 3.16 (out of 20). Public risk perception was 20.1 +/- 3.5 (out of 30); and personal risk perception was 6.96 +/ 1.8 (out of 10). The ANOVA test showed that public perception of the risk among students of different academic fields was different (F = 1.52, P < 0.05). CONCLUSIONS: According to the low knowledge of students of Medical Sciences in the Isfahan University of Medical Sciences about HCV, it was recommended that the University Policymakers design an educational intervention about it, in order to minimize the chances of being infected. PMID- 27462636 TI - A survey on the effect of implementation of a family-centered empowerment model on blood pressure and empowerment dimensions in the elderly people with hypertension. AB - BACKGROUND: Noncommunicable diseases such as Hypertension are among the important factors of mortality and morbidity of the elderly people. The family-centered empowerment model (FCEM) has not been performed for elderly people with hypertension. SETTINGS AND DESIGN: This clinical trial study was carried out on 62 elderly people with hypertension under the coverage of the Lenjan Health Network in 2013. After performing the sampling by using the cluster-randomized method, the samples were divided randomly into the experimental and control groups. METHODS: For the experimental group, the (FCEM) was implemented based on the four steps. For the control group, it was only implemented the usual care and one training session. Research tools included questionnaires of demographic data, empowerment assessment and a blood pressure-measuring device. The post-test was performed 1 week later. The blood pressure was recorded, and it was followed 1.5 month later again. STATISTICAL TESTS: Statistical tests for data analysis included chi(2)-test, independent t-test, Mann-Whitney, analysis of variance, and SPSS 20. RESULTS: 1 week later and 1.5 month after the intervention, the mean blood pressure was significant in both groups (P < 0.001). also, the difference in the mean score of empowerment dimensions was significant in the experimental group 1 week later and 1.5 month after the intervention (P < 0.001). CONCLUSION: Implementation of the FCEM for elderly people with hypertension has been possible from a practical point of view, and it has been associated with controlling and improving the blood pressure. PMID- 27462637 TI - Comparison of the effects of enteral feeding through the bolus and continuous methods on blood sugar and prealbumin levels in ICU inpatients. AB - BACKGROUND: Appropriate nutritional support is effective on achievement of expected outcomes in intensive care unit (ICU) patients. Although several studies have suggested different conclusions about the effectiveness of tube feeding methods, there is no specific program of nutritional support for patients who have been hospitalized. There is a possibility for complications due to an inadequate nutrition. The aim of our study is to compare the effects of enteral feeding through the bolus and continuous methods on blood sugar and prealbumin level among the ICU inpatients. MATERIALS AND METHODS: Fifty subjects were selected by convenient sampling from April to Aug 2013 in the ICU wards of Alzahra Hospital, Isfahan, Iran, and randomly assigned to study and control groups in this clinical trial. The subjects in the study group received infusion pump feeding while the control group received bolus feeding for 72 h. Blood sugar was checked for every 4 h for 72 h and the prealbumin level was assessed on the first and the fourth day in two groups. RESULTS: In the study group, the mean blood sugar significantly decreased on the fourth day, compared with the first (P = 0.03, F = 3.85) and third (P = 0.01, F = 3.15) day. In the control group, the mean blood sugar increased from the first day. It was significantly higher in the control group on the second day (P = 0.02, F = 3.55), compared with the study group. In the study group, there was a significant difference in the mean prealbumin before and after intervention (P = 0.048, t = 1.97), but no significant difference was observed in the control group. There was a significant difference between two groups after intervention (P = 0.04, t = 2.05). CONCLUSION: The obtained results showed that supportive nutrition through a continuous method had an effect on critical patients' blood sugar control and made a better nutritional status for these patients through an increase of prealbumin level. Positive effects of this feeding method can result in appropriate outcomes for patients' recovery and reduce the complications. PMID- 27462638 TI - Examining social-cognitive predictors of parenting skills among mothers with preschool and early elementary school-aged children. AB - CONTEXT: Identification of parenting skills determinants among mothers is an ongoing field of research. AIMS: The aim of this study was to identify the social cognitive predictors of parenting skills among mothers. SETTINGS AND DESIGN: Previous studies have demonstrated the health action process approach (HAPA) as a credible frame for predicting behavior, but the number of studies considering the predictive value of parenting skills determinants among mothers is rare. SUBJECTS AND METHODS: An 8 months prospective design was applied. Participants were mothers with preschool and early elementary school-aged children. At the 1(st) time, 120 participants completed self-report questionnaires regarding their risk perception, outcome expectancies, task self-efficacy, and intentions toward parenting skills. At the 2(nd) time, they returned a follow-up questionnaire, which measured planning, coping self-efficacy, and recovery self-efficacy and finally, 8 months later as the 3(rd) time, parenting skills were measured. Path analysis was used for analysis. RESULTS: Path analysis indicated that, in the motivational phase, there was no relationship between parenting skills intention and risk perception, outcome expectancies, and task self-efficacy. Furthermore, no relationship was found between parenting skills intention and planning. In the volitional phase, coping self-efficacy, recovery self-efficacy, and planning were statistically significant predictors of parenting skills. CONCLUSION: The results of this study confirm that volitional phase of the HAPA model is useful in determining parenting skills. However, the role motivational variables seem to be unimportant in performing these behaviors. It was concluded that everybody intended to apply parenting skills, in nature, and intervention strategies should be focused on turning intentions into behavior. PMID- 27462640 TI - A survey of the relationship between work schedule and its effect on the fatigue of rescue personnel in Isfahan with a standard method of CIS202. AB - CONTEXT: Fatigue is a factor that can have negative effects on family life, social relationship and work. Work schedule is one of the affective factors on personnel's fatigue in different jobs. In this study, the work schedule and its effect on rescue personnel in Isfahan are explored. AIMS: The purpose of this study was to investigate the relationship between work schedules and fatigue among rescue personnel. SETTINGS AND DESIGN: This study is periodical and has been conducted on 72 employees of rescue personnel in Isfahan. MATERIALS AND METHODS: Random sampling was done and the primary data that was collected through fatigue assessment questionnaire after being conducted as a pilot study on 10% of samples were collected to confirm the validity of this study. Finally, the data was given to SPSS11.5 software and were analyzed by descriptive statistics and linear digression. RESULTS: The results showed that from the statistical point of view some parts of work schedules like work hours satisfaction, resting time and work order on total fatigue are effective in linear and inverse way but the item "predictibility of work conditions" does not have a meaningful relationship with total fatigue. Furthermore, the results showed that there is a meaningful and inverse relationship with work hours, resting time and work order with mental fatigue and also the work schedule has a meaningful, linear and inverse relation with mental fatigue and total fatigue. CONCLUSIONS: By increasing the satisfaction of working hours, increasing resting time and also with an increase of work order the total fatigue of rescue personnel will decrease. PMID- 27462639 TI - Recognition of the efficacy of relaxation program on sleep quality of mothers with premature infants. AB - BACKGROUND AND AIM: The postpartum period is a critical then effects on the structure of the family. Most women in the postpartum period may place at risk of undesirable experiences such as changes in sleep patterns. Therefore, this study aimed to identify the efficacy of the relaxation program on sleep quality of mothers with premature infants. MATERIALS AND METHODS: This study is a clinical trial that 60 mothers with premature infants. The mothers in the intervention group were trained for muscle progressive relaxation by Jacobson method within 24 72 h after delivery. Research tool was the Pittsburgh Sleep Quality Index, which was completed by the mother at the beginning of the study, end of the first and the second 4-week. Data were analyzed using parametric statistics tests by SPSS software version 16. RESULTS: No significant difference was observed between two groups in terms of underlying characteristics (P < 0.05). The independent t-test at the beginning of the study showed that the comparison of the mean scores of mothers' sleep quality has no significant difference between two groups (P = 0.43). But, 1-month after the intervention (P = 0.024) and 2 months after the intervention (P > 0.001), mean sleep quality score in the intervention group was significantly less than the control group. CONCLUSION: Relaxation training can improve mothers' sleep quality at postpartum period. PMID- 27462641 TI - The role of religious beliefs in pregnancy loss. AB - INTRODUCTION: Birth can cause and post-traumatic stresses in many women even when the occasion of birth results in alive baby. Fetal death can challenge her understanding of justice and God's love toward his creatures. Religious beliefs have a considerable effect on decreasing individuals' tendency toward bereavement; thus, it is expected to have a relationship with sorrow and mental distress ensuing fetal death. The present research has been conducted to review the existing literature on religion and fetal death and then study Iranian women and their families' response to such a tragedy. MATERIALS AND METHODS: This is a unsystematic (narrative) review. Research was conducted to study the role of mothers' religious belief in their encounter with pregnancy loss in cases belonging to a 23-year period from 1990 to 2013. PubMed and Ovid databases and Iranian religious resources such as Tebyan were utilized for these studies. Of course, several articles were also derived by means of manual search. RESULTS: Nine out of 31 papers had the searched keywords in common in the preliminary search. A review of the existing papers indicated that only 4 out of 22 papers dealt exactly with the role of religion on reaction of parents to fetal death. The four papers belonged to the years 2008, 2010, 2011, and 2012 indicating the new approach to religion in pregnancy loss cases. CONCLUSION: Religion has a significant effect on parents' acceptance of such mishaps and it may have a considerable effect on their recovery from such tragic events. PMID- 27462642 TI - The study of physical activity and some relative factors in referred pregnant women to Isfahan Health-Care Centers and Shahid Beheshti Hospital. AB - BACKGROUND: Physical activity generally declines during pregnancy, but activity barriers during this period are not well understood. The objective was to determine physical activity and some relative factors in referred pregnant women. MATERIALS AND METHODS: This cross-sectional study was carried on 384 in referred pregnant women to Isfahan Health Care Centers and Shahid Beheshti Hospital in second stage sampling method in 2013. Demographic/prenatal characteristics, physical activity (36Q) and prenatal life quality questionnaire (26Q) were completed by participants. The statistical analysis was performed with various statistical tests such as the t-test, one-way ANOVA, individual correlation coefficient, and linear regression using SPSS statistical software (version 16). RESULTS: Based on the findings, 98.7% (n = 378) of pregnant women had low physical activity. Also, there were a correlation among physical activity and parity, age, gestational age (P <= 0.005). CONCLUSION: Since physical activity is recommended for the most of pregnant women, it is imperative to promote physical activity between pregnant women and some intervention suggestions. PMID- 27462643 TI - Assessment of dental student satisfaction with regard to process of thesis educational courses. AB - INTRODUCTION: Ensuring achievement of research experience by students is one of the most important goals of the thesis-conduction process and evaluation of student satisfaction with this process is one of the most imperative challenges herein. AIMS: The aim of this study is to investigate the satisfaction of dental students passing the thesis educational course from the Isfahan Dental School. SETTINGS AND DESIGN: Sixty-two dental students who had graduated in2011, from the Isfahan Dental School, participated in this descriptive cross-sectional study. MATERIALS AND METHODS: The postgraduate Research Experience Questionnaire (PREQ) was used for data collection. The questionnaire evaluated student satisfaction in seven domains: Thesis supervision, skill development, intellectual climate, infrastructure, thesis examination, goals and expectations, and overall satisfaction. STATISTICAL ANALYSIS USED: The data were analyzed on an SPSS software using descriptive and inferential statistics. RESULTS: The mean score of satisfaction of the participants was 75 +/- 12. On the basis of their scores, satisfaction in 3.2% of them was slow, in 33.9%was medium, in 61.3% was good and in 1.6% was high. The highest satisfaction was found to be in thesis supervision and the least was in the intellectual climate domain. There was no significant statistical difference between satisfaction and gender (P = 0.46). CONCLUSIONS: Considering the results, to increase student satisfaction for passing the thesis courses, it is necessary to improve the intellectual climate in dental schools and also increase the research budget for more financial support of students to carry out their projects. PMID- 27462644 TI - A survey on cancer-related nutritional information in Iranian popular magazines. AB - BACKGROUND: Due to the wide influence of public media, they become important communication channels for changing health beliefs and behaviors. One of the areas that have gained increased attention in public media is nutritional information. Cancer is one among the diseases related to nutrition. The goal of this study is to do a content analysis of the popular magazines in Iran for nutritional information related to cancer in year 2012-2013. MATERIALS AND METHODS: This is an applied survey performed using content analysis method. The data gathering tool is a checklist designed by the researcher. The statistical population consisted of all of the messages printed in 173 volumes of eight most popular magazines which were selected based on their characteristics by searching the Iranian publication database using certain inclusion and exclusion criteria. The sample size calculated using non-probability - purposive sampling was 295 messages from 96 magazine volumes. RESULTS: Findings showed that prevention trends had the highest (86.8%) and treatment had the lowest (4.7%) frequency in the messages. Pomegranate was the most commonly mentioned preventive food, while mayonnaises were the most commonly mentioned carcinogen and tangerine was the most commonly mentioned food used for cancer treatment. Among the different types of cancer, more than half of the messages (51.2%) mentioned "cancer" as a general term. After that, breast cancer (13.2%) and prostate cancer (10.51%) were the most commonly motioned cancers and messages regarding pancreatic cancer and hormone-related cancers were the least frequent (0.3%). CONCLUSIONS: The findings of this study show that the main goal of these messages was to increase the information provided to the readers, although some doubts regarding the scientific credibility of the claims made in these messages still remain. PMID- 27462645 TI - Determinants of healthy lifestyle and its related factors among elderly people. AB - BACKGROUND: Medical and health advances have led to relative increases in human longevity and elderly population. Common diseases in elders can be prevented using healthy lifestyle. Identifying current status of the elderly is necessary to design educational intervention programs to improve their health and quality of life. Therefore, this study aimed at assessing the lifestyle of the elderly in Islamshar (suburban of Tehran). MATERIALS AND METHODS: A descriptive - analytical study conducted among 480 elderly people over 60 years old referred to Islamshahr Health Center of Tehran University of Medical Sciences for a period of 12 months in 2012-2013. Data were collected through at two-part questionnaire including sociodemographic and health-related characteristics and healthy lifestyle instrument. Healthy lifestyle of the elderly was assessed using a 46 items self report standard instrument with five subscales reflecting domains including exercise, nutrition, prevention, stress management, and social relationship. Finally, the data obtained were analyzed using the SPSS 18 software using an independent t-test, analysis of variance and ordinal logistic regression test at a significant level of P < 0.05. RESULTS: Mean score of total healthy lifestyle was 148.56 +/- 11.5. Men and women scored 151.95 +/- 11.15 and 145 +/- 10.32, respectively (P < 0.001). 76.2% of participants had moderately healthy lifestyle, and 23.8% had desirable healthy lifestyle. Marital status and gender were important factors in elderly healthy lifestyle. DISCUSSION: The status of a healthy lifestyle among the elderly in Islamshar was relatively moderate. However, more studies are needed for further information to confirm study results. Study results were posed the necessity of tailoring specific interventional programs to achieve desirable healthy lifestyle. PMID- 27462646 TI - A consumer informed workshop can improve knowledge and attitude to patient centered care among hospital clinicians-in-training. AB - PURPOSE: Patient and family involvement in the education and training of medical practitioners increases the likelihood that the care delivered will meet the needs of service users and carers. The purpose of this study was to determine the effect of a consumer informed educational program on knowledge and attitude to patient-centered care among hospital clinical trainees. METHODS: A total of 66 junior medical staff and 35 orthoptists in training were invited to participate in a controlled before-and-after trial at the Royal Victorian Eye and Ear Hospital from October to November, 2011. Thirty-eight participants were allocated to the intervention program (interactive workshop) and 63 to the control program (assigned reading). Questionnaires regarding knowledge, attitude, and practice, patient-practitioner orientation and communication were administered. Differences between groups and differences before and after the program were evaluated using the t-test or Chi-square test, as appropriate. Narrative data obtained from the questionnaires were analyzed using Grounded Theory qualitative analysis techniques. RESULTS: A total of 24 participants (63%) completed the intervention program and eight (13%) the control program. The intervention group felt more prepared to introduce themselves and their role (Chi-square = 11.19, P = 0.01) and to acknowledge patients' waiting time prior to consultation (Chi-square 8.52, P = 0.04) compared with the control group. For the intervention group, there was an improvement in mean score on the Communication Assessment Tool (mean change = 0.55, P = 0.01). CONCLUSION: There were minor improvements in self-perceived knowledge and attitude to patient-centered care and communication among hospital clinicians-in-training following a consumer informed education program. The majority of participants who received this program agreed it would influence how they conducted future consultations. Further work is required to determine if these improvements translate to sustainable changes in clinical practice and patient satisfaction. PMID- 27462647 TI - The impacts of a health belief model-based educational program on adopting self care behaviors in pemphigus vulgaris patients. AB - INTRODUCTION: Since pemphigus vulgaris (PV) is a chronic disease and regarding its autoimmune nature, patients need to adopt self-care behaviors. This study aimed to assess the impacts of an educational program based on health belief model (HBM) on adopting self-care behaviors among patients with PV referred to Razi Hospital. MATERIALS AND METHODS: Eighty-eight patients with PV were randomized in an educational intervention study in two groups in 2013-2014. The intervention group attended a 6 months self-care educational program in a specialized outpatient clinic, in addition to the regular care presented for both groups. To collect information about demographic characteristics, PV-related variables, and HBM constructs items, a self-designed questionnaire was used. Data were analyzed by SPSS 20. A P < 0.05 was considered as statistically significant. RESULTS: Increase in perceived susceptibility, severity, and benefits score were significantly higher in intervention group compared with controls when adjusting for the difference in baseline scores of these HBM constructs and house ownership and employment status distribution in two groups using ANCOVA (P < 0.001). Furthermore, after intervention, the decrease in perceived barriers' scores was significantly more than controls (P < 0.001), However, the decrease in cues to action score was not found significant (P = 0.380). DISCUSSION: The results of this study show the effects of an HBM-based educational program as a tertiary preventive measure on adopting self-care behaviors in patients that can help them achieve self-efficacy in controlling their disease and enhancing their treatment process. PMID- 27462648 TI - The effect of continuing care on patient's quality-of-life after disc surgery in neurosurgery and very important person wards. AB - BACKGROUND: Today, lumbar herniation discs, a prevalent problem with a sign of lumbar and feet pain in society. Removal of disk by surgery decrease pain but reduce quality-of-life (QOL). In some cases, lake of following and caring of patient after surgery, herniation disc recurrent. Previous studies show that patient education and followings is important, therefore, this study aimed to investigate the effect of continuing care on patient QOL after disc surgery in neurosurgery and very important person (VIP) ward in Al-Zahra Hospital. MATERIALS AND METHODS: This study is a clinical trial conducted on 64 patients hospitalized in the neurosurgery and VIP wards of Al-Zahra Hospital, in Isfahan, Iran, in 2013. The patients were selected by simple sampling method and were randomly assigned to two groups (study and control). Patients' response to short form-36 questionnaire before and 4 weeks and 3 months after continuing care in study group, and simultaneously, in the control group. RESULTS: Repeated measures ANOVA showed a significant difference in mean of physical and psychological dimensions before and 4 weeks and 3 months after intervention in study group (P < 0.05), but in control group, the difference was not significant (P = 0.8). Pairwise comparison of mean physical and psychological dimensions at different time points by Fisher's least significant difference showed that there was a significant difference in the intervention group (P < 0.022). But in the control group, there was no significant difference between pairs of time points (P > 0.18). CONCLUSION: Continuing care improves dimensions of patients' QOL, and it is recommended as a nursing and nonmedical intervention in disc surgery patients. PMID- 27462649 TI - Potent spinal parenchymal AAV9-mediated gene delivery by subpial injection in adult rats and pigs. AB - Effective in vivo use of adeno-associated virus (AAV)-based vectors to achieve gene-specific silencing or upregulation in the central nervous system has been limited by the inability to provide more than limited deep parenchymal expression in adult animals using delivery routes with the most clinical relevance (intravenous or intrathecal). Here, we demonstrate that the spinal pia membrane represents the primary barrier limiting effective AAV9 penetration into the spinal parenchyma after intrathecal AAV9 delivery. We develop a novel subpial AAV9 delivery technique and AAV9-dextran formulation. We use these in adult rats and pigs to show (i) potent spinal parenchymal transgene expression in white and gray matter including neurons, glial and endothelial cells after single bolus subpial AAV9 delivery; (ii) delivery to almost all apparent descending motor axons throughout the length of the spinal cord after cervical or thoracic subpial AAV9 injection; (iii) potent retrograde transgene expression in brain motor centers (motor cortex and brain stem); and (iv) the relative safety of this approach by defining normal neurological function for up to 6 months after AAV9 delivery. Thus, subpial delivery of AAV9 enables gene-based therapies with a wide range of potential experimental and clinical utilizations in adult animals and human patients. PMID- 27462650 TI - Extracting conformational structure information of benzene molecules via laser induced electron diffraction. AB - We have measured the angular distributions of high energy photoelectrons of benzene molecules generated by intense infrared femtosecond laser pulses. These electrons arise from the elastic collisions between the benzene ions with the previously tunnel-ionized electrons that have been driven back by the laser field. Theory shows that laser-free elastic differential cross sections (DCSs) can be extracted from these photoelectrons, and the DCS can be used to retrieve the bond lengths of gas-phase molecules similar to the conventional electron diffraction method. From our experimental results, we have obtained the C-C and C H bond lengths of benzene with a spatial resolution of about 10 pm. Our results demonstrate that laser induced electron diffraction (LIED) experiments can be carried out with the present-day ultrafast intense lasers already. Looking ahead, with aligned or oriented molecules, more complete spatial information of the molecule can be obtained from LIED, and applying LIED to probe photo-excited molecules, a "molecular movie" of the dynamic system may be created with sub Angstrom spatial and few-ten femtosecond temporal resolutions. PMID- 27462651 TI - Program Director as Webmaster? Analysis of 131 Anesthesiology Department Web Sites and Program Director Web Site Involvement and Opinion Survey. AB - BACKGROUND: The last formal review of academic anesthesiology department Web sites (ADWs) for content was conducted in 2009. ADWs have been rated as very important by medical students in researching residency training programs; however, the rapid evolution of sites require that descriptive statistics must be more current to be considered reliable. We set out to provide an updated overview of ADW content and to better understand residency program directors' (PD) role and comfort with ADWs. METHODS: Two independent reviewers (ND and HL) analyzed all 131 Accreditation Council for Graduate Medical Education (ACGME) accredited ADWs. A binary system (Yes/No) was used to determine which features were present. Reviewer reliability was confirmed with inter-rater reliability and percentage agreement calculation. Additionally, a blinded electronic survey (Survey Monkey, Portland, OR) was sent to anesthesiology residency PDs via electronic mail investigating the audiences for ADWs, the frequency of updates and the degree of PD involvement. RESULTS: 13% of anesthesiology departments still lack a Web site with a homepage with links to the residency program and educational offerings (18% in 2009). Only half (55%) of Web sites contain information for medical students, including clerkship information. Furthermore, programs rarely contain up-to-date calendars (13%), accreditation cycle lengths (11%), accreditation dates (7%) or board pass rates (6%). The PD survey, completed by 42 of 131 PDs, noted a correlation (r = 0.36) between the number of years as PD and the frequency of Web site updates - less experienced PDs appear to update their sites more frequently (p = 0.03). Although 86% of PDs regarded a Web site as "very" important in recruitment, only 9% felt "very" comfortable with the skills required to advertise and market a Web site. CONCLUSIONS: Despite the overall increase in ADW content since 2009, privacy concerns, limited resources and time constraints may prevent PDs from providing the most up-to-date Web sites for applicants and other interested audiences. PDs are aware of value of Web sites for recruitment, are typically involved in determining ADW content, but few feel very comfortable marketing a training program on the Web. PMID- 27462652 TI - Erratum to: The use of growth standards and corrective formulae to calculate the height loss caused by idiopathic scoliosis. AB - [This corrects the article DOI: 10.1186/s13013-016-0068-9.]. PMID- 27462653 TI - Defining the Psychiatric Nursing Role in the Medical Home. PMID- 27462654 TI - Building the 'continuous learning' healthcare system. AB - Hospitals are data-rich but information-poor. To develop a 'continuous-learning health care system' we need to harness our myriad information sources so that every patient encounter becomes the basis for new evidence of what works. PMID- 27462655 TI - What is the impact of electronic health records on the quality of health data? PMID- 27462656 TI - [Why delay pregnancy?]. PMID- 27462657 TI - [App and web are unreliable]. PMID- 27462658 TI - [Does only nonfat milk cause acne?]. PMID- 27462659 TI - [Gallbladder cancer caused by soft drinks?]. PMID- 27462660 TI - [Time profile controls are not a reason for panic]. PMID- 27462661 TI - [AU partial form can go directly into the shredder]. PMID- 27462662 TI - [FeNO measurement for asthma therapy is probably unnecessary]. PMID- 27462663 TI - [RAPID study: the first time the value of substitution therapy is verified]. PMID- 27462664 TI - [Tiotropium - a possible new therapy option]. PMID- 27462665 TI - [Extended protection with Efmoroctocog alfa]. PMID- 27462666 TI - [First PCSK9 inhibitor]. PMID- 27462667 TI - [Rivaroxaban approved in general practice]. PMID- 27462668 TI - SnapshotDx Quiz: April 2016. PMID- 27462669 TI - Cells to Surgery Quiz: April 2016. PMID- 27462670 TI - Eliminating Pediatric HIV-1 Infection. PMID- 27462672 TI - CardioPulse: The future of percutaneous coronary interventions. PMID- 27462671 TI - Plasma cell myeloma with lymphoplasmacytic morphology and cyclin D1 expression. PMID- 27462673 TI - CardioPulse: Triple therapy for percutaneous coronary intervention in atrial fibrillation: a nightmare. PMID- 27462674 TI - CardioPulse: Different bleeding scores and which one should we use? PMID- 27462675 TI - CardioPulse:Thrombus aspiration does not improve 12-month outcomes. PMID- 27462676 TI - CardioPulse: Elevating endovascular aneurysm repair to new heights. PMID- 27462677 TI - CardioPulse:Leipzig Heart Centre - Department of Electrophysiology. PMID- 27462678 TI - CardioPulse: New perspectives for stroke prevention in atrial fibrillation. PMID- 27462679 TI - CardioPulse: Syncope and near drowning may signal sudden death risk. PMID- 27462680 TI - CardioPulse: Ear stimulation for atrial fibrillation favoured at ESC Congress London. PMID- 27462681 TI - CardioPulse: European legislation for trans fats in food. PMID- 27462682 TI - CardioPulse: Are all trans fatty acids in food bad? PMID- 27462683 TI - CardioPulse: New cardiovascular disease death rates show stark inequalities between European countries. PMID- 27462684 TI - CardioPulse: The economics of chronic diseases. PMID- 27462685 TI - CardioPulse: Coronary artery disease from prevention to intervention. PMID- 27462686 TI - [Not Available]. PMID- 27462687 TI - The Perils of Pills. PMID- 27462688 TI - Emergency Physicians Seek Their Place in a Pay-for-Value World. PMID- 27462689 TI - Problem-Based Learning comes highly recommended. PMID- 27462690 TI - Helicobacter pylori: a pathogenic threat to the gastric mucosal barrier. AB - Peptic ulcer disease is a multi-factorial disorder of the gastrointestinal tract with a global prevalence affecting about 4.6 million people annually and having a mortality of one death per 10,000 cases. Helicobacter pylori (H. pylori) plays a profound role in the pathogenesis of chronic gastritis, peptic ulcer, including gastric mucosa-associated lymphoid tissue and carcinoma. Any compromise to the gastric mucosal barrier will greatly affect the integrity of the stomach. H. pylori is an organism which mediates a compromise of the gastric mucosal barrier by stimulating increased gastric acid secretion, causing alteration of certain immune factors, penetration of the mucosal layer and provoking persistent inflammation even without invading the mucus membrane. All the different lines of therapy have not shown maximal efficacy in the eradication/cure of the infection in patients. Consequently, alternative therapies including phytomedicines and probiotics have been introduced both in the quest for better eradication therapies and in addressing the problem of H. pylori relapse. In the light of the increasing antibiotic resistance associated with current therapies, the use of herbal preparations or its concomitant use with current therapy has the potential to contribute additive and synergistic effect in the eradication of the H. pylori infection. This review highlights the anti-H. pylori herbal preparations tested and in current use. PMID- 27462691 TI - HIV/AIDS pandemic and current practice among Paediatric Surgeons in Nigeria. AB - BACKGROUND: HIV exposed children could require surgical procedures when ill. This study assessed how paediatric HIV/AIDS affected surgical practice among Nigerian paediatric surgeons. METHODS: Descriptive cross-sectional study among consenting paediatric surgeons completing a self-administered questionnaire on the current practices and perception on HIV/AIDS in relation to their surgical practice. Data were analyzed using descriptive and inferential statistics. RESULTS: Thirty eight out of forty two copies of questionnaire distributed were completed and included in analysis giving a response rate of 92.5%. Most of the respondents (73.7%) were Consultants and had practised more than 10 years. Mean (SD) age was 42.4 (7.5) years ranging from 31 to 63 years. Nearly all the 35 (92.1%) respondents were males while 3 (7.9%) were females. All of them had operated on known HIV positive children. Over half (57.9%) were in support of pre-operative HIV screening with most (76.3%) worried about getting infected during surgery. Most paediatric surgeons knew their HIV status (81.6%) and would undergo HIV screening preoperatively (84.2%) when requested by their patients or their caregivers. Only 5 (22.7%) out of 22 surgeons were screened previously because of needle stick or sharp instrument injury during surgical procedure. Only 6 (15.8%) surgeons rated their cross infection control practices as excellent. CONCLUSION: Increasing number of HIV positive children are presenting to pediatric surgeons for surgical treatment in Nigeria in which at present surgical practices are inadequate in terms of cross infection control practices. There is need to optimize cross infection control practices through adequate provision of safe surgical devices. PMID- 27462692 TI - Knowledge of hazards of antibiotics self-medication by mothers for under-fives in rural community of South-west Nigeria. AB - BACKGROUND: In Nigeria, self-medication of young children is common. Children under the age of five are often self-medicated with antibiotics because of their increased susceptibility to infections. OBJECTIVES: To assess mothers' knowledge on the hazards of antibiotics self-medication in a rural community of South-west Nigeria. METHODOLOGY: A community-based, cross-sectional study was conducted among 513 mothers selected through a purposive sampling technique from Koko community in Olodo, Ibadan between October and December, 2014. Data were collected using a semistructured interviewer administered questionnaire and analyzed with SPSS version 20. Descriptive statistics, Chi-square test and logistic regression were done at 5% level of significance. RESULTS: A very high proportion (96.5%) of mothers in this study practiced antibiotic self-medication for their children. Only 28.1% were knowledgeable about the risks and side effects of antibiotic self-medication. Chi-square test revealed that there was a significant association between respondents' educational status (P < 0.05) and knowledge of the hazards. Mothers with no formal education were less likely to be knowledgeable compared to those who had tertiary education (OR = 0.08; 95% CI = 0.02- 0.57). CONCLUSION: High proportions of mothers lack adequate knowledge on the hazards of antibiotics self-medication. Mothers, particularly those with lower educational levels and young age need to be educated on the risks and side effects of this practice. PMID- 27462693 TI - Potentials of raw and cooked walnuts (Tetracapidium conophorum) as sources of valuable nutrients for good health. AB - BACKGROUND: The present study estimated nutrient composition of walnuts before and after cooking with respect to its potential as valuable source of nutrients for daily intake. METHOD: Walnut fruits were purchased from five different markets in Ijebu-Ode local government area and its environs. The fruits samples were divided into two portions, labelled R (for raw) and C (cooked). The C samples were cooked at 100 degrees C for 1 hr and allowed to cool to room temperature. The seeds of both C and R samples were ground and analyzed for proximate, macro and micro minerals using methods of Association of Official Chemists. RESULTS: The results obtained showed that both raw and cooked walnuts are rich in fat, iron (Fe), manganese (Mn), and copper (Cu) in amounts that are within daily recommended intake per 100 g of walnut seeds. They also contained appreciable levels of protein, phosphorus (P), calcium (Ca), and magnesium (Mg) but with low content of moisture (MC), carbohydrate, fiber, sodium (Na) and potassium (K). Boiling significantly affected the levels of protein, carbohydrate, ash, moisture content, fat, nitrogen, calcium, sodium, copper, zinc, phosphorus, potassium, manganese and iron CONCLUSION: The study reveals that walnut is nutritious due to its appreciable level of protein and presence of various essential and macro minerals. Its low content of sodium and potassium is beneficiary in hypertensive condition as snack. The study suggests future bio fortification of walnut with zinc, which may bring about a co-increase in Ca and protein content. PMID- 27462694 TI - Sexual behaviour and use of electronic media among undergraduates in the University of Ibadan. AB - BACKGROUND: Sexual behaviour among the youth contributes largely to the burden of reproductive health problems in Nigeria. This may have been worsened by the introduction of electronic media like internet and television (TV). However, little is known about the effects of electronic media on sexual behaviour of youth in Nigeria. Therefore, exploring the influence of effect of electronic media on sexual behaviour of youth may help policy maker to provide interventions to these problems. Thus, this study was aimed at assessing the effect of electronic media on sexual behaviour of Undergraduates in the University of Ibadan. METHOD: This was an analytical cross-sectional study, using a multistage sampling method and data were collected through self-administered semi-structured questionnaire. Variables measured are socio-demographic characteristics, exposure to electronic media and sexual practices of youths. Frequency tables were generated, and data analyzed by logistic regression. RESULTS: Four hundred and thirty three questionnaires were returned out of 456 distributed, giving a response rate of 95%. Mean age of respondents was 18.75 (SD = 2.5) years. About 58.4% of males use the internet and 58.6% watch TV while 41.6% of female use the Internet and 41.4% watch TV. Watching sexually explicit program on internet increases risk of having premarital sex (OR = 3.1; CI = 1.2-7.7) while watching non sexually explicit programmes on T.V protects from having premarital sex (OR = 0.4 CI = 0.2-0.8). CONCLUSION: These observed influence of exposure to sexually charged materials on the internet and electronic media indicates the need for efforts to be directed to controlling access, of youths to these sexually explicit programmes on the internet and television programmes. PMID- 27462695 TI - Pattern of biliary tract carcinoma at the University College Hospital, Ibadan. AB - BACKGROUND: Biliary tract carcinomas are uncommon but highly fatal malignancies. Most patients in our environment are diagnosed late and are not candidates for curative resection. OBJECTIVE: To determine the pattern and risk factors of biliary tract carcinoma in Ibadan. METHODOLOGY: This was a retrospective study of histologically confirmed cases of biliary tract carcinoma diagnosed at the University College Hospital, Ibadan between January 1971 and December 20 10. Data was obtained from the records of the Ibadan Cancer Registry, surgical day books and post-mortem records of the Department of Pathology. Histological classification based on the 2010 'WHO classification for tumours of the intrahepatic bile duct, gallbladder and extrahepatic bile duct' was done. RESULTS: There were 37 cases of biliary tract carcinoma accounting for 0.18% of cancers seen during the period of study. These comprised of 26 (70.3%) females and 11 (29.7%) males. 20 females and 4 males had gallbladder carcinoma, while 6 females and 7 males had cholangiocarcinoma (P = 0.02). The age range was from 37 years to 75 years (mean = 52.5 +/- 9.7 years). The peak occurrences of gallbladder carcinoma and cholangiocarcinoma were in the fifth and sixth decades of life respectively. The identified risk factors included female gender (83%), gallstones (33%), and dysplasia (42%). CONCLUSION: The findings in this study agree with what has been described in the English literature in respect of gender distribution, histological types and some associated risk factors as well as in the fact of its being rare. PMID- 27462696 TI - Comparative evaluation of perceptions of dental students to three methods of teaching in Ile-Ife, Nigeria. AB - BACKGROUND: The World Health Organization in 1994 recommended that dental education should be problem based, socially and culturally relevant, and community oriented. OBJECTIVES: To explore the perceptions of Pre-phase II (pre clinical II) dental students on three methods of teaching used during two academic sessions. METHODS: All part IV dental students in two consecutive sessions undergoing pre phase II course in the Faculty of Dentistry, Obafemi Awolowo University, Ile-Ife were recruited into the study. Three different modes of teaching that is, Problem based learning (PBL), hybrid PBL and traditional teaching were used to teach the students. A twenty two itemed anonymous questionnaire on a five point Likert scale was administered to the students at the end of the course. Six perceived factors were extracted from the questionnaire using factor analysis. RESULTS: There was a statistically significant difference (p < 0.01) between the overall mean of PBL method compared to the other methods of teaching. The perceived factor "communication with peers" had the highest mean score for PBL in both sessions (4.57 +/- 0.58 and 4.09 +/- 0.93 respectively). However, PBL method was very helpful in all the six perceived factors while the students perceived that the traditional method of teaching was not helpful in "interaction with tutors" and "challenge to critical thinking". CONCLUSIONS: The findings showed that students preferred the PBL method to other forms of teaching. PBL enhanced the students' communication skill, was very useful as pedagogic tool and improved their critical thinking. PMID- 27462697 TI - Female circumcision in Nigeria and attitudes towards its discontinuation. AB - BACKGROUND: Female Circumcision (FC) is a harmful traditional practice and remains a public health problem particularly in the era of HIV/AIDS. Aside its numerous health implications, it can cause infertility, complications in childbirth and increased risk of newborn deaths. FC is widely practised in Nigeria. OBJECTIVE: The study assessed the level of FC, daughters' circumcision and attitude towards discontinuation of the practice among women of reproductive age. METHODS: Data were extracted from the 2008 Nigeria Demographic Health and Survey. Data were analysed using Chi-square and binary logistic regression models (a = 0.05). RESULTS: Among the respondents, prevalence of FC was 49.2% with 30.6% having circumcised their daughters and 25.8% wishing the practice to continue. About 56% of circumcised women also circumcised their daughters whereas only 2.9% of uncircumcised women circumcised their daughters. Approximately 69.8% of women who had circumcised their daughters would like FC to continue compared to 8.8% of those who never circumcised any of their daughters. The likelihood of FC was higher (OR = 2.07; C.I = 1.85-2.30) among Moslems compare to Christians. Igbo women were less likely to discontinue FC compared to women of Hausa/Fulani ethnic group despite controlling for the confounding variables (OR = 0.57; C.I = 0.35 0.91). CONCLUSION: Female circumcision is still practiced in all parts of Nigeria and a high proportion of women reported that the practice should continue. There is need to intensify efforts on the campaign against female circumcision in Nigeria. PMID- 27462698 TI - Effects of quail egg on kidney functions in alloxan induced diabetic Wistar rats. AB - Abstract INTRODUCTION: Uncontrolled diabetes mellitus has been reported to lead to renal dysfunction. Quail egg consumption has been reported to exert curative effects in some disease conditions like diabetes mellitus, tuberculosis, and asthma. This study investigated the effects of quail egg consumption on some kidney functions in alloxan induced diabetic rats. METHODS: Forty male Wistar rats with an average weight of 170g were randomly divided into four groups. Groups A-Control, B-Diabetic untreated, C-Diabetic treated and D-Normal treated. Groups B and C were made diabetic with a single dose of alloxan monohydrate (100 mg/kg i.p). Raw quail egg was administered orally (5 ml/kg) to groups C and D for 14 days. Body weight and blood glucose were monitored during the study. Blood and kidney samples were obtained from animals in each group, and analyzed for total protein, creatinine, blood urea nitrogen (BUN), renal malondialdehyde (MDA) and superoxide dismutase (SOD). Data were analyzed using ANOVA at P < 0.05. RESULTS: Diabetic group treated with quail egg showed significant (P < 0.05) increase in SOD, decrease in body weight, blood glucose, total protein, creatinine, BUN and MDA levels when compared to diabetic untreated group. However, values of these parameters obtained from diabetic group treated with quail were comparable to control. CONCLUSION: Quail egg consumption significantly reduced hyperglycemia, serum total protein, creatinine, BUN, MDA and increased SOD activities in alloxan induced diabetic Wistar rats which suggests that it lowers blood glucose and ameliorates renal impairment in diabetes mellitus. PMID- 27462699 TI - Neck trauma: a red-herring to diagnosis of chemodectoma. AB - Chemodectoma, a neuroendocrine tumour of the paraganglionic cells in the carotid body remains an uncommon tumour. We report the first case from University of Ilorin Teaching Hospital, Ilorin, Nigeria. Though with a red herring history of trauma induced swelling, clinical and radiologic features were characteristic of chemodectoma. Histologic features of the excised lesion are presented. PMID- 27462700 TI - A New Species of the Bay Goby Genus Eucyclogobius, Endemic to Southern California: Evolution, Conservation, and Decline. AB - A geographically isolated set of southern localities of the formerly monotypic goby genus Eucyclogobius is known to be reciprocally monophyletic and substantially divergent in mitochondrial sequence and nuclear microsatellite based phylogenies relative to populations to the north along the California coast. To clarify taxonomic and conservation status, we conducted a suite of analyses on a comprehensive set of morphological counts and measures from across the range of Eucyclogobius and describe the southern populations as a new species, the Southern Tidewater Goby, Eucyclogobius kristinae, now separate from the Northern Tidewater Goby Eucyclogobius newberryi (Girard 1856). In addition to molecular distinction, adults of E. kristinae are diagnosed by: 1) loss of the anterior supratemporal lateral-line canals resulting in higher neuromast counts, 2) lower pectoral and branched caudal ray counts, and 3) sets of measurements identified via discriminant analysis. These differences suggest ecological distinction of the two species. Previous studies estimated lineage separation at 2-4 million years ago, and mitochondrial sequence divergence exceeds that of other recognized fish species. Fish from Santa Monica Artesian Springs (Los Angeles County) northward belong to E. newberryi; those from Aliso Creek (Orange County) southward constitute E. kristinae. The lagoonal habitat of Eucyclogobius has been diminished or degraded, leading to special conservation status at state and federal levels beginning in 1980. Habitat of the newly described species has been impacted by a range of anthropogenic activities, including the conversion of closing lagoons to open tidal systems in the name of restoration. In the last 30 years, E. kristinae has only been observed in nine intermittently occupied lagoonal systems in northern San Diego County; it currently persists in only three sites. Thus, the new species is in imminent danger of extinction and will require ongoing active management. PMID- 27462701 TI - Randomized Trials in Developing Countries: Different Priorities and Study Design? AB - BACKGROUND: Clinical trials are increasingly conducted in the field of neurology in developing countries. To our knowledge, no review has been performed to date about the temporal evolution, geographical distribution, pathological fields, and types of trials conducted. Besides, the validity of those clinical trials needs to be evaluated. SUMMARY: Our main aim was to describe, using a systematic literature review, the clinical trials performed in the field of neurology in developing countries. The specific objectives were (1) to describe the pathologic fields, (2) to evaluate the methodology, and (3) to assess the validity of neurological clinical trials performed in developing countries. A systematic review of the literature was conducted accessing PubMed, Pascal, ScienceDirect, African Journal Online, and the Virtual Library of African Neurology. The 145 studies included allowed us to identify (1) an exponential evolution of the number of clinical trials, (2) the strong contributions from Asia, followed by Africa and Latin America, (3) a fairly good coverage of pathologic fields including noncommunicable diseases, (4) an increasing diversity of intervention type, (5) the lack of early-phase trials (phases I and IIa), and (5) the need of improvement for some critical methodological issues. KEY MESSAGE: There is a need (1) to develop structures dedicated to the early investigation of interventions in humans, and (2) for sustaining the development of structures specialized in the methodology of clinical research and of dedicated courses for researchers in tropical areas about good practice in clinical trials. This would help in improving methodological quality, appropriateness of data management, and statistical analysis. PMID- 27462703 TI - Epidemiology of Non-Hodgkin's Lymphoma in India. AB - Non-Hodgkin's lymphoma (NHL) is a common hematological malignancy. The age adjusted incidence rates for NHL in men and women in India are 2.9/100,000 and 1.5/100,000, respectively. These are about one fourth of the incidence rates reported from Western Europe or North America. Within India, the incidence is several-fold higher in urban cancer registries compared to rural areas; the incidence being higher in metropolitan cities and Indian immigrants suggesting that urban lifestyles and economic progress may increase the cancer incidence. Compared to developed nations, the key differences in the presentation in India include: median age of 54 years (almost a decade less), higher male to female ratio, higher proportion of patients with B-symptoms (40-60 vs. 20-30%), poor ECOG performance status (>=2) at diagnosis (50 vs. 20-30%), higher frequency of diffuse large B-cell lymphomas (60-70 vs. <40%), lower frequency of follicular NHL (<20 vs. 30-40%) and T-cell type in 10-20 vs. <10%. The estimated mortality rate due to NHL is higher in India than in North America and Western Europe. Diagnostic and treatment delays, incorrect diagnosis and inappropriate or suboptimal treatment may be possible reasons for the poor outcome. Any improvement in the outcomes for NHL in India will require a nationwide approach, e.g. creation of several regional and district-level centers with expertise in lymphoma management. Collection of data on patient- and disease-related characteristics, treatment outcome, development of infrastructure, centralized review of histopathology subtype, novel treatment protocols, rigorous follow-up, training of staff, and financial support towards treatment could be possible strategies to improve the outcome. PMID- 27462704 TI - How to Distinguish between Statistically Significant Results and Clinically Relevant Results. AB - BACKGROUND: A practicing clinician will often be confronted with the results of a new clinical trial in their relevant field and will be faced with the dilemma of determining whether these results are clinically relevant to their own work. This chapter aims to describe the concepts of statistical significance in randomized clinical trials from a mainly classical statistical inference perspective. This chapter describes approaches to assess clinical significance and illustrates these approaches with examples from the contemporary neurological literature. RESULTS: There are several approaches that have been described in the research literature to assess the clinical significance including the minimal important clinical difference, the fragility index, Bayesian approaches, and a graphical approach. Unfortunately none of these methods have been widely used in the neurological research literature. Examples are provided to illustrate how these methods can be applied to the contemporary neurological literature in order to provide the clinician with some guidance on their use. CONCLUSIONS: How the trial is designed can affect the external validity of the results and subsequently the clinical relevance of a randomized clinical trial. Large-scale streamlined clinical trials with inclusion criteria that are not too restrictive can improve the generalizability of trial results. Even highly statistically significant treatment effects can be unreliable if they are based on a small number of events. The approaches described in this chapter should provide the practicing clinician with a starting point in order to determine whether the reported statistically significant results are indeed clinically relevant. PMID- 27462702 TI - Oncological Outcomes of Patients with Concomitant Bladder and Urethral Carcinoma. AB - INTRODUCTION: The study aimed to investigate oncological outcomes of patients with concomitant bladder cancer (BC) and urethral carcinoma. METHODS: This is a multicenter series of 110 patients (74 men, 36 women) diagnosed with urethral carcinoma at 10 referral centers between 1993 and 2012. Kaplan-Meier analysis was used to investigate the impact of BC on survival, and Cox regression multivariable analysis was performed to identify predictors of recurrence. RESULTS: Synchronous BC was diagnosed in 13 (12%) patients, and the median follow up was 21 months (interquartile range 4-48). Urethral cancers were of higher grade in patients with synchronous BC compared to patients with non-synchronous BC (p = 0.020). Patients with synchronous BC exhibited significantly inferior 3 year recurrence-free survival (RFS) compared to patients with non-synchronous BC (63.2 vs. 34.4%; p = 0.026). In multivariable analysis, inferior RFS was associated with clinically advanced nodal stage (p < 0.001), proximal tumor location (p < 0.001) and synchronous BC (p = 0.020). CONCLUSION: The synchronous presence of BC in patients diagnosed with urethral carcinoma has a significant adverse impact on RFS and should be an impetus for a multimodal approach. PMID- 27462705 TI - The Added-Value of Using Participatory Approaches to Assess the Acceptability of Surveillance Systems: The Case of Bovine Tuberculosis in Belgium. AB - CONTEXT AND OBJECTIVE: Bovine tuberculosis (bTB) surveillance in Belgium is essential to maintain the officially free status and to preserve animal and public health. An evaluation of the system is thus needed to ascertain the surveillance provides a precise description of the current situation in the country. The evaluation should assess stakeholders' perceptions and expectations about the system due to the fact that the acceptability has an influence on the levels of sensitivity and timeliness of the surveillance system. The objective of the study was to assess the acceptability of the bTB surveillance in Belgium, using participatory tools and the OASIS flash tool ('analysis tool for surveillance systems'). METHODS: For the participatory process, focus group discussions and individual interviews were implemented with representatives involved with the system, both from cattle and wildlife part of the surveillance. Three main tools were used: (i) relational diagrams associated with smileys, (ii) flow diagrams associated with proportional piling, and (iii) impact diagrams associated with proportional piling. A total of six criteria were assessed, among which five were scored on a scale from -1 to +1. For the OASIS flash tool, one full day meeting with representatives from stakeholders involved with the surveillance was organised. A total of 19 criteria linked to acceptability were scored on a scale from 0 to 3. RESULTS AND CONCLUSION: Both methods highlighted a medium acceptability of the bTB surveillance. The main elements having a negative influence were the consequences of official notification of a bTB suspect case in a farm, the low remuneration paid to private veterinarians for execution of intradermal tuberculin tests and the practical difficulties about the containment of the animals. Based on the two evaluation processes, relevant recommendations to improve the surveillance were made. Based on the comparison between the two evaluation processes, the added value of the participatory approach was highlighted. PMID- 27462706 TI - BiCAMWI: A Genetic-Based Biclustering Algorithm for Detecting Dynamic Protein Complexes. AB - Considering the roles of protein complexes in many biological processes in the cell, detection of protein complexes from available protein-protein interaction (PPI) networks is a key challenge in the post genome era. Despite high dynamicity of cellular systems and dynamic interaction between proteins in a cell, most computational methods have focused on static networks which cannot represent the inherent dynamicity of protein interactions. Recently, some researchers try to exploit the dynamicity of PPI networks by constructing a set of dynamic PPI subnetworks correspondent to each time-point (column) in a gene expression data. However, many genes can participate in multiple biological processes and cellular processes are not necessarily related to every sample, but they might be relevant only for a subset of samples. So, it is more interesting to explore each subnetwork based on a subset of genes and conditions (i.e., biclusters) in a gene expression data. Here, we present a new method, called BiCAMWI to employ dynamicity in detecting protein complexes. The preprocessing phase of the proposed method is based on a novel genetic algorithm that extracts some sets of genes that are co-regulated under some conditions from input gene expression data. Each extracted gene set is called bicluster. In the detection phase of the proposed method, then, based on the biclusters, some dynamic PPI subnetworks are extracted from input static PPI network. Protein complexes are identified by applying a detection method on each dynamic PPI subnetwork and aggregating the results. Experimental results confirm that BiCAMWI effectively models the dynamicity inherent in static PPI networks and achieves significantly better results than state-of-the-art methods. So, we suggest BiCAMWI as a more reliable method for protein complex detection. PMID- 27462708 TI - Catalytic Synthesis of Saturated Oxygen Heterocycles by Hydrofunctionalization of Unactivated Olefins: Unprotected and Protected Strategies. AB - A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unactivated olefins using a Co(salen) complex, an N fluoropyridinium salt, and a disiloxane reagent is described. This reaction was carried out at room temperature and afforded five- and six-membered oxygen heterocyclic compounds, such as cyclic ethers and lactones. The Co complex was optimized for previously rare medium ring formation by hydrofunctionalization of unactivated olefins. The powerful Co catalyst system also enables the deprotective hydroalkoxylation of O-protected alkenyl alcohol and hydroacyloxylation of alkenyl ester to afford cyclic ethers and lactones directly. The substrate scope and mechanistic proof of deprotection were investigated. The experimental evidence supports the concerted transition state of the bond-forming step involving a cationic Co complex. PMID- 27462707 TI - Chemogenetic E-MAP in Saccharomyces cerevisiae for Identification of Membrane Transporters Operating Lipid Flip Flop. AB - While most yeast enzymes for the biosynthesis of glycerophospholipids, sphingolipids and ergosterol are known, genes for several postulated transporters allowing the flopping of biosynthetic intermediates and newly made lipids from the cytosolic to the lumenal side of the membrane are still not identified. An E MAP measuring the growth of 142'108 double mutants generated by systematically crossing 543 hypomorphic or deletion alleles in genes encoding multispan membrane proteins, both on media with or without an inhibitor of fatty acid synthesis, was generated. Flc proteins, represented by 4 homologous genes encoding presumed FAD or calcium transporters of the ER, have a severe depression of sphingolipid biosynthesis and elevated detergent sensitivity of the ER. FLC1, FLC2 and FLC3 are redundant in granting a common function, which remains essential even when the severe cell wall defect of flc mutants is compensated by osmotic support. Biochemical characterization of some other genetic interactions shows that Cst26 is the enzyme mainly responsible for the introduction of saturated very long chain fatty acids into phosphatidylinositol and that the GPI lipid remodelase Cwh43, responsible for introducing ceramides into GPI anchors having a C26:0 fatty acid in sn-2 of the glycerol moiety can also use lyso-GPI protein anchors and various base resistant lipids as substrates. Furthermore, we observe that adjacent deletions in several chromosomal regions show strong negative genetic interactions with a single gene on another chromosome suggesting the presence of undeclared suppressor mutations in certain chromosomal regions that need to be identified in order to yield meaningful E-map data. PMID- 27462709 TI - The 3-D Structural Basis for the Pgi Genotypic Differences in the Performance of the Butterfly Melitaea cinxia at Different Temperatures. AB - Although genotype-by-environment interaction has long been used to unveil the genetic variation that affects Darwinian fitness, the mechanisms underlying the interaction usually remain unknown. Genetic variation at the dimeric glycolytic enzyme phosphoglucoisomerase (Pgi) has been observed to interact with temperature to explain the variation in the individual performance of the butterfly Melitaea cinxia. At relatively high temperature, individuals with Pgi-non-f genotypes generally surpass those with Pgi-f genotypes, while the opposite applies at relatively low temperature. In this study, we did protein structure predictions and BlastP homology searches with the aim to understand the structural basis for this temperature-dependent difference in the performance of M. cinxia. Our results show that, at amino acid (AA) site 372, one of the two sites that distinguish Pgi-f (the translated polypeptide of the Pgi-f allele) from Pgi-non-f (the translated polypeptide of the Pgi-non-f allele), the Pgi-non-f-related residue strengthens an electrostatic attraction between a pair of residues (Glu373-Lys472) that are from different monomers, compared to the Pgi-f-related residue. Further, BlastP searches of animal protein sequences reveal a dramatic excess of electrostatically attractive combinations of the residues at the Pgi AA sites equivalent to sites 373 and 472 in M. cinxia. This suggests that factors enhancing the inter-monomer interaction between these two sites, and therefore helping the tight association of two Pgi monomers, are favourable. Our homology modelling results also show that, at the second AA site that distinguishes Pgi-f from Pgi-non-f in M. cinxia, the Pgi-non-f-related residue is more entropy favourable (leading to higher structural stability) than the Pgi-f-related residue. To sum up, this study suggests a higher structural stability of the protein products of the Pgi-non-f genotypes than those of the Pgi-f genotypes, which may explain why individuals carrying Pgi-non-f genotypes outperform those carrying Pgi-f genotypes at stressful high temerature. PMID- 27462710 TI - Tocopherol Cyclases-Substrate Specificity and Phylogenetic Relations. AB - In the present studies, we focused on substrate specificity of tocopherol cyclase, the key enzyme in the biosynthesis of the tocopherols and plastochromanol-8, the main plant lipid antioxidants, with special emphasis on the preference for tocopherols and plastochromanol-8 precursors, taking advantage of the recombinant enzyme originating from Arabidopsis thaliana and isolated plastoglobules, thylakoids and various model systems like micelles and thylakoids. Plastoglobules and triacylglycerol micelles were the most efficient reaction environment for the cyclase. In various investigated systems, synthesis of gamma-tocopherol proceeded considerably faster than that of plastochromanol-8, probably mainly due to different localization of the corresponding substrates in the analyzed lipid structures. Moreover, our study was complemented by bioinformatics analysis of the phylogenetic relations of the cyclases and sequence motifs, crucial for the enzyme activity, were proposed. The analysis revealed also a group of tocopherol cyclase-like proteins in a number of heterotrophic bacterial species, with a conserved region common with photosynthetic organisms, that might be engaged in the catalytic activity of both groups of organisms. PMID- 27462712 TI - Alternatives in the Management of Gastric Lymphoma. AB - Advances in endoscopic technology now enable non-surgical diagnosis of gastric lymphoma, while combination chemotherapy and modern radiotherapy techniques offer an alternative to gastrectomy as the primary treatment of gastric lymphoma. Cumulative data challenge the traditional concept that non-operative treatment of gastric lymphoma often leads to fatal complications, such as perforation and hemorrhage. The reported risk of major side effects is reviewed and the alternative approaches to the management of gastric lymphoma are analyzed. In addition, pathologic considerations unique to lymphomatous involvement of the stomach are discussed. PMID- 27462711 TI - Safety profile of methotrexate in inflammatory bowel disease. AB - INTRODUCTION: Methotrexate, which was initially developed in 1948 for the treatment of leukemia, is known to be an immunomodulatory and anti-inflammatory drug. It has been widely used for over 60 years as both a low and high-dose therapy in chronic inflammatory diseases. The aim of this review was to analyze and summarize the available data specifically on the safety of this drug in the management of inflammatory bowel diseases. AREAS COVERED: A structured search of articles was conducted using the PubMed database up to April 2016. All articles in English with isolated or combined keywords were included according to their relevance to the aims of this study. EXPERT OPINION: Numerous of studies have established the efficacy of parenteral methotrexate in the management of steroid dependent and steroid-resistant Crohn's disease, either for inducing or maintaining remission. However, its efficacy in ulcerative colitis has not been properly investigated. Additionally, methotrexate has been shown to reduce the effect of immunization with anti-TNF agents when combined. The drug has potential advantages over thiopurines such as its weekly administration, a possible shorter time of action, low cost, decreased risk for malignancy and overall a comparable safety profile. PMID- 27462713 TI - Neutrophil Function in Hematological Neoplasia. AB - Though the main reason for infection in hematologic malignancies remains the reduction in the neutrophil count, there are certain conditions where agranulocytosis alone could not account for this tendency. In non lymphatic disorders, obvious modifications in mature neutrophil functions have been described. They predict susceptibility to infection and bad prognosis in myelodysplastic syndromes (MDS) and in acute non lymphatic leukemia (ANLL) where the mature looking neutrophils represent the leukemic clone and function aberrantly. The defects in neutrophil function encountered in myeloproliferative diseases including chronic myeloid leukemia, are mostly of scientific interest, and usually do not alter the clinical course of the disease in these patients. The alterations in neutrophil function in the lymphoproliferative disorders result mostly from humoral defects, mainly immunoglobulin deficiency and a variety of neutrophil inhibitory substances, and are not due to primary cellular defects. Neutrophil dysfunction may also result from a protracted infectious course and various treatment modalities, includng splenectomy and chemo radiotherapy. Neutrophil function studies in splenectomised patients and in selected cases with MDS and ANLL, and studies of serum immunoglobulins and neutrophil inhibitors in patients with lymphoid diseases, may be useful in screening those cases who are prone to infectious problems, and who might therefore benefit from increased infectious precautions. PMID- 27462714 TI - Rearrangement of T-cell Receptor (Delta, Gamma and Beta) Genes and its Significance in T-cell Chronic Leukaemias. AB - The configuration of the delta, gamma and beta TCR genes and IgH genes was studied using appropriate DNA probes in 12 patients previously diagnosed as having T-cell chronic leukaemia. One or more TCR genes showed rearrangement and/or deletion in 11 patients, whereas rearrangement of IgH genes were seen in 3 patients only. TCR genes showed four distinct patterns: (a) rearrangement and/or deletion of each of the three TCR genes (7 patients), (b) re-arrangement of two TCR genes (3 patients), (c) rearrangement/deletion of one TCR gene only (1 patient), (d) germ-line state of all TCR genes (1 patient). These patterns had no demonstrable relationship with the clinical status either at the time of diagnosis or during the subsequent course of the disease. The findings provided unequivocal evidence of T-cell lineage of the leukaemic cells in 10 out of 12 patients. In one patient the lineage of leukaemic cells remained indeterminate. In the last patient the germ-line state of all TCR genes and rearrangement of both IgH alleles genes indicated that the leukaemia was of B-cell origin, even though the leukaemic cells had other features regarded as characteristic of T lymphocytes. The different patterns of TCR genes, seen in the context of the hierarchical nature of the rearrangement process, suggest that the leukaemic transformation occurred at different stages of T-cell ontogeny and was followed by arrest of subsequent TCR gene rearrangement. PMID- 27462715 TI - T-Cell Membrane CD45RA (2H4) and CD45RO (UCHL1) Determinants: I, Diverse Patterns of Expression in Mature (Post-Thymic) T-Cell Proliferations. AB - By simultaneous two- and three-colour flow cytometry, this study analysed the expression of membrane CD45RA (2H4) and CD45RO (UCHL1) determinants by normal thymocytes (n = 5) and peripheral blood lymphocyte subpopulations (CD4(+), n = 21; CD8(+), n = 12; CD8(dim+), n = 12) and compared these patterns with those of T-cells from representative CD4(+)CD8(-) (n = 8), CD4(+)CD8(+) (n = 2), CD4( )CD8(+) (n = 10) and CD4(-)CD8(-) (n = 1) proliferations. These comprised cases of prolymphocytic leukaemia (T-PLL, n = 5), adult T-cell leukaemia-lymphoma (ATLL, n = 2), Sezary Syndrome (SS, n = 4), chronic lymphocytic leukaemia (T-CLL, n = 4), and lymphoproliferative disease of granular lymphocytes (LDGL, n = 5). Normal thymocyte fractions, of which a mean of 85% cells co-expressed membrane CD4 and CD8, were predominantly (mean 89%) 2H4(-)UCHL1(+) with the remaining cells consisting of 2H4(int)UCHL1(+) and 2H4(+)UCHL1(-) components. Further analysis showed that virtually all CDla(+) thymocytes were UCHL1(+) whereas the CD1a(-) fraction comprised similar proportions of both UCHL1(-) and UCHL1(+) subpopulations. Similarly, normal blood CD4(+), CD8(+) and CD8(dim+) lymphocytes showed reciprocal CD45RA/CD45RO expression and could be phenotypically grouped into 2H4(+)UCHL1(-) 2H4(int)UCHL1(+) and 2H4(-)UCHL1(+) subpopulations. Mean proportions of 48% and 68%, for CD4(+) and CD8(+) lymphocytes respectively, showed a composite 2H4(+)UCHL1(-) phenotype, whereas the percentage of NK associated CD8(dim+) cells with this phenotypic pattern was considerably higher (mean, 85%). Normal lymphocyte subpopulations lacking both determinants (2H4( )UCHL1(-)) were only rarely noted. Comparing normal patterns of CD45RA/CD45RO expression with those of the T-cell proliferations revealed diverse and abnormal patterns of staining for 3/6 of the CD4(+)CD8(-) SS and ATLL, and for 5/5 of the T-PLL (CD4(+)CD8(-), n = 2; CD4(+)CD8(+), n = 2; and CD4(-)CD8(+), n = 1) cases studied. In contrast, the nine cases of CD4(-)CD8(+) T-CLL and LDGL all showed CD45RA/CD45RO staining patterns similar to that of normal CD8(+)/CD8(dim+) blood lymphocytes (i.e. a predominance of 2H4(+)UCHL1(-) cells). Although the variant CD45RA/CD45RO pattern types of the CD4(+) proliferations did not appear to be related to either the diagnostic category or other phenotypic characteristics, the high proportion of abnormal patterns within this case group suggests that recognition of these abnormalities may be potentially relevant to the differentiation of benign and malignant CD4(+) proliferations and, in addition, may be of aetiological importance with respect to the diverse acquired defects in immunity commonly seen in patients with such disorders. PMID- 27462716 TI - T-Cell Membrane CD45RA (2H4) and CD45RO (UCHL1) Determinants: II, Aberrant HLA ABC Expression by CD45RA and CD45RO Cell Subpopulations of Mature CD4(+) T-Cell Leukaemias. AB - Six thymocyte suspensions, 10 normal blood CD4(+) CD8(-) lymphocyte-enriched fractions and leukaemic cells from 24 patients with CD4(+) mature T-cell lymphoid malignancy (five Sezary Syndrome, six adult T-cell leukaemia-lymphoma and 13 cases of T-cell prolymphocytic leukaemia) were examined in this study for the expression of membrane HLA-ABC by CD45RA (2H4) and CD45RO (UCHL1) subpopulations. These analyses showed that the main increase in HLA-ABC expression by normal CD4(+) CD8(-) blood lymphocytes (mean 490 to 760 FITC units) paralleled the loss of membrane 2H4 whilst the acquisition of UCHL1 was not associated with any significant change in HLA-ABC staining intensity. The sequence of 2H4 differentiation by normal thymocytes, based on the observed increasing levels of HLA-ABC staining intensity appeared to be (a) CD1a (+) 2H4(-) UCHL1(+) (25 HLA ABC fluorescent units), (b)CD1a(-)2H4(int)UCHL1(+) (134 units), and (c) CD 1a(-) 2H4 (+) UCHL1 (-) (197 units). Quantitative estimates of membrane HLA-ABC expression by leukaemic T-cells revealed marked heterogeneity between individual cases irrespective of diagnostic subgroup. Based on the lower observed limits for normal CD4(+) 2H4(+) (318 units) and CD4 (+) 2H4(-) (478 units) fractions, 14% and 38% respectively of the leukaemic 2H4(+) and 2H4(-) components examined showed reduced HLA-ABC expression. Two cases showed very low membrane HLA-ABC levels that were within the range observed for normal CD1a(-) thymocytes. In contrast, HLA-ABC staining intensities exceeding that of corresponding normal CD4(+) 2H4(+) (710 units) and CD4(+) 2H4(-) (1286 units) subpopulations were seen in a high proportion (65%) of leukaemic 2H4 (+) components, with only 14% of 2H4( ) fractions showing raised levels and, in two cases, these staining intensities exceeded three times the normal observed limits. In addition to the quantitative differences in HLA-ABC expression, a remarkably consistent (81% of evaluable cases) feature of the leukaemic T-cells was that the 2H4(-)UCHL1(+) subpopulation in CD4(+) malignancies had a lower HLA-ABC level than the 2H4(+)UCHL1 subpopulation. This was in marked contrast to normal post-thymic T-cells where increasing HLA-ABC expression was seen with increasing UCHL1 (or decreasing 2H4) staining. These results suggest that leukaemic T-cells have an aberrant intra thymic and post-thymic sequence of 2H4/UCHL1 expression which has become 'uncoupled' from CD1a/HLA-ABC expression. PMID- 27462717 TI - Cytogenetic Remissions in Chronic Myelogenous Leukemia Using Interferon Alpha-2a and Hydroxyurea with or without Low-Dose Cytosine Arabinoside. AB - Twenty-four patients with Philadelphia positive (Ph +) chronic myelogenous leukemia including 12 who were previously untreated, received recombinant interferon alpha-2a (IFN) (5 * 10(6) U/m(2)/d) and hydroxyurea (HU) (50 mg/kg/d) at the induction phase. Low dose cytosine arabinoside (Ara-C) (10-20 mg/m(2)/d, 10 to 15 d/month) was added during IFN maintenance therapy at month 3 to 11 in cases with no cytogenetic response and/or hematological resistance. A complete hematological remission was achieved rapidly (med 5 weeks), with the induction regimen in 9/12 previously untreated patients, and obtained or maintained in 9/12 patients who had already received conventional chemotherapy. Thirteen patients (8 untreated, 5 previously treated) showed a cytogenetic improvement and 9 of them had complete suppression of the Ph + clone after 3 to 24 months of treatment. Six patients had durable complete cytogenetic remissions lasting 6 + to 15 + (med 9 +) months. Two of the patients with minor or no cytogenetic response progressed to blastic crisis and died shortly thereafter. The low-dose Ara-C-IFN regimen was well tolerated and no intercurrent infections or bleeding was recorded. This preliminary data suggests a high incidence of hematologic remissions and cytogenetic response with the combination of IFN alpha, HU and low dose Ara-C. PMID- 27462718 TI - The Effects of Interferon Alpha Therapy on Oncogene Expression in Chronic Granulocytic Leukaemia. AB - Nuclear expression of c-myc and c-fos oncoproteins was examined by two separate techniques. Flow cytometry revealed that neutrophils from normal (n = 15) and CGL patients before IFNalpha therapy (n = 10) exhibited similar levels of both oncoproteins. There was no significant alteration in either oncoprotein when CGL patients were treated with IFNalpha (n = 8). Using a peroxidase method on cytospin preparations from these patients, the pattern of c-myc oncoprotein expression during myeloid maturation was similar in all three groups. It is concluded that the response of CGL to IFNalpha therapy is probably independent of c-myc and c-fos oncoprotein expression. PMID- 27462719 TI - Parameters of Predictive Value in Chronic Myeloid Leukemia-The Prognostic Impact of Histopathological Variables in a Multivariate Regression Analysis. AB - The prognostic significance of disease features at the time of diagnosis was examined in 113 patients (75 males/38 females, median age 49 years) with chronic myeloid leukemia (CML) using multivariate regression analysis. In the course of this study we tested the validity of the prognostic model described by Sokal and coworkers(3), the predictive value of histopathological variables, and determined the disease-specific loss in life expectancy. The median survival time was 35 months in our patients. By using Cox's proportional hazards model for covariate analysis of censored survival data(26)'(32) two prognostic models were derived. The first consisted of the following parameters-age, presence of pseudo-Gaucher cells in the marrow, spleen size and the product of myeloblasts and normoblasts in the peripheral blood. The second model included age, the presence of myelofibrosis, the number of megakaryocytes in the bone marrow and the liver size. Both models provided a risk status that showed an excellent predictive relationship to relative survival rates and life expectancy. Application of the Sokal model(3) to our subpopulation of CML patients failed to reveal a significant segregation of the intermediate group from the other risk groups, even when assessing the disease-specific loss in life expectancy. Our results suggest that an amendment of the generally accepted model for prognostic evaluation of survival in CML should be made by inclusion of histological variables and the determination of relative survival rates. PMID- 27462720 TI - Acute Megakaryoblastic Leukemia: Importance of Bone Marrow Biopsy in Diagnosis. AB - Five cases of megakaryoblastic leukemia, presenting as "de novo" acute leukemias are reported. They represented 7.2% of all cases of adult acute non-lymphoblastic leukemias (ANLL) seen in our Hematology Service during the past 30 months. These cases showed features of predominantly blast proliferation with a marked increase of reticulin fibres in the bone marrow. One case had features of acute leukemia with trilineage myelodysplasia and one had a more chronic evolution with splenomegaly initially resembling a myeloproliferative syndrome. In all cases, the definitive diagnosis was made on bone marrow histology as cytology was poor and the blast cells were positive for factor VIII with the immunoperoxidase technique. The importance of bone marrow histology is emphasized. PMID- 27462721 TI - Better Alone or in Ill Company? The Effect of Migration and Inter-Species Comingling on Fascioloides magna Infection in Elk. AB - Migratory movements and alteration of host communities through livestock production are examples of ecological processes that may have consequences on wildlife pathogens. We studied the effect of co-grazing of cattle and wild elk, and of elk migratory behaviour on the occurrence of the giant liver fluke, Fascioloides magna, in elk. Migratory elk and elk herds with a higher proportion of migratory individuals were significantly less likely to be infected with F. magna. This may indicate a decreased risk of infection for migratory individuals, known as the "migratory escape" hypothesis. Elk herds overlapping with higher cattle densities also had a lower prevalence of this parasite, even after adjustment for landscape and climate variables known to influence its life cycle. Serological evidence suggests that even in low-prevalence areas, F. magna is circulating in both elk and cattle. Cattle are "dead-end" hosts for F. magna, and this may, therefore, indicate a dilution effect where cattle and elk are co grazing. Migratory behaviour and host community composition have significant effects on the dynamics of this wildlife parasite; emphasizing the potential impacts of decisions regarding the management of migratory corridors and livestock-wildlife interface. PMID- 27462722 TI - Far Red/Near-Infrared AIE Dots for Image-Guided Photodynamic Cancer Cell Ablation. AB - We report a facile encapsulation approach to realize bright far red/near-infrared (FR/NIR) fluorescence and efficient singlet oxygen ((1)O2) production of organic fluorogens with aggregation-induced emission (AIEgen) and intramolecular charge transfer (ICT) characteristics for image-guided photodynamic cancer cell ablation. The synthesized AIEgen BTPEAQ possesses donor-acceptor-donor structure, which shows bright fluorescence in solid state. Due to the strong ICT effect, BTPEAQ exhibits poor emission with almost no (1)O2 generation in aqueous solution. Encapsulation of BTPEAQ by DSPE-PEG block copolymer yields polymer shelled dots, which show enhanced brightness with a fluorescence quantum yield of 3.9% and a (1)O2 quantum yield of 38%. Upon encapsulation by silica, the formed SiO2-shelled dots show much improved fluorescence quantum yield of 12.1% but with no obvious (1)O2 generation. This study clearly demonstrates the importance of encapsulation approach for organic fluorophores, which affects not only the brightness but also the (1)O2 production. After conjugating the polymer-shelled AIE dots with cRGD peptide, the obtained BTPEAQ-cRGD dots show excellent photoablation toward MDA-MB-231 cells with integrin overexpression while keeping control cells intact. PMID- 27462723 TI - Facile Synthesis of MoS2/Reduced Graphene Oxide@Polyaniline for High-Performance Supercapacitors. AB - The molybdenum disulfide/reduced graphene oxide@polyaniline (MoS2/RGO@PANI) was facilely and effectively prepared through a two-stage synthetic method including hydrothermal and polymerized reactions. The rational combination of two components allowed polyaniline (PANI) to uniformly cover the outer face of molybdenum disulfide/reduced graphene oxide (MoS2/RGO). The interaction between the two initial electrode materials produced a synergistic effect and resulted in outstanding energy storage performance in terms of greatest capacitive property (1224 F g(-1) at 1 A g(-1)), good rate (721 F g(-1) at 20 A g(-1)), and cyclic performance (82.5% remaining content after 3000 loops). The symmetric cell with MoS2/RGO@PANI had a good capacitive property (160 F g(-1) at 1 A g(-1)) and energy and power density (22.3 W h kg (-1) and 5.08 kW kg(-1)). PMID- 27462724 TI - Optimizing Partner Notification Programs for Men Who Have Sex with Men: Factorial Survey Results from South China. AB - BACKGROUND: Syphilis is prevalent among men who have sex with men (MSM) in China. Syphilis partner notification (PN) programs targeting MSM has been considered as one of effective strategies to prevention and control of the infection in the population. We examined willingness and preferences for PN among MSM to measure feasibility and optimize uptake. METHODS: Participation in a syphilis PN program was measured using a factorial survey from both the perspective of the index patient and the partner. Respondents were recruited from April-July 2011 using convenience sampling at two sites-a MSM sexually transmitted disease (STD) clinic and a MSM community based organization (CBO). Respondents first evaluated three factorial survey vignettes to measure probability of participation and then an anonymous sociodemographic questionnaire. A two-level mixed linear model was fitted for the factorial survey analysis. RESULTS: In 372 respondents with mean age (+/- SD) 28.5 (+/- 6.0) years, most were single (82.0%) and closeted gays (66.7%). The Internet was the most frequent place to search for sex. Few (31.2%) had legal names for casual partners, but most had instant messenger (86.5%) and mobile phone numbers (77.7%). The mean probability of participation in a syphilis PN program was 64.5% (+/- 32.4%) for index patients and 63.7% (+/- 32.6%) for partners. Referral of the partner to a private clinic or MSM CBO for follow-up decreased participation compared to the local Center for Disease Control and Prevention (CDC) or public STD clinic. CONCLUSIONS: Enhanced PN services may be feasible among MSM in South China. Internet and mobile phone PN may contact partners untraceable by traditional PN. Referral of partners to the local CDC or public STD clinic may maximize PN participation. PMID- 27462725 TI - Atomic-Scale Control of Silicon Expansion Space as Ultrastable Battery Anodes. AB - Development of electrode materials with high capability and long cycle life are central issues for lithium-ion batteries (LIBs). Here, we report an architecture of three-dimensional (3D) flexible silicon and graphene/carbon nanofibers (FSiGCNFs) with atomic-scale control of the expansion space as the binder-free anode for flexible LIBs. The FSiGCNFs with Si nanoparticles surrounded by accurate and controllable void spaces ensure excellent mechanical strength and afford sufficient space to overcome the damage caused by the volume expansion of Si nanoparticles during charge and discharge processes. This 3D porous structure possessing built-in void space between the Si and graphene/carbon matrix not only limits most solid-electrolyte interphase formation to the outer surface, instead of on the surface of individual NPs, and increases its stability but also achieves highly efficient channels for the fast transport of both electrons and lithium ions during cycling, thus offering outstanding electrochemical performance (2002 mAh g(-1) at a current density of 700 mA g(-1) over 1050 cycles corresponding to 3840 mAh g(-1) for silicon alone and 582 mAh g(-1) at the highest current density of 28 000 mA g(-1)). PMID- 27462727 TI - Hyphenation of Production-Scale Free-Flow Electrophoresis to Electrospray Ionization Mass Spectrometry Using a Highly Conductive Background Electrolyte. AB - In this technical note, we demonstrate the hyphenation of production-scale free flow electrophoresis (FFE) and sheathless electrospray ionization mass spectrometry (ESI-MS). In contrast to previous hyphenation approaches, we used a highly conductive background electrolyte (BGE) required for production-scale FFE. We found that this kind of BGE as well as a production-scale setup leads to significant electric interference between FFE and MS. This interference prevents steady-state FFE operation. We examine this interference in detail and discuss possible solutions to this issue. We demonstrate that the straightforward grounding of the transfer line removes the influence of ESI-MS on FFE, but creates a current leak from the ESI interface, which adversely affects the ESI spray. Furthermore, we show that only the electrical disconnection of the ESI probe from the FFE-MS transfer line suppresses this undesirable current. In order to facilitate the electrical disconnection we used a low conductivity, silica based ESI probe with withdrawn inner capillary. This approach allowed the interference-free hyphenation of production-scale FFE (using a highly conductive BGE) with ESI-MS. PMID- 27462726 TI - Rhizovarins A-F, Indole-Diterpenes from the Mangrove-Derived Endophytic Fungus Mucor irregularis QEN-189. AB - Genome mining of the fungus Mucor irregularis (formerly known as Rhizomucor variabilis) revealed the presence of various gene clusters for secondary metabolite biosynthesis, including several terpene-based clusters. Investigation into the chemical diversity of M. irregularis QEN-189, an endophytic fungus isolated from the fresh inner tissue of the marine mangrove plant Rhizophora stylosa, resulted in the discovery of 20 structurally diverse indole-diterpenes including six new compounds, namely, rhizovarins A-F (1-6). Among them, compounds 1-3 represent the most complex members of the reported indole-diterpenes. The presence of an unusual acetal linked to a hemiketal (1) or a ketal (2 and 3) in an unprecedented 4,6,6,8,5,6,6,6,6-fused indole-diterpene ring system makes them chemically unique. Their structures and absolute configurations were elucidated by spectroscopic analysis, modified Mosher's method, and chemical calculations. Each of the isolated compounds was evaluated for antitumor activity against HL-60 and A-549 cell lines. PMID- 27462728 TI - Signatures of Biomass Burning Aerosols in the Plume of a Saltmarsh Wildfire in South Texas. AB - The most conventional and abundant tracers of biomass combustion in aerosol particles include potassium and biomarkers derived from thermally altered cellulose/hemicellulose (anhydrosugars) and lignin (methoxyphenols). However, little is known of the role biomass combustion plays as a particulate source of major plant polymers to the atmosphere. Here, concentrations of solvent extractable anhydrosugars and methoxyphenols are compared to the yields of polymeric lignin oxidation products (LOPs) during a smoke plume event in Houston, Texas. Downwind aerosol samples (PM2.5) were collected surrounding a two-day wildfire in the McFaddin National Wildlife Refuge, 125 km southeast of Houston, which was 12-16 h directly downwind during the peak of the burn. Concentrations of all organic markers, potassium, and calcium increased by a factor of 2-13 within 1-2 days of the start of the fire and dropped to prefire levels 3 days after the peak event. Source signatures of anhydrosugars and methoxyphenols during the peak of the plume were identical to those of grass charcoals collected from the site, confirming the use of charcoals as end-members for source input reconstruction during atmospheric transport. An enrichment factor of 20 in the anhydrosugar to methoxyphenol ratio of aerosols versus charcoals can be explained partially by differences in degradation rate constants between the biomarker groups. LOPs comprised 73-91% of all lignin material in the aerosols, pointing to fires as major sources of primary biogenic aerosol particles in which lignin phenols occur predominantly in polymeric form. PMID- 27462729 TI - Biofilm Formation and Disinfectant Susceptibility of Persistent and Nonpersistent Listeria monocytogenes Isolates from Gorgonzola Cheese Processing Plants. AB - The aim of this study was to investigate whether the biofilm-forming ability and/or the disinfectant susceptibility accounted for the persistence of Listeria monocytogenes in Gorgonzola cheese processing plants. For this purpose, a set of 16 L. monocytogenes isolates collected in the 2004-2007 period was analyzed, including 11 persistent isolates collected in different years, within the collection period, and displaying identical or highly correlated pulsotypes. The evaluation of biofilm-forming ability was assessed using crystal violet (CV) staining and the enumeration of viable cells on stainless steel coupons (SSC). Absorbance values obtained with CV staining for persistent and nonpersistent isolates were not significantly different (rm-ANOVA p > 0.05) and the cell counts from nonpersistent isolates showed to be higher compared with persistent isolates (rm-ANOVA p < 0.05). A simulation of disinfectant treatments was performed on spot inoculated coupons in clean and dirty conditions, according to EN 13697, and on biofilms on SSC, grown in nutrient-rich (dirty) and limiting (clean) conditions using acid acetic-hydrogen peroxide (P3) and acid citric-hydrogen peroxide (MS) commercial disinfectants. The treatment was considered effective when a 4 Log reduction in viable cell count was observed. The Log reductions of persistent and nonpersistent isolates, obtained with both the assays in clean and dirty conditions, were compared and no significant differences were detected (rm ANOVA p > 0.05). A greater influence of organic matter on MS could explain why P3 was efficient in reducing to effective levels the majority of the isolates at the lowest concentration suggested by the manufacturer (0.2% [v/v]), while the same purpose required a higher concentration (1% [v/v]) of MS. In conclusion, our results demonstrate that the persistence of these isolates in Gorgonzola cheese processing plants was linked neither to the biofilm-forming ability nor to their susceptibility to hydrogen peroxide-based disinfectants; therefore, other factors should contribute to the persistent colonization of the dairies. PMID- 27462730 TI - Editorial. PMID- 27462731 TI - Temporal auditory aspects in children with poor school performance and associated factors. AB - PURPOSE: To investigate the auditory temporal aspects in children with poor school performance aged 7-12 years and their association with behavioral aspects, health perception, school and health profiles, and sociodemographic factors. METHODS: This is an observational, analytical, transversal study including 89 children with poor school performance aged 7-12 years enrolled in the municipal public schools of a municipality in Minas Gerais state, participants of Specialized Educational Assistance. The first stage of the study was conducted with the subjects' parents aiming to collect information on sociodemographic aspects, health profile, and educational records. In addition, the parents responded to the Strengths and Difficulties Questionnaire (SDQ). The second stage was conducted with the children in order to investigate their health self perception and analyze the auditory assessment, which consisted of meatoscopy, Transient Otoacoustic Emissions, and tests that evaluated the aspects of simple auditory temporal ordering and auditory temporal resolution. Tests assessing the temporal aspects of auditory temporal processing were considered as response variables, and the explanatory variables were grouped for univariate and multivariate logistic regression analyses. The level of significance was set at 5%. RESULTS: Significant statistical correlation was found between the auditory temporal aspects and the variables age, gender, presence of repetition, and health self-perception. CONCLUSION: Children with poor school performance presented changes in the auditory temporal aspects. The temporal abilities assessed suggest association with different factors such as maturational process, health self-perception, and school records. PMID- 27462732 TI - Enunciative categories in the description of language functioning of mothers and infants aged 1-4 months. AB - OBJECTIVE: To present categories which explain the language functioning between infants and their mothers from Benveniste's concept of semiotic system, and verify whether such categories can be described numerically. METHOD: Four mother infant dyads were monitored in three stages. The first study consisted of a qualitative analysis of the transcribed video recordings conducted in each stage. We intended to identify the enunciative principles associated with the relationship between the semiotic system of the infant's body and their mother's language, namely, the principles of interpretancy and homology. The other study was conducted by means of a descriptive numerical analysis of the enunciative categories and the infant caregiver scale of behavior, using the ELAN software (EUDICO Linguistic Anotador). RESULTS: Mutuality in mother-infant interactions was observed in most of the scenes analyzed. Productive enunciative categories demonstrated in the infant's demand/mother's interpretation relation was identified in homology and interpretancy. It was also possible to use these categories to describe the mother-infant interactions numerically. In addition, other categories emerged because there are other subtypes of maternal productions not directly related to infant demand. This shows that infants are exposed to language of heterogeneous characteristics. CONCLUSION: The concept of semiotic system allowed the proposition of language functioning categories identifiable in the mother-infant relationship. Such categories were described numerically. PMID- 27462733 TI - Children's language development after cochlear implantation: a literature review. AB - AIM: review the literature for studies that describe the language development of children after they receive cochlear implants. RESEARCH STRATEGIES: Literature review on the PubMed, Web of Science, Scopus, and Science Direct databases, tracing the selection and critical analysis stages in the journals found and selected. SELECTION CRITERIA: We selected original articles looking at children with cochlear implants, which mentioned language development after surgery. Case studies, dissertations, books chapters, editorials, and original articles that did not mention aspects of oral communication development, perception of sounds and speech, and other stages of human development, in the title, abstract, or text, were excluded. DATA ANALYSIS: A protocol was created for this study including the following points: author, year, location, sample, type of study, objectives, methods used, main results, and conclusion. RESULTS: 5,052 articles were found based on the search descriptors and free terms. Of this total, 3,414 were excluded due to the title, 1,245 due to the abstract, and 358 from reading the full text; we selected 35, of which 28 were repeated. In the end, seven articles were analyzed in this review. CONCLUSION: We conclude that cochlear implant users have slower linguistic and educational development than their peers with normal hearing - though they are better than conventional prostheses users - and they are able to match them over time. There is great variability in the test methodologies, thus reducing the effectiveness and reliability of the results found. PMID- 27462735 TI - Scanning sports. PMID- 27462736 TI - Ringing in Some Changes. PMID- 27462734 TI - Phylogeography of the Subgenus Drosophila (Diptera: Drosophilidae): Evolutionary History of Faunal Divergence between the Old and the New Worlds. AB - The current subgenus Drosophila (the traditional immigrans-tripunctata radiation) includes major elements of temperate drosophilid faunas in the northern hemisphere. Despite previous molecular phylogenetic analyses, the phylogeny of the subgenus Drosophila has not fully been resolved: the resulting trees have more or less varied in topology. One possible factor for such ambiguous results is taxon-sampling that has been biased towards New World species in previous studies. In this study, taxon sampling was balanced between Old and New World species, and phylogenetic relationships among 45 ingroup species selected from ten core species groups of the subgenus Drosophila were analyzed using nucleotide sequences of three nuclear and two mitochondrial genes. Based on the resulting phylogenetic tree, ancestral distributions and divergence times were estimated for each clade to test Throckmorton's hypothesis that there was a primary, early Oligocene disjunction of tropical faunas and a subsequent mid-Miocene disjunction of temperate faunas between the Old and the New Worlds that occurred in parallel in separate lineages of the Drosophilidae. Our results substantially support Throckmorton's hypothesis of ancestral migrations via the Bering Land Bridge mainly from the Old to the New World, and subsequent vicariant divergence of descendants between the two Worlds occurred in parallel among different lineages of the subgenus Drosophila. However, our results also indicate that these events took place multiple times over a wider time range than Throckmorton proposed, from the late Oligocene to the Pliocene. PMID- 27462737 TI - Letters. PMID- 27462742 TI - CME: Supply Equals Demand. PMID- 27462738 TI - Brief reports. PMID- 27462743 TI - Downhill Demon. PMID- 27462744 TI - Circuit Weight Training: A Critical Review of Its Physiological Benefits. AB - In brief: Circuit weight training (CWT) can improve cardiorespiratory endurance, body composition, and strength, and sessions only take 25 to 30 minutes. Studies reviewed in this article showed that CWT increased aerobic capacity about 5%, compared with 15% to 25% in other aerobic exercise programs. Lean body mass increased 1 to 3.2 kg and fat decreased 0.8% to 2.9%. Strength improved 7% to 32%. Energy costs of CWT were similar to jogging at 5 mph. The authors conclude that improvements in strength and Vo2 max depend on work performed, not the equipment used. Although CWT does not develop high levels of aerobic fitness, it can help maintain fitness. PMID- 27462745 TI - Distance Runners as Models of Optimal Health. AB - In brief: Distance runners are suggested as a new model for optimal health standards because normal values are now derived from the American public, which is notorious for its obesity, low level of physical fitness, bad eating habits, use of cigarettes and drugs, and high incidence of cardiovascular and other degenerative diseases. As a group, the 50 distance runners studied showed lower than normal body weight, body fat, resting heart rate, serum cholesterol and triglycerides; higher HDL cholesterol; and lower cholesterol/HDL cholesterol ratios. However, the runners who ate the average American diet sometimes had normal values. PMID- 27462746 TI - Lower Extremity Stress Fractures in Athletes. AB - In brief: A review of the records of 62 runners treated for stress fractures showed that initial x-rays were positive in 47.2% of the cases, while bone scans were positive in 95.8%. A combination of errors in training and changes in footwear accounted for 44% of the fractures, and all the patients had alignment problems. The runners had waited until their performance was seriously impaired to seek treatment. The authors concluded that if point tenderness and soft-tissue swelling are recognized early, stress fractures can be prevented with rest, muscle rehabilitation, and orthotic control of excessive pronation. PMID- 27462747 TI - Eye Injuries in Racket Sports: A Continuing Problem. AB - In brief: Hyphema was the most common serious injury in this review of 67 squash and 18 racquetball eye injuries. Several patients had corneal lacerations and retinal detachments, and many had lid contusions, small lacerations, and subconjunctival hemorrhages. Eight sustained severe loss of vision. Open eye guards did not protect all players who wore them, and all types of prescription lenses were breakable. Since these patients had several years of experience, competitive players may be at higher risk. Carefully chosen eye guards and defensive playing could solve much of the problem. PMID- 27462748 TI - Downhill Skiing Injuries. AB - In brief: Lower extremity injuries are common in downhill skiing. Fifty-three percent of the skiing injuries in one study, and 81% in another, were below the knee. Twelve case reports are presented and their treatment is discussed. The author suggests that skiers undertake a physical fitness program to increase stamina and elasticity of muscles and ligaments. PMID- 27462749 TI - Ski Touring in Scandinavia. AB - Norway and Finland can't be surpassed for a ski touring vacation that combines vigorous exercise, beautiful surroundings, and a reasonable cost. PMID- 27462751 TI - Exercise Employees: Changing Standards in a Changing Industry. AB - Fitness employees have different levels of education and training. Are they qualified to give exercise advice? PMID- 27462750 TI - Louis F. Bishop, Jr: Sportsmedicine Pioneer. AB - Louis F. Bishop, MD, followed in his cardiologist father's pioneering footsteps as one of the founders of the American College of Sports Medicine. PMID- 27462752 TI - Surgical Tubing for Rehabilitating the Shoulder and Ankle. PMID- 27462753 TI - Education in Sportsmedicine: Coming Into Its Own. AB - Sportsmedicine rotations included in residency programs in medical schools and schools of osteopathy reflect the public's demand for more complete medical information. PMID- 27462754 TI - A need to know. PMID- 27462756 TI - FROM COCHRANE DATABASE OF SYSTEMATIC REVIEWS (CDSR) ISSUE 2-4, 2016. PMID- 27462757 TI - Pathological trans-lesion synthesis in cancer. PMID- 27462758 TI - Functional Reach and Lateral Reach Tests in Turkish Children. AB - AIMS: The functional reach test (FRT) and lateral reach test (LRT) provide important measures of postural stability. The aims of this study were to (1) establish the normative values for FRT and LRT, and (2) examine the effects of age, gender, and various anthropometric measurements on FRT and LRT. METHODS: Two hundred eighty children, aged 6-12 years, completed the study. One hundred fifty two subjects were females. The mean age was 9.0 +/- 2.0 years. Each child performed two trials of FRT and LRT. RESULTS: No significant differences were detected in any age group between males and females. The normal values of FRT ranged between 23.0 and 36.5 cm, and that of LRT between 18.0 and 28.0 cm. Height, length of upper and lower extremity, and arm span had a higher correlation with FRT. Age and weight showed a good correlation with FRT. Age, height, weight, length of upper and lower extremity, and arm span showed good correlation with LRT. CONCLUSIONS: These normative data will be useful for clinicians in the assessment of balance of individual children and in the diagnosis of potential balance deficits at an early age in the Turkish population. PMID- 27462759 TI - Influence of a 12.8-km military load carriage activity on lower limb gait mechanics and muscle activity. AB - The high stress fracture occurrence in military populations has been associated with frequent load carriage activities. This study aimed to assess the influence of load carriage and of completing a load carriage training activity on gait characteristics. Thirty-two Royal Marine recruits completed a 12.8-km load carriage activity as part of their military training. Data were collected during walking in military boots, pre and post-activity, with and without the additional load (35.5 kg). Ground contact time, lower limb sagittal plane kinematics and kinetics, and electromyographic variables were obtained for each condition. When carrying load, there was increased ground contact time, increased joint flexion and joint moments, and increased plantar flexor and knee extensor muscle activity. Post-activity, there were no changes to kinematic variables, knee extensor moments were reduced, and there was evidence of plantar flexor muscle fatigue. The observed gait changes may be associated with stress fracture development. Practitioner Summary: This study identified gait changes due to load carriage and after a military load carriage training activity. Such activities are associated with lower limb stress fractures. A pre-post study design was used. Gait mechanics changed to a greater extent when carrying load, than after completion of the activity when assessed without load. PMID- 27462760 TI - In Pursuit of Fully Flexible Protein-Ligand Docking: Modeling the Bilateral Mechanism of Binding. AB - Modern structure-based drug design aims at accounting for the intrinsic flexibility of therapeutic relevant targets. Over the last few years a considerable amount of docking approaches that encounter this challenging problem has emerged. Here we provide the readership with an overview of established methods for fully flexible protein-ligand docking and current developments in the field. All methods are based on one of two fundamental models which describe the dynamic behavior of proteins upon ligand binding. Methods for ensemble docking (ED) model the protein conformational change before the ligand is placed, whereas induced-fit docking (IFD) optimizes the protein structure afterwards. A third category of docking approaches is formed by recent approaches that follow both concepts. This categorization allows to comprehensively discover strengths and weaknesses of the individual processes and to extract information for their applicability in real world docking scenarios. PMID- 27462761 TI - Structure-Based Approaches to Target Fishing and Ligand Profiling. AB - Chemogenomics is an emerging interdisciplinary field aiming at identifying all possible ligands of all possible targets. If one groups targets in columns and ligands in rows, chemogenomic approaches to drug discovery just fill the interaction matrix. Since experimental data do not suffice, several computational methods are currently actively developed to supplement time-consuming and costly experiments. They are either designed to fill rows and thus profile a ligand towards a heterogeneous set of targets (target profiling) or to fill columns and thus identify novel ligands for an existing target (standard virtual screening). At the interface of both strategies are now true chemogenomic computational methods filling well defined areas in the matrix. The present review will focus on (protein) structure-based approaches and illustrates major advances in this novel exciting field which is supposed to massively impact rational drug design in the next decade. PMID- 27462762 TI - Automated Docking of Flexible Molecules Into Receptor Binding Sites by Ligand Self-Organization In Situ. PMID- 27462763 TI - Prediction of Water's Mobility and Disorder in Protein Crystals Using Novel Local Hydrophobic Descriptors. AB - The B-factors of crystal structures reflect the atomic fluctuations about their average positions and provide important information about molecular dynamics. Although numerous works have been addressed on theoretical and computational studies of B-factor profile of protein atoms, the methods used for predicting B factor values of water molecules in protein crystals still remain unexploited. In this article, we describe a new approach that we named local hydrophobic descriptors (LHDs) to characterize the hydrophobic landscapes of protein hydration sites. Using this approach coupled with partial least squares (PLS) regression and least-squares squares support vector machine (LSSVM), we perform a systematic investigation on the linear and nonlinear relationships between the LHDs and water B-factors. Based upon an elaborately selected, large-scale dataset of crystal water molecules, our method predicts B-factor profile with coefficient of determination rpred of 0.554. We demonstrate that (i) the dynamics of water molecules is primarily governed by the local features of hydrophobic potential landscapes, and (ii) the accuracy of predicted B-factor values depends on water packing density. PMID- 27462764 TI - Prediction of Microporous Aluminophosphate AlPO4 -5 Based on Resampling Using Partial Least Squares and Logistic Discrimination. AB - In this paper, Partial Least Squares (PLS) regression and Logistic Discrimination (LD) are employed to predict the formation of microporous aluminophosphate AlPO4 5 based on the database of AlPO synthesis, which aims to provide a useful guidance to the rational synthesis of microporous materials as well as other inorganic crystalline materials. To deal with the problem of class imbalance, four guided resampling methods considering not only the between-class imbalance but also the within-class imbalance are proposed. Experimental results indicate that the presented methods are competent for predicting the formation of microporous aluminophosphate AlPO4 -5. Specially, compared with some existing resampling methods, our proposed resampling methods exhibit much better predictive results. PMID- 27462765 TI - Design, Synthesis, and Evaluation of Antineoplastic Activity of Novel Carbocyclic Nucleosides. AB - Cancer is the leading cause of death among men and women under age 85. Every year, millions of individuals are diagnosed with cancer. But finding new drugs is a complex, expensive, and very time-consuming task. Over the past decade, the cancer research community has begun to address the in silico modeling approaches, such as Quantitative Structure-Activity Relationships (QSAR), as an important alternative tool for targeting potential anticancer drugs. With the compilation of a large dataset of nucleosides synthesized in our laboratories, or elsewhere, and tested in a single cytotoxic assay under the same experimental conditions, we recognized a unique opportunity to attempt to build predictive QSAR models. Early efforts with 2D classification models built from part of this dataset were very encouraging. Here we report a further detailed evaluation of classification models to flag potential anticancer activities derived from a variety of 3D molecular representations. A quantitative 3D-model model that discriminates anticancer compounds from the inactive ones was attained, which allowed the correct classification of 82 % of compounds in such a large and diverse dataset, with only 5 % of false inactives and 11 % of false actives. The model developed here was then used to select and design a new series of nucleosides, by classifying beforehand them as active/inactive anticancer compounds. From the compounds so designed, 22 were synthesized and evaluated for their inhibitory effects on the proliferation of murine leukemia cells (L1210/0), of which 86 % were well-classified as active or inactive, and only two were false actives, corroborating the good predictive ability of the present discriminant model. The results of this study thus provide a valuable tool for the design of novel potent anticancer nucleoside analogues. PMID- 27462766 TI - Ensemble Rule-Based Classification of Substrates of the Human ABC-Transporter ABCB1 Using Simple Physicochemical Descriptors. AB - Within the last decades, the detailed knowledge on the impact of membrane bound drug efflux transporters of the ATP binding cassette (ABC) protein family on the pharmacological profile of drugs has enormously increased. Especially, ABCB1 (P glycoprotein, P-gp, MDR1) has attracted particular interest in medicinal chemistry, since it determines the clinical efficacy, side effects and toxicity risks of drug candidates. Based on this, the development of in silico models that provide rapid and cost-effective screening tools for the classification of substrates and nonsubstrates of ABCB1 is an urgent need in contemporary ADMET profiling. A characteristic hallmark feature of this transporter is its polyspecific ligand recognition pattern. In this study we describe a method for classifying ABCB1 ligands in terms of simple, conjunctive rules (RuleFit) based on interpretable ADMET features. The retrieved results showed that models based on large, very diverse data sets gave better classification performance than models based on smaller, more homogenous training sets. The best model achieved gave a correct classification rate of 0.90 for an external validation set. Furthermore, from the interpretation of the best performing model it could be concluded that in comparison to nonsubstrates ABCB1 substrates generally show a higher number of hydrogen-bond acceptors, are more flexible and exhibit higher logP values. PMID- 27462767 TI - Quantitative Prediction of Regioselectivity Toward Cytochrome P450/3A4 Using Machine Learning Approaches. AB - In the drug discovery process, it is important to know the properties of both drug candidates and their metabolites. Fast and precise prediction of metabolites is essential. However, it has been difficult to predict metabolites because of the complexity of the mechanism of cytochrome P450/3A4 (CYP 3A4), which is the main metabolite enzyme of drugs. In this study, we focus on the regioselectivity of CYP 3A4, i.e., the selectivity of metabolic sites. We have developed a model to predict the regioselectivity of drug candidates by using machine learning (ML) approaches. PMID- 27462768 TI - Development of neuro-fuzzy model to explore gene-nutrient interactions modulating warfarin dose requirement. AB - AIM: To investigate the influence of alterations in vitamin K (K1, K2 and K3) in modulating warfarin dose requirement. PATIENTS & METHODS: Reverse phase HPLC to determine the plasma vitamin K; PCR-RFLP to detect polymorphisms; and the neuro fuzzy model to predict warfarin dose were used. RESULTS: The developed neuro fuzzy model showed a mean absolute error of 0.000024 mg/week. CYP2C9*2 and CYP2C9*3 mediated warfarin sensitivity was observed when vitamin K is in high and low tertiles, respectively. VKORC1-1639G>A exhibited warfarin sensitivity in all combinations. Higher vitamin K1 was observed in CYP4F2 V433M polymorphism. The requirement of warfarin is low in GGCX 8016 GG genotype compared with GA and AA genotypes. CONCLUSION: Vitamin K profile along with genetic testing ensures precision in warfarin dose optimization. PMID- 27462769 TI - "She Stopped Me From Killing Myself": Bullied Bloggers' Coping Behaviors and Support Sources. AB - Bullying is on the rise, and bullied targets often face consequences when they do not effectively manage their victimization. This study investigates bullied bloggers' use and evaluations of coping strategies and support sources. Informed by Lazarus and Folkman's (1984) appraisal theory, Tenenbaum, Varjas, Meyers, and Parris's (2011) model of bullied students' coping, and social support literature, bullied students' narratives (N = 100) from five bullying blogs (Pacer's, I'm Getting Bullied, ReachOut, BullyVille, No Place 4 Hate) are examined. The findings reveal similar negative outcomes with particular coping strategies and support sources for bullied male and female bloggers. These results reinforce coping strategies that many bullying organizations promote in their programs and websites (i.e., do not avoid disclosure, confront bullies, or retaliate), and promote future research about how to improve parents' and teachers' supportive communication with bullied youth. PMID- 27462770 TI - ABO blood type is associated with ovarian reserve in Chinese women with subfertility. AB - Ovarian reserve reflects both the quantity and quality of oocytes available for procreation, and is affected by many known and unknown factors. ABO blood type is related to a number of infertility processes, but it is unclear whether and how ABO blood type affects ovarian reserve. Here, we explored the relationship between ABO blood type and ovarian reserve in Chinese women with subfertility. Day-3 serum follicle-stimulating hormone (FSH) levels and blood type were examined in 14,875 women who underwent IVF or ICSI treatment. Blood type proportions in the patient population were as follows: 30.98% type A, 24.54% type B, 7.57% type AB, and 36.91% type O. A higher percentage of women with diminished ovarian reserve (DOR) were blood type O, while a lower percentage had the B antigen (B and AB). Multiple logistic regression analysis revealed that blood type O was associated with a greater risk of DOR than blood type B and B antigen positive types. By contrast, the B antigen (B and AB) was associated with a lower incidence of DOR than blood type O. These results suggest that blood type O is a risk factor for DOR while the B antigen (blood type B or AB) is a protective factor for ovarian reserve in Chinese women with subfertility. Further studies are needed to confirm this effect and identify the underlying mechanisms. PMID- 27462771 TI - Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells. AB - Zoledronic acid, a potent nitrogen-containing bisphosphonate (NBP), has been extensively used to limit bone turnover in a various diseases including tumors. Recent clinical studies have demonstrated direct anti-cancer effects of zoledronic acid, in addition to its clinical benefits for skeletal-related events. Here we investigated the effects of 4 clinically available NBPs on human tumor cell proliferation. Our data demonstrate a potent anti-proliferative effect of zoledronic acid against glioblastoma (GBM) cell lines, breast cancer cells and GBM patient-derived lines. Zoledronic acid also effectively inhibited GBM tumor growth in xenograft mouse models. Zoledronic acid strongly stimulated autophagy but not apoptotic signals in all tested cells. Only one intermediate product of cholesterols synthesis pathway, geranylgeranyl diphosphate (GGPP) rescued cells from the cytotoxic effects of zoledronic acid. To further investigate the effect of GGPP, we knocked down RABGGTA, which encodes a subunit of the Rabgeranylgeranyltransferase protein. This knockdown induced an effect similar to zoledronic acid in cancer cell lines. These data are promising and suggested a potential for zoledronic acid as an anti-cancer agent, through its ablation of the function of Rab proteins. PMID- 27462772 TI - A pancreatic ductal adenocarcinoma subpopulation is sensitive to FK866, an inhibitor of NAMPT. AB - Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866. PMID- 27462773 TI - Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness. AB - Memantine is approved for the treatment of advanced Alzheimer's disease (AD) and reduces glutamate-mediated neuronal excitotoxicity by antagonism of N-methyl-D aspartate receptors. In the pathophysiology of AD immune responses deviate and infectious side effects are observed during memantine therapy. However, the particular effects of memantine on human T lymphocytes are unresolved. Here, we provide evidence that memantine blocks Kv1.3 potassium channels, inhibits CD3 antibody- and alloantigen-induced proliferation and suppresses chemokine-induced migration of peripheral blood T cells of healthy donors. Concurrent with the in vitro data, CD4+ T cells from AD patients receiving therapeutic doses of memantine show a transient decline of Kv1.3 channel activity and a long-lasting reduced proliferative response to alloantigens in mixed lymphocyte reactions. Furthermore, memantine treatment provokes a profound depletion of peripheral blood memory CD45RO+ CD4+ T cells. Thus, standard doses of memantine profoundly reduce T cell responses in treated patients through blockade of Kv1.3 channels. This may normalize deviant immunopathology in AD and contribute to the beneficial effects of memantine, but may also account for the enhanced infection rate. PMID- 27462774 TI - Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing. AB - Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPalpha mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (<1%) present at diagnosis and undergoing expansion (60%) at relapse. Taken together, these findings provide molecular clues for designing optimal therapeutic strategies, in terms of target selection, adequate schedule design and reliable response-monitoring techniques. PMID- 27462775 TI - An integrative framework to identify cell death-related microRNAs in esophageal squamous cell carcinoma. AB - Cell death is a critical biological process involved in many important functions, and defects in this system are usually linked with numerous human diseases including cancers. Esophageal squamous cell carcinoma is one of the most chemo- and biological therapy resistant cancers. Based on knowledge repository and four miRNAs profiling data, we proposed a general framework to hunt for cell death miRNAs in a context dependent manner. We predicted 12 candidate miRNAs from hundreds of others. Follow-up experimental verification of 7 miRNAs indicated at least 3 miRNAs (MIR20b, MIR498 and MIR196) were involved in both apoptosis and autophagy processes. These results indicated miRNAs intimately connected the two cell death modules in esophageal squamous cell carcinoma. This integrative framework can also be easily extended to identify miRNAs in other key cellular signaling pathways or may find conditional specific miRNAs in other cancer types. PMID- 27462776 TI - MicroRNA-155 is a potential molecular marker of natural killer/T-cell lymphoma. AB - Natural killer/T-cell lymphoma (NKTCL) is characterized by its highly aggressive nature and rapid progression. MicroRNAs (miRNAs) play key roles in the development of NKTCL. We utilized next-generation Solexa high-throughput sequencing to compare miRNA expression in the SNK-6 and YTS NKTCL cell lines with expression in normal NK cells. We found that 195 miRNAs were upregulated in the SNK-6 cells and 286 miRNAs were upregulated in the YTS cells. Based on those results, we selected six miRNAs, including miRNA-155, and confirmed their expression using real-time polymerase chain reaction. Expression of miRNA-155 was higher in SNK-6 and YKS cells than in normal NK cells. We next determined the levels of miRNA-155 in the serum of healthy individuals and NKTCL patients, and correlated its expression with clinical parameters and inflammatory factors detected using enzyme-linked immunoabsorbent assays. Levels of miRNA-155 were higher in NKTCL patients' serum than in serum from healthy individuals. miRNA-155 expression was higher in patients with stable or progressive disease (SD+PD) than in those with partial or complete remission (PR+CR). While further studies are needed to clarify the underlying molecular mechanisms, it appears miRNA-155 may be a molecular marker of NKTCL. PMID- 27462777 TI - Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function. AB - AIMS: This study was designed to identify novel microRNAs (miRNAs) in plasma for detecting and monitoring hepatocellular carcinoma (HCC), independent of hepatic function and background liver diseases with different etiologies. RESULTS: (1) Four oncogenic miRNAs (miR-151, 155, 191 and 224) with high expression in HCC tissues were selected as candidates. (2) Quantitative RT-PCR using plasma samples from 107 HCC patients and 75 healthy volunteers revealed a significantly higher level of plasma miR-224 in HCC patients than in healthy volunteers according to a small-scale analysis (P < 0.0001), two independent large-scale cohort analysis (P < 0.0001, AUC 0.908). (3) miR-224 expression was significantly higher in HCC tissues and HCC cell lines than in normal hepatic tissues and fibroblasts, respectively. (P = 0.0011, 0.0150) (4) Plasma miR-224 reflected tumor dynamics; preoperative plasma levels of miR-224 were significantly reduced in postoperative samples (P = 0.0058), and plasma miR-224 levels were significantly correlated with paired miR-224 levels in HCC tissues (P = 0.0005). (5) Furthermore, plasma miR-224 levels significantly discriminated HCC patients from patients with chronic liver disease (P = 0.0008). A high plasma miR-224 level was significantly correlated with larger tumor size (P = 0.0005) and recurrences (P = 0.0027). The plasma miR-224 level could accurately detect small tumors less than 18 mm preoperatively. METHODS: We performed a systematic review of the NCBI database and selected candidate miRNAs reported as highly expressed in HCC tissue. CONCLUSIONS: Plasma miR-224 may be a sensitive biomarker for screening HCC and monitoring tumor dynamics. PMID- 27462778 TI - PDHA1 gene knockout in prostate cancer cells results in metabolic reprogramming towards greater glutamine dependence. AB - Alternative pathways of metabolism endowed cancer cells with metabolic stress. Inhibiting the related compensatory pathways might achieve synergistic anticancer results. This study demonstrated that pyruvate dehydrogenase E1alpha gene knockout (PDHA1 KO) resulted in alterations in tumor cell metabolism by rendering the cells with increased expression of glutaminase1 (GLS1) and glutamate dehydrogenase1 (GLUD1), leading to an increase in glutamine-dependent cell survival. Deprivation of glutamine induced cell growth inhibition, increased reactive oxygen species and decreased ATP production. Pharmacological blockade of the glutaminolysis pathway resulted in massive tumor cells apoptosis and dysfunction of ROS scavenge in the LNCaP PDHA1 KO cells. Further examination of the key glutaminolysis enzymes in human prostate cancer samples also revealed that higher levels of GLS1 and GLUD1 expression were significantly associated with aggressive clinicopathological features and poor clinical outcome. These insights supply evidence that glutaminolysis plays a compensatory role for cell survival upon alternative energy metabolism and targeting the glutamine anaplerosis of energy metabolism via GLS1 and GLUD1 in cancer cells may offer a potential novel therapeutic strategy. PMID- 27462779 TI - Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer. AB - Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2 positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer. PMID- 27462780 TI - Reduced miR-550a-3p leads to breast cancer initiation, growth, and metastasis by increasing levels of ERK1 and 2. AB - Hyperactivation of the Ras/ERK pathway contributes to breast cancer initiation and progression, and recent evidence suggests aberrant signaling of miRNAs that regulate the Ras/ERK pathway play important roles during carcinogenesis and cancer progression. In this study, we demonstrate that miR-550a-3p expression is negatively correlated with levels of ERK1 and ERK2, two pivotal effectors in the Ras/ERK pathway. MiR-550a-3p gradually decreased during breast cancer initiation and progression and this reduction was a prognostic indicator of poorer overall survival (OS) and disease-free survival (DFS) among breast cancer patients. Our mechanistic studies demonstrated that miR-550a-3p exerts its tumor-suppressor role by directly repressing ERK1 and ERK2 protein expression, thereby suppressing the oncogenic ERK/RSK cascades, which reduced breast cancer cell viability, survival, migration, invasion, tumorigenesis, and metastasis. The inhibitory effects of miR-550a-3p were rescued by ectopic expression of ERK1 and/or ERK2. The novel connection between miR-550a-3p and ERK defines a new diagnostic and prognostic role for miR-550a-3p and highlights ERK inhibition as a candidate therapeutic target for breast cancers exhibiting hyperactivated Ras/ERK signaling. PMID- 27462781 TI - Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells. AB - Cytarabine (Ara-C) is a first line clinical therapeutic agent for treatment of acute myeloid leukemia (AML). However, this therapy is limited due to high rate of resistance and relapse. Recent research has revealed that the poor prognosis and resistance to Ara-C in AML were associated with its abnormally activated MAPK pathways. In this study, we showed a strong synergistic effect of Ara-C with either our Mnk inhibitor (MNKI-8e) or short hairpin RNA (shRNA) mediated knockdown of Mnks in MV4-11 AML cells. We investigated the underlying mechanisms for this synergism. We showed that both MNKI-8e and Mnk shRNAs enhanced the ability of Ara-C to induce apoptosis. We found that Ara-C increased the phosphorylation of Erk1/2, p38 and eIF4E, which correlated with an enhanced level of anti-apoptotic Mcl-1 protein. Inhibition of Mnk activity suppressed the Ara-C induced MAPK activity, and thus enhanced apoptosis in MV4-11 cells. Taken together, our study suggests that MAPK-Mnk-eIF4E pathway plays a critical role in Ara-C-treated MV4-11 cells and targeting Mnk may be a promising therapeutic strategy for sensitizing leukemic cells to Ara-C therapy. PMID- 27462782 TI - Ovarian low and high grade serous carcinomas: hidden divergent features in the tumor microenvironment. AB - Only recently low-grade serous carcinoma (LGSOC) of the ovary has been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSOC), with significant differences in pathogenesis and clinical and pathologic features. The present study aimed at evaluating whether the different natural histories and patterns of response to therapy demonstrated for LGSOC and HGSOC, along with a diverse genomic landscape, may also reside in the supporting tumor stroma, specifically in the state of differentiation and activation of tumor associated macrophages (TAMs). TAMs play complex roles in tumorigenesis since they are believed to possess both tumor rejecting (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we showed that, when compared to HGSOC (n = 55), LGSOC patients (n = 25) exhibited lower density of tumor infiltrating CD68+ macrophage, along with an attenuated M2-skewed (CD163+) phenotype. Accordingly, assessment of intratumoral vascularization and of matrix metalloproteinase 9 expression (a key protein involved in tumor invasion and metastasis) revealed lower expression in LGSOC compared to HGSOC patients, in line with emerging evidence supporting a role for TAMs in all aspects of tumor initiation, growth, and development. In conclusion, results from the present study demonstrate that microenvironmental factors contribute greatly to determine clinical and pathological features that differentiate low and high grade serous ovarian carcinomas. This understanding may increase possibilities and opportunities to improve disease control and design new therapeutic strategies. PMID- 27462783 TI - MIEN1 drives breast tumor cell migration by regulating cytoskeletal-focal adhesion dynamics. AB - Migration and invasion enhancer 1 (MIEN1) is an important regulator of cell migration and invasion. MIEN1 overexpression represents an oncogenic event that promotes tumor cell dissemination and metastasis. The underlying mechanism by which MIEN1 regulates migration and invasion has yet to be deciphered. Here, we demonstrate that MIEN1 acts as a cytoskeletal-signaling adapter protein to drive breast cancer cell migration. MIEN1 localization is concentrated underneath the actin-enriched protrusive structures of the migrating breast cancer cells. Depletion of MIEN1 led to the loss of actin-protrusive structures whereas the over-expression of MIEN1 resulted in rich and thick membrane extensions. Knockdown of MIEN1 also decreased the cell-substratum adhesion, suggesting a role for MIEN1 in actin cytoskeletal dynamics. Our results show that MIEN1 supports the transition of G-actin to F-actin polymerization and stabilizes F-actin polymers. Additionally, MIEN1 promotes cellular adhesion and actin dynamics by inducing phosphorylation of FAK at Tyr-925 and reducing phosphorylation of cofilin at Ser-3, which results in breast cancer cell migration. Collectively, our data show that MIEN1 plays an essential role in maintaining the plasticity of the dynamic membrane-associated actin cytoskeleton, which leads to an increase in cell motility. Hence, targeting MIEN1 might represent a promising means to prevent breast tumor metastasis. PMID- 27462784 TI - Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells. AB - Loss of progesterone-receptors (PR) expression is associated with breast cancer progression. Herein we provide evidence that OHPg/PR-B through Beclin-1 evoke autophagy-senescence transition, in breast cancer cells. Specifically, OHPg increases Beclin-1 expression through a transcriptional mechanism due to the occupancy of Beclin-1 promoter by PR-B, together with the transcriptional coactivator SRC-2. This complex binds at a canonical half progesterone responsive element, which is fundamental for OHPg effects, as shown by site-directed mutagenesis. Beside, OHPg via non-genomic action rapidly activates JNK, which phosphorylates Bcl-2, producing the functional release from Beclin-1 interaction. This is not linked to an efficient autophagic flux, since p62 levels, marker of degradation via lysosomes, were not reduced after sustained OHPg stimulus. Instead, the cell cycle inhibitor p27 was induced, together with an irreversible G1 arrest, hallmark of cellular senescence. Specifically the increase of senescence-associated beta-galactosidase activity was blocked by Bcl-2 siRNA but also by Beclin-1 siRNA. Collectively these findings support the importance of PR B expression in breast cancer cells, thus targeting PR-B may be a useful strategy to provide additional approaches to existing therapies for breast cancer patients. PMID- 27462785 TI - Native and engineered tropism of vectors derived from a rare species D adenovirus serotype 43. AB - Unique molecular properties of species D adenoviruses (Ads)-the most diverse yet underexplored group of Ads-have been used to develop improved gene vectors. The low seroprevalence in humans of adenovirus serotype 43 (Ad43), an otherwise unstudied species D Ad, identified this rare serotype as an attractive new human gene therapy vector platform. Thus, in this study we wished to assess biological properties of Ad43 essential to its vectorization. We found that (1) Ad43 virions do not bind blood coagulation factor X and cause low random transduction upon vascular delivery; (2) they clear host tissues more quickly than do traditionally used Ad5 vectors; (3) Ad43 uses CD46 as primary receptor; (4) Ad43 can use integrins as alternative primary receptors. As the first step toward vectorization of Ad43, we demonstrated that the primary receptor specificity of the Ad43 fiber can be altered to achieve infection via Her2, an established oncotarget. Whereas this modification required use of the Ad5 fiber shaft, the presence of this domain in chimeric virions did not make them susceptible for neutralization by anti-Ad5 antibodies. PMID- 27462786 TI - Polo-like kinase 3 and phosphoT273 caspase-8 are associated with improved local tumor control and survival in patients with anal carcinoma treated with concomitant chemoradiotherapy. AB - We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV 16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT. PMID- 27462787 TI - Radiation driven epithelial-mesenchymal transition is mediated by Notch signaling in breast cancer. AB - Epithelial to mesenchymal transition (EMT) is developmental process associated with cancer metastasis. Here, we found that breast carcinoma cells adopt epithelial-to-mesenchymal transition (EMT) in response to fractionated-radiation. Importantly, we show that Notch signaling is highly activated in fractionally irradiated tumors as compared to non-irradiated tumors that are accompanied by an EMT. Moreover, we uncovered the mechanism of Notch-driven EMT, in which Notch enhanced EMT through IL-6/JAK/STAT3 signaling axis in mammary tumor cells. Collectively, we present converging evidence from our studies that Notch2 is a critical mediator of radiation-induced EMT and responsible for induced malignant tumor growth. PMID- 27462788 TI - MACC1 is post-transcriptionally regulated by miR-218 in colorectal cancer. AB - Metastasis is a multistep molecular network process, which is lethal for more than 90% of the cancer patients. Understanding the regulatory functions of metastasis-inducing molecules is in high demand for improved therapeutic cancer approaches. Thus, we studied the post-transcriptional regulation of the crucial carcinogenic and metastasis-mediating molecule metastasis associated in colon cancer 1 (MACC1). In silico analysis revealed MACC1 as a potential target of miR 218, a tumor suppressor miRNA. Expression of these two molecules inversely correlated in colorectal cancer (CRC) cell lines. In a cohort of CRC patient tissues (n = 59), miR-218 is significantly downregulated and MACC1 is upregulated compared with normal mucosa. Luciferase reporter assays with a construct of the MACC1-3'-UTR harboring either the wild type or the mutated miR-218 seed sequence confirmed the specificity of the targeting. miR-218 inhibited significantly MACC1 protein expression, and consistently, MACC1-mediated migration, invasion and colony formation in CRC cells. Anti-miR-218 enhanced the MACC1-mediated migration, invasion and colony formation. Similar findings were observed in the gastric cancer cell line MKN-45. Further, we performed methylation-specific PCR of the SLIT2 and SLIT3 promoter, where miR-218 is encoded in intronic regions. The SLIT2 and SLIT3 promoters are hypermethylated in CRC cell lines. miR-218 and SLIT2 expressions correlated positively. Methyltransferase inhibitor 5 Azacytidine induced miR-218 expression and inhibited the expression of its target MACC1. We also determined that MACC1 has alternative polyadenylation (APA) sites, which results in different lengths of 3'-UTR variants in a CRC cell line. Taken together, miR-218 is post-transcriptionally inhibiting the MACC1 expression and its metastasis-inducing abilities. PMID- 27462801 TI - Tunable Metal-Catalyzed Heterocyclization Reactions of Allenic Amino Alcohols: An Experimental and Theoretical Study. AB - Controlled preparation of 2,5-dihydro-1H-pyrroles, 3,6-dihydro-2H-pyrans, and pyrroles has been achieved through switchable chemo- and regioselectivity in the metal-catalyzed heterocyclization reactions of allenic amino alcohols. The gold catalyzed cycloisomerization reaction of alpha-amino-beta-hydroxyallenes was effective as 5-endo cyclization by addition of amino functionality to the distal allene carbon to yield enantiopure 2,5-dihydro-1H-pyrroles, whereas their palladium-catalyzed cyclizative coupling reactions furnished 3,6-dihydro-2H pyrans through a chemo- and regioselective 6-endo cycloetherification. Conversely, the gold-catalyzed heterocyclization reaction of beta-amino-gamma hydroxyallenes generated exclusively pyrrole derivatives. These results could be explained through a chemo- and regioselective 5-exo aminocyclization to the central allene carbon followed by aromatization. Chemo- and regioselectivity depend on both linker elongation as well as the type of catalyst. This behavior can be justified by means of density functional theory calculations. PMID- 27462789 TI - IL-17E synergizes with EGF and confers in vitro resistance to EGFR-targeted therapies in TNBC cells. AB - Estrogen receptor-, progesterone receptor- and HER2-negative breast cancers, also known as triple-negative breast cancers (TNBCs), have poor prognoses and are refractory to current therapeutic agents, including epidermal growth factor receptor (EGFR) inhibitors. Resistance to anti-EGFR therapeutic agents is often associated with sustained kinase phosphorylation, which promotes EGFR activation and translocation to the nucleus and prevents these agents from acting on their targets. The mechanisms underlying this resistance have not been fully elucidated. In addition, the IL-17E receptor is overexpressed in TNBC tumors and is associated with a poor prognosis. We have previously reported that IL-17E promotes TNBC resistance to anti-mitotic therapies. Here, we investigated whether IL-17E promotes TNBC resistance to anti-EGFR therapeutic agents by exploring the link between the IL-17E/IL-17E receptor axis and EGF signaling. We found that IL 17E, similarly to EGF, activates the EGFR in TNBC cells that are resistant to EGFR inhibitors. It also activates the PYK-2, Src and STAT3 kinases, which are essential for EGFR activation and nuclear translocation. IL-17E binds its specific receptor, IL-17RA/IL17RB, on these TNBC cells and synergizes with the EGF signaling pathway, thereby inducing Src-dependent EGFR transactivation and pSTAT3 and pEGFR translocation to the nucleus. Collectively, our data indicate that the IL-17E/IL-17E receptor axis may underlie TNBC resistance to EGFR inhibitors and suggest that inhibiting IL-17E or its receptor in combination with EGFR inhibitor administration may improve TNBC management. PMID- 27462802 TI - Copper-catalyzed intermolecular chloroazidation of alpha,beta-unsaturated amides. AB - A highly practical copper-catalyzed intermolecular chloroazidation of alpha,beta unsaturated amides has been described, giving a series of azidochlorides in good to-excellent yields. The stable azidoiodine(iii) reagent and SOCl2 were used as azide and chlorine sources, respectively. The synthetic applications of this protocol were also explored by a variety of synthetically useful transformations. PMID- 27462803 TI - Chemical tools for interrogating inositol pyrophosphate structure and function. AB - The inositol pyrophosphates (PP-InsPs) are a unique group of intracellular messengers that represent some of the most highly phosphorylated molecules in nature. Genetic perturbation of the PP-InsP biosynthetic network indicates a central role for these metabolites in maintaining cellular energy homeostasis and in controlling signal transduction networks. However, despite their discovery over two decades ago, elucidating their physiologically relevant isomers, the biochemical pathways connecting these molecules to their associated phenotypes, and their modes of signal transduction has often been stymied by technical challenges. Many of the advances in understanding these molecules to date have been facilitated by the total synthesis of the various PP-InsP isomers and by the development of new methods that are capable of identifying their downstream signalling partners. Chemical tools have also been developed to distinguish between the proposed PP-InsP signal transduction mechanisms: protein binding, and a covalent modification of proteins termed protein pyrophosphorylation. In this article, we review these recent developments, discuss how they have helped to illuminate PP-InsP structure and function, and highlight opportunities for future discovery. PMID- 27462804 TI - Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. AB - INTRODUCTION: ACE-031 is a fusion protein of activin receptor type IIB and IgG1 Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). METHODS: ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo controlled, ascending-dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. RESULTS: ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6-minute walk test (6MWT) distance in the ACE-031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. CONCLUSION: ACE-031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458-464, 2017. PMID- 27462805 TI - Structures and Surface Properties of "Cyclic" Polyoxyethylene Alkyl Ethers: Unusual Behavior of Cyclic Surfactants in Water. AB - The cyclization of amphiphiles has emerged as an attractive strategy for inducing remarkable properties in these materials without changing their chemical composition. In this study, we successfully synthesized three cyclic polyoxyethylene dodecyl ethers (c-POEC12's) with different ring sizes and explored the effects of their topology on their surface and self-assembly properties related to their function, comparing them with those of their linear counterparts (l-POEC12's). The surface activity of the c-POEC12's remained almost constant despite the change in their hydrophobic and hydrophilic balance (HLB) value, while that of the l-POEC12's decreased with an increase in the HLB value as general surfactants. In contrast to the normal micelles seen in the case of the l-POEC12's (3.4-9.7 nm), the cyclization of the POEC12's resulted in the formation of large spherical structures 72.8-256.8 nm in size. It also led to a dramatic decrease of 28 degrees C in the cloud point temperature. Furthermore, the cyclization of the POEC12's markedly suppressed the rate of protease hydrolysis caused by the surfactants. The initial rate of reduction of a detergent enzyme from Bacillus licheniformis was increased by more than 40% in the case of c-POE600C12 and c-POE1000C12, even though they exhibited surface activities almost equal to or higher than those of their linear counterparts. These results suggest that cyclization induces unusual aqueous behaviors in POEC12, making the surfactant milder with respect to detergent enzymes while ensuring it exhibits increased surface activity. PMID- 27462806 TI - An evolutionarily conserved pathway controls proteasome homeostasis. AB - The proteasome is essential for the selective degradation of most cellular proteins, but how cells maintain adequate amounts of proteasome is unclear. Here we show that there is an evolutionarily conserved signalling pathway controlling proteasome homeostasis. Central to this pathway is TORC1, the inhibition of which induced all known yeast 19S regulatory particle assembly-chaperones (RACs), as well as proteasome subunits. Downstream of TORC1 inhibition, the yeast mitogen activated protein kinase, Mpk1, acts to increase the supply of RACs and proteasome subunits under challenging conditions in order to maintain proteasomal degradation and cell viability. This adaptive pathway was evolutionarily conserved, with mTOR and ERK5 controlling the levels of the four mammalian RACs and proteasome abundance. Thus, the central growth and stress controllers, TORC1 and Mpk1/ERK5, endow cells with a rapid and vital adaptive response to adjust proteasome abundance in response to the rising needs of cells. Enhancing this pathway may be a useful therapeutic approach for diseases resulting from impaired proteasomal degradation. PMID- 27462807 TI - The structural basis of modified nucleosome recognition by 53BP1. AB - DNA double-strand breaks (DSBs) elicit a histone modification cascade that controls DNA repair. This pathway involves the sequential ubiquitination of histones H1 and H2A by the E3 ubiquitin ligases RNF8 and RNF168, respectively. RNF168 ubiquitinates H2A on lysine 13 and lysine 15 (refs 7, 8) (yielding H2AK13ub and H2AK15ub, respectively), an event that triggers the recruitment of 53BP1 (also known as TP53BP1) to chromatin flanking DSBs. 53BP1 binds specifically to H2AK15ub-containing nucleosomes through a peptide segment termed the ubiquitination-dependent recruitment motif (UDR), which requires the simultaneous engagement of histone H4 lysine 20 dimethylation (H4K20me2) by its tandem Tudor domain. How 53BP1 interacts with these two histone marks in the nucleosomal context, how it recognizes ubiquitin, and how it discriminates between H2AK13ub and H2AK15ub is unknown. Here we present the electron cryomicroscopy (cryo-EM) structure of a dimerized human 53BP1 fragment bound to a H4K20me2-containing and H2AK15ub-containing nucleosome core particle (NCP-ubme) at 4.5 A resolution. The structure reveals that H4K20me2 and H2AK15ub recognition involves intimate contacts with multiple nucleosomal elements including the acidic patch. Ubiquitin recognition by 53BP1 is unusual and involves the sandwiching of the UDR segment between ubiquitin and the NCP surface. The selectivity for H2AK15ub is imparted by two arginine fingers in the H2A amino terminal tail, which straddle the nucleosomal DNA and serve to position ubiquitin over the NCP-bound UDR segment. The structure of the complex between NCP-ubme and 53BP1 reveals the basis of 53BP1 recruitment to DSB sites and illuminates how combinations of histone marks and nucleosomal elements cooperate to produce highly specific chromatin responses, such as those elicited following chromosome breaks. PMID- 27462808 TI - A radio-pulsing white dwarf binary star. AB - White dwarfs are compact stars, similar in size to Earth but approximately 200,000 times more massive. Isolated white dwarfs emit most of their power from ultraviolet to near-infrared wavelengths, but when in close orbits with less dense stars, white dwarfs can strip material from their companions and the resulting mass transfer can generate atomic line and X-ray emission, as well as near- and mid-infrared radiation if the white dwarf is magnetic. However, even in binaries, white dwarfs are rarely detected at far-infrared or radio frequencies. Here we report the discovery of a white dwarf/cool star binary that emits from X ray to radio wavelengths. The star, AR Scorpii (henceforth AR Sco), was classified in the early 1970s as a delta-Scuti star, a common variety of periodic variable star. Our observations reveal instead a 3.56-hour period close binary, pulsing in brightness on a period of 1.97 minutes. The pulses are so intense that AR Sco's optical flux can increase by a factor of four within 30 seconds, and they are also detectable at radio frequencies. They reflect the spin of a magnetic white dwarf, which we find to be slowing down on a 107-year timescale. The spin-down power is an order of magnitude larger than that seen in electromagnetic radiation, which, together with an absence of obvious signs of accretion, suggests that AR Sco is primarily spin-powered. Although the pulsations are driven by the white dwarf's spin, they mainly originate from the cool star. AR Sco's broadband spectrum is characteristic of synchrotron radiation, requiring relativistic electrons. These must either originate from near the white dwarf or be generated in situ at the M star through direct interaction with the white dwarf's magnetosphere. PMID- 27462809 TI - Cell biology: The TORC1 pathway to protein destruction. PMID- 27462810 TI - A trans-synaptic nanocolumn aligns neurotransmitter release to receptors. AB - Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular 'nanocolumn'. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency. PMID- 27462811 TI - Heating of Jupiter's upper atmosphere above the Great Red Spot. AB - The temperatures of giant-planet upper atmospheres at mid- to low latitudes are measured to be hundreds of degrees warmer than simulations based on solar heating alone can explain. Modelling studies that focus on additional sources of heating have been unable to resolve this major discrepancy. Equatorward transport of energy from the hot auroral regions was expected to heat the low latitudes, but models have demonstrated that auroral energy is trapped at high latitudes, a consequence of the strong Coriolis forces on rapidly rotating planets. Wave heating, driven from below, represents another potential source of upper atmospheric heating, though initial calculations have proven inconclusive for Jupiter, largely owing to a lack of observational constraints on wave parameters. Here we report that the upper atmosphere above Jupiter's Great Red Spot--the largest storm in the Solar System--is hundreds of degrees hotter than anywhere else on the planet. This hotspot, by process of elimination, must be heated from below, and this detection is therefore strong evidence for coupling between Jupiter's lower and upper atmospheres, probably the result of upwardly propagating acoustic or gravity waves. PMID- 27462812 TI - Structure of the adenosine A(2A) receptor bound to an engineered G protein. AB - G-protein-coupled receptors (GPCRs) are essential components of the signalling network throughout the body. To understand the molecular mechanism of G-protein mediated signalling, solved structures of receptors in inactive conformations and in the active conformation coupled to a G protein are necessary. Here we present the structure of the adenosine A(2A) receptor (A(2A)R) bound to an engineered G protein, mini-Gs, at 3.4 A resolution. Mini-Gs binds to A(2A)R through an extensive interface (1,048 A2) that is similar, but not identical, to the interface between Gs and the beta2-adrenergic receptor. The transition of the receptor from an agonist-bound active-intermediate state to an active G-protein bound state is characterized by a 14 A shift of the cytoplasmic end of transmembrane helix 6 (H6) away from the receptor core, slight changes in the positions of the cytoplasmic ends of H5 and H7 and rotamer changes of the amino acid side chains Arg3.50, Tyr5.58 and Tyr7.53. There are no substantial differences in the extracellular half of the receptor around the ligand binding pocket. The A(2A)R-mini-Gs structure highlights both the diversity and similarity in G-protein coupling to GPCRs and hints at the potential complexity of the molecular basis for G-protein specificity. PMID- 27462813 TI - Corrigendum: Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. PMID- 27462814 TI - Corrigendum: Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. PMID- 27462815 TI - eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. AB - Eukaryotic mRNAs contain a 5' cap structure that is crucial for recruitment of the translation machinery and initiation of protein synthesis. mRNA recognition is thought to require direct interactions between eukaryotic initiation factor 4E (eIF4E) and the mRNA cap. However, translation of numerous capped mRNAs remains robust during cellular stress, early development, and cell cycle progression despite inactivation of eIF4E. Here we describe a cap-dependent pathway of translation initiation in human cells that relies on a previously unknown cap binding activity of eIF3d, a subunit of the 800-kilodalton eIF3 complex. A 1.4 A crystal structure of the eIF3d cap-binding domain reveals unexpected homology to endonucleases involved in RNA turnover, and allows modelling of cap recognition by eIF3d. eIF3d makes specific contacts with the cap, as exemplified by cap analogue competition, and these interactions are essential for assembly of translation initiation complexes on eIF3-specialized mRNAs such as the cell proliferation regulator c-Jun (also known as JUN). The c-Jun mRNA further encodes an inhibitory RNA element that blocks eIF4E recruitment, thus enforcing alternative cap recognition by eIF3d. Our results reveal a mechanism of cap dependent translation that is independent of eIF4E, and illustrate how modular RNA elements work together to direct specialized forms of translation initiation. PMID- 27462816 TI - Neuroscience: Nanocolumns at the heart of the synapse. PMID- 27462819 TI - Erratum. PMID- 27462817 TI - A novel excitatory network for the control of breathing. AB - Breathing must be tightly coordinated with other behaviours such as vocalization, swallowing, and coughing. These behaviours occur after inspiration, during a respiratory phase termed postinspiration. Failure to coordinate postinspiration with inspiration can result in aspiration pneumonia, the leading cause of death in Alzheimer's disease, Parkinson's disease, dementia, and other neurodegenerative diseases. Here we describe an excitatory network that generates the neuronal correlate of postinspiratory activity in mice. Glutamatergic cholinergic neurons form the basis of this network, and GABA (gamma-aminobutyric acid)-mediated inhibition establishes the timing and coordination relative to inspiration. We refer to this network as the postinspiratory complex (PiCo). The PiCo has autonomous rhythm-generating properties and is necessary and sufficient for postinspiratory activity in vivo.The PiCo also shows distinct responses to neuromodulators when compared to other excitatory brainstem networks. On the basis of the discovery of the PiCo, we propose that each of the three phases of breathing is generated by a distinct excitatory network: the pre-Botzinger complex, which has been linked to inspiration; the PiCo, as described here for the neuronal control of postinspiration; and the lateral parafacial region (pF(L)), which has been associated with active expiration, a respiratory phase that is recruited during high metabolic demand. PMID- 27462820 TI - Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel. AB - OBJECTIVE: The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by gamma-aminobutyric acidB receptor (GABAB R) agonists. The Ts mouse contains the core genomic triplication of the DS critical region, which includes 3 copies of the Kcnj6 gene that encodes the GABAB R-coupled G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) channel. We test the hypothesis that GIRK2 is necessary for the GABAB R agonist-induced infantile spasms phenotype in Ts. METHODS: We assessed the result of either genetic or pharmacological knockdown of the GIRK2 channel in Ts brain upon the GABAB R agonist-induced infantile spasms phenotype in the Ts mouse model of DS. As well, we examined GABAB R currents in hippocampal neurons prepared from GIRK2-trisomic Ts control mice and GIRK2-disomic Ts mice in which Kcnj6 had been genetically knocked down from 3 to 2 copies. RESULTS: The reduction of the copy number of Kcnj6 in Ts mice rescued the GABAB R agonist-induced infantile spasms phenotype. There was an increase in GABAB R-mediated GIRK2 currents in GIRK2 trisomic Ts mouse hippocampal neurons, which were normalized in the GIRK2-disomic Ts mice. Similarly, pharmacological knockdown of the GIRK2 channel in Ts brain using the GIRK antagonist tertiapin-Q also rescued the GABAB R agonist-induced infantile spasms phenotype in Ts mutants. INTERPRETATION: The GABAB R-coupled GIRK2 channel is necessary for the GABAB R agonist-induced infantile spasms phenotype in the Ts mouse and may represent a novel therapeutic target for the treatment of infantile spasms in DS. Ann Neurol 2016;80:511-521. PMID- 27462821 TI - Mitochondrial biogenesis and clearance: a balancing act. AB - Mitochondria are semi-autonomous organelles of prokaryotic origin that are postulated to have been acquired by eukaryotic cells through an early endosymbiotic event. Except for their main role in energy production, they are also implicated in fundamental cellular processes, including ion homeostasis, lipid metabolism, and initiation of apoptotic cell death. Perturbed mitochondrial function has been correlated with severe human pathologies such as type-2 diabetes, cardiovascular, and neurodegenerative diseases. Thus, proper mitochondrial physiology is a prerequisite for health and survival. Cells have developed sophisticated and elaborate mechanisms to adapt to stress conditions and alterations in metabolic demands, by regulating mitochondrial number and function. Hence, the generation of new and the removal of damaged or unwanted mitochondria are highly regulated processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Here, we survey recent research findings that advance our understanding and highlight the importance of the underlying molecular mechanisms. PMID- 27462822 TI - The influence of altered functional loading and posterior bite-blocks on the periodontal ligament space and alveolar bone thickness in rats. AB - OBJECTIVES: Posterior bite-blocks are resin-based structures elevating the occlusion and creating intrusive force on the posterior teeth. Bite-blocks were applied to the molars of growing rats and a hard and soft diet was used to create altered functional masticatory forces. The aim of the present investigation was to study the effect of this appliance on the periodontal ligament space and alveolar bone thickness when combined with altered masticatory forces. MATERIAL AND METHODS: Fifty-two four-week-old rats were divided into two groups, hard and soft diet. Two weeks later, half of them received a bite-block appliance, creating four groups: control hard (CH), control soft (CS), bite-block hard (BH) and bite-block soft (BS). All were sacrificed at age of 10 weeks. Their heads were scanned by micro-CT and periodontal ligament space (PDL) width, cross sectional alveolar socket surface and alveolar bone thickness were measured. Analysis of variance (ANOVA) was used to compare the groups. RESULTS: The PDL was 9.2% thinner in the CS group (p < 0.001) and 20.7% in the bite-block groups (p < 0.001) compared to the CH group. Within each of the four groups, the mesiodistal PDL space was larger than the palatobuccal. The alveolar bone was thinner by 5.8% (p = 0.018) in the CS group, 10.7% in the BH group (p < 0.001) and 16.7% in the BS group (p < 0.001) compared to the CH group. CONCLUSIONS: Young rats wearing posterior bite-blocks have narrower PDL space and thinner alveolar bone compared to controls. When fed a soft diet, the alveolar bone is even thinner but the PDL showed no difference. PMID- 27462823 TI - Air Pollution and Exercise: A Perspective From China. AB - China is experiencing an air pollution crisis, which has already had a significantly negative impact on the health of the Chinese people. Although exercising is considered a useful means to prevent chronic diseases, it could actually lead to adverse effects due to extra exposure to polluted air when done outdoors. After a brief description of the rather scary situation in China, critical issues and challenges related to exercising in polluted air are outlined. The author calls for the exercise science community to work together to address these issues and challenges so that the health status of the current populations can be improved, the relationship among environment, exercising, and human health can be better understood, and future generations can live in a healthier environment. PMID- 27462824 TI - Enantioselective rhodium/ruthenium photoredox catalysis en route to chiral 1,2 aminoalcohols. AB - A rhodium-based chiral Lewis acid catalyst combined with [Ru(bpy)3](PF6)2 as a photoredox sensitizer allows for the visible-light-activated redox coupling of alpha-silylamines with 2-acyl imidazoles to afford, after desilylation, 1,2-amino alcohols in yields of 69-88% and with high enantioselectivity (54-99% ee). The reaction is proposed to proceed via an electron exchange between the alpha silylamine (electron donor) and the rhodium-chelated 2-acyl imidazole (electron acceptor), followed by a stereocontrolled radical-radical reaction. Substrate scope and control experiments reveal that the trimethylsilyl group plays a crucial role in this reductive umpolung of the carbonyl group. PMID- 27462825 TI - Gate-Tuned Thermoelectric Power in Black Phosphorus. AB - The electric field effect is a useful means of elucidating intrinsic material properties as well as for designing functional devices. The electric-double-layer transistor (EDLT) enables the control of carrier density in a wide range, which is recently proved to be an effective tool for the investigation of thermoelectric properties. Here, we report the gate-tuning of thermoelectric power in a black phosphorus (BP) single crystal flake with the thickness of 40 nm. Using an EDLT configuration, we successfully control the thermoelectric power (S) and find that the S of ion-gated BP reached +510 MUV/K at 210 K in the hole depleted state, which is much higher than the reported bulk single crystal value of +340 MUV/K at 300 K. We compared this experimental data with the first principles-based calculation and found that this enhancement is qualitatively explained by the effective thinning of the conduction channel of the BP flake and nonuniformity of the channel owing to the gate operation in a depletion mode. Our results provide new opportunities for further engineering BP as a thermoelectric material in nanoscale. PMID- 27462826 TI - Analytic Gradients for the Effective Fragment Molecular Orbital Method. AB - The analytic gradient for the Coulomb, polarization, exchange-repulsion, and dispersion terms of the fully integrated effective fragment molecular orbital (EFMO) method is derived and the implementation is discussed. The derivation of the EFMO analytic gradient is more complicated than that for the effective fragment potential (EFP) gradient, because the geometry of each EFP fragment is flexible (not rigid) in the EFMO approach. The accuracy of the gradient is demonstrated by comparing the EFMO analytic gradient with the numeric gradient for several systems, and by assessing the energy conservation during an EFMO NVE ensemble molecular dynamics simulation of water molecules. In addition to facilitating accurate EFMO geometry optimizations, this allows calculations with flexible EFP fragments to be performed. PMID- 27462827 TI - Optimizing the diagnostic testing of Clostridium difficile infection. AB - INTRODUCTION: Clostridium difficile infection (CDI) is the leading cause of hospital-acquired diarrhea and is associated with a considerable health and cost burden. However, there is still not a clear consensus on the best laboratory diagnosis approach and a wide variation of testing methods and strategies can be encountered. AREAS COVERED: We aim to review the most practical aspects of CDI diagnosis providing our own view on how to optimize CDI diagnosis. Expert commentary: Laboratory diagnosis in search of C. difficile toxins should be applied to all fecal diarrheic samples reaching the microbiology laboratory in patients > 2 years old, with or without classic risk factors for CDI. Detection of toxins either directly in the fecal sample or in the bacteria isolated in culture confirm CDI in the proper clinical setting. Nuclear Acid Assay techniques (NAAT) allow to speed up the process with epidemiological and therapeutic consequences. PMID- 27462828 TI - Factors Controlling the Chemoselectivity in the Oxidation of Olefins by Nonheme Manganese(IV)-Oxo Complexes. AB - We report the oxidation of cyclic olefins, such as cyclohexene, cyclohexene-d10, and cyclooctene, by mononuclear nonheme manganese(IV)-oxo (Mn(IV)O) and triflic acid (HOTf)-bound Mn(IV)O complexes. In the oxidation of cyclohexene, the Mn(IV)O complexes prefer the C-H bond activation to the C?C double bond epoxidation, whereas the C?C double bond epoxidation becomes a preferred reaction pathway in the cyclohexene oxidation by HOTf-bound Mn(IV)O complexes. In contrast, the oxidation of cyclohexene-d10 and cyclooctene by the Mn(IV)O complexes occurs predominantly via the C?C double bond epoxidation. This conclusion is drawn from the product analysis and kinetic studies of the olefin oxidation reactions, such as the epoxide versus allylic oxidation products, the formation of Mn(II) versus Mn(III) products, and the kinetic analyses. Overall, the experimental results suggest that the energy barrier of the C?C double bond epoxidation is very close to that of the allylic C-H bond activation in the oxidation of cyclic olefins by high-valent metal-oxo complexes. Thus, the preference of the reaction pathways is subject to changes upon small manipulation of the reaction environments, such as the supporting ligands and metal ions in metal-oxo species, the presence of HOTf (i.e., HOTf-bound Mn(IV)O species), and the allylic C-H(D) bond dissociation energies of olefins. This is confirmed by DFT calculations in the oxidation of cyclohexene and cyclooctene, which show multiple pathways with similar rate limiting energy barriers and depending on the allylic C-H bond dissociation energies. In addition, the possibility of excited state reactivity in the current system is confirmed for epoxidation reactions. PMID- 27462829 TI - Hox-Mediated Spatial and Temporal Coding of Stem Cells in Homeostasis and Neoplasia. AB - Hox genes are fundamental components of embryonic patterning and morphogenesis with expression persisting into adulthood. They are also implicated in the development of diseases, particularly neoplastic transformations. The tight spatio-temporal regulation of Hox genes in concordance with embryonic patterning is an outstanding feature of these genes. In this review we have systematically analyzed Hox functions within the stem/progenitor cell compartments and asked whether their temporo-spatial topography is retained within the stem cell domain throughout development and adulthood. In brief, evidence support involvement of Hox genes at several levels along the stem cell hierarchy, including positional identity, stem cell self-renewal, and differentiation. There is also strong evidence to suggest a role for Hox genes during neoplasia. Although fundamental questions are yet to be addressed through more targeted and high- throughput approaches, existing evidence suggests a central role for Hox genes within a continuum along the developmental axes persisting into adult homeostasis and disease. PMID- 27462830 TI - Learning and Memory in Adolescent Moderate, Binge, and Extreme-Binge Drinkers. AB - BACKGROUND: Binge drinking has been linked to neurocognitive disadvantages in youth, but it is unclear whether drinking at particularly heavy levels uniquely affects neurocognitive performance. This study prospectively examined (1) whether initiating moderate, binge, or extreme-binge drinking in adolescence differentially influences subsequent learning and memory performances, and (2) whether dosage of alcohol consumption is linearly associated with changes in learning and memory over 6 years of adolescence. METHODS: Participants, who later transitioned into drinking, were administered verbal learning and memory (VLM) assessments at project intake prior to the onset of substance use (age 12 to 16 years), and at follow-up approximately 6 years later (N = 112). Participants were grouped based on alcohol involvement at follow-up as follows: moderate (<=4 drinks per occasion), binge (5+ drinks per occasion), or extreme-binge (10+ drinks per occasion) drinkers. RESULTS: Despite equivalent performances prior to onset of drinking, extreme-binge drinkers performed worse than moderate drinkers on verbal learning, and cued and free short delayed recall (ps < 0.05); binge drinkers did not differ from the other groups. No distinct thresholds in alcohol quantity to differentiate the 3 groups were detected, but estimated peak blood alcohol concentrations were linearly associated with verbal learning (beta^ = 0.24), and immediate (beta^ = -0.27), short delay free (beta^ = -0.28) and cued (beta^ = -0.30), and long delay free (beta^ = -0.24) and cued (beta^ = -0.27) recall (ps < 0.05). CONCLUSIONS: Drinking quantity during adolescence appears to adversely affect VLM in a dose-dependent manner. The acquisition of new verbal information may be particularly affected, notably for those who initiated drinking 10+ drinks in an occasion. Although classification of drinkers into categories remains critical in the study of alcohol, it is important to consider that subtle differences may exist within drinking categories. PMID- 27462831 TI - LILRA3 deficiency is not involved in the giant cell arteritis and systemic sclerosis predisposition. PMID- 27462832 TI - The insulin-like growth factor I receptor regulates glucose transport by astrocytes. AB - Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity. GLIA 2016;64:1962-1971. PMID- 27462833 TI - Chemotherapy With CMF for Triple-Negative Breast Cancer With Carcinoma Erysipelatoides. PMID- 27462834 TI - Multimodal Assessment Reveals Late-Onset Hemispheric Shift of Language in a Child with Meningocerebral Dysplasia. AB - We report on a girl with progressive left frontal tissue destruction starting at the age of almost 8 years. She manifested acutely with epileptic seizures accompanied by Broca aphasia as well as transient right hemiparesis. Due to refractory epilepsy developing over the next years, which originated from the left frontal lobe, the decision was made to proceed to epilepsy surgery. By then, her language functions had recovered despite progressive left frontal tissue destruction, raising the possibility of a hemispheric shift of language. Clinical functional magnetic resonance imaging (fMRI) was conducted to localize brain regions involved in language production. A complex pattern of clear right hemispheric dominance, but with some left-sided contribution was found. However, a Wada test suggested the left hemisphere to be critical, seemingly contradicting fMRI. Invasive electroencephalogram recordings could reconcile these results by identifying the fMRI-detected, residual left-sided activation as being relevant for speech production. Only by combining the localizing information from fMRI with the information obtained by two invasive procedures could the unusual pattern of late-onset language reorganization be uncovered. This allowed for extensive left frontal resection, with histology confirming meningocerebral angiodysplasia. Postoperatively, language functions were preserved and seizure outcome was excellent. The implications of our findings for presurgical assessments in children are discussed. PMID- 27462835 TI - Standardizing and monitoring the delivery of surgical interventions in randomized clinical trials. AB - BACKGROUND: The complexity of surgical interventions has major implications for the design of RCTs. Trials need to consider how and whether to standardize interventions so that, if successful, they can be implemented in practice. Although guidance exists for standardizing non-pharmaceutical interventions in RCTs, their application to surgery is unclear. This study reports new methods for standardizing the delivery of surgical interventions in RCTs. METHODS: Descriptions of 160 surgical interventions in existing trial reports and protocols were identified. Initially, ten reports were scrutinized in detail using a modified framework approach for the analysis of qualitative data, which informed the development of a preliminary typology. The typology was amended with iterative sequential application to all interventions. Further testing was undertaken within ongoing multicentre RCTs. RESULTS: The typology has three parts. Initially, the overall technical purpose of the intervention is described (exploration, resection and/or reconstruction) in order to establish its constituent components and steps. This detailed description of the intervention is then used to establish whether and how each component and step should be standardized, and the standards documented within the trial protocol. Finally, the typology provides a framework for monitoring the agreed intervention standards during the RCT. Pilot testing within ongoing RCTs enabled standardization of the interventions to be agreed, and case report forms developed to capture deviations from these standards. CONCLUSION: The typology provides a framework for use during trial design to standardize the delivery of surgical interventions and document these details within protocols. Application of this typology to future RCTs may clarify details of the interventions under evaluation and help successful interventions to be implemented. PMID- 27462836 TI - Hands-on Training in the Operating Room as a Method of Continuing Education for Surgeons in Practice. PMID- 27462837 TI - Postcombustion CO2 Capture Solvent Characterization Employing the Explicit Solvation Shell Model and Continuum Solvation Models. AB - A study on the explicit and implicit solvation models for calculation of solvation free energy of ions and pKa of amino acids presented recently [ Gupta , M. ; J. Chem. THEORY: Comput. 2013 , 9 , 5021 - 5031 ] is extended for the study of amines and alkanolamines. Solvation free energies and pKa's of a data set of 25 amines and alkanolamines are calculated using the explicit solvation shell (ESS) model given by da Silva et al. [ J. Phys. Chem. A 2009 , 113 , 6404 ] and continuum solvation models (polarized continuum solvation model (PCM), SM8T, and DivCon). An extensive overview involving the gas-phase basicity and proton affinity, calculated using density functional methods (B3LYP/6-311++G(d,p)) and composite methods (G3MP2B3, G3MP2, CBS-QB3, G4MP2) and compared with corresponding experimental results for amines and alkanolamines, is also included in the present work. This data set was selected based on the components' potential as solvents for postcombustion CO2 capture (PCC) processes. Results of gaseous-phase thermochemistry and pKa obtained from different models employed in this work are analyzed against experimental results for obtaining error estimates involved in each theoretical model. The ESS model for the calculation of the solvation free energy of ions combined with composite methods for gaseous-phase thermochemistry is found to give reasonable accuracy for pKa calculations of amines and alkanolamines and thereby constitutes a method for validation of pKa for new potential PCC solvents. PMID- 27462838 TI - Acute Rheumatic Fever: An Evidence-Based Approach To Diagnosis And Initial Management. AB - Acute rheumatic fever is an inflammatory reaction involving the joints, heart, and nervous system that occurs after a group A streptococcal infection. It typically presents as a febrile illness with clinical manifestations that could include arthritis, carditis, skin lesions, or abnormal movements. Of these, the cardiac manifestations of acute rheumatic fever are most concerning, as children may present in acute heart failure and may go on to develop valvular insufficiency or stenosis. Because this is a rare presentation to emergency departments in developed countries, it is crucial for clinicians to keep a broad differential when presented with clinical presentations suspicious for acute rheumatic fever. This issue focuses on the clinical evaluation and treatment of patients with acute rheumatic fever by offering a thorough review of the literature on diagnosis and recommendations on appropriate treatment. PMID- 27462840 TI - A tribute to Dr. Klaus E. Kuettner. PMID- 27462841 TI - Erratum: Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA. AB - [This corrects the article DOI: 10.1038/celldisc.2015.40.]. PMID- 27462842 TI - A systematic review on the factors associated with positive experiences in carers of someone with cancer. AB - The aim of this review was to identify the factors associated with positive experiences in non-professional carers of someone with a cancer diagnosis. A systematic search of the following electronic databases was undertaken: Cochrane Library, CINAHL, PsycINFO, SocINDEX and Medline. Literature was searched using terms relating to cancer, caring and positive experiences. Additional records were identified through a manual search of relevant reference lists. The search included studies published in English from 1990 to June 2015. Two raters were involved in data extraction, quality appraisal, coding, synthesis and analysis. Evolutionary concept analysis was used as a guiding framework in order to focus on attributes associated with positive experiences. Fifty-two articles were included in this review. Analysis identified four overarching attributes: "gender," "personal resources," "finding meaning" and "social context." Despite the challenges associated with caring, this combination of internal and external factors enabled some carers to report positive experiences related to caring. This knowledge may be clinically helpful when designing supportive interventions. Strengths and limitations of these claims are discussed. Systematic review registration number: CRD42014014129. PMID- 27462843 TI - [Prevalence of intimate partner violence and associated factors after disclosing the diagnosis of a sexually transmissible disease]. AB - The objective of this study was to investigate factors associated with intimate partner violence after disclosing the diagnosis of sexually transmissible diseases (STDs) in Fortaleza, Ceara State, Brazil. This cross-sectional study enrolled 221 individuals treated at STD clinics. Multivariate logistic regression was performed. A total of 28.1% of individuals committed some type of intimate partner violence after disclosure of the diagnosis. Committing intimate partner violence was associated with alcohol use (OR = 2.79; 95%CI: 1.25-6.22; p = 0.012), the partner having relations with someone else during the current relationship (OR = 4.71; 95%CI: 2.24-9.91; p = 0.000), a history of violence prior to the STD (OR = 2.87; 95%CI: 1.22-6.73; p = 0.015), and having suffered violence after diagnosis of the STD (OR = 6.53; 95%CI: 3.06-13.93; p = 0.000). Intimate partner violence following disclosure of the STD signals that health professionals should identify patients' difficulties in revealing an STD diagnosis to their partners. PMID- 27462844 TI - [Database linkage for surveillance of the influenza A(H1N1)pdm09 pandemic in Brazil, 2009-2010]. AB - Based on database linkage, the objective of this study was to describe the epidemiological profile of notified cases and deaths from the new viral subtype of influenza during the influenza pandemic. Secondary data were used from the SINAN (Information System for Notifiable Diseases) and SIM (Mortality Information System) for the years 2009 and 2010. Linkage identified 5,973 deaths of cases notified as pandemic influenza. Of these, 2,170 (36.33%) had been classified in the SINAN as confirmed pandemic influenza, 215 (3.6%) as due to other infectious agents, and 3,340 (55.92%) as ruled out. After linkage, some cases in the SINAN database that were closed as death from influenza (n = 658) or death from other causes (n = 847) could not be located in the SIM database. Database linkage can improve the surveillance system and monitoring of morbidity and mortality. We recommend strengthening influenza surveillance in Brazil using linkage of Ministry of Health databases. PMID- 27462845 TI - [Morbidity profile and hospital expenses with elderly patients in Parana State, Brazil, 2008-2012]. AB - Growth in the elderly population has increased both the demand for health services and healthcare expenses, with relevant consequences for economic stability. The current study aimed to analyze the morbidity profile and hospital expenses with elderly patients in relation to socioeconomic and demographic conditions in Parana State, Brazil, from 2008 to 2012, applying principal components analysis and groupings. Regions with higher and lower economic and human development showed high prevalence of hospitalizations and costs pertaining to the circulatory and respiratory systems and cardiac diseases for males and females. In regions with intermediary development, diseases of the nervous system in men and of the circulatory system in women had the highest morbidity and hospital expenses. Thus, measures for prevention and health promotion in this elderly population should be targeted to regional investigations. PMID- 27462846 TI - [Zika virus congenital syndrome]. PMID- 27462848 TI - Preliminary stages of a cross-cultural Brazilian Portuguese adaptation of a measurement tool for assessing public understanding of human papillomavirus. AB - The objective of this study was to conduct the initial stages of the cross cultural adaptation to Brazilian Portuguese of a scale to measure the level of knowledge about HPV. The stages included: translation from English into the Portuguese spoken in Brazil; synthesis of the translated version; back translation; analysis by an expert committee; and reliability analysis based on internal consistency and reproducibility. Cronbach's alpha coefficient for the instrument was 0.985. Subset analysis produced only minor variations. The correlation coefficients between the individual items and the overall result showed strong positive correlations, except for three items. Reproducibility analysis showed kappa values with substantial or moderate agreement for the majority of the items. A preliminary Brazilian version was obtained with satisfactory results, but other stages are necessary in the process of validation of the Brazilian version. PMID- 27462847 TI - [Primary care screening of problems in the elderly and a proposal for a screening protocol with a multidimensional approach]. AB - The objectives were to examine psychometric properties of a screening test for the elderly and to propose a protocol for use in primary care. The method consisted of four stages: (1) inter-evaluator reliability for performance tests and self-assessment questions for eight functions; (2) sensitivity and specificity of questions on depression and social support; (3) meeting of experts to select instrumental activities of daily living (IADL); and (4) elaboration of the protocol. Screening lasted 16 minutes. Inter-evaluator reliability was excellent for performance tests but poor for questions. Depression and social support showed satisfactory sensitivity and specificity (0.74/0.77 and 0.77/0.96). Four IADL were selected by more than 55% of the experts. Following the results, a screening protocol was elaborated that prioritized the use of performance tests, maintaining questions on mood, social support, and IADL. The study suggests better reproducibility of performance tests when compared to questions. For mood and social support, the questions may provide a first screening stage. The proposed protocol allows rapid screening of problems. PMID- 27462849 TI - "Austerity" in the English National Health Service: fragmentation and commodification - examples not to follow. PMID- 27462850 TI - [Factor structure validity of the social capital scale used at baseline in the ELSA-Brasil study]. AB - This study aims to analyze the factor structure of the Brazilian version of the Resource Generator (RG) scale, using baseline data from the Brazilian Longitudinal Health Study in Adults (ELSA-Brasil). Cross-validation was performed in three random subsamples. Exploratory factor analysis using exploratory structural equation models was conducted in the first two subsamples to diagnose the factor structure, and confirmatory factor analysis was used in the third to corroborate the model defined by the exploratory analyses. Based on the 31 initial items, the model with the best fit included 25 items distributed across three dimensions. They all presented satisfactory convergent validity (values greater than 0.50 for the extracted variance) and precision (values greater than 0.70 for compound reliability). All factor correlations were below 0.85, indicating full discriminative factor validity. The RG scale presents acceptable psychometric properties and can be used in populations with similar characteristics. PMID- 27462851 TI - [Telephone monitoring service for pregnant women and impact on prevalence of prematurity and associated risk factors in Piracicaba, Sao Paulo State, Brazil]. AB - This study aims to assess the impact of a telephone monitoring service on prevalence of prematurity and to analyze associated risk factors using data on 2,739 pregnant women. Estimation was based on hierarchical multiple logistic regression, with p <= 0.05 for variables to remain in the model. Prevalence of preterm birth was 8.34% in monitored pregnant women and 10.18% in unmonitored women (p = 0.0058). Prevalence of preterm birth was inversely proportional to the number of monitoring calls (p < 0.0001). Variables associated with prematurity were maternal age < 19 years, history of death of two or more children, multiple pregnancy, diabetes, hypertension, fewer monitoring calls, extended standing or lifting heavy weights at work, smoking, fewer prenatal visits, no ultrasound examination, gestational diabetes, multiple pregnancy, and fetal abnormality. This low-cost strategy proved effective for reducing the preterm birth rate. PMID- 27462852 TI - [Variation in hospital performance according to payment sources in the states of Sao Paulo and do Rio Grande do Sul, Brazil]. AB - In Brazil, the combined presence of public and private interests in financing and provision of healthcare services stands out clearly in hospital care. Financing arrangements adopted by hospitals (the public Brazilian Unified National Health System - SUS and/or health plans and/or out-of-pocket payment) can affect quality of care. Studies have analyzed the hospital standardized mortality ratio (HSMR) in relation to quality improvements. The objective was to analyze HSMR according to source of payment for the hospitalization and the hospital's financing arrangement. The study analyzed secondary data and causes that accounted for 80% of hospital deaths. HSMR was calculated for each hospital and payment source. Hospitals with worse-than-expected performance (HSMR > 1) were mostly large public hospitals. HSMR was higher in the SUS, including between admissions in the hospital. Despite the study's limitations, the findings point to inequalities in results of care. Efforts are needed to improve the quality of hospital services, regardless of the payment sources. PMID- 27462853 TI - [Documents make a difference: the case of Brazilian domestic workers in Massachusetts, USA]. AB - Brazilian immigrants in the United States experience various social, labor, and health challenges. This study aimed to analyze the profile of female Brazilian domestic workers in Massachusetts, USA, through a description of their working conditions and self-rated health. This was a cross-sectional study of 198 domestic workers in Massachusetts, recruited with "snowball" sampling. The instrument addressed participants' demographic characteristics, work conditions, and self-rated health. Data were analyzed with SPSS 21.0. Among the interviewees, 95.5% were women, 62.1% were 30 to 49 years of age, and 55.6% were undocumented. Documented and undocumented participants showed statistically significant differences in demographics, work conditions, and health. Irregular immigrant status appears to have a negative impact on domestic workers' living and health conditions. PMID- 27462854 TI - Psychometric evaluation of a unified Portuguese-language version of the Body Shape Questionnaire in female university students. AB - The objectives of this study were to develop a unified Portuguese-language version, for use in Brazil and Portugal, of the Body Shape Questionnaire (BSQ) and to estimate its validity, reliability, and internal consistency in Brazilian and Portuguese female university students. Confirmatory factor analysis was performed using both original (34-item) and shortened (8-item) versions. The model's fit was assessed with chi2/df, CFI, NFI, and RMSEA. Concurrent and convergent validity were assessed. Reliability was estimated through internal consistency and composite reliability (alpha). Transnational invariance of the BSQ was tested using multi-group analysis. The original 32-item model was refined to present a better fit and adequate validity and reliability. The shortened model was stable in both independent samples and in transnational samples (Brazil and Portugal). The use of this unified version is recommended for the assessment of body shape concerns in both Brazilian and Portuguese college students. PMID- 27462855 TI - [Hospital readmission rate and associated factors among health services enrollees in Colombia]. AB - Hospital readmissions are common and expensive, and there is little information on the problem in Colombia. The objective was to determine the frequency of 30 day all-cause hospital readmissions and associated factors. This was a retrospective analytical cohort study of 64,969 hospitalizations from January 2008 to January 2009 in 47 Colombian cities. 6,573 hospital readmissions, prevalence: 10.1% (men 10.9%, women 9.5%), 44.7% > 65 years of age. Hospital readmissions was associated with higher mortality (5.8% vs. 1.8%). There was an increase in the Hospital readmissions rate in patients with diseases of the circulatory system. Hospital readmissions was more likely in hematological diseases and neoplasms. Mean length of stay during the first readmission was 7 days in patients that were readmitted and 4.5 in those without readmission. Greater total cost of hospital readmissions (USA 21,998,275): 15.8% of the total cost of hospitalizations. Higher prevalence rates in referred patients (18.8%) and patients from the outpatient clinic (13.7%). Hospital readmissions is common and is associated with longer length of hospital stay and higher mortality and cost. Increased risk of hospital readmissions in men > 65 years, patients referred from other institutions, and in hematological diseases and neoplasms. PMID- 27462856 TI - [Psychosocial risks, quality of employment, and workplace stress in Chilean wage earning workers: a gender perspective]. AB - This study aimed to estimate the prevalence of work-related stress in Chile and its association with exposure to workplace psychosocial risks and quality of employment, considering gender differences. The cross-sectional study included a representative probabilistic national sample of 3,010 salaried workers (1,486 women and 1,524 men). Eighteen percent reported work-related stress (23.8% of women and 14.8% of men). People exposed to psychosocial risks had a higher probability of experiencing stress, and women were more likely to suffer stress than men. Women and men in precarious work showed increased likelihood of distress, compared to workers with less precarious jobs. However, women in precarious jobs were more likely to suffer stress than men in the same situation. The study concluded that women had more precarious jobs, experienced greater exposure to psychosocial risks, and suffered more stress than men. This is evidence of double discrimination (social and gender-based) in the Chilean labor market. PMID- 27462857 TI - [Drug use in the public health debate]. AB - This article addresses illegal drug use within the current debate in traditional public health and in proposals from Latin America, while emphasizing the need to approach the issue from an alternative public health perspective centered on individual users, groups, and social movements as protagonists. This counterhegemonic approach thus aims to orient the discussion on the need for inclusive and democratic public policies. Illegal drug use has been addressed from various perspectives: clinical medicine, viewing it as a problem that generates mental disorders and infectious diseases, both through risky sexual practices and/or use of injecting paraphernalia; from a legal perspective, as a problem related to delinquency; and according to traditional public health, as a problem that generates school dropout and work absenteeism and increases the demand on health services, in addition to increasing violence and death. However, not all forms of drug consumption involve problematic use, nor do they all trigger disorders related to substance use. PMID- 27462858 TI - [Comment on the article by Eickmann et al]. PMID- 27462859 TI - "Stay, MCTI", and Ulisses Guimaraes. PMID- 27462860 TI - CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients. AB - BACKGROUND: The CXCR4/CXCL12 axis plays a central role in systemic metastasis of prostate carcinoma (PCa), thereby representing a promising target for future therapies. Recent data suggest that the CXCR4/CXCL12 axis is functionally linked to the PD-1/PD-L1 immune checkpoint. We evaluated the prognostic value of aberrant CXCL12 DNA methylation with respect to PD-L1 expression in primary PCa. RESULTS: CXCL12 methylation showed a consistent significant correlation with Gleason grading groups in both cohorts (p < 0.001 for training and p = 0.034 for testing cohort). Short BCR-free survival was significantly associated with aberrant CXCL12 methylation in both cohorts and served as an independent prognostic factor in the testing cohort (hazard ratio = 1.92 [95%CI: 1.12-3.27], p = 0.049). Concomitant aberrant CXCL12 methylation and high PD-L1 expression was significantly associated with shorter BCR-free survival (p = 0.005). In comparative analysis, the CXCL12 methylation assay was able to provide approximately equivalent results in biopsy and prostatectomy specimens. MATERIALS AND METHODS: CXCL12 methylation was determined by means of a methylation specific quantitative PCR analysis in a radical prostatectomy patient cohort (n = 247, training cohort). Data published by The Cancer Genome Atlas served as a testing cohort (n = 498). CXCL12 methylation results were correlated to clinicopathological parameters including biochemical recurrence (BCR)-free survival. CONCLUSIONS: CXCL12 methylation is a powerful prognostic biomarker for BCR in PCa patients after radical prostatectomy. Further studies need to ascertain if CXCL12 methylation may aid in planning active surveillance strategies. PMID- 27462863 TI - Structural basis for exploring the allosteric inhibition of human kidney type glutaminase. AB - Cancer cells employ glutaminolysis to provide a source of intermediates for their upregulated biosynthetic needs. Glutaminase, which catalyzes the conversion of glutamine to glutamate, is gaining increasing attention as a potential drug target. Small-molecule inhibitors such as BPTES and CB-839, which target the allosteric site of glutaminase with high specificity, demonstrate immense promise as anti-tumor drugs. Here, we report the study of a new BPTES analog, N,N'-(5,5' (trans-cyclohexane-1,3-diyl)bis(1,3,4-tiadiazole-5,2-diyl))bis(2-phenylacetamide) (trans-CBTBP), and compared its inhibitory effect against that of CB-839 and BPTES. We show that CB-839 has a 30- and 50-fold lower IC50 than trans-CBTBP and BPTES, respectively. To explore the structural basis for the differences in their inhibitory efficacy, we solved the complex structures of cKGA with 1S, 3S-CBTBP and CB-839. We found that CB-839 produces a greater degree of interaction with cKGA than 1S, 3S-CBTBP or BPTES. The results of this study will facilitate the rational design of new KGA inhibitors to better treat glutamine-addicted cancers. PMID- 27462861 TI - Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors. AB - Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(-)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(-) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(-) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re assessment. PMID- 27462864 TI - Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma. AB - The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC.Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%+/ 13.31%) than that in the paired adjacent normal tissues (65.33%+/-3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127-2.591) and PFS (HR, 1.767; 95 % CI, 1.168 2.974) were observed in the low-methylation-level group compared to the high methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC. PMID- 27462865 TI - Alternative treatments in advanced hepatocellular carcinoma patients with progressive disease after sorafenib treatment: a prospective multicenter cohort study. AB - Sorafenib is an oral multikinase inhibitor that has been approved to treat advanced hepatocellular carcinoma (HCC), though it is unclear how much benefit advanced HCC patients with progressive disease (PD) derive from sorafenib treatment. This study aimed to assess survival risk factors and evaluate therapeutic strategies for advanced HCC patients with PD after sorafenib treatment. We analyzed the clinical data and treatment outcomes for 315 consecutive advanced HCC patients treated with sorafenib. Univariate analyses of overall survival identified therapeutic effect as an independent risk factor in all patients. Among all patients, 141 developed PD. Of those, 58 (41%) were treated with sorafenib monotherapy, 70 (50%) with agents other than sorafenib, and 13 (9%) were not treated at all. The median survival time was 6.1 months for PD patients with sorafenib monotherapy and 12.2 months for those administered alternative treatments (p < 0.0001). Our results indicated that sorafenib treatment may have negative long-term therapeutic effects in advanced HCC patients with PD, and that alternative treatments should be considered for these patients after sorafenib administration. PMID- 27462866 TI - PDIA6 promotes the proliferation of HeLa cells through activating the Wnt/beta catenin signaling pathway. AB - Protein disulfide isomerase family 6 (PDIA6) belongs to the protein disulfide isomerase (PDI) family, which function as isomerases and molecular chaperones. PDIA6 has recently been shown to promote the proliferation and growth of various types of human cancer cells; however the underlying molecular mechanism remains elusive. Here, we report that PDIA6 enhances the proliferation of HeLa cells through activation of the Wnt/beta-catenin signaling pathway. Ectopic overexpression of PDIA6 in HeLa cells led to increased cell proliferation accompanied with accelerated cell cycle progression. Further mechanistic investigation demonstrated that overexpression of PDIA6 resulted in decreased phosphorylation of beta-catenin at Ser45 and Ser33/Ser37/Thr41, while increased beta-catenin nuclear accumulation, and upregulation of Wnt/ beta-catenin signaling target genes cyclinD1 and c-myc, which was abolished by ubiquitin proteasome inhibitor MG132. These results demonstrated that PDIA6 overexpression promoted the proliferation of HeLa cells by suppressing the phosphorylation of beta-catenin, thereby inhibiting the degradation of beta-catenin through the ubiquitin-proteasome pathway. PMID- 27462867 TI - Genetic polymorphisms of mTOR and cancer risk: a systematic review and updated meta-analysis. AB - mTOR regulates several cellular processes that are critical for tumorigenesis. However, previous studies on the association of mTOR polymorphisms with predisposition to different cancer types are somewhat contradictory. Therefore, we performed a systematic review and updated meta-analysis of the available evidence regarding the relationship between mTOR single nucleotide polymorphisms (SNPs) and cancer risk. Up to November 2015, 23 original publications were identified covering 20 mTOR SNPs, of which seven SNPs (rs2536, rs2295080, rs1883965, rs1034528, rs17036508, rs3806317 and rs1064261) were included in the final meta-analysis. We estimated the summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for mTOR polymorphisms and cancer risk, and used the model-free approach to investigate the biological effect of each polymorphism. Our meta-analysis found that rs1883965, rs1034528, and rs17036508 were correlated with increased cancer risk in the complete over-dominant model (rs1883965 GA versus GG/AA: fixed-effects OR=1.15, 95% CI 1.02-1.29; rs1034528 GC versus GG/CC: fixed-effects OR=1.30, 95% CI 1.13-1.48; rs17036508 TC versus CC/TT: fixed-effects OR=1.23, 95% CI 1.06-1.43). Stratifying analyses by cancer type, we found that the rs2295080 G allele was associated with a significantly higher risk of acute leukemia in the recessive model (GG versus GT/TT: fixed effects OR=2.08, 95% CI 1.34-3.22) and a lower risk of genitourinary cancers in the dominant model (TG/GG versus TT: fixed-effects OR=0.77, 95% CI 0.68-0.86). Interestingly, further expression analysis showed that homozygous variant genotype carriers of rs1883965, rs1034528 and rs17036508 had lower mTOR transcript levels, based on HapMap data. PMID- 27462868 TI - BRAF-activated LncRNA functions as a tumor suppressor in papillary thyroid cancer. AB - Long non-coding RNAs (lncRNAs) participate in cancer cell tumorigenesis, cell cycle control, migration, proliferation, apoptosis, metastasis and drug resistance. The BRAF-activated non-coding RNA (BANCR) functions as both an oncogene and a tumor suppressor. Here, we investigated BANCR's role in papillary thyroid carcinoma (PTC) by assessing BANCR levels in PTC and matched normal thyroid epithelial tissues from 92 patients using qRT-PCR. We also used lentiviral vectors to establish PTC cell lines to investigate the effects of BANCR overexpression on cancer cell proliferation, apoptosis, migration and invasion. Our results indicate BANCR levels are lower in PTC tumor tissues than control tissues. Decreased BANCR levels correlate with tumor size, the presence of multifocal lesions and advanced PTC stage. BANCR overexpression reduced PTC cell proliferation and promoted apoptosis, which inhibited metastasis. It also inactivated ERK1/2 and p38, and this effect was enhanced by treatment with the MEK inhibitor U0126. Finally, BANCR overexpression dramatically inhibited tumor growth from PTC cells in xenograft mouse models. These results suggest BANCR inhibits tumorigenesis in PTC and that BANCR levels may be used as a novel prognostic marker. PMID- 27462869 TI - Volumetric modulated arc therapy for thoracic node metastases: a safe and effective treatment for a neglected disease. AB - PURPOSE: To evaluate the outcome of Stereotactic Body Radiation Therapy (SBRT) with Volumetric Modulated Arc Therapy (VMAT) for thoracic node metastases. RESULTS: 18 out of 29 patients presented with isolated thoracic node metastases with no other sites of disease. Median prescribed dose was 45Gy (range 30 60Gy).Acute toxicity was recorded as G0 in 28 patients, while one patient was scored as G1. Late toxicity was G0 in 26 patients, one patient was scored G1, one as G2, and one as G4 presented acute myocardial infarction.During follow up, the best local response was complete remission in 14 patients and partial remission in 11 patients. With a median follow up of 12 months (range 2-35) 9 patients died from disease progression, 10 were still alive with distant metastases, 5 had a locally controlled disease and 5 patients were disease free.The median OS estimated was 18 months (76%, 49% at one, two years). The median PFS was 9 months (28%, 17% at one, two years). MATERIALS AND METHODS: Twenty-nine patients with 32 thoracic nodes metastases were treated with SBRT in our institution. Toxicities and response were assessed. Overall Survival (OS) and Progression Free Survival (PFS) were evaluated. CONCLUSIONS: SBRT is an efficient treatment for thoracic node metastases. PMID- 27462870 TI - Current approach to the management of psoriatic arthritis according to a sample of Italian rheumatologists. AB - OBJECTIVES: The purpose of this study was to have an overview of the current approach to psoriatic arthritis (PsA) by a group of Italian rheumatologists. METHODS: Rheumatologists from all around Italy were asked to participate in a survey to give their opinion on a number of statements made by a panel of rheumatologists who are experts in PsA. The survey was conducted through two rounds using a Delphi-like method. The two rounds yielded a consensus on the management of PsA. RESULTS: Fifty rheumatologist from 50 rheumatology centres participated in the survey. Of the 117 proposed statements, only 10 did not reach the 66% concordance threshold. The main results of the survey were that diagnosis of PsA should be made using both the CASPAR criteria and clinical judgment, that all of the features of the psoriatic disease are relevant in the assessment and therapy of PsA, that treatment recommendations are taken into account, that all of the available biological agents may be used in bio-naive patients, that anti drug antibody testing is still not used in daily practice, that both switching or swapping are useful options in the case of bio-failure because of lack or loss of efficacy, and that swapping is considered the best choice in the case of bio failure due to adverse events. CONCLUSIONS: The results of this survey showed that a comprehensive evaluation of the patient and a therapy choice based on both patient clinical features and evidence of drug efficacy and safety are considered the current best of care for PsA patients. PMID- 27462871 TI - Solasodine Induces Apoptosis, Affects Autophagy, and Attenuates Metastasis in Ovarian Cancer Cells. AB - Solasodine, a steroidal alkaloid isolated from solanaceous species, exhibits anticancer activities on several cell lines. This study aimed to explore the antitumor potential of solasodine on ovarian cancer cells. The MTT assay, lactate dehydrogenase release assay, Hoechst 33342 staining, 5,5',6,6'-tetrachloro 1,1',3,3'-tetraethyl-imidacarbocyanine staining assay, and Annexin V/PI assay were conducted to investigate the antiproliferation and apoptosis-inducing effects of solasodine. Monodansylcadaverine staining was performed to label the acidic puncta on ovarian cancer HEY cells. A wound healing assay and Transwell assay were carried out to determine whether solasodine elicits an antimetastatic effect on HEY cells. A gelatin zymography assay was applied to detect the enzymatic activities of matrix metalloproteinases. Western blot was employed to examine relevant protein expression. Results revealed that solasodine inhibited cell viabilities in a time- and dose-dependent manner, triggered apoptotic body formation, reduced cell mitochondrial membrane potential, and interfered with autolysosome degradation in ovarian cancer cells. Solasodine also suppressed the migration and invasion of HEY cells by downregulating matrix metalloproteinase expression and activities. This study could be used as a basis for further studies on the molecular mechanisms of the antiproliferation, apoptosis-inducing, autophagy-modifying, and antimetastatic activities of solasodine. PMID- 27462872 TI - Nandinine, a Derivative of Berberine, Inhibits Inflammation and Reduces Insulin Resistance in Adipocytes via Regulation of AMP-Kinase Activity. AB - Nandinine is a derivative of berberine that has high efficacy for treating cardiovascular diseases. This study investigated the effects of berberine and nandinine on the regulation of insulin sensitivity in adipocytes. Through treatment with macrophage-derived conditioned medium in 3T3-L1 adipocytes, dysregulation of adipokine production and activation of the IkappaB kinase beta/nuclear factor-kappa B pathway was induced. However, these phenomena were effectively reversed by berberine, nandinine, and salicylate pretreatments. Furthermore, both berberine and nandinine inhibited serine phosphorylation of insulin receptor substrate-1 induced by IkappaB kinase beta and increased tyrosine phosphorylation of insulin receptor substrate-1 to activate the PI3K/Akt pathway, which finally led to insulin-mediated glucose uptake. In addition, berberine and nandinine significantly increased AMP-activated protein kinase activity, thereby contributing to their anti-inflammatory effect by inhibiting IkappaB kinase beta activation. Finally, in vivo studies demonstrated that both berberine (100 or 200 mg/kg) and nandinine (100 or 200 mg/kg) effectively ameliorated glucose intolerance and induced the insulin sensitivity index in mice. In conclusion, berberine and nandinine attenuated insulin resistance in adipocytes by inhibiting inflammation in an AMP-activated protein kinase dependent manner. Berberine and nandinine may be used as dietary supplements and nandinine is a new candidate for obesity treatment. PMID- 27462874 TI - Scalable Patterning of MoS2 Nanoribbons by Micromolding in Capillaries. AB - In this study, we report a facile approach to prepare dense arrays of MoS2 nanoribbons by combining procedures of micromolding in capillaries (MIMIC) and thermolysis of thiosalts ((NH4)2MoS4) as the printing ink. The obtained MoS2 nanoribbons had a thickness reaching as low as 3.9 nm, a width ranging from 157 to 465 nm, and a length up to 2 cm. MoS2 nanoribbons with an extremely high aspect ratio (length/width) of ~7.4 * 10(8) were achieved. The MoS2 pattern can be printed on versatile substrates, such as SiO2/Si, sapphire, Au film, FTO/glass, and graphene-coated glass. The degree of crystallinity of the as prepared MoS2 was discovered to be adjustable by varying the temperature through postannealing. The high-temperature thermolysis (1000 degrees C) results in high quality conductive samples, and field-effect transistors based on the patterned MoS2 nanoribbons were demonstrated and characterized, where the carrier mobility was comparable to that of thin-film MoS2. In contrast, the low-temperature treated samples (170 degrees C) result in a unique nanocrystalline MoSx structure (x ~ 2.5), where the abundant and exposed edge sites were obtained from highly dense arrays of nanoribbon structures by this MIMIC patterning method. The patterned MoSx was revealed to have superior electrocatalytic efficiency (an overpotential of ~211 mV at 10 mA/cm(2) and a Tafel slope of 43 mV/dec) in the hydrogen evolution reaction (HER) when compared to the thin-film MoS2. The report introduces a new concept for rapidly fabricating cost-effective and high-density MoS2/MoSx nanostructures on versatile substrates, which may pave the way for potential applications in nanoelectronics/optoelectronics and frontier energy materials. PMID- 27462875 TI - Nanometer-Size Effect on Hydrogen Sites in Palladium Lattice. AB - Nanometer-sized materials attract much attention because their physical and chemical properties are substantially different from those of bulk materials owing to their size and surface effects. In this work, neutron powder diffraction experiments on the nanoparticles of palladium hydride, which is the most popular metal hydride, have been performed at 300, 150, and 44 K to investigate the positions of the hydrogen atoms in the face-centered cubic (fcc) lattice of palladium. We used high-quality PdD0.363 nanocrystals with a diameter of 8.0 +/- 0.9 nm. The Rietveld analysis revealed that 30% of D atoms are located at the tetrahedral (T) sites and 70% at the octahedral (O) sites. In contrast, only the O sites are occupied in bulk palladium hydride and in most fcc metal hydrides. The temperature dependence of the T-site occupancy suggested that the T-sites are occupied only in a limited part, probably in the subsurface region, of the nanoparticles. This is the first study to determine the hydrogen sites in metal nanoparticles. PMID- 27462873 TI - Tissue damage drives co-localization of NF-kappaB, Smad3, and Nrf2 to direct Rev erb sensitive wound repair in mouse macrophages. AB - Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFbeta, and damage-associated molecular patterns (DAMPS). Unexpectedly, a complex damage signal promotes co-localization of NF-kappaB, Smad3, and Nrf2 at Rev-erb-sensitive enhancers and drives expression of genes characteristic of multiple polarization states in the same cells. Rev-erb-sensitive enhancers thereby integrate multiple damage-activated signaling pathways to promote a wound repair phenotype. PMID- 27462876 TI - Suppression Effect and Mechanism of Platinum and Nitrogen-Containing Silane on the Tracking and Erosion of Silicone Rubber for High-Voltage Insulation. AB - How to effectively improve the tracking and erosion resistance of silicone rubber (SR) was an urgent topic in the field of high-voltage insulation. In this work, the tracking and erosion resistance of SR was significantly improved by incorporating platinum (Pt) catalyst and nitrogen-containing silane (NS). The suppression effect and mechanism of Pt/NS on tracking and erosion were studied by inclined plane (IP) test, thermogravimetry (TG), thermogravimetry-Fourier transform infrared spectrometry, laser Raman spectroscopy, and scanning electron microscopy. It revealed that when 1.4 phr of NS and 6.7 ppm of Pt were added, the tracking resistance of SR was improved from 2.5 to 4.5 kV level in the IP test, and the eroded mass was significantly reduced. This might be attributed to the synergistic effect of Pt/NS on silicone chains. At a high temperature produced by arc discharge, Pt/NS would catalyze radical cross-linking, meanwhile suppressing oxidation and depolymerization of silicone chains. Hence, a tightly cross-linked network was formed and protected inner materials from arc ablation. Moreover, carbon deposit during pyrolysis was suppressed by Pt/NS, which served as the secondary mechanism of tracking suppression. PMID- 27462877 TI - Revision and Microtomography of the Pheidole knowlesi Group, an Endemic Ant Radiation in Fiji (Hymenoptera, Formicidae, Myrmicinae)Myrmicinae). AB - The Fijian islands, a remote archipelago in the southwestern Pacific, are home to a number of spectacular endemic radiations of plants and animals. Unlike most Pacific archipelagos, these evolutionary radiations extend to social insects, including ants. One of the most dramatic examples of ant radiation in Fiji has occurred in the hyperdiverse genus Pheidole. Most of the 17 native Fijian Pheidole belong to one of two species groups that descended from a single colonization, yet have evolved dramatically contrasting morphologies: the spinescent P. roosevelti species group, and the more morphologically conservative P. knowlesi species group. Here we revise the knowlesi group, in light of recent phylogenetic results, and enhanced with modern methods of X-ray microtomography. We recognize six species belonging to this group, including two of which we describe as new: Pheidole caldwelli Mann, Pheidole kava sp. n., Pheidole knowlesi Mann, P. ululevu sp. n., P. vatu Mann, and P. wilsoni Mann. Detailed measurements and descriptions, identification keys, and high-resolution images for queens, major and minor workers are provided. In addition, we include highly detailed 3D surface reconstructions for all available castes. PMID- 27462878 TI - Fetal Alcohol Spectrum Disorders and Challenges Faced by Caregivers: Clinicians' Perspectives. AB - BackgroundThere is a notable absence of evidence based early interventions for young children with FASD. ObjectiveThis study examines clinicians' perspectives regarding the needs of caregivers of children with FASD and how such perspectives informed the development of a family-centered early intervention for young children with prenatal alcohol exposure. Method19 professionals who work with children with prenatal alcohol exposure and / or in out-of-home care were recruited to participate in focus groups. The facilitator used a semi-structured topic guide to elicit feedback from participants. These data were transcribed, coded, and categorized to reflect themes in a manner informed by a grounded theory approach. A second investigator repeated the process. Codes were chosen and assigned to data by consensus. ResultsThe coded data yielded five distinct perceived challenges faced by caregivers: (1) seeking and possibly receiving a diagnosis; (2) processing emotions and coming to terms with the child's difficulties; (3) seeking support and belonging within a knowledgeable community; (4) developing a new understanding of the child's behavior; and (5) becoming an educator, advocate, and expert on the child and FASD. ConclusionProfessionals believe specific capacities are essential insofar as the human service systems that caregivers engage are perceived to be under-equipped to respond to the distinct set of challenges faced by children with FASD and their families. Findings are discussed in terms of how the proposed intervention was designed to address such challenges and to cultivate those key capacities in order for families to meet their children's needs. PMID- 27462880 TI - How to Fairly Allocate Scarce Medical Resources: Ethical Argumentation under Scrutiny by Health Professionals and Lay People. AB - BACKGROUND: Societies are facing medical resource scarcities, inter alia due to increased life expectancy and limited health budgets and also due to temporal or continuous physical shortages of resources like donor organs. This makes it challenging to meet the medical needs of all. Ethicists provide normative guidance for how to fairly allocate scarce medical resources, but legitimate decisions require additionally information regarding what the general public considers to be fair. The purpose of this study was to explore how lay people, general practitioners, medical students and other health professionals evaluate the fairness of ten allocation principles for scarce medical resources: 'sickest first', 'waiting list', 'prognosis', 'behaviour' (i.e., those who engage in risky behaviour should not be prioritized), 'instrumental value' (e.g., health care workers should be favoured during epidemics), 'combination of criteria' (i.e., a sequence of the 'youngest first', 'prognosis', and 'lottery' principles), 'reciprocity' (i.e., those who provided services to the society in the past should be rewarded), 'youngest first', 'lottery', and 'monetary contribution'. METHODS: 1,267 respondents to an online questionnaire were confronted with hypothetical situations of scarcity regarding (i) donor organs, (ii) hospital beds during an epidemic, and (iii) joint replacements. Nine allocation principles were evaluated in terms of fairness for each type of scarcity along 7-point Likert scales. The relationship between demographic factors (gender, age, religiosity, political orientation, and health status) and fairness evaluations was modelled with logistic regression. RESULTS: Medical background was a major predictor of fairness evaluations. While general practitioners showed different response patterns for all three allocation situations, the responses by lay people were very similar. Lay people rated 'sickest first' and 'waiting list' on top of all allocation principles-e.g., for donor organs 83.8% (95% CI: [81.2% 86.2%]) rated 'sickest first' as fair ('fair' is represented by scale points 5 7), and 69.5% [66.2%-72.4%] rated 'waiting list' as fair. The corresponding results for general practitioners: 'prognosis' 79.7% [74.2%-84.9%], 'combination of criteria' 72.6% [66.4%-78.5%], and 'sickest first' 74.5% [68.6%-80.1%); these were the highest-rated allocation principles for donor organs allocation. Interestingly, only 44.3% [37.7%-50.9%] of the general practitioners rated 'instrumental value' as fair for the allocation of hospital beds during a flu epidemic. The fairness evaluations by general practitioners obtained for joint replacements: 'sickest first' 84.0% [78.8%-88.6%], 'combination of criteria' 65.6% [59.2%-71.8%], and 'prognosis' 63.7% [57.1%-70.0%]. 'Lottery', 'reciprocity', 'instrumental value', and 'monetary contribution' were considered very unfair allocation principles by both groups. Medical students' ratings were similar to those of general practitioners, and the ratings by other health professionals resembled those of lay people. CONCLUSIONS: Results are partly at odds with current conclusions proposed by some ethicists. A number of ethicists reject 'sickest first' and 'waiting list' as morally unjustifiable allocation principles, whereas those allocation principles received the highest fairness endorsements by lay people and to some extent also by health professionals. Decision makers are advised to consider whether or not to give ethicists, health professionals, and the general public an equal voice when attempting to arrive at maximally endorsed allocations of scarce medical resources. PMID- 27462879 TI - The CaM Kinase CMK-1 Mediates a Negative Feedback Mechanism Coupling the C. elegans Glutamate Receptor GLR-1 with Its Own Transcription. AB - Regulation of synaptic AMPA receptor levels is a major mechanism underlying homeostatic synaptic scaling. While in vitro studies have implicated several molecules in synaptic scaling, the in vivo mechanisms linking chronic changes in synaptic activity to alterations in AMPA receptor expression are not well understood. Here we use a genetic approach in C. elegans to dissect a negative feedback pathway coupling levels of the AMPA receptor GLR-1 with its own transcription. GLR-1 trafficking mutants with decreased synaptic receptors in the ventral nerve cord (VNC) exhibit compensatory increases in glr-1 mRNA, which can be attributed to increased glr-1 transcription. Glutamatergic transmission mutants lacking presynaptic eat-4/VGLUT or postsynaptic glr-1, exhibit compensatory increases in glr-1 transcription, suggesting that loss of GLR-1 activity is sufficient to trigger the feedback pathway. Direct and specific inhibition of GLR-1-expressing neurons using a chemical genetic silencing approach also results in increased glr-1 transcription. Conversely, expression of a constitutively active version of GLR-1 results in decreased glr-1 transcription, suggesting that bidirectional changes in GLR-1 signaling results in reciprocal alterations in glr-1 transcription. We identify the CMK-1/CaMK signaling axis as a mediator of the glr-1 transcriptional feedback mechanism. Loss-of-function mutations in the upstream kinase ckk-1/CaMKK, the CaM kinase cmk 1/CaMK, or a downstream transcription factor crh-1/CREB, result in increased glr 1 transcription, suggesting that the CMK-1 signaling pathway functions to repress glr-1 transcription. Genetic double mutant analyses suggest that CMK-1 signaling is required for the glr-1 transcriptional feedback pathway. Furthermore, alterations in GLR-1 signaling that trigger the feedback mechanism also regulate the nucleocytoplasmic distribution of CMK-1, and activated, nuclear-localized CMK 1 blocks the feedback pathway. We propose a model in which synaptic activity regulates the nuclear localization of CMK-1 to mediate a negative feedback mechanism coupling GLR-1 activity with its own transcription. PMID- 27462881 TI - Physicians' engagement: Medical Care Groups. PMID- 27462882 TI - Bioethical considerations at times of Zika virus. PMID- 27462883 TI - Correlation of Thyroid Imaging Reporting and Data System [TI-RADS] and fine needle aspiration: experience in 1,000 nodules. AB - OBJECTIVE: To correlate the Thyroid Imaging Reporting and Data System (TI-RADS) and the Bethesda system in reporting cytopathology in 1,000 thyroid nodules. METHODS: A retrospective study conducted from November 2011 to February 2014 that evaluated 1,000 thyroid nodules of 906 patients who underwent ultrasound exam and fine needle aspiration. RESULTS: A significant association was found between the TI-RADS outcome and Bethesda classification (p<0.001). Most individuals with TI RADS 2 or 3 had Bethesda 2 result (95.5% and 92.5%, respectively). Among those classified as TI-RADS 4C and 5, most presented Bethesda 6 (68.2% and 91.3%, respectively; p<0.001). The proportion of malignancies among TI-RADS 2 was 0.8%, and TI-RADS 3 was 1.7%. Among those classified as TI-RADS 4A, proportion of malignancies was 16.0%, 43.2% in 4B, 72.7% in 4C and 91.3% among TI-RADS 5 (p<0.001), showing clear association between TI-RADS and biopsy results. CONCLUSION: The TI-RADS is appropriate to assess thyroid nodules and avoid unnecessary fine needle aspiration, as well as to assist in making decision about when this procedure should be performed. OBJETIVO: Apresentar a correlacao entre o Thyroid Imaging Reporting and Data System (TI-RADS) e o sistema Bethesda, para relatar citopatologia em 1.000 nodulos tireoidianos. METODOS: Estudo retrospectivo realizado no periodo de novembro de 2011 a fevereiro de 2014, que avaliou 1.000 nodulos tireoidianos de 906 pacientes submetidos a exame de ultrassonografia e a puncao aspirativa por agulha fina. RESULTADOS: Observou-se associacao significativa entre o TI-RADS e o resultado da classificacao de Bethesda (p<0,001). A maioria dos individuos com TI-RADS 2 ou 3 teve resultado citologico Bethesda 2 (95,5% e 92,5%, respectivamente). Entre aqueles classificados TI-RADS 4C e 5, a maioria teve resultado Bethesda 6 (68,2% e 91,3%, respectivamente; p<0,001). A proporcao de malignidades em TI-RADS 2 foi 0,8% e em TI-RADS 3 foi 1,7%. Entre TI-RADS 4A, foi de 16,0%, 43,2% em 4B, 72,7% em 4C e em 5 foi de 91,3% (p<0,001), mostrando clara associacao entre o TI-RADS e os resultados da biopsia. CONCLUSAO: O TI-RADS e apropriado para avaliar nodulos da tireoide e evitar puncao aspirativa por agulha fina desnecessaria, alem de auxiliar na decisao sobre quando este procedimento deve ser realizado. PMID- 27462884 TI - Endovascular revascularization of TASC C and D femoropopliteal occlusive disease using carbon dioxide as contrast. AB - OBJECTIVE: To analyze the results of ten angioplasties of TASC C and D femoropopliteal lesions using CO2 as primary contrast in patients with no formal contraindication to iodine, aiming to decrease allergic reactions and potential nephrotoxicity in high-risk patients. METHODS: We describe the results of ten angioplasties of TASC C and D femoropopliteal lesions using CO2 as primary contrast in patients with high risk for open revascularization and no formal contraindication to iodine. We analyzed feasibility of the procedures, complications, quality of the angiographic images, clinical and surgical outcomes, and costs of C and D lesions treated using CO2 as contrast medium. RESULTS: The use of CO2 in C and D lesions needed iodine complementation in most of the cases (nine cases) but decreased the potential nephrotoxicity of iodine contrast medium by the reduction of its volume in this group of high-risk patients. The extension of the arterial lesions was the factor that most contributed to the need for iodine supplementation due to the difficulty to visualize the refill after a long arterial occlusion. CONCLUSION: The use of CO2 as contrast in patients with C and D lesions with no restriction for iodine contrast medium was an alternative that did not dismiss the need of iodine supplementation in most of the cases, but could decrease the potential nephrotoxicity of iodine constrast medium. OBJETIVO: Analisar os resultados de dez angioplastias de lesoes femoro-popliteas TASC C e D utilizando CO2 como meio de contraste primario em pacientes sem restricao ao meio de contraste iodado com o objetivo de diminuir reacoes alergicas e potencial de nefrotoxicidade em pacientes de alto risco. METODOS: Descrevemos os resultados de dez angioplastias de lesoes femoro-popliteas TASC C e D utilizando CO2 como meio de contraste primario em pacientes de alto risco para revascularizacao aberta e sem contraindicacao formal a iodo. Analisamos possibilidade de execucao dos procedimentos, complicacoes, qualidade das imagens obtidas, desfechos clinicos e cirurgicos e custos das lesoes C e D tratadas com CO2 como meio de contraste. RESULTADOS: O uso de CO2 nas lesoes C e D necessitou de complementacao de iodo na maioria dos casos (nove casos), porem reduziu o potencial de nefrotoxicidade do meio de contraste iodado, diminuindo seu volume nesse grupo de pacientes de alto risco. A extensao das lesoes arteriais foi o fator que mais contribuiu para necessidade de suplementacao de iodo, devido a dificuldade de visualizar o reenchimento apos oclusao arterial longa. CONCLUSAO: O uso de CO2 como contraste em pacientes com lesoes C e D sem restricao ao meio de contraste iodado foi uma alternativa que nao excluiu a necessidade de suplementacao com iodo na maioria dos casos, porem pode diminuir o potencial de nefrotoxicidade do meio de contraste iodado. PMID- 27462885 TI - Initial experience with hysteroscopic tubal occlusion (Essure(r)). AB - OBJECTIVE: To evaluate results of early tubal occlusions performed by hysteroscopy (Essure(r)). METHODS: This prospective study included 38 patients, 73.7% of them were white, mean age 34.5 years, they have had on average 3 pregnancies and 2.7 of deliveries. A total of 86.8% of patients previously prepared the endometrium. All procedures were carried out at outpatient unit without anesthesia. RESULTS: Insertion rate of the device was 100% at a mean time of 4 minutes and 50 seconds. Based on the analogical visual scale, average pain reported was three, and 55.3% of women did not report pain after the procedure. After 3 months, 89.5% of patients were very satisfied with the method. Simple radiographs of the pelvis showed 92.1% of topical devices, and one case of unilateral expulsion had occurred. A four years follow-up did not show failure in the method. CONCLUSIONS: Tubal occlusion through hysteroscopy at outpatient unit and without anesthesia was a quickly and well-tolerated procedure. No serious complications were seen, the success rate was high, and patients were satisfied. OBJETIVO: Avaliar os resultados das primeiras oclusoes tubarias realizadas pela via histeroscopica (Essure(r)). METODOS: Estudo prospectivo com 38 pacientes, sendo 73,7% caucasianas, com media de idade de 34,5 anos, e com 3 gestacoes e 2,7 partos em media. Do total, 86,8% das pacientes fizeram preparo previo do endometrio. Todos os procedimentos foram ambulatoriais e sem anestesia. RESULTADOS: A taxa de insercao do dispositivo foi de 100%, com tempo medio de 4 minutos e 50 segundos. Segundo a Escala Visual Analogica, a dor media obtida foi de tres, e 55,3% das mulheres nao referiram qualquer dor apos o metodo. Ocorreu um caso de reflexo vagal e 89,5% das pacientes retornaram as atividades normais no mesmo dia. Apos 3 meses, 89,5% das pacientes encontravam-se muito satisfeitas com o metodo. A radiografia simples da pelve evidenciou 92,1% de dispositivos topicos, ocorrendo um caso de expulsao unilateral. Apos 4 anos de seguimento, nao houve falha do metodo. CONCLUSAO: A oclusao tubaria por via histeroscopica em regime ambulatorial e sem anestesia foi um procedimento rapido, bem tolerado, isento de complicacoes graves e com alta taxa de sucesso e satisfacao das pacientes. PMID- 27462886 TI - The destruction complex of beta-catenin in colorectal carcinoma and colonic adenoma. AB - OBJECTIVE: To evaluate the destruction complex of beta-catenin by the expression of the proteins beta-catetenin, adenomatous polyposis coli, GSK3beta, axin and ubiquitin in colorectal carcinoma and colonic adenoma. METHODS: Tissue samples from 64 patients with colorectal carcinoma and 53 patients with colonic adenoma were analyzed. Tissue microarray blocks and slides were prepared and subjected to immunohistochemistry with polyclonal antibodies in carcinoma, adjacent non neoplastic mucosa, and adenoma tissues. The immunoreactivity was evaluated by the percentage of positive stained cells and by the intensity assessed through of the stained grade of proteins in the cytoplasm and nucleus of cells. In the statistical analysis, the Spearman correlation coefficient, Student's t, chi2, Mann-Whitney, and McNemar tests, and univariate logistic regression analysis were used. RESULTS: In colorectal carcinoma, the expressions of beta-catenin and adenomatous polyposis coli proteins were significantly higher than in colonic adenomas (p<0.001 and p<0.0001, respectively). The immunoreactivity of GSK3beta, axin 1 and ubiquitin proteins was significantly higher (p=0.03, p=0.039 and p=0.03, respectively) in colorectal carcinoma than in the colonic adenoma and adjacent non-neoplastic mucosa. The immunohistochemistry staining of these proteins did not show significant differences with the clinical and pathological characteristics of colorectal cancer and colonic adenoma. CONCLUSIONS: These results suggest that, in adenomas, the lower expression of the beta-catenin, axin 1 and GSK3beta proteins indicated that the destruction complex of beta-catenin was maintained, while in colorectal carcinoma, the increased expression of beta catenin, GSK3beta, axin 1, and ubiquitin proteins indicated that the destruction complex of beta-catenin was disrupted. OBJETIVO: Avaliar o complexo de destruicao da betacatenina no carcinoma colorretal e no adenoma do colo pela expressao das proteinas betacatenina, adenomatous polyposis coli, GSK3beta, axina e ubiquitina. METODOS: Amostras de tecidos de 64 doentes com carcinoma colorretal e de 53 pacientes com adenoma do colo foram analisadas. Blocos de tecidos foram submetidos ao estudo imuno-histoquimico com anticorpos policlonais nos tecidos do carcinoma, mucosa nao neoplasica adjacente e adenoma. A imunorreatividade foi avaliada pela porcentagem de positividade de celulas coradas e pela intensidade do grau de coloracao das proteinas no citoplasma e no nucleo das celulas. Na analise estatistica, foram utilizados o coeficiente de correlacao de Spearman, os testes t de Student, chi2, Mann-Whitney e de McNemar, e a analise de regressao logistica univariada. RESULTADOS: No carcinoma colorretal, as expressoes da betacatenina e da adenomatous polyposis coli foram significativamente maiores do que em adenomas do colo (p<0,001 e p<0,0001, respectivamente). A imunorreatividade das proteinas GSK3beta, axina 1 e ubiquitina foi significativamente maior (p=0,03, p=0,039 e p=0,03, respectivamente) no carcinoma colorretal do que no adenoma e na mucosa nao neoplasica adjacente. A coloracao imuno-histoquimica dessas proteinas nao apresentou diferencas significantes em relacao as caracteristicas clinicopatologicas do cancer colorretal e do adenoma. CONCLUSOES: Em adenomas, as menores expressoes de betacatenina, axina 1 e GSK3beta indicaram que o complexo de destruicao da betacatenina estava conservado, enquanto que, no carcinoma colorretal, o aumento das expressoes da betacatenina, GSK3beta, 1 axina, e ubiquitina indicaram que o complexo de destruicao de betacatenina estava alterado. PMID- 27462887 TI - Condom use and alcohol consumption in adolescents and youth. AB - OBJECTIVE: To determine the association between not using the male condom and alcohol consumption in adolescents and schoolchildren. METHODS: An epidemiological study, with a cross-sectional, descriptive, and correlation design carried out from March to July 2014. The sample consisted of students in public primary and secondary education, aged between 12 and 24 years. The social and demographic survey and the Youth Risk Behavior Survey questionnaire were used. RESULTS: The study included 1,275 students, of these; 37.0% reported having had sexual relations. The prevalent age of sexual initiation was 14-16 years 55.7% and 65.6% used condom in the last sexual intercourse. Regarding the lack of condom use at the last intercourse, girls showed an association with drunkenness in the previous 30 days (2.19; 95%CI: 1.06-4.54). CONCLUSION: In females, the non use of condoms was associated with drunkenness in the previous 30 days. OBJETIVO: Identificar os fatores associados ao nao uso de preservativo masculino e ao consumo de bebida alcoolica em adolescentes e jovens escolares. METODOS: Estudo epidemiologico, com delineamento transversal, descritivo e correlacional, desenvolvido de marco a julho de 2014. A amostra foi composta por estudantes dos Ensinos Fundamental e Medio da rede publica estadual, com idades entre 12 e 24 anos. Empregaram-se o inquerito sociodemografico e o questionario Youth Risk Behavior Survey. RESULTADOS: Foram incluidos 1.275 estudantes; 37,0% deles relataram terem tido relacao sexual. A idade prevalente de iniciacao sexual foi de 14 a 16 anos, com 55,7%; 65,6% usaram preservativo na ultima relacao. Com relacao ao nao uso de preservativo na ultima relacao, as meninas apresentaram associacao com bebedeira nos ultimos 30 dias (2,19; IC95%: 1,06-4,54). CONCLUSAO: O nao uso de preservativos esteve associado com bebedeira nos ultimos 30 dias nas meninas. PMID- 27462888 TI - Pain assessment in elderly with dementia: Brazilian validation of the PACSLAC scale. AB - OBJECTIVE: To validate the Pain Assessment Checklist for Seniors with Limited Ability to Communicate - Portuguese in demented elderly and to analyze its measurement properties. METHODS: We evaluated 50 elderly with dementia, residing in a nursing home and with limited communication ability, when exposed to potentially painful situations. The tool was applied at two different moments. First, two interviewers applied it simultaneously, and the intensity of pain was asked based on the caregiver's opinion. After 14 days, with no analgesic intervention, one of the interviewers applied it again. RESULTS: The sample comprised more females, aged over 80 years, with dementia due to Alzheimer, presenting musculoskeletal pain of moderate to severe intensity. The psychometric properties of the tool demonstrated appropriate internal consistency (Cronbach's alpha coefficient of 0.827). The scale had excellent reproducibility, according to the intraclass correlation coefficient, and the tool has been duly validated. CONCLUSION: The Pain Assessment Checklist for Seniors with Limited Ability to Communicate - Portuguese had adequate measuring properties for use with elderly presenting limited communication. OBJETIVO: Validar o Pain Assessment Checklist for Seniors with Limited Ability to Communicate - Portuguese em idosos dementados e analisar as propriedades de suas medicoes. METODOS: Foram avaliados 50 idosos dementados, residentes de uma casa de repouso e com capacidade de comunicacao verbal limitada, quando expostos a situacoes potencialmente dolorosas. A ferramenta foi utilizada em dois momentos diferentes. Primeiro, foi aplicada por dois entrevistadores simultaneamente, e a intensidade da dor foi questionada com base na opiniao do cuidador. Depois de 14 dias, sem intervencao de analgesico, a ferramenta foi aplicada novamente por um dos entrevistadores. RESULTADOS: A amostra teve predominancia de mulheres, acima de 80 anos de idade, com demencia de Alzheimer, apresentando dores musculoesqueleticas com intensidade moderada a grave. As propriedades psicometricas do instrumento demonstraram consistencia interna adequada (coeficiente alfa de Cronbach de 0,827). A escala teve excelente reprodutibilidade, de acordo com o coeficiente de correlacao intraclasse, e o instrumento demonstrou validade adequada. CONCLUSAO: O Pain Assessment Checklist for Seniors with Limited Ability to Communicate - Portuguese teve propriedades de medicao adequadas para idosos com limitacoes de comunicacao. PMID- 27462889 TI - Content validity of the Geriatric Health Assessment Instrument. AB - OBJECTIVE: Assess the content validity of the Elderly Health Assessment Tool with low education. METHODS: The data collection instrument/questionnaire was prepared and submitted to an expert panel comprising four healthcare professionals experienced in research on epidemiology of aging. The experts were allowed to suggest item inclusion/exclusion and were asked to rate the ability of individual items in questionnaire blocks to encompass target dimensions as "not valid", "somewhat valid" or "valid", using an interval scale. Percent agreement and the Content Validity Index were used as measurements of inter-rater agreement; the minimum acceptable inter-rater agreement was set at 80%. RESULTS: The mean instrument percent agreement rate was 86%, ranging from 63 to 99%, and from 50 to 100% between and within blocks respectively. The Mean Content Validity Index score was 93.47%, ranging from 50 to 100% between individual items. CONCLUSION: The instrument showed acceptable psychometric properties for application in geriatric populations with low levels of education. It enabled identifying diseases and assisted in choice of strategies related to health of the elderly. OBJETIVO: Avaliar a validade de conteudo do Instrumento de Avaliacao da Saude do Idoso com baixa escolaridade. METODOS: Apos a elaboracao do instrumento de coleta de dados, o questionario foi submetido a avaliacao de um comite de especialistas, formado por quatro profissionais da area da saude com experiencia em pesquisas da epidemiologia do envelhecimento. Os especialistas puderam sugerir questoes a serem incluidas/excluidas do instrumento, e avaliar cada bloco do questionario, observando se as dimensoes a serem avaliadas foram abrangidas pelos itens do instrumento, em escala intervalar, como "nao valida", "pouco valida" e "valida". Como medidas para avaliar o grau de concordancia do instrumento, foram utilizados o porcentual de concordancia e o Indice de Validade de Conteudo. Considerou-se uma taxa aceitavel de concordancia o valor de 80%. RESULTADOS: O instrumento apresentou taxa media de concordancia de 86%, variando, dentre os blocos, de 63 a 99% e, dentre os itens, de 50 a 100%. O Indice de Validade de Conteudo apresentou escore medio de 93,47% e, dentre os itens do questionario, de 50 a 100%. CONCLUSAO: O instrumento apresentou qualidades psicometricas aceitaveis para ser utilizado entre a populacao de idosos com baixa escolaridade, permitindo a identificacao dos agravos e auxiliando na escolha de estrategias, no que diz respeito a saude do idoso. PMID- 27462891 TI - Potential intravenous drug incompatibilities in a pediatric unit. AB - OBJECTIVE: To investigate potential intravenous drug incompatibilities and related risk factors in a pediatric unit. METHODS: A cross-sectional analytical study conducted in the pediatric unit of a university hospital in Brazil. Data on prescriptions given to children aged 0-15 years from June to October 2014 were collected. Prescriptions that did not include intravenous drugs and prescriptions with incomplete dosage regimen or written in poor handwriting were excluded. Associations between variables and the risk of potential incompatibility were investigated using the Student's t test and ANOVA; the level of significance was set at 5% (p<0.05). Relative risks were calculated for each drug involved in potential incompatibility with 95% confidence interval. RESULTS: A total of 222 children participated in the study; 132 (59.5%) children were male and 118 (53.2%) were aged between 0 and 2 years. The mean length of stay was 7.7+/-2.3 days. Dipyrone, penicillin G and ceftriaxona were the most commonly prescribed drugs. At least one potential incompatibility was detected in about 85% of children (1.2 incompatibility/patient ratio). Most incompatibilities detected fell into the non-tested (93.4%), precipitation (5.5%), turbidity (0.7%) or chemical decomposition (0.4%) categories. The number of drugs and prescription of diazepam, phenytoin, phenobarbital or metronidazole were risk factors for potential incompatibility. CONCLUSION: Most pediatric prescriptions involved potential incompatibilities, with higher prevalence of non-tested incompatibilities. The number of drugs and prescription of diazepam, phenobarbital, phenytoin or metronidazole were risk factors for potential incompatibilities. OBJETIVO: Avaliar o potencial de incompatibilidade dos medicamentos intravenosos, identificando possiveis fatores de risco em uma unidade pediatrica. METODOS: Trata-se de um estudo observacional analitico do tipo transversal realizado na unidade de pediatria de um hospital de ensino no Brasil. Os dados foram coletados de junho a outubro de 2014 a partir da analise das prescricoes de criancas (0 a 15 anos) hospitalizadas. Foram excluidas prescricoes sem medicamento intravenoso e com posologia incompletas ou grafia inadequada. A associacao entre as variaveis e o risco de potenciais incompatibilidades foi determinada pelo teste t de Student e ANOVA, considerando significativo para p<0,05. Calculou-se o risco relativo com intervalo de confianca de 95% de cada medicamento envolvido. RESULTADOS: Duzentos e vinte e duas criancas participaram do estudo, 132 (59,5%) eram do genero masculino, 118 (53,2%) tinham idade entre 0 a 2 anos e estiveram internados em media 7,7+/-2,3 dias. Os medicamentos mais prescritos foram dipirona, penicilina G e ceftriaxona. Quase 85% das criancas apresentaram ao menos uma potencial incompatibilidade, razao de 1,2 incompatibilidades/paciente. Os tipos de incompatibilidades mais comuns foram: nao testada (93,4%), precipitacao (5,5%), turbidez (0,7%) e decomposicao quimica (0,4%). Os fatores associados a potenciais incompatibilidades foram: numero de medicamentos e a prescricao dos medicamentos diazepam, fenitoina, fenobarbital e metronidazol. CONCLUSAO: A maioria das prescricoes pediatricas apresentou potenciais incompatibilidades e a incompatibilidade nao testada foi o tipo mais comum. O numero de medicamentos e a prescricao dos medicamentos diazepam, fenobarbital, fenitoina e metronidazol foram fatores de risco para potenciais incompatibilidades. PMID- 27462890 TI - Assessment of physicians' addressing sexuality in elderly patients with chronic pain. AB - OBJECTIVE: To determine the frequency with which physicians address their older adult patients with chronic pain about the issue of sexuality. METHODS: It is a cross sectional, descriptive, analytical study in which physicians answered a questionnaire comprising questions related to addressing the issue of sexuality during appointments. RESULTS: A sample of 155 physicians was obtained, 63.9% stated they did not address sexuality in medical interviews and 23.2% did it most of the time. The main reasons for not addressing were lack of time, fear of embarrassing the patient and technical inability to address the issue. CONCLUSION: There is a need to develop strategies to increase and improve addressing of sexuality in elderly patients with chronic pain, in order to have better quality of life. OBJETIVO: Determinar a frequencia com que os medicos abordam o assunto de sexualidade com seus pacientes mais idosos com dor cronica. METODOS: Este e um estudo transversal, descritivo, analitico em que os medicos responderam a um questionario com perguntas relativas a abordagem de sexualidade nas consultas. RESULTADOS: Uma amostra de 155 medicos foi obtida, 63,9% afirmaram que nao realizavam a abordagem da sexualidade e 23,2% afirmaram faze-la na maior parte das vezes. As principais razoes para nao abordarem foram falta de tempo, medo de constranger o paciente e incapacidade tecnica para abordar o assunto. CONCLUSAO: Existe uma necessidade de desenvolver estrategias para aumentar e melhorar a abordagem de sexualidade em idosos com dor cronica, de forma a melhorar sua qualidade de vida. PMID- 27462892 TI - Overweight effect on spirometric parameters in adolescents undergoing exercise. AB - OBJECTIVE: To evaluate effects of overweight on spirometric parameters in adolescents who underwent bronchial provocation test for exercise. METHODS: We included 71 male adolescents. The diagnosis of asthma was done based on participants' clinical history and on the International Study Questionnaire Asthma and Allergies in Childhood, and the diagnosis of obesity was based on body mass index above 95th percentile. The bronchospasm induced by exercise was assessed using the run-walk test on a treadmill for eight minutes. The decrease in forced expiratory volume in one second > or equal to 10% before exercise was considered positive, and to calculate the intensity in exercise-induced bronchospasm we measured the maximum percentage of forced expiratory volume in one second and above the curve area. Data analysis was carried out using the Mann Whitney U test and Friedman test (ANOVA), followed by Wilcoxon test (p<0.05). In addition, we used Fisher's exact test to analyze the exercise-induced bronchospasm frequency. RESULTS: Significant differences were observed among obese adolescents in exercise-induced bronchospasm frequency (p=0,013) and in relation to time required for recovery after exercise (p=0,007). CONCLUSION: Overweight can influence the increase in the exercise-induced bronchospasm frequency in non-asthmatic adolescents compared with eutrophic adolescents. OBJETIVO: Avaliar o efeito do excesso de peso sobre parametros espirometricos em adolescentes submetidos ao teste de broncoprovocacao por exercicio. METODOS: Participaram do estudo 71 adolescentes do sexo masculino. O diagnostico de asma foi obtido por meio de historico clinico e do questionario International Study of Asthma and Allergies in Childhood, e o de obesidade, pelo indice de massa corporal acima do percentil 95. Para avaliar o broncoespasmo induzido pelo exercicio, utilizou-se o teste correr/caminhar em esteira ergometrica, com duracao de 8 minutos, considerando positivo se diminuicao do volume expiratorio forcado no primeiro segundo >10% do valor pre-exercicio e, para a intensidade do broncoespasmo induzido pelo exercicio, foram utilizados o calculo da queda percentual maxima do volume expiratorio forcado no primeiro segundo e a area acima da curva. A analise dos dados foi realizada pelo teste U Mann-Whitney e pela ANOVA de Friedman, seguido do teste de Wilcoxon (p<0,05). O teste de Fisher foi empregado para analisar a frequencia de broncoespasmo induzido pelo exercicio. RESULTADOS: Foram encontradas diferencas significativas quanto a frequencia de broncoespasmo induzido pelo exercicio (p=0,013) e ao tempo de recuperacao pos-exercicio (p=0,007) nos adolescentes obesos. CONCLUSAO: O excesso de peso pode influenciar no aumento da frequencia de broncoespasmo induzido pelo exercicio em adolescentes nao asmaticos, quando comparados a eutroficos. PMID- 27462893 TI - Is the algorithm used to process heart rate variability data clinically relevant? Analysis in male adolescents. AB - OBJECTIVE: To analyze whether the algorithm used for the heart rate variability assessment (fast Fourier transform versus autoregressive methods) influenced its association with cardiovascular risk factors in male adolescents. METHODS: This cross-sectional study included 1,152 male adolescents (aged 14 to 19 years). The low frequency, high frequency components (absolute numbers and normalized units), low frequency/high frequency ratio, and total power of heart rate variability parameters were obtained using the fast Fourier transform and autoregressive methods, while the adolescents were resting in a supine position. RESULTS: All heart rate variability parameters calculated from both methods were different (p<0.05). However, a low effect size (<0.1) was found for all parameters. The intra-class correlation between methods ranged from 0.96 to 0.99, whereas the variation coefficient ranged from 7.4 to 14.8%. Furthermore, waist circumference was negatively associated with high frequency, and positively associated with low frequency and sympatovagal balance (p<0.001 for both fast Fourier transform and autoregressive methods in all associations). Systolic blood pressure was negatively associated with total power and high frequency, whereas it was positively associated with low frequency and sympatovagal balance (p<0.001 for both fast Fourier transform and autoregressive methods in all associations). Body mass index was negatively associated with high frequency, while it was positively associated with low frequency and sympatovagal balance (p values ranged from <0.001 to 0.007). CONCLUSION: There are significant differences in heart rate variability parameters obtained with the fast Fourier transform and autoregressive methods in male adolescent; however, these differences are not clinically significant. OBJETIVO: Analisar se o algoritmo usado para avaliacao da variabilidade da frequencia cardiaca (transformada rapida de Fourier versus autoregressivo) influencia em sua associacao com fatores de risco cardiovascular adolescentes do genero masculino. METODOS: Estudo transversal, que incluiu 1.152 adolescentes do genero masculino (14 a 19 anos). Componentes de baixa e alta frequencia (absolutos e unidades normalizadas), razao componente de baixa frequencia/componente de alta frequencia e poder total da variabilidade da frequencia cardiaca foram obtidos em repouso, na posicao supina, usando os metodos transformada rapida de Fourier e autorregressivo. RESULTADOS: Todos os parametros da variabilidade da frequencia cardiaca para ambos os metodos foram diferentes (p<0,05). Entretanto, um pequeno tamanho do efeito (<0,1) foi observado para todos os parametros. Os coeficientes de correlacao intraclasse entre os metodos variaram de 0,96 a 0,99, enquanto os coeficientes de variacao foram de 7,4 a 14,8%. A circunferencia abdominal foi negativamente associada com o componente de alta frequencia, e positivamente associada com o componente de baixa frequencia e o balanco simpatovagal (p<0,001 para a transformada rapida de Fourier e o autorregressivo em todas as associacoes). A pressao arterial sistolica foi negativamente associada com o poder total e o componente de alta frequencia, enquanto foi positivamente associada com o componente de baixa frequencia e o balanco simpatovagal (p<0,001 para a transformada rapida de Fourier e o autorregressivo em todas as associacoes). O indice de massa corporal foi negativamente associado com o componente de alta frequencia, enquanto foi positivamente associado com o componente de baixa frequencia e o balanco simpatovagal (valores de p variando de <0,001 a 0,007). CONCLUSAO: Houve diferencas significantes nos parametros da variabilidade da frequencia cardiaca obtidos com os metodos transformada rapida de Fourier e autorregressivo em adolescentes masculinos, mas essas diferencas nao foram clinicamente significativas. PMID- 27462895 TI - Auditory evoked potential P300 in adults: reference values. AB - OBJECTIVE: To establish reference intervals for cognitive potential P300 latency using tone burst stimuli. METHODS: This study involved 28 participants aged between 18 and 59 years. P300 recordings were performed using a two-channel device (Masbe, Contronic). Electrode placement was as follows: Fpz (ground electrode), Cz (active electrode), M1 and M2 (reference electrodes). Intensity corresponded to 80 dB HL and frequent and rare stimulus frequencies to 1,000Hz and 2,000Hz, respectively. Stimuli were delivered binaurally. RESULTS: Mean age of participants was 35 years. Average P300 latency was 305ms. CONCLUSION: Maximum acceptable P300 latency values of 362.5ms (305 + 2SD 28.75) were determined for adults aged 18 to 59 years using the protocol described. OBJETIVO: Estabelecer valores de referencia para a latencia do potencial cognitivo P300 com estimulos tone burst. METODOS: Participaram do estudo 28 individuos entre 18 e 59 anos. O registro do P300 foi realizado no equipamento Masbe da marca Contronic. Os eletrodos foram fixados nas posicoes Fpz (eletrodo terra), Cz (eletrodo ativo), M1 e M2 (eletrodos referencia). A intensidade foi de 80 dB NA. A frequencia do estimulo frequente foi de 1.000Hz e a do estimulo raro de 2.000Hz. Os estimulos foram apresentados na forma binaural. RESULTADOS: A media de idade dos individuos foi de 35 anos. A media de latencia para P300 de 305ms. CONCLUSAO: Usando o protocolo descrito, o valor maximo de latencia aceitaveis para P300 foram de 362,5ms (305 + 2DP 28,75) na faixa etaria do adulto de 18 a 59 anos. PMID- 27462896 TI - Assessment of nurse's knowledge about Glasgow coma scale at a university hospital. AB - OBJECTIVE: To assess knowledge of nurses of emergency services and intensive care units about Glasgow Coma Scale. METHODS: This cross-sectional analytical study included 127 nurses of critical units of an university hospital. We used structured interview with 12 questions to evaluate their knowledge about the scale. Association of Knowledge with professionals' sociodemographic variables were verified by the Fisher-test, chi2 and likelihood ratio. RESULTS: Most of participants were women mean aged 31.1 years, they had graduated more than 5 years previously, and had 1 to 3 years of work experience. In the assessment of best score possible for Glasgow scale (question 3) nurses who had graduate more than 5 years ago presented a lower percentage success rate (p=0.0476). However, in the question 7, which evaluated what interval of the scale indicated moderate severity of brain trauma injury, those with more years of experience had higher percentage of correct answers (p=0.0251). In addition, nurses from emergency service had more correct answers than nurses from intensive care unit (p=0.0143) in the same question. Nurses graduated for more than 5 years ago had a lower percentage of correct answers in question 7 (p=0.0161). Nurses with more work experience had a better score (p=0.0119) to identify how assessment of motor response should be started. CONCLUSION: Number of year since graduation, experience, and work at critical care units interfered in nurses' knowledge about the scale, which indicates the need of training. OBJETIVO: Avaliar o conhecimento de enfermeiros de unidades criticas, servicos de emergencia e unidades de terapia intensiva em relacao a escala de coma de Glasgow. METODOS: Estudo transversal e analitico com 127 enfermeiros de unidades criticas de um hospital universitario. Utilizou-se entrevista estruturada com 12 questoes que avaliaram conhecimento sobre a escala. Associacao do conhecimento com variaveis sociodemograficas dos profissionais foi verificada pelo teste de Fisher, teste chi2 e razao de verossimilhanca. RESULTADOS: Houve predominancia de mulheres, media de idade de 31,1 anos, especialistas, mais de 5 anos de formado e experiencia profissional de 1 a 3 anos. Na avaliacao do melhor escore possivel para pontuacao na escala (questao 3), enfermeiros com tempo de formacao maior que 5 anos apresentaram menor porcentual de acertos (p=0,0476). Em relacao a questao 7, que avaliou qual intervalo da escala indicava gravidade moderada do trauma craniencefalico, observou-se que quanto maior o tempo de experiencia, maior o porcentual de acertos (p=0,0251), sendo que enfermeiros do servico de emergencia tiveram mais acertos nessa questao em relacao aos das unidades de terapia intensiva (p=0,0143). Alem disso, enfermeiros formados ha mais de 5 anos apresentaram menor porcentual de acertos nessa questao (p=0,0161). Quando se identificou como deve ser iniciada a avaliacao da resposta motora, enfermeiros com maior tempo de trabalho na unidade apresentaram mais acertos (p=0,0119). CONCLUSAO: Tempo de formacao, experiencia e trabalho na unidade interferiu no conhecimento de enfermeiros sobre a escala, evidenciando necessidade de capacitacao. PMID- 27462894 TI - Impact of respiratory therapy in vital capacity and functionality of patients undergoing abdominal surgery. AB - OBJECTIVE: To evaluate the vital capacity after two chest therapy techniques in patients undergoing abdominal surgical. METHODS: A prospective randomized study carried out with patients admitted to the Intensive Care Unit after abdominal surgery. We checked vital capacity, muscular strength using the Medical Research Council scale, and functionality with the Functional Independence Measure the first time the patient was breathing spontaneously (D1), and also upon discharge from the Intensive Care Unit (Ddis). Between D1 and Ddis, respiratory therapy was carried out according to the randomized group. RESULTS: We included 38 patients, 20 randomized to Positive Intermittent Pressure Group and 18 to Volumetric Incentive Spirometer Group. There was no significant gain related to vital capacity of D1 and Ddis of Positive Intermittent Pressure Group (mean 1,410mL+/ 547.2 versus 1,809mL+/-692.3; p=0.979), as in the Volumetric Incentive Spirometer Group (1,408.3mL+/-419.1 versus 1,838.8mL+/-621.3; p=0.889). We observed a significant improvement in vital capacity in D1 (p<0.001) and Ddis (p<0.001) and in the Functional Independence Measure (p<0.001) after respiratory therapy. The vital capacity improvement was not associated with gain of muscle strength. CONCLUSION: Chest therapy, with positive pressure and volumetric incentive spirometer, was effective in improving vital capacity of patients submitted to abdominal surgery. OBJETIVO: Avaliar a capacidade vital comparando duas tecnicas de fisioterapia respiratoria em pacientes submetidos a cirurgia abdominal. METODOS: Estudo prospectivo e randomizado realizado com pacientes admitidos em Unidade de Terapia Intensiva apos cirurgia abdominal. Verificamos a capacidade vital, a forca muscular por meio da escala do Medical Research Council e funcionalidade pela Medida de Independencia Funcional no primeiro momento em que o paciente encontrava-se em respiracao espontanea (D1) e na alta da Unidade de Terapia Intensiva (Dalta). Entre D1 e Dalta, foi realizada a fisioterapia respiratoria, conforme o grupo randomizado. RESULTADOS: Foram incluidos 38 pacientes, sendo 20 randomizados para Grupo Pressao Positiva Intermitente e 18 para o Grupo Incentivador Inspiratorio a Volume. A capacidade vital entre o D1 e Dalta do Grupo Pressao Positiva Intermitente nao teve ganho significativo (media de 1.410mL+/-547,2 versus 1.809mL+/-692,3; p=0,979), assim como no Grupo Incentivador Inspiratorio a Volume (1.408,3mL+/-419,1 versus 1.838,8mL+/-621,3; p=0,889). Houve melhora significativa da capacidade vital no D1 (p<0,001) e na Dalta (p<0,001) e da Medida de Independencia Funcional (p<0,001) apos a fisioterapia respiratoria. A melhora da capacidade vital nao apresentou relacao com o ganho da forca muscular. CONCLUSAO: A fisioterapia respiratoria, por meio de pressao positiva ou de incentivador inspiratorio a volume, foi eficaz na melhora da capacidade vital em pacientes submetidos a cirurgia abdominal. PMID- 27462897 TI - Impact of dental orientation given to mothers during pregnancy on oral health of their children. AB - OBJECTIVE: To analyze the perception of mothers about oral health of their children, as well as to check the influence of demographic variables, perception and preventive practice in oral health of mothers regarding guidance received during pregnancy. METHODS: Quantitative and cross-sectional field study, with a non-probability sample formed by all mothers who attended the primary healthcare unit of Ijui (RS), Brazil, from January to July 2014, comprising a sample of 79 women. Self-applied questionnaires were given to these mothers. Data analysis was carried out using descriptive and inferential statistics, the chi2 test at a significance level of 5%. RESULTS: The mothers who received dental orientation during pregnancy had greater perception of oral health of their children. The mean age of mothers was 26 years, most of them attended high school education (32.9%) and worked outside the home (60.8%). There was a statistically significant relation between the outcome variable, dental orientation during pregnancy, and the independent variables: schooling level of mothers, occupation, baby's first visit to the dentist, duration of breastfeeding, beginning of baby's tooth brushing and knowledge about dental decay (p<0.005). CONCLUSION: Mothers with higher schooling levels and who worked outside the home had more knowledge about oral care, because they received dental orientation during pregnancy. The dental guidance during pregnancy influences the mother in the procedures adopted with their children, as to early oral hygiene, first dentist appointment, duration of breastfeeding, knowledge about the factors that lead to dental decay. OBJETIVO: Analisar a percepcao das maes em relacao a saude bucal de seus filhos, bem como verificar a influencia das variaveis demograficas, de percepcao e pratica preventiva em saude bucal das maes, na orientacao odontologica recebida durante a gestacao. METODOS: Pesquisa de campo com abordagem quantitativa e delineamento transversal. A amostragem foi nao probabilistica com todas as maes que frequentaram o posto de saude do municipio de Ijui (RS), de janeiro a julho de 2014, compondo uma amostra de 79 mulheres. Foram distribuidos questionarios autoaplicativos as maes participantes da pesquisa. A analise dos dados foi feita atraves de estatistica descritiva e inferencial, pelo teste do chi2 com nivel de significancia de 5%. RESULTADOS: Maes que receberam orientacao odontologica durante a gestacao tiveram maior percepcao sobre a saude bucal de seus filhos. A media de idade das maes foi 26 anos, e a maioria delas frequentou o ensino medio completo (32,9%) e trabalhava fora de casa (60,8%). Houve uma relacao estatisticamente significativa entre a variavel desfecho, orientacao odontologica durante a gestacao e as variaveis independentes: escolaridade das maes, ocupacao, primeira visita do bebe ao dentista, tempo de amamentacao natural, inicio da escovacao do bebe e conhecimento sobre a carie dentaria (p<0,005). CONCLUSAO: As maes com maior nivel de escolaridade e que trabalhavam fora de casa tinham mais conhecimento sobre atencao odontologica, pois receberam orientacao odontologica na gestacao. A orientacao odontologica recebida na gestacao influencia as maes nos procedimentos adotados com seus filhos, em relacao ao inicio da higienizacao bucal, primeira consulta ao dentista, tempo de amamentacao, o conhecimento sobre os fatores que levam ao aparecimento da carie dentaria. PMID- 27462898 TI - Effectiveness of psychosocial interventions in eating disorders: an overview of Cochrane systematic reviews. AB - Eating disorders are psychiatric conditions originated from and perpetuated by individual, family and sociocultural factors. The psychosocial approach to treatment and prevention of relapse is crucial. To present an overview of the scientific evidence on effectiveness of psychosocial interventions in treatment of eating disorders. All systematic reviews published by the Cochrane Database of Systematic Reviews - Cochrane Library on the topic were included. Afterwards, as from the least recent date of these reviews (2001), an additional search was conducted at PubMed with sensitive search strategy and with the same keywords used. A total of 101 primary studies and 30 systematic reviews (5 Cochrane systematic reviews), meta-analysis, guidelines or narrative reviews of literature were included. The main outcomes were: symptomatic remission, body image, cognitive distortion, psychiatric comorbidity, psychosocial functioning and patient satisfaction. The cognitive behavioral approach was the most effective treatment, especially for bulimia nervosa, binge eating disorder and the night eating syndrome. For anorexia nervosa, the family approach showed greater effectiveness. Other effective approaches were interpersonal psychotherapy, dialectic behavioral therapy, support therapy and self-help manuals. Moreover, there was an increasing number of preventive and promotional approaches that addressed individual, family and social risk factors, being promising for the development of positive self-image and self-efficacy. Further studies are required to evaluate the impact of multidisciplinary approaches on all eating disorders, as well as the cost-effectiveness of some effective modalities, such as the cognitive behavioral therapy. RESUMO Transtornos alimentares sao doencas psiquiatricas originadas de e perpetuadas por fatores individuais, familiares e socioculturais. A abordagem psicossocial e essencial para o tratamento e a prevencao de recaidas. Apresentar uma visao geral das evidencias cientificas sobre a efetividade das intervencoes psicossociais no tratamento de transtornos alimentares. Foram incluidas todas as revisoes sistematicas publicadas no Banco de Dados de Revisoes Sistematicas da Cochrane Library. Posteriormente, a partir da data menos recente destas revisoes (2001), realizou-se uma busca adicional no PubMed, com estrategia de busca sensibilizada e com os mesmos descritores utilizados antes. No total, foram incluidos 101 estudos primarios e 30 revisoes sistematicas (5 revisoes sistematicas da Cochrane), metanalises, diretrizes ou revisoes narrativas da literatura. Os principais desfechos foram remissao de sintomas, imagem corporal, distorcao cognitiva, comorbidade psiquiatrica, funcionamento psicossocial e satisfacao do paciente. A abordagem cognitivo comportamental foi o tratamento mais efetivo, principalmente para bulimia nervosa, transtorno da compulsao alimentar periodica e sindrome do comer noturno. Para anorexia nervosa, a abordagem familiar demonstrou maior efetividade. Outras abordagens efetivas foram psicoterapia interpessoal, terapia comportamental dialetica, terapia de apoio e manuais de autoajuda. Alem disso, houve um numero crescente de abordagens preventivas e promocionais que contemplaram fatores de risco individuais, familiares e sociais, sendo promissoras para o desenvolvimento da autoimagem positiva e autoeficacia. Sao necessarios mais estudos que avaliem o impacto de abordagens multidisciplinares em todos transtornos alimentares, alem da relacao custo-efetividade de algumas modalidades efetivas, como a terapia cognitivo-comportamental. PMID- 27462900 TI - The advances and new technologies for the study of mitochondrial diseases. AB - ABSTRACTGenetic mitochondrial disorders are responsible for the most common inborn errors of metabolism, caused by mutations in either nuclear genes or in mitochondrial DNA. This article presents the prokaryotic origin of the organelle and the relation between nuclear and mitochondrial genomes, as well as current evolutionary models for such mechanisms. It also addresses the structure of mitochondrial genes, their expression pattern, clinical features of gene defects, risk of transmission and current techniques to avoid these events in assisted human reproduction. Finally, it discusses the ethical implications of these possibilities.RESUMOAs doencas geneticas mitocondriais sao responsaveis pelos erros inatos do metabolismo mais comuns, causados por mutacoes tanto em genes nucleares como no DNA mitocondrial. Este artigo apresenta a origem procariotica dessa organela, e a relacao entre os genomas nuclear e mitocondrial, bem como modelos evolutivos correntes para esses mecanismos. Tambem trata da estrutura dos genes mitocondriais, seu padrao de expressao, caracteristicas clinicas de defeitos geneticos, riscos de transmissao e tecnicas atualmente utilizadas para evitar esses eventos em reproducao humana assistida. Finalmente, discute as implicacoes eticas dessas possibilidades. PMID- 27462899 TI - Group A rotavirus gastroenteritis: post-vaccine era, genotypes and zoonotic transmission. AB - ABSTRACTThis article provides a review of immunity, diagnosis, and clinical aspects of rotavirus disease. It also informs about the changes in epidemiology of diarrheal disease and genetic diversity of circulating group A rotavirus strains following the introduction of vaccines. Group A rotavirus is the major pathogen causing gastroenteritis in animals. Its segmented RNA genome can lead to the emergence of new or unusual strains in human populations via interspecies transmission and/or reassortment events.RESUMOEste artigo fornece uma revisao sobre imunidade, diagnostico e aspectos clinicos da doenca causada por rotavirus. Tambem aponta as principais mudancas no perfil epidemiologico da doenca diarreica e na diversidade genetica das cepas circulantes de rotavirus do grupo A, apos a introducao vacinal. O rotavirus do grupo A e o principal patogeno associado a gastroenterite em animais. Seu genoma RNA segmentado pode levar ao surgimento de cepas novas ou incomuns na populacao humana, por meio de transmissao entre especies e eventos de rearranjo. PMID- 27462902 TI - Identification of Novel Transcribed Regions in Zebrafish (Danio rerio) Using RNA Sequencing. AB - Zebrafish (Danio rerio) has emerged as a model organism to investigate vertebrate development and human genetic diseases. However, the zebrafish genome annotation is still ongoing and incomplete, and there are still new gene transcripts to be found. With the introduction of massive parallel sequencing, whole transcriptome studies became possible. In the present study, we aimed to discover novel transcribed regions (NTRs) using developmental transcriptome data from RNA sequencing. In order to achieve this, we developed an in-house bioinformatics pipeline for NTR discovery. Using the pipeline, we detected 152 putative NTRs that at the time of discovery were not annotated in Ensembl and NCBI gene database. Four randomly selected NTRs were successfully validated using RT-PCR, and expression profiles of 10 randomly selected NTRs were evaluated using qRT PCR. The identification of these 152 NTRs provide new information for zebrafish genome annotation as well as new candidates for studies of zebrafish gene function. PMID- 27462901 TI - An update on clinical oncology for the non-oncologist. AB - ABSTRACTRecent advances in the understanding of tumor driver mutations, signaling pathways that lead to tumor progression, and the better understanding of the interaction between tumor cells and the immune system are revolutionizing cancer treatment. The pace at which new treatments are approved and the prices at which they are set have made it even more difficult to offer these treatments in countries like Brazil. In this review we present for the non-oncologist these new treatments and compare their availability in Brazilian public health system and private health system with that of developed countries.RESUMOAvancos recentes na compreensao de mutacoes promotoras de desenvolvimento do cancer, sinalizacao que leva a progressao de tumores, e o avanco no entendimento da interacao entre as celulas tumorais e o sistema imunologico estao revolucionando o tratamento do cancer. A velocidade com que novos tratamentos sao aprovados e o alto custo das medicacoes dificultam a disponibilizacao de terapeuticas em paises como o Brasil. Nesta revisao, apresentamos ao nao oncologista esses novos tratamentos e comparamos sua disponibilidade nos sistemas publico e privado de saude no Brasil com os paises desenvolvidos. PMID- 27462903 TI - Statistical Analysis for Subjective and Objective Evaluations of Dental Drill Sounds. AB - The sound produced by a dental air turbine handpiece (dental drill) can markedly influence the sound environment in a dental clinic. Indeed, many patients report that the sound of a dental drill elicits an unpleasant feeling. Although several manufacturers have attempted to reduce the sound pressure levels produced by dental drills during idling based on ISO 14457, the sound emitted by such drills under active drilling conditions may negatively influence the dental clinic sound environment. The physical metrics related to the unpleasant impressions associated with dental drill sounds have not been determined. In the present study, psychological measurements of dental drill sounds were conducted with the aim of facilitating improvement of the sound environment at dental clinics. Specifically, we examined the impressions elicited by the sounds of 12 types of dental drills in idling and drilling conditions using a semantic differential. The analysis revealed that the impressions of dental drill sounds varied considerably between idling and drilling conditions and among the examined drills. This finding suggests that measuring the sound of a dental drill in idling conditions alone may be insufficient for evaluating the effects of the sound. We related the results of the psychological evaluations to those of measurements of the physical metrics of equivalent continuous A-weighted sound pressure levels (LAeq) and sharpness. Factor analysis indicated that impressions of the dental drill sounds consisted of two factors: "metallic and unpleasant" and "powerful". LAeq had a strong relationship with "powerful impression", calculated sharpness was positively related to "metallic impression", and "unpleasant impression" was predicted by the combination of both LAeq and calculated sharpness. The present analyses indicate that, in addition to a reduction in sound pressure level, refining the frequency components of dental drill sounds is important for creating a comfortable sound environment in dental clinics. PMID- 27462904 TI - Surface Assembly Configurations and Packing Preferences of Fibrinogen Mediated by the Periodicity and Alignment Control of Block Copolymer Nanodomains. AB - The ability to control the specific adsorption and packing behaviors of biomedically important proteins by effectively guiding their preferred surface adsorption configuration and packing orientation on polymeric surfaces may have utility in many applications such as biomaterials, medical implants, and tissue engineering. Herein, we investigate the distinct adhesion configurations of fibrinogen (Fg) proteins and the different organization behaviors between single Fg molecules that are mediated by the changes in the periodicity and alignment of chemically alternating nanodomains in thin films of polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) block copolymer (BCP). Specifically, the adsorption characteristics of individual Fg molecules were unambiguously resolved on four different PS-b-PMMA templates of dsa PS-b-PMMA, sm PS-b-PMMA, com PS-b-PMMA, and PS-r-PMMA. By direct visualization through high resolution imaging, the distinct adsorption and packing configurations of both isolated and interacting Fg molecules were determined as a function of the BCP template-specific nanodomain periodicity, domain alignment (random versus fully aligned), and protein concentration. The three dominant Fg adsorption configurations, SP?, SP?, and TP, were observed and their occurrence ratios were ascertained on each PS-b-PMMA template. During surface packing, the orientation of the protein backbone was largely governed by the periodicity and alignment of the underlying PS-b-PMMA nanodomains whose specific direction was explicitly resolved relative to the polymeric nanodomain axis. The use of PS-b-PMMA with a periodicity much smaller than (and comparable to) the length of Fg led to a Fg scaffold with the protein backbone aligned parallel (and perpendicular) to the nanodomain major axis. In addition, we have successfully created fully Fg-decorated BCP constructs analogous to two-dimensional Fg crystals in which aligned protein molecules are arranged either side-on or end-on, depending on the BCP template. Our results demonstrate that the geometry and orientation of the protein can be effectively guided during Fg self-assembly by controlling the physical dimensions and orientations of the underlying BCP templates. Finally, the biofunctionality of the BCP surface-bound Fg was assessed and the Fg/BCP construct was successfully used in the Ca-P nanoparticle nucleation/growth and microglia cell activation. PMID- 27462906 TI - The Effect of Acclimation to Sublethal Temperature on Subsequent Susceptibility of Sitophilus zeamais Mostchulsky (Coleoptera: Curculionidae) to High Temperatures. AB - Heat treatment is a popular alternative to synthetic pesticides in disinfesting food-processing facilities and empty grain storages. Sitophilus zeamais Mostchulsky is one of the most cosmopolitan and destructive insects found in empty grain storage facilities and processing facilities. The effect of acclimation in S. zeamais adults to sublethal high temperature on their subsequent susceptibility to high temperatures was investigated. S. zeamais adults were acclimated to 36 degrees C for 0 (as a control), 1, 3, and 5 h, and then were exposed at 43, 47, 51, and 55 degrees C for different time intervals respectively. Acclimation to sublethal high temperature significantly reduced subsequent susceptibility of S. zeamais adults to lethal high temperatures of 43, 47, 51, and 55 degrees C, although the mortality of S. zeamais adults significantly increased with increasing exposure time at lethal high temperatures. The mortality of S. zeamais adults with 1, 3, and 5 h of acclimation to 36 degrees C was significantly lower than that of S. zeamais adults without acclimation when exposed to the same lethal high temperatures. The present results suggest that the whole facility should be heated to target lethal high temperature as soon as possible, avoiding decreasing the control effectiveness of heat treatment due to the acclimation in stored product insects to sublethal temperature. PMID- 27462905 TI - Cost Analysis of Universal Screening vs. Risk Factor-Based Screening for Methicillin-Resistant Staphylococcus aureus (MRSA). AB - BACKGROUND: The literature remains conflicted regarding the most effective way to screen for MRSA. This study was designed to assess costs associated with universal versus risk factor-based screening for the reduction of nosocomial MRSA transmission. METHODS: The study was conducted at The Ottawa Hospital, a large multi-centre tertiary care facility with approximately 47,000 admissions annually. From January 2006-December 2007, patients underwent risk factor-based screening for MRSA on admission. From January 2008 to August 2009 universal MRSA screening was implemented. A comparison of costs incurred during risk factor based screening and universal screening was conducted. The model incorporated probabilities relating to the likelihood of being tested and the results of polymerase chain reaction (PCR) testing with associated effects in terms of MRSA bacteremia and true positive and negative test results. Inputted costs included laboratory testing, contact precautions and infection control, private room costs, housekeeping, and length of hospital stay. Deterministic sensitivity analyses were conducted. RESULTS: The risk factor-based MRSA screening program screened approximately 30% of admitted patients and cost the hospital over $780 000 annually. The universal screening program screened approximately 83% of admitted patients and cost over $1.94 million dollars, representing an excess cost of $1.16 million per year. The estimated additional cost per patient screened was $17.76. CONCLUSION: This analysis demonstrated that a universal MRSA screening program was costly from a hospital perspective and was previously known to not be clinically effective at reducing MRSA transmission. These results may be useful to inform future model-based economic analyses of MRSA interventions. PMID- 27462907 TI - Ten-Year Mortality after a Breast Cancer Diagnosis in Women with Severe Mental Illness: A Danish Population-Based Cohort Study. AB - BACKGROUND: Breast cancer is the leading cause of cancer death in women worldwide. Nevertheless, it is unknown whether higher mortality after breast cancer contributes to the life-expectancy gap of 15 years in women with severe mental illness (SMI). METHODS: We estimated all-cause mortality rate ratios (MRRs) of women with SMI, women with breast cancer and women with both disorders compared to women with neither disorder using data from nationwide registers in Denmark for 1980-2012. RESULTS: The cohort included 2.7 million women, hereof 31,421 women with SMI (12,852 deaths), 104,342 with breast cancer (52,732 deaths), and 1,106 with SMI and breast cancer (656 deaths). Compared to women with neither disorder, the mortality was 118% higher for women with SMI (MRR: 2.18, 95% confidence interval (CI): 2.14-2.22), 144% higher for women with breast cancer (MRR: 2.44, 95% CI: 2.42-2.47) and 327% higher for women with SMI and breast cancer (MRR: 4.27, 95% CI: 3.98-4.57). Among women with both disorders, 15% of deaths could be attributed to interaction. In a sub-cohort of women with breast cancer, the ten-year all-cause-mortality was 59% higher after taking tumor stage into account (MRR: 1.59, 95% CI: 1.47-1.72) for women with versus without SMI. CONCLUSIONS: The mortality among women with SMI and breast cancer was markedly increased. More information is needed to determine which factors might explain this excess mortality, such as differences between women with and without SMI in access to diagnostics, provision of care for breast cancer or physical comorbidity, health-seeking-behavior, and adherence to treatment. PMID- 27462908 TI - Linear Energy Transfer-Dependent Change in Rice Gene Expression Profile after Heavy-Ion Beam Irradiation. AB - A heavy-ion beam has been recognized as an effective mutagen for plant breeding and applied to the many kinds of crops including rice. In contrast with X-ray or gamma-ray, the heavy-ion beam is characterized by a high linear energy transfer (LET). LET is an important factor affecting several aspects of the irradiation effect, e.g. cell survival and mutation frequency, making the heavy-ion beam an effective mutagen. To study the mechanisms behind LET-dependent effects, expression profiling was performed after heavy-ion beam irradiation of imbibed rice seeds. Array-based experiments at three time points (0.5, 1, 2 h after the irradiation) revealed that the number of up- or down-regulated genes was highest 2 h after irradiation. Array-based experiments with four different LETs at 2 h after irradiation identified LET-independent regulated genes that were up/down regulated regardless of the value of LET; LET-dependent regulated genes, whose expression level increased with the rise of LET value, were also identified. Gene ontology (GO) analysis of LET-independent up-regulated genes showed that some GO terms were commonly enriched, both 2 hours and 3 weeks after irradiation. GO terms enriched in LET-dependent regulated genes implied that some factor regulates genes that have kinase activity or DNA-binding activity in cooperation with the ATM gene. Of the LET-dependent up-regulated genes, OsPARP3 and OsPCNA were identified, which are involved in DNA repair pathways. This indicates that the Ku-independent alternative non-homologous end-joining pathway may contribute to repairing complex DNA legions induced by high-LET irradiation. These findings may clarify various LET-dependent responses in rice. PMID- 27462909 TI - Multimodal Imaging of Chemically Fixed Cells in Preparation for NanoSIMS. AB - In this work, we have employed time-of-flight secondary ion mass spectrometry (ToF-SIMS) to image chemically fixed adrenal cells prepared for transmission electron microscopy (TEM) and subsequent high-spatial-resolution NanoSIMS imaging. The sample fixation methodology preserves cell morphology, allows analysis in the ultrahigh vacuum environment, and reduces topographic artifacts, thus making these samples particularly favorable for ToF-SIMS analysis. ToF-SIMS imaging enables us to determine the chemistry and preservation capabilities of the chemical fixation as well as to locate specific ion species from OsO4. The OsO4 species have been localized in lysosomes of cortical cells, a type of adrenal cell present in the culture. NanoSIMS imaging of the (190)Os(16)O(-) ion species in cortical cells reveals the same localization as a wide range of OsO4 ions shown with ToF-SIMS. Even though we did not use during NanoSIMS imaging the exact OsxOy(-) ion species discovered with ToF-SIMS, ToF-SIMS allowed us to define the specific subcellular features in a high spatial resolution imaging mode. This study demonstrates the possibility for application of ToF-SIMS as a screening tool to optimize high-resolution imaging with NanoSIMS, which could replace TEM for localization in ultrahigh resolution imaging analyses. PMID- 27462910 TI - Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4 (3-Hydroxyphenyl)piperidine Opioid Receptor Antagonists. AB - In order to gain additional information concerning the active conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxyphenyl)3-azabicyclo[3.1.0]hexane and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a [35S]GTPgammaS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1. The studies of the rigid compounds also suggested that the 3-methyl group present in compound 1 type antagonists may not be necessary for their pure opioid antagonist properties. PMID- 27462911 TI - Organometallic Iridium Complex Containing a Dianionic, Tridentate, Mixed Organic Inorganic Ligand. AB - A pentamethylcyclopentadienyl-iridium complex containing a tricyclic, dianionic, tridentate, scorpionate (facial binding), mixed organic-inorganic ligand was synthesized and characterized by single-crystal X-ray crystallography, as well as polynuclear NMR, UV-vis, and IR spectroscopies. The central cycle of the tridentate ligand consists of a modified boroxine in which two of the boron centers are tetrahedral, anionic borates. The complex is stable to hydrolysis in aqueous solution for >9 weeks at 25 degrees C but reacts with a 50 mM solution of sodium periodate within 12 s to form a periodate-driven oxygen evolution catalyst that has a turnover frquency of >15 s(-1). However, the catalyst is almost completely deactivated within 5 min, achieving an average turnover number of ca. 2500 molecules of oxygen per atom of iridium. Nanoparticles were not observed on this time scale but did form within 4 h of catalyst activation under these experimental conditions. The parent complex was modeled using density functional theory, which accurately reflected the geometry of the complex and indicated significant interaction of iridium- and boracycle-centered orbitals. PMID- 27462912 TI - Deoxynivalenol, zearalenone and T-2 in grain based swine feed in Hungary. AB - Fusarium genera can produce trichothecenes like deoxynivalenol (DON), zearalenone (ZEN) and T-2 toxin, which can occur in feed cereal grains. Enzyme-linked immunosorbent assays (ELISA) tests of different Hungarian swine feedstuff proved that these mycotoxins were present. In this survey, 45 feed samples from 3 significant Hungarian swine feedstuff manufacturers were tested. ELISA methodology validation showed mean recovery rates in ranges from 85.3% to 98.1%, with intermediate precision of 86.9-96.9% and variation coefficients of 3.4-5.7% and 5.9-7.1%, respectively. The results showed that among Fusarium toxins, generally DON was present in the highest concentration, followed by T-2 and finally ZEN in all tested swine feeds. Each of the mycotoxins was found above the limit of detection in all swine feedstuffs. Boars feed's DON (average +/- standard deviation was 872 +/- 139 ug kg-1) and ZEN (172 +/- 18 ug kg-1) results of one of the manufacturers were above the guidance values. It indicates the necessity for efficient monitoring of DON, ZEN and T-2 mycotoxins in swine feeds. PMID- 27462913 TI - miR-646 is a key negative regulator of EGFR pathway in lung cancer. AB - BACKGROUND: As one of the leading cause of cancer-related deaths in the worldwide, lung cancer needs to be understood better. Nowadays, increasing point mutations of specific oncogenes are biomarkers used to predict the therapeutic effect of targeted therapy and lung cancer has entered the age of individual treatment. At present, many relevant researchers have suggested that EGFR is a biomarker used to predict the therapeutic effect of targeted therapy. A large number of evidence indicates that EGFR/Akt pathway plays important role in cancer growth and metastasis. AIM OF THE STUDY: In this paper, we found EGFR was a target of miR-646. RESULTS: Overexpression of miR-646 not only downregulated EGFR/Akt pathway, but also inhibited lung cancer cell proliferation and metastasis. At the same time, miR-646 was a prognosis factor for overall survival. CONCLUSION: Our finding could provide new insights into the molecular therapeutic of lung cancer. PMID- 27462914 TI - Efficacy of tocilizumab therapy in Korean patients with adult-onset Still's disease: a multicentre retrospective study of 22 cases. AB - OBJECTIVES: To evaluate the efficacy of tocilizumab (TCZ), a monoclonal antibody against the interleukin (IL)-6 receptor, for refractory adult-onset Still's disease (AOSD) in the Korean population. METHODS: This retrospective study included 22 Korean patients with refractory AOSD who were given TCZ at one of seven university hospital-based clinics for rheumatic disease. Patients were subdivided into groups according to disease course: monocyclic, systemic polycyclic, and chronic articular. Modified Pouchot scores, including laboratory and clinical findings, were analysed at 6 months and 12 months. RESULTS: TCZ was given at 4-8 mg/kg every 4-5 weeks (8 mg/kg every 4-5 weeks in 18 patients, 6 mg/kg every 4 weeks in 2, and 4 mg/kg every 4 weeks in 2) for 7.5 months (median, IQR: 4.0-12.3). A good response (measured as a decrease of >2 in the modified Pouchot score) was achieved in 50.0% of patients (11 of 22) at 6 months and in 64.3% (9 of 14) at 12 months. The dose of corticosteroid dose was reduced from 11.5 mg/day (median, IQR: 10.0-21.3) immediately before TCZ therapy to 7.5 mg/day (median, IQR: 5.0-10.0, p=0.002) at 6 months and finally to 6.3 mg/day (median, IQR: 5.0-7.5, p=0.002) at 12 months. Only one patient discontinued TCZ treatment due to facial swelling accompanied by high blood pressure. In all others, adverse events subsided with delayed TCZ therapy, and TCZ therapy was continued successfully without problems. CONCLUSIONS: TCZ was effective for treating Korean AOSD patients who were refractory to conventional therapy or other anti-cytokine biologics, showing a corticosteroid-sparing effect and an acceptable tolerance profile. PMID- 27462915 TI - Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue. AB - Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early loco-regional spread and distant metastases at diagnosis, leading to dismal prognosis with a 5-year overall survival rate moderately over than 5%. This malignancy is largely resistant to chemotherapy and radiation, but the reasons of the refractoriness to the therapies is still unknown. Evidence is accumulating to indicate that the PDAC microenvironment and vascularity strongly contribute to the clinical features of this disease. In particular, PDAC is characterized by excessive dense extracellular matrix deposition associated to vasculature collapse and hypoxia with low drug delivery, explaining at least partly the low efficacy of antiangiogenic drugs in this cancer. Strategies aimed to modulate tumor stroma favoring vasculature perfusion and chemotherapeutics delivery are under investigation. PMID- 27462918 TI - Variations within 3'-UTR of MDM4 gene contribute to clinical outcomes of advanced non-small cell lung cancer patients following platinum-based chemotherapy. AB - Single-nucleotide polymorphism (SNPs) in microRNA (miRNA)-binding sites may modulate the posttranscriptional regulation of gene expression and explain individual sensitivity to platinum agents. This study aimed to investigate the impact of SNPs located at 3'-untranslated region (UTR) of MDM4 gene, on clinical outcomes of advanced non-small cell lung cancer (NSCLC) patients. Four SNPs were genotyped by using DNA from blood samples of advanced NSCLC patients (642 in the Discovery set and 330 in the Replication set) and were analyzed the relationships with clinical outcomes. Carriers with rs10900598 CC genotype and rs4245739 AC genotype showed increased overall survival (OS) than those with AA genotype (P = 0.017 and P = 0.037, respectively) in the Discovery set and after pooling results from the Replication set. A combined effect on survival of variant alleles was also concluded and validated. Stratification analysis revealed that the effect of MDM4 SNPs was more pronounced in lung adenocarcinoma (LAC) subgroups. A reduced expression of the reporter gene for the C allele of rs4245739 was observed in NSCLC cells using luciferase reporter gene assays. Taken together, our results demonstrate that genetic variations in 3'-UTR of MDM4 gene may influence outcomes of advanced NSCLC by miRNAs-mediated regulation. PMID- 27462916 TI - p53 elevation in human cells halt SV40 infection by inhibiting T-ag expression. AB - SV40 large T-antigen (T-ag) has been known for decades to inactivate the tumor suppressor p53 by sequestration and additional mechanisms. Our present study revealed that the struggle between p53 and T-ag begins very early in the infection cycle. We found that p53 is activated early after SV40 infection and defends the host against the infection. Using live cell imaging and single cell analyses we found that p53 dynamics are variable among individual cells, with only a subset of cells activating p53 immediately after SV40 infection. This cell to-cell variabilty had clear consequences on the outcome of the infection. None of the cells with elevated p53 at the beginning of the infection proceeded to express T-ag, suggesting a p53-dependent decision between abortive and productive infection. In addition, we show that artificial elevation of p53 levels prior to the infection reduces infection efficiency, supporting a role for p53 in defending against SV40. We further found that the p53-mediated host defense mechanism against SV40 is not facilitated by apoptosis nor via interferon stimulated genes. Instead p53 binds to the viral DNA at the T-ag promoter region, prevents its transcriptional activation by Sp1, and halts the progress of the infection. These findings shed new light on the long studied struggle between SV40 T-ag and p53, as developed during virus-host coevolution. Our studies indicate that the fate of SV40 infection is determined as soon as the viral DNA enters the nucleus, before the onset of viral gene expression. PMID- 27462919 TI - Genetic variations in apoptosis pathway and the risk of ovarian cancer. AB - BACKGROUND: Apoptosis is a highly conserved form of cell death and aberrant regulation of apoptotic cell death mechanisms leads to variety of major human diseases, especially tumor formation. Genetic variations in apoptosis genes may increase susceptibility to ovarian cancer. RESULTS: In individual SNP analysis, 12 SNPs in 5 apoptosis pathway genes were significantly associated with ovarian cancer risk after adjustment for multiple comparisons at q-value <0.05. The most significant SNP was rs11152377 in the Bcl-2 gene. The homozygous variant TT genotype was associated with a significantly decreased risk of ovarian cancer (odds ratio [OR] =0.53; 95% confidence interval [CI], 0.37-0.77, P<0.001). Cumulative effect analysis showed joint effects of increased risk of ovarian cancer with increasing number of unfavorable genotypes in patients. Classification and regression tree (CART) analysis further revealed high-order gene-gene interactions and categorized the study subjects into low-, medium-, and high-risk groups. Compared with the low-risk group, medium-risk group and high risk group conferred 1.76-fold (95% CI: 1.06-2.90) and 3.64-fold (95% CI: 2.37 5.59) increased risk of ovarian cancer (P for trend <0.001)Materials and Methods: In a case-control study of 417 ovarian cancer patients and 417 matched controls, we evaluated the associations of 587 single nucleotide polymorphisms (SNPs) from 65 genes of the apoptosis pathway with the risk of ovarian cancer. CONCLUSIONS: Our results suggest that genetic variations in apoptosis pathway genes modulate the risk of ovarian cancer individually and jointly. PMID- 27462920 TI - Over-expression of ASIC1a promotes proliferation via activation of the beta catenin/LEF-TCF axis and is associated with disease outcome in liver cancer. AB - Acid-sensing ion channels 1a (ASIC1a) has been reported to promote migration and invasion in liver cancer. However, the clinical significance and molecular mechanism of ASIC1a in liver cancer remain unknown. In the study, we found that ASIC1a is frequently up-regulated in liver cancer tissues. The over-expression of ASIC1a is associated with advanced clinical stage and poor prognosis. The pro proliferative of ASIC1a is pH dependent. Knockout of ASIC1a by CRISPR/CAS9 inhibited liver cancer cell proliferation and tumorigenicity in vitro and in vivo through beta-catenin degradation and LEF-TCF inactivation. Our results indicated a potential diagnostic marker and chemotherapeutic target for liver cancer. PMID- 27462921 TI - Procoagulant and immunogenic properties of melanoma exosomes, microvesicles and apoptotic vesicles. AB - Extracellular vesicles (EV) are lipid particles released from eukaryotic cells into the extracellular fluid. Depending on the cell type or mechanism of release, vesicles vary in form and function and exert distinct functions in coagulation and immunity. Tumor cells may constitutively shed vesicles known as exosomes or microvesicles (MV). Alternatively, apoptosis induces the release of apoptotic blebs or vesicles (ApoV) from the plasma membrane. EV have been implicated in thrombotic events (the second highest cause of death in cancer patients) and tumor vesicles contribute to the anti-cancer immune response. In this study, we utilized the well characterized B16 melanoma model to determine the molecular composition and procoagulant and immunogenic potential of exosomes, MV and ApoV. Distinct patterns of surface and cytoplasmic molecules (tetraspanins, integrins, heat shock proteins and histones) were expressed between the vesicle types. Moreover, in vitro coagulation assays revealed that membrane-derived vesicles, namely MV and ApoV, were more procoagulant than exosomes-with tissue factor and phosphatidylserine critical for procoagulant activity. Mice immunized with antigen-pulsed ApoV and challenged with B16 tumors were protected out to 60 days, while lower protection rates were afforded by MV and exosomes. Together the results demonstrate distinct phenotypic and functional differences between vesicle types, with important procoagulant and immunogenic functions emerging for membrane-derived MV and ApoV versus endosome-derived exosomes. This study highlights the potential of EV to contribute to the prothrombotic state, as well as to anti-cancer immunity. PMID- 27462924 TI - Pharmacogenomics of platinum-based chemotherapy sensitivity in NSCLC: toward precision medicine. AB - Lung cancer is one of the leading causes of cancer-related death in the world. Platinum-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC), however, the therapeutic efficiency varies remarkably among individuals. A large number of pharmacogenomics studies aimed to identify genetic variations which can be used to predict platinum response. Those studies are leading NSCLC treatment to the new era of precision medicine. In the current review, we provided a comprehensive update on the main recent findings of genetic variations which can be used to predict platinum sensitivity in the NSCLC patients. PMID- 27462923 TI - Delphinidin induces apoptosis via cleaved HDAC3-mediated p53 acetylation and oligomerization in prostate cancer cells. AB - Delphinidin is a major anthocyanidin compound found in various fruits. It has anti-inflammatory, anti-oxidant, and various other biological activities. In this study, we identified the epigenetic modulators that mediate the apoptotic effect of delphinidin in human prostate cancer cells. We found that treatment of LNCaP cells (a p53 wild-type, human prostate cancer cell line) with delphinidin increased caspase-3, -7, and -8 activity, whereas it decreased histone deacetylase activity. Among class I HDACs, the activity of HDAC3 was specifically inhibited by delphinidin. Moreover, the induction of apoptosis by delphinidin was dependent on caspase-mediated cleavage of HDAC3, which results in the acetylation and stabilization of p53. We also observed that delphinidin potently upregulated pro-apoptotic genes that are positively regulated by p53, and downregulated various anti-apoptotic genes. Taken together, these results show that delphinidin induces p53-mediated apoptosis by suppressing HDAC activity and activating p53 acetylation in human prostate cancer LNCaP cells. Therefore, delphinidin may be useful in the prevention of prostate cancer. PMID- 27462925 TI - [Prelabour Rupture of Membranes at Term: In- or Outpatient Management? A Survey in Birth Institutions in the German-Speaking Part of Switzerland]. AB - Approximately 8-10% of pregnant women experience prelabour rupture of membranes at term (tPROM). The ideal timing to induce labour as a means to shorten the time interval to birth and thus to reduce maternal and neonatal risk of infection is a controversial topic. A distinction is made between an active and an expectant approach. There is little evidence comparing in- and outpatient management in the expectant approach. The goal of this investigation was to determine the current management approach in birth institutions in the German-speaking part of Switzerland. In this cross-sectional study, a self-designed online questionnaire was distributed to obstetricians and midwives in leading positions at all obstetric institutions in Switzerland. Outcome measures were: the currently offered approach at tPROM, experience with outpatient expectant management and the willingness to introduce outpatient management as an option for pregnant women. From a total of n=85 Swiss German birth institutions, n=47 (55%) responded to the questionnaire. 53% (n=25) provide outpatient expectant management. The women's satisfaction was seen as a decisive advantage. The respondents furthermore ascribed advantages for maternal outcome but no advantage for fetal outcome. 73% (n=16) of respondents working in institutions that hospitalize exclusively stated their willingness to introduce outpatient management provided that there was evidence of maternal and fetal outcome and that expectant mothers were satisfied. The number of birth institutions offering outpatient management is surprisingly high. In future studies examining general management at tPROM, the question of outpatient management should be included. Even though this survey seems to justify outpatient management under strict quality control conditions, prospective studies to assess safety issues are urgently needed. PMID- 27462927 TI - Exploring the Electronic Band Structure of Organometal Halide Perovskite via Photoluminescence Anisotropy of Individual Nanocrystals. AB - Understanding electronic processes in organometal halide perovskites, flourishing photovoltaic, and emitting materials requires unraveling the origin of their electronic transitions. Light polarization studies can provide important information regarding transition dipole moment orientations. Investigating individual methylammonium lead triiodide perovskite nanocrystals enabled us to detect the polarization of photoluminescence intensity and photoluminescence excitation, hidden in bulk samples by ensemble averaging. Polarization properties of the crystals were correlated with their photoluminescence spectra and electron microscopy images. We propose that distortion of PbI6 octahedra leads to peculiarities of the electronic band structure close to the band-edge. Namely, the lowest band transition possesses a transition dipole moment along the apical Pb-I-Pb bond resulting in polarized photoluminescence. Excitation of photoluminescence above the bandgap is unpolarized because it involves molecular orbitals delocalized both in the apical and equatorial directions of the perovskite octahedron. Trap-assisted emission at 77 K, rather surprisingly, was polarized similar to the bandgap emission. PMID- 27462928 TI - Autophagy in Saccharomyces cerevisiae requires the monomeric GTP-binding proteins, Arl1 and Ypt6. AB - Macroautophagy/autophagy is a cellular degradation process that sequesters organelles or proteins into a double-membrane structure called the phagophore; this transient compartment matures into an autophagosome, which then fuses with the lysosome or vacuole to allow hydrolysis of the cargo. Factors that control membrane traffic are also essential for each step of autophagy. Here we demonstrate that 2 monomeric GTP-binding proteins in Saccharomyces cerevisiae, Arl1 and Ypt6, which belong to the Arf/Arl/Sar protein family and the Rab family, respectively, and control endosome-trans-Golgi traffic, are also necessary for starvation-induced autophagy under high temperature stress. Using established autophagy-specific assays we found that cells lacking either ARL1 or YPT6, which exhibit synthetic lethality with one another, were unable to undergo autophagy at an elevated temperature, although autophagy proceeds normally at normal growth temperature; specifically, strains lacking one or the other of these genes are unable to construct the autophagosome because these 2 proteins are required for proper traffic of Atg9 to the phagophore assembly site (PAS) at the restrictive temperature. Using degron technology to construct an inducible arl1Delta ypt6Delta double mutant, we demonstrated that cells lacking both genes show defects in starvation-inducted autophagy at the permissive temperature. We also found Arl1 and Ypt6 participate in autophagy by targeting the Golgi-associated retrograde protein (GARP) complex to the PAS to regulate the anterograde trafficking of Atg9. Our data show that these 2 membrane traffic regulators have novel roles in autophagy. PMID- 27462929 TI - A systematic literature review of synovial chondromatosis and pigmented villonodular synovitis of the hip. AB - OBJECTIVES: Benign synovial diseases of the hip including Synovial Chondromatosis (SC) and Pigmented Villonodular Synovitis (PVNS) are devastating diseases. Initially, patients present with hip pain unrelieved by conservative measures. The diagnosis of PVNS and SC are often delayed, leading to progression of joint damage. The purpose of this review is to present the latest on the diagnosis, management, and prognosis of SC and PVNS of the hip. METHODS: An extensive systematic search of MEDLINE and PUBMED Databases was performed. Data parameters were set from 2005 to present day with set inclusion criteria. Systematic reviews were excluded. RESULTS: 427 abstracts were identified, with 12 articles meeting all inclusion criteria. Eight studies focused on SC, and 5 on PVNS. 233 patients with SC of the hip and 98 patients with PVNS of the hip were identified, a total of 331 patients. DISCUSSION: Benign Synovial disorders of the hip are rare. In patients with chronic hip pain secondary to benign synovial disorders, early diagnosis and surgical intervention demonstrate good outcomes, and patients may benefit due to prevention of morbidity from further joint destruction. There is no clear consensus between higher successes through open versus arthroscopic surgical debridement. In the final phase of benign synovial disorders of the hip, THA of different types based on the patient's age should be considered. PMID- 27462931 TI - Thermodynamics of Imidazolium-Based Ionic Liquids Containing PF6 Anions. AB - Imidazolium-based ionic liquids (ILs) with PF6(-) anions are considered as low cost solvents for separation processes, but they exhibit restricted thermal stabilities. Reliable measurements of vaporization thermodynamics by conventional methods have failed. In this work, we applied a quartz-crystal microbalance method to determine for the first time the absolute vapor pressures for the [Cnmim][PF6] family, with n = 2, 4, 6, 8, and 10, in the temperature range 403 461 K. An absence of decomposition of ILs in experimental conditions was determined by the attenuated total reflection-infrared spectroscopy. The consistency of the experimental results within the homologous series was established through enthalpy and entropy analyses of the liquid and gas phases as well as by molecular dynamics simulations. PMID- 27462930 TI - Should the United States Government Repeal Restrictions on Buprenorphine/Naloxone Treatment? AB - Attention must be focused on needed changes to the current United States law that restricts physicians who prescribe buprenorphine for the detoxification or treatment of Opioid Use Disorder, to accepting no more than 100 patients. The current system does not provide comprehensive treatment as defined by the American Society of Addiction Medicine (ASAM) criteria. In addition, it suffers from both fragmentation and stigma and will require a significant change to comply with ASAM's call for integrated delivery of comprehensive addiction treatment. This commentary calls for the development and implementation of "best practice," by recommending caution in lifting the 100 patient limit until substantial achievement of this goal occurs. The authors call for an increase to 200 in the patient limit to be restricted to those physicians who are Board Certified in Addiction Medicine by the American Board of Addiction Medicine (ABAM) or in Addiction Psychiatry by the American Board of Psychiatry and Neurology (ABPN), or other responsible medical organizations. Any additional restriction lifting should follow a systemic evolution that rewards and documents competency. Such a system would involve the integration of treatment, treatment systems, and recovery with prescription medication. In addition, it should monitor emotional blunting, treatment progress and initiation of genetic addiction risk testing. PMID- 27462932 TI - Lamb survival, glutathione redox state and immune function of neonates and lambs from periparturient Merino ewes supplemented with rumen-protected methionine. AB - Wool growth in Merino sheep demands a high level of sulphur amino acids, competing with body growth and the immune system, which may play a role in increasing the risk of lamb mortality. The hypothesis that dietary supplementation of methionine (Met) to Merino ewes during the late stages of pregnancy will improve foetal growth and alter immune competency of ewes and lambs was tested in a total of 120 grazing, pregnant Merino ewes. Sixty ewes were group-supplemented with 6.3 g/d rumen-protected Met (Met-Plus) per sheep from day 111 of pregnancy until day 7 after lambing, and the other 60 animals were used as a non-supplemented Control. Lambs from Met-supplemented ewes tended to be 10% heavier than Control lambs (p = 0.10), which did not affected the survival rate at weaning significantly. The supplemented ewes had slightly higher concentrations of total glutathione (GSH) in plasma at lambing (p < 0.06), but there were no differences between 1 and 3 months post-lambing in GSH, glutathione disulphide (GSSG) and the GSSG:GSH ratio. The GSSG:GSH ratio in the blood of ewes was elevated at lambing (p < 0.05), hinting that ewes were undergoing increased oxidative stress. The Met supplementation elevated the total IgG concentration (p < 0.05) in lambs aged 4 and 6 weeks, but did not change the IgG concentrations in colostrum and in plasma of 1-week-old lambs, and white blood cell counts and leukocyte types. The trend towards higher lamb birth weights in the Met supplemented group requires further investigation as this may influence survival at birth and weaning. PMID- 27462934 TI - Aromatic substitution of olefins. VI. Arylation of olefins with palladium(II) acetate. PMID- 27462933 TI - Optimized Protocol for Quantitative Multiple Reaction Monitoring-Based Proteomic Analysis of Formalin-Fixed, Paraffin-Embedded Tissues. AB - Despite a clinical, economic, and regulatory imperative to develop companion diagnostics, precious few new biomarkers have been successfully translated into clinical use, due in part to inadequate protein assay technologies to support large-scale testing of hundreds of candidate biomarkers in formalin-fixed paraffin-embedded (FFPE) tissues. Although the feasibility of using targeted, multiple reaction monitoring mass spectrometry (MRM-MS) for quantitative analyses of FFPE tissues has been demonstrated, protocols have not been systematically optimized for robust quantification across a large number of analytes, nor has the performance of peptide immuno-MRM been evaluated. To address this gap, we used a test battery approach coupled to MRM-MS with the addition of stable isotope-labeled standard peptides (targeting 512 analytes) to quantitatively evaluate the performance of three extraction protocols in combination with three trypsin digestion protocols (i.e., nine processes). A process based on RapiGest buffer extraction and urea-based digestion was identified to enable similar quantitation results from FFPE and frozen tissues. Using the optimized protocols for MRM-based analysis of FFPE tissues, median precision was 11.4% (across 249 analytes). There was excellent correlation between measurements made on matched FFPE and frozen tissues, both for direct MRM analysis (R(2) = 0.94) and immuno MRM (R(2) = 0.89). The optimized process enables highly reproducible, multiplex, standardizable, quantitative MRM in archival tissue specimens. PMID- 27462935 TI - Sensitivity in Binding Free Energies Due to Protein Reorganization. AB - Tremendous recent improvements in computer hardware, coupled with advances in sampling techniques and force fields, are now allowing protein-ligand binding free energy calculations to be routinely used to aid pharmaceutical drug discovery projects. However, despite these recent innovations, there are still needs for further improvement in sampling algorithms to more adequately sample protein motion relevant to protein-ligand binding. Here, we report our work identifying and studying such clear and remaining needs in the apolar cavity of T4 lysozyme L99A. In this study, we model recent experimental results that show the progressive opening of the binding pocket in response to a series of homologous ligands.1 Even while using enhanced sampling techniques, we demonstrate that the predicted relative binding free energies (RBFE) are sensitive to the initial protein conformational state. Particularly, we highlight the importance of sufficient sampling of protein conformational changes and demonstrate how inclusion of three key protein residues in the "hot" region of the FEP/REST simulation improves the sampling and resolves this sensitivity, given enough simulation time. PMID- 27462936 TI - Mature T-Cell Leukemias and Leukemia/Lymphoma Syndromes: Review of Our Experience in 175 Cases. PMID- 27462937 TI - The Management of Relapsed and Refractory Acute Myeloid Leukaemia in Adults. AB - The improved survival of patients with AML over the last 20-30 years can be attributed both to advances in cytotoxic therapy and in supportive care and up to 25% of responders may be cured. Nevertheless, most patients with AML eventually relapse and ultimately die from resistant leukaemia and up to 30% fail to attain initial complete remission (CR). This annotation reviews current therapeutic options in relapsed and refractory AML in adults. PMID- 27462938 TI - Survival Experience of 195 Patients with Hairy Cell Leukemia Treated in a Multi Institutional Study with Interferon-Alfa 2B. AB - One hundred ninety-five patients were entered into a multi-institutional study of interferon alfa 2b from 1983-1986; follow-up was completed through June 1989. A complete remission was documented in 7 patients, a partial remission in 152 patients, a minor response in 10 patients, and no response in 26 patients. One hundred fifty-nine of the 195 patients treated (81%) had a normalization of their peripheral blood counts by the criteria used. To date, 17 patients have died. Only 3 of the 159 patients (2%) with a PR or CR have expired. Three of 10 MR patients have expired and 11 of 26 NR patients have expired. Of the 11 who expired, 7 did so before receiving an adequate duration of treatment. Three of the NR patients died within 1 week of starting interferon from intracranial hemorrhages secondary to severe thrombocytopenia (present prior to initiation of interferon) and 4 NR patients died of infectious deaths within 2 months of initiating interferon therapy secondary to severe neutropenia (present prior to initiation of interferon). Of the 17 NR's who remained alive and on-study for at least 6 months, only 2 eventually died, both after failing subsequent pentostatin therapy. Systemic therapy with agents that induce a more rapid response such as pentostatin or 2-chlorodeoxy-adenosine, or the combination of interferon plus growth factor are indicated in these severely cytopenic patients. PMID- 27462939 TI - Adult Acute Lymphoblastic Leukaemia: The Value of Therapy Intensification. AB - Results of multiagent chemotherapy protocols as therapy for adult acute lymphoblastic leukaemia in non-randomised multi-institutional studies appear superior to historical controls of less aggressive treatment. However, randomised studies have produced conflicting data and increasing the dosage of chemotherapy in conjunction with bone marrow transplantation has been disappointing. We reviewed retrospectively our experience with 68 adult ALL patients treated over a ten year period. Twenty-six patients received a standard four drug induction regimen without intensification. A second group of thirty-four patients received induction, intensification and re-induction phases of treatment. The results suggest that intensification of therapy does not alter median survival or median duration of remission, although a trend towards more long term disease-free survivors is observed. PMID- 27462940 TI - Treatment of Philadelphia Chromosome Positive (Ph +) Chronic Myelogenous Leukemia in Blast Crisis and Ph + Acute Leukemia with High Dose Cytosine Arabinoside (HDARAC). AB - High dose cytosine arabinoside (HDARAC) was administered to eleven patients in the blastic phase of Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML). Four patients presented in blastic phase and in seven patients blastic transformation had evolved from a previous chronic phase. All patients had been heavily pretreated with chronic phase drugs (hydroxyurea, myleran) or a protocol designed to treat the chronic phase (L-5 protocol) and with blastic phase regimens (anthracycline/araC combination or vincristine/prednisone). One of 11 patients achieved a complete remission (365 + days) and two patients achieved a partial response. No cytogenetic remissions were observed. The other patients were considered treatment failures with 3/8 surviving less than one month after therapy. Blasts were, at least temporarily, eliminated in all patients receiving at least 7 doses of HDARAC, although repopulation was rapid. HDARAC may be satisfactory therapy for accelerated phase CML but is minimally active in blastic phase CML. PMID- 27462941 TI - Tumor Necrosis Factor Production in B Cell Chronic Lymphocytic Leukemia. AB - Tumor necrosis factor (TNF) has been suggested to act as an autocrine growth factor in chronic B cell malignancies. We have attempted to assess the role of TNFalpha in relation to the stage of chronic lymphocytic leukemia (CLL) by examining TNFalpha cytotoxic activity of media conditioned by stimulated and unstimulated peripheral blood mononuclear cells (PBMC) and by separated unstimulated malignant B cells from Rai stage 0 and IV patients. The response of PBMC from stage IV to stimulation with phytohemagglutinin, or bacterial lipopolysaccharide was weak or absent. However, stimulation of stage 0 PBMC induced significantly increased production of TNF. Furthermore, unstimulated stage 0 PBMC and B cells from these cases of stage 0 B CLL spontaneously released TNF in significant excess compared to normal PBMC controls while no TNF activity could be detected in supernatants from unstimulated stage IV PBMC or B cells. These data suggest a possible role for TNF in the progression of CLL. PMID- 27462942 TI - Epidemiology of Non-Hodgkin's Lymphoma in Parts of England and Wales (1984-1988). AB - The descriptive epidemiology of non-Hodgkin's lymphoma (NHL) (1984-1988) in parts of England and Wales is described by low grade (LG) and high grade (HG) subtypes. Major differences in age specific incidence are evident particularly in those under 35 years where LG-NHL is virtually absent in childhood and rare in young adulthood. Over the 5 year period of registration of cases significant increases in incidence were noted for males with both HG and LG disease. The geographical analyses demonstrate clear epidemiological differences between LG-NHL and HG-NHL. The SMRs for 22 English and Welsh counties are not correlated for LG and HG-NHL disease, whose distributions are significantly different. Regression analyses at the electoral ward level show a strong association between LG-NHL and high-socio economic status and there is a weaker link between HG-NHL and residence in an urban area. Formal comparison of LG and HG-NHL shows significant differences for the effect of socio-economic grouping but not for urban-rural status. There is strong evidence to show that major differences exist in patterns of LG and HG-NHL for age specific incidence, geographical distribution and area risk factors. Interpretation of these epidemiological features are highly suggestive of differing aetiologies. PMID- 27462943 TI - HIV-Related Lymphoblastic Lymphoma. AB - The clinical records of 17 patients with HIV-associated lymphoblastic mostly Burkitt-type lymphomas, are reviewed (54% of a total of 31 patients with HIV associated malignant lymphomas, treated between 1/85-1/90). The lymphomas were diagnosed histologically with additional immuno-histochemical analyses, or cytologically, with subsequent immunocyto-chemistry. All patients were homosexual and HIV antibody positive, and the average age was 39 y. At initial staging evaluation an Ann Arbor stage III or IV was present in 15 patients (88%); a CDC stage II of HIV-infection was present in 10 patients, CDC-stage III in 5 patients, and CDC-stage IV in 2 patients. An extranodal or mixed nodal/extranodal pattern of organ involvement was seen in 14 cases, with predominance of the gastrointestinal tract (30%) and the bone marrow (30%). The response rate to chemotherapy (CR + PR) was 81%, a CR was achieved in 53% of the patients, and relapses within a few months after CR were common. Survival following relapses in the CR- and PR group was similar, namely 5.2 and 4.9 months respectively. 2 patients in the CR-group and 1 patient in the PR group have been alive for 13, 19 and 30 months. An optimal therapeutic regimen for this disorder does not seem to have been found yet. PMID- 27462944 TI - Treatment of Early Stage Hodgkin's Disease According to Risk Factors. AB - Between January 1981 and December 1987, 95 patients with stage IA (34 patients), IIA (42 patients) and stage IIB (19 patients) Hodgkin's disease (HD) were evaluated in our institution. Thirty patients defined as "high risk" because of either bulky mediastinal disease, systemic symptoms or both were treated with combined modality therapy (CMT). The remaining 65 patients considered as "standard risk" because they presented at diagnosis without any known adverse prognostic factor, received radiotherapy (RT) only. The median follow-up was 39 months. The complete remission (CR) rate was 97% (92/95). The actuarial 3 year overall (OS) and disease free survival (DFS) were 93% and 72% respectively with no differences between the two groups of patients. All 65 "standard risk" patients achieved CR; thirteen (20%) relapsed after a median time of 22 months. Twenty seven of 30 "high risk" patients (90%) achieved CR and six of them (22%) had early relapses. No severe pancytopenia episodes or life-threatening complications occurred during therapy. As far as the risk of second neoplasms is concerned, we observed only a single case of acute non lymphoblastic leukemia 48 months after the completion of CMT. These results indicate that in unfavourable early stage HD, CMT is effective with a probability of more than a 70% DFS 3 years after therapy with an acceptable acute and late toxicity. Patients without "high" risk factors showed the expected response after RT. About 60% of the patients who failed RT could be salvaged by chemotherapy (CT) while refractory cases or patients who relapsed after CMT did poorly with a third line chemotherapeutic regimen. Therefore alternative therapeutic approaches including high dose CT followed by autologous bone marrow transplantation should be considered for this subset of patients. PMID- 27462945 TI - Neurocysticercosis Coincident with Acute Myeloid Leukemia: A Case Report. AB - We describe the unusual coincidence in a 25 year old Mexican immigrant who presented with neurocysticercosis and acute myeloid leukemia. Treatment for the acute leukemia was initiated after corticosteroids were administered to decrease cerebral edema caused by the neurocysticercosis. Complete remission of the leukemia was eventually achieved and specific antibiotic therapy for neurocysticercosis was initiated with praziquantel. We discuss our approach to the treatment of these two diseases, the complications that arose, and briefly review the literature on the current treatment of neurocysticercosis. PMID- 27462946 TI - Epidural Spinal Cord Infiltration: A Rare Complication of Acute Myeloblastic Leukaemia. AB - Epidural infiltration by leukemic cells in Acute Non Lymphoblastic Leukemia (ANLL), and extradural granulocytic sarcomas as a cause of spinal cord compression are extremely rare phenomena. Very few cases have been recorded in the literature. In this brief case report we describe a young patient with acute myeloblastic leukemia (M4, FAB) who presented with sudden spinal cord compression during relapse after bone marrow transplantation. The literature on this subject is also reviewed. PMID- 27462947 TI - Editor's Introduction. PMID- 27462948 TI - A Time and Place: The Role of Social Workers in Improving End-of-Life Care. AB - Americans are living longer, but dying after a prolonged period of management of multiple chronic illnesses and functional disabilities. Despite waves of public and professional activity targeted toward improving care for the dying and supporting the families, gaps in care and challenges in end-of-life care persist. Contentious issues such as the so-called "death panels" or physician payment for discussion of advance directives and care wishes at the end of life; aid in dying; and regarding individuals who actively choose death (case of Brittney Maynard) are continually debated in the public media. Progress toward improvement in the experience of dying remains incremental and change has been slow. With the release of a second Institute of Medicine ( 2014 ) report devoted to what it means to die in America in the 21st century, momentum and opportunity for change may increase. If this is to happen, social workers will need to deliver the range of biopsychosocial care that patients and families so desperately need. However, holistic care of the individual will only improve, if the nation also addresses ongoing systemic problems in financing, policy, and service delivery in end-of life care. PMID- 27462949 TI - Use of Contemporary Film as a Medium for Teaching an Online Death and Grief Course. AB - Online education is becoming commonplace in the academic world. Schools now offer totally online degree programs or provide a hybrid of face-to-face and online courses for fulfilling academic requirements. Developing courses and teaching online requires instructors to rethink the educational paradigms they have relied upon in the past. The Net Generation of learners brings a different set of expectations, styles, and needs to the classroom than those of previous generations; this mandates that instructors redesign courses and use contemporary teaching modalities. This article describes how film was successfully used as the primary medium to teach a graduate online Social Work course, Death and Grief. PMID- 27462950 TI - Hospice Core Professions' Views on Interdisciplinary Teams: A Qualitative Investigation. AB - The hospice interdisciplinary team (IDT) has been recognized as an ideal model for interprofessional collaboration. To address the manner in which interdisciplinary practices are perceived by team members, this study explored profession-based similarities and differences in perceptions among the four core hospice IDT members (physicians, nurses, social workers, and spiritual care providers) as well as experiences on the IDT. Semistructured interviews with 20 hospice professionals, 5 from each profession, were completed. Findings suggested that while hospice professions share some perceptions and experiences about hospice team membership, strengths of and barriers to teamwork, and individual members' contribution to the team, significant profession-based differences exist largely in the area of hospice team membership beyond the core members, type of language and descriptions used, perceptions of causes and effects of barriers to teamwork, and understandings of how team effectiveness is evaluated. Changes at the team-based, organizational, policy, and educational levels are needed to further maximize strengths of individual hospice IDT member and team qualities. PMID- 27462951 TI - The Wish to Die: Assisted Suicide and Mental Illness. PMID- 27462952 TI - Re-Imagining God: A Meditation on Existential Suffering at the End of Life. PMID- 27462953 TI - Room 432, Bed 1. PMID- 27462954 TI - Rethinking Suffering: Allowing for Suffering that is Intrinsic at End of Life. AB - The dilemma so central to the work of providers of palliative and end-of-life care is the paradox of their professional and ethical duty to try to relieve suffering and the limitations of so doing. While the capacity to sit with suffering at the end of life is critical to clinical work, the idea that some intrinsic suffering cannot necessarily always be relieved may model for patients and families that suffering can be borne. Clinicians who encounter unrelievable suffering may feel a sense of failure, helplessness, moral distress, and compassion fatigue. While tolerating suffering runs counter to the aims of palliative care, acknowledging it, bearing it, and validating it may actually help patients and families to do the same. "Sitting with suffering" signals a paradigm shift within the discipline of palliative care, as it asks clinicians to rethink their role in being able to relieve some forms of psychosocial suffering intrinsic to dying. PMID- 27462955 TI - Detained and Dying: Ethical Issues Surrounding End-of-Life Care in Prison. AB - Prisons are increasingly being called upon to provide end-of-life (EOL) care within the restrictive correctional environment. Several relatively recent phenomena have brought medical ethics to the forefront of prison EOL care including aging behind bars, a paradigm shift in prison culture, the increasing rate of in-prison deaths, and the corresponding prison hospice movement. This article examines prominent ethical issues that emerge for prison personnel who are tasked with providing care to terminally ill offenders by presenting three offender composite characters that exemplify dying offenders and emergent ethical issues surrounding their care. Identification and critical analysis of these ethical issues demonstrate the need for strong commitment to ethical practice and highlights specific issues for prisons to examine in their own EOL care practice. PMID- 27462956 TI - Emotional Support for Health Care Professionals: A Therapeutic Role for the Hospital Ethics Committee. AB - Hospital ethics committees (HECs) are typically charged with addressing ethical disputes, conflicts, and dilemmas that arise in the course of patient care. HECs are not widely viewed as having a therapeutic role for health care professionals who experience psychological distress or anticipatory grief in the course of discharging professional duties. A case is presented in which an ethics consultation was requested, chiefly, to secure emotional support for health care professionals who had been asked by a patient to discontinue life-sustaining treatments. As the case demonstrates, HECs may be called upon to provide emotional support and reassurance to health care professionals who willingly carry out psychologically difficult actions, even though these actions may be ethically uncontroversial. In providing this service, the HEC may not necessarily engage in its customary activity of deliberating an ethics issue and resolving a conflict but may still provide valuable assistance, as in the case presented. PMID- 27462957 TI - Exhaust All Measures: Ethical Issues in Pediatric End-of-Life Care. AB - The death of a child may have a profound impact on parents, family members, and health care providers who provided care for the child. Unique challenges are faced by parents of seriously ill children as they must serve as the legal authority for health care decisions of children under age 18, although the child's wishes must also be considered. Social workers must balance core social work values, bioethical values, and psychosocial issues presented by such situations. While studies have been conducted with physicians and nurses regarding ethical issues in pediatric end-of-life care settings, little is known about how social workers experience these conflicts. This article utilizes two vignettes to illustrate potential ethical issues in this setting and applies the National Association of Social Workers Standards for Palliative and End of Life Care (NASW, 2004 ) to explore options for their resolution. These vignettes provide descriptions of possible reactions in this setting and can be used as a basis for further exploration of ethics in pediatric end-of-life care from a social work perspective. PMID- 27462958 TI - When mTORC2-AKT signaling meets cell polarity. PMID- 27462959 TI - Use of 5-mm Laparoscopic Stapler to Perform Open Small Bowel Anastomosis in a Neonatal Animal Model. AB - PURPOSE: While adult bowel anastomoses are typically performed with staplers, neonatal small bowel anastomoses have traditionally been performed in a hand-sewn manner due to the large size of surgical staplers. The purpose of this study was to compare stapled anastomosis using a newly available, 5-mm laparoscopic stapler to a hand-sewn anastomosis in an open animal model. METHODS: Twenty anastomoses were performed by two general surgery residents (10 stapled and 10 hand-sewn) in an adult New Zealand white rabbit. The small bowel was divided with a scalpel. Surgical technique was alternated between single-layer hand-sewn and stapled anastomoses. Each anastomosis was resected for ex vivo testing. Measurements collected were outer diameter of the bowel before division, time to perform the anastomosis, anastomosis inner diameter (ID), and leak test. IDs were measured by cutting the anastomosis in cross-section, taking a photograph, and measuring the diameter by computer software. In addition, the surgeons qualitatively evaluated the anastomoses for hemostasis and overall quality. Statistical significance was determined using the Student's t-test. RESULTS: There were statistically significant differences between stapled and hand-sewn anastomosis, respectively, for average operative time (4 minutes 2 seconds versus 16 minutes 6 seconds, P < .01) and anastomosis ID (8.2 versus 3.7 mm, P < .01). There was one leak in the stapled group, which occurred at overlapping staple lines closing the enterotomy. A second stapled anastomosis required suture reinforcement, again at the enterotomy closure, due to operator error. Starting diameter, leak rate, hemostasis, and anastomosis quality were not statistically significant. CONCLUSION: In a neonatal open animal model, a 5-mm stapled anastomosis is an acceptable alternative to hand-sewn small bowel anastomosis. The stapler is faster and creates a larger diameter anastomosis, however, there was one leak when closing the enterotomy in the stapled group and overlapping staple lines should be avoided. PMID- 27462960 TI - Preoperative Gemcitabine-based Chemoradiation Therapy for Borderline Resectable Pancreatic Cancer: Impact of Venous and Arterial Involvement Status on Surgical Outcome and Pattern of Recurrence. AB - OBJECTIVE: To evaluate the outcome of preoperative gemcitabine-based chemoradiation therapy (CRT) for borderline resectable pancreatic cancer (BRPC), focusing on the associations among the tumor-vascular relationship, surgical outcomes, and pattern of recurrence. SUMMARY BACKGROUND DATA: Among the various multimodal treatment strategies for pancreatic cancer, preoperative CRT and subsequent surgery is 1 promising strategy for BRPC. METHODS: A total of 184 patients with BRPC received preoperative CRT. BRPC was classified as follows, based on radiographic findings before the initiation of preoperative CRT: BR-V, a tumor involving the portal-superior mesenteric vein without arterial involvement; and BR-A, a tumor with the involvement of a relevant major artery. We assessed the association of these 2 subgroups with the following parameters: (1) resection rate, (2) survival, and (3) pattern of recurrence. RESULTS: The resection rate of BR-V cases (84%) was significantly higher than that of BR-A cases (57%) (P < 0.001). The 5-year survival rates of the resected BR-V and BR-A cases were 51% and 25%, respectively (P = 0.003). The 5-year cumulative incidence of distant recurrence was significantly higher in the BR-A cases compared with the BR-V cases (67% vs 54%, P = 0.006); however, the 5-year cumulative incidence of local recurrence was not significantly different between the groups. CONCLUSIONS: In BRPC, arterial involvement was associated with impaired outcome regarding resection rate and survival, possibly due to the difference in the underlying pathophysiology between BR-V and the advanced nature of BR-A as a systemic disease. PMID- 27462962 TI - Contemporary Issues of Social Justice: A Focus on Race and Physical Education in the United States. AB - Ongoing events in the United States show the continual need to address issues of social justice in every social context. Of particular note in this article, the contemporary national focus on race has thrust social justice issues into the forefront of the country's conscious. Although legal segregation has ran its course, schools and many neighborhoods remain, to a large degree, culturally, ethnically, linguistically, economically, and racially segregated and unequal (Orfield & Lee, 2005). Even though an African American president presently occupies the White House, the idea of a postracial America remains an unrealized ideal. Though social justice and racial discussions are firmly entrenched in educational research, investigations that focus on race are scant in physical education literature. Here, we attempt to develop an understanding of social justice in physical education with a focus on racial concerns. We purposely confine the examination to the U.S. context to avoid the dilution of the importance of these issues, while recognizing other international landscapes may differ significantly. To accomplish this goal, we hope to explicate the undergirding theoretical tenants of critical race theory and culturally relevant pedagogy in relation to social justice in physical education. Finally, we make observations of social justice in the physical education and physical education teacher education realms to address and illuminate areas of concern. PMID- 27462961 TI - Treatment with soy isoflavones during early adulthood improves metabolism in early postnatally overfed rats. AB - PURPOSE: The incidences of obesity and related diseases have reached epidemic proportions, and new therapeutic approaches are needed. Soy isoflavones have been identified as an important dietary factor for preventing and treating metabolic dysfunction. This study examined the effects of high doses of isoflavone on glucose and fat metabolism in a model of programmed obesity and evaluated its effects on the autonomic nervous system. METHODS: Litters of Wistar rats were standardized at nine pups per dam in normal litters (NL) or reduced to three pups per dam at the third day of life (P3) in small litters (SL) to induce postnatal overfeeding. Gavage with a soy bean isoflavone mixture (1 g/day) diluted in water was started at P60 and continued for 30 days. The control animals received vehicle gavage. At P90, biometric and metabolic parameters as well as direct autonomic nerve activity were measured. RESULTS: Increases in glycaemia and insulinaemia observed in SL rats were reduced by isoflavone treatment, which also caused lower glucose-induced insulin secretion by pancreatic islets. Sympathetic activity in the major splanchnic nerve was increased, while vagus nerve activity was reduced by isoflavone treatment. The dyslipidaemia induced by overfeeding in SL rats was restored by isoflavone treatment. CONCLUSION: The present study shows that treatment with isoflavone reduces adiposity and improves glucose and lipid metabolism. Collectively, these effects may depend on autonomic changes. PMID- 27462963 TI - Concussion Knowledge and Communication Behaviors of Collegiate Wrestling Coaches. AB - Sport coaches can play an important role in shaping a team's approach to concussion safety through their communication with team members. However, across all sports, there is limited knowledge about factors that make coaches more or less likely to engage in safety-supportive communication. The objectives of this study were to assess the concussion-related knowledge and attitudes of wrestling coaches, as well as the extent to which they engage in autonomy-supportive coaching practices, and to determine how these factors are related to communication with athletes in support of concussion safety. Data were collected through an online survey of head coaches of National Collegiate Athletic Association (NCAA) wrestling teams (n = 89, 40.5% response rate). On average, coaches answered five out of a possible nine knowledge questions correctly and were significantly more likely to think it was acceptable for an athlete to continue playing after sustaining a concussion during a national qualifying competition as compared to during an early-season competition. Engaging in autonomy-supportive coaching behaviors was the coach factor explaining the largest percentage of variability in communication. Findings suggest that while knowledge deficits and attitudes about the acceptability of continued play while symptomatic during more consequential competitive matches should be addressed in educational programming for collegiate wrestling coaches, these changes alone may not be a sufficient for adequately increasing concussion safety communication. Targeting more distal factors such as autonomy-supportive approaches to coaching may hold promise for intervention design and should be explored in future prospective research. PMID- 27462975 TI - In vitro IFN-alpha release from IFN-alpha- and pegylated IFN-alpha-loaded poly(lactic-co-glycolic acid) and pegylated poly(lactic-co-glycolic acid) nanoparticles. AB - AIM: Interferon alpha (IFN-alpha) controlled release of nanoparticles was investigated under in vitro conditions. MATERIALS & METHODS: IFN-alpha and pegylated IFN-alpha (PEG-IFN-alpha) were encapsulated by poly(lactic-co-glycolic acid) (PLGA) and pegylated PLGA (PEG-PLGA) copolymers using double emulsion solvent evaporation method. RESULTS: The size of resulting four nanoparticles (IFN-alpha in poly(lactic-co-glycolic acids), IFN-alpha in poly(lactic-co glycolic acid)-polyethylene glycol, PEG-IFN-alpha in poly(lactic-co-glycolic acids) and PEG-IFN-alpha in poly(lactic-co-glycolic acid)-polyethylene glycol) was below 130 nm diameter. IFN-alpha encapsulation efficiency of the nanoparticles was between 78 and 91%. CONCLUSION: The in vitro drug release studies conducted in phosphate-buffered saline and human plasma highlighted the role of incubation medium on the IFN release from the nanoparticles. The PEG-IFN alpha in poly(lactic-co-glycolic acid)-polyethylene glycol was the most promising nanoparticle among the four formulations because of its remarkably constant release in both phosphate-buffered saline and plasma. PMID- 27462976 TI - Real-Time Imaging of the Bacillithiol Redox Potential in the Human Pathogen Staphylococcus aureus Using a Genetically Encoded Bacilliredoxin-Fused Redox Biosensor. AB - AIMS: Bacillithiol (BSH) is utilized as a major thiol-redox buffer in the human pathogen Staphylococcus aureus. Under oxidative stress, BSH forms mixed disulfides with proteins, termed as S-bacillithiolation, which can be reversed by bacilliredoxins (Brx). In eukaryotes, glutaredoxin-fused roGFP2 biosensors have been applied for dynamic live imaging of the glutathione redox potential. Here, we have constructed a genetically encoded bacilliredoxin-fused redox biosensor (Brx-roGFP2) to monitor dynamic changes in the BSH redox potential in S. aureus. RESULTS: The Brx-roGFP2 biosensor showed a specific and rapid response to low levels of bacillithiol disulfide (BSSB) in vitro that required the active-site Cys of Brx. Dynamic live imaging in two methicillin-resistant S. aureus (MRSA) USA300 and COL strains revealed fast and dynamic responses of the Brx-roGFP2 biosensor under hypochlorite and hydrogen peroxide (H2O2) stress and constitutive oxidation of the probe in different BSH-deficient mutants. Furthermore, we found that the Brx-roGFP2 expression level and the dynamic range are higher in S. aureus COL compared with the USA300 strain. In phagocytosis assays with THP-1 macrophages, the biosensor was 87% oxidized in S. aureus COL. However, no changes in the BSH redox potential were measured after treatment with different antibiotics classes, indicating that antibiotics do not cause oxidative stress in S. aureus. Conclusion and Innovation: This Brx-roGFP2 biosensor catalyzes specific equilibration between the BSH and roGFP2 redox couples and can be applied for dynamic live imaging of redox changes in S. aureus and other BSH producing Firmicutes. Antioxid. Redox Signal. 26, 835-848. PMID- 27462977 TI - Bone Marrow Mesenchymal Stromal Cells from Clinical Scale Culture: In Vitro Evaluation of Their Differentiation, Hematopoietic Support, and Immunosuppressive Capacities. AB - The differentiation capacity, hematopoietic support, and immunomodulatory properties of human bone marrow mesenchymal stromal cells (BM-MSCs) make them attractive therapeutic agents for a wide range of diseases. Clinical scale cultures (CSCs) have been used to expand BM-MSCs for their use in cell therapy protocols; however, little is known about the functionality of the expanded cells. The main goal of the present study was to evaluate the functional characteristics of BM-MSCs expanded from CSCs to determine the quality of the cells for cellular therapy protocols. To address this issue, we analyzed the morphology, immunophenotype, differentiation potential (adipogenic, osteogenic and chondrogenic), hematopoietic support, and immunosuppressive capacity of BM MSCs from short scale cultures (SSCs) and CSCs in a comparative manner. After 12 days of culture in CSCs (HYPERFlask System), BM-MSCs reached cell numbers of 125.52 * 10(6) +/- 25.6 * 10(6) MSCs, which corresponded to the number of cells required for transplantation (~1.7 * 10(6) MSCs/kg for a 70-kg patient). After expansion, BM-MSCs expressed the characteristic markers CD73, CD90, and CD105; however, expansion decreased their differentiation capacity toward the adipogenic, osteogenic, and chondrogenic lineages and their ability to inhibit T cell proliferation compared with SSCs-MSCs. Importantly, CSCs-MSCs maintained the ability to support the proliferation and expansion of hematopoietic progenitor cells and the capacity to express the molecules, cytokines, and extracellular matrix proteins involved in the regulation of hematopoiesis. Our study highlights the need to evaluate the functional properties of the expanded BM-MSCs for verification of their quality for cell therapy protocols. PMID- 27462978 TI - The Right Therapy for Neurological Disorders: From Randomized Trials to Clinical Practice - Patients versus Investigator Expectations and Needs. AB - BACKGROUND: People living with amyotrophic lateral sclerosis (ALS) are now more proactive in making decisions about their treatment options, in particular with increased awareness through social media and the Internet. Together with increased awareness about the disease comes increased frustration that there is still only one Food and Drug Administration (FDA)-approved drug that modestly improves survival. SUMMARY: While efforts are underway to improve clinical trial design, patient involvement in trial design, clinical outcomes, and risk/benefit evaluations have become more recognized and will play a major role in the future success of clinical trials. This chapter addresses the perspective of people living with ALS and their perceptions of clinical trials. We describe various organizations and programs available that provide increased education and patient involvement. KEY MESSAGE: Stronger partnerships between those living with ALS, clinicians, government, nonprofit organizations, and regulatory agencies will significantly impact treatment development. PMID- 27462979 TI - Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer. AB - The advent of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has led to a paradigm shift in the management of advanced adenocarcinoma of the lung. The key to success of these therapies lies in the precise identification of their molecular targets, i.e. sensitizing EGFR mutations. The variations in the prevalence of these mutations among different ethnicities necessitate regional studies for a better understanding of the molecular epidemiology of the disease and clinical decision-making. This is even more relevant for countries like India where genetic heterogeneity is a rule. Here, we make an attempt to review the epidemiology of EGFR mutations in India versus other Asian countries and the West. We also review the clinical experience with EGFR TKIs and suggest the way forward in a resource-limited setting. PMID- 27462980 TI - Targeting MT1-MMP as an ImmunoPET-Based Strategy for Imaging Gliomas. AB - BACKGROUND: A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type 1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models. METHODS: An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for 89Zr labeling. Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control. Two orthotopic brain GBM models, patient derived neurospheres (TS543) and U251 cells, with different degrees of blood brain barrier (BBB) disruption were also used for PET imaging experiments. RESULTS: 89Zr labeling of DFO-LEM2/15 was achieved with high yield (>90%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that 89Zr DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors. PET imaging also indicated a specific and prominent 89Zr-DFO LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors. Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors. 89Zr-DFO-LEM2/15 showed much higher accumulation in TS543 tumors with a highly disrupted BBB than in U251 orthotopic model in which the BBB permeability was only partially increased. Histological analysis confirmed the specificity of the immunoconjugate in all GBM models. CONCLUSION: A new anti MT1-MMP-mAb tracer, 89Zr-DFO-LEM2/15, was synthesized efficiently. In vivo validation showed high-specific-contrast imaging of MT1-MMP positive GBM tumors and provided strong evidence for utility of MT1-MMP-targeted immunoPET as an alternate to nonspecific imaging of GBM. PMID- 27462982 TI - Modeling and Prediction in Neurological Disorders: The Biostatistical Perspective. AB - BACKGROUND: Statistical methods are often considered as mere tools to address research questions. The lack of critical understanding can make their use sometimes highly questionable if not inappropriate. Biostatistics should be seen more as a paradigm than a set of tools. Knowledge of methods means a flexible utilization of them, in which modeling and prediction correspond more to an art than to a routine use dictated by circumstances and habits. SUMMARY: Tree-based methods (or tree-growing techniques) are discussed here as a flexible statistical framework for modeling and prediction to address key questions such as prognostic stratification and treatment effects heterogeneity in both randomized clinical trials and observational studies. KEY MESSAGES: We provide some examples in neurology and possible future extensions in which tree-based methods are shown to be crucial for the assessment of the best available therapy for a patient. We show how trees can represent a clinically interpretable and easy-to-implement approach for stratified medicine and treatment tailoring based on responsiveness, as well as for selecting populations for new studies. PMID- 27462981 TI - Responses of Herbivorous Fishes and Benthos to 6 Years of Protection at the Kahekili Herbivore Fisheries Management Area, Maui. AB - In response to concerns about declining coral cover and recurring macroalgal blooms, in 2009 the State of Hawaii established the Kahekili Herbivore Fisheries Management Area (KHFMA). Within the KHFMA, herbivorous fishes and sea urchins are protected, but other fishing is allowed. As part of a multi-agency monitoring effort, we conducted surveys at KHFMA and comparison sites around Maui starting 19 months before closure, and over the six years since implementation of herbivore protection. Mean parrotfish and surgeonfish biomass both increased within the KHFMA (by 139% [95%QR (quantile range): 98-181%] and 28% [95%QR: 3 52%] respectively). Most of those gains were of small-to-medium sized species, whereas large-bodied species have not recovered, likely due to low levels of poaching on what are preferred fishery targets in Hawaii. Nevertheless, coincident with greater biomass of herbivores within the KHFMA, cover of crustose coralline algae (CCA) has increased from ~2% before closure to ~ 15% in 2015, and macroalgal cover has remained low throughout the monitoring period. Strong evidence that changes in the KHFMA were a consequence of herbivore management are that (i) there were no changes in biomass of unprotected fish families within the KHFMA; and that (ii) there were no similar changes in parrotfish or CCA at comparison sites around Maui. It is not yet clear how effective herbivore protection might eventually be for the KHFMA's ultimate goal of coral recovery. Coral cover declined over the first few years of surveys-from 39.6% (SE 1.4%) in 2008, to 32.9% (SE 0.8%) in 2012, with almost all of that loss occurring by 2010 (1 year after closure), i.e. before meaningful herbivore recovery had occurred. Coral cover subsequently stabilized and may have slightly increased from 2012 through early 2015. However, a region-wide bleaching event in 2015 had already led to some coral mortality by the time surveys were conducted in late 2015, at which time cover had dropped back to levels recorded in the KHFMA in 2012. PMID- 27462984 TI - The Impacts of Oil Palm on Recent Deforestation and Biodiversity Loss. AB - Palm oil is the most widely traded vegetable oil globally, with demand projected to increase substantially in the future. Almost all oil palm grows in areas that were once tropical moist forests, some of them quite recently. The conversion to date, and future expansion, threatens biodiversity and increases greenhouse gas emissions. Today, consumer pressure is pushing companies toward deforestation free sources of palm oil. To guide interventions aimed at reducing tropical deforestation due to oil palm, we analysed recent expansions and modelled likely future ones. We assessed sample areas to find where oil palm plantations have recently replaced forests in 20 countries, using a combination of high-resolution imagery from Google Earth and Landsat. We then compared these trends to countrywide trends in FAO data for oil palm planted area. Finally, we assessed which forests have high agricultural suitability for future oil palm development, which we refer to as vulnerable forests, and identified critical areas for biodiversity that oil palm expansion threatens. Our analysis reveals regional trends in deforestation associated with oil palm agriculture. In Southeast Asia, 45% of sampled oil palm plantations came from areas that were forests in 1989. For South America, the percentage was 31%. By contrast, in Mesoamerica and Africa, we observed only 2% and 7% of oil palm plantations coming from areas that were forest in 1989. The largest areas of vulnerable forest are in Africa and South America. Vulnerable forests in all four regions of production contain globally high concentrations of mammal and bird species at risk of extinction. However, priority areas for biodiversity conservation differ based on taxa and criteria used. Government regulation and voluntary market interventions can help incentivize the expansion of oil palm plantations in ways that protect biodiversity-rich ecosystems. PMID- 27462983 TI - Tracking the Fragile X Mental Retardation Protein in a Highly Ordered Neuronal RiboNucleoParticles Population: A Link between Stalled Polyribosomes and RNA Granules. AB - Local translation at the synapse plays key roles in neuron development and activity-dependent synaptic plasticity. mRNAs are translocated from the neuronal soma to the distant synapses as compacted ribonucleoparticles referred to as RNA granules. These contain many RNA-binding proteins, including the Fragile X Mental Retardation Protein (FMRP), the absence of which results in Fragile X Syndrome, the most common inherited form of intellectual disability and the leading genetic cause of autism. Using FMRP as a tracer, we purified a specific population of RNA granules from mouse brain homogenates. Protein composition analyses revealed a strong relationship between polyribosomes and RNA granules. However, the latter have distinct architectural and structural properties, since they are detected as close compact structures as observed by electron microscopy, and converging evidence point to the possibility that these structures emerge from stalled polyribosomes. Time-lapse video microscopy indicated that single granules merge to form cargoes that are transported from the soma to distal locations. Transcriptomic analyses showed that a subset of mRNAs involved in cytoskeleton remodelling and neural development is selectively enriched in RNA granules. One third of the putative mRNA targets described for FMRP appear to be transported in granules and FMRP is more abundant in granules than in polyribosomes. This observation supports a primary role for FMRP in granules biology. Our findings open new avenues for the study of RNA granule dysfunctions in animal models of nervous system disorders, such as Fragile X syndrome. PMID- 27462985 TI - Motor Skill Development in Italian Pre-School Children Induced by Structured Activities in a Specific Playground. AB - This study examined the effects and specificity of structured and unstructured activities played at the playground Primo Sport 0246 in Northern Italy on motor skill competence in five years old children. The playground was specifically designed to promote gross motor skills in preschool children; in this study 71 children from local kindergartens came to the park once a week for ten consecutive weeks and were exposed to 30 minutes of free play and 30 minutes of structured activities. Before and after the ten visits, each child completed nine tests to assess levels of motor skills, three for fine-motor skills and six for gross-motor skills. As control, motor skills were also assessed on 39 children from different kindergartens who did not come to the park. The results show that the experimental group who practiced gross-motor activities in the playground for 1 hour a week for 10 weeks improved significantly in 4 out of the 6 gross motor tasks and in none of the fine motor tasks. The data indicate that limited transfer occurred between tasks referring to different domains of motor competences while suggesting cross feeding for improvement of gross-motor skills between different exercises when domains related to physical fitness and strength of specific muscle groups are involved. These results are relevant to the issue of condition(s) appropriate for maintaining and developing motor skills in this age group as well as for the planning, organization and implementation of play and physical activities in kindergartens. PMID- 27462986 TI - The Facial Appearance of CEOs: Faces Signal Selection but Not Performance. AB - Research overwhelmingly shows that facial appearance predicts leader selection. However, the evidence on the relevance of faces for actual leader ability and consequently performance is inconclusive. By using a state-of-the-art, objective measure for face recognition, we test the predictive value of CEOs' faces for firm performance in a large sample of faces. We first compare the faces of Fortune500 CEOs with those of US citizens and professors. We find clear confirmation that CEOs do look different when compared to citizens or professors, replicating the finding that faces matter for selection. More importantly, we also find that faces of CEOs of top performing firms do not differ from other CEOs. Based on our advanced face recognition method, our results suggest that facial appearance matters for leader selection but that it does not do so for leader performance. PMID- 27462987 TI - Comparison of fibrin clots derived from peripheral blood and bone marrow. AB - BACKGROUND: Autologous fibrin clots derived from peripheral blood (pb-fibrin clot) and bone marrow (bm-fibrin clot) are thought to be effective for tissue regeneration. However, there is no report detailing the amount of growth factors in pb-/bm-fibrin clot. In this study we evaluated the amount of growth factors in human pb-/bm-fibrin clot, and prove the validity of fibrin clot for clinical use. METHODS: Human pb-/bm-fibrin clots were obtained during surgery. In the first experiment, enzyme-linked immunosorbent assay (ELISA) was performed for detecting the amount of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor basic (bFGF), hepatocyte growth factor (HGF), transforming growth factor-beta (TGF beta), platelet derived-growth factors-AB (PDGF-AB), and stromal cell-derived factor-1 (SDF-1). In the second experiment, the efficacy of fibrin clot on the osteogenic differentiation and fibroblast proliferation was evaluated. Pb-/bm fibrin clots were incubated in human osteoblast derived from mesenchymal stromal cells (MSCs) or human skin fibroblast. Alizarin red staining and real-time PCR (COL1A1, RUNX2) were performed for the detection of osteogenic potential. Cell growth assay (WST-8) and real-time PCR (COL1A1) were also performed for the detection of the potential of fibroblast proliferation. RESULTS: ELISA analysis revealed that the amount of VEGF, HGF, bFGF, IGF-1, and SDF-1 of bm-fibrin clot group is higher than that of pb-fibrin clot group with statistical differences. Besides, we confirmed that bm-fibrin clot has much potential for the osteogenic differentiation and fibroblast proliferation. CONCLUSION: The positive outcomes confirm the efficacy of pb-/bm-fibrin clot, and bm-fibrin clot was proved to have much potential for tissue regeneration compared with pb-fibrin clot. The current study showed the potential of a strategy for regenerative medicine using bm fibrin clot. PMID- 27462988 TI - A Spatially Explicit Dual-Isotope Approach to Map Regions of Plant-Plant Interaction after Exotic Plant Invasion. AB - Understanding interactions between native and invasive plant species in field settings and quantifying the impact of invaders in heterogeneous native ecosystems requires resolving the spatial scale on which these processes take place. Therefore, functional tracers are needed that enable resolving the alterations induced by exotic plant invasion in contrast to natural variation in a spatially explicit way. 15N isoscapes, i.e., spatially referenced representations of stable nitrogen isotopic signatures, have recently provided such a tracer. However, different processes, e.g. water, nitrogen or carbon cycles, may be affected at different spatial scales. Thus multi-isotope studies, by using different functional tracers, can potentially return a more integrated picture of invader impact. This is particularly true when isoscapes are submitted to statistical methods suitable to find homogeneous subgroups in multivariate data such as cluster analysis. Here, we used model-based clustering of spatially explicit foliar delta15N and delta13C isoscapes together with N concentration of a native indicator species, Corema album, to map regions of influence in a Portuguese dune ecosystem invaded by the N2-fixing Acacia longifolia. Cluster analysis identified regions with pronounced alterations in N budget and water use efficiency in the native species, with a more than twofold increase in foliar N, and delta13C and delta15N enrichment of up to 20/00 and 80/00 closer to the invader, respectively. Furthermore, clusters of multiple functional tracers indicated a spatial shift from facilitation through N addition in the proximity of the invader to competition for resources other than N in close contact. Finding homogeneous subgroups in multi-isotope data by means of model-based cluster analysis provided an effective tool for detecting spatial structure in processes affecting plant physiology and performance. The proposed method can give an objective measure of the spatial extent of influence of plant-plant interactions, thus improving our understanding of spatial pattern and interactions in plant communities. PMID- 27462989 TI - Evaluating the Effectiveness of Wildlife Detection and Observation Technologies at a Solar Power Tower Facility. AB - Solar power towers produce electrical energy from sunlight at an industrial scale. Little is known about the effects of this technology on flying animals and few methods exist for automatically detecting or observing wildlife at solar towers and other tall anthropogenic structures. Smoking objects are sometimes observed co-occurring with reflected, concentrated light ("solar flux") in the airspace around solar towers, but the identity and origins of such objects can be difficult to determine. In this observational pilot study at the world's largest solar tower facility, we assessed the efficacy of using radar, surveillance video, and insect trapping to detect and observe animals flying near the towers. During site visits in May and September 2014, we monitored the airspace surrounding towers and observed insects, birds, and bats under a variety of environmental and operational conditions. We detected and broadly differentiated animals or objects moving through the airspace generally using radar and near solar towers using several video imaging methods. Video revealed what appeared to be mostly small insects burning in the solar flux. Also, we occasionally detected birds flying in the solar flux but could not accurately identify birds to species or the types of insects and small objects composing the vast majority of smoking targets. Insect trapping on the ground was somewhat effective at sampling smaller insects around the tower, and presence and abundance of insects in the traps generally trended with radar and video observations. Traps did not tend to sample the larger insects we sometimes observed flying in the solar flux or found dead on the ground beneath the towers. Some of the methods we tested (e.g., video surveillance) could be further assessed and potentially used to automatically detect and observe flying animals in the vicinity of solar towers to advance understanding about their effects on wildlife. PMID- 27462990 TI - Characteristics of Haptic Peripersonal Spatial Representation of Object Relations. AB - Haptic perception of space is known to show characteristics that are different to actual space. The current study extends on this line of research, investigating whether systematic deviations are also observed in the formation of haptic spatial representations of object-to-object relations. We conducted a haptic spatial reproduction task analogous to the parallelity task with spatial layouts. Three magnets were positioned to form corners of an isosceles triangle and the task of the participant was to reproduce the right angle corner. Weobserved systematic deviations in the reproduction of the right angle triangle. The systematic deviations were not observed when the task was conducted on the mid sagittal plane. Furthermore, the magnitude of the deviation was decreased when non-informative vision was introduced. These results suggest that there is a deformation in spatial representation of object-to-object relations formed using haptics. However, as no systematic deviation was observed when the task was conducted on the mid-saggital plane, we suggest that the perception of object-to object relations use a different egocentric reference frame to the perception of orientation. PMID- 27462991 TI - Sheath-Core Graphite/Silk Fiber Made by Dry-Meyer-Rod-Coating for Wearable Strain Sensors. AB - Recent years have witnessed the explosive development of flexible strain sensors. Nanomaterials have been widely utilized to fabricate flexible strain sensors, because of their high flexibility and electrical conductivity. However, the fabrication processes for nanomaterials and the subsequent strain sensors are generally complicated and are manufactured at high cost. In this work, we developed a facile dry-Meyer-rod-coating process to fabricate sheath-core structured single-fiber strain sensors using ultrafine graphite flakes as the sheath and silk fibers as the core by virtue of their flexibility, high production, and low cost. The fabricated strain sensor exhibits a high sensitivity with a gauge factor of 14.5 within wide workable strain range up to 15%, and outstanding stability (up to 3000 cycles). The single-fiber-based strain sensors could be attached to a human body to detect joint motions or easily integrated into the multidirectional strain sensor for monitoring multiaxial strain, showing great potential applications as wearable strain sensors. PMID- 27462992 TI - Synthesis and Antiproliferative Activity of [RuCp(PPh3)2(HdmoPTA)](OSO2CF3)2 (HdmoPTA = 3,7-H-3,7-Dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane). AB - The complex [RuCp(PPh3)2(HdmoPTA)](OSO2CF3)2 (2; HdmoPTA = 3,7-H-3,7-dimethyl 1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) was synthesized and characterized. Its crystal structure was determined by single-crystal X-ray diffraction. The complex showed a more potent antiproliferative activity than cisplatin against a representative panel of human cancer cells. PMID- 27462994 TI - Erratum: ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction. AB - [This corrects the article DOI: 10.1038/celldisc.2015.18.]. PMID- 27462993 TI - Water-Soluble Molecularly Imprinted Nanoparticle Receptors with Hydrogen-Bond Assisted Hydrophobic Binding. AB - Molecularly imprinted nanoparticles (MINPs) were prepared when surfactants with a tripropargylammonium headgroup and a methacrylate-functionalized hydrophobic tail were cross-linked in the micelle form on the surface and in the core in the presence of hydrophobic template molecules. With the surfactants containing an amide bond near the headgroup, the MINPs had a layer of hydrogen-bonding groups in the interior that strongly influenced their molecular recognition. Templates/guests with strong hydrogen-bonding groups in the midsection of the molecule benefited most, especially if the hydrophobe of the template could penetrate the amide layer to reach the hydrophobic core of the cross-linked micelles. The location and the orientation of the hydrophilic groups were also important, as they determined how the template interacted with the surfactant micelles and, ultimately, with the MINP receptors. PMID- 27462995 TI - Homogeneous Entropy-Driven Amplified Detection of Biomolecular Interactions. AB - While a range of artificial biochemical circuits is likely to play a significant role in biological engineering, one of the challenges in the field is the design of circuits that can transduce between biomolecule classes (e.g., moving beyond nucleic acid only circuits). Herein, we design a transduction mechanism whereby a protein signal is transduced into an amplified nucleic acid output using DNA nanotechnology. In this system, a protein is recognized by nucleic acid bound recognition elements to form a catalytic complex that drives a hybridization/displacement reaction on a multicomponent nucleic acid substrate, releasing multiple target single-stranded oligonucleotides in an amplified fashion. Amplification power and simple one-pot reaction conditions lead us to apply the scheme in an assay format, achieving homogeneous and rapid (~10 min) analyte detection that is also robust (operable in whole blood and plasma). In addition, we demonstrate the assay in a microfluidic digital assay format leading to improved quantification and sensitivity approaching single-molecule levels. The present scheme we believe will have a significant impact on a range of applications from fundamental molecular interaction studies to design of artificial circuits in vivo to high-throughput, multiplexed assays for screening or point-of-care diagnostics. PMID- 27462996 TI - An efficient method to genotype the polymorphisms of cholinergic nicotinic receptor subunit genes and their associations with COPD onset risk. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the cholinergic nicotinic receptor subunit genes on chromosome 15q25.1, including CHRNA3, CHRNB4 and CHRNA5, are well-established biomarkers of chronic obstructive pulmonary disease (COPD) and lung cancer. Thus, there is great demand for a rapid, easy and inexpensive method to detect these variations for purpose of risk prediction in large populations. AIM OF THE STUDY: The aim of this study was to establish an accurate and efficient method for genotyping CHRN SNPs and testing their association with age at onset of COPD in Chinese population as well as the clinical stage in COPD patients. MATERIALS AND METHODS: We designed a method to specifically genotype 5 SNPs of CHRN genes based on a modified high-resolution melt (HRM) method and then validated the genotyping results by direct sequencing of 120 samples. We further used the HRM method to genotype these 5 SNPs in 1,013 COPD patients. RESULTS: Requiring little time, few material costs and only a simplified protocol, the modified HRM method could accurately distinguish the genotypes of CHRN SNPs, demonstrating kappa coefficients >0.96 based on the results from direct sequencing. Furthermore, the data showed that the GG genotype of SNP rs56218866 was associated with a significantly earlier age of COPD onset than A (AA+AG) genotypes (61.0 +/- 8.93 vs. 67.8 +/- 9.88; P = 0.031), which was not found for the other SNPs. No significant association was observed between the COPD stages and any of the above SNPs. CONCLUSION: A simple, rapid and efficient HRM method was introduced for CHRN SNP genotyping and a suggestion that the SNP rs56218866A>G is associated with early-onset COPD in a Chinese population was found. PMID- 27462997 TI - MetDIA: Targeted Metabolite Extraction of Multiplexed MS/MS Spectra Generated by Data-Independent Acquisition. AB - With recent advances in mass spectrometry, there is an increased interest in data independent acquisition (DIA) techniques for metabolomics. With DIA technique, all metabolite ions are sequentially selected and isolated using a wide window to generate multiplexed MS/MS spectra. Therefore, DIA strategy enables a continuous and unbiased acquisition of all metabolites and increases the data dimensionality, but presents a challenge to data analysis due to the loss of the direct link between precursor ion and fragment ions. However, very few DIA data processing methods are developed for metabolomics application. Here, we developed a new DIA data analysis approach, namely, MetDIA, for targeted extraction of metabolites from multiplexed MS/MS spectra generated using DIA technique. MetDIA approach considers each metabolite in the spectral library as an analysis target. Ion chromatograms for each metabolite (both precursor ion and fragment ions) and MS(2) spectra are readily detected, extracted, and scored for metabolite identification, referred as metabolite-centric identification. A minimum metabolite-centric identification score responsible for 1% false positive rate of identification is determined as 0.8 using fully (13)C labeled biological extracts. Finally, the comparisons of our MetDIA method with data-dependent acquisition (DDA) method demonstrated that MetDIA could significantly detect more metabolites in biological samples, and is more accurate and sensitive for metabolite identifications. The MetDIA program and the metabolite spectral library is freely available on the Internet. PMID- 27462998 TI - First report of membranous nephropathy and systemic lupus erythematosus associated with abatacept in rheumatoid arthritis. PMID- 27462999 TI - Comparison of Information Available in the Medication Profile of an Electronic Health Record and the Inpatient Best Possible Medication History in a Mother and Child Teaching Hospital Center. AB - BackgroundMedication reconciliation (MedRec) can improve patient safety. In Canada, most provinces are implementing electronic health records (EHR). The Quebec Health Record (QHR) can theoretically be used for medication reconciliation. However, the quantity and the quality of information available in this EHR have not been studied. ObjectivesThe main objective was to compare the quantity and quality of the information collected between the inpatient best possible medication history (BPMH) and the QHR. MethodsThis is a descriptive prospective study conducted at CHU Sainte-Justine, a 500-bed tertiary mother-and child university hospital center. All inpatients from May 19-26, 2015 were considered for inclusion. Every prescription line in the BPMH and QHR were compared. ResultsThe study included 344 patients and 1,039 prescription lines were analyzed. The medications' name and dosing were more often available in the QHR (95%) than in the BPMH (61%). Concordance between the medication names between QHR and BPMH was found in 48% of the prescription lines; this rate fell to 29% when also factoring daily dosage. ConclusionsThis study suggests that the QHR can provide high-quality information to support the MedRec hospital process. However, it should be used as a second source to optimize the BPMH obtained from a thorough interview with the patient and/or his or her family. More studies are required to confirm the most optimal way to integrate the QHR to the MedRec process in hospitals. PMID- 27463000 TI - Engineered PQQ-Glucose Dehydrogenase as a Universal Biosensor Platform. AB - Biosensors with direct electron output hold promise for nearly seamless integration with portable electronic devices. However, so far, they have been based on naturally occurring enzymes that significantly limit the spectrum of detectable analytes. Here, we present a novel biosensor architecture based on analyte-driven intermolecular recombination and activity reconstitution of a re engineered component of glucometers: PQQ-glucose dehydrogenase. We demonstrate that this sensor architecture can be rapidly adopted for the detection of immunosuppressant drugs, alpha-amylase protein, or protease activity of thrombin and Factor Xa. The biosensors could be stored in dried form without appreciable loss of activity. We further show that ligand-induced activity of the developed biosensors could be directly monitored by chronoamperometry, enabling construction of disposable sensory electrodes. We expect that this architecture could be expanded to the detection of other biochemical activities, post translational modifications, nucleic acids, and inorganic molecules. PMID- 27463001 TI - Exosomes: small vesicles with big roles in hepatocellular carcinoma. AB - Despite improvements in the diagnosis and treatment of hepatocellular carcinoma (HCC), the prognosis is still poor. Pioneering work has demonstrated a potential role for tumour cell-derived exosomes (TEXs) in HCC. TEXs can mediate immune responses, antigen presentation and intracellular communication by serving as vehicles for the transfer of proteins, viruses, lipids and RNA between cells. An improved understanding of the roles played by exosomes could lead to a powerful new strategy for preventing and treating HCC. In this review, we summarise current understanding on the topic. The literature points to two faces of TEXs in HCC: 1) They can promote invasion, metastasis, immune evasion and modulation and 2) they can act as diagnostic and prognostic biomarkers, and can be used in anti cancer drug resistance and immunotherapy in the future. PMID- 27463002 TI - An updated meta-analysis of 37 case-control studies on the association between NFKB1 -94ins/del ATTG promoter polymorphism and cancer susceptibility. AB - As a cell survival signal, nuclear factor-kappa B (NFKB) is associated with the pathogenesis of numerous malignancies. According to several studies, NFKB1 94ins/del ATTG promoter polymorphism is associated with the risk of different malignancies, but the results were not consistent. Therefore, we performed an updated meta-analysis based on 37 case-control studies from 33 articles (16,271 cases and 22,781 controls) to clarify the relationship. The odds ratio (OR) and 95% confidence interval (CI) were used to determine the strength of the association. We found that the NFKB1 -94ins/del ATTG promoter polymorphism was significantly associated with increased susceptibility to cancer in the recessive (II vs. ID+DD, OR = 1.140, 95% CI = 1.029-1.263, p =0.012), homozygote (II vs. DD, OR = 1.259, 95% CI = 1.068-1.485, p =0.006), and allele (I vs. D, OR = 1.109, 95% CI = 1.025-1.199, p =0.010) genetic models. The subgroup analysis for ethnicity found that the NFKB1 -94ins/del ATTG promoter polymorphism was significantly associated with an increased susceptibility to cancer in Asians and with a decreased susceptibility in Caucasians. The stratified analyses revealed significant associations between the polymorphism and increased susceptibility to ovarian cancer, oral squamous cell carcinoma, and nasopharyngeal carcinoma. PMID- 27463003 TI - alpha2-adrenoreceptor modulated FAK pathway induced by dexmedetomidine attenuates pulmonary microvascular hyper-permeability following kidney injury. AB - Renal ischemia-reperfusion (rI/R) could cause remote acute lung injury (ALI) and combination of these two organ injuries can remarkably increase the mortality. This study aims to determine whether dexmedetomidine, an alpha2-adrenoreceptor agonist sedative, can ameliorate pulmonary microvascular hyper-permeability following rI/R injury and explore the underlying mechanisms. In vivo, C57BL/6J mice received dexmedetomidine (25ug/kg, i.p.) in the absence or presence of alpha2-adrenergic antagonist atipamezole (250ug/kg, i.p.) or focal adhesion kinase (FAK) inhibitor (30mg/kg, i.p.) before bilateral renal pedicle clamping for 45 minutes followed by 24 hours reperfusion. The lung histopathological changes and the permeability of pulmonary microvascular were assessed respectively. In vitro, the cultured C57BL/6J mice pulmonary microvascular endothelial cells (PMVECs) were treated with serum from mice with rI/R with or without dexmedetomidine and atipamezole. Trans-endothelial permeability and phospho-tyrosine397FAK, F-actin, VE-cadherin and ZO-1 in monolayer PMVECs were measured respectively in the presence or absence of rI/R serum, dexmedetomidine and FAK inhibitor. In vivo, dexmedetomidine remarkably attenuated lung injury and pulmonary microvascular hyper-permeability caused by rI/R injury, which was abolished by atipamezole or FAK inhibitor co-administration. In vitro, the permeability of PMVECs monolayer following exposure to serum from rI/R mice was increased significantly, and decreased by dexmedetomidine. Dexmedetomidine increased phospho-tyrosine397FAK in a time- and dose-dependent manner, which was correlated with the changes in trans-endothelial permeability. Our data indicated that dexmedetomidine is able to ameliorate remote pulmonary microvascular hyper permeability induced by rI/R, at least in part, via FAK modulation. PMID- 27463004 TI - Minocycline promotes the generation of dendritic cells with regulatory properties. AB - Minocycline, which has long been used as a broad-spectrum antibiotic, also exhibits non-antibiotic properties such as inhibition of inflammation and angiogenesis. In this study, we show that minocycline significantly enhances the generation of dendritic cells (DCs) from mouse bone marrow (BM) cells when used together with GM-CSF and IL-4. DCs generated from BM cells in the presence of minocycline (Mino-DCs) demonstrate the characteristics of regulatory DCs. Compared with control DCs, Mino-DCs are resistant to subsequent maturation stimuli, impaired in MHC class II-restricted exogenous Ag presentation, and show decreased cytokine secretion. Mino-DCs also show decreased ability to prime allogeneic-specific T cells, while increasing the expansion of CD4+CD25+Foxp3+ T regulatory cells both in vitro and in vivo. In addition, pretreatment with MOG35 55 peptide-pulsed Mino-DCs ameliorates clinical signs of experimental autoimmune encephalitis induced by MOG peptide injection. Our study identifies minocycline as a new pharmacological agent that could be potentially used to increase the production of regulatory DCs for cell therapy to treat autoimmune disorders, allergy, and transplant rejection. PMID- 27463006 TI - Partial loss of interleukin 2 receptor gamma function in pigs provides mechanistic insights for the study of human immunodeficiency syndrome. AB - In this study, we described the phenotype of monoallelic interleukin 2 receptor gamma knockout (mIL2RG+/Delta69-368 KO) pigs. Approximately 80% of mIL2RG+/Delta69-368 KO pigs (8/10) were athymic, whereas 20% (2/10) presented a rudimentary thymus. The body weight of IL2RG+/Delta69-368KO pigs developed normally. Immunological analysis showed that mIL2RG+/Delta69-368 KO pigs possessed CD25+CD44- or CD25-CD44+ cells, whereas single (CD4 or CD8) or double (CD4/8) positive cells were lacking in mIL2RG+/Delta69-368 KO pigs. CD3+ cells in the thymus of mIL2RG+/Delta69-368 KO pigs contained mainly CD44+ cells and/or CD25+ cells, which included FOXP3+ cells. These observations demonstrated that T cells from mIL2RG+/Delta69-368 KO pigs were able to develop to the DN3 stage, but failed to transition toward the DN4 stage. Whole-transcriptome analysis of thymus and spleen, and subsequent pathway analysis revealed that a subset of genes differentially expressed following the loss of IL2RG might be responsible for both impaired T-cell receptor and cytokine-mediated signalling. However, comparative analysis of two mIL2RG+/Delta69-368 KO pigs revealed little variability in the down- and up-regulated gene sets. In conclusion, mIL2RG+/Delta69-368 KO pigs presented a T-B+NK- SCID phenotype, suggesting that pigs can be used as a valuable and suitable biomedical model for human SCID research. PMID- 27463005 TI - Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers. AB - The prognosis of non-small cell lung cancer (NSCLC) remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of immune-related markers may provide valuable prognostic information of NSCLC. In 122 formalin-fixed, paraffin-embedded tumor tissue samples from early-stage NSCLC, tumor and tumor-near stromal areas were microdissected and gene expression levels of conventional and regulatory T cell markers were assessed by quantitative polymerase chain reaction. Also, the presence of infiltrating CD4+, CD8+, and FOXP3+ cells in tumor samples was assessed by immunohistochemistry. The relative proportion of conventional and regulatory T cells present in the tumor environment was assessed and found to be key to understand the importance that the immune system analysis has in the prognostics of NSCLC patients. The presence of CD8+ cells in the tumor compartment was associated with better outcome, whereas the presence of FOXP3+ cells was associated with worse overall survival. The negative prognostic value of combined biomarkers, indicating high levels of FOXP3 in the stroma and low levels of CD4 or CD8 in tumors, was observed at mRNA level and was validated by immunohistochemistry.In conclusion, the proportion of T helper and cytotoxic cells vs. regulatory T cells in different locations of the tumor microenvironment have opposite prognostic impacts in resected NSCLC. PMID- 27463009 TI - Epsin2 promotes polarity establishment and meiotic division through activating Cdc42 in mouse oocyte. AB - Epsins are a conserved family of endocytic adaptors essential for diverse biological events. However, its role in oocytes remains completely unknown. Here, we report that specific depletion of Epsin2 in mouse oocytes significantly disrupts meiotic progression. Confocal microscopy reveals that Epsin2 knockdown results in the failure of actin cap formation and polar body extrusion during meiosis, indicative of the importance of Epsin2 in polarity establishment and cytokinesis. In addition, spindle defects and chromosome misalignment are readily observed in oocytes depleted of Epsin2. Moreover, we find that Epsin2 knockdown markedly decreases the activity of Cdc42 in oocytes and importantly, that the dominant-positive mutant of Cdc42 (Cdc42Q61L) is capable of partially rescuing the deficient phenotypes of Epsin2-knockdown oocytes. Together, our data identify Epsin2 as a novel player in regulating oocyte maturation, and demonstrate that Epsin2 promotes polarity establishment and meiotic division via activating Cdc42. PMID- 27463007 TI - Rapamycin ameliorates chitosan nanoparticle-induced developmental defects of preimplantation embryos in mice. AB - Chitosan nanoparticles (CSNPs) are used as drug or gene delivery vehicles. However, a detailed understanding of the effects of CSNPs on embryonic development remains obscure. Here, we show that CSNPs can be internalized into mouse blastocysts, such as the zona pellucida, the perivitelline space, and the cytoplasm. Consequently, CSNPs-induced endoplasmic reticulum (ER) stress increases both of Bip/Grp78, Chop, Atf4, Perk, and Ire1a mRNAs expression levels, and reactive oxygen species. Moreover, CSNPs show double- and multi-membraned autophagic vesicles, and lead to cell death of blastocoels. Conversely, treatment with rapamycin, which plays an important role as a central regulator of cellular proliferation and stress responses, decreased CSNPs-induced mitochondrial Ca+2 overloading, apoptosis, oxidative stress, ER stress, and autophagy. In vivo studies demonstrated that CSNPs injection has significant toxic effect on primordial and developing follicles. Notably, rapamycin rescued oxidative stress induced embryonic defects via modulating gene expression of sirtuin and mammalian target of rapamycin. Interestingly, CSNPs treatment alters epigenetic reprogramming in mouse embryos. Overall, these observations suggest that rapamycin treatment could ameliorate CSNPs-induced developmental defects in preimplantation embryos. The data from this study would facilitate to understand the toxicity of these CSNPs, and enable the engineering of safer nanomaterials for therapeutic applications. PMID- 27463010 TI - Targeting LIM kinases in taxane resistant tumors. PMID- 27463011 TI - Porcine reproductive and respiratory syndrome virus triggers mitochondrial fission and mitophagy to attenuate apoptosis. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) causes acute mitochondrial dysfunction by elevating the level of reactive oxygen species. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial homeostasis. Here we show that PRRSV infection stimulated mitochondrial fission and mitophagy to attenuate apoptosis in Marc145 cells. PRRSV infection induced the expression of Drp1, enhanced phosphorylation of Drp1 at Ser616 and its subsequent translocation to mitochondria. Furthermore, PRRSV infection increased the expression of PINK1 and Parkin and also stimulated the recruitment of Parkin to mitochondria. In addition, a sensitive dual fluorescence vector expressing mito-mRFP-EGFP targeted mitochondria was employed to observe the complete mitophagy by delivering dysfunctional mitochondria to lysosome for degradation. Interfering the expression of Drp1 and or Parkin suppressed PRRSV replication. More importantly, silencing of Drp1 or Parkin caused significant elevation in apoptotic signaling. These results suggest that PRRSV infection stimulates mitochondrial fission and mitophagy to facilitate virus replication most probably by attenuating apoptosis. PMID- 27463012 TI - Old age at diagnosis increases risk of tumor progression in nasopharyngeal cancer. AB - Age at diagnosis has been found to be a prognostic factor of outcomes in various cancers. However, the effect of age at diagnosis on nasopharyngeal cancer (NPC) progression has not been explored. We retrospectively evaluated the relationship between age and disease progression in 3,153 NPC patients who underwent radiotherapy, chemotherapy, or chemoradiotherapy between 2007 and 2009. Patients were randomly assigned to either a testing cohort or a validation cohort by computer-generated random assignment. X-tile plots determined the optimal cut point of age based on survival status to be <=61 vs. >61 years. Further correlation analysis showed that age >61 years was significantly correlated with the tumor progression and therapeutic regimen in both testing and validation cohorts (P <0.05). In the present study, we observed that older age (>61 years) was a strong and independent predictor of poor disease-free survival (DFS) and cancer-specific survival (CSS), in both univariate and multivariate analyses. Age was also found to be a significant prognostic predictor as well (P <0.05) when evaluating patients with the same disease stage. ROC analysis confirmed the predictive value of age on NPC-specific survival in both cohorts (P <0.001) and suggested that age may improve the ability to discriminate outcomes in NPCs, especially regarding tumor progression. In conclusion, our study suggests that older age at NPC diagnosis is associated with a higher incidence of tumor progression and cancer-specific mortality. Age is a strong and independent predictor of poor outcomes and may allow for more tailored therapeutic decision making and individualized patient counseling. PMID- 27463014 TI - Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche. AB - Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche.We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease.This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche.This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands. PMID- 27463015 TI - Potential implications of Apolipoprotein E in early brain injury after experimental subarachnoid hemorrhage: Involvement in the modulation of blood brain barrier integrity. AB - Apolipoprotein E (Apoe) genetic polymorphisms have been implicated in the long term outcome of subarachnoid haemorrhage (SAH), but little is known about the effect of Apoe on the early brain injury (EBI) after SAH. This study investigated the potential role of APOE in EBI post-SAH. Multiple techniques were used to determine the early BBB disruption in EBI post-SAH in a murine model using wild type (WT) and Apoe-/- (KO) mice. Progressive BBB disruption (Evans blue extravasation and T2 hyperintensity in magnetic resonance imaging) was observed before the peak of endogenous APOE expression elevation at 48h after SAH. Moreover, Apoe-/- mice exhibited more severe BBB disruption charcteristics after SAH than WT mice, including higher levels of Evans blue and IgG extravasation, T2 hyperintensity in magnetic resonance imaging, tight junction proteins degradation and endothelial cells death. Mechanistically, we found that APOE restores the BBB integrity in the acute stage after SAH via the cyclophilin A (CypA)-NF-kappaB proinflammatory cytokines-MMP-9 signalling pathway. Consequently, although early BBB disruption causes neurological dysfunctions after SAH, we capture a different aspect of the effects of APOE on EBI after SAH that previous studies had overlooked and open up the idea of BBB disruption as a target of APOE-based therapy for EBI amelioration research in the future. PMID- 27463017 TI - Single-strand DNA library preparation improves sequencing of formalin-fixed and paraffin-embedded (FFPE) cancer DNA. AB - DNA derived from formalin-fixed and paraffin-embedded (FFPE) tissue has been a challenge to large-scale genomic sequencing, due to its low quality and quantities. Improved techniques enabling the genome-wide analysis of FFPE material would be of great value, both from a research and clinical perspective.Comparing a single-strand DNA library preparation method originally developed for ancient DNA to conventional protocols using double-stranded DNA derived from FFPE material we obtain on average 900-fold more library molecules and improved sequence complexity from as little as 5 ng input DNA. FFPE DNA is highly fragmented, usually below 100bp, and up to 60% of reads start after or end prior to adenine residues, suggesting that crosslinks predominate at adenine residues. Similar to ancient DNA, C > T substitutions are slightly increased with maximum rates up to 3% at the ends of molecules. In whole exome sequencing of single-strand libraries from lung, breast, colorectal, prostate and skin cancers we identify known cancer mutations. In summary, we show that single-strand library preparation enables genomic sequencing, even from low amounts of degraded FFPE DNA. This method provides a clear advantage both in research and clinical settings, where FFPE material (e.g. from biopsies) often is the only source of DNA available. Improving the genetic characterization that can be performed on conventional archived FFPE tissue, the single-strand library preparation allows scarce samples to be used in personalized medicine and enables larger sample sizes in future sequencing studies. PMID- 27463016 TI - Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. AB - Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3-4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy. PMID- 27463018 TI - Loss of ZFP36 expression in colorectal cancer correlates to wnt/ beta-catenin activity and enhances epithelial-to-mesenchymal transition through upregulation of ZEB1, SOX9 and MACC1. AB - The mRNA-destabilizing protein ZFP36 has been previously described as a tumor suppressor whose expression is lost during colorectal cancer development. In order to evaluate its role in this disease, we restored ZFP36 expression in different cell contexts, showing that the presence of this protein impairs the epithelial-to-mesenchymal transition (EMT) and induces a higher susceptibility to anoikis. Consistently, we found that ZFP36 inhibits the expression of three key transcription factors involved in EMT: ZEB1, MACC1 and SOX9. Finally, we observed for the first time that its expression negatively correlates with the activity of Wnt/beta-catenin pathway, which is constitutively activated in colorectal cancer. This evidence provides a clue on the mechanism leading to the loss of ZFP36 in CRC. PMID- 27463019 TI - Plasma MiRNA alterations between NSCLC patients harboring Del19 and L858R EGFR mutations. AB - Based on recognition of driver mutations, treatment paradigm for non-small-cell lung cancer (NSCLC) patients has been shifted. However, recently exon 19 deletion mutation (del19) of epidermal growth factor receptor (EGFR) clearly shows better clinical benefit over single-point substitution mutation L858R in exon 21 (L858R). The aim of this study was to investigate the difference by analyzing the expression of plasma microRNAs (miRNAs) of NSCLC patients with EGFR mutation del19 or L858R. MiRNA microarray of plasma from patients' blood identified 79 mapped, network-eligible miRNAs (fold > 5), of which 76 were up regulated and 3 were down regulated. Genetic network was performed with Ingenuity Pathway Analysis (IPA). Among analysis, MYC, Argonaute2 (AGO2), Y-box binding protein 1 (YBX1), cyclin E1 (CCNE1) were involved in organismal abnormalities and cancer. Our findings provide information on the epigenetic signature of the two major sensitive mutations among NSCLC and add to the understanding of mechanisms underlying the different outcomes. PMID- 27463021 TI - Band-Gap Widening at the Cu(In,Ga)(S,Se)2 Surface: A Novel Determination Approach Using Reflection Electron Energy Loss Spectroscopy. AB - Using reflection electron energy loss spectroscopy (REELS), we have investigated the optical properties at the surface of a chalcopyrite-based Cu(In,Ga)(S,Se)2 (CIGSSe) thin-film solar cell absorber, as well as an indium sulfide (InxSy) buffer layer before and after annealing. By fitting the characteristic inelastic scattering cross-section lambdaK(E) to cross sections evaluated by the QUEELS epsilon(k,omega)-REELS software package, we determine the surface dielectric function and optical properties of these samples. A comparison of the optical values at the surface of the InxSy film with bulk ellipsometry measurements indicates a good agreement between bulk- and surface-related optical properties. In contrast, the properties of the CIGSSe surface differ significantly from the bulk. In particular, a larger (surface) band gap than for bulk-sensitive measurements is observed, providing a complementary and independent confirmation of earlier photoelectron spectroscopy results. Finally, we derive the inelastic mean free path lambda for electrons in InxSy, annealed InxSy, and CIGSSe at a kinetic energy of 1000 eV. PMID- 27463020 TI - Prediction and diagnosis of renal cell carcinoma using nuclear magnetic resonance based serum metabolomics and self-organizing maps. AB - Diagnosis of renal cell carcinoma (RCC) at an early stage is challenging, but it provides the best chance for cure. We aimed to develop a predictive diagnostic method for early-stage RCC based on a biomarker cluster using nuclear magnetic resonance (NMR)-based serum metabolomics and self-organizing maps (SOMs). We trained and validated the SOM model using serum metabolome data from 104 participants, including healthy individuals and early-stage RCC patients. To assess the predictive capability of the model, we analyzed an independent cohort of 22 subjects. We then used our method to evaluate changes in the metabolic patterns of 23 RCC patients before and after nephrectomy. A biomarker cluster of 7 metabolites (alanine, creatine, choline, isoleucine, lactate, leucine, and valine) was identified for the early diagnosis of RCC. The trained SOM model using a biomarker cluster was able to classify 22 test subjects into the appropriate categories. Following nephrectomy, all RCC patients were classified as healthy, which was indicative of metabolic recovery. But using a diagnostic criterion of 0.80, only 3 of the 23 subjects could not be confidently assessed as metabolically recovered after nephrectomy. We successfully followed-up 17 RCC patients for 8 years post-nephrectomy. Eleven of these patients who diagnosed as metabolic recovery remained healthy after 8 years. Our data suggest that a SOM model using a biomarker cluster from serum metabolome can accurately predict early RCC diagnosis and can be used to evaluate postoperative metabolic recovery. PMID- 27463022 TI - CYP2D6 ultra-rapid metabolizer phenotype not associated with attempted suicide in a large sample of psychiatric inpatients. AB - AIM: Suicide accounts for over 800,000 deaths per year worldwide and is the tenth leading cause of mortality in USA. Several studies have investigated cytochrome P450 CYP2D6 ultra-rapid metabolizer (UM) phenotype in relation to suicidality, with mixed results. This study tested the hypothesis of increased suicide risk among CYP2D6 UMs. PATIENTS & METHODS: Among the 4264 state psychiatric hospital inpatients included, 2435 (57%) reported a prior suicide attempt. RESULTS: No association between UM status and attempted suicide was observed in bivariate (odds ratio: 0.87; 95% CI: 0.53-1.25), multivariate (adjusted odds ratio: 0.89; 95% CI: 0.55-1.46), or risk-stratified analyses. CONCLUSION: These results contrast with prior reports of increased suicidality among CYP2D6 UMs and highlight the pressing need to identify reliable screening methods to better address this persistent public health problem. PMID- 27463024 TI - Copper-Promoted Cyclization of alpha-Amino Nitrile-Tethered Enynes: Controllable Synthesis of 3-Azabicyclo[4.1.0]hepta-2,4-dienes and 4,5-Dihydro-3H-azepines. AB - The first example of Cu-promoted cyclization of alpha-amino nitrile-tethered enynes incorporating an electron-deficient alkene component is described. A wide range of functionalized 3-azabicyclo[4.1.0]hepta-2,4-dienes and 4,5-dihydro-3H azepines were prepared efficiently in a controllable manner. Moreover, the diverse cascade process enables efficient incorporation of tertiary amine moieties under mild reaction conditions. A possible reaction pathway is proposed on the basis of a series of control experiments. PMID- 27463023 TI - Patterns and Etiologies of Uveitis at a Tertiary Referral Center in Taiwan. AB - PURPOSE: To analyze the patterns and etiologies of uveitis at a tertiary referral center in Taiwan. METHODS: This retrospective chart review of uveitis patients from January 2001 to December 2014 updates a previous study a decade ago (2003). RESULTS: We identified 450 patients, among whom anterior uveitis was most common, followed by panuveitis, posterior uveitis, and intermediate uveitis. A specific diagnosis was identified in 331 patients. In 73 infectious uveitis cases, herpetic anterior uveitis was the leading cause, followed by endogenous bacterial endophthalmitis and acute retinal necrosis. In 258 non-infectious uveitis cases, HLA-B27-associated uveitis was most commonly seen, followed by Vogt-Koyanagi Harada disease and Posner-Schlossman syndrome. Compared with our previous study, we found more viral infection and sarcoidosis but fewer cases of Behcet disease, tuberculosis, and toxoplasmosis. CONCLUSIONS: Our results provide useful information about the patterns and etiologies of uveitis in a selected population in Taiwan. PMID- 27463026 TI - Chemical controls on abiotic and biotic release of geogenic arsenic from Pleistocene aquifer sediments to groundwater. AB - Over 150 million people in South and Southeast Asia consume unsafe drinking water from arsenic-rich Holocene aquifers. Although use of As-free water from Pleistocene aquifers is a potential mitigation strategy, such aquifers are vulnerable to geogenic As pollution, placing millions more people at potential risk. The goal of this research was to define chemical controls on abiotic and biotic release of geogenic As to groundwater. Batch incubations of sediments with natural chemical variability from a Pleistocene aquifer in Cambodia were conducted to evaluate how interactions among arsenic, manganese and iron oxides, and dissolved and sedimentary organic carbon influenced As mobilization from sediments. The addition of labile dissolved organic carbon produced the highest concentrations of dissolved As after >7 months, as compared to sediment samples incubated with sodium azide or without added carbon, and the extent of As release was positively correlated with the percent of initial extractable Mn released from the sediments. The mode of As release was impacted by the source of DOC supplied to the sediments, with biological processes responsible for 81% to 85% of the total As release following incubations with lactate and acetate but only up to 43% to 61% of the total As release following incubations with humic and fulvic acids. Overall, cycling of key redox-active elements and organic-carbon reactivity govern the potential for geogenic As release to groundwater, and results here may be used to formulate better predictions of the arsenic pollution potential of aquifers in South and Southeast Asia. PMID- 27463027 TI - Wild-type rabies virus induces autophagy in human and mouse neuroblastoma cell lines. AB - Different rabies virus (RABV) strains have their own biological characteristics, but little is known about their respective impact on autophagy. Therefore, we evaluated whether attenuated RABV HEP-Flury and wild-type RABV GD-SH-01 strains triggered autophagy. We found that GD-SH-01 infection significantly increased the number of autophagy-like vesicles, the accumulation of enhanced green fluorescent protein (EGFP)-LC3 fluorescence puncta and the conversion of LC3-I to LC3-II, while HEP-Flury was not able to induce this phenomenon. When evaluating autophagic flux, we found that GD-SH-01 infection triggers a complete autophagic response in the human neuroblastoma cell line (SK), while autophagosome fusion with lysosomes was inhibited in a mouse neuroblastoma cell line (NA). In these cells, GD-SH-01 led to apoptosis and mitochondrial dysfunction while triggering autophagy, and apoptosis could be decreased by enhancing autophagy. To further identify the virus constituent causing autophagy, 5 chimeric recombinant viruses carrying single genes of HEP-Flury instead of those of GD-SH-01 were rescued. While the HEP-Flury virus carrying the wild-type matrix protein (M) gene of RABV triggered LC3-I to LC3-II conversion in SK and NA cells, replacement of genes of nucleoprotein (N), phosphoprotein (P) and glycoprotein (G) produced only minor autophagy. But no one single structural protein of GD-SH-01 induced autophagy. Moreover, the AMPK signaling pathway was activated by GD-SH-01 in SK. Therefore, our data provide strong evidence that autophagy is induced by GD-SH-01 and can decrease apoptosis in vitro. Furthermore, the M gene of GD-SH-01 may cooperatively induce autophagy. PMID- 27463028 TI - In Silico and In Vitro Evaluation of Cytotoxic Activities of Farnesiferol C and Microlobin on MCF-7, HeLa and KYSE Cell Lines. AB - Background: Cancer is one of the leading causes of death worldwide. Despite certain advances in cancer therapy, still there is considerable demand for developing efficient therapeutic agents. Nowadays, there is a rising interest in the use of natural-based anti-cancer drugs. In this study, the cytotoxicity of farnesiferol C and microlobin isolated from Ferula szowitsiana was investigated against MCF-7, HeLa and KYSE cancer cell lines. In addition, the mechanism of binding of these compounds to apoptotic proteins (Bax, Bak and Bcl-2) was analyzed by an in silico method. Materials and methods: We used MTT assay in order to assess the cytotoxicity of compounds against cancer cell lines. For in silico study, the AutoDock 4 was adopted. Results and discussion: According to the in vitro findings, in general, farnesiferol C showed significant cytotoxicity at higher concentrations (>50 uM) following 48 and 72 h incubation with the selected cancer cells; however, microlobin exhibited almost no activity at concentrations up to 100 uM. The in silico results revealed that both compounds could bind to Bax more efficiently rather than to Bcl-2 or Bak proteins. Conclusion: The results obtained by our preliminary in vitro and in silico studies suggest that these compounds might induce apoptosis through Bax activation; however further studies, either in vitro or in vivo are needed to clarify these activities. PMID- 27463029 TI - Expeditious Synthesis, Antimicrobial and Antimalarial Activities of Novel Heterocycles Bearing Imidazole-oxadiazole Based Hybrid Pharmacophores. AB - A facile synthesis of 2-substituted-5-amino-oxadiazole derivatives has been achieved by refluxing/sonicating a mixture of semicarbazide with various aromatic acids in conc. sulphuric acid alone. The isolated products were further condensed with p-dimethylaminobenzaldehyde/p-hydroxybenzaldehyde to obtain respective imino derivatives. Finally, some potentially biologically active imidazole analogues were obtained by reacting ammonium acetate and 5-bromoisatin with the synthesized imino products. All the newly synthesized compounds were thoroughly characterized by standard analytical techniques. These imidazole-oxadiazole hybrid compounds were also evaluated for their antimicrobial and antimalarial activities. The compounds all exhibited moderate to significant antimicrobial activity (6-10 mm, zone of inhibition) and promising antimalarial activity (IC50 0.037-0.100 uM). This report entails a detailed synthetic procedure, spectroscopic elucidation and activities of the synthesized compounds. PMID- 27463030 TI - Pharmacokinetic/Pharmacodynamic Analysis of Metformin using Different Models in Diabetic Rats. AB - Backgroud and study aims: Metformin is believed to be the most widely used hypoglycemic agent in the world. We aimed to investigate the pharmacokinetic/pharmacodynamics properties of metformin in diabetic rats using different pharmacodynamics models, and compare models fitting quality. Methods: Streptozotocin diabetic rats received metformin via oral route and blood samples were collected at the schedule times. Plasma metformin concentration and blood glucose levels were measured. Pharmacokinetic/pharmacodynamic analysis was conducted using nonlinear mixed-effects modeling. Metformin pharmacokinetics was described using a 2-compartmental model with first-order absorption. Five pharmacodynamic models were employed to characterize the hypoglycemic effect of metformin: effect-compartment model (I), indirect response (IDR) model with stimulating the loss of blood glucose (II), IDR model with inhibiting the production of blood glucose (III), combined effect-compartment/IDR model with stimulating the removal of blood glucose (IV) and combined effect-compartment/IDR model with inhibiting the input of blood glucose (V). Akaike's information criterion (AIC) values and goodness-of-fit were applied to estimate the pharmacodynamic model. Results: The Model V provided a more appropriate and good fitting pharmacodynamic characterization of metformin than the others. All the parameter values were estimated with good precision and model evaluation by visual predictive check suggested that the proposed model is robust. Conclusion: The proposed pharmacokinetic/pharmacodynamic model may be useful in the description for the relationship between metformin concentration and its glucose lowering effects. For metformin, biophase distribution and inhibiting the production of glucose may be existed simultaneously. PMID- 27463031 TI - Anti-Respiratory Syncytial Virus Compounds from Two Endophytic Fungi Isolated from Nigerian Medicinal Plants. AB - Background: Respiratory syncytial virus (RSV) is known to cause severe respiratory infections particularly in infants younger than 2 years of age. The only approved drug, ribavirin, is expensive and is not likely to improve therapeutic outcome, thereby necessitating the search for safer and more potent alternatives from natural sources such as endophytic fungi. The present study aimed to investigate the anti-RSV activity of compounds from endophytic fungi. Methods: Two endophytic fungi Colletotrichum gloeosporioides and Pestalotiopsis thea were isolated from the fresh leaves of the host Nigerian plants Anthocleista djalonensis and Fagara zanthoxyloides, respectively. After fermentation in solid rice media, C. gloeosporioides afforded 4 known compounds 4-hydroxybenzoic acid (1), vanillic acid (2), ferulic acid (3) and Nb-acetyltryptamine (4) while P. thea afforded 3 known compounds chloroisosulochrin (5), ficipyrone A (6) and pestheic acid (7). The compounds were investigated for their anti-RSV activity using the HEP-2 cell lines and ribavirin as the standard drug. Results: Compound 5 was found to show the strongest inhibition of the RSV with IC50 of 4.22+/-1.03 uM (ribavirin 4.91+/-1.85 uM). Other compounds showed moderate inhibition of the virus (IC50 ranging from 45.00+/-0.98 to 259.23+/-2.36 uM). Conclusion: The results of the present study have shown that chloroisosulochrin (5), isolated from an endophytic fungus P. thea, possesses strong activity against RSV. PMID- 27463032 TI - Biowaiver Eligibility of a Lower Strength Ramipril/Hydrochlorothiazide Immediate Release Tablets Using a New Validated HPLC Analytical Method. AB - Bioequivalence studies are expensive, time consuming and invasive to humans. Accordingly, an alternative in vitro study (biowaivers) has been introduced for drugs which belong to BCS class I and III and for other strengths of already approved higher drug strength. The main objective of this study was to prove the biowaiver eligibility of a lower strength Ramipril/Hydrochlorothiazide (2.5/12.5 mg) tablets. Visual and pharmacopoeial quality tests were performed on the higher and lower generic and on the reference listed drug to determine whether they are pharmaceutically equivalent. All products were investigated using the biowaiver criteria. Dissolution profiles were conducted at pH values 1.2, 4.5 and 6.8. Difference factor (f1) and similarity factor (f2) were calculated. The tested products were successfully complied with pharmacopeial requirements. f1 was below 15 and f2 was above 50 in all dissolution conditions. Precisely, Ramipril showed release higher than 85% within 15 min. f1 and f2 for Hydrochlorothiazide were 8 and 61 respectively at the recommended discriminative pH media.These results suggest that the current biowaiver criteria could be a sufficient guarantee of bioequivalence of the lower strength of Ramizide assuming that the product is manufactured at the same site and contains same quality and grade of excipients and in a proportional amounts. PMID- 27463033 TI - Psychiatric medication preferences of sports psychiatrists. AB - OBJECTIVES: When prescribing psychiatric medications to athletes, it is important to consider issues that are especially important for this population, including side effects, safety concerns, and anti-doping policies. Only one report, from 2000, describes the prescribing preferences of psychiatrists who work with athletes. This manuscript aims to update the findings from that report, so as to help inform prescribing practices of primary care physicians, psychiatrists, and other clinicians who work with athletes. METHODS: Physician members of the International Society for Sports Psychiatry (ISSP) were sent an email invitation in 2016 to complete an anonymous web-based survey on psychiatric medication prescribing preferences in working with athletes with a variety of mental health conditions. RESULTS: Forty of 100 (40%) members of the ISSP who identified as physicians and who were emailed the survey ultimately completed it. Top choices of psychiatric medications for athletes across categories assessed included: bupropion for depression without anxiety and without bipolar spectrum disorder; escitalopram for generalized anxiety disorder; melatonin for insomnia; atomoxetine for attention-deficit/hyperactivity disorder; lamotrigine for bipolar spectrum disorders; and aripiprazole for psychotic disorders. CONCLUSION: Prescribers of psychiatric medications for athletes tended to favor medications that are relatively more energizing and less likely to cause sedation, weight gain, cardiac side effects, and tremor. Additionally, prescribing preferences for athletes diverged from many of the prescribing trends seen for patients within the general population, in keeping with the assumption that different factors are considered when prescribing for athletes versus for the general population. PMID- 27463034 TI - A Distinct Proof on Interplay between Trehalose and Guanidinium Chloride for the Stability of Stem Bromelain. AB - Guanidinium chloride (GdnHCl), a potential denaturant, is well-known to denature a number of proteins in vitro as well as in vivo studies. Its deleterious action on stem bromelain (BM) is quite prominent resulting decrease in protein structure and stability. The counteraction of this adverse effect of GdnHCl by the use of osmolytes is scarcely studied and the mechanism is still illusive and not exclusive. For the first time, to test elegant and simple counteraction hypothesis as a general mechanism we utilized fluorescence, circular dichroism, Fourier transform infrared spectroscopy, and dynamic light scattering to study the counteraction of GdnHCl-induced denaturation of BM by the trehalose. It is revealed from the investigation of the results that trehalose is efficiently counteracting GdnHCl undesirable impacts on BM stability at molar ratio 1:1 of trehalose and GdnHCl. On the contrary, proteolytic activity of BM is increased only for the counteraction study of BM at very high concentrations of GdnHCl although still less than BM in buffer. The mutual exclusion of both trehalose and GdnHCl may stand for the counteraction of denaturation of BM resulting in a compact conformation with less solvent exposed surface area and increased secondary and tertiary structures. In addition, a decrease in BM-solvent interactions may also be contributing to some extent as there is little binding of trehalose replacing some water molecules and reducing binding of GdnHCl. PMID- 27463035 TI - Genetic diversity among populations of Antarctic springtails (Collembola) within the Mackay Glacier ecotone. AB - Climate changes are likely to have major influences on the distribution and abundance of Antarctic terrestrial biota. To assess arthropod distribution and diversity within the Ross Sea region, we examined mitochondrial DNA (COI) sequences for three currently recognized species of springtail (Collembola) collected from sites in the vicinity, and to the north of, the Mackay Glacier (77 degrees S). This area acts as a transition between two biogeographic regions (northern and southern Victoria Land). We found populations of highly divergent individuals (5%-11.3% intraspecific sequence divergence) for each of the three putative springtail species, suggesting the possibility of cryptic diversity. Based on molecular clock estimates, these divergent lineages are likely to have been isolated for 3-5 million years. It was during this time that the Western Antarctic Ice Sheet (WAIS) was likely to have completely collapsed, potentially facilitating springtail dispersal via rafting on running waters and open seaways. The reformation of the WAIS would have isolated newly established populations, with subsequent dispersal restricted by glaciers and ice-covered areas. Given the currently limited distributions for these genetically divergent populations, any future changes in species' distributions can be easily tracked through the DNA barcoding of springtails from within the Mackay Glacier ecotone. PMID- 27463036 TI - Mesozeaxanthin Protects Retina from Oxidative Stress in a Rat Model. AB - PURPOSE: Mesozeaxanthin (MZ) is able to protect against chronic and cumulative eye damage and neutralize free radicals produced by oxidative stress. The objective of the present study was to evaluate the protective potential of MZ against retinal oxidative damage and growth and transcription factors of the retina in rats fed with high-fat diet (HFD). METHODS: Twenty-eight Sprague Dawley rats were randomly divided into the following 4 groups: (1) Control, (2) MZ (100 mg/kg bw/d), (3) HFD (42% of calories as fat), and (4) HFD+MZ (100 mg/kg bw/d) group rats were administered daily as supplement for 12 weeks. RESULTS: Consumption of HFD was associated with hyperglycemia and oxidative stress as reflected by increased serum MDA concentration (P < 0.001). No measurable zeaxanthin (Z)+MZ and lutein (L) could be detected in the serum of control and HFD rats, whereas they were observed in the serum of MZ-administered rats. Retinal antioxidant enzyme [superoxide dismutase (SOD) and catalase (CAT)] activities were significantly decreased in the HFD group compared to the normal group (P < 0.01). However, retinal antioxidant enzymes were restored close to normal levels in HFD+MZ-treated rats (P < 0.05). The retina of rats fed with HFD had increased levels of vascular endothelial growth factor (VEGF), inducible nitric oxide (iNOS), intercellular adhesion molecule-1 (ICAM-1), and nuclear factor-kappa B (NF-kappaB) levels and decreased nuclear factor erythroid 2 related factor 2 (Nrf2) and heme-oxygenase 1(HO-1) levels compared to the healthy rat retina (P < 0.001). Rats treated with MZ partially alleviated the inflammation as reflected by suppressed VEGF, iNOS, ICAM, and NF-kappaB levels and increased Nrf2 and HO-1 levels in the retina of rats fed (P < 0.05). CONCLUSIONS: Results from the present study suggest that MZ has protective effects on the retina and the ability to modulate oxidative stress of retina in rats fed an HFD by suppressing retinal lipid peroxidation and regulating growth and transcription factors. PMID- 27463038 TI - Long-Range Embedding of Molecular Ions and Excitations in a Polarizable Molecular Environment. AB - We present a method for evaluating electrostatic and polarization energies of a localized charge, charge transfer state, or exciton embedded in a neutral molecular environment. The approach extends the Ewald summation technique to polarization effects, rigorously accounts for the long-range nature of the charge quadrupole interactions, and addresses aperiodic embedding of the charged molecular cluster and its polarization cloud in a periodic environment. We illustrate the method by evaluating the density of states and ionization energies in thin films and heterostructures of organic semiconductors. By accounting for long-range mesoscale fields, we obtain the ionization energies in both crystalline and mesoscopically amorphous systems with high accuracy. PMID- 27463037 TI - Characterization of Receptor-Associated Protein Complex Assembly in Interleukin (IL)-2- and IL-15-Activated T-Cell Lines. AB - It remains a paradox that IL-2 and IL-15 can differentially modulate the immune response using the same signaling receptors. We have previously dissected the phosphotyrosine-driven signaling cascades triggered by both cytokines in Kit225 T cells, unveiling subtle differences that may contribute to their functional dichotomy. In this study, we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated T-lymphocytes that is highly orchestrated by site specific phosphorylation events. Comparing the cytokine-induced interactome of the interleukin receptor beta and gamma subunits shared by the two cytokines, we defined the components of the early IL-2 and IL-15 receptor-associated complex discovering novel constituents. Additionally, phosphopeptide-directed analysis allowed us to detect several cytokine-dependent and -independent phosphorylation events within the activated receptor complex including novel phosphorylated sites located in the cytoplasmic region of IL-2 receptor beta subunit (IL-2Rbeta). We proved that the distinct phosphorylations induced by the cytokines serve for recruiting different types of effectors to the initial receptor/ligand complex. Overall, our study sheds new light into the initial molecular events triggered by IL-2 and IL-15 and constitutes a further step toward a better understanding of the early signaling aspects of the two closely related cytokines in T lymphocytes. PMID- 27463040 TI - EVIDENCE-BASED REVIEWS FROM OTHER SOURCES. PMID- 27463039 TI - Control over Particle Size Distribution by Autoclaving Poloxamer-Stabilized Trimyristin Nanodispersions. AB - Lipid nanoparticles are under investigation as delivery systems for poorly water soluble drugs. The particle size in these dispersions strongly influences important pharmaceutical properties like biodistribution and drug loading capacity; it should be below 500 nm for direct injection into the bloodstream. Consequently, small particles with a narrow particle size distribution are desired. Hitherto, there are, however, only limited possibilities for the preparation of monodisperse, pharmaceutically relevant dispersions. In this work, the effect of autoclaving at 121 degrees C on the particle size distribution of lipid nanoemulsions and -suspensions consisting of the pharmaceutically relevant components trimyristin and poloxamer 188 was studied. Additionally, the amount of emulsifier needed to stabilize both untreated and autoclaved particles was assessed. In our study, four dispersions of mean particle sizes from 45 to 150 nm were prepared by high-pressure melt homogenization. The particle size distribution before and after autoclaving was characterized using static and dynamic light scattering, differential scanning calorimetry, and transmission electron microscopy. Asymmetrical flow field-flow fractionation was used for particle size distribution analyses and for the determination of free poloxamer 188. Upon autoclaving, the mean particle size increased to up to 200 nm, but not proportionally to the initial size. At the same time, the particle size distribution width decreased remarkably. Heat treatment thus seems to be a promising approach to achieve the desired narrow particle size distribution of such dispersions. Related to the lipid content, suspension particles needed more emulsifier for stabilization than emulsion droplets, and smaller particles more than larger ones. PMID- 27463041 TI - Malignant Hematologic Disorders Arising from Mediastinal Germ Cell Tumors. A Review of Clinical and Biologic Features. AB - Since 1985, the biological association of mediastinal germ cell tumors and certain hematologic malignancies has been recognized. Continued investigation of such patients and new cytogenetic information brings additional insights into the clinical aspects of this syndrome as well as hinting at the possible etiology. This syndrome only occurs in patients with non-seminomatous germ cell tumors arising within the mediastinum. The interval from the diagnosis of the germ cell tumor to the development of the hematologic malignancy is brief (usually less than 6 months). Careful characterization of the hematologic malignancies in this patient population suggests a predominance of abnormalities within the megakaryocytic lineage. Recent cytogenetic analysis in one patient identified the most common abnormality of germ cell cancers, isochromosome 12p, in the mediastinal germ cell tumor as well as in the subsequent leukemic blasts. i12p is not a cytogenetic abnormality associated with the development of leukemia. The clinical evidence as well as this new cytogenetic information suggest strongly that the two abnormalities are clonally related and that the hematologic malignancy may arise as a consequence of defferentiation of the multipotent malignant germ cell. PMID- 27463042 TI - Outcome of Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma Referred for Autologous Bone Marrow Transplantation. AB - Fifty-one patients with relapsed or refractory intermediate- or high-grade non Hodgkin's lymphoma were referred for autologous bone marrow transplantation (ABMT). The primary criterion for eligibility was sensitivity to conventional dose salvage chemotherapy. Of 47 patients who received salvage chemotherapy, 30 demonstrated chemotherapy-sensitive disease. Six eligible patients did not undergo ABMT for various reasons. A total of 24 patients underwent ABMT, with etoposide, melphalan +/- total body irradiation as the intensive therapy regimen. There was one early treatment-related death and three non-responders. Of the remaining patients, 9 relapsed, while 11 remain in continuous complete remission (CR) at a median follow-up of 21 months after transplant (range 5-37 months). Two patients with chemosensitive disease and bone marrow involvement underwent allogeneic BMT with marrow from HLA-identical siblings. Both are in continuous CR at 6 and 12 months follow-up. Of the 25 patients who did not undergo ABMT, all have died (median survival 5 months). The results indicate that approximately one half of relapsed or refractory aggressive histology lymphoma patients referred for ABMT eventually undergo transplantation, if chemotherapy-sensitive relapse is the major criterion for eligibility. Approximately 25% of the referred patients may become long-term disease-free survivors with this approach. Reports of marrow transplant series should include all patients referred for ABMT as the denominator for calculating disease-free survival in order to reduce the bias of patient selection. PMID- 27463043 TI - Treatment of Acute Promyelocytic Leukemia: A Report of 70 Cases. AB - Over a period of 14 years, we treated 70 cases of acute promyelocytic leukemia (APL) with 3 different chemotherapy protocols. In protocol 1, patients received high dose daunorubicin (DNR) alone for induction, followed by regular reinduction courses and continuous maintenance therapy with 6 mercaptopurine (6 MP) and methotrexate (MTX) during 3 years. In protocol 2, induction with high dose DNR and Ara C was also followed by regular reinduction courses, but without continuous maintenance therapy. Protocol 3 randomized high dose Amsacrine (AMSA) or Rubidazone in association with Ara C, for induction and consolidation, this was followed by reinduction courses and continuous maintenance therapy with 6 MP and MTX. During the induction all patients received, prophylactic heparinization and platelet transfusions. Fifty six patients (80%) achieved complete remission (CR), 13 patients (18.5%) had early death (ED) or hypoplastic death (HD), and 1 patient had true resistant leukemia. Only two patients died of hemorrhage. Median actuarial disease free survival (DFS) was 16.5 months and a plateau at 29.1% was reached after 29 months. Patients with fever at diagnosis had a significantly lower CR rate while age below 20 years and circulating blasts above 0.5 * 10(9)/1 were associated with shorter DFS. The CR rate did not significantly differ between protocols 1, 2 and 3 (87.5%, 80% and 60% respectively) but 9 of the 30 patients on protocols 2 or 3 had ED or HD, compared to 4 of the 40 treated with protocol 1 (p < 0.05). DFS was significantly shorter in protocol 2, which included no continuous maintenance chemotherapy, than in protocols 1 and 3. Median actuarial survival was significantly shorter in patients treated with protocols 2 or 3, compared to protocol 1. These results suggest that high dose DNR alone, associated with adequate prophylaxis of disseminated intravascular coagulation, gives very high CR rates in APL, with short periods of aplasia and limited toxicity. Combinations of an anthracycline or AMSA at the doses used with regular dose Ara C may be too toxic. Although this was not a randomized trial, our findings also suggest a possible benefit of prolonged continuous maintenance therapy with 6 MP and MTX in APL. PMID- 27463044 TI - Prognostic Factors in Acute Promyelocytic Leukemia: A Retrospective Study of 67 Cases. AB - In a cohort of 67 adult patients with newly diagnosed untreated acute promyelocytic leukemia (APL), the initial clinical and biological parameters were submitted to multivariate analysis for potential prognostic significance. Median age of the patients was 40 years and the hematologic characteristics of the patients were those regularly seen. Complete remission (CR) was achieved in 43 cases (64%). Fourteen patients died within 4 weeks of diagnosis, due to severe hemorrhage. Factors predictive of hemorrhagic death in the multivariate analysis were hyperuricemia (p = 0.001), splenomegaly (p = 0.009), anemia (p = 0.02), high serum levels of LDH (p = 0.02), increased prothrombin time (p = 0.04), and hypercreatininemia (p = 0.05). Pretreatment patient characteristics for poor prognosis and achieving CR were hyperuricemia (p = 0.0002), splenomegaly (p = 0.01), anemia (p = 0.02), and lymphadenopathy (p = 0.04). The median disease-free survival (DFS) was 15.6 months. Poor prognostic factors for DFS were hyperuricemia (p = 0.007), and splenomegaly (p = 0.03). Maintenance chemotherapy had no statistically significant impact on CR duration. Median survival duration was 10 months. Poor prognostic factors for survival were hyperuricemia (p = 0.0005), and elevated serum LDH levels (p = 0.01). PMID- 27463045 TI - Invasive Aspergillosis in Neutropenic Patients with Hematological Disorders. AB - Between 1983-1988, 72 patients with acute leukemia and 4 with aplastic anemia were treated in the Hematology Unit of The Chaim Sheba Medical Center. Ten patients with acute leukemia developed invasive pulmonary aspergillosis and 2 with aplastic anemia developed invasive aspergillosis of the nose and paranasal sinuses. These infections were diagnosed during a period of profound neutropenia while these patients were receiving broad spectrum antibiotics. The diagnosis of pulmonary aspergillosis was based on positive sputum cultures in 4 cases and on the appearance of typical clinical and radiologic features in six. In 2 culture positive and in one culture-negative patient, the diagnosis was confirmed at autopsy. Thus, the diagnosis was definitive in 5 patients and probable in the remaining five patients. The 5 patients who achieved remission responded to antifungal treatment and recovered, while of the 5 who eventually died from the fungal infection, 4 did not achieve remission, and one died while in complete remission. In the 2 patients with aplastic anemia, aspergillosis was detected in cultures from necrotic nasal tissue. Both patients remained neutropenic, failed to respond to antifungal treatment and died within a short time after diagnosis. From this experience it appears that invasive aspergillosis in neutropenic patients is potentially curable if treated early by amphotericin B, provided that the neutrophil count recovers. PMID- 27463046 TI - Serial Detection of Residual bcr/abl mRNA by Polymerase Chain Reaction in Patients with Chronic Myelogenous Leukemia after Bone Marrow Transplantation. AB - A modification of the polymerase chain reaction (PCR) has been successfully used to detect minimal residual leukemic cells in chronic myelogenous leukemia (CML) patients after bone marrow transplantation (BMT), by amplification of the transcript of the specific bcr/abl mRNA. The capability of detecting CML cells was 10(-6) by our procedure. We studied peripheral blood and bone marrow samples from 8 CML patients observed up to 62 months after BMT. In two patients who were studied for the first time at 62 and 59 months after BMT, bcr/ab mRNA could not be detected in all samples. In 4 patients, who were studied within 1.5 years, bcr/abl mRNA was detected in all serial samples. In the other two patients, bcr/abl mRNA was detected in their peripheral blood samples, but not in their bone marrow samples which were obtained simultaneously. The reason why bcr/abl mRNA was not detected in bone marrow samples remains unknown. There were no differences in the pattern of mRNA chimerism, that is, b2aII (2 patients) or b3aII (4 patients), both before and after BMT. Cytogenetic relapse was documented at 5 months after BMT in one patient but all the other patients have remained in remission. Our results suggest that CML cells persist throughout the conditioning regimen for a considerable period of time and eradication of CML cells may occur several years after BMT. PMID- 27463047 TI - On the Cellular Pharmacokinetics of 6-Thioguanine in Acute Myelogenous Leukemia. AB - The pharmacokinetics of 6-thioguanine were studied in 10 patients with acute myelogenous leukemia treated with 25-100 mg/m(2) orally. The concentration of 6 thioguanine in plasma was determined with reversed phase high performance liquid chromatography (HPLC). After isolation of leukemic cells and erythrocytes by density centrifugation, HClO4 extraction of nucleotides and isolation of thiol containing substances on mercurial cellulose, the intracellular concentration of phosphorylated 6-thioguanine metabolites was measured by anion exchange HPLC. The plasma peak concentration of 6-thioguanine was significantly correlated (r(2) = 0.60) to the dose administered. In the leukemic cells, the 5'-mono-(TGMP) and 5' triphosphates (TGTP) of 6-thioguanosine could be detected in nine of the patients. In one patient only TGMP was seen. The diphosphate could be detected in low concentrations in 6 patients. In all patients, the concentration of TGMP was higher than that of TGTP which was higher than the diphosphate. The interindividual variation in cellular TGMP and TGTP concentration was > 100-fold and independent of dose, while the variation in plasma 6-TG was < 15-fold. There was no correlation between dose or plasma area under the concentration versus time curve (AUC) of 6-TG and the cellular AUC of TGMP or TGTP. However, the AUC of TGMP and TGTP correlated significantly (r(2) = 0.64). The t1/2 of the intracellular metabolites and of 6-thioguanine in plasma were in the same order (4.4, 5.2 and 5.0 h for plasma 6-thioguanine, the intracellular mono- and triphosphate respectively). Phosphorylated metabolites of 6-thioguanine were detectable in erythrocytes from 8 patients. The kinetic pattern of the metabolites in erythrocytes was different from that in leukemic cells. While shortly after administration being eliminated according to first order kinetics in the leukemic cells, the concentration of intracellular metabolites in the erythrocytes was raising during the first 24 h after the treatment. The concentration of the metabolites were, however, much (100-fold) lower in erythrocytes compared to leukemic cells. Furthermore, the triphosphate was the predominant metabolite in the erythrocytes and considerable amounts of the diphosphate was seen while the concentration in the monophosphate was low. We conclude that there is a considerable interindividual variation in the cellular pharmacokinetics of TGMP and TGTP. The concentration of the phosphorylated metabolites in the leukemic cells cannot be predicted by determination of plasma 6-thioguanine concentration, nor by the concentration of the same metabolites in the erythrocytes. PMID- 27463048 TI - Expression of a New Cellular Protein by Monocytoid B-Lymphocytes Differentiated from the Acute Lymphoblastic Leukemia Cell Line (REH). AB - In an attempt to identify differentiation-related changes in cellular proteins, the common acute lymphoblastic leukemia (ALL) cell line, REH, was studied. REH cells were cultured in either the absence or presence of 12-0 tetradecanoylphorbol-13-acetate (TPA). Changes in surface phenotype were analyzed using monoclonal antibodies and flow cytometry. Cellular proteins were analyzed with two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) of [(3)H]leucine and [(32)P]orthophosphate labeled cells. Immunophenotype and 2D PAGE studies were replicated three times on untreated (control) and TPA-treated cells on day 5. Immunophenotypic analysis showed that TPA induced further differentiation of REH cells along the B-cell lineage as indicated by significant decrease in the expression of CD10, induction of CD11c and increase in the expression of CD22. 2D-PAGE of [(3)H]leucine but not the [(32)P]orthophosphate showed that TPA induced the expression of a unique protein. The apparent relative molecular mass (Mr) of the resolved protein was ~23 kd with a ~6.2 isoelectric point (PI). Based on the morphologic and phenotypic findings, our data suggest that the new protein (p23-6.2) and the quantitative changes in protein synthesis induced by TPA are differentiation-related. Our study also indicates that 2D-PAGE analysis is a sensitive and complementary tool to phenotypic markers in the study of differentiation of malignant B-cells. PMID- 27463049 TI - Treatment of Cutaneous T-cell Lymphoma with Cyclosporin A: Case Report and Literature Review. AB - A 48 year old Caucasian man with cutaneous T-cell lymphoma, stage IVB is described. Initially he presented with an ichthyosis-like dermatosis and developed lymphadenopathy, hypercalcaemia, hepatosplenomegaly and lymphomatoid papulosis over a period of 7 years. Following splenectomy he developed a leukemic phase which was refractory to polychemotherapy. Therapy with cyclosporin A initially caused deterioration of the skin infiltrations and the peripheral blood T-helper lymphocytosis. However after 3 weeks an improvement of the patient's general condition was noted including decreased skin involvement, reduction of hepatomegaly and a sustained decrease of the absolute lymphocytosis, which lasted for ten months. Lymphomatoid papulosis was not significantly affected by cyclosporin A. In conclusion, this case and several case reports from the literature suggest that cyclosporin A may be valuable in the palliative treatment of selected patients with advanced cutaneous T-cell lymphoma. PMID- 27463050 TI - Expansion Characteristics of Stents Used in Congenital Heart Disease: Serial Dilation Offers Improved Expansion Potential Compared to Direct Dilation: Results from a Pediatric Interventional Cardiology Early Career Society (PICES) Investigation. AB - OBJECTIVE: Intravascular stents are now routinely used to treat young patients with vascular stenoses. Future stent redilations are often necessary to account for somatic growth. The purpose of this study was to compile a database of characteristics for stents commonly used in the treatment of congenital heart disease patients, and compare serial dilation to direct dilation to the maximal diameter. DESIGN: A standardized bench testing protocol was established and utilized in the assessment of all stents. Ultra high pressure balloons were used to serially dilate each stent by set increments until the stent reached at least 24 mm in diameter, developed a napkin-ring configuration, or fractured. Length and diameter of each stent were measured at baseline and following each stage of dilation. Maximal stent diameters, foreshortening properties, and ability to fracture were reported. Stents were then tested for direct dilation from the primary diameter to the maximal diameter, and the same data was obtained. RESULTS: A total of 127 stents were bench-tested, 80 of which were serially dilated and 47 directly dilated. Most premounted stents could be serially dilated to approximately twice their stated nominal diameter. All tested unmounted stents could be serially dilated to >=20 mm. Foreshortening occurred at larger diameters, but varied significantly among different stent types. Serial dilation offered more consistent results with significantly less foreshortening and more symmetric expansion when compared with direct dilation. Most premounted stents could be fractured when serially dilated. CONCLUSIONS: All tested vascular stents can be dilated beyond their nominal implantation diameter. Serial dilation offers a much more reliable response with uniform expansion, less foreshortening, greater maximal diameter, and improved intentional fracture potential, as compared to direct dilation from the nominal to maximal diameter. In vivo studies are necessary to corroborate these findings in the congenital heart disease population. PMID- 27463051 TI - Prevalence of occult hepatitis C virus infection in the Iranian patients with human immunodeficiency virus infection. AB - Occult hepatitis C virus (HCV) infection is a new form of chronic HCV infection described by the presence of the genomic HCV-RNA in liver biopsy and/or peripheral blood mononuclear cell (PBMC) samples, and undetectable levels or absence of HCV-RNA and in the absence or presence of anti HCV antibodies in the plasma specimens. The aim of the present study was to evaluate the occurrence of occult HCV infection (OCI) among Iranian subjects infected with human immunodeficiency virus (HIV) using RT-nested PCR. From March 2014 until April 2015, 109 Iranian patients with established HIV infection were enrolled in this cross-sectional study. After extraction of viral RNA from the plasma and PBMC samples, HCV-RNA status was examined by RT-nested PCR using primers from the 5' NTR. HCV genotyping was conducted using RFLP analysis. For the confirmation of HCV genotyping by RFLP method, the PCR products were sequenced. Of the 109 patients, 50 were positive for antibodies against HCV. The HCV-RNA was detected in PBMC specimens in 6 (10.2%) out of the total 59 patients negative for anti-HCV Abs and undetectable plasma HCV-RNA and also from 4 (8.0%) out of the total 50 patients positive for anti-HCV Abs and undetectable plasma HCV-RNA. HCV genotyping analysis showed that 6 (60.0%) patients were infected with HCV subtype 3a, 3 (30.0%) were infected with HCV subtype 1a and 1 (10.0%) patient was infected with HCV subtype 1b. This study revealed the incidence of OCI (9.2%) in HIV-infected Iranian patients. Hence, designing prospective studies focusing on the detection of OCI in these patients would provide more information. J. Med. Virol. 88:1960-1966, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27463052 TI - Anti-myelin-associated glycoprotein-negative distal acquired demyelinating symmetric neuropathy in association with a neuroendocrine tumor. PMID- 27463053 TI - Graph Kernels for Molecular Similarity. AB - Molecular similarity measures are important for many cheminformatics applications like ligand-based virtual screening and quantitative structure-property relationships. Graph kernels are formal similarity measures defined directly on graphs, such as the (annotated) molecular structure graph. Graph kernels are positive semi-definite functions, i.e., they correspond to inner products. This property makes them suitable for use with kernel-based machine learning algorithms such as support vector machines and Gaussian processes. We review the major types of kernels between graphs (based on random walks, subgraphs, and optimal assignments, respectively), and discuss their advantages, limitations, and successful applications in cheminformatics. PMID- 27463054 TI - Impact of the Recent Mouse P-Glycoprotein Structure for Structure-Based Ligand Design. AB - P-Glycoprotein (P-gp), a transmembrane, ATP-dependent drug efflux transporter, has attracted considerable interest both with respect to its role in tumour cell multidrug resistance and in absorption-distribution and elimination of drugs. Although known since more than 30 years, the understanding of the molecular basis of drug/transporter interaction is still limited, which is mainly due to the lack of structural information available. However, within the past decade X-ray structures of several bacterial homologues as well as very recently also of mouse P-gp have become available. Within this review we give an overview on the current status of structural information available and on its impact for structure-based drug design. PMID- 27463055 TI - Target Profile Prediction: Cross-Activation of Peroxisome Proliferator-Activated Receptor (PPAR) and Farnesoid X Receptor (FXR). PMID- 27463056 TI - Increasing the Throughput of Shape-Based Virtual Screening with GPU Processing and Single Conformation Databases. PMID- 27463057 TI - Novel Approach for Clustering Zeolite Crystal Structures. AB - Informatics approaches play an increasingly important role in the design of new materials. In this work we apply unsupervised statistical learning for identifying four framework-type attractors of zeolite crystals in which several of the zeolite framework types are grouped together. Zeolites belonging to these super-classes manifest important topological, chemical and physical similarities. The zeolites form clusters located around four core framework types: LTA, FAU, MFI and the combination of EDI, HEU, LTL and LAU. Clustering is performed in a 9 dimensional space of attributes that reflect topological, chemical and physical properties for each individual zeolite crystalline structure. The implemented machine learning approach relies on hierarchical top-down clustering approach and the expectation maximization method. The model is trained and tested on ten partially independent data sets from the FIZ/NIST Inorganic Crystal Structure Database. PMID- 27463058 TI - Prioritizing Hits with Appropriate Trade-Offs Between HIV-1 Reverse Transcriptase Inhibitory Efficacy and MT4 Blood Cells Toxicity Through Desirability-Based Multiobjective Optimization and Ranking. AB - Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) constitute a promising therapeutic option for AIDS. However, the emergence of virus-NNRTIs resistance was found to be a major problem in the field. Toward that goal, a "knock-out" strategy stands out between the several options to circumvent the problem. However the high drug or drug-drug concentrations often used generate additional safety concerns. The need for approaches able to early integrate drug- or lead-likeness, toxicity and bioavailability criteria in the drug discovery phase is an emergent issue. Given that, we propose a combined strategy based on desirability-based multiobjective optimization (MOOP) and ranking for the prioritization of HIV-1 NNRTIs hits with appropriate trade-offs between inhibitory efficacy over the HIV-1 RT and toxic effects over MT4 blood cells. Through the MOOP process, the theoretical levels of the predictive variables required to reach a desirable RT inhibitor candidate with the best possible compromise between efficacy and safety were found. This information is used as a pattern to rank the library of compounds according to a similarity-based structural criterion, providing a ranking quality of 64 %/71 %/73 % in training/validation/test set. A comparative study between the sequential, parallel and multiobjective virtual screening revealed that the multiobjective approach can outperform the other approaches. These results suggest that the identification of NNRTIs hits with appropriate trade-offs between potency and safety, rather than fully optimized hits solely based on potency, can facilitate the hit to lead transition and increase the likelihood of the candidate to evolve into a successful antiretroviral drug. PMID- 27463059 TI - Finding Inspiration in the Protein Data Bank to Chemically Antagonize Readers of the Histone Code. AB - Members of the Royal family of proteins are readers of the histone code that contain aromatic cages capable of recognizing specific sequences and lysine methylation states on histone tails. These binding modules play a key role in epigenetic signalling, and are part of a larger group of epigenetic targets that are becoming increasingly attractive for drug discovery. In the current study, pharmacophore representations of the aromatic cages forming the methyl-lysine (Me Lys) recognition site were used to search the Protein Data Bank (PDB) for ligand binding pockets possessing similar chemical and geometrical features in unrelated proteins. The small molecules bound to these sites were then extracted from the PDB, and clustered based on fragments binding to the aromatic cages. The compounds collected are numerous and structurally diverse, but point to a limited set of preferred chemotypes; these include quaternary ammonium, sulfonium, and primary, secondary and tertiary amine moieties, as well as aromatic, aliphatic or orthogonal rings, and bicyclic systems. The chemical tool-kit identified can be used to design antagonists of the Royal family and related proteins. PMID- 27463060 TI - 3D-QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding-Pocket of Four Histamine H1 -Receptor Species. AB - Several phenylhistamines and histaprodifens were identified to act as (partial) agonists at the histamine H1 -receptor (H1 R). The large diversity of these compounds led to pKi values in a range between 4.5-7.5 at human, rat, bovine and guinea-pig histamine H1 R. Hybrid molecules, consisting of two different H1 R agonist partial structures, like suprahistaprodifens or phenoprodifens for example, or compounds with a dimeric histamine moiety are able to bind in two different orientations into the binding-pocket of the H1 R. In order to predict the percentage of ligand bound in orientation 1 or in orientation 2, 3D-QSAR studies at four H1 R species were performed. The training set contains ligands which can only bind in one orientation and the test set all ligands with two possible orientations. In general, the predicted pKi values of the test compounds were in good correlation to the experimental ones. Additionally, the predicted pKi values for all ligands with two possible orientations were used to calculate the percentage of the hybrid ligands bound in orientation 1 and 2. Our models suggest that the preferred orientation of these hybrid molecules is dependent on ligand and H1 R species. PMID- 27463061 TI - Structure-Activity Relationship Studies of a Number of alpha1 -Adrenoceptor Antagonists and Antiarrhythmic Agents. AB - Arylpiperazines represent one of the most studied classes of alpha1 -adrenoceptor (alpha1 -AR) antagonists. Currently, alpha1 -AR antagonists are useful in the treatment of benign prostatic hyperplasia, lower urinary tract symptoms or cardiac arrhythmia. The activity of various derivatives of 1-[3-(4-arylpiperazin 1-yl)propyl]pyrrolidin-2-one as alpha1 -adrenergic receptor antagonists and antiarrhythmic (AA) agents was described using the qualitative inverse Structure Activity Relationship (SAR) model. The three-dimensional structures of the pyrrolidin-2-one derivatives in the basic form were obtained using AM1 semi empirical quantum chemical calculations. All the molecules were geometry optimized until the root-mean-square (RMS) gradient value was smaller than 10(-6) a.u. Single-point energy (SPE) calculations were performed at the DFT/B3LYP level of theory using the 6-31G** basis set. The main focus of this inverse SAR study is to find which features cause enhancing of antiarrhythmic properties between subtly different types of activity (alpha1 -adrenoreceptor antagonists and antiarrhythmic activities). Our SAR study involves the charge distribution in the plane of the pharmacophore model for alpha1 -AR. Suitable maps of the electrostatic potential were plotted based on the electronic and nuclear charge distribution obtained from the energy calculations. The results of this modelling study indicate that if the terminal arylpiperazine moiety is surrounded by regions of negative electrostatic potential, then the antiarrhythmic activity is blocked. PMID- 27463062 TI - Bilateral ectopic cervical thymus presenting as a neck mass: Ultrasound and magnetic resonance imaging. AB - Ectopic cervical thymus (ECT) is a rare cause of neck mass in the pediatric age group. It is extremely uncommon in infants. Overall more than 100 cases have been reported in the literature, though fewer than 10% involved infants. Furthermore, ECT is usually unilateral and more frequently seen in men than in women. Ultrasound (US) is the preferred initial imaging modality, especially in pediatric neck masses given its wide availability, low cost and lack of radiation exposure. US can show the location, extension, and echotexture of the ECT. Magnetic resonance imaging (MRI) can be performed to verify the diagnosis and confirm communication between the ECT and the mediastinal thymus. Diffusion restriction can aid diagnosis when seen in a neck mass similar to that in the mediastinal thymus. Herein is described a case of bilateral ECT in a 2-month-old boy with associated US and MRI findings. PMID- 27463064 TI - Microdialysis to Optimize Cord Perfusion and Drug Delivery in Spinal Cord Injury. AB - OBJECTIVE: There is lack of monitoring from the injury site to guide management of patients with acute traumatic spinal cord injury. Here, we describe a bedside microdialysis monitoring technique for optimizing spinal cord perfusion and drug delivery at the injury site. METHODS: Fourteen patients were recruited within 72 hours of severe spinal cord injury. We inserted intradurally at the injury site a pressure probe, to monitor continuously spinal cord perfusion pressure, and a microdialysis catheter, to monitor hourly glycerol, glutamate, glucose, lactate, and pyruvate. The pressure probe and microdialysis catheter were placed on the surface of the injured cord. RESULTS: Microdialysis monitoring did not cause serious complications. Spinal cord perfusion pressure 90 to 100mm Hg and tissue glucose >4.5mM minimized metabolic derangement at the injury site. Increasing spinal cord perfusion pressure by ~10mm Hg increased the entry of intravenously administered dexamethasone at the injury site 3-fold. INTERPRETATION: This study determined the optimum spinal cord perfusion pressure and optimum tissue glucose concentration at the injury site. We also identified spinal cord perfusion pressure as a key determinant of drug entry into the injured spinal cord. Our findings challenge current guidelines, which recommend maintaining mean arterial pressure at 85 to 90mm Hg for a week after spinal cord injury. We propose that future drug trials for spinal cord injury include pressure and microdialysis monitoring to optimize spinal cord perfusion and maximize drug delivery at the injury site. Ann Neurol 2016;80:522-531. PMID- 27463063 TI - Juvenile striatal white matter is resistant to ischemia-induced damage. AB - White matter injury following ischemic stroke is a major cause of functional disability. Injury to both myelinated axons and oligodendrocytes, the myelin producing cells in the central nervous system, occurs in experimental models of ischemic stroke. Age-related changes in white matter vulnerability to ischemia have been extensively studied and suggest that both the perinatal and the aged periods are times of increased white matter vulnerability. However, sensitivity of white matter following stroke in the juvenile brain has not been evaluated. Interestingly, the late pediatric period is an important developmental stage, as it is the time of maximal myelination. The current study demonstrates that neurons in late pediatric/juvenile striatum are vulnerable to ischemic damage, with neuronal injury being comparable in juvenile and adult mice following ischemia. By contrast, actively myelinating striatal oligodendrocytes in the juvenile brain are resistant to ischemia, whereas adult oligodendrocytes are quite sensitive. As a result, myelin sheaths are remarkably intact and axons survive well in the injured striatum of juvenile mice. In addition to relative resistance of juvenile white matter, other glial responses were very different in juvenile and adult mice following cerebral ischemia, including differences in astrogliosis, fibrosis, NG2-cell reactivity, and vascular integrity. Together, these responses lead to long-term preservation of brain parenchyma in juvenile mice, compared to severe tissue loss and scarring in adult mice. Overall, the current study suggests that equivalent ischemic insults may result in less functional deficit in children compared to adults and an environment more conducive to long-term recovery. GLIA 2016;64:1972-1986. PMID- 27463065 TI - TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. AB - BACKGROUND: Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML). METHODS: Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis. RESULTS: TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53-mutated (n = 53) versus wild type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs >=60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P <= .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy). CONCLUSIONS: The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484-3491. (c) 2016 American Cancer Society. PMID- 27463066 TI - Intracellular magnesium and the rhythms of life. PMID- 27463067 TI - Weight Control Intervention for Truck Drivers: The SHIFT Randomized Controlled Trial, United States. AB - OBJECTIVES: To evaluate the effectiveness of the Safety and Health Involvement For Truckers (SHIFT) intervention with a randomized controlled design. METHODS: The multicomponent intervention was a weight-loss competition supported with body weight and behavioral self-monitoring, computer-based training, and motivational interviewing. We evaluated intervention effectiveness with a cluster-randomized design involving 22 terminals from 5 companies in the United States in 2012 to 2014. Companies were required to provide interstate transportation services and operate at least 2 larger terminals. We randomly assigned terminals to intervention or usual practice control conditions. We assessed participating drivers (n = 452) at baseline and 6 months. RESULTS: In an intent-to-treat analysis, the postintervention difference between groups in mean body mass index change was 1.00 kilograms per meters squared (P < .001; intervention = -0.73; control = +0.27). Behavioral changes included statistically significant improvements in fruit and vegetable consumption and physical activity. CONCLUSIONS: Results establish the effectiveness of a multicomponent and remotely administered intervention for producing significant weight loss among commercial truck drivers. PMID- 27463068 TI - Predictors of cervical cancer screening for Chinese American women. AB - Research on Chinese American women's cervical cancer screening behaviours is limited and there are few studies that examine factors associated with obtaining regular Pap tests. The purpose of this study was to use the transtheoretical model (TTM) as a framework to examine correlates of Pap testing and stages of change. Chinese American women (N = 121) were recruited to complete a cross sectional, self-report survey. Survey items assessed stages of change, self efficacy, perceived benefits and barriers, and demographic variables including screening and family history for cervical cancer. Eighty-one per cent of women reported that they had ever had a Pap test. Most participants were in the maintenance stage (55%), with 10% in each action and pre-contemplation, 8% in contemplation, 1% in preparation and 16% in the relapse stage. Women in the action/maintenance stage were more likely to be older, married and have a higher education level. Women in the action/maintenance stage had significantly lower perceived barrier scores compared to women in both the contemplation/preparation and pre-contemplation/relapse stages. Findings partially support the use of TTM for cervical cancer screening among this population and indicate the importance of perceived barriers. Results may inform interventions to increase screening rates among Chinese American women. PMID- 27463070 TI - Can You Hear That Peak? Utilization of Auditory and Visual Feedback at Peak Limb Velocity. AB - PURPOSE: At rest, the central nervous system combines and integrates multisensory cues to yield an optimal percept. When engaging in action, the relative weighing of sensory modalities has been shown to be altered. Because the timing of peak velocity is the critical moment in some goal-directed movements (e.g., overarm throwing), the current study sought to test whether visual and auditory cues are optimally integrated at that specific kinematic marker when it is the critical part of the trajectory. METHODS: Participants performed an upper-limb movement in which they were required to reach their peak limb velocity when the right index finger intersected a virtual target (i.e., a flinging movement). Brief auditory, visual, or audiovisual feedback (i.e., 20 ms in duration) was provided to participants at peak limb velocity. Performance was assessed primarily through the resultant position of peak limb velocity and the variability of that position. RESULTS: Relative to when no feedback was provided, auditory feedback significantly reduced the resultant endpoint variability of the finger position at peak limb velocity. However, no such reductions were found for the visual or audiovisual feedback conditions. Further, providing both auditory and visual cues concurrently also failed to yield the theoretically predicted improvements in endpoint variability. CONCLUSIONS: Overall, the central nervous system can make significant use of an auditory cue but may not optimally integrate a visual and auditory cue at peak limb velocity, when peak velocity is the critical part of the trajectory. PMID- 27463071 TI - Short-term effects of respiratory muscle training combined with the abdominal drawing-in maneuver on the decreased pulmonary function of individuals with chronic spinal cord injury: A pilot randomized controlled trial. AB - OBJECTIVE: To investigate the effects of respiratory muscle training (RMT) combined with the abdominal drawing-in maneuver (ADIM) on the pulmonary function in patients with chronic spinal cord injury (SCI). METHODS: Thirty-seven subjects with SCI (level of injury: C4-T6, time since injury: 4-5 years) were randomly allocated to three groups; the integrated training group (ITG), the RMT group (RMTG), and the control group (CG). The ITG performed RMT using an incentive respiratory spirometer (IRS) and the ADIM using a stabilizer. The RMTG received only RMT using an IRS. Subjects in the CG received alternative and routine physical therapy or usual care. The interventions were conducted over an eight week period. Pulmonary function was evaluated using spirometry to measure the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). RESULTS: The differences between the pre- and post-test values for FVC (0.47 +/- 0.05 versus 0.15 +/- 0.06 versus -0.03 +/- 0.01) and FEV1 (0.74 +/- 0.07 versus 0.27 +/- 0.17 versus 0.02 +/- 0.67)were significant among the groups. Post-test, in the ITG, the FVC and FEV1 values showed significant differences from those in the RMTG and CG (F = 11.48 and 11.49, P = 0.002 and 0.001). Furthermore, following the 8-week intervention, the change ratio values of the FVC and FEV1 of the ITG were increased further by an average of 9.75% and 7.91%, respectively, compared with those of the RMTG. CONCLUSION: These findings suggest positive evidence that RMT with additional ADIM training can improve pulmonary function in SCI pulmonary rehabilitation. PMID- 27463072 TI - College Males' Enduring and Novel Health Beliefs about the HPV Vaccine. AB - College males represent an important and overlooked catch-up population in the pursuit of human papillomavirus (HPV) prevention. An in-depth understanding of college males' health beliefs about HPV and HPV prevention can guide the development of HPV health promotion messages targeted toward college males. We convened 9 focus groups among 84 college-aged males to discuss their perceptions of benefits and barriers toward HPV prevention 4 years after vaccine approval. Through participants' discourse, we identified health beliefs that continue to endure as barriers to HPV prevention (e.g., lack of knowledge/awareness, apathy, dismissiveness, stigma, practical barriers, and skepticism). Prevention and protection endure as perceived benefits to HPV prevention. We also identified novel college male health beliefs that have emerged since vaccine approval and hold great potential for the development of more effective health messaging. One novel barrier that emerged was the perception that it was "too late" for college males to benefit from the vaccine. Several novel benefits also emerged including a perception of wider social benefit beyond the self and partner, reduced worry and anticipated regret, and the belief that "there is no reason not to [vaccinate]." This study was guided by the health belief model (HBM) and implications are discussed. PMID- 27463073 TI - Akt: A Therapeutic Target in Hepatic Ischemia-Reperfusion Injury. AB - BACKGROUND: Liver transplantation is the second most common transplant procedure in the United States. A leading cause of post-transplantation organ dysfunction is I/R injury. During I/R injury, the serine/threonine kinase Akt is activated, stimulating downstream mediators to promote cellular survival. Due to the cellular effects of Akt, therapeutic manipulation of the Akt pathway can help reduce cellular damage during hepatic I/R that occurs during liver transplantation. OBJECTIVE: A full description of therapeutic options available that target Akt to reduce hepatic I/R injury has not been addressed within the literature. The purpose of this review is to illuminate advances in the manipulation of Akt that can be used to therapeutically target I/R injury in the liver. METHODS: An in depth literature review was performed using the Scopus and PubMed databases. A total of 75 published articles were utilized for this manuscript. Terminology searched includes a combination of "hepatic ischemia/reperfusion injury", "Akt/PKB", "preconditioning" and "postconditioning." RESULTS: Four principal methods that reduce I/R injury include hepatic pre- and postconditioning, pharmacological intervention and future miRNA/gene therapy. Discussed therapies used serum alanine aminotransferase levels, liver histology and phosphorylation of downstream mediators to confirm the Akt protective effect. CONCLUSION: The activation of Akt from the reviewed therapies has resulted in predictable reduction in hepatocyte damage using the previously mentioned measurements. In a clinical setting, these therapies could potentially be used in combination to achieve better outcomes in hepatic transplant patients. Evidence supporting reduced I/R injury through Akt activation warrants further studies in human clinical trials. PMID- 27463074 TI - Rising stars. PMID- 27463075 TI - The new contenders. PMID- 27463076 TI - All countries, great and small. PMID- 27463077 TI - Where the money goes. PMID- 27463078 TI - Catch them if you can. PMID- 27463079 TI - A guide to the Nature Index. PMID- 27463087 TI - Effects of aqueous crude extract of Echeveria gibbiflora on mouse sperm function. AB - The present study evaluates the possible antifertility effect of aqueous crude extract (OBACE) of Echeveria gibbiflora, a plant that belongs to the crassulaceae family, used in traditional Mexican medicine as a vaginal post coital rinse to prevent pregnancy and shown to have an immobilization/agglutination effect on sperm of different mammal species. We evaluated the effect of OBACE on functional parameters of mouse sperm, such as viability, capacitation, and acrosome reaction. In addition, due to the high concentrations of calcium bis-(hydrogen-1 malate) hexahydrate [Ca (C4H5O5)2*6H2O] present in this plant extract, we evaluated its effect on Ca(2+) influx in mouse sperm under capacitating conditions. Moreover, we determined the acute toxicity of OBACE and its in vivo effect in mouse sperm motility administering a single daily dose of 50 and 100 mg/kg during seven days, intraperitoneally. The sperm viability was not affected by the presence of different concentrations of OBACE, however, the capacitation and acrosome reaction suffered a significant decrease in a concentration dependent manner, coinciding with the reduction of Ca(2+) influx. Furthermore, OBACE displayed an LD50 of 3,784.42 mg/kg and can be classified as a low toxic substance. Also, in vivo OBACE showed an inhibition of total and progressive motility on mouse sperm alongside a significant decrease of motility kinematic parameters and IVF rates. The results confirm the antifertility effect of this plant used in Mexican folk medicine. Further study on OBACE as a possible contraceptive treatment is warranted because of its activity and low in vivo toxicity. ABBREVIATIONS: ALH: lateral amplitude; AP: acid phosphatase; BCF: beat frequency; BSA: bovine serum albumine; CTC: chlortetracycline; FDA: fluorescein diacetate; Fura-2 AM: fura-2-acetoxymethyl ester; HIV: human immunodeficiency virus; IVF: in vitro fertilization; OBACE: aqueous crude extract of Echeveria gibbiflora; PI: propidum iodide; SN: supernatant; VAP: average path velocity; VCL: track speed; VSL: straight line velocity. PMID- 27463088 TI - Preclinical evaluation of gold-DTDTPA nanoparticles as theranostic agents in prostate cancer radiotherapy. AB - AIM: Gold nanoparticles have attracted significant interest in cancer diagnosis and treatment. Herein, we evaluated the theranostic potential of dithiolated diethylenetriamine pentaacetic acid (DTDTPA) conjugated AuNPs (Au@DTDTPA) for CT contrast enhancement and radiosensitization in prostate cancer. MATERIALS & METHODS: In vitro assays determined Au@DTDTPA uptake, cytotoxicity, radiosensitizing potential and DNA damage profiles. Human PC3 xenograft tumor models were used to determine CT enhancement and radiation modulating effects in vivo. RESULTS: Cells exposed to nanoparticles and radiation observed significant additional reduction in survival compared with radiation only. Au@DTDTPA produced a CT enhancement of 10% and a significant extension in tumor growth delay from 16.9 days to 38.3 compared with radiation only. CONCLUSION: This study demonstrates the potential of Au@DTDTPA to enhance CT-image contrast and simultaneously increases the radiosensitivity of prostate tumors. PMID- 27463090 TI - Pyomyositis: Are We Missing the Diagnosis? AB - BACKGROUND: Pyomyositis (PY) is a primary infection of the skeletal muscles, leading to inflammation of the muscle fibers followed by pus formation and even necrosis in late stages. Because of overlap in presentation of intermuscular abscess (IM) and PY, the exact incidence and severity of PY is under-appreciated. PATIENTS AND METHODS: We conducted a prospective analytical study in a tertiary care center in North India from October 2011 to January 2013, recruiting patients with abscesses involving the chest wall, abdomen (parietal wall including back), and extremities. Subcutaneous, hepatic, intra-abdominal abscess, and secondary abscesses were excluded. Primary PY was defined as a primary infection of skeletal muscle without any foci from adjacent skin, soft tissue, or bone. Clinical, radiologic, pathologic, and operative findings suggested diagnosis; loss of striations and lymphocytic infiltration in the muscle fibers was confirmatory. The chief outcome variables were death and length of hospital stay. RESULTS: Thirty patients with a mean age of 29.5 y (IM: 29.7 +/- 16.7, PY: 25.28 +/- 17.6) were classified as IM (18/30, 60%) or PY (12/30, 40%). Most PY occurred in the lower limb (41.7% had multi-site involvement); most had a history of trauma or immunocompromised state. Fever, tachycardia, tachypnea, hypotension, pallor, and hyperesthesia were significantly higher (p < 0.05) in PY. Mean Sequential Organ Failure Assessment (SOFA) score was 0.33 for IM, 2.5 for PY. Staphylococcus aureus was predominant in both groups; however, all four patients with methicillin-resistant S. aureus (MRSA) were in the PY group. Both deaths also occurred in the PY group. The mean duration of hospital stay was 3.22 +/- 1.11 d for IM and 10.27 +/- 2.32 d for PY patients (p = 0.03). CONCLUSION: PY is a specific and potentially fatal infection, which is common in our country and must be differentiated from IM. A high index of suspicion and early institution of specific antibiotics followed by operation is therapeutic. PMID- 27463091 TI - General Overview, Conclusions, and Future Directions. AB - BACKGROUND: The traditional design of the randomized clinical trial (RCT) is challenged by the peculiarities of the genotype and phenotype of neurological disorders. SUMMARY: RCTs are intended to verify the net effect of an investigational treatment on the outcome of a disease. This implies the inclusion of strictly homogeneous sample of patients that represent only in part the full disease spectrum. For this reason, pragmatic trials on representative samples of the general population are welcome. In neurodegenerative disorders, RCTs are generally performed in symptomatic individuals, when the pathologic process is already in course. Although genetic, biological and structural markers are the ideal instruments to detect the disease at a preclinical stage, the development of biomarkers is still in its infancy and even identified markers require in most of cases validation. Given the limited duration of an RCT, prospective studies with prolonged follow-up in well-defined inception cohorts are needed to assess the effectiveness of the treatment in all affected individuals seen in everyday practice. RCT are conducted mainly in Caucasians excluding other ethnicities. The difference of brain biology between men and women are still underestimated in RCTs. Patients, treating physicians, pharmaceutical companies, and regulatory authorities have differing needs, which may have important implications in planning and conducting RCTs. New therapeutic approaches are represented by personalized and precision medicine. Although largely investigational, these approaches may challenge the traditional RCT design. KEY MESSAGES: All those interested in the development of new treatments and treatment strategies for neurological disorders should be involved when planning an RCT and ad-hoc designs should be developed to address the peculiarities of neurological disorders. Differences in age, sex and ethnicity should have a primary role in the design of an RCT. The traditional structure of the RCT should be also revised taking into account the new perspectives of personalized and precision medicine. PMID- 27463092 TI - Indian Summer Monsoon Rainfall: Implications of Contrasting Trends in the Spatial Variability of Means and Extremes. AB - India's agricultural output, economy, and societal well-being are strappingly dependent on the stability of summer monsoon rainfall, its variability and extremes. Spatial aggregate of intensity and frequency of extreme rainfall events over Central India are significantly increasing, while at local scale they are spatially non-uniform with increasing spatial variability. The reasons behind such increase in spatial variability of extremes are poorly understood and the trends in mean monsoon rainfall have been greatly overlooked. Here, by using multi-decadal gridded daily rainfall data over entire India, we show that the trend in spatial variability of mean monsoon rainfall is decreasing as exactly opposite to that of extremes. The spatial variability of extremes is attributed to the spatial variability of the convective rainfall component. Contrarily, the decrease in spatial variability of the mean rainfall over India poses a pertinent research question on the applicability of large scale inter-basin water transfer by river inter-linking to address the spatial variability of available water in India. We found a significant decrease in the monsoon rainfall over major water surplus river basins in India. Hydrological simulations using a Variable Infiltration Capacity (VIC) model also revealed that the water yield in surplus river basins is decreasing but it is increasing in deficit basins. These findings contradict the traditional notion of dry areas becoming drier and wet areas becoming wetter in response to climate change in India. This result also calls for a re-evaluation of planning for river inter-linking to supply water from surplus to deficit river basins. PMID- 27463093 TI - Preoperative Chemotherapy and Metronomic Scheduling of Chemotherapy in Locally Advanced Oral Cancers. AB - Locally advanced oral cavity cancers are treated with a multi-modality approach. Surgery is the most efficient local modality in comparison to chemoradiation in oral cancers. Preoperative chemotherapy has failed its expectations to improve disease-free survival or overall survival in resectable oral cancers. Its use as an organ preservation tool is being studied. Induction chemotherapy followed by assessment for surgery is an appropriate option for borderline resectable or technically unresectable oral cancer. Metronomic chemotherapy is being studied as a bridge to surgery and as adjuvant chemotherapy in locally advanced oral cancers. The role of induction chemotherapy in unresectable oral cancers is unproven. Metronomic chemotherapy has shown improved progression-free survival and overall survival in oral cancers in comparison to intravenous cisplatin. A phase 3 study for confirmation of this finding has begun. PMID- 27463094 TI - Measurement and mapping of the GSM-based electromagnetic pollution in the Black Sea region of Turkey. AB - Electromagnetic pollution caused by mobile communication devices, a new form of environmental pollution, has been one of the most concerning problems to date. Consequences of long-term exposure to the electromagnetic radiation caused by cell phone towers are still unknown and can potentially be a new health hazard. It is important to measure, analyze and map the electromagnetic radiation levels periodically because of the potential risks. The electromagnetic pollution maps can be used for the detection of diseases caused by the radiation. With the help of the radiation maps of different regions, comparative analysis can be provided and distribution of the diseases can be investigated. In this article, Global System for Mobile communication (GSM)-based electromagnetic pollution map of the Rize Providence, which has high cancer rates because of the Chernobyl nuclear explosion, is generated. First, locations of the GSM base stations are identified and according to the antenna types of the base stations, safety distances are determined. Subsequently, 155 measurements are taken during November 2014 from the nearest living quarters of the Rize city center in Turkey. The measurements are then assessed statistically. Thenceforth, for visual judgment of the determined statistics, collected measurements are presented on the map. It is observed that national limits are not exceeded, but it is also discovered that the safety distance is waived at some of the measurement points and above the average radiation levels are noted. Even if the national limits are not exceeded, the long-term effects of the exposition to the electromagnetic radiation can cause serious health problems. PMID- 27463095 TI - We Made Your Bed, Why Won't You Lie in It? Food Availability and Disease May Affect Reproductive Output of Reintroduced Frogs. AB - Mitigation to offset the impacts of land development is becoming increasingly common, with reintroductions and created habitat programs used as key actions. However, numerous reviews cite high rates of poor success from these programs, and a need for improved monitoring and scientific testing to evaluate outcomes and improve management actions. We conducted extensive monitoring of a released population of endangered green and golden bell frogs, Litoria aurea, within a created habitat, as well as complementary surveys of a surrounding wild population. We then compared differences between the created habitat and natural ponds where extant frogs either bred or didn't breed in order to determine factors that contributed to the breeding failure within the created habitat. We evaluated differences of L. aurea abundance, abundance of other fauna, vegetation, water quality, habitat structure, invasive fish, and disease between the three pond types (created habitat, breeding ponds, non-breeding ponds). We discovered that vegetation and invertebrate diversity were low within the created habitat, potentially reducing energy and nutritional resources required for breeding. Also, a greater proportion of frogs in the created habitat were carrying the chytrid fungal pathogen, Batrachochytrium dendrobatidis, compared to the wild populations. In addition to causing the potentially fatal disease, chytridiomycosis, this pathogen has been shown to reduce reproductive functioning in male L. aurea, and subsequently may have reduced reproductive activities in the created habitat. Conspecific attraction, pond hydrology, and aquatic vegetation may also have had some influence on breeding behaviours, whilst the presence of the invasive mosquitofish, Gambusia holbrooki, and heterospecific tadpoles were unlikely to have deterred L. aurea from breeding within the created habitat. Through the use of scientific testing and monitoring, this study is able to make recommendations for future amphibian breed and release programs, and suggests planting a diversity of plant species to attract invertebrates, creating some permanent ponds, connecting habitat with existing populations, trialling artificial mating calls, and following recommendations to reduce the prevalence of disease within the population. PMID- 27463096 TI - Composite Scores and Other Outcome Measures in Stroke Trials. AB - BACKGROUND: Randomized controlled trials represent the most useful tool to evaluate the effectiveness of a treatment in medical research. When designing a clinical trial, the choice of end points, assessment tools, and scores is crucial as they represent the prerequisites for the evaluation of outcomes and for the critical appraisal of findings. SUMMARY: In stroke research, outcomes are mainly represented by composite end points focusing on the occurrence of cardiovascular and cerebrovascular events in trials on primary and secondary prevention and by measures of recovery and residual disability in acute stroke trials. Assessment tools which are more frequently used to evaluate recovery after acute stroke care include the National Institutes of Health Stroke Scale, the Modified Rankin Scale, the Barthel Index, the Glasgow Outcome Scale, and the Stroke Impact Scale. However, there is a wide heterogeneity of outcome measures across different trials, which makes it difficult to compare results and to draw definitive conclusions on the usefulness of the investigated strategies and treatments. Moreover, in some cases, details about outcomes are poorly reported with a tendency to focus on outcomes that are statistically significant while information about nonsignificant outcomes is frequently missed. KEY MESSAGES: There is an urgent need to improve the quality of designing, conducting, analyzing, and reporting data from randomized clinical trials in order to obtain complete, clear, and rigorous information on the effectiveness of management strategies in stroke care. Key properties of tools measuring outcome should include validity, reliability, and convenient statistical characteristics. PMID- 27463098 TI - Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry. AB - Importance: Accurate estimation of the incidence and prevalence of each subtype of epidermolysis bullosa (EB) is essential before clinical trials can be designed and sufficient funding allocated by government agencies and third-party insurers for the care of these individuals. Objective: To determine the incidence and prevalence of inherited EB stratified by subtype in the United States during a 16 year period. Design, Setting, and Participants: Prospective cross-sectional and longitudinal study. Data were obtained from 3271 patients consecutively enrolled in the National Epidermolysis Bullosa Registry from January 1, 1986, through December 31, 2002, using a detailed instrument created with the assistance of the National Institutes of Health. Analyses were performed in January 1999 and April 2015. Participants were patients of all ages with EB. Main Outcomes and Measures: Extensive clinical and laboratory data were collected on patients who were subclassified and serially revalidated based on published diagnostic recommendations by an international panel of experts. Pertinent to this report, estimates were made of the incidence and prevalence during 2 time frames. Results: During the first 5 years of funding of the registry, the overall incidence and prevalence of inherited EB were 19.60 and 8.22 per 1 million live births, respectively. When reassessed over the entire 16 years of the study, the prevalence rose to 11.07, whereas the overall incidence remained unchanged at 19.57 cases. Changes were also observed within some disease subsets as increased numbers of patients were identified, recruited, followed up longitudinally, and resubclassified as needed over time. For example, in 2002, the prevalence of EBS overall and localized EBS had increased considerably by 30.4% and 25.5%, respectively, whereas the prevalence of generalized intermediate EBS declined by 76.7% as a result of later subclassification of some of those patients into other subtypes. In contrast, no significant change was noted in the overall prevalence of JEB or generalized severe JEB, although there was a 73.0% decline in the prevalence of generalized intermediate JEB. Conclusions and Relevance: Precise estimates of the incidence and prevalence of each major subtype of inherited EB in the United States are now available that should assist investigators in choosing which subtypes are amenable to properly designed, large-scale, clinical trials. PMID- 27463097 TI - Levels of Ycg1 Limit Condensin Function during the Cell Cycle. AB - During mitosis chromosomes are condensed to facilitate their segregation, through a process mediated by the condensin complex. Although several factors that promote maximal condensin activity during mitosis have been identified, the mechanisms that downregulate condensin activity during interphase are largely unknown. Here, we demonstrate that Ycg1, the Cap-G subunit of budding yeast condensin, is cell cycle-regulated with levels peaking in mitosis and decreasing as cells enter G1 phase. This cyclical expression pattern is established by a combination of cell cycle-regulated transcription and constitutive degradation. Interestingly, overexpression of YCG1 and mutations that stabilize Ycg1 each result in delayed cell-cycle entry and an overall proliferation defect. Overexpression of no other condensin subunit impacts the cell cycle, suggesting that Ycg1 is limiting for condensin complex formation. Consistent with this possibility, we find that levels of intact condensin complex are reduced in G1 phase compared to mitosis, and that increased Ycg1 expression leads to increases in both levels of condensin complex and binding to chromatin in G1. Together, these results demonstrate that Ycg1 levels limit condensin function in interphase cells, and suggest that the association of condensin with chromosomes must be reduced following mitosis to enable efficient progression through the cell cycle. PMID- 27463099 TI - The IRIDICA PCR/Electrospray Ionization-Mass Spectrometry Assay on Bronchoalveolar Lavage for Bacterial Etiology in Mechanically Ventilated Patients with Suspected Pneumonia. AB - We studied the diagnostic performance of the IRIDICA PCR/electrospray ionization mass spectrometry (PCR/ESI-MS) assay applied on bronchoalveolar lavage (BAL) samples, from 51 mechanically ventilated patients with suspected pneumonia, in a prospective study. In 32 patients with X-ray verified pneumonia, PCR/ESI-MS was positive in 66% and BAL culture was positive in 38% (p = 0.045), and either of the methods was positive in 69%. The following BAL result combinations were noted: PCR/ESI-MS+/culture+, 34%; PCR/ESI-MS+/culture-, 31%; PCR/ESI-MS /culture+, 3.1%; PCR/ESI-MS-/culture-, 31%; kappa 0.36 (95% confidence interval (CI), 0.10-0.63). In pneumonia patients without prior antibiotic treatment, optimal agreement was noted with 88% PCR/ESI-MS+/culture+ and 12% PCR/ESI-MS /culture- (kappa 1.0). However, in patients with prior antibiotic treatment, the test agreement was poor (kappa 0.16; 95% CI, -0.10-0.44), as 10 patients were PCR/ESI-MS+/culture-. In 8/10 patients the pathogens detected by PCR/ESI-MS could be detected by other conventional tests or PCR tests on BAL. Compared with BAL culture, PCR/ESI-MS showed specificities and negative predictive values of >=87% for all individual pathogens, an overall sensitivity of 77% and positive predictive value (PPV) of 42%. When other conventional tests and PCR tests were added to the reference standard, the overall PPV increased to 87%. The PCR/ESI-MS semi-quantitative level tended to be higher for PCR/ESI-MS positive cases with pneumonia compared with cases without pneumonia (p = 0.074). In conclusion, PCR/ESI-MS applied on BAL showed a promising performance and has potential to be clinically useful in mechanically ventilated patients with suspected pneumonia. The usefulness of the method for establishment of pneumonia etiology and selection of antibiotic therapy should be further studied. PMID- 27463100 TI - Correlation between the Limbus-Insertion Distance of the Lateral Rectus Muscle and Lateral Rectus Recession Surgery in Intermittent Exotropia. AB - The aim of this study was to investigate whether the limbus-insertion distance (LID) of the lateral rectus (LR) muscle can be a useful indicator for predicting the surgical effect of recession surgery in intermittent exotropia (IXT). Patients who underwent unilateral or bilateral LR recession for the basic type of IXT were included. The distance between the corneal limbus and the posterior edge of the insertion of LR muscle (limbus-insertion distance) was measured intraoperatively using surgical calipers (graded with 0.25 mm precision). We calculated the actual dose-response effect as the difference between the angle of preoperative deviation and the angle of postoperative deviation, and then divided the figure by the total amount of recession at postoperative months 1, 3, and 6. The correlation between the limbus-insertion distance (LID) of LR muscle and each dose-response effect was statistically analyzed. A total of 60 subjects were enrolled in this study. The mean LID of LR muscle was 5.8+/-0.7 mm. The dose response effect was 3.2+/-1.0 prism diopters (PD)/mm at postoperative month 1, 3.4+/-1.0 PD/mm at postoperative month 3, and 3.4+/-1.1 PD/mm at postoperative month 6. The LID of the LR muscle was significantly correlated with dose-response effects in cases of unilateral and bilateral LR recession at postoperative months 3 and 6 (P = 0.01, <0.01, 0.04 and <0.01 respectively). As the LID of the LR muscle increased by 1 mm, the dose-response effect increased by 0.2PD/mm in unilateral LR recession, and by 0.4 PD/mm in bilateral LR recession at postoperative month 6. In conclusion, the LID of the LR muscle can be used as one predictor of the recession effect to assist in surgical planning for IXT. Moreover, undercorrection at the time of LR recession might be considered in patients with long LID of the LR muscle. PMID- 27463101 TI - UV-Triggered Self-Healing of a Single Robust SiO2 Microcapsule Based on Cationic Polymerization for Potential Application in Aerospace Coatings. AB - UV-triggered self-healing of single microcapsules has been a good candidate to enhance the life of polymer-based aerospace coatings because of its rapid healing process and healing chemistry based on an accurate stoichiometric ratio. However, free radical photoinitiators used in single microcapsules commonly suffer from possible deactivation due to the presence of oxygen in the space environment. Moreover, entrapment of polymeric microcapsules into coatings often involves elevated temperature or a strong solvent, probably leading to swelling or degradation of polymer shell, and ultimately the loss of active healing species into the host matrix. We herein describe the first single robust SiO2 microcapsule self-healing system based on UV-triggered cationic polymerization for potential application in aerospace coatings. On the basis of the similarity of solubility parameters of the active healing species and the SiO2 precursor, the epoxy resin and cationic photoinitiator are successfully encapsulated into a single SiO2 microcapsule via a combined interfacial/in situ polymerization. The single SiO2 microcapsule shows solvent resistance and thermal stability, especially a strong resistance for thermal cycling in a simulated space environment. In addition, the up to 89% curing efficiency of the epoxy resin in 30 min, and the obvious filling of scratches in the epoxy matrix demonstrate the excellent UV-induced healing performance of SiO2 microcapsules, attributed to a high load of healing species within the capsule (up to 87 wt %) and healing chemistry based on an accurate stoichiometric ratio of the photoinitiator and epoxy resin at 9/100. More importantly, healing chemistry based on a UV-triggered cationic polymerization mechanism is not sensitive to oxygen, extremely facilitating future embedment of this single SiO2 microcapsule in spacecraft coatings to achieve self-healing in a space environment with abundant UV radiation and oxygen. PMID- 27463102 TI - Strategies for Improving Surgical Care: When Is Regionalization the Right Choice? PMID- 27463103 TI - Two Silver Coordination Network Compounds with Colorful Photoluminescence. AB - The excitation-wavelength-dependent photoluminescence (EWDP) property of flexible organic ligand 1,4-bis(2-methyl-imidazol-1-yl)butane (Bmib) was observed. Herein, Bmib was chosen as a bridge linker to react with AgX (X = Br and I) to synthesize novel coordination network compounds (CNCs) with interesting EWDP properties. As anticipated, under the same hydrothermal synthesis conditions, two new isomorphic CNCs, i.e. [Ag2(Bmib)Br2]infinity (IAM16-1) and [Ag2(Bmib)I2]infinity (IAM16-2), as the first examples of CNCs showing EWDP properties, have been obtained. The EWDP properties may be attributed to the stretch and rotation of the long -(CH2)4 chains of Bmib and the spatial orientation adjustment of the methyl group of each imidazole ring at different excitation wavelengths. It is a great challenge to point out the emission mechanisms of CNCs merely from the experimental results due to their multiple charge transfer routes. To address this issue, we adopt DFT calculations to pursue in-depth investigation of the emission mechanisms for IAM16-1 and IAM16-2, respectively. PMID- 27463104 TI - How Dirhodium Catalyst Controls the Enantioselectivity of [3 + 2]-Cycloaddition between Nitrone and Vinyldiazoacetate: A Density Functional Theory Study. AB - The origin of enantioselectivity in the dirhodium-catalyzed [3 + 2]-cycloaddition of nitrone and vinyldiazoacetate has been investigated using dispersion-corrected density functional theory. Taking a more realistic account of bulky ligands in models of the dirhodium catalyst when investigating its catalytic behavior is crucial for describing the effects resulting from a high level of asymmetric induction. More than one active site can be located and the extra reactivity is provided by an electron-donation interaction between the substrate and an additional Rh2L4 catalyst. PMID- 27463105 TI - Assessment of Eating Habits and Physical Activity among Spanish Adolescents. The "Cooking and Active Leisure" TAS Program. AB - Worldwide obesity has more than doubled in the last forty years. Even more worrying is the fact that the number of overweight and obese children and adolescents has considerably increased. Socioeconomic development, as well as educational, agricultural and marketing policies have significantly changed dietary and physical activity habits among the youngest, who are thus susceptible to develop chronic and disabling diseases such as diabetes, some cancers and cardiovascular disorders. Adolescence is a critical age, in which the adoption of healthy habits may have dramatic effects on the health state in adulthood. For this reason, prompt interventions are urgently required to prevent the onset of obesity in this time of life. In this regard, the CAL-TAS program from Alicia Foundation was born to combat obesity and promote healthy lifestyles in Spanish adolescents. A total of 2519 students, aged 13-14 years, from 79 schools distributed all over the 17 autonomous communities in Spain were asked to report through the CAL-TAS platform their food intake and physical activity over one week. The body mass index, the consumption of food and beverages, the intake of macronutrients and micronutrients, and the values obtained from the PAQ-A questionnaire, which evaluated physical activity, were analyzed. Twenty percent of the participants were overweight or obese. In general, adolescents did not or poorly respected the recommendations provided by the Spanish Society of Community Nutrition. For example, in more than half of the subjects, the ingestion of fruits and beverages was less than recommended, whereas the consumption of meat, baked goods and fried foods was excessive. Moreover, adolescents with higher body mass index also presented worse eating habits and more inactivity. In conclusion, Spanish adolescents present low adherence to recommendations provided by the Spanish Society of Community Nutrition (SENC) and by the World Health Organization. In order to prevent obesity-related disorders, effective educational programmes have to be designed. Indeed, adolescents and their families should be aware that the early adoption of healthy dietary habits and of a correct physical activity may strongly improve their future quality of life. PMID- 27463106 TI - Perception of Egocentric Distance during Gravitational Changes in Parabolic Flight. AB - We explored the effect of gravity on the perceived representation of the absolute distance of objects to the observers within the range from 1.5-6 m. Experiments were performed on board the CNES Airbus Zero-G during parabolic flights eliciting repeated exposures to short periods of microgravity (0 g), hypergravity (1.8 g), and normal gravity (1 g). Two methods for obtaining estimates of perceived egocentric distance were used: verbal reports and visually directed motion toward a memorized visual target. For the latter method, because normal walking is not possible in 0 g, blindfolded subjects translated toward the visual target by pulling on a rope with their arms. The results showed that distance estimates using both verbal reports and blind pulling were significantly different between normal gravity, microgravity, and hypergravity. Compared to the 1 g measurements, the estimates of perceived distance using blind pulling were shorter for all distances in 1.8 g, whereas in 0 g they were longer for distances up to 4 m and shorter for distances beyond. These findings suggest that gravity plays a role in both the sensorimotor system and the perceptual/cognitive system for estimating egocentric distance. PMID- 27463107 TI - Work ability and health of security guards at a public University: a cross sectional study. AB - OBJECTIVE: to evaluate the work ability and health status of security guards at a public University. METHODS: a cross-sectional, descriptive, and analytical study was carried with 119 security guards. The following instruments were used: Work Ability Index (WAI), Patient Health Questionnaire (PHQ-9), International Physical Activity Questionnaire (IPAQ, short), Alcohol Use Disorders Identification Test (AUDIT), Medical Outcomes Study (MOS), and Demand-Control-Support (DCS). Descriptive statistics were used to describe the study samples and the Spearman's coefficient correlation was performed to assess the WAI. Significance level was set at 5%. RESULTS: samples were composed by men; the mean age was 54.9 years (SD=5.7); 80% had partners, and 75% had basic education. The majority (95%) had only one job, the average length of service was 24.8 years (SD=11), ranging from 3 to 43 years. 88.9% worked <=40 hours and 75% did not work at night shift or rotating shifts. The average score given to work ability was good (40.7 points), with significant correlation to social support at work (p-value=0.002), health conditions (p-value=0.094), and depression symptoms (p-value=0.054). CONCLUSION: this study showed that many characteristics might affect the work ability scores. Considering the results, we note that healthy life habits and a reorganization of work environments should be encouraged. PMID- 27463108 TI - The domestic participation in birth assistance in the mid-twentieth century. AB - OBJECTIVE: to describe how the progressive creation of the Social Security (providing widespread health care) affected the birth assistance in Spain from the 1940s to the 1970s in a rural area. METHOD: historical ethnography. Twenty seven people who lived at that time were selected and interviewed guided by a semistructured script. Based on their testimonies, a chart was built with the functional elements involved in birth assistance in this region. RESULTS: three agents performed such care: traditional midwives, women of the family/neighbors and health workers. CONCLUSION: although birth assistance had been transferred to the hands of the health workers from the forties in this region, women in labor continued to count on the domestic resources until the early seventies, when births were compulsorily transferred to hospitals. This research brings to light the names and recognizes the work performed by these female characters of the popular sphere, who helped women in labor of that community to give birth, for at least three decades. PMID- 27463109 TI - Labor stimulation with oxytocin: effects on obstetrical and neonatal outcomes. AB - OBJECTIVE: to evaluate the effects of labor stimulation with oxytocin on maternal and neonatal outcomes. METHOD: descriptive and analytical study with 338 women who gave birth at a tertiary hospital. Obstetric and neonatal variables were measured and compared in women submitted and non-submitted to stimulation with oxytocin. Statistics were performed using Chi-square test, Fisher exact test, Student t-test; and crude Odds Ratio with 95% confidence interval were calculated. A p < 0.05 was considered statistically significant. RESULTS: stimulation with oxytocin increases the rates of cesarean sections, epidural anesthesia and intrapartum maternal fever in primiparous and multiparous women. It has also been associated with low pH values of umbilical cord blood and with a shorter duration of the first stage of labor in primiparous women. However, it did not affect the rates of 3rd and 4th degree perineal lacerations, episiotomies, advanced neonatal resuscitation, 5-minute Apgar scores and meconium. CONCLUSION: stimulation with oxytocin should not be used systematically, but only in specific cases. These findings provide further evidence to health professionals and midwives on the use of oxytocin during labor. Under normal conditions, women should be informed of the possible effects of labor stimulation with oxytocin. PMID- 27463110 TI - Risk Factors for premature birth in a hospital. AB - OBJECTIVE: to determine the risk factors for premature birth. METHODS: retrospective case-control study of 600 pregnant women assisted in a hospital, with 298 pregnant women in the case group (who gave birth prematurely <37 weeks) and 302 pregnant women who gave birth to a full-term newborn in the control group. Stata software version 12.2 was used. The Chi-square test was used in bivariate analysis and logistic regression was used in multivariate analysis, from which Odds Ratios (OR) and Confidence Intervals (CI) of 95% were derived. RESULTS: risk factors associated with premature birth were current twin pregnancy (adjusted OR= 2.4; p= 0.02), inadequate prenatal care (< 6 controls) (adjusted OR= 3.2; p <0.001), absent prenatal care (adjusted OR= 3.0; p <0.001), history of premature birth (adjusted OR= 3.7; p <0.001) and preeclampsia (adjusted OR= 1.9; p= 0.005). CONCLUSION: history of premature birth, preeclampsia, not receiving prenatal care and receiving inadequate prenatal care were risk factors for premature birth. PMID- 27463111 TI - In-house coordination project for organ and tissue procurement: social responsibility and promising results. AB - OBJECTIVES: to report the results of evaluation regarding changes in the number of potential donor referrals, actual donors, and conversion rates after the implementation of an in-house organ and tissue donation for transplantation coordination project. METHODS: epidemiological study, both retrospective and transversal, was performed with organ donation data from the Secretariat of Health for the State and the in-house organ donation coordination project of a beneficent hospital. The data was compared using nonparametric statistical Mann Whitney test, and the Student's t-test, considering a significance level of 5% (p <0.05). RESULTS: there were statistically significant differences (p < 0.05), before and after the implementation of the project on the number of potential donor notification/month (3.05 - 4.7 ), number of actual donor/month (0.78 to 1.60) and rate of conversion ( 24.7 to 34.8 %). The hospitals 1, 2, 7 and 8 had significant results in potential donor, actual donor or conversion rate. CONCLUSION: the presence of an in-house coordinator is promising and beneficial, the specialist is important to change the indicators of efficiency, which consequently reduces the waiting lists for organ transplants. PMID- 27463112 TI - Nurses' experiences working with nursing students in a hospital: a phenomenological enquiry. AB - OBJECTIVE: this paper explores the experiences of registered nurses working with Spanish nursing students within the hospital. METHODS: a qualitative phenomenological approach was followed. Purposeful sampling was employed. Twenty one registered nurses, from a public hospital located in Spain, were included in the study. Data were collected by means of unstructured and semi-structured interviews and were analysed using Giorgi's proposal. The Consolidated Criteria for Reporting Qualitative Research were followed. RESULTS: three main themes described the experience of registered nurses: "The nurse's relationship with nursing students"; most nurses emphasized the importance of the first contact with students and they considered students' attitude to be key. "Defining the role of the student in clinical practice"; it is necessary to unify the nurse's role and interventions to avoid misleading students and establish priorities in clinical practice. "Building bridges between clinical settings and the University"; the need to establish a common ground and connection between the university and hospital clinical settings was emphasized. Nurses felt that the training program should also be designed by the clinical settings themselves. CONCLUSIONS: understanding the meaning of nursing students with registered nurses might gain a deeper insight into their expectations. PMID- 27463113 TI - Reducing bed rest time from five to three hours does not increase complications after cardiac catheterization: the THREE CATH Trial. AB - OBJECTIVE: to compare the incidence of vascular complications in patients undergoing transfemoral cardiac catheterization with a 6F introducer sheath followed by 3-hour versus 5-hour rest. METHODS: randomized clinical trial. Subjects in the intervention group (IG) ambulated 3 hours after sheath removal, versus 5 hours in the control group (CG). All patients remained in the catheterization laboratory for 5 hours and were assessed hourly, and were contacted 24, 48, and 72 h after hospital discharge. RESULTS: the sample comprised 367 patients in the IG and 363 in the GC. During cath lab stay, hematoma was the most common complication in both groups, occurring in 12 (3%) IG and 13 (4%) CG subjects (P=0.87). Bleeding occurred in 4 (1%) IG and 6 (2%) CG subjects (P=0.51), and vasovagal reaction in 5 (1.4%) IG and 4 (1.1%) CG subjects (P=0.75). At 24-h, 48-h, and 72-h bruising was the most commonly reported complication in both groups. None of the comparisons revealed any significant between-group differences. CONCLUSION: the results of this trial show that reducing bed rest time to 3 hours after elective cardiac catheterization is safe and does not increase complications as compared with a 5-hour rest. ClinicalTrials.gov Identifier: NCT-01740856. PMID- 27463114 TI - Epidermal Neuromedin U Attenuates IgE-Mediated Allergic Skin Inflammation. AB - Although keratinocyte-derived neuropeptide neuromedin U (NMU) mediates the proinflammatory effects of innate-type mast cell activation, no information is available on the physiological roles. Here, to investigate the effects of NMU on IgE-mediated allergic skin inflammation, we determined whether IgE-mediated inflammation associated with severe scratching was induced in Nmu-/- mice administered repeated hapten applications to the ear or footpad. Dry skin was induced by targeted deletion of Nmu. Mice administered repeated hapten application developed IgE-mediated allergic inflammation characterized by severe scratching and increased serum IgE levels only when the ear, and not the footpad, was subjected to scratching, indicating that depletion of NMU from the epidermis alone does not drive such allergic inflammation. Thus, the susceptibility of Nmu /- mice to allergic inflammation depends primarily on scratching dry skin. Further, allergic skin inflammation mediated by FcepsilonRI cross-linking in Nmu /-mice was inhibited by prior injection of NMU. These results indicate that NMU plays an important physiological role as a negative regulator during the late stage of IgE-mediated allergic skin inflammation. PMID- 27463116 TI - High-Performance Strain Sensors with Fish-Scale-Like Graphene-Sensing Layers for Full-Range Detection of Human Motions. AB - Strain sensors with large stretchability, broad sensing range, and high sensitivity are highly desirable because of their potential applications in electronic skins and health monitoring systems. In this paper, we report a high performance strain sensor with a fish-scale-like graphene-sensing layer. This strain sensor can be fabricated via stretching/releasing the composite films of reduced graphene oxide and elastic tape, making the process simple, cheap, energy saving, and scalable. It can be used to detect both stretching and bending deformations with a wide sensing range (up to 82% strain), high sensitivity (a gauge factor of 16.2 to 150), ultralow limit of detection (<0.1% strain), and excellent reliability and stability (>5000 cycles). Therefore, it is attractive and promising for practical applications, such as for the full-range detection of human motions. PMID- 27463115 TI - A Single, One-Off Measure of Depression and Anxiety Predicts Future Symptoms, Higher Healthcare Costs, and Lower Quality of Life in Coronary Heart Disease Patients: Analysis from a Multi-Wave, Primary Care Cohort Study. AB - OBJECTIVE: To determine whether a one-off, baseline measure of depression and anxiety in a primary care, coronary heart disease (CHD) population predicts ongoing symptoms, costs, and quality of life across a 3-year follow-up. DESIGN: Longitudinal cohort study. SETTING: 16 General Practice surgeries across South East London. PARTICIPANTS: 803 adults (70% male, mean age 71 years) contributing up to 7 follow-up points. MAIN OUTCOME MEASURES: Ongoing reporting of symptoms, health care costs, and quality of life. RESULTS: At baseline, 27% of the sample screened positive for symptoms of depression and anxiety, as measured by the Hospital Anxiety and Depression Scale (HADS). The probability of scoring above the cut-off throughout the follow-up was 71.5% (p<0.001) for those screening positive at baseline, and for those screening negative, the probability of scoring below the cut-off throughout the follow-up was 97.6% (p<0.001). Total health care costs were 39% higher during follow-up for those screening positive (p<0.05). Quality of life as measured by the SF-12 was lower on the mental component during follow-up for those screening positive (-0.75, CI -1.53 to 0.03, p = 0.059), and significantly lower on the physical component (-4.99, CI -6.23 to -.376, p<0.001). CONCLUSIONS: A one-off measure for depression and anxiety symptoms in CHD predicts future symptoms, costs, and quality of life over the subsequent three-years. These findings suggest symptoms of depression and anxiety in CHD persist throughout long periods and are detrimental to a patient's quality of life, whilst incurring higher health care costs for primary and secondary care services. Screening for these symptoms at the primary care level is important to identify and manage patients at risk of the negative effects of this comorbidity. Implementation of screening, and possible collaborative care strategies and interventions that help mitigate this risk should be the ongoing focus of researchers and policy-makers. PMID- 27463117 TI - Factors relating to impaired stroke volume during the 6-minute walk test in patients with systemic sclerosis. AB - OBJECTIVES: Systemic sclerosis impairs the dilatation of affected pulmonary blood vessels and myocardial diastolic function at rest, but few studies have examined cardiac hemodynamic response during exercise. This study aimed to evaluate the factors affecting cardiac response during submaximal exercise in patients with systemic sclerosis. METHODS: Fifty-nine consecutive patients and 27 age- and sex matched healthy controls underwent the 6-minute walk test with a non-invasive impedance cardiograph device. RESULTS: Stroke volume and cardiac output in patients with systemic sclerosis were significantly lower than those in controls at rest and at the end of the 6-minute walk test, and the distance walked was significantly shorter in patients. Percent predicted of forced vital capacity and diffusion capacity of the lung in patients showed correlations with stroke volume at the end of the 6-minute walk test and the increase in stroke volume during walking. The echocardiographic findings of right ventricular systolic pressure and left ventricular diastolic dysfunction showed no relationship to stroke volume during the 6-minute walk test. The increase in stroke volume during the 6 minute walk test was significantly smaller in patients with pulmonary hypertension diagnosed by right-heart catheterization than in those without pulmonary hypertension. CONCLUSIONS: Impaired stroke volume in patients with systemic sclerosis was observed at rest and during exercise, and the factors relating to the cardiac response seemed to be pulmonary function and the extent of pulmonary hypertension. PMID- 27463118 TI - Double-peaked Acetaminophen Concentration Secondary to Intestinal Trauma. AB - BackgroundReduced gastrointestinal motility can alter the toxicokinetics of acetaminophen poisoning. We report a case of altered acetaminophen toxicokinetics due to delayed gastrointestinal absorption, likely secondary to intestinal trauma/surgery. Case ReportA 37-year-old woman ingested an unknown amount of acetaminophen and ethanol then stabbed herself in the abdomen. The initial acetaminophen was 1,285.9 MUmol/L and the time of ingestion was not known. Intravenous acetylcysteine protocol was started. She developed an ileus post surgery for the stab wounds. At 31 hours post-presentation, the acetaminophen returned undetectable, and the transaminases were normal. After the resolution of the ileus, repeated acetaminophen peaked at 363.3 MUmol/L 52 hours post admission. At 76 hours post-admission, the acetaminophen was undetectable, and transaminases and coagulation parameters were normal. ConclusionsReduction in gastrointestinal motility secondary to trauma and/or surgery must be considered when determining when to initiate or discontinue treatment as well as how long to monitor acetaminophen concentrations. PMID- 27463119 TI - PLAG1: An Immunohistochemical Marker with Limited Utility in Separating Pleomorphic Adenoma from Other Basaloid Salivary Gland Tumors. AB - OBJECTIVE: Fine-needle aspiration (FNA) diagnosis of salivary gland neoplasms is often challenging. Differentiating between pleomorphic adenomas (PA) and other basaloid neoplasms, especially basal cell adenoma (BCA) and adenoid cystic carcinoma (AdCC), can be difficult in cellular aspirates. PLAG1 (PA gene 1) is a proto-oncogene, which is frequently rearranged in PAs, leading to the aberrant expression of its protein. PLAG1 IHC expression has been reported to be positive in most PAs. The aim of this study was to evaluate the sensitivity and specificity of PLAG1 to differentiate PA from other basaloid neoplasms. STUDY DESIGN: Immunohistochemical evaluation of PLAG1 was performed on 125 cases (52 FNAs and 73 surgical excisions). Nuclear staining of tumor cells was scored by the intensity and percentage of positive tumor cells. A combined score of >5 was defined as positive. RESULTS AND CONCLUSION: The sensitivity (55%) and specificity (75%) of PLAG1 in diagnosing PA in FNAs is relatively modest thus limiting its diagnostic utility. BCAs and AdCCs showed PLAG1 false positivity, in surgical excision specimens and less so in FNAs. This may be due to limited sampling or tumor heterogeneity. Hence, PLAG1 is a modest marker for PAs in FNAs. PMID- 27463120 TI - Development and Validation of an Interactive Internet Platform for Older People: The Healthy Ageing Through Internet Counselling in the Elderly Study. AB - BACKGROUND: A myriad of Web-based applications on self-management have been developed, but few focus on older people. In the face of global aging, older people form an important target population for cardiovascular prevention. This article describes the full development of an interactive Internet platform for older people, which was designed for the Healthy Ageing Through Internet Counselling in the Elderly (HATICE) study. We provide recommendations to design senior-friendly Web-based applications for a new approach to multicomponent cardiovascular prevention. METHODS: The development of the platform followed five phases: (1) conceptual framework; (2) platform concept and functional design; (3) platform building (software and content); (4) testing and pilot study; and (5) final product. RESULTS: We performed a meta-analysis, reviewed guidelines for cardiovascular diseases, and consulted end users, experts, and software developers to create the platform concept and content. The software was built in iterative cycles. In the pilot study, 41 people aged >=65 years used the platform for 8 weeks. Participants used the interactive features of the platform and appreciated the coach support. During all phases adjustments were made to incorporate all improvements from the previous phases. The final platform is a personal, secured, and interactive platform supported by a coach. DISCUSSION: When carefully designed, an interactive Internet platform is acceptable and feasible for use by older people with basic computer skills. To improve acceptability by older people, we recommend involving the end users in the process of development, to personalize the platform and to combine the application with human support. The interactive HATICE platform will be tested for efficacy in a multinational randomized controlled trial (ISRCTN48151589). PMID- 27463122 TI - In Situ Coupling of Strung Co4N and Intertwined N-C Fibers toward Free-Standing Bifunctional Cathode for Robust, Efficient, and Flexible Zn-Air Batteries. AB - Flexible power sources with high energy density are crucial for the realization of next-generation flexible electronics. Theoretically, rechargeable flexible zinc-air (Zn-air) batteries could provide high specific energy, while their large scale applications are still greatly hindered by high cost and resources scarcity of noble-metal-based oxygen evolution reaction (OER)/oxygen reduction reaction (ORR) electrocatalysts as well as inferior mechanical properties of the air cathode. Combining metallic Co4N with superior OER activity and Co-N-C with perfect ORR activity on a free-standing and flexible electrode could be a good step for flexible Zn-air batteries, while lots of difficulties need to be overcome. Herein, as a proof-of-concept experiment, we first propose a strategy for in situ coupling of strung Co4N and intertwined N-C fibers, by pyrolyzation of the novel pearl-like ZIF-67/polypyrrole nanofibers network rooted on carbon cloth. Originating from the synergistic effect of Co4N and Co-N-C and the stable 3D interconnected conductive network structure, the obtained free-standing and highly flexible bifunctional oxygen electrode exhibits excellent electrocatalytic activity and stability for both OER and ORR in terms of low overpotential (310 mV at 10 mA cm(-2)) for OER, a positive half-wave potential (0.8 V) for ORR, and a stable current density retention for at least 20 h, and especially, the obtained Zn-air batteries exhibit a low discharge-charge voltage gap (1.09 V at 50 mA cm( 2)) and long cycle life (up to 408 cycles). Furthermore, the perfect bendable and twistable and rechargeable properties of the flexible Zn-air battery particularly make it a potentially power portable and wearable electronic device. PMID- 27463123 TI - Synthesis of Water-Dispersible Molecularly Imprinted Electroactive Nanoparticles for the Sensitive and Selective Paracetamol Detection. AB - A novel kind of water-dispersible molecularly imprinted electroactive nanoparticles was prepared combining macromolecular self-assembly with molecularly imprinting technique employing paracetamol (PCM) as template molecule. An amphiphilic electroactive copolymer (P(NVC-EHA-AA), PNEA) containing carbazole group was first synthesized through a one-pot free radical copolymerization. The coassembly of the electroactive copolymers with the template molecules (PCM) in aqueous solution generated nanoparticles embedded with PCM, leading to the formation of molecularly imprinted electroactive nanoparticles (MIENPs). A robust MIP film was formed on the surface of electrode by electrodeposition of MIENPs and subsequent electropolymerization of the carbazole units in MIENPs. After the extraction of PCM molecules, a MIP sensor was successfully constructed. It should be noted that electropolymerization of the electroactive units in MIENPs creates cross-conjugated polymer network, which not only locks the recognition sites but also significantly accelerates the electron transfer and thus enhances the response signal of the MIP sensor. These advantages endowed the MIP sensor with good selectivity and high sensitivity for PCM detection. The MIP sensor could recognize PCM from its possible interfering substances with good selectivity. Under the optimal conditions, two linear ranges from 1 MUM to 0.1 mM and 0.1 to 10 mM with a detection limit of 0.3 MUM were obtained for PCM detection. The MIP sensor also showed good stability and repeatability, which has been successfully used to analyze PCM in tablets and human urine samples with satisfactory results. PMID- 27463124 TI - Hydrogen cleavage by solid-phase frustrated Lewis pairs. AB - We report the direct synthesis of a solid-phase frustrated Lewis pair (s-FLP) by combining a silica-supported Lewis acid ([triple bond, length as m dash]SiOB(C6F5)2, s-BCF) with a Lewis base (tri-tert-butylphosphine, (t)Bu3P) to give [[triple bond, length as m-dash]SiOB(C6F5)2][(t)Bu3P]. Reaction of this s FLP with H2 under mild conditions led to heterolytic H-H bond cleavage and the formation of [[triple bond, length as m-dash]SiOB(H)(C6F5)2][(t)Bu3PH]. PMID- 27463125 TI - Pd(II)-Catalyzed Intramolecular Tandem Olefin Amidation/C-H Activation Protocol for the Syntheses of the Protoberberine Class of Natural Products. AB - A Pd(II)-catalyzed intramolecular tandem olefin amidation/C-H activation protocol has been developed for the synthesis of an 8-oxoprotoberberine core. It was successfully applied for the syntheses of (+/-)-8-oxocanadine, (+/-)-8 oxotetrahydropalmitine, and (+/-)-8-oxostylopine, which can be easily converted to the respective protoberberine natural products. The short synthetic route demonstrated would be useful for the synthesis of a large number of natural products and their analogues featuring a protoberberine scaffold. PMID- 27463127 TI - MCMC for Ion-Channel Sojourn-Time Data: A Good Proposal. PMID- 27463126 TI - Absence of autophagy promotes apoptosis by modulating the ROS-dependent RLR signaling pathway in classical swine fever virus-infected cells. AB - A growing number of studies have demonstrated that both macroautophagy/autophagy and apoptosis are important inner mechanisms of cell to maintain homeostasis and participate in the host response to pathogens. We have previously reported that a functional autophagy pathway is trigged by infection of classical swine fever virus (CSFV) and is required for viral replication and release in host cells. However, the interplay of autophagy and apoptosis in CSFV-infected cells has not been clarified. In the present study, we demonstrated that autophagy induction with rapamycin facilitates cellular proliferation after CSFV infection, and that autophagy inhibition by knockdown of essential autophagic proteins BECN1/Beclin 1 or MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) promotes apoptosis via fully activating both intrinsic and extrinsic mechanisms in CSFV infected cells. We also found that RIG-I-like receptor (RLR) signaling was amplified in autophagy-deficient cells during CSFV infection, which was closely linked to the activation of the intrinsic apoptosis pathway. Moreover, we discovered that virus infection of autophagy-impaired cells results in an increase in copy number of mitochondrial DNA and in the production of reactive oxygen species (ROS), which plays a significant role in enhanced RLR signaling and the activated extrinsic apoptosis pathway in cultured cells. Collectively, these data indicate that CSFV-induced autophagy delays apoptosis by downregulating ROS-dependent RLR signaling and thus contributes to virus persistent infection in host cells. PMID- 27463128 TI - Optical Mapping of Cardiac Electromechanics. PMID- 27463129 TI - Watching Populations Melt Down. PMID- 27463130 TI - MEMLET: An Easy-to-Use Tool for Data Fitting and Model Comparison Using Maximum Likelihood Estimation. AB - We present MEMLET (MATLAB-enabled maximum-likelihood estimation tool), a simple to-use and powerful program for utilizing maximum-likelihood estimation (MLE) for parameter estimation from data produced by single-molecule and other biophysical experiments. The program is written in MATLAB and includes a graphical user interface, making it simple to integrate into the existing workflows of many users without requiring programming knowledge. We give a comparison of MLE and other fitting techniques (e.g., histograms and cumulative frequency distributions), showing how MLE often outperforms other fitting methods. The program includes a variety of features. 1) MEMLET fits probability density functions (PDFs) for many common distributions (exponential, multiexponential, Gaussian, etc.), as well as user-specified PDFs without the need for binning. 2) It can take into account experimental limits on the size of the shortest or longest detectable event (i.e., instrument "dead time") when fitting to PDFs. The proper modification of the PDFs occurs automatically in the program and greatly increases the accuracy of fitting the rates and relative amplitudes in multicomponent exponential fits. 3) MEMLET offers model testing (i.e., single exponential versus double-exponential) using the log-likelihood ratio technique, which shows whether additional fitting parameters are statistically justifiable. 4) Global fitting can be used to fit data sets from multiple experiments to a common model. 5) Confidence intervals can be determined via bootstrapping utilizing parallel computation to increase performance. Easy-to-follow tutorials show how these features can be used. This program packages all of these techniques into a simple-to-use and well-documented interface to increase the accessibility of MLE fitting. PMID- 27463131 TI - Quantifying Nonnative Interactions in the Protein-Folding Free-Energy Landscape. AB - Protein folding is a central problem in biological physics. Energetic roughness is an important aspect that controls protein-folding stability and kinetics. The roughness is associated with conflicting interactions in the protein and is also known as frustration. Recent studies indicate that an addition of a small amount of energetic frustration may enhance folding speed for certain proteins. In this study, we have investigated the conditions under which frustration increases the folding rate. We used a Calpha structure-based model to simulate a group of proteins. We found that the free-energy barrier at the transition state (DeltaF) correlates with nonnative-contact variation (DeltaA), and the simulated proteins are clustered according to their fold motifs. These findings are corroborated by the Clementi-Plotkin analytical model. As a consequence, the optimum frustration regime for protein folding can be predicted analytically. PMID- 27463132 TI - A Molecular Model for Lithium's Bioactive Form. AB - Lithium carbonate, a drug for the treatment of bipolar disorder, provides mood stability to mitigate recurrent episodes of mania and/or depression. Despite its long-term and widespread use, the mechanism by which lithium acts to elicit these psychological changes has remained unknown. Using nuclear magnetic resonance (NMR) methods, in this study we characterized the association of lithium with adenosine triphosphate (ATP) and identified a bimetallic (Mg.Li) ATP complex. Lithium's affinity to form this complex was found to be relatively high (Kd ~1.6 mM) compared with other monovalent cations and relevant, considering lithium dosing and physiological concentrations of Mg(2+) and ATP. The ATP.Mg.Li complex reveals, for the first time, to the best of our knowledge, that lithium can associate with magnesium-bound phosphate sites and then act to modulate purine receptor activity in neuronal cells, suggesting a molecular mode for in vivo lithium action. PMID- 27463133 TI - Extended Electron-Transfer in Animal Cryptochromes Mediated by a Tetrad of Aromatic Amino Acids. AB - The cryptochrome/photolyase protein family possesses a conserved triad of tryptophans that may act as a molecular wire to transport electrons from the protein surface to the FAD cofactor for activation and/or signaling-state formation. Members from the animal (and animal-like) cryptochrome subclade use this process in a light-induced fashion in a number of exciting responses, such as the (re-)setting of circadian rhythms or magnetoreception; however, electron transfer pathways have not been explored in detail yet. Therefore, we present an in-depth time-resolved optical and electron-paramagnetic resonance spectroscopic study of two cryptochromes from Chlamydomonas reinhardtii and Drosophila melanogaster. The results do not only reveal the existence of a fourth, more distant aromatic amino acid that serves as a terminal electron donor in both proteins, but also show that a tyrosine is able to fulfill this very role in Chlamydomonas reinhardtii cryptochrome. Additionally, exchange of the respective fourth aromatic amino acid to redox-inactive phenylalanines still leads to light induced radical pair formation; however, the lifetimes of these species are drastically reduced from the ms- to the MUs-range. The results presented in this study open up a new chapter, to our knowledge, in the diversity of electron transfer pathways in cryptochromes. Moreover, they could explain unique functions of animal cryptochromes, in particular their potential roles in magnetoreception because magnetic-field effects of light-induced radical pairs strongly depend on distance and orientation parameters. PMID- 27463134 TI - pH-Dependent Interactions in Dimers Govern the Mechanics and Structure of von Willebrand Factor. AB - Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that is activated for hemostasis by increased hydrodynamic forces at sites of vascular injury. Here, we present data from atomic force microscopy-based single-molecule force measurements, atomic force microscopy imaging, and small-angle x-ray scattering to show that the structure and mechanics of VWF are governed by multiple pH dependent interactions with opposite trends within dimeric subunits. In particular, the recently discovered strong intermonomer interaction, which induces a firmly closed conformation of dimers and crucially involves the D4 domain, was observed with highest frequency at pH 7.4, but was essentially absent at pH values below 6.8. However, below pH 6.8, the ratio of compact dimers increased with decreasing pH, in line with a previous transmission electron microscopy study. These findings indicated that the compactness of dimers at pH values below 6.8 is promoted by other interactions that possess low mechanical resistance compared with the strong intermonomer interaction. By investigating deletion constructs, we found that compactness under acidic conditions is primarily mediated by the D4 domain, i.e., remarkably by the same domain that also mediates the strong intermonomer interaction. As our data suggest that VWF has the highest mechanical resistance at physiological pH, local deviations from physiological pH (e.g., at sites of vascular injury) may represent a means to enhance VWF's hemostatic activity where needed. PMID- 27463135 TI - Two Deafness-Causing Actin Mutations (DFNA20/26) Have Allosteric Effects on the Actin Structure. AB - Point mutations in gamma-cytoplasmic actin have been shown to result in autosomal dominant, nonsyndromic, early-onset deafness. Two mutations at the same site, K118M and K118N, provide a unique opportunity to compare the effects of two dissimilar amino acid substitutions that produce a similar phenotype in humans. K118 resides in a helix that runs from K113 to T126, and mutations that alter the position, dynamics, and/or biochemistry of this helix can result in a wide range of pathologies. Using a combination of computational and experimental studies, both employing yeast actin, we find that these mutations at K118 result in changes in the structure and dynamics of the DNase-I loop, alterations in the structure of the H73 loop as well as the side-chain orientations of W79 and W86, changes in nucleotide exchange rates, and significant shifts in the twist of the actin monomer. Interestingly, in the case of K118N, the twist of the monomer is nearly identical to that of the F-actin protomer, and in vitro polymerization assays show that this mutation results in faster polymerization. Taken together, these results indicate that mutations at this site give rise to a series of small changes that can be tolerated in vivo but result in misregulation of actin assembly and dynamics. PMID- 27463136 TI - Bayesian Statistical Inference in Ion-Channel Models with Exact Missed Event Correction. AB - The stochastic behavior of single ion channels is most often described as an aggregated continuous-time Markov process with discrete states. For ligand-gated channels each state can represent a different conformation of the channel protein or a different number of bound ligands. Single-channel recordings show only whether the channel is open or shut: states of equal conductance are aggregated, so transitions between them have to be inferred indirectly. The requirement to filter noise from the raw signal further complicates the modeling process, as it limits the time resolution of the data. The consequence of the reduced bandwidth is that openings or shuttings that are shorter than the resolution cannot be observed; these are known as missed events. Postulated models fitted using filtered data must therefore explicitly account for missed events to avoid bias in the estimation of rate parameters and therefore assess parameter identifiability accurately. In this article, we present the first, to our knowledge, Bayesian modeling of ion-channels with exact missed events correction. Bayesian analysis represents uncertain knowledge of the true value of model parameters by considering these parameters as random variables. This allows us to gain a full appreciation of parameter identifiability and uncertainty when estimating values for model parameters. However, Bayesian inference is particularly challenging in this context as the correction for missed events increases the computational complexity of the model likelihood. Nonetheless, we successfully implemented a two-step Markov chain Monte Carlo method that we called "BICME", which performs Bayesian inference in models of realistic complexity. The method is demonstrated on synthetic and real single-channel data from muscle nicotinic acetylcholine channels. We show that parameter uncertainty can be characterized more accurately than with maximum-likelihood methods. Our code for performing inference in these ion channel models is publicly available. PMID- 27463137 TI - Acetylation within the First 17 Residues of Huntingtin Exon 1 Alters Aggregation and Lipid Binding. AB - Huntington's disease (HD) is a genetic neurodegenerative disorder caused by an expanded polyglutamine (polyQ) domain near the N-terminus of the huntingtin (htt) protein. Expanded polyQ leads to htt aggregation. The first 17 amino acids (Nt(17)) in htt comprise a lipid-binding domain that undergoes a number of posttranslational modifications that can modulate htt toxicity and subcellular localization. As there are three lysines within Nt(17), we evaluated the impact of lysine acetylation on htt aggregation in solution and on model lipid bilayers. Acetylation of htt-exon1(51Q) and synthetic truncated htt-exon 1 mimicking peptides (Nt(17)-Q35-P10-KK) was achieved using a selective covalent label, sulfo N-hydroxysuccinimide (NHSA). With this treatment, all three lysine residues (K6, K9, and K15) in Nt(17) were significantly acetylated. N-terminal htt acetylation retarded fibril formation in solution and promoted the formation of larger globular aggregates. Acetylated htt also bound lipid membranes and disrupted the lipid bilayer morphology less aggressively compared with the wild-type. Computational studies provided mechanistic insights into how acetylation alters the interaction of Nt(17) with lipid membranes. Our results highlight that N terminal acetylation influences the aggregation of htt and its interaction with lipid bilayers. PMID- 27463138 TI - Effect of Statins on the Nanomechanical Properties of Supported Lipid Bilayers. AB - Many drugs and other xenobiotics may reach systemic concentrations where they interact not only with the proteins that are their therapeutic targets but also modify the physicochemical properties of the cell membrane, which may lead to altered function of many transmembrane proteins beyond the intended targets. These changes in bilayer properties may contribute to nonspecific, promiscuous changes in membrane protein and cell function because membrane proteins are energetically coupled to their host lipid bilayer. It is thus important, for both pharmaceutical and biophysical reasons, to understand the bilayer-modifying effect of amphiphiles (including therapeutic agents). Here we use atomic force microscopy topography imaging and nanomechanical mapping to monitor the effect of statins, a family of hypolipidemic drugs, on synthetic lipid membranes. Our results reveal that statins alter the nanomechanical stability of the bilayers and increase their elastic moduli depending on the lipid bilayer order. Our results also suggest that statins increase bilayer heterogeneity, which may indicate that statins form nanometer-sized aggregates in the membrane. This is further evidence that changes in bilayer nanoscale mechanical properties may be a signature of lipid bilayer-mediated effects of amphiphilic drugs. PMID- 27463139 TI - Spontaneous Formation of a Globally Connected Contractile Network in a Microtubule-Motor System. AB - Microtubule (MT) networks play key roles in cell division, intracellular transport, and cell motility. These functions of MT networks occur through interactions between MTs and various associated proteins, notably motor proteins that bundle and slide MTs. Our objective in this study was to address the question of how motors determine the nature of MT networks. We conducted in vitro assays using homotetrameric kinesin Eg5, a motor protein involved in the formation and maintenance of the mitotic spindle. The mixing of Eg5 and MTs produced a range of spatiotemporal dynamics depending on the motor/filament ratio. Low motor/filament ratios produced globally connected static MT networks with sparsely distributed contractile active nodes (motor-accumulating points with radially extending MTs). Increasing the motor/filament ratio facilitated the linking of contractile active nodes and led to a global contraction of the network. When the motor/filament ratio was further increased, densely distributed active nodes formed local clusters and segmented the network into pieces with their strong contractile forces. Altering the properties of the motor through the use of chimeric Eg5, which has kinesin-1 heads, resulted in the generation of many isolated asters. These results suggest that the spatial distribution of contractile active nodes determines the dynamics of MT-motor networks. We then developed a coarse-grained model of MT-motor networks and identified two essential features for reproducing the experimentally observed patterns: an accumulation of motors that form the active nodes necessary to generate contractile forces, and a nonlinear dependency of contractile force on motor densities. Our model also enabled us to characterize the mechanical properties of the contractile network. Our study provides insight into how local motor-MT interactions generate the spatiotemporal dynamics of macroscopic network structures. PMID- 27463140 TI - Protons Trigger Mitochondrial Flashes. AB - Emerging evidence indicates that mitochondrial flashes (mitoflashes) are highly conserved elemental mitochondrial signaling events. However, which signal controls their ignition and how they are integrated with other mitochondrial signals and functions remain elusive. In this study, we aimed to further delineate the signal components of the mitoflash and determine the mitoflash trigger mechanism. Using multiple biosensors and chemical probes as well as label free autofluorescence, we found that the mitoflash reflects chemical and electrical excitation at the single-organelle level, comprising bursting superoxide production, oxidative redox shift, and matrix alkalinization as well as transient membrane depolarization. Both electroneutral H(+)/K(+) or H(+)/Na(+) antiport and matrix proton uncaging elicited immediate and robust mitoflash responses over a broad dynamic range in cardiomyocytes and HeLa cells. However, charge-uncompensated proton transport, which depolarizes mitochondria, caused the opposite effect, and steady matrix acidification mildly inhibited mitoflashes. Based on a numerical simulation, we estimated a mean proton lifetime of 1.42 ns and diffusion distance of 2.06 nm in the matrix. We conclude that nanodomain protons act as a novel, to our knowledge, trigger of mitoflashes in energized mitochondria. This finding suggests that mitoflash genesis is functionally and mechanistically integrated with mitochondrial energy metabolism. PMID- 27463142 TI - Snapshot Hyperspectral Light-Sheet Imaging of Signal Transduction in Live Pancreatic Islets. AB - The observation of ionic signaling dynamics in intact pancreatic islets has contributed greatly to our understanding of both alpha- and beta-cell function. Insulin secretion from beta-cells depends on the firing of action potentials and consequent rises of intracellular calcium activity ([Ca(2+)]i). Zinc (Zn(2+)) is cosecreted with insulin, and has been postulated to play a role in cell-to-cell cross talk within an islet, in particular inhibiting glucagon secretion from alpha-cells. Thus, measuring [Ca(2+)]i and Zn(2+) dynamics from both alpha- and beta-cells will elucidate mechanisms underlying islet hormone secretion. [Ca(2+)]i and intracellular Zn(2+) can be measured using fluorescent biosensors, but the most efficient sensors have overlapping spectra that complicate their discrimination. Hyperspectral imaging can be used to distinguish signals from multiple fluorophores, but available hyperspectral implementations are either too slow to measure the dynamics of ionic signals or not suitable for thick samples. We have developed a five-dimensional (x,y,z,t,lambda) imaging system that leverages a snapshot hyperspectral imaging method, image mapping spectrometry, and light-sheet microscopy. This system provides subsecond temporal resolution from deep within multicellular structures. Using a single excitation wavelength (488 nm) we acquired images from triply labeled samples with two biosensors and a genetically expressing fluorescent protein (spectrally overlapping with one of the biosensors) with high temporal resolution. Measurements of [Ca(2+)]i and Zn(2+) within both alpha- and beta-cells as a function of glucose concentration show heterogeneous uptake of Zn(2+) into alpha-cells that correlates to the known heterogeneities in [Ca(2+)]i. These differences in intracellular Zn(2+) among alpha-cells may contribute to the inhibition in glucagon secretion observed at elevated glucose levels. PMID- 27463141 TI - Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single Molecule Imaging. AB - Localization of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIalpha (alpha) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIbeta (beta). The betaE' splice variant bound more weakly than alpha, showing that binding by beta depends critically on the interdomain linker. The mutations betaT287D and alphaT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (betaK43R and alphaK42M) or Ca(2+)/calmodulin (betaA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the alphaT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIalpha isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F actin cytoskeleton that stabilize the initial weak (micromolar) monovalent interaction. PMID- 27463143 TI - The Secreted Signaling Protein Wnt3 Is Associated with Membrane Domains In Vivo: A SPIM-FCS Study. AB - Wnt3 is a morphogen that activates the Wnt signaling pathway and regulates a multitude of biological processes ranging from cell proliferation and cell fate specification to differentiation over embryonic induction to neural patterning. Recent studies have shown that the palmitoylation of Wnt3 by Porcupine, a membrane-bound O-acyltransferase, plays a significant role in the intracellular membrane trafficking of Wnt3 and subsequently, its secretion in live zebrafish embryos, where chemical inhibition of Porcupine reduced the membrane-bound and secreted fractions of Wnt3 and eventually led to defective brain development. However, the membrane distribution of Wnt3 in cells remains not fully understood. Here, we determine the membrane organization of functionally active Wnt3-EGFP in cerebellar cells of live transgenic zebrafish embryos and the role of palmitoylation in its organization using single plane illumination microscopy fluorescence correlation spectroscopy (SPIM-FCS), a multiplexed modality of FCS, which generates maps of molecular dynamics, concentration, and interaction of biomolecules. The FCS diffusion law was applied to SPIM-FCS data to study the subresolution membrane organization of Wnt3. We find that at the plasma membrane in vivo, Wnt3 is associated with cholesterol-dependent domains. This association reduces with increasing concentrations of Porcupine inhibitor (C59), confirming the importance of palmitoylation of Wnt3 for its association with cholesterol dependent domains. Reduction of membrane cholesterol also results in a decrease of Wnt3 association with cholesterol-dependent domains in live zebrafish. This demonstrates for the first time, to our knowledge, in live vertebrate embryos that Wnt3 is associated with cholesterol-dependent domains. PMID- 27463144 TI - Noise-Induced Increase of Sensitivity in Bacterial Chemotaxis. AB - Flagellated bacteria, like Escherichia coli, can swim toward beneficial environments by modulating the rotational direction of their flagellar motors through a chemotaxis signal transduction network. The noise of this network, the random fluctuation of the intracellular concentration of the signal protein CheY P with time, has been identified in studies of single cell behavioral variability, and found to be important in coordination of multiple motors in a bacterium and in enhancement of bacterial drift velocity in chemical gradients. Here, by comparing the behavioral difference between motors of wild-type E. coli and mutants without signal noise, we measured the magnitude of this noise in wild type cells, and found that the noise increases the sensitivity of the bacterial chemotaxis network downstream at the level of the flagellar motor. This provided a simple mechanism for the noise-induced enhancement of chemotactic drift, which we confirmed by simulating the E. coli chemotactic motion in various spatial profiles of chemo-attractant concentration. PMID- 27463145 TI - Optical Mapping of Membrane Potential and Epicardial Deformation in Beating Hearts. AB - Cardiac optical mapping uses potentiometric fluorescent dyes to image membrane potential (Vm). An important limitation of conventional optical mapping is that contraction is usually arrested pharmacologically to prevent motion artifacts from obscuring Vm signals. However, these agents may alter electrophysiology, and by abolishing contraction, also prevent optical mapping from being used to study coupling between electrical and mechanical function. Here, we present a method to simultaneously map Vm and epicardial contraction in the beating heart. Isolated perfused swine hearts were stained with di-4-ANEPPS and fiducial markers were glued to the epicardium for motion tracking. The heart was imaged at 750 Hz with a video camera. Fluorescence was excited with cyan or blue LEDs on alternating camera frames, thus providing a 375-Hz effective sampling rate. Marker tracking enabled the pixel(s) imaging any epicardial site within the marked region to be identified in each camera frame. Cyan- and blue-elicited fluorescence have different sensitivities to Vm, but other signal features, primarily motion artifacts, are common. Thus, taking the ratio of fluorescence emitted by a motion tracked epicardial site in adjacent frames removes artifacts, leaving Vm (excitation ratiometry). Reconstructed Vm signals were validated by comparison to monophasic action potentials and to conventional optical mapping signals. Binocular imaging with additional video cameras enabled marker motion to be tracked in three dimensions. From these data, epicardial deformation during the cardiac cycle was quantified by computing finite strain fields. We show that the method can simultaneously map Vm and strain in a left-sided working heart preparation and can image changes in both electrical and mechanical function 5 min after the induction of regional ischemia. By allowing high-resolution optical mapping in the absence of electromechanical uncoupling agents, the method relieves a long-standing limitation of optical mapping and has potential to enhance new studies in coupled cardiac electromechanics. PMID- 27463147 TI - Optical Pushing: A Tool for Parallelized Biomolecule Manipulation. PMID- 27463148 TI - Origins of the Relative Stabilities of Anhydrous and Hydrated d-Mannitol Crystals. AB - d-Mannitol, a common bulking agent used in the pharmaceutical and food industries, is known to crystallize in three anhydrous polymorphs (alpha, beta, and delta) and a hemihydrate form. In this work, solid-state density functional theory simulations and experimental terahertz spectroscopy were used to evaluate the stabilities, thermodynamic relationships, and spectral signatures of these various solids. The thermodynamic analyses of the anhydrous polymorphs identified enantiotropic transitions for beta-delta at approximately room temperature and alpha-delta near the alpha melting point, but showed alpha and beta to be monotropically related. Computational refinement of the d-mannitol hemihydrate crystal structure and comparison of its Gibbs free energy to the anhydrous forms showed the hemihydrate to be stable only at low temperatures (<253 K), in agreement with experiment, and reveals its conversion to the delta polymorph upon dehydration. Quantification of the intramolecular and intermolecular energies within these solids highlights the competition that exists between molecular conformation and cohesion energies and how a balance of these forces dictates the observed behaviors. PMID- 27463146 TI - Neuroprotective Role of Gap Junctions in a Neuron Astrocyte Network Model. AB - A detailed biophysical model for a neuron/astrocyte network is developed to explore mechanisms responsible for the initiation and propagation of cortical spreading depolarizations and the role of astrocytes in maintaining ion homeostasis, thereby preventing these pathological waves. Simulations of the model illustrate how properties of spreading depolarizations, such as wave speed and duration of depolarization, depend on several factors, including the neuron and astrocyte Na(+)-K(+) ATPase pump strengths. In particular, we consider the neuroprotective role of astrocyte gap junction coupling. The model demonstrates that a syncytium of electrically coupled astrocytes can maintain a physiological membrane potential in the presence of an elevated extracellular K(+) concentration and efficiently distribute the excess K(+) across the syncytium. This provides an effective neuroprotective mechanism for delaying or preventing the initiation of spreading depolarizations. PMID- 27463150 TI - Telocytes and lung disease. AB - Telocytes (TCs) represent a new distinct type of interstitial cells found in many organs, including lungs. TCs are mainly defined by a small cellular body from which arise very long (hundreds of micrometers) extensions named telopodes. During the last years, TCs were characterized in respect with their microRNA profiles, gene features and proteome signatures. Also, the ultrastructural 3D configuration was further elucidated by the aid of the FIB-SEM technology. TCs are able to communicate by homo- and heterocellular contacts with neighboring cells and are also able to transfer genetic information and signaling molecules to influence other cells by means of extracellular vesicle release. However, the exact function of lung TCs remains unclear. Here, we review the potential significance of TCs in the pathogenesis of pulmonary diseases. We will also discuss some future possibilities for targeting TCs as a potential therapeutic strategy. PMID- 27463151 TI - Names and faces. PMID- 27463149 TI - TCRgamma4delta1-engineered alphabetaT cells exhibit effective antitumor activity. AB - T cell engineering with T cell receptors (TCRs) specific for tumors plays an important role in adoptive T-cell transfer (ATC) therapy for cancer. Here, we present a novel strategy to redirect peripheral blood-derived alphabetaT cells against tumors via TCRgamma4delta1 gene transduction. The broad-spectrum anti tumor activity of TCRdelta1 cells in innate immunity is dependent on CDR3delta1. TCRgamma4delta1-engineered alphabetaT cells were prepared by lentiviral transduction and characterized by analyzing in vitro and in vivo cytotoxicity to tumors, ability of proliferation and cytokine production, and their potential role in autoimmunity. Results show TCRgamma4delta1 genes were transduced to approximately 36% of polyclonal alphabetaT cells. TCRgamma4delta1-engineered alphabetaT cells exhibited an effective in-vitro TCRgammadelta-dependent cytotoxicity against various tumor cells via the perforin-granzyme pathway. They also showed a strong proliferative capacity and robust cytokine production. TCRgamma4delta1-engineered alphabetaT cells neither expressed mixed TCR dimers nor bound/killed normal cells in vitro. More importantly, adoptive transfer of TCRgamma4delta1-engineered alphabetaT cells into nude mice bearing a human HepG2 cell line significantly suppressed tumor growth. Our results demonstrate a novel role for TCRgamma4delta1 in gene therapy and ATC for cancer. PMID- 27463152 TI - Letters. PMID- 27463153 TI - What Do You Think? PMID- 27463154 TI - Coming in sportsmedicine. PMID- 27463155 TI - Brief reports. PMID- 27463157 TI - The Parental Effect on Running. PMID- 27463158 TI - Scanning sports. PMID- 27463160 TI - How Big Is Too Big? PMID- 27463161 TI - Traveler's Diarrhea in Athletes. AB - In brief: Traveler's diarrhea is a common and troublesome feature of life for international athletes. About 30% to 60% of traveling groups that have been studied are affected with diarrhea. The most common pathogen is enterotoxigenic Escherichia coli. Recent experience confirms that doxycycline provides effective prophylaxis against enterotoxigenic E coli infection in many locales. Treatment is aimed at reducing discomfort, increasing stool consistency, and reducing stool frequency. PMID- 27463162 TI - Physical Activity for Patients Wearing Spinal Orthoses. AB - In brief: If idiopathic scoliosis and Scheuermann's kyphosis are diagnosed while a patient still has significant growth remaining, spinal bracing may be necessary to prevent progression of the deformity. Noncompliance to a brace-wearing regimen is a major impediment to effective treatment. At the Children's Rehabilitation Center a special program to help patients through the initial adjustment period starts with a three-to five-day inpatient stay. The program has achieved a 78% compliance record for kyphosis patients and 95% compliance for scoliosis patients. PMID- 27463163 TI - Menstrual Abnormalities, Nutritional Patterns, and Body Composition in Female Classical Ballet Dancers. AB - In brief: Classical ballet is a demanding discipline that until recently has been largely ignored by the medical and exercise communities. The authors studied the nutritional habits of 34 high-level classical ballet dancers during three days of a typical rehearsal week and found that they consumed only 71.6% of the recommended daily allowance for nutrients. Their average percent body fat was 16.9%. Many (17) had menstrual abnormalities, 15 had secondary amenorrhea, and 11 cited irregularities they felt were directly due to dancing. No statistical correlation could be found between the reported menstrual abnormalities and percent body fat or the age they began training. PMID- 27463164 TI - Modifications for Enhanced Data Collection and Analysis With the Cybex Isokinetic Dynamometer. AB - In brief: Two modifications of the standard Cybex II isokinetic dynamometry system permit a more complete evaluation of muscular strength, endurance, and power output, while minimizing manual data analysis. The addition of an X-Y plotter to the Cybex system provides a graphic display that combines torque and joint position on a single graph. Strength data need not be limited to "peak torque" values, because the plotter permits muscular torque output to be analyzed bilaterally through the full range of motion without the need for manually transposing data from strip-chart records. The second modification is a dual channel reciprocal work integration system that separately measures the muscular work output performed in each rotational direction of joint movement. This allows individual assessments of endurance or power output for each muscle group of a reciprocal pair in a bout of continuous reciprocal exercise. PMID- 27463165 TI - Sports Anemia: A Review of the Current Research Literature. AB - In brief: A small percentage of athletes are anemic, and a substantial number have hemoglobin concentrations that are less than optimal for endurance performance. Possible causes of sports anemia are plasma volume expansion, reduced hemoglobin synthesis and/or erythropoiesis, and increased destruction of RBCs. Physicians should screen athletes for anemia, suboptimal hemoglobin, and the factors that apparently increase the risk of these conditions: (1) a diet that is low in iron, protein, vitamin C, vitamin B12, and/or folic acid; (2) high rates of iron loss; and (3) very intense training, especially at the outset of an exercise program. Treatment depends on the cause but may include iron supplementation and training modifications. PMID- 27463166 TI - Interseason Training and Aerobic Fitness of Motocross Racers. AB - In brief: The excellent endurance capacities of ten members of the Finnish motocross team, studied before and after a three-month program stressing endurance and strength, showed further improvement with intense training. Before the program they had 12.2% body fat and maximal oxygen consumption of 64.7 ml. kg(-1). min(-1) during bicycle ergometry. After the program, fat decreased 7.7%, weight decreased insignificantly, VO2 max increased 12.4%, and anaerobic thresholds (AT) increased 21%, averaging 37.3 ml. kg(-1). min(-1) (56.1% of VO(2) max). Heart rates at the AT increased 11.7%. Most physiological variables improved more at the AT than at maximum. PMID- 27463167 TI - The 'Isolated' Posterior Cruciate Ligament Injury. AB - In brief: This case report describes the mechanism of injury of an isolated posterior cruciate ligament tear. This injury was videotaped during a soccer game and was followed by an immediate physical examination and surgical and arthroscopic documentation of the isolated avulsion. Three other cases supported the videotaped mechanism of injury. The athlete was injured as he received a violent blow to the anterior surface of the tibia during knee flexion while attempting to slide-tackle an opponent. PMID- 27463168 TI - The Hand and Foot in the Cold. AB - In brief: Physiological and physical methods were used to study the effects of chilling on the hands and feet and to compare various mittens and footwear. The woolen liner-leather shell mitten is effective protection for the hands, and the woolen sock-felt liner-shoepac combination was good for protecting the feet. Direct contact with the ground greatly increases heat loss, so the thickness of the sole is important. Superficial rewarming of the hand will stimulate blood flow to it, but blood flow will not return to the foot unless the whole body is sufficiently warm. Therefore, torso protection is as important as extremity protection for long exposures. PMID- 27463169 TI - Allan Levy: Loyalty to the Athlete. AB - New York Giants team physician Allan Levy places the welfare of the injured athlete ahead of the coach's desire to win. PMID- 27463170 TI - Exercise Rehabilitation for Special Populations. PMID- 27463171 TI - Grand Old Ski Lodges of the East and West. AB - Harken back to the luxury of the 1930s and ski to your heart's content in Oregon, California, Idaho, and upstate New York. PMID- 27463172 TI - Knee Injuries in Athletes. PMID- 27463173 TI - Patellofemoral Rehabilitation. PMID- 27463175 TI - Home Aerobic Exercise Programs. PMID- 27463190 TI - Shortened Activated Partial Thromboplastin Time May Help in Diagnosing Hereditary and Acquired Angioedema. AB - OBJECTIVE: To evaluate whether activated partial thromboplastin time (APTT) could be used in the laboratory diagnosis of hereditary or acquired angioedema (HAE or AAE) with and without C1 inhibitor (C1-INH) deficiency. METHODS: In a prospective investigation, APTT and other coagulation parameters were determined in 149 adult patients with various types of angioedema and in 26 healthy participants (HP). RESULTS: Mean APTT was significantly shortened in HAE-C1-INH type I (p < 0.0001) and type II (p = 0.0017) and in AAE-C1-INH (p < 0.0001) compared to the HP. APTT was shortened under the reference range (26-36 s) in 33/45 (73.3%) patients with HAE-C1-INH, 10/15 (66.7%) patients with AAE-C1-INH, 4/27 (14.8%) patients with HAE with normal C1-INH, 1/32 (3.1%) patients with histaminergic angioedema, 4/30 (13.3%) patients with nonhistaminergic angioedema and in 2/26 (7.7%) HP. Thus, a shortened APTT was obtained in 8-9 times more patients with angioedema due to C1 INH deficiency when compared to patients with various forms of angioedema with normal C1-INH and also to HP. CONCLUSIONS: A shortened APTT may help to diagnose HAE-C1-INH and AAE-C1-INH when determination of C1-INH is not yet available. PMID- 27463191 TI - Loss of Renal Tubular PGC-1alpha Exacerbates Diet-Induced Renal Steatosis and Age Related Urinary Sodium Excretion in Mice. AB - The kidney has a high energy demand and is dependent on oxidative metabolism for ATP production. Accordingly, the kidney is rich in mitochondria, and mitochondrial dysfunction is a common denominator for several renal diseases. While the mitochondrial master regulator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is highly expressed in kidney, its role in renal physiology is so far unclear. Here we show that PGC-1alpha is a transcriptional regulator of mitochondrial metabolic pathways in the kidney. Moreover, we demonstrate that mice with an inducible nephron-specific inactivation of PGC-1alpha in the kidney display elevated urinary sodium excretion, exacerbated renal steatosis during metabolic stress but normal blood pressure regulation. Overall, PGC-1alpha seems largely dispensable for basal renal physiology. However, the role of PGC-1alpha in renal mitochondrial biogenesis indicates that activation of PGC-1alpha in the context of renal disorders could be a valid therapeutic strategy to ameliorate renal mitochondrial dysfunction. PMID- 27463193 TI - Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization. AB - Bioisosteric replacement and scaffold hopping are twin methods used in drug design to improve the synthetic accessibility, potency and drug like properties of a compound and to move into novel chemical space. Bioisosteric replacement involves swapping functional groups of a molecule with other functional groups that have similar biological properties. Scaffold hopping is the replacement of the core framework of a molecule with another scaffold that will improve the properties of the molecule or to find similar potent compounds that exist in novel chemical space. This review outlines the key concepts, importance and challenges of both methods using examples and comparisons of techniques available for finding bioisosteric replacements and scaffold hops. There are many methods available for bioisosteric replacement and scaffold hopping, all with their own advantages and disadvantages. Drug design projects would benefit from a combination of these methods to retrieve diverse and complimentary results. Continuing progress in these fields will allow further validation of both methods as well as the accumulation of knowledge on bioisosteres and possible scaffold replacements. PMID- 27463192 TI - Erythropoietin as an adjunctive treatment for methanol-induced toxic optic neuropathy. AB - BACKGROUND: Methanol-induced optic neuropathy (MTON) is frequently seen in countries where alcohol consumption is banned or poorly regulated. MTON frequently results in blindness and there is no empirically validated treatment. OBJECTIVE: To evaluate the effect of erythropoietin (EPO) as an adjunctive treatment for MTON. METHODS: In this nonrandomized interventional comparative study, all participants were diagnosed with MTON and received the steroid methylprednisolone. Eleven participants received intravenous EPO (10000 IU twice a day) for three days as an adjuvant to methylprednisolone (EPO group); 11 participants in a historical control group received methylprednisolone only (control group). Main outcomes were best-corrected visual acuity (BCVA), peripapillary retinal nerve fiber layer thickness (PRNFLT), and visual field mean deviation (MD). RESULTS: Mean BCVA improved significantly in both groups: from 2.93 +/- 0.55 to 1.75 +/- 1.16 LogMAR at month 3 (p < 0.001) in the EPO group, and from 2.65 +/- 0.68 to 2.19 +/- 0.75 at final visit in the control group (p = 0.001). The final BCVA was significantly better in the EPO group (p = 0.012). The mean PRNFLT decreased in both groups. However, at the final follow-up, PRNFLT was significantly thinner in the control group (53 +/- 6 vs. 77 +/- 26 microns, respectively; p < 0.001). CONCLUSION: Intravenous EPO plus high-dose intravenous steroid may be an effective combination therapy for the patients with MTON. PMID- 27463194 TI - How to Deal with Batch Effect in Sequential Microarray Experiments? PMID- 27463195 TI - Application of Random Forest and Multiple Linear Regression Techniques to QSPR Prediction of an Aqueous Solubility for Military Compounds. AB - The relationship between the aqueous solubility of more than two thousand eight hundred organic compounds and their structures was investigated using a QSPR approach based on Simplex Representation of Molecular Structure (SiRMS). The dataset consists of 2537 diverse organic compounds. Multiple Linear Regression (MLR) and Random Forest (RF) methods were used for statistical modeling at the 2D level of representation of molecular structure. Statistical characteristics of the best models are quite good (MLR method: R(2) =0.85, Q(2) =0.83; RF method: R(2) =0.99, R(2) oob =0.88). The external validation set of 301 compounds (including 47 nitro-, nitroso- and nitrogen-rich compounds of military interest) which were not included in the training set and modeling process, was used for evaluation of the models predictivity. Thus, well-fitted and robust (R(2) test (MLR)=0.76 and R(2) test (RF)=0.82) models were obtained for both statistical techniques using descriptors based on the topological structural information only. The predicted solubility values for military compounds are in good agreement with experimental ones. Developed QSPR models represent powerful and easy-to-use virtual screening tool that can be recommended for prediction of aqueous solubility. PMID- 27463196 TI - Identifying Novel Type ZBGs and Nonhydroxamate HDAC Inhibitors Through a SVM Based Virtual Screening Approach. AB - Histone deacetylase inhibitors (HDACi) have been successfully used for the treatment of cancers and other diseases. Search for novel type ZBGs and development of non-hydroxamate HDACi has become a focus in current research. To complement this, it is desirable to explore a virtual screening (VS) tool capable of identifying different types of potential inhibitors from large compound libraries with high yields and low false-hit rates similar to HTS. This work explored the use of support vector machines (SVM) combined with our newly developed putative non-inhibitor generation method as such a tool. SVM trained by 702 pre-2008 hydroxamate HDACi and 64334 putative non-HDACi showed good yields and low false-hit rates in cross-validation test and independent test using 220 diverse types of HDACi reported since 2008. The SVM hit rates in scanning 13.56 M PubChem and 168K MDDR compounds are comparable to HTS rates. Further structural analysis of SVM virtual hits suggests its potential for identification of non hydroxamate HDACi. From this analysis, a series of novel ZBG and cap groups were proposed for HDACi design. PMID- 27463197 TI - 'tieredScreen' - Layered Virtual Screening Tool for the Identification of Novel Estrogen Receptor Alpha Modulators. AB - A novel tiered Structure-Based (SB) Virtual Screening (VS) workflow called tieredScreen was designed and implemented. The automated protocol utilises diverse computational tools in a synergistic manner to reduce false positives and increase the likelihood of converging on putative active molecules. The performance of the novel VS workflow was validated using the Directory of Useful Decoys (DUD) Estrogen Receptor alpha (ERalpha) antagonist dataset, and successfully deployed for the identification of novel antagonists of ERalpha from a screening collection of ca. 160 000 commercially available compounds. As well as yielding nanomolar (nM) active ligands identified previously through a docking only protocol, from a selection of eight virtual hits suggested by tieredScreen, four novel nM ERalpha binding chemotypes were identified and biologically validated - demonstrating the applicability of a tiered intervention for virtual screening. PMID- 27463198 TI - Iterative Shannon Entropy - a Methodology to Quantify the Information Content of Value Range Dependent Data Distributions. Application to Descriptor and Compound Selectivity Profiling. AB - We introduce an entropy-based methodology, Iterative Shannon entropy (ISE), to quantify the information contained in molecular descriptors and compound selectivity data sets taking data spread directly into account. The method is applicable to determine the information content of any value range dependent data distribution. An analysis of descriptor information content has been carried out to explore alternative binning schemes for entropy calculation. Using this entropic measure we have profiled 153 compound selectivity data sets for combinations of 68 target proteins belonging to 10 target families. With the ISE measure, we aim to assign high information content to compound data sets that span a wide range of selectivity values and different selectivity relationships and hence correspond to more than one biological phenotype. Target families with high average entropy scores are identified. For members of these families, active compounds display highly differentiated selectivity profiles. PMID- 27463199 TI - Probabilistic Modeling of Conformational Space for 3D Machine Learning Approaches. AB - We present a new probabilistic encoding of the conformational space of a molecule that allows for the integration into common similarity calculations. The method uses distance profiles of flexible atom-pairs and computes generative models that describe the distance distribution in the conformational space. The generative models permit the use of probabilistic kernel functions and, therefore, our approach can be used to extend existing 3D molecular kernel functions, as applied in support vector machines, to build QSAR models. The resulting kernels are valid 4D kernel functions and reduce the dependency of the model quality on suitable conformations of the molecules. We showed in several experiments the robust performance of the 4D kernel function, which was extended by our approach, in comparison to the original 3D-based kernel function. The new method compares the conformational space of two molecules within one kernel evaluation. Hence, the number of kernel evaluations is significantly reduced in comparison to common kernel-based conformational space averaging techniques. Additionally, the performance gain of the extended model correlates with the flexibility of the data set and enables an a priori estimation of the model improvement. PMID- 27463200 TI - Prevention and Treatment of Cancer in India. PMID- 27463201 TI - High-grade Dysplasia in Anogenital Warts of HIV-Positive Men. AB - Importance: Human papillomavirus (HPV)-induced anogenital lesions are very frequent in men who have sex with men (MSM) who are HIV-positive (HIV+). Anogenital warts (AGWs) are considered benign lesions caused by low-risk HPV types, whereas anogenital dysplasias are potential cancer precursors associated with high-risk HPV-types. Both types of lesions can usually be distinguished clinically. Objective: To describe a case series of HIV+ MSM with typical AGW that harbored different grades of dysplasia. Design, Setting, and Participants: For this retrospective virological analysis, we recruited 25 HIV+ MSM with AGWs (n = 38) harboring areas of dysplasia and 22 patients who were HIV-negative (HIV ) with AGWs seen between February 2013 and March 2015 at a tertiary dermatological referral center for anal cancer screening. Dysplasia-containing AGW tissue of HIV+ MSM were compared with randomly selected AGWs of patients who were HIV-. Main Outcomes and Measures: Histopathological analysis, immunohistochemical staining for p16INK4a and Ki67, HPV-typing, and viral load determination in AGWs of HIV+ compared with patients who were HIV-. Results: Overall, 25 HIV+ MSM with AGWs (mean [SD] age, 47.3 [11.1] years) harboring areas of dysplasia and 22 patients who were HIV- (5 women, 17 men; mean [SD] age, 35.5 [12.8] years) with AGWs were included in this study. The 38 dysplasia-containing AGWs of HIV+ MSM harbored low-grade dysplasia in 6 cases (16%), high-grade dysplasia in 31 cases (81%), and areas of invasive anal carcinoma in 1 (3%) case. With the exception of 1 biopsy, all low-grade lesions were p16INK4a-negative, whereas 25 of 31 (81%) AGWs with high-grade lesions or an anal carcinoma were p16INK4a-positive. Only low-risk HPV-types were present in 11 samples (29%; 2 low grade lesions and 9 high-grade lesions), low-risk and high-risk types were found in 19 samples (50%; 1 low-grade lesion and 18 high-grade lesions), and only high risk HPV-types were present in 8 samples (21%; 3 low-grade lesions, 4 high-grade lesion, and 1 cancer-containing lesion). High low-risk HPV DNA loads were found in low-grade and high-grade lesions, while high high-risk HPV DNA loads were only found in AGWs harboring high-grade lesions. The 22 AGWs of patients who were HIV- showed no signs of dysplasia, and p16INK4a-staining was always negative. All of these samples carried low-risk HPV types, and in 2 cases high-risk HPV-types were detected additionally. Conclusions and Relevance: In contrast to immunocompetent patients, AGWs of HIV+ MSM may harbor high-grade dysplasia or even invasive squamous cell carcinoma. A substantial proportion of theses lesions may only contain low-risk HPV-types. Anogenital warts in patients who are HIV+ should be evaluated histopathologically to exclude cancer precursors. PMID- 27463202 TI - Dual-Triggered and Thermally Reconfigurable Shape Memory Graphene-Vitrimer Composites. AB - Conventional thermoset shape memory polymers can maintain a stable permanent shape, but the intrinsically chemical cross-linking leads to shape that cannot be altered. In this paper, we prepared shape memory graphene-vitrimer composites whose shape can be randomly changed via dynamic covalent transesterification reaction. Consecutive shape memory cycles indicate stable shape memory with undetected strain shift and constant shape fixity and recovery values (Rf > 99%, Rr > 98%). Quantitative characterization of shape reconfiguration by dynamic mechanical thermal analysis (DMA) shows prime reconfigurable behavior with shape retention ratio of 100%. Thus, the arbitrary 2D or 3D newly permanent shape can be easily obtained from a simple plain sample by facile thermal treatment at 200 degrees C above transesterification temperature (Tv). Besides, it is found that graphene-vitrimers show a ductile fracture in tensile test with a large breaking strain and classical yield phenomenon because of the well-dispersed graphene sheets in the vitrimer that endow effective stress transfer. As the graphene loading increases from 0% to 1%, the yield strength and breaking stain increase from 12.0 MPa and 6% to 22.9 MPa and 44%, respectively. In addition, graphene also serves as energy convertor to convert near-infrared (NIR) irradiation into thermal energy to induce a helix shape sample that is recovered totally within 80 s sequent NIR irradiation. These dual-triggered and reconfigurable shape memory graphene-vitrimers are expected to significantly simplify processing of complex shape and broaden the applications of shape memory polymers. PMID- 27463204 TI - 2-Chlorodeoxyadenosine (2-CdA): A Potent Chemotherapeutic and Immunosuppressive Nucleoside. AB - Hereditary adenosine deaminase deficiency results in failure of the lymphocyte development. This occurs because of the accumulation of deoxyadenine nucleotides in cells with high deoxycytidine kinase and low 5'-nucleotidase activity. 2 Chlorodeoxyadenosine (2-CdA) resists the action of adenosine deaminase and accumulates in cells with high deoxycytidine kinase and low 5'-nucleotidase activity. It is equally toxic to dividing and nondividing cells and may act by preventing repair of DNA single-strand breaks. In doses of 0.1 mg/kg/day given for seven days 2-CdA manifests low toxicity. It has been found to be effective in the treatment of patients with lymphoid neoplasms, including advanced cutaneous T cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin lymphomas, and hairy cell leukemia. In the latter disorder it appears to be as or more effective than the tight-binding adenosine deaminase inhibitor, deoxycoformycin, and is probably less toxic. 2-CdA also appears to be effective in controlling autoimmune hemolytic anemia and shows promise in the treatment of other autoimmune diseases. PMID- 27463205 TI - Detection of Immunoglobulin Gene Rearrangement in B Cell Neoplasias by Polymerase Chain Reaction Gene Amplification. PMID- 27463203 TI - New Insights into the Enterococcus faecium and Streptococcus gallolyticus subsp. gallolyticus Host Interaction Mechanisms. AB - Enterococcus faecium and Streptococcus gallolyticus subsp. gallolyticus (S. gallolyticus) were classically clustered into the Lancefield Group D streptococci and despite their taxonomic reclassification still share a similar genetic content and environment. Both species are considered as opportunistic pathogens. E. faecium is often associated with nosocomial bacteraemia, and S. gallolyticus is sporadically found in endocarditis of colorectal cancer patients. In both cases, the source of infection is commonly endogenous with a translocation process that launches through the intestinal barrier. To get new insights into the pathological processes preceding infection development of both organisms, we used an in vitro model with Caco-2 cells to study and compare the adhesion, invasion and translocation inherent abilities of 6 E. faecium and 4 S. gallolyticus well-characterized isolates. Additionally, biofilm formation on polystyrene, collagen I and IV was also explored. Overall results showed that E. faecium translocated more efficiently than S. gallolyticus, inducing a destabilization of the intestinal monolayer. Isolates Efm106, Efm121 and Efm113 (p < .001 compared to Ef222) exhibited the higher translocation ability and were able to adhere 2-3 times higher than S. gallolyticus isolates. Both species preferred the collagen IV coated surfaces to form biofilm but the S. gallolyticus structures were more compact (p = .01). These results may support a relationship between biofilm formation and vegetation establishment in S. gallolyticus endocarditis, whereas the high translocation ability of E. faecium high-risk clones might partially explain the increasing number of bacteraemia. PMID- 27463206 TI - Demonstrated Benefit of Continuous Interferon-Alpha-2b Therapy in Hairy Cell Leukemia. A Two-Year Follow-Up. AB - Interferon-alpha-2b (IFN) was given to a series of 50 patients with hairy cell leukemia (HCL). The IFN dose for both induction and maintenance was 2.0 * 10(6) IU/m(2) s.c. three times weekly. At 24 months 38 patients remained in the study. The proportion of complete responders (CR) increased during the follow-up, and had at 24 months reached 58%, while 28% at the same time had a partial (PR) and 14% a minor response (MR). During the two years of continuous IFN treatment none of the 38 patients showed any signs of relapse. The response rate was similar between splenectomized (n = 15) and non-splenectomized (n = 23) patients, but the rise in platelets was much steeper and reached a significantly higher plateau in patients, who previously had undergone splenectomy. The IFN therapy was generally well tolerated, but when evaluated at 24 months at least some (mostly mild) toxicity was noted in 76% of the patients. None of the patients developed neutralizing antibodies to IFN. PMID- 27463207 TI - Cost-Effectiveness Analysis of Induction Regimens Containing Anthracyclines in Adult Acute Myelogenous Leukemia. AB - A cost-effectiveness analysis was performed to evaluate the impact on hospital costs of two alternative regimens, idarubicin + cytarabine and daunorubicin + cytarabine, in the induction treatment of newly-diagnosed patients with acute myeloid leukemia (AML). In evaluating the economic effects the perspectives of both hospital doctors and administrators were taken into account in order to achieve better value for money spent. For this study, the comparative results from four recently published randomized clinical studies were used as the source of clinical data. Data on the duration of hospitalization, hospital procedures and AML treatment costs were obtained from the patient records of two haematological centers. The idarubicin induction regimen appeared to be more cost effective than that of daunorubicin in achieving complete remission, especially when costs are linked to response rate. Although several methodological issues in terms of economic evaluation still need to be solved, this type of study might offer a social contribution to the problem of the efficient allocation of resources in the health care sector. PMID- 27463208 TI - Autologous Unpurged Bone Marrow Transplantation for Acute Non Lymphoblastic Leukemia in First Remission. AB - Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL) in first complete remission, underwent autologous bone marrow transplantation (ABMT) between March 1984 and April 1990. The conditioning regimen employed included cyclophosphamide and total body irradiation, followed by the administration of unpurged ABMT. The median time from diagnosis to transplant was 7 months (3-15 months), and the median time from complete remission to ABMT was 4 months (range 3-9 months). Twenty-two (51%) patients remain in complete remission 6-81 months (median 24 months) after ABMT. The causes of death were, recurrent leukemia (11 patients), parenchymal toxicities such as acute respiratory distress syndrome and veno-occlusive disease (3 patients), hemorrhage (2 patients) and infection (2 patients). Eleven patients relapsed after 3-12 months (median 5 months). This study has produced survival data comparable to those of other institutions employing TBI for either allo or autotransplants. PMID- 27463209 TI - Heterogeneity of CD5 Membrane Expression on B-Chronic Lymphocytic Leukemia Cells. AB - The CD5 antigen has been used to characterize the typical B-chronic lymphocytic leukemia B cell. CD5 antigen while found on mature T cells is also frequently found on malignant clonal B cells in B-CLL. We have sequentially evaluated the presence of CD5 antigen on a group of B-CLL cells using flow cytometry. Purified peripheral blood B cells from B-CLL patients were studied for the presence of both CD19 and CD5. This approach insured that the presence of CD5 antigen was only assessed on CD19 positive B cells. Our data suggests that there is considerable heterogeneity for presentation of CD5 antigen in clonal B cells in this disease. We define 3 B cell groups based on the presentation of CD5; low CD5, intermediate CD5 and high CD5 antigen positive B cells. In addition sequential analysis over several months of study indicates that the CD5 antigen is consistently present on these clonal B cells. Low CD5 B cells appear to have an excess of kappa phenotype. In conclusion CD5 antigen may be considerably more heterogeneous on clonal CLL B cells than previously thought. This variable presentation of CD5 antigen on CLL B cell clones needs to be considered in the assessment and characterization of B-CLL. PMID- 27463210 TI - Detection of Minimal Residual Disease in Adult Acute Lymphoblastic Leukemia by Analysis of Gene Rearrangements and Correlation with Early Relapses. AB - While more than 75% of the adult patients with acute lymphoblastic leukemia (ALL) achieve a complete remission after treatment with intensive chemotherapy, about 40% of them relapse within five years. These relapses are probably due to residual leukemic cells. Gene rearrangements are used as markers of clonality and thereby monoclonal leukemic lymphoid cells can be detected with high sensitivity. In this study, we have applied the analysis of gene rearrangements to detect minimal residual disease in patients considered to be in complete remission. Serial bone marrow samples were studied in 35 patients before and four weeks after initiation of a standardized induction chemotherapy. Gene probes for the joining regions of the human immunoglobulin heavy chain and the constant regions of the human T-cell receptor beta-chain were used. In five of the 35 patients, the same gene rearrangements found before therapy persisted and indicated residual disease. Four of them relapsed within a median time of 10 weeks. Six of the 30 other patients without detectable gene rearrangements after induction therapy also relapsed, but median time to relapse was 30 weeks. Two of them had a relapse in the central nervous system without detectable bone marrow infiltration. Our data suggest that minimal residual disease, detected by analysis of gene rearrangements, is associated with a high early relapse rate. Analysis of gene rearrangements at the time of assessing the response to primary therapy seems to be of prognostic value in ALL and may contribute to a stratification of further therapy. PMID- 27463211 TI - Two Translocations: a Follicular Variant 2; 18 and a Burkitt 8;14 in a Small Non Cleaved Non Hodgkin's Lymphoma. AB - The t(2;18)(p11;q21) has recently been described in two lymphoma cases as a variant of the t(14;18)(q32;q21) typical chromosome translocation in follicular lymphomas. Molecular investigations of t(2;18) confirmed juxtaposition of the bcl 2 gene to the immunoglobulin kappa (Igk) locus and described a new break point region on 18q21 found also in the recently reported, second follicular variant translocation (18;22)(q21;q11). Thus, cytogenetic and molecular studies established the same mechanism of (onco)gene activation by the heavy or light Ig gene in follicular lymphomas and Burkitt lymphomas. We describe a case of small non cleaved non Hodgkin's lymphoma in which translocation (2;18) coexisted with a typical (8;14) Burkitt translocation. Absent HLA-DR expression by the tumour cells was noted in this case. The possible implications of the cytogenetic and immunologic findings are discussed. PMID- 27463212 TI - Acute Intravascular Haemolysis Associated with High Dose Immunoglobulin after Bone Marrow Transplantation for Acute Myelogenous Leukemia. AB - A 12-year-old boy developed persistent thrombocytopenia after undergoing bone marrow transplantation for acute myelogenous leukemia. High doses of intravenous immunoglobulins were used to treat overt hemorrhage and a sudden intravascular hemolysis occurred. The serologic findings point to an acute hemolysis secondary to the presence of isohemoagglutinins in the intravenous immunoglobulin preparations. PMID- 27463213 TI - Teaching Cases from the Royal Marsden Hospital Case 2: a young man with bruising. PMID- 27463214 TI - Next-generation polyploid phylogenetics: rapid resolution of hybrid polyploid complexes using PacBio single-molecule sequencing. AB - Difficulties in generating nuclear data for polyploids have impeded phylogenetic study of these groups. We describe a high-throughput protocol and an associated bioinformatics pipeline (Pipeline for Untangling Reticulate Complexes (Purc)) that is able to generate these data quickly and conveniently, and demonstrate its efficacy on accessions from the fern family Cystopteridaceae. We conclude with a demonstration of the downstream utility of these data by inferring a multi labeled species tree for a subset of our accessions. We amplified four c. 1-kb long nuclear loci and sequenced them in a parallel-tagged amplicon sequencing approach using the PacBio platform. Purc infers the final sequences from the raw reads via an iterative approach that corrects PCR and sequencing errors and removes PCR-mediated recombinant sequences (chimeras). We generated data for all gene copies (homeologs, paralogs, and segregating alleles) present in each of three sets of 50 mostly polyploid accessions, for four loci, in three PacBio runs (one run per set). From the raw sequencing reads, Purc was able to accurately infer the underlying sequences. This approach makes it easy and economical to study the phylogenetics of polyploids, and, in conjunction with recent analytical advances, facilitates investigation of broad patterns of polyploid evolution. PMID- 27463215 TI - Evaluation of patients with refractory chronic inflammatory demyelinating polyneuropathy. AB - INTRODUCTION: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a common treatable neuropathy, however, nearly 20% of patients remain refractory to standard therapy for unclear reasons. METHODS: We did a retrospective review of 37 patients referred for CIDP refractory to intravenous immunoglobulin (IVIg), plasmapheresis, and/or corticosteroids. Clinical findings, electrophysiological studies, and response to further therapeutic interventions were assessed. RESULTS: Forty-six percent of patients had CIDP, while 54% had alternate diagnoses. Of patients with confirmed CIDP, 87% showed improvement with escalation of therapy. Distal leg weakness, vibratory sensory loss, and widespread areflexia were significantly more common in patients with confirmed CIDP. CONCLUSIONS: Reasons for therapeutic failure in CIDP are inadequate immunotherapy and alternative diagnoses. Certain clinical and electrophysiological features help to distinguish true CIDP from mimics. Once CIDP is confirmed, optimization of IVIg dosing, addition of corticosteroids, plasmapheresis, or chemotherapy results in consistent improvement. Caution is advised when using response to therapy to diagnose CIDP. Muscle Nerve 55: 476 482, 2017. PMID- 27463216 TI - Opsin gene repertoires in northern archaic hominids. AB - The Neanderthals' northern distribution, hunting techniques, and orbit breadths suggest that they were more active in dim light than modern humans. We surveyed visual opsin genes from four Neanderthals and two other archaic hominids to see if they provided additional support for this hypothesis. This analysis was motivated by the observation that alleles responsible for anomalous trichromacy in humans are more common in northern latitudes, by data suggesting that these variants might enhance vision in mesopic conditions, and by the observation that dim light active species often have fewer opsin genes than diurnal relatives. We also looked for evidence of convergent amino acid substitutions in Neanderthal opsins and orthologs from crepuscular or nocturnal species. The Altai Neanderthal, the Denisovan, and the Ust'-Ishim early modern human had opsin genes that encoded proteins identical to orthologs in the human reference genome. Opsins from the Vindija Cave Neanderthals (three females) had many nonsynonymous substitutions, including several predicted to influence colour vision (e.g., stop codons). However, the functional implications of these observations were difficult to assess, given that "control" loci, where no substitutions were expected, differed from humans to the same extent. This left unresolved the test for colour vision deficiencies in Vindija Cave Neanderthals. PMID- 27463217 TI - Yb9+xCuMg4-x (x = 0.034): A kappa-Phase Formed by Lanthanoids. AB - Atom order in the crystal structures of Yb2Cu2-xMg (x = 0.17; Mo2FeB2-type; P4/mbm; a = 0.75592(2) nm; c = 0.40282(1) nm) and Yb9+xCuMg4-x (x = 0.034; Hf9Mo4B-type; P63/mmc; a = 1.0169(5) nm; c = 1.0290(5) nm) was determined from powder and X-ray single-crystal counter data analyses supported by electron probe microanalyses. Among the group of the so-called kappa-phases, Yb9+xCuMg4-x is the first representative formed by a lanthanoid element. The structure of this kappa phase can be viewed as a typical network of corner-connected empty Yb6-octahedra, which encompass Yb6Mg6-icosahedra (filled by a mix of Mg/Yb atoms) and Yb6 trigonal prisms centered by Cu atoms to complete the three-dimensional metal framework. From another point of view, the same structure is considered as built from infinite polyicosahedral columns of Yb9Mg4 composition with Cu atoms located in trigonal prismatic interstices, highlighting similarities with other Yb-rich Yb-Cu-Mg phases. Density functional theory (DFT) calculations classify Yb9CuMg4 as a polar intermetallic. Metallic-like behavior is inferred from the Sommerfeld constant, gamma = 49.2 mJ/mol.K(2), derived from the electronic density of states, calculated at the Fermi level. DFT integration of the f-density of states indicates almost completely filled f-states, revealing 13.6 and 13.7 electrons in the valence band for Yb1 and Yb2 atoms, respectively, close to the Yb(2+) ground state ((1)S0) for both Yb atoms. Magnetic susceptibility data recorded on the same compound are consistent with a nonmagnetic divalent Yb(2+) state. Temperature-dependent heat capacity data display a metallic behavior characterized by a small Sommerfeld constant gamma = 64.8 mJ/mol.K(2) and a rather low Debye temperature ThetaD = 140 K as typical for soft materials. PMID- 27463218 TI - Global Proteome Response to Deletion of Genes Related to Mercury Methylation and Dissimilatory Metal Reduction Reveals Changes in Respiratory Metabolism in Geobacter sulfurreducens PCA. AB - Geobacter sulfurreducens PCA can reduce, sorb, and methylate mercury (Hg); however, the underlying biochemical mechanisms of these processes and interdependent metabolic pathways remain unknown. In this study, shotgun proteomics was used to compare global proteome profiles between wild-type G. sulfurreducens PCA and two mutant strains: a DeltahgcAB mutant, which is deficient in two genes known to be essential for Hg methylation and a DeltaomcBESTZ mutant, which is deficient in five outer membrane c-type cytochromes and thus impaired in its ability for dissimilatory metal ion reduction. We were able to delineate the global response of G. sulfurreducens PCA in both mutants and identify cellular networks and metabolic pathways that were affected by the loss of these genes. Deletion of hgcAB increased the relative abundances of proteins implicated in extracellular electron transfer, including most of the c-type cytochromes, PilA-C, and OmpB, and is consistent with a previously observed increase in Hg reduction in the DeltahgcAB mutant. Deletion of omcBESTZ was found to significantly increase relative abundances of various methyltransferases, suggesting that a loss of dissimilatory reduction capacity results in elevated activity among one-carbon (C1) metabolic pathways and thus increased methylation. We show that G. sulfurreducens PCA encodes only the folate branch of the acetyl-CoA pathway, and proteins associated with the folate branch were found at lower abundance in the DeltahgcAB mutant strain than the wild type. This observation supports the hypothesis that the function of HgcA and HgcB is linked to C1 metabolism through the folate branch of the acetyl-CoA pathway by providing methyl groups required for Hg methylation. PMID- 27463219 TI - Extrapontine myelinolysis associated with severe hypernatremia in infancy. AB - Extrapontine myelinolysis (EPM) is an uncommon disorder in children, with few pediatric cases reported to date. We report the first case of an infant with EPM without central pontine myelinolysis (CPM) presenting with severe hypernatremia. On admission, the infant had impaired consciousness, mild dehydration, and severe hypernatremia (190 mmol/L). The following day, the patient developed abnormal involuntary movements. Brain magnetic resonance imaging (MRI) confirmed EPM without CPM. He recovered without sequelae, and clinical examinations were within normal limits approximately 6 months after discharge. Brain MRI at 1 year after onset showed complete disappearance of the previous EPM regions. To the best of our knowledge, this represents the youngest patient with EPM without CPM presenting with severe hypernatremia. Given that treatment for osmotic demyelination syndrome (ODS) is yet to be established, preventing the development of ODS is crucial. PMID- 27463220 TI - A meta-analysis of the neuropsychological effects of chemotherapy in the treatment of childhood cancer. AB - BACKGROUND: Long-term neuropsychological deficits associated with pediatric cancers and the related treatments have been consistently reported. Whole brain cranial radiation therapy (CRT) is associated with neurocognitive impairment. As a result, physicians are reticent to use CRT in favor of systemic or intrathecal chemotherapy, which have a less clear impact on cognition. PROCEDURE: The current meta-analysis examined post-treatment neuropsychological performance of children diagnosed with cancer and treated with chemotherapy to better understand the impact of chemotherapy upon cognition. Relevant test scores from 18 empirical studies were utilized and analyzed in comparison to normative data yielding 199 unique effect sizes across nine neurocognitive domains. RESULTS: Children diagnosed with cancer, who received chemotherapy, demonstrated deficits in attentional capacity (g = -0.277). These deficits are noted in the context of relatively unaffected performance in other domains. When examining potential moderators, those tested more than 5 years after completion of treatment demonstrated better attentional performance than those tested within 5 years of treatment completion. CONCLUSIONS: These deficits in attentional capacity have implications related to the academic success of these children. Given the potential for remediation strategies within this domain, neuropsychological assessment can be an integral aspect of long-term care plans of survivors of childhood cancer. PMID- 27463221 TI - Ocular Penetration and Pharmacokinetics of Ripasudil Following Topical Administration to Rabbits. AB - PURPOSE: We evaluated the ocular pharmacokinetics of ripasudil (K-115), a selective Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, following topical administration to rabbits. METHODS: We determined the ocular distribution of [(14)C]ripasudil by whole-head autoradiography and the radioactivity of each ocular tissue after single and multiple instillation of [(14)C]ripasudil to pigmented rabbits. We also measured the aqueous humor concentrations after concomitant instillation of ripasudil and a combination agent (0.005% latanoprost and 0.5% timolol) to pigmented rabbits as well as the tear fluid concentrations after instillation into rabbits, dogs, and monkeys using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Membrane permeability was evaluated using an in vitro parallel artificial membrane permeability assay system and Ussing chamber with rabbit cornea and conjunctiva. RESULTS: [(14)C]Ripasudil was rapidly absorbed into the cornea and distributed throughout the eye after topical instillation. The melanin-containing ocular tissues, such as the iris-ciliary body and retina-choroid, showed much higher concentrations of radioactivity than the other nonpigmented tissues. Concomitant instillation showed minor effects on the aqueous humor concentrations of each compound in rabbits. Membrane permeability of ripasudil was higher than other glaucoma drugs in vitro and ex vivo. The aqueous humor concentrations of ripasudil in rabbits were higher than those in dogs and monkeys in the early period after instillation and associated with tear turnover rate. CONCLUSIONS: These results indicate favorable intraocular penetration characteristics of ripasudil following topical administration. PMID- 27463222 TI - Surface modification of SOI-FET sensors for label-free and specific detection of short RNA analyte. AB - AIM: A new type of surface modification of SOI-FET sensors with ultrathin sensor probe transition layer and uncharged probes for highly specific detection of short RNA (saRNA) was suggested. MATERIALS & METHODS: Carbonyldiimidazole (CDI) or glycidoxypropyltrimethoxysilane were used as precursors of sensor-probe interface layers, together with peptide nucleic acids and new NA analogues - phosphoryl guanidine oligo(2'-OMe)ribonucleotides (PGO) as probes for RNA hybridization. RNA sequences corresponding to mRNA NELFA (NM_005663) and microRNA 29a (cancer markers) were used as saRNA targets. Real-time saRNA detection by SOI FET sensors and fluorescence analysis were applied. RESULTS: Highly specific response with femtomolar sensitivity to saRNA was demonstrated for CDI-PGO modified sensors fabricated by optical lithography. CONCLUSION: The proposed CDI PGO protocol of modification of Si sensor surface is a promising procedure for biomedical applications. PMID- 27463223 TI - Activation, Impaired Tumor Necrosis Factor-alpha Production, and Deficiency of Circulating Mucosal-Associated Invariant T Cells in Patients with Scrub Typhus. AB - BACKGROUND: Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections. However, little is known about the role of MAIT cells in Orientia tsutsugamushi infection. Hence, the aims of this study were to examine the level and function of MAIT cells in patients with scrub typhus and to evaluate the clinical relevance of MAIT cell levels. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-eight patients with scrub typhus and 53 health control subjects were enrolled in the study. The patients were further divided into subgroups according to disease severity. MAIT cell level and function in the peripheral blood were measured by flow cytometry. Circulating MAIT cell levels were found to be significantly reduced in scrub typhus patients. MAIT cell deficiency reflects a variety of clinical conditions. In particular, MAT cell levels reflect disease severity. MAIT cells in scrub typhus patients displayed impaired tumor necrosis factor (TNF)-alpha production, which was restored during the remission phase. In addition, the impaired production of TNF alpha by MAIT cells was associated with elevated CD69 expression. CONCLUSIONS: This study shows that circulating MAIT cells are activated, numerically deficient, and functionally impaired in TNF-alpha production in patients with scrub typhus. These abnormalities possibly contribute to immune system dysregulation in scrub typhus infection. PMID- 27463224 TI - Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus. AB - Respiratory syncytial virus (RSV) is a significant cause of severe respiratory illness worldwide, particularly in infants, young children, and the elderly. Although no licensed vaccine is currently available, an engineered version of the metastable RSV fusion (F) surface glycoprotein-stabilized in the pre-fusion (pre F) conformation by "DS-Cav1" mutations-elicits high titer RSV-neutralizing responses. Moreover, pre-F-specific antibodies, often against the neutralization sensitive antigenic site O in the membrane-distal head region of trimeric F glycoprotein, comprise a substantial portion of the human response to natural RSV infection. To focus the vaccine-elicited response to antigenic site O, we designed a series of RSV F immunogens that comprised the membrane-distal head of the F glycoprotein in its pre-F conformation. These "head-only" immunogens formed monomers, dimers, and trimers. Antigenic analysis revealed that a majority of the 70 engineered head-only immunogens displayed reactivity to site O-targeting antibodies, which was similar to that of the parent RSV F DS-Cav1 trimers, often with increased thermostability. We evaluated four of these head-only immunogens in detail, probing their recognition by antibodies, their physical stability, structure, and immunogenicity. When tested in naive mice, a head-only trimer, half the size of the parent RSV F trimer, induced RSV titers, which were statistically comparable to those induced by DS-Cav1. When used to boost DS-Cav1 primed mice, two head-only RSV F immunogens, a dimer and a trimer, boosted RSV neutralizing titers to levels that were comparable to those boosted by DS-Cav1, although with higher site O-directed responses. Our results provide proof-of concept for the ability of the smaller head-only RSV F immunogens to focus the vaccine-elicited response to antigenic site O. Decent primary immunogenicity, enhanced physical stability, potential ease of manufacture, and potent immunogenicity upon boosting suggest these head-only RSV F immunogens, engineered to retain the pre-fusion conformation, may have advantages as candidate RSV vaccines. PMID- 27463225 TI - Synergistic interactions between temporal coupling of complex light and magnetic pulses upon melanoma cell proliferation and planarian regeneration. AB - Synergisms between a physiologically patterned magnetic field that is known to enhance planarian growth and suppress proliferation of malignant cells in culture and three light emitting diode (LED) generated visible wavelengths (blue, green, red) upon planarian regeneration and melanoma cell numbers were discerned. Five days of hourly exposures to either a physiologically patterned (2.5-5.0 MUT) magnetic field, one of three wavelengths (3 kLux) or both treatments simultaneously indicated that red light (680 nm), blue light (470 nm) or the magnetic field significantly facilitated regeneration of planarian compared to sham field exposed planarian. Presentation of both light and magnetic field conditions enhanced the effect. Whereas the blue and red light diminished the growth of malignant (melanoma) cells, the effect was not as large as that produced by the magnetic field. Only the paired presentation of the blue light and magnetic field enhanced the suppression. On the other hand, the changes following green light (540 nm) exposure did not differ from the control condition and green light presented with the magnetic field eliminated its effects for both the planarian and melanoma cells. These results indicate specific colors affect positive adaptation that is similar to weak, physiologically patterned frequency modulated (8-24 Hz) magnetic fields and that the two forms of energy can synergistically summate or cancel. PMID- 27463228 TI - Age, Comorbidity, Frailty in Observational and Analytic Studies of Neurological Diseases. AB - BACKGROUND: Comorbidities are rarely taken into account in studies of neurological conditions although they may be a confounder of the outcome and treatment. The relationship between comorbidities and neurological conditions is also problematic as comorbidities may be symptoms of the underlying cause of the neurologic condition or long-term adverse effects of the treatment. SUMMARY: There is evidence that several common neurological conditions have an increased burden of somatic and psychiatric comorbidities compared with matched samples from the general population. Depression is probably the most common comorbidity. Both psychiatric and somatic comorbidities have been shown to account for some of the premature mortality encountered in these neurological conditions. Comorbidities and age can also be important factors in the response and tolerance to treatment, and can alter the general outcome of a disease. KEY MESSAGES: Age and comorbidities should not be overlooked in the observation and assessment of neurological conditions and their treatment. PMID- 27463227 TI - Problematizing Social Justice in Health Pedagogy and Youth Sport: Intersectionality of Race, Ethnicity, and Class. AB - Social justice education recognizes the discrepancies in opportunities among disadvantaged groups in society. The purpose of the articles in this special topic on social justice is to (a) provide a critical reflection on issues of social justice within health pedagogy and youth sport of Black and ethnic minority (BME) young people; (b) provide a framework for the importance of intersectionality research (mainly the intersection of social class, race, and ethnicity) in youth sport and health pedagogy for social justice; and (c) contextualize the complex intersection and interplay of social issues (i.e., race, ethnicity, social classes) and their influence in shaping physical culture among young people with a BME background. The article argues that there are several social identities in any given pedagogical terrain that need to be heard and legitimized to avoid neglect and "othering." This article suggests that a resurgence of interest in theoretical frameworks such as intersectionality can provide an effective platform to legitimize "non-normative bodies" (diverse bodies) in health pedagogy and physical education and sport by voicing positionalities on agency and practice. PMID- 27463226 TI - Rabies Internalizes into Primary Peripheral Neurons via Clathrin Coated Pits and Requires Fusion at the Cell Body. AB - The single glycoprotein (G) of rabies virus (RABV) dictates all viral entry steps from receptor engagement to membrane fusion. To study the uptake of RABV into primary neuronal cells in culture, we generated a recombinant vesicular stomatitis virus in which the G protein was replaced with that of the neurotropic RABV CVS-11 strain (rVSV CVS G). Using microfluidic compartmentalized culture, we examined the uptake of single virions into the termini of primary neurons of the dorsal root ganglion and ventral spinal cord. By pharmacologically disrupting endocytosis at the distal neurites, we demonstrate that rVSV CVS G uptake and infection are dependent on dynamin. Imaging of single virion uptake with fluorescent endocytic markers further identifies endocytosis via clathrin-coated pits as the predominant internalization mechanism. Transmission electron micrographs also reveal the presence of viral particles in vesicular structures consistent with incompletely coated clathrin pits. This work extends our previous findings of clathrin-mediated uptake of RABV into epithelial cells to two neuronal subtypes involved in rabies infection in vivo. Chemical perturbation of endosomal acidification in the neurite or somal compartment further shows that establishment of infection requires pH-dependent fusion of virions at the cell body. These findings correlate infectivity to existing single particle evidence of long-range endosomal transport of RABV and clathrin dependent uptake at the plasma membrane. PMID- 27463229 TI - Elucidating the Role of Protandim and 6-Gingerol in Protection Against Osteoarthritis. AB - Protandim and 6-gingerol, two potent nutraceuticals, have been shown to decrease free radicals production through enhancing endogenous antioxidant enzymes. In this study, we evaluated the effects of these products on the expression of different factors involved in osteoarthritis (OA) process. Human OA chondrocytes were treated with 1 ng/ml IL-1beta in the presence or absence of protandim (0-10 MUg/ml) or 6-gingerol (0-10 MUM). OA was induced surgically in mice by destabilization of the medial meniscus (DMM). The animals were treated weekly with an intraarticular injection of 10 MUl of vehicle or protandim (10 MUg/ml) for 8 weeks. Sham-operated mice served as controls. In vitro, we demonstrated that protandim and 6-gingerol preserve cell viability and mitochondrial metabolism and prevented 4-hydroxynonenal (HNE)-induced cell mortality. They activated Nrf2 transcription factor, abolished IL-1beta-induced NO, PGE2 , MMP 13, and HNE production as well as IL-beta-induced GSTA4-4 down-regulation. Nrf2 overexpression reduced IL-1beta-induced HNE and MMP-13 as well as IL-1beta induced GSTA4-4 down-regulation. Nrf2 knockdown following siRNA transfection abolished protandim protection against oxidative stress and catabolism. The activation of MAPK and NF-kappaB by IL-1beta was not affected by 6-gingerol. In vivo, we observed that Nrf2 and GSTA4-4 expression was significantly lower in OA cartilage from humans and mice compared to normal controls. Interestingly, protandim administration reduced OA score in DMM mice. Altogether, our data indicate that protandim and 6-gingerol are essential in preserving cartilage and abolishing a number of factors known to be involved in OA pathogenesis. J. Cell. Biochem. 118: 1003-1013, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27463230 TI - Neutralization and Binding Profile of Monoclonal Antibodies Generated Against Influenza A H1N1 Viruses. AB - Monoclonal antibodies (MAbs) provide scope for the development of better therapeutics and diagnostic tools. Herein, we describe the binding and neutralization profile(s) for a panel of murine MAbs generated against influenza A H1N1 viruses elicited by immunization with pandemic H1 recombinant hemagglutinin (rHA)/whole virus or seasonal H1 rHA. Neutralizing MAbs, MA-2070 and MA-M, were obtained after pandemic A/California/07/2009 (H1N1) virus/rHA immunization(s). Both MAbs reacted specifically with rHA from A/California/07/2009 and A/England/195/2009 in ELISA. MA-2070 bound rHA of A/California/07/2009 with high affinity (KD = 51.36 +/- 9.20 nM) and exhibited potent in vitro neutralization (IC50 = 2.50 MUg/mL). MA-2070 bound within the stem domain of HA. MA-M exhibited both hemagglutination inhibition (HI, 1.50 MUg/mL) and in vitro neutralization (IC50 = 0.66 MUg/mL) activity against the pandemic A/California/07/2009 virus and showed higher binding affinity (KD = 9.80 +/- 0.67 nM) than MA-2070. MAb, MA-H generated against the seasonal A/Solomon Islands/03/2006 (H1N1) rHA binds within the head domain and bound the seasonal H1N1 (A/Solomon Islands/03/2006 and A/New Caledonia/20/1990) rHAs with high affinity (KD; 0.72-8.23 nM). MA-H showed high HI (2.50 MUg/mL) and in vitro neutralization (IC50 = 2.61 MUg/mL) activity against the A/Solomon Islands/03/2006 virus. All 3 MAbs failed to react in ELISA with rHA from various strains of H2N2, H3N2, H5N1, H7N9, and influenza virus B, suggesting their specificity for either pandemic or seasonal H1N1 influenza virus. The MAbs reported here may be useful in developing diagnostic assays. PMID- 27463231 TI - Detection of Healthcare-Related Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Transmission Events Using Combined Genetic and Phenotypic Epidemiology. AB - BACKGROUND: Since the year 2000 there has been a sharp increase in the prevalence of healthcare-related infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. However, the high community prevalence of ESBL producing E. coli isolates means that many E. coli typing techniques may not be suitable for detecting E. coli transmission events. Therefore, we investigated if High-throughput MultiLocus Sequence Typing (HiMLST) and/or Raman spectroscopy were suitable techniques for detecting recent E. coli transmission events. METHODS: This study was conducted from January until December 2010 at Erasmus University Medical Center, Rotterdam, the Netherlands. Isolates were typed using HiMLST and Raman spectroscopy. A genetic cluster was defined as two or more patients carrying identical isolates. We used predefined definitions for epidemiological relatedness to assess healthcare-related transmission. RESULTS: We included 194 patients; strains of 112 patients were typed using HiMLST and strains of 194 patients were typed using Raman spectroscopy. Raman spectroscopy identified 16 clusters while HiMLST identified 10 clusters. However, no healthcare-related transmission events were detected. When combining data from both typing techniques, we identified eight clusters (n = 34 patients), as well as 78 patients with a non-cluster isolate. However, we could not detect any healthcare-related transmission in these 8 clusters. CONCLUSIONS: Although clusters were genetically detected using HiMLST and Raman spectroscopy, no definite epidemiological relationships could be demonstrated which makes the possibility of healthcare-related transmission events highly unlikely. Our results suggest that typing of ESBL-producing E. coli using HiMLST and/or Raman spectroscopy is not helpful in detecting E. coli healthcare-related transmission events. PMID- 27463233 TI - An Efficient Low Storage and Memory Treatment of Gridded Interaction Fields for Simulations of Macromolecular Association. AB - Computer simulations of molecular systems often make use of regular rectangular grids with equidistant spacing to store information on their molecular interaction fields, e.g., electrostatic potential. These grids provide an easy way to store the data as they do not require any particular specification of the structure of the data. However, such grids may easily become large, and the storage and memory demands may become so high that calculations become infeasible. To overcome this problem, we show here how the data structure DT-Grid can be adapted and applied to efficiently represent macromolecular interaction grids by exploiting the nonuniformity of information on the grid; at the same time, this data structure ensures fast random data access. We demonstrate use of the DT-Grid data structure for potential of mean force and Brownian dynamics simulations of protein-surface binding and macromolecular association with the SDA software. We further demonstrate that the DT-Grid structure enables systems of large size, such as a viral capsid, and high resolution grids to be handled that are beyond current computational feasibility. PMID- 27463232 TI - The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation. AB - Mesenchymal stromal cells (MSCs) are a heterogeneous population, which contain several cell phenotypes: mesenchymal stem cells, progenitor cells, fibroblasts and other type of cells. Previously, we identified unique stem cells that we named multilineage-differentiating stress enduring (Muse) cells as one to several percent of MSCs of the bone marrow, adipose tissue and dermis. Among different cell populations in MSCs, Muse cells, positive for pluripotent surface marker SSEA-3, may represent cells responsible for pluripotent-like property of MSCs, since they express pluripotency genes, able to differentiated into triploblastic cells from a single cells and are self-renewable. MSCs release biologically active factors that have profound effects on local cellular dynamics. A thorough examination of MSC secretome seems essential for understanding the physiological functions exerted by these cells in our organism and also for rational cellular therapy design. In this setting, studies on secretome of Muse cells may shed light on pathways that are associated with their specific features. Our findings evidenced that secretomes of MSCs and Muse cells contain factors that regulate extracellular matrix remodeling, ox-redox activities and immune system. Muse cells appear to secrete factors that may preserve their stem cell features, allow survival under stress conditions and may contribute to their immunomodulation capacity. In detail, the proteins belonging to protein kinase A signaling, FXR/RXR activation and LXR/RXR activation pathways may play a role in regulation of Muse stem cell features. These last 2 pathways together with proteins associated with antigen presentation pathway and coagulation system may play a role in immunomodulation. PMID- 27463236 TI - Piecing together female extra-pair mate choice: females really do prefer more ornamented males. AB - Evolutionary biologists have long been fascinated by extravagant male traits that abound across the animal kingdom and yet convey no apparent benefits to survival. From isopods to elephants, from armaments to ornaments, researchers have spent decades studying male-male competition and female mate choice in an effort to understand the significance of these secondary sexual characteristics. Among socially monogamous species, a frequently proposed explanation for the existence of male ornaments is that they are indicators of male genetic quality subject to female extra-pair mate choice. However, despite over two decades of extensive research into extra-pair paternity (EPP), the evidence that females actually choose more ornamented extra-pair sires is surprisingly scant. Consequently, whether EPP and female choice have contributed to the evolution of male ornaments in socially monogamous species, and what fitness benefits (if any) they signal to females, remains unclear. Progress in this field has been hampered by the challenge of dissociating clear female choice for ornamentation from confounding factors. In this issue of Molecular Ecology, Whittingham & Dunn (2016) use an experimental approach in a bird species with very high rates of EPP to tease apart these correlative effects. In doing so, they demonstrate clearly that male ornamentation is subject to female extra-pair mate choice. Their findings further suggest that EPP can be adaptive for females, and represent an important step forward in validating the role of EPP as an evolutionary driver of ornamental elaboration in socially monogamous species. PMID- 27463234 TI - Efficacy of Exercise Interventions in Patients with Acute Leukemia: A Meta Analysis. AB - BACKGROUND: Decreased physical performance and impaired physiological and psychological fitness have been reported in patients with acute leukemia (AL). We performed a meta-analysis to assess the efficacy of exercise in patients with AL. METHODS: In this meta-analysis, the electronic databases MEDLINE, Embase, Cochrane, Web of Science, SPORTDiscus, CINAHL and PEDro were searched through November 2015. Three authors participated in the study selection, data extraction and quality assessment. The instrument used for quality assessment was derived from the Cochrane Handbook for Systematic Reviews of Interventions. Analyses were performed according to the recommendations of The Cochrane Collaboration using Review Manager 5.3. RESULTS: Nine trials (8 randomized controlled trials and 1 quasi-experimental design trial) with 314 AL participants were included in this meta-analysis. The pooled standardized mean differences between the exercise and control groups were 0.45 (95% confidence interval (CI): 0.09 to 0.80, P value = 0.01, P for heterogeneity = 0.23, I2 = 28%) for cardiorespiratory fitness and 0.67 (95% CI: 0.28 to 1.06, P value = 0.0007, P for heterogeneity = 0.14, I2 = 43%) for muscle strength. Based on the data for fatigue, anxiety, and depression, there were no significant differences in these parameters between the exercise and control groups. CONCLUSIONS: Exercise has beneficial effects on cardiorespiratory fitness, muscle strength and functional mobility; however, no significant improvements in fatigue, anxiety, depression or quality of life were observed. Further large-scale randomized trials are needed to assess the safety, feasibility and efficacy of exercise programs for AL patients. PMID- 27463235 TI - Proportion of Surgical Site Infections Occurring after Hospital Discharge: A Systematic Review. AB - BACKGROUND: Surgical site infection (SSI) is the most common type of healthcare associated infection, contributing to substantial annual morbidity, costs, and deaths. In the United States it is the number one reason for hospital re admission after surgery. Relatively little attention has been paid to the proportion of SSIs that occur after discharge. This paper systematically reviews two decades of publications to characterize better the proportion of SSIs that are identified after discharge and the need for better early detection and treatment. METHODS: A restricted systematic literature search was conducted in PubMed to identify English-language studies published after 1995 that include the occurrence of pre-discharge and post-discharge SSIs. The data abstracted were the date of publication, country of origin, procedure, study design, surveillance system, population size, follow-up rate, and SSI counts and proportions. Descriptive statistics and forest plots were used to characterize the data set, represent the overall proportion of SSIs occurring after discharge, and assess the heterogeneity of the studies. RESULTS: A total of 55 articles met the inclusion criteria, with data from 1,432,293 operations and 141,347 SSIs based on studies from 15 countries. The overall proportion of operations leading to SSI was 9.9%. Of the 141,347 infections, 84,984 (60.1%) appeared after discharge. The proportion of SSIs after discharge differed among studies, from 13.5 to 94.8, and was heterogeneous for all studies and for most individual surgery types. CONCLUSION: Post-discharge SSIs constitute the majority of these infections and pose a substantial disease burden for surgical patients globally and for different surgery types. Further examination is warranted to determine the methodologic and clinical factors moderating the proportion of post-discharge SSIs. PMID- 27463237 TI - Rapid adaptation to climate change. AB - In recent years, amid growing concerns that changing climate is affecting species distributions and ecosystems, predicting responses to rapid environmental change has become a major goal. In this issue, Franks and colleagues take a first step towards this objective (Franks et al. 2016). They examine genomewide signatures of selection in populations of Brassica rapa after a severe multiyear drought. Together with other authors, Franks had previously shown that flowering time was reduced after this particular drought and that the reduction was genetically encoded. Now, the authors have sequenced previously stored samples to compare allele frequencies before and after the drought and identify the loci with the most extreme shifts in frequencies. The loci they identify largely differ between populations, suggesting that different genetic variants may be responsible for reduction in flowering time in the two populations. PMID- 27463238 TI - Regulation of Autoimmunity by the Microbiome. AB - Intestinal microbes have profound effects on inflammatory autoimmunity in sites distant from the gut. The mechanisms whereby this happens are only now beginning to be understood and may include such diverse effects as innate stimulation of migrating immune cells and effects of circulating bacterial metabolites. Our studies add to this the demonstration that microbiota may provide a source of cross-reactive antigenic material that activates autoreactive lymphocytes within the gut environment. In a spontaneous model of autoimmune uveitis, T lymphocytes specific to a retinal autoantigen are activated through their specific antigen receptor in the gut and acquire the ability to fuel inflammatory autoimmunity in the eye. In view of the huge diversity of commensals, it is conceivable that they may provide surrogate antigens for activation of autoreactive lymphocytes(s) of other tissue specificities, and might therefore be involved in the etiology of autoimmune diseases more frequently than is currently appreciated. PMID- 27463240 TI - Primary care for persons with spinal cord injury - not a novel idea but still under-developed. AB - Primary care for persons with spinal cord injury (SCI) has long been recognized as an important issue. Over the last two decades, there has not been any consensus on its contents, pathway or delivery model. Despite the lack of attention on this issue, various health care organizations and settings have successfully developed their own version of primary care for persons with SCI. On the other hand, persons with SCI have also found different ways to obtain primary care through Family Physicians and specialists, often depending on the health care structure of their country. This has blurred the line between what is traditionally seen as primary vs. specialist care. The "medical home" model may be ideal for SCI primary care, and it may be establishsed in different care settings. In order to create this model, health care funding structure, appropriate access to physical facility and SCI knowledge, interdisciplinary provider availability and collaboration, as well as active engagement with persons with SCI are necessary. The SCI community should endorse SCI primary care with effective advocacy and implementation. PMID- 27463239 TI - Nutritional Supplement of Hatchery Eggshell Membrane Improves Poultry Performance and Provides Resistance against Endotoxin Stress. AB - Eggshells are significant part of hatchery waste which consist of calcium carbonate crust, membranes, and proteins and peptides of embryonic origins along with other entrapped contaminants including microbes. We hypothesized that using this product as a nutritional additive in poultry diet may confer better immunity to the chickens in the paradigm of mammalian milk that enhances immunity. Therefore, we investigated the effect of hatchery eggshell membranes (HESM) as a short term feed supplement on growth performance and immunity of chickens under bacterial lipopolysaccharide (LPS) challenged condition. Three studies were conducted to find the effect of HESM supplement on post hatch chickens. In the first study, the chickens were fed either a control diet or diets containing 0.5% whey protein or HESM as supplement and evaluated at 5 weeks of age using growth, hematology, clinical chemistry, plasma immunoglobulins, and corticosterone as variables. The second and third studies were done to compare the effects of LPS on control and HESM fed birds at 5 weeks of age following at 4 and 24 h of treatment where the HESM was also sterilized with ethanol to deplete bacterial factors. HESM supplement caused weight gain in 2 experiments and decreased blood corticosterone concentrations. While LPS caused a significant loss in body weight at 24 h following its administration, the HESM supplemented birds showed significantly less body weight loss compared with the control fed birds. The WBC, heterophil/lymphocyte ratio, and the levels of IgG were low in chickens fed diets with HESM supplement compared with control diet group. LPS challenge increased the expression of pro-inflammatory cytokine gene IL-6 but the HESM fed birds showed its effect curtailed, also, which also, favored the up-regulation of anti inflammatory genes compared with control diet fed chickens. Post hatch supplementation of HESM appears to improve performance, modulate immunity, and increase resistance of chickens to endotoxin. PMID- 27463241 TI - The 2016 Guidelines for Hospital-acquired and Ventilator-associated Pneumonia. A Selection Correction? PMID- 27463244 TI - Synthesis and Screening of Modified 6,6'-Bis(5,5,8,8-tetramethyl-5,6,7,8 tetrahydrobenzo[e][1,2,4]triazin-3-yl)-2,2'-bipyridine Ligands for Actinide and Lanthanide Separation in Nuclear Waste Treatment. AB - Effects of chloro and bromo substitution at the 4-position of the pyridine ring of 6,6'-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenzo[e][1,2,4]triazin-3-yl) 2,2'-bipyridine (CyMe4-BTBP) have been studied with regard to the extraction of Am(III) from Eu(III) and Cm(III) from 0.1-3 M HNO3. Similarly to CyMe4-BTBP, a highly efficient (DAm > 10 at 3 M HNO3) and selective (SFAm/Eu > 100 at 3 M HNO3) extraction was observed for Cl-CyMe4-BTBP and Br-CyMe4-BTBP in 1-octanol but in the absence of a phase-transfer agent. PMID- 27463245 TI - Inhalable Particles for "Pincer Therapeutics" Targeting Nitazoxanide as Bactericidal and Host-Directed Agent to Macrophages in a Mouse Model of Tuberculosis. AB - Nitazoxanide (NTZ) has moderate mycobactericidal activity and is also an inducer of autophagy in mammalian cells. High-payload (40-50% w/w) inhalable particles containing NTZ alone or in combination with antituberculosis (TB) agents isoniazid (INH) and rifabutin (RFB) were prepared with high incorporation efficiency of 92%. In vitro drug release was corrected for drug degradation during the course of study and revealed first-order controlled release. Particles were efficiently taken up in vitro by macrophages and maintained intracellular drug concentrations at one order of magnitude higher than NTZ in solution for 6 h. Dose-dependent killing of Mtb and restoration of lung and spleen architecture were observed in experimentally infected mice treated with inhalations containing NTZ. Adjunct NTZ with INH and RFB cleared culturable bacteria from the lung and spleen and markedly healed tissue architecture. NTZ can be used in combination with INH-RFB to kill the pathogen and heal the host. PMID- 27463247 TI - Postoperative Delirium in Patients after Pancreaticoduodenectomy. AB - BACKGROUND/AIMS: Postoperative delirium (POD) is one of the most common complications after various types of surgery. The aim of this study was to investigate the incidence and risk factors for delirium after pancreaticoduodenectomy (PD). METHODS: This was a retrospective study of 146 consecutive patients who underwent PD between April 2007 and June 2015 at Saiseikai Yokohamashi Tobu Hospital. RESULTS: Twenty-nine patients (19.9%) were diagnosed with delirium. Patients who were >70 years were divided into a delirium group (n = 24) and a non-delirium group (n = 41). Multivariate analysis showed that only the Charlson Age Comorbidity Index (CACI) (OR 1.8; 95% CI 1.067-3.036; p = 0.028) was an independent risk factor of delirium for patients >70 years. The receiver operating characteristic curve revealed an optimal cutoff value of 4.5 for the CACI score in all patients (sensitivity 62.1%; specificity 82.9%; area under the curve 0.782). The higher CACI score (>=5) is significantly different from the lower CACI score (p < 0.0001) with respect to POD occurrence. CONCLUSIONS: The CACI, especially in elderly patients, was associated with the incidence of POD. Therefore, utilizing this validated and practical tool preoperatively might be useful for POD. PMID- 27463246 TI - The Efficacy of Trastuzumab in Animal Models of Breast Cancer: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Breast cancer is the most frequent cancers and is the second leading cause of cancer death among women. Trastuzumab is an effective treatment, the first monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). To inform the development of other effective treatments we report summary estimates of efficacy of trastuzumab on survival and tumour volume in animal models of breast cancer. METHODS: We searched PubMed and EMBASE systematically to identify publications testing trastuzumab in animal models of breast cancer. Data describing tumour volume, median survival and animal features were extracted and we assessed quality using a 12-item checklist. We analysed the impact of study design and quality and evidence for publication bias. RESULTS: We included data from 83 studies reporting 169 experiments using 2076 mice. Trastuzumab treatment caused a substantial reduction in tumour growth, with tumours in treated animals growing to 32.6% of the volume of tumours in control animals (95%CI 27.8%-38.2%). Median survival was prolonged by a factor of 1.45 (1.30-1.62). Many study design and quality features accounted for between-study heterogeneity and we found evidence suggesting publication bias. CONCLUSION: We have found trastuzumab to be effective in animal breast cancer models across a range of experimental circumstances. However the presence of publication bias and a low prevalence of measures to reduce bias provide a focus for future improvements in preclinical breast cancer research. PMID- 27463248 TI - Lessons Learned in a Breastfeeding Media Campaign. AB - Breastfeeding is well accepted as the optimal nutrition for babies. The American Academy of Pediatrics states that infant feeding should no longer be thought of as a lifestyle choice, but rather as a public health issue. In Shelby County, Tennessee, rates of breastfeeding continue to be disparately low. To address this public health problem, a focus group study was conducted with the Shelby County population least likely to breastfeed. Following participants' suggestion to use a billboard campaign with pictures of local mothers and families, one highway billboard and ten bus stop signs were placed around the city in areas of the lowest breastfeeding rates. Self-administered surveys were completed by convenience sampling in target population areas with women least likely to breastfeed, both before placing the signs and 6 months later. No significant differences were noted in knowledge, attitudes, or practices after the media campaign, but trends toward increased intention to breastfeed were noted among expectant mothers. With collapsed data (pre and post), a majority of participants believed that breastfeeding is the best way to feed a baby and they were significantly more likely to plan to breastfeed if they knew about health benefits to the baby and to themselves. If they had heard about breastfeeding on the TV or radio, they were more likely to believe breastfeeding is important for long-term health. These findings suggest that a media campaign could have a complementary role in promoting breastfeeding among women with low initiation rates. PMID- 27463249 TI - The Complicated Calculus of Publicly Reporting Mortality After Percutaneous Coronary Intervention. PMID- 27463250 TI - p53 mutations promote proteasomal activity. AB - p53 mutations occur very frequently in human cancer. Besides abrogating the tumour suppressive functions of wild-type p53, many of those mutations also acquire oncogenic gain-of-function activities. Augmentation of proteasome activity is now reported as a common gain-of-function mechanism shared by different p53 mutants, which promotes cancer resistance to proteasome inhibitors. PMID- 27463251 TI - Hippo's Q for a big liver. AB - The Hippo pathway is a key regulator of organ size that has also been implicated in tumorigenesis. Yap, one of the effectors of Hippo signalling, is now reported to support these functions by promoting glutamine synthesis. PMID- 27463252 TI - Relationship between aortic augmentation index and blood pressure during metaboreflex activation in healthy young men. AB - BACKGROUND: Heightened aortic augmentation index (AIx; surrogate of arterial stiffness) is associated with an elevated risk of cardiovascular events; however, it is currently unclear whether peripheral blood pressure (BP) modulates AIx. AIM: Given this, we studied the relationship between AIx and BP under resting conditions as well as during skeletal muscle metaboreflex activation, which is a maneuver that generates steady elevations in BP. METHODS: In nine healthy male participants (23+/-2 years), the graded activation of the muscle metaboreflex was achieved by postexercise ischemia (PEI) following moderate and high-intensity static handgrip performed at 30 and 40% maximum voluntary contraction. Heart rate (ECG), arterial BP, and AIx (SphygmoCor) were measured. RESULTS: Compared with rest, mean arterial pressure was significantly increased during PEI30% (+24+/-4 mmHg, P<0.05 vs. rest) and was further augmented during PEI40% (+34+/-4 mmHg, P<0.05 vs. PEI30%). Similarly, AIx@HR75 increased significantly from rest during PEI30% (rest -9+/-3% vs. PEI30% +9+/-5%, P<0.05) and was further augmented during PEI40% (17+/-4%, P<0.05 vs. PEI30%). At rest, there was no relationship between AIx and BP. However, at PEI30%, there was a significant association between AIx and diastolic BP and mean arterial pressure (r=0.92, 0.87, respectively; P<0.05) and this association was maintained at PEI40% (r=0.94, 0.91, respectively; P<0.05). CONCLUSIONS: Our results indicate that acute elevations in peripheral BP are an important determinant of AIx during muscle metaboreflex activation in healthy men. PMID- 27463253 TI - Recent Advancements in Functionalized Paper-Based Electronics. AB - Building electronic devices on ubiquitous paper substrates has recently drawn extensive attention due to its light weight, low cost, environmental friendliness, and ease of fabrication. Recently, a myriad of advancements have been made to improve the performance of paper electronics for various applications, such as basic electronic components, energy storage devices, generators, antennas, and electronic circuits. This review aims to summarize this progress and discuss different perspectives of paper electronics as well as the remaining challenges yet to be overcome in this field. Other aspects included in this review are the fundamental characteristics of paper, modification of paper with functional materials, and various methods for device fabrication. PMID- 27463254 TI - Investments and costs of oral health care for Family Health Care. AB - OBJECTIVE: To estimate the investments to implement and operational costs of a type I Oral Health Care Team in the Family Health Care Strategy. METHODS: This is an economic assessment study, for analyzing the investments and operational costs of an oral health care team in the city of Salvador, BA, Northeastern Brazil. The amount worth of investments for its implementation was obtained by summing up the investments in civil projects and shared facilities, in equipments, furniture, and instruments. Regarding the operational costs, the 2009-2012 time series was analyzed and the month of December 2012 was adopted for assessing the monetary values in effect. The costs were classified as direct variable costs (consumables) and direct fixed costs (salaries, maintenance, equipment depreciation, instruments, furniture, and facilities), besides the indirect fixed costs (cleaning, security, energy, and water). The Ministry of Health's share in funding was also calculated, and the factors that influence cost behavior were described. RESULTS: The investment to implement a type I Oral Health Care Team was R$29,864.00 (US$15,236.76). The operational costs of a type I Oral Health Care Team were around R$95,434.00 (US$48,690.82) a year. The Ministry of Health's financial incentives for investments accounted for 41.8% of the implementation investments, whereas the municipality contributed with a 59.2% share of the total. Regarding operational costs, the Ministry of Health contributed with 33.1% of the total, whereas the municipality, with 66.9%. Concerning the operational costs, the element of heaviest weight was salaries, which accounted for 84.7%. CONCLUSIONS: Problems with the regularity in the supply of inputs and maintenance of equipment greatly influence the composition of costs, besides reducing the supply of services to the target population, which results in the service probably being inefficient. States are suggested to partake in funding, especially to cover the team's operational cost. OBJETIVO: Estimar os investimentos para implantacao e os custos operacionais de uma Equipe de Saude Bucal modalidade tipo I na Estrategia Saude da Familia. METODOS: Estudo de avaliacao economica, tipo analise de investimentos e custos operacionais de uma equipe de saude bucal no municipio de Salvador, Bahia, Brasil. O calculo dos investimentos para implantacao foi obtido pela soma dos investimentos em obras civis e instalacoes em rateio, equipamentos, moveis e instrumentais. Para os custos operacionais, foi analisada a serie historica de 2009 a 2012 e adotou-se o mes de dezembro de 2012 para levantamento dos valores monetarios vigentes. Os custos foram classificados em custos diretos variaveis (materiais de consumo) e custos fixos diretos (salarios, manutencao, depreciacao do capital fixo dos equipamentos, instrumentais, moveis e edificacoes), alem dos custos fixos indiretos (higienizacao, seguranca, energia e agua). Foi tambem calculada a participacao do Ministerio da Saude no financiamento e descritos os fatores que influenciam o comportamento dos custos. RESULTADOS: O investimento para implantacao de uma Equipe de Saude Bucal modalidade tipo I foi de R$29.864,00. Os custos operacionais de uma Equipe de Saude Bucal modalidade tipo I situaram-se em torno de R$95.434,00 por ano. Os incentivos financeiros do Ministerio da Saude para investimentos cobriram 41,8% dos investimentos com implantacao, enquanto o municipio participou com 59,2% do total. Para os custos operacionais, a participacao do Ministerio da Saude foi de 33,1%, enquanto o municipio participou com 66,9%. Dentro dos custos operacionais, o elemento de maior peso foram os salarios, representando 84,7%. CONCLUSOES: Problemas com a regularidade no abastecimento dos insumos e manutencao de equipamentos influenciam sobremaneira na composicao dos custos, alem de reduzir a oferta de servicos a populacao-alvo, resultando em provavel ineficiencia do servico. Sugere-se o cofinanciamento estadual, especialmente para cobrir o custo operacional da equipe. PMID- 27463255 TI - The genesis of the AIDS policy and AIDS Space in Brazil (1981-1989). AB - OBJECTIVE: To analyze the genesis of the policy for controlling AIDS in Brazil. METHODS: Socio-historical study (1981-1989), based on Bordieu's genetic sociology, by document analysis, bibliographical review, and in-depth interviews. It consisted of a connection between the analysis of the paths of 33 agents involved in the creation of a social space focusing on AIDS-related issues and the historical possibility conditions of the drafting of a specific policy. RESULTS: AIDS Space is a gathering point for the paths of agents from several social fields (medical, scientific, political, and bureaucratic fields). A specific space for relationships, which enabled the drafting of a policy for controlling the AIDS epidemic, but also a place where the authority to talk about the meaning of the disease, the methods to prevent and treat it was under dispute. The analysis showed how the various structures (democratic administrations in Sao Paulo and at the national level, with public health officers taking important positions) and the lack of a specific therapy contributed to social agents of different ranks and backgrounds to initially set prevention as a priority. CONCLUSIONS: The rise of the sanitary movement, the organization of SUS, and the dominance of the medical field at the AIDS Space contributed to foster treatment as a part of the measures to control the epidemic. These conditions allowed drafting a policy based on the integrality of care, by linking prevention and treatment in the following decade, with important participation from state bureaucracy and researchers. PMID- 27463256 TI - Public-private settlement and hospital mortality per sources of payment. AB - OBJECTIVE: To analyze if the adjusted hospital mortality varies according to source of payment of hospital admissions, legal nature, and financing settlement of hospitals. METHODS: Cros-ssectional study with information source in administrative databases. Specific hospital admission reasons were selected considering the volume of hospital admissions and the list of quality indicators proposed by the North-American Agency for Healthcare Research and Quality (AHRQ). Were analyzed 852,864 hospital admissions of adults, occurred in 789 hospitals between 2008 and 2010, in Sao Paulo and Rio Grande do Sul, applying multilevel logistic regression. RESULTS: At hospital admission level, showed higher chances of death male patients in more advanced age groups, with comorbidity, who used intensive care unit, and had the Brazilian Unified Health System as source of payment. At the level of hospitals, in those located in the mean of the distribution, the adjusted probability of death in hospital admissions financed by plan or private was 5.0%, against 9.0% when reimbursed by the Brazilian Unified Health System. This probability increased in hospital admissions financed by the Brazilian Unified Health System in hospitals to two standard deviations above the mean, reaching 29.0%. CONCLUSIONS: In addition to structural characteristics of the hospitals and the profile of the patients, interventions aimed at improving care should also consider the coverage of the population by health plans, the network shared between beneficiaries of plans and users of the Brazilian Unified Health System, the standard of care to the various sources of payment by hospitals and, most importantly, how these factors influence the clinical performance. OBJETIVO: Analisar se a mortalidade hospitalar ajustada varia segundo fonte de pagamento das internacoes, natureza juridica e arranjo de financiamento dos hospitais. METODOS: Estudo observacional transversal com fonte de informacoes em bases de dados administrativos. Motivos de internacao especificos foram selecionados considerando o volume de internacoes e a lista de indicadores de qualidade propostos pela agencia norte-americana de pesquisa em saude e qualidade (AHRQ). Foram analisadas 852.864 internacoes em adultos, ocorridas em 789 hospitais entre 2008 e 2010, em Sao Paulo e Rio Grande do Sul, aplicando regressao logistica multinivel. RESULTADOS: No nivel da internacao, apresentaram maiores chances de obito pacientes do sexo masculino, em faixas etarias mais avancadas, com comorbidade, que utilizaram unidade de terapia intensiva, e tinham o Sistema Unico de Saude como fonte de pagamento. No nivel dos hospitais, naqueles situados na media da distribuicao, a probabilidade de morte ajustada nas internacoes financiadas por plano ou particular foi de 5,0%, contra 9,0% quando reembolsadas pelo Sistema Unico de Saude. Essa probabilidade aumentou nas internacoes financiadas pelo Sistema Unico de Saude em hospitais a dois desvios padrao acima da media, passando para 29,0%. CONCLUSOES: Alem das caracteristicas estruturais dos hospitais e do perfil dos pacientes, intervencoes voltadas para a melhoria do cuidado deveriam considerar tambem a cobertura da populacao por planos de saude, a rede compartilhada entre beneficiarios de planos e usuarios do Sistema Unico de Saude, o padrao de atendimento as diversas fontes de pagamento pelos hospitais e, fundamentalmente, como esses fatores influenciam o desempenho clinico. PMID- 27463257 TI - Making Electronic Health Records (EHRs) Work: Informal Talk and Workarounds in Healthcare Organizations. AB - A key provision of the American Recovery and Reinvestment Act of 2009 mandated that electronic health records (EHR) be adopted in US healthcare organizations by 2015. The purpose of this study is to examine the communicative processes involved as healthcare workers implement an EHR and make changes, known as workarounds. Guided by theories in social influence, and diffusion of innovations, we conducted a survey of healthcare professionals using an EHR system in an organization. Our structural equation modeling (SEM) and multiple regression results reveal coworker communication, in the form of informal social support and feedback, play an important role in whether people engage in workarounds. Understanding this relationship is important because our study also demonstrates that workarounds predict healthcare employees' overall satisfaction with the EHR system. Specifically, workarounds are associated with higher perceptions of the EHR's relative advantage, higher perceptions of EHR implementation success, and lower levels of resistance to EHR change. This study offers a health communication contribution to the growing research on EHR systems and demonstrates the persuasive effects that coworkers have on new technology use in healthcare organizations. PMID- 27463258 TI - Morphological Evolution of Electrochemically Plated/Stripped Lithium Microstructures Investigated by Synchrotron X-ray Phase Contrast Tomography. AB - Due to its low redox potential and high theoretical specific capacity, Li metal has drawn worldwide research attention because of its potential use in next generation battery technologies such as Li-S and Li-O2. Unfortunately, uncontrollable growth of Li microstructures (LmSs, e.g., dendrites, fibers) during electrochemical Li stripping/plating has prevented their practical commercialization. Despite various strategies proposed to mitigate LmS nucleation and/or block its growth, a fundamental understanding of the underlying evolution mechanisms remains elusive. Herein, synchrotron in-line phase contrast X-ray tomography was employed to investigate the morphological evolution of electrochemically deposited/dissolved LmSs nondestructively. We present a 3D characterization of electrochemically stripped Li electrodes with regard to electrochemically plated LmSs. We clarify fundamentally the origin of the porous lithium interface growing into Li electrodes. Moreover, cleavage of the separator caused by growing LmS was experimentally observed and visualized in 3D. Our systematic investigation provides fundamental insights into LmS evolution and enables us to understand the evolution mechanisms in Li electrodes more profoundly. PMID- 27463259 TI - Satiety Impact of Different Potato Products Compared to Pasta Control. AB - OBJECTIVE: A variety of potato dishes are regularly consumed worldwide, but the satiety value of these foods is not well established. The primary objective of this study was to compare the satiating effects of 4 equi-energy meals containing different potato preparations with an equi-energy pasta control meal. METHODS: This study used a randomized crossover design to assess the impact of 4 equi energy potato-based meals (fried French fries, baked potato, mashed potato, or potato wedges) on subjective satiety sensations (visual analogue scale [VAS] ratings) and subsequent energy intake (ad libitum meal [kcal]), compared to a control pasta-based meal. Thirty-three healthy nonobese men and women participated in the study. RESULTS: VAS ratings indicated that the meal containing fried french fries was perceived to be substantially more satiating than the equi-energy pasta control meal, with all other potato-based meals not differing overall from control. All test meals had a comparable effect on energy intake at a later ad libitum meal. CONCLUSIONS: Consumers reported higher levels of satiety following a meal where the principal carbohydrate source was fried french fries, compared to when they had consumed an energy-matched meal containing carbohydrate in the form of pasta. All other potato preparations had similar effects on satiety as pasta. It is concluded that participants perceived a meal with fried french fries as providing greater satiety than a pasta control meal. PMID- 27463260 TI - Fluorescent Probe Encapsulated in SNAP-Tag Protein Cavity To Eliminate Nonspecific Fluorescence and Increase Detection Sensitivity. AB - Despite the promising improvements made recently on fluorescence probes for the detection of enzymes and reactive small molecules, two fundamental problems remain: weaker fluorescence of many dyes in aqueous buffers and strong nonspecific signals in samples containing high protein levels. In this paper, we introduce a novel fluorescent probe encapsulated in protein cavity (FPEPC) concept as demonstrated by SNAP-tag protein and three environment-sensitive fluorescence probes to overcome these two problems. The probes were constructed by following the current probe design for enzymes and reactive small molecules but with an additional benzylguanine moiety for selective SNAP-tag conjugation. The SNAP-tag conjugated probes achieved quantitative nitroreductase and hydrogen sulfide detection in blood plasma, whereas analyte concentrations were overestimated up to 700-fold when bare fluorescent probes were employed for detection. Furthermore, detection sensitivity was increased dramatically, as our probes displayed 390-fold fluorescence enhancement upon SNAP-tag conjugation, in stark contrast to the weak fluorescence of the free probes in aqueous solutions. Compared with the conventional approaches where fluorescent probes are encapsulated into polymers and nanoparticles, our simple and general approach successfully overcame many key issues such as dye leakage, long preparation steps, inconsistent dye-host ratios, difficulty in constructing in situ in a complex medium, and limited application to detect only small metabolites. PMID- 27463261 TI - A traceless photocleavable linker for the automated glycan assembly of carbohydrates with free reducing ends. AB - We report a traceless photocleavable linker for the automated glycan assembly of carbohydrates with free reducing ends. The reductive-labile functionality in the linker tolerates all commonly used reagents and protocols for automated glycan assembly, as demonstrated with the successful preparation of nine plant cell wall related oligosaccharides, and is cleaved by hydrogenolysis. PMID- 27463263 TI - Alcohol: A Pharmaceutical and Pharmacological Point of View During Lactation. AB - BackgroundA safe amount of alcohol that can be ingested by suckling infants is not known. As a result, alcohol consumption by lactating mothers during this crucial time can potentially harm infants. ObjectiveThis article provides an overview of alcohol pharmacokinetics and pharmacodynamics in breast milk. Methods/DiscussionThis paper reviews literature on alcohol exposure as it relates to suckling infants. Intended and unintended alcohol exposure through breast milk may occur by skin contact, inhalation and by use of alcohol co-formulated drugs. A method for calculating the time to alcohol elimination from breast milk is also discussed. ConclusionAs there is no evidence on a safe amount of alcohol in breast milk, alcohol exposure throughout lactation should be avoided, to ensure the welfare of suckling infants. PMID- 27463262 TI - Synthesis of 2-Cyclopentenone Derivatives via Palladium-Catalyzed Intramolecular Carbonyl alpha-Alkenylation. AB - 2-Cyclopentenone derivatives have been efficiently synthesized from 5-bromo-5 hexen-2-ones via palladium-catalyzed intramolecular carbonyl alpha-alkenylation followed by double-bond migration under mild reaction conditions. PMID- 27463264 TI - Efficient Access to Chiral Benzhydrols via Asymmetric Transfer Hydrogenation of Unsymmetrical Benzophenones with Bifunctional Oxo-Tethered Ruthenium Catalysts. AB - A concise asymmetric transfer hydrogenation of diaryl ketones, promoted by bifunctional Ru complexes with an etherial linkage between 1,2 diphenylethylenediamine (DPEN) and eta(6)-arene ligands, was successfully developed. Because of the effective discrimination of substituents at the ortho position on the aryl group, unsymmetrical benzophenones were smoothly reduced in a 5:2 mixture of formic acid and triethylamine with an unprecedented level of excellent enantioselectivity. For the non-ortho-substituted benzophenones, the oxo-tethered catalyst electronically discerned biased substrates, resulting in attractive performance yielding chiral diarylmethanols with >99% ee. PMID- 27463265 TI - Clinical pharmacology and efficacy of sugammadex in the reversal of neuromuscular blockade. AB - INTRODUCTION: Sugammadex is the first clinical representative of a class of drugs called steroidal muscle relaxant encapsulators. Due to its 1:1 binding of rocuronium or vecuronium, sugammadex can reverse any depth of neuromuscular block and has therefore revolutionized the way anesthetists think about drug reversal. AREAS COVERED: This review gives an overview of the clinical pharmacology and efficacy of sugammadex in healthy patients as well as in patients with pre existing diseases. EXPERT OPINION: After approval in Europe in 2008 and Asia in 2010, sugammadex has recently been approved in the USA and Canada. This will open the field for further research especially for the use in special patient populations and specific diseases. Due to its pharmacodynamic profile, sugammadex in combination with rocuronium might have the potential to displace succinylcholine as the gold standard muscle relaxant for rapid sequence inductions. The use of rocuronium or vecuronium with the potential to reverse its action with sugammadex seems to be safe in patients with impaired neuromuscular transmission, i.e. (neuro)muscular diseases including myasthenia gravis. Data from long-term use of sugammadex is not yet available. Evidence towards an economic advantage of using sugammadex, justifying the relatively high costs for an anesthesia-related drug, is missing. PMID- 27463266 TI - Air-Stable Pd Catalytic Systems for Sequential One-Pot Synthesis of Challenging Unsymmetrical Aminoaromatics. AB - The selective functionalization of dibromoaromatic scaffolds using air-stable palladium catalytic systems was carried out. This methodology involved rapid mono and diselective Buchwald-Hartwig aminations via microwave irradiation. The conditions were optimized to couple sequentially different moieties in one pot. Couplings with a wide scope of amines allowed accessing a new library of symmetrical and unsymmetrical derivatives (35 examples). Using this versatile method, a near-IR push-pull sensor was prepared installing the electron-donating and -withdrawing groups through a multicomponent reaction. These conditions revealed to be gram-scalable and adaptable to various groups; hence, promoting facile use in synthetic chemistry. PMID- 27463269 TI - Assemblage of Superalkali Complexes with Ever Low-Ionization Potentials. AB - A simple recipe is proposed for the obtention of new molecules with even lower vertical ionization potential (VIP): to decorate an atom of an electronegative element with superalkali species in number that exceeds its formal valence by one. For instance, density functional theory calculations show that by using the superalkali Li3O cluster (VIP = 3.83 eV) as building blocks decorating the O atom one obtains VIP = 3.33 eV for the Li9O4 cluster, which is lower than the calculated VIP for Cs (3.89 eV) and Li (5.39 eV). This feature is systematic, as confirmed by calculated results on Li-F and Li-S clusters as well. The calculated binding energy per atom of the large-sized species exceeds by far that of LiF (134.7 kcal/mol). PMID- 27463267 TI - Ortner's syndrome caused by pulmonary arterial hypertension associated with mixed connective tissue disease. PMID- 27463270 TI - [Not Available]. PMID- 27463271 TI - [Not Available]. PMID- 27463272 TI - [Not Available]. PMID- 27463273 TI - [Not Available]. PMID- 27463274 TI - [Not Available]. PMID- 27463275 TI - [Not Available]. PMID- 27463276 TI - [Not Available]. PMID- 27463277 TI - [Not Available]. PMID- 27463278 TI - [Not Available]. PMID- 27463279 TI - [Not Available]. PMID- 27463280 TI - [Not Available]. PMID- 27463281 TI - [Not Available]. PMID- 27463283 TI - [Not Available]. PMID- 27463282 TI - [Not Available]. PMID- 27463285 TI - Coming in Sportsmedicine. PMID- 27463287 TI - abstracts at a glance. PMID- 27463286 TI - Scanning Sports. PMID- 27463284 TI - TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5). AB - ABSTARCT Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with a number of pathological respiratory diseases, such as bronchitis, asthma, and chronic obstructive pulmonary disease, which share the common feature of airway inflammation induced by particle exposure. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is crucial for the study of PM2.5 toxicity. In the current study, we found that exposing human bronchial epithelial cells (immortalized Beas-2B cells and primary cells) to PM2.5 collected in the winter in Wuhan, a city in southern China, induced a significant upregulation of VEGFA (vascular endothelial growth factor A) production, a signaling event that typically functions to control chronic airway inflammation and vascular remodeling. Further investigations showed that macroautophagy/autophagy was induced upon PM2.5 exposure and then mediated VEGFA upregulation by activating the SRC (SRC proto-oncogene, non-receptor tyrosine kinase)-STAT3 (signal transducer and activator of transcription 3) pathway in bronchial epithelial cells. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 (tumor protein p53) activation and the expression of its downstream target DRAM1 (DNA damage regulated autophagy modulator 1) for the induction of autophagy. These results thus extend the role of TP53-DRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2.5 exposure strongly induced the activation of the ATR (ATR serine/threonine kinase) CHEK1/CHK1 (checkpoint kinase 1) axis, which subsequently triggered TP53 dependent autophagy and VEGFA production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure. PMID- 27463289 TI - Brief Reports. PMID- 27463291 TI - Running Wild. PMID- 27463292 TI - Editorial. PMID- 27463293 TI - A Nutritional and Hematologic Assessment of Elite Ballet Dancers. AB - In brief: We studied the nutritional and hematologic status of 22 professional ballet dancers (10 men, 12 women, mean age 25), from American Ballet Theatre by analyzing daily dietary intake and laboratory data including blood vitamin assays. The dancers had law percent body fat. Daily calorie intake was 2,967 +/- 667 kcal for men and 1,673 +/- 450 kcal for women. Carbohydrate consumption (38% of the total daily calorie intake for men and 50% for women) was too law for efficient energy use. Hemoglobin and red cell indexes were normal, but serum ferritin was below normal in eight women and three men. Serum chemistry values were normal. Blood vitamin assays were normal in all dancers, reflecting widespread use of vitamin supplements. By sports medicine standards, the dancers' law calorie diets were suboptimal for strenuous physical exercise. PMID- 27463294 TI - Ankle Joint Support: A Comparison of Reusable Lace-on Braces With Taping and Wrapping. AB - In brief: This study compared prophylactic taping and cotton wrapping with five lace-on braces to determine the best way to provide ankle support. Inversion torque was applied to a specially instrumented polyurethane foot form supported by the tape, wrap, and braces. Fresh adhesive tape provided the best level of support. However, after 350 inversion cycles, the percent of loss of support was also highest for the tape. No significant difference was found in the amount of support offered by tape and the two best ankle braces after the 350 cycles. PMID- 27463295 TI - Practical Assessment of Body Composition. AB - In brief: The assessment of body composition has become an important method for determining a desirable body weight of adults and athletes. Hydrostatic weighing is a popular and valid method, but it is often not feasible for the clinical setting or for mass testing; thus, anthropometry has become the preferred method. This article reviews the scientific basis for generalized body composition prediction equations and provides methods for evaluating body composition. The authors recommend using a sum of three skinfolds (triceps, chest, and subscapula for men and triceps, abdomen, and suprailium for women) and give detailed instructions for securing accurate measurements of body fat. PMID- 27463296 TI - High Blood Pressure in the Competitive Athlete: Guidelines and Recommendations. AB - In brief: Since short-term adverse effects of hypertension in competitive athletes have not been reported, it seems reasonable to permit most athletes with mild to moderate hypertension to participate in organized sports, Mild hypertension may be managed by restricting sodium intake, controlling weight, and using relaxation techniques. Some sympathetic inhibiting agents are preferable as first-step drugs because they lower arterial pressure at rest and during exercise. Occasionally small-dose diuretics may be added, usually with potassium supplements. Long-term observation of hypertensive athletes is needed to determine the presence or absence of late harmful effects of increased arterial pressure and exercise. PMID- 27463297 TI - Physicians' Perceptions of Using Physical Education for Managing Childhood Obesity. AB - In brief: The authors studied how physicians perceive the role of physical education in managing childhood obesity. Ninety-six pediatricians and 97 family physicians returned questionnaires that included four statements about multidisciplinary interaction among health care professionals and six statements about physical education programs. Although the results of the survey indicated that physicians may not be aware of the current role of physical education in obesity management, they said the role should be greater. The authors suggest that physicians and physical educators establish avenues of communication so they can work together for the benefit of obese children. PMID- 27463298 TI - Knee Disorders in Runners. AB - In brief: The authors opened a runners' clinic to evaluate and treat problems of runners who run 20 miles a week or more. Of 161 patients treated during the first year, 49 had disorders of one or both knees. Fifteen complained of patellofemoral pain, 14 of iliotibial band pain, and 20 of medial or lateral pain. Extremity malalignment and other preexisting problems were involved in several cases. Treatment was mainly conservative, with some restriction or change in activity. One way to help prevent such knee problems is to limit sudden changes in workout intensity. PMID- 27463299 TI - Are We Running From the Truth About the Risks and Benefits of Exercise? AB - Basic assumptions about the benefits of exercise are being questioned. What may be heresy to the sports medicine old guard is making sense to some who think that exercisers in the United States are going overboard-and for the wrong reasons. PMID- 27463300 TI - Commentary. AB - The British look with polite tolerance, condescension, and perhaps a bit of envy at the American romance with fitness. But enthusiasm for running is waning, and many runners are slipping off with a little gratitude and a little guilt. PMID- 27463301 TI - Of Magic, Miracles, and Exercise Myths. AB - Exercise physiologist James S. Skinner, PhD, scrutinizes some popular exercise myths end speculates about why they endure. His comments are enlightening, entertaining, and even a bit philosophical. PMID- 27463302 TI - Psychological Characteristics of the Average Female Runner. AB - A profile of the average female runner emerges from the results of five studies of women who raced in the Northwest between 1979 and 1981. PMID- 27463304 TI - Sportsmedicine Adviser. PMID- 27463303 TI - Getting Away. AB - It's a general rule that the farther north you travel in walleye country, the more plentiful and less wily the fish become. The rule proved itself within ten minutes in central Canada's wilderness fishing camps. PMID- 27463305 TI - Nutrition and Fitness. PMID- 27463323 TI - DMSO enhanced conformational switch of an interfacial enzyme. AB - Interfacial proteins function in unique heterogeneous solvent environments, such as water-oil interfaces. One important example is microbial lipase, which is activated in an oil-water emulsion phase and has many important enzymatic functions. A unique aprotic dipolar organic solvent, dimethyl sulfoxide (DMSO), has been shown to increase the activity of lipases, but the mechanism behind this enhancement is still unknown. Here, all-atom molecular dynamics simulations of lipase in a binary solution were performed to examine the effects of DMSO on the dynamics of the gating mechanism. The amphiphilic alpha5 region of the lipase was a focal point for the analysis, since the structural ordering of alpha5 has been shown to be important for gating under other perturbations. Compared to the closed-gorge ensemble in an aqueous environment, the conformational ensemble shifts towards open-gorge structures in the presence of DMSO solvents. Increased width of the access channel is particularly prevalent in 45% and 60% DMSO concentrations (w/w). As the amount of DMSO increases, the alpha5 region of the lipase becomes more alpha-helical, as we previously observed in studies that address water-oil interfacial and high pressure activation. We believe that the structural ordering of alpha5 plays an essential role on gating and lipase activity. PMID- 27463325 TI - Pharmacophores in Drug Research. AB - The pharmacophore concept in modern drug research is highlighted and the most important use examples and success stories are reviewed. These include papers from method development as well as from application areas. As indicated by the number of publications available, the pharmacophore approach has proven to be extremely useful as interface between medicinal and computational chemistry, both in virtual screening and library design for efficient hit discovery, but also in the optimization of lead compounds to clinical candidates. Recent studies focus on the usage of parallel screening using pharmacophore models for bio-activity profiling and early stage risk assessment of potential side effects and toxicity due to interaction of drug candidates with anti-targets. PMID- 27463326 TI - Best Practices for QSAR Model Development, Validation, and Exploitation. AB - After nearly five decades "in the making", QSAR modeling has established itself as one of the major computational molecular modeling methodologies. As any mature research discipline, QSAR modeling can be characterized by a collection of well defined protocols and procedures that enable the expert application of the method for exploring and exploiting ever growing collections of biologically active chemical compounds. This review examines most critical QSAR modeling routines that we regard as best practices in the field. We discuss these procedures in the context of integrative predictive QSAR modeling workflow that is focused on achieving models of the highest statistical rigor and external predictive power. Specific elements of the workflow consist of data preparation including chemical structure (and when possible, associated biological data) curation, outlier detection, dataset balancing, and model validation. We especially emphasize procedures used to validate models, both internally and externally, as well as the need to define model applicability domains that should be used when models are employed for the prediction of external compounds or compound libraries. Finally, we present several examples of successful applications of QSAR models for virtual screening to identify experimentally confirmed hits. PMID- 27463324 TI - Salivary stress biomarkers of recent nicotine use and dependence. AB - BACKGROUND: Although stress plays a critical role in vulnerability to nicotine use and dependence, the stress response factors that contribute to smoking behaviors remain poorly elucidated. To minimize the confounding effects of chronic nicotine use, assessing individuals with relatively short smoking histories is critical for characterizing the neurobiological substrates associated with nicotine dependence early in the course of illness. OBJECTIVES: This pilot study examined sympathetic nervous system (alpha-amylase) and hypothalamic-pituitary-adrenal axis (cortisol, dehydroepiandrosterone) responses to the Trier Social Stress Test (TSST) in young adult smokers. Associations among objective indices of recent smoking (salivary cotinine, carbon monoxide in the breath [CO]), behavioral measures of nicotine dependence and withdrawal, and salivary biomarkers in response to the TSST were investigated. METHODS: Smokers (N = 64; 28 males, 36 females) provided saliva samples at 30 min intervals for 2 h prior to the TSST and every 10 min for 1 h following the TSST. RESULTS: Alpha amylase responses to the TSST were positively associated with salivary cotinine levels but negatively associated with CO levels. Individuals with a lower level of nicotine dependence had increased cortisol responses to the stressor, whereas those with a higher level of nicotine dependence did not show any cortisol changes in response to the stressor. CONCLUSIONS: These findings indicate that different mechanisms may be involved at different levels of nicotine dependence severity. Recent nicotine use and lower dependence severity may be associated with increased activation of the stress response systems. In contrast, more severe levels of dependence may downregulate stress response systems. PMID- 27463327 TI - A Free-Wilson-like Approach to Analyze QSAR Models Based on Graph Decomposition Kernels. PMID- 27463328 TI - Towards Proteome-Wide Interaction Models Using the Proteochemometrics Approach. AB - A proteochemometrics model was induced from all interaction data in the BindingDB database, comprizing in all 7078 protein-ligand complexes with representatives from all major drug target categories. Proteins were represented by alignment independent sequence descriptors holding information on properties such as hydrophobicity, charge, and secondary structure. Ligands were represented by commonly used QSAR descriptors. The inhibition constant (pKi ) values of protein ligand complexes were discretized into "high" and "low" interaction activity. Different machine-learning techniques were used to induce models relating protein and ligand properties to the interaction activity. The best was decision trees, which gave an accuracy of 80 % and an area under the ROC curve of 0.81. The tree pointed to the protein and ligand properties, which are relevant for the interaction. As the approach does neither require alignments nor knowledge of protein 3D structures virtually all available protein-ligand interaction data could be utilized, thus opening a way to completely general interaction models that may span entire proteomes. PMID- 27463329 TI - Are Mechanistic and Statistical QSAR Approaches Really Different? MLR Studies on 158 Cycloalkyl-Pyranones. AB - Two parallel approaches for quantitative structure-activity relationships (QSAR) are predominant in literature, one guided by mechanistic methods (including read across) and another by the use of statistical methods. To bridge the gap between these two approaches and to verify their main differences, a comparative study of mechanistically relevant and statistically relevant QSAR models, developed on a case study of 158 cycloalkyl-pyranones, biologically active on inhibition (Ki ) of HIV protease, was performed. Firstly, Multiple Linear Regression (MLR) based models were developed starting from a limited amount of molecular descriptors which were widely proven to have mechanistic interpretation. Then robust and predictive MLR models were developed on the same set using two different statistical approaches unbiased of input descriptors. Development of models based on Statistical I method was guided by stepwise addition of descriptors while Genetic Algorithm based selection of descriptors was used for the Statistical II. Internal validation, the standard error of the estimate, and Fisher's significance test were performed for both the statistical models. In addition, external validation was performed for Statistical II model, and Applicability Domain was verified as normally practiced in this approach. The relationships between the activity and the important descriptors selected in all the models were analyzed and compared. It is concluded that, despite the different type and number of input descriptors, and the applied descriptor selection tools or the algorithms used for developing the final model, the mechanistical and statistical approach are comparable to each other in terms of quality and also for mechanistic interpretability of modelling descriptors. Agreement can be observed between these two approaches and the better result could be a consensus prediction from both the models. PMID- 27463330 TI - Quantum Semiempirical Energy Based (SEEB) Descriptors Performance with Benzamidine Inhibitors of Trypsin. AB - MLR is a classical approach to regression problems in QSARs. In this study, the behaviour of SEEB descriptors was analysed with a MLR model. For this purpose a SEEB/MLR 3D-QSAR model was developed to evaluate the efficiency of benzamide trypsin inhibitors. The development of inhibitors of trypsin-like serine proteases has been an active area of research. They are involved in many biological processes like protein digestion and blood coagulation and also serve as a useful model system to study protein-ligand interaction. The regression coefficients, obtained by this procedure, have an intuitively simple and therefore appealing meaning for the relative influence of each amino acid residue to the predictive model. The predictive capability of SEEB is shown to be comparable to those of other QSAR methods. PMID- 27463331 TI - Combination Rules for Group Fusion in Similarity-Based Virtual Screening. AB - This paper evaluates the screening effectiveness of 15 parameter-free, similarity based and rank-based rules for group fusion, where one combines the outputs of similarity searches from multiple reference structures using ECFC_4 fingerprints and a Bayesian inference network. Searches of the MDDR and WOMBAT databases show that group fusion is most effective when as many reference structures as possible are used, when only a small proportion of each ranked similarity list is submitted to the final fusion rule, and when a fusion rule based on reciprocal rank positions is used to combine the individual search outputs. An analysis of the reciprocal rank rule suggests that its effectiveness derives from the close relationship that exists between the reciprocal rank of a database structure and its probability of activity. PMID- 27463332 TI - In Silico Receptorome Screening of Antipsychotic Drugs. AB - The recent availability of a complete interaction matrix between 13 antipsychotic drugs and 34 protein targets (Roth et al. Nat. Rev. Drug Discov. 2004, 3, 353 359) allows to assess the performance of computational methods on their ability to anticipate the entire affinity profile of drugs across multiple targets. The analyses reveal that our current implementations, based on the similarity of drugs against a reference set of small molecules for which pharmacological data is available in the public domain, are able to predict 65 % of the 442 affinities within 1-log unit error, with a level of precision above 92 %. In spite of the relatively small scale of this validation study, the results are indicative that in silico receptorome screening of drugs offers an efficient and cost-effective complement to in vitro screening. PMID- 27463333 TI - Effects of Cannabis Use on Human Behavior: A Call for Standardization of Cannabis Use Metrics. PMID- 27463334 TI - Spare Adenosine A2a Receptors Are Associated With Positive Exercise Stress Test In Coronary Artery Disease. AB - During exercise, cardiac oxygen-consumption increases and the resulting low oxygen level in myocardium triggers coronary vasodilation. This response to hypoxia is controlled notably by the vasodilator adenosine and its A2A receptor (A2AR). According to the "spare receptor" pharmacological model, a strong A2AR mediated response can occur in the context of a large number of receptors remaining unoccupied, activation of only a weak fraction of A2AR (evaluated using KD) resulting in maximal cAMP production (evaluated using EC50), and hence in maximal coronary vasodilation. In coronary artery disease (CAD), myocardial ischemia limits adaptation to exercise, which is commonly detected using the exercise stress test (EST). We hypothesized that spare A2AR are present in CAD patients to correct ischemia. Seventeen patients with angiographically-documented CAD and 17 control subjects were studied. We addressed adenosine-plasma concentration and A2AR-expression at the mononuclear cell-surface, which reflects cardiovascular expression. The presence of spare A2AR was tested using an innovative pharmacological approach based on a homemade monoclonal antibody with agonist properties. EST was positive in 82% of patients, and in none of the controls. Adenosine plasma-concentration increased by 60% at peak exercise in patients only (p<0.01). Most patients (65%), and none of the controls, had spare A2AR (identified when EC50/KD<=0.1) and a low A2AR-expression (mean: -37% vs controls; p<0.01). All patients with spare A2AR had a positive EST whereas the subjects without spare A2AR had a negative EST (p<0.05). Spare A2AR are therefore associated with positive EST in CAD patients and their detection may be used as a diagnostic marker. PMID- 27463335 TI - Soluble Prokaryotic Expression and Purification of Human Interferon Alpha-2b Using a Maltose-Binding Protein Tag. AB - Human interferon alpha-2b (IFNalpha-2b) has therapeutic applications as an antiviral and antiproliferative drug and has been used for a wide range of indications. Efficient production of IFNalpha-2b in Escherichia coli has been difficult because the protein tends to form inclusion bodies. This obstacle has garnered interest in efficiently expressing IFNalpha-2b and overcoming its poor solubility. In this study, seven N-terminal fusion partners - hexahistidine (His6), thioredoxin, glutathione S-transferase (GST), maltose-binding protein (MBP), N-utilization substance protein A, protein disulfide bond isomerase (PDI), and b'a' domain of PDI - were tested for soluble overexpression of codon optimized IFNalpha-2b in E. coli. Low temperature increased the expression level of all of the tagged proteins except for the GST fusion. All the tags, except for His6 and GST, improved solubility. We purified IFNalpha-2b from the MBP-tagged fusion using immobilized metal affinity chromatography and anion exchange chromatography, and obtained a final yield of 7.2 mg from an initial 500-ml culture. The endotoxin level was 0.46 EU/ug. Biological activity was demonstrated using a luciferase assay, which showed a dose-dependent response with a calculated EC50 of 10.3 +/- 5.9 pM. Our results demonstrate that using an MBP tagged fusion is an efficient way to produce pure IFNalpha-2b. PMID- 27463337 TI - Preoperative Biometric Parameters Predict the Vault after ICL Implantation: A Retrospective Clinical Study. AB - PURPOSE: To investigate the correlation between the preoperative biometric parameters of the anterior segment and the vault after implantable Collamer lens (ICL) implantation via this retrospective study. DESIGN: Retrospective clinical study. METHODS: A total of 78 eyes from 41 patients who underwent ICL implantation surgery were included in this study. Preoperative biometric parameters, including white-to-white (WTW) diameter, central corneal thickness, keratometer, pupil diameter, anterior chamber depth, sulcus-to-sulcus diameter, anterior chamber area (ACA) and central curvature radius of the anterior surface of the lens (Lenscur), were measured. Lenscur and ACA were measured with Rhinoceros 5.0 software on the image scanned with ultrasound biomicroscopy (UBM). The vault was assessed by UBM 3 months after surgery. Multiple stepwise regression analysis was employed to identify the variables that were correlated with the vault. RESULTS: The results showed that the vault was correlated with 3 variables: ACA (22.4 +/- 4.25 mm2), WTW (11.36 +/- 0.29 mm) and Lenscur (9.15 +/- 1.21 mm). The regressive equation was: vault (mm) = 1.785 + 0.017 * ACA + 0.051 * Lenscur - 0.203 * WTW. CONCLUSIONS: Biometric parameters of the anterior segment (ACA, WTW and Lenscur) can predict the vault after ICL implantation using a new regression equation. PMID- 27463338 TI - Acid Phosphatase Isoenzyme Profiles in Acute and Chronic Leukemias. AB - We analyzed the acid phosphatase (AcP) isoenzyme profiles of normal and malignant hematopoietic cells using isoelectric focusing followed by diazo staining. Reproducibly defined bands and band complexes could be identified and were correlated with the cellular material analyzed. Different isoenzyme profiles were indeed associated with the various cell types and cell lineages. Lymphoid cells were characterized by the expression of one or two bands at pH 6.0, thus termed L1 or L2 pattern. Myeloid cells showed different isoenzyme profiles (consisting of 3-11 bands) designated M1 and M2. One particular isoenzyme near the cathodal end of the gel could not be inhibited by tarirate, the so-called tartrate resistant AcP (TRAP). Expression of the TRAP isoenzyme was found in nearly all cases of hairy cell leukemia, but also in a significant number of other B-cell or monocyte derived malignancies. TRAP appears to be an enzymatic parameter for activated B-cells and monocytes. The monocytic cell lineage was clearly documented by the detection of a unique triplet of strongly stained isoenzymes. The AcP isoenzyme profiles represent biochemical cell markers indicating states of activation and lineage of differentiation. PMID- 27463336 TI - Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome Related Pregnancy Complications and Thrombosis. AB - In the antiphospholipid syndrome (APS), patients produce antiphospholipid antibodies (aPL) that promote thrombosis and adverse pregnancy outcomes. Current therapy with anticoagulation is only partially effective and associated with multiple complications. We previously discovered that aPL recognition of cell surface beta2-glycoprotein I (beta2-GPI) initiates apolipoprotein E receptor 2 (apoER2)-dependent signaling in endothelial cells and in placental trophoblasts that ultimately promotes thrombosis and fetal loss, respectively. Here we sought to identify a monoclonal antibody (mAb) to beta2-GPI that negates aPL-induced processes in cell culture and APS disease endpoints in mice. In a screen measuring endothelial NO synthase (eNOS) activity in cultured endothelial cells, we found that whereas aPL inhibit eNOS, the mAb 1N11 does not, and instead 1N11 prevents aPL action. Coimmunoprecipitation studies revealed that 1N11 decreases pathogenic antibody binding to beta2-GPI, and it blocks aPL-induced complex formation between beta2-GPI and apoER2. 1N11 also prevents aPL antagonism of endothelial cell migration, and in mice it reverses the impairment in reendothelialization caused by aPL, which underlies the non-thrombotic vascular occlusion provoked by disease-causing antibodies. In addition, aPL inhibition of trophoblast proliferation and migration is negated by 1N11, and the more than 6 fold increase in fetal resorption caused by aPL in pregnant mice is prevented by 1N11. Furthermore, the promotion of thrombosis by aPL is negated by 1N11. Thus, 1N11 has been identified as an mAb that attenuates APS-related pregnancy complications and thrombosis in mice. 1N11 may provide an efficacious, mechanism based therapy to combat the often devastating conditions suffered by APS patients. PMID- 27463339 TI - Bcl-2 Gene and Prognosis of B-cell Lymphoma. AB - Both the polymerase chain reaction (PCR) and Southern blot analysis were used to detect bcl-2 gene rearrangement in B-cell lymphoma. Recent molecular studies have shown that the translocation of karyotypic abnormalities t(14;18) results in the juxtaposition of the candidate proto-oncogene bcl-2 on chromosome 18 with the immunoglobulin heavy-chain locus on chromosome 14. We detected the bcl-2 rearrangement in three of six follicular lymphomas (50%), two of five follicular and diffuse lymphomas (40%), one of 13 diffuse medium-sized cell lymphomas (7.7%) and two of 33 diffuse large cell lymphomas (6.0%) through Southern blot analysis. With PCR, the rearrangement was demonstrated in five of eight follicular (63%), three of five follicular and diffuse (60%), seven of 36 diffuse large cell lymphomas (19%) and two of 13 diffuse medium-sized lymphomas (15%). Diffuse large cell lymphomas with bcl-2 rearrangement detected by PCR have a good prognosis as do cases of follicular lymphoma The bcl-2 gene is closely related to follicular lymphoma as described in previous reports and has general prognostic importance in diffuse large cell lymphoma of B cell type. PMID- 27463340 TI - Familial Lymphoproliferative Disorders with Chromosomal Fragile Site Analysis. AB - We have identified a family in which three members developed B-cell lymphoproliferative disorders within a nine month period. The 33 year old proband and his mother have hairy cell leukemia, and his 37 year old brother developed a large cell lymphoma. Chromosomal fragile site analysis of peripheral blood lymphocytes of the three patients as well as two healthy family members was performed. The mean number of rare fragile sites present per cell analyzed was not significantly different from that observed in a group of healthy adults used as controls. However, the level of expression of the common fragile sites detected in each of the study patients was significantly elevated compared to the control population. Although the relationship between the level of expression of common fragile sites and the subsequent development of a malignant process is unknown, many of the agents that induce these sites are known mutagens, and the level of their expression may reflect a genetic susceptibility to mutagenic damage. Thus, it is possible that common exposure to an environmental mutagen may have contributed to the temporal clustering of malignancy in this family. PMID- 27463341 TI - Patterns of Membrane Antigen Expression by AML Blasts: Quantitation and Histogram Analysis. AB - Leukaemic myeloid blasts from non-monocytic (M1-M3, n = 36) and monocytic (M4 and M5, n = 21) AML cases were examined for the expression of 12 different membrane determinants by flow cytometry. Data analyses for each antigen included the determination of (a) the mean fluorescence intensity for the whole blast cell population, (b) the relative levels of membrane fluorescence for individual events (cells), and (c) a conventional assessment of the proportion of cells staining positively (i.e. exceeding a pre-defined level of fluorescence). Three main types of staining histogram were observed and, of these, the most commonly seen (348/432 and 176/252 of non-monocytic and monocytic AML histograms respectively) was characterised by an homogenous distribution of staining intensities which did not exceed two log decades of fluorescence (S-type). The second staining pattern was characterised by a continuous spectrum of fluorescence which exceeded two log decades of fluorescence (SE-type), and the third pattern showed evidence of two leukaemic populations with different levels of fluorescent staining (BI-type). With the exception of occasional AML cases which expressed CD7 or CD19 with low staining intensity, the expression of lymphoid-associated membrane CD3, CD10, and CD22 by AML blasts was insignificant. For comparison, analysing the histogram patterns of expression for the myeloid and non-lineage associated membrane determinants revealed that CD11c, CD13, CD14, and CD38 were mainly of S- or SE-type for the non-monocytic AML variants, with a minor but significant proportion of such cases expressing CD33 (7/36), CD34 (6/36) and HLA-Dr (6/36) with a BI-type staining pattern. Similarly, histogram patterns for CD13, CD33, CD34 and CD38 expression by the monocytic AML variants were predominantly of S- or SE- type, with minor proportions of cases expressing CD11c (7/21), CD14 (10/21), and HLA-Dr with BI-type staining. Comparisons between the mean fluorescence staining intensities for the whole blast cell population and conventional positive versus negative delineations for each antigen studied further suggested that semi-quantitative measurements of fluorescent staining were more informative and potentially of greater relevance to the study and diagnostic assessment of acute myeloid leukaemia subtypes. PMID- 27463342 TI - Thrombospondin as a Marker for Leukemic Megakaryoblasts. AB - Four cases of acute leukemia are reported in which the blast cells were reactive with a monoclonal antibody to the platelet alpha granule glycoprotein thrombospondin (TSP). Blasts in all four cases were also terminal deoxynucleotidyl transferase (TdT)-positive. Two cases demonstrated the presence of the Philadelphia chromosome, t(9;22). The only cells in normal bone marrow which reacted with antibody to TSP were megakaryocytes. Blasts in nine cases of acute myelogenous leukemia, six cases of acute lymphocytic leukemia, four cases of undifferentiated leukemia, and three cases of myelodysplastic syndrome were negative for TSP. Thus, TSP is useful in the identification of normal megakaryocytes and a subset of acute leukemia cells. The presence of both TSP and TdT in the leukemic blasts of our four patients suggests evolution from a pluripotent stem cell capable of multi-lineage differentiation. PMID- 27463343 TI - Low Dose Interferon Alfa-2B for the Induction of Remission of Hairy Cell Leukemia: A Multi-institutional Study of 49 Patients. AB - This multicenter study reports on 49 patients with hairy cell leukemia (HCL) who were treated subcutaneously with alfa-2b interferon (Intron A, Schering Corporation, Kenilworth, N.J.), three times a week at a reduced dosage of 200,000 units/m(2), one-tenth the dose of the standard 2 million units/m(2). The response rate (normalized blood counts) was 22% (11 of 49); an additional 12 patients had a minor response for an overall response rate of 47% (23 of 49). When response was assessed by prior IFN therapy, no significant difference was noted. Five of 21 (24%) with no prior IFN and 6 of 28 (21%) with prior IFN therapy achieved at least a normalization of blood counts (p = 0.07). The response rate with low-dose interferon is inferior to that with standard dose interferon and should not be used for remission induction, but should be evaluated for its role in long-term maintenance of response. PMID- 27463344 TI - A Pilot Study of Low Dose ARA-C, Interferon-Alpha and Cis-Retinoic Acid (AIR) Combination Therapy for Poor Risk Patients with Acute Myeloid Leukaemia. AB - 20 adult patients with acute myeloid leukaemia who were considered not suitable for or resistant to conventional chemotherapy were entered into a pilot study of low dose ARA-C, Interferon-alpha and cis-retinoic acid (AIR) combination therapy. The overall response rate was 35%, with 4/20 patients achieving complete remission and 3/20 partial remission. There was also favourable duration of survival among the responders. AIR therapy was well tolerated and was given on an out-patient basis. Hospital admission was minimum during the period of treatment. Most patients however required out-patient support of blood and platelet transfusion. These results indicate that AIR therapy may be beneficial in a selected group of poor risk patients with AML. Further evaluation is needed to identify parameters predictive of response. PMID- 27463345 TI - Acute Lymphoblastic Leukaemia in Adults. Prognostic Factors and 10 Year Treatment Results. AB - One hundred and twenty adult patients with acute lymphoblastic leukaemia were treated over a 10 year period with an intensive treatment protocol including induction with vincristine, prednisolone, adriamycin and L asparaginase, early intensification with 4 cycles of cytosine arabinoside plus VP 16 followed by BCNU and cyclical maintenance therapy consisting of sequential administration of 4 chemotherapy combinations, together with prophylactic in-trathecal methotrexate. 108/120 (90%) achieved initial complete remission (CR). Factors which predicted for CR were absence of bleeding at initial presentation and LDH < 300 Iu. The overall median duration of remission was 12 months with 19% of patients in continuous complete remission for 5 years or more. Among the poor prognostic factors for continuous complete remission were race (black patients) WCC > 30 * 10(9)/1, bleeding at presentation, splenomegaly at presentation, phenotype other than T and age > 35 years. The effect of adverse prognostic features was cumulative but race was the most significant factor overall with no black patients surviving for more than 24 months. There was a significantly higher rate of decreased compliance with maintenance therapy among black patients, which may have been responsible for the adverse influence of race. These results suggest that the role of maintenance chemotherapy is significant in maintaining prolonged complete remission in adult acute lymphoblastic leukaemia. PMID- 27463346 TI - Multidrug Resistance in Acute Leukaemia: A Comparative Study of Immunocytochemical and RNA Slot Blot Detection of P-glycoprotein Expression. AB - We have analysed and compared the applicability of mRNA quantitation and immunocytochemistry to the detection of the multidrug resistant gene mdr1 and its protein product P-glycoprotein (PGP) in patients with acute leukaemia. Elevated mdr1 mRNA was detected in 12 of 55 patients and PGP expression by immunocytochemistry in 10 of 27. Raised mdr1 transcript was associated with immunocytochemical positivity in 6 of 8 cases studied. 4 of 10 cases of immunocytochemical positivity were not associated with elevated mdr1 mRNA. Immunocytochemistry showed PGP expression to be heterogeneous within blast populations. In 4 cases PGP positivity was most marked in differentiated leukaemic subpopulations. PGP expression was increased in secondary acute myeloid leukaemia (AML) compared to other disease groups. No association with disease stage was detected except within the secondary leukaemias. In 40 patients studied mdr3 mRNA was raised in one patient with AML and in two remission marrows. These results indicate that further prospective studies in acute leukaemias are required using combined immunocytochemical and RNA quantitation of PGP expression. PMID- 27463347 TI - Is Surgery Necessary in the Treatment of Primary Gastric Non-Hodgkin Lymphoma? AB - Fifty-two patients with primary gastric lymphoma were randomly assigned to two different surgical approaches. Twenty-eight cases were diagnosed by endoscopy and treated with chemotherapy CHOP-Bleo (cyclophosphamide, adriamycin, vincristine, prednisone and bleomycin) alternating with CMED (cyclophosphamide, metothexate, etoposide and dexamethasone). Twenty four cases underwent debulking surgery (partial or total gastrectomy) followed by the same chemotherapy. No differences were observed in relapse free disease or survival in resected or unresected patients. Complications were more frequent and severe in patients who underwent surgery. We believe that surgery is not necessary in the treatment of patients with primary gastric lymphoma. PMID- 27463348 TI - Heterogeneity of Leukemic Cells with Basophilic Features: Cytochemical, Ultrastructural and Immunophonotypic Analysis of 8 Cases. AB - We have studied leukemic cells, derived from acute nonlymphocytic leukemia with basophilic features and basophilic crisis of chronic myelogenous leukemia (CML), by cytochemical and ultrastructural examination and analysis of surface markers. Cytochemical results varied from case to case, while the ultrastructural appearances of the granules were different from normal granules. The granules had more delicate granular matrices with or without myelinoid figures, whorled or scroll matrix, multivesicular bodies structures, theta granules, and crystalloid structures. Leukemic cells in all cases had myeloid surface markers with some degree of variability. In addition, they were occasionally positive for lymphoid markers, but not for CD10 and IgE receptors. The present results show that leukemic cells with basophilic features are heterogeneous in their morphology, cytochemistry and surface markers. PMID- 27463349 TI - Expression of P-Glycoprotein in Non-Hodgkin's Lymphomas. AB - Drug resistance has been shown to be associated with the expression of P glycoprotein (P-gp), the product of the mdr-1 gene. In the present study the expression of P-gp in 57 cases B-cell non Hodgkin lymphoma NHL was assessed before chemotherapy. Six cases of reactive lymphoid tissue and 11 cases of solid tumors were also studied. The expression of P-gp was evaluated by immunocyto- and histochemical methods, using three different Monoclonal Antibodies C219, JSB-1 and MRK16 directed against separate epitopes of P-gp. Comparable frequencies of cases positive for P-gp were found in low grade (6/40) and high grade (3/17) lymphomas. The pattern of staining was predominantly cytoplasmic, although a Golgi-associated dot like pattern of staining was also seen, mostly with JSB-1 MAb. Both cases of Hairy cell leukemia were P-gp positive. P-gp expression was also found in the endothelium of small capillaries and some high endothelial venules, as well as in macrophages, in both lymphomas and reactive lymphoid tissues. P-gp expression was found in a low frequency in NHL, suggesting that clinical drug resistance may already be predicted at the time of diagnosis and thus may serve as a guide in the choice of chemotherapeutical regiment. PMID- 27463350 TI - P-Glycoprotein Expression in Drug-Resistant Chronic Lymphoproliferative Disorder. AB - Peripheral blood lymphocytes from 60 patients with drug-resistant chronic lymphoproliferative disorders (LPD) were examined for expression of P glycoprotein (P-gp) by direct immunofluorescence (IF) test using monoclonal antibody (MoAb) C219. Four of the 15 patients with prolymphocytic leukaemia (PLL), and both patients with Adult T cell leukaemialymphoma (ATLL) expressed P gp. However, none of the 3 hairy cell leukaemia (HCL) patients expressed P-gp. Two of the 14 patients with anthracycline resistant chronic lymphocytic leukaemia (CLL) expressed P-gp but none of the 26 CLL patients resistant only to chlorambucil expressed it. The percentage of cells expressing P-gp varied considerably between different groups as well as different individuals (20-100%). Activation of peripheral blood lymphocytes from non-resistant CLL patients with phorbol myristic acetate (PMA) did not induce P-gp expression. It appears that multidrug resistance in ATLL is most likely mediated by over-expression of P-gp and this may also be an important mechanism in multidrug resistance in some PLL and CLL patients. PMID- 27463351 TI - Cellular and Molecular Characterization of Two Cases of Castleman's Disease, Plasma Cell Variant. AB - We report the cellular and molecular characterization of two cases of Castleman's disease, plasma cell variant, that differed in their clinical presentation and course. Patient 1 had Castleman's disease in association with Kaposis's sarcoma unrelated to human immunodeficiency virus (HIV) infection and died while he was receiving an aggressive chemotherapeutic regimen for Kaposi's sarcoma. Patient 2 had an isolated retroperitoneal lymphoid mass with an adjacent enlarged limph nodes and his symptoms disappeared completely following the surgical removal of both. Pathologic and immunohistochemical analyses in both cases, revealed that there was a massive infiltration of polyclonal plasma cells in the interfollicular areas of the lymph nodes. Immunoglobulin gene rearrangement studies confirmed the polyclonal nature of B-lineage cells in the involved lymph nodes. Southern blot experiments failed to demonstrate the presence of EBV genome copies in the same lymph nodes. These paradigmatic cases lend further support to the notion that Castleman's disease is an extremely heterogeneous entity. PMID- 27463352 TI - Expression Pattern of Mitochondrial ND2 Gene in Human Leukemia and in HL60 Cells During Growth and Differentiation. AB - We differentially screened 5,000 clones from a cDNA library of acute myelogenous leukemia (AML) cell line HL60 using cDNA probes derived from normal granulocytes or from acute myelomonocytic leukemia cells, the objective being to identify genes preferentially expressed in myeloid lineage leukemic cells. One clone, corresponding to a mitochondrial DNA fragment, including NADH dehydrogenase subunit 2 (ND2) gene, was selected for use as a probe. We examined expression of the ND2 gene in various leukemic cell populations and in normal peripheral blood cells. DNA-RNA hybridization studies revealed that ND2 messenger RNA (mRNA) was more markedly expressed in AML cells than in other leukemic cells and normal peripheral blood granulocytes. The expression of ND2 mRNA decreased in HL60 cells several hours after treatment with phorbol myristate acetate (PMA), or dimethyl sulfoxide (DMSO). However, the ND2 gene expression did not depend on the growth state of HL60 cells because the steady-state level of its expression was observed during transitions of growth. These results suggest that ND2 mRNA is involved in the maturation of myeloid cells and in cellular differentiation, in a lineage preferential manner. A comparison of the nucleotide sequence of this clone with the documented human mitochondrial DNA sequence revealed several single-base substitutions, insertions and a 39-bases insertion. PMID- 27463353 TI - HDS: Establishment of a New Cell Line from a Hairy Cell Leukemia Patient with Resistance to Alpha-Interferon Therapy. AB - A new cell line, designated "HDS", was established in a suspension culture derived from the peripheral blood of a patient with hairy cell leukemia (HCL) who developed clinical resistance to alpha-interferon (aIFN) therapy. The patient exhibited a clinical picture characteristic of HCL, including splenomegaly, cytopenias, and tartrate-resistant acid phosphatase (TRAP)-positive "hairy" cells in blood and marrow. Chromosomal studies revealed that the cultured cells possess the chromosomal abnormality +12. Cytochemical and immunologic studies show the HDS cell line had the phenotype of a B-lymphocyte. HDS cells expressed the HLA-DR and CD19 surface antigens, but were negative for early B (CD10) and T (CD2, CD3) cell markers. The cells are also negative for other T-cell, granulocytic and monocytic markers and for typical HCL markers such as CD11c and CD22. However, the expression of these antigens was induced by in-vitro treatment of the cells with the differentiation-inducing agent tetradecanoyl phorbol acetate (TPA). Ultrastructural analyses of the cultured cells revealed a display of surface microvilli mixed with ruffles in a classical hairy cell pattern. It is therefore highly likely that the HDS cells represent HCL cells in an atypical stage of differentiation. PMID- 27463354 TI - Characterization of a New Human B Cell Line (Bonna-12) with Trisomy 9 and Trisomy 12 Chromosomal Abnormality. AB - A new EBV positive human B-cell line, BONNA-12 was established from splenic cells of a patient with a hairy cell leukemia (HCL). BONNA-12 cells grew spontaneously and formed colonies in semisolid media. Although the BONNA-12 cell line was identical with the patient's spleen cells by HLA analysis and Southern blot examination of minisatellite DNA patterns, the immunoglobulin heavy and light chain rearrangement patterns differed from the original HCL. Cytogenetic analysis of the BONNA-12 cell line demonstrated in the major cell clone a 47, X, -Y, +9, +12 karyotype. Trisomy 12 is a characteristic abnormality in chronic lymphocytic leukemia that also rarely occurs in HCL. The BONNA-12 cell line is of potential value in the study of trisomy 12 in chronic B cell malignancies. PMID- 27463355 TI - Two Cases of Translocation t(3;6)(p14;p22): A Non Random Chromosomal Abnormality? AB - It is generally accepted that the short arm of chromosome 6 is a likely site to be involved in chromosomal rearrangements of MDS/ANLL following radio/chemotherapy. We report here two cases of t(3;6)(p14;p22). One patient is a 55 years old male with a previous history of occupational exposure who developed, an acute megakaryoblastic leukemia after a preleukemic phase. Chromosome analysis showed a t(3;6)(p14;p22), associated with del (5)(q14q31), -7, with variations and a trend to hypoploidy. The second patient is a 33 years old man, with chronic myeloid leukemia treated with Hydroxyurea (HU), HU + $aL-IFN and $aL-IFN alone. The first cytogenetic study before treatment, showed a t(9;22)(q34;q11). In the following months the patient had simultaneously t(9;22)(q34;q11) + t(3;6)(p14;p22) in a minority and thereafter in all the mitoses, with progressive deterioration, megakaryocyte abnormalities, but no blast crisis. Our patients are compared with the only 5 other published cases with t(3;6)(p14;p22), who shared some common features, namely a past history of chemo/radiotherapy or exposure to chemical mutagens and an association with other, so-called "secondary" chromosome aberrations, on segments 3p, 5q, 7q, 12p and 17p. We suggest that this uncommon translocation t(3;6) is nonrandom. It is worth noting that band 6p21 is the site of pim 1 oncogen, and that a fragile site is located on band 3p14. PMID- 27463356 TI - Acute Myeloid Leukaemia Following Matched Allogeneic Bone Marrow Transplantation for T-Cell Lymphoblastic Lymphoma. AB - It is now commonly acknowledged that cells from some acute leukaemias may bear both myeloid and lymphoid markers at diagnosis, or that relapse following initial treatment may occur, with blast cells phenotypically different from those seen at initial diagnosis. Patients showing evidence of bi-linear disease seem to carry a worse prognosis for cure. Here, a case of T-cell lymphoblastic lymphoma is reported, who relapsed with acute myeloblastic leukaemia, following allogeneic bone marrow transplantation. Early diagnosis of disease with lymphoid and myeloid features is therefore warranted, so that intensive treatment programmes may be offered, in anticipation of permanent cure. PMID- 27463357 TI - Blood Transfusion Induced Opportunistic Adult T Cell Leukaemia/Lymphoma after Hodgkin's Disease. AB - A patient previously treated for Hodgkin's disease (HD) developed secondary adult T cell leukaemia/lymphoma (ATL) after blood transfusion. Immunohistochemical analysis and polymerase chain reaction support the diagnosis. To the best of our knowledge this is the first occurrence of transfusion induced ATL occurring as a second malignancy after treatment for HD. The leukaemia/lymphoma probably developed on the basis of underlying immunosuppression. PMID- 27463358 TI - Cured Multiple Myeloma Followed by Primary Malignant Lymphoma of the Lung. AB - A 56-year-old patient was found to have smouldering myeloma which remained asymptomatic and untreated for 13 years. Localised osteolytic lesions then appeared, which responded to local irradiation. Six years later, an increased serum M-protein became evident (IgG$LD, 3 gr/dl) associated with 35% plasma cells in the bone marrow, which necessitated melphalan/prednisone therapy. A prolonged complete remission was achieved lasting 6 years. Thereafter, the patient developed a myelodysplastic syndrome with leukopenia and refractory anemia and he finally died of pulmonary disease. Autopsy revealed extensive thoracic involvement by a primary malignant lymphoma of the lungs (IgMK) with no evidence of myeloma. Such a long follow-up with subsequent cure is rare in multiple myeloma as is the appearance of a second B cell malignancy, which may either be associated with the myeloma and/or chemotherapy given, or a coincidental occurrence. PMID- 27463359 TI - Variation in leaf wettability traits along a tropical montane elevation gradient. AB - Leaf wetting is often considered to have negative effects on plant function, such that wet environments may select for leaves with certain leaf surface, morphological, and architectural traits that reduce leaf wettability. However, there is growing recognition that leaf wetting can have positive effects. We measured variation in two traits, leaf drip tips and leaf water repellency, in a series of nine tropical forest communities occurring along a 3300-m elevation gradient in southern Peru. To extend this climatic gradient, we also assembled published leaf water repellency values from 17 additional sites. We then tested hypotheses for how these traits should vary as a function of climate. Contrary to expectations, we found that the proportion of species with drip tips did not increase with increasing precipitation. Instead, drip tips increased with increasing temperature. Moreover, leaf water repellency was very low in our sites and the global analysis indicated high repellency only in sites with low precipitation and temperatures. Our findings suggest that drip tips and repellency may not solely reflect the negative effects of wetting on plant function. Understanding the drivers of leaf wettability traits can provide insight into the effects of leaf wetting on plant, community, and ecosystem function. PMID- 27463360 TI - Giant nerves in chronic inflammatory polyradiculoneuropathy. AB - INTRODUCTION: Nerve enlargement (NE) is described in inflammatory and inherited neuropathies. It is commonly multifocal and moderate in the former and homogeneous and generalized in the latter. We describe 4 cases of massive NE in inflammatory neuropathies. METHODS: Patients presented with symptoms of polyneuropathy that progressed over months to years. Nerve conduction studies (NCS), laboratory analysis, nerve MRI, and nerve ultrasound were performed. RESULTS: NCS revealed demyelinating neuropathy in all with multifocal conduction blocks or increased terminal latency indices. MRI/ultrasound revealed extensive NE in the roots and nerves. Detailed diagnostics including biopsies, positron emission tomography-computed tomography, and genetic testing revealed no other pathology. Chronic inflammatory demyelinating polyneuropathy variants were diagnosed in all, and immunotherapies were successfully initiated. CONCLUSIONS: MRI and ultrasound contributed to diagnosis and therapy. All patients had giant NE in common, which strongly suggested inherited neuropathy. However, the final diagnosis was inflammatory neuropathy. Impressive NE can occur in immune-mediated neuropathies and should be carefully differentiated from inherited neuropathies. Muscle Nerve 55: 285-289, 2017. PMID- 27463361 TI - DNA barcoding in the media: does coverage of cool science reflect its social context? AB - Paul Hebert and colleagues first described DNA barcoding in 2003, which led to international efforts to promote and coordinate its use. Since its inception, DNA barcoding has generated considerable media coverage. We analysed whether this coverage reflected both the scientific and social mandates of international barcoding organizations. We searched newspaper databases to identify 900 English language articles from 2003 to 2013. Coverage of the science of DNA barcoding was highly positive but lacked context for key topics. Coverage omissions pose challenges for public understanding of the science and applications of DNA barcoding; these included coverage of governance structures and issues related to the sharing of genetic resources across national borders. Our analysis provided insight into how barcoding communication efforts have translated into media coverage; more targeted communication efforts may focus media attention on previously omitted, but important topics. Our analysis is timely as the DNA barcoding community works to establish the International Society for the Barcode of Life. PMID- 27463362 TI - Sacral neuromodulation for faecal incontinence following obstetric sphincter injury - outcome of percutaneous nerve evaluation. AB - AIM: The purpose of this study was to assess the efficacy of percutaneous nerve evaluation (PNE) in women with faecal incontinence (FI) following obstetric anal sphincter injury and to relate the outcomes to baseline factors, with special emphasis on the extent of the sphincter defect. METHOD: This was a prospective study at a tertiary colorectal referral unit at the University Hospital of North Norway conducted from 2012 to 2014. Sixty-three women underwent a 3-week PNE using a tined lead and the Verify(r) external neurostimulator. The primary outcome was efficacy, defined as the percentage reduction in weekly FI episodes, and patients with a reduction of 50% or more were defined as responders. Baseline factors affecting the primary outcome were explored. Sphincter defects were classified with a validated three-dimensional endoanal ultrasound defect score. RESULTS: Fifty-six (89%) of the 63 women were responders with a reduction in weekly FI episodes of 94.5%, from a median (interquartile range) of 4.8 (2.0 11.0) to 0.5 (0-2.0) (P < 0.001). Twenty-nine (52%) reported no weekly FI episodes, and urgency episodes disappeared in 18 (32%). In the multivariable linear regression model, efficacy was related to concomitant urinary incontinence (P = 0.04), body mass index (BMI) (P = 0.03) and pain during PNE (P = 0.046) but not to the extent of the sphincter defect (P = 0.1). Responders had a higher St Mark's score than nonresponders (P = 0.046). CONCLUSIONS: The vast majority of women had successful PNE tests. Responders had higher baseline St Mark's scores than nonresponders. Efficacy was related to concomitant urinary incontinence, BMI and pain, not to the extent of the sphincter defect. PMID- 27463363 TI - HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy. AB - BACKGROUND: Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS). METHODS: Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007-2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression. RESULTS: A total of 332 patients with HER2 positive BC were reviewed. Median age was 54 (range 23-89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic impact was detected for tumor size (p = 0.02), nodal status (p<0.01), proliferation index (p<0.01), level (>=20%) of estrogen receptor expression (p = 0.03) and neoadjuvant therapeutic setting (p = 0.03), respectively. Importantly, univariate and multivariable analysis revealed that standard trastuzumab containing chemotherapy resulted in impaired disease free survival among tumors with FISH ratio >8 (p<0.01). Although less pronounced, a similar association was found also with respect to high HER2 gene copy numbers (>12) and DFS (p = 0.01). CONCLUSIONS: In early BC patients, tumors with high HER2 amplification ratios (>8), may less likely respond to standard trastuzumab-containing therapies. Although, we obtained a similar effect for high HER2 gene copy numbers, this provides only an indirect speculation and not a proof that high HER2/CEP17 ratios may induce HER2 resistance. PMID- 27463364 TI - Treatment of children with acute lymphoblastic leukemia with risk group based intensification and omission of cranial irradiation: A Korean study of 295 patients. AB - BACKGROUND: Recent studies indicate 70-80% event-free survival (EFS) for pediatric acute lymphoblastic leukemia (ALL). In this study, we report the outcome of 295 children and adolescents treated at our institution, with stratification into four risk groups, and omission of cranial irradiation in all patients. PROCEDURE: Patients were diagnosed from January 2005 to December 2011 and classified and treated as low, standard, high, and very high risk groups. A delayed intensification phase was given twice for high and very high risk groups. None of the patients received cranial irradiation for central nervous system (CNS) prophylaxis. RESULTS: The 10-year EFS and overall survival (OS) were 78.5 +/- 2.5% and 81.9 +/- 2.7%, respectively. EFS according to risk group was as follows: low risk 91.2 +/- 3.7%, standard risk 98.1 +/- 1.9%, high risk 81.5 +/- 4.3%, very high risk 59.4 +/- 5.3%. In a multivariate analysis, high hyperdiploidy and infant ALL were significant predictors of EFS. Cumulative incidence of any relapse, isolated CNS relapse, and any CNS relapse were 17.1 +/- 2.3%, 1.5 +/- 0.7%, and 2.3 +/- 0.9%, respectively. Other events included infection-related deaths during remission induction chemotherapy (3), primary refractory disease (2), and treatment-related deaths in first complete remission (8). CONCLUSIONS: In this single-institution study of Korean pediatric ALL patients, risk group based intensification with omission of cranial irradiation resulted in EFS comparable to previous studies, excellent survival of low- and standard-risk patients, and a low rate of CNS relapse. PMID- 27463365 TI - Signaling Pathways of Purinergic Receptors and Their Interactions with Cholinergic and Adrenergic Pathways in the Lacrimal Gland. AB - PURPOSE: Purinergic receptors play a key role in the function of the lacrimal gland (LG) as P1 purinergic receptors A1, A2A, and A2B, P2X1-7 receptors, and many of the P2Y receptors are expressed. METHODS: This review examines the current knowledge of purinergic receptors in the LG as well as the signaling pathways activated by these receptors. RESULTS: These receptors are expressed on the acinar, ductal, and myoepithelial cells. Considerable crosstalk exists between the pathways activated by P2X7 receptors with those activated by M3 muscarinic or alpha1D adrenergic receptors. The mechanism of the crosstalk between P2X7 and M3 muscarinic receptors differs from that of the crosstalk between P2X7 and alpha1D adrenergic receptors. CONCLUSIONS: Understanding purinergic receptors and how they modulate protein secretion could play a key role in normal and pathological responses of the LG. PMID- 27463368 TI - Mass Spectrometric Imaging of Wheat (Triticum spp.) and Barley (Hordeum vulgare L.) Cultivars: Distribution of Major Cell Wall Polysaccharides According to Their Main Structural Features. AB - Arabinoxylans (AX) and (1->3),(1->4)-beta-glucans (BG) are the main components of cereal cell walls and influence many aspects of their end uses. Important variations in the composition and structure of these polysaccharides have been reported among cereals and cultivars of a given species. In this work, the spatial distribution of AX and BG in the endosperm of mature grains was established for nine wheat varieties and eight barley varieties using enzymatically assisted mass spectrometry imaging (MSI). Important structural features of the AX and BG polymers that were previously shown to influence their physicochemical properties were assessed. Differences in the distribution of AX and BG structures were observed, both within the endosperm of a given cultivar and between wheat and barley cultivars. This study provides a unique picture of the structural heterogeneity of AX and BG polysaccharides at the scale of the whole endosperm in a series of wheat and barley cultivars. Thus, it can participate meaningfully in a strategy aiming at understanding the structure function relationships of these two polymers. PMID- 27463367 TI - The quest for the shortest fragments of A (13-19) and B (12-17) responsible for the aggregation of human insulin. AB - AIM: To identify the shortest components of A13-A19, B12-B17 fragments capable for fibrillation and to validate the dependability of aggregation on the presence of hydroxyl group engaged in the 'tyrosine kissing'. MATERIALS & METHODS: Fragments A13-A19 and B12-B17 of insulin and all shortened analogues were obtained by using DMT/NMM/TosO(-) as a coupling reagent. The aggregation was studied by three independent tests. RESULTS: Studies on the susceptibility to aggregation of truncated analogs of insulin amyloidogenic core show three groups of peptides. CONCLUSION: Truncation of A13-A419 fragment shows that fibrous structures are formed by all peptides bearing (13)H-LeuTyr-OH(14). Propensity to aggregation was found for (16)H-TyrLeu-OH(17) B12-B17 fragment. Tyrosine residue modification by incorporation of tert-butyl group on hydroxyl function gave analogues still predisposed to aggregation. PMID- 27463366 TI - Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma. AB - Human mucosal melanoma (MM), an uncommon, aggressive and diverse subtype, shares characteristics with spontaneous MM in dogs. Although BRAF and N-RAS mutations are uncommon in MM in both species, the majority of human and canine MM evaluated exhibited RAS/ERK and/or PI3K/mTOR signaling pathway activation. Canine MM cell lines, with varying ERK and AKT/mTOR activation levels reflective of naturally occurring differences in dogs, were sensitive to the MEK inhibitor GSK1120212 and dual PI3K/mTOR inhibitor NVP-BEZ235. The two-drug combination synergistically decreased cell survival in association with caspase 3/7 activation, as well as altered expression of cell cycle regulatory proteins and Bcl-2 family proteins. In combination, the two drugs targeted their respective signaling pathways, potentiating reduction of pathway mediators p-ERK, p-AKT, p-S6, and 4E-BP1 in vitro, and in association with significantly inhibited solid tumor growth in MM xenografts in mice. These findings provide evidence of synergistic therapeutic efficacy when simultaneously targeting multiple mediators in melanoma with Ras/ERK and PI3K/mTOR pathway activation. PMID- 27463370 TI - Recent Advances in Mechanobiology of Osteosarcoma. AB - Mechanotransduction is a key process by which cells perceive extracellular mechanical cues/intercellular physical interactions and transform them into intracellular biochemical signals. This physiological process is crucial during bone development and bone remodeling throughout childhood and adult life, whereas several aberrations during this process have emerged as a distinct pathogenic molecular entity in bone maladies and tumor formation. The present review focuses on recent advances regarding the mechanobiology of osteosarcoma, the most common type of bone cancer. Special emphasis is given on the mechano-responsive signal transduction pathways underlying osteosarcoma pathology and on specific mechanosensitive molecules engaged in osteosarcoma development. J. Cell. Biochem. 118: 232-236, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27463369 TI - Identification of Chalcones as Fasciola hepatica Cathepsin L Inhibitors Using a Comprehensive Experimental and Computational Approach. AB - BACKGROUND: Increased reports of human infections have led fasciolosis, a widespread disease of cattle and sheep caused by the liver flukes Fasciola hepatica and Fasciola gigantica, to be considered an emerging zoonotic disease. Chemotherapy is the main control measure available, and triclabendazole is the preferred drug since is effective against both juvenile and mature parasites. However, resistance to triclabendazole has been reported in several countries urging the search of new chemical entities and target molecules to control fluke infections. METHODOLOGY/PRINCIPLE FINDINGS: We searched a library of forty flavonoid derivatives for inhibitors of key stage specific Fasciola hepatica cysteine proteases (FhCL3 and FhCL1). Chalcones substituted with phenyl and naphtyl groups emerged as good cathepsin L inhibitors, interacting more frequently with two putative binding sites within the active site cleft of the enzymes. One of the compounds, C34, tightly bounds to juvenile specific FhCL3 with an IC50 of 5.6 MUM. We demonstrated that C34 is a slow-reversible inhibitor that interacts with the Cys-His catalytic dyad and key S2 and S3 pocket residues, determinants of the substrate specificity of this family of cysteine proteases. Interestingly, C34 induces a reduction in NEJ ability to migrate through the gut wall and a loss of motility phenotype that leads to NEJ death within a week in vitro, while it is not cytotoxic to bovine cells. CONCLUSIONS/SIGNIFICANCE: Up to date there are no reports of in vitro screening for non-peptidic inhibitors of Fasciola hepatica cathepsins, while in general these are considered as the best strategy for in vivo inhibition. We have identified chalcones as novel inhibitors of the two main Cathepsins secreted by juvenile and adult liver flukes. Interestingly, one compound (C34) is highly active towards the juvenile enzyme reducing larval ability to penetrate the gut wall and decreasing NEJ's viability in vitro. These findings open new avenues for the development of novel agents to control fluke infection and possibly other helminthic diseases. PMID- 27463371 TI - Enhanced Immune Response Following DNA Immunization Through In Vivo Electroporation. AB - DNA immunization offers the advantage of allowing for the initiation of animal immunogenicity studies while work to produce and purify the protein of interest is completed. In this study, we sought to evaluate in vivo electroporation (EP) as a means to enhance the antigen-specific immune response from DNA immunization. Mice were immunized thrice with DNA encoding the protein of interest through intramuscular (IM) or intradermal (ID) injections. Test animals were administered an electrical pulse into the muscle or dermis at the site of injection immediately following immunization. In addition, cardiotoxin was injected into the muscle of a subset of test animals 5 days before each DNA injection. Nine weeks following the final DNA immunization, mice were immunized with the encoded purified protein emulsified in Freund's adjuvant. Sera from EP mice taken 2 weeks following the final DNA immunization showed a significant enhancement in antibody response. Specifically, those mice treated with cardiotoxin, immunized IM and given EP showed a strong response, but this was only observed versus solid phase and not solution phase antigen, suggesting the resulting antibody was of low titer and affinity. Similar testing following the protein immunization revealed a significant improvement in relative affinity versus sera taken following DNA immunization. Our results suggest EP can enhance the immune response elicited by DNA immunization. PMID- 27463373 TI - How membrane asymmetry regulates ADAM17 sheddase function. PMID- 27463372 TI - Targeting Tumor Cells with Anti-CD44 Antibody Triggers Macrophage-Mediated Immune Modulatory Effects in a Cancer Xenograft Model. AB - CD44, a transmembrane receptor reported to be involved in various cellular functions, is overexpressed in several cancer types and supposed to be involved in the initiation, progression and prognosis of these cancers. Since the sequence of events following the blockage of the CD44-HA interaction has not yet been studied in detail, we profiled xenograft tumors by RNA Sequencing to elucidate the mode of action of the anti-CD44 antibody RG7356. Analysis of tumor and host gene-expression profiles led us to the hypothesis that treatment with RG7356 antibody leads to an activation of the immune system. Using cytokine measurements we further show that this activation involves the secretion of chemo-attractants necessary for the recruitment of immune cells (i.e. macrophages) to the tumor site. We finally provide evidence for antibody-dependent cellular phagocytosis (ADCP) of the malignant cells by macrophages. PMID- 27463375 TI - Disease Course, Outcome Measures, and Prognostic Predictors in Epilepsy: Opportunities for Improving Outcome of Drug Trials. AB - BACKGROUND: A major concern over the development of new antiepileptic drugs (AEDs) is that the new AEDs have not added substantial clinical benefit over available antiseizure treatment. Additionally, current AEDs have neither improved the health of epilepsy patients nor been shown to prevent epilepsy or to improve the disease. SUMMARY: This chapter reviews new data on patterns of epilepsy with remission and relapse, prognostic factors for seizure outcome, and innovative patient-related outcome measures. Applying this knowledge presents opportunities to improve the drug treatment of epilepsy. KEY MESSAGES: Patient-relevant outcome measures and trial designs may be optimized to provide both evidence for efficacy and safety of AEDs and, in addition, for added clinical benefit over existing treatment. Added benefit of a new AED may be shown by evidence of higher antiseizure efficacy, better health, shorter disease duration, fewer side effects, and improved quality of life compared to available standard treatment. Moving from largely patient-irrelevant outcome measures such as 50% seizure reduction or use of placebo controls to innovative comparison of new AEDs versus standard treatment will revitalize the clinical development of new antiseizure treatments. Hopefully this will usher in a new era of much-needed antiepileptogenic agents that prevent or improve the patterns of epilepsy. PMID- 27463374 TI - Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection. AB - The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-alpha suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory. PMID- 27463376 TI - Strategies in the discovery of novel antifungal scaffolds. AB - The development of next-generation antifungal agents with novel chemical scaffolds and new mechanisms of action is vital due to increased incidence and mortality of invasive fungal infections and severe drug resistance. This review will summarize current strategies to discover novel antifungal scaffolds. In particular, high-throughput screening, drug repurposing, antifungal natural products and new antifungal targets are focused on. New scaffolds with validated antifungal activity, their discovery and optimization process as well as structure-activity relationships are discussed in detail. Perspectives that could inspire future antifungal drug discovery are provided. PMID- 27463378 TI - Correction to: Hanwell, et al. Zebrafish 2016 Jul;13/S1;S-153-S-163. PMID- 27463377 TI - Independent Associations between Sedentary Time, Moderate-To-Vigorous Physical Activity, Cardiorespiratory Fitness and Cardio-Metabolic Health: A Cross Sectional Study. AB - We aimed to study the independent associations of sedentary time (ST), moderate to-vigorous physical activity (MVPA), and objectively measured cardiorespiratory fitness (CRF) with clustered cardio-metabolic risk and its individual components (waist circumference, fasting glucose, HDL-cholesterol, triglycerides and blood pressure). We also investigated whether any associations between MVPA or ST and clustered cardio-metabolic risk were mediated by CRF. MVPA, ST, CRF and individual cardio-metabolic components were measured in a population-based sample of 341 adults (age 53.8 +/- 8.9 years; 61% men) between 2012 and 2014. MVPA and ST were measured with the SenseWear pro 3 Armband and CRF was measured with a maximal exercise test. Multiple linear regression models and the product of coefficients method were used to examine independent associations and mediation effects, respectively. Results showed that low MVPA and low CRF were associated with a higher clustered cardio-metabolic risk (beta = -0.26 and beta = -0.43, both p<0.001, respectively). CRF explained 73% of the variance in the association between MVPA and clustered cardio-metabolic risk and attenuated this association to non-significance. After mutual adjustment for MVPA and ST, CRF was the most important risk factor for a higher clustered cardio-metabolic risk (beta = -0.39, p<0.001). In conclusion, because of the mediating role of CRF, lifestyle interventions need to be feasible yet challenging enough to lead to increases in CRF to improve someone's cardio-metabolic health. PMID- 27463379 TI - Organic Control of Dioctahedral and Trioctahedral Clay Formation in an Alkaline Soil System in the Pantanal Wetland of Nhecolandia, Brazil. AB - Recent studies have focused on the formation of authigenic clays in an alkaline soil system surrounding lakes of the Nhecolandia region, Pantanal wetland. The presence of trioctahedral Mg-smectites (stevensite and saponite types), which requires low Al and Fe contents in the soil solution for its formation, contrasts with the neoformation of dioctahedral Fe-mica (glauconite, and Fe-illite), which instead requires solutions relatively enriched in Al and Fe. This study aims to understand the conditions of co-existence of both, Mg-smectite and Fe-mica a common clay association in former or modern alkaline soil systems and sediments. The study was carried out along an alkaline soil catena representative of the region. The soil organization revealed that Mg-smectite occur in top soil close to the lake, whereas Fe-mica dominate in the clay fraction of deeper greenish horizons a few meters apart. We propose here that this spatial distribution is controlled by the lateral transfer of Fe and Al with organic ligands. Alkaline organic rich solutions (DOC up to 738 mg L-1) collected in the watertable were centrifuged and filtered through membranes of decreasing pore size (0.45 MUm, 0.2 MUm, 30 KDa, 10 KDa, 3 KDa) to separate colloidal and dissolved fractions. Fe, Al, Si, Mg and K were analysed for each fraction. Although the filtration had no influence on Si and K contents, almost 90% of Fe (up to 2.3 mg L-1) and Al (up to 7 mg L-1) are retained at the first cutoff threshold of 0.45MUm. The treatment of the same solutions by oxygen peroxide before filtration shows that a large proportion of Fe and Al were bonded to organic colloids in alkaline soil solution at the immediate lake border, allowing Mg-smectite precipitation. The fast mineralization of the organic matter a few meters apart from the lake favors the release of Fe and Al necessary for Fe-mica neoformation. In comparison with chemical and mineralogical characteristics of alkaline environments described in the literature, the study suggests that the co-existence of trioctahedral Mg smectite and dioctahedral Fe-mica should be regarded as a standard occurrence in alkaline soil systems with organic rich waters. PMID- 27463380 TI - Giant Pulmonary Hydatid Cyst: An Unusual Presentation. PMID- 27463381 TI - Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol. AB - Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2 promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID- 27463389 TI - Appropriate Apixaban Dosing: Prescribers Take Note. PMID- 27463388 TI - Hypertension in rat offspring subjected to perinatal protein malnutrition is not related to the baroreflex dysfunction. AB - This study reports on the effects of maternal protein malnutrition on baroreflex (BR) control of the heart rate and sympathetic nerve activity in the hypertensive male offspring of Wistar rat dams. Wistar rat dams were fed a normal protein (NP) control (17% protein) or a low protein (LP; 8% protein) diet during pregnancy and lactation, and their male offspring were studied when 90 days old. In these animals we evaluated spontaneous and induced BR control, the variability of the cardiovascular system and analyzed a direct recording of lumbar sympathetic nervous activity. The 90 day-old LP conscious rats had increased arterial pressure compared to NP, with enhanced low frequency oscillations of the systolic pressure, but no changes in the spontaneous and induced BR control of heart rate. In relation to nerve recordings, we observed similar values in terms of mean, frequency and amplitude between the groups. In addition, we noted that spontaneous and induced BR control of lumbar sympathetic activity in the LP group was similar to the control group. The data indicate that hypertension in the adult rat offspring subjected to perinatal protein malnutrition is not related to baroreflex dysfunction. PMID- 27463390 TI - Psychological well-being over time among informal caregivers caring for persons with dementia living at home. AB - OBJECTIVES: To investigate informal caregivers' psychological well-being and predicted increase in psychological well-being, when caring for persons with dementia (PwDs) living at home, related to caregiver, PwD and formal care (FC) factors. METHOD: A cohort study at baseline and 3 months' follow-up in eight European countries. Caregivers included (n = 1223) were caring for PwDs aged >= 65 years at home. Data on caregivers, PwDs and FC were collected using standardized instruments. Regression analysis of factors associated with caregiver psychological well-being at baseline and 3 months later was performed. RESULTS: Factors associated with caregiver psychological well-being at baseline were positive experience of caregiving, low caregiver burden, high quality of life (QoL) for caregivers, male gender of PwD, high QoL of PwD, few neuropsychiatric symptoms and depressive symptoms for the PwD. At follow-up, caregivers with increased psychological well-being experienced of quality of care (QoC) higher and were more often using dementia specific service. Predicting factors for caregivers' increased psychological well-being were less caregiver burden, positive experience of caregiving, less supervision of the PwD and higher caregiver QoL, if PwD were male, had higher QoL and less neuropsychiatric symptoms. Furthermore, higher QoC predicted increased caregivers' psychological well-being. CONCLUSION: Informal caregiving for PwDs living at home is a complex task. Our study shows that caregivers' psychological well-being was associated with, among other things, less caregiver burden and higher QoL. Professionals should be aware of PwD neuropsychiatric symptoms that might affect caregivers' psychological well-being, and provide proper care and treatment for caregivers and PwDs. PMID- 27463391 TI - Effect of Preoperative Nutritional Status on Surgical Site Infection in Colorectal Cancer Resection. AB - BACKGROUND/AIMS: Postoperative complications of colorectal cancer (CRC) can sometimes be life threatening. Prevention of morbidity is therefore the most important issue, and among such complications, surgical site infections (SSIs) are the most critical. Predictive factors for SSI were evaluated. PATIENTS AND METHODS: This was a retrospective study of 432 patients with CRC. SSIs were classified into incisional SSIs (iSSIs) and organ/space SSIs (o/sSSIs). RESULTS: Preoperative serum albumin (relative risk (RR) 2.51, p = 0.01) and body mass index (BMI: RR 2.36, p = 0.02) were the independent risk factors for iSSIs, while rectal cancer (RR 6.34, p < 0.0001), preoperative serum albumin (RR 7.03, p = 0.004), age (RR 2.71, p = 0.02), and male sex (RR 2.41, p = 0.05) were the independent risk factors for o/sSSIs. Patients with both low serum albumin and high BMI had the highest incidence of iSSIs (34.2%), and the group with rectal cancer and low serum albumin had the highest incidence of o/sSSIs (57.1%). CONCLUSIONS: Preoperative nutritional status is a risk factor for SSIs in CRC, and its proper preoperative management may reduce the risk of SSIs. PMID- 27463392 TI - Welfare Assessment following Heterotopic or Orthotopic Inoculation of Bladder Cancer in C57BL/6 Mice. AB - Few studies have assessed whether mice used as cancer models experience pain. Despite this possibility, the usual practice is to withhold analgesics as these are generally viewed as confounding. However, pain also alters cancer progression, so preventing it might not only be beneficial to welfare but also to study validity. Establishing the extent to which different cancer models result in pain is an important first step towards their refinement. We used conditioned place preference (CPP) testing and body-weight and behaviour analyses to evaluate the assumption that heterotopically implanted tumours result in less pain and fewer welfare concerns than those implanted orthotopically. C57Bl/6 mice received MB49Luc luciferase expressing bladder cancer cells or saline implanted subcutaneously or into the bladder. These tumour-bearing or control groups underwent 2 daily 45 minute conditioning trials to saline or morphine (2mg/kg) and then a 15 minute drug-free preference test on day 3 of a 3 day cycle, continuing until the study ended. Tumours were imaged and behaviour data obtained following preference tests. Development of preference for the morphine-paired chamber (morphine-seeking) was determined over time. Heterotopic tumour development had no effect on morphine-seeking, and although the restraint used for heterotopic inoculation caused greater initial weight losses than anaesthesia, these mice steadily gained weight and behaved comparatively normally throughout the study. Orthotopic tumour inoculation caused no initial weight losses, but over the final 7 days these mice became less active and lost more body weight than cancer-free controls. This indicated orthotopic implantation probably caused a more negative impact on welfare or conceivably pain; but only according to the current test methods. Pain could not be confirmed because morphine-seeking in the tumour-bearing groups was similar to that seen in controls. Imaging was not found to be an effective method of monitoring tumour development surpassing manual tumour inspection. PMID- 27463393 TI - Organocatalytic Enantioselective Conjugate Addition of Azlactones to Enolizable Linear and Cyclic Enones. AB - Highly diastereo- and enantioselective conjugate additions of azlactones to enolizable cyclic and linear enones were conducted by employing proline aryl sulfonamide as the organocatalyst in trifluorotoluene. The conjugate adducts bearing contiguous quaternary and tertiary stereocenters were obtained in moderate to good yields with excellent diastereoselectivities and moderate to good enantioselectivities. This developed protocol filled in the substrate gap for the organocatalytic conjugate addition of azlactone to enones. PMID- 27463394 TI - European Open Science Cloud. PMID- 27463395 TI - Poised for development. AB - A new study tracks the distribution of bivalent H3K4me3/H3K27me3 chromatin in male germ cells of six vertebrate species. The results have big implications for understanding the mechanisms that specify animal development. PMID- 27463396 TI - Decoding germline de novo point mutations. AB - Analysis of a large whole-genome sequencing data set of 36,441 high-quality de novo mutations (DNMs) that arose in 816 family trios provides an unprecedented view into the landscape of DNMs in the germ line. This work both refines and challenges some of the views previously held on the nature and origin of DNMs. PMID- 27463397 TI - An unsettling picture emerges from population genomic studies of Plasmodium vivax. AB - Two new studies confirm that Plasmodium vivax populations are more diverse than Plasmodium falciparum and identify signs of recent selection at many loci, including those for drug resistance. P. vivax shows a trend of regional adaptations that poses challenges to global efforts to control and eliminate this major cause of relapsing malaria. PMID- 27463398 TI - Corrigendum: The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. PMID- 27463400 TI - Erratum: Cis-regulatory architecture of a brain signaling center predates the origin of chordates. PMID- 27463401 TI - Breast Augmentation: Cancer Concerns and Mammography-A Literature Review. AB - There has been a longstanding concern about whether there is an association between breast cancer and breast implants. This concern has served as the stimulus for many studies. Although there are data to support both sides, after our critical review of the literature, several conclusions can be drawn. (1) Augmented patients are not at a greater risk than the nonaugmented population for developing breast cancer. (2) Early detection of occult cancer is possible in augmented patients. (3) Submuscular placement allows for greater mammographic visualization. (4) Eklund views (displacement techniques) should be used when obtaining mammograms in augmented patients and should be interpreted by radiologists experienced in the evaluation of augmented patients. (5) Silicone and saline implants demonstrate the same radiodensity on mammograms; neither is superior to the other. (6) The current recommendations for getting screening/preoperative mammograms are no different for augmented patients, although the ultimate decision lies with each surgeon and patient. PMID- 27463402 TI - Mesocarbon Microbead Carbon-Supported Magnesium Hydroxide Nanoparticles: Turning Spent Li-ion Battery Anode into a Highly Efficient Phosphate Adsorbent for Wastewater Treatment. AB - Phosphorus in water eutrophication has become a serious problem threatening the environment. However, the development of efficient adsorbents for phosphate removal from water is lagging. In this work, we recovered the waste material, graphitized carbon, from spent lithium ion batteries and modified it with nanostructured Mg(OH)2 on the surface to treat excess phosphate. This phosphate adsorbent shows one of the highest phosphate adsorption capacities to date, 588.4 mg/g (1 order of magnitude higher than previously reported carbon-based adsorbents), and exhibits decent stability. A heterogeneous multilayer adsorption mechanism was proposed on the basis of multiple adsorption results. This highly efficient adsorbent from spent Li-ion batteries displays great potential to be utilized in industry, and the mechanism study paved a way for further design of the adsorbent for phosphate adsorption. PMID- 27463399 TI - Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. PMID- 27463403 TI - Erratum: An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology. AB - [This corrects the article DOI: 10.1038/celldisc.2016.12.]. PMID- 27463404 TI - Yoga as Coping: A Conceptual Framework for Meaningful Participation in Yoga. AB - Yoga facilitates relaxation and connection of mind, body, and spirit through the use of breathing, meditation, and physical postures. Participation in yoga has been extensively linked to decreased stress, and as a result, is considered a therapeutic intervention by many. However, few theories exist that explain the link between yoga participation and improved psychosocial wellbeing. The leisure stress coping conceptual framework suggests that through participation in leisure, an individual can decrease stress while concurrently restoring and building up sustainable mental and physical capacities. Three types of leisure coping strategies exist: palliative coping, mood enhancement, and companionship. The purpose of this article is to propose the leisure-stress coping conceptual framework as a model for explaining benefits received from yoga participation via leisure coping strategies, which may explain or support improved ability to manage stress. PMID- 27463405 TI - A National Survey of Yoga Instructors and their Delivery of Yoga Therapy. AB - Yoga therapy may improve a variety of symptoms and health conditions, but little is known about how yoga therapy is being delivered in the real world. The purpose of this study was to describe the delivery of yoga therapy by yoga instructors across the U.S. In this cross-sectional survey, certified instructors were recruited from the Iyengar Yoga National Association, United States (IYNAUS) (n = 966) via an email that contained a link to an anonymous online survey that collected information on demographics, their delivery of yoga therapy, and the health conditions and symptoms seen and records kept by the instructors. A total of 487 instructors (50.4%) completed the survey. Instructors ranged from 28 to 82 years in age (m = 56.4 + 10.1 years) and had been teaching for 17.0 + 10.0 years. The majority (n = 384, 81.4%) reported teaching some form of therapeutic yoga either in groups (n = 261, 55%) and/or privately (n = 340, 73.4%). All instructors (100%) reported modifying poses in their regular yoga classes for students because of health conditions or symptoms. Other than attendance, the majority (n = 255, 57.3%) reported keeping no records on their sessions. Students came to instructors for help with over 54 health conditions, most commonly musculoskeletal conditions and injuries (n = 267, 62.8%), followed by pregnancy (n = 56, 13.2%) and hypertension (n = 22, 5.2%). Nearly all (n = 373, 85.6%) reported pain to be the symptom that brought students to yoga therapy most frequently. Whereas yoga in randomized controlled trials typically is delivered to individuals in large, homogenous groups, the instructors reported that most yoga therapy is being provided individually or in small, general therapeutic classes that include a variety of health conditions. Research is needed to examine the effectiveness of yoga therapy under such conditions. A clear set of guidelines for assessing and documenting the effectiveness of yoga therapy using standardized, valid, and reliable methods is needed, particularly for pain related conditions. PMID- 27463407 TI - Screening for chronic kidney disease and inequity. PMID- 27463406 TI - Body Dysmorphic Symptoms Scale for patients seeking esthetic surgery: cross cultural validation study. AB - CONTEXT AND OBJECTIVE: Rhinoplasty is one of the most sought-after esthetic operations among individuals with body dysmorphic disorder. The aim of this study was to cross-culturally adapt and validate the Body Dysmorphic Symptoms Scale. DESIGN AND SETTING: Cross-cultural validation study conducted in a plastic surgery outpatient clinic of a public university hospital. METHODS: Between February 2014 and March 2015, 80 consecutive patients of both sexes seeking rhinoplasty were selected. Thirty of them participated in the phase of cultural adaptation of the instrument. Reproducibility was tested on 20 patients and construct validity was assessed on 50 patients, with correlation against the Yale Brown Obsessive Compulsive Scale for Body Dysmorphic Disorder. RESULTS: The Brazilian version of the instrument showed Cronbach's alpha of 0.805 and excellent inter-rater reproducibility (intraclass correlation coefficient, ICC = 0.873; P < 0.001) and intra-rater reproducibility (ICC = 0.939; P < 0.001). Significant differences in total scores were found between patients with and without symptoms (P < 0.001). A strong correlation (r = 0.841; P < 0.001) was observed between the Yale-Brown Obsessive Compulsive Scale for Body Dysmorphic Disorder and the Body Dysmorphic Symptoms Scale. The area under the receiver operating characteristic curve was 0.981, thus showing good accuracy for discriminating between presence and absence of symptoms of body dysmorphic disorder. Forty-six percent of the patients had body dysmorphic symptoms and 54% had moderate to severe appearance-related obsessive-compulsive symptoms. CONCLUSIONS: The Brazilian version of the Body Dysmorphic Symptoms Scale is a reproducible instrument that presents face, content and construct validity. PMID- 27463408 TI - Nonverbal Communication as a Pain Reliever: The Impact of Physician Supportive Nonverbal Behavior on Experimentally Induced Pain. AB - Despite the evidence for the potential of supportive communication to alleviate physical pain, no study to date has assessed the impact of supportive nonverbal behavior on the objective and subjective experience of pain. This analogue study examined the impact of an actor-physician's supportive nonverbal behavior on experimentally induced pain. Participants (N = 205) were randomly assigned to interact with a videotaped physician conveying high or low supportive nonverbal behaviors. Participant pain was assessed with subjective and objective measures. Participants interacting with the high nonverbal support physicians showed increased pain tolerance and a reduction in the amount of pain expressed compared to those interacting with the low nonverbal support physicians. For subjectively rated pain, a gender difference existed such that for men, high physician nonverbal support decreased pain ratings and memory of pain, but for women, high physician nonverbal support increased pain ratings and memory of pain. These results highlight the importance of nonverbal communication in altering pain with broad implications for clinical care. PMID- 27463409 TI - What, Why, How - Creative Activities in Occupational Therapy Practice in Sweden. AB - Creative activities have historically been used in occupational therapy, and although their usage has declined in recent decades, they are still used in Swedish practice. The aim of this study was to better understand how occupational therapists use creative activities in practice. A web-based survey was sent to 520 occupational therapists, of which 304 (58.5%) responded. The main reason identified for using creative activities was to strengthen the client's occupational performance, well-being and self-esteem. The expected outcomes of applying creative activities were to support the client in self-expression and experiencing joy and desire. More than half of the occupational therapist respondents did not use creative activities to the extent they desired. Creative activities in occupational therapy are still used as a vital treatment to strengthen the clients' occupational performance abilities. The survey has looked at only a professional perspective on effectiveness of applying creative activities in occupational therapy. More research is needed to evaluate how occupational therapists internationally apply creative activities. There is also a need to gain information from the client's perspective on the therapeutic value of creative activities. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27463410 TI - Unexpected suppression of spin-lattice relaxation via high magnetic field in a high-spin iron(iii) complex. AB - A counterintuitive three-order of magnitude slowing of the spin-lattice relaxation rate is observed in a high spin qubit at high magnetic field via multifrequency pulsed electron paramagnetic resonance measurements. PMID- 27463411 TI - Disruption of the circadian period of body temperature by the anesthetic propofol. AB - The circadian time structure of an organism can be desynchronized in a large number of instances, including the intake of specific drugs. We have previously found that propofol, which is a general anesthetic, induces a desynchronization of the circadian time structure in rats, with a 60-80 min significant phase advance of body temperature circadian rhythm. We thus deemed it worthwhile to examine whether this phase shift of body temperature was related to a modification of the circadian period Tau. Propofol was administered at three different Zeitgeber Times (ZTs): ZT6 (middle of the rest period), ZT10 (2 h prior to the beginning of activity period), ZT16 (4 h after the beginning of the activity period), with ZT0 being the beginning of the rest period (light onset) and ZT12 being the beginning of the activity period (light offset). Control rats (n = 20) were injected at the same ZTs with 10% intralipid, which is a control lipidic solution. Whereas no modification of the circadian period of body temperature was observed in the control rats, propofol administration resulted in a significant shortening of the period by 96 and 180 min at ZT6 and ZT10, respectively. By contrast, the period was significantly lengthened by 90 min at ZT16. We also found differences in the time it took for the rats to readjust their body temperature to the original 24-h rhythm. At ZT16, the speed of readjustment was more rapid than at the two other ZTs that we investigated. This study hence shows (i) the disruptive effects of the anesthetic propofol on the body temperature circadian rhythm, and it points out that (ii) the period Tau for body temperature responds to this anesthetic drug according to a Tau-response curve. By sustaining postoperative sleep-wake disorders, the disruptive effects of propofol on circadian time structure might have important implications for the use of this drug in humans. PMID- 27463412 TI - Daily Intake of Milk Enriched with n-3 Fatty Acids, Oleic Acid, and Calcium Improves Metabolic and Bone Biomarkers in Postmenopausal Women. AB - OBJECTIVE: Nutritional strategies can be effective for the prevention of menopause-related diseases, such as osteoporosis and cardiovascular disease. Our aim was to evaluate the effects of a dairy product enriched in polyunsaturated fatty acids, calcium, oleic acid, and vitamins on cardiovascular markers and bone metabolism in postmenopausal women with moderate cardiovascular risk. METHODS: One hundred seventeen healthy postmenopausal women (aged 45 +/- 7.7 years) were allocated to 2 groups: the intervention group (IG; n = 63), who consumed 0.5 L/day of a low-lactose skimmed milk enriched with 40 mg/100 mL of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), 0.54 g/100 mL oleic acid, and vitamins, and the control group (CG; n = 54), who consumed 0.5 L/day of semiskimmed milk 0.5 L/day enriched with vitamins A and D. RESULTS: After 12 months, in the IG there was an improvement in lipid profile: a -5.78% decrease in total cholesterol (p = 0.010), -9.79% (p = 0.004) in low-density lipoprotein (LDL) cholesterol, -9.56% (p < 0.001) in total cholesterol (TC)/high-density lipoprotein (HDL) ratio, and -3.38% in LDL/HDL ratio (p < 0.001). No changes were observed in the CG. In the IG we observed a decrease of -28.20% in high sensitivity C-reactive protein (hs-CRP; p = 0.012). There was no effect on bone turnover markers or serum osteoprotegerin (OPG) in either of the study groups. In the IG, receptor activator of nuclear factor kappaB ligand (RANKL) was reduced 17.64% (p = 0.003), with no effect in the CG. CONCLUSION: In postmenopausal women with moderate cardiovascular risk, dietary supplementation with a dairy drink enriched with fatty acids (EPA+DHA), oleic acid, minerals, and vitamins induces a positive effect on cardiovascular risk and parameters of bone metabolism. Its regular consumption may be a useful nutritional support for postmenopausal women. PMID- 27463413 TI - Controlled Formation of Heteroleptic [Pd2(La)2(Lb)2](4+) Cages. AB - Metallosupramolecular architectures are beginning to be exploited for a range of applications including drug delivery, catalysis, molecular recognition, and sensing. For the most part these achievements have been made with high-symmetry metallosupramolecular architectures composed of just one type of ligand and metal ion. Recently, considerable efforts have been made to generate metallosupramolecular architectures that are made up of multiple different ligands and/or metals ions in order to obtain more complex systems with new properties. Herein we show that the addition of an electron-rich 2-amino substituted tripyridyl ligand, 2,6-bis(pyridin-3-ylethynyl)pyridine (2A-tripy), to a solution of the [Pd2(tripy)4](4+) cage resulted in the clean generation of a heteroleptic [Pd2(tripy)2(2A-tripy)2](4+) architecture. The formation of the mixed-ligand cage [Pd2(tripy)2(2A-tripy)2](4+) was confirmed using (1)H NMR spectroscopy, diffusion-ordered spectroscopy, and rotating-frame nuclear Overhauser effect spectroscopy and high-resolution electrospray ionization mass spectrometry. Density functional theory calculations suggested the cis isomer was more stable that the trans isomer. Additionally, the calculations indicated that the heteroleptic palladium(II) cages are kinetically metastable intermediates rather than the thermodynamic product of the reaction. Competition experiments supported that finding and showed the cages are long-lived in solution at room temperature. Finally, it was shown that the addition of 2A-tripy to a range of preformed [Pd2(Ltripy)4](4+) cages cleanly generated the mixed-ligand systems. Three other systems displaying different exo and endo functionalities within the cage assembly were generated, suggesting that this method could be applied to synthesize a range of highly functionalized heteroleptic cis-[Pd2(La)2(Lb)2](4+) cages. PMID- 27463416 TI - Cost-effectiveness of Canagliflozin versus Sitagliptin When Added to Metformin and Sulfonylurea in Type 2 Diabetes in Canada. AB - BackgroundCanagliflozin, an agent that inhibits sodium glucose co-transporter 2, is approved as add-on to metformin plus sulfonylurea for the treatment of type 2 diabetes in Canada. Canagliflozin offers greater glycemic control, as well as important additional benefits such as weight loss and blood pressure reductions, versus dipeptidyl peptidase-4 inhibitors such as sitagliptin. ObjectiveThis analysis evaluated the cost-effectiveness of canagliflozin 300 mg and canagliflozin 100 mg versus sitagliptin 100 mg in patients with type 2 diabetes inadequately controlled on metformin plus sulfonylurea from the perspective of the Canadian Agency for Drugs and Technologies in Health. MethodsA 40-year cost effectiveness analysis was performed using the validated Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO-T2DM). Patient characteristics, treatment effects, and rates of hypoglycemia and adverse events were sourced from the canagliflozin clinical program. Canada-specific costs and utilities were applied. Sensitivity analyses were conducted using alternative values for key model inputs. ResultsBoth canagliflozin 300 and 100 mg dominated sitagliptin 100 mg over 40 years, providing quality-adjusted life-year gains of 0.31 and 0.28, and cost offsets of $2,217 and $2,560, respectively. Both canagliflozin doses dominated sitagliptin in each of the sensitivity analyses. ConclusionsSimulation results suggested that canagliflozin 300 and 100 mg provided better health outcomes and lower costs than sitagliptin 100 mg as a third-line therapy added-on to metformin and sulfonylurea in patients with type 2 diabetes in Canada. PMID- 27463417 TI - Theoretical Study of Low-Lying Electronic States of PtX (X = F, Cl, Br, and I) Including Spin-Orbit Coupling. AB - The low-lying electronic states of platinum ions (Pt(+)) and platinum monohalides (PtX; X = F, Cl, Br, and I) are calculated using the multireference configuration interaction method with relativistic effective core potentials. The spin-orbit coupling is taken into account through the perturbative state-interaction approach. For the Omega states of PtX below 35000 cm(-1), the potential energy curves and the corresponding spectroscopic constants are reported. It is found that the lowest Omega = 3/2 state is the ground one for the four species of PtX. Overall, the theoretical results are in reasonable agreement with the available experimental data. PMID- 27463414 TI - Baseline characteristics and interim (3-month) efficacy and safety data from STELLA-LONG TERM, a long-term post-marketing surveillance study of ipragliflozin in Japanese patients with type 2 diabetes in real-world clinical practice. AB - OBJECTIVE: To evaluate the efficacy and safety of ipragliflozin in real-world clinical practice in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted interim analyses at 3 months of a 3-year prospective study of patients who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015, and whose data were locked by 16 January 2016. MAIN OUTCOME MEASURES: Changes in glycemic control, blood pressure, and laboratory variables from baseline, and incidence of adverse drug reactions (ADRs). RESULTS: Of 11,412 patients initially registered, efficacy and safety data were available for 3481 (30.5%) and 4360 (38.2%) patients, respectively. Hemoglobin A1c and fasting plasma glucose decreased by 0.67% and 28.8 mg/dL, respectively, at 3 months/last assessment (both P < .001) from baseline (8.00% and 166.4 mg/dL, respectively). Blood pressure and lipid levels also improved significantly. There were 258 ADRs in 194 patients. The ADRs included 'renal and urinary disorders' (system organ class) in 110 patients (2.5%). CONCLUSIONS: These 3-month interim results indicate that ipragliflozin improved glycemic control, lipids, and blood pressure with low rates of ADRs in Japanese patients with type 2 diabetes in real-world clinical practice. The results were consistent with those of placebo-controlled, randomized clinical trials. Clinicaltrials.gov identifier: NCT02479399. PMID- 27463418 TI - Transition-Metal-Free Coupling Annulation of Arynes with Ketones and Alkynoates: Assembly of Functionalized Naphthalenes. AB - A transition-metal-free coupling annulation reaction of arynes, ketones, and alkynoates has been demonstrated. Using this formal [2 + 2 + 2] cycloaddition reaction, a wide variety of naphthalene derivatives were conveniently constructed in one pot with high efficiency. In addition, this novel and valid annulation has been successfully applied to the synthesis of 1-phenanthrenol derivatives. PMID- 27463419 TI - beta-Furan-Fused bis(Difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine Fluorescent Dyes in the Visible Deep-Red Region. AB - Novel beta-furan-fused bis(difluoroboron)-1,2-bis((1H-pyrrol-2 yl)methylene)hydrazine (BOPHY) fluorescent dyes (F-BOPHY1-3) were prepared through an efficient process, and their structures were confirmed by (1)H NMR spectroscopy, (13)C NMR spectroscopy, MALDI-TOF HRMS, and element analysis. Their optical properties were then characterized by UV-vis absorption and photoluminescence (PL) spectroscopy. The UV-vis absorption and PL spectra of the dyes shifted to longer wavelengths relative to those of BOPHY because of the fusion of their furan rings, which extended pi-conjugation of the molecules. All of the dyes exhibited large extinction coefficients (109700-12300 M(-1) cm(-1)), deep-red fluorescence emission (646-667 nm), moderate fluorescence quantum yields (0.30-0.45), as well as high chemical stability and photostability in solution. These advantageous properties show that these compounds are important to the design of efficient long-wavelength fluorescent dyes and are suitable for various applications in biotechnology and materials science. PMID- 27463420 TI - Effects of Cannabis Use on Human Behavior-Reply. PMID- 27463421 TI - Unusual presentation of familial Mediterranean fever: atypical hyperaemic recurrent skin lesions. PMID- 27463422 TI - Ocellatin-PT antimicrobial peptides: High-resolution microscopy studies in antileishmania models and interactions with mimetic membrane systems. AB - Although the mechanism of action of antimicrobial peptides (AMPs) is not clear, they can interact electrostatically with the cell membranes of microorganisms. New ocellatin-PT peptides were recently isolated from the skin secretion of Leptodactylus pustulatus. The secondary structure of these AMPs and their effect on Leishmania infantum cells, and on different lipid surface models was characterized in this work. The results showed that all ocellatin-PT peptides have an alpha-helix structure and five of them (PT3, PT4, PT6 to PT8) have leishmanicidal activity; PT1 and PT2 affected the cellular morphology of the parasites and showed greater affinity for leishmania and bacteria-mimicking lipid membranes than for those of mammals. The results show selectivity of ocellatin PTs to the membranes of microorganisms and the applicability of biophysical methods to clarify the interaction of AMPs with cell membranes. PMID- 27463424 TI - Bioinspired 2D-Carbon Flakes and Fe3O4 Nanoparticles Composite for Arsenite Removal. AB - Development of carbon-based materials has received tremendous attention owing to their multifunctional properties. Biomaterials often serve as an inspiration for the preparation of new carbon materials. Herein, we present a facile synthesis of a new bioinspired graphene oxide-like 2D-carbon flake (CF) using a natural resource, waste onion sheathing (Allium cepa). The 2D-CF was further decorated with crystalline Fe3O4 nanoparticles for applications. Superparamagnetic Fe3O4 nanoparticles (7 nm) were well-dispersed on the surface of the 2D-CF, which was characterized by X-ray diffractometry, X-ray photoelectron spectroscopy, Raman spectrometry, and transmission electron microscopy. Batch As(III) adsorption experiments showed that aqueous arsenic ions strongly adsorbed to the Fe3O4@2D-CF composite. The adsorption capacity of the Fe3O4@2D-CF composite for As(III) was 57.47 mg g(-1). The synergetic effect of both graphene oxide-like 2D-CF and Fe3O4 nanoparticles aided in excellent As(III) adsorption. An As(III) ion adsorption kinetics study showed that adsorption was very fast at the initial stage, and equilibrium was reached within 60 min following a pseudo-second-order rate model. Owing to the excellent superparamagnetic properties (52.6 emu g(-1)), the Fe3O4@2D-CF composite exhibited superb reusability with the shortest recovery time (28 s) among reported materials. This study indicated that Fe3O4@2D-CF composites can be used for practical applications as a global economic material for future generations. PMID- 27463423 TI - Impaired autophagy in macrophages promotes inflammatory eye disease. AB - Autophagy is critical for maintaining cellular homeostasis. Organs such as the eye and brain are immunologically privileged. Here, we demonstrate that autophagy is essential for maintaining ocular immune privilege. Deletion of multiple autophagy genes in macrophages leads to an inflammation-mediated eye disease called uveitis that can cause blindness. Loss of autophagy activates inflammasome mediated IL1B secretion that increases disease severity. Inhibition of caspase activity by gene deletion or pharmacological means completely reverses the disease phenotype. Of interest, experimental uveitis was also increased in a model of Crohn disease, a systemic autoimmune disease in which patients often develop uveitis, offering a potential mechanistic link between macrophage autophagy and systemic disease. These findings directly implicate the homeostatic process of autophagy in blinding eye disease and identify novel pathways for therapeutic intervention in uveitis. PMID- 27463426 TI - Coming in sportsmedicine. PMID- 27463425 TI - Noteworthy. PMID- 27463428 TI - Abstracts at a glance. PMID- 27463427 TI - A New Section Editor. PMID- 27463430 TI - Sportsmedicine forum. PMID- 27463432 TI - Correction. PMID- 27463431 TI - Brief reports. PMID- 27463433 TI - Scanning sports. PMID- 27463434 TI - Violence in Film and Sports-Any Connection? PMID- 27463436 TI - Pubic Stress Symphysitis in a Female Distance Runner. AB - In brief: Osteitis pubis is a general term that has been used for several disorders of the pubic symphysis. Pubic stress symphysitis, a more specific term, refers to the painful, nonseptic, inflammatory condition that occurs in runners and other endurance athletes. Septic cases, adductor tendon avulsion injuries, and stress fractures of the pubic rami must be clearly differentiated from pubic stress symphysitis to avoid confusion and misdiagnosis. Pelvic roentgenograms, radionuclide bone scans, laboratory evaluation, and physical findings make differentiation possible. The case described demonstrates the importance of proper diagnosis and therapy for patients with pubic stress. symphysitis. PMID- 27463435 TI - "Write That Down!". PMID- 27463437 TI - Do Mouth-Formed Mouth Guards Meet the NCAA Rules? AB - In brief: The arch lengths of the maxillary casts of 413 university football players were measured and compared with the arch lengths of 12 types of mouth formed mouth guards to determine how closely each type of mouth guard conformed to NCM rules. The study found that, for a significant number of university football players, currently available mouth-formed mouth guards are not large enough to meet the NCAA rules and that a population of black athletes has a significantly larger mean arch length than a population of racially mixed athletes. The largest mouth-formed mouth guard met the NCAA rule for only 5.5% of football players of a predominantly black team. PMID- 27463438 TI - Properties of Custom-Made Mouth-Protector Materials. AB - In brief: Increased interest in preventing dental injuries in sports has resulted in more testing of and improvement in protective equipment. In this study, hardness, tear strength, and tear energy were machine-tested in nine custom-made mouth-protector materials. Four of the materials made from polyvinyl acetate polyethylene or hard polyurethane had high values for all three properties. Two materials debonded during the tear energy test. The soft polyurethane and the rubber had low values for all three properties. Visibility of clear and colored mouth protectors was tested with human subjects and observers. Yellow mouth protectors were visible at almost twice the distance of the clear protectors. This information could benefit officials who must enforce mouth-protector regulations. PMID- 27463439 TI - How I Manage Abdominal Injuries. AB - In brief: Abdominal injuries make up only about 10% of sports injuries, but they can sideline athletes for long periods or be life threatening. Any athlete who sustains a severe blow to the abdomen should be judged to have a serious injury until examination proves otherwise. In sports, abdominal injuries occur most often in cycling, horseback riding, and skiing, and they involve children more often than adults. Organs injured most often are the spleen, kidneys, and liver. Two typical case histories are offered, followed by a brief review of abdominal anatomy. Guidelines are provided for recognizing and treating injuries to the abdominal muscles, kidneys, spleen, and liver and related organs. PMID- 27463440 TI - An Epidemiological Perspective on the Causes of Running Injuries. AB - In brief: Most information about running injuries comes from case reports. Although useful, the case series does not take into consideration the population from which the injuries arose and is therefore an inappropriate method on which to base causal inference. The epidemiological method is a more powerful approach because, by definition, it takes into account the population from which the injuries arose. A review of three epidemiological studies shows that the only reasonably well-established cause of running injuries is the number of miles run per week. More information is needed to establish the relationship between injury and characteristics of the runner, characteristics of running, and characteristics of the running environment. More research on the causes of running injuries is needed and should be directed to those factors over which the runner has control. PMID- 27463441 TI - Lateral Knee Braces in Football: Do They Prevent Injury? AB - In brief: Lateral knee braces are being used in increasing numbers by football teams attempting to decrease the number of valgum knee injuries. There has been little proof to date that these braces are effective. In this paper we review the results of three recently presented clinical studies as well as an in-depth biomechanical study, all of which raise serious doubts about the efficacy of preventive knee braces that are currently available. PMID- 27463442 TI - Altered Serum Lipoprotein Profiles in Male and Female Power Lifters Ingesting Anabolic Steroids. AB - In brief: Serum lipoprotein profiles were measured in nine male and three female power lifters who were taking anabolic steroids. Male steroid users had higher total serum cholesterol, lower HDL-C, and lower HDL-apoprotein A-I (apoA-I) levels than a weight-trained reference group that did not use steroids. Female steroid users showed similar trends. Mean serum HDL-C and HDL-C to total cholesterol ratio were lower in male steroid users than in a young male South African population at high risk for atherosclerosis. The ratio of HDL3-C to total HDL-C was higher in steroid users than in the reference group. Ratios of apoA-I to apoA-II were similar in the two groups. These unfavorable lipid profiles suggest that male and female steroid users may face an increased risk of coronary artery disease. PMID- 27463443 TI - Female Athletes: Targets for Drug Abuse. AB - Increased participation in sports and correspondingly greater pressures to win have made female athletes very vulnerable to drug abuse. The physiology and socialization of females contribute to their special drug concerns. PMID- 27463444 TI - Women in Sports: The Price of Participation. AB - Female athletes have more patellofemoral problems and bunions than male athletes because of differences in anatomy, conditioning, and socialization. PMID- 27463446 TI - Can Injured Athletes Benefit From Total Joint Replacements? AB - Injured athletes who are counting on an artificial joint for immediate pain relief or for a resumption of athletic competition might be in for an unpleasant surprise. PMID- 27463445 TI - From Activity to Eternity. AB - Your chances of living to a ripe old age may be improved with regular exercise no, make that activity. PMID- 27463447 TI - Getting Patients Back to Work After Myocardial Infarction or Coronary Artery Bypass Surgery. PMID- 27463448 TI - Posture Perfect Performance. PMID- 27463451 TI - Choroidal malignant melanoma with no extraocular extension presenting as orbital cellulitis. AB - This report describes a patient with choroidal malignant melanoma presenting as orbital cellulitis without extraocular tumor extension. It is an interventional case report with histopathologic correlation. A 68-year-old male presented with a 3-day history of painful hyperemia and swelling in the right eye. The examination showed edematous eyelids, mechanical ptosis and chemosis with conjunctival injection. B-scan ultrasonography showed a mass with medium level echogenicity that filled the vitreous cavity. Magnetic resonance imaging showed a solid choroidal mass with hemorrhagic and inflammatory changes with no obvious extraocular extension. Due to these suggestive findings of choroidal melanoma the right eye was enucleated. A spindle cell choroidal melanoma including intense pigmentation and necrosis was confirmed by histopathological examination. Although rare; choroidal melanoma may present as orbital cellulitis, particularly when the tumor is necrotic. PMID- 27463452 TI - Rigorous Free Energy Calculations in Structure-Based Drug Design. AB - Structure-based drug design could benefit greatly from computational methodologies that accurately predict the binding affinity of small compounds to target biomolecules. However, the current scoring functions used to rank compounds in virtual screens by docking are not sufficiently accurate to guide reliably the design of tight binding ligands. Thus, there is strong interest in methodologies based on molecular simulations of protein-ligand complexes which are perceived to be more accurate and, with advances in computing power, amenable to routine use. This report provides an overview of the technical details necessary to understand, execute and analyze binding free energy calculations, using free energy perturbation or thermodynamic integration methods. Examples of possible applications in structure-based drug design are discussed. Current methodological limitations are highlighted as well as a number of ongoing developments to improve the scope, reliability, and practicalities of free energy calculations. These efforts are paving the way for a more common use of free energy calculations in molecular design. PMID- 27463453 TI - The One-Class Classification Approach to Data Description and to Models Applicability Domain. AB - In this paper, we associate an applicability domain (AD) of QSAR/QSPR models with the area in the input (descriptor) space in which the density of training data points exceeds a certain threshold. It could be proved that the predictive performance of the models (built on the training set) is larger for the test compounds inside the high density area, than for those outside this area. Instead of searching a decision surface separating high and low density areas in the input space, the one-class classification 1-SVM approach looks for a hyperplane in the associated feature space. Unlike other reported in the literature AD definitions, this approach: (i) is purely "data-based", i.e. it assigns the same AD to all models built on the same training set, (ii) provides results that depend only on the initial descriptors pool generated for the training set, (iii) can be used for the huge number of descriptors, as well as in the framework of structured kernel-based approaches, e.g., chemical graph kernels. The developed approach has been applied to improve the performance of QSPR models for stability constants of the complexes of organic ligands with alkaline-earth metals in water. PMID- 27463454 TI - Free Energy Calculations of Mutations Involving a Tightly Bound Water Molecule and Ligand Substitutions in a Ligand-Protein Complex. AB - The accurate calculation of the free energy of interaction of protein-water ligand systems has an important role in molecular recognition and drug design that is often not fully considered. We report free energy thermodynamic integration calculations used to evaluate the effects of inclusion, neglect, and targeting and removal (i.e., systematic substitution by ligand functional groups) of an important, tightly bound, water molecule in the SH3 domain of Abl tyrosine kinase. The effects of this water molecule on the free energies of interaction of several Abl-SH3 domain-ligand systems reveal that there is an unfavourable free energy change associated with its removal into the bulk solvent. Only three substitutions by an additional functional group (out of methyl, ethyl, hydroxyl, amino, and amide groups) in the phenyl ring of a tyrosine in the peptide ligand resulted in a favourable change in the free energy of binding upon replacement of the ordered water molecule. This computational approach provides a direct route to the systematic and rigorous prediction of the thermodynamic influence of ordered, structural water molecules on ligand modification and optimization in drug design by calculating free energy changes in protein-water-ligand systems. PMID- 27463455 TI - Wavelet Approximation of GRID Fields: Application to Quantitative Structure Activity Relationships. AB - Molecular interaction fields such as those computed by the GRID program are widely used in applications such as virtual screening, molecular docking and 3D QSAR modelling. They characterise molecules according to their favourable interaction sites and therefore enable predictions to be made on how molecules might interact. The fields are, however, comprised of a very large number of data points which presents difficulties for many applications. For example, there are likely to be high degrees of correlation between the variables which can lead to misleading results in 3D-QSAR. We describe the use of wavelet methods for approximating such data into a much smaller number of variables. We present a number of validation experiments, including use of the approximated GRIDs in 3D QSAR, and demonstrate that wavelet approximation at high levels of data compression preserves the information content in GRID fields while significantly reducing computational requirements. PMID- 27463456 TI - 3D-QSAR Studies on C24-Monoalkylated Vitamin D3 26,23-Lactones and their C2alpha Modified Derivatives with Inhibitory Activity to Vitamin D Receptor. AB - The ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) for 82 inhibitors of 25-dehydro-1alpha-hydroxyvitamin D3 -26,23-lactone analogs has been studied by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The established CoMFA model in training set gives a cross-validated q(2) value of 0.516 and a non-cross-validated rncv (2) value of 0.667, while the CoMSIA model results in q(2) =0.517 and rncv (2) =0.632. In general, the predictive ability of the CoMFA model is superior to that of the CoMSIA model, with rpred (2) =0.639 for the CoMFA and rpred (2) =0.619 for the CoMSIA model. Based on the CoMFA contour maps, some key structural characters of vitamin D3 analogs responsible for inhibitory activity are identified, and some new C2alpha-modified 24 alkylvitamin D3 lactone analogs with high predicted pIC50 values are designed. The ligand functional group mutations by FEP simulation and docking studies reveal the rationality of the molecular design. PMID- 27463457 TI - QSPR Analysis of Copolymers by Recursive Neural Networks: Prediction of the Glass Transition Temperature of (Meth)acrylic Random Copolymers. AB - The glass transition temperature (Tg ) of acrylic and methacrylic random copolymers was investigated by means of Quantitative Structure-Property Relationship (QSPR) methodology based on Recursive Neural Networks (RNN). This method can directly take molecular structures as input, in the form of labelled trees, without needing predefined descriptors. It was applied to three data sets containing up to 615 polymers (340 homopolymers and 275 copolymers). The adopted representation was able to account for the structure of the repeating unit as well as average macromolecular characteristics, such as stereoregularity and molar composition. The best result, obtained on a data set focused on copolymers, showed a Mean Average Residual (MAR) of 4.9 K, a standard error of prediction (S) of 6.1 K and a squared correlation coefficient (R(2) ) of 0.98 for the test set, with an optimal rate with respect to the training error. Through the treatment of homopolymers and copolymers both as separated and merged data sets, we also showed that the proposed approach is particularly suited for generalizing prediction of polymer properties to various types of chemical structures in a uniform setting. PMID- 27463458 TI - Characterization of Mixtures. Part 2: QSPR Models for Prediction of Excess Molar Volume and Liquid Density Using Neural Networks. AB - In our earlier work, we have demonstrated that it is possible to characterize binary mixtures using single component descriptors by applying various mixing rules. We also showed that these methods were successful in building predictive QSPR models to study various mixture properties of interest. Here in, we developed a QSPR model of an excess thermodynamic property of binary mixtures i.e. excess molar volume (V(E) ). In the present study, we use a set of mixture descriptors which we earlier designed to specifically account for intermolecular interactions between the components of a mixture and applied successfully to the prediction of infinite-dilution activity coefficients using neural networks (part 1 of this series). We obtain a significant QSPR model for the prediction of excess molar volume (V(E) ) using consensus neural networks and five mixture descriptors. We find that hydrogen bond and thermodynamic descriptors are the most important in determining excess molar volume (V(E) ), which is in line with the theory of intermolecular forces governing excess mixture properties. The results also suggest that the mixture descriptors utilized herein may be sufficient to model a wide variety of properties of binary and possibly even more complex mixtures. PMID- 27463459 TI - Multi-class Mode of Action Classification of Toxic Compounds Using Logic Based Kernel Methods. AB - Toxicity prediction is essential for drug design and development of effective therapeutics. In this paper we present an in silico strategy, to identify the mode of action of toxic compounds, that is based on the use of a novel logic based kernel method. The technique uses support vector machines in conjunction with the kernels constructed from first order rules induced by an Inductive Logic Programming system. It constructs multi-class models by using a divide and conquer reduction strategy that splits multi-classes into binary groups and solves each individual problem recursively hence generating an underlying decision list structure. In order to evaluate the effectiveness of the approach for chemoinformatics problems like predictive toxicology, we apply it to toxicity classification in aquatic systems. The method is used to identify and classify 442 compounds with respect to the mode of action. The experimental results show that the technique successfully classifies toxic compounds and can be useful in assessing environmental risks. Experimental comparison of the performance of the proposed multi-class scheme with the standard multi-class Inductive Logic Programming algorithm and multi-class Support Vector Machine yields statistically significant results and demonstrates the potential power and benefits of the approach in identifying compounds of various toxic mechanisms. PMID- 27463472 TI - Biologic Features of Chronic Lymphocytic Leukemia. AB - The data reviewed place CLL in the context of other leukemias in humans. They suggest similarities but also some differences. Neither the issue of a preleukemia phase or the site of transformation in CLL is completely resolved. However, most data are consistent with the notion that CLL, like most human cancers, has a multi-step pathogenesis. Whether this phase(s) should be termed preleukemia is controversial. It also appears that transformation in CLL occurs in a progenitor-B-cell with considerable plasticity of phenotype expression and even genetic progression (albeit rarely). Perhaps CLL is best conceived as a B cell disorder parodying normal B-cell development where a clone of B-cells escapes its normal fate and is thereby immortalized. PMID- 27463471 TI - Wool Keratin 3D Scaffolds with Light-Triggered Antimicrobial Activity. AB - Photoactivatable keratin sponges were prepared from protein aqueous solutions by the freeze-drying method, followed by photofunctionalization with two different photosensitizers (PS): Azure A (AzA) and 5,10,15,20-tetrakis [4-(2-N,N,N trimethylethylthio)-2,3,5,6-tetrafluorophenyl]porphyrin tetraiodide salt (TTFAP). The prepared sponges have a porosity between 49% and 80% and a mean pore size in the 37-80 MUm range. As compared to AzA, TTFAP interacts more strongly with the sponges as demonstrated by a lower PS release (6% vs 20%), a decreased swelling ratio (1.6 vs 7.4), and a slower biodegradation rate. Nevertheless, AzA-loaded sponges showed the highest photoactivity, as also demonstrated by their higher antibactericidal activity toward both Gram-positive and Gram-negative bacteria. The obtained results suggest that the antimicrobial photodynamic effect can be finely triggered through a proper selection of the amount and type of photosensitizer, as well as through the irradiation time. Finally, all the prepared sponges support human fibroblast cells growth, while no significant cell viability impairment is observed upon light irradiation. PMID- 27463473 TI - Cytokines in B-Cell Chronic Lymphocytic Leukemia. AB - The pleomorphic action of different cytokines in regulating the growth and proliferation of normal B- and T-lymphocyte populations is becoming progressively more apparent. Thus, the possibility that some cytokines, either alone or in variable combination, may play a role in different lymphoproliferative disorders has been increasingly suggested and potential autocrine or paracrine loops hypothesized. Here, we shall discuss some of the known B-cell growth factors which have been postulated to be involved in the hematological progression, clinical course and complications in B-cell lymphocytic leukemia. PMID- 27463474 TI - In vitro Activation of B-CLL Cells. AB - Apart from surface Ig receptors, a variety of membrane molecules have now been described to deliver activation and progression signals to human B cells. Among them, CD40 antigen is likely to play a crucial role in the antigen-dependent maturation process. Recent studies performed in the laboratory have established that presentation of anti-CD40 mAbs in a crosslinked fashion by mouse Ltk(-) cells stably expressing human FcyRII/CDw32, allowed normal human B cells to enter into sustained proliferation. In their overwhelming majority, B-CLL cells are positive for CD40 expression. We have therefore examined the capacity of purified B-CLL cells to be stimulated by various cytokines for growth and differentiation, following crosslinking of slgs or CD40 antigen. In most B-CLL specimens studied, IL-2 was the sole factor, among a wide panel of cytokines tested, which reproducibly and significantly induced proliferation of leukemic B cells activated with anti-Ig reagents (SAC or anti-IgM antibodies). Unlike normal B cells, the great majority of anti-Ig activated B-CLL cells failed to proliferate in response to IL-4. In this activation system, IL-4 profoundly suppressed the IL 2 driven proliferation of B-CLL. An opposite pattern of growth-response was obtained following ligation of CD40 since IL-4 elicited proliferation of B-CLL whereas the growth-promoting effect of IL-2 was reduced. Under these culture conditions, IL-4 and IL-2 displayed additive effects on leukemic B cell growth. Surprisingly, IL-4 combined with anti-CD40 mAb allowed activation of certain leukemia specimens otherwise refractory to other stimulatory signals. Most B-CLL samples were induced for IgM synthesis upon SAC stimulation. This Ig response was potentiated by IL-2 and antagonized by IL-4. Anti-CD40 mAb used alone or in combination with cytokines (IL1-IL6, IFNgamma, TNFalpha, TGFbeta) failed to induce Ig secretion from B-CLL. No evidence for Ig isotype switching was obtained with the cytokines listed above, whatever the mode of B-CLL activation. Taken together, our results suggest that B-CLL can be released in vitro from their apparent maturation block, by IL-2 and anti-Ig reagents or by IL-4 and immobilized anti-CD40 mAb. Additionally, the data reported here suggest that development of the agonistic and antagonistic activities of IL-4 on B cell growth and differentiation may depend upon the nature of the activation signal provided. PMID- 27463476 TI - Multiple Myeloma and Chronic Lymphocytic Leukemia: Commonalities and Differences in Biology and Therapy. AB - Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) are monoclonal tumors of differentiated B-cells arising late in life with a protracted clinical course that frequently terminates with signs of dedifferentiation. The major clinical differences (extramedullary spread in CLL, bone marrow confinement in MM) may relate to distinctive tumor cell phenotypes and cytokine networks, explaining the frequent bone involvement and uncommon thrombocytopenia in advanced MM. Cytogenetically, CLL is characterized by relatively uniform chromosomal abnormalities with a predominance of trisomy 12 without further changes with disease progression, whereas complex and seemingly random numeric and structural chromosomal aberrations predominate in MM. Multilineage expression and the association with acute myelogenous leukemia suggest that MM may result from transformation of a pluripotent progenitor cell, whereas CLL is thought to develop from a transformed committed B-cell precursor compartment. Survival of patients with MM and CLL is shorter in the presence of higher tumor burden, reflected in increasing anemia in both diseases and in high levels of serum beta 2-microglobulin in MM. Both tumors respond to alkylating agents providing disease palliation but no cures. Glucocorticoids are highly effective in MM and control autoimmune disease associated more frequently with CLL. The marked efficacy of fludarabine in CLL and its lack of activity in MM may provide additional clues about the different biology of CLL and MM. PMID- 27463475 TI - Cytogenetic Findings and Survival in B-cell Chronic Lymphocytic Leukemia. Second IWCCLL Compilation of Data on 662 Patients. AB - Chromosome analysis on CLL-cells from 649 patients revealed clonal changes in 311 cases (48%). The most common abnormalities were trisomy 12 (n = 112), and structural changes on the long arm of chromosome 13 (n = 62), most of them interstitial deletions or translocations involving 13q14, the site of the retinoblastoma gene. Complex karyotypes were associated with poor prognosis, although karyotypic changes rarely develop during the course of the disease. Among patients with single chromosomal abnormalities those with trisomy 12 had a poor survival, whereas those with structural changes on chromosome 13 had as good a prognosis as patients with a normal karyotype. PMID- 27463477 TI - CD5(+) B Cell Lymphomas of Mice. AB - Spontaneous murine lymphomas commonly arise from CD5 B cells. They appear late in life and the frequency of their occurrence can be increased by transferring syngeneic lymphoid cells from old animals to young. Such transfer experiments show that although the lymphomas are not detected until late in life, the commitment to neoplasia is made much earlier and is followed by an indolent phase before the neoplastic phenotype becomes manifest. The repertoire of immunoglobulin (Ig) V genes expressed is not random, but certain VH genes appear repeatedly and, at least in some cases, are specifically associated with particular VK genes. This unbalanced repertoire is similar to that expressed by normal CD5 B cells of young adult mice, implying that the process of lymphomagenesis operates after the normal CD5 B cell repertoire has been established. Development of new CD5 B cells from pre-B cells only occurs before and shortly after birth; in the adult, the population is self sustaining and is not replenished from Ig negative precursors. The newly generated population of CD5 B cells present at birth more nearly approximates a random selection from the germ line genes. Skewing of the repertoire occurs during the first few weeks of post-natal life and results from antigen driven clonal selection by self antigens, predominantly type 2 thymus independent antigens. From 5-20% of normal adult CD5 B cells (and lymphomas) produce antibody reactive with phosphatidyl choline. Almost exclusively, these cells express VH11 or VH12 family genes in combination with specific VK genes and displaying severe constraints as to size and sequence of VDJ regions. These VH genes have not been seen expressed by conventional B cells. Neither do conventional B cells produce antibody of this specificity. In vivo, murine CD5 B cell lymphomas produce IgM; in vitro they can respond to differentiative signals and undergo isotype switching, with a marked predilection for IgA. Somatic mutation of assembled Ig genes has not been seen in these tumors and idiotype-loss variants have not been seen to result from anti idiotype therapy. PMID- 27463478 TI - Immunoglobulin Gene Rearrangement and Expression in B-CLL. AB - The malignant cells from most patients with B cell chronic lymphocytic leukemia (B-CLL) and related small lymphocytic lymphomas (SLL) co-express B cell differentiation antigens and the pan-T lymphocytes surface antigen CD5 (Leu 1). As such, B-CLL and related lymphomas generally may be considered malignancies of the CD5 B cell, a minor B cell subpopulation implicated in the production of autoantibodies. These malignancies are distinctive in that high proportions of patients have neoplastic B cells that express surface immunoglobulin (Ig) bearing one or more cross reactive idiotypes (CRIs) that commonly are present on monoclonal IgM autoantibodies. Molecular studies indicate that the frequent occurrence of these CRIs in CD5 B cell malignancies is secondary to the non random rearrangement and use of highly conserved Ig variable region genes (V genes) expressed with little or no somatic hypermutation. In addition, studies with other neoplastic CD5 B-CLL cell populations, not selected for their expression of autoantibody-associated CRIs, reveal that they too may express a restricted set of V genes that have not substantially diversified from those present in the germline DNA. Consistent with the distinct clonal origin of each B CLL, the Ig heavy chain sequence of each leukemia population is unique at the junction between the variable and constant regions of the Ig molecule in the third complementarity determining region (CDR3). Generated during the process of Ig VH gene rearrangement, the nucleic acid sequence encoding CDR3 is formed by possible N-terminal base insertions, one of several D minigenes and one of six JH gene segments. Despite the potential for great diversity in this region, there are structural similarities in the CDR3 of Ig heavy chains expressed by B-CLL bearing a major CRI, designated G6. This contrasts with the marked variation noted in the CDR3 of Ig heavy chains produced by normal non-malignant B cells that also bear the G6-CRI and use the same VH genes as G6-reactive B-CLL. Coupled with the observed potential bias in antibody light chain and heavy chain pairing in B-CLL, these data suggest that the autoantibodies expressed in this disease may be selected based on antigen binding activity. Collectively, these studies indicate that non-stochastic Ig V gene rearrangement and subsequent selection may influence the Ig repertoire expressed in this common B cell malignancy. PMID- 27463479 TI - B Cell Malignancies Frequently Target the Autoreactive B Cell Repertoire. AB - Autoreactive B cells constitute a substantial part of B cell repertoire. They frequently secrete polyspecific natural autoantibodies, which are the expression of germinal genes. During recent years considerable evidence has accumulated indicating that this autoreactive B cell repertoire frequently undergoes malignant transformation. Studies on antibody activity of paraproteins and some B cell malignancies have clearly demonstrated an impressive high frequency of autoantibody activity in these disorders. About 30% of IgM paraproteins and at least 10% of IgG and IgA monoclonal Ig display rheumatoid factor, cold agglutinin, anti-myelin associated glycoprotein or polyreactive activity. Similar high frequencies of autoantibody activity have been observed when CD5*** CLL B lymphocytes and CD5-follicular lymphoma B lymphocytes are induced to secrete Ig. The activation of this autoreactive B-cell repertoire through continuous challenge by self antigens could create suitable conditions for the occurrence of mutations and chromosomal translocations. PMID- 27463480 TI - Proposals for a Phenotypic Classification of B-Chronic Lymphocytic Leukemia, Relationship with Prognostic Factors. AB - Immunophenotypic analysis was performed in 53 cases of B chronic lymphocytic leukemia using a large panel of monoclonal antibodies recognizing B, T, activation and myeloid antigens. Our results showed four patterns of reactivity: (a) several molecules were constantly expressed: CD19, CD20, CD24, CD37, HLA-DR, mu heavy chain, CD5, CD23, B5, CD32; (b) one antigen, CD11b, was found in 50 to 80% of the cases; (c) some markers were detected in less than 50% of the cases: CD25, CD38, CD71, CD11a, c, CD14b-c; (d) CD2 and CD16 were never detected. From these results, a phenotypic classification in three groups has been proposed and these groups were correlated with the progression of the disease, mainly with the lymphocyte doubling time of less than one year. We hypothesized that the leukemia cells could be at various stages of differentiation and/or activation according to their expression of activation and myeloid markers. PMID- 27463481 TI - Expression of CD11a (LFA-1) on B-chronic Lymphocytic Leukemia and Lymphoma Cells: Correlation with Cell Surface Immunoglobulin Intensity and CD58 (LFA-3) Expression. AB - In the present study the expression of CD11a (LFA-1) was studied on B-chronic lymphocytic leukemia (CLL) cells and B-non-Hodgkin's small lymphocytic lymphoma in leukemic phase (NHL). The expression of CD11a was correlated with that of surface immunoglobulin (Smig) and CD58 (LFA-3). Patients with CLL were found to have a significantly lower proportion of CD11a+ cells than NHL patients, and the intensity of the staining of Smig was lower in CLL when compared with NHL. The proportion of CD11a+ cells in CLL, but not in NHL, was inversely correlated with the total white blood cell count. In CLL patients the percentage of CD11a+ cells was significantly lower in Rai stages 2-4 compared with stages 0-1. There was a strong correlation between the proportion of CD11a+ and CD58+ cells in both CLL and NHL. In contrast, there was no correlation between the proportion of CD11a cells and Smig intensity in both of these diseases when studied separately. However, when the results in these two diseases were pooled, the proportion of CD11a cells correlated with Smig intensity. The present study indicates that Smig intensity and proportion of CD11a+ cells are important criteria for the differential diagnosis between CLL and NHL. PMID- 27463482 TI - Involvement of Interleukin-6 in the Autocrine Stimulation of Chronic Lymphocytic Leukemia B Cells by Tumor Necrosis Factor. AB - Tumor necrosis factor alpha (TNFalpha) acts as an autocrine growth factor in chronic B cell malignancies. TNF also induces production of interleukin 6 (IL-6) which stimulates B cell growth and differentiation. We have previously demonstrated increased TNFalpha production by (Rai) stage 0 chronic lymphocytic leukemia (B-CLL) cells and the absence of TNF production by cells from stage IV patients. In an attempt to elucidate a possible role for TNF in the malignant progression of B-CLL we investigated the possibility of IL-6 involvment in the stimulatory action of TNF on B-CLL cells. We observed that: (1) the in vitro proliferative response of B-CLL cells to recombinant human (rh)THFalpha was consistently inhibited by a monoclonal antibody (MoAb) against IL-6, (2) the release of IL-6 by B-CLL cells could be augmented by rhTNFalpha, (3) no differences were detected in the foregoing parameters between stage 0 and stage IV-derived cells and (4) despite the inhibitory action of an anti-IL-6 MoAb on the TNF-induced proliferative response of B-CLL cells, IL-6 receptor expression was undetectable in these cells. Although these findings are suggestive of an autocrine or paracrine mechanism involving TNF and IL-6, the importance of the release and action of these cytokines in the regulation of B-CLL cell growth and malignant progression still remains to be elucidated. PMID- 27463483 TI - Use of the MTT Chemosensitivity Assay in B-Cell Chronic Lymphocytic Leukemia. AB - The possibility of evaluating the susceptibility of B-cell chronic lymphocytic leukemia (B-CLL) cells to chemotherapeutic agents pre-clinically, was assessed using the MTT colorimetric assay. The results so far obtained suggest that this rapid 3-4 days' test is accurate and reliable and may allow the physician to recognize individual B-CLL cases in which the neoplastic clone is resistant to Chlorambucil. Furthermore, the high efficacy of Fludarabine clearly emerges from these in vitro analyses. The possibility of employing Chlorambucil in combination with alpha Interferon is suggested and the relevance of using this simple test for better drug selection in B-CLL patients is discussed. PMID- 27463484 TI - Unresolved Issues in Chronic Lymphocytic Leukemia Treatment. PMID- 27463485 TI - Therapeutic Results from the Trials Managed by the French Cooperative Group on Chronic Lymphocytic Leukemia. AB - Since 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia (CLL), including 43 hematological departments, has conducted three randomized clinical trials. More than 2,500 patients are nowadays randomized in these trials (973 in the CLL80 protocol and 1330 in the CLL85 protocol). These trials clearly contributed to the better knowledge and understanding of the CLL, in each stage of the disease. In stage A-CLL, the protocol CLL80 included 611 patients, randomly allocated either to daily chlorambucil (n = 302) or abstention (n = 309). Results of the third interim analysis, based on the reference date of June 1, 1986, pointed out the complex action of chlorambucil, associating beneficial effects consisting in slowing down disease progression to stage B or C and favoring disease remission, with harmful effects given by a shorten survival and an excess of epithelial cancer, as compared with the no treatment group. However, the harmful effects of chlorambucil have not been yet observed in the CLL85 protocol, where 932 stages A were randomized between intermittent chlorambucil (n = 466) and no treatment (n = 466). Nevertheless, the potential harmful effects of the treatment raised out the question of therapeutical decision in stage A-CLL, and contributed to the design of the new protocol, CLL90, in which stage A-CLL are not treated until disease progression is observed. In stage C-CLL, the CLL80 protocol included 70 patients. It demonstrated that the polychemotherapy CHOP, i.e. COP + doxorubicin improved these patients (n = 34) as compared with those treated with COP (n = 36), in terms of disease remission as well as survival. The CLL85 protocol involved 90 stages C, and showed no benefit on survival from methotrexate when associated with CHOP. In stage B-CLL, the CLL80 protocol included 291 patients, who were randomized between daily chlorambucil (n = 150) and the COP polychemotherapy (n = 141). The interim analyses of this trial pointed out the closed results of these two treatments, either for disease remission or for survival. Thereafter, the protocol CLL85 randomized 287 stages B between two polychemotherapies, COP (n = 140) and CHOP (n = 147). However, although the follow-up of this latter trial is rather short considering the main endpoint (survival), no beneficial effect of the CHOP was observed in terms of overall survival, although a benefit was observed in terms of hematological response at the sixth month. Considering the poor prognosis of the stages B and C, the current protocol (CLL90) compares, in both stages B and C, the effect of three treatments, namely CHOP, CAP and Fludarabine. PMID- 27463486 TI - Treatment of Chronic Lymphocytic Leukemia: A Preliminary Report of Spanish (Pethema) Trials. AB - In 1988 the Spanish Cooperative Group PETHEMA initiated a series of trials in CLL patients stratified according to their clinical stage. Patients in stage A were allocated to treatment with intermittent chlorambucil plus prednisone or observation, in order to investigate whether treatment is of benefit; patients in stage B received chlorambucil alone or chlorambucil plus prednisone, the objective being to ascertain the contribution, if any, of prednisone to that combination; finally, patients in stage C received chlorambucil plus prednisone or mini-CHOP, to try to reproduce previously reported results. In this first interim analysis no survival advantage was observed for patients in stage A receiving treatment (n = 36) (projected survival 95% at 3 years) as compared to those not treated (n = 44) (projected survival: 100% at 3 years); this trial has recently been cancelled. In stage B no differences in either response rate and survival were observed between patients treated with chlorambucil alone (n = 23) (response rate; 56.5%; projected survival: 90% at 3 years) and chlorambucil plus prednisone (n = 20) (response rate: 60%; projected survival: 80 at 3 years). Finally, in stage C 14 evaluable patients treated with mini-CHOP had a response rate (50%) not different from that obtained in 19 patients treated with chlorambucil plus prednisone (42%) and no significant differences in survival between both groups (60% and 85% at 3 years, respectively) are observed. A meaningful analysis of these trials will require a larger number of patients and a longer follow-up. PMID- 27463487 TI - Chlorambucil/Prednisone versus CHOP in Symptomatic Chronic Lymphocytic Leukemias of B-Cell type. A Randomized Trial. AB - The therapeutic efficacy of intensive chemotherapy (CHOP) versus palliative low dose therapy (chlorambucil/prednisone, ChP) was studied in a randomized trial including 258 previously untreated patients with asymptomatic low-grade non Hodgkin lymphomas stage III and IV. The patients were stratified according to histological subgroup (the Kiel classification). 113 patients with chronic lymphocytic leukemia (CLL), including B-CLL and leukemic lymphoplasmacytoid immunocytoma (1C), were evaluated separately and presented here. The therapeutic goal was to achieve an asymptomatic state in the ChP group, while in patients allocated to CHOP the intention was to reach complete remission. Thus, in the CHOP group a higher response rate was noted than in the ChP group but no statistically significant difference in overall survival was seen. The results do not support the use of intensive chemotherapy as first line therapy in symptomatic CLL. PMID- 27463488 TI - CHOP Versus Chlorambucil + Prednisolone in Chronic Lymphocytic Leukemia. AB - One hundred and fifty-seven previously untreated stage B or C B-CLL patients were randomized to treatment with either chlorambucil + prednisolone (CLBP) 5 days every 4 weeks or CHOP every 4 weeks. Significantly more patients achieved complete remission on CHOP, but duration of response and survival were equal in the two regimens. Non-responders on CLBP were switched to CHOP, so that finally most patients received nearly the same amount and quality of treatment, which possibly explains the lack of difference in survival. However, compared to previous studies, the study-designed intensive chemotherapy seems to prolong survival for patients with advanced disease, especially those in stage C. PMID- 27463489 TI - Combination of Cytosine-Arabinoside (ARA-C), Cyclophosphamide and Prednisone in the Treatment of B-Chronic Lymphocytic Leukemia in Advanced Stages and Progressive Disease. AB - Recently the major advances in B-chronic lymphocytic leukemia (B-CLL) have been in defining biological characteristics and prognostic criteria. However it remains to be established which is the best therapeutic approach following the first line treatment, particularly when the patients are completely unresponsive to the standard treatment using Chlorambucil (CHL) and Prednisone (PDN) and the disease is progressive. We report the results of a combination regimen using Cytosine-Arabinoside (ARA-C), Cyclophosphamide (CTX) and PDN in 19 B-CLL patients with advanced disease, resistant to CHL + PDN. The treatment schedules were as follows: Schedule A) ARA-C 60mg/sqm from day 1 to 4 s.c., CTX 75 mg/sqm from day 1 to 4 i.v., PDN 40 mg/sqm from day 1 to 4 p.o.: courses were repeated every 4 weeks for 6 months; Schedule B) ARA-C 100 mg/sqm from day 1 to 7 s.c., CTX 100 mg/sqm from day 8 to 14 i.v., PDN 40 mg/sqm from day 1 to 21 p.o.: courses were repeated every 4 weeks for 6 months. Fourteen pts were treated with schedule A and 5 pts with schedule B. We observed 9 partial remissions (PR), 5 cases with no response and 5 patients with progression. The median duration of PR is 20 months and two patients remain in PR after 18 and 60 months, respectively. The combination of ARA-C, CTX plus PDN is highly effective in advanced stages and in pretreated B-CLL but we need larger randomized studies to draw more definitive conclusions. PMID- 27463490 TI - CLL Trials in the United Kingdom the Medical Research Council CLL Trials 1, 2 and 3. AB - The MRC has conducted randomised trials in CLL sine 1978: CLL 1 (1978-84), 660 patients; CLL 2 (1984-90), 640 patients; CLL 3 (from June 1990), 90 patients. Centralised morphological diagnosis and membrane marker studies have allowed the exclusion of non-CLL disorders. Some of the treatment questions were repeated in more than one trial. Chlorambucil (chl) given intermittently was compared with the combination COP in CLL 1: no differences in survival or response were observed although the response rate (CR + PR) of COP rose from 53% to 73% when the dose of cyclophosphamide was doubled; CR + PR with chl was 62%. Chlorambucil was used with or without prednisolone (pred) in CLL 2 (stages B and C) and no differences were observed in either response rate (chl 74%; chl + pred 80%) or survival. Comparing all cases which in both trials were allocated to receive a combination including pred (241) or chl alone (248), no advantage in survival could be detected with the addition of pred to alkylating agents. Splenic irradiation (SI) (116 patients) was compared to Chlorambucil (136 patients) in both trials. Although a survival advantage for SI was suggested in CLL 1, this was not confirmed in CLL 2. A new trial, CLL 3, will be testing the addition of an anthracycline, epirubicin, to chl in stages B and C. The effect of early therapy with chl was compared with deferred (or no) treatment in CLL 1 (stages I and II static) and CLL 2 (Stage A). The combined results in 306 patients show a survival advantage for the deferred treatment group (2p = 0.05) when allowance was made for age, stage and sex. Analysis of causes of death indicates that the main difference between the randomised groups is the number of deaths attributed to CLL itself. There was no significant difference in the incidence of cancer between the two groups. PMID- 27463491 TI - Prolonged Intermittent Chlorambucil Administration in B-Chronic Lymphocytic Leukemia: Experience from a Single Hematology Unit. AB - In the present study we investigated whether prolonged intermittent chlorambucil (Chl) administration is more effective for B-chronic lymphocytic leukemia (B-CLL) patients, compared to the traditional mode of shorter duration. One hundred and seventeen patients, entered the study, were scheduled to receive Chl orally for 10 days/mo, in a dose of 10 mg/daily, for a maximum period of 24 mo. Eighty-one patients (54M/27F), who had completed at least 10 mo of therapy were analyzed. Their median age was 60 yrs (30-80). Nine patients were stage A, 27 stage B and 45 stage C. Their median follow-up time from initiation of treatment was 40 mo (12-108). They received Chl for a median period of 18 mo (12-24). The overall response rate of our patients at six and 18 mo was similar (approximately 90%). However, there was a significant increase of complete responders at 18 mo compared to those at six mo of therapy (14/67 or 21% and 6/81 or 7.4%, respectively) (p < 0.025). Overall survival from the initiation of therapy according to the stage was as follows: stage A 50 mo, stage B 51 mo and stage C 33 mo. No statistically significant differences in survival among the three stages was found. No toxicity or increased incidence of second malignancy was observed except for one patient who was extremely sensitive to Chl and in whom therapy had to be discontinued temporarily. We concluded that at 18 mo of Chl administration the highest response had been achieved and that overall survival of stage C patients was similar to that at stages A and B. PMID- 27463492 TI - Current Status of U.S. Clinical Trials in Chronic Lymphocytic Leukemia. AB - Current therapies for chronic lymphocytic leukemia (CLL) have not substantially improved the survival of these patients (pts). As a result treatment has been primarily palliative. One major obstacle in designing innovative therapies has been a lack of new and effective agents. Recent interest in clinical trials has been stimulated by the impressive activity in pts with CLL of three unique purine analogues; fludarabine (FLUDARA), 2'-deoxycoformycin (DCF) and 2 chlorodeoxyadenosine (CDA). Of the three, the largest experience in CLL is with FLUDARA. More than 1200 CLL patients have received FLUDARA either on clinical trials or through the NCI-Group C protocol mechanism. In contrast to the published data, preliminary analysis of the first 87 evaluable Group-C patients revealed only 2% complete and 37% partial responses; this discrepancy can be explained by the fact that most patients were still receiving treatment at the time of the analysis, and many were continuing to respond (9 of 12 patients who received treatment for > 6 cycles responded); there was no central pathology review to confirm the diagnosis, 89% were Rai "high risk", and most patients had received extensive prior therapy. An updated analysis of response in the first 300 cases is underway. Of 497 pts evaluable for toxicity, 41% developed infections which were serious in 17%, and there were episodes of serious neurotoxicity in 9%. Based on the high level of activity and relative tolerability of FLUDARA, a national U.S. phase III trial is underway comparing chlorambucil (CLB) vs FLUDARA vs CLB + FLUDARA in untreated patients with advanced disease. A comparison of FLUDARA vs CDA in relapsed/refractory pts is being planned. Combination regimens are being piloted in relapsed/refractory CLL including DCF + FLUDARA, DCF + CLB, FLUDARA + CDA, FLUDARA + interferon-alpha, FLUDARA + gallium, FLUDARA + cyclophosphamide. Since FLUDARA achieves true complete responses in a substantial number of previously untreated pts, it is being considered as part of an induction program prior to autologous bone marrow transplantation. FLUDARA has a high degree of bioavailability in dogs, and an oral preparation is being evaluated in clinical trials. Hopefully, new purine analogue-based combination regimens will improve the response rate and survival in patients with CLL. PMID- 27463493 TI - Sharing Data in Biomedical Research. AB - In the spirit of openness and service to mankind, scientific investigators should rise above their self-interests and share their research data. The leap necessary to ascend above one's personal best interests defies gravity. This short paper discusses the complexities of creating a zero gravity environment in the scientific community. PMID- 27463494 TI - Allogeneic Bone Marrow Transplantation in Chronic Lymphocytic Leukemia: 17 Cases. Report of the EBMT. AB - Allogeneic bone marrow transplantation (BMT) was performed in 17 patients with chronic lymphocytic leukemia (CLL): 15 resistant and 2 untreated forms; 12 males and 5 females with a mean age of 40 years (32-49). The conditioning regimen and graft versus host disease (GVHD) prophylaxis were varied. Successful engraftment was obtained in 15 evaluable cases. Lymphocytosis and clinical symptoms subsided in all but one case. All 15 evaluable patients developed acute GVHD. Among the 17 patients grafted, one early death was observed at the 15th day post-BMT, and one refractory form died 2 months after BMT. Of the remaining 15 patients in complete remission (CR0, 4 died from GVHD, hemorrhage, and graft failure, and 2 relapsed at 7 and 54 months after BMT and died. 9 patients are alive in CR with a mean follow-up of 25.6 months (4-48). Chimerism was complete in 8 patients and partial in the 2 T-depleted cases. In one case, an immunoglobulin gene rearrangement study was performed showing no residual disease. These results suggest that allogeneic BMT might be proposed as an alternative and possibly curative therapy for refractory CLL in young patients when performed earlier in the disease course. PMID- 27463495 TI - 2-Chlorodeoxyadenosine Treatment of Refractory Chronic Lymphocytic Leukemia. AB - Ninety patients with advanced refractory chronic lymphocytic leukemia (CLL) were treated with 2-chlorodeoxyadenosine (2-CdA) administered either as a 0.1 mg/kg/day 7-day continuous intravenous infusion or as a 0.028 mg to 0.14 mg/kg/day 2-hour bolus for 5 consecutive days. One patient had stage A disease, seven patients had stage B disease, and 82 patients had stage C disease. Twenty seven patients were female and 63 were male, with an age range of 40 to 84 years, median 63 years. All patients had received prior therapy and failed, with a range of one to four and a median of two prior therapies. Six patients had previously failed fludarabine therapy. Four patients (4%) experienced complete remissions, and 40 patients (40%) experienced partial remissions, yielding an over all response rate of 44%. The median duration of response was four months, with a range of two to 30 months. Of 50 patients who were non-responders, 27 (54%) had a greater than 50% sustained reduction in the absolute lymphocyte count despite insufficient improvement in hemoglobin concentration or platelet count to achieve a response status. Therapy was well tolerated with myelosuppression being the principal toxicity. Twenty-two patients (24%) experienced thrombocytopenia and 16 patients (18%) had documented infections. We confirm our early pilot results with 2-CdA demonstrating in a large group of patients that 2-CdA achieves a significant response rate with two different drug administration schemes in failed CLL patients. Responses are achieved with acceptable toxicity. 2-CdA merits further evaluation in previously untreated patients and in combination regimens for failed patients. PMID- 27463496 TI - New Agents and Strategies in CLL Treatment. AB - Fludarabine Monophosphate (FLU) is an adenosine analogue with a high-level of anti-leukemic activity in patients (pts) with CLL. FLU (25-30 mg/m(2)/day * 5 every 4 weeks) was given to 78 previously treated pts with CLL. The overall response rate was 58% (CR 11%, nodular CR 26%, PR 21%). Subsequently, prednisone (P, 30 mg/m(2)/day * 5) was added to the FLU regimen and administered to 169 pts. The response rate, up to this time, was similar to the FLU regimen 52% (CR 12%, nodular CR 28%, PR 12%). The major toxicity was febrile episodes which occurred in one course in 5 for both groups of pts. The median survival was also similar in both groups (FLU 74 weeks and FLU + P 103 weeks). Thus, no advantage was noted with the addition of P to FLU. FLU and FLU + P have been administered to 36 pts and 62 pts respectively who have had no prior treatment. The response rate for FLU was 83% (CR 39%, nodular CR 36%, PR 8%) and FLU + P was 82% (CR 29%, nodular CR 34%, PR 19%). Several of the FLU + P group developed persistent thrombocytopenia despite a good anti-leukemic response. The rates of decrease of the circulating and marrow lymphocyte counts were similar for the FLU and FLU + P groups. No survival difference has been noted to date in these groups. Time to development of progressive disease in the previously treated pts FLU and FLU + P is 104 weeks and is similar for the CR and nodular CR pts 118 weeks vs. 97 weeks and for the PR pts 89 weeks. All pts appear eventually to recur. Insufficient data is available to evaluate the time to progression of the previously treated pts. Two parameter flow-cytometry for CD19 and CD5, Kappa/Lamda ratio and immunoglobulin gene rearrangement studies are able to detect residual bone marrow disease in a majority of pts with CR and nodular CR (BM lymphocytes <30%). As relapse appears to be inevitable in the previously treated group who respond, post-remission therapy will include autologous bone marrow transplantation for pts <60 years of age and recombinant alpha-Interferon for pts >60 years of age. Post-remission therapy for the previously untreated responders will not be given to allow an estimate of the unmaintained time to progression. Bone marrow will be stored in first remission for future use, if the pts recur. Combination therapy studies utilizing FLU combined with Ara-C or Doxorubicin are being conducted. PMID- 27463498 TI - The Treatment of CLL: Summing up. PMID- 27463497 TI - Combined use of Alpha 2b Interferon and Chlorambucil in the Management of Previously Treated B-Cell Chronic Lymphocytic Leukemia. AB - We hereby here the successful use of a combined therapeutic approach with alpha 2b Interferon (IFN) and Chlorambucil in the management of previously treated B cell chronic lymphocytic leukemia (B-CLL). The two patients under study had been managed with repeated and frequent cycles of Chlorambucil. Rather than with more toxic multidrug regimens, the hematological picture was controlled with 3 MU of IFN every three-five days and 5 mg of Chlorambucil every two-five days. Using such an approach, which is feasible on an out-patients basis and devoid of significant side effects, a consistent control of the WBC count was achieved for 32 and 16 months, respectively. PMID- 27463499 TI - The Classification of Lymphoid Leukaemias. AB - Advances in immunological and molecular techniques and a greater attention to peripheral blood morphology, bone marrow histology and lymph node pathology have resulted in a more objective classification of the lymphoproliferative disorders. This, in turn, has facilitated the understanding of the biology and the natural history of these diseases and helped to predict the response to therapy. Among the chronic B-cell disorders, two main groups of diseases can be distinguished: primary leukaemias and non-Hodgkin's lymphoma (NHL) in leukaemic phase. Distinct differences in morphological and histopathological features together with characteristic immunophenotypic profiles constitute the best basis for their precise diagnosis and classification. Because of their great heterogeneity some problems still arise, particularly in cases of low grade NHL and chronic lymphocytic leukaemia when the disease undergoes malignant transformation. Leukaemias of mature T cells are less common in Western countries. They can be distinguished from B-lymphoid disorders by standard immunological markers. Cytogenetic and DNA analyses are essential to establish T-cell clonality not shown by marker studies. The morphology of the neoplastic cells and the variable histopathological features together with epidemiological factors, such as the human retrovirus HTLV-1, are key elements to characterise and classify more precisely the various clinico-pathological entities included in this group. PMID- 27463500 TI - Histopathology and Immunocytochemistry of Lymph Node Biopsies in Chronic Lymphocytic Leukemia and Immunocytoma. AB - When lymph node biopsies of lymphocytic neoplasms are studied with subtle morphological and immunohistochemical methods meaningful information is obtained, that is not only of theoretical value, but which also relates to the clinical behavior ("leukemia," paraproteinemia, prognosis). Such an analysis allows us to differentiate three subtypes of chronic lymphocytic leukemia (diffuse, pseudofollicular and tumor forming) and to recognize two subtypes of immunocytoma (lympho plasmacytoid and lympho plasmacytic). The plasmacytoid-plasmacytic differentiation is usually not recognizable in blood smears. CLL cells show only IgM + IgD on their surfaces, whereas in immunocytoma monotypic cytoplasmic immunoglobulins are evident, and they are not only of the IgM type. The CD5 negative lymphoplasmacytic subtype differs clearly from chronic lymphocytic leukemia and from the majority of cases of lymphoplasmacytoid immunocytoma, which are CD5 positive. PMID- 27463501 TI - Chronic Lymphocytic Leukemia (B-CLL) and Immunocytoma (LP-IC): Clinical and Prognostic Relevance of this Distinction. AB - The Kiel classification of non-Hodgkin lymphomas (NHL) has established chronic lymphocytic leukemia (B-CLL) and immunocytoma (LP-IC) as separate entities of low grade malignant NHL by morphological and immunohistochemical criteria. The clinical and prognostic relevance of this discrimination was evaluated in a prospective multicenter observation study by the Kiel Lymphoma Study Group. From 1975 to 1980, 430 previously untreated patients with B-CLL (n = 217) and LP-IC (n = 213)a were recruited and followed for up to 14 years. While the age and sex distribution and the incidence of clinical stages were quite similar in both entities major differences between initial manifestations in B-CLL and LP-IC became evident, e.g. in the incidence of bone marrow infiltration (99.5 vs. 86%), peripheral blood lymphocytosis (99.5 vs. 60%), or monoclonal gammopathy (1 vs. 30%). A strictly localized tumor (Ann Arbor stage I/IE) was seen in only 1.5% of the LP-IC patients who were successfully treated by local radiotherapy. In all other patients an expectative-palliative treatment concept was pursued. Long-term survival data analysis revealed significant differences between B-CLL and LP-IC and identified the pseudofollicular in B-CLL and the lymphoplasmacytic in LP-IC as the most favorable histological subtypes. The discriminative prognostic potential of clinical stage (Rai or Binet classification) for B-CLL and LP-IC varied and the pattern of prognostic risk factors obtained by multivariate analysis was not identical. Thus, the morphological distinction between B-CLL and LP-IC correlates with characteristic differences between these entities both in their initial clinical presentation and long-term prognosis. PMID- 27463502 TI - Chronic Lymphocytic Leukemia in Younger Adults: Preliminary Results of a Study Based on 454 Patients-IWCLL/Working Group. AB - Whether all younger adult patients with chronic lymphocytic leukemia (CLL) should be offered intensive and/or experimental treatments is currently undecided. In order to investigate the natural history and prognosis of CLL in younger adults, information on 454 B-CLL patients less than 50 yrs old, from 13 different International groups was collected and analyzed. The male/female proportion is 1.46 (270/184) and the median age is 46 yrs (range, 20-49). Number of cases increases with age: nine patients (2%) are <30 yrs; 70 (14%) are 30 to 40 yrs; and 375 (84%) are 41 to 49 yrs. Clinical stages distribution is as follows: Rai O, 113 (25%), Rai I, 98 (21.5%), Rai II, 182 (40%), Rai III, 25 (5.5%), and Rai IV, 36 (8%); Binet's A, 235 (52%), Binet's B, 160 (35%), Binet's C 59 (13%). Bone marrow biopsy was available in 251 cases, being nodular in 46 (18.5%), interstitial in 76 (30%), mixed in 60 (24%), and diffuse in 69 (27.5%). Clinical characteristics of these patients do not differ from those described for entire series of CLL patients including all ages. The majority of patients (93%) were diagnosed between 1975 and 1989 and at the time of this analysis 138 (30.3%) have died. Infection accounts for the large majority of deaths (48%). Overall median survival is 12 yrs. Survival probability (+/-SD) is 73.55 +/- 2.47% at 5 yrs, 51.04 +/- 3.46% at 10 yrs, and 45.53 +/- 4.08% at 15 yrs. Prognostic parameter identified in whole series of patients with CLL are also useful when applied to this special subset. Thus, patients in stage A, B, and C have, at 10 yrs after diagnosis, survival probabilities of 72.4%, 33.7%, and 21.2%, respectively. Rai stages also discriminate different risk-groups with a survival probability at 10 yrs of 76% for patients in stage 0, 45% for those in stage I + II, and 24% for patient in Stage III + IV. Patients with non-diffuse bone marrow pattern have a survival probability of 76% at 10 yrs compared to 28% for those with a diffuse pattern. Further analysis will refine both the prognostic assessment and the optimal treatment approach for these patients. PMID- 27463503 TI - Chronic Lymphocytic Leukemia in Young Adults: Report of Six Cases Under the Age of 30 Years. AB - We describe six rare patients with B-type CLL under the age of 30 years. All were males and four showed a relatively aggressive clinical course requiring initial chemotherapy at an early stage of their disease. Four of the six patients developed prominent generalized lymphadenopathy accompanied by splenomegaly and a rapid increase in the peripheral blood lymphocyte count or a doubling time of less than 12 months and were symptomatic. Of the six cases, one still has Stage A (0) disease, 16 months after diagnosis and has not yet been treated, while another 29 year old male, initially stage C (3) at diagnosis, progressed rapidly, despite chemotherapy and died after 42 months. Of the remaining four patients all responded well to treatment initially, however one 24 year old male has progressed rapidly from stage A (2) to Stage B (2), 14 months after initial response to chlorambucil and prednisone. Two patients remain in Stage A (0), two and eight years respectively after chemotherapy; while the patient with the longest follow up is currently 39 years old in good partial remission with Stage A (0) disease ten years after initial diagnosis, having responded well to Fludarabine, following a major flare up of his disease recently. The rare phenomenon of young patients with CLL is reviewed and management options relating to new therapeutic approaches for this sub-population of young patients are discussed. PMID- 27463505 TI - Preface. PMID- 27463504 TI - "Smouldering" Chronic Lymphocytic Leukemia. AB - Although clinical staging systems are useful to assess the prognosis of chronic lymphocyctic leukemia (CLL), for the large majority (up to 60%) of patients in early clinical stage no system is able to predict those who will progress ("active" disease) and those who will remain at the same stage ("smouldering" disease). To identify the latter subset of patients is important since in these patients treatment should be withhold until progression occurs. In the past few years, there have been several attempts to define "smouldering" CLL. Basically, patients in early stage (Binet's A) with: (a) moderate bone marrow infiltration (non-diffuse pattern in the biopsy or less than 80% lymphocytes in bone marrow aspirate), (b) low blood lymphocyte count (<30 * 10(9)/L), (c) Hb level in a non anemic range (> 12 or 13 g/dL), and d) prolonged lymphocyte doubling time (> 12 months) are not likely to progress and have a life-expectancy not different from matched controls. In three different series analyzed so far, disease-progression rate is approximately 15% to 5 yrs, and survival is not different from that of controls. Approximately, 20 to 30% of all CLL patients with CLL fulfill "smouldering" criteria. Besides the above criteria, there are others that merit consideration. Thus, Rai's substages (AO vs AI + II) have been found to predict different outcomes within Binet's stage A. On the other hand, chromosome abnormalities may be useful to further assess the prognosis. Finally, the contribution of phenotypic studies to the definition of "smouldering" CLL remains uncertain, and a female sex has been associated with a better outcome. Whether or not patients with "active" stage A (e.g., those not fulfilling "smouldering" CLL criteria) should be treated is unknown. The morbidity associated to treatment (e.g. increase number of second neoplasms) and the lack of survival advantage found in recent randomized trials cast doubts on the real benefit of treating patients in early stage (Binet's A; Rai's 0). To answer this question, the separate analysis of patients with "smouldering" stage A and patients with "active" stage A included in recent trials could be of help. Moreover, prospective studies of patients in early stage followed-up with no treatment could be useful to refine the definition of "smouldering" CLL. PMID- 27463506 TI - Systematic Exploration of the Glycoproteome of the Beneficial Gut Isolate Lactobacillus rhamnosus GG. AB - Glycoproteins form an interesting class of macromolecules involved in bacterial host interactions, but they are not yet widely explored in Gram-positive and beneficial species. Here, an integrated and widely applicable approach was followed to identify putative bacterial glycoproteins, combining proteome fractionation with 2D protein and glycostained gels and lectin blots. This approach was validated for the microbiota isolate Lactobacillus rhamnosus GG. The approach resulted in a list of putative glycosylated proteins receiving a 'glycosylation score'. Ultimately, we could identify 41 unique glycosylated proteins in L. rhamnosus GG (6 top-confidence, 10 high-confidence and 25 putative hits; classification based on glycosylation score). Most glycoproteins are associated with the cell wall and membrane. Identified glycoproteins include proteins involved in transport, translation, and sugar metabolism processes. A robust screening resulted in a comprehensive mapping of glycoproteins in L. rhamnosus GG. Our results reflect the glycosylation of sugar metabolism enzymes, transporters, and other proteins crucial for cell physiology. We hypothesize that protein glycosylation can confer an extra level of regulation, for example by affecting enzyme functions. This is the first systematic study of the glycoproteome of a probiotic and beneficial gut isolate. PMID- 27463507 TI - Flavin Adenine Dinucleotide and N5 ,N10 -Methenyltetrahydrofolate are the in planta Cofactors of Arabidopsis thaliana Cryptochrome 3. AB - Members of the cryptochrome/photolyase family (CPF) of proteins utilize noncovalently bound light-absorbing cofactors for their biological function. Usually, the identity of these cofactors is determined after expression in heterologous systems leaving the question unanswered whether these cofactors are identical to the indigenous ones. Here, cryptochrome 3 from Arabidopsis thaliana was expressed as a fusion with the green fluorescent protein in Arabidopsis plants. Besides the confirmation of the earlier report of its localization in chloroplasts, our data indicate that fractions of the fusion protein are present in the stroma and associated with thylakoids, respectively. Furthermore, it is shown that the fusion protein expressed in planta contains the same cofactors as the His6 -tagged protein expressed in Escherichia coli, that is, flavin adenine dinucleotide and N5 ,N10 -methenyltetrahydrofolate. This demonstrates that the heterologously expressed cryptochrome 3, characterized in a number of previous studies, is a valid surrogate of the corresponding protein expressed in plants. To our knowledge, this is also a first conclusive analysis of cofactors bound to an Arabidopsis protein belonging to the CPF and purified from plant tissue. PMID- 27463508 TI - Three interacting genomic loci incorporating two novel mutations underlie the evolution of diet-induced diabetes. AB - We investigated the pathophysiology of diet-induced diabetes in the Cohen diabetic rat (CDs/y) from its induction to its chronic phase, using a multi layered integrated genomic approach. We identified by linkage analysis two diabetes-related quantitative trait loci on RNO4 and RNO13. We determined their functional contribution to diabetes by chromosomal substitution, using congenic and consomic strains. To identify within these loci genes of relevance to diabetes, we sequenced the genome of CDs/y and compared it to 25 other rat strains. Within the RNO4 locus, we detected a novel high impact deletion in the Ndufa4 gene that was unique to CDs/y. Within the RNO13 locus, we found multiple SNPs and INDELs that were unique to CDs/y but were unable to prioritize any of the genes. Genome wide screening identified a novel third locus not detected by linkage analysis that consisted of a novel high impact deletion on RNO11 that was unique to CDs/y and that involved the Sdf2l1 gene. Using co-segregation analysis, we investigated in silico the relative contribution to the diabetic phenotype and the interaction between the three genomic loci on RNO4, RNO11 and RNO13. We found that the RNO4 locus plays a major role during the induction of diabetes, whereas the genomic loci on RNO13 and RNO11, while interacting with the RNO4 locus, contribute more significantly to the diabetic phenotype during the chronic phase of the disease. The mechanisms whereby the mutations on RNO4 and 11 and the RNO13 locus contribute to the development of diabetes are under continuing investigation. PMID- 27463509 TI - Comparing Distribution of Harbour Porpoises (Phocoena phocoena) Derived from Satellite Telemetry and Passive Acoustic Monitoring. AB - Cetacean monitoring is essential in determining the status of a population. Different monitoring methods should reflect the real trends in abundance and patterns in distribution, and results should therefore ideally be independent of the selected method. Here, we compare two independent methods of describing harbour porpoise (Phocoena phocoena) relative distribution pattern in the western Baltic Sea. Satellite locations from 13 tagged harbour porpoises were used to build a Maximum Entropy (MaxEnt) model of suitable habitats. The data set was subsampled to one location every second day, which were sufficient to make reliable models over the summer (Jun-Aug) and autumn (Sep-Nov) seasons. The modelled results were compared to harbour porpoise acoustic activity obtained from 36 static acoustic monitoring stations (C-PODs) covering the same area. The C-POD data was expressed as the percentage of porpoise positive days/hours (the number of days/hours per day with porpoise detections) by season. The MaxEnt model and C-POD data showed a significant linear relationship with a strong decline in porpoise occurrence from west to east. This study shows that two very different methods provide comparable information on relative distribution patterns of harbour porpoises even in a low density area. PMID- 27463510 TI - Chronic peripheral nerve compression disrupts paranodal axoglial junctions. AB - INTRODUCTION: Peripheral nerves are often exposed to mechanical stress leading to compression neuropathies. The pathophysiology underlying nerve dysfunction by chronic compression is largely unknown. METHODS: We analyzed molecular organization and fine structures at and near nodes of Ranvier in a compression neuropathy model in which a silastic tube was placed around the mouse sciatic nerve. RESULTS: Immunofluorescence study showed that clusters of cell adhesion complex forming paranodal axoglial junctions were dispersed and overlapped frequently with juxtaparanodal components. These paranodal changes occurred without internodal myelin damage. The distribution and pattern of paranodal disruption suggests that these changes are the direct result of mechanical stress. Electron microscopy confirmed loss of paranodal axoglial junctions. CONCLUSIONS: Our data show that chronic nerve compression disrupts paranodal junctions and axonal domains required for proper peripheral nerve function. These results provide important clues toward better understanding of the pathophysiology underlying nerve dysfunction in compression neuropathies. Muscle Nerve 55: 544-554, 2017. PMID- 27463512 TI - Alpha-Smooth Muscle Actin mRNA and Protein Are Increased in Isolated Brain Vessel Extracts of Alzheimer Mice. AB - Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain, characterized by extracellular beta-amyloid (Abeta) plaques, intracellular tau pathology, neurodegeneration and inflammation. There is clear evidence that the blood-brain barrier is damaged in AD and that vessel function is impaired. Alpha smooth muscle actin (alphaSMA) is a prominent protein expressed on brain vessels, especially in cells located closer to the arteriole end of the capillaries, which possibly influences the blood vessel contraction. The aim of the present study was to observe alphaSMA protein and mRNA expression in isolated brain vessel extracts and cortex in an Alzheimer mouse model with strong Abeta plaque deposition. Our data revealed a prominent expression of alphaSMA protein in isolated brain vessel extracts of AD mice by Western blot analysis. Immunostaining showed that these vessels were associated with Abeta plaques. Quantitative real-time PCR analysis confirmed this increase at the mRNA expression level and showed a significant increase of transforming growth factor beta-1 mRNA expression in AD mice. In situ hybridization demonstrated a strong expression pattern of alphaSMA mRNA in the whole cortex and hippocampus. In conclusion, our data provide evidence that alphaSMA protein and mRNA are enhanced in vessels in an AD mouse model, possibly counteracting vessel malfunction in AD. PMID- 27463513 TI - Aging Selectively Modulates Vitamin C Transporter Expression Patterns in the Kidney. AB - In the kidney, vitamin C is reabsorbed from the glomerular ultrafiltrate by sodium-vitamin C cotransporter isoform 1 (SVCT1) located in the brush border membrane of the proximal tubules. Although we know that vitamin C levels decrease with age, the adaptive physiological mechanisms used by the kidney for vitamin C reabsorption during aging remain unknown. In this study, we used an animal model of accelerated senescence (SAMP8 mice) to define the morphological alterations and aging-induced changes in the expression of vitamin C transporters in renal tissue. Aging induced significant morphological changes, such as periglomerular lymphocytic infiltrate and glomerular congestion, in the kidneys of SAMP8 mice, although no increase in collagen deposits was observed using 2-photon microscopy analysis and second harmonic generation. The most characteristic histological alteration was the dilation of intracellular spaces in the basolateral region of proximal tubule epithelial cells. Furthermore, a combination of laser microdissection, qRT-PCR, and immunohistochemical analyses allowed us to determine that SVCT1 expression specifically increased in the proximal tubules from the outer strip of the outer medulla (segment S3) and cortex (segment S2) during aging and that these tubules also express GLUT1. We conclude that aging modulates vitamin C transporter expression and that renal over-expression of SVCT1 enhances vitamin C reabsorption in aged animals that may synthesize less vitamin C. J. Cell. Physiol. 232: 2418-2426, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27463514 TI - In Situ Gelation of Poly(vinylidene fluoride) Nanospheres for Dye-Sensitized Solar Cells: The Analysis on the Efficiency Enhancement upon Gelation. AB - The in situ gelation that utilizes the dissolution of polymers inside the cell is allowed high concentration polymer gel without concerns regarding high viscous electrolyte incorporation into the cell as in the conventional approach. We demonstrate the in situ gelation of polymer composite electrolytes using poly(vinylidene fluoride) nanospheres (PVdF NSs). The PVdF NSs were synthesized by high pressure emulsion polymerization using gaseous vinylidene fluoride monomers. Compared to the liquid electrolyte (LE) DSCs without PVdF gelation, the PVdF polymer gel electrolyte (PGE) DSCs displayed higher eta than the LE DSCs; specifically, the 10 wt % PVdF PGE DSCs display 8.1% of the eta, while the LE DSCs only display 6.5%. We characterized the effect of PVdF PGE on the photovoltaic parameters in detail. We also compared the long-term stability of DSCs containing LE and PVdF PGE. The DSCs with PVdF PGE exhibited high stability compared to the LE DSCs, similar to a conventional PGE system. We believe that this facile in situ gelation approach could be utilized for not only the practical application of polymer gel electrolytes DSCs but also for various energy-storage devices. PMID- 27463515 TI - Conservation of the Red Kite Milvus milvus (Aves: Accipitriformes) Is Not Affected by the Establishment of a Broad Hybrid Zone with the Black Kite Milvus migrans migrans in Central Europe. AB - Among Accipitriformes sensu stricto, only a few species have been reported to form hybrid zones; these include the red kite Milvus milvus and black kite Milvus migrans migrans. M. milvus is endemic to the western Palearctic and has an estimated total population of 20-24,000 breeding pairs. The species was in decline until the 1970s due to persecution and has declined again since the 1990s due to ingestion of rodenticide-treated baits, illegal poisoning and changes in agricultural practices, particularly in its core range. Whereas F1 M. milvus * M. migr. migrans hybrid offspring have been found, F2 and F3 hybrids have only rarely been reported, with low nesting success rates of F1 hybrids and partial hybrid sterility likely playing a role. Here, we analyzed the mitochondrial (CO1 and CytB) and nuclear (Myc) DNA loci of 184 M. milvus, 124 M. migr. migrans and 3 F1 hybrid individuals collected across central Europe. In agreement with previous studies, we found low heterozygosity in M. milvus regardless of locus. We found that populations of both examined species were characterized by a high gene flow within populations, with all of the major haplotypes distributed across the entire examined area. Few haplotypes displayed statistically significant aggregation in one region over another. We did not find mitochondrial DNA of one species in individuals with the plumage of the other species, except in F1 hybrids, which agrees with Haldane's Rule. It remains to be investigated by genomic methods whether occasional gene flow occurs through the paternal line, as the examined Myc gene displayed only marginal divergence between M. milvus and M. migr. migrans. The central European population of M. milvus is clearly subject to free intraspecific gene flow, which has direct implications when considering the origin of individuals in M. milvus re-introduction programs. PMID- 27463516 TI - Effects of structurally different noncoplanar and coplanar PCBs on HELF cell proliferation, cell cycle, and potential molecular mechanisms. AB - Polychlorinated biphenyls (PCBs) are a group of chemicals that persist in the environment, indoors, and humans. Lung exposure to airborne and food contaminants, such as PCBs, may cause possible lung disorders, such as cancer. In the present study, we investigated the effects of structurally different lower chlorinated (<=4Cl), noncoplanar PCB40, and coplanar PCB77 on human lung fibroblast cell line (HELF) cell proliferation, cell cycle progression, and possible molecular mechanisms. Noncoplanar PCB40 and coplanar PCB77 exhibited concentration- and time-dependent biphasic dose-response effects on HELF cell proliferation. Noncoplanar PCB40 and coplanar PCB77 induced 23 and 45% cytotoxicity at higher concentrations than the control. The flow cytometry analysis showed that exposure to PCB40 caused a significant increase in time spent in the G1 phase but decreased length of the S phase in a concentration- and time-dependent manner, whereas PCB77 exposure decreased time spent in the G1 and S phases but increased time spent in the G2 phase. Western blot analysis indicated that PCB77 increased the expression of cyclin E, CDK2, p21, and caspase 9, while PCB40 decreased the expression of these proteins (except CDK2 and p21). An increase in CDK expression after exposure to PCB77 suggests that it may cause carcinogenic effects on HELF cells at higher doses. Our results also demonstrate that the different cytotoxic effects induced by coplanar and nonplanar PCBs were correlated with their structural characteristics; the coplanar congener was more cytotoxic than the nonplanar congener. The study elaborates threshold levels for these chemicals and suggests that the cytotoxicity mechanisms by which PCB congeners act on HELF cells depend on their planarity and chemical structures. Furthermore, the study will be important for developing antidotes to the adverse effects and risk assessment practices for PCBs. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1183-1190, 2017. PMID- 27463517 TI - The 17D-204 Vaccine Strain-Induced Protection against Virulent Yellow Fever Virus Is Mediated by Humoral Immunity and CD4+ but not CD8+ T Cells. AB - A gold standard of antiviral vaccination has been the safe and effective live attenuated 17D-based yellow fever virus (YFV) vaccines. Among more than 500 million vaccinees, only a handful of cases have been reported in which vaccinees developed a virulent wild type YFV infection. This efficacy is presumed to be the result of both neutralizing antibodies and a robust T cell response. However, the particular immune components required for protection against YFV have never been evaluated. An understanding of the immune mechanisms that underlie 17D-based vaccine efficacy is critical to the development of next-generation vaccines against flaviviruses and other pathogens. Here we have addressed this question for the first time using a murine model of disease. Similar to humans, vaccination elicited long-term protection against challenge, characterized by high neutralizing antibody titers and a robust T cell response that formed long lived memory. Both CD4+ and CD8+ T cells were polyfunctional and cytolytic. Adoptive transfer of immune sera or CD4+ T cells provided partial protection against YFV, but complete protection was achieved by transfer of both immune sera and CD4+ T cells. Thus, robust CD4+ T cell activity may be a critical contributor to protective immunity elicited by highly effective live attenuated vaccines. PMID- 27463518 TI - Insights into an Optimization of Plasmodium vivax Sal-1 In Vitro Culture: The Aotus Primate Model. AB - Malaria is one of the most significant tropical diseases, and of the Plasmodium species that cause human malaria, P. vivax is the most geographically widespread. However, P. vivax remains a relatively neglected human parasite since research is typically limited to laboratories with direct access to parasite isolates from endemic field settings or from non-human primate models. This restricted research capacity is in large part due to the lack of a continuous P. vivax in vitro culture system, which has hampered the ability for experimental research needed to gain biological knowledge and develop new therapies. Consequently, efforts to establish a long-term P. vivax culture system are confounded by our poor knowledge of the preferred host cell and essential nutrients needed for in vitro propagation. Reliance on very heterogeneous P. vivax field isolates makes it difficult to benchmark parasite characteristics and further complicates development of a robust and reliable culture method. In an effort to eliminate parasite variability as a complication, we used a well-defined Aotus-adapted P. vivax Sal-1 strain to empirically evaluate different short-term in vitro culture conditions and compare them with previous reported attempts at P. vivax in vitro culture Most importantly, we suggest that reticulocyte enrichment methods affect invasion efficiency and we identify stabilized forms of nutrients that appear beneficial for parasite growth, indicating that P. vivax may be extremely sensitive to waste products. Leuko-depletion methods did not significantly affect parasite development. Formatting changes such as shaking and static cultures did not seem to have a major impact while; in contrast, the starting haematocrit affected both parasite invasion and growth. These results support the continued use of Aotus-adapted Sal-1 for development of P. vivax laboratory methods; however, further experiments are needed to optimize culture conditions to support long-term parasite development. PMID- 27463519 TI - Eight-Week Training Cessation Suppresses Physiological Stress but Rapidly Impairs Health Metabolic Profiles and Aerobic Capacity in Elite Taekwondo Athletes. AB - Changes in an athlete's physiological and health metabolic profiles after detraining have not been studied in elite Taekwondo (TKD) athletes. To enable a better understanding of these physiological changes to training cessation, this study examined the effects of 8-weeks detraining on the aerobic capacity, body composition, inflammatory status and health metabolic profile in elite TKD athletes. Sixteen elite TKD athletes (age: 21.0 +/- 0.8 yrs, BMI: 22.4 +/- 3.9 kg/m2; Mean +/- SD; 11 males and 5 females) participated in this study. Physical activity level assessment using computerized physical activity logs was performed during the competitive preparation season (i.e. one-week before national competition) and at two week intervals throughout the detraining period. Participant aerobic capacity, body fat, and blood biomarkers were measured before and after detraining, and the blood biomarker analyses included leukocyte subpopulations, blood glucose, insulin, dehydroepiandrosterone-sulfate (DHEA-S), and cortisol. Eight-week detraining increased DHEA-S/cortisol ratio (+57.3%, p = 0.004), increased insulin/cortisol ratio (+59.9%, p = 0.004), reduced aerobic power (-2.43%, p = 0.043), increased body fat accumulation (body fat%: +21.3%, p < 0.001), decreased muscle mass (muscle mass%: -4.04%, p < 0.001), and elevated HOMA-IR (the biomarker of systemic insulin resistance; +34.2%, p = 0.006). The neutrophil-to-lymphocyte ratio (NLR), a systemic inflammatory index, increased by 48.2% (p = 0.005). The change in aerobic capacity was correlated with the increased fat mass (r = -0.429, p = 0.049) but not with muscle loss. An increase in the NLR was correlated to the changes in HOMA-IR (r = 0.44, p = 0.044) and aerobic capacity (r = -0.439, p = 0.045). We demonstrate that 8-week detraining suppresses physiological stress but rapidly results in declines in athletic performance and health metabolic profiles, including reduced aerobic capacity, increased body fat, muscle loss, insulin resistance development and elevated systemic inflammatory status in these young elite TKD athletes. The inflammation state was positively associated with insulin resistance development, fat mass, WHR (the index for central fat accumulation), and the decline in VO2max. PMID- 27463520 TI - Distending Pressure Did Not Activate Acute Phase or Inflammatory Responses in the Airways and Lungs of Fetal, Preterm Lambs. AB - BACKGROUND: Mechanical ventilation at birth causes airway injury and lung inflammation in preterm sheep. Continuous positive airway pressure (CPAP) is being increasingly used clinically to transition preterm infants at birth. OBJECTIVE: To test if distending pressures will activate acute phase reactants and inflammatory changes in the airways of fetal, preterm lambs. METHODS: The head and chest of fetal lambs at 128+/-1 day GA were surgically exteriorized. With placental circulation intact, fetal lambs were then randomized to one of five 15 minute interventions: PEEP of 0, 4, 8, 12, or 16 cmH2O. Recruitment volumes were recorded. Fetal lambs remained on placental support for 30 min after the intervention. The twins of each 0 cmH2O animal served as controls. Fetal lung fluid (FLF), bronchoalveolar lavage fluid (BAL), right mainstem bronchi and peripheral lung tissue were evaluated for inflammation. RESULTS: Recruitment volume increased from 0.4+/-0.04 mL/kg at 4 cmH2O to 2.4+/-0.3 mL/kg at 16 cmH2O. The lambs were surfactant deficient, and all pressures were below the opening inflection pressure on pressure-volume curve. mRNA expression of early response genes and pro-inflammatory cytokines did not increase in airway tissue or lung tissue at any pressure compared to controls. FLF and BAL also did not have increases in early response proteins. No histologic changes or Egr-1 activation was present at the pressures used. CONCLUSION: Distending pressures as high as 16 cmH2O did not recruit lung volume at birth and did not increase markers of injury in the lung or airways in non-breathing preterm fetal sheep. PMID- 27463521 TI - Pre-Holocene Origin for the Coronopus navasii Disjunction: Conservation Implications from Its Long Isolation. AB - Integration of unexpected discoveries about charismatic species can disrupt their well-established recovery plans, particularly when this requires coordinate actions among the different governments responsible. The Critically Endangered Coronopus navasii (Brassicaceae) was considered a restricted endemism to a few Mediterranean temporary ponds in a high mountain range of Southeast Spain, until a new group of populations were discovered 500 km North in 2006. Ten years after this finding, its management has not been accommodated due to limited information of the new populations and administrative inertia. In this study, DNA sequences and species distribution models are used to analyse the origin of the C. navasii disjunction as a preliminary step to reassess its recovery plan. Molecular results placed the disjunction during Miocene-Pleistocene (6.30-0.49 Mya, plastid DNA; 1.45-0.03 Mya, ribosomal DNA), which discards a putative human-mediated origin. In fact, the haplotype network and the low gene flow estimated between disjunct areas suggest long-term isolation. Dispersal is the most likely explanation for the disjunction as interpreted from the highly fragmented distribution projected to the past. Particularly, a northward dispersal from Southeast is proposed since C. navasii haplotype network is connected to the sister-group through the southern haplotype. Although the reassessment of C. navasii conservation status is more optimistic under the new extent of occurrence, its long-term survival may be compromised due to the: (1) natural fragmentation and rarity of the species habitat, (2) genetic isolation between the two disjunct areas, and (3) northward shift of suitable areas under future climate change scenarios. Several ex-situ and in-situ conservation measures are proposed for integrating Central East Spanish populations into the on-going recovery plan, which still only contemplates Southeast populations and therefore does not preserve the genetic structure and diversity of the species. PMID- 27463522 TI - Assessing Functional Decline in Neurological Diseases Clinical Trials: Duration of Follow-Up - The Case of Multiple Sclerosis. AB - BACKGROUND: The main objective in the treatment of multiple sclerosis is to prevent or postpone the long-term disability caused by the disease, which in most cases occurs over years. However, most randomized clinical trials (RCTs) assessing the efficacy and safety of disease-modifying drugs have been designed to measure the short-term efficacy of disease-modifying drugs (up to 2-4 years) in reducing relapse rate and disease activity at magnetic resonance imaging (MRI). SUMMARY: In this chapter we will discuss how drug efficacy in reducing short-term relapse rate and MRI activity impact on delaying the accumulation of long-term disability, and we will summarize the available literature on the long term efficacy of the drugs as assessed by the few long-term observational and long-term extension RCTs on available drugs, focusing on interferon-beta treatment as the one with a more extensive literature. KEY MESSAGES: Additional long-term observational studies and long-term extension of follow-up periods for patients included in RCTs are needed to explore the long-term efficacy of available drugs which are known to be effective at the short-term level. PMID- 27463523 TI - A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma. AB - BACKGROUND: Anterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders. METHODS: We studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes. RESULTS: Mutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma. CONCLUSIONS: Our study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development. PMID- 27463525 TI - The Basic Structure of a Randomized Clinical Trial. AB - BACKGROUND: According to the Directive 2001/20/EC of the European Union, a clinical trial is any investigation in human subjects intended to (1) discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more investigational medicinal product(s), (2) identify any adverse reactions to one or more investigational medicinal product(s), (3) and/or study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy. SUMMARY: The major steps in the planning and conduction of a randomized clinical trial (RCT) include the definition of the study population, the random assignment of treatments, the choice of the measures of treatment effects, the duration of the experiment, the assessment of the tolerability and safety of the treatment, and the choice of alternative design models. In doing this, a constant reference will be made to the peculiarities (and diversities) of neurological disorders. KEY MESSAGES: An RCT is the best model to test the efficacy, tolerability, and safety of a drug, and reflects the need to disentangle the effects of the treatment from the effects of other prognostic variables. This requires a number of restrictions that are, at the same time, limitations for the application of the study results to the individuals who will receive the treatment in clinical practice. PMID- 27463524 TI - Representation of Stimulus Speed and Direction in Vibrissal-Sensitive Regions of the Trigeminal Nuclei: A Comparison of Single Unit and Population Responses. AB - The rat vibrissal (whisker) system is one of the oldest and most important models for the study of active tactile sensing and sensorimotor integration. It is well established that primary sensory neurons in the trigeminal ganglion respond to deflections of one and only one whisker, and that these neurons are strongly tuned for both the speed and direction of individual whisker deflections. During active whisking behavior, however, multiple whiskers will be deflected simultaneously. Very little is known about how neurons at central levels of the trigeminal pathway integrate direction and speed information across multiple whiskers. In the present work, we investigated speed and direction coding in the trigeminal brainstem nuclei, the first stage of neural processing that exhibits multi-whisker receptive fields. Specifically, we recorded both single-unit spikes and local field potentials from fifteen sites in spinal trigeminal nucleus interpolaris and oralis while systematically varying the speed and direction of coherent whisker deflections delivered across the whisker array. For 12/15 neurons, spike rate was higher when the whisker array was stimulated from caudal to rostral rather than rostral to caudal. In addition, 10/15 neurons exhibited higher firing rates for slower stimulus speeds. Interestingly, using a simple decoding strategy for the local field potentials and spike trains, classification of speed and direction was higher for field potentials than for single unit spike trains, suggesting that the field potential is a robust reflection of population activity. Taken together, these results point to the idea that population responses in these brainstem regions in the awake animal will be strongest during behaviors that stimulate a population of whiskers with a directionally coherent motion. PMID- 27463526 TI - Pituitary disorders as a predictor of apathy and executive dysfunction in adult survivors of childhood brain tumors. AB - BACKGROUND: The relationship between apathy and endocrine dysfunction, both frequent outcomes of neurological insult, has not yet been investigated in brain tumor survivors. The present study aimed to assess the relationship between pituitary disorders and apathy and other facets of executive function in long term adult survivors of childhood brain tumors and to differentiate between apathy and depression in this population. PROCEDURE: Seventy-six adult survivors of childhood brain tumors at least 5 years past diagnosis participated. An informant completed the Frontal Systems Behavior Scale (FrSBe), and 75 of the 76 participants completed a Structured Clinical Interview for the DSM-IV-TR (SCID). Information on neuroendocrine dysfunction was obtained through medical chart review. RESULTS: Clinically significant levels of apathy on the FrSBe were identified in 41% of survivors. Pituitary dysfunction significantly explained 9% of the variance in apathy scores and affected whether an individual presented with clinical levels of apathy. Pituitary dysfunction predicted higher levels of executive dysfunction but did not impact whether a participant reached clinical levels of executive dysfunction. A past major depressive episode (MDE) significantly predicted current apathy but showed no relationship with pituitary disorders. Radiation treatment predicted pituitary dysfunction but not the differences in apathy or executive functions. CONCLUSIONS: Apathy and executive dysfunction in survivors of childhood brain tumors are strongly predicted by pituitary dysfunction, and individuals with pituitary dysfunction are more likely to present with clinical levels of apathy as adults. Clinical levels of apathy may present absent of current depression, and pituitary dysfunction impacts apathy uniquely. PMID- 27463527 TI - First Molecular Characterization of Echinococcus multilocularis in Turkey. AB - This study aimed to find out the occurrence of Echinococcus multilocularis in foxes in Erzurum province, the highest endemic region for human alveolar echinococcosis in Turkey. The sedimentation and counting technique was used to reveal adult Echinococcus spp. in the intestines of foxes. One out of the 10 foxes was infected with E. multilocularis. The adult worms were analyzed morphologically and molecularly and were confirmed to be E. multilocularis by species-specific PCR. Pairwise comparisons between the 12S rRNA sequences of the E. multilocularis isolate from Erzurum and other E. multilocularis isolates showed 100% similarity of the Erzurum isolate with European isolates. With this study, the presence of E. multilocularis in a fox in Erzurum was confirmed by PCR, and molecular identification of E. multilocularis is reported for the first time in Turkey. PMID- 27463529 TI - Preparation of Optically Pure Tertiary Phosphine Oxides via the Addition of P Stereogenic Secondary Phosphine Oxide to Activated Alkenes. AB - Functionalized P,C-stereogenic tertiary phosphine oxides were prepared by the addition of (RP)-menthyl phenylphosphine oxide to activated olefins, in high drP and drC, and were isolated in excellent yields. The reaction was readily catalyzed by Ca(OH)2 or occurred with gentle heating. A wide range of substrates, including vinyl ketones, esters, nitriles, and nitro alkenes, can be used in the reaction. PMID- 27463528 TI - Endoscopic ultrasonography-guided transmural drainage of walled-off pancreatic necrosis: Comparison between a specially designed fully covered bi-flanged metal stent and multiple plastic stents. AB - BACKGROUND AND AIM: Endoscopic ultrasonography (EUS)-guided drainage of walled off necrosis (WON) may be carried out by placement of multiple plastic stents (MPS) or specially designed fully covered bi-flanged metal stents (BFMS). Comparative data on efficacy of these two stent types for WON drainage are limited. This retrospective study compares outcomes of WON drainage using BFMS and MPS. METHODS: During a 10-year period, 133 patients underwent EUS-guided WON drainage. MPS or BFMS were placed in a WON cavity through a single puncture, and direct endoscopic necrosectomy (DEN) was carried out whenever clinically necessary. Data in the two cohorts were retrospectively compared for primary outcomes - clinical success, adverse events and mortality; and secondary outcomes - DEN requirement, mean DEN sessions, need for salvage surgery and hospital stay. RESULTS: MPS were placed in 61 and BFMS in 72 patients. Patients undergoing BFMS drainage required fewer DEN sessions (mean 1.46 vs 2.74, P < 0.05), had fewer adverse events (5.6% vs 36.1%, P < 0.05), needed salvage surgery less often (2.7% vs 26.2%, P < 0.05), and had significantly shorter hospital stay (4.1 vs 8 days, P < 0.05) compared to those undergoing MPS drainage. There was no difference in DEN requirement (P = 0.217) and mortality (P = 0.5) in both groups. Overall clinical success with BFMS was superior to MPS (94% vs 73.7%, P < 0.05). CONCLUSION: BFMS appear to be superior to MPS for EUS-guided WON drainage in terms of clinical success, number of DEN sessions, adverse events, need for salvage surgery and hospital stay. PMID- 27463530 TI - End-of-Life Medical Treatments in the Last Two Weeks of Life in Palliative Care Units in Japan, 2005-2006: A Nationwide Retrospective Cohort Survey. AB - BACKGROUND: Comprehensive information on end-of-life care in specialized palliative care settings is needed to assess the quality of care. OBJECTIVE: This study aimed to investigate medical treatments in the last two weeks of life in a national sample of palliative care units in Japan. DESIGN: Retrospective cohort study. SETTING/SUBJECTS: Medical charts of 2802 consecutive cancer patients who died in 37 palliative care units were reviewed. MEASUREMENTS: Drug usage and treatments during the last two weeks of life were collected. A mixed-effect model was used to estimate the variations in care between institutions. RESULTS: Opioid administration increased from 68% (two weeks before death) to 80% (last 48 hours); during the same period, nonsteroidal anti-inflammatory drugs and acetaminophen administration decreased from 59% to 45%, and corticosteroid administration decreased from 62% to 51%. As death neared, parenteral opioid administration increased (41%-74%). Morphine use increased (45%-70%), fentanyl use remained about the same (47%-40%), and oxycodone use decreased (18%-5%). Two thirds of patients received artificial hydration; doses >1000 mL/day (15%) and intravenous hyperalimentation (7%) were relatively rare during the last 48 hours. Variations in end-of-life medical treatments increased between palliative care units as death neared, especially anticholinergic, artificial hydration, oxygen inhalation, and palliative sedation use. CONCLUSIONS: These findings regarding the general course of palliative treatments for dying cancer patients are useful for clinical audits in general wards, by comparing end-of-life care. Variations in some end-of-life medical treatments between institutions increased as death neared, even in palliative care settings. PMID- 27463531 TI - Ionic-Liquid-Modified Hybrid Materials Prepared by Physical Vapor Codeposition: Cobalt and Cobalt Oxide Nanoparticles in [C1C2Im][OTf] Monitored by In Situ IR Spectroscopy. AB - The synthesis of ionic-liquid-modified nanomaterials has attracted much attention recently. In this study we explore the potential to prepare such systems in an ultraclean fashion by physical vapor codeposition (PVCD). We codeposit metallic cobalt and the room-temperature ionic liquid (IL) 1-ethyl-3-methylimidazolium trifluoromethanesulfonate [C1C2Im][OTf] simultaneously onto a Pd(111) surface at 100 K. This process is performed under ultrahigh-vacuum (UHV) conditions in the presence of CO, or in the presence of O2 and CO. We use time-resolved (TR) and temperature-programmed (TP) infrared reflection absorption spectroscopy (IRAS) to investigate the formation and stability of the IL-modified Co deposits in situ during the PVD-based synthesis. CO is used as a probe molecule to monitor the growth. After initial growth of flat Co films on Pd(111), multilayers of Co nanoparticles (NPs) are formed. Characteristic shifts and intensity changes are observed in the vibrational bands of both CO and the IL, which originate from the electric field at the IL/Co interface (Stark effect) and from specific adsorption of the [OTf](-) anion. These observations indicate that the Co aggregates are stabilized by mixed adsorbate shells consisting of CO and [OTf](-). The CO coverage on the Co particle decreases with increasing temperature, but some CO is preserved up to the desorption temperature of the IL (370 K). Further, the IL shell suppresses the oxidation of the Co NPs if oxygen is introduced in the PVCD process. Only chemisorbed oxygen is formed at oxygen partial pressures that swiftly lead to formation of Co3O4 in the absence of the IL (5 * 10(-6) mbar O2). This chemisorbed oxygen is found to destabilize the CO ligand shell. The oxidation of Co is not suppressed if IL and Co are deposited sequentially under otherwise identical conditions. In this case we observe the formation of fully oxidized cobalt oxide particles. PMID- 27463532 TI - Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I. AB - We investigated whether a linear relationship between muscle strength and cross sectional area (CSA) is preserved in calf muscles of patients with Becker muscular dystrophy (BMD, n = 14) and limb-girdle type 2I muscular dystrophy (LGMD2I, n = 11), before and after correcting for muscle fat infiltration. The Dixon magnetic resonance imaging technique was used to quantify fat and calculate a fat-free contractile CSA. Strength was assessed by dynamometry. Muscle strength/CSA relationships were significantly lower in patients versus controls. The strength/contractile-CSA relationship was still severely lowered in BMD, but was almost normalized in LGMD2I. Our findings suggest close to intact contractile properties in LGMD2I, which are severely disrupted in BMD. Ann Neurol 2016;80:466 471. PMID- 27463533 TI - PEGylated chitosan nanoparticles potentiate repurposing of ormeloxifene in breast cancer therapy. AB - AIM: Development and optimization of ormeloxifene-loaded PEGylated chitosan nanoparticles (CNPs) for enhancing its literature profound therapeutic activity against breast cancer. METHODS: CNPs were prepared by ionotropic gelation method and characterized. RESULTS: Optimized formulation (CNPs10) had average 304 nm particle size with 0.247 polydispersity index and spherical shape with +31 mV surface charge. CNPs10 had 88.37% entrapment efficiency and 20.93% loading efficiency. CNPs10 demonstrated dose-dependent enhancement in cytotoxicity, cellular uptake, apoptosis, disruption of mitochondrial membrane potential and activation of caspase-3 in breast cancer MDA-MB-231 and MCF-7 cells over free ormeloxifene. In vivo studies divulged improved pharmacokinetic parameters, reduced toxicity, suppressed tumor burden and increased survival in CNPs10 treated female Sprague-Dawley rats. CONCLUSION: PEGylated CNPs enhanced anticancer activity of ormeloxifene. PMID- 27463534 TI - Limiting PCNA-unloading at the G1/S transition. PMID- 27463535 TI - Frequency of joint hypermobility in Turkish patients with knee osteoarthritis: a cross sectional multicenter study. AB - AIM: Osteoarthritis (OA) of the knee is one of the major causes of joint dysfunction and physically disabling conditions in the older population. The risk factors for the development of knee OA are very diverse. We aimed to determine the frequency of joint hypermobility in patients with knee OA. METHODS: Five hundred and three patients (402 female and 101 male) with bilateral knee OA were enrolled in five different clinics from three regions of Turkey. In this study, joint hypermobility was evaluated in the participants by using the Beighton scoring system and a Beighton score of at least 4 was considered as joint hypermobility. Radiological scoring was performed according to Kellgren and Lawrence. RESULTS: The percentages of generalized joint hypermobility were determined as 21.5% in all of the patients, 23.9% in female patients and 11.9% in male patients. The percentage of hypermobility (67.9%) was found to be highest in patients with knee OA aged between 22-30 years as against other age groups. Highest hypermobility percentage was found as 73.9% (17/23) in female patients and as 40% (2/5) in male patients between 22-30 years. The hypermobility of knee was found to have the highest frequency in patients aged between 22-40 years as compared to other joint regions and also to be second-highest frequency in all patients aged between 41-92 years. As a result, generalized joint hypermobility was determined to be of high frequency in patients with knee OA. Furthermore, we have seen that knee mobility was established to be of considerably high frequency in patients with knee OA. CONCLUSIONS: This study showed generalized joint hypermobility and knee hypermobility may be associated with knee OA. According to the results of this study, we can suggest that generalized joint hypermobility and also knee hypermobility may increase the risk of knee OA. According to this study, it should be considered that knee OA will develop in individuals who have generalized joint hypermobility and these individuals should be educated from this point before OA it occurs. PMID- 27463536 TI - Effect of a Mobile Web App on Kidney Transplant Candidates' Knowledge About Increased Risk Donor Kidneys: A Randomized Controlled Trial. AB - BACKGROUND: Kidney transplant candidates (KTCs) must provide informed consent to accept kidneys from increased risk donors (IRD), but poorly understand them. We conducted a multisite, randomized controlled trial to evaluate the efficacy of a mobile Web application, Inform Me, for increasing knowledge about IRDs. METHODS: Kidney transplant candidates undergoing transplant evaluation at 2 transplant centers were randomized to use Inform Me after routine transplant education (intervention) or routine transplant education alone (control). Computer adaptive learning method reinforced learning by embedding educational material, and initial (test 1) and additional test questions (test 2) into each chapter. Knowledge (primary outcome) was assessed in person after education (tests 1 and 2), and 1 week later by telephone (test 3). Controls did not receive test 2. Willingness to accept an IRD kidney (secondary outcome) was assessed after tests 1 and 3. Linear regression test 1 knowledge scores were used to test the significance of Inform Me exposure after controlling for covariates. Multiple imputation was used for intention-to-treat analysis. RESULTS: Two hundred eighty eight KTCs participated. Intervention participants had higher test 1 knowledge scores (mean difference, 6.61; 95% confidence interval [95% CI], 5.37-7.86) than control participants, representing a 44% higher score than control participants' scores. Intervention participants' knowledge scores increased with educational reinforcement (test 2) compared with control arm test 1 scores (mean difference, 9.50; 95% CI, 8.27-10.73). After 1 week, intervention participants' knowledge remained greater than controls' knowledge (mean difference, 3.63; 95% CI, 2.49 4.78) (test 3). Willingness to accept an IRD kidney did not differ between study arms at tests 1 and 3. CONCLUSIONS: Inform Me use was associated with greater KTC knowledge about IRD kidneys above routine transplant education alone. PMID- 27463537 TI - Immune Desensitization Allows Pediatric Blood Group Incompatible Kidney Transplantation. AB - BACKGROUND: Blood group incompatible transplantation (ABOi) in children is rare as pretransplant conditioning remains challenging and concerns persist about the potential increased risk of rejection. METHODS: We describe the results of 11 ABOi pediatric renal transplant recipients in the 2 largest centers in the United Kingdom, sharing the same tailored desensitization protocol. Patients with pretransplant titers of 1 or more in 8 received rituximab 1 month before transplant; tacrolimus and mycophenolate mofetil were started 1 week before surgery. Antibody removal was performed to reduce titers to 1 or less in 8 on the day of the operation. No routine postoperative antibody removal was performed. RESULTS: Death-censored graft survival at last follow-up was 100% in the ABOi and 98% in 50 compatible pediatric transplants. One patient developed grade 2A rejection successfully treated with antithymocyte globulin. Another patient had a titer rise of 2 dilutions treated with 1 immunoadsorption session. There was no histological evidence of rejection in the other 9 patients. One patient developed cytomegalovirus and BK and 2 others EBV and BK viremia. CONCLUSIONS: Tailored desensitization in pediatric blood group incompatible kidney transplantation results in excellent outcomes with graft survival and rejection rates comparable with compatible transplants. PMID- 27463538 TI - Adipokines in connective tissue diseases. AB - Adipokines, pleiotropic molecules produced by white adipose tissue (WAT) have attracted the attention of scientists since 1994. The role of adipokines in metabolic syndrome is known and fixed. Adipokines exerting a variety of metabolic activities have contributed to the ethiopathogenesis and the consequences of metabolic syndrome. Furthermore, adipokines are involved in the regulation of inflammatory processes and autoimmunity in the light of pathogenesis of connective tissue diseases. Given some evidence for the influence of adipokines in metabolic syndrome, there may be a link between CVDs and rheumatic diseases. This review provides an overview of the literature focusing on the role of adipokines in rheumatic diseases by putting special emphasis on the potential role of leptin, resistin, adiponectin, chemerin, visfatin and novel adipokines in connective tissue diseases. PMID- 27463539 TI - Extracellularly Extruded Syntaxin-4 Binds to Laminin and Syndecan-1 to Regulate Mammary Epithelial Morphogenesis. AB - Epithelial morphogenesis in the mammary gland proceeds as a consequence of complex cell behaviors including apoptotic cell death and epithelial-mesenchymal transition (EMT); the extracellular matrix (ECM) protein laminin is crucially involved. Syntaxins mediate intracellular vesicular fusion, yet certain plasmalemmal members have been shown to possess latent extracellular functions. In this study, the extracellular subpopulation of syntaxin-4, extruded in response to the induction of differentiation or apoptosis in mammary epithelial cells, was detected. Using a tetracycline-repressive transcriptional system and clonal mammary epithelial cells, SCp2, we found that the expression of cell surface syntaxin-4 elicits EMT-like cell behaviors. Intriguingly, these cells did not up-regulate key transcription factors associated with the canonical EMT such as snail, slug, or twist, and repressed translation of E-cadherin. Concurrently, the cells completely evaded the cellular aggregation/rounding triggered by a potent EMT blocker laminin-111. We found that the recombinant form of syntaxin-4 not only bound to laminin but also latched onto the glycosaminoglycan (GAG) side chains of syndecan-1, a laminin receptor that mediates epithelial morphogenesis. Thus, temporal extracellular extrusion of syntaxin-4 emerged as a novel regulatory element for laminin-induced mammary epithelial cell behaviors. J. Cell. Biochem. 118: 686-698, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27463540 TI - Phosphorylated human tau associates with mouse prion protein amyloid in scrapie infected mice but does not increase progression of clinical disease. AB - Tauopathies are a family of neurodegenerative diseases in which fibrils of human hyperphosphorylated tau (P-tau) are believed to cause neuropathology. In Alzheimer disease, P-tau associates with A-beta amyloid and contributes to disease pathogenesis. In familial human prion diseases and variant CJD, P-tau often co-associates with prion protein amyloid, and might also accelerate disease progression. To test this latter possibility, here we compared progression of amyloid prion disease in vivo after scrapie infection of mice with and without expression of human tau. The mice used expressed both anchorless prion protein (PrP) and membrane-anchored PrP, that generate disease associated amyloid and non amyloid PrP (PrPSc) after scrapie infection. Human P-tau induced by scrapie infection was only rarely associated with non-amyloid PrPSc, but abundant human P tau was detected at extracellular, perivascular and axonal deposits associated with amyloid PrPSc. This pathology was quite similar to that seen in familial prion diseases. However, association of human and mouse P-tau with amyloid PrPSc did not diminish survival time following prion infection in these mice. By analogy, human P-tau may not affect prion disease progression in humans. Alternatively, these results might be due to other factors, including rapidity of disease, blocking effects by mouse tau, or low toxicity of human P-tau in this model. PMID- 27463542 TI - Effect of changes in intra-abdominal pressure on diameter, cross-sectional area, and distensibility of the lower esophageal sphincter of healthy dogs as determined by use of an endoscopic functional luminal imaging probe. AB - OBJECTIVE To evaluate the effect of intra-abdominal pressure (IAP) on morphology and compliance of the lower esophageal sphincter (LES) by use of impedance planimetry in healthy dogs and to quantify the effect of changes in IAP. ANIMALS 7 healthy, purpose-bred sexually intact male hound-cross dogs. PROCEDURES Dogs were anesthetized, and cross-sectional area (CSA), minimal diameter (MD), LES length, LES volume, and distensibility index (DI) of the LES were evaluated by use of an endoscopic functional luminal imaging probe. For each dog, measurements were obtained before (baseline) and after creation of a pneumoperitoneum at an IAP of 4, 8, and 15 mm Hg. Order of the IAPs was determined by use of a randomization software program. RESULTS CSA and MD at 4 and 8 mm Hg were not significantly different from baseline measurements; however, CSA and MD at 15 mm Hg were both significantly greater than baseline measurements. The LES length and LES volume did not differ significantly from baseline measurements at any IAP. The DI differed inconsistently from the baseline measurement but was not substantially affected by IAP. CONCLUSIONS AND CLINICAL RELEVANCE Pneumoperitoneum created with an IAP of 4 or 8 mm Hg did not significantly alter LES morphology in healthy dogs. Pneumoperitoneum at an IAP of 15 mm Hg caused a significant increase in CSA and MD of the LES. Compliance of the LES as measured by the DI was not greatly altered by pneumoperitoneum at an IAP of up to 15 mm Hg. PMID- 27463543 TI - Effect of sensor location in dogs on performance of an interstitial glucose monitor. AB - OBJECTIVE To identify variations in glucose values concurrently obtained by use of a continuous glucose monitoring system (CGMS) at the same site, reliability of results for each site, lag time for each site, and influence of site thickness on CGMS accuracy. ANIMALS 8 random-source research dogs. PROCEDURES In experiment 1, 8 CGMS sensors were implanted bilaterally at 1 site (4 sensors/side) in 4 dogs. In experiment 2, 2 CGMS sensors were implanted bilaterally at each of 4 sites (1 sensor/side) in 8 dogs; 4 of those 8 dogs then were subjected to a glycemic clamp technique. The CGMS results were compared among sensors and with criterion referenced results during periods of euglycemia for all 8 dogs and during hyperglycemia and hypoglycemia for 4 dogs during the glycemic clamp procedure. RESULTS Differences (median, -7 mg/dL; interquartile range [IQR], -18.75 to 3 mg/dL) between CGMS and criterion-referenced glucose concentrations differed significantly among dogs and sites; during euglycemia, they were not different from the expected normal variation between multiple sensors concurrently implanted at the same site. Differences (median, -35 mg/dL; IQR, -74 to -15 mg/dL) between CGMS and criterion-referenced concentrations were greater during changes in glucose concentrations. Thoracic sensors were most accurate but had the shortest mean functional life. CONCLUSIONS AND CLINICAL RELEVANCE Significant differences were detected between CGMS and criterion-referenced glucose concentrations. Overall clinical utility of CGMS was acceptable at all sites, with most of the values from all sensors, sites, and dogs meeting guidelines for point-of-care glucometers. PMID- 27463544 TI - High-resolution manometric evaluation of the effects of cisapride on the esophagus during administration of solid and liquid boluses in awake healthy dogs. AB - OBJECTIVE To validate the use of high-resolution manometry (HRM) in awake, healthy dogs and compare the effects of bolus type (liquid vs solid) and drug treatment (saline [0.9% NaCl] solution [SS] vs cisapride) on esophageal pressure profiles. ANIMALS 8 healthy dogs. PROCEDURES In a crossover study, each dog received SS (10 mL) IV, and HRM was performed during oral administration of 10 boluses (5 mL each) of water or 10 boluses (5 g each) of canned food. Cisapride (1 mg/kg in 60 mL of SS) was subsequently administered IV to 7 dogs; HRM and bolus administration procedures were repeated. Two to 4 weeks later, HRM was repeated following administration of SS and water and food boluses in 4 dogs. Pressure profile data were obtained for all swallows, and 11 outcome variables were statistically analyzed. RESULTS After SS administration, predicted means for the esophageal contractile integral were 850.4 cm/mm Hg/s for food boluses and 660.3 cm/mm Hg/s for water boluses. Predicted means for esophageal contraction front velocity were 6.2 cm/s for water boluses and 5.6 cm/s for food boluses after SS administration. Predicted means for residual LES pressure were significantly higher following cisapride administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that HRM was feasible and repeatable in awake healthy dogs of various breeds and sizes. Stronger esophageal contractions and faster esophageal contraction velocity occurred during solid bolus and liquid bolus swallows, respectively. Lower esophageal sphincter pressure increased significantly following cisapride administration. Esophageal contractions and bolus transit latency should be further evaluated by HRM in clinically dysphagic dogs. PMID- 27463545 TI - Effects of fentanyl administration on locomotor response in horses with the G57C MU-opioid receptor polymorphism. AB - OBJECTIVE To determine the locomotor response to the administration of fentanyl in horses with and without the G57C polymorphism of the MU-opioid receptor. ANIMALS 20 horses of various breeds and ages (10 horses heterozygous for the G57C polymorphism and 10 age-, breed-, and sex-matched horses that did not have the G57C polymorphism). PROCEDURES The number of steps each horse took was counted over consecutive 2-minute periods for 20 minutes to determine a baseline value. The horse then received a bolus of fentanyl (20 MUg/kg, IV), and the number of steps was again counted during consecutive 2-minute periods for 60 minutes. The mean baseline value was subtracted from each 2-minute period after fentanyl administration; step counts with negative values were assigned a value of 0. Data were analyzed by use of a repeated-measures ANOVA. RESULTS Data for 19 of 20 horses (10 horses with the G57C polymorphism and 9 control horses without the G57C polymorphism) were included in the analysis. Horses with the G57C polymorphism had a significant increase in locomotor activity, compared with results for horses without the polymorphism. There was a significant group-by time interaction. CONCLUSIONS AND CLINICAL RELEVANCE Horses heterozygous for the G57C polymorphism of the MU-opioid receptor had an increased locomotor response to fentanyl administration, compared with the response for horses without this polymorphism. The clinical impact of this finding should be investigated. PMID- 27463546 TI - Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir. AB - OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS 7 male domestic shorthair cats. PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK PD) indices were determined for penciclovir and compared among all dosage regimens. RESULTS Compared with penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus. PMID- 27463547 TI - Effects of conventional and slanted ventral slot procedures on the biomechanical behavior of the C5-C6 vertebral motion unit in dogs. AB - OBJECTIVE To compare the effects of conventional and slanted ventral slot procedures on the biomechanical behavior of the C5-C6 vertebral motion unit (VMU) in dogs. SAMPLE 14 vertebral columns (C4 through C7) from canine cadavers. PROCEDURES Specimens were assigned to a conventional or slanted ventral slot group (n = 7/group). For each specimen, the C5-C6 VMU was tested in ventral and dorsal bending and positive and negative axial torsion before and after surgery. Range of motion (ROM), stiffness, and energy absorption were compared between the 2 groups. RESULTS Both procedures significantly increased the ROM and stiffness and significantly decreased the energy absorption of the C5-C6 VMU in ventral and dorsal bending. Both procedures also increased the ROM in positive and negative axial torsion. In negative torsion, total stiffness and stiffness over the maximum ROM tested decreased less for the slanted slot procedure than for the conventional slot procedure. There were no significant differences between procedures for any of the other biomechanical outcomes examined. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the biomechanical response of the C5-C6 VMU to the conventional and slanted ventral slot procedures was not significantly different, especially when considering postsurgical instability induced by both procedures. This was most likely due to disruption of the nucleus pulposus and dorsal annulus fibrosus of the disk with both procedures. On the basis of these findings, neither procedure appeared biomechanically superior. Comparative clinical studies are warranted to further evaluate the 2 procedures. PMID- 27463548 TI - Influence of storage conditions on in vitro stability of atrial natriuretic peptide and of anesthesia on plasma atrial natriuretic peptide concentration in cats. AB - OBJECTIVE To investigate the in vitro stability of atrial natriuretic peptide (ANP) in plasma samples under various storage conditions and the influence of anesthesia on plasma ANP concentration in cats. ANIMALS 1 cat with congestive heart failure and 5 healthy adult mixed-breed cats. PROCEDURES A plasma sample from the cat with heart failure was serially diluted, and dilutional parallelism of ANP concentration was evaluated. Plasma samples containing aprotinin or serum samples from the 5 healthy cats were kept at room temperature (27 degrees C) for <= 12 hours. Plasma samples from the same healthy cats were stored at -70 degrees , -20 degrees , or 4 degrees C for <= 14 days. Plasma samples were obtained from the healthy cats before and during isoflurane anesthesia. Plasma ANP concentrations were measured at a commercial laboratory by use of a human ANP chemiluminescence assay. RESULTS Intra- and interassay coefficients of variation were 1.5% and 2.5%, respectively, and dilutional parallelism was established. Although ANP concentration decreased by 82.4 +/- 13.6% (mean +/- SD) after sample storage for 12 hours at room temperature, this decrease was prevented by aprotinin. Plasma ANP concentrations were stable for 7 days at -20 degrees C and for 14 days at -70 degrees C. However, concentrations decreased markedly to 57.6 +/- 6.9% at -20 degrees C and to 18.0 +/- 3.0% at 4 degrees C after 14 days. Plasma ANP concentration decreased significantly in cats during anesthesia and was correlated with blood pressure. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that aprotinin should be added routinely in preparation of plasma samples from cats for measurement of ANP concentration, and those samples, if stored, should be frozen immediately at <= -20 degrees C. General anesthesia or systemic blood pressure may affect plasma ANP concentration in cats. PMID- 27463549 TI - Platelet function and activation in Cavalier King Charles Spaniels with subclinical chronic valvular heart disease. AB - OBJECTIVE To assess platelet closure time (CT), mean platelet component (MPC) concentration, and platelet component distribution width (PCDW) in dogs with subclinical chronic valvular heart disease. ANIMALS 89 Cavalier King Charles Spaniels (CKCSs) and 39 control dogs (not CKCSs). PROCEDURES Platelet count, MPC concentration, PCDW, and Hct were measured by use of a hematology analyzer, and CT was measured by use of a platelet function analyzer. Murmur grade and echocardiographic variables (mitral valve regurgitant jet size relative to left atrial area, left atrial-to-aortic diameter ratio, and left ventricular internal dimensions) were recorded. Associations between explanatory variables (sex, age, murmur grade, echocardiographic variables, platelet count, and Hct) and outcomes (CT, MPC concentration, and PCDW) were examined by use of multivariate regression models. RESULTS A model with 5 variables best explained variation in CT (R(2), 0.74), with > 60% of the variance of CT explained by mitral valve regurgitant jet size. The model of best fit to explain variation in MPC concentration included only platelet count (R(2), 0.24). The model of best fit to explain variation in PCDW included platelet count and sex (R(2), 0.25). CONCLUSIONS AND CLINICAL RELEVANCE In this study, a significant effect of mitral valve regurgitant jet size on CT was consistent with platelet dysfunction. However, platelet activation, as assessed on the basis of the MPC concentration and PCDW, was not a feature of subclinical chronic valvular heart disease in CKCSs. PMID- 27463550 TI - Effects of size and location of regions of interest examined by use of contrast enhanced ultrasonography on renal perfusion variables of dogs. AB - OBJECTIVE To determine effects of the size and location of regions of interest (ROIs) in the renal cortex of unsedated dogs on renal perfusion variables determined by use of contrast-enhanced ultrasonography (CEUS). ANIMALS 12 client owned adult (1.5 to 2 years old) Labrador Retrievers (8 males and 4 females; mean +/- SD body weight, 27 +/- 1.6 kg). PROCEDURES Each dog received 2 bolus injections of sulfur hexafluoride during CEUS. Three small oval ROIs (area of each ROI, 0.11 cm(2)) located in a row with a distance of 1 mm between adjacent ROIs and 1 large oval ROI (area, 1 cm(2)) that encompassed the 3 smaller ROIs were manually drawn in the renal cortex. The ROIs were located at a depth of 1.5 to 2.0 cm in the near field of the renal cortex. Software analysis of time intensity curves within each ROI was used to identify peak enhancement, time to peak enhancement, regional blood flow, and mean transit time. RESULTS The location and size of the ROIs of unsedated dogs did not cause significant differences in the mean values of the renal perfusion variables. CONCLUSIONS AND CLINICAL RELEVANCE The development of CEUS has provided a unique means for visually examining and quantifying tissue perfusion. Results of this study indicated that it was possible to use small or large ROIs during renal CEUS to evaluate renal perfusion in dogs. PMID- 27463551 TI - Prevalence of naturally occurring antibodies against dog erythrocyte antigen 7 in a population of dog erythrocyte antigen 7-negative dogs from Spain and Italy. AB - OBJECTIVE To determine the prevalence of naturally occurring anti-dog erythrocyte antigen (DEA) 7 antibodies in DEA 7-negative dogs from Spain and Italy. ANIMALS 252 DEA 7-negative dogs from a population of 312 dogs that were previously tested for DEA 1, DEA 4, and DEA 7. PROCEDURES A plasma sample was obtained from each dog and evaluated for anti-DEA 7 antibodies by the use of gel column agglutination. Each plasma sample underwent major crossmatching with RBCs from DEA 7-positive dogs. Samples that resulted in agglutination were then crossmatched with RBCs from DEA 1-negative, DEA 4-positive, and DEA 7-negative dogs to confirm the presence of anti-DEA 7 antibodies. Results were then used to calculate the risk for a delayed transfusion reaction in a DEA 7-negative dog with anti-DEA 7 antibodies after a transfusion with blood that was not crossmatched or typed for DEA 7. RESULTS 96 of 252 (38.1%) plasma samples contained anti-DEA 7 antibodies. A DEA 7-negative dog with anti-DEA 7 antibodies had a 5.9% chance of developing a delayed hemolytic reaction after transfusion with blood not crossmatched or typed for DEA 7. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that canine blood used for transfusion should be crossmatched with the blood or plasma of the intended recipient prior to transfusion to minimize the likelihood that the recipient will develop a hemolytic reaction associated with anti-DEA 7 antibodies. Ideal canine blood donors should be negative for both DEA 1 and DEA 7. PMID- 27463552 TI - Detection of hemoplasma infection of goats by use of a quantitative polymerase chain reaction assay and risk factor analysis for infection. AB - OBJECTIVE To develop and validate a real-time quantitative PCR (qPCR) assay for the detection and quantification of Mycoplasma ovis in goats and investigate the prevalence and risk factors for hemoplasma infection of goats located in Indiana. ANIMALS 362 adult female goats on 61 farms. PROCEDURES Primers were designed for amplification of a fragment of the dnaK gene of M ovis by use of a qPCR assay. Blood samples were collected into EDTA-containing tubes for use in total DNA extraction, blood film evaluation, and determination of PCV. Limit of detection, intra-assay variability, interassay variability, and specificity of the assay were determined. RESULTS Reaction efficiency of the qPCR assay was 94.45% (R(2), 0.99; slope, -3.4623), and the assay consistently detected as few as 10 copies of plasmid/reaction. Prevalence of infection in goats on the basis of results for the qPCR assay was 18.0% (95% confidence interval, 14% to 22%), with infected goats ranging from 1 to 14 years old, whereby 61% (95% confidence interval, 47% to 73%) of the farms had at least 1 infected goat. Bacterial load in goats infected with M ovis ranged from 1.05 * 10(3) target copies/mL of blood to 1.85 * 10(5) target copies/mL of blood; however, no bacteria were observed on blood films. Production use of a goat was the only risk factor significantly associated with hemoplasma infection. CONCLUSIONS AND CLINICAL RELEVANCE The qPCR assay was more sensitive for detecting hemoplasma infection than was evaluation of a blood film, and production use of a goat was a risk factor for infection. PMID- 27463553 TI - In vitro effects of cysteine protease inhibitors on Trichomonas foetus-induced cytopathic changes in porcine intestinal epithelial cells. AB - OBJECTIVE To investigate the effects of specific cysteine protease (CP) inhibitors on cytopathic changes to porcine intestinal epithelial cells induced by Tritrichomonas foetus isolated from naturally infected cats. SAMPLE T foetus isolates from 4 naturally infected cats and nontransformed porcine intestinal epithelial cells. PROCEDURES T foetus isolates were treated with or without 0.1 to 1.0mM of the CP inhibitors antipain, cystatin, leupeptin, and chymostatin and the vinyl sulfone inhibitors WRR-483 and K11777. In-gel gelatin zymography was performed to evaluate the effects of these inhibitors on CP activity of T foetus isolates. Each treated or untreated isolate was also cocultured with monolayers of porcine intestinal epithelial cells for 24 hours, and cytopathic effects of T foetus were evaluated by light microscopy and crystal violet spectrophotometry. RESULTS Results of in-gel gelatin zymography suggested an ability of WRR-483, K11777, and cystatin to target specific zones of CP activity of the T foetus isolates. These inhibitors had no effect on T foetus growth, and the cytopathic changes to the intestinal epithelium induced by all 4 T foetus isolates were significantly inhibited. CONCLUSIONS AND CLINICAL RELEVANCE This study revealed that certain protease inhibitors were capable of inhibiting regions of CP activity (which has been suggested to cause intestinal cell damage in cats) in T foetus organisms and of ameliorating T foetus-induced cytopathic changes to porcine intestinal epithelium in vitro. Although additional research is needed, these inhibitors might be useful in the treatment of cats with trichomonosis. PMID- 27463554 TI - Correction: Effects of repetition within trials and frequency of trial sessions on quantitative parameters of vertical force peak in horses with naturally occurring lameness. PMID- 27463555 TI - Comparison of humoral insulin-like growth factor-1, platelet-derived growth factor-BB, transforming growth factor-beta1, and interleukin-1 receptor antagonist concentrations among equine autologous blood-derived preparations. AB - OBJECTIVE To compare humoral insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta1, and interleukin 1 receptor antagonist (IL-1Ra) concentrations in plasma and 3 types of equine autologous blood-derived preparations (ABPs). SAMPLE Blood and ABP samples from 12 horses. PROCEDURES Blood samples from each horse were processed by use of commercial systems to obtain plasma, platelet concentrate, conditioned serum, and aqueous platelet lysate. Half of the platelet concentrate samples were additionally treated with a detergent to release intracellular mediators. Humoral IGF-1, PDGF-BB, TGF-beta1, and IL-1Ra concentrations were measured with ELISAs and compared statistically. RESULTS Median IGF-1 concentration was highest in conditioned serum and detergent-treated platelet concentrate, followed by platelet concentrate and plasma; IGF-1 was not detected in platelet lysate. Mean PDGF-BB concentration was highest in platelet lysate, followed by detergent treated platelet concentrate and conditioned serum; PDGF-BB was not detected in plasma and platelet concentrate. Median TGF-beta1 concentration was highest in detergent-treated platelet concentrate, followed by conditioned serum, platelet lysate, and platelet concentrate; TGF-beta1 was not detected in most plasma samples. Median IL-1Ra concentration was highest in platelet lysate, followed by conditioned serum; IL-1Ra was not detected in almost all plasma, detergent treated platelet concentrate, and platelet concentrate samples. CONCLUSIONS AND CLINICAL RELEVANCE Each ABP had its own cytokine profile, which was determined by the specific processing method. Coagulation and cellular lysis strongly increased humoral concentrations of cell-derived cytokines. No ABP had the highest concentrations for all cytokines. Further studies are needed to assess clinical relevance of these findings. PMID- 27463556 TI - Effects of oral administration of metronidazole and doxycycline on olfactory capabilities of explosives detection dogs. AB - OBJECTIVE To determine effects of oral administration of metronidazole or doxycycline on olfactory function in explosives detection (ED) dogs. ANIMALS 18 ED dogs. PROCEDURES Metronidazole was administered (25 mg/kg, PO, q 12 h for 10 days); the day prior to drug administration was designated day 0. Odor detection threshold was measured with a standard scent wheel and 3 explosives (ammonium nitrate, trinitrotoluene, and smokeless powder; weight, 1 to 500 mg) on days 0, 5, and 10. Lowest repeatable weight detected was recorded as the detection threshold. There was a 10-day washout period, and doxycycline was administered (5 mg/kg, PO, q 12 h for 10 days) and the testing protocol repeated. Degradation changes in the detection threshold for dogs were assessed. RESULTS Metronidazole administration resulted in degradation of the detection threshold for 2 of 3 explosives (ammonium nitrate and trinitrotoluene). Nine of 18 dogs had a degradation of performance in response to 1 or more explosives (5 dogs had degradation on day 5 or 10 and 4 dogs had degradation on both days 5 and 10). There was no significant degradation during doxycycline administration. CONCLUSIONS AND CLINICAL RELEVANCE Degradation in the ability to detect odors of explosives during metronidazole administration at 25 mg/kg, PO, every 12 hours, indicated a potential risk for use of this drug in ED dogs. Additional studies will be needed to determine whether lower doses would have the same effect. Doxycycline administered at the tested dose appeared to be safe for use in ED dogs. PMID- 27463557 TI - Correction: Pharmacokinetics of meloxicam in red-eared slider turtles (Trachemys scripta elegans) after single intravenous and intramuscular injections. PMID- 27463558 TI - The Silver Lining of Shame: Framing HPV to Influence Vaccination Intentions. AB - College students suffer disproportionately from human papillomavirus (HPV), a sexually transmitted infection (STI) that could result in genital warts or cancers in both males and females. Research contends that stigma and shame may serve as barriers to disclosure intentions, as well as vaccination intentions. The goal of this study was to examine whether two framing strategies-whether to mention that HPV is sexually transmitted and whether to highlight the cause of infection as internal or external-would influence young adults' intentions to disclose a potential diagnosis and their intentions to get the recommended HPV vaccine. Results indicate that STI framing and gender had consistent impacts on disclosure and vaccination intentions. Further, causal attribution framing also influenced participants' intention to get the vaccine at no cost immediately and their intention to get the vaccine at the retail price of $375 in the future. Theoretical and practical implications of these results are discussed. PMID- 27463559 TI - The impact of prenatal circadian rhythm disruption on pregnancy outcomes and long term metabolic health of mice progeny. AB - Animal studies demonstrate that circadian rhythm disruption during pregnancy can be deleterious to reproductive capacity and the long-term health of the progeny. Our previous studies in rats have shown that exposure of pregnant dams to an environment that significantly disrupts maternal circadian rhythms programs increased adiposity and poor glucose metabolism in offspring. In this study, we used mice with a ClockDelta19 mutation to determine whether foetal development within a genetically disrupted circadian environment affects pregnancy outcomes and alters the metabolic health of offspring. Ten female ClockDelta19+MEL mutant mice were mated with 10 wildtype males, and 10 wildtype females were mated with 10 ClockDelta19+MEL mutant males. While genetically identical, the heterozygote foetuses were exposed to either a normal (wildtype dams) or disrupted (ClockDelta19+MEL mutant dams) circadian environment during gestation. Pregnancy outcomes including time to mate, gestation length, litter size and birth weight were assessed. One male and one female offspring from each litter were assessed for postnatal growth, body composition, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test at 3 and 12 months of age. There was no effect of maternal genotype on pregnancy outcomes, with days to plug, gestation length, litter size and perinatal mortality not significantly different between wildtype and ClockDelta19+MEL mutant dams. Similarly, there was no effect of maternal genotype on weight of the offspring at birth or at any stage of postnatal growth. While there was an effect of sex on various tissue weights at 3 and 12 months of age, there were minimal effects of maternal genotype. Relative adrenal weight was significantly reduced (-32%) in offspring from ClockDelta19+MEL mutant dams, whereas gastrocnemius muscle was significantly increased (+16%) at 3 months of age only. Intraperitoneal glucose tolerance tests at 3 months of age revealed female offspring from ClockDelta19+MEL mutant dams had significantly reduced area under the curve following glucose administration ( 25%), although no differences were found at 12 months of age. There was no effect of maternal genotype on intraperitoneal insulin tolerance at 3 or 12 months of age for either sex. These results demonstrate that foetal growth within a genetically disrupted circadian environment during gestation has no effect on pregnancy success, and only marginal impacts upon the long-term metabolic health of offspring. These results do not support the hypothesis that circadian rhythm disruption during pregnancy programs poor metabolic homeostasis in offspring. However, when maintained on a 12L:12D photoperiod, the ClockDelta19+MEL mutant dams display relatively normal patterns of activity and melatonin secretion, which may have reduced the impact of the mutation upon foetal metabolic programming. PMID- 27463560 TI - When policy, demographics, and disease collide: the penalty of poor diabetes care in immigrant children. PMID- 27463561 TI - Facile Separation of Regioisomeric Compounds by a Heteronuclear Organometallic Capsule. AB - Owing to the often-similar physical and chemical properties of structural isomers of organic molecules, large efforts have been made to develop efficient strategies to isolate specific isomers. However, facile separation of regioisomeric compounds remains difficult. Here we demonstrate a universal organometallic capsule in which two silver centers are rigidly separated from each other by two tetranuclear [Rh4] pyramidal frustums, which selectively encapsulate a specific isomer from mixtures. Not only is the present heterometallic capsule suitable as a host for the encapsulation of a series of aromatic compounds, but also the receptor shows widely differing specificity for the various isomers. Direct experimental evidence is provided for the selective encapsulation of a series of para (p)-disubstituted benzene derivatives, such as p-xylene, p-dichlorobenzene, p-dibromobenzene, and p-diiodobenzene. The size and shape matching, as well as the Ag-pi interactions, are the main forces governing the extent of molecular recognition. The encapsulated guest p-xylene can be released by using the solid-liquid solvent washing strategy, and the other guest molecules are easily liberated by using light stimulus. PMID- 27463562 TI - Demonstration of d-Octaarginine-Linked Polymers as Promising Adjuvants for Mucosal Vaccination through Influenza Virus Challenge. AB - Mucosal vaccination is one of the most effective ways to reduce the risk of pandemics as a result of incorrect prediction of epidemic strains of influenza viruses or virus mutation. However, adjuvants and antigen carriers with potent immunostimulatory activities are a prerequisite for significant induction of mucosal immunity because most antigens are poorly immunogenic when solely applied to the mucosa. Our previous studies demonstrated that poly(N-vinylacetamide-co acrylic acid) bearing d-octaarginine induced the secretion of antigen-specific immunoglobulin A (IgA) on the mucosa when nasally administered with virus antigens and that intranasal IgA reacts to viral strains other than the one used for immunization. Therefore, the present study evaluated capabilities of secreted IgA for protection against virus infection. When mice were inoculated with a mixture of inactivated H1N1 A/Puerto Rico/8/34 influenza viruses and d octaarginine-linked polymers, antigen-specific secreted IgA was induced on the nasal mucosa. Immunized mice were completely protected from virus infection of the inoculated strain. To the contrary, mice nasally inoculated with inactivated viruses alone were infected with the homologous viruses presumably because of insignificant induction of secreted IgA. Results demonstrated that our polymer would be a promising adjuvant for mucosal vaccination. PMID- 27463563 TI - Composite Gel Polymer Electrolyte Based on Poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP) with Modified Aluminum-Doped Lithium Lanthanum Titanate (A-LLTO) for High-Performance Lithium Rechargeable Batteries. AB - A composite gel polymer electrolyte (CGPE) based on poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP) polymer that includes Al-doped Li0.33La0.56TiO3 (A-LLTO) particles covered with a modified SiO2 (m-SiO2) layer was fabricated through a simple solution-casting method followed by activation in a liquid electrolyte. The obtained CGPE possessed high ionic conductivity, a large electrochemical stability window, and interfacial stability-all superior to that of the pure gel polymer electrolyte (GPE). In addition, under a highly polarized condition, the CGPE effectively suppressed the growth of Li dendrites due to the improved hardness of the GPE by the addition of inorganic A-LLTO/m-SiO2 particles. Accordingly, the Li-ion polymer and Li-O2 cells employing the CGPE exhibited remarkably improved cyclability compared to cells without CGPE. In particular, the CGPE as a protection layer for the Li metal electrode in a Li-O2 cell was effective in blocking the contamination of the Li electrode by oxygen gas or impurities diffused from the cathode side while suppressing the Li dendrites. PMID- 27463564 TI - Alzheimer's disease and the law: positive and negative consequences of structural stigma and labeling in the legal system. AB - OBJECTIVE: To explore the meaning and consequences of labeling on structural stigma in the context of Alzheimer's disease (AD) in the legal system. METHOD: This qualitative study was made up of three focus groups including social workers and lawyers (n = 26). Participants were asked to report their experience in circumstances in which persons with AD and their family members engage with the legal system. Thematic analysis using the constant comparative method was used. RESULTS: The discussions in the focus groups raised two overall themes. (1) The significance of the medical diagnostic labeling of AD in the legal system and (2) the consequences of labeling of AD within the legal system. This last theme included four sub-themes: (a) negative consequences of labeling; (b) reasons associated with negative consequences of labeling; (c) positive consequences of labeling; and (d) reasons associated with positive consequences of labeling. CONCLUSION: Findings of the study provide a first foundation for future research on the meaning and consequences of labeling in legal cases involving persons with AD. They suggest that increasing judges' knowledge about AD and reforming the existing 'status-based' legal capacity legislation might benefit by limiting the legal weight given today to the medical diagnosis. PMID- 27463565 TI - Error in Complementary DNA Nomenclature. PMID- 27463567 TI - Coming in sportsmedicine. PMID- 27463570 TI - Noteworthy. PMID- 27463572 TI - A Texan's Use of Television. PMID- 27463566 TI - Targeting efflux pumps to overcome antifungal drug resistance. AB - Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps. PMID- 27463574 TI - Scanning sports. PMID- 27463573 TI - Sportsmedicine forum. PMID- 27463576 TI - How I Manage Breast Problems in Athletes. AB - In brief: Although breast problems usually are associated with women, men have them also. This paper reviews the anatomy of the breast and describes injuries and disorders that occur in both men and women, including runner's nipples, tumors, and trauma (common in contact and racket sports). The author also discusses management of these problems and describes various types of sports bras. PMID- 27463575 TI - Maturity Assessment: A Viable Preventive Measure Against Physical and Psychological Insult to the Young Athlete? AB - In brief: Maturity assessment is often cited as an important part of the preparticipation health examination (PHE) for student-athletes. However, maturity assessment apparently is not routinely included in the PHE in most states. This literature review indicates the value of maturity assessment as a way to reduce the risk of physical and psychological insult to young athletes. Maturity assessment can be used to match adolescents for participation in contact sports and to determine when a youth is experiencing the growth spurt, which may make him or her more susceptible to injury. Accordingly, maturity assessment should be included in the PHE, and schools and community organizations should develop procedures for requesting and using maturity information. PMID- 27463577 TI - Athletes' Use and Abuse of Drugs. AB - In brief: This article presents a review of the literature on drug misuse by athletes and information from 16 sports and medical organizations whose representatives met in 1985 to discuss the problem. Studies of drug use by athletes are relatively few. Existing data do not show a difference in drug use between athletes and nonathletes, but anabolic steroids probably are used more widely among athletes. Our review disclosed little evidence that drugs can improve an athlete's performance without also posing the threat of serious harm. Major sports organizations have banned the use of anabolic steroids, stimulants, diuretics, analgesics, beta-adrenergic blockers, cocaine, marijuana, and heroin, and some have begun testing athletes. Physicians should assist efforts to prevent the illegal distribution of drugs and should help with existing education and testing programs. PMID- 27463578 TI - A Primary Care Perspective of Chronic Compartment Syndrome of the Leg. AB - In brief: Chronic compartment syndrome (CCS) of the leg is a recently recognized cause of recurrent leg pain in the exercising patient. Apart from rest, the only effective treatment is fasciotomy. This study reviews 39 fasciotomies that were performed on 16 patients with clinically determined CSS. Fourteen (88%) of the patients returned to full activity with few or no residual complaints. These results indicate that clinically identified features can distinguish CCS from other forms of recurrent leg pain. Compartment pressure measurements taken during exercise can confirm the diagnosis of CCS and determine the need for fasciotomy. PMID- 27463579 TI - An Analysis of Individual Stretching Programs of Intercollegiate Athletes. AB - In brief: Stretching may influence an athlete's susceptibility to injury. To evaluate individual stretching programs of intercollegiate athletes, 238 athletes (164 male, 74 female) in ten sports were surveyed about their stretching practices. Almost all of the athletes stretched, but to varying degrees. Only 39% stretched every day, and only 33% stretched both before and after activity. Overall, the women stretched significantly more than the men, but male swimmers appeared to have the most well-rounded stretching programs. Muscle groups that were stretched by the fewest athletes were the adductors, plantar flexors, hips, and neck. Comparison of these results with flexibility and injury in this study group could prove valuable. PMID- 27463580 TI - The Efficacy and Risk of Intense Aerobic Circuit Training in Coronary Artery Disease Patients Following Bypass Surgery. AB - In brief: This study describes the influence of highly intense aerobic circuit training on the cardiorespiratory fitness of 31 coronary artery disease (CAD) patients who had undergone bypass surgery. The patients trained at 84.2% of heart rate (HR) reserve three times a week for 12 weeks. Duration per session progressed from 25 to 60 minutes over the first six weeks. Results showed that the subjects improved significantly in estimated peak mets, percent body fat, resting HR, HR and rate pressure product (RPP) response to standard submaximal exercise (7.2 mets), and maximal RPP. In addition, there were no abnormal responses related to cardiovascular or musculoskeletal complications. Thus, this type of exercise is an effective, safe, and attractive cardiorespiratory training method for CAD patients following bypass surgery. PMID- 27463581 TI - Artificial Ligaments: Promise or Panacea? AB - The FDA has approved a prosthetic ligament for limited use in persons with a damaged anterior cruciate ligament, and it will likely approve a second device this year. Some orthopedic surgeons say these developments herald a new era of surgery, while others warn that it is too early to tell. PMID- 27463582 TI - Arthroscopy: Is It Overrated? AB - Arthroscopic surgery has become very popular-almost trendy. But beyond the reports of miraculous recovery lie the medical facts: Arthroscopy is only a surgical technique; healing time depends on the procedure. PMID- 27463583 TI - Does 'Sports Massage' Have a Role in Sports Medicine? AB - More and more athletes are turning to massage, apparently in hopes of gaining a winning edge. But although research does not support claims that massage improves performance, it can offer athletes some physiological and psychological benefits. PMID- 27463584 TI - Mountain Biking: Does Rough Terrain Make Rugged Riders? AB - All-terrain bikes are gaining ground on their streamlined counterparts, the enormously popular road bikes. But does the fact that they can handle rougher countryside increase their riders' fitness benefits or their injury risks? PMID- 27463585 TI - Circus Medicine: Health Care Under the Big Top. AB - Some circus performers are also skilled athletes. Where do the injured ones turn for medical care? PMID- 27463587 TI - Food Allergies and the Athlete. PMID- 27463588 TI - What's the Importance of Percent Body Fat? PMID- 27463590 TI - Rates of Invasive Management of Cardiogenic Shock in New York Before and After Exclusion From Public Reporting. AB - IMPORTANCE: Reduced rates of cardiac catheterization, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) are an unintended consequence of public reporting of cardiogenic shock outcomes in New York. OBJECTIVES: To evaluate whether the referral rates for cardiac catheterization, PCI, or CABG have improved in New York since cardiogenic shock was excluded from public reporting in 2008 and compare them with corresponding rates in Michigan, New Jersey, and California. DESIGN, SETTING, AND PARTICIPANTS: Patients with cardiogenic shock complicating acute myocardial infarction from 2002 to 2011 were identified using the National Inpatient Sample. Propensity score matching was used to assemble a cohort of patients with cardiogenic shock with similar baseline characteristics in New York and Michigan. MAIN OUTCOMES AND MEASURES: Percutaneous coronary intervention (primary outcome), invasive management (cardiac catheterization, PCI, or CABG), revascularization (PCI or CABG), and CABG were evaluated with reference to 3 calendar year periods: 2002-2005 (time 1: cardiogenic shock included in publicly reported outcomes), 2006-2007 (time 2: cardiogenic shock excluded on a trial basis), and 2008 and thereafter (time 3: cardiogenic shock excluded permanently) in New York and compared with Michigan. RESULTS: Among 2126 propensity score-matched patients representing 10 795 (weighted) patients with myocardial infarction complicated by cardiogenic shock in New York and Michigan, 905 (42.6%) were women and mean (SE) age was 69.5 (0.3) years. A significantly higher proportion of the patients underwent PCI (time 1 vs 2 vs 3: 31.1% vs 39.8% vs 40.7% [OR, 1.50; 95% CI, 1.12-2.01; P = .005 for time 3 vs 1]), invasive management (time 1 vs 2 vs 3: 59.7% vs 70.9% vs 73.8% [OR, 1.84; 95% CI, 1.37-2.47; P < .001 for time 3 vs 1]), or revascularization (43.1% vs 55.9% vs 56.3% [OR, 1.66; 95% CI, 1.26-2.20; P < .001 for time 3 vs 1]) after the exclusion of cardiogenic shock from public reporting in New York. However, during the same periods, a greater proportion of patients underwent PCI (time 1 vs 2 vs 3: 41.2% vs 52.6% vs 57.8% [OR, 1.93; 95% CI, 1.45-2.56; P < .001 for time 3 vs 1]), invasive management (time 1 vs 2 vs 3: 64.4% vs 80.5% vs 78.6% [OR, 2.01; 95% CI, 1.47-2.74; P < .001 for time 3 vs 1]), or revascularization (51.2% vs 65.8% vs 68.0% [OR, 2.00; 95% CI, 1.50-2.66; P < .001 for times 3 vs 1]) in Michigan. Results were largely similar in several sensitivity analyses comparing New York with New Jersey or California. CONCLUSIONS AND RELEVANCE: Although the rates of PCI, invasive management, and revascularization have increased substantially after the exclusion of cardiogenic shock from public reporting in New York, these rates remain consistently lower than those observed in other states without public reporting. PMID- 27463591 TI - Behavioral and psychological aspects of exercise across stages of eating disorder recovery. AB - This study examined the relationship between behavioral and psychological aspects of exercise and eating disorder recovery. Participants were categorized as having an eating disorder (n = 53), partially recovered (n = 15), fully recovered (n = 20), or non-eating disorder controls (n = 67). Groups did not differ significantly in time spent exercising, but did differ in exercise intensity, guilt-related exercise, obsessive exercise cognitions, and appearance/weight management and stress/mood management motivations for exercise. Results support the importance of measuring psychological aspects of exercise in particular across the course of an eating disorder. PMID- 27463592 TI - New prognostic biomarkers in multiple myeloma. AB - Multiple myeloma is a malignant neoplastic disease, characterized by uncontrolled proliferation and accumulation of plasma cells in the bone marrow, which is usually connected with production of a monoclonal protein. It is the second most common hematologic malignancy. It constitutes approximately 1% of all cancers and 10% of hematological malignancies. Despite the huge progress that has been made in the treatment of multiple myeloma in the past 30 years including the introduction of new immunomodulatory drugs and proteasome inhibitors, it is still an incurable disease. According to current data, the five-year survival rate is 45%. Multiple myeloma is a very heterogeneous disease with a very diverse clinical course, which is expressed by differences in effectiveness of therapeutic strategies and ability to develop chemoresistance. This diversity implies the need to define risk stratification factors that would help to create personalized and optimized therapy and thereby improve treatment outcomes. Prognostic markers that aim to objectively evaluate the risk of a poor outcome, relapse and the patient's overall outcome are useful for this purpose. The existing, widely used prognostic classifications, such as the Salmon-Durie classification or ISS, do not allow for individualization of treatment. As a result of the development of diagnostic techniques, especially cytogenetics and molecular biology, we were able to discover a lot of new, more sensitive and specific prognostic factors. The paper presents recent reports on the role of molecular, cytogenetic and biochemical alterations in pathogenesis and prognosis of the disease. PMID- 27463593 TI - Origin of Kinetic Resolution of Hydroxy Esters through Catalytic Enantioselective Lactonization by Chiral Phosphoric Acids. AB - Kinetic resolution is a widely used strategy for separation and enrichment of enantiomers. Using density functional theory computations, the origin of how a chiral BINOL-phosphoric acid catalyzes the selective lactonization of one of the enantiomers of alpha-methyl gamma-hydroxy ester is identified. In a stepwise mechanism, the stereocontrolling transition state for the addition of the hydroxyl group to the si face of the ester carbonyl in the case of the S isomer exhibits a network of more effective noncovalent interactions between the substrate and the chiral catalyst. PMID- 27463606 TI - Positron Emission Tomographic Imaging of the Serotonergic System and Prediction of Risk and Lethality of Future Suicidal Behavior. AB - Importance: Biomarkers that predict suicidal behavior, especially highly lethal behavior, are urgently needed. In cross-sectional studies, individuals with depression who attempt suicide have lower midbrain serotonin transporter binding potential compared with those who do not attempt suicide, and higher serotonin1A binding potential in the raphe nuclei (RN) is associated with greater lethality of past suicide attempts and suicidal intent and ideation. Objectives: To determine whether serotonin transporter binding potential in the lower midbrain predicts future suicide attempts and whether higher RN serotonin1A binding potential predicts future suicidal ideation and intent and lethality of future suicide attempts. Design, Setting, and Participants: In this prospective 2-year observational study, a well-characterized cohort of 100 patients presenting for treatment of a major depressive episode of at least moderate severity underwent positron emission tomography using carbon 11-labeled N-(2-(1-(4-(2-methoxyphenyl) 1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexanecarboxamide ([11C]WAY-100635), a serotonin1A antagonist; a subset of 50 patients also underwent imaging with carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)- benzonitrile ([11C]DASB), a serotonin transporter radioligand. Imaging was performed at Columbia University Medical Center from May 3, 1999, to March 11, 2008. Follow-up was completed on May 28, 2010, and data were analyzed from August 1, 2013, to March 1, 2016. Exposures: Patients were treated naturalistically in the community and followed up for 2 years with documentation of suicidal behavior, its lethality, and suicidal ideation and intent. Main Outcomes and Measures: Suicide attempt or suicide. Results: Of the 100 patients undergoing follow-up for more than 2 years (39 men; 61 women; mean [SD] age, 40.2 [11.2] years), 15 made suicide attempts, including 2 who died by suicide. Higher RN serotonin1A binding potential predicted more suicidal ideation at 3 (b = 0.02; t = 3.45; P = .001) and 12 (b = 0.02; t = 3.63; P = .001) months and greater lethality of subsequent suicidal behavior (b = 0.08; t = 2.89; P = .01). Exploratory analyses suggest that the serotonin1A binding potential of the insula (t = 2.41; P = .04), anterior cingulate (t = 2.27; P = .04), and dorsolateral prefrontal cortex (t = 2.44; P = .03) were also predictive of lethality. Contrary to our hypotheses, suicidal intent was not predicted by serotonin1A binding potential in any brain region (F1,10 = 0.83; P = .38), and midbrain serotonin transporter binding potential did not predict future attempts (log-rank chi21 = 0.4; P = .54), possibly owing to low power. Conclusions and Relevance: Greater RN serotonin1A binding potential predicted higher suicidal ideation and more lethal suicidal behavior during a 2-year period. This effect may be mediated through less serotonin neuron firing and release, which affects mood and suicidal ideation and thereby decision making. PMID- 27463607 TI - Platelet surface expression of SDF-1 is associated with clinical outcomes in the patients with cardiovascular disease. AB - Platelet surface expression levels of stromal cell derived factor 1 (SDF-1) are elevated in acute coronary syndrome and associated with LVEF% improvement after myocardial infarction (MI). Platelet SDF-1 might facilitate thrombus formation and endomyocardial expression of SDF-1 is enhanced in inflammatory cardiomyopathy and positively correlates with myocardial fibrosis. The influence of platelet SDF 1 on outcome in the patients with symptomatic coronary artery disease (CAD) is to the best of our knowledge unknown. Blood samples of 608 consecutive CAD patients were collected during the percutaneous coronary intervention and analyzed for surface expression of SDF-1 by flow cytometry. The primary combined endpoint was defined as the composite of either MI, or ischemic stroke, or all-cause death. Secondary endpoints were defined as the aforementioned single events. The patients with baseline platelet SDF-1 levels above the third quartile showed a significantly worse cumulative event-free survival when compared to the patients with lower baseline SDF-1 levels (first to third quartile) (log rank 0.009 for primary combined endpoint and log rank 0.016 for secondary endpoint all-cause death). Multivariate Cox regression analysis showed that SDF-1 levels above the third quartile were independently associated with the primary combined endpoint and the secondary endpoint all-cause death. We provide first clinical evidence that high platelet expression levels of SDF-1 influence clinical outcomes in CAD patients in a negative way. PMID- 27463608 TI - The "Case of Two Compounds with Similar Configuration but Nearly Mirror Image CD Spectra" Refuted. Reassignment of the Absolute Configuration of N-Formyl-3',4' dihydrospiro[indan-1,2'(1'H)-pyridine]. AB - In 1997, Sandstrom and co-workers reported the case of two chiral spiro compounds with very similar skeletons but showing almost mirror-image electronic circular dichroism (ECD) spectra for the corresponding absolute configuration. The paper has been often cited as a proof and good educational example of the pronounced sensitivity of ECD toward molecular conformation, and a clear warning against the use of ECD spectral correlations to assign absolute configurations. Although both concepts remain valid, they are not exemplified by the quoted paper. We demonstrate that the original configurational assignment of one compound was wrong and revise it by using TDDFT calculations. The main reason for the observed failure is the use of the matrix method, a popular approach to predict ECD spectra of compounds which can be treated with an independent system approximation (ISA), including proteins. Using a modern version of the matrix method, we demonstrate that the ISA is not valid for the title compound. Even in the absence of apparent conjugation between the component chromophores, the validity of the ISA should never be taken for granted and the effective extent of orbital overlap should always be verified. PMID- 27463609 TI - A lanthanide complex for metal encapsulations and anion exchanges. AB - A cationic lanthanide metalloligand with 3 dangling carboxylate groups on its periphery co-assembles with nitrate into a porous thermochromic solid responsive to both external cations and anions, owing to the presence of exchangeable NO3(-) as well as cation cavities arising from cooperative orientation of free carboxylate groups. An especially interesting feature is the structural memory effect during crystallization exhibited by the metalloligand, even after dissolution and binding to secondary cations (Cu(2+), Cd(2+)...). Moreover, the porous solid can undergo ion-exchange with various anions, leading to tunable thermochromic temperature and color range. PMID- 27463610 TI - pH-Sensitive ZnO Quantum Dots-Doxorubicin Nanoparticles for Lung Cancer Targeted Drug Delivery. AB - In this paper, we reported a ZnO quantum dots-based pH-responsive drug delivery platform for intracellular controlled release of drugs. Acid-decomposable, luminescent aminated ZnO quantum dots (QDs) were synthesized as nanocarriers with ultrasmall size (~3 nm). The dicarboxyl-terminated poly(ethylene glycol) (PEG) had been introduced to NH2-ZnO QDs, which rendered it stable under physiological fluid. Moreover, a targeting ligand, hyaluronic acid (HA), was conjugated to ZnO QDs for specifically binding to the overexpressed glycoprotein CD44 by cancer cells. Doxorubicin (DOX) molecules were successfully loaded to PEG functionalized ZnO QDs via formation of metal-DOX complex and covalent interactions. The pH sensitive ZnO QDs dissolved to Zn(2+) in acidic endosome/lysosome after uptake by cancer cells, which triggered dissociation of the metal-drug complex and a controlled DOX release. As result, a synergistic therapy was achieved due to incorporation of the antitumor effect of Zn(2+) and DOX. PMID- 27463611 TI - Neutrophilic panniculitis and autoinflammation: what's the link?: reply from authors. PMID- 27463612 TI - Design of a high-throughput human neural crest cell migration assay to indicate potential developmental toxicants. AB - Migration of neural crest cells (NCCs) is one of the pivotal processes of human fetal development. Malformations arise if NCC migration and differentiation are impaired genetically or by toxicants. In the currently available test systems for migration inhibition of NCC (MINC), the manual generation of a cell-free space results in extreme operator dependencies, and limits throughput. Here a new test format was established. The assay avoids scratching by plating cells around a commercially available circular stopper. Removal of the stopper barrier after cell attachment initiates migration. This microwell-based circular migration zone NCC function assay (cMINC) was further optimized for toxicological testing of human pluripotent stem cell (hPSC)-derived NCCs. The challenge of obtaining data on viability and migration by automated image processing was addressed by developing a freeware. Data on cell proliferation were obtained by labelling replicating cells, and by careful assessment of cell viability for each experimental sample. The role of cell proliferation as an experimental confounder was tested experimentally by performing the cMINC in the presence of the proliferation-inhibiting drug cytosine arabinoside (AraC), and by a careful evaluation of mitotic events over time. Data from these studies led to an adaptation of the test protocol, so that toxicant exposure was limited to 24 h. Under these conditions, a prediction model was developed that allows classification of toxicants as either inactive, leading to unspecific cytotoxicity, or specifically inhibiting NC migration at non-cytotoxic concentrations. PMID- 27463613 TI - One year in review 2016: systemic sclerosis. AB - Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year, novel insights into the pathogenesis, diagnosis and treatment of this severe disease are published. Herewith, we provide an overview of the most significant literature contributions published over the last year. PMID- 27463614 TI - Chronic invasive fungal sinusitis: characterization and shift in management of a rare disease. AB - BACKGROUND: Chronic invasive fungal sinusitis (CIFS) is a rare subtype of mycotic diseases involving the paranasal sinuses. It is characterized by a slow onset and invasive organisms with non-granulomatous inflammation seen on histopathology. Historically, treatment has involved radical surgical resection. The purpose of this study was to describe the presentation, comorbidities, and role of more conservative treatment options. METHODS: This is a multi-institutional retrospective case series of 6 patients with CIFS over 15 years. Patients' medical comorbidities, imaging results, operative procedures, pathological findings including organisms identified, antimicrobial medications used, and outcomes were reviewed. RESULTS: The mean time from onset of symptoms to diagnosis was 6 months. Cultures and fungal PCR identified Aspergillus species in every case. All 6 patients were found to have systemic comorbidities, with many being diabetic. Imaging findings ranged from thickening of sinus mucosa to invasion of the orbit and skull base. Treatment included long-term antifungal therapy and conservative endoscopic surgery in all but 1 patient, who had an open approach. Every patient was free of invasive fungal disease at last follow-up, with a range of 1 to 27 months. CONCLUSION: CIFS is an insidious disease often with months between symptom onset and diagnosis. It is differentiated from chronic granulomatous invasive fungal sinusitis (CGIFS) by a lack of granulomas on histopathology and an association with diabetes mellitus. Endoscopic debridement combined with long-term oral voriconazole was an effective treatment strategy in this series. PMID- 27463615 TI - Enantioselective Organocatalyzed Transformations of beta-Ketoesters. AB - The beta-ketoester structural motif continues to intrigue chemists with its electrophilic and nucleophilic sites. Proven to be a valuable tool within organic synthesis, natural product, and medicinal chemistry, reports on chiral beta ketoester molecular skeletons display a steady increase. With the reignition of organocatalysis in the past decade, asymmetric methods available for the synthesis of this structural unit has significantly expanded, making it one of the most exploited substrates for organocatalytic transformations. This review provides comprehensive information on the plethora of organocatalysts used in stereoselective organocatalyzed construction of beta-ketoester-containing compounds. PMID- 27463616 TI - The Number, Organization, and Size of Polymorphic Membrane Protein Coding Sequences as well as the Most Conserved Pmp Protein Differ within and across Chlamydia Species. AB - Variation is a central trait of the polymorphic membrane protein (Pmp) family. The number of pmp coding sequences differs between Chlamydia species, but it is unknown whether the number of pmp coding sequences is constant within a Chlamydia species. The level of conservation of the Pmp proteins has previously only been determined for Chlamydia trachomatis. As different Pmp proteins might be indispensible for the pathogenesis of different Chlamydia species, this study investigated the conservation of Pmp proteins both within and across C. trachomatis,C. pneumoniae,C. abortus, and C. psittaci. The pmp coding sequences were annotated in 16 C. trachomatis, 6 C. pneumoniae, 2 C. abortus, and 16 C. psittaci genomes. The number and organization of polymorphic membrane coding sequences differed within and across the analyzed Chlamydia species. The length of coding sequences of pmpA,pmpB, and pmpH was conserved among all analyzed genomes, while the length of pmpE/F and pmpG, and remarkably also of the subtype pmpD, differed among the analyzed genomes. PmpD, PmpA, PmpH, and PmpA were the most conserved Pmp in C. trachomatis,C. pneumoniae,C. abortus, and C. psittaci, respectively. PmpB was the most conserved Pmp across the 4 analyzed Chlamydia species. PMID- 27463618 TI - Good for Me vs. Good for Us. PMID- 27463619 TI - Research in Psychiatry: Concepts and Conceptual Analysis. AB - Current research in psychiatry is increasingly focused on empirical studies with methods and technologies adopted from medicine. This paper argues that psychiatry has a different epistemological basis from medicine, and it is on account of this that research in psychiatry demands a different approach, one that perforce focuses on the clarification of concepts central to psychiatric practice. This means undertaking conceptual analysis and conceptual history and only then moving on to empirical study. This paper highlights the crucial epistemological differences between the practice of medicine and psychiatry, showing that the latter is enacted at the level of language and communication. Consequently, the structures of psychiatric objects, namely, mental disorders and mental symptoms, are complexes of meaning derived from heterogeneous sources - both organic and semantic. Conceptual analysis of such structures is essential as ultimately the validity of empirical research is directly dependent on the conceptual clarification of its objects of inquiry. PMID- 27463620 TI - Attitudes, Beliefs, and Measures Taken by Parents to Protect Their Children from the Sun in Guangzhou City, China. AB - Excessive sun exposure can cause sunburn, suntan, skin photoaging, and even skin cancer. Skin photoaging conflicts with the human pursuit of a young and beautiful appearance. Some research data indicate that the incidence of skin cancer in the Chinese has been increasing, although it remains lower than in whites. To estimate the prevalence of sun protection used on Chinese children aged 3-13 years and identify its predictors, a population-based cross-sectional questionnaire was given to 3684 parents/guardians of children in Guangzhou, China, of which 3083 questionnaires were returned. Of those returned, 35.5% of parents/guardians reported regularly using sun protection on their children and the primary reason cited was to prevent sunburn. Hats and handheld umbrellas were the most frequently used measures; sunscreen was less common, and when used, 48.8% of parents/guardians still reapplied sunscreen on their children every 2.0 3.0 h. Parental age, parents using sun protection measures themselves when outdoors, and the child's sex were factors associated with regular use of sun protection on children. These results suggest that sun protection campaigns targeted toward parents and children need to be conducted in Guangzhou, or throughout China, to strengthen awareness about sun protection and address any inadequate protocols of sun protection. PMID- 27463621 TI - Effect of macular hole volume on postoperative central macular thickness. AB - PURPOSE: To evaluate the association between macular hole volume (MHV) and postoperative central macular thickness (CMT) using spectral-domain optical coherence tomography (SD-OCT). METHODS: Thirty-three eyes of 30 patients with a large full-thickness idiopathic macular hole with or without vitreomacular traction who underwent surgical intervention were included in this cross sectional study. Complete ophthalmological examination, including SD-OCT, was performed for all participants during the pre- and postoperative visits. MHV was preoperatively measured using SD-OCT, which captured the widest cross-sectional image of the hole. For normal distribution analysis of the data, the Kolmogorov Smirnov test was performed, and for statistical analyses, chi-square, Student's t test, Mann-Whitney U test, and Pearson's correlation coefficient test were performed. RESULTS: Mean preoperative best-corrected visual acuity (BCVA) and MHV were found to be 0.99 +/- 0.36 (range, 0.3-2.0) logMAR and 0.139 +/- 0.076 (range, 0.004-0.318) mm3, respectively. Mean follow-up was 16.3 +/- 14.3 (range, 3-50) months. No statistical correlations were found between MHV and postoperative BCVA (p=0.588) and between MHV and disease recurrence (p=0.544). A weak negative correlation existed between MHV and final CMT scores (p=0.04, r= 0.383). CONCLUSIONS: Greater MHV was found to be weakly associated with lower postoperative CMT scores. PMID- 27463622 TI - Choroidal changes in pre-eclampsia during pregnancy and the postpartum period: comparison with healthy pregnancy. AB - PURPOSE: To investigate subfoveal choroidal thickness (SFCT) in patients with pre eclampsia using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: A sample of 73 pregnant women was studied over 28 weeks of gestation. The sample was divided into two groups: one comprising pre-eclamptic pregnant women (n=32), and the other comprising healthy pregnant women (n=41). The SFCT was determined for all patients using EDI-OCT during pregnancy and at the third month of the postpartum period. RESULTS: The SFCTs in pre-eclamptic pregnant women were 351.97 +/- 22.44 and 332.28 +/- 20.32 um during the pregnancy and postpartum periods (p<0.001), respectively, whereas these values in healthy pregnant women were 389.73 +/- 49.64 and 329.78 +/- 22.36 um (p<0.001), respectively. During pregnancy SFCT in pre-eclamptic pregnant women was significantly thinner than that in healthy pregnant women (p<0.001). However, there was no statistically significant difference during the postpartum period (p=0.623). CONCLUSIONS: The results suggest that SFCT is significantly decreased in pre-eclamptic pregnant women than in healthy pregnant women, despite no statistically significant difference in SFCT existing between the groups during the postpartum period. PMID- 27463617 TI - Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. AB - Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2* 10 16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 * 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID- 27463624 TI - Factors affecting visual acuity after accelerated crosslinking in patients with progressive keratoconus. AB - PURPOSE: The present study aimed to report the outcomes of patients with progressive keratoconus who were treated via accelerated crosslinking (CXL) 6 months earlier and to determine the factors that promoted improved visual acuity after treatment. METHODS: This retrospective study included 35 eyes of 34 patients with progressive keratoconus who underwent CXL. Topographical measurements were obtained preoperatively and in the first, third, and sixth months postoperatively using a rotating Scheimpflug camera. The uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), flat keratometry (K) value (K1), steep K value (K2), average K value (avgK), topographic cylindrical value (Cyl), apical keratoscopy front (AKf), apical keratoscopy back (AKb), symmetry index front (SIf), symmetry index back (SIb), and thinnest point of the cornea (ThkMin) were recorded. RESULTS: At the 6-month follow-up, the mean UCVA and BCVA values were improved, and the K values remained stable. Statistically significant decreases in AKf (p=0.04) and the thinnest point of the cornea (p=0.001) and a statistically significant increase in AKb (p=0.01) were observed. A correlation analysis revealed that the preoperative BCVA, UCVA, K1, K2, avgK, AKf, and AKb values significantly affected visual acuity at the 6-month follow up. CONCLUSIONS: Accelerated CXL is an effective treatment for the prevention or even reversal of keratoconus progression. The preoperative K values and apexes of the anterior and posterior cornea were found to affect visual acuity at 6 months after accelerated CXL. Both AKb steepening and AKf flattening appear to be important factors in the stabilization of keratometric values and improvement of visual outcomes. PMID- 27463623 TI - Six-month outcomes of corneal crosslinking with dextran-free isotonic riboflavin solution. AB - PURPOSE: To analyze the short-term clinical and topographic outcomes in patients with keratoconus after corneal collagen cross-linking treatment (CXL) with dextran-free isotonic riboflavin solution. METHODS: In this retrospective case series, 26 eyes from 26 patients with keratoconus were studied. The best corrected visual acuity (BCVA) and refractive and topographic findings were analyzed at a 6-month follow-up. RESULTS: The mean BCVA (Snellen lines) values before and 1, 3, and 6 months after CXL were 0.51 +/- 0.2, 0.48 +/- 0.2, 0.57 +/- 0.2, and 0.64 +/- 0.2, respectively, and the difference between the preoperative and 6-month values was statistically significant (p=0.006). The mean spherical equivalent refraction decreased from -5.6 +/- 2.4 diopters (D) preoperatively to 5.0 +/- 2.1 D, and mean simulated keratometry decreased from 48.5 +/- 2.5 D to 47.8 +/- 2.6 D at 6 months. (p=0.145 and p=0.001, respectively). In addition, the maximum keratometry decreased progressively and significantly from the preoperative value during follow-up (p=0.003). The central and minimal corneal thicknesses, including those of the epithelium, also decreased from 442.8 +/- 25.6 um and 430.5 +/- 23.9 um preoperatively to 420.7 +/- 31.8 um and 409.3 +/- 28.7 um at the most recent follow-up (p<0.001), respectively. No intraoperative or postoperative complications were observed. CONCLUSIONS: CXL with dextran-free isotonic riboflavin solution appears to be a safe treatment alternative for keratoconus and yields sustained short-term improvements in visual acuity, keratometric readings, and corneal thickness. However, long-term results are needed to confirm these outcomes. PMID- 27463625 TI - Effect of intravitreal anti-VEGF on choroidal thickness in patients with diabetic macular edema using spectral domain OCT. AB - PURPOSE: To evaluate choroidal thickness (CT) using spectral domain optical coherence tomography (SD-OCT) imaging at baseline and 6 months after intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with diabetic macular edema (DME). METHODS: A retrospective chart review was performed to identify patients with DME who underwent intravitreal injection of anti-VEGF (bevacizumab or ranibizumab) in a pro re nata (PRN) regimen. Subfoveal choroidal thickness was compared between values obtained at baseline and at 6-month follow up visits. RESULTS: Thirty-nine eyes (15 females, 24 males) from 39 patients were enrolled (mean age, 62.43 +/- 8.7 years; range, 44-79 years). Twenty-three and 16 eyes were treated with ranibizumab and bevacizumab respectively. The mean number of anti-VEGF injections was 2.28 +/- 1.27 (range, 1-5). Mean nasal, subfoveal, and temporal choroidal thickness (CT) measurements at baseline were 234.10 +/- 8.63 um, 246.89 +/- 8.94 um, and 238.12 +/- 8.20 um, respectively, and those at 6 months post-treatment were 210.46 +/- 8.00 um, 215.66 +/- 8.29 um, and 212.43 +/- 8.14 um, respectively. Significant differences in CT were observed between baseline and the 6-month follow-up at all measured points (p=0.0327). CONCLUSIONS: Over a 6-month period, the use of intravitreal anti-VEGF was associated with significant thinning of the choroid in patients with DME. The clinical significance of a thinner choroid in DME is currently unknown; however, it may contribute to long-term adverse effects on choroidal and retinal function, representing an area requiring future investigation. PMID- 27463626 TI - Implantation of foldable posterior chamber intraocular lens in aphakic vitrectomized eyes without capsular support. AB - PURPOSE: To evaluate the outcomes of three different surgical techniques for foldable posterior chamber intraocular lens (PCIOL) implantation in vitrectomized eyes without capsular support. METHODS: A total of 60 patients with aphakic and vitrectomized eyes without capsular support were enrolled. All patients underwent three-piece foldable PCIOL implantation into the posterior chamber through a small corneal incision. Transscleral fixation (TSF), iris fixation (IF), and intrascleral tunnel fixation (ISF) surgical techniques were performed. RESULTS: Postoperative PCIOL subluxation or dislocation occurred in one case in the TSF group and two cases in the ISF group. Intraoperative PCIOL dislocation occurred in two patients in the IF group. The incidence of temporary postoperative complications, such as mild intraocular hemorrhage and cystoid macular edema, was higher in the ISF group. No statistically significant difference in PCIOL-related astigmatism was observed between groups. Visual acuity improved in all groups. CONCLUSIONS: Postoperative outcomes were comparable between TSF, IF, and ISF for PCIOL in vitrectomized eyes without capsular support. PMID- 27463627 TI - Bacteriological profile in conjunctival, lacrimal sac, and nasal specimens and conjunctival normalization time following external, endoscopic, and transcanalicular multidiode laser dacryocystorhinostomy. AB - PURPOSE: To compare the conjunctival, lacrimal sac, and nasal flora cultures and conjunctival normalization time following external (EX-), endoscopic (EN-), and transcanalicular multidiode laser (TC-) dacryocystorhinostomy (DCR) and to evaluate the relationship between culture positivity and surgical success. We further performed antibiotic sensitivity analyses for lacrimal sac culture samples. METHODS: A total of 90 patients with primary acquired nasolacrimal duct obstruction were recruited and divided into EX-DCR (n=32), EN-DCR (n=28), and TC DCR (n=30) groups. Conjunctival, nasal, and lacrimal sac cultures and antibiograms were analyzed. RESULTS: In all three groups, coagulase-negative Staphylococcus (CNS) was predominantly isolated preoperatively from the conjunctiva, nose, and lacrimal sac and postoperatively from the conjunctiva. Preoperative and postoperative conjunctival culture positivity rates were similar between all the groups (p>0.05). A statistically significant difference in the growth rate of culture in the lacrimal sac was observed between the three groups (p=0.001). CNS and Staphylococcus aureus cultures were predominantly sensitive to linezolid, teicoplanin, tigecycline, vancomycin, and mupirocin. Conjunctival normalization times were similar between the three groups (p>0.05). Anatomical and functional success rates were not found to be significantly correlated with preoperative conjunctival and lacrimal sac culture positivity (p>0.05). CONCLUSIONS: Similar rates of preoperative and 1-week postoperative conjunctival culture positivity were observed in all the groups; a significantly lower bacterial growth rate was observed in postoperative conjunctival cultures. CNS was the most commonly isolated organism. Bacterial growth rates in the lacrimal sac samples were significantly higher in the EN-DCR group. Bacterial growth rates obtained preoperatively from the conjunctival and lacrimal sac culture samples were not correlated with DCR success. PMID- 27463628 TI - Comparative study on optical performance and visual outcomes between two diffractive multifocal lenses: AMO Tecnis (r) ZMB00 and AcrySof (r) IQ ReSTOR (r) Multifocal IOL SN6AD1. AB - PURPOSE: To compare the optical performance and visual outcomes between two diffractive multifocal lenses: AMO Tecnis(r) ZMB00 and AcrySof(r) ReSTOR(r) SN6AD1. METHODS: This prospective, non-randomized comparative study included the assessment of 74 eyes in 37 patients referred for cataract surgery and candidates for multifocal intraocular lens implants. Exclusion criteria included existence of any other eye disease, previous eye surgery, high axial myopia, preoperative corneal astigmatism of >1.00 cylindrical diopter (D), and intraoperative or postoperative complications. Ophthalmological evaluation included the measurement of uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), distance-corrected near visual acuity (DCNVA), and distance-corrected intermediate visual acuity (DCIVA), with analysis of contrast sensitivity (CS), wavefront, and visual defocus curve. RESULTS: Postoperative UDVA was 0.09 and 0.08 logMAR in the SN6AD1 and ZMB00 groups, respectively (p=0.868); postoperative CDVA was 0.04 and 0.02 logMAR in the SN6AD1 and ZMB00 groups, respectively (p=0.68); DCIVA was 0.17 and 0.54 logMAR in the SN6AD1 and ZMB00 groups, respectively (p=0.000); and DCNVA was 0.04 and 0.09 logMAR in the SN6AD1 and ZMB00 groups, respectively (p=0.001). In both cases, there was an improvement in the spherical equivalent and UDVA (p<0.05). Under photopic conditions, the SN6AD1 group had better CS at low frequencies without glare (p=0.04); however, the ZMB00 group achieved better sensitivity at high frequencies with glare (p=0.003). The SN6AD1 and ZMB00 lenses exhibited similar behavior for intermediate vision, according to the defocus curve; however, the ZMB00 group showed a shorter reading distance than the SN6AD1 group. There were no significant differences regarding aberrometry between the two groups. CONCLUSION: Both lenses promoted better quality of vision for both long and short distances and exhibited a similar behavior for intermediate vision. The SN6AD1 and ZMB00 groups showed better results for CS under photopic conditions at low and high spatial frequencies, respectively. PMID- 27463629 TI - Evaluation of anterior segment parameters in patients with pseudoexfoliation syndrome using Scheimpflug imaging. AB - PURPOSE: To evaluate anterior segment parameters in patients with pseudoexfoliation syndrome (PXS) using Scheimpflug imaging. METHODS: Forty-three PXS patients and 43 healthy control subjects were included in this cross sectional study. All participants underwent a detailed ophthalmologic examination. Anterior segment parameters were measured using a Scheimpflug system. RESULTS: Considering the PXS and control groups, the mean corneal thicknesses at the apex point (536 +/- 31 and 560 +/- 31 um, respectively, p=0.001), at the center of the pupil (534 +/- 31 and 558 +/- 33 um, respectively, p=0.001), and at the thinnest point (528 +/- 30 and 546 +/- 27 um, respectively, p=0.005) were significantly thinner in PXS patients. Visual acuity was significantly lower (0.52 +/- 0.37 versus 0.88 +/- 0.23, p<0.001) and axial length was significantly longer (23.9 +/- 0.70 mm versus 23.2 +/- 0.90 mm, p=0.001) in the PXS eyes than in the control eyes. There were no statistically significant differences in the mean values of keratometry, anterior chamber angle, anterior chamber depth, corneal volume, and anterior chamber volume between the PXS and control eyes. CONCLUSIONS: The patients with PXS had thinner corneas, worse visual acuity, and longer axial length compared with those in the healthy controls. PMID- 27463630 TI - The effects of riboflavin and ultraviolet light on keratocytes cultured in vitro. AB - PURPOSE: To culture quiescent human keratocytes and evaluate the effects of ultraviolet light and riboflavin on human corneal keratocytes in vitro. METHODS: Keratocytes were obtained from remaining corneoscleral ring donor corneas previously used in corneal transplant surgeries and cultured in DMEM/F12 with 2% FBS until confluence. Characterization of cultured cells was performed by immunofluorescence analysis for anti-cytokeratin-3, anti-Thy-1, anti-alpha-smooth muscle actin, and anti-lumican. Immunofluorescence was performed before and after treatment of cultured cells with either ultraviolet light or riboflavin. Corneal stromal cells were covered with collagen (200 uL or 500 uL) and 0.1% riboflavin, and then exposed to ultraviolet light at 370 nm for 30 minutes. After 24 hours, cytotoxicity was determined using MTT colorimetric assays, whereas cell viability was assessed using Hoechst 33342 and propidium iodide. RESULTS: Cell cultures achieved confluence in approximately 20 days. Expression of the lumican was high, whereas no expression of CK3, Thy-1, and alpha-SMA was observed. After crosslinking, MTT colorimetric assays demonstrated a low toxicity rate, whereas Hoechst 33342/propidium iodide staining demonstrated a low rate of apoptosis and necrosis, respectively, in all collagen-treatment groups. CONCLUSION: Keratocytes can be successfully cultured in vitro and characterized by immunofluorescence using lumican. MTT colorimetric assays, and Hoechst 33342, and propidium iodide staining demonstrated a higher rate of cell death in cells cultured without collagen, indicating collagen protects keratocytes from the cytotoxic effects of ultraviolet light. PMID- 27463631 TI - Rothmund-Thomson syndrome and ocular surface findings: case reports and review of the literature. AB - Rothmund-Thomson syndrome (RTS) is a rare dermatosis with about 300 cases reported to date. The authors describe two siblings with RTS and inflammatory conjunctival disease featuring fornix shortening and symblepharon as well as palpebral disease with sparse eyelashes. These cases demonstrate RTS ocular surface findings different to those usually described. PMID- 27463632 TI - Combined branch retinal vein and artery occlusion in toxoplasmosis. AB - A 22-year-old man complained of low visual acuity and pain in his left eye for five days. His ophthalmological examination revealed 2+ anterior chamber reaction and a white, poorly defined retinal lesion at the proximal portion of the inferotemporal vascular arcade. There were retinal hemorrhages in the inferotemporal region extending to the retinal periphery. In addition, venous dilation, increased tortuosity, and ischemic retinal whitening along the inferotemporal vascular arcade were also observed. A proper systemic work-up was performed, and the patient was diagnosed with ocular toxoplasmosis. He was treated with an anti-toxoplasma medication, and his condition slowly improved. Inferior macular inner and middle retinal atrophy could be observed on optical coherence tomography as a sequela of ischemic injury. To our knowledge, this is the first report of combined retinal branch vein and artery occlusion in toxoplasmosis resulting in a striking and unusual macular appearance. PMID- 27463633 TI - DRESS syndrome in ophthalmic patients. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially fatal adverse drug reaction associated with skin rash, fever, eosinophilia, and multiple organ injury. A number of pharmacological agents are known to cause DRESS syndrome such as allopurinol, anticonvulsants, vancomycin, trimethoprime-sulfamethoxazole, and pyrimethamine-sulfadiazine. Here, we describe two patients who developed DRESS syndrome during ocular treatment. The first case was being treated for late postoperative endophthalmitis with topical antibiotics, intravenous cephalothin, meropenem, and intravitreal injection of vancomycin and ceftazidime before symptoms developed. We were unable to identify the causal drug owing to the large number of medications concurrently administered. The second case presented with DRESS syndrome symptoms during ocular toxoplasmosis treatment. In this case, a clearer association with pyrimethamine-sulfadiazine was observed. As a result of the regular prescription of pharmacological agents associated with DRESS syndrome, ophthalmologists should be aware of the potentially serious complications of DRESS syndrome. PMID- 27463634 TI - Keratoacanthoma of the conjunctiva in a young patient. AB - Keratoacanthomas rarely occur in the conjunctiva. We report a case of a 24-year old man with a rapidly growing conjunctival mass. The tumor was excised with a safety margin to exclude squamous cell carcinoma and was histopathologically diagnosed as a keratoacanthoma. There has been no recurrence over 2 years of follow-up. To the best of our knowledge, he is the youngest patient to be diagnosed with conjunctival keratoacanthoma who had no known risk factors such as skin disorders, trauma, surgery, or infection. In similar cases, we recommend complete early surgical excision and careful follow-up to exclude malignancy. PMID- 27463635 TI - Enhanced depth imaging optical coherence tomography of choroidal osteoma with secondary neovascular membranes: report of two cases. AB - We report enhanced depth imaging optical coherence tomography (EDI-OCT) features based on clinical and imaging data from two newly diagnosed cases of choroidal osteoma presenting with recent visual loss secondary to choroidal neovascular membranes. The features described in the two cases, compression of the choriocapillaris and disorganization of the medium and large vessel layers, are consistent with those of previous reports. We noticed a sponge-like pattern previously reported, but it was subtle. Both lesions had multiple intralesional layers and a typical intrinsic transparency with visibility of the sclerochoroidal junction. PMID- 27463636 TI - Silent polypoidal choroidal vasculopathy in a patient with angioid streaks. AB - We present a case of silent polypoidal choroidal vasculopathy (PCV) in a patient with angioid streaks. PCV was detected during a routine ophthalmic examination and confirmed by fluorescein angiography, indocyanine green angiography, and optical coherence tomography. After 2 years of follow-up, the PCV remained silent without any complications. We report this rare coexistence and review literature on this topic. PMID- 27463637 TI - Update and review of Urrets-Zavalia syndrome. AB - For more than half a century, Urrets-Zavalia syndrome (fixed dilated pupil) has been described as a postoperative complication of ophthalmic surgery. Since first reported as a complication of penetrating keratoplasty for keratoconus in patients receiving atropine, the characteristic features of Urrets-Zavalia syndrome have been expanded. In previous literature, a total of 110 cases resulted in a fixed and dilated pupil. Increased intraocular pressure (IOP) in the immediate postoperative period, phakia, and air or gas in the anterior chamber appear to be the most important risk factors for Urrets-Zavalia syndrome following ophthalmic procedures. Mannitol, IOP control, the removal of air or gas in the anterior chamber, and iridectomy have all demonstrated utility in managing Urrets-Zavalia syndrome. PMID- 27463638 TI - The fever of pain: ocular chronic pain, light at the end of the tunnel. PMID- 27463639 TI - Collaborative Interpersonal Psychotherapy for HIV-Positive Women in Kenya: A Case Study From the Mental Health, HIV and Domestic Violence (MIND) Study. AB - We examine the efficacy of nonspecialists delivering interpersonal psychotherapy (IPT) to HIV-positive (HIV+) women. We describe a case in which local personnel without prior mental health training delivered IPT for the treatment of depression and posttraumatic stress disorder in an HIV+ woman who reported experiencing gender-based violence and was enrolled in HIV care at the Family AIDS, Care, Education and Services program in Kisumu, Kenya. PMID- 27463640 TI - Effects of a glyphosate-based herbicide on the uterus of adult ovariectomized rats. AB - Glyphosate is the active ingredient of several herbicide formulations. Different reports suggest that glyphosate-based herbicides (GBHs) may act as endocrine disruptors. We evaluated the potential estrogenic effects of a GBH formulation using the uterotrophic assay. Adult ovariectomized rats were sc injected for 3 consecutive days with: saline solution (vehicle control), 2.10-5 g E2 /kg/day (uterotrophic dose; UE2 ), 2.10-7 g E2 /kg/day (nonuterotrophic dose; NUE2 ), or 0.5, 5, or 50 mg GBH/kg/day of the. Twenty-four hours after the last injection, the uterus was removed and weighed and processed for histopathology and mRNA extraction. Epithelial cell proliferation and height and expression of estrogen responsive genes were evaluated (estrogen receptors, ERalpha and ERbeta; progesterone receptor, PR; complement 3, C3). Uterine weight and epithelial proliferation were not affected by GBH. However, the luminal epithelial cell height increased at GBH0.5. ERalpha mRNA was downregulated by all GBH doses and E2 groups, whereas PR and C3 mRNA were diminished by GBH0.5. GBH5-, GBH50-, and UE2 -treated rats showed downregulated ERalpha protein expression in luminal epithelial cells, while the receptor was upregulated in the stroma. GBH upregulated ERbeta (GBH0.5-50) and PR (GBH5) expressions in glandular epithelial cells, similar effect to that of NUE2 group. These results indicate that, although the uterine weight was not affected, GBH modulates the expression of estrogen-sensitive genes. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1191-1201, 2017. PMID- 27463641 TI - Identifying High-Risk Neighborhoods Using Electronic Medical Records: A Population-Based Approach for Targeting Diabetes Prevention and Treatment Interventions. AB - BACKGROUND: Increasing attention is being paid to the marked disparities in diabetes prevalence and health outcomes in the United States. There is a need to identify the small-area geographic variation in diabetes risk and related outcomes, a task that current health surveillance methods, which often rely on a self-reported diagnosis of diabetes, are not detailed enough to achieve. Broad adoption of electronic health records (EHR) and routine centralized reporting of patient-level data offers a new way to examine diabetes risk and highlight hotspots for intervention. METHODS AND FINDINGS: We examined small-area geographic variation in hemoglobin A1c (HgbA1C) levels in three counties though a retrospective observational analysis of the complete population of diabetic patients receiving at least two ambulatory care visits for diabetes in three counties (two urban, one rural) in Minnesota in 2013, with clinical performance measures re-aggregated to patient home zip code area. Patient level performance measures included HgbA1c, blood pressure, low-density lipoprotein cholesterol and smoking. Diabetes care was provided to 63,053 patients out of a total population of 1.48 million people aged 18-74. Within each zip code area, on average 4.1% of the population received care for diabetes. There was significant and largely consistent geographic variation in the proportion of patients within their zip code area of residence attaining HgbA1C <8.0%, ranging from 59-90% of patients within each zip code area (interquartile range (IQR) 72.0%-78.1%). Attainment of performance measures for a zip code area were correlated with household income, educational attainment and insurance coverage for the same zip code area (all p < .001). CONCLUSIONS: We identified small geographic areas with the least effective control of diabetes. Centrally-aggregated EHR provides a new means of identifying and targeting at-risk neighborhoods for community-based interventions. PMID- 27463642 TI - The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review. AB - INTRODUCTION: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC. AREAS COVERED: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development. EXPERT OPINION: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC. PMID- 27463644 TI - Inordinate Spinescence: Taxonomic Revision and Microtomography of the Pheidole cervicornis Species Group (Hymenoptera, Formicidae). AB - The ant genus Pheidole-for all of its hyperdiversity and global ubiquity-is remarkably conservative with regard to morphological disparity. A striking exception to this constrained morphology is the spinescent morphotype, which has evolved multiple times across distantly related lineages of Indoaustralian Pheidole. The Pheidole cervicornis group contains perhaps the most extraordinary spinescent forms of all Pheidole. Here we present a taxonomic revision of the P. cervicornis group, and use microtomographic scanning technology to investigate the internal anatomy of the thoracic spines. Our findings suggest the pronotal spines of Pheidole majors, are possibly skeletomuscular adaptations for supporting their disproportionately large heads. The 'head support hypothesis' is an alternative to the mechanical defense hypothesis most often used to explain spinescence in ants. The P. cervicornis group is known only from New Guinea and is represented by the following four species, including two described here as new: P. barumtaun Donisthorpe, P. drogon sp. nov., P. cervicornis Emery, and P. viserion sp. nov. The group is most readily identified by the minor worker caste, which has extremely long pronotal spines and strongly bifurcating propodeal spines. The major and minor workers of all species are illustrated with specimen photographs, with the exception of the major worker of P. cervicornis, which is not known. PMID- 27463645 TI - Science advice for Europe. PMID- 27463643 TI - Hyphopodium-Specific VdNoxB/VdPls1-Dependent ROS-Ca2+ Signaling Is Required for Plant Infection by Verticillium dahliae. AB - Verticillium dahliae is a phytopathogenic fungus obligate in root infection. A few hyphopodia differentiate from large numbers of hyphae after conidia germination on the root surface for further infection. However, the molecular features and role of hyphopodia in the pathogenicity of V. dahliae remain elusive. In this study, we found that the VdPls1, a tetraspanin, and the VdNoxB, a catalytic subunit of membrane-bound NADPH oxidases for reactive oxygen species (ROS) production, were specifically expressed in hyphopodia. VdPls1 and VdNoxB highly co-localize with the plasma membrane at the base of hyphopodia, where ROS and penetration pegs are generated. Mutant strains, VdDeltanoxb and VdDeltapls1, in which VdPls1 and VdNoxB were deleted, respectively, developed defective hyphpodia incapable of producing ROS and penetration pegs. Defective plasma membrane localization of VdNoxB in VdDeltapls1 demonstrates that VdPls1 functions as an adaptor protein for the recruitment and activation of the VdNoxB. Furthermore, in VdDeltanoxb and VdDeltapls1, tip-high Ca2+ accumulation was impaired in hyphopodia, but not in vegetative hyphal tips. Moreover, nuclear targeting of VdCrz1 and activation of calcineurin-Crz1 signaling upon hyphopodium induction in wild-type V. dahliae was impaired in both knockout mutants, indicating that VdPls1/VdNoxB-dependent ROS was specifically required for tip high Ca2+ elevation in hyphopodia to activate the transcription factor VdCrz1 in the regulation of penetration peg formation. Together with the loss of virulence of VdDeltanoxb and VdDeltapls1, which are unable to initiate colonization in cotton plants, our data demonstrate that VdNoxB/VdPls1-mediated ROS production activates VdCrz1 signaling through Ca2+ elevation in hyphopodia, infectious structures of V. dahliae, to regulate penetration peg formation during the initial colonization of cotton roots. PMID- 27463647 TI - INFECTIOUS DISEASE. Vaginal microbiome affects HIV risk. PMID- 27463648 TI - PUBLIC HEALTH. African HIV/tuberculosis institutes merge. PMID- 27463649 TI - CONSERVATION. To save caribou, Alberta wants to fence them in. PMID- 27463650 TI - EVOLUTIONARY BIOLOGY. Do genomic conflicts drive evolution? PMID- 27463652 TI - ARCHAEOLOGY. Huge statue suggests early rise for Buddhism. PMID- 27463651 TI - ANIMAL BEHAVIOR. Wild bird comes when honey hunters call for help. PMID- 27463653 TI - SYMBIOSIS. A lichen menage a trois. PMID- 27463655 TI - Red star rising. PMID- 27463654 TI - Rules of the game. PMID- 27463656 TI - Who's missing from this picture? PMID- 27463657 TI - ECOLOGY. Can Apulia's olive trees be saved? PMID- 27463658 TI - MICROBIOME. Is triclosan harming your microbiome? PMID- 27463659 TI - EVOLUTION. Hominid superorganisms. PMID- 27463660 TI - GENETICS. Demystifying the demise of paternal mitochondrial DNA. PMID- 27463661 TI - 324 million minorities. PMID- 27463662 TI - Misrepresenting A. Fisher v. U. Texas. PMID- 27463663 TI - Misrepresenting A. Fisher v. U. Texas--Response. PMID- 27463664 TI - Minorities and bias: The big picture. PMID- 27463665 TI - Comment on "A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme". AB - Watanabe et al (Reports, 12 April 2013, p. 195) study the yeast SWR1/SWR-C complex responsible for depositing the histone variant H2A.Z by replacing nucleosomal H2A with H2A.Z. They report that reversal of H2A.Z replacement is mediated by SWR1 and related INO80 on an H2A.Z nucleosome carrying H3K56Q. Using multiple assays and reaction conditions, we find no evidence of such reversal of H2A.Z exchange. PMID- 27463666 TI - Response to Comment on "A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme". AB - Wang et al report a failure to reproduce our biochemical observation that the INO80C and SWR1C/SWR1/SWR-C chromatin remodeling enzymes catalyze replacement of nucleosomal H2A.Z with H2A when the substrate contains H3-K56Q. They point to technical problems with our dimer exchange assay. In response, we have recapitulated our findings using a mobility shift assay that was developed and employed by Wang and colleagues. PMID- 27463667 TI - Layered and scrolled nanocomposites with aligned semi-infinite graphene inclusions at the platelet limit. AB - Two-dimensional (2D) materials can uniquely span the physical dimensions of a surrounding composite matrix in the limit of maximum reinforcement. However, the alignment and assembly of continuous 2D components at high volume fraction remain challenging. We use a stacking and folding method to generate aligned graphene/polycarbonate composites with as many as 320 parallel layers spanning 0.032 to 0.11 millimeters in thickness that significantly increases the effective elastic modulus and strength at exceptionally low volume fractions of only 0.082%. An analogous transverse shear scrolling method generates Archimedean spiral fibers that demonstrate exotic, telescoping elongation at break of 110%, or 30 times greater than Kevlar. Both composites retain anisotropic electrical conduction along the graphene planar axis and transparency. These composites promise substantial mechanical reinforcement, electrical, and optical properties at highly reduced volume fraction. PMID- 27463668 TI - A lightweight shape-memory magnesium alloy. AB - Shape-memory alloys (SMAs), which display shape recovery upon heating, as well as superelasticity, offer many technological advantages in various applications. Those distinctive behaviors have been observed in many polycrystalline alloy systems such as nickel titantium (TiNi)-, copper-, iron-, nickel-, cobalt-, and Ti-based alloys but not in lightweight alloys such as magnesium (Mg) and aluminum alloys. Here we present a Mg SMA showing superelasticity of 4.4% at -150 degrees C and shape recovery upon heating. The shape-memory properties are caused by reversible martensitic transformation. This Mg alloy includes lightweight scandium, and its density is about 2 grams per cubic centimeter, which is one third less than that of practical TiNi SMAs. This finding raises the potential for development and application of lightweight SMAs across a number of industries. PMID- 27463669 TI - Observation of the Efimovian expansion in scale-invariant Fermi gases. AB - Scale invariance plays an important role in unitary Fermi gases. Discrete scaling symmetry manifests itself in quantum few-body systems such as the Efimov effect. Here, we report on the theoretical prediction and experimental observation of a distinct type of expansion dynamics for scale-invariant quantum gases. When the frequency of the harmonic trap holding the gas decreases continuously as the inverse of time t, the expansion of the cloud size exhibits a sequence of plateaus. The locations of these plateaus obey a discrete geometric scaling law with a controllable scale factor, and the expansion dynamics is governed by a log periodic function. This marked expansion shares the same scaling law and mathematical description as the Efimov effect. PMID- 27463670 TI - Electron microscopy of electromagnetic waveforms. AB - Rapidly changing electromagnetic fields are the basis of almost any photonic or electronic device operation. We report how electron microscopy can measure collective carrier motion and fields with subcycle and subwavelength resolution. A collimated beam of femtosecond electron pulses passes through a metamaterial resonator that is previously excited with a single-cycle electromagnetic pulse. If the probing electrons are shorter in duration than half a field cycle, then time-frozen Lorentz forces distort the images quasi-classically and with subcycle time resolution. A pump-probe sequence reveals in a movie the sample's oscillating electromagnetic field vectors with time, phase, amplitude, and polarization information. This waveform electron microscopy can be used to visualize electrodynamic phenomena in devices as small and fast as available. PMID- 27463671 TI - Connections between groundwater flow and transpiration partitioning. AB - Understanding freshwater fluxes at continental scales will help us better predict hydrologic response and manage our terrestrial water resources. The partitioning of evapotranspiration into bare soil evaporation and plant transpiration remains a key uncertainty in the terrestrial water balance. We used integrated hydrologic simulations that couple vegetation and land-energy processes with surface and subsurface hydrology to study transpiration partitioning at the continental scale. Both latent heat flux and partitioning are connected to water table depth, and including lateral groundwater flow in the model increases transpiration partitioning from 47 +/- 13 to 62 +/- 12%. This suggests that lateral groundwater flow, which is generally simplified or excluded in Earth system models, may provide a missing link for reconciling observations and global models of terrestrial water fluxes. PMID- 27463672 TI - Cospeciation of gut microbiota with hominids. AB - The evolutionary origins of the bacterial lineages that populate the human gut are unknown. Here we show that multiple lineages of the predominant bacterial taxa in the gut arose via cospeciation with humans, chimpanzees, bonobos, and gorillas over the past 15 million years. Analyses of strain-level bacterial diversity within hominid gut microbiomes revealed that clades of Bacteroidaceae and Bifidobacteriaceae have been maintained exclusively within host lineages across hundreds of thousands of host generations. Divergence times of these cospeciating gut bacteria are congruent with those of hominids, indicating that nuclear, mitochondrial, and gut bacterial genomes diversified in concert during hominid evolution. This study identifies human gut bacteria descended from ancient symbionts that speciated simultaneously with humans and the African apes. PMID- 27463673 TI - Competition between engrams influences fear memory formation and recall. AB - Collections of cells called engrams are thought to represent memories. Although there has been progress in identifying and manipulating single engrams, little is known about how multiple engrams interact to influence memory. In lateral amygdala (LA), neurons with increased excitability during training outcompete their neighbors for allocation to an engram. We examined whether competition based on neuronal excitability also governs the interaction between engrams. Mice received two distinct fear conditioning events separated by different intervals. LA neuron excitability was optogenetically manipulated and revealed a transient competitive process that integrates memories for events occurring closely in time (coallocating overlapping populations of neurons to both engrams) and separates memories for events occurring at distal times (disallocating nonoverlapping populations to each engram). PMID- 27463674 TI - Reciprocal signaling in honeyguide-human mutualism. AB - Greater honeyguides (Indicator indicator) lead human honey-hunters to wild bees' nests, in a rare example of a mutualistic foraging partnership between humans and free-living wild animals. We show experimentally that a specialized vocal sound made by Mozambican honey-hunters seeking bees' nests elicits elevated cooperative behavior from honeyguides. The production of this sound increased the probability of being guided by a honeyguide from about 33 to 66% and the overall probability of thus finding a bees' nest from 17 to 54%, as compared with other animal or human sounds of similar amplitude. These results provide experimental evidence that a wild animal in a natural setting responds adaptively to a human signal of cooperation. PMID- 27463675 TI - Accurate design of megadalton-scale two-component icosahedral protein complexes. AB - Nature provides many examples of self- and co-assembling protein-based molecular machines, including icosahedral protein cages that serve as scaffolds, enzymes, and compartments for essential biochemical reactions and icosahedral virus capsids, which encapsidate and protect viral genomes and mediate entry into host cells. Inspired by these natural materials, we report the computational design and experimental characterization of co-assembling, two-component, 120-subunit icosahedral protein nanostructures with molecular weights (1.8 to 2.8 megadaltons) and dimensions (24 to 40 nanometers in diameter) comparable to those of small viral capsids. Electron microscopy, small-angle x-ray scattering, and x ray crystallography show that 10 designs spanning three distinct icosahedral architectures form materials closely matching the design models. In vitro assembly of icosahedral complexes from independently purified components occurs rapidly, at rates comparable to those of viral capsids, and enables controlled packaging of molecular cargo through charge complementarity. The ability to design megadalton-scale materials with atomic-level accuracy and controllable assembly opens the door to a new generation of genetically programmable protein based molecular machines. PMID- 27463677 TI - Alternatives within academia. PMID- 27463676 TI - Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. AB - Cancers often evade immune surveillance by adopting peripheral tissue- tolerance mechanisms, such as the expression of programmed cell death ligand 1 (PD-L1), the inhibition of which results in potent antitumor immunity. Here, we show that cyclin-dependent kinase 5 (Cdk5), a serine-threonine kinase that is highly active in postmitotic neurons and in many cancers, allows medulloblastoma (MB) to evade immune elimination. Interferon-gamma (IFN-gamma)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells. PMID- 27463678 TI - Synthetic recombinase-based state machines in living cells. AB - State machines underlie the sophisticated functionality behind human-made and natural computing systems that perform order-dependent information processing. We developed a recombinase-based framework for building state machines in living cells by leveraging chemically controlled DNA excision and inversion operations to encode states in DNA sequences. This strategy enables convenient readout of states (by sequencing and/or polymerase chain reaction) as well as complex regulation of gene expression. We validated our framework by engineering state machines in Escherichia coli that used one, two, or three chemical inputs to control up to 16 DNA states. These state machines were capable of recording the temporal order of all inputs and performing multi-input, multi-output control of gene expression. We also developed a computational tool for the automated design of gene regulation programs using recombinase-based state machines. Our scalable framework should enable new strategies for recording and studying how combinational and temporal events regulate complex cell functions and for programming sophisticated cell behaviors. PMID- 27463679 TI - Latency reversal and viral clearance to cure HIV-1. AB - Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication--a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society. PMID- 27463680 TI - Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication. AB - Influenza A virus (IAV) affects 5%-10% of the world's population every year. Through genome changes, many IAV strains develop resistance to currently available anti-influenza therapeutics. Therefore, there is an urgent need to find new targets for therapeutics against this important human respiratory pathogen. In this study, 2'-O-methyl and locked nucleic acid antisense oligonucleotides (ASOs) were designed to target internal regions of influenza A/California/04/2009 (H1N1) genomic viral RNA segment 8 (vRNA8) based on a base-pairing model of vRNA8. Ten of 14 tested ASOs showed inhibition of viral replication in Madin Darby canine kidney cells. The best five ASOs were 11-15 nucleotides long and showed inhibition ranging from 5- to 25-fold. In a cell viability assay they showed no cytotoxicity. The same five ASOs also showed no inhibition of influenza B/Brisbane/60/2008 (Victoria lineage), indicating that they are sequence specific for IAV. Moreover, combinations of ASOs slightly improved anti-influenza activity. These studies establish the accessibility of IAV vRNA for ASOs in regions other than the panhandle formed between the 5' and 3' ends. Thus, these regions can provide targets for the development of novel IAV antiviral approaches. PMID- 27463681 TI - Levels of DNA Methylation Vary at CpG Sites across the BRCA1 Promoter, and Differ According to Triple Negative and "BRCA-Like" Status, in Both Blood and Tumour DNA. AB - Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies. PMID- 27463682 TI - Comparison of miRNAs and Their Targets in Seed Development between Two Maize Inbred Lines by High-Throughput Sequencing and Degradome Analysis. AB - MicroRNAs (miRNAs) play an important role in plant growth, development, and response to environment. For identifying and comparing miRNAs and their targets in seed development between two maize inbred lines (i.e. PH6WC and PH4CV), two sRNAs and two degradome libraries were constructed. Through high-throughput sequencing and miRNA identification, 55 conserved and 24 novel unique miRNA sequences were identified in two sRNA libraries; moreover, through degradome sequencing and analysis, 137 target transcripts corresponding to 38 unique miRNA sequences were identified in two degradome libraries. Subsequently, 16 significantly differentially expressed miRNA sequences were verified by qRT-PCR, in which 9 verified sequences obviously target 30 transcripts mainly involved with regulation in flowering and development in embryo. Therefore, the results suggested that some miRNAs (e.g. miR156, miR171, miR396 and miR444) related reproductive development might differentially express in seed development between the PH6WC and PH4CV maize inbred lines in this present study. PMID- 27463683 TI - Transcriptome Analysis and Postprandial Expression of Amino Acid Transporter Genes in the Fast Muscles and Gut of Chinese Perch (Siniperca chuatsi). AB - The characterization of the expression and regulation of growth-related genes in the muscles of Chinese perch is of great interest to aquaculturists because of the commercial value of the species. The transcriptome annotation of the skeletal muscles is a crucial step in muscle growth-related gene analysis. In this study, we generated 52 504 230 reads of mRNA sequence data from the fast muscles of the Chinese perch by using Solexa/Illumina RNA-seq. Twenty-one amino acid transporter genes were annotated by searching protein and gene ontology databases, and postprandial changes in their transcript abundance were assayed after administering a single satiating meal to Chinese perch juveniles (body mass, approximately 100 g), following fasting for 1 week. The gut content of the Chinese perch increased significantly after 1 h and remained high for 6 h following the meal and emptied within 48-96 h. Expression of eight amino acid transporter genes was assayed in the fast muscles through quantitative real-time polymerase chain reaction at 0, 1, 3, 6, 12, 24, 48, and 96 h. Among the genes, five transporter transcripts were markedly up-regulated within 1 h of refeeding, indicating that they may be potential candidate genes involved in the rapid response signaling system regulating fish myotomal muscle growth. These genes display coordinated regulation favoring the resumption of myogenesis responding to feeding. PMID- 27463684 TI - Biomarkers in Randomized Clinical Trials: Magnetic Resonance Imaging. AB - BACKGROUND: It is essential that randomized clinical trials (RCTs) incorporate biomarkers of disease progression that would be sensitive to the effects of disease-modifying treatments. Magnetic resonance imaging (MRI) can be safely repeated over time, and is routinely performed in clinical centers, making it an ideal modality to be incorporated into RCTs. SUMMARY: This chapter discusses potential structural MRI biomarkers that have been proposed for a number of different neurodegenerative disorders, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), progressive supranuclear palsy syndrome (PSPS), and Parkinson's disease (PD). All of these disorders represent targets for ongoing and future RCTs. Rates of hippocampal atrophy and ventricular expansion provide excellent biomarkers of disease progression in AD, and may also provide biomarkers in prodromal and preclinical phases of the disease, as well as in DLB. Rates of ventricular expansion also perform well in FTD, although regional frontal and temporal measurements could also be useful. Rates of midbrain atrophy provide the most feasible MRI biomarker in PSPS. In contrast, PD is not associated with specific patterns of cerebral atrophy and further work is needed in order to define useful MRI biomarkers. Sample size calculations using these MRI biomarkers are presented and discussed. KEY MESSAGES: Rates of cerebral atrophy provide valuable potential biomarkers of disease progression in neurodegenerative disorders, and have already begun to be utilized as outcome measures in RCTs. Measurements from other structural and functional MRI modalities require more longitudinal validation, but may prove to be useful in the future. PMID- 27463685 TI - Effects of Relocation and Individual and Environmental Factors on the Long-Term Stress Levels in Captive Chimpanzees (Pan troglodytes): Monitoring Hair Cortisol and Behaviors. AB - Understanding the factors associated with the long-term stress levels of captive animals is important from the view of animal welfare. In this study, we investigated the effects of relocation in addition to individual and environmental factors related to social management on long-term stress level in group-living captive chimpanzees by examining behaviors and hair cortisol (HC). Specifically, we conducted two studies. The first compared changes in HC levels before and after the relocation of 8 chimpanzees (Study 1) and the second examined the relationship between individual and environmental factors and individual HC levels in 58 chimpanzees living in Kumamoto Sanctuary (KS), Kyoto University (Study 2). We hypothesized that relocation, social situation, sex, and early rearing conditions, would affect the HC levels of captive chimpanzees. We cut arm hair from chimpanzees and extracted and assayed cortisol with an enzyme immunoassay. Aggressive behaviors were recorded ad libitum by keepers using a daily behavior monitoring sheet developed for this study. The results of Study 1 indicate that HC levels increased during the first year after relocation to the new environment and then decreased during the second year. We observed individual differences in reactions to relocation and hypothesized that social factors may mediate these changes. In Study 2, we found that the standardized rate of receiving aggression, rearing history, sex, and group formation had a significant influence on mean HC levels. Relocation status was not a significant factor, but mean HC level was positively correlated with the rate of receiving aggression. Mean HC levels were higher in males than in females, and the association between aggressive interactions and HC levels differed by sex. These results suggest that, although relocation can affect long-term stress level, individuals' experiences of aggression and sex may be more important contributors to long-term stress than relocation alone. PMID- 27463686 TI - Peculiarities of Neurological Disorders and Study Designs. AB - BACKGROUND: Neurological disorders are heterogeneous clinical conditions with variable course and outcome. SUMMARY: The basic aspects of the commonest neurological disorders are addressed along with the proposed structure of randomized clinical trials (RCTs). Dementing disorders, including Alzheimer's disease (AD), are clinical conditions in which altered cognitive functions are associated with behavioral and personality changes. Parkinson's disease (PD) is a multisystem disorder characterized by motor dysfunction associated with dysautonomia, sleep and olfactory disturbances, cognitive changes, and depression. Amyotrophic lateral sclerosis (ALS) is an invariably fatal clinical condition involving motor neurons. The available treatments are purely symptomatic for PD but virtually ineffective for AD and ALS. Headache disorders, multiple sclerosis, and epilepsy, three diseases characterized by recurrent symptoms and chronic or episodic course, can be fairly easily controlled by current treatments, but cannot be prevented nor cured. The objectives of treatments of neurodegenerative disorders include primary prevention, slowing or arrest of disease progression, and control of symptoms. Stroke is an acute clinical condition causing frequent disability and death, with only one approved treatment. There are many challenges to acute stroke clinical trials; among them, the very short therapeutic window and the issue of stroke heterogeneity. In this chapter, only the core elements of the study designs are outlined. KEY MESSAGES: The design of an RCT must be adapted to the basic characteristics of each clinical condition. PMID- 27463687 TI - Use of Hypoprothrombinemia-Inducing Cephalosporins and the Risk of Hemorrhagic Events: A Nationwide Nested Case-Control Study. AB - OBJECTIVE: Existing data regarding the risk of hemorrhagic events associated with exposure to hypoprothrombinemia-inducing cephalosporins are limited by the small sample size. This population-based study aimed to examine the association between exposure to hypoprothrombinemia-inducing cephalosporins and hemorrhagic events using National Health Insurance Research Database in Taiwan. DESIGN: A nationwide nested case-control study. SETTING: National Health Insurance Research database. PARTICIPANTS: We conducted a nested case-control study within a cohort of 6191 patients who received hypoprothrombinemia-inducing cephalosporins and other antibiotics for more than 48 hours. Multivariable conditional logistic regressions were used to calculate the adjusted odds ratio (aOR) and 95% confidence interval (CI) for hemorrhagic events associated with exposure to hypoprothrombinemia-inducing cephalosporins (overall, cumulative dose measured as defined daily dose (DDD), and individual cephalosporins). RESULTS: Within the cohort, we identified 704 patients with hemorrhagic events and 2816 matched controls. Use of hypoprothrombinemia-inducing cephalosporins was associated with increased risk of hemorrhagic events (aOR, 1.71; 95% CI, 1.42-2.06), which increased with higher cumulative doses (<3 DDDs, aOR 1.62; 3-5 DDDs, aOR 1.78; and >5 DDDs, aOR 1.89). The aOR for individual cephalosporin was 2.88 (95% CI, 2.08-4.00), 1.35 (1.09-1.67) and 4.57 (2.63-7.95) for cefmetazole, flomoxef, and cefoperazone, respectively. Other risk factors included use of anticoagulants (aOR 2.08 [95% CI, 1.64-2.63]), liver failure (aOR 1.69 [1.30-2.18]), poor nutritional status (aOR 1.41 [1.15-1.73]), and history of hemorrhagic events (aOR 2.57 [1.94-3.41]) 6 months prior to the index date. CONCLUSIONS: Use of hypoprothrombinemia-inducing cephalosporins increases risk of hemorrhagic events. Close watch for hemorrhagic events is recommended when prescribing these cephalosporins, especially in patients who are at higher risk. PMID- 27463688 TI - Transition and transfer of childhood cancer survivors to adult care: A national survey of pediatric oncologists. AB - BACKGROUND: Pediatric oncologists are responsible for ensuring that adolescent and young adult (AYA) childhood cancer survivors have the knowledge and skills necessary to manage their follow-up care in adult healthcare systems. PROCEDURES: To describe transition practices and barriers to transfer, we electronically surveyed U.S. Children's Oncology Group members: 507/1449 responded (35%) and 347/507 (68%) met eligibility criteria. RESULTS: Of 347 respondents, 50% are male, median years in practice 10 (range 5-22), 37% practice in freestanding children's hospitals. Almost all care for survivors up to age 21 years (96%), 42% care for survivors over age 25 years, and only 16% over age 30 years. While 66% of oncologists reported providing transition education to their patients, very few (8%) reported using standardized transition assessments. The most frequent barriers to transfer were perceived attachment to provider (91%), lack of adult providers with cancer survivor expertise (86%), patient's cognitive delay (81%), or unstable social situation (80%). Oncologists who continue to care for patients older than 25 years are more likely to perceive parents' attachment to provider (P = 0.037) and patients' social situation as barriers to transfer (P = 0.044). Four themes emerged from a content analysis of 75 respondents to the open-ended question inviting comments on transition/transfer practices: desire for flexible transfer criteria; providers as barriers; provider lack of transition knowledge, skills, and resources; and desire for collaboration. CONCLUSIONS: Although most pediatric oncologists reported transferring AYA cancer survivors to adult care and providing some transition education, they endorse deficits in transition skills, emotional readiness, and institutional resources. PMID- 27463689 TI - First Report of Toxoplasma gondii, Dirofilaria immitis, and Chlamydia felis Infection in Stray and Companion Cats in Northeastern and Eastern China. AB - Feline vector-borne diseases have increasingly become a focus of interest in recent years. Toxoplasma gondii, Dirofilaria immitis, and Chlamydia felis are common pathogens of cats that can affect humans among different countries all over the world. However, information about prevalence of T. gondii and C. felis is available in China, but information about coinfection of T. gondii, D. immitis, and C. felis in cats is limited. Thus, this study was conducted to estimate the prevalence of these pathogens' infection among stray and companion cats in northeastern and eastern China and identify the influence of age, gender, types, and regions on seropositivity. The circulating antigens of D. immitis and specific antibodies to T. gondii and C. felis were examined using kits commercially available. The overall prevalence of T. gondii, D. immitis, and C. felis was 15.43%, 1.93%, and 9.90%, respectively. Coinfection was common, and infection with both T. gondii and C. felis was the most common coinfection (22.32%). Stray cats have significantly higher seroprevalences than companion cats (p < 0.05). Moreover, the infection rates of these pathogens keep increasing year by year. This is the first report of T. gondii, D. immitis, and C. felis infection in cats in northeastern and eastern China. The findings of this study reveal that T. gondii, D. immitis, and C. felis are prevalent in stray and companion cats in northeastern China, which provided baseline data for the effective prevention and control of these parasites' prevalence in these regions and other parts of China. PMID- 27463690 TI - Ruxolitinib is effective in patients with intermediate-1 risk myelofibrosis: a summary of recent evidence. AB - Ruxolitinib is the only therapy with an approved indication for myelofibrosis (MF), a myeloproliferative neoplasm associated with progressive bone marrow fibrosis and extramedullary hematopoiesis. Although the pivotal phase 3 COMFORT studies included only patients with intermediate-2 or high-risk MF, the US indication includes all patients with intermediate- or high-risk disease. Data from recent nonrandomized studies confirm that the benefits of ruxolitinib established in the COMFORT studies in terms of spleen size reduction and symptom improvement also extend to patients with intermediate-1 risk MF, who tend to have less advanced disease than patients with higher-risk MF. Given the disease modifying potential of ruxolitinib therapy, timely initiation of ruxolitinib therapy may not only improve patients' current clinical status but also lead to better long-term outcomes. The decision of whether or when to initiate ruxolitinib treatment should be based on the expected benefit-risk ratio for each patient, specifically considering potential adverse effects. PMID- 27463691 TI - Five-Year Progress Update on the Surgeon General's Call to Action to Support Breastfeeding, 2011. AB - In 2011, Surgeon General Regina Benjamin issued a Call to Action to Support Breastfeeding (Call to Action) in an effort to mobilize families, communities, clinicians, healthcare systems, and employers to take action to improve support for breastfeeding. The Call to Action identified 20 key action steps to address society-wide breastfeeding barriers in six areas: mothers and families, communities, healthcare, employment, research, and public health infrastructure. This report highlights major federal activities that show progress toward answering the Call to Action in the first 5 years since its launch. PMID- 27463692 TI - C-H Acetoxylation-Based Chemical Synthesis of 17 beta-Hydroxymethyl-17 alpha methyl-18-norandrost-13-ene Steroids. AB - Palladium-catalyzed C-H acetoxylation has been proposed as a key transformation in the first chemical synthesis of steroids bearing a unique 17beta-hydroxymethyl 17alpha-methyl-18-nor-13-ene D-fragment. This C-H functionalization step was crucial for inverting the configuration at the quaternary stereocenter of a readily available synthetic intermediate. The developed approach was applied to prepare the metandienone metabolite needed as a reference substance in anti doping analysis to control the abuse of this androgenic anabolic steroid. PMID- 27463693 TI - Macromolecular crowding effect is critical for maintaining SIRT1's nuclear localization in cancer cells. AB - SIRT1 is a principle class III histone deacetylase which exhibits versatile functions in stress response, development, and pathological processes including cancer. Although SIRT1 deacetylates a wide range of nuclear and cytoplasmic proteins, its subcellular localization in cancer cells has been controversial. In this study, we uncovered the inconsistent reports about SIRT1 subcellular localization is partially due to different analysis approaches. While immunofluorescence and live cell imaging reveal a predominant nuclear localization of SIRT1, conventional cell fractionation often results in a severe leaking of SIRT1 into the cytoplasm. Such a leakage is mainly caused by loss of cytoplasmic macromolecular crowding effect as well as hypotonic dwelling during the isolation of the nuclei. We also developed an improved cell fractionation procedure which maintains SIRT1 in its original subcellular localization. Analyzing a variety of human cancer cell lines using this approach and other methods demonstrate that SIRT1 predominantly localizes to the nucleus in cancer cells. PMID- 27463694 TI - Folate-PEG-decorated docetaxel lipid nanoemulsion for improved antitumor activity. AB - AIM: To develop a folate-based docetaxel lipid nanoemulsion (FLNE) for tumor targeted treatment. MATERIALS & METHODS: The docetaxel LNEs were prepared and characterized. In vitro cytotoxic and cell uptake studies were performed. The tissue distribution and targeting of drug were studied by fluorescence imaging and tumor regression in mice. RESULTS: The IC50 values of FLNE on cancer cells were significant. The cell uptake studies showed an increase in fluorescence with time. Imaging studies found that FLNE was superior in tumor targeting by 4.81- and 2.08-fold over controls. The tumor regression proved the superiority of FLNEs. CONCLUSION: The folate strategy was superior over PEGylation, albumin and transferrin strategies. The study demonstrated great potential of FLNE as a prospective targeted delivery system. PMID- 27463696 TI - On Localized Vapor Pressure Gradients Governing Condensation and Frost Phenomena. AB - Interdroplet vapor pressure gradients are the driving mechanism for several phase change phenomena such as condensation dry zones, interdroplet ice bridging, dry zones around ice, and frost halos. Despite the fundamental nature of the underlying pressure gradients, the majority of studies on these emerging phenomena have been primarily empirical. Using classical nucleation theory and Becker-Doring embryo formation kinetics, here we calculate the pressure field for all possible modes of condensation and desublimation in order to gain fundamental insight into how pressure gradients govern the behavior of dry zones, condensation frosting, and frost halos. Our findings reveal that in a variety of phase-change systems the thermodynamically favorable mode of nucleation can switch between condensation and desublimation depending upon the temperature and wettability of the surface. The calculated pressure field is used to model the length of a dry zone around liquid or ice droplets over a broad parameter space. The long-standing question of whether the vapor pressure at the interface of growing frost is saturated or supersaturated is resolved by considering the kinetics of interdroplet ice bridging. Finally, on the basis of theoretical calculations, we propose that there exists a new mode of frost halo that is yet to be experimentally observed; a bimodal phase map is developed, demonstrating its dependence on the temperature and wettability of the underlying substrate. We hope that the model and predictions contained herein will assist future efforts to exploit localized vapor pressure gradients for the design of spatially controlled or antifrosting phase-change systems. PMID- 27463695 TI - Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity. AB - Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 MUM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts. PMID- 27463697 TI - Regulation of podocalyxin trafficking by Rab small GTPases in epithelial cells. AB - The characteristic feature of polarity establishment in MDCK II cells is transcytosis of apical glycoprotein podocalyxin (PCX) from the outer plasma membrane to the newly formed apical domain. This transcytotic event consists of multiple steps, including internalization from the plasma membrane, transport through early endosomes and Rab11-positive recycling endosomes, and delivery to the apical membrane. These steps are known to be tightly coordinated by Rab small GTPases, which act as molecular switches cycling between active GTP-bound and inactive GDP-bound states. However, our knowledge regarding which sets of Rabs regulate particular steps of PCX trafficking was rather limited. Recently, we have performed a comprehensive analysis of Rab GTPase engagement in the transcytotic pathway of PCX during polarity establishment in 2-dimensional (2D) and 3-dimensional (3D) MDCK II cell cultures. In this Commentary we summarize our findings and set them in the context of previous reports. PMID- 27463698 TI - The effects of rapid maxillary expansion on voice function. AB - OBJECTIVE: To evaluate the effects of rapid maxillary expansion (RME) on vocal function in patients with bilateral maxillary crossbite. MATERIALS AND METHODS: We designed our research as a prospective, controlled, clinical study. The treatment group and the control group each had 20 subjects for a total of 40 subjects. Acoustic voice samples were recorded from all patients at T1 and T2 by the Multi-Dimensional Voice Program (MDVP Model 5105) for acoustic analysis in Computerized Speech Lab (CSL). RESULTS: No statistically significant differences were found between the treatment and control groups in the means of any parameters. CONCLUSIONS: RME does not change vocal quality or resonance, so it can be safely used with patients. PMID- 27463699 TI - Maxillary sinus volume in patients with impacted canines. AB - OBJECTIVES: To evaluate the maxillary sinus volumes in unilaterally impacted canine patients and to compare the volumetric changes that occur after the eruption of canines to the dental arch using cone beam computed tomography (CBCT). MATERIALS AND METHODS: Pre- (T0) and posttreatment (T1) CBCT records of 30 patients were used to calculate maxillary sinus volumes between the impacted and erupted canine sides. The InVivoDental 5.0 program was used to measure the volume of the maxillary sinuses. The distance from impacted canine cusp tip to the target point on the palatal plane was also measured. RESULTS: Right maxillary sinus volume was statistically significantly smaller compared to that of the left maxillary sinus when the canine was impacted on the right side at T0. According to the T1 measurements there was no significant difference between the mean volumes of the impaction side and the contralateral side. The distance from the canine tip to its target point on the palatal plane were 17.17 mm, and the distance from the tip to the target point was 15.14 mm for the left- and right side impacted canines, respectively, and there was a significant difference between the mean amount of change of both sides of maxillary sinuses after treatment of impacted canines. CONCLUSIONS: Orthodontic treatment of impacted canines created a significant increase in maxillary sinus volume when the impacted canines were closer with respect to the maxillary sinus. PMID- 27463700 TI - Are three-dimensional airway evaluations obtained through computed and cone-beam computed tomography scans predictable from lateral cephalograms? A systematic review of evidence. AB - OBJECTIVE: To systematically review the literature correlating upper airway parameters between lateral cephalograms (LC) and cone-beam computed tomography (CBCT) or computed tomography (CT) scans to determine the utility of using LC to predict three-dimensional airway parameters. MATERIALS AND METHODS: Both electronic and manual searches of the included studies were performed by two reviewers, and the quality of the studies that met selection criteria were assessed. RESULTS: A total of 11 studies from the literature met the selection criteria. Assessed outcome variables showed correlation r < .7 between the LC and CT scans. The correlation between the LC and CBCT ranged from weak to strong with -.78 <= r and r <= .93 reported in the nasopharyngeal segment. In the oropharyngeal segment, a weak to strong correlation was reported with a range of 37 <= r and r <= .83 between the CBCT and LC. All associations in the hypopharyngeal segment showed a weak correlation. Four of studies were of weak quality, five were of moderate quality, and two were rated to be of strong quality. CONCLUSION: No strong correlations were reported between the LC and CT scans. However, the LC-derived adenoid-nasopharyngeal ratio and the linear measurement (posterior nasal spine, PNS, to posterior pharyngeal wall) had a strong correlation with upright nasopharyngeal area and volume in the CBCTs. The area measurement in conventional LC can be also used as an initial screening tool to predict the upright three-dimensional oropharyngeal volumetric data. The variability of the hypopharyngeal segment cannot be predicted by LCs. However, more well-designed studies are needed to determine the clinical utility of using LC to predict airway size. PMID- 27463701 TI - KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction. AB - Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect, causing mitochondrial dysfunction in the setting of an abnormal kinesin "motor." These results highlight the role of expanded testing and whole-exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation. Ann Neurol 2016;80:633 637. PMID- 27463702 TI - Exploring the Chiral Recognition of Carboxylates by C2-Symmetric Receptors Bearing Glucosamine Pendant Arms. AB - Two urea-based receptors containing a glucosamine derivative were synthesized and investigated in terms of their ability to recognize chiral and achiral anions. Both receptors demonstrated a high affinity toward carboxylates in very competitive DMSO/water mixtures. The chiral recognition properties of these compounds were studied using structurally differentiated guests derived from mandelic acid and alpha-amino acids. We found that receptor 1 exhibits significantly higher enantioselectivities than compound 2 for all anions investigated, with a KS/KR ratio of up to 2. This low enantiodiscrimination in the case of receptor 2 is attributed to a lack of interactions between its sugar moieties and the side chain of chiral anions, due to their inadequate spatial arrangement. PMID- 27463703 TI - Social Inclusion Predicts Lower Blood Glucose and Low-Density Lipoproteins in Healthy Adults. AB - Loneliness has been shown to have direct effects on one's personal well-being. Specifically, a greater feeling of loneliness is associated with negative mental health outcomes, negative health behaviors, and an increased likelihood of premature mortality. Using the neuroendocrine hypothesis, we expected social inclusion to predict decreases in both blood glucose levels and low-density lipoproteins (LDLs) and increases in high-density lipoproteins (HDLs). Fifty-two healthy adults provided self-report data for social inclusion and blood samples for hematological tests. Results indicated that higher social inclusion predicted lower levels of blood glucose and LDL, but had no effect on HDL. Implications for theory and practice are discussed. PMID- 27463704 TI - Is there a difference between EQ-5D and SF-6D in the clinical setting? a comparative study on the quality of life measured by AIMS2-SF, EQ-5D and SF-6D scales for osteoarthritis patients. AB - BACKGROUND: The use of both generic and disease-specific instruments in assessing quality of life (QoL) in subjects may pose a barrier in a busy clinical setting with heavy case load. Our current study attempted to evaluate the responsiveness of generic scales, EQ-5D and SF-6D, as compared with a disease-specific instrument, AIM2-SF, in patients with osteoarthritis, to judge which of the two generic instruments would be more suitable to be used alone in the clinical setting. METHODS: Correlation tests with Pearson correlation coefficient were carried out between EQ-5D and SF-6D scales, and AIMS2-SF scale for both 100 first diagnosed osteoarthritis patients and 22 patients with two follow-up interviews. Multivariate stepwise regression analysis was further performed on the impact of dimensions that affect the change of QoL. RESULTS: In the evaluation of QoL for 100 patients with osteoarthritis by the EQ-5D scale, anxiety was the dimension with the highest sensitivity; while the SF-6D scale had higher sensitivity on two dimensions of psychological health and role limitations. Therefore, SF-6D would appear more suitable for evaluating QoL of arthritis patients at first presentation. For patients at follow-up interviews, EQ-5D scale maintained the highest sensitivity on anxiety and SF-6D scale only had high sensitivity on the psychological health dimension. As such, the two scales would have equivalent effects for the patients at follow-up interviews. In comparison, all the dimensions of SF-6D showed significant correlation with practically every dimension of AIMS2-SF. Hence, the overall results indicate SF-6D may be more suitable for use in patients with clinical osteoarthritis. PMID- 27463705 TI - Estrogen Receptor Signaling and the PI3K/Akt Pathway Are Involved in Betulinic Acid-Induced eNOS Activation. AB - Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid with anti inflammatory, antiviral and anti-cancer properties. Beneficial cardiovascular effects such as increased nitric oxide (NO) production through enhancement of endothelial NO synthase (eNOS) activity and upregulation of eNOS expression have been demonstrated for this compound. In the present study, immortalized human EA.hy 926 endothelial cells were incubated for up to 1 h with 1-100 uM BA and with the phosphatidylinositol-3-kinase (PI3K) inhibitors LY294002 and wortmannin, or the estrogen receptor (ER) antagonist ICI 182,780. Phosphorylation status of eNOS and total eNOS protein were analyzed by Western blotting using a serine 1177 phosphosite-specific antibody. Bioactive NO production was assessed by determination of cGMP content in rat lung fibroblasts (RFL-6) reporter cells. Short-term incubation of EA.hy 926 cells with BA resulted in eNOS phosphorylation at the serine 1177 residue in a concentration- and time-dependent manner with a half-maximal effective concentration of 0.57 uM. This was associated with an enhanced production of NO. BA-induced eNOS phosphorylation and NO production was completely blocked by pretreatment with ICI 182,780, and was attenuated by pretreatment with the PI3K inhibitors wortmannin and LY294002. These results indicate that fast non-genomic effects of ER with downstream signaling through the PI3K/Akt pathway and consecutive eNOS phosphorylation at serine 1177 are involved in BA-induced eNOS activation. PMID- 27463707 TI - Halichoblelide D, a New Elaiophylin Derivative with Potent Cytotoxic Activity from Mangrove-Derived Streptomyces sp. 219807. AB - During our search for interesting bioactive secondary metabolites from mangrove actinomycetes, the strain Streptomyces sp. 219807 which produced a high elaiophylin yield of 4486 mg/L was obtained. A new elaiophylin derivative, halichoblelide D (1), along with seven known analogues 2-8 was isolated and identified from the culture broth. Their chemical structures were determined by detailed analysis of 1D and 2D NMR and HRMS data. The absolute configuration of halichoblelide D (1) was confirmed by comparing the CD spectrum with those of the reported analogues. Compounds 1-7 exhibited potent cytotoxic activities against HeLa and MCF-7 cells with IC50 values ranging from 0.19 to 2.12 MUM. PMID- 27463706 TI - Quorum Sensing Inhibition and Structure-Activity Relationships of beta-Keto Esters. AB - Traditional therapeutics to treat bacterial infections have given rise to multi drug resistant pathogens, which pose a major threat to human and animal health. In several pathogens, quorum sensing (QS)-a cell-cell communication system in bacteria-controls the expression of genes responsible for pathogenesis, thus representing a novel target in the fight against bacterial infections. Based on the structure of the autoinducers responsible for QS activity and other QS inhibitors, we hypothesize that beta-keto esters with aryl functionality could possess anti-QS activity. A panel of nineteen beta-keto ester analogs was tested for the inhibition of bioluminescence (a QS-controlled phenotype) in the marine pathogen Vibrio harveyi. Initial screening demonstrated the need of a phenyl ring at the C-3 position for antagonistic activity. Further additions to the phenyl ring with 4-substituted halo groups or a 3- or 4-substituted methoxy group resulted in the most active compounds with IC50 values ranging from 23 uM to 53 uM. The compounds additionally inhibit green fluorescent protein production by E. coli JB525. Evidence is presented that aryl beta-keto esters may act as antagonists of bacterial quorum sensing by competing with N-acyl homoserine lactones for receptor binding. Expansion of the beta-keto ester panel will enable us to obtain more insight into the structure-activity relationships needed to allow for the development of novel anti-virulence agents. PMID- 27463708 TI - Influences of Electromagnetic Energy on Bio-Energy Transport through Protein Molecules in Living Systems and Its Experimental Evidence. AB - The influences of electromagnetic fields (EMFs) on bio-energy transport and its mechanism of changes are investigated through analytic and numerical simulation and experimentation. Bio-energy transport along protein molecules is performed by soliton movement caused by the dipole-dipole electric interactions between neighboring amino acid residues. As such, EMFs can affect the structure of protein molecules and change the properties of the bio-energy transported in living systems. This mechanism of biological effect from EMFs involves the amino acid residues in protein molecules. To study and reveal this mechanism, we simulated numerically the features of the movement of solitons along protein molecules with both a single chain and with three channels by using the Runge Kutta method and Pang's soliton model under the action of EMFs with the strengths of 25,500, 51,000, 76,500, and 102,000 V/m in the single-chain protein, as well as 17,000, 25,500, and 34,000 V/m in the three-chain protein, respectively. Results indicate that electric fields (EFs) depress the binding energy of the soliton, decrease its amplitude, and change its wave form. Also, the soliton disperses at 102,000 V/m in a single-chain protein and at 25,500 and 34,000 V/m in three-chain proteins. These findings signify that the influence of EMFs on the bio-energy transport cannot be neglected; however, these variations depend on both the strength and the direction of the EF in the EMF. This direction influences the biological effects of EMF, which decrease with increases in the angle between the direction of the EF and that of the dipole moment of amino acid residues; however, randomness at the macroscopic level remains. Lastly, we experimentally confirm the existence of a soliton and the validity of our conclusion by using the infrared spectra of absorption of the collagens, which is activated by another type of EF. Thus, we can affirm that both the described mechanism and the corresponding theory are correct and that EMFs or EFs can influence the features of energy transport in living systems and thus have certain biological effects. PMID- 27463709 TI - Expression Analysis of PIN Genes in Root Tips and Nodules of Medicago truncatula. AB - Polar auxin transport is dependent on the family of PIN-formed proteins (PINs), which are membrane transporters of anionic indole-3-acetic acid (IAA(-)). It is assumed that polar auxin transport may be essential in the development and meristematic activity maintenance of Medicago truncatula (M. truncatula) root nodules. However, little is known about the involvement of specific PIN proteins in M. truncatula nodulation. Using real-time quantitative PCR, we analyzed the expression patterns of all previously identified MtPIN genes and compared them between root nodules and root tips of M. truncatula. Our results demonstrated significant differences in the expression level of all 11 genes (MtPIN1-MtPIN11) between examined organs. Interestingly, MtPIN9 was the only PIN gene with higher expression level in root nodules compared to root tips. This result is the first indication of PIN9 transporter potential involvement in M. truncatula nodulation. Moreover, relatively high expression level in root nodules was attributed to MtPINs encoding orthologs of Arabidopsis thaliana PIN5 subclade. PIN proteins from this subclade have been found to localize in the endoplasmic reticulum, which may indicate that the development and meristematic activity maintenance of M. truncatula root nodules is associated with intracellular homeostasis of auxins level and their metabolism in the endoplasmic reticulum. PMID- 27463710 TI - Non-Ligand-Induced Dimerization is Sufficient to Initiate the Signalling and Endocytosis of EGF Receptor. AB - The binding of epidermal growth factor (EGF) to EGF receptor (EGFR) stimulates cell mitogenesis and survival through various signalling cascades. EGF also stimulates rapid EGFR endocytosis and its eventual degradation in lysosomes. The immediate events induced by ligand binding include receptor dimerization, activation of intrinsic tyrosine kinase and autophosphorylation. However, in spite of intensified efforts, the results regarding the roles of these events in EGFR signalling and internalization is still very controversial. In this study, we constructed a chimeric EGFR by replacing its extracellular domain with leucine zipper (LZ) and tagged a green fluorescent protein (GFP) at its C-terminus. We showed that the chimeric LZ-EGFR-GFP was constitutively dimerized. The LZ-EGFR GFP dimer autophosphorylated each of its five well-defined C-terminal tyrosine residues as the ligand-induced EGFR dimer does. Phosphorylated LZ-EGFR-GFP was localized to both the plasma membrane and endosomes, suggesting it is capable of endocytosis. We also showed that LZ-EGFR-GFP activated major signalling proteins including Src homology collagen-like (Shc), extracellular signal-regulated kinase (ERK) and Akt. Moreover, LZ-EGFR-GFP was able to stimulate cell proliferation. These results indicate that non-ligand induced dimerization is sufficient to activate EGFR and initiate cell signalling and EGFR endocytosis. We conclude that receptor dimerization is a critical event in EGF-induced cell signalling and EGFR endocytosis. PMID- 27463711 TI - Role of Lipids in the Onset, Progression and Treatment of Periodontal Disease. A Systematic Review of Studies in Humans. AB - The risk of different oral problems (root caries, tooth mobility, and tooth loss) can be increased by the presence of periodontal disease, which has also been associated with a growing list of systemic diseases. The presence of some bacteria is the primary etiology of this disease; a susceptible host is also necessary for disease initiation. In this respect, the progression of periodontal disease and healing of the periodontal tissues can be modulated by nutritional status. To clarify the role of lipids in the establishment, progression, and/or treatment of this pathology, a systematic review was conducted of English-written literature in PubMed until May 2016, which included research on the relationship of these dietary components with the onset and progression of periodontal disease. According to publication type, randomized-controlled trials, cohort, case-control and cross-sectional studies were included. Among all the analyzed components, those that have any effect on oxidative stress and/or inflammation seem to be the most interesting according to current evidence. On one hand, there is quite a lot of information in favor of a positive role of n-3 fatty acids, due to their antioxidant and immunomodulatory effects. On the other hand, saturated fat-rich diets increase oxidative stress as well the as intensity and duration of inflammatory processes, so they must be avoided. PMID- 27463712 TI - Moracin C, A Phenolic Compound Isolated from Artocarpus heterophyllus, Suppresses Lipopolysaccharide-Activated Inflammatory Responses in Murine Raw264.7 Macrophages. AB - Artocarpus heterophyllus, a popular tropical fruit commonly known as the jackfruit tree, is normally planted in subtropical or tropical areas. Since a variety of phytochemicals isolated from A. heterophyllus have been found to possess potently anti-inflammatory, antiviral and antimalarial activities, researchers have devoted much interest to its potential pharmaceutical value. However, the exact mechanism underlying its anti-inflammatory activity is not well characterized. In this study, seven natural products isolated from A. heterophyllus, including 25-Hydroxycycloart-23-en-3-one (HY), Artocarpin (AR), Dadahol A (DA), Morachalcone A (MA), Artoheterophyllin B (AB), Cycloheterophyllin (CY) and Moracin C (MC) were collected. Lipopolysaccharide (LPS)-stimulated inflammatory response in RAW264.7 macrophages were used in this study. Among these compounds, MC significantly inhibited LPS-activated reactive oxygen species (ROS) and nitric oxide (NO) release without marked cytotoxicity. Furthermore, MC effectively reduced LPS stimulated up-regulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and serval pro-inflammatory cytokines (interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha)). Mechanistic studies revealed that the anti-inflammatory effect of MC was associated with the activation of the mitogen activated protein kinases (MAPKs) (including p38, ERK and JNK) and nuclear factor-kappaB (NF-kappaB) pathways, especially reducing the nuclear translocation of NF-kappaB p65 subunit as revealed by nuclear separation experiment and confocal microscopy. PMID- 27463713 TI - Anti-Diabetic Effect of Portulaca oleracea L. Polysaccharideandits Mechanism in Diabetic Rats. AB - Diabetes mellitus (DM) is a metabolic syndrome caused by multiple genetic and environmental factors. Traditional Chinese medicine preparations have shown a comprehensive and function-regulating characteristic. Purslane (Portulaca oleracea L.) is an annual succulent herb. Currently, there have been some related reports on the treatment of diabetes with purslane. The current study was designed to separate and purify the polysaccharide, a systematic study of its physical and chemical properties, antioxidant activity, and anti-diabetic mechanism, in order to provide a theoretical basis for the development of drugs of purslane. A crude water soluble polysaccharide extracted from purslane was named CPOP (crude Portulaca oleracea L. polysaccharide). Effects of CPOP on bodyweight, glucose tolerance test (GTT), fasting blood glucose (FBG), fasting serum insulin (FINS), insulin sensitivity index (ISI), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), methane dicarboxylic aldehyde (MDA), and superoxygen dehydrogenises (SOD) were investigated. The results indicate that the oral administration of CPOP could significantly increase the body weight and significantly improve the glucose tolerance in diabetic rats. Meanwhile, CPOP could significantly reduce the FBG level, and elevate the FINS level and ISI value in diabetic rats. In addition, CPOP could significantly reduce TNF-alpha and IL-6 levels in diabetic rats; CPOP could also reduce MDA and SOD activities in the liver tissue of diabetic rats. These results suggest that the anti diabetic effect of CPOP may be associated with its antioxidant and anti inflammatory effects. PMID- 27463714 TI - Real Time 3D Facial Movement Tracking Using a Monocular Camera. AB - The paper proposes a robust framework for 3D facial movement tracking in real time using a monocular camera. It is designed to estimate the 3D face pose and local facial animation such as eyelid movement and mouth movement. The framework firstly utilizes the Discriminative Shape Regression method to locate the facial feature points on the 2D image and fuses the 2D data with a 3D face model using Extended Kalman Filter to yield 3D facial movement information. An alternating optimizing strategy is adopted to fit to different persons automatically. Experiments show that the proposed framework could track the 3D facial movement across various poses and illumination conditions. Given the real face scale the framework could track the eyelid with an error of 1 mm and mouth with an error of 2 mm. The tracking result is reliable for expression analysis or mental state inference. PMID- 27463715 TI - System Description and First Application of an FPGA-Based Simultaneous Multi Frequency Electrical Impedance Tomography. AB - A new prototype of a multi-frequency electrical impedance tomography system is presented. The system uses a field-programmable gate array as a main controller and is configured to measure at different frequencies simultaneously through a composite waveform. Both real and imaginary components of the data are computed for each frequency and sent to the personal computer over an ethernet connection, where both time-difference imaging and frequency-difference imaging are reconstructed and visualized. The system has been tested for both time-difference and frequency-difference imaging for diverse sets of frequency pairs in a resistive/capacitive test unit and in self-experiments. To our knowledge, this is the first work that shows preliminary frequency-difference images of in-vivo experiments. Results of time-difference imaging were compared with simulation results and shown that the new prototype performs well at all frequencies in the tested range of 60 kHz-960 kHz. For frequency-difference images, further development of algorithms and an improved normalization process is required to correctly reconstruct and interpreted the resulting images. PMID- 27463716 TI - A Sensor Array for the Detection and Discrimination of Methane and Other Environmental Pollutant Gases. AB - We address the sensitive detection and discrimination of gases impacting the environment, such as CH4, NH3, SO2, and CO, using a sensor array and aided by principal component analysis (PCA). A 32-element chemiresistive sensor array consisting of nine different sensor materials including seven types of modified single-walled carbon nanotubes and two types of polymers has been constructed. PCA results demonstrate excellent discriminating ability of the chemiresistor sensor chip in the 1-30 ppm concentration range. The accuracy of the sensor was verified against data collected using cavity ring down spectroscopy. The sensor chip has also been integrated with a smartphone and has been shown to reproduce the sensing performance obtained with the laboratory measurement system. PMID- 27463717 TI - A Network Coverage Information-Based Sensor Registry System for IoT Environments. AB - The Internet of Things (IoT) is expected to provide better services through the interaction of physical objects via the Internet. However, its limitations cause an interoperability problem when the sensed data are exchanged between the sensor nodes in wireless sensor networks (WSNs), which constitute the core infrastructure of the IoT. To address this problem, a Sensor Registry System (SRS) is used. By using a SRS, the information of the heterogeneous sensed data remains pure. If users move along a road, their mobile devices predict their next positions and obtain the sensed data for that position from the SRS. If the WSNs in the location in which the users move are unstable, the sensed data will be lost. Consider a situation where the user passes through dangerous areas. If the user's mobile device cannot receive information, they cannot be warned about the dangerous situation. To avoid this, two novel SRSs that use network coverage information have been proposed: one uses OpenSignal and the other uses the probabilistic distribution of the users accessing SRS. The empirical study showed that the proposed method can seamlessly provide services related to sensing data under any abnormal circumstance. PMID- 27463718 TI - Computation and Communication Evaluation of an Authentication Mechanism for Time Triggered Networked Control Systems. AB - In modern networked control applications, confidentiality and integrity are important features to address in order to prevent against attacks. Moreover, network control systems are a fundamental part of the communication components of current cyber-physical systems (e.g., automotive communications). Many networked control systems employ Time-Triggered (TT) architectures that provide mechanisms enabling the exchange of precise and synchronous messages. TT systems have computation and communication constraints, and with the aim to enable secure communications in the network, it is important to evaluate the computational and communication overhead of implementing secure communication mechanisms. This paper presents a comprehensive analysis and evaluation of the effects of adding a Hash-based Message Authentication (HMAC) to TT networked control systems. The contributions of the paper include (1) the analysis and experimental validation of the communication overhead, as well as a scalability analysis that utilizes the experimental result for both wired and wireless platforms and (2) an experimental evaluation of the computational overhead of HMAC based on a kernel level Linux implementation. An automotive application is used as an example, and the results show that it is feasible to implement a secure communication mechanism without interfering with the existing automotive controller execution times. The methods and results of the paper can be used for evaluating the performance impact of security mechanisms and, thus, for the design of secure wired and wireless TT networked control systems. PMID- 27463719 TI - An Analysis on Sensor Locations of the Human Body for Wearable Fall Detection Devices: Principles and Practice. AB - Wearable devices for fall detection have received attention in academia and industry, because falls are very dangerous, especially for elderly people, and if immediate aid is not provided, it may result in death. However, some predictive devices are not easily worn by elderly people. In this work, a huge dataset, including 2520 tests, is employed to determine the best sensor placement location on the body and to reduce the number of sensor nodes for device ergonomics. During the tests, the volunteer's movements are recorded with six groups of sensors each with a triaxial (accelerometer, gyroscope and magnetometer) sensor, which is placed tightly on different parts of the body with special straps: head, chest, waist, right-wrist, right-thigh and right-ankle. The accuracy of individual sensor groups with their location is investigated with six machine learning techniques, namely the k-nearest neighbor (k-NN) classifier, Bayesian decision making (BDM), support vector machines (SVM), least squares method (LSM), dynamic time warping (DTW) and artificial neural networks (ANNs). Each technique is applied to single, double, triple, quadruple, quintuple and sextuple sensor configurations. These configurations create 63 different combinations, and for six machine learning techniques, a total of 63 * 6 = 378 combinations is investigated. As a result, the waist region is found to be the most suitable location for sensor placement on the body with 99.96% fall detection sensitivity by using the k-NN classifier, whereas the best sensitivity achieved by the wrist sensor is 97.37%, despite this location being highly preferred for today's wearable applications. PMID- 27463720 TI - Optical Analog to Electromagnetically Induced Transparency in Cascaded Ring Resonator Systems. AB - The analogue of electromagnetically induced transparency in optical methods has shown great potential in slow light and sensing applications. Here, we experimentally demonstrated a coupled resonator induced transparency system with three cascaded ring coupled resonators in a silicon chip. The structure was modeled by using the transfer matrix method. Influences of various parameters including coupling ratio of couplers, waveguide loss and additional loss of couplers on transmission characteristic and group index have been investigated theoretically and numerically in detail. The transmission character of the system was measured by the vertical grating coupling method. The enhanced quality factor reached 1.22 * 105. In addition, we further test the temperature performance of the device. The results provide a new method for the manipulation of light in highly integrated optical circuits and sensing applications. PMID- 27463721 TI - Wideband Fully-Programmable Dual-Mode CMOS Analogue Front-End for Electrical Impedance Spectroscopy. AB - This paper presents a multi-channel dual-mode CMOS analogue front-end (AFE) for electrochemical and bioimpedance analysis. Current-mode and voltage-mode readouts, integrated on the same chip, can provide an adaptable platform to correlate single-cell biosensor studies with large-scale tissue or organ analysis for real-time cancer detection, imaging and characterization. The chip, implemented in a 180-nm CMOS technology, combines two current-readout (CR) channels and four voltage-readout (VR) channels suitable for both bipolar and tetrapolar electrical impedance spectroscopy (EIS) analysis. Each VR channel occupies an area of 0.48 mm 2 , is capable of an operational bandwidth of 8 MHz and a linear gain in the range between -6 dB and 42 dB. The gain of the CR channel can be set to 10 kOmega, 50 kOmega or 100 kOmega and is capable of 80-dB dynamic range, with a very linear response for input currents between 10 nA and 100 MU A. Each CR channel occupies an area of 0.21 mm 2 . The chip consumes between 530 MU A and 690 MU A per channel and operates from a 1.8-V supply. The chip was used to measure the impedance of capacitive interdigitated electrodes in saline solution. Measurements show close matching with results obtained using a commercial impedance analyser. The chip will be part of a fully flexible and configurable fully-integrated dual-mode EIS system for impedance sensors and bioimpedance analysis. PMID- 27463722 TI - Spatiotemporal Interpolation Methods for the Application of Estimating Population Exposure to Fine Particulate Matter in the Contiguous U.S. and a Real-Time Web Application. AB - Appropriate spatiotemporal interpolation is critical to the assessment of relationships between environmental exposures and health outcomes. A powerful assessment of human exposure to environmental agents would incorporate spatial and temporal dimensions simultaneously. This paper compares shape function (SF) based and inverse distance weighting (IDW)-based spatiotemporal interpolation methods on a data set of PM2.5 data in the contiguous U.S. Particle pollution, also known as particulate matter (PM), is composed of microscopic solids or liquid droplets that are so small that they can get deep into the lungs and cause serious health problems. PM2.5 refers to particles with a mean aerodynamic diameter less than or equal to 2.5 micrometers. Based on the error statistics results of k-fold cross validation, the SF-based method performed better overall than the IDW-based method. The interpolation results generated by the SF-based method are combined with population data to estimate the population exposure to PM2.5 in the contiguous U.S. We investigated the seasonal variations, identified areas where annual and daily PM2.5 were above the standards, and calculated the population size in these areas. Finally, a web application is developed to interpolate and visualize in real time the spatiotemporal variation of ambient air pollution across the contiguous U.S. using air pollution data from the U.S. Environmental Protection Agency (EPA)'s AirNow program. PMID- 27463723 TI - Potential Harmful Effects of PM2.5 on Occurrence and Progression of Acute Coronary Syndrome: Epidemiology, Mechanisms, and Prevention Measures. AB - The harmful effects of particulate matter with an aerodynamic diameter of <2.5 um (PM2.5) and its association with acute coronary syndrome (ACS) has gained increased attention in recent years. Significant associations between PM2.5 and ACS have been found in most studies, although sometimes only observed in specific subgroups. PM2.5-induced detrimental effects and ACS arise through multiple mechanisms, including endothelial injury, an enhanced inflammatory response, oxidative stress, autonomic dysfunction, and mitochondria damage as well as genotoxic effects. These effects can lead to a series of physiopathological changes including coronary artery atherosclerosis, hypertension, an imbalance between energy supply and demand to heart tissue, and a systemic hypercoagulable state. Effective strategies to prevent the harmful effects of PM2.5 include reducing pollution sources of PM2.5 and population exposure to PM2.5, and governments and organizations publicizing the harmful effects of PM2.5 and establishing air quality standards for PM2.5. PM2.5 exposure is a significant risk factor for ACS, and effective strategies with which to prevent both susceptible and healthy populations from an increased risk for ACS have important clinical significance in the prevention and treatment of ACS. PMID- 27463724 TI - Genetic Variations in the Promoter of the APE1 Gene Are Associated with DMF Induced Abnormal Liver Function: A Case-Control Study in a Chinese Population. AB - Acute or long-term exposure to N,N-dimethylformamide (DMF) can induce abnormal liver function. It is well known that DMF is mainly metabolized in the liver and thereby produces reactive oxygen species (ROS). The base excision repair (BER) pathway is regarded as a very important pathway involved in repairing ROS-induced DNA damage. Several studies have explored the associations between GSTM1, GSTT1, CYP2E1 polymorphisms and DMF-induced abnormal liver function; however, little is known about how common hOGG1, XRCC1 and APE1 polymorphisms and DMF induce abnormal liver function. The purpose of this study was to investigate whether the polymorphisms in the hOGG1 (rs159153 and rs2072668), XRCC1 (rs25487, rs25489, and rs1799782), APE1 (rs1130409 and 1760944) genes in the human BER pathway were associated with the susceptibility to DMF-induced abnormal liver function in a Chinese population. These polymorphisms were genotyped in 123 workers with DMF induced abnormal liver function and 123 workers with normal liver function. We found that workers with the APE1 rs1760944 TG/GG genotypes had a reduced risk of abnormal liver function, which was more pronounced in the subgroups that were exposed to DMF for <10 years, exposed to >=10 mg/m3 DMF, never smoked and never drank. In summary, our study supported the hypothesis that the APE1 rs1760944 T > G polymorphism may be associated with DMF-induced abnormal liver function in the Chinese Han population. PMID- 27463725 TI - Multilevel Analysis of Socioeconomic Determinants on Diabetes Prevalence, Awareness, Treatment and Self-Management in Ethnic Minorities of Yunnan Province, China. AB - OBJECTIVES: The objective of this manuscript is to investigate socioeconomic differences in prevalence, awareness, treatment and self-management of diabetes among ethnic minority groups in Yunnan Province, China. METHODS: We conducted a cross-sectional survey in a sample of 5532 Na Xi, Li Su, Dai and Jing Po ethnic minorities. Multilevel modeling was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for diabetes prevalence, as well as the other outcomes. RESULTS: Higher individual educational level was associated with a higher rate of awareness, treatment, adherence to medicines and monitoring of blood glucose (OR = 1.87, 4.89, 4.83, 6.45; 95% CI: 1.26-2.77, 1.87-12.7, 1.95-11.9, 2.23-18.6, respectively). Diabetic respondents with better household assets tended to receive more treatment (OR = 2.81, 95% CI: 1.11-7.12) and to monitor their blood glucose (OR = 3.29, 95% CI: 1.48-7.30). Diabetic patients with better access to medical services were more likely to treat (OR = 7.09, 95% CI: 2.46-20.4) and adhere to medication (OR = 4.14, 95% CI: 1.46-11.7). Income at the contextual level was significantly correlated with diabetes prevalence, treatment and blood glucose monitoring (OR = 1.84, 3.04, 4.34; 95% CI: 1.20-2.83, 1.20-7.73, 1.45 13.0, respectively). CONCLUSIONS: Future diabetes prevention and intervention programs should take both individual and township-level socioeconomic factors into account in the study regions. PMID- 27463726 TI - Zerumbone, a Phytochemical of Subtropical Ginger, Protects against Hyperglycemia Induced Retinal Damage in Experimental Diabetic Rats. AB - Diabetic retinopathy (DR), the most ordinary and specific microvascular complication of diabetes, is a disease of the retina. Zerumbone (ZER) is a monocyclic sesquiterpene compound, and based on reports, it is the predominant bioactive compound from the rhizomes of Zingiber zerumbet. The aim of the current study is to evaluate the protective effect of zerumbone against DR in streptozotocin (STZ)-induced diabetic rats. STZ-diabetic rats were treated with ZER (40 mg/kg) once a day orally for 8 weeks. ZER administration significantly (p < 0.05) lowered the levels of plasma glucose (32.5% +/- 5.7% lower) and glycosylated hemoglobin (29.2% +/- 3.4% lower) in STZ-diabetic rats. Retinal histopathological observations indicated that disarrangement and reduction in thickness of retinal layers were reversed in ZER-treated diabetic rats. ZER downregulated both the elevated levels of advanced glycosylated end products (AGEs) and the higher levels of the receptors for AGEs (RAGE) in retinas of diabetic rats. What's more, ZER significantly (p < 0.05) ameliorated diabetes induced upregulation of tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6. ZER also attenuated overexpression of vascular endothelial growth factor and intercellular adhesion molecule-1, and suppressed activation of nuclear factor (NF)-kappaB and apoptosis in the retinas of STZ-diabetic rats. Our results suggest ZER possesses retinal protective effects, which might be associated with the blockade of the AGEs/RAGE/NF-kappaB pathway and its anti-inflammatory activity. PMID- 27463727 TI - Protection of the Furin Cleavage Site in Low-Toxicity Immunotoxins Based on Pseudomonas Exotoxin A. AB - Recombinant immunotoxins (RITs) are fusions of an Fv-based targeting moiety and a toxin. Pseudomonas exotoxin A (PE) has been used to make several immunotoxins that have been evaluated in clinical trials. Immunogenicity of the bacterial toxin and off-target toxicity have limited the efficacy of these immunotoxins. To address these issues, we have previously made RITs in which the Fv is connected to domain III (PE24) by a furin cleavage site (FCS), thereby removing unneeded sequences of domain II. However, the PE24 containing RITs do not contain the naturally occurring disulfide bond around the furin cleavage sequence, because it was removed when domain II was deleted. This could potentially allow PE24 containing immunotoxins to be cleaved and inactivated before internalization by cell surface furin or other proteases in the blood stream or tumor microenvironment. Here, we describe five new RITs in which a disulfide bond is engineered to protect the FCS. The most active of these, SS1-Fab-DS3-PE24, shows a longer serum half-life than an RIT without the disulfide bond and has the same anti-tumor activity, despite being less cytotoxic in vitro. These results have significance for the production of de-immunized, low toxicity, PE24-based immunotoxins with a longer serum half-life. PMID- 27463729 TI - Biotin Protein Ligase Is a Target for New Antibacterials. AB - There is a desperate need for novel antibiotic classes to combat the rise of drug resistant pathogenic bacteria, such as Staphylococcus aureus. Inhibitors of the essential metabolic enzyme biotin protein ligase (BPL) represent a promising drug target for new antibacterials. Structural and biochemical studies on the BPL from S. aureus have paved the way for the design and development of new antibacterial chemotherapeutics. BPL employs an ordered ligand binding mechanism for the synthesis of the reaction intermediate biotinyl-5'-AMP from substrates biotin and ATP. Here we review the structure and catalytic mechanism of the target enzyme, along with an overview of chemical analogues of biotin and biotinyl-5'-AMP as BPL inhibitors reported to date. Of particular promise are studies to replace the labile phosphoroanhydride linker present in biotinyl-5'-AMP with alternative bioisosteres. A novel in situ click approach using a mutant of S. aureus BPL as a template for the synthesis of triazole-based inhibitors is also presented. These approaches can be widely applied to BPLs from other bacteria, as well as other closely related metabolic enzymes and antibacterial drug targets. PMID- 27463728 TI - Replication Termination: Containing Fork Fusion-Mediated Pathologies in Escherichia coli. AB - Duplication of bacterial chromosomes is initiated via the assembly of two replication forks at a single defined origin. Forks proceed bi-directionally until they fuse in a specialised termination area opposite the origin. This area is flanked by polar replication fork pause sites that allow forks to enter but not to leave. The precise function of this replication fork trap has remained enigmatic, as no obvious phenotypes have been associated with its inactivation. However, the fork trap becomes a serious problem to cells if the second fork is stalled at an impediment, as replication cannot be completed, suggesting that a significant evolutionary advantage for maintaining this chromosomal arrangement must exist. Recently, we demonstrated that head-on fusion of replication forks can trigger over-replication of the chromosome. This over-replication is normally prevented by a number of proteins including RecG helicase and 3' exonucleases. However, even in the absence of these proteins it can be safely contained within the replication fork trap, highlighting that multiple systems might be involved in coordinating replication fork fusions. Here, we discuss whether considering the problems associated with head-on replication fork fusion events helps us to better understand the important role of the replication fork trap in cellular metabolism. PMID- 27463731 TI - Dermoscopic Evaluation of Melanocytic Nevi Changes With Combined Mitogen Activated Protein Kinase Pathway Inhibitors Therapy for Melanoma. PMID- 27463732 TI - Copromyxa laresi n. sp. (Amoebozoa: Tubulinea) and Transfer of Cashia limacoides (Page, 1967) to Copromyxa Zopf, 1885. AB - Five amoeboid organisms of different origin (isolated from fish organs, soil and digestive tract of earthworm) that shared light microscopical and ultrastructural features including type and arrangement of mitochondrial cristae were subjected to phylogenetic analyses based on sequences of SSU rDNA and protein coding genes (actin, cytochrome oxidase I, and eukaryotic elongation factor 2). The reconstruction of multigene phylogeny of the strains studied (i) revealed that they belong to the same single-genus Copromyxa clade; (ii) strongly supported position of Copromyxa cantabrigiensis (syn. Hartmannella cantabrigiensis) within the genus; (iii) together with comparisons of light and electron microscopy data justified reclassification of Cashia limacoides (syn. Vexillifera expectata) to Copromyxa limacoides n. comb., and (iv) justified description of a new species, Copromyxa laresi n. sp. PMID- 27463733 TI - Assessment of sensitivity to change of the European Scleroderma Study Group activity index. AB - OBJECTIVES: The European Scleroderma Study Group (EScSG) activity index meets nearly all the OMERACT-standards of truth, discrimination and feasibility. The sensitivity to change remains to be attested. This study assesses sensitivity to change of the EScSG activity index in patients with early and severe diffuse cutaneous Systemic Sclerosis (dcSSc) treated with rituximab. METHODS: 12-month follow-up (open-label study) of 14 consecutive patients with early dcSSc. Patients received an infusion of two times 1000 mg rituximab at month 0 and 6, together with 100 mg methylprednisolone. Clinical read outs (modified Rodnan skin score [mRSS], lung function and echocardiography) and EScSG activity index were performed at month 0, 3, 6 and 12. Mixed models analyses (MMA) were used to evaluate changes in parameters over time. RESULTS: There was a clinically significant change in skin score with a mean (SD) mRSS of 24.8 (4.44) at baseline and 10.4 (3.12) at month 12 (MMA p<0.001). Also the EScSG activity index decreased significantly, with a mean (SD) of 4.3 (1.79) at baseline and 0.7 (0.83) at month 12 (MMA p<0.001). The estimated mean change of the EScSG activity index was -3.6 (95%CI -4.9; -2.4) over 12 months. Indices of internal organ involvement remained stable throughout the study. CONCLUSIONS: A significant improvement of the EScSG activity index was observed, in line with the significant improvement of the mRSS and the stabilisation of internal organ involvement. To our knowledge, this is the first study to attest sensitivity to change of the EScSG activity index in the subset of 'early' dcSSc. TRIAL REGISTRATION: ClinicalTrials.gov Registration, http://clinicaltrials.gov, number NCT00379431. PMID- 27463734 TI - Treatment and Outcomes of Acute Myocardial Infarction Complicated by Shock After Public Reporting Policy Changes in New York. AB - IMPORTANCE: In 2006, New York began excluding patients with cardiogenic shock from the publicly reported percutaneous coronary intervention (PCI) risk-adjusted mortality analyses. OBJECTIVE: To examine the effects of the New York shock exclusion policy change on rates of revascularization and mortality for patients with acute myocardial infarction (AMI) complicated by cardiogenic shock. DESIGN, SETTING, AND PARTICIPANTS: This study used several comprehensive statewide hospitalization databases to identify patients with AMI and shock from January 1, 2002, through December 31, 2012, in New York and a series of comparator states (Massachusetts, Michigan, and New Jersey from January 1, 2002, through December 31, 2012, and California from January 1, 2003, through December 31, 2011). Data analysis was performed from October 1, 2015, to March 15, 2016. MAIN OUTCOMES AND MEASURES: A difference-in-differences approach was used to evaluate whether the likelihood of receiving PCI and surviving to discharge differed after the policy change in New York in 2006 compared with comparator states that did not enact such a change. RESULTS: Among 45 977 patients with AMI and cardiogenic shock (11 298 in New York), 21 974 (47.8%) underwent PCI. The mean (SD) age of the patients was 69.7 (13.2) years, and 18 139 (39.5%) were female. After adjusting for patient factors, patients in New York were significantly more likely to undergo PCI after the public reporting policy changes than they were previously (adjusted relative risk [aRR], 1.28; 95% CI, 1.19-1.37; P < .001) compared with a 9% increase in comparator states during the same period (aRR, 1.09; 95% CI, 1.05 1.13; P < .001; interaction P < .001). Nevertheless, rates of PCI remained lower in New York compared with comparator states throughout the study period. The adjusted risk of in-hospital death among patients in New York with AMI and shock decreased significantly faster after the policy change (aRR, 0.76; 95% CI, 0.72 0.81; P < .001) compared with comparator states (aRR, 0.91; 95% CI, 0.87-0.94; P < .001; interaction P < .001). CONCLUSIONS AND RELEVANCE: The exclusion of patients with ongoing cardiogenic shock from New York PCI public reports in 2006 was associated with a significant increase in the use of PCI for cardiogenic shock and a concomitant decrease in in-hospital mortality, exceeding simultaneously observed trends in the comparator states. However, rates of PCI for AMI and shock were lower in New York throughout the study. Alterations in policies related to reporting mortality outcomes after cardiovascular procedures may have significant implications for physician behavior and the public health. PMID- 27463735 TI - Improved persistence with non-vitamin-K oral anticoagulants compared with warfarin in patients with atrial fibrillation: recent Australian experience. AB - OBJECTIVE: Long-term anticoagulant therapy in patients with non-valvular atrial fibrillation (AF) is essential to prevent thromboembolic complications, especially ischemic stroke, but treatment persistence with warfarin is poor. This study examines Australian nationwide persistence in AF patients using a non vitamin-K oral anticoagulant (NOAC) drug. RESEARCH DESIGN AND METHODS: We assessed national Pharmaceutical Benefit Scheme records November-December 2013 through March 2015 for prescription of NOAC drugs in a 10% random sample of long term concession card holders. An historical comparison was made with patients prescribed warfarin in 2008. Key outcome measures were (i) the proportion not filling first repeat prescription and (ii) discontinuation within 12 months. RESULTS: A total of 1471 patients with AF were new users of a NOAC drug (228 apixaban, 645 dabigatran, 598 rivaroxaban) and 1348 were new users of warfarin. Mean age on a NOAC was 76 years (58% male), on warfarin 74 years (54% male). Only 9% (95% CI 7-10) failed to collect the first repeat prescription on a NOAC, 30% (27-32) discontinued within 12 months; corresponding proportions on warfarin were 14% (12-16) and 62% (60-65). In a regression model adjusted for age, gender, heart failure, hypertension and diabetes, warfarin-treated patients were 2.5 times more likely to discontinue over 12 months than those who were NOAC treated (hazard ratio =2.47 [95% CI 2.19-2.79]). CONCLUSIONS: Persistence with NOAC drugs in patients with AF appears to be superior to warfarin. If continued long-term, this alone will be of clinical importance in the prevention of stroke and death. PMID- 27463736 TI - GDNF From Human Periodontal Ligament Cells Treated With Pro-Inflammatory Cytokines Promotes Neurocytic Differentiation of PC12 Cells. AB - Glial cell line-derived neurotrophic factor (GDNF) is known to mediate multiple biological activities such as promotion of cell motility and proliferation, and morphogenesis. However, little is known about its effects on periodontal ligament (PDL) cells. Recently, we reported that GDNF expression is increased in wounded rat PDL tissue and human PDL cells (HPDLCs) treated with pro-inflammatory cytokines. Here, we investigated the associated expression of GDNF and the pro inflammatory cytokine interleukin-1 beta (IL-1beta) in wounded PDL tissue, and whether HPDLCs secrete GDNF which affects neurocytic differentiation. Rat PDL cells near the wounded area showed intense immunoreactions against an anti-GDNF antibody, where immunoreactivity was also increased against an anti-IL-1beta antibody. Compared with untreated cells, HPDLCs treated with IL-1beta or tumor necrosis factor-alpha showed an increase in the secretion of GDNF protein. Conditioned medium of IL-1beta-treated HPDLCs (IL-1beta-CM) increased neurite outgrowth of PC12 rat adrenal pheochromocytoma cells. The expression levels of two neural regeneration-associated genes, growth-associated protein-43 (Gap-43), and small proline-rich repeat protein 1A (Sprr1A), were also upregulated in IL 1beta-CM-treated PC12 cells. These stimulatory effects of IL-1beta-CM were significantly inhibited by a neutralizing antibody against GDNF. In addition, U0126, a MEK inhibitor, inhibited GDNF-induced neurite outgrowth of PC12 cells. These findings suggest that an increase of GDNF in wounded PDL tissue might play an important role in neural regeneration probably via the MEK/ERK signaling pathway. J. Cell. Biochem. 118: 699-708, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27463738 TI - Targeting the fungal calcium-calcineurin signaling network in overcoming drug resistance. PMID- 27463740 TI - Scanning sports. PMID- 27463737 TI - TLR2 promotes macrophage recruitment and Streptococcus pneumoniae clearance during mouse otitis media. AB - BACKGROUND: The natural course of otitis media (OM) in most children is acute and self-limiting; however, approximately 10-20% of children can experience persistent or recurrent OM. Determining the host factors that influence outcome of OM will help us design better therapies. This study focused on the role of Toll-like receptor 2 (TLR2) in a pneumococcal OM mouse model. METHODS: The middle ears (MEs) of wild-type (WT) and TLR2-/- mice were inoculated with Streptococcus pneumoniae (Spn) serotype 19F via transbullar injection. ME TLR2 expression in WT mice was determined by qRT-PCR and immunofluorescence. ME pathological manifestations, inflammatory response, and pneumococcal clearance between WT and TLR2-/- mice were compared after Spn inoculation. RESULTS: TLR2 expression in ME mucosa was markedly enhanced following infection with Spn in WT mice. In contrast to WT mice, TLR2-/- mice exhibited unaffected early ME inflammatory response. During late stage of ME infection, however, the absence of TLR2 can lead to reduced macrophage recruitment, impaired Spn clearance, and prolonged ME inflammation. CONCLUSION: Our results demonstrate that TLR2 signaling is critical for bacterial clearance and timely resolution of inflammation in OM induced by Spn. PMID- 27463741 TI - Coming in sportsmedicine. PMID- 27463744 TI - What Do We Know About Sports Injuries? PMID- 27463743 TI - sportsmedicine forum. AB - A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your Ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Sportsmedicine Forum, The Physician and Sportsmedicine, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27463746 TI - 1987 Annual Meeting of the American College of Sports Medicine. PMID- 27463747 TI - The Eureka Experience. PMID- 27463748 TI - Noteworthy. PMID- 27463749 TI - The Benefits of Health Maintenance. AB - In brief: Despite major medical advances, life expectancy has increased relatively little over the past 35 years. Most of today's serious illnesses are related to such chronic conditions as heart disease, cancer, and arteriosclerosis, rather than to acute infectious diseases. These chronic diseases affect the national economy as well as the health of individuals. Many authorities believe that 50% to 80% of the deaths related to these conditions could be prevented or postponed through proper nutrition, weight control, exercise, smoking cessation, and stress management. Accordingly, physicians should take a more active role in disease prevention efforts. A procedure for physicians to use in health assessment and risk management for M individual patients is outlined. PMID- 27463750 TI - Avulsion Fracture of the Anterior Calcaneal Process. AB - In brief: Avulsion fractures of the anterior cal-caneal process involving the extensor digitorum brevis do not occur often. However, it is important to consider this entity in athletes who have sustained ankle injuries. This injury can easily be overlooked and misdiagnosed as a sprained ankle. While the cause of this injury (supination/inversion forces) and its symptoms are essentially the same as those of a sprained ankle, maximal tenderness is usually confined to the area below the anterior talofibular ligament. Conservative treatment is recommended in most cases; however, surgical intervention occasionally may be necessary to treat large avulsed fragments or malunions. PMID- 27463751 TI - How I Manage Acute Anterior Shoulder Dislocations. AB - In brief: Anterior shoulder dislocations occur as a result of indirect as well as direct forces and are common in contact sports. Although diagnosis is usually easy, x-rays should be obtained to confirm the diagnosis and rule out associated fractures. The authors present the guidelines they follow in treating this problem. In addition, they discuss complications that may follow a dislocation or its reduction, including fracture, vascular or neural injury, and recurrent dislocation. PMID- 27463752 TI - Training, Experience, and Medical History of Pairs Skaters. AB - In brief: Little research has been done on the injuries sustained by competitive figure skaters, and none on injuries to pairs skaters in particular. This study is an attempt to systematically address injuries to pairs skaters. Fourteen pairs skaters, nine of whom were nationally ranked, completed questionnaires about their training, experience, and medical history. The results showed that males tended to have pain in the shoulders, wrists, and back, while females had pain in the hips and feet. These differences could be related to the different demands on males and females when performing lifts and throws. The results also indicated that males had more injuries than females in singles skating, while females had more injuries in pairs skating. PMID- 27463753 TI - Adult Participation in Physical Activities Requiring Moderate to High Levels of Energy Expenditure. AB - In brief: Despite claims that 100 million American adults swim, 75 million bicycle, and 35 million jog, evidence suggests that these figures do not accurately indicate how many exercise on a regular basis. This paper provides interview data on the physical-activity behavior of 15,381 American adults. Projections based on the results of those interviews indicate that during 1984, approximately 77 million adults (almost 53%) participated at least once in moderate to high levels of physical activity, but only about 27 million (18.6%) were active on more than 60 days. The US Department of Health and Human Services has set a goal of having 60% of adults engaging regularly in vigorous forms of activity by 1990. These data should be helpful in providing some notion as to how close we are to this goal. PMID- 27463754 TI - How Does Heredity Affect Athletic Performance? AB - Research on twins is providing clues to the heritability of natural athletic talent, adaptability to training, and even the psychological makeup needed to compete successfully in a given sport. PMID- 27463755 TI - Sugarbush Summer. AB - Skiers may flock to the slopes of Vermont's Sugarbush Mountain, but summertime visitors will find plenty to do as well. PMID- 27463756 TI - Plan for Accrediting Fellowships Worries Sports Orthopedists. AB - A process for accrediting postresident fellowships in orthopedic sports medicine may be in place by the middle of next year. But as currently formulated, the accreditation requirements would shut out fellowships that are not connected with a residency program. PMID- 27463757 TI - Are Playground Injuries Inevitable? AB - Some physicians and equipment designers are saying that traditional playgrounds are dangerous places for children to play. New designs may improve safety. PMID- 27463759 TI - Where to Turn for Sports Injury Statistics. PMID- 27463758 TI - The Cincinnati Academy of Physical Education: Using Fitness to Aid Learning. AB - A Cincinnati public school mixes a healthy dose of activity with a rigorous academic curriculum. The result, school officials hope, will be adults who are both physically and mentally fit. PMID- 27463761 TI - What Is Exercise Capacity? PMID- 27463763 TI - RGD-Targeted Liposome Binding and Uptake on Breast Cancer Cells Is Dependent on Elastin Linker Secondary Structure. AB - The linker between the targeting moiety and the nanoparticle is often overlooked when engineering targeted drug delivery vehicles. We hypothesized that pH triggered conformational changes of an elastin-like peptide (ELP) linker, with repeating VPGVG sequences, could alter the binding affinity of the well established targeting moiety arginine-glycine-aspartic acid (RGD), which is known to enhance the delivery of nanoparticles to tumor cells via integrin overexpression. The pH change from blood (pH 7.4) to the tumor environment (pH 6) was used to elicit a conformational change in the ELP linker, as described by circular dichroism. Atomic force microscopy confirmed that RGD-ELP resulted in stronger adhesion to both MDA-MB-231 and HCC1806 breast cancer cells at pH 6 relative to pH 7.4. No change in adhesion force was measured as a function of pH for the non-neoplastic MCF-10A cell line and the nontargeting GDR-ELP peptide. This translated to significant binding and uptake of RGD-ELP modified liposomes at pH 6.0 relative to pH 7.4. These results indicate that the pH-triggered conformational structure of the ELP linker shifts RGD-mediated cancer cell targeting from non-active (pH 7.4) to active (pH 6). The reversible shift in ELP secondary structure may be used to engineer targeted drug delivery vehicles with tunable uptake. PMID- 27463764 TI - Frontline clinicians' perspectives on and utilization of trauma-focused therapy with individuals with eating disorders. AB - With this study, we sought to survey clinicians regarding their perspectives and use of concurrent or integrated psychotherapy for co-occurring eating disorders (EDs) and posttraumatic stress disorder. We conducted a quantitative survey of 184 frontline ED clinicians to investigate whether, and to what extent, they view concurrent EDs and trauma-focused therapy as clinically important. We also assessed clinicians' specific concerns regarding concurrent EDs and trauma focused treatment, as well as barriers to implementation of an evidence-based concurrent treatment. On the whole, clinicians reported that addressing trauma related symptoms in individuals with EDs is highly important and should be administered concurrently. Although clinicians reported anticipating many important benefits of concurrent treatment, they also reported anticipating several potential negative side effects, and they reported a number of perceived barriers to implementation. Clinicians working in hospital settings anticipated more complications, expected fewer benefits, and perceived more barriers to the administration of concurrent treatment. PMID- 27463765 TI - Beneficial Effects of Lithium on Severe Irritability in a Patient with Rett Syndrome. PMID- 27463766 TI - Block Co-PolyMOCs by Stepwise Self-Assembly. AB - We report a stepwise assembly strategy for the integration of metal-organic cages (MOCs) into block copolymers (BCPs). This approach creates "block co-polyMOC" (BCPMOC) materials whose microscopic structures and mechanical properties are readily tunable by adjusting the size and geometry of the MOCs and the composition of the BCPs. In the first assembly step, BCPs functionalized with a pyridyl ligand on the chain end form star-shaped polymers triggered by metal coordination-induced MOC assembly. The type of MOC junction employed precisely determines the number of arms for the star polymer. In the second step, microphase separation of the BCP is induced, physically cross-linking the star polymers and producing the desired BCPMOC networks in the bulk or gel state. We demonstrate that large spherical M12L24 MOCs, small paddlewheel M2L4 MOCs, or a mixture of both can be incorporated into BCPMOCs to provide materials with tailored branch functionality, phase separation, microdomain spacing, and mechanical properties. Given the synthetic and functional diversity of MOCs and BCPs, our method should enable access to BCPMOCs for a wide range of applications. PMID- 27463767 TI - Apitherapy Products for Medicinal Use. AB - For the past 10 years, beekeeping has increased due to a growing awareness of the disappearance of bees since Colony Collapse Disorder. Most of the disappearance of honey bees can be attributed to the use of pesticides. Apitherapy is the science and art of maintaining health with the use of products from the honeybee hive: honey, bee pollen, propolis, royal jelly, and bee venom. We have been beekeeping for the last 10 years. We use every product from the beehive for both personal and patient use. PMID- 27463768 TI - Formation of Coronene Clusters in Concentration and Temperature Controlled Two Dimensional Porous Network. AB - In this research, with the assistance of scanning tunneling microscopy (STM), we observed the two-dimensional (2D) self-assembly transition of a star-shaped oligofluorene derivative (StOF) from disordered structure to honeycomb network by adjusting StOF concentration in solution. By introducing guest molecules coronene (COR), we for the first time achieved novel triangle-shaped COR trimers on liquid/highly oriented pyrolytic graphite (HOPG) interface in both honeycomb network and the disordered structure. In thermal tests, the COR/StOF-disorder system underwent a structural conformation to form well-ordered ladder structures, while the COR/StOF-honeycomb system remained the perfect hexagonal network with COR trimers included in the cavities. Density functional theory (DFT) calculations have been employed to investigate the forming mechanism of the molecular nanoarrays. These studies are expected to enhance controlling on 2D self-assembly and provide a facial approach toward constructing on-surface molecular clusters. PMID- 27463779 TI - Self-assembly of carbon nanotubes in polymer melts: simulation of structural and electrical behaviour by hybrid particle-field molecular dynamics. AB - Self-assembly processes of carbon nanotubes (CNTs) dispersed in different polymer phases have been investigated using a hybrid particle-field molecular dynamics technique (MD-SCF). This efficient computational method allowed simulations of large-scale systems (up to ~1 500 000 particles) of flexible rod-like particles in different matrices made of bead spring chains on the millisecond time scale. The equilibrium morphologies obtained for longer CNTs are in good agreement with those proposed by several experimental studies that hypothesized a two level "multiscale" organization of CNT assemblies. In addition, the electrical properties of the assembled structures have been calculated using a resistor network approach. The calculated behaviour of the conductivities for longer CNTs is consistent with the power laws obtained by numerous experiments. In particular, according to the interpretation established by the systematic studies of Bauhofer and Kovacs, systems close to "statistical percolation" show exponents t ~ 2 for the power law dependence of the electrical conductivity on the CNT fraction, and systems in which the CNTs reach equilibrium aggregation show exponents t close to 1.7 ("kinetic percolation"). The confinement effects on the assembled structures and their corresponding conductivity behaviour in a non homogeneous matrix, such as the phase separating block copolymer melt, have also been simulated using different starting configurations. The simulations reported herein contribute to a microscopic interpretation of the literature results, and the proposed modelling procedure may contribute meaningfully to the rational design of strategies aimed at optimizing nanomaterials for improved electrical properties. PMID- 27463780 TI - Dissecting the Core Fear in Anorexia Nervosa: Can We Optimize Treatment Mechanisms? PMID- 27463781 TI - C-reactive protein, platelets, and patent ductus arteriosus. AB - The association between inflammation, platelets, and patent ductus arteriosus (PDA) has not been studied so far. The purpose of this study was to evaluate whether C-reactive protein (CRP) is related to low platelet count and PDA. This was a retrospective study of 88 infants with a birth weight <=1500 g and a gestational age <=30 weeks. Platelet count, CRP, and an echocardiogram were assessed in all infants. The subjects were matched by sex, gestational age, and birth weight. Differences were compared using the chi2, t-test, or Mann-Whitney U test, as appropriate. Significant variables were entered into a logistic regression model. The association between CRP and platelets was evaluated by correlation and regression analysis. Platelet count (167 000 vs. 213 000 ul-1, p = 0.015) was lower and the CRP (0.45 vs. 0.20 mg/dl, p = 0.002) was higher, and the platelet count correlated inversely with CRP (r = -0.145, p = 0.049) in the infants with vs. without PDA. Only CRP was independently associated with PDA in a logistic regression model (OR 64.1, 95% confidence interval 1.4-2941, p = 0.033). PMID- 27463782 TI - An Explicit Interpretation of the Directing Group Effect for the Pd(OAc)2 Catalyzed Aromatic C-H Activations. AB - A comprehensive DFT investigation has been performed for a series of the Pd(OAc)2 catalyzed C-H activations, updating and extending the understanding of directing group effect. In the beginning, the directed and undirected C-H activation mechanisms, based on 10 model reactions, have been discussed comparatively, which disclosed that directing group can exert a thermodynamic driving force, not necessarily a kinetic promotion, on the C-H activation process. Formation of the open palladation species via the undirected pathway is thermodynamically unspontaneous (DeltaG = 4-9 kcal/mol), in sharp contrast to that of the cyclopalladation species via the directed pathway (DeltaG < 0). Further calculations revealed that the free-energy barriers of proton-transfer are in fact not so high on the undirected pathway (17-24 kcal/mol), while mediation of some O-center groups in the directed pathway would increase the free-energy barriers of proton-transfer. For pyridine N-oxide systems, the undirected mechanism was estimated to be more plausible than the 4-member-directed one both thermodynamically and kinetically. In addition, the uncommon 7-membered cyclopalladation has been tentatively explored using two current examples, predicting that electron-rich directing groups can help to stabilize the 7 membered palladacycles formed. PMID- 27463783 TI - Large Pulsed Electron Beam Welded Percolation Networks of Silver Nanowires for Transparent and Flexible Electrodes. AB - Mechanical properties of transparent electrodes, including flexibility, are important in flexible electronics for sustaining electrical conductivity under bending with small radius of curvature. Low contact resistance of junctions in metal nanowire percolation networks is the most important factor to produce electrodes with excellent optical, electrical and mechanical performance. Here, we report the fabrication of welded silver nanowire percolation networks using large pulsed electron beam (LPEB) irradiation as a welding process of silver nanowires (AgNWs). It results in modification of electrical and mechanical properties because of the low contact resistance at welded junctions. Consequently, the flexible and transparent AgNW electrodes fabricated by LPEB irradiation showed lower sheet resistance of 12.63 Omega sq(-1) at high transmittance of 93% (at 550 nm), and superb mechanical flexibility, compared with other AgNW electrodes prepared by thermal treatement and without any treatment. Polymer light-emitting diodes (PLEDs) using AgNWs by LPEB irradiation were fabricated to confirm that the AgNW electrode by LPEB irradiation was able to become alternative to indium tin oxide (ITO) and they showed good device performance as a maximum luminous efficiency of 7.37 cd A(-1), and excellent mechanical flexibility under bending with small radius of curvature. PMID- 27463784 TI - Synthesis of figure-of-eight helical bisBODIPY macrocycles and their chiroptical properties. AB - A macrocyclic bisBODIPY (bis(boron-dipyrromethene)) complex [1B2] with a figure of-eight helicity was synthesized and successfully resolved. [1B2] was proven to be one of the most efficient red-emitting CPL (circularly polarized luminescence) fluorophores reported to date (lambda = 663 nm, |glum| = 9 * 10(-3), PhiF = 0.58). PMID- 27463785 TI - Influence of ZrO2, SiO2, Al2O3 and TiO2 nanoparticles on maize seed germination under different growth conditions. AB - The focus of this investigation is to evaluate the phytotoxicity of selected metal oxide nanoparticles and microparticles as a function of maize seed germination and root elongation under different growth conditions (Petri plate, cotton and soil). The results of seed germination and root elongation experiments reveal that all the growth conditions show almost similar results. Alumina (Al2O3) and titania (TiO2) nanoparticles significantly reduce the germination percentage, whereas silica (SiO2) nanoparticles and microparticles enhance the same. The results of nanoparticles and microparticles of zirconia (ZrO2) are found to be same as those of controls. Root elongation is enhanced by SiO2 nanoparticles and microparticles treatment, whereas inhibition is observed with Al2O3 and TiO2 nanoparticles and microparticles. The X-ray fluorescence spectrometry data of the treated and control seed samples show that seeds uptake SiO2 particles to a greater extent followed by TiO2, Al2O3 and ZrO2. In addition, the uptake of nanoparticles is found to be greater than that of microparticles. Thus, the tested metal oxides penetrated seeds at the nanoscale as compared with the microscale. This study clarifies phytotoxicity of nanoparticles treated in different growth substrates and highlights the impact of nanoparticles on environment and agricultural systems. PMID- 27463786 TI - In situ detection of the Zn(2+) release process of ZnO NPs in tumour cells by confocal laser scanning fluorescence microscopy. AB - The use of zinc oxide (ZnO) nanoparticles (NPs) for cancer is not yet clear for human clinical applications, which is primarily due to the lack of a better understanding of the action mechanisms and cellular consequences of the direct exposure of cells to these NPs. In this work, the authors have selected zinquin ethyl ester, a Zn(2+)-specific fluorescent molecular probe, to efficiently differentiate ZnO NPs and Zn(2+), and combined with confocal laser scanning microscopy (CLSM) to in situ study the Zn(2+) release process of ZnO NPs in cancer cell system through detecting the change of Zn(2+) level over time. During the experiments, the authors have designed the test group ZnO-2 in addition to assess the influence of a long-term storage on the characteristics of ZnO NPs in aqueous solution, and the Zn(2+) release process of ZnO NPs in cancer cell system. After three-month storage at room temperature, the release process became earlier and faster, which was consistent with previous results of transmission electron microscope, UV-Vis and PL spectra. It is a good detection method that combination of Zn(2+)-specific fluorescent molecular probe and CLSM, which will be helpful for ZnO NPs using in clinical research. PMID- 27463787 TI - Green synthesis and antimicrobial activity of silver nanoparticles using wild medicinal mushroom Ganoderma applanatum (Pers.) Pat. from Similipal Biosphere Reserve, Odisha, India. AB - In the present study, green synthesis and cost effective approach of silver nanoparticles using wild medicinal mushroom Ganoderma applanatum (Pers.) Pat. from Similipal Biosphere Reserve, Odisha, India is reported. The biosynthesised AgNPs were characterised using UV-visible spectroscopy, particle analyser and scanning electron microscopy studies. It was found by dynamic light scattering analysis, that the average size and charges of the AgNPs were 133.0 +/- 0.361 nm and -6.01 +/- 5.30 mV, respectively. Moreover, the Fourier transform infrared study was also conducted to identify the biomolecules or functional groups responsible for the reduction of Ag and stabilisation of the AgNPs. The potential biomedical application with reference to antimicrobial activity of the synthesised AgNPs was investigated against some pathogenic microorganisms viz. Escherichia coli, Bacillus subtilis, Staphylococcus epidermidis, Vibrio cholerae, Staphylococcus aureus and Shigella flexneri. PMID- 27463788 TI - Gentamicin-gold nanoparticles conjugate: a contrast agent for X-ray imaging of infectious foci due to Staphylococcus aureus. AB - There is no optimal imaging method for the detection of unknown infectious foci in some diseases. This study introduces a novel method in X-ray imaging of infection foci due to Staphylococcus aureus by developing a contrast agent based on gold nanoparticles (GNPs). GNPs in spherical shape were synthesised by the reduction of tetrachloroauric acid with sodium citrate. Then gentamicin was bound directly to citrate functionalised GNPs and the complex was stabilised by polyethylene glycol. The interaction of gentamicin with GNPs was confirmed by ultraviolet-visible and Fourier transform infrared spectroscopies. The stability of complex was studied in human blood up to 6 h. The stability of conjugate was found to be high in human blood with no aggregation. The biodistribution study showed localisation of gentamicin-GNPs conjugate at the site of Staphylococcal infection. The infection site was properly visualised in X-ray images in mouse model using the gentamicin-GNPs conjugate as a contrast agent. The results demonstrated that one may consider the potential of new nanodrug as a contrast agent for X-ray imaging of infection foci in human beings which needs more investigations. PMID- 27463789 TI - Empty nano and micro-structured lipid carriers of virgin coconut oil for skin moisturisation. AB - Virgin coconut oil (VCO) is the finest grade of coconut oil, rich in phenolic content, antioxidant activity and contains medium chain triglycerides (MCTs). In this work formulation, characterisation and penetration of VCO-solid lipid particles (VCO-SLP) have been studied. VCO-SLP were prepared using ultrasonication of molten stearic acid and VCO in an aqueous solution. The electron microscopy imaging revealed that VCO-SLP were solid and spherical in shape. Ultrasonication was performed at several power intensities which resulted in particle sizes of VCO-SLP ranged from 0.608 +/- 0.002 um to 44.265 +/- 1.870 um. The particle size was directly proportional to the applied power intensity of ultrasonication. The zeta potential values of the particles were from -43.2 +/- 0.28 mV to -47.5 +/- 0.42 mV showing good stability. The cumulative permeation for the smallest sized VCO-SLP (0.608 um) was 3.83 +/- 0.01 ug/cm(2) whereas for larger carriers it was reduced (3.59 +/- 0.02 ug/cm(2)). It is concluded that SLP have the potential to be exploited as a micro/nano scale cosmeceutical carrying vehicle for improved dermal delivery of VCO. PMID- 27463790 TI - Comparative antibacterial activity of silver nanoparticles synthesised by biological and chemical routes with pluronic F68 as a stabilising agent. AB - The authors report the comparative antibacterial activity of silver nanoparticles synthesised by biological (using Fusarium oxysporum) and chemical routes in the presence and absence of pluronic F68 as a stabilising agent. The production of silver nanoparticles was evidenced by UV-visible spectra, with absorbance at about 420 nm in the case of both biological and chemical synthesis. X-ray diffraction pattern confirmed the presence of face-centred cubic structure (FCC plane). The nanoparticles characterised by transmission and scanning electron microscopy showed spherical silver nanoparticles with size range of 5-40 and 10 70 nm in the case of biologically and chemically synthesised nanoparticles, respectively. Addition of pluronic F68 showed the stabilisation of silver nanoparticles. Antibacterial efficacy of silver nanoparticles demonstrated different inhibitory activity against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Overall, biologically synthesised silver nanoparticles showed higher activity as compared with chemically synthesised nanoparticles. Silver nanoparticles synthesised in the presence of pluronic F68 by the chemical route exhibited synergism in antibacterial activity as compared with those synthesised without pluronic F68. On the contrary, biogenic silver nanoparticles without pluronic F68 showed higher antibacterial potential. PMID- 27463791 TI - Luteinizing hormone-releasing hormone targeted poly(methyl vinyl ether maleic acid) nanoparticles for doxorubicin delivery to MCF-7 breast cancer cells. AB - The purpose of this study was to design a targeted anti-cancer drug delivery system for breast cancer. Therefore, doxorubicin (DOX) loaded poly(methyl vinyl ether maleic acid) nanoparticles (NPs) were prepared by ionic cross-linking method using Zn(2+) ions. To optimise the effect of DOX/polymer ratio, Zn/polymer ratio, and stirrer rate a full factorial design was used and their effects on particle size, zeta potential, loading efficiency (LE, %), and release efficiency in 72 h (RE72, %) were studied. Targeted NPs were prepared by chemical coating of tiptorelin/polyallylamin conjugate on the surface of NPs by using 1-ethyl-3-(3 dimethylaminopropyl) carboiimid HCl as cross-linking agent. Conjugation efficiency was measured by Bradford assay. Conjugated triptorelin and targeted NPs were studied by Fourier-transform infrared spectroscopy (FTIR). The cytotoxicity of DOX loaded in targeted NPs and non-targeted ones were studied on MCF-7 cells which overexpress luteinizing hormone-releasing hormone (LHRH) receptors and SKOV3 cells as negative LHRH receptors using Thiazolyl blue tetrazolium bromide assay. The best results obtained from NPs prepared by DOX/polymer ratio of 5%, Zn/polymer ratio of 50%, and stirrer rate of 960 rpm. FTIR spectrum confirmed successful conjugation of triptorelin to NPs. The conjugation efficiency was about 70%. The targeted NPs showed significantly less IC50 for MCF-7 cells compared to free DOX and non-targeted NPs. PMID- 27463792 TI - Biogenic synthesis, optimisation and antibacterial efficacy of extracellular silver nanoparticles using novel fungal isolate Aspergillus fumigatus MA. AB - To eliminate the elaborate processes employed in other non-biological-based protocols and low cost production of silver nanoparticles (AgNPs), this study reports biogenic synthesis of AgNPs using silver salt precursor with aqueous extract of Aspergillus fumigates MA. Influence of silver precursor concentrations, concentration ratio of fungal extract and silver nitrate, contact time, reaction temperature and pH are evaluated to find their effects on AgNPs synthesis. Ultraviolet-visible spectra gave surface plasmon resonance at 420 nm for AgNPs. Fourier transform infrared spectroscopy and X-ray diffraction techniques further confirmed the synthesis and crystalline nature of AgNPs, respectively. Transmission electron microscopy observed spherical shapes of synthesised AgNPs within the range of 3-20 nm. The AgNPs showed potent antimicrobial efficacy against various bacterial strains. Thus, the results of the current study indicate that optimisation process plays a pivotal role in the AgNPs synthesis and biogenic synthesised AgNPs might be used against bacterial pathogens; however, it necessitates clinical studies to find out their potential as antibacterial agents. PMID- 27463793 TI - Single-wall and multi-wall carbon nanotubes promote rice root growth by eliciting the similar molecular pathways and epigenetic regulation. AB - Organisms are constantly exposed to environmental stimuli and have evolved mechanisms of protection and adaptation. Various effects of nanoparticles (NPs) on crops have been described and some results confirm that NPs could enhance plant growth at the physiological and genetic levels. This study comparatively analysed the effect of carbon nanotubes (CNTs) on rice growth. The results showed that single-wall CNTs were located in the intercellular space while multi-wall CNTs penetrated cell walls in roots. CNTs could promote rice root growth through the regulation of expression of the root growth related genes and elevated global histone acetylation in rice root meristem zones. These responses were returned to normal levels after CNTs were removed from medium. CNTs caused the similar histone acetylation and methylation statuses across the local promoter region of the Cullin-RING ligases 1 (CRL1) gene and increased micrococcal nuclease accessibility of this region, which enhanced this gene expression. The authors results suggested that CNTs could cause plant responses at the cellular, genetic, and epigenetic levels and these responses were independent on interaction modes between root cells and CNTs. PMID- 27463794 TI - Separation by nanoparticles plasmonic resonance with low stress in microfluidics channel (analytical and design). AB - In this study, nanoparticles near-field plasmonic resonance is used to improve the traditional cell separation main outputs such as viability and efficiency. The live cells viability is severely depend on stresses, which are applied on cells in the microfluidics channel. Hence, for improving the cell viability, the enforced stresses inside of the structure should be declined. The major factors of the enforced stresses are related to the electric field non-uniformity, which are attributed to the hurdles and applied voltage magnitude. Therefore, in this study, a new structure is presented and thereby, the magnitude of the applied stresses on live cells is minimised which is contributed to the decreasing the non-uniformity strength of channel. It should be noted that in the new structure two arrays of nanoparticles were used to produce a short range and localised non uniform electrical field because of their near-field plasmonic resonance. Hence, the enforced stress on the live cell severely decreased at the far-field and confined at the small section of the channel. It is due to, the near-field plasmonic amplitude is dramatically disappeared by increasing distance, hence, the cells far from the nanoparticles will be endured the low level but effective amount of the optical force. PMID- 27463795 TI - Plant-mediated green synthesis of silver nanoparticles using Trifolium resupinatum seed exudate and their antifungal efficacy on Neofusicoccum parvum and Rhizoctonia solani. AB - In recent years, biosynthesis and the utilisation of silver nanoparticles (AgNPs) has become an interesting subject. In this study, the authors investigated the biosynthesis of AgNPs using Trifolium resupinatum (Persian clover) seed exudates. The characterisation of AgNPs were analysed using ultraviolet-visible spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM) and Fourier transform infra-red spectroscopy. Also, antifungal efficacy of biogenic AgNPs against two important plant-pathogenic fungi (Rhizoctonia solani and Neofusicoccum Parvum) in vitro condition was evaluated. The XRD analysis showed that the AgNPs are crystalline in nature and have face-centred cubic geometry. TEM images revealed the spherical shape of the AgNPs with an average size of 17 nm. The synthesised AgNPs were formed at room temperature and kept stable for 4 months. The maximum distributions of the synthesised AgNPs were seen to range in size from 5 to 10 nm. The highest inhibition effect was observed against R. solani at 40 ppm concentration of AgNPs (94.1%) followed by N. parvum (84%). The results showed that the antifungal activity of AgNPs was dependent on the amounts of AgNPs. In conclusion, the AgNPs obtained from T. resupinatum seed exudate exhibit good antifungal activity against the pathogenic fungi R. solani and N. Parvum. PMID- 27463796 TI - Removal of toxic zinc from water/wastewater using eucalyptus seeds activated carbon: non-linear regression analysis. AB - In the present study, a novel activated carbon was prepared from low-cost eucalyptus seeds, which was utilised for the effectively removal of toxic zinc from the water/wastewater. The prepared adsorbent was studied by Fourier transform infrared spectroscopy and scanning electron microscopic characterisation studies. Adsorption process was experimentally performed for optimising the influencing factors such as adsorbent dosage, solution pH, contact time, initial zinc concentration, and temperature for the maximum removal of zinc from aqueous solution. Adsorption isotherm of zinc removal was ensued Freundlich model, and the kinetic model ensued pseudo-second order model. Langmuir monolayer adsorption capacity of the adsorbent for zinc removal was evaluated as 80.37 mg/g. The results of the thermodynamic studies suggested that the adsorption process was exothermic, thermodynamically feasible and impulsive process. Finally, a batch adsorber was planned to remove zinc from known volume and known concentration of wastewater using best obeyed model such as Freundlich. The experimental details showed the newly prepared material can be effectively utilised as a cheap material for the adsorption of toxic metal ions from the contaminated water. PMID- 27463797 TI - Enhanced efficacy of clindamycin hydrochloride encapsulated in PLA/PLGA based nanoparticle system for oral delivery. AB - Clindamycin hydrochloride (CLH) is a clinically important oral antibiotic with wide spectrum of antimicrobial activity that includes gram-positive aerobes (staphylococci, streptococci etc.), most anaerobic bacteria, Chlamydia and certain protozoa. The current study was focused to develop a stabilised clindamycin encapsulated poly lactic acid (PLA)/poly (D,L-lactide-co-glycolide) (PLGA) nano-formulation with better drug bioavailability at molecular level. Various nanoparticle (NPs) formulations of PLA and PLGA loaded with CLH were prepared by solvent evaporation method varying drug: polymer concentration (1:20, 1:10 and 1:5) and characterised (size, encapsulation efficiency, drug loading, scanning electron microscope, differential scanning calorimetry [DSC] and Fourier transform infrared [FTIR] studies). The ratio 1:10 was found to be optimal for a monodispersed and stable nano formulation for both the polymers. NP formulations demonstrated a significant controlled release profile extended up to 144 h (both CLH-PLA and CLH-PLGA). The thermal behaviour (DSC) studies confirmed the molecular dispersion of the drug within the system. The FTIR studies revealed the intactness as well as unaltered structure of drug. The CLH-PLA NPs showed enhanced antimicrobial activity against two pathogenic bacteria Streptococcus faecalis and Bacillus cereus. The results notably suggest that encapsulation of CLH into PLA/PLGA significantly increases the bioavailability of the drug and due to this enhanced drug activity; it can be widely applied for number of therapies. PMID- 27463798 TI - Current opinion: where are we in our understanding and treatment of osteoarthritis? AB - There has been important recent progress in our understanding of the molecular pathology of osteoarthritis (OA) and how it might be treated. New technologies have been developed and others refined to identify patients for recruitment in clinical trials who exhibit measurable progression. Combined with the ability to determine more effectively short-term efficacy of treatment, significant obstacles are being removed that have negated or led to the failure of earlier trials. The future for disease-modifying osteoarthritis drug (DMOAD) development and more effective pain control is therefore much more encouraging. But it is extremely important that these new therapeutic and clinical trial opportunities receive timely recognition and support from regulatory authorities. The importance and clearly demonstrated value of the coordination of clinical research and private/public initiatives, such as the OA Initiative and the European APPROACH project, and involvement of informed patients in research and policy decision making cannot be over emphasised. PMID- 27463799 TI - Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis. AB - Chemotherapy-induced intestinal mucositis is characterized by pain and a pro inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy induced mucositis. PMID- 27463800 TI - Up-Regulation of CD74 Expression in Parietal Epithelial Cells in a Mouse Model of Focal Segmental Glomerulosclerosis. AB - BACKGROUND/AIMS: De novo expression of CD44 is considered as a marker of parietal epithelial cell (PEC) activation. The aim of our study was to explore CD74 expression, which can form a complex with CD44, in PECs during the progression of focal segmental glomerulosclerosis (FSGS). To clarify the role of CD74 expression and of its interaction with CD44, we generated a new mouse model with enhanced PEC activation through lipopolysaccharide (LPS) application to adriamycin (ADR) induced nephropathy mice (LPS-treated ADR mice). METHODS: As a new model, LPS was intraperitoneally injected into the mice 3 weeks after ADR injection. The mice were divided into 3 categories: control mice, ADR mice and LPS-treated ADR mice. Renal function parameters, histologic changes and immunohistochemical expression of CD74 and other PEC activation markers were analyzed after LPS application. RESULTS: After LPS stimulation, the glomeruli were characterized by enlarged epithelial cells with strong CD74 expression, followed by pseudo-crescent formation. By double staining, CD74-positive enlarged cells showed co-expression of classical PEC markers, but not of Lotus tetragonolobus lectin (marker of proximal tubular cells), suggesting amplification of PEC activation. Time-course analysis displayed marked upregulation of CD74 expression during rapid PEC activation compared with CD44. Additionally, the time-dependent change in ERK phosphorylation showed a similar pattern to CD74. CONCLUSION: Our results indicate that CD74 can be a marker for PEC activation in FSGS. By modifying the ADR mouse model through LPS treatment, we found that CD74 upregulation better reflects a rapid amplification of PEC activation than CD44 expression. PMID- 27463801 TI - NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations. AB - Mutations in the NR5A1 gene, which encodes the steroidogenic factor 1 (SF1), are responsible for different phenotypes of disorders of sex development (DSD), such as bilateral anorchia and hypospadias. Furthermore, they can be associated with primary amenorrhea, premature ovarian failure, male infertility, adrenal tumors, and endometriosis. Direct sequencing of the 7 NR5A1 exons including ~1,000 bp of the 5'-upstream and 3'-downstream regions and all intron-exon boundaries was performed in patients with DSD. Three different in silico tools were used to assess the consequences of a splice site mutation. As a result, 3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38* and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding domain, and the intronic nucleotide substitution c.1138+1G>T at the intron 6 donor splice site is considered to modify correct splicing. We assume that the anomalous mRNA produced as a result of p.Lys38* and p.Leu80Trpfs*8 will be degraded by nonsense-mediated mRNA decay even before translation, leading to SF1 haploinsufficiency. The c.1138+1G>T mutation is expected to produce a truncated protein. Heterozygous SF1 loss-of-function mutations in these cases resulted in mild DSD manifestations, such as dysgenetic testes, spontaneous puberty, and preserved adrenal function. PMID- 27463803 TI - Clarification of the Phylogenetic Framework of the Tribe Baorini (Lepidoptera: Hesperiidae: Hesperiinae) Inferred from Multiple Gene Sequences. AB - Members of the skipper tribe Baorini generally resemble each other and are characterized by dark brown wings with hyaline white spots. These shared characteristics have caused difficulties with revealing the relationships among genera and species in the group, and some conflicting taxonomic views remain unresolved. The present study aims to infer a more comprehensive phylogeny of the tribe using molecular data, to test the monophyly of the tribe as well as the genera it includes in order to clarify their taxonomic status, and finally to revise the current classification of the group. In order to reconstruct a phylogenetic tree, the mitochondrial COI-COII and 16S genes as well as the nuclear EF-1alpha and 28S genes were analyzed using parsimony, maximum likelihood, and Bayesian inference. The analysis included 67 specimens of 41 species, and we confirmed the monophyly of Baorini, and revealed that 14 genera are well supported. The genus Borbo is separated into three clades: Borbo, Pseudoborbo, and Larsenia gen. nov. We confirmed that Polytremis is polyphyletic and separated into three genera: Polytremis, Zinaida, and Zenonoida gen. nov., and also confirmed that the genus Prusiana is a member of the tribe. Relationships among some genera were strongly supported. For example, Zenonia and Zenonoida were found to be sister taxa, closely related to Zinaida and Iton, while Pelopidas and Baoris were also found to cluster together. PMID- 27463804 TI - Identification of Methylated Dithioarsenicals in the Urine of Rats Fed with Sodium Arsenite. AB - Biotransformation of inorganic arsenic results in the formation of methylarsenicals of both oxygen and sulfur analogues. Aiming to improve our understanding of metabolism of inorganic arsenic in animals, we conducted an animal feeding study with an emphasis on identifying new arsenic metabolites. Female F344 rats were given 0, 1, 10, 25, 50, and 100 MUg/g of arsenite (iAs(III)) in the diet. Arsenic species in rat urine were determined using high performance liquid chromatography (HPLC) separation and inductive coupled plasma mass spectrometry (ICPMS) and electrospray ionization tandem mass spectrometry (ESI MS/MS) detection. Nine arsenic species were detected in the urine of the iAs(III)-dosed rats. Seven of these arsenic species were consistent with previous reports, including iAs(III), arsenate, monomethyarsonic acid, dimethylarsinic acid, trimethylarsine oxide, monomethylmonothioarsonic acid, and dimethylmonothioarsinic acid. Two new methyldithioarsencals, monomethyldithioarsonic acid (MMDTA(V)) and dimethyldithioarsinic acid (DMDTA(V)), were identified for the first time in the urine of rats treated with iAs(III). The concentrations of both MMDTA(V) and DMDTA(V) in rat urine were dependent on the dosage of iAs(III) in diet. The concentration of DMDTA(V) was approximately 5 times higher than that of MMDTA(V). MMDTA(V) has not been identified in any biological samples of animals, and DMDTA(V) has not been reported as a metabolite of inorganic arsenic in the rats. The identification of novel methylated dithioarsenicals as metabolites of inorganic arsenic in the rat urine provided further insights into the understanding of the metabolism of arsenic. PMID- 27463802 TI - KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation. AB - Studies have suggested that Epithelial-Mesenchymal Transition (EMT) and transformation is an important step in progression to cancer. Par3 (partitioning defective protein) is a crucial factor in regulating epithelial cell polarity. However, the mechanism by which the latency associated nuclear antigen (LANA) encoded by Kaposi's Sarcoma associated herpesvirus (KSHV) regulates Par3 and EMTs markers (Epithelial-Mesenchymal Transition) during viral-mediated B-cell oncogenesis has not been fully explored. Moreover, several studies have demonstrated a crucial role for EMT markers during B-cell malignancies. In this study, we demonstrate that Par3 is significantly up-regulated in KSHV-infected primary B-cells. Further, Par3 interacted with LANA in KSHV positive and LANA expressing cells which led to translocation of Par3 from the cell periphery to a predominantly nuclear signal. Par3 knockdown led to reduced cell proliferation and increased apoptotic induction. Levels of SNAIL was elevated, and E-cadherin was reduced in the presence of LANA or Par3. Interestingly, KSHV infection in primary B-cells led to enhancement of SNAIL and down-regulation of E-cadherin in a temporal manner. Importantly, knockdown of SNAIL, a major EMT regulator, in KSHV cells resulted in reduced expression of LANA, Par3, and enhanced E-cadherin. Also, SNAIL bound to the promoter region of p21 and can regulate its activity. Further a SNAIL inhibitor diminished NF-kB signaling through upregulation of Caspase3 in KSHV positive cells in vitro. This was also supported by upregulation of SNAIL and Par3 in BC-3 transplanted NOD-SCID mice which has potential as a therapeutic target for KSHV-associated B-cell lymphomas. PMID- 27463805 TI - Changes in Structure and Functioning of Protist (Testate Amoebae) Communities Due to Conversion of Lowland Rainforest into Rubber and Oil Palm Plantations. AB - Large areas of tropical rainforest are being converted to agricultural and plantation land uses, but little is known of biodiversity and ecological functioning under these replacement land uses. We investigated the effects of conversion of rainforest into jungle rubber, intensive rubber and oil palm plantations on testate amoebae, diverse and functionally important protists in litter and soil. Living testate amoebae species richness, density and biomass were all lower in replacement land uses than in rainforest, with the impact being more pronounced in litter than in soil. Similar abundances of species of high and low trophic level in rainforest suggest that trophic interactions are more balanced, with a high number of functionally redundant species, than in rubber and oil palm. In contrast, plantations had a low density of high trophic level species indicating losses of functions. This was particularly so in oil palm plantations. In addition, the relative density of species with siliceous shells was >50% lower in the litter layer of oil palm and rubber compared to rainforest and jungle rubber. This difference suggests that rainforest conversion changes biogenic silicon pools and increases silicon losses. Overall, the lower species richness, density and biomass in plantations than in rainforest, and the changes in the functional composition of the testate amoebae community, indicate detrimental effects of rainforest conversion on the structure and functioning of microbial food webs. PMID- 27463807 TI - Biomarkers in Randomized Clinical Trials: Positron Emission Tomography and Nuclear Medicine Techniques. AB - BACKGROUND: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are nuclear medicine techniques that utilize the tracer principle to image biological processes using radiolabeled molecules. Numerous PET and SPECT radiopharmaceuticals have been developed over the years that qualify as biomarkers for neurological disorders. SUMMARY: This chapter reviews the use of PET and SPECT in neurological clinical trials, and emphasizes the concepts and lessons learned from these experiences. KEY MESSAGES: Key considerations for successful use of PET or SPECT imaging as biomarkers in neurological randomized trials include: (1) in vivo behavior of the radiotracer and the PET or SPECT imaging parameter studied should reflect an essential aspect of the underlying pathology and/or pathophysiology of the disease under question, (2) the underlying biological target and radiotracer distribution should have the potential to vary with treatment under study conditions, and adjustments must be made for any other known changes (e.g. physiological) that may occur over time, (3) image reconstruction techniques and quantitative or semiquantitative image analysis approaches should be robust and standardized across trial sites, and (4) newer molecular targets should be explored based on insights obtained from basic science research and translational observations. Successful implementation of PET and SPECT in clinical trials and practice has a highly significant potential to contribute towards improving outcomes and clinical care for patients with neurological disorders. PMID- 27463806 TI - Inhibition of the Binding between RGS2 and beta-Tubulin Interferes with Spindle Formation and Chromosome Segregation during Mouse Oocyte Maturation In Vitro. AB - RGS2 is a negative regulator of G protein signaling that contains a GTPase activating domain and a beta-tubulin binding region. This study aimed to determine the localization and function of RGS2 during mouse oocyte maturation in vitro. Immunofluorescent staining revealed that RGS2 was widely expressed in the cytoplasm with a greater abundance on both meiotic spindles and first/second polar bodies from the fully-grown germinal vesicle (GV) stage to the MII stages. Co-expression of RGS2 and beta-tubulin could also be detected in the spindle and polar body of mouse oocytes at the MI, AI, and MII stages. Inhibition of the binding site between RGS2 and beta-tubulin was accomplished by injecting anti RGS2 antibody into GV-stage oocytes, which could result in oocytes arrest at the MI or AI stage during in vitro maturation, but it did not affect germinal vesicle breakdown. Moreover, injecting anti-RGS2 antibody into oocytes resulted in a significant reduction in the rate of first polar body extrusion and abnormal spindle formation. Additionally, levels of phosphorylated MEK1/2 were significantly reduced in anti-RGS2 antibody injected oocytes compared with control oocytes. These findings suggest that RGS2 might play a critical role in mouse oocyte meiotic maturation by affecting beta-tubulin polymerization and chromosome segregation. PMID- 27463808 TI - The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development. AB - Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6 week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs. PMID- 27463809 TI - Noise Induces Biased Estimation of the Correction Gain. AB - The detection of an error in the motor output and the correction in the next movement are critical components of any form of motor learning. Accordingly, a variety of iterative learning models have assumed that a fraction of the error is adjusted in the next trial. This critical fraction, the correction gain, learning rate, or feedback gain, has been frequently estimated via least-square regression of the obtained data set. Such data contain not only the inevitable noise from motor execution, but also noise from measurement. It is generally assumed that this noise averages out with large data sets and does not affect the parameter estimation. This study demonstrates that this is not the case and that in the presence of noise the conventional estimate of the correction gain has a significant bias, even with the simplest model. Furthermore, this bias does not decrease with increasing length of the data set. This study reveals this limitation of current system identification methods and proposes a new method that overcomes this limitation. We derive an analytical form of the bias from a simple regression method (Yule-Walker) and develop an improved identification method. This bias is discussed as one of other examples for how the dynamics of noise can introduce significant distortions in data analysis. PMID- 27463812 TI - The Treatment of Hairy Cell Leukemia: A Review. AB - Hairy cell leukemia is a chronic lymphoproliferative malignancy first described by Bouroncle et al. over 30 years ago(1). Representing less than 2% of adult leukemias, hairy cell leukemia has become the focus of intense interest over the past few years as a result of therapeutic advances. The malignant cell has characteristic irregular cytoplasmic projections visible on the peripheral blood smear and cytoplasmic vesicles staining positive for tartrate-resistant acid phosphatase. The origin of the hairy cell appears to be a preplasma cell B lymphocyte based on immunoglobulin gene rearrangements and B-cell-specific antigens, although very rare T-cell variants have been reported. While the diagnosis may be suspected from the clinical manifestations and examination of the peripheral smear, a bone-marrow biopsy is frequently necessary for definitive diagnosis. The typical patient is a middle-aged man with complaints of fatigue or weakness; symptoms of splenic pain, bleeding or bruising, or recurrent infections are less common at presentation(2). Splenomegaly without peripheral adenopathy occurs in 70-80 % of newly diagnosed patients(2). Pancytopenia is present in approximately two-thirds of patients, although 10% of patients present with a leukocytosis resulting from a high circulating hairy cell count. PMID- 27463810 TI - Efficacy and Safety of OnabotulinumtoxinA in Patients with Neurogenic Detrusor Overactivity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Neurogenic detrusor overactivity (NDO) affects the quality of life (QoL) of millions of individuals worldwide. The purpose of this study was to assess the efficacy and safety of onabotulinumtoxinA in patients with NDO using a network meta-analytic approach, which can also quantify and compare the efficacy of onabotulinumtoxinA across different dosages. METHODS: PubMed, EMBASE, and the Controlled Trials Register were searched to identify randomized controlled trials comparing onabotulinumtoxinA to a control for NDO in adult patients. The primary outcome was the mean number of urinary incontinence (UI) episodes per week. Urodynamic parameters included the maximum cystometric capacity (MCC) and the maximum detrusor pressure (MDP). The safety of onabotulinumtoxinA was determined by the incidence of various frequent adverse events (AEs). Two authors extracted data independently, and the statistical analyses were performed using RevMan 5.1.0 software. RESULTS: A total of 1,915 patients from six randomized controlled trials were included in this meta-analysis. The onabotulinumtoxinA-treated groups had a significantly decreased mean number of urinary incontinence episodes per week (at week 6) (onabotulinumtoxinA200U: MD: -10.72, 95% CI: -13.4 to -8.04, P<0.00001; 300 U: MD: -11.42, 95% CI: -13.91 to -8.93, P<0.00001), MDP (200 U: MD: -33.46, 95% CI: -39.74 to -27.18, P<0.00001; 300 U: MD: -31.72, 95% CI: 37.69 to -25.75, P<0.00001), and greater increased MCC (200 U: MD: 141.30, 95% CI: 121.28 to 161.32, P<0.00001; 300 U: MD: 151.39, 95% CI: 130.43 to 172.34, P<0.00001) compared to the placebo-treated groups. However, there were no significant differences between the onabotulinumtoxinA-treated groups for the number of weekly UI episodes at 6 weeks (MD: 0.08, 95% CI: -2.57 to 2.73, P = 0.95). Similarly, we also observed that there were no significant differences in MCC (MD: -9.97, 95% CI: -33.15 to 13.20, P = 0.40) and MDP (MD: -1.86, 95% CI: 8.09 to 4.37, P = 0.56). Considering the AEs, the onabotulinumtoxinA-treated groups were often associated with more complications, including urinary tract infections (UTIs) (RR: 1.47, 95% CI: 1.29 to 1.67, P<0.00001), urinary retention (RR: 5.58, 95% CI: 3.53 to 8.83, P<0.00001), hematuria (RR: 1.70, 95% CI: 1.01 to 2.85, P = 0.05), and muscle weakness (RR: 2.59, 95% CI: 1.36 to 4.91, P = 0.004). CONCLUSIONS: OnabotulinumtoxinA can significantly reduce the frequency of urge urinary incontinence and improve urodynamic parameters (MCC and MDP) in patients with NDO at 6 weeks after treatment. This meta-analysis indicates that onabotulinumtoxinA is effective and safe for treating patients with NDO compared to placebo. Additionally, we did not observe any statistical or clinical differences in efficacy between 300 and 200 U dosages. PMID- 27463813 TI - The Role of Growth Factors in Bone-Marrow Transplantation. AB - Growth factors may be of value in reducing transplant-related complications. Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and recombinant granulocyte colony-stimulating factor (G-CSF) are the most widely studied growth factors to date, and show promise in terms of accelerating haemopoietic recovery; however, their overall value is less clear. Non recombinant colony-stimulating factors derived from human urine are also under investigation. Any antileukaemic or immune modulatory role for growth factors is currently speculative. The value of growth factors in allogeneic bone-marrow transplantation has not yet been adequately investigated. The use of growth factcm in combination is potentially of great value but as yet there are no human data. In addition to having proliferative effects, some colony-stimulating factors have important effects on mature phagocyte function. Large randomized studies will be needed to document the real value of growth factors in marrow transplanation. PMID- 27463811 TI - Population Structure, Genetic Diversity, Effective Population Size, Demographic History and Regional Connectivity Patterns of the Endangered Dusky Grouper, Epinephelus marginatus (Teleostei: Serranidae), within Malta's Fisheries Management Zone. AB - The objective of this study is to describe the genetic population structure and demographic history of the endangered marine fish, Epinephelus marginatus, within Malta's Fisheries Management Zone for the purpose of localised conservation planning. Epinephelus marginatus is a long-lived, sedentary, reef-associated protogynous hermaphrodite with high commercial and recreational value that is at risk of extinction throughout its global distribution. Based on global trends, population substructuring and gaps in local knowledge this has led to an increased interest in evaluation of local stock. Assessment of Maltese demography was based on historical and contemporary catch landings data whilst genetic population structure and regional connectivity patterns were evaluated by examining 175 individuals collected within the central Mediterranean region between 2002 and 2009 using 14 nuclear microsatellite loci. Demographic stock assessment of Maltese E. marginatus' revealed a 99% decline in catch landings between 1947 and 2009 within the Fisheries Management Zone. A contemporary modest mean size was observed, 3 +/- 3 kg, where approximately 17% of the population was juvenile, 68% female/sex-changing and 15% were male with a male-to-female sex ratio of 1:5. Genetic analysis describes the overall population of E. marginatus' within the Fisheries Management Zone as decreasing in size (OH = 2.2), which has gone through a significant size reduction in the past (M = 0.41) and consequently shows signs of moderate inbreeding (FIS = 0.10, p < 0.001) with an estimated effective population size of 130 individuals. Results of spatially explicit Bayesian genetic cluster analysis detected two geographically distinct subpopulations within Malta's Fisheries Management Zone and that they are connected to a larger network of E. marginatus' within the Sicily Channel. Results suggest conservation management should be designed to reflect E. marginatus' within Malta's Fisheries Management Zone as two management units. PMID- 27463814 TI - Interferon in the Treatment of Refractory Multiple Myeloma: An Eastern Cooperative Oncology Group Study. AB - Twenty-three patients with relapsed or refractory multiple myeloma were treated with recombinant alpha-2 interferon (rIFNalpha2b) administered subcutaneously at a dose of 10 * 10(6) IU/m(2) 3x/week for 12 weeks. Of the 20 evaluable patients 12 had received two or more prior chemotherapy regimens and nine had failed to respond to all prior treatment. Two patients had an objective response (OR) to rIFNalpha2b manifest by >50% decrease in M-protein or extramedullary plasmacytomas. Three other patients had objective improvement (I) with 25-50% decrease in M-protein and marked decrease in bone pain (OR + I = 25%). Two other patients had disease stabilization and freedom from symptoms for more than one year. Four of 13 patients with moderate-to-severe bone pain had marked pain reduction for 4-48 months. All patients had the flu-like syndrome associated with initial doses of interferon. Three had dose-limiting fatigue. Six patients had severe neutropenia <1000/mcl and six had platelets <50 000/mcl. Chronic dose modification was required in 75% of patients. The maximum tolerated dose in most patients was 5 * 10(6) IU/m(2). This study demonstrates that rIFNalpha2b is active in late multiple myeloma, producing clinical benefit in a third of patients. Since myelotoxicity was mild and transient when the 5 * 10(6) IU/m(2) dose level was used, interferon should be considered a potentially useful treatment option in this marrow-impaired group of patients. PMID- 27463815 TI - The Differences between Lymphoma and Leukemia Type of Adult T-cell Leukemia. AB - The difference between lymphoma type and leukemia type of adult T-cell leukemia (ATL) were analysed with 102 Japanese patients all positive for human T-cell leukemia virus type I (HTLV-I) antibody. They were classified into three groups on findings at first medical examination: lymphoma type cases, leukemia type cases, and mixed type (leukemia type plus lymphadeno-pathy) cases. Lymphoma type patients had several or more enlarged lymph nodes the largest of which was greater than 1 cm in diameter and with practically no abnormal lymphocytes (ATL. cells), which are characteristic of ATL, in the peripheral blood. Leukemia type patients had 10% or more ATL cells in the peripheral blood and had no detectablle lymphadenopathy Lymphoma type patients often complained of detectable lymphadenopathy, while leukemia type patients complained frequently of general fatigue and skin eruption. Mixed type patients more frequently had signs and symptoms which were characteristic of both types: lymphadenopathy and 10% or more ATL cells in the peripheral blood. Mixed type: ATL had a poorer prognosis than either lymphoma type or leukemia type. The median survival time was 3 months for mixed type patients, 10.5 months for lymphoma type patients, and 13.5 months for leukemia type patients. Complications and causes of death have also been touched upon. Clinicians are thus advised to consider ATL patients separately according to their clinical manifestations. PMID- 27463816 TI - Induction and Persistence of Complete Remission in a Resistant Acute Myeloid Leukemia Patient after Treatment with Recombinant Interleukin-2. AB - A complete and persistent clinico-hematologic remission was obtained in an M4 acute myeloid leukemia patient after treatment with recombinant interleukin 2 (rIL2) alone. After two autologous bone-marrow transplantations and in the third relapse with 10% persistent blasts in the marrow, the patient was treated with two intensive courses of rIL2 given by continuous infusion over a period of 13 days. rIL2 administration was accompanied by significant side effects and followed by notable hematological, clinical and immunological modifications. Complete remission was achieved after these two courses and has been maintained with monthly low-dose cycles of rIL2 given on an out-patient basis. Eighteen months after starting treatment with rIL2 the patient is well and in persistent remission. PMID- 27463817 TI - Efficacy of ABVD Therapy in Resistant Hodgkin's Disease. AB - Between January 1979 and June 1987, 46 patients with Hodgkin's disease '(HD) resistant to first-line combination chemotherapy or in early relapse were treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Twenty-two of 42 patients (52%) evaluable for response achieved a complete remission (CR), and eight (19%) a partial remission (PR). Median survival was 42.9 months with a probability of being alive at 5 years of 25 % (95 % CI: 10-40%). Median CR duration was 36.6 months and the probability of being alive and in CR at 5 years for the whole series was 20% (95 % CI: 8-32%). No clinical or laboratory data present before therapy with ABVD were associated with a higher index of response or longer survival. This studv confirms the efficacy of ABVD combination chemotherapy in resistant or relapsed HD. PMID- 27463818 TI - Hodgkin's Lymphoma: Results of ABVD Chemotherapy in 40 Patients with Advanced or Bulky Disease. AB - During 1980-1986, 40 patients with advanced Hodgkin's disease or bulky disease were treated with six cycles of ABVD chemotherapy, and adjuvant radiotherapy was added to sites of bulky disease when required. Twenty-seven of the 40 patients (67.5%) were treated with ABVD as primary therapy and 13 (32.5%) received it as salvage therapy after initial failure. Twenty-seven patients (67.5%) had advanced stages 3 or 4 disease, while 13 (32.5%) had stage 2 with bulky mediastinal disease (more than 30% chest diameter). Only 7.5 % of the patients had no response to ABVD while 75% achieved CR and 17.5% PR. Seventy-four per cent of the patients with advanced stages 3 and 4 achieved CR and 15% reached PR, with only two failures to ABVD. The median survival for the entire group is currently more than 41 months, with a median disease-free interval (DFI) of 27.5 months for all treated patients. The results compare favorably with those reported from other major centers dealing with larger series of patients. New approaches for future treatment employing alternating shorter courses of MOPP/ABV are discussed, and the importance of radiotherapy for bulky disease is emphasized. PMID- 27463819 TI - Fine-Needle Aspiration Cytology with Immunocytochemistry of Extranodal Manifestations of Non-Hodgkin's Lymphoma. AB - Sixty-three patients with extranodal manifestations of non-Hodgkin's lymphoma were examined with fine-needle aspiration cytology and diagnosed according to the Kiel classification. Cytospin preparations were made from the aspirates and used for immunocytochemical analysis. Primary extranodal manifestations were found in 25 cases, while 16 patients had primary extranodal and nodal disease. Twenty-two patients experienced extranodal relapse of lymphoma originally limited to lymph nodes (16) or extranodal sites (6). Cytologic high-grade lymphomas were diagnosed in 17 (68%) of the primary extranodal lymphomas, 14 (64%) of those with extranodal relapse and 11 (69 %) of those with extranodal and nodal disease. Three cases were diagnosed as histiocytic lymphomas. None of the lymphoma subgroups had any preponderance for specific extranodal sites. Forty patients had a histologic examination and in 34 of these cases the cytologic and histologic diagnoses were in agreement. There were four cases with divergent histologic and cytologic diagnoses. Two patients were diagnosed as Hodgkin's disease on sections while smears from the extranodal recurrences showed an unequivocal picture of high-grade non-Hodgkin's lymphoma. Two smears showed an immunocytoma and a lymphoblastic lymphoma, respectively, while histology was inconclusive. In two patients with histologic diagnosis of centroblastic/centrocytic lymphoma, aspiration cytology at relapse (> 1 year later) revealed centroblastic lymphoma in both cases. Immunocytochemistry identified 57 B-cell, 3 T-cell and 3 true histiocytic lymphomas. A monoclonal light chain expression was present in 50 (88 %) of the B-cell lymphomas. Immunohistochemical evaluation of light chain expression was performed in 21 cases and the results were in agreement with the immunocytochemical analysis. Our results show that fine-needle aspiration cytology aided by immunocytochemistry offers a method with a very high accuracy for the diagnosis and classification of extranodal manifestations of non Hodgkin's lymphoma. PMID- 27463820 TI - Prognostic Features in the Myelodysplastic Syndromes: Importance of Morphological Atypia in the Marrow Cell Lineages. AB - In order to clarify the relationship between myelodysplastic morphologic features of marrow cells and prognoses and 1.0 define other prognostic factors, 124 patients with the FAB criteria of myelodysplastic syndrome (MIX) were analysed. These included 57 patients with refractory anemia (RA), 5 RA with ring sideroblasts (RARS), 25 RA with excess of blasts (RAEB), 14 chronic myelomonocytic: leukemia (CMML) and 23 with RAEB in transformation (RAEB in T). Univariate analysis of all MDS patients or those of RA demonstrated that the following factors, which were not reported or fully investigated previously, were significantly associated with prognosis. These included neutrophil alkaline phosphatase (NAP) score (significant only for all MDS), the percentage of marrow erythroblasts and lymphocytes present, the percentage of cells with morphological abnormalities in individual cell lineages and the number of cell lineages showing atypia (significant for all MDS and RA). Multiple regression analysis showed that (%) of marrow erythroblasts, NAP score, hemoglobin levels and number of marrow granulocytes with atypia were significant for predicting the prognosis of all MDS patients while the number of marrow megakaryocytes and granulocytes with atypia were significant for prognosis in the subgroup with RA. PMID- 27463821 TI - Early Erythroblastic Leukemia Presenting as De Novo Acute Leukemia. AB - Early erythroblastic leukemia is a newly defined type of leukemia in which the blasts have the same characteristics as erythroid precursors at the level of CFU E. The blasts are characterized by the presence of carbonic anhydrase I, CD 36 antigen, platelet peroxidase (PPO)-like activity, and ferritin-containing granules. Early erythroblastic leukemia appears to have characteristic clinical features; in the original report of nine cases, only one patient had typical de novo acute leukemia. We report here a case of early erythroblastic leukemia that presented! as de novo acute leukemia. The blasts from this patient had almost the same ultrastructural and phenotypical characteristics as those of the originally reported cases, even though our case was not examined for anti-carbonic anhydrase I antibodies. As a single marker, PPOl activity can no longer be considered specific for the megakaryocyte-platelet lineage, even though the significance of transient expression of PPO-like activity in immature erythroblastic cells at the level of CFU-E still remains to be clarified. When leukemic blasts show positivity for CD36 and negativity for megakaryocytic or monocytic markers, the diagnosis of early erythroblastic leukemia should be suspected and electron microscopical characteristics should be studied. PMID- 27463822 TI - Scleroderma Associated with Idiopathic Myelofibrosis. AB - A patient is described who developed scleroderma one and a half years: after the diagnosis of idiopathic myelofibrosis (IM). In addition to suffering from the hematological features characteristic of the osteosclerotic phase of IM, the patient also developed Raynaud's phenomenon, marked distal sclerosis in the hands and painful ulcers on the fingertips, with physical findings consistent with scleroderma and positive anti-nuclear antibodies (fine-speckled pattern). The skin lesions showed a dramatic improvement after prednisone treatment but the patient eventually died of progressive myelofibrosis. The present case adds to those previously reported on the occurrence of immunological abnormalities in patients with IM. PMID- 27463823 TI - Current Issues in Randomized Clinical Trials of Neurodegenerative Disorders at Enrolment and Reporting: Diagnosis, Recruitment, Representativeness of Patients, Ethnicity, and Quality of Reporting. AB - BACKGROUND: The investigator is faced with several challenges when planning a randomized clinical trial (RCT). In the early phase, issues are particularly challenging for RCTs in neurodegenerative disorders (NDD). SUMMARY: At the time of inclusion in the study, an early and accurate diagnosis is mandatory. Variability of diagnostic criteria, mostly based on clinical grounds, lag time between onset and enrolment, and phenotypic heterogeneity are the main drivers of diagnostic complexity. High-quality data in terms of diagnostic reliability, phenotypic description, follow-up, and evaluation of outcomes are key determinants and are highly conditioned by the expertise of the investigators and center recruitment rate. Representativeness of NDD patients is mandatory to postulate the generalizability of the results of RCTs. There is, however, a systematic selection bias in terms of age (more likely to be younger), sex (more likely to be male), ethnicity (more likely to be of European/Caucasian origin), and other prognostic factors (more likely to be favorable). In the publication phase, researchers need to report properly all of the main features of the RCT. Consolidated Standards of Reporting Trials (CONSORT) facilitates the report and interpretation of RCTs, but adherence to these guidelines needs to be improved. KEY MESSAGES: Several issues discussed in this review may alter the internal and external validity of an RCT. To date, the impact on phenotype at study entry has often been overlooked. A differential effect of the selection of subjects and of specific clinical and nonclinical features needs to be systematically explored in the RCT planning phase. PMID- 27463824 TI - Molecular Resolution in situ Imaging of Spontaneous Graphene Exfoliation. AB - All reported methods of graphene exfoliation require external energy input, most commonly from sonication,1 shaking,2 or stirring.3 The reverse process aggregation of single or few layer graphene sheets-occurs spontaneously in most solvents. This makes producing, and especially storing, graphene in economic quantities challenging,4,5 which is a significant barrier to widespread commercialization. This study reveals ionic liquids (ILs) can spontaneously exfoliate graphene from graphite at room temperature. The process is thermally activated and follows an Arrhenius-type behavior, resulting in thermodynamically stable IL/graphene suspensions. Using atomic force microscopy, the kinetics of the exfoliation could be followed in situ and with subnanometer resolution, showing that both the size and the charge of the constituent IL ions play a key role. Our results provide a general molecular mechanism underpinning spontaneous graphene exfoliation at room temperature in electrically conducting ILs, paving the way for their adoption in graphene-based technology. PMID- 27463825 TI - Ultrasound-guided synovial biopsy of the wrist does not alter subsequent clinical or ultrasound disease activity assessments: a prospective study for incorporation of imaging in clinical trials. AB - OBJECTIVES: Ultrasound-guided synovial biopsy (UGSB) is a minimally-invasive procedure capable of retrieving good quality tissue from small and large joints. The use of UGSB in prospective clinical trials poses a dilemma as to whether biopsied joints may be later included in core data sets for clinical or imagining response, as the procedure itself may alter disease activity assessment. In this study, we examine the impact of UGSB of the wrist on subsequent clinical and ultrasound (US) assessments in a cohort of rheumatoid arthritis (RA) patients prior to initiation of anti-TNF-alpha therapy. METHODS: Patients had active disease (DAS>5.1) involving their wrist. Both wrists were scanned and the most inflamed one underwent an UGSB. Ultrasonographic and clinical assessments were repeated at the patients' subsequent visit, without any changes in disease modifying treatment between visits. US images were scored semi-quantitatively and quantitatively for synovial thickness (ST) and power Doppler (PD). Mixed-effects model and paired-Wilcoxon signed rank test were used to assess the effect of UGSB on these scores. RESULTS: Twenty-nine patients were enrolled. No significant difference in mean ST (p=0.32) or PD (p=0.21) was demonstrated pre- and post biopsy (mean time 14.7 days). Similar results were obtained using quantitative measures. The DAS-28 and its components did not change significantly post-biopsy. CONCLUSIONS: In this population, UGSB of the wrist did not significantly alter subsequent clinical or US assessments, indicating that a wrist joint, which has undergone UGSB, may be incorporated into an US dataset or clinical outcome assessment tools, such as the DAS-28, without prejudice. PMID- 27463826 TI - Direct (Hetero)arylation Polymerization: Trends and Perspectives. AB - Conjugated polymers have attracted much attention in recent years, as they can combine the best features of metals or inorganic semiconducting materials (excellent electrical and optical properties) with those of synthetic polymers (mechanical flexibility, simple processing, and low-cost production), thereby creating altogether new scientific synergies and technological opportunities. In the search for more efficient synthetic methods for the preparation of conjugated polymers, this Perspective reports advances in the field of direct (hetero)arylation polymerization. This recently developed polymerization method encompasses the formation of carbon-carbon bonds between simple (hetero)arenes and (hetero)aryl halides, reducing both the number of synthetic steps and the production of organometallic byproducts. Along these lines, we describe the most general and adaptable reaction conditions for the preparation of high-molecular weight, defect-free conjugated polymers. We also discuss the bottleneck presented by the utilization of certain brominated thiophene units and propose some potential solutions. It is, however, firmly believed that this polymerization method will become a versatile tool in the field of conjugated polymers by providing a desirable atom-economical alternative to standard cross-coupling polymerization reactions. PMID- 27463827 TI - Can we measure cognitive constructs consistently within and across cultures? Evidence from a test battery in Bangladesh, Ghana, and Tanzania. AB - We developed a test battery for use among children in Bangladesh, Ghana, and Tanzania, assessing general intelligence, executive functioning, and school achievement. The instruments were drawn from previously published materials and tests. The instruments were adapted and translated in a systematic way to meet the needs of the three assessment contexts. The instruments were administered by a total of 43 trained assessors to 786 children in Bangladesh, Ghana, and Tanzania with a mean age of about 13 years (range: 7-18 years). The battery provides a psychometrically solid basis for evaluating intervention studies in multiple settings. Within-group variation was adequate in each group. The expected positive correlations between test performance and age were found and reliability indices yielded adequate values. A confirmatory factor analysis (not including the literacy and numeracy tests) showed a good fit for a model, merging the intelligence and executive tests in a single factor labeled general intelligence. Measurement weights invariance was found, supporting conceptual equivalence across the three country groups, but not supporting full score comparability across the three countries. PMID- 27463828 TI - Effects of depuration on histopathological changes in tilapia (Oreochromis niloticus) after exposure to cylindrospermopsin. AB - Cylindrospermopsin (CYN) is a highly water-soluble cytotoxin produced by several species of freshwater cyanobacteria and it is considered the second most studied cyanotoxin worldwide. CYN acts as a potent protein and glutathione synthesis inhibitor, as well as inducing genotoxicity, oxidative stress and histopathological alterations. Studies concerning the depuration of cyanobacterial toxins in aquatic organisms, especially in fish, are of great interest for fish economy and public health, but are scarce in the case of CYN. This is the first study reporting the ability of depuration (3 - 7 days) in reversing or ameliorating the histopathological lesions induced in liver, kidney, heart, intestines, and gills of tilapia (Oreochromis niloticus) due to exposure by immersion to repeated doses of a CYN-containing culture of A. ovalisporum for 14 days. The main histopathological changes induced by CYN were glucogenic degeneration and loss of the normal hepatic cord-structure (liver), hyperemia, dilated Bowman's capsule and cellular tumefaction (kidney), myofibrolysis, hemorrhages and edema (heart), necrosis and partial loss of microvilli (gastrointestinal tract), and hyperemia and inflammatory cells infiltrates (gills). After 3 days of depuration, gills were totally recovered, while the liver, kidney, and gastrointestinal tract required 7 days, and longer depuration periods may be needed for a full recovery of the heart. In addition, the morphometric study indicated that depuration managed to reverse the affectation in the hepatocytes nuclear diameters and cross sections of the proximal and distal convoluted tubules induced in CYN-exposed fish. In general, these results validate depuration as an effective practice for detoxification of fish contaminated with CYN. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1318 1332, 2017. PMID- 27463829 TI - The Talk About the Psychiatric Patient. AB - Essential to psychiatric nursing practice and care, verbal handovers and ward rounds are reporting systems for communication that shapes psychiatric staff's ability to recognize, understand, and construct patients, as well as patients' ability to construct themselves. Given the centrality of such language in psychiatric practice, the aim of this study was to describe how psychiatric staff talk about patients in psychiatric wards, what their talk encompasses, and what consequences it might pose for patient care. Empirical data were collected from audio recordings of staff discussions of patients during nine verbal handovers and three ward rounds in six different general psychiatric wards in mid and southern Sweden. Findings showed that to describe patients' mood, characteristics, and behavior, nurses used culturally common words and concepts related to three themes-good patients, bad patients, and to stay or be discharged and six subthemes-looking well, looking poorly, desirable patients, undesirable patients, continuing work, and being discharged. However, since assessments of and decisions about patients' conditions and care used everyday language and did not involve patients' participation, opportunities for patients to participate in their own care were rare. PMID- 27463830 TI - Narratives of Violence, Pathology, and Empowerment: Mental Health Needs Assessment of Home-Based Female Sex Workers in Rural India. AB - This study explores the narratives of psychological distress and resilience among a group of female sex workers who use residential spaces to attend to clients in rural India. The narratives reflect the lived experiences of these women. They describe the women's reasons for opting into sex work; guilt, shame, and stigma related to their sex worker status; experiences with intimate partner and domestic violence; health-related problems; communication with their family members about their sex worker status; mental health referral practices among the women; and elements of resilience and strength that they experience within themselves and within their community of fellow sex workers. The article also offers elements of our own experiences of recruiting the women to participate in the focus group, training local outreach workers in conducting focus group discussions, and forging a collaboration with a local community-based organization to highlight important barriers, challenges, and strategies for planning a group-based discussion to explore the mental health needs of home based sex workers. PMID- 27463831 TI - Effect of energetic cost to maintain the trap for Myrmeleon brasiliensis (Neuroptera, Myrmeleontidae) in its development and adult size. AB - Antlion larvae Myrmeleon brasiliensis Navas, 1914 (Neuroptera, Myrmeleontidae) are sit-and-wait predators who build traps to catch their prey. The aim of this study was to observe under laboratory conditions, how the energy cost spent on maintenance of their traps affects: the larval developmental time, time spent as a pupa, mortality rate of larvae and adult size. M. brasiliensis larvae were collected in the municipality of Aquidauana, Mato Grosso do Sul, Brazil and were individually maintained in plastic containers and subjected to two treatments. In the control treatment larvae did not have their traps disturbed while in the manipulated treatment, larvae had their traps disturbed three times a week. The experiments were followed until adult emergence. When the adults emerged, their body size (head-abdomen), anterior and posterior wing span and width were measured. Furthermore, the number of larvae that died during the experiment was recorded. The results showed that the larvae whose traps were manipulated had longer larval development time, smaller pupal development time and were smaller adults. It can be concluded that the energy expenditure spent on maintenance of the trap constructed by M. brasiliensis larvae can affect the development of negative ways, represented by a longer larval development and reduced adult size. PMID- 27463832 TI - First forensic records of termite activity on non-fossilized human bones in Brazil. AB - The aim of this study was to describe the first records of termite activity on non-fossilized human bones in Brazil. The cases reported in this study resulted from forensic analysis of six human skeletons found in northeastern Brazil between 2012 and 2014. Traces of tunnels and nests commonly produced by termites were found on several human bone surfaces as well as the specimens and characteristic signs of osteophagic activity. In four cases, the species were identified: Amitermes amifer Silvestri, 1901, Nasutitermes corniger (Motschulsky, 1855) (on two skeletons), and Microcerotermes indistinctus Mathews, 1977. In two other cases, the activity of termites on bone surfaces was evidenced by remains of nests and tunnels produced by these insects. At least in the samples of human remains available for this report, the number of termites collected was greater on bones found during autumn, the rainy season in the Northeast of Brazil. The human bones examined showed termites like insects with lots of strength at bone degradation, capable of continuing the process of decomposition of human remains even in completely skeletonized bodies. PMID- 27463833 TI - Antiproliferative and genotoxic effects of nature identical and artificial synthetic food additives of aroma and flavor. AB - This study aimed to analyze the antiproliferative and genotoxic potential of synthetic food flavorings, nature identical passion fruit and artificial vanilla. This assessment used root meristem cells of Allium cepa L., in exposure times of 24 and 48 hours and using doses of 0.2; 0.4 and 0.6 mL. Roots were fixed in Carnoy's solution, hydrolyzed in hydrochloric acid, stained with acetic orcein and analyzed with optical microscope at 400* magnification, 5,000 cells for each treatment. For data analysis, it was used Chi-square test at 5%. Doses of 0.2 mL at ET 48 h; 0.4 and 0.6 mL at ET 24 and 48 h of passion fruit flavor, and the three doses of the vanilla flavor at ET 24 and 48 h significantly reduced the cell division rate in the meristems of roots, proving to be cytotoxic. Doses of 0.2; 0.4 and 0.6 mL of the passion fruit additive, and the three doses of vanilla tested, in the two exposure times, induced mitotic spindle changes and micronuclei formation in the cells of the test organism used, proving to be genotoxic. Therefore, under the studied conditions, flavoring solutions of vanilla and passion fruit, marketed nationally and internationally, significantly altered the functioning of the cell cycle in root meristem cells of A. cepa. PMID- 27463834 TI - Aspects of the color evolution after the imaginal molt of Pachycoris torridus (Scopoli, 1772) (Hemiptera: Scutelleridae). PMID- 27463835 TI - Bonobo nest site selection and the importance of predictor scales in primate ecology. AB - The role of spatial scale in ecological pattern formation such as the geographical distribution of species has been a major theme in research for decades. Much progress has been made on identifying spatial scales of habitat influence on species distribution. Generally, the effect of a predictor variable on a response is evaluated over multiple, discrete spatial scales to identify an optimal scale of influence. However, the idea to identify one optimal scale of predictor influence is misleading. Species-environment relationships across scales are usually sigmoid increasing or decreasing rather than humped-shaped, because environmental conditions are generally highly autocorrelated. Here, we use nest count data on bonobos (Pan paniscus) to build distribution models which simultaneously evaluate the influence of several predictors at multiple spatial scales. More specifically, we used forest structure, availability of fruit trees and terrestrial herbaceous vegetation (THV) to reflect environmental constraints on bonobo ranging, feeding and nesting behaviour, respectively. A large number of models fitted the data equally well and revealed sigmoidal shapes for bonobo environment relationships across scales. The influence of forest structure increased with distance and became particularly important, when including a neighbourhood of at least 750 m around observation points; for fruit availability and THV, predictor influence decreased with increasing distance and was mainly influential below 600 and 300 m, respectively. There was almost no difference in model fit, when weighing predictor values within the extraction neighbourhood by distance compared to simply taking the arithmetic mean of predictor values. The spatial scale models provide information on bonobo nesting preferences and are useful for the understanding of bonobo ecology and conservation, such as in the context of mitigating the impact of logging. The proposed approach is flexible and easily applicable to a wide range of species, response and predictor variables and over diverse spatial scales and ecological settings. PMID- 27463836 TI - Passive Sampling and High Resolution Mass Spectrometry for Chemical Profiling of French Coastal Areas with a Focus on Marine Biotoxins. AB - Passive samplers (solid phase adsorption toxin tracking: SPATT) are able to accumulate biotoxins produced by microalgae directly from seawater, thus providing useful information for monitoring of the marine environment. SPATTs containing 0.3, 3, and 10 g of resin were deployed at four different coastal areas in France and analyzed using liquid chromatography coupled to high resolution mass spectrometry. Quantitative targeted screening provided insights into toxin profiles and showed that toxin concentrations and profiles in SPATTs were dependent on the amount of resin used. Between the three amounts of resin tested, SPATTs containing 3 g of resin appeared to be the best compromise, which is consistent with the use of 3 g of resin in SPATTs by previous studies. MassHunter and Mass Profiler Professional softwares were used for data reprocessing and statistical analyses. A differential profiling approach was developed to investigate and compare the overall chemical diversity of dissolved substances in different coastal water bodies. Principal component analysis (PCA) allowed for spatial differentiation between areas. Similarly, SPATTs retrieved from the same location at early, medium, and late deployment periods were also differentiated by PCA, reflecting seasonal variations in chemical profiles and in the microalgal community. This study used an untargeted metabolomic approach for spatial and temporal differentiation of marine environmental chemical profiles using SPATTs, and we propose this approach as a step forward in the discovery of chemical markers of short- or long-term changes in the microbial community structure. PMID- 27463837 TI - Distinct Role of Sesn2 in Response to UVB-Induced DNA Damage and UVA-Induced Oxidative Stress in Melanocytes. AB - Ultraviolet (UV) radiation, including both UVB and UVA irradiation, is the major risk factor for causing skin cancer including melanoma. Recently, we have shown that Sesn2, a member of the evolutionarily conserved stress-inducible protein family Sestrins (Sesn), is upregulated in human melanomas as compared to melanocytes in normal human skin, suggesting an oncogenic role of Sesn2. However, the role of Sesn2 in UVB and UVA response is unknown. Here, we demonstrated that both UVB and UVA induce Sesn2 upregulation in melanocytes and melanoma cells. UVB induces Sesn2 expression through the p53 and AKT3 pathways. Sesn2 negatively regulates UVB-induced DNA damage repair. In comparison, UVA induces Sesn2 upregulation through mitochondria but not Nrf2. Sesn2 ablation increased UVA induced Nrf2 induction and inhibits UVA-induced ROS production, indicating that Sesn2 acts as an upstream regulator of Nrf2. These findings suggest previously unrecognized mechanisms in melanocyte response to UVB and UVA irradiation and potentially in melanoma formation. PMID- 27463838 TI - Defeat mutant KRAS with synthetic lethality. AB - Ras proteins are considered as the founding members of a large superfamily of small GTPases that control fundamental cellular functions. Mutationally activated RAS genes were discovered in human cancer cells more than 3 decades ago, but intensive efforts on Ras structure, biochemistry, function and signaling continue even now. Because mutant Ras proteins are inherently difficult to inhibit and have yet been therapeutically conquered, it was designated as "the Everest of oncogenes" in the cancer genome landscape, further promoting a "renaissance" in RAS research. Different paths to directly or indirectly targeting mutant Ras signaling are currently under investigation in the hope of finding an efficacious regimen. Inhibitors directly binding to KRASG12C to block its downstream signaling have been revealed, supporting the notion of Ras' druggability. An alternative indirect approach by targeting synthetic lethal interactors of mutant RAS is underway. We recently employed a synthetic lethal drug screen plus a combinatorial strategy using a panel of clinical agents and discovered that KRAS mutant cancers were fragile to the combined inhibition of polo-like kinase 1 (Plk1) and RhoA/Rho kinase (ROCK). The combined regimen of BI-2536 (a Plk1 inhibitor) and fasudil (a ROCK inhibitor) promoted a significant inhibition of patient-derived lung cancer xenografts and prolonged the survival of LSL-KRASG12D mice. In this commentary, we will summarize the state-of-the art for the direction of synthetic lethality, and also speculate on the future development of this approach. PMID- 27463839 TI - The Challenge of Predicting Pressure Ulcers in Critically Ill Patients. A Multicenter Cohort Study. AB - RATIONALE: Pressure ulcers are preventable events. Critically ill patients are particularly vulnerable. The Braden scale has been used to identify hospitalized patients at high risk for the development of pressure ulcers; however, this predictive tool has not been adequately validated for critically ill patients. OBJECTIVES: We aimed to validate and improve the Braden scale for critically ill patients by adding clinical variables to the original scale. METHODS: We conducted a cohort study in 12 intensive care units (ICUs) within a network of hospitals in Brazil during 2013. We excluded patients who stayed less than 48 hours, patients with one or more pressure ulcers at admission, and those who developed a pressure ulcer within the first 48 hours. We evaluated the Braden scale and clinical variables through a competing risk analysis. Discrimination and calibration were evaluated using the Concordance index (C-index) and a calibration plot, respectively. We used bootstrapping to assess internal validation. MEASUREMENTS AND MAIN RESULTS: Our primary outcome was incident pressure ulcer within 30 days of ICU admission. We analyzed 9,605 patients and observed 157 pressure ulcers (rate of 3.33 pressure ulcers/1,000 patient-days). The majority of pressure ulcers were detected at stage I or II (28.7 and 66.2%, respectively). The Braden scale had good discrimination (C-index, 0.753; 95% confidence interval, 0.712-0.795), although its performance decreased for the most severely ill patients. We derived a modified predictive tool by adding eight clinical variables to the Braden scale: age, sex, diabetes mellitus, hematological malignancy, peripheral artery disease, hypotension at ICU admission, and need for mechanical ventilation or renal replacement therapy in the first 24 hours after ICU admission. The derived score had better discrimination and calibration than the original Braden scale. The best score cutoff was at least 6 points, with a sensitivity of 87% and a specificity of 71%. CONCLUSIONS: The original Braden scale measured at ICU admission is a valuable tool for pressure ulcer prediction, although it is not accurate for severely ill patients. To overcome the limitations of the original scale, we derived a modified score with better performance, which may identify high-risk ICU patients and support target interventions. External validation of the proposed clinical prediction score is needed. PMID- 27463840 TI - Is it primary neuropsychiatric systemic lupus erythematosus? Performance of existing attribution models using physician judgment as the gold standard. AB - OBJECTIVES: Models for the attribution of neuropsychiatric manifestations to systemic lupus erythematosus (NPSLE) that incorporate timing and type of manifestation, exclusion/confounding or favouring factors have been proposed. We tested their diagnostic performance against expert physician judgment. METHODS: SLE patients with neuropsychiatric manifestations were identified through retrospective chart review. Manifestations were classified according to physician judgment as attributed to SLE, not attributed or uncertain. Results were compared against the Systemic Lupus International Collaborating Clinics (SLICC) attribution models A and B, and one introduced by the Italian Study Group on NPSLE. RESULTS: 191 patients experienced a total 242 neuropsychiatric manifestations, 136 of which were attributed to SLE according to physician. Both SLICC models showed high specificity (96.2% and 79.2% for model A and B, respectively) but low sensitivity (22.8% and 34.6%, respectively) against physician judgment. Exclusion of cases of headache, anxiety disorders, mild mood and cognitive disorders and polyneuropathy without electrophysiologic confirmation led to modest increases in sensitivity (27.7% and 42.0% for SLICC models A and B, respectively) and reductions in specificity (94.8% and 65.5%, respectively). The Italian Group model showed good accuracy in NPSLE attribution with an area under the curve of the receiver operating characteristics analysis of 0.862; values >=7 showed the best combination of sensitivity and specificity (82.4% and 82.9%, respectively). CONCLUSIONS: Attribution models can be useful in NPSLE diagnosis in routine clinical practice and their performance is superior in major neuropsychiatric manifestations. The Italian Study Group model is accurate, with values >=7 showing the best combination of sensitivity and specificity. PMID- 27463842 TI - Flexing the PECs: Predicting environmental concentrations of veterinary drugs in Canadian agricultural soils. AB - Veterinary drugs administered to food animals primarily enter ecosystems through the application of livestock waste to agricultural land. Although veterinary drugs are essential for protecting animal health, their entry into the environment may pose a risk for nontarget organisms. A means to predict environmental concentrations of new veterinary drug ingredients in soil is required to assess their environmental fate, distribution, and potential effects. The Canadian predicted environmental concentrations in soil (PECsoil) for new veterinary drug ingredients for use in intensively reared animals is based on the approach currently used by the European Medicines Agency for VICH Phase I environmental assessments. The calculation for the European Medicines Agency PECsoil can be adapted to account for regional animal husbandry and land use practices. Canadian agricultural practices for intensively reared cattle, pigs, and poultry differ substantially from those in the European Union. The development of PECsoil default values and livestock categories representative of typical Canadian animal production methods and nutrient management practices culminates several years of research and an extensive survey and analysis of the scientific literature, Canadian agricultural statistics, national and provincial management recommendations, veterinary product databases, and producers. A PECsoil can be used to rapidly identify new veterinary drugs intended for intensive livestock production that should undergo targeted ecotoxicity and fate testing. The Canadian PECsoil model is readily available, transparent, and requires minimal inputs to generate a screening level environmental assessment for veterinary drugs that can be refined if additional data are available. PECsoil values for a hypothetical veterinary drug dosage regimen are presented and discussed in an international context. Integr Environ Assess Manag 2017;13:331-341. (c) 2016 Her Majesty the Queen in Right of Canada. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of SETAC. Reproduced with the permission of the Minister of Health. PMID- 27463841 TI - Quantitative chemical proteomics profiling of de novo protein synthesis during starvation-mediated autophagy. AB - Autophagy is an intracellular degradation mechanism in response to nutrient starvation. Via autophagy, some nonessential cellular constituents are degraded in a lysosome-dependent manner to generate biomolecules that can be utilized for maintaining the metabolic homeostasis. Although it is known that under starvation the global protein synthesis is significantly reduced mainly due to suppression of MTOR (mechanistic target of rapamycin serine/threonine kinase), emerging evidence demonstrates that de novo protein synthesis is involved in the autophagic process. However, characterizing these de novo proteins has been an issue with current techniques. Here, we developed a novel method to identify newly synthesized proteins during starvation-mediated autophagy by combining bio orthogonal noncanonical amino acid tagging (BONCAT) and isobaric tags for relative and absolute quantitation (iTRAQTM). Using bio-orthogonal metabolic tagging, L-azidohomoalanine (AHA) was incorporated into newly synthesized proteins which were then enriched with avidin beads after a click reaction between alkyne-bearing biotin and AHA's bio-orthogonal azide moiety. The enriched proteins were subjected to iTRAQ labeling for protein identification and quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Via the above approach, we identified and quantified a total of 1176 proteins and among them 711 proteins were found to meet our defined criteria as de novo synthesized proteins during starvation-mediated autophagy. The characterized functional profiles of the 711 newly synthesized proteins by bioinformatics analysis suggest their roles in ensuring the prosurvival outcome of autophagy. Finally, we performed validation assays for some selected proteins and found that knockdown of some genes has a significant impact on starvation-induced autophagy. Thus, we think that the BONCAT-iTRAQ approach is effective in the identification of newly synthesized proteins and provides useful insights to the molecular mechanisms and biological functions of autophagy. PMID- 27463844 TI - Molecular Informatics - From Models to Molecules and Systems. PMID- 27463843 TI - Video gaming in school children: How much is enough? AB - OBJECTIVE: Despite extensive debate, the proposed benefits and risks of video gaming in young people remain to be empirically clarified, particularly as regards an optimal level of use. METHODS: In 2,442 children aged 7 to 11 years, we investigated relationships between weekly video game use, selected cognitive abilities, and conduct-related problems. A large subgroup of these children (n = 260) was further examined with magnetic resonance imaging approximately 1 year later to assess the impact of video gaming on brain structure and function. RESULTS: Playing video games for 1 hour per week was associated with faster and more consistent psychomotor responses to visual stimulation. Remarkably, no further change in motor speed was identified in children playing >2 hours per week. By comparison, the weekly time spent gaming was steadily associated with conduct problems, peer conflicts, and reduced prosocial abilities. These negative implications were clearly visible only in children at the extreme of our game playing distribution, with 9 hours or more of video gaming per week. At a neural level, changes associated with gaming were most evident in basal ganglia white matter and functional connectivity. INTERPRETATION: Significantly better visuomotor skills can be seen in school children playing video games, even with relatively small amounts of use. Frequent weekly use, by contrast, was associated with conduct problems. Further studies are needed to determine whether moderate video gaming causes improved visuomotor skills and whether excessive video gaming causes conduct problems, or whether children who already have these characteristics simply play more video games. Ann Neurol 2016;80:424-433. PMID- 27463845 TI - Drug-Target Networks. AB - Far from the traditional view of selective drug-target interactions, the recent accumulation of large amounts of interaction data for small-molecule drugs and protein targets requires innovative visualisation and analysis tools that are able to deal with what has become a truly complex system. In this context, network theory offers both a robust and illustrative framework to investigate drug-target connections and has been swiftly and widely embraced by the chemical biology and molecular informatics communities. A survey of the most recent applications of drug-target networks to detect cross-pharmacology relationships among targets and to identify new targets for known drugs is provided. Finally, some of the current limitations are also discussed, including the actual completeness of interaction data and the information loss intrinsically associated with the one-mode projection of drug-target networks. PMID- 27463846 TI - Probing Small-Molecule Binding to the Liver-X Receptor: A Mixed-Model QSAR Study. AB - The LXR model has been added in the VirtualToxLab, a fully automated technology that allows for the identification of the endocrine-disrupting potential of drugs, chemicals and natural products. This protocol has then been applied to screen a series of 161 natural compounds probing their binding to the LXR. The results of the simulation were compared with experimental data (where available) and suggest that the LXR model can be applied to predict the binding affinity of existing or hypothetical compounds for screening purposes. The binding of 52 ligands towards the liver X receptors (LXRs) was identified trough docking to the three-dimensional protein structure and quantified by multidimensional QSAR (mQSAR), an approach referred to as 'mixed-model QSAR'. The model was validated by the prediction of 17 external compounds (oxysterols) present neither in the training nor in the test set. The robustness of the model was verified by consensus scoring using a conceptually different methodology, and chance correlation was ruled out by a series of scramble tests. PMID- 27463847 TI - Structuring Chemical Space: Similarity-Based Characterization of the PubChem Database. AB - The ensemble of conceivable molecules is referred to as the Chemical Space. In this article we describe a hierarchical version of the Affinity Propagation (AP) clustering algorithm and apply it to analyze the LINGO-based similarity matrix of a 500 000-molecule subset of the PubChem database, which contains more than 19 million compounds. The combination of two highly efficient methods, namely the AP clustering algorithm and LINGO-based molecular similarity calculations, allows the unbiased analysis of large databases. Hierarchical clustering generates a numerical diagonalization of the similarity matrix. The target-independent, intrinsic structure of the database , derived without any previous information on the physical or biological properties of the compounds, maps together molecules experimentally shown to bind the same biological target or to have similar physical properties. PMID- 27463848 TI - Support Vector Machine (SVM) as Alternative Tool to Assign Acute Aquatic Toxicity Warning Labels to Chemicals. AB - Quantitative structure-activity relationship (QSAR) analysis has been frequently utilized as a computational tool for the prediction of several eco-toxicological parameters including the acute aquatic toxicity. In the present study, we describe a novel integrated strategy to describe the acute aquatic toxicity through the combination of both toxicokinetic and toxicodynamic behaviors of chemicals. In particular, a robust classification model (TOXclass) has been derived by combining Support Vector Machine (SVM) analysis with three classes of toxicokinetic-like molecular descriptors: the autocorrelation molecular electrostatic potential (autoMEP) vectors, Sterimol topological descriptors and logP(o/w) property values. TOXclass model is able to assign chemicals to different levels of acute aquatic toxicity, providing an appropriate answer to the new regulatory requirements. Moreover, we have extended the above mentioned toxicokinetic-like descriptor set with a more toxicodynamic-like descriptors, as for example HOMO and LUMO energies, to generate a valuable SVM classifier (MOAclass) for the prediction of the mode of action (MOA) of toxic chemicals. As preliminary validation of our approach, the toxicokinetic (TOXclass) and the toxicodynamic (MOAclass) models have been applied in series to inspect both aquatic toxicity hazard and mode of action of 296 chemical substances with unknown or uncertain toxicodynamic information to assess the potential ecological risk and the toxic mechanism. PMID- 27463849 TI - Attractors in Sequence Space: Agent-Based Exploration of MHC I Binding Peptides. AB - Ant Colony Optimization (ACO) is a meta-heuristic that utilizes a computational analogue of ant trail pheromones to solve combinatorial optimization problems. The size of the ant colony and the representation of the ants' pheromone trails is unique referring to the given optimization problem. In the present study, we employed ACO to generate novel peptides that stabilize MHC I protein on the plasma membrane of a murine lymphoma cell line. A jury of feedforward neural network classifiers served as fitness function for peptide design by ACO. Bioactive murine MHC I H-2K(b) stabilizing as well as nonstabilizing octapeptides were designed, synthesized and tested. These peptides reveal residue motifs that are relevant for MHC I receptor binding. We demonstrate how the performance of the implemented ACO algorithm depends on the colony size and the size of the search space. The actual peptide design process by ACO constitutes a search path in sequence space that can be visualized as trajectories on a self-organizing map (SOM). By projecting the sequence space on a SOM we visualize the convergence of the different solutions that emerge during the optimization process in sequence space. The SOM representation reveals attractors in sequence space for MHC I binding peptides. The combination of ACO and SOM enables systematic peptide optimization. This technique allows for the rational design of various types of bioactive peptides with minimal experimental effort. Here, we demonstrate its successful application to the design of MHC-I binding and nonbinding peptides which exhibit substantial bioactivity in a cell-based assay. PMID- 27463850 TI - Predicting Cyclooxygenase Inhibition by Three-Dimensional Pharmacophoric Profiling. Part I: Model Generation, Validation and Applicability in Ethnopharmacology. AB - 3D pharmacophore modeling has evolved as an established and state-of-the-art method for performing in-silico predictions of biological activity. Using one single model is limited to single binding modes, while the combination of several models bears a broader application scope. We demonstrate the generation of a complete and predictive 3D model set for cyclooxygenase 1 and 2 inhibitors, along with a selection and validation protocol optimized for parallel virtual screening. This model set was applied to explain the cyclooxygenase activity of an ethnopharmacologically known mixture of natural products, the Thai traditional medicine "Prasaplai". Results show that rationalizing natural product activity by modern in-silico approaches is promising and can be tremendously useful in the identification of the mechanisms of action for known biological effects of complex herbal remedies. PMID- 27463851 TI - A Statistical Survey on the Binding Constants of Covalently Bound Protein-Ligand Complexes. AB - We have conducted a statistical survey to compare the binding constants of covalently and noncovalently bound protein-ligand complexes as two groups. In our study, a total of 1602 complexes formed between various types of proteins and small-molecule ligands were selected from the PDBbind database (version 2008), all of which had high-resolution three-dimensional structures and reliable experimentally measured binding constants. These complexes were further classified as 79 covalent complexes, 131 Zn-containing complexes, and 1392 noncovalent complexes. Covalent complexes formed through reversible mechanisms are found to be associated with higher binding constants than noncovalent complexes. Two-sample T-test indicates that the difference is statistically significant. The advantage, however, is only modest (<20 folds). The same trend is also observed on a set of covalent and noncovalent complexes formed by thrombin. Our results indicate that reversible covalent bonding formed between protein and ligand will not automatically lead to a much tighter binding in general. Thus, our survey does not provide any supporting evidence for Houk's hypothesis which states that covalent bonding formed between enzyme and transition state accounts for the extraordinary proficiency of enzymes. PMID- 27463852 TI - Using In Silico Tools in a Weight of Evidence Approach to Aid Toxicological Assessment. AB - Integrated testing strategies are an important and useful approach to reduce animal usage in toxicity testing. Increased usage of integrated testing strategies is foreseen in current chemical legislation, e.g. REACH. Skin sensitisation is a well studied endpoint and many in silico models have been developed for the prediction of the skin sensitising potential of chemicals. This paper discusses the use of the OECD (Q)SAR Application Toolbox, Derek for Windows, the CAESAR global model and SMARTS rules for reactivity within a weight of evidence approach to predict skin sensitisation. Conclusions drawn from a weight of evidence approach can be used within an integrated testing strategy to reduce the requirement for in vivo tests. Using all four models in this manner enabled 76% of the conclusive predictions made regarding the test data to be in agreement with the observed toxicities. In addition, using all four models in conjunction identified areas where further information is required, as confounding results were produced. The actual data requirements for an integrated testing strategy are discussed along with what considerations need to be made for the remaining compounds that were misclassified or for which the programs contradicted one another and a definitive conclusion could not be reached. PMID- 27463853 TI - Exhaustive Structure Generation for Inverse-QSPR/QSAR. AB - Chemical structure generation based on quantitative structure property relationship (QSPR) or quantitative structure activity relationship (QSAR) models is one of the central themes in the field of computer-aided molecular design. The objective of structure generation is to find promising molecules, which according to statistical models, are considered to have desired properties. In this paper, a new method is proposed for the exhaustive generation of chemical structures based on inverse-QSPR/QSAR. In this method, QSPR/QSAR models are constructed by multiple linear regression method, and then the conditional distribution of explanatory variables given the desired properties is estimated by inverse analysis of the models using the framework of a linear Gaussian model. Finally, chemical structures are exhaustively generated by a sophisticated algorithm that is based on a canonical construction path method. The usefulness of the proposed method is demonstrated using a dataset of the boiling points of acyclic hydrocarbons containing up to 12 carbon atoms. The QSPR model was constructed with 600 hydrocarbons and their boiling points. Using the proposed method, chemical structures which had boiling points of 100, 150, or 200 degrees C were exhaustively generated. PMID- 27463854 TI - Forecasting CYP2D6 and CYP3A4 Risk with a Global/Local Fusion Model of CYP450 Inhibition. AB - This work presents a method to utilize the ever-expanding corporate collections of CYP450 inhibition data to forecast the future risk of compounds not yet synthesized. The global/local fusion method differs from existing QSAR methods, in that each prediction is derived from a custom-built QSAR model, constructed on the-fly, using a customized training set assembled for each prediction. It uses a consensus of global and local descriptor-based models along with pharmacophore based fingerprint similarity to form a prediction and to assess the uncertainty of the prediction on a case-by-case basis. We also present a new forward prediction testing and validation scheme in which the corporate dataset is split chronologically, and predictions for a molecule are based on the pool of existing data available before the molecule is registered and tested. The validation accuracy of the CYP2D6 and CYP3A4 models approaches the underlying accuracy of the data, about 0.4 log IC50 units standard error (or nearly 70% r(2) correlation) for the most confident predictions, and extends to about 0.6 log IC50 units standard error (or under 30% r(2) correlation) for the least confident predictions. As a classification model for CYP2D6 and CYP3A4 activity, the validation accuracy is about 79% for predicted actives and 85% for predicted inactives, which is consistent with existing published models. PMID- 27463855 TI - Author Guidelines. PMID- 27463856 TI - Characterization and non-clinical assessment of the proposed etanercept biosimilar GP2015 with originator etanercept (Enbrel((r))). AB - BACKGROUND AND OBJECTIVE: Biosimilars are approved biologics that are comparable to an originator product with respect to quality, safety and efficacy. Herein, the authors describe the functional and non-clinical studies designed to determine the biosimilarity of GP2015 and originator etanercept (Enbrel(r)). METHODS: The development of an Enbrel biosimilar (GP2015) involved extensive characterization of the originator. A step-wise target-directed and iterative technical development program involving state-of-the-art functional characterization studies and non-clinical evaluations (pharmacokinetics, pharmacodynamics and safety/toxicology) was applied with the aim of confirming that GP2015 is comparable to originator (Enbrel) at the non-clinical level. RESULTS: In in vitro tests, GP2015 and Enbrel had comparable binding affinities to TNF-alpha, C1q complement and a complete panel of Fc-Receptors. Comprehensive functional characterization testing confirmed the comparability of GP2015 with Enbrel in terms of its ability to bind to and neutralize TNF-alpha, which reflects the primary mechanism of action of etanercept. Non-clinical data confirmed that the proposed biosimilar to Enbrel, GP2015, is comparable with regards to its pharmacokinetic properties and pharmacodynamic activity, and efficacy as well as safety/toxicity. CONCLUSION: The proposed Enbrel biosimilar, GP2015, was shown to be comparable to its originator product in studies designed to confirm biosimilarity. PMID- 27463857 TI - Molecular typing of human herpesvirus 8 among HIV positive in comparison to HIV negative individuals in Iran. AB - It is still unclear whether different HHV-8 genotypes may have different pathogenic and tumorigenic properties associated with a diverse rate of disease progression. In some areas where genotype C was found to be prominent among classic KS patients, genotype A was shown to be more frequent among AIDS associated KS patients. Genotype C was previously reported to be widespread in Iran, with genotype A being less frequent among patients with classic KS although no data are available with regards to the HHV-8 genotyping among Iranian HIV infected patients. In order to analyze HHV-8 genotypes (ORF K1), six HIV-infected patients (with or without KS), and 22 HIV-negative subjects (classic/iatrogenic KS patients and IVDUs) were investigated using nested PCR. Genotype A was detected more frequently among HIV-infected patients with or without KS (three out of six) whereas genotype C was found more common among HIV-negative subjects including classic/iatrogenic KS patients and IVDSs (21 out of 22), and this difference was statistically significant (P = 0.044). In conclusion, our data further support the dominancy of HHV-8 genotype C in Iranian general population. Moreover, genotype A was more common among HIV-infected patients with or without KS. J. Med. Virol. 89:703-709, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27463858 TI - Process Development for Separation of Conformers from Derivatives of Resorcin[4]arenes and Pyrogallol[4]arenes. AB - Macrocyclic compounds, such as resorcin[4]arenes and pyrogallol[4]arenes, have proven to be useful building blocks in the construction of supramolecular organic frameworks (SOFs) because of their unique bowl-like shape and ability to interact through variety of intermolecular interactions. Herein, we report the synthesis and crystal structures of two functionalized resorcin[4]arenes and pyroagllol[4]arenes, 4-hydroxyphenylresorcin[4]arenes, and 4 hydroxyphenylpyrogallol[4]arenes. These phenyl-functionalized macrocycles usually have different conformers, such as cone, boat, chair, saddle, and diamond. The successful separation of predominant conformers from the crude product was carried out with solvent-extraction technique. The shape and molecular arrangement of these conformers in the individual crystal structure was verified with single-crystal X-ray diffraction studies. PMID- 27463859 TI - Experimental Active-Site Mapping by Fragments: Hot Spots Remote from the Catalytic Center of Endothiapepsin. AB - Successful optimization of a given lead scaffold requires thorough binding-site mapping of the target protein particular in regions remote from the catalytic center where high conservation across protein families is given. We screened a 361-entry fragment library for binding to the aspartic protease endothiapepsin by crystallography. This enzyme is frequently used as a surrogate for the design of renin and beta-secretase inhibitors. A hit rate of 20% was achieved, providing 71 crystal structures. Here, we discuss 45 binding poses of fragments accommodated in pockets remote from the catalytic dyad. Three major hot spots are discovered in remote binding areas: Asp81, Asp119, and Phe291. Compared to the dyad binders, bulkier fragments occupy these regions. Many of the discovered fragments suggest an optimization concept on how to grow them into larger ligands occupying adjacent binding pockets that will possibly endow them with the desired selectivity for one given member of a protein family. PMID- 27463860 TI - Having Fun on Facebook?: Mothers' Enjoyment as a Moderator of Mental Health and Facebook Use. AB - This study reports results of a study that examined the extent to which contextual factors (i.e., income level and number of children) might predict a mother's mental health quality, which, in turn, may predict level of engagement with Facebook. Results supported this model, finding that mothers with more children and lower income possess lower mental health quality, and lower mental health quality predicted more frequent Facebook use. However, this pattern was qualified by a mother's level of enjoyment of Facebook, such that mental health quality did not significantly predict Facebook intensity when enjoyment of Facebook was low. This research extends practitioners' knowledge of mothers' mental health quality by identifying a behavior that may indicate lower mental health quality and enhance abilities to recognize mothers who may need support or treatment. Future directions for this research are included. PMID- 27463862 TI - Error in Complementary DNA Nomenclature in "Dermatologic Features of ADA2 Deficiency in Cutaneous Polyarteritis Nodosa". PMID- 27463861 TI - Development of innovative hybrid and intrinsically magnetic nanobeads as a drug delivery system. AB - AIM: Synthesis of superparamagnetic hybrid nanobeads (MHNs) made of iron substituted hydroxyapatite nanophase mineralizing a self-assembling alginate (Alg) matrix to be used as drug carriers, with ability of remote activation by magnetic signaling. MATERIALS & METHODS: Iron-doped apatite was heterogeneously nucleated on the self-assembling Alg matrix by a bioinspired mineralization process and MHNs are formed by a subsequent emulsification by oil-in-water technique. RESULTS: The obtained MHNs exhibited biomimetic composition, adequate swelling properties in physiological-like environment and superparamagnetic properties. The assembling of Alg induced the egg-like rearrangement of the mineralized composite that was then stabilized through cross-linking reaction with calcium ions. CONCLUSION: The new MHNs can be considered as a promising biocompatible and bio-resorbable drug delivery system with magnetic properties, thus opening to smart applications in nanomedicine. PMID- 27463863 TI - Coming in sportsmedicine. PMID- 27463866 TI - Scanning sports. PMID- 27463865 TI - Sportsmedicine forum. AB - A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondance to Sports medicine Forum, THE PHYSIC/AN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27463867 TI - Controlling the Supply of Anabolic Steroids. PMID- 27463870 TI - On-the-Job Training. PMID- 27463871 TI - Pathogenic Weight-Control Behaviors of Young Competitive Swimmers. AB - In brief: To study the use of weight-modification techniques by young swimmers, data were collected from 487 girls and 468 boys, aged 9 to 18, at a competitive swimming camp. The survey revealed that (1) many young swimmers had misperceptions about their body weights, with girls particularly likely to misperceive themselves as overweight; (2) swimmers' decisions to lose or gain weight were based on their perceptions more than on their actual weights; (3) opinions of others strongly influenced swimmers' opinions of their own weights; and (4) 15.4% of the girls (24.8% of postmenarcheal girls) and 3.6% of the boys used pathogenic weight-loss techniques. The swimmers' concerns about weight seemed to be more related to societal influences than to the demands of their sport. PMID- 27463872 TI - Exercise and Serum Androgens in Women. AB - In brief: Little information exists about the role of androgens in women relative to exercise, particularly resistance exercise. This study examines (1) the effect of a ten-week hydraulic resistance exercise program on serum androgen levels, strength, and lean body weight and (2) the relationship of serum androgen levels to strength and lean body weight before and after the ten-week program. Thirteen experimental and five control subjects, all college women, participated. Training did not result in significant increases in androgen hormones, although there were significant gains in strength. In addition, no significant correlations were observed between testosterone, androstenedione, or sex hormone-binding globulin and pretraining and delta values of strength or lean body weight (r <.49). PMID- 27463873 TI - Heart Rate and Lactate Levels During Weight-Training Exercise in Trained and Untrained Men. AB - In brief: The effects of squatting exercise on heart rate and blood lactate levels were studied in five trained and five untrained men between the ages of 22 and 37. The subjects performed squats (sets of ten repetitions until exhaustion), resting for 2 1/2 minutes between sets. Total positive work was estimated with the following formula: (bar mass + body mass) X vertical displacement X repetitions. Heart rate, lactate, and rating of perceived exertion were measured immediately before exercise, after each set, and five minutes after reaching exhaustion. The trained subjects performed more total work and had higher heart rates and lactate levels at exhaustion than the untrained subjects, though heart rates and lactate levels were lower for trained subjects at a given bar mass or submaximal work load. The findings suggest that weight training may cause adaptations that result in reduced fatigue and/or enhanced recovery. PMID- 27463874 TI - Metabolie and Cardiorespiratory Responses of Young Women to Skipping and Jogging. AB - In brief: To compare jogging and skipping with respect to metabolic demand, musculoskeletal stress, and perceived exertion, nine women (aged 18 to 29) were studied while jogging and skipping at treadmill speeds of 4.0, 4.8, and 5.4 mph. Data for V O2, heart rate, and perceived exertion were collected, and the subjects provided subjective ratings of musculoskeletal stress. The results showed that skipping imposed significantly greater metabolic demands and caused higher heart rates than jogging at each speed. In additon, skipping was rated as more stressful to the legs and ankles and less enjoyable. Thus skipping appears to be a stronger cardiorespiratory training stimulus than jogging for a given pace, but a less enjoyable activity. PMID- 27463875 TI - Athletes and Their Families: Adapting to the Stresses of Professional Sports. AB - In brief: Professional athletes and their families face many unique stresses associated with geographic relocation, dramatic increase in income, and balancing the demands of the sport with family life. Often the athlete's spouse feels especially isolated without the advantage of team affiliation. The children may feel that the athlete is only a "part-time" parent. When the pressures become too great, the athlete and the family may benefit from a treatment program. This article presents a fictitious case, discusses the problems faced by professional athletes and their families, and suggests ways in which the athlete's physician can help. Indeed, the physician has the opportunity at the initial history-taking and physical examination to make the athlete feel that the physician's office is a safe place to discuss these problems and start resolving them. PMID- 27463876 TI - Selected Sports Bras: A Biomechanical Analysis of Breast Motion While Jogging. AB - In brief: Eight sports bras were compared and evaluated to determine the amount of biomechanical support they provide for small-, medium-, and large-breasted women. Fifty-nine subjects were filmed as they jogged on a treadmill at 6 mph in each of the bras and nude from the waist up. The subjects were divided into cup size groups A, B, C, and D. The mean vertical displacement of the breast relative to the body during one average running stride was calculated (in cm) for each condition. Results showed that the Exercise Sports Top and the Lady Duke bras allowed the least amount of breast movement. The authors list various design features of the bras studied and offer recommendations for active women in selecting a style appropriate for their breast size. PMID- 27463877 TI - Synthetic Anabolic-Androgenic Steroids: A Plea for Controlled Substance Status. AB - One way to combat the abuse of anabolic-androgenic steroids is to reclassify them as controlled substances under federal law. The author contends that the widespread abuse of steroids, their habit-forming properties, and their other adverse effects are good reasons for reclassification. PMID- 27463878 TI - Would Controlled Substance Status Affect Steroid Trafficking? AB - Loss of control over anabolic steroids has prompted the federal government to take steps to stem the black market manufacture and distribution of these drugs. But-at least for now-these steps are likely to stop short of bestowing controlled substance status on steroids. PMID- 27463879 TI - Fitness and Exercise in Advertising: Mining a National Mania. AB - Advertisers are using images of fitness to promote just about every product from cosmetics to candy bars. But these campaigns may increase public acceptance of products that do little to promote health-or that may even harm it. PMID- 27463880 TI - The Medical Risks and Benefits of Sauna, Steam Bath, and Whirlpool Use. AB - Saunas, steam baths, and whirlpools-popular fixtures at health clubs-are safe means of relaxation, if used prudently. But ignoring the recommendations for moderate, commonsense enjoyment of these baths may expose users to health risks. PMID- 27463881 TI - Sauna Use by Competitive Athletes. AB - Some competitive athletes use the sauna as a means to lose weight or to acclimatize to warm weather conditions. These practices, if used at all, should be carefully implemented to prevent health problems. PMID- 27463882 TI - The Vegetarian Athlete. PMID- 27463884 TI - Fast-Twitch and Slow-Twitch Muscle Fibers. PMID- 27463886 TI - The effects of preoperative oral antibiotic use on the development of surgical site infection after elective colorectal resections: A retrospective cohort analysis in consecutively operated 90 patients. AB - PURPOSE: The influence of oral antibiotic use together with mechanical bowel preparation (MBP) on surgical site infection (SSI) rate, length of hospital stay and total hospital costs in patients undergoing elective colorectal surgery were evaluated in this study. METHODS: Data from 90 consecutive patients undergoing elective colorectal resection between October 2006 and September 2009 was analyzed retrospectively. All patients received MBP. Patients in group A were given oral antibiotics (a total 480 mg of gentamycin, 4 gr of metronidazole in two divided doses and 2 mg of bisacodyl PO), whereas patients in group B received no oral antibiotics. Exclusion criteria were emergent operations, laparoscopic operations, preoperative chemoradiotherapy, intraoperative colonoscopy prior to the creation of an anastomosis or antibiotic use within the previous 10 days. SSI, length of hospital stays and total hospital charges were evaluated. RESULTS: Patients in both study groups, group A (n = 45) and group B (n = 45), were similar in terms of age, BMI, diverting ileostomy creation, localization and stage of the disease. Patients receiving oral antibiotics demonstrated a lower rate of wound infections (36% vs. 71%, p < 0.001), shorter hospital stay (8.1 +/- 2.4 days vs. 14.2 +/- 10.9 days, respectively, p < 0.001) and similar rates for anastomotic leakage (2% vs. 11%, p = 0.20). The mean +/- SD total hospital charges were significantly lower in Group A (2.699 +/- 0.892$) than that in Group B (4.411 +/- 4.995$, p = 0.029). CONCLUSION: Preoperative oral antibiotic use with MBP may provide faster recovery with less SSI and hospital charges. PMID- 27463887 TI - A prospective study on the reciprocal influence between personality and attitudes, behaviors, and psychological characteristics salient in eating disorders in a sample of non-clinical adolescents. AB - Eating disorders are mosy likely to occur for the first time in adolescence. Delineating vulnerable personality profiles of unhealthy conditions helps prevent their onset and development. This study investigated a non-clinical sample of 142 adolescents and how some theoretically salient individual differences in personality contribute to predict changes in behaviors, attitudes, and psychological characteristics that are clinically significant in eating disorders (EDs). The results from cross-lagged pattern analyses supported the influence of depression, obsessiveness, and self-esteem in the trajectories favoring the development of psychological characteristics, such as ineffectiveness and interoceptive awareness, which are salient in the ED risk process. Results also confirmed that body mass index, perfectionism, and body dissatisfaction predict increases in dysfunctional concerns with weight control and food consumption. Empirical support for the impact of ED-relevant variables on personality self views emerged as well. Trajectories linking EDs and personality in relation to sex differences and permeability to transitory psychological conditions in adolescence were also confirmed. PMID- 27463888 TI - Science translational medicine issue. PMID- 27463889 TI - Evaluation of erlotinib treatment response in non-small cell lung cancer using metabolic and anatomic criteria. AB - BACKGROUND: In this paper the clinical value of PET for early prediction of tumor response to erlotinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen is evaluated. The aim was to compare the early metabolic treatment response using European Organization for Research and Treatment of Cancer (EORTC) 1999 recommendations and PET Response Criteria in Solid Tumors (PERCIST), and the standard treatment response using Response Evaluation Criteria in Solid Tumors (RECIST). METHODS: Twenty patients with stage IV NSCLC were enrolled prospectively. PET/CT studies were performed before, then 48 hours, and 45 days after the initiation of erlotinib treatment. The lesion with the highest uptake in each patient was evaluated according to EORTC 1999 recommendations, PERCIST and RECIST to assess metabolic and anatomic response. Response classifications were compared statistically using Wilcoxon signed-rank test. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier Test. RESULTS: At 48 hours, the Kaplan-Meier analysis showed that EORTC proved to be a significant prognostic factor for predicting DFS and OS. At 45 days, there was a significant difference in response evaluation between RECIST and metabolic classifications. RECIST and PERCIST were significant prognostic factors for predicting DFS and OS. EORTC was not able to discriminate responder from non responder patients. CONCLUSIONS: This study shows that, according to the EORTC protocol, the PET exam is able to provide early identification of patients who benefit from Erlotinib treatment. Used at the end of therapy, PERCIST could be considered an appropriate metabolic evaluation method to discriminate responders from non-responders. PMID- 27463892 TI - Relative Contribution of Lateral Packing Density to Albumin Adsorption on Monolayers. AB - The effect of functional group density on protein adsorption is systematically studied to support ongoing efforts in molecular imprinting of surfaces and bulk materials. In these applications, functional commodity chemicals are molded to complement the shape and chemistry of the target molecule. Here, we study the relationship between bovine serum albumin adsorption and ligand density for carboxylate, alcohol, and alkyl terminal groups. Control surfaces consisting of densely packed self-assembled monolayers (SAMs) are contrasted with low-density SAMs formed through thiol-yne chemistry. Direct comparison consistently yielded greater protein adsorption on low-density SAMs than conventional pure component SAMs of the same functional group. Critically, the carboxylate and alcohol low density SAMS are more hydrophobic than their analogous dense SAMs. Mixed functional group, dense SAMs were formed with alkyl diluents to match the hydrophobicity of the low-density SAMs. Once hydrophobicity is matched, the dense carboxylate and alcohol SAMs have higher adsorption than the low-density SAMs. We conclude (1) surface charge and hydrophobicity trends dominate over surface density contributions; (2) when hydrophobicity is matched, greater adsorption occurs on dense hydrophilic groups than on lower density hydrophilic groups; (3) when hydrophobicity is matched, greater adsorption occurs on lower density hydrophobic groups than on higher density hydrophobic groups. PMID- 27463893 TI - 1200 degrees C high-temperature distributed optical fiber sensing using Brillouin optical time domain analysis. AB - In this paper, up to 1100 degrees C and 1200 degrees C high-temperature distributed Brillouin sensing based on a GeO2-doped single-mode fiber (SMF) and a pure silica photonic crystal fiber (PCF) are demonstrated, respectively. The Brillouin frequency shift's (BFS) dependence on temperatures of the SMF and PCF agrees with a nonlinear function instead of a linear function, which is mainly due to the change of the acoustic velocity in a silica fiber. BFS hopping is observed in both kinds of fibers between 800 degrees C-900 degrees C in the first annealing process, and after that, the BFS exhibits stability and repeatability with a measurement accuracy as high as +/-2.4 degrees C for the SMF and +/-3.6 degrees C for the PCF. The BFS hopping is a highly temperature dependent behavior, which means that a high temperature (>800 degrees C) would accelerate this process to reach a stable state. After BFS hopping, both the SMF and PCF show good repeatability for temperatures higher than 1000 degrees C without annealing. The process of coating burning of a silica fiber not only introduces a loss induced by micro-bending, but also imposes a compressive stress on the bare fiber, which contributes to an additional BFS variation at the temperature period of the coating burning (~300 degrees C-500 degrees C). PMID- 27463891 TI - Fragment-based approach to calculate hydrophobicity of anionic and nonionic surfactants derived from chromatographic retention on a C18 stationary phase. AB - To predict the fate and potential effects of organic contaminants, information about their hydrophobicity is required. However, common parameters to describe the hydrophobicity of organic compounds (e.g., octanol-water partition constant [KOW ]) proved to be inadequate for ionic and nonionic surfactants because of their surface-active properties. As an alternative approach to determine their hydrophobicity, the aim of the present study was therefore to measure the retention of a wide range of surfactants on a C18 stationary phase. Capacity factors in pure water (k'0 ) increased linearly with increasing number of carbon atoms in the surfactant structure. Fragment contribution values were determined for each structural unit with multilinear regression, and the results were consistent with the expected influence of these fragments on the hydrophobicity of surfactants. Capacity factors of reference compounds and log KOW values from the literature were used to estimate log KOW values for surfactants (log KOWHPLC). These log KOWHPLC values were also compared to log KOW values calculated with 4 computational programs: KOWWIN, Marvin calculator, SPARC, and COSMOThermX. In conclusion, capacity factors from a C18 stationary phase are found to better reflect hydrophobicity of surfactants than their KOW values. Environ Toxicol Chem 2017;36:329-336. (c) 2016 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 27463890 TI - The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair. AB - USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2 independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1. PMID- 27463894 TI - Differentiation of tumor vasculature heterogeneity levels in small animals based on total hemoglobin concentration using magnetic resonance-guided diffuse optical tomography in vivo. AB - Insight into the vasculature of the tumor in small animals has the potential to impact many areas of cancer research. The heterogeneity of the vasculature of a tumor is directly related to tumor stage and disease progression. In this small scale animal study, we investigated the feasibility of differentiating tumors with different levels of vasculature heterogeneity in vivo using a previously developed hybrid magnetic resonance imaging (MRI) and diffuse optical tomography (DOT) system for small animal imaging. Cross-sectional total hemoglobin concentration maps of 10 Fisher rats bearing R3230 breast tumors are reconstructed using multi-wavelength DOT measurements both with and without magnetic resonance (MR) structural a priori information. Simultaneously acquired MR structural images are used to guide and constrain the DOT reconstruction, while dynamic contrast-enhanced MR functional images are used as the gold standard to classify the vasculature of the tumor into two types: high versus low heterogeneity. These preliminary results show that the stand-alone DOT is unable to differentiate tumors with low and high vascular heterogeneity without structural a priori information provided by a high resolution imaging modality. The mean total hemoglobin concentrations comparing the vasculature of the tumors with low and high heterogeneity are significant (p-value 0.02) only when MR structural a priori information is utilized. PMID- 27463895 TI - Simulating receptive fields of human visual cortex for 3D image quality prediction. AB - Quality assessment of 3D images presents many challenges when attempting to gain better understanding of the human visual system. In this paper, we propose a new 3D image quality prediction approach by simulating receptive fields (RFs) of human visual cortex. To be more specific, we extract the RFs from a complete visual pathway, and calculate their similarity indices between the reference and distorted 3D images. The final quality score is obtained by determining their connections via support vector regression. Experimental results on three 3D image quality assessment databases demonstrate that in comparison with the most relevant existing methods, the devised algorithm achieves high consistency alignment with subjective assessment, especially for asymmetrically distorted stereoscopic images. PMID- 27463896 TI - Research on beam characteristics in a large-Fresnel-number unstable-waveguide hybrid resonator with parabolic mirrors. AB - Large-Fresnel-number unstable-waveguide hybrid resonators employing spherical resonator mirrors suffer from spherical aberration, which adversely affects beam quality and alignment sensitivity. In this paper, we present experimental and numerical wave-optics simulations of the beam characteristics of a negative branch hybrid resonator having parabolic mirrors with a large equivalent Fresnel number in the unstable direction. These results are compared with a resonator using spherical mirrors. Using parabolic mirrors, the output beam has a smaller beam spot size and higher power density at the focal plane. We found that the power extraction efficiency is 3.5% higher when compared with a resonator using spherical mirrors as the cavity length was varied between -1 and 1 mm from the ideal confocal resonator. In addition, the power extraction efficiency is 5.6% higher for mirror tilt angles varied between -6 and 6 mrad. Furthermore, the output propagating field is similar to a converging wave for a spherical mirror resonator and the output beam direction deviates 3.5 mrad from the optical axis. The simulation results are in good agreement with the experimental results. PMID- 27463897 TI - Saturable absorber: transparent glass-ceramics based on a mixture of Co:beta Zn2SiO4 and Co:ZnO nanocrystals. AB - We report on the development of novel saturable absorbers for erbium lasers based on transparent glass-ceramics (GCs) containing a mixture of cobalt-doped beta willemite, Co2+:beta-Zn2SiO4, and zinc oxide, Co2+:ZnO, nanosized (10-14 nm) crystals. The structure of the parent glass and GCs is studied by x-ray diffraction, differential scanning calorimetry, transmission electron microscopy, and Raman spectroscopy. Variations of absorption spectra with heat-treatment reveal that Co2+ ions from the parent glass enter the crystals of ZnO and beta-willemite. GCs are characterized by a broad absorption band due to the A24(F4)->T14(F4) transition of Co2+ ions in tetrahedral sites spanning up to ~1.74 MUm, relatively low saturation fluence, FS=0.75 J/cm2 at 1.54 MUm, short recovery time, tau=830 ns, and high laser damage threshold, ~14 J/cm2. By using the developed GCs in a diode-side-pumped Er, Yb:glass laser, 0.77 mJ/45 ns pulses are generated. PMID- 27463898 TI - Stokes-vector-based polarimetric imaging system for adaptive target/background contrast enhancement. AB - A novel method to optimize the polarization state of a polarimetric imaging system is proposed to solve the problem of target/background contrast enhancement in an outdoor environment adaptively. First, the last three elements of the Stokes vector are selected to be the observed object's polarization features, the discriminant projection of which is regarded as the detecting function of our imaging system. Then, the polarization state of the system, which can be seen as a physical classifier, is calculated by training samples with a support vector machine method. Finally, images processed by the system with the designed optimal polarization state become discriminative output directly. By this means, the target/background contrast is enhanced greatly, which results in a more accurate and convenient target discrimination. Experimental results demonstrate that the effectiveness and discriminative ability of the optimal polarization state are credible and stable. PMID- 27463899 TI - Research of dual-band microwave photonic filter for WLAN based on optical frequency comb. AB - This paper presents a dual-band microwave photonic filter for a wireless local area networks with independently tunable passband center frequencies and bandwidths. The two bands of the filter were 2.4 GHz and 5.725 GHz, respectively. The filter was based on a stimulated Brillouin scattering and an optical frequency comb (OFC) scheme. We created this filter using OFC pumps instead of a single pump. The OFC scheme consists of a cascaded Mach-Zehnder modulator (MZM) and a dual-parallel MZM (DPMZM) hybrid modulation that generated seven and 11 lines. The experimental results show that the two passbands of the filter were 80 and 130 MHz. PMID- 27463900 TI - Multipoint sensing with a low-coherence source using single-arm frequency-shifted interferometry. AB - We demonstrate that multiple-site sensing along an optical fiber can be done with incoherent continuous-wave light. Using a broadband low-coherence noise source, a slow detector, and an optical modulator, we construct a single-arm frequency shifted interferometer (SA-FSI) capable of simultaneously sensing multiple weak reflection sites distributed either in parallel or in series along fiber links. By scanning the driving frequency of an electro-optic amplitude modulator in the range of 2.7-3.2 GHz at steps of 41.7 KHz, we demonstrate a spatial resolution of 0.3 m and a measurement range of over 1 km. PMID- 27463901 TI - Edge-wave method for calculating the output mode of strip unstable resonators. AB - We develop an edge-wave method for calculating the output mode of a positive branch off-axis unstable resonator. According to the iterative property of the edge-wave function, the transmission line of the apertures is adopted to solve the Fox-Li iteration for calculating the lowest loss mode on the output plane. Furthermore, the so-called mask effect is eliminated by revising the edge-wave function derived from the last order aperture, so that the modified formula can be utilized to calculate the output mode directly. The method can be employed in most cases, with an exception at the mode crossing point. PMID- 27463902 TI - Rapid and automatic 3D body measurement system based on a GPU-Steger line detector. AB - This paper proposes a rapid and automatic measurement system to acquire a 3D shape of a human body. A flexible calibration method was developed to decrease the complexity in system calibration. To reduce the computation cost, a GPU Steger line detector was proposed to more rapidly detect the center of the laser pattern and at subpixel level. The processing time of line detection is significantly shortened by the GPU-Steger line detector, which can be over 110 times faster than that by CPU. The key technologies are introduced, and the experimental results are presented in this paper to illustrate the performance of the proposed system. The system can be used to measure human body surfaces with nonuniform reflectance such as hair, skin, and clothes with rich texture. PMID- 27463903 TI - Modeling and empirical characterization of the polarization response of off-plane reflection gratings. AB - Off-plane reflection gratings were previously predicted to have different efficiencies when the incident light is polarized in the transverse-magnetic (TM) versus transverse-electric (TE) orientations with respect to the grating grooves. However, more recent theoretical calculations which rigorously account for finitely conducting, rather than perfectly conducting, grating materials no longer predict significant polarization sensitivity. We present the first empirical results for radially ruled, laminar groove profile gratings in the off plane mount, which demonstrate no difference in TM versus TE efficiency across our entire 300-1500 eV bandpass. These measurements together with the recent theoretical results confirm that grazing incidence off-plane reflection gratings using real, not perfectly conducting, materials are not polarization sensitive. PMID- 27463904 TI - Incoherent wavefront reconstruction by a retroemission device containing a thin fluorescent film: theory. AB - A retroemission device (REM) is an incoherent holographic device that represents a lenslet array situated on a substrate containing fluorescent material. Each lenslet focuses each wavelet of an optical wavefront incident on the REM device into a diffraction-limited volume (voxel) in the fluorescent material, so that the voxel coordinates encode the angle of incidence and curvature of the wavelet. The back-propagating fraction of the excited fluorescence is collected by the lenslet and quasi-collimated into a back-propagating wavelet. All wavelets are combined to reconstruct the incident wavefront propagating in the backward direction. We present a theoretical model of REM based on Fresnel-Kirchhoff approximation describing the reconstructed 3D image characteristics versus the thickness of the fluorescence film at the focal plane of the lenslets. Results of the computer simulations of the REM-based images of a point source, two axially separated point sources and an extended object (a circular rim) situated in the sagittal plane are presented. These results speak in favor of using a fluorescence film of minimum diffraction-limited thickness at the lenslet back focal plane. This REM structure minimizes the fluorescence background and improves the 3D imaging resolution in virtue of the exclusion of out-of-voxel fluorescence contributions to the reconstructed wavefront. PMID- 27463905 TI - Increasing signal amplitude in fiber Bragg grating detection of Lamb waves using remote bonding. AB - Networks of fiber Bragg grating (FBG) sensors can serve as structural health monitoring systems for large-scale structures based on the collection of ultrasonic waves. The demodulation of structural Lamb waves using FBG sensors requires a high signal-to-noise ratio because the Lamb waves are of low amplitudes. This paper compares the signal transfer amplitudes between two adhesive mounting configurations for an FBG to detect Lamb waves propagating in an aluminum plate: a directly bonded FBG and a remotely bonded FBG. In the directly bonded FBG case, the Lamb waves create in-plane and out-of-plane displacements, which are transferred through the adhesive bond and detected by the FBG sensor. In the remotely bonded FBG case, the Lamb waves are converted into longitudinal and flexural traveling waves in the optical fiber at the adhesive bond, which propagate through the optical fiber and are detected by the FBG sensor. A theoretical prediction of overall signal attenuation also is performed, which is the combination of material attenuation in the plate and optical fiber and attenuation due to wave spreading in the plate. The experimental results demonstrate that remote bonding of the FBG significantly increases the signal amplitude measured by the FBG. PMID- 27463906 TI - All-optical low noise fiber Bragg grating microphone. AB - We present an all-fiber design for a microphone using a fiber Bragg grating Fabry Perot resonator attached to a diaphragm transducer. We analytically model and verify the fiber-diaphragm mechanical interaction, using the Hansch-Couillaud readout technique to provide necessary sensitivity. We achieved a noise equivalent strain sensitivity of 7.1*10-12 epsilon/Hz, which corresponds to a sound pressure of 74 MUPa/Hz at 1 kHz limited by laser frequency noise and yielding a signal-to-noise ratio of 47+/-2 dB with a 1 Pa drive at 1 kHz, in close agreement with modeled results. PMID- 27463907 TI - Distortion-free femtosecond laser inscription in free-standing optical fiber. AB - In this paper, we report the first experimental demonstration, to the best of our knowledge, of low-energy distortion-free femtosecond laser inscription in a free standing fiber without the need for oil immersion. The methodology proposed features radial-plane beam shaping to eliminate the focal-point distortion induced by the cylindrical geometry of the fiber, thus achieving optimal focusing and spot-like inscription within the fiber. Based on the proposed methodology, a strong, first-order fiber Bragg grating is achieved for the first time, to the best of our knowledge, in a coated free-standing single-mode fiber by using the point-by-point inscription technique with only 50 nJ laser pulse energy. PMID- 27463908 TI - Innovative high-gain optically pumped far-infrared laser. AB - A new optically pumped far-infrared (FIR) laser with separate pump beam reflector and FIR output coupler has been developed. The new design greatly simplifies the tuning of the laser and enables the optimization of the pump beam absorption without affecting the laser alignment. Working with formic acid (HCOOH) vapor pumped by a 30 W CO2 laser at the 9R20 line, a high laser gain of 3 dB/m and power conversion efficiency of 16.4% of the Manley-Rowe limit are achieved for the FIR wavelength of 433 MUm. PMID- 27463909 TI - Ultralong time response of magnetic fluid based on fiber-optic evanescent field. AB - The ultralong time (a few hours) response properties of magnetic fluid using etched optical fiber are visualized and investigated experimentally. The operating structure is made by injecting magnetic fluid into a capillary tube that contains etched single-mode fiber. An interesting extreme asymmetry is observed, in which the transmitted light intensity after the etched optical fiber cannot reach the final steady value when the external magnetic field is turned on (referred to as the falling process), while it can reach the stable state quickly once the magnetic field is turned off (referred to as the rising process). The relationship between the response times/loss rates of the transmitted light and the strength of the applied magnetic field is obtained. The physical mechanisms of two different processes are discussed qualitatively. PMID- 27463910 TI - Two-window InSbBi quantum-dot photodetector. AB - Quantum efficiency (QE) was modeled for an n-type doping InSb1 xBix quantum-dot (QD) photodetector with a p-type doping AlGaAs bulk region. First, the relations of the electron and hole contributions to the current were stated. The absorption coefficient was calculated for the structure, and two windows were predicted in the quantum efficiency spectrum, which is important in the detection applications. High quantum efficiency was obtained due to the Bi inclusion in the structure of the photodetector. PMID- 27463911 TI - Two spatial light modulator system for laboratory simulation of random beam propagation in random media: comment. AB - In a recent paper [Appl. Opt.55, 1112 (2016)APOPAI0003-693510.1364/AO.55.001112], the authors present a procedure for synthesizing Gaussian phase screens to generate Schell-model sources. Their synthesis method is analyzed, revealing interesting phenomena not fully described by the authors. PMID- 27463912 TI - Waveguide-coupled hybrid plasmonic modulator based on graphene. AB - In this paper, we propose a low-transmission-loss, high-speed, graphene-based electro-absorption modulator with a hybrid plasmonic waveguide at 1.55 MUm. In the proposed device, double-layer graphene is placed on top of the horizontal hybrid plasmonic waveguide to enhance the light-graphene interaction. The adjustment of the in-plane permittivity of the anisotropy graphene causes a significant modulation of the absorption at the operating bandwidth of 0.4 THz, with modulation length of 8.5 MUm and modulator footprint of 1.6 MUm2. A taper silicon coupler is used for waveguide coupling, and 80% coupling efficiency is achieved. In addition, the modulation potential on a smaller footprint is further shown. PMID- 27463913 TI - Fiber-optic fluorescence-quenching oxygen partial pressure sensor using platinum octaethylporphyrin. AB - The development and bench testing of a fiber-optic oxygen sensor is described. The sensor is designed for measurement of tissue oxygen levels in the mucosa of the digestive tract. The materials and construction are optimized for insertion through the mouth for measurement in the lower esophagus. An oxygen-sensitive fluorescence-quenching film was applied as a solution of platinum octaethylporphyrin (PtOEP) poly(ethyl methacrylate) (PEMA) and dichloromethane and dip coated onto the distal tip of the fiber. The sensor was tested by comparing relative fluorescence when immersed in liquid water at 37 degrees C, at a range of partial pressures (0-101 kPa). Maximum relative fluorescence at most oxygen concentrations was seen when the PtOEP concentration was 0.1 g.L 1, four layers of coating solution were applied, and a fiber core radius of 600 MUm was selected, giving a Stern-Volmer constant of 0.129 kPa-1. The performance of the sensor is suitable for many in vivo applications, particularly mucosal measurements. It has sufficient sensitivity, is sterilizable, and is sufficiently flexible and robust for insertion via the mouth without damage to the probe or risk of harm to the patient. PMID- 27463914 TI - In-plane displacement measurement using optical vortex phase shifting. AB - In this paper, we propose a new method for in-plane displacement measurement by application of phase shifting based on an optical vortex. The phase shifts are obtained by displaying computer-generated fork holograms on the screen of a liquid-crystal spatial light modulator (LC-SLM). Furthermore, the vortex beam that is generated by the LC-SLM can be used as a reference light in the experiment. Eight speckle patterns with phase-shift increments of 0, pi/2, pi, and 3pi/2 were captured by a CCD camera before and after the deformation. The displacement of the deformed object was obtained by unwrapping. Experimental results demonstrated the efficacy of the proposed method for in-plane displacement measurement. PMID- 27463915 TI - Performance evaluation of hybrid DPSK-MPPM techniques in long-haul optical transmission. AB - In this paper, we evaluate the performance of hybrid differential phase shift keying-multipulse pulse position modulation (DPSK-MPPM) techniques in long-haul nonlinear-dispersive optical fiber transmission. An expression for the nonlinear interference variance is obtained analytically using the Gaussian noise (GN) model. We derive upper-bound expressions that take into account the fiber nonlinearity impact on the DPSK-MPPM system's performance for both bit- and symbol-error rates (BER and SER). The tightness of the BER's upper bound is verified using Monte Carlo simulation. The numerical analysis is carried out based on the proposed setup supplemented by a realistic simulation scenario for the DPSK-MPPM long-haul optical transmission system. Our results reveal that while the hybrid DPSK-MPPM technique outperforms both traditional DPSK and MPPM techniques under amplified spontaneous emission (ASE) noise (linear limit), it is less robust when fiber nonlinearity is considered. However, under the impact of low nonlinearity, the performance of a hybrid technique still surpasses the traditional ones. We also discuss the effect of some wavelength-division multiplexing (WDM) parameters on optimal system performance. The nonlinear interference penalties on the maximum reachable distances by both hybrid and traditional modulation systems are then investigated at a forward-error correction (FEC) requirement (BER=10-3). In particular, at an average launch power of -8 dBm, the hybrid DQPSK-MPPM system with a total frame length of eight time slots including two signal time slots outreaches a traditional DQPSK system by 950 km. PMID- 27463916 TI - Optical stabilization system based on deformable mirrors for retina-like sensors. AB - This paper presents an optical stabilization system based on deformable mirrors (DMs) for retina-like sensors. This system achieves image stabilization by changing the reflective plate of the DM's compensating tilt angle. The mathematical model is constructed with relative parameters, and the simulation experiments and parameter analysis are discussed to verify the system's reliability. The experimental results show that this system achieved optical image stabilization. The maximum relative error of the compensation angle is 8.78%. The system is close to the diffraction limit, and the distortion is less than 0.33%. This study presents an image stabilization system and offers possible improvement in the aberrations in the system, which will provide great support to retina-like sensors. PMID- 27463917 TI - Two-beam combined 3.36 J, 100 Hz diode-pumped high beam quality Nd:YAG laser system. AB - In this paper, we develop a diode-pumped all-solid-state high-energy and high beam quality Nd:YAG laser system. A master oscillator power amplifier structure is used to provide a high pulse energy laser output with a high repetition rate. In order to decrease the amplifier working current so as to reduce the impact of the thermal effect on the beam quality, a beam splitting-amplifying-combining scheme is adopted. The energy extraction efficiency of the laser system is 50.68%. We achieve 3.36 J pulse energy at a 100 Hz repetition rate with a pulse duration of 7.1 ns, a far-field beam spot 1.71 times the diffraction limit, and 1.07% energy stability (RMS). PMID- 27463918 TI - Low-level birefringence measurement by cyclic-path polarization interferometer. AB - A modified cyclic-path interferometer is employed for complete measurement of spatially varying birefringence. An expanded and collimated laser beam intercepted by a birefringent specimen is incident on a polarization-masked cube beam splitter, resulting in two mutually orthogonal polarization components propagating along clockwise and counterclockwise directions in the interferometer. These two wavefronts are made to interfere for four specific orientations of an analyzer. Suitable combinations of the interferograms result in determination of the direction of birefringence and its magnitude. Experimental results are presented. PMID- 27463919 TI - Gain-compensated sinusoidal scanning of a galvanometer mirror in proportional integral-differential control using the pre-emphasis technique for motion-blur compensation. AB - We propose a method to achieve precise sine-wave path tracking for real-time motion-blur compensation to extend the corresponding frequency spectrum in proportional-integral-differential (PID) control by using a pre-emphasis technique. We calculate pre-emphasis coefficients in advance to follow a sine wave with a gain of 0 dB and multiply the input signal by these pre-emphasis coefficients. In experiments, we were thus able to extend the greatest frequency from 100 to 500 Hz and achieve gain improvement of approximately 3 dB at 400 and 500 Hz. For the application of inspection, we confirmed that motion blur is significantly reduced when the system operates at high frequency, and we achieved a responsiveness 3.3 times higher than that of our previous system. PMID- 27463920 TI - Single plasma mirror providing 104 contrast enhancement and 70% reflectivity for intense femtosecond lasers. AB - To efficiently eliminate picosecond pre-pulses that accompany ultrashort pulses emitted from high-power chirped-pulse-amplification laser systems, we have developed a high-performance plasma mirror system. By reducing the reflectivity of the antireflection coating on the substrate for the plasma mirror to the limit of current technology (~0.006%), we achieved the highest pre-pulse contrast enhancement reported to date for a single plasma mirror of 104 at 1 ps before the pulse peak. By optimizing the laser incidence to the plasma mirror and the laser fluence, the reflectivity of the plasma mirror has been improved to 70%. The contrast improvement indicates extensibility to 100 PW class lasers by doubling this plasma mirror system. Contrast enhancement of 108 should be possible without a serious reduction in energy (no more than 50%). PMID- 27463921 TI - Multiple scattering of polarized light in turbid birefringent media: a Monte Carlo simulation. AB - Multiple scattering of polarized light in a birefringent turbid plane medium was studied using a Monte Carlo simulation. The reduced effective scattering Mueller matrix obtained in the simulation was factorized in two dimensions using the Lu Chipman decomposition, yielding polarization parameters that exhibited dependences on the azimuth and the radial distance around the illumination point. We propose a double-scattering model for the propagation of polarized photons in turbid infinite plane media. When the birefringence slow axis is along the azimuth of 90 degrees on the plane surface, the retardance becomes the largest negative along the azimuth of 0 degrees and the largest positive along the azimuth of 90 degrees and increases with increasing the azimuth from 0 degrees to 90 degrees . This azimuthal dependence may result from the overlap of the contributions from the light propagations vertical to, and lateral along, the plane surface. Thus, the dependences on the azimuth and the radial distance of the polarization parameters, such as the retardance, its orientation, optical rotation, and the depolarization coefficients, are correctly predicted. PMID- 27463922 TI - Natural dye extracted from karkadah and its application in dye-sensitized solar cells: experimental and density functional theory study: publisher's note. AB - This note corrects an error in the math of [Appl. Opt.55, 838 (2016)APOPAI0003 693510.1364/AO.55.000838] and reports a deletion of text that should have occurred in production. PMID- 27463923 TI - Accurate quantitative phase digital holographic microscopy with single- and multiple-wavelength telecentric and nontelecentric configurations. AB - In this work, we investigate, both theoretically and experimentally, single wavelength and multiwavelength digital holographic microscopy (DHM) using telecentric and nontelecentric configurations in transmission and reflection modes. A single-wavelength telecentric imaging system in DHM was originally proposed to circumvent the residual parabolic phase distortion due to the microscope objective (MO) in standard nontelecentric DHM configurations. However, telecentric configurations cannot compensate for higher order phase aberrations. As an extension to the telecentric and nontelecentric arrangements in single wavelength DHM (SW-DHM), we propose multiple-wavelength telecentric DHM (MW-TDHM) in reflection and transmission modes. The advantages of MW-TDHM configurations are to extend the vertical measurement range without phase ambiguity and optically remove the parabolic phase distortion caused by the MO in traditional MW-DHM. These configurations eliminate the need for a second reference hologram to subtract the two-phase maps and make digital automatic aberration compensation easier to apply compared to nontelecentric configurations. We also discuss a reconstruction algorithm that eliminates the zero-order and virtual images using spatial filtering and another algorithm that minimizes the intensity of fluctuations using apodization. In addition, we employ two polynomial models using 2D surface fitting to compensate digitally for chromatic aberration (in the multiwavelength case) and for higher order phase aberrations. A custom-developed user-friendly graphical user interface is employed to automate the reconstruction processes for all configurations. Finally, TDHM is used to visualize cells from the highly invasive MDA-MB-231 cultured breast cancer cells. PMID- 27463924 TI - Effect of temperature on terahertz photonic and omnidirectional band gaps in one dimensional quasi-periodic photonic crystals composed of semiconductor InSb. AB - Engineering of thermally tunable terahertz photonic and omnidirectional bandgaps has been demonstrated theoretically in one-dimensional quasi-periodic photonic crystals (PCs) containing semiconductor and dielectric materials. The considered quasi-periodic structures are taken in the form of Fibonacci, Thue-Morse, and double periodic sequences. We have shown that the photonic and omnidirectional bandgaps in the quasi-periodic structures with semiconductor constituents are strongly depend on the temperature, thickness of the constituted semiconductor and dielectric material layers, and generations of the quasi-periodic sequences. It has been found that the number of photonic bandgaps increases with layer thickness and generation of the quasi-periodic sequences. Omnidirectional bandgaps in the structures have also been obtained. Results show that the bandwidths of photonic and omnidirectional bandgaps are tunable by changing the temperature and lattice parameters of the structures. The generation of quasi periodic sequences can also change the properties of photonic and omnidirectional bandgaps remarkably. The frequency range of the photonic and omnidirectional bandgaps can be tuned by the change of temperature and layer thickness of the considered quasi-periodic structures. This work will be useful to design tunable terahertz PC devices. PMID- 27463925 TI - Design of optical reversible logic gates using electro-optic effect of lithium niobate based Mach-Zehnder interferometers. AB - In recent years reversible logic has come as a promising solution in the optical computing domain. In reversible gates, there is one-to-one mapping between input and output, causing no loss of information. Reversible gates are useful for application in low power complementary metal-oxide semiconductors, with less dissipation, and in quantum computing. These benefits can be utilized by implementing reversible gate structures in the optical domain. In this paper, basic reversible Feynman and Fredkin logic gates using a lithium niobate based Mach-Zehnder interferometer are proposed. The different applications utilizing the proposed structures are also explained in this study. PMID- 27463926 TI - Platinum-scatterer-based random lasers from dye-doped polymer-dispersed liquid crystals in capillary tubes. AB - The resonance characteristics of platinum-scatter-based random lasers from dye doped polymer-dispersed liquid crystals (DDPDLCs) in capillary tubes were researched for the first time, to the best of our knowledge. After adding platinum nanoparticles (Pt NPs) into the liquid crystal mixtures, the emission spectra of DDPDLCs revealed a lower lasing threshold in comparison with those of DDPDLCs without Pt NPs due to light scattering of liquid crystal droplets and the local field enhancement around Pt NPs. Furthermore, the full width at half maximum (FWHM) and the lasing threshold were determined by the doping density of the Pt NPs. The threshold was decreased by about half from 17.5 MUJ/pulse to 8.7 MUJ/pulse on the condition that around 1.0 wt. % was the optimum concentration of Pt NPs doped into the DDPDLCs. The FWHM of the peaks sharply decreased to 0.1 nm. Our work provides an extremely simple method to enhance random lasers from DDPDLCs doped with Pt NPs, and it has potential applications in random fiber lasers or laser displays. PMID- 27463927 TI - Acousto-optic tunable filter for dispersion characterization of time-domain optical coherence tomography systems. AB - A broadband supercontinuum light source with an acousto-optic tunable filter (AOTF) are used to characterize dispersion in two time-domain OCT systems, at 850 and 1300 nm. The filter is designed to sweep across two spectral ranges, which are restricted here from 800 to 900 nm and from 1200 to 1500 nm, respectively. Dispersion compensation for 850 nm was achieved with a spectral delay line. Dispersion compensation for 1300 nm was achieved using BK 7 rod glasses in the reference arm. The AOTF allows evaluation of dispersion in under as well as overcompensated systems. The AOTF method is based on wavelength dependence of the optical path difference corresponding to the maximum strength of the interference signal recorded using a mirror as object. Comparison is made between the AOTF method and the more usual method based on measurement of the full width at half maximum of the autocorrelation peak. This comparison shows that the AOTF method is more accurate in terms of evaluation of the dispersion left uncompensated after each adjustment. The AOTF method additionally provides information on the direction of dispersion compensation. PMID- 27463928 TI - ZnSe-material phase mask applied to athermalization of infrared imaging systems. AB - This paper reports a ZnSe-material phase mask that is applied to athermalization of a conventional infrared imaging system. Its principle, design, manufacture, measurement, and performance validation are successively discussed. This paper concludes that a ZnSe-material phase mask has a permissible manufacturing error 2.14 times as large as a Ge-material phase mask. By constructing and solving an optimization problem, the ZnSe-material phase mask is optimally designed. The optimal phase mask is manufactured and measured with a form manufacturing error of 1.370 MUm and a surface roughness value of 9.926 nm. Experiments prove that the wavefront coding athermalized longwave infrared (LWIR) imaging system works well over the temperature range from -40 degrees C to +60 degrees C. PMID- 27463929 TI - Phase error analysis and compensation for phase shifting profilometry with projector defocusing. AB - Phase shifting profilometry (PSP) using binary fringe patterns with projector defocusing is promising for high-speed 3D shape measurement. To obtain a high quality phase, the projector usually requires a high defocusing level, which leads to a drastic fall in fringe contrast. Due to its convenience and high speed, PSP using squared binary patterns with small phase shifting algorithms and slight defocusing is highly desirable. In this paper, the phase accuracies of the classical phase shifting algorithms are analyzed theoretically, and then compared using both simulation and experiment. We also adapt two algorithms for PSP using squared binary patterns, which include a Hilbert three-step PSP and a double three-step PSP. Both algorithms can increase phase accuracy, with the latter featuring additional invalid point detection. The adapted algorithms are also compared with the classical algorithms. Based on our analysis and comparison results, proper algorithm selection can be easily made according to the practical requirement. PMID- 27463930 TI - Wavelength optimization using available laser diodes in spectral near-infrared optical tomography. AB - For employing optimized wavelengths, a near-infrared (NIR) tomographic imaging system with multiwavelengths in a continuous wave (CW) enables us to provide accurate information of chromophores. In this paper, we discuss wavelength optimization with a selection from commercial laser diodes. Through theoretical analysis, the residual norm (R) and the condition number (kappa) represent the uniqueness of a matrix problem and the smooth singular-value distribution of each chromophore, respectively. The optimum wavelengths take place for large R and small kappa. We considered a total of 38 wavelengths of laser diodes in the range of 633-980 nm commercially available to discover optimum sets for a broad range of chromophore combinations. In the 38 wavelengths, there exists 501,942 (C538), 2,760,681 (C638), and 12,620,256 (C738) combinations of five, six, and seven wavelength sets, respectively, for accurately estimating chromophores (HbO2, HbR, H2O, and lipids), water, lipids, and the scattering prefactor A. With the numerical calculation, the top 10 wavelength sets were selected based on the principle of large R and small kappa. In the study, the chromophore concentration for young and elderly women are investigated; finally, choosing the laser diodes with a wavelength of 650, 690, 705, 730, 870/880, 915, and 937 nm is recommended either for young or elderly women to construct a spectral NIR tomographic imaging system in the CW domain. Simulated data were used to validate the claims. PMID- 27463931 TI - Modeling and simulations on retina-like sensors based on curved surface. AB - A space-variant lens array on a curved surface (SVLACS) with a large field of view is proposed to decrease the size and improve the performance of a space variant lens array on a plane (SVLAP). The whole mathematical models are developed and tested, and comparative simulations between SVLACS and SVLAP are carried out. Under the identical simulated situations, the radius of SVLACS decreases to 58% of SVLAP. Meanwhile, the performance of optical information loss rate is improved from 0.22 to 0.08. The results are beneficial for designing a retina-like image sensor based on SVLACS. PMID- 27463932 TI - Ladar scene projector for a hardware-in-the-loop simulation system. AB - In order to test a direct-detection ladar in a hardware-in-the-loop simulation system, a ladar scene projector is proposed. A model based on the ladar range equation is developed to calculate the profile of the ladar return signal. The influences of both the atmosphere and the target's surface properties are considered. The insertion delays of different channels of the ladar scene projector are investigated and compensated for. A target range image with 108 pixels is generated. The simulation range is from 0 to 15 km, the range resolution is 1.04 m, the range error is 1.28 cm, and the peak-valley error for different channels is 15 cm. PMID- 27463933 TI - Tunable Fano-like resonance enabled by coupling a microsphere with a fiber Mach Zehnder interferometer. AB - We demonstrate a simple scheme to achieve Fano-like resonance by coupling a microsphere resonator with a fiber Mach-Zehnder interferometer (FMZI), which includes a tapered microfiber in one pathway to evanescently couple with the microsphere. In this system, Fano-like asymmetric lineshapes could be converted into different types by introducing an extra phase shift in the FMZI. In addition, the sharpness of the Fano-like lineshapes could be controlled by changing the coupling strength between the microsphere and the microfiber. This Fano-like resonance with advantages of fiber integration, tunable lineshape, and ease of operation may have great potential in optical signal processing and sensing. PMID- 27463934 TI - Physical interpretation of gray cloud observed from airplanes. AB - When obliquely observed from an airplane, gray clouds near the horizon are sometimes observed to overlap with white clouds. Photographic observation from an airplane and simulations using a three-dimensional radiative transfer model are conducted to understand why such clouds appear gray. From observations, the brightness depression rate of gray clouds relative to surrounding whitish clouds is about 25%, whereas in simulations, it is as high as about 30%. Conditions necessary for the observation of gray clouds are as follows: (1) two clouds at different altitudes do not overlap, but the higher cloud overlaps with the lower cloud along the line of sight when these clouds are observed in near-horizontal direction, and (2) the higher cloud is optically thin in the vertical direction, but optically thick along the line of sight. PMID- 27463935 TI - Cross-splicing method for compensating fiber birefringence in polarization maintaining fiber ring laser mode locked by nonlinear polarization evolution. AB - We propose a cross-splicing method, for the first time to our knowledge, to compensate the effect of fiber birefringence in a polarization-maintaining fiber ring laser mode locked by nonlinear polarization evolution. This method has been investigated numerically and experimentally. The results indicate that stable mode-locking pulses can be obtained in the cavity with this method; otherwise, no mode-locking states are achieved. The design processes of the laser cavity are presented. Pulses with single pulse energy of 2.1 nJ are generated at pump power of 460 mW. The spectral bandwidth and pulse duration are 17.5 nm and 11.7 ps, respectively. The tunability of the laser is also studied. The central wavelength can be tuned from 1023.2 to 1045.9 nm. PMID- 27463936 TI - All-optical implementation of a time-domain ptychographic pulse reconstruction setup: publisher's note. AB - This note reports author corrections that were omitted from Appl. Opt.55, 5008 (2016) 10.1364/AO.55.005008 in error during production. The article was corrected online 23 June 2016. PMID- 27463937 TI - Bayesian approach to the design of chemical species tomography experiments. AB - Reconstruction accuracy in chemical species tomography depends strongly on the arrangement of optical paths transecting the imaging domain. Optimizing the path arrangement requires a scheme that can predict the quality of a proposed arrangement prior to measurement. This paper presents a new Bayesian method for scoring path arrangements based on the estimated a posteriori covariance matrix. This technique focuses on defining an objective function that incorporates the same a priori information about the flow needed to carry out limited data tomography. Constrained and unconstrained path optimization studies verify the predictive capabilities of the objective function, and that superior reconstruction quality is obtained with optimized path arrangements. PMID- 27463938 TI - Generation and manipulation of super-resolution spherical magnetization chains. AB - Based on the inverse Faraday effect, the light-induced magnetization field distributions are investigated for a 4pi tight focusing configuration with azimuthally polarized beams. It is found that a superlong (16lambda) magnetization chain, composed of 19 subwavelength (0.44lambda) spherical spots with longitudinal magnetization field, can be achieved in the focal volume of the objective. Moreover, the magnetic force on a magnetic particle or particle trains produced by tightly focused azimuthally polarized beams are calculated and exploited for the stable trapping of magnetic particles. These unique focal field distributions may find potential applications in confocal microscopy, atom control, and magneto-optical data storage. PMID- 27463939 TI - Advanced similarity metric and its application to the band selection issue of multiple spectra identification. AB - A multiple spectra oriented similarity metric, referred to as n-dimensional solid spectral angle (NSSA), is addressed in this study. NSSA extends the traditional spectral angle metric (SAM)-calculating two spectra's angle-to the calculation of the high-dimensional solid angle jointly constituted by a set of spectra with any number of bands. Some significant inherent properties of NSSA are also discussed. Furthermore, as a merit of NSSA, an NSSA-based band add-on (BAO-NSSA) band selection method is derived, which displays an advantage in capturing spectra absorption features-particularly for similar classes-by operating a set of spectra instead of distinct band variables. Finally, an annular architecture in contrast with hierarchical architecture is presented by embedding the idea of BAO NSSA into the issue of multiple class identification. Comprehensive analyses were conducted on three real hyperspectral data sets with similar and distinct classes. The proposed approach is shown to be effective for eliminating redundant bands and improving the accuracy of spectra identification. PMID- 27463940 TI - Child attention to pain and pain tolerance are dependent upon anxiety and attention control: An eye-tracking study. AB - BACKGROUND: Pain is common and can be debilitating in childhood. Theoretical models propose that attention to pain plays a key role in pain outcomes, however, very little research has investigated this in youth. This study examined how anxiety-related variables and attention control interacted to predict children's attention to pain cues using eye-tracking methodology, and their pain tolerance on the cold pressor test (CPT). METHODS: Children aged 8-17 years had their eye gaze tracked whilst they viewed photographs of other children displaying painful facial expressions during the CPT, before completing the CPT themselves. Children also completed self-report measures of anxiety and attention control. RESULTS: Findings indicated that anxiety and attention control did not impact children's initial fixations on pain or neutral faces, but did impact how long they dwelled on pain versus neutral faces. For children reporting low levels of attention control, higher anxiety was associated with less dwell time on pain faces as opposed to neutral faces, and the opposite pattern was observed for children with high attention control. Anxiety and attention control also interacted to predict pain outcomes. For children with low attention control, increasing anxiety was associated with anticipating more pain and tolerating pain for less time. CONCLUSIONS: This is the first study to examine children's attention to pain cues using eye-tracking technology in the context of a salient painful experience. Data suggest that attention control is an important moderator of anxiety on multiple outcomes relevant to young people's pain experiences. SIGNIFICANCE: This study uses eye tracking to study attention to pain cues in children. Attention control is an important moderator of anxiety on attention bias to pain and tolerance of cold pressor pain in youth. PMID- 27463941 TI - Miscarriage Associated with Zika Virus Infection. PMID- 27463942 TI - Apixaban 5 mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine: A Secondary Analysis of a Randomized Clinical Trial. AB - IMPORTANCE: In the Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of apixaban was 5 mg twice daily; patients with at least 2 dose-reduction criteria 80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL or higher received a reduced dose of apixaban of 2.5 mg twice daily. Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban. OBJECTIVE: To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria. DESIGN, SETTING, AND PARTICIPANTS: Among 18 201 patients in the ARISTOTLE trial, 17 322 were included in this analysis. Annualized event rates of stroke or systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were evaluated. Interactions between the effects of apixaban vs warfarin and the presence of 1 or no dose-reduction criteria were assessed. The first patient was enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 2016. MAIN OUTCOMES AND MEASURES: Analysis of major bleeding included events during study drug treatment. Analysis of stroke or systemic embolism was based on intention to treat. RESULTS: Of the patients with 1 or no dose-reduction criteria assigned to receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 dose-reduction criterion; these patients had higher rates of stroke or systemic embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 1.62 2.20) compared with those with no dose-reduction criteria (n = 13 356). The benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with warfarin (n = 8657) on stroke or systemic embolism in patients with 1 dose reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). Similarly, the benefit of 5 mg twice daily dose of apixaban compared with warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 0.68; 95% CI, 0.53 0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen for each dose-reduction criterion and across the spectrum of age, body weight, creatinine level, and creatinine clearance. CONCLUSIONS AND RELEVANCE: Patients with atrial fibrillation and isolated advanced age, low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding but show consistent benefits with the 5 mg twice daily dose of apixaban vs warfarin compared with patients without these characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and appropriate for patients with only 1 dose reduction criterion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00412984. PMID- 27463943 TI - Influence of Study Design on Outcomes Following Reflexology Massage: An Integrative and Critical Review of Interventional Studies. AB - BACKGROUND: Interpretation of the efficacy of reflexology is hindered by inconsistent research designs and complicated by professional views that criteria of randomized controlled trials (RCTs)are not ideal to research holistic complementary and alternative medicine practice. The influence of research designs on study outcomes is not known. This integrative review sought to evaluate this possibility. MATERIALS AND METHODS: Thirty-seven interventional studies (2000-2014) were identified; they had RCT or non-RCT design and compared reflexology outcomes against a control/comparison group. Viability of integrating RCT and non-RCT studies into a single database was first evaluated by appraisal of 16 reporting fields related to study setting and objectives, sample demographics, methodologic design, and treatment fidelity and assessment against Jadad score quality criteria for RCTs. For appraisal, the database was stratified into RCT/non-RCT or Jadad score of 3 or more or less than 3. Deficits in reporting were identified for blind assignment of participants, dropout/completion rate, and School of Reflexology. For comparison purposes, these fields were excluded from subsequent analysis for evidence of association between design fields and of fields with study outcomes. RESULTS: Thirty-one studies applied psychometric tools and 20 applied biometric tools (14 applied both). A total of 116 measures were used. Type of measure was associated with study objectives (p < 0.001; chi-square), in particular of psychometric measures with a collated "behavioral/cognitive" objective. Significant outcomes were more likely (p < 0.001; chi-square) for psychometric than for biometric measures. Neither type of outcome was associated with choice of RCT or non-RCT method, but psychometric responses were associated (p = 0.007) with a nonmassage control strategy. CONCLUSIONS: The review supports psychometric responses to reflexology when study design uses a nonmassage control strategy. Findings suggest that an evaluation of outcomes against sham reflexology massage and other forms of massage, as well as a narrower focus of study objective, may clarify whether there is a relationship between study design and efficacy of reflexology. PMID- 27463944 TI - Erratum: Modulation of tumorigenesis by the pro-inflammatory microRNA miR-301a in mouse models of lung cancer and colorectal cancer. AB - [This corrects the article DOI: 10.1038/celldisc.2015.5.]. PMID- 27463945 TI - Sn Spheres Embedded in a SiO2 Matrix: Synthesis and Potential Application As Self Destructing Materials. AB - We introduce a simple process for the fabrication of SiO2 films embedded with beta-Sn-rich nano/microspheres. Sn spheres with maximum and minimum sizes of 10 MUm (near the SiO2 surface) and 5 nm (at the Si/SiO2 interface) were grown within a 0.7-5.7 MUm-thick SiO2 layer by evaporating SnO powders onto an Si (100) substrate for 1-600 min at 600-900 degrees C and 0.001-5.0 Torr. A possible growth mechanism of these materials is discussed. The current-voltage characteristics of the as-fabricated samples were investigated to identify potential applications. During these tests, small flashes of light and the presence of damaged areas were observed at the oxide surfaces of the samples using an optical camera and a field emission scanning electron microscope, respectively. The electrical breakdown and shutdown of the devices observed in the current-voltage curves were attributed to the destruction of the SiO2 surface. In addition, the current-time responses show that the size of the damaged regions can be controlled by the voltage and duration of the applied stress, and are independent of the size and shape of the electrodes. The present materials thus possess great potential for applications in self-destructing devices. PMID- 27463946 TI - Determination of Trace Water Content in Petroleum and Petroleum Products. AB - Measurement of water in petroleum and petroleum-based products is of industrial and economic importance; however, the varied and complex matrixes make the analyses difficult. These samples tend to have low amounts of water and contain many compounds which react with iodine, causing Karl Fischer titration (KFT) to give inaccurate, typically higher, results. A simple, rapid, automated headspace gas chromatography (HSGC) method which requires modified instrumentation and ionic liquid stationary phases was developed. Measurement of water in 12 petroleum products along with 3 National Institute of Standards and Technology reference materials was performed with the developed method. The range of water found in these samples was ~12-3300 ppm. This approach appeared to be unaffected by complicated matrixes. The solvent-free nature of the HSGC method also negates the solubility limitations which are common with KFT. PMID- 27463947 TI - How promising are combinatorial drug strategies in combating Candida albicans biofilms? PMID- 27463950 TI - A new kind of transparent and self-cleaning film for solar cells. AB - A kind of one step and in situ etching method is developed to fabricate a highly optically transparent and flexible self-cleaning superhydrophobic film (SSF). This SSF exhibits a very rough surface morphology with hierarchical structure, which makes it have a contact angle of 154.6 degrees and a sliding angle of smaller than 1 degrees . And the SSF can also be self-cleaned in the wind. The SSF hierarchical structure scatters the incident light, but it almost doesn't attenuate the light. So the SSF has antireflection properties and a high light transmittance of 94%. The excellent self-cleaning property, high light transmittance and antireflection property mean that the SSF greatly enhances the performance of solar cells in practical working conditions. The solar cell's efficiency maintains at 95.8% of its initial value after covering with the SSF, which is about 1.7 times higher than that of the solar cell covered with dust, as in practical conditions. PMID- 27463949 TI - Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation including Citrus bergamia, in subjects with moderate cardiometabolic risk factors. AB - We examined the clinical safety and efficacy of F105 in 11 subjects with moderate dyslipidemia. F105 is a combination of bergamot fruit extract (Citrus bergamia, BFE) and 9 phytoextracts selected for their ability to improve the antioxidant and anti-inflammatory activity of BFE. In vitro F105 exhibited a synergistic inhibition of oxygen radical absorbing capacity, peroxynitrite formation, and myeloperoxidase activity. Following 12 weeks of F105 daily, no treatment-related adverse events or changes in body mass were seen. Statistically significant changes were noted in total cholesterol (-7.3%), LDL-cholesterol (-10%), non-HDL cholesterol (-7.1%), cholesterol/HDL (-26%), and apolipoprotein B (-2.8%). A post hoc analysis of 8 subjects with HbA1c > 5.4 and HOMA-IR score > 2 or elevated triglycerides revealed additional statistically significant changes in addition to those previously observed in all subjects including triglycerides (-27%), oxLDL (-19%), LDL/HDL (-25%), triglycerides/HDL (-27%), oxLDL/HDL (-25%), and PAI 1 (-37%). A follow-up case report of a 70-year-old female patient, nonresponsive to statin therapy and placed on F105 daily, demonstrated improved cardiometabolic variables over 12 weeks similar to the subgroup. In summary, F105 was clinically well-tolerated and effective for ameliorating dyslipidemia in subjects with moderate cardiometabolic risk factors, particularly in the individuals with HbA1c > 5.4%. PMID- 27463948 TI - Inherited platelet dysfunction and hematopoietic transcription factor mutations. AB - Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet dysfunction are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for the defects in platelet production, morphology, and function. The hematopoietic TFs implicated in the patients with impaired platelet function include Runt related TF 1 (RUNX1), Fli-1 proto-oncogene, ETS TF (FLI1), GATA binding protein 1 (GATA1), and growth factor independent 1B transcriptional repressor (GFI1B). These TFs act in a combinatorial manner to bind sequence specific DNA within a promoter region to regulate lineage-specific gene expression, either as activators or as repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these TFs affect diverse aspects of megakaryocyte biology and platelet production and function, culminating in thrombocytopenia, platelet dysfunction, and associated clinical features. Mutations in TFs may occur more frequently in the patients with inherited platelet dysfunction than generally appreciated. This review focuses on the alterations in hematopoietic TFs in the pathobiology of inherited platelet dysfunction. PMID- 27463961 TI - Poly(ethylene oxide) Functionalized Graphene Nanoribbons with Excellent Solution Processability. AB - Structurally well-defined graphene nanoribbons (GNRs) have attracted great interest as next-generation semiconductor materials. The functionalization of GNRs with polymeric side chains, which can widely broaden GNR-related studies on physiochemical properties and potential applications, has remained unexplored. Here, we demonstrate the bottom-up solution synthesis of defect-free GNRs grafted with flexible poly(ethylene oxide) (PEO) chains. The GNR backbones possess an armchair edge structure with a width of 1.0-1.7 nm and mean lengths of 15-60 nm, enabling near-infrared absorption and a low bandgap of 1.3 eV. Remarkably, the PEO grafting renders the GNRs superb dispersibility in common organic solvents, with a record concentration of ~1 mg mL(-1) (for GNR backbone) that is much higher than that (<0.01 mg mL(-1)) of reported GNRs. Moreover, the PEO functionalized GNRs can be readily dispersed in water, accompanying with supramolecular helical nanowire formation. Scanning probe microscopy reveals raft like self-assembled monolayers of uniform GNRs on graphite substrates. Thin-film based field-effect transistors (FETs) of the GNRs exhibit a high carrier mobility of ~0.3 cm(2) V(-1) s(-1), manifesting promising application of the polymer functionalized GNRs in electronic devices. PMID- 27463963 TI - Quality of Care and Cost at Safety-Net Hospitals-Is Redistribution of Cases Possible? PMID- 27463964 TI - Preference of Ruthenium-Based Metathesis Catalysts toward Z- and E-Alkenes as a Guide for Selective Reactions to Alkene Stereoisomers. AB - As a guide for selective reactions toward either Z- or E-alkene in a metathesis reaction, the relative preference of metathesis Ru catalysts for each stereoisomer was determined by a method using time-dependent fluorescence quenching. We found that Ru-1 prefers the Z-isomer over the E-isomer, whereas Ru 2 prefers the E-isomer over the Z-isomer. The Z/E-alkene preference of the catalysts precisely predicted the Z/E isomeric selectivity in the metathesis reactions of diene substrates possessing combinations of Z/E-alkenes. For the diene substrates, the rate order of the reactions using Ru-1 was Z,Z-1,6-diene > Z,E-1,6-diene > E,E-1,6-diene, while the completely opposite order of E,E-1,6 diene > Z,E-1,6-diene > Z,Z-1,6-diene was exhibited in the case of Ru-2. PMID- 27463962 TI - Role of LRP-1 in cancer cell migration in 3-dimensional collagen matrix. AB - The low-density lipoprotein receptor-related protein-1 (LRP-1) is a member of Low Density Lipoprotein Receptor (LDLR) family, which is ubiquitously expressed and which is described as a multifunctional endocytic receptor which mediates the clearance of various extracellular matrix molecules including serine proteinases, proteinase-inhibitor complexes, and matricellular proteins. Several studies showed that high LRP-1 expression promotes breast cancer cell invasiveness, and LRP-1 invalidation leads to cell motility abrogation in both tumor and non-tumor cells. Furthermore, our group has reported that LRP-1 silencing prevents the invasion of a follicular thyroid carcinoma despite increased pericellular proteolytic activities from MMP2 and uPA using a 2D-cell culture model. As the use of 3D culture systems is becoming more and more popular due to their promise as enhanced models of tissue physiology, the aim of the present work is to characterize for the first time how the 3D collagen type I matrix may impact the ability of LRP-1 to regulate the migratory properties of thyroid carcinoma using as a model FTC-133 cells. Our results show that inhibition of LRP-1 activity or expression leads to morphological changes affecting cell-matrix interactions, reorganizations of the actin-cytoskeleton especially by inhibiting FAK activation and increasing RhoA activity and MLC-2 phosphorylation, thus preventing cell migration. Taken together, our results suggest that LRP-1 silencing leads to a decrease of cell migratory capacity in a 3D configuration. PMID- 27463965 TI - Quantification of Valleys of Randomly Textured Substrates as a Function of Opening Angle: Correlation to the Defect Density in Intrinsic nc-Si:H. AB - Optical and electrical properties of hydrogenated nanocrystalline silicon (nc Si:H) solar cells are strongly influenced by the morphology of underlying substrates. By texturing the substrates, the photogenerated current of nc-Si:H solar cells can increase due to enhanced light scattering. These textured substrates are, however, often incompatible with defect-less nc-Si:H growth resulting in lower Voc and FF. In this study we investigate the correlation between the substrate morphology, the nc-Si:H solar-cell performance, and the defect density in the intrinsic layer of the solar cells (i-nc-Si:H). Statistical surface parameters representing the substrate morphology do not show a strong correlation with the solar-cell parameters. Thus, we first quantify the line density of potentially defective valleys of randomly textured ZnO substrates where the opening angle is smaller than 130 degrees (rho<130). This rho<130 is subsequently compared with the solar-cell performance and the defect density of i nc-Si:H (rhodefect), which is obtained by fitting external photovoltaic parameters from experimental results and simulations. We confirm that when rho<130 increases the Voc and FF significantly drops. It is also observed that rhodefect increases following a power law dependence of rho<130. This result is attributed to more frequently formed defective regions for substrates having higher rho<130. PMID- 27463966 TI - ADAMTS14 Gene Polymorphism and Environmental Risk in the Development of Oral Cancer. AB - BACKGROUND: Oral cancer is a common malignancy that is shown to be causally associated with hereditary and acquired factors. ADAMTS14 is a member of the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin motifs) metalloproteinase family that plays an important role in extracellular matrix (ECM) assembly and degradation. Elevation or deficiency of certain ADAMTS proteinases has been known to be implicated in a wide range of pathological processes including atherosclerosis, arthritis, and cancer. The present study aimed to explore the impact of ADAMTS14 gene polymorphisms, combined with environmental risks on the susceptibility to oral tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: Four single-nucleotide polymorphisms (SNPs) of the ADAMTS14 gene, including rs10823607, rs12774070, rs4747096, and rs61573157 were evaluated from 1200 normal controls and 850 patients with oral cancer. We failed to detect a significant association of four individual SNPs with oral cancer between case and control group. However, while considering behavioral exposure of environmental carcinogens, the presence of four ADAMTS14 SNPs, combined with betel nut chewing and/or smoking, profoundly leveraged the risk of oral cancer. Moreover, we observed a significant association of rs12774070, which is predicted to alter the expression and function of ADAMTS14 by in silico and bioinformatics analyses, with poor tumor cell differentiation (AOR: 0.59; 95% CI: 0.38-0.92; p = 0.02) in patients who chewed betel nuts. CONCLUSIONS: These results implicate the interaction between ADAMTS14 gene polymorphisms and environmental mutagens as a risk factor of oral tumorigenesis and suggest a correlation of rs12774070 with the degree of oral tumor cell differentiation. PMID- 27463968 TI - Instantaneous Flow Structures and Opportunities for Larval Settlement: Barnacle Larvae Swim to Settle. AB - Water flow affects settlement of marine larvae on several scales. At the smallest scale local flow regime may control the probability of adhesion to the substrate. Our aim was to mechanistically understand the transition from suspended to attached larvae in turbulent flow. Recently it was proposed that opportunities for larval settlement in turbulent boundary layers depend on time windows with suitable instantaneous flow properties. In flume flow we characterized the proportion of suitable time windows in a series of flow velocities with focus on the near-bed flow. The change in the proportion of potential settling windows with increasing free-stream velocities was compared to the proportion of temporary attachment of barnacle cypris larvae at different flow velocities. We found large instantaneous flow variations in the near-bed flow where cyprid attachment took place. The probability of temporary attachment in cyprids declined with local flow speed and this response was compatible with a settling window lasting at least 0.1 s with a maximum local flow speed of 1.9-2.4 cm s-1. Cyprids swam against the near-bed flow (negative rheotaxis) and the swimming speed (1.8 cm s-1) was close to the critical speed that permitted temporary attachment. We conclude that temporary attachment in barnacle cyprids requires upstream swimming to maintain a fixed position relative to the substrate for at least 0.1 s. This behaviour may explain the ability of barnacles to recruit to high-flow environments and give cyprids flexibility in the pre-settlement choice of substrates based on flow regime. PMID- 27463967 TI - New England Cod Collapse and the Climate. AB - To improve fishery management, there is an increasing need to understand the long term consequences of natural and anthropogenic climate variability for ecological systems. New England's iconic cod populations have been in decline for several decades and have recently reached unprecedented lows. We find that 17% of the overall decline in Gulf of Maine cod biomass since 1980 can be attributed to positive phases of the North Atlantic Oscillation (NAO). This is a consequence of three results: i) a 1-unit increase in the NAO winter index is associated with a 17% decrease in the spring biomass of age-1 cod the following year; ii) this NAO driven decrease persists as the affected cohort matures; iii) fishing practices appear to exacerbate NAO's direct biological effect such that, since 1913, a 1 unit increase in the NAO index lowers subsequent cod catch for up to 19 years. The Georges Bank cod stock displays similar patterns. Because we statistically detect a delay between the NAO and subsequent declines in adult biomass, our findings imply that observed current NAO conditions can be used in stock forecasts, providing lead time for adaptive policy. More broadly, our approach can inform forecasting efforts for other fish populations strongly affected by natural and anthropogenic climatic variation. PMID- 27463969 TI - Prevention of Cervix Cancer in India. AB - Cervical cancer is the fourth most common cancer among women globally and the second most common cancer among Indian women. India alone bears 23% of the global cervical cancer burden. In India, population-based cervical cancer screening is largely nonexistent in most regions due to competing healthcare priorities, insufficient financial resources and a limited number of trained providers. Hence, most of the cases present in advanced stages of the disease, thus leading to increased mortality and reduced survival. Various screening options like cytology, visual-based screening and testing for high-risk HPV are available. Several cross-sectional studies have looked at the comparative efficacy of different screening tests. Three important randomized controlled trials from India have shown the efficacy of screening once in a life time with HPV DNA, one time screening with VIA by trained nurses and four-time screening with VIA by trained primary health workers, reducing mortality due to cervical cancers. Prevention of cervical cancers with two-dose HPV vaccination and early detection of precancerous cervical lesions of the eligible population through screening and their appropriate treatment with a single-visit 'screen-and-treat' approach appear to be promising for low-middle-income countries including India. PMID- 27463970 TI - The Characteristics of Peripapillary Retinal Perfusion by Optical Coherence Tomography Angiography in Tessellated Fundus Eyes. AB - PURPOSE: To evaluate the peripapillary and perifoveal retinal perfusions of young healthy eyes with a tessellated fundus using optical coherence tomography (OCT) angiography. METHODS: Thirty-five Chinese subjects with a tessellated fundus and 35 subjects without a tessellated fundus from a population-based cross-sectional study in Shanghai were included. All participants underwent OCT angiography. The flow index and vessel density were examined in the peripapillary and perifoveal retinal areas, and their relationships with other ocular parameters were analyzed. RESULTS: In the peripapillary area, the eyes with a tessellated fundus had a lower retinal nerve fiber layer (RNFL) flow index (0.055 +/- 0.009 vs. 0.061 +/- 0.007, P = 0.006), RNFL vessel density (61.8 +/- 7.3 vs. 65.9 +/- 5.2, P = 0.010), retinal flow index (0.086 +/- 0.010 vs. 0.092 +/- 0.008, P = 0.012), and retinal vessel density (83.7 +/- 5.0 vs. 86.4 +/- 3.7, P = 0.018) than the control eyes, and the difference remained significant even after adjustments were made for gender and RNFL thickness. No difference was found in the perifoveal area. Multivariable linear regression analysis showed that the retinal flow index and vessel density in the peripapillary area were significantly correlated with the tessellated fundus diagnosis (flow index: beta = -0.006, P = 0.005; vessel density: beta = -2.597, P = 0.006), gender (flow index: beta = 0.005, P = 0.019; vessel density: beta = 3.129, P = 0.002) and RNFL thickness (flow index: beta = 0.000, P = 0.002; vessel density: beta = 0.190, P = 0.002). The RNFL flow index and vessel density were significantly associated with the tessellated fundus diagnosis (flow index: beta = -0.005, P = 0.005; vessel density: beta = -3.572, P = 0.008) and the thickness of RNFL (flow index: beta = 0.001, P < 0.001; vessel density: beta = 0.421, P < 0.001). CONCLUSIONS: Eyes with tessellated fundus with a relative decreased peripapillary retinal perfusion compared with eyes without a tessellated fundus were observed. The findings whether indicate causality that the reduction in the peripapillary perfusion and the peripapillary atrophy in myopia, need further study. PMID- 27463971 TI - Impact of Thulium Laser Enucleation of the Prostate on Erectile, Ejaculatory and Urinary Functions. AB - OBJECTIVE: To test the impact of Thulium laser enucleation of the prostate (ThuLEP) on erectile and ejaculatory functions, on lower urinary tract symptoms and on quality of life (QoL). METHODS: From July 2013 to May 2015, we prospectively evaluated 177 patients with LUTS related to benign prostatic hyperplasia. All patients were assessed with the International Index of Erectile Function (IIEF-5), Male Sexual Health Questionnaire-Ejaculatory Disease (MSHQ EjD), International Prostate Symptom Score (IPSS), QoL, PSA and uroflowmetry before and at 4 and 8 months after surgery. RESULTS: Erectile function did not show variation with IIEF-5 preoperative score 22.49 +/- 1.8 and postoperative score 22.14 +/- 3.1 (p = 0.195) and 22.18 +/- 3.2 (p = 0.26) at 4 and 8 months after treatment. The ejaculatory function on the MSHQ-EjD test indicated the reduction of ejaculation, changing from 14.90 +/- 6.88 to 5.51 +/- 4.17 (p < 0.0001) and 5.38 +/- 3.93 (p < 0.0001) at 4 and 8 months follow-up. IPSS score decreased from preoperative 21.12 +/- 5.81 to 3.14 +/- 3.16 (p < 0.0001) and 3.08 +/- 3.12 (p < 0.0001) 4 and 8 months after surgery. PSA decreased from 4.50 +/- 3.72 to 1.39 +/- 1.04 (p < 0.0001) and 1.47 +/- 1.14 ng/ml (p < 0.0001) at 4 and 8 months follow-up, while QoL score improved from 5.41 +/- 0.69 to 0.57 +/- 0.84 (p < 0.0001) and 0.51 +/- 0.80 (p < 0.0001) at 4 and 8 months follow-up. CONCLUSIONS: ThuLEP does not affect erectile function and determines the resolution of LUTS with improvement of QoL. Loss of ejaculation did not impair the sexual intercourse activities of the patients. PMID- 27463972 TI - Characterization and Adaptation of Anaerobic Sludge Microbial Communities Exposed to Tetrabromobisphenol A. AB - The increasing occurrence of tetrabromobisphenol A (TBBPA) in the environment is raising questions about its potential ecological and human health impacts. TBBPA is microbially transformed under anaerobic conditions to bisphenol A (BPA). However, little is known about which taxa degrade TBBPA and the adaptation of microbial communities exposed to TBBPA. The objectives of this study were to characterize the effect of TBBPA on microbial community structure during the start-up phase of a bench-scale anaerobic sludge reactor, and identify taxa that may be associated with TBBPA degradation. TBBPA degradation was monitored using LC/MS-MS, and the microbial community was characterized using Ion Torrent sequencing and qPCR. TBBPA was nearly completely transformed to BPA via reductive debromination in 55 days. Anaerobic reactor performance was not negatively affected by the presence of TBBPA and the bulk of the microbial community did not experience significant shifts. Several taxa showed a positive response to TBBPA, suggesting they may be associated with TBBPA degradation. Some of these taxa had been previously identified as dehalogenating bacteria including Dehalococcoides, Desulfovibrio, Propionibacterium, and Methylosinus species, but most had not previously been identified as having dehalogenating capacities. This study is the first to provide in-depth information on the microbial dynamics of anaerobic microbial communities exposed to TBBPA. PMID- 27463973 TI - Diagnostic and Prognostic Properties of Osteoprotegerin in Patients with Acute Dyspnoea: Observations from the Akershus Cardiac Examination (ACE) 2 Study. AB - BACKGROUND: Circulating osteoprotegerin (OPG) levels are increased in patients with chronic heart failure (HF). The diagnostic and prognostic merit of OPG measurement in patients admitted with acute dyspnoea is unknown. OBJECTIVES: To evaluate the diagnostic and prognostic value of measuring OPG in patients admitted to hospital with acute dyspnoea. METHODS: OPG was analysed by ELISA in 308 patients admitted due to acute dyspnoea. Investigators blinded to OPG results adjudicated the diagnosis for the index hospitalization. Clinical outcomes were obtained from hospital records. RESULTS: In total, 139 patients (45%) were hospitalized with acute HF. OPG levels on hospital admission were higher in patients with acute HF vs. no acute HF, 7.8 (5.5-10.4) vs. 5.4 (3.8-7.2) pmol/L, p<0.001. The area under the receiver operator characteristic curve (ROC AUC) of OPG to discriminate between HF vs. non-HF was 0.695 [95% CI 0.636-0.754]. OPG did not provide incremental information to the ED physician's prediction or N terminal pro-B-type natriuretic peptide regarding the diagnosis of acute HF. OPG levels (log transformed) were associated with mortality in crude analysis (HR (95% CI) 1.87 (1.34 to 2.61), p<0.001), but this association was attenuated and no longer significant after including established cardiac biomarkers into the model. CONCLUSION: In patients admitted to hospital with acute dyspnoea, OPG levels are higher in patients with acute HF than in those with dyspnoea from other causes. However, OPG does not provide incremental information beyond ED physician assessment for the diagnosis of acute HF or beyond clinical risk variables and established cardiac biomarkers concerning prognosis. PMID- 27463974 TI - Cerebrospinal Fluid Biomarkers for Target Engagement and Efficacy in Clinical Trials for Alzheimer's and Parkinson's Diseases. AB - BACKGROUND: Cerebrospinal fluid (CSF) is increasingly being used to detect biochemical changes that occur in different neurological conditions. In Alzheimer's disease (AD), three CSF biomarkers (Abeta42, total tau, and phosphorylated tau) are used in clinical practice to support the diagnosis in the prodromal stages of the disease. In Parkinson's disease (PD), the investigation is following the pathway of AD research and some promising markers have been identified, with the main aim to favor an early diagnosis, i.e. in the premotor phase. Some of these CSF markers have also been incorporated in AD and PD clinical trials to demonstrate target engagement of the drug and/or to enrich the patient populations. In this chapter, we will review the main CSF biomarkers for AD and PD and their potential application to clinical trials. SUMMARY: In clinical trials assessing the efficacy of disease-modifying agents for AD, CSF biomarkers are currently used both as a diagnostic criterion for inclusion and for monitoring the biochemical impact of the drug on the upstream neurodegenerative mechanisms. Accordingly, recent trials devoted to PD are following such a procedure, although in this neurodegenerative disorder CSF biomarkers are not ready yet for routine clinical use. KEY MESSAGES: AD and PD are neurodegenerative disorders that share a long asymptomatic/prodromal phase in which neurodegenerative phenomena already take place in the brain. Clinical trials assessing the efficacy of disease-modifying agents should include the CSF measurement of related biomarkers as biochemical proof of the underlying pathology as well as of the impact of the drug on these pathogenic mechanisms. PMID- 27463975 TI - Fuzzy Bayesian Network-Bow-Tie Analysis of Gas Leakage during Biomass Gasification. AB - Biomass gasification technology has been rapidly developed recently. But fire and poisoning accidents caused by gas leakage restrict the development and promotion of biomass gasification. Therefore, probabilistic safety assessment (PSA) is necessary for biomass gasification system. Subsequently, Bayesian network-bow-tie (BN-bow-tie) analysis was proposed by mapping bow-tie analysis into Bayesian network (BN). Causes of gas leakage and the accidents triggered by gas leakage can be obtained by bow-tie analysis, and BN was used to confirm the critical nodes of accidents by introducing corresponding three importance measures. Meanwhile, certain occurrence probability of failure was needed in PSA. In view of the insufficient failure data of biomass gasification, the occurrence probability of failure which cannot be obtained from standard reliability data sources was confirmed by fuzzy methods based on expert judgment. An improved approach considered expert weighting to aggregate fuzzy numbers included triangular and trapezoidal numbers was proposed, and the occurrence probability of failure was obtained. Finally, safety measures were indicated based on the obtained critical nodes. The theoretical occurrence probabilities in one year of gas leakage and the accidents caused by it were reduced to 1/10.3 of the original values by these safety measures. PMID- 27463976 TI - Genetic Diversity and Phylogenetic Evolution of Tibetan Sheep Based on mtDNA D Loop Sequences. AB - The molecular and population genetic evidence of the phylogenetic status of the Tibetan sheep (Ovis aries) is not well understood, and little is known about this species' genetic diversity. This knowledge gap is partly due to the difficulty of sample collection. This is the first work to address this question. Here, the genetic diversity and phylogenetic relationship of 636 individual Tibetan sheep from fifteen populations were assessed using 642 complete sequences of the mitochondrial DNA D-loop. Samples were collected from the Qinghai-Tibetan Plateau area in China, and reference data were obtained from the six reference breed sequences available in GenBank. The length of the sequences varied considerably, between 1031 and 1259 bp. The haplotype diversity and nucleotide diversity were 0.992+/-0.010 and 0.019+/-0.001, respectively. The average number of nucleotide differences was 19.635. The mean nucleotide composition of the 350 haplotypes was 32.961% A, 29.708% T, 22.892% C, 14.439% G, 62.669% A+T, and 37.331% G+C. Phylogenetic analysis showed that all four previously defined haplogroups (A, B, C, and D) were found in the 636 individuals of the fifteen Tibetan sheep populations but that only the D haplogroup was found in Linzhou sheep. Further, the clustering analysis divided the fifteen Tibetan sheep populations into at least two clusters. The estimation of the demographic parameters from the mismatch analyses showed that haplogroups A, B, and C had at least one demographic expansion in Tibetan sheep. These results contribute to the knowledge of Tibetan sheep populations and will help inform future conservation programs about the Tibetan sheep native to the Qinghai-Tibetan Plateau. PMID- 27463977 TI - One year in review 2016: systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a highly variable course and prognosis. The management of the disease is still a clinical challenge for the treating physicians as many aspects regarding the disease pathogenesis, clinical picture and outcomes remain to be elucidated. New and interesting data are emerging; here the recent literature on SLE pathogenesis, clinical and laboratory aspects, as well as treatments and comorbidities, are reviewed and the main findings summarised in order to provide a bird's eye on the relevant papers on these topics. PMID- 27463978 TI - FN400 and LPC memory effects for concrete and abstract words. AB - According to dual-process models, recognition memory depends on two neurocognitive mechanisms: familiarity, which has been linked to the frontal N400 (FN400) effect in studies using ERPs, and recollection, which is reflected by changes in the late positive complex (LPC). Recently, there has been some debate over the relationship between FN400 familiarity effects and N400 semantic effects. According to one view, these effects are one and the same. Proponents of this view have suggested that the frontal distribution of the FN400 could be due to stimulus concreteness: recognition memory experiments commonly use highly imageable or concrete words (or pictures), which elicit semantic ERPs with a frontal distribution. In the present study, we tested this claim using a recognition memory paradigm in which subjects memorized concrete and abstract nouns; half of the words changed font color between study and test. FN400 and LPC old/new effects were observed for abstract as well as concrete words, and were stronger over right hemisphere electrodes for concrete words. However, there was no difference in anteriority of the FN400 effect for the two word types. These findings challenge the notion that the frontal distribution of the FN400 old/new effect is fully explained by stimulus concreteness. PMID- 27463979 TI - Community-based reports of morbidity, mortality, and health-seeking behaviours in four Monrovia communities during the West African Ebola epidemic. AB - The goal of this study was to assess morbidity, mortality, and health-seeking behaviours during the 2014 Ebola outbreak in Monrovia, Liberia. This study examined commonly reported symptoms of illness, pre-clinical diagnostic practices, typical healthcare-seeking strategies, and health resources available to populations, in order to identify salient needs and gaps in healthcare that would inform local emergency response efforts. Semi-structured interviews were conducted with household members in four Monrovia neighbourhoods. Researchers used a multi-stage cluster approach to recruit participants. Within 555 households sampled, 505 individuals were reported sick (69%) or recently sick (38%) or deceased (7%). Common self-diagnoses included malaria, hypertension, influenza, typhoid, and Ebola. The most cited health-seeking strategy was to purchase medications from the private sector. Respondents also obtained healthcare from community members known to have medical experience. Findings suggest that non-formal healthcare systems played an important role in managing morbidity during the West African Ebola virus disease (EVD) outbreak. Lay community members engaged in complex assessments of health symptoms and sought biomedical care at rates perhaps higher than anticipated during the response. This study highlights how informal networks of healthcare providers can play an important role in preventing and curbing future emerging disease outbreaks. PMID- 27463980 TI - Autologous Bone-Marrow Transplantation in Acute Lymphoblastic Leukaemia: 1980-89. AB - The outcome of conventional therapy in adult acute lymphoblastic leukaemia (ALL) is disappointing. Allogeneic bone-marrow transplantation may give improved results but has only limited applicability because of the lack of a suitable donor in most patients. We have therefore investigated intensive chemotherapy and chemo/radiotherapy protocols with autologous bone-marrow rescue. 31 patients have been treated, 14 beyond first remission and 17 in first remission. The result of this therapy in both groups is poor with only 2 longterm survivors in each group. There is no reason to believe from this study that ablative therapy with autologous bone-marrow rescue will yield superior results to conventional therapy in adult ALL but further experience with TBI containing regimes is required. PMID- 27463981 TI - Multidrug Resistance in Leukaemia. AB - The treatment of many haematological malignancies is complicated by the development of resistance to cytotoxic agents. Cells which acquire the multidrug resistant (MDR) phenotype lose sensitivity to a spectrum of structurally unrelated chemotherapeutic drugs. Several distinct drug resistance mechanisms are now recognised which may be involved in clinically resistant leukaemia. It is possible that leukaemic cells may utilise one or more of these resistance processes as a survival mechanism and to maintain a proliferative advantage. If relevance of resistance mechanisms can be established, then the potential therapeutic benefit by circumvention of MDR is considerable with patients rendered chemosensitive and curable. There are many drugs which in vitro can reverse resistance processes, but their efficacy in vivo is yet to be fully demonstrated. It is likely that the final picture of the involvement of drug resistance in leukaemia will be complicated. Further investigation is warranted as the potential rewards are high. PMID- 27463982 TI - Chronic Lymphocytic Leukaemia in Tropical Africa: A Review. AB - Chronic lymphocytic leukaemia (CLL) has a male:female (M:F) ratio 1:1 in tropical Africa. Below the age of 45 years, the M:F is 1:2, while above 45 years; it is 2:1 CLL in younger adults is associated with low socio-economic status (SES) and rural habitation. Clinical and haematological features are the same as in other continents, except that many patients have gross splenomegaly and two populations of lymphocytes in the peripheral blood on light microscopy: it is postulated that with the altered immunity of CLL, recurrent malaria causes a secondary but benign lymphoid hyperplasia. It is hypothesised that the probability of B-cell mutation is increased in an enlarged pool of B-cells resulting from recurrent malaria and other infections. The greatest enhancement occurs in subjects of low SES, who are more exposed to infections, and in grandemultiparae, whose cell-mediated immunity has been depressed repeatedly during pregnancies. A second event could follow transmission of an unidentified virus: transmission is more likely with overcrowding and proliferation more rapid with depression of immunity by malaria and pregnancy. HTLV-1 is associated with CLL, but does not appear to contribute significantly to the peculiar epidemiology of CLL in Africa. PMID- 27463983 TI - Why Does alpha-Interferon Work in Chronic Granulocytic; Leukaemia? AB - Experimental evidence is presented to demonstrate that alpha-interferon (alphaIFN) has its most potent antiproliferative effect upon the late progenitor compartment of myelopoiesis. As this compartment is greatly expanded in chronic granulocytic leukaemia (CGL), it is suggested that the clinical efficacy of alphaIFN therapy in CGL derives from inhibition of late progenitor division and an attendant reduction in neutrophil production. Furthermore, the reduction in Philadelphia positive: (Ph +) metaphases and increase in Philadelphia negative (Ph -) metaphases seen in some patients on alphaIFN therapy may be due to there being proportionally more alphaIFN-sensitive cells within the Ph+ compartment. As the tumour bulk of the Ph+ clone decreases, the suppressive effect that it has over the Ph - compartment ma,y be eroded, allowing upgrowth of Ph- myelopoiesis and reconstitution of a normal karyotype. PMID- 27463984 TI - Treatment of Hairy Cell Leukaemia with 2'-Deoxycoformycin. AB - The adenosine deaminase inhibitor 2'-deoxycoformycin (DCF) has been used to treat 40 patients with hairy cell leukaemia (HCL) who have been followed up for a minimum of 6 months. 21 patients had previously undergone splenectomy. 33 had received treatment with alpha-interferon (IFN), half of whom had relapsed and the remainder had either been partially treated due to intolerance or had an incomplete response. Deoxycoformycin was administered by slow intravenous injection at a dose of 4 mg/m(2) weekly for 4 consecutive weeks and then 2-weekly for 4 doses followed by 4-weekly injections until a complete remission was achieved. No maintenance therapy was given. The overall response rate was 97yi, with 82% complete remission (CR) and 15% partial remission (PR). CR have lasted from 3+ to 30+ months (median 12 +) with no relapses recorded so far. Only one evaluable patient, suffering from a variant form of HCL, failed to respond to DCF, whilst two other HCL-variant cases who had been resistant to alpha-IFN have achieved a PR and are still on treatment. DCF was generally well tolerated, the major toxicity being related to cytopenia and associated infection. Four patients developed severe infections, one of whom died of septicaemia before it was possible to evaluate the response to DCF. A group of 12 patients who had received alpha-IFN immediately prior to treatment with DCF and had obtained clinical and haematological benefit had fewer infections with DCF than the group who had either not received IFN immediately before or who had failed to respond to it. In view of the infections associated with DCF, we would now recommend initial therapy for HCL patients with alpha-IFN for 2-4 months to obtain clinical and haematological improvement, followed by DCF given 2-weekly, to eradicate residual disease. This approach may achieve a higher proportion of sustained CR with a short treatment time and minimal toxicity. PMID- 27463985 TI - Childhood Leukaemia: Is it a Problem in Tropical Africa? AB - This is a report on the frequency and biogical aspects of childhood leukaemia in tropical Africa based on experience from Kenya and the literature. Out of the 934 cases of leukaemia diagnosed, treated and followed up at Kenyatta National Hospital between 1976 and 1985, 347 occurred in children below the age of 15 years and comprised 37% of leukaemia in all ages. Childhood acute leukaemia formed 52.3% of all the acute leukaemias. Acute non-lymphocytic (ANLL) and acute lymphocytic leukaemias (ALL) occurred. in almost equal proportions 42 % and 46 % respectively. FAB ANLL, M4 and FAB, ALL, L1 subtypes predominated although ALL, L2 (45%) was encountered almost as frequently as ALL, L1 (50%). The acute leukaemias had a peak occurrence in the 5-9 age group at a median frequency of 41 74. These observations are generally true for childhood leukaemia patterns in sub Saharan Africa. T-cell ALL phenotype was the most commonly diagnosed, being 46'x of ALL. Clinically advanced disease, severe malnutrition and common ocular chloromata were notably prominent. Remission induction and survival results were noted to be inferior to those obtained in Western countries and are attributed to the presence of many risk factors and unsatisfactory management facilities. PMID- 27463986 TI - Familial Lymphomas A review of the literature with report of cases in Jerusalem. AB - Non-Hodgkin's lymphoma Although non-Hodgkin's lymphoma (NHL) is a common disorder, there are relatively few reports occurring in family groups. Extensive review of the literature by Ladish et al. in 1978(1) revealed 38 multiple-case families with NHL, most of whom were sibpairs, either sibs alone (6.3%) or sibs plus other relatives (13%), including a pair of monozygotic twins(2). The mean age of diagnosis in these cases was 23.5 years compared with 42.3 years for the general population with NHL. About half of the familial cases were extranodal (44 cases), primarily involving the gastro-intestinal tract in 26 cases, with the distal small bowel and cecum being most frequently affected. No histologic type was predominant in the affected families(3). As described for Hodgkin's disease (HD)(4,5) increased incidence with small family size has been observed for NHL; however, no change in risk has been seen with increasing family size(6). PMID- 27463987 TI - Epirubicin in Childhood Acute Lymphoblastic and Myeloid Leukemia in Relapse. AB - Nineteen children with acute lymphoblastic leukemia (ALL) and 11 with acute non lymphoblastic leukemia (ANLL) in first or subsequent hematological relapse, and previously exposed to high doses of anthracyclines, were treated with Epirubicin. Eleven patients (7 ANLL and 4 ALL) were treated with Epirubicin as a single drug at the dose of 30 mg/m(2)/day for 3 days a week for 1-3 weeks. 5/7 with ANLL and 0/4 with ALL achieved complete remission (C.R.). Nineteen patients (15 ALL and 4 ANLL) were treated with Epirubicin in combination with Vincristine and Prednisone or Cytosine-arabinoside, Cyclophosphamide and VP-16. 14/15 with ALL and 3/4 with ANLL achieved C.R. One patient previously treated with 750 mg/m(2) of daunornycin developed congestive heart failure (CHF) with a decrease in the cardiac ejection fraction at 11% after receiving 270 mg/m(2) of Epirubicin. No other patients developed CHF. These data are in keeping with the reports in the literature which suggest that Epirubicin is less cardiotoxic than Doxorubicin, while retaining a similar clinical activity. PMID- 27463988 TI - A New Mononuclear Cell (MNC) RNase H Activity-Based Parameter (psi) With Possible Prognostic Value in Assessing Progression in Acute Myeloid Leukaemia. AB - A new biological parameter (psi) has been obtained and proposed here to serve in the assessment of acute myeloid leukemia (AML) progression. It is a function of the activity of RNase H (EC 3.1.4.34), the latter determined in mononuclear cells from the peripheral blood of AML patients. Using a series of patients at the time of diagnosis and after 1-2 cycles of chemotherapy, the enzyme was assayed before the several times during chemotherapy. The derivation of 4 was based on evidence suggesting that the enzyme level correlates with the proliferating leukaemic blasts and their progenitors. Values psi>1 signify the presence of clonogenic leukaemic progenitor cells in the peripheral circulation. When these high (> 1) psi values were found during chemotherapy, in these cases it was possible to predict an increase of the peripheral blast pool, with 82% success, occurring 5 35 days before cytologic relapse. In the patients in whom at some stage during treatment, psi acquired values above unity or in whom psi increased progressively, survival time was in linear correlation with the time period from the initiation of treatment to the documentation of this high psi estimate. These results suggest that a patient's relapse risk can be defined by psi with some degree of precision. PMID- 27463989 TI - Idarubicin plus Cytarabine versus Doxorubicin plus Cytarabine in Induction Therapy for Acute Non- Lymphoid Leukaemia: A Randomized Trial. AB - A randomized trial comparing idarubicin plus cytarabine (IDA/Ara-C) with doxorubicin plus cytarabine (ADM/Ara-C) in induction therapy for ANL,L was carried out. The IDA/Ara-C regimen consisted of idarubicin 20 mg/m(2) p.o. given on days 1, 2 and 3 plus cytarabine 25 mg/m(2) as a loading dose followed by 100 mg/m(2) by continuous infusion daily * 7 days. The ADM/Ara-C regimen consisted of adriamycin 30 mg/m(2) on days 1, 2 and 3 and the same dose of cytarabine. Patients who responded to the first cycle with at least 502, reduction of marrow blasts received a second treatment cycle followed by a consolidation cycle of the same treatment for those in CR at the end of 2 cycles. 35/52 (6770 receiving ADM/Ara-C achieved CR, with 25 (48%) patients in CR after a single treatment cycle. 28/48 (58%) receiving ADM/Ara-C achieved CR of whom 11 (23%) went into remission after the first treatment cycle. IDA/Ara-C caused less nausea and vomiting, less stomatitis, a shorter duration of neutropenia and less need for platelet support than ADM/Ara-C. The median duration of CR is 62 weeks for IDA/Ara-C and 48 weeks for ADM/Ara.-C. These differences are not statistically significant. Clinical cardiotoxicity occurred in 4/48 patients treated with ADM/Ara-C. No clinical cardiac toxicity was observed in those receiving IDA/Ara C. The mean post-treatment ejection fraction was, in addition, lower for ADM/Ara C than for IDA/Ara-C. It is concluded that IDA/Ara-C is an effective and safe induction therapy for ANLL. PMID- 27463990 TI - Systemic Irradiation Therapy of Myelomatosis-The Therapeutic Implications of Technique. AB - The pattern of disease relapse in nine patients with multiple myeloma who had received double hemi body irradiation therapy is analysed. This analysis highlights the localisation of these relapses to skeletal areas excluded from initial radiation fields. This phenomenon was also documented in a patient who received systemic irradiation as part of a conditioning regimen per allogeneic bone marrow transplantation. PMID- 27463991 TI - Immunologic Findings in B-Chronic Lymphocytic Leukemia Patients Treated with alpha2b-Interferon. AB - The immune function of seventeen previously untreated stage A, B-chronic lymphocytic leukemia (B-CLL) patients receiving alpha2b-interferon (alpha2b-IFN) was studied before therapy and three months later. In eleven patients a decrease of absolute blood lymphocyte numbers was observed, due to leukemic (CD5 +) cell reduction. No consistent changes in the number of T cells and their subsets were found. Immunoglobulin levels remained stable during therapy and serum beta2 microglobulin levels increased (p< 0.001). In 13 patients high serum soluble interleukin-2 receptor (s-IL2R) levels were found (>x + 5sd of controls) which further increased during therapy (p x + 5sd of controls) that did not change significantly during therapy. Interleukin-2 production by blood mononuclear cells, stimulated with phytohemaglutinin in vitro, was increased after IFN treatment in 5 patients and decreased in two. The in vivo immune findings and the in vitro response of B-CLL cells to alpha2b-IFN (DNA, RNA, protein synthesis and morphological transformation) did not clearly correlate with the clinical effects of IFN. PMID- 27463992 TI - Expression of c-myc p62 Protein in Non-Hodgkin's Lymphomas. AB - The expression of c-myc oncogene in neoplastic and non-neoplastic lymphoid tissue was studied using the specific monoclonal antibody myc 1-9E10 and the 3 step streptavidin-biotin immunoperoxidase method in paraffin sections. Twelve samples of non-neoplastic reactive lymph nodes of various etiology, 181 of non-Hodgkin's lymphomas (NHL), and five of hairy cell leukemia (HCL) were studied. The staining pattern was mainly nuclear but cytoplasmic reactions were also occasionally observed. The percentage of positive cells per total, cell population was estimated and all cases were classified into four groups: 0.-15%, 16-.30%, 31-45% and more than 45% positive cells. In the reactive lymph nodes, mainly germinal center cells were stained, but the percentage in eleven of the 12 cases was less than 15%. All cases of HCL were negative. In NHL lymphoma, only malignant cells were evaluated. Fifty-six per cent of cases of NHL had more than 15% positive cells. The percentage of positive cells was greater in high grade than in intermediate and low grade NHL (80.6x, 47.6%, and 10.6 respectively had more than 30:< positive cells). This correlation proved to be statistically significant (p < 0.001). The above findings suggest a relation between the expression of the c myc oncogene and lymphomagenesis and indicate that (evaluation of the expression of c-myc in NHL may be helpful in determining the grade of malignancy. PMID- 27463993 TI - Reactivity of Human Monoclonal Antibody Campath-1 with Human Leukemia Lymphoma Cell Lines of Varying Maturation. AB - Human leukemia-lymphoma cell lines reflecting hematopoietic clones at various stages of differentiation were examined for binding and complement mediated lysis by Campath-1. Expression of the cell surface antigen was determined with fluorescein isothiocyanate conjugated Campath-1, by ultraviolet microscopy and with a fluorescent activated cell sorter (FACS). The results indicate that there is a correlation between Campath-1 binding and the stage of lymphoid-cell differentiation. The null and T lines bound Campath-1 weakly and the fluorescence intensity was low. In the B lines there was a gradual increase in labelling correlating with the stage of differentiation. The redistribution pattern of Campath-1 on the membrane of null and T lines was in the form of rings and small caps whereas that on the B lines was that of moderate patches. Complement mediated cytolysis occurred with the majority of the cell lines, but did not correlate with the extent of surface antibody binding nor with the stage of lymphoid differentiation. The recovery and proliferative capacity of the residual cells after treatment with Campath-1 and complement was low for the null and T lines. This was variable for the B lines, but some did not regain proliferative capacity, whereas others recovered after treatment. The present results suggest that Campath-1 may have considerable utility in marrow depletion of residual. leukemic cells, more specifically of null and T-cell origin, prior to autologous transplantation. Determination of both the sensitivity of the patient's leukemic: cells to cytolysis and the recovery of proliferative capacity of Campath-1 resistant cells may contribute essential information concerning the possible efficacy of purging with this antibody in patients with significant marrow involvement prior to transplantation. PMID- 27463994 TI - Flow Cytometric Analysis of Surface Immunoglobulin Light Chains of Peripheral Blood Nonphagocytic Mononuclear Cells in Patients with Non-Hodgkin's Lymphoma. AB - Flow cytometric analysis of surface immunoglobulin light chains (kappa-lambda analysis, KLA) of peripheral blood nonphagocytic cells was performed to detect monoclonal B cell populations. The differential constants between the two histograms of kappa and lambda bearing cells (D values) of 24 samples from 20 patients with B cell lymphoma (BCL) in clinical stage (CS) III/IV were higher than those of 13 BCL patients in CS I/II (p < 0.001) and those of 11 samples from 10 HCL patients in complete remission (p < 0.001). By sequential KLA of patients with active BCL in CS III/IV, high D values decreased to the normal range when they achieved complete remission. Thus KLA is a useful parameter to evaluate the stage of advanced B cell lymphoma in complete remission or not. 24. samples from 22 patients with T cell lymphoma also showed high D values. Therefore, abnormal KLA does not indicate the lineage of lymphoma cells. PMID- 27463995 TI - B-Type Lymphocytic Leukaemia Developing Seven Years after Chemoradiotherapy for Hodgkin's Disease: Report of a Case and Review of the Literature. AB - This report describes the development of B-cell lymphocytic, leukemia, probably a leukaemic phase of non-Hodgkin's lymphoma, in a patient with Hodgkin's disease (HD) who was successfully treated and cured with MOPP combination chemotherapy and mantle radiotherapy. The leukaemia occurred seven years after the completion of chemoradiotherapy, and manifested as peripheral blood and bone-marrow involvement alone without any initial evidence of lymphadenopathy, organomegaly or extranodal disease at the time of diagnosis. The occurrence of B-lymphocytic leukaemia in a cured patient with HD is rare, and the association of these two disorders is reviewed and discussed in the light of current knowledge. PMID- 27463996 TI - B-cell Chronic Lymphocytic Leukemia in Chronic Immune Thrombocytopenic Purpura: a Case Report. AB - A patient suffering from chronic immune thrombocytopenia developing B-cell chronic lymphocytic leukemia seventeen years later, is reported. The possible mechanisms of association between the two disorders are discussed. PMID- 27463998 TI - Universal Repulsive Contribution to the Solvent-Induced Interaction Between Sizable, Curved Hydrophobes. AB - In addition to the direct attraction, sizable hydrophobes in water experience an attractive force mediated by interfacial water. Using simple geometric arguments, we identify the conditions at which the water-induced interaction between curved hydrocarbon surfaces becomes repulsive. The repulsive contribution arises from the thermodynamic penalty due to the emergence of the liquid/vapor boundary created as water gets expelled between curved hydrophobes. By augmenting the mean field approach with atomistic simulations of pristine and alkyl-coated graphitic nanoparticles in three distinct geometries, spherical, cylindrical and planar, immersed in water, we show the macroscopic thermodynamics remarkably works down to the molecular scale. The new insights improve the prediction and control of wetting and dispersion properties for a broad class of nonpolar nanoparticles. PMID- 27463997 TI - Determinants of unemployment amongst Australian systemic sclerosis patients: results from a multicentre cohort study. AB - OBJECTIVES: We sought to assess employment status, risk factors for unemployment and the associations of unemployment with patients' health related quality of life (HRQoL). METHODS: All patients enrolled in a systemic sclerosis (SSc) longitudinal cohort study, completed an employment questionnaire on enrolment. Clinical manifestations were defined based on presence at the time of enrolment. Summary statistics, chi-square tests, univariate and multivariable logistic regression were used to determine the associations of various risk factors with employment. RESULTS: Among 1587 SSc patients, 160 (20%) were unemployed at the time of cohort enrolment excluding retired patients. Of these, 63% had limited disease subtype. Mean (+/-SD) age at enrollment was 51.9 (+/-10.4) years; 13 years below the average retirement age in Australia. Mean (+/-SD) disease duration at recruitment was 11.1 (+/-10.9) years. Multivariable regression analysis revealed the presence of digital amputation (OR 3.9, 95%CI 1.7-9.1, p=0.002), diffuse disease subtype (OR 2.2, 95%CI 1.3-3.5, p-value=0.002), sicca symptoms (OR 2.7, 95%CI 1.6-4.4, p<0.001), a physical job (OR 1.8, 95%CI 1.1-3.1, p=0.03) and pulmonary arterial hypertension (OR 2.2, 95%CI 1.1-4.5, p=0.02) to be associated with unemployment. Unemployed patients had consistently poorer HRQoL scores in all domains (physical, emotional and mental health) of the SF-36 form than those who were employed. CONCLUSIONS: SSc is associated with substantial work disability and unemployment, which is in turn associated with poor quality of life. Raising awareness, identifying modifiable risk factors and implementing employment strategies and work place modifications are possible ways of reducing this burden. PMID- 27463999 TI - Food Insecurity in Singapore: The Communicative (Dis)Value of the Lived Experiences of the Poor. AB - Food insecurity is a form of health disparity that results in adverse health outcomes, particularly among disenfranchised and vulnerable populations. Using the culture-centered approach, this article engages with issues of food insecurity, health, and poverty among the low-income community in Singapore. Through 30 in-depth interviews, the narratives of the food insecure are privileged in articulating their lived experiences of food insecurity and in co constructing meanings of health informed by their sociocultural context, in a space that typically renders them invisible. Arguing that poverty is communicatively sustained through the erasure of subaltern voices from mainstream discourses and policy platforms, we ask the research question: What are the meanings of food insecurity in the everyday experiences of health among the poor in Singapore? Our findings demonstrate that the meanings of health among the food insecure are constituted in culture and materiality, structurally constrained, and ultimately complexify their negotiations of health and health decision making. PMID- 27464001 TI - Parkinson's disease, antiparkinson medicines, and driving. AB - INTRODUCTION: Parkinson's disease is a progressive neurodegenerative disorder with multiple motor and non-motor features. It is well known that the ability to drive safely is impaired in Parkinson's disease patients. While the impairing effects on psychomotor performance and vision are well established, there is uncertainty about the increased risk of road traffic accidents among drivers with Parkinson's disease. These issues, considering the progressive nature of Parkinson's disease, comorbidities and the profile of unwanted effects of the pharmacological treatments used, indicate that driving automobiles is a unique concern. AREAS COVERED: The Driving under the Influence of Drugs, Alcohol and Medicines (DRUID) categorization and specific advice for medications used in treating Parkinson's disease are presented. Expert commentary: Most medicines currently in use are considered DRUID category II: Likely to produce moderate effects on fitness to drive. Health professionals treating Parkinson's disease patients must be involved in providing proper advice and information to the patient, family and caregivers on the effects of the disorder and its medications on driving, and all possible actions should be undertaken to transition drivers with Parkinson's disease from driving to non-driving. PMID- 27464002 TI - Hierarchical spatial heterogeneity in liquid crystals composed of graphene oxides. AB - Graphene oxide (GO) is a class of two-dimensional materials with a thickness of about 1 nm and a broad distribution of lateral dimension commonly approaching several micrometers. A dispersion of GOs in water often forms a liquid crystal, which is expected to be a promising precursor for the fabrication of carbon-based materials with well-ordered structures. To accelerate the application of GO-based liquid crystals, their structures and physical properties at various sizes must be well understood. To that end, we examined the local rheological properties of GO-based liquid crystals in the nematic phase using a particle tracking technique, where local properties can be accessed by observing the thermal motion of embedded probe particles. Particle diffusion was spatially heterogeneous, and depended on the size of the particles. Such a size-dependent heterogeneity can be associated with a hierarchical local environment, which is time-dependent for this system. The anisotropic particle diffusion originated from particles trapped in between the GO layers and in isotropic-like regions. The aggregation states of the GO dispersion composed of nematic and isotropic-like regions were observed using confocal laser scanning microscopy. PMID- 27464000 TI - Mir143-BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: Implications for methamphetamine-mediated neurotoxicity. AB - BBC3 (BCL2 binding component 3) is a known apoptosis inducer; however, its role in microglial survival remains poorly understood. In addition to the classical transcription factor TRP53, Mir143 is involved in BBC3 expression at the post transcriptional level. Here, we identify unique roles of Mir143-BBC3 in mediating microglial survival via the regulation of the interplay between apoptosis and autophagy. Autophagy inhibition accelerated methamphetamine-induced apoptosis, whereas autophagy induction attenuated the decrease in microglial survival. Moreover, anti-Mir143-dependent BBC3 upregulation reversed the methamphetamine induced decrease in microglial survival via the regulation of apoptosis and autophagy. The in vivo relevance of these findings was confirmed in mouse models, which demonstrated that the microinjection of anti-Mir143 into the hippocampus ameliorated the methamphetamine-induced decrease in microglia as well as that observed in heterozygous Mir143(+/-) mice. These findings provide new insight regarding the specific contributions of Mir143-BBC3 to microglial survival in the context of drug abuse. PMID- 27464003 TI - Hot Electron Generation and Cathodoluminescence Nanoscopy of Chiral Split Ring Resonators. AB - Three-dimensional chiral plasmonic nanostructures have been shown to be able to dramatically boost photon-spin selective light-matter interactions, potentially leading to novel photonics, molecular spectroscopy, and light-harvesting applications based on circularly polarized light. Here, we show that chiral split ring gold nanoresonators interfaced to a wide band gap semiconductor exhibit a contrast in hot-electron transfer rate between left-handed and right-handed visible light that essentially mimics the far-field circular dichroism of the structures. We trace down the origin of this effect to the differential excitation of the thinnest part of the split-ring structures using dichroic sensitive cathodoluminescence imaging with nanometer spatial resolution. The results highlight the intricate interplay between the near-field and far-field chiral response of a nanostructure and establishes a clear link to the emerging field of hot carrier plasmonics with numerous potential applications in photocatalysis and solar light harvesting. PMID- 27464004 TI - Ecosystem services in risk assessment and management. AB - The ecosystem services (ES) concept holds much promise for environmental decision making. Even so, the concept has yet to gain full traction in the decisions and policies of environmental agencies in the United States, Europe, and elsewhere. In this paper we examine the opportunities for and implications of including ES in risk assessments and the risk management decisions that they inform. We assert that use of ES will: 1) lead to more comprehensive environmental protection; 2) help to articulate the benefits of environmental decisions, policies, and actions; 3) better inform the derivation of environmental quality standards; 4) enable integration of human health and ecological risk assessment; and 5) facilitate horizontal integration of policies, regulations, and programs. We provide the technical basis and supporting rationale for each assertion, relying on examples taken from experiences in the United States and European Union. Specific recommendations are offered for use of ES in risk assessment and risk management, and issues and challenges to advancing use of ES are described together with some of the science needed to improve the value of the ES concept to environmental protection. Integr Environ Assess Manag 2017;13:62-73. (c) 2016 SETAC. PMID- 27464005 TI - Successful management of methicillin-resistant Staphylococcus aureus bacteremia complicated with diffuse myelitis. PMID- 27464006 TI - Autolysis of Aspergillus oryzae Mycelium and Effect on Volatile Flavor Compounds of Soy Sauce. AB - The autolyzed mycelia of Aspergillus oryzae are rich in proteins, nucleic acids, sugar, and other biomacromolecules, and are one of the main contributors to the flavor profile of commercially important fermented goods, including soy sauce and miso. We induced autolysis of the mycelia of A. oryzae over 1 to 10 d, and found that the maximum dissolved amounts of total protein and nucleic acid ratio accounted for 28.63% and 88.93%, respectively. The organic acid content, such as citric acid, tartaric acid, succinic acid, lactic acid, and acetic acid, initially increased and then decreased as autolysis progressed, corresponding to changes in pH levels. The main characteristic flavor compounds in soy sauce, namely, ethanol, 2-phenylethanol, and 2-methoxy-4-vinylphenol, were all detected in the autolysate. Subsequently, we tested the effect of adding mycelia of A. oryzae during the fermentation process of soy sauce for 60 d, and found that addition of 1.20/00 A. oryzae mycelia provided the richest flavor. Overall, our findings suggest that compounds found in the autolysate of A. oryzae may promote the flavor compounds of soy sauce, such as alcohols, aldehydes, phenols, and esters. PMID- 27464007 TI - Heavy metals accumulation affects bone microarchitecture in osteoporotic patients. AB - Bone metabolism is affected by mechanical, genetic, and environmental factors and plays a major role in osteoporosis. Nevertheless, the influence of environmental pollution on the occurrence of osteoporosis is still unclear and controversial. In this context, heavy metals are the most important pollutants capable to affect bone mass. The aim of this study was to investigate whether heavy metals accumulation in bone tissues could be related to the altered bone metabolism and architecture of osteoporotic patients. To this end, we analyzed 25 bone head biopsies osteoporotic patients and 25 bone head biopsies of osteoarthritic patients. Moreover we enrolled 15 patients underwent hip arthroplasty for high energy hip fracture or osteonecrosis of the femoral head as a control group. Bone head biopsies were studied by BioQuant-osteo software, scanning electron microscopy and Energy Dispersive X-ray microanalysis. We found a prevalence of lead, cadmium and chromium accumulation in osteoporotic patients. Noteworthy, high levels of sclerostin, detected by immunohistochemistry, correlate with the accumulation of heavy metal found in the bone of osteoporotic patients, suggesting a molecular link between heavy metal accumulation and bone metabolism impairment. In conclusion, the presence of heavy metals into bone shed new light on the comprehension of the pathogenesis of osteoporosis since these elements could play a non redundant role in the development of osteoporosis at cellular/molecular and epigenetic level. Nevertheless, in vivo and in vitro studies need to better elucidate the molecular mechanism in which heavy metals can participate to osteoporosis. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1333-1342, 2017. PMID- 27464008 TI - Neuroanatomic Correlates of Female Sexual Dysfunction in Multiple Sclerosis. AB - OBJECTIVE: This study intended to determine associations between alterations of female sexual arousal as well as vaginal lubrication and the site of cerebral multiple sclerosis (MS) lesions. METHODS: In 44 women with MS (mean age: 36.5 +/- 9.9 years), we assessed their medical history and evaluated sexual function using the Female Sexual Function Index scores for arousal and vaginal lubrication. We determined potential confounding factors of sexual dysfunction: age; disease duration; physical disability; depression; bladder or urinary dysfunction; and total volume of cerebral lesions. Arousal and lubrication scores were correlated with one another and with potential confounding factors. Cerebral MS lesions were recorded on imaging scans. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating cerebral sites of MS lesions with arousal and lubrication scores. RESULTS: Decreased arousal scores correlated with decreased lubrication scores; decreased lubrication scores were associated with bladder or urinary symptoms. Arousal and lubrication scores were not associated with any other variables. Multivariate VLSM analysis, including arousal and lubrication scores as covariables of interest, showed right occipital lesions associated with impaired arousal and left insular lesions associated with decreased lubrication. Impaired lubrication remained associated with left insular lesions after adjustment for bladder or urinary dysfunction. INTERPRETATION: Our data indicate that impaired female sexual arousal is associated with MS lesions in the occipital region, integrating visual information and modulating attention toward visual input. Impaired lubrication correlated with lesions in the left insular region, contributing to mapping and generating visceral arousal states. Ann Neurol 2016;80:490-498. PMID- 27464009 TI - Training for Elite Sport Performance: Injury Risk Management Also Matters! AB - No abstract available for this article. PMID- 27464010 TI - The Influence of Unsportsmanlike Fouls on Basketball Teams' Performance According to Context-Related Variables. AB - The aim of the current study was to analyze the temporal effects that unsportsmanlike fouls may have on basketball teams' scoring performance under consideration of context-related variables. The authors analyzed 130 unsportsmanlike fouls from 362 elite basketball games (men's and women's Olympic Games, European and World Championships). The context-related variables studied were score-line, quality of opposition, timeout situation, minutes remaining, and player status. The data were analyzed with linear-regression models. The results showed that both teams (the team that made the foul and the opponent) had similar positive scoring performances during 1 and 3 ball possessions after the unsportsmanlike foul (short-term effect). However, 5 ball possessions after the foul (midterm effect), the team that made the foul had a scoring disadvantage ( 0.96) and the opponent team an advantage (0.78). The context-related variable quality of opposition was significant only during 1 ball possession, with negative effects for the team that made the foul and positive effects for the opponent. The final outcome showed a positive effect for score-line when the unsportsmanlike foul was made (0.96) and for quality of opposition (0.64). PMID- 27464011 TI - Missing Value Estimation for Compound-Target Activity Data. AB - Relationships between drug targets and associated diseases have traditionally been investigated by means of sequence similarity, comparative protein modeling, and pathway analysis. Recently, a complementary paradigm has emerged to link targets and drugs via biological responses within activity data and visualize findings in networks. It has been indicated that one of the obstacles towards the identification of novel interactions is the sparsity of available data. In this article, we provide a survey of estimation methods that address the challenge of data sparsity. Each method is described in terms of its advantages and limitations, and an exemplary application on compound-target activity data is demonstrated. With such imputation methods in-hand, the opportunity to combine efforts in molecular informatics can be realized, yielding novel insights into ligand-target space. PMID- 27464012 TI - Multi-pH QSAR: A Method to Differentiate the Activity of Neutral and Ionized Species and Obtain True Correlations when Both Species are Involved. AB - Classical Hansch analysis for most series of ionizable compounds cannot identify the active species as being neutral or ionized. The log P(N) and log P(I) of these series are too highly correlated. We have found a simple solution to this problem by just combining data obtained at more than one pH (multi-pH QSAR). A bonus is that the statistical power of a series is increased one fold for each pH level added. Datasets of simple homologous series serve as proofs of concept. Two of these reveal hidden correlations involving both the neutral and ionized species. These "true" correlations would be impossible to find at a single pH. An example is the inhibition of monoamine oxidase by a series of primary n alkylamines. Multi-pH QSAR indicates that the protonated amine enhances inhibition and the neutral species diminishes it. This paper illustrates the first substantial use in QSAR of the species-specific terms, log D(N) (neutral) and log D(I) (ionized). Multi-pH QSAR can give direction to lead development and facilitate the In-Silico modeling of ADMET processes by associating rate-limiting steps with the correct ionization state. PMID- 27464013 TI - Predicting Putative Inhibitors of 17beta-HSD1. AB - Reducing the concentration of estradiol by inhibiting its enzymatic synthesis has been proposed as a new therapeutic approach to treat estrogen-dependent diseases. A promising potential target is 17beta-hydroxysteroid dehydrogenase type 1 which catalyzes the biosynthesis of estradiol on-site. However, the rational computer aided design of novel inhibitors is still very difficult due to the scarcity of public data. Moreover, the chemical space covered in experiments has been quite limited as the design of new inhibitors was primarily guided by the intuition of experts in the field. Here, we present two different ligand-based approaches to predict putative ligands of 17beta-hydroxysteroid dehydrogenase type 1. According to our knowledge the data set employed in our study is the largest compilation used so far allowing for thoroughly assessing the reliability of our predictive models. By combining several local models, we were able to predict putative inhibitors with an excellent expected prediction error of only 15 %. Our positive results can be considered as an encouragement for future scientific work in this field. Furthermore, the methods employed here can be easily adopted for predicting potential ligands of other enzymes. PMID- 27464014 TI - Predicting the Flexibility Profile of Ribosomal RNAs. AB - Flexibility in biomolecules is an important determinant of biological functionality, which can be measured quantitatively by atomic Debye-Waller factor or B-factor. Although numerous works have been addressed on theoretical and computational studies of the B-factor profiles of proteins, the methods used for predicting B-factor values of nucleic acids, especially the complicated ribosomal RNAs (rRNAs), which are very functionally similar to proteins in providing matrix structures and in catalyzing biochemical reactions, still remain unexploited. In this article, we present a quantitative structure-flexibility relationship (QSFR) study with the aim at the quantitative prediction of rRNA B-factor based on primary sequences (sequence-based) and advanced structures (structure-based) by using both linear and nonlinear machine learning approaches, including partial least squares regression (PLS), least squares support vector machine (LSSVM), and Gaussian process (GP). By rigorously examining the performance and reliability of constructed statistical models and by comparing our models in detail to those developed previously for protein B-factors, we demonstrate that (i) rRNA B factors could be predicted at a similar level of accuracy with that of protein, (ii) a structure-based approach performed much better as compared to sequence based methods in modeling of rRNA B-factors, and (iii) rRNA flexibility is primarily governed by the local features of nonbonding potential landscapes, such as electrostatic and van der Waals forces. PMID- 27464015 TI - Quantitative Structure-Fluorescence Property Relationship Analysis of a Large BODIPY Library. AB - A quantitative structure-fluorescence property relationship (QSPR) analysis of a large 288-membered library based on a single fluorescent BODIPY scaffold is presented for the first time. BODIPY is a versatile fluorescent scaffold with outstanding photophysical properties. Absorption (lambdaabs ) and fluorescence emission (lambdaem ) wavelength maxima were modeled with help of stepwise multiple linear regression (MLR) and support vector regression (SVR). The models were rigorously validated by 10-times 10-fold cross-validation (CV), y-scrambling CV and with an external validation set. Non-linear SVR models (R(2) =0.92 and Q(2) =0.71 for lambdaabs ; R(2) =0.89 and Q(2) =0.69 for lambdaem ) performed significantly better than linear models. A small root mean squared error (RMSE) of 5.62 nm and 11.07 nm was achieved for lambdaabs and lambdaem , respectively, and confirmed by external validation. A novel intramolecular charge transfer descriptor was developed based on the QSPR analysis and its inclusion in the modeling significantly improved models of lambdaem . We conclude that QSPR is a useful tool for modeling lambdaabs and lambdaem of BODIPY fluorophores and suggest QSPR as an ideal partner for the design of compounds with tailored fluorescence properties in a diversity-oriented fluorescence library approach (DOFLA). PMID- 27464016 TI - Estimation of Acid Dissociation Constants Using Graph Kernels. AB - The biopharmaceutical profile of a compound depends directly on the dissociation constants of its acidic and basic groups. We estimate these constants using kernel ridge regression and graph kernels. The performance of our approach is similar to that of a semi-empirical model (Tehan et al, QSAR & Comb. Sci. 21(5): 457-472, 473-485) based on frontier electron theory, but uses only the annotated structure graph. In particular, no structure optimization is necessary. We discuss advantages and shortcomings of our approach. PMID- 27464017 TI - Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) treatment has been revolutionized by the development of highly efficacious biotherapeutics. However, a significant subset of RA patients has persistently active disease and ongoing erosive joint damage despite the available therapies. Sarilumab targets interleukin-6, one of the main cytokines mediating inflammation in RA. Positive results with sarilumab in RA clinical trials support the licensing application currently under review with the US Food and Drug Administration. AREAS COVERED: The rationale for IL-6 targeting in RA, the pharmacologic properties of sarilumab, and the clinical trial results are reviewed focusing on the pending application for the RA indication. Comparisons with other IL-6 targeting biologics as well as additional potential therapeutic directions are discussed. EXPERT OPINION: Sarilumab is a highly active therapeutic in patients with RA. While pharmacologic data demonstrate that sarilumab has a higher affinity than tocilizumab for the target receptor, available clinical results suggest that efficacy and adverse event profiles are similar to this other IL-6 blocker, which is currently approved for the treatment of RA. Whether there are other distinct differences or advantages of sarilumab that will support the approval and successful marketing of this drug, over existing therapies, remains to be determined. PMID- 27464018 TI - Smoking, 17 Alpha-Hydroxyprogesterone Caproate, and Preterm Birth. AB - Objective The objective of this study was to determine if maternal smoking modifies the effectiveness of 17 alpha-hydroxyprogesterone caproate (17OHP-C). Study Design Secondary analysis of the Maternal-Fetal Medicine Units Network trial of 17OHP-C. The prevalence of preterm birth (PTB) by smoking status and treatment group was compared by chi-squared analysis and analysis of variance was used to compare gestational age (GA) at birth. Multivariable modeling was used to estimate the effect of smoking on 17OHP-C treatment. Results In this study, 459 women were included. Maternal smoking significantly modified the effectiveness of 17OHP-C treatment. In smokers, 17OHP-C significantly reduced the prevalence of multiple outcomes (PTB < 37 and < 35 weeks, spontaneous PTB < 37 and < 35 weeks), while in nonsmokers, only PTB < 37 weeks was reduced. Delivery GA was later in 17OHP-C versus placebo treated smokers (36.4 vs. 34.3 weeks, p = 0.041) but not nonsmokers (36.3 vs. 35.5 weeks, p = nonsignificant). In multivariable modeling, 17OHP-C was more effective in smokers than nonsmokers as measured by multiple outcomes (PTB < 37 weeks [p = 0.041] and < 35 weeks [p = 0.036] and spontaneous PTB < 37 weeks [p = 0.029]). Conclusion In this cohort of women with a prior PTB, maternal smoking status significantly modified the effectiveness of 17OHP-C treatment. PMID- 27464019 TI - Maternal Super Obesity and Neonatal Morbidity after Term Cesarean Delivery. AB - Objective To estimate the association between maternal super obesity (body mass index [BMI] >= 50 kg/m(2)) and neonatal morbidity among neonates born via cesarean delivery (CD). Methods Retrospective cohort of singleton neonates delivered via CD >= 37 weeks in the Maternal-Fetal Medicine Unit Cesarean Registry. Maternal BMI at delivery was stratified as 18.5 to 29.9 kg/m(2), 30 to 39.9 kg/m(2), 40 to 49.9 kg/m(2), and >= 50 kg/m(2). Primary outcomes included acute (5-minute Apgar score < 5, cardiopulmonary resuscitation and ventilator support < 24 hours, neonatal injury, and/or transient tachypnea of the newborn) and severe (grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, seizure, respiratory distress syndrome, hypoxic ischemic encephalopathy, meconium aspiration, ventilator support >= 2 days, sepsis and/or neonatal death) neonatal morbidity. Odds of neonatal morbidity were estimated for each BMI category adjusting for clinical and operative characteristics. Results Of 41,262 maternal neonatal dyads, 36% of women were nonobese, 49% had BMI of 30 to 39.9 kg/m(2), 12% had BMI of 40 to 49.9 kg/m(2), and 3% were super obese. Compared with nonobese women, super obese women had twofold odds of acute (5 vs. 10%; adjusted odds ratio [aOR]: 1.81, 95% confidence interval [CI]: 1.59-2.73) and severe (3 vs. 6%; aOR: 2.08; 95% CI: 1.59-2.73) neonatal morbidity. Conclusion Among term infants delivered via CD, maternal super obesity is associated with increased risk of neonatal morbidity. PMID- 27464020 TI - Decreased Glutathione S-transferase Level and Neonatal Hyperbilirubinemia Associated with Glucose-6-phosphate Dehydrogenase Deficiency: A Perspective Review. AB - Classically, genetically decreased bilirubin conjugation and/or hemolysis account for the mechanisms contributing to neonatal hyperbilirubinemia associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, these mechanisms are not involved in most cases of this hyperbilirubinemia. Additional plausible mechanisms for G6PD deficiency-associated hyperbilirubinemia need to be considered. Glutathione S-transferases (GST) activity depends on a steady quantity of reduced form of glutathione (GSH). If GSH is oxidized, it is reduced back by glutathione reductase, which requires the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). The main source of NADPH is the pentose phosphate pathway, in which G6PD is the first enzyme. Rat kidney GSH, rat liver GST, and human red blood cell GST levels have been found to positively correlate with G6PD levels in their respective tissues. As G6PD is expressed in hepatocytes, it is expected that GST levels would be significantly decreased in hepatocytes of G6PD-deficient neonates. As hepatic GST binds bilirubin and prevents their reflux into circulation, hypothesis that decreased GST levels in hepatocytes is an additional mechanism contributing to G6PD deficiency-associated hyperbilirubinemia seems plausible. Evidence for and against this hypothesis are discussed in this article hoping to stimulate further research on the role of GST in G6PD deficiency-associated hyperbilirubinemia. PMID- 27464021 TI - Association between human papillomavirus (HPV) 16, HPV18, and other HR-HPV viral load and the histological classification of cervical lesions: Results from a large-scale cross-sectional study. AB - The relationship between HPV viral load and histological grades in the development of cervical cancer is in argument. It is helpful to better understand the association by quantitatively detecting viral load of HPV16, 18, and a pool of 12 other high-risk HPV type (OT) independently on the samples of precancer and cancer. A cross-sectional study was performed in five medical centers of China. Histological diagnosis made by local pathologists was adjudicated via a pathology expert panel. A fully automated real-time PCR test was used for the measurement of HPV16, 18, OT, and human beta-globin gene. A total of 2,513 women [1,341 normal, 209 low grade intraepithelial lesion (LSIL), 392 high grade intraepithelial lesion (HSIL), 520 squamous cell carcinoma (SCC), and 51 adenocarcinoma (ADC)] were included. There is a linear increase in the total 14 HPV viral load with histological grade from normal to SCC. This trend was not observed in HPV18 infection but HPV16. The viral load for OT was low in normal, peaked in LSIL and HSIL, and declined in SCC and ADC. In the co-infection of HPV16 and HPV18, HPV16 viral load was significantly higher than HPV18 in LSIL and HSIL. In co-infection of HPV16 and OT, higher HPV16 viral load was also seen in SCC and ADC. Viral load of HPV16 increases with cervical lesion grade and is predominant in cervical cancer. HPV18 viral load is low in precancer, but going up in cancer. OT viral load shows inverse trend of HPV18. J. Med. Virol. 89:535 541, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27464022 TI - Antibody response in silver catfish (Rhamdia quelen) immunized with a model antigen associated with different adjuvants. AB - Adjuvants are essential to boost the immune response to inoculated antigen and play a central role in vaccine development. In this study, we investigated the efficacy of several adjuvants in the production of anti-bovine serum albumin (BSA) antibodies in silver catfish. Two hundred and seventy juvenile silver catfish (60-80 g) of both sexes were intraperitoneally vaccinated with BSA (200 ug/fish) alone or mixed to the following adjuvants: Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), aluminum hydroxide (AlOH), Montanide, four types of cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) and three concentrations of beta-glucan, and the immune enhancing property was evaluated by measuring anti-BSA antibodies in blood samples at biweekly intervals. Our results demonstrated that CpGs ODNs and beta-glucan were as effective as classical adjuvants (FCA, FIA, AlOH and Montanide) in promoting anti BSA antibodies and that the kinetics of antibody production induced by all adjuvants used in our study had a similar trend to that observed in other fish species, with a peak at 28 days post-vaccination. These results may be useful for the selection of adjuvants for vaccine formulation intended for silver catfish and for the development of vaccine and vaccination strategies to other fish species. PMID- 27464023 TI - Pharmacological study of the mechanisms involved in the vasodilator effect produced by the acute application of triiodothyronine to rat aortic rings. AB - A relationship between thyroid hormones and the cardiovascular system has been well established in the literature. The present in vitro study aimed to investigate the mechanisms involved in the vasodilator effect produced by the acute application of 10-8-10-4 M triiodothyronine (T3) to isolated rat aortic rings. Thoracic aortic rings from 80 adult male Wistar rats were isolated and mounted in tissue chambers filled with Krebs-Henseleit bicarbonate buffer in order to analyze the influence of endothelial tissue, inhibitors and blockers on the vascular effect produced by T3. T3 induced a vasorelaxant response in phenylephrine-precontracted rat aortic rings at higher concentrations (10-4.5-10 4.0 M). This outcome was unaffected by 3.1*10-7 M glibenclamide, 10-3 M 4 aminopyridine (4-AP), 10-5 M indomethacin, or 10-5 M cycloheximide. Contrarily, vasorelaxant responses to T3 were significantly (P<0.05) attenuated by endothelium removal or the application of 10-6 M atropine, 10-5 M L-NG nitroarginine methyl ester (L-NAME), 10-7 M 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin 1-one (ODQ), 10-6 M (9S,10R,12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl 1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4 i](1,6)benzodiazocine-10-carboxylic acid, methyl ester KT 5823, 10-2 M tetraethylammonium (TEA), or 10-7 M apamin plus 10-7 M charybdotoxin. The results suggest the involvement of endothelial mechanisms in the vasodilator effect produced by the acute in vitro application of T3 to rat aortic rings. Possible mechanisms include the stimulation of muscarinic receptors, activation of the NO cGMP-PKG pathway, and opening of Ca2+-activated K+ channels. PMID- 27464024 TI - Combination therapy of orally administered glycyrrhizin and UVB improved active stage generalized vitiligo. AB - Glycyrrhizin has been used clinically for several years due to its beneficial effect on immunoglobulin E (IgE)-induced allergic diseases, alopecia areata and psoriasis. In this study, glycyrrhizin, ultraviolet B light (UVB) or a combination of both were used to treat active-stage generalized vitiligo. One hundred and forty-four patients between the ages of 3 and 48 years were divided into three groups: group A received oral compound glycyrrhizin (OCG); group B received UVB applications twice weekly, and group C received OCG+UVB. Follow-ups were performed at 2, 4, and 6 months after the treatment was initiated. The Vitiligo Area Scoring Index (VASI) and the Vitiligo Disease Activity (VIDA) instrument were used to assess the affected body surface, at each follow-up. Results showed that 77.1, 75.0 and 87.5% in groups A, B and C, respectively, presented repigmentation of lesions. Responsiveness to therapy seemed to be associated with lesion location and patient compliance. Adverse events were limited and transient. This study showed that, although the three treatment protocols had positive results, OCG and UVB combination therapy was the most effective and led to improvement in disease stage from active to stable. PMID- 27464025 TI - Clinical and prognostic significance of serum transforming growth factor-beta1 levels in patients with pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of 5%. Biomarkers for the early detection of pancreatic cancer are urgently needed. Transforming growth factor-beta1 (TGF-beta1) is elevated in the tissues and plasma of patients with PDAC. However, no studies systemically report prognostic significance of plasma TGF-beta1 levels in PDAC. In the present study, we assessed the prognostic significance of serum TGF-beta levels in patients with PDAC. TGF-beta levels were determined in serum from 146 PDAC patients, and 58 patients with benign pancreatic conditions. Regression models were used to correlate TGF-beta levels to gender, age, stage, class, and metastasis. Survival analyses were performed using multivariate Cox models. Serum levels of TGF-beta1 distinguished PDAC from benign pancreatic conditions (P<0.001) and healthy control subjects (P<0.001). Serum levels of TGF-beta also distinguished tumor stage (P=0.002) and lymph node metastasis (P=0.001). High serum levels of TGF beta1 were significantly correlated with reduced patient survival. Multivariate analysis revealed that TGF-beta1, lymph node metastasis and tumor stage were independent factors for PDAC survival. Our results indicate that serum TGF-beta1 may be used as a potential prognostic marker for PDAC. PMID- 27464026 TI - Cost-Effective Treatment of Scalar Relativistic Effects for Multireference Systems: A CASSCF Implementation Based on the Spin-free Dirac-Coulomb Hamiltonian. AB - We present an implementation of the complete active space-self-consistent field (CASSCF) method specifically designed to be used in four-component scalar relativistic calculations based on the spin-free Dirac-Coulomb (SFDC) Hamiltonian. Our implementation takes full advantage of the properties of the SFDC Hamiltonian that allow us to use real algebra and to exploit point-group and spin symmetry to their full extent while including in a rigorous way scalar relativistic effects in the treatment. The SFDC-CASSCF treatment is more expensive than its non-relativistic counterpart only in the orbital optimization step, while exhibiting the same computational cost for the rate-determining full configuration interaction part. The numerical aspects are discussed, and the capabilities of the SFDC-CASSCF methodology are demonstrated through a pilot application. PMID- 27464027 TI - Nanoconfinement Inside Molecular Metal Oxide Clusters: Dynamics and Modified Encapsulation Behavior. AB - Encapsulation behavior, as well as the presence of internal catalytically active sites, has been spurring the applications of a 3 nm hollow spherical metal oxide cluster {Mo132 } as an encapsulation host and a nanoreactor. Due to its well defined and tunable cluster structures, and nanoscaled internal void space comparable to the volumes of small molecules, this cluster provides a good model to study the dynamics of materials under nanoconfinement. Neutron scattering studies suggest that bulky internal ligands inside the cluster show slower and limited dynamics compared to their counterparts in the bulk state, revealing the rigid nature of the skeleton of the internal ligands. NMR studies indicate that the rigid internal ligands that partially cover the interfacial pore on the molybdenum oxide shells are able to block some large guest molecules from going inside the capsule cluster, which provides a convincing protocol for size selective encapsulation and separation. PMID- 27464028 TI - Estimating primate population densities: the systematic use of playbacks along transects in population surveys. AB - Accurate measures of animal population densities are essential to assess their status, demography, and answer ecological questions. Among several methods proposed to collect abundance data, line transect sampling is used the most. The assumptions required to obtain accurate density estimates through this method, however, are rarely met when studying primates. As most primate species are vocally active, density estimates can be improved by associating transect sampling with playback point counts to scan the entire study area. Yet, attention to playback procedure and data collection design is necessary. Here, we describe a protocol to assess primate densities using playback and test its application on surveys of Callicebus nigrifrons, a small Neotropical primate that shows site fidelity and active vocal behavior. We list important steps and discuss precautions that should be considered, from the adjustments in the recordings in the lab to field procedures in the playback broadcasting sessions. Prior to the surveys, we conducted playback trials with three habituated wild groups at three forest remnants to test their response to the playback stimuli at different distances. Based on these trials, we defined the radius distance covered by the playback sessions. Then, we conducted two surveys in 12 forest remnants, in the northeast of Sao Paulo State Brazil. The results of density estimates were consistent between the two surveys. As the playback survey protocol we described has proved to be a simple and useful tool for surveying vocal primate and generated reliable data, we suggest that it is a good alternative method to estimate density of species, particularly for those that are responsive to playbacks and show site fidelity. PMID- 27464029 TI - Macrolide Treatment Inhibits Pseudomonas aeruginosa Quorum Sensing in Non-Cystic Fibrosis Bronchiectasis. An Analysis from the Bronchiectasis and Low-Dose Erythromycin Study Trial. AB - RATIONALE: The mechanism by which low-dose macrolide therapy reduces exacerbations in non-cystic fibrosis bronchiectasis is not known. Pseudomonas aeruginosa quorum sensing controls the expression of a range of pathogenicity traits and is inhibited by macrolide in vitro. Quorum sensing inhibition renders P. aeruginosa less pathogenic, potentially reducing its contribution to airway damage. OBJECTIVES: The aim of this study was to determine whether long-term low dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis. METHODS: Analysis was performed on induced sputum from P. aeruginosa-positive subjects at recruitment to the BLESS (Bronchiectasis and Low-Dose Erythromycin Study) trial and after 48 weeks of treatment with erythromycin or placebo. To avoid changes in gene expression during culture, bacterial mRNA was extracted directly from sputum, and the relative expression of functionally critical quorum sensing genes was determined by quantitative polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: In keeping with the BLESS study, a significant reduction in total exacerbations was seen in this subgroup (placebo: 6, [interquartile range (IQR), 4-8]; erythromycin: 3, [IQR, 3-4]; P = 0.008; Mann-Whitney test). Erythromycin therapy did not change P. aeruginosa bacterial load determined by polymerase chain reaction. A significant reduction was observed in the expression of the quorum sensing genes, lasR (erythromycin: fold change, 0.065 [IQR, 0.01-0.85], n = 11; placebo: fold change, 1.000 [IQR, 0.05-3.05]; P = 0.047, Mann-Whitney U test) and pqsA (erythromycin: fold change, 0.07 [IQR, 0.02-0.25]; placebo: fold change, 1.000 [IQR, 0.21-4.31], P = 0.017, Mann-Whitney U test), after 48 weeks of erythromycin, compared with placebo. CONCLUSIONS: We demonstrate inhibition of P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis receiving long-term, low-dose erythromycin, without a reduction in bacterial load, representing a potential mechanism of therapeutic impact beyond a classical antimicrobial or antiinflammatory pathway. PMID- 27464030 TI - Pyrethroid Pesticides as Endocrine Disruptors: Molecular Mechanisms in Vertebrates with a Focus on Fishes. AB - Pyrethroids are now the fourth most used group of insecticides worldwide. Employed in agriculture and in urban areas, they are detected in waterways at concentrations that are lethally and sublethally toxic to aquatic organisms. Highly lipophilic, pyrethroids accumulate in sediments and bioaccumulate in fishes. Additionally, these compounds are demonstrated to act as endocrine disrupting compounds (or EDCs) in mammals and fishes, and therefore interfere with endocrine signaling by blocking, mimicking, or synergizing endogenous hormones through direct receptor interactions, and indirectly via upstream signaling pathways. Pyrethroid metabolites have greater endocrine activity than their parent structures, and this activity is dependent on the enantiomer present, as some pyrethroids are chiral. Many EDCs studied thus far in fish have known estrogenic or antiestrogenic effects, and as such cause the inappropriate or altered expression of genes or proteins (i.e., Vtg-vitellogenin, Chg choriogenin), often leading to physiological or reproductive effects. Additionally, these compounds can also interfere with other endocrine pathways and immune response. This review highlights studies that focus on the mechanisms of pyrethroid biotransformation and endocrine toxicity to fishes across a broad range of different pyrethroid types, and integrates literature on the in vitro and mammalian responses that inform these mechanisms. PMID- 27464031 TI - Evaluation of simparteam - a needs-orientated team training format for obstetrics and neonatology. AB - INTRODUCTION: A standardized team-training program for healthcare professionals in obstetric units was developed based on an analysis of common causes for adverse events found in claims registries. The interdisciplinary and inter professional training concept included both technical and non-technical skill training. Evaluation of the program was carried out in hospitals with respect to the immediate personal learning of participants and also regarding changes in safety culture. METHODS: Trainings in n=7 hospitals including n=270 participants was evaluated using questionnaires. These were administered at four points in time to staff from participating obstetric units: (1) 10 days ahead of the training (n=308), (2) on training day before (n=239), (3) right after training (n=248), and (4) 6 months after (n=188) the intervention. Questionnaires included several questions for technical and non-technical skills and the Hospital Survey on Patient Safety (HSOPS). RESULTS: Strong effects were found in the participants' perception of their own competence regarding technical skills and handling of emergencies. Small effects could be observed in the scales of the HSOPS questionnaire. Most effects differed depending on professional groups and hospitals. CONCLUSIONS: Integrated technical and team management training can raise employees' confidence with complex emergency management skills and processes. Some indications for improvements on the patient safety culture level were detected. Furthermore, differences between professional groups and hospitals were found, indicating the need for more research on contributing factors for patient safety and for the success of crew resource management (CRM) trainings. PMID- 27464032 TI - Prematurity. PMID- 27464033 TI - Prevalence of idiopathic intracranial hypertension and associated factors in obese children and adolescents. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is one of the most important and rare complications of obesity. Prevalence of IIH in childhood obesity is not known. The purpose of this study was to determine the prevalence of IIH in obese children and adolescents and to investigate the relevant factors. METHODS: In this study, 1058 obese children and adolescents between 2 and 18 years of age were included. Funduscopic examination was conducted for all subjects. In cases with papilledema, increase in intracranial pressure was clarified by measuring CSF pressure with a lumbar puncture. Other causes of IIH were ruled out with clinical, laboratory tests and imaging techniques. RESULTS: Idiopathic intracranial hypertension was diagnosed in 14 subjects (1.32%). Rates of headache and systemic hypertension in subjects with IIH was determined to be 78.6% and 28.6%, respectively. Morning cortisol, fasting insulin and HOMA-IR values were found to be significantly higher in this cases (p<0.05). CONCLUSIONS: In childhood obesity, IIH should be kept in mind as a serious complication. Funduscopic examination is an easy method that suggests IIH. In particular, obese children with systemic hypertension and refractory headache should be considered for IIH. PMID- 27464034 TI - Protection against arsenic-induced hematological and hepatic anomalies by supplementation of vitamin C and vitamin E in adult male rats. AB - BACKGROUND: Chronic arsenic exposure via contaminated drinking water is a global environmental health problem associated with hematological, hepatic and many serious systemic disorders. This study on adult male rats evaluated the protective effects of vitamin E (VE) and vitamin C (VC) against arsenic-mediated hematological and hepatic toxicities. METHODS: Arsenic was administered orally as arsenic trioxide (3 mg/kg body weight/day), as a single dose for 30 consecutive days or along with VC/ascorbic acid (200 mg/kg body weight/day dissolved in water) and VE/alpha-tocopherol (400 mg/kg body weight/day dissolved in olive oil) as supplements. Multiple hematological and hepatic parameters were assessed. RESULTS: Arsenic exposure caused significant reduction of erythrocyte counts (p<0.05), leukocyte counts (p<0.01) and hemoglobin (Hb) levels (p<0.01). Arsenic exposure also led to marked echinocytic transformation of erythrocytes resulting in increased morphological index (p<0.001). Altered serum oxidative balance was observed with a higher oxidative stress index (p<0.001). The results also showed a significant increase of serum cholesterol (p<0.05), low-density lipoprotein (p<0.001) and triglycerides (p<0.01), and decreased high-density lipoprotein (p<0.01) along with total protein (p<0.01). A marked elevation of hepatic thiobarbituric acid reactive substance (p<0.05) along with decreased reduced glutathione (p<0.001) levels were also observed. Interestingly, co-administration of VC and VE significantly prevented all the arsenic-induced alterations (p<0.05) except Hb content and serum protein. CONCLUSIONS: The present investigation offers strong evidence regarding the protective efficacy of co-administration of VC and VE against hematotoxicity and hepatotoxicity in adult male rats caused by chronic arsenic exposure. PMID- 27464035 TI - A Chromogenic and Fluorogenic Peptide Substrate for the Highly Sensitive Detection of Proteases in Biological Matrices. AB - The synthesis and application of a novel type of chromogenic and fluorogenic substrate for protease detection is described. The outstanding performance of the tripeptide substrates is exemplified by specific fluorescence detection of thrombin and factor Xa at only 500 fM concentration. The substrate is also applicable to the sensitive detection of the thrombin inhibitor dabigatran in human plasma and whole blood samples, highlighting its potential for a point-of care test for instant monitoring the blood levels of this blockbuster anticoagulant drug in specific clinical situations. PMID- 27464036 TI - Pathway Linking Internet Health Information Seeking to Better Health: A Moderated Mediation Study. AB - The Internet increasingly has been recognized as an important medium with respect to population health. However, little is known about the mechanisms that underlie the potential impact of health-related Internet use on health outcomes. Based on the three-stage model of health promotion using interactive media, this study empirically tested a moderated mediation pathway model. Results showed that the effect of Internet health information seeking on three health outcomes (general, emotional, and physical) was completely mediated by respondents' access to social support resources. In addition, users' online health information seeking experience positively moderated this mediation path. The findings have significant theoretical and practical implications for the design of Internet based health promotion resources to improve health outcomes. PMID- 27464038 TI - Sex and Cold Feet. PMID- 27464039 TI - Forum. AB - A Forum for Our Readers Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through a series of patients, or you may have an interesting case to share. Whatever your ideas, we invite you to send them to us. We welcome illustrations. Address correspondence to Forum, The Physician and Sportsmedicine, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27464037 TI - Electrochemical sensing of biomarker for diagnostics of bacteria-specific infections. AB - AIM: Pseudomonas aeruginosa is a pathogen that is prevalent in serious infections in compromised patients worldwide. A unique virulence factor of this bacterium is the redox-active molecule pyocyanin, which is a potential biomarker for the identification of P. aeruginosa infections. Here we report a direct, selective and rapid detection technique of pyocyanin. MATERIALS & METHODS: Pyocyanin was detected by amperometry at a relatively high potential where the pyocyanin signal was unaffected by background contributions. RESULTS & CONCLUSION: Pyocyanin was detected at concentrations down to 125 nM in a 50 uM mixture of interfering compounds with a reproducibility of r(2) = 0.999 (n = 5) within 200 s. The results document a step toward a point-of-care technique for diagnosis of P. aeruginosa infections. PMID- 27464040 TI - Huba Buba: Not for the Young and Light. PMID- 27464042 TI - Coming in sportsmedicine. PMID- 27464043 TI - Scanning sports. PMID- 27464044 TI - QuikQuiz. PMID- 27464047 TI - Wrap-up. PMID- 27464048 TI - Cervical Spine Injuries in Athletes. AB - In brief: Careful study of the pathomechanics and epidemiology of sports-related spine injuries brings to light many common features: The incidence increases as the sport becomes increasingly aggressive. Improperly conditioned neck muscles and lack of knowledge of the proper techniques of the sport put the athlete who sustains a blow to the head at significant risk for a spine injury. While recognition of such features has resulted in a dramatic reduction in catastrophic spine injuries, the athlete remains at risk for a less severe spine injury. The author presents guidelines for the management of athletes with, for example, transient neurologic defects or asymptomatic cervical spinal stenosis. However, the physician's decision to allow a return to sports must be highly individualized. PMID- 27464049 TI - Foot and Ankle Injuries in Figure Skaters. AB - In brief: With the increasing interest in figure skating over the past 20 years has come an increase in the number of injuries. The foot, ankle, and lower leg are the most common injury sites; this paper focuses on boot-related injuries to the foot and ankle. Of particular importance is the fact that almost all overuse injuries related to this sport respond to nonoperative treatment, which consists primarily of altering the skating boot. Changes in the skater's training and/or technique may also be necessary. PMID- 27464050 TI - Sudden Death: Myocardial Infarction in a Runner With Normal Coronary Arteries. AB - In brief: Sudden death during or following exercise is a dramatic event. In people over 40 years of age, coronary artery disease Is implicated in nearly 90% of exercise-related deaths. For those under 30 years of age, hypertrophic cardiomyopathy, abnormal coronary arteries, and coronary artery disease are the largest contributors. The authors report a case of myocardial infarction during exercise in which no clear cause could be determined. Only three similar cases have been previously reported. The authors speculate that coronary artery spasm was the cause, and they provide a literature review on sudden death and exercise. PMID- 27464051 TI - Cardiac Arrest. AB - In brief: Immediate cardiopulmonary resuscitation (CPR) is required to provide a victim of cardiac arrest with artificial ventilation and circulation. The author reviews the basic principles of CPR (establishing an airway, providing ventilation, and initiating cardiac massage) and discusses the underlying dysrhythmias associated with cardiac arrest. Depending on the dysrhythmia involved, appropriate treatment may include electrical therapy (defibrillation) and/or pharmacologic therapy (eg, intravenous epinephrine, lidocaine, bretylium, and sodium bicarbonate). PMID- 27464052 TI - Magnetic Resonance Imaging of Meniscal Tears. AB - In brief: Magnetic resonance imaging (MRI) is highly accurate for diagnosing meniscal tears. It can be performed reliably even when the patient is in acute pain and when joint effusion and hemarthrosis are present. Though it is dependent on a machine and a protocol, MRI is essentially operator-independent, unlike arthrography and arthroscopy, which rely on operator skill. MRI has the potential to improve the accuracy of arthroscopy because it can localize pathology and prompt more thorough examination of difficult areas. PMID- 27464053 TI - Neck Pain in a Football Player. AB - The unavailability of a team physician for contact/collision sports such as football can sometimes mean that an injured player will continue in a game. By doing so, the player may risk greater, perhaps even permanent disabling injury. PMID- 27464054 TI - Injuries in the Amateur Golfer. AB - In brief: To determine the types and frequency of injuries among amateurs, openended questionnaires were sent to 4,036 golfers; 1,144 responded (942 men and 202 women; average age, 52 years). The respondents played an average of two rounds per week; 708 (62%) had sustained one or more injuries. Among men, the most common injury site was the lower back; among women it was the elbow. Excessive practice and poor swing mechanics were the most common causes. Golf injuries perhaps could be prevented or reduced by proper technique, controlled practice routines, and physical conditioning. PMID- 27464055 TI - Raynaud's Disease: A Simple Approach to Management. AB - In brief: Everyone, regardless of climate, occasionally feels cold. The hands and feet, with their somewhat remote location from the heart, are particularly prone to cold sensation. But in addition to those who are just cold, there is a group of individuals who have significant problems with peripheral blood flow. These are people who have either primary or secondary Raynaud's disease. The author has developed a simple conditioning treatment that patients can do at home and that can make cold-weather activities possible without pain. PMID- 27464056 TI - Jim Palmer-Fit and 'Famed' at 45. AB - Jim Palmer looks, feels, and acts about the same as he did when he first joined the ranks of professional pitchers 25 years ago. And he gives much of the credit to his dedication to fitness. PMID- 27464057 TI - Sports Medicine Fellowships for Primary Care Physicians. AB - This is the fourth year The Physician and Sportsmedicine has published a list of fellowship programs and residencies for primary care physicians. Since our 1989 list was published (August, page 121), we have added three fellowships and updated all the other entries. While The Physician and Sportsmedicine does not endorse any of the programs, we do encourage you to contact those that interest you. We plan to publish an updated list every March. If there are changes in your program or if you would like your program to be added to the list, please submit that information by December 1, 1990, to The Physician and Sportsmedicine, Editorial Dept, Fellowships List, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27464058 TI - Sexual Activity and Athletic Performance: Is There a Relationship? AB - Sexual abstinence before an athletic event It has been advocated by crusty football coaches, Olympic athletes, and even Muhammad Ali in his prime. The truth is no one really knows how the practice got started or whether it is in the athlete's best interest, but everyone has an opinion about it. PMID- 27464059 TI - Physical Exercise: An Important Factor for Health. PMID- 27464061 TI - Physicians' Fantasy: Baseball Camp for Grown-Up Kids. PMID- 27464060 TI - Winning and Performance-Enhancing Drugs-Our Dual Addiction. AB - Athletes still use performance-enhancing drugs despite stiffer laws, education programs, and society's pervasive antidrug sentiment. In this commentary a drug use expert says it's not the athletes' fault-it's ours. PMID- 27464062 TI - So You Hate to Run.... PMID- 27464064 TI - The Effect of Core Correlation on the MP2 Hydration Free Energies of Li(+), Na(+), and K(.). AB - Simple nonpolarizable molecular mechanics potentials were developed for Li(+), Na(+), and K(+) with the adaptive force matching (AFM) method using the second order Moller-Plesset perturbation theory (MP2) with the frozen core approximation as reference. The effects of different choices of core orbitals and basis sets in the MP2 calculations were investigated for Na(+) and Li(+). For Na(+), correlating the 2s2p electrons in MP2 changes its hydration free energy by 18 kJ/mol, which is surprisingly large, constituting to about 5% of the intrinsic hydration free energy of the ion. Whereas correlating the 2s2p electrons with the aug-cc-pCVTZ basis set leads to the best agreement with experiments, with the aug cc-pVTZ basis set, a better hydration free energy will be obtained if the 2s2p are kept as frozen core orbitals. Even with nonpolarizable energy expressions, the AFM derived ion potentials predict the experimental hydration free energies of the various salts within 2% of experimental values, suggesting the robustness of the fitting procedure. However, the 2% agreement can only be achieved if the core correlation is modeled appropriately in the MP2 reference calculations. PMID- 27464065 TI - No effects of psychosocial stress on memory retrieval in non-treated young students with Generalized Social Phobia. AB - Generalized Social Phobia (GSP) is a common anxiety disorder that produces clear social life disruptions. There is no consensus on the specific processes involved in its development, but the role of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested. This study analyzed the effects of the cortisol response to the Trier Social Stress Test (TSST) on the memory retrieval of pictures with different emotional valences in 45 non-treated young students with GSP and 50 non anxious (NA) subjects (mean=19.35years, SD=0.18). No differences were found in the cortisol response of GSP and NA subjects to the TSST and control sessions. In addition, psychosocial stress impaired memory retrieval in both the GSP and NA groups, with no differences between them. Regarding the sex factor, no effects were found in the cortisol response to the TSST. However, during the encoding session, GSP men had higher cortisol levels than GSP women and NA subjects. There was also a significant interaction between sex and stress exposure on memory retrieval. Women recognized more unpleasant and neutral pictures than men; however, under stress, the women's advantage disappeared, and the men's performance improved. Sex also interacted with social phobia on positive mood, with GSP women exposed to the TSST showing the lowest positive mood. These results suggest that GSP subjects do not present an HPA axis sensitization to psychosocial stress, and they emphasize the importance of Sex in understanding stress effects on memory. PMID- 27464066 TI - The breast cancer fanfare: Sociocultural factors and women's health in Ghana. AB - Traditional notions of the "full" woman and sociocultural beliefs about gender roles contribute to a unique experience of breast cancer in Africa. I used the critical feminist lens to analyze dis-courses about breast cancer in mainstream Ghanaian media. I found that breast cancer awareness is promoted amidst fanfare and that cultural notions of the female breasts, including their sexual appeal, are implied in breast cancer discourse. This obscures a nuanced understanding of the disease and women's health globally, limits the power of women to name their experiences, and contributes to the late presentation of the dis-ease in sub Saharan Africa. I discuss the implications of the findings for international, interdisciplinary scholarship. PMID- 27464067 TI - DNA replication stress: NoCut to the rescue. PMID- 27464068 TI - Integrating Chemotherapy in the Management of Cervical Cancer: A Critical Appraisal. AB - The management of locally advanced cervix cancer has undergone a paradigm shift during the last decade. Concurrent chemoradiation (CCRT) (with cisplatin alone or in combination) is currently the standard treatment approach. CCRT results in a 5 year overall survival rate of 66% and a disease-free survival of 58%. About 30 40% of patients with locally advanced cervical cancer fail to achieve complete response to CCRT; alternative approaches are needed to improve the outcome for such patients. Weekly paclitaxel and carboplatin for 4-6 weeks as dose-dense chemotherapy prior to CCRT could be one such potential approach. The role of adjuvant chemotherapy after CCRT in patients with positive lymph nodes, larger tumor volume and stage III-IVA disease needs further exploration. Adjuvant chemotherapy is also being investigated for early-stage (stages IA2, IB1 or IIA) cervical cancer with presence of risk factors such as lymph node metastasis, lymphovascular space invasion and invasion depth of more than 10 mm, microscopic parametrial invasion, non-squamous histology and positive surgical margins. For patients with early-stage disease (IA2-IIA), short-course chemotherapy prior to surgery is associated with an improved outcome in many studies. Neo-adjuvant chemotherapy followed by fertility preservation surgery is feasible in carefully selected young patients with bulky stage IB1 disease. Recently, a number of molecular pathways have been identified as potential therapeutic targets. Bevacizumab - an inhibitor of vascular endothelial growth factor - is associated with improved survival in patients with recurrent/metastatic cervical cancer. Whether bevacizumab and other similar novel agents targeting molecular pathways could be used in front-line treatment along with cytotoxic chemotherapy is likely to be an area of research in future studies. PMID- 27464070 TI - Variation in the Use of Vena Cava Filters for Venous Thromboembolism in Hospitals in Kentucky. PMID- 27464069 TI - Association between Benign Prostatic Hyperplasia and Neutrophil-Lymphocyte Ratio, an Indicator of Inflammation and Metabolic Syndrome. AB - AIM: There is a large body of evidence of clinical studies regarding the relation between metabolic syndrome (MetS) and benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) in men. A possible link between inflammation and these 2 clinical entities has also been proposed. Here, we aimed at evaluating the role of neutrophil-lymphocyte ratio (NLR), an indicator of inflammation and MetS, in the pathogenesis of LUTS and other BPH-related parameters. METHOD: We evaluated 244 patients with benign prostate hyperplasia admitted to our outpatient clinic between January 2014 and June 2015. NLR was calculated from the peripheral blood sample for all patients. Patients' anthropometric characteristics, serum lipid levels, waist circumferences, total prostate-specific antigen (PSA) and testosterone values, prostate volumes, max values and International Prostate Symptom Score (IPSS) were recorded. All statistical analyses were conducted by SPSS version 17.0 package program, and p value <0.05 was chosen as the criterion for statistical significance. RESULTS: There was statistical significance between NLR and patients with severe IPSS score (>20) and over age 60 years (p = 0.02). Patients younger than 60 years had statistical significance between NLR and PSA <2.5 ng/dl (p = 0.004). When body mass index was selected, there was statistical significance between prostate volume <35 ml (p = 0.009) and age >60 years (p = 0.028). If 60 years of age was selected as cut-off value, there is statistical significance between age and severe IPSS, and in terms of mild erectile dysfunction, PSA >2.5 ng/dl, and prostate volume >35 ml. CONCLUSION: We found positive correlation between NLR and severe symptoms and progression of BPH. In this manner, anti-inflammatory therapy could contribute to the medical treatment of BPH. Higher NLR may be a candidate marker for severity of symptoms in BPH patients. PMID- 27464072 TI - Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials. AB - BACKGROUND: Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. SUMMARY: Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. KEY MESSAGES: The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification. PMID- 27464071 TI - Watch Me Move: A Program For Parents of Young Children With Gross-Motor Delays. AB - AIMS: Watch Me Move (WMM) is a 6-week parent education program for caregivers of children with gross-motor delays. The aims are to improve parent-child interaction in a gross-motor context, increase parents' knowledge of behavioral cues and gross-motor development, and decrease perceived parental stress. METHODS: Forty mothers of children, 6 months to 3 years of age, with a gross motor delay participated in a randomized control trial comparing parents who received the WMM program plus standard of care physiotherapy (n = 24) with parents whose children received standard of care physiotherapy (n = 16). RESULTS: Mothers who received the WMM program had significantly higher change scores on two subscales of the Nursing Child Assessment Teaching Scale (NCATS; i.e., cognitive growth fostering, and responsiveness to caregiver) and on the Parent Knowledge Questionnaire assessing knowledge of behavioral cues and gross-motor development. There were no significant group differences on the other four NCATS subscales (i.e., sensitivity to cues, response to child's distress, social emotional growth fostering, and clarity of cues) or the Parenting Stress Index. CONCLUSIONS: The addition of WMM to traditional physiotherapy improved aspects of mothers' ability to interact with their children and their knowledge of behavioral cues and gross-motor development. PMID- 27464073 TI - Fabrication and Characterization of ZnO Langmuir-Blodgett Film and Its Use in Metal-Insulator-Metal Tunnel Diode. AB - Metal-insulator-metal tunnel diodes have great potential for use in infrared detection and energy harvesting applications. The quantum based tunneling mechanism of electrons in MIM (metal-insulator-metal) or MIIM (metal-insulator insulator-metal) diodes can facilitate rectification at THz frequencies. In this study, the required nanometer thin insulating layer (I) in the MIM diode structure was fabricated using the Langmuir-Blodgett technique. The zinc stearate LB film was deposited on Au/Cr coated quartz, FTO, and silicon substrates, and then heat treated by varying the temperature from 100 to 550 degrees C to obtain nanometer thin ZnO layers. The thin films were characterized by XRD, AFM, FTIR, and cyclic voltammetry methods. The final MIM structure was fabricated by depositing chromium/nickel over the ZnO on Au/Cr film. The current voltage (I-V) characteristics of the diode showed that the conduction mechanism is electron tunneling through the thin insulating layer. The sensitivity of the diodes was as high as 32 V(-1). The diode resistance was ~80 Omega (at a bias voltage of 0.78 V), and the rectification ratio at that bias point was about 12 (for a voltage swing of +/-200 mV). The diode response exhibited significant nonlinearity and high asymmetry at the bias point, very desirable diode performance parameters for IR detection applications. PMID- 27464074 TI - Antisuperbug Cotton Fabric with Excellent Laundering Durability. AB - Multidrug-resistant superbugs are currently a severe threat to public health. Here, we report a novel kind of antisuperbug material prepared by irradiation induced graft polymerization of 1-butyl-3-vinyl imidazole chloride onto cotton fabric. The reduction of superbugs on this fabric is higher than 99.9%. Attributed to the strong covalent bonding between the graft chains and the cellulose macromolecules, the antisuperbug performance did not decrease even after 150 equiv of domestic laundering cycles. Covalent bonding also prevented the release of the antibacterial groups during application and guarantees the safety of the material, which was proved by animal skin irritation and acute oral toxicity tests. PMID- 27464076 TI - Femtosecond point-by-point inscription of Bragg gratings by drawing a coated fiber through ferrule. AB - A ferrule-based method of direct fs FBG inscription through protective plastic coating is demonstrated. Fluctuations of fiber core position relative to the writing fs beam are compensated by the developed auto-alignment system. As a result, high-quality FBGs with length from 0.1 to 50 mm are fabricated in polyimide-coated fibers, whose spectra are well described by the theory. The fabricated FBGs have great potential in sensor applications at high temperature and harsh environments both point-action and distributed ones. PMID- 27464075 TI - Design optimization and fabrication of Mach- Zehnder interferometer based on MIM plasmonic waveguides. AB - We proposed and designed a compact unbalanced Mach-Zehnder interferometer (MZI) based on metal/insulator/metal (MIM) plasmonic waveguides for ultrafast optical signal processing. The MZI was fabricated by a lithography technique and we provide, for the first time experimental evaluation of the transmission performance of the MZI using MIM PWGs. The experimental results were in good agreement with the numerical simulations. The proposed structure could be considered as a key device for on-chip optical integrated circuits. PMID- 27464077 TI - 3D resolution enhancement of deep-tissue imaging based on virtual spatial overlap modulation microscopy. AB - During the last decades, several resolution enhancement methods for optical microscopy beyond diffraction limit have been developed. Nevertheless, those hardware-based techniques typically require strong illumination, and fail to improve resolution in deep tissue. Here we develop a high-speed computational approach, three-dimensional virtual spatial overlap modulation microscopy (3D vSPOM), which immediately solves the strong-illumination issue. By amplifying only the spatial frequency component corresponding to the un-scattered point spread-function at focus, plus 3D nonlinear value selection, 3D-vSPOM shows significant resolution enhancement in deep tissue. Since no iteration is required, 3D-vSPOM is much faster than iterative deconvolution. Compared to non iterative deconvolution, 3D-vSPOM does not need a priori information of point spread-function at deep tissue, and provides much better resolution enhancement plus greatly improved noise-immune response. This method is ready to be amalgamated with two-photon microscopy or other laser scanning microscopy to enhance deep-tissue resolution. PMID- 27464078 TI - Dynamic range beyond 100 dB for polarization mode coupling measurement based on white light interferometer. AB - This paper presents a method to improve the dynamic range of white light interferometer (WLI) based polarization mode coupling (PMC) measurement system beyond 100 dB. The limitation of interference beat noise is overcame by analyzing in detail the inherent noises that have impacts on the detection sensitivity. An improved PMC measurement system and method are proposed for testing ultra-high polarization extinction ratio (PER) of polarization-related devices. The method can improve dynamic range dramatically through eliminating interference beat noise and enhancing the tested interference intensity simultaneously, which are verified theoretically and experimentally. In addition, a Y-junction with ~80 dB PER of LiNbO3 chip corresponding to a weak signal is tested as an application example. The results demonstrate that the high PER interferogram can be identified clearly and steadily with standard deviation 0.9 dB (3sigma) @ ~80 dB. This proposed method is highly beneficial in fabrication and evaluation for polarization devices with ultra-high PER. PMID- 27464079 TI - Flip-chip integration of tilted VCSELs onto a silicon photonic integrated circuit. AB - In this article we describe a cost-effective approach for hybrid laser integration, in which vertical cavity surface emitting lasers (VCSELs) are passively-aligned and flip-chip bonded to a Si photonic integrated circuit (PIC), with a tilt-angle optimized for optical-insertion into standard grating-couplers. A tilt-angle of 10 degrees is achieved by controlling the reflow of the solder ball deposition used for the electrical-contacting and mechanical-bonding of the VCSEL to the PIC. After flip-chip integration, the VCSEL-to-PIC insertion loss is -11.8 dB, indicating an excess coupling penalty of -5.9 dB, compared to Fibre-to PIC coupling. Finite difference time domain simulations indicate that the penalty arises from the relatively poor match between the VCSEL mode and the grating coupler. PMID- 27464080 TI - Silicon on-chip 1D photonic crystal nanobeam bandstop filters for the parallel multiplexing of ultra-compact integrated sensor array. AB - We propose a novel multiplexed ultra-compact high-sensitivity one-dimensional (1D) photonic crystal (PC) nanobeam cavity sensor array on a monolithic silicon chip, referred to as Parallel Integrated 1D PC Nanobeam Cavity Sensor Array (PI 1DPC-NCSA). The performance of the device is investigated numerically with three dimensional finite-difference time-domain (3D-FDTD) technique. The PI-1DPC-NCSA consists of multiple parallel-connected channels of integrated 1D PC nanobeam cavities/waveguides with gap separations. On each channel, by connecting two additional 1D PC nanobeam bandstop filters (1DPC-NBFs) to a 1D PC nanobeam cavity sensor (1DPC-NCS) in series, a transmission spectrum with a single targeted resonance is achieved for the purpose of multiplexed sensing applications. While the other spurious resonances are filtered out by the stop-band of 1DPC-NBF, multiple 1DPC-NCSs at different resonances can be connected in parallel without spectrum overlap. Furthermore, in order for all 1DPC-NCSs to be integrated into microarrays and to be interrogated simultaneously with a single input/output port, all channels are then connected in parallel by using a 1 * n taper-type equal power splitter and a n * 1 S-type power combiner in the input port and output port, respectively (n is the channel number). The concept model of PI-1DPC NCSA is displayed with a 3-parallel-channel 1DPC-NCSs array containing series connected 1DPC-NBFs. The bulk refractive index sensitivities as high as 112.6nm/RIU, 121.7nm/RIU, and 148.5nm/RIU are obtained (RIU = Refractive Index Unit). In particular, the footprint of the 3-parallel-channel PI-1DPC-NCSA is 4.5MUm * 50MUm (width * length), decreased by more than three orders of magnitude compared to 2D PC integrated sensor arrays. Thus, this is a promising platform for realizing ultra-compact lab-on-a-chip applications with high integration density and high parallel-multiplexing capabilities. PMID- 27464081 TI - Fifty-ps Raman fiber laser with hybrid active-passive mode locking. AB - Actively mode locked Raman lasing in a ring PM-fiber cavity pumped by a linearly polarized Yb-doped fiber laser is studied. At co-propagating pumping, a stochastic pulse with duration defined by the AOM switching time (~15 ns) is generated with the round-trip period. At counter-propagating pumping, one or several sub-ns pulses (within the AOM switching envelope) are formed. It has been found that the formation of such stable multi-pulse structure is defined by the single-pulse energy limit (~20 nJ) set by the second-order Raman generation. Adding a NPE-based saturable absorber in the actively mode locked cavity, results in sufficient shortening of the generated pulses both in single- and multi-pulse regimes (down to 50 ps). A model is developed adequately describing the regimes. PMID- 27464082 TI - High-damage-resistant tungsten disulfide saturable absorber mirror for passively Q-switched fiber laser. AB - In this paper, we demonstrate a high-damage-resistant tungsten disulfide saturable absorber mirror (WS2-SAM) fabricated by magnetron sputtering technique. The WS2-SAM has an all-fiber-integrated configuration and high-damage-resistant merit because the WS2 layer is protected by gold film so as to avoid being oxidized and destroyed at high pump power. Employing the WS2-SAM in an Erbium-doped fiber laser (EDFL) with linear cavity, the stable Q-switching operation is achieved at central wavelength of 1560 nm, with the repetition rates ranging from 29.5 kHz to 367.8 kHz and the pulse duration ranging from 1.269 MUs to 154.9 ns. For the condition of the maximum pump power of 600 mW, the WS2-SAM still works stably with an output power of 25.2 mW, pulse energy of 68.5 nJ, and signal-noise-ratio of 42 dB. The proposed WS2-SAM configuration provides a promising solution for advanced pulsed fiber lasers with the characteristics of high damage resistance, high output energy, and wide tunable frequency. PMID- 27464083 TI - Electromagnetic exploration of far-field super-focusing nanostructured metasurfaces. AB - Planar multi-annular nanostructured metasurfaces have provided a new way to realize far-field optical super-resolution focusing and nanoscopic imaging, due to the delicate interference of propagating waves diffracted from the metasurface mask. However, so far there are no proper methods that can be used to essentially interpret the super-focusing and nano-imaging mechanisms. This research proposes an electromagnetic methodology for the super-resolution investigation of nanostructured metasurfaces. We have physically modeled the polarization dependent transmission effect of the subwavelength nanostructure and the vectorial imaging process of a high-numerical-aperture microscopic system. We have found theoretically and experimentally that the current design theories may produce imprecise results; the microscopic imaging experimental method can only detect transversely polarized electric field component and cannot map out three dimensional total electric energy density distribution behind metasurfaces. This method will potentially be used in far-field nanoscopy, nanolithography, high density optical storage, etc. PMID- 27464084 TI - Polarization-independent and high-efficiency dielectric metasurfaces for visible light. AB - Dielectric metasurfaces are capable of completely manipulating the phase, amplitude, and polarization of light with high spatial resolutions. The emerging design based on high-index and low-loss dielectrics has led to the realization of novel metasurfaces with high transmissions, but these devices usually operate at the limited bandwidth, and are sensitive to the incident polarization. Here, we report the realization of the polarization-independent and high-efficiency silicon metasurfaces spanning the visible wavelengths about 200 nm. The fabricated computer-generated meta-holograms exhibit a 90% diffraction efficiency, which are verified by gradient metasurfaces with measured efficiencies up to 93% at 670 nm, and exceeding 75% at the wavelengths from 600 to 800 nm for the two orthogonally polarized incidences. These dielectric metasurfaces effectively decouple the phase modulation from the polarization states and frequencies for visible light, which hold great potential for novel flat optical devices operating over a broad spectrum. PMID- 27464085 TI - High-fidelity angle-modulated analog optical link. AB - There has long existed a debate over whether analog or digital optical link is more suitable for wireless convergence applications. Digital link achieves the highest fidelity, with the sacrifice of huge bandwidth due to the high resolution of digitization, and large power consumption due to the exhaustive digital data recovery. Analog link avoids these drawbacks, but it inevitably suffers from the SNR degradation. In this paper, we propose the angle modulation for analog optical link, which successfully breaks the SNR ceiling of amplitude modulation, and achieves ultrahigh link fidelity. Using the digital link (CPRI) equivalent bandwidth, angle modulation exhibits around 30-dB SNR advantage over the conventional amplitude modulation. Combined with its high tolerance on link nonlinearity, angle modulation has great potential in the future SNR-hungry analog optical applications. PMID- 27464086 TI - 25 Gbps direct modulation and 10 km data transmission with 1310 nm waveband wafer fused VCSELs. AB - Direct modulation at >25 Gbps is achieved with 1310 nm wavelength wafer fused VCSELs by adjusting the strain in the quantum well active region and the cavity photon lifetime. 25 + Gbps large signal modulation with 10-12 BER at 1310 nm across 10 km of standard single mode fiber is demonstrated. PMID- 27464087 TI - Localized plasmonic field enhancement in shaped graphene nanoribbons. AB - Graphene nanoribbon (GNR), as a fundamental component to support the surface plasmon waves, are envisioned to play an important role in graphene plasmonics. However, to achieve extremely confinement of the graphene surface plasmons (GSPs) is still a challenging. Here, we propose a scheme to realize the excitation of localized surface plasmons with very strong field enhancement at the resonant frequency. By sinusoidally patterning the boundaries of GNRs, a new type of plasmon mode with field energy concentrated on the shaped grating crest (crest mode) can be efficiently excited, creating a sharp notch on the transmission spectra. Specifically, the enhanced field energies are featured by 3 times of magnitude stronger than that of the unpatterned classical GNRs. Through theoretical analyses and numerical calculations, we confirm that the enhanced fields of the crest modes can be tuned not only by changing the width, period and Fermi energy as traditional ribbons, but also by varying the grating amplitude and period. This new technique of manipulating the light-graphene interaction gives an insight of modulating plasmon resonances on graphene nanostrutures, making the proposed pattern method an attractive candidate for designing optical filters, spatial light modulators, and other active plasmonic devices. PMID- 27464088 TI - Optical temperature sensor with enhanced sensitivity by employing hybrid waveguides in a silicon Mach-Zehnder interferometer. AB - We report on a novel design of an on-chip optical temperature sensor based on a Mach-Zehnder interferometer configuration where the two arms consist of hybrid waveguides providing opposite temperature-dependent phase changes to enhance the temperature sensitivity of the sensor. The sensitivity of the fabricated sensor with silicon/polymer hybrid waveguides is measured to be 172 pm/ degrees C, which is two times larger than a conventional all-silicon optical temperature sensor (~80 pm/ degrees C). Moreover, a design with silicon/titanium dioxide hybrid waveguides is by calculation expected to have a sensitivity as high as 775 pm/ degrees C. The proposed design is found to be design-flexible and robust to fabrication errors. PMID- 27464089 TI - Ultra-broadband room-temperature terahertz quantum cascade laser sources based on difference frequency generation. AB - We present ultra-broadband room temperature monolithic terahertz quantum cascade laser (QCL) sources based on intra-cavity difference frequency generation, emitting continuously more than one octave in frequency between 1.6 and 3.8 THz, with a peak output power of ~200 MUW. Broadband terahertz emission is realized by nonlinear mixing between single-mode and multi-mode spectra due to distributed feedback grating and Fabry-Perot cavity, respectively, in a mid-infrared QCL with dual-upper-state active region design. Besides, at low temperature of 150 K, the device produces a peak power of ~1.0 mW with a broadband THz emission centered at 2.5 THz, ranging from 1.5 to 3.7 THz. PMID- 27464090 TI - Fabry-Perot resonator: spectral line shapes, generic and related Airy distributions, linewidths, finesses, and performance at low or frequency dependent reflectivity. AB - We systematically characterize the Fabry-Perot resonator. We derive the generic Airy distribution of a Fabry-Perot resonator, which equals the internal resonance enhancement factor, and show that all related Airy distributions are obtained by simple scaling factors. We analyze the textbook approaches to the Fabry-Perot resonator and point out various misconceptions. We verify that the sum of the mode profiles of all longitudinal modes is the fundamental physical function that characterizes the Fabry-Perot resonator and generates the Airy distribution. Consequently, the resonator losses are quantified by the linewidths of the underlying Lorentzian lines and not by the measured Airy linewidth. Therefore, we introduce the Lorentzian finesse which provides the spectral resolution of the Lorentzian lines, whereas the usually considered Airy finesse only quantifies the performance of the Fabry-Perot resonator as a scanning spectrometer. We also point out that the concepts of linewidth and finesse of the Airy distribution of a Fabry-Perot resonator break down at low reflectivity. Furthermore, we show that a Fabry-Perot resonator has no cut-off resonance wavelength. Finally, we investigate the influence of frequency-dependent mirror reflectivities, allowing for the direct calculation of its deformed mode profiles. PMID- 27464091 TI - Birth and evolution of an optical vortex. AB - When a phase singularity is suddenly imprinted on the axis of an ordinary Gaussian beam, an optical vortex appears and starts to grow radially, by effect of diffraction. This radial growth and the subsequent evolution of the optical vortex under focusing or imaging can be well described in general within the recently introduced theory of circular beams, which generalize the hypergeometric Gaussian beams and which obey novel kinds of ABCD rules. Here, we investigate experimentally these vortex propagation phenomena and test the validity of circular-beam theory. Moreover, we analyze the difference in radial structure between the newly generated optical vortex and the vortex obtained in the image plane, where perfect imaging would lead to complete closure of the vortex core. PMID- 27464092 TI - Mid-infrared imaging system based on polarizers for detecting marine targets covered in sun glint. AB - When a marine target is detected by a mid-infrared detector on a sunny day, the target's information could be lost if it is located in sun glint. Therefore, we developed a new mid-infrared imaging system capable of effectively detecting marine targets in regions of strong sun glint, which is presented in this report. Firstly, the theory of the analysis methods employed in different detection scenarios is briefly described to establish whether one or two polarizers should be utilized to suppress further the p-polarized component of sun glint. Secondly, for the case in which a second polarizer is employed, the formula for the optimum angle between the two polarizers is given. Then, the results of our field experiment are presented, demonstrating that the developed system can significantly reduce sun glint and can enhance the contrast of target images. A commonly used image processing algorithm proved capable of identifying a target in sun glint, confirming the effectiveness of our proposed mid-infrared polarization imaging system. PMID- 27464093 TI - Almost-total absorption of light in thin, biperiodic, weakly-absorbing semiconductor gratings. AB - We consider the design of optical systems capable of providing near 100% absorption of visible light, consisting of a structured thin layer of a weakly absorbing semiconductor placed on top of a dielectric spacer layer and a metallic mirror layer. We generalise a system recently studied semi-analytically and experimentally by Sturmberg et al [Optica 3, 556 2016] which incorporated a grating layer of antimony sulphide and delivered high, narrow-band absorptance of normally-incident light for a single polarisation. We demonstrate that bi periodic gratings can be optimised to deliver near-perfect absorptance of unpolarised light in the system, and comment on the wavelength and angular ranges over which the absorptance remains near 100%. We show that the properties of the systems studied depend on the interaction of multiple modes, and cannot be accurately modelled within the quasistatic approximation. PMID- 27464094 TI - Co-occurrence of circular dichroism and asymmetric transmission in twist nanoslit nanorod Arrays. AB - Circular dichroism (CD) and asymmetric transmission (AT) are important in the field of negative refractive index media and perfect polarization converters. A large difference between T++ and T-- in the transmission matrix T leads to a large CD effect, whereas a large difference between T + and T+- leads to a large AT effect. To achieve large CD and AT effects simultaneously, we theoretically analyzed the transmission matrix T and proposed the chiral plasmonic nanostructure of twist nanoslit-nanorod arrays (TNNAs) in this study. Results calculated by the finite element method show that, at around resonant wavelengths, the spectra of T++ and T-- correspondingly present peaks and valleys leading to a large CD effect. Meanwhile one of the spectra for T-+ and T+- presents valleys and another presents peaks leading to a large AT effect. More importantly, the magnitude of CD is equivalent to that of AT. In addition, the CD and AT effects strongly depend on the geometric parameters of TNNAs. Overall, these results are useful for designing chiral plasmonic nanostructures with large CD and AT effects. PMID- 27464095 TI - Second harmonic generation of diamond-blade diced KTiOPO4 ridge waveguides. AB - We report on the fabrication of ridge waveguides in KTiOPO4 nonlinear optical crystals through carbon ion irradiation followed by precise diamond blade dicing. The diced side-walls have low roughness, which allows for low propagation loss of ~1dB/cm in fabricated of ridges. The waveguide property investigation has been performed at 1064 nm as well as 532 nm, showing good guidance at both TE and TM polarizations. Based on type II phase matching configuration, efficient second harmonic generation of green light at room temperature has been realized. High conversion efficiencies of ~1.12%W-1 and ~12.4% have been obtained for frequency doubling under the pump of continuous-wave (CW) and pulsed fundamental waves at 1064 nm, respectively. PMID- 27464096 TI - Quantum optics of lossy asymmetric beam splitters. AB - We theoretically investigate quantum interference of two single photons at a lossy asymmetric beam splitter, the most general passive 2*2 optical circuit. The losses in the circuit result in a non-unitary scattering matrix with a non trivial set of constraints on the elements of the scattering matrix. Our analysis using the noise operator formalism shows that the loss allows tunability of quantum interference to an extent not possible with a lossless beam splitter. Our theoretical studies support the experimental demonstrations of programmable quantum interference in highly multimodal systems such as opaque scattering media and multimode fibers. PMID- 27464097 TI - Link optimization for DWDM transmission with an optical phase conjugation. AB - We characterize in-span signal power asymmetry in random distributed feedback ultralong Raman laser-amplified WDM transmission and numerically optimize fiber span length and operating band to achieve the lowest inter-span signal power asymmetry between transmitted and optically conjugated channels in systems relying upon mid-link optical conjugation to combat fiber nonlinear impairments. PMID- 27464098 TI - High resolution fiber optic surface plasmon resonance sensors with single-sided gold coatings. AB - The surface plasmon resonance (SPR) performance of gold coated tilted fiber Bragg gratings (TFBG) at near infrared wavelengths is evaluated as a function of the angle between the tilt plane orientation and the direction of single- and double sided, nominally 50 nm-thick gold metal depositions. Scanning electron microscope images show that the coating are highly non-uniform around the fiber circumference, varying between near zero and 50 nm. In spite of these variations, the experimental results show that the spectral signature of the TFBG-SPR sensors is similar to that of simulations based on perfectly uniform coatings, provided that the depositions are suitably oriented along the tilt plane direction. Furthermore, it is shown that even a (properly oriented) single-sided coating (over only half of the fiber circumference) is sufficient to provide a theoretically perfect SPR response with a bandwidth under 5 nm, and 90% attenuation. Finally, using a pair of adjacent TFBG resonances within the SPR response envelope, a power detection scheme is used to demonstrate a limit of detection of 3 * 10-6 refractive index units. PMID- 27464099 TI - Three-dimensional quasi-conformal transformation optics through numerical optimization. AB - In this paper we demonstrate the possibility to achieve 3-dimensional quasi conformal transformation optics through parametrization and numerical optimization without using sliding boundary conditions. The proposed technique, which uses a quasi-Newton method, is validated in two cylindrical waveguide bends as design examples. Our results indicate an arbitrarily small average anisotropy can be achieved in 3D transformation optics as the number of degrees of freedom provided by the parametrization was increased. The waveguide simulations confirm modal preservation when the residual anisotropy is neglected. PMID- 27464100 TI - Light-controlled photonics-based mm-wave beam switch. AB - We present experimental investigation of light-controlled photonics-enhanced quasi-optical mm-wave beam switch operating at a resonant frequency in the mm wave band of 75 to 110 GHz. The switch is implemented as a Bragg structure with a resonant layer of high-resistivity silicon that creates a narrow transmission peak within the mm-wave propagation gap. The peak amplitude is sensitive to the intensity of light pulses illuminating the structure. When using a silicon wafer of 30 KOhm . cm resistivity and light pulses created by a 400W LED-array light source, we achieved mm-wave transmission peak modulation exceeding 15 dB. PMID- 27464101 TI - Unusual imaging properties of superresolution microspheres. AB - We employ a self-assembly method to fabricate dielectric microsphere arrays that can be transferred to any desired positions. The arrays not only enable far field, broad-band, high-speed, large-area, and wide-angle field of views but also achieve superresolution reaching lambda/6.4. We also find that many proposed theories are insufficient to explain the imaging properties; including the achieved superresolution, effects of immersion, and unusual size-dependent magnification. The half-immersed microspheres certainly do not behave like any ordinary solid immersion lenses and new mechanisms must be incorporated to explain their unusual imaging properties. PMID- 27464102 TI - Label-free cellular structure imaging with 82 nm lateral resolution using an electron-beam excitation-assisted optical microscope. AB - We present label-free and high spatial-resolution imaging for specific cellular structures using an electron-beam excitation-assisted optical microscope (EXA microscope). Images of the actin filament and mitochondria of stained HeLa cells, obtained by fluorescence and EXA microscopy, were compared to identify cellular structures. Based on these results, we demonstrated the feasibility of identifying label-free cellular structures at a spatial resolution of 82 nm. Using numerical analysis, we calculated the imaging depth region and determined the spot size of a cathodoluminescent (CL) light source to be 83 nm at the membrane surface. PMID- 27464103 TI - Orthogonal basis with a conicoid first mode for shape specification of optical surfaces: comment. AB - Potentially misleading results follow from an error in a recent paper, namely [Opt. Express24, 5448-5462 (2016)], that contains a comparative analysis of schemes for specifying shape. Some corrections are presented for clarification. Additional comments are offered in relation to practical goals in this area of research. PMID- 27464104 TI - Orthogonal basis with a conicoid first mode for shape specification of optical surfaces: reply. AB - We present some comments to the paper "Orthogonal basis with a conicoid first mode for shape specification of optical surfaces: comment." PMID- 27464105 TI - Generation of nanosecond and subnanosecond laser pulses by AlGaAs/GaAs laser thyristor with narrow mesa stripe contact. AB - Lasers-thyristors with a narrow (20 MUm) mesa stripe contact have been studied. It was shown that the laser peak power reaches a value of 2.5 W in the long-pulse mode at a pulse width of 13 ns. It was demonstrated that generation of a controlled train of laser pulses with peak power of 1.6 W and width of 90 ps is possible in the short-pulse mode. The maximum value of the pulse repetition frequency was 470 kHz at the following working characteristics of the laser thyristor: blocking voltage 5.8 V, control current pulse 25 mA. A number of specific features were observed in the short-pulse mode. It was found that the blocking voltage and amplitude of the control current pulse affect the lasing process. We observed that in short pulse mode the lasing spectra have a two-band structure and the lateral near field may degenerate into a single spot with size substantially smaller than the mesa stripe width. It was shown that the main reason for the observed specific features of lasing is the clearly pronounced effect of the spatial localization of the current. PMID- 27464106 TI - Hybrid III-V/SOI resonant cavity enhanced photodetector. AB - A hybrid III-V/SOI resonant-cavity-enhanced photodetector (RCE-PD) structure comprising a high-contrast grating (HCG) reflector, a hybrid grating (HG) reflector, and an air cavity between them, has been proposed and investigated. In the proposed structure, a light absorbing material is integrated as part of the HG reflector, enabling a very compact vertical cavity. Numerical investigations show that a quantum efficiency close to 100 % and a detection linewidth of about 1 nm can be achieved, which are desirable for wavelength division multiplexing applications. Based on these results, a hybrid RCE-PD sample has been fabricated by heterogeneously integrating an InP-based material onto a silicon-on-insulator wafer and has been characterized, which shows a clear enhancement in photo current at the designed wavelength. This indicates that the HG reflector provides a field enhancement sufficient for RCE-PD operation. In addition, a capability of feasibly selecting the detection wavelength during fabrication as well as a possibility of realizing silicon-integrated bidirectional transceivers are discussed. PMID- 27464107 TI - Coherent diffraction imaging by moving a lens. AB - A moveable lens is used for determining amplitude and phase on the object plane. The extended fractional Fourier transform is introduced to address the single lens imaging. We put forward a fast algorithm for the transform by convolution. Combined with parallel iterative phase retrieval algorithm, it is applied to reconstruct the complex amplitude of the object. Compared with inline holography, the implementation of our method is simple and easy. Without the oversampling operation, the computational load is less. Also the proposed method has a superiority of accuracy over the direct focusing measurement for the imaging of small size objects. PMID- 27464108 TI - High-accuracy simultaneous measurement of particle size and location using interferometric out-of-focus imaging. AB - A method based on unidirectional gradient-matched algorithm and Fourier transform technique is proposed to simultaneously extract the location and the number of fringes/fringe spacing of a particle interferogram. The position coordinate (x,y) of a particle can be determined with high accuracy because of the elimination of the fringe within the particle fringe pattern. Furthermore, the method can be employed to achieve sub-pixel frequency extraction when combined with an improved Rife algorithm. The performance of the method has been verified by numerical simulations and experimental measurements. The results suggest that the method presented here is highly beneficial to applications such as spray, in accurately measuring both the particle size and its location. PMID- 27464109 TI - 910nm femtosecond Nd-doped fiber laser for in vivo two-photon microscopic imaging. AB - Pre-chirp technique was used in an Nd-doped fiber amplifier to optimize high quality 910 nm pulses with the pulses width of 114 fs and pulse energy of 4.4 nJ. The in vivo zebrafish imaging results from our totally home-made microscopy proves our femtosecond Nd fiber laser an ideal source in two-photon microscopic imaging. PMID- 27464110 TI - Theoretical and numerical treatment of modal instability in high-power core and cladding-pumped Raman fiber amplifiers. AB - Raman fiber lasers have been proposed as potential candidates for scaling beyond the power limitations imposed on near diffraction-limited rare-earth doped fiber lasers. One limitation is the modal instability (MI) and we explore the physics of this phenomenon in Raman fiber amplifiers (RFAs). By utilizing the conservation of number of photons and conservation of energy in the absence of loss, the 3 * 3 governing system of nonlinear equations describing the pump and the signal modal content are decoupled and solved analytically for cladding pumped RFAs. By comparing the extracted signal at MI threshold for the same step index-fiber, it is found that the MI threshold is independent of the length of the amplifier or whether the amplifier is co-pumped or counter-pumped; dictated by the integrated heat load along the length of fiber. We extend our treatment to gain-tailored RFAs and show that this approach is of limited utility in suppressing MI. Finally, we formulate the physics of MI in core-pumped RFAs where both pump and signal interferences participate in writing the time-dependent index of refraction grating. PMID- 27464111 TI - Coupled mode theory in non-Hermitian optical cavities. AB - We study the coupling of mode in time for non-Hermitian cavities. Using variational principle, we provide a self-consistent approach to study the mode hybridization in non-Hermitian cavities from the first-principle of Maxwell's equations. We first extend the reaction concept for time reversal adjoint system using the scalar inner product. We apply our theory to the non-Hermitian parity time symmetric cavities, and obtain excellent agreement with results obtained by finite element fullwave simulations. In contrast, the conventional coupled mode theory using complex inner product fails to capture the bifurcation of the dispersion of parity-time symmetric cavities, as non-Hermicity increases. Our theory may have potential applications in non-Hermitian optical systems. PMID- 27464112 TI - Feasibility study on 3-D shape analysis of high-aspect-ratio features using through-focus scanning optical microscopy. AB - In-line metrologies currently used in the semiconductor industry are being challenged by the aggressive pace of device scaling and the adoption of novel device architectures. Metrology and process control of three-dimensional (3-D) high-aspect-ratio (HAR) features are becoming increasingly important and also challenging. In this paper we present a feasibility study of through-focus scanning optical microscopy (TSOM) for 3-D shape analysis of HAR features. TSOM makes use of 3-D optical data collected using a conventional optical microscope for 3-D shape analysis. Simulation results of trenches and holes down to the 11 nm node are presented. The ability of TSOM to analyze an array of HAR features or a single isolated HAR feature is also presented. This allows for the use of targets with area over 100 times smaller than that of conventional gratings, saving valuable real estate on the wafers. Indications are that the sensitivity of TSOM may match or exceed the International Technology Roadmap for Semiconductors (ITRS) measurement requirements for the next several years. Both simulations and preliminary experimental results are presented. The simplicity, lowcost, high throughput, and nanometer scale 3-D shape sensitivity of TSOM make it an attractive inspection and process monitoring solution for nanomanufacturing. PMID- 27464113 TI - Optical constants of CH3NH3PbBr3 perovskite thin films measured by spectroscopic ellipsometry. AB - The lack of optical constants information for hybrid perovskite of CH3NH3PbBr3 in thin films form can delay the progress of efficient LED or laser demonstration. Here, we report on the optical constants (complex refractive index and dielectric function) of CH3NH3PbBr3 perovskite thin films using spectroscopic ellipsometry. Due to the existence of voids, the refractive index of the thin films is around 8% less than the single crystals counterpart. The energy bandgap is around 2.309 eV as obtained from photoluminescence and spectrophotometry spectra, and calculated from the SE analysis. The precise measurement of optical constants will be useful in designing optical devices using CH3NH3PbBr3 thin films. PMID- 27464114 TI - Modal evolution in asymmetric three- and four-layer plasmonic waveguides. AB - Through the employment of a novel approach in solving the dispersion for the three-layer plasmonic waveguides, considering lossy metals, we demonstrate that, besides well-known modes, the complete dispersion always contains high-lossy periodic solutions. Consideration of these solutions is shown to be crucial for the understanding of every aspect of dispersion evolution at broad spectral range when the thickness of the middle layer is varied. In particular, we show that generally considered modes of the three-layer waveguide transform into the single interface modes via interaction with high-lossy periodic solutions. Furthermore, the negative index mode is shown to experience a transition between low- and high lossy regimes depending on the waveguide's thickness. Our results, avoiding complicated analytical analysis, perfectly integrate and importantly complement past theoretical works. PMID- 27464115 TI - Real-time experimental demonstration of PS-QPSK transmission with manipulated rotating and novel correlated CMA. AB - In this paper, we propose a novel manipulated rotating polarization switched quadrature phase shift keying (MR-PS-QPSK) technique, and corresponding correlated constant modulus algorithm (CMA) for signal recovery. The latter utilizes the correlation between the PS-QPSK symbols in the two polarizations to lock the phase of output signals. Then the signals in the two polarizations are merged according to the recovered switching bit, which suppresses the noise and simplifies the subsequent process. A field programmable gate array (FPGA) based real-time platform is built for experimental demonstration. The experimental results show that the proposed MR-PS-QPSK modulation format with correlated CMA can provide 3.2 dB optical signal-to-noise ratio (OSNR) improvement over dual polarization QPSK (DP-QPSK) at back-to-back case and 3.8 dB OSNR improvement after fiber transmission at the same symbol rate, which corresponds to be about 2 dB OSNR improvement at the same bit rate. The resource consumption analysis in FPGA digital signal processing blocks and logic utilizations shows that the MR-PS QPSK with correlated CMA only requires a small additional computational effort. PMID- 27464116 TI - General optimization of tapered anti-reflective coatings. AB - An efficient, general optimized method is outlined that achieves antireflective tapers using lossless, non-dispersive dielectrics. The method modifies the derivative of a perfect antireflective wave amplitude distribution rather than the index of refraction distribution. Modifying the derivative of the wave amplitude distribution minimizes the potential index of refraction distributions and ensures perfect antireflection at one frequency, incidence angle, and linear polarization combination. Additional combinations of frequency, incident angle, and linear polarization can be targeted at a particular reflection coefficient within the optimization. After the method is outlined, three examples are shown with one being fabricated and validated at radiofrequencies. PMID- 27464117 TI - 34-fs, all-fiber all-polarization-maintaining single-mode pulse nonlinear amplifier. AB - We present an all-fiber all-polarization-maintaining (PM) single mode (SM) fiber pulse nonlinear amplification system. The seed laser with a repetition rate of 200 MHz is amplified by two-section erbium-doped PM gain fibers with different peak-absorption rate. The amplified pulse duration can be compressed into 34-fs with 320-mW output power, which corresponds to 1.6-nJ pulse energy and approximate 23.5-kW peak power. In addition, the amplified and compressed pulse is further coupled into the high nonlinear fiber and an octave-spanning supercontinuum generation can be obtained. To the best of our knowledge, it is the highest peak power and the shortest pulse duration obtained in the field of all-fiber all-PM SM pulse-amplification systems. PMID- 27464118 TI - Ultrafast, high repetition rate, ultraviolet, fiber-laser-based source: application towards Yb+ fast quantum-logic. AB - Trapped ions are one of the most promising approaches for the realization of a universal quantum computer. Faster quantum logic gates could dramatically improve the performance of trapped-ion quantum computers, and require the development of suitable high repetition rate pulsed lasers. Here we report on a robust frequency upconverted fiber laser based source, able to deliver 2.5 ps ultraviolet (UV) pulses at a stabilized repetition rate of 300.00000 MHz with an average power of 190 mW. The laser wavelength is resonant with the strong transition in Ytterbium (Yb+) at 369.53 nm and its repetition rate can be scaled up using high harmonic mode locking. We show that our source can produce arbitrary pulse patterns using a programmable pulse pattern generator and fast modulating components. Finally, simulations demonstrate that our laser is capable of performing resonant, temperature-insensitive, two-qubit quantum logic gates on trapped Yb+ ions faster than the trap period and with fidelity above 99%. PMID- 27464119 TI - QPSK 3R regenerator using a phase sensitive amplifier. AB - A black box phase sensitive amplifier based 3R regeneration scheme is proposed for non-return to zero quadrature phase shift keyed formatted signals. Performance improvements of more than 2 dB are achieved at the presence of input phase distortion. PMID- 27464120 TI - Dynamic optical resource allocation for mobile core networks with software defined elastic optical networking. AB - Driven by the forthcoming of 5G mobile communications, the all-IP architecture of mobile core networks, i.e. evolved packet core (EPC) proposed by 3GPP, has been greatly challenged by the users' demands for higher data rate and more reliable end-to-end connection, as well as operators' demands for low operational cost. These challenges can be potentially met by software defined optical networking (SDON), which enables dynamic resource allocation according to the users' requirement. In this article, a novel network architecture for mobile core network is proposed based on SDON. A software defined network (SDN) controller is designed to realize the coordinated control over different entities in EPC networks. We analyze the requirement of EPC-lightpath (EPCL) in data plane and propose an optical switch load balancing (OSLB) algorithm for resource allocation in optical layer. The procedure of establishment and adjustment of EPCLs is demonstrated on a SDON-based EPC testbed with extended OpenFlow protocol. We also evaluate the OSLB algorithm through simulation in terms of bandwidth blocking ratio, traffic load distribution, and resource utilization ratio compared with link-based load balancing (LLB) and MinHops algorithms. PMID- 27464121 TI - Pulsed and CW adjustable 1942 nm single-mode all-fiber Tm-doped fiber laser system for surgical laser soft tissue ablation applications. AB - A surgical laser soft tissue ablation system based on an adjustable 1942 nm single-mode all-fiber Tm-doped fiber laser operating in pulsed or CW mode with nitrogen assistance is demonstrated. Ex vivo ablation on soft tissue targets such as muscle (chicken breast) and spinal cord (porcine) with intact dura are performed at different ablation conditions to examine the relationship between the system parameters and ablation outcomes. The maximum laser average power is 14.4 W, and its maximum peak power is 133.1 W with 21.3 MUJ pulse energy. The maximum CW power density is 2.33 * 106 W/cm2 and the maximum pulsed peak power density is 2.16 * 107 W/cm2. The system parameters examined include the average laser power in CW or pulsed operation mode, gain-switching frequency, total ablation exposure time, and the input gas flow rate. The ablation effects were measured by microscopy and optical coherence tomography (OCT) to evaluate the ablation depth, superficial heat affected zone diameter (HAZD) and charring diameter (CD). Our results conclude that the system parameters can be tailored to meet different clinical requirements such as ablation for soft tissue cutting or thermal coagulation for future applications of hemostasis. PMID- 27464122 TI - Theoertical investigation of quantum waveform shaping for single photon emitters. AB - We investigate a new technique for quantum-compatible waveform shaping that extends the time lens method, and relies only on phase operations. Under realistic experimental conditions, we show that it is possible to both temporally compress and shape optical waveforms in the nanosecond to tens of picoseconds range, which is generally difficult to achieve using standard dispersive pulse shaping techniques. PMID- 27464123 TI - CCT-tunable LED device with excellent ACU by using micro-structure array film. AB - We apply a microstructure array (MSA) film to improve the angular color uniformity (ACU) of a correlated-color-temperature-tunable LED (CCT-tunable LED) with tunable CCT ranging from 2700 to 6500 K. The effects of the MSA film area and the height between the film and LED are investigated and optimized. The resulting ACU is greatly improved for all CCT ranges with little luminous flux loss. For a typical CCT range of 3000-4000 K, with a full-covering MSA film and height H = 5 mm, the CCT deviation is significantly reduced from 1090 K to 218 K, with only 1.8% luminous flux loss. PMID- 27464124 TI - Group delay dispersion measurements in the mid-infrared spectral range of 2-20 um. AB - We present two measurement devices which both allow the direct measurement of the group delay (GD) and group delay dispersion (GDD) of laser optics, covering the near- and mid-infrared (MIR) spectral range from 2 to 20 um (500-5,000 cm 1). Two different kinds of devices were developed to measure the GDD of multilayer interference coatings. One is a resonant scanning interferometer (RSI) and the other is a white light interferometer (WLI). The WLI is also capable of measuring the GDD in transmission, for instance of bulk material. GDD measurements of a high dispersive mirror for wavelengths from 2.0 to 2.15 um and one of a multilayer mirror from 8.5 to 12.0 um are presented. A measurement of a zinc selenide (ZnSe) substrate in transmission was made with the WLI demonstrating the full bandwidth of the device from 1.9 to 20 um. The comparison of all measurements with their related theoretical values shows a remarkable correspondence. PMID- 27464125 TI - Experimental characterization of an all-optical wavelength converter of OFDM signals using two-mode injection-locking in a Fabry-Perot laser. AB - While optical OFDM has been demonstrated for superior transmission performance, its analogue waveform in the time domain challenges many conventional all-optical wavelength converters (AOWC) that are needed for future flexible optical networks. There only exist a few reports on AOWC of OFDM signals, which are mainly based on the low-efficient four-wave mixing. In this paper, we propose an AOWC for OFDM signals by using two-mode injection-locking in a low-cost Fabry Perot laser. The control signal and the probe signal at a milliwatt power level are combined and injected into the FP laser. By a proper control, they can be injection-locked to two longitudinal modes in the FP laser and subsequently, the transmission of the probe signal is conditioned by the control signal. We conduct an experimental study on various aspects of this AOWC. Despite a vendor-specified electrical-to-optical (E/O) modulation bandwidth of 2.5 GHz, we find that the optical-to-optical (O/O) modulation bandwidth of AOWC is free from this limit and can be much wider. We examine the linear transfer curve of the AOWC by simply using the OFDM waveforms as the stimulus. The performance tolerance to the wavelength detuning and injected power ratio is also measured. The proposed AOWC can provide a linear transfer function from the control signal to the probe signal to support the random-fluctuated OFDM waveform. We also investigate the maximum capacity of the AOWC by using the adaptive bit-loading OFDM. Finally, we measure the power penalty after the AOWC at two different bit rates to show the tradeoff between the penalty and capacity. PMID- 27464126 TI - Large aperture liquid crystal lens with an imbedded floating ring electrode. AB - We propose a hole-patterned large aperture (LA) liquid crystal (LC) lens with a diameter of 6 mm. In our design, a floating ring electrode is embedded into the interface between the dielectric layer and the LC layer. This structure increases the electric field strength around the floating ring electrode located near the aperture center and assists in distributing the fringing electric field throughout the LC layer. Therefore, the thick dielectric layer used in the conventional hole-patterned LA LC lens can be effectively decreased. Consequently, the proposed LA LC lens has low operation voltage, large lens power, and introduces a low wavefront error of approximately 0.07 lambda. PMID- 27464127 TI - Programmable eye-opener lattice filter for multi-channel dispersion compensation using an integrated compact low-loss silicon nitride platform. AB - A tunable eye-opening lattice filter for dispersion compensation is demonstrated on an ultra low-loss waveguide platform based on a compact high-aspect ratio Si3N4 core. A programmable 10th order lattice filter is demonstrated by cascading a total of 21 Mach-Zehnder interferometers with programmable delay lines of lengths designed at the baseband data rate. The filter has a footprint of 2.23 cm2 with continuously tunable dispersion from -500 ps/nm to 500 ps/nm. The filter shows a periodic transfer function with a measured FSR of 100 GHz capable of compensating multiple WDM channels with a single device. PMID- 27464128 TI - Enhancement of two-photon photoluminescence and SERS for low-coverage gold films. AB - Electromagnetic field enhancement (FE) effects occurring in thin gold films 3-12 nm are investigated with two-photon photoluminescence (TPL) and Raman scanning optical microscopies. The samples are characterized using scanning electron microscopy images and linear optical spectroscopy. TPL images exhibit a strong increase in the level of TPL signals for films thicknesses 3-8-nm, near the percolation threshold. For some thicknesses, TPL measurements reveal super-cubic dependences on the incident power. We ascribe this feature to the occurrence of very strongly localized and enhanced electromagnetic fields due to multiple light scattering in random nanostructures that might eventually lead to white-light generation. Raman images exhibit increasing Raman signals when decreasing the film thickness from 12 to 6-nm and decreasing signal for the 3-nm-film. This feature correlates with the TPL observations indicating that highest FE is to be expected near the percolation threshold. PMID- 27464129 TI - Broadband beamsplitter for high intensity laser applications in the infra-red spectral range. AB - We report on design, production and characterization of an extremely broadband multilayer beamsplitter, covering wavelength range from 0.67 - 2.6 um. The group delay dispersion has small oscillations in the above mentioned working range. We used a new algorithm with floating constants allowing us to obtain a smooth and near constant GDD. The optical element based on the beamsplitter is used for dividing a low-energy super-octave spectrum into several sub-spectral regions which are later amplified and coherently combined. PMID- 27464130 TI - Phaseless computational imaging with a radiating metasurface. AB - Computational imaging modalities support a simplification of the active architectures required in an imaging system and these approaches have been validated across the electromagnetic spectrum. Recent implementations have utilized pseudo-orthogonal radiation patterns to illuminate an object of interest notably, frequency-diverse metasurfaces have been exploited as fast and low-cost alternative to conventional coherent imaging systems. However, accurately measuring the complex-valued signals in the frequency domain can be burdensome, particularly for sub-centimeter wavelengths. Here, computational imaging is studied under the relaxed constraint of intensity-only measurements. A novel 3D imaging system is conceived based on 'phaseless' and compressed measurements, with benefits from recent advances in the field of phase retrieval. In this paper, the methodology associated with this novel principle is described, studied, and experimentally demonstrated in the microwave range. A comparison of the estimated images from both complex valued and phaseless measurements are presented, verifying the fidelity of phaseless computational imaging. PMID- 27464131 TI - Multicolor cavity soliton. AB - We show a new class of complex solitary wave that exists in a nonlinear optical cavity with appropriate dispersion characteristics. The cavity soliton consists of multiple soliton-like spectro-temporal components that exhibit distinctive colors but coincide in time and share a common phase, formed together via strong inter-soliton four-wave mixing and Cherenkov radiation. The multicolor cavity soliton shows intriguing spectral locking characteristics and remarkable capability of spectrum management to tailor soliton frequencies, which would be very useful for versatile generation and manipulation of multi-octave spanning phase-locked Kerr frequency combs, with great potential for applications in frequency metrology, optical frequency synthesis, and spectroscopy. PMID- 27464132 TI - Low chromatic Fresnel lens for broadband attosecond XUV pulse applications. AB - Fresnel zone plates show a great potential in achieving high spatial resolution imaging or focusing for XUV and soft/hard X-ray radiation, however they are usually strictly monochromatic due to strong chromatic dispersion and thus do not support broad radiation spectra, preventing their application to attosecond XUV pulses. Here we report on the design and theoretical simulations based on the design of an achromatic hybrid optics combining both, a refractive and diffractive lens in one optical element. We are able to show by calculation that the chromatic dispersion along the optical axis can be greatly reduced compared to a standard Fresnel zone plate while preserving the temporal structure of the attosecond XUV pulses at focus. PMID- 27464133 TI - Hybrid optical CDMA-FSO communications network under spatially correlated gamma gamma scintillation. AB - In this paper, we propose a new hybrid network solution based on asynchronous optical code-division multiple-access (OCDMA) and free-space optical (FSO) technologies for last-mile access networks, where fiber deployment is impractical. The architecture of the proposed hybrid OCDMA-FSO network is thoroughly described. The users access the network in a fully asynchronous manner by means of assigned fast frequency hopping (FFH)-based codes. In the FSO receiver, an equal gain-combining technique is employed along with intensity modulation and direct detection. New analytical formalisms for evaluating the average bit error rate (ABER) performance are also proposed. These formalisms, based on the spatially correlated gamma-gamma statistical model, are derived considering three distinct scenarios, namely, uncorrelated, totally correlated, and partially correlated channels. Numerical results show that users can successfully achieve error-free ABER levels for the three scenarios considered as long as forward error correction (FEC) algorithms are employed. Therefore, OCDMA FSO networks can be a prospective alternative to deliver high-speed communication services to access networks with deficient fiber infrastructure. PMID- 27464134 TI - Electrically tunable transmission of gold binary-grating metasurfaces integrated with liquid crystals. AB - Planar photonics using metasurfaces is of great interest because a metasurface can control the flow of light beyond that attainable with natural materials. The resonance wavelength of a binary-grating metasurface is adjustable by changing the width and thickness of the nanostructure. We propose a novel combination of nematic liquid crystals and a binary-grating metasurface with which the diffraction efficiency can be controlled by adjusting the applied voltage. PMID- 27464135 TI - Avoided resonance crossing and non-reciprocal nearly perfect absorption in plasmonic nanodisks with near-field and far-field couplings. AB - Avoided resonance crossings (ARC) in plasmonic nanodisk structures due to near field or far field couplings were numerically demonstrated. Near field coupling in disk dimmer with both vertical or side-by-side arrangement leads to both energy and linewidth anti-crossing by varying one disk size across the other. Far field coupling in double layered disk arrays of extremely small gap size or gap size with Fabry Perot resonant condition close to the frequency selective surface (FSS) stopband center leads to non-reciprocal absorption spectrum as one disk size varying across the other. We observe linewidth anti-crossing but energy crossing of the absorption peak from different side illumination by varying either the size of one disk array or the gap in hetero disk arrays. The disappearing of Fabry-Perot resonant mode from one side illumination and the appearing of nonreciprocal nearly perfect absorption from the other side illumination are well explained by a FSS-Fabry-Perot model. PMID- 27464136 TI - Widefield lensless imaging through a fiber bundle via speckle correlations. AB - Flexible fiber-optic endoscopes provide a solution for imaging at depths beyond the reach of conventional microscopes. Current endoscopes require focusing and/or scanning mechanisms at the distal end, which limit miniaturization, frame-rate, and field of view. Alternative wavefront-shaping based lensless solutions are extremely sensitive to fiber-bending. We present a lensless, bend-insensitive, single-shot imaging approach based on speckle-correlations in fiber bundles that does not require wavefront shaping. Our approach computationally retrieves the target image by analyzing a single camera frame, exploiting phase information that is inherently preserved in propagation through convnetional fiber bundles. Unlike conventional fiber-based imaging, planar objects can be imaged at variable working distances, the resulting image is unpixelated and diffraction-limited, and miniaturization is limited only by the fiber diameter. PMID- 27464137 TI - Completely CMOS compatible SiN-waveguide-based fiber coupling structure for Si wire waveguides. AB - For Si wire waveguides, we designed a highly efficient fiber coupling structure consisting of a Si inverted taper waveguide and a CMOS-compatible thin SiN waveguide with an SiO2 spacer inserted between them. By using a small SiN waveguide with a 310 nm-square core, the optical field can be expanded to correspond to a fiber with a 4.0-MUm mode field diameter. A coupled waveguide system with the SiN waveguide and Si taper waveguide can provide low-loss and low polarization-dependent mode conversion. Both losses in fiber-SiN waveguide coupling and SiN-Si waveguide mode conversion are no more than 1 dB in a wide wavelength bandwidth from 1.36 MUm to 1.65 MUm. Through a detailed analysis of the effective refractive indices in the coupled waveguide system, we can understand mode conversion accurately and also derive guidelines for reducing the polarization dependence and for shortening device length. PMID- 27464138 TI - Topology optimized mode multiplexing in silicon-on-insulator photonic wire waveguides. AB - We design and experimentally verify a topology optimized low-loss and broadband two-mode (de-)multiplexer, which is (de-)multiplexing the fundamental and the first-order transverse-electric modes in a silicon photonic wire. The device has a footprint of 2.6 um x 4.22 um and exhibits a loss <1.2 dB in a 100 nm bandwidth measured around 1570 nm. The measured cross talk is <-12 dB and the extinction ratio is >14 dB in the C-band. Furthermore, we demonstrate that the design method can be expanded to include more modes, in this case including also the second order transverse-electric mode, while maintaining functionality. PMID- 27464139 TI - 1016nm all fiber picosecond MOPA laser with 50W output. AB - This paper presents an all fiber high power picosecond laser at 1016 nm in master oscillator power amplifier (MOPA) configuration. A direct amplification of this seed source encounters obvious gain competition with amplified spontaneous emission (ASE) at ~1030 nm, leading to a seriously reduced amplification efficiency. To suppress the ASE and improve the amplification efficiency, we experimentally investigate the influence of the gain fiber length and the residual ASE on the perforemance of the 1016 nm amplifier. The optimized 1016 nm MOPA laser exhibits an average power of 50 W and an optical conversion efficiency of 53%. PMID- 27464140 TI - Low noise electro-optic comb generation by fully stabilizing to a mode-locked fiber comb. AB - A fully stabilized EO comb is demonstrated by phase locking the two degrees of freedom of an EO comb to a low noise mode-locked fiber comb. Division/magnification of residual phase noise of locked beats is observed by measuring an out-of-loop beat. By phase locking the 200 th harmonics of the EO comb and a driving cw frequency to a fiber comb, a record low phase noise EO comb across +/- 200 harmonics (from 1544.8 nm to 1577.3 nm) is demonstrated. PMID- 27464141 TI - Light absorption enhancement in Ge nanomembrane and its optoelectronic application. AB - In this study, the light absorption property of Ge nanomembrane (Ge NM), which incorporates hydrogen (H), in near-infrared (NIR) wavelength range was analyzed. Due to the presence of a large amount of structural defects, the light absorption coefficient of the Ge layer becomes much higher (10 times) than that of bulk Ge in the wavelength range of 1000 ~1600 nm. Increased light absorption was further measured from released Ge NM that has H incorporation in comparison to that of bulk Ge, proving the enhanced light absorption coefficient of H incorporated Ge. Finally, metal-semiconductor-metal (MSM) photodetectors were demonstrated using the H incorporated Ge on GeOI. PMID- 27464142 TI - Resonant magneto-optic Kerr effects of a single Ni nanorod in the Mie scattering regime. AB - We present a systematic, theoretical investigation of the polar magneto-optical (MO) Kerr effects of a single Ni nanorod in the Mie regime. The MO Kerr rotation, ellipticity, amplitude ratio, and phase shift are calculated as a function of the length and width of the nanorod. The electric field amplitude ratio of the MO Kerr effect is locally maximized when the nanorod supports a plasmonic resonance in the polarization state orthogonal to the incident light. The plasmonic resonances directly induced by the incident light do not enhance the amplitude ratio. In the Mie regime, multiple local maxima of the MO Kerr activity are supported by the resonant modes with different modal characteristics. From the viewpoint of first-order perturbation analysis, the spatial overlap between the incident-light-induced electric field and the Green function determines the local maxima. PMID- 27464143 TI - Wideband tunable mid-infrared cross polarization converter using rectangle-shape perforated graphene. AB - The strong plasmonic response and wide electrostatic tunability of graphene make it a promising material for developing infrared optoelectronic components. In this paper, we present a mid-infrared wideband tunable cross polarization converter using periodically perforated graphene. The polarization converter consists of a metal ground plane, an insulator layer, and a rectangle-shape periodically perforated graphene sheet. By superimposing two localized surface plasmon modes, the polarization converter transforms a linear polarization to its cross polarization over a bandwidth as wide as ~5% of the central frequency (46.8THz) with a peak conversion ratio exceeding 90%. The polarization conversion performance is maintained over a wide range of incident angles up to 50 degrees , and is highly tunable by electrostatic tuning of the graphene Fermi energy. Our proposed device enables the manipulation of light polarization for potential mid infrared applications. PMID- 27464144 TI - Observation of second-harmonic generation in silicon nitride waveguides through bulk nonlinearities. AB - We present experimental results on the observation of a bulk second-order nonlinear susceptibility, derived from both free-space and integrated measurements, in silicon nitride. Phase-matching is achieved through dispersion engineering of the waveguide cross-section, independently revealing multiple components of the nonlinear susceptibility, namely chi(2) yyy = 0.14 +/- 0.08 pm/V and chi(2) xxy = 0.30 +/- 0.18 pm/V. Additionally, we show how the second-harmonic signal may be tuned through the application of bias voltages across silicon nitride. The material properties measured here are anticipated to allow for the realization of new nanophotonic devices in CMOS-compatible silicon nitride waveguides, adding to their viability for telecommunication, data communication, and optical signal processing applications. PMID- 27464145 TI - Encoding/decoding using superpositions of spatial modes for image transfer in km scale few-mode fiber. AB - Space domain is regarded as the only known physical dimension left of lightwave to exploit in optical communications. Recently, lots of research efforts have been devoted to using spatial modes of fibers to increase data transmission capacity in optical fiber communications. In this paper, we propose and demonstrate a different approach to exploiting the space dimension, i.e. transferring image by space dimension encoding/decoding using superpositions of spatial modes in km-scale few-mode fiber. Three grayscale images are successfully transmitted through a 1.1-km few-mode fiber by employing either 4 modes, i.e. three linearly polarized (LP) modes of LP01, LP11a, LP11b and one orbital angular momentum (OAM) mode of OAM-1, or 2 modes (OAM+1, OAM-1). The bit-error rate is evaluated and zero error among all received data is achieved, showing favorable fiber link communication performance using the spatial modes of fiber for encoding/decoding. Moreover, we also demonstrate the 4 modes (LP01, LP11a, LP11b and OAM-1) encoding/decoding for image transfer in a 10-km few-mode fiber in the experiment. PMID- 27464146 TI - Simultaneous nonlinearity mitigation in 92 * 180-Gbit/s PDM-16QAM transmission over 3840 km using PPLN-based guard-band-less optical phase conjugation. AB - We experimentally demonstrated the simultaneous nonlinearity mitigation of PDM 16QAM WDM signals using complementary-spectrally-inverted optical phase conjugation (CSI-OPC). We achieved reserved-band-less, guard-band-less, and polarization independent OPC based on periodically poled LiNbO3 waveguides. By employing the CSI-OPC, 2.325-THz-band (93 * 25 GHz) complementary spectral inversion was achieved while retaining the original WDM bandwidth. A Q2-factor improvement of over 0.4 dB and a 5120 km transmission with a Q2-factor above the FEC limit were confirmed using a 10-channel WDM transmission at the signal band center and signal band edge. We then demonstrated the mitigation of the nonlinear impairments in a 3840 km long-haul WDM signal transmission for all 92-channel 180-Gbit/s PDM-16QAM quasi-Nyquist-WDM signals. PMID- 27464147 TI - Characteristics of the orbital rotation in dual-beam fiber-optic trap with transverse offset. AB - The orbital rotation is an important type of motion of trapped particles apart from translation and spin rotation. It could be realized by introducing a transverse offset to the dual-beam fiber-optic trap. The characteristics (e.g. rotation perimeter and frequency) of the orbital rotation have been analyzed in this article. We demonstrate the influences of offset distance, beam waist separation distance, light power, and radius of the microsphere by both experimental and numerical work. The experiment results, i.e. orbital rotation perimeter and frequency as functions of these parameters, are consistent with the theoretical model in the present work. The orbital rotation amplitude and frequency could be exactly controlled by varying these parameters. This controllable orbital rotation can be easily applied to the area where microfluidic mixing is required. PMID- 27464148 TI - Independent tuning of double plasmonic waves in a free-standing graphene-spacer grating-spacer-graphene hybrid slab. AB - The independent excitation and tuning of double plasmonic waves are realized in a free-standing graphene-spacer-grating-spacer-graphene (GSGSG) hybrid slab, which consists of two graphene field effect transistors placed back-to-back to each other. Resulted from the high transparency and the tight confinement of surface plasmonic mode for the graphene, double plasmonic waves can be independently excited by guided-mode resonances (GMRs). Theoretical and numerical investigations are performed in the mid-infrared band. Furthermore, the tuning of individual GMR resonant wavelengths with respect to the system parameters is studied. The results provide opportunities to engineer the proposed hybrid slab for wavelength selective and multiplexing applications. PMID- 27464149 TI - Mid-infrared dual-gas sensor for simultaneous detection of methane and ethane using a single continuous-wave interband cascade laser. AB - A continuous-wave (CW) interband cascade laser (ICL) based mid-infrared sensor system was demonstrated for simultaneous detection of atmospheric methane (CH4) and ethane (C2H6). A 3.337 um CW ICL with an emitting wavenumber range of 2996.0-3001.5 cm-1 was used to simultaneously target two absorption lines, C2H6 at 2996.88 cm-1 and CH4 at 2999.06 cm-1, respectively. The sensor performance was first evaluated for single-gas detection by only targeting the absorption line of one gas species. Allan deviations of 11.2 parts per billion in volume (ppbv) for CH4 and 1.86 ppbv for C2H6 with an averaging time of 3.4 s were achieved for the detection of these two gases. Dual-gas detection was realized by using a long term scan signal to target both CH4 and C2H6 lines. The Allan deviations increased slightly to 17.4 ppbv for CH4 and 2.4 ppbv for C2H6 with an averaging time of 4.6 s due to laser temperature and power drift caused by long-term wavelength scanning. Measurements for both indoor and outdoor concentration changes of CH4 and C2H6 were conducted. The reported single ICL based dual gas sensor system has the advantages of reduced size and cost compared to two separate sensor systems. PMID- 27464150 TI - Erratum on "Orthogonal basis with a conicoid first mode for shape specification of optical surfaces". AB - We found an error affecting the results presented in Figure 7 of our article "Orthogonal basis with a conicoid first mode for shape specification of optical surfaces". Here we publish the revised Fig. 7. PMID- 27464151 TI - Hybrid curved nano-structured micro-optical elements. AB - Tailoring the spatial degree of freedom of light is an essential step towards the realization of advanced optical manipulation tools. A topical challenge consists of device miniaturization for improved performance and enhanced functionality at the micron scale. We demonstrate a novel approach that combines the additive three-dimensional (3D) structuring capability of laser polymerization and the subtractive subwavelength resolution patterning of focused ion beam lithography. As a case in point hybrid (dielectric/metallic) micro-optical elements that deliver a well-defined topological shaping of light are produced. Here we report on hybrid 3D binary spiral zone plates with unit and double topological charge. Their optical performances are compared to corresponding 2D counterparts both numerically and experimentally. Cooperative refractive capabilities without compromising topological beam shaping are shown. Realization of advanced designs where the dielectric architecture itself is endowed with singular properties is also discussed. PMID- 27464152 TI - New lattice Boltzmann method for the simulation of three-dimensional radiation transfer in turbid media. AB - Based on the kinetic theory of photons, a new lattice Boltzmann method for the simulation of 3D radiation transport is presented. The method was successfully validated with Monte Carlo simulations of radiation transport in optical thick absorbing and non-absorbing turbid media containing either isotropic or anisotropic scatterers. Moreover, for the approximation of Mie-scattering, a new iterative algebraic approach for the discretization of the scattering phase function was developed, ensuring full conservation of energy and asymmetry after discretization. It was found that the main error sources of the method are caused by linearization and ray effects and suggestions for further improvement of the method are made. PMID- 27464153 TI - TDM-PON compatible generation of 10 Gbps NRZ and 1.25 Gbps UWB signals by a single light source. AB - A novel and cost-efficient technique is presented to generate non-return-to-zero (NRZ) and ultra-wideband (UWB) signals in different time slots of time division multiplexing-passive optical network (TDM-PON) by using a single chirped controlled semiconductor laser associated with an optical bandpass filter. In this technique, the chirp of the laser is controlled by different bias burst amplitudes (BBA) for different time slots. Through the proper selection of the burst amplitudes, 10 Gbps NRZ and 1.25 Gbps UWB signals are generated in different time slots. Principle of operation is discussed, the complete chirp behavior of the laser is experimentally investigated, data transmission of the generated signals is demonstrated and bit-error-rate (BER) level of 10 9 is achieved. PMID- 27464154 TI - Low complexity digital backpropagation for high baud subcarrier-multiplexing systems. AB - In this paper, we propose two modifications to reduce the complexity of the subcarrier-multiplexing (SCM) based digital backpropagation (DBP) for high symbol rate SCM systems. The first one is to reduce the number of interfering subcarriers (RS-SCM-DBP) when evaluating the cross-subcarrier nonlinearity (CSN). The second one is to replace the original frequency domain CSN filters with the infinite impulse response (IIR) filters (IIR-RS-SCM-DBP) in the CSN compensation. The performance of the proposed schemes are numerically evaluated in three channel dual-polarization (DP) 16QAM wavelength-division multiplexing (WDM) transmissions. The aggregate symbol rate for each channel is 120 GBaud and the transmission distance is 1600 km. For the SCM system with 16 subcarriers, the IIR RS-SCM-DBP with only 4 interfering subcarriers and 2 steps can achieve a 0.3 dB Q factor improvement in the WDM transmission. Compared to the original SCM-DBP, the proposed IIR-RS-SCM-DBP reduces the complexity by 48% at a performance loss of only 0.07 dB. PMID- 27464155 TI - 4.3 MUm quantum cascade detector in pixel configuration. AB - We present the design simulation and characterization of a quantum cascade detector operating at 4.3MUm wavelength. Array integration and packaging processes were investigated. The device operates in the 4.3MUm CO2 absorption region and consists of 64 pixels. The detector is designed fully compatible to standard processing and material growth methods for scalability to large pixel counts. The detector design is optimized for a high device resistance at elevated temperatures. A QCD simulation model was enhanced for resistance and responsivity optimization. The substrate illuminated pixels utilize a two dimensional Au diffraction grating to couple the light to the active region. A single pixel responsivity of 16mA/W at room temperature with a specific detectivity D* of 5?107 cmHz/W was measured. PMID- 27464156 TI - MHz-ultrasound generation by chirped femtosecond laser pulses from gold nano colloidal suspensions. AB - Strong absorption of femtosecond laser pulses in Au nano-colloidal suspensions was used to generate coherent ultrasound signals at 1-20 MHz frequency range. The most efficient ultrasound generation was observed at negative chirp values and was proportional to the pulse duration. Maximization of a dimensionless factor A = alphac0tp defined as the ratio of pulse duration tp and the time required for sound at speed c0 to cross the optical energy deposition length (an inverse of the absorption coefficient alpha) given by 1/(alphac0). Chirp controlled pulse duration allows effective enhancement of ultrasound generation at higher frequencies (shorter wavelengths) and is promising for a high spatial resolution acoustic imaging. PMID- 27464157 TI - Odd harmonics-enhanced supercontinuum in bulk solid-state dielectric medium. AB - We report on generation of ultrabroadband, more than 4 octave spanning supercontinuum in thin CaF2 crystal, as pumped by intense mid-infrared laser pulses with central wavelength of 2.4 MUm. The supercontinuum spectrum covers wavelength range from the ultraviolet to the mid-infrared and its short wavelength side is strongly enhanced by cascaded generation of third, fifth and seventh harmonics. Our results capture the transition from Kerr-dominated to plasma-dominated filamentation regime and uncover that in the latter the spectral superbroadening originates from dramatic plasma-induced compression of the driving pulse, which in turn induces broadening of the harmonics spectra due to cross-phase modulation effects. The experimental measurements are backed up by the numerical simulations based on a nonparaxial unidirectional propagation equation for the electric field of the pulse, which accounts for the cubic nonlinearity-induced effects, and which reproduce the experimental data in great detail. PMID- 27464158 TI - Design of hybrid structure for fast and deep surface plasmon polariton modulation. AB - The electric and optical performance of different surface plasmon polariton (SPP) electric modulation structures have been investigated by comparing the response speed and modulation figures of merit (FoM). To overcome the capacitance limitation and improve the response speed, we proposed a novel silver-graphene dielectric-graphene-semiconductor vertical structure. Semiconductor nano waveguide is introduced to help reduce ohmic loss in silver waveguide and reflect the leaked optical field back, enhancing the modulation depth. Through optimization, a device with estimated modulation FoM of more than 70% and hundreds of GHz response speed and 3 dB bandwidth is designed, which may bring great improvement to previous optical modulators. PMID- 27464159 TI - Plasmonic channel waveguides in random arrays of metallic nanoparticles. AB - We report detailed characterization of surface plasmon-polariton guiding along 1 , 1.5- and 2-MUm-wide channels in high-density (~75 MUm-2) random arrays of gold 70-nm-high and 50-nm-wide nanoparticles fabricated on a 70-nm-thin gold film supported by a 170-MUm-thick silica substrate. The mode propagation losses, effective index dispersion, and scattering parameters are characterized using leakage-radiation microscopy, in direct and Fourier planes, in the wavelength range of 740-840 nm. It is found that the mode supported by 2-MUm-wide channels propagates over > 10 MUm in straight waveguides, with the corresponding S-bends and Y-splitters functioning reasonably well. The results show that the SPP waves can efficiently be guided by narrow scattering-free channels cut through randomly corrugated surface regions. The potential of this waveguiding mechanism is yet to be fully explored by tuning the scattering mean-free path and localization length via the density and size of random nanoparticles. Nevertheless, the results obtained are encouraging and promising diverse applications of these waveguide components in plasmonic circuitry. PMID- 27464160 TI - Multi-angle fluorometer technique for the determination of absorption and scattering coefficients of subwavelength nanoparticles. AB - A thorough analysis of the resonance light scattering (RLS) technique for quantitative scattering measurements of subwavelength nanoparticles is reported. The systematic error associated with using a measurement at a single angle to represent all of the scattered light is investigated. In-depth analysis of the reference material was performed to identify and minimize the error associated with the reference material. Semiconductor ZnO nanobullets and spherical Au nanoparticles of various sizes were used to verify the approach. A simple and inexpensive modification to standard fluorometers is demonstrated using a glass prism allowing scattering measurements in the slightly forward and backwards directions. This allows quantification of the systematic error associated with RLS which is consistently overlooked. PMID- 27464161 TI - Turnable perfect absorption at infrared frequencies by a Graphene-hBN Hyper Crystal. AB - In this article, we have theoretically demonstrated that the perfect absorption at infrared frequencies can be achieved and controlled by using a graphene hexagonal Boron Nitride (hBN) hyper crystal. hBN, the latest natural hyperbolic material, can be regarded as an excellent substrate to form a hyper crystal with graphene. Although the perfect absorption by a half-space of hBN crystal can be achieved due to its high optical anisotropy, but the perfect absorption can only appear at certain fixed wavenumber and incidence angle. By introducing a graphene hBN hyper crystal, we can get perfect absorption at different wavenumbers and incidence angles by varying the Fermi energy level of graphene sheets via electrostatic biasing. We show that the perfect absorption can be realized at different Fermi energies for TM waves. PMID- 27464162 TI - Angle-tolerant polarization-tuned color filter exploiting a nanostructured cavity. AB - A polarization-mediated color filter featuring a high angular tolerance is proposed incorporating a metal-dielectric-metal etalon based on a nanostructured cavity, where a one-dimensional subwavelength grating of a high refractive index is embedded in a base layer of a low refractive index. The aim of the nanostructured cavity is mimicking of the equivalent birefringent medium whereby different effective refractive indices are exhibited depending on the incident polarization. As the transmission peak of the etalon is effectively tuned through the tailoring of the refractive index of the cavity, the proposed filter is capable of providing a continuum of vivid output colors through a dynamic control of the polarization. The effective medium theory is chiefly applied for an investigation of the birefringent characteristics of the nanostructured cavity. A dielectric overlay that acts as an anti-reflection coating is specifically adopted for the etalon to enhance the transmission efficiency. The proposed polarization-tuned filter evidently provides a high transmission of ~71% and a high angular tolerance of ~35 degrees in conjunction with a wide polarization mediated color tuning. PMID- 27464163 TI - Parity time-symmetric vertical cavities: intrinsically single-mode regime in longitudinal direction. AB - We explore a new class of distributed feedback (DFB) structures that employ the recently-developed concept of parity-time (PT) symmetry in optics. We show that, based on PT-symmetric pure reflective volume gratings, a vertical surface emitting cavity can be constructed. We provide a detailed analysis of the threshold conditions as well as the wavelength and angular spectral characteristics using the Kogelnik coupled-wave approximation, backed up by an exact solution of the Helmholtz equation. We show that such a PT-symmetric cavity can be configured to support one and only one longitudinal mode, leading to inherently single-mode lasing. PMID- 27464164 TI - Controlling the nonlinear optical properties of plasmonic nanoparticles with the phase of their linear response. AB - We numerically investigate the second harmonic generation from different plasmonic systems and evidence the key role played in their nonlinear response by the phase at the fundamental wavelength. In the case of a single plasmonic nanorod, the interference between the second harmonic dipolar and quadrupolar emission modes depends on their relative phase, which is deeply related to the excitation wavelength. The knowledge obtained in this simple case is then used to describe and understand the nonlinear response from a more complex structure, namely a gold nanodolmen. The complex phase evolution associated with a Fano resonance arising at the fundamental wavelength enables dramatically modifying the second harmonic emission patterns from plasmonic metamolecules within minute wavelength shifts. These results emphasize the importance of the phase in the nonlinear optical processes arising in plasmonic nanostructures, in addition to the increase in conversion yield associated with the excitation of localized surface plasmon resonances. PMID- 27464165 TI - Phase-matched frequency conversion below 150 nm in KBe2BO3F2. AB - Sum frequency mixing has been demonstrated below 150 nm in KBeBO3F2 by using the fundamental with its fourth harmonic of a 6 kHz Ti: sapphire laser system. The wavelength of 149.8 nm is the shortest ever obtained to our knowledge by phase matching in nonlinear crystals. The output powers were 3.6 MUW at 149.8 nm and 110 MUW at 154.0 nm, respectively. The phase matching angles measured from 149.8 to 158.1 nm are larger by 3-4 degrees than those expected from the existing Sellmeier equation. The measured transmission spectra of KBeBO3F2 crystals support the generation of coherent radiation below 150 nm. PMID- 27464166 TI - Optical digital coherent detection technology enabled flexible and ultra-fast quantitative phase imaging. AB - Quantitative phase imaging has been an important labeling-free microscopy modality for many biomedical and material science applications. In which, ultra fast quantitative phase imaging is indispensable for dynamic or transient characteristics analysis. Conventional wide field optical interferometry is a common scheme for quantitative phase imaging, while its data acquisition rate is usually hindered by the frame rate of arrayed detector. By utilizing novel balanced-photo-detector based digital optics coherent detection techniques, we report on a method of constructing ultra-fast quantitative phase microscopy at the line-scan rate of 100 MHz with ~2 MUm spatial resolution. PMID- 27464167 TI - Spatial resolution, signal-to-noise and information capacity of linear imaging systems. AB - A simple model for image formation in linear shift-invariant systems is considered, in which both the detected signal and the noise variance are varying slowly compared to the point-spread function of the system. It is shown that within the constraints of this model, the square of the signal-to-noise ratio is always proportional to the "volume" of the spatial resolution unit. In the case of Poisson statistics, the ratio of these two quantities divided by the incident density of the imaging particles (e.g. photons) represents a dimensionless invariant of the imaging system, which was previously termed the intrinsic imaging quality. The relationship of this invariant to the notion of information capacity of communication and imaging systems, which was previously considered by Shannon, Gabor and others, is investigated. The results are then applied to a simple generic model of quantitative imaging of weakly scattering objects, leading to an estimate of the upper limit for the amount of information about the sample that can be obtained in such experiments. It is shown that this limit depends only on the total number of imaging particles incident on the sample, the average scattering coefficient, the size of the sample and the number of spatial resolution units. PMID- 27464168 TI - Hybrid surface phononic waveguide using hyperbolic boron nitride. AB - Sub-diffraction limited waveguides have been studied as a means to manipulate light into nanoscale regions. Hybrid waveguides are popular candidates in optical regimes for subwavelength confinement and long range propagation. However, advances in the mid-IR are lacking due to high propagation losses and limited confinement. Here we present the first analysis of hybrid phononic waveguide using a hyperbolic material h-BN to generate surface phonon polaritons. The strong coupling between the photonic cylinder and phononic surface enhances the confined field up to 10-3 lambdao 2 (lambdao is free-space wavelength) and enables propagation distances up to 100 lambdao. Our work is fully compatible with integrated polaritonic devices in the mid-IR and provides a systematic approach to design hybrid phononic waveguides. PMID- 27464169 TI - Four 45 Gbps PAM4 VCSEL based transmission through 300 m wideband OM4 fiber over SWDM4 wavelength grid. AB - We demonstrate successful transmission of four 45 Gbps PAM4 single-channels through OM4 multimode fibers (MMFs) and wideband MMF using a PAM4 PHY chip and four vertical cavity surface emitting lasers (VCSELs) with wavelengths ranging over short wavelength division multiplexing (SWDM) grid. Real-time bit error ratios (BERs) < 2 * 10-4 were achieved for all four 45 Gbps PAM4 SWDM grid channels over 100 m, 200 m, and 300 m of wideband OM4 MMFs. All four channel received PAM4 optical eyes are shown after propagating through 100 m, 200 m, and 300 m of wideband OM4 as well as 100 m and 200 m conventional OM4 MMFs. The measured BERs as a function of the inner eye optical modulation amplitudes (OMAs) are shown for all four SWDM grid channels. Inner eye OMAs ranged from -16.2 dBm to -13.5 dBm for different channels over different OM4 MMF types at the KP4 BER threshold of 2 * 10-4. PMID- 27464170 TI - Evaluation of the accuracy of BOTDA systems based on the phase spectral response. AB - We evaluate the Brillouin frequency shift (BFS) determination error when utilizing the Brillouin phase spectrum (BPS) instead of the Brillouin gain spectrum (BGS) in BOTDA systems. Systems based on the BPS perform the determination of the BFS through a linear fit around the zero de-phase frequency region. An analytical expression of the error obtained in the BFS determination as a function of the different experimental parameters is provided and experimentally validated. The experimental results show a good agreement with the theoretical predictions as a function of the number of sampling points, signal-to noise ratio (SNR) and Brillouin spectral linewidth. For an equal SNR and linewidth, the phase response only provides a better BFS estimation than the gain response when the fit is performed over a restricted frequency range around the center of the spectral profile. This may reduce the measurement time of specific BOTDA systems requiring a narrow frequency scanning. When the frequency scan covers most of the Brillouin spectral profile, gain and phase responses give very similar estimations of the BFS and the BPS offers no crucial benefit. PMID- 27464171 TI - Visual method for measuring the roughness of a grinding piece based on color indices. AB - The existing machine-vision surface roughness measurement technique extracts relevant evaluation indices from grayscale images without using the strong sensitivity of color information. In addition, most of these measurements use a micro-vision imaging method to measure a small area and cannot make an overall assessment of the workpiece's surface. To address these issues, a method of measuring surface roughness that uses an ordinary light source and a macro-vision perspective to generate a red and green color index for each pixel is proposed in the present study. A comparison test is conducted on a set of test samples before and after surface contamination using the color index and gray-level algebraic averaging, the square of the main component of the Fourier transform in the frequency domain, and the entropy. A strong correlation between the color index and the surface roughness is established; this correlation is not only higher than that of other indices but also present despite contamination and very robust. Verification using a regression model based on a support vector machine proves that the proposed method not only has a simple apparatus and makes measurement easy but also provides high precision and is suitable over a wide measurement range. The impact of the red and green color blocks, the lighting, and the direction of the surface texture on the correlation between the color index and the roughness are also assessed and discussed in this paper. PMID- 27464172 TI - On-site monitoring of atomic density number for an all-optical atomic magnetometer based on atomic spin exchange relaxation. AB - We present a method for monitoring the atomic density number on site based on atomic spin exchange relaxation. When the spin polarization P ? 1, the atomic density numbers could be estimated by measuring magnetic resonance linewidth in an applied DC magnetic field by using an all-optical atomic magnetometer. The density measurement results showed that the experimental results the theoretical predictions had a good consistency in the investigated temperature range from 413 K to 463 K, while, the experimental results were approximately 1.5 ~ 2 times less than the theoretical predictions estimated from the saturated vapor pressure curve. These deviations were mainly induced by the radiative heat transfer efficiency, which inevitably leaded to a lower temperature in cell than the setting temperature. PMID- 27464173 TI - Direct measurement of loop gain and bandwidth of phase-locked loop for mode locked laser. AB - A simple and robust technique for measuring the loop gain and bandwidth of a phase-locking loop (PLL) for mode-locked laser is proposed. This technique can be used for the real-time measurement of the PLL's real loop gain and bandwidth in a closed loop without breaking its locking state. The agreement of the experimental result and theoretical calculation proves the validity of the proposed technique for measuring the loop gain and bandwidth. This technique with a simple configuration can be easily expanded to other laser's locking system whose loop gain and bandwidth should be measured in advance. PMID- 27464174 TI - Bidirectional fiber-wireless and fiber-IVLLC integrated system based on polarization-orthogonal modulation scheme. AB - A bidirectional fiber-wireless and fiber-invisible laser light communication (IVLLC) integrated system that employs polarization-orthogonal modulation scheme for hybrid cable television (CATV)/microwave (MW)/millimeter-wave (MMW)/baseband (BB) signal transmission is proposed and demonstrated. To our knowledge, it is the first one that adopts a polarization-orthogonal modulation scheme in a bidirectional fiber-wireless and fiber-IVLLC integrated system with hybrid CATV/MW/MMW/BB signal. For downlink transmission, carrier-to-noise ratio (CNR), composite second-order (CSO), composite triple-beat (CTB), and bit error rate (BER) perform well over 40-km single-mode fiber (SMF) and 10-m RF/50-m optical wireless transport scenarios. For uplink transmission, good BER performance is obtained over 40-km SMF and 50-m optical wireless transport scenario. Such a bidirectional fiber-wireless and fiber-IVLLC integrated system for hybrid CATV/MW/MMW/BB signal transmission will be an attractive alternative for providing broadband integrated services, including CATV, Internet, and telecommunication services. It is shown to be a prominent one to present the advancements for the convergence of fiber backbone and RF/optical wireless feeder. PMID- 27464175 TI - Near perfect light trapping in a 2D gold nanotrench grating at oblique angles of incidence and its application for sensing. AB - A two-dimensional nanotrench cavity grating on a thick gold film was fabricated by using e-beam lithography. Optical reflection spectra from the fabricated device were measured at oblique angles of incidence for TE and TM polarizations. Near perfect light absorption was observed at different wavelengths for TE and TM polarizations at oblique angles of incidence. The peak absorption wavelength of TM polarization red-shifts significantly as angle of incidence increases. The peak absorption wavelength of TE polarization blue-shifts slightly as incident angle increases. Using finite-difference time-domain (FDTD) simulations, two orders of magnitude magnetic field enhancement was revealed inside nanotrenches, indicating strong light trapping inside the nanostructure. The fabricated device was investigated as a refractive index chemical sensor. It was found that sensitivity increases for TM polarization and decreases for TE polarization when angle of incidence increases from zero. PMID- 27464176 TI - Generation of linearly polarized orbital angular momentum modes in a side-hole ring fiber with tunable topology numbers. AB - A refractive index (RI) tunable functional materials infiltrated side-hole ring fiber (SHRF) is proposed to generate 10 LP OAM states with 6 topology numbers. On the basis of perturbation theory, the basis of the SHRF is demonstrated to be the LP modes. After a fixed propagation distance of 0.03 m, 0.009 m and 0.012 m, the phase difference between the odd and even LP11x, LP21x,y, LP31x,y modes in the SHRF accumulate to +/- pi/2 respectively with na ranging from 1.412 to 1.44. Correspondingly, the output states are OAM +/- 1x, OAM +/- 2x,y, OAM +/- 3x,y with a bandwidth of 380 nm, 100 nm and 80 nm respectively. The proposed fiber is easy to be fabricated with the mature fiber drawing technology and could facilitate the realization of all fiber based OAM system. PMID- 27464177 TI - Photonic crystal fiber for supporting 26 orbital angular momentum modes. AB - We propose and numerically investigate a photonic crystal fiber (PCF) based on As2S3 for supporting the orbital angular momentum (OAM) modes up to 26. The designed PCF is composed of four well-ordered air hole rings in the cladding and an air hole at the center. The OAM modes can be well separated due to the large effective index difference of above 10-4 between the eigenmodes and maintain single-mode condition radially. In addition, the dispersions of the modes increase slowly with wavelengths, while the confinement loss keeps as low as 10-9 dB/m. The proposed PCF increases the supported OAM modes which could have some potential applications in short distance, high-capacity transmission. PMID- 27464178 TI - Calibration and optimization of an x-ray bendable mirror using displacement measuring sensors. AB - We propose a method to control and to adjust in a closed-loop a bendable x-ray mirror using displacement-measuring devices. For this purpose, the usage of capacitive and interferometric sensors is investigated and compared. We installed the sensors in a bender setup and used them to continuously measure the position and shape of the mirror in the lab. The sensors are vacuum-compatible such that the same concept can also be applied in final conditions. The measurement is used to keep the calibration of the system and to create a closed-loop control compensating for external influences: in a demonstration measurement, using a 950 mm long bendable mirror, the mirror sagitta is kept stable inside a range of 10 nm Peak-To-Valley (P-V). PMID- 27464179 TI - Spectrally resolved white light interferometry to measure material dispersion over a wide spectral band in a single acquisition. AB - In this paper we apply spectrally resolved white light interferometry to measure refractive and group index over a wide spectral band from 400 to 1000 nm. The output of a Michelson interferometer is spectrally decomposed by a homemade prism spectrometer with a high resolution camera. The group index is determined directly from the phase extracted from the spectral interferogram while the refractive index is estimated once its value at a given wavelength is known. PMID- 27464180 TI - Tuning the transmission of surface plasmon polaritons across nano and micro gaps in gold stripes. AB - We applied a far-field technique to measure the surface plasmon propagation over a wide range of gap sizes in thin gold stripes. This is realized with a grating technique which allows the excitation and out coupling of surface plasmon polaritons (SPPs). With this method the intensity can be monitored before and after the gap. The observations show that the SPPs can transmit over gaps with a width of 1MUm with a probability of about 40% for Au stripe-waveguides (7 um width) at a wavelength of 780 nm. The transmission decays exponentially above a gap size of 1 um. The results also demonstrate that the transmission has non monotonic behavior for gap sizes smaller than 1 um that we attribute to excitation of Fabry-Perot modes and resonant localized plasmons within the gap. The experimental results are supported by numerical simulations using a Finite Difference Time-Domain (FDTD) approach. PMID- 27464181 TI - Thermochromic modulation of surface plasmon polaritons in vanadium dioxide nanocomposites. AB - We propose and implement a new concept for thermochromic plasmonic elements. It is based on vanadium dioxide (VO2) nanocrystals located in the near field of surface plasmon polaritons supported by an otherwise unstructured gold thin film. When the VO2 undergoes the metal-insulator phase transition, the coupling conditions for conversion of light into propagating surface plasmon polaritons change markedly. In particular, we realize thermochromic plasmonic grating couplers with substantial switching contrast as well as tunable plasmonic couplers in a Kretschmann configuration. The use of VO2 nanocrystals permits highly repetitive switching and room temperature operation. Simulations based on the actual dielectric function of our VO2 nanocrystals agree well with the experiment. PMID- 27464182 TI - Review on photonic properties of nanowires for photovoltaics. AB - III-V semiconductor nanowires behave as optical antennae because of their shape anisotropy and high refractive index. The antennae like behavior modifies the absorption and emission properties of nanowires compared to planar materials. Nanowires absorb light more efficiently compared to an equivalent volume planar material, leading to higher short circuit current densities. The modified emission from the nanowires has the potential to increase the open circuit voltage from nanowire solar cells compared to planar solar cells. In order to achieve high efficiency nanowire solar cells it is essential to control the surface state density and doping in nanowires. We review the physics of nanowire solar cells and progress made in addressing the surface recombination and doping of nanowires, with emphasis on GaAs and InP materials. PMID- 27464183 TI - 112 Gb/s transmission over 80 km SSMF using PDM-PAM4 and coherent detection without optical amplifier. AB - Polarization-division-multiplexed (PDM) four-level pulse amplitude modulation (PAM4) with coherent detection is a promising low cost solution for 80 km inter datacenter transmissions at 100 Gb/s and beyond. In this paper, three modified adaptive equalization algorithms for the PDM-PAM4 optical coherent systems, i.e. signal-phase aid least-mean-square (SP-LMS) algorithm, training multi-modulus algorithm (TMMA) and cascaded four-modulus algorithm (CMMA-4), are proposed and compared. Based on the proposed algorithms, 112 Gb/s PDM-PAM4 transmission over 80 km standard single mode fiber (SSMF) in C-band for a bit error rate (BER) below 3.8e-3 is successfully demonstrated without optical amplifier, chromatic dispersion (CD) pre-compensation and extra carrier recovery operations. PMID- 27464184 TI - Monocular 3D see-through head-mounted display via complex amplitude modulation. AB - The complex amplitude modulation (CAM) technique is applied to the design of the monocular three-dimensional see-through head-mounted display (3D-STHMD) for the first time. Two amplitude holograms are obtained by analytically dividing the wavefront of the 3D object to the real and the imaginary distributions, and then double amplitude-only spatial light modulators (A-SLMs) are employed to reconstruct the 3D images in real-time. Since the CAM technique can inherently present true 3D images to the human eye, the designed CAM-STHMD system avoids the accommodation-convergence conflict of the conventional stereoscopic see-through displays. The optical experiments further demonstrated that the proposed system has continuous and wide depth cues, which enables the observer free of eye fatigue problem. The dynamic display ability is also tested in the experiments and the results showed the possibility of true 3D interactive display. PMID- 27464185 TI - Analysis of 3D-printed metal for rapid-prototyped reflective terahertz optics. AB - We explore the potential of 3D metal printing to realize complex conductive terahertz devices. Factors impacting performance such as printing resolution, surface roughness, oxidation, and material loss are investigated via analytical, numerical, and experimental approaches. The high degree of control offered by a 3D-printed topology is exploited to realize a zone plate operating at 530 GHz. Reflection efficiency at this frequency is found to be over 90%. The high performance of this preliminary device suggest that 3D metal printing can play a strong role in guided-wave and general beam control devices in the terahertz range. PMID- 27464186 TI - Narrow-band 1 W source at 257 nm using frequency quadrupled passively Q-switched Yb:YAG laser. AB - We describe generation of 1.1 W of 257 nm emission by frequency quadrupling the 1030 nm emission from a compact passively Q-switched Yb:YAG laser. The laser utilized a volume Bragg grating to achieve a 0.1 nm linewidth required for UV Raman spectroscopic applications, generated 100 kW peak power, 250 MUJ pulses and 3.6 W of average power at 1030 nm. Fourth harmonic generation (FHG) was carried out using a 10 mm lithium triborate (LBO) crystal to generate 515 nm second harmonic with 70% conversion efficiency, followed by a 7 mm beta-barium borate (BBO) crystal to generate 257 nm fourth harmonic with 45% efficiency, resulting in an overall nonlinear conversion efficiency of 31%. Far-field and near-field of the FHG emission were characterized. PMID- 27464187 TI - Subkilohertz linewidth reduction of a DFB diode laser using self-injection locking with a fiber Bragg grating Fabry-Perot cavity. AB - A simple and low-cost 1550 nm semiconductor laser with subkilohertz intrinsic linewidth is experimentally demonstrated. A commercial distributed feedback diode laser is self-injection locked to the resonance transmission peaks of a fiber Bragg grating Fabry-Perot cavity through a polarization-maintaining fiber ring with the optical path length of 4 m, with the laser frequency noise suppressed by over 70 dB in the Fourier frequency band from 5 Hz and 1 kHz. The laser features an intrinsic Lorentzian linewidth of 125 Hz as well as a relative intensity noise of <-142 dBc/Hz above 2 MHz, and provides over 0.8 nm quasi-continuous tunability, which is suitable for advanced applications requiring a narrow linewidth laser with ultralow frequency noise. PMID- 27464188 TI - Low threshold Fabry-Perot optofluidic resonator fabricated by femtosecond laser micromachining. AB - We report the realization and characterization of an optofluidic microlaser based on a Fabry-Perot resonator fabricated by exploiting two direct writing fabrication techniques: the femtosecond laser micromachining and the inkjet printing technology. In this way a standard Fabry-Perot cavity has been integrated into an optofluidic chip. When using rhodamine 6G dissolved in ethanol at concentration of 5?10-3 mol/l, laser emission was detected at a threshold energy density of 1.8 MUJ/mm2 at least one order of magnitude lower than state-of-the-art optofluidic lasers. Linewidth below ~0.6 nm was measured under these conditions with a quality factor Q~103. These performances and robustness of the device makes it an excellent candidate for biosensing, security and environment monitoring applications. PMID- 27464189 TI - Ion beam fabrication of aluminum-doped zinc oxide layer for high-performance liquid crystals alignment. AB - In this paper, a 1.8 keV ion beam (IB) sputtered thin layer of aluminum-doped zinc oxide (AZO) with columnar AZO bumps covering the surface working as an alignment layer for the homogeneous alignment of liquid crystals (LC) is investigated. Bumpy AZO alignment layers in twisted nematic (TN) cells generated larger LC pre-tilt angles and thus enabled accelerated switching of LC, and the highly conductive bumpy AZO thin layers allowed super-fast release of accumulated charges, and led to low residual DC performance. These results indicate the promising applications of AZO bumps layer as alignment layer in LC devices. PMID- 27464190 TI - Quasi-Bessel beams from asymmetric and astigmatic illumination sources. AB - We study the spatial intensity distribution and the self-reconstruction of quasi Bessel beams produced from refractive axicon lenses with edge emitting laser diodes as asymmetric and astigmatic illumination sources. Comparing these to a symmetric mono-mode fiber source, we find that the asymmetry results in a transition of a quasi-Bessel beam into a bow-tie shaped pattern and eventually to a line shaped profile at a larger distance along the optical axis. Furthermore, we analytically estimate and discuss the effects of astigmatism, substrate modes and non-perfect axicons. We find a good agreement between experiment, simulation and analytic considerations. Results include the derivation of a maximal axicon angle related to astigmatism of the illuminating beam, impact of laser diode beam profile imperfections like substrate modes and a longitudinal oscillation of the core intensity and radius caused by a rounded axicon tip. PMID- 27464191 TI - Dual-core antiresonant hollow core fibers. AB - In this work, dual-core antiresonant hollow core fibers (AR-HCFs) are numerically demonstrated, based on our knowledge, for the first time. Two fiber structures are proposed. One is a composite of two single-core nested nodeless AR-HCFs, exhibiting low confinement loss and a circular mode profile in each core. The other has a relatively simple structure, with a whole elliptical outer jacket, presenting a uniform and wide transmission band. The modal couplings of the dual core AR-HCFs rely on a unique mechanism that transfers power through the air. The core separation and the gap between the two cores influence the modal coupling strength. With proper designs, both of the dual-core fibers can have low phase birefringence and short modal coupling lengths of several centimeters. PMID- 27464192 TI - Pulsed laser interferometry with sub-picometer resolution using quadrature detection. AB - Femtosecond pulsed laser interferometry has important applications in measuring picometer-level displacements on sub-nanosecond time scales. In this paper, we experimentally examine its achievable displacement resolution, as well as the relationship between the laser's optical spectrum and the interferometer's effective wavelength. The resulting broadband displacement noise and noise floor of the pulsed laser Michelson interferometer are equivalent to that achieved with a stabilized continuous wave HeNe laser, where values of 1.01 nm RMS and 27.75 fm/?Hz have been demonstrated. It is also shown that a single effective wavelength can accurately describe the fringes of the pulsed laser interferometer but the effective wavelength value can only be determined from the optical spectrum under certain conditions. These results will be used for time-resolved displacement metrology with picosecond temporal resolution in the future. PMID- 27464193 TI - Active fiber-based retroreflector providing phase-retracing anti-parallel laser beams for precision spectroscopy. AB - We present an active fiber-based retroreflector providing high quality phase retracing anti-parallel Gaussian laser beams for precision spectroscopy of Doppler sensitive transitions. Our design is well-suited for a number of applications where implementing optical cavities is technically challenging and corner cubes fail to match the demanded requirements, most importantly retracing wavefronts and preservation of the laser polarization. To illustrate the performance of the system, we use it for spectroscopy of the 2S-4P transition in atomic hydrogen and demonstrate an average suppression of the first order Doppler shift to 4 parts in 106 of the full collinear shift. This high degree of cancellation combined with our cryogenic source of hydrogen atoms in the metastable 2S state is sufficient to enable determinations of the Rydberg constant and the proton charge radius with competitive uncertainties. Advantages over the usual Doppler cancellation based on corner cube type retroreflectors are discussed as well as an alternative method using a high finesse cavity. PMID- 27464194 TI - Theoretical analysis of saturable absorbtion in passively mode-locked fiber lasers. AB - We propose a general analytical method for estimation of the saturable absorber output energy as a function of the input energy. The method is based on a representation of the saturable absorber output energy as a series of powers of the recovery time. We also derive a simplified expression of the saturable absorber output energy that gives a good approximation for large input energies. The analytical results are verified by the numerical simulation. The results have been applied to the particular cases of an input function that include the Gaussian input pulse and the hyperbolic secant input pulse. We show that the analytical results can improve the prediction of the output energy in the fiber lasers. PMID- 27464195 TI - Nonlinear optical properties of calcium barium niobate epitaxial thin films. AB - We investigate the potential of epitaxial calcium barium niobate (CBN) thin film grown by pulsed laser deposition for optical frequency conversion. Using second harmonic generation (SHG), we analyze the polarization response of the generated signal to determine the ratios d15 / d32 and d33 / d32 of the three independent components of the second-order nonlinear susceptibility tensor in CBN thin film. In addition, a detailed comparison to the signal intensity obtained in a y-cut quartz allows us to measure the absolute value of these components in CBN thin film: d15 = 5 +/- 2 pm / V, d32 = 3.1 +/- 0.6 pm / V and d33 = 9 +/- 2 pm / V. PMID- 27464196 TI - Mobile-phone based visible light communication using region-grow light source tracking for unstable light source. AB - In order to increase the data rate of the camera-based visible light communication (VLC) system, using rolling shutter effect has been demonstrated successfully, in which the pixel rows of the complementary-metal-oxide semiconductor (CMOS) image sensor are activated sequentially. Previous camera based VLCs focused on using a stable LED light source, and its illumination area is positioned at the center of an image frame. In this work, we investigate the performance of a camera-based VLC with light source at different parts of an image frame. We propose and demonstrate using region-grow algorithm to track the light source. We also evaluate and discuss different scenarios when the light source is moved. Besides, a recorded > 5 kbit/s net data rate can be achieved by using only a single phosphor-based white-light LED source. Here, we demonstrate that 4.502 pixel/bit can be achieved. PMID- 27464197 TI - Tunable polarization beam splitter based on optofluidic ring resonator. AB - An efficient polarization beam splitter (PBS) based on an optofluidic ring resonator (OFRR) is proposed and experimentally demonstrated. The PBS relies on the large effective refractive index difference between transverse-electric (TE) and transverse-magnetic (TM) polarization states, since the silica-microcapillary based OFRR possesses a slab-like geometry configuration in the cross section through which the circulating light travels. To the best of our knowledge, this is the first OFRR-based PBS. In our work, the maximum polarization splitting ratio of up to 30 dB is achieved. Besides, water and ethanol are pumped into the core of the silica microcapillary respectively, and the maximum wavelength tuning range of 7.02 nm is realized when ethanol flows through the core, verifing the tuning principle of the PBS effectively. With such a good performance and simple scheme, this OFRR-based PBS is promising for applications such as tunable optical filters, demultiplexers, and routers. PMID- 27464198 TI - Laser patterning of Y3Al5O12:Ce3+ ceramic phosphor platelets for enhanced forward light extraction and angular color uniformity of white LEDs. AB - We present a facile fabrication process to directly fabricate cone-shaped microwells arrays on single crystal Y3Al5O12:Ce3+ (YAG:Ce) ceramic phosphor platelets (CPPs) by short-pulse laser direct patterning. Compared to unpatterned YAG:Ce CPP with smooth surface, the forward-to-total ratio of emission photons of patterned YAG:Ce CPPs was enhanced from 53.2% up to 78.2%, and the total emission within 4-pi degree is 6% higher. The fabricated patterns are also beneficial in increasing the color conversion efficiency of YAG:Ce CPPs by 7.6%. The patterned YAG:Ce CPPs display much better correlated color temperature (CCT) uniformity under varied currents. The angular correlated color temperature uniformity (ACU) of patterned YAG:Ce CPPs reaches as high as 0.933 compared to 0.730 of the unpatterned one. These results suggest that laser patterning of YAG:Ce CPP could effectively manipulate its luminance, chromaticity and illumination pattern, which may lead to further technological advancements for diversified applications of film-type CPPs in highly efficient white LEDs. PMID- 27464199 TI - Femtosecond wavelength-tunable OPCPA system based on picosecond fiber laser seed and picosecond DPSS laser pump. AB - We present a compact and stable femtosecond wavelength-tunable optical parametric chirped pulse amplification (OPCPA) system. A novel OPCPA front-end was constructed using a multi-channel picosecond all-in-fiber source for seeding DPSS pump laser and white light supercontinuum generation. Broadband chirped pulses were parametrically amplified up to 1 mJ energy and compressed to less than 40 fs duration. Pulse wavelength tunability in the range from 680 nm to 930 nm was experimentally demonstrated. PMID- 27464200 TI - Synthesis and structure of a new trinuclear nickel(II) complex bridged by N-[3 (Dimethylamino)propyl]-N'-(2-hydroxyphenyl)oxamido: in vitro anticancer activities, and reactivities toward DNA and protein. AB - A new trinickel(II) complex bridged by N-[3-(dimethylamino)propyl]- N'-(2 hydroxylphenyl)oxamido (H3 pdmapo), namely [Ni3 (pdmapo)2 (H2 O)2 ]?4CH3 OH, was synthesized and characterized by X-ray single-crystal diffraction and other methods. In the molecule, two symmetric cis-pdmapo3- mononickel(II) complexes as a "complex ligand" using the carbonyl oxygen atoms coordinate to the center nickel(II) ion situated on an inversion point. The Ni...Ni distance through the oxamido bridge is 5.2624(4) A. The center nickel(II) ion and the lateral ones have octahedral and square-planar coordination geometries, respectively. In the crystal, a three-dimensional supramolecular network dominated by hydrogen bonds is observed. The reactivity toward DNA/protein bovine serum albumin (BSA) revealed that the complex could interact with herring sperm DNA (HS-DNA) through the intercalation mode and quench the intrinsic fluorescence of BSA via a static mechanism. The in vitro anticancer activities suggested that the complex is active against the selected tumor cell lines. PMID- 27464201 TI - Incorporating Indications into Medication Ordering--Time to Enter the Age of Reason. PMID- 27464203 TI - Treatment of Opioid-Use Disorders. PMID- 27464204 TI - IMAGES IN CLINICAL MEDICINE. Herpes Zoster Mandibularis. PMID- 27464202 TI - Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement. AB - BACKGROUND: Postprocedural aortic regurgitation occurs in 10 to 20% of patients undergoing transcatheter aortic-valve replacement (TAVR) for aortic stenosis. We hypothesized that assessment of defects in high-molecular-weight (HMW) multimers of von Willebrand factor or point-of-care assessment of hemostasis could be used to monitor aortic regurgitation during TAVR. METHODS: We enrolled 183 patients undergoing TAVR. Patients with aortic regurgitation after the initial implantation, as identified by means of transesophageal echocardiography, underwent additional balloon dilation to correct aortic regurgitation. HMW multimers and the closure time with adenosine diphosphate (CT-ADP), a point-of care measure of hemostasis, were assessed at baseline and 5 minutes after each step of the procedure. Mortality was evaluated at 1 year. A second cohort (201 patients) was studied to validate the use of CT-ADP in order to identify patients with aortic regurgitation. RESULTS: After the initial implantation, HMW multimers normalized in patients without aortic regurgitation (137 patients). Among the 46 patients with aortic regurgitation, normalization occurred in 20 patients in whom additional balloon dilation was successful but did not occur in the 26 patients with persistent aortic regurgitation. A similar sequence of changes was observed with CT-ADP. A CT-ADP value of more than 180 seconds had sensitivity, specificity, and negative predictive value of 92.3%, 92.4%, and 98.6%, respectively, for aortic regurgitation, with similar results in the validation cohort. Multivariable analyses showed that the values for HMW multimers and CT ADP at the end of TAVR were each associated with mortality at 1 year. CONCLUSIONS: The presence of HMW-multimer defects and a high value for a point-of care hemostatic test, the CT-ADP, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure. (Funded by Lille 2 University and others; ClinicalTrials.gov number, NCT02628509.). PMID- 27464205 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 23-2016. A 46-Year-Old Man with Somnolence after Orthopedic Surgery. PMID- 27464206 TI - Von Willebrand Factor--A Rapid Sensor of Paravalvular Regurgitation during TAVR? PMID- 27464207 TI - Early versus Late Parenteral Nutrition in Critically Ill Children. PMID- 27464208 TI - Early versus Late Parenteral Nutrition in Critically Ill Children. PMID- 27464209 TI - Early versus Late Parenteral Nutrition in Critically Ill Children. PMID- 27464210 TI - Early versus Late Parenteral Nutrition in Critically Ill Children. PMID- 27464211 TI - Risk of Stroke after Transient Ischemic Attack or Minor Stroke. PMID- 27464212 TI - Risk of Stroke after Transient Ischemic Attack or Minor Stroke. PMID- 27464213 TI - Colorectal Adenomas. PMID- 27464214 TI - Colorectal Adenomas. PMID- 27464215 TI - Colorectal Adenomas. PMID- 27464216 TI - Colorectal Adenomas. PMID- 27464217 TI - Case 8-2016: A Man with Recurrent Fevers, Hypoxemia, and Lung Infiltrates. PMID- 27464218 TI - Case 8-2016: A Man with Recurrent Fevers, Hypoxemia, and Lung Infiltrates. PMID- 27464219 TI - Case 8-2016: A Man with Recurrent Fevers, Hypoxemia, and Lung Infiltrates. PMID- 27464220 TI - Case 18-2016: A 52-Year-Old Woman with a Pleural Effusion. PMID- 27464221 TI - Paclitaxel-Eluting versus Everolimus-Eluting Coronary Stents in Diabetes. PMID- 27464222 TI - Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy. PMID- 27464223 TI - IMAGES IN CLINICAL MEDICINE. Dysphagia Lusoria. PMID- 27464224 TI - Contributions of the Framingham Heart Study to the Epidemiology of Coronary Heart Disease. AB - Since its launch in 1948, the Framingham Heart Study has proved critical to shaping and enhancing our understanding of the history and root causes of coronary heart disease (CHD). A modern prototype for population-based studies, the Framingham Heart Study garnered widespread recognition in its early years for identifying risk factors for CHD and stroke and formulating CHD risk scores. Although the study remains iconic for its robust design and successes in uncovering risk factors for CHD, it has undergone transformations during the past 2 decades. The 21st century ushered in a new era in "molecular epidemiology" centered on cutting-edge genetic and "-omics technologies." Framingham Heart Study investigators embraced these opportunities by pioneering genome-wide association studies at the population level and examining CHD through the lens of genetic variation, gene expression, and microRNA signatures. The Framingham Heart Study continues to evolve as it seeks to pinpoint new causes of disease with the hope of advancing personalized approaches to the treatment and prevention of CHD. PMID- 27464225 TI - Memory Impairment, Dementia, and Alzheimer's Disease in Classical and Contemporary Traditional Chinese Medicine. AB - OBJECTIVES: To identify and analyze records of the treatment of dementia and memory disorders in the classical Chinese medical literature that were consistent with the signs and symptoms of Alzheimer's disease (AD), with the aim of determining which traditional medicines have histories of use for these disorders. METHODS: Encyclopedia of Traditional Chinese Medicine (Zhong Hua Yi Dian), a database of more than 1000 classical and premodern Chinese medical books, was systematically searched. Search terms were identified from dictionaries, medical nomenclatures, guidelines, and specialist clinical manuals on aging, neurology, or brain disorders. Inclusion and exclusion criteria were used to identify citations of conditions whose signs and symptoms were consistent with the clinical features of AD. Passages of text identified by these terms were copied to Microsoft Excel spreadsheets, together with the identity of the source book and all relevant information on the disorder and the intervention. Each distinct passage of text was considered a citation. The frequencies of the traditional formulas used as interventions and their constituent ingredients were calculated. RESULTS: The selection criteria identified 1498 citations of dementia and memory impairments derived from 277 different books written from circa 363 to 1945 AD. In 91 of these citations, memory impairment was associated with aging and was broadly consistent with the clinical features of AD. Although the interventions varied in name, Poria cocos, Polygala tenuifolia, Rehmannia glutinosa, Panax ginseng, and Acorus species consistently appeared as ingredients in multiple formulas for memory impairment in the context of aging. CONCLUSIONS: Memory impairment in older age was a recognized condition in the classical literature. Many of the traditional medicines frequently used as ingredients in classical formulas for memory impairment consistent with clinical features of AD remain in contemporary use, and experimental studies suggest biological activities relevant to AD. PMID- 27464226 TI - Kr/Xe Separation over a Chabazite Zeolite Membrane. AB - Herein we demonstrate that chabazite zeolite SAPO-34 membranes effectively separated Kr/Xe gas mixtures at industrially relevant compositions. Control over membrane thickness and average crystal size led to industrial range permeances and high separation selectivities. Specifically, SAPO-34 membranes can separate Kr/Xe mixtures with Kr permeances as high as 1.2 * 10 (-7) mol/m(2) s Pa and separation selectivities of 35 for molar compositions close to typical concentrations of these two gases in air. In addition, SAPO-34 membranes separated Kr/Xe mixtures with Kr permeances as high as 1.2 * 10 (-7) mol/m(2) s Pa and separation selectivities up to 45 for molar compositions as might be encountered in nuclear reprocessing technologies. Molecular sieving and differences in diffusivities were identified as the dominant separation mechanisms. PMID- 27464227 TI - Enhanced Photoelectrochemical Proximity Assay for Highly Selective Protein Detection in Biological Matrixes. AB - This work proposes the first photoelectrochemical proximity assay (PECPA) method via the sensitization of CdTe quantum dots (QDs) on photoelectrochemical response of ITO/TiO2/CdS electrode for highly selective and sensitive detection of proteins. This detection was performed on a sensing interface formed via the hybridization of capture DNA immobilized on ITO/TiO2/CdS electrode with labeled antibody-DNA (DNA-Ab1). Upon the recognition of Ab1 to target protein, the immunocomplex of DNA-Ab1, target, and the detection antibody-DNA (DNA-Ab2) was formed, which led to the proximity hybridization of the DNA in DNA-Ab2, capture DNA, and signal DNA-CdTe QDs, and brought CdTe QDs to the ITO/TiO2/CdS electrode to produce a sensitized photocurrent. The photocurrent intensity increased with the increasing concentration of the specific target protein. Using insulin as a target, this sensitized method showed a detectable range of 10 fM to 10 nM and a detection limit of 3.0 fM without the need of a washing step. It possessed high selectivity and good accuracy for detection of proteins in biological matrixes. This method is extremely flexible and can be extended to varieties of protein targets. PMID- 27464228 TI - Building robust architectures of carbon-wrapped transition metal nanoparticles for high catalytic enhancement of the 2LiBH4-MgH2 system for hydrogen storage cycling performance. AB - Nanoscale catalyst doping is regarded as one of the most effective strategies to improve the kinetics performance of hydrogen storage materials, but the agglomeration of nanoparticles is usually unavoidable during the repeated de/rehydrogenation processes. Herein, hierarchically structured catalysts (Fe/C, Co/C and Ni/C) were designed and fabricated to overcome the agglomeration issue of nanocatalysts applied to the 2LiBH4-MgH2 system for the first time. Uniform transition metal (TM) nanoparticles (~10 nm) wrapped by few layers of carbon are synthesized by pyrolysis of the corresponding metal-organic frameworks (MOFs), and introduced into the 2LiBH4-MgH2 reactive hydride composites (RHCs) by ball milling. The particular features of the carbon-wrapped architecture effectively avoid the agglomeration of the TM nanoparticles during hydrogen storage cycling, and high catalysis is maintained during the subsequent de/rehydrogenation processes. After de/rehydrogenation cycling, FeB, CoB and MgNi3B2 can be formed as the catalytically active components with a particle size of 5-15 nm, which show a homogeneous distribution in the hydride matrix. Among the three catalysts, in situ-formed MgNi3B2 shows the best catalytic efficiency. The incubation period of the Fe/C, Co/C and Ni/C-doped 2LiBH4-MgH2 system between the two dehydrogenation steps was reduced to about 8 h, 4 h and 2 h, respectively, which is about 8 h, 12 h and 14 h shorter than that of the undoped 2LiBH4-MgH2 sample. In addition, the two-step dehydrogenation peak temperatures of the Ni/C-doped 2LiBH4-MgH2 system drop to 323.4 degrees C and 410.6 degrees C, meanwhile, the apparent activation energies of dehydrogenated MgH2 and LiBH4 decrease by 58 kJ mol(-1) and 71 kJ mol(-1), respectively. In particular, the cycling hydrogen desorption of the Ni/C-doped 2LiBH4-MgH2 sample exhibits very good stability compared with the undoped sample. The present approach, which ideally addresses the agglomeration of nanoparticles with efficient catalysis on the RHCs, provides a new inspiration to practical hydrogen storage application for high performance complex hydrides. PMID- 27464229 TI - Cobalt Ferrite Bearing Nitrogen-Doped Reduced Graphene Oxide Layers Spatially Separated with Microporous Carbon as Efficient Oxygen Reduction Electrocatalyst. AB - The present work discloses how high-quality dispersion of fine particles of cobalt ferrite (CF) could be attained on nitrogen-doped reduced graphene oxide (CF/N-rGO) and how this material in association with a microporous carbon phase could deliver significantly enhanced activity toward electrochemical oxygen reduction reaction (ORR). Our study indicates that the microporous carbon phase plays a critical role in spatially separating the layers of CF/N-rGO and in creating a favorable atmosphere to ensure the seamless distribution of the reactants to the active sites located on CF/N-rGO. In terms of the ORR current density, the heat-treated hybrid catalyst at 150 degrees C (CF/N-rGO-150) is found to be clearly outperforming (7.4 +/- 0.5 mA/cm(2)) the state-of-the-art 20 wt % Pt-supported carbon catalyst (PtC) (5.4 +/- 0.5 mA/cm(2)). The mass activity and stability of CF-N-rGO-150 are distinctly superior to PtC even after 5000 electrochemical cycles. As a realistic system level exploration of the catalyst, testing of a primary zinc-air battery could be demonstrated using CF/N-rGO-150 as the cathode catalyst. The battery is giving a galvanostatic discharge time of 15 h at a discharge current density of 20 mA/cm(2) and a specific capacity of ~630 mAh g(-1) in 6 M KOH by using a Zn foil as the anode. Distinctly, the battery performance of this system is found to be superior to that of PtC in less concentrated KOH solution as the electrolyte. PMID- 27464241 TI - Letter to the Editor: Endocrine and metabolic emergencies in children: hypocalcemia, hypoglycemia, adrenal insufficiency, and metabolic acidosis including diabetic ketoacidosis. PMID- 27464242 TI - How can we bolster the antifungal drug discovery pipeline? PMID- 27464243 TI - National trends and in-hospital outcomes in patients with rheumatoid arthritis undergoing elective atlantoaxial spinal fusion surgery. AB - OBJECTIVES: Atlantoaxial subluxation is a well-known cervical spinal disorder in rheumatoid arthritis (RA) and certain patients with this condition may need to receive atlantoaxial spinal fusion (AASF). However, there is limited information available regarding demographics and outcome trends. The purpose of this study is to present an analysis of RA patients who underwent elective AASF using national in-hospital data. METHODS: Clinical data were derived from the US Nationwide Inpatient Sample (NIS) between 2000 and 2009. Patients who had a diagnosis of RA and underwent elective AASF, total hip arthroplasty (THA), and total knee arthroplasty (TKA) were identified. Data regarding patient- and healthcare system related characteristics, comorbidities, in-hospital complications, and mortality were retrieved. The trends of the procedures were analysed. RESULTS: There were 1,460 RA patients aged >=18 who underwent elective AASF between 2000 and 2009. During the last decade, the incidence of elective AASF in RA patients remained stable. The overall in-hospital complication rate of AASF in RA patients was 10.9%, which was more than twice that of THA and TKA in RA patients (THA: 4.8%; TKA: 4.9%). Respiratory complication rate (5.3%) was the highest among the complications. In-hospital mortality rate of such patients was 1.1%. CONCLUSIONS: During the last decade, the incidence of elective AASF in RA patients remained stable. In-hospital morbidity and mortality rates of AASF in RA patients were higher than those of other major orthopaedic surgeries in RA patients. Respiratory management is particularly important after AASF in RA patients. PMID- 27464244 TI - Epstein-Barr Virus Gene Expression in Lymphoproliferative Disease. AB - Epstein-Barr virus (EBV) is associated with Burkitt lymphoma, nasopharyngeal carcinoma, and lymphoprolifcrative disease in patients with congenital or acquired immunodeficiencies. B lymphocytes in tissues from these patients often contain EBV genomes. Expression of the EBV genes EBNA-1, EBNA-2, and LMP and the B cell genes CD23, ICAM-1, and LFA-3 has been demonstrated in lymphoblastoid cells in vitro and in B lymphocytes in tissues from patients with lymphoproliferative disease. In contrast, B cells in tissue from patients with Burkitt lymphoma usually show expression of EBNA-1, but not the other viral or B cell genes. Expression of EBNA-1 with variable expression of LMP has been reported in tissue from patients with nasopharyngeal carcinoma. The different patterns of viral and cellular gene expression in these diseases have important implications for their treatment. PMID- 27464245 TI - Peripheral Blood Stem Cell Autografts in Children with Acute Lymphoblastic Leukemia and Lymphoma: Updated Experience. AB - Peripheral blood stem cells (PBSC) in autografts (PBSCT) were given to 16 children with high-risk acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL). Harvest of PBSC is a safe, reliable procedure with low morbidity in children with cancer, and cryopreserved PBSC are useful in reducing cytopenia following marrow-ablative chemotherapy. The CFU-GM content of the thawed grafts is an important determinant of hematopoietic recovery after PBSCT. Whereas not all collections from children who had received intensive chemotherapy yielded sufficient progenitors for a safe graft, the value of preleukapheresis use of granulocyte colony-stimulating factor to expand the transplantable stem cell pool was not proven. After marrow-ablative chemotherapy without total body irradiation, three children who underwent PBSCT at refractory relapse died within 3 months. However, eight of the remaining 13 children are currently alive and disease-free, 5-29 months after PBSCT. PMID- 27464246 TI - T-Cell Receptor and Immunoglobulin Gene Rearrangements in Acute Myeloid and Undifferentiated Leukemias of Adults: Correlation with Weak Surface Expression of CD45 and CDw52 Antigens. AB - We examined 150 cases of acute myeloid leukemia (AML) and 8 cases of acute undifferentiated leukemi (AUL) of adults for both phenotypic and genotypic evidence of commitment to the lymphoid lineages. There was no correlation between expression of lymphoid differentiation antigens and rearrangement of T-cell receptor (TCR) and immunoglobulin (Ig) DNA sequences. In particular 8 cases of CD7(+) AML were germline for all TCR alpha, beta,MU, and delta Also none of the 11 cases with IgJH rearrangement expressed CD19 either on the cell surface or within the cytoplasm. Ten out of 13 cases with TCR/Ig gene rearrangement were either cytologically undifferentiated AML of FAB type M1 or AUL. None had clear immunophenotypic evidence for commitment to lymphoid lineages but 9 expressed only very small amounts of CD45 'framework' antigens and 7 expressed small amounts of CDw52 (CAMPATH-1). This phenotypic combination is otherwise seen only in precursor B cell ALL. TCR/Ig gene rearrangement in AML and AUL of adults appears to have become dissociated from the rest of the lymphoid differentiation 'program'. Recognition of these cases may be facilitated by the weak expression of both CD45 and CDw52 antigens. PMID- 27464247 TI - Correlations Between Gene Rearrangements and Immunoreactivity of Reed-Sternberg Cells in Paraffin Sections: A Genotypic and Phenotypic Study of 14 Cases of Hodgkin's Disease. AB - Recent immunohistological analyses using monoclonal antibodies (MAbs) in paraffin sections have shown that Reed-Sternberg cells (RSC) sometimes express B-cell markers, thereby suggesting a lymphoid origin in at least some cases of Hodgkin's disease (HD). In order to clarify the meaning of RSC immunoreactivities in paraffin sections, 14 cases of HD selected on the basis of a minimal RSC content of 5% (6 with mixed cellularity and 8 with nodular sclerosing HD) were B5 fixed, paraffin embedded and analysed by immunophenotyping with a panel of MAbs (LCA, MB1, MB2, L26, LN2, UCHL1, MT1, MT2, LeuM1, Ber-H2). Prior to fixation, a part of each specimen was frozen and submitted to genotypic analysis using immunoglobulin (Ig), T-cell receptor (TCR) gamma and TCR beta genes probes. RSC were strongly positive with LeuM1, BerH2 and LN2 in all cases and weakly positive with L26 in 4 cases and MB2 in 1 case. Many MT1-UCHL1 positive small lymphocytes were densely distributed close to RSC in all cases. The 14 cases retained a germline configuration with all enzyme-probe combinations tested. This finding cannot only be explained by the low number of RSC, which represented at least 5% of the cell population. Thus, neither the clonal nor the lymphoid nature of our HD cases could be determined unequivocally. LN2, L26 and MB2 expression do not correlate with Ig gene rearrangements and therefore cannot be considered as an argument supporting the B-cell derivation of RSC. PMID- 27464248 TI - ANTI-IL-2 Receptor Antibody Treatment for Lymphoproliferative Disease: Transient Response in A Case of Ki-1+ Anaplastic Large Cell Lymphoma. AB - Most cases of Ki-1 + anaplastic large cell lymphomas (ALCL) express the CD25 antigen, and we have recently shown that IL-2 producing cells can also be detected in these lymphomas. The latter cells may thus constitute targets for anti-CD25 Mab treatment. In one patient with a chemoresistant disseminated Ki-1 + ALCL such a therapeutic approach was undertaken. We report the dramatic antitumoral effect of anti-CD25 Mab obtained in this patient. This confirms the observation, previously reported in adult T cell leukemia, showing that this therapeutic regimen is also efficient in CD25 + solid tumors. PMID- 27464249 TI - Serum Levels of Interferon-gamma, Cytotoxic Factor and Soluble Interleukin-2 Receptor in Childhood Hemophagocytic Syndromes. AB - Serum levels of interferon (IFN)-gamma, cytotoxic factor (CF) and soluble interleukin-2 receptor (sIL2R) were assayed in relation to hyperferritinemia in eleven cases of malignant histiocytosis (MH), seven of virus-associated hemophagocytic syndrome (VAHS) and one of familial erythrophagocytic lymphohistiocytosis (FEL). IFN-gamma was markedly elevated (>10,000 U/ml) in 5 MH cases and only in one case of VAHS. CF was significantly elevated (> 150 U/ml) in 5 MH and 4 VAHS/FEL patients. sIL2R were remarkably elevated (> 10,000 U/ml) in 5 MH and 4 VAHS patients. In individual cases, the patterns of these parameters were quite different, suggesting the existence of a variable pathophysiology in cases with hemophagocytic syndromes. In terms of the patients' outcome, high IFN gamma or sIL2R levels were associated with a poor prognosis while high CF appeared to be associated with a better prognosis. PMID- 27464250 TI - Rapid Screening of Mutant N-ras Alleles by Analysis of PCR-Induced Restriction Sites: Allele Specific Restriction Analysis (ASRA). AB - We have developed a rapid screening method for analysis of codon 12, 13 and 61 N ras gene mutations, since these mutations have been observed in approximately 25% of patients with acute myeloid leukemia and myelodysplastic syndromes. The method, termed allele specific restriction analysis (ASRA), involves polymerase chain reaction amplification of DNA or RNA using a mismatched primer which introduces appropriately positioned base substitutions in N-ras and creates a restriction site provided the adjacent sequence is normal. Simultaneous analysis of codons 12 and 61 is also possible by the use of a multiprimer reaction mixture. Resistance of the amplified product to digestion indicates the presence of a mutation in the original template. Since ASRA allows simultaneous analysis of mutant and wild type sequences in DNA and RNA, an estimate of the ratio of gene copies and relative expression of N-ras alleles can be obtained for heterozygous individuals. PMID- 27464251 TI - Early Pre-B Lymphoblastic Transformation in A Patient with Refractory Anemia. AB - A 77 year-old male with refractory anemia receiving only supportive therapy presented with an acute transformation six years following diagnosis. The lineage of the blast cells could not be ascertained by morphological and cytochemical studies. Nevertheless, immunophenotypical studies, including monoclonal antibodies against myeloid, monocytic, erythroid, megakaryo-cytic and T and B lymphoid antigens, and analysis of immunoglobulin and T-cell receptors genes demonstrated the early pre-B nature of the blasts. Lymphoblastic transformation is extremely rare in myelodysplastic syndromes (MDS). The case presented here and other similar cases previously reported are consistent with the concept that MDS are clonal disorders arising from a pluripotent stem cell. PMID- 27464252 TI - Acute Cardiotoxicity After Daunorubicin in Acute Myeloid Leukaemia. AB - Use of the anthracycline antibiotics daunorubicin and adriamycin as antineoplastic agents is limited by dose-dependent, late cardiac toxicity. We describe a patient who developed fatal cardiogenic shock after comparatively low dose daunorubicin early in the treatment of acute myeloid leukaemia (A.M.L.). She was young with no previous cardiac history: investigations for an infectious aetiology were negative and at post-mortem there was no evidence of leukaemic infiltration. This unusual case demonstrates that standard doses of daunorubicin in A.M.L. may be followed early in the treatment by severe cardiac damage. PMID- 27464253 TI - Does the Mechanism of the Garratt-Braverman Cyclization Differ with Substrates? A Computational Study on Bispropargyl Sulfones, Sulfides, Ethers, Amines, and Methanes. AB - We studied the variation in mechanism among different bispropargyl substrates sulfone, sulfide, ether, amine, and methane-toward Garratt-Braverman (GB) cyclization using density functional theory calculations. Isomerization and cycloaddition are the key steps in the GB cyclization. To compare the reactivity among the various substrates, we computed the free energy of activation (DeltaG(?)) for the cycloaddition and the cyclization steps, whereas we used the theoretically computed pKa values for the isomerization steps. Our results suggest that the sulfones undergo a relatively fast isomerization followed by slower cyclization, while the ethers undergo a slow isomerization followed by easy cyclization. The methanes and amines are similar to the ethers, and the sulfides showed intermediate behavior. We extended our study to unsymmetrical substrates and compare the results with experiments that suggest the isomerization to be the rate-limiting step for bispropargyl ethers, while cyclization through a diradical intermediate is crucial to the rate for the bispropargyl sulfones. On the basis of these findings, we made predictions on the selectivity of unsymmetrical bispropargyl sulfones, amines, methanes, and sulfides. This is the first detailed mechanistic study on the GB cyclization of bispropargyl substrates other than sulfones. PMID- 27464254 TI - The influence of tissue microenvironment on stem cell-based cartilage repair. AB - Mesenchymal stem/progenitor cells and induced pluripotent stem cells have become viable cell sources for prospective cell-based cartilage engineering and tissue repair. The development and function of stem cells are influenced by the tissue microenvironment. Specifically, the local tissue microenvironment can dictate how stem cells integrate into the existing tissue matrix and how successfully they can restore function to the damaged area in question. This review focuses on the microenvironmental features of articular cartilage and how they influence stem cell-based cartilage tissue repair. Also discussed are current tissue-engineering strategies used in combination with cell-based therapies, all of which are designed to mimic the natural properties of cartilage tissue in order to achieve a better healing response. PMID- 27464256 TI - The role of androgen deprivation therapy plus radiation therapy in patients with non-metastatic prostate cancer. AB - INTRODUCTION: Androgen deprivation therapy (ADT) has a long and illustrious history in the treatment for prostate cancer and continues to be a mainstay treatment for locally advanced and high-risk patients. Because the survival for even high-risk prostate patients is lengthy, details of treatment such as duration and timing must be considered carefully and weighed against the various side effects. AREAS COVERED: In the following article, we discuss the evolution of ADT from its initial applications in metastatic prostate cancer to its more recent incorporation into front line treatment in conjunction with radiation therapy (RT) for intermediate and high risk disease. We emphasize the results of phase III trials, which have defined the role of ADT in combination with RT in this patient population. We emphasize not only the potential benefits of ADT with RT, but also the potential risks, and underscore the need to consider both in order to maximize the therapeutic ration for each patient. Studies were identified via a search of PubMed as well as the bibliographies of articles discussed herein. Expert commentary: Even with advanced radiation techniques and dose escalation, adjuvant ADT continues to confer an overall survival benefit in intermediate and high-risk patients, although some evidence suggest that duration of treatment may be shortened, particularly for the high-risk group. The coming years will shed further information on this complicated topic with maturing of results from several ongoing trials. PMID- 27464257 TI - Structure and electronic properties of bilayer graphene functionalized with half sandwiched transition metal-cyclopentadienyl complexes. AB - Tuning the electronic and magnetic properties of graphene is a crucial problem in the design of practical on-off electronic devices. Using density functional theory calculations, we explore the electronic and magnetic properties of bilayer graphene functionalized by cyclopentadienyl (Cp = cyclopentadienyl, C5H5) based half-sandwich ligands, CpTM (TM = Sc-Ni). It is found that the adsorption of CpTM ligands can introduce high magnetic moments and open the band gap of bilayer graphene, due to the electron doping as well as the asymmetric charge distribution between two graphene layers. Furthermore, the p-n doping of bilayer graphene by co-binding F/NO2 and CpTM on two external sides of BLG can further widen the band gap up to 366.1 meV. This study proposes an effective way to the modulation of the electronic and magnetic properties of graphene. PMID- 27464255 TI - Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss of ATG5. AB - Melanoma is a paradigm of aggressive tumors with a complex and heterogeneous genetic background. Still, melanoma cells frequently retain developmental traits that trace back to lineage specification programs. In particular, lysosome associated vesicular trafficking is emerging as a melanoma-enriched lineage dependency. However, the contribution of other lysosomal functions such as autophagy to melanoma progression is unclear, particularly in the context of metastasis and resistance to targeted therapy. Here we mined a broad spectrum of cancers for a meta-analysis of mRNA expression, copy number variation and prognostic value of 13 core autophagy genes. This strategy identified heterozygous loss of ATG5 at chromosome band 6q21 as a distinctive feature of advanced melanomas. Importantly, partial ATG5 loss predicted poor overall patient survival in a manner not shared by other autophagy factors and not recapitulated in other tumor types. This prognostic relevance of ATG5 copy number was not evident for other 6q21 neighboring genes. Melanocyte-specific mouse models confirmed that heterozygous (but not homozygous) deletion of Atg5 enhanced melanoma metastasis and compromised the response to targeted therapy (exemplified by dabrafenib, a BRAF inhibitor in clinical use). Collectively, our results support ATG5 as a therapeutically relevant dose-dependent rheostat of melanoma progression. Moreover, these data have important translational implications in drug design, as partial blockade of autophagy genes may worsen (instead of counteracting) the malignant behavior of metastatic melanomas. PMID- 27464258 TI - Stable Radiolabeling of Sulfur-Functionalized Silica Nanoparticles with Copper 64. AB - Nanoparticles labeled with radiometals enable whole-body nuclear imaging and therapy. Though chelating agents are commonly used to radiolabel biomolecules, nanoparticles offer the advantage of attaching a radiometal directly to the nanoparticle itself without the need of such agents. We previously demonstrated that direct radiolabeling of silica nanoparticles with hard, oxophilic ions, such as the positron emitters zirconium-89 and gallium-68, is remarkably efficient. However, softer radiometals, such as the widely employed copper-64, do not stably bind to the silica matrix and quickly dissociate under physiological conditions. Here, we overcome this limitation through the use of silica nanoparticles functionalized with a soft electron-donating thiol group to allow stable attachment of copper-64. This approach significantly improves the stability of copper-64 labeled thiol-functionalized silica nanoparticles relative to native silica nanoparticles, thereby enabling in vivo PET imaging, and may be translated to other softer radiometals with affinity for sulfur. The presented approach expands the application of silica nanoparticles as a platform for facile radiolabeling with both hard and soft radiometal ions. PMID- 27464259 TI - The Tracing of VOC Composition of Acacia Honey During Ripening Stages by Comprehensive Two-Dimensional Gas Chromatography. AB - In this study, VOC profiles of acacia flowers and honey samples at different processing stages and related comb wax samples were studied using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry. It was found that some monoterpene compounds like alpha-pinene, myrcene, cis-beta ocimene, and 4-terpineol were common for acacia flower and all acacia honey samples, and the presence of verbenone and ocimene was first established in acacia honey. The most enriched VOC profile was obtained for raw honey before cell capping, where the final composition of lactones was achieved. On the contrary, number of alcohols, esters, and variety of terpenes, as well as their concentration in the honey samples decrease through ripening processes. Strained honey was characterized by the absence of camphor, alpha-bisabolol, and 3-carene, while isophorone and hexanoic acid were identified only in this type of honey. The composition of final VOC profile of honey was also influenced by the age of comb wax. The additional aromatic and lactone compounds, e.g., phenol, 1 phenylethanol, delta-hexalactone, and gamma-heptalactone were observed for honey maturated in old dark comb wax. PMID- 27464260 TI - Seasonal patterns and association of meteorological factors with infection caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in childhood community-acquired pneumonia in a tropical region. PMID- 27464261 TI - Wild Prunus Fruit Species as a Rich Source of Bioactive Compounds. AB - Sugars, organic acids, carotenoids, tocopherols, chlorophylls, and phenolic compounds were quantified in fruit of 4 wild growing Prunus species (wild cherry, bird cherry, blackthorn, and mahaleb cherry) using HPLC-DAD-MSn. In wild Prunus, the major sugars were glucose and fructose, whereas malic and citric acids dominated among organic acids. The most abundant classes of phenolic compounds in the analyzed fruit species were anthocyanins, flavonols, derivatives of cinnamic acids, and flavanols. Two major groups of anthocyanins measured in Prunus fruits were cyanidin-3-rutinoside and cyanidin-3-glucoside. Flavonols were represented by 19 derivatives of quercetin, 10 derivatives of kaempferol, and 2 derivatives of isorhamnetin. The highest total flavonol content was measured in mahaleb cherry and bird cherry, followed by blackthorn and wild cherry fruit. Total phenolic content varied from 2373 (wild cherry) to 11053 mg GAE per kg (bird cherry) and ferric reducing antioxidant power antioxidant activity from 7.26 to 31.54 mM trolox equivalents per kg fruits. PMID- 27464263 TI - Why China guidelines for type 2 diabetes represent an opportunity for treating this disease. AB - More than one quarter of people affected by type 2 diabetes worldwide live in China, where an alarming increase in diabetes incidence is taking place. However, most of the evidence about diabetes management derives from studies conducted on non-Asian people, raising concerns about their validity in other ethnic groups, including the Chinese. The guidelines proposed by the Chinese Diabetes Society suggest tools for medical doctors in China and worldwide to appropriately face diabetes in Chinese people, whose number in non-Chinese countries is continuously increasing. However, additional efforts are still needed to achieve an evidence based tailored therapy for type 2 diabetes in Chinese people. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27464264 TI - Evolution in the Chinese Diabetes Society Standards of Care for Type 2 Diabetes. AB - China has been experiencing the biggest shift in the world in diabetes and obesity epidemic over the past three decades. Chinese Diabetes Society developed and published four editions of stand of care for type 2 diabetes management as clinical guidance for practice in China in the last twelve years. During the development and implementation of guidelines, the keyword is 'evolution', which includes evolution of evidence, expertise, excellence and endpoints. It will be a complete quality improvement cycle starting with 'understanding the situation' and ending with 'tipping points of diabetes in primary prevention (prevalence), secondary prevention (diabetic complications) and tertiary prevention (diabetes related death)'. This series of 'Stand of care for type 2 diabetes' allows for a fundamental understanding into the ways in which the domino effects of the epidemic could be curbed. More work for doing with 'Mens et Manus' will be carried out in the near future. This English version will be useful for the international scientific community to glean insights into type 2 diabetes management practices in China, and alternative methods of tackling challenges. (c) 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd. PMID- 27464262 TI - Long-term evolution of multiple sclerosis disability in the treatment era. AB - OBJECTIVE: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value. METHODS: This is a prospective study of 517 actively managed MS patients enrolled at a single center. RESULTS: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS >= 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS). INTERPRETATION: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499 510. PMID- 27464266 TI - Stochastic Proximity Embedding: Methods and Applications. AB - Since its inception in 1996, the stochastic proximity embedding (SPE) algorithm and its variants have been applied to a wide range of problems in computational chemistry and biology with notable success. At its core, SPE attempts to generate Euclidean coordinates for a set of points so that they satisfy a prescribed set of geometric constraints. The algorithm's appeal rests on three factors: 1) its conceptual and programmatic simplicity; 2) its superior speed and scaling properties; and 3) its broad applicability. Here, we review some of the key applications, outline known limitations and ways to circumvent them, and highlight additional problem domains where the use of this technique could lead to significant breakthroughs. PMID- 27464267 TI - Virtual Activity Profiling of Bioactive Molecules by 1D Fingerprinting. PMID- 27464268 TI - An Improved Weighted-Residue Profile Based Method of Using Protein-Ligand Interaction Information in Increasing Hits Selection from Virtual Screening: A Study on Virtual Screening of Human GPCR A2A Receptor Antagonists. AB - The use of protein-ligand interaction information has been reported to improve and optimize the docking results in virtual screening experiments. Here we propose an improved weighted-residue profile based method to profile the protein ligand interactions based on the available dataset of known actives and utilize this weighted residue profile information, together with the scoring function, as selection criteria to increase hit rates in virtual screening experiments. The generated fingerprint data is not directly based on the protein-ligand complexes but taken from the available interaction data derived from the docking results. The ability of the method to recover the active compounds was tested on two data sets of a compound library designed for antagonists of the A2A receptor. The results show better hits enrichments by using the weighted-residue based profiles of protein-ligand interactions as compared to the normal binding energy based scoring schemes of the two docking programs. PMID- 27464265 TI - Standards of care for type 2 diabetes in China. PMID- 27464269 TI - Visualization of Molecular Selectivity and Structure Generation for Selective Dopamine Inhibitors. AB - Activity landscapes were used in combination with atom colourings for the visualization of molecular selectivity. Multiple inhibitory activities in the dopamine family were selected in order to derive its molecular selectivity. All molecular structures were mapped in 2D chemical space by preserving the relative distance between any pair of molecules using multidimensional scaling. The values for the inhibitory activity against each dopamine isoenzyme (D2, D3, and D4) were added independently to the data points in 2D chemical space. Three activity landscapes were generated after carrying out colour-graded interpolation between the data points. The activity landscapes facilitated the detection of three specific active regions and the corresponding specific inhibitors for D2, D3, and D4 isoenzymes. Three support vector regression models were separately constructed using extended connectivity fingerprint descriptors and each inhibitory data set. By applying the atom scores along with the graded-colours to the specific inhibitors, the molecular selectivity differentiating each dopamine isoenzyme could be understood visually. Furthermore, the landscape technique was combined with structure generation to produce chemical structures that stay within the D3 specific active region. PMID- 27464270 TI - Consensus QSAR Related to Global or MOA Models: Application to Acute Toxicity for Fish. AB - Under REACH legislation, alternative methods (in silico or in vitro) like QSAR (Quantitative Structure-Activity Relationships) models are expected to play a significant role. QSARs are based on the assumption that substances with similar chemical structures may have the same biological activities. However, identification of chemical classes could be problematic because chemicals often exhibit different chemical moieties, thereby confounding efforts to achieve a meaningful classification. This publication is focus on the notion of global model with the integration of a recent genetic algorithm for the generation of QSAR models. Starting from three datasets (EPAFHM, ECBHPV, AQUIRE), prediction of acute toxicity for fish (Pimephales promelas) with a global consensus model was carried out leading to very interesting statistics. The integration of the notion of Mode of Action was the second point of this study. A Bayesian classification associated to the genetic algorithm for consensus models was created leading to a good estimation of toxicity associated to derivatives with nonspecific MOA. PMID- 27464271 TI - Will pulmonary drug delivery for systemic application ever fulfill its rich promise? PMID- 27464272 TI - Maturation of green waste compost as affected by inoculation with the white-rot fungi Trametes versicolor and Phanerochaete chrysosporium. AB - Green waste was separately inoculated on day 0 and day 14 with either Trametes versicolor or Phanerochaete chrysosporium to determine their effects on composting time and compost quality. Inoculation with T. versicolor and P. chrysosporium caused more rapid and higher increases in compost temperatures, increased the duration of the thermophilic temperature stage, and reduced the maturity time. Inoculation with T. versicolor and P. chrysosporium greatly increased the quality of the final composts in terms of pH, electrical conductivity, organic matter concentration, C/N ratio, germination index, and nutrient content. Inoculation with T. versicolor and P. chrysosporium also significantly increased the degradation of lignin by 7.1% and 8.2%, respectively, and increased the degradation of cellulose by 10.6% and 13.6%, respectively. PMID- 27464273 TI - [Aortic embolism: conservative therapy is too risky - in reply]. PMID- 27464274 TI - [Aortic embolism: conservative therapy is too risky]. PMID- 27464275 TI - [Gene mutation protects by reducing lipids]. PMID- 27464276 TI - [86-year old woman with orthopnea]. PMID- 27464277 TI - [Rapid identification of patients at risk]. PMID- 27464278 TI - [Pathophysiology of sepsis]. AB - Current evidence suggests that a dysregulated, i.e. systemic and extensive, immune response causes sepsis-induced multiple organ failure. Notably, this does not only imply the initial inflammatory reaction but also the delayed sepsis associated depression of the immune system. Endothelial dysfunction and sepsis induced coagulopathy represent additional major pathomechanisms. Based on multiple interactions between mediators und receptors all of these mechanisms can be discussed individually only for didactical purposes. Clinically, there are charateristic microcirculatory disorders and macrocirclatory changes resulting in an impaired oxygen transport capacity. Due to an additional cytopathic hypoxia, organ function might be impaired even if physiological partial pressures of oxygen are restored. Although these changes are often functional and potentially reversible, mortality increases up to 70% in case of multiple organ failure. PMID- 27464279 TI - [Sepsis in Emergency Medicine]. AB - Sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host-response to infection". Presence of organ dysfunction is associated with a mortality of 10% and higher in hospitalized sepsis patients.Introduction of standards in diagnosis and treatment of sepsis in intensive care units has not considerably reduced sepsis mortality. About 80% of patients with sepsis are transferred to intensive care units from usual care wards and emergency departments. Thus, it is tempting to speculate whether opportunities for further improvement of sepsis management exist outside of intensive care units. Performing a "quick sequential organ assessment" (qSOFA; two of following criteria have to be present: respiratory rate >22/min; sytolic blood pressure <100mmHg; altered mental status) supports to identify patients with suspicion of an infection and an increased risk of death within the hospital. Subsequent treatment according to current guidelines on sepsis management will reduce in hospital mortality of sepsis patients. Indeed, we were able to show a substantial decrease of in-hospital mortality of about 20% in patients presenting with community acquired pneumonia to the emergency department.In summary, decision of further management of sepsis patients has to be done outside intensive care units at the time of initial presentation to professional care givers. Sepsis management in acute care settings should include a structured and standardized protocol to further improve survival in affected patients with even mild organ dysfunction. PMID- 27464280 TI - [State of the art - intensive care therapy of septic patients]. AB - After recognition of the diagnosis sepsis early resuscitation of the patient is mandatory. Patients should have a mean arterial pressure (MAP) >=65 mmHg. Patients with hypotension should receive initial fluid challenge with approximately 30 mL/kg of balanced electrolyte solutions. However, iatrogenic volume overload should be avoided. If MAP remains < 65mmHg despite adequate volume norepinephrine is the first choice catecholamine. Oxygen should be delivered when oxygen saturation is below 90% to avoid hypoxemia. Intubation and invasive ventilation is reasonable in hemodynamically unstable or unconscious patients. Two blood cultures should be drawn immediately in every septic patient plus further microbiological test depending on the primary focus. After that broad spectrum antibiotics should be given (<60 min after diagnosis). Strong effort must be done to identify the primary source of sepsis including examination, history and different imaging technics. Physicians have to check actively, if the source can be controlled (<12h) by surgery or intervention. Ventilated patients must be monitored for depth of sedation, pain and delir with standardized tools (RASS, CPOT, BPS, CAM-ICU). Lung protective ventilation (TV 6 8ml/kg Ideal-BW, Pmax<30mbar, application of PEEP) is standard in septic patients. It should be combined with low sedation and early mobilisation to allow spontaneous breathing. Permanent monitoring for further organ dysfunction is mandatory. In case of sepsis induced kidney injury, early CRRT should be started with an average dose of 20-25ml/kg/h. Under CRRT many antibiotics must be given at a high dose to prevent underdosing. Concerning nutrition, enteral nutrition starting with 48h is recommended with a dose of 15-25kcal/kg. However, it remains uncertain if hypocaloric nutrition or parenteral application may be equivalent. Transfusion should be done restrictively (with a trigger Hb < 7g/dl). For the prevention of nosocomial sepsis high standard hygiene and antibiotic stewardship programs as well as enough and sufficiently qualified staff are essential. Quality management for septic patients generates transparency and helps to motivate the ICU team. PMID- 27464281 TI - [Clinical examination of vertigo]. AB - Acute vertigo may originate from peripheral or central vestibular disorders. As central vestibular symptoms may indicate severe brainstem or cerebellar ischemia, rapid clinical differentiation is required. To this end, evaluation of spontaneous or gaze-evoked nystagm, head-impulse test as well identification of skew deviation are most helpful. PMID- 27464282 TI - [77-year-old man with rare Littre's hernia]. AB - HISTORY AND CLINICAL FINDINGS: A 77-year-old man presented with acute pain and femoral swelling in his right groin. EXAMINATIONS: The clinical finding resulted in the suspicion of an irreducible, possibly incarcerated inguinal hernia. Transcutaneous ultrasound did not reveal any hints confirming the clinical suspicion. Because of the impressive clinically finding, the patient was subjected to open exploration of the groin. TREATMENT AND COURSE: Intraoperatively, the initial clinical finding could be confirmed. Herniotomia showed incarcerated ileal segment with Meckel's diverticle, a so-called Littre's hernia. Subsequently, median laparotomy and ileum segment resection with side-to side ileoileostomy were performed. The postoperative course was uneventful. The patient was discharged in good health status on the seventh postoperative day. CONCLUSION: Littre's hernia is a rare pathological finding, which can also be considered as an infrequent manifestation of a variant of a commonly encountered clinical/surgical finding such as hernia. The presented case elucidates the difficulty in the timely establishment of the correct preoperative diagnosis. The clinician needs to be aware of this albeit exceptionally rare variation because the symptoms can vary greatly and severe complications can occur. This threat must be encountered via rapid diagnosis-finding and initiation of appropriate therapy. PMID- 27464283 TI - [An unexpected cause of pulmonary hypertension]. AB - HISTORY AND ADMISSION FINDINGS: We report on a 48-year-old man presenting with progressive hepatopathy and encephalopathy for two weeks based on a chronic hepatitis C. He takes ledipasvir and sofosbuvir (Harvoni) and ribavirin for almost 24 weeks. After admission to hospital his state deteriorated rapidly. He is directly transferred to the medical intensive care unit, where he died on day 3. INVESTIGATIONS: During the physical examination, a pronounced jaundice and significant peripheral edema were found. Laboratory tests showed anemia, an increased C-reactive proteine and bilirubin, a limited coagulation and renal insufficiency with elevated creatinine. Quantitative HCV-PCR was negative. Echocardiographically a severe tricuspid- and mitral-valve regurgitation was found in a massively increased pulmonary artery pressure and pulmonary heart disease. The gastroscopy revealed a Forrest IIb situation with corresponding clip supply. DIAGNOSIS, TREATMENT AND COURSE: In the autopsy we find signs of portal hypertension in presence of progressive liver cirrhosis. In addition, portopulmonary hypertension is diagnosed. The patient died on right ventricular failure resulting from a massively increased pulmonary pressure Conclusion: Advanced liver disease and an increased pulmonary pressure are often associated. Therefore, an early as possible diagnosis and classification are essential for adequate therapy in these patients. PMID- 27464284 TI - [Acute and chronic limb ischemia in endurance athletes - a serious diagnosis of exercise-induced lower limb pain]. AB - Lower extremity pain due to acute or chronic ischemia in high performance endurance athletes is an often forgotten differential diagnosis. A variety of symptoms constitues a multi-disciplinary challenge. Intermittent claudication or acute ischemia are clinical symptoms indicative of this vascular disease. The most important basic methods of investigation are anamnesis and clinical examination. Furthermore, the determination of the ankle-brachial index (ABI) and duplexsonography should be considered. In addition, modern cross-sectional imaging techniques such as computed tomography angiography (CTA) or magnetic resonance angiography (MRA) are recommended. In case of suspect findings, the digital substraction angiography (DSA) represents a high resolution image technique for illustration of the vessel lumen. If necessary, interventional therapy (balloon angioplasty or clot lysing) can be performed simultaneously. Surgical revision remains the gold-standard of therapy and the fastest way in which athletes regain maximum performance abilities. Correct diagnosis of lower limb ischemia affecting endurance athletes should be performed without delays. Determining the ankle-brachial index following maximal exertion represents the most important diagnostic tool. Surgical treatment techniques as decompression and revascularisation provide the best long-term results. PMID- 27464285 TI - [Bleeding in patients receiving dual antiplatelet therapy after acute coronary syndrome - significance, prevention and interdisciplinary management]. AB - For secondary prevention of acute coronary syndrome, guidelines recommend dual antiplatelet therapy with acetylsalicylic acid and a P2Y12 receptor antagonist such as clopidogrel, prasugrel or ticagrelor for a period of 12 months. Premature discontinuation of dual antiplatelet therapy is associated with an increased risk of ischaemic events. However, antiplatelet therapy is also associated with an increased risk of bleeding that should not be under- or overestimated. To ensure an optimal care of patients receiving dual antiplatelet therapy after an acute coronary syndrome, an interdisciplinary group of experienced experts in the fields of cardiology, cardiac surgery, gastroenterology, anaesthesiology, intensive care and haemostaseology gathered bleeding-related information and developed recommendations relevant to daily clinical practice. These include the significance of bleeding events in the course of treatment, measures for bleeding prevention and the adequate care of patients with bleedings. PMID- 27464286 TI - [Ambulant treatment of alcohol withdrawal]. AB - Most of the patients addicted to alcohol are socially well integrated. The offer of a low threshold ambulant withdrawal therapy opens an opportunity to build a sustainable therapeutic relationship. The so started empathic addiction therapy will be well accepted and will lead to a satisfying outcome. Using Clomethiazole or Oxazepam in a daily reduced dose and with daily personal contacts, the ambulant withdrawal in patients without seizures or delir in medical history is a secure and successful therapeutic option. PMID- 27464287 TI - [Sedentary Behavior and the health of adolescents]. AB - BACKGROUND: In modern societies, adolescents spend about half of their waking hours with sedentary behavior (SB). Therefore, the current study aims at investigating the relationship between SB and adolescents' health. METHODS: A cross-sectional sample of 1296 students (8(th) grade) from 29 schools in Schleswig-Holstein, Germany was surveyed. Mean age was 13.75 years (SD = 0.67), 47.0 % were female. To asses screen-based and non-screen-based SB, moderate to vigorous physical activity as well as further indicators of health behavior (tobacco and alcohol use, diet) a questionnaire was used. Anthropometric data and blood pressure at rest were assessed during a medical testing and cardiorespiratory fitness was assessed by the 20 m-Shuttle-Run-Test. RESULTS: The students spent almost 7 hours a day sedentary. Total SB was positively associated with behavior that is detrimental to health. These associations were detectable only for screen-based SB, not for non-screen-based SB. Cardiorespiratory fitness was associated negatively with total SB, screen-based as well as non-screen-based SB. Associations remained widely stable when moderate to vigorous physical activity was controlled for. There were almost no associations between SB and blood pressure. DISCUSSION: Total SB, but especially screen-based SB seems to be a health risk factor in adolescence independent of physical activity. Besides fostering physical activity, reduction of SB should be a core target behavior in prevention and health promotion. PMID- 27464288 TI - [Discharge medication - what do patients know about their medication on discharge?]. AB - BACKGROUND: Patients' lack of knowledge about their discharge medication can endanger patients' safety after their hospital stay. This is especially the case with regard to medications that were newly prescribed during the hospital stay and are intended to be used after discharge or medications with an increased risk for adverse drug reactions (high-risk drugs). The aim of this study was to analyse the patients' level of knowledge about their discharge medication and to identify influence factors. METHODS: In a bicentric survey patients were interviewed prior to their discharge from an acute and a geriatric rehabilitation hospital. They were asked about their discharge medication in a structured interview. Influence factors were statistically analysed by Tobit regression. RESULTS: In total, 179 patients were interviewed. On average, patients named 48% of their discharge medication correctly (95% CI: 46-50%). Influence factors for knowledge deficits were the lack of a medication plan, an older age, the hospitalization in a rehabilitation hospital and a long hospitalization. 81% of the patients had at least one drug in their discharge medication, which was newly prescribed during the hospital stay. 11% of those drugs were named correctly, the potency was named correctly in 6%, the indication in 8%. For almost two-thirds of the patients at least one high-risk drug was recommended in the discharge letter, among them most frequently oral anticoagulants and opioid analgesics. 38% of these high-risk drugs were named correctly. CONCLUSION: Our results demonstrate an urgent need to train patients about their discharge medication, especially if medications are included that were newly prescribed during the hospital stay and recommended for further use after discharge or medications with an increased risk of adverse drug reactions. Particularly older patients and patients of a rehabilitation hospital after long hospitalization should be intensively counselled and obtain a medication plan upon discharge. PMID- 27464289 TI - Anti-ganglioside antibodies in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients. AB - INTRODUCTION: In this study we investigated the relationships between anti ganglioside antibodies and Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. RESULTS: In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. CONCLUSIONS: These results suggest that IgG anti-GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55: 470-475, 2017. PMID- 27464290 TI - Socioeconomic disparities in access to a hepatocellular carcinoma screening program in Brazil. AB - OBJECTIVES: Cirrhotic patients must receive an abdominal ultrasound every 6 months as part of hepatocellular carcinoma (HCC) screening. The aim of this study was to assess if HCC screening was performed as recommended by the literature and to observe the differences between the private and public services in Brazil. METHODS: We analyzed data from the HCC screenings of 253 cirrhotic patients from the University Hospital (n=177) and private sector (n=76) in Vitoria, ES, Brazil. RESULTS: Ultrasound screening was performed every 13.1 months on average (SD 9.02). In 37 out of 253 patients, the screenings were performed close to the recommended frequency; 16 were performed every 6 months, and 21 were mostly performed during the follow-up period every 6 months. In the remaining 216 cases, ultrasounds were not performed according to the guidelines; for 106 patients, less than 50% of all ultrasounds were performed every 6 months and 110 patients showed an interval greater than one year. Patients from the private sector received ultrasound screenings near the ideal in 28.9% of cases, while patients from the University Hospital received ultrasounds in only 8.4% of cases (p<0.0001). HCC was diagnosed in 30 patients (11.8%). For these 30 patients, 11 screenings were properly performed within 6 months (36.6%) and only 1 out of the 11 (9%) met the criteria for transplant. In the remaining 19 patients who did not receive the screening within 6 months, 6 (31.5%) did not meet the criteria for transplant. CONCLUSION: HCC screening in our environment was irregularly performed, mainly in the public service setting, which prevented early diagnosis in a large number of patients. PMID- 27464292 TI - Determinants of quality of life in Brazilian patients with myasthenia gravis. AB - OBJECTIVES: The aims of the current study were 1) to evaluate the reliability and validity of the Brazilian version of the 15-item Myasthenia Gravis Quality of Life Scale and 2) to investigate the quality of life of Brazilian patients with myasthenia gravis and its determinants. METHODS: This cross-sectional study included 69 patients with myasthenia gravis who underwent neurological evaluation and completed questionnaires regarding quality of life (the 36-item Short Form of the Medical Outcomes Study and the 15-item Myasthenia Gravis Quality of Life Scale), anxiety and depressive symptoms. RESULTS: The Brazilian version of the 15 item Myasthenia Gravis Quality of Life Scale showed high internal consistency and good concurrent validity with the 36-item Short Form of the Medical Outcomes Study and its subscales. Determinants of quality of life in Brazilian patients with myasthenia gravis included the current status of myasthenia gravis as assessed by the Myasthenia Gravis Composite, the current prednisone dose and the levels of anxiety and depression. CONCLUSION: The Brazilian version of the 15 item Myasthenia Gravis Quality of Life Scale is a valid instrument. Symptom severity, prednisone dosage and anxiety and depression levels impact the quality of life of patients with myasthenia gravis. PMID- 27464291 TI - The Lowest Prevalence of Cholelithiasis in the Americas - An Autopsy-based Study. AB - OBJECTIVES: This study used autopsy to evaluate the prevalence of cholelithiasis and its associated risk factors in a population of healthy, young subjects who suffered a violent or natural death. METHODS: This study is a prospective evaluation of autopsies of 446 individuals from 2011 to 2013 in Brazil. Of that sample, 330 (74%) subjects died from violent deaths and 116 (26%) died naturally. The presence of biliary calculi, previous cholecystectomy, gender, age, ethnicity, body mass index (BMI) and alcohol use were evaluated. RESULTS: In the natural death group, 6.9% (95% CI 3.39 to 13.28) (3.08% of the male subjects and 11.76% of the female subjects) exhibited evidence of gallbladder disease. In the violent death group, only 2.12% (95% CI 0.96 to 4.43) (2.17% of the male subjects and 1.85% of the female subjects) of the subjects exhibited evidence of gallbladder disease. Age was correlated with the prevalence of gallbladder disease, but BMI was correlated with only gallbladder disease in the natural death group. CONCLUSIONS: This population has the lowest prevalence of cholelithiasis in the Americas. Dietary habits, physical activity, ethnicity, alcohol consumption and genetic factors may be responsible for this low prevalence. PMID- 27464293 TI - Association of hemoglobin with ankle-brachial index in general population. AB - OBJECTIVES: Previous studies have demonstrated that both low and high hemoglobin concentrations are predictive of adverse cardiovascular outcomes in various populations. However, an association of hemoglobin with the ankle-brachial index, which is widely used as a screening test for peripheral arterial disease, has not yet been identified. METHODS: We examined 786 subjects (236 women and 550 men) who received routine physical check-ups. The ankle-brachial index and several hematological parameters, including the hemoglobin level, hematocrit and red blood cell count and other demographic and biochemical characteristics were collected. Univariate and multivariate linear regression analyses were performed to assess the relationships between the ankle-brachial index and the independent determinants. Receiver operating characteristic curve analysis was conducted to calculate the cut-off level of hemoglobin for detecting a relatively low ankle brachial index (less than 20% of all subjects, which was 1.02). RESULTS: The hemoglobin level, hematocrit and red blood cell count were correlated with the ankle-brachial index in the males (r=-0.274, r=-0.224 and r=-0.273, respectively, p<0.001 for all), but these associations were not significant in the females. Multivariate linear regression analysis revealed that the independent determinants of the ankle-brachial index included age, total cholesterol, high density lipoprotein cholesterol and the white blood cell count for the females and age, hypertension, total cholesterol and hemoglobin (beta=-0.001, p<0.001) for the males after adjusting for confounding factors. Receiver operating characteristic curve analysis revealed that the cut-off level of hemoglobin for predicting a low ankle-brachial index was 156.5 g/L in the males. CONCLUSIONS: A high hemoglobin concentration was independently correlated with a low ankle brachial index in the healthy males, indicating that an elevation in this level may be associated with an increased atherosclerosis risk. PMID- 27464294 TI - Factors associated with the need for ventilation at birth of neonates weighing >=2,500 g. AB - OBJECTIVES: Approximately 20-40% of annual global neonatal deaths occur among infants with birthweights >=2,500 g, and most of these deaths are associated with intrapartum asphyxia in low- and middle-income countries. This study aims to evaluate the peripartum variables associated with the need for resuscitation at birth of neonates weighing >=2,500 g. METHOD: This case-control retrospective study was performed on data from all public reference maternity units in the state of Ceara, Northeast Brazil, between March 2009 and March 2010. The subjects were singleton neonates without malformations weighing >=2,500 g, who required positive-pressure ventilation in the delivery room. The controls had a 1-minute Apgar score of >=8 and did not undergo resuscitation. Variables associated with positive-pressure ventilation in the delivery room were evaluated via conditional multivariate logistic regression. RESULTS: Of the 2,233 live births with birth weights >=2,500 g, 1-minute Apgar scores <=7, and no malformations, 402 patients met the inclusion criteria, and they were paired with 402 controls. Risk variables for positive-pressure ventilation at birth were a gestational age <37 weeks (OR: 3.54; 95% CI: 1.14-10.92) and meconium-stained amniotic fluid (8.53; 4.17-17.47). Cervical examination at maternal admission (0.57; 0.38-0.84) and a written follow-up of the labor (0.68; 0.46-0.98) were identified as protective variables. CONCLUSIONS: Significant flaws in obstetric care are associated with the need for positive-pressure ventilation at birth for neonates weighing >=2,500 g. PMID- 27464295 TI - Investigating Compliance with Standard Precautions During Residency Physicians in Gynecology and Obstetrics. AB - OBJECTIVES: Physician compliance with standard precautions is important in the specialty of gynecology and obstetrics because of the high frequency of invasive procedures. The current study investigated compliance with standard precautions among resident physicians working in gynecology and obstetrics. METHOD: A cross sectional study was conducted among resident physicians in gynecology and obstetrics in their first (R1), second (R2) and third (R3) years of residency at a teaching hospital in a city in Sao Paulo. A structured questionnaire that included demographic and professional aspects and the Standard Precautions Adherence Scale were used to collect data. Statistical analysis was performed using IBM(r) SPSS version 20. Ethical aspects were considered. RESULTS: Fifty eight resident physicians participated in the study. Of the enrolled participants, 27 (46.6%) were in R1, 12 (20.7%) were in R2 and 19 (32.8%) were in R3. The standard precautions compliance score was 4.1, which was classified as intermediate. There were no significant differences in the compliance scores of the resident physicians across the three years of residency (H=2.34, p=0.310). CONCLUSION: Compliance with standard precautions among resident physicians was intermediate. Preventive measures in clinical practice are not fully adopted in the specialty of gynecology and obstetrics. More important, many professionals claimed lack of sufficient training in standard precautions in the workplace. Such circumstances should draw the attention of hospital management with regard to occupational health risks. PMID- 27464296 TI - Evaluation of pulmonary sequestration with multidetector computed tomography angiography in a select cohort of patients: A retrospective study. AB - OBJECTIVES: This study aimed to evaluate the role of multidetector computed tomography angiography in diagnosing patients with pulmonary sequestration. METHODS: We retrospectively analyzed the computed tomography studies and clinical materials of 43 patients who had undergone preoperative multidetector computed tomography angiography in our hospital and had pathologically proven pulmonary sequestration. Each examination of pulmonary sequestration was reviewed for type, location, parenchymal changes, arterial supply and venous drainage on two dimensional and three-dimensional computed tomography images. RESULTS: Multidetector computed tomography successfully detected all pulmonary sequestrations in the 43 patients (100%). This included 40 patients (93.0%) with intralobar sequestration and 3 patients (7.0%) with extralobar sequestration. The locations of pulmonary sequestration were left lower lobe (28 cases, 70% of intralobar sequestrations), right lower lobe (12 cases, 30% of intralobar sequestrations) and costodiaphragmatic sulcus (3 cases). Cases of sequestered lung presented as mass lesions (37.2%), cystic lesions (32.6%), pneumonic lesions (16.3%), cavitary lesions (9.3%) and bronchiectasis (4.6%). The angioarchitecture of pulmonary sequestration, including feeding arteries from the thoracic aorta (86.1%), celiac truck (9.3%), abdominal aorta (2.3%) and left gastric artery (2.3%) and venous drainage into inferior pulmonary veins (86.0%) and the azygos vein system (14.0%), was visualized on multidetector computed tomography. Finally, the multidetector computed tomography angiography results of the sequestered lungs and angioarchitectures were surgically confirmed in all the patients. CONCLUSIONS: As a noninvasive modality, multidetector computed tomography angiography is helpful for making diagnostic decisions regarding pulmonary sequestration with high confidence and for visualizing the related parenchymal characteristics, arterial supply, and venous drainage features to help plan surgical strategies. PMID- 27464297 TI - The Incidence and Prevalence of Thromboangiitis Obliterans in Taiwan: A Nationwide, Population-based Analysis of Data Collected from 2002 to 2011. AB - OBJECTIVE: To estimate the incidence and prevalence of thromboangiitis obliterans in Taiwan in the period spanning from 2002 to 2011. METHODS: We identified all incident and prevalent cases with a diagnosis of thromboangiitis obliterans (International Classification of Diseases, Ninth Revision code 443.1) in the period spanning from 2002 to 2011 using Taiwan's National Health Insurance Research Database. We calculated the age- and sex-specific incidence and prevalence rates of thromboangiitis obliterans during the study period. RESULTS: From 2002 to 2011, 158 patients were diagnosed with thromboangiitis obliterans; of these, 76% were men. Most (63%) of the patients were <50 years old when they were first diagnosed. After reaching 20 years of age, the incidence rate increased with age and peaked among those aged >=60 years. The average incidence rate of thromboangiitis obliterans during the 2002-2011 period was 0.068 per 105 years. The incidence of thromboangiitis obliterans decreased with time, from 0.10 per 105 years in 2002 to 0.04 per 105 years in 2011. The prevalence increased from 0.26 * 10-5 in 2002 to 0.65 * 10-5 in 2011. CONCLUSION: This is the first epidemiologic study of thromboangiitis obliterans using claims data from a general population in Taiwan. This nationwide, population-based study found that the incidence and prevalence of thromboangiitis obliterans in Taiwan in the 2002 2011 period were lower than those in other countries before 2000. This study also revealed a trend of decreasing incidence with simultaneous increasing prevalence of thromboangiitis obliterans in Taiwan from 2002 to 2011. PMID- 27464298 TI - Accuracy of magnetic resonance imaging for measuring maturing cartilage: A phantom study. AB - OBJECTIVES: To evaluate the accuracy of magnetic resonance imaging measurements of cartilage tissue-mimicking phantoms and to determine a combination of magnetic resonance imaging parameters to optimize accuracy while minimizing scan time. METHOD: Edge dimensions from 4 rectangular agar phantoms ranging from 10.5 to 14.5 mm in length and 1.25 to 5.5 mm in width were independently measured by two readers using a steel ruler. Coronal T1 spin echo (T1 SE), fast spoiled gradient recalled echo (FSPGR) and multiplanar gradient-recalled echo (GRE MPGR) sequences were used to obtain phantom images on a 1.5-T scanner. RESULTS: Inter- and intra reader reliability were high for both direct measurements and for magnetic resonance imaging measurements of phantoms. Statistically significant differences were noted between the mean direct measurements and the mean magnetic resonance imaging measurements for phantom 1 when using a GRE MPGR sequence (512x512 pixels, 1.5-mm slice thickness, 5:49 min scan time), while borderline differences were noted for T1 SE sequences with the following parameters: 320x320 pixels, 1.5 mm slice thickness, 6:11 min scan time; 320x320 pixels, 4-mm slice thickness, 6:11 min scan time; and 512x512 pixels, 1.5-mm slice thickness, 9:48 min scan time. Borderline differences were also noted when using a FSPGR sequence with 512x512 pixels, a 1.5-mm slice thickness and a 3:36 min scan time. CONCLUSIONS: FSPGR sequences, regardless of the magnetic resonance imaging parameter combination used, provided accurate measurements. The GRE MPGR sequence using 512x512 pixels, a 1.5-mm slice thickness and a 5:49 min scan time and, to a lesser degree, all tested T1 SE sequences produced suboptimal accuracy when measuring the widest phantom. PMID- 27464299 TI - Temporal profile of intestinal tissue expression of intestinal fatty acid-binding protein in a rat model of necrotizing enterocolitis. AB - OBJECTIVES: Necrotizing enterocolitis is a severe multifactorial intestinal disorder that primarily affects preterm newborns, causing 20-40% mortality and morbidity. Intestinal fatty acid-binding protein has been reported to be a biomarker for the detection of intestinal injuries. Our aim was to assess intestinal tissue injury and the molecular expression of intestinal fatty acid binding protein over time in a necrotizing enterocolitis model. METHODS: A total of 144 Newborn rats were divided into two groups: 1) Control, which received breastfeeding (n=72) and 2) Necrotizing Enterocolitis, which received formula feeding and underwent hypoxia and hypothermia (n=72). A total of six time points of ischemia (2 times a day for 3 days; 12 pups for each time point) were examined. Samples were collected for analysis of body weight, morphological and histological characteristics, intestinal weight, intestinal weight/body weight ratio, injury grade, and intestinal fatty acid-binding protein levels. RESULTS: Body and intestinal weights were lower in the Necrotizing Enterocolitis group than in the Control group (p<0.005 and p<0.0005, respectively). The intestinal weight/body weight ratio was higher in the Necrotizing Enterocolitis group than in the Control group (p<0.005) only at the sixth ischemia time point. The Necrotizing Enterocolitis group displayed higher expression of intestinal fatty acid-binding protein (p<0.0005) and showed greater tissue damage than the Control group. CONCLUSION: Intestinal fatty acid-binding protein was an efficient marker of ischemic injury to the intestine and a good correlation was demonstrated between the time of ischemic injury and the grade of intestinal injury. PMID- 27464300 TI - High Performance Fe Porphyrin/Ionic Liquid Co-catalyst for Electrochemical CO2 Reduction. AB - The efficient and selective catalytic reduction of CO2 is a highly promising process for both of the storage of renewable energy as well as the production of valuable chemical feedstocks. In this work, we show that the addition of an ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate, in an aprotic electrolyte containing a proton source and FeTPP, promotes the in situ formation of the [Fe(0) TPP](2-) homogeneous catalyst at a less negative potential, resulting in lower overpotentials for the CO2 reduction (670 mV) and increased kinetics of electron transfer. This co-catalysis exhibits high Faradaic efficiency for CO production (93 %) and turnover number (2 740 000 after 4 hour electrolysis), with a four-fold increase in turnover frequency (TOF) when compared with the standard system without the ionic liquid. PMID- 27464301 TI - A Deterministic Projector Configuration Interaction Approach for the Ground State of Quantum Many-Body Systems. AB - In this work we propose a novel approach to solve the Schrodinger equation which combines projection onto the ground state with a path-filtering truncation scheme. The resulting projector configuration interaction (PCI) approach realizes a deterministic version of the full configuration interaction quantum Monte Carlo (FCIQMC) method [Booth, G. H.; Thom, A. J. W.; Alavi, A. J. Chem. Phys. 2009, 131, 054106]. To improve upon the linearized imaginary-time propagator, we develop an optimal projector scheme based on an exponential Chebyshev expansion in the limit of an infinite imaginary time step. After writing the exact projector as a path integral in determinant space, we introduce a path filtering procedure that truncates the size of the determinantal basis and approximates the Hamiltonian. The path filtering procedure is controlled by one real threshold that determines the accuracy of the PCI energy and is not biased toward any determinant. Therefore, the PCI approach can equally well describe static and dynamic electron correlation effects. This point is illustrated in benchmark computations on N2 at both equilibrium and stretched geometries. In both cases, the PCI achieves chemical accuracy with wave functions that contain less than 0.5% determinants of full CI space. We also report computations on the ground state of C2 with up to quaduple-zeta basis sets and wave functions as large as 200 million determinants, which allow a direct comparison of the PCI, FCIQMC, and density matrix renormalization group (DMRG) methods. The size of the PCI wave function grows modestly with the number of unoccupied orbitals, and its accuracy may be tuned to match that of FCIQMC and DMRG. PMID- 27464302 TI - Childhood body mass index in adolescent-onset anorexia nervosa. AB - OBJECTIVE: Although weight history is relevant in predicting eating disorder symptom severity, little is known about its role in the etiology of anorexia nervosa (AN). This study aimed to determine whether BMI or BMI trajectory differed between individuals who later developed adolescent-onset AN and a comparison group of HCs between school grades 1 through 6. METHOD: This study was based on longitudinal data that identified 51 adolescents with AN and 51 matched HCs. Cases were identified through community screening in Sweden and included individuals born in 1969 through 1977. Measured weights and heights were retrieved and BMIs and weight trajectories of the AN and HC groups were compared using growth curve analysis. Main outcome measures included measured BMI and BMI trajectories from grades 1-6. Secondary outcomes examined included ponderal index at birth and maternal body weight. RESULTS: Individuals who later developed AN had higher BMIs than HCs between grades 1 and 6, by an average of 1.42 BMI-units. There was no difference in rate of weight gain between groups. Ponderal index at birth was higher for the AN as compared with HC group. Maternal weight did not differ significantly between groups. DISCUSSION: These findings, combined with those previously reported on the premorbid BMIs of those with bulimia nervosa, suggest that a predisposition toward elevated premorbid BMIs during childhood characterizes those who later develop anorexia or bulimia nervosa. These findings are consistent with a transdiagnostic perspective and suggest shared risk factors for AN and obesity. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1002-1009). PMID- 27464303 TI - Serum NSE, MMP-9 and HER2 extracellular domain are associated with brain metastases in metastatic breast cancer patients: predictive biomarkers for brain metastases? AB - Breast cancer (BC) is the second most common cause of brain metastases (BM). Predictive factors for BM have been widely studied in metastatic BC; however, there is no known serum tumor marker to accurately predict BM. Elevated serum S100beta protein and neuron-specific enolase (NSE) could reflect the brain damages induced by BM. Matrix metalloproteinase 9 (MMP-9) is involved in tumor invasion and metastatic dissemination, including BM. Also, HER2-amplified BC were shown to have a particular tropism for central nervous system (CNS). This study evaluated the correlation of these biomarkers with the presence of BM in metastatic BC patients. In this case-control study, 88 consecutive metastatic BC patients with BM (BM group) treated in our institution (2008-2015) were retrospectively selected, based on the availability of frozen serum samples for tumor marker determination. Patients were matched by age, tumor biology and number of previous metastatic chemotherapy lines to 162 metastatic BC patients without CNS involvement (control group). Serum NSE, MMP-9 and HER2 extracellular domain (ECD) levels were significantly higher in the BM group (p = 0.0051, p = 0.0062 and p = 0.0057, respectively). In multivariate analysis, serum HER2 and MMP-9 levels accurately discriminated patients with BM: odds ratios 4.4 (p < 0.001; 95%CI: 1.9-9.6) for HER2 ECD and 3.5 (p = 0.005; 95%CI: 1.5-8.4) for MMP 9. In multivariate analysis, HER2 ECD and NSE serum levels were independent prognostic factors in patients with BM. Serum HER2 ECD and MMP-9 appear to be associated with BM in metastatic BC patients. Their predictive value for BM still needs to be evaluated in further prospective studies. PMID- 27464304 TI - Primary Ciliary Dyskinesia: First Health-related Quality-of-Life Measures for Pediatric Patients. AB - RATIONALE: Primary ciliary dyskinesia (PCD) is a rare disease. There are no available data on disease-specific pediatric patient-reported outcomes. OBJECTIVES: Our objective was to create developmentally appropriate, health related quality-of-life questionnaires (QOL-PCD) for children (6-12 yr) and adolescents (13-17 yr) with PCD and a parent proxy measure. METHODS: The QOL-PCD was developed using a cross-cultural protocol-driven approach satisfying both North American and European drug regulatory agency guidelines. A conceptual framework was generated by literature review, focus groups (expert clinicians and patients/parents), and open-ended interviews with children, adolescents, and parents of patients with PCD. We recruited participants from international research consortiums, PCD clinics, and patient advocacy groups, aiming for representation of a wide spectrum of disease severity, sociodemographic status, and ethnicity. Qualitative interviews were conducted by trained and experienced research assistants and psychologists. Transcripts were content-analyzed with Atlas.ti/NVivo to assess saturation of content. A self-completed item relevance survey was administered to E.U. PARTICIPANTS: Qualitative and quantitative data were used to construct draft instruments. Questionnaires were further refined after cognitive interviews. MEASUREMENTS AND MAIN RESULTS: Focus groups (n = 62 experts; n = 20 patients/parents) and open-ended interviews with patients/parents (n = 69; 34 males; age at diagnosis, 0-15 yr; FEV1, 58-118% predicted) revealed a wide spectrum of issues unique to this population. Content analysis of transcripts identified the following domains, depending on age: Respiratory Symptoms, Physical Functioning, Emotional Functioning, Treatment Burden, Ears and Hearing, Sinus Symptoms, Social Functioning, Role Functioning, Vitality, Health Perceptions, School Functioning, and Eating and Weight. Various items were retained in questionnaires, based on age and role of respondent: 37, 43, and 41 items for children, adolescents, and parent proxy, respectively. The item relevance survey (n = 57) yielded results similar to those of open-ended interviews. Cognitive testing (n = 47; 20 males; age at diagnosis, 0-11 yr; FEV1, 49-124% predicted) confirmed that items and response choices were clear and understood by respondents, and that all relevant items were included. CONCLUSIONS: The QOL-PCD measures, developed using rigorous, protocol-driven methods and international collaborations, have demonstrated content validity and cross-cultural equivalence for implementation in English-speaking populations. Psychometric testing is underway to determine their measurement properties for evaluating clinical interventions and informing quality of care. PMID- 27464305 TI - Thunderstorms Increase Mercury Wet Deposition. AB - Mercury (Hg) wet deposition, transfer from the atmosphere to Earth's surface by precipitation, in the United States is highest in locations and seasons with frequent deep convective thunderstorms, but it has never been demonstrated whether the connection is causal or simple coincidence. We use rainwater samples from over 800 individual precipitation events to show that thunderstorms increase Hg concentrations by 50% relative to weak convective or stratiform events of equal precipitation depth. Radar and satellite observations reveal that strong convection reaching the upper troposphere (where high atmospheric concentrations of soluble, oxidized mercury species (Hg(II)) are known to reside) produces the highest Hg concentrations in rain. As a result, precipitation meteorology, especially thunderstorm frequency and total rainfall, explains differences in Hg deposition between study sites located in the eastern United States. Assessing the fate of atmospheric mercury thus requires bridging the scales of global transport and convective precipitation. PMID- 27464308 TI - STARDing Again: Revised Guidelines for Reporting Information in Studies of Diagnostic Test Accuracy. PMID- 27464306 TI - Anti-inflammatory and analgesic activity of carnosol and carnosic acid in vivo and in vitro and in silico analysis of their target interactions. AB - BACKGROUND AND PURPOSE: The diterpenoids carnosol (CS) and carnosic acid (CA) from Salvia spp. exert prominent anti-inflammatory activities but their molecular mechanisms remained unclear. Here we investigated the effectiveness of CS and CA in inflammatory pain and the cellular interference with their putative molecular targets. EXPERIMENTAL APPROACH: The effects of CS and CA in different models of inflammatory pain were investigated. The inhibition of key enzymes in eicosanoid biosynthesis, namely microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5 lipoxygenase (5-LO) was confirmed by CS and CA, and we determined the consequence on the eicosanoid network in activated human primary monocytes and neutrophils. Molecular interactions and binding modes of CS and CA to target enzymes were analyzed by docking studies. KEY RESULTS: CS and CA displayed significant and dose-dependent anti-inflammatory and anti-nociceptive effects in carrageenan induced mouse hyperalgesia 4 h post injection of the stimuli, and also inhibited the analgesic response in the late phase of the formalin test. Moreover, both compounds potently inhibited cell-free mPGES-1 and 5-LO activity and preferentially suppressed the formation of mPGES-1 and 5-LO-derived products in cellular studies. Our in silico analysis for mPGES-1 and 5-LO supports that CS and CA are dual 5-LO/mPGES-1 inhibitors. CONCLUSION AND IMPLICATIONS: In summary, we propose that the combined inhibition of mPGES-1 and 5-LO by CS and CA essentially contributes to the bioactivity of these diterpenoids. Our findings pave the way for a rational use of Salvia spp., traditionally used as anti inflammatory remedy, in the continuous expanding context of nutraceuticals. LINKED ARTICLES: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. PMID- 27464307 TI - Development of a Single-Chain Peptide Agonist of the Relaxin-3 Receptor Using Hydrocarbon Stapling. AB - Structure-activity studies of the insulin superfamily member, relaxin-3, have shown that its G protein-coupled receptor (RXFP3) binding site is contained within its central B-chain alpha-helix and this helical structure is essential for receptor activation. We sought to develop a single B-chain mimetic that retained agonist activity. This was achieved by use of solid phase peptide synthesis together with on-resin ruthenium-catalyzed ring closure metathesis of a pair of judiciously placed i,i+4 alpha-methyl, alpha-alkenyl amino acids. The resulting hydrocarbon stapled peptide was shown by solution NMR spectroscopy to mimic the native helical conformation of relaxin-3 and to possess potent RXFP3 receptor binding and activation. Alternative stapling procedures were unsuccessful, highlighting the critical need to carefully consider both the peptide sequence and stapling methodology for optimal outcomes. Our result is the first successful minimization of an insulin-like peptide to a single-chain alpha helical peptide agonist which will facilitate study of the function of relaxin-3. PMID- 27464309 TI - Genetic polymorphisms influence on the response to clopidogrel in peripheral artery disease patients following percutaneous transluminal angioplasty. AB - AIM: To study the association of ABCB1 and CYP2C19 polymorphisms and the clopidogrel response in Spanish peripheral artery disease patients following percutaneous transluminal angioplasty (PTA) and to perform a meta-analysis. MATERIALS & METHODS: 72 patients were recruited and 122 patients included in the meta-analysis. We evaluated the effect of ABCB1 3435 C>T, CYP2C19*2 and CYP2C19*3 and primary end point (restenosis/occlusion of the treated lesions) during 12 months after PTA. RESULTS: CYP2C19*2 and/or ABCB1 TT patients were associated with primary end point (OR: 5.00; 95% CI: 1.75-14.27). The meta-analysis confirmed the association of CYP2C19*2 and new atherothrombotic ischemic events (OR: 5.40; 95% CI: 2.30-12.70). CONCLUSION: The CYP2C19 and ABCB1 polymorphisms could be genetic markers of cardiovascular events in peripheral artery disease patients following PTA treated with clopidogrel. PMID- 27464311 TI - Oligomeric Conjugated Polyelectrolytes Display Site-Preferential Binding to an MS2 Viral Capsid. AB - Opportunistic bacteria and viruses are a worldwide health threat prompting the need to develop new targeting modalities. A class of novel synthetic poly(phenylene ethynylene) (PPE)-based oligomeric conjugated polyelectrolytes (OPEs) have demonstrated potent wide-spectrum biocidal activity. A subset of cationic OPEs display high antiviral activity against the MS2 bacteriophage. The oligomers have been found to inactivate the bacteriophage and perturb the morphology of the MS2 viral capsid. However, details of the initial binding and interactions between the OPEs and the viruses are not well understood. In this study, we use a multiscale computational approach, including random sampling, molecular dynamics, and electronic structure calculations, to gain an understanding of the molecular-level interactions of a series of OPEs that vary in length, charge, and functional groups with the MS2 capsid. Our results show that OPEs strongly bind to the MS2 capsid protein assembly with binding energies of up to -30 kcal/mol. Free-energy analysis shows that the binding is dominated by strong van der Waals interactions between the hydrophobic OPE backbone and the capsid surface and strong electrostatic free energy contributions between the OPE charged moieties and charged residues on the capsid surface. This knowledge provides molecular-level insight into how to tailor the OPEs to optimize viral capsid disruption and increase OPE efficacy to target amphiphilic protein coats of icosahedral-based viruses. PMID- 27464310 TI - Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model. AB - PURPOSE: The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, and ATM. METHODS: The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods. RESULTS: The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. CONCLUSIONS: The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/).Genet Med 18 12, 1190 1198. PMID- 27464312 TI - Addressing the High Costs of Pancreaticoduodenectomy at Safety-Net Hospitals. AB - Importance: Safety-net hospitals care for vulnerable patients, providing complex surgery at increased costs. These hospitals are at risk due to changing health care reimbursement policies and demand for better value in surgical care. Objective: To model different techniques for reducing the cost of complex surgery performed at safety-net hospitals. Design, Setting, and Participants: Hospitals performing pancreaticoduodenectomy (PD) were queried from the University HealthSystem Consortium database (January 1, 2009, to December 31, 2013) and grouped according to safety-net burden. A decision analytic model was constructed and populated with clinical and cost data. Sensitivity analyses were then conducted to determine how changes in the management or redistribution of patients between hospital groups affected cost. Main Outcomes and Measures: Overall cost per patient after PD. Results: During the 5 years of the study, 15 090 patients underwent PD. Among safety-net hospitals, low-burden hospitals (LBHs), medium-burden hospitals (MBHs), and high-burden hospitals (HBHs) treated 4220 (28.0%), 9505 (63.0%), and 1365 (9.0%) patients, respectively. High-burden hospitals had higher rates of complications or comorbidities and more patients with increased severity of illness. Perioperative mortality was twice as high at HBHs (3.7%) than at LBHs (1.6%) and MBHs (1.7%) (P < .001). In the base case, when all clinical and cost data were considered, PD at HBHs cost $35 303 per patient, 30.1% and 36.2% higher than at MBHs ($27 130) and LBHs ($25 916), respectively. Reducing perioperative complications or comorbidities by 50% resulted in a cost reduction of up to $4607 for HBH patients, while reducing mortality rates had a negligible effect. However, redistribution of HBH patients to LBHs and MBHs resulted in significantly more cost savings of $9155 per HBH patient, or $699 per patient overall. Conclusions and Relevance: Safety-net hospitals performing PD have inferior outcomes and higher costs, and improving perioperative outcomes may have a nominal effect on reducing these costs. Redirecting patients away from safety-net hospitals for complex surgery may represent the best option for reducing costs, but the implementation of such a policy will undoubtedly meet significant challenges. PMID- 27464313 TI - Psychotherapies for Panic Disorder: A Tale of Two Sites. AB - OBJECTIVE: To compare cognitive-behavioral therapy (CBT), panic-focused psychodynamic psychotherapy (PFPP), and applied relaxation training (ART) for primary DSM-IV panic disorder with and without agoraphobia in a 2-site randomized controlled trial. METHOD: 201 patients were stratified for site and DSM-IV agoraphobia and depression and were randomized to CBT, PFPP, or ART (19-24 sessions) over 12 weeks in a 2:2:1 ratio at Weill Cornell Medical College (New York, New York) and University of Pennsylvania ("Penn"; Philadelphia, Pennsylvania). Any medication was held constant. RESULTS: Attrition rates were ART, 41%; CBT, 25%; and PFPP, 22%. The most symptomatic patients were more likely to drop out of ART than CBT or PFPP (P = .013). Outcome analyses revealed site-by treatment interactions in speed of Panic Disorder Severity Scale (PDSS) change over time (P = .013). At Cornell, no differences emerged on improvement on the primary outcome, estimated speed of change over time on the PDSS; at Penn, ART (P = .025) and CBT (P = .009) showed greater improvement at treatment termination than PFPP. A site-by-treatment interaction (P = .016) for a priori-defined response (40% PDSS reduction) showed significant differences at Cornell: ART 30%, CBT 65%, PFPP 71% (P = .007), but not at Penn: ART 63%, CBT 60%, PFPP 48% (P = .37). Penn patients were more symptomatic, differed demographically from Cornell patients, had a 7.2-fold greater likelihood of taking medication, and had a 28 fold greater likelihood of taking benzodiazepines. However, these differences did not explain site-by-treatment interactions. CONCLUSIONS: All treatments substantially improved panic disorder with or without agoraphobia, but patients, particularly the most severely ill, found ART less acceptable. CBT showed the most consistent performance across sites; however, the results for PFPP showed the promise of psychodynamic psychotherapy for this disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00353470. PMID- 27464315 TI - Introduction. PMID- 27464314 TI - Nonmedical Stimulant Use in College Students: Association With Attention Deficit/Hyperactivity Disorder and Other Disorders. AB - Objective: The nonmedical use of stimulants (misuse) in the college setting remains of utmost public health and clinical concern. The objective of this study was to evaluate comprehensively the characteristics of college students who misused stimulants, attending to rates of attention-deficit/hyperactivity disorder (ADHD), other psychopathology, and substance use disorders. Methods: The data presented are from a cross-sectional study of college students who misused prescription stimulant medications (not including cocaine or methamphetamine) and controls (college students without stimulant misuse). Between May 2010 and May 2013, college students were assessed blindly for psychopathology and substance use disorder by way of Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P) and completion of self report questionnaires. Results: The analysis included 198 controls (mean +/- SD age = 20.7 +/- 2.6 years) and 100 stimulant misusers (20.7 +/- 1.7 years). Misusers, when compared to controls, were more likely to endorse alcohol, drug, alcohol + drug, and any substance use disorder (all P values < .01). When a subset of stimulant misusers (n = 58) was examined, 67% had a full or subthreshold prescription stimulant use disorder. Misusers also had higher rates of conduct disorder (10% vs 3%; P = .02) and ADHD (including subthreshold cases; 27% vs 16%; P = .02) in addition to lower Global Assessment of Functioning score (P < .01). Higher rates of misuse of immediate-release-relative to extended release-stimulants were reported. Conclusions: Our data suggest that, compared to controls, college students who misuse stimulant medications are more likely to have ADHD, conduct disorder, stimulant and other substance use disorder, and overall dysfunction. PMID- 27464317 TI - Cardiometabolic Risks in Schizophrenia and Directions for Intervention, 1: Magnitude and Moderators of the Problem. AB - Patients with schizophrenia have increased prevalence rates for many cardiac risk factors. As an example, the metabolic syndrome is common in schizophrenia, with elevated rates for the syndrome and its components evident in first-episode schizophrenia patients, itself. These rates are further elevated in multiepisode patients. Weight gain is a clinical marker of cardiometabolic risk. Antipsychotic drug treatment may drive at least part of the increased cardiometabolic risk; the effects are externally evident in the form of weight gain, with different drugs having different effects on weight and metabolic parameters. Finally, sedentariness and smoking are 2 common behaviors that increase cardiometabolic risks in schizophrenia. It is important for psychiatrists who treat schizophrenia to evaluate the cardiometabolic risks in their patients so that appropriate lifestyle and pharmacologic interventions can be planned. PMID- 27464316 TI - Sexual Functioning in Adolescents With Major Depressive Disorder. AB - OBJECTIVE: To examine sexual functioning in adolescents with depression. METHODS: Between September 2010 and March 2014, 235 participants who were between 15 and 20 years old and were unmedicated or within 1 month of beginning antidepressant treatment completed the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Changes in Sexual Functioning Questionnaire (CSFQ). They were also assessed to establish the presence of a DSM-IV-TR major depressive episode (MDE). The Student t test and chi2 test were used to compare continuous and categorical variables, respectively, across participants with versus without MDE. Multivariable linear regression analysis examined the association between depression and sexual functioning. RESULTS: After the investigators controlled for age, female sex, antidepressant use, and the presence of generalized anxiety disorder, the presence of MDE was associated with a lower score on the CSFQ overall (P < .0007) and on its desire (P < .09), arousal (P < .001), and orgasm (P < .007) subscales. Antidepressants were not associated with sexual functioning either in the sample overall or in those with MDE. Beck Depression Inventory items related to affective symptoms (P < .03), rather than those tapping into neurovegetative or cognitive functioning, accounted for the association between depression and lower sexual functioning. Furthermore, with higher BDI scores, males exhibited a steeper decline than females in both the CSFQ total score and the desire subscale (sex * BDI score interaction effect: P < .03). Anxiety was not significantly associated with sexual functioning. CONCLUSIONS: Major depressive disorder in older adolescents is associated with lower sexual functioning, particularly in males. This appears most related to affective symptoms. The potential impact of such impairment on future sexual functioning deserves further examination. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02147184. PMID- 27464318 TI - Group A Streptococcal Infections Are Associated With Increased Risk of Pediatric Neuropsychiatric Disorders: A Taiwanese Population-Based Cohort Study. AB - OBJECTIVE: This study evaluated the association between group A streptococcal (GAS) infections and the risks of developing tic disorders, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a follow-up cohort study in 2014 using Taiwan's National Health Insurance Research Database. The study cohort consisted of patients younger than 18 years with newly diagnosed GAS infection (ICD-9-CM codes 034 [streptococcal sore throat and scarlet fever] and 482.31 [pneumonia due to Streptococcus, group A]) from 2001 to 2010. All patients having GAS infection codes between 1996 and 2000 were excluded. We assessed the patients' risks of developing tic disorders, OCD, and ADHD (ICD-9-CM codes 300.3 [obsessive-compulsive disorders], 301.4 [obsessive-compulsive personality disorder], 307.2 [tic disorder, unspecified], and 314 [attention deficit disorder]) and compared these risks with those of a control cohort. The primary outcomes of this study were the overall neuropsychiatric disorder occurrence and the occurrence of separate subtypes. RESULTS: We examined 2,596 patients and 25,960 controls. The incidence of neuropsychiatric disorders in the GAS infection cohort (60.42 per 10,000 person years) was significantly higher than that in the comparison cohort (49.32 per 10,000 person-years) (hazard ratio [HR] = 1.22; 95% CI, 1.00-1.49). The largest increased risk was for tic disorders (HR = 1.63; 95% CI, 1.02-2.62). Patients hospitalized for GAS infection had a 1.96-fold higher risk of neuropsychiatric disorders than did people without GAS infection (HR = 1.96; 95% CI, 1.23-3.12), and there was no difference in risk between outpatients with GAS infection and people without GAS infection (HR = 1.14; 95% CI, 0.92-1.41). Patients with moderate or high frequencies of GAS infection-related clinic visits had much higher risks of developing a neuropsychiatric disorder and, specifically, tic disorders and ADHD (all P values for trend < .05). These risks were not increased in patients with a low frequency of clinic visits. CONCLUSIONS: Our results confirmed an association between previous group A streptococcal infection and neuropsychiatric disorders. PMID- 27464319 TI - Anger and Impulsivity Among Japanese Adolescents: A Nationwide Representative Survey. AB - OBJECTIVE: This study aimed to clarify the prevalence of anger and impulsivity and its associated factors through a nationwide survey of junior and senior high school adolescent students in Japan. METHODS: A self-administered questionnaire covering (1) personal data, (2) lifestyle, (3) mental health status, and (4) feelings of anger and impulsivity was distributed to junior and senior high school students in Japan. Among the total of 10,955 junior high schools and 5,115 senior high schools nationwide, 130 and 110 were randomly selected, respectively. Of those, 92 junior and 80 senior high schools participated in the survey. The survey period was from December 2008 to the end of January 2009. A total of 95,680 questionnaires were collected. After excluding invalid responses, the remaining 94,777 responses (response rate: 62.3%) were analyzed. RESULTS: From the questions regarding anger and impulsivity, 8.7% (95% CI, 8.5%-8.9%) and 7.5% (95% CI, 7.3%-7.7%) of the participants were considered to have experienced intense anger and impulsivity, respectively. Logistic regression analysis indicated that the odds ratios for experiencing intense feelings of anger were significantly higher (all P values < .05) among students who smoked, consumed alcohol, skipped breakfast, did not wish to go to university, had short sleep duration, had decreased positive feelings, had increased depressive feelings, or used mobile phones for longer hours. The odds ratios for experiencing intense impulsivity were significantly higher among students who smoked, consumed alcohol, skipped breakfast, did not participate in club activities, had short sleep duration, had decreased positive feelings, had increased depressive feelings, or used mobile phones for longer hours. CONCLUSIONS: The results suggest that healthy lifestyle habits, good sleep habits, and improved mental health are important for preventing intense feelings of anger and impulsivity among adolescents. PMID- 27464320 TI - Psychometric Reevaluation of the Columbia-Suicide Severity Rating Scale: Findings From a Prospective, Inpatient Cohort of Severely Mentally Ill Adults. AB - OBJECTIVE: Accurate prediction of suicide remains elusive due to lack of predictive measures. Given the Columbia-Suicide Severity Rating Scale's (C-SSRS) emerging "gold-standard" status for risk assessment, studies are needed to assess its psychometric properties, particularly predictive validity. The current study adds to the limited literature by assessing the C-SSRS's internal consistency, factor structure, concurrent validity, and predictive validity. METHODS: In this longitudinal study of 1,055 adults with DSM-IV diagnoses consecutively admitted to a specialized psychiatric hospital between July 1, 2012, and June 30, 2014, patients completed standardized assessments, including the C-SSRS, at admission and 2, 12, and 24 weeks postdischarge. RESULTS: The C-SSRS evidenced excellent internal consistency (ordinal alpha = .95). Principal components analysis (PCA) revealed a 2-factor solution, accounting for 65.3% of the variance across items. The severity of ideation and behavioral items loaded onto the first factor, and the intensity of ideation items loaded onto the second factor. The total score, factors, and the most severe ideation single item were moderately correlated with other measures of suicidality (0.27 <= r <= 0.58; P < .0001). The summary score from the ideation/behavior factor was found to be modestly correlated with any suicide-related behavior within the 6 months following hospitalization. Receiver operator characteristics indicated that the C-SSRS performed adequately in correctly classifying any suicide-related behavior within 6 months of discharge from the hospital (AUC = 0.757, P < .001) with the total score and summary score from the ideation/behavior factor providing the best balance between sensitivity (0.694) and specificity (0.652-0.674). CONCLUSIONS: This study is the first to assess the factor structure of the C-SSRS in a large, high-risk sample. The measure has solid psychometric properties and merits use as a suicide risk assessment measure. PMID- 27464321 TI - Acute Swedish Massage Monotherapy Successfully Remediates Symptoms of Generalized Anxiety Disorder: A Proof-of-Concept, Randomized Controlled Study. AB - OBJECTIVE: Generalized anxiety disorder (GAD) is a prevalent and costly disorder for which many patients may prefer nontraditional treatment. A proof-of-concept study of was conducted to evaluate the acute effects of Swedish massage therapy (SMT) as a monotherapy for the treatment of subjects with GAD. METHODS: A randomized, single-masked, clinical trial was conducted between March 2012 and May 2013 at the Mood and Anxiety Disorders Program of Emory University. Forty seven currently untreated subjects with a DSM-IV diagnosis of GAD were randomly assigned to twice-weekly SMT versus a light touch control condition for 6 weeks. The primary outcome measure was reduction in Hamilton Anxiety Rating Scale (HARS) scores after 6 weeks of treatment for SMT versus light touch, as determined by mixed model repeated-measures analysis of 40 evaluable subjects. RESULTS: Mean HARS baseline scores were 20.05 (SD = 3.34) for SMT and 19.58 (SD = 4.90) for light touch. At week 6, the difference in mean (standard error of the mean [SEM]) HARS score reduction was 3.26 points (SMT: -11.67 [1.09]; light touch: -8.41 [1.01]; t106 = -2.19; P = .030; effect size = -0.69). Treatment group differences were significant (P < .05) starting at the end of week 3. CONCLUSION: This first monotherapy trial suggests that a complementary and alternative manual therapy, SMT, is an effective acute treatment for GAD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01337713. PMID- 27464322 TI - Prevalence of and Factors Associated With Sleep-Related Eating Disorder in Psychiatric Outpatients Taking Hypnotics. AB - OBJECTIVE: To clarify the prevalence and clinical features of sleep-related eating disorder (SRED) in psychiatric outpatients taking hypnotics as well as factors associated with the disorder. METHODS: From February 1, 2012, to February 29, 2012, a cross-sectional study was undertaken. A questionnaire addressing demographics, the Japanese version of the Pittsburgh Sleep Quality Index (PSQI), presence of abnormal behavior during sleep focusing on SRED and sleepwalking, and duration of hypnotic medication and subjective side effects of the drug was distributed to psychiatric outpatients who were taking hypnotics at the time of the survey. RESULTS: Of 1,318 patients taking hypnotics, 1,048 patients (79.5%) provided valid responses, and 88 of them (8.4%) had experienced SRED. The SRED group was significantly younger, had a significantly higher total PSQI score, and took higher bedtime diazepam-equivalent doses of hypnotics than the non-SRED group (P < .01 for all comparisons). In the SRED group, subjective side effects due to hypnotics were present at significantly higher proportions than in the non SRED group. Multiple logistic regression analysis showed that younger age (adjusted odds ratio [aOR] = 0.98, 95% CI = 0.96-0.99, P = .021), taking 2 or more kinds of antipsychotics (aOR = 3.41, 95% CI = 1.93-6.05, P < .001), and the bedtime diazepam-equivalent dose of a hypnotic (aOR = 1.03, 95% CI = 1.01-1.05, P = .039) were significantly associated with the experience of SRED. CONCLUSION: The prevalence of SRED in psychiatric outpatients taking hypnotics is elevated, particularly in younger patients, and the hypnosedative effects of the drugs could be responsible for the occurrence of the disorder in this population. PMID- 27464323 TI - Sudden-Onset Catatonia Following Clozapine Withdrawal: A Case Report. PMID- 27464324 TI - A Case of Creutzfeldt-Jakob Disease Presenting as Catatonia. PMID- 27464325 TI - Greater Than "Even Greater" Need? PMID- 27464326 TI - Does the Clinical Benefit of Ketamine Treatment Offer Any Clues to Autism Spectrum Disorder Etiology? PMID- 27464327 TI - Who Gets ECT Without Failing Medication First? PMID- 27464328 TI - Drs Haq and Mickey Reply. PMID- 27464329 TI - Smoking and Suicide Mortality Risk in Alcohol-Dependent Individuals. PMID- 27464330 TI - Drs Hung and Kuo Reply. PMID- 27464331 TI - Importance of Restoring Function in Patients With Major Depressive Disorder. AB - Patients with depression experience symptoms that hinder their ability to function at home, at work, and in social settings. Even when mood symptoms improve, patients' function may not return to normal. Clinicians must make restoration of function a treatment goal along with symptom remission. Rating scales that assess function can help clinicians monitor areas such as work performance, role fulfillment, social activities, and more. The process of treating functional impairments will take time and may require specific interventions, but patients will feel "recovered" only when these areas are restored. PMID- 27464332 TI - Benign Ethnic Neutropenia and Clozapine Use: A Systematic Review of the Evidence and Treatment Recommendations. AB - OBJECTIVE: To evaluate the epidemiology, pathobiology, and management of benign ethnic neutropenia and determine the extent to which these factors should influence measures designed to avoid clozapine-induced agranulocytosis. DATA SOURCES: A structured MEDLINE search with no language limitation was performed from database inception until March 31, 2015, using the terms clozapine and benign ethnic neutropenia. Retrieved articles were cross-checked for additional relevant studies. STUDY SELECTION: Included in the study were articles that reported on the prevalence, etiology, and complications of benign ethnic neutropenia and the hematologic outcome of clozapine treatment in patients with this condition. DATA EXTRACTION: Study results that documented the epidemiology, pathobiology, and clozapine utilization in persons of African, Arabian, and Mediterranean descent with a neutrophil count in the 1,000-1,800/mm3 range. RESULTS: The search identified 342 publications. Forty-two articles described the epidemiology, pathobiology, and management of benign ethnic neutropenia. Of these, 12 articles described patients with benign ethnic neutropenia whose neutrophil count decreased during treatment with clozapine. Persons with benign ethnic neutropenia do not have signs of impaired phagocytosis, and the frequency, severity, and outcome of their infections are similar to those observed in the general population. These features suggest that a neutrophil count > 1,000/mm3 is safe for initiating and/or resuming clozapine therapy. CONCLUSIONS: The presence of benign ethnic neutropenia should not prevent treatment with clozapine. Patients with benign ethnic neutropenia who develop a clozapine-induced decrease in the neutrophil count, but have no evidence of infection or impaired phagocytosis, may resume clozapine as soon as they have > 1,000 neutrophils/mm3. PMID- 27464334 TI - Prevalence and Antimicrobial Resistance of Salmonella Isolated from Cattle Feces in United States Feedlots in 2011. AB - The objective of this study was to determine the prevalence and characteristics of Salmonella spp. isolated from feces of cattle in feedlots in the United States. Fecal samples were collected from up to three pens of cattle in each of 68 feedlots in 12 states. Samples included up to 25 individual fecal pats from the pen floors and up to five composite samples from the floors of the same pens. The prevalence of Salmonella-positive samples was 9.1% (460/5050) and 11.3% (114/1009) for individual and composite samples, respectively. The prevalences of Salmonella at the pen level were 35.6% (72/202) and 22.8% (46/202) for individual and composite samples, respectively. Dietary factors, including inclusion of cottonseed hulls, coccidiostats, and antimicrobial drugs, were associated with differences in prevalence of Salmonella isolation. Overall, 32 serotypes of Salmonella were identified, but six serotypes accounted for 69.1% (495/716) of the isolates. Nearly two-thirds (64.7%, 44/68) of feedlots had at least one positive sample. All isolates were evaluated for susceptibility to a panel of 15 antimicrobial drugs. Most isolates (74.4%, 533/716) were susceptible to all antimicrobial drugs in the panel. When resistance was detected, it was most commonly to tetracycline (21.7%, 155/716 of isolates) or sulfisoxazole (12.4%, 89/716 of isolates). Less than 10% of the isolates were resistant to any other antimicrobials in the panel. The results of this study indicate that the prevalence of Salmonella in individual fecal samples was less than 10%, but that Salmonella is widely distributed among feedlot cattle. Furthermore, when Salmonella is present in feedlot cattle, there is a low occurrence of antimicrobial resistance with the exception of tetracycline and sulfisoxazole. More research is indicated to understand the ecology of Salmonella and antimicrobial resistance, when present, in cattle-feeding operations. PMID- 27464337 TI - Resolving Chromatin Bridges With SIMs, SUMOs and PICH. PMID- 27464336 TI - Decreased Whole-Body Fat Mass Produced by Chronic Alcohol Consumption is Associated with Activation of S6K1-Mediated Protein Synthesis and Increased Autophagy in Epididymal White Adipose Tissue. AB - BACKGROUND: Chronic alcohol consumption leads to a loss of white adipose tissue (WAT) but the underlying mechanisms for this lipodystrophy are not fully elucidated. This study tested the hypothesis that the reduction in WAT mass in chronic alcohol-fed mice is associated with a decreased protein synthesis specifically related to impaired function of mammalian target of rapamycin (mTOR). METHODS: Adult male mice were provided an alcohol-containing liquid diet for 24 weeks or an isonitrogenous isocaloric control diet. In vivo protein synthesis was determined at this time and thereafter epididymal WAT (eWAT) was excised for analysis of signal transduction pathways central to controling protein synthesis and degradation. RESULTS: While chronic alcohol feeding decreased whole-body and eWAT mass, this was associated with a discordant increase in protein synthesis in eWAT. This increase was not associated with a change in mTOR, 4E-BP1, Akt, or PRAS40 phosphorylation. Instead, a selective increase in phosphorylation of S6K1 and its downstream substrates, S6 and eIF4B was detected in alcohol-fed mice. Alcohol also increased eEF2K phosphorylation and decreased eEF2 phosphorylation consistent with increased translation elongation. Alcohol increased Atg12-5, LC3B-I and -II, and ULK1 S555 phosphorylation, suggesting increased autophagy, while markers of apoptosis (cleaved caspase-3 and -9, and PARP) were unchanged. Lipolytic enzymes (ATGL and HSL phosphorylation) were increased and lipogenic regulators (PPARgamma and C/EBPalpha) were decreased in eWAT by alcohol. Although alcohol increased TNF alpha, IL-6, and IL-1beta mRNA, no change in key components of the NLRP3 inflammasome (NLRP3, ACS, and cleaved caspase-1) was detected suggesting alcohol did not increase pyroptosis. Plasma insulin did not differ between groups. CONCLUSIONS: These results demonstrate that the alcohol-induced decrease in whole body fat mass resulted in part from activation of autophagy in eWAT as protein synthesis was increased and mediated by the specific increase in the activity of S6K1. PMID- 27464338 TI - Infectious Disease Expert Sees Threat From Colistin-Resistant Superbug. PMID- 27464339 TI - (IPr)CuF-catalyzed alpha-site regiocontrolled trans-hydrofluorination of ynamides. AB - With Et3N.3HF as the fluorination reagent, (IPr)CuF-catalyzed alpha-site regiocontrolled trans-hydrofluorination of ynamides has been achieved, affording (Z)-alpha-fluoroenamides in moderate to excellent yields. It was interesting to note that the regioselectivity of the reaction is reversed to that observed in the (Ph3P)3CuF-catalyzed hydrofluorination of ynamides. Additionally, a variety of different ynamides including oxazolidinonyl-, imidazolyl-, and N-sulfonyl ynamides were suitable for the reaction system and the subsequent oxidation of the fluorinated products enables a convenient synthesis to alpha-fluoroimides. PMID- 27464340 TI - Elucidating the degradation mechanism of the cathode catalyst of PEFCs by a combination of electrochemical methods and X-ray fluorescence spectroscopy. AB - In this study, we report a methodology which enables the determination of the degradation mechanisms responsible for catalyst deterioration under different accelerated stress protocols (ASPs) by combining measurements of the electrochemical surface area (ECSA) and Pt content (by X-ray fluorescence). The validation of this method was assessed on high surface area unsupported Pt nanoparticles (Pt-NPs), Pt nanoparticles supported on TaC (Pt/TaC) and Pt nanoparticles supported on Vulcan carbon (Pt/Vulcan). In the load cycle protocol, the degradation of Pt-NPs and Pt/Vulcan follows associative processes (e.g. agglomeration) in the first 2000 cycles, however, in successive cycles the degradation goes through dissociative processes such as Pt dissolution, as is evident from a similar decay of ECSA and Pt content. In contrast, the degradation mechanism for Pt nanoparticles dispersed on TaC occurs continuously through the dissociative processes (e.g. Pt dissolution or particle detachment), with similar decay rates of both Pt content and ECSA. In the start-up/shut-down protocol, high surface area Pt-NPs follow associative processes (e.g. Ostwald ripening) in the first 4000 cycles, after which the degradation continues through dissociative processes. On the other hand, dissociative mechanisms always govern the degradation of Pt/TaC under start-up/shut-down protocol conditions. Finally, we report that Pt nanoparticles supported on TaC exhibit the highest catalytic activity and long term durability of the three nanoparticle systems tested. This makes Pt/TaC a potentially valuable catalyst system for application in polymer electrolyte fuel cell cathodes. PMID- 27464341 TI - On Dioxygen Permeation of MaL Laccase from the Thermophilic Fungus Melanocarpus albomyces: An all-Atom Molecular Dynamics Investigation. AB - In this article, biased molecular dynamics (MD) simulations of O2 egress from the active center of MaL laccase toward the bulk solvent were described. Parameterization of the set of four Cu(II) ions, in the framework of CHARMM-36 FF, was carried out on a recent dummy-atom model that takes into account the Jahn Teller effect. By carrying out a number of statistically relevant MD simulations, under a tiny randomly oriented external force applied to the molecule O2 , three preferred gates for O2 egress from the enzyme and a few intermediate binding pockets (BPs) for O2 were visible; all the gates and pockets were located on two of the three domains. This wide distribution of preferred gates notwithstanding the molecule O2 was seen to follow specific pathways, exploiting consistently the interstices created by the enzyme thermal fluctuations. These are features that can be imagined to have evolved to make MaL laccase extremely efficient as catalysts in various reactions that require O2 . PMID- 27464343 TI - Follow Your Passion. PMID- 27464344 TI - Midwifery Provision of Home Birth Services. PMID- 27464345 TI - Endocrine-Disrupting Chemicals and Reproductive Health (2016/041). PMID- 27464342 TI - Model-Based Characterization of Inflammatory Gene Expression Patterns of Activated Macrophages. AB - Macrophages are cells with remarkable plasticity. They integrate signals from their microenvironment leading to context-dependent polarization into classically (M1) or alternatively (M2) activated macrophages, representing two extremes of a broad spectrum of divergent phenotypes. Thereby, macrophages deliver protective and pro-regenerative signals towards injured tissue but, depending on the eliciting damage, may also be responsible for the generation and aggravation of tissue injury. Although incompletely understood, there is emerging evidence that macrophage polarization is critical for these antagonistic roles. To identify activation-specific expression patterns of chemokines and cytokines that may confer these distinct effects a systems biology approach was applied. A comprehensive literature-based Boolean model was developed to describe the M1 (LPS-activated) and M2 (IL-4/13-activated) polarization types. The model was validated using high-throughput transcript expression data from murine bone marrow derived macrophages. By dynamic modeling of gene expression, the chronology of pathway activation and autocrine signaling was estimated. Our results provide a deepened understanding of the physiological balance leading to M1/M2 activation, indicating the relevance of co-regulatory signals at the level of Akt1 or Akt2 that may be important for directing macrophage polarization. PMID- 27464348 TI - Petri Nets - A Mathematical Formalism to Analyze Chemical Reaction Networks. AB - In this review we introduce and discuss Petri nets - a mathematical formalism to describe and analyze chemical reaction networks. Petri nets were developed to describe concurrency in general systems. We find most applications to technical and financial systems, but since about twenty years also in systems biology to model biochemical systems. This review aims to give a short informal introduction to the basic formalism illustrated by a chemical example, and to discuss possible applications to the analysis of chemical reaction networks, including cheminformatics. We give a short overview about qualitative as well as quantitative modeling Petri net techniques useful in systems biology, summarizing the state-of-the-art in that field and providing the main literature references. Finally, we discuss advantages and limitations of Petri nets and give an outlook to further development. PMID- 27464346 TI - Zika virus: An emergent neuropathological agent. AB - The emergence of Zika virus in the Americas has followed a pattern that is familiar from earlier epidemics of other viruses, where a new disease is introduced into a human population and then spreads rapidly with important public health consequences. In the case of Zika virus, an accumulating body of recent evidence implicates the virus in the etiology of serious pathologies of the human nervous system, that is, the occurrence of microcephaly in neonates and Guillain Barre syndrome in adults. Zika virus is an arbovirus (arthropod-borne virus) and a member of the family Flaviviridae, genus Flavivirus. Zika virions are enveloped and icosahedral, and contain a nonsegmented, single-stranded, positive-sense RNA genome, which encodes 3 structural and 7 nonstructural proteins that are expressed as a single polyprotein that undergoes cleavage. Zika genomic RNA replicates in the cytoplasm of infected host cells. Zika virus was first detected in 1947 in the blood of a febrile monkey in Uganda's Zika Forest and in crushed suspensions of the Aedes mosquito, which is one of the vectors for Zika virus. The virus remained obscure, with a few human cases confined to Africa and Asia. There are two lineages of the Zika virus, African and Asian, with the Asian strain causing outbreaks in Micronesia in 2007 and French Polynesia in 2013-2014. From here, the virus spread to Brazil with the first report of autochthonous Zika transmission in the Americas in March 2015. The rapid advance of the virus in the Americas and its likely association with microcephaly and Guillain-Barre syndrome make Zika an urgent public health concern. Ann Neurol 2016;80:479-489. PMID- 27464347 TI - Evidence for dying-back axonal degeneration in age-associated skeletal muscle decline. AB - INTRODUCTION: Age-associated muscle strength decline is a major contributing factor to increased late-life functional decline and comorbidity, and is strongly associated with early mortality. Although all parts of the neuromuscular system seem to be affected by aging, dying-back of motor axons likely plays a major role. METHODS: We compared the degeneration in ventral roots and neuromuscular junction denervation in young and aged mice and correlated the findings with strength and electrophysiological measures. RESULTS: With normal aging, there is little decline in motor axon numbers in the ventral roots, but the neuromuscular junctions show marked partial denervation that is associated with increased jitter on stimulated single fiber electromyography and a decrease in muscle strength. CONCLUSIONS: These findings suggest that dying-back axonal degeneration may be partially responsible for the electrophysiological and strength changes observed with aging. Muscle Nerve 55: 894-901, 2017. PMID- 27464349 TI - QSAR Analysis Involving Assay Results Which are only Known to be Greater Than, or Less Than Some Cut-off Limit. AB - It is often impossible to measure compound properties above or below some detection limit, or cut-off level, in which cases result values can only be recorded as lying above or below that censoring limit. Such result values carry information, but are often excluded from QSAR studies or forcing the use of classification methods where regression models are more appropriate. This paper describes a regression method which makes use of censored values. The method works by estimating (imputing) the values underlying censored results. The algorithm was tested for stability and accuracy in the context of Free-Wilson R group activity score calculations. PMID- 27464350 TI - ISIDA Property-Labelled Fragment Descriptors. AB - ISIDA Property-Labelled Fragment Descriptors (IPLF) were introduced as a general framework to numerically encode molecular structures in chemoinformatics, as counts of specific subgraphs in which atom vertices are coloured with respect to some local property/feature. Combining various colouring strategies of the molecular graph - notably pH-dependent pharmacophore and electrostatic potential based flagging - with several fragmentation schemes, the different subtypes of IPLFs may range from classical atom pair and sequence counts, to monitoring population levels of branched fragments or feature multiplets. The pH-dependent feature flagging, pursued at the level of each significantly populated microspecies involved in the proteolytic equilibrium, may furthermore add some competitive advantage over classical descriptors, even when the chosen fragmentation scheme is one of the state-of-the-art pattern extraction procedures (feature sequence or pair counts, etc.) in chemoinformatics. The implemented fragmentation schemes support counting (1) linear feature sequences, (2) feature pairs, (3) circular feature fragments a.k.a. "augmented atoms" or (4) feature trees. Fuzzy rendering - optionally allowing nonterminal fragment atoms to be counted as wildcards, ignoring their specific colours/features - ensures for a seamless transition between the "strict" counts (sequences or circular fragments) and the "fuzzy" multiplet counts (pairs or trees). Also, bond information may be represented or ignored, thus leaving the user a vast choice in terms of the level of resolution at which chemical information should be extracted into the descriptors. Selected IPLF subsets were - tree descriptors, in particular - successfully tested in both neighbourhood behaviour and QSAR modelling challenges, with very promising results. They showed excellent results in similarity-based virtual screening for analogue protease inhibitors, and generated highly predictive octanol-water partition coefficient and hERG channel inhibition models. PMID- 27464351 TI - Cheminformatics Approach to Gene Silencing: Z Descriptors of Nucleotides and SVM Regression Afford Predictive Models for siRNA Potency. AB - Short interfering RNA mediated gene silencing technology has been through tremendous development over the past decade, and has found broad applications in both basic biomedical research and pharmaceutical development. Critical to the effective use of this technology is the development of reliable algorithms to predict the potency and selectivity of siRNAs under study. Existing algorithms are mostly built upon sequence information of siRNAs and then employ statistical pattern recognition or machine learning techniques to derive rules or models. However, sequence-based features have limited ability to characterize siRNAs, especially chemically modified ones. In this study, we proposed a cheminformatics approach to describe siRNAs. Principal component scores (z1, z2, z3, z4) have been derived for each of the 5 nucleotides (A, U, G, C, T) from the descriptor matrix computed by the MOE program. Descriptors of a given siRNA sequence are simply the concatenation of the z values of its composing nucleotides. Thus, for each of the 2431 siRNA sequences in the Huesken dataset, 76 descriptors were generated for the 19-NT representation, and 84 descriptors were generated for the 21-NT representation of siRNAs. Support Vector Machine regression (SVMR) was employed to develop predictive models. In all cases, the models achieved Pearson correlation coefficient r and R about 0.84 and 0.65 for the training sets and test sets, respectively. A minimum of 25 % of the whole dataset was needed to obtain predictive models that could accurately predict 75 % of the remaining siRNAs. Thus, for the first time, a cheminformatics approach has been developed to successfully model the structure-potency relationship in siRNA-based gene silencing data, which has laid a solid foundation for quantitative modeling of chemically modified siRNAs. PMID- 27464352 TI - The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer. AB - Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n = 306) and Germany (n = 111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pretreatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan((r)) Human MicroRNA assay, Applied Biosystem; PC n = 133, controls n = 72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMarkTM System; PC n = 198, controls n = 184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMarkTM System; PC n = 86, controls n = 51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and four diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, 191, -323.3p, -345 and -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (Index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and Index II best discriminated Stages I and II PC from HS [AUC 0.93 (0.90-0.96), sensitivity 0.77 (0.69-0.84), specificity 0.94 (0.90-0.96) and accuracy 0.88 (0.84-0.91)]. In conclusion, we identified four diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP. PMID- 27464354 TI - Three-Dimensional Numerical Simulations of Peristaltic Contractions in Obstructed Ureter Flows. AB - Ureteral peristalsis can be considered as a series of waves on the ureteral wall, which transfers the urine along the ureter toward the bladder. The stones that form in the kidney and migrate to the ureter can create a substantial health problem due to the pain caused by interaction of the ureteral walls and stones during the peristaltic motion. Three-dimensional (3D) computational fluid dynamics (CFD) simulations were carried out using the commercial code ansys fluent to solve for the peristaltic movement of the ureter, with and without stones. The effect of stone size was considered through the investigation of varying obstructions of 5%, 15%, and 35% for fixed spherical stone shape. Also, an understanding of the effect of stone shape was obtained through separate CFD calculations of the peristaltic ureter with three different types of stones, a sphere, a cube, and a star, all at a fixed obstruction percentage of 15%. Velocity vectors, mass flow rates, pressure gradients, and wall shear stresses were analyzed along one bolus of urine during peristalsis of the ureteral wall to study the various effects. It was found that the increase in obstruction increased the backflow, pressure gradients, and wall shear stresses proximal to the stone. On the other hand, with regard to the stone shape study, while the cube-shaped stones resulted in the largest backflow, the star-shaped stone showed highest pressure gradient magnitudes. Interestingly, the change in stone shape did not have a significant effect on the wall shear stress at the obstruction level studied here. PMID- 27464353 TI - Factors underlying metastatic breast cancer patients' perceptions of symptom importance: a qualitative analysis. AB - The symptom literature in cancer has primarily examined symptom severity, frequency and distress. Assessing cancer patients' perceptions of symptom importance-how important it is for them to see improvement in a symptom following an intervention-and factors influencing these judgments would also inform patient centred care, but this analysis has not been undertaken. This qualitative study aimed to identify factors underlying perceptions of symptom importance among 25 symptomatic metastatic breast cancer (MBC) patients. Participants were recruited from a cancer centre in the Midwestern USA. Semi-structured interviews focused on patients' rationale for considering common symptoms (i.e., anxiety, sadness, sleep problems, pain or fatigue) to be important. Thematic analyses revealed five interrelated factors underlying MBC patients' perceptions of symptom importance: activity restriction, concentration difficulties, exacerbation of other physical symptoms, symptom-related long-term health concerns and negative impact on their relationships with others. Patients most frequently stated that a physical or psychological symptom was important because of the resulting activity restriction. Additionally, some patients considered pain to be important because it signalled potential long-term health concerns, such as worsening metastatic disease. Findings suggest that clinicians should take into account MBC patients' perceptions of symptom importance and factors underlying these judgments when making shared treatment decisions. PMID- 27464355 TI - Regenerative Capacity of the Enteric Nervous System after Ileoileal Anastomoses in a Rat Model. AB - Purpose The aim of the study was to investigate the regeneration and migration of neuronal progenitor cells of the enteric nervous system during wound healing after intestinal anastomosis in the rat ileum. Methods Experiments were performed in a rat model of ileoileal anastomosis. Rats were humanely killed on day 2 or day 10 after anastomosis, and the anastomotic region was compared with ileum of healthy rats. Immunofluorescent staining was performed with protein gene product 9.5, nestin, and S100 antibodies. Ganglia of the anastomotic region in both the myenteric and submucosal plexus were counted, and their diameters were measured and compared between groups. Results Analysis of number and diameter of ganglia in both myenteric and submucosal plexus showed individual alterations as a reaction to the surgical manipulation. Significantly less ganglia were found in the submucosal plexus in the operated groups at both day 2 (p < 0.01) and day 10 (p < 0.01) than in the control group. In the myenteric plexus in the operated group, there was a difference in the number of ganglia at day 2, but ganglia count had recovered at day 10 and was not significantly different from the control group. However, the diameter of ganglia in the myenteric plexus still significantly decreasing on day 10 after surgery than in the control group (p = 0.046). Nestin and S100 double-staining showed an increased expression of nestin around the anastomotic wound. Conclusion Our findings suggest a regenerative potential of the enteric nervous system after the surgical ileoileal anastomosis. The myenteric plexus appears to recover faster than the submucosal plexus. This recovery might be driven by nestin-positive neuronal progenitor cells. PMID- 27464356 TI - Evolution of laparoscopic liver resection. PMID- 27464358 TI - Exploring the effect of laser excitation wavelength on signal recovery with deep tissue transmission Raman spectroscopy. AB - The aim of this research was to find the optimal Raman excitation wavelength to attain the largest possible sensitivity in deep Raman spectroscopy of breast tissue. This involved careful consideration of factors such as tissue absorption, scattering, fluorescence and instrument response function. The study examined the tissue absorption profile combined with Raman scattering and detection sensitivity at seven different, laser excitation wavelengths in the near infrared region of the spectrum. Several key scenarios in regards to the sample position within the tissue were examined. The highest Raman band visibility over the background ratio in respect to biological tissue provides the necessary information for determining the optimum laser excitation wavelength for deep tissue analysis using transmission Raman spectroscopy, including detection of breast calcifications. For thick tissues with a mix of protein and fat, such as breast tissue, 790-810 nm is concluded to be the optimum excitation wavelength for deep Raman measurements. PMID- 27464359 TI - Biophysical and chemical handles to control the size of DNA nanoparticles produced by rolling circle amplification. AB - Although rolling circle amplification (RCA) is an efficient method to produce DNA materials for biomedical applications, it does not yield nano-sized products suitable for intracellular delivery. We here provide the ways to control the size of RCA products and show a potential application of the size-controlled DNA nanoparticles. PMID- 27464360 TI - Development of a supramolecular ensemble of an AIEE active hexaphenylbenzene derivative and Ag@Cu2O core-shell NPs: an efficient photocatalytic system for C-H activation. AB - A supramolecular ensemble having Ag@Cu2O core-shell nanoparticles stabilized by aggregates of a hexaphenylbenzene derivative has been developed which exhibits excellent photocatalytic efficiency in reactions involving preparation of imidazole and benzimidazole derivatives via C-H activation. PMID- 27464362 TI - Editorial Message: How Do You Treat Others? PMID- 27464361 TI - A New Lridium(III) Complex as a Deep-Red Phosphorescent Emitter in Organic Light Emitting Diodes. AB - We synthesized a novel red-emitting iridium(III) complex, bis[2-(5-(9H-carbazole 9-yl)thiophene-2-yl)benzo[d]thiazole]iridium(III)acetylacetonate ([(CTBT)21 r(acac)]), for use in phosphorescent organic light-emitting diodes. The photophysical and electrochemical properties of [(CTBT)2Ir(acac)] were characterized using photoluminescence (PL) and cyclic voltammetry. The photophysical properties of [(CTBT)2Ir(acac)] included PL emission at 630 nm. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of [(CTBT)2Ir(acac)] were calculated to be -5.14 and -2.83 eV, respectively. Phosphorescent organic light-emitting diodes with a configuration of ITO/PEDOT:PSS (30 nm)/TAPC (30 nm)/TPBi (12.5 nm):TCTA (12.5 nm):dopant (3%, 5%, 10%)/TSPO1 (35 nm)/LiF (1 nm)/Al (100 nm) were fabricated and characterized. The fabricated device doped with 5% [(CTBT)2Ir(acac)] showed a high luminous efficiency of 2.06 cd/A, maximum external quantum efficiency of 4.32% at 4 V, maximum outstanding luminance of 398.8 cd/m2, and maximum power efficiency of 1.79 lm/W with Commission Internationale de L'Eclairage (CIE) coordinates of (0.69, 0.31). PMID- 27464357 TI - The novel monoclonal antibody 9F5 reveals expression of a fragment of GPNMB/osteoactivin processed by furin-like protease(s) in a subpopulation of microglia in neonatal rat brain. AB - To differentiate subtypes of microglia (MG), we developed a novel monoclonal antibody, 9F5, against one subtype (type 1) of rat primary MG. The 9F5 showed high selectivity for this cell type in Western blot and immunocytochemical analyses and no cross-reaction with rat peritoneal macrophages (Mphi). We identified the antigen molecule for 9F5: the 50- to 70-kDa fragments of rat glycoprotein nonmetastatic melanoma protein B (GPNMB)/osteoactivin, which started at Lys(170) . In addition, 9F5 immunoreactivity with GPNMB depended on the activity of furin-like protease(s). More important, rat type 1 MG expressed the GPNMB fragments, but type 2 MG and Mphi did not, although all these cells expressed mRNA and the full-length protein for GPNMB. These results suggest that 9F5 reactivity with MG depends greatly on cleavage of GPNMB and that type 1 MG, in contrast to type 2 MG and Mphi, may have furin-like protease(s) for GPNMB cleavage. In neonatal rat brain, amoeboid 9F5+ MG were observed in specific brain areas including forebrain subventricular zone, corpus callosum, and retina. Double-immunomicronstaining with 9F5 antibody and anti-Iba1 antibody, which reacts with MG throughout the CNS, revealed that 9F5+ MG were a portion of Iba1+ MG, suggesting that MG subtype(s) exist in vivo. We propose that 9F5 is a useful tool to discriminate between rat type 1 MG and other subtypes of MG/Mphi and to reveal the role of the GPNMB fragments during developing brain. GLIA 2016;64:1938 1961. PMID- 27464363 TI - From Pictures to Knowledge, Bio-Image Informatics Coming of Age. PMID- 27464364 TI - Since its discovery in 1952, acrosomal exocytosis (also called acrosome reaction) has been a fascinating process. PMID- 27464365 TI - [Preface]. PMID- 27464366 TI - In Memoriam:DonaldW.Lewis,MD(1951-2012). PMID- 27464367 TI - In Memoriam:Steven LeRoy Linder,MD(1945-2015). PMID- 27464368 TI - Telehealth Dials Up Discussion About Payment to Providers. PMID- 27464369 TI - Chronic Illness New Battleground For Retail Clinics, Primary Care Physicians. PMID- 27464371 TI - Health Plans' Digital Efforts Should Be App-y Experience. PMID- 27464370 TI - Doctors in the House. PMID- 27464372 TI - A CONVERSATION WITH ATEEV MEHROTRA, MD. Convenience Rules in Health Care: Will Quality Suffer During Its Reign? PMID- 27464373 TI - Where Have All the Primary Care Physicians Gone? PMID- 27464374 TI - Disrupt Yourself or Be Disrupted: Insurers' Role in Changing the Business Model. PMID- 27464375 TI - A CONVERSATION WITH THERESA BROWN, RN. You Can Learn a Lot in 12 Hours: The Shift Reveals Paradoxes of Hospital Care. PMID- 27464376 TI - Researchers Mining HCCI Trove Of Private Payer Data for Pricing Insights. PMID- 27464377 TI - The Shortened Dental Arch concept from the perspective of Swedish General Dental Practitioners: a qualitative study. AB - The aim was to study the cognizance of and attitudes towards the Shortened Dental Arch (SDA) concept among Swedish General Dental Practitioners (GDPs) and the application of the SDA concept in their treatment planning using Qualitative Content Analysis. Eleven Swedish GDPs were purposively selected and all agreed to participate. In-depth semi-structured interviews were conducted and covered treatment considerations concerning two patient cases and the participants' reflections regarding pre-formulated statements about the SDA concept. Qualitative content analysis was used to analyze this data.The emerging theme was "the SDA concept is irrelevant" in the sense of the GDPs disregarding treatments providing dentitions with loss of posterior teeth. There was a strong reluctance to extract teeth, without consideration of the SDA concept, and a firmly patient focused attitude towards the needs, age and financial situation of the patients. Within the limitations of this study, Swedish GDPs show little or no cognizance of the SDA concept and it does not seem to be applied in their treatment planning. The results show that the qualitative methodology can be beneficial for further understanding of cognizance and attitudes towards the SDA concept. PMID- 27464378 TI - Aural symptoms in patients referred for temporomandibular pain/dysfunction. AB - With the aim of studying frequency of aural symptoms and associations with symptoms of TMD new patients referred to the Orofacial Pain Clinic, Odontologen, Goteborg, were asked, at their first appointment and before meeting a specialist, to report any symptoms regarding pain or fullness/swelling of the ear, impaired hearing, sensitivity to sound, and irritation/itching of the ear. They also answered a standardized questionnaire regarding temporomandibular pain and/or dysfunction, and classified their degree of TMD symptoms on a five-point verbal scale and a visual analogue scale. 108 consecutive patients were included in the study, they completed the questionnaires and were examined and diagnosed by different specialists at the clinic. Any ear symptoms were reported by 68% of the patients, fullness of ear by 44% and impaired hearing by 37%. 38% of the patients had previously consulted a physician, and most of them had had pharmacological treatment due to their ear symptoms. Females reported more pain in the ear (P = 0.034) and more sensitivityto sound (P = 0.046) than men. No significant association was found between age and aural symptoms. The degree of TMD- symptoms, as reported by the five grade scale, showed significant association with aural symptoms (P < 0.001), as did the clinical dysfunction index of Helkimo (P = 0.005). The diagnoses of myalgia, arthralgia, arthritis and headache showed significant association with aural symptoms, while no association with crepitus (osteoartrosis) and disc displacement. Itching in the ear was frequently reported (24%) and was associated with myalgia (P = 0.003) and tension headache (P = 0.018). A medical examination by an ear-nose-throat specialist of 19 patients reporting a sensation of fullness of ear, did not reveal any objectifiable ear disease. To conclude, aural symptoms are common in patients with temporomandibular pain and/or dysfunction, are associated with TMD-symptoms and should be regarded as possible symptoms of TMD. A cooperation between physicians and dentists can give these patients a good treatment. PMID- 27464379 TI - Adult heavy and low users of dental services: treatment provided. AB - The aim of this study was to compare treatment provided to adult heavy and low users of dental services in the Finnish Public Dental Service (PDS) and to analyse changes in patients' oral health status. We assigned all adults who attended the PDS in Espoo in 2004 to a group of heavy users (n = 3,173) if they had made six or more dental visits and to a comparison group of low users (n = 22,820), if they had made three or fewer dental visits. Data were obtained from the patient register of the PDS. A sample of 320 patients was randomly selected from each group. Baseline information (year 2004) on age, sex, number and types of visits, oral health status and treatment provided was collected from treatment records. Both groups were followed-up for five years. Restorative treatment measures dominated the heavy and low users'treatments; 88.8% of heavy users and 79.6% low users had received restorations during the five-year period. Fixed prosthetic treatments were provided to just 2% of the heavy users and 0.8% of the low users. Emergency visits were more common for heavy users (74.8%) than for low users (21.6%) (p < 0.001). Fewer than half of the heavy (46.1%) or low (46.5%) users were examined twice. Typical for heavy use of oral health services was a cycle of repetitive repair or replacement of restorations, often as emergency treatment, a lack of proper examinations and preventive care; crown therapy was seldom used. Immediately after the major dental care reform in Finland, the PDS in Espoo had problems providing good quality dental care for the new adult patients. Older patients with lower social class background were not accustomed to regular dental care and the PDS did not actively propose proper comprehensive regular care for adults. PMID- 27464380 TI - Cephalometric analysis of adults with Turner syndrome. AB - Turner syndrome (TS) is a genetic disorder of females with a prevalence of 1/2000 3000 live female births. The aim of this study was to compare cephalometric variables from adult women diagnosed with TS to a standardized reference group of 31-year old healthy women, and to evaluate the possible effects of human growth hormone (hGH) therapy in women with TS. Registered TS subjects in the Southeast region of Sweden were invited to take part in the study. Twenty-one women aged 36 +/- 13(18-57) years accepted participation. Lateral radiographs of the head were analyzed using standard cephalometric methods (Hasund analysis) and with the commercially available soft-ware program FACAD. Comparisons were made with roentgen-cephalometric standards from a reference group of nineteen 31-year old Swedish women. Analysis of the cephalometric radiographs from the TS subjects showed a more retrognathic maxilla (SNA 80.3 +/- 5.4) (p = 0.0460) and mandible (SNB 77.0 +/- 5.2) (p = 0.0014), and a correspondingly backward position of the chin (SN/Pg 78.9 +/- 5.5) (p = 0.0046) as compared to the reference values of 31 year old women (SNA 83.2 +/- 3.0, SN B 81.5 +/- 2.3 and SNPg 83.0 +/- 2.3, respectively). In addition there was an increased posterior inclination of the maxilla (SN/NL 8.6 +/- 4.1), as compared to the reference values (SN/NL 5.3 +/- 2.7) (p = 0.0048). There were no significant differences regarding sagittal or vertical jaw relations, mandibular inclination or cranial base angle between the TS-group and the 31-year olds with the reference values. No significant difference was seen in jaw relationship, as measured by the ANB value, however the Wits(index) (3.3 +/- 3.5) was higher (p = 0.0001) than the reference values ( 0.1 +/- 1.8). Subjects with or without previous hGH administration did,not show any significant differences in cephalometric values. In conclusion, women with TS had a significantly more retrognathic maxilla (SNA) and mandible (SNB) and a correspondingly significantly posterior position of the chin (SN/Pg), a significantly increased posterior inclination of the maxilla (SN/NL) and a significantly increased Wits(index) as compared to the reference group of 31-year old women. No craniofacial variables differed significantly between previously hGH-treated and not hGH-treated women with TS. PMID- 27464381 TI - Vital root resection with MTA: a pilot study. AB - OBJECTIVES: To investigate the outcome of vital root resection followed by immediate pulp capping with MTA in furcation involved maxillary molars. MATERIAL AND METHODS: This pilot clinical study of 12 months duration was designed to evaluate the outcome of vital root resection in maxillary molars with degree II furcation involvement combined with conservative endodontic treatment by means of pulp capping with mineral trioxide aggregate (MTA). Seven teeth in six adult patients suffering from adult chronic periodontitis were included in this study. RESULTS: At the final 12 month examination interval, one tooth had received root canal therapy subsequent to the 6-month evaluation. The remaining six teeth remained clinically vital for the duration of the study and required no further treatment at 12 months. CONCLUSION: Results of this study provide limited data that can be used in a further investigation with similar methodology and a sufficient sample size in a randomized clinical trial model. PMID- 27464382 TI - Self-perceived oral health among 19-year-olds in a Swedish County--A comparative study between 2004 and 2011. AB - For decades, Swedish dental professionals have collected clinical epidemiological data from the dental records. To supplement the epidemiology, Ostergotland County Council decided to examine patient perceptions of oral health: self-rated knowledge, self-perceived oral health, and opinions about oral health. The aim was to compare self-perceived oral health among 19-year-olds to determine differences between genders, various municipalities and between 2004 and 2011. This study analysed the responses from two cross-sectional surveys of the entire population of 19-year-olds in Ostergotland County, Sweden, performed in 2004 and 2011. Of the 2,413 (53%) (50% men, 50% women) 19-year-olds who responded to the questionnaire in 2004 and the 3,803 (67%) (50% men, 50% women) in 2011, most 19 year-olds (88.1% [2004] and 87.5 % [2011]) reported satisfaction with their oral health. Around half of the respondents rated their knowledge on periodontitis as low. Boys rated their knowledge about avoiding periodontitis higher than girls (p < 0.05 in 2004 and p < 0.001 in 2011). In 2004, 84.7% reported shooting pain. In 2011 that figure was 83.7%.The respondents expressed some uncertainty about the benefits of fluoride toothpaste (7.5% in 2004 and 9.3% in 2011), especially the boys (10.3% in 2004 and 10.5% in 2011). Girls reported both a higher social impact and greater concern about aesthetics related to their oral health. They also reported headache (27.5%) nearly twice as often as boys (14.2%) (p > 0.001). Responses between the municipalities did not differ, with the exception of items regarding periodontitis. Thus, this study found indications that perceptions of oral health and knowledge in Ostergotland County complied with Swedish Dental Act. The study also found patient perceptions of oral health among 19-year-olds to be good. PMID- 27464383 TI - Success rate, costs and long-term stability of treatment with activator/headgear combinations. AB - The aims of this study were to evaluate treatment outcome with activator-headgear combinations carried out by general dental practitioners, overall costs, long term stability and patients' satisfaction with treatment outcome. Patients who were recommended to start treatment in 2006 were included in this study (n = 97). Inclusion criteria were: Class II Division 1 with at least half a cusp width distal molar relationship, overjet >= 6 mm and presence of dental records. Data were collected, pre-treatment, post-treatment and 3 years after treatment for those with favorable outcome. Patients at follow-up completed a questionnaire about satisfaction with treatment outcome, perceived pain and discomfort during treatment, and subjective need for additional treatment. Eighty-five patients were analyzed, 52 boys and 33 girls (mean age 11.2 years SD 1.39). Thirty-five patients had successful treatment outcome, 15 partially successful and 35 had an unsuccessful outcome. Total costs for all 85 patients amounted to SEK 1 405 000 including both direct and indirect costs. Thirty-eight patients participated in the 3-year follow-up. Treatment outcomes were then categorized as successful in 28 patients, partially successful in 9 patients and 1 patient was judged as unsuccessful. Median values on VAS (0-100) for overall satisfaction with treatment and treatment outcome were high, 78 and 84 respectively. Median value for perceived pain and discomfort during treatment was 42. Just over half of the patients had a favorable treatment outcome. Patients with favorable outcome were stable over time and satisfied with treatment. PMID- 27464384 TI - Treatment of adolescent patients with class II division 1 malocclusion using Eruption guidance appliance: A comparative study with Twin-block and Activator Headgear appliances. AB - The aim of this study was to evaluate the compliance and short-term effects of eruption guidance appliance (EGA) in adolescents with class II division 1 malocclusion in comparison with twin-block appliance (TBA) and activator-headgear appliance (A-HG). Dental records of 1886 patients were viewed in this retrospective study 129 patients treated with one of these three functional appliances were identified. 123 fulfilled the inclusion criteria and data were extracted from the dental records. Gender, age, compliance, overjet change at every visit, number of appliance breakages and number of emergency visits apart from appliance breakage were studied. The data were analyzed with Chi-square test, General Linear Model and Fisher scoring test. Results showed that 47 patients were treated with EGA, 38 patients with TBA and 38 patients with A-HG. Mean ages starting the treatment were slightly lower with EGA (11.5 years) than with TBA (12.3 years) and A-HG (11.8 years). Non-compliance was higher in the EGA group (31.9%) than TBA group (26.3%) and A-HG group (23.7%). Mean overjet reduction per month was 0.6 mm for EGA which was lower than TBA group (0.7 mm) and A-HG groups (0.7 mm).The number of emergency visits and appliance breakage were lower in EGA group. However, there was no statistically significant difference between the 3 groups regarding ages,compliance, mean overjet reduction, emergency visits and appliance breakage aspects. In conclusion, this study indicates that EGA is an alternative choice in the treatment of adolescent patients with class II division 1 malocclusion. However, long-term follow-up and cephalometric prospective study should be performed to continue our understanding more about the mechanisms of EGA and more definite conclusions can be made. PMID- 27464385 TI - Native-born versus foreign-born patients' perception of communication and care in Swedish dental service. AB - Like many other countries Sweden is becoming more multicultural and many residents do not fully master the national language and are not completely familiar with national norms and habits. The key to good interaction between dentists and patients is communication. Therefore this study aimed to examine whether there are differences in the experience of communication and care between native-born (NB) and foreign-born (FB) patients in the Swedish Public Dental Service (PDS). Consecutive patients at four PDS clinics in a major Swedish city (Gothenburg) were asked to complete the Dental Visit Satisfaction Scale (DVSS), eight additional items concerning communication and care, and a questionnaire eliciting background information.The questionnaires were available in English, Swedish, Arabic and Farsi. The response rate was 74% (204 patients, mean age: 42 years, range 18-86). Of the participants, 96 (47%) were NB and 108 (53%) were FB; 80 (40%) were men and 121 (60%) women. The NB group was significantly older, had higher education and more regular dental care habits, and reported higher dental fear than the FB group. Fewer FB than NB patients thought the dentist treated them in the same manner as he or she would treat other patients and this applied particularly to those who had lived in Sweden for more than 5 years. FB patients were as satisfied with the information and communication they received from the dentist as those born in Sweden, but they were more sceptical about the dentist's technical competence. The differences between the two groups were otherwise smaller than might have been expected in view of probable language difficulties and differences in dental care background. PMID- 27464386 TI - Patient-reported outcomes of caries prophylaxis among Swedish caries active adults in a long-term perspective. AB - The aim of this study was to measure patient-reported outcomes of caries prophylaxis and to compare them with previously documented efforts in dental offices. A questionnaire was mailed to 134 caries active (CA) and 40 caries inactive (CI) adult patients treated at a Swedish public dental service clinic. The overall response rate was 69%. The questionnaire included items regarding patient perceived caries prophylaxis in relation to: 1) treatment and recommendations given by the dental personnel, 2) performed self-care and 3) perceived and expected effects.The responses were studied for their association to clinical data, extracted retrospectively from the patients' dental records.The mean follow up time was > 16 years. Information about caries prophylaxis (p = 0.01) and recommendations for self-care (p = 0.04) were given more often to the CA group than to the CI group. Supplementary examinations and recommendations of self-care risk treatments were more frequent in the CA group (p < 0.001). CA patients also made more frequent extra efforts at home to avoid caries by changing their eating habits (p < 0.001), improving their oral hygiene (p = 0.04) and using extra fluoride (p = 0.001). In the CA group, 60% did not considerthat the extra prophylaxis efforts had made them caries inactive, and 40% were not satisfied with the outcome. Most patients (> 90%) hoped that the outcome of caries prophylactics would be a reduced number of cavities.The patient-perceived experiences of caries prophylaxis-were in concordance with dental records. Both the dentists and the caries active middle-aged Swedish adults were aware of the need for extra prophylaxis.The caries active patients perceived having made extra home care efforts, but had not experienced that they had become free from caries. PMID- 27464387 TI - A year in review. PMID- 27464388 TI - THE DECISION TO CERTIFY. PMID- 27464389 TI - The Intractable Pain conundrum. PMID- 27464390 TI - Early Survey Results from the Minnesota Medical Cannabis Program. AB - As part of its legislative mandate, the Minnesota Department of Health's Office of Medical Cannabis (OMC) is required to study and report on the state's medical cannabis program. This article describes preliminary findings from the OMC's research about who is using the program and whether patients and their certifying health care practitioners are noticing benefits and harms. PMID- 27464391 TI - Critical Reflections. PMID- 27464392 TI - Core Midwifery Skills. PMID- 27464393 TI - Marion's Message. Essential Midwifery Skills. PMID- 27464394 TI - Hands on, Hands off: Midwifing the Inner Life of Women. PMID- 27464395 TI - The Heart of the Core. PMID- 27464396 TI - Midwifery Tomorrow. PMID- 27464397 TI - After Action Review: A Guide for Midwifery Students and Preceptors. PMID- 27464398 TI - Birth: Our Journey Home. PMID- 27464399 TI - The Energy Model. PMID- 27464400 TI - Rebirth of a Midwife in China. PMID- 27464401 TI - A Mother-Daughter Breech Team. PMID- 27464402 TI - Normalizing Birth for the Global Citizen. PMID- 27464403 TI - The Medicine of the Ukhu Pacha. Andean Sacred Teachings around Pregnancy, Birth and Postpartum. PMID- 27464404 TI - Changing the Language of Childbirth. PMID- 27464405 TI - Birthcraft in Brazil: An Update on the Brazilian Humanization of Birth Movement. PMID- 27464406 TI - Trota of Salerno: Women's Medicine in Medieval Italy. PMID- 27464407 TI - Holding the Space. PMID- 27464408 TI - Midwifery: The Role of Proctoclysis (Rectal Fluid Infusion). PMID- 27464409 TI - Prevention of the Primary Cesarean Section: Facts, Myths and Tips. PMID- 27464410 TI - IXCHEL: The Mayan Goddess of Midwifery. PMID- 27464411 TI - Dear Editor. PMID- 27464412 TI - How soon after giving birth did you resume having intercourse? Was it the standard six weeks? Sooner? Later? PMID- 27464413 TI - Primus-Eugen Mullis, MD (1954-2016). PMID- 27464414 TI - Finding a Needle in a Haystack: the Advantages of Liquid Chromatography--Tandem Mass Spectrometry (LC-MS/MS) in Determination of Sex Hormones in Children. AB - Determination of steroid sex hormones concentrations in children is very important for diagnosis of a wide range of pubertal, adrenal and sex development disorders. The majority of hormone measurements are carried out using traditional immunoassays, due to their technical simplicity, cost and availability of commercial reagents. But, due to limited specificity and sensitivity, traditional immunoassays often fail to determine low concentration analytes such as sex hormones in pediatric blood. In the last decade, the LC-MS/MS assay has risen as a new player in the analytic diagnostic field. The assay has proven appropriate for detection of very low hormones concentrations in blood, is quite easy to perform and can detect multiple steroids from a single sample. For the routine determination of an individual or panel of steroids, LC-MS/MS is now the recommended method for most diagnostic laboratories. PMID- 27464415 TI - Role of Nuclear Factor Kappa B (NF-kappaB) in Growth Plate Chondrogenesis. AB - Abstract Nuclear Factor kappa B (NF-kappaB) is a group of seven transcription factors. Upon activation by a variety of stimuli, NF-kappaB translocates to the nucleus and modulates the expression of target genes involved in cell growth, survival, and death. Previous evidence indicates that NF-kappaB regulates bone growth and development. We have shown that the NF-kappaB p65 is expressed in the growth plate and facilitates longitudinal bone growth by inducing chondrocyte proliferation and differentiation and by preventing apoptosis. Furthermore, we have demonstrated in rodents that NF-kappaB expressed in growth plate chondrocytes mediates the promoting effects of GH and IGF-1 on longitudinal bone growth and growth plate chondrogenesis. Lastly, functional studies carried out in two children with growth failure and GH insensitivity, and affected by two different mutations impairing NF-kappaB activation, indicate that NF-kappaB also mediates the growth-promoting effects of GH in humans. PMID- 27464416 TI - Persistent Mullerian Duct Syndrome Caused by a Novel Mutation of an Anti MuIlerian Hormone Receptor Gene: Case Presentation and Literature Review. AB - Persistent Mullerian duct syndrome (PMDS) is a rare genetic disorder of male internal sexual development defined as lack of regression of Mullerian derivatives in the 46XY male with normally virilized external genitalia and unilateral or bilateral cryptorchidism. Approximately 85% of all cases are caused by mutations in genes encoding anti-Mullerian hormone (AMH) or its receptor (AMHR2) with autosomal recessive transmission. This condition is frequently diagnosed incidentally, during surgical repair of inguinal hernia or cryptorchidism. There is no consensus on surgical approach: malignancy risk in the Mullerian duct remnant or undescended testis encourages early removal of the former and bilateral orchiopexy; however, removal of Mullerian structures can impair testicular and vas deferens blood supply, potentially causing infertility. Herein, we report on a male infant with PMDS caused by a novel homozygous missense mutation in AMHR2 (c.928C>T; p.Q310X), review the literature, and discuss the diverse clinical and surgical approaches to this condition. PMID- 27464417 TI - Polymorphism of the IGF-I System and Sports Performance. AB - The potential use genetic polymorphism, and in particularly polymorphism of hormone genes, as tool to predict athletic performance is currently very challenging. Recent studies suggest that single nucleotide polymorphisms in IGF-I and myostatin may be beneficial for endurance and short distance running, and may even be associated with elite performance. Polymorphism in IGF-I receptor may differentiate between the two edges of the endurance-power athletic performance running spectrum suggesting beneficial effects for endurance and prevent from success in power events. In contrast, and despite similar metabolic demands, the myostatin-IGF-I-IGF-IR system seems not to play an important role in swimming excellence. This suggests that combining different sport disciplines for sports genetic research purposes should be done with extreme caution. Finally, since any phenotype reflects a complex relationship between genes, environment, epigenetic factors, and the interactions between them, consulting the young athlete regarding future success cannot be based solely on genetic polymorphism. PMID- 27464418 TI - LHX4 Gene Alterations: Patient Report and Review of the Literature. AB - LHX4 mutations are rare in combined pituitary hormone deficiency, and even rarer in isolated GHD. We describe a 14 years old boy who was referred for investigation of short stature. Convergent strabismus, nystagmus was present. At the age of 5 years his gait was unstable. A progressive myopathy ensued. Tests of pituitary reserve showed partial IGHD (8.2 ng/ml). Other pituitary hormones were within normal range. Muscle biopsy showed congenital myopathy of undefined etiology. MRI of the brain revealed the empty sella syndrome. Targeted resequencing with a panel containing probe sets for enrichment and analysis of > 4,800 clinically relevant genes, targeting 12Mb of the human genome revealed the c.250C>T (R84C) LHX4 mutation. His father is healthy, with no myopathy or pituitary deficiencies, but has the same LHX4 mutation. This report extends the range of phenotypes associated with LHX4 gene mutations. To the best of our knowledge, we are the first to report on congenital myopathy in an LHX4 gene mutation. Forthwith, we offer a comprehensive review of the patients published so far with their clinical and genetic characteristics. PMID- 27464419 TI - Stunted Growth. Proceedings of the 23rd Aschauer Soiree, Held at Aschauhof, Germany, November 7th 2015. AB - Twenty-four scientists met at Aschauhof, Altenhof, Germany, to discuss the associations between child growth and development, and nutrition, health, environment and psychology. Meta-analyses of body height, height variability and household inequality, in historic and modern growth studies published since 1794, highlighting the enormously flexible patterns of child and adolescent height and weight increments throughout history which do not only depend on genetics, prenatal development, nutrition, health, and economic circumstances, but reflect social interactions. A Quality of Life in Short Stature Youth Questionnaire was presented to cross-culturally assess health-related quality of life in children. Changes of child body proportions in recent history, the relation between height and longevity in historic Dutch samples and also measures of body height in skeletal remains belonged to the topics of this meeting. Bayesian approaches and Monte Carlo simulations offer new statistical tools for the study of human growth. PMID- 27464420 TI - [The Cause of Death of Taira no Kiyomori: A Possible Connection with the Death of Fujiwara no Kunitsuna]. AB - Taira no Kiyomori was struck by an unimaginable fever and died in the spring of Jisho Year 5 (1181). In the coup d'etat of Jisho Year 3 (1179), Kiyomori ended the Go-shirakawa cloistered government through military force and established the Takakura cloistered government as a puppet regime in the following year. The regime lasted only a short while, however, as the retired Takakura Emperor passed away within less than a year. Kiyomori's death immediately followed the restoration of the Go-shirakawa cloistered government. The cause of Kiyomori's death has previously been discussed in the fields of literature and medicine and has been diagnosed variously as malaria, cerebrovascular disease, pneumonia, or meningitis contracted from complications of influenza, scarlatina fulminans (scarlet fever), and so on. However, considering the fact that Kiyomori--who was anxious about restoring relations with the retired Go-shirakawa Emperor as well as subjugation by the forces of the Minamoto clan, which were growing daily in strength--and his close aide Fujiwara no Kunitsuna simultaneously fell ill and died one after the other, it is speculated that both figures had streptococcal infection. It is, therefore, surmised that, during the clan's twilight years, Taira tactics were determined through secret discussions between Kiyomori and Kunitsuna. PMID- 27464421 TI - ["Hinmin Yojosho Kiroku": A Record of Medical Institution for the Poor]. PMID- 27464422 TI - [Colorful instead of gray]. PMID- 27464423 TI - [Challenges of the new long-life society. "Becoming old is the best and the most foolish"]. PMID- 27464424 TI - ["For work as a midwife I need inner peace"]. PMID- 27464425 TI - ["Fluid care" study. Individual, flexible, digital]. PMID- 27464426 TI - [Interview with Heinz Ruegger. Nursing is not immune to age discrimination]. PMID- 27464427 TI - [Integration of health personnel without diploma, 7. Common values and goals]. PMID- 27464428 TI - [Primary nursing needs a team base]. PMID- 27464429 TI - [Clinical assessment in the Winterthur canton hospital. Resources for better patient care]. PMID- 27464430 TI - [Students effort measurement system study. Students and learners are valuable for companies]. PMID- 27464431 TI - [Recommendations for spitex practice. Supporting the coping process after partner loss]. PMID- 27464432 TI - [Sexual health. Multilingual information platform]. PMID- 27464433 TI - [Cochrane reviews. Preventing headaches after lumbar puncture]. PMID- 27464434 TI - [Ode to old age]. PMID- 27464435 TI - [The challenge of aging for society and the health care systems. A major issue that concerns us all]. PMID- 27464436 TI - [Aging and the technologic innovation. The "silver economy", between robotics and ethics]. PMID- 27464437 TI - [Interview with Pia Coppex. "The stereotypes must change"]. PMID- 27464438 TI - [Satisfying the needs of the elderly waiting for long-term accommodation]. PMID- 27464439 TI - [Availability: a widespread and underestimated phenomenon. Sick at work]. PMID- 27464440 TI - [Sharing and reflections. On the path to commitment]. PMID- 27464442 TI - [From baby boom to senior boom]. PMID- 27464441 TI - [The 13th day of schizophrenia. Schiz & the city]. PMID- 27464443 TI - Physicians and Advocacy. PMID- 27464444 TI - Budget Woes and Medicaid Cuts Will Be the Focus of the MedChi 2015 Session. PMID- 27464445 TI - A Balanced Life. PMID- 27464446 TI - Introduction. PMID- 27464448 TI - Physician Volunteerism: Making a Difference One Patient at a Time. PMID- 27464447 TI - Component Medical Society's Legislative Internship Program Helps to Establish Relationships. PMID- 27464449 TI - "Laws are Like Sausages. Better Not to See Them Being Made". Who said it first? Otto von Bismarck? John Godfrey Saxe? Claudius O. Johnson? PMID- 27464450 TI - Autoimmunity against laminins. AB - Laminins are ubiquitous constituents of the basement membranes with major architectural and functional role as supported by the fact that absence or mutations of laminins lead to either lethal or severely impairing phenotypes. Besides genetic defects, laminins are involved in a wide range of human diseases including cancer, infections, and inflammatory diseases, as well as autoimmune disorders. A growing body of evidence implicates several laminin chains as autoantigens in blistering skin diseases, collagenoses, vasculitis, or post infectious autoimmunity. The current paper reviews the existing knowledge on autoimmunity against laminins referring to both experimental and clinical data, and on therapeutic implications of anti-laminin antibodies. Further investigation of relevant laminin epitopes in pathogenic autoimmunity would facilitate the development of appropriate diagnostic tools for thorough characterization of patients' antibody specificities and should decisively contribute to designing more specific therapeutic interventions. PMID- 27464451 TI - Rare mutations and hypermethylation of the ARC gene associated with schizophrenia. AB - Activity-regulated cytoskeleton-associated protein (ARC), which interacts with the N-methyl-d-aspartate receptor (NMDAR) complex, is a critical effector molecule downstream of multiple neuronal signaling pathways. Dysregulation of the ARC/NMDAR complex can disrupt learning, memory, and normal brain functions. This study examined the role of ARC in susceptibility to schizophrenia. We used a resequencing strategy to identify the variants of ARC in 1078 subjects, including patients with schizophrenia and normal controls. We identified 16 known SNPs and 27 rare mutations. SNP-based analysis showed no association of ARC with schizophrenia. In addition, the rare mutations did not increase the burden in patients compared with controls. However, one patient-specific allele in the putative ARC promoter region and seven patient-specific mutants in ARC exon regions significantly reduced the reporter gene activity compared with ARC wild type. Methylation of a putative ARC promoter attenuated reporter activity in vitro, suggesting that ARC expression is regulated by DNA methylation. Pyrosequencing revealed eight hypermethylated CpG sites in the putative ARC promoter region in 64 schizophrenic patients compared with 63 controls. Taken together, our results suggest that both rare variants and epigenetic regulation of ARC contribute to the pathogenesis of schizophrenia in some patients. PMID- 27464452 TI - Titanium T-Plate as a Platform for Globe Stabilization in Acquired Nystagmus and Oscillopsia Without a Null Zone. AB - A 49-year-old woman with debilitating nystagmus and oscillopsia failed conservative therapy. A titanium T-plate was anchored to the lateral orbital rim and cantilevered into the orbit where it was secured to the inferior rectus muscle tendon with a suture. After the procedure was performed on both eyes, the patient had significant decreases in the amplitudes of her nystagmus and oscillopsia, thereby improving her daily function. She had sustained duration of effect through 7 years of follow up. This novel surgical technique holds promise in the treatment of acquired nystagmus and debilitating oscillopsia for which conventional therapy may be ineffective. The case report is in compliance with the Health Insurance Portability and Accountability Act. PMID- 27464453 TI - Clear-Cell (Reticulated) Transformation of Eyelid Eccrine Sweat Glands. AB - A 24-year-old man with a painful, recurrent left upper eyelid nodule underwent an excision. Histopathologic evaluation disclosed a granulomatous process, most likely in response to a ruptured epidermoid cyst. In the vicinity of the nodule were multiple eccrine sweat glands displaying a curious clear-cell appearance in the adlumenal cells, the first example of such a phenomenon in the eyelids. Alcian blue, periodic acid Schiff, and documented staining failed to disclose, respectively, any cytoplasmic mucosubstances, glycogen accumulation, or lipid in the adlumenal secretory cells. Cytokeratin 7 immunostained the adlumenal cells of the eccrine secretory coil, while cytokeratin 5/6 stained the ablumenal myoepithelial and ductular cells. Gross cystic disease fluid protein 15, normally demonstrable in the eccrine secretory cells, was not detectable. Clear-cell transformation should not be confused with syringoma of the lower eyelids, in which glycogen is responsible for the ablumenal clear-cell change. PMID- 27464454 TI - Diplopia and Symblepharon Following Mueller's Muscle Conjunctival Resection in Patients on Long-Term Multiple Antiglaucoma Medications. AB - To report the occurrence of diplopia and symblepharon following conjunctival Muellerectomy for ptosis repair in 3 patients under chronic antiglaucoma treatment. In this retrospective observational case series, 3 patients were identified who were being treated chronically with multiple antiglaucoma agents and concurrently underwent Mueller's muscle conjunctival resection (MMCR) for the management of ptosis. These patients developed conjunctival scarring and symblepharon extending from the operative site to the bulbar conjunctiva postoperatively. All 3 patients reported diplopia after surgery. Two of the patients were treated with prismatic correction and one underwent surgical correction. All patients were closely monitored postoperatively and 1 out of the 3 required symblepharon lysis and mucous membrane graft for ocular surface reconstruction with a consequent improvement in symptoms. Long-term use of topical antiglaucoma medications may alter the integrity of the conjunctiva, rendering conjunctival procedures more prone to postoperative scarring. In patients treated with multiple antiglaucoma medications who are in need of ptosis repair surgery, consideration should be given to an external approach to avoid the potential for postoperative symblepharon and diplopia. PMID- 27464455 TI - Neonatal Orbital Abscess Secondary to Pseudomonas Aeruginosa Conjunctivitis. AB - Pseudomonas aeruginosa conjunctivitis, although rare in healthy infants, may cause serious ocular and systemic complications. A 30-day-old, otherwise healthy male infant was referred with the diagnosis of right orbital abscess. The patient had been diagnosed as having Pseudomonas conjunctivitis 9 days previously at the referring center. Despite antibiotic treatment, his ocular findings had worsened and marked proptosis had developed. Other examination findings were ptosis, restriction of eye movements, periorbital erythema, and chemosis. Radiologic studies showed a large, homogenous mass with a thick capsule in the lateral retrobulbar orbit. The abscess was drained through a lateral orbitotomy. A culture of the abscess yielded P. aeruginosa. After surgery, the ocular findings improved rapidly without any complication. No other focus of infection or immune system abnormality was found. The patient did not experience any other significant disease during a follow up of 23 months. PMID- 27464456 TI - Transarterial Embolization of a Spontaneous Intraorbital Arteriovenous Fistula With n-BCA Glue. AB - Arteriovenous fistulae of the orbit are exceedingly rare. They are high-flow vascular malformations involving a fistula from the ophthalmic artery to one of the draining ophthalmic veins. Presenting symptoms can mimic those of carotid cavernous fistulae or of ophthalmic venous varices, and include diplopia, proptosis, chemosis, decreased visual acuity, and retro-orbital pain. Very few case reports are published on the treatment of this aggressive vascular malformation, and they uniformly describe techniques involving a transvenous access for the embolization of the fistula. To the best of authors' knowledge, they report the first case of transarterial embolization of an intraorbital AVF. PMID- 27464457 TI - The Nutrition Society journals: vive la difference! PMID- 27464458 TI - Effects of isoleucine on glucose uptake through the enhancement of muscular membrane concentrations of GLUT1 and GLUT4 and intestinal membrane concentrations of Na+/glucose co-transporter 1 (SGLT-1) and GLUT2. AB - Knowledge of regulation of glucose transport contributes to our understanding of whole-body glucose homoeostasis and human metabolic diseases. Isoleucine has been reported to participate in regulation of glucose levels in many studies; therefore, this study was designed to examine the effect of isoleucine on intestinal and muscular GLUT expressions. In an animal experiment, muscular GLUT and intestinal GLUT were determined in weaning pigs fed control or isoleucine supplemented diets. Supplementation of isoleucine in the diet significantly increased piglet average daily gain, enhanced GLUT1 expression in red muscle and GLUT4 expression in red muscle, white muscle and intermediate muscle (P<0.05). In additional, expressions of Na+/glucose co-transporter 1 and GLUT2 were up regulated in the small intestine when pigs were fed isoleucine-supplemented diets (P<0.05). C2C12 cells were used to examine the expressions of muscular GLUT and glucose uptake in vitro. In C2C12 cells supplemented with isoleucine in the medium, cellular 2-deoxyglucose uptake was increased (P<0.05) through enhancement of the expressions of GLUT4 and GLUT1 (P<0.05). The effect of isoleucine was greater than that of leucine on glucose uptake (P<0.05). Compared with newborn piglets, 35-d-old piglets have comparatively higher GLUT4, GLUT2 and GLUT5 expressions. The results of this study demonstrated that isoleucine supplementation enhanced the intestinal and muscular GLUT expressions, which have important implications that suggest that isoleucine could potentially increase muscle growth and intestinal development by enhancing local glucose uptake in animals and human beings. PMID- 27464459 TI - Combination of soya pulp and Bacillus coagulans lilac-01 improves intestinal bile acid metabolism without impairing the effects of prebiotics in rats fed a cholic acid-supplemented diet. AB - Intestinal bacteria are involved in bile acid (BA) deconjugation and/or dehydroxylation and are responsible for the production of secondary BA. However, an increase in the production of secondary BA modulates the intestinal microbiota due to the bactericidal effects and promotes cancer risk in the liver and colon. The ingestion of Bacillus coagulans improves constipation via the activation of bowel movement to promote defaecation in humans, which may alter BA metabolism in the intestinal contents. BA secretion is promoted with high-fat diet consumption, and the ratio of cholic acid (CA):chenodeoxycholic acid in primary BA increases with ageing. The dietary supplementation of CA mimics the BA environment in diet induced obesity and ageing. We investigated whether B. coagulans lilac-01 and soya pulp influence both BA metabolism and the maintenance of host health in CA supplemented diet-fed rats. In CA-fed rats, soya pulp significantly increased the production of secondary BA such as deoxycholic acid and omega-muricholic acids, and soya pulp ingestion alleviated problems related to plasma adiponectin and gut permeability in rats fed the CA diet. The combination of B. coagulans and soya pulp successfully suppressed the increased production of secondary BA in CA-fed rats compared with soya pulp itself, without impairing the beneficial effects of soya pulp ingestion. In conclusion, it is possible that a combination of prebiotics and probiotics can be used to avoid an unnecessary increase in the production of secondary BA in the large intestine without impairing the beneficial functions of prebiotics. PMID- 27464460 TI - The effects of trans-fatty acids on TAG regulation in mice depend on dietary unsaturated fatty acids. AB - The aim of this study was to investigate the effects of trans-fatty acids (TFA) on liver and serum TAG regulation in mice fed diets containing different proportions of n-3, n-6 and n-9 unsaturated fatty acids (UFA) from olive (O), maize (C) or rapeseed (R) oils partially substituted or not with TFA (Ot, Ct and Rt, respectively). Male CF1 mice were fed (30 d) one of these diets. The effects of the partial substitution (1 %, w/w) of different UFA with TFA on the activity and expression of hepatic enzymes involved in lipogenesis and fatty acids oxidation were evaluated, as well as their transcription factor expressions. Some of the mechanisms involved in the serum TAG regulation, hepatic VLDL rich in TAG (VLDL-TAG) secretion rate and lipoprotein lipase (LPL) activity were assessed. In liver, TFA induced an increase in TAG content in the Ot and Rt groups, and this effect was associated with an imbalance between lipogenesis and beta-oxidation. In the Ot group, exacerbated lipogenesis may be one of the mechanisms responsible for the liver steatosis induced by TFA, whereas in Rt it has been related to a decreased beta-oxidation, compared with their respective controls. The enhanced hepatic VLDL-TAG secretion in the Ot and Rt groups was compensated with a differential removal of TAG by LPL enzyme in extrahepatic tissues, leading to unchanged serum TAG levels. In brief, the effects of low levels of TFA on liver and serum TAG regulation in mice depend on the dietary proportions of n-3, n-6 and n-9 UFA. PMID- 27464461 TI - Effects of a dietary strawberry powder on parameters of vascular health in adolescent males. AB - Previous studies have shown that the intake of freeze-dried strawberry powder (FDSP) improves select markers of cardiovascular health in adults with cardiovascular risk factors; however, whether these improvements can be observed in at-risk adolescents is unknown. A randomised, double-blind, cross-over study enrolled twenty-five overweight or obese males, aged 14-18 years, to consume 50 g of a FDSP or a control powder, daily for 1 week. Before and after each test period, measures of microvascular function, plasma nitrate/nitrite, platelet reactivity and blood lipids were collected at baseline and acutely 1 h after FDSP intake. Acute plasma nitrate/nitrite levels increased 1 h after consuming the FDSP during Study Visit 1 before daily FDSP intake (P<0.001) and during Study Visit 2 after 1 week of FDSP intake (P<0.001) compared with control powder intake. As a group, fasting nitrate/nitrite levels did not significantly change after 1 week of control or FDSP intake. However, for those individuals where fasting nitrate levels increased after short-term FDSP intake compared with controls, an increase in reactive hyperaemia index (RHI) was observed (P=0.014), whereas RHI was unchanged in those individuals who did not have a significant increase in nitrate (P=0.396). Taken together, these data support the concept that strawberries can provide vascular health benefits to heavier adolescent males. PMID- 27464462 TI - Low fruit consumption and omission of daily meals as risk factors for increased blood pressure in adults. AB - A population-based cross-sectional survey with cluster sampling design and with inverse sampling was conducted in 2010, in a sample of 1590 adults (19-60 years old) exposed to a high prevalence of food insecurity, in the municipality of Duque de Caxias, metropolitan region of Rio de Janeiro, Brazil. The objective of the study was to evaluate the association of socio-demographic factors, the consumption of fruits and vegetables and the number of meals with increased blood pressure (BP). A hierarchical model that considered variables related to the basic, intermediate and immediate determinants of increased BP was adopted. By using Poisson's regression, univariate models were tested to obtain the prevalence ratio (PR) and its respective 95 % CI. After fitting the model, age (age group 50-59 years) (PR 1.62; 95 % CI 1.09, 2.41), low consumption of fruits in a week (PR 1.37; 95 % CI 1.07, 1.74), fewer meals per day (PR 1.72; 95 % CI 1.21, 2.43) and overweight (PR 1.78; 95 % CI 1.31, 2.20) remained significantly associated with increased BP. Therefore, the results found here reinforce the importance of encouraging and developing strategies that ensure access to healthy foods to minimise increased BP in similar populations. PMID- 27464463 TI - Development and characterization of muscle-based actuators for self-stabilizing swimming biorobots. AB - Biorobots that harness the power generated by living muscle cells have recently gained interest as an alternative to traditional mechanical robots. However, robust and reliable operation of these biorobots still remains a challenge. Toward this end, we developed a self-stabilizing swimming biorobot that can maintain its submersion depth, pitch, and roll without external intervention. The biorobot developed in this study utilized a fin-based propulsion mechanism. It consisted of a base made from two composite PDMS materials and a thin PDMS cantilever seeded with a confluent layer of heart muscle cells. The characterization of the heart muscle cell sheet revealed the gradual increase of the dynamic contraction force and the static cell traction force, which was accompanied by a linear increase in the expression levels of contractile and cytoskeletal proteins. In the design of the biorobot, instead of relying only on the geometry, we used two composite PDMS materials whose densities were modulated by adding either microballoons or nickel powder. The use of two materials with different mass densities enabled precise control of the weight distribution to ensure a positive restoration force on the biorobot tilted at any angle. The developed biorobot exhibited unique propulsion modes depending on the resting angle of its "fin" or the cantilever, and achieved a maximum velocity of 142 MUm s(-1). The technique described in this study to stabilize and propel the biorobot can pave the way for novel developments in biorobotics. PMID- 27464464 TI - Statistical inference of dynamic resting-state functional connectivity using hierarchical observation modeling. AB - Spontaneous fluctuations of blood-oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) signals are highly synchronous between brain regions that serve similar functions. This provides a means to investigate functional networks; however, most analysis techniques assume functional connections are constant over time. This may be problematic in the case of neurological disease, where functional connections may be highly variable. Recently, several methods have been proposed to determine moment-to-moment changes in the strength of functional connections over an imaging session (so called dynamic connectivity). Here a novel analysis framework based on a hierarchical observation modeling approach was proposed, to permit statistical inference of the presence of dynamic connectivity. A two-level linear model composed of overlapping sliding windows of fMRI signals, incorporating the fact that overlapping windows are not independent was described. To test this approach, datasets were synthesized whereby functional connectivity was either constant (significant or insignificant) or modulated by an external input. The method successfully determines the statistical significance of a functional connection in phase with the modulation, and it exhibits greater sensitivity and specificity in detecting regions with variable connectivity, when compared with sliding-window correlation analysis. For real data, this technique possesses greater reproducibility and provides a more discriminative estimate of dynamic connectivity than sliding-window correlation analysis. Hum Brain Mapp 37:4566 4580, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27464465 TI - Improvement of Aluminum-Air Battery Performances by the Application of Flax Straw Extract. AB - The effect of a flax straw extract on Al corrosion inhibition in a strong alkaline solution was studied by using electrochemical measurements, weight-loss analysis, SEM, and FTIR spectroscopy. Flax straw extract added (3 vol %) to the 5 m KOH solution to act as a mixed-type Al corrosion inhibitor. The electrochemistry of Al in the presence of a flax straw extract in the alkaline solution, the effect of the extract on the Al morphology and surface films formed, and the corrosion inhibition mechanism are discussed. Finally, the Al-air battery discharge capacity recorded from a cell that used the flax straw extract in the alkaline electrolyte is substantially higher than that with only a pure alkaline electrolyte. This improved sustainability of the Al anode is attributed to Al corrosion inhibition and, consequently, to hydrogen evolution suppression. PMID- 27464466 TI - Evolutionary prediction of medicinal properties in the genus Euphorbia L. AB - The current decrease of new drugs brought to the market has fostered renewed interest in plant-based drug discovery. Given the alarming rate of biodiversity loss, systematic methodologies in finding new plant-derived drugs are urgently needed. Medicinal uses of plants were proposed as proxy for bioactivity, and phylogenetic patterns in medicinal plant uses have suggested that phylogeny can be used as predictive tool. However, the common practice of grouping medicinal plant uses into standardised categories may restrict the relevance of phylogenetic predictions. Standardised categories are mostly associated to systems of the human body and only poorly reflect biological responses to the treatment. Here we show that medicinal plant uses interpreted from a perspective of a biological response can reveal different phylogenetic patterns of presumed underlying bioactivity compared to standardised methods of medicinal plant use classification. In the cosmopolitan and pharmaceutically highly relevant genus Euphorbia L., identifying plant uses modulating the inflammatory response highlighted a greater phylogenetic diversity and number of potentially promising species than standardised categories. Our interpretation of medicinal plant uses may therefore allow for a more targeted approach for future phylogeny-guided drug discovery at an early screening stage, which will likely result in higher discovery rates of novel chemistry with functional biological activity. PMID- 27464467 TI - Antioxidant responses following active and passive smoking of tobacco and electronic cigarettes. AB - CONTEXT: It has been indicated that acute active and passive tobacco cigarette smoking may cause changes on redox status balance that may result in significant pathologies. However, no study has evaluated the effects of active and passive e cigarette smoking on redox status of consumers. OBJECTIVE: To examine the acute effects of active and passive e-cigarette and tobacco cigarette smoking on selected redox status markers. METHODS: Using a randomized single-blind crossover design, 30 participants (15 smokers and 15 nonsmokers) were exposed to three different experimental conditions. Smokers underwent a control session, an active tobacco cigarette smoking session (smoked 2 cigarettes within 30-min) and an active e-cigarette smoking session (smoked a pre-determined number of puffs within 30-min using a liquid with 11 ng/ml nicotine). Similarly, nonsmokers underwent a control session, a passive tobacco cigarette smoking session (exposure of 1 h to 23 +/- 1 ppm of CO in a 60 m(3) environmental chamber) and a passive e-cigarette smoking session (exposure of 1 h to air enriched with pre- determined number of puffs in a 60 m(3) environmental chamber). Total antioxidant capacity (TAC), catalase activity (CAT) and reduced glutathione (GSH) were assessed in participants' blood prior to, immediately after, and 1-h post exposure. RESULTS: TAC, CAT and GSH remained similar to baseline levels immediately after and 1-h-post exposure (p > 0.05) in all trials. CONCLUSIONS: Tobacco and e-cigarette smoking exposure do not acutely alter the response of the antioxidant system, neither under active nor passive smoking conditions. Overall, there is not distinction between tobacco and e-cigarette active and passive smoking effects on specific redox status indices. PMID- 27464468 TI - [Prosthetic joint infection in patients with hip fracture. Differences from infection of elective prosthesis]. AB - OBJECTIVE: Most publications about prosthetic joint infections (PJI) are referred to elective prosthesis and they exclude arthroplasties due to hip fracture. METHODS: We conducted a descriptive study about prosthetic joint infections after joint fracture in Alcala de Henares Hospital (Madrid) between 2009 and 2014 and we compared with elective prosthetic infections in the same period. RESULTS: There were 30 PJI after hip fracture and 14 elective PJI. The incidence of infection was 4.7% in arthroplasties due to hip fracture from 1.3% in elective prosthesis (RR 3.8, p=0.005). The PJI after fracture affected older patients (82.5 years vs 71.5, p=0.006), with greater comorbidity (5.4 vs 3.6, p=0.003), higher anesthetic risk (ASA>2 70% vs 21.4%, p=0.004) and higher incidence of dementia (50% vs 0%, p=0.02). Staphylococcus aureus was the most common causative agent in both groups, but there was higher incidence of Gram negative-cases in PJI after fracture group (43.3% vs 21.4%, p no significance) and cefazolin resistance (63.3% vs 28.6%, p=0.03). In logistic regression analysis the treatment had less chance of success in PJI after fracture than elective PJI (33.3% vs 78.6%, OR 0.09, p=0.06). CONCLUSIONS: The PJI after fracture are more frequent than elective PJI, affect older patients, with poor general condition, are produced by more resistant bacteria and have worst evolution than EPJI. PMID- 27464469 TI - Randomised clinical trial: a Lactobacillus GG and micronutrient-containing mixture is effective in reducing nosocomial infections in children, vs. placebo. AB - BACKGROUND: Nosocomial infections are a major public health issue and preventative strategies using probiotics and micronutrients are being evaluated. AIM: To investigate the efficacy of a mixture of Lactobacillus GG and micronutrients in preventing nosocomial infections in children. METHODS: A randomised, double-blind, placebo-controlled trial was conducted in hospitalised children. Children (6 months to 5 years of age) received Lactobacillus GG (6 * 10(9) CFU/day) together with vitamins B and C and zinc or placebo, for 15 days, starting on the first day of hospitalisation. The incidence of gastrointestinal and respiratory nosocomial infections after discharge was determined by follow-up telephone call at 7 days. After 3 months, another telephone call estimated the incidence of further infections during follow-up. RESULTS: Ninety children completed the follow-up. Of 19/90 children with a nosocomial infection (20%), 4/45 children (9%) were in the treatment group and 15/45 (33%) in the placebo group (P = 0.016). Specifically, 2/45 (4%) children in the treatment group vs. 11/45 (24%) children in the placebo group (P = 0.007) presented with diarrhoea. The duration of hospitalisation was significantly shorter in the treatment group (3.9 days +/- 1.7 vs. 4.9 +/- 1.2; P = 0.003). At the follow-up, a total of 11/45 (24.4%) children in the treatment group had at least one episode of infection compared to 22/45 (48.9%) in the placebo group (P = 0.016). CONCLUSION: A mixture containing Lactobacillus GG and micronutrients may reduce the incidence of nosocomial infections, supporting the hypothesis that this may represent a valid strategy to prevent nosocomial infections. PMID- 27464470 TI - Hearing Restoration with Auditory Brainstem Implant. AB - Auditory brainstem implant (ABI) technology attempts to restore hearing in deaf patients caused by bilateral cochlear nerve injury through the direct stimulation of the brainstem, but many aspects of the related mechanisms remain unknown. The unresolved issues can be grouped into three topics: which patients are the best candidates; which type of electrode should be used; and how to improve restored hearing. We evaluated our experience with 11 cases of ABI placement. We found that if at least seven of eleven electrodes of the MED-EL ABI are effectively placed in a patient with no deformation of the fourth ventricle, open set sentence recognition of approximately 20% and closed set word recognition of approximately 65% can be achieved only with the ABI. Appropriate selection of patients for ABI placement can lead to good outcomes. Further investigation is required regarding patient selection criteria and methods of surgery for effective ABI placement. PMID- 27464471 TI - Medical Engineering and Microneurosurgery: Application and Future. AB - Robotics and medical engineering can convert traditional surgery into digital and scientific procedures. Here, we describe our work to develop microsurgical robotic systems and apply engineering technology to assess microsurgical skills. With the collaboration of neurosurgeons and an engineering team, we have developed two types of microsurgical robotic systems. The first, the deep surgical systems, enable delicate surgical procedures such as vessel suturing in a deep and narrow space. The second type allows for super-fine surgical procedures such as anastomosing artificial vessels of 0.3 mm in diameter. Both systems are constructed with master and slave manipulator robots connected to local area networks. Robotic systems allowed for secure and accurate procedures in a deep surgical field. In cadaveric models, these systems showed a good potential of being useful in actual human surgeries, but mechanical refinements in thickness and durability are necessary for them to be established as clinical systems. The super-fine robotic system made the very intricate surgery possible and will be applied in clinical trials. Another trial included the digitization of surgical technique and scientific analysis of surgical skills. Robotic and human hand motions were analyzed in numerical fashion as we tried to define surgical skillfulness in a digital format. Engineered skill assessment is also feasible and should be useful for microsurgical training. Robotics and medical engineering should bring science into the surgical field and training of surgeons. Active collaboration between medical and engineering teams and academic and industry groups is mandatory to establish such medical systems to improve patient care. PMID- 27464472 TI - Dealing with daily challenges in dementia (deal-id study): an experience sampling study to assess caregiver functioning in the flow of daily life. AB - OBJECTIVE: Accurate assessment of caregiver functioning is of great importance to gain better insight into daily caregiver functioning and to prevent high levels of burden. The experience sampling methodology (ESM) is an innovative approach to assess subjective experiences and behavior within daily life. In this study, the feasibility of the ESM in spousal caregivers of people with dementia was examined, and the usability of ESM data for clinical and scientific practice was demonstrated. METHODS: Thirty-one caregivers collected ESM data for six consecutive days using an electronic ESM device that generated ten random alerts per day. After each alert, short reports of the caregiver's current mood state and context were collected. Feasibility was assessed by examining compliance and subjective experiences with the ESM. Usability was described using group and individual ESM data. RESULTS: Participants on average completed 78.8% of the reports. One participant completed less than 33% of the reports and was excluded from data analyses. Participants considered the ESM device to be a user-friendly device in which they could accurately describe their feelings and experiences. The ESM was not experienced as too burdensome. Zooming in on the ESM data, personalized patterns of mood and contextual factors were revealed. CONCLUSIONS: The ESM is a feasible method to assess caregiver functioning. In addition to standard retrospective measurements, it offers new opportunities to gain more insight into the daily lives of people with dementia and their caregivers. It also provides new possibilities to tailor caregiver support interventions to the specific needs of the caregiver. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27464474 TI - Corrigendum. PMID- 27464473 TI - Imaging in multiple sclerosis: A new spin on lesions. AB - This article evaluates the most relevant state-of-the-art magnetic resonance (MR) techniques that are clinically available to investigate multiple sclerosis (MS). The presence of hypo- and hyperintense lesions on T1- and T2-weighted magnetic resonance imaging (MRI) sequences in white matter (WM) is a common finding that is occasionally a diagnostic challenge for the radiologist. The technical requirements and how they may help to understand, classify or follow-up these pathologies are briefly summarized. The gold standard for MS diagnosis is pathological correlation. Yet due to limited availability of biopsy and autopsy material, there is a high demand for imaging as a diagnostic as well as prognostic indicator. With the progress in MRI during the last decade, MRI now plays a leading role in the diagnosis and follow-up of MS. A number of correlative pathological and MR studies have helped to define pathological substrates of MS in focal lesions and normal appearing white matter (NAWM). Vascular spaces mimicking MS lesions have been minimized by the enhanced differentiation of WM and grey (GM) matter parenchyma. The aim of this article is to enhance the current understanding of histopathology and radiological characteristics of MS lesions in space and time. PMID- 27464475 TI - The changing birth suite experience for Australian medical students. AB - Competition with midwifery students, combined with increasing numbers of medical students, has led to declining standards of clinical experience in the birth suite for our senior medical students. In the Australian setting, increased and improved communication and collaboration between the two disciplines is urgently needed to rectify the situation. PMID- 27464476 TI - A Heterojunction Design of Single Layer Hole Tunneling ZnO Passivation Wrapping around TiO2Nanowires for Superior Photocatalytic Performance. AB - Nanostructured hybrid heterojunctions have been studied widely for photocatalytic applications due to their superior optical and structural properties. In this work, the impact of angstrom thick atomic layer deposited (ALD) ZnO shell layer on photocatalytic activity (PCA) of hydrothermal grown single crystalline TiO2 nanowires (NWs) is systematically explored. We showed that a single cycle of ALD ZnO layer wrapped around TiO2 NWs, considerably boosts the PCA of the heterostructure. Subsequent cycles, however, gradually hinder the photocatalytic activity (PCA) of the TiO2 NWs. Various structural, optical, and transient characterizations are employed to scrutinize this unprecedented change. We show that a single atomic layer of ZnO shell not only increases light harvesting capability of the heterostructure via extension of the absorption toward visible wavelengths, but also mitigates recombination probability of carriers through reduction of surface defects density and introduction of proper charge separation along the core-shell interface. Furthermore, the ultrathin ZnO shell layer allows a strong contribution of the core (TiO2) valence band holes through tunneling across the ultrathin interface. All mechanisms responsible for this enhanced PCA of heterostructure are elucidated and corresponding models are proposed. PMID- 27464477 TI - Novel murine tumour models depend on strain and route of inoculation. AB - This study describes variations in tumour growth patterns which occur when changes in the routes of inoculation and mouse strain are used to introduce tumours into established murine model systems that are known to vary in location and aggression. Intraperitoneal, subcutaneous, intravenous and hydrodynamic inoculations of B16F10 cells were compared among CD-1, C57BL/6 and Balb/c mice. Most surprisingly, allogeneic tumour growth in Balb/c mice after intravenous and hydrodynamic inoculation of B16F10 cells was faster than tumour growth in the syngeneic C57BL/6 mice. These and other variations in the tumour growth patterns described here can help provide the researcher with more experimental control when planning to use the optimal tumour model for any particular study. PMID- 27464478 TI - Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient. AB - The nuclear lamina is essential for the proper structure and organization of the nucleus. Deregulation of A-type lamins can compromise genomic stability, alter chromatin organization and cause premature vascular aging. Here, we show that accumulation of the lamin A precursor, prelamin A, inhibits 53BP1 recruitment to sites of DNA damage and increases basal levels of DNA damage in aged vascular smooth muscle cells. We identify that this genome instability arises through defective nuclear import of 53BP1 as a consequence of abnormal topological arrangement of nucleoporin NUP153. We show for the first time that this nucleoporin is important for the nuclear localization of Ran and that the deregulated Ran gradient is likely to be compromising the nuclear import of 53BP1. Importantly, many of the defects associated with prelamin A expression were significantly reduced upon treatment with Remodelin, a small molecule recently reported to reverse deficiencies associated with abnormal nuclear lamina. PMID- 27464479 TI - Angiomotin like-1 is a novel component of the N-cadherin complex affecting endothelial/pericyte interaction in normal and tumor angiogenesis. AB - Transmission of mechanical force via cell junctions is an important component that molds cells into shapes consistent with proper organ function. Of particular interest are the cadherin transmembrane proteins, which play an essential role in connecting cell junctions to the intra-cellular cytoskeleton. Understanding how these biomechanical complexes orchestrate intrinsic and extrinsic forces is important for our understanding of the underlying mechanisms driving morphogenesis. We have previously identified the Amot protein family, which are scaffold proteins that integrate polarity, junctional, and cytoskeletal cues to modulate cellular shape in endothelial as well as epithelial cells. In this report, we show that AmotL1 is a novel partner of the N-cadherin protein complex. We studied the role of AmotL1 in normal retinal as well as tumor angiogenesis using inducible endothelial-specific knock-out mice. We show that AmotL1 is essential for normal establishment of vascular networks in the post-natal mouse retina as well as in a transgenic breast cancer model. The observed phenotypes were consistent with a non-autonomous pericyte defect. We show that AmotL1 forms a complex with N-cadherin present on both endothelial cells and pericytes. We propose that AmotL1 is an essential effector of the N-cadherin mediated endothelial/pericyte junctional complex. PMID- 27464481 TI - Rheumatoid arthritis: Tocilizumab and the risk of intestinal perforation. PMID- 27464480 TI - Electro-hydrodynamic concentration of genomic length DNA. AB - We report a method of concentrating genomic length DNA within a microfluidic device, using a novel mechanism that combines polyelectrolyte migration with electrophoretic recirculation. Suitable combinations of geometry, pressure and voltage will trap long DNA molecules (>10 kbp) within a small volume (approximately 1 nL), amplifying the local concentration at rates in excess of 1000 fold per minute. The rate at which DNA accumulates is length dependent, while charged particles of similar size pass freely through the device. Experimental observations confirm that the rapid accumulation of DNA at the inlet is caused by an outward migration of the polyelectrolyte towards the capillary boundaries, followed by electrophoresis of DNA within the stagnant fluid layer next to the wall. PMID- 27464482 TI - Diagnosis: Defining sarcopenia and refining its measurement. PMID- 27464483 TI - Systemic lupus erythematosus: New GWAS loci and insights into ancestry. PMID- 27464485 TI - Determination of 21 drugs in oral fluid using fully automated supported liquid extraction and UHPLC-MS/MS. AB - Collection of oral fluid (OF) is easy and non-invasive compared to the collection of urine and blood, and interest in OF for drug screening and diagnostic purposes is increasing. A high-throughput ultra-high-performance liquid chromatography tandem mass spectrometry method for determination of 21 drugs in OF using fully automated 96-well plate supported liquid extraction for sample preparation is presented. The method contains a selection of classic drugs of abuse, including amphetamines, cocaine, cannabis, opioids, and benzodiazepines. The method was fully validated for 200 MUL OF/buffer mix using an Intercept OF sampling kit; validation included linearity, sensitivity, precision, accuracy, extraction recovery, matrix effects, stability, and carry-over. Inter-assay precision (RSD) and accuracy (relative error) were <15% and 13 to 5%, respectively, for all compounds at concentrations equal to or higher than the lower limit of quantification. Extraction recoveries were between 58 and 76% (RSD < 8%), except for tetrahydrocannabinol and three 7-amino benzodiazepine metabolites with recoveries between 23 and 33% (RSD between 51 and 52 % and 11 and 25%, respectively). Ion enhancement or ion suppression effects were observed for a few compounds; however, to a large degree they were compensated for by the internal standards used. Deuterium-labelled and 13 C-labelled internal standards were used for 8 and 11 of the compounds, respectively. In a comparison between Intercept and Quantisal OF kits, better recoveries and fewer matrix effects were observed for some compounds using Quantisal. The method is sensitive and robust for its purposes and has been used successfully since February 2015 for analysis of Intercept OF samples from 2600 cases in a 12-month period. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27464486 TI - Porcine antigen-specific IFN-gamma ELISpot as a potentially valuable tool for monitoring cellular immune responses in pig-to-non-human primate islet xenotransplantation. AB - BACKGROUND: Recent progress in xenotransplantation of porcine islets to non-human primates (NHPs) gives hope for human clinical trials in the near future. Thus, implementation of an appropriate monitoring method to detect the development of detrimental porcine antigen-specific cellular immune responses is necessary. The enzyme-linked immunospot (ELISpot) assay has been widely used to monitor antigen specific alloreactive T-cell responses in humans; however, the utility of porcine islet-specific ELISpot assay has not yet been thoroughly evaluated for pig-to NHPs intraportal islet xenotransplantation. METHODS: The optimal ELISpot assay conditions, including the number of responder and stimulator cells and the provision of costimulation, were determined. Then, ELISpot assays were conducted on serial stocks of peripheral blood mononuclear cell (PBMC) samples previously isolated from NHP recipients transplanted with porcine islets. Either splenocytes from donor pigs or pancreatic islets from third-party pigs were used for antigen stimulation. At the same time, the ratio of CD4(+) /CD8(+) T cells and the percentage of CD4(+) FoxP3(+) T cells in the peripheral blood were evaluated. Finally, liver biopsy samples were evaluated to assess the immunopathology of the grafts. RESULTS: The optimal conditions for the ELISpot assay were defined as 2.5 * 10(5) responder cells incubated with 5.0 * 10(5) stimulator cells in 96-well, flat-bottom plates without further costimulation. Using donor splenocytes as stimulators, a serial interferon-gamma (IFN-gamma) ELISpot assay with PBMCs from the monkeys with prolonged porcine islet grafts (>180 days) demonstrated that the number of donor antigen-specific IFN-gamma-producing cells significantly increased upon overt graft rejection. However, use of third-party porcine islets as stimulators did not reflect graft rejection, suggesting that the use of donor specific PBMCs, and not tissue (porcine islet)-specific cells, as stimulators could better serve the purpose of this assay in adult porcine islet transplantation. IFN-gamma spot number was neither influenced by the peripheral blood CD4(+) /CD8(+) T-cell ratio nor the percentage of CD4(+) FoxP3(+) T cells. Finally, in cases of overt graft rejection, the number of IFN-gamma spots and the graft-infiltrating T cells in biopsied liver samples increased simultaneously. CONCLUSION: Use of PBMCs in a porcine antigen-specific IFN-gamma ELISpot assay is a reliable method for monitoring T-cell-mediated rejection in pig-to-NHP islet xenotransplantation. PMID- 27464484 TI - ANCA-associated vasculitis - clinical utility of using ANCA specificity to classify patients. AB - The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of rare syndromes characterized by necrotizing inflammation of small and medium-sized blood vessels and the presence of ANCAs. Several clinicopathological classification systems exist that aim to define homogeneous groups among patients with AAV, the main syndromes being microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Two main types of ANCA can be detected in patients with AAV. These ANCAs are defined according to their autoantigen target, namely leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). Patients with GPA are predominantly PR3-ANCA-positive, whereas those with MPA are predominantly MPO-ANCA-positive, although ANCA specificity overlaps only partially with these clinical syndromes. Accumulating evidence suggests that ANCA specificity could be better than clinical diagnosis for defining homogeneous groups of patients, as PR3-ANCA and MPO-ANCA are associated with different genetic backgrounds and epidemiology. ANCA specificity affects the phenotype of clinical disease, as well as the patient's initial response to remission-inducing therapy, relapse risk and long-term prognosis. Thus, the classification of AAV by ANCA specificity rather than by clinical diagnosis could convey clinically useful information at the time of diagnosis. PMID- 27464487 TI - Analysis of the prognostic factors of long-term native liver survival in survivors of biliary atresia. AB - PURPOSE: Long-term survivors of biliary atresia (BA) sometimes experience liver dysfunction. We evaluated the prognostic factors for long-term native liver survival (NLS) in BA patients after the Kasai procedure. METHODS: This study included 67 patients with jaundice disappearance after the Kasai procedure performed between 1972 and 1995, and NLS for over 10 years. We retrospectively evaluated the clinical parameters, including the type of BA, age at the Kasai procedure, medical conditions, and treatments. The adjusted odds ratios (aOR) were obtained for 20-year NLS using logistic regression analysis. RESULTS: The median age of the patients at the Kasai procedure was 63 days. Of the 67 study patients, 62 patients (92.5 %) had jaundice-free NLS at the age of 20 years, 4 patients died before the age of 20 years from liver failure, and 1 patient underwent living related liver transplantation. The presence of gastro-esophageal varices requiring endoscopic injection sclerotherapy was a significant factor (aOR 33.8; p = 0.0033), while hypersplenism and cholangitis were not identified as significant factors. CONCLUSIONS: The existence of symptomatic portal hypertension would influence long-term NLS in BA patients after the Kasai procedure. In such patients, accurate evaluation of hepatic function and adequate treatment for sequelae are needed. PMID- 27464488 TI - Promoting weight loss through diet and exercise in overweight or obese breast cancer survivors (InForma): study protocol for a randomized controlled trial. AB - BACKGROUND: Most women with breast cancer experience a progressive weight gain during and after treatment. Obesity is associated with an increased risk of recurrence, contralateral breast cancer, and death. Physical activity after cancer diagnosis has been reported to have positive effects on body composition and quality of life. We present the protocol of the InForma study, a trial testing the efficacy of an intervention on weight loss (>=5 % of the baseline body weight) in a group of overweight or obese breast cancer survivors. METHODS/DESIGN: This is a four-arm randomized controlled trial. Patients will receive a 6-month intervention and be followed for a further 18 months. Intervention is designed to improve adherence to a healthy diet and/or to increase physical activity, taking advantage of a wrist-based activity monitor. Participants will be recruited among overweight or obese breast cancer patients treated at the European Institute of Oncology, after completion of eventual adjuvant chemotherapy and/or radiotherapy. It is envisaged that 260 patients will be randomized into four arms: Dietary Intervention; Physical Activity Intervention; Physical Activity and Dietary Intervention; and Less Intensive Intervention. Women will be offered individualized counseling consisting of face to face discussion and phone calls in addition to group meetings. A motivational interviewing approach will be used to encourage health behavior change. All participants will be given a pedometer device to monitor their physical activity. Participants' dietary intake will be repeatedly assessed using a validated food frequency questionnaire. Participants' quality of life and anxiety will be assessed with the Functional Assessment of Cancer Therapy-Breast and the State Trait Anxiety Inventory questionnaires. Blood samples will be collected at baseline and follow-up visits to assess lipid and hormone profiles. Body composition will be repeatedly assessed using bioelectrical impedance vector analysis for identifying changes of fat and fat-free mass. Women allocated to the less intensive intervention arm will be considered as the control group. DISCUSSION: While there is a rising concern about the role of obesity in cancer recurrence and survival, this trial with its multi-arm design, motivational approach and use of a pedometer device will provide important insights regarding the most effective approach in promoting weight control in breast cancer survivors. TRIAL REGISTRATION: ISRCTN53325751 (registration date: 16 October 2015); ClinicalTrials.gov NCT02622711 (registration date: 2 December 2015). PMID- 27464489 TI - Interim analysis of post-marketing surveillance of eculizumab for paroxysmal nocturnal hemoglobinuria in Japan. AB - Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1 month's treatment with eculizumab (p < 0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1 year of treatment with eculizumab (p < 0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count >=150 * 109/L. Approximately 97 % of patients showed maintenance or improvement of renal function. Overall survival rate was about 90 % (median follow-up 1.9 years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention. PMID- 27464490 TI - Prenatal anxiety, maternal stroking in infancy, and symptoms of emotional and behavioral disorders at 3.5 years. AB - Animal findings of long-term effects of maternal behaviors mediated via altered GR gene expression will, if translated into humans, have far reaching implications for our understanding of child and adolescent psychopathology. We have previously shown that mothers' self-reported stroking of their infants modifies associations between prenatal depression and anxiety and child outcomes at 29 weeks and 2.5 years. Here, we examine whether the effect of early maternal stroking is evident at 3.5 years, and in a much larger sample than in previous publications. A general population sample of 1233 first-time mothers completed anxiety measures at 20 weeks gestation, 865 reported on infant stroking at 9 weeks, and 813 on child symptoms at 3.5 years. Maternal stroking moderated the association between pregnancy-specific anxiety and internalizing (p = 0.010) and externalizing (p = 0.004) scores, such that an effect of PSA to increase symptoms was markedly reduced for mothers who reported high levels of stroking. There was no effect of maternal stroking on general anxiety. The findings confirm the previously reported effect of maternal stroking, and in a much larger sample. They indicate that there are long-term effects of early maternal stroking, modifying associations between prenatal anxiety and child emotional and behavioral symptoms. PMID- 27464491 TI - Comparing the testing effect under blocked and mixed practice: The mnemonic benefits of retrieval practice are not affected by practice format. AB - The act of retrieving information modifies memory in critical ways. In particular, testing-effect studies have demonstrated that retrieval practice (compared to restudy or to no testing) benefits long-term retention and protects from retroactive interference. Although such testing effects have previously been demonstrated in both between- and within-subjects manipulations of retrieval practice, it is less clear whether one or the other testing format is most beneficial on a final test. In two paired-associate learning experiments conducted under typical testing-effect conditions, we manipulated restudy and test trials using either blocked or mixed practice conditions while equating other factors. Retrieval-practice and restudy trials were presented either separately in different blocks (blocked practice) or randomly intermixed (mixed practice). In Experiment 1, recall was assessed after short and long delay intervals; in Experiment 2, the final memory test occurred after a short delay, but with or without an interfering activity before the final test. In both experiments, typical testing effects emerged, and critically, they were found to be unaffected by practice format. These results support the conclusion that testing effects are robust and emerge to equal extents in both blocked and mixed designs. The generality of testing effects further encourages the application of retrieval practice as a memory enhancer in a variety of contexts, including education. PMID- 27464492 TI - The dynamics of choice in a changing world: Effects of full and partial feedback. AB - We explored the dynamics of choice behavior while the values of the options changed, unannounced, several times. In particular, choice dynamics were compared when the outcome values of all available options were known (full feedback) and when the outcome value of only the chosen option was known (partial feedback). The frequency of change, the values of the options, and the difference between them were also manipulated. In an experiment with N = 427, we found that the patterns of choices were different for the two levels of feedback. Whereas behavior in the full-feedback condition showed a tendency to switch choices following a missed opportunity-replicating previous findings-the behavior in the partial-feedback condition was different. It was sensitive to the outcome value of the chosen option in comparison to some memory of the last-experienced outcome value of the unchosen option. However, the comparison of these two values influenced choice behavior only when the outcome of the currently chosen option was satisfactory and the last outcome of the unchosen one was not. As expected, the other manipulated variables (change frequency, the options' values, and the difference between them) had no effect on the dynamics of behavior. PMID- 27464494 TI - MiR-30s Family Inhibit the Proliferation and Apoptosis in Human Coronary Artery Endothelial Cells Through Targeting the 3'UTR Region of ITGA4 and PLCG1. AB - Atherosclerosis (As) is a common disease, which is serious hazard to human health. As the main pathological basis of ischemic cardiac and cerebral vascular disease, including coronary heart disease, cerebrovascular disease, and thromboembolic disease, it is a chronic inflammatory lesion of the arterial vessel wall. So far the pathogenesis of As has not been fully understood. Therefore, it is still lack of effective clinical prevention and treatment of drugs. More and more evidence indicate that miRNA plays an important role in the pathophysiology of many diseases, especially the occurrence and development of cardiovascular diseases. MiRNAs are widely detected in human coronary artery endothelial cells, which might participate in diverse biological functions through targeting different As associated genes. The aim of this study was to investigate the molecular mechanisms underlying miR-30s roles in As. Our study found the high expression of miR-30b and miR-30e in As clinical samples, identified the regulatory relationship of miR-30b and miR-30e to ITGA4 and PLCG1, respectively, and initially explored the effects of miR-30b and miR-30e on cell cycle and apoptosis through targeting ITGA4 and PLCG1. These data may provide a theoretical basis for clarifying the mechanism of miR-30s in As. PMID- 27464495 TI - Heparin-induced Thrombocytopenia Presenting With Deep Venous Thrombosis and Pulmonary Embolism Successfully Treated With Rivaroxaban: Clinical Case Report and Review of Current Experiences. AB - Heparin-induced thrombocytopenia (HIT) is a life or limb-threatening thrombotic thrombocytopenia. HIT is traditionally treated with factor-IIa inhibitors such as bivalirudin, lepirudin, or argatroban. However, these agents usually require parenteral administration and are not generally available in all countries. Recently, several experiences with novel oral anticoagulants (NOACs) administration to treat HIT had been reported. NOACs generally offer advantages such as consistent and predictable anticoagulation, oral administration with good patient compliance, and a good safety profile. We report a case of HIT with severe thrombotic complications successfully treated with rivaroxaban and discuss the current knowledge about the use of NOACs for the treatment of this potentially fatal thrombocytopenia. PMID- 27464496 TI - Hypergastrinemia and a duodenal ulcer caused by gastric duplication. AB - BACKGROUND: Hypergastrinemia and the resultant peptic ulcer related to an enteric duplication has been quite rarely reported in the literature. CASE PRESENTATION: We herein report the case of a 4-year-old girl who presented with hypergastrinemia and a duodenal ulcer at 2 years of age. She had been followed up with a proton pump inhibitor, which resulted in resolution of the ulcer; however, unexplained hypergastrinemia had continued. A cystic lesion at the antrum was discovered at 4 years of age, which we suspected to be a gastric duplication. After we resected the lesion, the hypergastrinemia resolved without recurrence of the duodenal ulcer. The histology was compatible with a gastric duplication, and the lumen was lined with antral mucosa that strongly stained positive for gastrin. We presumed that the antral mucosa inside the duplication in our case had no hydrogen ion feedback inhibition of gastrin release from gastrin cells and increased release of gastrin from the mucosa inside the duplication led to the duodenal ulcer. Only two cases have been reported in the literature that had hypergastrinemia related to enteric duplication. CONCLUSION: Gastric duplication should be included in the differential diagnosis of sustained hypergastrinemia in children. PMID- 27464497 TI - Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium. AB - The vascular endothelium and shear stress are critical determinants of physiological hemostasis and platelet function in vivo, yet current diagnostic and monitoring devices do not fully incorporate endothelial function under flow in their assessment and, therefore, they can be unreliable and inaccurate. It is challenging to include the endothelium in assays for clinical laboratories or point-of-care settings because living cell cultures are not sufficiently robust. Here, we describe a microfluidic device that is lined by a human endothelium that is chemically fixed, but still retains its ability to modulate hemostasis under continuous flow in vitro even after few days of storage. This device lined with a fixed endothelium supports formation of platelet-rich thrombi in the presence of physiological shear, similar to a living arterial vessel. We demonstrate the potential clinical value of this device by showing that thrombus formation and platelet function can be measured within minutes using a small volume (0.5 mL) of whole blood taken from subjects receiving antiplatelet medications. The inclusion of a fixed endothelial microvessel will lead to biomimetic analytical devices that can potentially be used for diagnostics and point-of-care applications. PMID- 27464500 TI - Synthesis and Macrodomain Binding of Mono-ADP-Ribosylated Peptides. AB - Mono-ADP-ribosylation is a dynamic posttranslational modification (PTM) with important roles in signaling. Mammalian proteins that recognize or hydrolyze mono ADP-ribosylated proteins have been described. We report the synthesis of ADP ribosylated peptides from the proteins histone H2B, RhoA and, HNP-1. An innovative procedure was applied that makes use of pre-phosphorylated amino acid building blocks. Binding assays revealed that the macrodomains of human MacroD2 and TARG1 exhibit distinct specificities for the different ADP-ribosylated peptides, thus showing that the sequence surrounding ADP-ribosylated residues affects the substrate selectivity of macrodomains. PMID- 27464498 TI - Multimodal Imaging Reveals Improvement of Blood Supply to an Artificial Cell Transplant Site Induced by Bioluminescent Mesenchymal Stem Cells. AB - PURPOSE: An artificial site for cell or pancreatic islet transplantation can be created using a polymeric scaffold, even though it suffers subcutaneously from improper vascularisation. A sufficient blood supply is crucial for graft survival and function and can be enhanced by transplantation of mesenchymal stem cells (MSCs). The purpose of this study was to assess the effect of syngeneic MSCs on neoangiogenesis and cell engraftment in an artificial site by multimodal imaging. PROCEDURES: MSCs expressing a gene for luciferase were injected into the artificial subcutaneous site 7 days after scaffold implantation. MRI experiments (anatomical and dynamic contrast-enhanced images) were performed on a 4.7-T scanner using gradient echo sequences. Bioluminescent images were acquired on an IVIS Lumina optical imager. Longitudinal examination was performed for 2 months, and one animal was monitored for 16 months. RESULTS: We confirmed the long-term presence (lasting more than 16 months) of viable donor cells inside the scaffolds using bioluminescence imaging with an optical signal peak appearing on day 3 after MSC implantation. When compared to controls, the tissue perfusion and vessel permeability in the scaffolds were significantly improved at the site with MSCs with a maximal peak on day 9 after MSC transplantation. CONCLUSIONS: Our data suggest that the maximal signal obtained by bioluminescence and magnetic resonance imaging from an artificially created site between 3 and 9 days after MSC transplantation can predict the optimal time range for subsequent cellular or tissue transplantation, including pancreatic islets. PMID- 27464502 TI - Effect of humic acid on ciprofloxacin removal by magnetic multifunctional resins. AB - Background organic matter significantly influences the removal of emerging contaminants in natural water. In this work, the adsorption of ciprofloxacin (CPX) onto a series of magnetic multifunctional resins (GMA10-GMA90) in the presence and absence of humic acid (HA) was conducted to demonstrate the effect of HA. Both hydrophobic and ion exchange interactions contributed to CPX adsorption. Negative charge-assisted hydrogen bonds also participated in the adsorption process, resulting in the high adsorption amount of anionic CPX onto the negatively charged GMA30 under basic solutions. HA could impact CPX adsorption not only as a competitive adsorbate but also as an additional adsorbent. At pH 5.6, the additional adsorption sites provided by adsorbed HA molecules on the resins dominated and thus facilitated the adsorption process. While at pH 10, HA inhibited the adsorption of CPX by directly competing for ion exchange sites and coexisting with CPX in the solution. The ratio of the amount of CPX adsorbed by dissolved HA to that by the resin reached as high as 1.61 for GMA90. The adsorbed HA molecules onto the resins could provide additional adsorption sites for CPX as proven by the enhanced CPX adsorption in HA preloading systems at pH 5.6. PMID- 27464501 TI - Effect of gadolinium-based nanoparticles on nuclear DNA damage and repair in glioblastoma tumor cells. AB - BACKGROUND: Tumor targeting of radiotherapy represents a great challenge. The addition of multimodal nanoparticles, such as 3 nm gadolinium-based nanoparticles (GdBNs), has been proposed as a promising strategy to amplify the effects of radiation in tumors and improve diagnostics using the same agents. This singular property named theranostic is a unique advantage of GdBNs. It has been established that the amplification of radiation effects by GdBNs appears due to fast electronic processes. However, the influence of these nanoparticles on cells is not yet understood. In particular, it remains dubious how nanoparticles activated by ionizing radiation interact with cells and their constituents. A crucial question remains open of whether damage to the nucleus is necessary for the radiosensitization exerted by GdBNs (and other nanoparticles). METHODS: We studied the effect of GdBNs on the induction and repair of DNA double-strand breaks (DSBs) in the nuclear DNA of U87 tumor cells irradiated with gamma-rays. For this purpose, we used currently the most sensitive method of DSBs detection based on high-resolution confocal fluorescence microscopy coupled with immunodetection of two independent DSBs markers. RESULTS: We show that, in the conditions where GdBNs amplify radiation effects, they remain localized in the cytoplasm, i.e. do not penetrate into the nucleus. In addition, the presence of GdBNs in the cytoplasm neither increases induction of DSBs by gamma-rays in the nuclear DNA nor affects their consequent repair. CONCLUSIONS: Our results suggest that the radiosensitization mediated by GdBNs is a cytoplasmic event that is independent of the nuclear DNA breakage, a phenomenon commonly accepted as the explanation of biological radiation effects. Considering our earlier recognized colocalization of GdBNs with the lysosomes and endosomes, we revolutionary hypothesize here about these organelles as potential targets for (some) nanoparticles. If confirmed, this finding of cytoplasmically determined radiosensitization opens new perspectives of using nano-radioenhancers to improve radiotherapy without escalating the risk of pathologies related to genetic damage. PMID- 27464503 TI - Characterization of VP1 sequence of Coxsackievirus A16 isolates by Bayesian evolutionary method. AB - BACKGROUND: Coxsackievirus A16 (CV-A16), a major etiopathologic cause of pediatric hand, foot, and mouth disease (HFMD) worldwide, has been reported to have caused several fatalities. Revealing the evolutionary and epidemiologic dynamics of CV-A16 across time and space is central to understanding its outbreak potential. METHODS: In this study, we isolated six CV-A16 strains in China's Jilin province and construct a maximum clade credibility (MCC) tree for CV-A16 VP1 gene by the Bayesian Markov Chain Monte Carlo method using 708 strains from GenBank with epidemiological information. The evolution characteristics of CV-A16 VP1 gene was also analysed dynamicly through Bayesian skyline plot. RESULTS: All CV-A16 strains identified could be classified into five major genogroups, denoted by GI-GV. GIV and GV have co-circulated in China since 2007, and the CV-A16 epidemic strain isolated in the Jilin province, China, can be classified as GIV 3. The CV-A16 genogroups circulating recently in China have the same ancestor since 2007. The genetic diversity of the CV-A16 VP1 gene shows a continuous increase since the mid-1990s, with sharp increases in genetic diversity in 1997 and 2007 and reached peak in 2007. Very low genetic diversity existed after 2010. The CV-A16 VP1 gene evolutionary rate was 6.656E-3 substitutions per site per year. CONCLUSIONS: We predicted the dynamic phylogenetic trends, which indicate outbreak trends of CV-A16, and provide theoretical foundations for clinical prevention and treatment of HFMD which caused by a CV-A16. PMID- 27464504 TI - Wild cricket social networks show stability across generations. AB - BACKGROUND: A central part of an animal's environment is its interactions with conspecifics. There has been growing interest in the potential to capture these interactions in the form of a social network. Such networks can then be used to examine how relationships among individuals affect ecological and evolutionary processes. However, in the context of selection and evolution, the utility of this approach relies on social network structures persisting across generations. This is an assumption that has been difficult to test because networks spanning multiple generations have not been available. We constructed social networks for six annual generations over a period of eight years for a wild population of the cricket Gryllus campestris. RESULTS: Through the use of exponential random graph models (ERGMs), we found that the networks in any given year were able to predict the structure of networks in other years for some network characteristics. The capacity of a network model of any given year to predict the networks of other years did not depend on how far apart those other years were in time. Instead, the capacity of a network model to predict the structure of a network in another year depended on the similarity in population size between those years. CONCLUSIONS: Our results indicate that cricket social network structure resists the turnover of individuals and is stable across generations. This would allow evolutionary processes that rely on network structure to take place. The influence of network size may indicate that scaling up findings on social behaviour from small populations to larger ones will be difficult. Our study also illustrates the utility of ERGMs for comparing networks, a task for which an effective approach has been elusive. PMID- 27464505 TI - Chemiluminescence Immunoassay for S-Adenosylhomocysteine Detection and Its Application in DNA Methyltransferase Activity Evaluation and Inhibitors Screening. AB - Aberrant methylation by DNA transferase is associated with cancer initiation and progression. For high-throughput screening of DNA methyltransferase (MTase) activity and its inhibitors, a novel chemiluminescence immunoassay (CLIA) was established to detect S-adenosylhomocysteine (SAH), the product of S adenosylmethionine (SAM) transmethylation reactions. We synthesized two kinds of immunogens for SAH and characterized the polyclonal antibodies in each group. The antibody with higher titer was used to develop a competitive CLIA for SAH, in which SAH in samples would compete with SAH coated on microplate in binding with SAH antibodies. Successively, horseradish peroxidase labeled goat antirabbit IgG (HRP-IgG) was conjugated with SAH antibodies on the microplate. In substrate solution containing luminol and H2O2, HRP-IgG catalyzed luminol oxidation by H2O2, generating a high chemiluminescence signal. The method could detect as low as 9.8 ng mL(-1) SAH with little cross-reaction (3.8%) to SAM. Since higher DNA MTase activity leads to more production of SAH, a correlation between the chemiluminescence intensity and DNA MTase activity was obtained in the range from 0.1 to 8.0 U/mL of DNA MTase. The inhibition study showed that, in the presence of SAM as methyl donor, Lomeguatrib, 5-Azacytidine, and 5-Aza-2'-deoxycytidine could inhibit the DNA MTase activity with IC50 values of 40.57 nM, 2.26 MUM, and 0.48 MUM, respectively. These results are consistent with the published studies. The proposed assay does not depend on recognizing methylated cytosines in oligonucleotides (methyl acceptor) and showed the potential as an accessible platform for sensitive detection of DNA MTase activity and screening its inhibitors. PMID- 27464506 TI - Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first/charge-balanced/biphasic pulses for 0.566 <= k <= 2.3 in oxygenated and deoxygenated sulfuric acid. AB - The application of a train of cathodic-first/charge-balanced/biphasic pulses applied to a platinum electrode resulted in a positive creep of the anodic phase potential that increases with increasing charge injection but reaches a steady state value before 1000 pulses have been delivered. The increase follows from the fact that charge going into irreversible reactions occurring during the anodic phase must equal the charge going into irreversible reactions during the cathodic phase for charge-balanced pulses. In an oxygenated electrolyte the drift of the measured positive potential moved into the platinum oxidation region of the i(V e) profile when the charge injection level exceeds k = 1.75. Platinum dissolution may occur in this region and k = 1.75 defines a boundary between damaging and non damaging levels on the Shannon Plot. In a very low oxygen environment, the positive potential remained below the platinum oxidation region for the highest charge injection values studied, k = 2.3. The results support the hypothesis that platinum dissolution is the defining factor for the Shannon limit, k = 1.75. Numerous instrumentation issues were encountered in the course of making measurements. The solutions to these issues are provided. PMID- 27464508 TI - A cost analysis of introducing an infectious disease specialist-guided antimicrobial stewardship in an area with relatively low prevalence of antimicrobial resistance. AB - BACKGROUND: Antimicrobial stewardship programs have been widely introduced in hospitals as a response to increasing antimicrobial resistance. Although such programs are commonly used, the long-term effects on antimicrobial resistance as well as societal economics are uncertain. METHODS: We performed a cost analysis of an antimicrobial stewardship program introduced in Malmo, Sweden in 20 weeks 2013 compared with a corresponding control period in 2012. All direct costs and opportunity costs related to the stewardship intervention were calculated for both periods. Costs during the stewardship period were directly compared to costs in the control period and extrapolated to a yearly cost. Two main analyses were performed, one including only comparable direct costs (analysis one) and one including comparable direct and opportunity costs (analysis two). An extra analysis including all comparable direct costs including costs related to length of hospital stay (analysis three) was performed, but deemed as unrepresentative. RESULTS: According to analysis one, the cost per year was SEK 161 990 and in analysis two the cost per year was SEK 5 113. Since the two cohorts were skewed in terms of size and of infection severity as a consequence of the program, and since short-term patient outcomes have been demonstrated to be unchanged by the intervention, the costs pertaining to patient outcomes were not included in the analysis, and we suggest that analysis two provides the most correct cost calculation. In this analysis, the main cost drivers were the physician time and nursing time. A sensitivity analysis of analysis two suggested relatively modest variation under changing assumptions. CONCLUSION: The total yearly cost of introducing an infectious disease specialist-guided, audit-based antimicrobial stewardship in a department of internal medicine, including direct costs and opportunity costs, was calculated to be as low as SEK 5 113. PMID- 27464507 TI - The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis. AB - Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ in their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory macrophages, WAT-resident macrophages counteract inflammation and insulin resistance, yet, the mechanisms underlying their transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor-glucocorticoid receptor (GR)-interacting protein (GRIP)1-cooperates with GR to repress inflammatory genes. Here, we show that GRIP1 facilitates macrophage programming in response to IL4 via a GR-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4-a driver of tissue-resident macrophage differentiation. Moreover, obese mice conditionally lacking GRIP1 in macrophages develop massive macrophage infiltration and inflammation in metabolic tissues, fatty livers, hyperglycaemia and insulin resistance recapitulating metabolic disease. Thus, GRIP1 is a critical regulator of immunometabolism, which engages distinct transcriptional mechanisms to coordinate the balance between macrophage populations and ultimately promote metabolic homeostasis. PMID- 27464509 TI - Opposite Associations between Individual KIAA0319 Polymorphisms and Developmental Dyslexia Risk across Populations: A Stratified Meta-Analysis by the Study Population. AB - KIAA0319 at the DYX2 locus is one of the most extensively studied candidate genes for developmental dyslexia (DD) owing to its important role in neuronal migration. Previous research on associations between KIAA0319 genetic variations and DD has yielded inconsistent results. It is important to establish a more precise estimate of the DD risk associated with these genetic variations. We carried out a meta-analysis of association studies involving KIAA0319 polymorphisms and DD risk. The results of pooled analysis indicated that none of the six investigated markers in or near the KIAA0319 gene are associated with DD. However, a stratified analysis by the study population revealed opposite associations involving KIAA0319 rs4504469 in European and Asian subgroups. The stratified analysis also showed that the KIAA0319 rs9461045 minor allele (T allele) has a protective effect in Asians. This meta-analysis has allowed us to establish the effects of specific KIAA0319 polymorphisms on DD risk with greater precision, as they vary across populations; analyzing one single nucleotide polymorphism at a time could not fully explain the genetic association for DD. PMID- 27464511 TI - Identification of novel antifungal lead compounds through pharmacophore modeling, virtual screening, molecular docking, antimicrobial evaluation, and gastrointestinal permeation studies. PMID- 27464512 TI - Documentation of Focal Takotsubo Syndrome and Its Diagnostic Implications. PMID- 27464513 TI - Documentation of Focal Takotsubo Syndrome and Its Diagnostic Implications - Reply. PMID- 27464510 TI - Rationale, design, and methods for Canadian alliance for healthy hearts and minds cohort study (CAHHM) - a Pan Canadian cohort study. AB - BACKGROUND: The Canadian Alliance for Healthy Hearts and Minds (CAHHM) is a pan Canadian, prospective, multi-ethnic cohort study being conducted in Canada. The overarching objective of the CAHHM is to understand the association of socio environmental and contextual factors (such as societal structure, activity, nutrition, social and tobacco environments, and access to health services) with cardiovascular risk factors, subclinical vascular disease, and cardiovascular and other chronic disease outcomes. METHODS/DESIGN: Participants between 35 and 69 years of age are being recruited from existing cohorts and a new First Nations Cohort to undergo a detailed assessment of health behaviours (including diet and physical activity), cognitive function, assessment of their local home and workplace environments, and their health services access and utilization. Physical measures including weight, height, waist/hip circumference, body fat percentage, and blood pressure are collected. In addition, eligible participants undergo magnetic resonance imaging (MRI) of the brain, heart, carotid artery and abdomen to detect early subclinical vascular disease and ectopic fat deposition. DISCUSSION: CAHHM is a prospective cohort study designed to investigate the impact of community level factors, individual health behaviours, and access to health services, on cognitive function, subclinical vascular disease, fat distribution, and the development of chronic diseases among adults living in Canada. PMID- 27464514 TI - Cloning and Characterization of Lxr and Srebp1, and Their Potential Roles in Regulation of LC-PUFA Biosynthesis in Rabbitfish Siganus canaliculatus. AB - Rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the ability to biosynthesize C20-22 long-chain polyunsaturated fatty acid (LC-PUFA) from C18 PUFA precursors, which is generally absent or low in marine teleosts. Thus, understanding the molecular basis of LC-PUFA biosynthesis in rabbitfish will contribute to efforts aimed at optimizing LC-PUFA biosynthesis in teleosts, especially marine species. In the present study, the importance of the transcription factors liver X receptor (Lxr) and sterol regulatory element binding protein 1 (Srebp1) in regulation of LC-PUFA biosynthesis in rabbitfish was investigated. First, full-length cDNA of Lxr and Srebp1 were cloned and characterized. The Lxr mRNA displayed a ubiquitous tissue expression pattern while Srebp1 was highly expressed in eyes, brain and intestine. In rabbitfish primary hepatocytes treated with Lxr agonist T0901317, the expression of Lxr and Srebp1 was activated, accompanied by elevated mRNA levels of Delta4 and Delta6/Delta5 fatty acyl desaturase (Fad), key enzymes of LC-PUFA biosynthesis, as well as peroxisome proliferator-activated receptor gamma (PPARgamma). In addition, Srebp1 displayed higher expression levels in liver of rabbitfish fed a vegetable oil diet or reared at 10 ppt salinity, which were conditions reported to increase the liver expression of Delta4 and Delta6/Delta5 Fad and LC-PUFA biosynthetic ability, than fish fed a fish oil diet or reared at 32 ppt, respectively. These results suggested that Lxr and Srebp1 are involved in regulation of LC-PUFA biosynthesis probably by promoting the expression of two Fad in rabbitfish liver, which, to our knowledge, is the first report in marine teleosts. PMID- 27464515 TI - Functional Significance of Medial Olivocochlear System Morphology in the Mouse Cochlea. AB - OBJECTIVES: Baso-apical gradients exist in various cochlear structures including medial olivocochlear (MOC) efferent system. This study investigated the cochlear regional differentials in the function and morphology of the MOC system, and addressed the functional implications of regional MOC efferent terminals (ETs) in the mouse cochlea. METHODS: In CBA/J mice, MOC reflex (MOCR) was assessed based on the distortion product otoacoustic emission in the absence and presence of contralateral acoustic stimulation. High, middle, and low frequencies were grouped according to a mouse place-frequency map. Cochlear whole mounts were immunostained for ETs with anti-alpha-synuclein and examined using confocal laser scanning microscopy. The diameters of ETs and the number of ETs per outer hair cell were measured from the z-stack images of the basal, middle and apical regions, respectively. RESULTS: The middle cochlear region expressed large, clustered MOC ETs with strong MOCR, the base expressed small, less clustered ETs with strong MOCR, and the apex expressed large, but less clustered ETs with weak MOCR. CONCLUSION: The mouse cochlea demonstrated regional differentials in the function and morphology of the MOC system. Strong MOCR along with superior MOC morphology in the middle region may contribute to 'signal detection in noise,' the primary efferent function, in the best hearing frequencies. Strong MOCR in spite of inferior MOC morphology in the base may reflect the importance of 'protection from noise trauma' in the high frequencies. PMID- 27464517 TI - The Dominance of Ossicular Route in Sound Transmission. PMID- 27464516 TI - Normative Hearing Threshold Levels in Koreans with Normal Tympanic Membranes and Estimated Prevalence of Hearing Loss. AB - OBJECTIVES: We investigated the normative data on the hearing threshold levels of Koreans with normal tympanic membranes and the prevalence of hearing loss (HL) and nonserviceable hearing using the data from the Korea National Health and Nutrition Examination Surveys (KNHANES) during 2010-2012. METHODS: Data obtained from 16,673 participants >=12-year-of-age with normal tympanic membranes who completed audiometric testing. We defined HL as the pure tone average (PTA) >25 dB hearing level at 500, 1,000, 2,000, and 3,000 Hz and non-serviceable hearing as PTA >40 dB hearing level. RESULTS: The hearing levels at some frequencies (0.5, 3, and 6 kHz) did not differ in between the 10's and 20's, but the hearing thresholds at all frequencies increased gradually from the 30's. The hearing thresholds were higher in men than in women at high frequencies (3, 4, and 6 kHz) in the 30's and older. The prevalence of HL in either ear was 16.5% (estimates of 5.9 million), from 2.4% in the 10's up to 75.4% in the 70's and older. The prevalence of nonserviceable hearing in either ear was 6.8% (estimates of 2.5 million) and that of bilateral nonserviceable hearing was 2.5% (estimates of 0.9 million). CONCLUSION: Hearing loss aggravated from the 30's at all frequencies and men showed poorer hearing levels than women at high frequencies. Hearing loss was a common condition and the prevalence of non-serviceable hearing in either ear, which needs hearing rehabilitation to help social communication, was 6.8%. Normative pure tone thresholds at each frequency can be used as referent values when counseling patients complaining of hearing loss. PMID- 27464518 TI - In Reply: Dominance of Ossicular Route in Sound Transmission. PMID- 27464519 TI - A Systematic Review for Mobile Monitoring Solutions in M-Health. AB - A systematic review allows us to identify, assess, and interpret all possible relevant work associated with a question in particular or the subject of an area. Different authors can use several methodologies to learn about research related to their own research in different fields. The main objective of this review is to identify work, research and publications made in the field of the mobile monitoring of patients through some application or commercial or non-commercial solutions in m-Health. Next, we compare the different solutions with our solution, MoMo (Mobile Monitoring) Framework. MoMo is a solution that allows for patient mobile monitoring through mobile phones and biometric devices (blood pressure meter, glucometer and others). Our systematic review is based on the methodology of B. Kitchenham. She proposed specific guidelines for carrying out a systematic review in software engineering. We prepare our systematic review base in the selection of primary and secondary research related to mobile monitoring solutions following criteria with a specific weight to compare with each part of our research. PMID- 27464520 TI - Immunoregulatory and Effector Activities of Nitric Oxide and Reactive Nitrogen Species in Cancer. AB - Nitric Oxide (NO) is a signaling radical, highly diffusible pleiotropic regulator of a large set of different molecular and biological pathways, including, neurotransmission, vasodilatation and macrophagemediated responses against infections. It is produced from the amino acid L-Arginine and oxygen by the enzymatic action of three isoforms of the Nitric Oxide Synthase (NOS), differently expressed and regulated in tissues. Increasing evidence highlights the wide spectrum of action of NO in different pathologic conditions, including cancer. In this regard, a dual role for this molecule as a pro- and anti tumorigenic mediator has been described, in a context and concentration-dependent manner. Moreover, NO exerts numerous immunologic effects, by operating as an effector molecule in innate immune responses as well as a regulator of adaptive immune components. Here, we will review recent advances in the field of biology of this pleiotropic signaling molecule in cancer, also providing a concise description of the immunoregulatory and effector activities of NO and Reactive Nitrogen Species (RNS). In particular, we will summarize recent knowledge of the molecular mechanisms underlying the complex functions of NO in cancer pathogenesis. We will also address emerging immune-mediated mechanisms regulated by NO to provide a comprehensive view of the complex cellular interactions which control cancer progression and that can be influenced by NO at multiple levels. In the light of different immunologic effects of this molecule, the potential therapeutic implications of novel drugs targeting NO to treat cancer and to improve anti-tumor immune responses will be discussed. PMID- 27464522 TI - Samarium and Nitrogen Co-Doped Bi2 WO6 Photocatalysts: Synergistic Effect of Sm(3+) /Sm(2+) Redox Centers and N-Doped Level for Enhancing Visible-Light Photocatalytic Activity. AB - Samarium and nitrogen co-doped Bi2 WO6 nanosheets were successfully synthesized by using a hydrothermal method. The crystal structures, morphology, elemental compositions, and optical properties of the prepared samples were investigated. The incorporation of samarium and nitrogen ions into Bi2 WO6 was proved by X-ray diffraction, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. UV/Vis diffuse reflectance spectroscopy indicated that the samarium and nitrogen co-doped Bi2 WO6 possessed strong visible-light absorption. Remarkably, the samarium and nitrogen co-doped Bi2 WO6 exhibited higher photocatalytic activity than single-doped and pure Bi2 WO6 under visible-light irradiation. Radical trapping experiments indicated that holes (h(+) ) and superoxide radicals ((.) O2 (-) ) were the main active species. The results of photoluminescence spectroscopy and photocurrent measurements demonstrated that the recombination rate of the photogenerated electrons and holes pairs was greatly depressed. The enhanced activity was attributed to the synergistic effect of the in-built Sm(3+) /Sm(2+) redox pair centers and the N-doped level. The mechanism of the excellent photocatalytic activity of Sm-N-Bi2 WO6 is also discussed. PMID- 27464523 TI - Facultative parthenogenesis in the Ryukyu drywood termite Neotermes koshunensis. AB - Parthenogenesis is a relatively rare reproductive mode in nature compared to sex. In social insects, the evolution of parthenogenesis has a notable impact on their life histories. Some termites with parthenogenetic ability produce numerous non dispersing supplementary queens asexually, whereas other castes are produced via sexual reproduction. This asexual queen succession (AQS) system is adaptive because hundreds of the asexual queens improve the reproductive potential of the colony and maintain the genetic diversity within the colony. However, the evolutionary process of the AQS system remains unclear because parthenogenetic species without this system are unknown. Here, we report facultative parthenogenesis in the drywood termite Neotermes koshunensis. Although the eggs produced by females isolated from males hatched, the hatching rate of those eggs was lower than that of the eggs produced by females kept with males. These parthenogenetic offspring inherited only the maternal alleles and showed high homozygosity, which indicates that the mechanism of ploidy restoration is terminal fusion. A previous study showed that most colonies of this species have a single queen or orphan; thus, the AQS system has not evolved despite their parthenogenetic ability. Further investigations of N. koshunensis will reveal how parthenogenesis evolved and its role in the insect societies. PMID- 27464524 TI - Controlled chiral supramolecular assemblies of water soluble achiral porphyrins induced by chiral counterions. AB - We demonstrate a controlled chiral supramolecular assembly of achiral porphyrins induced by chiral d- and l-arginine (Arg) in water. Induction of chirality was confirmed by circular dichroism. TEM and SEM images confirm that these twisted ribbons are indeed formed by right- and left-handed helices with d- and l-Arg in water, respectively. The chiral assembly pathways described here are hierarchical, opening up the possibility that simple changes on microscopic (nm) length scales can be used to control structures on macroscopic (mm) length scales. PMID- 27464521 TI - Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression. AB - SIGNIFICANCE: Breast cancer is the second leading cause of cancer-related deaths among women in the United States. Development and progression of malignancy are associated with diverse cell signaling pathways that control cell proliferation, survival, motility, invasion, and metastasis. Recent Advances: An increasing number of clinical studies have implicated a strong relationship between elevated tumor nitric oxide synthase-2 (NOS2) expression and poor patient survival. CRITICAL ISSUES: Herein, we review what we believe to be key mechanisms in the role(s) of NOS2-derived nitric oxide (NO) as a driver of breast cancer disease progression. High NO increases cyclooxygenase-2 activity, hypoxia inducible factor-1 alpha protein stabilization, and activation of important cell signaling pathways, including phosphoinositide 3-kinase/protein kinase B, mitogen-activated protein kinase, epidermal growth factor receptor, and Ras, through post translational protein modifications. Moreover, dysregulated NO flux within the tumor microenvironment has other important roles, including the promotion of angiogenesis and modulation of matrix metalloproteinase/tissue inhibitor matrix metalloproteinase associated with tumor progression. FUTURE DIRECTIONS: The elucidation of these and other NO-driven pathways implicates NOS2 as a key driver of breast cancer disease progression and provides a new perspective in the identification of novel targets that may be therapeutically beneficial in the treatment of estrogen receptor-negative disease. Antioxid. Redox Signal. 26, 1044 1058. PMID- 27464525 TI - Craniofacial shape differs in patients with tooth agenesis: geometric morphometric analysis. AB - Aim : To evaluate the shape of the craniofacial complex in patients with tooth agenesis and compare it to matched controls. Subjects and methods : The sample comprised 456 patients that were allocated to three groups: the agenesis group of 100 patients with at least one missing tooth, excluding third molars, the third molar agenesis group (3dMAG; one to four missing third molars) of 52 patients and the control group (CG) of 304 patients with no missing teeth. The main craniofacial structures depicted on lateral cephalograms were digitized and traced with 15 curves and 127 landmarks. These landmarks were subjected to Procrustes superimposition and principal component analysis in order to describe shape variability of the cranial base, maxilla and mandible, as well as of the whole craniofacial complex. For statistical analysis, permutation tests were used (10 000 permutations without replacement). Results : Approximately half of the sample's variability was described by the first three principal components. Comparisons within the whole sample revealed sexual dimorphism of the craniofacial complex and its structures (P < 0.01). Differences between the agenesis group and matched controls were found in the shape of all craniofacial structures except for the cranial base (P < 0.05). Specifically, patients with agenesis presented with Class III tendency and hypodivergent skeletal pattern. However, the comparison between the 3dMAG and matched CG revealed no differences. Conclusion : The shape of the craniofacial complex differs in patients with tooth agenesis suggesting that common factors are implicated in tooth development and craniofacial morphology. PMID- 27464527 TI - Effects of extreme pH on ionic transport through protein nanopores: the role of ion diffusion and charge exclusion. AB - We combine electrophysiological experiments with the structure-based Poisson Nernst-Planck 3D calculations to investigate the transport properties of the bacterial porin OmpF under large pH gradients and particularly low salt concentrations. We show that under extreme pH conditions protons and hydroxyls contribute decisively to the overall measured current, challenging the traditional interpretation of some electrokinetic parameters such as channel selectivity and rectification properties. We analyze with unprecedented detail the two intertwined factors ruling the ionic permeation through the channel, namely the differences between cation and anion mobilities and the electrostatic exclusion due to the interaction between permeating ions and channel ionizable residues. PMID- 27464528 TI - Antioxidant and antiproliferative activity of indigocarpan, a pterocarpan from Indigofera aspalathoides. AB - OBJECTIVES: This study aimed to investigate the anticancer potential of indigocarpan (1), a pterocarpan isolated from Indigofera aspalathoides, a plant found in India which has been used in Ayurveda for centuries for the treatment of oedematous tumours. METHODS: The antiproliferative activity in a panel of four human cancer cell lines was studied. The mechanism of its antiproliferative activity in human colorectal adenocarcinoma LS174T cells was investigated in detail. KEY FINDINGS: Indigocarpan (1) showed antiproliferative activity in a panel of four human cancer cell lines with IC50 s ranging from 180 to 250 MUm. Indigocarpan induces p53-dependent p21 upregulation and apoptosis in LS174T cells, upregulates p53 and p21(WAF1) protein levels, enhances cleavage of caspase 3 and downregulates cyclin D1, cyclin B1 and PCNA protein levels, indicating its role in modulating cell cycle progression. Indigocarpan also exhibited a strong antioxidative effect in LS174T cells. CONCLUSIONS: Along with the antiproliferative capacity, the strong antioxidative property of the compound makes it a promising candidate for further development as an anticancer and chemopreventive compound. PMID- 27464529 TI - 12-O-tetradecanoylphorbol-13-acetate activates hair follicle melanocytes for hair pigmentation via Wnt/beta-catenin signaling. AB - Melanocyte stem cells (McSCs) undergo cyclical activation and quiescence together with hair follicle stem cells (HFSCs). This process is strictly controlled by the autonomous and extrinsic signaling environment. However, the modulation of factors important for the activation of McSCs for hair pigmentation remains unclear. 12-O-tetradecanoylphorbol-13-acetate (TPA) mimics vital signaling pathways involved in melanocyte growth and melanogenesis in vitro. To investigate whether TPA regulates quiescent McSCs for hair pigmentation, we topically smeared TPA on 7-week-old mouse dorsal skin and found that TPA stimulated hair growth and hair matrix pigmentation. These changes were associated with a significant increase in the number of hair bulb melanocytes. Moreover, in the TPA-treated group, hair bulge McSCs and hair bulb melanoblasts actively proliferated. At the molecular level, nuclear beta-catenin, a key factor of Wnt/beta-catenin signaling, was highly synthesized in melanocytes and keratinocytes in TPA-induced hair bulbs. Inhibition of Wnt/beta-catenin signaling by injecting Dickkopf1 plasmids into TPA-treated skin decreased hair matrix pigmentation and inhibited the proliferation and differentiation of McSCs. Our findings suggest that the topical application of TPA stimulates the proliferation and differentiation of McSCs and their progeny for hair matrix pigmentation by activating Wnt/beta catenin signaling. This might provide a useful experimental model for the study of signals controlling the activation of McSCs. PMID- 27464530 TI - Preventing Breast Implant Contamination in Breast Reconstruction: A National Survey of Current Practice. AB - BACKGROUND: Implant-based breast reconstruction is commonly performed by plastic surgeons worldwide. Bacterial contamination is of paramount concern because of its role in biofilm formation and capsular contracture. Plastic surgeons have adopted a variety of perioperative interventions in efforts to reduce implant contamination; however, definitive evidence supporting these practices is lacking. OBJECTIVE: The goal of this study was to assess current practice patterns aimed at reducing implant-related infections. METHODS: A 20-question survey assessing practices aimed at preventing breast implant-associated infections was generated and distributed via SurveyMonkey to members of the American Society of Plastic Surgery whose e-mail addresses were listed on the American Society of Plastic Surgery member Web site in April 2015. RESULTS: A total of 1979 invitations to participate in the survey were sent, and 253 responses were received during the 4-month study period. Of respondents, 81% were in private practice. Respondents averaged 21 +/- 9 years in practice, and 34 +/- 50 implant-based breast reconstructions were performed per year. A majority of surgeons used chlorhexidine to prepare the surgical site (52%), a triple antibiotic soak for the implant prior to placement (50%) and povidone-iodine for implant pocket irrigation (44%). A no-touch technique utilizing the Keller funnel was adopted by 69% of surgeons. Regarding antibiotic use in the postoperative period, first-generation cephalosporins (eg, cephalexin, cefadroxil) were used by a majority of surgeons (84%), and the most common duration was until drain removal (45%). CONCLUSIONS: There is considerable heterogeneity in surgical practices aimed at preventing bacterial contamination in implant-based breast reconstruction. Surgeons may benefit from high-level studies designed to create standardized evidence-based practice guidelines. PMID- 27464526 TI - Conserved genes and pathways in primary human fibroblast strains undergoing replicative and radiation induced senescence. AB - BACKGROUND: Cellular senescence is induced either internally, for example by replication exhaustion and cell division, or externally, for example by irradiation. In both cases, cellular damages accumulate which, if not successfully repaired, can result in senescence induction. Recently, we determined the transcriptional changes combined with the transition into replicative senescence in primary human fibroblast strains. Here, by gamma irradiation we induced premature cellular senescence in the fibroblast cell strains (HFF and MRC-5) and determined the corresponding transcriptional changes by high-throughput RNA sequencing. RESULTS: Comparing the transcriptomes, we found a high degree of similarity in differential gene expression in replicative as well as in irradiation induced senescence for both cell strains suggesting, in each cell strain, a common cellular response to error accumulation. On the functional pathway level, "Cell cycle" was the only pathway commonly down regulated in replicative and irradiation-induced senescence in both fibroblast strains, confirming the tight link between DNA repair and cell cycle regulation. However, "DNA repair" and "replication" pathways were down-regulated more strongly in fibroblasts undergoing replicative exhaustion. We also retrieved genes and pathways in each of the cell strains specific for irradiation induced senescence. CONCLUSION: We found the pathways associated with "DNA repair" and "replication" less stringently regulated in irradiation induced compared to replicative senescence. The strong regulation of these pathways in replicative senescence highlights the importance of replication errors for its induction. PMID- 27464531 TI - Vascularized Second Metatarsophalangeal Joint Transfer for Salvage of Failed Centralization in Radial Longitudinal Deficiency: Case Report. AB - Management of recurrent radial deviation after centralization for radial longitudinal deficiency patients usually involves some form of wrist fusion. We report on a child with recurrence after centralization, where correction and successful maintenance of a good functional and cosmetic position were obtained by vascularized second metatarsophalangeal joint transfer. PMID- 27464533 TI - [Embracing the era of precision medicine in the diagnosis and treatment of Takayasu arteritis]. PMID- 27464532 TI - Blast Injuries Caused by Vape Devices: 2 Case Reports. AB - Vaporizing devices have become a popular alternative to conventional nicotine products. They are thought to be safer as they produce aerosolized nicotine powered by a lithium ion battery. Many people have used these electronic devices as a tool to quit smoking; however, the batteries can be unstable and explode.We present 2 case reports where explosions of electronic vapor devices caused significant injuries. The first patient sustained a combustion injury to the maxilla resulting in bone and anterior maxillary tooth loss requiring reconstruction. The second patient had a severe blast injury to the hand which ultimately resulted in loss of a digit. Toxicology was consulted due to concerns for systemic absorption of metals in the soft tissue of the hand. Cobalt and manganese were initially elevated but decreased after surgical debridement. The patient did not have any systemic symptoms.Currently, there is no federal regulation of electronic cigarettes or vape devices in the United States. With the increasing use of these devices and no standard regulations, we anticipate more blast injuries occurring in the future. Medical providers will need to be able to be prepared to manage the devastating clinical injuries that ensue. PMID- 27464534 TI - [The importence of collaboration between rheumatology and vascular surgery in the treatment of vasculitis]. PMID- 27464535 TI - [A comparative study of diagnostic efficacy of different diagnostic/ classification criteria in Takayasu arteritis]. AB - OBJECTIVE: This study aimed to analyze and evaluate the diagnostic efficacy of Ishikawa's, the modified Ishikawa's criteria, 1990 American College of Rheumatology (ACR ) classification criteria and the diagnostic model based on Chinese population in Chinese TA patients. METHODS: One hundred and forty-nine patients with Takayasu arteritis and 126 patients with other vascular disorders which involved aorta or its branches were recruited in this study.All the patients were admitted to the Department of rheumatism and Immunology clinic or inpatient department of Zhongshan Hospital affiliated to Fudan University from January 1(st), 2008 to June 31(st), 2015.General characteristics, clinical manifestations, laboratory results and imaging data of all the patients were collected.Sensitivity, specificity, accuracy and area under receiver operating characteristics (ROC) curve of different criteria were analyzed. RESULTS: Sensitivity, specificity, accuracy and area under ROC curve of Chinese diagnostic model were 90.60%, 80.95%, 86.18%, and 85.80%, respectively, while those of Ishikawa criteria were 34.23%, 99.21%, 64.00%, and 66.70%, respectively.These four indicators of the modified Ishikawa criteria were 84.13%, 79.87%, 81.82%, and 82.00%, respectively and that of ACR criteria were 83.89%, 83.33%, 83.64%, and 83.60%, respectively.No significant difference was found between any two of Chinese diagnostic model, the modified Ishikawa criteria and ACR criteria in all the indicators.Sensitivity of Chinese diagnostic model was highest, while specificity of Ishikawa criteria was the highest.Among these four criteria, the diagnostic efficacy of Chinese model was the best and that of Ishikawa criteria was the worst. CONCLUSION: Chinese diagnostic model, which is based on Chinese population and adopts advanced imaging modality, has better diagnostic efficacy. PMID- 27464536 TI - [Clinical data analysis of valvular involvement in Takayasu arteritis]. AB - OBJECTIVE: To investigate the clinical features of valvular lesions in Takayasu's arteritis. METHODS: We analyzed 22 medical records of patients with Takayasu's arteritis and valvular lesions in Anzhen Hospital, Capital Medical University from January 2012 to January 2015. RESULTS: The spectrums of valvular involvements were aortic valve regurgitation (11, 50%), aortic valve stenosis (1, 4.5%), mitral valve regurgitation (1, 4.5%), mitral valve stenosis (1, 4.5%) and multiple valvular diseases (7, 36.5%).64.7% of patients with aortic valve regurgitation had aortic root dilation.Heart failure was the most common manifestation (63.6%). Glucocorticoid and/or immunosuppressant were administrated on 11 (50%) patients.One (4.5%) patient received Tocilizumab injection.Surgeries were performed on 12 (54.5%) patients with cardiac architecture.Reversible changes in cardiac structure were found by echocardiography within one week after surgery (P<0.05). Three patients died during 10-46 month follow-up, with none of whom taking any anti-inflammatory treatments. CONCLUSIONS: Aortic regurgitation is the prominent valvular lesion in Takayasu's arteritis, mostly secondary to aortic root dilation.Operation could block myocardium reconstruction promptly.The early surgical complication is rare, while perivalvular leakage may occur during longstanding follow-up.Poor inflammatory control might lead to poor long-term outcome. PMID- 27464537 TI - [The clinical manifestation and analysis of eosinophilic granulomatous vasculitis]. AB - OBJECTIVE: To evaluate the clinical features, treatment and prognosis of Eosinophilic Granulomatous Vasculitis. METHODS: We analyzed retrospectively the clinical and laboratory features, treatment and prognosis of 43 patients with Eosinophilic Granulomatous Vasculitis who admitted to the Department of Rheumatology of the First Affiliated University Hospital of Sun Yat-sen University between 2005 and 2014. RESULTS: Of the 43 patients, 31 patients (72.1%) had allergic symptoms in the disease course and 16 patients (37.2%) had asthma and lung wheezing sound when performing the physical examination.Organs involvements included skin, acra, lung, kidney, central and peripheral nervous system, digestive system and heart.Positive antineutrophilic cytoplasmic antibody (ANCA) which mainly with MPO-ANCA was found in 18 patients (41.9%). Thirty-nine patients (90.7%)had high blood eosinophil level while all patients (100%) had elevated IgE.Two patients died of multiple organ failure in their acute phase, and the others had favorable prognosis after receiving the treatment of glucocorticoid combine with cyclophosphamide or methotrexate. CONCLUSIONS: Eosinophilic Granulomatous Vasculitiscould make damage to organs and tissues.Only 72.1% patients had allergic symptoms and 37.2% patients had asthma and lung wheezing sound.More than half patients have the negative ANCA.Glucocorticoidcombine with cyclophosphamide or methotrexate can achieve satisfactory therapeutic effects. PMID- 27464538 TI - [The clinical analysis of 46 cases with antineutrophil cytoplasmic antibody associated vasculitis]. AB - OBJECTIVE: To investigate the clinical features of patients with antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), and to explore the disease activity of AAV patients and the relationship with prognosis. METHODS: The clinical data of 46 cases of AAV patients in the First Affiliated Hospital of PLA General Hospital were analyzed retrospectively.The clinical and laboratory features of each clinical subtype were compared.The disease activity of AAV and the relationship between disease activity and prognosis were evaluated. RESULTS: Among the 46 patients with AAV, 24 were male, and 22 were female, with the average age of 56+/-18.Among the subtypes of AAV, the number of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) were 22, 17 and 4 respectively, while the positive rate of ANCA are 72.7%, 88.2% and 50.0% respectively.For GPA, the results of ANCA were mainly C-ANCA or ANCA directed toward proteinase-3 (PR3), and for MPA, the results of ANCA were mainly P-ANCA or ANCA directed toward myeloperoxidase (MPO). Upper and lower respiratory disease, renal involvement and non-deformity arthropathy were the common clinical manifestations of all primary AAV subtypes.Epistaxis, nasal blood scab, saddle nose, pulmonary nodule and intrapulmonary cavities were the characteristic manifestations of GPA, while rapid progress of renal failure was prominent in MPA.Whatever their ANCA results, there were no significant differences between each other as to system-organ involvements and laboratory indexes.Seven patients (15.2%) died during hospitalization or in follow-up visits.Serious involvements of heart, lung, kidney, and complicated with infections were the main risk factors of death in AAV patients. CONCLUSIONS: Upper and lower respiratory involvements and kidney diseases are the primary manifestations of AAV patients.ANCA results are irrelevant with disease activity and system-organ involvements.Serious involvements of heart, lung, kidney, and complicated with infections are the main risk factors of death in AAV patients. PMID- 27464539 TI - [Comparison of efficacy between the serum cortisol and 24 hour urine free cortisol in combined dexamethasone suppression test in the diagnosis of Cushing syndrome]. AB - OBJECTIVE: To compare the sensitivity and specificity between the 24 hour urine free cortisol (24 h UFC) and serum cortisol in dexamethasone suppression test (DST) in the diagnosis of Cushing syndrome (CS). METHODS: Combined low dose DST (LDDST) and high dose DST (HDDST) were carried out in 67 cases of CS with surgically confirmed cases in recent 3 years(from January 2011 to November 2015). The serum cortisol and 24 h UFC were collected simultaneously for each subject and the sensitivity and specificity of serum cortisol and 24 h UFC were compared. RESULTS: There were Cushing disease (CD) group (n=53), ectopic adrenocorticotropic hormone (ACTH) syndrome group (n=7) and ACTH-independent Cushing syndrome group (n=7) according to the etiology of hypercorticordism.There were no significant differences among 3 groups in gender and age.The sensitivity of serum cortisol of different cut off points(50, 110, 140 nmol/L and 50% of control)after LDDST was 97.01%, 86.57%, 83.58% and 70.15% respectively.Meanwhile, the sensitivity of cutoff point of 24 h UFC <32 nmol in combined LDDST was 92.54% in the diagnosis of Cushing syndrome.There was no significant differences in two groups between serum cortisol <110 nmol/L and 24 h UFC <32 nmol.However, the sensitivity of serum cortisol <50 nmol/L was significantly higher than 24 h UFC<32 nmol (P<0.05). Furthermore, in combined HDDST, if the suppression rate was >=50%, the sensitivity of serum cortisol and 24 h UFC in differentiating the etiology of Cushing disease was 60.38% and 90.57%, and the specificity was 91.43% and 96.00% respectively.There were significant differences between serum cortisol and 24 h UFC in both of sensitivity and specificity (both P<0.05). In addition, if the suppression rate of 24 h UFC in HDDST was adjusted to 60.85% according to receiver operating characteristic (ROC) curve, it could have the best levels of sensitivity (92.6%) with the specificity of 85.7%. If the suppression rate of serum cortisol was adjusted to 61.53% in HDDST according to ROC curve, it could have the best sensitivity (64.8%) with the specificity of 78.6% accordingly. CONCLUSION: In combined LDDST, the serum cortisol <50 nmol/L had a higher sensitivity than the 24 h UFC<32 nmol when they were used as the criteria in determining the diagnosis of CS.In HDDST, the sensitivity and specificity of suppression rate of 24 h UFC >=50% were better than serum cortisol to differentiate the etiology of CS. PMID- 27464540 TI - [Correlations between hormone levels and psychiatric symptoms as well as cognitive function in drug-free first-episode schizophrenics]. AB - OBJECTIVE: To explore hormone such as follicle-stimulating hormone (FSH), luteinizing (LH), prolactin (PRL), estradiol (E2), progesterone (PROG) and testosterone (TESTO) levels in first-episode drug-free schizophrenics, and the relationship between clinical symptoms and sex hormones, in order to further study the pathogenesis of schizophrenia. METHODS: Eighty-one first-episode drug free schizophrenics including thirty-nine male and forty-two female from First Affiliated Hospital of Zhengzhou University and seventy healthy subjects (thirty male and forty female) were enrolled.Serum levels of hormone were measured using electrical chemiluminescence immunoassay, and Positive and Negative Syndrome Scale (PANSS) was used to evaluate the mental symptoms and Matrics Consensus Cognitive Battery (MCCB) was used to evaluate cognitive function. RESULTS: (1) The serum levels of PRL in male patients group ((24+/-9) ng/ml) was higher than that of control group ((10+/-3) ng/ml) (P<0.05), the serum levels of E2, TESTO of male patients group ((29+/-10) ng/ml), ((3.2+/-1.7) ng/ml) was lower than that of control group ((35+/-11) ng/ml), ((4.4+/-1.6) ng/ml) (P<0.05); The serum levels of PRL, TESTO of female patients group ((29+/-16) ng/ml), ((0.5+/-0.4) ng/ml) were dramatically higher than that of control group ((13+/-5) ng/ml), ((0.3+/ 0.1) ng/ml) (P<0.05), the serum levels of E2 of female patients group ((51+/-40) ng/ml) was lower than that of control group ((63+/-66) ng/ml) (P=0.05). (2) The serum levels of PRL, E2, TESTO in male patients group were negatively associated with negative symptoms (r=-0.478,-0.443,-0.576, P<0.05), PRL were negatively related to positive symptoms (r=-0.542, P<0.05); In female patients group, the serum levels of PRL were negatively associated with negative symptoms (r=-0.343, P<0.05), the serum levels of E2 was negatively related to positive symptoms, general psychopathology grade, total PANSS grade (r=-0.351,-0.487,-0.405, P<0.05), TESTO had a positive correlation with positive symptoms (r=0.445, P<0.05). (3) In male patients group, PRL had an negative correlation with working memory P point, reasoning and problem solving P points (r=-0.384,-0.374, P<0.05), the serum levels of E2 was positively related to Information processing rate P points, Visual memory P points, Reasoning and problem solving P points (r=0.379, 0.336, 0.407, P<0.05), TESTO had a positive correlation with Information processing rate P points, Visual memory P points, Reasoning and problem solving P points (r=0.564, 0.513, 0.552, P<0.05). In female patients group, PRL had an negative correlation with working memory P point, Reasoning and problem solving P points and social cognition P points (r=-0.303,-0.358,-0.368, P<0.05), the serum levels of E2 was positively related to working memory, Reasoning and problem solving P points, social cognition P points (r=0.376, 0.453, 0.355, P<0.05). CONCLUSIONS: Our study shows that first-episode drug-free schizophrenics have hormone secretion abnormal, which suggests that hypothalamus-hypophysis-gonad axis may probably involve in physiopathologic mechanism of first-episode medicine free schizophrenics.Slightly elevated serum PRL level may be the reaction of stress response in first-episode medicine-free schizophrenics.Endogenous testosterone and estradiol may protect cognitive function against recession, and declining of testosterone and estradiol in blood is the hazards of cognitive dysfunction in first-episode drug-free male schizophrenics. PRL, E2, TESTO may be one of the measurements of the severity of clinical symptoms. PMID- 27464541 TI - [Multivariate analysis of blood culture positive rate of ICU patients]. AB - OBJECTIVE: To investigate the factors associated with positive results of blood culture and the impact of positive results on the prognosis of patients in ICU of Peking University People's Hospital. METHODS: We retrospectively analyzed 1 008 blood culture results of 379 critical ill adult patients in ICU from July 1st, 2013 to June 30th, 2014. According to blood culture results, the patients were divided into positive and negative groups. The patients' maximal body temperature, sample collection times, number of bottles within 24 hours, routine hematological variables [(white blood cell count (WBC), percentage of neutrophils (NEU%), lymphocyte count (LYM), platelet count (PLT)], serum C-reactive protein (CRP), usage of antibiotics were compared between the two groups, as well as the patients' gender, age, duration of mechanical ventilation, length of ICU stay and hospital mortality rate. RESULTS: The total positiverate of blood culture of our study was 15.38%, and the positive rate of patients was 24.27%.When compared between positive group and negative group, the medians of sample collection times were 3 and 1(P<0.000 1); the medians of sample bottles were 4 and 4(P=0.001 2); the medians of WBC were 8.61*10(9)/L and 9.95*10(9)/L(P=0.001 7); and the medians of mechanical ventilation time were 179.5 hours and 47 hours(P<0.000 1); the medians of length of ICU stay were 17 days and 7 days(P<0.000 1), respectively. Hospital mortality rates in positive patients and negative patients were 35.87% and 20.21%(P=0.002 2), respectively. There was no significant difference(P>0.05) between the two groups in body temperature, NEU%, LYM, PLT, CRP or usage of antibiotics. CONCLUSIONS: Increasing the frequency of sampling and the bottles of blood culture will improve the positive rate of blood culture. The body temperature, WBC, NEU%, LYM, PLT, CRP, us age of antibiotics, gender and age have no effect on the positive rate of blood culture. The patients with positive blood culture results have longer duration of mechanical ventilation, longer ICU stayand higher hospital mortality rate. PMID- 27464542 TI - [Study of ultrasonographic features in predicting reginal lymph node metastasis in patients with papillary thyroid carcinoma]. AB - OBJECTIVE: To demonstrate the ultrasonographic features of papillary thyroid carcinoma (PTC) in predicting associated cervical lymph nodes metastasis (LNM). METHODS: A total of 136 patients diagnosed with PTC in Beijing Tongren Hospital between January 2014 and September 2014 were enrolled.Of 136 cases, forty patients were confirmed with cervical lymph node metastasis.Seven were males, 33 were females, aged from 18 to 65 years old, mean age was (39.6+/-10.3) years .The remaining 96 were reported without lymph node metastasis.Twenty-one were males, 75 were females, aged from 23 to 86 years old, mean age was (47.7+/-12.8) years.Medical record was reviewed for demographic characteristics and pathological findings.The ultrasonographic features of each case were evaluated retrospectively.The difference of ultrasonographic features between the patients with and without LNM was examined. RESULTS: There were 178 PTCs confirmed with pathology, 159 lesions (89.3%) were detected by ultrasonography, the remaining 19 lesions (10.7%) were under-detected.Of 136 patients with PTC, 40 cases (40/136, 29.4%) were confirmed with cervical LNM, while the remaining 96 cases (96/136, 70.6%) were determined without cervical LNM.PTC with cervical LNM was more frequently seen in the patients who were younger (P=0.000 5) and presenting with multifocal tumors (P=0.014 6). Ultrasonographic features of PTC which significantly associated with LNM were ill-defined margins (P=0.018), solid appearance (P=0.003), and presence of calcification (P=0.000). Of 40 cases with LNM, central cervical LNM was seen in 32 cases (80%), 72.5% of whom appeared as unilateral distribution. CONCLUSIONS: Patients diagnosed with PTC with younger age and identified with multiple foci of tumors at the time of diagnosis are in an increased risk of associated cervical LNM.Ultrasonographic features of ill defined margins, solid appearance and calcification in PTC are significant predictors of LNM. PMID- 27464543 TI - [Clinical, pathological and imaging features of primary pelvic Ewing's sarcoma]. AB - OBJECTIVE: To explore the clinical, pathological and imaging features of Ewing's sarcoma in pelvis and to improve knowledge and diagnosis of the disease. METHODS: A retrospective analysis of the clinical, pathological and imaging data of pathologically confirmed 13 cases of Ewing's sarcoma in pelvis was carried out between May 2008 and March 2016 in the Affiliated Hospital of Hangzhou Normal University, the Third Hospital of Hebei Medical University and the Second Hospital of Hebei Medical University. RESULTS: The median age 13 cases of pelvic primary Ewing's sarcoma was 17 years old.The X-ray and CT imagings showed osteolytic and mixed bone destruction, CT showed mixed type in 10 cases, 8 cases of bone tumors as a flocculent, 10 cases of bone expansion failure, 10 cases of periosteal reaction, the layered 5 cases, radial in 5 cases.Thirteen cases showed soft tissue mass, soft tissue mass was equal or slightly lower density.Four cases showed heterogeneous contrast enhancement.The lesions showed low signal in T1WI and mixed high signal in T2WI of magnetic resonance imaging(MRI). The boundary of the lesions were obscure, and 5 cases had patchy necrosis area, and 9 cases had incomplete false capsule, surrounding soft tissue was violated.Four cases showed heterogeneous contrast enhancement after MRI enhancement scan. CONCLUSIONS: The age of onset of Ewing's sarcoma of the pelvis is more concentrated in about 15 years.The imaging feaures are mixed bone destruction and more bone is swelling and permeability damage, soft tissue mass is larger, bone tumor is cloudy or acicular, periosteal reaction in a layered and radial, most cases show that the false envelope is not complete.Combined with clinical and imaging examination, the diagnosis of the disease can be made. PMID- 27464544 TI - [Study on the application effect of Once Vex(GM)(-)(CSF) and adriamycin in the interventional therapy of malignant tumor in clinical curative effect]. AB - OBJECTIVE: To investigate the application effect of oncolytic herpes simplex virus Once Vex(GM-CSF) and adriamycin in malignant tumor. METHODS: A total of 102 cases of malignant tumor were analyzed retrospectively from April 2013 to April 2015 of Cancer Treatment Center of Affiliated Hospital of Beihua University, and these cases were randomly divided into trial group (n=51) and control group (n=51). The control group was treated with adriamycin and the trial group patients received conditionally replicating adenoviruses on the basis of the control group.The adenovirus proliferation was analyzed via quantitative PCR to investigate the malignant tumor cell inhibitory action in two groups. RESULTS: Treatment group total effective rate (96.1%, 49/51) was significantly higher than the control group (78.4%, 40/51) (chi(2)=7.845, P=0.014). There were statistically significant difference of the killing capability between trial group (86.3%, 44/51) and control group (23.5%, 12/51) (chi(2)=7.859, P=0.013). Tumor shrinkage rate of trial group(76.5%, 39/51) was superior to that of the control group(19.6%, 10/51), the difference was statistically significant (chi(2)=7.654, P=0.019). There was statistically significant difference of the decrease of tumor marker CA125 between trial group (74.5%, 38/51) and control group (23.5%, 12/51) (chi(2)=7.342, P=0.023). CONCLUSION: Once Vex(GM-CSF) can effectively kill the tumor cells in the treatment of malignant tumor, and shrink the tumor significantly. PMID- 27464545 TI - [Clinical analysis of aphakic glaucoma following infantile congenital cataract surgery]. AB - OBJECTIVE: To investigate the incidence, occurrence time and types of aphakic glaucoma following infantile congenital cataract surgery. METHODS: The records of children who underwent surgery for congenital cataract within the first 24 months of life between January 2010 and January 2014 at the First Affiliated Hospital of Zhengzhou University were retrospectively reviewed.Children with preoperative conditions associated with glaucoma were excluded.The following parameters were ascertained: age received cataract surgery, operation method, the incidence, occurrence time and types of glaucoma. RESULTS: A total of 205 patients (324 eyes) with an average surgery age of 13.9 months were included, and the mean follow-up time was 47.6 months.The operation method was cataract extraction combined with posterior continuous circular capsulorhexis and anterior vitrectomy.Twenty-nine patients (37 eyes, 11.42%) had subsequent development of aphakic glaucoma, 9 eyes of which (2.78%) developed early onset angle closed glaucoma, and the occurrence time was (4.2+/-2.6) months after cataract surgery; 28 eyes (8.64%) developed late onset open angle glaucoma, 26 of which was angle open glaucoma, and the rest two was angle closed glaucoma.The occurrence time was (37.5+/-11.0) months after cataract surgery. Twenty-nine patients (37 eyes) developed aphakic glaucoma had cataract surgery within 2 to 12 months (6.8 months on average). The rest 176 patients (287 eyes) who did not develop glaucoma had cataract surgery at 10 to 24 months (14.1 months on average). CONCLUSIONS: The incidence of aphakic glaucoma following infantile congenital cataract surgery is 11.42%.Aphakic glaucoma is divided into two types of early onset angle closed glaucoma and late onset open angle glaucoma.The occurence time of glaucoma was 2 months to 64 months after cataract surgery.Late onset open angle glaucoma is the most common type. PMID- 27464546 TI - [Clinical value of T-cell interferon releases detection of tuberculosis infection assay in quick diagnosis of spinal tuberculosis]. AB - OBJECTIVE: To evaluate the value of T-cell interferon releases detection of tuberculosis infection(T-SPOT.TB)assay in quick diagnosis of spinal tuberculosis. METHODS: From January 2012 to June 2015, a group of 122 diagnosed patients with spinal tuberculosis in the Qingdao Municipal Chest Hospital and a group of 86 patients suspected with spinal tuberculosis in Department of Orthopaedic, the Qingdao Third People's Hospital were accepted to undergone TB-DOT, T-SPOT.TB and TB-DNA PCR tests Department of Clinical Laboratory. RESULTS: The sensitivity of TB-DOT, T-SPOT.TB and TB-DNA PCR tests were 69.7%, 86.1% and 56.6%, respectively.The sensitivity of T-SPOT.TB was significantly higher than TB-DOT and TB-DNA PCR tests (chi(2)=9.51, P<0.05; chi(2)=25.96, P<0.05). The specificity of TB-DOT, T-SPOT.TB and TB-DNA PCR tests were 62.8%, 88.3% and 91.9%, respectively.The specificity of T-SPOT.TB was significantly higher than TB-DOT test (chi(2)=15.25, P<0.05). CONCLUSIONS: T-SPOT.TB assay possesses high sensitivity and specificity in quick diagnosis of patients with spinal tuberculosis, which is valuable in diagnosis of spinal tuberculosis. PMID- 27464547 TI - [NF-kappaB signaling pathway regulate endplate chondrocytes in rat vitro natural degeneration model]. AB - OBJECTIVE: To explore the relationship between nuclear factor (NF)-kappaB and vitro nature degeneration model of endplate chondrocyte in rats. METHODS: Rats endplate chondrocytes were isolated and cultured in vitro.Rebulated vitro natural degeneration model and cells were divided into control group (P2 cells group), naturally passaged group (P5 cells group) and NF-kappaB signaling pathway inhibition group (added Bay11-7082 when the passaged to P5 cells). The changes of cellular morphology were observed by inverted phase contrast microscope, the phenotype of endplate chondrocyte were identified by toluidine blue staining, electromagnetic compatibility (EMC) were observed by alcian blue staining.Type II collagen, sry related HMG box (SOX)-9, matrix metalloproteinase(MMP)13 and aggrecan genes were detected by real time-polymerase chain reaction (RT-PCR) to verify the degeneration mode.NF-kappaB transcriptional activity was assessed by examining cytosolic phosphorylated IkappaBalpha and nuclear phosphorylated p65 levels by Western blot. RESULTS: With chondrocytes passing, the cells lost the original morphology gradually.Alcian blue stains observed EMC decreased in naturally passaged group.The leave of Type II collagen (P5/P2=0.182, P<0.01), aggrecan (P5/P2=0.287, P<0.01) and SOX-9 (P5/P2=0.488, P<0.01) were significantly reduced, MMP13 (P5/P2=1.324, P<0.05) significantly increased.Western blot analysis showed that in P5 cells nuclear phosphorylation p65 and cytosolic levels of phosphorylated IkappaBalpha increased and Bay11-7082 treatment attenuated increase in nuclear phosphorylation p65 and blocked acidinduced increase in cytosolic levels of phosphorylated IkappaBalpha.Moreover, the leave of Type II collagen (Bay11-7082/P5=4.173, P<0.01), aggrecan (Bay11-7082/P5=2.732, P<0.05) and SOX-9 (Bay11-7082/P5=1.567, P<0.05) significantlyincreased, MMP13 (Bay11 7082/P5=0.611, P<0.05) significantly reduced in treatment group. CONCLUSION: Inhibitor NF-kappaB signaling pathway plays an important role in the vitro degeneration of endplate cartilage.Reasonable regulation of NF-kappaB signaling pathway may be a new way to prevent Intervertebral disc degeneration. PMID- 27464548 TI - [A dual PI3K/mTOR inhibitor, PI-103, cooperates with TRAIL in laryngeal squamous carcinoma cells in vitro]. AB - OBJECTIVE: To investigate the effects of a dual phosphoinosmde-3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) inhibitor, PI-103, cooperating with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the laryngeal squamous carcinoma Hep-2 cells. METHODS: Hep-2 cells were divided into 7 groups: LY294002 group, Rapamycin group, PI-103 group, LY294002+ TRAIL group, Rapamycin+ TRAIL group, PI-103+ TRAIL group and control group.The cell cycle and apoptosis of Hep-2 cells were assessed by flow cytometry.For PI-103 group, PI-103+ TRAIL group and control group, migration and invasion ability were measured by transwell migration and invasion assay respectively.The expression of relative proteins in apoptosis and PI3K/AKT/mTOR signal pathway was examined by Western blotting. RESULTS: Combination of PI-103 and TRAIL could make cell cycle arrest at S phase (G1: 1.80%+/-0.30%; G2: 0.00), inhibit cell proliferation, and enhance apoptosis (66.78%+/-2.93%) (P<0.05). Combination of PI-103 and TRAIL could statistically decrease the migration and invasion number of Hep-2 cells (17.0+/ 3.4, 18.4+/-5.4) than that of PI-103 group (41.2+/-3.8, 41.6+/-4.7). PI-103 could inhibit PI3K/AKT/mTOR signal pathway by decreasing the protein expression of p AKT and p-4E-BP1.Comparing with the control group, the expression of cysteinyl aspartate specific proteinase (Caspase) 9, 8, 3 were increased while the expression of Cyclin D1, Cyclin E1, p-AKT, p-4E-BP1 were decreased in PI-103 and PI-103+ TRAIL group (P<0.05). CONCLUSION: Enhanced anti-tumor effects was observed by combination of PI-103 and TRAIL on laryngeal cancer cells in vitro and this combined administration might be a promising strategy for clinical treatment of laryngeal cancer. PMID- 27464549 TI - [Effect of hyperbaric oxygen therapy on antioxidant capacity in brains of rats after acute carbon monoxide poisoning]. AB - OBJECTIVE: This study was designed to observe the antioxidant effects of hyperbaric oxygen (HBO) on brains of rats after acute carbon monoxide (CO) poisoning. METHODS: Sixty-six Sprague-Dawley (SD) male rats were divided into three groups including control group, CO group and HBO group.Morris water maze experiments were used for monitoring cognitive function.Antioxidant capacities were evaluated by detecting T-AOC, GSH-PX, GR and CAT activities in the brain. RESULTS: Compared with the control group (45+/-17, 43+/-14, 35+/-12, 34+/-11, 29+/-13) s and the HBO group (40+/-10, 39+/-6, 35+/-9, 31+/-11, 21+/-10) s, the CO group (57+/-5, 54+/-8, 52+/-8, 52+/-10, 46+/-8) s had the longer escape latency (P<0.05). Compared with the control group (51+/-6) s and the HBO group(40+/-10) s, the CO group (8+/-5) s had the shorter swimming time in I quadrant (P<0.05). Compared with the control group (1.25+/-0.40) U/mg and the HBO group(0.97+/-0.31, 0.97+/-0.39, 1.45+/-0.15, 1.40+/-0.25, 1.20+/-0.20) U/mg, the CO group (0.68+/-0.09, 0.45+/-0.17, 0.71+/-0.18, 0.69+/-0.29, 0.48+/-0.29) U/mg had the lower T-AOC activity of brain tissue.The GSH-PX activity (42+/-13, 106+/ 46, 197+/-49, 173+/-42, 429+/-58) U/mg in the CO group decreased compared with the control group (182+/-53) U/mg and the HBO group (203+/-63, 325+/-86, 389+/ 29, 385+/-100, 453+/-32) U/mg.GR activity (4.3+/-0.7, 2.6+/-0.5, 3.0+/-1.2, 1.8+/ 0.8, 3.2+/-1.9) U/mg in the CO group decreased compared with the control group(14.5+/-3.0) U/mg and the HBO group (13.9+/-3.3, 4.3+/-1.0, 3.9+/-0.7, 4.8+/ 0.9, 4.6+/-0.9) U/mg.CAT activity (1.6+/-0.8, 4.3+/-1.6, 3.9+/-1.0, 8.5+/-2.6, 5.4+/-1.7) U/mg in the CO group decreased compared with the control group(5.2+/ 1.3) U/mg and the HBO group (5.2+/-2.2, 8.8+/-2.8, 5.3+/-1.0, 9.2+/-2.1, 14.1+/ 3.8) U/mg. CONCLUSIONS: HBO can improve the behavior of rats after acute CO poisoning.The antioxidant capacity in rat brain tissue after acute CO poisoning decreases, while after the HBO therapy, the antioxidant capacity in rat brain tissue can increase. PMID- 27464550 TI - Comparative performance of transcriptome assembly methods for non-model organisms. AB - BACKGROUND: The technological revolution in next-generation sequencing has brought unprecedented opportunities to study any organism of interest at the genomic or transcriptomic level. Transcriptome assembly is a crucial first step for studying the molecular basis of phenotypes of interest using RNA-Sequencing (RNA-Seq). However, the optimal strategy for assembling vast amounts of short RNA Seq reads remains unresolved, especially for organisms without a sequenced genome. This study compared four transcriptome assembly methods, including a widely used de novo assembler (Trinity), two transcriptome re-assembly strategies utilizing proteomic and genomic resources from closely related species (reference based re-assembly and TransPS) and a genome-guided assembler (Cufflinks). RESULTS: These four assembly strategies were compared using a comprehensive transcriptomic database of Aedes albopictus, for which a genome sequence has recently been completed. The quality of the various assemblies was assessed by the number of contigs generated, contig length distribution, percent paired-end read mapping, and gene model representation via BLASTX. Our results reveal that de novo assembly generates a similar number of gene models relative to genome guided assembly with a fragmented reference, but produces the highest level of redundancy and requires the most computational power. Using a closely related reference genome to guide transcriptome assembly can generate biased contig sequences. Increasing the number of reads used in the transcriptome assembly tends to increase the redundancy within the assembly and decrease both median contig length and percent identity between contigs and reference protein sequences. CONCLUSIONS: This study provides general guidance for transcriptome assembly of RNA-Seq data from organisms with or without a sequenced genome. The optimal transcriptome assembly strategy will depend upon the subsequent downstream analyses. However, our results emphasize the efficacy of de novo assembly, which can be as effective as genome-guided assembly when the reference genome assembly is fragmented. If a genome assembly and sufficient computational resources are available, it can be beneficial to combine de novo and genome guided assemblies. Caution should be taken when using a closely related reference genome to guide transcriptome assembly. The quantity of read pairs used in the transcriptome assembly does not necessarily correlate with the quality of the assembly. PMID- 27464551 TI - Neural markers of social and monetary rewards in children with Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder. AB - Recent theories of decision making propose a shared value-related brain mechanism for encoding monetary and social rewards. We tested this model in children with Attention-Deficit/Hyperactivity Disorder (ADHD), children with Autism Spectrum Disorder (ASD) and control children. We monitored participants' brain dynamics using high density-electroencephalography while they played a monetary and social reward tasks. Control children exhibited a feedback Error-Related Negativity (fERN) modulation and Anterior Cingulate Cortex (ACC) source activation during both tasks. Remarkably, although cooperation resulted in greater losses for the participants, the betrayal options generated greater fERN responses. ADHD subjects exhibited an absence of fERN modulation and reduced ACC activation during both tasks. ASD subjects exhibited normal fERN modulation during monetary choices and inverted fERN/ACC responses in social options than did controls. These results suggest that in neurotypicals, monetary losses and observed disloyal social decisions induced similar activity in the brain value system. In ADHD children, difficulties in reward processing affected early brain signatures of monetary and social decisions. Conversely, ASD children showed intact neural markers of value-related monetary mechanisms, but no brain modulation by prosociality in the social task. These results offer insight into the typical and atypical developments of neural correlates of monetary and social reward processing. PMID- 27464552 TI - Nephroprotection of punicalagin in rat model of endotoxemic acute kidney injury. AB - The potential nephroprotection of punicalagin (PNG) against lipopolysaccharide (LPS)-induced acute kidney injury in rats was investigated. Rats received a single i.v. dose of LPS (5 mg/kg), and treated with PNG (50 mg/kg, i.p.), 1 h before, and 1 h following LPS administration. LPS caused significant increases of serum creatinine and neutrophil gelatinase-associated lipocalin. LPS also resulted in significant increases in interleukin-18, tumor necrosis factor-alpha, interleukin-6, malondialdehyde, nitric oxide, Bax/Bcl-2 ratio and myeloperoxidase, inducible nitric oxide synthase, caspases 3, 8 and 9 activities, and a significant decrease in total antioxidant capacity in kidney tissues. PNG significantly ameliorated the alterations in the measured parameters. Additionally, PNG attenuated the histopathological injury and reduced kidney injury molecule-1 expression in kidneys of rats that received LPS. It was concluded that PNG ameliorated endotoxemic acute kidney injury in rats by counteracting inflammation, oxidative/nitrative stress and apoptosis. PMID- 27464554 TI - Resorbable Materials for Reconstruction of the Orbital Floor in Children. AB - The best treatment of pediatric orbital fractures is debated and different strategies are proposed in the literature. Resorbable materials, due to their features and the specific requirements of the pediatric population, seem a very suitable choice. The authors present their experience by describing 3 cases and explaining their mesh modeling technique. Two fractures were caused by accidental falls, whereas the other resulted from aggression. Clinical and radiological evaluation (computed tomography scanning) was performed before surgery. No complications occurred either immediately after surgery or in the long term (maximum follow-up of 3 y). As there has been little experience of the use of resorbable mesh in maxillofacial pediatric traumatology, the authors describe their technique, which may facilitate the use of this material in orbital fractures. PMID- 27464553 TI - The association of infrared imaging findings of the breast with prognosis in breast cancer patients: an observational cohort study. AB - BACKGROUND: To evaluate whether infrared (IR) imaging findings are associated with prognosis in patients with invasive breast carcinomas. METHODS: This study was approved by the institutional review board of the research ethics committee of our hospital, and all participants gave written informed consent. From March 2005 to June 2007, we enrolled 143 patients with invasive breast cancer that underwent preoperative IR imaging. We used five IR signs to interpret breast IR imaging. Cox proportional hazards model was used to evaluate the effect of IR signs on long-term mortality. RESULTS: During a median follow-up of 2451 days (6.7 years), 31 patients died. Based on the Cox Proportional Hazards Model, IR1 sign (the temperature of cancer site minus that of the contralateral mirror imaging site) was positively associated with mortality in the univariate analysis (overall mortality hazard ratio [HR], 2.29; p = 0.03; disease-specific mortality HR, 2.57; p = 0.04) as well as the multivariate analysis after controlling for clinicopathological factors (overall mortality HR, 3.85; p = 0.01; disease specific mortality HR, 3.91, p = 0.02). In patients with clinical stage I and II disease, IR1 was also positively associated with mortality (overall mortality HR, 3.76; p = 0.03; disease-specific mortality HR, 4.59; p = 0.03). Among patients with node-negative disease, IR1 and IR5 (asymmetrical thermographic pattern) were associated with mortality (p = 0.04 for both IR1 and IR5, chi-squared test). CONCLUSION: Breast IR findings are associated with mortality in patients with invasive breast carcinomas. The association remained in patients with node negative disease. TRIAL REGISTRATION: NCT00166998 . PMID- 27464555 TI - Application of Vacuum-Assisted Closure Therapy and Hyperbaric Oxygen Therapy for an Exposed Titanium Plate After Mandible Reconstruction. AB - The authors report a case of an 84-year-old woman with an exposed mandibular plate after reconstruction, which finally healed with combination therapy using vacuum-assisted closure therapy and hyperbaric oxygen therapy. The woman was diagnosed with mucosal carcinoma of the right oral cavity. During reconstruction after segmental excision of the mandible, a titanium plate was selected based on several risk factors. After the operation, the plate became exposed at the center of the chin. A second surgery was deemed inappropriate because of her age, malnutrition, and recurrent aspiration pneumonia. Instead, combination therapy consisting of vacuum-assisted closure therapy and hyperbaric oxygen therapy was initiated, leading to epithelizaion of the wound. Adapt Barrier Rings was effectively used to generate a stable negative pressure at the complicated craniofacial wound. A surgical or conservative approach is chosen as salvage treatment of an exposed plate. In this patient, only conservative treatment involving combination therapy resulted in complete healing of the wound with plate exposure. This patient highlights 2 important clinical issues: combination therapy was effective for an exposed mandibular plate, and a dressing technique using Adapt Barrier Rings enabled stable negative pressure in the craniofacial wound. PMID- 27464556 TI - Safety of Outpatient Isolated Orbital Floor Fracture Repair. AB - Orbital fractures are common, accounting for nearly 40% of all facial fractures. Open repair is required to restore preinjury orbital volume and relieve any extra ocular muscle entrapment. Monitoring for postoperative intraorbital hemorrhage, and its consequent potential for visual impairment, has triggered most surgeons to observe their patients in the hospital overnight postoperatively. The real risk of postoperative hemorrhage in this patient group, however, is uncertain and the need to contain healthcare costs clear. The objective of this study was thus to determine the incidence of emergent postoperative complications in patients undergoing orbital fracture repair to determine the feasibility of performing this operation on an outpatient basis. Patients who sustained isolated orbital fractures and underwent open repair at this level-1 trauma center between January 2002 and January 2012 using International Classification of Disease-9 and Current Procedural Terminology 2012 coding were identified. Demographic data and postoperative complications were identified by reviewing the electronic medical record. Furthermore, critical analysis of available published evidence was performed. Ninety-three patients who satisfied the inclusion criteria were selected. There were no patients of an intraorbital hematoma or other immediate postoperative complications that required operative intervention. Average hospital length of stay was 0.85 days. Repair of orbital fractures on an outpatient basis appears to be safe. The theoretical risk of a complicating intraorbital hematoma seems to be between 0 and 3.2%. This can be minimized through: the use of open surgical access site and perforated floor replacement materials, careful early monitoring, education of patients, and admission of those at potentially elevated risk. PMID- 27464557 TI - Treatment of Large Thyroglossal Duct Cyst. AB - The thyroglossal duct cyst is the neck congenital abnormality most common in the childhood. Clinically, it shows itself as a solitary neck mass in the region of hyoid bone, it is painless and can be dislocated during de physical examination and tongue protrusion. The most common treatment is its removal through the Sistrunk technique. Patient with diagnosis of thyroglossal duct cyst in neck region with extension to the mouth floor was treated by total surgical removal through intraoral access. The intraoral approach to the treatment of the thyroglossal duct cyst showed itself practicable and permitted the total removal of the lesion with no recurrence signs. PMID- 27464558 TI - Pedunculated Primary Mucosal Malignant Melanoma Originated From the Posterior Nasal Septum. AB - Primary mucosal malignant melanoma of the nasal cavity is a rare disease. The authors present the patient of a pedunculated primary mucosal malignant melanoma originated from the posterior nasal septum, which was successfully removed via the endoscopic approach. Clinicians should consider the possibility that a primary mucosal malignant melanoma may originate in the nasal cavity, mimicking the other more frequently observed lesions. PMID- 27464559 TI - Pneumocephalus Following Air Travel in a Patient With Preexisting Facial Fractures and Dural Tears. AB - Changes in cabin pressure can potentially cause expansion of any preexisting intracranial air resulting in tension pneumocephalus. The authors describe a 28 year-old man, who was involved in a motor vehicle accident complicated by multiple facial fractures and a dural tear while on his way to the airport. Instead of seeking medical attention after the accident, he proceeded with a 2 hour commercial flight. He did not suffer from any neurologic deterioration inflight, but upon presentation to our center, a computed tomography scan was done which revealed extensive pneumocephalus, for which he required intensive monitoring and subsequent surgery. Controversy still exists regarding whether it is safe to travel by air in patients with intracranial air. It is hoped that this patient will add to the discussion regarding the safety for air travel in patients with traumatic pneumocephalus. PMID- 27464560 TI - Zigzag Temporal Incision With Preauricular Incision Extension as a Variant Approach to the Temporomandibular Joint. AB - Surgical visibility of the joint is often compromised by the efforts to protect the facial nerve and its branches. Several approaches to the temporomandibular joint have been proposed over the years and perhaps the standard and most commonly used incision is the preauricular which is then extended with coronal incision to improve visibility and safety during surgery. The authors present a new modification based on the achievement of an aesthetically acceptable and inconspicuous scar in the temporal area. This is achieved by using a preauricular incision extended with a zigzag incision as a routine approach to the temporomandibular joint instead of the straight coronal incision. The zigzag incision is proposed for cosmetic purposes and results in a natural separation of the hair. PMID- 27464561 TI - Idiopathic Orbital Inflammatory Pseudotumor With Bone Erosion. AB - PURPOSE/BACKGROUND: To report a rare patient with idiopathic orbital inflammatory pseudotumor showing obvious bone erosion of the orbital wall. METHODS: Clinical features and imaging findings, orbital surgery, and histopathological examination are presented. RESULTS: A 56-year-old Chinese man showed a gradually growing unilateral proptosis of the left eye for 6 months. Visual acuity, intraocular pressure, anterior segment, and fundi were normal in both eyes. Proptosis was 17 mm in the right eye and 23 mm in the left. No palpable mass was present on the left orbital rim. Ocular motility showed a moderate limitation of left adduction. Computed tomography scan revealed multifocal smoothly outlined homogeneous soft tissue masses measuring from 10 * 6 to 30 * 10 mm with obvious bone destruction in the lateral and inferior walls of the left orbit. An anterior orbitotomy by an inferio-temporal skin incision was used to partially remove the mass. Histopathological evaluation confirmed the diagnosis of an idiopathic inflammatory pseudotumor. After surgery, administration of systemic corticosteroids was initiated, which resulted in a dramatic improvement in the proptosis and ocular movements. There was no recurrence as determined at 6 years postsurgery and visual acuity was 25/20 in both eyes. CONCLUSIONS: Idiopathic orbital inflammatory pseudotumor may show an orbital bone erosion, similar to that of soft-tissue malignancy or orbital metastasis. PMID- 27464563 TI - Bone Healing Promotion by Negatively Charged Polysterene Microspheres. AB - Bone healing under optimal conditions is fairly predictable. Yet when the healing process is disturbed by inadequate immobilization, inadequate blood supply, or scar tissue, little therapeutic alternatives to surgery exist.It appears that redistribution of electric charges along the bone during a callus consolidation promotes bone healing. It has been shown in the past that negatively charged polysterene spheres promote bone growth in animal models.In this preliminary report, we tested weather or not a commercial device of negatively charged polysterene spheres promotes bone healing in a porcine model.This preliminary study seems to suggest that the negatively charged polystyrene microspheres may have a potential in promoting bone healing, either alone or as an adjunct to other bone graft materials. These speculations should be further validated by large-scale studies in animal models and clinical trials. PMID- 27464564 TI - Galeal Lip Augmentation: The Pancake Technique. PMID- 27464565 TI - Health-Related Quality of Life and the Desire for Revision Surgery Among Children With Cleft Lip and Palate. AB - PURPOSE: Children with cleft lip with or without palate (CLCP) require multiple reconstructive procedures, however, little is known about their desire for surgical revision. The purpose of this study was to examine the relationship between health-related quality of life (HRQOL) and the desire for revision. METHODS: The authors surveyed children with CLCP (n = 71) and their caregivers regarding general and cleft-specific HRQOL and the desire for revision surgery. The authors used logistic regression models to evaluate the relationship between HRQOL and the desire for revision stratified by age, and determined the level of agreement between caregivers and children. RESULTS: In this cohort, 54.9% of children desired revision, primarily of the nose (n = 23), lip (n = 20), and dentoalveolar structures (n = 19). Children 11 years or older were more likely to desire revision than younger children (OR 3.39, 95% CI [1.19, 9.67], P <0.05). Children who reported poorer HRQOL with respect to appearance (OR 2.31, 95% CI [1.25-4.29], P = 0.008), social development (OR 0.91, 95% CI [0.84-0.99], P = 0.02), and communication (OR 0.94, 95% CI [0.89-0.99], P = 0.02) were significantly more likely to desire revision than children who reported more positive HRQOL. Caregivers' and children's desires for revision were only modestly correlated (r = 0.41). CONCLUSIONS: Children with CLCP who report poorer HRQOL are more likely to desire revision than children with higher HRQOL; these differences are further magnified among older children. Given the modest correlation between patient and caregiver goals for revision, it is important to evaluate both perspectives when considering revision surgery. PMID- 27464566 TI - Quality of life and related factors of nursing home residents in Singapore. AB - BACKGROUND: Litter is known about the well-being of nursing home (NH) residents in Singapore. This study aimed to identify predictors of self-reported quality of life (QOL) of NH residents in Singapore. METHODS: In face-to-face interviews, trained medical students assessed each consenting resident recruited from 6 local NHs using a modified Minnesota QOL questionnaire, and rating scales and questions assessing independence, cognitive function, depression, and communication. Predictors of residents' QOL in five aspects (comfort, dignity, food enjoyment, autonomy, and security) were identified using the censored least absolute deviations (CLAD) models. RESULTS: A total of 375 residents completed the interviews. A higher score on comfort was negatively associated with major depression while a higher score on dignity was positively associated with no difficulty in communication with staff. Higher scores in food enjoyment were negatively associated with major depression and poorer cognitive function. Higher scores in autonomy were negatively associated with major depression, greater dependence, and difficulty in communication with staff. A higher score on security were negatively associated with major depression. CONCLUSION: It appears that depression and difficulty in communication with staff are the two main modifiable risk factors of poor quality of life of local NH residents. PMID- 27464568 TI - Environmental predictors of stunting among children under-five in Somalia: cross sectional studies from 2007 to 2010. AB - BACKGROUND: Stunting among children under five years old is associated with long term effects on cognitive development, school achievement, economic productivity in adulthood and maternal reproductive outcomes. Accurate estimation of stunting and tools to forecast risk are key to planning interventions. We estimated the prevalence and distribution of stunting among children under five years in Somalia from 2007 to 2010 and explored the role of environmental covariates in its forecasting. METHODS: Data from household nutritional surveys in Somalia from 2007 to 2010 with a total of 1,066 clusters covering 73,778 children were included. We developed a Bayesian hierarchical space-time model to forecast stunting by using the relationship between observed stunting and environmental covariates in the preceding years. We then applied the model coefficients to environmental covariates in subsequent years. To determine the accuracy of the forecasting, we compared this model with a model that used data from all the years with the corresponding environmental covariates. RESULTS: Rainfall (OR = 0.994, 95 % Credible interval (CrI): 0.993, 0.995) and vegetation cover (OR = 0.719, 95 % CrI: 0.603, 0.858) were significant in forecasting stunting. The difference in estimates of stunting using the two approaches was less than 3 % in all the regions for all forecast years. CONCLUSION: Stunting in Somalia is spatially and temporally heterogeneous. Rainfall and vegetation are major drivers of these variations. The use of environmental covariates for forecasting of stunting is a potentially useful and affordable tool for planning interventions to reduce the high burden of malnutrition in Somalia. PMID- 27464567 TI - Women's perceptions of antenatal care: are we following guideline recommended care? AB - BACKGROUND: Detection and management of antenatal risk factors is critical for improved maternal and infant outcomes. This study describes the proportion of pregnant women who self-reported being screened for and offered advice to manage antenatal risk factors in line with antenatal care recommendations; and the characteristics associated with rates of screening. METHODS: A survey was undertaken with 223 (64 % of eligible) pregnant women recruited from an outpatient obstetrics clinic at a public hospital. Participants self-reported whether they were: (i) screened for 23 guideline-recommended risk factors during their antenatal visit; (ii) offered assistance to manage identified risk factor(s); and (iii) received assistance that was of benefit. Association between rate of screening and participant characteristics was examined using multivariate quantile regression. RESULTS: Overall, 23 % of women reported that they were asked about every risk factor. Weight gain (48 %), diet (60 %) and oral health (31 %) were least frequently screened risk factors. The number of women who reported they were offered advice to manage identified risks and the value of that advice was perceived by women as suboptimal. Those women receiving shared care between a midwife and general practitioner, of Aboriginal or Torres Strait Islander descent, and without private health insurance reported being screened for a greater number of risk factors. CONCLUSIONS: Pregnant women report suboptimal rates of screening and management of antenatal risk factors. Initiatives to improve consistency in detection of antenatal risk factors and the application of appropriate interventions to manage those risk factors that are detected are required. PMID- 27464569 TI - Influence of the Madden-Julian oscillation on Tibetan Plateau snow cover at the intraseasonal time-scale. AB - The Tibetan Plateau (TP), known as the third pole of the Earth, has snow cover with intraseasonal to decadal variability that affects weather and climate both inside and outside the TP. However, the factors that generate the TP snow cover (TPSC) anomalies at the intraseasonal time-scale are unclear. This report reveals the influence of the Madden-Julian oscillation (MJO), which is the most dominant component of the tropical intraseasonal variability, on TPSC. We focus on wintertime snow cover over the central and eastern TP, where the intraseasonal variability is large. TPSC increases/decreases in the MJO phases 8-1/4-5, when the eastward-propagating MJO suppressed/enhanced convection locates over the Maritime Continent. Such a change in TPSC leads to the most dominant positive/negative anomalies of TPSC in the following phases 2-3/6-7 due to the non-significant change of TPSC in these phases. There is anomalous moisture advection over the upstream of the TP caused by MJO-excited large-scale atmospheric circulation. The advection process generates the low-frequency eastward-propagating anomalous water vapour from upstream to the TP that influences precipitation and, eventually, TPSC. PMID- 27464570 TI - New chronic disease medication prescribing by nurse practitioners, physician assistants, and primary care physicians: a cohort study. AB - BACKGROUND: Medications to treat and prevent chronic disease have substantially reduced morbidity and mortality; however, their diffusion has been uneven. Little is known about prescribing of chronic disease medications by nurse practitioners (NPs) and physician assistants (PAs), despite their increasingly important role as primary care providers. Thus, we sought to conduct an exploratory analysis to examine prescribing of new chronic disease medications by NPs and PAs compared to primary care physicians (PCPs). METHODS: We obtained prescribing data from IMS Health's XponentTM on all NPs, PAs, and PCPs in Pennsylvania regularly prescribing anticoagulants, antihypertensives, oral hypoglycemics, and/or HMG-Co A reductase inhibitors pre- and post-introduction of five new drugs in these classes that varied in novelty (i.e., dabigatran, aliskiren, sitagliptin or saxagliptin, and pitavastatin). We constructed three measures of prescriber adoption during the 15-month post-FDA approval period: 1) any prescription of the medication, 2) proportion of prescriptions in the class for the medication, and 3) time to adoption (first prescription) of the medication. RESULTS: From 2007 to 2011, the proportion of antihypertensive prescriptions prescribed by NPs and PAs approximately doubled from 2.0 to 4.2 % and 2.2 to 4.9 %, respectively. Similar trends were found for anticoagulants, oral hypoglycemics, and HMG-Co-A reductase inhibitors. By 2011, more PCPs had prescribed each of the newly approved medications than NPs and PAs (e.g., 44.3 % vs. 18.5 % vs. 20 % for dabigatran among PCPs, NPs, and PAs). Across all medication classes, the newly approved drugs accounted for a larger share of prescriptions in the class for PCPs followed by PAs, followed by NPs (e.g., dabigatran: 4.9 % vs. 3.2 % vs. 2.8 %, respectively). Mean time-to-adoption for the newly approved medications was shorter for PCPs compared to NPs and PAs (e.g., dabigatran, 7.3 vs. 8.2 vs. 8.5 months; P all medications <0.001). CONCLUSIONS: PCPs were more likely to prescribe each of the newly approved medications per each measure of drug adoption, regardless of drug novelty. Differences in the rate and speed of drug adoption between PCPs, NPs, and PAs may have important implications for care and overall costs at the population level as NPs and PAs continue taking on a larger role in prescribing. PMID- 27464571 TI - Polyhydroquinone-graphene composite as new redox species for sensitive electrochemical detection of cytokeratins antigen 21-1. AB - Polyhydroquinone-graphene composite as a new redox species was synthesized simply by a microwave-assisted one-pot method through oxidative polymerization of hydroquinone by graphene oxide, which exhibited excellent electrochemical redox activity at 0.124 V and can remarkably promote electron transfer. The as-prepared composite was used as immunosensing substrate in a label-free electrochemical immunosensor for the detection of cytokeratins antigen 21-1, a kind of biomarker of lung cancer. The proposed immunosensor showed wide liner range from 10 pg mL( 1) to 200 ng mL(-1) with a detection limit 2.3 pg mL(-1), and displayed a good stability and selectivity. In addition, this method has been used for the analysis of human serum sample, and the detection results showed good consistence with those of ELISA. The present substrate can be easily extended to other polymer-based nanocomposites. PMID- 27464572 TI - Vision Therapy for Binocular Dysfunction Post Brain Injury. AB - PURPOSE: To prospectively evaluate the effectiveness of home-based computer vergence therapy for the treatment of binocular vision disorders in adults at least 3 months after an acquired brain injury. METHODS: Eligibility criteria included presence of binocular dysfunction characterized by receded near point of convergence (>=6 cm break), insufficient positive fusional vergence at near (failing Sheard's criterion or <15? blur or break), insufficient negative fusional vergence at near (<12? blur or break), and/or reduced vergence facility at near (<15 cycles per minute with 12?BO/3?BI). Participants were prescribed 12 weeks of home-based computer vergence therapy. Phoria (cover test), negative fusional vergence, positive fusional vergence, near point of convergence, vergence facility, and symptoms (convergence insufficiency symptom survey [CISS]) were assessed at baseline and after 4, 8, and 12 weeks of prescribed therapy. ANOVA was used to evaluate change in each measure. Percentage successful was also determined. RESULTS: Nineteen participants were enrolled (mean age 45.4 +/- 12.9 years); six participants were lost to follow-up. Baseline findings were orthophoria at distance, 7.2? exophoria at near, near point of convergence break = 17.5 cm, near point of convergence recovery = 21.8 cm, negative fusional vergence = 12.3?, positive fusional vergence blur = 8.4?, vergence facility = 3.9 cycles per minute, and CISS = 32.1. ANOVA showed a statistically significant improvement for near point of convergence break (p = 0.002) and recovery (p < 0.001), positive fusional vergence blur (p < 0.0001), break (p < 0.0001), and recovery (p < 0.0001), negative fusional vergence blur (p = 0.037), break (p = 0.003), and recovery (p = 0.006), vergence facility (p < 0.0001), and CISS (p = 0.0001). The percentage of patients who were classified as "successful" or "improved" was 69% for near point of convergence (<6 cm or decrease of >=4 cm), 77% for positive fusional vergence (>15? and passing Sheard's criterion or increase of >=10?), 77% for negative fusional vergence (>=12? or increase of >=6?), 62% for positive fusional vergence and near point of convergence composite, and 92% for vergence facility (15 cycles per minute or increase of 3 cycles per minute). CONCLUSIONS: The majority of participants who completed the study experienced meaningful improvements in signs and symptoms. PMID- 27464573 TI - King-Devick and Pre-season Visual Function in Adolescent Athletes. AB - PURPOSE: The King-Devick test (KD) has been studied as a remove-from-play sideline test in college-age athletes and older; however, studies in younger athletes are limited. A cross-sectional study of the KD and other vision correlates was completed on school-aged athletes during pre-season physicals for a variety of sports to determine the repeatability of the KD. The study also evaluated how convergence, alignment, or pupil function contributed to a slower King-Devick baseline reading. METHODS: Seven hundred eighty-five athletes underwent vision screenings in a hospital or school setting by trained/certified staff as part of pre-season physicals. Six hundred nineteen had KD testing completed per the manufacturer's suggested protocol and repeated. Other baseline vision testing included visual acuity, Modified Thorington testing for alignment, convergence testing, and pupil function using the NeurOptics (NPI-200) NPi. RESULTS: The mean fastest, error-minimized KD time for all participants was 43.9 seconds(s) (SD +/- 11.6, range 24-120). Median KD time got faster (+) with age (p < 0.0001). The inter-class correlation coefficient for all scores was 0.92. The absolute mean time difference for any two tests was 3.5 s (SD +/- 2.5, range 0 23). There was no association between the best KD time and reduced NPC (p = 0.63), Modified Thorington measure of alignment (p = 0.55), or NPi pupil function (p = 0.79). The Bland Altman repeated measure limits of agreement was +/-6.5 seconds for those in the 10th to12th grades, and +/-10.2 seconds for those in the 6th to 9th grades. CONCLUSIONS: King-Devick score in junior high and high school athletes is variable but gets faster and more repeatable with increasing age. The KD does not correlate significantly with reduced convergence, alignment, or pupil function. Based on grouped data, a slowing of 10 seconds for younger athletes and 6 seconds for older athletes on a second administration represents a true difference in testing speed. Within-player variability should be considered when removal-from-play decisions are influenced by KD results. PMID- 27464575 TI - Blue and Red Light-Evoked Pupil Responses in Photophobic Subjects with TBI. AB - PURPOSE: Photophobia is a common symptom in individuals suffering from traumatic brain injury (TBI). Recent evidence has implicated blue light-sensitive intrinsically photosensitive retinal ganglion cells (ipRGCs) in contributing to the neural circuitry mediating photophobia in migraine sufferers. The goal of this work is to test the hypothesis that ipRGC function is altered in TBI patients with photophobia by assessing pupillary responses to blue and red light. METHODS: Twenty-four case participants (mean age 43.3; 58% female), with mild TBI and self-reported photophobia, and 12 control participants (mean age 42.6; 58% female) were in this study. After 10 minutes of dark adaptation, blue (470 nm, 1 * 10 phots/s/cm) and red (625 nm, 7 * 10 phots/s/cm) flashing (0.1 Hz) light stimuli were delivered for 30 seconds to the dilated left eye while the right pupil was recorded. The amplitude of normalized pupil fluctuation (constriction and dilation) was quantified using Fourier fast transforms. RESULTS: In both case and control participants, the amplitude of pupil fluctuation was significantly less for the blue light stimuli as compared to the red light stimuli, consistent with a contribution of ipRGCs to these pupil responses. There was no significant difference in the mean pupil fluctuation amplitudes between the two participant groups, but case participants displayed greater variability in their pupil responses to the blue stimulus. CONCLUSIONS: Case and control participants showed robust ipRGC-mediated components in their pupil responses to blue light. The results did not support the hypothesis that ipRGCs are "hypersensitive" to light in TBI participants with photophobia. However, greater pupil response variability in the case subjects suggests that ipRGC function may be more heterogeneous in this group. PMID- 27464574 TI - Objective Assessment of Vergence after Treatment of Concussion-Related CI: A Pilot Study. AB - PURPOSE: To evaluate changes in objective measures of disparity vergence after office-based vision therapy (OBVT) for concussion-related convergence insufficiency (CI) and determine the feasibility of using this objective assessment as an outcome measure in a clinical trial. METHODS: This was a prospective, observational trial. All participants were treated with weekly OBVT with home reinforcement. Participants included two adolescents and three young adults with concussion-related, symptomatic CI. The primary outcome measure was average peak velocity for 4 degrees symmetrical convergence steps. Other objective outcome measures of disparity vergence included time to peak velocity, latency, accuracy, settling time, and main sequence. We also evaluated saccadic eye movements using the same outcome measures. Changes in clinical measures (near point of convergence, positive fusional vergence at near, Convergence Insufficiency Symptom Survey [CISS] score) were evaluated. RESULTS: There were statistically significant and clinically meaningful changes in all clinical measures for convergence. Four of the five subjects met clinical success criteria. For the objective measures, we found a statistically significant increase in peak velocity, response accuracy to 4 degrees symmetrical convergence and divergence step stimuli, and the main sequence ratio for convergence step stimuli. Objective saccadic eye movements (5 and 10 degrees ) appeared normal pre-OBVT and did not show any significant change after treatment. CONCLUSIONS: This is the first report of the use of objective measures of disparity vergence as outcome measures for concussion-related convergence insufficiency. These measures provide additional information that is not accessible with clinical tests about underlying physiological mechanisms leading to changes in clinical findings and symptoms. The study results also demonstrate that patients with concussion can tolerate the visual demands (over 200 vergence and versional eye movements) during the 25-minute testing time and suggest that these measures could be used in a large-scale randomized clinical trial of concussion-related CI as outcome measures. PMID- 27464576 TI - Investigation of the Effect of Thermal Annealing on Poly(3-hexylthiophene) Nanofibers by Scanning Probe Microscopy: From Single-Chain Conformation and Assembly Behavior to the Interfacial Interactions with Graphene Oxide. AB - Poly(3-hexylthiophene) (P3HT) has been widely used in devices owing to its excellent properties and structural features. However, devices based on pure P3HT have not exhibited high performance. Strategies, such as thermal annealing and surface doping, have been used to improve the electrical properties of P3HT. In this work, different from previous studies, the effect of thermal annealing on P3HT nanofibers are examined, ranging from the single polymer chain conformation to chain packing, and the interfacial interactions with graphene oxide (GO) at nanoscale dimensions, by using scanning tunneling microscopy (STM), atomic force microscopy (AFM) and Kelvin probe force microscopy (KPFM). High-resolution STM images directly show the conformational changes of single polymer chains after thermal annealing. The morphology of P3HT nanofibers and the surface potential changes of the P3HT nanofibers and GO is further investigated by AFM and KPFM at the nanoscale, which demonstrate that the surface potentials of P3HT decrease, whereas that of GO increases after thermal annealing. All of the results demonstrate the stronger interfacial interactions between P3HT and GO occur after thermal treatments due to the changes in P3HT chain conformation and packing order. PMID- 27464578 TI - Repair of recoarctation after the Norwood operation: The right-sided posterior approach. PMID- 27464577 TI - Disruption of desmin-mitochondrial architecture in patients with regurgitant mitral valves and preserved ventricular function. AB - OBJECTIVE: Recent studies have demonstrated improved outcomes in patients receiving early surgery for degenerative mitral regurgitation (MR) rather than adhering to conventional guidelines for surgical intervention. However, studies providing a mechanistic basis for these findings are limited. METHODS: Left ventricular (LV) myocardium from 22 patients undergoing mitral valve repair for American Heart Association class I indications was evaluated for desmin, the voltage-dependent anion channel, alpha-B-crystallin, and alpha, beta-unsaturated aldehyde 4-hydroxynonenal by fluorescence microscopy. The same was evaluated in 6 normal control LV autopsy specimens. Cardiomyocyte ultrastructure was examined by transmission electron microscopy. Magnetic resonance imaging with tissue tagging was performed in 55 normal subjects and 22 MR patients before and 6 months after mitral valve repair. RESULTS: LV end-diastolic volume was 1.5-fold (P < .0001) higher and LV mass-to-volume ratio was lower in MR (P = .004) hearts versus normal hearts and showed improvement 6 months after mitral valve surgery. However, LV ejection fraction decreased from 65% +/- 7% to 52% +/- 9% (P < .0001) and LV circumferential (P < .0001) and longitudinal strain decreased significantly below normal values (P = .002) after surgery. Hearts with MR had a 53% decrease in desmin (P < .0001) and a 2.6-fold increase in desmin aggregates (P < .0001) versus normal, along with substantial, intense perinuclear staining of alpha, beta-unsaturated aldehyde 4-hydroxynonenal in areas of mitochondrial breakdown and clustering. Transmission electron microscopy demonstrated numerous electron-dense deposits, myofibrillar loss, Z-disc abnormalities, and extensive granulofilamentous debris identified as desmin-positive by immunogold transmission electron microscopy. CONCLUSIONS: Despite well-preserved preoperative LV ejection fraction, severe oxidative stress and disruption of cardiomyocyte desmin-mitochondrial sarcomeric architecture may explain postoperative LV functional decline and further supports the move toward earlier surgical intervention. PMID- 27464579 TI - Multidisciplinary Team Tumour Boards are a Lifeline for Our Cancer Patients in Lower and Middle Income Countries. PMID- 27464580 TI - Form and function of the human and chimpanzee forefoot: implications for early hominin bipedalism. AB - During bipedal walking, modern humans dorsiflex their forefoot at the metatarsophalangeal joints (MTPJs) prior to push off, which tightens the plantar soft tissues to convert the foot into a stiff propulsive lever. Particular features of metatarsal head morphology such as "dorsal doming" are thought to facilitate this stiffening mechanism. In contrast, chimpanzees are believed to possess MTPJ morphology that precludes high dorsiflexion excursions during terrestrial locomotion. The morphological affinity of the metatarsal heads has been used to reconstruct locomotor behavior in fossil hominins, but few studies have provided detailed empirical data to validate the assumed link between morphology and function at the MTPJs. Using three-dimensional kinematic and morphometric analyses, we show that humans push off with greater peak dorsiflexion angles at all MTPJs than do chimpanzees during bipedal and quadrupedal walking, with the greatest disparity occurring at MTPJ 1. Among MTPJs 2-5, both species exhibit decreasing peak angles from medial to lateral. This kinematic pattern is mirrored in the morphometric analyses of metatarsal head shape. Analyses of Australopithecus afarensis metatarsals reveal morphology intermediate between humans and chimpanzees, suggesting that this species used different bipedal push-off kinematics than modern humans, perhaps resulting in a less efficient form of bipedalism. PMID- 27464581 TI - South Pacific influence on the termination of El Nino in 2014. AB - The El Nino/Southern Oscillation (ENSO) is the dominant mode of climate variability affecting worldwide extreme weather events; therefore, improving ENSO prediction is an important issue. In this regard, a peculiar time evolution of ENSO in 2014 posed a challenge to the climate science community. Despite the observance of several precursors for a strong El Nino to develop during the summer and autumn, cold sea surface temperature (SST) anomalies appeared unexpectedly to the south of the equatorial cold tongue, which prevented development of an El Nino event in the late summer. Several hypotheses have been raised to explain the unmaterialized El Nino in 2014, but complete understanding of processes responsible for terminating this event has not yet been obtained. Here we show, using observations and extended seasonal prediction experiments with a climate model, that cold off-equatorial subsurface water in the South Pacific Ocean penetrated into the equatorial region along the slanted isopycnal surface via the mean advection, and it prevented the El Nino evolution in 2014. The negative subsurface temperature anomalies in the off-equatorial South Pacific Ocean were persistent throughout the last decade, and additional numerical simulations indicated that they contributed to the suppression of El Nino events during the 2000s. PMID- 27464582 TI - A phase I, placebo-controlled, randomized, double-blind, single ascending dose ranging study to evaluate the safety and tolerability of a novel biophysical bronchodilator (S-1226) administered by nebulization in healthy volunteers. AB - BACKGROUND: A major challenge in treating acute asthma exacerbations is the need to open constricted airways rapidly enough to reestablish ventilation and allow delivery of conventional medication to diseased airways. The solution requires a new approach that considers both biophysical and pharmacological aspects of treatments used in acute asthma. The result of testing several formulations was S 1226: carbon dioxide-enriched air delivered in nebulized perflubron, a synthetic surfactant. These agents act synergistically to rapidly reopen closed airways within seconds. The bronchodilator effect is independent of beta-adrenergic and cholinergic mediated-signaling pathways, offering a unique mechanism of action. S 1226 has a low toxicity profile and was effective in treating bronchoconstriction in animal models of asthma. The goal of the present study was to evaluate the safety and tolerability of S-1226 in healthy human subjects. METHODS: The phase I study was a single-center, randomized, double-blind, placebo-controlled, sequential, single-ascending-dose study conducted in Canada. Thirty-six subjects were distributed into three cohorts. Within each cohort, subjects were randomized to receive a single dose of S-1226 or a matching placebo administered over a 2 minute nebulization period. S-1226 was formulated with perflubron and 4 %, 8 %, or 12 % CO2. The dose of CO2 was sequentially escalated by cohort. The safety and tolerability of S-1226 were evaluated through assessment of adverse events, vital signs, 12-lead electrocardiograms, clinical laboratory parameters, and physical examinations. RESULTS: S-1226 was safe and well tolerated at all three CO2 levels (4 %, 8 %, and 12 %). A total of 28 adverse events were reported, and all were judged mild in severity. Twenty-four adverse events occurred in the S-1226 cohort, of which five were considered remotely related and six possibly related to S-1226. CONCLUSIONS: S-1226 is a novel drug being developed for the treatment of acute asthma exacerbations. It consists of CO2-enriched air and perflubron and has potential to offer rapid and potent bronchodilation. The results of the study indicate that S-1226 is safe and well tolerated. All adverse events were mild, reversible, and likely due to known side effects of CO2 inhalation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02616770 . Registered on 25 November 2015. PMID- 27464583 TI - Kirschner wire pin site infection in hand and wrist fractures: incidence rate and risk factors. AB - : Kirschner wires are widely used for skeletal fixation of unstable fractures, but the pin tracks create a potential pathway through the skin and into the bone for bacteria to cause an infection. We tested the null hypothesis that there are no demographic, patient-related, injury, or treatment variables independently associated with the occurrence of pin site infection after percutaneous fixation of hand and wrist fractures using Kirschner wires. A retrospective review of 1213 patients with one or more fractures of the hand and wrist treated with percutaneous Kirschner wire fixation identified 85 patients (7%) who had additional treatment with oral antibiotics, early pin removal, or reoperation related to a pin site infection. We found no factors were independently associated with higher or lower risks of pin site infection in multivariable logistic regression analysis. Pin site infections - most benign - occur in a notable number of patients and we could not identify any modifiable risk factors. LEVEL OF EVIDENCE: III. PMID- 27464585 TI - Contact allergy to ingredients of topical medications: results of the European Surveillance System on Contact Allergies (ESSCA), 2009-2012. AB - PURPOSE: The aim of this study was to give an overview of the prevalence of contact allergy to active ingredients and excipients of topical medications across Europe. METHODS: Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (www.essca-dc.org) with substances applied to consecutively patch tested patients, 2009-2012, in 54 departments in 12 European countries. RESULTS: In view of the varying composition of the baseline series used in the previously mentioned departments and countries, between 58 833 (lanolin alcohols) and 16 498 patients (sodium metabisulfite) were patch tested with the topical agents covered in this study. Among these, positive (allergic) reactions were most commonly observed to sodium metabisulfite (3.12% positive), followed by propolis (2.48%), Compositae mix (1.73%), lanolin alcohols (1.65%) and caine mix III (benzocaine, cinchocaine and tetracaine; 1.27%). CONCLUSIONS: Several of the substances warrant routine screening for contact allergy, i.e. patch testing in a baseline series. However, in view of a vast number of other topical agents, additional patch testing with the suspect topical drug preparations (including natural remedies and cosmetics) is warranted. In the event of a positive test to the (pharmaceutical) product, single ingredients should be tested individually to precisely identify the hapten(s). Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27464584 TI - Commonalities in EEG Spectral Power Abnormalities Between Women With ADHD and Women With Bipolar Disorder During Rest and Cognitive Performance. AB - While attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) denote distinct psychiatric conditions, diagnostic delineation is impeded by considerable symptomatic overlap. Direct comparisons across ADHD and BD on neurophysiological measures are limited. They could inform us on impairments that are specific to or shared between the disorders and, therefore, potential biomarkers that may aid in the identification of the diagnostic boundaries. Our aim was to test whether quantitative EEG (QEEG) identifies differences or similarities between women with ADHD and women with BD during resting-state and task conditions. QEEG activity was directly compared between 20 ADHD, 20 BD and 20 control women during an eyes-open resting-state condition (EO) and a cued continuous performance task (CPT-OX). Both ADHD (t38 = 2.50, p = 0.017) and BD (t38 = 2.54, p = 0.018) participants showed higher absolute theta power during EO than controls. No significant differences emerged between the two clinical groups. While control participants showed a task-related increase in absolute theta power from EO to CPT-OX (t19 = -3.77, p = 0.001), no such change in absolute theta power was observed in the ADHD (t19 = -0.605, p = 0.553) or BD (t19 = 1.82, p = 0.084) groups. Our results provide evidence for commonalities in brain dysfunction between ADHD and BD. Absolute theta power may play a role as a marker of neurobiological processes in both disorders. PMID- 27464586 TI - Facile synthesis of magnetic-/pH-responsive hydrogel beads based on Fe3O4 nanoparticles and chitosan hydrogel as MTX carriers for controlled drug release. AB - In the present study, methotrexate (MTX)-encapsulated magnetic-/pH-responsive hydrogel beads based on Fe3O4 nanoparticles and chitosan were successfully prepared through a one-step gelation process, which is a very facile, economic and environmentally friendly route. The developed hydrogel beads exhibited homogeneous porous structure and super-paramagnetic responsibility. MTX can be successfully encapsulated into magnetic chitosan hydrogel beads, and the drug encapsulation efficiency (%) and encapsulation content (%) were 93.8 and 6.28%, respectively. In addition, the drug release studies in vitro indicated that the MTX-encapsulated magnetic chitosan hydrogel beads had excellent pH-sensitivity, 90.6% MTX was released from the magnetic chitosan hydrogel beads within 48 h at pH 4.0. WST-1 assays in human liver hepatocellular carcinoma cells (HepG2) demonstrated that the MTX-encapsulated magnetic chitosan hydrogel beads had good cytocompatibility and high anti-tumor activity. Therefore, our results revealed that the MTX-encapsulated magnetic chitosan hydrogel beads would be a competitive candidate for controlled drug release in the area of targeted cancer therapy in the near future. PMID- 27464587 TI - Aspirations and realities in a North-South partnership for health promotion: lessons from a program to promote safe male circumcision in Botswana. AB - BACKGROUND: International donors support the partnership between the Government of Botswana and two international organisations: U.S. Centers for Disease Control and Prevention and Africa Comprehensive HIV/AIDS Partnership to implement Voluntary Medical Male Circumcision with the target of circumcising 80 % of HIV negative men in 5 years. Botswana Government had started integration of the program into its health system when international partners brought in the Models for Optimizing Volume and Efficiency to strengthen delivery of the service and push the target. The objective of this paper is to use a systems model to establish how the functioning of the partnership on Safe Male Circumcision in Botswana contributed to the outcome. METHODS: Data were collected using observations, focus group discussions and interviews. Thirty participants representing all three partners were observed in a 3-day meeting; followed by three rounds of in-depth interviews with five selected leading officers over 2 years and three focus group discussions. RESULTS: Financial resources, "ownership" and the target influence the success or failure of partnerships. A combination of inputs by partners brought progress towards achieving set program goals. Although there were tensions between partners, they were working together in strategising to address some challenges of the partnership and implementation. Pressure to meet the expectations of the international donors caused tension and challenges between the in-country partners to the extent of Development Partners retreating and not pursuing the mission further. CONCLUSION: Target achievement, the link between financial contribution and ownership expectations caused antagonistic outcome. The paper contributes enlightenment that the functioning of the visible in-country partnership is significantly influenced by the less visible global context such as the target setters and donors. PMID- 27464588 TI - Safety of Long-term Treatment With Certolizumab Pegol in Patients With Crohn's Disease, Based on a Pooled Analysis of Data From Clinical Trials. AB - BACKGROUND & AIMS: Treatments for Crohn's disease (CD) have been linked to serious infections, malignancies, and dermatologic complications. We pooled and analyzed clinical trials of certolizumab pegol, a pegylated humanized Fab' fragment against tumor necrosis factor, to quantify safety events in patients with CD. METHODS: We collected data from 5 placebo-controlled trials, 9 open label studies, and 1 dose-regimen study, conducted globally through April 2014. A total of 2570 patients with moderate to severe CD were treated with certolizumab pegol, with 4378.1 patient-years of exposure. Data were analyzed in 2 groups: patients from placebo-controlled (PC) trials treated with placebo (n = 875) or certolizumab pegol (n = 919) for 6 to 38 weeks (the PC group) or all patients exposed to certolizumab pegol (n = 2570), for durations of 6 to 362 weeks (the all-studies group). Incidence rates (IRs; incidence/100 patient-years) of adverse events (AEs) were calculated from first dose through 70 days (approximately 5 half-lives) after the last dose. RESULTS: In the PC group, IRs for serious AEs were similar among patients given certolizumab pegol (31.35/100 patient-years) vs placebo (24.33/100 patient-years). IRs of serious infections or malignancies were low among patients receiving short-term treatment with certolizumab pegol (8.49/100 patient-years and 1.01/100 patient-years, respectively, in the PC group) and did not increase with long-term treatment (6.47/100 patient-years and 0.80/100 patient-years, respectively, in the all-studies group). IRs of psoriasis or psoriasiform dermatitis were low in the PC group (1.01/100 patient-years and 0/100 patient-years, respectively); in the placebo group, these IRs were 0.38 per 100 patient-years and 0 per 100 patient-years, respectively. IRs of psoriasis or psoriasiform dermatitis did not increase with long-term treatment (0.93/100 patient-years and 0.09/100 patient-years, respectively, in the all-studies group). CONCLUSIONS: Based on an analysis of data pooled from 15 trials of patients with CD, the safety profile for long-term therapy with certolizumab pegol therapy is similar to that reported from short-term studies. Overall rates of AEs, serious infections, malignancies, and psoriasis did not increase with long-term treatment, suggesting a favorable risk-benefit ratio with long-term certolizumab pegol therapy in CD. Clinicaltrials.gov identifiers: NCT00291668, NCT00152490, NCT00152425, NCT00308581, NCT00349752, NCT00552058, NCT00329550, NCT00329420, NCT00160524, NCT00160706, NCT00297648, NCT00333788, NCT00307931, NCT00356408, and NCT00552344 (https://www.clinicaltrials.gov/ct2/search). PMID- 27464590 TI - Direct and Indirect Economic Burden of Chronic Liver Disease in the United States. AB - BACKGROUND & AIMS: Chronic liver (CLD) is a major public health concern. We assessed its effects on quality of life and work productivity, as well as its economic burden in the United States. METHODS: We performed a cross-sectional study of data from the Medical Expenditure Panel Survey (MEPS; 2004-2013). We extracted participants' sociodemographic parameters and medical histories. Subjects with CLD were identified based on Clinical Classification Software codes. MEPS participants were compared between those with and without CLD, and then between employed and unemployed patients with CLD. Outcomes were quality-of life scores, employment, and health care use. RESULTS: We collected data from 230,406 adult participants (age, >=18 y) in the MEPS; 1846 had current CLD (36.7% with viral hepatitis and 5.3% with liver cancer). Individuals with CLD were less likely to be employed (44.7% vs 69.6% patients without CLD), were not working owing to illness/disability (30.5% vs 6.6% without CLD), lost more work because of disability (10.2 vs 3.4 d without CLD), and had more health care use, producing greater health care expenses ($19,390 vs $5567/y without CLD) (all P < .0001). Patients with CLD also had more comorbidities and worse self-reported general and mental health status, and reported more health-related limitations in their daily activities than individuals without CLD (all P < .0001). They also indicated more psychologic distress and depressive symptoms and had a lower quality of life and health utility scores (P < .0001). In multivariate analysis, after adjustment for sociodemographic factors and comorbidities, the presence of CLD was an important predictor of unemployment (odds ratio, 0.60; 95% confidence interval, 0.50-0.70), annual health care expenditure (beta = $9503 +/- $2028), and impairment in all aspects of health-related quality of life (all P < .0001). In patients with CLD, the presence of liver cancer had the most profound impact on health care expenditures (beta = $17,278 +/- $5726/y) and physical health (beta = -7.2 +/- 1.7 for SF-12 physical component) (all P < .005). CONCLUSIONS: In a cross-sectional analysis of MEPS participants, we associated CLD with large economic and quality-of-life burdens. PMID- 27464589 TI - Stool DNA Analysis is Cost-Effective for Colorectal Cancer Surveillance in Patients With Ulcerative Colitis. AB - BACKGROUND & AIMS: Patients with chronic ulcerative colitis are at increased risk for colorectal neoplasia (CRN). Surveillance by white-light endoscopy (WLE) or chromoendoscopy may reduce risk of CRN, but these strategies are underused. Analysis of DNA from stool samples (sDNA) can detect CRN with high levels of sensitivity, but it is not clear if this approach is cost-effective. We simulated these strategies for CRN detection to determine which approach is most cost effective. METHODS: We adapted a previously published Markov model to simulate the clinical course of chronic ulcerative colitis, the incidence of cancer or dysplasia, and costs and benefits of care with 4 surveillance strategies: (1) analysis of sDNA and diagnostic chromoendoscopy for patients with positive results, (2) analysis of sDNA with diagnostic WLE for patients with positive results, (3) chromoendoscopy with targeted collection of biopsies, or (4) WLE with random collection of biopsies. Costs were based on 2014 Medicare reimbursement. The primary outcome was the incremental cost-effectiveness ratio (incremental cost/incremental difference in quality-adjusted life-years) compared with no surveillance and a willingness-to-pay threshold of $50,000. RESULTS: All strategies fell below the willingness-to-pay threshold at 2-year intervals. Incremental cost-effectiveness ratios were $16,362 per quality-adjusted life-year for sDNA analysis with diagnostic chromoendoscopy; $18,643 per quality-adjusted life-year for sDNA analysis with diagnostic WLE; $23,830 per quality-adjusted life-year for chromoendoscopy alone; and $27,907 per quality-adjusted life-year for WLE alone. In sensitivity analyses, sDNA analysis with diagnostic chromoendoscopy was more cost-effective than chromoendoscopy alone, up to a cost of $1135 per sDNA test. sDNA analysis remained cost-effective at all rates of compliance; when combined with diagnostic chromoendoscopy, this approach was preferred over chromoendoscopy alone, when the specificity of the sDNA test for CRN was >65%. CONCLUSIONS: Based on a Markov model, surveillance for CRN is cost effective for patients with chronic ulcerative colitis. Analysis of sDNA with chromoendoscopies for patients with positive results was more cost-effective than chromoendoscopy or WLE alone. PMID- 27464591 TI - No Benefit From Platelet Transfusion for Gastrointestinal Bleeding in Patients Taking Antiplatelet Agents. AB - BACKGROUND & AIMS: Antiplatelet agents decrease cardiovascular events but increase gastrointestinal bleeding (GIB). Guidelines propose platelet transfusion for patients who take antiplatelet agents and have serious GIB. We investigated whether such patients are at decreased risk for rebleeding or increased risk for cardiovascular events after platelet transfusion. METHODS: We performed a retrospective cohort study of patients with GIB admitted to Yale-New Haven Hospital from 2008 to 2013 who were taking antiplatelet agents and had platelet counts higher than 100 * 109/L. Cases (patients who received platelet transfusion, n = 204) were matched with controls (no platelet transfusions, n = 204) for sex, age, and GIB location. The primary outcome was recurrent GIB. Multivariable regression analyses were performed to adjust for differences in baseline characteristics. RESULTS: Cases and controls had similar proportions of GIB due to non-variceal upper GIB (117 of 204, 57% vs 115 of 204, 56%) and colonic GIB (80 of 204, 39% vs 81 of 204, 40%). Cases had more severe GIB than controls, which was based on lower blood pressure and hemoglobin levels and higher heart rates and the proportion admitted to intensive care. Univariate analyses showed that higher proportions of cases had major cardiovascular events (23% vs 13% for controls), died (7% vs 1% for controls), or had hospital stay longer than 4 days (47% vs 33% for controls). However, multivariable analyses showed a significant difference between cases and controls in only risk of death (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was 1.47 (95% confidence interval, 0.73-3.05) for cases vs controls. CONCLUSIONS: The use of platelet transfusions in patients with GIB who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality. At least some of the increase in mortality could be due to the residual bias of an observational study, but because of the lack of benefit, we do not support the use of platelet transfusions in patients with GIB who are taking antiplatelet agents. PMID- 27464592 TI - The Crohn's Disease-Ulcerative Colitis Clinical Appraisal Update: Emerging Trends in Clinical Practice. PMID- 27464593 TI - Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients With Systemic Inflammatory Response Syndrome. AB - BACKGROUND & AIMS: Patients with systemic inflammatory response syndrome (SIRS) along with decompensated cirrhosis and renal dysfunction have a poor prognosis and a lower response to treatment. We evaluated the effect of SIRS on the response of hepatorenal syndrome type 1 (HRS-1) to terlipressin. METHODS: We performed a retrospective study of data from a trial of the effects of terlipressin (1 mg every 6 hours or placebo with concomitant albumin) in 198 patients with HRS-1, performed at 50 investigational sites in the United States and 2 in Canada from October 2010 through February 2013. We identified patients with 2 or more criteria for SIRS, without untreated infections (28 received terlipressin and 30 received placebo), and patients with less than 2 criteria for SIRS (control subjects). Primary endpoints included HRS reversal (a decrease in serum level of creatinine to <=1.5 mg/dL), confirmed HRS reversal (defined as 2 serum creatinine levels <=1.5 mg/dL, >= 48 hours apart), and survival for 90 days after treatment. RESULTS: Baseline characteristics were similar between groups, apart from slightly higher white blood cell counts and heart rates, and slightly lower serum levels of bicarbonate in patients with SIRS versus without SIRS. HRS was reversed in 42.9% of patients who received terlipressin with SIRS (12/28) versus 6.7% of patients who received placebo (2/30) (P = .0018); confirmed HRS reversal occurred in 32.1% of patients who received terlipressin with SIRS (9/28) versus 3.3% who received placebo (1/30) (P = .0048). A larger proportion of patients with SIRS who received terlipressin survived for 90 days without a transplant (13/28; 46.4%) than patients with SIRS who received placebo (7/30; 23.3%) (P = .076). CONCLUSIONS: In an analysis of data from a placebo-controlled study, we found that terlipressin improved renal function and reversed HRS in a higher proportion of patients with HRS-1 and SIRS than patients who received albumin plus placebo. ClincialTrials.gov, number NCT 01143246. PMID- 27464595 TI - Critical behaviour in the nonlinear elastic response of hydrogels. AB - In this paper we study the elastic response of synthetic hydrogels to an applied shear stress. The hydrogels studied here have previously been shown to mimic the behaviour of biopolymer networks when they are sufficiently far above the gel point. We show that near the gel point they exhibit an elastic response that is consistent with the predicted critical behaviour of networks near or below the isostatic point of marginal stability. This point separates rigid and floppy states, distinguished by the presence or absence of finite linear elastic moduli. Recent theoretical work has also focused on the response of such networks to finite or large deformations, both near and below the isostatic point. Despite this interest, experimental evidence for the existence of criticality in such networks has been lacking. Using computer simulations, we identify critical signatures in the mechanical response of sub-isostatic networks as a function of applied shear stress. We also present experimental evidence consistent with these predictions. Furthermore, our results show the existence of two distinct critical regimes, one of which arises from the nonlinear stretch response of semi-flexible polymers. PMID- 27464594 TI - A Predictive Model to Identify Patients With Fecal Incontinence Based on High Definition Anorectal Manometry. AB - BACKGROUND & AIMS: Three-dimensional high-definition anorectal manometry (3D HDAM) is used to assess anal sphincter function; it determines profiles of regional pressure distribution along the length and circumference of the anal canal. There is no consensus, however, on the best way to analyze data from 3D HDAM to distinguish healthy individuals from persons with sphincter dysfunction. We developed a computer analysis system to analyze 3D-HDAM data and to aid in the diagnosis and assessment of patients with fecal incontinence (FI). METHODS: In a prospective study, we performed 3D-HDAM analysis of 24 asymptomatic healthy subjects (control subjects; all women; mean age, 39 +/- 10 years) and 24 patients with symptoms of FI (all women; mean age, 58 +/- 13 years). Patients completed a standardized questionnaire (FI severity index) to score the severity of FI symptoms. We developed and evaluated a robust prediction model to distinguish patients with FI from control subjects using linear discriminant, quadratic discriminant, and logistic regression analyses. In addition to collecting pressure information from the HDAM data, we assessed regional features based on shape characteristics and the anal sphincter pressure symmetry index. RESULTS: The combination of pressure values, anal sphincter area, and reflective symmetry values was identified in patients with FI versus control subjects with an area under the curve value of 1.0. In logistic regression analyses using different predictors, the model identified patients with FI with an area under the curve value of 0.96 (interquartile range, 0.22). In discriminant analysis, results were classified with a minimum error of 0.02, calculated using 10-fold cross validation; different combinations of predictors produced median classification errors of 0.16 in linear discriminant analysis (interquartile range, 0.25) and 0.08 in quadratic discriminant analysis (interquartile range, 0.25). CONCLUSIONS: We developed and validated a novel prediction model to analyze 3D-HDAM data. This system can accurately distinguish patients with FI from control subjects. PMID- 27464596 TI - Analysis of the duodenal microbiotas of weaned piglet fed with epidermal growth factor-expressed Saccharomyces cerevisiae. AB - BACKGROUND: The bacterial community of the small intestine is a key factor that has strong influence on the health of gastrointestinal tract (GIT) in mammals during and shortly after weaning. The aim of this study was to analyze the effects of the diets of supplemented with epidermal growth factor (EGF)-expressed Saccharomyces cerevisiae (S. cerevisiae) on the duodenal microbiotas of weaned piglets. RESULTS: Revealed in this study, at day 7, 14 and 21, respectively, the compositional sequencing analysis of the 16S rRNA in the duodenum had no marked difference in microbial diversity from the phylum to species levels between the INVSc1(EV) and other recombinant strains encompassing INVSc1-EE(+), INVSc1-TE(-), and INVSc1-IE(+). Furthermore, the populations of potentially enterobacteria (e.g., Clostridium and Prevotella) and probiotic (e.g., Lactobacilli and Lactococcus) also remained unchanged among recombinant S. cerevisiae groups (P > 0.05). However, the compositional sequencing analysis of the 16S rRNA in the duodenum revealed significant difference in microbial diversity from phylum to species levels between the control group and recombinant S. cerevisiae groups. In terms of the control group (the lack of S. cerevisiae), these data confirmed that dietary exogenous S. cerevisiae had the feasibility to be used as a supplement for enhancing potentially probiotic (e.g., Lactobacilli and Lactococcus) (P < 0.01), and reducing potentially pathogenic bacteria (e.g., Clostridium and Prevotella) (P < 0.01). CONCLUSION: Herein, altered the microbiome effect was really S. cerevisiae, and then different forms of recombinant EGF, including T EGF, EE-EGF and IE-EGF, did not appear to make a significant difference to the microbiome of weaned piglets. PMID- 27464597 TI - Alarming consequences - autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1. AB - PURPOSE OF REVIEW: To give an overview about the expanding spectrum of autoinflammatory diseases due to mutations in proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) and new insights into their pathogenesis. RECENT FINDINGS: In addition to classical pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome has been described as a distinct clinical phenotype of PSTPIP1-associated inflammatory diseases (PAID) and other entities are emerging. In addition to dysregulation of IL-1beta release from activated PAPA monocytes that requires NLR family, pyrin domain containing 3 (NLRP3), PSTPIP1 mutations have an general impact on cellular dynamics of cells of the innate immune system. In addition, overwhelming expression and release of the alarmins myeloid-related protein (MRP) 8 and 14 by activated phagocytes and keratinocytes, which promote innate immune mechanisms in a Toll like receptor (TLR) 4-dependent manner, are a characteristic feature of these diseases and form a positive feed-back mechanism with IL-1beta. SUMMARY: Autoinflammatory diseases due to PSTPIP1 mutations are not restricted to the classical PAPA phenotype but might present with other distinct clinical features. MRP8/14 serum levels are a hallmark of PAPA and PAMI and can be used as screening tool to initiate targeted genetic testing in suspected cases. The feedback mechanism of IL-1beta and MRP alarmin release may offer novel targets for future therapeutic approaches. PMID- 27464599 TI - Detecting clinical change with the CDR-FTLD: differences between FTLD and AD dementia. AB - OBJECTIVE: To investigate the psychometric properties of the Clinical Dementia Scale-frontotemporal lobar degeneration (CDR-FTLD) psychometric properties using Rasch analysis and its sensitivity distinguishing disease progression between FTLD and Alzheimer's disease (AD). METHODS: Of 603 consecutive patients from the National Alzheimer Coordinating Center dataset (FTLD = 350; AD = 253), 120 FTLDs were included in a Rasch analysis to verify CDR-FTLD psychometric properties; 483 (FTLD = 230; AD = 253) were included to analyse disease progression, with 195 (FTLD = 82; AD = 113) followed-up (24 months). RESULTS: The CDR-FTLD demonstrated good consistency, construct and concurrent validity and correlated well with mini mental state examination (MMSE) and disease duration (ps < 0.05). At baseline, FTLD showed greater dementia severity than AD after matched for MMSE and disease duration (p < 0.001). Independent Rasch analyses demonstrated different patterns of progression for FTLD and AD in terms of the domains initially and then subsequently affected with disease progression. At follow-up, although MMSE showed significant changes (p < 0.05), these were greater on the CDR-FTLD (p < 0.001). CONCLUSION: The CDR-FTLD satisfactorily measures dementia severity and change in FTLD, distinguishing disease progression between FTLD and AD, with clear implications for care, prognosis and future clinical trials. (c) 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd. PMID- 27464600 TI - Enzyme catalysis-electrophoresis titration for multiplex enzymatic assay via moving reaction boundary chip. AB - In this work, we developed the concept of enzyme catalysis-electrophoresis titration (EC-ET) under ideal conditions, the theory of EC-ET for multiplex enzymatic assay (MEA), and a related method based on a moving reaction boundary (MRB) chip with a collateral channel and cell phone imaging. As a proof of principle, the model enzymes horseradish peroxidase (HRP), laccase and myeloperoxidase (MPO) were chosen for the tests of the EC-ET model. The experiments revealed that the EC-ET model could be achieved via coupling EC with ET within a MRB chip; particularly the MEA analyses of catalysis rate, maximum rate, activity, Km and Kcat could be conducted via a single run of the EC-ET chip, systemically demonstrating the validity of the EC-ET theory. Moreover, the developed method had these merits: (i) two orders of magnitude higher sensitivity than a fluorescence microplate reader, (ii) simplicity and low cost, and (iii) fairly rapid (30 min incubation, 20 s imaging) analysis, fair stability (<5.0% RSD) and accuracy, thus validating the EC-ET method. Finally, the developed EC-ET method was used for the clinical assay of MPO activity in blood samples; the values of MPO activity detected via the EC-ET chip were in agreement with those obtained by a traditional fluorescence microplate reader, indicating the applicability of the EC-ET method. The work opens a window for the development of enzymatic research, enzyme assay, immunoassay, and point-of-care testing as well as titration, one of the oldest methods of analysis, based on a simple chip. PMID- 27464601 TI - Impairment of SOD1-G93A motility is linked to mitochondrial movement in axons of hippocampal neurons. AB - Superoxide dismutase 1 (SOD1) is a well-known antioxidant enzyme. Mutation of SOD1 is closely associated with the pathogenesis of neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's disease. However, the pathologic pathways linking neurodegenerative diseases with mutation of SOD1 remain elusive. Here, we investigated the motility of SOD1-WT and -G93A (a pathogenic mutant of SOD1), and observed correlation of axonal transport of the mutant protein with mitochondria in primary cultured hippocampal neurons. The SOD1-G93A mutant showed significant accumulation at vGlut1-positive synaptic boutons and in cell bodies, compared to SOD1-WT. The proportions of motile WT and G93A proteins were similar (~30 %) while the motility velocity of SOD1-G93A was significantly slower (~40 %) than that of the WT counterpart. This motility defect of SOD1-G93A was highly correlated with mitochondrial movement. Our results collectively suggest that the SOD1-G93A mutant has a defect in motility that is linked to mitochondrial transport in axons. PMID- 27464602 TI - Diagnostic laparoscopy in pre-surgical planning for higher stage endometriosis: Is it still relevant? AB - It has become necessary to re - examine the relevance of diagnostic laparoscopy in the two-stage approach to surgical management of symptomatic women with higher stage endometriosis following emerging evidence demonstrating acceptable diagnostic performance of alternative less invasive and less expensive imaging modalities. We highlight the relative merits of these presurgical diagnostic imaging modalities and propose strategies that address the challenge of transitioning to a new diagnostic paradigm in the management of symptomatic women with higher stage endometriosis. PMID- 27464603 TI - Computational exploration of wave propagation and heating from transcranial focused ultrasound for neuromodulation. AB - OBJECTIVE: While ultrasound is largely established for use in diagnostic imaging, its application for neuromodulation is relatively new and crudely understood. The objective of the present study was to investigate the effects of tissue properties and geometry on the wave propagation and heating in the context of transcranial neuromodulation. APPROACH: A computational model of transcranial focused ultrasound was constructed and validated against empirical data. The models were then incrementally extended to investigate a number of issues related to the use of ultrasound for neuromodulation, including the effect on wave propagation of variations in geometry of skull and gyral anatomy as well as the effect of multiple tissue and media layers, including scalp, skull, CSF, and gray/white matter. In addition, a sensitivity analysis was run to characterize the influence of acoustic properties of intracranial tissues. Finally, the heating associated with ultrasonic stimulation waveforms designed for neuromodulation was modeled. MAIN RESULTS: The wave propagation of a transcranially focused ultrasound beam is significantly influenced by the cranial domain. The half maximum acoustic beam intensity profiles are insensitive overall to small changes in material properties, though the inclusion of sulci in models results in greater peak intensity values compared to a model without sulci (1% 30% greater). Finally, heating using currently employed stimulation parameters in humans is highest in bone (0.16 degrees C) and is negligible in brain (4.27 * 10(-3) degrees C) for a 0.5 s exposure. SIGNIFICANCE: Ultrasound for noninvasive neuromodulation holds great promise and appeal for its non-invasiveness, high spatial resolution and deep focal lengths. Here we show gross brain anatomy and biological material properties to have limited effect on ultrasound wave propagation and to result in safe heating levels in the skull and brain. PMID- 27464604 TI - High Life Expectancy of Bacteria on Lichens. AB - Self-sustaining lichen symbioses potentially can become very old, sometimes even thousands of years in nature. In the joint structures, algal partners are sheltered between fungal structures that are externally colonized by bacterial communities. With this arrangement lichens survive long periods of drought, and lichen thalli can be revitalized even after decades of dry storage in a herbarium. To study the effects of long-term ex situ storage on viability of indigenous bacterial communities we comparatively studied herbarium-stored material of the lung lichen, Lobaria pulmonaria. We discovered that a significant fraction of the lichen-associated bacterial community survives herbarium storage of nearly 80 years, and living bacteria can still be found in even older material. As the bacteria reside in the upper surface layers of the lichen material, we argue that the extracellular polysaccharides of lichens contribute to superior life expectancy of bacteria. Deeper understanding of underlying mechanisms could provide novel possibilities for biotechnological applications. PMID- 27464606 TI - Breast Conservation Therapy Versus Mastectomy: Shared Decision-Making Strategies and Overcoming Decisional Conflicts in Your Patients. AB - Although breast-conserving therapy is considered the preferred treatment for the majority of women with early-stage breast cancer, mastectomy rates in this group remain high. The patient, physician, and systems factors contributing to a decision for mastectomy are complicated. Understanding the individual patient's values and goals when making this decision is paramount to providing a shared decision-making process that will yield the desired outcome. The cornerstones of this discussion include education of the patient, access to decision-aid tools, and time to make an informed decision. However, it is also paramount for the physician to understand that a significant majority of women with an informed and complete understanding of their surgical choices will still prefer mastectomy. The rates of breast conservation versus mastectomy should not be considered a quality measure alone. Rather, the extent by which patients are informed, involved in decision-making, and undergoing treatments that reflect their goals is the true test of quality. Here we explore some of the factors that impact the patient preference for breast conservation versus mastectomy and how shared decision-making can be maximized for patient satisfaction. PMID- 27464607 TI - Advances in Imaging and Endoluminal Therapies for Early Esophageal and Gastric Cancers. PMID- 27464608 TI - Postmastectomy Reconstruction Outcomes After Intraoperative Evaluation with Indocyanine Green Angiography Versus Clinical Assessment. AB - BACKGROUND: Mastectomy flap necrosis is a major complication in patients undergoing tissue expander-based reconstruction. This study compared the complication rates following mastectomy and immediate reconstruction with intraoperative indocyanine green (ICG) angiography evaluation to those with clinical assessment only. METHODS: We performed a single-institution retrospective study of mastectomy patients who underwent immediate tissue expander-based reconstruction between September 2009 and December 2013. ICG angiography was adopted in March 2012. The rates of complications in the ICG and clinical assessment only groups were compared. Factors associated with complications were identified with the Fischer exact test and univariate analysis. RESULTS: A total of 114 patients were identified; clinical assessment only, 53 patients; ICG angiography, 61 patients. The overall complication rates were not significantly different between the two groups (ICG angiography, 50.8 %; clinical assessment, 43.4 %; p = 0.46). There was no significant difference in the rates of unexpected return to the operating room, cellulitis, hematomas, and seromas. The overall rates of flap necrosis were not significantly different (ICG angiography, 27.9 %; clinical assessment, 18.9 %; p = 0.28). However, the rates of severe flap necrosis were significantly lower with intraoperative ICG angiography (4.9 %) than with clinical assessment only (18.9 %, p = 0.02). On univariate analysis, breast weight (>=500 g) was significantly associated with increased rates of severe flap necrosis (p = 0.04), whereas body mass index, age, smoking status, prior breast surgery, history of radiation therapy, and receipt of nipple-sparing mastectomy were not. CONCLUSIONS: We observed that the implementation of intraoperative ICG angiography was associated with a significant decrease in the rate of severe flap necrosis. PMID- 27464609 TI - Population-Based Analysis of Completion Lymphadenectomy in Intermediate-Thickness Melanoma. AB - BACKGROUND: Multicenter selective lymphadenectomy trial 1 (MSLT-I) defined the prognostic and potential therapeutic values of sentinel lymph node biopsy (SLNB) for intermediate-thickness melanoma. The role of completion lymphadenectomy (CLND) is, however, unclear and the subject of the ongoing MSLT-II trial. METHODS: From 2003 to 2012, patients with tumors 1-4 mm thick with positive SLNB were identified in the Surveillance Epidemiology and End Results Program registry. The patients were divided into two groups: group 1 (CLND) and group 2 (observation). RESULTS: The study enrolled 2172 patients, the majority of whom were white and male with extremity primaries, no ulceration, Clark level 4 invasion, and nodes 2.01-4.0 mm deep. In the univariate analysis, CLND was associated with lower mean age, male gender, primary site, number of positive nodes, and geographic region (p < 0.05). In the multivariate analysis, male gender [odds ratio (OR), 1.27] and geographic area (Michigan OR, 2.31; Iowa OR, 1.69) were associated with CLND (p < 0.05). In the survival analysis, male gender, primary site, ulceration, Clark level, and depth and number of positive nodes were associated with survival (p < 0.05), but CLND was not (p = 0.83). In the Cox regression analysis, the relationship between male gender [hazard ratio (HR), 1.14], primary site trunk versus extremity (HR, 1.3), ulceration (HR, 1.79), Clark level (2 vs. 4 HR, 3.51; 2 vs. 5 HR, 6.48), depth (HR, 1.43) and number of nodes (1 vs. 2: HR, 1.23; 1 vs. >=3: HR, 2.52) persisted (p < 0.05). However, when CLND was included in this model, it was not associated with improved survival. CONCLUSIONS: Age, gender, and geographic area predict the likelihood of CLND. In this retrospective study, CLND did not add survival benefit. PMID- 27464611 TI - Erratum to: A Prospective Randomized Trial of Enteral Nutrition After Thoracoscopic Esophagectomy for Esophageal Cancer. PMID- 27464610 TI - Reoperative Surgery in Patients with Multiple Endocrine Neoplasia Type 1 Associated Primary Hyperparathyroidism. AB - BACKGROUND: Persistent/recurrent primary hyperparathyroidism (pHPT) occurs frequently in multiple endocrine neoplasia type 1 (MEN1). We assessed the usefulness of intraoperative PTH (IOPTH) and preoperative localizing studies based on the outcome of patients with MEN1-associated pHPT undergoing reoperative surgery. METHODS: A retrospective analysis identified MEN1 patients with persistent/recurrent pHPT. Patient outcome was defined as postoperative serum calcium and PTH levels (cured, persistent or recurrent) at last follow-up. Positive predictive value (PPV) was calculated for imaging studies and IOPTH. RESULTS: Thirty patients with MEN1-associated recurrent/persistent pHPT underwent 69 reoperative parathyroidectomies. Median follow-up time was 33 months. Persistent pHPT occurred in four (13 %) patients. IOPTH had a 92 % PPV for postoperative eucalcemia. Ultrasound and Tc99m-sestamibi had sensitivities of 100 and 85 % for localizing an enlarged parathyroid gland. However, five (17 %) patients had additional enlarged glands, not visualized preoperatively that were removed after IOPTH did not drop appropriately. Bone mineral density scores did not improve after reoperation (p = 0.60), but the rate of postoperative nephrocalcinosis did (p = 0.046). Patients with pancreatic neuroendocrine tumors had significantly higher rates of persistent/recurrent pHPT compared with those without (40 vs. 0 %, p = 0.021). Intraoperative and delayed parathyroid autotransplantation was performed in nine (30 %) and four (14 %) patients, respectively. CONCLUSIONS: Although preoperative localizing studies are helpful for guiding reoperative strategy in MEN1 with persistent/recurrent pHPT, additional enlarged glands may be missed by conventional imaging. IOPTH should therefore be employed routinely in this setting. Routine cryopreservation should be considered in all patients. Pancreatic manifestation may be associated with earlier recurrence or persistent disease. PMID- 27464612 TI - Could Magnetic Resonance Imaging Help to Identify the Presence of Prostate Cancer Before Initial Biopsy? The Development of Nomogram Predicting the Outcomes of Prostate Biopsy in the Chinese Population. AB - PURPOSE: This study was designed to investigate the effectiveness of magnetic resonance imaging (MRI) in diagnosing prostate cancer (PCa) and high-grade prostate cancer (HGPCa) before transrectal ultrasound (TRUS)-guided biopsy. METHODS: The clinical data of 894 patients who received TRUS-guided biopsy and prior MRI test from a large Chinese center was reviewed. Based on Prostate Imaging Reporting and Data System (PI-RADS) scoring, all MRIs were re-reviewed and assigned as Grade 0-2 (PI-RADS 1-2; PI-RADS 3; PI-RADS 4-5). We constructed two models both in predicting PCa and HGPCa (Gleason score >= 4 + 3): Model 1 with MRI and Model 2 without MRI. Other clinical factors include age, digital rectal examination, PSA, free-PSA, volume, and TRUS. RESULTS: PCa and HGPCa were present in 434 (48.5 %) and 218 (24.4 %) patients. An MRI Grade 0, 1, and 2 were assigned in 324 (36.2 %), 193 (21.6 %) and 377 (42.2 %) patients, which was associated with the presence of PCa (p < 0.001) and HGPCa (p < 0.001). Particularly in patients aged <=55 years, the assignment of MRI Grade 0 was correlated with extremely low rate of PCa (1/27) and no HGPCa. The c-statistic of Model 1 and Model 2 for predicting PCa was 0.875 and 0.841 (Z = 4.2302, p < 0.001), whereas for predicting HGPCa was 0.872 and 0.850 (Z = 3.265, p = 0.001). Model 1 exhibited higher sensitivity and specificity at same cutoffs, and decision-curve analysis also suggested the favorable clinical utility of Model 1. CONCLUSIONS: Prostate MRI before biopsy could predict the presence of PCa and HGPCa, especially in younger patients. The incorporation of MRI in nomograms could increase predictive accuracy. PMID- 27464613 TI - The Role of Aqueous Aerosols in the "Glyoxylate Scenario": An Experimental Approach. AB - The origin of life is one of the fundamental questions in science. Eschenmoser proposed the "glyoxylate scenario", in which plausible abiotic synthesis pathways were suggested to be compatible with the constraints of prebiotic chemistry. In this proposal, the stem compound is HCN. In this work, we explore the "glyoxylate scenario" through several syntheses of HCN polymers, paying particular attention to the role of the aqueous aerosols, together with statistical methods, as a step to elucidate the synthetic problem of the origin of life. The soluble and insoluble HCN polymers synthetized were analyzed by GC-MS. We identified, for the first time, glyoxylic acid in these polymers, together with some constituents of the reductive tricarboxylic acid cycle, amino acids and several N-heterocycles. The findings presented herein, as the first global approach to the "glyoxylate scenario", give full effect to this hypothesis and prove that aqueous aerosols could play an important role in this plausible scene of the origin of life. PMID- 27464614 TI - FAST MRI breast screening revisited. AB - INTRODUCTION: Screening for breast cancer in high-risk women takes about 40 minutes to acquire an MRI scan and is time-intensive to report. There is recent interest in the performance of an abbreviated MRI protocol (FAST) in the screening setting. FAST scans have a reported negative predictive value of 99.8%. This study evaluates the false positive rates (FPR) and recall rates for FAST scans as compared to full diagnostic studies (FD). METHODS: A database of all screening breast MRI scans performed at our institution between 30 June 2013 and 1 July 2014 (n = 591) was created by one of the researchers, who did not subsequently analyse the MRI scans. The T1W and first post-contrast and subtracted images from each of these scans (FAST protocol) were assessed by experienced breast MRI radiologists, blinded to the final diagnosis. The findings were then compared with the FD result. RESULTS: The recall rates were 6.6% for FAST scans and 5.8% for FD scans. FPR rates were 4.7% and 3.9% respectively. There is no statistically significant difference in the recall rates or FPR of FAST scans in comparison with full diagnostic studies. CONCLUSIONS: Given the absence of statistically significant difference in the FPR and recall rates in comparison with FD, FAST scans can replace FD for screening of breast cancer. PMID- 27464615 TI - Engines of Discovery and Innovation. PMID- 27464616 TI - Impact of Surgical Technique on Long-term Complication Rate After Laparoscopic Adjustable Gastric Banding (LAGB): Results of a Single-blinded Randomized Controlled trial (ANOSEAN Study). AB - OBJECTIVE: The aim of the study was to explore the impact of the absence of band fixation on the reoperation rate and to identify other risk factors for long-term complications. BACKGROUND: Laparoscopic adjustable gastric banding has been demonstrated to permit important weight loss and comorbidity improvement, but some bands will have to be removed mainly for failure or in case of planned 2 step surgery. Then, the absence of a gastro-gastric suture (GGS) would allow easier band removal. There are insufficient data to conclude that GGS should be abandoned, as the associated risk of band slippage has not been prospectively assessed. METHODS: The ANOSEAN study was a randomized controlled single-blind trial (CPP 2009-A00346-51). Primary outcome was reintervention rate for band removal or repositioning at 3 years. It included 706 patients in 17 bariatric centers. Patients in group 1 received a gastric band with GGS. Inclusion criteria were adapted from National Institutes of Health recommendations. Surgical technique was standardized among all surgeons. RESULTS: At 3 years, the reintervention rate for band retrieval or repositioning was significantly higher in the absence of band fixation (19.4% vs11.3%; P = 0.013), partly because of the slippage rate (10.3% vs 3.6%; P = 0.005). Body mass index <40 kg/m at baseline was also an independent risk factor of slippage (odds ratio 2.769, 95% confidence interval 1.373, 5.581). CONCLUSIONS: GGS prevents band slippage and lower reintervention rate at 3 years. Fixation could be discussed for patients with high BMI who are scheduled to undergo 2-step surgery, but it needs to be specifically assessed. PMID- 27464617 TI - Manometric Changes to the Lower Esophageal Sphincter After Magnetic Sphincter Augmentation in Patients With Chronic Gastroesophageal Reflux Disease. AB - OBJECTIVE: To evaluate the manometric changes, function, and impact of magnetic sphincter augmentation (MSA) on the lower esophageal sphincter (LES). BACKGROUND: Implantation of a MSA around the gastroesophageal junction has been shown to be a safe and effective therapy for gastroesophageal reflux disease, but its effect on the LES has not been elucidated. METHODS: Retrospective case control study (n = 121) evaluating manometric changes after MSA. Inclusion criteria consisted of a confirmed diagnosis of gastroesophageal reflux disease by an abnormal esophageal pH study (body mass index <35 kg/m, hiatal hernia <3 cm, and absence of endoscopic Barrett disease). Manometric changes, pH testing, and proton pump inhibitor use were assessed preoperatively and 6 and 12 months after MSA. RESULTS: MSA was associated with an overall increase in the median LES resting pressure (18 pre-MSA vs 23 mm Hg post-MSA; P = 0.0003), residual pressure (4 vs 9 mm Hg; P < 0.0001), and distal esophageal contraction amplitude (80 vs 90 mm Hg; P = 0.02). The percent peristalsis remained unaltered (94% vs 87%; P = 0.71).Overall, patients with a manometrically defective LES were restored 67% of the time to a normal sphincter with MSA. Those with a structurally defective or severely defective LES improved to a normal LES in 77% and 56% of patients, respectively. Only 18% of patients with a normal preoperative manometric LES deteriorated to a lower category. CONCLUSION: MSA results in significant manometric improvement of the LES without apparent deleterious effects on the esophageal body. A manometrically defective LES can be restored to normal sphincter, whereas a normal LES remains stable. PMID- 27464618 TI - Hepatobiliary Scintigraphy in Associating Liver Partition and Portal vein ligation for Staged hepatectomy: All That Glitters Is not Gold. PMID- 27464619 TI - The Beginnings of a Transplant Revolution. PMID- 27464620 TI - Jerome Seymour Bruner [1915-2016]. PMID- 27464621 TI - Attention and word learning in toddlers who are late talkers. AB - The purpose of this study was to examine attention allocation in toddlers who were late talkers and toddlers with typical language development while they were engaged in a word-learning task in order to determine if differences exist. Two year-olds who were late talkers (11) and typically developing toddlers (11) were taught twelve novel pseudo-words for unfamiliar objects over ten training sessions. The toddlers' attention allocation during the word-learning sessions was measured as well as their comprehension of the newly learned words. Late talkers showed reduced attention allocation to objects during word-training sessions, and also comprehended fewer of the novel words than toddlers with typical language development. Attention allocation was found to be a stronger predictor of word learning as compared to cognition and auditory comprehension. Reduced attention allocation may contribute to the early lexical delay characteristic in late talkers. PMID- 27464622 TI - Peripheral blood flow changes in response to postexercise cold water immersion. AB - This study compared the effect of postexercise water immersion (WI) at different temperatures on common femoral artery blood flow (CFA), muscle (total haemoglobin; tHb) and skin perfusion (cutaneous vascular conductance; CVC), assessed by Doppler ultrasound, near-infrared spectroscopy (NIRS) and laser Doppler flowmetry, respectively. Given that heat stress may influence the vascular response during cooling, nine men cycled for 25 min at the first ventilatory threshold followed by intermittent 30-s cycling at 90% peak power until exhaustion at 32.8 +/- 0.4 degrees C and 32 +/- 5% RH. They then received 5 min WI at 8.6 +/- 0.2 degrees C (WI9 ), 14.6 +/- 0.3 degrees C (WI15 ), 35.0 +/- 0.4 degrees C (WI35 ) or passive rest (CON) in a randomized, crossover manner. Heart rate (HR), mean arterial pressure (MAP), muscle (Tmu ), thigh skin (Tthigh ), rectal (Tre ) and mean body (Tbody ) temperatures were assessed. At 60 min postimmersion, decreases in Tre after WI35 (-0.6 +/- 0.3 degrees C) and CON (-0.6 +/- 0.3 degrees C) were different from WI15 (-1.0 +/- 0.3 degrees C; P<0.05), but not from WI9 (-1.0 +/- 0.3 degrees C; P = 0.074-0.092). WI9 and WI15 had reduced Tbody , Tthigh and Tmu compared with WI35 and CON (P <0.05). CFA, tHb and CVC were lower in WI9 and WI15 compared with CON (P<0.05). tHb following WI9 remained lower than CON (P = 0.044) at 30 min postimmersion. CVC correlated with tHb during non-cooling (WI35 and CON) (r2 = 0.532; P<0.001) and cooling recovery (WI9 and WI15 ) (r2 = 0.19; P = 0.035). WI9 resulted in prolonged reduction in muscle perfusion. This suggests that CWI below 10 degrees C should not be used for short-term (i.e. <60 min) recovery after exercise. PMID- 27464623 TI - Longitudinal analysis of bone metabolism using SPECT/CT and (99m)Tc-diphosphono propanedicarboxylic acid: comparison of visual and quantitative analysis. AB - BACKGROUND: The therapy response of osseous metastases (OM) is commonly monitored by bone scintigraphies (BS). The aim of this study was to compare visual evaluation of changes in tracer uptake with quantitation in absolute units in OMs; 52 OMs from 19 patients who underwent BS with SPECT/CT at time points one and two (TP1/2) were analyzed retrospectively, with an average of 10.3 months between TP1 and 2. Tracer uptake in lesions was visually compared by two independent readers in both planar scintigraphies and SPECT/CT across both TPs and classified as regressive, stable, or progressive. Quantitative analysis was performed by measuring peak standardized uptake values (SUV). Based on quantitation, lesions were similarly classified as regressive (>30 % decrease), progressive (>30 % increase), or stable (rest). If available, uptake in reference regions in the lower thoracic or lumbar spine was used for normalization. RESULTS: In OMs at TP1 and TP2, mean SUVpeak (+/-SD) was found to be 20.4 (+/ 20.8) and 16.4 (+/-11.5), respectively. For the reference region, mean SUVmean was 5.6 (+/-1.9) and 4.9 (+/-2.2). Agreement between quantitative and visual assessment was only moderate, with an average Cohen's kappa of 0.42 for planar scintigraphy and 0.62 for SPECT/CT. Discrepancies occurred in between 11 and 22 of the 52 lesions, depending on the reader and whether planar or SPECT imaging was considered. CONCLUSIONS: Compared to measuring uptake in absolute units, visual evaluation of skeletal scintigraphies for change in tumor metabolism yields inconsistent results in roughly one third of the cases. PMID- 27464625 TI - The protective effects of human umbilical cord mesenchymal stem cells on damaged ovarian function: A comparative study. AB - Numerous studies have reported that human umbilical cord mesenchymal stem cell (hUCMSC) therapy can rescue the structure and function of injured tissues. The aims of this study were to explore the protective role of hUCMSC transplantation in a model of accelerated ovarian aging and to compare 2 methods of transplanting hUCMSCs, i.e. i) via intravenous injection (IV) and ii) in situ ovarian micro injection (MI). Female mice were subjected to superovulation and ozone inhalation to create a model of accelerated ovarian aging with a decline in both the quantity and quality of oocytes. Cells were transplanted via IV or MI, and ovaries were removed after 2 weeks or 1 month of treatment. Ovarian reserve and function were evaluated based on the follicle counts, hormone levels, the estrous cycle, and reproductive performance. Cell tracking, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), real-time polymerase chain reaction (PCR), and Western blot analysis were used to assess the inner mechanisms of injury and repair. Results indicated that ovarian function increased significantly after treatment with hUCMSCs. Immunofluorescence revealed reduced TUNEL staining and a decreased percentage of apoptotic cells. A higher level of expression of anti-apoptotic and antioxidant enzymes was noted in the ovaries of groups treated with hUCMSCs. These parameters were enhanced more when mice were treated with hUCMSCs for 1 month than when they treated with hUCMSCs for 2 weeks. IV was better able to restore ovarian function than MI. These results suggest that both methods of transplantation may improve ovarian function and that IV transplantation of hUCMSCs can significantly improve ovarian function and structural parameters more than MI transplantation of hUCMSCs can. PMID- 27464624 TI - Bifidobacterial recombinant thymidine kinase-ganciclovir gene therapy system induces FasL and TNFR2 mediated antitumor apoptosis in solid tumors. AB - BACKGROUND: Directly targeting therapeutic suicide gene to a solid tumor is a hopeful approach for cancer gene therapy. Treatment of a solid tumor by an effective vector for a suicide gene remains a challenge. Given the lack of effective treatments, we constructed a bifidobacterial recombinant thymidine kinase (BF-rTK) -ganciclovir (GCV) targeting system (BKV) to meet this requirement and to explore antitumor mechanisms. METHODS: Bifidobacterium (BF) or BF-rTK was injected intratumorally with or without ganciclovir in a human colo320 intestinal xenograft tumor model. The tumor tissues were analyzed using apoptosis antibody arrays, real time PCR and western blot. The colo320 cell was analyzed by the gene silencing method. Autophagy and necroptosis were also detected in colo320 cell. Meanwhile, three human digestive system xenograft tumor models (colorectal cancer colo320, gastric cancer MKN-45 and liver cancer SSMC-7721) and a breast cancer (MDA-MB-231) model were employed to validate the universality of BF-rTK + GCV in solid tumor gene therapy. The survival rate was evaluated in three human cancer models after the BF-rTK + GCV intratumor treatment. The analysis of inflammatory markers (TNF-alpha) in tumor indicated that BF-rTK + GCV significantly inhibited TNF-alpha expression. RESULTS: The results suggested that BF-rTK + GCV induced tumor apoptosis without autophagy and necroptosis occurrence. The apoptosis was transduced by multiple signaling pathways mediated by FasL and TNFR2 and mainly activated the mitochondrial control of apoptosis via Bid and Bim, which was rescued by silencing Bid or/and Bim. However, BF + GCV only induced apoptosis via Fas/FasL signal pathway accompanied with increased P53 expression. We further found that BF-rTK + GCV inhibited the expression of the inflammatory maker of TNF-alpha. However, BF-rTK + GCV did not result in necroptosis and autophagy. CONCLUSIONS: BF-rTK + GCV induced tumor apoptosis mediated by FasL and TNFR2 through the mitochondrial control of apoptosis via Bid and Bim without inducing necroptosis and autophagy. Furthermore, BF-rTK + GCV showed to repress the inflammation of tumor through downregulating TNF-alpha expression. Survival analysis results of multiple cancer models confirmed that BF rTK + GCV system has a wide field of application in solid tumor gene therapy. PMID- 27464626 TI - The role of family physicians contracted healthcare in China: A "Cardiotonic" or a "Band-Aid" for healthcare reform? AB - On June 6, 2016, as a mode expected to open a new prospect for tiered system of medical care in China, family physicians contracted healthcare was officially launched, intending to facilitate such healthcare be universal coverage by 2020.There are some doubts as to whether this goal is possible. The role of family physicians contracted healthcare in China should also be carefully identified. We hold that family physicians contracted healthcare will promote healthcare reform if it provides a "Cardiotonic" that alleviates the long standing inequitable allocation of healthcare resources. However, this form of care faces many obstacles given the current state of medical care in China. It will just be a "Band-Aid" if the aforementioned issues of the shortage of family physicians, coordination with referring hospitals, and incomplete oversight are not resolved. PMID- 27464627 TI - [Lay emphasis on the basic research in the field of burn surgery in China]. AB - The therapeutic methods and effects have been improved greatly in burn care and management with several important advancements in the past few decades, resulting in more effective patient stabilization and significantly decreased mortality in China. However, the challenging clinical problems still exist, such as a lack of ideally efficient scheme and drugs to protect damaged tissue and internal organs after severe burn, the limited functional cosmetic outcomes of current treatment techniques and synthetic skin substitutes for deep burn wound repair and reconstruction, the high mortality of severe sepsis accompanying with burn injury patients, and the uncontrolled scar formation and modification or potential regeneration in burn wound healing, a further exploration into both underling mechanisms and curable therapies. This article emphasizes the important roles of the basic study in exploration of above clinical issues in the viewpoint of the advanced development of modern life sciences and relevant techniques. PMID- 27464628 TI - [Effects of transforming growth factor beta1 receptor inhibitor SD-208 on human hypertrophic scar]. AB - OBJECTIVE: To investigate the effects of transforming growth factor beta1 (TGF beta1) receptor inhibitor SD-208 on human hypertrophic scar and its mechanisms. METHODS: Scar fibroblasts were isolated from deprecated human hypertrophic scar tissue and then sub-cultured. Cells of the fifth passage were used in the following experiments. (1) Cells were divided into blank control group (BC) and 0.5, 1.0, 3.0, and 5.0 MUmol/L SD-208 groups according to the random number table (the same grouping method below), with 6 wells in each group. Cells in group BC were added with 1 MUL phosphate buffer solution, while cells in the latter four groups were added with 0.5, 1.0, 3.0, and 5.0 MUmol/L SD-208, respectively. After being cultured for 12 hours, the proliferation activity of cells was detected by cell counting kit 8 and microplate reader (denoted as absorbance value). Suitable amount of substance concentration of SD-208 according to the results of proliferation activity of cells was chosen for the following experiments. (2) Another batch of cells were divided into group BC and 1, 3 MUmol/L SD-208 groups and treated as in (1), with 8 wells in each group. The number of migration cells was detected by transwell method. (3) Another batch of cells were grouped and treated as in (2), and the microfilament morphology of cells was observed by rhodamine-phalloidin staining. (4) Another batch of cells were grouped and treated as in (2), and the protein expression of TGF-beta1 was assessed with Western blotting. (5) Forty-eight BALB/c nude mice were divided into normal saline group (NS) and 1 MUmol/L SD-208 group, and one longitudinal incision with length of 1 cm was made on their back. Then human hypertrophic scar tissue was embedded into the incision. On post injury day 7, multipoint injection of NS in a volume of 0.05 mL was performed in wounds of rats in group NS, while rats in 1 MUmol/L SD-208 group were given 0.05 mL 1 MUmol/L SD-208, once a day. On the day 0 (the same day), 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 post first time of injection, the weight of 8 nude mice was weighed by electronic scale, and scar area was measured by vernier caliper and the ratio of rest scar area was calculated. (6) In week 1, 2, and 3 post first time of injection, the protein expression of TGF-beta1 of human hypertrophic scar tissue was assessed with Western blotting. Data were processed with one-way analysis of variance and two independent-sample t test. RESULTS: (1) The proliferation activity of cells in group BC, 0.5, 1.0, 3.0, and 5.0 MUmol/L SD-208 groups was respectively 1.00+/ 0.03, 0.90+/-0.08, 0.68+/-0.11, 0.54+/-0.04, and 0.42+/-0.09, and the proliferation activity of cells in 0.5, 1.0, 3.0, and 5.0 MUmol/L SD-208 groups was significantly lower than that in group BC (with t values from 2.9 to 22.1, P<0.05 or P<0.01). (2) The number of migration cells in 1, 3 MUmol/L SD-208 groups was significantly less than that in group BC (with t values respectively 6.5 and 6.4, P values below 0.01). (3) Compared with that in group BC, fluorescence intensity of microfilaments of cells in 1, 3 MUmol/L SD-208 groups was attenuated, and the pseudopod extended less. (4) The protein expressions of TGF-beta1 of cells in group BC and 1, 3 MUmol/L SD-208 groups were respectively 1.00+/-0.08, 0.80+/-0.08, and 0.61+/-0.05, and the protein expressions of TGF beta1 of cells in 1, 3 MUmol/L SD-208 groups were significantly lower than those in group BC (with t values respectively 4.0 and 9.2, P values below 0.01). (5) The weights of nude mice in group NS and 1 MUmol/L SD-208 group were similar on each time day (with t values from 0.2 to 1.1, P values above 0.05). The ratios of rest scar area of nude mice in two groups were decreased along with the injection time, and the ratios of rest scar area of nude mice in 1 MUmol/L SD-208 group were significantly less than those in group NS from the day 6 to 20 post first time of injection (with t values from 1.8 to 15.9, P<0.05 or P<0.01). In week 1, 2, and 3 post first time of injection, the protein expressions of TGF-beta1 of human hypertrophic scar tissue in nude mice in two groups showed a tendency of decrease, and the protein expressions of TGF-beta1 of human hypertrophic scar tissue in nude mice in 1 MUmol/L SD-208 group were significantly lower than those in group NS (with t values from 6.2 to 19.1, P values below 0.01). CONCLUSIONS: SD-208 has significant inhibition effect on human hypertrophic scars, and the mechanism is correlated to the inhibition of protein expression of endogenous TGF beta1. PMID- 27464629 TI - [Effects of pretreatment with dimethyloxalylglycine on the survival of multi territory perforator flap in rat and related mechanism]. AB - OBJECTIVE: To observe the effects of pretreatment with dimethyloxalylglycine (DMOG) on the survival of multi-territory perforator flap and the vessels of choke zone (CZ) 2 in rat, and to explore related mechanism. METHODS: Sixty adult SD rats were divided into group DMOG and normal saline group (NS) according to the random number table, with 30 rats in each group. Perforator flap with three angiosomes was made on the right dorsal side of rat, including deep iliac circumflex artery perforator, intercostal artery perforator, thoracodorsal artery perforator, as well as CZ 1 and CZ 2. Rats in group DMOG were intraperitoneally injected with 2 mL NS containing DMOG (40 mg/kg) 2 days before operation, 2 hours before operation, and 2 days after operation. Rats in group NS were intraperitoneally injected with equivalent volume of NS at the same time point. On post operation day (POD) 7, gross observation was conducted, and the survival rate of flap was calculated. On POD 7, the vascularity in CZ 2 and potential zone of flap was observed using angiography. On POD 7, new vessel in CZ 2 of flap was observed with HE staining, and the microvessel density (MVD) was calculated. On POD 7, the expression of vascular endothelial growth factor (VEGF) in CZ 2 of flap was detected by immunohistochemistry and Western blotting (respectively denoted as integral absorbance values and ratio of gray value), and blood flow volume of vessel in CZ 2 of flap was examined by laser Doppler perfusion imager. The sample number of each index was 6 in each group. Data were processed with t test. RESULTS: (1) On POD 7, rats in two groups all survived, and the flaps were not infected. In group DMOG, the necrotic area of flaps of rats with dark yellow crust and soft texture was observed approximately at the distal end of skin entry point of thoracodorsal artery perforator. In group NS, the necrotic area of flaps of rats with brownish black crust and hard texture was observed approximately at the distal end of CZ 2. The survival rate of flap of rats in group DMOG was (88+/ 3) %, which was significantly higher than that in group NS [(82+/-3) %, t=3.38, P<0.01]. (2) On POD 7, there were clear vascular structure and many new vessels in CZ 2 of flaps of rats in group DMOG, with intact vascular structure in potential zone. On POD 7, there were unclear vascular structure and few new vessels in CZ 2 of flaps of rats in group NS, with disorder vascular structure in potential zone. (3) On POD 7, MVD in CZ 2 of flaps in rats of group DMOG was (29.2+/-2.2)/mm(2,) which was significantly higher than that of group NS [(20.3+/ 3.6)/mm(2,) t=5.10, P<0.01]. (4) On POD 7, the expressions of VEGF in CZ 2 of flaps in rats of group DMOG detected by immunohistochemistry and Western blotting were 5 060+/-432 and 0.48+/-0.04 respectively, which were significantly higher than those of group NS (2 811+/-382 and 0.26+/-0.06, with t values respectively 9.54 and 5.67, P values below 0.01). (5) On POD 7, blood flow volume of vessel in CZ 2 of flaps in rats of group DMOG was (58+/-4) perfusion units (PU), which was significantly more than that of group NS [(46+/-4) PU, t=5.20, P<0.01]. CONCLUSIONS: DMOG can increase the survival rate of multi-territory perforator flap through promoting angiogenesis in CZ 2 of flap on the back of rat and improving blood supply of flap. PMID- 27464630 TI - [Effects of rabbit adipose-derived mesenchymal stem cells on the healing of skin deep partial-thickness scald wound of rabbit]. AB - OBJECTIVE: To investigate the effects of local injection of rabbit adipose derived mesenchymal stem cells (ADSCs) on the healing of skin deep partial thickness scald wound of rabbit. METHODS: ADSCs were isolated from adipose tissue of one New Zealand rabbit and then sub-cultured. ADSCs of the third passage were used in the following experiments. Twenty-four rabbits were divided into ADSCs group (n=12) and control group (n=12) according to the random number table, and one deep partial-thickness scald wound with diameter of 5 cm on the two sides of the back near the buttocks was made. From post injury day (PID) 2, 2 mL suspension of EdU-labeled ADSCs with the number of 5*10(5) per mL was subcutaneously injected in wounds of rabbits in ADSCs group, while the rabbits in control group were given 2 mL serum-free DMEM until the wounds were healed. Wound healing processes of rabbits in two groups were observed every day, and the healing time was recorded. On PID 7, 14, 21, and 28, areas of wound of three rabbits in two groups were measured and the healing rates were calculated, respectively. The healed wound tissue was harvested to observe the morphology by HE staining, and the expression of collagen fiber was observed by Masson staining. The distribution of EdU-labeled ADSCs in healed wound tissue on PID 28 was observed by inverted fluorescence microscope. The expressions of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) of healed wound tissue on PID 7, 14, and 21 were detected by enzyme-linked immunosorbent assay. Data were processed with analysis of variance of factorial design and paired samples t test. RESULTS: (1) The wound healing time of rabbits in ADSCs group was (19.5+/-1.1) d post injury, which was significantly shorter than that in control group [(23.3+/-1.5) d, t=4.50, P<0.05]. On PID 7, wounds of rabbits in two groups were dry with no obvious exudation, and redness and swelling around wounds disappeared gradually, the wound healing rate of rabbits in ADSCs group was (15.1+/-2.4)%, which was close to that in control group [(13.7+/-3.1)%, t=1.20, P>0.05]. On PID 14, wounds of rabbits in ADSCs group were dry and scabbed obviously, and the wound healing rate was (73.1+/-5.7)%, while wounds of rabbits in control group were little scabbed with little exudation, and the wound healing rate was significantly lower than that in ADSCs group [(52.9+/-5.1)%, t=8.06, P<0.01]. On PID 21, wounds of rabbits in ADSCs group were generally healed, and the wound healing rate was (95.6+/-3.0)%, while a few wounds still existed in rabbits of control group, and the wound healing rate was significantly lower than that in ADSCs group [(78.6+/-3.7)%, t=9.73, P<0.01]. On PID 28, wounds of rabbits in two groups were totally healed with the healing rate of 100%, and texture and microvascular responses of healed wound tissue in ADSCs group were better than those in control group. (2) On PID 7, fibroblasts in healed wound tissue of rabbits in two groups were all increased, and there were little vascular and collagen fiber proliferation with no obvious differences. On PID 14, the number of fibroblasts in healed wound tissue of rabbits in ADSCs group was more than that in control group, and the collagen fibers in healed wound tissue of rabbits in ADSCs group were arranged in dense and uniform, while those in control group were sparse and irregular. On PID 21, skin layers were differentiated in healed wound tissue of rabbits in two groups, and collagen fibers in healed wound tissue of rabbits in ADSCs group were still denser than that in control group. On PID 28, newborn skin was well differentiated in healed wound tissue of rabbits in ADSCs group, which was better than that in control group. There were a lot of thick collagen fibers in healed wound tissue of rabbits in two groups, and EdU labeled ADSCs were involved in skin texture of rabbits in ADSCs group. (3) The expressions of VEGF and EGF in healed wound tissue of rabbits in two groups were similar on PID 7 (with t values respectively 0.70 and 0.91, P values above 0.05), which in ADSCs group were significantly higher than those in control group on PID 14 and 21 (with t values from 2.85 to 4.81, P values below 0.01). CONCLUSIONS: The transplantation of ADSCs can promote the wound healing of skin deep partial thickness scald wound of rabbit and shorten the wound healing time. PMID- 27464631 TI - [Effects of hydrogen sulfide on the secretion of cytokines in macrophages of deep partial-thickness burn wound in rats]. AB - OBJECTIVE: To analyze the effects of exogenous hydrogen sulfide on the secretion of growth factors basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGF-beta1), as well as inflammatory mediators tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) in macrophages of deep partial thickness burn wound in rats. METHODS: Seventy-eight SD rats were divided into normal control group (n=6), pure burn group, sodium hydrosulfide group, propargylglycine (PPG) group, and sodium hydrosulfide+ PPG group according to the random number table, with 18 rats in each of the latter four groups. Rats in normal control group did not receive any treatment, while rats in the other four groups were inflicted with 5% total burn surface area deep partial-thickness scald (hereinafter referred to as burn) on the back. Immediately after burn, rats in pure burn group, sodium hydrosulfide group, and group PPG were intraperitoneally injected with saline 2 mL/kg, sodium hydrosulfide 56 MUmol/kg, and PPG 45 mg/kg respectively, while those in sodium hydrosulfide+ PPG group were intraperitoneally injected with sodium hydrosulfide 56 MUmol/kg and PPG 45 mg/kg, once a day till the day before harvesting specimen. Six rats of normal control group fed for one week, and 6 rats from each of the rest four groups on post injury day (PID) 3, 7, 14 were collected respectively. Normal skin on the back of rats in normal control group and tissue in the base of wound of rats in the other four groups were harvested to isolate macrophages, and then the content of bFGF, TGF-beta1, TNF-alpha, and IL-1beta in culture supernatant of macrophages was detected with enzyme-linked immunosorbent assay. Data were processed with one-way analysis of variance, analysis of variance of factorial design, and LSD test. RESULTS: Compared with that of normal control group [(42.6+/-2.5) and (18+/-4) pg/mL], the content of bFGF and TGF-beta1 in culture supernatant of macrophages of rats in pure burn group was obviously increased at each time point (with P values below 0.01), peaking on PID 14 at (141.6+/-7.7) and (580+/-16) pg/mL respectively. Compared with that of pure burn group, the content of bFGF and TGF beta1 in culture supernatant of macrophages of rats in sodium hydrosulfide group was obviously increased at each time point (with P values below 0.01), peaking on PID 14 at (193.7+/-10.9) and (793+/-12) pg/mL respectively, while the content of bFGF and TGF-beta1 in culture supernatant of macrophages of rats in group PPG was obviously decreased at each time point (with P values below 0.01), reaching the nadir on PID 3 at (62.0+/-7.1) and (170+/-10) pg/mL respectively. The content of bFGF and TGF-beta1 in culture supernatant of macrophages of rats in sodium hydrosulfide+ PPG group was obviously lower than that of sodium hydrosulfide group but obviously higher than that of group PPG at each time point (with P values below 0.01), peaking on PID 14 at (151.3+/-9.0) and (579+/-9) pg/mL respectively. Compared with that of normal control group [(97+/-6) and (31+/-6) pg/mL], the content of TNF-alpha and IL-1beta in culture supernatant of macrophages of rats in pure burn group was obviously increased at each time point (with P values below 0.01), peaking on PID 3 at (924+/-8) and (290+/-10) pg/mL respectively. Compared with that of pure burn group, the content of TNF-alpha and IL-1beta in culture supernatant of macrophages of rats in sodium hydrosulfide group was obviously decreased at each time point (with P values below 0.01), reaching the nadir on PID 14 at (346+/-10) and (120+/-5) pg/mL respectively, while the content of TNF-alpha and IL-1beta in culture supernatant of macrophages of rats in group PPG was obviously increased at each time point (with P values below 0.01), peaking on PID 3 at (1 232+/-13) and (410+/-10) pg/mL respectively. The content of TNF-alpha and IL-1beta in culture supernatant of macrophages of rats in sodium hydrosulfide+ PPG group was obviously higher than that of sodium hydrosulfide group but obviously lower than that of group PPG at each time point (with P values below 0.01), reaching the nadir on PID 14 at (488+/-16) and (144+/ 6) pg/mL respectively. CONCLUSIONS: Supplementation of exogenous hydrogen sulfide in small dosage can increase the secretion of growth factors bFGF and TGF-beta1 in macrophages of wound in rats with deep partial-thickness burn in the early stage and reduce the release of inflammatory mediators TNF-alpha and IL-1beta in the meantime, thus affecting the healing of wound. PMID- 27464632 TI - [Effects of Sp1 on the basic transcriptional activity of intestinal trefoil factor promoter]. AB - OBJECTIVE: To explore response element that maintains basic transcriptional activity of intestinal trefoil factor (ITF) promoter. METHODS: Truncated and mutant 5' flanking sequences of ITF gene were cloned from ITF promoter sequences by PCR, and then they were inserted into the pGL3-basic vector to construct truncated and mutant luciferase vectors to conduct the following experiments. (1) Human embryonic kidney 293 (HEK293) cells were divided into pGL3-basic group, pGL3-300 group, pGL3-280 group, pGL3-260 group, pGL3-240 group, pGL3-220 group, and pGL3-200 group according to the random number table (the same grouping method below), with 3 wells in each group, and they were respectively transfected with 500 ng corresponding plasmids and 15 ng renilla luciferase reporter plasmids pRL TK. After being cultured for 48 hours, the relative luciferase activity of cells was measured by single tube detection system. (2) Another batch of HEK293 cells were divided into pGL3-basic group, pGL3-300 group, mutant 1, 2, 3, and 4 groups, with 3 wells in each group, and they were respectively transfected with 500 ng pGL3-basic, pGL3-300, mutant 1, 2, 3, and 4 plasmids and 15 ng pRL-TK plasmids. After being cultured for 48 hours, the relative luciferase activity of cells was measured as in (1). (3) Another batch of HEK293 cells were divided into blank control group and 10, 50 MUmol/L mithramycin groups, with 3 wells in each group. After being transfected with 500 ng pGL3-300 plasmids and 15 ng pRL-TK plasmids, cells in blank control group were not transfected with mithramycin, while cells in the latter two groups were respectively transfected with 10 and 50 MUmol/L mithramycin. After being cultured for 24 hours, the relative luciferase activity of cells was measured as in (1). (4) Another batch of HEK293 cells were divided into blank control group and 0.1, 0.2, and 0.3 MUg pcDNA3.1-Sp1 groups, with 3 wells in each group. After being transfected with 500 ng pGL3-300 plasmids and 15 ng pRL-TK plasmids, cells in blank control group were not transfected with pcDNA3.1-Sp1 plasmids, while cells in the latter three groups were respectively transfected with 0.1, 0.2, and 0.3 MUg pcDNA3.1-Sp1 plasmids. After being cultured for 48 hours, the relative luciferase activity of cells was measured as in (1). Data were processed with one-way analysis of variance and LSD test. RESULTS: (1) The relative luciferase activity of cells in pGL3-basic group, pGL3 300 group, pGL3-280 group, pGL3-260 group, pGL3-240 group, pGL3-220 group, and pGL3-200 group was 1.00, 7.99+/-0.51, 2.03+/-0.55, 2.50+/-0.40, 2.50+/-0.15, 1.72+/-0.19 and 2.10+/-0.21, respectively. The relative luciferase activity of cells in pGL3-280 group, pGL3-260 group, pGL3-240 group, pGL3-220 group, and pGL3 200 group was significantly lower than that in pGL3-300 group (with P values below 0.01). (2) The relative luciferase activity of cells in pGL3-basic group, pGL3-300 group, mutant 1, 2, 3, and 4 groups was 1.00, 7.99+/-0.51, 2.10+/-0.56, 7.03+/-1.05, 5.09+/-1.40 and 8.15+/-1.48, respectively. The relative luciferase activity of cells in mutant 1 group was significantly lower than that in pGL3-300 group (P<0.01). The relative luciferase activity of cells in pGL3-300 group, mutant 2, 3, and 4 groups was similar (with P values above 0.05). (3) The relative luciferase activity of cells in 10 and 50 MUmol/L mithramycin groups was respectively 3.07+/-0.60 and 2.93+/-0.55, which was significantly lower than that in blank control group (8.05+/-0.83, with P values below 0.01). (4) The relative luciferase activity of cells in 0.1, 0.2, and 0.3 MUg pcDNA3.1-Sp1 groups was respectively 12.74+/-1.12, 14.52+/-1.25, and 15.66+/-1.82, which was significantly higher than that in blank control group (8.13+/-0.71, with P values below 0.05). CONCLUSIONS: One Sp1 binding site, locating in the region from -301 to -293 bp of ITF promoter, is the core element for regulating the basic transcriptional activity of ITF. PMID- 27464633 TI - [Advances in the research of effects of cholinergic anti-inflammatory pathway on vital organ function and its mechanism]. AB - Serious major burns, trauma and surgical stress can easily develop into sepsis, and further result in septic shock or even multiple organ dysfunction syndrome (MODS). The mechanism of MODS is complicated, including excessive inflammation, immune dysfunction, coagulation disorder, and ischemia-reperfusion injury. Recent studies have demonstrated that the nervous system could significantly and quickly suppress systemic inflammatory response via the vagus nerve, which might improve multiple organ damage following acute injury. This article is to brief our understanding concerning the structure characteristics of cholinergic anti inflammatory pathway, and its effects on vital organ function and the regulatory mechanism, which might be of great significance to seek a novel way for interventional strategy of MODS. PMID- 27464634 TI - [Bibliometric analysis of scientific articles on evidence-based nursing of burn in the mainland of China]. AB - OBJECTIVE: To analyze the current research status of evidence-based nursing of burn in the mainland of China, in order to provide basis for the improvement of scientificity of burn nursing practice. METHODS: Chinese scientific articles on evidence-based nursing of burn in the mainland of China published from January 1997 to December 2015 were retrieved from Chinese Biology Medicine disc, Chinese Journals Full-text Database, Wanfang Database, and VIP Database. From the results retrieved, date with regard to publication year, region of affiliation of the first author, journal distribution, literature type, literature quality assessment, topic of evidence-based research, fund program support, implementation of evidence-based practice steps, and language and quantity of reference. Data were processed with Microsoft Excel software. RESULTS: A total of 50 articles conforming to the criteria were retrieved. (1) Articles about evidence-based nursing of burn arose in 2004. Compared with that in the previous year, there was no obvious increase in the number of relevant articles in each year from 2004 to 2011. The number of literature in 2012 was obviously increased than that in each year from 2004 to 2011, while the number of literature in each year from 2012 to 2015 was not obviously increased compared with that in the previous year. (2) The regions of affiliation of the first author were distributed in 13 provinces, 3 minority autonomous regions, and 3 municipalities, with the largest distribution in East China, and Northwest China and Southwest China in the follow. (3) The articles were published in 32 domestic journals, with 9 (28.12%) nursing journals, 5 (15.62%) burn medical related journals, and 18 (56.25%) other journals. Twenty (40%) articles were published in Source Journal for Chinese Scientific and Technical Papers. (4) Regarding the literature type, 31 (62%) articles dealt with clinical experiences, 17 (34%) articles dealt with scientific research, and 2 (4%) articles dealt with case report. (5) There were 21 quantitative study articles and 29 narrative study articles, all with low quality. (6) The topics of evidence-based research in these articles were mainly burn rehabilitation, burn nursing technology, pediatric burn, inhalation injury and airway management, and complications of burn injury. Only one study was supported by fund program. (7) Only one article described complete evidence-based practice steps. (8) The literature cited 57 English articles as references, with an average of 1.14, and 316 Chinese articles, with an average of 6.32. CONCLUSIONS: The concept of evidence-based nursing of burn has been initially formed in the mainland of China. The number of relevant articles is on the rise, but the quality needs to be further improved. There is an urgent need to improve nurses' understanding of evidence-based nursing and their command of the method of evidence-based practice through on-job training, so as to improve the scientificity and effectiveness of burn nursing. PMID- 27464635 TI - Can serum dynamics of carcinoembryonic antigen level during neoadjuvant chemoradiotherapy in rectal cancer predict tumor response and recurrence? A multi institutional retrospective study. AB - PURPOSE: We evaluate whether the change of carcinoembryonic antigen (CEA) level before and after preoperative chemoradiotherapy (CRT) in rectal cancer affects tumor response and recurrence or not. METHODS: We retrospectively analyzed 1447 rectal cancer patients who underwent preoperative CRT followed by curative surgery. All patients received preoperative radiotherapy of 50.4 Gy in 28 fractions with 5-fluorouracil or capecitabine. Total mesorectal excision was performed 4 to 8 weeks after preoperative CRT. CEA levels were checked before and after CRT. Clinical and pathologic factors were analyzed for tumor response and recurrence. RESULTS: Post-CRT CEA level (cutoff value, 2.5 ng/mL) was not a significant factor for tumor response on the multivariate analysis (p = 0.095). Patients were categorized according to the pre- and post-CRT CEA level (group A: pre-CRT CEA <=5 ng/mL; group B: pre-CRT CEA >5 ng/mL and post-CRT CEA <=2.5 ng/mL; group C: pre-CRT CEA >5 ng/mL and post-CRT CEA >2.5 ng/mL). The relapse free survival (RFS) at 5 years was significantly higher in group A than in groups B and C (82.6 vs. 73.7 % vs. 72.2 %, p < 0.001). The overall survival (OS) at 5 years was significantly higher in group A than in groups B and C (90.1 vs. 84.4 % vs. 83.4 %, p < 0.001). However, there is no significant difference for RFS and OS between groups B and C (all, p > 0.05). CONCLUSIONS: Decline of elevated CEA level (>5 ng/mL) during preoperative chemoradiotherapy has no significant effect on tumor response and recurrence in rectal cancer. PMID- 27464636 TI - Orofacial pain induced by Eagle syndrome in an elderly patient with temporomandibular disorders - a case report. AB - BACKGROUND: Eagle syndrome (ES) is a rare disorder that can be responsible for orofacial pain. OBJECTIVE: To describe the treatment of an elderly patient affected by ES and temporomandibular disorders (TMD). MATERIALS AND METHODS: A patient complained of constant pain of the right temporomandibular joint (TMJ) and of the sensation of having a foreign body in the throat. Based on the patient's medical history and symptoms, a TMJs internal derangement and concomitant ES were suspected. A magnetic resonance and a computerised tomography confirmed the clinical diagnosis. A conservative treatment was initially performed to re-establish a functional occlusion. RESULTS: The rehabilitative treatment alleviated the pain almost totally. A slight residual uncomfortable sensation of the presence of a foreign body in the throat persisted after the oral rehabilitation but without any influence on the quality of life. CONCLUSION: In elderly patients complaining a chronic orofacial pain, the possibility of a concomitant TMD and ES has to be considered to correctly identify the source of pain. A conservative approach to identify weather TMD is the main source of pain is preferable, avoiding unnecessary invasive treatments. PMID- 27464639 TI - Can 'Fellow of the European Board of Ophthalmology Subspecialty Diploma in Glaucoma,' a subspecialty examination on glaucoma induce the qualification standard of glaucoma clinical practice in Europe? PMID- 27464638 TI - Food insecurity as a driver of obesity in humans: The insurance hypothesis. AB - Integrative explanations of why obesity is more prevalent in some sectors of the human population than others are lacking. Here, we outline and evaluate one candidate explanation, the insurance hypothesis (IH). The IH is rooted in adaptive evolutionary thinking: The function of storing fat is to provide a buffer against shortfall in the food supply. Thus, individuals should store more fat when they receive cues that access to food is uncertain. Applied to humans, this implies that an important proximate driver of obesity should be food insecurity rather than food abundance per se. We integrate several distinct lines of theory and evidence that bear on this hypothesis. We present a theoretical model that shows it is optimal to store more fat when food access is uncertain, and we review the experimental literature from non-human animals showing that fat reserves increase when access to food is restricted. We provide a meta-analysis of 125 epidemiological studies of the association between perceived food insecurity and high body weight in humans. There is a robust positive association, but it is restricted to adult women in high-income countries. We explore why this could be in light of the IH and our theoretical model. We conclude that although the IH alone cannot explain the distribution of obesity in the human population, it may represent a very important component of a pluralistic explanation. We also discuss insights it may offer into the developmental origins of obesity, dieting-induced weight gain, and anorexia nervosa. PMID- 27464640 TI - Procedural aspects of the organization of the comprehensive European Board of Ophthalmology Diploma examination. AB - The comprehensive European Board of Ophthalmology Diploma (EBOD) examination is one of 38 European medical specialty examinations. This review aims at disclosing the specific procedures and content of the EBOD examination. It is a descriptive study summarizing the present organization of the EBOD examination. It is the 3rd largest European postgraduate medical assessment after anaesthesiology and cardiology. The master language is English for the Part 1 written test (knowledge test with 52 modified type X multiple-choice questions) (in the past the written test was also available in French and German). Ophthalmology training of minimum 4 years in a full or associated European Union of Medical Specialists (UEMS) member state is a prerequisite. Problem-solving skills are tested in the Part 2 oral assessment, which is a viva of 4 subjects conducted in English with support for native language whenever feasible. The comprehensive EBOD examination is one of the leading examinations organized by UEMS European Boards or Specialist Sections from the point of number of examinees, item banking, and item contents. PMID- 27464641 TI - Erratum to: Jesus the Healer: A Sermon in Honor of the Memory of Donald Eric Capps (1939-2015). PMID- 27464642 TI - Younger African American Adults' Use of Religious Songs to Manage Stressful Life Events. AB - The aim of this study was to explore the use of religious songs in response to stressful life events among young African American adults. Fifty-five young African American adults aged 18-49 participated in a qualitative study involving criterion sampling and open-ended interviews. Data analysis included content analysis and descriptive statistics. Stressful life events were related to work or school; caregiving and death of a family member; and relationships. Religious songs represented five categories: Instructive, Communication with God, Thanksgiving and Praise, Memory of Forefathers, and Life after Death. The tradition of using religious songs in response to stressful life events continues among these young adults. Incorporating religious songs into health-promoting interventions might enhance their cultural relevance to this population. PMID- 27464643 TI - Religion in Motion: Continuities and Symbolic Affinities in Religion and Sport. AB - One of the major transformations in religion in contemporary societies has been the decline of church institutions and their reconstruction within a diverse network of associations, therapies, markets and other unconventional spiritual services. Based on extensive ethnographic fieldwork on religious behaviours and dynamics in sports contexts, and taking the similarities between sport and religion as the point of departure, this paper analyses, reflects on and theorises about the symbolic affinities of these two contemporary social institutions. The results show that symbolism converges in the religious element, tending to improve aspects related to sports ethics and establishing affective experiences among participants, with positive results for their physical and mental wellbeing. The findings indicate that a symbolic analysis of the various facets of sport is a useful approach for gaining a better understanding of this phenomenon, since besides being biological, diseases are also cultural and social, and thus, disease, religion and ritual are emotionally related. PMID- 27464644 TI - An Age-Period-Cohort Analysis of Religious Involvement and Adult Self-Rated Health: Results from the USA, 1972-2008. AB - This study conducts an age, period, cohort analysis of how religious involvement affects adult health across the life course and over time in the USA. Cross classified random-effect models are used to examine data drawn from the General Social Survey, 1972-2008. The research shows clear life course patterns, time trends and birth cohort changes in the religious involvement and health relationship with period effects surpassing cohort effects. For the most part, the results show a loss of advantage in health with age for those who are more involved in religion. Period effects are mainly demonstrated by an overall downward trend of self-rated health (SRH) attributable to religious denominational differences and various levels of social integration. Unlike the period effects, the health disparities associated with religious denominational differences fluctuated when cohort progressed. These findings suggest that in general, the positive effect of religious involvement on SRH decreases with age and periods, but its influence on individual SRH fluctuates by cohort. It is expected that a downward trend in SRH attributable to religious involvement will carry on in future. PMID- 27464645 TI - Membraneless Gas-Separation Microfluidic Paper-Based Analytical Devices for Direct Quantitation of Volatile and Nonvolatile Compounds. AB - This work presents new chemical sensing devices called "membraneless gas separation microfluidic paper-based analytical devices" (MBL-GS MUPADs). MBL-GS MUPADs were designed to make fabrication of the devices simple and user-friendly. MBL-GS MUPADs offer direct quantitative analysis of volatile and nonvolatile compounds. Porous hydrophobic membrane is not needed for gas-separation, which makes fabrication of the device simple, rapid and low-cost. A MBL-GS MUPAD consists of three layers: "donor layer", "spacer layer", and "acceptor layer". The donor and acceptor layers are made of filter paper with a printed pattern. The donor and acceptor layers are mounted together with a spacer layer in between. This spacer is a two-sided mounting tape, 0.8 mm thick, with a small disc cut out for the gas from the donor zone to diffuse to the acceptor zone. Photographic image of the color that is formed by the reagent in the acceptor layer is analyzed using the ImageJ program for quantitation. Proof of concept of the MBL-GS MUPADs was demonstrated by analyzing standard solutions of ethanol, sulfide, and ammonium. Optimization of the MBL-GS MUPADs was carried out for direct determination of ammonium in wastewaters and fertilizers to demonstrate the applicability of the system to real samples. PMID- 27464646 TI - Patterns of multimorbidity and their association with health outcomes within Yorkshire, England: baseline results from the Yorkshire Health Study. AB - BACKGROUND: Multimorbidity is increasingly being recognized as a serious public health concern. Research into its determinants, prevalence, and management is needed and as the risk of experiencing multiple chronic conditions increases over time, attention should be given to investigating the development of multimorbidity through prospective cohort design studies. Here we examine the baseline patterns of multimorbidity and their association with health outcomes for residents in Yorkshire, England using data from the Yorkshire Health Study. METHODS: Baseline data from the Yorkshire Health Study (YHS) was collected from 27,806 patients recruited between 2010 and 2012. A two-stage sampling strategy was implemented which first involved recruiting 43 general practice surgeries and then having them consent to mailing invitations to their patients to complete postal or online questionnaires. The questionnaire collected information on chronic health conditions, demographics, health-related behaviours, healthcare and medication usage, and a range of other health related variables. Descriptive statistics (chi-square and t tests) were used to examine associations between these variables and multimorbidity. RESULTS: In the YHS cohort, 10,332 participants (37.2 %) reported having at least two or more long-term health conditions (multimorbidity). Older age, BMI and deprivation were all positively associated with multimorbidity. Nearly half (45.7 %) of participants from the most deprived areas experienced multimorbidity. Based on the weighted sample, average health-related quality of life decreased with the number of health conditions reported; the mean EQ-5D score for participants with no conditions was 0.945 compared to 0.355 for participants with five or more. The mean number of medications used for those without multimorbidity was 1.81 (range 1-13, SD = 1.25) compared to 3.81 (range 1-14, SD = 2.44) for those with at least two long term conditions and 7.47 (range 1-37, SD = 7.47) for those with 5+ conditions. CONCLUSION: Patterns of multimorbidity within the Yorkshire Health Study support research on multimorbidity within previous observational cross-sectional studies. The YHS provides both a facility for participant recruitment to intervention trials, and a large population-based longitudinal cohort for observational research. It is planned to continue to record chronic conditions and other health related behaviours in future waves which will be useful for examining determinants and trends in chronic disease and multimorbidity. PMID- 27464647 TI - Pubertal development in children with chronic kidney disease. AB - Impairment of pubertal growth and sexual maturation resulting in reduced adult height is an significant complication in children suffering from chronic kidney disease (CKD). Delayed puberty and reduced pubertal growth are most pronounced in children with pre-existing severe stunting before puberty, requiring long-term dialysis treatment, and in transplanted children with poor graft function and high glucocorticoid exposure. In pre-dialysis patients, therapeutic measures to improve pubertal growth are limited and mainly based on the preservation of renal function and the use of growth hormone treatment. In patients with end-stage CKD, early kidney transplantation with steroid withdrawal within 6 months of renal transplantation allows for normal pubertal development in the majority of patients. This review focuses on the underlying pathophysiology and strategies for improving height and development in these patients. PMID- 27464649 TI - Erratum to: Endovascular Interventions in Acute Ischemic Stroke: Recent Evidence, Current Challenges, and Future Prospects. PMID- 27464648 TI - The Bariatric Patient in the Intensive Care Unit: Pitfalls and Management. AB - The increasing number of bariatric/metabolic operations as important alternatives for the treatment of obesity and type 2 diabetes brought several concerns about the intensive care of patients undergoing those procedures. Intensive Care Unit admission criteria are needed in order to better allocate resources and avoid unnecessary interventions. Furthermore, well-established protocols, helpful in many clinical situations, are not directly applicable to obese patients. Indeed, difficult airway management, mechanical ventilation, fluid therapy protocols, prophylaxis, and treatment of venous thromboembolic events have unique aspects that should be taken into consideration. Finally, new data related to planning nutrition therapy of the critically obese have been highlighted and deserve consideration. In this review, we provide an outline of recent studies related to those important aspects of the care of the bariatric/metabolic patients in critical conditions. PMID- 27464650 TI - Synthesis of sodium polyhydrides at high pressures. AB - The only known compound of sodium and hydrogen is archetypal ionic NaH. Application of high pressure is known to promote states with higher atomic coordination, but extensive searches for polyhydrides with unusual stoichiometry have had only limited success in spite of several theoretical predictions. Here we report the first observation of the formation of polyhydrides of Na (NaH3 and NaH7) above 40 GPa and 2,000 K. We combine synchrotron X-ray diffraction and Raman spectroscopy in a laser-heated diamond anvil cell and theoretical random structure searching, which both agree on the stable structures and compositions. Our results support the formation of multicenter bonding in a material with unusual stoichiometry. These results are applicable to the design of new energetic solids and high-temperature superconductors based on hydrogen-rich materials. PMID- 27464651 TI - Ectopic expression of NnPER1, a Nelumbo nucifera 1-cysteine peroxiredoxin antioxidant, enhances seed longevity and stress tolerance in Arabidopsis. AB - Seed longevity, the maintenance of viability during storage, is a major factor for conservation of genetic resources and biodiversity. Seed longevity is an important trait of agriculture crop and is impaired by reactive oxygen species (ROS) during seed desiccation, storage and germination (C. R. Biol., 331, 2008 and 796). Seeds possess a wide range of systems (protection, detoxification, repair) allowing them to survive during storage and to preserve a high germination ability. In many plants, 1-cys peroxiredoxin (1-Cys Prx, also named PER1) is a seed-specific antioxidant which eliminates ROS with cysteine residues. Here we identified and characterized a seed-specific PER1 protein from seeds of sacred lotus (Nelumbo nucifera Gaertn.). Purified NnPER1 protein protects DNA against the cleavage by ROS in the mixed-function oxidation system. The transcription and protein accumulation of NnPER1 increased during seed desiccation and imbibition and under abiotic stress treatment. Ectopic expression of NnPER1 in Arabidopsis enhanced the seed germination ability after controlled deterioration treatment (CDT), indicating that NnPER1 improves seed longevity of transgenic plants. Consistent with the function of NnPER1 on detoxifying ROS, we found that the level of ROS release and lipid peroxidation was strikingly lower in transgenic seeds compared to wild-type with or without CDT. Furthermore, transgenic Arabidopsis seeds ectopic-expressing NnPER1 displayed enhanced tolerance to high temperature and abscisic acid (ABA), indicating that NnPER1 may participate in the thermotolerance and ABA signaling pathway. PMID- 27464653 TI - Controlling the Adsorption of Carbon Monoxide on Platinum Clusters by Dopant Induced Electronic Structure Modification. AB - A major drawback of state-of-the-art proton exchange membrane fuel cells is the CO poisoning of platinum catalysts. It is known that CO poisoning is reduced if platinum alloys are used, but the underlying mechanism therefore is still under debate. We study the influence of dopant atoms on the CO adsorption on small platinum clusters using mass spectrometry experiments and density functional calculations. A significant reduction in the reactivity for Nb- and Mo-doped clusters is attributed to electron transfer from those highly coordinated dopants to the Pt atoms and the concomitant lower CO binding energies. On the other hand Sn and Ag dopants have a lower Pt coordination and have a limited effect on the CO adsorption. Analysis of the density of states demonstrates a correlation of dopant-induced changes in the electronic structure with the enhanced tolerance to CO poisoning. PMID- 27464652 TI - Engineering Salmonella as intracellular factory for effective killing of tumour cells. AB - Salmonella have many desirable properties as antitumour-agent due to its ability to proliferate inside tumours and induce tumour regression. Additionally, this bacterium can be genetically engineered to deliver therapeutic proteins intratumourally. The main limitation of this approach is the efficient release of therapeutic molecules from intratumoural bacteria. Here we have developed an inducible autolysis system based in the lysis operon of the lambda phage that, in response to anhydrotetracycline, lysates Salmonella thus releasing its content. The system was combined with a salicylate cascade system that allows efficient production of therapeutic molecules in response to aspirin and with a sifA mutation that liberates bacteria from the vacuoles to a cytosolic location. The combination of these three elements makes this strain a putative powerful instrument in cancer treatment. We have used this engineered strain for the intracellular production and delivery of Cp53 peptide. The engineered strain is able to sequentially produce and release the cytotoxic peptide while proliferating inside tumour cells, thus inducing host cell death. Our results show that temporal separation of protein production from protein release is essential to efficiently kill tumour cells. The combined system is a further step in the engineering of more efficient bacteria for cancer therapy. PMID- 27464654 TI - CEACAM1 is overexpressed in oral tumors and related to tumorigenesis. AB - Carcinoembryonic antigen-related adhesion molecule 1 (CEACAM1) is a type 1 transmembrane glycoprotein belonging to the CEA family, which has been known to exist as either soluble forms in body fluids or membrane-bound forms on the cell surface. Aberrant CEACAM1 expression is associated with tumorigenesis and has been reported in a variety of human tumors, especially malignancies. The aim of this study is to determine the expression of CEACAM1 in oral tumors, trying to study CEACAM1 different expressions as a function of histotype. CEACAM1 expression was observed by immunohistochemistry (IHC) with mouse anti-human antibody for CEACAM1. IHC was performed using avidin-biotin-diaminobenzidine staining. The results were expressed as average score +/- SD (0 = negative/8 = highest) for each histotype. Oral tumors expressed more CEACAM1 than normal tissues including squamous and salivary epithelia (P < 0.05). In malignancies, the squamous cell carcinoma overexpressed CEACAM1, compared to well differentiated squamous cell with more membranous expression; the intermediately and poorly differentiated squamous cell carcinoma showed more cytoplasmic expression (P < 0.05). In addition, the salivary tumors significantly expressed more CEACAM1 than squamous cell carcinoma (P < 0.05). So, we thought oral tumors overexpressed CEACAM1 and the cytoplasmic CEACAM1 might be involved in tumorigenesis, and also CEACAM1 might be regarded as a marker of salivary glandular tumors. PMID- 27464655 TI - Dissipation and runoff transport of metazachlor herbicide in rapeseed cultivated and uncultivated plots in field conditions. AB - The environmental fate of metazachlor herbicide was investigated under field conditions in rapeseed cultivated and uncultivated plots, over a period of 225 days. The cultivation was carried out in silty clay soil plots with two surface slopes, 1 and 5 %. The herbicide was detectable in soil up to 170 days after application (DAA), while the dissipation rate was best described by first-order kinetics and its half-life ranged between 10.92 and 12.68 days. The herbicide was detected in the soil layer of 10-20 cm from 5 to 48 DAA, and its vertical movement can be described by the continuous stirred tank reactor (CSTR) in series model. Relatively low amounts of metazachlor (less than 0.31 % of the initial applied active ingredient) were transferred by runoff water. More than 80 % of the total losses were transferred at the first runoff event (12 DAA), with herbicide concentrations in runoff water ranging between 70.14 and 79.67 MUg L-1. Minor amounts of the herbicide (less than 0.07 % of the initial applied active ingredient) were transferred by the sediment, with a maximum concentration of 0.57 MUg g-1 (12 DAA), in plots with 5 % inclination. Finally, in rapeseed plants, metazachlor was detected only in the first sampling (28 DAA) at concentrations slightly higher than the limit of quantification; when in seeds, no residues of the herbicide were detected. PMID- 27464656 TI - Benchmark dose for cadmium exposure and elevated N-acetyl-beta-D-glucosaminidase: a meta-analysis. AB - Cadmium (Cd) is a well-known nephrotoxic contaminant, and N-acetyl-beta-D glucosaminidase (NAG) is considered to be an early and sensitive marker of tubular dysfunction. The link between Cd exposure and NAG level enables us to derive the benchmark dose (BMD) of Cd. Although several reports have already documented urinary Cd (UCd)-NAG relationships and BMD estimations, high heterogeneities arise due to the sub-populations (age, gender, and ethnicity) and BMD methodologies being employed. To clarify the influences that these variables exert, firstly, a random effect meta-analysis was performed in this study to correlate the UCd and NAG based on 92 datasets collected from 30 publications. Later, this established correlation (Ln(NAG) = 0.51 * Ln(UCd) + 0.83) was applied to derive the UCd BMD5 of 1.76 MUg/g creatinine and 95 % lower confidence limit of BMD5 (BMDL5) of 1.67 MUg/g creatinine. While the regressions for different age groups and genders differed slightly, it is age and not gender that significantly affects BMD estimations. Ethnic differences may require further investigation given that limited data is currently available. Based on a comprehensive and systematic literature review, this study is a new attempt to quantify the UCd-NAG link and estimate BMD. PMID- 27464657 TI - Indoor pollutant exposure among children with and without asthma in Porto, Portugal, during the cold season. AB - Considering the time spent in enclosed spaces, indoor air pollutants are of major interest because of its possible impact on health. However, to date, few studies have analysed the air concentrations of a large set of indoor pollutants of respiratory health relevance in dwellings, particularly in Portugal. This study aimed to measure the concentrations of air pollutants that are present in residential buildings and to investigate whether some clustering pattern of indoor air pollutants exists in the dwellings of children with (case group) and without asthma (control group). Measurements were taken in 30 and 38 dwellings of asthmatic and non-asthmatic schoolchildren, respectively, located in the city of Porto, Portugal, during the cold season (October 2012-April 2013), to assess the concentrations of 12 volatile organic compounds (VOC), aldehydes, PM2.5, PM10, bacteria and fungi. Toluene, d-limonene, formaldehyde, PM2.5, bacteria and fungi are widely present in dwellings, sometimes in relatively high concentrations in reference to WHO guideline values. Moreover, concentrations of CO2 exceeding 1000 ppm were often encountered, indicating that 70 % of all dwellings had poor ventilation (<4 L/s person). While exposures to common dwelling indoor pollutants are similar for schoolchildren with and without asthma, except for d-limonene levels, the identification and control of VOC and PM sources is important and prudent, especially for vulnerable individuals. PMID- 27464658 TI - Dynamism of household carbon emissions (HCEs) from rural and urban regions of northern and southern China. AB - China contributes 23 % of global carbon emissions, of which 26 % originate from the household sector. Due to vast variations in both climatic conditions and the affordability and accessibility of fuels, household carbon emissions (HCEs) differ significantly across China. This study compares HCEs (per person) from urban and rural regions in northern China with their counterparts in southern China. Annual macroeconomic data for the study period 2005 to 2012 were obtained from Chinese government sources, whereas the direct HCEs for different types of fossil fuels were obtained using the IPCC reference approach, and indirect HCEs were calculated by input-output analysis. Results suggest that HCEs from urban areas are higher than those from rural areas. Regardless of the regions, there is a similarity in per person HCEs in urban areas, but the rural areas of northern China had significantly higher HCEs than those from southern China. The reasons for the similarity between urban areas and differences between rural areas and the percentage share of direct and indirect HCEs from different sources are discussed. Similarly, the reasons and solutions to why decarbonising policies are working in urban areas but not in rural areas are discussed. PMID- 27464659 TI - Ozonation effects on emerging micropollutants and effluent organic matter in wastewater: characterization using changes of three-dimensional HP-SEC and EEM fluorescence data. AB - The degradation of effluent organic matter (EfOM) in a municipal wastewater treated by ozonation was characterized using the methods of high-performance size exclusion chromatography (HP-SEC) and excitation/emission matrix (EEM) fluorescence combined with parallel factor analysis (PARAFAC). The removal of 40 diverse trace-level contaminants of emerging concern (CEC) present in the wastewater was determined as well. Ozonation caused a rapid decrease of the absorbance and fluorescence of the wastewater, which was associated primarily with the oxidation of high and low apparent molecular weight (AMW) EfOM fractions. PARAFAC analysis also showed that components C1 and C2 decreased prominently in these conditions. The EfOM fraction of intermediate molecular weight ascribable to a terrestrial humic-like component (C3) tended to be less reactive toward ozone. Relative changes of EEM fluorescence were quantified using F max values of PARAFAC-identified components (?F/F 0max). Unambiguous relationships between ?F/F 0max values and the extent of the degradation of the examined CECs (?C/C0) were established. This allowed correlating main parameters of the ?C/C0 vs. ?F/F 0max relationships with the rates of oxidation of these CECs. The results demonstrate the potential of online measurements of EEM fluorescence for quantitating effects of ozonation on EfOM and micropollutants in wastewater effluents. PMID- 27464661 TI - Discussion on: Dahab AA, Elhag DEA, Ahmed AB, Al-Obaid HA. Determination of elemental toxicity migration limits, bioaccessibility and risk assessment of essential childcare products. Environmental science and pollution research, 2016, 23, 3406-3413. PMID- 27464662 TI - Potential for CSO treatment with horizontal flow constructed wetlands: influence of hydraulic load, plant presence and loading frequency. AB - This study aimed at analysing the performance of horizontal subsurface flow constructed wetlands (CWs) to treat combined sewer overflow (CSO). Four horizontal subsurface flow CWs, organized in two groups (A and B) each with a planted (Phragmites australis) and a non-planted bed, were loaded with simulated CSO, with group B receiving twice the hydraulic load of group A. Beds were monitored for pH, dissolved oxygen, conductivity, redox potential, chemical oxygen demand (COD), total suspended solids (TSS) and enterococci. Porosity variations were also estimated. Monitoring was conducted during spring and wintertime, with regular and irregular loading frequencies. Results showed an average treatment efficiency of 90-100 % for TSS, 60-90 % for COD and 2-6 log for enterococci. Removal rates were especially relevant in the first 24 h for COD and TSS. TSS and enterococci removal did not exhibit the influence of macrophytes or the applied hydraulic load while COD's removal efficiency was lower in the higher load group and in planted beds. PMID- 27464660 TI - Quantification of Hg excretion and distribution in biological samples of mercury dental-amalgam users and its correlation with biological variables. AB - This is the first study conducted to quantify the excretion and distribution of mercury (Hg) with time (days) in the biological samples collected from Hg dental amalgam users (MDA). The individuals, with Hg-based dental filling were selected, and their biological samples (red blood cells (RBCs), plasma, urine, hair, and nails) were collected on first, third, and 12th day of fillings. The concentrations of Hg observed in the biological samples of MDA were also correlated with the biological variables such as age, weight, restoration, fish consumption, number, and surface area of fillings. The concentrations of Hg in the biological samples of MDA were found 6-8 times higher than the non-amalgam users (control). The concentrations of Hg in the RBCs (4.39 MUg/L), plasma (3.02 MUg/L), and urine (22.5 MUg/L) on first day of filling were found comparatively higher than the concentrations observed on third day (2.15, 1.46, and 12.3 MUg/L for RBCs, plasma, urine, respectively) and 12th day (3.05, 2.5, 9.12 MUg/L for RBCs, plasma, urine, respectively), while Hg concentrations were found lower in the hair and nails on third day of fillings (1.53 MUg/g for hair and 2.35 MUg/g for nails) as compared to the 12th day (2.95 MUg/g for hair and 3.5 MUg/g for nails). The correlations were found significant (p ? 0.05) between Hg concentrations in the biological samples of MDA and biological variables (the number of restoration, fish consumption, number, and surface area of fillings), while no significant (p ? 0.05) correlations were observed for Hg concentrations in the biological samples with age and weight of MDA. These observations unveil the fact that the use of Hg-based dental filling is the undesirable exposure to Hg which should be replaced by composite (a safer filling material). PMID- 27464663 TI - The cardioprotective effects of L-carnitine on rat cardiac injury, apoptosis, and oxidative stress caused by amethopterin. AB - Amethopterin is used as a chemotherapeutic agent, and its antioxidant activity is used to treat many cancer types. This study aimed to study the ameliorating effect of L-carnitine against amethopterin-induced cardiac injury and oxidative stress in male rats. Sixty male albino rats were equally divided into six groups; the first and second groups were the control and L-carnitine groups, respectively, while the third group was treated with amethopterin rat group; the fourth and fifth groups were co-treated and post-treated with amethopterin rat with L-carnitine, respectively, and the sixth group was self-treated with amethopterin rat group. Cholesterol, triglycerides, low-density lipoprotein (LDL), glutathione, and total protein levels in amethopterin group showed a significant decrease when compared with control group, while high-density lipoprotein (HDL), glutamic oxaloacetic transaminase (GOT), malondialdehyde (MDA), catalase, and nitric oxide (NO) levels in amethopterin group showed a significant increase when compared with control group. Cholesterol, triglycerides, LDL, GOT, MDA, and catalase levels in the self-treated group showed a significant increase when compared with amethopterin group, while glutathione, total protein, and NO levels in the self-treated group showed significant decrease when compared with amethopterin group. Many of abnormalities as moderate hydrophobic changes of myofibrillar structure with striations, myocardial atrophy, cytoplasmic vacuoles, edema, and leukocyte infiltration were detected in cardiac tissues in amethopterin rat group. A significant increase of the apoptotic protein p53 and CD68 immunoreactivity, despite a significant decrease in the antiapoptotic Bcl-2 proteins after amethopterin injection when compared with control group, was observed. Treatment (co and post) with L carnitine improved the biochemical, histopathological, and immunohistochemical alterations in the heart treated with amethopterin. PMID- 27464664 TI - Qualitative and quantitative studies of chemical composition of sandarac resin by GC-MS. AB - The chemical composition of sandarac resin was investigated qualitatively and quantitatively by gas chromatography-mass spectrometry (GC-MS). Six compounds with labdane and pimarane skeletons were identified in the resin. The obtained mass spectra were interpreted and the mass spectrometric behaviour of these diterpenoids under EI conditions was described. Quantitative analysis by the method of internal standard revealed that identified diterpenoids represent only 10-30% of the analysed sample. The sandarac resin from different suppliers was analysed (from Kremer, Okhra, Color Rare, La Marchande de Couleurs, L'Atelier Montessori, Hevea). The analysis of different lumps of resins showed that the chemical composition differs from one lump to another, varying mainly in the relative distributions of the components. PMID- 27464666 TI - Content of selected elements and low-molecular-weight organic acids in fruiting bodies of edible mushroom Boletus badius (Fr.) Fr. from unpolluted and polluted areas. AB - The aim of the study was to (i) investigate the potential of edible mushroom Boletus badius (Fr.) Fr. to accumulate 53 elements from unpolluted acidic sandy soil and polluted alkaline flotation tailing sites in Poland, (ii) to estimate the low-molecular-weight organic acid (LMWOA) profile and contents in fruit bodies, and finally (iii) to explore the possible relationship between elements and LMWOA content in mushrooms. The content of most elements in fruiting bodies collected from the flotation tailings was significantly higher than in mushrooms from the unpolluted soils. The occurrence of elements determined in fruiting bodies of B. badius has been varied (from 0.01 mg kg-1 for Eu, Lu, and Te up to 18,932 mg kg-1 for K). The results established the high importance of element contents in substrate. Among ten organic acids, nine have been found in wide range: from below 0.01 mg kg-1 for fumaric acid to 14.8 mg g-1 for lactic acid. Lactic and succinic acids were dominant in both areas, and citric acid was also in high content in polluted area. The correlation between element contents and the individual and total content of LMWOAs was confirmed. PMID- 27464665 TI - Effect of substituted hydroxyl groups in the changes of solution turbidity in the oxidation of aromatic contaminants. AB - This paper deals with the changes of turbidity that are generated in aqueous solutions of phenol when they are oxidized by using different Fenton technologies. Results revealed that if the Fenton reaction was promoted with UV light, the turbidity that was generated in the water doubled. Alternatively, the use of ultrasonic waves produced an increase in turbidity which initially proceeded slowly, reaching intensities eight times higher than in the conventional Fenton treatment. As well, the turbidity showed a high dependence on pH. It is therefore essential to control acidity throughout the reaction. The maximum turbidity was generated when operating at pH = 2.0, and it slowly decreased with increasing to a value of pH = 3.0, at which the turbidity was the lowest. This result was a consequence of the presence of ferric ions in solution. At pH values greater than 3.5, the turbidity increased almost linearly until at pH = 5.0 reached its maximum intensity. In this range, ferrous ions may generate an additional contribution of radicals that promote the degradation of the phenol species that produce turbidity. Turbidity was enhanced at ratios R = 4.0 mol H2O2/mol C6H6O. This value corresponds to the stoichiometric ratio that leads to the production of turbidity-precursor species. Therefore, muconic acid would be a species that generate high turbidity in solution according to its isomerism. Also, the results revealed that the turbidity is not a parameter to which species contribute additively since interactions may occur among species that would enhance their individual contributions to it. Analyzing the oxidation of phenol degradation intermediates, the results showed that meta-substituted compounds (resorcinol) generate high turbidity in the wastewater. The presence of polar molecules, such as muconic acid, would provide the structural features that are necessary for resorcinol to act as a clip between two carboxylic groups, thus establishing directional hydrogen bonds that would generate an adduct in the 2:2 ratio. In addition, some similarity is observed between the turbidity and the presence of dihydroxybenzoquinone. This molecule has a structure that could establish hydrogen bond links with the carboxylic groups in 1:2 ratio. Such supramolecular structures would possess high molecular weight and robustness that would hinder the passage of light through the water, generating high turbidity. PMID- 27464667 TI - Effect of ageing on the availability of heavy metals in soils amended with compost and biochar: evaluation of changes in soil and amendment properties. AB - Remediation strategies using soil amendments should consider the time dependence of metal availability to identify amendments that can sustainably reduce available pollutant concentrations over time. Drying-wetting cycles were applied on amendments, soils and soil + amendment mixtures, to mimic ageing at field level and investigate its effect on extractable Cd, Cu, Ni, Pb and Zn concentrations from three contaminated soils. The amendments investigated were municipal waste organic compost and biochars. The amendments, soils and mixtures were characterised by their physicochemical properties at different ageing times. The amendments were also characterised in terms of sorption capacity for Cd and Cu. The sorption capacity and the physicochemical properties of the amendments remained constant over the period examined. When mixed with the soils, amendments, especially the compost, immediately reduced the extractable metals in the soils with low pH and acid neutralisation capacity, due to the increase in pH and buffering capacity of the mixtures. The amendments had a relatively minor impact on the metal availability concentrations for the soil with substantially high acid neutralisation capacity. The most important changes in extractable metal concentrations were observed at the beginning of the experiments, ageing having a minor effect on metal concentrations when compared with the initial effect of amendments. PMID- 27464668 TI - Simultaneous removal of ammonia and hydrogen sulfide gases using biofilter media from the biodehydration stage and curing stage of composting. AB - Biofiltration of NH3 and H2S with different packing media, biodehydration stage compost (BSC), and curing stage compost (CSC) was studied. Meanwhile, fluorescence excitation-emission matrix (EEM) spectroscopy was used to characterize the conversion mechanisms of organic matter during these biofiltration processes. Both biofilters were effective for the simultaneous removal of NH3 and H2S when inlet concentrations of NH3 and H2S were 0-50 and 50 250 mg/m3, respectively. An abrupt increase in the inlet gas concentrations of NH3 and H2S to 100-150 and 200-250 mg/m3, respectively, caused the decrease in the removal efficiencies (REs) of NH3 and H2S in the BSC biofilter, followed by a slow upturn. By contrast, relatively steady REs of both NH3 and H2S were observed in the CSC biofilter. After 60 days of operation, the average REs of NH3 and H2S were more than 95 % in the CSC biofilter. During the operation of CSC, nitrate and nitrite peaked around the 30th day, whereas sulfate showed a steady increase. The excitation-emission matrix fluorescence and parallel factor analysis (EEM PARAFAC) indicated that the simultaneous inlet of NH3 and H2S facilitated the degradation of protein-like substances, whereas humic-like substances played an important role in the packing filters for the treatment of the two odorous pollutants. PMID- 27464669 TI - Insulator speckles associated with long-distance chromatin contacts. AB - Nuclear foci of chromatin binding factors are, in many cases, discussed as sites of long-range chromatin interaction in the three-dimensional nuclear space. Insulator binding proteins have been shown to aggregate into insulator bodies, which are large structures not involved in insulation; however, the more diffusely distributed insulator speckles have not been analysed in this respect. Furthermore, insulator binding proteins have been shown to drive binding sites for Polycomb group proteins into Polycomb bodies. Here we find that insulator speckles, marked by the insulator binding protein dCTCF, and Polycomb bodies show differential association with the insulator protein CP190. They differ in number and three-dimensional location with only 26% of the Polycomb bodies overlapping with CP190. By using fluorescence in situ hybridization (FISH) probes to identify long-range interaction (kissing) of the Hox gene clusters Antennapedia complex (ANT-C) and Bithorax complex (BX-C), we found the frequency of interaction to be very low. However, these rare kissing events were associated with insulator speckles at a significantly shorter distance and an increased speckle number. This suggests that insulator speckles are associated with long-distance interaction. PMID- 27464670 TI - Identification and characterization of Xenopus tropicalis common progenitors of Sertoli and peritubular myoid cell lineages. AB - The origin of somatic cell lineages during testicular development is controversial in mammals. Employing basal amphibian tetrapod Xenopus tropicalis we established a cell culture derived from testes of juvenile male. Expression analysis showed transcription of some pluripotency genes and Sertoli cell, peritubular myoid cell and mesenchymal cell markers. Transcription of germline specific genes was downregulated. Immunocytochemistry revealed that a majority of cells express vimentin and co-express Sox9 and smooth muscle alpha-actin (Sma), indicating the existence of a common progenitor of Sertoli and peritubular myoid cell lineages. Microinjection of transgenic, red fluorescent protein (RFP) positive somatic testicular cells into the peritoneal cavity of X. tropicalis tadpoles resulted in cell deposits in heart, pronephros and intestine, and later in a strong proliferation and formation of cell-to-cell net growing through the tadpole body. Immunohistochemistry analysis of transplanted tadpoles showed a strong expression of vimentin in RFP-positive cells. No co-localization of Sox9 and Sma signals was observed during the first three weeks indicating their dedifferentiation to migratory-active mesenchymal cells recently described in human testicular biopsies. PMID- 27464671 TI - Critical importance of appropriate fixation conditions for faithful imaging of receptor microclusters. AB - Receptor clustering is known to trigger signalling events that contribute to critical changes in cellular functions. Faithful imaging of such clusters by means of fluorescence microscopy relies on the application of adequate cell fixation methods prior to immunolabelling in order to avoid artefactual redistribution by the antibodies themselves. Previous work has highlighted the inadequacy of fixation with paraformaldehyde (PFA) alone for efficient immobilisation of membrane-associated molecules, and the advantages of fixation with PFA in combination with glutaraldehyde (GA). Using fluorescence microscopy, we here highlight how inadequate fixation can lead to the formation of artefactual clustering of receptors in lymphatic endothelial cells, focussing on the transmembrane hyaluronan receptors LYVE-1 and CD44, and the homotypic adhesion molecule CD31, each of which displays their native diffuse surface distribution pattern only when visualised with the right fixation techniques, i.e. PFA/GA in combination. Fluorescence recovery after photobleaching (FRAP) confirms that the artefactual receptor clusters are indeed introduced by residual mobility. In contrast, we observed full immobilisation of membrane proteins in cells that were fixed and then subsequently permeabilised, irrespective of whether the fixative was PFA or PFA/GA in combination. Our study underlines the importance of choosing appropriate sample preparation protocols for preserving authentic receptor organisation in advanced fluorescence microscopy. PMID- 27464672 TI - Polyglycolic acid sheet for closure of esophagobronchial fistula in a patient with Behcet's disease. PMID- 27464673 TI - Independent predictors of physical health in community-dwelling patients with coronary heart disease in Singapore. AB - BACKGROUND: Patients with coronary heart disease (CHD) experienced poor physical health which was found to be associated with higher hospital readmission rates and increased mortality. The study aimed to identify the independent predictors of physical health in Singaporean patients with CHD. METHODS: A consecutive sample of 129 patients with CHD was recruited from the medical heart clinic of a tertiary public hospital in Singapore. A set of questionnaires including the Short Form 12-item health survey version 2, Perceived Stress Scale, Hospital Anxiety and Depression Scale, and Cardiac Self-Efficacy Scale were used to measure the study outcomes. The patients' socio-demographic and clinical data were also collected. RESULTS: A multivariate linear regression analysis indicated that depression (B = -0.766, p < 0.05) and self-efficacy for maintaining function (B = 2.351, p < 0.05) remained significant while the other variables were adjusted and identified as the independent predictors of physical health in Singaporean patients with CHD. CONCLUSIONS: This study has shed some light on the key factors influencing the physical health of Singaporean patients with CHD. The finding suggests tailored interventions that target mitigating a patient's depression and promote self-efficacy for maintaining function may be helpful in improving patients' physical health and quality of life. PMID- 27464674 TI - Cognitive Effects of Adenotonsillectomy for Obstructive Sleep Apnea. AB - OBJECTIVE: Research reveals mixed evidence for the effects of adenotonsillectomy (AT) on cognitive tests in children with obstructive sleep apnea syndrome (OSAS). The primary aim of the study was to investigate effects of AT on cognitive test scores in the randomized Childhood Adenotonsillectomy Trial. METHODS: Children ages 5 to 9 years with OSAS without prolonged oxyhemoglobin desaturation were randomly assigned to watchful waiting with supportive care (n = 227) or early AT (eAT, n = 226). Neuropsychological tests were administered before the intervention and 7 months after the intervention. Mixed model analysis compared the groups on changes in test scores across follow-up, and regression analysis examined associations of these changes in the eAT group with changes in sleep measures. RESULTS: Mean test scores were within the average range for both groups. Scores improved significantly (P < .05) more across follow-up for the eAT group than for the watchful waiting group. These differences were found only on measures of nonverbal reasoning, fine motor skills, and selective attention and had small effects sizes (Cohen's d, 0.20-0.24). As additional evidence for AT related effects on scores, gains in test scores for the eAT group were associated with improvements in sleep measures. CONCLUSIONS: Small and selective effects of AT were observed on cognitive tests in children with OSAS without prolonged desaturation. Relative to evidence from Childhood Adenotonsillectomy Trial for larger effects of surgery on sleep, behavior, and quality of life, AT may have limited benefits in reversing any cognitive effects of OSAS, or these benefits may require more extended follow-up to become manifest. PMID- 27464675 TI - A Quality Improvement Collaborative to Improve the Discharge Process for Hospitalized Children. AB - OBJECTIVE: To assess the impact of a quality improvement collaborative on quality and efficiency of pediatric discharges. METHODS: This was a multicenter quality improvement collaborative including 11 tertiary-care freestanding children's hospitals in the United States, conducted between November 1, 2011 and October 31, 2012. Sites selected interventions from a change package developed by an expert panel. Multiple plan-do-study-act cycles were conducted on patient populations selected by each site. Data on discharge-related care failures, family readiness for discharge, and 72-hour and 30-day readmissions were reported monthly by each site. Surveys of each site were also conducted to evaluate the use of various change strategies. RESULTS: Most sites addressed discharge planning, quality of discharge instructions, and providing postdischarge support by phone. There was a significant decrease in discharge-related care failures, from 34% in the first project quarter to 21% at the end of the collaborative (P < .05). There was also a significant improvement in family perception of readiness for discharge, from 85% of families reporting the highest rating to 91% (P < .05). There was no improvement in unplanned 72-hour (0.7% vs 1.1%, P = .29) and slight worsening of the 30-day readmission rate (4.5% vs 6.3%, P = .05). CONCLUSIONS: Institutions that participated in the collaborative had lower rates of discharge-related care failures and improved family readiness for discharge. There was no significant improvement in unplanned readmissions. More studies are needed to evaluate which interventions are most effective and to assess feasibility in non-children's hospital settings. PMID- 27464677 TI - Rotation measurements of a thermally driven rotary nanomotor with a spring wing. AB - Due to the extremely small dimensions and super high frequency of the rotor in a thermally driven rotary nanomotor made from carbon nanostructures, measuring the rotational frequency of the nanomotor is still an open issue. To this end, a measuring system is constructed in which a spring wing is connected with the rotor to provide collisions with a probe tip whose deflection reflects the rotational frequency of the rotor. The spring wing is formed by connecting an end tube from a carbon nanotube and a graphene with differently hydrogenated surfaces. Due to the alternative hydrogenation of the two surfaces, the graphene shrinks like a spring. When the rotational frequency increases, the centrifugal force applied on the wing increases and then the spring is stretched (becoming longer). As the end-tube rotates with the rotor and reaches the probe tip, a collision occurs between the end-tube and the probe tip. After collision, the probe tip undergoes a variation of vertical deflection that can be measured through atomic force microscopy. The relation between the maximal deflection of the probe tip and the rotational frequency of the rotor is determined via numerical experiments. The effects of the configuration (namely hydrogenation and length) of graphene on the rotation of the rotor are investigated. The results provide some insight into the fabrication of nanomachines. PMID- 27464676 TI - Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders. AB - The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol. PMID- 27464678 TI - Erratum to: 'Lodging Resistance of Japonica Rice (Oryza Sativa L.): Morphological and Anatomical Traits Due to Top-Dressing Nitrogen Application Rates'. PMID- 27464679 TI - Measurement and valuation of health providers' time for the management of childhood pneumonia in rural Malawi: an empirical study. AB - BACKGROUND: Human resources are a major cost driver in childhood pneumonia case management. Introduction of 13-valent pneumococcal conjugate vaccine (PCV-13) in Malawi can lead to savings on staff time and salaries due to reductions in pneumonia cases requiring admission. Reliable estimates of human resource costs are vital for use in economic evaluations of PCV-13 introduction. METHODS: Twenty eight severe and twenty-four very severe pneumonia inpatients under the age of five were tracked from admission to discharge by paediatric ward staff using self administered timesheets at Mchinji District Hospital between June and August 2012. All activities performed and the time spent on each activity were recorded. A monetary value was assigned to the time by allocating a corresponding percentage of the health workers' salary. All costs are reported in 2012 US$. RESULTS: A total of 1,017 entries, grouped according to 22 different activity labels, were recorded during the observation period. On average, 99 min (standard deviation, SD = 46) were spent on each admission: 93 (SD = 38) for severe and 106 (SD = 55) for very severe cases. Approximately 40 % of activities involved monitoring and stabilization, including administering non-drug therapies such as oxygen. A further 35 % of the time was spent on injecting antibiotics. Nurses provided 60 % of the total time spent on pneumonia admissions, clinicians 25 % and support staff 15 %. Human resource costs were approximately US$ 2 per bed-day and, on average, US$ 29.5 per severe pneumonia admission and US$ 37.7 per very severe admission. CONCLUSIONS: Self-reporting was successfully used in this context to generate reliable estimates of human resource time and costs of childhood pneumonia treatment. Assuming vaccine efficacy of 41 % and 90 % coverage, PCV-13 introduction in Malawi can save over US$ 2 million per year in staff costs alone. PMID- 27464680 TI - Impact of cordon-bleu expression on actin cytoskeleton architecture and dynamics. AB - Cordon-bleu (COBL) is a multifunctional WASP-Homology 2 (WH2) domain-containing protein implicated in a wide variety of cellular functions ranging from dendritic arborization in neurons to the assembly of microvilli on the surface of transporting epithelial cells. In vitro biochemical studies suggest that COBL is capable of nucleating and severing actin filaments, among other activities. How the multiple activities of COBL observed in vitro contribute to its function in cells remains unclear. Here, we used live imaging to evaluate the impact of COBL expression on the actin cytoskeleton in cultured cells. We found that COBL induces the formation of dynamic linear actin structures throughout the cytosol. We also found that stabilizing these dynamic structures with the parallel actin bundling protein espin slows down their turnover and enables the robust formation of self-supported protrusions on the dorsal cell surface. Super-resolution imaging revealed a global remodeling of the actin cytoskeleton in cells expressing these two factors. Taken together, these results provide insight as to how COBL contributes to the assembly of actin-based structures such as epithelial microvilli. (c) 2016 Wiley Periodicals, Inc. PMID- 27464681 TI - Exome-based Variant Detection in Core Promoters. AB - Core promoter controls the initiation of transcription. Core promoter sequence change can disrupt transcriptional regulation, lead to impairment of gene expression and ultimately diseases. Therefore, comprehensive characterization of core promoters is essential to understand normal and abnormal gene expression in biomedical studies. Here we report the development of EVDC (Exome-based Variant Detection in Core promoters) method for genome-scale analysis of core-promoter sequence variation. This method is based on the fact that exome sequences contain the sequences not only from coding exons but also from non-coding region including core promoters generated by random fragmentation in exome sequencing process. Using exome data from three cell types of CD4+ T cells, CD19+ B cells and neutrophils of a single individual, we characterized the features of core promoter-mapped exome sequences, and analysed core-promoter variation in this individual genome. We also compared the core promoters between YRI (Yoruba in Ibadan, Nigeria) and the CEU (Utah residents of European decedent) populations using the exome data generated by the 1000 Genome project, and observed much higher variation in YRI population than in CEU population. Our study demonstrates that the EVDC method provides a simple but powerful means for genome-wile de novo characterization of core promoter sequence variation. PMID- 27464682 TI - Predictive model of mortality in patients with spontaneous bacterial peritonitis. AB - BACKGROUND: Hospital mortality in patients with spontaneous bacterial peritonitis (SBP) is high despite albumin treatment, particularly in those with worse liver and/or renal function. AIM: To determine the independent predictive factors of in hospital mortality and to create and validate a predictive model of mortality in patients with SBP. METHODS: We analysed all cirrhotic patients with high-risk SBP (serum urea >=11 mmol/L and/or serum bilirubin >=68 MUmol/L) between 2001 and 2011. We developed a predictive model of in-hospital mortality and validated this in a different cohort. RESULTS: We included 118 high-risk SBP episodes treated with antibiotics and albumin. In-hospital mortality was 33/118 (28%). The independent predictive factors of in-hospital mortality at SBP diagnosis were serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure. A predictive model including these four variables showed a discrimination accuracy (AUC) of 0.850, 95% CI 0.777-0.922. A cut-off point of 0.245 showed a sensitivity of 0.85 and specificity of 0.75. The in-hospital mortality was 28/49 (57.1%) in patients with a model value >=0.245, and 5/69 (7.2%) in patients with a model value <0.245 (P < 0.001). The validation series included 161 patients with an in hospital mortality of 40/161 (24.8%), 30/77 (39.0%) in patients with a model value >=0.245, and 10/84 (11.9%) in those with a model value <0.245 (P < 0.001). CONCLUSIONS: We developed and validated a predictive model of mortality that includes serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure in high-risk patients with spontaneous bacterial peritonitis. These findings may help to identify patients who would benefit from additional therapeutic strategies. PMID- 27464683 TI - Human Respiratory Syncytial Virus: An Introduction. AB - Human respiratory syncytial virus (RSV) is understood to be a significant human pathogen in infants, young children, and the elderly and the immunocompromised. Over the last decade many important mechanisms contributing to RSV infection, replication, and disease pathogenesis have been revealed; however, there is still insufficient knowledge which has in part hampered vaccine development. Considerable information is accumulating regarding how RSV proteins modulate molecular signaling and immune responses to infection. Understanding how RSV interacts with its host is crucial to facilitate the development of safe and effective vaccines and therapeutic treatments.In this chapter, we provide a brief introduction into RSV replication, pathogenesis, and host immune response, and summarize the state of RSV vaccine and antiviral compounds in clinical stages of development. This chapter frames features of this book and the molecular methods used for understanding RSV interaction with the host. PMID- 27464684 TI - RSV Growth and Quantification by Microtitration and qRT-PCR Assays. AB - Defective interfering viral particles have been reported as important determinants of the course of viral infection, and they can markedly temper the virulence of the infection. Here, we describe a simple method, based on limiting dilution, for the removal of defective interfering particles from RSV. This method results in a high-titer viral preparation from both HEp-2 and Vero cell lines. We evaluated two concentrations of sucrose to stabilize the virus preparation, and demonstrate that RSV is stable when prepared and stored in 25 % sucrose at -152 degrees C. In addition, this chapter describes some commonly used methods of RSV titration, detection using microtitration and quantitative real-time RT-PCR, and the use of immunostaining for antigenic characterization. PMID- 27464685 TI - Quantification of RSV Infectious Particles by Plaque Assay and Immunostaining Assay. AB - One of the most commonly used approaches for determining the quantity of infectious RSV particles in a given sample is the plaque assay. RSV infectious particles can be quantified by various direct and indirect methods. Here, we explain two simple methods for RSV titration: plaque assay and immunostaining assay. PMID- 27464686 TI - Detection of RSV Antibodies in Human Plasma by Enzyme Immunoassays. AB - Enzyme immunoassays (EIAs) to detect and quantify antibodies against respiratory syncytial virus (RSV) and RSV proteins in human plasma or sera are described. The first EIA uses RSV lysate antigens produced in HEp-2 cell line. The second EIA uses RSV F or G gene-expressed antigen in HEp-2 cells. The third EIA uses 30 amino acid synthetic peptides from central conserved region of G protein of RSV A2 or RSV B1 virus and a peptide from the SARS CoV nucleoprotein as a negative control peptide. All three EIAs have been evaluated for detecting and quantifying the respective antibodies in human sera or plasma. PMID- 27464687 TI - Secretory Expression and Purification of Respiratory Syncytial Virus G and F Proteins in Human Cells. AB - Respiratory syncytial virus (RSV) is one of the leading causes of range of symptoms from mild upper to serious lower respiratory virus infections in infants, immunocompromised individuals, and the elderly. Despite many decades of research and development, a licensed RSV vaccine is not available for use in human. Since the RSV F and G proteins induce neutralizing antibodies and confer protection from infection, they are important for understanding disease and for developing vaccines and access to purified, expressed proteins is important to RSV research and diagnostics. We describe methods to produce recombinant RSV F and G proteins in human cells and purify these proteins using Ni Sepharose affinity chromatography. PMID- 27464688 TI - Development of Human Monoclonal Antibodies Against Respiratory Syncytial Virus Using a High Efficiency Human Hybridoma Technique. AB - Human monoclonal antibodies against RSV have high potential for use as prophylaxis or therapeutic molecules, and they also can be used to define the structure of protective epitopes for rational vaccine design. In the past, however, isolation of human monoclonal antibodies was difficult and inefficient. Here, we describe contemporary methods for activation and proliferation of primary human memory B cells followed by cytofusion to non-secreting myeloma cells by dielectrophoresis to generate human hybridomas secreting RSV-specific monoclonal antibodies. We also provide experimental methods for screening human B cell lines to obtain RSV-specific lines, especially lines secreting neutralizing antibodies. PMID- 27464689 TI - Respiratory Syncytial Virus (RSV): Neutralizing Antibody, a Correlate of Immune Protection. AB - Assays that measure RSV-specific neutralizing antibody activity are very useful for evaluating vaccine candidates, performing seroprevalence studies, and detecting infection. Neutralizing antibody activity is normally measured by a plaque reduction neutralization assay or by a microneutralization assay with or without complement. These assays measure the functional capacity of serum (or other fluids) to neutralize virus infectivity in cells as compared to ELISA assays that only measure the binding capacity against an antigen. This chapter discusses important elements in standardization of the RSV-specific microneutralization assay for use in the laboratory. PMID- 27464690 TI - Host Factors Modulating RSV Infection: Use of Small Interfering RNAs to Probe Functional Importance. AB - Although respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and the elderly worldwide [1], the protein-protein interactions between the host cell and virus remain poorly understood. We have used a focused small interfering RNA (siRNA) approach to knock-down and examine the role(s) of various host cell proteins. Here, we describe approaches for casein kinase 2alpha (CK2alpha) as a key example. We show how to study the effect of host gene (CK2alpha) knockdown using siRNA on cell-associated and released virus titers, using both quantitative RT-PCR, which measures the level of viral RNA, and plaque assay, which measures infectious virus directly. Both assays identified reduced viral titers with CK2alpha gene knock-down, indicating that it is likely required for efficient viral assembly and/or release. Effects were confirmed in RSV infected cells using the specific CK2alpha inhibitor 4,5,6,7 tetrabromobenzotriazole, revealing a similar reduction in viral titers as CK2alpha specific siRNA. This demonstrates that siRNA can be used to characterize critical host cell-RSV protein-protein interactions, and establishes CK2alpha as a future druggable target. PMID- 27464692 TI - Reverse Genetics of Respiratory Syncytial Virus. AB - Respiratory syncytial virus (RSV) is a negative-strand RNA virus that is associated with severe lower respiratory tract infections in young infants and the elderly. RSV remains a leading cause worldwide of infant mortality, and despite the high clinical and economic burden of the virus there are currently no available vaccines. Here, we describe the methods for recovery of recombinant RSV viruses using a bacterial artificial chromosome and methods related to procurement and expansion of stocks of RSV mutants. PMID- 27464691 TI - In Vitro Modeling of RSV Infection and Cytopathogenesis in Well-Differentiated Human Primary Airway Epithelial Cells (WD-PAECs). AB - The choice of model used to study human respiratory syncytial virus (RSV) infection is extremely important. RSV is a human pathogen that is exquisitely adapted to infection of human hosts. Rodent models, such as mice and cotton rats, are semi-permissive to RSV infection and do not faithfully reproduce hallmarks of RSV disease in humans. Furthermore, immortalized airway-derived cell lines, such as HEp-2, BEAS-2B, and A549 cells, are poorly representative of the complexity of the respiratory epithelium. The development of a well-differentiated primary pediatric airway epithelial cell models (WD-PAECs) allows us to simulate several hallmarks of RSV infection of infant airways. They therefore represent important additions to RSV pathogenesis modeling in human-relevant tissues. The following protocols describe how to culture and differentiate both bronchial and nasal primary pediatric airway epithelial cells and how to use these cultures to study RSV cytopathogenesis. PMID- 27464693 TI - Use of Minigenome Systems to Study RSV Transcription. AB - Minigenome assays have been essential tools in the understanding of viral transcription and RNA replication for respiratory syncytial virus (RSV). Here, we describe the RSV minigenome assay for determining transcription by the viral polymerase in the absence of infection. We detail two different methods of detecting viral RNA synthesis: a firefly luciferase assay for rapid and sensitive measurement of RSV polymerase activity; and a real-time quantitative PCR method for determination of specific effects on the transcription of individual viral genes and the polar transcription gradient of RSV. PMID- 27464694 TI - Screening for Host Factors Directly Interacting with RSV Protein: Microfluidics. AB - We present a high-throughput microfluidics platform to identify novel host cell binding partners of respiratory syncytial virus (RSV) matrix (M) protein. The device consists of thousands of reaction chambers controlled by micro-mechanical valves. The microfluidic device is mated to a microarray-printed custom-made gene library. These genes are then transcribed and translated on-chip, resulting in a protein array ready for binding to RSV M protein.Even small viral proteome, such as that of RSV, presents a challenge due to the fact that viral proteins are usually multifunctional and thus their interaction with the host is complex. Protein microarrays technology allows the interrogation of protein-protein interactions, which could possibly overcome obstacles by using conventional high throughput methods. Using microfluidics platform we have identified new host interactors of M involved in various cellular pathways. A number of microfluidics based assays have already provided novel insights into the virus-host interactome, and the results have important implications for future antiviral strategies aimed at targets of viral protein interactions with the host. PMID- 27464695 TI - A Proteomic-Based Workflow Using Purified Respiratory Syncytial Virus Particles to Identify Cellular Factors as Drug Targets. AB - The identification of cellular factors that play a role in respiratory syncytial virus (RSV) replication is an alternative strategy in the identification of druggable cellular protein that are essential for RSV replication. In this regard experimental strategies that are able to screen relevant proteins from the vast array of proteins in the cellular milieu will facilitate the identification of potential drug targets. In this chapter we describe a procedure where RSV particles are purified from cells that are permissive for RSV infection, and the protein composition of the purified virus particles characterized using a proteomics-based strategy. This procedure revealed that actin, several actin binding proteins, and the chaperones HSP70 and HSP90 also co-purified with the virus particles. The relevance of the HSP90 protein to virus replication was then further validated using imaging, gene silencing and by using an established small molecule HSP90 inhibitor. PMID- 27464696 TI - MicroRNA Profiling from RSV-Infected Biofluids, Whole Blood, and Tissue Samples. AB - Several studies have shown that respiratory syncytial virus (RSV) can modulate the host innate immune response by dysregulation of host microRNAs (miRNAs) related to the antiviral response, a feature that also affects the memory immune response to RSV (Thornburg et al. MBio 3(6), 2012). miRNAs are small, endogenous, noncoding RNAs that function in posttranscriptional gene regulation. Here, we explain a compilation of methods for the purification, quantification, and characterization of miRNA expression profiles in biofluids, whole blood samples, and tissue samples obtained from in vivo studies. In addition, this chapter describes methods for the isolation of exosomal miRNA populations. Understanding alterations in miRNA expression profiles and identifying miRNA targets genes, and their contribution to the pathogenesis of RSV, may help elucidate novel mechanism of host-virus interaction (Rossi et al., Pediatr Pulmonol, 2015). PMID- 27464697 TI - Mouse and Cotton Rat Models of Human Respiratory Syncytial Virus. AB - Human respiratory syncytial virus (hRSV) is a common respiratory virus that is usually no cause for alarm. Symptoms of hRSV usually resemble those of the common cold and can go undiagnosed. However, infants as well as the elderly are at risk for developing severe cases, which can lead to high morbidity and mortality rates especially if there are underlying health issues. Despite many years of effort, no vaccine or specific treatments exist and RSV is still the leading cause of infant hospitalizations worldwide. Here, we describe methods to infect two widely used small animal models: laboratory mice and cotton rats. PMID- 27464698 TI - In Vivo Assessment of Airway Function in the Mouse Model. AB - This chapter describes two procedures commonly used to examine airway function in mice. Airway function can be assessed in vivo using noninvasive or invasive methods. Noninvasive methods can be used to monitor respiratory function in mice without the involvement of restraint, anesthesia, or surgery. The methods allow for multiple animals to be monitored simultaneously and can be used in longitudinal studies requiring repeated measurements on the same animals. Invasive methods are used to assess airway function under anesthesia, in mechanically ventilated mice. Although used as terminal procedure, the invasive methods are most appropriate for direct assessment of lower airway dysfunction. PMID- 27464699 TI - Evaluation of the Adaptive Immune Response to Respiratory Syncytial Virus. AB - Evaluation of the adaptive immune response is critical to the advancement of our basic knowledge and understanding of respiratory syncytial virus (RSV). The cellular composition in the lung following RSV infection is often evaluated using flow cytometry. However, a limitation of this approach has been the inability to readily distinguish cells that are within the lung parenchyma from cells that remain in the pulmonary blood vessels. Herein, we detail a procedure to evaluate the adaptive immune response via flow cytometric analysis that incorporates an in vivo intravascular staining technique. This technique allows for discrimination of immune cells in the lung tissue from cells that remain in the pulmonary vasculature following perfusion. Therefore at any given time point following an RSV infection, the leukocytic populations in the lung parenchyma can be quantified and phenotypically assessed with high resolution. While we focus on the T lymphocyte response in the lung, this technique can be readily adapted to examine various leukocytic cell types in the lung following RSV infection. PMID- 27464700 TI - Expression of Transient Receptor Potential Channels in the Purified Human Pancreatic beta-Cells. AB - OBJECTIVE: Members of the transient receptor potential (TRP) channels are involved in mediating the electrical excitability and stimulus-secretion coupling in the pancreatic beta-cells. The expression and the relative abundance of different TRP channels in the human beta-cells are unknown. The objective of this study was to examine the expression of the TRP channels and their relative abundance in the human beta-cell. METHODS: RNA sequencing data obtained from human islets, fluorescence-activated cell sorting-purified human beta-cell and human pancreatic acinar cells were analyzed. Gene counts and fragments per kilobase per million mapped reads were obtained. RESULTS: Among the TRPC family only the TRPC1 was expressed in the human beta-cell. TRPV1 channels were not expressed in the human beta-cells. Among the TRPM family, TRPM4, TRPM7, TRPM2, and TRPM3 were expressed in the human beta-cell. Of the remaining TRP channels, TRPP2, TRPML1, and TRPML3 were expressed in these cells. CONCLUSIONS: By analyzing the RNA sequencing data, we have detected for the first time the TRP channels that are expressed in the purified human beta-cells, in comparison to the other relevant pancreatic cell types. Our study provides an opportunity to focus on these TRP channels for a better understanding of the electrophysiology and stimulus-secretion coupling in these cells. PMID- 27464702 TI - C-terminal domain of p42 Ebp1 is essential for down regulation of p85 subunit of PI3K, inhibiting tumor growth. AB - Potential tumor suppressor p42, ErbB3-binding protein 1 (EBP1) inhibits phosphoinositide 3-kinase (PI3K) activity reducing the p85 regulatory subunit. In this study, we demonstrated that overexpression of p42 promoted not only a reduction of wild type of p85 subunit but also oncogenic mutant forms of p85 which were identified in human cancers. Moreover, we identified the small fragment of C-terminal domain of p42 is sufficient to exhibit tumor suppressing activity of p42-WT, revealing that this small fragment (280-394) of p42 is required for the binding of both HSP70 and CHIP for a degradation of p85. Furthermore, we showed the small fragment of p42 markedly inhibited the tumor growth in mouse xenograft models of brain and breast cancer, resembling tumor suppressing activity of p42. Through identification of the smallest fragment of p42 that is responsible for its tumor suppressor activity, our findings represent a novel approach for targeted therapy of cancers that overexpress PI3K. PMID- 27464703 TI - MR1 discovery. AB - The moment of MR1 discovery is described. The MR1 gene is the first and the last reported human MHC-related gene intentionally isolated from the human genome composed of three billion base pairs. Evolutionary considerations formed the basis of its isolation. Some details surrounding the moment and some retrospective descriptions with various kinds of encounters are also included. PMID- 27464701 TI - Epigenetic roles in the malignant transformation of gastric mucosal cells. AB - Gastric carcinogenesis occurs when gastric epithelial cells transition through the initial, immortal, premalignant, and malignant stages of transformation. Epigenetic regulations contribute to this multistep process. Due to the critical role of epigenetic modifications , these changes are highly likely to be of clinical use in the future as new biomarkers and therapeutic targets for the early detection and treatment of cancers. Here, we summarize the recent findings on how epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, regulate gastric carcinogenesis, and we discuss potential new strategies for the diagnosis and treatments of gastric cancer. The strategies may be helpful in the further understanding of epigenetic regulation in human diseases. PMID- 27464705 TI - Handling the Media: Communication and Presentation Skills for Healthcare Professionals. PMID- 27464704 TI - Boiling Method-Based Zinc Oxide Nanorods for Enhancement of Adipose-Derived Stem Cell Proliferation. AB - Adipose-derived stem cells (ASCs) are typically expanded to acquire large numbers of cells for therapeutic applications. Diverse stimuli such as sphingosylphosphocholine and vitamin C have been used to increase the production yield and regenerative potential of ASCs. In the present study, we hypothesized that ZnO nanorods have promising potential for the enhancement of ASC proliferation. ZnO nanorods were prepared using three different methods: grinding and boiling at low temperature with and without surfactant. The physicochemical properties of the nanorods such as their crystallinity, morphology, size, and solvent compatibility were evaluated, and then, the ability of the synthesized ZnO nanorods to enhance ASC proliferation was investigated. Scanning electron microscopy images of all of the ZnO powders showed rod-shaped nanoflakes with lengths of 200-500 nm. Notably, although ZnO-G produced by the grinding method was well dispersed in ethanol, atomic force microscopy images of dispersions of both ZnO-B from boiling methods and ZnO-G indicated the presence of clusters of ZnO nanorods. In contrast, ZnO-B was freely dispersible in 5% dextrose of water and dimethyl sulfoxide, whereas ZnO-G and ZnO-M, produced by boiling with ethanolamine, were not. All three types of ZnO nanorods increased the proliferation of ASCs in a dose-dependent manner. These results collectively suggest that ZnO nanorods have promising potential for use as an agent for the enhancement of ASC proliferation. PMID- 27464706 TI - Proton pump inhibitor-responsive oesophageal eosinophilia: too early to change clinical practice. PMID- 27464707 TI - Epithelial NEMO/IKKgamma limits fibrosis and promotes regeneration during pancreatitis. AB - OBJECTIVE: Inhibitory kappaB kinase (IKK)/nuclear factor kappaB (NF-kappaB) signalling has been implicated in the pathogenesis of pancreatitis, but its precise function has remained controversial. Here, we analyse the contribution of IKK/NF-kappaB signalling in epithelial cells to the pathogenesis of pancreatitis by targeting the IKK subunit NF-kappaB essential modulator (NEMO) (IKKgamma), which is essential for canonical NF-kappaB activation. DESIGN: Mice with a targeted deletion of NEMO in the pancreas were subjected to caerulein pancreatitis. Pancreata were examined at several time points and analysed for inflammation, fibrosis, cell death, cell proliferation, as well as cellular differentiation. Human samples were used to corroborate findings established in mice. RESULTS: In acute pancreatitis, NEMO deletion in the pancreatic parenchyma resulted in minor changes during the early phase but led to the persistence of inflammatory and fibrotic foci in the recovery phase. In chronic pancreatitis, NEMO deletion aggravated inflammation and fibrosis, inhibited compensatory acinar cell proliferation, and enhanced acinar atrophy and acinar-ductal metaplasia. Gene expression analysis revealed sustained activation of profibrogenic genes and the CXCL12/CXCR4 axis in the absence of epithelial NEMO. In human chronic pancreatitis samples, the CXCL12/CXCR4 axis was activated as well, with CXCR4 expression correlating with the degree of fibrosis. The aggravating effects of NEMO deletion were attenuated by the administration of the CXCR4 antagonist AMD3100. CONCLUSIONS: Our results suggest that NEMO in epithelial cells exerts a protective effect during pancreatitis by limiting inflammation and fibrosis and improving acinar cell regeneration. The CXCL12/CXCR4 axis is an important mediator of that effect and may also be of importance in human chronic pancreatitis. PMID- 27464708 TI - Deep mural injury and perforation after colonic endoscopic mucosal resection: a new classification and analysis of risk factors. AB - OBJECTIVES: Perforation is the most serious complication associated with endoscopic mucosal resection (EMR). We propose a new classification for the appearance and integrity of the muscularis propria (MP) after EMR including various extents of deep mural injury (DMI). Risk factors for these injuries were analysed. DESIGN: Endoscopic images and histological specimens of consecutive patients undergoing EMR of colonic laterally spreading lesions >=20 mm at a large Australian tertiary referral endoscopy unit were retrospectively analysed using our new DMI classification system. DMI was graded according to MP injury (I/II intact MP without/with fibrosis, III target sign, IV/V obvious transmural perforation without/with contamination). Histological specimens were examined for included MP and patient outcomes were recorded. All type III-V DMI signs were clipped if possible, types I and II DMI were clipped at the endoscopists' discretion. RESULTS: EMR was performed in 911 lesions (mean size 37 mm) in 802 patients (male sex 51.4%, mean age 67 years). DMI signs were identified in 83 patients (10.3%). Type III-V DMI was identified in 24 patients (3.0%); clipping was successfully performed in all patients. A clinically significant perforation occurred in two patients (0.2%). Only one of the 59 type I/II cases experienced a delayed perforation. 85.5% of patients with DMI were discharged on the same day, all without sequelae. On multivariable analysis, type III-V DMI was associated with transverse colon location (OR 3.55, p=0.028), en bloc resection (OR 3.84, p=0.005) and high-grade dysplasia or submucosal invasive cancer (OR 2.97, p 0.014). CONCLUSIONS: In this retrospective analysis, use of the new classification and management with clips appeared to be a safe approach. Advanced DMI types (III-V) occurred in 3.0% of patients and were associated with identifiable risk factors. Further prospective clinical studies should use this new classification. TRIAL REGISTRATION NUMBER: NCT01368289; results. PMID- 27464709 TI - Brexit from current guideline recommendations? PMID- 27464712 TI - Relative bioavailability of coenzyme Q10 formulation for paediatric individualized therapy. AB - OBJECTIVES: Conduct a preliminary comparison of the bioavailability between two formulations: commercial grade coenzyme Q10 (CoQ10) powder (solid formulation) and a new oil-in-water liquid emulsion and their effect on other antioxidants. METHODS: Six healthy individuals participated in a randomized, crossover, open, consecutive design, with a 2-week washout period. Pharmacokinetic parameters were assessed after a single and multiple intakes of 250 mg CoQ10 given daily for 1 week. KEY FINDINGS: The differences in the pharmacokinetic parameters of maximum plasma concentration, area under the curve between 0-360 and 0-4 h, elimination half-life were statistically significant with a relative bioavailability of 489% increase over solid CoQ10 formulation. A multiple dose supplementation increased plasma CoQ10 levels in both formulations, liquid emulsion performing better (2.4- vs 3.9-fold for solid and liquid formulation, respectively) without modifications on other antioxidants. Furthermore, the plasma CoQ10 at 7th day was statistically different between formulations (P < 0.05). CONCLUSIONS: The results obtained showed that liquid emulsion improves the bioavailability of CoQ10 respect to solid form which not only facilitates the individualized administration for the child but in turn could increase the therapeutic efficacy, which should be confirmed by further studies. PMID- 27464713 TI - Effect of final irrigation procedures on fracture resistance of root filled teeth: an ex vivo study. AB - AIM: To evaluate the effect of chlorhexidine (CHX) on fracture resistance of roots treated with different concentrations of ethylenediaminetetraacetic acid (EDTA). METHODOLOGY: One hundred and twenty intact single-rooted premolar teeth were sectioned below the cementum-enamel junction to standardize the length of the teeth to 12 mm. The canals of one hundred specimens were instrumented with ProTaper Universal rotary instruments up to size F4 and were randomly divided into five groups (n = 20) according to the final irrigating solutions: Group 1: distilled water (DW); Group 2: 5% EDTA and 2.5% NaOCl; Group 3: 17% EDTA and 2.5% NaOCl; Group 4: 5% EDTA, 2.5% NaOCl, DW and 2% CHX; Group 5: 17% EDTA and 2.5% NaOCl, DW and 2% CHX. Root canals were filled with gutta-percha and epoxy resin based root canal sealer using a single-cone technique. Twenty teeth served as negative controls and were not instrumented nor root filled (Group 6). All specimens were embedded in self-curing acrylic resin and loaded vertically at 0.5 mm min-1 until fracture occurred. The data were evaluated statistically using one way anova test followed by Holm-Sidak's multiple comparison test (P < 0.05). RESULTS: Group 1 (only DW) had the lowest vertical fracture strength, followed by Group 3 (17% EDTA and 2.5% NaOCl; P < 0.05). Group 6 (negative control group) had the highest fracture resistance. Final irrigation with CHX following irrigation with 17% EDTA or 5% EDTA and 2.5% NaOCl (groups 4 and 5) significantly increased the fracture resistance of roots (P < 0.05). However, the difference between Group 4 and Group 5 was not significant (P > 0.05). CONCLUSIONS: Intracanal CHX rinse of EDTA/NaOCl-treated root dentine enhanced the fracture resistance of roots filled with AH Plus. PMID- 27464711 TI - Evaluating the implementation of a national clinical programme for diabetes to standardise and improve services: a realist evaluation protocol. AB - BACKGROUND: Over the last three decades in response to the growing burden of diabetes, countries worldwide have developed national and regional multifaceted programmes to improve the monitoring and management of diabetes and to enhance the coordination of care within and across settings. In Ireland in 2010, against a backdrop of limited dedicated strategic planning and engrained variation in the type and level of diabetes care, a national programme was established to standardise and improve care for people with diabetes in Ireland, known as the National Diabetes Programme (NDP). The NDP comprises a range of organisational and service delivery changes to support evidence-based practices and policies. This realist evaluation protocol sets out the approach that will be used to identify and explain which aspects of the programme are working, for whom and in what circumstances to produce the outcomes intended. METHODS/DESIGN: This mixed method realist evaluation will develop theories about the relationship between the context, mechanisms and outcomes of the diabetes programme. In stage 1, to identify the official programme theories, documentary analysis and qualitative interviews were conducted with national stakeholders involved in the design, development and management of the programme. In stage 2, as part of a multiple case study design with one case per administrative region in the health system, qualitative interviews are being conducted with frontline staff and service users to explore their responses to, and reasoning about, the programme's resources (mechanisms). Finally, administrative data will be used to examine intermediate implementation outcomes such as service uptake, acceptability, and fidelity to models of care. DISCUSSION: This evaluation is using the principles of realist evaluation to examine the implementation of a national programme to standardise and improve services for people with diabetes in Ireland. The concurrence of implementation and evaluation has enabled us to produce formative feedback for the NDP while also supporting the refinement and revision of initial theories about how the programme is being implemented in the dynamic and unstable context of the Irish healthcare system. PMID- 27464710 TI - Eating soup with nails of pig: thematic synthesis of the qualitative literature on cultural practices and beliefs influencing perinatal nutrition in low and middle income countries. AB - BACKGROUND: The perinatal period, i.e. pregnancy, childbirth and early infancy, is a significant transition period where the biological and the social strongly intersect. In low and middle-income countries the disease burden arising from the perinatal period, is still substantial. The perinatal period is also a crucial window of opportunity for reducing undernutrition and its long term adverse effects. METHODS: We explored qualitative research conducted in low resource settings around the perinatal continuum over the past two decades, with a particular focus on the 'cultural' realm, to identify common themes influencing maternal and infant nutrition. We systematically searched electronic databases from 1990 to 2014, including MEDLINE, EMBASE, PsycINFO, Scopus and Cumulative Index to Nursing and Allied Health Literature, using relevant search terms including traditional beliefs, practices, pregnancy, childbirth, developing countries etc. Adapted Consolidated Criteria for Reporting Qualitative Health Research and Critical Appraisal Skills Programme criteria were used to determine quality of studies. We synthesised the literature thematically, enabled by NVivo 10 software. RESULTS: Most studies showed cultural support for breastfeeding, although most traditional societies delayed breastfeeding due to colostrum being considered 'dirty'. A range of restrictive practices through pregnancy and the post- partum period were revealed in Asia, Latin America and Africa. There was a strong cultural understanding of the healing power of everyday foods. A wide range of good foods and bad foods continued to have currency through the perinatal continuum, with little consensus between groups of what was beneficial versus harmful. Cross-cutting themes that emerged were 1) the role of the woman/mother/wife as strong and good; 2) poverty restricting women's nutrition choices; 3) change being constant, but the direction of change unpredictable. CONCLUSIONS: A rich and diverse repertoire of cultural practices and beliefs influenced perinatal nutrition. Results from this synthesis should influence public health policymakers and practitioners, to tailor contextually specific, culturally responsive perinatal nutrition interventions to optimise health and wellbeing of mother-infant dyads. Ideally these interventions should build on culturally sanctioned life affirming behaviours such as breastfeeding, promoting post-partum rest and recovery, while modifying the potentially harmful aspects of other cultural practices in the perinatal period. PMID- 27464715 TI - Sagittal lumbo-pelvic alignment in the sitting position of elderly persons. AB - INTRODUCTION: In elderly persons, the sitting position in daily life is very important due to the weakness in locomotion. In previous studies, sagittal spinal alignment was mainly analyzed in the standing position. However, in order to study the sagittal spinal alignment of elderly persons, the estimation of spinal alignment in the sitting posture is also important. We proposed that there is a characteristic spinal alignment in elderly persons in the sitting position. The purpose of this study was to evaluate the sagittal lumbo-pelvic alignment in the standing and sitting positions in elderly persons. SUBJECTS & METHODS: This study included 73 young adult subjects (48 men and 25 women; age 34.4 +/- 8.1 years) and 107 elderly subjects (65 men and 42 women; age 67.6 +/- 8.3 years). The following radiographic parameters were determined by computer-assisted measurement: L1L5 angle (L1L5), lumbosacral angle (LSA), sacral slope (SS), pelvic tilt (PT), and pelvic incidence (PI). RESULTS: L1L5 decreased and the pelvis rotated posteriorly in the sitting position in both young adults and elderly persons. However, the extent of alignment difference between standing and sitting in elderly persons was nearly half that of young adults (in particular, the lumbo-pelvic junction, LSA, was smaller). Regarding the extent of correlation between aging and lumbo-pelvic alignment parameters, there were significant correlations. In elderly persons, the correlation between L1L5 and PT had a tendency to be poor in the sitting position. CONCLUSION: The elderly in the sitting position showed greater lumbar lordosis and higher sacral slope than in young adults, and the correlations among lumbo-pelvic parameters were poorer than those of young adults. Thus, when moving from sitting to standing, the lumbo pelvic mobility in the sagittal plane is suspected to be poor in elderly persons. PMID- 27464714 TI - Discovery of midgut genes for the RNA interference control of corn rootworm. AB - RNA interference (RNAi) is a promising new technology for corn rootworm control. This paper presents the discovery of new gene targets - dvssj1 and dvssj2, in western corn rootworm (WCR). Dvssj1 and dvssj2 are orthologs of the Drosophila genes snakeskin (ssk) and mesh, respectively. These genes encode membrane proteins associated with smooth septate junctions (SSJ) which are required for intestinal barrier function. Based on bioinformatics analysis, dvssj1 appears to be an arthropod-specific gene. Diet based insect feeding assays using double stranded RNA (dsRNA) targeting dvssj1 and dvssj2 demonstrate targeted mRNA suppression, larval growth inhibition, and mortality. In RNAi treated WCR, injury to the midgut was manifested by "blebbing" of the midgut epithelium into the gut lumen. Ultrastructural examination of midgut epithelial cells revealed apoptosis and regenerative activities. Transgenic plants expressing dsRNA targeting dvssj1 show insecticidal activity and significant plant protection from WCR damage. The data indicate that dvssj1 and dvssj2 are effective gene targets for the control of WCR using RNAi technology, by apparent suppression of production of their respective smooth septate junction membrane proteins located within the intestinal lining, leading to growth inhibition and mortality. PMID- 27464716 TI - Pharmaceutical Targeting of the Brain. AB - Besides being indispensable for the protection and nutrition of the central nervous system (CNS), blood-brain barrier (BBB)-forming cerebral endothelial cells (CECs) have a major role in hampering drugs to reach therapeutically relevant concentrations in the brain. In this respect, the most important defense systems of CECs are tight junctions (TJs) sealing the paracellular way of transport, efflux pumps (ABC transporters) and metabolic enzymes. Here we review current strategies aiming at overcoming the BBB with the purpose of effectively delivering drugs to the CNS. Besides chemical modification of drug candidates to improve CNS availability, the main strategies include: bypassing the BBB (intracranial or nasal routes), reversible opening of TJs (using hyperosmotic mannitol, ultrasounds, peptides and other physical methods or chemical agents), vector-mediated drug delivery systems (nanocarriers, exploitation of receptor- and carrier-mediated transport) and inhibition of efflux transporters. We discuss the main advantages, disadvantages and clinical relevance of each strategy. Special emphasis will be given to the description of the chemical characteristics of nanoparticles (lipidic, polymeric, inorganic, etc.) and the main strategies of targeting them to the CNS. PMID- 27464717 TI - Plant-Derived Biomolecules and Drug Delivery Systems in the Treatment of Liver and Kidney Diseases. AB - Chronic liver and kidney diseases are among the most fearful pathologies affecting an increasing number of people, having severe consequences on life quality. Although much progress has been made in recent years, availability of cost-effective and innovative therapies is still an unmet medical need. One of the major challenges in the therapy of liver and kidney diseases is to selectively deliver drugs to achieve therapeutically relevant concentration in the target organ, in order to decrease the amount of drug needed and to reduce unwanted side effects. In this review we summarize recent advances in selective drug targeting to liver or to kidney including cell-selective therapeutic approaches as well. We pay special attention to plant-derived bioactive molecules which constitute promising tools for the treatment of chronic liver and kidney diseases. We discuss cellular, subcellular and molecular mechanisms underlying the observed pharmacological effects of plant-derived drugs and give an overview of formulations, which can increase therapeutic effectiveness of these biomolecules in the treatment of chronic liver and kidney disorders. PMID- 27464718 TI - Pharmacological Targeting of the Inflamed Intestinal Barrier. AB - The intestinal epithelium serves as an important barrier between luminal contents and underlying tissue compartments. Barrier properties are established and maintained by the multiprotein complexes in the tight junction (TJ), adherens junction (AJ) and desmosomes (DM). Compromised intestinal epithelial barrier function resulting from changes in junctional protein expression and organization is associated with exposure to luminal antigens that result in mucosal inflammation, which in turn further exacerbates the epithelial barrier compromise. In this review we discuss regulatory mechanisms by which intercellular junction proteins are influenced by inflammatory mediators to influence intestinal epithelial barrier function and address potential therapeutic strategies to strengthen the barrier and restore mucosal homeostasis. PMID- 27464719 TI - Targeted Vascular Drug Delivery in Cerebral Cancer. AB - This review presents the present-day literature on the anatomy and physiological mechanisms of the blood-brain barrier and the problematic of cerebral drug delivery in relation to malignant brain tumors. First step in treatment of malignant brain tumors is resection, but there is a high risk of single remnant infiltrative tumor cells in the outer zone of the brain tumor. These infiltrative single-cells will be supplied by capillaries with an intact BBB as opposed to the partly leaky BBB found in the tumor tissue before resection. Even though BBB penetrance of a chemotherapeutic agent is considered irrelevant though the limited success rate for chemotherapeutic treatability of GBM tumors indicate otherwise. Therefore drug delivery strategies to cerebral cancer after resection should be tailored to being able to both penetrate the intact BBB and target the cancer cells. In this review the intact bloodbrain barrier and cerebral cancer with main focus on glioblastoma multiforme (GBM) is introduced. The GBM induced formation of a blood-tumor barrier and the consequences hereof is described and discussed with emphasis on the impact these changes of the BBB has on drug delivery to GBM. The most commonly used drug carriers for drug delivery to GBM is described and the current drug delivery strategies for glioblastoma multiforme including possible routes through the BBB and epitopes, which can be targeted on the GBM cells is outlined. Overall, this review aims to address targeted drug delivery in GBM treatment when taking the differing permeability of the BBB into consideration. PMID- 27464720 TI - Solving the Blood-Brain Barrier Challenge for the Effective Treatment of HIV Replication in the Central Nervous System. AB - Recent decades mark a great progress in the treatment of HIV infection. What was once a deadly disease is now a chronic infection. However, HIV-infected patients are prone to develop comorbidities, which severely affect their daily functions. For example, a large population of patients develop a variety of neurological and cognitive complications, called HIV associated neurological disorders (HAND). Despite efficient repression of viral replication in the periphery, evidence shows that the virus can remain active in the central nervous system (CNS). This low level of replication is believed to result in a progression of neurocognitive dysfunction in infected individuals. Insufficient viral inhibition in the brain results from the inability of several treatment drugs in crossing the blood-brain barrier (BBB) and reaching therapeutic concentrations in the CNS. The current manuscript discusses several strategies that are being developed to enable therapeutics to cross the BBB, including bypassing BBB, inhibition of efflux transporters, the use of active transporters present at the BBB, and nanotechnology. The increased concentration of therapeutics in the CNS is desirable to prevent viral replication; however, potential side effects of anti retroviral drugs need also to be taken into consideration. PMID- 27464723 TI - Application of Vibrational Spectroscopy to Study Solid-state Transformations of Pharmaceuticals. AB - Understanding the properties, stability and transformations of the solid-state forms of an active pharmaceutical ingredient (API) in the development pipeline is of crucial importance for process-development, formulation development and FDA approval. Investigation of the polymorphism and polymorphic stability is a routine part of the preformulation studies. Vibrational spectroscopy allows the real-time in situ monitoring of phase transformations and probes intermolecular interactions between API molecules, between API and polymer in amorphous solid dispersions or between API and coformer in cocrystals or coamorphous systems and thus plays a major role in efforts to gain a predictive understanding of the relative stability of solid-state forms and formulations. Infrared (IR), near infrared (NIR) and Raman spectroscopies, alone or in combination with other analytical methods, are important tools for studying transformations between different crystalline forms, between the crystalline and amorphous form, between hydrate and anhydrous form and for investigating solid-state cocrystal formation. The development of simple-to-use and cost-effective instruments on the one hand and recent technological advances such as access to the low-frequency Raman range down to 5 cm-1, on the other, have led to an exponential growth of the literature in the field. This review discusses the application of IR, NIR and Raman spectroscopies in the study of solid-state transformations with a focus on the literature published over the last eight years. PMID- 27464722 TI - Mechanochemical Approaches to Pharmaceutical Cocrystal Formation and Stability Analysis. AB - Solid-state mechanochemical grinding is important for promoting cocrystal formation, particularly in the design of new solids in the pharmaceutical industry. Pharmaceutical cocrystals are defined as crystalline materials comprising an active pharmaceutical ingredient (API) and one or more appropriate coformers in a definite stoichiometric ratio, formed via non-covalent interactions. Recently, both the US FDA (2013) and the EU EMA (2015) provided a Guidance for Industry and a Reflection Paper, respectively, emphasizing that cocrystals are a new type of substance with potential applications in the pharmaceutical industry. This paper contains a brief and systematic overview of pharmaceutical cocrystals prepared by four grinding processes: neat grinding, solvent-assisted grinding, thermal stress after neat grinding, and polymer assisted grinding. The paper also highlights some examples of pharmaceutical cocrystals prepared by the above grinding approaches, and discusses the stability of cocrystals prepared by mechanical grinding. Also, an overview of cocrystals that are commercially available or undergoing clinical trials is given. A novel methodology for real-time and in situ monitoring of mechanochemical grinding reactions using various analytical techniques is addressed and can be expected to be applied in the near future. PMID- 27464721 TI - Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier. AB - The blood-brain interfaces restrict the cerebral bioavailability of pharmacological compounds. Various drug delivery strategies have been developed to improve drug penetration into the brain. Most strategies target the microvascular endothelium forming the bloodbrain barrier proper. Targeting the blood-cerebrospinal fluid (CSF) barrier formed by the epithelium of the choroid plexuses in addition to the blood-brain barrier may offer addedvalue for the treatment of central nervous system diseases. For instance, targeting the CSF spaces, adjacent tissue, or the choroid plexuses themselves is of interest for the treatment of neuroinflammatory and infectious diseases, cerebral amyloid angiopathy, selected brain tumors, hydrocephalus or neurohumoral dysregulation. Selected CSF-borne materials seem to reach deep cerebral structures by mechanisms that need to be understood in the context of chronic CSF delivery. Drug delivery through both barriers can reduce CSF sink action towards parenchymal drugs. Finally, targeting the choroid plexus-CSF system can be especially relevant in the context of neonatal and pediatric diseases of the central nervous system. Transcytosis appears the most promising mechanism to target in order to improve drug delivery through brain barriers. The choroid plexus epithelium displays strong vesicular trafficking and secretory activities that deserve to be explored in the context of cerebral drug delivery. Folate transport and exosome release into the CSF, plasma protein transport, and various receptor-mediated endocytosis pathways may prove useful mechanisms to exploit for efficient drug delivery into the CSF. This calls for a clear evaluation of transcytosis mechanisms at the blood-CSF barrier, and a thorough evaluation of CSF drug delivery rates. PMID- 27464724 TI - Formation, Physicochemical Characterization, and Thermodynamic Stability of the Amorphous State of Drugs and Excipients. AB - Drugs and excipients used for pharmaceutical applications generally exist in the solid (crystalline or amorphous) state, more rarely as liquid materials. In some cases, according to the physicochemical nature of the molecule, or as a consequence of specific technological processes, a compound may exist exclusively in the amorphous state. In other cases, as a consequence of specific treatments (freezing and spray drying, melting and co-melting, grinding and compression), the crystalline form may convert into a completely or partially amorphous form. An amorphous material shows physical and thermodynamic properties different from the corresponding crystalline form, with profound repercussions on its technological performance and biopharmaceutical properties. Several physicochemical techniques such as X-ray powder diffraction, thermal methods of analysis, spectroscopic techniques, gravimetric techniques, and inverse gas chromatography can be applied to characterize the amorphous form of a compound (drug or excipient), and to evaluate its thermodynamic stability. This review offers a survey of the technologies used to convert a crystalline solid into an amorphous form, and describes the most important techniques for characterizing the amorphous state of compounds of pharmaceutical interest. PMID- 27464725 TI - Investigation of Polymorphism and Cocrystallization of Active Pharmaceutical Ingredients Using Vibrational Spectroscopic Techniques. AB - Active pharmaceutical ingredients (APIs) can exist in various types of crystalline forms including polymorphs and cocrystals. These multiple crystalline forms of APIs have district physical and physicochemical characteristics. Vibrational spectroscopic techniques used in solid-state pharmaceutical analysis include mid-infrared, Raman and terahertz spectroscopy. In this review, we will focus on the recent vibrational spectroscopic investigation on the polymorphism and cocrystallization of APIs in pharmaceutical fields. The distinctive spectral and structural information of pharmaceutical polymorphs and cocrystals could be obtained based on these vibrational spectroscopic techniques. PMID- 27464726 TI - Polycystic Ovary Syndrome as a Proinflammatory State: The Role of Adipokines. AB - BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a complex heterogeneous disorder and the most common endocrinopathy amongst women of reproductive age. It is characterized by androgen excess, chronic anovulation and an altered cardiometabolic profile. PCOS is linked to impaired adipose tissue (AT) physiology and women with this disorder present with greater risk for insulin resistance (IR), hyperinsulinemia, central adiposity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) than matched for age and body mass index (BMI) women without PCOS. Hyperandrogenaemia appears to be driving adipocyte hypertrophy observed in PCOS under the influence of a hyperinsulinaemic state. Changes in the function of adipocytes have an impact on the secretion of adipokines, adipose tissue-derived proinflammatory factors promoting susceptibility to low grade inflammation. METHODS: In this article, we review the existing knowledge on the interplay between hyperandrogenaemia, insulin resistance, impaired adipocyte biology, adipokines and chronic low-grade inflammation in PCOS. RESULTS: In PCOS, more than one mechanisms have been suggested in the development of a chronic low-grade inflammation state with the most prevalent being that of a direct effect of the immune system on adipose tissue functions as previously reported in obese women without PCOS. Despite the lack of conclusive evidence regarding a direct mechanism linking hyperandrogenaemia to pro-inflammation in PCOS, there have been recent findings indicating that hyperandrogenaemia might be involved in chronic inflammation by exerting an effect on adipocytes morphology and attributes. CONCLUSION: Increasing evidence suggests that there is an important connection and interaction between proinflammatory pathways, hyperinsulinemia, androgen excess and adipose tissue hypertrophy and, dysfunction in PCOS. While lifestyle changes and individualized prescription of insulin-sensitizing drugs are common in managing PCOS, further studies are warranted to eventually identify an adipokine that could serve as an indirect marker of adipocyte dysfunction in PCOS, used as a reliable and pathognomic sign of metabolic alteration in this syndrome. PMID- 27464727 TI - Membrane Transporters in Physiological Barriers of Pharmacological Importance. AB - Membrane transporters expressed in barrier forming cell types provide a dual filtration system as unwanted xenobiotics are effluxed by ABC transporters, and compounds essential for the organism, such as nutrients or physiological substrates, are taken up by influx transporters. The majority of efflux transporters apically-localized in barrier forming cell types are ABC transporters that may limit absorption or distribution, and promote excretion. Pharmaceutical scientists are increasingly aware of the limitations these efflux transporters represent. Influx transporters are also critically important, as apically-located influx transporters may counteract the effect of co-localized efflux transporters, promoting absorption or reabsorption, as well as facilitating distribution of low passive permeability substrates into tissues that are otherwise heavily guarded by efflux transporters. In excretory organs, basolaterally-localized influx transporters cooperate with apically-localized efflux trransporters to efficiently drive transcellular movement of xenobiotics and their metabolites. Pharmacological inhibition of absorption or reabsorption of unwanted nutrients and endobiotics has become a great opportunity for pharmaceutical development. For drug developers, these transporters also offer the opportunity to target specific organs and cell types. Targeting drugs to cells and tissues harboring the pharmacological target not only makes drugs more efficient, but can also make them less toxic, as it allows for administration of lower doses and less distribution of drugs into non-target organs. PMID- 27464728 TI - Solid Dispersions for Oral Administration: An Overview of the Methods for their Preparation. AB - Oral drug delivery remains the most physiological and therefore the most preferred, simplest and easiest administration route. Nevertheless, a multitude of potentially clinically important drugs will not reach the market or achieve their full potential unless their oral bioavailability is improved by formulation. The aim of this review is to present an overview of properties, formulation, excipients and characterization of solid dispersions corresponding to one of the different formulation strategies for design and development of poorly soluble drugs. This work will review and compare in detail the evolution of solid dispersions focused on the different methods of formulation and production of solid dispersions, their stability, their release properties, their pharmacokinetics and methods for their physicochemical characterization. PMID- 27464729 TI - Pharmacological Targeting of the Epidermal Barrier. AB - The most important function of the skin is to form a barrier between the body and the external environment. The epidermal barrier prevents transepidermal water loss from the skin, but also serves as a barrier to the entry of harmful environmental allergic, toxic or infectious substances. Inherited defects in the genes encoding the components of the epidermal barrier result in the development of rare genetic disorders, whereas polymorphisms in these genes together with environmental factors cause frequent inflammatory skin diseases, such as atopic dermatitis. In this review, components of the skin-barrier function will be reviewed with special emphasis on how the altered epidermal barrier might be repaired. The different strategies to increase the transdermal penetration of drugs is also discussed. PMID- 27464730 TI - The Role of Solid State Characterization in Predicting Stability of Solid Dosage Forms. AB - Stability of a dosage form is its ability to preserve its quality attributes within preset limits. The time span over which these attributes remain within specifications is the shelf-life of the drug product. Stability is a very complex feature and is influenced not only by the stability of the drug substance but also by the stability of excipients and the interaction of the components within the system. Another important contributing factor is the packaging material, which is responsible for the protection of the drug product. Not only drug substances, but also excipients are susceptible to different degradation mechanisms. Amorphous polymers, a relatively frequently used group of excipients, are especially prone to physical instability. Through the process of physical ageing, a slow volume and enthalpy relaxation can be experienced, which can lead to remarkable alterations in solid dosage form properties. Functional changes within the solid dosage form associated with instability include changes in mechanical properties, homogeneity and drug release characteristics, discoloration, phase separation or changes in melting time of suppositories. Stability assessment is a crucial issue during formulation development, which is strictly regulated by authorities responsible for drug registration. The primary purpose of this paper is to give an overview of the different types of physical changes influencing solid state stability of dosage forms, and how such changes can be monitored. We will also illustrate how the quality of a solid dosage form varies with time under the influence of different environmental factors. PMID- 27464731 TI - Advanced Applications of Raman Imaging for Deeper Understanding and Better Quality Control of Formulations. AB - The importance of using the Raman imaging technique is increasing in pharmaceutical sciences, particularly in the quality control of active pharmaceutical ingredients, formulation design, and manufacturing development. Formulation design based on Raman imaging data is important for achieving quality by design. Recently, several novel Raman imaging measurement and analytical techniques have been reported. It is undoubtedly essential for pharmaceutical researchers and manufacturing engineers to use modern Raman imaging technology to produce the best quality pharmaceutical products. This short review seeks to inform researchers and engineers about recent developments in Raman imaging techniques applicable to formulation design and manufacturing. PMID- 27464733 TI - M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma. AB - Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL. PMID- 27464734 TI - Grading of proximal internal carotid artery (ICA) stenosis by Doppler/duplex ultrasound (DUS) and computed tomographic angiography (CTA): correlation and interrater reliability in real-life practice. AB - Doppler/duplex ultrasound (DUS) and computed tomographic angiography (CTA) are frequently applied methods to assess the degree of proximal internal carotid artery (ICA) stenoses in patients with acute ischemic stroke. This study evaluated the agreement and interrater reliability (IR) of both methods using a revised DUS grading system as well as different criteria (ECST/NASCET) under real life conditions. CTA and DUS data of 281 proximal ICA stenoses [143 patients; 65.7 % male; age (mean (years) +/- SD, range) 72.2 +/- 11.1, 40-99] were retrospectively analyzed. For both methods, two independent raters estimated the degree of stenosis according to NASCET and ECST criteria. DUS raters applied revised German DUS criteria. For agreement and IR assessment, the linear weighted Kappa statistic was used. Correlation between DUS and CTA was substantial irrespective of the applied classification [weighted Kappa: 0.77 (NASCET)/0.79 (ECST)]. IR for DUS was almost perfect (weighted Kappa: 0.94) and better than for CTA [weighted Kappa: 0.78 (NASCET)/0.78 (ECST)]. In a real-life setting, CTA and DUS assessments of the degree of proximal ICA stenoses agreed substantially irrespective of the criteria applied (ECST/NASCET). For DUS, IR was better than for CTA. PMID- 27464732 TI - Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu positive breast cancer cells. AB - BACKGROUND: HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment. METHODS: Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines. RESULTS: Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and CHOP dependent apoptosis as well as a partial activation of the ER stress response network via XBP1 and ATF6. This response appears to be a general feature of HER2/neu-positive breast cancer cells but not cells that overexpress only HER2/neu. Exogenous palmitate reduces HER2 and HER3 protein levels without changes in phosphorylation and sensitizes HER2/neu-positive breast cancer cells to treatment with the HER2-targeted therapy trastuzumab. CONCLUSIONS: Several studies have shown that HER2, FASN and fatty acid synthesis are functionally linked. Exogenous palmitate exerts its toxic effects in part through inducing ER stress, reducing HER2 expression and thereby sensitizing cells to trastuzumab. These data provide further evidence that HER2 signaling and fatty acid metabolism are highly integrated processes that may be important for disease development and progression. PMID- 27464735 TI - Coping with Accident Reactions (CARE) early intervention programme for preventing traumatic stress reactions in young injured children: study protocol for two randomised controlled trials. AB - BACKGROUND: Accidental injury represents the most common type of traumatic event experienced by children under the age of 6 years. Around 10-30 % of young injured children will go on to develop post-traumatic stress disorder (PTSD) and other co morbid conditions. Parents of injured children are also at risk of PTSD, and this is associated with short- and long-term consequences for their children's physical and psychological recovery. Despite the significance of this problem, to date, the mental health needs of injured young children have been neglected. One reason for this is due to the uncertainty and considerable debate around how to best provide early psychological intervention to traumatised children and adults. To address these gaps, researchers and psychologists in Australia and Switzerland have developed the Coping with Accident Reactions (CARE) programme, which is a two-session early intervention designed to prevent persistent PTSD reactions in young injured children screened as 'at risk'. Two separate international studies are being conducted to evaluate the effectiveness and feasibility of this programme. METHODS/DESIGN: The study design for the two proposed studies will employ a randomised controlled trial design and children (aged 1-6 years) who are screened as at risk for PTSD 1 week after an unintentional injury, and their parents will be randomised to either (1) CARE intervention or (2) treatment as usual. Assessment will be completed at baseline (2 weeks) and 3 and 6 months post injury. DISCUSSION: This international collaboration provides an excellent opportunity to test the benefit of screening and providing early intervention to young children in two different countries and settings. It is expected that outcomes from this research will lead to significant original contributions to the scientific evidence base and clinical treatment and recovery of very young injured children. TRIAL REGISTRATION: The Australian study was registered with the Australian New Zealand Clinical Trials Registry ( ACTRN12614000325606 ) on 26 March 2014. The Swiss study was registered with ClinicalTrials.gov ( NCT02088814 ) on 12 March 2014. PMID- 27464736 TI - Real time and label free profiling of clinically relevant exosomes. AB - Tumor-derived exosomes possess significant clinical relevance due to their unique composition of genetic and protein material that is representative of the parent tumor. Specific isolation as well as identification of proportions of these clinically relevant exosomes (CREs) from biological samples could help to better understand their clinical significance as cancer biomarkers. Herein, we present a simple approach for quantification of the proportion of CREs within the bulk exosome population isolated from patient serum. This proportion of CREs can potentially inform on the disease stage and enable non-invasive monitoring of inter-individual variations in tumor-receptor expression levels. Our approach utilises a Surface Plasmon Resonance (SPR) platform to quantify the proportion of CREs in a two-step strategy that involves (i) initial isolation of bulk exosome population using tetraspanin biomarkers (i.e., CD9, CD63), and (ii) subsequent detection of CREs within the captured bulk exosomes using tumor-specific markers (e.g., human epidermal growth factor receptor 2 (HER2)). We demonstrate the isolation of bulk exosome population and detection of as low as 10% HER2(+) exosomes from samples containing designated proportions of HER2(+) BT474 and HER2(-) MDA-MB-231 cell derived exosomes. We also demonstrate the successful isolation of exosomes from a small cohort of breast cancer patient samples and identified that approximately 14-35% of their bulk population express HER2. PMID- 27464738 TI - Modulating the strength of tetrel bonding through beryllium bonding. AB - Quantum chemical calculations were performed to investigate the stability of the ternary complexes BeH2...XMH3...NH3 (X = F, Cl, and Br; M = C, Si, and Ge) and the corresponding binary complexes at the atomic level. Our results reveal that the stability of the XMH3...BeH2 complexes is mainly due to both a strong beryllium bond and a weak tetrel-hydride interaction, while the XMH3...NH3 complexes are stabilized by a tetrel bond. The beryllium bond with a halogen atom as the electron donor has many features in common with a beryllium bond with an O or N atom as the electron donor, although they do exhibit some different characteristics. The stability of the XMH3...NH3 complex is dominated by the electrostatic interaction, while the orbital interaction also makes an important contribution. Interestingly, as the identities of the X and M atoms are varied, the strength of the tetrel bond fluctuates in an irregular manner, which can explained by changes in electrostatic potentials and orbital interactions. In the ternary systems, both the beryllium bond and the tetrel bond are enhanced, which is mainly ascribed to increased electrostatic potentials on the corresponding atoms and charge transfer. In particular, when compared to the strengths of the tetrel and beryllium bonds in the binary systems, in the ternary systems the tetrel bond is enhanced to a greater degree than the beryllium bond. Graphical Abstract A tetrel bond can be strengthened greatly by a beryllium bond. PMID- 27464737 TI - Mycobacterium tuberculosis lineages and anti-tuberculosis drug resistance in reference hospitals across Viet Nam. AB - BACKGROUND: Mycobacterium tuberculosis, the tuberculosis (TB) pathogen, despite a low level of genetic diversity, has revealed a high variety of biological and epidemiological characteristics linked to their lineages, such as transmissibility, fitness and propensity to acquire drug resistance. This has important implications for the epidemiology of TB. We conducted this first countrywide cross-sectional study to identify the prevalent M. tuberculosis lineages and to assess their epidemiological associations and their relation to drug resistance. The study was conducted among isolates acquired in reference hospitals across Vietnam. Isolates with drug susceptibility testing profiles were identified for their lineages by spoligotyping. Logistic regression was used to investigate the association of M. tuberculosis lineages with location, age and sex of the patients and drug resistance levels. RESULTS: Results showed that the most prevalent lineage was Beijing (55.4 %), followed by EAI (27.5 %), T (6.4 %), LAM (1.3 %), Haarlem (1 %) and Zero type (0.3 %). The proportion of Beijing isolates in the North (70.4 %) and the South (68 %) was higher than in the Centre (28 %) (OR = 1.7 [95 % CI: 1.4-2.0], p < 0.0001), whereas the proportion of EAI isolates in the North (7.1 %) and the South (17 %) was much lower compared with the Centre (59 %) (OR = 0.5 [95 % CI: 0.4-0.6], p < 0.0001). Overall, Beijing isolates were the most likely to be drug-resistant and EAI isolates were the least likely to be drug-resistant, except in the South of Vietnam where EAI is also highly drug-resistant. The proportion of Beijing isolates was significantly higher (p < 0.01), and the proportion of EAI isolates was significantly lower (p < 0.05) in younger patients. The proportion of drug-resistance was higher in isolates collected from male patients and from patients in the middle age groups. CONCLUSIONS: The findings suggest ongoing replacement of EAI lineage, which is mainly more drug-susceptible with highly drug-resistant Beijing lineage in all studied regions of Vietnam. Male patients of working ages should be the focus for better control to prevent the emergence of drug-resistant TB. PMID- 27464739 TI - [Electrolyte disturbances in geriatric patients with focus on hyponatremia]. AB - Disturbances of water and electrolyte balance are commonly encountered in older patients due to a multitude of physiological changes and preexisting morbidities with hyponatremia being the most common disorder. Even mild chronic hyponatremia can lead to cognitive deficits and gait instability and is associated with an increased rate of falls and fractures. Additionally, experimental and epidemiological data suggest that hyponatremia promotes bone resorption and therefore increases the risk of osteoporosis. Furthermore, osteoporosis and sarcopenia can be stimulated by hypomagnesemia. Hypernatremia often only results in unspecific symptoms but the condition is associated with a clearly increased mortality. As electrolyte disturbances have a high prevalence in the geriatric population and can contribute to geriatric syndromes and frailty, relevant electrolyte alterations should be excluded in all geriatric patients, in particular after a change in medication schedules. PMID- 27464741 TI - Music Listening modulates Functional Connectivity and Information Flow in the Human Brain. AB - Listening to familiar music has recently been reported to be beneficial during recovery from stroke. A better understanding of changes in functional connectivity and information flow is warranted in order to further optimize and target this approach through music therapy. Twelve healthy volunteers listened to seven different auditory samples during an fMRI scanning session: a musical piece chosen by the volunteer that evokes a strong emotional response (referred to as: "self-selected emotional"), two unfamiliar music pieces (Invention #1 by J. S. Bach* and Gagaku - Japanese classical opera, referred to as "unfamiliar"), the Bach piece repeated with visual guidance (DML: Directed Music Listening) and three spoken language pieces (unfamiliar African click language, an excerpt of emotionally charged language, and an unemotional reading of a news bulletin). Functional connectivity and betweenness (BTW) maps, a measure for information flow, were created with a graph-theoretical approach. Distinct variation in functional connectivity was found for different music pieces consistently for all subjects. Largest brain areas were recruited for processing self-selected music with emotional attachment or culturally unfamiliar music. Maps of information flow correlated significantly with fMRI BOLD activation maps (p<0.05). Observed differences in BOLD activation and functional connectivity may help explain previously observed beneficial effects in stroke recovery, as increased blood flow to damaged brain areas stimulated by active engagement through music listening may have supported a state more conducive to therapy. PMID- 27464740 TI - [Kidney transplantation in old age]. AB - Older patients clearly benefit from a kidney transplantation despite multiple comorbidities and complications, particularly with respect to life expectancy. Older patients remaining on dialysis on average die earlier compared to patients who underwent a kidney transplantation. In addition, patients experience a significant increase in the quality of life after renal transplantation. However, every patient has to be thoroughly evaluated to assess the individual benefits of a renal transplantation. Geriatric tools are particularly helpful to evaluate the suitability of older individuals. In 1999 the Eurotransplant senior program (ESP or "old for old") was initiated, aiming at shortening waiting time and cold ischemia time for patients on the waiting list. In this program, kidneys of donors aged 65 years and older are locally allocated to recipients also of 65 years and older. The results in ESP are promising, to the effect that this program helps older patients to receive a kidney transplant earlier than by the normal procedure; however, a better alternative to the ESP program is living donor transplantation, provided that a suitable donor is available. There is no age limit for the evaluation of potential donors. Compared to deceased donor kidney transplantation a living donor kidney will most likely function with a higher spontaneous rate and for a longer period of time and therefore provides a clear advantage for older recipients. PMID- 27464742 TI - Anxiolytic activity of the neuroprotective peptide HLDF-6 and its effects on brain neurotransmitter systems in BALB/c and C57BL/6 mice. AB - This study is focused on a new amide derivative of the peptide HLDF-6 (Thr-Gly Glu-Asn-His-Arg). This hexapeptide is a fragment of Human Leukaemia Differentiation Factor (HLDF). It displays a broad range of nootropic and neuroprotective activities. We showed, for the first time, that the peptide HLDF 6-amide has high anxiolytic activity. We used 'open field' and 'elevated plus maze' tests to demonstrate anxiolytic effects of HLDF-6-amide (0.1 and 0.3 mg/kg intranasally), which were comparable to those of the reference drug diazepam (0.5 mg/kg). Five daily equipotent doses of HLDF-6-amide selectively mitigated anxiety and increased the density of NMDA receptors in the hippocampus of stress susceptible BALB/c mice, and had no effect on stress-resilient C57BL/6 mice. The subchronic administration of HLDF-6-amide showed no effect on the density of GABAA and nicotine receptors but was accompanied by a nonselective decrease of the 5-HT2A serotonin receptor density in frontal cortex of both strains. The mechanism of the specific anxiolytic activity of HLDF-6-amide may include its action on the NMDA-glutamatergic receptor system of the hippocampus and on serotonin 5-HT2A-receptors in the prefrontal cortex. The psychotropic activity of HLDF-6-amide is promising for its introduction to medical practice as a highly effective anxiolytic medicine for mental and neurological diseases. PMID- 27464743 TI - Comparative analysis of pharmacological properties of xanomeline and N desmethylclozapine in rat brain membranes. AB - BACKGROUND: 3(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1 methylpyridine (xanomeline) and N-desmethylclozapine are of special interest as promising antipsychotics with better efficacy, especially for negative symptoms and/or cognitive/affective impairment. METHODS: The guanosine-5'-O-(3 [(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding experiments were performed using (1) conventional filtration technique, (2) antibody-capture scintillation proximity assay, and (3) immunoprecipitation method, in brain membranes prepared from rat cerebral cortex, hippocampus, and striatum. RESULTS: Xanomeline had agonistic activity at the M1 muscarinic acetylcholine receptor (mAChR) in all brain regions, as well as at the 5-HT1A receptor in the cerebral cortex and hippocampus. On the other hand, N-desmethylclozapine exhibited slight agonistic effects on the M1 mAChR, and agonistic properties at the 5-HT1A receptor in the cerebral cortex and hippocampus. This compound also behaved as an agonist at the delta-opioid receptor in the cerebral cortex and striatum. In addition, the stimulatory effects of N-desmethylclozapine on [(35)S]GTPgammaS binding to Galphai/o were partially mediated through mAChRs (most likely M4 mAChR subtype), at least in striatum. CONCLUSIONS: The agonistic effects on the mAChRs (particularly M1 subtype, and also probably M4 subtype), the 5-HT1A receptor and the delta-opioid receptor expressed in native brain tissues, some of which are common to both compounds and others specific to either, likely shape the unique beneficial effectiveness of both compounds in the treatment for schizophrenic patients. These characteristics provide us with a clue to develop newer antipsychotics, beyond the framework of dopamine D2 receptor antagonism, that are effective not only on positive symptoms but also on negative symptoms and/or cognitive/affective impairment. PMID- 27464744 TI - Being a caregiver to patients with ovarian cancer: A scoping review of the literature. AB - OBJECTIVE: Ovarian cancer differs from many other cancer diagnoses due to its late diagnosis and high rates and frequencies of recurrences. The physical and psychosocial wellbeing of patients are well documented in the literature, however limited research exists specifically on their friends and family, or caregivers. The goal of this review was to examine the state of the literature on ovarian cancer caregivers. METHOD: A scoping review was conducted on any articles describing caregivers of patients with ovarian cancer. Databases were searched systematically using key terms related to ovarian cancer and caregiving. Both authors screened articles for eligibility. Grey literature was also consulted. RESULTS: 19 articles were identified after screening: nine quantitative, five qualitative, two mixed-methods, two case studies and a personal account. Quantitative studies were conducted over different time-points in the disease trajectory, whereas qualitative studies and the personal account spanned the whole trajectory. Collectively, the studies suggested that the experience of being a caregiver to patients with ovarian cancer changes overtime, as the first year post-diagnosis shows little compromise in wellbeing and quality of life, which then steadily declines throughout the rest of the disease trajectory. Studies commented on quality of life, distress, needs, social wellbeing, spirituality, relationships with healthcare providers, relationships with patients, physical health and financial wellbeing. CONCLUSIONS: This scoping review of the literature demonstrates little peer-reviewed evidence on the experiences and quality-of-life of ovarian cancer caregivers. This population experiences physical and psychosocial challenges that merit exploration, to subsequently aid in designing interventions. PMID- 27464745 TI - Comment on "NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis". AB - Experimental cancer models must consider the role of the immune system. PMID- 27464746 TI - Response to comment on "NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis". AB - Multiple factors may affect the outcome of diabetic patients with cancer treated with antioxidant antidiabetic agents. PMID- 27464747 TI - Disciplined approach to drug discovery and early development. AB - Our modern health care system demands therapeutic interventions that improve the lives of patients. Unfortunately, decreased productivity in therapeutics research and development (R&D) has driven drug costs up while delivering insufficient value to patients. Here, I discuss a model of translational medicine that connects four components of the early R&D pipeline-causal human biology, therapeutic modality, biomarkers of target modulation, and proof-of-concept clinical trials. Whereas the individual components of this model are not new, technological advances and a disciplined approach to integrating all four areas offer hope for improving R&D productivity. PMID- 27464749 TI - Noninvasive low-level laser therapy for thrombocytopenia. AB - Thrombocytopenia is a common hematologic disorder that is managed primarily by platelet transfusions. We report here that noninvasive whole-body illumination with a special near-infrared laser cures acute thrombocytopenia triggered by gamma-irradiation within 2 weeks in mice, as opposed to a 5-week recovery time required in controls. The low-level laser (LLL) also greatly accelerated platelet regeneration in the presence of anti-CD41 antibody that binds and depletes platelets, and prevented a severe drop in platelet count caused by a common chemotherapeutic drug. Mechanistically, LLL stimulated mitochondrial biogenesis specifically in megakaryocytes owing to polyploidy of the cells. LLL also protected megakaryocytes from mitochondrial injury and apoptosis under stress. The multifaceted effects of LLL on mitochondria bolstered megakaryocyte maturation; facilitated elongation, branching, and formation of proplatelets; and doubled the number of platelets generated from individual megakaryocytes in mice. LLL-mediated platelet biogenesis depended on megakaryopoiesis and was inversely correlated with platelet counts, which kept platelet biogenesis in check and effectively averted thrombosis even after repeated uses, in sharp contrast to all current agents that stimulate the differentiation of megakaryocyte progenitors from hematopoietic stem cells independently of platelet counts. This safe, drug free, donor-independent modality represents a paradigm shift in the prophylaxis and treatment of thrombocytopenia. PMID- 27464748 TI - Maternal HIV infection influences the microbiome of HIV-uninfected infants. AB - More than 1 million HIV-exposed, uninfected infants are born annually to HIV positive mothers worldwide. This growing population of infants experiences twice the mortality of HIV-unexposed infants. We found that although there were very few differences seen in the microbiomes of mothers with and without HIV infection, maternal HIV infection was associated with changes in the microbiome of HIV-exposed, uninfected infants. Furthermore, we observed that human breast milk oligosaccharides were associated with bacterial species in the infant microbiome. The disruption of the infant's microbiome associated with maternal HIV infection may contribute to the increased morbidity and mortality of HIV exposed, uninfected infants. PMID- 27464751 TI - Considering Friends Within the Context of Peers in School for the Development of Ethnic/Racial Identity. AB - The importance of ethnicity/race for adolescents' identity (i.e., centrality), and how that importance changes over time, may in part be a function of the social contexts that they inhabit. Although centrality has shown to be an adaptive component of ethnic/racial identity, little is known about how centrality changes during adolescence in relation to these social contexts. The current study examined the role of same-ethnic/racial peers and friends in the longitudinal development of ethnic/racial identity centrality. Drawing on four waves of data over 2 years collected with a diverse sample of 350 adolescents (M age at W1 = 15.2; 69 % female), the findings indicated that when adolescents had a greater proportion of same-ethnic/racial friends, they reported feeling that their ethnic/racial identity was more central to their sense of self six months later. However, this effect was strongest among adolescents with a low proportion of same-ethnic/racial peers in school, and weakest among adolescents with a high proportion of same-ethnic/racial peers in school. The implications of these findings for our understanding of the joint effects of peer and friend diversity in relation to ethnic/racial identity are discussed. PMID- 27464750 TI - Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1. AB - We tested the hypothesis that ex vivo hepatocyte gene therapy can correct the metabolic disorder in fumarylacetoacetate hydrolase-deficient (Fah(-/-)) pigs, a large animal model of hereditary tyrosinemia type 1 (HT1). Recipient Fah(-/-) pigs underwent partial liver resection and hepatocyte isolation by collagenase digestion. Hepatocytes were transduced with one or both of the lentiviral vectors expressing the therapeutic Fah and the reporter sodium-iodide symporter (Nis) genes under control of the thyroxine-binding globulin promoter. Pigs received autologous transplants of hepatocytes by portal vein infusion. After transplantation, the protective drug 2-(2-nitro-4-trifluoromethylbenzyol)-1,3 cyclohexanedione (NTBC) was withheld from recipient pigs to provide a selective advantage for expansion of corrected FAH(+) cells. Proliferation of transplanted cells, assessed by both immunohistochemistry and noninvasive positron emission tomography imaging of NIS-labeled cells, demonstrated near-complete liver repopulation by gene-corrected cells. Tyrosine and succinylacetone levels improved to within normal range, demonstrating complete correction of tyrosine metabolism. In addition, repopulation of the Fah(-/-) liver with transplanted cells inhibited the onset of severe fibrosis, a characteristic of nontransplanted Fah(-/-) pigs. This study demonstrates correction of disease in a pig model of metabolic liver disease by ex vivo gene therapy. To date, ex vivo gene therapy has only been successful in small animal models. We conclude that further exploration of ex vivo hepatocyte genetic correction is warranted for clinical use. PMID- 27464752 TI - Digital Diabetes Communication: There's an App for That. PMID- 27464753 TI - Hypoglycemia-Induced Changes in the Electroencephalogram: An Overview. AB - Hypoglycemia is defined by an abnormally low blood glucose level. The condition develops when rates of glucose entry into the systematic circulation are reduced relative to the glucose uptake by the tissues. A cardinal manifestation of hypoglycemia arises from inadequate supply of glucose to the brain, where glucose is the primary metabolic fuel. The brain is one of the first organs to be affected by hypoglycemia. Shortage of glucose in the brain, or neuroglycopenia, results in a gradual loss of cognitive functions causing slower reaction time, blurred speech, loss of consciousness, seizures, and ultimately death, as the hypoglycemia progresses. The electrical activity in the brain represents the metabolic state of the brain cells and can be measured by electroencephalography (EEG). An association between hypoglycemia and changes in the EEG has been demonstrated, although blood glucose levels alone do not seem to predict neuroglycopenia. This review provides an overview of the current literature regarding changes in the EEG during episodes of low blood glucose. PMID- 27464754 TI - Flash Glucose Monitoring Improves Outcomes in a Type 1 Diabetes Clinic. PMID- 27464755 TI - Hypoglycemia Detection and Carbohydrate Suggestion in an Artificial Pancreas. AB - Fear of hypoglycemia is a major concern for many patients with type 1 diabetes and affects patient decisions for use of an artificial pancreas system. We propose an alternative way for prevention of hypoglycemia by issuing predictive hypoglycemia alarms and encouraging patients to consume carbohydrates in a timely manner. The algorithm has been tested on 6 subjects (3 males and 3 females, age 24.2 +/- 4.5 years, weight 79.2 +/- 16.2 kg, height 172.7 +/- 9.4 cm, HbA1C 7.3 +/- 0.48%, duration of diabetes 209.2 +/- 87.9 months) over 3-day closed-loop clinical experiments as part of a multivariable artificial pancreas control system. Over 6 three-day clinical experiments, there were only 5 real hypoglycemia episodes, of which only 1 hypoglycemia episode occurred due to being missed by the proposed algorithm. The average hypoglycemia alarms per day and per subject was 3. Average glucose value when the first alarms were triggered was recorded to be 117 +/- 30.6 mg/dl. Average carbohydrate consumption per alarm was 14 +/- 7.8 grams. Our results have shown that most low glucose concentrations can be predicted in advance and the glucose levels can be raised back to the desired levels by consuming an appropriate amount of carbohydrate. The proposed algorithm is able to prevent most hypoglycemic events by suggesting appropriate levels of carbohydrate consumption before the actual occurrence of hypoglycemia. PMID- 27464758 TI - Thai district Leaders' perceptions of managing the direct observation treatment program in Trang Province, Thailand. AB - BACKGROUND: Thailand is 18th out of the 22 countries with the highest tuberculosis (TB) burden. It will be a challenge for Thailand to achieve the UN Millennium Development target for TB, as well as the new WHO targets for eliminating TB by 2035. More knowledge and a new approach are needed to tackle the complex challenges of managing the DOT program in Thailand. Contextual factors strongly influence the local implementation of evidence in practice. Using the PARIHS model, the aim has been to explore district leaders' perceptions of the management of the DOT program in Trang province, Thailand. METHODS: A phenomenographic approach was used to explore the perceptions among district DOT program leaders in Trang province. We conducted semi-structured interviews with district leaders responsible for managing the DOT program in five districts. The analysis of the data transcriptions was done by grouping similarities and differences of perceptions, which were constructed in a hierarchical outcome space that shows a set of descriptive categories. RESULTS: The first descriptive category revealed a common perception of the leaders' duty and wish to comply with the NTP guidelines when managing and implementing the DOT program in their districts. More varied perceptions among the leaders concerned how to achieve successful treatment. Other perceptions concerned practical dilemmas, which included fear of infection, mutual distrust, and inadequate knowledge about TB. Further, the leaders perceived a need for improved management practices in implementing the TB guidelines. CONCLUSION: Using the PARIHS framework to gain a retrospective perspective on the district-level policy implementation of the DOT program and studying the leadership's perceptions about applying the guidelines to practice, has brought new knowledge about management practices. Additional support and resources from the regional level are needed to manage the challenges. PMID- 27464756 TI - When does female multiple mating evolve to adjust inbreeding? Effects of inbreeding depression, direct costs, mating constraints, and polyandry as a threshold trait. AB - Polyandry is often hypothesized to evolve to allow females to adjust the degree to which they inbreed. Multiple factors might affect such evolution, including inbreeding depression, direct costs, constraints on male availability, and the nature of polyandry as a threshold trait. Complex models are required to evaluate when evolution of polyandry to adjust inbreeding is predicted to arise. We used a genetically explicit individual-based model to track the joint evolution of inbreeding strategy and polyandry defined as a polygenic threshold trait. Evolution of polyandry to avoid inbreeding only occurred given strong inbreeding depression, low direct costs, and severe restrictions on initial versus additional male availability. Evolution of polyandry to prefer inbreeding only occurred given zero inbreeding depression and direct costs, and given similarly severe restrictions on male availability. However, due to its threshold nature, phenotypic polyandry was frequently expressed even when strongly selected against and hence maladaptive. Further, the degree to which females adjusted inbreeding through polyandry was typically very small, and often reflected constraints on male availability rather than adaptive reproductive strategy. Evolution of polyandry solely to adjust inbreeding might consequently be highly restricted in nature, and such evolution cannot necessarily be directly inferred from observed magnitudes of inbreeding adjustment. PMID- 27464757 TI - Magnetic nanoparticles as a drug delivery system that enhance fungicidal activity of polyene antibiotics. AB - This study was designed to assess the antifungal/anti-biofilm and hemolytic properties of two polyene antibiotics, amphotericin B (AMF) and nystatin (NYS), attached to the surface of magnetic nanoparticles (MNP) against clinical isolates of Candida species and human red blood cells, respectively. The developed nanosystems, MNP@AMF and MNP@NYS, displayed stronger fungicidal activity than unbound AMF or NYS. Synergistic activity was observed with a combination of polyenes and MNPs against all tested Candida strains. Nanosystems were more potent than unbound agents when tested against Candida strains in the presence of pus, and as agents able to prevent Candida biofilm formation. The observed inactivation of catalase Cat1 in Candida cells upon treatment with the nanosystems suggests that disruption of the oxidation-reduction balance is a mechanism leading to inhibition of Candida growth. The significant decrease of polyenes lytic activity against host cells after their attachment to MNPs surface indicates improvement in their biocompatibility. PMID- 27464759 TI - Quality of life, depression and dietary intake in Obstructive Sleep Apnea patients. AB - BACKGROUND: The aim of this study was to analyze the association between depression, quality of life and dietary intake in newly diagnosed Obstructive Sleep Apnea (OSA) patients. METHODS: From 153 eligible patients suffering from sleep disturbances, 64 met inclusion and exclusion criteria. The polysomnography was used for OSA diagnosis. The quality of life (QOL) was assessed by WHOQOL-BREF questionnaire, self-reported chronotype by morningness-eveningness questionnaire and level of depression by Beck's Depression Inventory. Blood pressure and parameters of glucose and lipid metabolism were assessed by routine methods. The dietary intake was evaluated by 24-hr dietary recalls. RESULTS: Significantly negative associations were found between depression inventory and QOL. Better QOL for physical health and social relationships was observed in the "definitely morning" chronotype. The "morning type" of patients was positively related to the intake of fat, monounsaturated fatty acids and vitamin B12. Correlations between QOL and diastolic blood pressure, HDL-cholesterol, TG, fasting glucose, as well as protein and vitamin B6 intake were found. CONCLUSIONS: In conclusion, both chornotype and depression influence QOL in OSA patients where morning type is associated with better physical health and social relationships and increase in depression index deteriorate physical health, psychological and social relationship QOL domains. QOL as well as depression and chornotype are also influenced by selected cardio-metabolic factors and dietary intake. PMID- 27464761 TI - Novel Instruments for the Implementation of Electrochemotherapy Protocols: From Bench Side to Veterinary Clinic. AB - Electrochemotherapy (ECT) is a medical strategy that allows an increased efficacy of chemotherapy agents after the application of permeabilizing electric pulses having appropriate characteristics (form, voltage, frequency). In the past 10 years, the clinical efficacy of this therapeutic approach in several spontaneous models of tumors in animals has been shown. Moreover, some of the molecular and cellular mechanisms responsible for this phenomenon have been elucidated. Our group has been deeply involved in the development of new ECT protocols for companion animals, implementing the use of the technique as first line treatment, and evaluating different chemotherapy agents in laboratory animals as well as pets. This article summarizes the most important advances in veterinary ECT, including the development of novel equipment, therapeutic protocols, and their translation to humans. J. Cell. Physiol. 232: 490-495, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27464760 TI - MicroRNA Exert Macro Effects on Cancer Bone Metastasis. AB - Bone metastasis is a deadly complication of cancers arising from many different primary tumor locations. Cross talk between cancer and bone cells is a well established driver of bone metastasis, and recent work reveals microRNA (miRNA) as key players in this communication. Functional significance of miRNA was first demonstrated in cancer cells and has now also been documented in bone cell differentiation and skeletal remodeling. Review of recent literature highlights how different miRNAs can impact each step of the metastatic process by acting in both tumor and the metastatic niche to exert pleiotropic effects. Additionally, whether a miRNA is ultimately pro- or anti-metastatic dependents on the context varied or even opposite outcomes can be conferred by the same miRNA in different cancer/cell types. In spite of this complexity, emerging research has provided a wealth of knowledge to uncover the exciting potential of miRNA as new diagnostic tools and therapeutic treatments for cancer bone metastasis. PMID- 27464763 TI - A mathematical model for electrical impedance spectroscopy of zwitterionic hydrogels. AB - We report a mathematical model for ion transport and electrical impedance in zwitterionic hydrogels, which possess acidic and basic functional groups that carry a net charge at a pH not equal to the isoelectric point. Such hydrogels can act as an electro-mechanical interface between a relatively hard biosensor and soft tissue in the body. For this application, the electrical impedance of the hydrogel must be characterized to ensure that ion transport to the biosensor is not significantly hindered. The electrical impedance is the ratio of the applied voltage to the measured current. We consider a simple model system, wherein an oscillating voltage is applied across a hydrogel immersed in electrolyte and sandwiched between parallel, blocking electrodes. We employ the Poisson-Nernst Planck (PNP) equations coupled with acid-base dissociation reactions for the charge on the hydrogel backbone to model the ionic transport across the hydrogel. The electrical impedance is calculated from the numerical solution to the PNP equations and subsequently analyzed via an equivalent circuit model to extract the hydrogel capacitance, resistance, and the capacitance of electrical double layers at the electrode-hydrogel interface. For example, we predict that an increase in pH from the isoelectric point, pH = 6.4 for a model PCBMA hydrogel, to pH = 8 reduces the resistance of the hydrogel by ~40% and increases the double layer capacitance by ~250% at an electrolyte concentration of 0.1 mM. The significant impact of charged hydrogel functional groups to the impedance is damped at higher electrolyte concentration. PMID- 27464762 TI - DHEA prevents bone loss by suppressing the expansion of CD4(+) T cells and TNFa production in the OVX-mouse model for postmenopausal osteoporosis. AB - Recent studies have suggested that dehydroepiandrosterone (DHEA) might serve as a form of immunomodulatory therapy for postmenopausal osteoporosis (PMO). The current study investigated the effects of DHEA administration on ovariectomy (OVX)-induced bone loss and its corresponding immunological changes. Adult OVX mice were treated with DHEA or 17-beta-estradiol (E2) for 12 weeks, with or without the aromatase inhibitor letrozole. DHEA improved bone mass after OVX and displayed action like that of E2 with regard to decreasing osteoclast-related parameters. DHEA also suppressed an OVX-induced increase in CD4(+) T cell subsets and TNF-alpha production. However, DHEA elevated serum E2 levels to a lesser extent than E2. Although letrozole decreased serum E2 levels in OVX mice treated with DHEA, it did not alter DHEA's effects on corresponding immunological changes due to OVX. In conclusion, DHEA may prevent bone loss by suppressing the OVX induced expansion of CD4(+) T cells and TNF-alpha production in mice, independent of E2. PMID- 27464764 TI - Xanthan Pyruvilation Is Essential for the Virulence of Xanthomonas campestris pv. campestris. AB - Xanthan, the main exopolysaccharide (EPS) synthesized by Xanthomonas spp., contributes to bacterial stress tolerance and enhances attachment to plant surfaces by helping in biofilm formation. Therefore, xanthan is essential for successful colonization and growth in planta and has also been proposed to be involved in the promotion of pathogenesis by calcium ion chelation and, hence, in the suppression of the plant defense responses in which this cation acts as a signal. The aim of this work was to study the relationship between xanthan structure and its role as a virulence factor. We analyzed four Xanthomonas campestris pv. campestris mutants that synthesize structural variants of xanthan. We found that the lack of acetyl groups that decorate the internal mannose residues, ketal-pyruvate groups, and external mannose residues affects bacterial adhesion and biofilm architecture. In addition, the mutants that synthesized EPS without pyruvilation or without the external mannose residues did not develop disease symptoms in Arabidopsis thaliana. We also observed that the presence of the external mannose residues and, hence, pyruvilation is required for xanthan to suppress callose deposition as well as to interfere with stomatal defense. In conclusion, pyruvilation of xanthan seems to be essential for Xanthomonas campestris pv. campestris virulence. PMID- 27464765 TI - Electrocatalytic Nanostructured Ferric Tannates: Characterization and Application of a Polyphenol Nanosensor. AB - A novel core-shell hybrid nanomaterial composed of peculiar maghemite nanoparticles (surface-active maghemite nanoparticles (SAMNs)) as the core and tannic acid (TA) as the shell was developed by self-assembly of ferric tannates onto the surface of SAMNs by simple incubation in water. The hybrid nanomaterial (SAMN@TA) was characterized by using UV/Vis, FTIR, and Mossbauer spectroscopies, magnetization measurements, and X-ray powder diffraction, which provide evidence of a drastic reorganization of the iron oxide surface upon reaction with TA and the formation of an outer shell that consists of a cross-linked network of ferric tannates. According to a Langmuir isotherm analysis, SAMN@TA offers one of most stable iron complexes of TA reported in the literature to date. Moreover, SAMN@TA was characterized by using electrical impedance spectroscopy, voltammetry, and chronoamperometry. The nanostructured ferric tannate interface showed improved conductivity and selective electrocatalytic activity toward the oxidation of polyphenols. Finally, a carbon-paste electrode modified with SAMN@TA was used for the determination of polyphenols in blueberry extracts by square-wave voltammetry. PMID- 27464766 TI - Erratum to: Development and Evaluation of a New Technological Way of Engaging Patients and Enhancing Understanding of Drug Tolerability in Early Clinical Development: PROACT. PMID- 27464767 TI - Renal Thrombotic Microangiopathy in Proliferative Lupus Nephritis: Risk Factors and Clinical Outcomes: A Case-Control Study. AB - BACKGROUND: Renal thrombotic microangiopathy (TMA) may be associated with lupus nephritis. Its relationship to other disease factors and its specific effect on prognosis are not precisely known. Evidence regarding these aspects is controversial, and information focusing on kidney-limited TMA in systemic lupus erythematosus (SLE) patients is scarce. OBJECTIVES: The aims of this study were to identify risk factors for renal TMA in patients with lupus nephritis and to determine its impact on clinical outcomes. METHODS: A case-control study was performed. We studied 245 renal biopsies from SLE patients. We included patients with renal TMA, as well as control subjects adjusted for glomerulonephritis class, estimated glomerular filtration rate, activity and chronicity indices, and follow-up time. Serological and clinical features were measured at the time of the biopsy and during follow-up. RESULTS: Twenty-three patients with renal TMA and 21 control subjects were included. There were no differences in Systemic Lupus Erythematosus Disease Activity Index score, end-stage renal disease, or mortality between groups during follow-up. After multivariate analysis, lymphopenia (odds ratio, 10.69; 95% CI, 1.35-84.74) and anti-Ro antibody positivity (odds ratio, 8.96; 95% CI, 1.49-53.57) remained significantly associated with renal TMA. CONCLUSIONS: Lymphopenia and anti-Ro positivity are independent risk factors for renal TMA in SLE patients. This increased risk could be a consequence of the potential role of these factors in endothelial dysfunction and damage. Outcomes were similar for patients with the same estimated glomerular filtration rate and biopsy characteristics, regardless of the presence of TMA. PMID- 27464768 TI - Sleep Quality Is Related to Disease Activity in Patients With Ankylosing Spondylitis: A Polysomnographic Study. AB - BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease that is associated with poor sleep quality. OBJECTIVES: The present study aimed to investigate the relationship between disease activity and sleep quality in patients with AS and to evaluate the potential effect of anti-tumor necrosis factor (TNF) treatment on sleep quality and pattern. METHODS: Fifty-nine patients with AS were consecutively included in the study. Twenty-eight patients (47.5%) were receiving anti-TNF, and 31 (52.5%) patients were receiving only nonsteroidal anti-inflammatory drugs (NSAIDs). Demographic and treatment characteristics, spinal mobility measurements, disease activity measurements, and sleep questionnaire results of each patient were recorded. Each patient underwent a polysomnography examination for the evaluation of sleep patterns. RESULTS: When compared with the patients on NSAID treatment, patients receiving anti-TNF treatment had significantly greater total sleep time and sleep efficiency (P = 0.003 and P < 0.001, respectively). They had a significantly lower (better) Pittsburgh Sleep Quality Index, sleep onset latency, number of awakenings, and arousal index (P < 0.001, for all). Moreover, they had a significantly shorter superficial sleep period (stage 1) and a significantly longer rapid eye movement sleep period (P < 0.001 and P = 0.02, respectively). Higher indexes of disease activity (Bath AS Disease Activity Index, Bath AS Functional Index, and visual analog scale) were reflecting poorer sleep quality. CONCLUSIONS: Sleep quality and pattern was markedly better in patients with AS on anti-TNF compared with the patients on NSAID treatments. Increased disease activity can impair the quality of sleep in AS. Improved sleep quality and pattern in patients on anti-TNF treatment may be related to improved disease activity. PMID- 27464769 TI - The Influence of Different Solvents on Systemic Sclerosis: An Updated Meta analysis of 14 Case-Control Studies. AB - BACKGROUND: Several studies have collected detailed data to examine which specific solvents account for the association between solvents and risk of systemic sclerosis (SSc). These studies generally reported elevated risks associated with many of the specific solvents examined, such as toluene, xylene, and trichloroethylene. The previous meta-analysis was not able to conduct separate analyses for specific solvent subtypes. OBJECTIVE: The aims of the new meta-analysis were to investigate a more comprehensive estimate and to consider the effect of different solvents on SSc. METHODS: We searched PubMed, Biosis Previews, China National Knowledge Infrastructure, and Wanfang for all articles published before July 2015. Fourteen case-control studies (1657 patients and 3838 controls) were included. The quality of studies was scored according to the Newcastle-Ottawa scale. The final odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by a fixed- or random-effects model according to heterogeneity test. Publication bias was assessed using Begg test. RESULTS: The risk of SSc was significantly different among sex, age, and exposure assessment methods. Separate analyses for specific solvent subtypes indicated that SSc was associated with aromatic solvents (OR, 2.72; 95% CI, 1.21-6.09), trichloroethylene (OR, 2.07; 95% CI, 1.34-3.17), halogenated solvents (OR, 1.49; 95% CI, 1.12-1.99), and ketones (OR, 4.20; 95% CI, 2.19-8.06). CONCLUSIONS: Exposure to identified types solvents does seem to be a risk factor for developing SSc. Needed efforts to decrease such exposures are discussed. PMID- 27464770 TI - Rheumatology Resources in a Region of Buenos Aires Province, Argentina. AB - BACKGROUND: Accurate knowledge of the available rheumatology workforce and their working conditions results in better care for patients with rheumatic diseases. OBJECTIVE: The aim of this study was to assess the rheumatology resources and their distribution within district V of the College of Physicians (COLMED5) of Buenos Aires Province, Argentina. METHODS: All the registered rheumatologists and all the registered public and private institutions within COLMED5 were identified. Aside from these data, phone calls, letters, Internet-derived information, and databases from public and private health insurance providers and the Argentine Society of Rheumatology were included as well. Rheumatologists' per capita rates were built for both the whole district and every town. A rate of at least 1 rheumatologist per 50,000 people was deemed an optimal resource. RESULTS: Thirty-six rheumatologists were identified; the calculated rate was 1 rheumatologist per 68,403 people; 44% of the health care institutions had a rheumatologist; 33% of them were public institutions. Only 25.5% of COLMED5 total population had optimal rheumatology resources in their town, 70.3% did not reach the optimal resource level but at least had a rheumatologist in their town, and 4.2% had no resources whatsoever; 49% of the total population lacked public health care facilities with inpatient settings and rheumatologists in their town. CONCLUSIONS: Although COLMED5 has 72% of the optimal number of rheumatologists, because of their uneven distribution, only 25.5% of the district's total population has the optimal rheumatology resources in their town. Nearly half COLMED5 total population lacks public health care facilities with inpatient settings and rheumatologists in their town, and 4.2% has no available rheumatology resource at all. PMID- 27464771 TI - Leprosy Masquerading as Systemic Rheumatic Diseases. AB - Rheumatologic manifestations not only are encountered in leprosy but also can be the first and even the sole presenting manifestation. The hallmark of leprosy is skin and peripheral nerve affection; however, it can affect a wide range of other organs, with the joints being the commonest. We have searched PubMed with the key words leprosy, arthritis, vasculitis, rheumatic diseases, and autoantibodies in a proper combination. Relevant studies were retrieved from scanning of their abstracts. The relevant references provided in these articles were also selected and reviewed. We summarize the clinical and laboratory manifestations that make leprosy masquerade as a systemic rheumatic disease. Moreover, we report 4 Egyptian patients who presented with rheumatologic manifestations, namely, arthritis and vasculitis that turned out to be leprosy related. PMID- 27464772 TI - Carpal Tunnel Syndrome and Motor Dysfunction Caused by Tophaceous Gout Infiltrating 12 Tendons. PMID- 27464773 TI - Digital Pulp Ulcerations and Inverse Gottron Papules in Melanoma Differentiation Associated Gene 5-Related Dermatomyositis. PMID- 27464774 TI - "Quiet Reflections" by an Artist With Seropositive Rheumatoid Arthritis, Highlighting the Potential Role of Cadmium Inhalation in the Workplace as a Trigger for Rheumatoid Arthritis. PMID- 27464775 TI - Calcium Pyrophosphate Dihydrate Deposition Disease in a Knee With Total Joint Replacement. PMID- 27464777 TI - Calcinosis Clues. PMID- 27464776 TI - Sarcoidosis of Hands. PMID- 27464778 TI - Stents Coated With Mammalian Target of Rapamycin Inhibitors (mTOR) Appear to Be the Best Choice in Patients With Antiphospholipid Syndrome and Myocardial Infarction. PMID- 27464779 TI - Ustekinumab as a Therapeutic Option for Children With Refractory Enthesitis Related Arthritis. PMID- 27464780 TI - Amyloid Arthropathy: When the Rheumatologist Meets the Hematologist. PMID- 27464781 TI - Hydroxychloroquine-Induced Cardiomyopathy in Systemic Lupus Erythematosus. PMID- 27464782 TI - Sustained Improvement of Fibromyalgia Syndrome After Electroconvulsive Therapy for Intractable Depression. PMID- 27464783 TI - Benefit of Tocilizumab Therapy for Adult-Onset Still Disease Complicated With Acute Respiratory Distress Syndrome. PMID- 27464784 TI - Hydrogen-Bonded Organic Frameworks (HOFs): A New Class of Porous Crystalline Proton-Conducting Materials. AB - Two porous hydrogen-bonded organic frameworks (HOFs) based on arene sulfonates and guanidinium ions are reported. As a result of the presence of ionic backbones appended with protonic source, the compounds exhibit ultra-high proton conduction values (sigma) 0.75* 10(-2) S cm(-1) and 1.8*10(-2) S cm(-1) under humidified conditions. Also, they have very low activation energy values and the highest proton conductivity at ambient conditions (low humidity and at moderate temperature) among porous crystalline materials, such as metal-organic frameworks (MOFs) and covalent organic frameworks (COFs). These values are not only comparable to the conventionally used proton exchange membranes, such as Nafion used in fuel cell technologies, but is also the highest value reported in organic based porous architectures. Notably, this report inaugurates the usage of crystalline hydrogen-bonded porous organic frameworks as solid-state proton conducting materials. PMID- 27464785 TI - Hepatitis C virus infection among patients with diabetes mellitus in Dammam, Saudi Arabia. AB - BACKGROUND: Data regarding comorbidities of hepatitis C virus infection (HCV) in the kingdom of Saudi Arabia (KSA) are lacking. The present study aimed to determine the prevalence and risk factors of HCV among Saudi patients with diabetes mellitus (DM) in Dammam, KSA. METHODS: In this cross-sectional study done in 2011, a total of 1054 Saudi DM patients were randomly selected from the Diabetes Center in Dammam Medical Complex, KSA, for interview and HCV screening using the HCV Rapid Test. Positive cases were later confirmed via INNO-LIA HCV score line immune assay. RESULTS: Seropositivity of HCV was 1.9 %. DM duration of >5 years increased the probability of HCV risk to 3.7 fold while insulin users were 3.2 times more likely to have HCV infection. Increased hospital admission (3 4 times) also increased HCV risk by 11.5 times and 13.6 times among patients with >=5 admissions. Similarly, having 3-4 surgical procedures increased HCV risk by 8.6 times and 39.3 times with >=5 procedures. HCV transmission is 4 times more likely by blood transfusion. Those who shared personal items were 8.5 times more likely to have HCV. Tattooing increased HCV risk by 6.7 times. The likelihood of HCV infection was also higher among DM patients with liver diseases and elevated liver enzymes. CONCLUSION: The study confirmed a significant association between HCV risk and DM. Frequency of HCV among DM Saudis was 1.9 %. Predictors of HCV among DM patients were sharing personal items, occupational exposure to blood or its products, elevated transaminases, tattooing, disease duration > 5 years, increased hospital admission and blood transfusion. PMID- 27464787 TI - MRI artifact correction using sparse + low-rank decomposition of annihilating filter-based hankel matrix. AB - PURPOSE: Magnetic resonance imaging (MRI) artifacts are originated from various sources including instability of an magnetic resonance (MR) system, patient motion, inhomogeneities of gradient fields, and so on. Such MRI artifacts are usually considered as irreversible, so additional artifact-free scan or navigator scan is necessary. To overcome these limitations, this article proposes a novel compressed sensing-based approach for removal of various MRI artifacts. THEORY: Recently, the annihilating filter based low-rank Hankel matrix approach was proposed. The annihilating filter based low-rank Hankel matrix exploits the duality between the low-rankness of weighted Hankel structured matrix and the sparsity of signal in a transform domain. Because MR artifacts usually appeared as sparse k-space components, the low-rank Hankel matrix from underlying artifact free k-space data can be exploited to decompose the sparse outliers. METHODS: The sparse + low-rank decomposition framework using Hankel matrix was proposed for removal of MRI artifacts. Alternating direction method of multipliers algorithm was employed for the minimization of associated cost function with the initialized matrices from a factorization-based matrix completion. RESULTS: Experimental results demonstrated that the proposed algorithm can correct MR artifacts including herringbone (crisscross), motion, and zipper artifacts without image distortion. CONCLUSION: The proposed method may be a robust correction solution for various MRI artifacts that can be represented as sparse outliers. Magn Reson Med 78:327-340, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27464789 TI - Secondhand Marijuana Smoke Is Not Benign. PMID- 27464788 TI - One Minute of Marijuana Secondhand Smoke Exposure Substantially Impairs Vascular Endothelial Function. AB - BACKGROUND: Despite public awareness that tobacco secondhand smoke (SHS) is harmful, many people still assume that marijuana SHS is benign. Debates about whether smoke-free laws should include marijuana are becoming increasingly widespread as marijuana is legalized and the cannabis industry grows. Lack of evidence for marijuana SHS causing acute cardiovascular harm is frequently mistaken for evidence that it is harmless, despite chemical and physical similarity between marijuana and tobacco smoke. We investigated whether brief exposure to marijuana SHS causes acute vascular endothelial dysfunction. METHODS AND RESULTS: We measured endothelial function as femoral artery flow-mediated dilation (FMD) in rats before and after exposure to marijuana SHS at levels similar to real-world tobacco SHS conditions. One minute of exposure to marijuana SHS impaired FMD to a comparable extent as impairment from equal concentrations of tobacco SHS, but recovery was considerably slower for marijuana. Exposure to marijuana SHS directly caused cannabinoid-independent vasodilation that subsided within 25 minutes, whereas FMD remained impaired for at least 90 minutes. Impairment occurred even when marijuana lacked cannabinoids and rolling paper was omitted. Endothelium-independent vasodilation by nitroglycerin administration was not impaired. FMD was not impaired by exposure to chamber air. CONCLUSIONS: One minute of exposure to marijuana SHS substantially impairs endothelial function in rats for at least 90 minutes, considerably longer than comparable impairment by tobacco SHS. Impairment of FMD does not require cannabinoids, nicotine, or rolling paper smoke. Our findings in rats suggest that SHS can exert similar adverse cardiovascular effects regardless of whether it is from tobacco or marijuana. PMID- 27464790 TI - Photochemical Tissue Passivation Reduces Vein Graft Intimal Hyperplasia in a Swine Model of Arteriovenous Bypass Grafting. AB - BACKGROUND: Bypass grafting remains the standard of care for coronary artery disease and severe lower extremity ischemia. Efficacy is limited by poor long term venous graft patency secondary to intimal hyperplasia (IH) caused by venous injury upon exposure to arterial pressure. We investigate whether photochemical tissue passivation (PTP) treatment of vein grafts modulates smooth muscle cell (SMC) proliferation and migration, and inhibits development of IH. METHODS AND RESULTS: PTP was performed at increasing fluences up to 120 J/cm(2) on porcine veins. Tensiometry performed to assess vessel elasticity/stiffness showed increased stiffness with increasing fluence until plateauing at 90 J/cm(2) (median, interquartile range [IQR]). At 90 J/cm(2), PTP-treated vessels had a 10 fold greater Young's modulus than untreated controls (954 [IQR, 2217] vs 99 kPa [IQR, 63]; P=0.03). Each pig received a PTP-treated and untreated carotid artery venous interposition graft. At 4-weeks, intimal/medial areas were assessed. PTP reduced the degree of IH by 66% and medial hypertrophy by 49%. Intimal area was 3.91 (IQR, 1.2) and 1.3 mm(2) (IQR, 0.97; P<=0.001) in untreated and PTP-treated grafts, respectively. Medial area was 9.2 (IQR, 3.2) and 4.7 mm(2) (IQR, 2.0; P<=0.001) in untreated and PTP-treated grafts, respectively. Immunohistochemistry was performed to assess alpha-smooth muscle actin (SMA) and proliferating cell nuclear antigen (PCNA). Objectively, there were less SMA-positive cells within the intima/media of PTP-treated vessels than controls. There was an increase in PCNA-positive cells within control vein grafts (18% [IQR, 5.3]) versus PTP treated vein grafts (5% [IQR, 0.9]; P=0.02). CONCLUSIONS: By strengthening vein grafts, PTP decreases SMC proliferation and migration, thereby reducing IH. PMID- 27464791 TI - Nocturnal Hypoxemia Due to Obstructive Sleep Apnea Is an Independent Predictor of Poor Prognosis After Myocardial Infarction. AB - BACKGROUND: Obstructive sleep apnea (OSA) is an important risk factor for the development of cardiovascular diseases including myocardial infarction (MI). The aim of this study was to investigate the effects of OSA on prognosis after MI, and to determine which specific measures of OSA severity best predicted outcomes. METHODS AND RESULTS: We performed a prospective study, in which 112 patients without a prior diagnosis of sleep apnea underwent comprehensive polysomnography within a median of 7 days after MI. Patients were followed up at 6-monthly intervals (+/-2 weeks) for a total of 48 months. Patients classified with central apnea (n=6) or those using continuous positive airway pressure (n=8) after polysomnography were excluded from analyses. The primary end point was major adverse cardiac events, including death from any cause, recurrent MI, unstable angina, heart failure, stroke, and significant arrhythmic events. Forty of 98 patients (41%) had OSA (apnea-hypopnea index >=15 events/h). OSA patients had higher major adverse cardiac event rates when compared to those without OSA (47.5% versus 24.1%; chi(2)=5.41, P=0.020). In a multivariate model that adjusted for clinically relevant variables including age, left ventricular ejection fraction, diabetes mellitus, oxygen desaturation index, and arousal index, significant hypoxemia, as defined by nocturnal nadir oxygen saturation <=85%, was an independent risk factor for major adverse cardiac events (hazard ratio=6.05, P=0.004) in follow-up 15 months after baseline. CONCLUSIONS: Nocturnal hypoxemia in OSA is an important predictor of poor prognosis for patients after MI. These findings suggest that routine use of low-cost nocturnal oximetry may be an economical and practical approach to stratify risk in post-MI patients. PMID- 27464792 TI - Critical Role of Coaptive Strain in Aortic Valve Leaflet Homeostasis: Use of a Novel Flow Culture Bioreactor to Explore Heart Valve Mechanobiology. AB - BACKGROUND: Aortic valve (AV) disease presents critical situations requiring surgery in over 2% of the US population and is increasingly the reason for cardiac surgery. Throughout the AV cycle, mechanical forces of multiple types and varying intensities are exerted on valve leaflets. The mechanisms whereby forces regulate leaflet homeostasis are incompletely understood. We used a novel flow bioreactor culture to investigate alteration of AV opening or closure on leaflet genes. METHODS AND RESULTS: Culture of rat AV was conducted in a flow bioreactor for 7 days at 37 degrees C under conditions approximating the normal stroke volume. Three force condition groups were compared: Cycling (n=8); always open (Open; n=3); or always closed (Closed; n=5). From each culture, AV leaflets were pooled by force condition and RNA expression evaluated using microarrays. Hierarchical clustering of 16 transcriptome data sets from the 3 groups revealed only 2 patterns of gene expression: Cycling and Closed groups clustered together, whereas Open AV were different (P<0.05). Sustained AV opening induced marked changes in expression (202 transcripts >2-fold; P<0.05), whereas Closed AV exhibited similar expression pattern as Cycling (no transcripts >2-fold; P<0.05). Comparison with human sclerotic and calcific AV transcriptomes demonstrated high concordance of >40 Open group genes with progression toward disease. CONCLUSIONS: Failure of AV to close initiates an extensive response characterized by expression changes common to progression to calcific aortic valve disease. AV coaptation, whether phasic or chronic, preserved phenotypic gene expression. These results demonstrate, for the first time, that coaptation of valve leaflets is a fundamentally important biomechanical cue driving homeostasis. PMID- 27464793 TI - Resistance training concomitant to radiotherapy of spinal bone metastases - survival and prognostic factors of a randomized trial. AB - PURPOSE: To compare the effects of resistance training versus passive physical therapy on bone survival in the metastatic bone during radiation therapy (RT) as combined treatment in patients with spinal bone metastases. Secondly, to evaluate overall survival and progression-free-survival (PFS) as well as to quantify prognostic factors of bone survival after combined treatment. METHODS: In this randomized trial 60 patients were allocated from September 2011 until March 2013 into one of the two groups: resistance training (group A) or passive physical therapy (group B) with thirty patients in each group during RT. We estimated patient survival using Kaplan-Meier survival method. The Wald-test was used to evaluate the prognostic importance of pathological fracture, primary site, Karnofsky performance status, localization of metastases, number of metastases, and cerebral metastases. RESULTS: Median follow-up was 10 months (range 2-35). Bone survival showed no significant difference between groups (p = .303). Additionally no difference between groups could be detected in overall survival (p = .688) and PFS (p = .295). Local bone progression was detected in 16.7 % in group B, no irradiated bone in group A showed a local progression over the course (p = 0.019). In univariate analysis breast cancer, prostate cancer, and the presence of cerebral metastases had a significant impact on bone survival in group B, while no impact could be demonstrated in group A. CONCLUSIONS: In this group of patients with spinal bone metastases we were able to show that guided resistance training of the paravertebral muscles had no essential impact on survival concomitant to RT. Importantly, no local bone progression in group A was detected, nevertheless no prognostic factor for combined treatment could be evaluated. TRIAL REGISTRATION: Clinical trial identifier NCT 01409720 . Registered 8 February 2011. PMID- 27464794 TI - Erratum to: Rates of BRCA1/2 mutation testing among young survivors of breast cancer. PMID- 27464795 TI - Clinical and biological significance of RAD51 expression in breast cancer: a key DNA damage response protein. AB - Impaired DNA damage response (DDR) may play a fundamental role in the pathogenesis of breast cancer (BC). RAD51 is a key player in DNA double-strand break repair. In this study, we aimed to assess the biological and clinical significance of RAD51 expression with relevance to different molecular classes of BC and patients' outcome. The expression of RAD51 was assessed immunohistochemically in a well-characterised annotated series (n = 1184) of early-stage invasive BC with long-term follow-up. A subset of cases of BC from patients with known BRCA1 germline mutations was included as a control group. The results were correlated with clinicopathological and molecular parameters and patients' outcome. RAD51 protein expression level was also assayed in a panel of cell lines using reverse phase protein array (RPPA). RAD51 was expressed in the nuclei (N) and cytoplasm (C) of malignant cells. Subcellular co-localisation phenotypes of RAD51 were significantly associated with clinicopathological features and patient outcome. Cytoplasmic expression (RAD51C(+)) and lack of nuclear expression (RAD51 N(-)) were associated with features of aggressive behaviour, including larger tumour size, high grade, lymph nodal metastasis, basal-like, and triple-negative phenotypes, together with aberrant expression of key DDR biomarkers including BRCA1. All BRCA1-mutated tumours had RAD51C(+)/N(-) phenotype. RPPA confirmed IHC results and showed differential expression of RAD51 in cell lines based on ER expression and BRCA1 status. RAD51 N(+) and RAD51C(+) tumours were associated with longer and shorter breast cancer-specific survival (BCSS), respectively. The RAD51 N(+) was an independent predictor of longer BCSS (P < 0.0001). Lack of RAD51 nuclear expression is associated with poor prognostic parameters and shorter survival in invasive BC patients. The significant associations between RAD51 subcellular localisation and clinicopathological features, molecular subtype and patients' outcome suggest that the trafficking of DDR proteins between the nucleus and cytoplasm might play a role in the development and progression of BC. PMID- 27464796 TI - Network measures for protein folding state discrimination. AB - Proteins fold using a two-state or multi-state kinetic mechanisms, but up to now there is not a first-principle model to explain this different behavior. We exploit the network properties of protein structures by introducing novel observables to address the problem of classifying the different types of folding kinetics. These observables display a plain physical meaning, in terms of vibrational modes, possible configurations compatible with the native protein structure, and folding cooperativity. The relevance of these observables is supported by a classification performance up to 90%, even with simple classifiers such as discriminant analysis. PMID- 27464797 TI - Chemical Screening in Zebrafish. AB - Phenotypic small molecule screens in zebrafish have gained popularity as an unbiased approach to probe biological processes. In this chapter we outline basic methods for performing chemical screens with larval zebrafish including breeding large numbers of embryos, plating larval fish into multi-well dishes, and adding small molecules to these wells. We also highlight important considerations when designing and interpreting the results of a phenotypic screen and possible follow up approaches, including popular methods used to identify the mechanism of action of a chemical compound. PMID- 27464798 TI - TALEN-Mediated Mutagenesis and Genome Editing. AB - Transcription activator-like effectors (TALEs) are important genomic tools with customizable DNA-binding motifs for locus-specific modifications. In particular, TALE nucleases or TALENs have been successfully used in the zebrafish model system to introduce targeted mutations via repair of double-stranded breaks (DSBs) either through nonhomologous end joining (NHEJ) or by homology-directed repair (HDR) and homology-independent repair in the presence of a donor template. Compared with other customizable nucleases, TALENs offer high binding specificity and fewer sequence constraints in targeting the genome, with comparable mutagenic activity. Here, we describe a detailed in silico design tool for zebrafish genome editing for TALENs and CRISPR/Cas9 custom restriction enzymes using Mojo Hand 2.0 software. PMID- 27464800 TI - Detection of Multiple Genome Modifications Induced by the CRISPR/Cas9 System. AB - The recent remarkable innovation of an RNA-guided nuclease system, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system, enables us the modification of specific genomic loci in various model animals including zebrafish. With this system, multiple guide RNAs simultaneously injected with the Cas9 nuclease into zebrafish embryos cause multiple genome modifications at different genomic loci with high efficiency; therefore, a simple method to detect individual mutations at distinct loci is desired. In this chapter, we describe a procedure for inducing multiple CRISPR/Cas9-mediated genome modifications in zebrafish and a convenient method to detect CRISPR/Cas9 induced insertion and/or deletion (indel) mutations using a heteroduplex mobility assay (HMA). PMID- 27464799 TI - Homology-Independent Integration of Plasmid DNA into the Zebrafish Genome. AB - Targeting nucleases like zinc-finger nucleases (ZFNs), transcription activator like effector nucleases (TALENs), and the clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) system have revolutionized genome-editing possibilities in many model organisms. They allow the generation of loss-of-function alleles by the introduction of double-strand breaks at defined sites within genes, but also more sophisticated genome-editing approaches have become possible. These include the integration of donor plasmid DNA into the genome by homology-independent repair mechanisms after CRISPR/Cas9-mediated cleavage. Here we present a protocol outlining the most important steps to target a genomic site and to integrate a donor plasmid at this defined locus. PMID- 27464801 TI - Generation of Targeted Genomic Deletions Through CRISPR/Cas System in Zebrafish. AB - Using TALEN or CRISPR/Cas system to induce small indels into coding sequences has been implicated in broad applications for reverse genetic studies of many organisms including zebrafish. However, complete deletion of a large gene or noncoding gene(s) or removing a large genomic fragment spanning several genes or other chromosomal elements is preferred in various cases, as well as inducing chromosomal inversions. Here, we describe the detailed protocols for the generation of chromosomal deletion mutations mediated by Cas9 and a pair of gRNAs and the evaluation for the efficiencies in F0 founder fish and of germline transmission. PMID- 27464802 TI - Testing of Cis-Regulatory Elements by Targeted Transgene Integration in Zebrafish Using PhiC31 Integrase. AB - Herein we present several strategies for testing the function of cis-regulatory elements using the PhiC31 integrase system. Firstly, we present two different strategies to analyze the activity of candidate enhancer elements. Targeted integration of candidate enhancers into the same genomic location circumvents the variability-associated random integration and position effects. This method is suitable for testing of candidate enhancers identified through computational or other analyses a priori. Secondly, we present methodology for targeted integration of BACs into the same genomic location(s). By using additional reporters integrated into a BAC, this enables experimental testing whether cis regulatory elements are functional in the sequence inserted in the BAC. PMID- 27464804 TI - Construction of the Inbred Strain. AB - Genetically homogeneous populations such as inbred strains are valuable experimental tools in various fields of biomedical analyses. In many animals, inbred strains are established by consecutive sib-pair mating for a minimum of 20 generations. As the generation proceeds, fitness of the population reduces usually. Therefore, in order to establish inbred strains, the important point is the selection of pairs in good condition at each generation. Here, I describe the procedure and tips for generating inbred strains in zebrafish. PMID- 27464803 TI - Fluorescence-Activated Cell Sorting and Gene Expression Profiling of GFP-Positive Cells from Transgenic Zebrafish Lines. AB - Gene expression profiling is a useful approach for deeper understanding of the specificity of cells, tissues, and organs in the transcriptional level. Recent development of high-throughput next-generation sequence (NGS) allows the RNA-seq method for this profiling. This method provides precise information of transcripts about the quantitation and the structure such as the splicing variants. In this chapter, we describe a method for gene expression profiling of GFP-positive cells from transgenic zebrafish by RNA-seq. We labeled specific cells in the brain with GFP by crossing a Gal4 driver line with the UAS:GFP line, isolated those cells by fluorescence-activated cell sorting (FACS), and analyzed by RNA-seq. PMID- 27464805 TI - Zebrafish as a Model for the Study of Solid Malignancies. AB - Zebrafish cancer models have provided critical insight into understanding the link between aberrant developmental pathways and tumorigenesis. The unique strengths of zebrafish as compared to other vertebrate model systems include the combination of fecundity, readily available and efficient transgenesis techniques, transparency that facilitates in vivo cell lineage tracing, and amenability for high-throughput applications. In addition to early embryo readouts, zebrafish can develop tumors at ages ranging from 2 weeks old to adulthood. Tumorigenesis is driven by genetically introducing oncogenes using selected promoter/tissue-specific expression, with either mosaic expression or with the generation of a stable transgenic line. Here, we detail a research pipeline to facilitate the study of human oncogenes in zebrafish systems. The goals of this approach are to identify conserved developmental pathways that may be critical for tumor development and to create platforms for testing novel therapies. PMID- 27464806 TI - Melanoma Regression and Recurrence in Zebrafish. AB - Melanoma is the most lethal form of skin cancer with high mortality rates. Most melanoma cases have activating mutations in BRAF (V600E) and the selective inhibitors of BRAF(V600E) have been successfully used in patients. However, after initial tumor regression, the majority of patients develop drug resistance resulting in tumor regrowth. It is therefore important to understand the mechanisms underlying these processes. We have recently described the role of the master melanocyte transcription factor MITF in tumor growth, regression, and recurrence. Here, we describe protocols to study regression and recurrence in vivo, as well as for histology and immunohistochemistry, using a temperature sensitive zebrafish model of human melanoma. PMID- 27464807 TI - Imaging of Human Cancer Cell Proliferation, Invasion, and Micrometastasis in a Zebrafish Xenogeneic Engraftment Model. AB - The xenograft model, using the early life stages of the zebrafish, allows imaging of tumor cell behavior both on a single cell and whole organism level, over time, within a week. This robust and reproducible assay can be used as an intermediate step between in vitro techniques and the expensive, and time consuming, murine models of cancer invasion and metastasis.In this chapter, a detailed protocol to inject human cancer cells into the blood circulation of a zebrafish embryo is described; the engraftment procedure is then followed by visualization and quantification methods of tumor cell proliferation, invasion, and micrometastasis formation during subsequent larval development. Interaction with the host microenvironment is also considered. PMID- 27464808 TI - Modeling Leukemogenesis in the Zebrafish Using Genetic and Xenograft Models. AB - The zebrafish is a widely accepted model to study leukemia. The major advantage of studying leukemogenesis in zebrafish is attributed to its short life cycle and superior imaging capacity. This chapter highlights using transgenic- and xenograft-based models in zebrafish to study a specific leukemogenic mutation and analyze therapeutic responses in vivo. PMID- 27464809 TI - Enumerating Hematopoietic Stem and Progenitor Cells in Zebrafish Embryos. AB - Over the past 20 years, zebrafish have proven to be a valuable model to dissect the signaling pathways involved in hematopoiesis, including Hematopoietic Stem and Progenitor Cell (HSPC) formation and homeostasis. Despite tremendous efforts to generate the tools necessary to characterize HSPCs in vitro and in vivo the zebrafish community still lacks standardized methods to quantify HSPCs across laboratories. Here, we describe three methods used routinely in our lab, and in others, to reliably enumerate HSPCs in zebrafish embryos: large-scale live imaging of transgenic reporter lines, Fluorescence-Activated Cell Sorting (FACS), and in vitro cell culture. While live imaging and FACS analysis allows enumeration of total or site-specific HSPCs, the cell culture assay provides the unique opportunity to test the functional potential of isolated HSPCs, similar to those employed in mammals. PMID- 27464810 TI - Live Imaging of Host-Pathogen Interactions in Zebrafish Larvae. AB - Zebrafish larvae are a powerful platform for studying the innate immune response to infection. The small size and optical transparency of larval zebrafish allow for multiple subject, multidimensional, and longitudinal imaging experiments. This chapter describes protocols for infecting zebrafish larvae with their natural pathogen Mycobacterium marinum, rapid short-term imaging, long-term extended imaging, and drug treatment assays. These protocols can be easily adapted to image and manipulate host interactions with other pathogens. PMID- 27464811 TI - Methodologies for Inducing Cardiac Injury and Assaying Regeneration in Adult Zebrafish. AB - The zebrafish has emerged as an important model organism for understanding the cellular and molecular mechanisms of tissue regeneration. Adult zebrafish efficiently replace cardiac muscle after partial resection of their ventricle, or after transgenic ablation of cardiomyocytes. Here, we describe methodology for inducing these injuries and assaying indicators of regeneration. PMID- 27464812 TI - Studying Lipid Metabolism and Transport During Zebrafish Development. AB - The zebrafish model facilitates the study of lipid metabolism and transport during development. Here, we outline methods to introduce traceable fluorescent or radiolabeled fatty acids into zebrafish embryos and larvae at various developmental stages. Labeled fatty acids can be injected into the large yolk cell prior to the development of digestive organs when the larvae is entirely dependent on the yolk for its nutrition (lecithotrophic state). Once zebrafish are able to consume exogenous food, labeled fatty acids can be incorporated into their food. Our group and others have demonstrated that the transport and processing of these injected or ingested fatty acid analogs can be followed through microscopy and/or biochemical analysis. These techniques can be easily combined with targeted antisense approaches, transgenics, or drug treatments (see Note 1 ), allowing studies of lipid cell biology and metabolism that are exceedingly difficult or impossible in mammals. PMID- 27464813 TI - Targeted Electroporation in Embryonic, Larval, and Adult Zebrafish. AB - This chapter describes three fast and straightforward methods to introduce nucleic acids, dyes, and other molecules into small numbers of cells of zebrafish embryos, larvae, and adults using electroporation. These reagents are delivered through a glass micropipette and electrical pulses are given through electrodes to permeabilize cell membranes and promote uptake of the reagent. This technique allows the experimenter to target cells of their choice at a particular time of development and at a particular location in the zebrafish with high precision and facilitates long-term noninvasive measurement of biological activities in vivo. Applications include cell fate mapping, neural circuit mapping, neuronal activity measurement, manipulation of activity, ectopic gene expression, and genetic knockdown experiments. PMID- 27464814 TI - Studying Axonal Regeneration by Laser Microsurgery and High-Resolution Videomicroscopy. AB - Heterogeneous and unpredictable environmental insult, disease, or trauma can affect the integrity and function of neuronal circuits, leading to irreversible neural dysfunction. The peripheral nervous system can robustly regenerate axons after damage to recover the capacity to transmit sensory information to the brain. The mechanisms that allow axonal repair remain incompletely understood. Here we present a preparation in zebrafish that combines laser microsurgery of sensory axons and videomicroscopy of neurons in multicolor transgenic specimens. This simple protocol allows controlled damage of axons and dynamic high resolution visualization and quantification of repair. PMID- 27464815 TI - In Vivo Whole-Cell Patch-Clamp Recording in the Zebrafish Brain. AB - Zebrafish (Danio rerio) is a newly emerged vertebrate animal model with a conserved gross architecture of the brain and a rich repertoire of behaviors. Due to the optical transparency and structural simplicity of its brain, larval zebrafish has become an ideal in vivo model for dissecting neural mechanisms of brain functions at a whole-brain scale based on a strategy that spans scales from synapses, neurons, and circuits to behaviors. Whole-cell patch-clamp recording is an indispensable approach for studying synaptic and circuit mechanisms of brain functions. Due to the small size of neurons in the zebrafish brain, it is challenging to get whole-cell recordings from these cells. Here, we describe a protocol for obtaining in vivo whole-cell patch-clamp recordings from neurons in larval zebrafish. PMID- 27464816 TI - Quantifying Aggressive Behavior in Zebrafish. AB - Aggression is a complex behavior that influences social relationships and can be seen as adaptive or maladaptive depending on the context and intensity of expression. A model organism suitable for genetic dissection of the underlying neural mechanisms of aggressive behavior is still needed. Zebrafish has already proven to be a powerful vertebrate model organism for the study of normal and pathological brain function. Despite the fact that zebrafish is a gregarious species that forms shoals, when allowed to interact in pairs, both males and females express aggressive behavior and establish dominance hierarchies. Here, we describe two protocols that can be used to quantify aggressive behavior in zebrafish, using two different paradigms: (1) staged fights between real opponents and (2) mirror-elicited fights. We also discuss the methodology for the behavior analysis, the expected results for both paradigms, and the advantages and disadvantages of each paradigm in face of the specific goals of the study. PMID- 27464817 TI - Correlating Whole Brain Neural Activity with Behavior in Head-Fixed Larval Zebrafish. AB - We present a protocol to combine behavioral recording and imaging using 2-photon laser-scanning microscopy in head-fixed larval zebrafish that express a genetically encoded calcium indicator. The steps involve restraining the larva in agarose, setting up optics that allow projection of a visual stimulus and infrared illumination to monitor behavior, and analysis of the neuronal and behavioral data. PMID- 27464818 TI - A Practical Guide to Light Sheet Microscopy. AB - Light sheet fluorescence microscopy is an efficient method for imaging large volumes of biological tissue, including brains of larval zebrafish, at high spatial and fairly high temporal resolution with minimal phototoxicity.Here, we provide a practical guide for those who intend to build a light sheet microscope for fluorescence imaging in live larval zebrafish brains or other tissues. PMID- 27464819 TI - Calcium Imaging of Neuronal Activity in Free-Swimming Larval Zebrafish. AB - Visualization of neuronal activity during animal behavior is a critical step in understanding how the brain generates behavior. In the model vertebrate zebrafish, imaging of the brain has been done mostly by using immobilized fish. Here, we describe a novel method to image neuronal activity of the larval zebrafish brain during prey capture behavior. We expressed a genetically encoded fluorescent calcium indicator, GCaMP, in the optic tectum of the midbrain using the Gal4-UAS system. Tectal activity was then imaged in unrestrained larvae during prey perception. Since larval zebrafish swim only intermittently, detection of the neuronal activity is possible between swimming bouts. Our method makes functional brain imaging under natural behavioral conditions feasible and will greatly benefit the study of neuronal activities that evoke animal behaviors. PMID- 27464820 TI - Fiber Optic-Based Photostimulation of Larval Zebrafish. AB - The perturbation of neural activity is a powerful experimental approach for understanding brain function. Light-gated ion channels and pumps (optogenetics) can be used to control neural activity with high temporal and spatial precision in animal models. This optogenetic approach requires suitable methods for delivering light to the brain. In zebrafish, fiber optic stimulation of agarose embedded larvae has successfully been used in several studies to control neural activity and behavior. This approach is easy to implement and cost-efficient. Here, a protocol for fiber optic-based photostimulation of larval zebrafish is provided. PMID- 27464821 TI - Genetic Ablation, Sensitization, and Isolation of Neurons Using Nitroreductase and Tetrodotoxin-Insensitive Channels. AB - Advances in genetic technologies enable the highly selective expression of transgenes in targeted neuronal cell types. Transgene expression can be used to noninvasively ablate, silence or activate neurons, providing a tool to probe their contribution to the control of behavior or physiology. Here, we describe the use of the tetrodotoxin (TTX)-resistant voltage-gated sodium channel Nav1.5 for either sensitizing neurons to depolarizing input, or isolating targeted neurons from surrounding neural activity, and methods for selective neuronal ablation using the bacterial nitroreductase NfsB. PMID- 27464823 TI - Severe antiretroviral-associated skin reactions in South African patients: a case series and case-control analysis. AB - PURPOSE: Severe skin reactions may complicate combination antiretroviral therapy (cART). Nevirapine is known to be associated with severe skin reactions, but there are conflicting data on risk factors in African patients. We reviewed cases of severe skin reactions admitted to a tertiary hospital in Cape Town, South Africa. We identified associations with severe skin reactions in patients on cART. METHODS: We described severe skin reaction cases in patients taking cART admitted to Groote Schuur Hospital in Cape Town, South Africa, between 2006 and 2012. We included those patients who developed a severe skin reaction within 120 days of cART initiation in a case-control analysis. We identified control patients matched on date of cART initiation and primary care facility by linkage with the Western Cape electronic provincial HIV database. We conducted a conditional (fixed effects) logistic regression modelling. RESULTS: We identified 169 severe skin reactions in patients on cART. The most common presentations were Stevens Johnson syndrome/toxic epidermal necrolysis (49%) and drug hypersensitivity syndrome (36%). One hundred forty-one patients were female, of which 27 were pregnant. Median duration of hospitalization was 12 days (interquartile range 8 to 19) and six patients died. We included 91 cases and 361 matched controls in the analysis. Severe skin reaction was associated with nevirapine exposure, adjusted odds ratio of 7.6 (95%CI 3.7 to 15.7) and with pregnancy, adjusted odds ratio 3.7 (95%CI 1.3 to 10.8) compared with men. CONCLUSIONS: Severe skin reactions resulted in prolonged admission to hospital in this setting. We found that nevirapine use and pregnancy are independently associated with severe skin reaction. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27464824 TI - CRR1 encoding callose synthase functions in ovary expansion by affecting vascular cell patterning in rice. AB - The ovary of rice undergoes rapid expansion immediately after fertilization, and this process determines the final sink strength potential of caryopses. To date, work on rice grain development has mainly focused on endosperm filling, whereas information on the essential elements for ovary expansion remains limited. We report here a functional analysis of the ovary expansion retarded mutant crr1 in rice. Map-based cloning revealed that CRR1 encodes a protein homologous to the Arabidopsis callose synthases AtGSL8 and AtGSL10. Point mutation in crr1 resulted in alternative splicing, which led to the formation of the truncated crr1 protein without the beta-glucan synthase domain. Iodine staining showed that there were few starch granules and these were unevenly distributed in the pericarp of crr1, and a 5,6-carboxyfluorescein diacetate transport assay revealed that carbohydrates were less efficiently unloaded from the lateral vasculature into the developing caryopsis. CRR1 transcripts were detected in all plant organs, with the highest level found in receptacles, which are mainly composed of vascular tissues. Analysis of pCRR1::GUS transgenic plants showed that CRR1 was specifically expressed in vascular bundle cells. Consistently, loss of function of CRR1 led to disordered patterns of vascular cells in the ovaries and receptacles of the mutant. Furthermore, a small portion of cells in the vascular bundles of crr1 showed defective cell wall formation, and callose deposition was specifically reduced at the plasmodesmata (PD) of cells with aberrant walls. Our results suggest that CRR1 performs a pivotal role in determining initial ovary expansion in rice, possibly via the PD-mediated permeability of cell fate determinants for vascular cell differentiation. PMID- 27464822 TI - Angiogenic cytokines and their influence on circulating tumour cells in sera of patients with the primary diagnosis of breast cancer before treatment. AB - BACKGROUND: Circulating tumour cells (CTCs) have been found to be a prognostic marker for reduced disease free survival, breast cancer-specific survival, and overall survival before the start of systemic treatment. METHODS: A total of 200 patients' sera were included in this study, 100 patients being CTC positive and 100 patients being CTC negative. Matching criteria were histo-pathological grading, lymph node metastasis, hormone receptor status, TNM classification and survived breast cancer patients vs. deceased tumor associated patients. A multi cytokine/chemokine array was used to screen the sera for the angiogenic markers. RESULTS: Statistical significant correlation was exposed for sFlt1 values in regard to the CTC-Status. CTC negative patients displayed increased sFlt1 expression opposed to CTC positive breast cancer patients. Furthermore, significant enhanced PIGF values were also disclosed in CTC negative patients compared to patients being CTC positive. Analyzing the living patient collective we found significant differences in sFlt1 and PlGF values in regard to CTC negative and CTC positive patients. CONCLUSION: Both vascular markers showed enhanced expression in the CTC negative patient collective. To continue, the collective graded G2 showed significantly enhanced sFlt1 expressions amongst patients with no CTCs. Moreover, the patient collective with no lymph node metastasis and CTC negativity indicated statistically significant increased sFlt1 values. A functional interaction of sFlt1 and PlGF was found, suggesting that their overexpression in tumour cells inhibits CTCs entering the peripheral blood. Furthermore, in regard to CTC negativity, sFlt1 and PlGF values may potentially serve as predictive markers. TRIAL REGISTRATION: The TRN of this study is NCT02181101 and the date of registration was the 4(th) of June 2014. The study was retrospectively registered. PMID- 27464825 TI - Estimation of delays in generalized asynchronous Boolean networks. AB - A new generalized asynchronous Boolean network (GABN) model has been proposed in this paper. This continuous-time discrete-state model captures the biological reality of cellular dynamics without compromising the computational efficiency of the Boolean framework. The GABN synthesis procedure is based on the prior knowledge of the logical structure of the regulatory network, and the experimental transcriptional parameters. The novelty of the proposed methodology lies in considering different delays associated with the activation and deactivation of a particular protein (especially the transcription factors). A few illustrative examples of some well-studied network motifs have been provided to explore the scope of using the GABN model for larger networks. The GABN model of the p53-signaling pathway in response to gamma-irradiation has also been simulated in the current paper to provide an indirect validation of the proposed schema. PMID- 27464826 TI - The biochemical characterization of three imine-reducing enzymes from Streptosporangium roseum DSM43021, Streptomyces turgidiscabies and Paenibacillus elgii. AB - Recently imine reductases (IREDs) have emerged as promising biocatalysts for the synthesis of a wide variety of chiral amines. To promote their application, many novel enzymes were reported, but only a few of them were biochemically characterized. To expand the available knowledge about IREDs, we report the characterization of two recently identified (R)-selective IREDs from Streptosporangium roseum DSM43021 and Streptomyces turgidiscabies and one (S) selective IRED from Paenibacillus elgii. The biochemical properties including pH profiles, temperature stabilities, and activities of the enzymes in the presence of organic solvents were investigated. All three enzymes showed relatively broad pH spectra with maximum activities in the neutral range. While the (R)-selective IREDs displayed only limited thermostabilities, the (S)-selective enzyme was found to be the most thermostable IRED known to date. The activity of this IRED proved also to be most tolerant towards the investigated co-solvents DMSO and methanol. We further studied activities and selectivities towards a panel of cyclic imine model substrates to compare these enzymes with other IREDs. In biotransformations, IREDs showed high conversions and the amine products were obtained with up to 99 % ee. By recording the kinetic constants for these compounds, substrate preferences of the IREDs were investigated and it was shown that the (S)-IRED favors the transformation of bulky imines contrary to the (R) selective IREDs. Finally, novel exocyclic imine substrates were tested and also high activities and selectivities detected. PMID- 27464827 TI - Anaerobic digestion of chemically enhanced primary treatment (CEPT) sludge and the microbial community structure. AB - The effectiveness and treatment conditions of FeCl3- and AlCl3-coagulated municipal sewage sludge from chemically enhanced primary treatment (CEPT) using anaerobic digestion (AD) and the structure of microbial community were investigated. The results based on 297 measurements under different operational conditions demonstrate good average AD performance of CEPT sludge, that is, percent volatile solid reduction of 58 %, specific biogas production (or biogas yield) of 0.92 m(3)/kg volatile solids (VS) destroyed, and methane content of 65.4 %. FeCl3 dosing, organic loading rate, temperature, and hydraulic retention time all significantly affected AD performance. FeCl3 dosing greatly improved specific methane production (methane yield) by 38-54 % and significantly reduced hydrogen sulfide (H2S) content in biogas (from up to 13,250 to <200 ppm), contributing to higher methane recovery and simplified biogas cleaning for power generation. Metagenomic analysis suggested that anaerobic digesters of both CEPT sludge and combined primary and secondary sludge were dominated by Bacteroidetes, Proteobacteria, Firmicutes, Actinobacteria, Thermotogae, and Chloroflexi. However, Methanomicrobia methanogens were better enriched in the anaerobic digesters of CEPT sludge than in the combined sludge. Further, different sources of CEPT sludge with various chemical properties nurtured shared and unique microbial community composition. Combined, this study supports AD as an efficient technology for CEPT sludge treatment and poses first insights into the microbial community structure. PMID- 27464828 TI - Structure of bacterial communities in soil following cover crop and organic fertilizer incorporation. AB - Incorporation of organic material into soils is an important element of organic farming practices that can affect the composition of the soil bacterial communities that carry out nutrient cycling and other functions crucial to crop health and growth. We conducted a field experiment to determine the effects of cover crops and fertilizers on bacterial community structure in agricultural soils under long-term organic management. Illumina sequencing of 16S rDNA revealed diverse communities comprising 45 bacterial phyla in corn rhizosphere and bulk field soil. Community structure was most affected by location and by the rhizosphere effect, followed by sampling time and amendment treatment. These effects were associated with soil physicochemical properties, including pH, moisture, organic matter, and nutrient levels. Treatment differences were apparent in bulk and rhizosphere soils at the time of peak corn growth in the season following cover crop and fertilizer application. Cover crop and fertilizer treatments tended to lower alpha diversity in early season samples. However, winter rye, oilseed radish, and buckwheat cover crop treatments increased alpha diversity in some later season samples compared to a no-amendment control. Fertilizer treatments and some cover crops decreased relative abundance of members of the ammonia-oxidizing family Nitrosomonadaceae. Pelleted poultry manure and Sustane(r) (a commercial fertilizer) decreased the relative abundance of Rhizobiales. Our data point to a need for future research exploring how (1) cover crops influence bacterial community structure and functions, (2) these effects differ with biomass composition and quantity, and (3) existing soil conditions and microbial community composition influence how soil microbial populations respond to agricultural management practices. PMID- 27464829 TI - Precultivation of Bacillus coagulans DSM2314 in the presence of furfural decreases inhibitory effects of lignocellulosic by-products during L(+)-lactic acid fermentation. AB - By-products resulting from thermo-chemical pretreatment of lignocellulose can inhibit fermentation of lignocellulosic sugars to lactic acid. Furfural is such a by-product, which is formed during acid pretreatment of lignocellulose. pH controlled fermentations with 1 L starting volume, containing YP medium and a mixture of lignocellulosic by-products, were inoculated with precultures of Bacillus coagulans DSM2314 to which 1 g/L furfural was added. The addition of furfural to precultures resulted in an increase in L(+)-lactic acid productivity by a factor 2 to 1.39 g/L/h, an increase in lactic acid production from 54 to 71 g and an increase in conversion yields of sugar to lactic acid from 68 to 88 % W/W in subsequent fermentations. The improved performance was not caused by furfural consumption or conversion, indicating that the cells acquired a higher tolerance towards this by-product. The improvement coincided with a significant elongation of B. coagulans cells. Via RNA-Seq analysis, an upregulation of pathways involved in the synthesis of cell wall components such as bacillosamine, peptidoglycan and spermidine was observed in elongated cells. Furthermore, the gene SigB and genes promoted by SigB, such as NhaX and YsnF, were upregulated in the presence of furfural. These genes are involved in stress responses in bacilli. PMID- 27464830 TI - Novel and efficient screening of PQQ high-yielding strains and subsequent cultivation optimization. AB - A novel and efficient screening method for pyrroloquinoline quinone (PQQ) high yielding methylotrophic strains was developed by using glucose dehydrogenase apoenzyme (GDHA) which depended on PQQ as the cofactor. Using this high throughput method, PQQ high-yielding strains were rapidly screened out from thousands of methylotrophic colonies at a time. The comprehensive phylogenetic analysis revealed that the highest PQQ-producing strain zju323 (CCTCC M 2016079) could be assigned to a novel species in the genus Methylobacillus of the Betaproteobacteria. After systematic optimization of different medium components and cultivation conditions, about 33.4 mg/L of PQQ was obtained after 48 h of cultivation with Methylobacillus sp. zju323 at the shake flask scale. Further cultivations of Methylobacillus sp. zju323 were carried out to investigate the biosynthesis of PQQ in 10-L bench-top fermenters. In the batch operation, the PQQ accumulation reached 78 mg/L in the broth after 53 h of cultivation. By adopting methanol feeding strategy, the highest PQQ concentration was improved up to 162.2 mg/L after 75 h of cultivation. This work developed a high-throughput strategy of screening PQQ-producing strains from soil samples and also demonstrated one potential bioprocess for large-scale PQQ production with the isolated PQQ strain. PMID- 27464831 TI - Homogeneous Catalyzed Reactions of Levulinic Acid: To gamma-Valerolactone and Beyond. AB - Platform chemicals derived from lignocellulosic plant biomass are viewed as a sustainable replacement for crude oil-based feedstocks. Levulinic acid (LA) is one such biomass-derived chemical that has been widely studied for further catalytic transformation to gamma-valerolactone (GVL), an important 'green' fuel additive, solvent, and fine chemical intermediate. Although the transformation of LA to GVL can be achieved using heterogeneous catalysis, homogeneous catalytic systems that operate under milder reactions, give higher selectivities and can be recycled continuously are attracting considerable attention. A range of new homogeneous catalysts have now been demonstrated to efficiently convert LA to GVL and to transform LA directly to other value-added chemicals such as 1,4 pentanediol (1,4-PDO) and 2-methyltetrahydrofuran (2-MTHF). This Minireview covers recent advances in the area of homogeneous catalysis for the conversion of levulinic acid and levulinic ester derivatives to GVL and chemicals beyond GVL. PMID- 27464832 TI - A Decentralized Approach to the Formulation of Hypotheses: A Hierarchical Structural Model for a Prion Self-Assembled System. AB - Innovation in hypotheses is a key transformative driver for scientific development. The conventional centralized hypothesis formulation approach, where a dominant hypothesis is typically derived from a primary phenomenon, can, inevitably, impose restriction on the range of conceivable experiments and legitimate hypotheses, and ultimately impede understanding of the system of interest. We report herein the proposal of a decentralized approach for the formulation of hypotheses, through initial preconception-free phenomenon accumulation and subsequent reticular logical reasoning processes. The two-step approach can provide an unbiased, panoramic view of the system and as such should enable the generation of a set of more coherent and therefore plausible hypotheses. As a proof-of-concept demonstration of the utility of this open-ended approach, a hierarchical model has been developed for a prion self-assembled system, allowing insight into hitherto elusive static and dynamic features associated with this intriguing structure. PMID- 27464833 TI - Cellular response to alkylating agent MNNG is impaired in STAT1-deficients cells. AB - The SN 1 alkylating agents activate the mismatch repair system leading to delayed G2 /M cell cycle arrest and DNA repair with subsequent survival or cell death. STAT1, an anti-proliferative and pro-apoptotic transcription factor is known to potentiate p53 and to affect DNA-damage cellular response. We studied whether STAT1 may modulate cell fate following activation of the mismatch repair system upon exposure to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Using STAT1-proficient or -deficient cell lines, we found that STAT1 is required for: (i) reduction in the extent of DNA lesions, (ii) rapid phosphorylation of T68-CHK2 and of S15-p53, (iii) progression through the G2 /M checkpoint and (iv) long-term survival following treatment with MNNG. Presence of STAT1 is critical for the formation of a p53-DNA complex comprising: STAT1, c-Abl and MLH1 following exposure to MNNG. Importantly, presence of STAT1 allows recruitment of c-Abl to p53-DNA complex and links c-Abl tyrosine kinase activity to MNNG-toxicity. Thus, our data highlight the important modulatory role of STAT1 in the signalling pathway activated by the mismatch repair system. This ability of STAT1 to favour resistance to MNNG indicates the targeting of STAT1 pathway as a therapeutic option for enhancing the efficacy of SN1 alkylating agent-based chemotherapy. PMID- 27464834 TI - Photoplethysmography and ultrasonic-measurement-integrated simulation to clarify the relation between two-dimensional unsteady blood flow field and forward and backward waves in a carotid artery. AB - Understanding the spatiotemporal change in hemodynamics is essential for the basic research of atherosclerosis. The objective of this study was to establish a methodology to clarify the relation between a two-dimensional (2D) unsteady blood flow field and forward and backward propagating waves in a carotid artery. This study utilized photoplethysmography (PPG) for blood pressure measurement and two dimensional ultrasonic-measurement-integrated (2D-UMI) simulation for flow field analysis. The validity of the methodology was confirmed in an experiment for a carotid artery of a healthy volunteer. Synchronization between the pressure measurement and flow field analysis was achieved with an error of <10 ms. A 2D unsteady blood flow field in the carotid artery was characterized in relation to forward and backward waves. 2D-UMI simulation reproduced the flow field in which the wall shear stress takes a maximum at the time of the backward wave superiority in the systolic phase, whereas 2D ordinary simulation failed to reproduce this feature because of poor reproducibility of velocity distribution. In conclusion, the proposed methodology using PPG and 2D-UMI simulation was shown to be a potential tool to clarify the relation between 2D unsteady blood flow field and the forward and backward waves in a carotid artery. PMID- 27464835 TI - Better survival in right-sided versus left-sided stage I - III colon cancer patients. AB - BACKGROUND: The distinction between right-sided and left-sided colon cancer has recently received considerable attention due to differences regarding underlying genetic mutations. There is an ongoing debate if right- versus left-sided tumor location itself represents an independent prognostic factor. We aimed to investigate this question by using propensity score matching. METHODS: Patients with resected, stage I - III colon cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2012). Both univariable and multivariable Cox regression as well as propensity score matching were used. RESULTS: Overall, 91,416 patients (51,937 [56.8 %] with right-sided, 39,479 [43.2 %] with left-sided colon cancer; median follow-up 38 months) were eligible. In univariable analysis, patients with right-sided cancer had worse overall (hazard ratio [HR] = 1.32, 95 % CI:1.29-1.36, P < 0.001) and cancer-specific survival (HR = 1.26, 95 % CI:1.21-1.30, P < 0.001) compared to patients with left-sided cancer. After propensity score matching, the prognosis of right-sided carcinomas was better regarding overall (HR = 0.92, 95 % CI: 0.89 - 0.94, P < 0.001) and cancer-specific survival (HR = 0.90, 95 % CI:0.87 - 0.93, P < 0.001). In stage I and II, the prognosis of right-sided cancer was better for overall (HR = 0.89, 95 % CI:0.84-0.94 and HR = 0.85, 95 % CI:0.81-0.89) and cancer-specific survival (HR = 0.71, 95 % CI:0.64 - 0.79 and HR = 0.75, 95 % CI:0.70-0.80). Right- and left sided colon cancer had a similar prognosis for stage III (overall: HR = 0.99, 95 % CI:0.95-1.03 and cancer-specific: HR = 1.04, 95 % CI:0.99-1.09). CONCLUSIONS: This population-based analysis on stage I - III colon cancer provides evidence that the prognosis of localized right-sided colon cancer is better compared to left-sided colon cancer. This questions the paradigm from previous research claiming a worse survival in right-sided colon cancer patients. PMID- 27464836 TI - The role of ultrasound in pharmaceutical production: sonocrystallization. AB - OBJECTIVES: The main aim of this review was to develop a critical discussion of the key role ultrasound (US) can play on the production of active pharmaceutical ingredients (APIs) by discussing the versatile effect this type of energy produces. METHODS: The different crystallization techniques that can be assisted and improved by US are discussed in the light of the available US devices and the effect pursued by application of US energy. Simple and complex analytical methods to monitor API changes are also discussed. KEY FINDINGS: The countless achievements of API US-assisted production are summarized in a table, and outstanding effects such as narrower particle size distribution; decreased particle size, induction time, metastable zone and supersaturation levels; or a solubility increase are critically discussed. CONCLUSIONS: The indisputable advantages of sonocrystallization over other ways of API production have been supported on multiple examples, and pending goals in this field (clarify the effect of US frequency on crystallization, know the mechanism of sonocrystallization, determine potential degradation owing to US energy, avoid calculation of the process yield by determining the concentration of the target drug remaining in the solution, etc.) should be achieved. PMID- 27464837 TI - Avoiding Errors in Electrochemical Measurements: Effect of Frit Material on the Performance of Reference Electrodes with Porous Frit Junctions. AB - In many commercially available and in-house-prepared reference electrodes, nanoporous glass frits (often of the brand named Vycor) contain the electrolyte solution that forms a salt bridge between the sample and the reference solution. Recently, we showed that in samples with low ionic strength, the half-cell potentials of reference electrodes comprising nanoporous Vycor frits are affected by the sample and can shift in response to the sample composition by more than 50 mV (which can cause up to 900% error in potentiometric measurements). It was confirmed that the large potential variations result from electrostatic screening of ion transfer through the frit due to the negatively charged surfaces of the glass nanopores. Since the commercial production of porous Vycor glass was recently discontinued, new materials have been used lately as porous frits in commercially available reference electrodes, namely frits made of Teflon, polyethylene, or one of two porous glasses sold under the brand names CoralPor and Electro-porous KT. In this work, we studied the effect of the frit characteristics on the performance of reference electrodes, and show that the unwanted changes in the reference potential are not unique to electrodes with Vycor frits. Increasing the pore size in the glass frits from the <10 nm into the 1 MUm range or switching to polymeric frits with pores in the 1 to 10 MUm range nearly eliminates the potential variations caused by electrostatic screening of ion transport through the frit pores. Unfortunately, bigger frit pores result in larger flow rates of the reference solution through the pores, which can result in the contamination of test solutions. PMID- 27464839 TI - Assisted Peritoneal Dialysis as an Alternative to In-Center Hemodialysis. PMID- 27464838 TI - Hospitalization Rates for Patients on Assisted Peritoneal Dialysis Compared with In-Center Hemodialysis. AB - BACKGROUND AND OBJECTIVES: Assisted peritoneal dialysis is a treatment option for individuals with barriers to self-care who wish to receive home dialysis, but previous research suggests that this treatment modality is associated with a higher rate of hospitalization. The objective of our study was to determine whether assisted peritoneal dialysis has a different rate of hospital days compared to in-center hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a multicenter, retrospective cohort study by linking a quality assurance dataset to administrative health data in Ontario, Canada. Subjects were accrued between January 1, 2004 and July 9, 2013. Individuals were grouped into assisted peritoneal dialysis (family or home care assisted) or in center hemodialysis on the basis of their first outpatient dialysis modality. Inverse probability of treatment weighting using a propensity score was used to create a sample in which the baseline covariates were well balanced. RESULTS: The study included 872 patients in the in-center hemodialysis group and 203 patients in the assisted peritoneal dialysis group. Using an intention to treat approach, patients on assisted peritoneal dialysis had a similar hospitalization rate of 11.1 d/yr (95% confidence interval, 9.4 to 13.0) compared with 12.9 d/yr (95% confidence interval, 10.3 to 16.1) in the hemodialysis group (P=0.19). Patients on assisted peritoneal dialysis were more likely to be hospitalized for dialysis related reasons (admitted for 2.4 d/yr [95% confidence interval, 1.8 to 3.2] compared with 1.6 d/yr [95% confidence interval, 1.1 to 2.3] in the hemodialysis group; P=0.04). This difference was partly explained by more hospital days because of peritonitis. Modality switching was associated with high rates of hospital days per year. CONCLUSIONS: Assisted peritoneal dialysis was associated with similar rates of all-cause hospitalization compared with in-center hemodialysis. Patients on assisted peritoneal dialysis who experienced peritonitis and technique failure had high rates of hospitalization. PMID- 27464840 TI - Observational evidence confirms modelling of the long-term integrity of CO2 reservoir caprocks. AB - Storage of anthropogenic CO2 in geological formations relies on a caprock as the primary seal preventing buoyant super-critical CO2 escaping. Although natural CO2 reservoirs demonstrate that CO2 may be stored safely for millions of years, uncertainty remains in predicting how caprocks will react with CO2-bearing brines. This uncertainty poses a significant challenge to the risk assessment of geological carbon storage. Here we describe mineral reaction fronts in a CO2 reservoir-caprock system exposed to CO2 over a timescale comparable with that needed for geological carbon storage. The propagation of the reaction front is retarded by redox-sensitive mineral dissolution reactions and carbonate precipitation, which reduces its penetration into the caprock to ~7 cm in ~10(5) years. This distance is an order-of-magnitude smaller than previous predictions. The results attest to the significance of transport-limited reactions to the long term integrity of sealing behaviour in caprocks exposed to CO2. PMID- 27464842 TI - Massive mitral valve thrombosis following reversal of warfarin in a patient with rheumatic mitral valve stenosis. PMID- 27464841 TI - Effects of subchronic exposure to zinc nanoparticles on tissue accumulation, serum biochemistry, and histopathological changes in tilapia (Oreochromis niloticus). AB - Zinc nanoparticles (ZnNPs) are among the least investigated NPs and thus their toxicological effects are not known. In this study, tilapia (Oreochromis niloticus) were exposed to 1 and 10 mg/L suspensions of small size (SS, 40-60 nm) and large size (LS, 80-100 nm) ZnNPs for 14 days under semi-static conditions. Total Zn levels in the intestine, liver, kidney, gill, muscle tissue, and brain were measured. Blood serum glucose (GLU), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) were examined to elucidate the physiological disturbances induced by ZnNPs. Organ pathologies were examined for the gills, liver, and kidney to identify injuries associated with exposure. Significant accumulation was observed in the order of intestine, liver, kidney, and gills. Zn levels exhibited time- and concentration dependent increase in the organs. Accumulation in kidney was also dependent on particle size; NPs SS-ZnNPs were trapped more effectively than LS-ZnNPs. No significant accumulation occurred in the brain (p > 0.05) while Zn levels in muscle tissue increased only marginally (p >= 0.05). Significant disturbances were noted in serum GOT and LDH (p < 0.05). The GPT levels fluctuated and were not statistically different from those of controls (p > 0.05). Histopathological tubular deformations and mononuclear cell infiltrations were observed in kidney sections. In addition, an increase in melano-macrophage aggregation intensity was identified on the 7th day in treatments exposed to LS-ZnNPs. Mononuclear cell infiltrations were identified in liver sections for all treatments. Both ZnNPs caused basal hyperplasia in gill sections. Fusions appeared in the gills after the 7th day in fish treated with 10 mg/L suspensions of SS-ZnNPs. In addition, separations in the secondary lamella epithelia were observed. The results indicated that exposure to ZnNPs could lead to disturbances in blood biochemistry and cause histopathological injuries in the tissues of O. niloticus. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1213-1225, 2017. PMID- 27464843 TI - Epidermal Mineralocorticoid Receptor Plays Beneficial and Adverse Effects in Skin and Mediates Glucocorticoid Responses. AB - Glucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases; however, adverse effects of chronic GC treatments limit their therapeutic use. GCs bind and activate the GC receptor and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements. Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knockout mice exhibited increased keratinocyte proliferation and differentiation and showed resistance to GC-induced epidermal thinning. However, crucially, loss of epidermal MR rendered mice more sensitive to inflammatory stimuli and skin damage. MR epidermal knockout mice showed increased susceptibility to phorbol 12 myristate 13-acetate-induced inflammation with higher cytokine induction. Likewise, cultured MR epidermal knockout keratinocytes had increased phorbol 12 myristate 13-acetate-induced NF-kappaB activation, highlighting an anti inflammatory function for MR. GC-induced transcription was reduced in MR epidermal knockout keratinocytes, at least partially due to decreased recruitment of GC receptor to hormone responsive element-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate nonredundant roles for MR and GC receptor in mediating GC actions. PMID- 27464844 TI - Perceptual shrinkage of a one-way motion path with high-speed motion. AB - Back-and-forth motion induces perceptual shrinkage of the motion path, but such shrinkage is hardly perceived for one-way motion. If the shrinkage is caused by temporal averaging of stimulus position around the endpoints, it should also be induced for one-way motion at higher motion speeds. In psychophysical experiments with a high-speed projector, we tested this conjecture for a one-way motion stimulus at various speeds (4-100 deg/s) along a straight path. Results showed that perceptual shrinkage of the motion path was robustly observed in higher speed motion (faster than 66.7 deg/s). In addition, the amount of the forwards shift at the onset position was larger than that of the backwards shift at the offset position. These results demonstrate that high-speed motion can induce shrinkage, even for a one-way motion path. This can be explained by the view that perceptual position is represented by the integration of the temporal average of instantaneous position and the motion representation. PMID- 27464845 TI - [Medicalization of social problems using the example of patients with pain]. AB - The number of invalidity pensions for mental and psychosomatic disorders has dramatically increased in the last decade. Given the experience in sociomedical assessment of people with chronical pain diseases, we developed the impression that primarily social problems-especially long-term unemployment-play an important role in the processes of chronification of pain diseases. We evaluated 100 expert opinions from 2002-2007 according to quantitative and qualitative critieria. We found that at the time of applying for retirement nearly the whole sample was long-term unemployed and that the especially these people suffered from diseases characterized by pain at the beginning of their patient career and they all had received a large range of diagnostic and therapeutic interventions. Only during the course of their disease-usually after the rejection of their application for pension by expert medical opinions-did they receive the diagnosis in the field of psychiatry and psychosomatics. In a next step they were assessed by experts in the field of psychiatry and psychosomatics. In this article, the important social factors that influence this development are discussed. PMID- 27464846 TI - Host-guest binding motifs based on hyperbranched polymers. AB - Host-guest chemistry involves the binding of a substrate molecule (guest) to a receptor molecule (host). Various molecules, including crown ethers, cryptands, cyclophanes, calixarenes, cyclodextrins, and so on, have been used as molecular hosts. However, only limited small molecules or simple ions can be encapsulated in these hosts. Fortunately, as a class of unique host molecules, hyperbranched polymers (HBPs) can bind to numerous guests through topological entrapment, electrostatic bonding, hydrogen bonding or hydrophobic interactions in the core, at the branching points or at the periphery. Hence, hyperbranched polymeric hosts have received increasing attention in the past few decades because of their specific and unique properties. This review briefly summarizes these unique properties related to HBPs serving as hosts. In addition, HBP-based host-guest systems will be classified according to the types of guests encapsulated. Besides, the corresponding applications will be presented as well. We hope to motivate an increased understanding of molecular recognition in HBPs, and further facilitate the optimization of future host-guest systems. PMID- 27464847 TI - Toxic Metal Pollution in Pakistan and Its Possible Risks to Public Health. AB - Environmental pollution has increased many folds in recent years and in some places has reached levels that are toxic to living things. Among pollutant types, toxic heavy metals and metalloids are among the chemicals that pose the highest threat to biological systems (Jjemba 2004). Unlike organic pollutants, which are biodegradable, heavy metals are not degraded into less hazardous end products (Gupta et al. 2001). Low concentrations of some heavy metals are essential for life, but some of them like Hg, As, Pb and Cd are biologically non-essential and very toxic to living organisms. Even the essential metals may become toxic if they are present at a concentration above the permissible level (Puttaiah and Kiran 2008). For example, exposure to Zn and Fe oxides produce gastric disorder and vomiting, irritation of the skin and mucous membranes. Intake of Ni, Cr, Pb, Cd and Cu causes heart problems, leukemia and cancer, while Co and Mg can cause anemia and hypertension (Drasch et al. 2006). Similarly, various studies indicated that overexposure to heavy metals in air can cause cardiovascular disorders (Miller et al. 2007; Schwartz 2001), asthma (Wiwatanadate and Liwsrisakun 2011), bronchitis/emphysema (Pope 2000), and other respiratory diseases (Dominici et al. 2006). PMID- 27464848 TI - Gene Expression Profiling in Fish Toxicology: A Review. AB - In this review, we present an overview of transcriptomic responses to chemical exposures in a variety of fish species. We have discussed the use of several molecular approaches such as northern blotting, differential display reverse transcription-polymerase chain reaction (DDRT-PCR), suppression subtractive hybridization (SSH), real time quantitative PCR (RT-qPCR), microarrays, and next generation sequencing (NGS) for measuring gene expression. These techniques have been mainly used to measure the toxic effects of single compounds or simple mixtures in laboratory conditions. In addition, only few studies have been conducted to examine the biological significance of differentially expressed gene sets following chemical exposure. Therefore, future studies should focus more under field conditions using a multidisciplinary approach (genomics, proteomics and metabolomics) to understand the synergetic effects of multiple environmental stressors and to determine the functional significance of differentially expressed genes. Nevertheless, recent developments in NGS technologies and decreasing costs of sequencing holds the promise to uncover the complexity of anthropogenic impacts and biological effects in wild fish populations. PMID- 27464849 TI - Vonoprazan prevents bleeding from endoscopic submucosal dissection-induced gastric ulcers. AB - BACKGROUND: Vonoprazan, a potassium-competitive acid blocker, is expected to improve the healing of endoscopic submucosal dissection (ESD)-induced gastric ulcers compared with proton pump inhibitors (PPIs). AIM: To compare the healing status of ESD-induced gastric ulcers and the incidence of post-ESD bleeding between subjects treated with vonoprazan for 5 weeks and those treated with PPIs for 8 weeks. METHODS: Patients in the vonoprazan group (n = 75) were prospectively enrolled, whereas patients in the PPI group (n = 150) were selected for a 2:1 matched historical control cohort according to baseline characteristics including gastric ulcer size immediately following ESD, age, sex and status of Helicobacter pylori infection. Two controls per case of vonoprazan-treated group were matched with a margin of 20% in terms of ulcer size and a margin of 5 years in terms of their age. RESULTS: Although a higher number of completely healed ulcers was observed in the PPI group (95/150, 63.3%) than that in the vonoprazan group (14/75, 18.7%; P < 0.001), the ulcer size reduction rates, which were 96.0 +/- 6.7% in the vonoprazan group and 94.7 +/- 11.6% in the PPI group, were not significantly different (P = 0.373). The post-ESD bleeding incidence in the vonoprazan group (1/75, 1.3%) was less than that in the PPI group (15/150, 10.0%; P = 0.01). The factors affecting post-ESD bleeding incidence were the type of acid secretion inhibitor (P = 0.016) and use of an anti-thrombotic agent (P = 0.014). CONCLUSION: Vonoprazan significantly reduced post-endoscopic submucosal dissection bleeding compared with PPIs. PMID- 27464851 TI - The evolution of general intelligence. AB - The presence of general intelligence poses a major evolutionary puzzle, which has led to increased interest in its presence in nonhuman animals. The aim of this review is to critically evaluate this question and to explore the implications for current theories about the evolution of cognition. We first review domain general and domain-specific accounts of human cognition in order to situate attempts to identify general intelligence in nonhuman animals. Recent studies are consistent with the presence of general intelligence in mammals (rodents and primates). However, the interpretation of a psychometric g factor as general intelligence needs to be validated, in particular in primates, and we propose a range of such tests. We then evaluate the implications of general intelligence in nonhuman animals for current theories about its evolution and find support for the cultural intelligence approach, which stresses the critical importance of social inputs during the ontogenetic construction of survival-relevant skills. The presence of general intelligence in nonhumans implies that modular abilities can arise in two ways, primarily through automatic development with fixed content and secondarily through learning and automatization with more variable content. The currently best-supported model, for humans and nonhuman vertebrates alike, thus construes the mind as a mix of skills based on primary and secondary modules. The relative importance of these two components is expected to vary widely among species, and we formulate tests to quantify their strength. PMID- 27464850 TI - The effect of imiquimod on taste bud calcium transients and transmitter secretion. AB - BACKGROUND AND PURPOSE: Imiquimod is an immunomodulator approved for the treatment of basal cell carcinoma and has adverse side effects, including taste disturbances. Paracrine transmission, representing cell-cell communication within taste buds, has the potential to shape the final signals that taste buds transmit to the brain. Here, we tested the underlying assumption that imiquimod modifies taste transmitter secretion in taste buds of mice. EXPERIMENTAL APPROACH: Taste buds were isolated from C57BL/6J mice. The effects of imiquimod on transmitter release in taste buds were measured using calcium imaging with cellular biosensors, and examining the net effect of imiquimod on taste-evoked ATP secretion from mouse taste buds. KEY RESULTS: Up to 72% of presynaptic (Type III) taste cells responded to 100 MUM imiquimod with an increase in intracellular Ca2+ concentrations. These Ca2+ responses were inhibited by thapsigargin, an inhibitor of the sarco/endoplasmic reticulum Ca2+ -ATPase, and by U73122, a PLC inhibitor, suggesting that the Ca2+ mobilization elicited by imiquimod was dependent on release from internal Ca2+ stores. Moreover, combining studies of Ca2+ imaging with cellular biosensors showed that imiquimod evoked secretion of 5-HT, which then provided negative feedback onto receptor (Type II) cells to reduce taste evoked ATP secretion. CONCLUSION AND IMPLICATIONS: Our results provide evidence that there is a subset of taste cells equipped with a range of intracellular mechanisms that respond to imiquimod. The findings are also consistent with a role of imiquimod as an immune response modifier, which shapes peripheral taste responses via 5-HT signalling. PMID- 27464852 TI - Versatile microrobotics using simple modular subunits. AB - The realization of reconfigurable modular microrobots could aid drug delivery and microsurgery by allowing a single system to navigate diverse environments and perform multiple tasks. So far, microrobotic systems are limited by insufficient versatility; for instance, helical shapes commonly used for magnetic swimmers cannot effectively assemble and disassemble into different size and shapes. Here by using microswimmers with simple geometries constructed of spherical particles, we show how magnetohydrodynamics can be used to assemble and disassemble modular microrobots with different physical characteristics. We develop a mechanistic physical model that we use to improve assembly strategies. Furthermore, we experimentally demonstrate the feasibility of dynamically changing the physical properties of microswimmers through assembly and disassembly in a controlled fluidic environment. Finally, we show that different configurations have different swimming properties by examining swimming speed dependence on configuration size. PMID- 27464853 TI - Extracellular Potassium and Seizures: Excitation, Inhibition and the Role of Ih. AB - Seizure activity leads to increases in extracellular potassium concentration ([K[Formula: see text]]o), which can result in changes in neuronal passive and active membrane properties as well as in population activities. In this study, we examined how extracellular potassium modulates seizure activities using an acute 4-AP induced seizure model in the neocortex, both in vivo and in vitro. Moderately elevated [K[Formula: see text]]o up to 9[Formula: see text]mM prolonged seizure durations and shortened interictal intervals as well as depolarized the neuronal resting membrane potential (RMP). However, when [K[Formula: see text]]o reached higher than 9[Formula: see text]mM, seizure like events (SLEs) were blocked and neurons went into a depolarization-blocked state. Spreading depression was never observed as the blockade of ictal events could be reversed within 1-2[Formula: see text]min after the raised [K[Formula: see text]]o was changed back to control levels. This concentration-dependent dual effect of [K[Formula: see text]]o was observed using in vivo and in vitro mouse brain preparations as well as in human neocortical tissue resected during epilepsy surgery. Blocking the Ih current, mediated by hyperpolarization activated cyclic nucleotide-gated (HCN) channels, modulated the elevated [K[Formula: see text]]o influence on SLEs by promoting the high [K[Formula: see text]]o inhibitory actions. These results demonstrate biphasic actions of raised [K[Formula: see text]]o on neuronal excitability and seizure activity. PMID- 27464854 TI - Seizure Forecasting and the Preictal State in Canine Epilepsy. AB - The ability to predict seizures may enable patients with epilepsy to better manage their medications and activities, potentially reducing side effects and improving quality of life. Forecasting epileptic seizures remains a challenging problem, but machine learning methods using intracranial electroencephalographic (iEEG) measures have shown promise. A machine-learning-based pipeline was developed to process iEEG recordings and generate seizure warnings. Results support the ability to forecast seizures at rates greater than a Poisson random predictor for all feature sets and machine learning algorithms tested. In addition, subject-specific neurophysiological changes in multiple features are reported preceding lead seizures, providing evidence supporting the existence of a distinct and identifiable preictal state. PMID- 27464855 TI - Duality quantum algorithm efficiently simulates open quantum systems. AB - Because of inevitable coupling with the environment, nearly all practical quantum systems are open system, where the evolution is not necessarily unitary. In this paper, we propose a duality quantum algorithm for simulating Hamiltonian evolution of an open quantum system. In contrast to unitary evolution in a usual quantum computer, the evolution operator in a duality quantum computer is a linear combination of unitary operators. In this duality quantum algorithm, the time evolution of the open quantum system is realized by using Kraus operators which is naturally implemented in duality quantum computer. This duality quantum algorithm has two distinct advantages compared to existing quantum simulation algorithms with unitary evolution operations. Firstly, the query complexity of the algorithm is O(d(3)) in contrast to O(d(4)) in existing unitary simulation algorithm, where d is the dimension of the open quantum system. Secondly, By using a truncated Taylor series of the evolution operators, this duality quantum algorithm provides an exponential improvement in precision compared with previous unitary simulation algorithm. PMID- 27464856 TI - Testing for biases in selection on avian reproductive traits and partitioning direct and indirect selection using quantitative genetic models. AB - Key life history traits such as breeding time and clutch size are frequently both heritable and under directional selection, yet many studies fail to document microevolutionary responses. One general explanation is that selection estimates are biased by the omission of correlated traits that have causal effects on fitness, but few valid tests of this exist. Here, we show, using a quantitative genetic framework and six decades of life-history data on two free-living populations of great tits Parus major, that selection estimates for egg-laying date and clutch size are relatively unbiased. Predicted responses to selection based on the Robertson-Price Identity were similar to those based on the multivariate breeder's equation (MVBE), indicating that unmeasured covarying traits were not missing from the analysis. Changing patterns of phenotypic selection on these traits (for laying date, linked to climate change) therefore reflect changing selection on breeding values, and genetic constraints appear not to limit their independent evolution. Quantitative genetic analysis of correlational data from pedigreed populations can be a valuable complement to experimental approaches to help identify whether apparent associations between traits and fitness are biased by missing traits, and to parse the roles of direct versus indirect selection across a range of environments. PMID- 27464857 TI - Zika. An emerging teratogenic virus. AB - [No Abstract Available]. PMID- 27464858 TI - A review of glycemic efficacy of liraglutide once daily in achieving glycated hemoglobin targets compared with exenatide twice daily, or sitagliptin once daily in the treatment of type 2 diabetes. AB - Incretin-based therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors have gained prominence in recent years for the treatment of type 2 diabetes (T2D). Such therapies offer the potential to stimulate endogenous insulin activity in proportion to circulating glucose levels; thereby, lowering the risk of hypoglycemic episodes. The synthetic GLP-1 RA exenatide, the human GLP-1 RA liraglutide, and the DPP-4 inhibitor sitagliptin are the first agents in their respective classes to be approved for the treatment of T2D and their efficacy and safety has been studied extensively in clinical trials. This article reviewed the efficacy of liraglutide once daily in achieving clinical guidelines-recommended glycated hemoglobin A1c levels in patients with T2D compared with exenatide twice daily, or sitagliptin once daily, based on published literature, with an aim to elucidate the preferred choice of incretin-related therapy in treating uncontrolled T2D. PMID- 27464859 TI - A preliminary exploration of ulnar variance in healthy wrists at a tertiary hospital in Jeddah. AB - OBJECTIVES: To gain preliminary insight by exploring ulnar variance changes in a Saudi-based sample. METHODS: This 6-month (December 2013 to June 2014) cross sectional study was conducted on a randomly selected healthy adult volunteers with a sample size of 104, at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Posteroanterior (PA), anteroposterior (AP), and PA grip views are taken. The variables of interest were the PA, AP, and PA fist measurements of both right and left wrists. An independent t-test was used to compare means between groups. RESULTS: A total of 104 volunteers were recruited. Among 17 participants who had a negative ulnar variance on right PA views, a significantly high proportion (n=9; 56.2%) maintained a negative value on fist views; 7 participants (43.8%) had a neutral ulnar variance while none (0%) had a positive value (p less than 0.001). Similarly, a significant proportion of participants who had neutral, or positive values on right PA views maintained the same values on right fist views (p less than 0.001). On radiographs of the right wrist, the ulnar variance decreased with a change in wrist position, with an absolute difference in magnitude of 2.13 (p less than 0.001) between PA and AP views. Similarly, the ulnar variance on the left side decreased significantly between PA and AP views (absolute difference in magnitude, 1.68; p less than 0.001). CONCLUSIONS: Ulnar variance changes in our sample are similar to what is reported in the literature. PMID- 27464861 TI - Mitral valve repair for ischemic moderate mitral regurgitation in patients undergoing coronary artery bypass grafting. AB - OBJECTIVES: To investigate whether mitral valve repair (MVR) at the time of coronary artery bypass grafting (CABG) in patients with ischemic moderate mitral regurgitation (MR) and coronary artery disease could improve short- and mid-term postoperative outcomes. METHODS: Between March 2013 and December 2015, 90 patients with moderate ischemic MR underwent first-time CABG in Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey. Out of 90 patients, 44 (48.9%) underwent combined CABG+MVR. The remaining 46 (51.1%) underwent CABG alone. Ventricular functions and effort capacities of patients in both groups were evaluated echocardiographically and clinically in the preoperative period, and in the first postoperative year. RESULTS: Postoperative regurgitant volume changes according to preoperative values were -24.76+/-19 ml/beat in the combined CABG+MVR group, and -8.70+/-7.2 ml/beat in the CABG alone group (p=0.001). The change of vena contracta width was -3.40+/-0.2 mm in the combined CABG+MVR group whereas in the CABG alone -1.45+/-0.7 mm (p=0.019). The changes of left ventricular end-systolic volume index were -30.77+/-25.9 ml/m2 in the combined CABG+MVR group and -15.6+/-9.4 ml/m2 in the CABG alone group (p=0.096). Ejection fraction changes in the combined CABG+MVR group was +1.51+/-5.3% and in the CABG alone group was +1.15+/-4.3%. No statistically significant difference was found between both groups (p=0.604). Preoperative New York Heart Association class values in the combined CABG+MVR group was 2.18+/-0.45, and in the CABG alone group was 2.13+/-0.54. CONCLUSIONS: Moderate MR in patients undergoing CABG affects the outcome adversely and it does not reliably improve after CABG alone. Therefore, patients with ischemic moderate MR should undergo simultaneous MVR at the time of CABG. PMID- 27464860 TI - Effects of different dosages of oxycodone and fentanyl on the hemodynamic changes during intubation. AB - OBJECTIVES: To investigate the effectiveness of oxycodone compared with fentanyl for attenuating the hemodynamic response during endotracheal intubation. METHODS: This study was conducted from June 2014 to February 2015 on healthy adults undergoing general anesthesia at the Yeungnam University Hospital, Daegu, Republic of Korea. Ninety-five patients were randomly assigned to one of 3 groups to receive the following drugs; Group F: fentanyl 2 MUg/kg; Group O/70: oxycodone 140 MUg/kg; Group O/100: oxycodone 200 MUg/kg. Five minutes after injection of the study drug, general anesthesia was induced with propofol 1.5 mg/kg and rocuronium 0.8 mg/kg. The mean blood pressure (MBP), heart rate (HR), peripheral oxygen saturation (SpO2), and bispectral index (BIS) were compared before administration of the study drug (T1), just before endotracheal intubation (T2), one minute after endotracheal intubation (T3), and 7.5 minutes after endotracheal intubation (T4). Complications were assessed. RESULTS: The 2 oxycodone groups showed no significant differences in MBP, HR, SpO2, and BIS compared to Group F at the time points assessed. The incidence of complications was comparable among the groups. CONCLUSIONS: Oxycodone could successfully be used to attenuate the sympathetic response during anesthetic induction. The hemodynamic profiles and incidence of complications were clinically similar among the groups, but Group O/70 tended to show a lower rate of complications of apnea. PMID- 27464862 TI - The prevalence of urinary tract infection, or urosepsis following transrectal ultrasound-guided prostate biopsy in a subset of the Saudi population and patterns of susceptibility to flouroquinolones. AB - OBJECTIVES: To study the prevalence of urinary tract infections (UTI), or sepsis secondary to trans-rectal ultrasound-guided (TRUS) biopsy of the prostate, the pathogens involved, and patterns of antibiotic resistance in a cohort of patients. METHODS: This is a descriptive study of a consecutive cohort of patients who underwent elective TRUS biopsy at King Abdulaziz Medical City, Riyadh, Saudi Arabia between January 2012 and December 2014. All patients who underwent the TRUS guided prostate biopsy were prescribed the standard prophylactic antibiotics. Variables included were patients' demographics, type of antibiotic prophylaxis, results of biopsy, the rate of UTI, and urosepsis with the type of pathogen(s) involved and its/their antimicrobial sensitivity. RESULTS: Simple descriptive statistics were used in a total of 139 consecutive patients. Urosepsis requiring hospital admission was encountered in 7 (5%) patients and uncomplicated UTI was observed in 4 (2.8%). The most common pathogens were Escherichia coli (90.1%) and Klebsiella pneumoniae (9.1%). Resistance to the routinely used prophylaxis (ciprofloxacin) was observed in 10 of these patients (90.9%). CONCLUSION: This showed an increase in the rate of infectious complications after TRUS prostate biopsy. Ciprofloxacin resistance was found in 90.9% of patients with no sepsis. PMID- 27464863 TI - The declining rates of hepatitis B carriage among adolescents and young people in the Eastern region of Saudi Arabia. AB - OBJECTIVES: To study age specific rates of hepatitis B virus (HBV) carriage in the eastern region of Saudi Arabia following a 24 year immunization program. METHODS: Hepatitis B surveillance data between January 2004 and December 2013 were analyzed in a retrospective study, which included 24,504,914 patients. Seropositive cases of hepatitis B were reported by laboratory personnel as part of various investigations. Hepatitis B cases including acute and chronic carriers were identified upon serological positivity of hepatitis B surface antigen (HBsAg). RESULTS: The study shows that the overall prevalence rate decreased from 18.8 to 9.9/100,000 population between 2004 and 2013 (p=0.01). It was also found that the prevalence rate increased with age. For instance, the highest prevalence of hepatitis B was seen among patients greater than 15 years of age and the lowest was seen among children less than 15 years of age. Over the period, the prevalence rate decreased in all age groups with the greatest decline among the age groups less than 4 years old. However, this was statistically insignificant (p greater than 0.05). Another significant reduction in the prevalence rate occurred among age groups 5-14 years old (p=0.00). An insignificant decrease in the rate by 43% was also seen among older patients of 15-44 years old and 35% in greater than 45 years old. The overall prevalence of hepatitis B is significantly higher in men than in women (p=0.00). CONCLUSION: There is a particular decreased trend in the prevalence of HBV infection in different age groups over a decade of surveillance following more than 20 years of the universal HBV vaccination program. PMID- 27464864 TI - Is a history of cesarean section a risk factor for abnormal uterine bleeding in patients with uterine leiomyoma? AB - OBJECTIVES: To determine whether a history of cesarean section was a risk factor for abnormal uterine bleeding in patients with uterine leiomyomas, and to identify other risk factors for this symptom. METHODS: We analyzed retrospectively, the medical records of patients who underwent hysterectomies due to the presence of uterine leiomyomas during a 6-year period (2009 and 2014) at Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey. Uterine leiomyoma was diagnosed based on histopathological examination of hysterectomy specimens. Demographic characteristics, and laboratory and histopathological findings were compared between patients with uterine leiomyoma with and without abnormal uterine bleeding. RESULTS: In total, 501 (57.9%) patients had abnormal uterine bleeding and 364 (42.1%) patients had other symptoms. A history of cesarean section was more common in patients with abnormal uterine bleeding than in those with other symptoms (17.6% versus 9.3%, p=0.001; odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.4-3.3). The presence of a submucosal leiomyoma (OR: 2.1; 95% CI: 1.5-3.1) and coexistent adenomyosis (OR: 1.6; 95% CI: 1.1-2.4) were also associated with abnormal uterine bleeding. CONCLUSION: A history of cesarean section was an independent risk factor for abnormal uterine bleeding in patients with uterine leiomyomas; submucosal leiomyoma and coexisting adenomyosis were also independent risk factors. PMID- 27464865 TI - Depression and anxiety in patients with hematological malignancies, prevalence, and associated factors. AB - OBJECTIVES: To study the prevalence and associated factors of depression and anxiety in hematological cancers (HC) patients. METHODS: We conducted a cross sectional survey in all HC patients at King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia between March 2014 and June 2015. We excluded patients with depression, or generalized anxiety disorder. We conducted a structured face to face interview using an internally developed and validated questionnaire (Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 patient's questionnaire with all participants). RESULTS: Among 211 participants, depression was detected in 98 (46.5%) and anxiety was detected in 47 (22.3%). Thirty-eight (18.1%) had concurrent anxiety and depression. Multiple co-morbidities and tense home atmosphere were predictive for anxiety and depression. We found no association between gender, smoking, income, or being on active therapy and depression or anxiety. CONCLUSIONS: Depression and anxiety are highly prevalent in HC patients in KAMC. Health care providers should screen HC cancers for depression and anxiety; as early intervention possibly improve their disease outcome and will likely enhance their psychological wellbeing. PMID- 27464866 TI - Family profile of victims of child abuse and neglect in the Kingdom of Saudi Arabia. AB - OBJECTIVES: To describe the family profile of child abuse and neglect (CAN) subjects in Saudi Arabia. METHODS: Data were collected retrospectively between July 2009 and December 2013 from patients' files, which were obtained from the Child Protection Centre (CPC) based in King Abdulaziz Medical City, Riyadh, Saudi Arabia. Four main sets of variables were examined: demographics of victim, family profile, parental information, and information on perpetrator and forms of abuse. RESULTS: The charts of 220 CAN cases were retrospectively reviewed. Physical abuse was the most common form of abuse (42%), followed by neglect (39%), sexual abuse (14%), and emotional abuse (4%). Children with unemployed fathers were 2.8 times as likely to experience physical abuse. Children living in single/step parent households were 4 times as likely to experience physical abuse. Regarding neglect children living in larger households (>=6) were 1.5 times as likely to be neglected by their parents as were children living in smaller households (less than 6). Regarding sexual abuse, male children were 2.9 times as likely to be abused as were female children. CONCLUSIONS: The recent acknowledgment of CAN as a public health problem in Saudi Arabia suggests that time will be needed to employ effective and culturally sensitive prevention strategies based on family risk factors. PMID- 27464867 TI - Chronic periodontitis and smoking. Prevalence and dose-response relationship. AB - OBJECTIVES: To determine the prevalence and dose-response relationship of chronic periodontitis among smokers in Pakistan. METHODS: This is a cross-sectional study among participants seeking dental care in Karachi Medical and Dental College, Karachi, Pakistan. A total of 443 participants with a mean age of 44.3 (+/-6.5) participated in the study from April 2011 to December 2011. Males comprised 64.7%, and females comprised 35.2%. Participants were interviewed on social demographics and oral habits. Participants with shallow pockets (3.5-5.5 mm) and deep pockets (greater than 5.5 mm) were considered suffering from chronic periodontitis. The characteristics of participants were assessed using frequency distribution for categorical variables and mean (standard deviation) for continuous variables. RESULTS: Among 443 participants, smokers were distributed as 55.1% and non-smokers as 44.9%. Smoking was found to be significantly related to young adults (p less than 0.007), male gender (p less than 0.001), and lower education level (p less than 0.01). Overall prevalence of chronic periodontitis among smokers was estimated at 81.6%. Heavy smoking was found to have significantly high prevalence (p less than 0.001) and severity (p less than 0.001) of periodontitis as compared with moderate and light smokers. The multivariate unadjusted model depicted 3.5 times higher risk of chronic periodontitis among smokers (p less than 0.001). CONCLUSION: Chronic periodontitis had a high prevalence among smokers. Heavy smoking was found to have a higher risk for having periodontitis. PMID- 27464868 TI - Retention practices and factors affecting retainer choice among orthodontists in Saudi Arabia. AB - OBJECTIVES: To identify the retention protocols practiced by orthodontists in Saudi Arabia, and the factors affecting retainer choice. METHODS: This cross sectional study took place between February and March of 2015 at the College of Dentistry, University of Dammam, Dammam, Saudi Arabia. A previously tested electronic survey of 34 items was sent to all 1,200 orthodontic members of the Saudi Orthodontic Society. The questionnaire elicited data on the subjects' demographics, orthodontic treatment practices, retention, and post-retention protocols. RESULTS: One hundred and sixty-seven (13.9%) responses were received during the study period. The results showed predominant use of Hawley in the maxillary arch (61.3%), and fixed lingual in the mandibular arch (58.5%). Approximately 90.3% recommended full-time maxillary removable retainer wear. Overall, orthodontists who performed fewer extractions tended to use fixed retainers, and those who performed more extractions used removable retainers (p=0.018). Interproximal enamel reduction was used by 28% of the respondents as an adjunct procedure to enhance retention. Approximately 64% practiced a post retention phase of retainer wear. Participants who used removable retainers most commonly prescribed lifetime retention. CONCLUSION: Hawley in the maxilla, and fixed lingual in the mandible were the most common retention protocols prescribed. Lifetime retention was the most common choice for participants who used removable retainers, especially when extractions were carried out. PMID- 27464869 TI - Bilateral combined laryngocele. AB - Laryngocele is an uncommon condition that represents a benign dilatation of the laryngeal saccule with air and/or fluid, arising in the region of the laryngeal ventricle. Laryngoceles, or laryngomucocele can be classified as internal, or combined. The aim of presenting this rare case of a bilateral combined laryngocele, are to emphasize the importance of diagnostic laryngoscopy in upper airway pathologies evaluation, increase awareness in the general otolaryngologist community, and to highlight the external surgical method. PMID- 27464870 TI - An unexpected reason for elevated human chorionic gonadotropin in a young woman. Cervical squamous carcinoma. AB - Human chorionic gonadotropin has been used for decades, in addition to specific investigations, to detect pregnancy, trophoblastic tumors, as well as congenital defects. Rarely, it can be elevated in non-trophoblastic tumors such as squamous cell cancers and germ cell tumors. A 33-year-old Asian Syrian female had irregular menses accompanied with feelings of heaviness in the vagina. In addition to routine investigations, we measured the serum beta human chorionic gonadotropin (beta-HCG) level (based on the patient's complaint of amenorrhea), which was 50.05 ml UI/ml. Cervical biopsy revealed a non-keratinized large cell squamous carcinoma. After excluding other causes, beta-hCG elevation was explained by the ectopic secretion of cancer cells line. Cervical biopsy was suggestive of large cell non-keratinizing squamous cell carcinoma and positive for human chorionic gonadotropin on immunohistochemistry. As a result, we manage the possibility of ectopic secretion of beta-HCG from non- trophoblastic disease. PMID- 27464871 TI - Omitting histopathology in wrist ganglions. A risky proposition. AB - OBJECTIVES: To identify incidence and utility of histopathology in wrist ganglions. METHODS: A retrospective study of 112 patients operated for wrist swellings between January 2009 and March 2014 at Aga Khan University Hospital, Karachi, Pakistan, was conducted. Medical records were reviewed for demographics, history, location and associated symptoms, provisional diagnosis and operative details. Histopathology reports were reviewed to confirm the final diagnosis. RESULTS: One hundred and twelve patients were included in the study (34 males and 78 females) with a mean age of 28 +/- 12 years. Ninety-five percent of ganglia were dorsally located and 85% were solitary in nature. Histopathology reports confirmed 107 as ganglion cysts, whereas 3 had giant cell tumor of tendon sheath and 2 were reported to be tuberculous tenosynovitis. CONCLUSION: Although most of the time the clinical diagnosis conforms to the final diagnosis, the possibility of an alternate diagnosis cannot be ignored (4% in this study). We suggest routine histopathological analysis so that such diagnoses are not missed. PMID- 27464872 TI - Unusual cause of anterior knee pain. AB - [No Abstract Available]. PMID- 27464873 TI - The association between body mass index and duration spent on electronic devices in children and adolescents in Western Saudi Arabia. AB - [No Abstract Available]. PMID- 27464874 TI - The association between body mass index and duration spent on electronic devices in children and adolescents in Western Saudi Arabia. AB - [No Abstract Available]. PMID- 27464875 TI - Does social support affect development of cognitive dysfunction in individuals with diabetes mellitus? AB - [No Abstract Available]. PMID- 27464876 TI - Epidemiology of non-transported emergency medical services calls in Saudi Arabia. AB - [No Abstract Available]. PMID- 27464877 TI - Physical therapists' assessments, analyses and use of behavior change techniques in initial consultations on musculoskeletal pain: direct observations in primary health care. AB - BACKGROUND: Behavioral medicine (BM) treatment is recommended to be implemented for pain management in physical therapy. Its implementation requires physical therapists (PTs), who are skilled at performing functional behavioral analyses based on physical, psychological and behavioral assessments. The purpose of the current study was to explore and describe PTs' assessments, analyses and their use of behavioral change techniques (BCTs) in initial consultations with patients who seek primary health care due to musculoskeletal pain. METHODS: A descriptive and explorative research design was applied, using data from video recordings of 12 primary health care PTs. A deductive analysis was performed, based on a specific protocol with definitions of PTs' assessment of physical and psychological prognostic factors (red and yellow flags, respectively), analysis of the clinical problem, and use of BCTs. An additional inductive analysis was performed to identify and describe the variation in the PTs' clinical practice. RESULTS: Red and yellow flags were assessed in a majority of the cases. Analyses were mainly based on biomedical assessments and none of the PTs performed functional behavioral analyses. All of the PTs used BCTs, mainly instruction and information, to facilitate physical activity and improved posture. The four most clinically relevant cases were selected to illustrate the variation in the PTs' clinical practice. The results are based on 12 experienced primary health care PTs in Sweden, limiting the generalizability to similar populations and settings. CONCLUSION: Red and yellow flags were assessed by PTs in the current study, but their interpretation and integration of the findings in analyses and treatment were incomplete, indicating a need of further strategies to implement behavioral medicine in Swedish primary health care physical therapy. PMID- 27464878 TI - The influence of social support on healthcare service use following transport related musculoskeletal injury. AB - BACKGROUND: Social support has been identified as a significant factor in the recovery of individuals with musculoskeletal injury (MSI). However, relatively limited research has examined the mechanisms through which social support influences healthcare service use. This research examines the direct effects, mediating effects and effect modification of social support on healthcare service use among people with MSI sustained in a transport accident. METHODS: The study design was secondary data analysis of cross-sectional surveys of compensated transport accident victims in Victoria in 2010 and 2011, linked to compensation claims and payment records. Analyses included (i) zero-inflated negative binomial and logistic regressions to model healthcare service use (direct effect), (ii) the Karlson, Holme and Breen (KHB) method to assess social support as a mediator of predisposing factors, need factors and healthcare service use (mediation effect), and (iii) interactions to assess social support as a modifier between predisposing factors, need factors and healthcare service use (effect modification). RESULTS: Results of the direct analyses showed that support from family was associated with lower uptake of allied healthcare services (odds ratio (OR) 2.17; 95 % confidence intervals (CI) 1.21-3.91). Support from friends was associated with lower uptake (OR 1.87; 95 % CI 1.09-3.21) and lower rate (i.e. number of services per person) of allied healthcare services (incidence rate ratio (IRR) 0.65; 95 % CI 0.52-0.83). Support from friends (OR 0.60; 95 % CI 0.38 0.95) was also associated with lower uptake of mental healthcare services. No statistically significant mediation effects were identified for family or friends' support on the uptake of allied and mental healthcare services. Family support was found to modify the association between socio-economic indexes for areas and mental healthcare service use. In the group that reported having no social support, mental healthcare service uptake in the socioeconomically advantaged group was lower than in the disadvantaged group (OR 0.36; 95 % CI 0.16 0.83). CONCLUSIONS: The findings suggest that social support has a direct and modifying effect on healthcare service use but does not mediate the association between predisposing factors, need factors and healthcare service use. The study findings have implications for the role of social support in the prevention, treatment and intervention of individuals with MSI. PMID- 27464880 TI - Depression and diabetes in the remote Torres Strait Islands. AB - Issue addressed Diabetes is associated with significant depression, which can result in poorer clinical outcomes, including increased mortality. Little is known about the prevalence of depression among Torres Strait Islander adults with diabetes. Methods Self-reported depression was measured using the Patient Health Questionnaire (PHQ)-9 translated into Torres Strait Creole, and associations with socioeconomic, behavioural and clinical indicators in Torres Strait Islander adults with diabetes in five remote Torres Strait Islands were examined. Results Seventy-three men and 115 women completed interviews. The median PHQ-9 score was 5.5 (IQR 0-7); 42% of respondents scored 0-4 (none-minimal), 46% scored 5-9 (mild) and 12% scored 10+ (moderate-severe). Mean HbA1c was 8.3% (67.4mmol). HbA1c was not related to PHQ-9 scores (beta=0.20, P=0.323), however exercise in hours (beta=-0.34, P<0.001) and screen time in hours (beta=0.11, P<0.001) were significant predictors of depression after adjusting for other study variables. Conclusions This sample of remote living Torres Strait Islanders reported relatively low rates of depression compared with national samples, and depression was not related to glycaemic control. Exercise and screen time were the strongest predictors of depression based on PHQ-9 scores. This represents an opportunity for health promotion. So what? These findings provide an indication of the health impact of physical activity in rural and remote communities. Local health and education services, councils and sporting bodies should work collaboratively to promote sustainable physical activity programs. PMID- 27464882 TI - Editorial (Thematic Issue: Bacterial Metallo-Enzymes as Drug Targets). PMID- 27464881 TI - Recombinant expression of Chlamydia trachomatis major outer membrane protein in E. Coli outer membrane as a substrate for vaccine research. AB - BACKGROUND: Chlamydia trachomatis is a human pathogen which causes a number of pathologies, including genital tract infections in women that can result in tubal infertility. Prevention of infection and disease control might be achieved through vaccination; however, a safe, efficacious and cost-effective vaccine against C. trachomatis infection remains an unmet medical need. C. trachomatis major outer membrane protein (MOMP), a beta-barrel integral outer membrane protein, is the most abundant antigen in the outer membrane of the bacterium and has been evaluated as a subunit vaccine candidate. Recombinant MOMP (rMOMP) expressed in E. coli cytoplasm forms inclusion bodies and rMOMP extracted from inclusion bodies results in a reduced level of protection compared to the native MOMP in a mouse challenge model. RESULTS: We sought to target the recombinant expression of MOMP to the E. coli outer membrane (OM). Successful surface expression was achieved with codon harmonization, utilization of low copy number vectors and promoters with moderate strength, suitable leader sequences and optimization of cell culture conditions. rMOMP was extracted from E. coli outer membrane, purified, and characterized biophysically. The OM expressed and purified rMOMP is immunogenic in mice and elicits antibodies that react to the native antigen, Chlamydia elementary body (EB). CONCLUSIONS: C. trachomatis MOMP was functionally expressed on the surface of E. coli outer membrane. The OM expressed and purified rMOMP elicits antibodies that react to the native antigen, Chlamydia EB, in a mouse immunogenicity model. Surface expression of MOMP could provide useful reagents for vaccine research, and the methodology could serve as a platform to produce other outer membrane proteins recombinantly. PMID- 27464884 TI - Development and Validation of an HPLC Method for the Simultaneous Determination of Fipronil, Chlorfenapyr, and Pyriproxyfen in Insecticide Formulations. AB - In this study, the analytical method development and validation of an HPLC assay for simultaneous determination of fipronil, chlorfenapyr, and pyriproxyfen in formulation products is described. On the basis of solubility and chromatographic separation with good resolution, acetonitrile-water (80 + 20) was selected as the mobile phase in isocratic mode with a flow rate of 1 mL/min. Chromatographic separations were performed on a Beckman C18 analytical column (4.6 mm * 15 cm, 5 MUm particle size; Musa Jee & Sons, Karachi, Pakistan). The retention times for fipronil, chlorfenapyr, and pyriproxyfen were 3.70, 8.61 and 10.09 min, respectively. Calibration curves of all studied insecticides were linear in the concentration range of 20 to 800 MUg/mL, with R(2) > 0.997. The LODs of fipronil, chlorfenapyr, and pyriproxyfen were 15.1, 13.3, and 20.0 MUg/mL, respectively, whereas the LOQs were 45.9, 40.3, and 60.6 MUg/mL. Interday precision was RSD, % <2 for all formulation types, whereas intraday precision was <3. The accuracy of the proposed method was determined by interlaboratory comparison. The z-score for all formulation results were <2.The proposed method is low-cost, green, accurate, and precise and can suitably be used for the simultaneous quantitative determination of fipronil, chlorfenapyr, and pyriproxyfen in their formulations. PMID- 27464885 TI - Emotion knowledge, emotion regulation, and psychosocial adjustment in children with nonverbal learning disabilities. AB - Nonverbal learning disability is a childhood disorder with basic neuropsychological deficits in visuospatial processing and psychomotor coordination, and secondary impairments in academic and social-emotional functioning. This study examines emotion recognition, understanding, and regulation in a clinic-referred group of young children with nonverbal learning disabilities (NLD). These processes have been shown to be related to social competence and psychological adjustment in typically developing (TD) children. Psychosocial adjustment and social skills are also examined for this young group, and for a clinic-referred group of older children with NLD. The young children with NLD scored lower than the TD comparison group on tasks assessing recognition of happy and sad facial expressions and tasks assessing understanding of how emotions work. Children with NLD were also rated as having less adaptive regulation of their emotions. For both young and older children with NLD, internalizing and externalizing problem scales were rated higher than for the TD comparison groups, and the means of the internalizing, attention, and social problem scales were found to fall within clinically concerning ranges. Measures of attention and nonverbal intelligence did not account for the relationship between NLD and Social Problems. Social skills and NLD membership share mostly overlapping variance in accounting for internalizing problems across the sample. The results are discussed within a framework wherein social cognitive deficits, including emotion processes, have a negative impact on social competence, leading to clinically concerning levels of depression and withdrawal in this population. PMID- 27464883 TI - Plasma vitamin D status and recurrent depressive symptoms in the French SU.VI.MAX cohort. AB - PURPOSE: Depression is a major public health issue because it is a common cause of disability worldwide. It has been suggested that an optimal vitamin D status may be related to fewer depressive symptoms, but findings are inconsistent. We aimed to investigate the association between plasma vitamin D at midlife and recurrent depressive symptoms and to test for a modulating effect by overall dietary quality. METHODS: The relationship between plasma 25-hydroxyvitamin D (25(OH)D) and recurrent depressive symptoms was evaluated among 1196 participants of the Supplementation en Vitamines et Mineraux Antioxydants cohort with available data on the Center for Epidemiologic Studies-Depression Scale (CES-D) at baseline (1996-1997) and follow-up (2007-2009). Recurrent depressive symptoms were defined as a CES-D score >=16 at baseline and follow-up. Prevalence ratios (PR) and 95 % confidence intervals (95 %-CI) were estimated using extensively adjusted Poisson regression models. Dietary quality was estimated using an index measuring adherence to the French national recommendations. RESULTS: Having 25(OH)D concentrations above 10 ng/mL was related to a lower probability of recurrent depressive symptoms: PR (95 %-CI) = 0.48 (0.33; 0.69); P < 0.0001). When comparing individuals with concentrations < versus >=20 or < versus >=30 ng/mL, no significant results were obtained. In contrast, among individuals with low dietary quality, a better vitamin D status was related to a lower probability of recurrent depressive symptoms independently of the applied cutoff. CONCLUSIONS: Plasma vitamin D might have a preventive role against recurrent depressive symptoms, notably among individuals with poor dietary quality. Our findings are relevant for the development of depression prevention programs. PMID- 27464886 TI - Storm drains as larval development and adult resting sites for Aedes aegypti and Aedes albopictus in Salvador, Brazil. AB - BACKGROUND: Dengue (DENV), Chikungunya (CHIKV), Zika (ZIKV), as well as yellow fever (YFV) viruses are transmitted to humans by Aedes spp. females. In Salvador, the largest urban center in north-eastern Brazil, the four DENV types have been circulating, and more recently, CHIKV and ZIKV have also become common. We studied the role of storm drains as Aedes larval development and adult resting sites in four neighbourhoods of Salvador, representing different socioeconomic, infrastructure and topographic conditions. RESULTS: A sample of 122 storm drains in the four study sites were surveyed twice during a 4-month period in 2015; in 49.0 % of the visits, the storm drains contained water. Adults and immatures of Aedes aegypti were captured in two of the four sites, and adults and immatures of Aedes albopictus were captured in one of these two sites. A total of 468 specimens were collected: 148 Ae. aegypti (38 adults and 110 immatures), 79 Ae. albopictus (48 adults and 31 immatures), and 241 non-Aedes (mainly Culex spp.) mosquitoes (42 adults and 199 immatures). The presence of adults or immatures of Ae. aegypti in storm drains was independently associated with the presence of non Aedes mosquitoes and with rainfall of <= 50 mm during the preceding week. CONCLUSIONS: We found that in Salvador, one of the epicentres of the 2015 ZIKV outbreak, storm drains often accumulate water and serve as larval development sites and adult resting areas for both Ae. aegypti and Ae. albopictus. Vector control campaigns usually overlook storm drains, as most of the effort to prevent Ae. agypti reproduction is directed towards containers in the domicile environment. While further studies are needed to determine the added contribution of storm drains for the maintenance of Aedes spp. populations, we advocate that vector control programs incorporate actions directed at storm drains, including regular inspections and use of larvicides, and that human and capital resources are mobilized to modify storm drains, so that they do not serves as larval development sites for Aedes (and other) mosquitoes. PMID- 27464888 TI - Enhanced photoelectrochemical and photocatalytic behaviors of MFe2O4 (M = Ni, Co, Zn and Sr) modified TiO2 nanorod arrays. AB - Modified TiO2 nanomaterials are considered to be promising in energy conversion and ferrites modification may be one of the most efficient modifications. In this research, various ferrites, incorporated with various cations (MFe2O4, M = Ni, Co, Zn, and Sr), are utilized to modify the well aligned TiO2 nanorod arrays (NRAs), which is synthesized by hydrothermal method. It is found that all MFe2O4/TiO2 NRAs show obvious red shift into the visible light region compared with the TiO2 NRAs. In particular, NiFe2O4 modification is demonstrated to be the best way to enhance the photoelectrochemical and photocatalytic activity of TiO2 NRAs. Furthermore, the separation and transfer of charge carriers after MFe2O4 modification are clarified by electrochemical impedance spectroscopy measurements. Finally, the underlying mechanism accounting for the enhanced photocatalytic activity of MFe2O4/TiO2 NRAs is proposed. Through comparison among different transition metals modified TiO2 with the same synthesis process and under the same evaluating condition, this work may provide new insight in designing modified TiO2 nanomaterials as visible light active photocatalysts. PMID- 27464887 TI - Repeatability of selective laser trabeculoplasty for open-angle glaucoma. AB - BACKGROUND: To analyze the results of repeat selective laser trabeculoplasty (SLT). METHODS: INCLUSION CRITERIA: participants with primary or secondary open angle glaucoma (excluding uveitic) who had undergone SLT 360 degrees (SLT 1) with diminution of response over time followed by repeat SLT 360 degrees (SLT 2). Six months of follow-up were required and at least 6 months in between SLT 1 and 2. The main outcome measures were IOP reduction at 6 and 12 months and a comparison of the response between SLT 1 and 2. RESULTS: One hundred thirty-seven patients met the inclusion criteria. If only one eye had repeat treatment, that eye was chosen; if both eyes qualified, one was chosen at random. The baseline intraocular pressure (IOP) for SLT 1 = 20.3+/- 5.2 mmHg and SLT 2 = 19.4 +/- 5.0 was reduced to 16.4 +/- 3.9 and 16.7 +/- 4.7 at 1 year, respectively (p < .001). Medication use was not significantly changed, and was 2.2 +/- 1.2 at baseline for SLT 1 and 2.1 +/- 1.3 for SLT 2, and at 1 year was 1.9 +/- 1.3 and 2.2 +/- 1.2, respectively. A subanalysis of 62 patients matched for equivalent baselines showed a baseline IOP = 18.7 +/- 3.8 for SLT 1 and 18.7 +/- 3.5 for SLT 2, reduced to 16.0 +/- 4.3 and 15.3 +/- 3.8 at 1 year (p < .001). CONCLUSION: Repeat SLT laser (360-degree treatment, followed by a loss of effect over time, then a second 360-degree treatment) in this population resulted in IOP lowering similar to that of the initial treatment. PMID- 27464889 TI - Fluid Dynamics in Rotary Piston Blood Pumps. AB - Mechanical circulatory support can maintain a sufficient blood circulation if the native heart is failing. The first implantable devices were displacement pumps with membranes. They were able to provide a sufficient blood flow, yet, were limited because of size and low durability. Rotary pumps have resolved these technical drawbacks, enabled a growing number of mechanical circulatory support therapy and a safer application. However, clinical complications like gastrointestinal bleeding, aortic insufficiency, thromboembolic complications, and impaired renal function are observed with their application. This is traced back to their working principle with attenuated or non-pulsatile flow and high shear stress. Rotary piston pumps potentially merge the benefits of available pump types and seem to avoid their complications. However, a profound assessment and their development requires the knowledge of the flow characteristics. This study aimed at their investigation. A functional model was manufactured and investigated with particle image velocimetry. Furthermore, a fluid-structure interaction computational simulation was established to extend the laboratory capabilities. The numerical results precisely converged with the laboratory measurements. Thus, the in silico model enabled the investigation of relevant areas like gap flows that were hardly feasible with laboratory means. Moreover, an economic method for the investigation of design variations was established. PMID- 27464890 TI - Optimizing Team Dynamics: An Assessment of Physician Trainees and Advanced Practice Providers Collaborative Practice. AB - OBJECTIVES: The presence of advanced practice providers has become increasingly common in many ICUs. The ideal staffing model for units that contain both advanced practice providers and physician trainees has not been described. The objectives of this study were to evaluate ICU staffing models that include physician trainees and advanced practice providers and their effects on patient outcomes, resident and fellow education, and training experience. A second aim was to assess strategies to promote collaboration between team members. DATA SOURCES: PubMed, CINAHL, OVID MEDLINE, and Cochrane Review from 2002 to 2015. STUDY SELECTION: Experimental study designs conducted in an ICU setting. DATA EXTRACTION: Two reviewers screened articles for eligibility and independently abstracted data using the identified search terms. DATA SYNTHESIS: We found 21 articles describing ICU team structure and outcomes. Four articles were found describing the impact of advanced practice providers on resident or fellow education. Two articles were found discussing strategies to promote collaboration between advanced practice providers and critical care fellows or residents. CONCLUSIONS: Several articles were identified describing the utilization of advanced practice providers in the ICU and the impact of models of care on patient outcomes. Limited data exist describing the impact of advanced practice providers on resident and fellow education and training experience. In addition, there are minimal data describing methods to enhance collaboration between providers. Future research should focus on determining the optimal ICU team structure to improve patient outcomes, education of trainees, and job satisfaction of team members and methods to promote collaboration between advanced practice providers and physicians in training. PMID- 27464891 TI - Hierarchical Self-Assembly of 3D-Printed Lock-and-Key Colloids through Shape Recognition. AB - Progress in colloid self-assembly crucially depends on finding preparation methods for anisotropic particles with recognition motifs to facilitate the formation of superstructures. Here, we demonstrate for the first time that direct 3D laser writing can be used to fabricate uniform populations of anisotropic cone shaped particles that are suitable for self-assembly through shape recognition. The driving force for the self-assembly of the colloidal particles into linear supracolloidal polymers are depletion forces. The resulting supracolloidal fibrils undergo hierarchical ordering and form nematic liquid-crystalline domains. Such a behavior could so far not be observed in the absence of an electric field. The study opens possibilities for using direct laser writing to prepare designed colloids on demand, and to study their self-assembly. PMID- 27464892 TI - Differences in epidemiology of candidaemia in the Nordic countries - what is to blame? AB - National data from Denmark, Finland, Norway and Sweden demonstrate remarkable differences in candidaemia epidemiology. Only Denmark has reported a high incidence of 10 per 100 000 inhabitants and a species shift towards increased C. glabrata candidaemias. The reasons for this development remain unclear. The aim of this study was to explore possible contributing factors for the differences in Candida epidemiology in the Nordic countries. We used public data from 2011 from Denmark, Finland, Norway and Sweden on epidemiology, demographics, health facilities, predisposing risk factors, consumption of antimicrobial drugs and fungicides in agricultural industry. Only the prevalence of haematological malignancies (P < 0.001) was significantly higher in Denmark compared to the other Nordic countries. The antibacterial drug use of metronidazole, piperacillin tazobactam, ciprofloxacin, colistin and carbapenems, and antifungal use of fluconazole in humans (P < 0.001), were significantly higher in Denmark compared to the other Nordic countries (all P < 0.001). Our findings suggest haematological malignancy, the use of certain antibacterial drugs and azoles in humans as possible contributing factors for the differences in Candida epidemiology. However, our results should be interpreted with caution due to the lack of long-term, case-specific data. Further studies are needed. PMID- 27464893 TI - Preconditioned total field inversion (TFI) method for quantitative susceptibility mapping. AB - PURPOSE: To investigate systematic errors in traditional quantitative susceptibility mapping (QSM) where background field removal and local field inversion (LFI) are performed sequentially, to develop a total field inversion (TFI) QSM method to reduce these errors, and to improve QSM quality in the presence of large susceptibility differences. THEORY AND METHODS: The proposed TFI is a single optimization problem which simultaneously estimates the background and local fields, preventing error propagation from background field removal to QSM. To increase the computational speed, a new preconditioner is introduced and analyzed. TFI is compared with the traditional combination of background field removal and LFI in a numerical simulation and in phantom, 5 healthy subjects, and 18 patients with intracerebral hemorrhage. RESULTS: Compared with the traditional method projection onto dipole fields+LFI, preconditioned TFI substantially reduced error in QSM along the air-tissue boundaries in simulation, generated high-quality in vivo QSM within similar processing time, and suppressed streaking artifacts in intracerebral hemorrhage QSM. Moreover, preconditioned TFI was capable of generating QSM for the entire head including the brain, air-filled sinus, skull, and fat. CONCLUSION: Preconditioned total field inversion improves the accuracy of QSM over the traditional method where background and local fields are separately estimated. Magn Reson Med 78:303-315, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27464894 TI - Hepatic immunophenotyping for streptozotocin-induced hyperglycemia in mice. AB - Emerging evidence revealed that diabetes induces abnormal immune responses that result in serious complications in organs. However, the effect of hyperglycemia on hepatic immunity remains obscure. We evaluated the population and function of hepatic immune cells in streptozotocin (STZ)-induced hyperglycemic mice. CC chemokine receptor 2 (CCR2)-knockout mice and mice with a depletion of regulatory T cells (DEREG) were used to investigate the migration and role of regulatory T cells (Tregs) in hyperglycemic mice. The inflammatory cytokines and hepatic transaminase levels were significantly increased in the hyperglycemic mice. The population and number of infiltrating monocytes, granulocytes, and Tregs were enhanced in the livers of the hyperglycemic mice. Hepatic monocytes other than macrophages showed the increased expression of inflammatory cytokines and chemokines in the hyperglycemic mice. The CCR2 knockout and DEREG chimeric mice exhibited increased populations of activated T cells and neutrophils compared to the WT chimeric mice, which promoted hepatic inflammation in the hyperglycemic mice. The migration of CCR2 knockout Tregs into the liver was significantly reduced compared to the WT Tregs. We demonstrated that hyperglycemia contributes to increase in infiltrating monocytes and Tregs, which are associated with hepatic immune dysfunction in mice. CCR2-mediated migration of Tregs regulates hyperglycemia-induced hepatic inflammation. PMID- 27464896 TI - A selection of recent original research papers. PMID- 27464898 TI - The prevalence of musculoskeletal disorders in the retail sector: an Italian cross sectional study on 3380 workers. AB - BACKGROUND: Cashiers are not the only workers in the Retail Sector (RS) who are exposed to biomechanical overload risk of the upper limbs and spine. OBJECTIVES: To investigate the prevalence of musculoskeletal disorders among employees in the RS. METHODS: 3380 Italian workers were asked to complete a standardized medical history questionnaire to collect data on symptoms and diagnosed disorders affecting upper limbs, spine and knees. These were then compared with data on subjects not exposed to biomechanical overload risk. RESULTS: 21.1% of the workers reported at least one disorder affecting the upper limbs (OR 5.05), i.e., shoulder (OR 3.39), elbow (OR 4.25), wrist/hand (OR 8.39) and CTS (OR 8.70). The prevalence of disc hernia was 16% (OR 3.82). A high prevalence of knee complaints was also found among subjects employed in the RS (OR 1.73). CONCLUSIONS: The high prevalence of musculoskeletal disorders seems to confirm the presence of a risk of biomechanical overload for most job positions in the retail sector, although a possible selection bias cannot be completely ignored. Recommendations for future studies aiming to confirm our results include: involving all workers in every store and collecting information about diagnostic procedures. PMID- 27464895 TI - A PII-Like Protein Regulated by Bicarbonate: Structural and Biochemical Studies of the Carboxysome-Associated CPII Protein. AB - Autotrophic bacteria rely on various mechanisms to increase intracellular concentrations of inorganic forms of carbon (i.e., bicarbonate and CO2) in order to improve the efficiency with which they can be converted to organic forms. Transmembrane bicarbonate transporters and carboxysomes play key roles in accumulating bicarbonate and CO2, but other regulatory elements of carbon concentration mechanisms in bacteria are less understood. In this study, after analyzing the genomic regions around alpha-type carboxysome operons, we characterize a protein that is conserved across these operons but has not been previously studied. On the basis of a series of apo- and ligand-bound crystal structures and supporting biochemical data, we show that this protein, which we refer to as the carboxysome-associated PII protein (CPII), represents a new and distinct subfamily within the broad superfamily of previously studied PII regulatory proteins, which are generally involved in regulating nitrogen metabolism in bacteria. CPII undergoes dramatic conformational changes in response to ADP binding, and the affinity for nucleotide binding is strongly enhanced by the presence of bicarbonate. CPII therefore appears to be a unique type of PII protein that senses bicarbonate availability, consistent with its apparent genomic association with the carboxysome and its constituents. PMID- 27464899 TI - Subjective symptoms in Magnetic Resonance Imaging operators: prevalence, short term evolution and possible related factors. AB - BACKGROUND: The number of Magnetic Resonance Imaging (MRI) operators is rapidly increasing. In these workers, a high prevalence of certain subjective symptoms has been described but until now scant research is available on this topic. OBJECTIVES: To assess the prevalence and the evolution of symptoms over time in a group of operators recently engaged in MRI, also considering the possible role played by factors such as age, gender and occupational stress. METHODS: In 17 physicians exclusively engaged in MRI - 6 working with 1.5 T scanners only and 11 with both 1.5 and 3T - subjective symptoms were evaluated at the beginning of MRI activity and after 2 months by using an ad hoc questionnaire. The questionnaire also included items on occupational stress. RESULTS: At the start of MRI activity, 81% of the subjects reported at least one of the investigated symptoms; after 2 months, 85% of the symptomatic operators reported the regression of one or more symptoms. In operators with high exposure (1.5 and 3 T scanners), the mean number of symptoms tended to be higher compared with those with lower exposure (1.5 T only), and the reduction after 2 months was significantly greater. In the whole group, occupational stress was significantly correlated with the total number of symptoms and to some of the symptoms more specifically. As stress did not differ between highly- and lowly- exposed, there is no reason to assume an influence on the observed differences in the prevalence and reduction of symptoms. CONCLUSIONS: Our data suggest that MRI operators may experience various symptoms at the beginning of activity, rapidly reversible in a few weeks. The trend over longer periods deserves further study. Occupational stress may play a role in symptoms. The duration of previous MRI work (particularly short-term) as well as work-related stress should be adequately addressed in future studies on subjective symptoms in operators. PMID- 27464900 TI - Is prevention of acute pesticide poisoning effective and efficient, with Locally Adapted Personal Protective Equipment? A randomized crossover study among farmers in Chitwan, Nepal. AB - BACKGROUND: Farmers' risk of pesticide poisoning can be reduced with personal protective equipment but in low-income countries farmers' use of such equipment is limited. OBJECTIVE: To examine the effectiveness and efficiency of Locally Adapted Personal Protective Equipment to reduce organophosphate exposure among farmers. METHODS: In a crossover study, 45 male farmers from Chitwan, Nepal, were randomly allocated to work as usual applying organophosphate pesticides wearing Locally Adapted Personal Protective Equipment or Daily Practice Clothing. For seven days before each experiment, each farmer abstained from using pesticides. Before and after organophosphate application, an interview surveys and blood tests were carried out, and analyzed with paired t-test, frequencies and percentages. RESULTS: The difference between follow-up mean for acute organophosphate poisoning symptoms in the two groups was 0.13 [95% CI -0.22;0.49] and for plasma cholinesterase (U/ml) -0.03 [95% CI -0.11;0.06]. The difference between follow-up mean minus baseline mean for acute organophosphate poisoning symptoms in the two groups was 0.29 [95% CI -0.26;0.84] and for plasma cholinesterase (U/ml) -0.01 [95% CI --0.08;0.06]. Wearing the Locally Adapted Personal Protective Equipment versus Daily Practice Clothing gave the following results, respectively: comfort 75.6% versus 100%, sense of heat 64.4% versus 31.3%, other problems 44.4% versus 33.3%, likeability 95.6% versus 77.8%. CONCLUSION: We cannot support the expectation that our farmers in Chitwan, Nepal working with Locally Adapted Personal Protective Equipment would have fewer acute organophosphate poisoning symptoms, higher plasma cholinesterase (U/mL) and find it more efficient to work with the equipment than farmers working with their Daily Practice Clothing. Based on the farmers' working behavior, compounds used, intensity and exposure duration we conclude that Locally Adapted Personal Protective Equipment does not provide additional protection during usual work practices. However, our Locally Adapted Personal Protective Equipment might offer protection from (certain) accidental overexposure. Trial Registration NCT02137317. PMID- 27464901 TI - Evaluation of safety at work in a psychiatric setting: the "Workplace Safety Assessment". AB - OBJECTIVES: Workplace violence is a common risk for mental health professionals, and psychiatrists often encounter it in a variety of settings. The aim of this study was to estimate the prevalence and features of violent episodes toward psychiatrists in various mental healthcare system settings. METHODS: All psychiatrists from the Region of Puglia (Apulia) were contacted (N=285) via email and were administered an on-line standardized questionnaire. RESULTS: The response rate by psychiatrists was 57%. The main types of violence revealed were "threats" and "verbal aggression" and, of particular importance, "stalking". Female psychiatrists seemed to be at a higher risk of becoming victims of workplace violence, especially as regards verbal abuse (OR: 2.7, 95% CI: 1.2-6.5, c2 6.7, p=0.0095) and reported more serious psychological consequences with need for rest after the episode of aggression. CONCLUSIONS: Our data confirm that mental health workers, particularly psychiatrists, are healthcare professionals at high risk for workplace violence. Future implementation of preventive strategies with the aim of reducing aggressive episodes towards psychiatrists should be a high priority for managers and policy-makers operating in the Italian healthcare sector. PMID- 27464902 TI - [Not Available]. AB - BACKGROUND: Diabetes is a disease with high social impact and it is important to consider how work may be influenced by it or whether work itself may promote or accelerate its course. OBJECTIVES: The objective was to investigate the prevalence of diabetes in four critical categories of workers. The survey involved construction workers, truck drivers, bus drivers and shift workers in the manufacturing sector. METHODS: In the years 2012-14 we investigated 2034 males workers, through personal history, physical examination, laboratory tests. The subjects with fasting glucose >125 mg/dl underwent a second control and haemoglobin A1c determination. Positive cases were referred to specialist control. Expected prevalence and standardized prevalence ratio (SPR) were calculated using official data regarding diabetes prevalence in Italy. RESULTS: The prevalence of diabetes in 608 truck drivers was 4.4% (expected 2.6%, SPR 1.69, IC95% 1.08 to 2.31); in 860 construction workers 1.9% (expected 2.1%, SPR 0.90, IC95% 0.48 to 1.33); in 378 bus drivers 2.6% (expected 3.5%, SPR 0.74, IC95% 0.29 to 1.20); in 188 shift workers 3.2% (expected 2.1%, SPR 1.52, IC95% 0.33 to 2.71). In the age range 35-59 years the prevalence in 467 truck drivers was 5.1% (expected 2.4%, SPR 2.13, IC 95% 1.29 to 2.96). DISCUSSION: Diabetes was confirmed to be highly prevalent at working ages. The study highlighted an increased diabetes prevalence among truck drivers, whereas other jobs might represent protective factors; this hypothesis, however, needs further investigation. PMID- 27464903 TI - [Not Available]. AB - BACKGROUND: Unemployment often implies several psychological issues, including hopelessness and low self-esteem. These issues may contribute to maintain the current unemployed status. OBJECTIVES: In this study we present the effects of a mindfulness-based stress reduction treatment for unemployed people and welfare professionals, aimed to improve resilience and quality of life. METHODS: We assessed both unemployed people and welfare professionals for psychological outcomes at both pre- and post-treatment. RESULTS: After treatment, participants reported higher quality of life and higher levels of well-being, together with better resilience and coping style, compared to pre-test values. CONCLUSIONS: Meditation training can effectively improve well-being and resilience of unemployed people and welfare professionals. PMID- 27464904 TI - [Not Available]. AB - BACKGROUND: Asbestos-related diseases among shipyard workers are well known in Italy but descriptive long-term studies are limited; asbestos has been extensively used but the past exposure intensity has never been estimated because data from environmental and biological monitoring are almost absent. OBJECTIVES: To describe the asbestos-related dis-eases (1996-2015) diagnosed among shipbuilding workers from a very important shipyard in Northern Italy, and to assess past asbestos exposure levels by cumulative dose indices, fibres and asbestos bodies. METHODS: The cases of workers suffering from asbestos-related diseases diagnosed from 1996 to 2015 were collected on the occasion of some legal trials; the diagnosis, and the asbestos occupational and non-occupational exposure, were carefully evaluated.Lung samples were obtained from subjects, taking advantage of the autopsies; asbestos fibers were counted by means of a Scanning Electron Microscope, equipped with x-ray fluorescence microanalyses at 12.0000 amplification, and asbestos bodies by means of an Optical Microscope at 500 amplification. RESULTS: 192 malignant mesotheliomas (6 in women), 196 lung cancers and 14 asbestosis (without cancer) were observed (1996-2015); autopsies were carried out on 80% of all subjects and 98% of mesotheliomas were confirmed by autopsies. Pleural plaques occurred on 90% of mesotheliomas and 87% of lung cancers; histologically mild asbestosis were diagnosed on 28% of mesotheliomas and 48% of lung cancers. In malignant mesothelioma and lung cancer cases respectively, the duration of occupational exposure was on average 24 and 23 ys, the latency time 48 and 46 ys, hiring at the shipyard before 1970 24 and 23 ys. Out of 114 lung analysis, the burden of asbestos fibres was >10 million for 33.3% of subjects and out of 99 lung analysis asbestos bodies was >10.000 for 71.7%; the average time since last exposure was 31 ys. Both asbestos fibres and asbestos bodies concentrations were significantly higher (GMR 2,5) among mesothelioma vs lung cancer. CONCLUSION: A relevant number of asbestos-related diseases among shipbuilding workers, mainly mesothelioma and lung cancer, exposed in shipyard until the 1980's were identified by an active search. Thanks to several autopsies, the diagnoses of cancer are confirmed as a cause of death, and a high frequency of histological asbestosis, previously ignored,was shown. The lung burden analysis of asbestos bodies and asbestos fibres, the largest ever performed among ship-building workers, confirms the spread and relevance of asbestos exposure. The best estimate of past exposure intensity was provided by both biological indices. PMID- 27464905 TI - Errata corrige: Med Lav 2016;107(3):235-242 - P. Petromilli Nordi Sasso Garcia, C. Dupim Presoto, J. Maroco, J. Alvares Duarte Bonini Campos - Work-related activities that may contribute to musculoskeletal symptoms among dental students: validation study. AB - The authors reported an error that need to fully replace the data already published. The mistake is in Table 2 and the incorrect information may interfere with the results' interpretation, taking the reader to error. The values of factor 1 (Repetitiveness) should be in the first column, not in the third, corresponding to Q1, Q2, Q3 and Q4 items. The values of Factor 2 (Working Posture) should be in the second column, not in the first, corresponding to Q5, Q6, Q7, Q8 and Q9 items. The values of Factor 3 (External Factors) should be in the third column, not in the second, corresponding to Q9, Q10, Q11, Q12, Q13, Q14 and Q15. Therefore, the authors requested an erratum in order to allow a real understanding by the readers of the information presented. The new table with corrections is presented below.Table 2 - Structural matrix with varimax orthogonal rotation of the factors* of the "Questionnaire on work-related activities that may contribute to musculoskeletal symptoms".[...]. PMID- 27464906 TI - A comparison of health-related quality of life in 5- and 10-year-old Swedish children with and without cleft lip and/or palate. AB - BACKGROUND: The current understanding on health-related quality of life (HRQoL) in young Swedish children with cleft lip and/or palate (CL/P) is sparse, and therefore, research on impact of CL/P on HRQoL in children is needed. AIMS: To investigate HRQoL in 5- and 10-year-old Swedish children with CL/P in comparison with non-cleft controls. Also to analyse whether there were any differences in HRQoL between children with cleft lip (with or without cleft palate, CL +/- P) and cleft palate only (CP) and/or gender differences. DESIGN: A total of 137 children with CL/P and 305 non-cleft controls participated. HRQoL was measured with KIDSCREEN-52. RESULTS: All children in the study exhibited HRQoL within or above the age-matched reference interval of the method with similar results in both groups; however, in the dimension 'social support and peers', the 10-year old children with CL/P perceived lower HRQoL than the non-cleft controls, but it did not reach statistical significance. Type of cleft or gender did not influence HRQoL. CONCLUSIONS: Both 5- and 10-year-old Swedish children with CL/P had HRQoL in the normal reference interval. Their general life situations were well adjusted to their clefts, but the older children with CL/P felt more excluded and less supported by peers. PMID- 27464908 TI - Interferometric Motion Detection in Atomic Layer 2D Nanostructures: Visualizing Signal Transduction Efficiency and Optimization Pathways. AB - Atomic layer crystals are emerging building blocks for enabling new two dimensional (2D) nanomechanical systems, whose motions can be coupled to other attractive physical properties in such 2D systems. Optical interferometry has been very effective in reading out the infinitesimal motions of these 2D structures and spatially resolving different modes. To quantitatively understand the detection efficiency and its dependence on the device parameters and interferometric conditions, here we present a systematic study of the intrinsic motion responsivity in 2D nanomechanical systems using a Fresnel-law-based model. We find that in monolayer to 14-layer structures, MoS2 offers the highest responsivity among graphene, h-BN, and MoS2 devices and for the three commonly used visible laser wavelengths (633, 532, and 405 nm). We also find that the vacuum gap resulting from the widely used 300 nm-oxide substrate in making 2D devices, fortunately, leads to close-to-optimal responsivity for a wide range of 2D flakes. Our results elucidate and graphically visualize the dependence of motion transduction responsivity upon 2D material type and number of layers, vacuum gap, oxide thickness, and detecting wavelength, thus providing design guidelines for constructing 2D nanomechanical systems with optimal optical motion readout. PMID- 27464907 TI - BIGCHEM: Challenges and Opportunities for Big Data Analysis in Chemistry. AB - The increasing volume of biomedical data in chemistry and life sciences requires the development of new methods and approaches for their handling. Here, we briefly discuss some challenges and opportunities of this fast growing area of research with a focus on those to be addressed within the BIGCHEM project. The article starts with a brief description of some available resources for "Big Data" in chemistry and a discussion of the importance of data quality. We then discuss challenges with visualization of millions of compounds by combining chemical and biological data, the expectations from mining the "Big Data" using advanced machine-learning methods, and their applications in polypharmacology prediction and target de-convolution in phenotypic screening. We show that the efficient exploration of billions of molecules requires the development of smart strategies. We also address the issue of secure information sharing without disclosing chemical structures, which is critical to enable bi-party or multi party data sharing. Data sharing is important in the context of the recent trend of "open innovation" in pharmaceutical industry, which has led to not only more information sharing among academics and pharma industries but also the so-called "precompetitive" collaboration between pharma companies. At the end we highlight the importance of education in "Big Data" for further progress of this area. PMID- 27464909 TI - Regulation of highly homologous major urinary proteins in house mice quantified with label-free proteomic methods. AB - Major urinary proteins (MUPs) are highly homologous proteoforms that function in binding, transporting and releasing pheromones in house mice. The main analytical challenge for studying variation in MUPs, even for state-of-the-art proteomics techniques, is their high degree of amino acid sequence homology. In this study we used unique peptides for proteoform-specific identification. We applied different search engines (ProteinPilotTMvs. PEAKS(r)) and protein databases (MUP database vs. SwissProt + unreviewed MUPs), and found that proteoform identification is influenced by addressing background proteins (unregulated urinary proteins, non-MUPs) during the database search. High resolution Q-TOF mass spectrometry was used to identify and precisely quantify the regulation of MUP proteoforms in male mice that were reared in standard housing and then transferred to semi-natural enclosures (within-subject design). By using a designated MUP database we were able to distinguish 19 MUP proteoforms, with A2CEK6 (a Mup11 gene product) being the most abundant based on spectral intensities. We compared three different quantification strategies based on MS1- (from IDA and SWATHTM spectra) and MS2 (SWATHTM) data, and the results of these methods were correlated. Furthermore, three data normalization methods were compared and we found that increased statistical significance of fold-changes can be achieved by normalization based on urinary protein concentrations. We show that male mice living in semi-natural enclosures significantly up-regulated some but not all MUPs (differential regulation), e.g., A2ANT6, a Mup6 gene product, was upregulated between 9-fold (MS1) and 13-fold (MS2) using the designated MUP database. Finally, we show that 85 +/- 7% of total MS intensity can be attributed to MUP-derived peptides, which supports the assumption that MUPs are the primary proteins in mouse urine. Our results provide new tools for assessing qualitative and quantitative variation of MUPs and suggest that male mice regulate the expression of specific MUP proteoforms, depending upon social conditions. PMID- 27464910 TI - Low-dose brachytherapy for early stage penile cancer: a 20-year single institution study (73 patients). AB - PURPOSE/OBJECTIVES: The aim of this study is to analyze the results of exclusive interstitial brachytherapy (IBT) as a conservative approach in the treatment of penile cancer confined to the glans or the shaft with long-term follow-up in a single institution. MATERIALS/METHODS: Between July 1992 and November 2013, 73 consecutive patients with non-metastatic invasive penile cancer were treated by Low dose rate (LDR) IBT in our institution. The localization of the primary lesion was glands in 67 patients (91.8 %) and shaft in 6 patients (8.2 %). All 73 patients presented with squamous cell carcinoma with grades of differentiation as follows: 34 patients with grade 1 (44.7 %), 9 patients with grade 2 (11.8 %), 9 patients with grade 3 (11.8 %) and 21 patients unknown (28.8 %). Six patients (7.8 %) presented with in situ carcinoma, 55 patients (75,3 %) presented with T1, 11 patients (15 %) presented with T2, and one patient (1.3 %) presented with Tx. Inguinal nodal dissection was performed in 29 patients (38.2 %); 13 patients (17.8 %) presented with histologically confirmed positive ganglion. After circumcision, IBT was performed using a hypodermic needle. The median dose delivered was 60 Gy (range, 40 to 70 Gy). The median activity of the iridium-192 wire was 1.12 mCi/cm, and the median reference isodose rate was 0.4 Gy/h (range, 0.2-1.2). Patients with histological inguinal metastases received external beam radiotherapy to the selected inguinal affected area with a median dose of 45 Gy (30-55 Gy). RESULTS: The median follow-up time was 51.8 months (range 34.4 to 68.7). The 5-year overall survival was 82.0 %, with eight deaths from cancer and five non-cancer-related deaths. Disease-specific survival was 91.4 %, relapse free survival was 64.4 %, and local relapse-free survival as 74 %. Total or partial penile preservation was 87.9 % at 5-years. Complications rates at 5 years were 6.6 % urethral stenosis (five patients), two patients (2.6 %) with pain related to sexual intercourse and four patients (5.3 %) with dysuria grade 2. Five patients (6.8 %) required penile amputation for necrosis. CONCLUSIONS: IBT provides good local control with organ preservation, excellent tolerance and low complication rates in early-stage penile cancers. PMID- 27464911 TI - Trends in traffic fatalities in Mexico: examining progress on the decade of action for road safety 2011-2020. AB - OBJECTIVES: We explore demographic, temporal and geographic patterns of 256,588 road traffic fatalities from 1998 to 2013 in Mexico, in context of UN's decade of action for road safety 2010-2020 (DARS). METHODS: Combined traffic mortality data and population counts were analyzed using mixed-effects logistic regression, distinguishing sex-age groups, vulnerable and protected road users, and municipal size. RESULTS: Rapid growth from 1998 to 2008 in traffic mortality rates has been reversed since 2009. Most deaths averted are among young male protected road users (reduction of 0.95 fatalities per 100,000 per year in males 12-49). In spite of a steady decrease over the full study period, mortality rates remain high in vulnerable road users over 50, with a high mortality rate of 26 per 100,000 males over 75 years in 2013. CONCLUSIONS: Progress on the reduction of deaths advances in Mexico, in line with DARS targets. National road safety efforts require strengthening. Initiatives should target vulnerable road users, specifically adults >50 years in urban areas. Strengthening of drink driving programs aimed at young drivers/occupants is promising. PMID- 27464912 TI - Insufficient Lymph Node Sampling in Patients with Colorectal Cancer Perforation is Associated with an Adverse Oncological Outcome. AB - BACKGROUND: The impact of lymph node (LN) dissection on long-term outcomes for patients with colorectal cancer (CRC) perforation remains unclear. We aim to investigate factors associated with poor prognosis and recurrence in patients with CRC, with special reference to cancer perforation and LN dissection. METHODS: The subjects comprised 550 patients who underwent colorectal surgery for CRC at Stage II or III (TNM classification) between February 2006 and November 2013. Short- and long-term outcomes of patients with or without CRC perforation were evaluated. We also sought risk factors on poor prognosis, focusing on LN dissection in patients with CRC perforation. RESULTS: A total of 508 underwent surgery for CRC without perforation (the non-perforation group) and 39 for CRC with perforation (the perforation group). Both overall survival and recurrence free survival rates were significantly lower in the perforation group than in the non-perforation group (overall survival, P = 0.009; recurrence-free survival, P < 0.001). The relapse rates at the peritoneum (P = 0.002), lung (P = 0.007) and LNs (P = 0.021) were significantly higher in the perforation group than in the non perforation group. Multivariable Cox proportional hazards model revealed that CRC perforation (hazard ratio [HR] 2.55, 95 % confidential interval [CI] 1.16-4.98, P = 0.022), LN dissection <12 (HR 1.83, 95 % CI 1.07-3.13, P = 0.027), and Stage III (HR 1.79, 95 % CI 1.06-3.08, P = 0.031) were significant and independent risk factors for poor prognosis. CONCLUSIONS: Conducting <12 LN dissections independently increased the risk of reduction in overall survival for patients with CRC perforation. Thus, radical LN dissections should be performed to improve patients' survival rates, when patients' general and surgical conditions allow. PMID- 27464913 TI - Learning Curve for Pilonidal Sinus Surgery: The Best Option for Budding Surgeons. AB - BACKGROUND: Surgery for pilonidal sinus has no gold standard, and results depend purely on surgeon preference of procedure and experience. Till date, there has been no study comparing the surgical outcomes when performed by residents. Therefore, we designed our study to compare the short-term outcomes of Karydakis' and Limberg's flap procedures in the treatment of pilonidal disease when performed by surgical residents. METHOD: A prospective, double-blinded, observational study was carried out at Command Hospital, Pune, India. Twenty-five consecutive patients undergoing each of the Karydakis' and Limberg's flap procedures (n = 50) were enrolled in the study. All patients had a primary sinus opening. Patients with a frank pilonidal abscess were excluded, but patients with history of intermittent purulent discharge even during time of surgery were included. RESULTS: There was a significantly higher rate of infection in the Karydakis' group (9/25) as compared to the Limberg's flap group (3/25) and also a higher rate of complete wound dehiscence (2/25 vs 1/25). CONCLUSION: Limberg's flap procedure appears to be superior to Karydakis' procedure, and the results are reproducible even by budding surgeons with little experience in the procedure. PMID- 27464914 TI - Outcomes After Surgical and Antibiotic Treatment of Appendicitis. PMID- 27464915 TI - Temporary Intraoperative Porto-Caval Shunts in Piggy-Back Liver Transplantation Reduce Intraoperative Blood Loss and Improve Postoperative Transaminases and Renal Function: A Meta-Analysis. AB - BACKGROUND: The value of temporary intraoperative porto-caval shunts (TPCS) in cava-sparing liver transplantation is discussed controversially. Aim of this meta analysis was to analyze the impact of temporary intraoperative porto-caval shunts on liver injury, primary non-function, time of surgery, transfusion of blood products and length of hospital stay in cava-sparing liver transplantation. METHODS: A systematic search of MEDLINE/PubMed, EMBASE and PsycINFO retrieved a total of 909 articles, of which six articles were included. The combined effect size and 95 % confidence interval were calculated for each outcome by applying the inverse variance weighting method. Tests for heterogeneity (I 2) were also utilized. RESULTS: Usage of a TPCS was associated with significantly decreased AST values, significantly fewer transfusions of packed red blood cells and improved postoperative renal function. There were no statistically significant differences in primary graft non-function, length of hospital stay or duration of surgery. CONCLUSION: This meta-analysis found that temporary intraoperative porto caval shunts in cava-sparing liver transplantation reduce blood loss as well as hepatic injury and enhance postoperative renal function without prolonging operative time. Randomized controlled trials investigating the use of temporary intraoperative porto-caval shunts are needed to confirm these findings. PMID- 27464916 TI - Clinical Significance of the Endoscopic Finding in Predicting Complete Tumor Response to Preoperative Chemoradiation Therapy in Rectal Cancer. AB - BACKGROUND: There are reports that suggest conservative treatment when a tumor shows clinically complete response (CR) after preoperative chemoradiotherapy in rectal cancer. The aim of this study is to investigate the association between endoscopic complete response (E-CR) and pathologic CR (pCR) and to determine the sensitivity and specificity of E-CR and its clinical utility after preoperative chemoradiotherapy in rectal cancer. METHODS: We analyzed prospectively collected data of patients with middle and lower rectal cancers who underwent preoperative chemoradiotherapy, between January 2010 and January 2015. RESULTS: Nineteen patients (17.9 %) showed E-CR, and 87 patients showed E-non CR. Twenty-three patients (21.7 %) were confirmed to have pCR. E-CR was closely associated with pCR (p < 0.001). E-CR reflected pCR with an accuracy of 88.7 %, sensitivity of 65.2 %, specificity of 95.2 %, PPV of 78.9 %, NPV of 90.8 %, and a p value of <0.001. CONCLUSIONS: E-CR after preoperative chemoradiotherapy in rectal cancer is significantly associated with pCR. However, a wait and see policy should be performed carefully with current endoscopic prediction for pCR to avoid inadequate treatment in patients who show E-CR after preoperative chemoradiotherapy. PMID- 27464917 TI - ALPPS Procedure in Insufficient Hypertrophy After Portal Vein Embolization (PVE). AB - BACKGROUND: The main limiting factor for major liver resections is the volume and function of the future remnant liver (FLR). Portal vein embolization (PVE) is now standard in most centers for preoperative hypertrophy of FLR. However, it has a failure rate of about 20-30 %. In these cases, the "Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy" (ALPPS) may represent a suitable and possibly the only alternative. METHODS: We performed a retrospective analysis of nine patients who had ALPPS following an insufficient hypertrophy after PVE. Computed tomography volumetry were performed before and after PVE as well as the first step of ALPPS. Furthermore, complications, 30-day mortality and outcome were analyzed. RESULTS: The FLR volume rose significantly by 77.7 +/- 40.7 % (FLR/TLV: 34.9 +/- 9.7 %) as early as 9 days after the first stage despite insufficient hypertrophy after preoperative portal vein embolization. Major complications (Grade > IIIb) occurred in 33 % of the patients, and 30-day mortality was 11.1 %. The OS at 1 and 2 years was 78 and 44 %. Four patients are presently still alive at a median of 33.4 (range 15-48) months (survival rate 44.4 %). CONCLUSION: The ALPPS procedure could be a suitable alternative for patients following insufficient PVE or indeed the last chance of a potentially curative treatment in this situation. Nevertheless, the high morbidity and mortality rates and the lack of data on the long-term oncological outcome must also be taken into account. PMID- 27464918 TI - Pleural Empyema Following Liver Resection: A Rare But Serious Complication. AB - BACKGROUND: Postoperative pleural empyema following liver resection has not been thoroughly described in the literature yet. Hence, we aimed to describe characteristics of patients experiencing this complication. METHODS: Characteristics and outcomes of 21 patients who developed pleural empyema after hepatectomy, defined as a bacteriologically proven pleural infection with clinical and biological inflammatory signs requiring antibiotherapy and thoracic drainage, from 2001 to 2014, were retrospectively analyzed. RESULTS: Overall incidence of pleural empyema was 1 %. Nineteen (90.5 %) patients underwent right or extended right hepatectomy. All 21 patients developed postoperatively pleural effusion and 13 (62 %) infected abdominal collection. They had significantly more bile leakage and intra-abdominal abscesses compared to a matched control group of patients undergoing a right hepatectomy. Accidental diaphragmatic opening was observed in six patients (intra-operatively n = 4, transdiaphragmatic abdominal drainage n = 2). Treatment included percutaneous pleural drainage and in six (29 %) patients a thoracotomy for surgical drainage. Three patients (14 %) died due to sepsis and multiorgan failure. No patient treated by thoracotomy died postoperatively. CONCLUSION: Postoperative pleural empyema is a rare but serious complication occurring mostly after right hepatectomy complicated with intraabdominal sepsis. Pleural paracentesis for diagnosis and treatment should be rapidly considered. Early thoracotomy for optimal drainage would reduce postoperative mortality. PMID- 27464919 TI - Psychosocial Factors Related to Underuse of Medical Services. AB - In this longitudinal study, we applied structural equation modeling (SEM) to examine the historical, predisposing, enabling/barrier, and need factors as related to the underuse of medical services during early midlife. We gathered longitudinal data on a prospective cohort of community-dwelling men and women (N = 548) followed from adolescence to early midlife. The findings supported a mediational model: A mutually affectionate parent-child relationship in early adolescence was inversely related to underuse of medical services in early midlife via the mediational roles played by later predisposing factors (i.e., depressive mood and cigarette smoking), need factor (i.e., physical health problems), barriers (i.e., financial difficulty), and enabling factors (i.e., social support for health services in early midlife). In addition, satisfaction with medical services in the neighborhood had an association with less underuse of medical services in early midlife. Family therapy focused on an increase in the affectionate relationship between the adolescents and his/her parents and cognitive-behavioral treatment of depressive mood may lead to a decrease in the underuse of medical services. PMID- 27464940 TI - Anesthetic Management of Conjoined Twins for Computed Tomography Scan. AB - Anesthetic management of the conjoined twins in the radiology suite presents some unique problems for anesthesia. We report a case of 3-month and 10-day-old xiphopagus twins undergoing computed tomography scan under general anesthesia. The issues in their management in radiology included the unknown effects of anesthetic agents on circulation because of sharing of organs, duplication of staff, equipment in a limited space, placing the children on the scan table, airway control and ventilator management, and changeover of equipment during procedure. PMID- 27464938 TI - Lentivirus-mediated shRNA interference of ghrelin receptor blocks proliferation in the colorectal cancer cells. AB - Ghrelin, an orexigenic peptide, acts via the growth hormone secretagogue receptor (GHSR) to stimulate the release of growth hormone. Moreover, it has a range of biological actions, including the stimulation of food intake, modulation of insulin signaling and cardiovascular effects. Recently, it has been demonstrated that ghrelin has a proliferative and antiapoptotic effects in cancers, suggesting a potential role in promoting tumor growth. However, it remains unknown whether GHSR contributes to colorectal cancer proliferation. In this study, the therapeutic effect of lentivirus-mediated short hairpin RNA (shRNA) targeting ghrelin receptor 1a (GHSR1a) was analyzed in colorectal cancer cell line SW480 both in vitro and in vivo. Our study demonstrated that ghrelin and GHSR1a are significantly upregulated in cancerous colorectal tissue samples and cell lines. In vitro, human colorectal cancer cell line SW480 with downregulation of GHSR1a by shRNA showed significant inhibition of cell viability compared with blank control (BC) or scrambled control (SC) regardless of the application of exogenous ghrelin. Furthermore, GHSR1a silencing by target specific shRNA was shown capable of increasing PTEN, inhibiting AKT phosphorylation and promoting the release of p53 in SW480 cells. In addition, the effects of GHSR1a knockdown were further explored in vivo using colorectal tumor xenograft mouse model. The tumor weights were decreased markedly in GHSR1alpha knockdown SW480 mouse xenograft tumors compared with blank control or negative control tumors. Our results suggested that the expression of GHSR1a is significantly correlated with the growth of colorectal cancer cells, and the GHSR1a knockdown approach may be a potential therapy for the treatment of colorectal cancer. PMID- 27464941 TI - A Novel and Multidisciplinary Strategy for Cesarean Delivery With Placenta Percreta: Intraoperative Embolization in a Hybrid Suite. AB - Cesarean deliveries in patients with placenta accreta often are accompanied by life-threatening bleeding and sometimes death. A novel, multidisciplinary approach that uses uterine embolization after cesarean delivery recently has been advocated; however, embolization in the radiology department requires transfer of postoperative patients, which could increase maternal mortality and morbidity. In a case of severe placenta accreta, we planned a stepwise treatment, including cesarean delivery without separation of the placenta followed by intraoperative uterine arterial embolization in a hybrid operating room, followed by hysterectomy a few weeks after cesarean delivery. With no postpartum bleeding, complete hysterectomy was performed uneventfully 25 days later. PMID- 27464942 TI - Airway Management and Definitive Care of a Toddler Following Impalement Injury by a Metal Straw. AB - Although pediatric trauma benefits from specialized pediatric care, at times, nonpediatric centers are required to provide initial management. In this unusual airway impalement injury, the combination of smooth coordination between emergency medicine and anesthesia, an articulated airway strategy, parental involvement, and clear, calm teamwork maximized patient safety during airway securement and transfer for definitive care. The airway strategy included the anticipation that the first attempt at endotracheal intubation may not be successful and the need to keep the "auditory space" clear. Public health warnings regarding the hazards of noncollapsible straws in the pediatric population should perhaps be considered. PMID- 27464943 TI - One-Lung Ventilation for Lung Lobectomy Using Endobronchial Blocker Through Adjustable Silicon Hyperflex Tracheostomy Tube in Postlaryngectomy Patient. AB - One-lung ventilation is challenging in patients with difficult airway who require lung surgery. The choice of airway technique remains limited in patients with permanent tracheostomy after total laryngectomy. Conventional airway management techniques and available airway equipment have limited the options for securing airway in such patients, and dedicated airway equipment is not available for the management of such patients. Here, using endobronchial blocker through adult silicon hyperflex tracheostomy tube with an adjustable flange, we report a successful airway management for 1-lung ventilation in a patient with total laryngectomy with permanent tracheostomy. PMID- 27464944 TI - A Novel Approach to Brachial Plexus Catheter Management: A Brachial Plexus Test Dose for Phrenic Nerve Paralysis and Patient-Controlled, Demand-Only Dosing for a Patient With Extreme Obesity. AB - A 53-year-old woman with extreme obesity (body mass index = 82 kg/m) presented for an open reduction and internal fixation of the proximal humerus. This report describes the novel management of her continuous brachial plexus catheter in the setting of her comorbidities. Phrenic nerve paralysis from brachial plexus blocks can cause clinically significant dyspnea in obese patients. Brachial plexus catheters can be used effectively for these patients with some modification to routine management. We detail our use of a short-acting chloroprocaine test dose for phrenic paralysis and demand-only dosing to provide effective analgesia while avoiding respiratory complications associated with these blocks. PMID- 27464945 TI - Polyomavirus detection in multiple sclerosis patients under natalizumab therapy: Profile and frequency of urinary shedding. AB - Patients undergoing Natalizumab (NTZ) therapy are at risk of progressive multifocal leukoencephalopathy (PML). Besides John Cunningham virus (JCV), BK polyomavirus might represent an additional concern for such patients since it can also infect CNS cells. Currently, data regarding the presence of anti-JCV antibodies added to previous immunosuppressive therapy and prolonged NTZ therapy has been used to classify patients at risk of developing PML. Here, we investigated the profile shedding of JCV and BKV in multiple sclerosis (MS) patients during treatment with NTZ. Serial blood and urine samples from 97 MS patients receiving either NTZ or beta-interferon were investigated for polyomavirus shedding. While all blood samples tested negative, 36% of the patients shed polyomavirus in the urine in at least one time point. From these, 21.7%, 9.3%, and 5.1% shed JCV, BKV, and both polyomavirus, respectively. No difference was observed between the rates of urinary shedding of patients treated with NTZ (38.9%) and patients treated with other drugs (34.5%), also no PML event was diagnosed during the follow-up. Therefore, urinary shedding might not be interfered by therapy condition. In our study, we also observed 14/27 (52%) of anti-JCV antibodies prevalence, and nearly half of them (42%) did not present any event of urinary shedding during the follow-up. J. Med. Virol. 89:528-534, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27464947 TI - Assessment of Protein Binding of 5-Hydroxythalidomide Bioactivated in Humanized Mice with Human P450 3A-Chromosome or Hepatocytes by Two-Dimensional Electrophoresis/Accelerator Mass Spectrometry. AB - Bioactivation of 5-hydroxy-[carbonyl-(14)C]thalidomide, a known metabolite of thalidomide, by human artificial or native cytochrome P450 3A enzymes, and nonspecific binding in livers of mice was assessed using two-dimensional electrophoresis combined with accelerator mass spectrometry. The apparent major target proteins were liver microsomal cytochrome c oxidase subunit 6B1 and ATP synthase subunit alpha in mice containing humanized P450 3A genes or transplanted humanized liver. Liver cytosolic retinal dehydrogenase 1 and glutathione transferase A1 were targets in humanized mice with P450 3A and hepatocytes, respectively. 5-Hydroxythalidomide is bioactivated by human P450 3A enzymes and trapped with proteins nonspecifically in humanized mice. PMID- 27464946 TI - Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes. AB - The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N terminal fragments (amino acid residues 1-83) of apoA-I containing this mutation deposit as amyloid fibrils in patients' tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis. PMID- 27464948 TI - Induction of artificial cancer stem cells from tongue cancer cells by defined reprogramming factors. AB - BACKGROUND: The cancer stem cells (CSCs), a small subpopulation of cells in tumor are responsible for the tumor initiation, growth, recurrence and metastasis of cancer, as well as resistance of cancers to drugs or radiotherapy. CSCs are an important target for the development of novel strategies in cancer treatment. However, CSCs-targeted new anti-cancer drug discovery is currently hindered by the lack of easy and reliable methods for isolating, collecting and maintaining sufficient number of CSCs. Here, we examined whether introduction of defined reprogramming factors (Oct4, shp53, Sox2, Klf4, l-Myc and Lin28) into HSC2 tongue cancer cells could transform the HSC2 into HSC2 with CSCs properties. METHODS: We introduced the defined reprogramming factors into HSC2 tongue cancer cells via episomal vectors by electroporation method to generate transfectant cells. We investigated the malignant properties of the transfectant cells by cell proliferation assay, migration assay, wound healing assay, sphere formation assay, chemosensitivity and radiosensitivity assay in vitro; and also examined the tumorigenic potential of the transfectants in vivo. RESULTS: The transfectant cells (HSC2/hOCT3/4-shp53-F, HSC2/hSK, HSC2/hUL, HSC2/hOCT3/4-shp53-F + hSK, HSC2/hOCT3/4-shp53-F + hUL, HSC2/hSK + hUL, HSC2/hOCT3/4-shp53-F + hSK + hUL) displayed a malignant phenotype in culture and form tumors on the back of nude mice more efficiently than parental HSC2 and control HSC2/EGFP transfectant cells. They exhibited increased resistance to chemotherapeutic agents; 5 fluorouracil, cisplatin, docetaxel, trifluorothymidine, zoledronic acid, cetuximab, bortezomib and radiation when compared with HSC2 and HSC2/EGFP. Among all the transfected cells, HSC2/hOCT3/4-shp53-F + hSK + hUL cell containing all of the reprogramming factors showed the most aggressive and malignant properties and presented the highest number of spheres in the culture medium containing human recombinant fibroblast Growth Factor-2 (FGF-2) and epidermal Growth Factor (EGF). CONCLUSION: These findings suggest that artificial cancer stem cells obtained by the induction of cellular reprogramming may be useful for investigating the acquisition of potential malignancy as well as screening the CSCs-targeting drugs. PMID- 27464949 TI - Laparoscopic RFA with splenectomy for hepatocellular carcinoma. AB - BACKGROUND: The treatment of hepatocellular carcinoma (HCC) is complicated and challenging because of the frequent presence of cirrhosis. Therefore, we propose a novel surgical approach to minimize the invasiveness and risk in patients with HCC, hypersplenism, and esophagogastric varices. METHODS: This was a retrospective study carried out in 25 patients with HCC and hypersplenism and who underwent simultaneous laparoscopic-guided radio-frequency ablation and laparoscopic splenectomy with endoscopic variceal ligation. Tumor size was restricted to a single nodule of <3 cm. Characteristics of the patients (cirrhosis etiology, liver function, tumor size, spleen size), surgery (complications, blood loss, time of stay), and follow-up (recurrence and survival) were examined. RESULTS: Mean operative time was 128 +/- 18 min. Mean blood loss was 206 +/- 57 mL. Length of stay was 7.0 +/- 1.5 days. Mean total costs were 8064 USD. Cytopenia and thrombocytopenia recovered quickly after surgery. No procedure was converted to open surgery. Two patients showed worsening liver function after surgery, three patients showed worsening of ascites, and five patients suffered from portal vein thrombosis. The 1-year tumor free survival was 78.8 %, and the 21-month tumor-free survival was 61.4 %. According to a literature review, these outcomes were comparable to those of simultaneous open hepatic resection and splenectomy. CONCLUSIONS: Laparoscopic guided radio-frequency ablation with laparoscopic splenectomy and endoscopic variceal ligation could be an available technique for patients with HCC <3 cm, hypersplenism, and esophagogastric varices. This approach may help to minimize the surgical risks and results in a fast increase in platelet counts with an acceptable rate of complications. PMID- 27464950 TI - Competition-driven build-up of habitat isolation and selection favoring modified dispersal patterns in a young avian hybrid zone. AB - Competition-driven evolution of habitat isolation is an important mechanism of ecological speciation but empirical support for this process is often indirect. We examined how an on-going displacement of pied flycatchers from their preferred breeding habitat by collared flycatchers in a young secondary contact zone is associated with (a) access to an important food resource (caterpillar larvae), (b) immigration of pied flycatchers in relation to habitat quality, and (c) the risk of hybridization in relation to habitat quality. Over the past 12 years, the estimated access to caterpillar larvae biomass in the habitat surrounding the nests of pied flycatchers has decreased by a fifth due to shifted establishment possibilities, especially for immigrants. However, breeding in the high quality habitat has become associated with such a high risk of hybridization for pied flycatchers that overall selection currently favors pied flycatchers that were forced to immigrate into the poorer habitats (despite lower access to preferred food items). Our results show that competition-driven habitat segregation can lead to fast habitat isolation, which per se caused an opportunity for selection to act in favor of future "voluntarily" altered immigration patterns and possibly strengthened habitat isolation through reinforcement. PMID- 27464951 TI - Peptide-oligonucleotide conjugates as nanoscale building blocks for assembly of an artificial three-helix protein mimic. AB - Peptide-based structures can be designed to yield artificial proteins with specific folding patterns and functions. Template-based assembly of peptide units is one design option, but the use of two orthogonal self-assembly principles, oligonucleotide triple helix and a coiled coil protein domain formation have never been realized for de novo protein design. Here, we show the applicability of peptide-oligonucleotide conjugates for self-assembly of higher-ordered protein like structures. The resulting nano-assemblies were characterized by ultraviolet melting, gel electrophoresis, circular dichroism (CD) spectroscopy, small-angle X ray scattering and transmission electron microscopy. These studies revealed the formation of the desired triple helix and coiled coil domains at low concentrations, while a dimer of trimers was dominating at high concentration. CD spectroscopy showed an extraordinarily high degree of alpha-helicity for the peptide moieties in the assemblies. The results validate the use of orthogonal self-assembly principles as a paradigm for de novo protein design. PMID- 27464952 TI - Assessment of genetic variation for pathogen-specific mastitis resistance in Valle del Belice dairy sheep. AB - BACKGROUND: Mastitis resistance is a complex and multifactorial trait, and its expression depends on both genetic and environmental factors, including infection pressure. The objective of this research was to determine the genetic basis of mastitis resistance to specific pathogens using a repeatability threshold probit animal model. RESULTS: The most prevalent isolated pathogens were coagulase negative staphylococci (CNS); 39 % of records and 77 % of the animals infected at least one time in the whole period of study. There was significant genetic variation only for Streptococci (STR). In addition, there was a positive genetic correlation between STR and all pathogens together (ALL) (0.36 +/- 0.22), and CNS and ALL (0.92 +/- 0.04). CONCLUSION: The results of our study support the presence of significant genetic variation for mastitis caused by Streptococci and suggest the importance of discriminating between different pathogens causing mastitis due to the fact that they most likely influence different genetic traits. Low heritabilities for pathogen specific-mastitis resistance may be considered when including bacteriological status as a measure of mastitis presence to implement breeding strategies for improving udder health in dairy ewes. PMID- 27464954 TI - Hematite(001)-liquid water interface from hybrid density functional-based molecular dynamics. AB - The atom-scale characterisation of interfaces between transition metal oxides and liquid water is fundamental to our mechanistic understanding of diverse phenomena ranging from crystal growth to biogeochemical transformations to solar fuel production. Here we report on the results of large-scale hybrid density functional theory-based molecular dynamics simulations for the hematite(001) liquid water interface. A specific focus is placed on understanding how different terminations of the same surface influence surface solvation. We find that the two dominant terminations for the hematite(001) surface exhibit strong differences both in terms of the active species formed on the surface and the strength of surface solvation. According to present simulations, we find that charged oxyanions (-O(-)) and doubly protonated oxygens (-OH[Formula: see text]) can be formed on the iron terminated layer via autoionization of neutral -OH groups. No such charged species are found for the oxygen terminated surface. In addition, the missing iron sublayer in the iron terminated surface strongly influences the solvation structure, which becomes less well ordered in the vicinity of the interface. These pronounced differences are likely to affect the reactivity of the two surface terminations, and in particular the energetics of excess charge carriers at the surface. PMID- 27464955 TI - Impacts of global warming on phenology of spring leaf unfolding remain stable in the long run. AB - The impact of spring temperature forcing on the timing of leaf unfolding of plants (temperature sensitivity, ST) is one important indicator of how and to what degree plant species track climate change. Fu et al. (Nature 526:104-107, 2015) found that ST has significantly decreased from the 1980-1994 to the 1999 2013 period for seven mid-latitude tree species in Europe. However, long-term changes in ST over the past 60 years are still not clear. Here, using in situ observations of leaf unfolding for seven dominant European tree species, we analyze the temporal change in ST over decadal time scales extending the data series back to 1951. Our results demonstrate that ST shows no statistically significant change within shifting 30-year windows from 1951 to 2013 and remains stable between 1951-1980 and 1984-2013 (3.6 versus 3.7 days degrees C-1). This result suggests that the significant decrease in ST over the past 33 years could not be sustained when examining the trends of phenological responses in the long run. Therefore, we could not conclude that tree spring phenology advances will slow down in the future, and the ST changes in warming scenarios are still uncertain. PMID- 27464953 TI - Study protocol for a multicentre randomized controlled trial on effectiveness of an outpatient multimodal rehabilitation program for adolescents with chronic musculoskeletal pain (2B Active). AB - BACKGROUND: Chronic musculoskeletal pain (CMP) in adolescents can influence functioning and well-being, and has negative consequences for families and society as well. According to the Fear Avoidance Model, fear of movement and pain catastrophizing can influence the occurrence and maintenance of chronic pain complaints and functional disability. Primary objective is to evaluate the effectiveness of a multimodal rehabilitation program in reducing functional disability for adolescents with CMP compared with care as usual. METHODS/DESIGN: Pragmatic multicentre parallel group randomized controlled trial. Randomization by minimization (ratio 1:1) and treatment allocation will be concealed, computer generated and performed by an independent organization. After randomization, data collection and researchers remain blinded. Inclusion of 124 adolescents and their parents is intended. This sample size is based on a 25 % difference in group mean on the primary outcome, with alpha = 5 %, beta = 80 % and expected 15 % loss to follow up. Study population are adolescents (12-21 years) with CMP with an indication for outpatient rehabilitation treatment in the Netherlands. The intervention group receives a Multimodal Rehabilitation Program (MRP), a multidisciplinary outpatient individual rehabilitation program. MRP consists of 2 different treatment approaches: A graded exposure module or a combination module of graded exposure and physical training. Selection of a module depends on the needs of the patient. To both modules a parent module is added. The control group receives care as usual, which is the care currently provided in Dutch rehabilitation centres. Treatment duration varies between 7 and 16 weeks, depending on treatment allocation. Self-reported measurements are at baseline, and at 2, 4, 10 and 12 months after start of treatment. Intention to treat analysis for between group differences on all outcome variables will be performed. Primary outcome is functional disability (Functional Disability Inventory). Secondary outcome variables are fear of pain, catastrophizing, perceived harmfulness, pain intensity, depressive symptoms, and quality of life. Total direct and indirect costs and health related quality of life will be measured. Process evaluation focuses on protocol adherence, patient centeredness and treatment expectations. DISCUSSION: A pragmatic approach was chosen, to ensure that results obtained are most applicable to daily practice. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02181725 (7 February 2014). Funded by Fonds Nuts Ohra, Stichting Vooruit, and Adelante. PMID- 27464956 TI - The effect of geographical indices on left ventricular structure in healthy Han Chinese population. AB - The left ventricular posterior wall thickness (LVPWT) and interventricular septum thickness (IVST) are generally regarded as the functional parts of the left ventricular (LV) structure. This paper aims to examine the effects of geographical indices on healthy Han adults' LV structural indices and to offer a scientific basis for developing a unified standard for the reference values of adults' LV structural indices in China. Fifteen terrain, climate, and soil indices were examined as geographical explanatory variables. Statistical analysis was performed using correlation analysis. Moreover, a back propagation neural network (BPNN) and a support vector regression (SVR) were applied to developing models to predict the values of two indices. After the prediction models were built, distribution maps were produced. The results show that LV structural indices are characteristically associated with latitude, longitude, altitude, average temperature, average wind velocity, topsoil sand fraction, topsoil silt fraction, topsoil organic carbon, and topsoil sodicity. The model test analyses show the BPNN model possesses better simulative and predictive ability in comparison with the SVR model. The distribution maps of the LV structural indices show that, in China, the values are higher in the west and lower in the east. These results demonstrate that the reference values of the adults' LV structural indices will be different affected by different geographical environment. The reference values of LV structural indices in one region can be calculated by setting up a BPNN, which showed better applicability in this study. The distribution of the reference values of the LV structural indices can be seen clearly on the geographical distribution map. PMID- 27464957 TI - A small-scale randomised controlled trial of home telemonitoring in patients with severe chronic obstructive pulmonary disease. AB - Introduction This was a pilot study to examine the effects of home telemonitoring (TM) of patients with severe chronic obstructive pulmonary disease (COPD). Methods A randomised controlled 12-month trial of 42 patients with severe COPD was conducted. Home TM of oximetry, temperature, pulse, electrocardiogram, blood pressure, spirometry, and weight with telephone support and home visits was tested against a control group receiving only identical telephone support and home visits. Results The results suggest that TM had a reduction in COPD-related admissions, emergency department presentations, and hospital bed days. TM also seemed to increase the interval between COPD-related exacerbations requiring a hospital visit and prolonged the time to the first admission. The interval between hospital visits was significantly different between the study arms, while the other findings did not reach significance and only suggest a trend. There was a reduction in hospital admission costs. TM was adopted well by most patients and eventually, also by the nursing staff, though it did not seem to change patients' psychological well-being. Discussion Ability to draw firm conclusions is limited due to the small sample size. However the trends of reducing hospital visits warrant a larger study of a similar design. When designing such a trial, one should consider the potential impact of the high quality of care already made available to this patient cohort. PMID- 27464958 TI - Causal mediation analysis on failure time outcome without sequential ignorability. AB - Mediation analysis is an important topic as it helps researchers to understand why an intervention works. Most previous mediation analyses define effects in the mean scale and require a binary or continuous outcome. Recently, possible ways to define direct and indirect effects for causal mediation analysis with survival outcome were proposed. However, these methods mainly rely on the assumption of sequential ignorability, which implies no unmeasured confounding. To handle the potential confounding between the mediator and the outcome, in this article, we proposed a structural additive hazard model for mediation analysis with failure time outcome and derived estimators for controlled direct effects and controlled mediator effects. Our methods allow time-varying effects. Simulations showed that our proposed estimator is consistent in the presence of unmeasured confounding while the traditional additive hazard regression ignoring unmeasured confounding produces biased results. We applied our method to the Women's Health Initiative data to study whether the dietary intervention affects breast cancer risk through changing body weight. PMID- 27464959 TI - Separating sensitization and regulatory T-cell functions in patients with food allergy. PMID- 27464960 TI - Specific IgE and IgG measured by the MeDALL allergen-chip depend on allergen and route of exposure: The EGEA study. AB - BACKGROUND: The nature of allergens and route and dose of exposure may affect the natural development of IgE and IgG responses. OBJECTIVE: We sought to investigate the natural IgE and IgG responses toward a large panel of respiratory and food allergens in subjects exposed to different respiratory allergen loads. METHODS: A cross-sectional analysis was conducted in 340 adults of the EGEA (Epidemiological study of the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy) (170 with and 170 without asthma) cohort. IgE and IgG responses to 47 inhalant and food allergen components were analyzed in sera using allergen microarray and compared between 5 French regions according to the route of allergen exposure (inhaled vs food allergens). RESULTS: Overall 48.8% of the population had allergen-specific IgE levels of 0.3 ISAC standardized units (ISU) or more to at least 1 of the 47 allergens with no significant differences across the regions. For ubiquitous respiratory allergens (ie, grass, olive/ash pollen, house dust mites), specific IgE did not show marked differences between regions and specific IgG (>=0.5 ISU) was present in most subjects everywhere. For regionally occurring pollen allergens (ragweed, birch, cypress), IgE sensitization was significantly associated with regional pollen exposure. For airborne allergens cross-reacting with food allergens, frequent IgG recognition was observed even in regions with low allergen prevalence (Bet v 1) or for allergens less frequently recognized by IgE (profilins). CONCLUSIONS: The variability in allergen-specific IgE and IgG frequencies depends on exposure, route of exposure, and overall immunogenicity of the allergen. Allergen contact by the oral route might preferentially induce IgG responses. PMID- 27464961 TI - High alcohol consumption causes high IgE levels but not high risk of allergic disease. AB - BACKGROUND: High alcohol consumption is associated with high IgE levels in observational studies; however, whether high alcohol consumption leads to high IgE levels and allergic disease is unclear. OBJECTIVE: We tested the hypothesis that high alcohol consumption is associated with high IgE levels and allergic disease both observationally and genetically using a Mendelian randomization design free of reverse causation and largely free of confounding. METHODS: Among 111,408 subjects aged 20 to 100 years from the general population, 50,019 had plasma IgE measurements, and 102,270 were genotyped for the alcohol-metabolizing enzymes alcohol dehydrogenase 1B (ADH-1B; rs1229984) and alcohol dehydrogenase 1c (ADH-1C; rs698). Observationally, we investigated associations between IgE levels and allergic disease (allergic asthma, rhinitis, and eczema) and between alcohol consumption and IgE levels and allergic disease. Genetically, we explored potential causal relationships between alcohol consumption and IgE levels and allergic disease. RESULTS: The multivariable adjusted odds ratio for IgE levels greater than versus less than 150 kU/L and compared with subjects without allergic disease was 2.3 (95% CI, 2.2-2.5) for 1 allergic disease, 3.9 (95% CI, 3.5-4.4) for 2 allergic diseases, and 7.5 (95% CI, 6.2-9.0) for 3 allergic diseases. High alcohol consumption was associated with high IgE levels but not with high risk of allergic disease. The odds ratio for high versus low IgE levels per 1 alcoholic drink per week higher consumption was 1.12 (95% CI, 1.02-1.23) genetically and 1.01 (95% CI, 1.01-1.02) observationally; for allergic disease, the corresponding odds ratios were 0.96 (95% CI, 0.92-1.00) genetically and 1.00 (95% CI, 1.00-1.00) observationally. CONCLUSION: High alcohol consumption is associated observationally and genetically with high IgE levels but not with high risk of allergic disease. PMID- 27464962 TI - Identification of susceptibility SNPs in IL10 and IL23R-IL12RB2 for Behcet's disease in Han Chinese. AB - BACKGROUND: Although previous genome-wide association studies in various cohorts have identified several susceptibility loci underlying Behcet's disease (BD), this has not yet led to a breakthrough in the management of BD. OBJECTIVE: This study aimed to further investigate the association of 26 candidate single nucleotide polymorphisms with previous genome-wide association studies-identified nearly positive P values (5.0 * 10-8 < P < 1.0 * 10-5) in Chinese Han patients with BD. METHODS: A case-control association study was performed in 1206 patients with BD and 2475 healthy controls. Genotyping was performed using iPLEX Gold genotyping assay. Gene expression and cytokine production was quantified by real time PCR and ELISA. RESULTS: The results showed that significantly higher frequencies of the IL23R-IL12RB2/rs924080 TT genotype (P = 2.03 * 10-8; odds ratio [OR] = 1.50), IL23R-IL12RB2/rs12141431 CC genotype (P = 2.18 * 10-8; OR = 1.53), IL10/rs1800871 TT genotype (P = 5.88 * 10-8; OR = 1.47), and IL10/rs3024490 TT genotype (P = 2.80 * 10-5; OR = 1.34) were found in BD. Functional experiments showed an increased IL23R expression and IL-17 production in rs12141431/CC genotype carriers compared with GG genotype carriers. A decreased IL10 expression and IL-10 production was observed in rs3024490/TT genotype carriers as compared with GG genotype carriers. CONCLUSIONS: Our findings not only confirmed the association of IL10/rs1800871 and IL23R IL12RB2/rs924080 with BD but also identified 2 susceptibility single nucleotide polymorphisms in IL10 and IL23R-IL12RB2 (rs3024490 and rs12141431) with BD in Han Chinese. PMID- 27464963 TI - Speckle tracking determination of mitral tissue annular displacement: comparison with strain and ejection fraction, and association with outcomes in haemodialysis patients. AB - Abnormal Global longitudinal strain (GLS) and reduced left ventricular ejection fraction (LVEF) are established poor prognostic risk factors in haemodialysis patients. Tissue motion annular displacement of mitral valve annulus (TMAD), determined by speckle tracking echocardiography (STE), can be performed rapidly and is an indicator of systolic dysfunction, but has been less well explored. This study aims to compare TMAD with GLS and LVEF and its association with outcomes in haemodialysis patients. 198 haemodialysis patients (median age 64.2 years, 69 % men) had 2D echocardiography, with STE determined GLS and TMAD. Bland Altman analysis and linear regression assessed relationship between GLS, LVEF and TMAD. Cox regression analysis investigated association of TMAD with mortality and cardiac events. TMAD had low inter- and intra-observer variability with small biases and narrow limits of agreement (LOA) (bias of -0.01 +/- 1.32 (95 % LOA was -2.60 to 2.58) and -0.07 +/- 1.27 (95 % LOA -2.55 to 2.41) respectively). There was a moderate negative correlation between GLS and LVEF (r = -0.383, p < 0.001) and a weak positive correlation between TMAD and LVEF (r = 0.248, p < 0.001). There was strong negative correlation of TMAD with GLS (r = -0.614, p < 0.001). In a multivariable Cox regression analysis, TMAD was not associated with mortality (HR 1.04, 95 % CI 0.91-1.19), cardiac death (HR 1.03, 95 % CI 0.80 1.32) or cardiac events (HR 0.91, 95 % CI 0.80-1.02). TMAD is a quick and reproducible alternative to GLS which may be very useful in cardiovascular risk assessment, but does not have the same prognostic value in HD patients as GLS. PMID- 27464965 TI - Population based ultrasonographic screening of abdominal aortic aneurysms. PMID- 27464964 TI - A granular approach to improve reproducibility of the echocardiographic assessment of paravalvular regurgitation after TAVI. AB - Paravalvular leak (PVL) after transcatheter aortic valve implantation (TAVI) is challenging to quantitate. Transthoracic echocardiography (TTE) is the main tool used for the assessment of PVL but is modestly reproducible. We sought to develop a reproducible echocardiographic approach to assess PVL in the post-TAVI setting. Four observers independently analyzed eleven parameters of PVL severity in 50 pre discharge TTE studies performed after TAVI. The parameters included color-Doppler parameters [jet circumferential extent (CE) and planimetered vena contracta area in the short-axis view and jet breadth and qualitative features in the long-axis views], continuous-wave Doppler parameters [jet velocity time integral (VTI) and pressure half time (PHT)], quantitative Doppler parameters (regurgitation volume and fraction and effective regurgitant orifice area), aortic diastolic flow reversal and valve stent eccentricity. Intraclass correlation coefficient (ICC) and coefficient of variation (CV) for numerical parameters and kappa coefficient (kappa) for categorical parameters were calculated for inter- and intra-observer comparisons. Inter-observer ICC was highest and CV lowest for CE (0.88 and 0.36), jet origin breadth (0.82 and 0.39), jet qualitative features in long-axis views (0.87 and 0.26), jet VTI (0.87 and 0.04) and PHT (0.73 and 0.10). Similar results were found in intra-observer comparisons. A 2-step granular approach combining the most reproducible parameters was used to grade PVL by the four observers. Inter-observer agreement was achieved in 86 % of cases (kappa = 0.79). Combining color Doppler and continuous wave Doppler parameters in a granular algorithm yields excellent reproducibility of PVL assessment by TTE. PMID- 27464967 TI - Not the Last Word: Two Patients, Two Operating Rooms, One Surgeon-Does The Math Add Up? PMID- 27464966 TI - Gendered Innovations in Orthopaedic Science: Equal But Different. PMID- 27464968 TI - The kidney-specific expression of genes can be modulated by the extracellular osmolality. AB - With this study, we wanted to prove the hypothesis that the unique extracellular osmolality within the renal medulla modulates a specific gene expression pattern. The physiologic functions of the kidneys are mediated by the segment-specific expression of key proteins. So far, we have limited knowledge about the mechanisms that control this gene expression pattern. The hyperosmolality in the renal medullary interstitium is of major importance as a driving force for urine concentration. We made use of primarily cultured rat renal inner medullary collecting-duct cells and microarray analysis to identify genes affected by the environmental osmolality of the culture medium. We identified hundreds of genes that were either induced or repressed in expression by hyperosmolality in a time- and osmolality-dependent fashion. Further analysis demonstrated that many of them, physiologically, showed a kidney- and even collecting-duct-specific expression, including secreted proteins, kinases, and transcription factors. On the other hand, we identified factors, down-regulated in expression, that have a diuretic effect. In conclusion, the kidney is the only organ that has such a hyperosmotic environment, and study provides an excellent method for controlling tissue-specific gene expression.-Schulze Blasum, B., Schroter, R., Neugebauer, U., Hofschroer, V., Pavenstadt, H., Ciarimboli, G., Schlatter E., Edemir, B. The kidney-specific expression of genes can be modulated by the extracellular osmolality. PMID- 27464969 TI - Marked Differences in CNS Activity among EGFR Inhibitors: Case Report and Mini Review. PMID- 27464971 TI - Introduction to the special issue 'medical pluralism and beyond'. PMID- 27464970 TI - An Open-Label, Multicenter, Randomized, Phase II Study of Cisplatin and Pemetrexed With or Without Cixutumumab (IMC-A12) as a First-Line Therapy in Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer. AB - INTRODUCTION: Type 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting. METHODS: In this open-label, phase II study, patients with stage IV nonsquamous NSCLC and a performance status of 0 to 1 were randomized (1:1) to receive 20 mg/kg cixutumumab, 500 mg/m2 pemetrexed, and 75 mg/m2 cisplatin (cixutumumab [n = 87]) or pemetrexed and cisplatin (control [n = 85]). Eligible patients received pemetrexed-based maintenance therapy with cixutumumab (cixutumumab arm) or without it (control arm). The primary end point was progression-free survival. Secondary end points assessed overall survival, objective response rate, and safety. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model. Exploratory correlative analyses were also performed. RESULTS: The mean age of the intent-to treat population (n = 172) was 59 years (range 32-83). Median progression-free survival was 5.45 months with cixutumumab versus 5.22 months in the control (hazard ratio = 1.15, 95% confidence interval: 0.81-1.61; p = 0.44). Median overall survival was 11.33 months with cixutumumab versus 10.38 months in the control (hazard ratio = 0.93, 95% confidence interval: 0.64-1.36). Objective response rate did not differ between treatments (p = 0.338). Grade 3 or 4 hyperglycemia occurred at a higher rate with cixutumumab than in the control (9.4% versus 1.2%). One death possibly related to cixutumumab occurred. CONCLUSIONS: Efficacy was not improved in patients with nonsquamous NSCLC when cixutumumab was added to pemetrexed/cisplatin. Combination therapy was well tolerated and no new safety concerns were reported. PMID- 27464972 TI - The Effect of Preoperative Pregabalin on Postoperative Nausea and Vomiting: A Meta-analysis. AB - BACKGROUND: Nonopioid adjuvant medications are increasingly included among perioperative Enhanced Recovery After Surgery protocols. Preoperative pregabalin has been shown to improve postoperative pain and limit reliance on opioid analgesia. Our group investigated the ability of preoperative pregabalin to also prevent postoperative nausea and vomiting (PONV). METHODS: Our group performed a meta-analysis of randomized trials that report outcomes on the effect of preoperative pregabalin on PONV endpoints in patients undergoing general anesthesia. RESULTS: Among all included trials (23 trials; n = 1693), preoperative pregabalin was associated with a significant reduction in PONV (risk ratio [RR] = 0.53; 95% confidence interval [CI], 0.39-0.73; P = 0.0001), nausea (RR = 0.62; 95% CI, 0.46-0.83; P = 0.002), and vomiting (RR = 0.68; 95% CI, 0.52 0.88; P = 0.003) at 24 hours. Subgroup analysis designed to account for major PONV confounders, including the exclusion trials with repeat dosing, thiopental induction, nitrous oxide maintenance, and prophylactic antiemetics and including high-risk surgery, resulted in similar antiemetic efficacy. Preoperative pregabalin is also associated with significantly increased rates of postoperative visual disturbance (RR = 3.11; 95% CI, 1.34-7.21; P = 0.008) compared with a control. CONCLUSIONS: Preoperative pregabalin is associated with significant reduction of PONV and should not only be considered as part of a multimodal approach to postoperative analgesia but also for prevention of PONV. PMID- 27464973 TI - Is Selective Pulmonary Perfusion Required to Mitigate Lung Injury Postcardiopulmonary Bypass? PMID- 27464974 TI - Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands. AB - Anesthetic photoaffinity ligands have had an increasing presence within anesthesiology research. These ligands mimic parent general anesthetics and allow investigators to study anesthetic interactions with receptors and enzymes; identify novel targets; and determine distribution within biological systems. To date, nearly all general anesthetics used in medicine have a corresponding photoaffinity ligand represented in the literature. In this review, we examine all aspects of the current methodologies, including ligand design, characterization, and deployment. Finally we offer points of consideration and highlight the future outlook as more photoaffinity ligands emerge within the field. PMID- 27464975 TI - deltaGABAA Receptors Are Necessary for Synaptic Plasticity in the Hippocampus: Implications for Memory Behavior. AB - BACKGROUND: Extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that contain the delta subunit (deltaGABAA receptors) contribute to memory performance. Dysregulation of deltaGABAA receptor expression, which occurs in some neurological disorders, is associated with memory impairment. Mice lacking deltaGABAA receptors (Gabrd) exhibit deficits in their ability to distinguish between similar memories, a process which is referred to as pattern separation. The CA3 and dentate gyrus subfields of the hippocampus regulate pattern separation, raising the possibility that synaptic plasticity is impaired in these regions in Gabrd mice. Although long-term potentiation (LTP), the most widely studied form of synaptic plasticity, is normal in the dentate gyrus of Gabrd mice, LTP in the CA3 subfield has not been studied. Here, we tested the hypothesis that LTP is reduced in the CA3 subfield of Gabrd mice. METHODS: LTP of extracellular field postsynaptic potentials was studied in the mossy fiber (MF) CA3 pathway using hippocampal slices from Gabrd and wild-type (WT) mice. We also examined paired pulse responses and input-output relationships at MF-CA3 synapses. RESULTS: MF-CA3 LTP was reduced in Gabrd mice, as evidenced by decreased potentiation of field postsynaptic potentials (WT: 178.3% +/- 16.1% versus Gabrd: 126.3% +/- 6.9%; P = 0.0091). Thus, the deletion of deltaGABAA receptors is associated with impaired plasticity. Bicuculline (BIC), a GABAA receptor antagonist, reduced plasticity in WT but not in Gabrd mice (WT + BIC: 123.9% +/- 7.6% versus Gabrd + BIC: 136.5% +/- 7.0%). Paired pulse responses and input-output relationships did not differ between the genotypes (all Ps > 0.05). CONCLUSIONS: Both genetic deletion and pharmacological blockade of deltaGABAA receptors impair MF-CA3 LTP, suggesting that deltaGABAA receptors are necessary for synaptic plasticity in the CA3 subfield. Drugs that enhance deltaGABAA receptor function may reverse deficits in synaptic plasticity in the CA3 subfield and improve pattern separation in neurological disorders. PMID- 27464976 TI - Transcutaneous PCO2 Monitoring in Newborn Infants During General Anesthesia Is Technically Feasible. AB - BACKGROUND: Transcutaneous (TC) measurement of PCO2 (TC PCO2) is a well established method to monitor assisted ventilation in neonatal intensive care, but its use in the operating room is limited, and the data regarding its performance during general anesthesia of the newborn are lacking. The aim of this study is to evaluate the performance of continuous TC PCO2 monitoring during general anesthesia in newborn infants. METHODS: Infants (n = 25) with a gestational age of 23 to 41 weeks and a birth weight of 548 to 4114 g were prospectively enrolled. During general anesthesia and surgery, TC PCO2 was measured continuously and recorded at 1-minute intervals. Five-minute mean values were compared with simultaneously obtained blood gas (BG) analyses of PCO2. Only the first paired TC and BG samples were used in this analysis. We defined precision as 2.1 times the standard deviation of the difference of the 2 samples. P < .01 was considered statistically significant. RESULTS: We obtained samples from 25 infants. The difference between TC and BG was 0.3 +/- 0.7 kPa (mean +/- standard deviation) giving a precision of 1.47 kPa. Nineteen of twenty-five (76%) sample pairs displayed a difference of <1 kPa (99% confidence interval, 48%-92%, P = .016). The difference in paired samples was similar for different gestational and postnatal ages and did not appear to be affected by electrocautery. CONCLUSIONS: In this small study, we did not demonstrate that TC CO2 monitoring was accurate at P < .01. This partly reflects the small size of the study, resulting in wide 99% confidence bounds. PMID- 27464977 TI - Mesopontine Switch for the Induction of General Anesthesia by Dedicated Neural Pathways. AB - We review evidence that the induction of anesthesia with GABAergic agents is mediated by a network of dedicated axonal pathways, which convey a suppressive signal to remote parts of the central nervous system. The putative signal originates in an anesthetic-sensitive locus in the brainstem that we refer to as the mesopontine tegmental anesthesia area (MPTA). This architecture stands in contrast to the classical notion that anesthetic molecules themselves directly mediate anesthetic induction after global distribution by the vascular circulation. The MPTA came to light in a systematic survey of the rat brain as a singular locus at which microinjection of minute quantities of GABAergic anesthetics is able to reversibly induce a state resembling surgical anesthesia. The rapid onset of anesthesia, the observed target specificity, and the fact that effective doses are far too small to survive dilution during vascular redistribution to distant areas in the central nervous system are all incompatible with the classical global suppression model. Lesioning the MPTA selectively reduces the animal's sensitivity to systemically administered anesthetics. Taken together, the microinjection data show that it is sufficient to deliver gamma-aminobutyric acid A receptor (GABAA-R) agonists to the MPTA to induce an anesthesia-like state and the lesion data indicate that MPTA neurons are necessary for anesthetic induction by the systemic route at clinically relevant doses. Known connectivity of the MPTA provides a scaffold for defining the specific projection pathways that mediate each of the functional components of anesthesia. Because MPTA lesions do not induce coma, the MPTA is not a key arousal nucleus essential for maintaining the awake state. Rather, it appears be a "gatekeeper" of arousal function, a major element in a flip-flop switching mechanism that executes rapid and reversible transitions between the awake and the anesthetic state. PMID- 27464978 TI - Implementation of Programmed Intermittent Epidural Bolus for the Maintenance of Labor Analgesia. AB - Programmed intermittent epidural bolus (PIEB) is an exciting new technology that has the potential to improve the maintenance of epidural labor analgesia. PIEB compared with a continuous epidural infusion (CEI) has the potential advantage of greater spread within the epidural space and therefore better sensory blockade. Studies have demonstrated a local anesthetic-sparing effect, fewer instrumental vaginal deliveries, less motor blockade, and improvements in maternal satisfaction with PIEB compared with CEI. However, the optimal PIEB regimen and pump settings remain unknown, and there are a number of logistical issues and practical considerations that should be considered when implementing PIEB. The PIEB bolus size and interval, PIEB start time delay period, and patient controlled epidural analgesia bolus size and lockout time can influence the efficacy of PIEB used for epidural labor analgesia. Educating all members of the health care team is critical to the success of the technique. This review summarizes the role of PIEB for the maintenance of labor analgesia, outlines implementation strategies, suggests optimal settings, and presents potential limitations of the technique. PMID- 27464979 TI - A Procedural Electroencephalogram Simulator for Evaluation of Anesthesia Monitors. AB - BACKGROUND: Recent research and advances in the automation of anesthesia are driving the need to better understand electroencephalogram (EEG)-based anesthesia end points and to test the performance of anesthesia monitors. This effort is currently limited by the need to collect raw EEG data directly from patients. METHODS: A procedural method to synthesize EEG signals was implemented in a mobile software application. The application is capable of sending the simulated signal to an anesthesia depth of hypnosis monitor. Systematic sweeps of the simulator generate functional monitor response profiles reminiscent of how network analyzers are used to test electronic components. RESULTS: Three commercial anesthesia monitors (Entropy, NeuroSENSE, and BIS) were compared with this new technology, and significant response and feature variations between the monitor models were observed; this includes reproducible, nonmonotonic apparent multistate behavior and significant hysteresis at light levels of anesthesia. CONCLUSIONS: Anesthesia monitor response to a procedural simulator can reveal significant differences in internal signal processing algorithms. The ability to synthesize EEG signals at different anesthetic depths potentially provides a new method for systematically testing EEG-based monitors and automated anesthesia systems with all sensor hardware fully operational before human trials. PMID- 27464980 TI - Intralesional Injection of Bevacizumab for the Treatment of an Apical Orbital Cavernous Venous Malformation. AB - Surgical excision of orbital cavernous venous malformations located in the orbital apex is challenging due to difficulty obtaining surgical exposure and higher risk of morbidity. Intralesional bevacizumab injection has been utilized for the treatment of choroidal and intracranial cavernous venous malformations. A 52-year-old woman with an orbital apical mass consistent with a cavernous venous malformation causing decreased visual acuity, diminished color vision, and visual field loss was treated with intralesional bevacizumab injected under direct surgical visualization. Subsequently, she demonstrated improved visual acuity, color vision, and slow but dramatic visual field improvement over one year. Injection of bevacizumab may be a viable alternative treatment for orbital cavernous venous malformations. PMID- 27464981 TI - Dynamics of vortex quadrupoles in nonrotating trapped Bose-Einstein condensates. AB - Dynamics of vortex clusters is essential for understanding diverse superfluid phenomena. In this paper, we examine the dynamics of vortex quadrupoles in a trapped two-dimensional (2D) Bose-Einstein condensate. We find that the movement of these vortex-clusters fall into three distinct regimes which are fully described by the radial positions of the vortices in a 2D isotropic harmonic trap, or by the major radius (minor radius) of the elliptical equipotential lines decided by the vortex positions in a 2D anisotropic harmonic trap. In the "recombination" and "exchange" regimes the quadrupole structure maintains, while the vortices annihilate each other permanently in the "annihilation" regime. We find that the mechanism of the charge flipping in the "exchange" regime and the disappearance of the quadrupole structure in the "annihilation" regime are both through an intermediate state where two vortex dipoles connected through a soliton ring. We give the parameter ranges for these three regimes in coordinate space for a specific initial configuration and phase diagram of the vortex positions with respect to the Thomas-Fermi radius of the condensate. We show that the results are also applicable to systems with quantum fluctuations for the short-time evolution. PMID- 27464982 TI - Hatchability and survival of oncomiracidia of Paradiplozoon ichthyoxanthon (Monogenea: Diplozoidae) exposed to aqueous aluminium. AB - BACKGROUND: Monogenea is a diverse group of ectoparasites showing great potential as sentinel organisms for monitoring environmental health. Exposure to metals negatively affects infrapopulations of monogeneans and exposure to aluminium has been found to negatively impact the survival of gyrodactylids. METHODS: Samples of infected host fish, the smallmouth yellowfish Labeobarbus aeneus (Cyprinidae), were collected from the Vaal Dam, South Africa and transported back to the laboratory in dark 160 l containers. Eggs of the monogenean Paradiplozoon ichthyoxanthon infecting L. aeneus were collected and exposed to varying concentrations of aluminium along with a control group in static tanks. The eggs were checked every 24 h and hatching commenced 13-14 days after exposure. Water samples were taken from exposure tanks and acidified for analysis of Al levels with inductively-coupled plasma mass spectrometry. RESULTS: Hatching of eggs was variable between exposures, and in 30 MUg Al/l and 60 MUg Al/l was found to occur before eggs in control beakers, whereas, exposure to 120 MUg Al/l delayed hatching and reduced hatchability. Survival of hatched oncomiracidia was concentration dependent and negatively correlated with aluminium concentrations. Lowest survival was recorded for 60 MUg Al/l and 120 MUg Al/l where all larvae died shortly after or during hatching. Normal development of embryos of P. ichthyoxanthon within eggs exposed to all doses of aluminium indicates that the egg shell is moderately impermeable to metals and inhibits movement of aluminium across the shell and interacting with developing embryos. CONCLUSIONS: Higher larval mortality rate in 120 MUg/l exposure can be related to aluminium crossing the egg shell in the late stages and causing death of unhatched yet fully developed embryos, possibly due to changes in the permeability of the egg shell as embryos neared developmental completion. Accelerated death of oncomiracidia after hatching indicates sensitivity toward high concentrations of aluminium. PMID- 27464983 TI - Brain invasion in otherwise benign meningiomas does not predict tumor recurrence. PMID- 27464985 TI - The Impact of a Concussion-U Educational Program on Knowledge of and Attitudes about Concussion. AB - BACKGROUND: The diagnosis of a sports-related concussion is often dependent on the athlete self-reporting their symptoms. It has been suggested that improving youth athlete knowledge and attitudes toward concussion may increase self reporting behaviour. The objective of this study was to determine if a novel Concussion-U educational program improves knowledge of and attitudes about concussion among a cohort of elite male Bantam and Midget AAA hockey players. METHODS: Fifty-seven male Bantam and Midget AAA-level hockey players (mean age=14.52+/-1.13 years) were recruited from the local community. Each participant completed a modified version of the Rosenbaum Concussion Knowledge and Attitudes Survey-Student Version immediately before and after a Concussion-U educational presentation. Follow-up sessions were arranged 4 to 6 months after the presentation, and assessed retention of knowledge and attitude changes. RESULTS: Forty-three players completed all three surveys. Concussion knowledge and attitude scores significantly (p<0.01) increased from pre- to post-presentation by 12.79 and 8.41%, respectively. At long-term follow-up, knowledge levels remained significantly (p<0.01) higher than baseline by 8.49%. Mean attitude scores were also increased at follow-up; however, this increase was not statistically significant. CONCLUSIONS: A Concussion-U educational program led to an immediate improvement in concussion knowledge and attitudes among elite male Bantam and Midget AAA hockey players. Increased knowledge was maintained at long term follow-up, but improved attitude was not. Future studies should investigate whether similar educational programs influence symptom reporting and concussion incidence. In addition, they should focus on how to maintain improved concussion attitudes. PMID- 27464986 TI - Bimodal behaviour of charge carriers in graphene induced by electric double layer. AB - A theoretical investigation is performed into the electronic properties of graphene in the presence of liquid as a function of the contact area ratio. It is shown that the electric double layer (EDL) formed at the interface of the graphene and the liquid causes an overlap of the conduction bands and valance bands and increases the density of state (DOS) at the Fermi energy (EF). In other words, a greater number of charge carriers are induced for transport and the graphene changes from a semiconductor to a semimetal. In addition, it is shown that the dependence of the DOS at EF on the contact area ratio has a bimodal distribution which responses to the experimental observation, a pinnacle curve. The maximum number of induced carriers is expected to occur at contact area ratios of 40% and 60%. In general, the present results indicate that modulating the EDL provides an effective means of tuning the electronic properties of graphene in the presence of liquid. PMID- 27464984 TI - Randomised clinical study: inulin short-chain fatty acid esters for targeted delivery of short-chain fatty acids to the human colon. AB - BACKGROUND: Short-chain fatty acids (SCFA) produced through fermentation of nondigestible carbohydrates by the gut microbiota are associated with positive metabolic effects. However, well-controlled trials are limited in humans. AIMS: To develop a methodology to deliver SCFA directly to the colon, and to optimise colonic propionate delivery in humans, to determine its role in appetite regulation and food intake. METHODS: Inulin SCFA esters were developed and tested as site-specific delivery vehicles for SCFA to the proximal colon. Inulin propionate esters containing 0-61 wt% (IPE-0-IPE-61) propionate were assessed in vitro using batch faecal fermentations. In a randomised, controlled, crossover study, with inulin as control, ad libitum food intake (kcal) was compared after 7 days on IPE-27 or IPE-54 (10 g/day all treatments). Propionate release was determined using (13) C-labelled IPE variants. RESULTS: In vitro, IPE-27-IPE-54 wt% propionate resulted in a sevenfold increase in propionate production compared with inulin (P < 0.05). In vivo, IPE-27 led to greater (13) C recovery in breath CO2 than IPE-54 (64.9 vs. 24.9%, P = 0.001). IPE-27 also led to a reduction in energy intake during the ad libitum test meal compared with both inulin (439.5 vs. 703.9 kcal, P = 0.025) and IPE-54 (439.5 vs. 659.3 kcal, P = 0.025), whereas IPE-54 was not significantly different from inulin control. CONCLUSIONS: IPE-27 significantly reduced food intake suggesting colonic propionate plays a role in appetite regulation. Inulin short-chain fatty acid esters provide a novel tool for probing the diet-gut microbiome-host metabolism axis in humans. PMID- 27464989 TI - Electromagnetic field tapering using all-dielectric gradient index materials. AB - The concept of transformation optics (TO) is applied to control the flow of electromagnetic fields between two sections of different dimensions through a tapering device. The broadband performance of the field taper is numerically and experimentally validated. The taper device presents a graded permittivity profile and is fabricated through three-dimensional (3D) polyjet printing technology using low-cost all-dielectric materials. Calculated and measured near-field mappings are presented in order to validate the proposed taper. A good qualitative agreement is obtained between full-wave simulations and experimental tests. Such all-dielectric taper paves the way to novel types of microwave devices that can be easily fabricated through low-cost additive manufacturing processes. PMID- 27464987 TI - Regulation of lymphangiogenesis in the diaphragm by macrophages and VEGFR-3 signaling. AB - Lymphatic vessels play important roles in fluid drainage and in immune responses, as well as in pathological processes including cancer progression and inflammation. While the molecular regulation of the earliest lymphatic vessel differentiation and development has been investigated in much detail, less is known about the control and timing of lymphatic vessel maturation in different organs, which often occurs postnatally. We investigated the time course of lymphatic vessel development on the pleural side of the diaphragmatic muscle in mice, the so-called submesothelial initial diaphragmatic lymphatic plexus. We found that this lymphatic network develops largely after birth and that it can serve as a reliable and easily quantifiable model to study physiological lymphangiogenesis in vivo. Lymphangiogenic growth in this tissue was highly dependent on vascular endothelial growth factor receptor (VEGFR)-3 signaling, whereas VEGFR-1 and -2 signaling was dispensable. During diaphragm development, macrophages appeared first in a linearly arranged pattern, followed by ingrowth of lymphatic vessels along these patterned lines. Surprisingly, ablation of macrophages in colony-stimulating factor-1 receptor (Csf1r)-deficient mice and by treatment with a CSF-1R-blocking antibody did not inhibit the general lymphatic vessel development in the diaphragm but specifically promoted branch formation of lymphatic sprouts. In agreement with these findings, incubation of cultured lymphatic endothelial cells with conditioned medium from P7 diaphragmatic macrophages significantly reduced LEC sprouting. These results indicate that the postnatal diaphragm provides a suitable model for studies of physiological lymphangiogenic growth and maturation, and for the identification of modulators of lymphatic vessel growth. PMID- 27464988 TI - Role of NF-kappaB activation and Th1/Th2 imbalance in pulmonary toxicity induced by nano NiO. AB - With the progress of nanotechnology, nano nickel oxide (NiO) has been extensively used as sensors, battery electrodes, catalysts, and cosmetics. Previous researches verified that nano NiO could exert pulmonary toxicity, but its mechanism was unclear. To shed light upon this, the role of nuclear factor-kappaB (NF-kappaB) activation and Th1/Th2 imbalance were to explore in pulmonary damage induced by nano NiO. Male Wistar rats were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg kg-1 ) and micro NiO group (0.024 mg kg-1 ) and treated by intratracheal instillation twice a week for 6 weeks. The results showed that the abnormal changes induced by nano NiO were found on indicators of nitrative stress (NO, TNOS, and iNOS), inflammatory cytokines (TNF-alpha, IL-2, and IL-10) and cytokine-induced neutrophil chemoattractants (CINC-1, CINC 2alphabeta, and CINC-3) in lung tissue. In addition, nano NiO instillation induced the upregulated mRNA and protein expression of NF-kappaB, inhibitor of kappaB kinase-alpha (IKK-alpha) and nuclear factor-inducing kinase (NIK). The protein content of GATA-3 increased as well as T-bet decreased in nano NiO groups, and the ratio of T-bet/GATA-3, as a key evaluation indicator of Th1/Th2 balance, was lower than the control group. The findings indicated that nano NiO could enhance the nitrative stress and inflammatory response in lung tissue, and its mechanism was related to the NF-kappaB activation and Th1/Th2 imbalance. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1354-1362, 2017. PMID- 27464990 TI - Masking of endotoxin in surfactant samples: Effects on Limulus-based detection systems. AB - Over the last few decades Limulus Amebocyte Lysate (LAL) has been the most sensitive method for the detection of endotoxins (Lipopolysaccharides) and is well accepted in a broad field of applications. Recently, Low Endotoxin Recovery (LER) in biopharmaceutical drug products has been noticed, whereby the detection of potential endotoxin contaminations is not ensured. Notably, most of these drug products contain surfactants, which can have crucial effects on the detectability of endotoxin. In order to analyze the driving forces of LER, endotoxin detection in samples containing nonionic surfactants in various buffer systems was investigated. The results show that the process of LER is kinetically controlled and temperature-dependent. Furthermore, only the simultaneous presence of nonionic surfactants and components capable of forming metal complexes resulted in LER. In addition, capacity experiments show that even hazardous amounts of endotoxin can remain undetectable within such formulation compositions. In conclusion, the LER phenomenon is caused by endotoxin masking and not by test interference. In this process, the supramolecular structure of endotoxin is altered and exhibits only a limited susceptibility in binding to the Factor C of Limulus-based detection systems. We propose a two-step mechanism of endotoxin masking by complex forming agents and nonionic surfactants. PMID- 27464991 TI - Recombinant production and characterization of human anti-influenza virus monoclonal antibodies identified from hybridomas fused with human lymphocytes. AB - In previous studies, hybridomas producing human immunoglobulin G, the antibodies 5E4 and 5A7 against influenza A and B virus were established using a novel human lymphocyte fusion partner, SPYMEG. In the present study, we succeeded in achieving the recombinant production and secretion of 5E4 and 5A7 in Chinese hamster ovary cells. Our N-glycan analysis by intact-mass detection and liquid chromatography mass spectrometry showed that recombinant 5E4 and 5A7 have one N glycan and the typical mammalian-type N-glycan structures similar to those in hybridomas. However, the glycan distribution was slightly different among these antibodies. The amount of high-mannose-type structures was under 10% of the total N-glycans of recombinant 5E4 and 5A7, compared to 20% of the 5E4 and 5A7 produced in hybridomas. The amount of galactosylated N-glycans was increased in recombinants. Approximately 80% of the N-glycans of all antibodies was fucosylated, and no sialylated N-glycan was found. Recombinant 5E4 and 5A7 neutralized pandemic influenza A virus specifically, and influenza B virus broadly, quite similar to the 5E4 and 5A7 produced in hybridomas, respectively. Here we demonstrated that recombinants of antibodies identified from hybridomas fused with SPYMEG have normal N-glycans and that their neutralizing activities bear comparison with those of the original antibodies. PMID- 27464992 TI - Process characterization and Design Space definition. AB - Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody (MAb). This chapter describes the tools used for the characterization and validation of MAb manufacturing process under the QbD paradigm. This comprises risk assessments for the identification of potential Critical Process Parameters (pCPPs), statistically designed experimental studies as well as studies assessing the linkage of the unit operations. Outcome of the studies is the classification of process parameters according to their criticality and the definition of appropriate acceptable ranges of operation. The process and product knowledge gained in these studies can lead to the approval of a Design Space. Additionally, the information gained in these studies are used to define the 'impact' which the manufacturing process can have on the variability of the CQAs, which is used to define the testing and monitoring strategy. PMID- 27464993 TI - Effects of orthokeratology on the progression of low to moderate myopia in Chinese children. AB - BACKGROUND: To investigate the effectiveness of orthokeratology (ortho-k) in reducing the development of myopia in Chinese children with low to moderate myopia. METHODS: This was a retrospective study. In the ortho-k group, there were141 subjects, and the average age was (9.43 +/- 1.10) years. The average spherical equivalent refractive error (SER) was (-2.74 +/- 1.15)D, with examinations performed 1, 7, 30, and 90 days and 12 months after the patients started wearing ortho-k lenses. In the control group, there were 130 subjects, and the average age was (9.37 +/- 1.00) years. The average SER was (-2.88 +/- 1.39)D, with examinations performed every 6 months. Axial elongation, which is an important parameter reflecting the progression of myopia, was measured at baseline from the same IOLMaster each time by the same masked examiner and was compared between the groups after 1 year. The subjects were divided into two sub groups according to age to further study the development of myopia at different ages. An unpaired t-test, paired t-test, Chi-square test and Spearman test were performed to analyze the data. RESULTS: After 1 year, the average axial elongation was (0.27 +/- 0.17) mm in the ortho-k lens group and (0.38 +/- 0.13) mm in the control group, with a significant difference between the groups (P < 0.001). Axial elongation was not correlated with SER but had a negative correlation with initial age (ortho-k group: r s = -0.309, p < 0.01; control group: r s = -0.472, p < 0.01). The percentages of individuals with fast myopic progression (axial elongation > 0.36 mm per year) were 38.0 % among younger children (7.00 to 9.40 years) and 24.3 % among older children (9.40 to 12.00 years), whereas the respective percentages were 76.5 and 12.9 % in the control group. When SER ranged from -5.0D to -6.0D, the axial elongation in the ortho-k group was 57.1 % slower than that in the control group. CONCLUSIONS: Ortho-k lenses are effective in controlling myopic progression in Chinese children, particularly in younger children and in children with higher myopia. PMID- 27464995 TI - Potential of Taming MicroRNA on Driver Seat to Control Mitochondrial Horses in Breast Carcinoma. AB - Breast cancer among women is one of the most common carcinomas worldwide. Compared to developed countries, the breast cancer cases reported in India have boosted rapidly. At the same time, alarming statistics show that ratio of mortality cases over the total incidences is significantly high in comparison to developed world (Global Heath Estimates, WHO 2015). In recent times, several oncogenic signaling pathways have shown convergent effects on various types of cancer cell metabolism including breast cancer leading to tumor development. In 1931, German biochemist Otto Warburg revealed that cancer cells burn sugar (glycolysis) differently than normal cells. Cancer cells prefer to burn sugar over energy rich fats even when cellular oxygen conditions favor mitochondrial fat burning. Further, Warburg hypothesized that cancer is caused by mitochondrial dysfunction forcing the cells to use aerobic glycolysis instead of oxidative phosphorylation (OXPHOS). MicroRNAs (miRNAs) are critical classes of small ~22 nt non-coding endogenous RNAs implicated in gene expression regulation. To date, miRNAs have shown to regulate many cellular metabolic pathways critical for breast carcinoma patho-physiology. There is common consent that miRNAs dedicated to mitochondria and cellular metabolism have profound positive effects on breast carcinoma survival and metastasis. Therefore, in future there is huge scope for identification of miRNA types playing as a driver in mitochondria for breast tumor development. Further, several strategies to taming as well as knocking down these miRNA in breast tumor would be one of the fascinating approaches in medical sciences and cancer therapy. Here, we review updated scientific findings and possible therapeutic interventions with reference to miRNAs, mitochondria, cellular metabolism and breast carcinoma. PMID- 27464996 TI - Safety and Effectiveness of Percutaneously Inserted Peritoneal Ports Compared to Surgically Inserted Ports in a Retrospective Study of 87 Patients with Ovarian Carcinoma over a 10-Year Period. AB - PURPOSE: Placement of peritoneal ports has become a favorable technique for direct chemotherapy infusion in treating peritoneal metastases from ovarian cancer. We aim to outline an approach to the percutaneous insertion of peritoneal ports and to characterize success and complication rates compared to surgically inserted ports. MATERIALS AND METHODS: Retrospective analysis was collected from 87 patients who had peritoneal port insertion (28 inserted surgically and 59 percutaneously) for treatment of peritoneal metastases from ovarian cancer from July 2004 to July 2014. Complications were classified according to the SIR Clinical Practice Guidelines as major or minor. RESULTS: Technical success rates for surgically and percutaneously inserted ports were 100 and 96.7 %, respectively (p = 0.44), with the two percutaneous failures successful at a later date. There were no major complications in either group. Minor complication rates for surgically versus percutaneously inserted ports were 46.4 versus 22.0 %, respectively (p = 0.02). The infection rate for surgically inserted versus percutaneously inserted ports was 14.3 and 0 %, respectively (p = 0.002). The relative risk of developing a complication from percutaneous peritoneal port insertion without ascites was 3.4 (p = 0.04). For percutaneously inserted ports, the mean in-room procedure time was 81 +/- 1.3 min and mean fluoroscopy time was 5.0 +/- 4.5 min. CONCLUSION: Percutaneously inserted peritoneal ports are a safe alternative to surgically inserted ports, demonstrating similar technical success and lower complication rates. PMID- 27464997 TI - In situ decoration of graphene sheets with gold nanoparticles synthetized by pulsed laser ablation in liquids. AB - The demand for nanocomposites of graphene and carbonaceous materials decorated with metallic nanoparticles is increasing on account of their applications in science and technology. Traditionally, the production of graphene-metal assemblies is achieved by the non-environmentally friendly reduction of metallic salts in carbonaceous suspensions. However, precursor residues during nanoparticle growth may reduce their surface activity and promote cross-chemical undesired effects. In this work we present a laser-based alternative to synthesize ligand-free gold nanoparticles that are anchored onto the graphene surface in a single reaction step. Laser radiation is used to generate highly pure nanoparticles from a gold disk surrounded by a graphene oxide suspension. The produced gold nanoparticles are directly immobilized onto the graphene surface. Moreover, the presence of graphene oxide influences the size of the nanoparticles and its interaction with the laser, causes only a slight reduction of the material. This work constitutes a green alternative synthesis of graphene metal assemblies and a practical methodology that may inspire future developments. PMID- 27464994 TI - Survival of the Fittest: How Bacterial Pathogens Utilize Bile To Enhance Infection. AB - Bacterial pathogens have coevolved with humans in order to efficiently infect, replicate within, and be transmitted to new hosts to ensure survival and a continual infection cycle. For enteric pathogens, the ability to adapt to numerous host factors under the harsh conditions of the gastrointestinal tract is critical for establishing infection. One such host factor readily encountered by enteric bacteria is bile, an innately antimicrobial detergent-like compound essential for digestion and nutrient absorption. Not only have enteric pathogens evolved to resist the bactericidal conditions of bile, but these bacteria also utilize bile as a signal to enhance virulence regulation for efficient infection. This review provides a comprehensive and up-to-date analysis of bile-related research with enteric pathogens. From common responses to the unique expression of specific virulence factors, each pathogen has overcome significant challenges to establish infection in the gastrointestinal tract. Utilization of bile as a signal to modulate virulence factor expression has led to important insights for our understanding of virulence mechanisms for many pathogens. Further research on enteric pathogens exposed to this in vivo signal will benefit therapeutic and vaccine development and ultimately enhance our success at combating such elite pathogens. PMID- 27464998 TI - Four new lanthanide-organic frameworks: selective luminescent sensing and magnetic properties. AB - Four new isostructural lanthanide-organic frameworks, [Ln(L)(H2O)2].H2O.CH3CN (1 Ln) (Ln = Eu, Tb, Dy, and Gd), have been successfully synthesized via solvothermal reactions with a semi-rigid V-shaped multicarboxylate ligand 2 (2',4'-dicarboxylphenoxy) benzoic acid (H3L) and Ln(NO3)3.6H2O. 1-Ln shows 2D layer-by-layer frameworks with interlayer channels decorated by carboxylate groups. 1-Eu exhibits excellent luminescence properties, and therefore, is chosen as a probe for sensing different metal ions and anions. Consequently, 1-Eu displays high selectivity and sensitivity for Fe(3+) and Cr(6+) ions, simultaneously, through the luminescence quenching effect, and thus, should be an excellent candidate for probing these pollutant metal ions. In addition, antiferromagnetic exchange interactions also exist between the Dy(3+) ions in 1 Dy. PMID- 27464999 TI - An Outpatient Management Protocol for Emergency Department Patients With a Newly Diagnosed Lower Extremity Deep Venous Thrombosis. PMID- 27465000 TI - Idarucizumab (Praxbind) Formulary Review. AB - Idarucizumab (Praxbind), a humanized monoclonal antibody fragment was granted accelerated approval from the Food and Drug Administration in October 2015 as the first agent to reverse the effects of a novel oral anticoagulant. The drug is indicated for dabigatran reversal in patients requiring emergency surgery/urgent procedures or with life-threatening or uncontrolled bleeding. In a randomized study with healthy volunteers, compared with placebo, idarucizumab reduced the clotting times for all tests assays (assessed pre-, end of-, and 24 hours after infusion), while the results for the placebo group remained unchanged. Another randomized clinical trial assessed the safety and efficacy of idarucizumab in patients with either overt bleeding or undergoing emergency surgery where hemostasis was required. This study is ongoing, but preliminary results showed reversal efficacy demonstrated a reasonable safety profile from the time of the infusion to 90 days after. The wholesale acquisition cost of two 2.5 g vials of idarucizumab is currently $3482.50. To treat 10 or 20 patients per year with a single 5 g dose is estimated to cost $34,825 and $69,650, respectively. In the clinical trial described above, approximately 20% of patients required a second dose, which would further increase the cost of use. In this formulary review for a health system's pharmacy and therapeutics committee, idarucizumab clinical trials and medication package insert were summarized and, after consulting with clinical experts from our institutions, practical recommendations for use were generated to ensure appropriate and safe use of this agent. PMID- 27465001 TI - Bridging Experience With Eptifibatide After Stent Implantation. AB - BACKGROUND: Patients who have undergone intracoronary stent implantation often require surgery within the first year after the procedure. Planned or emergent surgical intervention requires interruption of antiplatelet therapy and is associated with an increased risk of stent thrombosis. Eptifibatide, an intravenous glycoprotein IIb/IIIa inhibitor (GPIIb/IIIa), can be considered for antiplatelet bridging of high-risk patients in the periprocedural period. OBJECTIVES: The aim of this report is to describe the management of antiplatelet therapy and outcomes of patients who were bridged with eptifibatide perioperatively within 1 year of intracoronary stent implantation. METHODS: We performed a retrospective analysis of patients identified through the hospital's computer system consecutively from January 1, 2011 to December 31, 2014. We included 18 patients who were bridged from an oral P2Y12-receptor antagonist with eptifibatide before surgery. Outcome measures were the incidence of thromboembolic events or stent thrombosis within 30 days of surgery and death within 90 days of hospital discharge. Safety measures were the incidence of thrombolysis in myocardial infarction major, minor, or minimal bleeding. RESULTS: Of the 18 patients assessed, no patients experienced thromboembolic events or stent thrombosis. There was one major bleeding event and one minimal bleeding event postoperatively. Antiplatelet therapy management was highly variable in the perioperative period with 72.2% receiving the recommended GPIIb/IIIa loading dose, 50% of patients not continuing aspirin throughout the surgery, 27.8% of patients stopping antiplatelet therapy less than 5 days before surgery, and 50% not receiving a loading dose of an oral P2Y12-receptor antagonist postoperatively. CONCLUSIONS: Within a limited sample size, bridging with an intravenous GPIIb/IIIa inhibitor appeared feasible. Further study is needed on the optimal strategy to manage patients with recent stenting who need surgical procedures. PMID- 27465002 TI - Comparison of 1-year Major Adverse Cardiac Events in Patients Undergoing Primary Percutaneous Coronary Intervention Receiving Intracoronary Bolus Only Versus Intracoronary Bolus Plus Infusion of Glycoprotein IIb/IIIa Inhibitors. AB - OBJECTIVE: The aim of this study is to compare intracoronary (IC) bolus only with IC bolus plus maintenance intravenous (IV) infusion of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors with respect to 1-year major adverse cardiac events including mortality, nonfatal myocardial infarction, revascularization, and bleeding events after primary percutaneous coronary intervention (PCI). METHODS: This is an observational study of 233 consecutive patients who presented with ST elevation myocardial infarction and underwent primary PCI between April 2009 and December 2012. Patients were grouped into (1) patients who received IC bolus only (n = 102) and (2) patients who received IC bolus plus maintenance IV infusion of GP IIb/IIIa inhibitors (n = 131). In-hospital post procedural myocardial infarction occurred in 4 (1.7 %) of patients. RESULTS: Mortality occurred in one patient who was treated with IV infusion. Major bleeding occurred in only 5 patients, among whom 4 patients had received GP IIb/IIIa inhibitors IV infusion. However, the difference was not statistically significant (P = 0.389). CONCLUSION: Both univariate analysis and the adjusted model for the potential confounders revealed no significant association between the way of GP IIb/IIIa inhibitors administration and 1-year major adverse cardiac events. Our findings suggested that IV infusion of GP IIb/IIIa inhibitors after the bolus dose is not associated with better 1-year outcome after adjustment for confounding variables. Moreover, IV infusion may increase the risk of major bleedings after primary PCI. This finding implies that the need for IV infusion of GP IIb/IIIa inhibitors in patients undergoing primary PCI is under question. PMID- 27465003 TI - Process Improvements to Reduce Cardiac Troponin Turnaround Time in the Emergency Department. AB - BACKGROUND: An efficient testing process is a key to a timely diagnosis of acute myocardial infarction in the emergency department (ED). This includes a rapid evaluation cardiac biomarkers. METHODS: We conducted a quality and process improvement project to reduce troponin-T turnaround time (TAT) in the central laboratory at our facility. An interdisciplinary team, including front-line staff members, reviewed each step of troponin-T processing in both the ED and the central laboratory. A series of improvements were implemented during 2013, including changes to specimen labeling, elimination of duplicate test ordering, and efficiencies within the laboratory. Data from January 2013 to December 2014 on 31,496 patients with troponin tests were included in the analysis. RESULTS: Over the 2-year period of the projects, median troponin-T TAT decreased from 74 minutes to consistently less than 60 minutes. CONCLUSIONS: With an interdisciplinary team of health care professionals, we successfully reduced troponin-T TAT for possible acute coronary syndrome patients in our ED by 19%, consistently achieving laboratory results in less than 60 minutes. PMID- 27465004 TI - Impact of a "Team-focused CPR" Protocol on Out-of-hospital Cardiac Arrest Survival in a Rural EMS System. AB - BACKGROUND: More than 300,000 persons in the United States experience an out-of hospital cardiac arrest every year. The American Heart Association emphasizes on the rapid, effective delivery of cardiac arrest interventions by bystanders and emergency medical services (EMS) on scene. In July 2013, the EMS of Randolph County, a rural county in central North Carolina, implemented a team-focused cardiopulmonary resuscitation(CPR) protocol. The protocol emphasized early chest compressions and resuscitation on scene until the return of spontaneous circulation (ROSC) or until efforts were deemed futile. METHODS: Data were collected on all cardiac out-of-hospital cardiac arrest cases from June 30, 2012 to June 30, 2014. Outcomes for the year before the institution of the team focused CPR protocol were compared with rates for the year following implementation. RESULTS: A significantly higher proportion of patients achieved ROSC after protocol implementation: 25/38 [66%, 95% confidence interval (CI), 49% 80%] versus 19/67 (28%; 95% CI, 18-41%, P < 0.001). More patients survived to hospital admission in the team-focused CPR group (16/38, 42.1%, 95% CI, 26%-59%) versus the preprotocol period (10/67, 14.9%, 95% CI, 7.4%-26%, P = 0.004). Although survival to discharge was higher in the team-focused protocol period (6/38, 15.8%, 95% CI, 6.0%-31%) than the preprotocol period (4/67, 6.0%, 95% CI, 1.7%-14.6%), this did not meet statistical significance (P = 0.16). CONCLUSION: The introduction of a team-focused CPR protocol in a single rural county-based EMS system dramatically improved ROSC and hospital admission rates, but not survival to discharge. Continued surveillance, as well as evaluation and optimization of inpatient care, is warranted. PMID- 27465005 TI - A Novel Survey Tool to Quantify the Degree and Duration of STEMI Regionalization Across California. AB - INTRODUCTION: California has been a global leader in regionalization efforts for time-critical medical conditions. A total of 33 local emergency medical service agencies (LEMSAs) exist, providing an organized EMS framework across the state for almost 40 years. We sought to develop a survey tool to quantify the degree and duration of ST-elevation myocardial infarction (STEMI) regionalization over the last decade in California. METHODS: The project started with the development of an 8-question survey tool via a multi-disciplinary expert consensus process. Next, the survey tool was distributed at the annual meeting of administrators and medical directors of California LEMSAs to get responses valid through December, 2014. The first scoring approach was the Total Regionalization Score (TRS) and used answers from all 8 questions. The second approach was called the Core Score, and it focused on only 4 survey questions by assuming that the designation of STEMI Receiving Centers must have occurred at the beginning of any LEMSA's regionalization effort. Scores were ranked and grouped into tertiles. RESULTS: All 33 LEMSAs in California participated in this survey. The TRS ranged from 15 to 162. The Core Score range was much narrower, from 2 to 30. In comparing TRS and Core Score rankings, the top-tertiles were quite similar. More rank variation occurred between mid- and low-tertiles. CONCLUSION: This study evaluated the degree and duration of STEMI network regionalization from 2004 to 2014 in California, and ranked 33 LEMSAs into tertiles based upon their TRS and their Core Score. Successful application of the 8-item survey and ranking strategies across California suggests that this approach can be used to assess regionalization in other states or countries around the world. PMID- 27465006 TI - Treatment of Non-ST Elevation Myocardial Infarction: A Process Analysis of Patient and Program Factors in a Teaching Hospital. AB - As part of a quality improvement project, we performed a process analysis to evaluate how patients presenting with type 1 non-ST elevation myocardial infarction (STEMI) are diagnosed and managed early after the diagnosis has been made. We performed a retrospective chart review and collected detailed information regarding the timing of the first 12-lead electrocardiogram, troponin order entry and first positive troponin result, administration of anticoagulation and antiplatelet medications, and referral for coronary angiography to identify areas of treatment variability and delay. A total of 242 patients with type 1 non STEMI were included. The majority of patients received aspirin early after presentation to the emergency department; however, there was significant variability in the time from presentation to administration of other medications, including anticoagulation and P2Y12 therapy, even after an elevated troponin level was documented in the chart. Lack of a standardized non-STEMI admission order set, inconsistency regarding whether the emergency department physician or the cardiology admitting team order these medications after the diagnosis is made, and per current protocol, the initial call regarding the patient made to the cardiology fellow, not the admitting house staff, were identified as possible contributors to the delay. Patients who presented during "nighttime" hours had higher rates of atypical symptoms (P = 0.036) and longer delays to coronary angiography (46.5 versus 24 hours, P < 0.001) even in those deemed intermediate to high risk. A process analysis revealed considerable variation in non-STEMI treatment in our teaching hospital and identified specific areas for quality improvement measures. PMID- 27465007 TI - Lack of Left Ventricular Ejection Fraction Measurement Following a High B-type Natriuretic Peptide Value. AB - BACKGROUND: The objective of this study was to determine how often providers did not obtain a recommended measure of left ventricular ejection fraction (LVEF) following a high B-type natriuretic peptide (BNP) value when the LVEF was not known to be low (<40%). Such patients may benefit from life-prolonging treatment. METHODS: We identified consecutive patients (inpatient or outpatient) with a BNP value of at least 200 pg/mL within a single VA health care system (3 inpatient facilities and 8 community clinics) during a 10-month period (September 2008-June 2009). We performed chart review to determine results of any imaging study performed (inside or outside the health system) prior to or after the high BNP value. RESULTS: Of the 296 patients with a high BNP, 212 were not known to have a low LVEF. Of these, 99 (47%) did not have the guideline recommended follow-up LVEF study. Among those that survived at least 6 months following BNP and a follow-up echocardiogram was indicated (no prior LVEF or prior LVEF was > 40%), mortality was 20% if an echocardiogram was performed within 6 months of the BNP and 27% if it was not performed within 6 months of BNP testing (P = 0.21). CONCLUSION: Approximately half of patients with a high BNP and an LVEF not known to be low did not have a follow-up guideline recommended LVEF study and may have unrecognized heart failure. Our findings suggest that a trial is warranted of a clinical pathway where those patients with a high BNP and without appropriate follow-up are randomized to have their physician receive a notification of the high BNP value. PMID- 27465008 TI - Diagnostic Yield of Routine Stress Testing in Low and Intermediate Risk Chest Pain Patients Under 40 Years: A Systematic Review. AB - OBJECTIVE: Chest pain is one of the most frequent causes for presentation to emergency departments (EDs). The majority of patients will undergo diagnostic workup including stress testing to rule out an acute coronary syndrome, but very few patients will be diagnosed with a cardiac cause for their pain. Patients under 40 years represent a lower risk group in which routine stress testing may be of little benefit. This systematic review sought to determine the diagnostic yield of routine stress testing in low- and intermediate-risk chest pain patients under 40 years. METHODS: Electronic databases were searched for relevant studies. The quality of the included primary studies was assessed using the National Health and Medical Research Council evidence hierarchy and the McMaster Critical Appraisal Tool for Quantitative Studies. Descriptive statistics summarized the findings. RESULTS: Five primary studies were included in the review (all level III-3 evidence); 7 additional sources of relevant data were also included. Diagnostic yield of routine stress testing in low- and intermediate-risk patients under 40 years is reported between 0% and 1.1%. Combined data from included primary studies demonstrated just 4 out of 1683 true positive stress tests (0.24%), only one of which was definitively confirmed by coronary angiogram; additional data sources identified just 1 out of 310 true positive stress tests (0.32%). CONCLUSIONS: Diagnostic yield of routine stress testing in low- and intermediate-risk chest pain patients under 40 years is low. However, better quality studies are required to be able to draw definitive conclusions. PMID- 27465009 TI - Agreement Between Patient-reported and Cardiology-adjudicated Medical History in Patients With Possible Ischemic Chest Pain: An Observational Study. AB - OBJECTIVE: Obtaining an accurate medical history is essential in the assessment of patients, particularly in emergency department (ED) patients with acute chest pain, as there can be a time imperative for diagnosis and commencement of treatment. We aimed to evaluate reliability of patient-reported compared with physician-adjudicated medical history by assessing patient's recall and communication of personal events and its influence on the accuracy of the medical history. METHODS: A total of 776 patients presenting at ED with suspected cardiac chest pain were recruited. Data collection included self-reported patient history, electrocardiogram testing, and troponin I measurements. Independent assessment of risk factors and medical history was adjudicated by cardiologists. Diagnosis of acute coronary syndrome (ACS) at 30 days after presentation was assessed. Cohen's kappa measured patient-cardiologist agreement. Cardiologist adjudicated events were taken as true to assess accuracy. RESULTS: A total of 83 participants (10.7%) were diagnosed with ACS at 30 days after presentation. "Previous coronary artery bypass grafting" showed highest agreement (K = 1.00) between patient-reported and cardiologist-adjudicated events. Lowest agreement between patient-reported and cardiologist-adjudicated events was found for "prior ventricular dysrhythmia" (K = 0.33). Accuracy of reported "prior congestive heart failure" differed significantly between patients with and without diagnosed ACS at 30 days (92.8% and 97.5%, respectively). CONCLUSIONS: Accuracy of patient's recall and communication of medical history and risk factors was substantial but not perfect in the assessment of patients with ACS in the ED context. Our study reinforces the importance in the utilization of medical records and collateral information to address possible discrepancies in the medical history and improve patient care. PMID- 27465010 TI - Gender Discrepancy in Diabetic Patients Hospitalized With Heart Failure: Does Age Matter? AB - BACKGROUND: Gender discrepancy in the cardiovascular diseases has been evaluated in several studies. We studied the impact of gender disparity on the presentation and outcome of diabetic heart failure (DHF) patients. METHODS: A retrospective analysis was conducted including all DHF patients admitted to the Heart Hospital between 1991 and 2013. Patients' demographics, presentation, management, and hospital outcomes were analyzed and compared based on gender and age. RESULTS: Out of 8266 HF patients, 4684 (56.7%) were diabetic, of whom 1817 (39%) were females. Mean age was comparable in both genders. DHF female patients were more likely to be hypertensive (79% vs. 65%, P = 0.001) and obese (13% vs. 4.6%, P = 0.001). DHF females were less likely to receive beta-blockers and angiotensin converting-enzyme inhibitors/angiotensinogen-receptor blockers (25% vs. 30%, P = 0.001, 54% vs. 57%, P = 0.01, respectively), but were more likely to be on insulin therapy (21% vs. 16%, P = 0.001). In-hospital atrial fibrillation (P =0.90), ventricular tachycardia (P = 0.07), stroke (P = 0.45), and cardiac arrest (P = 0.26) were comparable. Overall in-hospital mortality was comparable in both genders (P = 0.83). In age <=50 years, male gender was associated with a 3-fold increase in death (13% vs. 4%, P = 0.01), however, this mortality difference disappeared in DHF patients aged >50 years (P = 0.62). CONCLUSIONS: In DHF, female gender is characterized by having a high prevalence of metabolic syndrome components. Also, females are more likely to have better Left ventricular ejection fraction but less likely to receive cardiovascular evidence based medications. There is no significant difference in the overall hospital mortality between both genders, however, in the younger age; males have a significantly higher mortality. PMID- 27465012 TI - Chlorhexidine hexametaphosphate as a wound care material coating: antimicrobial efficacy, toxicity and effect on healing. AB - AIM: In this study, chlorhexidine hexametaphosphate (CHX-HMP) is investigated as a persistent antimicrobial coating for wound care materials. MATERIALS & METHODS: CHX-HMP was used as a wound care material coating and compared with chlorhexidine digluconate materials with respect to antimicrobial efficacy, toxicity and wound closure. RESULTS: Antimicrobial efficacy at day 1, 3 and 7 was observed with experimental and commercial materials. CHX-HMP coated materials had less toxic effect on human placental cells than commercial chlorhexidine dressings. CHX-HMP in pluronic gel did not delay healing but reduced wound colonization by E. faecalis. CONCLUSION: CHX-HMP could become a useful component of wound care materials with sustained antimicrobial efficacy, lower toxicity than chlorhexidine digluconate materials, and reduction in wound colonization without affecting closure. PMID- 27465011 TI - Common risk factors and edentulism in adults, aged 50 years and over, in China, Ghana, India and South Africa: results from the WHO Study on global AGEing and adult health (SAGE). AB - BACKGROUND: Edentulism (loss of all teeth) is a final marker of disease burden for oral health common among older adults and poorer populations. Yet most evidence is from high-income countries. Oral health has many of the same social and behavioural risk factors as other non-communicable diseases (NCDs) which are increasing rapidly in low- and middle-income countries with ageing populations. The "common risk factor approach" (CRFA) for oral health addresses risk factors shared with NCDs within the broader social and economic environment. METHODS: The aim is to improve understanding of edentulism prevalence, and association between common risk factors and edentulism in adults aged 50 years and above using nationally representative samples from China (N = 11,692), Ghana (N = 4093), India (N = 6409) and South Africa (N = 2985). The data source is the World Health Organization (WHO) Study on global AGEing and adult health (SAGE) Wave 1 (2007 2010). Multivariable logistic regression describes association between edentulism and common risk factors reported in the literature. RESULTS: Prevalence of edentulism: in China 8.9 %, Ghana 2.9 %, India 15.3 %, and South Africa 8.7 %. Multivariable analysis: in China, rural residents were more likely to be edentulous (OR 1.36; 95 % CI 1.09-1.69) but less likely to be edentulous in Ghana (OR 0.53; 95 % CI 0.31-0.91) and South Africa (OR 0.52; 95 % CI 0.30-0.90). Respondents with university education (OR 0.31; 95 % CI 0.18-0.53) and in the highest wealth quintile (OR 0.68; 95 % CI 0.52-0.90) in China were less likely to be edentulous. In South Africa respondents with secondary education were more likely to be edentulous (OR 2.82; 95 % CI 1.52-5.21) as were those in the highest wealth quintile (OR 2.78; 95 % CI 1.16-6.70). Edentulism was associated with former smokers in China (OR 1.57; 95 % CI 1.10-2.25) non-drinkers in India (OR 1.65; 95 % CI 1.11-2.46), angina in Ghana (OR 2.86; 95 % CI 1.19-6.84) and hypertension in South Africa (OR 2.75; 95 % CI 1.72-4.38). Edentulism was less likely in respondents with adequate nutrition in China (OR 0.68; 95 % CI 0.53 0.87). Adjusting for all other factors, compared with China, respondents in India were 50 % more likely to be edentulous. CONCLUSIONS: Strengthening the CRFA should include addressing common determinants of health to reduce health inequalities and improve both oral and overall health. PMID- 27465013 TI - [Epilepsy and Pregnancy]. AB - BACKGROUND: On average, female patients with epilepsy have 0.9 children, which is below the birth rate of healthy women. One reason is insufficient counselling. OBJECTIVES: To summarize the current data relevant to counselling pregnant women with epilepsy. MATERIALS AND METHODS: Discussion of research and recommendations concerning seizure control during pregnancy, pregnancy and birth complications, congenital malformations, and breastfeeding. RESULTS: Changes in seizure frequency during pregnancy are variable and partly due to changes in the serum concentrations of antiepileptic drugs. Epilepsy patients have a slightly higher risk for some pregnancy and birth complications including spontaneous abortion, pre- and postpartum bleeding, induction of labour, and caesarean section. In particular, the administration of valproic acid can lead to congenital malformations and a lower IQ of the child. Folic acid seems to have a protective effect. Data concerning breastfeeding are insufficient. CONCLUSIONS: If possible, epilepsy patients should be treated with a low-dose monotherapy during pregnancy and valproic acid should be avoided. Treatment with lamotrigine requires frequent control of serum concentration. Supplementary folic acid (5 mg daily dose) is recommended. Epilepsy is not an indication for a caesarean section. PMID- 27465014 TI - Factors associated with duration of inpatient hospital stay for patients with diabetes mellitus admitted to a medical unit in a community public hospital. AB - The aim was to examine predictors of duration of inpatient hospital stay in people with diabetes mellitus to assist implementation of strategies to reduce hospital stay. This audit prospectively studied patients with diabetes mellitus admitted to a medical unit of an Australian community public hospital. Other outcome measures included glucose treatment optimisation and access to GP and diabetes-specific healthcare professionals. Comparison was made to patients without diabetes mellitus who were admitted concomitantly. Diabetes patients represented 26% of admissions over a 2-month period. In total, 73% had seen a GP within the prior 6 months. Patients with diabetes mellitus (n=79) had a median age of 69 years; 53% were male and median HbA1c was 65mmolmol-1 (8.1%). Diabetes mellitus was associated with a longer inpatient stay (P=0.03), particularly among patients admitted with vascular disease. Age >65 years and seeing <3 members of the community-based diabetes mellitus multidisciplinary team (MDT) in the 2-years pre-admission were independently associated with a longer stay (P=0.02). In total, 10% were referred to an endocrinologist on discharge. Involvement of more of the diabetes-specific MDT, with a skilled GP, in primary care is recommended as it may shorten inpatient hospital stay, improve glycaemia and reduce demand for limited specialist endocrinologists. PMID- 27465015 TI - 4 Years after the Deepwater Horizon Spill: Molecular Transformation of Macondo Well Oil in Louisiana Salt Marsh Sediments Revealed by FT-ICR Mass Spectrometry. AB - Gulf of Mexico saltmarsh sediments were heavily impacted by Macondo well oil (MWO) released from the 2010 Deepwater Horizon (DWH) oil spill. Detailed molecular-level characterization of sediment extracts collected over 48 months post-spill highlights the chemical complexity of highly polar, oxygen-containing compounds that remain environmentally persistent. Electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS), combined with chromatographic prefractionation, correlates bulk chemical properties to elemental compositions of oil-transformation products as a function of time. Carboxylic acid incorporation into parent MWO hydrocarbons detected in sediment extracts (corrected for mass loss relative to C30 hopane) proceeds with an increase of ~3-fold in O2 species after 9 months to a maximum of a ~5.5-fold increase after 36 months, compared to the parent MWO. More importantly, higher order oxygenated compounds (O4-O6) not detected in the parent MWO increase in relative abundance with time as lower-order oxygenated species are transformed into highly polar, oxygen-containing compounds (Ox, where x > 3). Here, we present the first molecular-level characterization of temporal compositional changes that occur in Deepwater Horizon derived oil contamination deposited in a saltmarsh ecosystem from 9 to 48 months post-spill and identify highly oxidized Macondo well oil compounds that are not detectable by routine gas-chromatography based techniques. PMID- 27465017 TI - Introducing the Wiley Transplant Peer Review Network. PMID- 27465016 TI - The influence of prolonged vibration on motor unit behavior. AB - INTRODUCTION: The purpose of this study was to determine the effects of vibration (VIB) on motor unit (MU) behavior of the vastus lateralis (VL) muscle during a 40% maximal voluntary contraction (MVC). METHODS: Eleven healthy (age 21.3 +/- 2.6 years) individuals participated in the study. Surface electromyography (EMG) data were recorded from the VL during isometric trapezoidal muscle contractions at 40% MVC. Firing events of single MUs and EMG amplitude were reported for the first, middle, and final seconds of a 12-second steady force segment at 40% MVC. VIB was applied at 55 Hz to the patellar tendon for 15 minutes before and continued throughout the remainder of testing (VIB) or remained off (CON). RESULTS: There were significant increases in MU firing rates during VIB in comparison to CON and no differences in EMG amplitude between VIB and CON. CONCLUSION: The VIB-mediated reduction in muscle spindle function altered MU behavior at 40% MVC. Muscle Nerve 55: 500-507, 2017. PMID- 27465018 TI - Professor Jules Traeger: a giant in Nephrology and Transplantation Medicine. PMID- 27465019 TI - Integrated information for integrated care in the general practice setting in Italy: using social network analysis to go beyond the diagnosis of frailty in the elderly. AB - BACKGROUND: Frailty has been defined in different ways and several diagnostic tools exist, but most of them are not applicable in routine primary care. Nonetheless, general practitioners (GPs) have a natural advantage in identifying frailty, due to their continued access to patients, patient-centered approach and training. GPs have also an advantage in conducting population-based evaluation as consequence of their role of gatekeepers of the health care system. This paper aims to identify those socio-demographic and clinical profiles and the relative information sources that, from the GPs' perspective, act as frailty markers, not solely as a diagnosis of state but as the ability to identify a patient's trajectory, over time, through the aging process. METHODS: This study was performed as a survey within a population aged 75 and over, attending 148 GPs in Italy. A total of 23,996 patients were classified by GPs in distinct frailty status, without the use of a specific evaluation tool, but only referring to general indications. Co-morbidity was objectively assessed by a record-linkage with previous hospitalizations, in order to assess the occurrence of previous illnesses that could be associated with the likelihood of being identified as frails or at risk. The methodological approach is based on social network analysis (SNA), suited to explore relational aspects of complex phenomena. RESULTS: Our findings reveal that GPs are able to perform low cost population based evaluation, by exploiting the advantages of their approach to patients, combined with the information derived from their daily practice and from other sources currently available. CONCLUSION: We believe that informative integration among different sources of available data can provide a comprehensive picture of the health state of patients in a shorter time and at lower cost. The identification of limited patient trajectories based on these observations can enable the development of critical biomarkers/diagnostics and prognostic indicators that will enhance patient care and potentially reduce inappropriate healthcare use. We also believe that network analysis is an extremely flexible research tool and a rich theoretical paradigm, and it may be used in the healthcare planning. PMID- 27465020 TI - Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. AB - Nicotinamide adenine dinucleotide (NAD(+)) is a central metabolic cofactor in eukaryotic cells that plays a critical role in regulating cellular metabolism and energy homeostasis. NAD(+) in its reduced form (i.e. NADH) serves as the primary electron donor in mitochondrial respiratory chain, which involves adenosine triphosphate production by oxidative phosphorylation. The NAD(+)/NADH ratio also regulates the activity of various metabolic pathway enzymes such as those involved in glycolysis, Kreb's cycle, and fatty acid oxidation. Intracellular NAD(+) is synthesized de novo from L-tryptophan, although its main source of synthesis is through salvage pathways from dietary niacin as precursors. NAD(+) is utilized by various proteins including sirtuins, poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases. The NAD(+) pool is thus set by a critical balance between NAD(+) biosynthetic and NAD(+) consuming pathways. Raising cellular NAD(+) content by inducing its biosynthesis or inhibiting the activity of PARP and cADP-ribose synthases via genetic or pharmacological means lead to sirtuins activation. Sirtuins modulate distinct metabolic, energetic and stress response pathways, and through their activation, NAD(+) directly links the cellular redox state with signaling and transcriptional events. NAD(+) levels decline with mitochondrial dysfunction and reduced NAD(+)/NADH ratio is implicated in mitochondrial disorders, various age-related pathologies as well as during aging. Here, I will provide an overview of the current knowledge on NAD(+) metabolism including its biosynthesis, utilization, compartmentalization and role in the regulation of metabolic homoeostasis. I will further discuss how augmenting intracellular NAD(+) content increases oxidative metabolism to prevent bioenergetic and functional decline in multiple models of mitochondrial diseases and age-related disorders, and how this knowledge could be translated to the clinic for human relevance. PMID- 27465021 TI - Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed. AB - BACKGROUND: Ganglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of patients. METHODS: Clinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010. RESULTS: Of 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p < 0.001), less frequently with adrenal tumors (31 % vs. 43 %, p = 0.001) and positive mIBG-uptake (34 % vs. 90 %, p < 0.001), and had less often elevated urine catecholamine metabolites (homovanillic acid 39 % vs. 62 %, p < 0.001, vanillylmandelic acid 27 % vs. 64 %, p < 0.001). Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001). Complete tumor resection was achieved at diagnosis in 70 % of 162 GN and 67 % of 55 GNBI, and after 4 to 32 months of observation in 4 GN (2 %) and 5 GNBI (9 %). Eleven patients received chemotherapy without substantial effect. Fifty-five residual tumors (42 GN, 13 GNBI) are currently under observation (median: 44 months). Five patients (3 GN, 2 GNBI) showed local progression; all had tumor residuals > 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression. CONCLUSIONS: GN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006). PMID- 27465022 TI - The mutational structure of metabolism in Caenorhabditis elegans. AB - A properly functioning organism must maintain metabolic homeostasis. Deleterious mutations degrade organismal function, presumably at least in part via effects on metabolic function. Here we present an initial investigation into the mutational structure of the Caenorhabditis elegans metabolome by means of a mutation accumulation experiment. We find that pool sizes of 29 metabolites vary greatly in their vulnerability to mutation, both in terms of the rate of accumulation of genetic variance (the mutational variance, VM) and the rate of change of the trait mean (the mutational bias, DeltaM). Strikingly, some metabolites are much more vulnerable to mutation than any other trait previously studied in the same way. Although we cannot statistically assess the strength of mutational correlations between individual metabolites, principal component analysis provides strong evidence that some metabolite pools are genetically correlated, but also that there is substantial scope for independent evolution of different groups of metabolites. Averaged over mutation accumulation lines, PC3 is positively correlated with relative fitness, but a model in which metabolites are uncorrelated with fitness is nearly as good by Akaike's Information Criterion. PMID- 27465024 TI - CORRECTION. PMID- 27465023 TI - Plasma Membrane Microdomains Are Essential for Rac1-RbohB/H-Mediated Immunity in Rice. AB - Numerous plant defense-related proteins are thought to congregate in plasma membrane microdomains, which consist mainly of sphingolipids and sterols. However, the extent to which microdomains contribute to defense responses in plants is unclear. To elucidate the relationship between microdomains and innate immunity in rice (Oryza sativa), we established lines in which the levels of sphingolipids containing 2-hydroxy fatty acids were decreased by knocking down two genes encoding fatty acid 2-hydroxylases (FAH1 and FAH2) and demonstrated that microdomains were less abundant in these lines. By testing these lines in a pathogen infection assay, we revealed that microdomains play an important role in the resistance to rice blast fungus infection. To illuminate the mechanism by which microdomains regulate immunity, we evaluated changes in protein composition, revealing that microdomains are required for the dynamics of the Rac/ROP small GTPase Rac1 and respiratory burst oxidase homologs (Rbohs) in response to chitin elicitor. Furthermore, FAHs are essential for the production of reactive oxygen species (ROS) after chitin treatment. Together with the observation that RbohB, a defense-related NADPH oxidase that interacts with Rac1, is localized in microdomains, our data indicate that microdomains are required for chitin-induced immunity through ROS signaling mediated by the Rac1-RbohB pathway. PMID- 27465025 TI - Counting Carbs: Tracking Fluctuations in Starch-Derived Metabolite Levels Uncovers Their Crucial Roles in Osmotic Stress Tolerance. PMID- 27465026 TI - Examination of Protein Complexes Gets SiMPull. PMID- 27465027 TI - Rapid Evolution of Genomic Imprinting in Two Species of the Brassicaceae. AB - Genomic imprinting is an epigenetic phenomenon occurring in mammals and flowering plants that causes genes to adopt a parent-of-origin-specific mode of expression. While the imprinting status of genes is well conserved in mammals, clear estimates for the degree of conservation were lacking in plants. We therefore analyzed the genome-wide imprinting status of Capsella rubella, which shared a common recent ancestor with Arabidopsis thaliana ~10 to 14 million years ago. However, only ~14% of maternally expressed genes (MEGs) and ~29% of paternally expressed genes (PEGs) in C. rubella were commonly imprinted in both species, revealing that genomic imprinting is a rapidly evolving phenomenon in plants. Nevertheless, conserved PEGs exhibited signs of selection, suggesting that a subset of imprinted genes play an important functional role and are therefore maintained in plants. Like in Arabidopsis, PEGs in C. rubella are frequently associated with the presence of transposable elements that preferentially belong to helitron and MuDR families. Our data further reveal that MEGs and PEGs differ in their targeting by 24-nucleotide small RNAs and asymmetric DNA methylation, suggesting different mechanisms establishing DNA methylation at MEGs and PEGs. PMID- 27465028 TI - Randomized controlled trial of a book-sharing intervention in a deprived South African community: effects on carer-infant interactions, and their relation to infant cognitive and socioemotional outcome. AB - BACKGROUND: Consistent with evidence from high-income countries (HICs), we previously showed that, in an informal peri-urban settlement in a low-middle income country, training parents in book sharing with their infants benefitted infant language and attention (Vally, Murray, Tomlinson, & Cooper, ). Here, we investigated whether these benefits were explained by improvements in carer infant interactions in both book-sharing and non-book-sharing contexts. We also explored whether infant socioemotional development benefitted from book sharing. METHODS: We conducted a randomized controlled trial in Khayelitsha, South Africa. Carers of 14-16-month-old infants were randomized to 8 weeks' training in book sharing (n = 49) or a wait-list control group (n = 42). In addition to the cognitive measures reported previously, independent assessments were made at base line and follow-up of carer-infant interactions during book sharing and toy play. Assessments were also made, at follow-up only, of infant prosocial behaviour in a 'help task', and of infant imitation of doll characters' nonsocial actions and an interpersonal interaction. Eighty-two carer-infant pairs (90%) were assessed at follow-up. (Trial registration ISRCTN39953901). RESULTS: Carers who received the training showed significant improvements in book-sharing interactions (sensitivity, elaborations, reciprocity), and, to a smaller extent, in toy-play interactions (sensitivity). Infants in the intervention group showed a significantly higher rate of prosocial behaviour, and tended to show more frequent imitation of the interpersonal interaction. Improvements in carer behaviour during book sharing, but not during toy play, mediated intervention effects on all infant cognitive outcomes, and tended to mediate intervention effects on infant interpersonal imitation. CONCLUSIONS: Training in book sharing, a simple, inexpensive intervention that has been shown to benefit infant cognitive development in a low-middle income country, also shows promise for improving infant socioemotional outcomes in this context. Benefits are mediated by improvements in carer-infant interactions, particularly in book-sharing contexts. PMID- 27465029 TI - Rapidly progressive neurological deterioration in anti-AMPA receptor encephalitis with additional CRMP5 antibodies. AB - Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis positive for additional onconeural antibodies is rarely reported. Here we report the clinical features of a patient who developed limbic encephalitis with both glutamate receptor 2 (GluR2) and collapsin response mediator protein 5 (CRMP5) antibodies. Brain magnetic resonance imaging revealed multifocal encephalopathy. Chest computed tomography showed a highly suspicious malignant thymoma. He experienced rapid neurological deterioration during hospitalization. This report indicates that the clinical diversity of anti-AMPAR encephalitis and the presence of onconeural antibodies may lead to poor prognosis. PMID- 27465030 TI - Provider risk factors for medication administration error alerts: analyses of a large-scale closed-loop medication administration system using RFID and barcode. AB - PURPOSE: To determine the risk factors and rate of medication administration error (MAE) alerts by analyzing large-scale medication administration data and related error logs automatically recorded in a closed-loop medication administration system using radio-frequency identification and barcodes. METHODS: The subject hospital adopted a closed-loop medication administration system. All medication administrations in the general wards were automatically recorded in real-time using radio-frequency identification, barcodes, and hand-held point-of care devices. MAE alert logs recorded during a full 1 year of 2012. We evaluated risk factors for MAE alerts including administration time, order type, medication route, the number of medication doses administered, and factors associated with nurse practices by logistic regression analysis. RESULTS: A total of 2 874 539 medication dose records from 30 232 patients (882.6 patient-years) were included in 2012. We identified 35 082 MAE alerts (1.22% of total medication doses). The MAE alerts were significantly related to administration at non-standard time [odds ratio (OR) 1.559, 95% confidence interval (CI) 1.515-1.604], emergency order (OR 1.527, 95%CI 1.464-1.594), and the number of medication doses administered (OR 0.993, 95%CI 0.992-0.993). Medication route, nurse's employment duration, and working schedule were also significantly related. CONCLUSION: The MAE alert rate was 1.22% over the 1-year observation period in the hospital examined in this study. The MAE alerts were significantly related to administration time, order type, medication route, the number of medication doses administered, nurse's employment duration, and working schedule. The real-time closed-loop medication administration system contributed to improving patient safety by preventing potential MAEs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27465031 TI - Effectiveness of adjuvant chemotherapy for elderly patients with lymph node positive colorectal cancer. AB - BACKGROUND: Several guidelines state that postoperative adjuvant chemotherapy (AC) confers survival benefits to patients with lymph node-positive colorectal cancer. However, older patients are usually not administered AC due to the higher risk of side effects. The aim of this study was to evaluate the benefit of AC for elderly patients (EP) and examine its tolerability. METHODS: Data from 204 patients with lymph node-positive colon cancer were retrospectively analyzed. Patients were subdivided into two groups: EP, >75 years old (n = 53) and young patients (YP), <75 years old (n = 151). Clinicopathological features, type of chemotherapy, and outcomes were compared between groups. RESULTS: Frequency of comorbidities and performance status were significantly higher in EP (p < 0.01 each), a greater proportion of YP (76 %) than EP received AC (40 %, p < 0.01), and YP received combination therapy more frequently than EP (p < 0.01). In terms of side effects, few EP showed severe side effects. Both YP and EP gained survival benefits from AC (p = 0.07 and p < 0.01, respectively). CONCLUSIONS: AC should not be withheld from eligible EP purely because of age. PMID- 27465032 TI - Physiological and Metabolic Changes During the Transition from Hyperthyroidism to Euthyroidism in Graves' Disease. AB - BACKGROUND: The serum metabolomic profile and its relationship to physiological changes during hyperthyroidism and restoration to euthyroidism are not known. This study aimed to examine the physiological, adipokine, and metabolomic changes that occur when subjects with Graves' disease transition from hyperthyroidism to euthyroidism with medical treatment. METHODS: Chinese women between 21 and 50 years of age and with newly diagnosed Graves' disease attending the endocrine outpatient clinics in a single institution were recruited between July 2012 and September 2014. All subjects were treated with thioamides to achieve euthyroidism. Clinical parameters (body weight, body composition via bioelectrical impedance analysis, resting energy expenditure and respiratory quotient via indirect calorimetry, and reported total energy intake via 24 h food diary), biochemical parameters (thyroid hormones, lipid profile, fasting insulin and glucose levels), serum leptin, adiponectin, and metabolomics profiles were measured during hyperthyroidism and repeated in early euthyroidism. RESULTS: Twenty four Chinese women with an average age of 36.3 +/- 8.6 years were included in the study. The average duration of treatment that was required to reach euthyroidism for these subjects was 38 +/- 16.3 weeks. There was a significant increase in body weight (52.6 +/- 9.0 kg to 55.3 +/- 9.4 kg; p < 0.001) and fat mass (14.3 +/- 6.9 kg to 16.8 +/- 6.5 kg; p = 0.005). There was a reduction in resting energy expenditure corrected for weight (28.7 +/- 4.0 kcal/kg to 21.5 +/- 4.1 kcal/kg; p < 0.001) and an increase in respiratory quotient (0.76 to 0.81; p = 0.037). Resting energy expenditure increased significantly with increasing free triiodothyronine levels (p = 0.007). Significant increases in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were noted. There was no significant change in leptin levels, but adiponectin levels increased significantly (p = 0.018). Significant reductions in fasting C2, medium-chain, long-chain, and total acylcarnitines were observed, but no changes in the fat-free mass, branched chain amino acid levels, or insulin sensitivity during recovery from hyperthyroidism were noted. CONCLUSIONS: Serum metabolomics profile changes complemented the physiological changes observed during the transition from hyperthyroidism to euthyroidism. This study provides a comprehensive and integrated view of the changes in fuel metabolism and energy balance that occur following the treatment of hyperthyroidism. PMID- 27465033 TI - Fast, label-free super-resolution live-cell imaging using rotating coherent scattering (ROCS) microscopy. AB - Living cells are highly dynamic systems with cellular structures being often below the optical resolution limit. Super-resolution microscopes, usually based on fluorescence cell labelling, are usually too slow to resolve small, dynamic structures. We present a label-free microscopy technique, which can generate thousands of super-resolved, high contrast images at a frame rate of 100 Hertz and without any post-processing. The technique is based on oblique sample illumination with coherent light, an approach believed to be not applicable in life sciences because of too many interference artefacts. However, by circulating an incident laser beam by 360 degrees during one image acquisition, relevant image information is amplified. By combining total internal reflection illumination with dark-field detection, structures as small as 150 nm become separable through local destructive interferences. The technique images local changes in refractive index through scattered laser light and is applied to living mouse macrophages and helical bacteria revealing unexpected dynamic processes. PMID- 27465034 TI - Assessment of implantable infusion pumps for continuous infusion of human insulin in rats: potential for group housing. AB - Group housing is considered to be important for rats, which are highly sociable animals. Single housing may impact behaviour and levels of circulating stress hormones. Rats are typically used in the toxicological evaluation of insulin analogues. Human insulin (HI) is frequently used as a reference compound in these studies, and a comparator model of persistent exposure by HI infusion from external pumps has recently been developed to support toxicological evaluation of long-acting insulin analogues. However, this model requires single housing of the animals. Developing an insulin-infusion model which allows group housing would therefore greatly improve animal welfare. The aim of the present study was to investigate the suitability of implantable infusion pumps for HI infusion in group-housed rats. Group housing of rats implanted with a battery-driven pump proved to be possible. Intravenous infusion of HI lowered blood glucose levels persistently for two weeks, providing a comparator model for use in two-week repeated-dose toxicity studies with new long-acting insulin analogues, which allows group housing, and thereby increasing animal welfare compared with an external infusion model. PMID- 27465036 TI - Aggregation of model asphaltenes: a molecular dynamics study. AB - Natural asphaltenes are defined as polyaromatic compounds whose chemical composition and structure are dependent on their geological origin and production history, hence are regarded as complex molecules with aromatic cores and aliphatic tails that occur in the heaviest fraction of crude oil. The aggregation of asphaltenes presents a range of technical challenges to the production and processing of oil. In this work we study the behaviour of the model asphaltene like molecule hexa-tert-butylhexa-peri-hexabenzocoronene (HTBHBC) using molecular dynamics simulation. It was found that the regular arrangement of the tert-butyl side chains prevents the formation of strongly-bound dimers by severely restricting the configurational space of the aggregation pathway. In contrast, a modified molecule with only 3 side chains is readily able to form dimers. This work therefore confirms the influence of the molecular structure of polyaromatic compounds on their aggregation mechanism, and reveals the unexpected design rules required for model systems that can mimic the behavior of asphaltenes. PMID- 27465035 TI - Early pancreatic volume reduction on CT predicts relapse in patients with type 1 autoimmune pancreatitis treated with steroids. AB - BACKGROUND: Type 1 autoimmune pancreatitis (AIP) is clinically characterized by a response to steroid therapy. Despite having a favorable prognosis, AIP has a high relapse rate and factors predicting relapse in AIP patients treated with steroids have not yet been established. METHODS: A retrospective chart review was conducted of 32 newly diagnosed type 1 AIP patients who had undergone enhanced computed tomography (CT) pre- and post-steroid therapy. RESULTS: Ten patients experienced relapse. Pancreatic volume was reduced significantly in all patients (pre-treatment volume, 88.5 +/- 32.9 cm(3) vs. post-treatment volume, 45.4 +/- 21.1 cm(3); P < 0.001), although the pre-treatment pancreatic volume did not differ between the relapse and non-relapse groups (92.6 +/- 10.5 cm(3) vs. 86.6 +/- 7.1 cm(3), P = 0.401). However, the post-treatment pancreatic volume was significantly greater in the relapse group than that in the non-relapse group (56.9 +/- 6.3 cm(3) vs. 40.2 +/- 4.2 cm(3), P = 0.008). Similarly, the percent reduction in pancreatic volume was significantly smaller in the relapse group than that in the non-relapse group (36.6 +/- 4.7 % vs. 52.1 +/- 3.2 %, P = 0.002). Multivariate analysis identified post-treatment pancreatic volume (HR, 1.04, 95 % CI: 1.01-1.08, P = 0.010) and percent reduction in pancreatic volume (HR, 0.87, 95 % CI: 0.79-0.94, P < 0.001) as predictive factors for relapse of type 1 AIP. A post-treatment pancreatic volume of 50 cm(3) < (P = 0.009) and a percent reduction in the pancreatic volume of <35 % (P = 0.004) had a significantly high relapse rate. These data suggest that early pancreatic volume changes after steroid therapy may be a useful prognostic value, because type 1 AIP patients with a high post-treatment pancreatic volume or low pancreatic volume reduction showed significant relapse. CONCLUSIONS: Early pancreatic volume reduction on CT after steroid therapy indicates the therapeutic effects of steroids, and a low decrease in the pancreatic volume may be associated with a limited response that predicts future relapse in patients with type 1 AIP. Reduction of steroids in these cases must be observed carefully with consideration of immunomodulator use. PMID- 27465037 TI - Methane Potential and Microbial Community Dynamics in Anaerobic Digestion of Silage and Dry Cornstalks: a Substrate Exchange Study. AB - Silage and dry are the two typical cornstalk forms. Either form could be used as substrate in biogas plants and might be replaced by another when shortage occurred. This study focused on the feeding sequence of these two kinds of feedstocks, aiming to discuss their specific methane potential (SMP). A 15-day hydraulic retention time was chosen for semi-continuous experiments based on the batch test results. In semi-continuous experiments, before and after feedstocks were exchanged, the significantly decreased and comparable SMPs of silage and dry cornstalks indicated that a basis of unstable digestion would result in incomplete methane release from the subsequent digestion. A higher similarity of bacterial community structure and greater quantity of bacteria were shown in acidified silage cornstalk digestion through band similarity analysis. Methanosaetaceae and methanomicrobiales were the predominant methanogens, and aceticlastic methanogenesis was the main route for methane production. The different feeding sequences affected the hydrolysis course and further influenced the methanogenic proliferation. Our work suggests that silage cornstalk digestion should be conducted before dry cornstalk digestion. PMID- 27465038 TI - Recycled de-Oiled Algal Biomass Extract as a Feedstock for Boosting Biodiesel Production from Chlorella minutissima. AB - The investigation for the first time assesses the efficacy of recycled de-oiled algal biomass extract (DABE) as a cultivation media to boost lipid productivity in Chlorella minutissima and its comparison with Bold's basal media (BBM) used as control. Presence of organic carbon (3.8 +/- 0.8 g/l) in recycled DABE resulted in rapid growth with twofold increase in biomass productivity as compared to BBM. These cells expressed four folds higher lipid productivity (126 +/- 5.54 mg/l/d) as compared to BBM. Cells cultivated in recycled DABE showed large sized lipid droplets accumulating 54.12 % of lipid content. Decrement in carbohydrate (17.76 %) and protein content (28.12 %) with loss of photosynthetic pigments compared to BBM grown cells were also recorded. The fatty acid profiles of cells cultivated in recycled DABE revealed the dominance of C16:0 (39.66 %), C18:1 (29.41 %) and C18:0 (15.82 %), respectively. This model is self-sustained and aims at neutralizing excessive feedstock consumption by exploiting recycled de-oiled algal biomass for cultivation of microalgae, making the process cost effective. PMID- 27465040 TI - Climate change-associated trends in net biomass change are age dependent in western boreal forests of Canada. AB - The impacts of climate change on forest net biomass change are poorly understood but critical for predicting forest's contribution to the global carbon cycle. Recent studies show climate change-associated net biomass declines in mature forest plots. The representativeness of these plots for regional forests, however, remains uncertain because we lack an assessment of whether climate change impacts differ with forest age. Using data from plots of varying ages from 17 to 210 years, monitored from 1958 to 2011 in western Canada, we found that climate change has little effect on net biomass change in forests <= 40 years of age due to increased growth offsetting increased mortality, but has led to large decreases in older forests due to increased mortality accompanying little growth gain. Our analysis highlights the need to incorporate forest age profiles in examining past and projecting future forest responses to climate change. PMID- 27465039 TI - Butein provides neuroprotective and anti-neuroinflammatory effects through Nrf2/ARE-dependent haem oxygenase 1 expression by activating the PI3K/Akt pathway. AB - BACKGROUND AND PURPOSE: Butein, 3,4,2',4'-tetrahydroxychalcone, has various pharmacological effects. However, no study has demonstrated the specific neurobiological mechanisms of the effects of butein in neuronal cells. The present study examined the role of butein as an antioxidative and anti inflammatory inducer of haem oxygenase 1 (HO1) in mouse hippocampal HT22, BV2 microglial and primary mouse hippocampus neurons. EXPERIMENTAL APPROACH: We investigated the neuroprotective effects of butein on glutamate-induced HT22 cell and primary mouse hippocampal neuron death and its anti-neuroinflammatory effects on LPS-induced activation of BV2 cells. We elucidated the underlying mechanisms by assessing the involvement of NF-kappaB, HO1, nuclear factor-E2-related factor 2 (Nrf2) and Akt signalling. KEY RESULTS: Butein decreased cellular oxidative injury and the production of ROS in glutamate-treated HT22 cells and primary mouse hippocampal neurons. Furthermore, butein suppressed LPS-induced pro inflammatory enzymes and mediators in BV2 microglia. Butein inhibited IL-6, IL 1beta and TNF-alpha production and mRNA expression. In addition, butein decreased NO and PGE2 production and inducible NOS and COX-2 expression through the NF kappaB signalling pathway. Butein up-regulated Nrf2/ARE-mediated HO1 expression through the PI3K/Akt pathway and this was positively associated with its cytoprotective effects and anti-neuroinflammatory actions. CONCLUSION AND IMPLICATIONS: Our results indicate that butein effectively prevents glutamate induced oxidative damage and LPS-induced activation and that the induction of HO1 by butein through the PI3K/Akt pathway and Nrf2 activation appears to play a pivotal role in its effects on neuronal cells. Our results provide evidence for the neuroprotective properties of butein. PMID- 27465041 TI - Expression of Ku70 predicts results of radiotherapy in prostate cancer. AB - BACKGROUND AND PURPOSE: Therapeutic strategy for prostate cancer is decided according to T stage, Gleason score, and prostate-specific antigen (PSA) level. These clinical factors are not accurate enough to predict individual risk of local failure of prostate cancer after radiotherapy. Parameters involved with radiosensitivity are required to improve the predictive capability for local relapse. PATIENTS AND METHODS: We analyzed 58 patients with localized adenocarcinoma of the prostate between August 2007 and October 2010 treated with 76 Gy of intensity-modulated radiotherapy (IMRT) as a discovery cohort and 42 patients between March 2001 and May 2007 treated with three-dimensional conformal radiotherapy (3D-CRT) as a validation cohort. Immunohistochemical examination for proteins involved in nonhomologous end-joining was performed using biopsy specimens. RESULTS: Ku70 expression was not correlated with various clinical parameters, such as the Gleason score and D'amico risk classification, indicating that Ku70 expression was an independent prognostic factor. The predictive value for PSA relapse was markedly improved after the combination of Gleason score and Ku70 expression, as compared with Gleason score alone. In patients treated with radiotherapy and androgen deprivation therapy (ADT), no relapses were observed in patients with Gleason score <=7 or low Ku70 expression. In contrast, patients with Gleason score >=8 and high Ku70 expression had high PSA relapse rates. In the validation cohort, similar results were obtained. CONCLUSION: Treatment with 76 Gy and ADT can be effective for patients with Gleason score <=7 or low Ku70 expression, but is not enough for patients with Gleason score >=8 and high Ku70 expression and, thus, require other treatment approaches. PMID- 27465042 TI - India's Computational Biology Growth and Challenges. AB - India's computational science is growing swiftly due to the outburst of internet and information technology services. The bioinformatics sector of India has been transforming rapidly by creating a competitive position in global bioinformatics market. Bioinformatics is widely used across India to address a wide range of biological issues. Recently, computational researchers and biologists are collaborating in projects such as database development, sequence analysis, genomic prospects and algorithm generations. In this paper, we have presented the Indian computational biology scenario highlighting bioinformatics-related educational activities, manpower development, internet boom, service industry, research activities, conferences and trainings undertaken by the corporate and government sectors. Nonetheless, this new field of science faces lots of challenges. PMID- 27465043 TI - Single and multiple resistance QTL delay symptom appearance and slow down root colonization by Aphanomyces euteiches in pea near isogenic lines. AB - BACKGROUND: Understanding the effects of resistance QTL on pathogen development cycle is an important issue for the creation of QTL combination strategies to durably increase disease resistance in plants. The oomycete pathogen Aphanomyces euteiches, causing root rot disease, is one of the major factors limiting the pea crop in the main producing countries. No commercial resistant varieties are currently available in Europe. Resistance alleles at seven main QTL were recently identified and introgressed into pea agronomic lines, resulting in the creation of Near Isogenic Lines (NILs) at the QTL. This study aimed to determine the effect of main A. euteiches resistance QTL in NILs on different steps of the pathogen life cycle. RESULTS: NILs carrying resistance alleles at main QTL in susceptible genetic backgrounds were evaluated in a destructive test under controlled conditions. The development of root rot disease severity and pathogen DNA levels in the roots was measured during ten days after inoculation. Significant effects of several resistance alleles at the two major QTL Ae-Ps7.6 and Ae-Ps4.5 were observed on symptom appearance and root colonization by A. euteiches. Some resistance alleles at three other minor-effect QTL (Ae-Ps2.2, Ae Ps3.1 and Ae-Ps5.1) significantly decreased root colonization. The combination of resistance alleles at two or three QTL including the major QTL Ae-Ps7.6 (Ae Ps5.1/Ae-Ps7.6 or Ae-Ps2.2/Ae-Ps3.1/Ae-Ps7.6) had an increased effect on delaying symptom appearance and/or slowing down root colonization by A. euteiches and on plant resistance levels, compared to the effects of individual or no resistance alleles. CONCLUSIONS: This study demonstrated the effects of single or multiple resistance QTL on delaying symptom appearance and/or slowing down colonization by A. euteiches in pea roots, using original plant material and a precise pathogen quantification method. Our findings suggest that single resistance QTL can act on multiple or specific steps of the disease development cycle and that their actions could be pyramided to increase partial resistance in future pea varieties. Further studies are needed to investigate QTL effects on different steps of the pathogen life cycle, as well as the efficiency and durability of pyramiding strategies using QTL which appear to act on the same stage of the pathogen cycle. PMID- 27465044 TI - A novel hedgehog inhibitor iG2 suppresses tumorigenesis by impairing self-renewal in human bladder cancer. AB - Tumor recurrence is still a major challenge for clinical treatment of bladder cancer. Cumulative evidences indicate cancer stem cells (CSCs) contribute to drug resistance and leave a putative source for disease relapse. Identifying novel agents targeting CSCs may represent a new paradigm in the therapy of bladder cancer. Here, we separated a novel hedgehog (Hh) inhibitor, iG2, from streptomyces roseofulvus, which dramatically blocked the activation of Gli2 in bladder cancer cells. The iG2 strongly repressed the growth of cancer cells rather than the peri-tumor stroma cells. Attenuated proliferation and enhanced apoptosis of tumor cells were observed upon iG2 stimulation. Furthermore, iG2 reduced the self-renewal ability of bladder CSCs as well as the tumor formation. Collectively, iG2 is potentially used as a novel therapeutic agent for bladder cancer by targeting self-renewal through inhibiting Hh pathway. PMID- 27465045 TI - Neurochemical and behavioral studies on the 5-HT1A-dependent antipsychotic action of the mGlu4 receptor agonist LSP4-2022. AB - LSP4-2022 is a novel, orthosteric agonist of mGlu4 receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT1A receptors in LSP4-2022-induced antipsychotic actions and the neurochemical background of that interaction were investigated. In several behavioral tests the actions of effective doses of the compound (0.5-2 mg/kg) were antagonized via the administration of the 5-HT1A antagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT1A agonist (R)-(S) 8-OH-DPAT (0.01 mg/kg) intensified the activity of ineffective doses of LSP4 2022, having no influence on the efficacy of the active doses. The co administration of effective doses of both compounds did not intensify each other's action. In the microdialysis in vivo tests, MK-801 (0.6 mg/kg) induced an enhancement of the release of dopamine, serotonin, glutamate and GABA in the prefrontal cortex. Administration of LSP4-2022 (2 mg/kg) abolished this MK-801 induced effect on neurotransmitter release. Co-administration with WAY100635 (0.1 mg/kg), a 5-HT1A antagonist, completely (dopamine, serotonin) or partially (glutamate, GABA) counteracted this LSP4-2022-induced effect. Subsequently, the patch-clamp recordings of spontaneous EPSCs were performed. sEPSCs were evoked in slices from the mouse prefrontal cortex by DOI (10 MUM). LSP4-2022 (2.5; 5 and 10 MUm) reversed DOI-induced changes in both the frequency and amplitude of the sEPSCs, but the more robust effect on the frequency was observed. The administration of WAY100635 had no effect on the LSP4-2022-induced effects on sEPSCs, indicating that the mGlu4-5-HT1A interaction does not occur via single neuron signaling but involves neuronal circuits that regulate neurotransmitter release. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'. PMID- 27465046 TI - Measured and predicted environmental concentrations of carbamazepine, diclofenac, and metoprolol in small and medium rivers in northern Germany. AB - This study evaluated the impact of secondary municipal effluent discharge on carbamazepine, diclofenac, and metoprolol concentrations in small and medium rivers in northern Germany and compared the measured environmental concentrations (MECs) to the predicted environmental concentrations (PECs) calculated with four well-established models. During a 1-year sampling period, secondary effluent grab samples were collected at four wastewater treatment plants (WWTPs) together with grab samples from the receiving waters upstream and downstream from the wastewater discharge points. The carbamazepine, diclofenac, and metoprolol concentrations were analyzed with high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS-MS) after solid phase extraction. In the secondary effluents, 84-790 ng/L carbamazepine, 395-2100 ng/L diclofenac, and 745-5000 ng/L metoprolol were detected. The carbamazepine, diclofenac, and metoprolol concentrations analyzed in the rivers downstream from the secondary effluent discharge sites ranged from <5 to 68, 370, and 520 ng/L, respectively. Most of the downstream pharmaceutical concentrations were markedly higher than the corresponding upstream concentrations. The impact of wastewater discharge on the MECs in rivers downstream from the WWTPs was clearly demonstrated, but the correlations of the MECs with dilution factors were poor. The smallest rivers exhibited the largest maximum MECs and the widest ranges of MECs downstream from the wastewater discharge point. Three of the four tested models were conservative, as they showed higher PECs than the MECs in the rivers downstream from the WWTPs. However, the most detailed model underestimated the diclofenac concentrations. PMID- 27465047 TI - "Melanoma: Questions and Answers." Development and evaluation of a psycho educational resource for people with a history of melanoma. AB - PURPOSE: People with melanoma often report pervasive fears about cancer recurrence, unmet information needs, and difficulties accessing psychological care. Interventions addressing the supportive care needs of people with melanoma are rare, and needs are often overlooked. The study evaluated a newly developed, evidence-based, psycho-educational resource for people with melanoma. METHODS: The evaluation study comprised three groups: adults at high risk of new primary disease due to multiple previous melanomas or one melanoma and dysplastic nevus syndrome (DNS), adults at moderate risk due to one previous melanoma and no DNS, and health professionals involved in melanoma care. Participants evaluated a 68 page psycho-educational booklet, Melanoma: Questions and Answers, developed by a multidisciplinary team in accordance with published evidence, clinical guidelines, and intervention development frameworks. The booklet comprised seven modules featuring information on melanoma diagnosis, treatment, prognosis, and ongoing clinical management; risk factors and the role of genetic counseling services for melanoma; psycho-education on emotional, behavioral, and cognitive responses to melanoma, including psycho-education on fear of cancer recurrence; description of healthy coping responses; a suite of tailored tools to support skin self-examination, doctor-patient communication, and identification of the signs and symptoms of anxiety and depression; a list of community-based services and resources; and tools to support melanoma-related record keeping and monitoring. Resource acceptability, relevance, quality, dissemination preferences, emotional responses, unmet information needs, and demographic characteristics were assessed. RESULTS: Nineteen melanoma survivors (response rate 50 %) and 10 health professionals (response rate 83 %) evaluated the resource. Responses were overwhelmingly positive; the booklet was thoroughly read and highly rated in terms of quality and quantity of information, utility of health education tools, and capacity to address unmet needs. Ninety-five percent of melanoma survivors would recommend the booklet to others. Most preferred a paper-based format, provided by their treating doctor at diagnosis. CONCLUSIONS: Melanoma: Questions and Answers was feasible and acceptable and demonstrated a strong capacity to address the information and psycho-educational needs of people with melanoma at low fiscal cost. PMID- 27465048 TI - Geriatric assessment factors are associated with mortality after hospitalization in older adults with cancer. AB - PURPOSE: Survival in older adults with cancer varies given differences in functional status, comorbidities, and nutrition. Prediction of factors associated with mortality, especially in hospitalized patients, allows physicians to better inform their patients about prognosis during treatment decisions. Our objective was to analyze factors associated with survival in older adults with cancer following hospitalization. METHODS: Through a retrospective cohort study, we reviewed 803 patients who were admitted to Barnes-Jewish Hospital's Oncology Acute Care of Elders (OACE) unit from 2000 to 2008. Data collected included geriatric assessments from OACE screening questionnaires as well as demographic and medical history data from chart review. The primary end point was time from index admission to death. The Cox proportional hazard modeling was performed. RESULTS: The median age was 72.5 years old. Geriatric syndromes and functional impairment were common. Half of the patients (50.4 %) were dependent in one or more activities of daily living (ADLs), and 74 % were dependent in at least one instrumental activity of daily living (IADLs). On multivariate analysis, the following factors were significantly associated with worse overall survival: male gender; a total score <20 on Lawton's IADL assessment; reason for admission being cardiac, pulmonary, neurologic, inadequate pain control, or failure to thrive; cancer type being thoracic, hepatobiliary, or genitourinary; readmission within 30 days; receiving cancer treatment with palliative rather than curative intent; cognitive impairment; and discharge with hospice services. CONCLUSIONS: In older adults with cancer, certain geriatric parameters are associated with shorter survival after hospitalization. Assessment of functional status, necessity for readmission, and cognitive impairment may provide prognostic information so that oncologists and their patients make more informed, individualized decisions. PMID- 27465049 TI - Classification of painful bone metastases as mild, moderate, or severe using both EORTC QLQ-C15-PAL and EORTC QLQ-BM22. AB - PURPOSE: Previous studies have determined optimal cut points (CPs) for the classification of pain severity as mild, moderate, or severe using only the Brief Pain Inventory (BPI) or the BPI in conjunction with a quality of life (QOL) tool. The purpose of our study was to determine the optimal CPs based on correlation with only QOL outcomes. METHODS: We conducted an analysis of 298 patients treated with radiation therapy for painful bone metastases on a phase III randomized trial. Prior to treatment, patients provided their worst pain score on a scale of 0 (no pain) to 10 (worst possible pain), as well as completed the European Organization of Cancer Research and Treatment (EORTC) QOL Questionnaire Bone Metastases module (QLQ-BM22) and the EORTC QOL Questionnaire Core-15 Palliative (QLQ-C15-PAL). Optimal CPs were determined to be those that yielded the largest F ratio for the between category effect on each subscale of the QLQ-BM22 and QLQ C15-PAL using the multivariate analysis of variance (MANOVA). RESULTS: The two largest F ratios for Wilk's lambda, Pillai's Trace, and Hotelling's Trace were for CPs 5,6 and 5,7. Combining both, the optimal CPs to differentiate between mild, moderate, and severe pain were 5 and 7. Pain scores of 1-5, 6, and 7-10 were classified as mild, moderate, and severe, respectively. Patients with severe pain experienced greater functional interference and poorer QOL when compared to those with mild pain. CONCLUSION: Our results suggest that, based on the impact of pain on QOL measures, pain scores should be classified as follows: 1-5 as mild pain, 6 as moderate pain, and 7-10 as severe pain. Optimal CPs vary depending on the type of outcome measurement used. PMID- 27465050 TI - Prevalence of cancer chemotherapy-related problems, their relation to health related quality of life and associated supportive care: a cross-sectional survey. AB - PURPOSE: The purpose of this study was to identify the treatment-associated problems that most impact on patients undergoing cancer chemotherapy, how problems relate to experiences of supportive care and variations in experience between cancer treatment centres. METHODS: A survey administered to patients at six cancer centres in England explored variations of prevalence of 17 cancer chemotherapy-associated problems and associated supportive care. Problem items were identified as the most frequently experienced and severe when experienced in a scoping and consensus exercise. A health-related quality of life (HRQoL) measure, the EQ5D, was included to measure impact of problems. RESULTS: A total of 363 completed questionnaires were returned (response rate 43 %, median 61 %). The most prevalent problem was 'tiredness/fatigued' (90 %), followed by 'changes in taste & smell' (69 %) and 'difficulty managing everyday tasks' (61 %). Significant variations in problem prevalence existed between centres, and some common problems were rarely reported in the literature. Regression analysis found that almost all problems were significantly associated with HRQoL, with social/emotional problems having as much impact on HRQoL as physical/psychological side effects of treatment. Greatest effect size was for difficulty managing everyday tasks. Respondents reported significant variations in supportive care between centres, with more supportive care received for physical/psychological problems than for social/emotional problems. Findings indicated that patients who received increased supportive care experienced less severe problems. CONCLUSION: The most common and distressing chemotherapy associated problems were identified. These problems are mitigated by quality supportive care. Routine measurement and monitoring of problem items and supportive care are warranted to facilitate benchmarking and service improvements both within and between cancer centres. PMID- 27465052 TI - New vascular endothelial growth factor isoforms promise to increase myocardial perfusion without stealing. PMID- 27465051 TI - Examining racial variation in antiemetic use and post-chemotherapy health care utilization for nausea and vomiting among breast cancer patients. AB - PURPOSE: Racial minority cancer patients may experience underuse of antiemetic medications to prevent chemotherapy-induced nausea and vomiting (CINV). In addition to its adverse implications for quality of life, antiemetic underuse may contribute to observed disparities in acute illness during chemotherapy. To understand the potential contribution of CINV prophylaxis to breast cancer disparities, we assessed racial variation in potent antiemetic use and post chemotherapy utilization related to CINV and the relationship between the two. METHODS: We used SEER-Medicare data to evaluate the health care utilization in the 14 days following chemotherapy initiation among black and white women receiving highly emetogenic chemotherapy for breast cancer. We used modified Poisson regression to assess the relationship between (1) race and CINV-related utilization and (2) NK1 use and CINV-related utilization, overall and stratified by race. We report adjusted risk ratios (aRR) and 95 % confidence intervals (CI). RESULTS: The study included 1130 women. Black women were 11 % less likely than white women to use neurokinin-1 receptor antagonists (NK1s) for CINV prophylaxis (p = 0.02); however, they experienced fewer CINV-related encounters following chemotherapy (unadjusted RR = 0.63, 95 %CI = 0.40-0.99; p = 0.05). After adjustment for clinical covariates, estimates were similar but no longer statistically significant (p = 0.07). Among white women, NK1 use was associated with increased CINV-related utilization (aRR NK1 users vs. non-users: 1.35, 95 % CI = 1.07-1.69, p = 0.01), likely resulting from unmeasured confounders. CONCLUSION: Black women were less likely to use NK1s- and CINV-related services. Racial variation in CINV-related services use may be partly explained by differential symptom reporting or access to care. PMID- 27465054 TI - Increasing the evidence base in adult congenital heart disease. PMID- 27465053 TI - Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality. AB - OBJECTIVE: Experimental evidence has shown potential cardioprotective actions of phosphodiesterase type-5 inhibitors (PDE5is). We investigated whether PDE5i use in patients with type 2 diabetes, with high-attendant cardiovascular risk, was associated with altered mortality in a retrospective cohort study. RESEARCH DESIGN AND METHODS: Between January 2007 and May 2015, 5956 men aged 40-89 years diagnosed with type 2 diabetes before 2007 were identified from anonymised electronic health records of 42 general practices in Cheshire, UK, and were followed for 7.5 years. HRs from multivariable survival (accelerated failure time, Weibull) models were used to describe the association between on-demand PDE5i use and all-cause mortality.DC1SM110.1136/heartjnl-2015 309223.supp1Supplementary appendix RESULTS: Compared with non-users, men who are prescribed PDE5is (n=1359) experienced lower percentage of deaths during follow up (19.1% vs 23.8%) and lower risk of all-cause mortality (unadjusted HR=0.69 (95% CI: 0.64 to 0.79); p<0.001)). The reduction in risk of mortality (HR=0.54 (0.36 to 0.80); p=0.002) remained after adjusting for age, estimated glomerular filtration rate, smoking status, prior cerebrovascular accident (CVA) hypertension, prior myocardial infarction (MI), systolic blood pressure, use of statin, metformin, aspirin and beta-blocker medication. PDE5i users had lower rates of incident MI (incidence rate ratio (0.62 (0.49 to 0.80), p<0.0001) with lower mortality (25.7% vs 40.1% deaths; age-adjusted HR=0.60 (0.54 to 0.69); p=0.001) compared with non-users within this subgroup. CONCLUSION: In a population of men with type 2 diabetes, use of PDE5is was associated with lower risk of overall mortality and mortality in those with a history of acute MI. PMID- 27465055 TI - Galectin-3 predicts left ventricular remodelling after anterior-wall myocardial infarction treated by primary percutaneous coronary intervention. AB - OBJECTIVES: Despite modern reperfusion therapies, left ventricular remodelling (LVR) occurs frequently after an ST-elevated myocardial infarction (STEMI) and represents a strong predictor of mortality and heart failure. Galectin-3 (Gal-3), a novel biomarker involved in inflammation, tissue repair and fibrogenesis, might be a valuable predictor of LVR. METHODS: We enrolled consecutively admitted patients with a first anterior STEMI and left anterior descending artery occlusion treated by primary percutaneous coronary intervention (pPCI). Gal-3, N terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography and cardiovascular events were evaluated 48 hours after admission, at 1 and 6 months. LVR was defined as a >=15% increase in LV end-systolic volume. RESULTS: We recruited 103 patients (28% women, aged 64.6+/-12 years, LV ejection fraction 47+/-11%). Median baseline Gal-3 and NT-proBNP levels were 13.2 ng/mL (10.8-17.1 ng/mL) and 2132 pg/mL (1019-4860 pg/mL) respectively. During 6 months of follow up, 4 patients dropped out, 7 died and 26 (28.3%) of the 92 survivors developed LVR (LVR+). LVR+ patients had higher Gal-3 levels at baseline, 1 and 6 months than LVR- (p<0.0001). By univariable logistic regression, age, female gender, higher baseline Gal-3 and NT-proBNP, smaller LV end-diastolic volume (LVEDV) were associated to an increased risk of LVR. By multivariable analysis, only LVEDV (OR 0.96, 95% CI 0.93 to 0.99/1 mL change) and Gal-3 levels (OR 1.22, 95% CI 1.06 to 1.42/1 ng/mL change) independently predicted LVR (C-statistics 0.84, 95% CI 0.75 to 0.93). CONCLUSION: Gal-3 serum levels measured during hospitalisation could be clinically useful in predicting LVR among patients admitted with anterior STEMI treated by pPCI. PMID- 27465056 TI - Potts shunt for pulmonary hypertension: the interventionist's interest in imaging. PMID- 27465057 TI - Nature of the Insulating Ground State of the Two-Dimensional Sn Atom Lattice on SiC(0001). AB - Semiconductor surfaces with narrow surface bands provide unique playgrounds to search for Mott-insulating state. Recently, a combined experimental and theoretical study of the two-dimensional (2D) Sn atom lattice on a wide-gap SiC(0001) substrate proposed a Mott-type insulator driven by strong on-site Coulomb repulsion U within a single-band Hubbard model. However, our systematic density-functional theory (DFT) study with local, semilocal, and hybrid exchange correlation functionals shows that the Sn dangling-bond state largely hybridizes with the substrate Si 3p and C 2p states to split into three surface bands due to the crystal field. Such a hybridization gives rise to the stabilization of the antiferromagnetic order via superexchange interactions. The band gap and the density of states predicted by the hybrid DFT calculation agree well with photoemission data. Our findings not only suggest that the Sn/SiC(0001) system can be represented as a Slater-type insulator driven by long-range magnetism, but also have an implication that taking into account long-range interactions beyond the on-site interaction would be of importance for properly describing the insulating nature of Sn/SiC(0001). PMID- 27465058 TI - Caregiver Burdens and Preventive Dental Care for Children with Autism Spectrum Disorder, Developmental Disability and/or Mental Health Conditions: National Survey of CSHCN, 2009-2010. AB - Objective The purpose of this study is to examine the burdens of caregivers on perception of the need and receipt of preventive dental care for a subset of children with special health care needs-children with Autism Spectrum disorder, developmental disability and/or mental health conditions (CASD/DD/MHC). Methods The authors used the 2009-2010 National Survey of CSHCN. The survey included questions addressing preventive dental care and caregivers' financial, employment, and time-related burdens. The associations of these burdens on perceptions and receipt of preventive dental care use were analyzed with bivariate Chi square analyses and multinomial logistic regressions for CASD/DD/MHC (N = 16,323). Results Overall, 16.3 % of CASD/DD/MHC had an unmet preventive dental care need. There were 40.0 % of caregivers who reported financial burden, 20.3 % who reported employment burden, and 10.8 % who reported time burden. A higher percentage of caregivers with financial burden, employment burden, and time-related burden reported that their CASD/DD/MHC did not receive needed preventive dental care (14.1, 16.5, 17.7 % respectively) compared to caregivers without financial, employment, or time burdens (9.0, 9.6 %, 11.0 % respectively). Caregivers with financial burden (adjusted multinomial odds ratio, 1.38 [95 % CI 1.02, 1.86] and employment burden (adjusted multinomial odds ratio, 1.45 [95 % CI 1.02, 2.06] were more likely to report that their child did not receive preventive dental care despite perceived need compared to caregivers without financial or employment burdens. Conclusions for practice Unmet needs for preventive dental care were associated with employment and financial burdens of the caregivers of CASD/DD/MHC. PMID- 27465059 TI - Low-Income Women's Feeding Practices and Perceptions of Dietary Guidance: A Qualitative Study. AB - Objectives Describe themes characterizing feeding behaviors of low-income women participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), and identify the attitudes, beliefs, and sources of information that inform these practices. Methods Formative research was conducted including focus groups and semi-structured individual phone interviews with a total of 68 low-income women participating in WIC. Qualitative data were recorded, transcribed, imported into NVivo 8.0, and analyzed for common themes. Results Mothers reported feeding behaviors inconsistent with guidance from WIC and the American Academy of Pediatrics. Three main themes were identified. First, mothers reported receiving conflicting messaging/advice from medical professionals, WIC nutritionists, and family members, which was confusing. Mothers also reported dissatisfaction with the "one size fits most" approach. Lastly, mothers reported relying on their "instincts" and that "all babies are different" when deciding and rationalizing what feeding guidance to follow. Conclusions Future interventions targeting this high-risk population should consider developing personalized (individualized) messaging, tailored to the needs of each mother-child dyad. Focused efforts are needed to build partnerships between WIC providers and other health care providers to provide more consistent messages about responsive feeding to prevent early obesity. PMID- 27465060 TI - Indication of Risk of Mother-to-Child Toxoplasma gondii Transmission in the Greater Accra Region of Ghana. AB - Objectives Congenital infection with Toxoplasma gondii is known to result in neurological and brain disorders including ophthalmic disorders later in life. Research in Ghana revealed high sero-prevalence among pregnant women and eye patients. This study determines the risk of congenital transmission of T. gondii infection in Accra, Ghana. Methods One hundred consented pregnant women aged 18 45 years (mean 29.85 +/- 5.76) participated. Venous blood and tissue samples were taken from the maternal side of each placenta after delivery. Cord blood samples were also taken after they were separated from the infants. Finger-prick blood was taken from infants of participating women at 2 or 6 weeks post-natal. ELISA was used to detect T. gondii antibodies in all blood samples while Nested-PCR was used to detect T. gondii DNA from placental tissues. Data was analysed using SPSS v. 16. Results Overall, 37.6 % of maternal blood, 39.5 % of umbilical cord blood, and 57.5 % of post-natal infant blood were positive for anti-T. gondii IgG. No anti-T. gondii IgM was detected in any of those samples. Toxoplasma gondii DNA was detected in 39.8 % of placental tissue samples. Strong association was observed in the occurrence of placental T. gondii DNA and anti-T. gondii IgG positive women (o = 0.810, p < 0.00001) as well as high Relative risk shown in the likelihood of foetal exposure to infection in latently-infected women (RR 10.39; CI 4.47-24.17; p < 0.00001). Conclusions for Practice The presence of anti T. gondii IgG antibodies only, and T. gondii DNA in placental tissues indicate the women might have been infected early during the pregnancy, placing about 39.8 % of the babies at risk. These results can strongly influence policy to screen and treat pregnant women for T. gondii infection. PMID- 27465061 TI - Association of Household Savings and Expected Future Means with Delivery Using a Skilled Birth Attendant in Ghana and Nigeria: A Cross-Sectional Analysis. AB - Objectives This study examined the association between household savings and related economic measures with utilization of skilled birth attendants (SBAs) at last birth among women living in peri-urban households (n = 381) in Ghana and Nigeria. Methods Data were drawn from the 2011-2014 Family Health and Wealth Study. Multivariable logistic regression models were used to estimate the odds of delivery with an SBA for individual and composite measures of household savings, expected financial means, debt, lending, and receipt of financial assistance, adjusting for demographic and reproductive characteristics. Results Seventy-three percent (73 %) of women delivered with an SBA during their last birth (89 %, Ghana; 63 %, Nigeria), and roughly one third (34 %) of households reported having any in-cash or in-kind savings. In adjusted analyses, women living in households with savings were significantly more likely to deliver with an SBA compared to women in households without any savings (aOR = 2.02, 95 % CI 1.09-3.73). There was also a consistent downward trend, although non-significant, in SBA utilization with worsening financial expectations in the coming year (somewhat vs. much better: aOR = 0.70, 95 % CI 0.40-1.22 and no change/worse vs. much better: aOR = 0.46, 95 % CI 0.12-1.83). Findings were null for measures relating to debt, lending, and financial assistance. Conclusion Coupling birth preparedness and complication readiness strategies with savings-led initiatives may improve SBA utilization in conjunction with targeting non-economic barriers to skilled care use. PMID- 27465062 TI - Effects of Prenatal Nicotine Exposure on Infant Language Development: A Cohort Follow Up Study. AB - Objectives To study the longitudinal effects of prenatal nicotine exposure on cognitive development, taking into consideration prenatal and postnatal second hand smoke exposure. Methods A cohort follow up study was carried out. One hundred and fifty-eight pregnant women and their infants were followed during pregnancy and infant development (at 6, 12, 30 months). In each trimester of pregnancy and during postnatal follow-up, a survey was administered to obtain sociodemographic data and the details of maternal and close familial toxic habits. Obstetric and neonatal data were obtained from hospital medical records. To assess cognitive development, the Bayley Scales of Infant Development were applied at 6, 12 and 30 months; to assess language development, the MacArthur Bates Communicative Development Inventories were applied at 12 months and the Peabody Picture Vocabulary Test at 30 months. Results After adjustment for confounding variables, the results showed that infants prenatally exposed to cigarette smoke recorded poor cognitive development scores. Language development was most consistently affected, specifically those aspects related to auditory function (vocalizations, sound discrimination, word imitation, prelinguistic vocalizations, and word and sentence comprehension). Conclusions for Practice Irrespective of prenatal, perinatal and sociodemographic data (including infant postnatal nicotine exposure), prenatal exposure to cigarette smoke and second hand smoke affect infant cognitive development, especially language abilities. PMID- 27465063 TI - End-task versus in-task feedback to increase procedural learning retention during spinal anaesthesia training of novices. AB - Communication of feedback during teaching of practical procedures is a fine balance of structure and timing. We investigate if continuous in-task (IT) or end task feedback (ET) is more effective in teaching spinal anaesthesia to medical students. End-task feedback was hypothesized to improve both short-term and long term procedural learning retention as experiential learning promotes active learning after encountering errors during practice. Upon exposure to a 5-min instructional video, students randomized to IT or ET feedbacks were trained using a spinal simulator mannequin. A blinded expert tested the students using a spinal anaesthesia checklist in the short term (immediate) and long-term (average 4 months). Sixty-five students completed the training and testing. There were no differences in demographics of age or gender within IT or ET distributions. Both short-term and long-term learning retention of spinal anaesthesia ET feedback proved to be better (P < 0.01) than IT feedback. The time taken for ET students was shorter at long-term testing. End-task feedback improves both short-term and long-term procedural learning retention. PMID- 27465064 TI - Clarifying changes in student empathy throughout medical school: a scoping review. AB - Despite the increasing awareness of the relevance of empathy in patient care, some findings suggest that medical schools may be contributing to the deterioration of students' empathy. Therefore, it is important to clarify the magnitude and direction of changes in empathy during medical school. We employed a scoping review to elucidate trends in students' empathy changes/differences throughout medical school and examine potential bias associated with research design. The literature published in English, Spanish, Portuguese and French from 2009 to 2016 was searched. Two-hundred and nine potentially relevant citations were identified. Twenty articles met the inclusion criteria. Effect sizes of empathy scores variations were calculated to assess the practical significance of results. Our results demonstrate that scoped studies differed considerably in their design, measures used, sample sizes and results. Most studies (12 out of 20 studies) reported either positive or non-statistically significant changes/differences in empathy regardless of the measure used. The predominant trend in cross-sectional studies (ten out of 13 studies) was of significantly higher empathy scores in later years or of similar empathy scores across years, while most longitudinal studies presented either mixed-results or empathy declines. There was not a generalized international trend in changes in students' empathy throughout medical school. Although statistically significant changes/differences were detected in 13 out of 20 studies, the calculated effect sizes were small in all but two studies, suggesting little practical significance. At the present moment, the literature does not offer clear conclusions relative to changes in student empathy throughout medical school. PMID- 27465065 TI - Understanding the curvature effect of silica nanoparticles on lysozyme adsorption orientation and conformation: a mesoscopic coarse-grained simulation study. AB - In nanobiotechnology applications, curvature of nanoparticles has a significant effect on protein activities. In this work, lysozyme adsorption on different sized silica nanoparticles (SNPs) was simulated at the microsecond timescale by using mesoscopic coarse-grained molecular dynamics simulations. It is found that, with the increase of nanoparticle size, which indicates a decrease of surface curvature, adsorbed lysozyme shows a narrower orientation distribution and a greater conformation change, as the electrostatic attraction dominates lysozyme adsorption, and this trend is more pronounced on larger SNPs. Interestingly, the effect induced by different SNP surface curvatures is not related to the direct contact area between lysozyme and SNPs, but to the interfacial hydration layer above the silica surface, since a smaller curvature can lead to a stronger interfacial hydration and make the distribution of interfacial water molecules more ordered. Besides, at higher ionic strength, lysozyme conformation is less affected by strongly negatively charged SNPs, especially for larger nanoparticles. This work might shed some light on how to prepare protein coronas with higher bioactivities in nanobiotechnology. PMID- 27465067 TI - [Automated fertility and health surveillance systems in dairy cows. A review]. AB - Automated surveillance systems have become increasingly important in dairy farming. This can be attributed to an increasing farm size with unaltered employee numbers, higher susceptibility of high-yielding animals to diseases and a general constraint to work more cost effectively. A variety of surveillance systems for different areas of application in dairy cow management are currently available. However, their applicability has not always been supported by scientific validation. With regards to the considerable costs in installing and running surveillance systems and to evaluate their practical aspects, further analyses are desirable. Considering the progress in computer-based systems in recent years, we are anticipating rapid developments in automated animal surveillance in the near future. Consequently, the need arises for veterinarians to understand the principles underlying such systems, to be able to assess their efficacy and to be capable of evaluating data derived from these systems in order to advise farmers appropriately. The aim of this study was to assess the benefits and limitations of current surveillance systems for oestrus-detection, partus alarm and monitoring health status mainly with regards to metabolic disorders in dairy cows, but also for other selected areas of health monitoring. PMID- 27465066 TI - Recombinant Newcastle disease virus expressing P53 demonstrates promising antitumor efficiency in hepatoma model. AB - BACKGROUND: Numerous studies have demonstrated that the NDV-mediated gene therapy is a promising new approach for treatment of cancers. P53 plays a vital role in tumor suppression and surveillance. Therefore, we hypothesize that a recombinant NDV expressing P53 would be an ideal agent for the hepatoma therapy. RESULTS: In the essay, the human P53 gene was incorporated into the genome of a lentogenic strain (named rNDV-P53), which did not affect viral replication kinetics and magnitude in HepG2 cells. Compared to the vehicle virus, rNDV-P53 increased cell growth suppressor ratio and early apoptosis by 2 folds, and decreased the mitochondrial membrane potential in HepG2 cells. In vivo studies, treatment with rNDV-P53 reduced tumor volume of tumor-bearing mice by more than 4 folds, tumor weight by more than 5 folds comparing with rNDV. The 120-day survival rate of rNDV-P53-treated mice was 75 %, survival rate of rNDV-treated mice was 12.5 %. TUNEL analysis showed a significant increase in the apoptosis rate in the tumor tissues of rNDV-P53-treated mice than that of rNDV-treated mice. Moreover, serum chemistries revealed an insignificant change of blood urea nitrogen (BUN), creatinine levels, alanine aminotransferase (ALT) and aspartate transaminase (AST) in rNDV-P53-treated group compared to normal mice, suggesting treatment with the recombinant virus was not toxic. CONCLUSION: rNDV-P53 is a potent candidate for carcinoma therapy especially for hepatocarcinoma. PMID- 27465068 TI - Complement C3 is expressed by mast cells in cutaneous vasculitis and is degraded by chymase. AB - The complement factor C3 and chymase released from tryptase(+), chymase(+) mast cells may be involved in the pathogenesis of cutaneous leukocytoclastic vasculitis. To study whether mast cells contain C3 in vasculitis and whether chymase interacts with C3, cryosections from vasculitis biopsies were double stained histochemically for C3c in tryptase(+) mast cells, as well as for chymase and vessel wall C3c, or they were treated with 5 ug/ml rh-chymase for 24 h followed by immunofluorescence (IF) analysis of C3c, IgG, IgM and IgA. The effect of rh-chymase on purified human C3, C3a and IgG was studied using SDS-PAGE electrophoresis and LAD2 mast cell cultures. The results show that 34.2 +/- 17.9, 37.4 +/- 15.5 and 43.4 +/- 18.6 % (mean +/- SD) of the mast cells express C3c immunoreactivity in the healthy skin, initial petechial (IP) and palpable purpura (PP) lesions, respectively. About 9.4-12.1 % of the chymase(+) mast cells were in apparent contact with C3c(+) vessels in IP and PP. The treatment of cryosections with rh-chymase decreased the IF staining of C3c, but not that of immunoglobulins. In SDS-PAGE, 1-10 ug/ml rh-chymase degraded the alpha- and beta chains of C3, but did not degrade IgG. Unexpectedly, the rh-chymase treatment of C3 produced fragments that resulted in the release of tryptase and histamine from LAD2 cells. However, rh-chymase degraded C3a and consequently inhibited C3a activity on LAD2. In conclusion, mast cells can be one source for C3 in the early and late phases of vasculitis pathogenesis. However, rh-chymase degraded native C3, vessel wall C3c, and biologically active C3a. Therefore, chymase may control C3-related pathology. PMID- 27465069 TI - Pleiotrophin is downregulated in human keloids. AB - Keloid is an abnormal hyperproliferative scarring process with involvement of complex genetic and triggering environmental factors. Previously published dysregulated gene expression profile of keloids includes genes involved in tumor formation. Pleiotrophin (PTN) is a secreted, heparin-binding growth factor which is involved in various biological functions such as cell growth, differentiation, and tumor progression. Although PTN expression was reported to be increased in hypertrophic scars, there is no study on PTN expression in keloids, and previous microarray results are controversial. To clarify differential expression of PTN in keloids, we investigated the expression of PTN and its interacting molecules in keloid and control fibroblasts, and performed immunohistochemical staining of PTN using tissue arrays. The expressions of PTN, its upstream regulator platelet derived growth factor subunit B (PDGF-B) and corresponding PDGF receptors were significantly downregulated in keloid fibroblasts compared to normal human fibroblasts, and the decreased PTN protein expression was confirmed by immunohistochemistry as well as Western blot. Moreover, functional downstream receptor protein tyrosine phosphatase beta/zeta was significantly upregulated in keloid fibroblasts, supporting overall downregulation of PTN signaling pathway. The lowered PTN expression in keloids suggests a different pathomechanism from that of hypertrophic scars. PMID- 27465071 TI - Clinical-Grade Human Multipotent Adult Progenitor Cells Block CD8+ Cytotoxic T Lymphocytes. AB - : : MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8+ cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was even after major histocompatibility complex class I upregulation-insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8-CD69+ T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs. SIGNIFICANCE: Because multipotent adult progenitor cells (MAPCs) are among the noteworthy adult mesenchymal stem cell populations for immune therapy and have the advantage over mesenchymal stem cells (MSCs) of large-scale manufacturing and banking potential and thus prompt availability, it is important to understand how MAPCs interact with immune cells to validate their widespread therapeutic applicability. Cytotoxic immune effector cells play a crucial role in immune homeostasis and in the pathogenesis of some autoimmune diseases. This study assessed for the first time the in vitro influence of a clinical-grade human MAPC product (MultiStem) on the cytotoxic function of CD8+ T cells (CTLs) by evaluating the immunogenicity of MAPCs and the susceptibility of MAPCs toward CTL mediated lysis and by analyzing the mechanism of MAPC-mediated modulation of CTL functionality. These results may represent a highly relevant contribution to the current knowledge and, in combination with the results of future phase II/III trials using MultiStem, could lead to an intriguing continuation of stem cell based research for immunotherapy. PMID- 27465072 TI - Translating Periosteum's Regenerative Power: Insights From Quantitative Analysis of Tissue Genesis With a Periosteum Substitute Implant. AB - : : An abundance of surgical studies during the past 2 centuries provide empirical evidence of periosteum's regenerative power for reconstructing tissues as diverse as trachea and bone. This study aimed to develop quantitative, efficacy-based measures, thereby providing translational guidelines for the use of periosteum to harness the body's own healing potential and generate target tissues. The current study quantitatively and qualitatively demonstrated tissue generation modulated by a periosteum substitute membrane that replicates the structural constituents of native periosteum (elastin, collagen, progenitor cells) and its barrier, extracellular, and cellular properties. It shows the potentiation of the periosteum's regenerative capacity through the progenitor cells that inhabit the tissue, biological factors intrinsic to the extracellular matrix of periosteum, and mechanobiological factors related to implant design and implementation. In contrast to the direct intramembranous bone generated in defects surrounded by patent periosteum in situ, tissue generation in bone defects bounded by the periosteum substitute implant occurred primarily via endochondral mechanisms whereby cartilage was first generated and then converted to bone. In addition, in defects treated with the periosteum substitute, tissue generation was highest along the major centroidal axis, which is most resistant to prevailing bending loads. Taken together, these data indicate the possibility of designing modular periosteum substitute implants that can be tuned for vectorial and spatiotemporal delivery of biological agents and facilitation of target tissue genesis for diverse surgical scenarios and regenerative medicine approaches. It also underscores the potential to develop physical therapy protocols to maximize tissue genesis via the implant's mechanoactive properties. SIGNIFICANCE: In the past 2 centuries, the periosteum, a niche for stem cells and super-smart biological material, has been used empirically in surgery to repair tissues as diverse as trachea and bone. In the past 25 years, the number of articles indexed in PubMed for the keywords "periosteum and tissue engineering" and "periosteum and regenerative medicine" has burgeoned. Yet the biggest limitation to the prescriptive use of periosteum is lack of easy access, giving impetus to the development of periosteum substitutes. Recent studies have opened up the possibility to bank periosteal tissues (e.g., from the femoral neck during routine resection for implantation of hip replacements). This study used an interdisciplinary, quantitative approach to assess tissue genesis in modular periosteum substitute implants, with the aim to provide translational strategies for regenerative medicine and tissue engineering. PMID- 27465074 TI - Biosynthetic engineering of nonribosomal peptide synthetases. AB - From the evolutionary melting pot of natural product synthetase genes, microorganisms elicit antibiotics, communication tools, and iron scavengers. Chemical biologists manipulate these genes to recreate similarly diverse and potent biological activities not on evolutionary time scales but within months. Enzyme engineering has progressed considerably in recent years and offers new screening, modelling, and design tools for natural product designers. Here, recent advances in enzyme engineering and their application to nonribosomal peptide synthetases are reviewed. Among the nonribosomal peptides that have been subjected to biosynthetic engineering are the antibiotics daptomycin, calcium dependent antibiotic, and gramicidin S. With these peptides, incorporation of unnatural building blocks and modulation of bioactivities via various structural modifications have been successfully demonstrated. Natural product engineering on the biosynthetic level is not a reliable method yet. However, progress in the understanding and manipulation of biosynthetic pathways may enable the routine production of optimized peptide drugs in the near future. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27465073 TI - Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells. AB - : : The establishment of an abundant source of autologous cardiac progenitor cells would represent a major advance toward eventual clinical translation of regenerative medicine strategies in children with prenatally diagnosed congenital heart disease. In support of this concept, we sought to examine whether functional, transgene-free human cardiomyocytes (CMs) with potential for patient specific and autologous applications could be reliably generated following routine amniocentesis. Under institutional review board approval, amniotic fluid specimens (8-10 ml) at 20 weeks gestation were expanded and reprogrammed toward pluripotency using nonintegrating Sendai virus (SeV) expressing OCT4, SOX2, cMYC, and KLF4. Following exposure of these induced pluripotent stem cells to cardiogenic differentiation conditions, spontaneously beating amniotic fluid derived cardiomyocytes (AF-CMs) were successfully generated with high efficiency. After 6 weeks, quantitative gene expression revealed a mixed population of differentiated atrial, ventricular, and nodal AF-CMs, as demonstrated by upregulation of multiple cardiac markers, including MYH6, MYL7, TNNT2, TTN, and HCN4, which were comparable to levels expressed by neonatal dermal fibroblast derived CM controls. AF-CMs had a normal karyotype and demonstrated loss of NANOG, OCT4, and the SeV transgene. Functional characterization of SIRPA+ AF-CMs showed a higher spontaneous beat frequency in comparison with dermal fibroblast controls but revealed normal calcium transients and appropriate chronotropic responses after beta-adrenergic agonist stimulation. Taken together, these data suggest that somatic cells present within human amniotic fluid can be used to generate a highly scalable source of functional, transgene-free, autologous CMs before a child is born. This approach may be ideally suited for patients with prenatally diagnosed cardiac anomalies. SIGNIFICANCE: This study presents transgene-free human amniotic fluid-derived cardiomyocytes (AF-CMs) for potential therapy in tissue engineering and regenerative medicine applications. Using 8-10 ml of amniotic fluid harvested at 20 weeks gestation from normal pregnancies, a mixed population of atrial, ventricular, and nodal AF-CMs were reliably generated after Sendai virus reprogramming toward pluripotency. Functional characterization of purified populations of beating AF-CMs revealed normal calcium transients and appropriate chronotropic responses after beta-adrenergic agonist stimulation in comparison with dermal fibroblast controls. Because AF-CMs can be generated in fewer than 16 weeks, this approach may be ideally suited for eventual clinical translation at birth in children with prenatally diagnosed cardiac anomalies. PMID- 27465075 TI - A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death. AB - BACKGROUND This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. CASE REPORT A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. CONCLUSIONS We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID- 27465076 TI - Delayed gastric emptying as a proposed mechanism of action during intragastric balloon therapy: Results of a prospective study. AB - OBJECTIVE: The effects of intragastric balloon (IGB) therapy on gastric emptying (GE) and weight loss remain to be fully understood. The effects of IGB on GE were investigated in this study. METHODS: This was a single-center, randomized, controlled study in which subjects with obesity either underwent IGB placement or were matched controls. IGB was removed at 6 months. GE was measured at baseline and at weeks 0, 8, 16, 27, and 39. Percent total body weight loss (%TBWL) was measured at 6 and 12 months. RESULTS: Twenty-nine subjects with obesity were enrolled; 15 were randomized to IGB placement and 14 to control. Two subjects had the IGB removed early. At baseline, 1- and 2-h gastric retention values were comparable between the groups but increased in the IGB group at weeks 8 and 16 (during IGB treatment) and then returned to baseline levels at 27 and 39 weeks. A greater increase in gastric retention from baseline to 8 weeks was associated with higher %TBWL. CONCLUSIONS: GE in subjects with IGB is delayed but returns to normal after IGB removal. Greater changes in increased gastric retention were associated with greater %TBWL. Altering gastric motility is a significant mechanism of action by which the IGB results in weight loss. PMID- 27465077 TI - Development and validation of a quantification method for oleanolic acid and hederagenin in rat plasma: application to the pharmacokinetic study. AB - A rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification of oleanolic acid and hederagenin in rat plasma. After the two analytes were extracted with liquid liquid extraction, chromatographic separation was performed on a C18 column with acetonitrile and water (85:15, v/v) as mobile phase at a flow rate of 0.4 mL/min. Calibration curves exhibited good linearity (r > 0.995) over the ranges of 0.41 82.0 ng/mL for oleanolic acid and 0.32-64.0 ng/mL for hederagenin, respectively. The lower limit of quantifications (LLOQs) in plasma were 0.41 ng/mL for oleanolic acid and 0.32 ng/mL for hederagenin. The established LLOQs were within the concentration needed for the assay in plasma, which met the requirements to evaluate their pharmacokinetics of oleanolic acid and hederagenin. This developed assay was successfully applied in the pharmacokinetic study of oleanolic acid and hederagenin in rats after oral administration of Rhizoma Clematidis extract. PMID- 27465078 TI - The oesophageal microbiome: an unexplored link in obesity-associated oesophageal adenocarcinoma. AB - The influence of diets rich in saturated fats and simple sugars on the intestinal microbiota plays a central role in obesity. Being overweight or obese predisposes individuals to several diseases including oesophageal adenocarcinoma (OAC), which develops through a cascade of events starting with gastro-oesophageal reflux disease, progressing to Barrett's oesophagus (BO), and then OAC. A range of mechanisms for the increased risk of OAC in obese individuals have been proposed; however, a role for the oesophageal microbiota has been largely ignored. This is despite the fact that it is clear that the composition of the oesophageal microbiota shifts with the development of OAC. Given the well-established impact that unhealthy diets have on the intestinal microbiota, it is plausible that exposure to unhealthy foods, and the ensuing obesity, would result in an imbalance in the oesophageal microbiota. It is also likely that these changes may mimic the changes observed in the intestinal microbiota (i.e. increase in short chain fatty acid (SCFA) producers and bile acid biosynthesis). The modulation of SCFAs and bile acids in the oesophagus by diet could promote the transdifferentiation from squamous to intestinal-like columnar cells observed in BO, given that intestinal cells proliferate in the presence of SCFAs. PMID- 27465079 TI - Diversity and succession of autotrophic microbial community in high-elevation soils along deglaciation chronosequence. AB - Global warming has resulted in substantial glacier retreats in high-elevation areas, exposing deglaciated soils to harsh environmental conditions. Autotrophic microbes are pioneering colonizers in the deglaciated soils and provide nutrients to the extreme ecosystem devoid of vegetation. However, autotrophic communities remain less studied in deglaciated soils. We explored the diversity and succession of the cbbL gene encoding the large subunit of form I RubisCO, a key CO2-fixing enzyme, using molecular methods in deglaciated soils along a 10-year deglaciation chronosequence on the Tibetan Plateau. Our results demonstrated that the abundance of all types of form I cbbL (IA/B, IC and ID) rapidly increased in young soils (0-2.5 years old) and kept stable in old soils. Soil total organic carbon (TOC) and total nitrogen (TN) gradually increased along the chronosequence and both demonstrated positive correlations with the abundance of bacteria and autotrophs, indicating that soil TOC and TN originated from autotrophs. Form IA/B autotrophs, affiliated with cyanobacteria, exhibited a substantially higher abundance than IC and ID. Cyanobacterial diversity and evenness increased in young soils (<6 years old) and then remained stable. Our findings suggest that cyabobacteria play an important role in accumulating TOC and TN in the deglaciated soils. PMID- 27465080 TI - Women in Medicine: Enormous Progress, Stubborn Challenges. PMID- 27465081 TI - Changing Laws Is Not Equal to Changing Minds: 22 Years of Women in Surgical Fields in Iran. PMID- 27465082 TI - Is Academic Medicine Sabotaging Its Own Diversity Efforts? PMID- 27465083 TI - On the Value of Coaching in Medicine. PMID- 27465084 TI - State Licensing Issues: Controversy and Compromise. PMID- 27465085 TI - MD-PhD Programs Should Encourage and Support Training in Nonbiomedical or Clinical Sciences. PMID- 27465086 TI - The Importance of Self-Forgiveness Training. PMID- 27465087 TI - Paving a New Path Towards Academic Medicine-A Novel Approach to Graduate Medical Education in the United States. PMID- 27465088 TI - For Medical Literature Expertise, Ask a Librarian. PMID- 27465089 TI - Artist's Statement: Thoughts on Illness and Identity. PMID- 27465090 TI - Commentary on The Healer. PMID- 27465091 TI - Coloring the Silence. PMID- 27465092 TI - Thoracic Paravertebral Block for Perioperative Analgesia in the Surgical Management of Left Ventricular Assist Device Infections. AB - Left ventricular assist device (LVAD) implantation is increasingly being used as a bridging therapy to heart transplantation. Infection is a major complication in patients with implanted LVADs, and it is associated with short- and long-term mortality. Surgical management for infection control is sometimes necessary; however, providing pain management during the surgical procedures is challenging. Anesthesiologists may be able to contribute to better pain management during surgical interventions to treat LVAD infections. We successfully performed a continuous thoracic paravertebral block (TPVB) for perioperative pain relief during invasive surgical procedures on three patients with infections of implanted LVADs. Despite several limitations that need to be addressed in the future, TPVB was able to relieve surgical pain in these patients without obvious complications. PMID- 27465093 TI - Surgical Treatment of Mediastinitis with Omentoplasty in Ventricular Assist Device Patients: Report of Referral Center Experience. AB - Mediastinitis is more frequent in patients with implantable ventricular assist devices (VADs) than in other cardiac surgery patients and carries significant mortality. We report our experience with a stepwise approach including aggressive debridement, jet lavage, vacuum assisted closure dressing, and finally coverage with well-vascularized and immune-active omental flaps in VAD patients with infective mediastinitis. We retrospectively collected and analyzed data of patients with continuous flow VAD who underwent plasty with the omental flap because of mediastinitis at Deutsches Herzzentrum Berlin between January 1, 2008 and October 30, 2015. Eight hundred forty-five patients underwent VAD implantation during the study period. Omentoplasty due to infective mediastinitis was performed in 17 cases. Nine had a HeartWare HVAD as left ventricular assist device (LVAD), three patients had two Heart-Ware HVAD as biventricular assist device (BIVAD), four had a HeartMate II LVAD device, and one patient had a Berlin Heart Incor LVAD. The microorganisms most frequently isolated from the sternal wound were Gram-positive Staphylococcus spp. Four cases of bleeding requiring surgical revision were recorded: three of intraabdominal and one of wound bleeding. Eight patients (47%) survived, whereas the other nine patients (53%) died. Sixteen (94%) required intensive care unit admission, and median hospital stay was 21 (1-182) days. Postoperative renal failure requiring dialysis and septic shock requiring vasopressors were associated with hospital mortality (p = 0.009 and p = 0.05, respectively). Early surgical treatment of mediastinitis after VAD implantation with omentoplasty is a valuable strategy in an otherwise dead-end situation. Bleeding should be meticulously controlled in these anticoagulated and fragile patients. PMID- 27465094 TI - High Levels of Residue within Polymeric Hollow Fiber Membranes Used for Blood Oxygenation. AB - A number of research teams are developing surface coatings for hollow fiber membrane (HFM) blood oxygenators to improve their biocompatibility and service life. Surface coating techniques can be quite sensitive to the presence of contaminants on the exterior surface of the hollow fibers. We found large amounts of leachable oils associated with several commercial HFMs, i.e., as much as 2.5 7.5 weight percent. Leachable residues were suspected when a surface coating, a surface-initiated atom transfer radical polymerization (s-ATRP) of poly(ethylene glycol) methacrylate, resulted in areas of 100 um devoid of coatings on the exterior surfaces of HFMs. After leaching residual oils, s-ATRP coatings were uniform and continuous across the hollow fibers. Therefore, removal of residual material should be considered before applying coating technologies to commercial HFMs. The effects of such leachable agents on the performance of blood oxygenators are not known. PMID- 27465095 TI - Single-Site Cannulation Venovenous Extracorporeal CO2 Removal as Bridge to Lung Volume Reduction Surgery in End-Stage Lung Emphysema. AB - Lung volume reduction surgery (LVRS) is an important treatment option for end stage lung emphysema in carefully selected patients. Here, we first describe the application of low-flow venovenous extracorporeal CO2 removal (LFVV-ECCO2R) as bridge to LVRS in patients with end-stage lung emphysema experiencing severe hypercapnia caused by acute failure of the breathing pump. Between March and October 2015, n = 4 patients received single-site LFVV-ECCO2R as bridge to LVRS. Indication for extracorporeal lung support was severe hypercapnia with respiratory acidosis and acute breathing pump failure. Two patients required continuous mechanical ventilation over a temporary tracheostomy and were bed ridden. The other two patients were nearly immobile because of severe dyspnea at rest. Length of preoperative ECCO2R was 14 (1-42) days. All patients underwent unilateral LVRS. Anatomical resection of the right (n = 3) or left (n = 1) upper lobe was performed. Postoperatively, both patients with previous mechanical ventilatory support were successfully weaned. ECCO2R in patients with end-stage lung emphysema experiencing severe hypercapnia caused by acute breathing pump failure is a safe and effective bridging tool to LVRS. In such patients, radical surgery leads to a significant improvement of the performance status and furthermore facilitates respiratory weaning from mechanical ventilation. PMID- 27465096 TI - Suspected Arterial Vasospasm in Femoro-Femoral Venoarterial Extracorporeal Life Support. AB - Extracorporeal life support (ECLS) is increasingly used worldwide in patients with life-threatening hemodynamic or respiratory conditions. The femoral venoarterial cannulation, whether percutaneous or surgical, is the simplest and quickest method; however, a number of vascular complications may occur. We present two cases in which, despite a well-placed reperfusion cannula in the superior femoral artery, apparent limb ischemia of the cannulated limb developed rapidly after ECLS implantation and was suspected to be caused by arterial vasospasm. Both cases were successfully managed with the injection of a vasodilator cocktail of verapamil, nitroglycerin, and lidocaine directly in the reperfusion cannula. PMID- 27465097 TI - Profound Accidental Hypothermia: Systematic Approach to Active Recognition and Treatment. AB - We sought to organize a functional system of recognition and advanced treatment of hypothermic patients with extracorporeal rewarming as a treatment option. All patients with suspected hypothermia are consulted with the hypothermia coordinator (HC), whose role is to provide expertise on hypothermia recognition and treatment to all rescue and medical services. Patients with Swiss staging system of hypothermia class III and IV are subjected to extracorporeal rewarming. Patients with class I and II are managed in local hospitals, after the HC provides instructions. From program initiation (July 29, 2013) to November 1, 2015, HC consulted 104 hypothermic patients; 21 in hypothermia class III and IV were subjected to extracorporeal rewarming in the John Paul II Hospital in Cracow, Poland. The remaining people were rewarmed in the referring hospitals. Cardiac arrest upon referral was present in 10 cases (resuscitation times from arrest to extracorporeal membrane oxygenation implantation ranged 107-345 minutes). Seven patients died, and the remaining 14 have been rewarmed with the restoration of hemodynamic stability. Systematic approach to active recognition and treatment of profound accidental hypothermia patients, on the basis of HC cooperation with emergency medical services, enables advanced management with good outcomes, especially in patients with cardiac arrest. PMID- 27465098 TI - Adverse Outcomes in Neonates and Children with Pulmonary Artery Hypertension Supported with ECMO. AB - Extracorporeal membrane oxygenation (ECMO) has been increasingly used to rescue neonates and children with cardiac or respiratory failure, and critical illnesses including pulmonary artery hypertension (PAH) unresponsive to conventional therapies. This study assesses mortality and outcomes in neonates and children with PAH supported with ECMO. Neonates and children from the 2012 Health Care Cost and Use Project Kids' Database were identified using ICD-9 codes. Children with congenital heart disease were excluded. Univariate logistic regression was applied to assess the relationship between ECMO and outcomes using matched cohorts for age, elective admission, and Elixhauser comorbidity score. We identified 9,355 neonates and children with PAH (0.15%). The incidence of ECMO was 1.4% (132/9,355). After propensity-matched analysis, 130 neonates and children were included in each group. The incidence of mortality was 39% in the group supported with ECMO and 8% in the control group (odds ratio [OR]: 6.98, 95% confidence interval [CI]: 3.43-14.21, p < 0.001). Neonates and children on ECMO had higher odds for acute kidney injury (OR: 2.41, 95% CI: 1.30-4.47, p = 0.005), neurologic complications (OR: 7.11, 95% CI: 1.57-32.18, p = 0.011), sepsis (OR: 2.69, 95% CI: 1.46-4.96, p = 0.002), and thrombotic complications (OR: 2.90, 95% CI: 1.10-7.67, p = 0.032). Neonates and children with PAH supported with ECMO have higher mortality rate and complications compared with matched controls with PAH. PMID- 27465099 TI - The risk of malignancy in ultrasound detected gallbladder polyps: A systematic review. AB - INTRODUCTION: Gallbladder polyps (GBPs) are a common incidental finding on ultrasound (US) examination. The malignant potential of GBPs is debated, and there is limited guidance on surveillance. This systematic review sought to assess the natural history of ultrasonographically diagnosed GBPs and their malignant potential. METHODS: The keywords: "Gallbladder" AND ("polyp" OR "polypoid lesion") were used to conduct a search in four reference libraries to identify studies which examined the natural history of GBPs diagnosed by US. Twelve studies were eligible for inclusion in this review. RESULTS: Of the 5482 GBPs reported, malignant GBPs had an incidence of just 0.57%. True GBPs had an incidence of 0.60%. Sixty four patients of adenomatous and malignant polyps were reported. Only in one patient was a malignant GBP reported to be <6mm. Risk factors associated with increased risk of malignancy were GBP >6mm, single GBPs, symptomatic GBPs, age >60 years, Indian ethnicity, gallstones and cholecystitis. CONCLUSION: With the reported incidence of GBP malignancy at just 0.57%, a management approach based on risk assessment, clear surveillance planning, and multi disciplinary team (MDT) discussion should be adopted. The utilization of endoscopic ultrasound(EUS) should be Only considered on the grounds of its greater sensitivity and specificity when compared to US scans. PMID- 27465100 TI - Quality of life in women of non-reproductive age with transvaginal mesh repair for pelvic organ prolapse: A cohort study. AB - BACKGROUND: Transvaginal mesh repair has been discredited due to high complications rates in the past years. Therefore, we evaluated the quality of life (QoL) and complication rates after transvaginal mesh (TVM) repair for pelvic organ prolapse (POP). METHODS: A total of 148 women who underwent TVM repair for symptomatic POP were retrospectively enrolled. Complication rates and functional outcomes were retrospectively assessed and validated, standardised questionnaires were used prospectively for evaluation of QoL. Univariate analysis by the chi(2) test as well as a multivariate Cox regression analysis was conducted to predict mesh exposure using various variables as predictors. RESULTS: Intraoperative complications with bowel or bladder injury appeared in 3.4%. Mesh exposure occurred in 2.7% whereas surgical revision was necessary only in 1.4%. No predictor for mesh exposure could be identified. Postoperative complications according to Clavien-Dindo classification >= III occurred in only 2.8%. An improvement of POP-symptoms was reported by 84.6% according the "patients' global impression of improvement" (PGI-I) and 88.2% women would repeat the surgery. The results of the "prolapse-quality of life"-questionnaire were comparable to asymptomatic women. Only 33% reported vaginal pain with a mean vaginal pain score of 0.6 according the international index of pain. Of sexually active women, 29% reported sexual impairments and mean score of sexual impairment was 1.52. CONCLUSION: Low complication rates and a quality of life comparable to asymptomatic women following TVM repair could be achieved in our cohort. However, a high number of sexual impairments was identified although the impact of impairment was marginal. PMID- 27465101 TI - Microsatellite alteration and immunohistochemical expression profile of chromosome 9p21 in patients with sporadic renal cell carcinoma following surgical resection. AB - BACKGROUND: Long-term prognostic significance of loss of heterozygosity on chromosome 9p21 for localized renal cell carcinoma following surgery remains unreported. The study assessed the frequency of deletions of different loci of chromosome 9p along with immunohistochemical profile of proteins in surgically resected renal cancer tissue and correlated this with long-term outcomes. METHODS: DNA was extracted from renal tumours and corresponding normal kidney tissues in prospectively collected samples of 108 patients who underwent surgical resection for clinically localized disease between January 2001 and December 2005, providing a minimum of 9 years follow-up for each participant. After checking quality of DNA, amplified by PCR, loss of heterozygosity (LOH) on chromosome 9p was assessed using 6 microsatellite markers in 77 clear cell carcinoma. Only 5 of the markers showed LOH (D9S1814, D9S916, D9S974, D9S942, and D9S171). Protein expression of p15(INK4b), p16(INK4a), p14(ARF), CAIX, and adipose related protein (ADFP) were demonstrated by immunostaining in normal and cancer tissues. Loss of heterozygosity for microsatellite analysis was correlated with tumour characteristics, recurrence free, cancer specific, and overall survival, including significance of immunohistochemical profile of protein expressions. RESULTS: The main deletion was found at loci telomeric to CDKN2A region at D9S916. There was a significant correlation between frequency of LOH stage (p = 0.005) and metastases (p = 0.006) suggesting a higher LOH for advanced and aggressive renal cell carcinoma. Most commonly observed LOH in the 3 markers: D9S916, D9S974, and D9S942 were associated with poor survival, and were statistically significant on multivariate analysis. Immunohistochemical expression of p14, p15, and p16 proteins were either low or absent in cancer tissue compared to normal. CONCLUSIONS: Loss of heterozygosity of p921 chromosome is associated with aggressive tumours, and predicts cancer specific or recurrence free survival on long-term follow-up. PMID- 27465103 TI - Association Between Kidney Cancer and Occupational Exposure to Trichloroethylene. AB - OBJECTIVE: This study investigates the association between occupational exposure to trichloroethylene (TCE) and kidney cancer, as this correlation has been questioned. METHODS: The incidence of cancers was studied in a dynamic cohort of 997 male workers who for many years had been occupationally exposed to TCE. RESULTS: During a 50-year observation period, 13 cases of kidney cancer were observed (7.5 expected) with a standardized incidence ratio of 1.7 and a 95% confidence interval of 1.0 to 3.0. Four other cases, not included in the SIR analysis, were also observed. Long-term TCE exposure was positively confirmed for 14 of the 17 incident cases. There is reason to assume that the remaining cases also had been exposed to TCE. CONCLUSIONS: The present study supports the view that TCE is a kidney carcinogen. PMID- 27465102 TI - Biomarkers of Human Cardiopulmonary Response After Short-Term Exposures to Medical Laser-Generated Particulate Matter From Simulated Procedures: A Pilot Study. AB - OBJECTIVE: We conducted an exposure chamber study in humans using a simulated clinical procedure lasing porcine tissue to demonstrate evidence of effects of exposure to laser-generated particulate matter (LGPM). METHODS: We measured pre- and post-exposure changes in exhaled nitric oxide (eNO), spirometry, heart rate variability (HRV), and blood markers of inflammation in five volunteers. RESULTS: Change in pre- and post-exposure measurements of eNO and spirometry was unremarkable. Neutrophil and lymphocyte counts increased and fibrinogen levels decreased in four of the five subjects. Measures of HRV showed decreases in the standard deviation of normal between beat intervals and sequential 5-minute intervals. CONCLUSION: These data represent the first evidence of human physiologic response to LGPM exposure. Further exploration of coagulation effects and HRV is warranted. PMID- 27465104 TI - Catalytic Hydroxylation of Benzene to Phenol by Dioxygen with an NADH Analogue. AB - Hydroxylation of benzene by molecular oxygen (O2 ) occurs efficiently with 10 methyl-9,10-dihydroacridine (AcrH2 ) as an NADH analogue in the presence of a catalytic amount of Fe(ClO4 )3 or Fe(ClO4 )2 with excess trifluoroacetic acid in a solvent mixture of benzene and acetonitrile (1:1 v/v) to produce phenol, 10 methylacridinium ion and hydrogen peroxide (H2 O2 ) at 298 K. The catalytic oxidation of benzene by O2 with AcrH2 in the presence of a catalytic amount of Fe(ClO4 )3 is started by the formation of H2 O2 from AcrH2 , O2 , and H(+) . Hydroperoxyl radical (HO2 (.) ) is produced from H2 O2 with the redox pair of Fe(3+) /Fe(2+) by a Fenton type reaction. The rate-determining step in the initiation is the proton-coupled electron transfer from Fe(2+) to H2 O2 to produce HO(.) and H2 O. HO(.) abstracts hydrogen rapidly from H2 O2 to produce HO2 (.) and H2 O. The Fe(3+) produced was reduced back to Fe(2+) by H2 O2 . HO2 (.) reacts with benzene to produce the radical adduct, which abstracts hydrogen from AcrH2 to give the corresponding hydroperoxide, accompanied by generation of acridinyl radical (AcrH(.) ) to constitute the radical chain reaction. Hydroperoxyl radical (HO2 (.) ), which was detected by using the spin trap method with EPR analysis, acts as a chain carrier for the two radical chain pathways: one is the benzene hydroxylation with O2 and the second is oxidation of an NADH analogue with O2 to produce H2 O2 . PMID- 27465106 TI - Energy cost of intracellular metal and metalloid detoxification in wild-type eukaryotic phytoplankton. AB - Microalgae use various cellular mechanisms to detoxify both non-essential and excess essential metals or metalloids. There exists however, a threshold in intracellular metal(loid) concentrations beyond which detoxification mechanisms are no longer effective and inhibition of cell division inevitably occurs. It is therefore important to determine whether the availability of energy in the cell could constrain metal(loid) detoxification capacity and to better define the thresholds beyond which a metal(loid) becomes toxic. To do this we performed the first extensive bioenergetics analysis of intracellular metal(loid) detoxification mechanisms (e.g., metal-binding peptides, polyphosphate granules, metal efflux, metal and metalloid reduction, metalloid methylation, enzymatic and non-enzymatic antioxidants) in wild-type eukaryotic phytoplankton based on the biochemical mechanisms of each detoxification strategy and on experimental measurements of detoxifying biomolecules in the literature. The results show that at the onset of metal(loid) toxicity to growth, all the detoxification strategies considered required only a small fraction of the total cellular energy available for growth indicating that intracellular detoxification ability in wild-type eukaryotic phytoplankton species is not constrained by the availability of cellular energy. The present study brings new insights into metal(loid) toxicity mechanisms and detoxification strategies in wild-type eukaryotic phytoplankton. PMID- 27465105 TI - Prospective clinical trial of Intravitreal aflibercept treatment for PolypoIdal choroidal vasculopathy with hemorrhage or exudation (EPIC study): 6 month results. AB - BACKGROUND: Polypoidal choroidal vasculopathy is a variant of choroidal neovascularization and neovascular age related macular degeneration presenting with hemorrhagic and exudative changes within the macula and/or peripapillary region leading to vision loss. In contrast to neovascular age related macular degeneration, polypoidal choroidal vasculopathy has differing clinical manifestations and treatment strategies. Historically, polypoidal choroidal vasculopathy complexes are less responsive to anti-vascular endothelial growth factor therapy with no prospective clinical trials evaluating aflibercept in management of polypoidal choroidal vasculopathy. Herein we prospectively evaluate the efficacy and safety of intravitreal aflibercept in polypoidal choroidal vasculopathy. METHODS: A prospective, open-label, investigator-sponsored trial of intravitreal aflibercept for polypoidal choroidal vasculopathy in 21 eyes was conducted. Injections were administered monthly for 3 initial treatments, then every other month with monthly evaluations. The primary outcome measures were the mean change in best corrected visual acuity and adverse events. Secondary outcome measures included stabilization of vision, presence of subretinal hemorrhage, serous detachment, retinal pigment epithelial detachment, and regression of polypoidal complexes on indocyanine green angiography. RESULTS: At 6 months, the median visual acuity was 20/40 (range 20/25-20/200) with a mean Early Treatment Diabetic Retinopathy Study vision of 68.4 letters. There was a gain of 2.76 Early Treatment Diabetic Retinopathy Study letters at 6 months (p = 0.15). No patient developed severe vision loss (<=15 letters) and vision was stable or improved in 19/21 eyes (91 %). Subretinal fluid resolved in 13/18 eyes (72 %), and subretinal hemorrhage resolved in 6/8 eyes (75 %) respectively. The polyps regressed in 14/21 eyes (67 %) and the branching vascular network decreased in 1 eye and was stable in all other eyes. The retinal pigment epithelial detachment improved in 13/15 eyes (87 %). Bimonthly treatment occurred in 15/21 patients (71 %). There were no adverse events. CONCLUSIONS: Intravitreal aflibercept results in stabilization of vision, resolution of exudative and hemorrhagic complications with regression of polyps in polypoidal choroidal vasculopathy. Eyes with polypoidal choroidal vasculopathy previously treated with ranibizumab and bevacizumab can show marked improvement in the retinal pigment epithelial detachments and persistent polyps with aflibercept therapy. TRIAL REGISTRATION: Clinical trials.gov NCT01871376 , June 4(th) 2013. PMID- 27465107 TI - Light-induced negative differential resistance in graphene/Si-quantum-dot tunneling diodes. AB - One of the interesing tunneling phenomena is negative differential resistance (NDR), the basic principle of resonant-tunneling diodes. NDR has been utilized in various semiconductor devices such as frequency multipliers, oscillators, relfection amplifiers, logic switches, and memories. The NDR in graphene has been also reported theoretically as well as experimentally, but should be further studied to fully understand its mechanism, useful for practical device applications. Especially, there has been no observation about light-induced NDR (LNDR) in graphene-related structures despite very few reports on the LNDR in GaAs-based heterostructures. Here, we report first observation of LNDR in graphene/Si quantum dots-embedded SiO2 (SQDs:SiO2) multilayers (MLs) tunneling diodes. The LNDR strongly depends on temperature (T) as well as on SQD size, and the T dependence is consistent with photocurrent (PC)-decay behaviors. With increasing light power, the PC-voltage curves are more structured with peak-to valley ratios over 2 at room temperature. The physical mechanism of the LNDR, governed by resonant tunneling of charge carriers through the minibands formed across the graphene/SQDs:SiO2 MLs and by their nonresonant phonon-assisted tunneling, is discussed based on theoretical considerations. PMID- 27465108 TI - Stability Indicating Determination of Human Growth Hormone by Novel SE-LC Method. AB - A selective, rapid size-exclusion chromatographic method was developed and validated for the separation of the human growth hormone (hGH) somatropin from its high-molecular-weight aggregates. Separation was achieved using a nontoxic mobile phase compared with the official method of the European Pharmacopoeia that uses 2-propanol in a mobile phase. The developed method used a YMC-Pack Diol (YMC Karasuma, Kyoto, Japan; 300 * 8.0 mm, 5 MUm) analytical column. The mobile phase was formed with a pH 7phosphate buffer that was pumped at a flow rate of 1 mL/min with UV detection at 214 nm. The overall run time was 20 min and the average retention times were found to be 10.21 min for the monomer peak, 9.52 min for the dimer peak, and 9.14 min for the higher aggregate. This method was validated in terms of selectivity, linearity, and intra- and interday variations according to the International Conference on Harmonization guidelines. The developed method was applied as a rapid tool for evaluating the stability of stressed samples of hGH subjected to different temperature, agitation, and repeated freeze-thaw cycles. The developed method was successfully applied for the assessment of the quality and quantity of hGH during downstream processing, formulation, and storage. PMID- 27465109 TI - The effect of volatile oil mixtures on the performance and ilio-caecal microflora of broiler chickens. AB - The aim of this study was to investigate the individual and combined effects of rosemary, oregano and fennel volatile oil (FVO) supplementation on the performance and ilio-caecal bacteriological flora of broiler chickens. A total of 800 male Ross-308 broiler chickens were divided equally into 8 groups; each contained 100 chickens. The study included a control treatment (NC) with no dietary additives that was supplemented with oils according to the following 7 treatments: 200 mg alpha-tocopherol acetate/kg (PC), 100 mg oregano volatile oil (OVO)/kg, 100 mg rosemary volatile oil (RVO)/kg, 100 mg FVO/kg and an equal mixture of oregano+rosemary+fennel VO (100, 200, 400 mg/kg, VOM-1, VOM-2 and VOM 3, respectively). The experiment lasted for 6 weeks. At the end of the experiment, dietary supplementation with alpha-tocopherol, oregano, rosemary and FVO and two different volatile oil mixtures (VOMs) (VOM-2; VOM-3) significantly increased the body weights (BWs) of broilers at 7, 14 and 21 d of age compared to the negative control (NC) (-) and VOM-1 groups. At 0-42 d, birds fed on VOM-3 were considerably heavier and also gained more weight than NC (-) and VOM-1 groups. The blend of VOs at 400 mg/kg significantly increased Lactobacillus spp. in faeces. The blends of oregano, rosemary and FVOs (VOM-3) at 400 mg/kg concentration and also VOM-3 group exhibited stronger antibacterial activity against coliform bacteria compared to the NC (-) group. In conclusion, the blend of oregano, rosemary and fennel VOs at higher concentrations (400 mg/kg concentration) in diets can be used to stimulate the growth and can improve the intestinal microbial balance (including a reduction of coliform bacteria and an increase in Lactobacillus spp. counts) of broiler chickens. PMID- 27465110 TI - Gender at the intersection with race and class in the schooling and wellbeing of immigrant-origin students. AB - BACKGROUND: In French-language secondary schools in Quebec, among all immigrant origin students, those originating from South Asia have the highest dropout rate. However, girls belonging to this group consistently outperform their male peers of similar ethnic background. This stirs questions about the reasons for this relative outperformance and its linkage with overall wellbeing among these girls. METHODS: A mixed methods approach guided data collection. It involved in-depth interviews with female and male students of South Asian origin (n = 19) and with individuals holding educational roles in the lives of youth (n = 25). An additional anonymous questionnaire aggregated parent perspectives (n = 36), though this article focuses primarily on qualitative lessons. RESULTS: This article shows three main reasons for why South Asian female adolescents in Quebec French-language secondary schools outperform their male counterparts in schooling attainment: parental expectations after migration, socialization at home, and relationships at school. According to our findings, academic perseverance among these girls does not necessarily translate into their improved wellbeing or their involvement in an advantageous process of acculturation. CONCLUSIONS: This study highlights that although gender, ethnicity, and class can create an interlocking system of oppression in certain social spheres for a specific group of women, it can emerge as advantageous in other contexts for the same group. This provides educational policy makers, as well as school and community workers, with guidance and avenues for action that can promote the wellbeing of immigrant-origin girls through involvement in beneficial processes of acculturation aligned with their improved academic performance. PMID- 27465111 TI - Proteomic analysis highlights the role of detoxification pathways in increased tolerance to Huanglongbing disease. AB - BACKGROUND: Huanglongbing (HLB) disease is still the greatest threat to citriculture worldwide. Although there is not any resistance source in the Citrus germplasm, a certain level of moderated tolerance is present. A large-scale analysis of proteomic responses of Citrus may help: 1) clarifying physiological and molecular effects of disease progression, 2) validating previous data at transcriptomic level, and 3) identifying biomarkers for development of early diagnostics, short-term therapeutics and long-term genetic resistance. RESULTS: In this work we have conducted a proteomic analysis of mature leaves of two Citrus genotypes with well-known differing tolerances to HLB: Navel orange (highly susceptible) and Volkameriana (moderately tolerant). Pathway enrichment analysis showed that amino acid degradation processes occurred to a larger degree in the Navel orange. No clear differences between the two genotypes were observed for primary metabolic pathways. The most important finding was that four glutathione-S-transferases were upregulated in Volkameriana and not in Navel orange. These proteins are involved in radical ion detoxification. CONCLUSIONS: Upregulation of proteins involved in radical ion detoxification should be considered as an important mechanism of increased tolerance to HLB. PMID- 27465112 TI - The Effect of Total Household Decolonization on Clearance of Colonization With Methicillin-Resistant Staphylococcus aureus. AB - OBJECTIVE To determine the impact of total household decolonization with intranasal mupirocin and chlorhexidine gluconate body wash on recurrent methicillin-resistant Staphylococcus aureus (MRSA) infection among subjects with MRSA skin and soft-tissue infection. DESIGN Three-arm nonmasked randomized controlled trial. SETTING Five academic medical centers in Southeastern Pennsylvania. PARTICIPANTS Adults and children presenting to ambulatory care settings with community-onset MRSA skin and soft-tissue infection (ie, index cases) and their household members. INTERVENTION Enrolled households were randomized to 1 of 3 intervention groups: (1) education on routine hygiene measures, (2) education plus decolonization without reminders (intranasal mupirocin ointment twice daily for 7 days and chlorhexidine gluconate on the first and last day), or (3) education plus decolonization with reminders, where subjects received daily telephone call or text message reminders. MAIN OUTCOME MEASURES Owing to small numbers of recurrent infections, this analysis focused on time to clearance of colonization in the index case. RESULTS Of 223 households, 73 were randomized to education-only, 76 to decolonization without reminders, 74 to decolonization with reminders. There was no significant difference in time to clearance of colonization between the education-only and decolonization groups (log-rank P=.768). In secondary analyses, compliance with decolonization was associated with decreased time to clearance (P=.018). CONCLUSIONS Total household decolonization did not result in decreased time to clearance of MRSA colonization among adults and children with MRSA skin and soft-tissue infection. However, subjects who were compliant with the protocol had more rapid clearance Trial registration. ClinicalTrials.gov identifier: NCT00966446 Infect Control Hosp Epidemiol 2016;1-8. PMID- 27465113 TI - Using Simulation to Model and Validate Invasive Breast Cancer Progression in Women in the Study and Control Groups of the Canadian National Breast Screening Studies I and II. AB - BACKGROUND: Modeling breast cancer progression and the effect of various risk is helpful in deciding when a woman should start and end screening, and how often the screening should be undertaken. METHODS: We modeled the natural progression of breast cancer using a hidden Markov process, and incorporated the effects of covariates. Patients are women aged 50-59 (older) and 40-49 (younger) years from the Canadian National Breast Screening Studies. We included prevalent cancers, estimated the screening sensitivities and rates of over-diagnosis, and validated the models using simulation. RESULTS: We found that older women have a higher rate of transition from a healthy to preclinical state and other causes of death but a lower rate of transition from preclinical to clinical state. Reciprocally, younger women have a lower rate of transition from a healthy to preclinical state and other causes of death but a higher rate of transition from a preclinical to clinical state. Different risk factors were significant for the age groups. The mean sojourn times for older and younger women were 2.53 and 2.96 years, respectively. In the study group, the sensitivities of the initial physical examination and mammography for older and younger women were 0.87 and 0.81, respectively, and the sensitivity of the subsequent screens were 0.78 and 0.53, respectively. In the control groups, the sensitivities of the initial physical examination for older and younger women were 0.769 and 0.671, respectively, and the sensitivity of the subsequent physical examinations for the control group aged 50-59 years was 0.37. The upper-bounds for over-diagnosis in older and younger women were 25% and 27%, respectively. CONCLUSIONS: The present work offers a basis for the better modeling of cancer incidence for a population with the inclusion of prevalent cancers. PMID- 27465115 TI - Erratum to: Transmission of alpha-synucleinopathy from olfactory structures deep into the temporal lobe. PMID- 27465114 TI - Codon Optimization to Enhance Expression Yields Insights into Chloroplast Translation. AB - Codon optimization based on psbA genes from 133 plant species eliminated 105 (human clotting factor VIII heavy chain [FVIII HC]) and 59 (polio VIRAL CAPSID PROTEIN1 [VP1]) rare codons; replacement with only the most highly preferred codons decreased transgene expression (77- to 111-fold) when compared with the codon usage hierarchy of the psbA genes. Targeted proteomic quantification by parallel reaction monitoring analysis showed 4.9- to 7.1-fold or 22.5- to 28.1 fold increase in FVIII or VP1 codon-optimized genes when normalized with stable isotope-labeled standard peptides (or housekeeping protein peptides), but quantitation using western blots showed 6.3- to 8-fold or 91- to 125-fold increase of transgene expression from the same batch of materials, due to limitations in quantitative protein transfer, denaturation, solubility, or stability. Parallel reaction monitoring, to our knowledge validated here for the first time for in planta quantitation of biopharmaceuticals, is especially useful for insoluble or multimeric proteins required for oral drug delivery. Northern blots confirmed that the increase of codon-optimized protein synthesis is at the translational level rather than any impact on transcript abundance. Ribosome footprints did not increase proportionately with VP1 translation or even decreased after FVIII codon optimization but is useful in diagnosing additional rate-limiting steps. A major ribosome pause at CTC leucine codons in the native gene of FVIII HC was eliminated upon codon optimization. Ribosome stalls observed at clusters of serine codons in the codon-optimized VP1 gene provide an opportunity for further optimization. In addition to increasing our understanding of chloroplast translation, these new tools should help to advance this concept toward human clinical studies. PMID- 27465116 TI - Physical activity, body composition and lipids changes in adolescents: analysis from the MyHeART Study. AB - Insufficient physical activity and growing obesity levels among Malaysian adolescents are becoming a public health concern. Our study is to identify the trends of self-reported physical activity (PA) levels, blood lipid profiles, and body composition (BC) indices from a cohort of 820 adolescents. The self-reported PA was assessed using a validated Malay version of the PA Questionnaire for Older Children (PAQ-C). Fasting blood samples were collected to investigate their lipid profiles. Height, weight, waist and hip circumferences as well as body fat percentage were measured. The baseline and the first follow-up were conducted in 2012 and 2014, respectively. A downward trend in the PA level was seen in all categories with a significant reduction among all rural adolescents (P = 0.013) and more specifically, PA among girls residing in rural areas dropped significantly (P = 0.006). Either a significant reduction in high-density lipoprotein (HDL) or a significant increment in BC indices (i.e., body mass index [BMI], waist circumference [WC], hip circumference, and body fat percentage [BF %]) were seen in this group. Female adolescents experienced more body fat increment with the reduction of physical activity. If not intervened early, adolescents from rural areas may increase their risk of developing cardiovascular diseases earlier. PMID- 27465118 TI - [Use of GnRH antagonists versus agonists]. PMID- 27465117 TI - Construction of co-expression network based on natural expression variation of xylogenesis-related transcripts in Eucalyptus tereticornis. AB - Natural genetic variation is randomly distributed and gene expression patterns vary widely in natural populations. These variations are an effect of multifactorial genetic perturbations resulting in different phenotypes. Genome wide analysis can be used to comprehend the genetic basis governing this naturally occurring developmental variation. Secondary growth is a highly complex trait and systems genetics models are presently being applied to understand the molecular architecture of wood formation. In the present study, the natural variation in expression patterns of 18,987 transcripts expressed in the developing xylem tissues were documented across four phenotypes of Eucalyptus tereticornis with distinct holocellulose/klason lignin content. The differentially expressed genes across all the phenotypes were used to construct co-expression networks and sub-network 2 with 380 nodes and 17,711 edges was determined as the network of relevance, including 30 major cell wall biogenesis related transcripts with 2394 interactions and 10 families of transcription factors with 3360 interactions. EYE [EMBRYO YELLOW] was identified as major hub transcript with 173 degrees which interacted with known cell wall biogenesis genes. K-mean clustering was also performed for differentially expressed transcripts and two clusters discriminated the phenotypes based on their holocellulose/klason lignin content. The cluster based networks were enriched with GOs related to cell wall biogenesis and sugar metabolism. The networks developed in the present study enabled identification of critical regulators and novel transcripts whose expression variation could presumably govern the phenotypic variation in wood properties across E. tereticornis. PMID- 27465119 TI - [Interventions to enhance return-to-work for cancer patients]. PMID- 27465120 TI - Performance of a Heating Block System Designed for Studying the Heat Resistance of Bacteria in Foods. AB - Knowledge of bacteria's heat resistance is essential for developing effective thermal treatments. Choosing an appropriate test method is important to accurately determine bacteria's heat resistances. Although being a major factor to influence the thermo-tolerance of bacteria, the heating rate in samples cannot be controlled in water or oil bath methods due to main dependence on sample's thermal properties. A heating block system (HBS) was designed to regulate the heating rates in liquid, semi-solid and solid foods using a temperature controller. Distilled water, apple juice, mashed potato, almond powder and beef were selected to evaluate the HBS's performance by experiment and computer simulation. The results showed that the heating rates of 1, 5 and 10 degrees C/min with final set-point temperatures and holding times could be easily and precisely achieved in five selected food materials. A good agreement in sample central temperature profiles was obtained under various heating rates between experiment and simulation. The experimental and simulated results showed that the HBS could provide a sufficiently uniform heating environment in food samples. The effect of heating rate on bacterial thermal resistance was evaluated with the HBS. The system may hold potential applications for rapid and accurate assessments of bacteria's thermo-tolerances. PMID- 27465121 TI - Industrial action by healthcare workers in Nigeria in 2013-2015: an inquiry into causes, consequences and control-a cross-sectional descriptive study. AB - BACKGROUND: Nigeria has suffered from several healthcare workers' strikes in the past 36 months, involving all categories of health workers. Frequent healthcare workers' strikes result in the closure of public healthcare institutions preventing Nigerians' access to quality health services. The purpose of this study was to identify the root cause(s) of strikes by healthcare workers, their effects on the health system and possible solutions to prevent, or at least reduce, industrial action. METHODS: A cross-sectional descriptive survey was used to execute this study between February and March 2015. A self-administered questionnaire with both closed- and open-ended questions was used for this study. Data were analysed using EpiDataTM and SPSS 21. Simple frequencies and chi-square analysis were carried out. RESULTS: A total of 150 healthcare workers participated in the study. Sixty-two (41.3 %) participants were males, 86 (57.3 %) married, 90 (60.0 %) Christians and 119 (79.3 %) graduates, and about half of the participants earn less than N129 000.00 (US$ 737.00) per month. Less than half of the participants (43.6 %) supported industrial actions. Poor healthcare leadership and management were cited as the most common (92 %), as well as the most important (43.3 %), cause of healthcare worker strikes in Nigeria. Other causes cited were a demand for higher salaries and wages (82 %), infrastructural issues (63.3 %) and inter-personal issues (61.3 %). Only 2.0 % rated current healthcare management as excellent, while 24.0 % rated it as very good. Several strategies were cited towards improving healthcare management. CONCLUSIONS: The findings of this study differ from previous studies that identified demand for increased salaries and wages as the most common cause of healthcare workers' strikes in Nigeria. Identified causes of these continued strikes, especially inadequate healthcare leadership/management, must be tackled in order to eliminate industrial action by healthcare workers. Training doctors in health management and leadership towards building skilled physician leaders is a strategy that is long overdue in Nigeria. PMID- 27465122 TI - Post-mortem magnetic resonance foetal imaging: a study of morphological correlation with conventional autopsy and histopathological findings. AB - The aim of the present study is to offer our experience concerning post-mortem magnetic resonance (PMMR) in foetal death cases and an evaluation of the differences between the findings acquired by PMMR and by forensic autopsy. Fifteen foetuses were recruited from July 2014 to December 2015. These had suffered intrauterine death in women in the 21st to 38th week of gestation who were treated in the emergency department for non-perception of foetal movements. We performed a PMMR on foetuses, 3 +/- 1 days on average from the time of death, and then a complete forensic autopsy was performed. All 15 foetuses were examined with a whole-body study protocol, starting from the skull, down to and including the lower limbs. The total time of examination ranged from 20 to 30 min in each case. The external evaluation and description of post-mortem phenomena (maceration), record of the weight and detection and the various measurements of foetal diameters were evaluated before performing autopsy. A complete histopathological study was performed in each case. Out of 15 cases examined, eight were negative for structural anatomical abnormalities and/or diseases, both in the preliminary radiological examination and the traditional autopsy. In the remaining seven cases, pathological findings were detected by PMMR with corresponding results at autopsy. PMMR can provide useful information on foetal medical conditions and result in improved diagnostic classification. It may enable the planning of a more suitable technique before proceeding to autopsy, including focusing on certain aspects of organ pathology otherwise not detectable. The association between PMMR, post-mortem examination and related histological study of the foetus-placenta unit could help reduce the percentage of cases in which the cause of foetal death remains unexplained. Lastly, it may allow a selective sampling of the organ in order to target histological investigations. PMID- 27465123 TI - Nanometric emulsions encapsulating solid particles as alternative carriers for intracellular delivery. AB - AIM: Formulate nanometric oil droplets for encapsulating solid nanoparticles and assess their interactions with cells. MATERIALS & METHODS: Soybean oil droplets, stabilized by Pluronic F68 surfactant, incorporating hydrophobically modified fluorescent silica, nanoparticles were obtained. Cytotoxicity over time, internalization, subsequent intracellular localization and internalization pathways were assessed by microscopy (fluoresence and TEM) in vitro with HeLa cells. RESULTS: Oil droplets encapsulating solid nanoparticles are readily internalized by HeLa cells like free nanoparticles but the intracellular localization differs (nanoemulsions less colocalized with lysosomes) as well as internalization pathway is used (nanoemulsions partially internalized by nonendocytic transport). No cytotoxicity could be observed for either particles tested. CONCLUSION: Our results confirm that nanometric emulsions encapsulating solid nanoparticles can be used for alternative and multifunctional intracellular delivery. PMID- 27465124 TI - From Cluster to Polymer: Ligand Cone Angle Controlled Syntheses and Structures of Copper(I) Alkynyl Complexes. AB - Copper(I) alkynyl complexes have attracted tremendous attention in structural studies, as luminescent materials, and in catalysis, and homoleptic complexes have been reported to form polymers or large clusters. Herein, six unprecedented structures of Cu(I) alkynyl complexes and a procedure to measure the cone angles of alkynyl ligands based on the crystal structures of these complexes are reported. An increase of the alkynyl cone angle in the complexes leads to a modulation of the structures from polymeric [((PhC=CC=C)Cu)2 (NH3 )]infinity , to a large cluster [(TripC=CC=C)Cu]20 (MeCN)4 , to a relatively small cluster [(TripC=C)Cu]8 (Trip=2,4,6-iPr3 -C6 H2 ). The complexes exhibit yellow-to-red phosphorescence at ambient temperature in the solid state and the luminescence behavior of the Cu20 cluster is sensitive to acetonitrile. PMID- 27465125 TI - Association between glycemic variability and peripheral nerve dysfunction in type 1 diabetes. AB - INTRODUCTION: Glycemic variability (GV) may be a novel factor in the pathogenesis of diabetic complications. However, the effect of GV on peripheral nerve function has not been explored systematically. METHODS: The relationship between GV and acute glucose levels on motor and sensory nerve function in 17 patients with type 1 diabetes mellitus (T1DM) was assessed using continuous glucose monitoring and nerve excitability techniques to provide insight into the behavior of axonal voltage-gated ion channels. The mean amplitude of glycemic excursions (MAGE) was calculated to quantify GV. RESULTS: MAGE strongly correlated with excitability markers of altered motor and sensory axonal function, including superexcitability (r = 0.54), S2 accommodation (r = -0.76), minimum current threshold (I/V) slope (r = 0.71), strength duration time constant (r = 0.66), and latency (r = 0.65; P < 0.05). Acute glucose levels did not correlate with markers of axonal function. CONCLUSIONS: These findings suggest that GV may be an important mediator of axonal dysfunction in T1DM and a contributing factor in development of diabetic neuropathy. Muscle Nerve, 2016 Muscle Nerve 54: 967-969, 2016. PMID- 27465127 TI - Two-dimensional chiral topological superconductivity in Shiba lattices. AB - The chiral p-wave superconductor is the archetypal example of a state of matter that supports non-Abelian anyons, a highly desired type of exotic quasiparticle. With this, it is foundational for the distant goal of building a topological quantum computer. While some candidate materials for bulk chiral superconductors exist, they are subject of an ongoing debate about their actual paring state. Here we propose an alternative route to chiral superconductivity, consisting of the surface of an ordinary superconductor decorated with a two-dimensional lattice of magnetic impurities. We furthermore identify a promising experimental platform to realize this proposal. PMID- 27465126 TI - Carbohydrate supplementation stabilises plasma sodium during training with high intensity. AB - BACKGROUND: Investigations of the effect of beverages containing carbohydrates, only, on the sodium and fluid balance during intermittent exercise of high intensity are rare. Therefore, we compared the effects of water and carbohydrate supplementation on plasma, blood volume, and electrolyte shifts during intermittent exercise. METHODS: Ten male subjects performed an intermittent exercise test twice. In one trial, tap water (4 ml/kg/15 min) was consumed (Plac trial). In the other trial, the same amount of water supplemented with maltodextrin to achieve a 9.1 % carbohydrate solution (CHO trial) was ingested. Training schedule: warm-up at 50 % for 15 min. Afterwards, power changed between 100 % of the maximum power from a previous incremental test minus 10 and 10 W for each 30 s. Venous blood was sampled to measure electrolytes, osmolality, [protein], hct, [Lactate], [glucose], [Hb] and catecholamines. Hydration status was evaluated by BIA before and after exercise. RESULTS: After beverage ingestion [glucose] was significantly higher in CHO until the end of the trial. Starting with similar resting values, osmolality increased significantly more during CHO (p = 0.002). PV decreased by 5 % under both conditions, but recovered partly during exercise under Plac (p = 0.002). [Na+] and [Cl(-)] decreased with Plac during exercise (both p < 0.001) but remained constant during exercise with CHO. CONCLUSIONS: Sole carbohydrate supplementation seems to stabilise plasma [Na+]. This cannot be explained simply by a cotransport of glucose and [Na+], because that should lead to a recovery of the blood and plasma volume under CHO. In contrast, this was found during exercise with Plac. PMID- 27465128 TI - ? PMID- 27465129 TI - Image analysis procedure for studying Back-Diffusion phenomena from low permeability layers in laboratory tests. AB - In this study, the long-term tailing derived from the storage process of contaminants in low-permeability zones is investigated. The release from these areas in the groundwater can be considered a long-term source that often undermines remediation efforts. An Image Analysis technique is used to analyze the process and evaluate the concentrations of a tracer at different points of the test section. Furthermore, the diffusive flux from the low-permeability lenses is determined. To validate the proposed technique, the results are compared with samples, and the diffusive fluxes resulting from the low permeability zones of the reconstructed aquifer are compared with a theoretical approach. PMID- 27465130 TI - NTTMUNSW BioC modules for recognizing and normalizing species and gene/protein mentions. AB - In recent years, the number of published biomedical articles has increased as researchers have focused on biological domains to investigate the functions of biological objects, such as genes and proteins. However, the ambiguous nature of genes and their products have rendered the literature more complex for readers and curators of molecular interaction databases. To address this challenge, a normalization technique that can link variants of biological objects to a single, standardized form was applied. In this work, we developed a species normalization module, which recognizes species names and normalizes them to NCBI Taxonomy IDs. Unlike most previous work, which ignored the prefix of a gene name that represents an abbreviation of the species name to which the gene belongs, the recognition results of our module include the prefixed species. The developed species normalization module achieved an overall F-score of 0.954 on an instance level species normalization corpus. For gene normalization, two separate modules were respectively employed to recognize gene mentions and normalize those mentions to their Entrez Gene IDs by utilizing a multistage normalization algorithm developed for processing full-text articles. All of the developed modules are BioC-compatible .NET framework libraries and are publicly available from the NuGet gallery.Database URL: https://sites.google.com/site/hjdairesearch/Projects/isn-corpus. PMID- 27465131 TI - PvTFDB: a Phaseolus vulgaris transcription factors database for expediting functional genomics in legumes. AB - The common bean [Phaseolus vulgaris (L.)] is one of the essential proteinaceous vegetables grown in developing countries. However, its production is challenged by low yields caused by numerous biotic and abiotic stress conditions. Regulatory transcription factors (TFs) symbolize a key component of the genome and are the most significant targets for producing stress tolerant crop and hence functional genomic studies of these TFs are important. Therefore, here we have constructed a web-accessible TFs database for P. vulgaris, called PvTFDB, which contains 2370 putative TF gene models in 49 TF families. This database provides a comprehensive information for each of the identified TF that includes sequence data, functional annotation, SSRs with their primer sets, protein physical properties, chromosomal location, phylogeny, tissue-specific gene expression data, orthologues, cis regulatory elements and gene ontology (GO) assignment. Altogether, this information would be used in expediting the functional genomic studies of a specific TF(s) of interest. The objectives of this database are to understand functional genomics study of common bean TFs and recognize the regulatory mechanisms underlying various stress responses to ease breeding strategy for variety production through a couple of search interfaces including gene ID, functional annotation and browsing interfaces including by family and by chromosome. This database will also serve as a promising central repository for researchers as well as breeders who are working towards crop improvement of legume crops. In addition, this database provide the user unrestricted public access and the user can download entire data present in the database freely.Database URL: http://www.multiomics.in/PvTFDB/. PMID- 27465133 TI - Conservation of DNA Methylation Programming Between Mouse and Human Gametes and Preimplantation Embryos. AB - In mice, assisted reproductive technologies (ARTs) applied during gametogenesis and preimplantation development can result in disruption of genomic imprinting. In humans, these technologies and/or subfertility have been linked to perturbations in genomic imprinting. To understand how ARTs and infertility affect DNA methylation, it is important to understand DNA methylation dynamics and the role of regulatory factors at these critical stages. Recent genome studies performed using mouse and human gametes and preimplantation embryos have shed light onto these processes. Here, we comprehensively review the current state of knowledge regarding global and imprinted DNA methylation programming in the mouse and human. Available data highlight striking similarities in mouse and human DNA methylation dynamics during gamete and preimplantation development. Just as fascinating, these studies have revealed sex-, gene-, and allele-specific differences in DNA methylation programming, warranting future investigation to untangle the complex regulation of DNA methylation dynamics during gamete and preimplantation development. PMID- 27465132 TI - The treatment gap in patients with chronic systolic heart failure: a systematic review of evidence-based prescribing in practice. AB - The extent and impact of under-prescribing of evidence-based pharmacological therapies among heart failure patients with reduced ejection fraction (HFREF) in contemporary practice is unclear. We sought to examine the prescribing patterns of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers (BBs) and mineralocorticoid receptor antagonists (MRAs), and to quantify the estimated 'treatment gap' among HFREF patients in the 'real world' setting. The MEDLINE, PubMed, EMBASE, CINAHL and CENTRAL databases were searched for registry- or survey-based studies which examined the prescribing rates of ACE inhibitors, ARBs, BBs and MRAs among HFREF patients. Searches were limited to those published in the years 2000-2015. A total of 23 reports, including 83,605 patients, were evaluated. Overall, ACE inhibitors/ARBs, BBs and MRAs were prescribed to 79.8, 81.4 and 36.4 % of patients, respectively. The estimated treatment gaps in the overall population were 13.1 % for ACE inhibitors/ARBs, 3.9 % for BBs and 16.8 % for MRAs. The proportion of patients who received >=50 % of the guideline-recommended target doses was 72 % for ACE inhibitors, 51 % for ARBs, 49 % for BBs, 53 % for the combination of ACE inhibitors/ARBs and BBs and 83 % for MRAs. Prescribing these drugs according to contemporary guidelines was associated with lower mortality risk. Patients who were elderly, female and with comorbidities were less likely to receive optimal treatment as recommended by the guidelines. ACE inhibitors, ARBs, BBs and MRAs are under-prescribed in eligible HFREF patients. Efforts should be made to improve approaches to closing the treatment gap at both systems of care and individual levels. PMID- 27465134 TI - The Study of Cyclooxygenase 2 in Human Decidua of Preeclampsia. AB - Preeclampsia (PE), a pregnancy-specific disorder characterized by hypertension and proteinuria beginning after 20 wk of pregnancy, is a major cause of maternal and fetal morbidity and mortality. Delivery of the placenta reverses the immediate clinical manifestations and remains the only reliable treatment for PE. Up to now, the causes of PE are not entirely clear. Human cyclooxygenase 2 (COX2, encoded by PTGS2) is a highly inducible enzyme and regulates inflammation, differentiation, mitogenesis, and angiogenesis. COX2 deficiency affects all stages of early pregnancy and leads to various impairments. We hypothesized that COX2 had a role in the occurrence of PE and investigated its expression and function. We found that the expression of COX2 in decidual tissues of PE was significantly lower compared to that of the normal pregnancy. After decidualization stimulation with N6, 2'-O-dibutyryl-cAMP and medroxyprogesterone 17-acetate of human endometrial stromal cells, the expression of COX2, decidualization marker molecules prolactin (PRL) and insulinlike growth factor binding protein 1 (IGFBP1) increased significantly. This augmentation was time dependent relative to decidualization. When PTGS2 was depleted, the decidualization was compromised, based on changes in morphology and in decidualization markers. We found that the mRNA and protein levels of vascular endothelial growth factor (VEGF) decreased markedly when PTGS2 was knocked down, providing a potential mechanism for decidual impairment. This was consistent with the decrease in mRNA and protein in decidual tissues of PE relative to normal tissues. Our results suggest that COX2 plays a vital role in human decidualization and that its decreased expression jeopardizes decidualization and vascularization of the endometrial stroma; it may be a significant factor in the occurrence of PE. PMID- 27465135 TI - MicroRNA-16 Modulates Melatonin-Induced Cell Growth in the Mouse-Derived Spermatogonia Cell Line GC-1 spg Cells by Targeting Ccnd1. AB - Melatonin exerts a range of physiological effects. However, the functional significance of melatonin in spermatogenesis and the underlying mechanisms remain unclear. MicroRNAs (miRNAs) are essential in the initiation and progression of testicular development, including spermatogenesis. Thus far, limited information is known about the role of miRNAs in melatonin-mediated spermatogenesis. In this study, the expression levels of testicular miRNA machinery genes, namely, Dgcr8 and Xpo5, were significantly increased by melatonin. The miRNA expression profile was identified in the testes of melatonin-treated mice. Ten miRNAs were significantly up-regulated, and 15 miRNAs were down-regulated. Melatonin (25 MUM) enhanced cell growth and reduced apoptosis in GC-1 spg cells. Among the down regulated miRNAs, miR-16 expression was influenced by melatonin in GC-1 spg cells. The miR-16 mimics in GC-1 spg cells significantly suppressed cell growth and promoted cell apoptosis. Conversely, transfection of the miR-16 inhibitor significantly increased cell growth and decreased cell apoptosis. The protein expression level of CCND1 (Cyclin D1) in GC-1 spg cells was decreased by the miR 16 mimics and increased by knockdown of miR-16. Moreover, bioinformatics and reporter activity analyses showed that Ccnd1 was a potential target of miR-16. These results suggested that miR-16 may function as a novel regulator of testicular functions during melatonin stimulation by targeting Ccnd1. PMID- 27465137 TI - Obesity Disrupts the Rhythmic Profiles of Maternal and Fetal Progesterone in Rat Pregnancy. AB - Maternal obesity increases the risk of abnormal fetal growth, but the underlying mechanisms remain unclear. Because steroid hormones regulate fetal growth, and both pregnancy and obesity markedly alter circadian biology, we hypothesized that maternal obesity disrupts the normal rhythmic profiles of steroid hormones in rat pregnancy. Obesity was established by cafeteria (CAF) feeding for 8 wk prior to mating and throughout pregnancy. Control (CON) animals had ad libitum access to chow. Daily profiles of plasma corticosterone, 11-dehydrocorticosterone, progesterone, and testosterone were measured at Days 15 and 21 of gestation (term = 23 days) in maternal (both days) and fetal (Day 21) plasma. CAF mothers exhibited increased adiposity relative to CON and showed fetal and placental growth restriction. There was no change, however, in total fetal or placental mass due to slightly larger litter sizes in CAF. Nocturnal declines in progesterone were observed in maternal (39% lower) and fetal (45% lower) plasma in CON animals, but these were absent in CAF animals. CAF mothers were hyperlipidemic at both days of gestation, but this effect was isolated to the dark period at Day 21. CAF maternal testosterone was slightly lower at Day 15 (8%) but increased above CON by Day 21 (16%). Despite elevated maternal testosterone, male fetal testosterone was suppressed by obesity on Day 21. Neither maternal nor fetal glucocorticoid profiles were affected by obesity. In conclusion, obesity disrupts rhythmic profiles of maternal and fetal progesterone, preventing the normal nocturnal decline. Obesity subtly changed testosterone profiles but did not alter maternal and fetal glucocorticoids. PMID- 27465136 TI - Effects of Aging and Oxidative Stress on Spermatozoa of Superoxide-Dismutase 1- and Catalase-Null Mice. AB - Advanced paternal age is linked to complications in pregnancy and genetic diseases in offspring. Aging results in excess reactive oxygen species (ROS) and DNA damage in spermatozoa; this damage can be transmitted to progeny with detrimental consequences. Although there is a loss of antioxidants with aging, the impact on aging male germ cells of the complete absence of either catalase (CAT) or superoxide dismutase 1 (SOD1) has not been investigated. We used CAT null (Cat(-/-)) and SOD1-null (Sod(-/-)) mice to determine whether loss of these antioxidants increases germ cell susceptibility to redox dysfunction with aging. Aging reduced fertility and the numbers of Sertoli and germ cells in all mice. Aged Sod(-/-) mice displayed an increased loss of fertility compared to aged wild type mice. Treatment with the pro-oxidant SIN-10 increased ROS in spermatocytes of aged wild-type and Sod(-/-) mice, while aged Cat(-/-) mice were able to neutralize this ROS. The antioxidant peroxiredoxin 1 (PRDX1) increased with age in wild-type and Cat(-/-) mice but was consistently low in young and aged Sod(-/ ) mice. DNA damage and repair markers (gamma-H2AX and 53BP1) were reduced with aging and lower in young Sod(-/-) and Cat(-/-) mice. Colocalization of gamma-H2AX and 53BP1 suggested active repair in young wild-type mice but reduced in young Cat(-/-) and in Sod(-/-) mice and with age. Oxidative DNA damage (8-oxodG) increased in young Sod(-/-) mice and with age in all mice. These studies show that aged Sod(-/-) mice display severe redox dysfunction, while wild-type and Cat(-/-) mice have compensatory mechanisms to partially alleviate oxidative stress and reduce age-related DNA damage in spermatozoa. Thus, SOD1 but not CAT is critical to the maintenance of germ cell quality with aging. PMID- 27465138 TI - PiggyBac Transposon-Mediated Mutagenesis in Rats Reveals a Crucial Role of Bbx in Growth and Male Fertility. AB - Bobby sox homolog (Bbx) is an evolutionally conserved gene, but its biological function remains elusive. Here, we characterized defects of Bbx mutant rats that were created by PiggyBac-mediated insertional mutagenesis. Smaller body size and male infertility were the two major phenotypes of homozygous Bbx mutants. Bbx expression profile analysis showed that Bbx was more highly expressed in the testis and pituitary gland than in other organs. Histology and hormonal gene expression analysis of control and Bbx-null pituitary glands showed that loss of Bbx appeared to be dispensable for pituitary histogenesis and the expression of major hormones. BBX was localized in the nuclei of postmeiotic spermatids and Sertoli cells in wild-type testes, but absent in mutant testes. An increased presence of aberrant multinuclear giant cells and apoptotic cells was observed in mutant seminiferous tubules. TUNEL-positive cells costained with CREM (round spermatid marker), but not PLZF (spermatogonia marker), gammaH2Ax (meiotic spermatocyte marker), or GATA4 (Sertoli cell marker). Finally, there were drastically reduced numbers and motility of epididymal sperm from Bbx-null rats. These results suggest that loss of BBX induces apoptosis of postmeiotic spermatids and results in spermiogenesis defects and infertility. PMID- 27465139 TI - Proteomic Analysis of Pachytene Spermatocytes of Sterile Hybrid Male Mice. AB - Incompatibilities in interspecific hybrids, such as reduced hybrid fertility and lethality, are common features resulting from reproductive isolation that lead to speciation. Subspecies crosses of house mice produce offspring in which one sex is infertile or absent, yet the molecular mechanisms of hybrid sterility are poorly understood. In this study, we observed extensive asynapsis of chromosomes and disturbance of the sex body in pachytene spermatocytes of sterile F1 males (PWK/Ph female * C57BL/6J male). We report the high-confidence identification of 4005 proteins in the pachytene spermatocytes of fertile F1 males (PWK/Ph male * C57BL/6J female) and sterile F1 males (PWK/Ph female * C57BL/6J male), of which 215 were upregulated and 381 were downregulated. Bioinformatics analysis of the proteome led to the identification of 43 and 59 proteins known to be essential for male meiosis and spermatogenesis in mice, respectively. Characterization of the proteome of pachytene spermatocytes associated with hybrid male sterility provides an inventory of proteins that is useful for understanding meiosis and the mechanisms of hybrid male infertility. PMID- 27465140 TI - Tanshinone IIA ameliorates apoptosis of cardiomyocytes induced by endoplasmic reticulum stress. AB - The fat-soluble diterpenoids tanshinone IIA (TSA) is the major active element of Danshen, which has widespread cardioprotective effect. However, the mechanism of its beneficial effect on cardiomyocytes has not been fully investigated. Here, we aim to demonstrate that TSA ameliorates apoptosis of cardiomyocytes activated by endoplasmic reticulum stress (ERS). Primary cultures of neonatal rat cardiomyocytes are used, in which ERS-mediated apoptosis is induced by tunicamycin (Tm). Apoptosis of cardiomyocytes are detected by Hoechst staining and caspase 3 activity analysis. Protein expression of ERS markers are detected by Western blot, and level of miroRNA-133 (miR-133) is detected by real-time polymerase chain reaction. Tm treatment significantly triggers the apoptosis and ERS of cardiomyocytes. TSA dramatically ameliorates apoptosis and ERS of cardiomyocytes induced by Tm. Interestingly, level of miR-133 is reduced by Tm treatment, which is reversed by TSA. The cardioprotective effect of TSA on apoptosis and ERS of cardiomyocytes is blocked by anti-miR-133. These results suggest that TSA protects cardiomyocytes through ameliorated ERS-mediated apoptosis, which may be resulted from upregulation of miR-133. PMID- 27465141 TI - Identification of differentially regulated genes in human patent ductus arteriosus. AB - In order to identify differentially expressed genes that are specific to the ductus arteriosus, 18 candidate genes were evaluated in matched ductus arteriosus and aortic samples from infants with coarctation of the aorta. The cell specificity of the gene's promoters was assessed by performing transient transfection studies in primary cells derived from several patients. Segments of ductus arteriosus and aorta were isolated from infants requiring repair for coarctation of the aorta and used for mRNA quantitation and culturing of cells. Differences in expression were determined by quantitative PCR using the DeltaDeltaCt method. Promoter regions of six of these genes were cloned into luciferase reporter plasmids for transient transfection studies in matched human ductus arteriosus and aorta cells. Transcription factor AP-2b and phospholipase A2 were significantly up-regulated in ductus arteriosus compared to aorta in whole tissues and cultured cells, respectively. In transient transfection experiments, Angiotensin II type 1 receptor and Prostaglandin E receptor 4 promoters consistently gave higher expression in matched ductus arteriosus versus aorta cells from multiple patients. Taken together, these results demonstrate that several genes are differentially expressed in ductus arteriosus and that their promoters may be used to drive ductus arteriosus-enriched transgene expression. PMID- 27465142 TI - The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-alpha and TRAIL-induced apoptosis. AB - The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF -kappa B (NF-kappaB) pathway, as indicated by stabilizing NF-kappaB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-alpha (TNF-alpha) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance. PMID- 27465143 TI - gamma-Carboxyethyl hydroxychroman, a metabolite of gamma-tocopherol, preserves nitric oxide bioavailability in endothelial cells challenged with high glucose. AB - Endothelial dysfunction occurs when there are imbalances between factors that regulate the synthesis and degradation of nitric oxide (NO*), and has been reported in patients with hyperglycemia and insulin resistance. We reported that supplementation with gamma-tocopherol (gamma-T) in humans limits impairments in endothelial function otherwise induced by postprandial hyperglycemia. Given the rapid metabolism of gamma-T into gamma-carboxyethyl hydroxychroman (gamma-CEHC), we hypothesized that the vasoprotective activities of gamma-T could be attributed to its metabolite gamma-CEHC. To test this, human aortic endothelial cells (HAECs) treated with 0 (vehicle control) or 3 uM gamma-CEHC for 24 h prior to incubation with normal (5 mM) or high (25 mM) glucose for 48 h. High-glucose increased levels of uncoupled endothelial nitric oxide synthase (eNOS) as evidenced by reduced ( p < 0.05) eNOS dimer:monomer. High glucose also prevented insulin-stimulated increases in p-AktSer473: total Akt, p-eNOSSer1177: total eNOS, and NO* production. These adverse changes were accompanied by increased ( p < 0.05) reactive oxygen species and mRNA expression of inflammatory mediators (VCAM-1, E-selectin, IL-8). However, each deleterious response evoked by high glucose was prevented when HAECs were incubated with gamma-CEHC prior to the high glucose challenge. Taken together, our data support the hypothesis that vascular protection provided by gamma-T in vivo may be elicited through the bioactivity of its metabolite, gamma-CEHC. Furthermore, it is possible that the antioxidant and anti-inflammatory activities of gamma-CEHC may mediate this protective activity. PMID- 27465144 TI - Larval sensilla of the moth Heliothis virescens respond to sex pheromone components. AB - Female-released sex pheromones orchestrate the mating behaviour of moths. Recent studies have shown that sex pheromones not only attract adult males but also caterpillars. Single sensillum recordings revealed that larval antennal sensilla of the moth Heliothis virescens respond to specific sex pheromone components. In search for the molecular basis of pheromone detection in larvae, we found that olfactory sensilla on the larval antennae are equipped with the same molecular elements that mediate sex pheromone detection in adult male moths, including the Heliothis virescens receptors 6 (HR6) and HR13, as well as sensory neurone membrane protein 1 (SNMP1). Thirty-eight olfactory sensory neurones were identified in three large sensilla basiconica; six of these are considered as candidate pheromone responsive cells based on the expression of SNMP1. The pheromone receptor HR6 was found to be expressed in two cells and the receptor HR13 in three cells. These putative pheromone responsive neurones were accompanied by cells expressing pheromone-binding protein 1 (PBP1) and PBP2. The results indicate that the responsiveness of larval sensilla to female-emitted sex pheromones is based on the same molecular machinery as in the antennae of adult males. PMID- 27465146 TI - Correspondence to the Editor Re: Implementing systematic review techniques in chemical risk assessment: Challenges, opportunities and recommendations. PMID- 27465145 TI - Characterisation of Clostridium difficile strains isolated from Groote Schuur Hospital, Cape Town, South Africa. AB - The C. difficile infection rate in South Africa is concerning. Many strains previously isolated from diarrhetic patients at Groote Schuur Hospital were ribotype 017. This study further characterised these strains with respect to their clonal relationships, antibiotic susceptibility, toxin production and various attributes impacting on pathogen colonisation. Multilocus variable-number tandem-repeat analysis (MLVA) was used to characterise all C. difficile isolates. Antibiotic susceptibility was determined by E-test and PCR-based analysis of the ermB, gyrA and gyrB genes. Auto-aggregation of cells was measured in broth, and biofilm formation observed in 24-well plates. Toxins were measured using the Wampole C DIFF TOX A/B II kit. Most isolates belonged to the ribotype 017 group. Identical MLVA types occurred in different wards over time, and several patients were infected with identical strains. All isolates were susceptible to vancomycin and metronidazole, but some ribotype 017 isolates showed reduced metronidazole susceptibility (>=2 mg l(-1)). Sixty-nine percent of ribotype 017 isolates were resistant to moxifloxacin, and 94 % to erythromycin, compared to 0 % and 17 % resistance, respectively, in non-ribotype 017 isolates. The ermB gene and mutations in the gyrA and/or gyrB genes were linked to erythromycin and moxifloxacin resistance, respectively. Ribotype 017 isolates auto-aggregated more strongly than other isolates and produced lower levels of the TcdB toxin than a reference strain. Certain strains produced strong biofilms. Patient-to-patient transfer and unique infection events could cause the predominance of ribotype 017 strains in the cohort. Multi-drug resistant strains are a potential reservoir for future infections. PMID- 27465147 TI - Biodegradable polymeric microcapsules for sustained release of riboflavin. AB - In the current study, a series of polylactic acid and polylactic-co-glycolic acid were prepared in an easy, simple, safe and economically feasible way with yield% greater than 90%. Studying the effect of a catalyst on polymerization process was performed. Riboflavin (RF) was chosen as a model drug and microencapsulated in different (drug: polymer) ratios to modify its performance via o/w emulsion solvent evaporation technique and characterized in terms of the morphology and entrapment efficiency (E.E.) and evaluated via in vitro RF release studies. It has been found that, the release rate consists a burst release at the first 12h, followed by a gradual release over 3days. The cumulative riboflavin release from these microcapsules formulations at the end of 3days was 70% and 80% for PDLA and PDLAGA respectively. The kinetics of release profiles were zero order. The highest (E.E.) of RF obtained among all formulations was 85%. PMID- 27465148 TI - Effectiveness of work-related medical rehabilitation in cancer patients: study protocol of a cluster-randomized multicenter trial. AB - BACKGROUND: Work is a central resource for cancer survivors as it not only provides income but also impacts health and quality of life. Additionally, work helps survivors to cope with the perceived critical life event. The German Pension Insurance provides medical rehabilitation for working-age patients with chronic diseases to improve and restore their work ability, and support returning to or staying at work, and thus tries to sustainably avoid health-related early retirement. Past research showed that conventional medical rehabilitation programs do not support returning to work sufficiently and that work-related medical rehabilitation programs report higher return-to-work rates across several health conditions, when compared to medical rehabilitation. Therefore, the current study protocol outlines an effectiveness study of such a program for cancer survivors. METHODS: To evaluate the effectiveness of work-related medical rehabilitation in cancer patients we conduct a cluster-randomized multicenter trial. In total, 504 rehabilitation patients between 18 and 60 years with a Karnofsky Performance Status of >=70 %, a preliminary positive social-medical prognosis of employability for at least 3 h/day within the next 6 months and an elevated risk of not returning to work will be recruited in four inpatient rehabilitation centers. Patients are randomized to the work-related medical rehabilitation program or the conventional medical rehabilitation program based on their week of arrival at each rehabilitation center. The work-related medical rehabilitation program comprises additional work-related diagnostics, multi professional team meetings, an introductory session as well as work-related functional capacity training, work-related psychological groups, and social counseling. All additional components are aimed at the adjustment of the patients' capacity in relation to their individual job demands. Role functioning defines the main study outcome and will be assessed with the EORTC-QLQ30. Secondary outcome measures are the remaining scales of the EORTC-QLQ30, fatigue, self-rated work ability, disease coping, participation in working life, realization of work-related goals and therapies during rehabilitation, and treatment satisfaction. DISCUSSION: A positive evaluation of work-related medical rehabilitation in cancer patients is expected due to the promising findings on the effectiveness of such programs for patients with other health conditions. Results may support the dissemination of work-related medical rehabilitation programs in German cancer rehabilitation. TRIAL REGISTRATION: German Clinical Trials Register DRKS00007770 . Registered 13 May 2015. PMID- 27465149 TI - Angiographic severity does not correlate with fractional flow reserve in heavily calcified coronary arteries. AB - OBJECTIVES: To determine the relationship between severity of stenosis and hemodynamic significance in calcified coronary arteries. BACKGROUND: Severity of stenosis is widely used to determine the need for revascularization but the effect of lesion calcification on hemodynamic significance is not well understood. METHODS: Two hundred consecutive patients undergoing fractional flow reserve (FFR) testing of an intermediate coronary lesion with a pressure wire and intravenous infusion of adenosine were studied. Coronary calcium was quantified based upon radiopacities at the site of the stenosis on cineangiography using the method of Mintz et al. (0 = none or mild calcium, 1 = moderate calcium, 2 = severe calcium). RESULTS: Mean age was 61 +/- 11 years, 66% were males, 87.5% had hypertension, 44.5% had diabetes, and 20.5% were current smokers. The mean coronary stenosis by quantitative coronary angiography was 60 +/- 12% and the mean FFR was 0.83 +/- 0.08. There were 109, 45, and 46 patients classified as Calcium Score of 0, 1, or 2, respectively. Compared to those with no/mild or moderate calcification, patients with severe coronary calcium were older and more likely to have chronic kidney disease and pulmonary disease. The correlation between angiographic severity and FFR decreased as lesion calcification increased [calcium score = 0 (R2 = 0.25, P < 0.005); calcium score = 1 (R2 = 0.11, P < 0.005); calcium score = 2 (R2 = 0.02, P = 0.35)]. CONCLUSIONS: In patients with heavily calcified coronary lesions, there was no association between angiographic stenosis and hemodynamic significance and FFR is needed to determine hemodynamic significance of intermediate lesions. (c) 2016 Wiley Periodicals, Inc. PMID- 27465150 TI - Nuclear factor-kappaB regulates expression of platelet phospholipase C-beta2 (PLCB2). AB - Phospholipase C (PLC)-beta2 (gene PLCB2) is a critical regulator of platelet responses upon activation. Mechanisms regulating of PLC-beta2 expression in platelets/MKs are unknown. Our studies in a patient with platelet PLC-beta2 deficiency revealed the PLCB2 coding sequence to be normal and decreased platelet PLC-beta2 mRNA, suggesting a defect in transcriptional regulation. PLCB2 5'- upstream region of the patient revealed a heterozygous 13 bp deletion (-1645/ 1633 bp) encompassing a consensus sequence for nuclear factor-kappaB (NF-kappaB). This was subsequently detected in three of 50 healthy subjects. To understand the mechanisms regulating PLC-beta2, we studied the effect of this variation in the PLCB2. Gel-shift studies using nuclear extracts from human erythroleukaemia (HEL) cells or recombinant p65 showed NF-kappaB binding to oligonucleotide with NF kappaB site; in luciferase reporter studies its deletion reduced PLCB2 promoter activity. PLCB2 expression was decreased by siRNA knockdown of NF-kappaB p65 subunit and increased by p65 overexpression. By immunoblotting platelet PLC-beta2 in 17 healthy subjects correlated with p65 (r=0.76, p=0.0005). These studies provide the first evidence that NF-kappaB regulates MK/platelet PLC-beta2 expression. This interaction is important because of the major role of PLC-beta2 in platelet activation and of NF-kappaB in processes, including inflammation and atherosclerosis, where both are intimately involved. PMID- 27465152 TI - Expression of macrophage migration inhibitory factor (MIF) in bovine oviducts is higher in the postovulatory phase than during the oestrus and luteal phase. AB - Whether macrophage migration inhibitory factor (MIF) in the bovine oviduct is important for early embryogenesis has not been well substantiated. The aim of the present study was to test the hypothesis that bovine oviduct expresses higher levels of MIF during the post-ovulation phase. Both ampullary and isthmic samples were collected from Japanese black heifers during oestrus (Day 0; n=5), postovulation (Day 3; n=6) and luteal phase (Days 9-12; n=5). MIF mRNA and protein were extracted from the ampullary and isthmic samples and their levels measured by real-time polymerase chain reaction and western blot analysis respectively. Fluorescent immunohistochemistry was performed on frozen ampullary and isthmic sections using antibodies against MIF. MIF mRNA and protein expression was higher in the postovulatory phase than during oestrus and the luteal phase (P<0.05). Fluorescent immunohistochemistry confirmed that in all phases of the oestrous cycle evaluated, the primary site of MIF expression in the ampulla and isthmus was the tunica mucosa. In conclusion, the bovine ampulla and isthmus have higher MIF expression during the postovulatory phase. Further studies are needed to clarify the role of MIF in bovine oviducts. PMID- 27465153 TI - Successful treatment of acute promyelocytic leukemia with arsenic trioxide and all-trans retinoic acid in a double lung and kidney transplanted patient. PMID- 27465151 TI - Role of dietary phenols in mitigating microglia-mediated neuroinflammation. AB - Chronic neuroinflammation is a pathological feature of a number of central nervous system (CNS) diseases and is mediated by sustained activation of microglial cells, the innate immune cells of the CNS. Studies have mainly focused on identifying the molecular and epigenetic mechanisms of microglial activation. This is crucial in designing therapeutic strategies for neuropathologies in which prolonged microglial activation is known to exacerbate disease condition. In recent years, increasing evidence show that naturally occurring compounds present in regular diet could function as "nutraceuticals," arresting microglial activation, and thus conferring neuroprotection. This review summarizes our understanding of the role of dietary phenolic nutraceuticals in mitigating microglia-mediated neuroinflammation. Studies show that these natural phenols inhibit key signaling pathways in activated microglia such as the NFkappaB, MAPK and JAK-STAT that trigger microglia-mediated inflammation in various neuropathological conditions such as injury, infection, stroke, autism and neurodegenerative diseases, i.e., Alzheimer's disease and Parkinson's disease. The anti-inflammatory and antioxidant effect exerted by these natural phenols have shown considerable success in improving disease condition in animal models of neuropathologies, and thus seem to be suitable candidates for developing therapeutic strategies. PMID- 27465154 TI - Unusual co-occurrence of Evans syndrome and pure red cell aplasia in elderly patient with prostate cancer. PMID- 27465155 TI - Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients. PMID- 27465157 TI - Discussion: Acellular Dermal Matrix-Assisted Direct-to-Implant Breast Reconstruction and Capsular Contracture: A 13-Year Experience. PMID- 27465156 TI - Red blood cell aquaporin-1 expression is decreased in hereditary spherocytosis. AB - Aquaporin-1 (AQP1) is the membrane water channel responsible for changes in erythrocyte volume in response to the tonicity of the medium. As the aberrant distribution of proteins in hereditary spherocytosis (HS) generates deficiencies of proteins other than those codified by the mutated gene, we postulated that AQP1 expression might be impaired in spherocytes. AQP1 expression was evaluated through flow cytometry in 5 normal controls, 1 autoimmune hemolytic anemia, 10 HS (2 mild, 3 moderate, 2 severe, and 3 splenectomized), and 3 silent carriers. The effect of AQP1 inhibitors was evaluated through water flow-based tests: osmotic fragility and hypertonic cryohemolysis. Serum osmolality was measured in 20 normal controls and 13 HS. The effect of erythropoietin (Epo) on AQP1 expression was determined in cultures of erythroleukemia UT-7 cells, dependent on Epo to survive. Independent of erythrocyte size, HS patients showed a lower content of AQP1 in erythrocyte membranes which correlated with the severity of the disease. Accordingly, red blood cells from HS subjects were less sensitive to cryohemolysis than normal erythrocytes after inhibition of the AQP1 water channel. A lower serum osmolality in HS with respect to normal controls suggests alterations during reticulocyte remodeling. The decreased AQP1 expression could contribute to explain variable degrees of anemia in hereditary spherocytosis. The finding of AQP1 expression induced by Epo in a model of erythroid cells may be interpreted as a mechanism to restore the balance of red cell water fluxes. PMID- 27465158 TI - Lumbar Artery Perforator Flap: An Anatomical Study Using Multidetector Computed Tomographic Scan and Surgical Pearls for Breast Reconstruction. AB - BACKGROUND: Breast reconstruction with the lumbar artery perforator flap is indicated in patients with unfavorable abdominal donor site. In addition to their clinical experience with lumbar artery perforator free flap breast reconstruction, the authors present an anatomical study of the origin and course of the perforators. METHODS: Images of multidetector computerized tomography scans were used to visualize the location of the dominant lumbar artery perforator in 20 patients. The medical files of the authors' patients who underwent lumbar artery perforator flap breast reconstruction were also analyzed. RESULTS: Multidetector computed tomographic imaging in 20 female patients with a mean age of 47 years revealed an equal number of dominant perforators (10 left and 10 right); 60 percent were third lumbar artery perforators, 30 percent were fourth, and the remaining were second. The dominant perforators were mainly located 42.6 mm from the y axis at their origin at the transverse process, and 69.5 mm when emerging in the subcutaneous tissue. Six patients had nine successful lumbar artery perforator flaps for breast reconstruction. Average operative time was 270 minutes. Due to shortness of pedicle and mismatching between diameter of lumbar artery and internal mammary artery, vascular bypass (harvested from the deep inferior epigastric vessels) was required in 50 percent of the cases. The major complication at the donor site was seroma (80 percent). CONCLUSIONS: The lumbar artery perforator has a constant anatomical location. The free lumbar artery perforator flap provides an ample amount of tissue for breast reconstruction; however, its major disadvantages are the small artery diameter, shortness of the pedicle, and high seroma rate at the donor site. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27465159 TI - Race and Breast Cancer Reconstruction: Is There a Health Care Disparity? AB - BACKGROUND: Racial disparity continues to be a well-documented problem afflicting contemporary health care. Because the breast is a symbol of femininity, breast reconstruction is critical to mitigating the psychosocial stigma of a breast cancer diagnosis. Whether different races have equitable access to breast reconstruction remains unknown. METHODS: Two thousand five hundred thirty-three women underwent first-time autologous versus implant-based reconstruction following mastectomy. Information regarding age, smoking, diabetes, obesity, provider, race, pathologic stage, health insurance type, charge to insurance, and socioeconomic status was recorded. Established statistics compared group medians and proportions. A backward-stepwise multivariate logistic regression model identified independent predictors of breast reconstruction type. RESULTS: Compared with whites, African Americans were more likely to be underinsured (p < 0.01), face a lesser charge for reconstruction (p < 0.01), smoke (p < 0.01), have diabetes (p < 0.01), suffer from obesity (p < 0.01), live in a zip code with a lower median household income (p < 0.01), and undergo autologous-based reconstruction (p = 0.01). On multivariate analysis, only African American race (OR, 2.23; p < 0.01), charge to insurance (OR, 1.00; p < 0.01), and provider (OR, 0.96; p < 0.01) independently predicted type of breast reconstruction, whereas age (OR, 1.02; p = 0.06) and diabetes (OR, 0.48; p = 0.08) did not. CONCLUSIONS: African American race remains the most clinically significant predictor of autologous breast reconstruction, even after controlling for age, obesity, pathologic stage, health insurance type, charge to patient, socioeconomic status, smoking, and diabetes. Future research may address whether this disparity stems from patient preferences or more profound sociocultural and economic forces, including discrimination. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 27465160 TI - Discussion: Race and Breast Cancer Reconstruction: Is There a Health Care Disparity? PMID- 27465161 TI - New Suturing Techniques to Reconstruct the Keystone Area in Extracorporeal Septoplasty. AB - BACKGROUND: Severe septal deformations require adequate treatment to restore shape and function using extracorporeal septoplasty. Because it has been criticized for being technically demanding to execute and has increased risk for aesthetic complications, the authors have developed two new suture techniques for refixation of the neoseptum. METHODS: A retrospective analysis of multisurgeon consecutive extracorporeal septoplasties performed from January of 2014 to December of 2014 was conducted at a single institution using the criss-cross or transcutaneous transosseous cerclage suture (group 1) compared with fixation at the upper lateral cartilages only (group 2). RESULTS: One hundred ten extracorporeal septoplasties were performed in 110 patients over 12 months. Group 1 consisted of 58 patients (53 percent), whether receiving the criss-cross [12 patients (21 percent)] or the transcutaneous transosseous cerclage suture [46 patients (79 percent)], and group 2 consisted of 52 patients (47 percent). The median follow-up was 11 months (range, 6 to 16 months). Operative revision because of complications at the dorsum or the keystone area had to be performed in no case in group 1 and in five cases (9.6 percent) in group 2, resulting in a statistically significant difference between the two groups (p = 0.0212). There were no complications such as bleeding or infection observed in any of the 110 cases. CONCLUSIONS: To facilitate and to reduce the complication rate after extracorporeal septoplasty, the authors have developed the criss-cross and transcutaneous transosseous cerclage suture to overcome the important and technically demanding reimplantation of the neoseptum. Thus, the authors believe that these new operative techniques are safe and reproducible procedures that may take a permanent place among extracorporeal septoplasty procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27465162 TI - Discussion: New Suturing Techniques to Reconstruct the Keystone Area in Extracorporeal Septoplasty. PMID- 27465163 TI - Adipose-Derived Stem Cells Enhance Axonal Regeneration through Cross-Facial Nerve Grafting in a Rat Model of Facial Paralysis. AB - BACKGROUND: Cross-face nerve grafting combined with functional muscle transplantation has become the standard in reconstructing an emotionally controlled smile in complete irreversible facial palsy. However, the efficacy of this procedure depends on the ability of regenerating axons to breach two nerve coaptations and reinnervate endplates in denervated muscle. The current study tested the hypothesis that adipose-derived stem cells would enhance axonal regeneration through a cross-facial nerve graft and thereby enhance recovery of the facial nerve function. METHODS: Twelve rats underwent transection of the right facial nerve, and cross-facial nerve grafting using the sciatic nerve as an interpositional graft, with coaptations to the ipsilateral and contralateral buccal branches, was carried out. Rats were divided equally into two groups: a grafted but nontreated control group and a grafted and adipose-derived stem cell treated group. Three months after surgery, biometric and electrophysiologic assessments of vibrissae movements were performed. Histologically, the spectra of fiber density, myelin sheath thickness, fiber diameter, and g ratio of the nerve were analyzed. Immunohistochemical staining was performed for the evaluation of acetylcholine in the neuromuscular junctions. RESULTS: The data from the biometric and electrophysiologic analysis of vibrissae movements, immunohistochemical analysis, and histologic assessment of the nerve showed that adipose-derived stem cells significantly enhanced axonal regeneration through the graft. CONCLUSION: These observations suggest that adipose-derived stem cells could be a clinically translatable route toward new methods to enhance recovery after cross-facial nerve grafting. PMID- 27465165 TI - Impact of Safety Net Hospitals in the Care of the Hand-Injured Patient: A National Perspective. AB - A clear disparity in the pattern and provision of surgical care exists, particularly for patients with vulnerable socioeconomic backgrounds. For hand injured patients in particular, this discrepancy has been frequently shown in their receiving appropriate care. With the advent of the Affordable Care Act and with Medicaid expansion on the horizon, more patients will be requiring access to care. Safety net programs have been shown to provide equivalent levels of care for patients compared with non-safety net providers, and the survival of these hospitals for the disadvantaged is essential to providing quality care for this growing patient population. In this article, the authors review the factors that affect the barriers to care, the importance of safety net hospitals, the epidemiology of the hand-injured patient, and how the Affordable Care Act will impact these safety net programs. PMID- 27465164 TI - Developing a Nanoparticle-Delivered High-Efficacy Treatment for Infantile Hemangiomas Using a Mouse Hemangioendothelioma Model. AB - BACKGROUND: Current treatments for infantile hemangiomas have unpredictable outcomes. The authors' aim was to develop a nanoporphyrin-delivered, high efficacy treatment for infantile hemangiomas using a mouse hemangioendothelioma model. METHODS: The authors injected mouse hemangioendothelioma cells intradermally to axillary regions of 5-week-old, female, nude mice (n = 19) to induce hemangioendothelioma growth. They documented nanoporphyrin accumulation in hemangioendotheliomas using positron emission tomography. For the treatment study, the authors randomized hemangioendothelioma-bearing nude mice (n = 9) into three groups (n = 3 each). Group I received only saline injections. Group II received only laser treatment after saline injection, and group III received laser treatment after nanoporphyrin injection through the tail vein. The authors followed up the treatment response with digital caliper measurements. RESULTS: Hemangioendotheliomas started to grow approximately 1 week after inoculation and resembled infantile hemangiomas histologically. Nanoporphyrin uptake in hemangioendotheliomas was 19.7 +/- 2.2, 16.7 +/- 2.02, 8.4 +/- 0.3, and 4.9 +/- 0.6 percent injected dose per gram of tissue at 3, 6, 24, and 48 hours after injection, respectively. Nanoporphyrin uptake was significantly higher than in blood at 24 and 48 hours after injection (p < 0.05). Results of ex vivo biodistribution study were consistent with positron emission tomographic imaging. Hemangioendotheliomas in group III started to regress 1 day after the treatment and disappeared totally by day 21. The difference between tumor volumes in group III and other groups was significant on days 17 and 21 (p < 0.05). CONCLUSIONS: Nanoporphyrin accumulated in hemangioendotheliomas at high concentrations, enabling a high-efficacy photodynamic therapy. Given the similarities between hemangioendotheliomas and infantile hemangiomas, this treatment potentially can be a high-efficacy treatment for infantile hemangiomas. PMID- 27465166 TI - Behavioral Adjustment of School-Age Children with and without Single-Suture Craniosynostosis. AB - BACKGROUND: Previous research has observed higher than average rates of behavior problems in school-age children with single-suture craniosynostosis. However, most studies used a single informant (mothers) and did not include comparison groups to control for sociodemographic factors. METHODS: The authors gave standardized behavior checklists to the mothers, fathers, and teachers of 179 elementary school children with single-suture craniosynostosis and 183 controls. We used linear regression to compare children with and without single-suture craniosynostosis on continuous measures of adjustment, and logistic regression to compare the proportions of children who scored above a well-established clinical threshold based on the report of one or more informants. All analyses were adjusted for demographic confounds (age, sex, socioeconomic status, maternal intelligence quotient). RESULTS: Cases received higher average behavior problem scores than controls from all informants. However, differences were small in magnitude (0.01 to 0.2 SD; p = 0.12 to p = 0.96). Thirty-three percent of children with single-suture craniosynostosis were rated above a clinical threshold by one or more informants, compared with 21 percent of controls (adjusted odds ratio, 1.67; p = 0.04). Among cases, children with metopic synostosis had the highest level of observed behavior problems (41 percent greater than threshold); those with sagittal synostosis had the lowest level (29 percent). CONCLUSIONS: The authors observed little difference in average ratings of behavior problems between children with and without single-suture craniosynostosis. However, children with single-suture craniosynostosis were more likely to score above a clinical threshold than unaffected controls. No specific areas of maladjustment were associated with case status or location of suture fusion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 27465167 TI - Ethical Issues in Pediatric Face Transplantation: Should We Perform Face Transplantation in Children? AB - BACKGROUND: In 2005, face transplantation ceased to be fiction and became a scientific reality. Today, 10 teams from six different countries have performed 32 face transplantations. Immunosuppressive treatments are similar to other solid organ transplants, and patients have experienced a significant functional improvement. The authors are logically considering expanding face transplantation to children; however, children are not simply small adults. METHODS: The authors searched for pediatric patients in need of restoration of fundamental functions of the face, such as orbicularis oris or oculi muscle closure by, first, selecting cases from a pediatric plastic surgery reference center and, second, analyzing the feasibility of face transplantation in those patients. The authors then identified the specific problems that they would encounter during a pediatric face transplant. The authors identified three potential candidates for pediatric face transplantation. RESULTS: Children's youth imposes additional ethical and psychological considerations, such as the balance of risk to benefit when it is quality of life, not life itself, that is at stake; the process of informed consent; the selection process; and the protection of privacy against media exposure. The question becomes not whether children should be included as candidates for face transplantation but whether any ethical barriers should preclude children as candidates for a full face transplant. CONCLUSION: After careful consideration of the physical, psychological, and ethical aspects of such a procedure, the authors found no such barrier that would either disqualify such vulnerable subjects as profoundly disfigured children or conflict with their best interests. PMID- 27465168 TI - Discussion: Ethical Issues in Pediatric Face Transplantation: Should We Perform Face Transplantation in Children? PMID- 27465169 TI - Systematic Review and Meta-Analysis of Unconventional Perfusion Flaps in Clinical Practice. AB - BACKGROUND: Although unconventional perfusion flaps have been in clinical use since 1975, many surgeons are still deterred from using them, because of some reports of high necrosis rates. METHODS: The authors performed a systematic review and meta-analysis of all articles written in English, French, German, Spanish, and Portuguese on the clinical use of unconventional perfusion flaps and indexed to PubMed from 1975 until July 15, 2015. RESULTS: A total of 134 studies and 1445 patients were analyzed. The estimated survival rate of unconventional perfusion flaps was 89.5 percent (95 percent CI, 87.3 to 91.3 percent; p < 0.001). Ninety-two percent of unconventional perfusion flaps (95 percent CI, 89.9 to 93.7 percent; p < 0.001) presented complete or nearly complete survival. Most defects mandating unconventional perfusion flap reconstruction were caused by trauma (63.6 percent), especially of the hand and fingers (75.1 percent). The main complication of all types of flaps was a variable degree of necrosis (7.5 percent of all unconventional perfusion flaps presented marginal necrosis; 9.2 percent and 5.5 percent had significant and complete necrosis, respectively). There was a positive correlation between the rate of postoperative infection and the need for a new flap (Pearson coefficient, 0.405; p = 0.001). Flaps used to reconstruct the upper limb showed better survival than those transferred to the head and neck or to the lower limb (p < 0.001). CONCLUSION: Unconventional perfusion flaps show high survival rates and should probably be used more liberally, particularly in the realm of upper limb reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27465170 TI - One versus Two Venous Anastomoses in Anterolateral Thigh Flap Reconstruction after Oral Cancer Ablation. AB - BACKGROUND: Whether one-vein or two-vein drainage yields better outcomes in anterolateral thigh flap reconstruction after oral cancer ablation is still being debated. Thus, the authors investigated this question. METHODS: In this retrospective cohort study, the authors reviewed the charts of 321 patients with oral cancer who, between August of 2010 and July of 2014, had undergone ablative surgery and then immediate reconstruction with the anterolateral thigh flap. Patients who underwent simultaneous reconstruction with additional free flaps were excluded. The patients were subgrouped into newly diagnosed (n = 221) and previously treated (n = 100) groups and then subgrouped into one-vein and two vein groups. RESULTS: Overall, operative time was significantly longer (366.8 +/- 112.7 minutes versus 336.3 +/- 99.7 minutes; p = 0.009) and hospitalization was significantly shorter (22.0 +/- 13.3 days versus 24.5 +/- 13.8 days; p = 0.027) in the two-vein group. In the newly diagnosed two-vein group, operative time was also significantly longer (355.5 +/- 91.7 minutes versus 319.9 +/- 95.9 minutes; p = 0.008), anterolateral thigh flap take-backs for vascular compromise (3.2 percent versus 10.9 percent; p = 0.041) and venous congestion (1.1 percent versus 7.8 percent; p = 0.027) were fewer, and flap survival was greater (100 percent versus 95.3 percent; p = 0.041). Differences between the one-vein and two-vein previously treated subgroups were not significant. CONCLUSION: In newly diagnosed patients undergoing anterolateral thigh flap reconstruction after oral cancer ablation, better outcomes are achieved with two venous anastomoses rather than one. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27465171 TI - Discussion: One versus Two Venous Anastomoses in Anterolateral Thigh Flap Reconstruction after Oral Cancer Ablation. PMID- 27465172 TI - Methicillin-Resistant Staphylococcus aureus Infections: A Comprehensive Review and a Plastic Surgeon's Approach to the Occult Sites. AB - BACKGROUND: Up to 20 percent of the general population is persistently colonized with Staphylococcus aureus, and 1 to 3 percent of the population is colonized with community-acquired methicillin-resistant S. aureus. Currently, the knowledge of methicillin-resistant Staphylococcus aureus carriage sites other than the nose, and their effect on surgical site infections in cosmetic surgery, is lacking. METHODS: A comprehensive literature review using the PubMed database to analyze prevalence, anatomical carrier sites, current screening and decontamination protocols and guidelines, and methicillin-resistant S. aureus in cosmetic surgery was performed. The senior author's (L.R.) methicillin-resistant S. aureus infection experience and prevention protocols were also reviewed. RESULTS: Nasal swabs detect only 50.5 percent of methicillin-resistant S. aureus colonization, and broad screening has noted the presence of methicillin-resistant S. aureus in the ear canal and umbilicus. Decolonization protocols within the orthopedic and cardiothoracic surgery literature have reduced rates of methicillin-resistant S. aureus surgical-site infections. There are no decolonization guidelines for plastic surgeons. Since instituting their decolonization protocol, the authors have had no cases of methicillin-resistant S. aureus infection in nearly 1000 cosmetic surgery procedures. CONCLUSIONS: There are very limited, if any, Level I or II data regarding methicillin resistant S. aureus screening and decolonization. As the sequelae of a surgical site infection can be disastrous, expert opinions recommend that plastic surgeons vigorously address methicillin-resistant S. aureus colonization and infection. The authors have developed and recommend a simple decolonization protocol that includes treatment of the umbilicus, ear canal, and nares to limit surgical-site infection and improve surgical outcomes. PMID- 27465173 TI - Discussion: Methicillin-Resistant Staphylococcus aureus Infections: A Comprehensive Review and a Plastic Surgeon's Approach to the Occult Sites. PMID- 27465174 TI - Time- versus Competency-Based Residency Training. AB - Graduate medical education is at the brink of a paradigm shift in educating the next generation of physicians. Over 100 years ago, the Flexner report helped usher in the Halstedian residency, based on timed exposure and knowledge assessment as the cornerstones of medical education. The addition of operative case logs and respective board examinations to the current model of surgical education has served to establish practice minimums; however, they do not provide any assessment of actual operative capability or clinical competence. Although these facets have been tempered over time, one could argue that they currently exist only as surrogates for the true goal of all graduate medical education: the development of competent, graduating physicians, capable of independent and ethical practice. There now exists a growing body of evidence that competency based medical education is this century's Flexnerian revolution. By the objective, subjective, and global assessment of competence, it is thought that we can more effectively and efficiently educate our trainees, provide much needed accountability to our individual patients and to the public as a whole, and establish a lasting model of self-motivated, lifelong learning. PMID- 27465175 TI - Aesthetic Plastic Surgery in Asians: Principles & Techniques. PMID- 27465176 TI - The Nose-Revision & Reconstruction: A Manual and Casebook. PMID- 27465177 TI - Uneventful versus Successful Reconstruction and Outcome Pathways in Implant-Based Breast Reconstruction with Acellular Dermal Matrices. AB - BACKGROUND: Meaningful data to help guide resource allocation for staged tissue expander/implant-based breast reconstruction are currently lacking. The authors seek to differentiate uneventful from successful reconstruction and identify common outcome pathways and factors that portend a deviation from an uneventful, two-stage, two-operation course. METHODS: A retrospective analysis of expander/implant reconstructions with or without acellular dermal matrix (2003 to 2009) was performed. Related postreconstructive events (including mastectomy flap necrosis, seroma, wound dehiscence, cellulitis, explantation, hematoma, and capsular revisions) were assessed for 2 years. Uneventful reconstruction was defined as exchange to breast implant within 2 years of tissue expander placement without complications, whereas successful reconstruction was defined as exchange to breast implant within 2 years with or without complications. Factors affecting reconstructive success were analyzed, and patterns of postreconstructive events were summarized as outcome pathways. RESULTS: Four hundred thirteen patients (295 with acellular dermal matrix and 118 without), with 602 breasts (432 with acellular dermal matrix and 170 without) underwent reconstruction. Forty-six percent of patients (48 percent with acellular dermal matrix and 40 percent without), experienced uneventful reconstruction. Reconstructive success was achieved in 337 patients (82 percent; 82.0 percent with acellular dermal matrix and 80.5 percent without), with reconstructive failure occurring in 58 patients. Multiple logistic regression analyses determined that cellulitis, seroma, and skin necrosis (OR, 15.8, 7.7, and 8.4, respectively) were highly predictive of reconstructive failure. The authors identified 10 distinct pathways experienced by tissue expander/implant patients that were characterized by specific postreconstructive events. CONCLUSION: The present study will facilitate discussions among patients, providers, and payers by providing a framework for understanding the myriad outcome pathways in implant-based reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27465178 TI - "Breast in a Day": Examining Single-Stage Immediate, Permanent Implant Reconstruction in Nipple-Sparing Mastectomy. AB - BACKGROUND: Nipple-sparing mastectomy with immediate, permanent implant reconstruction offers patients a prosthetic "breast in a day" compared to tissue expander techniques requiring multiple procedures. METHODS: Patients undergoing nipple-sparing mastectomy with immediate, permanent implant reconstruction were reviewed with patient demographics and outcomes analyzed. RESULTS: Of 842 nipple sparing mastectomies from 2006 to June of 2015, 160 (19.0 percent) underwent immediate, permanent implant reconstruction. The average age and body mass index were 46.5 years and 23.3 kg/m. The majority of implants were either Allergan Style 20 (48.1 percent) or Style 15 (22.5 percent). The average implant size was 376.2 ml, and 91.3 percent of reconstructions used acellular dermal matrix. The average number of reconstructive operations was 1.3. Follow-up was 21.9 months. The most common major complication was major mastectomy flap necrosis (8.1 percent). The rate of reconstructive failure was 5.6 percent and implant loss was 4.4 percent. The most common minor complication was minor mastectomy flap necrosis (14.4 percent). The rates of full-thickness and partial-thickness nipple necrosis were 4.4 and 7.5 percent, respectively. Age older than 50 years (p = 0.0276) and implant size greater than 400 ml (p = 0.0467) emerged as independent predictors of overall complications. Obesity (p = 0.4073), tobacco use (p = 0.2749), prior radiation therapy (p = 0.4613), and acellular dermal matrix (p = 0.5305) were not associated with greater complication rates. CONCLUSION: Immediate, permanent implant reconstruction in nipple-sparing mastectomy provides patients with a breast in a day in less than two procedures, with a low complication rate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27465179 TI - Early Detection of Lymphatic Disorder and Treatment for Lymphedema following Breast Cancer. AB - BACKGROUND: Upper extremity edema following surgical treatment for breast cancer does not always result in chronic breast cancer-related lymphedema. Changes in the findings of indocyanine green lymphography and upper extremity volume following breast cancer surgery were observed prospectively to understand the early changes in lymphatic function and to establish a new strategy for early diagnosis and treatment of breast cancer-related lymphedema. METHODS: Lymphatic function for 196 consecutive breasts was examined using indocyanine green lymphography and bilateral upper extremity volume before surgery and 1, 3, 6, 9, and 12 months after surgery. When a "stardust," "diffuse," or "no flow" pattern was observed, patients were diagnosed with lymphatic disorder and subsequently underwent conservative treatments such as compression sleeve therapy. RESULT: In 35 patients, lymphatic disorder was observed after a mean of 5.2 +/- 3.0 months after surgery. In 21 of these patients, no significant limb volume change was observed. In 14 patients, lymphatic disorder and volume change appeared simultaneously. In 11 of 35 patients, lymphatic function improved later, and compression therapy was discontinued. Lymph node dissection, radiation therapy to axillary lymph node, and the use of docetaxel chemotherapy were significant risk factors for lymphatic disorder. No patients experienced cellulitis during the study period. CONCLUSIONS: Lymphatic function disorder could be detected before volume changes. By early intervention with conservative treatments, lymphatic function improved in just under one-third of cases. Indocyanine green lymphography for high-risk patients may be useful for detecting lymphatic disorder early, thereby increasing the chance for disease cure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27465180 TI - Distance to a Plastic Surgeon and Type of Insurance Plan Are Independently Predictive of Postmastectomy Breast Reconstruction. AB - BACKGROUND: The psychosocial benefits of postmastectomy breast reconstruction are well established; however, health care barriers persist. The authors evaluated statewide patient population to further identify obstacles to reconstruction. METHODS: A linked data set combining the North Carolina Central Cancer Registry with administrative claims from Medicare, Medicaid, and private insurance plans identified women diagnosed with breast cancer from 2003 to 2006. For inclusion in the study, women must have had a mastectomy within 6 months of diagnosis and had continuous insurance enrollment at least 2 years postoperatively (n = 5381). Multivariable logistic regression was used to model odds of reconstruction. RESULTS: Approximately 20 percent underwent reconstruction (n = 1130). Distance to a plastic surgeon-10 to 20 miles (OR, 0.78) and greater than 20 miles (OR, 0.73; p < 0.05)-was significantly predictive of no reconstruction, independent of other well-known disparities, including age, race, rural location, and lower household income. Women with government-funded health care, such as Medicare (OR, 0.58) and Medicaid (OR, 0.24; p < 0.001), were also significantly less likely to undergo reconstruction. Consistent with previous study, advanced cancer stage and receipt of radiation therapy decreased the likelihood of reconstruction. Furthermore, when the authors compared immediate to delayed reconstruction, rural location, chemotherapy, and radiation therapy were significantly predictive of delay. CONCLUSIONS: This is the first population-based study to demonstrate distance to care and insurance plan as significant predictors of receipt of reconstruction. Additional research is needed to understand health care barriers and to determine whether distance to a plastic surgeon can be ameliorated by outreach programs. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 27465181 TI - Discussion: Distance to a Plastic Surgeon and Type of Insurance Plan Are Independently Predictive of Postmastectomy Breast Reconstruction. PMID- 27465182 TI - Management of Complications Caused by Permanent Fillers in the Face: A Treatment Algorithm. AB - BACKGROUND: Nonresorbable substances are still injected to enhance soft-tissue volumes and fill subcutaneous defects. Inflammatory reactions (often termed granulomas) to these materials can be functionally and socially disabling. Most therapeutic options used until now are nonspecific antiinflammatory treatments, targeting an ill-defined immune reaction of undefined cause. The minimally invasive intralesional laser treatment can remove the foreign substance and the inflammatory reaction with an 808-nm diode laser. METHODS: Two hundred nineteen consecutive patients referred from September of 2006 until June of 2013 for inflammatory reactions to permanent facial fillers and treated with this technique at the authors' institution with a minimum 6-month follow-up were studied. All patients were screened with an ultrasound soft-tissue examination and the lesions were classified as either cystic (implants inserted by bolus injections) or infiltrating (as in microdeposit injection). The authors' therapeutic approach is summarized in an algorithm: infiltrating patterns were treated with intralesional laser treatment alone, whereas cystic distribution cases were also drained through stab wound incisions. The mean patient age was 49 years (range, 23 to 72 years); 204 patients were women. RESULTS: Partial improvement was obtained in 30 percent of patients, whereas 8 percent discontinued the treatment because of a lack of satisfaction. Lesions disappeared completely in 62 percent. Complications included transient swelling in all cases, hematoma in 2 percent, secondary sterile abscess in 9.5 percent, and minimal scarring in 10 percent. CONCLUSION: A problem-oriented systematic approach to inflammatory complications from permanent fillers is proposed, based on the comprehensive work from the past 7 years, with an overall improvement rate of 92 percent. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27465183 TI - Technical Maneuvers to Decrease Warping of Peripheral Costal Cartilage Grafts. AB - BACKGROUND: Cartilage warping has plagued reconstructive and cosmetic rhinoplasty since the introduction of extraanatomical cartilage use. The authors' group theorized that, rather than focusing on the prevention of the innate tendency of rib graft warping, it may be possible to redirect the stressors toward themselves and use these forces with oppositional suturing techniques to compensate for these intrinsic characteristics. METHODS: Fresh cadaver cartilage was obtained from the costosternal junction of two rib cages (aged 77 and 99 years). The cartilage was cut manually into 4 * 2.5 * 20-mm cross-sections from the cephalic edges of each of the harvested specimens. The specimens from the right chest were used as the control and the left segments underwent an oppositional suturing technique (n = 10) of the cephalic peripheral segment of the cartilage. RESULTS: Overall, the control group experienced a 724.2 percent increase in the mean degree of warping (p < 0.001). In contrast, the oppositional suturing group experienced a mean decrease in warping angle relative to baseline of only 35.7 percent. At 1 month, the oppositional suturing group displayed significantly decreased warping compared with the control group. CONCLUSIONS: This is a novel cadaveric study evaluating the benefit of oppositional suturing techniques in peripheral costal cartilage grafts. Multiple techniques and maneuvers have been borne out of the frustration of these inherent characteristics of costal cartilage grafts. Oppositional suturing techniques are a useful tool available to surgeons performing nasal reconstruction and revision rhinoplasty to maximize the amount of useful costal cartilage graft. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27465184 TI - Advances and Refinement in Hyaluronic Acid Facial Fillers. AB - Fillers temporarily augment deflated or ptotic facial compartments to restore a youthful appearance. Hyaluronic acids predominate the fillers market because of their focal volumization, duration of effect, low incidence of adverse reactions, and reversibility. Being able to properly perform these in-office procedures will ensure safety for patients and provide aesthetically optimal results. This communication provides the senior author's (R.J.R.) stepwise approach to facial aging and deflation with soft-tissue injectable fillers. PMID- 27465185 TI - Phenotypic Analysis of Stromal Vascular Fraction after Mechanical Shear Reveals Stress-Induced Progenitor Populations. AB - BACKGROUND: Optimization of fat grafting continues to gain increasing attention in the field of regenerative medicine. "Nanofat grafting" implements mechanical emulsification and injection of standard lipoaspirate for the correction of superficial rhytides and skin discoloration; however, little is known about the cellular constituents of the graft. Based on recent evidence that various stressors can induce progenitor activity, the authors hypothesized that the shear forces used in common fat grafting techniques may impact their regenerative capacities. METHODS: Lipoaspirates were obtained from 10 patients undergoing elective procedures. Half of each sample was subjected to nanofat processing; the other half was left unchallenged. The viscosity of each sample was measured for computational analysis. The stromal vascular fraction of each sample was isolated, quantified, and analyzed by means of flow cytometry with two multicolor fluorescence antibody panels. RESULTS: Standard lipoaspirate is ideally suited for mechanical stress induction. The mechanical emulsification involved in nanofat processing did not affect cell number; however, viability was greatly reduced when compared with the stromal vascular fraction of standard lipoaspirate. Interestingly, nanofat processing resulted in stress-induced stromal vascular fraction with a higher proportion of endothelial progenitor cells, mesenchymal stem cells, and multilineage differentiating stress-enduring cells. Single-parameter analysis also revealed significant increases in CD34, CD13, CD73, and CD146 of the stress-induced stromal vascular fraction, markers associated with mesenchymal stem cell activity. CONCLUSIONS: Mechanical processing used in techniques such as nanofat grafting induces the up-regulation of progenitor phenotypes consistent with multipotency and pluripotency. These data provide a first step in characterizing the potential regenerative benefits realized through stress induction in fat grafting. CLINCAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27465186 TI - Effects of the Ultra-High-Frequency Electrical Field Radiofrequency Device on Mouse Skin: A Histologic and Molecular Study. AB - BACKGROUND: Radiofrequency technology is one of the most recently developed methods for noninvasive skin tightening and facial contouring, and works by generating thermal energy in the deep dermis. Although clinical improvements have been reported using radiofrequency devices, there are few histologic and molecular studies about the mechanisms of dermal collagen remodeling. The authors investigated the histologic effects of an ultra-high-frequency electrical field (40.68 MHz) radiofrequency device (Polargen) on collagen remodeling in hairless mouse skin and evaluated its relative molecular mechanism. METHODS: The radiofrequency was applied to the dorsal skin of hairless mice three times per week for 2 weeks. At 21 days after initial treatment, treated skin and nontreated control skin samples were excised for semiquantitative analysis of histologic features, including collagen. The authors also checked the mRNA expression levels of collagen type 1, transforming growth factor (TGF)-beta, matrix metalloproteinase-1, vascular endothelial growth factor, tumor necrosis factor alpha, and interleukin-1. RESULTS: Histologic examination revealed epidermal hyperplasia, increased collagen staining, and fat atrophy in treated skin area compared with the nontreated skin area. In addition, mRNA expression of collagen type I, TGF-beta, and vascular endothelial growth factor in radiofrequency treated areas was significantly increased compared with that in untreated control areas (p < 0.05, p < 0.05, and p < 0.01, respectively). CONCLUSIONS: These results suggest that the device may facilitate replacement of subcutaneous fat tissue with new collagen in association with the increased mRNA levels in TGF beta and vascular endothelial growth factor. Therefore, this device may effectively reduce adipose tissue and achieve facial contouring in addition to skin tightening. PMID- 27465187 TI - A Comparison of Outcomes of Triceps Motor Branch-to-Axillary Nerve Transfer or Sural Nerve Interpositional Grafting for Isolated Axillary Nerve Injury. AB - BACKGROUND: Deltoid paralysis following isolated axillary nerve injury can be managed with triceps motor branch transfer or interpositional grafting. No consensus exists on the treatment that results in superior deltoid function. The purpose of this study was to review the authors' experience with axillary nerve injury management and compare functional outcomes following these two treatment options. METHODS: Twenty-nine adult isolated axillary nerve injury patients that had either interpositional nerve grafting or triceps motor branch transfer with greater than 1 year of follow-up between 2002 and 2013 were reviewed for demographic and clinical factors and functional outcomes of deltoid reinnervation, including clinical examination (shoulder abduction and forward flexion graded by the Medical Research Council system) and electromyographic recovery. Disabilities of the Arm, Shoulder, and Hand scale grades were also compared. RESULTS: Twenty-one patients had a triceps motor transfer and eight had interpositional nerve grafting. At a mean follow-up of 22 months, Medical Research Council scores were greater in the grafting group compared with the nerve transfer group (4.3 versus 3.0), and more graft patients achieved useful deltoid function (Medical Research Council score >=3) recovery (100 percent versus 62 percent); however, both groups had similar improvement in self-reported disability: change in Disabilities of the Arm, Shoulder, and Hand score of 11 following nerve transfer versus 15 following nerve graft. CONCLUSIONS: Although the question of nerve transfer versus grafting for restoration of axillary nerve function is controversial, this study demonstrates that grafting can result in good objective functional outcomes, particularly during an earlier time course after injury. This question requires further investigation in a larger, prospective patient population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27465188 TI - Discussion: A Comparison of Outcomes of Triceps Motor Branch-to-Axillary Nerve Transfer or Sural Nerve Interpositional Grafting for Isolated Axillary Nerve Injury. PMID- 27465189 TI - Cadaveric Investigation of Active Finger Range of Motion for Detection of Intratendinous Needle Placement. AB - BACKGROUND: The authors' purpose was to determine if investigators can predict whether a needle is within a finger's flexor tendon by postinsertion tactile and visualization evaluation in an active range-of-motion cadaver model. METHODS: In 48 cadaver fingers, a 25-gauge needle, with a 1-cc syringe attached, was placed into one of three randomly assigned positions at the A2 pulley level: within the flexor digitorum profundus, within the flexor digitorum superficialis, or outside both flexors and the sheath. Each finger was cycled through full active range of motion as three hand surgeons, blinded to each other's responses and needle position, recorded whether they thought the needle was intratendinous. The initial investigator confirmed needle position after each surgeon's assessment. RESULTS: Active cadaver finger range of motion did not allow surgeons to accurately determine whether a needle was in a flexor tendon. There was no statistically significant agreement among the surgeons about whether the needle was intratendinous. CONCLUSION: Because of poor interobserver agreement, sensitivity, and negative predictive value, we conclude that finger range of motion is not a reliable test to detect intratendinous needle placement in this cadaver model. PMID- 27465190 TI - Improved Short-Term Outcomes following Orthognathic Surgery Are Associated with High-Volume Centers. AB - BACKGROUND: Previous studies assessing outcomes following orthognathic surgery rely primarily on single-center/surgeon experience. In addition to issues of generalizability, these studies are limited in evaluating the effect of operative volume on patient outcomes. METHODS: Orthognathic procedures were identified in the 1999 to 2011 Healthcare Cost and Utilization Project Nationwide Inpatient Sample. Outcomes included occurrence of any in-hospital complication, extended length of stay (>2 days), and increased costs (>$10,784). High-volume hospitals were defined as the 90th percentile of case volume or higher (>31 cases/year). Univariate and multivariate analyses were conducted to identify independent predictors of outcomes. Trend analyses were performed to assess changes in the annual rate of patients treated at high-volume hospitals over the study period. RESULTS: Among 101,692 orthognathic surgery patients, 19.6 percent underwent concurrent ancillary procedures (i.e., genioplasty, rhinoplasty, or septoplasty), and 37.6 percent underwent double-jaw surgery. Fifty-three percent were treated at high-volume hospitals. High-volume hospitals more often performed ancillary procedures (21.4 percent versus 17.4 percent; p < 0.001) and double-jaw surgery (41.3 percent versus 33.4 percent; p < 0.001). After adjustments for clinical and hospital characteristics, patients treated at high-volume hospitals were less likely to experience any complication (OR, 0.75; 95 percent CI, 0.70 to 0.81; p < 0.001) and extended length of stay (OR, 0.71; 95 percent CI, 0.68 to 0.75; p < 0.001). There was a 2 percent annual increase in the rate of patients treated at high-volume hospitals over the study period (incidence rate ratio, 1.02; 95 percent CI, 1.01 to 1.03; p < 0.001). CONCLUSIONS: The majority of orthognathic cases nationwide are performed at a small number of high-volume hospitals. These hospitals discharge patients earlier, perform more complex procedures, and have fewer complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 27465191 TI - A Treatment Protocol for Velopharyngeal Insufficiency and the Outcome. AB - BACKGROUND: A simple algorithm is applied to treat velopharyngeal insufficiency. The purpose of this study was to assess its success rate and complications. METHODS: The diagnosis includes speech perceptual assessment and nasopharyngoscopy, focusing on velopharyngeal closure ratio. The treatment is composed of a double-opposing Z-plasty for marginal velopharyngeal insufficiency or a pharyngeal flap for moderate to severe velopharyngeal insufficiency. A retrospective chart review was conducted for 84 consecutive nonsyndromic postpalatoplasty patients undergoing velopharyngeal insufficiency surgery from August of 2007 to December of 2014. The demographic, perioperative, and follow-up data were collected. Statistical analyses were performed. RESULTS: Mean age at velopharyngeal insufficiency surgery was 7.0 years. The overall improvement rate for patients was 86.9 percent. Nine patients in the double-opposing Z-plasty group and two patients in the pharyngeal flap group were refractory to velopharyngeal insufficiency surgery. The improvement rates for each surgical group were 80.4 percent for the double-opposing Z-plasty group and 94.7 percent for the pharyngeal flap group. There were no significant differences in postoperative velopharyngeal function between the coronal and noncoronal groups. Airway-associated complications were observed in nine patients (10.7 percent). The complications in the double-opposing Z-plasty group were observed in two patients (4.3 percent), and none of the patients presented obstructive sleep apnea. Seven patients (18.4 percent) in the pharyngeal flap group showed postoperative snoring, and one (2.6 percent) of them presented with obstructive sleep apnea. CONCLUSION: The authors' algorithm is a simple patient- and surgeon friendly strategy to obtain satisfactory improvement of velopharyngeal function for velopharyngeal insufficiency patients, with a low risk of airway complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27465192 TI - Surgical Reconstruction of Traumatic Partial Ear Defects Based on a Novel Classification of Defect Sizes and Surrounding Skin Conditions. AB - BACKGROUND: Although a standard classification system and corresponding reconstruction methods are well described for microtia, establishing a classification system and corresponding surgical strategies for traumatic ear defects is difficult because the size, shape, and local skin conditions of each defect differ considerably. In this article, the authors describe a useful new classification system and corresponding surgical approaches. METHODS: Ear defects were classified into four types according to defect size and surrounding skin conditions. Defects in which the postauricular skin is of good quality are classified as types I, II, and III. The rest are type IV defects. Four ears (type I defects) were reconstructed using conchal cartilage and posterior auricular flaps. In 51 ears, costal cartilage and posterior auricular flaps were used for single-stage (type II defects, n = 31) or two-stage (type III defects, n = 20) reconstructions. In five instances of severe posterior auricular cutaneous scarring (type IV defects), temporoparietal fascial flaps were created to cover costal cartilage frameworks. RESULTS: Sixty subjects with traumatic partial ear defects were followed for 6 months to 6 years. Most (n = 55) were satisfied with their results. Two patients complained of an unnatural junction between the graft framework and residual ear stump. One was dissatisfied with the reduced ear size, caused by improper fixation and skin flap contraction. Another developed minor framework exposure because of skin necrosis, which healed with conservative management. CONCLUSION: Using our new classification system for partial traumatic ear defects based on defect size and contiguous skin condition, the corresponding surgical repair approach was applied consistently, yielding acceptable results and few complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27465193 TI - Complications Related to Pectus Carinatum Correction: Lessons Learned from 15 Years' Experience. Management and Literature Review. AB - BACKGROUND: Various methods of corrective thoracoplasty for pectus carinatum deformity have been described, but to date no studies describe a review of complications and how to manage them. Complications are dependent not only on the technique used and the patient's age, but also on the experience of the treating surgeon. The authors present their 15 years' experience with surgical correction of pectus carinatum and the complications that have occurred. A literature review regarding complications with pectus carinatum surgery is performed. METHODS: A retrospective review of 95 patients (mean age, 19 years) was performed. One hundred four surgical procedures for repair of pectus carinatum were performed from July of 2000 to July of 2015 using a modified Ravitch technique, bioabsorbable material, postoperative bracing, and in some cases a diced rib cartilage graft technique. Intraoperative and postoperative complications were evaluated. RESULTS: The mean patient follow-up was 13.6 months (range, 4 months to 9.75 years). Intraoperative complications were pleura lesion and laceration of the internal mammary vein. Postoperative complications were recurrent mild protrusion, persistent protrusion of one or two costal cartilages, minor wound healing delay, skin ulcer, hypertrophic scar, transient intercostal dysesthesia, marginal pneumothorax, seroma, meningitis, and epidural hematoma. CONCLUSIONS: In our reported series of pectus carinatum repair, increasing experience and progressively less extensive techniques have resulted in fewer complications, low morbidity, and early return to activity. Complications were observed in the early period of application, predominantly because of a lack of experience, and usually subsided with increasing numbers of patients and frequency of surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27465194 TI - Malignant Melanoma: Beyond the Basics. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Discuss the initial management of cutaneous malignant melanoma with regard to diagnostic biopsy and currently accepted resection margins. 2. Be familiar with the management options for melanoma in specific situations such as subungual melanoma, auricular melanoma, and melanoma in the pregnant patient. 3. Discuss the differentiating characteristics of desmoplastic melanoma and its treatment options. 4. List the indications for sentinel lymph node biopsy and be aware of the ongoing trials and current literature. 5. Discuss the medical therapies available to patients with metastatic melanoma. SUMMARY: Management of the melanoma patient is a complex and evolving subject. Plastic surgeons should be aware of the recent changes in the field. Excisional biopsy remains the gold standard for diagnosis, although there is no evidence that use of other biopsy types alters survival or recurrence. Wide local excisions should be carried out with margins as recommended by National Comprehensive Cancer Network guidelines according to lesion Breslow depth, with sentinel lymph node biopsy being offered to all medically suitable candidates with intermediate thickness melanomas (1.0 to 4.0 mm), and with sentinel lymph node biopsy being considered for high-risk lesions (ulceration and/or high mitotic figures) with melanomas of 0.75 to 1.0 mm. Melanomas diagnosed during pregnancy can be treated with preoperative lymphoscintigraphy and wide local excision under local anesthesia, with sentinel lymph node biopsy under general anesthesia delayed until after delivery. Management of desmoplastic melanoma is currently controversial with regard to the indications for sentinel lymph node biopsy and the efficacy of postoperative radiation therapy. Subungual and auricular melanoma have evolved from being treated by amputation of the involved appendage to less radical procedures-ear reconstruction is now attempted in the absence of gross invasion into the perichondrium, and subungual melanomas may be treated with wide local excision down to and including the periosteum, with immediate full-thickness skin grafting over bone. Although surgical treatment remains the current gold standard, recent advances in immunotherapy and targeted molecular therapy for metastatic melanoma show great promise for the development of medical therapies for melanoma. PMID- 27465195 TI - Industry Financial Relationships in Plastic Surgery: Analysis of the Sunshine Act Open Payments Database. AB - BACKGROUND: Limited data exist regarding industry financial relationships in plastic surgery. The Sunshine Act Open Payments Database currently represents the largest repository of these data, but is limited primarily to queries of individual providers. The purpose of this study was to analyze these data and present them in a manner that better delineates these relationships, and to compare plastic surgery with other surgical subspecialties. METHODS: A review of the Open Payments Database was performed for the period from January 1, 2014, to December 31, 2014. These data were analyzed with respect to types of payments, characteristics of plastic surgeons and companies, and comparison with other surgical subspecialties. RESULTS: A total of 49,053 payments from 274 companies were identified that were made to 4812 plastic surgeons (475 academic and 4337 private practice). The total value of payments was $17,091,077. Food and beverage represented the most common type of payment (82.2 percent). Royalties and licensing represented the highest valued type of payment (35.7 percent), but were received by only a minority of plastic surgeons (0.5 percent). No significant differences were identified between academic and private practice plastic surgeons in the value or quantity of payments. Plastic surgery (54.5 percent) exhibited the lowest prevalence of industry financial relationships compared with otolaryngology (57.9 percent), orthopedics (62.4 percent), neurosurgery (87.8 percent), and urology (63.1 percent) (p < 0.001). CONCLUSIONS: Approximately half of all plastic surgeons have industry financial relationships. The prevalence of these relationships is comparatively less than in other surgical subspecialties. PMID- 27465196 TI - Performance on a Surgical In-Training Examination Varies by Training Year and Pathway. AB - BACKGROUND: Few studies in surgery have addressed medical knowledge competency training as defined by the Accreditation Council for Graduate Medical Education. As in-training examinations are ubiquitous educational tools for surgical residents in the United States, insights into examination performance may help fill this void. The purpose of this study was to determine the relationship between In-Service Examination performance and training characteristics in plastic surgery. METHODS: This retrospective cohort study reviewed performance data for the Plastic Surgery In-Service Training Examination for the years 2012 to 2015. Comparisons were made both within and between training pathways by means of Kruskal-Wallis and Mann-Whitney U tests. RESULTS: Data were available for 1367 independent (37.9 percent) and 2240 integrated residents (62.1 percent). Among integrated residents, performance increased with additional years of training (p < 0.001), but no difference existed between postgraduate year-5 and postgraduate year-6 residents (p > 0.05). Similarly, independent resident examination performance increased by year of training (p < 0.001), with no difference between postgraduate year-2 and postgraduate year-3 residents (p > 0.05). At each level of training (postgraduate years 4 to 6), integrated residents outperformed their independent resident colleagues (postgraduate years 1 to 3) (p < 0.001). CONCLUSIONS: Performance on the Plastic Surgery In-Service Training Examination increases during residency, with integrated residents outperforming independent residents. These findings may have implications for medical knowledge competency training as defined by the Accreditation Council for Graduate Medical Education. PMID- 27465197 TI - Reply: Efficacy and Safety of Povidone-Iodine Irrigation in Reducing the Risk of Capsular Contracture in Aesthetic Breast Augmentation: A Systematic Review and Meta-Analysis. PMID- 27465198 TI - Reply: Epidemiologic Overview of Synkinesis in 353 Patients with Longstanding Facial Paralysis under Treatment with Botulinum Toxin for 11 Years. PMID- 27465202 TI - Nanoparticles in the lung and their protein corona: the few proteins that count. AB - The formation of protein coronae on nanoparticles (NPs) has been investigated almost exclusively in serum, despite the prevailing route of exposure being inhalation of airborne particles. In addition, an increasing number of nanomedicines, that exploit the airways as the site of delivery, are undergoing medical trials. An understanding of the effects of NPs on the airways is therefore required. To further this field, we have described the corona formed on polystyrene (PS) particles with different surface modifications and on titanium dioxide particles when incubated in human bronchoalveolar lavage fluid (BALF) from patients with pulmonary alveolar proteinosis (PAP). We show, using high resolution quantitative mass spectrometry (MS(E)), that a large number of proteins bind with low copy numbers but that a few "core" proteins bind to all particles tested with high fidelity, averaging the surface properties of the different particles independent of the surface properties of the specific particle. The averaging effect at the particle surface means that differing cellular effects may not be due to the protein corona but due to the surface properties of the nanoparticle once inside the cell. Finally, the adherence of surfactant associated proteins (SP-A, B and D) suggests that there may be interactions with lipids and pulmonary surfactant (PSf), which could have potential in vivo health effects for people with chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), or those who have increased susceptibility toward other respiratory diseases. PMID- 27465203 TI - Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity. AB - Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055). Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly. The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature. PMID- 27465199 TI - The use of mosquito repellents at three sites in India with declining malaria transmission: surveys in the community and clinic. AB - BACKGROUND: Repellents such as coils, vaporizers, mats and creams can be used to reduce the risk of malaria and other infectious diseases. Although evidence for their effectiveness is limited, they are advertised as providing an additional approach to mosquito control in combination with other strategies, e.g. insecticide-treated nets. We examined the use of repellents in India in an urban setting in Chennai (mainly Plasmodium vivax malaria), a peri-urban setting in Nadiad (both P. vivax and P. falciparum malaria), and a more rural setting in Raurkela (mainly P. falciparum malaria). METHODS: The use of repellents was examined at the household level during a census, and at the individual level in cross-sectional surveys and among patients visiting a clinic with fever or other symptoms. Factors associated with their use were examined in a multivariate analysis, and the association between malaria and the use of repellents was assessed among survey- and clinic participants. RESULTS: Characteristics of participants differed by region, with more people of higher education present in Chennai. Use of repellents varied between 56-77 % at the household level and between 32-78 % at the individual level. Vaporizers were the main repellents used in Chennai, whereas coils were more common in Nadiad and Raurkela. In Chennai and Nadiad, vaporizers were more likely to be used in households with young male children. Vaporizer use was associated with higher socio-economic status (SES) in households in Chennai and Nadiad, whereas use of coils was greater in the lower SES strata. In Raurkela, there was a higher use of coils among the higher SES strata. Education was associated with the use of a repellent among survey participants in Chennai and clinic study participants in Chennai and Nadiad. Repellent use was associated with less malaria in the clinic study in Chennai and Raurkela, but not in the surveys, with the exception of the use of coils in Nadiad. CONCLUSIONS: Repellents are widely used in India. Their use is influenced by the level of education and SES. Information on effectiveness and guidance on choices may improve rational use. PMID- 27465204 TI - Comparison of Effectiveness Between Delamanid and Bedaquiline Among Patients with Multidrug-Resistant Tuberculosis: A Markov Model Simulation Study. AB - BACKGROUND: No clear evidence on the comparative effectiveness of delamanid (DLM) and bedaquiline (BDQ) has been published. OBJECTIVE: This study aims to estimate the incremental effectiveness of DLM versus BDQ in patients with multidrug resistant tuberculosis (MDR-TB). METHODS: We developed a Markov model based on a cohort with MDR-TB, which consisted of success, failure, loss to follow-up, and death. The cohort simulation was conducted assuming each patient was 36 years old and, lived until age 82, and that the cycle length was 1 year. Patients with an inadequate response to DLM, the background regimen, or BDQ for 2 years were transitioned through the next treatment sequence. We evaluated the incremental effectiveness of the drugs using the quality-adjusted life-year (QALY) resulting from this Markov model over a lifetime. RESULTS: The incremental effectiveness of DLM (13.96 QALYs) was greater by 2.44 QALYs per patient than the background regimen (11.52 QALY), while the incremental effectiveness of BDQ (10.40 QALY) was higher by 1.14 QALY per patient than the background regimen (9.26 QALY). Consequently, the incremental effectiveness of DLM was relatively more positive by 1.30 QALY than those of BDQ per patient over a lifetime. LIMITATIONS: This study is a simulation study. Therefore, the treatment sequence for patients may be different in the real world. CONCLUSIONS: Our lifetime simulated data found that DLM was relatively more favorable than BDQ. A Markov model can be considered an alternative approach when there is an absence of head-to-head clinical data. PMID- 27465205 TI - High production of fatty alcohols in Escherichia coli with fatty acid starvation. AB - BACKGROUND: Microbial biofuel synthesis attracting increasing attention. Great advances have been made in producing fatty alcohols from fatty acyl-CoAs and fatty acids in Escherichia coli. However, the low titers and limited knowledge regarding the basic characteristics of fatty alcohols, such as location and toxicity, have hampered large-scale industrialization. Further research is still needed. RESULTS: In this study, we designed a novel and efficient strategy to enhance fatty alcohol production by inducing fatty acid starvation. We report the first use of deletions of acyl-ACP thioesterases to enhance fatty alcohol production. Transcriptional analysis was conducted to investigate the mechanism of the designed strategy. Then, fatty alcohol production was further enhanced by deletion of genes from competing pathways. Fatty alcohols were shown to be extracellular products with low toxicity. The final strain, E. coli MGL2, produced fatty alcohols at the remarkable level of 6.33 g/L under fed-batch fermentation, representing the highest reported titer of fatty alcohols produced by microorganisms. CONCLUSIONS: Deletions of genes responsible for synthesis of fatty acids and competing products are promising strategies for fatty alcohol production. Our investigation of the location and toxicity of fatty alcohols suggest bright future for fatty alcohol production in E. coli. PMID- 27465206 TI - A Room Temperature Ultrasensitive Magnetoelectric Susceptometer for Quantitative Tissue Iron Detection. AB - Iron is a trace mineral that plays a vital role in the human body. However, absorbing and accumulating excessive iron in body organs (iron overload) can damage or even destroy an organ. Even after many decades of research, progress on the development of noninvasive and low-cost tissue iron detection methods is very limited. Here we report a recent advance in a room-temperature ultrasensitive biomagnetic susceptometer for quantitative tissue iron detection. The biomagnetic susceptometer exploits recent advances in the magnetoelectric (ME) composite sensors that exhibit an ultrahigh AC magnetic sensitivity under the presence of a strong DC magnetic field. The first order gradiometer based on piezoelectric and magnetostrictive laminate (ME composite) structure shows an equivalent magnetic noise of 0.99 nT/rt Hz at 1 Hz in the presence of a DC magnetic field of 0.1 Tesla and a great common mode noise rejection ability. A prototype magnetoelectric liver susceptometry has been demonstrated with liver phantoms. The results indicate its output signals to be linearly responsive to iron concentrations from normal iron dose (0.05 mg Fe/g liver phantom) to 5 mg Fe/g liver phantom iron overload (100X overdose). The results here open up many innovative possibilities for compact-size, portable, cost-affordable, and room temperature operated medical systems for quantitative determinations of tissue iron. PMID- 27465208 TI - Responsiveness to Intervention in Children with Dyslexia. AB - We examined the responsiveness to a 12-week phonics intervention in 54 s-grade Dutch children with dyslexia, and compared their reading and spelling gains to a control group of 61 typical readers. The intervention aimed to train grapheme phoneme correspondences (GPCs), and word reading and spelling by using phonics instruction. We examined the accuracy and efficiency of grapheme-phoneme correspondences, decoding words and pseudowords, as well as the accuracy of spelling words before and after the intervention. Moreover, responsiveness to intervention was examined by studying to what extent scores at posttest could directly or indirectly be predicted from precursor measures. Results showed that the children with dyslexia were significantly behind in all reading and spelling measures at pretest. During the intervention, the children with dyslexia made more progress on GPC, (pseudo)word decoding accuracy and efficiency, and spelling accuracy than the typical reading group. Furthermore, we found a direct effect of the precursor measures rapid automatized naming, verbal working memory and phoneme deletion on the dyslexic children's progress in GPC speed, and indirect effects of rapid automatized naming and phoneme deletion on word and pseudoword efficiency and word decoding accuracy via the scores at pretest. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27465209 TI - Why Are Reading Difficulties Associated with Mental Health Problems? AB - A growing literature indicates that children with reading difficulties are at elevated risk for mental health problems; however, little attention has been given to why this might be the case. Associations between reading difficulties and mental health differ substantially across studies, raising the possibility that these relationships may be ameliorated or exacerbated by risk or resilience promoting factors. Using socio-ecological theory as a conceptual framework, we outline four potential lines of research that could shed light on why children with reading difficulties are at risk of mental health problems and identify potential targets for intervention. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27465207 TI - Multislice CEST MRI improves the spatial assessment of tumor pH. AB - PURPOSE: Multislice maps of extracellular pH (pHe) are needed to interrogate the heterogeneities of tumors and normal organs. To address this need, we have developed a multislice chemical exchange saturation transfer (CEST) MRI acquisition method with a CEST spectrum-fitting method that measures in vivo pHe over a range of 6.3 to 7.4. METHODS: The phase offset multiplanar (POMP) method was adapted for CEST fast imaging with steady-state free precession (FISP) MRI to acquire multiple image slices with a single CEST saturation pulse. The Bloch McConnell equations were modified to include pH based on a calibration of pH and chemical exchange rate for the contrast agent iopamidol. These equations were used to estimate the pixel-wise pHe values throughout the multislice acidoCEST MR images of the tumor, kidney, bladder, and other tissues of a MDA-MB-231 tumor model. RESULTS: Multislice acidoCEST MRI successfully mapped a gradient of pHe from 6.73 to 6.81 units from the tumor core to rim, and also mapped a gradient of pHe 6.56 to 6.97 across the mouse kidney. The bladder was found to be pHe 6.3. CONCLUSION: AcidoCEST MRI with POMP acquisition and Bloch-McConnel analysis can map pHe in multiple imaging slices through the tumor, kidney, and bladder. This multislice evaluation facilitates assessments of spatial heterogeneity of tissue pHe. Magn Reson Med 78:97-106, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27465210 TI - Calibration of Self-Reports of Anxiety and Physiological Measures of Anxiety While Reading in Adults With and Without Reading Disability. AB - Reading difficulty has been linked to anxiety in adults yet and has not been systematically studied especially in compensated adults with dyslexia. This study examined the relationships between anxiety ratings and physiological arousal while reading among adults with reading disability (RD) compared to skilled readers (SR). Nineteen compensated adults with RD and 20 SR adults were administered a battery of reading tasks and anxiety self-report questionnaires. Physiological measures of arousal were recorded during text reading task. Adults with RD scored significantly lower than SR on all cognitive and reading related measures. They showed no differences on any of the self-report anxiety measures. Interestingly, in the skilled readers' sample, physiological arousal while reading correlated with trait anxiety. No correlations between physiological and self-reported data were found in the RD sample. These findings suggest a model of resiliency in compensated adults with reading disabilities that includes lower anxiety levels and a discord between anxiety reports and actual arousal rates. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27465211 TI - Causes of excessive late death after trauma compared with a matched control cohort. AB - BACKGROUND: Studies on mortality following trauma have been restricted mainly to in-hospital or 30-day death. Mortality risk may be sustained several years after trauma, but the causes of late death have not been elucidated. The aim was to investigate mortality and analyse causes of late death after trauma. METHODS: All injured patients from a regional trauma registry with long-term follow-up were matched in a 1 : 5 ratio with uninjured controls by age, sex and municipality. By linkage to national registries, long-term mortality, causes of death and co morbidity status were identified. Excess mortality was examined by calculating the all-cause mortality rate ratio (MRR). RESULTS: Among the trauma cohort of 7382 patients, 662 (9.0 per cent) died within 3 years after the index trauma; the 30-day mortality rate was 5.0 per cent. Compared with the control group (36 759 individuals), there was a sustained increase in mortality up to 3 years after trauma; the MRR was 2.88 (95 per cent c.i. 2.37 to 3.50) for days 31-365, 1.59 (1.24 to 2.04) for years 1-2 and 1.43 (1.06 to 1.92) for years 2-3. External causes, including new trauma, were far more common causes of late death in injured patients than in matched controls. CONCLUSION: Postinjury mortality is increased for several years after trauma. Excess mortality is largely attributed to recurrent trauma and other external causes of death. PMID- 27465212 TI - The Airway App : Laura Duggan / Pendar Labs. Available for iOS and Android, free download, 7.3 MB. PMID- 27465213 TI - Comparison of isoflurane and sevoflurane in cardiac surgery: a randomized non inferiority comparative effectiveness trial. AB - PURPOSE: Volatile anesthetics possess cardioprotective properties, but it is unknown if the cardioprotective effects extend equally to all members of the class. Although sevoflurane is a relatively newer anesthetic than isoflurane, its introduction into practice was not preceded by a head-to-head comparison with isoflurane in a trial focusing on clinically important outcomes. Our objective was to determine whether sevoflurane was non-inferior to isoflurane on a clinically important primary outcome in a heterogeneous group of adults undergoing cardiac surgery. METHODS: This was a pragmatic randomized non inferiority comparative effectiveness clinical trial in 464 adults having coronary artery bypass graft and/or single valve surgery during November 2011 to March 2014. The intervention was maintenance of anesthesia with sevoflurane (n = 231) or isoflurane (n = 233) administered at a dose of 0.5-2.0 MAC throughout the entire operation. All caregivers were blinded except for the anesthesiologist and perfusionist. The primary outcome was a composite of intensive care unit (ICU) length of stay >= 48 hr and all-cause 30-day mortality. We hypothesized that sevoflurane would be non-inferior to isoflurane (non-inferiority margin < 10% based on an expected event rate of 25%). Secondary outcomes included prolonged ICU stay, 30- and 365-day all-cause mortality, inotrope or vasopressor usage, new onset hemodialysis or atrial fibrillation, stroke, and readmission to the ICU. RESULTS: No losses to follow-up occurred. The primary outcome occurred in 25% of sevoflurane patients and 30% of isoflurane patients (absolute difference, -5.4%; one-sided 95% confidence interval, 1.4), thus non-inferiority was declared. Sevoflurane was not superior to isoflurane for the primary outcome (P = 0.21) or for any secondary outcomes. CONCLUSION: Sevoflurane is non-inferior to isoflurane on a composite outcome of prolonged ICU stay and all-cause 30-day mortality. Sevoflurane is not superior to isoflurane on any other of the clinically important outcomes. This trial was registered at clinicaltrials.gov; NCT01477151. PMID- 27465214 TI - The successful accomplishment of nutritional and clinical outcomes via the implementation of a multidisciplinary nutrition support team in the neonatal intensive care unit. AB - BACKGROUND: Nutritional support is critical for preterm infants in the neonatal intensive care unit (NICU). A multidisciplinary nutritional support team (NST) that focuses on providing optimal and individualized nutrition care could be helpful. We conducted a thorough evaluation of clinical and nutritional outcomes in a tertiary NICU following the implementation of an NST. METHODS: This study used a retrospective approach with historical comparisons. Preterm neonates < 30 weeks gestational age or weighing < 1250 g were enrolled. Clinical and nutritional outcomes were compared before and after the establishment of the NST. Medical records were reviewed, and clinical and nutritional outcomes were compared between the two groups. RESULTS: In total, 107 patients from the pre-NST period and 122 patients from the post-NST period were included. The cumulative energy delivery during the first week of life improved during the post-NST period (350.17 vs. 408.62 kcal/kg, p < 0.001). The cumulative protein and lipid deliveries also significantly increased. The time required to reach full enteric feedings decreased during the post-NST period (6.4 +/- 5.8 vs. 4.7 +/- 5.1 days, p = 0.016). Changes of Z-score in weight from admission to discharge exhibited more favorable results in the post-NST period (-1.13 +/- 0.99 vs.-0.91 +/- 0.74, p = 0.055), and the length of ICU stay significantly decreased in the post-NST period (81.7 +/- 36.6 vs. 72.2 +/- 32.9 days, p = 0.040). CONCLUSIONS: NST intervention in the NICU resulted in significant improvements in the provision of nutrition to preterm infants in the first week of life. There were also favorable clinical outcomes, such as increased weight gain and reduced length of ICU stay. Evaluable data remain sparse in the NICU setting with premature neonatal populations; therefore, the successful outcomes identified in this study may provide support for NST practices. PMID- 27465215 TI - Allele-specific locus binding and genome editing by CRISPR at the p16INK4a locus. AB - The clustered regularly interspaced short palindromic repeats (CRISPR) system has been adopted for a wide range of biological applications including genome editing. In some cases, dissection of genome functions requires allele-specific genome editing, but the use of CRISPR for this purpose has not been studied in detail. In this study, using the p16INK4a gene in HCT116 as a model locus, we investigated whether chromatin states, such as CpG methylation, or a single nucleotide gap form in a target site can be exploited for allele-specific locus binding and genome editing by CRISPR in vivo. First, we showed that allele specific locus binding and genome editing could be achieved by targeting allele specific CpG-methylated regions, which was successful for one, but not all guide RNAs. In this regard, molecular basis underlying the success remains elusive at this stage. Next, we demonstrated that an allele-specific single-nucleotide gap form could be employed for allele-specific locus binding and genome editing by CRISPR, although it was important to avoid CRISPR tolerance of a single nucleotide mismatch brought about by mismatched base skipping. Our results provide information that might be useful for applications of CRISPR in studies of allele-specific functions in the genomes. PMID- 27465216 TI - The Role of 5-Hydroxytryptamine in the Pathophysiology of Migraine and its Relevance to the Design of Novel Treatments. AB - BACKGROUND: Migraine is a highly prevalent neurovascular disorder. OBJECTIVE: Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5 HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5-HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder. Indeed, the development of sumatriptan and second generation triptans in the 1990's led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors). Although the triptans represent the current mainstay of acute antimigraine treatment, a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies. CONCLUSION: This mini-review outlines further developments in the design of novel (non vasoconstrictor) antimigraine treatments acting via 5-HT receptors, including selective agonists at 5-HT1D and 5-HT1F receptors, agonists at 5-HT1B/1D receptors combined with other properties as well as antagonists at 5-HT2B/2C, 5 HT3 and 5-HT7 receptors. It also touches upon the recent development of antagonists and antibodies at calcitonin gene-related peptide (CGRP) and its receptors, which produce a direct blockade of the CGRPergic vasodilator mechanisms involved in migraine. These alternative pharmacological approaches will hopefully lead to less side-effects. PMID- 27465217 TI - Vibrio sonorensis sp. nov. isolated from a cultured oyster Crassostrea gigas. AB - Strain CAIM 1076T was isolated from a cultured oyster Crassostrea gigas in Puerto Penasco, Sonora state, Mexico. The strain was taxonomically characterised by means of a genomic approach, comprising 16S rRNA gene sequence analysis, multilocus sequence analysis (MLSA), the DNA G+C content and whole genome analyses (ANI and GGDC), and by phenotypic characterisation. Strain CAIM 1076T was found to be catalase and oxidase positive, and cells were observed to be motile and facultative anaerobic. Analysis of the almost-complete 16S rRNA gene sequence placed this strain within the genus Vibrio; closely related species were Vibrio maritimus, Vibrio variabilis, Vibrio proteolyticus, and Vibrio nigripulchritudo with similarity values of 98.9, 98.5, 98.1, and 98.0 %, respectively. MLSA of six housekeeping genes (ftsZ, gapA, gyrB, recA, rpoA and topA) was performed with the closely related species. A draft genome sequence of strain CAIM 1076T was obtained. The DNA G+C content of this strain was determined to be 44.5 mol %. The genomic similarity values with V. maritimus were 71.6 % (ANIb), 85.1 % (ANIm) and a GGDC value of 20.3 +/- 2.3 %; with V. variabilis the genomic similarities were 71.8 % (ANIb), 85.4 % (ANIm) and 20.0 +/- 2.3 % (GGDC); with V. proteolyticus, 71.6 % (ANIb), 84.1 % (ANIm) and 18.8 +/- 2.2 % (GGDC); and with V. nigripulchritudo, 70.8 % (ANIb), 84.9 % (ANIm) and 20.5 +/- 2.3 % (GGDC). These ANI and GGDC values are below the thresholds for the delimitation of prokaryotic species, i.e., 95-96 and 70 %, respectively. Phenotypic characters also showed differences with the closely related species analysed. The results presented here support the description of a novel species, for which the name Vibrio sonorensis sp. nov. is proposed, with strain CAIM 1076T (=CECT 9100T, =DSM 102190T) as the type strain. PMID- 27465218 TI - Full inactivation of alphaviruses in single particle and crystallized forms. AB - Inherent in the study of viruses is the risk of pathogenic exposure, which necessitates appropriate levels of biosafety containment. Unfortunately, this also limits the availability of useful research instruments that are located at facilities not equipped to handle infectious pathogens. Abrogation of viral infectivity can be accomplished without severely disrupting the physical structure of the virus particle. Virus samples that are verifiably intact but not infectious may be enabled for study at research facilities where they would otherwise not be allowed. Inactivated viruses are also used in the development of vaccines, where immunogenicity is sought in the absence of active infection. We demonstrate the inactivation of Sindbis alphavirus particles in solution, as well as in crystallized form. Inactivation was accomplished by two different approaches: crosslinking of proteins by glutaraldehyde treatment, and crosslinking of nucleic acids by UV irradiation. Biophysical characterization methods, including dynamic light scattering and transmission electron microscopy, were used to demonstrate that the glutaraldehyde and UV inactivated Sindbis virus particles remain intact structurally. SDS-PAGE was also used to show evidence of the protein crosslinking that was expected with glutaraldehyde treatment, but also observed with UV irradiation. PMID- 27465219 TI - Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013. AB - AIMS/HYPOTHESIS: The relative contribution of increasing incidence and declining mortality to increasing prevalence of type 2 diabetes in Scotland is unclear. Trends in incidence and mortality rates are described for type 2 diabetes in Scotland between 2004 and 2013 by age, sex and socioeconomic deprivation. METHODS: Data for incident and prevalent cases of type 2 diabetes were obtained from the Scottish national diabetes register with number of deaths identified from linkage to mortality records. Population size and death data for Scotland by age, sex and socioeconomic deprivation were obtained from National Records of Scotland. Age- and sex-specific incidence and mortality rates stratified by year and deciles of socioeconomic status were calculated using Poisson models. RESULTS: There were 180,290 incident cases of type 2 diabetes in Scotland between 2004 and 2013. Overall, incidence of type 2 diabetes remained stable over time and was 4.88 (95% CI 4.84, 4.90) and 3.33 (3.28, 3.32) per 1000 in men and women, respectively. However, incidence increased among young men, remained stable in young women, and declined in older men and women. Incidence rates declined in all socioeconomic groups but increased after 2008 in the most deprived groups. Standardised mortality ratios associated with diabetes, adjusted for age and socioeconomic group, were 1.38 (1.36, 1.41) in men and 1.49 (1.45, 1.52) in women, and remained constant over time. CONCLUSIONS/INTERPRETATION: Incidence of type 2 diabetes has stabilised in recent years suggesting that increasing prevalence may be primarily attributed to declining mortality. Prevention of type 2 diabetes remains important, particularly among socioeconomically deprived populations. PMID- 27465222 TI - A cobalt(ii) iminoiodane complex and its scandium adduct: mechanistic promiscuity in hydrogen atom abstraction reactions. AB - In addition to oxometal [M(n+)[double bond, length as m-dash]O] and imidometal [M(n+)[double bond, length as m-dash]NR] units, transient metal-iodosylarene [M((n-2)+)-O[double bond, length as m-dash]IPh] and metal-iminoiodane [M((n-2)+) N(R)[double bond, length as m-dash]IPh] adducts are often invoked as a possible "second oxidant" responsible for the oxo and imido group transfer reactivity. Although a few metal-iodosylarene adducts have been recently isolated and/or spectroscopically characterized, metal-iminoiodane adducts have remained elusive. Herein, we provide UV-Vis, EPR, NMR, XAS and DFT evidence supporting the formation of a metal-iminoiodane complex 2 and its scandium adduct 2-Sc. 2 and 2 Sc are reactive toward substrates in the hydrogen-atom and nitrene transfer reactions, which confirm their potential as active oxidants in metal-catalyzed oxidative transformations. Oxidation of para-substituted 2,6-di-tert-butylphenols by 2 and 2-Sc can occur by both coupled and uncoupled proton and electron transfer mechanisms; the exact mechanism depends on the nature of the para substituent. PMID- 27465220 TI - National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities. AB - Eight manufacturing facilities participating in the National Institutes of Health sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed. PMID- 27465221 TI - Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance). AB - Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31 2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab. PMID- 27465223 TI - Intra-Abdominal Hypertension and Abdominal Compartment Syndrome after Abdominal Wall Reconstruction: Quaternary Syndromes? AB - BACKGROUND AND AIMS: Reconstruction with reconstitution of the container function of the abdominal compartment is increasingly being performed in patients with massive ventral hernia previously deemed inoperable. This situation places patients at great risk of severe intra-abdominal hypertension and abdominal compartment syndrome if organ failure ensues. Intra-abdominal hypertension and especially abdominal compartment syndrome may be devastating systemic complications with systematic and progressive organ failure and death. We thus reviewed the pathophysiology and reported clinical experiences with abnormalities of intra-abdominal pressure in the context of abdominal wall reconstruction. MATERIAL AND METHODS: Bibliographic databases (1950-2015), websites, textbooks, and the bibliographies of previously recovered articles for reports or data relating to intra-abdominal pressure, intra-abdominal hypertension, and the abdominal compartment syndrome in relation to ventral, incisional, or abdominal hernia repair or abdominal wall reconstruction. RESULTS: Surgeons should thus consider and carefully measure intra-abdominal pressure and its resultant effects on respiratory parameters and function during abdominal wall reconstruction. The intra-abdominal pressure post-operatively will be a result of the new intra peritoneal volume and the abdominal wall compliance. Strategies surgeons may utilize to ameliorate intra-abdominal pressure rise after abdominal wall reconstruction including temporizing paralysis of the musculature either temporarily or semi-permanently, pre-operative progressive pneumoperitoneum, permanently removing visceral contents, or surgically releasing the musculature to increase the abdominal container volume. In patients without complicating shock and inflammation, and in whom the abdominal wall anatomy has been so functionally adapted to maximize compliance, intra-abdominal hypertension may be transient and tolerable. CONCLUSIONS: Intra-abdominal hypertension/abdominal compartment syndrome in the specific setting of abdominal wall reconstruction without other complication may be considered as a quaternary situation considering the classification nomenclature of the Abdominal Compartment Society. Greater awareness of intra-abdominal pressure in abdominal wall reconstruction is required and ongoing study of these concerns is required. PMID- 27465224 TI - Uniqueness of Nash equilibrium in vaccination games. AB - One crucial condition for the uniqueness of Nash equilibrium set in vaccination games is that the attack ratio monotonically decreases as the vaccine coverage level increasing. We consider several deterministic vaccination models in homogeneous mixing population and in heterogeneous mixing population. Based on the final size relations obtained from the deterministic epidemic models, we prove that the attack ratios can be expressed in terms of the vaccine coverage levels, and also prove that the attack ratios are decreasing functions of vaccine coverage levels. Some thresholds are presented, which depend on the vaccine efficacy. It is proved that for vaccination games in homogeneous mixing population, there is a unique Nash equilibrium for each game. PMID- 27465225 TI - Response time variability under slow and fast-incentive conditions in children with ASD, ADHD and ASD+ADHD. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) show significant behavioural and genetic overlap. Both ADHD and ASD are characterised by poor performance on a range of cognitive tasks. In particular, increased response time variability (RTV) is a promising indicator of risk for both ADHD and ASD. However, it is not clear whether different indices of RTV and changes to RTV according to task conditions are able to discriminate between the two disorders. METHODS: Children with ASD (n = 19), ADHD (n = 18), ASD + ADHD (n = 29) and typically developing controls (TDC; n = 26) performed a four-choice RT task with slow-baseline and fast-incentive conditions. Performance was characterised by mean RT (MRT), standard deviation of RT (SD-RT), coefficient of variation (CV) and ex-Gaussian distribution measures of Mu, Sigma and Tau. RESULTS: In the slow-baseline condition, categorical diagnoses and trait measures converged to indicate that children with ADHD-only and ASD + ADHD demonstrated increased MRT, SD-RT, CV and Tau compared to TDC and ASD-only. Importantly, greater improvement in MRT, SD-RT and Tau was demonstrated in ADHD and ASD + ADHD from slow-baseline to fast-incentive conditions compared to TDC and ASD-only. CONCLUSIONS: Slower and more variable RTs are markers of ADHD compared to ASD and typically developing controls during slow and less rewarding conditions. Energetic factors and rewards improve task performance to a greater extent in children with ADHD compared to children with ASD. These findings suggest that RTV can be distinguished in ASD, ADHD and ASD + ADHD based on the indices of variability used and the conditions in which they are elicited. Further work identifying neural processes underlying increased RTV is warranted, in order to elucidate disorder-specific and disorder-convergent aetiological pathways. PMID- 27465227 TI - Procedural Competence Among Faculty in Academic Health Centers: Challenges and Future Directions. AB - Increasingly, faculty are taking on more direct responsibilities in patient care because of reductions in resident work hours, increasing admissions, and an endless push for efficiency. Furthermore, the rise of different career tracks in academia (i.e., patient care, research, education, or administration) and a drive for efficiency and subspecialization have placed additional strains on academic health centers. Combined, these factors have led to faculty increasingly being placed in the position of supervising bedside procedures that they may have not performed in years or with tools they have never trained with at all. Despite these challenges, procedural retraining for faculty remains nonstandardized across most academic health centers. The resulting lack of procedural competence among faculty creates a number of challenges for the different parties involved.In this Perspective, the authors discuss the nature of the current problem of faculty procedural competence and the challenges it poses for faculty and academic health centers, medicolegal ramifications, and the challenges it poses to the faculty-trainee relationship. The authors then suggest several strategies to delineate and resolve this problem. To delineate the problem, they suggest single-center surveys to address the current paucity of data. To resolve the problem, they suggest the consideration of some modest, low-cost interventions such as having backup systems in place for procedure supervision (e.g., procedural service teams or interventional radiologists) and providing faculty with opportunities to retrain. PMID- 27465228 TI - A Reduced Duty Hours Model for Senior Internal Medicine Residents: A Qualitative Analysis of Residents' Experiences and Perceptions. AB - PURPOSE: To assess senior internal medicine residents' experience of the implementation of a reduced duty hours model with night float, the transition from the prior 26-hour call system, and the new model's effects on resident quality of life and perceived patient safety in the emergency department and clinical teaching unit at McMaster University. METHOD: Qualitative data were collected during May 2013-July 2014, through resident focus groups held prior to implementation of a reduced duty hours model and 10 to 12 months postimplementation. Data analysis was guided by a constructivist grounded theory based in a relativist paradigm. Transcripts were coded; codes were collapsed into themes. RESULTS: Thematic analysis revealed five themes. Residents described reduced fatigue in the early morning, counterbalanced with worsened long-term fatigue on night float blocks; anticipation of negative impacts of the loss of distributed on-call experience and on-call shift volume; an urgency to sleep postcall in anticipation of consecutive night float shifts accompanied by conflicting role demands to stay postcall for care continuity; increased handover frequency accompanied by inaccurate/incomplete communication of patients' issues; and improvement in the senior resident experience on the clinical teaching unit, with increased ownership over patient care and improved relationships with junior housestaff. CONCLUSIONS: A reduced duty hours model with night float has potential to improve residents' perceived fatigue on call and care continuity on the clinical teaching unit. This must be weighed against increased handover frequency and loss of the postcall day, which may negatively affect patient care and resident quality of life. PMID- 27465229 TI - Competent for Unsupervised Practice: Use of Pediatric Residency Training Milestones to Assess Readiness. AB - PURPOSE: To describe clinical skills progression during pediatric residency using the distribution of pediatric milestone assessments by subcompetency and year of training and to determine reasonable milestone expectations at time of graduation. METHOD: Multi-institutional cohort study of the milestones reported to the Accreditation Council for Graduate Medical Education for all 21 pediatric subcompetencies. Most subcompetencies were measured using five milestone levels (1 = novice, 2 = advanced beginner, 3 = competent, 4 = proficient, 5 = master); 3 subcompetencies had only four levels defined. RESULTS: Milestone assessments for 2,030 pediatric residents in 47 programs during academic year 2013-2014 were obtained. There was significant variation in end-of-year milestone ratings for residents within each level of training, which decreased as training level increased. Most (78.9%; 434/550) graduating third-year pediatric residents received a milestone rating of >= 3 in all 21 subcompetencies; fewer (21.1%; 116/550) received a rating of >= 4 in all subcompetencies. Across all training levels, professionalism and interpersonal communication skills were rated highest; quality improvement was rated lowest. CONCLUSIONS: Trainees entered residency with a wide range of skills. As they advanced, skill variability within a training level decreased. Most graduating pediatric residents were still advancing on the milestone continuum toward proficiency and mastery, and an expectation of milestone ratings >= 4 in all categories upon graduation is unrealistic; milestone ratings >= 3 upon graduation may be more realistic. Understanding current pediatric residents' and graduates' skills can help to identify key areas that should be specifically targeted during training. PMID- 27465230 TI - Common Evaluation Designs in Medical Education III. PMID- 27465231 TI - Commitment to Change and Challenges to Implementing Changes After Workplace-Based Assessment Rater Training. AB - PURPOSE: Faculty development for clinical faculty who assess trainees is necessary to improve assessment quality and impor tant for competency-based education. Little is known about what faculty plan to do differently after training. This study explored the changes faculty intended to make after workplace-based assessment rater training, their ability to implement change, predictors of change, and barriers encountered. METHOD: In 2012, 45 outpatient internal medicine faculty preceptors (who supervised residents) from 26 institutions participated in rater training. They completed a commitment to change form listing up to five commitments and ranked (on a 1-5 scale) their motivation for and anticipated difficulty implementing each change. Three months later, participants were interviewed about their ability to implement change and barriers encountered. The authors used logistic regression to examine predictors of change. RESULTS: Of 191 total commitments, the most common commitments focused on what faculty would change about their own teaching (57%) and increasing direct observation (31%). Of the 183 commitments for which follow-up data were available, 39% were fully implemented, 40% were partially implemented, and 20% were not implemented. Lack of time/competing priorities was the most commonly cited barrier. Higher initial motivation (odds ratio [OR] 2.02; 95% confidence interval [CI] 1.14, 3.57) predicted change. As anticipated difficulty increased, implementation became less likely (OR 0.67; 95% CI 0.49, 0.93). CONCLUSIONS: While higher baseline motivation predicted change, multiple system-level barriers undermined ability to implement change. Rater-training faculty development programs should address how faculty motivation and organizational barriers interact and influence ability to change. PMID- 27465232 TI - Assessment for Systems Learning: A Holistic Assessment Framework to Support Decision Making Across the Medical Education Continuum. AB - Viewing health care from a systems perspective-that is, "a collection of different things which, working together, produce a result not achievable by the things alone"-raises awareness of the complex interrelationships involved in meeting society's goals for accessible, cost-effective, high-quality health care. This perspective also emphasizes the far-reaching consequences of changes in one sector of a system on other components' performance. Medical education promotes this holistic view of health care in its curricula and competency requirements for graduation at the undergraduate and graduate training levels. But how completely does medical education apply a systems lens to itself?The continuum of medical training has undergone a series of changes that have moved it more closely to a systems organizational model. Competency assessment criteria have been expanded and more explicitly defined for learners at all levels of training. Outcomes data, in multiple domains, are monitored by external reviewers for program accreditation. However, translating increasing amounts of individual outcomes into actionable intelligence for decision making poses a formidable information management challenge.Assessment in systems is designed to impart a "big picture" of overall system performance through the synthesis, analysis, and interpretation of outcomes data to provide actionable information for continuous systems improvement, innovation, and long-term planning. A systems-based framework is presented for use across the medical education continuum to facilitate timely improvements in individual curriculum components, continuous improvement in overall program performance, and program decision making on changes required to better address society's health care needs. PMID- 27465233 TI - What IAPT CBT High-Intensity Trainees Do After Training. AB - BACKGROUND: The UK Department of Health Improving Access to Psychological Therapies (IAPT) initiative set out to train a large number of therapists in cognitive behaviour therapies (CBT) for depression and anxiety disorders. Little is currently known about the retention of IAPT CBT trainees, or the use of CBT skills acquired on the course in the workplace after training has finished. AIMS: This study set out to conduct a follow-up survey of past CBT trainees on the IAPT High Intensity CBT Course at the Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London (KCL), one of the largest IAPT High Intensity courses in the UK. METHOD: Past trainees (n = 212) across 6 cohorts (2008-2014 intakes) were contacted and invited to participate in a follow-up survey. A response rate of 92.5% (n = 196) was achieved. RESULTS: The vast majority of IAPT trainees continue to work in IAPT services posttraining (79%) and to practise CBT as their main therapy modality (94%); 61% have become CBT supervisors. A minority (23%) have progressed to other senior roles in the services. Shortcomings are reported in the use of out-of-office CBT interventions, the use of disorder-specific outcome measures and therapy recordings to inform therapy and supervision. CONCLUSIONS: Past trainees stay working in IAPT services and continue to use CBT methods taught on the course. Some NICE recommended treatment procedures that are likely to facilitate patients' recovery are not being routinely implemented across IAPT services. The results have implications for the continued roll out of the IAPT programme, and other future large scale training initiatives. PMID- 27465226 TI - Antenatal endogenous and exogenous glucocorticoids and their impact on immune ontogeny and long-term immunity. AB - Endogenous levels of glucocorticoids rise during pregnancy to warrant development and maturation of the fetal organs close to birth. However, during most of the gestation, the fetus is protected from excessive biologically active endogenous glucocorticoids by placental and fetal expression of 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2). Maternal stress, which may overwhelm placental 11beta-HSD2 activity with high glucocorticoid levels, or administration of synthetic glucocorticoids to improve the survival chances of the premature newborn, are associated to postnatal increased risk for immune diseases. Fetal exposure to excessive glucocorticoids may underlie this altered postnatal immunity. Here, we revise the role that placental and fetal 11beta-HSD2, fetal glucocorticoid exposure, and programming of the offspring's the hypothalamic pituitary-adrenal (HPA) axis play on concerted steps in immune fetal development. We could identify gaps in knowledge about glucocorticoid-induced programming of immune diseases. Finally, based on current evidence about glucocorticoid and HPA axis-mediated immune regulation, we hypothesize on mechanisms that could drive the enhanced risk for atopies, infections, and type I diabetes in offspring that were prenatally exposed to glucocorticoids. PMID- 27465234 TI - Enantioselective determination of cathinone derivatives in human hair by capillary electrophoresis combined in-line with solid-phase extraction. AB - A suitable method has been developed and validated for the chiral separation and determination of R,S-mephedrone and one of its metabolites, R,S-4 methylephedrine, and R,S-methylenedioxypyrovalerone (R,S-MDPV) in human hair samples by the in-line coupling between SPE and CD-assisted CE with a previous sample pretreatment procedure based on pressurized liquid extraction. Optimum separation was achieved on a fused silica-capillary of 50 MUm id and 80 cm total length using 12 mg/mL beta-CD in an aqueous solution of 80 mM disodium phosphate at pH 2.5 as the BGE and an applied voltage of 30 kV. The SPE-CE device consists of a short length of a capillary of 2 mm packed with Oasis HLB sorbent, which was inserted near to the inlet end of the CE capillary. Several parameters affecting the in-line preconcentration were evaluated. The LOQs reached for hair samples were 0.05 ng/mg for the enantiomers of mephedrone and its metabolite, and 0.40 ng/mg for the enantiomers of MDPV. The RSDs (%) obtained in intra- and interday studies were less than 10% and the relative recoveries were greater than 80%. The method established in this paper is advantageous for its simplicity, overall analysis time and ability to provide information of both enantiomers of a chiral drug in hair samples. PMID- 27465235 TI - Generated effect modifiers (GEM's) in randomized clinical trials. AB - In a randomized clinical trial (RCT), it is often of interest not only to estimate the effect of various treatments on the outcome, but also to determine whether any patient characteristic has a different relationship with the outcome, depending on treatment. In regression models for the outcome, if there is a non zero interaction between treatment and a predictor, that predictor is called an "effect modifier". Identification of such effect modifiers is crucial as we move towards precision medicine, that is, optimizing individual treatment assignment based on patient measurements assessed when presenting for treatment. In most settings, there will be several baseline predictor variables that could potentially modify the treatment effects. This article proposes optimal methods of constructing a composite variable (defined as a linear combination of pre treatment patient characteristics) in order to generate an effect modifier in an RCT setting. Several criteria are considered for generating effect modifiers and their performance is studied via simulations. An example from a RCT is provided for illustration. PMID- 27465236 TI - Suboptimal CT pulmonary angiography in the emergency department: a retrospective analysis of outcomes in a large academic medical center. AB - Optimal CT pulmonary angiography (CTPA) is a prerequisite for accurate diagnosis and management of suspected venous thromboembolic disease (VTE) in the emergency department (ED). However, a certain proportion of CTPA studies are diagnostically limited or non-diagnostic due to various technical causes. In this study, we analyze the incidence and cause of suboptimal CTPA studies in the ED and assess the need for additional imaging. Reports of 1444 consecutive CTPAs performed in an ED on adult patients over a 25-month period beginning November 30, 2011, were reviewed. The observed suboptimal CTPA rate was 4.2 % (60/1444). The most common causes of limited or non-diagnostic CTPA in the ED were related to timing of contrast bolus or IV infiltration (26/60, 43.4 %), respiratory motion (16/60, 26.7 %), multifactorial causes (10/60, 16.7 %), and patient motion (8/60, 13.3 %). Of the 60 studies included, only 7 patients (11.7 %) underwent additional diagnostic imaging during the same hospital visit for VTE, while 3 patients (5.0 %) underwent additional imaging for suspected VTE over the next 2 months. A total of 2/60 (3.4 %) patients had documented acute PE on additional imaging performed either on the same hospital visit or within 2 months. Regardless of the factors contributing to suboptimal CTPA, only a very small proportion of patients receive additional imaging to evaluate for VTE, either on the same visit or during the next 2 months (16.7 %, 10/60 patients). A small number (3.4 %) of these patients have documented acute PE within 2 months when additional imaging tests were performed. PMID- 27465237 TI - Existence of renal dysfunction in diabetics undergoing coronary artery bypass. AB - INTRODUCTION: The effect of diabetes mellitus on morbidity and mortality in patients undergoing coronary artery bypass grafting has remained uncertain, and conflicting conclusions have been reported in clinical trials. Evidence suggests that coronary artery bypass in patients with diabetes mellitus carries a higher risk of stroke, renal failure, perioperative complications, and sternal wound infection. This study evaluated the frequency of acute renal dysfunction after coronary artery bypass in diabetic patients, and the associated risk factors. METHOD: This cross-sectional observational study included 135 patients with diabetes (111 males and 24 females with a mean age 51 years and a body mass index of 27.44 kg m(-2)), who underwent elective coronary artery bypass from March 2015 to October 2015. Data were collected prospectively in 2 tertiary care centers. Renal dysfunction was assessed by serum creatinine levels preoperatively and at 24 and 48 h postoperatively. RESULTS: Fifteen percent of patients were found to have postoperative renal dysfunction. Univariate analysis revealed that patients with increased serum creatinine preoperatively were at greater risk of developing renal dysfunction after coronary artery bypass (p = 0.00). On multivariable binary logistic regression analysis, preoperative serum creatinine level was the only independent predictor of postoperative renal dysfunction; age, body mass index, dyslipidemia, hypertension, cardiopulmonary bypass time, and aortic crossclamp time showed no significant association. CONCLUSION: Diabetic patients with increased serum creatinine preoperatively are at greater risk of kidney damage postoperatively; therefore, these patients should be monitored and treated critically in the perioperative period. PMID- 27465238 TI - Mycobacterium avium infection complicating congenital bronchial atresia. AB - Bronchial atresia is a rare congenital malformation that is often complicated by infectious disease; however, mycobacterial infection is rare. Here we report a case of Mycobacterium avium infection complicating congenital bronchial atresia. A 50-year-old woman consulted our institution for further investigation of a nodular lesion in an emphysematous lung due to congenital bronchial atresia. Because we were unable to rule out malignant disease, we performed video-assisted thoracoscopic surgery. After left S8 segmentectomy, the nodular lesion were diagnosed as Mycobacterial avium infection. Three years after surgery, there has been no recurrence of mycobacterium infection in the absence of medication. PMID- 27465239 TI - Expert's Comment concerning Grand Rounds Case entitled "Permanent twelfth nerve palsy secondary to C0 and C1 fracture in patient with craniocervical pneumatisation" (R. Kaiser and H. Mehdian, Eur Spine J; 2014: DOI 10.1007/s00586 014-3360-5) : An otorhinolaryngological approach to the assessment and management of a hypoglossal nerve palsy. PMID- 27465240 TI - Role of muscle damage on loading at the level adjacent to a lumbar spine fusion: a biomechanical analysis. AB - PURPOSE: It is well established that posterior spinal surgery results in damage to the paraspinal musculature. The effects of such iatrogenic changes on spinal loading have not been previously investigated, particularly at levels adjacent to a spinal fusion. Therefore, the objective of this study was to investigate the effect of simulated muscle damage on post-operative spinal loading at the adjacent levels to a spinal fusion during upright postures using a mathematical model. METHODS: A musculoskeletal model of the spine using ArtiSynth with 210 muscle fascicles was used to predict spinal loading in an upright posture. The loading at L1-L2 and L5-S1 were estimated before and after simulated paraspinal muscle damage (i.e., removal of muscle attachments at L2-L5) along the lumbar spine, both with a spinal fusion at L2-L5 and without a spinal fusion. RESULTS: The axial compressive forces at the adjacent levels increased after simulated muscle damage, with the largest changes being at the rostral level (78 % increase in presence of spinal fusion; 73 % increase without spinal fusion) compared to the caudal level (41 % in presence of fusion and 32 % without fusion). Shear forces increased in a similar manner at both the rostral and caudal levels. These changes in loading were due to a redistribution of muscle activity from the local lumbar to the global spinal musculature. CONCLUSIONS: The results suggest that the paraspinal muscles of the lumbar spine play an important role in adjacent segment loading of a spinal fusion, independent of the presence of rigid spinal instrumentation. PMID- 27465241 TI - Citrobacter freundii carrying blaKPC-2 and blaNDM-1: characterization by whole genome sequencing. AB - A carbapenem-resistant Citrobacter freundii strain WCHCF65 was recovered from hospital sewage and was characterized by genome sequencing and conjugation experiments. The strain carried nine genes encoding beta-lactamases including two carbapenemase genes, blaNDM-1 and blaKPC-2. blaNDM-1 was carried on an IncX3 plasmid, which was identical to a plasmid found in a local Escherichia coli, suggesting interspecies horizontal transfer. blaKPC-2 was bracketed by two copies of insertion sequence ISKpn19, which could form a composite transposon with the potential to mobilize blaKPC-2, on a new type of plasmid. The coexistence of blaNDM-1 and blaKPC-2 conferred higher levels of resistance to carbapenems compared with blaNDM-1 or blaKPC-2 alone. The coexistence of these carbapenemase genes, on two different plasmids, in one strain may allow new genetic platforms to be generated to mediate their spread. PMID- 27465242 TI - Establishing a Scale for Assessing the Social Validity of Skill Building Interventions for Young Children with Autism Spectrum Disorder. AB - This study evaluated the psychometric properties of the Scale of Treatment Perceptions (STP), a measure of treatment acceptability targeting skill-building interventions for Autism Spectrum Disorder (ASD). This scale utilizes a strength based approach to intervention assessment, and was established by modifying the Behavior Intervention Rating Scale (Elliott and Von Brock Treuting in J School Psychol 29(1):43-51, 1991. doi: 10.1016/0022-4405(91)90014-I ) and the Treatment Evaluation Inventory (Kazdin in J Appl Behav Anal 13(2):259-273, 1980. doi: 10.1901/jaba.1980.13-259 ) to be appropriate for assessing multiple dimensions of acceptability across skill-building ASD treatments. Overall, the STP demonstrated good psychometric properties: the scale had appropriate internal consistency, demonstrated a stable three-factor structure that was invariant across samples, and discriminated among different skill-building treatments for ASD. This has important implications for dissemination, as perceived acceptability of a treatment relates to treatment utilization and adherence. PMID- 27465243 TI - Dual Cognitive and Biological Correlates of Anxiety in Autism Spectrum Disorders. AB - Young people with autism spectrum disorder (ASD) have a high prevalence (~40 %) of anxiety disorders compared to their non-ASD peers. It is unclear whether cognitive and biological processes associated with anxiety in ASD are analogous to anxiety in typically developing (TD) populations. In this study 55 boys with ASD (34 with a co-occurring anxiety disorder, 21 without) and 28 male controls, aged 10-16 years and with a full-scale IQ >= 70, completed a series of clinical, cognitive (attention bias/interpretation bias) and biological measures (salivary cortisol/HR response to social stress) associated with anxiety in TD populations. Structural equation modelling was used to reveal that that both attentional biases and physiological responsiveness were significant, but unrelated, predictors of anxiety in ASD. PMID- 27465244 TI - Brief Report: The Prevalence of Neurofibromatosis Type 1 among Children with Autism Spectrum Disorder Identified by the Autism and Developmental Disabilities Monitoring Network. AB - Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). The frequency of ASD/NF1 co-occurrence has been subject to debate since the 1980s. This relationship was investigated in a large population-based sample of 8-year old children identified with ASD (N = 12,271) by the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring (ADDM) Network. Twenty-two (1-in-558) children with ASD had diagnosed NF1, exceeding NF1 general population estimates by four to five fold. Children with ASD/NF1 versus ASD without NF1 were significantly less likely to receive a community-based ASD diagnosis (p = 0.04) and understand non-verbal communication (p = 0.001). These findings underscore the importance of including social-communication ability among relevant developmental concerns in children with NF1. PMID- 27465246 TI - Neurosyphilis as a great imitator: a case report. AB - BACKGROUND: Neurosyphilis is defined as any involvement of the central nervous system by the bacterium Treponema pallidum. Movement disorders as manifestations of syphilis have been reported quite rarely. CASE PRESENTATION: We report a case of a 42-year-old Russian man living in Estonia with rapidly progressive dementia and movement disorders manifesting as myoclonus, cerebellar ataxia and parkinsonism. The mini mental state examination score was 12/30. After excluding different neurodegenerative causes, further diagnostic testing was consistent with neurosyphilis. Treatment with penicillin was started and 6 months later his mini mental state examination score was 25/30 and he had no myoclonus, parkinsonism or cerebellar dysfunction. CONCLUSION: Since syphilis is easily diagnosed and treatable, it should be considered and tested in patients with cognitive impairment and movement disorders. PMID- 27465247 TI - Exenatide Alters Gene Expression of NCAM, ICAM, and VCAM in the Hippocampus of Type 2 Diabetic Model Mice. AB - BACKGROUND Glucagon-like peptide-1 (GLP-1), a potent and selective agonist for the GLP-1 receptor, ameliorates the symptoms of diabetes through stimulation of insulin secretion. Exenatide is a potent and selective agonist for the GLP-1 receptor. Cell adhesion molecules are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. MATERIAL AND METHODS The present study demonstrated the effects of exenatide treatment (0.1 ug/kg, subcutaneously, twice daily for 2 weeks) on the gene expression levels of cell adhesion molecules, neural cell adhesion molecule (NCAM), intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in the brain tissue of diabetic BALB/c male mice by real-time quantitative polymerase chain reaction (PCR). Diabetes was induced by streptozotocin/nicotinamide (STZ-NA) injection to male mice. RESULTS The results of this study revealed that hippocampal gene expression of NCAM, ICAM, and VCAM were found to be up-regulated in STZ-NA-induced diabetic mice compared to those of controls. A significant decrease in the gene expression levels of NCAM, ICAM, and VCAM were determined after 2 weeks of exenatide administration. CONCLUSIONS Cell adhesion molecules may be involved in the molecular mechanism of diabetes. Exenatide has a strong beneficial action in managing diabetes induced by STZ/NA by altering gene expression of NCAM, ICAM, and VCAM. PMID- 27465248 TI - Role of PKCtheta in macrophage-mediated immune response to Salmonella typhimurium infection in mice. AB - BACKGROUND: The serine/threonine protein kinase C (PKC) theta has been firmly implicated in T cell-mediated immunity. Because its role in macrophages has remained undefined, we employed PKCtheta-deficient (PKCtheta (-/-)) mice in order to investigate if PKCtheta plays a role in macrophage-mediated immune responses during bacterial infections. RESULTS: Our results demonstrate that PKCtheta plays an important role in host defense against the Gram-negative, intracellular bacterium Salmonella typhimurium, as reflected both by markedly decreased survival and a significantly enhanced number of bacteria in spleen and liver of PKCtheta (-/-) mice, when compared to wild-type mice. Of note, albeit macrophages do not express detectable PKCtheta, PKCtheta mRNA expression was found to be profoundly upregulated during the first hours of lipopolysaccharide (LPS)/interferon-gamma (IFNgamma)-, but not IL-4-mediated cell polarization conditions in vitro. Mechanistically, despite expressing normal levels of classically activated macrophage (CAM) markers, PKCtheta-deficient CAMs expressed significantly higher levels of the anti-inflammatory cytokine IL-10 in vivo and in vitro when challenged with S. typhimurium or LPS/IFNgamma. Neutralization of IL-10 recovered immune control to S. typhimurium infection in PKCtheta-deficient macrophages. CONCLUSIONS: Taken together, our data provide genetic evidence that PKCtheta promotes a potent pro-inflammatory CAM phenotype that is instrumental to mounting protective anti-bacterial immunity. Mechanistically, PKCtheta exerts a host-protective role against S. typhimurium infection, and acts as an essential link between TLR4/IFNgammaR signaling and selective suppression of the anti inflammatory cytokine IL-10 at the onset of CAM differentiation in the course of a bacterial infection. PMID- 27465245 TI - 'Big data' in mental health research: current status and emerging possibilities. AB - PURPOSE: 'Big data' are accumulating in a multitude of domains and offer novel opportunities for research. The role of these resources in mental health investigations remains relatively unexplored, although a number of datasets are in use and supporting a range of projects. We sought to review big data resources and their use in mental health research to characterise applications to date and consider directions for innovation in future. METHODS: A narrative review. RESULTS: Clear disparities were evident in geographic regions covered and in the disorders and interventions receiving most attention. DISCUSSION: We discuss the strengths and weaknesses of the use of different types of data and the challenges of big data in general. Current research output from big data is still predominantly determined by the information and resources available and there is a need to reverse the situation so that big data platforms are more driven by the needs of clinical services and service users. PMID- 27465250 TI - Epinephrine Vasoconstriction Effect Time in the Scalp Differs According to Injection Site and Concentration. AB - BACKGROUND: There have been few studies of the action of epinephrine injected into scalp tissue, or whether the action of epinephrine differs according to vascular anatomy within the same surgical field. Effective perioperative control of bleeding is critical during hair transplantation due to its time-consuming nature. OBJECTIVE: To identify the vasoconstriction time of epinephrine by concentration and injection site in the scalp tissue. METHODS: Twenty-five volunteers were injected with epinephrine at concentrations of 1:400,000, 1:200,000, 1:100,000, and 1:50,000 in the path of the supraorbital artery on the anterior hairline in the midfrontal area (Point A) and at the frontotemporal junction of the frontal hairline (Point B). Laser Doppler was used to measure scalp blood flow, and vasoconstriction time at Points A and B with each concentration of epinephrine was recorded. RESULTS: The duration of action of epinephrine increased in direct proportion with the concentration of epinephrine. The duration of vasoconstriction was shorter at Point A than at Point B, but this difference was only statistically significant at an epinephrine concentration of 1:50,000. CONCLUSION: The vasoconstriction time of epinephrine in the scalp correlated positively with concentration, and the duration of vasoconstriction was longer at Point B than at Point A. PMID- 27465249 TI - PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma. AB - BACKGROUND: Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases. METHODS: We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway. RESULTS: Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance. CONCLUSIONS: Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer. PMID- 27465251 TI - A Clinical Review of Laser and Light Therapy for Nail Psoriasis and Onychomycosis. AB - BACKGROUND: There are considerable emerging data in the use of lasers and lights to treat onychomycosis and psoriasis of the nail subunit. OBJECTIVE: We aimed to review all of the medical literature on laser therapy of nail psoriasis and onychomycosis published since 1992. METHODS AND MATERIALS: We performed a PubMed literature search using the search terms "nail," "laser therapy," "laser surgery," "light," with search terms "psoriasis" and "onychomycosis." In addition, we performed extensive MeSH and bibliographic searches as delineated in the manuscript. Because of the poor quality of evidence, we were not able to complete a quantitative review and thus present our findings qualitatively. RESULTS: Although the trials are small, PDL (595 nm) and IPL with a 550-nm filter demonstrate compelling data in treating nail psoriasis. Laser studies of onychomycosis fall short on many levels. Q-switched Nd:YAG lasers with very short pulse durations and fractionated CO2 demonstrate the most promise for the treatment of onychomycosis. CONCLUSION: The data for treating nail psoriasis and onychomycosis with laser and light therapy are rapidly emerging. With increased subject data, improved study methodology, and more precise output parameters, lasers may become an important modality in the treatment of nail psoriasis and onychomycosis. PMID- 27465252 TI - Costs of Keratinocyte Carcinoma (Nonmelanoma Skin Cancer) and Actinic Keratosis Treatment in the Veterans Health Administration. AB - BACKGROUND: The Veterans Health Administration (VHA) provides health care to large numbers of veterans afflicted with keratinocyte carcinoma (KC). OBJECTIVE: To estimate the number of veterans treated for KCs and the related diagnosis, actinic keratosis (AK) and the costs of treating these conditions over a 1-year period. MATERIALS AND METHODS: The authors conducted a cross-sectional analysis of veterans diagnosed with KC or AK during fiscal year 2012 using administrative data on outpatient encounters and prescription drugs provided or paid by VHA. Marginal costs of each condition were estimated from a regression model. The authors estimated counts of outpatient encounters, procedures, and costs related to KC and AK care. RESULTS: In 2012, there were 49,229 veterans with basal cell carcinoma, 26,310 veterans with squamous cell carcinoma, and 8,050 veterans with unspecified invasive KC. There were also 197,041 veterans with AK and 6,388 veterans with KC-related diagnoses. The VHA spent $356 million on KC and AK outpatient treatment for procedures, prescription drugs, and other dermatologic care during FY2012. CONCLUSION: There was high prevalence of KC and AK and considerable spending to treat these conditions in VHA. Treatment costs are not generalizable to care provided by non-VHA providers where a facility fee was not incurred. PMID- 27465253 TI - Reconstruction of a Full-Thickness Nasal Defect. PMID- 27465254 TI - Filler Rhinoplasty Evaluated by Anthropometric Analysis. AB - BACKGROUND: There are no reports of objectively evaluating the efficacy of filler rhinoplasty by anthropometric techniques. OBJECTIVE: To objectively demonstrate the effectiveness of filler rhinoplasty by anthropometric analysis. MATERIALS AND METHODS: A total of 242 patients who revisited the clinic within 2 months of undergoing hyaluronic acid filler rhinoplasty were analyzed based on the injection site, injected volume, and the change in anthropometry. RESULTS: Among the 242 patients, 112 (46.3%) were in the nasal dorsum augmentation group, 8 (3.3%) were in the tip rotation group, and 122 (50.4%) were in the whole nose augmentation group. Average injection volume was 1 +/- 0.4 mL for nasal dorsum and 0.9 +/- 0.3 mL for tip rotation, whereas 1.6 +/- 0.5 mL was used for whole nose augmentation. On follow-up, the radix height, nasofrontal angle, and nasolabial angle (NLA) had increased by 78.3%, 5.7 +/- 4.1 degrees , and 9.4 +/- 4.5 degrees , respectively, whereas the modified nasofacial angle had decreased by 1.9 +/- 2.9 degrees . Three cases (1.2%) of vascular complications were encountered. CONCLUSION: Filler rhinoplasty is a simple and effective treatment modality producing outcomes comparable with surgical augmentation rhinoplasty. Among various anthropometric measurements, the nasal radix height was the most useful for evaluating dorsum augmentation, whereas the NLA was the best for nasal tip rotation. PMID- 27465255 TI - Improvement of "En Coup de Sabre" Morphea and Associated Headaches With Botulinum Toxin Injections. PMID- 27465256 TI - Comparability of the age and sex distribution of the UK Clinical Practice Research Datalink and the total Dutch population. AB - PURPOSE: The UK Clinical Practice Research Datalink (CPRD) is increasingly being used by Dutch researchers in epidemiology and pharmacoepidemiology. It is however unclear if the UK CPRD is representative of the Dutch population and whether study results would apply to the Dutch population. Therefore, as first step, our objective was to compare the age and sex distribution of the CPRD with the total Dutch population. METHODS: As a measure of representativeness, the age and sex distribution of the UK CPRD were visually and numerically compared with Dutch census data from the StatLine database of the Dutch National Bureau of Statistics in 2011. RESULTS: The age distribution of men and women in the CPRD population was comparable to the Dutch male and female population. Differences of more than 10% only occurred in older age categories (75+ in men and 80+ in women). CONCLUSIONS: Results from observational studies that have used CPRD data are applicable to the Dutch population, and a useful resource for decision making in the Netherlands. Nevertheless, differences in drug exposure likelihood between countries should be kept in mind, as these could still cause variations in the actual population studied, thereby decreasing its generalizability. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27465257 TI - On the physical origins of interaction-induced vibrational (hyper)polarizabilities. AB - This paper presents the results of a pioneering exploration of the physical origins of vibrational contributions to the interaction-induced electric properties of molecular complexes. In order to analyze the excess nuclear relaxation (hyper)polarizabilities, a new scheme was proposed which relies on the computationally efficient Bishop-Hasan-Kirtman method for determining the nuclear relaxation contributions to electric properties. The extension presented herein is general and can be used with any interaction-energy partitioning method. As an example, in this study we employed the variational-perturbational interaction energy decomposition scheme (at the MP2/aug-cc-pVQZ level) and the extended transition state method by employing three exchange-correlation functionals (BLYP, LC-BLYP, and LC-BLYP-dDsC) to study the excess properties of the HCN dimer. It was observed that the first-order electrostatic contribution to the excess nuclear relaxation polarizability cancels with the negative exchange repulsion term out to a large extent, resulting in a positive value of Deltaalpha(nr) due to the contributions from the delocalization and the dispersion terms. In the case of the excess nuclear relaxation first hyperpolarizability, the pattern of interaction contributions is very similar to that for Deltaalpha(nr), both in terms of their sign as well as relative magnitude. Finally, our results show that the LC-BLYP and LC-BLYP-dDsC functionals, which yield smaller values of the orbital relaxation term than BLYP, are more successful in predicting excess properties. PMID- 27465259 TI - The nuts and bolts of the endogenous spliceosome. AB - The complex life of pre-mRNA from transcription to the production of mRNA that can be exported from the nucleus to the cytoplasm to encode for proteins entails intricate coordination and regulation of a network of processing events. Coordination is required between transcription and splicing and between several processing events including 5' and 3' end processing, splicing, alternative splicing and editing that are major contributors to the diversity of the human proteome, and occur within a huge and dynamic macromolecular machine-the endogenous spliceosome. Detailed mechanistic insight of the splicing reaction was gained from studies of the in vitro spliceosome assembled on a single intron. Because most pre-mRNAs are multiintronic that undergo alternative splicing, the in vivo splicing machine requires additional elements to those of the in vitro machine, to account for all these diverse functions. Information about the endogenous spliceosome is emerging from imaging studies in intact and live cells that support the cotranscriptional commitment to splicing model and provide information about splicing kinetics in vivo. Another source comes from studies of the in vivo assembled spliceosome, isolated from cell nuclei under native conditions-the supraspliceosome-that individually package pre-mRNA transcripts of different sizes and number of introns into complexes of a unique structure, indicating their universal nature. Recent years have portrayed new players affecting alternative splicing and novel connections between splicing, transcription and chromatin. The challenge ahead is to elucidate the structure and function of the endogenous spliceosome and decipher the regulation and coordination of its network of processing activities. WIREs RNA 2017, 8:e1377. doi: 10.1002/wrna.1377 For further resources related to this article, please visit the WIREs website. PMID- 27465258 TI - Structural basis for LIN54 recognition of CHR elements in cell cycle-regulated promoters. AB - The MuvB complex recruits transcription factors to activate or repress genes with cell cycle-dependent expression patterns. MuvB contains the DNA-binding protein LIN54, which directs the complex to promoter cell cycle genes homology region (CHR) elements. Here we characterize the DNA-binding properties of LIN54 and describe the structural basis for recognition of a CHR sequence. We biochemically define the CHR consensus as TTYRAA and determine that two tandem cysteine rich regions are required for high-affinity DNA association. A crystal structure of the LIN54 DNA-binding domain in complex with a CHR sequence reveals that sequence specificity is conferred by two tyrosine residues, which insert into the minor groove of the DNA duplex. We demonstrate that this unique tyrosine-mediated DNA binding is necessary for MuvB recruitment to target promoters. Our results suggest a model in which MuvB binds near transcription start sites and plays a role in positioning downstream nucleosomes. PMID- 27465260 TI - Increased aerobic capacity reduces susceptibility to acute high-fat diet-induced weight gain. AB - OBJECTIVE: Aerobic capacity is the most powerful predictor of all-cause mortality in humans; however, its role in the development of obesity and susceptibility for high-fat diet (HFD)-induced weight gain is not completely understood. METHODS: Herein, a rodent model system of divergent intrinsic aerobic capacity [high capacity running (HCR) and low capacity running (LCR)] was utilized to evaluate the role of aerobic fitness on 1-week HFD-induced (45% and 60% kcal) weight gain. Food/energy intake, body composition analysis, and brown adipose tissue gene expression were assessed as important potential factors involved in modulating HFD-induced weight gain. RESULTS: HCR rats had reduced 1-week weight gain on both HFDs compared with LCR. Reduced HFD-induced weight gain was associated with greater adaptability to decrease food intake following initiation of the HFDs. Further, the HCR rats were observed to have reduced feeding efficiency and greater brown adipose mass and expression of genes involved in thermogenesis. CONCLUSIONS: Rats with high intrinsic aerobic capacity have reduced susceptibility to 1-week HFD-induced weight gain, which is associated with greater food intake adaptability to control intake of energy-dense HFDs, reduced weight gain per kcal consumed, and greater brown adipose tissue mass and thermogenic gene expression. PMID- 27465261 TI - Associations Between the KIAA0319 Dyslexia Susceptibility Gene Variants, Antenatal Maternal Stress, and Reading Ability in a Longitudinal Birth Cohort. AB - Maternal stress during pregnancy has been associated with detrimental cognitive developmental outcomes in offspring. This study investigated whether antenatal maternal perceived stress and variants of the rs12193738 and rs2179515 polymorphisms on the KIAA0319 gene interact to affect reading ability and full scale IQ (FSIQ) in members of the longitudinal Auckland Birthweight Collaborative study. Antenatal maternal stress was measured at birth, and reading ability was assessed at ages 7 and 16. Reading data were available for 500 participants at age 7 and 479 participants at age 16. FSIQ was measured at ages 7 and 11. At age 11, DNA samples were collected. Analyses of covariance revealed that individuals with the TT genotype of the rs12193738 polymorphism exposed to high maternal stress during pregnancy possessed significantly poorer reading ability (as measured by Woodcock-Johnson Word Identification standard scores) during adolescence compared with TT carriers exposed to low maternal stress. TT carriers of the rs12193738 SNP also obtained lower IQ scores at age 7 than C allele carriers. These findings suggest that the KIAA0319 gene is associated with both reading ability and general cognition, but in different ways. The effect on IQ appears to occur earlier in development and is transient, whereas the effect of reading ability occurs later and is moderated by antenatal maternal stress. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27465262 TI - (S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study. AB - OBJECTIVE: The aim was to describe the safety and efficacy of (S)-ketamine [(S) KET] in a series of patients with refractory and super-refractory status epilepticus (RSE and SRSE) in a specialized neurological intensive care unit (NICU). METHODS: We retrospectively analyzed the data of patients with RSE and SRSE treated with (S)-KET in the NICU, Salzburg, Austria, from 2011 to 2015. Data collection included demographic features, clinical presentation, diagnosis, electroencephalogram (EEG) data, anticonvulsant treatment, timing, and duration of treatment with (S)-KET. Outcomes were seizure control and death. RESULTS: A total of 42 patients (14 women) with RSE and SRSE were treated with (S)-KET. The median duration of status epilepticus (SE) was 10 days [first quartile (Q1) 5.0, Q3 21.0]; the median latency from SE onset to the first administration of (S)-KET was 3 days (Q1 2.0, Q3 6.8). Prior to (S)-KET administration, patients had received a median of two (Q1 2.0, Q3 3.0) anesthetics and three (Q1 2.0, Q3 4.0) antiepileptic drugs. Forty percent of patients (17/42) received propofol: 65 % prior to (S)-KET; 35 % at the same time with (S)-KET. Seven patients received a median bolus of (S)-KET of 200 mg (Q1 200, Q3 250) followed by a continuous infusion, while 35 started with a continuous infusion (maximum rate median 2.55 mg/kg/h; Q1 2.09, Q3 3.22). In 64 % of patients (27/42), (S)-KET was the last drug before SE cessation; in five patients, it was given with propofol at the same time. Median duration of administration was 4 days (Q1 2.0, Q3 6.8). Overall (S)-KET treatment was well tolerated, adverse effects were not observed, and overall mortality was 45.2 %. CONCLUSIONS: Treatment of SRSE in adult patients with (S)-KET led to resolution of status in 64 %. No adverse events were found, indicating a favorable safety profile. PMID- 27465263 TI - Solution-Processible Crystalline NiO Nanoparticles for High-Performance Planar Perovskite Photovoltaic Cells. AB - In this work, we report on solution-based p-i-n-type planar-structured CH3NH3PbI3 perovskite photovoltaic (PV) cells, in which precrystallized NiO nanoparticles (NPs) without post-treatment are used to form a hole transport layer (HTL). X-ray diffraction and high-resolution transmission electron microscopy showed the crystallinity of the NPs, and atomic force microscopy and scanning electron microscopy confirmed the uniform surfaces of the resultant NiO thin film and the subsequent perovskite photoactive layer. Compared to the conventional poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) HTL, the NiO HTL had excellent energy-level alignment with that of CH3NH3PbI3 and improved electron blocking capability, as analyzed by photoelectron spectroscopy and diode modeling, resulting in Voc ~0.13 V higher than conventional PEDOT: PSS-based devices. Consequently, a power conversion efficiency (PCE) of 15.4% with a high fill factor (FF, 0.74), short-circuit current density (Jsc, 20.2 mA.cm(-2)), and open circuit voltage (Voc, 1.04 V) having negligible hysteresis and superior air stability has been achieved. PMID- 27465264 TI - Enhanced production of polyhydroxybutyrate by multiple dividing E. coli. AB - BACKGROUND: Most bacteria are grown in a binary fission way meaning a bacterial cell is equally divided into two. Polyhydroxyalkanoates (PHA) can be accumulated as inclusion bodies by bacteria. The cell division way and morphology have been shown to play an important role in regulating the bacterial growth and PHA storages. RESULTS: The common growth pattern of Escherichia coli was changed to multiple fission patterns by deleting fission related genes minC and minD together, allowing the formation of multiple fission rings (Z-rings) in several positions of an elongated cell, thus a bacterial cell was observed to be divided into more than two daughter cells at same time. To further improve cell growth and PHA production, some genes related with division process including ftsQ, ftsL, ftsW, ftsN and ftsZ, together with the cell shape control gene mreB, were all overexpressed in E. coli JM109 ?minCD. The changing pattern of E. coli cell growth and morphology resulted in more cell dry weights (CDW) and more than 80 % polyhydroxybutyrate (PHB) accumulation increases compared to its binary fission control grown under the same conditions. CONCLUSIONS: This study clearly demonstrated that combined over-expression genes ftsQ, ftsW, ftsN, ftsL and ftsZ together with shape control gene mreB in multiple division bacterial E. coli JM109 ?minCD benefited PHA accumulation. Our study provides useful information on increasing the yield of PHA by changing the cell division pattern and cell morphology of E. coli. PMID- 27465267 TI - Effect of Methyl, Hydroxyl, and Chloro Substituents in Position 3 of 3',4',7 Trihydroxyflavylium: Stability, Kinetics, and Thermodynamics. AB - The effect of methyl, hydroxyl, and chloride substituents in position 3 of the 3',4',7-trihydroxyflavylium core structure was studied. The stability, relative energy of each of chemical species (thermodynamics), and their rates of interconversion (kinetics) are very dependent on these substituents. By comparing the mole fraction distribution at equilibrium of the three multistate systems with the parent 3',4',7-trihydroxyflavylium, introduction of a methyl substituent in position 3 increases the mole fraction of hemiketal at the expense of the trans-chalcone and increases the hydration rate very significantly; a hydroxyl substituent in position 3 gives rise to a degradation process, as observed in anthocyanidins. In the case of 3-chloro-3',4',7-trihydroxyflavylium, a dramatic increase of the flavylium cation acidity was observed and a photochromic system can be operated upon irradiation of the respective trans-chalcone in 1 m HCl. According to the photochromic response of 3,3',4',7-tetrahydroxyflavylium and 3',4',7-trihydroxyflavylium, some requirements for a good photochromic performance are discussed. PMID- 27465265 TI - Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. AB - OBJECTIVE: The Insulin Resistance Intervention after Stroke (IRIS) trial recently found that pioglitazone reduced risk for stroke and myocardial infarction in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack (TIA). This report provides detailed results on the metabolic effects of pioglitazone and the trial's prespecified secondary aim of diabetes prevention. RESEARCH DESIGN AND METHODS: A total of 3,876 patients with recent ischemic stroke or TIA, no history of diabetes, fasting plasma glucose (FPG) <126 mg/dL, and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) score >3.0 were randomly assigned to pioglitazone or placebo. Surveillance for diabetes onset during the trial was accomplished by periodic interviews and annual FPG testing. RESULTS: At baseline, the mean FPG, HbA1c, insulin, and HOMA-IR were 98.2 mg/dL (5.46 mmol/L), 5.8% (40 mmol/mol), 22.4 MUIU/mL, and 5.4, respectively. After 1 year, mean HOMA-IR and FPG decreased to 4.1 and 95.1 mg/dL (5.28 mmol/L) in the pioglitazone group and rose to 5.7 and 99.7 mg/dL (5.54 mmol/L), in the placebo group (all P < 0.0001). Over a median follow-up of 4.8 years, diabetes developed in 73 (3.8%) participants assigned to pioglitazone compared with 149 (7.7%) assigned to placebo (hazard ratio [HR] 0.48 [95% CI 0.33-0.69]; P < 0.0001). This effect was predominately driven by those with initial impaired fasting glucose (FPG >100 mg/dL [5.6 mmol/L]; HR 0.41 [95% CI 0.30-0.57]) or elevated HbA1c (>5.7% [39 mmol/mol]; HR 0.46 [0.34-0.62]). CONCLUSIONS: Among patients with insulin resistance but without diabetes who had had a recent ischemic stroke or TIA, pioglitazone decreased the risk of diabetes while also reducing the risk of subsequent ischemic events. Pioglitazone is the first medication shown to prevent both progression to diabetes and major cardiovascular events as prespecified outcomes in a single trial. PMID- 27465266 TI - Modulation of platelet functions by crude rice (Oryza sativa) bran policosanol extract. AB - BACKGROUND: Rice bran is bioactive-rich and has proven health benefits for humans. Moreover, its source, the brown rice has antioxidant, hypolipidemic and other functional properties that are increasingly making it a nutritional staple especially in Asian countries. This study investigated the antiplatelet aggregation mechanisms of crude hexane/methanolic rice bran extract, in which policosanol was the targeted bioactive. Platelets play a vital role in pathogenesis of atherosclerosis and cardiovascular diseases, and their increased activities could potentially cause arterial thrombus formation or severe bleeding disorders. Thus, in this study, platelet aggregation and adhesion of platelets to major components of basal lamina were examined in vitro. In addition, cellular protein secretion was quantified as a measurement of platelet activation. METHODS: Adenosine diphosphate (ADP), collagen, and arachidonic acid (AA)-induced aggregation were studied using the microtiter technique. Rat platelets were pre treated with various concentrations of policosanol extract, and the adhesion of platelets onto collagen- and laminin-coated surface (extracellular matrix) was studied using the acid phosphatase assay. The effect of crude policosanol extract on released proteins from activated platelets was measured using modified Lowry determination method. RESULTS: Rice bran policosanol extract significantly inhibited in vitro platelet aggregation induced by different agonists in a dose dependent manner. The IC50 of ADP-, collagen-, and AA-induced platelet aggregation were 533.37 +/- 112.16, 635.94 +/- 78.45 and 693.86 +/- 70.57 MUg/mL, respectively. The present study showed that crude rice bran policosanol extract significantly inhibited platelet adhesion to collagen in a dose dependent manner. Conversely, at a low concentration of 15.625 MUg/mL, the extract significantly inhibited platelet adhesion to laminin stimulated by different platelet agonists. In addition to the alteration of cell adhesive properties, cellular protein secretion of the treated platelets towards different stimulants were decreased upon crude extract treatment. CONCLUSION: Our results showed that crude rice bran policosanol extract could inhibit in vitro platelet adhesion, aggregation and secretion upon activation using agonists. These findings serve as a scientific platform to further explore alternative therapies in cardiovascular diseases related to platelet malfunction. PMID- 27465268 TI - Percutaneous left atrial appendage occlusion: Effect of device positioning on outcome. AB - OBJECTIVE: The study in patients with percutaneous left atrial appendage (LAA) occlusion investigates clinical outcomes according to the position of the Amplatzer Cardiac Plug (ACP) disc. BACKGROUND: The ACP consists of a disc and an anchoring lobe. The disc is meant to cover the ostium of the LAA, but frequently retracts partially or completely into the neck of the LAA. It is not known whether a retracted disc affects outcome. METHODS: Outcomes of 169 consecutive patients (age 73.1 +/- 10.4 years; 76% male) with successful LAA closure were analyzed according to the position of the ACP disc: group A had complete coverage of the LAA ostium; in group B the disc prolapsed partially or completely into the LAA-neck. Transesophageal echocardiography was performed 1-6 months after ACP implantation. The safety endpoint was the composite of clinically significant pericardial effusion, device embolization, procedure-related stroke/transient ischemic attack (TIA), major bleeding, or device thrombus. The efficacy endpoint was the composite of death, neurological events (ischemic and hemorrhagic stroke, TIA), or systemic embolism during follow-up. RESULTS: Group A comprised 76 patients (age 73.0 +/- 9.9 years; 74% male) and group B 93 patients (age 73.3 +/- 10.9 years; 79% male). Mean CHA2 DS2 -Vasc score and HASBLED score were 4.2 +/- 1.7 (group A 4.3 +/- 1.6; group B 4.2 +/- 1.8) and 2.9 +/- 1.1 (group A 2.9 +/- 1.0; group B 3.0 +/- 1.2), respectively. Mean follow-up of the study population was 13.0 +/- 10.4 months. Overall, the composite safety and efficacy endpoints occurred in 20 (12%) and 6 patients (4%), respectively. There was no significant difference between groups A and B in the occurrence of the safety endpoint (13% vs. 11%, P = 0.64), or the efficacy endpoint (4% vs. 3%, P = 1.0). CONCLUSIONS: No evidence for a difference in the occurrence of the safety and efficacy endpoint was found between patients with complete vs. incomplete ACP disc coverage of the LAA ostium. The risk of repositioning attempts in case of incomplete coverage does not seem to be warranted. Current findings need further confirmation in a larger scale clinical trial. (c) 2016 Wiley Periodicals, Inc. PMID- 27465269 TI - Poly(glycidyl methacrylate)-grafted hydrophobic charge-induction agarose resins with 5-aminobenzimidazole as a functional ligand. AB - Hydrophobic charge-induction chromatography is a new technology for antibody purification. To improve antibody adsorption capacity of hydrophobic charge induction resins, new poly(glycidyl methacrylate)-grafted hydrophobic charge induction resins with 5-aminobenzimidazole as a functional ligand were prepared. Adsorption isotherms, kinetics, and dynamic binding behaviors of the poly(glycidyl methacrylate)-grafted resins prepared were investigated using human immunoglobulin G as a model protein, and the effects of ligand density were discussed. At the moderate ligand density of 330 MUmol/g, the saturated adsorption capacity and equilibrium constant reached the maximum of 140 mg/g and 25 mL/mg, respectively, which were both much higher than that of non-grafted resin with same ligand. In addition, effective pore diffusivity and dynamic binding capacity of human immunoglobulin G onto the poly(glycidyl methacrylate) grafted resins also reached the maximum at the moderate ligand density of 330 MUmol/g. Dynamic binding capacity at 10% breakthrough was as high as 76.3 mg/g when the linear velocity was 300 cm/h. The results indicated that the suitable polymer grafting combined with the control of ligand density would be a powerful tool to improve protein adsorption of resins, and new poly(glycidyl methacrylate) grafted hydrophobic charge-induction resins have a promising potential for antibody purification applications. PMID- 27465270 TI - Protein-peptide nutritional material prepared from surimi wash-water using immobilized chymotrypsin-trypsin. AB - BACKGROUND: In the production process of surimi, large quantities of wastewater are produced. Thus it would be interesting to develop an efficient protocol for the recovery of protein from hairtail surimi wash-water. RESULTS: A technique involving the use of immobilized chymotrypsin-trypsin (I-CT) was developed, providing a practical method for the preparation of protein-peptide nutritional material (PPNM). Under optimized reaction conditions, the recovery rate of nitrogen of surimi wash-water was measured as 98.3 +/- 2.9%. Nutritional evaluation of the protein-peptide fraction demonstrated that it contained all essential amino acids (EAA) for humans, accounting for 44.1% of the total amino acid (TAA) content, which was determined to be 78.2 g per 100 g dry matter. The essential amino acid index (EAAI) and biological value (BV) were 101.7 (>95) and 76.7 respectively. A wide range of volatile flavor compounds (>50), including aldehydes, ketones, alcohols, hydrocarbons and heterocyclic compounds, were identified in PPNM by gas chromatography/mass spectrometry (GC/MS) analysis. CONCLUSION: An efficient and practical protocol for the recovery of protein from hairtail surimi wash-water has been developed. The PPNM prepared in this work could be used as a nutraceutical and as an ingredient of functional foods. (c) 2016 Society of Chemical Industry. PMID- 27465271 TI - [Not Available]. PMID- 27465272 TI - [Not Available]. PMID- 27465273 TI - Optimization of simultaneous multislice EPI for concurrent functional perfusion and BOLD signal measurements at 7T. AB - PURPOSE: To overcome limitations of previous ultra-high-field arterial spin labeling (ASL) techniques concerning temporal resolution and brain coverage by utilizing the simultaneous multi-slice (SMS) approach. METHODS: An optimized, flow-alternating inversion recovery quantitative imaging of perfusion using a single subtraction II scheme was developed that tackles the challenges of 7 tesla (T) ASL. The implementation of tailored labeling radiofrequency pulses reduced the effect of transmit field ( B1+) inhomogeneities. The proposed approach utilizes an SMS echo-planar imaging (EPI) readout to efficiently achieve large brain coverage. RESULTS: A pulsed ASL (PASL) technique with large brain coverage is described and optimized that can be applied at temporal resolutions below 2.5 s, similar to those achievable at 1.5 and 3T magnetic field strength. The influences of within- and through-slice acceleration factors and reconstruction parameters on perfusion and blood-oxygenation-level-dependent (BOLD)-signal image and temporal signal-to-noise ratio (SNR) are presented. The proposed approach yielded twice the brain coverage as compared to conventional PASL at 7T, without notable loss in image quality. CONCLUSION: The presented SMS EPI PASL at 7T overcomes current limitations in SNR, temporal resolution, and spatial coverage for functional perfusion and BOLD signal as well as baseline perfusion measurements. Magn Reson Med 78:121-129, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID- 27465274 TI - Immune pathogenesis of heparin-induced thrombocytopenia. AB - The immune response to heparin is one of the most common drug-induced allergies, and yet, atypical for a drug hypersensitivity reaction. Whereas most drug-induced allergies are rare, idiosyncratic and life-long, the allergic response to heparin is common, predictable in certain clinical settings and transient. Advances in the last decade with regards to structural characterisation of the PF4/heparin antigenic complex, contributions of innate immunity and development of animal models have provided insights into the distinctive features of the HIT immune response. Recent descriptions of the crystal structure of the PF4/heparin complex, alongside other biophysical studies, have clarified the structural requirements for immunogenicity and heparin-dependency of antibody formation. Studies of interactions of PF4 with bacterial cell walls as well as epidemiologic associations of anti-PF4/heparin antibody formation and infection suggest a role for immune priming and explain the rapid evolution of an isotype-switched immune response in sensitised patients. Murine models have greatly facilitated investigations of cellular basis of the HIT response and identified a major role for T-cells and marginal zone B-cells, but key findings have yet to be validated in human disease. This chapter will summarise recent investigations of the HIT immune response in the context of major pathways of immune activation and identify areas of uncertainty. PMID- 27465275 TI - [Non-neoplastic lesions of the mediastinum]. AB - The mediastinum is a complex body region of limited space but containing numerous organs of different embryonic origins. A variety of lesions that are difficult to distinguish from each other can occur here. Non-neoplastic lesions of the mediastinum represent important differential diagnostic pitfalls to mediastinal tumors, clinically, radiologically and histopathologically. It is important to bear these lesions in mind and to adequately verify or exclude them before starting further differential diagnostic considerations on mediastinal neoplasms. The most common non-neoplastic lesions in this region include cysts and lymphadenopathies. Mediastinal cysts result from abnormal events in the branching of the tracheobronchial tree, the pharyngeal pouches, the primary intestines, the pleuropericardial membranes and the brain meninges or are complications of inflammatory and hydrostatic processes. The histogenesis of the lining epithelium and the cyst wall structure are decisive for the exact classification. The histopathologically most prevalent patterns of mediastinal lymphadenopathies are those accompanied by increased histiocytes and Castleman's disease. Sclerosis is a non-specific reaction pattern of the mediastinum and can be associated with many processes; therefore, when establishing the diagnosis of sclerosing mediastinitis, several differential diagnoses have to be excluded. Simple thymic hyperplasia can be accompanied by considerable increase in organ size with severe local symptoms, while follicular thymic hyperplasia is often associated with myasthenia gravis and represents the most common findings in non-thymoma thymectomy specimens. PMID- 27465277 TI - Complexes of the tripodal phosphine ligands PhSi(XPPh2)3 (X = CH2, O): synthesis, structure and catalytic activity in the hydroboration of CO2. AB - The coordination chemistry of Fe(2+), Co(2+) and Cu(+) ions was explored with the triphosphine and triphosphinite ligands PhSi{CH2PPh2}3 (1) and PhSi{OPPh2}3 (2), so as to evaluate the impact of the electronic properties of the tripodal phosphorus ligands on the structure and reactivity of the corresponding complexes. The synthesis and characterization of the complexes [Fe(kappa(3) PhSi{CH2PPh2}3)(MeCN)3][OTf]2 (3) (OTf = O3SCF3), [Fe(kappa(3) PhSi{OPPh2}3)(MeCN)3][OTf]2 (3'), [Co(kappa(2)-PhSi{CH2PPh2}3)Cl2] (4), [Co(kappa(3)-PhSi{OPPh2}3)Cl2] (4'), [Cu(kappa(3)-PhSi{CH2PPh2}3)Br] (5) and [Cu(kappa(3)-PhSi{OPPh2}3)I] (5') were carried out. The crystal structures of 3, 3', 4, 4', and of the solvates 5.3THF and 5'.THF are reported. Complexes 3-5' were shown to promote the catalytic hydroboration of CO2 with (9-BBN)2 (9-BBN = 9 borabicyclo[3.3.1]nonane). While the iron and cobalt complexes of the triphosphine 1 are more active than the analogous complexes with 2, the opposite trend is observed with the copper catalysts. Overall, the copper catalysts 5 and 5' are both more reactive and more selective than the Fe and Co catalysts, enabling the formation of the acetal H2C(OBBN)2 with a high molar ratio of H2C(OBBN)2 : CH3OBBN up to 92 : 8. PMID- 27465276 TI - Coupling of transient near infrared photonic with magnetic nanoparticle for potential dissipation-free biomedical application in brain. AB - Combined treatment strategies based on magnetic nanoparticles (MNPs) with near infrared ray (NIR) biophotonic possess tremendous potential for non-invasive therapeutic approach. Nonetheless, investigations in this direction have been limited to peripheral body region and little is known about the potential biomedical application of this approach for brain. Here we report that transient NIR exposure is dissipation-free and has no adverse effect on the viability and plasticity of major brain cells in the presence or absence superparamagnetic nanoparticles. The 808 nm NIR laser module with thermocouple was employed for functional studies upon NIR exposure to brain cells. Magnetic nanoparticles were characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), dynamic laser scattering (DLS), and vibrating sample magnetometer (VSM). Brain cells viability and plasticity were analyzed using electric cell-substrate impedance sensing system, cytotoxicity evaluation, and confocal microscopy. When efficacious non-invasive photobiomodulation and neuro-therapeutical targeting and monitoring to brain remain a formidable task, the discovery of this dissipation free, transient NIR photonic approach for brain cells possesses remarkable potential to add new dimension. PMID- 27465278 TI - hTERT promoter methylation in meningiomas and central nervous hemangiopericytomas. AB - In meningiomas, prognostic impact of mutations in the human telomerase reverse transcriptase (hTERT) promoter region was recently shown, while studies of promoter methylation and analyses of hemangiopericytomas are lacking. hTERT promoter methylation was analyzed in 78 meningioma and 38 meningeal hemangiopericytoma samples by methylation-specific polymerase chain reaction (MS PCR) and compared with histopathological and clinical variables and with immunohistochemical hTERT expression. Promoter methylation was found in 62 samples (53 %) and tended to be higher in meningiomas (N = 19/41, 46 %) than in hemangiopericytomas (N = 8/33, 24 %, p = .057). In meningiomas, methylation was 16, 60 and 77 % in grade I, II and III tumors (p < .001) and higher in recurrent (N = 33/37, 89 %) than in primary diagnosed (N = 19/41, 46 %) tumors (OR 5.14, 95 % CI 1.34-19.71, p = .017). Univariate analyses showed shorter mean progression free and overall survival in methylated than in unmethylated individuals (26 vs. 100 months; p = .045 and 110 vs. 113 months; p = .025, respectively). Moreover, hTERT expression was found in 70 % (N = 53) and was more frequent in methylated than in unmethylated samples (78 vs. 52 %, OR 3.36, 95 % CI 1.20-9.40, p = .021). In hemangiopericytomas, methylation was similar in grade II (24 %) and III (25 %, p > .05) and in primary (24 %) and recurrent tumors (40 %, p > .05). hTERT expression was similar as compared to meningiomas (74 %, N = 28, p > .05) but was independent of promoter methylation (OR 4.26, 95 % CI 0.47-39.0, p = .199). In meningeal tumors, hTERT promoter methylation is more common than mutations and in meningiomas but not in hemangiopericytomas positively correlated with WHO grade and hTERT expression. PMID- 27465279 TI - Increased antiretroviral therapy prescription and HIV viral suppression among persons receiving clinical care for HIV infection. AB - OBJECTIVE: To assess trends during 2009-2013 in antiretroviral therapy (ART) prescription and viral suppression among adults receiving HIV clinical care in the United States. DESIGN: We used data from the Medical Monitoring Project, a surveillance system producing national estimates of characteristics of HIV infected adults receiving clinical care in the United States. METHODS: We estimated weighted proportions of persons receiving HIV medical care who were prescribed ART and achieved HIV viral suppression (<200 copies/ml) at both last test and at all tests in the previous 12 months during 2009-2013. We assessed trends overall and by gender, age, race/ethnicity, and sexual behavior/orientation. RESULTS: ART prescription and viral suppression increased significantly during 2009-2013, overall and in subgroups. ART prescription increased from 89 to 94% (P for trend <0.01). Viral suppression at last measurement increased from 72 to 80% (P for trend <0.01). The largest increases were among 18-29 year olds (56-68%), 30-39 year olds (62-75%), and non-Hispanic blacks (64-76%). Sustained viral suppression increased from 58 to 68% (P for trend <0.01). The largest increases were among 18-29 year olds (32-51%), 30-39 year olds (47-63%), and non-Hispanic blacks (49-61%). CONCLUSION: Adults receiving HIV medical care are increasingly likely to be prescribed ART and achieve viral suppression. Recent efforts to promote early antiretroviral therapy use may have contributed to these increases, bringing us closer to realizing key goals of the National HIV/AIDS Strategy. PMID- 27465280 TI - In-utero exposure to tenofovir is associated with impaired fetal and infant growth: need for follow-up studies in combination antiretroviral therapy/HIV exposed infants. PMID- 27465281 TI - Direct-acting antivirals for acute hepatitis C in HIV-infected MSM. PMID- 27465282 TI - A pilot trial of pentoxifylline on endothelial function and inflammation in HIV infected patients initiating antiretroviral therapy. PMID- 27465283 TI - A case of hereditary coproporphyria precipitated by efavirenz. PMID- 27465284 TI - Excessive collagen turnover products are released during colorectal cancer progression and elevated in serum from metastatic colorectal cancer patients. AB - During cancer progression, the homeostasis of the extracellular matrix becomes imbalanced with an excessive collagen remodeling by matrix metalloproteinases. As a consequence, small protein fragments of degraded collagens are released into the circulation. We have investigated the potential of protein fragments of collagen type I, III and IV as novel biomarkers for colorectal cancer. Specific fragments of degraded type I, III and IV collagen (C1M, C3M, C4M) and type III collagen formation (Pro-C3) were assessed in serum from colorectal cancer patients, subjects with adenomas and matched healthy controls using well characterized and validated ELISAs. Serum levels of the biomarkers were significantly elevated in colorectal cancer patients compared to subjects with adenomas (C1M, Pro-C3, C3M) and controls (C1M, Pro-C3). When patients were stratified according to their tumour stage, all four biomarkers were able to differentiate stage IV metastatic patients from all other stages. Combination of all markers with age and gender in a logistic regression model discriminated between metastatic and non-metastatic patients with an AUROC of 0.80. The data suggest that the levels of these collagen remodeling biomarkers may be a measure of tumour activity and invasiveness and may provide new clinical tools for monitoring of patients with advanced stage colorectal cancer. PMID- 27465285 TI - Contralateral prophylactic mastectomy. PMID- 27465286 TI - Candidate microRNAs as biomarkers of thyroid carcinoma: a systematic review, meta analysis, and experimental validation. AB - Thyroid cancer is one of the most common carcinomas of the endocrine system with an increasing incidence. A growing number of studies have focused on the diagnostic and prognostic values of dysregulated microRNAs (miRNAs) in thyroid carcinoma. However, differences in the measurement platforms, variations in lab protocols, and small sample sizes can make gene profiling data incomparable. A meta-review of the published studies that compared miRNA expression data of thyroid carcinoma and paired normal tissues was performed to identify potential miRNA biomarkers of thyroid carcinoma with the vote-counting strategy. Two hundred and thirty-six aberrantly expressed miRNAs were reported in 19 microRNA expression profiling studies. Among them, 138 miRNAs were reported in at least two studies. We also provided a meta-signature of differentially expressed miRNAs between individual histological types of thyroid carcinoma and normal tissues. The experimental validation with qRT-PCR analysis verified that the profiles identified with the meta-review approach could effectively discriminate papillary thyroid carcinoma tissues from paired noncancer tissues. The meta-review of miRNA expression profiling studies of thyroid carcinoma would provide information on candidate miRNAs that could potentially be used as biomarkers in thyroid carcinoma. PMID- 27465287 TI - Sociosexuality, Commitment, and Sexual Desire for an Attractive Person. AB - Sociosexuality refers to a personal predisposition to engage in uncommitted sex. Romantically involved individuals are more likely to engage in infidelity when more unrestricted in their sociosexuality and less committed to their current partners. However, commitment reliably predicts relationship maintenance and the activation of pro-relationship behaviors, regardless of sociosexuality levels. In two studies (Study 1: N = 566 heterosexuals; M age = 21.24, SD = 4.45; Study 2: N = 168 heterosexuals; M age = 23.28, SD = 5.60), the association between sociosexuality and commitment was examined. Replicating previous findings, men were more sociosexually unrestricted than women, and single individuals were more sociosexually unrestricted than their romantically involved counterparts (Study 1). Results also showed that more committed individuals were more restricted in their sociosexuality (Studies 1 and 2) and that commitment was negatively associated with physical and sexual attraction to an attractive person, regardless of sociosexuality levels (Study 2). Furthermore, commitment, but not sociosexuality, predicted sexual infidelity in the current relationship and this effect emerged even among sociosexually unrestricted individuals (Studies 1 and 2). No additional gender differences were found across studies. These results converge with findings suggesting that individuals shift their mating strategies and restrict their sociosexuality when in a romantic relationship and that commitment prevents relationship threatening behaviors such as sexual attraction or sexual infidelity. PMID- 27465290 TI - The structures of interstitial hydrogen centers in VO2 in the dilute limit from their vibrational properties and theory. AB - The introduction of a large concentration of H into VO2 is known to suppress the insulating phase of the metal-insulator transition that occurs upon cooling below 340 K. We have used infrared spectroscopy and complementary theory to study the properties of interstitial H and D in VO2 in the dilute limit to determine the vibrational frequencies, thermal stabilities, and equilibrium positions of isolated interstitial H and D centers. The vibrational lines of several OH and OD centers were observed to have thermal stabilities similar to that of the hydrogen that suppresses the insulating phase. Theory associates two of the four possible OH configurations for Hi in the insulating VO2 monoclinic phase with OH lines seen by experiment. Furthermore, theory predicts the energies and vibrational frequencies for configurations with Hi trapped near a substitutional impurity and suggests such defects as candidates for additional OH centers that have been observed. PMID- 27465289 TI - How organizational learning is associated with patient rights: a qualitative content analysis. AB - BACKGROUND: Nowadays, patient rights, particularly receiving favorable health care based on modern knowledge, informed consent, and privacy, are important issues in health care delivery systems. Organizational learning is considered an important factor influencing health care quality and patient rights. However, there is little evidence regarding this issue. OBJECTIVE: The present study was conducted to explore the role of organizational learning in patient rights from clinical nurses' viewpoint. DESIGN: This qualitative study was conducted through conventional content analysis. In total, 18 nurses who met the inclusion criteria participated in this study through purposive sampling with maximum variation. Data were gathered through 20 in-depth, semi-structured interviews, which continued until data saturation was achieved. Data collection also included constant and simultaneous comparative analyses. RESULTS: Data analysis led to four major themes: conservation of patient safety, providing favorable care, being the patient's advocate, and informing the patients. All the participants believed that organizational learning could play a vital role in respecting patient rights and interests. CONCLUSIONS: Participants believed that their efforts to conduct organizational learning, tried to improve respecting the patient rights via conservation of patient safety, trying to improve quality of care, being an advocate, and informing the patient. It would be appreciable if nursing managers honored the commitment of the nurses for learning, highlight their role as defenders of patient rights, and encourage them to initiate organizational learning. PMID- 27465288 TI - FSH treatment in infertile males candidate to assisted reproduction improved sperm DNA fragmentation and pregnancy rate. AB - The purpose of this study is to evaluate whether follicle-stimulating hormone treatment improves sperm DNA parameters and pregnancy outcome in infertile male candidates to in-vitro fertilization.Observational study in 166 infertile male partners of couples undergoing in-vitro fertilization. Eighty-four patients were receiving follicle-stimulating hormone treatment (cases) and 82 refused treatment (controls). Semen parameters, sexual hormones, and sperm nucleus (fluorescence in situ hybridization, acridine orange, TUNEL, and gammaH2AX) were evaluated at baseline (T0) and after 3 months (T1), when all subjects underwent assisted reproduction techniques. Statistical analysis was performed by analysis of variance.Compared to baseline, cases showed significant improvements in seminal parameters and DNA fragmentation indexes after follicle-stimulating hormone therapy (all P < 0.05), whereas no changes were observed in controls. Within cases, follicle-stimulating hormone treatment allowed to perform intrauterine insemination in 35 patients with a pregnancy rate of 23.2 %. Intracytoplasmic sperm injection was performed in all controls and in 49 patients from cases, with pregnancy rates of 23.2 and 40.8 %, respectively (P < 0.05). After 3 months (T0 vs. T1) of follicle-stimulating hormone therapy, cases with positive outcome had reduced DNA fragmentation index and lower double strand breaks (P < 0.05 and P < 0.001 vs. negative outcome, respectively).In this observational study, we showed that follicle-stimulating hormone treatment improves sperm DNA fragmentation, which in turn leads to increased pregnancy rates in infertile males undergoing in vitro fertilization. In particular, double strand breaks (measured with gammaH2AX test) emerged as the most sensible parameter to follicle-stimulating hormone treatment in predicting reproductive outcome. PMID- 27465292 TI - Attitudes toward suicidal behaviour among professionals at mental health outpatient clinics in Stavropol, Russia and Oslo, Norway. AB - BACKGROUND: Attitudes toward suicidal behaviour can be essential regarding whether patients seek or are offered help. Patients with suicidal behaviour are increasingly treated by mental health outpatient clinics. Our aim was to study attitudes among professionals at outpatient clinics in Stavropol, Russia and Oslo, Norway. METHODS: Three hundred and forty-eight (82 %) professionals anonymously completed a questionnaire about attitudes. Professionals at outpatient clinics in Stavropol (n = 119; 94 %) and Oslo (n = 229; 77 %) were enrolled in the study. The Understanding Suicidal Patients (USP) scale (11 = positive to 55 = negative) and the Attitudes Towards Suicide Scale (ATTS) (1 = totally disagree, 5 = totally agree) were used. Questions about religious background, perceived competence and experiences of and views on suicidal behaviour and treatment (0 = totally disagree, 4 = totally agree) were examined. RESULTS: All groups reported positive attitudes, with significant differences between Stavropol and Oslo (USP score, 21.8 vs 18.7; p < 0.001). Professionals from Stavropol vs. Oslo reported significantly less experience with suicidal patients, courses in suicide prevention (15 % vs 79 %) guidelines in suicidal prevention (23 % vs 90 %), interest for suicide prevention (2.0 vs 2.7; p < 0.001), and agreed more with the ATTS factors: avoidance of communication on suicide (3.1 vs 2.3; p < 0.001), suicide is acceptable (2.9 vs 2.6; p = 002), suicide is understandable (2.9 vs 2.7; p = 0.012) and (to a lesser extent) suicide can be prevented (4.2 vs 4.5; p < 0.001). In both cities, psychiatric disorders (3.4) were considered as the most important cause of suicide. Use of alcohol (2.2 vs 2.8; p < 0.001) was considered less important in Stavropol. Psychotherapy was considered significant more important in Stavropol than Oslo (3.6 vs 3.4; p = 0.001). CONCLUSIONS: Professionals reported positive attitudes towards helping suicidal patients, with significant differences between cities. A need for further education was reported in both cities, but education was less integrated in mental health care in Stavropol than it was in Oslo. In both cities, psychiatric disorders were considered the major reasons for suicide, and psychotherapy was the most important treatment measure. PMID- 27465291 TI - Melanoma dormancy in a mouse model is linked to GILZ/FOXO3A-dependent quiescence of disseminated stem-like cells. AB - Metastatic cancer relapses following the reactivation of dormant, disseminated tumour cells; however, the cells and factors involved in this reactivation are just beginning to be identified. Using an immunotherapy-based syngeneic model of melanoma dormancy and GFP-labelled dormant cell-derived cell lines, we determined that vaccination against melanoma prevented tumour growth but did not prevent tumour cell dissemination or eliminate all tumour cells. The persistent disseminated melanoma tumour cells were quiescent and asymptomatic for one year. The quiescence/activation of these cells in vitro and the dormancy of melanoma in vivo appeared to be regulated by glucocorticoid-induced leucine zipper (GILZ) mediated immunosuppression. GILZ expression was low in dormant cell-derived cultures, and re-expression of GILZ inactivated FOXO3A and its downstream target, p21CIP1. The ability of dormancy-competent cells to re-enter the cell cycle increased after a second round of cellular dormancy in vivo in association with shortened tumour dormancy period and faster and more aggressive melanoma relapse. Our data indicate that future cancer treatments should be adjusted according to the stage of disease progression. PMID- 27465293 TI - Evaluation of Nano Structured Slow Release Fertilizer on the Soil Fertility, Yield and Nutritional Profile of Vigna radiata. AB - BACKGROUND: The excessive use of fertilizers and pesticides has distorted soil composition, fertility and integrity with non-desirable environmental and ecological consequences. A strategy was designed to prepare a nano structured slow release fertilizer system that delivers nutrients and plant growth promoting rhizobacteria simultaneously. Slow release nano phosphate and potash fertilizer was prepared by blending the nano emulsion of fertilizer with neem cake and PGPR. Slow release nano phosphate and potash fertilizer was prepared by blending the nano emulsion of fertilizer with neem cake and PGPR. Few patents relevant to the topic have been reviewed and cited. METHODS: The influence of nano structured slow release fertilizer on the biochemical characteristics, soil and yield attributes of Vigna radiata was studied in the field by randomized block design. The treatments used to evaluate the effect of nano SRF were a control (without any fertilizer), neem cake, chemical fertilizer, PGPR and nano SRF. Germination, specific activity of enzymes, carbohydrates, protein, photosynthetic pigments, root nodule number and microbial population were assessed by standard methods. RESULTS: The size of the nano urea slow release fertilizer ranged from 52.41 nm to 69.86 nm, and the size of the phosphate and potash fertilizer ranged from 81.85 nm to 87 nm. The weights of 1000 grains were 31.8 g, 33.28 g, 33.39 g, 36.65 g and 44.90 g in the control, neem cake, chemical fertilizer, PGPR and nano SRF, respectively. The protein concentrations were 162 mg g-1 in the control, 231 mg g-1 in the neem cake, 192 mg g-1 in the chemical fertilizer, 285 mg g-1 in the PGPR and 336 mg g-1 in the nano SRF. Nano slow release fertilizer treatment has stimulated germination and biochemical characteristics in Vigna radiata that are positively reflected in the yield attributes. PMID- 27465297 TI - To the Point: Integrating Patient Safety Education Into the Obstetrics and Gynecology Undergraduate Curriculum. AB - This article is part of the To the Point Series prepared by the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee. Principles and education in patient safety have been well integrated into academic obstetrics and gynecology practices, although progress in safety profiles has been frustratingly slow. Medical students have not been included in the majority of these ambulatory practice or hospital-based initiatives. Both the Association of American Medical Colleges and Accreditation Council for Graduate Medical Education have recommended incorporating students into safe practices. The Accreditation Council for Graduate Medical Education milestone 1 for entering interns includes competencies in patient safety. We present data and initiatives in patient safety, which have been successfully used in undergraduate and graduate medical education. In addition, this article demonstrates how using student feedback to assess sentinel events can enhance safe practice and quality improvement programs. Resources and implementation tools will be discussed to provide a template for incorporation into educational programs and institutions. Medical student involvement in the culture of safety is necessary for the delivery of both high-quality education and high-quality patient care. It is essential to incorporate students into the ongoing development of patient safety curricula in obstetrics and gynecology. PMID- 27465296 TI - Experimental demonstration of multi-dimensional resources integration for service provisioning in cloud radio over fiber network. AB - Cloud radio access network (C-RAN) becomes a promising scenario to accommodate high-performance services with ubiquitous user coverage and real-time cloud computing in 5G area. However, the radio network, optical network and processing unit cloud have been decoupled from each other, so that their resources are controlled independently. Traditional architecture cannot implement the resource optimization and scheduling for the high-level service guarantee due to the communication obstacle among them with the growing number of mobile internet users. In this paper, we report a study on multi-dimensional resources integration (MDRI) for service provisioning in cloud radio over fiber network (C RoFN). A resources integrated provisioning (RIP) scheme using an auxiliary graph is introduced based on the proposed architecture. The MDRI can enhance the responsiveness to dynamic end-to-end user demands and globally optimize radio frequency, optical network and processing resources effectively to maximize radio coverage. The feasibility of the proposed architecture is experimentally verified on OpenFlow-based enhanced SDN testbed. The performance of RIP scheme under heavy traffic load scenario is also quantitatively evaluated to demonstrate the efficiency of the proposal based on MDRI architecture in terms of resource utilization, path blocking probability, network cost and path provisioning latency, compared with other provisioning schemes. PMID- 27465295 TI - De novo transcriptome sequencing facilitates genomic resource generation in Tinospora cordifolia. AB - Tinospora cordifolia is known for its medicinal properties owing to the presence of useful constituents such as terpenes, glycosides, steroids, alkaloids, and flavonoids belonging to secondary metabolism origin. However, there is little information available pertaining to critical genomic elements (ESTs, molecular markers) necessary for judicious exploitation of its germplasm. We employed 454 GS-FLX pyrosequencing of entire transcripts and altogether ~25 K assembled transcripts or Expressed sequence tags (ESTs) were identified. As the interest in T. cordifolia is primarily due to its secondary metabolite constituents, the ESTs pertaining to terpenoids biosynthetic pathway were identified in the present study. Additionally, several ESTs were assigned to different transcription factor families. To validate our transcripts dataset, the novel EST-SSR markers were generated to assess the genetic diversity among germplasm of T. cordifolia. These EST-SSR markers were found to be polymorphic and the dendrogram based on dice similarity index revealed three distinct clustering of accessions. The present study demonstrates effectiveness in using both NEWBLER and MIRA sequence read assembler software for enriching transcript-dataset and thus enables better exploitation of EST resources for mining candidate genes and designing molecular markers. PMID- 27465294 TI - Comprehensive transcriptome-based characterization of differentially expressed genes involved in microsporogenesis of radish CMS line and its maintainer. AB - Microsporogenesis is an indispensable period for investigating microspore development and cytoplasmic male sterility (CMS) occurrence. Radish CMS line plays a critical role in elite F1 hybrid seed production and heterosis utilization. However, the molecular mechanisms of microspore development and CMS occurrence have not been thoroughly uncovered in radish. In this study, a comparative analysis of radish floral buds from a CMS line (NAU-WA) and its maintainer (NAU-WB) was conducted using next generation sequencing (NGS) technology. Digital gene expression (DGE) profiling revealed that 3504 genes were significantly differentially expressed between NAU-WA and NAU-WB library, among which 1910 were upregulated and 1594 were downregulated. Gene ontology (GO) analysis showed that these differentially expressed genes (DEGs) were mainly enriched in extracellular region, catalytic activity, and response to stimulus. KEGG enrichment analysis revealed that the DEGs were predominantly associated with flavonoid biosynthesis, glycolysis, and biosynthesis of secondary metabolites. Real-time quantitative PCR analysis showed that the expression profiles of 13 randomly selected DEGs were in high agreement with results from Illumina sequencing. Several candidate genes encoding ATP synthase, auxin response factor (ARF), transcription factors (TFs), chalcone synthase (CHS), and male sterility (MS) were responsible for microsporogenesis. Furthermore, a schematic diagram for functional interaction of DEGs from NAU-WA vs. NAU-WB library in radish plants was proposed. These results could provide new information on the dissection of the molecular mechanisms underlying microspore development and CMS occurrence in radish. PMID- 27465298 TI - Epidemiology of Adverse Events and Medical Errors in the Care of Cardiology Patients. AB - OBJECTIVES: There have been epidemiological studies of adverse events (AEs) among general patients but those of patients cared by cardiologist are not well scrutinized. We investigated the occurrence of AEs and medical errors (MEs) among adult patients with cardiology in Japan. METHODS: We conducted a cross-sectional study of adult outpatients at a Japanese teaching hospital from February through November 2006. We measured AE and ME incidents from patient report, which were verified by medical records, laboratory data, incident reports, and prescription queries. Two independent physicians reviewed the incidents to determine whether they were AEs or MEs and to assess severity and symptoms. RESULTS: We identified 144 AEs and 30 MEs (16.3 and 3.9 per 100 patients, respectively). Of the 144 AEs, 99 were solely adverse drug events (ADEs), 20 were solely non-ADEs, and the remaining 25 were both causes. The most frequent symptoms of ADEs were skin and allergic reactions due to medication. The most frequent symptoms of non-ADEs were bleeding due to therapeutic interventions. Among AEs, 12% was life threatening. Life-threatening AEs were 25% of non-ADEs and 5% of ADEs (P = 0.0003). Among the 30 MEs, 21MEs (70%) were associated with drugs. CONCLUSIONS: Adverse events were common among cardiology patients. Adverse drug events were the most frequent AEs, and non-ADEs were more critical than ADEs. Such data should be recognized among practicing physicians to improve the patients' outcomes.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. PMID- 27465299 TI - Laboratory and field validation of a simple method for detecting four species of non-native freshwater fish using eDNA. AB - This paper presents the first phase in the development and validation of a simple and reliable environmental (e)DNA method using conventional PCR to detect four species of non-native freshwater fish: pumpkinseed Lepomis gibbosus, sunbleak Leucaspius delineatus, fathead minnow Pimephales promelas and topmouth gudgeon Pseudorasbora parva. The efficacy of the approach was demonstrated in indoor tank (44 l) trials in which all four species were detected within 24 h. Validation was through two field trials, in which L. gibbosus was detected 6-12 h after its introduction into outdoor experimental ponds and P. parva was successfully detected in disused fish rearing ponds where the species was known to exist. Thus, the filtration of small (30 ml) volumes of pond water was sufficient to capture fish eDNA and the approach emphasised the importance of taking multiple water samples of sufficient spatial coverage for detecting species of random or patchy distribution. PMID- 27465300 TI - Transfer of IVF-contaminated blastocysts with removal of the zona pellucida resulted in live births. AB - PURPOSE: Bacterial contamination may cause loss or damage to cultured oocytes or embryos, resulting in cancelation or delaying of a fresh embryo transfer. While live births have been reported following the transfer of embryos contaminated with yeast, very little information is available on how to handle embryos with bacterial contamination. We report two cases of successful pregnancy in patients with bacterial contamination of embryo culture dishes. METHODS: We retrospectively reviewed 878 oocyte retrievals performed between January 2011 and December 2014. Bacterial contamination was recorded in two split IVF/ICSI cases, where contamination occurred in embryo culture drops containing embryos from conventional insemination but not from ICSI on day 3. RESULTS: To minimize the adverse effects of bacterial contamination on transfer outcomes, we removed the zona pellucida of contaminated frozen blastocysts and successfully obtained clinical pregnancies following transfer of zona-free blastocysts that were previously contaminated during IVF culture. CONCLUSIONS: Removal of the zona pellucida is an appropriate approach to handle blastocysts contaminated with bacteria during in vitro culture. PMID- 27465301 TI - Follicular growth after xenotransplantation of cryopreserved/thawed human ovarian tissue in SCID mice: dynamics and molecular aspects. AB - PURPOSE: To study the influence of xenotransplantation on follicular recruitment and growth in cryopreserved/thawed human ovarian tissue. METHOD: Two 3-mm pieces of cryopreserved/thawed human ovarian tissue obtained from female cancer patients (n = 11) were xenotransplanted into a subcutaneous neck pouch of 6-week-old ovarectomized SCID mice (n = 33) for 4 (n = 18) and 12 (n = 15) weeks. RESULT: Thirty-two out of 33 mice survived the entire observation periods. Graft recovery rate was 95.58 % (65 of 68 grafts). The percentages of primordial follicles after 4 weeks (P < 0.001) and 12 weeks (P = 0.009) of grafting were significantly lower in comparison to pregraft controls. The percentage of secondary follicle was significantly higher after 4 weeks of grafting (P = 0.018) and after 12 weeks (P = 0.001) of grafting in comparison to pregraft controls. Ki67 immunohistochemistry showed that proliferative follicles were significantly higher after 4 and 12 weeks of grafting compared to pregraft controls (P < 0.001). All follicles analyzed by TUNEL staining appeared healthy after xenotransplantation. The expression level of PTEN was reduced by 2.47-fold after 4 weeks of xenotransplantation, and this result was significant when 2-DeltaCt were analyzed (P = 0.042). CONCLUSION: The higher proportion of growing follicles compared to resting follicles observed after xenotransplantation is most likely due to downregulation of PTEN gene expression followed by acceleration of follicular recruitment. PMID- 27465302 TI - Clinical evaluation of two formulations of slow-freezing solutions for cleavage stage embryos. AB - PURPOSE: The aim was to investigate if improved survival rates could be achieved using a new formulation of solutions for slow freezing of human cleavage stage embryos. METHODS: The evaluation was divided into two parts. The first part was a retrospective analysis of results obtained after freezing and thawing of day 3 embryos from 400 women using an old formulation of cryopreservation solutions compared to results from 108 women for which cryopreservation had been performed using new compositions of solutions. The second part was prospective, adding cycles until similar numbers of patients had been included in both groups. In total, 2274 embryos from 897 patients were thawed using the old formulation of solutions while 1273 embryos from 542 patients were frozen and thawed using the new solutions. The primary endpoint was survival rate. RESULTS: With the new solutions, the survival rate increased from 82.1 to 94.4 % and the complete embryo survival rate increased from 54.9 to 81.3 %. The implantation rate, clinical pregnancy rate per embryo transfer, and per cycle were 28.2, 45.2, and 43.7 %, respectively, using the old formulations of cryosolutions. With the new solutions, the results reached 33.7, 54.1, and 54.1 %, respectively. All differences in results were statistically significant. The number of cancelled embryo transfers due to no survived embryos was 18 with the old solutions and 0 using the new solutions. CONCLUSION: With the new composition of solutions for slow freezing and thawing of embryos, significantly improved results were obtained. Additionally, the number of cancelled embryo transfers was reduced. PMID- 27465303 TI - Pulmonary embolism with floating right atrial thrombus successfully treated with streptokinase: a case report. AB - BACKGROUND: Massive pulmonary embolism (PE) is associated with significant mortality, especially if compounded by haemodynamic instability, right ventricular (RV) dysfunction and right atrial (RA) thrombus. Thrombolysis can be lifesaving in patients with major embolism and cardiogenic shock, and accelerates the resolution of thrombus. Only three fibrinolytic agents-namely streptokinase, urokinase, and recombinant tissue plasminogen activator (alteplase) have been approved in the treatment of PE, with studies demonstrating similar safety profiles. CASE PRESENTATION: We report the case of a 33-year-old Bangladeshi Bengali female with a history of recent ankle fracture and immobilization, who presented with massive PE, leading to cardiac arrest. Upon rapid resuscitation, urgent echocardiogram revealed RV dysfunction with floating RA thrombus, and she was successfully treated with 1.5 million IU of streptokinase over 2 h as per accelerated regimen recommended by the European Society of Cardiology guidelines, resulting in successful resolution of the right heart thrombus, and significant clinical improvement. Subsequent CT pulmonary angiogram confirmed the diagnosis of PE, and she was anticoagulated to a PT/INR of 2.0-3.0 for 3 months. CONCLUSIONS: Echocardiography is a suitable alternative for rapid diagnosis of acute massive PE associated with RA thrombus and cardiovascular collapse, especially when a delay to CT pulmonary angiogram may be anticipated, and in the setting of immediate cardio-pulmonary resuscitation. Thrombolysis is a rapid and life-saving therapeutic measure in such cases. PMID- 27465305 TI - Pelvic floor muscle strength in primigravidae and non-pregnant nulliparous women: a comparative study. AB - INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the pelvic floor muscles (PFM) in primigravidae and compare them with those in nonpregnant nulliparous women. METHODS: The sample consisted of 141 women with a mean age of 22.8 years, divided into four groups: 36 nonpregnant nulliparous (C), 31 primigravidae in the first trimester (1T), 42 primigravida in the second trimester (2T), and 32 primigravidae in the third trimester (3T). The participants were examined by digital palpation for pelvic floor muscle contraction using the Modified Oxford Scale, by measuring maximal vaginal squeeze pressure with a vaginal perineometer, and by measuring PFM maximal strength using a vaginal dynamometer. The best value of three maximal strengths was considered for analysis, the Kruskal-Wallis and Mann-Whitney U tests were used and differences were considered significant at p <= 0.05. RESULTS: The mean values for group C were 3.2 (digital palpation), 45.6 cmH2O (perineometry), and 11.7 N (dynamometry); for group 1T the corresponding values were 2.5, 21.1 cmH2O, and 8.8 N; for group 2T: 2.8, 22.9 cmH2O, and 7.8 N; and for group 3T: 2.1, 17.3 cmH2O, and 6.8 N. Groups were compared in pairs for digital palpation, perineometry, and dynamometry. There were significant differences between group C and group 1T, and between group C and group 3T. There was a significant difference between group C and group 2T with regard to perineometry and dynamometry, but not digital palpation. Dynamometry demonstrated a difference between groups 1T and 3T, digital palpation between groups 2T and 3T. CONCLUSION: Pelvic floor muscles in primigravidae are not as strong as those in nonpregnant nulliparous women. PMID- 27465304 TI - Epidemiology and outcomes of out-of-hospital cardiac arrest in a developing country-a multicenter cohort study. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death and disability worldwide. Overall survival after an OHCA has been reported to be poor and limited studies have been conducted in developing countries. We aimed to investigate the rates of survival from OHCA and explore components of the chain of survival in a developing country. METHODS: We conducted a multicenter prospective cohort study in the emergency departments (ED) of five major public and private sector hospitals of Karachi, Pakistan from January 2013 to April 2013. Twenty-four hour data collection was performed by trained data collectors, using a structured questionnaire. All patients >=18 years of age, presenting with OHCA of cardiac origin, were included. Patients with do-not resuscitate status or referred from other hospitals were excluded. Our primary outcome was survival of OHCA patients at the end of ED stay. RESULTS: During the three month period, data was obtained from 310 OHCA patients. The overall survival to ED discharge was 1.6 % which decreased to 0 % at 2-months after discharge. More than half (58.3 %) of these OHCA patients were brought to the hospital in a non-EMS (emergency medical service) vehicle i.e. public or private transportation. Patients utilizing non-EMS transportation reached the hospital earlier with a median time of 23 min compared to patients utilizing any type of ambulances which had a delay of 7 min hospital reaching time (median time 30 min). However, patients utilizing ambulances with life-support facilities, as compared to all other types of pre-hospital transportation, had the shortest time to first life-support intervention (15 min). Most of the patients (92.9 %) had a witnessed cardiac arrest out of which only a small percentage (2.3 %) received bystander CPR (cardio pulmonary resuscitation). Median time from arrest to receiving first CPR was 20 min. Only 1 % of patients were found to have a shockable rhythm on first assessment. CONCLUSION: This study showed that the overall survival of OHCA is null in this population. Lack of bystander CPR and weaker emergency medical services (EMS) leading to a delay in receiving life support interventions were some of the important observations. Poor survival emphasizes the need to standardize EMS systems, initiate public awareness programs and strengthen links in the chain of survival. PMID- 27465306 TI - Integrating Epigenomic Elements and GWASs Identifies BDNF Gene Affecting Bone Mineral Density and Osteoporotic Fracture Risk. AB - To identify susceptibility genes for osteoporosis, we conducted an integrative analysis that combined epigenomic elements and previous genome-wide association studies (GWASs) data, followed by validation at population and functional levels, which could identify common regulatory elements and predict new susceptibility genes that are biologically meaningful to osteoporosis. By this approach, we found a set of distinct epigenomic elements significantly enriched or depleted in the promoters of osteoporosis-associated genes, including 4 transcription factor binding sites, 27 histone marks, and 21 chromatin states segmentation types. Using these epigenomic marks, we performed reverse prediction analysis to prioritize the discovery of new candidate genes. Functional enrichment analysis of all the prioritized genes revealed several key osteoporosis related pathways, including Wnt signaling. Genes with high priority were further subjected to validation using available GWASs datasets. Three genes were significantly associated with spine bone mineral density, including BDNF, PDE4D, and SATB2, which all closely related to bone metabolism. The most significant gene BDNF was also associated with osteoporotic fractures. RNA interference revealed that BDNF knockdown can suppress osteoblast differentiation. Our results demonstrated that epigenomic data could be used to indicate common epigenomic marks to discover additional loci with biological functions for osteoporosis. PMID- 27465307 TI - Significance of kinase activity in the dynamic invadosome. AB - Invadosomes are actin rich protrusive structures that facilitate invasive migration in multiple cell types. Comprised of invadopodia and podosomes, these highly dynamic structures adhere to and degrade the extracellular matrix, and are also thought to play a role in mechanosensing. Many extracellular signals have been implicated in invadosome stimulation, activating complex signalling cascades to drive the formation, activity and turnover of invadosomes. While the structural components of invadosomes have been well studied, the regulation of invadosome dynamics is still poorly understood. Protein kinases are essential to this regulation, affecting all stages of invadosome dynamics and allowing tight spatiotemporal control of their activity. Invadosome organisation and function have been linked to pathophysiological states such as cancer invasion and metastasis; therapeutic targeting of invadosome regulatory components is thus warranted. In this review, we discuss the involvement of kinase signalling in every stage of the invadosome life cycle and evaluate its significance. PMID- 27465309 TI - Contamination-Focused Exposure as a Treatment for Disgust-Based Fears: A Preliminary Test in Spider-Fearful Women. AB - BACKGROUND: Disgust is thought to play a prominent role in multiple anxiety disorders and fears, including spider phobia, though little attention has been given to specific treatment strategies that may be effective for multiple disgust based fears. AIMS: In the present study, we evaluated contamination-focused exposure as a potential transdiagnostic treatment strategy for disgust-based fears in a spider fearful sample. METHOD: Women with significant spider fear were randomized to three 30-minute sessions of exposure therapy involving repeated contact with a dirt mixture (n=17) or a waitlist control condition (n=17). Assessments of spider fear and disgust were administered at baseline and at one week posttreatment. RESULTS: At high (but not low) levels of pretreatment disgust propensity, exposure led to lower in vivo spider fear and perceived danger than waitlist, though exposure had no effects on spider-related disgust. Similar effects of exposure on spider fear were found at high levels of pretreatment spider-related disgust. Exposure also reduced fear and danger perceptions, but not disgust, related to a separate contamination assessment (touching a toilet). No effects of treatment were found on self-report measures of spider fear or disgust propensity. CONCLUSIONS: These findings suggest contamination-focused exposure therapy may be an effective transdiagnostic treatment strategy for individuals with elevated disgust propensity. Limitations and directions for future research are discussed. PMID- 27465308 TI - Post-exposure treatment of Ebola virus disease in guinea pigs using EBOTAb, an ovine antibody-based therapeutic. AB - Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. An ovine polyclonal antibody therapy has been developed against EBOV, named EBOTAb. When tested in the stringent guinea pig model of EBOV disease, EBOTAb has been shown to confer protection at levels of 83.3%, 50% and 33.3% when treatment was first started on days 3, 4 and 5 post-challenge, respectively. These timepoints of when EBOTAb treatment was initiated correspond to when levels of EBOV are detectable in the circulation and thus mimic when treatment would likely be initiated in human infection. The effects of EBOTAb were compared with those of a monoclonal antibody cocktail, ZMapp, when delivered on day 3 post-challenge. Results showed ZMapp to confer complete protection against lethal EBOV challenge in the guinea pig model at this timepoint. The data reported demonstrate that EBOTAb is an effective treatment against EBOV disease, even when delivered late after infection. PMID- 27465311 TI - Accelerated Chemical Reactions and Organic Synthesis in Leidenfrost Droplets. AB - Leidenfrost levitated droplets can be used to accelerate chemical reactions in processes that appear similar to reaction acceleration in charged microdroplets produced by electrospray ionization. Reaction acceleration in Leidenfrost droplets is demonstrated for a base-catalyzed Claisen-Schmidt condensation, hydrazone formation from precharged and neutral ketones, and for the Katritzky pyrylium into pyridinium conversion under various reaction conditions. Comparisons with bulk reactions gave intermediate acceleration factors (2-50). By keeping the volume of the Leidenfrost droplets constant, it was shown that interfacial effects contribute to acceleration; this was confirmed by decreased reaction rates in the presence of a surfactant. The ability to multiplex Leidenfrost microreactors, to extract product into an immiscible solvent during reaction, and to use Leidenfrost droplets as reaction vessels to synthesize milligram quantities of product is also demonstrated. PMID- 27465313 TI - Fatal anaphylaxis from hymenoptera stings. AB - Venomous insect stings are a cause of morbidity and mortality worldwide. The sting reactions are unpredictable and vary among individuals. A case of fatal insect sting in an elderly female is presented to discuss the associated challenges during necropsy. PMID- 27465312 TI - Persistent and pervasive compositional shifts of western boreal forest plots in Canada. AB - Species compositional shifts have important consequences to biodiversity and ecosystem function and services to humanity. In boreal forests, compositional shifts from late-successional conifers to early-successional conifers and deciduous broadleaves have been postulated based on increased fire frequency associated with climate change truncating stand age-dependent succession. However, little is known about how climate change has affected forest composition in the background between successive catastrophic fires in boreal forests. Using 1797 permanent sample plots from western boreal forests of Canada measured from 1958 to 2013, we show that after accounting for stand age-dependent succession, the relative abundances of early-successional deciduous broadleaves and early successional conifers have increased at the expense of late-successional conifers with climate change. These background compositional shifts are persistent temporally, consistent across all forest stand ages and pervasive spatially across the region. Rising atmospheric CO2 promoted early-successional conifers and deciduous broadleaves, and warming increased early-successional conifers at the expense of late-successional conifers, but compositional shifts were not associated with climate moisture index. Our results emphasize the importance of climate change on background compositional shifts in the boreal forest and suggest further compositional shifts as rising CO2 and warming will continue in the 21st century. PMID- 27465310 TI - High sensitization to house-dust mites in patients with allergic rhinitis in the eastern Black Sea region of Turkey: A retrospective study. AB - OBJECTIVES: Identification of the most common aeroallergens to which patients are sensitized in a specific area is important in the diagnosis and treatment of allergic rhinitis (AR). We determined the distribution of aeroallergens, detected by skin-prick tests (SPT), in adult patients with AR in the Eastern Black Sea region of Turkey and compared the results with the other regions of Turkey and in the world. METHODS: The medical records of SPT performed on 1457 patients with symptoms of AR (with regard to the Allergic Rhinitis and its Impact on Asthma 2008 guidelines) between March 2010 and March 2013 were analyzed retrospectively. SPT were carried out with the same panel, which included grass; weeds; trees; mold; epidermal mixtures; and with two house-dust mite (HDM) extracts, Dermatophagoides pteronyssinus and Dermatophagoides farinae. RESULTS: In 1229 of 1457 patients (84.4%), there were positive reactions for at least one aeroallergen on the SPT. The most common aeroallergen was the HDM D. pteronyssinus (84% [n = 1033]) followed by D. farinae (78.2% [n = 962]). Grass pollen sensitivity (70.8% [n = 871]) was higher than tree or weed pollen sensitivity in this region. CONCLUSIONS: The most common aeroallergens in AR are HDMs of D. pteronyssinus and D. farinae in the Eastern Black Sea region in Turkey. Our study may help in developing environmental control strategies for AR. PMID- 27465314 TI - Ingestion of safety razor blade and delayed hanging in a complex suicide. AB - Ingestion of a foreign body is mostly accidental in children and intentional in prisoners to achieve hospitalization; however, use of this method of suicide is rare. We report a case where the victim first ingested a safety razor blade, but failed to die and then hanged himself, but failed again and finally succumbed to the complications on the sixth day. He had also attempted suicide by inflicting multiple incised wounds on his neck four days before the safety blade ingestion, but none were fatal. PMID- 27465316 TI - SINGLE INSTITUTION VARIABILITY IN INTENSITY MODULATED RADIATION TARGET DELINEATION FOR CANINE NASAL NEOPLASIA. AB - Contouring variability is a significant barrier to the accurate delivery and reporting of radiation therapy. The aim of this descriptive study was to determine the variation in contouring radiation targets and organs at risk by participants within our institution. Further, we also aimed to determine if all individuals contoured the same normal tissues. Two canine nasal tumor datasets were selected and contoured by two ACVR-certified radiation oncologists and two radiation oncology residents from the same institution. Eight structures were consistently contoured including the right and left eye, the right and left lens, brain, the gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV). Spinal cord, hard and soft palate, and bulla were contoured on 50% of datasets. Variation in contouring occurred in both targets and normal tissues at risk and was particularly significant for the GTV, CTV, and PTV. The mean metric score and dice similarity coefficient were below the threshold criteria in 37.5-50% and 12.5-50% of structures, respectively, quantitatively indicating contouring variation. This study refutes our hypothesis that minimal variation in target and normal tissue delineation occurs. The variation in contouring may contribute to different tumor response and toxicity for any given patient. Our results also highlight the difficulty associated with replication of published radiation protocols or treatments, as even with replete contouring description the outcome of treatment is still fundamentally influenced by the individual contouring the patient. PMID- 27465317 TI - Oxycodone for neuropathic pain in adults. AB - BACKGROUND: This is an update of an earlier review that considered both neuropathic pain and fibromyalgia (Issue 6, 2014), which has now been split into separate reviews for the two conditions. This review considers neuropathic pain only.Opioid drugs, including oxycodone, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for oxycodone, at any dose, and by any route of administration. Separate reviews consider other opioids. OBJECTIVES: To assess the analgesic efficacy and adverse events of oxycodone for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from inception to 6 November 2013 for the original review and from January 2013 to 21 December 2015 for this update. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries. This update differs from the earlier review in that we have included studies using oxycodone in combination with naloxone, and oxycodone used as add-on treatment to stable, but inadequate, treatment with another class of drug. SELECTION CRITERIA: We included randomised, double-blind studies of two weeks' duration or longer, comparing any dose or formulation of oxycodone with placebo or another active treatment in chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and numbers needed to treat for one additional event, using standard methods.We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table. MAIN RESULTS: The updated searches identified one additional published study, and one clinical trial registry report. We included five studies reporting on 687 participants; 637 had painful diabetic neuropathy and 50 had postherpetic neuralgia. Two studies used a cross-over design and three used a parallel group design; all studies used a placebo comparator, although one study used an active placebo (benztropine). Modified-release oxycodone (oxycodone MR) was titrated to effect and tolerability. One study used a fixed dose combination of oxycodone MR and naloxone. Two studies added oxycodone therapy to ongoing, stable treatment with either pregabalin or gabapentin. All studies had one or more sources of potential major bias.No study reported the proportion of participants experiencing 'substantial benefit' (at least 50% pain relief or who were very much improved). Three studies (537 participants) in painful diabetic neuropathy reported outcomes equivalent to 'moderate benefit' (at least 30% pain relief or who were much or very much improved), which was experienced by 44% of participants with oxycodone and 27% with placebo (number needed to treat for one additional beneficial outcome (NNT) 5.7).All studies reported group mean pain scores at the end of treatment. Three studies reported a greater pain intensity reduction and better patient satisfaction with oxycodone MR alone than with placebo. There was a similar result in the study adding oxycodone MR to stable, ongoing gabapentin, but adding oxycodone MR plus naloxone to stable, ongoing pregabalin did not show any additional effect.More participants experienced adverse events with oxycodone MR alone (86%) than with placebo (63%); the number needed to treat for an additional harmful outcome (NNH) was 4.3. Serious adverse events (oxycodone 3.4%, placebo 7.0%) and adverse event withdrawals (oxycodone 11%, placebo 6.4%) were not significantly different between groups. Withdrawals due to lack of efficacy were less frequent with oxycodone MR (1.1%) than placebo (11%), with a number needed to treat to prevent one withdrawal of 10. The add-on studies reported similar results.We downgraded the quality of the evidence to very low for all outcomes, due to limitations in the study methods, heterogeneity in the pain condition and study methods, and sparse data. AUTHORS' CONCLUSIONS: There was only very low quality evidence that oxycodone (as oxycodone MR) is of value in the treatment of painful diabetic neuropathy or postherpetic neuralgia. There was no evidence for other neuropathic pain conditions. Adverse events typical of opioids appeared to be common. PMID- 27465315 TI - Organometallic Complex Formed by an Unconventional Radical S-Adenosylmethionine Enzyme. AB - Pyrococcus horikoshii Dph2 (PhDph2) is an unusual radical S-adenosylmethionine (SAM) enzyme involved in the first step of diphthamide biosynthesis. It catalyzes the reaction by cleaving SAM to generate a 3-amino-3-carboxypropyl (ACP) radical. To probe the reaction mechanism, we synthesized a SAM analogue (SAMCA), in which the ACP group of SAM is replaced with a 3-carboxyallyl group. SAMCA is cleaved by PhDph2, yielding a paramagnetic (S = 1/2) species, which is assigned to a complex formed between the reaction product, alpha-sulfinyl-3-butenoic acid, and the [4Fe 4S] cluster. Electron-nuclear double resonance (ENDOR) measurements with (13)C and (2)H isotopically labeled SAMCA support a pi-complex between the C?C double bond of alpha-sulfinyl-3-butenoic acid and the unique iron of the [4Fe-4S] cluster. This is the first example of a radical SAM-related [4Fe-4S](+) cluster forming an organometallic complex with an alkene, shedding additional light on the mechanism of PhDph2 and expanding our current notions for the reactivity of [4Fe-4S] clusters in radical SAM enzymes. PMID- 27465318 TI - Effects of therapeutic recreation on adults with ASD and ID: a preliminary randomized control trial. AB - BACKGROUND: The purpose of this research was to examine effects of a therapeutic recreation (TR) program designed to increase executive function (EF), social skills, adaptive behaviours and well-being of adults with autism spectrum disorder (ASD) and intellectual disability (ID). METHOD: A preliminary pre-test, post-test randomized control group experimental design was used to measure effects of a 40-week TR program designed to increase EF (TR-EF). The TR-EF used instructional electronically based games delivered during 200 1-h sessions (5/week). RESULTS: Participants (experimental group, n = 19; wait-list group, n = 18) were evaluated at baseline and 10 months later. There was a positive and direct impact of the program on several EF and indirect effect on social skills, adaptive behaviour and personal well-being. CONCLUSIONS: Findings provide support for inclusion of EF enrichment as a way to enhance effects of TR interventions for adults with ASD and ID. Preliminary results of this study can be considered in planning TR services in the future. In addition to TR-EF program primary effects on EF, there were indirect benefits on adaptive behaviours, personal well being and social skills. PMID- 27465319 TI - Association of polymorphisms of rs179247 and rs12101255 in thyroid stimulating hormone receptor intron 1 with an increased risk of Graves' disease: A meta analysis. AB - The polymorphisms of thyroid stimulating hormone receptor (TSHR) intron 1 rs179247 and rs12101255 have been found to be associated with Graves' disease (GD) in genetic studies. In the present study, we conducted a meta-analysis to examine this association. Two reviewers systematically searched eligible studies in PubMed, Web of Science, Embase and China Biomedical Literature Database (CBM). A meta-analysis on the association between GD and TSHR intron 1 rs179247 or rs12101255 was performed. The odd ratios (OR) were estimated with 95% confidence interval (CI). Meta package in R was used for the analyses. Seven articles (13 studies) published between 2009 and 2014, involving 5754 GD patients and 5768 controls, were analyzed. The polymorphism of rs179247 was found to be associated with an increased GD risk in the allele analysis (A vs. G: OR=1.40, 95% CI=1.33 1.48) and all genetic models (AA vs. GG: OR=1.94, 95% CI=1.73-2.19; AA+AG vs. GG: OR=1.57, 95% CI=1.41-1.74; AA vs. AG+GG: OR=1.54, 95% CI=1.43-1.66). The site rs12101255 also conferred a risk of GD in the allele analysis (T vs. C: OR=1.50, 95% CI=1.40-1.60) and all genetic models (TT vs. CC: OR=2.22, 95% CI=1.92-2.57; TT+TC vs. CC: OR=1.66, 95% CI=1.50-1.83; TT vs. TC+CC: OR=1.74, 95% CI=1.53 1.98). Analysis of the relationship between rs179247 and Graves' ophthalmopathy (GO) showed no statistically significant correlation (A vs. G: OR=1.02, 95% CI=0.97-1.07). Publication bias was not significant. In conclusion, GD is associated with polymorphisms of TSHR intron 1 rs179247 and rs12101255. There is no association between rs179247 SNPs and GO. PMID- 27465321 TI - Inhibitory effects of neferine on Nav1.5 channels expressed in HEK293 cells. AB - Neferine, a bisbenzylisoquinoline alkaloid in Lotus Plumule, was proved to have a wide range of biological activities. In the present study, using whole-cell patch clamp technique, we investigated the effects of neferine on Nav1.5 channels that are stably expressed in HEK 293 cells. We found that neferine potently and reversibly inhibited Nav1.5 currents in a concentration dependent manner with a half-maximal inhibition (IC50) being 26.15 MUmol/L. The inhibitory effects of neferine on Nav1.5 currents were weaker than those of quinidine at the same concentration. The steady-state inactivation curve was significantly shifted towards hyperpolarizing direction in the presence of 30 MUmol/L neferine, while the voltage-dependent activation was unaltered. Neferine prolonged the time to peak of activation, increased the inactivation time constants of Nav1.5 currents and markedly slowed the recovery from inactivation. The inhibitory effect of neferine could be potentiated in a frequency-dependent manner. These results suggested that neferine can block Nav1.5 channels under the open state and inactivating state and it is an open channel blocker of Nav1.5 channels. PMID- 27465320 TI - Neuroprotective potential of cerium oxide nanoparticles for focal cerebral ischemic stroke. AB - During the previous years, with the emerging of nanotechnology, the enormous capabilities of nanoparticles have drawn great attention from researchers in terms of their potentials in various aspects of pharmacology. Cerium oxide nanoparticles (nanoceria), considered as one of the most widely used nanomaterials, due to its tempting catalytic antioxidant properties, show a promising potential in diverse disorders, such as cerebral ischemic stroke (CIS), cancer, neurodegenerative and inflammatory diseases. Overwhelming generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during cerebral ischemia and reperfusion periods is known to aggravate brain damage via sophisticated cellular and molecular mechanisms, and therefore exploration of the antioxidant capacities of nanoceria becomes a new approach in reducing cerebral ischemic injury. Furthermore, utilizing nanoceria as a drug carrier might display the propensity to overcome limitations or inefficacy of other conceivable neuroprotectants and exhibit synergistic effects. In this review, we emphasize on the principle features of nanoceria and current researches concerning nanoceria as a potential therapeutic agent or carrier in improving the prognosis of CIS. PMID- 27465323 TI - Retrospective analysis of plasma exchange combined with glucocorticosteroids for the treatment of systemic lupus erythematosus-related acute pancreatitis in central China. AB - Systemic lupus erythematosus-related acute pancreatitis (SLEAP) has a poor prognosis with a high mortality. We described the clinical features of SLEAP, and discussed the feasibility of plasma exchange (PE) combined with glucocorticosteroids (GC) in short-term prognosis and possible mechanism in reducing serum inflammatory cytokine IL-6 and removing serum lipids. A retrospective study was performed by an independent rheumatologist. Medical records of SLEAP from March 2010 to December 2014 were retrieved from Tongji Hospital information system, and patients were divided into two groups according to whether PE therapy was adopted. Sixteen patients treated with PE in combination with GC were classified as group A, and the other 10 patients who were treated with merely GC were classified as group B. Patients' clinical remission rate and average daily GC dosage after two-week therapy were compared between the two groups. Patients' serum inflammatory cytokines and lipid concentration were compared between baseline and after two-week treatment in both groups. Pearson correlation test was performed to determine association between serum cytokines and Ranson score. SLEDAI score in group A patients at baseline (14.8+/-3.1) showed no statistical difference from that in group B (14.1+/-3.3). At baseline serum IL-6 levels had no significant difference between group A [13.14 (11.12, 16.57) mg/L] and group B [14.63 (11.37, 16.37) mg/L]; after two week therapy IL-6 decreased significantly in group A [9.16 (7.93, 10.75)mg/L] while it did not show decreasing trend in group B [13.62 (9.29,17.63) mg/L]. Serum lipid concentration after two-week therapy in group A [(TC=5.02+/-0.53, TG=1.46+/-0.44) mmol/L] decreased significantly compared to baseline [(TC=6.11+/ 0.50, TG=2.14+/-1.03) mmol/L], while similar tendency was not observed in group B. The remission rate after two-week therapy was higher in group A (70.0%) than in group B (25.0%). Acute pancreatitis (AP) was one of the clinical manifestations of active SLE. PE combined with GC could reduce serum IL-6 level, and remove serum lipid to improve short-term prognosis. Therefore, it might be a safe and effective way in treating SLEAP and was worth continuing to explore its feasibility. PMID- 27465322 TI - Mcl-1 as a potential therapeutic target for human hepatocelluar carcinoma. AB - Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality in part due to its high resistance to chemotherapeutic drugs. The anti-apoptotic Mcl 1 expression has been reported as a resistance factor in various types of tumors. Here, we investigated the expression of Mcl-1 in hepatoma cells and HCC tissues and its relationship with p53, and analyzed the possibility of the gene as a molecular target for HCC therapy. HCC specimens of 30 patients were examined by immunohistochemistry for Mcl-1 and p53 expression. Mcl-1 expression in hepatoma cell lines was measured by RT-PCR and Western blotting. The suppression of Mcl-1 by RNA interference or specific phosphatidylinositol-3 kinase (PI3K) inhibitor, LY294002, was evaluated as monotherapy, and it was combined with mitomycin C (MMC) in treating hepatoma cell line HepG2. Cell viability and apoptosis were assessed by MTT and FACS analysis. Finally, changes of Mcl-1 or p53 expression in various hepatoma cell lines were examined after transfection with Mcl-1 siRNA, the Mcl-1 expression plasmid, or the wide-type p53 expression plasmid, respectively. Mcl-1 protein was remarkably enhanced in HCC tissues as compared with adjacent non-tumor liver tissues. In addition, Mcl-1 was prominently expressed in HepG2 and Hep3B cells, weakly in SMMC7721 cells, and not in L02 cells. P53 protein was also overexpressed in HCC tissues and there was a significant correlation between the expression of p53 and Mcl-1. Silencing Mcl-1 by RNAi or LY294002 downregulated Mcl-1 expression and led to decreased cell viability and increased apoptosis. Combination of MMC and Mcl-1 RNAi or LY294002 exhibited a significant chemosensitizing effect. The expression of p53 was not influenced by Mcl-1 siRNA in HepG2 cells or transfection with the Mcl-1 expression plasmid in L02 cells. Furthermore, the expression of Mcl-1 in Hep3B cells was also not significantly changed after transfection with the wild-type p53 expression plasmid. It is concluded that Mcl-1 is overexpressed in HCC tissues. The mechanisms by which silencing Mcl-1 sensitizes hepatoma cells towards chemotherapy may be not attributed to the upregulated expression of p53 but the dysfunction of p53 through Mcl-1/p53 interaction. Mcl-1 may be a potential target of gene therapy for HCC. PMID- 27465325 TI - Radiofrequency ablation vs. hepatic resection for resectable colorectal liver metastases. AB - The treatments of resectable colorectal liver metastases (CRLM) are controversial. This study aimed to evaluate the relative efficacy and safety of hepatic resection (HR) and radiofrequency ablation (RFA) for treating resectable CRLM. Between January 2004 and May 2010, the enrolled patients were given hepatic resection (HR group; n=32) or percutaneous RFA (RFA group; n=21) as a first-line treatment for CRLM. All the tumors had a maximum diameter of 3.5 cm and all patients had five or less tumors. The patient background, tumor characteristics, cumulative survival rate and recurrence-free survival rate were assessed in both groups. There were significantly more patients with comorbidities in the RFA group than those in the HR group (17 in RFA group vs. 10 in HR group; P<0.000). The mean maximum tumor diameter in the HR group and RFA group was 2.25+/-0.68 and 1.89+/-0.62 cm (P=0.054), and the mean number of tumors was 2.28+/-1.05 and 2.38+/-1.12 (P=0.744), respectively. The 1-, 3- and 5-year cumulative survival rates in the HR group were 87.5%, 53.1% and 31.3%, respectively, and those in the RFA group were 85.7%, 38.1% and 14.2%, respectively with the differences being not significant between the two groups (P=0.062). The 1-, 3- and 5-year recurrence-free survival rates in the HR group were 90.6%, 56.3% and 28.1%, respectively, and those in the RFA group were 76.1%, 23.8% and 4.8%, respectively, with the differences being significant between the two groups (P=0.036). In conclusion, as HR has greater efficacy than RFA in the treatment of resectable CRLM, we recommend it as the first option for this malignancy. PMID- 27465324 TI - Up-regulation of NKG2A inhibitory receptor on circulating NK cells contributes to transfusion-induced immunodepression in patients with beta-thalassemia major. AB - Accumulating evidence has shown that allogeneic blood transfusions can induce significant immunosuppression in recipients, and thereby increase the risk of postoperative infection and/or tumor relapse. Although it is well known that natural killer (NK) cells are responsible for the immunodepression effects of transfusion, the underlying mechanisms remain obscure. In this study, we investigated the role of NK cells in transfusion-induced immunodepression in beta thalassemia major. The proportion of circulating NK cells and the expression of NK receptors (NKG2A, CD158a, NKP30, NKP46 and NKG2D) as well as CD107a were detected by multicolor flow cytometry. IFN-gamma production by circulating NK cells was detected by intracellular cytokine staining. Our results showed that the proportion and cytotoxicity (CD107a expression) of circulating NK cells in transfusion-dependent beta-thalassemia major patients were remarkably lower than those of beta-thalassemia minor patients or healthy volunteers. Expression of NKG2A inhibitory receptor on circulating NK cells in patients with beta thalassemia major was remarkably up-regulated, but there were no significant differences in the expression levels of NKP30, NKP46, NKG2D, CD158a and IFN gamma. These results indicate NKG2A inhibitory receptor may play a key role in transfusion-induced immunodepression of NK cells in patients with beta thalassemia major. PMID- 27465326 TI - Laparoscopic versus traditional open splenectomy for hepatocellular carcinoma with hypersplenism. AB - This study aimed to examine the efficacy of the laparoscopic vs. traditional open splenectomy for hepatocellular carcinoma (HCC) with hypersplenism. Between 2002 and 2013, 51 Chinese HCC patients with hypersplenism underwent either simultaneous laparoscopic splenectomy plus anticancer therapies (Lap-S&A) (n=25) or traditional open splenectomy plus anti-cancer therapies (TOS&A) (n=26). The outcomes were reviewed during and after the operation. Anti-cancer therapies for HCC included laparoscopic hepatectomy (LH) and laparoscopic microwave ablation (LMA). The results showed that there was no significant difference in the operating time between the two groups, but the blood loss and blood transfusion were less, pain intensity after surgery was weaker, the time to first bowel movement, time to the first flatus and postoperative hospital stay were shorter, and the postoperative complication rate and the readmission rate were lower in the Lap-S&A group than in the TO-S&A group. Two patients in the Lap-S&A group and one patient in the TO-S&A group died 30 days after surgery. However, no significant difference in the mortality rate was noted between the two groups. It was concluded that simultaneous Lap-S&A holds the advantages of more extensive indications, lower complication incidence and less operative expenditure than conventional open approach and it is a feasible and safe approach for HCC with hypersplenism. PMID- 27465327 TI - Impact of operative and peri-operative factors on the long-term prognosis of primary liver cancer patients undergoing hepatectomy. AB - This study examined the impact of the operative and peri-operative factors on the long-term prognosis of patients with primary liver cancer undergoing hepatectomy. A total of 222 patients with primary liver cancer who underwent hepatectomy were followed up from January 1986 to December 2010 at Chinese PLA General Hospital. The post-operative complication rate was 14.0% for all cases, 13.7% for hepatocellular carcinoma (HCC), 10.0% for cholangiocarcinoma. The 1-, 3-, 5- and 10-year overall survival rates in patients with primary liver cancer after resection were 76.6%, 57.6%, 41.4%, and 21.0%. The survival rates were significantly higher in the HCC group than in the cholangiocarcinoma group (P=0.000), in the non-anatomical resection group than in the anatomical resection group (P=0.005), in the female group than in the male group (P=0.002), in patients receiving no blood transfusion than in those who were given intra operative blood transfusion (P=0.000), in patients whose intra-operative blood loss was less than 400 mL than in those who intra-operatively lost more than 400 mL (P=0.000). No significant difference was found in the survival rate between the HBsAg-positive group and the HBsAg-negative group (P=0.532). Our study showed that anatomical resection, blood loss and blood transfusion were predictors of poor survival after hepatectomy for primary liver cancer patients, and concomitant hepatitis B virus infection bore no relation with the post-resection survival. PMID- 27465328 TI - Gastric submucosa is inferior to the liver as transplant site for autologous islet transplantation in pancreatectomized diabetic Beagles. AB - Intraportal transplantation of islets is no longer considered to be an ideal procedure and finding the extrahepatic alternative site is becoming a subject of high priority. Herein, in this study, we would introduce our initial outcomes of using gastric submucosa (GS) and liver as sites of islet autotransplantation in pancreatectomized diabetic Beagles. Total pancreatectomy was performed in Beagles and then their own islets extracted from the excised pancreas were transplanted into GS (GS group, n=8) or intrahepatic via portal vein (PV group, n=5). Forty eight hours post transplantation, graft containing tissue harvested from the recipients revealed the presence of insulin-positive cells. All recipients in GS group achieved euglycemia within 1 day, but returned to a diabetic state at 6 to 8 days post-transplantation (mean survival time, 7.16+/-0.69 days). However, all of the animals kept normoglycemic until 85 to 155 days post-transplantation in PV group (mean survival time, 120+/-28.58 days; P<0.01 vs. GS group). The results of intravenous glucose tolerance test (IVGTT) confirmed that the marked improvement in glycometabolism was obtained in intrahepatic islet autotransplantation. Thus, our findings indicate that the liver is still superior to the GS as the site of islet transplantation, at least in our islet autotransplant model in pancreatectomized diabetic Beagles. PMID- 27465329 TI - Efficacy of Bosentan in patients after Fontan procedures: a double-blind, randomized controlled trial. AB - Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease (CHD). However, it does not decrease postoperative complication rate. Previous studies suggested that elevated mean pulmonary artery pressure (mPAP) and vascular resistance lead to decreased exercise tolerance and myocardial dysfunction. Therapy with endothelial receptor antagonists (Bosentan) has been demonstrated to improve the patients' prognosis. A double-blind, randomized controlled trial was performed to explore the efficacy of Bosentan in treating patients who underwent the Fontan procedure. Eligible participants were randomly divided into Bosentan group and control group. Liver function was tested at a local hospital and the results were reported to the phone inspector every month. If the results suggested abnormal liver function, treatment would be adjusted or terminated. All the participants finished the follow-up study, with no patients lost to follow up. Unblinding after 2-year follow-up, no mortality was observed in either group. However, secondary end-points were found to be significantly different in the comparable groups. The cardiac function and 6-min walking distance in the Bosentan group were significantly superior to those in the control group (P=0.018 and P=0.027). Bosentan could improve New York Heart Association (NYHA) functional status and improve the results of the 6-min walking test (6MWT) in Fontan patients post-surgery, and no other benefits were observed. Furthermore, a primary meta-analysis study systematically reviewed all the similar clinical trails worldwide and concluded an overall NYHA class improvement in Fontan patients who received Bosentan treatments. PMID- 27465332 TI - Ischemic preconditioning inhibits over-expression of arginyl-tRNA synthetase gene Rars in ischemia-injured neurons. AB - The expression changes of Rars gene in ischemia-injured neurons were investigated by detecting its translational product arginyl-tRNA synthetase (ArgRS), and the inhibitory effects of ischemic preconditioning (IPC) on Rars gene were explored. Both IPC model and prolonged ischemia (PI) model were established by using the classic oxygen glucose deprivation (OGD) method. The primary cultured neurons were assigned into the following groups: the experimental group (IPC+PI group), undergoing PI after a short period of IPC; the conditional control group (PI control group), subjected to PI without IPC; blank control group, the normally cultured neurons. The Rars transcriptional activities and ArgRS expression levels were measured at different time points after re-oxygenation (3 h/6 h/12 h/24 h). Data were collected and statistically analyzed. Compared to the blank control group, the Rars activities and ArgRS levels were significantly increased in PI control group, peaking at the time point of 6 h after re-oxygenation. Rars activities and ArgRS levels were significantly lower in the experimental group than in the PI control group at different time points after re-oxygenation. PI insult can induce an escalating activity of Rars and lead to ArgRS over expression in primary cultured neurons. IPC can inhibit the increased Rars activity and down-regulate ArgRS expression of ischemia-insulted neurons. This mechanism may confer ischemic tolerance on neurons. PMID- 27465330 TI - One-stage surgical treatment for thoracic and lumbar Spinal tuberculosis by transpedicular fixation, debridement, and combined interbody and posterior fusion via a posterior-only approach. AB - This study examined the clinical outcomes of one-stage surgical treatment for patients with spinal tuberculosis via a posterior-only approach. Twenty-four patients with thoracic or lumbar spinal tuberculosis whose lesions were confined to adjacent segments were admitted to our hospital and treated. The American Spinal Injury Association (ASIA) impairment scale was used to assess the neurological function. All patients were treated with one-stage surgical treatment via a posterior-only approach. The clinical efficacy was evaluated by the Japanese Orthopaedic Association (JOA) scores and oswestry disability index (ODI) of nerve function. Patients were evaluated preoperatively and postoperatively by measurement of spinal deformity using Cobb angle and radiological examination. All the patients were followed up for 13 to 27 months. They had significantly postoperative improvement in JOA score, ODI and ASIA classification scores. The kyphotic angles were significantly corrected and maintained at the final follow-up. Bone fusion was achieved within 4-12 months. It was concluded that one-stage surgical treatment via a posterior-only approach is effective and feasible for the treatment of spinal tuberculosis. PMID- 27465331 TI - Stereotactic injection of shrna GSK-3beta-AAV promotes axonal regeneration after spinal cord injury. AB - Evidence suggested that glycogen synthase kinase-3beta (GSK-3beta) is involved in Nogo-66 inhibiting axonal regeneration in vitro, but its effect in vivo was poorly understood. We showed that stereotactic injection of shRNA GSK-3beta-adeno associated virus (GSK-3beta-AAV) diminished syringomyelia and promoted axonal regeneration after spinal cord injury (SCI), using stereotactic injection of shRNA GSK-3beta-AAV (tested with Western blotting and RT-PCR) into the sensorimotor cortex of rats with SCI and by the detection of biotin dextran amine (BDA)-labeled axonal regeneration. We also determined the right position to inject into the sensorimotor cortex. Our findings consolidate the hypothesis that downregulation of GSK-3beta promotes axonal regeneration after SCI. PMID- 27465335 TI - Effect and mechanism of Bushen Huoxue recipe on ovarian reserve in mice with premature ovarian failure. AB - The aim of the present study was to explore the effect and mechanism of Bushen Huoxue recipe (BHR) on ovarian reserve in mice with premature ovarian failure (POF). Mice were divided into 3 groups: normal group, model group and BHR group. Intraperitoneal injection of cyclophosphamide was performed to create the POF model. Primordial follicular (PDF) number, ovarian wet weight, ovarian index, and estrous cycle were analyzed to evaluate the effect of BHR on POF. Meanwhile, the mRNA and protein level of Mouse Vasa Homologue (MVH) in the bone marrow, peripheral blood and ovary were detected, to explore the underlying mechanism of the treatment efficacy of BHR on ovarian reserve. By the time of BHR treatment for 28 days, BHR increased the PDF number and shortened the estrous cycle of POF mice. BHR also decreased the mRNA level of MVH in the bone marrow, and increased mRNA and protein level of MVH in the ovary of POF mice. Our results demonstrated a treatment efficacy of BHR on POF mice, and revealed that BHR might repair the dysfunction of germline stem cells in the bone marrow, and thus to improve the ovarian reserve and enhance the ovarian function of POF mice through neo oogenesis. PMID- 27465334 TI - Gel-based chemical cross-linking analysis of 20S proteasome subunit-subunit interactions in breast cancer. AB - The ubiquitin-proteasome system plays a pivotal role in breast tumorigenesis by controlling transcription factors, thus promoting cell cycle growth, and degradation of tumor suppressor proteins. However, breast cancer patients have failed to benefit from proteasome inhibitor treatment partially due to proteasome heterogeneity, which is poorly understood in malignant breast neoplasm. Chemical crosslinking is an increasingly important tool for mapping protein three dimensional structures and proteinprotein interactions. In the present study, two cross-linkers, bis (sulfosuccinimidyl) suberate (BS(3)) and its water-insoluble analog disuccinimidyl suberate (DSS), were used to map the subunit-subunit interactions in 20S proteasome core particle (CP) from MDA-MB-231 cells. Different types of gel electrophoresis technologies were used. In combination with chemical cross-linking and mass spectrometry, we applied these gel electrophoresis technologies to the study of the noncovalent interactions among 20S proteasome subunits. Firstly, the CP subunit isoforms were profiled. Subsequently, using native/SDSPAGE, it was observed that 0.5 mmol/L BS(3) was a relatively optimal cross-linking concentration for CP subunit-subunit interaction study. 2-DE analysis of the cross-linked CP revealed that alpha1 might preinteract with alpha2, and alpha3 might pre-interact with alpha4. Moreover, there were different subtypes of alpha1alpha2 and alpha3alpha4 due to proteasome heterogeneity. There was no significant difference in cross-linking pattern for CP subunits between BS(3) and DSS. Taken together, the gel-based characterization in combination with chemical cross-linking could serve as a tool for the study of subunit interactions within a multi-subunit protein complex. The heterogeneity of 20S proteasome subunit observed in breast cancer cells may provide some key information for proteasome inhibition strategy. PMID- 27465333 TI - Over-expression of LRIG1 suppresses biological function of pituitary adenoma via attenuation of PI3K/AKT and Ras/Raf/ERK pathways in vivo and in vitro. AB - Pituitary adenomas (PAs) are well known as a common intracranial benign tumor, and a portion of PAs are refractory to current therapeutic methods. ErbB receptors family signaling pathway regulates the expression of PAs activation associated gene. Inhibition of epidermal growth factor receptor (EGFR) can inhibit proliferation of PAs. Leucine-rich repeats and immunoglobulin-like domains protein 1 ( LRIG1), a negative mediated gene of ErbB receptors family, plays a role in many tumors. However, there are seldom researches about the functional role of LRIG1 in PAs. The aim of this study is to explore the potential effect of LRIG1 and its regulating mechanism in PAs. First, we investigated the role of LRIG1 in cell migration, invasion of PAs with transfected LRIG1 or control. Then, we explored its impact on cell proliferation and apoptosis of PAs in vivo. To study the regulating mechanism of LRIG1, we examined the expression of molecular factor of PI3K/AKT and Ras/Raf/ERK pathway using Western blotting in vitro and RT-PCR in vitro and in vivo. It was found that LRIG1 over-expression inhibited cell migration, invasion and proliferation, and promoted apoptosis of PAs in vivo and in vitro. Furthermore, LRIG1 suppressed the expression of signaling of PI3K/AKT and Ras/Raf/ERK pathways in PAs. LRIG1, as a negative mediated gene of tumor, can inhibit biological function of PAs via inhibiting PI3K/AKT and Ras/Raf/ERK pathways, and it might be a new target for gene therapy of PAs. PMID- 27465337 TI - Effect of preemptive ketamine administration on postoperative visceral pain after gynecological laparoscopic surgery. AB - The pain following gynecological laparoscopic surgery is less intense than that following open surgery; however, patients often experience visceral pain after the former surgery. The aim of this study was to determine the effects of preemptive ketamine on visceral pain in patients undergoing gynecological laparoscopic surgery. Ninety patients undergoing gynecological laparoscopic surgery were randomly assigned to one of three groups. Group 1 received placebo. Group 2 was intravenously injected with preincisional saline and local infiltration with 20 mL ropivacaine (4 mg/mL) at the end of surgery. Group 3 was intravenously injected with preincisional ketamine (0.3 mg/kg) and local infiltration with 20 mL ropivacaine (4 mg/mL) at the end of surgery. A standard anesthetic was used for all patients, and meperidine was used for postoperative analgesia. The visual analogue scale (VAS) scores for incisional and visceral pain at 2, 6, 12, and 24 h, cumulative analgesic consumption and time until first analgesic medication request, and adverse effects were recorded postoperatively. The VAS scores of visceral pain in group 3 were significantly lower than those in group 2 and group 1 at 2 h and 6 h postoperatively (P<0.05 and P<0.01, respectively). At 2 h and 6 h, the VAS scores of incisional pain did not differ significantly between groups 2 and 3, but they were significantly lower than those in group 1 (P<0.01). Groups 1 and 2 did not show any differences in visceral pain scores at 2 h and 6 h postoperatively. Moreover, the three groups showed no statistically significant differences in visceral and incisional pain scores at 12 h and 24 h postoperatively. The consumption of analgesics was significantly greater in group 1 than in groups 2 and 3, and the time to first request for analgesics was significantly longer in groups 2 and 3 than in group 1, with no statistically significant difference between groups 2 and 3. However, the three groups showed no significant difference in the incidence of shoulder pain or adverse effects. Preemptive ketamine may reduce visceral pain in patients undergoing gynecological laparoscopic surgery. PMID- 27465336 TI - Telmisartan reduced cerebral edema by inhibiting NLRP3 inflammasome in mice with cold brain injury. AB - The aim of this study was to investigate the possible beneficial role of telmisartan in cerebral edema after traumatic brain injury (TBI) and the potential mechanisms related to the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) pyrin domain-containing 3 (NLRP3) inflammasome activation. TBI model was established by cold-induced brain injury. Male C57BL/6 mice were randomly assigned into 3, 6, 12, 24, 48 and 72 h survival groups to investigate cerebral edema development with time and received 0, 5, 10, 20 and 40 mg/kg telmisartan by oral gavage, 1 h prior to TBI to determine the efficient anti-edemic dose. The therapeutic window was identified by post-treating 30 min, 1 h, 2 h and 4 h after TBI. Blood-brain barrier (BBB) integrity, the neurological function and histological injury were assessed, at the same time, the mRNA and protein expression levels of NLRP3 inflammasome, IL-1beta and IL-18 concentrations in peri-contused brain tissue were measured 24 h post TBI. The results showed that the traumatic cerebral edema occurred from 6 h, reached the peak at 24 h and recovered to the baseline 72 h after TBI. A single oral dose of 5, 10 and 20 mg/kg telmisartan could reduce cerebral edema. Post-treatment up to 2 h effectively limited the edema development. Furthermore, prophylactic administration of telmisartan markedly inhibited BBB impairment, NLRP3, apoptotic speck-containing protein (ASC) and Caspase-1 activation, as well as IL-1beta and IL-18 maturation, subsequently improved the neurological outcomes. In conclusion, telmisartan can reduce traumatic cerebral edema by inhibiting the NLRP3 inflammasome-regulated IL-1beta and IL-18 accumulation. PMID- 27465338 TI - Theoretical distribution of gutta-percha within root canals filled using cold lateral compaction based on numeric calculus. AB - This study aimed to present a new method based on numeric calculus to provide data on the theoretical volume ratio of voids when using the cold lateral compaction technique in canals with various diameters and tapers. Twenty-one simulated mathematical root canal models were created with different tapers and sizes of apical diameter, and were filled with defined sizes of standardized accessory gutta-percha cones. The areas of each master and accessory gutta-percha cone as well as the depth of their insertion into the canals were determined mathematically in Microsoft Excel. When the first accessory gutta-percha cone had been positioned, the residual area of void was measured. The areas of the residual voids were then measured repeatedly upon insertion of additional accessary cones until no more could be inserted in the canal. The volume ratio of voids was calculated through measurement of the volume of the root canal and mass of gutta-percha cones. The theoretical volume ratio of voids was influenced by the taper of canal, the size of apical preparation and the size of accessory gutta-percha cones. Greater apical preparation size and larger taper together with the use of smaller accessory cones reduced the volume ratio of voids in the apical third. The mathematical model provided a precise method to determine the theoretical volume ratio of voids in root-filled canals when using cold lateral compaction. PMID- 27465340 TI - Tuberous sclerosis complex: Imaging characteristics in 11 cases and review of the literature. AB - Tuberous sclerosis complex (TSC) is an uncommon multiorgan disorder that may present many and different manifestations on imaging. Radiology plays an important role in diagnosis and management, and can substantially improve the clinical outcome of TSC. Therefore, a comprehensive understanding of this disease is essential for the radiologist. The manifestations of TSC on computer tomography (CT) and magnetic resonance (MR) images were analyzed. Eleven patients with a clinical diagnosis of TSC were retrospectively reviewed. Central nervous system lesions included subependymal nodules (SENs) (11/11), subependymal giant cell astrocytomas (SEGAs) (2/11), cortical and subcortical tuber lesions (5/11), and white matter lesions (4/11). Of the 6 patients with abdominal scans, there were 6 cases of renal angiomyolipomas (AMLs), and one case of hepatic AMLs. Of the 4 patients undergoing chest CT, lung lymhangioleiomyomatosis (LAM) (2/4), and multiple small sclerotic bone lesions (2/4) were observed. Different modalities show different sensitivity to the lesion. Analysis of images should be integrated with patients' history in order to diagnose TSC. PMID- 27465339 TI - Discrimination of metastatic from non-metastatic mesorectal lymph nodes in rectal cancer using quantitative dynamic contrast-enhanced magnetic resonance imaging. AB - Preoperative detection of lymph nodes (LNs) metastasis is always highly challenging for radiologists nowadays. The utility of quantitative dynamic contrast-enhanced magnetic resonance imaging (QDCE-MRI) in identifying LNs metastasis is not well understood. In the present study, 59 patients with histologically proven rectal carcinoma underwent preoperative QDCE-MRI. The short axis diameter ratio, long axis diameter ratio, short-to-long axis diameter ratio and QDEC-MRI parameters (K(trans), Kep, fPV and Ve) values were compared between the non-metastatic (n=44) and metastatic (n=35) LNs groups based on pathological examination. Compared with the non-metastatic group, the metastatic group exhibited significantly higher short axis diameter (7.558+/-0.668 mm vs. 5.427+/ 0.285 mm), K(trans) (0.483+/-0.198 min(-1) vs. 0.218+/-0.116 min(-1)) and Ve (0.399+/-0.118 vs. 0.203+/-0.096) values (all P<0.05). The short-to-long axis diameter ratio, long axis diameter ratio, Kep and fPV values did not show significant differences between the two groups. In conclusion, our results showed that for LNs larger than 5 mm in rectal cancer, there are distinctive differences in the K(trans) and Ve values between the metastatic and non-metastatic LNs, suggesting that QDCE-MRI may be potentially helpful in identifying LNs status. PMID- 27465341 TI - Bioinformatic analysis of non-VP1 capsid protein of coxsackievirus A6. AB - This study bioinformatically analyzed the non-VP1 capsid proteins (VP2-VP4) of Coxasckievirus A6 (CVA6), with an attempt to predict their basic physicochemical properties, structural/functional features and linear B cell eiptopes. The online tools SubLoc, TargetP and the others from ExPASy Bioinformatics Resource Portal, and SWISS-MODEL (an online protein structure modeling server), were utilized to analyze the amino acid (AA) sequences of VP2-VP4 proteins of CVA6. Our results showed that the VP proteins of CVA6 were all of hydrophilic nature, contained phosphorylation and glycosylation sites and harbored no signal peptide sequences and acetylation sites. Except VP3, the other proteins did not have transmembrane helix structure and nuclear localization signal sequences. Random coils were the major conformation of the secondary structure of the capsid proteins. Analysis of the linear B cell epitopes by employing Bepipred showed that the average antigenic indices (AI) of individual VP proteins were all greater than 0 and the average AI of VP4 was substantially higher than that of VP2 and VP3. The VP proteins all contained a number of potential B cell epitopes and some eiptopes were located at the internal side of the viral capsid or were buried. We successfully predicted the fundamental physicochemical properties, structural/functional features and the linear B cell eiptopes and found that different VP proteins share some common features and each has its unique attributes. These findings will help us understand the pathogenicity of CVA6 and develop related vaccines and immunodiagnostic reagents. PMID- 27465342 TI - Establishment of reference intervals and transfusion criterion for Sonoclot analysis. AB - Sonoclot analyzer has been widely used in many countries. But the reference intervals provided by the manufacturer were derived from only 45 participants, and there was no cut-off value for transfusion for Sonoclot analysis. This study aimed to establish reference intervals and transfusion criterion for Sonoclot analysis. Volunteers were recruited from healthy Chinese adults and patients undergoing cardiac surgery. Blood samples were withdrawn from forearm vein and measured for activated clotting time (ACT), clot rate (CR), platelet function (PF), activated partial thromboplastin time (APTT), fibrinogen concentration (FIB), and platelet count (PLT). The reference intervals were determined by the nonparametric method. Cut-off values were determined by the receiver operating characteristics curve. A total of 135 healthy volunteers and 281 patients were enrolled. The 95% reference intervals were 96-195 s, 22-51 signal U/min, >1.6 for ACT, CR, PF respectively. In the 281 patients, the results of APTT, FIB, PLT, ACT, CR, and PF ranged from 20.5-300.0 s, 0.28-4.11 g/L, (19.0-387.3)*109/L, 80 514 s, 2.9-74 signal U/min, and 0.1-5.1 respectively. The cut-off values for transfusion were >208, <=14, and <=1.3 for ACT, CR, PF respectively. The cut-off values of Sonoclot analysis were within the manufacturer's reference intervals, while they were outside the reference intervals established in this study. The results suggested that the manufacturer's reference intervals were not suitable for Chinese. The reference intervals and cut-off values established in this study will be helpful to Chinese patients. PMID- 27465343 TI - Erratum to: Human brucellosis mimicking axial spondyloarthritis: a challenge for rheumatologists when applying the 2009 ASAS criteria. PMID- 27465345 TI - Design of suitable carrier buffer for free-flow zone electrophoresis by charge-to mass ratio and band broadening analysis. AB - In this work, charge-to-mass ratio (C/M) and band broadening analyses were combined to provide better guidance for the design of free-flow zone electrophoresis carrier buffer (CB). First, the C/M analyses of hemoglobin and C phycocyanin (C-PC) under different pH were performed by CLC Protein Workbench software. Second, band dispersion due to the initial bandwidth, diffusion, and hydrodynamic broadening were discussed, respectively. Based on the analyses of the C/M and band broadening, a better guidance for preparation of free-flow zone electrophoresis CB was obtained. Series of experiments were performed to validate the proposed method. The experimental data showed high accordance with our prediction allowing the CB to be prepared easily with our proposed method. To further evaluate this method, C-PC was purified from crude extracts of Spirulina platensis with the selected separation condition. Results showed that C-PC was well separated from other phycobiliproteins that have similar physicochemical properties, and analytical grade product with purity up to 4.5 (A620/A280) was obtained. PMID- 27465344 TI - Antimicrobial nodule-specific cysteine-rich peptides disturb the integrity of bacterial outer and inner membranes and cause loss of membrane potential. AB - BACKGROUND: Certain legume plants produce a plethora of AMP-like peptides in their symbiotic cells. The cationic subgroup of the nodule-specific cysteine-rich (NCR) peptides has potent antimicrobial activity against gram-negative and gram positive bacteria as well as unicellular and filamentous fungi. FINDINGS: It was shown by scanning and atomic force microscopies that the cationic peptides NCR335, NCR247 and Polymyxin B (PMB) affect differentially on the surfaces of Sinorhizobium meliloti bacteria. Similarly to PMB, both NCR peptides caused damages of the outer and inner membranes but at different extent and resulted in the loss of membrane potential that could be the primary reason of their antimicrobial activity. CONCLUSIONS: The primary reason for bacterial cell death upon treatment with cationic NCR peptides is the loss of membrane potential. PMID- 27465347 TI - Influence of age on sex-related differences among patients with hepatitis C. PMID- 27465348 TI - Lower response to the hepatitis B vaccine in future inflammatory bowel disease patients. PMID- 27465349 TI - Diagnosis, management, and long-term issues in pediatric Budd-Chiari syndrome. PMID- 27465352 TI - Rational Design of Lanthanoid Single-Ion Magnets: Predictive Power of the Theoretical Models. AB - We report two new single-ion magnets (SIMs) of a family of oxydiacetate lanthanide complexes with D3 symmetry to test the predictive capabilities of complete active space ab initio methods (CASSCF and CASPT2) and the semiempirical radial effective charge (REC) model. Comparison of the theoretical predictions of the energy levels, wave functions and magnetic properties with detailed spectroscopic and magnetic characterisation is used to critically discuss the limitations of these theoretical approaches. The need for spectroscopic information for a reliable description of the properties of lanthanide SIMs is emphasised. PMID- 27465350 TI - Infections in hospitalized patients with decompensated cirrhosis should be used in determining prognosis: a validation on a large Chinese cohort. PMID- 27465346 TI - Bacterial Cu(+)-ATPases: models for molecular structure-function studies. AB - The early discovery of the human Cu(+)-ATPases and their link to Menkes and Wilson's diseases brought attention to the unique role of these transporters in copper homeostasis. The characterization of bacterial Cu(+)-ATPases has significantly furthered our understanding of the structure, selectivity and transport mechanism of these enzymes, as well as their interplay with other elements of Cu(+) distribution networks. This review focuses on the structural functional insights that have emerged from studies of bacterial Cu(+)-ATPases at the molecular level and how these observations have contributed to drawing up a comprehensive picture of cellular copper homeostasis. PMID- 27465353 TI - Efficacy and Safety of Local Intracoronary Drug Delivery in Treatment of No Reflow Phenomenon: A Pilot Study. AB - BACKGROUND: Successful reopening of epicardial coronary artery does not always mean optimal myocardial reperfusion in a sizable portion of patients, mostly because of no-reflow phenomenon. OBJECTIVES: We investigated whether local injection of adrenaline +/- verapamil in the distal coronary bed is more effective than their intracoronary (IC) injection through the guiding catheter in the treatment of no-reflow phenomenon following percutaneous coronary intervention (PCI). METHODS: A total of 40 patients with no-reflow following PCI were randomized into two groups. Group 1 received IC adrenaline +/- verapamil through a well-cannulated guiding catheter while Group 2 received the above mentioned drugs in the distal coronary bed through a perfusion balloon or selective microcatheter. The primary end points were the achievement of TIMI III flow with MBG II or III. Secondary end points were the occurrence of hypotension, arrhythmias, and major adverse cardiac events (MACEs) during hospital stay. RESULTS: After drug injection, the percentage of patients achieving Thrombolysis in Myocardial Infarction (TIMI) III flow in Group 1 was 40% versus 80% in Group 2, P = 0.032. MBG II and III was significantly lower in Group 1; 10% and 25% versus 15% and 65% in Group 2, respectively, P = 0.033. Primary end points were achieved in only 35% of patients in Group 1 and in 80% of patients in Group 2 (odds ratio, 7.43, 95% confidence interval 1.78-31.04, P < 0.01). Secondary end points were not different between both groups. CONCLUSION: Local intra-coronary delivery of adrenaline +/- verapamil is a safe and effective method for the treatment of no-reflow phenomenon complicating PCI. PMID- 27465355 TI - Quantification of 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5), a newly synthetized P-glycoprotein inducer/activator, in biological samples: method development and validation. AB - A simple, rapid and economical method was developed and validated for the analysis and quantification of 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9 one (TX5), a P-glycoprotein inducer/activator, in biological samples, using reverse-phase high-performance liquid chromatography (HPLC). A C18 column and a mobile phase composed of methanol-water (90/10, v/v) with 1% (v/v) triethylamine, at a flow rate of 1 mL/min, were used for chromatographic separation. TX5 standards (0.5-150 MUm) were prepared in human serum. Methanol was used for TX5 extraction and serum protein precipitation. After filtration, samples were injected into the HPLC apparatus and TX5 was quantified by a conventional UV detector at 255 nm. The TX5 retention time was 13 min in this isocratic system. The method was validated according to ICH guidelines for specificity/selectivity, linearity, accuracy, precision, limits of detection and quantification (LOD and LOQ) and recovery. The method was proved to be selective, as there were no interferences of endogenous compounds with the same retention time of TX5. Also, the developed method was linear (r2 >= 0.99) for TX5 concentrations between 0.5 and 150 MUm and the LOD and LOQ were 0.08 and 0.23 MUm, respectively. The results indicated that the reported method could meet the requirements for TX5 analysis in the trace amounts expected to be present in biological samples. PMID- 27465354 TI - Systematic mapping review of the factors influencing dietary behaviour in ethnic minority groups living in Europe: a DEDIPAC study. AB - BACKGROUND: Europe has a growing population of ethnic minority groups whose dietary behaviours are potentially of public health concern. To promote healthier diets, the factors driving dietary behaviours need to be understood. This review mapped the broad range of factors influencing dietary behaviour among ethnic minority groups living in Europe, in order to identify research gaps in the literature to guide future research. METHODS: A systematic mapping review was conducted (protocol registered with PROSPERO 2014: CRD42014013549). Nine databases were searched for quantitative and qualitative primary research published between 1999 and 2014. Ethnic minority groups were defined as immigrants/populations of immigrant background from low and middle income countries, population groups from former Eastern Bloc countries and minority indigenous populations. In synthesizing the findings, all factors were sorted and structured into emerging clusters according to how they were seen to relate to each other. RESULTS: Thirty-seven of 2965 studies met the inclusion criteria (n = 18 quantitative; n = 19 qualitative). Most studies were conducted in Northern Europe and were limited to specific European countries, and focused on a selected number of ethnic minority groups, predominantly among populations of South Asian origin. The 63 factors influencing dietary behaviour that emerged were sorted into seven clusters: social and cultural environment (16 factors), food beliefs and perceptions (11 factors), psychosocial (9 factors), social and material resources (5 factors), accessibility of food (10 factors), migration context (7 factors), and the body (5 factors). CONCLUSION: This review identified a broad range of factors and clusters influencing dietary behaviour among ethnic minority groups. Gaps in the literature identified a need for researchers to explore the underlying mechanisms that shape dietary behaviours, which can be gleaned from more holistic, systems-based studies exploring relationships between factors and clusters. The dominance of studies exploring 'differences' between ethnic minority groups and the majority population in terms of the socio-cultural environment and food beliefs suggests a need for research exploring 'similarities'. The evidence from this review will feed into developing a framework for the study of factors influencing dietary behaviours in ethnic minority groups in Europe. PMID- 27465357 TI - Towards an integrative view of cognitive biases in pain. PMID- 27465356 TI - Chlorella species as hosts for genetic engineering and expression of heterologous proteins: Progress, challenge and perspective. AB - The species of Chlorella represent a highly specialized group of green microalgae that can produce high levels of protein. Many Chlorella strains can grow rapidly and achieve high cell density under controlled conditions and are thus considered to be promising protein sources. Many advances in the genetic engineering of Chlorella have occurred in recent years, with significant developments in successful expression of heterologous proteins for various applications. Nevertheless, a lot of obstacles remain to be addressed, and a sophisticated and stable Chlorella expression system has yet to emerge. This review provides a brief summary of current knowledge on Chlorella and an overview of recent progress in the genetic engineering of Chlorella, and highlights the advances in the development of a genetic toolbox of Chlorella for heterologous protein expression. Research directions to further exploit the Chlorella expression system with respect to both challenges and perspectives are also discussed. This paper serves as a comprehensive literature review for the Chlorella community and will provide valuable insights into future exploration of Chlorella as a promising host for heterologous protein expression. PMID- 27465360 TI - Comparison of physicochemical and functional properties of duck feet and bovine gelatins. AB - BACKGROUND: Previous studies have indicated that duck feet are a rich source of gelatin extractable from avian sources. In this study, the physicochemical and functional properties of avian gelatin extracted from duck feet (DFG) with acetic acid were compared with those of commercial bovine gelatin (BG). RESULTS: The yield of DFG obtained in this study was 7.01 +/- 0.31%. High-performance liquid chromatography analysis indicated that the imino acid content was slightly lower for DFG compared with BG (P < 0.05). Differences in molecular size and amino acids between DFG and BG were also observed. The isoelectric points of DFG and BG were at pH 8 and 5 respectively, and the overall protein solubility of BG was higher than that of DFG. Gels prepared from BG exhibited higher bloom strength, viscosity and clarity and were darker in colour compared with DFG gels (P < 0.05). The gelling and melting points of BG were 21.8 and 29.47 degrees C respectively, while those of DFG were 20.5 and 27.8 degrees C respectively. BG exhibited slightly better emulsifying and foaming properties compared with DFG. CONCLUSION: Although some differences between DFG and BG were observed, the disparities were small, which indicates that DFG could be exploited commercially as an alternative source of gelatin. (c) 2016 Society of Chemical Industry. PMID- 27465359 TI - How do fission yeast cells grow and connect growth to the mitotic cycle? AB - To maintain size homeostasis in a unicellular culture, cells should coordinate growth to the division cycle. This is achieved via size control mechanisms (also known as size checkpoints), i.e. some events during the mitotic cycle supervene only if the cell has reached a critical size. Rod-shaped cells like those of fission yeast are ideal model organisms to study these checkpoints via time-lapse microphotography. By applying this method, once we can analyse the growth process between two consecutive divisions at a single (or even at an 'average') cellular level, moreover, we can also position the size checkpoint(s) at the population level. Finally, any of these controls can be abolished in appropriate cell cycle mutants, either in steady-state or in induction synchronised cultures. In the latter case, we produce abnormally oversized cells, and microscopic experiments with them clearly show the existence of a critical size above which the size checkpoint ceases (becomes cryptic). In this review, we delineate the development of our knowledge both on the growth mode of fission yeast and on the operating size control(s) during its mitotic cycle. We finish these historical stories with our recent findings, arguing that three different size checkpoints exist in the fission yeast cell cycle, namely in late G1, in mid G2 and in late G2, which has been concluded by analysing these controls in several cell cycle mutants. PMID- 27465361 TI - Expression of circadian clock genes and proteins in urothelial cancer is related to cancer-associated genes. AB - BACKGROUND: The purpose of this study was to evaluate invasive and metastatic potential of urothelial cancer by investigating differential expression of various clock genes/proteins participating in the 24 h circadian rhythms and to compare these gene expressions with transcription of other cancer-associated genes. METHODS: Twenty seven paired samples of tumour and benign tissue collected from patients who underwent cystectomy were analysed and compared to 15 samples of normal bladder tissue taken from patients who underwent cystoscopy for benign prostate hyperplasia (unrelated donors). Immunohistochemical analyses were made for clock and clock-related proteins. In addition, the gene-expression levels of 22 genes (clock genes, casein kinases, oncogenes, tumour suppressor genes and cytokeratins) were analysed by real-time quantitative PCR (qPCR). RESULTS: Considerable up- or down-regulation and altered cellular distribution of different clock proteins, a reduction of casein kinase1A1 (CSNK1A1) and increase of casein kinase alpha 1 E (CSNK1E) were found. The pattern was significantly correlated with simultaneous up-regulation of stimulatory tumour markers, and a down-regulation of several suppressor genes. The pattern was mainly seen in aneuploid high-grade cancers. Considerable alterations were also found in the neighbouring bladder mucosa. CONCLUSIONS: The close correlation between altered expression of various clock genes and common tumour markers in urothelial cancer indicates that disturbed function in the cellular clock work may be an important additional mechanism contributing to cancer progression and malignant behaviour. PMID- 27465362 TI - Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome. AB - Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the expected loss of visually evoked bursting at the same age as wild type, two days before eye-opening. At later ages, during the third and fourth post-natal weeks, signs of mild hyper-excitability emerged. These included an increase in the visually-evoked firing of regular spiking, presumptive excitatory, neurons, and a reduced firing of fast-spiking, presumptive inhibitory, neurons. Our results show that early network changes in the FMR-KO rat arise at ages equivalent to fetal humans and have consequences for excitability that are opposite those found in adults. This suggests identification and treatment should begin early, and be tailored in an age appropriate manner. PMID- 27465358 TI - Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7 pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding proteins. AB - BACKGROUND: We used lentiviral vectors (LVs) to generate a new SCA7 animal model overexpressing a truncated mutant ataxin-7 (MUT ATXN7) fragment in the mouse cerebellum, in order to characterize the specific neuropathological and behavioral consequences of the genetic defect in this brain structure. RESULTS: LV-mediated overexpression of MUT ATXN7 into the cerebellum of C57/BL6 adult mice induced neuropathological features similar to that observed in patients, such as intranuclear aggregates in Purkinje cells (PC), loss of synaptic markers, neuroinflammation, and neuronal death. No neuropathological changes were observed when truncated wild-type ataxin-7 (WT ATXN7) was injected. Interestingly, the local delivery of LV-expressing mutant ataxin-7 (LV-MUT-ATXN7) into the cerebellum of wild-type mice also mediated the development of an ataxic phenotype at 8 to 12 weeks post-injection. Importantly, our data revealed abnormal levels of the FUS/TLS, MBNL1, and TDP-43 RNA-binding proteins in the cerebellum of the LV-MUT-ATXN7 injected mice. MUT ATXN7 overexpression induced an increase in the levels of the pathological phosphorylated TDP-43, and a decrease in the levels of soluble FUS/TLS, with both proteins accumulating within ATXN7-positive intranuclear inclusions. MBNL1 also co-aggregated with MUT ATXN7 in most PC nuclear inclusions. Interestingly, no MBNL2 aggregation was observed in cerebellar MUT ATXN7 aggregates. Immunohistochemical studies in postmortem tissue from SCA7 patients and SCA7 knock-in mice confirmed SCA7-induced nuclear accumulation of FUS/TLS and MBNL1, strongly suggesting that these proteins play a physiopathological role in SCA7. CONCLUSIONS: This study validates a novel SCA7 mouse model based on lentiviral vectors, in which strong and sustained expression of MUT ATXN7 in the cerebellum was found sufficient to generate motor defects. PMID- 27465363 TI - The Effects of Shoulder Rotation on the Acoustic Window for Thoracic Paramedian Epidural Approach in the Lateral Decubitus Position. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to examine whether shoulder rotation increases the length of the posterior longitudinal ligament (PLL) in the lateral decubitus position. METHODS: Thirty-four adult male volunteers were placed in the right or left lateral decubitus and flexion position on a horizontal operating table. Thoracic spinal ultrasonography was performed using the paramedian oblique sagittal plane to obtain the optimal ultrasound view for the PLL on the dependent side. The lengths of the PLL were measured at the T6/7 and T9/10 interspaces before and after ipsilateral 30-degree shoulder rotation. RESULTS: In the right lateral decubitus position, the ipsilateral shoulder rotation increased the mean (SD) of the PLL from 7.4 (2.8) to 8.4 (2.6) mm (P = 0.006) at the T6/7 level and from 8.4 (2.9) to 10.6 (2.8) mm (P < 0.0001) at the T9/10 level. Similarly, in the left lateral decubitus position, the ipsilateral shoulder rotation increased the mean (SD) of the PLL from 8.0 (2.6) to 9.1 (2.6) mm (P = 0.001) at the T6/7 level and from 9.3 (2.8) to 11.8 (3.1) mm (P < 0.0001) at the T9/10 level. CONCLUSIONS: Shoulder rotation significantly increased the dimension of the acoustic target window for paramedian thoracic epidural access in the lateral decubitus position at both T6/7 and T9/10 levels. Further clinical studies are needed to investigate the effect of shoulder rotation on thoracic epidural access. PMID- 27465366 TI - Immunosuppressive therapy alleviates murine cytomegalovirus recurrence by reducing TNF-alpha post cell transplantation with lethal GVHD. AB - Cytomegalovirus (CMV) reactivation leads to obvious morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Current immunosuppressive therapy reduces the frequency of graft-versus-host disease (GVHD), and is generally accepted as a high risk factor for viral recurrence. In the present study, we investigated the influence of cyclosporin A (CsA) and rapamycin (RAPA), two commonly used immunosuppressive agents, on murine cytomegalovirus (MCMV) recurrence by two allo-HCT models: one with mild and one with severe GVHD. In models with mild GVHD and partial immune recovery, transplanted mice with CsA and RAPA showed a higher viral load and impaired CMV specific immune recovery compared to those with placebo. In contrast, in HCT models with severe GVHD, groups treated with immunosuppressive therapy showed alleviation of viral recurrence as well as GVHD-related symptoms. In addition, no CMV-specific immune reconstitution was found in any group, implying immunosuppressive therapy was not relevant to antiviral response. Furthermore, a significant correlation between MCMV DNA copies and tumor necrosis factor alpha (TNF-alpha) was found, and recipients with immunosuppressive therapy showed a lower level of TNF-alpha. Finally, using lenalidomide (an inhibitor of TNF alpha), a lower viral load was found in animals with lenalidomide. Having received lenalidomide, recipients showed no statistical difference in viral load between groups with and without immunosuppressive therapy. Taken together, we provide evidence of the dual effect of immunosuppressive therapy on viral reactivation. Importantly, we found that immunosuppressive therapy had the ability to alleviate viral load by reducing TNF-alpha in a mouse model with severe GVHD. PMID- 27465367 TI - The solvation structure of alprazolam. AB - Alprazolam is a benzodiazepine that is commonly prescribed for the treatment of anxiety and other related disorders. Like other benzodiazepines, it is thought to exert its effect through interaction with GABAA receptors. However, it has also been described as a potent and selective protein interaction inhibitor of bromodomain and extra-terminal (BET) proteins. Indeed, the only crystal structure of alprazolam bound to a protein is a complex between alprazolam and the BRD4 bromodomain. The structure shows that the complex also involves many water interactions that mediate contacts between the drug and the protein, a scenario that exists in many drug-protein complexes. How such waters relate to solvation patterns of small molecules may improve our understanding of what dictates their appearance or absence in bridging positions within complexes and thus will be important in terms of future rational drug-design. Here, we use neutron diffraction in conjunction with molecular dynamics simulations to provide a detailed analysis of how water molecules interact with alprazolam in methanol/water mixtures. The agreement between the neutron diffraction and the molecular dynamics is extremely good. We discuss the results in the context of drug design. PMID- 27465364 TI - Insufficient Penetration of Bone Cement Into the Trabecular Bone: A Potential Risk for Delayed Bone Cement Displacement After Kyphoplasty? AB - OBJECTIVE: Balloon kyphoplasty is a minimally invasive procedure used in the treatment of vertebral compression fractures. Although cement leakage is a well known complication of the procedure, delayed displacement of the injected bone cement material, occurring several weeks after kyphoplasty, is a rare occurrence. In this report, we describe a case of delayed dislodgement of the bone cement occurring 4 weeks after successful kyphoplasty for an osteoporotic compression fracture of L4. CASE REPORT: A balloon kyphoplasty was successfully performed for the clinical management of an osteoporotic compression fracture of the L4 vertebral body in a 74-year-old patient with Kummel disease. However, further progression of the collapse of L4 vertebra was identified on radiographic imaging obtained 4 weeks after the kyphoplasty. A cystic filling pattern of the bone cement was observed, rather than the expected matrix-like pattern, which contributed to the continued progression of the collapse of the vertebral body. CONCLUSIONS: As delayed displacement of bone cement can result in progression of an osteoporotic compression fracture of the vertebrae, we propose that sufficient penetration of bone cement into the microstructure of the trabecular bone of the vertebral body during kyphoplasty could reduce the risk of this phenomenon. PMID- 27465365 TI - Herbal composition of Cinnamomum cassia, Pinus densiflora, Curcuma longa and Glycyrrhiza glabra prevents atherosclerosis by upregulating p27 (Kip1) expression. AB - BACKGROUND: Kiom-18 is a novel composition of Cinnamomum cassia, Pinus densiflora, Curcuma longa and Glycyrrhiza glabra. Curcuma longa and Glycyrrhiza glabra, which are traditional medicines in Asia, have been reported to demonstrate preventive effects against atherosclerosis; however, they have not yet been developed into functional atherosclerosis treatments. We therefore studied the anti-atherosclerotic effects and possible molecular mechanisms of Kiom-18 using vascular smooth muscle cells (VSMCs). METHODS: To assess the anti proliferative effect of Kiom-18 in vitro, we performed thymidine incorporation, cell cycle progression, immunoblotting and immunofluorescence assays in VSMCs stimulated by platelet derived-growth factor (PDGF)-BB. In addition, we used LDLr knockout mice to identify the effects of Kiom-18 as a preliminary result in an atherosclerosis animal model. RESULTS: Kiom-18 inhibited platelet-derived growth factor (PDGF)-BB-stimulated-VSMC proliferation and DNA synthesis. Additionally, Kiom-18 arrested the cell cycle transition of G0/G1 stimulated by PDGF-BB and its cell cycle-related proteins. Correspondingly, the level of p27(kip1) expression was upregulated in the presence of the Kiom-18 extract. Moreover, in an atherosclerosis animal model of LDLr knockout mice, Kiom-18 extract showed a preventive effect for the formation of atherosclerotic plaque and suppressed body weight, fat weight, food treatment efficiency, neutrophil count, and triglyceride level. CONCLUSIONS: These results indicate that Kiom-18 exerts anti atherosclerotic effects by inhibiting VSMC proliferation via G0/G1 arrest, which upregulates p27(Kip1) expression. PMID- 27465371 TI - Timing, intensity and frequency of exercise for glucose control. PMID- 27465370 TI - Reply to Elsamma Chacko: "Timing, intensity and frequency of exercise for glucose control". PMID- 27465369 TI - Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3. AB - Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 +/- 11.1 uM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 +/- 0.17 uM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed. PMID- 27465377 TI - Quantifying the mediating effect of body mass index on the relation between a Mediterranean diet and development of maternal pregnancy complications: the Australian Longitudinal Study on Women's Health. AB - BACKGROUND: The contribution of body mass index (BMI) to the observed associations between dietary patterns and risk of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP) remains unclear. OBJECTIVE: The objective of this study was to formally quantify the mediating effect of prepregnancy BMI in these associations. DESIGN: Women (aged 25-30 y) participating in the Australian Longitudinal Study on Women's Health were not pregnant at baseline in 2003 and reported >=1 pregnancy up to 2012. GDM and HDP diagnoses were self-reported for each pregnancy and validated in a subset. A Mediterranean diet score was created by use of a baseline-validated food frequency questionnaire and dichotomized to reflect low adherence (<25th percentile) and higher adherence (>=25th percentile). A causal inference framework for mediation analysis was used to estimate total, natural direct, and natural indirect effects of the prepregnancy Mediterranean diet on incident GDM and HDP and proportions mediated through prepregnancy BMI. RESULTS: In 3378 women without a history of diabetes, 240 (7.1%) developed GDM. HDP was reported in 273 (8.6%) of 3167 women with no history of hypertension. Low adherence to the Mediterranean diet was associated with higher risk of GDM (OR: 1.35; 95% CI: 1.02, 1.60) and HDP (OR: 1.41; 95% CI: 1.18, 1.56), after adjustment for education, parity, polycystic ovary syndrome, energy intake, and physical activity. Proportions mediated through prepregnancy BMI (per 1-kg/m(2) increase) were 32% and 22% for GDM and HDP, respectively. CONCLUSION: These findings suggest that prepregnancy BMI as a single mediator contributes substantially to the total effects of the prepregnancy Mediterranean diet on GDM and HDP risk. PMID- 27465376 TI - The void in using urine concentration to assess population fluid intake adequacy or hydration status. AB - Urine concentration can be used to assess fluid intake adequacy or to diagnose dehydration. However, too often urine concentration is used inappropriately to draw dubious conclusions that could have harmful health and economic consequences. Inappropriate uses of urine concentration relate primarily to convenience sampling (timing) and problems related to convenience sampling (misapplication of thresholds), but a conceptual problem also exists with using urine concentration in isolation. The purpose of this Perspective article is to briefly explain the problematic nature of current practices and to offer a possible solution to improve practice with minimal added complication. When urine is used exclusively to assess fluid intake adequacy and hydration status in adults, we propose that only when urine concentration is high (>850 mmol/kg) and urine excretion rate is low (<850 mL/24 h) should suspicion of inadequate drinking or impending dehydration be considered. Prospective tests of the 850 * 850 thresholds will provide supporting evidence and/or help refine the best thresholds for men and women, young and old. PMID- 27465373 TI - Plasma folate, vitamin B-6, and vitamin B-12 and breast cancer risk in BRCA1- and BRCA2-mutation carriers: a prospective study. AB - BACKGROUND: B vitamins [vitamins B-6, B-9 (folate), and B-12] play important roles in nucleotide biosynthesis and biological methylation reactions, aberrancies of which have all been implicated in carcinogenesis. In the general population, evidence has suggested that high circulating folate and folic acid (synthetic form of folate) supplement use may increase breast cancer risk, but the role of folate in BRCA-associated breast cancer is not clear. OBJECTIVE: We prospectively evaluated the relation between plasma folate, pyridoxal 5' phosphate (PLP; the biologically active form of vitamin B-6), and vitamin B-12 and breast cancer risk in women with a BRCA1/2 mutation. DESIGN: Baseline blood samples and biennial follow-up questionnaires were available for 164 BRCA1/2 mutation carriers with no previous history of cancer other than nonmelanoma skin cancer. Plasma folate, PLP, and vitamin B-12 concentrations were categorized dichotomously as high compared with low based on the upper 25% and the lower 75% of distribution, respectively. Cox proportional hazards were used to estimate the HR and 95% CI for the association between plasma biomarkers of each B vitamin and incident breast cancer. RESULTS: Over a mean follow-up of 6.3 y, 20 incident primary invasive breast cancers were observed. Women with high plasma folate concentrations (>24.4 ng/mL) were associated with significantly increased breast cancer risk (HR: 3.20; 95% CI: 1.03, 9.92; P = 0.04, P-trend across quintiles = 0.07) compared with that of women with low plasma folate concentrations (<=24.4 ng/mL). Plasma PLP and vitamin B-12 concentrations were not associated with breast cancer risk. CONCLUSIONS: Our data suggest that elevated plasma folate concentrations may be associated with increased risk of breast cancer in women with a BRCA1/2 mutation. Additional studies with a larger sample size and longer follow-up periods are warranted to clarify the relation between folate status and breast cancer risk in high-risk women. PMID- 27465375 TI - Breakfast consumption has no effect on neuropsychological functioning in children: a repeated-measures clinical trial. AB - BACKGROUND: Although many studies have investigated the relation between breakfast consumption and various domains of cognitive functioning within children, some of the reported findings are inconsistent. OBJECTIVE: We sought to determine the short-term effects of a breakfast meal on the neuropsychological functioning of healthy school-aged children after an overnight fast. DESIGN: The study was conducted in a clinical research center with the use of a counterbalanced repeated-measures design among children who either consumed breakfast or were fasting. The administered neuropsychological tests included measures of attention, impulsivity, short-term memory, cognitive processing speed, and verbal learning. The sample consisted of children aged 8-10 y (n = 128), of whom 52% were female, 38% were African American, 31% were Hispanic, 28% were white, and 3% were of another race/ethnicity. RESULTS: There were no significant (P >= 0.004) differences between breakfast meal consumption and fasting for any of the neuropsychological measures administered. CONCLUSION: Breakfast consumption had no short-term effect on neuropsychological functioning in healthy school-aged children. This trial was registered at clinicaltrials.gov as NCT01943604. PMID- 27465372 TI - Soluble corn fiber increases bone calcium retention in postmenopausal women in a dose-dependent manner: a randomized crossover trial. AB - BACKGROUND: Dietary soluble corn fiber (SCF) significantly improves calcium absorption in adolescents and the bone strength and architecture in rodent models. OBJECTIVE: In this study, we aimed to determine the skeletal benefits of SCF in postmenopausal women. DESIGN: We used our novel technology of determining bone calcium retention by following the urinary appearance of (41)Ca, a rare long lived radioisotope, from prelabeled bone to rapidly and sensitively evaluate the effectiveness of SCF in reducing bone loss. A randomized-order, crossover, double blinded trial was performed in 14 healthy postmenopausal women to compare doses of 0, 10, and 20 g fiber from SCF/d for 50 d. RESULTS: A dose-response effect was shown with 10 and 20 g fiber from SCF/d, whereby bone calcium retention was improved by 4.8% (P < 0.05) and 7% (P < 0.04), respectively. The bone turnover biomarkers N-terminal telopeptide and osteocalcin were not changed by the interventions; however, a significant increase in bone-specific alkaline phosphatase, which is a bone-formation marker, was detected between 0 and 20 g fiber from SCF/d (8%; P = 0.035). CONCLUSION: Daily SCF consumption significantly increased bone calcium retention in postmenopausal women, which improved the bone calcium balance by an estimated 50 mg/d. This study was registered at clinicaltrials.gov as NCT02416947. PMID- 27465368 TI - [Regional differences in the health care of basal cell carcinoma]. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer in Germany. So far, it is unclear whether regional variations exist in the health care of the BCC. OBJECTIVES: Analysis of regional variations in health care (e. g., skin cancer screening) and their causes using the example of BCC. MATERIALS AND METHODS: Qualitative and quantitative analysis of the regional health care situation of BCC based on three studies was undertaken. These studies include the analysis of n = 7015 histopathological indications whose average tumor thickness is regarded as a characteristic of the quality of care, and a secondary data analysis of GK insured (n = 6.1 million DAK-insured persons), and a nationwide survey (FORSA) of n = 1004 participants focusing on the use of skin cancer screening. RESULTS: Analysis of the histopathological examination showed regional variations in average tumor depth of penetration. These are associated with the rural/urban characteristics of the region and individual sociodemographic indicators (e. g., employment sector or education). The results for age- and gender-specific use (DAK data) showed higher participation rates regarding skin cancer screening in western than in eastern federal states (Bundeslander). Moreover, it was revealed that the trend for using skin cancer screening was higher in urban than in rural areas. The results of population-related surveys confirm this trend. CONCLUSION: Although it is not possible to compare the studies directly, all three showed an association between city/state and the use of skin cancer screenings. In addition, sociodemographic characteristics that are related to the quality of health care were identified. PMID- 27465374 TI - Diets higher in animal and plant protein are associated with lower adiposity and do not impair kidney function in US adults. AB - BACKGROUND: Higher-protein diets are associated with decreased adiposity and greater HDL cholesterol than lower protein diets. Whether these benefits can be attributed to a specific protein source (i.e., nondairy animal, dairy, or plant) is unknown, and concerns remain regarding the impact of higher-protein diets on kidney function. OBJECTIVE: The objective of this study was to evaluate trends of protein source on markers of cardiometabolic disease risk and kidney function in US adults. DESIGN: Total, nondairy animal, dairy, and plant protein intake were estimated with the use of 24-h recall data from NHANES 2007-2010 (n = 11,111; >=19 y). Associations between source-specific protein intake and health outcomes were determined with the use of models that adjusted for sex, race and ethnicity, age, physical activity, poverty-to-income ratio, individual intake (grams per kilogram) for each of the other 2 protein sources, body mass index (BMI) (except for weight-related variables), and macronutrient (carbohydrate, fiber, and total and saturated fat) intake. RESULTS: Mean +/- SE total protein intake was 82.3 +/- 0.8 g/d (animal: 37.4 +/- 0.5 g/d; plant: 24.7 +/- 0.3 g/d; and dairy: 13.4 +/- 0.3 g/d). Both BMI and waist circumference were inversely associated [regression coefficient (95% CI)] with animal [-0.199 (-0.265, -0.134), P < 0.0001; -0.505 ( 0.641, -0.370), P < 0.0001] and plant [-0.346 (-0.455, -0.237), P < 0.0001; 0.826 (-1.114, -0.538), P < 0.0001] protein intake. Blood urea nitrogen concentrations increased across deciles for animal [0.313 (0.248, 0.379), P < 0.0001; decile 1-10: 11.6 +/- 0.2 to 14.9 +/- 0.3 mg/dL] and dairy [0.195 (0.139, 0.251), P < 0.0001; decile 1-10: 12.7 +/- 0.2 to 13.9 +/- 0.2 mg/dL] but not plant protein intake. Glomerular filtration rate and blood creatinine were not associated with intake of any protein source. CONCLUSIONS: Diets higher in plant and animal protein, independent of other dietary factors, are associated with cardiometabolic benefits, particularly improved central adiposity, with no apparent impairment of kidney function. PMID- 27465378 TI - Associations between nut consumption and inflammatory biomarkers. AB - BACKGROUND: Increased nut consumption has been associated with reduced risk of cardiovascular disease and type 2 diabetes, as well as a healthy lipid profile. However, the associations between nut consumption and inflammatory biomarkers are unclear. OBJECTIVE: We investigated habitual nut consumption in relation to inflammatory biomarkers in 2 large cohorts of US men and women. DESIGN: We analyzed cross-sectional data from 5013 participants in the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) who were free of diabetes. Nut intake, defined as intake of peanuts and other nuts, was estimated from food frequency questionnaires, and cumulative averages from 1986 and 1990 in the NHS and from 1990 and 1994 in the HPFS were used. Plasma biomarkers were collected in 1989-1990 in the NHS and 1993-1995 in the HPFS. Multivariate linear regression was used to assess the associations of nut consumption with fasting plasma C reactive protein (CRP, n = 4941), interleukin 6 (IL-6, n = 2859), and tumor necrosis factor receptor 2 (TNFR2, n = 2905). RESULTS: A greater intake of nuts was associated with lower amounts of a subset of inflammatory biomarkers, after adjusting for demographic, medical, dietary, and lifestyle variables. The relative concentrations (ratios) and 95% CIs comparing subjects with nut intake of >=5 times/wk and those in the categories of never or almost never were as follows: CRP: 0.80 (0.69, 0.90), P-trend = 0.0003; and IL-6: 0.86 (0.77, 0.97), P trend = 0.006. These associations remained significant after further adjustment for body mass index. No significant association was observed with TNFR2. Substituting 3 servings of nuts/wk for 3 servings of red meat, processed meat, eggs, or refined grains/wk was associated with significantly lower CRP (all P < 0.0001) and IL-6 (P ranges from 0.001 to 0.017). CONCLUSION: Frequent nut consumption was associated with a healthy profile of inflammatory biomarkers. PMID- 27465379 TI - Relation between mealtime distribution of protein intake and lean mass loss in free-living older adults of the NuAge study. AB - BACKGROUND: Studies have shown that an even protein intake distribution across meals increased 24-h muscle protein synthesis in young adults compared with a skewed intake. Whether this short-term result translates into long-term preservation of lean mass (LM) in older adults remains unknown. OBJECTIVE: The aim was to examine the extent to which protein quantity and distribution are associated with LM and appendicular LM (aLM), and their 2-y decline, in community dwelling older adults. DESIGN: Baseline and 2-y follow-up data from 351 men and 361 women (aged 67-84 y) in the NuAge study (Quebec Longitudinal Study on Nutrition as a Determinant of Successful Aging) with available body-composition data (by dual-energy X-ray absorptiometry) were used. Food intake was assessed with the use of three 24-h food recalls collected at baseline and 3 collected at the 2-y follow-up. Protein distribution across meals was calculated as the CV of protein ingested per meal, with lower values reflecting evenness of protein intake. Linear mixed-model analysis was performed to examine changes in LM and aLM across time, by sex, as conditioned by the quantity and distribution of protein intake, adjusted for potential covariates. RESULTS: Over 2 y, LM declined in both men (-2.5% +/- 4.0%) and women (-2.0% +/- 3.4%) (P < 0.05), whereas aLM loss was not significant (men: -1.5% +/- 4.8%; women: -1.2% +/- 5.3%; P > 0.05). The decline in LM was not independently affected by the quantity and distribution of protein intake. Yet men and women with evenly distributed protein intakes and men with high protein intakes showed higher LM or aLM throughout the entire follow-up period, even after potential confounders were controlled for (P < 0.05). CONCLUSIONS: Our results suggest that greater protein intakes and a more even distribution across meals are modifiable factors associated with higher muscle mass in older adults but not with losses over 2 y. Interventional studies should determine longer-term effects on preserving LM with aging. PMID- 27465380 TI - Interactions between genetic variants associated with adiposity traits and soft drinks in relation to longitudinal changes in body weight and waist circumference. AB - BACKGROUND: Intake of sugar-sweetened beverages is associated with obesity, and this association may be modified by a genetic predisposition to obesity. OBJECTIVE: We examined the interactions between a molecular genetic predisposition to various aspects of obesity and the consumption of soft drinks, which are a major part of sugar-sweetened beverages, in relation to changes in adiposity measures. DESIGN: A total of 4765 individuals were included in the study. On the basis of 50 obesity-associated single nucleotide polymorphisms that are associated with body mass index (BMI), waist circumference (WC), or the waist to-hip ratio adjusted for BMI (WHRBMI), the following 4 genetic predisposition scores (GRSs) were constructed: a complete genetic predisposition score including all 50 single nucleotide polymorphisms (GRSComplete), a genetic predisposition score including BMI-associated single nucleotide polymorphisms (GRSBMI), a genetic predisposition score including waist circumference-associated single nucleotide polymorphisms (GRSWC), and a genetic predisposition score including the waist-to-hip ratio adjusted for BMI-associated single nucleotide polymorphisms (GRSWHR). Associations between soft drink intake and the annual change (Delta) in body weight (BW), WC, or waist circumference adjusted for BMI (WCBMI) and possible interactions with the GRSs were examined with the use of linear regression analyses and meta-analyses. RESULTS: For each soft drink serving per day, soft drink consumption was significantly associated with a higher DeltaBW of 0.07 kg/y (95% CI: 0.01, 0.13 kg/y; P = 0.020) but not with the DeltaWC or DeltaWCBMI In analyses of the DeltaBW, we showed an interaction only with the GRSWC (per risk allele for each soft drink serving per day: -0.06 kg/y; 95% CI: -0.10, -0.02 kg/y; P = 0.006). In analyses of the DeltaWC, we showed interactions only with the GRSBMI and GRSComplete [per risk allele for each soft drink serving per day: 0.05 cm/y (95% CI: 0.02, 0.09 cm/y; P = 0.001) and 0.05 cm/y (95% CI: 0.02, 0.07 cm/y; P = 0.001), respectively]. Nearly identical results were observed in analyses of the DeltaWCBMI CONCLUSIONS: A genetic predisposition to a high WC may attenuate the association between soft drink intake and BW gain. A genetic predisposition to high BMI as well as a genetic predisposition to high BMI, WC, and WHRBMI combined may strengthen the association between soft drink intake and WC gain. However, the public health impact may be limited. PMID- 27465383 TI - A dose-response crossover iodine balance study to determine iodine requirements in early infancy. AB - BACKGROUND: Optimal iodine intake during infancy is critical for brain development, but no estimated average requirement (EAR) is available for this age group. OBJECTIVE: We measured daily iodine intake, excretion, and retention over a range of iodine intakes in early infancy to determine the minimum daily intake required to achieve iodine balance. DESIGN: In a dose-response crossover study, we randomly assigned healthy infants (n = 11; mean +/- SD age 13 +/- 3 wk) to sequentially consume over 33 d 3 infant formula milks (IFMs) containing 10.5, 19.3, and 38.5 MUg I/100 kcal, respectively. Each IFM was consumed for 11 d, consisting of a 6-d run-in period followed by a 4-d balance period and 1 run-out day. RESULTS: Iodine intake (mean +/- SD: 54.6 +/- 8.1, 142.3 +/- 23.1, and 268.4 +/- 32.6 MUg/d), excretion (55.9 +/- 8.6, 121.9 +/- 21.7, and 228.7 +/- 39.3 MUg/d), and retention (-1.6 +/- 8.3, 20.6 +/- 21.6, and 39.8 +/- 34.3 MUg/d) differed among the low, middle, and high iodine IFM groups (P < 0.001 for all). There was a linear relation between daily iodine intake and both daily iodine excretion and daily iodine retention. Zero balance (iodine intake = iodine excretion, iodine retention = 0 MUg/d) was achieved at a daily iodine intake of 70 MUg (95% CI: 60, 80 MUg). CONCLUSION: Our data indicate the iodine requirement in 2- to 5-mo-old infants is 70 MUg/d. Adding an allowance for accumulation of thyroidal iodine stores would produce an EAR of 72 MUg and a recommended dietary allowance of 80 MUg. This trial was registered at clinicaltrials.gov as NCT02045784. PMID- 27465381 TI - Sugar-sweetened beverage consumption and genetic predisposition to obesity in 2 Swedish cohorts. AB - BACKGROUND: The consumption of sugar-sweetened beverages (SSBs), which has increased substantially during the last decades, has been associated with obesity and weight gain. OBJECTIVE: Common genetic susceptibility to obesity has been shown to modify the association between SSB intake and obesity risk in 3 prospective cohorts from the United States. We aimed to replicate these findings in 2 large Swedish cohorts. DESIGN: Data were available for 21,824 healthy participants from the Malmo Diet and Cancer study and 4902 healthy participants from the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk Study. Self-reported SSB intake was categorized into 4 levels (seldom, low, medium, and high). Unweighted and weighted genetic risk scores (GRSs) were constructed based on 30 body mass index [(BMI) in kg/m(2)]-associated loci, and effect modification was assessed in linear regression equations by modeling the product and marginal effects of the GRS and SSB intake adjusted for age-, sex-, and cohort-specific covariates, with BMI as the outcome. In a secondary analysis, models were additionally adjusted for putative confounders (total energy intake, alcohol consumption, smoking status, and physical activity). RESULTS: In an inverse variance-weighted fixed-effects meta-analysis, each SSB intake category increment was associated with a 0.18 higher BMI (SE = 0.02; P = 1.7 * 10(-20); n = 26,726). In the fully adjusted model, a nominal significant interaction between SSB intake category and the unweighted GRS was observed (P-interaction = 0.03). Comparing the participants within the top and bottom quartiles of the GRS to each increment in SSB intake was associated with 0.24 (SE = 0.04; P = 2.9 * 10(-8); n = 6766) and 0.15 (SE = 0.04; P = 1.3 * 10( 4); n = 6835) higher BMIs, respectively. CONCLUSIONS: The interaction observed in the Swedish cohorts is similar in magnitude to the previous analysis in US cohorts and indicates that the relation of SSB intake and BMI is stronger in people genetically predisposed to obesity. PMID- 27465388 TI - One hundred years of retinal detachment surgery. PMID- 27465382 TI - Serum 25-hydroxyvitamin D concentrations and treatment outcomes of women undergoing assisted reproduction. AB - BACKGROUND: Vitamin D deficiency impairs fertility in animal models, but the role of vitamin D in human fertility or treatment of infertility is less clear. OBJECTIVE: We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] concentrations and the outcome in women undergoing assisted reproduction technologies (ARTs). DESIGN: We randomly selected 100 women undergoing infertility treatment with ART enrolled in an ongoing prospective cohort study who underwent 168 treatment cycles. Serum 25(OH)D concentrations were measured in samples collected from women between days 3 and 9 of gonadotropin treatment. Generalized linear mixed models were used to evaluate the association of 25(OH)D concentrations with ART outcomes while adjusting for potential confounders and accounting for repeated treatment cycles per woman. RESULTS: Median (range) serum 25(OH)D concentrations were 86.5 (33.5-155.5) nmol/L. Ninety-one percent of participants consumed multivitamins. Serum 25(OH)D concentrations were positively related to fertilization rate. The adjusted fertilization rate for women in increasing quartiles of serum 25(OH)D were 0.62 (95% CI: 0.51, 0.72), 0.53 (95% CI: 0.43, 0.63), 0.67 (95% CI: 0.56, 0.76), and 0.73 (95% CI: 0.63, 0.80), respectively (P-trend = 0.03). This association persisted when analyses were restricted to women with serum 25(OH)D between 50 and 125 nmol/L when models were further adjusted for season of blood draw and when analyses were restricted to the first treatment cycle. However, 25(OH)D concentrations were unrelated to probability of pregnancy (P-trend = 0.83) or live birth after ART (P-trend = 0.47). CONCLUSION: Vitamin D may be associated with higher fertilization rates, but this apparent benefit does not translate into higher probability of pregnancy or live birth. This trial was registered at www.clinicaltrials.gov as NCT00011713. PMID- 27465387 TI - Service user involvement for mental health system strengthening in India: a qualitative study. AB - BACKGROUND: There is a wide recognition that involvement of service users and their caregivers in health system policy and planning processes can strengthen health systems; however, most evidence and experience has come from high-income countries. This study aimed to explore baseline experiences, barriers and facilitators to service user-caregiver involvement in the emerging mental health system in India, and stakeholders' perspectives on how greater involvement could be achieved. METHODS: A qualitative study was conducted in Sehore district of Madhya Pradesh, India. In-depth interviews (n = 27) and a focus group discussion were conducted among service users, caregivers and their representatives at district, state and national levels and policy makers, service providers and mental health researchers. The topic guide explored the baseline situation in India, barriers and facilitators to service user and caregiver involvement in the following aspects of mental health systems: policy-making and planning, service development, monitoring and quality control, as well as research. Framework analysis was employed. RESULTS: Respondents spoke of the limited involvement of service users and caregivers in the current Indian mental health system. The major reported barriers to this involvement were (1) unmet treatment and economic needs arising from low access to mental health services coupled with the high burden of illness, (2) pervasive stigmatising attitudes operating at the level of service user, caregiver, community, healthcare provider and healthcare administrators, and (3) entrenched power differentials between service providers and service users. Respondents prioritised greater involvement of service users in the planning of their own individual-level mental health care before considering involvement at the mental health system level. A stepwise progression was endorsed, starting from needs assessment, through empowerment and organization of service users and caregivers, leading finally to meaningful involvement. CONCLUSIONS: Societal and system level barriers need to be addressed in order to facilitate the involvement of service users and caregivers to strengthen the Indian mental health system. Shifting from a largely 'provider centric' to a more 'user-centric' model of mental health care may be a fundamental first step to sustainable user involvement at the system level. PMID- 27465385 TI - Sudden unexpected death from an undiagnosed histiocytic sarcoma in an adolescent female. AB - A previously well 15-year-old female who was awaiting medical investigations for a proptosed right eye collapsed and died suddenly while walking. Postmortem examination revealed diffuse distortion and infiltration of multiple organs by a suspected neoplastic process. Histology confirmed the invasion of multiple organs by atypical cells and myocardial infiltration was the likely cause of death. An extensive panel of immunohistochemistry established the diagnosis of a histiocytic sarcoma. Sudden unexpected death due to a clinically undiagnosed neoplasia in childhood and adolescence is uncommon. This is the first report of a histiocytic sarcoma causing sudden unexpected death and highlights the importance of considering undiagnosed hematological malignancies when examining a case of sudden death at postmortem. PMID- 27465384 TI - Effects of matched weight loss from calorie restriction, exercise, or both on cardiovascular disease risk factors: a randomized intervention trial. AB - BACKGROUND: Weight loss from calorie restriction (CR) and/or endurance exercise training (EX) is cardioprotective. However CR and EX also have weight loss independent benefits. OBJECTIVE: We tested the hypothesis that weight loss from calorie restriction and exercise combined (CREX) improves cardiovascular disease (CVD) risk factors more so than similar weight loss from CR or EX alone. DESIGN: Overweight, sedentary men and women (n = 52; aged 45-65 y) were randomly assigned to undergo 6-8% weight loss by using CR, EX, or CREX. Outcomes were measured before and after weight loss and included maximal oxygen consumption (VO2max), resting blood pressure, fasting plasma lipids, glucose, C-reactive protein, and arterial stiffness [carotid-femoral pulse wave velocity (PWV) and carotid augmentation index (AI)]. Values are means +/- SEs. RESULTS: Reductions in body weight (~7%) were similar in all groups. VO2max changed in proportion to the amount of exercise performed (CR, -1% +/- 3%; EX, +22% +/- 3%; and CREX, +11% +/- 3%). None of the changes in CVD risk factors differed between groups. For all groups combined, decreases were observed for systolic and diastolic blood pressure (-5 +/- 1 and -4 +/- 1 mm Hg, respectively; both P < 0.0008), total cholesterol (-17 +/- 4 mg/dL; P < 0.0001), non-HDL cholesterol (-16 +/- 3 mg/dL; P < 0.0001), triglycerides (-18 +/- 8 mg/dL; P = 0.03), and glucose (-3 +/- 1 mg/dL; P = 0.0003). No changes were observed for HDL cholesterol (P = 0.30), C reactive protein (P = 0.10), PWV (P = 0.30), or AI (P = 0.84). These changes would be expected to decrease the lifetime risk of CVD from 46% to 36%. CONCLUSION: Matched weight losses from CR, EX, and CREX have substantial beneficial effects on CVD risk factors. However, the effects are not additive when weight loss is matched. This trial was registered at clinicaltrials.gov as NCT00777621. PMID- 27465386 TI - Nanoparticle-based probes to enable noninvasive imaging of proteolytic activity for cancer diagnosis. AB - Proteases play a key role in tumor biology, with high expression levels often correlating with poor prognosis for cancer patients - making them excellent disease markers for tumor diagnosis. Despite their significance, quantifying proteolytic activity in vivo remains a challenge. Nanoparticles, with their ability to serve as scaffolds having unique chemical, optical and magnetic properties, offer the promise of merging diagnostic medicine with material engineering. Such nanoparticles can interact preferentially with proteases enriched in tumors, providing the ability to assess disease state in a noninvasive and spatiotemporal manner. We review recent advances in the development of nanoparticles for imaging and quantification of proteolytic activity in tumor models, and prognosticate future advancements. PMID- 27465389 TI - Are all children with visual impairment known to the eye clinic? AB - INTRODUCTION: There is a growing body of evidence that children with special needs are more likely to have visual problems, be that visual impairment, visual processing problems or refractive error. While there is widespread provision of vision screening in mainstream schools, patchy provision exists in special schools. The aim of the study was to determine the unmet need and undiagnosed visual problems of children attending primary special schools in Bradford, England. METHODS: Children attending special schools who were not currently under the care of the hospital eye service were identified. Assessments of visual function and refractive error were undertaken on site at the schools by an experienced orthoptist and/or paediatric ophthalmologist. RESULTS: A total of 157 children were identified as eligible for the study, with a mean age of 7.8 years (range 4-12 years). Of these, 33% of children were found to have visual impairment, as defined by WHO and six children were eligible for severe sight impairment certification. DISCUSSION: The study demonstrates significant unmet need or undiagnosed visual impairment in a high-risk population. It also highlights the poor uptake of hospital eye care for children identified with significant visual needs and suggests the importance of providing in-school assessment and support, including refractive correction, to fully realise the benefits of a visual assessment programme. PMID- 27465390 TI - Promising role of drug-coated balloons in the tibial vessels? AB - In order to assess the role of drug-coated balloons (DCB) in below-the-knee (BTK) artery interventions, we analyzed randomized trials which compare coated to non coated balloons and additionally a direct comparison of drug-eluting stents (DES) with DCB. As angioplasty with non-coated balloons is per guideline-recommendation still standard of care for below-the-knee artery endovascular treatment, we focused on the direct comparison of efficacy and clinical outcome data of both treatment modalities. Data from peer reviewed and published trials were consulted. For each single study, primary and secondary endpoints were reported and compared. Three single-center, non-core lab adjudicated trials showed encouraging data which suggests that DCB in BTK arteries effectively inhibit the risk of early restenosis, but the pivotal, prospectively randomized, multicenter, core lab adjudicated trials failed to match with these result. Limitations of DEB treatment and trials in BTK arteries had been reported, hence a technical evaluation of possible side effects of DCB treatment and of trial design was taken into account. On the basis of the results available, the distinguishing findings of drug eluting effects in the femoropopliteal region cannot be transferred to BTK arteries. Refinement of the existing DCB technology and of future trial design should be considered. To adjudicate on DCB technology applied for BTK treatment is premature and it is mandatory to be kept under evaluation, because the potential benefit, with respect to the compelling results in the femoropoliteal arteries, could be huge to improve endovascular BTK and especially CLI treatment. PMID- 27465391 TI - Towards an entirely endovascular aortic world: an update of techniques and outcomes for endovascular and open treatment of type I, II, and III endoleaks. AB - Endovascular aneurysm repair (EVAR) is largely the most adopted strategy for aneurysmal disease of the aorta. Nevertheless, the high incidence of reintervention makes it difficult to identify EVAR as a definitive solution; in particular, the most frequent indication of reintervention is endoleak, which is defined as persistent flow into the aneurysmal sac from different sources. Several treatment strategies are described. A contemporary literature search was performed with the intent of describing techniques and outcomes of endovascular and open strategies to type I, II, and III endoleak. Described techniques and outcomes were organized by indication (type I, II, and III endoleak) and by type of approach (endovascular, open, and laparoscopic) to give an overview of the current status of the treatment for the three most frequent types of endoleak. Several endovascular means are described in the literature for the treatment of endoleak. PMID- 27465392 TI - The use of EndoAnchors to rescue complicated TEVAR procedures. AB - BACKGROUND: The aim of this study was to assess the applicability and outcomes of EndoAnchor use in the endovascular repair of thoracic and thoracoabdominal aortic aneurysms. METHODS: A retrospective review was performed of all thoracic endovascular aortic repairs (TEVARs) performed with the use of EndoAnchors between December 2012 and January 2016. Primary study endpoints included freedom from migration, freedom from aortic- related intervention, and freedom from post operative type I or type III endoleak. RESULTS: During this study period, a total of 54 patients underwent TEVAR for thoracic or thoracoabdominal aneurysm with the use of EndoAnchors at our institution. Twenty-seven cases were performed as the index operation. Twenty-seven cases were considered redo operations. EndoAnchors were deployed for therapeutic and prophylactic indications. Mean follow-up was 9.6+/-8.8 months. EndoAnchors were used for therapeutic indications in 31.5% of patients and for prophylactic indications in 68.5%. The technical success of EndoAnchor deployment was 99.8%. The overall initial technical success of the operation was 98.1%. There were no instances of graft migration. The overall endoleak rate was 5.4% with prophylactic EndoAnchor use and 11.8% with therapeutic use. Aortic-related reintervention was required in 13.5% of patients who received prophylactic EndoAnchor placement and 23.5% of patients who received therapeutic EndoAnchor placement. Only one reintervention was performed for EndoAnchor failure. A p value of <0.05 was considered significant. CONCLUSIONS: EndoAnchors can be safely utilized in TEVAR with high rates of technical success. These results demonstrate the potential to enhance thoracic endograft efficacy and durability with the use of therapeutic and prophylactic EndoAnchors. Long term data is needed to further define the use of this technology in the thoracic aorta. PMID- 27465393 TI - Does design matter? Cervical disc replacements under review. AB - The present article reviews the design rationale of currently available cervical disc replacements. Recent prospective randomized control trials comparing cervical disc replacement and anterior fusion have demonstrated safety as well as equal or superior clinical results. Increasingly, more devices are becoming available on the market. Understanding design rationale will provide context for the surgeon to optimize decision making for the most appropriate prosthesis. Cervical arthroplasty is a technique that is undergoing rapid design refinement and development. Further improvements in device design will enable patient specific device selection. Understanding the design rationale and complication profile of each device will improve clinical and radiographic outcomes. PMID- 27465394 TI - Optical coherence tomography impacts the evaluation of visual pathway tumors. AB - The objective of this systematic literature review is to assess the role of retinal optical coherence tomography (OCT) in the evaluation of patients with tumors of the visual pathway. We performed a PubMed database search according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses. The search was restricted to articles published in English between 2000 and 2016, with at least 10 human adult participants enrolled. Twenty-seven articles met the eligibility criteria. All studies investigated tumors of the anterior visual pathway. Both time-domain and spectral-domain OCT technologies were used and the role of OCT as diagnostic and/or prognostic tool was studied. Retinal OCT provides structural information about ganglion cell axon integrity and is complementary to visual function examination. OCT is a prognostic factor for post-operative visual outcome. PMID- 27465395 TI - Choices enhance punching performance of competitive kickboxers. AB - While self-controlled practice has been shown to enhance motor learning with various populations and novel tasks, it remains unclear if such effects would be found with athletes completing familiar tasks. Study 1 used a single case-study design with a world-champion kickboxer. We investigated whether giving the athlete a choice over the order of punches would affect punching velocity and impact force. Separated by 1 min of rest, the athlete completed 2 rounds of 12 single, maximal effort punches (lead straight, rear straight, lead hook and rear hook) delivered to a punching integrator in a counterbalanced order over six testing days. In one round the punches were delivered in a predetermined order while in the second round the order was self-selected by the athlete. In the choice condition, the world champion punched with greater velocities (6-11 %) and impact forces (5-10 %). In Study 2, the same testing procedures were repeated with 13 amateur male kickboxers over 2 testing days. Similar to Study 1, the athletes punched with significantly greater velocities (6 %, p < 0.05) and normalised impact forces (2 %, p < 0.05) in the choice condition. These findings complement research on autonomy support in motor learning by demonstrating immediate advantages in force production and velocity with experienced athletes. PMID- 27465396 TI - Neurotoxicity of Ammonia. AB - Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected. Experiments with a number of pertinent animal models have revealed several potential mechanisms which could underlie the pathological phenomena occurring in hepatic encephalopathy. PMID- 27465397 TI - MARK2 Rescues Nogo-66-Induced Inhibition of Neurite Outgrowth via Regulating Microtubule-Associated Proteins in Neurons In Vitro. AB - The ability of neurons in the adult mammalian central nervous system (CNS) to regenerate after injury is limited by inhibitors in CNS myelin. Nogo-66 is the most important myelin inhibitor but the mechanisms of Nogo-66 inhibition of neurite outgrowth remain poorly understood. Particularly, the relationship between Nogo-66 and microtubule-affinity regulating kinase 2 (MARK2) has not been examined. This study investigated the role of MARK2 in Nogo-66 inhibition and the function of MARK2 in neurite elongation in neurons in vitro. MARK2 and phosphorylated MARK2 at Ser212 (p-Ser212) alterations in Neuro 2a cells were assessed at different Nogo-66 exposure times; the relationships between MARK2 and microtubule-associated proteins (MAPs) were determined via the overexpression or interference of MARK2. Our study reports that Nogo-66 inhibited the expression of total MARK2 but also reduced Ser212 phosphorylation of MARK2, whereas levels of MAP1-b and tau varied depending on MARK2 overexpression or reduced expression. Furthermore, MARK2 increased the proportion of tyrosinated alpha-tubulin, thereby disrupting the stability of tubulin, most likely affecting axonal growth. In line with these results, overexpression of MARK2 promoted neurite elongation and therefore is able to rescue the inhibitory effect of Nogo-66 on neurite growth. In conclusion, the intracellular PKB/MARK2/MAPs/alpha-tubulin pathway appears to be essential for neurite elongation in neurons in vitro. These results suggest a critical role for MARK2 in overcoming Nogo-66-induced inhibition of axon outgrowth in neurons. Pharmacological activators of MARK2 may be applicable to promote successful axonal outgrowth following many types of CNS injuries. PMID- 27465398 TI - Physical activity, mental health, and weight gain in a longitudinal observational cohort of nonobese young adults. AB - OBJECTIVE: To investigate the relationship among moderate-to-vigorous physical activity (MVPA), mental health symptoms, and weight gain in young adults. METHODS: Fifty-nine healthy men and women (age 26.8 +/- 4.7 years, body mass index [BMI] 22.4 +/- 2.3 kg/m(2) ) were assessed at baseline and year 2. Weight, BMI, fat mass by dual-energy X-ray absorptiometry, anxiety and depression by the SCL-90, and MVPA by accelerometry were assessed. Sex-stratified linear regression models were used to examine associations between baseline anxiety/depression and body composition change, then repeated controlling for baseline MVPA. RESULTS: Overall, weight, BMI, fat mass, and subcutaneous adiposity significantly increased at year 2 (P < 0.05). For women, a higher depression and anxiety score predicted increased weight, BMI, fat mass, and subcutaneous adiposity (P < 0.05). Controlling for MVPA attenuated these associations to nonsignificance. For men, MVPA did not alter the associations between anxiety and increased weight, BMI, fat mass, and subcutaneous adiposity (P < 0.05) or the associations between depression and decreased weight, BMI, fat mass, and subcutaneous adiposity (P < 0.05). CONCLUSIONS: Anxiety and depression were related to body composition change for young adults. In women, MVPA attenuated these associations to nonsignificance. MVPA may buffer the adverse effects of depression and anxiety symptoms on young women's weight gain. PMID- 27465399 TI - Short telomere length and its correlation with gene mutations in myelodysplastic syndrome. AB - BACKGROUND: Telomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. Thus, we aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS. METHODS: We measured the TL of bone marrow nucleated cells for diagnostic samples at a single-cell level by quantitative fluorescence in situ hybridization (Q-FISH) for 58 MDS patients and analyzed the minimum, median, average, standard deviation, average of the 0th to 10th percentile TL within a patient, and the proportion of cells with TL that is shorter than the lowest 10th percentile of the normal control (NC). The correlations of TL to clinical parameters, cytogenetic results, and genetic mutations were assessed. RESULTS: MDS patients showed eroded telomeres and narrow distribution compared to the NC (P < 0.001, P = 0.018, respectively). Patients with mutation showed significantly lesser cells with short TL, below the lowest 10th percentile of the NC (P = 0.017), but no differences in TL were found according to mutations/cytogenetic abnormalities except for CSF3R mutation. However, those patients with a high percentage (>=80 %) of cells with short TL showed poorer overall survival (P = 0.021), and this was an independent prognostic factor, along with TP53, U2AF1 mutation, and high BM blast count (P = 0.044, 0.001, 0.004, 0.012, respectively). CONCLUSIONS: The shortest TL, which determines the fate of the cell, was significantly shorter, and higher burden of cells with short TL were found in MDS, which correlated with poor survival, suggesting the need to measure TL in single cells by Q-FISH. PMID- 27465400 TI - Migration Suppression of Small Cell Lung Cancer by Polysaccharides from Nostoc commune Vaucher. AB - Nostoc commune Vauch., classified into cyanobacteria, has been always well appreciated as a healthy food and medicine worldwide owing to its rich nutrition and potent bioactivities. Nevertheless, the inhibitory effect of polysaccharides from N. commune Vauch. (NVPS) against cancer cell progression and metastasis is still being unraveled. The results in this study showed that NVPS remarkably suppressed cell migration through blocking the epithelial-mesenchymal transition program in NCI-H446 and NCI-H1688 human small cell lung cancer cells. The inhibitory effects were attributed to the suppression of integrin beta1/FAK signaling through regulating cell-matrix adhesion. Furthermore, NVPS treatment could increase E-cadherin expression, but down-regulate N-cadherin, Vimentin, and MMP-9 expression, which resulted in the blockage of STAT3 nuclear translocation and JAK1 signaling. These findings suggest that NVPS may be a good candidate for development as a possible antitumor agent against small cell lung cancer. PMID- 27465401 TI - Constraints on phase stability, defect energies, and elastic constants of metals described by EAM-type potentials. AB - We demonstrate that the embedded-atom method and related potentials predict many dimensionless properties of simple metals to depend predominantly on a single coefficient MU, which typically lies between 0.3 and 0.45. Among other relations presented in this work, we find that [Formula: see text], [Formula: see text], and [Formula: see text] hold within 25% accuracy and also find a linear dependence of the melting temperature on MU. The used variables are cohesive energy E c, coordination number Z, vacancy energy E v, and bulk modulus B, while G is the average of ordinary and tetragonal shear modulus. We provide analytical arguments for these findings, which are obeyed reasonably well by several metals. PMID- 27465402 TI - Assessing gelling properties of chia (Salvia hispanica L.) flour through rheological characterization. AB - BACKGROUND: Chia (Salvia hispanica L.) seeds are considered a promising ingredient for the development of functional products owing to their high nutritional value: 343 g kg-1 lipids, 251 g kg-1 protein and 226 g kg-1 fibre. Considering chia's technological capacities, mainly the ability to swell when absorbing water and gel-forming properties, its addition to a food matrix can affect texture and rheological behaviour, acting as a texturing and stabilizing agent. The aim of the present work was to assess the gelling properties of chia flour through the rheological characterization of 100, 130 and 150 g kg-1 chia flour gels. RESULTS: According to the mechanical spectra, all gels presented weak gel-like structures, as G' was always less than a decade higher than G", but higher chia flour concentrations showed a considerable increase in viscoelastic moduli. The gels had relatively low maturation times, almost instantaneous for lower concentrations, but the cooling rate affected the dynamics of formation of the gel structure. CONCLUSION: Based on texture and rheological properties, gels with 130 g kg-1 of chia flour processed at 90 degrees C for 30 min showed the most suitable characteristics for use in the development of new food applications. (c) 2016 Society of Chemical Industry. PMID- 27465403 TI - Hospice Family Caregiver Involvement in Care Plan Meetings: A Mixed-Methods Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVE: Untrained family caregivers struggle with complicated medical management regimens for hospice patients. An intervention was tested to improve caregiver's perception of pain management and patient's pain. DESIGN, SETTING, AND PARTICIPANTS: The intervention was tested with a 2-group (usual care vs intervention) randomized controlled trial using parallel mixed-methods analysis of 446 caregivers in 3 Midwestern hospice programs representing rural and urban settings. INTERVENTION: Web conferencing or telephones were used to connect caregivers with the hospice care team during care plan meetings. MEASUREMENTS: Caregiver's perceptions of pain management were the primary outcome. Secondary outcomes included caregiver quality of life, patient's pain, and anxiety. Video recordings, field notes, and caregiver and staff interviews provided qualitative data. RESULTS: The overall perception of pain management was not changed by the participation in hospice team meetings. Perceptions of fatalism improved for intervention participants, and the intervention participants perceived their patients' pain was better controlled than those in the control group. The intervention was found to be feasible to deliver in rural areas. Caregiver's anxiety and patient's pain were correlated ( r = .18; P = .003), and subanalysis indicated that caregivers of patients with cancer may benefit more from the intervention than other hospice caregivers. Qualitative analyses provided understanding of caregiver's perceptions of pain, cost, and facilitators and barriers to routine involvement of family in care plan meetings. Limitations and Conclusion: The hospice philosophy is supportive of caregiver involvement in care planning, and technology makes this feasible; the intervention needs modification to become translational as well as additional measurement to assess effectiveness. Caregiver education and emotional support should occur outside the meeting, and a strong leader should facilitate the meeting to control efficiency. Finally, the intervention may benefit caregivers of patients with cancer more than others. PMID- 27465404 TI - Physician Burnout and the Calling to Care for the Dying: A National Survey. AB - BACKGROUND: Physician burnout raises concerns over what sustains physicians' career motivations. We assess whether physicians in end-of-life specialties had higher rates of burnout and/or calling to care for the dying. We also examined whether the patient centeredness of the clinical environment was associated with burnout. METHODS: In 2010 to 2011, we conducted a national survey of US physicians from multiple specialties. Primary outcomes were a validated single item measure of burnout or sense of calling to end-of-life care. Primary predictors of burnout (or calling) included clinical specialty, frequency of encounters with dying patients, and patient centeredness of the clinical environments ("My clinical environment prioritizes the need of the patient over maximizing revenue"). RESULTS: Adjusted response rate among eligible respondents was 62% (1156 of 1878). Nearly a quarter of physicians (23%) experienced burnout, and rates were similar across all specialties. Half of the responding physicians (52%) agreed that they felt called to take care of patients who are dying. Burned out physicians were more likely to report working in profit-centered clinical environments (multivariate odds ratio [OR] of 1.9; confidence interval [CI]: 1.3 2.8) or experiencing emotional exhaustion when caring for the dying (multivariate OR of 2.1; CI: 1.4-3.0). Physicians who identified their work as a calling were more likely to work in end-of-life specialties, to feel emotionally energized when caring for the dying, and to be religious. CONCLUSION: Physicians from end of-life specialties not only did not have increased rates of burnout but they were also more likely to report a sense of calling in caring for the dying. PMID- 27465405 TI - Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells. AB - BACKGROUND: Acquired radioresistance during radiotherapy is considered as the most important reason for local tumor recurrence or treatment failure. Circular RNAs (circRNAs) have recently been identified as microRNA sponges and involve in various biological processes. The purpose of this study is to investigate the role of circRNAs in the radioresistance of esophageal cancer. METHODS: Total RNA was isolated from human parental cell line KYSE-150 and self-established radioresistant esophageal cancer cell line KYSE-150R, and hybridized to Arraystar Human circRNA Array. Quantitative real-time PCR was used to confirm the circRNA expression profiles obtained from the microarray data. Bioinformatic tools including gene ontology (GO) analysis, KEGG pathway analysis and network analysis were done for further assessment. RESULTS: Among the detected candidate 3752 circRNA genes, significant upregulation of 57 circRNAs and downregulation of 17 circRNAs in human radioresistant esophageal cancer cell line KYSE-150R were observed compared with the parental cell line KYSE-150 (fold change >=2.0 and P < 0.05). There were 9 out of these candidate circRNAs were validated by real-time PCR. GO analysis revealed that numerous target genes, including most microRNAs were involved in the biological processes. There were more than 400 target genes enrichment on Wnt signaling pathway. CircRNA_001059 and circRNA_000167 were the two largest nodes in circRNA/microRNA co-expression network. CONCLUSIONS: Our study revealed a comprehensive expression and functional profile of differentially expressed circRNAs in radioresistant esophageal cancer cells, indicating possible involvement of these dysregulated circRNAs in the development of radiation resistance. PMID- 27465406 TI - Functional and structural assessment of patients with and without persistent pain after thoracotomy. AB - BACKGROUND: Persistent pain is frequent after thoracotomy, with a reported prevalence of up to 60%. It remains unclear why some patients develop pain, whereas others do not. We therefore examined patients with and without pain after thoracotomy to identify pathophysiological contributors to persistent pain. METHODS: Twenty patients with persistent pain, 12 patients without pain and 20 healthy controls underwent detailed functional and structural assessment including psychometric and neuropathic pain questionnaires, bedside examination for pinprick hyperalgesia and brush allodynia, quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain, measurement of capsaicin-evoked flare response, intradermal nerve density as determined by skin biopsies and laser- and heat-evoked potentials. RESULTS: Bedside testing revealed evoked pain in 16 of 20 patients with pain, but only in 2 of 12 patients without pain (p < 0.001). Quantitative sensory testing showed increased mechanical pain sensitivity (p = 0.018) on the operated side in patients with pain, but there were no differences between the two patient groups with regard to intradermal nerve fibre density, area and flux following capsaicin application and laser- and heat-evoked potentials. CONCLUSION: Different and individual pathophysiological mechanisms of pain may obscure the clinical picture and thus preclude identification of a specific pain profile in patients with persistent post-thoracotomy pain. SIGNIFICANCE: Evoked pain is more frequent in patients with pain. Assessment of intradermal nerve density, capsaicin-induced flare response and contact and laser heat-evoked potentials revealed no differences between pain patients and pain-free patients. PMID- 27465407 TI - Local biodiversity is higher inside than outside terrestrial protected areas worldwide. AB - Protected areas are widely considered essential for biodiversity conservation. However, few global studies have demonstrated that protection benefits a broad range of species. Here, using a new global biodiversity database with unprecedented geographic and taxonomic coverage, we compare four biodiversity measures at sites sampled in multiple land uses inside and outside protected areas. Globally, species richness is 10.6% higher and abundance 14.5% higher in samples taken inside protected areas compared with samples taken outside, but neither rarefaction-based richness nor endemicity differ significantly. Importantly, we show that the positive effects of protection are mostly attributable to differences in land use between protected and unprotected sites. Nonetheless, even within some human-dominated land uses, species richness and abundance are higher in protected sites. Our results reinforce the global importance of protected areas but suggest that protection does not consistently benefit species with small ranges or increase the variety of ecological niches. PMID- 27465408 TI - Passing of Dr. Irving I. Gottesman. PMID- 27465409 TI - Diagnostic accuracy of surgeons and trainees in assessment of patients with acute abdominal pain. AB - BACKGROUND: Diagnostic accuracy in the assessment of patients with acute abdominal pain in the emergency ward is not adequate. It has been argued that this is because the investigations are carried out predominantly by a trainee. Resource utilization could be lowered if surgeons had a higher initial diagnostic accuracy. METHODS: Patients with acute abdominal pain were included in a prospective cohort study. A surgical trainee and a surgeon made independent assessments in the emergency department, recording the clinical diagnosis and proposed diagnostic investigations. A reference standard diagnosis was established by an expert panel, and the proportion of correct diagnoses was calculated. Diagnostic accuracy was expressed in terms of sensitivity, specificity, positive predictive value and negative predictive value. Interobserver agreement for the diagnosis and elements of history-taking and physical examination were expressed by means of Cohen's kappa. Certainty of diagnosis was recorded using a visual analogue scale. RESULTS: A trainee and a surgeon independently assessed 126 patients. Trainees made a correct diagnosis in 44.4 per cent of patients and surgeons in 42.9 per cent (P = 0.839). Surgeons, however, recorded a higher level of diagnostic certainty. Diagnostic accuracy was comparable in distinguishing urgent from non-urgent diagnoses, and for the most common diseases. Interobserver agreement for the clinical diagnosis varied from fair to moderate (kappa = 0.28-0.57). CONCLUSION: The diagnostic accuracy of the initial clinical assessment is not improved when a surgeon rather than a surgical trainee assesses a patient with abdominal pain in the emergency department. PMID- 27465410 TI - Association between major depression and cardiovascular risk: the role of antidepressant medication. AB - RATIONALE AND OBJECTIVES: Major depressive disorder (MDD) is associated with an increased risk for cardiovascular disease (CVD). Apart from biological and life style factors, the use of antidepressants and their potentially adverse effects might contribute to the increased CVD risk. Therefore, we compared cardiovascular risk profiles between relatively young depressed patients without CVD with and without antidepressant medication and healthy participants. METHODS: We investigated 44 depressed patients (with antidepressants N = 20 (13 women), mean age 43.2 years; without antidepressants N = 24 (15 women), mean age 40.0) and 41 healthy participants (matched for sex, age, education). As markers of CVD risk, blood pressure, body mass index (BMI), and plasma levels of fasting glucose, cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and high sensitivity C-reactive protein (h-CRP) were measured. RESULTS: We found significant differences between groups for BMI (p < .01), systolic (p = .02) and diastolic blood pressure (p < .01), and glucose (p < .001). Post hoc analyses indicated differences between both patient groups compared to the healthy control group, but not between patients groups. Further controlling for BMI diminished the effect of diagnosis on blood pressure; however, this was not the case for glucose level. There were no between-group differences in cholesterol, LDL, HDL, and h-CRP. CONCLUSIONS: We found a clearly increased CVD risk in this group of rather young depressed patients. Importantly, there was no significant difference in CVD risk between patients with vs. without antidepressants. This suggests that major depression per se and not antidepressant medication is associated with increased CVD risk. PMID- 27465412 TI - The need for coordination of research activities in pediatric lung diseases. PMID- 27465411 TI - PAC down-regulates estrogen receptor alpha and suppresses epithelial-to mesenchymal transition in breast cancer cells. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Therefore, novel molecules and therapeutic options are urgently needed for this category of patients. Recently, we have identified PAC as a curcumin analogue with potent anti-cancer features. METHODS: HPLC was used to evaluate the stability of PAC and curcumin in PBS and also in circulating blood. Cytotoxicity/apoptosis was assessed in different breast cancer cell lines using propidium iodide/annexinV associated with flow cytometry. Furthermore, immunoblotting analysis determined the effects of PAC on different oncogenic proteins and pathways. Additionally, the real time xCELLigence RTCA technology was applied to investigate the effect of PAC on the cellular proliferation, migration and invasion capacities. RESULTS: PAC is more stable than curcumin in PBS and in circulating blood. Furthermore, we have shown differential sensitivity of estrogen receptor-alfa positive (ERalpha(+)) and estrogen receptor alfa negative (ERalpha(-)) breast cancer cells to PAC, which down-regulated ERalpha in both cell types. This led to complete disappearance of ERalpha in ERalpha(-) cells, which express very low level of this receptor. Interestingly, specific down-regulation of ERalpha in receptor positive cells increased the apoptotic response of these cells to PAC, confirming that ERalpha inhibits PAC-dependent induction of apoptosis, which could be mediated through ERalpha down-regulation. Additionally, PAC inhibited the proliferation and suppressed the epithelial-to-mesenchymal transition process in breast cancer cells, with higher efficiency on the TNBC subtype. This effect was also observed in vivo on tumor xenografts. Additionally, PAC suppressed the expression/secretion of 2 important cytokines IL-6 and MCP-1, and consequently inhibited the paracrine procarcinogenic effects of breast cancer cells on breast stromal fibroblasts. CONCLUSION: These results indicate that PAC could be considered as important candidate for future therapeutic options against the devastating TNBC subtype. PMID- 27465413 TI - Household food security and breast-feeding duration among Canadian Inuit. AB - OBJECTIVE: There have been few studies investigating the association between food security and breast-feeding duration and none have been conducted among Canadian Inuit, a population disproportionately burdened with food insecurity. We evaluated the association between household food security and breast-feeding duration in Canadian Inuit children. DESIGN: Data were obtained from the Nunavut Inuit Child Health Survey, a population-based cross-sectional survey. SETTING: The Canadian Territory of Nunavut in 2007 and 2008. SUBJECTS: Caregivers of Inuit children aged 3-5 years. Participating children were randomly sampled from community medical centre lists. RESULTS: Out of 215 children, 147 lived in food insecure households (68.4 %). Using restricted mean survival time models, we estimated that children in food-secure households were breast-fed for 16.8 (95 % CI 12.5, 21.2) months and children in food-insecure households were breast-fed for 21.4 (95 % CI 17.9, 24.8) months. In models adjusting for social class, traditional knowledge and child health, household food security was not associated with breast-feeding duration (hazard ratio=0.82, 95 % CI 0.58, 1.14). CONCLUSIONS: Our research does not support the hypothesis that children living in food-insecure households were breast-fed for a longer duration than children living in food-secure households. However, we found that more than 50 % of mothers in food-insecure households continued breast-feeding well beyond 1 year. Many mothers in food-secure households also continued to breast-feed beyond 1 year. Given the high prevalence of food insecurity in Inuit communities, we need to ensure infants and their caregivers are being adequately nourished to support growth and breast-feeding, respectively. PMID- 27465414 TI - Rearing Generations: Lakota Grandparents' Commitment to Family and Community. AB - Disproportionately, American Indian grandparents assume the responsibility of raising their grandchildren. Few studies have examined the experiences of American Indian grandparents living on reservations. Utilizing Indigenous Methodologies and exploratory, in-depth interviews with 25 Lakota elders living on the reservation. This study explored the realities of raising grandchildren including: reasons they began caring for their grandchildren, challenges they face, and they reveal the care and concern for the broader community's grandchildren within the cultural and social context of the reservation. PMID- 27465415 TI - Health research needs more comprehensive accessibility measures: integrating time and transport modes from open data. AB - BACKGROUND: In this paper, we demonstrate why and how both temporality and multimodality should be integrated in health related studies that include accessibility perspective, in this case healthy food accessibility. We provide evidence regarding the importance of using multimodal spatio-temporal accessibility measures when conducting research in urban contexts and propose a methodological approach for integrating different travel modes and temporality to spatial accessibility analyses. We use the Helsinki metropolitan area (Finland) as our case study region to demonstrate the effects of temporality and modality on the results. METHODS: Spatial analyses were carried out on 250 m statistical grid squares. We measured travel times between the home location of inhabitants and open grocery stores providing healthy food at 5 p.m., 10 p.m., and 1 a.m. using public transportation and private cars. We applied the so-called door-to door approach for the travel time measurements to obtain more realistic and comparable results between travel modes. The analyses are based on open access data and publicly available open-source tools, thus similar analyses can be conducted in urban regions worldwide. RESULTS: Our results show that both time and mode of transport have a prominent impact on the outcome of the analyses; thus, understanding the realities of accessibility in a city may be very different according to the setting of the analysis used. In terms of travel time, there is clear variation in the results at different times of the day. In terms of travel mode, our results show that when analyzed in a comparable manner, public transport can be an even faster mode than a private car to access healthy food, especially in central areas of the city where the service network is dense and public transportation system is effective. CONCLUSIONS: This study demonstrates that time and transport modes are essential components when modeling health-related accessibility in urban environments. Neglecting them from spatial analyses may lead to overly simplified or even erroneous images of the realities of accessibility. Hence, there is a risk that health related planning and decisions based on simplistic accessibility measures might cause unwanted outcomes in terms of inequality among different groups of people. PMID- 27465416 TI - Two new methods to fit models for network meta-analysis with random inconsistency effects. AB - BACKGROUND: Meta-analysis is a valuable tool for combining evidence from multiple studies. Network meta-analysis is becoming more widely used as a means to compare multiple treatments in the same analysis. However, a network meta-analysis may exhibit inconsistency, whereby the treatment effect estimates do not agree across all trial designs, even after taking between-study heterogeneity into account. We propose two new estimation methods for network meta-analysis models with random inconsistency effects. METHODS: The model we consider is an extension of the conventional random-effects model for meta-analysis to the network meta-analysis setting and allows for potential inconsistency using random inconsistency effects. Our first new estimation method uses a Bayesian framework with empirically-based prior distributions for both the heterogeneity and the inconsistency variances. We fit the model using importance sampling and thereby avoid some of the difficulties that might be associated with using Markov Chain Monte Carlo (MCMC). However, we confirm the accuracy of our importance sampling method by comparing the results to those obtained using MCMC as the gold standard. The second new estimation method we describe uses a likelihood-based approach, implemented in the metafor package, which can be used to obtain (restricted) maximum-likelihood estimates of the model parameters and profile likelihood confidence intervals of the variance components. RESULTS: We illustrate the application of the methods using two contrasting examples. The first uses all-cause mortality as an outcome, and shows little evidence of between-study heterogeneity or inconsistency. The second uses "ear discharge" as an outcome, and exhibits substantial between-study heterogeneity and inconsistency. Both new estimation methods give results similar to those obtained using MCMC. CONCLUSIONS: The extent of heterogeneity and inconsistency should be assessed and reported in any network meta-analysis. Our two new methods can be used to fit models for network meta-analysis with random inconsistency effects. They are easily implemented using the accompanying R code in the Additional file 1. Using these estimation methods, the extent of inconsistency can be assessed and reported. PMID- 27465417 TI - Five-Year Institutional Bibliometric Profiles for 119 North American Neurosurgical Residency Programs: An Update. AB - BACKGROUND: We recently performed a comprehensive bibliometric analysis of 103 U.S. neurosurgical departments and found the ih(5)-index as meaningful and reproducible using public data. The present report expands this analysis by adding 14 Canadian and 2 additional U.S. programs. METHODS: Departments were included if listed in the American Association of Neurological Surgeons Residency Directory. Each institution was considered a single entity, and original research articles with authors who were neurosurgeon faculty were counted only once per institution, although a single article may have been credited toward multiple institutions, if applicable. The following bibliometric indices were calculated and used to rank departments: ih(5), ig(5), ie(5), and i10(5). In addition, intradepartmental comparison of productivity among faculty members was analyzed by computing Gini coefficients for publications and citations. RESULTS: The top 5 most academically productive North American neurosurgical programs based on ih(5) index were found to be the University of Toronto, University of California at San Francisco, University of California at Los Angeles, University of Pittsburgh, and Brigham and Women's Hospital. The top 5 Canadian programs were the University of Toronto, University of Calgary, McGill University, University of Sherbrooke, and University of British Columbia. The median ih(5)-index for U.S. and Canadian programs was 12 and 10.5, respectively. CONCLUSIONS: This is the most accurate comprehensive analysis to date of contemporary bibliometrics among North American neurosurgery departments. Using the ih(5)-index for institutional ranking allows for informative comparison of recent scholarly efforts. PMID- 27465418 TI - Surgical Treatment of Occipitocervical Dislocation with Atlas Assimilation and Klippel-Feil Syndrome Using Occipitalized C1 Lateral Mass and C2 Fixation and Reduction Technique. AB - OBJECTIVE: To introduce and assess a surgical treatment of occipitocervical (OC) dislocation with atlas assimilation and Klippel-Feil syndrome (KFS) using occipitalized C1 lateral mass and C2 fixation and reduction technique. METHODS: From January 2007 to August 2013, 58 symptomatic patients with OC dislocation and KFS of C2-3 congenital fusion and atlas assimilation were surgically treated in our institution via this technique. After opening the C1-2 facet joints via a posterior approach, OC reduction was conducted by intraoperative manipulation and C1 lateral mass and C2 pedicle screw and rod fixation. The instrument position, fusion status, and clinical outcome were analyzed. RESULTS: The average follow-up was 36 months (range, 18-52 months). Radiologically, effective reduction was achieved in 56 patients (96.6%) and <50% reduction in 2 (3.4%) who had additional transoral decompression. Neurologic improvement and solid bone fusion were achieved in all patients. The clinical symptoms improved for all patients, with the averaged Japanese Orthopedic Association myelopathy scores increasing from 11.5 to 15.6 (P < 0.01). CONCLUSIONS: In patients with OC dislocation and KFS of C2-3 fusion and atlas assimilation, posterior manipulative reduction combined with occipitalized C1 lateral mass and C2 fixation provides a reliable and effective treatment. PMID- 27465419 TI - Head Injury in the Elderly: What Are the Outcomes of Neurosurgical Care? AB - BACKGROUND: Epidemiologic studies show that an increasing proportion of those presenting with head trauma are elderly. This study details the outcomes of elderly patients with head trauma admitted to a regional United Kingdom neurosurgical unit. METHODS: The notes and imaging were reviewed of all patients with head injury aged >=75 years, admitted from 1 January 2007 to 31 December 2010, including mortality data up to at least 2 years after discharge. Outcomes comprised death as an inpatient, by 30 days and 1 year after discharge; Glasgow Outcome Score; discharge Glasgow Coma Scale (GCS) score; recurrence; readmission; reoperation; and complication. RESULTS: A total of 263 patients were admitted: 26 with acute subdural hematoma (ASDH); 175 with chronic subdural hematoma (CSDH); and 46 with mixed subdural collections (ACSDH). Sixteen patients had other head injury diagnoses. Patients with ASDH had a significantly lower survival rate than did those with CSDH or ACSDH: the odds of inpatient death for patients with ASDH was 15.38 (vs. those with CSDH). For all subdural hematomas (SDHs), low American Society of Anesthesiologists score was an independent predictor of early death. Death at 1 year was predicted by head injury severity measured by admission GCS score (P = 0.028), long anesthetic (P = 0.002), and the presence of bilateral SDH (P = 0.002). Unfavorable Glasgow Outcome Scale score (1-3) was predicted by age greater than 85 years (P = 0.029); larger depth of subdural (P < 0.001); and presence of any complication (P = 0.003). Those aged greater than 90 years with presentation GCS score lower than 10 all had poor outcomes. CONCLUSIONS: Most elderly patients admitted under neurosurgery after head injury have SDHs. Our results are better than many previously reported; however, the rate of death for those with ASDH is still high. PMID- 27465420 TI - Intracranial Inflammatory Myofibroblastic Tumor with Sarcomatous Local Recurrence. AB - CASE DESCRIPTION: A 20-year-old woman presented with a rare intracranial inflammatory myofibroblastic tumor (IMT) manifesting as headache and insomnia. Magnetic resonance imaging showed a tumorous lesion with heterogeneous enhancement at the right temporal lobe, as well as perifocal edema with midline shift. The tumor was totally resected with the margin free. Pathologic examination showed IMT with myofibroblastic cells admixed with collagen fibers. Sarcomatous change in morphology was observed in tumor recurrence within 7 months. CONCLUSIONS: Surgical resection and whole brain radiation are recommended in patients with IMT. PMID- 27465421 TI - Rare Primary Pleomorphic Adenoma in Posterior Fossa. AB - BACKGROUND: Pleomorphic adenoma is a benign neoplastic tumor of the salivary gland. Salivary gland tumors in the intracranial cavity are generally restricted to the pituitary gland and sellar region. To our knowledge, there has been only 1 previous case report of a primary central nervous system pleomorphic adenoma outside of the sellar region. In that case report of a posterior fossa pleomorphic adenoma, typical myxochondroid stroma was not identified on histology, and its pathogenesis was not explored. CASE DESCRIPTION: A 71-year-old woman presented with a 6-week history of occipital headache and unsteadiness. Contrast-enhanced computed tomography and magnetic resonance imaging studies revealed a solitary large posterior fossa tumor in the left cerebellopontine angle measuring 47 * 43 * 45 mm. The tumor resulted in moderate hydrocephalus and significant mass effect with compression of the pons and medulla. She underwent a stereotactic right ventriculoperitoneal shunt insertion followed by a stereotactic craniotomy and complete excision of the tumor. The operation went uneventfully, and the patient had an uncomplicated recovery. Histopathologic examination revealed a benign pleomorphic adenoma (benign salivary gland tumor) with a classic appearance comprising an admixture of ductal epithelial cells, myoepithelial elements, and nodules of myxochondroid stroma. No extracranial source has been identified despite extensive investigation and 8 years of follow up. CONCLUSIONS: This case study illustrates a classic primary central nervous system pleomorphic adenoma in an unusual intracranial site. Its pathogenesis is postulated to involve salivary gland heterotopia. PMID- 27465423 TI - Therapeutic potential of Benincasa cerifera: A review. AB - Benincasa cerifera (Savi.), belonging to Cucurbitaceae, is an annual creepy wine that posses highm edicinal value and istraditionally used as fruit and medicine throughout India. In Indian system of medicine, its fruit is used as nutritive, tonic, diuretic, aphrodisiac, styptic, vermifuge and in various diseases and disorders like asthma, bronchitis, insanity, epilepsy, dry cough, fever, urethrorrhea, syphilis, hyperdipsia and vitiated conditions of pitta, etc. Phytochemically the plant is found to contain lupeol, beta-sitosterol, cucurbitacin B, iso-vitexin, etc. It has been demonstrated to posses numerous pharmacological activities such as antiepileptic, hepatoprotective, antioxidant, analgesic, immunopotentiator and anxiolytic, etc. In the present review there is a detailed description of its botany, phytochemistry, ethno-botany and pharmacological activities. PMID- 27465422 TI - Acute Traumatic Subdural Hematoma: Surgical Management in the Presence of Cerebral Herniation-A Single-Center Series and Multivariate Analysis. AB - BACKGROUND: Traumatic acute subdural hematoma (aSDH) is a severe disease. Surgical treatment is still controversially discussed, especially in patients with additional signs of cerebral herniation. However, previously investigated patient populations were heterogeneous. We therefore performed an analysis of our institutional data in a large homogenous selection of patients with traumatic aSDH to analyze factors determining clinical outcome. METHODS: Between 2010 and 2014, 196 patients with aSDH underwent surgical treatment in our department. Information including patient characteristics, treatment modality, radiologic features, and functional outcome were analyzed. Outcome was assessed according to the Glasgow Outcome Scale (GOS) at 6 months and was dichotomized into favorable (GOS score, 1-3) and unfavorable (GOS score 4-5) outcome. Furthermore, a multivariate analysis was performed to identify independent predictors of functional outcome. RESULTS: Overall, 26% of patients with aSDH achieved favorable outcome. In further analysis, unilateral or bilateral dilated pupils as a sign of cerebral herniation were present in 47% of the included patients. In the multivariate analysis, age >70 years and the presence of cerebral herniation were significant prognostic predictors for unfavorable outcome in patients with aSDH. However, 15% of patients with aSDH and signs of cerebral herniation achieved favorable outcome during follow-up. CONCLUSIONS: We provide detailed data on patients with aSDH and signs of cerebral herniation. Despite mydriasis, favorable outcome may be achieved in many patients. Nevertheless, careful individual decision making is necessary for each patient, especially when signs of cerebral herniation have persisted for a long time. PMID- 27465425 TI - Hematopoietic effect of fermented deer antler extract in iron deficient diet induced anemic rats. AB - OBJECTIVE: To assess the hematopoietic effects of fermented deer antler extract using a dietinduced anemic animal model to facilitate the utilization of fermented deer antler extract and its derived products. METHODS: Thirty 3-week old female Sprague-Dawley rats were treated for 5 weeks. The rats were randomly divided into 6 groups and treated as follows: control, saline; NFA200, non fermented deer antler extract 200 mg/kg; NFA500, non-fermented deer antler extract 500 mg/kg; FAB200, fermented deer antler extract 200 mg/kg; FAB500, fermented deer antler extract 500 mg/kg; and PC, heme iron 0.2 mg/kg. Blood parameters, iron content in the liver and spleen, hepatic delta-aminolevulinic acid dehydrogenase (ALAD) activity and divalent metal transporter 1 (DMT1) mRNA expression were analyzed. RESULTS: No detectable significant differences were observed in blood parameters among groups. The decrease in the hepatic ALAD activity in anemic rats was significantly improved by fermented deer antler extract supplementation (P<0.05); however, non-fermented deer antler extract supplementation did not result in a significant improvement (P>0.05). The hepatic DMT1 mRNA expression level was increased significantly by supplementation with both the fermented deer antler extract and the non-fermented deer antler extract in a dose-dependent manner compared with nontreatment in anemic rats (P<0.05). CONCLUSION: The hematopoietic activity induced by deer antler extract in dietinduced anemic rats might be increased through the fermentation process. PMID- 27465424 TI - Pure total flavonoids from Citrus paradisi Macfad induce leukemia cell apoptosis in vitro. AB - OBJECTIVE: To investigate the potential effect of pure total flavonoids from Citrus paradisi Macfad peel (PTFC) on the proliferation of human myeloid leukemia cells Kasumi-1, HL-60 and K562, and the underlying mechanisms. METHODS: PTFC was extracted from Citrus paradisi Macfad peel and was identified by high performance liquid chromatography. The effect of PTFC on the proliferation and apoptosis of leukemia cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, fluorescent microscopy and flow cytometry, respectively. The effect of PTFC on the expression levels of apoptosis-related regulators was determined by Western blot assay. RESULTS: Treatment with PTFC inhibited leukemia cell proliferation in a dose- and time-dependent manner and triggered Kasumi-1 cell apoptosis. Treatment with PTFC significantly increased the levels of activated poly adenosine diphosphate-ribosepolymerase and caspase 3/-9, but reduced the levels of Mcl-1 expression in Kasumi-1 cells. However, PTFC did not obviously induce HL-60 cell apoptosis. CONCLUSION: PTFC inhibited leukemia cell proliferation and induced their apoptosis by modulating apoptosisrelated regulator expression in leukemia cells in vitro. PMID- 27465426 TI - Stereotactic Body Radiotherapy (SBRT) Is as Yet of Unproven Benefit for Patients With Lung Metastases. PMID- 27465427 TI - More Pitfalls Related to Next-generation Sequencing (NGS). PMID- 27465428 TI - Comment on "The Birth of the Illegitimate Linear No-threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure". PMID- 27465429 TI - Response to "The Birth of the Illegitimate Linear No-threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure". PMID- 27465430 TI - The foundress's dilemma: group selection for cooperation among queens of the harvester ant, Pogonomyrmex californicus. AB - The evolution of cooperation is a fundamental problem in biology, especially for non-relatives, where indirect fitness benefits cannot counter within-group inequalities. Multilevel selection models show how cooperation can evolve if it generates a group-level advantage, even when cooperators are disadvantaged within their group. This allows the possibility of group selection, but few examples have been described in nature. Here we show that group selection can explain the evolution of cooperative nest founding in the harvester ant Pogonomyrmex californicus. Through most of this species' range, colonies are founded by single queens, but in some populations nests are instead founded by cooperative groups of unrelated queens. In mixed groups of cooperative and single-founding queens, we found that aggressive individuals had a survival advantage within their nest, but foundress groups with such non-cooperators died out more often than those with only cooperative members. An agent-based model shows that the between-group advantage of the cooperative phenotype drives it to fixation, despite its within group disadvantage, but only when population density is high enough to make between-group competition intense. Field data show higher nest density in a population where cooperative founding is common, consistent with greater density driving the evolution of cooperative foundation through group selection. PMID- 27465431 TI - Energy transmission using recyclable quantum entanglement. AB - It is known that faster-than-light (FTL) transmission of energy could be achieved if the transmission were considered in the framework of non-relativistic classical mechanics. Here we show that FTL transmission of energy could also be achieved if the transmission were considered in the framework of non-relativistic quantum mechanics. In our transmission protocol a two-spin Heisenberg model is considered and the energy is transmitted by two successive local unitary operations on the initially entangled spins. Our protocol does not mean that FTL transmission can be achieved in reality when the theory of relativity is considered, but it shows that quantum entanglement can be used in a recyclable way in energy transmission. PMID- 27465432 TI - New N^C^N-coordinated Pd(ii) and Pt(ii) complexes of a tridentate N-heterocyclic carbene ligand featuring a 6-membered central ring: synthesis, structures and luminescence. AB - We describe Pd(ii) and Pt(ii) complexes of an N^C^N-coordinating pincer-like ligand featuring two lateral pyridine rings and a 6-membered carbene core. Their crystal structures display 1-dimensional chains with short pi-pi and M(ii)M(ii) interactions. Such interactions also impact on the photophysical properties, with the Pt(ii) complex being luminescent in the solid state at room temperature. PMID- 27465433 TI - Regional differences in interhemispheric structural fibers in healthy, term infants. AB - Using fiber tracking we investigated the early interhemispheric to cortical development by segmenting the corpus callosum (CC) in five substructures, genu, rostrum, body, isthmus, and splenium, and to examine gender differences in healthy, term neonates. Twenty neonates (11 boys aged 39 +/- 2 days, nine girls aged 39 +/- 1 days) were scanned in natural sleep with diffusion tensor imging and 35 gradient directions. Fiber tracking was performed using the FACT algorithm. The CC was segments in five substructures on midsagittal imaging. The fiber axial and radial diffusion were measured along with apparent diffusion coefficient and fractional anisotropy. Volume measures were performed for each of these substructures using high-resolution isotropic 3D T1-weighted images. Radial and mean diffusivity in all measured interhemispheric connections were significantly higher in male newborn infants than in female. Second, a gender dependent regional difference of the measured interhemispheric connections exists. There was no volume difference between boys and girls in any of the five studied sudsubstructures. In addition there was no association between macrostructural and microstructural differences either in boys or girls. The cytoarchitecture and the integrity of the interhemispheric fibers is more developed in female infants in all subdivisions of the CC, except for the isthmus. This might result from a larger axonal diameter, highly packed fibers, or more well-developed myelin sheath. (c) 2016 Wiley Periodicals, Inc. PMID- 27465435 TI - Virtual Screening of Small Drug-Like Compounds Stimulating the Enzymatic Activity of Kallikrein-Related Peptidase 3 (KLK3). AB - Kallikrein-related peptidase 3 (KLK3) is a prostatic serine protease shown to possess antiangiogenic properties which are exerted via its proteolytic activity. The antiangiogenic effect indicates that KLK3 may slow down the growth of prostate cancer; this makes it an interesting target for new therapies for prostate cancer. In this work, new drug-like compounds were discovered that stimulate the proteolytic activity of KLK3. The compounds were identified using 2D similarity search and 3D pharmacophore-based virtual screening, and their ability to stimulate KLK3 was verified by enzymatic activity assays. The effect of the molecules alone was modest, but in synergy with a cyclic peptide the most potent molecule was found to stimulate KLK3 activity significantly: up to 351 % of the activity of KLK3. This demonstrates that small drug-like compounds can be beneficial tools in studying the antiangiogenic properties of KLK3. PMID- 27465434 TI - Short-term moderate diet restriction in adulthood can reverse oxidative, cardiovascular and metabolic alterations induced by postnatal overfeeding in mice. AB - We aimed to determine whether moderate diet restriction could restore cardiac, oxidative and metabolic alterations induced by postnatal overfeeding (PNOF). Litters of C57BL/6 male mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) in order to induce PNOF. At 6 months, half of the NL and SL mice were subjected to 20% calorie-restriction (CR: NLCR, SLCR) for one month, while the other half continued to eat ad libitum (AL: NLAL, SLAL). Six month old SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance, increased cardiac ROS production and decreased left ventricular ejection fraction (LVEF). After CR, SL mice body weight was normalized; however, their fat mass and leptinemia were not decreased, glucose metabolism was improved and LVEF was increased. In SL mice, CR increased the cardiac mitochondrial respiratory rate and decreased cardiac ROS production. Hearts from SLCR mice showed better recovery and smaller postischemic infarct size. Intriguingly, no difference was observed between NLAL and NLCR mice for most of the parameters investigated. Short-term moderate CR not only normalized body weight in SL mice but also improved metabolic programming and reversed oxidative and cardiac dysfunction induced by PNOF. PMID- 27465436 TI - Selenomethionine reduces the deposition of beta-amyloid plaques by modulating beta-secretase and enhancing selenoenzymatic activity in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by the production of large amounts of beta-amyloid (Abeta) and the accumulation of extracellular senile plaques, which have been considered to be potential targets in the treatment of AD. Selenium (Se) is a nutritionally essential trace element with known antioxidant potential and Se status has been shown to decrease with age and has a close relationship with cognitive competence in AD. Selenomethionine (Se-Met), a major reserve form of Se in organisms, has been shown in our previous study to ameliorate the decline in cognitive function, increase oxidation resistance, and reduce tau hyperphosphorylation in a triple transgenic mouse model of AD. However, it has not been reported whether Se-Met has any effects on Abeta pathology in AD mice. To study the effect of Se-Met on Abeta pathology and the function of selenoproteins/selenoenzymes in 3* Tg-AD mice, 3* Tg-AD mice at 8 months of age were treated with Se-Met for 3 months. Se-Met led to significantly reduced production and deposition of Abeta, down-regulation of beta-secretase levels and enhanced activity of selenoenzymes as well as increased levels of Se in the hippocampus and cortex. Se-Met reduces amyloidogenic processing of amyloid precursor protein while modulating beta-secretase and selenoenzymatic activity in AD mice. These results indicate that Se-Met might exert its therapeutic effect through multiple pathways in AD. PMID- 27465437 TI - Bendable Electro-chemical Lactate Sensor Printed with Silver Nano-particles. AB - Here we report a flexible amperometric lactate biosensor using silver nanoparticle based conductive electrode. Mechanically bendable cross-serpentine shaped silver electrode is generated on flexible substrate for the mechanical durability such as bending. The biosensor is designed and fabricated by modifying silver electrode with lactate oxidase immobilized by bovine serum albumin. The in sensor pseudo Ag/AgCl reference electrode is fabricated by chloridization of silver electrode, which evinced its long-term potential stability against a standard commercial Ag/AgCl reference electrode. The amperometric response of the sensor shows linear dependence with lactate concentration of 1~25 mM/L. Anionic selectivity is achieved by using drop-casted Nafion coated on silver electrode against anionic interferences such as ascorbate. This non-invasive electrochemical lactate sensor also demonstrates excellent resiliency against mechanical deformation and temperature fluctuation which leads the possibility of using it on human epidermis for continuous measurement of lactate from sweat. Near field communication based wireless data transmission is demonstrated to reflect a practical approach of the sensor to measure lactate concentration portably using human perspiration. PMID- 27465438 TI - Size-dependent catalytic kinetics and dynamics of Pd nanocubes: a single-particle study. AB - Due to the well-known significant effect of the size on the catalytic activity of nanocatalysts, here we use single-molecule fluorescence microscopy to study the size-dependent catalytic kinetics and dynamics of individual Pd nanocubes. A series of size-dependent catalytic properties were revealed in both product formation and product desorption processes. It was found that, due to the different adsorption mechanisms of substrate molecules on Pd nanocubes, H2 adsorption is independent of the size of Pd nanocubes, while the large flat resazurin molecules show stronger adsorption on larger sized Pd nanocubes. Apparently, the Pd nanocubes can be divided into three types: when the size of the Pd nanocube is small, substrate binding can prohibit product desorption and product desorption prefers the direct pathway; when the size is in an appropriate range, the product desorption process could be independent of substrate binding and shows no selectivity between two parallel desorption pathways; if the size is large enough, substrate binding can promote product desorption and product desorption prefers the indirect pathway. We also observed the surface restructuring-induced dynamic heterogeneity of individual Pd nanocubes in both product formation and desorption processes with timescales of about tens to one hundred seconds. The activity fluctuation of individual Pd nanocubes was found to be mainly due to the spontaneous surface-restructuring rather than the catalysis. Furthermore, we estimated the size-dependent activation energies and time scales of spontaneous dynamic surface restructuring, which are fundamental to heterogeneous catalysis. The work presented here reveals new insight into nanocatalysis and exemplifies the advantages of the single-molecule approach in probing the catalytic properties of nanocatalysts. PMID- 27465439 TI - Endothelin-1 Overexpression Exaggerates Diabetes-Induced Endothelial Dysfunction by Altering Oxidative Stress. AB - BACKGROUND: Increased endothelin (ET)-1 expression causes endothelial dysfunction and oxidative stress. Plasma ET-1 is increased in patients with diabetes mellitus. Since endothelial dysfunction often precedes vascular complications in diabetes, we hypothesized that overexpression of ET-1 in the endothelium would exaggerate diabetes-induced endothelial dysfunction. METHODS: Diabetes was induced by streptozotocin treatment (55mg/kg/day, i.p.) for 5 days in 6-week-old male wild type (WT) mice and in mice overexpressing human ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Small mesenteric artery (MA) endothelial function and vascular remodeling by pressurized myography, reactive oxygen species (ROS) production by dihydroethidium staining and mRNA expression by reverse transcription/quantitative PCR were determined. RESULTS: Endothelium-dependent vasodilatory responses to acetylcholine of MA were reduced 24% by diabetes in WT ( P < 0.05), and further decreased by 12% in eET-1 ( P < 0.05). Diabetes decreased MA media/lumen in WT and eET-1 ( P < 0.05), whereas ET 1 overexpression increased MA media/lumen similarly in diabetic and nondiabetic WT mice ( P < 0.05). Vascular ROS production was increased 2-fold by diabetes in WT ( P < 0.05) and further augmented 1.7-fold in eET-1 ( P < 0.05). Diabetes reduced endothelial nitric oxide synthase (eNOS, Nos3 ) expression in eET-1 by 31% ( P < 0.05) but not in WT. Induction of diabetes caused a 52% ( P < 0.05) increase in superoxide dismutase 1 ( Sod1 ) and a 32% ( P < 0.05) increase in Sod2 expression in WT but not in eET-1. CONCLUSIONS: Increased expression of ET-1 exaggerates diabetes-induced endothelial dysfunction. This may be caused by decrease in eNOS expression, increase in vascular oxidative stress, and decrease in antioxidant capacity. PMID- 27465440 TI - From the Publisher. PMID- 27465441 TI - Through the Looking Glass: 30 Years for The Journal of Perinatal & Neonatal Nursing. PMID- 27465442 TI - Interprofessional Collaboration in Perinatal Care: The Future of Midwifery. AB - Healthcare delivered by teams is becoming more common, and an estimated 50% of obstetricians in the United States (US) work with or employ nurse practitioners or nurse-midwives. The number of midwife-attended births in the United States is also growing. Interprofessional collaboration between midwives and physicians can increase access to safe, quality maternity care for women in the United States. A review of the literature indicates that successful collaborative practice includes effective communication, trust, and respect between providers. A review of concepts and theoretical frameworks offers a foundation for scholarly inquiry, suggests a research agenda for future study, and provides suggestions for organizational leaders to translate current knowledge into the clinical setting. Midwifery, through increasing collaborative practices, has the potential to change care delivery in the years to come. PMID- 27465443 TI - Debriefing and Feedback in the Current Healthcare Environment. AB - Over the past several decades, simulation-based learning and postsimulation debriefing have become a mainstay of clinical education in healthcare. With origins in both the military and aviation industries, debriefing in particular has been used across multiple nursing and medicine disciplines to promote team training and reflective learning. Self-reflection and improvement in practice are at the core of effective debriefing. Feedback and simulation experts have continued to develop more effective debriefing strategies. Several models are described in the literature, and healthcare educators now have a variety of resources at their disposal. Many of these debriefing techniques offer thoughtful guidance for providing constructive, real-time clinical feedback to students. Incorporating reflective feedback strategies in clinical learning promotes meaningful learning. This, in turn, will only strengthen the capabilities of students and better prepare them for the complexities they will face in clinical practice. PMID- 27465444 TI - Challenges and Creative Strategies in Undergraduate Nursing Education in Maternal Child Health. AB - Maternal-child health (MCH) is an integral part of most nursing undergraduate curricula. However, there are variations in implementation related to classroom and clinical experiences. The purpose of this article is to describe recent trends in MCH education, explore potential challenges, and highlight creative solutions for MCH nursing education. Perinatal nursing requires a solid skill base and sound knowledge base in many subjects, including health promotion and behavior change theory. Educators need to provide students with a firm educational foundation to meet both workforce demands and the needs of childbearing women, infants, and families. PMID- 27465445 TI - Academic-Practice Partnerships: Driving and Supporting Educational Changes. AB - The 3 recognized missions of academic nursing-education, practice, and research are not new. Yet, the continued separation of nursing education and service, with a lack of integration between schools of nursing and clinical practice, continues to be discussed as contributing to academic programs that produce graduates unready for clinical practice, research that does not adequately support clinical care needs, and isolation of both the nurse faculty from the clinical enterprise and clinicians from the education and research missions. Recently, academic practice partnerships have been reemphasized as a concept and mechanism for supporting changes in nursing education and improving clinical care. This article highlights some of the driving forces behind the focus on academic-practice partnerships and summarizes 3 changes in education. PMID- 27465446 TI - Educational Changes to Support Advanced Practice Nursing Education. AB - Educational factors limit the number of advanced practice registered nurse (APRN) graduates to meet the growing workforce demands. Healthcare dynamics are necessitating a shift in how nursing education envisions, creates, and implements clinical learning opportunities. The current clinical education model in APRN programs continues to be the same as it was 45 years ago when the student numbers were much smaller. New approaches in graduate nursing education are needed to address the shortage of APRNs in primary and acute care areas. Determining competency based on the number of clinical hours can be inefficient, ineffective, and costly and limits the ability to increase capacity. Little research exists in graduate nursing education to support the effectiveness and efficiency of current hours of clinical required for nurse practitioner students. Simulation and academic-practice partnership models can offer innovative approaches to nurse practitioner education for clinical training, with the goal of producing graduates who can provide safe, quality care within the complex practice-based environment of the nation's evolving healthcare system. PMID- 27465447 TI - Evidence-Based Practice and Quality Improvement in Nursing Education. AB - For more than a decade, nursing education has experienced several significant changes in response to challenges faced by healthcare organizations. Accrediting organizations have called for improved quality and safety in care, and the Institute of Medicine has identified evidence-based practice and quality improvement as 2 core competencies to include in the curricula for all healthcare professionals. However, the application of these competencies reaches far beyond the classroom setting. For nurses to possess the knowledge, skills, and attitudes to apply evidence-based practice and quality improvement to the real-world setting, academic-clinical institution partnerships are vital. PMID- 27465448 TI - Interprofessional Education in Neonatal Care. AB - Interprofessional education is not a new concept. Yet, the operationalization of interprofessional education with related competencies for collaborative team based practice in neonatal units is often difficult. Changes in healthcare with an emphasis on patient-focused care and the concern for patient safety and quality care are accelerating the need for more interprofessional education. This article briefly outlines the evolution of interprofessional education to support collaborative team-based practice and how that facilitates safety and quality care in neonatal units. PMID- 27465449 TI - There's an App for That!: New Directions Using Social Media in Patient Education and Support. AB - Social media has opened the door of information to patients and fundamentally changed communication in ways never imagined 30 years ago. Apps and Web sites from professional organizations as well as private individuals and commercial businesses abound. Opportunities for both research and unique forms of social and emotional support are part of the trend. While there are obvious advantages to having so much information available, social media has disadvantages as well. Today's clinicians need to understand how to access and evaluate social media for patient education and provide guidance for patients seeking health information from the cloud. PMID- 27465451 TI - Perinatal and Neonatal Health Information Technology: Past, Present, and Future. AB - The 3 decades of The Journal of Perinatal & Neonatal Nursing history share the same 3 decades as the birth of the information age and health information technology (HIT). This article summarizes the history of HIT and the corresponding publication history of The Journal of Perinatal & Neonatal Nursing. Health information technology content has evolved from being the "how-to operate" topic of a publication to being integrated within a nursing practice publication. The article concludes with current HIT challenges and implications for the future. PMID- 27465450 TI - Beyond Baby Steps: Today's Use of Social Networking Sites and the Nursing Profession. AB - Nurses' use of online social networking sites, such as Facebook and Twitter, are increasing and with it the controversy surrounding the compatibility of social networking sites within a profession that values privacy and confidentiality. This article draws on case studies, experiments, surveys, and policies from professional organizations, academic research, and nursing education programs spanning the last 5 years to highlight best practices that address 2 critical areas where the values of the nursing profession and those of social media most directly collide: regulatory issues and the blurring of professional and personal online identities. It also suggests ways of using social media to complement patient outcomes and the professional development of nurses while remaining consistent with professional ethics and values. PMID- 27465452 TI - Supporting Neonatal Intensive Care Unit Parents Through Social Media. AB - Parents of infants in the neonatal intensive care unit may often find themselves seeking healthcare information from online and social media sources. Social media applications are available to healthcare consumers and their families, as well as healthcare providers, in a variety of formats. Information that parents gather on their own, and information that is explained by providers, is then used when parents make healthcare decisions regarding their infants. Parents also seek support from peers and family while making healthcare decisions. The combination of knowledge obtained and social support given may empower the parent to feel more confident in their decision making. Healthcare professionals can guide parents to credible resources. The exchange of information between providers and parents can occur using a variety of communication methods. Misperceptions can be corrected, support given, open sharing of information occurs, and parent empowerment may result. PMID- 27465453 TI - Women's Voices in Maternity Care: The Triad of Shared Decision Making, Informed Consent, and Evidence-Based Practices. AB - The United States is the only industrialized nation that has experienced dramatic increases in the use of maternity interventions resulting in poor birth outcomes. It is speculated that the increased rates of maternal mortality and other outcomes are attributed to the current maternity model of care focused on the overuse of interventions, such as induction of labor, in otherwise healthy pregnant women. The overuse of induction of labor to artificially speed up the birth process has been linked to an increase in preterm and cesarean births. The cost of these interventions and poor outcomes has been substantial. The purpose of this article is to present concepts that demonstrate the challenges and value of informed, shared decision making, informed consent, and women's use of evidence within the context of maternity care. To highlight these important concepts, this article presents original findings from a secondary analysis of data on induction of labor. Findings from this analysis further highlight the importance of including women as part of informed, shared decision making in models of maternity care. PMID- 27465454 TI - Birth Environments: A Woman's Choice in the 21st Century. AB - A woman has many important decisions to make once discovering a pregnancy. One of those decisions with significant implications is where the birth will take place. The primary consideration for the majority of pregnant women when making a decision about birth environment is safety. However, other factors such as attitudes of family and friends, religious reasons, and confidence in the body's ability to give birth play a factor in the choice of birth environment. It is recommended that birth attendants use the process of shared decision making to assist pregnant women in making choices related to the birth environment. This process empowers the pregnant woman and provides a woman-centered and evidence based approach to choices related to obstetrical care. PMID- 27465455 TI - Shared Decision Making: Through the Patient's Eyes. AB - Birth is an intimate moment in a woman's life, and healthcare providers play a pivotal role in pregnant women having safe and memorable birth experiences. Utilizing the shared decision-making model during the prenatal period involves listening to the voices of identified high-risk patients and giving them options for care during labor and birth. "Through the Patient's Eyes" is an innovative program that evolved from the care planning process for these identified high risk obstetric patients who are invited back postpartum to describe to the team birth through "their" eyes. Through this program, the team learned that compassionate care comes from truly listening to pregnant women and their families and that nurses play a pivotal role as educators and advocates. Sharing birth stories with the staff who cared for them not only had a positive effect on the staff but also many women described profound healing afterward. PMID- 27465457 TI - Shared Decision Making in Neonatal Quality Improvement. AB - Since the Institute of Medicine published Crossing the Quality Chasm in 2001, healthcare systems have become more focused on improving the quality of healthcare delivery. At Oregon Health & Science University and Doernbecher Children's Hospital, we recognize the need to take an interprofessional, team based approach to improving the care we provide to our current and future patients. We describe here an ongoing quality improvement project in the Doernbecher Neonatal Intensive Care Unit (NICU), with specific attention to the factors we believe have contributed to the implementation and early success of the project. These factors include the history of quality improvement work in our NICU and in the field of neonatology, the "dyad leadership" structure under which we operate in our NICU, and our developing understanding of the concept of "team intelligence." These elements have led to the formation of a team that can practice shared decision making and work as one to realize a shared goal. PMID- 27465456 TI - Relational Communications Strategies to Support Family-Centered Neonatal Intensive Care. AB - The philosophy of family-centered care in neonatal intensive care units is intended to facilitate parental involvement, shared decision-making, and improved outcomes for infants and families. To support family-centered care, there are multiple interventions with different components and associated outcomes that have been described in the research literature. This evidence leaves many unanswered questions about how best to implement and evaluate strategies to enhance family-centered care. This article provides a brief overview of interventions designed to support family-centered care in neonatal intensive care units and offers an evidence-informed staff education strategy to enhance family centered care. The evidence-informed relational communications strategies of circular pattern diagrams, questioning, and commendations are described, along with specific examples of how nurses can use them in in their day-to-day practice in neonatal intensive care units. PMID- 27465458 TI - Using an Informed Advocacy Framework to Advance the Practice of Family-Centered Care. AB - The philosophical framework of family-centered care (FCC) has been promoted consistently since the 1980s in perinatal and neonatal settings as a gold standard approach for developing programs and providing care that supports the meaningful involvement of parents in the care of their infants and children. Recent literature suggests that despite years of promotion, FCC remains an elusive practice. Sources frequently state that FCC is based on principles of communication and empowerment, but the literature overall does not suggest substantial underlying philosophical or theoretical underpinnings. There have been theoretical advances in nursing and other disciplines that hold potential for moving our practice of FCC forward. In this article, we describe the informed advocacy framework and apply the framework to FCC. PMID- 27465459 TI - Trends in Baby-Friendly(r) Care in the United States: Historical Influences on Contemporary Care. AB - The protection that breast-feeding affords both mother and infant against acute and chronic illness is well documented. The grassroots, public health, and governmental supports for breast-feeding have influenced changes in maternal and newborn care. History indicates that the additional influence has come in the form of governmental workshops and initiatives, professional organizations, as well as The Joint Commission. This includes the influence that the Baby Friendly(r) Hospital Initiative and the Ten Steps to Successful Breastfeeding have had on infant care throughout the years. The requirements that hospitals must follow to implement all, or some, of the Ten Steps lead to change in care that not only increases breast-feeding rates but also leads to health improvements. This article reviews how an upward trend in the adoption of Baby Friendly practices to support breast-feeding impacts infant care. PMID- 27465460 TI - Trends in Perinatal Care and Implications for Frontline Nurse Leaders. AB - The perinatal trends presented in this article are based on recent topics from conferences, journals, the media, as well as from input from perinatal nurses. Trends in patient care are influenced by evidence known for decades, new research, emerging and innovative concepts in healthcare, patient and family preferences, and the media. Trends discussed in this article are rethinking the due date, birth outside the hospital setting, obstetric hospitalists as birth attendants, nitrous oxide for pain in childbirth, hydrotherapy and waterbirth in the hospital setting, delayed cord clamping, disrupters of an optimal infant microbiome, skin-to-skin care during cesarean surgery, and breast-sleeping and the breast-feeding dyad. In addition, the authors developed implications for perinatal nurses related to each trend. The goal is to stimulate reflection on evidence that supports or does not support current practice and to stimulate future research by discussing some of the current trends that may influence the care that perinatal nurses provide during the birthing year. PMID- 27465461 TI - The More Things Change, the More They Stay the Same: Thirty Years of Fetal Monitoring in Perspective. AB - Thirty years ago, the inaugural issue of The Journal of Perinatal & Neonatal Nursing was published and the entire perinatal portion of the journal was devoted to electronic fetal monitoring (EFM). This article provides a historical perspective on EFM in perinatal care since the 1980s by exploring the similarities and differences of the state of the science presented in that first issue. Both EFM and intermittent auscultation are discussed. PMID- 27465462 TI - Cesarean Birth: A Journey in Historical Trends. AB - Thirty years ago seems like yesterday: a time of immense socioeconomic changes, explosion of an "Internet" computer concept, and identification of human immunodeficiency virus. Like all events of the past, transformations in obstetrics developed over time. Cesarean birth can be better understood in a broader context when one considers how the art of obstetric practice has evolved. Cesarean birth progressed from delivering a fetus perimortem or postmortem to a time of operative births that simultaneously juggle a woman's safety, satisfaction, and freedom of choice concerning birth options. Thirty years of increasing cesarean birth rates have prompted government agencies, national organizations, state-level perinatal collaborative groups, and experts to address these rates and the impact on maternal-child health and healthcare systems. The purpose of this article is to explain cesarean birth's remarkable impact on obstetrics by reviewing key historical periods, current advances, and upcoming trends. PMID- 27465463 TI - Trends in Family-Centered Care in Neonatal Intensive Care. AB - Family-centered care in neonatal intensive care changed over the last decades. Initially, parents and infants were separated and parents were even being blamed for cau-sing infections in their infants. The importance, though, of the parents being the constant in the infant's life emerged and with that the importance of early bonding and attachment for the parents to take on their role and responsibi lities as primary caregivers. Facilitation of family-centered care includes involving the parents in daily care activities, kangaroo care, developmental care, interaction and communication with the infant, as well as involving grandparents and siblings. Implementation of family-centered care requires appropriate policies, facilities and resources, education of all involved, and a positive attitude. PMID- 27465464 TI - Transition From Hospital to Home in Preterm Infants and Their Families. AB - When the day of discharge from a neonatal intensive care unit (NICU) comes for the parents of newborn infants, they are filled with long-awaited joy and happiness. They go home feeling as parents, away from scheduled routines of the hospital, monitor alarms, clinical rounds, numerous tests, and so on. What do we know about what happens after these little patients and their families leave the NICU? What happens from the point of leaving the hospital until when things get settled and life becomes perceived as normal? This article presents a short summary of research conducted with the vulnerable population of high-risk and preterm infants and their families postdischarge. Available evidence suggests that transition to home after hospital discharge, a phenomenon that many families experience, is challenging and requires attention from clinicians and researchers if we are to provide effective, efficient, and high-quality care. PMID- 27465465 TI - Historical Trends in Neonatal Nursing: Developmental Care and NIDCAP. AB - The focus of neonatal nursing has shifted from a highly technical approach to one of supportive interventions and a more individualized developmental approach. Developmental care is described as a philosophy of care that requires rethinking the relationships between infants, families, and healthcare professionals. Various models of developmental care exist; however, they all include a variety of activities designed to manage the environment and individualize the care provided to premature and/or sick infants. PMID- 27465466 TI - Associations between depressive symptoms and fronto-temporal activities during a verbal fluency task in patients with schizophrenia. AB - Though depressive symptoms are common in patients with schizophrenia, they are often left untreated and are associated with a high relapse rate, suicidal ideation, increased mortality, reduced social adjustment, and poor quality of life. The present study aims to elucidate the association between depressive symptoms and fronto-temporal activities during a cognitive task in patients with schizophrenia. The fronto-temporal activities of 41 Japanese patients with schizophrenia was evaluated during a verbal fluency task using 52-channel near infrared spectroscopy (NIRS). Depressive symptoms were assessed using the depression/anxiety component of the Positive and Negative Syndrome Scale (PANSS) five-factor model. The depression/anxiety component of the PANSS five-factor model was negatively correlated with activities of the ventrolateral prefrontal cortex (PFC), right dorsolateral PFC, and left temporal regions. Our findings suggest that reduced fronto-temporal activities on NIRS during a verbal fluency task is related to depressive symptom severity in patients with schizophrenia. PMID- 27465467 TI - Phospholipid supplementation can attenuate vaccine-induced depressive-like behavior in mice. AB - Human papillomavirus vaccine (HPVv) is used worldwide for prevention of infection. However several reports link this vaccine, with immune-mediated reactions, especially with neurological manifestations. Our previous results showed that HPVv-Gardasil and aluminum-immunized mice developed behavioral impairments. Studies have shown a positive effect of phospholipid supplementation on depression and cognitive functions in mice. Therefore, our goal was to evaluate the effect of a dietary supplement on vaccine-induced depression. Sixty C57BL/6 female mice were immunized with HPVv-Gardasil, aluminum or the vehicle (n = 20 each group), and half of each group were fed 5 times per week with 0.2 ml of a dietary supplement enriched with phosphatidylcholine. The mice were evaluated for depression at 3 months of age, by the forced swimming test. Both the Gardasil and the aluminum-treated mice developed depressive-like behavior when compared to the control group. The HPVv-Gardasil-immunized mice supplemented with phosphatidylcholine significantly reduced their depressive symptoms. This study confirms our previous studies demonstrating depressive-like behavior in mice vaccinated with HPVv-Gardasil. In addition, it demonstrates the ability of phosphatidylcholine-enriched diet to attenuate depressive-like behavior in the HPVv-Gardasil-vaccinated mice. We suggest that phosphatidylcholine supplementation may serve as a treatment for patients suffering vaccine-related neurological manifestations. PMID- 27465469 TI - Re: Impact of preoperative hemoglobin and CRP levels on cancer-specific survival in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder: results of a single-center study. PMID- 27465468 TI - Graft-versus-host disease after radiation therapy in patients who have undergone allogeneic stem cell transplantation: two case reports. AB - BACKGROUND: Patients who undergo allogeneic stem cell transplantation and subsequent radiation therapy uncommonly develop graft-versus-host disease within the irradiated area. We quantified the incidence of this complication, which is a novel contribution to the field. From 2010 to 2014, 1849 patients underwent allogeneic stem cell transplantation, and 41 (2 %) received radiation therapy afterward. Of these, two patients (5 %) developed graft-versus-host disease within the irradiated tissues during or immediately after radiation therapy. CASE PRESENTATION: The first patient is a 37-year-old white man who had Hodgkin lymphoma; he underwent allogeneic stem cell transplantation from a matched unrelated donor and received radiation therapy for an abdominal and pelvic nodal recurrence. After 28.8 Gy, he developed grade 4 gastrointestinal graft-versus host disease, refractory to tacrolimus and steroids, but responsive to pentostatin and photopheresis. The other patient is a 24-year-old white man who had acute leukemia; he underwent allogeneic stem cell transplantation from a matched related donor and received craniospinal irradiation for a central nervous system relapse. After 24 cobalt Gy equivalent, he developed severe cutaneous graft-versus-host disease, sharply delineated within the radiation therapy field, which was responsive to tacrolimus and methylprednisolone. CONCLUSIONS: We conclude that graft-versus-host disease within irradiated tissues is an uncommon but potentially serious complication that may follow radiation therapy in patients who have undergone allogeneic stem cell transplantation. Clinicians must be aware of this complication and prepared with strategies to mitigate risk. Patients who have undergone allogeneic stem cell transplantation represent a unique population that may offer novel insight into the pathways involved in radiation-related inflammation. PMID- 27465470 TI - Integrative analysis of transcriptome and miRNome unveils the key regulatory connections involved in different stages of hepatocellular carcinoma. AB - Dysregulated molecular processes are the major factors that drive and feed the signaling processes involved in carcinogenesis. In recent years, regulation of mRNAs by microRNAs (miRNAs) has been found to play a vital role in many cancers including hepatocellular carcinoma (HCC). However, genomewide studies defining molecular regulatory circuits at both mRNA and miRNA levels are just emerging. To uncover the molecular and functional processes involved in liver tumorigenesis at mRNA and miRNA level, a co-expression-based network of miRNAs was constructed from multiple miRNA profiles. The applicability of the network approach to microRNA expression profiles was assessed. Although the clustering consistency of miRNAs across the profiles was found moderate, miRNA networking has been found informative. Furthermore, microRNA network modules were integrated with the functionally defined mRNA modules derived from an mRNA co-expression network of an earlier study. Three highly clustered regulatory circuits of mRNA-miRNA modules have been identified as involved in hepatocyte, inflammatory-stress and proliferative process activated subcategories of HCC. A subset of the proliferative miRNA module was found clustered in the 14q32.31 chromosomal region. The current integrative network analysis of mRNA-miRNA modules shows the intricate miRNA-mRNA functional circuits and signaling interactions involved in liver tumorigenesis. PMID- 27465471 TI - A Cushing's syndrome patient's severe insomnia and morning blood pressure surge both improved after her left adrenal tumor resection. AB - Underlying mechanisms of the elevated risks of hypertension and cardiovascular disease (CVD) in Cushing's syndrome (CS) are unclear. We treated an adult woman with CS because of a cortisol-secreting adrenal tumor. After tumor resection, the 24-h blood pressure (BP) level improved from 156/91 to 131/84 mmHg; the morning BP surprisingly improved from 174/98 to 127/93 mmHg, although we reduced her antihypertensive medication. Her sleep quality (by the Pittsburgh Sleep Quality Index) improved from 7 to 2 points. Disturbed circadian BP rhythm is often observed in CS, but was reported only as altered nocturnal BP fall. This is the first report showing the disappearance of the morning BP surge evaluated by ambulatory BP monitoring with postsurgery sleep quality improvement. Poor-quality sleep, followed by exaggerated morning BP surge may thus be a cause of CS-related cardiovascular events. Sleep quality and BP circadian rhythm evaluations may clarify hypertension and high CVD risk in CS. PMID- 27465472 TI - Integrin-alphaIIbbeta3-mediated outside-in signalling activates a negative feedback pathway to suppress platelet activation. AB - Integrin-alphaIIbbeta3-mediated outside-in signalling is widely accepted as an amplifier of platelet activation; accumulating evidence suggests that outside-in signalling can, under certain conditions, also function as an inhibitor of platelet activation. The role of integrin-alphaIIbbeta3-mediated outside-in signalling in platelet activation is disputable. We employed flow cytometry, aggregometry, immunoprecipitation, and immunoblotting to investigate the role of integrin-alphaIIbbeta3-mediated outside-in signalling in platelet activation. Integrin alphaIIbbeta3 inhibition enhances agonist-induced platelet ATP secretion. Human platelets lacking expression of alphaIIbbeta3 exhibited more platelet ATP secretion than their wild-type counterparts. Moreover, integrin alphaIIbbeta3-mediated outside-in signals activate SHIP-1, which in turn mediates p-Akt dephosphorylation, leading to inactivation of PI3K/Akt signalling. Furthermore, 3AC (SHIP-1 inhibitor) inhibits platelet disaggregation, and promotes platelet ATP secretion. Upon ADP stimulation, Talin is recruited to alphaIIbbeta3, and it is dissociated from alphaIIbbeta3 when platelets disaggregate. In addition, treatment with RUC2, an inhibitor of alphaIIbbeta3, which blocks alphaIIbbeta3-mediated outside-in signalling, can markedly prevent the dissociation of talin from integrin. SHIP1 Inhibitor 3AC inhibits the dissociation of talin from integrin-beta3. These results suggest that integrin alphaIIbbeta3-mediated outside-in signalling can serve as a brake to restrict unnecessary platelet activation by activated SHIP-1, which mediated the disassociation of talin from beta3, leading to integrin inactivation and blocking of PI3K/Akt signalling to restrict platelet ATP secretion. PMID- 27465473 TI - Mastectomy technique using a self-designed self-retaining retractor system. AB - Mastectomy is one of the most common procedures for treating breast cancer. It is often performed by a breast surgeon with an assistant holding the retractor to provide adequate tension for dissection of the skin flap. However, the technique is highly dependent on the retraction from the assistant. We herein describe a novel technique using a self-retained retractor system with a specially designed retractor ring and elastic stay hooks to allow adequate and constant tension of retraction throughout the entire mastectomy procedure. This new technique was introduced at our breast center in 2008, and the skin flap necrosis rate and time required for skin flap dissection remain comparable to those in other regions. The retractor ring costs less than $200 USD, and the disposable elastic hooks cost around $50 USD. In conclusion, this new technique is simple, versatile, and effective. PMID- 27465474 TI - Preoperative neutrophil-to-lymphocyte ratio as a predictor of survival after reductive surgery plus percutaneous isolated hepatic perfusion for hepatocellular carcinoma: a retrospective analysis. AB - PURPOSE: We assessed the predictive value of the preoperative neutrophil-to lymphocyte ratio (NLR) in patients who underwent a two-stage treatment combining reductive surgery and percutaneous isolated hepatic perfusion for multiple hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). METHODS: Forty-two patients underwent the two-stage treatment between January 2000 and December 2014 at Kobe University Hospital (Hyogo, Japan). The NLR was calculated from lymphocyte and neutrophil counts in the preoperative routine blood test. Clinical data and overall survival were compared statistically and multivariate analysis was done to identify prognostic factors. RESULTS: The median survival of patients with a preoperative NLR > 2.3 was 14.9 months (n = 13), whereas that of patients with a preoperative NLR <= 2.3 was 26.1 months (n = 29; P = 0.022). A preoperative NLR > 2.3 was an independent prognostic factor in patients with multiple HCC with PVTT [hazard ratio (HR) 2.329; 95 % confidence interval (CI) 1.058-5.667; P = 0.036]. CONCLUSION: Based on the results of this study, an elevated preoperative NLR is an independent predictive risk factor for patients undergoing two-stage treatment for multiple HCC with PVTT. PMID- 27465475 TI - Psychological impact of positive cervical cancer screening results among Japanese women. AB - BACKGROUND: While cervical cancer screening is useful for detecting and then treating the disease at an early stage, most women with screen-positive results are free from cervical cancer but nevertheless subject to the unnecessary worry entailed in receiving such results. The purpose of this study was to examine whether receiving a screen-positive result was actually related to psychological distress among Japanese women who underwent cervical cancer screening. METHODS: We conducted a questionnaire survey at health facilities in a semiurban city of Ibaraki prefecture, involving 1744 women who underwent cervical cancer screening and 72 who received screen-positive results and then underwent further testing. We used the K6 scale to assess their psychological distress (K6 score >=5) and performed multiple logistic regression analyses to estimate the relative effect of receiving screen-positive results on psychological distress. RESULTS: Psychological distress was more prevalent among women with screen-positive results (OR 2.22; 95 % CI 1.32-3.74), while it was also related to history of mental health consultation (OR 2.26; 95 % CI 1.69-3.01) and marital status (OR 1.32; 95 % CI 1.02-1.70). CONCLUSIONS: Receiving a positive cervical cancer screening result was associated with psychological distress. To alleviate this psychological impact, the current form of communicating the screening results should be reconsidered. PMID- 27465476 TI - Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy in the SENRI trial: analysis of risk factors for vomiting and nausea. AB - BACKGROUND: We previously reported in the SENRI trial on the usefulness of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in colorectal cancer patients receiving an oxaliplatin-based regimen which is classified as moderately emetogenic cancer chemotherapy. In the present subgroup analysis of the SENRI trial, we assessed the risk factors for CINV in colorectal cancer patients who received oxaliplatin-based chemotherapy. METHODS: Multivariate logistic regression models were used to assess the impact of aprepitant use and patient characteristics on vomiting and nausea. We also assessed the proportion of CINV in patients by gender. RESULTS: Female gender and aprepitant use were associated with the incidence of vomiting and no significant nausea. Significantly more men achieved no vomiting than women (92.9 vs 84.5 % in men and women, respectively; P = 0.0001). The rate of no nausea, complete response, complete protection, and total control was also higher in men. The rate rescue therapy use was significantly higher in women than men. We compared the rate of CINV between aprepitant and control groups and found a significant difference in male patients who achieved no vomiting and complete protection in the overall phase. In women, the rate of no nausea, no vomiting, and total control was higher in the aprepitant group than in the control group. CONCLUSIONS: Gender and aprepitant use were risk factors for CINV in colorectal patients who received oxaliplatin-based chemotherapy. Aprepitant therapy was more effective for women than for men in the prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen. PMID- 27465477 TI - flowVS: channel-specific variance stabilization in flow cytometry. AB - BACKGROUND: Comparing phenotypes of heterogeneous cell populations from multiple biological conditions is at the heart of scientific discovery based on flow cytometry (FC). When the biological signal is measured by the average expression of a biomarker, standard statistical methods require that variance be approximately stabilized in populations to be compared. Since the mean and variance of a cell population are often correlated in fluorescence-based FC measurements, a preprocessing step is needed to stabilize the within-population variances. RESULTS: We present a variance-stabilization algorithm, called flowVS, that removes the mean-variance correlations from cell populations identified in each fluorescence channel. flowVS transforms each channel from all samples of a data set by the inverse hyperbolic sine (asinh) transformation. For each channel, the parameters of the transformation are optimally selected by Bartlett's likelihood-ratio test so that the populations attain homogeneous variances. The optimum parameters are then used to transform the corresponding channels in every sample. flowVS is therefore an explicit variance-stabilization method that stabilizes within-population variances in each channel by evaluating the homoskedasticity of clusters with a likelihood-ratio test. With two publicly available datasets, we show that flowVS removes the mean-variance dependence from raw FC data and makes the within-population variance relatively homogeneous. We demonstrate that alternative transformation techniques such as flowTrans, flowScape, logicle, and FCSTrans might not stabilize variance. Besides flow cytometry, flowVS can also be applied to stabilize variance in microarray data. With a publicly available data set we demonstrate that flowVS performs as well as the VSN software, a state-of-the-art approach developed for microarrays. CONCLUSIONS: The homogeneity of variance in cell populations across FC samples is desirable when extracting features uniformly and comparing cell populations with different levels of marker expressions. The newly developed flowVS algorithm solves the variance-stabilization problem in FC and microarrays by optimally transforming data with the help of Bartlett's likelihood-ratio test. On two publicly available FC datasets, flowVS stabilizes within-population variances more evenly than the available transformation and normalization techniques. flowVS-based variance stabilization can help in performing comparison and alignment of phenotypically identical cell populations across different samples. flowVS and the datasets used in this paper are publicly available in Bioconductor. PMID- 27465478 TI - The effect of the menstrual cycle and water consumption on physiological responses during prolonged exercise at moderate intensity in hot conditions. AB - BACKGROUND: Reproductive hormones are likely to be involved in thermoregulation through body fluid dynamics. In the present study, we aimed to investigate the effect of the menstrual cycle and water consumption on physiological responses to prolonged exercise at moderate intensity in hot conditions. METHODS: Eight healthy young women with regular menstrual cycles performed cycling exercise for 90 minutes at 50% VO2peak intensity during the low progesterone (LP) level phase and high progesterone (HP) level phase, with or without water consumption, under hot conditions (30 degrees C, 50% relative humidity). For the water consumption trials, subjects ingested water equivalent to the loss in body weight that occurred in the earlier non-consumption trial. For all four trials, rectal temperature, cardiorespiratory responses, and ratings of perceived exertion (RPE) were measured. RESULTS: Throughout the 90-minute exercise period, rectal temperatures during HP were higher than during LP by an average of 0.4 degrees C in the non-consumption trial (P<0.01) and 0.2 degrees C in the water consumption trial (P<0.05). During exercise, water consumption affected the changes in rectal temperature and heat rate (HR) during HP, but it did not exert these effects during LP. Furthermore, we found a negative correlation between estradiol levels and rectal temperature during LP. CONCLUSIONS: During prolonged exercise at moderate intensity under hot conditions, water consumption is likely to be useful for suppressing the associated increase in body temperature and HR, particularly during HP, whereas estradiol appears to be useful for suppressing the increase in rectal temperature during LP. PMID- 27465479 TI - Different versions of the Italian Foot Function Index. PMID- 27465482 TI - PACS for Bhutan: a cost effective open source architecture for emerging countries. AB - This paper reports the design and implementation of an innovative and cost effective imaging management infrastructure suitable for radiology centres in emerging countries. It was implemented in the main referring hospital of Bhutan equipped with a CT, an MRI, digital radiology, and a suite of several ultrasound units. They lacked the necessary informatics infrastructure for image archiving and interpretation and needed a system for distribution of images to clinical wards. The solution developed for this project combines several open source software platforms in a robust and versatile archiving and communication system connected to analysis workstations equipped with a FDA-certified version of the highly popular Open-Source software. The whole system was implemented on standard off-the-shelf hardware. The system was installed in three days, and training of the radiologists as well as the technical and IT staff was provided onsite to ensure full ownership of the system by the local team. Radiologists were rapidly capable of reading and interpreting studies on the diagnostic workstations, which had a significant benefit on their workflow and ability to perform diagnostic tasks more efficiently. Furthermore, images were also made available to several clinical units on standard desktop computers through a web-based viewer. MESSAGES/TEACHING POINTS: * Open source imaging informatics platforms can provide cost-effective alternatives for PACS * Robust and cost-effective open architecture can provide adequate solutions for emerging countries * Imaging informatics is often lacking in hospitals equipped with digital modalities. PMID- 27465480 TI - Transcriptome Analysis Reveals Candidate Genes involved in Blister Blight defense in Tea (Camellia sinensis (L) Kuntze). AB - To unravel the molecular mechanism of defense against blister blight (BB) disease caused by an obligate biotrophic fungus, Exobasidium vexans, transcriptome of BB interaction with resistance and susceptible tea genotypes was analysed through RNA-seq using Illumina GAIIx at four different stages during ~20-day disease cycle. Approximately 69 million high quality reads were assembled de novo, yielding 37,790 unique transcripts with more than 55% being functionally annotated. Differentially expressed, 149 defense related transcripts/genes, namely defense related enzymes, resistance genes, multidrug resistant transporters, transcription factors, retrotransposons, metacaspases and chaperons were observed in RG, suggesting their role in defending against BB. Being present in the major hub, putative master regulators among these candidates were identified from predetermined protein-protein interaction network of Arabidopsis thaliana. Further, confirmation of abundant expression of well-known RPM1, RPS2 and RPP13 in quantitative Real Time PCR indicates salicylic acid and jasmonic acid, possibly induce synthesis of antimicrobial compounds, required to overcome the virulence of E. vexans. Compendiously, the current study provides a comprehensive gene expression and insights into the molecular mechanism of tea defense against BB to serve as a resource for unravelling the possible regulatory mechanism of immunity against various biotic stresses in tea and other crops. PMID- 27465483 TI - Usage of Plant Food Supplements (PFS) for weight control in six European countries: results from the PlantLIBRA PFS Consumer Survey 2011-2012. AB - BACKGROUND: Obesity is increasing worldwide and weight-control strategies, including the consumption of plant food supplements (PFS), are proliferating. This article identifies the herbal ingredients in PFS consumed for weight control and by overweight/obese dieters in six European countries, and explores the relationship between their consumption and their self-reported BMI. METHODS: Data used were a subset from the PlantLIBRA PFS Consumer Survey 2011-2012, a retrospective survey of 2359 PFS consumers. The survey used a bespoke frequency of-PFS-usage questionnaire. Analyses were performed in two consumer subsamples of 1) respondents taking the products for "body weight reasons", and 2) "dieters for overweight/obesity", to identify the herbal ingredients consumed for these reasons. The relationship between the 5 most consumed herbal ingredients and self reported BMI in groups 1 and 2 is explored by comparing BMI proportions of consumers vs. non-consumers (using Chi-squared test). RESULTS: 252 PFS (8.8 %) were consumed for "body weight reasons" (by 240 PFS consumers); 112 PFS consumers (4.8 %) were "dieting for overweight/obesity". Spain is the country where consuming herbal ingredients for body weight control and dieting were most popular. Artichoke was the most consumed herbal ingredient. Considering only the 5 top products consumed by those who responded "body weight", when using the total survey sample, a greater proportion of BMI >= 25 was observed among consumers of PFS containing artichoke and green tea as compared to non-consumers (58.4 % vs. 49.1 % and 63.2 % vs. 49.7 % respectively). Considering only the 5 top products consumed by "dieters" and using only the "dieters" sample, a lower proportion of BMI >= 25 was observed among pineapple-containing PFS consumers (38.5 % vs. 81.5 %); however, when using the entire survey sample, a greater proportion of BMI >= 25 was observed among artichoke-containing PFS consumers (58.4 % vs. 49.1 %). CONCLUSIONS: A comparison of results among the scarce publications evaluating the use of weight-loss supplements at the population level is limited. Nevertheless every hint is important in finding out which are the self-treatment strategies used by overweight/obese individuals in European countries. Although limited by a small sample size, our study represents a first attempt at analysing such data in six EU countries. Our findings should encourage the conduction of further studies on this topic, long-term and large sample-sized studies, ideally conducted in the general population. PMID- 27465484 TI - CLINICOPATHOLOGICAL CORRELATION IN A PATIENT WITH PREVIOUSLY TREATED BIRDSHOT CHORIORETINOPATHY. AB - PURPOSE: Birdshot chorioretinopathy (BCR) is a bilateral, chronic uveitis primarily involving the posterior segment that often results in progressive vision loss. Histopathology on eyes with BCR has been limited, but we had the rare opportunity to study the eyes of a donor with BCR. We sought to compare immunolabeling in the eyes of this donor who was treated with immunosuppression for over 30 years to age-matched controls. METHODS: From each eye, a macular punch and superotemporal regions were used for cryostat sectioning, and immunohistochemistry was performed on the sections using antibodies directed against CD45, intercellular adhesion molecule-1, IBA1, and GFAP. The vasculature binding lectin, Ulex europaeus agglutinin-I (UEA-I), was also used to perform lectin histochemistry. RESULTS: At death, her visual acuity was 20/25 right eye, 20/250 left eye with extensive chorioretinal atrophy, vascular attenuation, and disk pallor. Compared with controls, the BCR donor had extensive degeneration of the outer nuclear layer and retinal pigment epithelium as well as choroidal thinning with inner retinal preservation. Loss of UEA-I+ choroidal endothelial cells was extensive, and atypical intercellular adhesion molecule-1 labeling and IBA+ microglia/macrophages were present along with widespread GFAP labeling throughout the retina. CONCLUSION: The BCR may cause progressive chorioretinal and optic atrophy with long-standing increased leukocyte abundance throughout the retina and microglial activation especially at the retina-choroid interface. PMID- 27465485 TI - Evaluating appropriate red blood cell transfusions: a quality audit at 10 Ontario hospitals to determine the optimal measure for assessing appropriateness. AB - BACKGROUND: Evaluating the appropriateness of red blood cell (RBC) transfusion requires labor-intensive medical chart audits and expert adjudication. We sought to determine the appropriateness of RBC transfusions at 10 hospitals using retrospective chart review and to determine whether simple metrics (proportion of single-unit transfusions, RBCs/100 acute inpatient days, proportion of transfusions with pretransfusion hemoglobin <80 g/L or posttransfusion hemoglobin <90 g/L) could be used as surrogate markers of appropriateness by comparing their values with the results from the audit. STUDY DESIGN AND METHODS: An initial block of 30 RBC units was dually adjudicated for appropriateness followed by additional blocks of 10 units until the difference between the cumulative percentage of appropriate RBC units in the preceding block and final block was <3%. Pearson correlation tests were used to evaluate associations between the metrics and percentages of appropriate transfusions per hospital. Two-by-two tables were used to assess the utility of the metrics to classify transfusions for appropriateness. RESULTS: Of the 498 units audited, 78% were adjudicated as appropriate (kappa = 0.9603), with significant variability between institutions (p < 0.0001). Fifty audits or less were required at nine of the institutions. The values of the metrics were not found to have significant correlations with appropriateness, and the metric that misclassified the smallest proportion of transfusions for appropriateness was pretransfusion hemoglobin <80 g/L, at 24%. CONCLUSIONS: Our findings suggest that a chart audit of 50 RBC transfusions with adjudication using robust criteria is the optimal means of evaluating RBC transfusion appropriateness at an institution for benchmarking and quality improvement initiatives. PMID- 27465486 TI - The Tetracyanopyridinide Dimer Dianion, sigma-[TCNPy]2 (2.). AB - The reaction of 2,3,5,6-tetracyanopyridine (TCNPy) and Cr(C6 H6 )2 forms diamagnetic sigma-[TCNPy]2 (2-) possessing a 1.572(3) A intrafragment sp(3) sp(3) bond. This is in contrast to the structurally related 1,2,4,5 tetracyanobenzene and 1,2,4,5-tetracyanopyrazine that form pi-dimer dianions possessing long, multicenter bonds. PMID- 27465488 TI - Microbiology, philosophy and education. AB - There are not only many links between microbiological and philosophical topics, but good educational reasons for microbiologists to explore the philosophical issues in their fields. I examine three broad issues of classification, causality and model systems, showing how these philosophical dimensions have practical implications. I conclude with a discussion of the educational benefits for recognising the philosophy in microbiology. PMID- 27465487 TI - Modeling Laterality of the Globus Pallidus Internus in Patients With Parkinson's Disease. AB - OBJECTIVE: Neurosurgical interventions such as deep brain stimulation surgery of the globus pallidus internus (GPi) play an important role in the treatment of medically refractory Parkinson's disease (PD), and require high targeting accuracy. Variability in the laterality of the GPi across patients with PD has not been well characterized. The aim of this report is to identify factors that may contribute to differences in position of the motor region of GPi. MATERIALS AND METHODS: The charts and operative reports of 101 PD patients following deep brain stimulation surgery (70 males, aged 11-78 years) representing 201 GPi were retrospectively reviewed. Data extracted for each subject include age, gender, anterior and posterior commissures (AC-PC) distance, and third ventricular width. Multiple linear regression, stepwise regression, and relative importance of regressors analysis were performed to assess the predictive ability of these variables on GPi laterality. RESULTS: Multiple linear regression for target vs. third ventricular width, gender, AC-PC distance, and age were significant for normalized linear regression coefficients of 0.333 (p < 0.0001), 0.206 (p = 0.00219), 0.168 (p = 0.0119), and 0.159 (p = 0.0136), respectively. Third ventricular width, gender, AC-PC distance, and age each account for 44.06% (21.38 65.69%, 95% CI), 20.82% (10.51-35.88%), 21.46% (8.28-37.05%), and 13.66% (2.62 28.64%) of the R2 value, respectively. Effect size calculation was significant for a change in the GPi laterality of 0.19 mm per mm of ventricular width, 0.11 mm per mm of AC-PC distance, 0.017 mm per year in age, and 0.54 mm increase for male gender. CONCLUSION: This variability highlights the limitations of indirect targeting alone, and argues for the continued use of MRI as well as intraoperative physiological testing to account for such factors that contribute to patient-specific variability in GPi localization. PMID- 27465489 TI - A secretome view of colonisation factors in Shiga toxin-encoding Escherichia coli (STEC): from enterohaemorrhagic E. coli (EHEC) to related enteropathotypes. AB - Shiga toxin-encoding Escherichia coli (STEC) regroup strains that carry genes encoding Shiga toxin (Stx). Among intestinal pathogenic E. coli, enterohaemorrhagic E. coli (EHEC) constitute the major subgroup of virulent STEC. EHEC cause serious human disease such as haemorrhagic colitis and haemolytic uremic syndrome. While EHEC have evolved from enteropathogenic E. coli, hybrids with enteroaggregative E. coli have recently emerged. Of note, some enteroinvasive E. coli also belong to the STEC group. While the LEE (locus of enterocyte effacement) is a key and prominent molecular determinant in the pathogenicity, neither all EHEC nor STEC contain the LEE, suggesting that they possess additional virulence and colonisation factors. Currently, nine protein secretion systems have been described in diderm-lipopolysaccharide bacteria (archetypal Gram-negative) and can be involved in the secretion of extracellular effectors, cell-surface proteins or assembly of cell-surface organelles, such as flagella or pili. In this review, we focus on the secretome of STEC and related enteropathotypes, which are relevant to the colonisation of biotic and abiotic surfaces. Considering the wealth of potential protein trafficking mechanisms, the different combinations of colonisation factors and modulation of their expression is further emphasised with regard to the ecophysiology of STEC. PMID- 27465492 TI - Lack of a "Weekend Effect" for Renal Transplant Recipients. AB - The "weekend (WE) effect" defines the association between WE hospital admissions and higher rate of mortality. The aim of this study was to evaluate the relationship between WE effect and renal transplant recipients (RTRs) using the database of the Emilia-Romagna region (ERR), Italy. We included ERR admissions of RTRs ( International Classification of Diseases, Ninth Revision, Clinical Modification [ ICD-9-CM] code V420) between 2000 and 2013. In-hospital mortality, admissions due to cardiovascular events (CVEs), and the Elixhauser score were evaluated on the basis of ICD-9-CM codification. Out of 9063 hospital admissions related to 3648 RTRs (mean age 53 +/- 13 years, 62.9% male), 1491 (16.5%) were recorded during the WE. During the follow-up period, 1581 (17.4%) patients deceased and 366 (4%) had CVEs. Length of hospital stay (LOS) was 9.7 +/- 12.1 days. Logistic regression analysis showed that only LOS was independently associated with WE admissions (odds ratio: 1594, confidence interval: 1.385 1.833; P < .001). Renal transplant recipients are not exposed to higher risk of adverse outcome during WE admissions. However, WE admissions were characterized by an increased duration of hospitalization. PMID- 27465490 TI - The NarE protein of Neisseria gonorrhoeae catalyzes ADP-ribosylation of several ADP-ribose acceptors despite an N-terminal deletion. AB - The ADP-ribosylating enzymes are encoded in many pathogenic bacteria in order to affect essential functions of the host. In this study, we show that Neisseria gonorrhoeae possess a locus that corresponds to the ADP-ribosyltransferase NarE, a previously characterized enzyme in N. meningitidis The 291 bp coding sequence of gonococcal narE shares 100% identity with part of the coding sequence of the meningococcal narE gene due to a frameshift previously described, thus leading to a 49-amino-acid deletion at the N-terminus of gonococcal NarE protein. However, we found a promoter region and a GTG start codon, which allowed expression of the protein as demonstrated by RT-PCR and western blot analyses. Using a gonococcal NarE-6xHis fusion protein, we demonstrated that the gonococcal enzyme underwent auto-ADP-ribosylation but to a lower extent than meningococcal NarE. We also observed that gonoccocal NarE exhibited ADP-ribosyltransferase activity using agmatine and cell-free host proteins as ADP-ribose acceptors, but its activity was inhibited by human beta-defensins. Taken together, our results showed that NarE of Neisseria gonorrhoeae is a functional enzyme that possesses key features of bacterial ADP-ribosylating enzymes. PMID- 27465491 TI - Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal. AB - Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs). ALDH activity is not only a marker for CSCs but also important in CSC biology. SUMO does not modify Oct-1 directly, but regulates the expression of TRIM21 that enhances Oct-1 ubiquitination and, consequently, reducing Oct-1 stability. In summary, our findings suggest that SUMOylation could be a target to inhibit CSCs and ultimately to reduce treatment resistance, tumour metastasis and relapse. PMID- 27465493 TI - Upregulation of cystathionine beta-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury. AB - Encephalopathy of prematurity (EOP) is a complex form of cerebral injury that occurs in the setting of hypoxia-ischemia (HI) in premature infants. Using a rat model of EOP, we investigated whether neonatal HI of the brain may alter the expression of cystathionine beta-synthase (CBS) and the components of the mammalian target of rapamycin (mTOR) signaling. We performed unilateral carotid ligation and induced HI (UCL/HI) in Long-Evans rats at P6 and found increased CBS expression in white matter (i.e. corpus callosum, cingulum bundle and external capsule) as early as 24 h (P7) postprocedure. CBS remained elevated through P21, and, to a lesser extent, at P40. The mTOR downstream target 70 kDa ribosomal protein S6 kinase (p70S6K and phospho-p70S6K) and 40S ribosomal protein S6 (S6 and phospho-S6) were also overexpressed at the same time points in the UCL/HI rats compared to healthy controls. Overexpression of mTOR components was not observed in rats treated with the mTOR inhibitor everolimus. Behavioral assays performed on young rats (postnatal day 35-37) following UCL/HI at P6 indicated impaired preference for social novelty, a behavior relevant to autism spectrum disorder, and hyperactivity. Everolimus restored behavioral patterns to those observed in healthy controls. A gait analysis has shown that motor deficits in the hind paws of UCL/HI rats were also significantly reduced by everolimus. Our results suggest that neonatal HI brain injury may inflict long-term damage by upregulation of CBS and mTOR signaling. We propose this cascade as a possible new molecular target for EOP-a still untreatable cause of autism, hyperactivity and cerebral palsy. PMID- 27465494 TI - Production of functional, stable, unmutated recombinant human papillomavirus E6 oncoprotein: implications for HPV-tumor diagnosis and therapy. AB - BACKGROUND: High-risk human papillomaviruses (HR-HPVs) types 16 and 18 are the main etiological agents of cervical cancer, with more than 550,000 new cases each year worldwide. HPVs are also associated with other ano-genital and head-and-neck tumors. The HR-HPV E6 and E7 oncoproteins are responsible for onset and maintenance of the cell transformation state, and they represent appropriate targets for development of diagnostic and therapeutic tools. METHODS: The unmutated E6 gene from HPV16 and HPV18 and from low-risk HPV11 was cloned in a prokaryotic expression vector for expression of the Histidine-tagged E6 protein (His6-E6), according to a novel procedure. The structural properties were determined using circular dichroism and fluorescence spectroscopy. His6-E6 oncoprotein immunogenicity was assessed in a mouse model, and its functionality was determined using in vitro GST pull-down and protein degradation assays. RESULTS: The His6-tagged E6 proteins from HPV16, HPV18, and HPV11 E6 genes, without any further modification in the amino-acid sequence, were produced in bacteria as soluble and stable molecules. Structural analyses of HPV16 His6-E6 suggests that it maintains correct folding and conformational properties. C57BL/6 mice immunized with HPV16 His6-E6 developed significant humoral immune responses. The E6 proteins from HPV16, HPV18, and HPV11 were purified according to a new procedure, and investigated for protein-protein interactions. HR-HPV His6-E6 bound p53, the PDZ1 motif from MAGI-1 proteins, the human discs large tumor suppressor, and the human ubiquitin ligase E6-associated protein, thus suggesting that it is biologically active. The purified HR-HPV E6 proteins also targeted the MAGI-3 and p53 proteins for degradation. CONCLUSIONS: This new procedure generates a stable, unmutated HPV16 E6 protein, which maintains the E6 properties in in vitro binding assays. This will be useful for basic studies, and for development of diagnostic kits and immunotherapies in preclinical mouse models of HPV-related tumorigenesis. PMID- 27465495 TI - Protein Patterns and Oscillations on Lipid Monolayers and in Microdroplets. AB - The Min proteins from E.coli position the bacterial cell-division machinery through pole-to-pole oscillations. In vitro, Min protein self-organization can be reconstituted in the presence of a lipid membrane as a catalytic surface. However, Min dynamics have so far not been reconstituted in fully membrane enclosed volumes. Microdroplets interfaced by lipid monolayers were employed as a simple 3D mimic of cellular compartments to reconstitute Min protein oscillations. We demonstrate that lipid monolayers are sufficient to fulfil the catalytic role of the membrane and thus represent a facile platform to investigate Min protein regulated dynamics of the cell-division protein FtsZ-mts. In particular, we show that droplet containers reveal distinct Min oscillation modes, and reveal a dependence of FtsZ-mts structures on compartment size. Finally, co-reconstitution of Min proteins and FtsZ-mts in droplets yields antagonistic localization, thus demonstrating that droplets indeed support the analysis of complex bacterial self-organization in confined volumes. PMID- 27465497 TI - Pivotal debates and controversies on the structure and function of the avian respiratory system: setting the record straight. AB - Among the extant air-breathing vertebrates, the avian respiratory system is structurally the most complex and functionally the most efficient gas exchanger. Having been investigated for over four centuries, some aspects of its biology have been extremely challenging and highly contentious and others still remain unresolved. Here, while assessing the most recent findings, four notable aspects of the structure and function of the avian respiratory system are examined critically to highlight the questions, speculations, controversies and debates that have arisen from past research. The innovative techniques and experiments that were performed to answer particular research questions are emphasised. The features that are outlined here concern the arrangement of the airways, the path followed by the inspired air, structural features of the lung and the air and blood capillaries, and the level of cellular defence in the avian respiratory system. Hitherto, based on association with the proven efficiency of naturally evolved and human-made counter-current exchange systems rather than on definite experimental evidence, a counter-current gas exchange system was suggested to exist in the avian respiratory system and was used to explain its exceptional efficiency. However, by means of an elegant experiment in which the direction of the air-flow in the lung was reversed, a cross-current system was shown to be in operation instead. Studies of the arrangement of the airways and the blood vessels corroborated the existence of a cross-current system in the avian lung. While the avian respiratory system is ventilated tidally, like most other invaginated gas exchangers, the lung, specifically the paleopulmonic parabronchi, is ventilated unidirectionally and continuously in a caudocranial (back-to-front) direction by synchronized actions of the air sacs. The path followed by the inspired air in the lung-air sac system is now known to be controlled by a mechanism of aerodynamic valving and not by anatomical valves or sphincters, as was previously supposed. The structural strength of the air and blood capillaries is derived from: the interdependence between the air and blood capillaries; a tethering effect between the closely entwined respiratory units; the presence of epithelial-epithelial cell connections (retinacula or cross-bridges) that join the blood capillaries while separating the air capillaries; the abundance and intricate arrangement of the connective tissue elements, i.e. collagen, elastin, and smooth muscle fibres; the presence of type-IV collagen, especially in the basement membranes of the blood-gas barrier and the epithelial-epithelial cell connections; and a putative tensegrity state in the lung. Notwithstanding the paucity of free surface pulmonary macrophages, the respiratory surface of the avian lung is well protected from pathogens and particulates by an assortment of highly efficient phagocytic cells. In commercial poultry production, instead of weak pulmonary cellular defence, stressful husbandry practices such as overcrowding, force-feeding, and intense genetic manipulation for rapid weight gain and egg production may account for the reported susceptibility of birds to aerosol-transmitted diseases. PMID- 27465496 TI - Porphyromonas gingivalis infection exacerbates the onset of rheumatoid arthritis in SKG mice. AB - Epidemiological studies have linked periodontitis to rheumatoid arthritis (RA). Porphyromonas gingivalis (Pg) was reported recently to produce citrullinated protein (CP) and increase anti-cyclic CP antibody (ACPA), both of which have been identified as causative factors of RA. In the present study, we determined the effects of Pg infection on the exacerbation of RA in a mouse model. RA model mice (SKG mice) were established by an intraperitoneal (i.p.) injection of laminarin (LA). Mice were divided into six groups, Ctrl (PBS injection), LA (LA injection), Pg/LA (Pg + LA injection), Pg (Pg injection), Ec/LA (Escherichia coli and LA injection) and Ec (E. coli injection). In order to evaluate RA, joint swelling by the arthritis score, bone morphology by microcomputed tomography (microCT), haematoxylin and eosin staining, ACPA, matrix metalloproteinase-3 (MMP-3) and cytokine level in serum by enzyme-linked immunosorbent assay were determined. Osteoclast differentiation from bone marrow mononuclear cells (BMCs) was examined to clarify the underlying mechanisms of RA. The presence of Pg and CP in joint tissue was also investigated. The arthritis score was threefold higher in the Pg/LA group than in the LA group. Severe bone destruction was observed in joint tissue of the Pg/LA group. A microCT analysis of the Pg/LA group revealed a decrease in bone density. ACPA, MMP-3, interleukin (IL)-2, IL-6, CXCL1 and macrophage inflammatory protein (MIP)-1alpha levels from the Pg/LA group were the highest. The osteoclastogenesis of BMCs was enhanced in the Pg/LA group. Furthermore, large amounts of Pg components and CP were detected in the Pg/LA group. In conclusion, Pg infection has the potential to exacerbate RA. PMID- 27465498 TI - Is there a link between childhood adversity, attachment style and Scotland's excess mortality? Evidence, challenges and potential research. AB - BACKGROUND: Scotland has a persistently high mortality rate that is not solely due to the effects of socio-economic deprivation. This "excess" mortality is observed across the entire country, but is greatest in and around the post industrial conurbation of West Central Scotland. Despite systematic investigation, the causes of the excess mortality remain the subject of ongoing debate. DISCUSSION: Attachment processes are a fundamental part of human development, and have a profound influence on adult personality and behaviour, especially in response to stressors. Many studies have also shown that childhood adversity is correlated with adult morbidity and mortality. The interplay between childhood adversity and attachment is complex and not fully elucidated, but will include socio-economic, intergenerational and psychological factors. Importantly, some adverse health outcomes for parents (such as problem substance use or suicide) will simultaneously act as risk factors for their children. Data show that some forms of "household dysfunction" relating to childhood adversity are more prevalent in Scotland: such problems include parental problem substance use, rates of imprisonment, rates of suicide and rates of children being taken into care. However other measures of childhood or family wellbeing have not been found to be substantially different in Scotland compared to England. We suggest in this paper that the role of childhood adversity and attachment experience merits further investigation as a plausible mechanism influencing health in Scotland. A model is proposed which sets out some of the interactions between the factors of interest, and we propose parameters for the types of study which would be required to evaluate the validity of the model. PMID- 27465499 TI - Emergence and interhospital spread of OXA-48-producing Klebsiella pneumoniae ST395 clone in Western Hungary. PMID- 27465500 TI - Age-dependent differential expression of death-associated protein 6 (Daxx) in various peripheral tissues and different brain regions of C57BL/6 male mice. AB - Death-associated protein 6 (DAXX) is a ubiquitous protein implicated in various cellular processes such as apoptosis, tumorigenesis, development and transcription. The role of DAXX is however ambiguous and many contradictory results regarding its function in apoptosis upon various cellular stresses are described in the literature. In order to have a better understanding of the role of DAXX throughout the entire organism under physiological stress conditions, we have characterized the mRNA levels, protein expression and the proteolytic processing of DAXX in the normal aging process in peripheral organs and brain regions in C57BL/6 male mice. Overall, Daxx mRNA expression decreases with aging in the liver, kidney, heart, cortex and cerebellum. In contrast, an increase is observed in the striatum. The protein expression of DAXX and of its proteolytic fragments increases with aging in the kidney, heart and cortex. In liver and spleen, no changes are observed while in the striatum and cerebellum, certain forms increase and others decrease with age, suggesting that the functions of DAXX may be cell type dependent. This study provides important details regarding the expression and post-translational modifications of DAXX in aging in the entire organism and provides reference data for the deregulation observed in age associated diseases. PMID- 27465502 TI - A case report: delayed high fever and maculopapules during Sorafenib treatment of ectopic hepatocellular carcinoma. AB - BACKGROUND: Sorafenib is the standard first-line therapy for hepatocellular carcinoma (HCC) and probably ectopic hepatocellular carcinoma (EHCC) as well. No report involves a side effect of delayed high fever of sorafenib. This manuscript describes a case of EHCC in the thoracic and abdominal cavities, who showed a delayed high fever and maculopapules during sorafenib treatment. CASE PRESENTATION: The patient is a 63-year-old Chinese male with advanced EHCC, taking sorafenib 400 mg twice daily. On the tenth day, red maculopapules appeared all over the body. On the same day, the patient began to suffer from continuous high fever. Due to these effects, the patient was asked to cease sorafenib treatment, and the high fever and maculopapules were alleviated quickly. However, the symptoms were present again upon re-challenge of sorafenib. Prednisone was then administered to control the symptoms, with the dosage gradually reduced from 30 to 5 mg/day in 1.5 months. No recurrence of fever or maculopapules has been found. Tumor response reached partial response (PR) and progression free survival (PFS) reached 392 days + by the date of Apr. 14th, 2016. CONCLUSION: EHCC could be treated like orthotopic HCC by oral administration of sorafenib, which shows good tumor response and survival benefit. Delayed high fever and maculopapules are potential, rare and severe side effects of sorafenib, and could be effectively controlled by glucocorticoid. PMID- 27465503 TI - The effect of tacrolimus on facial nerve injury: Histopathological findings in a rabbit model. AB - HYPOTHESIS: Tacrolimus helps healing of facial nerve injury. BACKGROUND: Positive effects of tacrolimus on axon regeneration and healing of injured peripheral nerves (eg. sciatic nerve) have been reported in the literature. Tacrolimus may be an additional treatment method that could improve the nerve healing after surgical treatment of cut injury of facial nerve. METHODS: 20 New Zealand rabbits were randomly separated into control and study groups of 10. In control group, no medical treatment was given after facial nerve anastomosis, and the animals were followed up for 2months. In the study group rabbits were given 1mg/kg/day tacrolimus subcutaneously for 2months after the facial nerve anastomosis. The histopathologic findings of axon regeneration like axon myelination were analyzed in both groups under electron and light microscopy. The data obtained in the groups were compared. RESULTS: Greater axon diameters, thicker myelin sheaths, and higher total number of myelinated axons were found in the tacrolimus group, suggesting better regeneration in this group when compared to the control group. There was less vacuolar degeneration in the study group. All these findings suggest that tacrolimus positively affects healing after facial nerve anastomosis. CONCLUSION: The results of this study indicate that tacrolimus has favorable effects on the healing process of the facial nerve after end-to-end anastomosis. Tacrolimus may be a promising agent in the future for nerve regeneration following traumatic facial paralysis surgery. PMID- 27465501 TI - Transcatheter valve implantation for right atrium-to-right ventricle conduit obstruction or regurgitation after modified Bjork-fontan procedure. AB - BACKGROUND: The most common reason for reintervention after a Bjork modification of the Fontan procedure, in which the right ventricle (RV) is incorporated into the pulmonary circulation by connecting the right atrial (RA) appendage to the RV directly or with an extra-anatomic graft, is obstruction or regurgitation of the RA-RV connection. Transcatheter implantation of a valved stent is an appealing option for the treatment of RA-RV conduit dysfunction in these patients. In the present study, we assessed early and intermediate results after transcatheter valve implantation within an obstructed or regurgitant RA-RV modified Fontan pathway. METHODS: Through a retrospective multicenter registry, we collected data from 16 patients with a modified Fontan circulation who were treated with percutaneous Melody or Sapien valve implantation for dysfunction of an extra anatomic RA-RV conduit or valve. RESULTS: All patients had successful and uncomplicated implantation of a Melody (n = 15) or Sapien 3 (n = 1) valve with hemodynamic and, in most cases, clinical improvement. During a median follow-up of 3.3 years, 3 patients died of cardiovascular causes unrelated to the procedure or the valve, and no major valve dysfunction was observed. CONCLUSION: Percutaneous transcatheter valve deployment to treat a dysfunctional RA-RV connection after a Bjork modification of the Fontan procedure is a viable alternative to surgery, with low procedural risk, and appears to offer good early and intermediate results.(c) 2016 Wiley Periodicals, Inc. PMID- 27465504 TI - Integrated assessment of emerging science and technologies as creating learning processes among assessment communities. AB - Emerging science and technologies are often characterised by complexity, uncertainty and controversy. Regulation and governance of such scientific and technological developments needs to build on knowledge and evidence that reflect this complicated situation. This insight is sometimes formulated as a call for integrated assessment of emerging science and technologies, and such a call is analysed in this article. The article addresses two overall questions. The first is: to what extent are emerging science and technologies currently assessed in an integrated way. The second is: if there appears to be a need for further integration, what should such integration consist in? In the article we briefly outline the pedigree of the term 'integrated assessment' and present a number of interpretations of the concept that are useful for informing current analyses and discussions of integration in assessment. Based on four case studies of assessment of emerging science and technologies, studies of assessment traditions, literature analysis and dialogues with assessment professionals, currently under-developed integration dimensions are identified. It is suggested how these dimensions can be addressed in a practical approach to assessment where representatives of different assessment communities and stakeholders are involved. We call this approach the Trans Domain Technology Evaluation Process (TranSTEP). PMID- 27465505 TI - Treatment of CGD-associated Colitis with the IL-23 Blocker Ustekinumab. PMID- 27465506 TI - Spatial heterogeneity in repeated measures of perceived stress among car commuters in Scania, Sweden. AB - BACKGROUND: Long commutes by car are stressful. Most research studying health effects of commuting have summarized cross-sectional data for large regions. This study investigated whether the levels of stress and individual characteristics among 30-60 min car commuters were similar across different places within the county of Scania, Sweden, and if there were changes over time. METHODS: The study population was drawn from a public health survey conducted in 2000, with follow ups in 2005 and 2010. The study population was selected from the 8206 study participants that completed the questionnaire at all three time points. Commuting questions in the 2010 questionnaire assessed exposure concurrently for that year and retrospectively for 2000 and 2005. In total, 997 persons aged 18-65 and working 15-60 h/week had commuted by car 30-60 min at least at one time point. Geographically weighted proportions of stress among 30-60 min car commuters were calculated for each year and classified into geographically continuous groups based on Wards algorithm. Stress levels, sociodemographic characteristics and commuting characteristics were compared for areas with high and low stress in relation to the rest of the county. This novel methodology can be adapted to other study settings where individual-level data are available over time. RESULTS: Spatial heterogeneity in stress levels was observed and the locations of high and low stress areas changed over time. Local differences in stress among participants were only partly explained by sociodemographic characteristics. Stressed commuters in the high stress area in 2000 were more likely to maintain their commuting mode and time than those not stressed. Stressed commuters in the high stress area in 2000 were also more likely to have the same workplace location in 2010, while stressed commuters in the high stress area in 2010 were more likely to have the same residential location as in 2000. CONCLUSION: The relationship between commuting mode and time and stress is variable in place and time. Better understanding of commuting contexts such as congestion is needed in research on the health effects of commuting. PMID- 27465507 TI - "I am yet to encounter any survey that actually reflects my life": a qualitative study of inclusivity in sexual health research. AB - BACKGROUND: Heteronormativity describes a set of norms and assumptions pertaining to heterosexual identities and binary gender. In 2015, we conducted our annual Sex, Drugs and Rock'n'Roll study, an online health survey of over 1000 Victorians aged 15-29 years. Feedback from participants suggested that our survey contained heteronormative language. In response to this, we aimed to make inclusive changes to our survey via consultation with young gender and sexually diverse (GSD) people. METHODS: We conducted two semi-structured focus groups in Melbourne with a total of 16 participants (age range: 21-28 years). Participants were mostly cisgender women, and there were two transgender participants and one non-binary participant. Participants also had a range of sexual identities including lesbian, queer, bisexual, pansexual, and asexual. Focus group discussions were transcribed verbatim and analysed thematically. RESULTS: Most participants indicated heteronormativity affects their lives in multiple ways, noting its impacts on access to sexual healthcare, invalidating sexual experiences and miscommunication in forms and surveys. Overall, participants emphasised the need for sexual health research to avoid assumptions about behaviour, to be clear and eliminate question ambiguity and avoiding treating gender as binary. Participants also discussed how the Sex, Drugs and Rock'n'Roll survey could address a range of sexual behaviours and experiences, rather than focusing on penetrative sex, which many participants found invalidating. CONCLUSIONS: Our findings have important implications for future health surveys aimed at general populations. We present recommendations that encourage research to be more inclusive to ensure data collection from GSD participants is respectful and rigorous. PMID- 27465508 TI - Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD positive clones. AB - BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder presenting with accumulation of proliferating undifferentiated blasts. Xenograft transplantation studies have demonstrated a rare population of leukemia initiating cells called leukemic stem cells (LSCs) capable of propagating leukemia that are enriched in the CD34+/CD38- fraction. LSCs are quiescent, resistant to chemotherapy and likely responsible for relapse and therefore represent an ideal target for effective therapy. LSCs are reported to overexpress the alpha subunit of the IL-3 receptor (CD123) compared to normal CD34+/CD38- hematopoietic stem cells. It has not been demonstrated whether CD123-positive (CD34+/CD38-) subpopulation is enriched for any clonal markers of AML or any LSC properties. The aims of this study were to investigate whether FMS-like tyrosine kinase (FLT3)/internal tandem duplication (ITD) mutations are present at LSC level and whether FLT3/ITD mutation is confined to LSC as defined by CD34+/CD38 /CD123+ and not CD34+/CD38-/CD123-. METHODS: Thirty-four AML cases were analyzed by five-color flow cytometry and sequential gating strategy to characterize of CD34+/CD38-/CD123+ cells. These cells were sorted, analyzed by PCR, and sequenced for FLT3/ITD. RESULTS: In this study, we confirm significant expression of CD123 in 32/34 cases in the total blast population (median expression = 86 %). CD123 was also expressed in the CD34+/CD38- cells (96 +/- 2 % positive) from 28/32 for CD123+ AML. CD123 was not expressed/low in normal bone marrow CD34+/CD38- cells (median expression = 0 %, range (0-.004 %). AML samples were tested for FLT3/ITD (10 positive/25). FLT3/ITD+ AML cases were sorted into two putative LSC populations according to the expression of CD123 and analyzed for FLT3/ITD again in the stem cell fractions CD34+/CD38-/CD123+ and CD34+/CD38-/CD123-. Interestingly, FLT3/ITD was only detected in CD34+/CD38-/CD123+ (7/7) and not in CD34+/CD38-/CD123- subpopulation (6/7). CONCLUSIONS: This finding shows that FLT3/ITD are present at LSC level and may be a primary and not secondary event in leukemogenesis, and the oncogenic events of FLT3/ITD happen at a cell stage possessing CD123. It shows that CD123 immunoprofiling provides further delineation of FLT3+ LSC clone. This novel finding provides a rationale for treatment involving CD123-targeting antibodies with intracellular FLT3 inhibitors directed against CD34+/CD38-/CD123+. This may result in more effective anti-LSC eradication. PMID- 27465510 TI - Assessment of radiological hazard parameters due to natural radioactivity in soils from granite-rich regions in Kutahya Province, Turkey. AB - The analysis of natural radioactivity from 238U, 232Th and 40K in 357 soil samples collected from the province of Kutahya was carried out using a NaI(Tl) gamma-ray spectroscopy system at the Nuclear Physics Research Laboratory, Dumlupinar University, Kutahya, Turkey. The specific activities of 238U, 232Th and 40K in the soil samples were evaluated. From the activity concentrations of 238U, 232Th and 40K, the total absorbed outdoor gamma-ray dose rates and the corresponding annual effective dose rates were determined. The corresponding values of the external and internal hazard indices of all the soil samples were also calculated. The external gamma-ray dose rate at 1 m above the ground was directly measured at each collected soil sample location. The results obtained in this study were compared within the limits of values obtained in other cities of Turkey, those in other countries. Radiological maps of Kutahya Province were constructed from the results of this study. PMID- 27465511 TI - Prolonged stimulation with low-intensity ultrasound induces delayed increases in spontaneous hippocampal culture spiking activity. AB - Ultrasound is a promising neural stimulation modality, but an incomplete understanding of its range and mechanism of effect limits its therapeutic application. We investigated the modulation of spontaneous hippocampal spike activity by ultrasound at a lower acoustic intensity and longer time scale than has been previously attempted, hypothesizing that spiking would change conditionally upon the availability of glutamate receptors. Using a 60-channel multielectrode array (MEA), we measured spontaneous spiking across organotypic rat hippocampal slice cultures (N = 28) for 3 min each before, during, and after stimulation with low-intensity unfocused pulsed or sham ultrasound (spatial-peak pulse average intensity 780 MUW/cm2 ) preperfused with artificial cerebrospinal fluid, 300 MUM kynurenic acid (KA), or 0.5 MUM tetrodotoxin (TTX) at 3 ml/min. Spike rates were normalized and compared across stimulation type and period, subregion, threshold level, and/or perfusion condition using repeated-measures ANOVA and generalized linear mixed models. Normalized 3-min spike counts for large but not midsized, small, or total spikes increased after but not during ultrasound relative to sham stimulation. This result was recapitulated in subregions CA1 and dentate gyrus and replicated in a separate experiment for all spike size groups in slices pretreated with aCSF but not KA or TTX. Increases in normalized 18-sec total, midsized, and large spike counts peaked predominantly 1.5 min following ultrasound stimulation. Our low-intensity ultrasound setup exerted delayed glutamate receptor-dependent, amplitude- and possibly region specific influences on spontaneous spike rates across the hippocampus, expanding the range of known parameters at which ultrasound may be used for neural activity modulation. (c) 2016 Wiley Periodicals, Inc. PMID- 27465512 TI - Surviving nebulization-induced stress: dexamethasone in pH-sensitive archaeosomes. AB - AIM: To increase the subcellular delivery of dexamethasone phosphate (DP) and stability to nebulization stress, pH-sensitive nanoliposomes (LpH) exhibiting archaeolipids, acting as ligands for scavenger receptors (pH-sensitive archaeosomes [ApH]), were prepared. MATERIALS & METHODS: The anti-inflammatory effect of 0.18 mg DP/mg total lipid, 100-150 nm DP-containing ApH (dioleylphosphatidylethanolamine: Halorubrum tebenquichense total polar archaeolipids:cholesteryl hemisuccinate 4.2:2.8:3 w:w) was tested on different cell lines. Size and HPTS retention of ApH and conventional LpH (dioleylphosphatidylethanolamine:cholesteryl hemisuccinate 7:3 w:w) before and after nebulization were determined. RESULTS & CONCLUSION: DP-ApH suppressed IL-6 and TNF-alpha on phagocytic cells. Nebulized after 6-month storage, LpH increased size and completely lost its HPTS while ApH3 conserved size and polydispersity, fully retaining its original HPTS content. PMID- 27465513 TI - Analysis of the Metabolic Pathways Affected by Poly(gamma-glutamic Acid) in Arabidopsis thaliana Based on GeneChip Microarray. AB - Plant growth is promoted by poly(gamma-glutamic acid) (gamma-PGA). However, the molecular mechanism underlying such promotion is not yet well understood. Therefore, we used GeneChip microarrays to explore the effects of gamma-PGA on gene transcription in Arabidopsis thaliana. Our results revealed 299 genes significantly regulated by gamma-PGA. These differently expressed genes participate mainly in metabolic and cellular processes and in stimuli responses. The metabolic pathways linked to these differently expressed genes were also investigated. A total of 64 of the 299 differently expressed genes were shown to be directly involved in 24 pathways such as brassinosteroid biosynthesis, alpha linolenic acid metabolism, phenylpropanoid biosynthesis, and nitrogen metabolism, all of which were influenced by gamma-PGA. The analysis demonstrated that gamma PGA promoted nitrogen assimilation and biosynthesis of brassinosteroids, jasmonic acid, and lignins, providing a better explanation for why gamma-PGA promotes growth and enhances stress tolerance in plants. PMID- 27465509 TI - A systematic review of intervention thresholds based on FRAX : A report prepared for the National Osteoporosis Guideline Group and the International Osteoporosis Foundation. AB - This systematic review identified assessment guidelines for osteoporosis that incorporate FRAX. The rationale for intervention thresholds is given in a minority of papers. Intervention thresholds (fixed or age-dependent) need to be country-specific. INTRODUCTION: In most assessment guidelines, treatment for osteoporosis is recommended in individuals with prior fragility fractures, especially fractures at spine and hip. However, for those without prior fractures, the intervention thresholds can be derived using different methods. The aim of this report was to undertake a systematic review of the available information on the use of FRAX(r) in assessment guidelines, in particular the setting of thresholds and their validation. METHODS: We identified 120 guidelines or academic papers that incorporated FRAX of which 38 provided no clear statement on how the fracture probabilities derived are to be used in decision-making in clinical practice. The remainder recommended a fixed intervention threshold (n = 58), most commonly as a component of more complex guidance (e.g. bone mineral density (BMD) thresholds) or an age-dependent threshold (n = 22). Two guidelines have adopted both age-dependent and fixed thresholds. RESULTS: Fixed probability thresholds have ranged from 4 to 20 % for a major fracture and 1.3-5 % for hip fracture. More than one half (39) of the 58 publications identified utilised a threshold probability of 20 % for a major osteoporotic fracture, many of which also mention a hip fracture probability of 3 % as an alternative intervention threshold. In nearly all instances, no rationale is provided other than that this was the threshold used by the National Osteoporosis Foundation of the USA. Where undertaken, fixed probability thresholds have been determined from tests of discrimination (Hong Kong), health economic assessment (USA, Switzerland), to match the prevalence of osteoporosis (China) or to align with pre-existing guidelines or reimbursement criteria (Japan, Poland). Age-dependent intervention thresholds, first developed by the National Osteoporosis Guideline Group (NOGG), are based on the rationale that if a woman with a prior fragility fracture is eligible for treatment, then, at any given age, a man or woman with the same fracture probability but in the absence of a previous fracture (i.e. at the 'fracture threshold') should also be eligible. Under current NOGG guidelines, based on age-dependent probability thresholds, inequalities in access to therapy arise especially at older ages (>=70 years) depending on the presence or absence of a prior fracture. An alternative threshold using a hybrid model reduces this disparity. CONCLUSION: The use of FRAX (fixed or age-dependent thresholds) as the gateway to assessment identifies individuals at high risk more effectively than the use of BMD. However, the setting of intervention thresholds needs to be country-specific. PMID- 27465515 TI - Understanding the thermal decomposition mechanism of a halogen-free chelated orthoborate-based ionic liquid: a combined computational and experimental study. AB - In the last few decades, ionic liquids (ILs) have gained significant attention as lubricants and lubricant additives due to their polar nature, low vapour pressure and tunable physicochemical properties. In this work, quantum chemistry calculations and atomistic Molecular Dynamics (MD) simulations were employed to predict thermal degradation mechanisms of a potential lubricating agent - the tributyloctylphosphonium bis(oxalato)borate ([P4,4,4,8][BOB]) IL. It was found that the onset of decomposition of the studied IL coincides with a cleavage of the B-O bonds in the [BOB](-) anion. Consequently, a series of chemical reactions of the [P4,4,4,8](+) cation with the [BOB](-) anion was triggered yielding alkylboranes, alkenes, trialkylphosphines, CO and CO2. Another ionic system, consisting of [P4,4,4,8][Cl], was also tested for a comparison. Thermogravimetric measurements have shown a higher thermal stability of [P4,4,4,8][BOB] compared to that of [P4,4,4,8][Cl] at least at the initial stage of decomposition, in accord with the presented calculations. Quantum chemical frequency calculations also agreed with the experimental Fourier Transform Infrared (FTIR) spectroscopy results. PMID- 27465514 TI - The aqueous extract of cinnamon bark ameliorated cisplatin-induced cytotoxicity in vero cells without compromising the anticancer efficiency of cisplatin. AB - AIM: Cis-diammine dichloroplatinum (CDDP) is one of the most important chemotherapeutic agents for cancer treatment. Nonetheless, its notable side effect, nephrotoxicity, undermines its clinical use. The current study was undertaken to evaluate the protective potential of the aqueous extract (AEC) of Cinnamomum cassia (cinnamon) against the cytotoxic effect of CDDP in vitro and to elaborate the molecular mechanism underlying protection. METHODS: MTT assay was performed to assess viability of the normal kidney Vero cells treated with CDDP and/or AEC. Cells were stained with Coomassie blue, acridine orange and ethidium bromide to highlight morphological features of apoptosis. Caspase-3 activity, DNA fragmentation and reactive oxygen species (ROS) level were monitored to assess biochemical hallmarks of apoptosis. Quantitative RT-PCR and Western blot analyses were performed to elucidate expression of cellular molecules underlying the protective potential of AEC. RESULTS: CDDP-treated Vero cells exhibited hallmarks of apoptosis; these hallmarks were significantly suppressed in the presence of AEC. AEC did not alter activity of CDDP-induced cytotoxicity of breast and liver cancer cells. AEC treatment of Vero cells prevented CDDP-induced increased expression of mitochondrial Bax protein, release of mitochondrial cytochrome c, caspase-3 activation, DNA fragmentation and generation of ROS. AEC up-regulated expression of the cytoprotective gene (heme oxygenase (HO)-1). CONCLUSION: These findings suggest AEC has protective effects against CDDP-induced toxicity via preventing the activation of various cellular mechanisms mediating apoptotic cell death, without compromising the anticancer efficiency of CDDP. Thus, cinnamon may represent one of the most feasible ways to reduce the risk of CDDP-induced toxicity. PMID- 27465516 TI - The combination of vitamins and omega-3 fatty acids has an enhanced anti inflammatory effect on microglia. AB - Neuroinflammation is a common phenomenon in the pathology of many brain diseases. In this paper we explore whether selected vitamins and fatty acids known to modulate inflammation exert an effect on microglia, the key cell type involved in neuroinflammation. Previously these nutrients have been shown to exert anti inflammatory properties acting on specific inflammatory pathways. We hypothesized that combining nutrients acting on converging anti-inflammatory pathways may lead to enhanced anti-inflammatory properties as compared to the action of a single nutrient. In this study, we investigated the anti-inflammatory effect of combinations of nutrients based on the ability to inhibit the LPS-induced release of nitric oxide and interleukin-6 from BV-2 cells. Results show that omega-3 fatty acids, vitamins A and D can individually reduce the LPS-induced secretion of the pro-inflammatory cytokines by BV-2 cells. Moreover, we show that vitamins A, D and omega-3 fatty acids (docosahexaenoic and eicosapentaenoic) at concentrations where they individually had little effect, significantly reduced the secretion of the inflammatory mediator, nitric oxide, when they were combined. The conclusion of this study is that combining different nutrients acting on convergent anti-inflammatory pathways may result in an increased anti inflammatory efficacy. PMID- 27465517 TI - Distal coronary perforation in patients with prior coronary artery bypass graft surgery: The importance of early treatment. AB - In patients with prior coronary artery bypass graft (CABG) surgery, distal coronary perforations are commonly considered to be at low risk for causing cardiac tamponade due to a potential protective role of pericardial adhesions, which obliterate the pericardial space. Loculated effusions can however form in such patients, compressing various cardiac structures and causing hemodynamic compromise. We present two cases of distal coronary perforation in prior CABG patients undergoing chronic total occlusion percutaneous coronary intervention. In the first case a distal coronary perforation was initially observed, resulting in a loculated pericardial effusion that caused ST-segment elevation and death, despite successful sealing of the perforation. In the second case a similar perforation was immediately sealed with a covered stent, followed by uneventful patient recovery. A literature review of coronary perforation leading to hemodynamic compromise in patients with prior CABG surgery revealed high mortality (22%), suggesting that prompt sealing of the perforation is critical in these patients. PMID- 27465518 TI - Spatial Competition: Roughening of an Experimental Interface. AB - Limited dispersal distance generates spatial aggregation. Intraspecific interactions are then concentrated within clusters, and between-species interactions occur near cluster boundaries. Spread of a locally dispersing invader can become motion of an interface between the invading and resident species, and spatial competition will produce variation in the extent of invasive advance along the interface. Kinetic roughening theory offers a framework for quantifying the development of these fluctuations, which may structure the interface as a self-affine fractal, and so induce a series of temporal and spatial scaling relationships. For most clonal plants, advance should become spatially correlated along the interface, and width of the interface (where invader and resident compete directly) should increase as a power function of time. Once roughening equilibrates, interface width and the relative location of the most advanced invader should each scale with interface length. We tested these predictions by letting white clover (Trifolium repens) invade ryegrass (Lolium perenne). The spatial correlation of clover growth developed as anticipated by kinetic roughening theory, and both interface width and the most advanced invader's lead scaled with front length. However, the scaling exponents differed from those predicted by recent simulation studies, likely due to clover's growth morphology. PMID- 27465519 TI - Reactivity of Single-Walled Carbon Nanotubes in the Diels-Alder Cycloaddition Reaction: Distortion-Interaction Analysis along the Reaction Pathway. AB - Diels-Alder cycloaddition is one of the most powerful tools for the functionalization of single-walled carbon nanotubes (SWCNTs). Density functional theory at the B3-LYP level of theory has been used to investigate the reactivity of different-diameter SWCNTs (4-9,5) in Diels-Alder reactions with 1,3-butadiene; the reactivity was found to decrease with increasing SWCNT diameter. Distortion/interaction analysis along the whole reaction pathway was found to be a better way to explore the reactivity of this type of reaction. The difference in interaction energy along the reaction pathway is larger than that of the corresponding distortion energy. However, the distortion energy plots for these reactions show the same trend. Therefore, the formation of the transition state can be determined from the interaction energy. A lower interaction energy leads to an earlier transition state, which indicates a lower activation energy. The computational results also indicate that the original distortion of the SWCNTs leads to an increase in the reactivity of the SWCNTs. PMID- 27465520 TI - Polymorphisms in TCF7L2 gene are associated with gestational diabetes mellitus in Chinese Han population. AB - This study aimed to investigate the possible association between diabetes susceptibility gene transcription factor 7-like 2 (TCF7L2) and gestational diabetes mellitus (GDM) in a Chinese Han population. A total of 556 GDM patients and 500 Non-GDM were included. Eighteen single nucleotide polymorphisms (SNPs) were evaluated. Fifteen tag SNPs were selected from HapMap CHB database with a minor allele frequency of >0.2 and r(2) of >0.8. Three additional SNPs were also chosen because these SNPs are associated with type 2 diabetes in East Asians. TCF7L2 rs290487, rs6585194, and rs7094463 polymorphisms were found to be significantly associated with GDM. In multivariate analysis, rs290487 genetic variation (OR = 2.686 per each C allele, P = 0.002), pre-BMI > 24 kg/m(2) (OR = 1.592, P = 0.018), age > 25 years (OR = 1.780, P = 0.012) and LDL-C > 3.6 mmol/L (OR = 2.034, P = 0.009) were identified as independent risk factors of GDM, rs7094463 genetic variation (OR = 0.429 per each G allele, P = 0.005) was identified as independent protect factor of GDM. This finding suggests that TCF7L2 rs290487, and rs7094463 were a potential clinical value for the prediction of GDM. PMID- 27465521 TI - Melatonin enhances hyperthermia-induced apoptotic cell death in human leukemia cells. AB - Melatonin is an endogenous indoleamine with a wide range of biological functions. In addition to modulating circadian rhythms, it plays important roles in the health as an antioxidant. Melatonin has also the ability to induce apoptosis in cancer cells and to enhance the antitumoral activity of chemotherapeutic agents. In this study, the effect of melatonin on hyperthermia-induced apoptosis was explored using human leukemia cells. The results demonstrate that melatonin greatly improved the cytotoxicity of hyperthermia in U937 cells. The potentiation of cell death was achieved with 1 mmol/L concentrations of the indoleamine but not with concentrations close to physiological levels in blood (1 nmol/L). This effect was associated to an enhancement of the apoptotic response, revealed by an increase in cells with hypodiploid DNA content and activation of multiple caspases (caspase-2, caspase-3, caspase-8, and caspase-9). Melatonin also increased hyperthermia-induced Bid activation as well as translocation of Bax from the cytosol to mitochondria and cytochrome c release. Hyperthermia-provoked apoptosis and potentiation by melatonin were abrogated by a broad-spectrum caspase inhibitor (z-VAD-fmk) as well as by specific inhibitors against caspase-8 or caspase-3. In contrast, blocking of the mitochondrial pathway of apoptosis either with a caspase-9 inhibitor or overexpressing the anti-apoptotic protein Bcl-2 (U937/Bcl-2) reduced the number of apoptotic cells in response to hyperthermia but it was unable to suppress melatonin enhancement. Melatonin appears to modulate the apoptotic response triggered by hyperthermia in a cell type-specific manner as similar results were observed in HL-60 but not in K562 or MOLT-3 cells. PMID- 27465522 TI - Current evidence is not in support of lipid rescue therapy in local anaesthetic systemic toxicity. PMID- 27465523 TI - Pain rather than induced emotions and ICU sound increases skin conductance variability in healthy volunteers. AB - BACKGROUND: Assessing pain in critically ill patients is difficult. Skin conductance variability (SCV), induced by the sympathetic response to pain, has been suggested as a method to identify pain in poorly communicating patients. However, SCV, a derivate of conventional skin conductance, could potentially also be sensitive to emotional stress. The purpose of the study was to investigate if pain and emotional stress can be distinguished with SCV. METHODS: In a series of twelve 1-min sessions with SCV recording, 18 healthy volunteers were exposed to standardized electric pain stimulation during blocks of positive, negative, or neutral emotion, induced with pictures from the International Affective Picture System (IAPS). Additionally, authentic intensive care unit (ICU) sound was included in half of the sessions. All possible combinations of pain and sound occurred in each block of emotion, and blocks were presented in randomized order. RESULTS: Pain stimulation resulted in increases in the number of skin conductance fluctuations (NSCF) in all but one participant. During pain-free baseline sessions, the median NSCF was 0.068 (interquartile range 0.013-0.089) and during pain stimulation median NSCF increased to 0.225 (interquartile range 0.146 0.3175). Only small increases in NSCF were found during negative emotions. Pain, assessed with the numeric rating scale, during the sessions with pain stimulation was not altered significantly by other ongoing sensory input. CONCLUSION: In healthy volunteers, NSCF appears to reflect ongoing autonomous reactions mainly to pain and to a lesser extent, reactions to emotion induced with IAPS pictures or ICU sound. PMID- 27465525 TI - The Authors Respond. PMID- 27465524 TI - Optimal transfusion practices after allogeneic hematopoietic cell transplantation: a systematic scoping review of evidence from randomized controlled trials. AB - BACKGROUND: Integrating evidence from randomized controlled trials (RCTs) into patient care is needed to optimize patient outcomes. Transfusion support during allogeneic hematopoietic cell transplantation (alloHCT) is a cornerstone of essential supportive care, yet optimal transfusion practices remain unclear. STUDY DESIGN AND METHODS: A scoping review of RCTs in alloHCT was conducted and 14 full-length articles on transfusion practice were identified that reported clinical outcomes after alloHCT. RESULTS: Eight RCTs compared various interventions related to platelet (PLT) transfusion, addressing product storage duration, dosage, and threshold for transfusion. Restrictive prophylactic PLT transfusion strategies were successful at reducing PLT consumption without impacting clinical outcomes. One study, however, reported increased bleeding associated with a strategy whereby patients did not receive prophylactic PLT transfusions. One study of thrombopoietin was associated with reduced PLT transfusion events but no difference in clinical outcomes compared to placebo. Six RCTs examined the utility of recombinant erythropoietin (EPO) in reducing red blood cell (RBC) transfusion dependence. Four trials reported an increase in hemoglobin levels while five studies demonstrated a reduction in RBC utilization; however, clinical outcomes were variably reported and no differences were identified. There were no RCTs examining RBC transfusion strategies, plasma transfusion, or plasma-derived protein administration. CONCLUSION: Prophylactic PLT transfusion when PLTs are fewer than 10 * 109 /L can prevent bleeding and is consistent with recent guidelines. Thrombopoietin and EPO can reduce transfusion requirements; however, potential safety concerns remain and the lack of improvement in clinical outcomes and high cost may limit use. Additional RCTs are needed, particularly with regard to RBC transfusion thresholds, to refine best practices after alloHCT. PMID- 27465526 TI - Brief Report: Estimating Differences and Ratios in Median Times to Event. AB - Time differences and time ratios are often more interpretable estimates of effect than hazard ratios for time-to-event data, especially for common outcomes. We developed a SAS macro for estimating time differences and time ratios between baseline-fixed binary exposure groups based on inverse probability-weighted Kaplan-Meier curves. The macro uses pooled logistic regression to calculate inverse probability of censoring and exposure weights, draws Kaplan-Meier curves based on the weighted data, and estimates the time difference and time ratio at a user-defined survival proportion. The macro also calculates the risk difference and risk ratio at a user-specified time. Confidence intervals are constructed by bootstrap. We provide an example assessing the effect of exclusive breastfeeding during diarrhea on the incidence of subsequent diarrhea in children followed from birth to 3 years in Vellore, India. The SAS macro provided here should facilitate the wider reporting of time differences and time ratios. PMID- 27465527 TI - Re: Unconventional Natural Gas Development and Birth Outcomes in Pennsylvania, USA. PMID- 27465528 TI - Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors. AB - Immunotherapies have shown considerable efficacy for the treatment of various cancers, but a multitude of patients remain unresponsive for various reasons, including poor homing of T cells into tumors. In this study, we investigated the roles of the leukotriene B4 receptor, BLT1, and CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, under endogenous as well as vaccine-induced antitumor immune response in a syngeneic murine model of B16 melanoma. Significant accelerations in tumor growth and reduced survival were observed in both BLT1(-/-) and CXCR3(-/ ) mice as compared with wild-type (WT) mice. Analysis of tumor-infiltrating leukocytes revealed significant reduction of CD8(+) T cells in the tumors of BLT1(-/-) and CXCR3(-/-) mice as compared with WT tumors, despite their similar frequencies in the periphery. Adoptive transfer of WT but not BLT1(-/-) or CXCR3( /-) CTLs significantly reduced tumor growth in Rag2(-/-) mice, a function attributed to reduced infiltration of knockout CTLs into tumors. Cotransfer experiments suggested that WT CTLs do not facilitate the infiltration of knockout CTLs to tumors. Anti-programmed cell death-1 (PD-1) treatment reduced the tumor growth rate in WT mice but not in BLT1(-/-), CXCR3(-/-), or BLT1(-/-)CXCR3(-/-) mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti-PD-1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti-PD-1 based antitumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL-based immunotherapies. PMID- 27465529 TI - Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism. AB - Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice exposed to NO2 and that administration of uricase inhibited the development of OVA-driven allergic airway disease subsequent to OVA challenge, as well as the generation of OVA-specific Abs. However, uricase was itself immunogenic, inducing a uricase-specific adaptive immune response that occurred even when the enzymatic activity of uricase had been inactivated. Inhibition of the OVA-specific response was not due to the capacity of uricase to inhibit the early steps of OVA uptake or processing and presentation by dendritic cells, but occurred at a later step that blocked OVA specific CD4(+) T cell proliferation and cytokine production. Although blocking uric acid formation by allopurinol did not affect outcomes, administration of ultra-clean human serum albumin at protein concentrations equivalent to that of uricase inhibited NO2-promoted allergic airway disease. These results indicate that, although uric acid levels are elevated in the airways of NO2-exposed mice, the powerful inhibitory effect of uricase administration on allergic sensitization is mediated more through Ag-specific immune deviation than via suppression of allergic sensitization, a mechanism to be considered in the interpretation of results from other experimental systems. PMID- 27465530 TI - Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell Th17 Balance. AB - Zinc (Zn) is an essential metal for development and maintenance of both the innate and adaptive compartments of the immune system. Zn homeostasis impacts maturation of dendritic cells (DCs) that are important in shaping T cell responses. The mechanisms by which Zn regulates the tolerogenic phenotype of DCs remain largely unknown. In this study, we investigated the effect of Zn on DC phenotype and the generation of Foxp3(+) regulatory T cells (Tregs) using a model of Histoplasma capsulatum fungal infection. Exposure of bone marrow-derived DCs to Zn in vitro induced a tolerogenic phenotype by diminishing surface MHC class II (MHCII) and promoting the tolerogenic markers, programmed death-ligand (PD L)1, PD-L2, and the tryptophan degrading enzyme, IDO. Zn triggered tryptophan degradation by IDO and kynurenine production by DCs and strongly suppressed the proinflammatory response to stimulation by TLR ligands. In vivo, Zn supplementation and subsequent H. capsulatum infection supressed MHCII on DCs, enhanced PD-L1 and PD-L2 expression on MHCII(lo) DCs, and skewed the Treg-Th17 balance in favor of Foxp3(+) Tregs while decreasing Th17 cells. Thus, Zn shapes the tolerogenic potential of DCs in vitro and in vivo and promotes Tregs during fungal infection. PMID- 27465531 TI - The Repair of Skeletal Muscle Requires Iron Recycling through Macrophage Ferroportin. AB - Macrophages recruited at the site of sterile muscle damage play an essential role in the regeneration of the tissue. In this article, we report that the selective disruption of macrophage ferroportin (Fpn) results in iron accumulation within muscle-infiltrating macrophages and jeopardizes muscle healing, prompting fat accumulation. Macrophages isolated from the tissue at early time points after injury express ferritin H, CD163, and hemeoxygenase-1, indicating that they can uptake heme and store iron. At later time points they upregulate Fpn expression, thus acquiring the ability to release the metal. Transferrin-mediated iron uptake by regenerating myofibers occurs independently of systemic iron homeostasis. The inhibition of macrophage iron export via the silencing of Fpn results in regenerating muscles with smaller myofibers and fat accumulation. These results highlight the existence of a local pathway of iron recycling that plays a nonredundant role in the myogenic differentiation of muscle precursors, limiting the adipose degeneration of the tissue. PMID- 27465532 TI - RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors. AB - T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation. PMID- 27465534 TI - High-Density Lipoprotein Infusion Therapy and Atherosclerosis: Current Research and Future Directions. AB - Atherosclerosis is the leading cause of heart disease, contributing to hundreds of thousands of deaths annually. The use of long-term antilipid therapy has decreased low-density lipoprotein as a target, but high-density lipoprotein (HDL) has many properties which can protect against the formation of atherosclerotic plaque and decrease plaque burden. Numerous studies have shown an inverse correlation with HDL level and the future risk of heart disease. HDL has the unique property of playing a key role in reverse cholesterol transport, essentially bringing cholesterol from the periphery back to the liver for excretion in bile. In addition, HDL has many anti-inflammatory and vasoprotective properties. Recently, the idea of using HDL as a target of therapy has been met with great interest. Although oral medications have not shown promise, newly developed HDL infusions are currently being tested in clinical trials to determine their effect on the amount of plaque, the composition of the plaque, and the general state of inflammation. HDL infusions achieve stable levels rapidly in the plasma, making them most suitable in the post-acute coronary syndrome stage when most ischemic events are likely to recur. These infusion therapies have repeatedly demonstrated viability and reproducibility in increasing the amount of circulating HDL, decreasing the plaque burden, and decreasing markers of inflammation in plasma. However, none thus far have demonstrated a mortality benefit, possibly reflecting the complexity of the relationship among HDL, inflammation, and atherosclerosis. This remains a viable and promising avenue for continued research. PMID- 27465535 TI - Ghrelin and the Cardiovascular System. AB - Ghrelin is a small peptide released primarily from the stomach. It is a potent stimulator of growth hormone secretion from the pituitary gland and is well known for its regulation of metabolism and appetite. There is also a strong relationship between ghrelin and the cardiovascular system. Ghrelin receptors are present throughout the heart and vasculature and have been linked with molecular pathways, including, but not limited to, the regulation of intracellular calcium concentration, inhibition of proapoptotic cascades, and protection against oxidative damage. Ghrelin shows robust cardioprotective effects including enhancing endothelial and vascular function, preventing atherosclerosis, inhibiting sympathetic drive, and decreasing blood pressure. After myocardial infarction, exogenous administration of ghrelin preserves cardiac function, reduces the incidence of fatal arrhythmias, and attenuates apoptosis and ventricular remodeling, leading to improvements in heart failure. It ameliorates cachexia in end-stage congestive heart failure patients and has shown clinical benefit in pulmonary hypertension. Nonetheless, since ghrelin's discovery is relatively recent, there remains a substantial amount of research needed to fully understand its clinical significance in cardiovascular disease. PMID- 27465533 TI - Mst1 Kinase Regulates the Actin-Bundling Protein L-Plastin To Promote T Cell Migration. AB - Exploring the mechanisms controlling lymphocyte trafficking is essential for understanding the function of the immune system and the pathophysiology of immunodeficiencies. The mammalian Ste20-like kinase 1 (Mst1) has been identified as a critical signaling mediator of T cell migration, and loss of Mst1 results in immunodeficiency disease. Although Mst1 is known to support T cell migration through induction of cell polarization and lamellipodial formation, the downstream effectors of Mst1 are incompletely defined. Mice deficient for the actin-bundling protein L-plastin (LPL) have phenotypes similar to mice lacking Mst1, including decreased T cell polarization, lamellipodial formation, and cell migration. We therefore asked whether LPL functions downstream of Mst1. The regulatory N-terminal domain of LPL contains a consensus Mst1 phosphorylation site at Thr(89) We found that Mst1 can phosphorylate LPL in vitro and that Mst1 can interact with LPL in cells. Removal of the Mst1 phosphorylation site by mutating Thr(89) to Ala impaired localization of LPL to the actin-rich lamellipodia of T cells. Expression of the T89A LPL mutant failed to restore migration of LPL-deficient T cells in vitro. Furthermore, expression of T89A LPL in LPL-deficient hematopoietic cells, using bone marrow chimeras, failed to rescue the phenotype of decreased thymic egress. These results identify LPL as a key effector of Mst1 and establish a novel mechanism linking a signaling intermediate to an actin-binding protein critical to T cell migration. PMID- 27465536 TI - Neurocardiac Injury After Cerebral and Subarachnoid Hemorrhages. AB - Cerebrovascular events are associated with high mortality and morbidity rates. Neurocardiac injury after a subarachnoid hemorrhage and cerebral hemorrhage further worsen clinical outcomes. Excess catecholamine-induced cardiotoxicity is currently the most widely accepted pathophysiologic mechanism. Awareness of neurocardiac injury and the cardiac manifestations associated with it will allow for early diagnosis and appropriate management. PMID- 27465537 TI - MicroRNAs in Ischemic Heart Disease: From Pathophysiology to Potential Clinical Applications. AB - Despite rapid advances in cardiovascular research and therapeutic strategies, ischemic heart disease (IHD) remains the leading cause of mortality worldwide. MicroRNAs (miRNAs) are small, noncoding RNAs which post transcriptionally regulate gene expression. In the past few years, miRNAs have emerged as key tools for the understanding of the pathophysiology of IHD, with potential uses as new biomarkers and therapeutic targets. Several studies report a regulatory role of miRNAs, with regard to fundamental components of IHD pathogenesis and progression, such as lipoprotein metabolism, atherogenesis, vascular calcification, platelet function, and angiogenesis. Due to their high stability in biofluids, circulating miRNAs have attracted attention as promising biomarkers of IHD, especially in cardiovascular risk prediction and the diagnosis of myocardial infarction. Furthermore, experimental studies have demonstrated the potential of miRNA-targeted therapy in improving hyperlipidemia, atherosclerosis, and angiogenesis. In this review, the current knowledge on the role of miRNAs in IHD and translational perspectives of their use is discussed. PMID- 27465538 TI - Pulmonary Pressure Monitoring for Patients With Heart Failure. AB - Heart failure (HF) affects over 5.8 million patients in the United States, and can be very costly due to the number of hospitalizations and rehospitalizations during the final years of life. Due to the large number of hospitalizations for HF exacerbations, effective methods for preventing these occurrences are necessary. Improvements in the outpatient treatment of HF, aided by noninvasive and invasive home monitoring methods, can reduce the number of hospitalizations. Pulmonary pressure monitoring through the CardioMEMS system provides one method of hemodynamic assessment of patients. The efficacy of the CardioMEMS system in reducing the number of HF exacerbations has been explored in the CHAMPION trial (CardioMEMS Heart Sensor Allows Monitoring of Pressures to Improve Outcomes in NYHA Functional Class III Heart Failure Patients), which demonstrated a reduction in hospitalizations for HF exacerbations in patients whose medical management was guided by adjusting medications based on pulmonary pressures compared with clinical signs and symptoms. Retrospective analyses suggest that HF patients of certain subgroups, including those with left heart dysfunction and those with preserved left ventricular ejection fraction, could benefit from pulmonary pressure monitoring in controlling their HF. Larger studies are needed to determine whether mortality can be reduced with pulmonary pressure monitoring. PMID- 27465539 TI - Advances in Continuous Flow Left Ventricular Assist Device Support for End-Stage Heart Failure: A Therapy in Evolution. AB - The purpose of this review is to highlight recent advances and challenges in the clinical implementation of continuous flow left ventricular assist devices (CF LVADs) in patients with advanced heart failure. Post approval studies of CF LVAD therapy continue to show a progressive improvement in survival and reduction in adverse events. Major trials are ongoing to compare outcomes of an axial flow device (Heart Mate II) and smaller centrifugal flow pumps (HeartWare VADs and Heart Mate III). Numerous studies have investigated strategies to reduce major hematologic and neurologic adverse events by evaluating hemolysis, antithrombotic therapy, and blood pressure control. This review will present the current findings that are centered around the impact of CF LVADs on improving survival and reducing adverse events through an evolution in management and design. PMID- 27465540 TI - Treating Diuretic Resistance: An Overview. AB - Loop diuretics are central to the management of fluid overload in acute decompensated heart failure. However, a variance in the response to loop diuretics can alter a patient's clinical course and has an adverse effect on clinical outcomes. Thus, a diminished response to loop diuretics is an important clinical issue. Factors thought to contribute to diuretic resistance include erratic oral absorption in congested states and postdiuretic sodium retention. Further contributing to diuretic resistance in patients with advanced heart failure are decreases in renal perfusion and alterations in sodium handling that occur in an attempt to maintain circulatory homeostasis. Several pharmacologic interventions have been used to improve diuretic response. Intravenous diuretic administration, increasing diuretic doses, or changing diuretic agents can potentially overcome pharmacokinetic obstacles which contribute to drug resistance. Combination diuretic therapy may be useful to overcome increased sodium retention, dopamine may improve renal perfusion, and hypertonic saline may transiently increase intravascular volume and improve sodium delivery to the tubules of the nephron. Despite the prevalence of diuretic resistance, there remains a paucity of clinical trial evidence to help guide therapy in these patients. PMID- 27465542 TI - CRISPaint allows modular base-specific gene tagging using a ligase-4-dependent mechanism. AB - The site-specific insertion of heterologous genetic material into genomes provides a powerful means to study gene function. Here we describe a modular system entitled CRISPaint (CRISPR-assisted insertion tagging) that allows precise and efficient integration of large heterologous DNA cassettes into eukaryotic genomes. CRISPaint makes use of the CRISPR-Cas9 system to introduce a double strand break (DSB) at a user-defined genomic location. A universal donor DNA, optionally provided as minicircle DNA, is cleaved simultaneously to be integrated at the genomic DSB, while processing the donor plasmid at three possible positions allows flexible reading-frame selection. Applying this system allows to create C-terminal tag fusions of endogenously encoded proteins in human cells with high efficiencies. Knocking out known DSB repair components reveals that site-specific insertion is completely dependent on canonical NHEJ (DNA-PKcs, XLF and ligase-4). A large repertoire of modular donor vectors renders CRISPaint compatible with a wide array of applications. PMID- 27465543 TI - Erratum to: Report of novel genetic variation in NPHS2 gene associated with idiopathic nephrotic syndrome in South Indian children. PMID- 27465541 TI - A reduction in CD90 (THY-1) expression results in increased differentiation of mesenchymal stromal cells. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are multipotent progenitor cells used in several cell therapies. MSCs are characterized by the expression of CD73, CD90, and CD105 cell markers, and the absence of CD34, CD45, CD11a, CD19, and HLA DR cell markers. CD90 is a glycoprotein present in the MSC membranes and also in adult cells and cancer stem cells. The role of CD90 in MSCs remains unknown. Here, we sought to analyse the role that CD90 plays in the characteristic properties of in vitro expanded human MSCs. METHODS: We investigated the function of CD90 with regard to morphology, proliferation rate, suppression of T-cell proliferation, and osteogenic/adipogenic differentiation of MSCs by reducing the expression of this marker using CD90-target small hairpin RNA lentiviral vectors. RESULTS: The present study shows that a reduction in CD90 expression enhances the osteogenic and adipogenic differentiation of MSCs in vitro and, unexpectedly, causes a decrease in CD44 and CD166 expression. CONCLUSION: Our study suggests that CD90 controls the differentiation of MSCs by acting as an obstacle in the pathway of differentiation commitment. This may be overcome in the presence of the correct differentiation stimuli, supporting the idea that CD90 level manipulation may lead to more efficient differentiation rates in vitro. PMID- 27465544 TI - IGDD: a database of intronless genes in dicots. AB - BACKGROUND: Intronless genes are a significant characteristic of prokaryotes. Systematic identification and annotation are primary and crucial steps for determining the functions of intronless genes and understanding their occurrence in eukaryotes. DESCRIPTION: In this paper, we describe the construction of the Intronless Genes Database in Dicots (IGDD; available at http://bio.njfu.edu.cn/igdd/ ), which contains data for five well-annotated plants including Arabidopsis thaliana, Carica papaya, Populus trichocarpa, Salix suchowensis and Vitis vinifera. Using highly visual settings, IGDD displays the structural and functional annotations, the homolog groups, the syntenic relationships, the expression patterns, and the statistical characteristics of intronless genes. In addition, useful tools such as an advanced search and local BLAST are available through a user-friendly and intuitive web interface. CONCLUSION: In conclusion, the IGDD provides a comprehensive and up-to-date platform for researchers to assist the exploration of intronless genes in dicot plants. PMID- 27465545 TI - Intestinal and vascular smooth muscle relaxant effect of Viscum album explains its medicinal use in hyperactive gut disorders and hypertension. AB - BACKGROUND: Viscum album has shown inhibitory effect on different smooth muscles but underlying mechanisms in gut and vascular smooth muscles are not well defined. Additionally, the plant has also importance in managing hyperactive gut and cardiovascular disorders. The current study was aimed to probe a pharmacological base of the smooth muscle relaxant effect of V. album in gut and vascular preparations. METHODS: V. album crude extract (Va. Cr) and its ethyl acetate fraction (Va. EtAc) were studied using in vitro techniques. The antispasmodic activity was performed using isolated rabbit jejunum while the vasorelaxant effects were studied in rabbit aortic rings. RESULTS: Va. Cr and Va. EtAc inhibited spontaneous and high K(+)-induced contractions with EC50 values of 0.31 mg/mL (0.15-0.57) and 0.62 mg/mL (0.3-0.95), respectively. This advocates an antispasmodic effect probably operated through calcium channels blockade (CBB). The proposed mechanism was confirmed by a pretreatment of the tissue with Va. Cr (0.01-0.3 mg/mL), which shifted the Ca(++) concentration-response curves (CRCs) rightward, similar to verapamil. Moreover, Va. Cr showed a partial relaxation against high K(+) and PE (1 MUM) induced contractions in isolated rabbit aorta rings. Va. EtAc caused complete relaxation of high K(+) precontraction and partially relaxed PE (1 MUM) induced contractions, suggesting inhibitory effect on Ca(++) entry, in addition to other possible mechanisms. CRCs were shifted to the right correspondingly to verapamil when the aortic rings were pretreated with Va. Cr and Va. EtAc. CONCLUSIONS: These data indicated that Va. Cr possesses smooth muscle relaxant effect mediated through voltage-dependent Ca(++) channel blockade (CCB), which explains its spasmolytic and vasorelaxant activity. The CCB activity is concentrated more in Va. EtAc. This study provides an evidence for the medicinal importance of V. album in gut spasm and possibly hypertension. PMID- 27465546 TI - miR-302b regulates cell cycles by targeting CDK2 via ERK signaling pathway in gastric cancer. AB - To investigate the molecular mechanism of miR-302b in the regulation of cell proliferation and cell cycle regulation in gastric cancer. Samples of tumor and adjacent normal tissues were collected from 30 gastric cancer patients. Bioinformatics and the dual luciferase report were used for verification of the relationship between miR-302b expression and cyclin-dependent kinase 2 (CDK2). RT PCR and western blot were used to examine CDK2 mRNA and protein levels. The impacts of miR-302b on CDK2 expression and extracellular signal-regulated kinase (ERK) signaling pathway were assessed in cells transfected with miR-302b analogs and CDK2 overexpression carrier, respectively. We used 3-(4,5-dimethylthiazol-2 yl)-2, 5-diphenyltetrazolium bromide (MTT) to assay gastric cancer cell growth after transfection, flow cytometry to analyze cell cycle. Compared with normal tissues, miR-302b expression was significantly lower in gastric cancer tissues, which was significantly related to lymph node metastasis, metastasis distance, and TNM staging. miR-302b expression was increased in miR-302b mimics transfected cells and was significantly decreased in miR-302b inhibitors transfected cells. CDK2 is a target gene of miR-302b. Decreased miR-302b and increased CDK2 expressions can significantly promote proliferation and G1/S phase transformation in gastric cancer. miR-302b promoted the proliferation of gastric cancer cells through upregulation of CDK2, thereby inhibiting ERK pathway, which can in turn inhibit the promoting ability of miR-302b on proliferation. The upregulation of miR-302b reduced the expression of CDK2, and inhibited ERK signaling pathway, thereby inhibiting cell proliferation and G1/S phase conversion rate. Therefore, miR-302b provides new perspectives for research of cell regulation and proliferation in gastric cancer, and new targets for gastric cancer diagnosis and treatment. PMID- 27465547 TI - Discrepancies between asthma control criteria in asthmatic patients with and without obesity. AB - OBJECTIVE: To compare the prevalence of discrepancies between clinical, physiological, and inflammatory asthma control parameters between patients with asthma and obesity and patients with asthma but not obesity using the Asthma Control Scoring System (ACSS). METHODS: A retrospective analysis of demographic data and ACSS scores was performed in two groups of patients with asthma (74 with obesity and 74 without obesity) paired for sex, age, and asthma severity. Scores from each asthma control parameter-clinical (respiratory symptoms), physiological (forced expiratory volume in 1 s), and inflammatory (sputum eosinophil percentage)-were compared. Discrepancy was defined as a >20% difference between two scores. RESULTS: The prevalence of discrepancies between scores was similar between asthma patients with or without obesity. A sub-analysis on patients with uncontrolled asthma (ACSS global score <80%) showed a higher prevalence of discrepancies between the clinical and physiological scores in subjects with obesity, the clinical score being higher than the physiological one in most (87%) cases. CONCLUSIONS: Subjects with obesity and uncontrolled asthma show higher clinical scores than physiological scores, suggesting an under-evaluation of asthma symptoms. Future studies are needed to evaluate the influence of obesity on each type of asthma symptom. PMID- 27465548 TI - DNA repair pathways to regulate response to chemoradiotherapy in patients with locally advanced head and neck cancer. AB - Platinum-based chemoradiotherapy (CRT) is a preferred standard of care for locally advanced head and neck cancer (HNC). However, survival benefit is small, with substantial toxicity and biomarkers of CRT resistance that could guide treatment selection and spare morbidity. Increased DNA repair in solid tumors may contribute to cancer cells' ability to survive in genotoxic stress environments afforded by therapy. We assessed mRNA expression levels of DNA repair-related genes BRCA1, RAP80, 53 binding protein 1 (53BP1), mediator of DNA damage checkpoint 1 (MDC1), and RNF8. We correlated our findings with response and overall survival in 72 head and neck patients treated with weekly carboplatin AUC 2 and radiotherapy. Complete response (CR) to CRT was 50 % in patients with low levels of 53BP1 compared to 6.3 % in patients with high levels (p = 0.0059). Of high BRCA1 mRNA expressors, 41.2 % had CR compared to 29.4 % of low expressors (p = 0.72). For a small group of patients with low 53BP1 and either high BRCA1 or RAP80, CRs were 66.7 and 71.4 %, respectively. A trend for better overall survival (OS) was found for patients with low 53BP1 (15 vs 8 m; p = 0.056). Our findings highlight the potential usefulness of 53BP1 mRNA as a predictive biomarker of response and overall survival in HNC patients treated with chemoradiotherapy. Those with high 53BP1 expression could derive only a meager benefit from treatment. Analysis of BRCA1 and RAP80 could further reinforce the predictive value of 53BP1. Although this was a retrospective study with small sample size, it could inform larger translational studies in HNC. PMID- 27465549 TI - Downregulation of SLC5A8 inhibits hepatocellular carcinoma progression through regulation of Wnt/beta-catenin signaling. AB - SLC5A8 has been shown to be associated with a large number of cancer progressions. However, the biological functions of SLC5A8 in hepatocellular carcinoma (HCC) remain largely unclear. Therefore, we performed this research to explore the functions of SLC5A8 in HCC progression. In this study, SLC5A8 protein and mRNA expression were examined by immunohistochemistry and quantitative real time PCR, respectively, and we found significantly lower expression levels in HCCs than in the corresponding normal liver tissues. Low SLC5A8 expression was significantly correlated with the clinicopathological features of HCC patients. Patients with low SLC5A8 expression have a shorter overall survival time. This interpretation is confirmed by the results obtained from our in vitro experiments; functional assays indicated that overexpression of SLC5A8, by infection with a recombinant plasmid containing SLC5A8, significantly suppressed HCC cell growth, invasion, and migration and induced HCC cell apoptosis. Moreover, the expression levels of beta-catenin, cyclin D1, c-Myc, MMP-2, and FAK detected by western blotting were downregulated in SLC5A8-transfected HCC cells compared with control-transfected cells, indicating that SLC5A8 has a tumor suppressive function that acts by interfering with Wnt/beta-catenin signaling in HCC. PMID- 27465550 TI - MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer. AB - Hypoxia-inducible factor 2alpha (HIF2alpha) plays critical roles in cancer progression. Although the mechanisms of HIF2alpha translation and degradation have been well studied, the mechanism for HIF2alpha regulation at transcriptional level is still not fully understood. Here, we present evidence that DNA methylation in promoter contributes to transcription of EPAS1 coding HIF2alpha. Methylated CpG binding protein 3 (MBD3) contributes to the intricate regulatory mechanism. We showed that MBD3 bound to the EPAS1 promoter in breast cancer cells and amplified EPAS1 transcription through demethylating CpG located around transcriptional start site in MDA-MB-468 cells. This enabled MDA-MB-468 cells to activate HIF2alpha-mediated angiogenesis. However, in 7860 cells, the demethylation function of MBD3 on EPAS1 was not observed because of the poor methylated-CpG promoter. Nevertheless, depletion of MBD3 induced by shRNA decreased EPAS1 transcription and therefore decreased HIF2alpha-mediated cellular response in both MDA-MB-468 and 7860 cancer cells. These results indicated that the endogenous MBD3 was involved in regulating the transcription and therefore the transcriptional activities of HIF2alpha, suggesting that MBD3 may be a potential therapeutic target of tumor. PMID- 27465551 TI - MicroRNA-106b promotes pituitary tumor cell proliferation and invasion through PI3K/AKT signaling pathway by targeting PTEN. AB - The purpose of this study was to investigate the expression of microRNA-106b (miR 106b) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in pituitary tumor and to confirm whether miR-106b promotes proliferation and invasion of pituitary tumor cells through the PI3K/AKT signaling pathway by targeted regulation of PTEN expression, and thereby to find new targets for the treatment of pituitary tumor. Fifty-five cases of pituitary tumor tissue samples were collected, including 29 cases of invasive pituitary tumor, non-invasive 26 cases, and 8 normal pituitaries. The expression level of miR-106b in pituitary tumor tissue was detected by quantitative real-time PCR, and the expression of PTEN protein was detected by immunohistochemistry. PTEN 3'-untranslated region (UTR) luciferase vector was constructed, and dual-luciferase reporter gene assay was employed to examine the effect of miR-106b on PTEN 3'-UTR luciferase activity. AtT-20 cells were transfected with miR-106b mimics, miR-106b inhibitor, PTEN expression plasmid, and miR-106b mimics + PTEN expression plasmid respectively, and the changes in cellular proliferation and invasion were observed via MTT method and transwell assay respectively. PTEN messenger RNA (mRNA) expression was determined by quantitative real-time PCR, and western blotting was performed to detect the expression of PTEN, PI3K, AKT, and pAKT. miR 106b showed up-regulation in invasive pituitary tumor tissue: the expression level was significantly up-regulated compared with normal tissues and the non invasive pituitary tumor tissue (P < 0.05). The positive rate of PTEN protein expression in invasive pituitary tumor tissues was significantly lower than in normal and non-invasive tissues (P < 0.01). Dual-luciferase reporter gene assay showed that miR-106b could bind to the 3'-UTR of PTEN specifically and significantly inhibited the luciferase activity, cutting the 46 % (P < 0.01). Down-regulation of miR-106b or up-regulation of PTEN could suppress cell proliferation and invasion of AtT-20 cells, and PTEN expression plasmid could partially simulate the function of miR-106b. Expression of PTEN mRNA and protein decreased significantly in AtT-20 cells overexpressing miR-106b. The expression levels of PI3K and p-AKT were significantly inhibited by miR-106b inhibitor and increased by miR-106b mimics. The expression of miR-106b showed up-regulation in pituitary tumor tissues, while the protein expression of PTEN presented opposite results. The findings of this study further demonstrated that miR-106b as an oncogene regulated the pituitary tumor cell proliferation and invasion in vitro by directly targeting PTEN through the PI3K/AKT signaling pathway. Our study suggests that miR-106b and PTEN are likely to serve as potential diagnostic biomarkers or therapeutic targets for pituitary tumor treatment in the future. PMID- 27465552 TI - PTP1B promotes aggressiveness of breast cancer cells by regulating PTEN but not EMT. AB - Metastasis is a complicated, multistep process and remains the major cause of cancer-related mortality. Exploring the molecular mechanisms underlying tumor metastasis is crucial for development of new strategies for cancer prevention and treatment. In this study, we found that protein tyrosine phosphatase 1B (PTP1B) promoted breast cancer metastasis by regulating phosphatase and tensin homolog (PTEN) but not epithelial-mesenchymal transition (EMT). By detecting PTP1B expression of the specimens from 128 breast cancer cases, we found that the level of PTP1B was higher in breast cancer tissues than the corresponding adjacent normal tissues. Notably, PTP1B was positively associated with lymph node metastasis (LNM) and estrogen receptor (ER) status. In vitro, disturbing PTP1B expression obviously attenuated cell migration and invasion. On the contrary, PTP1B overexpression significantly increased migration and invasion of breast cancer cells. Mechanistically, PTP1B knockdown upregulated PTEN, accompanied with an abatement of AKT phosphorylation and the expression of matrix metalloproteinase 2 (MMP2) and MMP7. Conversely, forced expression of PTP1B reduced PTEN and increased AKT phosphorylation as well as the expression of MMP2 and MMP7. Notably, neither EMT nor stemness of breast cancer cells was regulated by PTP1B. We also found that PTP1B acted as an independent prognostic factor and predicted poor prognosis in ER-positive breast cancer patients. Taken together, our findings provide advantageous evidence for the development of PTP1B as a potential therapeutic target for breast cancer, especially for ER-positive breast cancer patients. PMID- 27465553 TI - Mechanisms underlying the association between obesity and Hodgkin lymphoma. AB - A solid body of knowledge indicates that overweight and obese subjects are prone to develop cancer, aggressive disease, and death more than their lean counterparts. While obesity has been causally associated with various cancers, only a limited number of studies beheld the link with classical Hodgkin lymphoma (HL). Contemporary meta-analysis and prospective studies confirmed the association of body mass index with HL. Besides epidemiological evidence, excess adiposity is known to influence tumor behavior through adipokines, adipose derived stem cell migration, and metabolism regulation, and by modulating immunoinflammatory response. Nevertheless, the obesity paradox has been described in few cancers. Considering that adipose tissue is an immunomodulatory organ, and that inflammation is the cornerstone of HL pathophysiology, the rationale for being causally related due to endocrine/paracrine interactions cannot be negligible. In this hypothesis-generating review, we explore the biologically plausible links between excess adiposity and HL in light of recent basic and clinical data, in order to create a basis for understanding the underlying mechanisms and foster applied research. The establishment of an association of excess adiposity with HL will determine public health preventive measures to fight obesity and eventually novel therapeutic approaches in HL patients. PMID- 27465554 TI - High expression of Rad51c predicts poor prognostic outcome and induces cell resistance to cisplatin and radiation in non-small cell lung cancer. AB - Rad51c is critical for homologous recombination repair and genomic stability and may play roles in tumorigenesis and cancer therapy. We investigated the expression level and clinical significance of Rad51c in non-small cell lung cancer (NSCLC) and determined the effect of Rad51c on NSCLC cell chemosensitivity and radiosensitivity. Rad51c expression was detected using immunohistochemistry and was higher in NSCLC patient samples than in adjacent normal tissues. Kaplan Meier analysis revealed that high Rad51c expression was an independent predictor of short overall survival (OS) and disease-free survival (DFS) in NSCLC patients receiving chemotherapy and/or radiotherapy. Furthermore, Rad51c knockdown increased the killing effect of ionizing radiation (IR) and enhanced cisplatin induced apoptotic cells in NSCLC cells by disrupting the repair of cisplatin- and IR-induced DNA damage. In addition, ectopic expression of Rad51c dramatically enhanced NSCLC cell resistance to cisplatin and radiotherapy. These findings suggest that increased expression of Rad51c may confer resistance to chemotherapy and/or radiotherapy of NSCLC, and also be an independent prognostic factor for patient outcome. Therefore, targeting Rad51c may represent an improved therapeutic strategy for NSCLC patients with locally advanced disease. PMID- 27465555 TI - Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma. AB - Hepatocellular carcinoma (HCC) and hepatic cholangiocarcinoma (CC) are the most aggressive malignancies with a poor prognosis in humans, and hepatic cholangiocarcinoma (CC) exhibits greater malignant behaviour. Yes-associated protein (YAP) is an important downstream target of the Hippo signalling pathway. As an oncogene, it plays a vital role in the occurrence and development of tumours. Our study focuses on the clinical significance of YAP protein expression in HCC and CC. Furthermore, we sought to explore the different survival rates between HCC and CC. A total of 137 patients with HCC and 122 with CC after resection were evaluated by immunohistochemistry for the expression of YAP. Our results showed that positive expression rates of YAP were more frequently noted in CC 67.2 % (82/122) than in HCC 56.9 % (78/137) (P = 0.024). High YAP expression in HCC and CC was significantly associated with tumour size (P < 0.001 and P = 0.019, respectively), liver cirrhosis (P = 0.002 and P = 0.009, respectively), vascular invasion (P = 0.047 and P = 0.018, respectively), multiplicity (P = 0.019 and P = 0.015, respectively), and intrahepatic metastasis (P = 0.015 and P = 0.047, respectively). Importantly, recurrence-free survival and disease-specific survival rates were lower in CC with high YAP expression than in HCC with high YAP expression (P < 0.001 and P < 0.001, respectively). Overall, high YAP expression was more frequently found in CC than in HCC, and YAP overexpression was associated with poor survival rates in patients with HCC and CC. Targeting YAP treatment requires further prospective investigations in larger patient populations. PMID- 27465556 TI - Fibronectin protects lung cancer cells against docetaxel-induced apoptosis by promoting Src and caspase-8 phosphorylation. AB - Fibronectin is involved in orchestrating many diverse cellular behaviors, including adhesion, invasion, differentiation, and proliferation and recently has also been shown to participate in the development of chemoresistance. In this study, we found that fibronectin expression was inversely correlated with clinical responses to docetaxel treatment in non-small cell lung cancer patients. Subsequently, we showed that fibronectin pretreatment could enhance cell viability and reduce apoptosis in docetaxel-treated lung cancer cells because fibronectin induced phosphorylated Src and caspase-8, rendering the later inactive, thus inhibiting docetaxel-induced apoptosis. The inhibition of apoptosis by fibronectin was found to be enhanced by Src overexpression and reversed by Src knockdown in lung cancer cells. Further investigation revealed that a downregulation of phospho-Src via treatment with a Src kinase inhibitor could also abolish fibronectin activity and recover docetaxel-induced apoptosis. Molecular studies revealed that this reversion was due to decreased phospho-Src levels rather than a reduction in total Src expression. Inhibition of phospho-Src reduced phospho-caspase-8 and promoted caspase-8 activity, restoring apoptosis following docetaxel and fibronectin co-treatment. Finally, xenografts experiments demonstrated that fibronectin promoted lung cancer cell proliferation during docetaxel treatment in vivo. Our findings indicate that fibronectin promotes Src and caspase-8 phosphorylation in lung cancer cells, which decreases caspase-8 activation and protects tumor cells from docetaxel-induced apoptosis. Therefore, the fibronectin/Src/caspase-8 pathway may play a crucial role in docetaxel resistance in lung cancer. PMID- 27465557 TI - The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide, and its incidence continues to increase. However, the mechanism underlying the development and progression of HCC remains unknown. The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family and influences the carcinogenesis of multiple types of tumors, but the biological roles of SOCS2 in HCC remain unclear. In this study, we found that SOCS2 expression was reduced in HCC tissues compared with matched noncancerous liver tissues. Moreover, decreased SOCS2 expression was significantly associated with the presence of intrahepatic metastasis and high histological grade in HCC patients. Colony formation assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that overexpression of SOCS2 or knockdown of endogenous SOCS2 did not significantly affect cell proliferation and tumorigenicity in HCC cells in vitro and in vivo. However, SOCS2 overexpression significantly inhibited the migration and invasion of HCC cells in vitro and inhibited metastasis in vivo. Consistent with these findings, the knockdown of endogenous SOCS2 enhanced migration and invasion in HCC cells in vitro. Our study demonstrated that SOCS2 inhibited human HCC metastasis, and SOCS2 might provide a new potential therapeutic strategy for treating HCC. PMID- 27465558 TI - Altered brain network dynamics in youths with autism spectrum disorder. AB - The heterogeneity of behavioral manifestation of autism spectrum disorders (ASDs) requires a model which incorporates understanding of dynamic differences in neural processing between ASD and typically developing (TD) populations. We use network approach to characterization of spatiotemporal dynamics of EEG data in TD and ASD youths. EEG recorded during both wakeful rest (resting state) and a social-visual task was analyzed using cross-correlation analysis of the 32 channel time series to produce weighted, undirected graphs corresponding to functional brain networks. The stability of these networks was assessed by novel use of the L1-norm for matrix entries (edit distance). There were a significantly larger number of stable networks observed in the resting condition compared to the task condition in both populations. In resting state, stable networks persisted for a significantly longer time in children with ASD than in TD children; networks in ASD children also had larger diameter, indicative of long range connectivity. The resulting analysis combines key features of microstate and network analyses of EEG. PMID- 27465559 TI - Movement patterns of limb coordination in infant rolling. AB - Infants must perform dynamic whole-body movements to initiate rolling, a key motor skill. However, little is known regarding limb coordination and postural control in infant rolling. To address this lack of knowledge, we examined movement patterns and limb coordination during rolling in younger infants (aged 5 7 months) that had just begun to roll and in older infants (aged 8-10 months) with greater rolling experience. Due to anticipated difficulty in obtaining measurements over the second half of the rolling sequence, we limited our analysis to the first half. Ipsilateral and contralateral limbs were identified on the basis of rolling direction and were classified as either a stationary limb used for postural stability or a moving limb used for controlled movement. We classified the observed movement patterns by identifying the number of stationary limbs and the serial order of combinational limb movement patterns. Notably, older infants performed more movement patterns that involved a lower number of stationary limbs than younger infants. Despite the wide range of possible movement patterns, a small group of basic patterns dominated in both age groups. Our results suggest that the fundamental structure of limb coordination during rolling in the early acquisition stages remains unchanged until at least 8-10 months of age. However, compared to younger infants, older infants exhibited a greater ability to select an effective rotational movement by positioning themselves with fewer stationary limbs and performing faster limb movements. PMID- 27465560 TI - [The wearable cardioverter/defibrillator : Temporary protection from sudden cardiac death]. AB - In the majority of cases sudden cardiac death (SCD) is caused by ventricular tachyarrhythmia. Implantable cardioverter-defibrillators (ICD) represent an evidence-based and established method for prevention of SCD. For patients who do not fulfill the criteria for guideline-conform implantation of an ICD but still have an increased, e.g. transient risk for SCD, a wearable cardioverter defibrillator (WCD) vest was developed to temporarily prevent SCD. Numerous studies have shown the safety and efficacy of the WCD, although there is still a gap in evidence concerning a reduction in overall mortality and improvement in prognosis. This article gives an overview on the currently available literature on WCD, the indications, potential risks and complications. PMID- 27465561 TI - Evaluation of the Farmers' Markets for Kids programme. AB - OBJECTIVE: To assess the impact of Farmers' Markets for Kids, a farmers' market based, child-oriented nutrition education programme, on attitudes and behaviours related to preparing and consuming produce among child participants and their caregivers in New York City (NYC). DESIGN: Retrospective pre-test/post-test cross sectional survey with caregivers of children participating in Farmers' Markets for Kids classes. SETTING: Four NYC farmers' markets where Farmers' Markets for Kids classes are implemented; these markets serve low-income communities. SUBJECTS: Two hundred and twelve adult caregivers of children who participated in Farmers' Markets for Kids classes. RESULTS: Caregivers reported that children's consumption of fruits and vegetables had increased since participating in Farmers' Markets for Kids and that their children more frequently assisted with food preparation; both of these improvements were statistically significant. Caregivers also reported significant improvements in attitudes: since participating in Farmers' Markets for Kids, their children were more willing to try new fruits and vegetables and caregivers found it easier to prepare fruits and vegetables for their children. Almost all respondents (99 %) reported purchasing more fruits and vegetables since participating in Farmers' Markets for Kids and 95 % had prepared the programme's recipes at home. CONCLUSIONS: Findings suggest that Farmers' Markets for Kids may be an effective approach for increasing produce consumption among participating children and improving related attitudes among children and caregivers. This evaluation provides support for future efforts to undertake more rigorous evaluations of such programmes. PMID- 27465562 TI - Origin of host-parasite associations of Marsupialges misonnei (Acariformes: Psoroptidae)-a parasitological detective story. AB - Host associations of permanent ectoparasitic mite Marsupialges misonnei Fain, 1963 (Acariformes: Psoroptidae: Marsupialginae) are analyzed. This species was first recorded from an ethanol-preserved museum specimen of Caluromys philander (Linnaeus, 1758) (Didelphimorphia: Didelphidae) originating from French Guiana. We discovered specimens of M. misonnei from both species known in the carnivore genus Nasua (Carnivora: Procyonidae): N. narica (Linnaeus, 1766) from Panama (collected in the field) and N. nasua (Linnaeus, 1766) from Brazil (collected from dry museum specimen). Two alternative hypotheses about an initial host of this mite (bare-tailed woody opossum or coatis) are discussed. We argue that M. misonnei was originally parasitic on Nasua spp. and occasionally contaminated C. philander from these hosts in the collecting process. PMID- 27465563 TI - Differentiation of Trypanosoma cruzi I (TcI) and T. cruzi II (TcII) genotypes using genes encoding serine carboxypeptidases. AB - The parasite Trypanosoma cruzi (Kinetoplastida, Trypanosomatidae) can be classified based on biochemical and molecular markers, into six lineages or discrete typing units (DTUs), T. cruzi I-VI (TcI-VI), from which TcI and TcII are the parental genotypes. Trying to understand the dispersion of the subpopulations of T. cruzi in nature and its complex transmission cycles, the serine carboxypeptidase genes of T. cruzi were used as a molecular marker in the present study. DTUs of 25 T. cruzi isolates derived from different hosts and from different regions of Brazil were classified. Using specific primers, the complete serine carboxypeptidase open reading frame of 1401 bp was sequenced. The obtained data shows significant differences in the sequences of TcI and TcII. The analysis of the T. cruzi significantly different serine carboxypeptidase genes allowed distinguishing between the parental DTUs TcI to TcII and the hybrid DTU TcVI which grouped within the latter branch. The sequence diversity within the T. cruzi subpopulations was rather low. The analysis using the genes encoding proteases seems to be an interesting approach for the reconstruction of the origin and genotype evolution of T. cruzi. PMID- 27465565 TI - A mathematical model provides new insights into solid organ transplant-associated acute graft-versus-host disease. AB - Solid organ transplantation-associated acute graft-versus-host disease (SOT aGvHD) is a rare but highly fatal condition. Our poor understanding of this entity in addition to its rarity has hampered treatment progress and most patients succumb to the disease. A mechanistic mathematical model is developed to replicate and explain the complex pathogenesis of SOT-aGvHD. The model captures a number of important features of SOT-aGvHD including (i) the occurrence of stable and persistent mixed chimerism in some, but not all, cases, (ii) fluctuation in chimerism in some persistently mixed chimeric cases, (iii) rare occurrence of full donor chimerism, and (iv) beneficial effect of escalating immunosuppression in some cases of SOT-aGvHD and detrimental effect in others. In addition, the model predicts the conditions under which escalation or de-escalation of immunosuppression would be the preferred treatment strategy. In an exceedingly rare condition such as SOT-aGvHD, where prospective trials are not feasible, mathematical modeling can provide useful insights into pathogenesis and treatment. PMID- 27465564 TI - Immunolocalization of alpha18- and alpha12-giardin in Giardia lamblia trophozoites. AB - To study subcellular localization of alpha18- and alpha12-giardin in Giardia lamblia trophozoites, the alpha18- and alpha12-giardin genes were amplified from G. lamblia assemblage A, respectively. The PCR products were cloned into the prokaryotic expression vector pET-28a(+), and the positive recombinant plasmids were transformed into E. coli Rosetta (DE3) strain for the expression, and expressed alpha18- and alpha12-giardin fusion protein were purified by Ni-Agarose resin, respectively. Mice were immunized with purified fusion proteins for preparation of polyclonal antibody, and then the subcellular localization of alpha18- and alpha12-giardin was determined by fluorescence immunoassay. Results showed that the concentrations of purified alpha18- and alpha12-giardin fusion proteins were 1.20 and 0.86 mg/ml, respectively. The titers of anti-alpha18- and anti-alpha12-giardin polyclonal antibody were both as high as 1:25600 dilutions. Immunofluorescent analysis showed that alpha18- and alpha12-giardin proteins were mainly localized at four pairs of flagella and the cytoplasm of G. lamblia trophozoites, suggesting that alpha18- and alpha12-giardin are the flagella and cytoplasm-associated proteins, respectively. The above information would lay the foundation for research about the crystal structure and biological function of alpha18- and alpha12-giardin. PMID- 27465566 TI - Tropical/Subtropical Peatland Development and Global CH4 during the Last Glaciation. AB - Knowledge of peatland development over the tropical/subtropical zone during the last glaciation is critical for understanding the glacial global methane cycle. Here we present a well-dated 'peat deposit-lake sediment' alternate sequence at Tengchong, southwestern China, and discuss the peatland development and its linkage to the global glacial methane cycle. Peat layers were formed during the cold Marine Isotope Stage (MIS)-2 and -4, whereas lake sediments coincided with the relatively warm MIS-3, which is possibly related to the orbital/suborbital variations in both temperature and Asian summer monsoon intensity. The Tengchong peatland formation pattern is broadly synchronous with those over subtropical southern China and other tropical/subtropical areas, but it is clearly in contrast to those over the mid-high Northern Hemisphere. The results of this work suggest that the shifts of peatland development between the tropical/subtropical zone and mid-high Northern Hemisphere may have played important roles in the glacial/interglacial global atmospheric CH4 cycles. PMID- 27465567 TI - Vaccinia virus dissemination requires p21-activated kinase 1. AB - The orthopoxvirus vaccinia virus (VACV) interacts with both actin and microtubule cytoskeletons in order to generate and spread progeny virions. Here, we present evidence demonstrating the involvement of PAK1 (p21-activated kinase 1) in the dissemination of VACV. Although PAK1 activation has previously been associated with optimal VACV entry via macropinocytosis, its absence does not affect the production of intracellular mature virions (IMVs) and extracellular enveloped virions (EEVs). Our data demonstrate that low-multiplicity infection of PAK1(-/-) MEFs leads to a reduction in plaque size followed by decreased production of both IMVs and EEVs, strongly suggesting that virus spread was impaired in the absence of PAK1. Confocal and scanning electron microscopy showed a substantial reduction in the amount of VACV-induced actin tails in PAK1(-/-) MEFs, but no significant alteration in the total amount of cell-associated enveloped virions (CEVs). Furthermore, the decreased VACV dissemination in PAK1(-/-) cells was correlated with the absence of phosphorylated ARPC1 (Thr21), a downstream target of PAK1 and a key regulatory subunit of the ARP2/3 complex, which is necessary for the formation of actin tails and viral spread. We conclude that PAK1, besides its role in virus entry, also plays a relevant role in VACV dissemination. PMID- 27465568 TI - PARS PLANA VITRECTOMY FOR LATE VITREORETINAL SEQUELAE OF INFECTIOUS ENDOPHTHALMITIS: Surgical Management and Outcomes. AB - PURPOSE: To report the visual acuity outcomes after pars plana vitrectomy for delayed vitreoretinal sequelae of infectious endophthalmitis. All eyes were initially treated with intravitreal antibiotics (Abx). METHODS: Multicenter, retrospective, consecutive case series. RESULTS: Forty-two eyes met the study criteria. The mean follow-up was 48 weeks (SD +/- 61.8). Mean interval from Abx to pars plana vitrectomy was 13 weeks (SD +/- 14.3, range 2-70). Indications for pars plana vitrectomy included vitreous opacities (VO) (n = 22), epiretinal membrane (n = 9), and retinal detachment (n = 11). LogMAR visual acuity improved from 1.87 (Snellen equivalent: 20/1,482) preoperatively to 1.35 (Snellen equivalent: 20/447) at final evaluation (P < 0.001). LogMAR visual acuity improved significantly for patients with vitreous opacities (P < 0.01) and retinal detachment (P = 0.02) but not for patients with epiretinal membranes (P = 0.08). CONCLUSION: Patients with infectious endophthalmitis can gain vision if they have a pars plana vitrectomy for delayed sequelae such as vitreous opacities or for retinal detachment. PMID- 27465569 TI - TOLERANCE OF INTRAVITREAL DEXAMETHASONE IMPLANTS IN PATIENTS WITH OCULAR HYPERTENSION OR OPEN-ANGLE GLAUCOMA. AB - PURPOSE: Evaluate the pressure tolerance of dexamethasone implants in open-angle glaucoma (OAG+) patients and ocular hypertension (OHT+) patients compared with nonglaucomatous and nonhypertensive patients. METHODS: Retrospective observational 2-center, controlled study including 100 patients treated with intravitreal injections of dexamethasone, divided into 2 groups: Group 1, OAG+/OHT+ (n = 50), and Group 2, OAG-/OHT- (n = 50), matched for age and disease. Intraocular pressure (IOP) and hypotensive treatment were evaluated initially, at 8 days, and every month for 6 months after intravitreal treatment. The primary endpoint was IOP increase greater than 10 mmHg. RESULTS: Thirty-four percent of glaucomatous patients experienced a transient IOP increase greater than 10 mmHg versus 16% in the OAG-/OHT- group (P = 0.06). Intraocular pressure greater than 25 mmHg was recorded early on Day 8 in 6% of the OAG+ patients versus 2% of the OAG- patients. Fifty-four percent of the glaucoma patients increased their treatment, and hypotensive treatment was initiated in 38% of the OAG- patients (P = 0.1). Filtering surgery was only required in the OAG+/OHT+ group (6% versus 0%), particularly in dual-therapy and triple-therapy patients, who had a higher risk of filtering surgery (P = 0.008). CONCLUSION: Half of the OAG+ and OHT+ patients needed an add-on treatment, with early onset beginning on Day 8 in 6%. This emphasizes the need for IOP monitoring during treatment, especially for OAG+/OHT+ patients. PMID- 27465571 TI - FACTORS ASSOCIATED WITH PENTOSIDINE ACCUMULATION IN THE HUMAN VITREOUS. AB - PURPOSE: To explore factors associated with pentosidine accumulation in the human vitreous. METHODS: Vitreous samples were obtained during trans pars plana vitrectomy for macular hole or rhegmatogenous retinal detachment. Patient characteristics included age, gender, and diabetes mellitus. Ocular characteristics included pseudophakia, posterior vitreous detachment, and presence of intraocular fibrosis (epiretinal membrane, proliferative vitreoretinopathy, or both). Pentosidine concentration as a measure of accumulation of advanced glycation end products was determined by high performance liquid chromatography. RESULTS: Pentosidine concentrations were measured in 222 vitrectomy samples (118 female and 104 male patients [median age 66 years], treated for macular hole [n = 105] or rhegmatogenous retinal detachment [n = 117]). Pentosidine was found to accumulate significantly with age (P < 0.001). After correction for age, a multivariable linear regression model revealed significantly higher pentosidine values in eyes with intraocular fibrosis (P = 0.001), in phakic as compared with pseudophakic eyes (P = 0.02), and in the absence of a complete posterior vitreous detachment (P = 0.018). The authors found no association with diabetes mellitus or gender. CONCLUSION: This study confirmed an age-related pentosidine accumulation in the vitreous and found new factors relating to pentosidine levels. Findings support the hypothesis of enzyme-induced vitreous liquefaction and the hypothesis of pentosidine as a pro fibrotic factor. PMID- 27465570 TI - EVALUATION OF SHORT-TERM OUTCOMES OF INTRAVITREAL AFLIBERCEPT INJECTIONS FOR AGE RELATED MACULAR DEGENERATION USING FOCAL MACULAR ELECTRORETINOGRAPHY. AB - PURPOSE: To evaluate the relationship between morphological changes and functional improvements assessed using focal macular electroretinograms after intravitreal aflibercept (IVA) injections in eyes with wet age-related macular degeneration. METHODS: The clinical records of 42 eyes of 42 consecutive patients with naive, wet age-related macular degeneration received 3 monthly IVA were reviewed. The best-corrected visual acuity, central foveal thickness, outer retinal thickness, inner retinal thickness at baseline and 1 month after each IVA, and focal macular electroretinograms at baseline and 1 month after the first and third IVA were compared. RESULTS: Best-corrected visual acuity was improved after the third IVA (P = 0.0091). Central foveal thickness and outer retinal thickness showed decreases after every IVA (P < 0.001, respectively). Inner retinal thickness showed a decrease after the second IVA (P = 0.002), after and third IVA (P = 0.001). On focal macular electroretinograms, a- and b-wave amplitudes showed increases after the third IVA (P = 0.0028, P = 0.0012, respectively). Significant correlations were observed between best-corrected visual acuity and central foveal thickness, a-wave amplitude and outer retinal thickness, and b-wave amplitude and inner retinal thickness changes after the third IVA. CONCLUSION: All parameters significantly recovered after three monthly IVA, with a correlation between functional improvements and morphological changes. PMID- 27465572 TI - COMPLEX RETINAL DETACHMENT IN PHAKIC PATIENTS: Previtrectomy Phacoemulsification Versus Combined Phacovitrectomy. AB - PURPOSE: To assess the impact of phacoemulsification performed one week before pars plana vitrectomy versus combined phacovitrectomy on postoperative anterior segment status and final functional and anatomical outcomes in phakic patients affected by complex rhegmatogenous retinal detachment. METHODS: The authors retrospectively reviewed the records of 59 phakic patients affected by complex rhegmatogenous retinal detachment. Twenty-nine patients underwent cataract surgery 7 days before vitrectomy (preemptive cataract surgery-Group 1), whereas 30 patients underwent combined phacovitrectomy (Group 2). Preoperative, intraoperative, early- and late-postoperative outcomes were measured and compared. RESULTS: Numbers of previous retinal surgical procedures, nuclear sclerosis grade, proliferative vitreoretinopathy grade, eyes with inferior breaks, surgical time, and ratio of silicone oil/gas tamponade were all similar between the two groups. After surgery, there was less extension of posterior synechia in Group 1. There was no significant difference in fibrin, number of patients with posterior synechia, final intraocular pressure, retinal redetachment rate, final retinal status, or final best-corrected visual acuity. CONCLUSION: Preemptive cataract surgery was associated with less extensive postoperative posterior synechia, however, its final functional and anatomical outcomes were not significantly different from those of phacovitrectomy. Both approaches were efficacious. PMID- 27465573 TI - TWENTY-SEVEN-GAUGE VERSUS 25-GAUGE VITRECTOMY FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT. AB - PURPOSE: To compare the safety and efficacy of 27-gauge (G) pars plana vitrectomy (PPV) with 25-G PPV for the treatment of primary rhegmatogenous retinal detachment (RRD). METHODS: In this prospective randomized comparative interventional study, 15 eyes from 30 patients were treated with 27-G PPV (Group A); the other 15 eyes underwent 25-G PPV (Group B). All patients were examined preoperatively and then 1 day, 1 week, 1 month, 3 months, and 6 months after PPV. RESULTS: In each group, retinal reattachment was observed in 14 out of 15 eyes after surgery. After six months, both groups showed a statistically significant improvement in mean BCVA (P < 0.001); the difference between the two groups was not statistically significant. No cases of ocular hypotony were seen, whereas intraocular hypertension occurred in two patients in Group B. No intraoperative nor postoperative complications were registered. There was no significant difference in operating times (P = 0.52). CONCLUSION: The safety and efficacy of 27-G PPV for rhegmatogenous retinal detachment appear similar to 25-GPPV. We found no anatomical or functional difference in terms of postoperative BCVA, IOP, complications, and operating time. Twenty-seven-G vitrectomy is therefore a valid option in the treatment of rhegmatogenous retinal detachment. PMID- 27465574 TI - AIMING FOR THE BULL'S EYE: The Cost-Utility of Screening for Hydroxychloroquine Retinopathy. AB - BACKGROUND: Throughout medicine, the cost of various treatments has been increasingly studied with the result that certain management guidelines might be reevaluated in their context. Cost-utility is a term referring to the expense of preventing the loss of quality of life, quantified in dollars per quality adjusted life year. In 2002, the American Academy of Ophthalmology published hydroxychloroquine screening recommendations which were revised in 2011. The purpose of this report is to estimate the cost-utility of these recommendations. METHODS: A hypothetical care model of screening for hydroxychloroquine retinopathy was formulated. The costs of screening components were calculated using 2016 Medicare fee schedules from the Centers for Medicare and Medicaid Services. RESULTS: The cost-utility of screening for hydroxychloroquine retinopathy with the 2011 American Academy of Ophthalmology guidelines was found to vary from 33,155 to 344,172 dollars per quality-adjusted life year depending on the type and number of objective screening tests chosen, practice setting, and the duration of hydroxychloroquine use. Screening had a more favorable cost utility when the more sensitive and specific diagnostics were used, and for patients with an increased risk of toxicity. CONCLUSION: American Academy of Ophthalmology guidelines have a wide-ranging cost-utility. Prudent clinical judgment of risk stratification and tests chosen is necessary to optimize cost utility without compromising the efficacy of screening. PMID- 27465575 TI - Depth perception, dark adaptation, vigilance and accident proneness of Chinese coal mine workers. AB - To explore the relationships between human factors and accident proneness of coal mine workers, the depth perception, dark adaptation and vigilance abilities of 239 Chinese coal mine workers were tested and their accident proneness was surveyed with an accident proneness questionnaire. The results indicated that dark adaptation and vigilance abilities of the mine workers declined with increasing age. Vigilance had a significant negative relationship with accident proneness. There were significant differences in vigilance between coal mine workers doing different types of work. Individual difference in vigilance was relevant to the type of work that an individual did in a coal mine. The dark adaptation index had a significant positive relationship with accident proneness. Coal mine workers with weaker dark adaptation ability were also more accident prone. Some ergonomics recommendations concerning coal mine safety management in China are proposed. PMID- 27465576 TI - Analysis of second- and third-line antihypertensive treatments after initial therapy with an angiotensin II receptor blocker using real-world Japanese data. AB - Combination therapy using two or three classes of drugs is often required to treat hypertension to prevent cardiovascular disease. In this study, we examined combination therapies administered following initial therapy with an angiotensin II receptor blocker (ARB) in hypertensive Japanese patients. To determine which classes of antihypertensives are being prescribed as second- or third-line treatments for patients who were initially treated with a single ARB, we analyzed prescription claims data from two Japanese health-care databases for 2008 to 2015. Among the 26 998 patients who were initially treated with a single ARB (from one database), calcium channel blockers (CCBs) were the most frequently prescribed second-line antihypertensive, as these medicines were added for >20% of patients within 1 year of ARB prescription initiation. The addition rates of CCBs as a second-line therapy differed depending on the initial ARB type. In contrast, <10% of patients received a diuretic as a second-line antihypertensive. Among the 48 813 patients who were prescribed an ARB in combination with a CCB (as shown in the other database), diuretics were prescribed as third-line antihypertensives more frequently than increased doses of CCBs or ARBs. Diuretics were added for 8% of patients within 2 years of CCB addition, and the addition rates differed based on the CCB dose used for combination therapy. We also found that the addition rates of diuretics differed depending on patient clinical histories among ARB and CCB recipients. PMID- 27465577 TI - Endothelial nitric oxide synthase gene G894T polymorphism and risk assessment for pregnancy-induced hypertension: evidence from 11 700 subjects. AB - Recent studies have reported the association between endothelial nitric oxide synthase (eNOS) gene G894T polymorphism and pregnancy-induced hypertension (PIH). However, the results have been inconsistent. We conducted a comprehensive meta analysis to explore this association. A total of 36 case-control studies involving 4028 PIH cases and 7672 controls were ultimately included. In the overall analysis, no association was identified between eNOS gene G894T polymorphism and PIH risk in any of the genetic models. In the subgroup analysis, the results showed that T-allele carriers had a higher risk of PIH than those with the G allele in Asians (G vs. T: odds ratio (OR)=0.76, 95% confidence interval (CI)=0.63-0.91, P=0.002; GT+TT vs. GG: OR=1.32, 95% CI=1.09-1.59, P=0.004; TT vs. GT+GG: OR=1.96, 95% CI=1.26-3.06, P=0.003; TT vs. GG: OR=1.99, 95% CI=1.27-3.11, P=0.003; GT vs. GG: OR=1.23, 95% CI=1.05-1.43, P=0.009). For Latin American and African populations, the association between G894T polymorphism and susceptibility to PIH was only observed in the dominant model. However, no association was observed in Europeans and Americans. Therefore, eNOS gene G894T polymorphism was related to PIH risk, especially for Asians. PMID- 27465578 TI - Haematological malignancies in pregnancy: An overview with an emphasis on thrombotic risks. AB - With increase of maternal age, the incidence of haematological malignancies during pregnancy is rising and posing diagnostic and treatment challenges. Lymphoma is the fourth most common malignancy diagnosed in pregnancy; Hodgkin lymphoma is more frequent in pregnant women than non-Hodgkin lymphoma (NHL). The proportion of highly aggressive lymphomas in pregnant women is significantly higher than in non-pregnant women of reproductive age. Reproductive organ involvement is observed in almost half of pregnant women with NHL. The association of acute leukaemia and pregnancy is infrequent and it is assumed that pregnancy does not accelerate the disease course. Both cancer and pregnancy induce a procoagulant state which can lead to maternal venous thromboembolism (VTE) and placental occlusion. Pregnancy in woman with myeloproliferative neoplasms (MPN) promotes thrombotic environment, associating with an augmented risk of placental thrombosis, intrauterine growth retardation or loss and maternal thrombotic events.Haematological malignancies during pregnancy often require urgent diagnosis and management and are associated with potential adverse fetal outcomes. Most chemotherapeutic agents are teratogenic and should be avoided during the first trimester. Their use during the second and third trimesters may cause intrauterine growth restriction, premature birth and intrauterine fetal death. All chemotherapeutic drugs should be administered only after a detailed discussion with the patient and with close fetal monitoring. Chemotherapy and biological agents might also augment thrombotic risk. Guidelines for VTE prophylaxis in pregnant women with hematologic malignancies, apart from MPN, are currently unavailable, and therefore, clinical judgment should be made in each case. PMID- 27465579 TI - Sodium ferulate and n-butylidenephthalate combined with bone marrow stromal cells (BMSCs) improve the therapeutic effects of angiogenesis and neurogenesis after rat focal cerebral ischemia. AB - BACKGROUND: Studies have indicated that bone marrow stromal cell (BMSC) administration is a promising approach for stroke treatment. For our study, we chose sodium ferulate (SF) and n-butylidenephthalide (BP) combined with BMSC, and observed if the combination treatment possessed more significant effects on angiogenesis and neurogenesis post-stroke. METHODS: We established rat permanent middle cerebral artery occlusion (MCAo) model and evaluated ischemic volumes of MCAo, BMSC, SF + BP, Simvastatin + BMSC and SF + BP + BMSC groups with TTC staining on the 7th day after ischemia. Immunofluorescence staining of vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF), as well as immunohistochemistry staining of von Willebrand factor (vWF) and neuronal class III beta-tubulin (Tuj1) were performed in ischemic boundary zone (IBZ), furthermore, to understand the mechanism, western blot was used to investigate AKT/mammalian target of rapamycin (mTOR) signal pathway in ischemic cortex. We also tested BMSC derived-VEGF and BDNF expressions by western blot assay in vitro. RESULTS: SF + BP + BMSC group obviously decreased infarction zone, and elevated the expression of VEGF and the density and perimeter of vWF-vessels as same as Simvastatin + BMSC administration; moreover, its effects on BDNF and Tuj1 expressions were superior to Simvastatin + BMSC treatment in IBZ. Meanwhile, it showed that SF and BP combined with BMSC treatment notably up-regulated AKT/mTOR signal pathway compared with SF + BP group and BMSC alone post-stroke. Western blot results showed that SF and BP treatment could promote BMSCs to synthesize VEGF and BDNF in vitro. CONCLUSIONS: We firstly demonstrate that SF and BP combined with BMSC can significantly improve angiogenesis and neurogenesis in IBZ following stroke. The therapeutic effects are associated with the enhancement of VEGF and BDNF expressions via activation of AKT/mTOR signal pathway. Furthermore, triggering BMSC paracrine function of SF and BP might contribute to amplifying the synergic effects of the combination treatment. PMID- 27465580 TI - Viremic co-infections in children with allogeneic haematopoietic stem cell transplantation are predominated by human polyomaviruses. AB - BACKGROUND: Viral infections remain the cause of key complications following haematopoietic stem cell transplantation (HSCT). The impact of multiple, concurrent viral reactivations/infections remains to be delineated. METHODS: The clinical correlates of single or multiple viremic infections following HSCT and especially the occurrence of respiratory viruses in the bloodstream were investigated. We retrospectively searched for 23 viruses in a total of 184 sera from 53 paediatric patients. The time-points of interest were pre-HSCT, one, two and three months post-HSCT, and at discharge or death. The viruses were analyzed by quantitative or qualitative PCR. RESULTS: Of the 53 patients, 13 (25%) had viraemias by multiple viruses and 27 (51%) by a single virus. Thirteen patients (25%) had no viruses detected by PCR during the study period. In the children with viremic co-infections, polyomaviruses predominated over herpes viruses. Nearly half the patients, 24/53 (45%) had a polyomavirus in their serum at one or more time-points. At 12/15 time-points and in 11/13 patients with co-infections polyomaviruses were involved, compared with 6/15 time-points and 6/13 patients for cytomegalovirus. Acute graft-versus-host disease (GvHD) and steroid use were significant risk factors for the viraemias caused by more than one virus. CONCLUSIONS: Viral co-detection is a common finding in children undergoing HSCT. With large-scale viral screening also viruses other than CMV could be found as potential pathogens. In this study, BKPyV predominated over CMV as a contributor in viraemias caused by multiple viruses in children receiving HSCT. PMID- 27465581 TI - Poly(ADP-ribose) polymerase inhibition suppresses inflammation and promotes recovery from adrenal injury in a rat model of acute necrotizing pancreatitis. AB - BACKGROUND: Poly(ADP-ribose) polymerase (PARP) participates in multi-organ failure in various inflammatory diseases including acute necrotizing pancreatitis (ANP). Since pancreatitis-associated adrenal insufficiency is partly caused by inflammatory damage to the adrenal cortex, we examined whether PARP antagonism could alleviate adrenal insufficiency in a rat model of ANP. METHODS: ANP was induced by retrograde infusion of sodium taurocholate into the bile-pancreatic duct. At 30 min prior to taurocholate infusion, rats were pretreated with the PARP inhibitor 3-Aminobenzamide (3-AB, 20 mg/kg) or vehicle. Pancreatic pathological injury, adrenal histology, neutrophil infiltration, cell apoptosis, and serum corticosterone level were assessed at various times points. Activities of poly(ADP-ribosyl)ated protein (PAR), nuclear factor-kappaB (NF-kB), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in the adrenal were also examined. RESULTS: PARP overactivation in ANP rats is associated with reduced serum corticosterone level and marked cellular alterations in adrenocortical tissue. Inflammatory stress caused by ANP reduced adrenal corticosterone release. 3-AB reduced the activation of PARP and inflammatory markers, decreased myeloperoxidase activity, attenuated adrenal morphologic lesions and cells apoptosis, simultaneously improved the impaired adrenal function. CONCLUSIONS: Our data demonstrate the involvement of PARP overactivation in the pathogenesis of adrenal dysfunction after ANP. PARP inhibition may suppress inflammation and promote functional recovery from adrenal injury. PMID- 27465582 TI - Pathological implications of linear immunoglobulin G staining on the glomerular capillary walls in a case of infection-related glomerulonephritis. AB - We report a 32-year-old man with nephrotic syndrome and preceding symptom of infection. He had renal insufficiency, hypocomplementemia, and elevated titer of anti-streptolysin O. Renal biopsy showed mesangial hypercellularity and focal segmental endocapillary hypercellularity with double contour of the glomerular basement membrane (GBM). Immunofluorescence study showed granular C3 staining on the mesangial areas and glomerular capillary walls (GCWs) and linear immunoglobulin G (IgG) staining on GCWs. Electron microscopy revealed sporadic subepithelial humps, discontinuous small and thin deposits in the endothelial side of the GBM and mesangial deposits. He was diagnosed with infection-related glomerulonephritis (IRGN) with the striking finding of linear IgG staining, which is unusual in IRGN. The patient did not have diabetes mellitus or anti-GBM disease. The patient's serum seemed not to contain IgG, which can bind to GCW. He showed normalization of complement within two months after relief from infection symptoms and a trend toward improvement in proteinuria, hematuria and renal function over 14 months. We discuss the possible mechanisms of linear IgG staining in our case based on clinical and experimental studies on IRGN with cationic bacterial protein as antigen. PMID- 27465583 TI - Consecutive Reaction to Construct Hierarchical Nanocrystalline CuS "Branch" with Tunable Catalysis Properties. AB - New CuS nanocrystals with a 3D hierarchical branched structure are successfully synthesized through in situ consecutive reaction method with copper foam as template. The formation mechanism of the 3D hierarchical branched structure obtained from the secondary reaction is investigated by adjusting the reaction time. The morphology of CuS nanosheet arrays with the 3D hierarchical branched structure is changed through Cu(2+) exchange. In this method, the copper foam reacted completely, and the as-synthesized CuS@Cu9S5 nanocrystals are firmly grown on the surface of the 3D framework. This tunable morphology significantly influence the physical and chemical properties, particularly catalytic performance, of the materials. The as-obtained material of Cu@CuS-2 with the 3D hierarchical branched structure as catalyst for methylene blue degradation exhibits good catalytic performance than that of the material of Cu@CuS with 2D nanosheets in dark environment. Furthermore, the cation exchange between Cu and Cu(2+) indicates that Cu(2+) in wastewater could be absorbed by Cu@CuS-2 with the 3D hierarchical branched structure. The exchanged resultant of CuS@Cu9S5 retains its capability to degrade organic dyes. This in situ consecutive reaction method may have a significant impact on controlling the crystal growth direction of inorganic material. PMID- 27465584 TI - Cationic mono and dicarbonyl pincer complexes of rhodium and iridium to assess the donor properties of PCcarbeneP ligands. AB - The donor properties of five different PCcarbeneP ligands are assessed by evaluation of the CO stretching frequencies in iridium(i) and rhodium(i) carbonyl cations. The ligands feature dialkyl phosphine units (R = (i)Pr or (t)Bu) linked to the central benzylic carbon by either an ortho-phenylene bridge, or a 2,3 benzo[b]thiophene linker; in the former, substituent patterns on the phenyl linker are varied. The carbonyl complexes are synthesized from the (PCcarbeneP)M Cl starting materials via abstraction of the chlorides in the presence of CO gas. In addition to the expected mono carbonyl cations, products with two carbonyl ligands are produced, and for the rhodium example, a novel product in which the second carbonyl ligand adds reversibly across the Rh[double bond, length as m dash]C bond to give an eta(2) ketene moiety was characterized. The IR data for the complexes shows the 2,3-benzo[b]thiophene linked system to be the poorest overall donor, while the phenyl bridged ligands incorporating electron donating dialkyl amino groups para to the anchoring carbene are very strongly donating pincer arrays. PMID- 27465585 TI - Pitfalls in genetic testing: the story of missed SCN1A mutations. AB - BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing. RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated. PMID- 27465586 TI - Developing a mHealth intervention to promote uptake of HIV testing among African communities in the UK: a qualitative study. AB - BACKGROUND: HIV-related mHealth interventions have demonstrable efficacy in supporting treatment adherence, although the evidence base for promoting HIV testing is inconclusive. Progress is constrained by a limited understanding of processes used to develop interventions and weak theoretical underpinnings. This paper describes a research project that informed the development of a theory based mHealth intervention to promote HIV testing amongst city-dwelling African communities in the conditions. METHODS: A community-based participatory social marketing design was adopted. Six focus groups (48 participants in total) were undertaken and analysed using a thematic framework approach, guided by constructs from the Health Belief Model. Key themes were incorporated into a set of text messages, which were pre-tested and refined. RESULTS: The focus groups identified a relatively low perception of HIV risk, especially amongst men, and a range of social and structural barriers to HIV testing. In terms of self-efficacy around HIV testing, respondents highlighted a need for communities and professionals to work together to build a context of trust through co-location in, and co involvement of, local communities which would in turn enhance confidence in, and support for, HIV testing activities of health professionals. Findings suggested that messages should: avoid an exclusive focus on HIV, be tailored and personalised, come from a trusted source, allay fears and focus on support and health benefits. CONCLUSIONS: HIV remains a stigmatized and de-prioritized issue within African migrant communities in the UK, posing barriers to HIV testing initiatives. A community-based participatory social marketing design can be successfully used to develop a culturally appropriate text messaging HIV intervention. Key challenges involved turning community research recommendations into brief text messages of only 160 characters. The intervention needs to be evaluated in a randomized control trial. Future research should explore the application of the processes and methodologies described in this paper within other communities. PMID- 27465587 TI - Risk of hemophagocytic lymphohistiocytosis in adults with fevers of unknown origin: the clinical utility of a new scoring system on early detection. AB - The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is delayed by most physicians. This study aimed to identify early parameters and suitable scoring systems for the risk of HLH. Clinical and laboratory data collected <=3 days after admission were defined as early parameters and used to calculate the number of HLH-2004 criteria met and bone marrow (BM) score. Between January 2006 and February 2016, 233 immunocompetent adults with naive fever of unknown origin who underwent a BM study were enrolled to mimic patients at risk of HLH and randomly assigned into the developmental or validation cohort. Hemophagocytic lymphohistiocytosis was finally diagnosed in 47 patients, with non-Hodgkin lymphoma as the major etiology (51.1%). Upon admission, four-fifths of patients who developed subsequent HLH fulfilled <=3 of 8 HLH-2004 criteria, and 6 early parameters were independent predictors of HLH: anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelet count < 100 * 103 /MUL), leukoerythroblastosis, hyperbilirubinemia (total bilirubin > 2 * upper normal limit), hyperferritinemia (ferritin > 1000 ng/mL), and splenomegaly. Compared with the HLH criteria met upon admission, the BM score was an independent predictor (odds ratio = 1.621; 95% confidence interval, 1.355-1.940) with excellent discrimination (area under the receiver operating characteristic curve = 0.920; 95% confidence interval, 0.883-0.958). The sensitivity and specificity for a BM score cutoff of 10 points were 95% and 75%, respectively. When approaching immunocompetent adults with a continuously high fever, the BM score at initial admission assists with early identification of patients at risk of HLH. PMID- 27465588 TI - Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. AB - Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event-free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1-3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. OS was compared to age-and-sex-matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78-4.88; Lyon SMR = 8.74, 95%CI: 5.41-13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56-0.94, Lyon SMR = 1.02, 95%CI: 0.58-1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97-25.02, Lyon SMR = 19.10, 95%CI:9.86 33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31-17.74, Lyon SMR = 7.22, 95%CI:4.13-11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096-1101, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27465589 TI - Effectiveness of demand generation interventions on use of modern contraceptives in low- and middle-income countries. AB - OBJECTIVES: To synthesise evidence on the implementation, costs and cost effectiveness of demand generation interventions and their effectiveness in improving uptake of modern contraception methods. METHODS: A Cochrane systematic review was conducted. Searches were performed in electronic databases (MEDLINE, EMBASE) and the grey literature. Randomised controlled trials, cluster randomised trials and quasi-experimental studies, including controlled before-after studies (CBAs) and cost and cost-effectiveness studies that aimed to assess demand interventions (including community- and facility-based interventions, financial mechanisms and mass media campaigns) in low- and middle-income countries were considered. Meta-analyses and narrative synthesis were conducted. RESULTS: In total, 20 papers meeting the inclusion criteria were included in this review. Of those, 13 were used for meta-analysis. Few data were available on implementation and on the influence of context on demand interventions. Involving family members during counselling, providing education activities and increasing exposure to those activities could enhance the success of demand interventions. Demand generation interventions were positively associated with increases in current use (pooled OR 1.57; 95% CI: 1.46-1.69, P < 0.01). Financial mechanism interventions (vouchers) appeared effective to increase use of modern contraceptive methods (pooled OR 2.16; 95% CI: 1.91-2.45, P < 0.01; I2 = 0%). Demand interventions improved knowledge (pooled OR 1.02; 95% CI 0.63-1.64, P = 0.93) and attitudes towards family planning and improved discussion with partners/husbands around modern contraceptive methods. However, given the limited number of studies included in each category of demand generation interventions, the dates of publication of the studies and their low quality, caution is advised in considering the results. Very limited evidence was available on costs; studies including data on costs were old and inconsistent. CONCLUSION: Demand generation interventions contribute to increases in modern contraceptive methods use. However, more studies with robust designs are needed to identify the most effective demand generation intervention to increase uptake of modern contraceptive methods. More evidence is also needed about implementation, costs and cost-effectiveness to inform decisions on sustainability and scaling-up. PMID- 27465590 TI - Last gasps of the hepatitis C virus dragon: Direct acting antiviral failures and hepatitis C virus-positive donors. PMID- 27465591 TI - Genotyping by Sequencing (GBS) in Apricots and Genetic Diversity Assessment with GBS-Derived Single-Nucleotide Polymorphisms (SNPs). AB - Genotyping by sequencing (GBS), which is a highly promising technique for molecular breeding, has been implemented in apricots, including Turkish, European, and Plum Pox Virus-resistant accessions. DNA samples were digested with the ApeKI restriction enzyme to construct a genome-complexity-reduced 90-plex GBS library. After filtering the raw sequences, approximately 28 G of clean data were generated, and 17,842 high-quality single-nucleotide polymorphism (SNP) loci were discovered. A total of 561 SNP loci with 0 or 1 missing reads for the 90 accessions produced 1162 markers that were used for the cluster and population structure analysis of the same collection. The results of the SNP analysis indicated that the relation of the European accessions with the western Turkish apricots was accurately positioned. The resistant accessions from different sources were clustered together, confirming the previous finding that SEO/Harlayne-type resistance probably originated from the same source. The Malatya accessions produce most of the world's dried apricots and are likely to be a genetically distinct group. Simple sequence repeat (SSR) and self incompatibly (SI) locus characterization of the accessions was also included. SI genotyping supported the SNP findings, demonstrating both the reliability of SNP genotyping and the usefulness of SI genotyping for understanding the history of apricot breeding. The SSR genotyping revealed a characterization similar to that of SNP genotyping with a slightly lower resolution in the dendrogram. In conclusion, the GBS approach was validated in apricots, with the discovery of a large number of SNPs, and was demonstrated to be reliable by fingerprinting the accessions in a more informative manner. PMID- 27465592 TI - The Use of Redox Expression and Associated Molecular Damage to Evaluate the Inflammatory Response in Critically Ill Patient with Severe Burn. AB - The patient with severe burns always represents a challenge for the trauma team due to the severe biochemical and physiopathological disorders. Although there are many resuscitation protocols of severe burn patient, systemic inflammatory response, oxidative stress, decreased immune response, infections, and multiple organ dysfunction syndromes are still secondary complications of trauma, present at maximum intensity in this type of patients. Currently there are numerous studies regarding the evaluation, monitoring, and minimizing the side effects induced by free radicals through antioxidant therapy. In this study, we want to introduce biochemical and physiological aspects of oxidative stress in patients with severe burns and to summarize the biomarkers used presently in the intensive care units. Systemic inflammations and infections are according to the literature the most important causes of death in these type of patients, being directly involved in multiple organ dysfunction syndrome and death. PMID- 27465594 TI - T wave amplitude in lead aVR as a novel diagnostic marker for cardiac sarcoidosis. AB - It is vital to identify cardiac involvement (CI) in patients with sarcoidosis as the condition could initially lead to sudden cardiac death. Although the T wave amplitude in lead aVR (TWAaVR) is reportedly associated with adverse cardiac events in various cardiovascular diseases, only scarce data are available concerning the utility of lead aVR in identifying CI in patients with sarcoidosis. We retrospectively investigated the diagnostic values of TWAaVR in patients with sarcoidosis in comparison with conventional electrocardiography parameters such as bundle branch block (BBB). From January 2006 to December 2014, 93 consecutive patients with sarcoidosis were enrolled (mean age, 55.7 +/- 15.7 years; male, 31 %; cardiac involvement, n = 26). TWAaVR showed the greatest sensitivity (39 %) and specificity (92 %) in distinguishing between sarcoidosis patients with and without CI, at a cutoff value of -0.08 mV. The diagnostic value of BBB for cardiac involvement was significantly improved when combined with TWAaVR (sensitivity: 61-94 %, specificity: 97-89 %, area under the curve: 0.79 0.92, p = 0.018). Multivariate logistic regression analysis indicated that TWAaVR and BBB were independent electrocardiography parameters associated with CI. In summary, we observed that sarcoidosis patients exhibiting a high TWAaVR were likely to have CI. Thus, the application of a combination of BBB with TWAaVR may be useful when screening for CI in sarcoidosis patients. PMID- 27465593 TI - Integrative epigenomic analysis reveals unique epigenetic signatures involved in unipotency of mouse female germline stem cells. AB - BACKGROUND: Germline stem cells play an essential role in establishing the fertility of an organism. Although extensively characterized, the regulatory mechanisms that govern the fundamental properties of mammalian female germline stem cells remain poorly understood. RESULTS: We generate genome-wide profiles of the histone modifications H3K4me1, H3K27ac, H3K4me3, and H3K27me3, DNA methylation, and RNA polymerase II occupancy and perform transcriptome analysis in mouse female germline stem cells. Comparison of enhancer regions between embryonic stem cells and female germline stem cells identifies the lineage specific enhancers involved in germline stem cell features. Additionally, our results indicate that DNA methylation primarily contributes to female germline stem cell unipotency by suppressing the somatic program and is potentially involved in maintenance of sexual identity when compared with male germline stem cells. Moreover, we demonstrate down-regulation of Prmt5 triggers differentiation and thus uncover a role for Prmt5 in maintaining the undifferentiated status of female germline stem cells. CONCLUSIONS: The genome-wide epigenetic signatures and the transcription regulators identified here provide an invaluable resource for understanding the fundamental features of mouse female germline stem cells. PMID- 27465595 TI - Clickable 4-Oxo-beta-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes. AB - Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC, or 'click' chemistry) approach based on the 4-oxo-beta lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure-activity relationships set the basis to develop fluorescent and biotinylated activity-based probes as tools for molecular functional analysis. Attaching the tags to the 4-oxo-beta-lactam scaffold did not affect HNE inhibitory activity, as revealed by the IC50 values in the nanomolar range (56-118 nm) displayed by the probes. The nitrobenzoxadiazole (NBD)-based probe presented the best binding properties (ligand efficiency (LE)=0.31) combined with an excellent lipophilic ligand efficiency (LLE=4.7). Moreover, the probes showed adequate fluorescence properties, internalization in human neutrophils, and suitable detection of HNE in the presence of a large excess of cell lysate proteins. This allows the development of activity-based probes with promising applications in target validation and identification, as well as diagnostic tools. PMID- 27465596 TI - A rare case of extremely high counts of circulating tumor cells detected in a patient with an oral squamous cell carcinoma. AB - BACKGROUND: Despite aggressive regimens, the clinical outcome of head and neck squamous cell carcinoma remains poor. The detection of circulating tumor cells could potentially improve the management of patients with disseminated cancer, including diagnosis, treatment strategies, and surveillance. Currently, CellSearch((r)) is the most widely used and the only Food and Drug Administration cleared system for circulating tumor cells detection in patients with metastatic breast, colorectal, or prostate cancer. In most cases of head and neck squamous cell carcinoma, only low counts of circulating tumor cells have been reported. CASE PRESENTATION: A 56-year-old white male with no particular medical history, was diagnosed with a squamous cell carcinoma of oral cavity. According to the imaging results (computed tomography and (18)F-fluorodeoxyglucose positron emission tomography / computed tomography) and panendoscopy, the TNM staging was classified as T4N2M0. A non-interruptive pelvimandibulectomy was conducted according to the multidisciplinary meeting advices and the postoperative observations were normal. The patient complained of a painful cervical edema and a trismus 6 weeks after the surgery. A relapse was found by computed tomography and the patient died two weeks later. The search for circulating tumor cells in peripheral venous blood by using the CellSearch((r)) system revealed a very high count compared with published reports at three time points (pre-operative: 400; intra-operative: 150 and post-operative day 7: 1400 circulating tumor cells). Of note, all detected circulating tumor cells were epidermal growth factor receptor negative. CONCLUSION: We report here for the first time a rare case of oral squamous cell carcinoma with extremely high circulating tumor cells counts using the CellSearch((r)) system. The absolute number of circulating tumor cells might predict a particular phase of cancer development as well as a poor survival, potentially contributing to a personalized healthcare. PMID- 27465597 TI - Anti-microbial peptide gene expression during oral vaccination: analysis of a randomized controlled trial. AB - We have observed previously that micronutrient supplementation ameliorated suppression of alpha-defensin expression during diarrhoea. However, how interactions between anti-microbial peptide (AMP) expression and diarrhoeal disease are altered by micronutrient supplementation remain unclear. Using oral vaccination as a model of intestinal infection, we measured changes in AMP expression during multiple micronutrient supplementation. In the first part, volunteers underwent duodenal jejunal biopsy before and at 1, 2, 4 or 7 days after administration of one of three live, attenuated oral vaccines against rotavirus, typhoid and enterotoxigenic Escherichia coli. In the second part, participants were randomized to receive a multiple micronutrient supplement or placebo for 6 weeks before undergoing intestinal biopsy, vaccination against typhoid and rebiopsy after 14 days. Expression of human alpha-defensin (HD)5, HD6, hBD1, hBD2 and LL-37 was measured by quantitative reverse transcription polymerase chain reaction. Taken together, the bacterial vaccines, but not rotavirus vaccine, reduced HD5 expression (P = 0.02, signed-rank test) and reduced LL-37 expression in seven of the eight individuals whose biopsies had expression prevaccination (P = 0.03). hBD2 was not detected. In the controlled trial, HD5 and HD6 expression after vaccination was lower [median ratio 0.5, interquartile range (IQR) = 0.07-2.2 and 0.58, IQR = 0.13-2.3, respectively] than before vaccination. There was no significant effect detected of micronutrient supplementation on expression of HD5, HD6, hBD1 or LL-37. We conclude that live attenuated bacterial vaccines, but not rotavirus vaccine, can reduce intestinal alpha-defensins, and typhoid vaccine reduced LL-37 expression. We found no evidence that micronutrient supplementation in the short term had any impact on anti-microbial peptide expression. PMID- 27465598 TI - Cytogenetics in the management of hematologic malignancies: an update by the Groupe francophone de cytogenetique hematologique (GFCH). AB - Cytogenetic analysis is still important in the management of many hematological malignancies, despite the new techniques available such as the high-throughput sequencing analysis, and the discovery of many acquired gene mutations in these diseases. The Groupe francophone de cytogenetique hematologique (GFCH) published in 2004 the recommendations for the cytogenetic management of hematological malignancies. It reports here the update of these recommendations, with a review of the literature for each disease. PMID- 27465599 TI - On the effect of ion pairing of Keggin type polyanions with quaternary ammonium cations on redox potentials in organic solvents. AB - The electrochemical properties of Keggin type polyoxometalates Qn[XW12O40] (X = P, Si, B; Q = n-tetraoctylammonium and n-trioctylmethylammonium) in organic solvents were investigated in order to understand the interrelation between the redox potentials, solvents and ion pairing. A logarithmic correlation between the dielectric constant of the solvent (epsilon ranged from 4.8 to 46.6) and the reduction potential of the [PW12O4](3-)/[PW12O4](4-) couple was found. This reduction potential increased significantly when the surface charge of the polyoxometalate went from 3- to 5-. The investigation of the ion pairing properties by diffusion NMR revealed the presence of intimate ion pairs in less polar solvents (e.g. dichloromethane) and less compact ion pairs in more polar solvents (e.g. DMSO). Using a V atom within the polyoxometalate an NMR experiment showed that a n-trioctylmethyl ammonium cation bonded to the polyoxometalate anion more intimately than a n-tetraoctyl ammonium cation. PMID- 27465600 TI - Inhibition of HIV Virus by Neutralizing Vhh Attached to Dual Functional Liposomes Encapsulating Dapivirine. AB - Although highly active antiretroviral therapy (HAART) has greatly improved the life expectancy of HIV/AIDS patients, the treatment is not curative. It is a global challenge which fosters an urgent need to develop an effective drug or neutralizing antibody delivery approach for the prevention and treatment of this disease. Due to the low density of envelope spikes with restricted mobility present on the surface of HIV virus, which limit the antibody potency and allow virus mutation and escape from the immune system, it is important for a neutralizing antibody to form bivalent or multivalent bonds with the virus. Liposome constructs could fulfil this need due to the flexible mobility of the membrane with its attached antibodies and the capacity for drug encapsulation. In this study, we evaluated the neutralization activity of a range of liposome formulations in different sizes coated with anti-gp120 llama antibody fragments (Vhhs) conjugated via either non-covalent metal chelation or a covalent linkage. The non-covalent construct demonstrated identical binding affinity to HIV-1 envelope glycoprotein gp120 and neutralizing ability for HIV virus as free Vhh. Although covalently linked Vhh showed significant binding affinity to gp120, it unexpectedly had a lower neutralization potency. This may be due to the comparability in size of the viral and liposome particles restricting the number which can be bound to the liposome surface so involving only a fraction of the antibodies, whereas non-covalently attached antibodies dissociate from the surface after acting with gp120 and free the remainder to bind further viruses. Covalently conjugated Vhh might also trigger the cellular uptake of a liposome virion complex. To explore the possible ability of the antibody-coated liposomes to have a further function, we encapsulated the hydrophobic antiviral drug dapivirine into both of the non-covalently and covalently conjugated liposome formulations, both of which revealed high efficacy in reducing viral replication in vitro. Thus, dual function liposomes may lead to a novel strategy for the prophylaxis of HIV/AIDS by combining the neutralizing activity of Vhh with antiviral effects of high drug concentrations. PMID- 27465601 TI - Performance of Nano-Submicron-Stripe Pd Thin-Film Temperature Sensors. AB - Dozens of small dual-beam thin-film temperature sensors with a total width down to 430 nm were fabricated and tested. The sensors were all made from 90-nm-thick Pd thin films, where the width of the narrow stripes was 70-100 nm and that of the wide ones was 210-800 nm. Two different calibration methods showed consistent and repeatable sensitivities of 0.7-1.2 MUV/K for the sensors, confirming that the sensitivity mainly depended on the width configuration of each sensor. By integrating arrays of such sensors on a practical testing platform using hybrid e beam lithography and photolithography techniques, we demonstrated that these sensors were capable of detecting a weak surface temperature difference of 0.1 0.2 K at microscale, and they could be scaled up as built-in temperature sensors in many practical devices. PMID- 27465602 TI - Why are adult women physically active? A systematic review of prospective cohort studies to identify intrapersonal, social environmental and physical environmental determinants. AB - OBJECTIVE: This study aims to systematically review available evidence from prospective cohort studies to identify intrapersonal, social environmental and physical environmental determinants of moderate-to-vigorous intensity physical activity (MVPA) among working-age women. METHODS: Six databases were searched to identify all prospective cohort studies that reported on intrapersonal (e.g. self efficacy and socioeconomic status [SES]), social (e.g. crime, area SES and social support) and/or physical (e.g. weather, work and recreation) environmental determinants of MVPA in working-age (mean 18-65 years) women. A qualitative synthesis including harvest plots was completed. PROSPERO: CRD42014009750 RESULTS: Searching identified 17,387 potential articles; 97 were used in the analysis. The majority (n = 87 studies) reported on >=1 intrapersonal determinant. Very few (n = 34) examined factors in the social or physical environments, and none looked at social policy. Positive and consistent influencers included higher self-efficacy (n = 18/23), self-rated health (n = 8/13) and intentions (n = 10/11) and perceived behavioural control (n = 5/7) to be physically active. Having children in the household was negatively related to MVPA (n = 9/15). CONCLUSIONS: Physical activity intervention studies should consider a woman's level of self-efficacy and perceived behavioural control to be physically active. Additional studies are needed on the impact of children in the household, having a spouse/partner and using group goal setting. More evidence is needed to evaluate the impact of environmental factors. PMID- 27465603 TI - Cytotoxic effects of zearalenone and its metabolites and antioxidant cell defense in CHO-K1 cells. AB - Zearalenone (ZEA) and its metabolites (alpha-zearalenol; alpha-ZOL, beta zearalenol; beta-ZOL) are secondary metabolites of Fusarium fungi that produce cell injury. The present study explores mycotoxin-induced cell damage and cellular protection mechanisms in CHO-K1 cells. Cytotoxicity has been determined by reactive oxygen species (ROS) production and DNA damage. ROS production was determined using the fluorescein assay and DNA strand breakage by comet assay. Intracellular protection systems were glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD). The results demonstrated that all mycotoxins increased the ROS levels up to 5.3-fold the control levels in CHO-K1 cells. Zearalenone metabolites, but not ZEA, increased DNA damage 43% (alpha-ZOL) and 28% (beta-ZOL) compared to control cells. The GSH levels decreased from 18% to 36%. The GPx and SOD activities respectively increased from 26% to 62% and from 23% to 69% in CHO-K1 cells, whereas CAT activity decreased from 14% to 52%. In addition, intracellular ROS production was induced by ZEA and its metabolites. The endogenous antioxidant system components GSH, GPx and SOD were activated against ZEA and its metabolites. These antioxidant system components thus could contribute to decrease cell injury by ZEA and its metabolites. PMID- 27465604 TI - Chemical composition of the essential oil from carnation coniferous (Dianthus acicularis Fisch. ex Ledeb) growing wild in Northern Kazakhstan. AB - The aim of the study was to investigate volatile compounds from the aerial parts of Dianthus acicularis of the genus Dianthus of the family Caryophyllaceae grown wild in Northern Kazakhstan for the first time. D. acicularis is a typical Trans Volga-Kazakhstani endemic. D. acicularis has high resistance to the bacterial wilt, a serious disease caused by Burkholderia caryophylli. The qualitative and quantitative compositions of the specimens of the essential oils were analysed by the method of GC-MS. The main constituents of D. acicularis essential oil were methyl ketones - 2-pentadecanone (26.9-32.2%) and 2-tridecanone (4.7-17.7%), identified for the first time in the Dianthus genus. The methyl ketone activity provides protection of the plants from herbivores and fungal pathogens. One can suppose that the presence of 2-pentadecanone and 2-tridecanone in the essential oil of carnation coniferous provides its resistance to different insects and pathogens, including the resistance to the bacterial wilt. PMID- 27465606 TI - Diagnosis and surgical indications of oxyphilic follicular tumors in Japan: Surgical specimens and cytology. AB - Oxyphilic cell carcinoma is a relatively rare type of differentiated thyroid carcinoma. We investigated the diagnosis of oxyphilic cell carcinoma based on surgical specimens and cytology to elucidate the indications for surgery for oxyphilic tumors. Among 330 patients pathologically diagnosed as having an oxyphilic cell carcinoma or adenoma, the incidence of carcinoma was 21%. The pathological diagnosis of oxyphilic cell carcinoma was related to tumor size (>4 cm). On cytology, 79% of the tumors were classified as category IV or greater by the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), but no significant difference was established between category IV or greater and categories I-III regarding the incidence of carcinoma. Of 998 patients cytologically diagnosed as having oxyphilic cell tumors (BSRTC category IV), 426 underwent surgery and 66 (15%) were diagnosed as malignancies. In a univariate analysis, serum thyroglobulin (Tg) levels (>500 ng/dL) for anti-Tg antibody negative patients, tumor size (>4 cm) and US class (>=3) significantly predicted malignant histology. A multivariate logistic analysis revealed that US finding was an independent predictor of malignant histology, and tumor size (>4 cm) also predicted malignancy when the Tg level was excluded from the variables. These findings suggest that, for thyroid tumors diagnosed as oxyphilic follicular neoplasms on cytology, surgical indications are tumors with US class >=3, tumor size >4 cm, and Tg >500 ng/dL (with negative Tg-antibody). It is not appropriate to perform surgery for all cases for a precise histological classification, unlike the BSRTC recommendation. PMID- 27465605 TI - Multi-walled carbon nanotubes increase antibody-producing B cells in mice immunized with a tetravalent vaccine candidate for dengue virus. AB - BACKGROUND: In recent times, studies have demonstrated that carbon nanotubes are good candidates for use as vehicles for transfection of exogenous material into the cells. However, there are few studies evaluating the behavior of carbon nanotubes as DNA vectors and few of these studies have used multi-walled carbon nanotubes (MWCNTs) or carboxylated MWCNTs. Thus, this study aims to assess the MWCNTs' (carboxylated or not) efficiency in the increase in expression of the tetravalent vaccine candidate (TVC) plasmid vector for dengue virus in vitro using Vero cells, and in vivo, through the intramuscular route, to evaluate the immunological response profile. RESULTS: Multi-walled carbon nanotubes internalized by Vero cells, have been found in the cytoplasm and nucleus associated with the plasmid. However, it was not efficient to increase the messenger ribonucleic acid (mRNA) compared to the pure vaccine candidate associated with Lipofectamine((r)) 2000. The in vivo experiments showed that the use of intramuscular injection of the TVC in combination with MWCNTs reduced the immune response compared to pure TVC, in a general way, although an increase was observed in the population of the antibody-producing B cells, as compared to pure TVC. CONCLUSIONS: The results confirm the data found by other authors, which demonstrate the ability of nanotubes to penetrate target cells and reach both the cytoplasm and the cell nucleus. The cytotoxicity values are also in accordance with the literature, which range from 5 to 20 ug/mL. This has been found to be 10 ug/mL in this study. Although the expression levels are higher in cells that receive the pure TVC transfected using Lipofectamine((r)) 2000, the nanotubes show an increase in B-cells producing antibodies. PMID- 27465607 TI - Simultaneous tunable structure and composition of PtAg alloyed nanocrystals as superior catalysts. AB - PtAg alloyed nanostructural catalysts were firstly prepared by co-reduction of AgNO3 and H2PtCl6 precursors in growth solution using a seed-mediated method. By simply changing the molar ratio of the metal precursors, the morphologies of the porous alloyed nanocrystals can be tuned from multipetals to multioctahedra. Simultaneously, the alloy composition can be varied from Pt76Ag24 to Pt66Ag34. The catalytic properties of the prepared PtAg alloyed nanocrystals with a tunable structure and composition were tentatively examined by choosing the reduction of 4-nitrophenol with NaBH4. The reaction rate normalized to the concentration of catalysts was calculated to be 318.9 s(-1) mol(-1) L and 277.4 s(-1) mol(-1) L for Pt70Ag30 and Pt66Ag34 porous catalysts, which is much higher than the pure Pt catalysts. Moreover, PtAg nanostructures can also serve as efficient electrocatalysts toward the methanol oxidation reaction, especially for Pt70Ag30 and Pt66Ag34 porous nanocrystals. The electrocatalytic activity and the durability were both highly enhanced compared to the commercial Pt/C catalyst. In addition, we also investigated the enhancement mechanism. PMID- 27465608 TI - Outcomes from a three-arm randomized controlled trial of frequent immersion in thermoneutral water on cardiovascular risk factors. AB - BACKGROUND: Cardiovascular diseases are a main cause of mortality worldwide. Spa bathing and immersion in thermoneutral water (ITW) have a long history in the treatment of cardiovascular risk factors. METHODS: We conducted a three-arm parallel-group, randomized controlled study to investigate the effects of frequent ITW on moderately elevated blood pressure (BP). Here, we report on the secondary outcomes, i.e. the influence of immersion in thermoneutral water on further cardiovascular risk factors: body mass index (BMI), waist circumference, blood lipids, fasting blood glucose and C-reactive protein. Patients (age 57.6 +/ 9.6 years, BMI 29.5 +/- 5.7 kg/m(2)) with mild to moderately elevated BP received ITW for 45-60 min in pools of thermal-mineral water at 34.0-36.0 degrees C four times a week for 4 weeks. One group (Bath1) reduced the intensity to one bath a week for a further 20 weeks, while the other group (Bath2) continued bathing four times a week. The control group was instructed to relax for 45-60 min four times a week for 24 weeks using a relaxation CD. RESULTS: The secondary analysis of the intention-to-treat population (N = 59) did not show a significant reduction of BMI, waist circumference, blood lipids, fasting blood glucose or C-reactive protein in patients with a mild to moderately elevated BP after 4 and 24 weeks ITW, respectively. There were no significant differences between the groups. CONCLUSION: Thus, we did not find evidence to support our ITW program being an efficacious intervention to induce cardiovascular alterations in this population of hypertensive patients. TRIAL REGISTRATION: DRKS00003980 at drks-neu.uniklinik-freiburg.de, German Clinical Trials Register (registration date 2012-07-10). PMID- 27465610 TI - Preface. PMID- 27465609 TI - Improved Secretory Production of the Sweet-Tasting Protein, Brazzein, in Kluyveromyces lactis. AB - Brazzein is an intensely sweet protein with high stability over a wide range of pH values and temperatures, due to its four disulfide bridges. Recombinant brazzein production through secretory expression in Kluyveromyces lactis is reported, but is inefficient due to incorrect disulfide formation, which is crucial for achieving the final protein structure and stability. Protein disulfide bond formation requires protein disulfide isomerase (PDI) and Ero1p. Here, we overexpressed KlPDI in K. lactis or treated the cells with dithiothreitol to overexpress KlERO1 and improve brazzein secretion. KlPDI and KlERO1 overexpression independently increased brazzein secretion in K. lactis by 1.7-2.2- and 1.3-1.6-fold, respectively. Simultaneous overexpression of KlPDI and KlERO1 accelerated des-pE1M-brazzein secretion by approximately 2.6-fold compared to the previous system. Moreover, intracellular misfolded/unfolded recombinant des-pE1M-brazzein was significantly decreased. In conclusion, increased KlPDI and KlERO1 expression favors brazzein secretion, suggesting that correct protein folding may be crucial to brazzein secretion in K. lactis. PMID- 27465611 TI - Introduction: Do we need multi-stakeholder colloquia in MS? AB - BACKGROUND: In the increasingly complex environment of MS there is a need for better cross-talk and communication between the different stakeholders who each address MS according to their own perspective. OBJECTIVE & METHODS: The first and second Pan-European MS Multi-stakeholder Colloquia were specifically set-up for this. RESULTS: In May 2014 and May 2015, the different stakeholders in MS (patients, healthcare professionals, regulators, payers and pharmaceutical industry professionals) met to present and discuss each other's perspective, formulate 10 integrated Calls to Actions (first Colloquium) and discuss guidance propositions/recommendations developed by working groups for the Calls to Action (second Colloquium). CONCLUSION: The perspectives of the different stakeholders and the 10 integrated Calls to Action are summarised in this supplement. PMID- 27465612 TI - The patient's perspective: How to create awareness for improving access to care and treatment of MS patients? AB - BACKGROUND: There is currently no known cure for multiple sclerosis (MS). Four stakeholders play a major role in MS: healthcare professionals, regulators, payers and patients. OBJECTIVE: In Europe, patients are represented by the European Multiple Sclerosis Platform (EMSP), which aims to improve MS management and patients' quality of life. RESULTS: The EMSP has recently shown that there are major disparities in Europe in terms of access to care and treatment. Implementing the Code of Good Practice and a standardised MS nurse training may be useful in harmonising MS management across Europe. Additionally, the burden for novel therapeutic options to be approved by regulatory agencies has to decrease in order to provide faster access of treatment to patients. Data collection (e.g. national registers) also appears crucial to help research and shape the most effective policy in each country. Finally, people with MS should get appropriate (financial) support in order to complete their studies and find a job, as their active participation in society requires proper access to education and employment. Moreover, as they are the ones affected by MS, they seem to be best placed to represent themselves and their needs and should be consulted more often during decision-making processes by policy makers, regulators and payers. PMID- 27465613 TI - The clinical perspective: How to personalise treatment in MS and how may biomarkers including imaging contribute to this? AB - BACKGROUND: Multiple sclerosis (MS) is a highly heterogeneous disease, both in its course and in its response to treatments. Effective biomarkers may help predict disability progression and monitor patients' treatment responses. OBJECTIVE: The aim of this review was to focus on how biomarkers may contribute to treatment individualisation in MS patients. METHODS: This review reflects the content of presentations, polling results and discussions on the clinical perspective of MS during the first and second Pan-European MS Multi-stakeholder Colloquia in Brussels in May 2014 and 2015. RESULTS: In clinical practice, magnetic resonance imaging (MRI) measures play a significant role in the diagnosis and follow-up of MS patients. Together with clinical markers, the rate of MRI-visible lesion accrual once a patient has started treatment may also help to predict subsequent treatment responsiveness. In addition, several molecular (immunological, genetic) biomarkers have been established that may play a role in predictive models of MS relapses and progression. To reach personalised treatment decisions, estimates of disability progression and likely treatment response should be carefully considered alongside the risk of serious adverse events, together with the patient's treatment expectations. CONCLUSION: Although biomarkers may be very useful for individualised decision making in MS, many are still research tools and need to be validated before implementation in clinical practice. PMID- 27465614 TI - The importance of a multi-disciplinary perspective and patient activation programmes in MS management. AB - BACKGROUND: Multiple sclerosis (MS) is a progressive disease associated with a large variety of symptoms and changing patients' needs during the disease course. In order to provide appropriate care in every disease stage and let patients live their lives to the full, a multi-disciplinary approach and patient activation is needed. OBJECTIVE: To summarise the multi-disciplinary perspective of MS, with focus on the organisation of a multi-disciplinary care team and possibilities to support patient activation. METHODS: This review reflects the content of the presentations, audience polling results and discussions on the multi-disciplinary perspective of MS during the second Pan-European MS Multi-stakeholder Colloquium. RESULTS: In many countries, the neurologist with or without the support of an MS nurse is responsible for the long-term care of MS patients. When needed, they should refer to other (non-)medical specialists. However, the patient should be empowered as well to manage his/her disease and to implement a physically active lifestyle in order to improve treatment outcomes and quality of life. CONCLUSION: To create equal access to care for MS patients across Europe, evidence-based standards of care, symptom self-monitoring tools and educational programmes for patients and healthcare professionals including non-medical treatment strategies should be developed at the European level. PMID- 27465615 TI - The regulator's perspective: How should new therapies and follow-on products for MS be clinically evaluated in the future? AB - BACKGROUND: Although there is still no cure for multiple sclerosis (MS), the introduction of several innovative drugs with modes of action different from that of the existing drug arsenal and the progress in monitoring disease progression by imaging and using biomarkers are currently causing a knowledge surge. This provides opportunities for improving patient disease management. New therapies are also under development and pose challenges to the regulatory bodies regarding the optimal design of clinical trials with more patient-focused clinical endpoints. Moreover, with the upcoming patent expiry of some of the key first line MS treatments in Europe, regulatory bodies will also face the challenge of recommending marketing authorisation for generic and abridged versions based on appropriate requirements for demonstrating equality/similarity to the innovator's product. OBJECTIVE: The goal of this article is to improve the understanding of the relevant guidance documents of the European Medicines Agency (EMA) on clinical investigation of medicinal products and to highlight the issues that the agency will need to clarify regarding follow-on products of first-line MS treatments. CONCLUSION: Today, it is clear that close collaboration between patients, healthcare professionals, regulatory bodies and industry is crucial for developing new safe and effective drugs, which satisfy the needs of MS patients. PMID- 27465616 TI - The payer's perspective: What is the burden of MS and how should the patient's perspective be integrated in health technology assessment conducted for taking decisions on access to care and treatment? AB - BACKGROUND: In Europe, there exists considerable variability in access to care and treatment for multiple sclerosis (MS). OBJECTIVES: To improve this situation, we identified key issues payers should take into account when making decisions on access to care and treatment for MS. We also give an overview of the different dimensions determining total MS burden and discuss why it is key to integrate the patient's perspective in estimating this burden. RESULTS: The total burden of MS relates to three dimensions: clinical, humanistic and economic. Although the clinical burden is extensively studied, crucial information is still missing about MS pathophysiology, how MS-related symptoms will develop during the disease course and which patients will progress more rapidly. With regard to the humanistic burden, information on patient-reported quality of life systematically collected in clinical trials for registration purposes is still scarce. Early engagement between pharmaceutical companies, the European Medicines Agency and health technology agencies to prospectively identify key evidence needs for the regulatory and reimbursement processes is required as a first step towards more equal access to care and treatment in MS in Europe. Patients' expectations regarding treatment outcomes should be better researched and integrated into decision-making and patients should be counselled in this process. PMID- 27465617 TI - Conclusions: Calls to action for improving the life of MS patients and their families. AB - BACKGROUND: The first and second Pan-European MS Multi-stakeholder Colloquia were set up to increase cross-talk and communication between the different stakeholders in MS and developed joint Calls to Action to improve (equal) access to quality care and treatment for MS in Europe. OBJECTIVE & METHODS: To summarise the 10 integrated and interrelated Calls to Action developed. RESULTS & CONCLUSION: Call 1: increase awareness in the European community about the burden MS places on patients, caregivers and society. Call 2: improve communication towards the European community on the direct and indirect cost burden of MS. Call 3: perform patient research to (re)define treatment goals/endpoints from a humanistic/patient perspective point of view. Call 4: develop new tools to better capture the total clinical burden of MS. Call 5: develop a protocol for standardisation of MRI for optimising its use as a marker of disability progression in MS. Call 6: support research to find other (molecular) biomarkers which can predict long-term disability progression and (monitor) individual treatment response. Call 7: align CHMP/EMA and HTA decision-making process. Call 8: develop separate EMA guidelines for evaluating follow-on products of non biological complex drugs. Call 9: support people with MS remaining (physically) active and at work and stimulate the implementation of specialised care centres. Call 10: support the continuation of multi-stakeholder colloquia. PMID- 27465618 TI - Preliminary consultation on preferred product characteristics of benzathine penicillin G for secondary prophylaxis of rheumatic fever. AB - Rheumatic fever is caused by an abnormal immune reaction to group A streptococcal infection. Secondary prophylaxis with antibiotics is recommended for people after their initial episode of rheumatic fever to prevent recurrent group A streptococcal infections, recurrences of rheumatic fever and progression to rheumatic heart disease. This secondary prophylaxis must be maintained for at least a decade after the last episode of rheumatic fever. Benzathine penicillin G is the first line antibiotic for secondary prophylaxis, delivered intramuscularly every 2 to 4 weeks. However, adherence to recommended secondary prophylaxis regimens is a global challenge. This paper outlines a consultation with global experts in rheumatic heart disease on the characteristics of benzathine penicillin G formulations which could be changed to improve adherence with secondary prophylaxis. Characteristics included dose interval, pain, administration mechanism, cold chain independence and cost. A sample target product profile for reformulated benzathine penicillin G is presented. PMID- 27465619 TI - Formulation and statistical optimization of self-microemulsifying drug delivery system of eprosartan mesylate for improvement of oral bioavailability. AB - The present investigation is aimed to design a statistically optimized self microemulsifying drug delivery system (SMEDDS) of eprosartan mesylate (EM). Preliminary screening was carried out to find a suitable combination of various excipients for the formulation. A 3(2) full factorial design was employed to determine the effect of various independent variables on dependent (response) variables. The independent variables studied in the present work were concentration of oil (X 1) and the ratio of S mix (X 2), whereas the dependent variables were emulsification time (s), globule size (nm), polydispersity index (pdi), and zeta potential (mV), and the multiple linear regression analysis (MLRA) was employed to understand the influence of independent variables on dependent variables. Furthermore, a numerical optimization technique using the desirability function was used to develop a new optimized formulation with desired values of dependent variables. The optimized SMEDDS formulation of eprosartan mesylate (EMF-O) by the above method exhibited emulsification time, 118.45 +/- 1.64 s; globule size, 196.81 +/- 1.29 nm; zeta potential, -9.34 +/- 1.2 mV, and polydispersity index, 0.354 +/- 0.02. For the in vitro dissolution study, the optimized formulation (EMF-O) and pure drug were separately entrapped in the dialysis bag, and the study indicated higher release of the drug from EMF O. In vivo pharmacokinetic studies in Wistar rats using PK solver software revealed 2.1-fold increment in oral bioavailability of EM from EMF-O, when compared with plain suspension of pure drug. PMID- 27465620 TI - Influence of Teriparatide and Ibandronate on Cortical Bone in New Zealand White Rabbits: A HR-QCT Study. AB - Teriparatide (TPTD) is known to increase the cortical thickness and porosity. The purpose of the present study was to determine whether switching from TPTD to ibandronate (IBN) would be useful for improving cortical bone parameters as assessed using high-resolution quantitative computed tomography (HR-QCT) analyses in mature rabbits. Forty-two female New Zealand white rabbits (18-22 weeks old) were randomized into six groups of 7 animals each as follows: 4-week vehicle administration group, 4-week TPTD administration group (20 MUg/kg, subcutaneously [s.c.], daily), 12-week vehicle administration group, 4-week TPTD administration + 8-week vehicle administration group, 4-week TPTD administration + 8-week lower dose IBN administration group (20 MUg/kg, s.c., every 4 weeks), and 4-week TPTD administration + 8-week higher-dose IBN administration group (100 MUg/kg, s.c., every 4 weeks). After the 4- or 12-week experimental period, the cortical bone of the distal femoral diaphysis was processed for HR-QCT analysis. The 4-week TPTD administration increased the pore ratio, number, and density as well as the cortical area, thickness, and bone mineral content (BMC), without significant influencing the volumetric bone mineral density (BMD). The 4-week TPTD administration + 8-week vehicle administration decreased the pore ratio, number, and density as well as the cortical area and thickness, compared with the 4-week TPTD administration, but the pore ratio, cortical area, and thickness were still higher compared with the 12-week vehicle administration. The 4-week TPTD administration + 8-week higher-dose IBN administration, but not the 4-week TPTD administration + 8-week lower-dose IBN administration, increased the cortical area, thickness, BMC, and volumetric BMD and decreased the pore ratio, but not the pore number or density, compared with the 4-week TPTD administration + 8-week vehicle administration. These results suggest that higher-dose IBN after TPTD therapy has a beneficial effect on the BMC, volumetric BMD, cortical area, thickness, and porosity in mature rabbits. PMID- 27465621 TI - Severe motor aphasia after reinfusion of cryopreserved autologous stem cells after myeloablative conditioning. AB - BACKGROUND: Autologous peripheral blood stem cells (PBSCs) are usually cryopreserved before high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (PBSCT). The freezing process requires the addition of cryoprotectants such as dimethyl sulfoxide (DMSO), which is vital for cell viability in frozen aliquots. DMSO has a number of well-described side effects. However, severe neurologic side effects assigned to DMSO are exceedingly rare. CASE REPORT: A 64-year-old female underwent HDCT followed by PBSCT as consolidation therapy in relapsed high-grade (Grade 3B) Stage IIIA follicular lymphoma. PBSCs were mobilized using granulocyte-colony stimulating factor and plerixafor after the second cycle of R-DHAP (rituximab, dexamethasone, high-dose Ara-C, cisplatin) salvage chemotherapy. A total of 7.18 * 106 /kg body weight CD34+ cells were cryopreserved using 10% DMSO. HDCT was administered some weeks later followed by reinfusion of two bags of PBSCs, each containing 98 mL with 1.6 * 106 /kg body weight CD34+ cells. Within a few minutes the patient developed a motor aphasia and became very agitated. Brain imaging did not reveal any pathologic finding. After being transferred to the intensive care unit the patient's condition steadily improved and the motor aphasia resolved completely within 6 hours after its onset. CONCLUSION: This is, to our knowledge, the first report to describe an episode of severe motor aphasia during PBSCT. Given the close timely correlation with PBSCT, this episode appears to be caused by dimethyl sulfoxide (DMSO) and might possibly have been prevented by use of lower concentrations of DMSO. PMID- 27465622 TI - HRQoL impact of stressful life events in children beginning primary school: results of a prospective study in Poland. AB - PURPOSE: To evaluate the relationship between recent stressful life events (SLEs), stress-related symptoms (SRSs), and health-related quality of life (HRQoL) in children beginning primary school. METHODS: A community-based sample of 6- to 8-year-old children (176 boys and 175 girls at baseline) participated in a prospective longitudinal study with three waves of data collection and 1-year interval between subsequent surveys, conducted in the Wielkopolska Province, Poland. Main exposures included nine recent stressful life events and psychosomatic and behavioural symptoms related to stress (SRSs), both self reported by children. The outcome was total HRQoL assessed by a Polish version of the PedsQLTM 4.0 (Pediatric Quality of Life Inventory) Generic Core Scales questionnaire, 5- to 7-year-old version. To evaluate the relationship between total HRQoL and predictor variables, a latent growth curve (LGC) model using multiple group design (boys and girls) with three waves and two time-varying covariates, the SLEs and SRSs, was applied. RESULTS: An unconditional multi-group LGC model revealed that the total HRQoL changed over time in a linear trajectory. After incorporating to the model, two time-varying covariates, SLEs and SRSs, the first predictor for HRQoL was only significant at the last wave in girls and at two subsequent waves, except for baseline, in boys. The second predictor revealed significant negative impacts on HRQoL over the entire period of time in both boys and girls suggesting that the pathway underlying the association of SLEs with HRQoL may be mediated by SRSs. Mean values of HRQoL at each time points did not show gender differences. CONCLUSIONS: The findings of the present study may help to develop and implement a health and safety protection training programmes addressed to parents, caregivers, and practitioners to make children's lives easier. PMID- 27465623 TI - A Porphyrin-Based Discrete Tetragonal Prismatic Cage: Host-Guest Complexation and Its Application in Tuning Liquid-Crystalline Behavior. AB - The host-guest complexation between a porphyrin-based 3D tetragonal prism (H) and electron-rich pyrene is investigated. This host-guest molecular recognition is further utilized to suppress the liquid-crystalline behavior of a nematic molecule (G) containing cyanobiphenyl mesogens functionalized with a pyrenyl unit. Furthermore, coronene, with an increased number of pi-electrons, is used as a competitive guest to recover the liquid-crystalline behavior of G. This supramolecular approach provides a glimpse of the new possibilities to modulate the structures of the mesophases. PMID- 27465624 TI - Erratum to: A comparative evaluation of data-merging and meta-analysis methods for reconstructing gene-gene interactions. PMID- 27465625 TI - Theoretical and Practical Aspects of Different Cluster Set Structures: A Systematic Review. AB - Tufano, JJ, Brown, LE, and Haff, GG. Theoretical and practical aspects of different cluster set structures: a systematic review. J Strength Cond Res 31(3): 848-867, 2017-When performing a set of successive repetitions, fatigue ensues and the quality of performance during subsequent repetitions contained in the set decreases. Oftentimes, this response may be beneficial because fatigue may stimulate the neuromuscular system to adapt, resulting in a super-compensatory response. However, there are instances in which accumulated fatigue may be detrimental to training or performance adaptations (i.e., power development). In these instances, the ability to recover and maintain repetition performance would be considered essential. By providing intermittent rest between individual repetitions or groups of repetitions within a set, an athlete is able to acutely alleviate fatigue, allowing performance to remain relatively constant throughout an exercise session. Within the scientific literature, a set that includes intermittent rest between individual repetitions or groups of repetitions within a set is defined as a cluster set. Recently, cluster sets (CS) have received more attention as researchers have begun to examine the acute and chronic responses to this relatively novel set structure. However, much of the rest period terminology within the literature lacks uniformity and many authors attempt to compare largely different protocols with the same terminology. Additionally, the present body of scientific literature has mainly focused on the effects of CS on power output, leaving the effects of CS on strength and hypertrophy relatively unexplored. Therefore, the purpose of this review was to further delineate cluster set terminology, describe the acute and chronic responses of CS, and explain the need for further investigation of the effects of CS. PMID- 27465626 TI - Examining the Relationship Between the Functional Movement Screen and the Landing Error Scoring System in an Active, Male Collegiate Population. AB - Everard, EM, Harrison, AJ, and Lyons, M. Examining the relationship between the functional movement screen and the landing error scoring system in an active, male collegiate population. J Strength Cond Res 31(5): 1265-1272, 2017-In recent years, there has been an increasing focus on movement screening as the principal aspect of preparticipation testing. Two of the most common movement screening tools are the Functional Movement Screen (FMS) and the Landing Error Scoring System (LESS). Several studies have examined the reliability and validity of these tools, but so far, there have been no studies comparing the results of these 2 screening tools against each other. Therefore, the purpose of this study was to determine the relationship between FMS scores and LESS scores. Ninety eight male college athletes actively competing in sport (Gaelic games, soccer, athletics, boxing/mixed martial arts, Olympic weightlifting) participated in the study and performed the FMS and LESS screens. Both the 21-point and 100-point scoring systems were used to score the FMS. Spearman's correlation coefficients were used to determine the relationship between the 2 screening scores. The results showed a significant moderate correlation between FMS and LESS scores (rho 100 and 21 point = -0.528; -0.487; p < 0.001). In addition, r values of 0.26 and 0.23 indicate a poor shared variance between the 2 screens. The results indicate that performing well in one of the screens does not necessarily equate to performing well in the other. This has practical implications as it highlights that both screens may assess different movement patterns and should not be used as a substitute for each other. PMID- 27465627 TI - Utility of the Overhead Squat and Forward Arm Squat in Screening for Limited Ankle Dorsiflexion. AB - Rabin, A and Kozol, Z. Utility of the overhead squat and forward arm squat in screening for limited ankle dorsiflexion. J Strength Cond Res 31(5): 1251-1258, 2017-Limited ankle dorsiflexion (DF) range of motion (ROM) has been implicated in several lower extremity disorders. Effective screening for DF ROM may, therefore, help to identify "at risk" individuals. The primary purpose of this study was to determine the utility of 2 screening tests in detecting limited ankle DF ROM. Fifty-three healthy participants underwent an overhead squat (OS) test and a forward arm squat (FAS) test, as well as bilateral testing of weight-bearing and non-weight-bearing ankle DF ROM. Participants whose DF ROM fell below 1 SD from the sample average were considered to have limited DF ROM. The sensitivity, specificity, positive, and negative likelihood ratio (LR) of the OS and FAS in detecting individuals with limited DF ROM was calculated. The sensitivity of the OS was 1.00 regardless of the mode or the side of testing, whereas specificity ranged from 0.34 to 0.36. The positive LR of the OS ranged from 1.52 to 1.56, whereas negative LR was 0.00. The sensitivity of the FAS ranged from 0.56 to 0.70, whereas specificity ranged from 0.84 to 0.88. The positive and negative LR of the FAS ranged from 3.49 to 6.02, and 0.34 to 0.53, respectively. Our findings suggest that the OS and FAS may be used as complementing tests in screening for ankle DF limitation. Because of its excellent sensitivity, the OS should be performed first, and if negative, may confidently rule out limited DF ROM. However, given a positive OS, testing should proceed with the FAS, to more confidently rule in limited DF ROM. PMID- 27465628 TI - Effects of Low-Volume, High-Intensity Training on Performance in Competitive Swimmers: A Systematic Review. AB - Nugent, FJ, Comyns, TM, Burrows, E, and Warrington, GD. Effects of low-volume, high-intensity training on performance in competitive swimmers: a systematic review. J Strength Cond Res 31(3): 837-847, 2017-The purpose of this systematic review was to examine the extent and quality of the current research literature to determine the effects of low-volume, high-intensity training (HIT) on physiological performance and swimming performance in competitive swimmers. The methodology followed the preferred reporting items for systematic review and meta analysis protocol. A search of relevant databases and conference proceedings was performed until December 2015. The inclusion criteria were (a) competitive swimmers, (b) >=4 weeks HIT intervention, (c) comparison group had to involve a higher training volume, (d) outcome measures of physiological and swimming performance, and (e) all experimental study designs. Quality assessment was performed using the Quality Index checklist. Results indicate that of the 538 studies retrieved, 7 studies met the inclusion criteria. Six of the 7 studies found that an HIT intervention resulted in significant improvements in physiological performance. Four of the 7 studies found that HIT resulted in significant improvements in swimming performance, whereas none of the 7 studies resulted in a reduction in physiological or swimming performance. Despite the positive findings of this review, the short study duration is a limitation to a number of studies. The current evidence on the effects of HIT on performance is promising; however, it is difficult to draw accurate conclusions until further research has been conducted. PMID- 27465630 TI - Comparison of Female Collegiate Athletes and College Age Cohort in Tuck Jump Assessment. AB - Smith, CA, Olson, BK, Olson, LA, Chimera, NJ, and Warren, M. Comparison of female collegiate athletes and college age cohort in tuck jump assessment. J Strength Cond Res 31(4): 1048-1054, 2017-The tuck jump assessment (TJA) is a plyometric jumping assessment with 10 flaw criteria against which technique is assessed over a 10-second interval. The TJA has been reported as a tool for identifying neuromuscular deficits that increase risk for anterior cruciate ligament injury, but group specific data on female TJA scores are limited. No cut point has been developed for groups with different activity levels or participation in athletics. This study investigated the association between TJA score and athletic participation in college-aged females. One hundred twenty-one females (53 collegiate athletes and 68 college students) completed the TJA. TJA score was the sum of flaws for the 10 criteria observed, and the number of jumps was recorded. Poisson regression was used to assess the association between TJA score and number of jumps. The association between each of the 10 flaws between groups was assessed with the chi-square test. No significant association was found between groups for TJA score (mean +/- SD: 4.66 +/- 1.07 athletes; 5.45 +/- 1.05 college cohort; p = 0.06; beta = 0.82). Athletes jumped significantly more times (12.23 +/- 1.04 athletes; 9.35 +/- 1.04 college cohort). Athletes had a lower proportion of 2 flaws: "thighs do not reach parallel" and "pause between jumps." Lower statistical power may limit interpretation of the remaining flaws. The lack of control of the number of jumps may impact TJA score. To improve the TJA usefulness on the field and clinic, the protocol may need to standardize the number of jumps. PMID- 27465631 TI - Concurrent Validity of Wearable Activity Trackers Under Free-Living Conditions. AB - Brooke, SM, An, H-S, Kang, S-K, Noble, JM, Berg, KE, and Lee, J-M. Concurrent validity of wearable activity trackers under free-living conditions. J Strength Cond Res 31(4): 1097-1106, 2017-The purpose of this study is to evaluate the concurrent validity of wearable activity trackers in energy expenditure (EE) and sleep period time (SPT) under free-living conditions. Ninety-five (28.5 +/- 9.8 years) healthy men (n = 34) and women (n = 61) participated in this study. The total EE and SPT were measured using 8 monitors: Nike+ FuelBand SE (NFB), Garmin VivoFit (VF), Misfit Shine (MF), Fitbit Flex (FF), Jawbone UP (JU), Polar Loop (PL), Fitbit Charge HR (FC), and SenseWear Armband Mini (SWA) (criterion measures: SWA for EE and a sleep log for SPT). The mean absolute percent error (MAPE) for EE was 13.0, 15.2, 15.5, 16.1, 16.2, 22.8, and 24.5% for PL, MF, FF, NFB, FC, JU, and VF, respectively. Mean absolute percent errors were calculated for SPT to be 4.0, 8.8, 10.2, 11.5, 12.9, 13.6, 17.5, and 21.61% for VF, FF, JU, FC, MF, SWA laying down, PL, and SWA, respectively. Concurrent validity was examined using equivalence testing on EE (equivalence zone: 2,889.7-3,531.9 kcal); 2 trackers fell short of falling in the zone: PL (2,714.4-3,164.8 kcal) and FC (2,473.8-3,066.5 kcal). For SPT (equivalence zone: 420.6-514.0 minutes), several monitors fell in the zone: PL (448.3-485.6 minutes), MS (442.8-492.2 minutes), and FF (427.7-486.7 minutes). This study suggests that the PL and FC provide a reasonable estimate of EE under free-living conditions. The PL, FC, and MF were the most valid monitors used for measuring SPT. PMID- 27465633 TI - Variable Resistance Training Promotes Greater Strength and Power Adaptations Than Traditional Resistance Training in Elite Youth Rugby League Players. AB - Riviere, M, Louit, L, Strokosch, A, and Seitz, LB. Variable resistance training promotes greater strength and power adaptations than traditional resistance training in elite youth rugby league players. J Strength Cond Res 31(4): 947-955, 2017-The purpose of this study was to examine the strength, velocity, and power adaptations in youth rugby league players in response to a variable resistance training (VRT) or traditional free-weight resistance training (TRAD) intervention. Sixteen elite youth players were assigned to a VRT or TRAD group and completed 2 weekly upper- and lower-body strength and power sessions for 6 weeks. Training programs were identical except that the VRT group trained the bench press exercise with 20% of the prescribed load coming from elastic bands. Bench press 1 repetition maximum (1RM) and bench press mean velocity and power at 35, 45, 65, 75, and 85% of 1RM were measured before and after the training intervention, and the magnitude of the changes was determined using effect sizes (ESs). The VRT group experienced larger increases in both absolute (ES = 0.46 vs. 0.20) and relative (ES = 0.41 vs. 0.19) bench press 1RM. Similar results were observed for mean velocity as well as both absolute and relative mean power at 35, 45, 65, 75, and 85% of 1RM. Furthermore, both groups experienced large gains in both velocity and power in the heavier loads but small improvements in the lighter loads. The improvements in both velocity and power against the heavier loads were larger for the VRT group, whereas smaller differences existed between the 2 groups in the lighter loads. Variable resistance training using elastic bands may offer a greater training stimulus than traditional free-weight resistance training to improve upper-body strength, velocity, and power in elite youth rugby league players. PMID- 27465632 TI - A Novel Mass-Spring-Damper Model Analysis to Identify Landing Deficits in Athletes Returning to Sport After Anterior Cruciate Ligament Reconstruction. AB - Schneider, DK, Gokeler, A, Otten, E, Ford, KR, Hewett, TE, Divine, JG, Colosimo, AJ, Heidt, RS, and Myer, GD. A Novel mass-spring-damper model analysis to identify landing deficits in athletes returning to sport after anterior cruciate ligament reconstruction. J Strength Cond Res 31(9): 2590-2598, 2017-A mass-spring damper (MSD) model may serve as an extension of biomechanical data from 3 dimensional motion analysis and epidemiological data which helps to delineate populations at risk for anterior cruciate ligament (ACL) injuries. The purpose of this study was to evaluate such a model. Thirty-six ACL reconstruction (ACLR) group subjects and 67 controls (CTRL) completed single-leg drop landing and single-leg broad jump tasks. Landing ground reaction force data were collected and analyzed with an MSD model. Medians, interquartile ranges, and limb symmetry indices (LSIs) were calculated and comparisons were made within and between groups. During a single-leg drop landing, the ACLR group had a lower spring LSI than the CTRL group (p = 0.015) and landed with decreased stiffness in the involved limb relative to the uninvolved limb (p = 0.021). The ACLR group also had an increased damping LSI relative to the CTRL group (p = 0.045). The ACLR subjects landed with increased stiffness (p = 0.006) and decreased damping (p = 0.003) in their involved limbs compared to CTRL subjects' nondominant limbs. During a single-leg forward broad jump, the ACLR group had a greater spring LSI value than the CTRL group (p = 0.045). The CTRL group also recorded decreased damping values in their nondominant limbs compared with the involved limbs of the ACLR group (p = 0.046). Athletes who have undergone ACLR display different lower limb dynamics than healthy controls, according to an MSD model. Quadriceps dominance and leg dominance are components of ACLR athletes' landing strategies and may be identified with an MSD model and addressed during rehabilitation. PMID- 27465634 TI - Acute Physiological and Performance Responses to High-Intensity Resistance Circuit Training in Hypoxic and Normoxic Conditions. AB - Ramos-Campo, DJ, Rubio-Arias, JA, Freitas, TT, Camacho, A, Jimenez-Diaz, JF, and Alcaraz, PE. Acute physiological and performance responses to high-intensity resistance circuit training in hypoxic and normoxic conditions. J Strength Cond Res 31(4): 1040-1047, 2017-The aim of this study was to analyze physical performance and physiological variables during high-intensity resistance circuit training (HRC) with the addition of 2 levels (moderate and high) of systemic hypoxia. Twelve resistance-trained young male subjects participated in the study. After a 6 repetition maximum testing session, participants performed 3 randomized trials of HRC: normoxia (NORM: fraction of inspired oxygen [FiO2] = 0.21; ~0 m altitude), moderate hypoxia (MH: FiO2 = 0.16; ~2.100 m altitude), or high hypoxia (HH: FiO2 = 0.13; ~3.800 m altitude), as controlled by a hypoxic generator. Bench press force, heart rate and heart rate variability, rating of perceived exertion, resting metabolic rate, energy cost, and countermovement jump were assessed in each session. Heart rate variability in HH was significantly lower (standard deviation of all normal NN intervals [intervals between two "normal" beats] = 111.9 vs. 86.7 milliseconds; standard deviation of the difference between consecutive NN intervals = 19.5 vs. 17.0 milliseconds; p <= 0.05) in comparison with NORM. There were significant differences in rating of perceived exertion between NORM and HH (11.6 vs. 13.8 points). Peak and mean force on the bench press were significantly lower (p <= 0.05) in HH when compared with MH (peak: 725 vs. 488 N; mean: 574 vs. 373 N). Energy cost was significantly higher (p <= 0.01) in both hypoxic conditions compared with NORM (NORM: 10.4; MH: 11.7; HH: 13.3 kJ.min). There were no differences between conditions in heart rate and countermovement jump variables. These results indicate that hypoxic stimuli during HRC exercise alter physical performance and physiological variables and affect how strenuous the exercise is perceived to be. High-intensity resistance circuit training in hypoxia increases the stress on the performance and physiological responses, and these differences must be taken into account to avoid an excessive overload. PMID- 27465635 TI - Effects of Short-Term Free-Weight and Semiblock Periodization Resistance Training on Metabolic Syndrome. AB - South, MA, Layne, AS, Stuart, CA, Triplett, NT, Ramsey, MW, Howell, ME, Sands, WA, Mizuguchi, S, Hornsby, WG, Kavanaugh, AA, and Stone, MH. Effects of short term free-weight and semiblock periodization resistance training on metabolic syndrome. J Strength Cond Res 30(10): 2682-2696, 2016-The effects of short-term resistance training on performance and health variables associated with prolonged sedentary lifestyle and metabolic syndrome (MS) were investigated. Resistance training may alter a number of health-related, physiological, and performance variables. As a result, resistance training can be used as a valuable tool in ameliorating the effects of a sedentary lifestyle including those associated with MS. Nineteen previously sedentary subjects (10 with MS and 9 with nonmetabolic syndrome [NMS]) underwent 8 weeks of supervised resistance training. Maximum strength was measured using an isometric midthigh pull and resulting force-time curve. Vertical jump height (JH) and power were measured using a force plate. The muscle cross-sectional area (CSA) and type were examined using muscle biopsy and standard analysis techniques. Aerobic power was measured on a cycle ergometer using a ParvoMedics 2400 Metabolic system. Endurance was measured as time to exhaustion on a cycle ergometer. After training, maximum isometric strength, JH, jump power, and V[Combining Dot Above]O2peak increased by approximately 10% (or more) in both the metabolic and NMS groups (both male and female subjects). Over 8 weeks of training, body mass did not change statistically, but percent body fat decreased in subjects with the MS and in women, and lean body mass increased in all groups (p <= 0.05). Few alterations were noted in the fiber type. Men had larger CSAs compared those of with women, and there was a fiber-specific trend toward hypertrophy over time. In summary, 8 weeks of semiblock free-weight resistance training improved several performance variables and some cardiovascular factors associated with MS. PMID- 27465636 TI - Magnetic Resonance Imaging of Phosphocreatine and Determination of BOLD Kinetics in Lower Extremity Muscles using a Dual-Frequency Coil Array. AB - Magnetic resonance imaging (MRI) provides the unique ability to study metabolic and microvasculature functions in skeletal muscle using phosphorus and proton measurements. However, the low sensitivity of these techniques can make it difficult to capture dynamic muscle activity due to the temporal resolution required for kinetic measurements during and after exercise tasks. Here, we report the design of a dual-nuclei coil array that enables proton and phosphorus MRI of the human lower extremities with high spatial and temporal resolution. We developed an array with whole-volume coverage of the calf and a phosphorus signal to-noise ratio of more than double that of a birdcage coil in the gastrocnemius muscles. This enabled the local assessment of phosphocreatine recovery kinetics following a plantar flexion exercise using an efficient sampling scheme with a 6 s temporal resolution. The integrated proton array demonstrated image quality approximately equal to that of a clinical state-of-the-art knee coil, which enabled fat quantification and dynamic blood oxygen level-dependent measurements that reflect microvasculature function. The developed array and time-efficient pulse sequences were combined to create a localized assessment of calf metabolism using phosphorus measurements and vasculature function using proton measurements, which could provide new insights into muscle function. PMID- 27465637 TI - Bordetella pertussis modulates human macrophage defense gene expression. AB - Bordetella pertussis, the etiological agent of whooping cough, still causes outbreaks. We recently found evidence that B. pertussis can survive and even replicate inside human macrophages, indicating that this host cell might serve as a niche for persistence. In this work, we examined the interaction of B. pertussis with a human monocyte cell line (THP-1) that differentiates into macrophages in culture in order to investigate the host cell response to the infection and the mechanisms that promote that intracellular survival. To that end, we investigated the expression profile of a selected number of genes involved in cellular bactericidal activity and the inflammatory response during the early and late phases of infection. The bactericidal and inflammatory response of infected macrophages was progressively downregulated, while the number of THP-1 cells heavily loaded with live bacteria increased over time postinfection. Two of the main toxins of B. pertussis, pertussis toxin (Ptx) and adenylate cyclase (CyaA), were found to be involved in manipulating the host cell response. Therefore, failure to express either toxin proved detrimental to the development of intracellular infections by those bacteria. Taken together, these results support the relevance of host defense gene manipulation to the outcome of the interaction between B. pertussis and macrophages. PMID- 27465638 TI - UDP-galactopyranose mutase, a potential drug target against human pathogenic nematode Brugia malayi. AB - Lymphatic filariasis, a vector-borne neglected tropical disease affects millions of population in tropical and subtropical countries. Vaccine unavailability and emerging drug resistance against standard antifilarial drugs necessitate search of novel drug targets for developing alternate drugs. Recently, UDP galactopyranose mutases (UGM) have emerged as a promising drug target playing an important role in parasite virulence and survival. This study deals with the cloning and characterization of Brugia malayi UGM and further exploring its antifilarial drug target potential. The recombinant protein was actively involved in conversion of UDP-galactopyranose (substrate) to UDP-galactofuranose (product) revealing Km and Vmax to be ~51.15 MUM and ~1.27 MUM/min, respectively. The purified protein appeared to be decameric in native state and its 3D homology modeling using Aspergillus fumigatus UGM enzyme as template revealed conservation of active site residues. Two specific prokaryotic inhibitors (compounds A and B) of the enzyme inhibited B. malayi UGM enzymatic activity competitively depicting Ki values ~22.68 and ~23.0 MUM, respectively. These compounds were also active in vitro and in vivo against B. malayi The findings suggest that B. malayi UGM could be a potential antifilarial therapeutic drug target. PMID- 27465639 TI - Generational evolution of stents and sex-specific analyses. PMID- 27465640 TI - Stenting of the proximal left anterior descending and restenosis: in the shadow of the left main bifurcation. PMID- 27465642 TI - Mechanistic basis of hypermethioninemia. AB - Hypermethioninemia is a condition defined as elevated plasma methionine levels and may be a consequence of different conditions that include non-genetic and genetic causes. In severe cases, hypermethioninemia may lead to development of neurological and hepatic impairments, but mechanisms are still not well elucidated. Therefore, this review aims to reunite the knowledge acquired about the methionine-induced brain and liver toxicity focusing on the results obtained by studies from patients, in vitro experiments, and in vivo animal models. In general, some studies have shown that methionine decreases Na+,K+-ATPase activity, induces oxidative stress, increases acetylcholinesterase activity, and leads to dendritic spine downregulation in brain. Concerning to liver, hypermethioninemia seems to provoke changes in cell morphology, lipid accumulation, oxidative stress, inflammation, and ATP depletion. It is possible to infer that oxidative damage is one of the most important mechanisms responsible for methionine toxicity, since different studies showed that this amino acid induces oxidative stress in brain and liver tissues. Besides, reactive oxygen species may mediate other alterations induced by methionine, such as the reduction in brain Na+,K+-ATPase activity, and liver inflammation. PMID- 27465643 TI - Experimental realization of equiangular three-state quantum key distribution. AB - Quantum key distribution using three states in equiangular configuration combines a security threshold comparable with the one of the Bennett-Brassard 1984 protocol and a quantum bit error rate (QBER) estimation that does not need to reveal part of the key. We implement an entanglement-based version of the Renes 2004 protocol, using only passive optic elements in a linear scheme for the positive-operator valued measure (POVM), generating an asymptotic secure key rate of more than 10 kbit/s, with a mean QBER of 1.6%. We then demonstrate its security in the case of finite key and evaluate the key rate for both collective and general attacks. PMID- 27465641 TI - Likelihood of Attending Treatment for Anxiety Among Veteran Primary Care Patients: Patient Preferences for Treatment Attributes. AB - Anxiety is common, but under-treated, in primary care. Behavioral health providers embedded in primary care can help address this treatment gap. Guidance on anxiety treatment preferences would help inform tailoring of clinical practice and new interventions to be more patient-centered and increase treatment engagement. We surveyed 144 non-treatment seeking Veteran primary care patients (82.6 % male, 85.4 % White, age M = 59.8 years, SD = 13.9) reporting current anxiety symptoms (M = 13.87, SD = 3.66, on the Generalized Anxiety Disorder-7 Questionnaire) on their likelihood of attending anxiety treatment featuring various levels of 11 attributes (modality, type, location, format, provider, visit frequency, visit length, treatment duration, type of psychotherapy, symptom focus, and topic/skill). Participants indicated clear preferences for individual, face-to-face treatment in primary care, occurring once a month for at least 30 min and lasting at least three sessions. They also tended to prefer a stress management approach focused on trouble sleeping or fatigue, but all topics/skills were rated equivalently. For most attributes, the highest rated options were consistent with characteristics of integrated care. Implications for research and practice are discussed. PMID- 27465645 TI - Chemoprophylaxis With Oral Emtricitabine and Tenofovir Alafenamide Combination Protects Macaques From Rectal Simian/Human Immunodeficiency Virus Infection. AB - Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that efficiently delivers tenofovir diphosphate to lymphoid cells following oral administration. We investigated whether the combination of TAF and emtricitabine (FTC) could prevent simian/human immunodeficiency virus (SHIV) infection in macaques to determine the potential use of TAF for pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus infection. Macaques were exposed rectally to SHIV once per week for up to 19 weeks and received saline or FTC/TAF 24 hours before and 2 hours after each virus inoculation. All 6 controls were infected, while the 6 PrEP-treated animals were protected from infection. Our results support the clinical investigation of FTC/TAF for PrEP. PMID- 27465644 TI - Association of Human Immunoglobulin G1 Heavy Chain Variants With Neutralization Capacity and Antibody-Dependent Cellular Cytotoxicity Against Human Cytomegalovirus. AB - Human cytomegalovirus (HCMV) infection is limited by HCMV-specific antibody functions. Here the association between the genetic marker (GM) 3/17 variants in the immunoglobulin G1 (IgG1) heavy chain constant region, virus neutralization, and natural killer (NK)-cell activation was investigated. In 100 HCMV seropositive individuals, the GM3/17 polymorphism, serum 50% HCMV antibody neutralization titer (NT50), and in vitro HCMV-specific antibody NK-cell activation were assessed. The HCMV NT50 was higher in heterozygous GM3/17 persons than in GM3/3 persons (P = .0276). Furthermore, individuals expressing GM3/17 exhibited significantly higher NK-cell activation than persons carrying GM3/3 (P < .0001) or GM17/17 (P = .0095). Thus, persons expressing GM3/17 have potentially a selective advantage in HCMV defense. PMID- 27465646 TI - Long-term follow-up of HIV seroconverters in microbicide trials - rationale, study design, and challenges in MTN-015. AB - BACKGROUND: As the effect of biomedical prevention interventions on the natural history of HIV-1 infection in participants who seroconvert is unknown, the Microbicide Trials Network (MTN) established a longitudinal study (MTN-015) to monitor virologic, immunological, and clinical outcomes, as well as behavioral changes among women who become HIV-infected during MTN trials. We describe the rationale, study design, implementation, and enrollment of the initial group of participants in the MTN seroconverter cohort. METHODS: Initiated in 2008, MTN-015 is an ongoing observational cohort study enrolling participants who acquire HIV-1 infection during effectiveness studies of candidate microbicides. Eligible participants from recently completed and ongoing MTN trials are enrolled after seroconversion and return for regular follow-up visits with clinical and behavioral data collection. Biologic samples including blood and genital fluids are stored for future testing. RESULTS: MTN-015 was implemented initially at six African sites and enrolled 100/139 (72%) of eligible women who seroconverted in HIV Prevention Trials Network protocol 035 (HPTN 035, conducted by the MTN). The median time from seroconversion in HPTN 035 to enrollment in MTN-015 was 18 months. Retention was good with >70% of visits completed. Implementation challenges included regulatory reviews, translation, and testing of questionnaires, and site readiness. CONCLUSIONS: Enrollment of HIV-seroconverters into a longitudinal observational follow-up study is feasible and acceptable to participants. Data and samples collected in this protocol will be used to assess safety of investigational HIV microbicides and answer other important public health questions for HIV infected women. PMID- 27465649 TI - What is the future for Schneiderian first-rank symptoms, in the Diagnostic and Statistical Manual of Mental Disorders and otherwise? PMID- 27465647 TI - Ferumoxytol-enhanced magnetic resonance imaging methodology and normal values at 1.5 and 3T. AB - BACKGROUND: Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) can detect tissue-resident macrophage activity and identify cellular inflammation. Clinical studies using this technique are now emerging. We aimed to report a range of normal R2* values at 1.5 and 3 T in the myocardium and other tissues following ferumoxytol administration, outline the methodology used and suggest solutions to commonly encountered analysis problems. METHODS: Twenty volunteers were recruited: 10 imaged each at 1.5 T and 3 T. T2* and late gadolinium enhanced (LGE) MRI was conducted at baseline with further T2* imaging conducted approximately 24 h after USPIO infusion (ferumoxytol, 4 mg/kg). Regions of interest were selected in the myocardium and compared to other tissues. RESULTS: Following administration, USPIO was detected by changes in R2* from baseline (1/T2*) at 24 h in myocardium, skeletal muscle, kidney, liver, spleen and blood at 1.5 T, and myocardium, kidney, liver, spleen, blood and bone at 3 T (p < 0.05 for all). Myocardial changes in R2* due to USPIO were 26.5 +/- 7.3 s-1 at 1.5 T, and 37.2 +/- 9.6 s-1 at 3 T (p < 0.0001 for both). Tissues showing greatest ferumoxytol enhancement were the reticuloendothelial system: the liver, spleen and bone marrow (216.3 +/- 32.6 s-1, 336.3 +/- 60.3 s-1, 69.9 +/- 79.9 s-1; p < 0.0001, p < 0.0001, p = ns respectively at 1.5 T, and 275.6 +/- 69.9 s-1, 463.9 +/- 136.7 s-1, 417.9 +/- 370.3 s-1; p < 0.0001, p < 0.0001, p < 0.01 respectively at 3 T). CONCLUSION: Ferumoxytol-enhanced MRI is feasible at both 1.5 T and 3 T. Careful data selection and dose administration, along with refinements to echo-time acquisition, post-processing and analysis techniques are essential to ensure reliable and robust quantification of tissue enhancement. TRIAL REGISTRATION: ClinicalTrials.gov Identifier - NCT02319278 . Registered 03.12.2014. PMID- 27465650 TI - Heart failure: Heart failure after MI might increase risk of cancer. PMID- 27465648 TI - The genetic variations in DNA repair genes ERCC2 and XRCC1 were associated with the overall survival of advanced non-small-cell lung cancer patients. AB - It was reported that DNA repair can confer cancer cell resistance to therapeutic treatments by activating antiapoptotic cellular defense. We hypothesized that genetic variants of DNA repair genes may be associated with lung cancer prognosis. Seventeen tagging single-nucleotide polymorphism (tagSNPs) selected from 12 DNA repair genes were genotyped in 280 advanced non-small-cell lung cancer (NSCLC) patients by TaqMan assay. The associations of these SNPs and overall survival of advanced NSCLC patients were investigated. Advanced NSCLC patients carrying ERCC2 rs50872 CT+TT genotypes had significantly longer median survival time (MST) and decreased death risk than patients with rs50872 CC genotype [log-rank P = 0.031; adjusted HR(95% CI) = 0.73 (0.55-0.98), P = 0.033]. These effects were mainly seen among younger patients (<=65 years old) [HR(95% CI) = 0.57 (0.37-0.87), P = 0.010], patients without surgery [HR(95% CI) = 0.68 (0.47-0.98), P = 0.036] but with chemotherapy [HR(95% CI) = 0.64 (0.46-0.91), P = 0.012] or radiotherapy [HR(95% CI) = 0.58 (0.38-0.89), P = 0.013]. Meanwhile, compared to advanced NSCLC patients with rs25487 GG genotype, patients carrying XRCC1 rs25487 GA+AA genotypes had significantly shorter MST (MST = 11.7 vs. 16.7, log-rank P = 0.048). In addition, advanced NSCLC patients carrying the ERCC2 rs50872 CC in combination with XRCC1 rs25487 GA+AA genotype had the shortest MST (11.2 month) and highest death risk [HR(95% CI) = 1.70 (1.15-2.52), P = 0.008] when compared with those carrying rs50872 CT+TT and rs25487 GG genotype (MST = 22.0 month). The ERCC2 rs50872 T allele was associated with favorable but XRCC1 rs25487 A allele with bad survival for advanced NSCLC in Chinese population, which may offer novel biomarkers for predicting clinical outcomes. PMID- 27465651 TI - Heart failure: Improvement of LVEF in patients with HF is linked to better prognosis. PMID- 27465652 TI - Atrial fibrillation: Stroke prevention in atrial fibrillation: can we do better? PMID- 27465653 TI - Cardiac resuscitation: Cyclosporine cocktail for cardiac arrest? PMID- 27465654 TI - Gaussian-Schell analysis of the transverse spatial properties of high-harmonic beams. AB - High harmonic generation (HHG) is an established means of producing coherent, short wavelength, ultrafast pulses from a compact set-up. Table-top high-harmonic sources are increasingly being used to image physical and biological systems using emerging techniques such as coherent diffraction imaging and ptychography. These novel imaging methods require coherent illumination, and it is therefore important to both characterize the spatial coherence of high-harmonic beams and understand the processes which limit this property. Here we investigate the near- and far-field spatial properties of high-harmonic radiation generated in a gas cell. The variation with harmonic order of the intensity profile, wavefront curvature, and complex coherence factor is measured in the far-field by the SCIMITAR technique. Using the Gaussian-Schell model, the properties of the harmonic beam in the plane of generation are deduced. Our results show that the order-dependence of the harmonic spatial coherence is consistent with partial coherence induced by both variation of the intensity-dependent dipole phase as well as finite spatial coherence of the driving radiation. These findings are used to suggest ways in which the coherence of harmonic beams could be increased further, which would have direct benefits to imaging with high-harmonic radiation. PMID- 27465655 TI - Phase behavior of ABC-type triple-hydrophilic block copolymers in aqueous solutions. AB - The phase behavior of symmetric ABC triple-hydrophilic triblock copolymers in concentrated aqueous solutions is investigated using a simulated annealing technique. Two typical cases, in which the hydrophilicity of the middle B-block is either stronger or weaker than that of the end A- and C-blocks, are studied. In these two cases, a variety of phase diagrams are constructed as a function of the volume fraction of the B-block and the copolymer concentration ([Formula: see text] for both non-frustrated and frustrated copolymers. Structures, such as two color alternatingly packed cylinders or gyroid, and lamellae-in-lamellae etc. that do not occur in the melt system, are obtained in solutions. Rich phase transition sequences, especially re-entrant phase transitions involving complex continuous networks of alternating gyroid and alternating diamond are observed for a given copolymer with decreasing [Formula: see text] . The difference in hydrophilicity among different blocks can result in inhomogeneous distribution of solvent molecules in the morphology, and with the decrease of [Formula: see text] , the distribution of solvent molecules presents a non-monotonic variation. This results in a non-monotonic variation of the effective volume fraction of each domain with the decrease of [Formula: see text] , which induces the re-entrant phase transitions. The presence of a good solvent for all the blocks can cause changes in the effective segregation strengths between different blocks and also in chain conformations, hence can alter the bulk phases and results in the occurrence of new structures and phase transitions. Especially, structures having A-C interfaces or A-C mixed domains can be obtained even in the non-frustrated copolymer systems, and structures obtained in the frustrated systems may be similar to those obtained in the non-frustrated systems. The window of the alternating gyroid structures may occupy a large part of the phase diagram for non-frustrated copolymers with stronger B-hydrophilicity. This behavior can be used to tune the self-assembled structures of block copolymers. PMID- 27465656 TI - DH(*) in chiral smectics under electric field. AB - The behavior of double helices (DH(*) formed in the temperature interval N(*) SmA(*) in compounds of non-chiral liquid crystals doped with chiral molecules was investigated. Two different systems presenting left-handed and right-handed chirality were studied. A statistics of the handedness of the DH(*) revealed a correlation with the mixture chirality, as predicted theoretically in C. Meyer, Yu. A. Nastishin, M. Kleman, Phys. Rev. E 82, 031704 (2010). By applying a gradually increasing AC electric field, one can observe the shrinking of the cylinder circumscribing the DH(*) . This shrink is accompanied by a reduction of the DH(*) 's pitch. This effect was similar to the one produced by the decrease of temperature in the absence of the field. PMID- 27465657 TI - Social Network, Surgeon, and Media Influence on the Decision to Undergo Contralateral Prophylactic Mastectomy. AB - OBJECTIVES: The rate of contralateral prophylactic mastectomy (CPM) has risen sharply in the past decade. The current study was designed to examine social network, surgeon, and media influence on patients' CPM decision-making, examining not only who influenced the decision, and to what extent, but also the type of influence exerted. METHODS: Patients (N=113) who underwent CPM at 4 Indiana University-affiliated hospitals between 2008 and 2012 completed structured telephone interviews in 2013. Questions addressed the involvement and influence of the social network (family, friends, and nonsurgeon health professionals), surgeon, and media on the CPM decision. RESULTS: Spouses, children, family, friends, and health professionals were reported as exerting a meaningful degree of influence on patients' decisions, largely in ways that were positive or neutral toward CPM. Most surgeons were regarded as providing options rather than encouraging or discouraging CPM. Media influence was present, but limited. CONCLUSIONS: Patients who choose CPM do so with influence and support from members of their social networks. Reversing the increasing choice of CPM will require educating these influential others, which can be accomplished by encouraging patients to include them in clinical consultations, and by providing patients with educational materials that can be shared with their social networks. Surgeons need to be perceived as having an opinion, specifically that CPM should be reserved for those patients for whom it is medically indicated. PMID- 27465658 TI - Metabolite Profiling of the Plasma and Leukocytes of Chronic Myeloid Leukemia Patients. AB - The discovery of tyrosine kinase inhibitors (TKIs) brought a major breakthrough in the treatment of patients with chronic myeloid leukemia (CML). Pathogenetic CML events are closely linked with the Bcr-Abl protein with tyrosine kinase activity. TKIs block the ATP-binding site; therefore, the signal pathways leading to malignant transformation are no longer active. However, there is limited information about the impact of TKI treatment on the metabolome of CML patients. Using liquid chromatography mass spectrometric metabolite profiling and multivariate statistical methods, we analyzed plasma and leukocyte samples of patients newly diagnosed with CML, patients treated with hydroxyurea and TKIs (imatinib, dasatinib, nilotinib), and healthy controls. The global metabolic profiles clearly distinguished the newly diagnosed CML patients and the patients treated with hydroxyurea from those treated with TKIs and the healthy controls. The major changes were found in glycolysis, the citric acid cycle, and amino acid metabolism. We observed differences in the levels of amino acids and acylcarnitines between those patients responding to imatinib treatment and those who were resistant to it. According to our findings, the metabolic profiling may be potentially used as an additional tool for the assessment of response/resistance to imatinib. PMID- 27465659 TI - Frontal white matter injuries predestine gait difficulties in Parkinson's disease. AB - OBJECTIVES: This study applies diffusion tensor imaging (DTI) to determine differences in neuronal integrity between motor phenotypes in Parkinson's disease. MATERIAL AND METHODS: One hundred and twenty-two patients (47 females, mean age = 70.3 years) were included at baseline. Forty patients were tremor dominant (TD), 64 had postural imbalance and gait difficulty (PIGD), and 18 patients were indeterminate. The DTI was repeated after one, three and 5 years, including reassessment of phenotype. DTI was quantified using fractional anisotropy (FA), and mean, radial and axial diffusion. Targeted white matter involved six regions of interests (ROIs) in prefrontal cortex (PFC), the entrance to the external capsule (EEC) and lateral to the horn of the anterior ventricle (LVAH). Grey matter involved the basal ganglia. Data were analysed using mixed linear models with P < 0.05 (Bonferroni corrected) as significance threshold. RESULTS: PIGD and Indeterminate had reduced FA and axial diffusion in PFC, EEC and LVAH compared to Tremor dominant (P < 0.05). Basal ganglia showed no differences. Post hoc analysis showed that FA correlated negatively, and mean and radial diffusion positively, to PIGD symptoms in EEC, LVAH and four ROIs in PFC (P < 0.05). Tremor symptoms showed no correlations. Patients converting to PIGD and Indeterminate had lower FA, and higher mean and radial diffusion, at baseline in EEC, LVAH and four areas in PFC compared to non-converting patients (P < 0.05). CONCLUSION: Degeneration in frontal white matter is connected to PIGD symptoms in Parkinson's disease and if present at an early stage, the risk for conversion to the PIGD phenotype increases. PMID- 27465660 TI - Fine-needle aspiration of cervical lymph nodes yields adequate materials for accurate HPV testing in metastatic head and neck squamous cell carcinomas. AB - BACKGROUND: High-risk Human papillomavirus (HR-HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a distinct epidemiologic and pathologic disease. The data of HR-HPV testing on fine-needle aspiration (FNA) materials of cervical lymph nodes in patients with metastatic HNSCC are limited. METHODS: We retrospectively reviewed metastatic HNSCC cases with cervical lymph node FNAs which were tested for p16 immunohistochemistry (IHC) and HR-HPV DNA in situ hybridization (ISH). RESULTS: Of the 87 cases studied, the overall adequacy rate of cell block material was 86% for HR-HPV ISH, 93% for p16 IHC, 84% for both and 95% for either one. Pathologist-performed FNAs showed significantly higher percentage of satisfactory specimens for p16 and HR-HPV tests than clinician performed FNAs. Of the 73 cases adequate for both p16 IHC and HR-HPV ISH, the concordant rate between p16 and HR-HPV results was 78%. P16 positivity had sensitivity of 90% and specificity of 75% to predict primary oropharyngeal HNSCC, while HR-HPV test showed a similar high sensitivity (91%) but a better specificity (94%). CONCLUSION: FNAs of cervical lymph nodes yield adequate materials for reliable HR-HPV testing in metastatic HNSCCs and should be incorporated into routine pathologic evaluation for these patients. The high concordance between p16 IHC and HR-HPV ISH suggests p16 IHC may serve as a surrogate for HR-HPV ISH in metastatic HNSCC cases with oropharyngeal origin and is helpful to pinpoint primary tumor site. Diagn. Cytopathol. 2016;44:792-798. (c) 2016 Wiley Periodicals, Inc. PMID- 27465661 TI - Young adults' responses to alternative messages describing a sugar-sweetened beverage price increase. AB - OBJECTIVE: Many jurisdictions in the USA and globally are considering raising the prices of sugar-sweetened beverages (SSB) through taxes as a strategy to reduce their consumption. The objective of the present study was to identify whether the rationale provided for an SSB price increase affects young adults' behavioural intentions and attitudes towards SSB. DESIGN: Participants were randomly assigned to receive one of eight SSB price increase rationales. Intentions to purchase SSB and attitudes about the product and policy were measured. SETTING: A forty-six item cross-sectional Internet survey. SUBJECTS: Undergraduate students (n 494) at a large US Midwestern university. RESULTS: Rationale type was significantly associated with differences in participants' purchasing intentions for the full sample (F 7,485=2.53, P=0.014). Presenting the rationale for an SSB price increase as a user fee, an effort to reduce obesity, a strategy to offset health care costs or to protect children led to lower SSB purchasing intentions compared with a message with no rationale. Rationale type was also significantly associated with differences in perceptions of soda companies (F 7,485=2.10, P=0.043); among low consumers of SSB, messages describing the price increase as a user fee or tax led to more negative perceptions of soda companies. CONCLUSIONS: The rationale attached to an SSB price increase could influence consumers. However, these message effects may depend on individuals' level of SSB consumption. PMID- 27465662 TI - Halogen Bonding in Organic Synthesis and Organocatalysis. AB - Halogen bonding is a noncovalent interaction similar to hydrogen bonding, which is based on electrophilic halogen substituents. Hydrogen-bonding-based organocatalysis is a well-established strategy which has found numerous applications in recent years. In light of this, halogen bonding has recently been introduced as a key interaction for the design of activators or organocatalysts that is complementary to hydrogen bonding. This Concept features a discussion on the history and electronic origin of halogen bonding, summarizes all relevant examples of its application in organocatalysis, and provides an overview on the use of cationic or polyfluorinated halogen-bond donors in halide abstraction reactions or in the activation of neutral organic substrates. PMID- 27465663 TI - The cardioprotective effect of melatonin and exendin-4 treatment in a rat model of cardiorenal syndrome. AB - We investigated the cardioprotective effect of melatonin (Mel) and exendin-4 (Ex4) treatment in a rat model of cardiorenal syndrome (CRS). Adult male SD rats (n=48) were randomly and equally divided into sham control (SC), dilated cardiomyopathy (DCM) (doxorubicin 7 mg/kg i.p. every five days/4 doses), CRS (defined as DCM+CKD) only, CRS-Mel (20 mg/kg/d), CRS-Ex4 (10 MUg/kg/d), and CRS Mel-Ex4 groups. In vitro results showed protein expressions of oxidative stress (NOX-1/NOX-2/oxidized protein), DNA/mitochondrial damage (gamma-H2AX/cytosolic cytochrome c), apoptosis (cleaved caspase-3/PARP), and senescence (beta galactosidase cells) biomarkers were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/p-cresol-treated H9c2 cells that were revised by Mel and Ex4 treatments (all P<.001). By day 60, LVEF was highest in the SC and lowest in the CRS, significantly lower in the DCM than in other treatment groups, lower in the CRS-Mel and CRS-Ex4 than in the CRS-Mel-Ex4, and lower in the CRS-Mel than in the CRS-Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all P<.001). Plasma creatinine level was highest in the CRS and lowest in the SC and progressively decreased from the CRS-Mel, CRS-Ex4, CRS-Mel-Ex4 to DCM (P<.0001). Protein expressions of inflammation (TNF-alpha/NF-kappaB/MMP-2/MMP-9/IL-1beta), apoptosis/DNA damage (Bax/c-caspase-3/c-PARP/gamma-H2AX), fibrosis (Smad3/TGF-beta), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), cardiac hypertrophy/pressure overload (BNP/beta-MHC), and cardiac integrity (Cx43/alpha-MHC) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all P<.001). Fibrotic area, DNA damage (gamma-H2AX+ /53BP1+ CD90+ /XRCC1+ CD90+ ), and inflammation (CD14+ /CD68+ ) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all P<.001). Combined melatonin and exendin-4 treatment suppressed CRS-induced deterioration of LVEF and LV remodeling. PMID- 27465664 TI - Design, synthesis, and negative inotropic evaluation of 4-phenyl-1H-1,2,4-triazol 5(4H)-one derivatives containing triazole or piperazine moieties. AB - In this study, four novel series of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of -48.22 +/- 0.36% at a concentration of 3 * 10-5 mol/L (metoprolol: -9.74 +/- 0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP-sensitive K+ channel and L-type Ca2+ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria. PMID- 27465665 TI - Treatment with the GPR55 antagonist CID16020046 increases neutrophil activation in mouse atherogenesis. AB - Endocannabinoids modulate atherogenesis by triggering different receptors. Recently, orphan G protein-coupled receptors (GPRs) were suggested to be activated by endocannabinoids, possibly regulating vasorelaxation. Here, we investigated whether GPR55 antagonism with CID16020046 would impact on atherosclerotic size and inflammation in two mouse models of early and more advanced atherogenesis. Eleven-week old ApoE-/- mice were fed either a normal diet ([ND] for 16 weeks) or a high-cholesterol diet ([HD] for 11 weeks), resulting in different degrees of hypercholesterolaemia and size of atherosclerosis. CID16020046 (0.5 mg/kg) or vehicle were intraperitoneally administrated five times per week in the last three weeks before euthanasia. Treatment with CID1602004 was well-tolerated, but failed to affect atherosclerotic plaque and necrotic core size, fibrous cap thickness, macrophage and smooth muscle cell content as well as Th cell polarisation. In ND mice, treatment with CID1602004 was associated with increased chemokine production, neutrophil and MMP-9 intraplaque content as well as reduced collagen as compared to vehicle-treated animals. In HD mice, CID1602004 increased intraplaque MMP-9 and abrogated collagen content without affecting neutrophils. In vitro, serum from CID1602004-treated ND mice increased mouse neutrophil chemotaxis towards CXCL2 as compared to serum from vehicle-treated animals. CID1602004 dose dependently induced neutrophil degranulation that was reverted by co-incubation with the GPR55 agonist Abn-CBD. In supernatants from degranulation experiments, increased levels of the endocannabinoid and putative GPR55 ligand anandamide (AEA) were found, suggesting its possible autocrine control of neutrophil activity. These results indicate that GPR55 is critical for the negative control of neutrophil activation in different phases of atherogenesis. PMID- 27465666 TI - Putting on weight stigma: A randomized study of the effects of wearing a fat suit on eating, well-being, and cortisol. AB - OBJECTIVE: Although a considerable amount of research has revealed connections between weight stigma and mental and physical health outcomes, no studies to date have experimentally manipulated the experience of obesity to understand how weight stigma causally affects eating behavior, physiology, and psychological well-being. Research has also not yet identified effective strategies for reducing weight stigma. METHODS: In this research, the effect of weight stigma on psychological outcomes, unhealthy eating behavior, and the stress hormone cortisol was examined by randomly assigning participants to appear obese by wearing a fat suit or not. It was hypothesized that the physical alteration of participants' apparent body size would lead to similar consequences as those associated with the experience of weight stigma and reduce antifat attitudes. RESULTS: Supporting these hypotheses, experimentally manipulating apparent body size led participants to consume more unhealthy foods and report higher levels of negative effect. However, the study did not show any differences in cortisol reactivity or reduction in antifat attitudes as a function of the fat suit manipulation. CONCLUSIONS: These findings contribute to an understanding of the potentially deleterious psychological and behavioral effects of weight stigma while also informing future interventions to reduce weight stigma. PMID- 27465667 TI - Azithromycin for the treatment of eosinophilic nasal polyposis: Clinical and histologic analysis. AB - INTRODUCTION: Macrolides used as immunomodulators are a promising tool for chronic inflammatory airway diseases. Eosinophilic nasal polyposis (ENP) is still considered a disease that is difficult to control with the currently standardized treatments. OBJECTIVES: To evaluate prolonged treatment with low-dose azithromycin for ENP based on clinical and histopathologic variables. METHODS: The present investigation was a self-paired case study of 33 patients with ENP. A comparison was performed between patients before and after treatment with azithromycin for 8 weeks. The patients were subjected to clinical examinations, staging (three-dimensional imaging by endoscopy), application of the questionnaire, and biopsy of nasal polyps at the beginning and at the end of the treatment. RESULTS: The treatment yielded a clinical improvement regarding the two variables studied: polyposis staging (69.7%) and questionnaire (57.6%). We did not find significant differences in the inflammatory pattern and in the percentage or absolute number of eosinophils per field between samples obtained before and after the treatment (p > 0.05). There was no difference between the answers obtained from groups with and without asthma and/or aspirin intolerance (p > 0.3). The patients with advanced initial staging exhibited lower subjective improvement index and staging reduction (p = 0.031 and p = 0.012, respectively). CONCLUSION: Based on this study, azithromycin may be considered as another therapeutic option for ENP. However, further studies are necessary to define the real mechanism of action involved. PMID- 27465668 TI - The use of serum anti-Mullerian hormone (AMH) levels and antral follicle count (AFC) to predict the number of oocytes collected and availability of embryos for cryopreservation in IVF. AB - AIM: To investigate the predictive value of anti-Mullerian hormone (AMH) and antral follicle count (AFC) on the final number of oocytes retrieved and the availability of embryos for cryopreservation in in vitro fertilization (IVF) cycles. PATIENTS AND METHODS: In this prospective study, one hundred and twenty women in their first IVF treatment were enrolled. The short stimulation agonist protocol was used for controlled ovarian hyperstimulation in all cases. Serum AMH levels were measured during the menstrual cycle preceding treatment. AFC was measured in cycle day 2, just before starting ovarian stimulation. RESULTS: A strong, positive correlation between AMH, AFC and the number of collected oocytes was found. The patients with available and suitable supplementary embryos for cryopreservation had higher levels of AMH and larger numbers of AFC. CONCLUSION: AMH and AFC appear to be valuable markers mainly for ovarian reserve and response to IVF treatment. Serum AMH levels and AFC are significantly associated with the number of retrieved oocytes. Also, a positive correlation with the availability of supernumerary embryos suitable for cryopreservation was observed. PMID- 27465669 TI - Statins are not a risk factor for liver damage associated with intravenous glucocorticoid pulse therapy for Graves' orbitopathy. AB - OBJECTIVE: Acute liver damage (ALD) is associated with high-dose intravenous (iv) glucocorticoid (GC) (ivGC) pulse therapy in ~1 % of patients for Graves' orbitopathy (GO). It has been proposed that statins may increase the risk of ALD. Here we investigated the frequency of ALD according to the assumption of statins in a large retrospective cohort study. METHODS: We studied 1076 consecutive patients with GO given ivGC. ALD was defined as an increase in alanine aminotransferase >=300 U/l. RESULTS: At the time of ivGC, 62 patients were taking statins and 1014 were not. The frequency of ALD has been reported to be 1.2 cases/100,000 statins users and 1300/100,000 in GO patients given ivGC. Thus, the expected frequency of ALD in patients given both statins and ivGC is 1560/100,000. Transferring these data to our series, one would have expected at least 0.96 cases of ALD (~one case), in the 62 patients given both ivGC and statins. However, no cases of ALD were observed in patients given statins, and the previously reported 14 cases of ALD in this series were seen in patients who were not taking statins. CONCLUSIONS: The lack of observation of cases of ALD in patients given ivGC and statins is quite reassuring. Although caution should be applied to any patient candidate to ivGC treatment and this should be particularly accurate in patients given statins, our findings somehow justify the use of ivGC in patients under statins, although further studies in larger cohorts are needed to confirm our conclusions. PMID- 27465671 TI - Enhanced germination of barley (Hordeum vulgare L.) using chitooligosaccharide as an elicitor in seed priming to improve malt quality. AB - OBJECTIVES: To study enhanced barley germination by chitooligosaccharide as an elicitor for improving the quality of malt. RESULTS: Barley germination for both radical and leaf sprouts was enhanced when chitooligosaccharide was added to the steeping water in the first steeping cycle. The activities of hydrolases (alpha /beta-amylase, proteinase and beta-glucanase) and antioxidases (superoxide dismutase and catalase) in the resultant malt were increased in a dose-dependent manner when chitooligosaccharide was supplemented in the steeping water. Maximal promotion was at 1 mg chitooligosaccharide/l for alpha-/beta-amylase and proteinase, and at 10 mg/l for beta-glucanase, superoxide dismutase and catalase. Malt quality, including free alpha-amino nitrogen content, Kolbach index, malt extract content, diastatic power, wort viscosity and the ratio of glucose, maltose and maltotriose, was significantly improved by chitooligosaccharide in seed priming at 1 mg/l. CONCLUSION: Application of chitooligosaccharide in the steeping water promotes barley germination and improves the quality of malt. PMID- 27465670 TI - The phenotype of newly diagnosed Graves' disease in Italy in recent years is milder than in the past: results of a large observational longitudinal study. AB - OBJECTIVE: The Merseburg triad (hyperthyroidism, goiter, and orbitopathy) characterizes classical description of Graves' disease (GD). Aim of this observational, longitudinal study was to evaluate the current clinical features of newly diagnosed GD in Italy. MATERIALS AND METHODS: In two Northern Italy centers (Varese and Pavia), 283 consecutive patients (211 women, 72 men; mean age 47.4 years) with newly diagnosed GD were recruited in the years 2010-2014. Diagnosis was based on established criteria, and thyroid volume was assessed by ultrasonography. A clinical severity score (CSS) to assess the overall disease severity was developed by grading each component of the Merseburg triad. RESULTS: At diagnosis, 45 % of patients had no goiter, and 30 % had a small goiter. The proportion of goitrous patients was much lower than in two Italian studies performed 20-30 years ago. Hyperthyroidism was subclinical in 16 % and mild in 29 % of patients, and Graves' orbitopathy was present in 20 %, usually mild, and active in only 2.5 % of patients. Using the CSS, less than half (44 %) of the patients had severe GD, while 22 % had mild and 34 % moderate disease. CSS was associated with a significantly higher risk of poorly controlled hyperthyroidism at 6 months. CONCLUSIONS: In Italy, a relevant proportion of Graves' patients at diagnosis have mild to moderate GD; about half of them have no goiter, slightly less than one-fifth have subclinical hyperthyroidism, and only 20 % have GO. Thus, the clinical phenotype of GD is milder than in the past, possibly due to both earlier diagnosis and treatment, and improved iodine nutrition. PMID- 27465672 TI - Development of a core outcome set for use in determining the overall success of gastroschisis treatment. AB - BACKGROUND: Gastroschisis research is limited in quality by the presence of significant heterogeneity in outcome measure reporting (PloS One 10(1):e0116908, 2015). Using core outcome sets in research is one proposed method for addressing this problem (Trials 13:103, 2012; Clin Rheumatol 33(9):1313-1322, 2014; Health Serv Res Policy 17(1):1-2, 2012). Ultimately, standardising outcome measure reporting will improve research quality and translate into improvements in patient care. METHODS/DESIGN: Candidate outcome measures have been identified through systematic reviews. These outcome measures will form the starting point for an online, three-phase Delphi process that will be carried out in parallel by three panels of experts. Panel 1 is a neonatal panel, panel 2 is a non-neonatal panel and panel 3 is a lay panel. In round 1, experts will be asked to score the previously identified outcome measures from 1-9 based on how important they think the measures are in determining the overall success of their/their child's/their patient's gastroschisis treatment. In round 2, experts will be presented with the same list of outcome measures and with graphical representations of how their panel scored that outcome in round 1. They will be asked to re-score the outcome measure taking into account how important other members of their panel felt it to be. In round 3, experts will again be asked to re-score each outcome measure, but this time they will receive a graphical representation of the distribution of scores from all three panels which they should take into account when re-scoring. Following round 3 of the Delphi process, 40 experts will be invited to attend a face-to-face consensus meeting. Participants will be invited in a purposive manner to obtain balance between the different panels. The results of the Delphi process will be discussed, and outcomes re-scored. Outcome measures where > 70 % of the participants at the meeting scored them as 7-9 and < 15 % scored them as 1 3 will form the core outcome set. DISCUSSION: Development of a core outcome set will help to reduce the heterogeneity of the outcome measure reporting in gastroschisis. This will increase the quality of research taking place and ultimately improve care provided to infants with gastroschisis. PMID- 27465673 TI - Anticholinesterase, antioxidant, analgesic and anti-inflammatory activity assessment of Xeranthemum annuum L. and isolation of two cyanogenic compounds. AB - CONTEXT: Xeranthemum annuum L. (Asteraceae) (XA) is an ornamental and medicinal species with limited bioactivity and phytochemical data. OBJECTIVE: Identification of anticholinesterase, antioxidant, anti-inflammatory and analgesic effects of the flower and root-stem (R-S) extracts of XA. MATERIALS AND METHODS: Anticholinesterase (at 100 MUg mL-1) and antioxidant (at 1000 MUg mL-1) effects of various extracts were evaluated via microtiter assays, while anti inflammatory and analgesic effects of the R-S extracts were tested using carrageenan-induced hind paw oedema (100 and 200 mg kg-1) and p-benzoquinone (PBQ) writhing models (200 mg kg-1) in male Swiss albino mice. The R-S ethanol extract of XA was subjected to isolation studies using conventional chromatographic methods. RESULTS: Most of the extracts showed inhibition over 85% against butyrylcholinesterase and no inhibition towards acetylcholinesterase. The flower chloroform and the R-S ethyl acetate extracts were most effective (97.85 +/- 0.94% and 96.89 +/- 1.09%, respectively). The R-S ethanol extract displayed a remarkable scavenging activity against DPPH (77.33 +/- 1.99%) and in FRAP assay, while the hexane extract of the R-S parts possessed the highest metal-chelating capacity (72.79 +/- 0.33%). The chloroform extract of the R-S caused a significant analgesic effect (24.4%) in PBQ writhing model. No anti-inflammatory effect was observed. Isolation of zierin and zierin xyloside, which were inactive in anticholinesterase assays, was achieved from the R-S ethanol extract. DISCUSSION AND CONCLUSION: This is the first report of anticholinesterase, antioxidant, analgesic and anti-inflammatory activities and isolation of zierin and zierin xyloside from XA. Therefore, XA seems to contain antioxidant and BChE inhibiting compounds. PMID- 27465674 TI - Early CCR6 expression on B cells modulates germinal centre kinetics and efficient antibody responses. AB - The CC-chemokine receptor 6 (CCR6) can be detected on naive and activated B cells. Counterintuitively, its absence accelerates the appearance of germinal centres (GCs) and increases the production of low-affinity antibodies. The detailed mechanism of CCR6 function during the humoral response has remained elusive, but previously we identified a distinct CCR6high B-cell population in vivo early after antigenic challenge. In this study, we defined this population specifically as early, activated pre-GC B cells. In accordance, we show that CCR6 is upregulated rapidly within hours on the protein or mRNA level after activation in vitro. In addition, only activated B cells migrated specifically towards CCL20, the specific ligand for CCR6. Lack of CCR6 increased the dark zone/light zone ratio of GC and led to decreased antigen-specific IgG1 and IgG2a antibody generation in a B-cell intrinsic manner in mixed bone marrow chimeras. In contrast, antigen-specific IgM responses were normal. Hence, CCR6 negatively regulates entry of activated, antigen-specific pre-GC B cells into the GC reaction. PMID- 27465675 TI - Bergmann's ossicle (ossiculum terminale persistens): a brief review and differentiation from other findings of the odontoid process. AB - PURPOSE: The purpose of this paper was to review the literature on Bergmann's ossicle and provide an overview on its development, etiology, and clinical presentation while also differentiating it from similar structural anomalies. METHODS: A thorough review of the literature available on Bergmann's ossicle was performed. RESULTS: Bergmann's ossicle, also referred to as ossiculum terminale persistens, was defined as a developmental anomaly of the odontoid process in which an ossification center that gives rise to the tip of the dens fails to fuse properly with the body of the axis. CONCLUSION: Bergmann's ossicle is most often a benign condition, although it rarely may present with clinical symptoms such as neck pain and neurological signs. It may be associated with Down's syndrome and contribute to atlantoaxial instability. PMID- 27465676 TI - Effects of manual therapy on treatment duration and motor development in infants with severe nonsynostotic plagiocephaly: a randomised controlled pilot study. AB - PURPOSE: Despite growing evidence regarding nonsynostotic plagiocephaly and their repercussions on motor development, there is little evidence to support the use of manual therapy as an adjuvant option. The aim of this study was to evaluate the effects of a therapeutic approach based on manual therapy as an adjuvant option on treatment duration and motor development in infants with severe nonsynostotic plagiocephaly. METHODS: This is a randomised controlled pilot study. The study was conducted at a university hospital. Forty-six infants with severe nonsynostotic plagiocephaly (types 4-5 of the Argenta scale) referred to the Early Care and Monitoring Unit were randomly allocated to a control group receiving standard treatment (repositioning and an orthotic helmet) or to an experimental group treated with manual therapy added to standard treatment. Infants were discharged when the correction of the asymmetry was optimal taken into account the previous clinical characteristics. The outcome measures were treatment duration and motor development assessed with the Alberta Infant Motor Scale (AIMS) at baseline and at discharge. RESULTS: Asymmetry after the treatment was minimal (type 0 or 1 according to the Argenta scale) in both groups. A comparative analysis showed that treatment duration was significantly shorter (p < 0.001) in the experimental group (109.84 +/- 14.45 days) compared to the control group (148.65 +/- 11.53 days). The motor behaviour was normal (scores above the 16th percentile of the AIMS) in all the infants after the treatment. CONCLUSIONS: Manual therapy added to standard treatment reduces the treatment duration in infants with severe nonsynostotic plagiocephaly. PMID- 27465678 TI - Erratum to: High Jagged1 expression is associated with poor outcome in primary glioblastoma. PMID- 27465677 TI - Palliative epilepsy surgery in Dravet syndrome-case series and review of the literature. AB - PURPOSE: Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy (SMEI), is a rare genetic disorder that results in severe childhood-onset epilepsy. Children with DS initially present with seizures in the first year of life that are often associated with fevers. With age, multiple seizure types develop. There are few reports and no guidelines regarding palliative surgical treatment for DS. Therefore, we reviewed our surgical experience with DS. METHODS: We conducted a retrospective review of all patients with genetically confirmed DS who underwent either vagal nerve stimulator (VNS) implantation or corpus callosotomy (CC) from May 2001 to April 2014 at our institution. All inpatient and outpatient relevant documentation were reviewed. Demographic information, genetic mutation, operation performed, and preoperative and postoperative seizure frequency were recorded. Inclusion criteria required greater than one-year postoperative follow-up. RESULTS: Seven children with DS were assessed. Six patients were treated with VNS and one patient was treated with CC. In one child, VNS was followed by CC as a secondary procedure. Therefore, in total, eight surgeries were performed on seven patients during the study period. At least 1 year elapsed from presentation to our hospital and surgery for all patients. Average time after the first seizure to VNS was 4.1 years, and the average time after the first seizure to CC was 7.6 years. The mean age of patients undergoing VNS implantation was 4.3 years, and the mean age for patients undergoing CC was eight. Average follow-up for all seven patients was 6.6 years. Seizures were decreased in five of the six patients with VNS and decreased in the two patients after CC. Four of the six patients who had VNS implanted had a greater than 50 % reduction in seizure frequency, and one of the six patients who had VNS implanted had a less than 50 % reduction in seizure frequency. One patient did not respond effectively to the VNS and had very limited change in seizure frequency. Both patients who had a CC had a greater than 50 % reduction in seizure frequency. CONCLUSIONS: Both VNS and CC in patients with DS can be effective at reducing seizure frequency. Patients with DS may benefit from earlier and more aggressive surgical intervention. Studies using larger patient cohorts will help clarify the role that surgery may play in the multidisciplinary approach to controlling seizures in DS. Further studies will help determine the appropriate timing of and type of surgical intervention. PMID- 27465679 TI - Adaptation and standardization of a Western tool for assessing child development in non-Western low-income context. AB - BACKGROUND: Due to lack of culturally relevant assessment tools, little is known about children's developmental profiles in low income settings such as Ethiopia. The objective of this study was to adapt and standardize the Denver II for assessing child development in Jimma Zone, South West Ethiopia. METHODS: Culture specific test items in Denver II were modified. After translation into two local languages, all test items were piloted and fine-tuned. Using 1597 healthy children 4 days to 70.6 months of age, the 25, 50, 75 and 90 % passing ages were determined for each test item as milestones. Milestones attainment on the adapted version and the Denver II were compared on the 90 % passing age. Reliability of the adapted tool was examined. RESULTS: A total of 36 (28.8 %) test items, mostly from personal social domain, were adapted. Milestones attainment ages on the two versions differed significantly on 42 (34 %) test items. The adapted tool has an excellent inter-rater on 123 (98 %) items and substantial to excellent test retest reliability on 119 (91 %) items. CONCLUSIONS: A Western developmental assessment tool can be adapted reliably for use in low-income settings. Age differences in attaining milestones indicate a correct estimation of child development requires a population-specific standard. PMID- 27465680 TI - The association between indicators of health and housing in people with Parkinson's disease. AB - BACKGROUND: There are knowledge gaps about the life situation for people ageing with Parkinson's disease (PD), with virtually no understanding of home and health dynamics. Therefore, the aim of the present study was to explore the association between aspects of health and objective as well as perceived housing in people with PD. METHODS: Participants were recruited from three hospitals in the region of Skane in southern Sweden. The sample for the present study included 231 (62 % men) participants with PD, with a mean age of 75 (min-max, 45-93) years. The data collection procedure included a self-administered postal survey and a subsequent home visit where structured interviews, observations and clinical assessments were administered. To study the association between aspects of health and housing canonical correlation was applied. Twelve variables (6 in the health and 6 in the housing set) were included. This corresponds to about 20 individuals per variable and is considered sufficient to accurately interpret the largest (i.e., first) canonical correlation. RESULTS: The analysis between the health variables and housing variables set yielded two significant pairs of variates with the canonical correlations 0.68 (p < 0.0001) and 0.33 (p = 0.0112), respectively. For the first pair of variates the canonical R(2) was 0.46. The results showed that external control beliefs and behavioral aspects of meaning of home contributed the most to the housing variate, whereas difficulties/dependence in activities of daily living (ADL) and functional limitations contributed the most to the health variate. Although a significant relationship was found for the second canonical correlation, the shared variance between the two variates was considerably lower; R(2) = 0.11. CONCLUSIONS: This study suggests that people with PD who have more functional limitations, difficulties in ADL and are more dependent perceive their homes as less meaningful from a behavioral perspective. Moreover, they tend to rely on external influences managing their housing situation. With this kind of knowledge at hand, health care and social services professionals are in a better position to observe and efficiently address problems related to health and housing among people with PD. PMID- 27465681 TI - 2-Anilino-3-Aroylquinolines as Potent Tubulin Polymerization Inhibitors. AB - Several 2-anilino-3-aroylquinolines were designed, synthesized, and screened for their cytotoxic activity against five human cancer cell lines: HeLa, DU-145, A549, MDA-MB-231, and MCF-7. Their IC50 values ranged from 0.77 to 23.6 MUm. Among the series, compounds 7 f [(4-fluorophenyl)(2-((4 fluorophenyl)amino)quinolin-3-yl)methanone] and 7 g [(4-chlorophenyl)(2-((4 fluorophenyl)amino)quinolin-3-yl)methanone] showed remarkable antiproliferative activity against human lung cancer and prostate cancer cell lines. The IC50 values for inhibiting tubulin polymerization were 2.24 and 2.10 MUm for compounds 7 f and 7 g, respectively, and were much lower than that of the reference compound E7010 [N-(2-(4-hydroxyphenylamino)pyridin-3-yl)-4 methoxybenzenesulfonamide]. Furthermore, flow cytometric analysis revealed that these compounds arrest the cell cycle at the G2 /M phase, leading to apoptosis. Apoptosis was also confirmed by mitochondrial membrane potential, Annexin V-FITC assay, and intracellular ROS generation. Immunohistochemistry, western blot, and tubulin polymerization assays showed that these compounds disrupt tubulin polymerization. Molecular docking studies revealed that these compounds bind efficiently to beta-tubulin at the colchicine binding site. PMID- 27465682 TI - Fatigue and Fatigability in Persons With Multiple Sclerosis. PMID- 27465684 TI - The Cortisol Awakening Response and Depressive Symptomatology: The Moderating Role of Sleep and Gender. AB - The association between depression and the cortisol awakening response (CAR) has been widely examined, yet the results are mixed and factors responsible for such inconsistencies are poorly understood. The current study investigated whether the link between depressive symptomatology and CAR varied as a function of two such factors: sleep and gender. The sample included 58 young adults (30 females; Mage = 18.7; SDage = 0.91). Participants completed the Beck Depression Inventory as well as the Consensus Sleep Diary to assess depressive symptomatology and daily sleep patterns, respectively. Participants also provided four salivary cortisol samples (0, 30, 45 and 60 min after awakening) during two consecutive weekdays. Results demonstrated that greater depressive symptoms were associated with a greater CAR but only when depressive symptoms were linked to a shorter sleep time. In addition, gender significantly moderated the association between depressive symptoms and CAR. While greater depressive symptoms were associated with an elevated CAR among females, they were associated with a blunted CAR among males. These findings provide some insight into potential mechanisms linking depressive symptomatology and CAR, and suggest that future studies examining CAR as a biomarker of depression should account for differences in sleep and gender. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27465685 TI - Chromophore-immobilized luminescent metal-organic frameworks as potential lighting phosphors and chemical sensors. AB - An organic chromophore H4tcbpe-F was synthesized and immobilized into metal organic frameworks along with two bipyridine derivatives as co-ligands to generate two strongly luminescent materials [Zn2(tcbpe-F)(4,4'-bpy).xDMA] (1) and [Zn2(tcbpe-F)(bpee).xDMA] (2) [4,4'-bpy = 4,4'-bipyridine, bpee = 4,4'-bipyridyl ethylene, tcbpe-F = 4',4''',4''''',4'''''''-(ethene-1,1,2,2-tetrayl)tetrakis(3 fluoro-[1,1'-biphenyl]-4-carboxylic acid), DMA = N,N-dimethylacetamide]. Compounds 1 and 2 are isoreticular and feature a 2-fold interpenetrated three dimensional porous structure. Both compounds give green-yellow emission under blue light excitation. Compound 1 has a high internal quantum yield of ~51% when excited at 455 nm and shows selective luminescence signal change (e.g. emission energy and/or intensity) towards different solvents, including both aromatic and nonaromatic volatile organic species. These properties make it potentially useful as a lighting phosphor and a chemical sensor. PMID- 27465683 TI - Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin-7. AB - Kalirin (Kal), a dual Rho GDP/GTP exchange factor (GEF), plays essential roles within and outside the nervous system. Tissue-specific, developmentally regulated alternative splicing generates isoforms with one (Kal7) or two (Kal9, Kal12) GEF domains along with a kinase (Kal12) domain; while Kal9 and Kal12 are crucial for neurite outgrowth, Kal7 plays important roles in spine maintenance and synaptic plasticity. Tissue-specific usage of alternate Kalrn promoters (A, B, C, D) places four different peptides before the Sec14 domain. cSec14, with an amphipathic helix encoded by the C-promoter (Kal-C-helix), is the only variant known to interact with phosphoinositides. We sought to elucidate the biological significance of Kalirin promoter usage and lipid binding. While Ex1B expression was predominant early in development, Ex1C expression increased when synaptogenesis occurred. Kal-C-helix-containing Kal7 (cKal7) was enriched at the postsynaptic density, present in the microsomal fraction and absent from cytosol; no significant amount of cKal9 or cKal12 could be identified in mouse brain. Similarly, in primary hippocampal neurons, endogenous cKalirin colocalized with postsynaptic density 95 in dendritic spines, juxtaposed to Vglut1-positive puncta. When expressed in young neurons, bSec14-EGFP was diffusely distributed, while cSec14-EGFP localized to internal puncta. Transfected bKal7-EGFP and cKal7 EGFP localized to dendritic spines and increased spine density in more mature cultured neurons. Although promoter usage did not alter the Rac-GEF activity of Kal7, the synaptic puncta formed by cKal7-EGFP were smaller than those formed by bKal7-EGFP. Molecular modeling predicted a role for Kal-C-helix residue Arg15 in the interaction of cSec14 with phosphoinositides. Consistent with this prediction, mutation of Arg15 to Gln altered the localization of cSec14-EGFP and cKal7-EGFP. These data suggest that phosphoinositide-dependent interactions unique to cKal7 contribute to protein localization and function. Cover Image for this issue: doi. 10.1111/jnc.13791. PMID- 27465686 TI - Experimental bluetongue virus superinfection in calves previously immunized with bluetongue virus serotype 8. AB - The effect of a superinfection with bluetongue virus serotype 1 (BTV1) was evaluated on two groups of four calves. One group received a commercial inactivated BTV serotype 8 (BTV8) vaccine. This group and the non-vaccinated group of calves were challenged twice (4 months apart) with the European BTV8 strain isolated during the 2006-2007 epidemics. Calves were then infected with a BTV1 inoculum which was found to be unexpectedly contaminated by BTV serotype 15 (BTV15). BTV1 and BTV15 single infections were performed on two other groups of three BTV naive calves. A severe clinical picture was obtained after superinfection with BTV1/BTV15 in both vaccinated and non-vaccinated animals and after challenge with BTV8 in non-vaccinated animals. BTV1 and BTV15 single infection caused only very slight clinical signs. After superinfection and at the viraemic peak, there were an average of above 1000 times more BTV15 genomic copies than BTV1 ones. BTV1 RNA could be detected only in the spleen of one calf whereas BTV15 RNA was found in 15 organs of seven different animals. BTV8 immunization whether it was acquired through vaccination and challenges or challenges alone did not change BTV1 or BTV15 RNA detection in superinfected animals. However in these animals a partial cross neutralization between BTV8 and BTV1 might be involved in the lower BTV1 replication versus BTV15. Infection with different serotypes can occur also in the field. Interference between virus strains, genetic reassortment and cross-protection were considered as mechanisms to explain the clinical outcomes and the other virological and immunological findings in the course of BTV1/BTV15 superinfection. PMID- 27465687 TI - Alterations of the gut microbiome of largemouth bronze gudgeon (Coreius guichenoti) suffering from furunculosis. AB - High-throughput sequencing was applied to compare the intestinal microbiota in largemouth bronze gudgeon either healthy or affected by furunculosis. Proteobacteria, Actinobacteria, Tenericutes, Firmicutes and Bacteroidetes were detected as the predominant bacterial phyla in the gut of both diseased and healthy fish. The abundance of Proteobacteria differed significantly between the two groups of fish, mainly due to the overwhelming prevalence of Aeromonas in the diseased fish (81% +/- 17%), while the genus was unevenly spread among the apparently healthy fish (33% +/- 33%). The bacterial diversity in the intestine of diseased fish was markedly lower than in healthy fish. Analysis revealed the significant dissimilarity between the gut microbiota of diseased and healthy fish. The bacterial profiles in the gut were further characterized with the 28 phylotypes that were shared by the two groups. In diseased fish, two shared OTUs (OTU0001 and OTU0013) were closely related to Aeromonas salmonicida, their total proportion exceeding 70% of the sequences in diseased fish, while averaging 5.2% +/- 4.6% in the healthy fish. This result suggested the presence of healthy carriers of pathogenic A. salmonicida among the farmed fish, and the gut appeared as a probable infection source for furunculosis in largemouth bronze gudgeon. PMID- 27465689 TI - High sensitivity of Indian summer monsoon to Middle East dust absorptive properties. AB - The absorptive properties of dust aerosols largely determine the magnitude of their radiative impacts on the climate system. Currently, climate models use globally constant values of dust imaginary refractive index (IRI), a parameter describing the dust absorption efficiency of solar radiation, although it is highly variable. Here we show with model experiments that the dust-induced Indian summer monsoon (ISM) rainfall differences (with dust minus without dust) change from -9% to 23% of long-term climatology as the dust IRI is changed from zero to the highest values used in the current literature. A comparison of the model results with surface observations, satellite retrievals, and reanalysis data sets indicates that the dust IRI values used in most current climate models are too low, tending to significantly underestimate dust radiative impacts on the ISM system. This study highlights the necessity for developing a parameterization of dust IRI for climate studies. PMID- 27465690 TI - Enantioselective analysis of proteinogenic amino acids in cerebrospinal fluid by capillary electrophoresis-mass spectrometry. AB - d-Amino acids (AAs) are increasingly being recognized as essential molecules in biological systems. Enantioselective analysis of proteinogenic AAs in biological samples was accomplished by CE-MS employing beta-CD as chiral selector and ESI via sheath-liquid (SL) interfacing. Prior to analysis, AAs were fully derivatized with FMOC, improving AA-enantiomer separation and ESI efficiency. In order to optimize the separation and MS detection of FMOC-AAs, the effects of type and concentration of CD in the BGE, the composition of the SL, and MS-interfacing parameters were evaluated. Using a BGE of 10 mM beta-CD in 50 mM ammonium bicarbonate (pH 8) containing 15% v/v isopropanol, a SL of isopropanol-water-1 M ammonium bicarbonate (50:50:1, v/v/v) at a flow rate of 3 MUL/min, and a nebulizer gas pressure of 2 psi, 15 proteinogenic AAs could be detected with enantioresolutions up to 3.5 and detection limits down to 0.9 MUM (equivalent to less than 3 pg AA injected). The selectivity of the method was demonstrated by the analysis of spiked cerebrospinal fluid, allowing specific detection of d-AAs. Repeatability and linearity obtained for cerebrospinal fluid were similar to standard solutions, with peak area and migration-time RSDs (n = 5) below 16.2 and 1.6%, respectively, and a linear response (R(2) >= 0.977) in the 3-90 MUM range. PMID- 27465691 TI - A self-healing photoinduced-deformable material fabricated by liquid crystalline elastomers using multivalent hydrogen bonds as cross-linkers. AB - Liquid crystalline elastomers (LCEs) using multivalent hydrogen bonds as cross linkers were successfully fabricated, which showed both self-healing and photoinduced-deformable properties. More interestingly, this LCE could be readily molded into different shapes through a versatile and efficient procedure, and the fibrous and filmy samples showed different photoinduced-deformable behavior originating from the difference in molecular orientations. PMID- 27465688 TI - MK-2206 sensitizes BRCA-deficient epithelial ovarian adenocarcinoma to cisplatin and olaparib. AB - BACKGROUND: Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation of the AKT pathway promotes platinum resistance while inhibition of AKT sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus a defect in the homologous recombination (HR) repair pathway, demonstrate greater clinical response to platinum and olaparib therapy than patients with BRCA wild-type EOC. MK-2206, an allosteric inhibitor of AKT phosphorylation, sensitizes a variety of cell types to various anticancer agents and is currently undergoing phase II trials as monotherapy for platinum-resistant ovarian, fallopian tube, and peritoneal cancer. This study examines the differential effects of AKT inhibition with cisplatin and olaparib therapy in BRCA1/2-deficient versus wild-type EOC. METHODS: PEO1, a chemosensitive BRCA2 mutant serous ovarian adenocarcinoma, and PEO4, a reverted BRCA2-proficient line from the same patient after the development of chemotherapeutic resistance, were primarily used for the study. In PEO1, MK-2206 demonstrated moderate to strong synergism with cisplatin and olaparib at all doses, while demonstrating antagonism at all doses in PEO4. RESULTS: Baseline phospho-AKT activity in untreated cells was upregulated in both BRCA1- and 2-deficient cell lines. MK 2206 prevented cisplatin- and olaparib-induced AKT activation in the BRCA2 deficient PEO1 cells. We propose that BRCA-deficient EOC cells upregulate baseline AKT activity to enhance survival in the absence of HR. Higher AKT activity is also required to withstand cytotoxic agent-induced DNA damage, leading to strong synergism between MK-2206 and cisplatin or olaparib therapy in BRCA-deficient cells. CONCLUSIONS: MK-2206 shows promise as a chemosensitization agent in BRCA-deficient EOC and merits clinical investigation in this patient population. PMID- 27465692 TI - ScBx gene based association analysis of hydroxamate content in rye (Secale cereale L.). AB - Hydroxamates (HX) are major secondary metabolites synthesized by rye and are responsible for some of the unique properties of this cereal, including good tolerance of biotic and abiotic stresses and allelopathy. Recently, five genes encoding enzymes taking part in HX biosynthesis have been sequenced and characterized, which was the starting point to undertake the present study. Association analysis of the content of six HX-HBOA (2-hydroxy-1,4-benzoxazin-3 one), GDIBOA (2,4-dihydroxy-1,4-benzoxazin-3(4H)-one glucoside), DIBOA (2,4 dihydroxy-1,4-benzoxazin-3(4H)-one), GDIMBOA (2,4-dihydroxy-7-methoxy-1,4 benzoxazin-3(4H)-one glucoside), DIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin 3(4H)-one) and MBOA (6-methoxy-benzoxazolin-2(3H)-one) in the above-ground parts of plants and roots was performed on a population consisting of 102 and 121 diverse inbred lines, in 2013 and 2014, respectively. Altogether, 48 single nucleotide polymorphisms (SNPs) were found to be associated with the content of at least one HX: 20 SNPs were associated with HX synthesized in the above-ground parts of rye plants (AG-SNP), and 28 were associated with HX synthesized in the roots (R-SNP). The highest number of SNPs was present in genes ScBx1 (9) and ScBx5 (11). The majority of SNPs were affected by environmental factors, except for two: ScBx4_1702 associated with GDIBOA and MBOA contents, and ScBx5_1105 associated with HBOA content in roots. PMID- 27465693 TI - Costs of accountable care organization participation for primary care providers: early stage results. AB - BACKGROUND: Little is known about the impact of joining an Accountable Care Organization (ACO) on primary care provider organization's costs. The purpose of this study was to determine whether joining an ACO is associated with an increase in a Rural Health Clinic's (RHC's) cost per visit. METHODS: The analyses focused on cost per visit in 2012 and 2013 for RHCs that joined an ACO in 2012 and cost per visit in 2013 for RHCs that joined an ACO in 2013. The RHCs were located in nine states. Data were obtained from Medicare Cost Reports. The analysis was conducted taking a treatment effects approach where the treatment is joining an ACO. Propensity-score matching was employed to provide multiple single and pooled estimates of the average treatment effect on the treated. RESULTS: Four-hundred thirty four to 544 RHCs (depending on the type of analysis and the variables used) were used in the several analyses. Seven of the RHCs joined an ACO in 2012 and 14 joined an ACO in 2013. The mean cost per visit for RHCs that did not join an ACO rose 4.40 % from 2011 to 2012 whereas the mean cost per visit for RHCs that joined an ACO rose by triple: 13.5 %. All of the pooled estimates of the average treatment effect on the treated from the propensity-score matching showed that joining an ACO was associated with higher mean cost per visit. The range of the estimated mean cost per visit differences was $17.19 (p value = 0.00) to $25.19 (p value = 0.00). CONCLUSIONS: This study is one of the first to describe the cost of ACO participation from the perspective of primary care provider organizations. It appears that for at least one type of primary care provider - the RHC - there are substantial costs associated with ACO participation during the first two years. PMID- 27465694 TI - Effect of feeding tannin-degrading bacteria Streptococcus gallolyticus strain TDGB 406 on meat quality of goats fed with Quercus semicarpifolia leaves. AB - The effect of feeding tannin-degrading bacteria (Streptococcus gallolyticus strain TDGB 406) on carcass characteristics of goats fed with oak (Quercus semicarpifolia) leaves was studied on 18 male goats (4 months old, average body weight 9.50 +/- 1.50 kg), distributed into three groups of six animals each. The animals of group 1 served as control, while the animals of groups 2 and 3 were given (at 5 ml/kg live weight) autoclaved and live culture of isolate TDGB 406 (10(6) cells/ml), respectively. The animals were fed with oak leaves as a basal roughage source and maize hay along with fixed quantity of concentrate mixture. After 4 months of feeding, the animals were slaughtered for carcass studies. The feeding of live culture of isolate TDGB 406 did not cause any effect (P > 0.05) on pre-slaughter weight, empty body weight, carcass weight, dressing percent, and yield of wholesale cuts (neck, rack, shoulder, breast, shank, loin, leg, and flank) of the goat meat. The chemical composition of longissimus dorsi muscle was comparable (P > 0.05) among the groups. The organoleptic evaluation of pressure cooked meat in terms of tenderness and overall palatability was increased significantly (P < 0.05) in the meat of group 3 where live culture was supplemented. The other attributes were similar among the groups. It was concluded that supplementation of tannin-degrading bacteria S. gallolyticus strain TDGB 406 to goats fed with oak leaves did not affect the carcass characteristics and meat quality. PMID- 27465695 TI - Genetic differences in the body weight and haematological traits of Nigerian indigenous chickens infected with Eimeria tenella. AB - In an effort to shed more light on the tolerance of indigenous chickens to coccidiosis, we compared the body weight, faecal oocyst load and haematological parameters based on sex and genotypes of Eimeria tenella-infected chickens. Three hundred chicks from three genotypes (normal-feathered, frizzle-feathered and naked-neck) of Nigerian indigenous chickens which comprised 100 birds per genotype were raised for 6 weeks. At 3 weeks old, each chick was weighed and faecal, and blood samples were collected before inoculation. Subsequently, the birds were weighed and faecal samples collected at days 1, 3, 6, 9, 12 and 15 post-inoculation. Blood samples were collected from 50 chicks per genotype at 3 and 5 weeks post-inoculation. Blood parameters were determined and faecal samples subjected to McMaster egg counting technique. Results showed genotype, and sex had significant effects on body weight from day 1 to 15 post-inoculation. Normal feathered chicks had the highest body weight while frizzle-feathered chicks showed lowest body weight at post-inoculation. E. tenella was identified in caecal and lower intestinal mucosa of the genotypes, but genotype had no significant effect (p > 0.05) on the lesion score. There were no significant differences in haematological values among genotypes (p > 0.05) except for lymphocytes where naked-neck chicks had the highest lymphocytes' count (1.83 +/- 0.02 %), followed by normal-feathered (1.79 +/- 0.02 %) and the frizzle-feathered (1.68 +/- 0.02 %). The present values of body weight, faecal oocyst and haematological parameters obtained seemed not to be convincing enough to suggest that the genotypes were different in terms of tolerance to coccidiosis. PMID- 27465697 TI - Myokine: a novel target for exercise to improve cognitive function? PMID- 27465696 TI - Story behind meldonium-from pharmacology to performance enhancement: a narrative review. AB - Recent reports from the World Anti-Doping Agency (WADA) indicate an alarming prevalence in the use of meldonium among elite athletes. Therefore, in January 2016, meldonium was added to WADA's prohibited list after being monitored since 2015. Meldonium has been shown to have beneficial effects in cardiovascular, neurological and metabolic diseases due to its anti-ischaemic and cardioprotective properties, which are ascribed mainly to its inhibition of beta oxidation and its activation of glycolysis. Despite its widespread use, there are only a few clinical studies or clinical trials available. Meldonium is registered in most Baltic countries and is easily accessible through the internet with no serious adverse effects reported by the manufacturer so far. Among athletes, meldonium is used with the purpose of increasing recovery rate or exercise performance. The benefit of taking meldonium in view of performance enhancement in athletes is quite speculative and is discussed without sound scientific evidence. This narrative review provides a detailed overview of the drug meldonium, focusing on the main topics pharmacology and biochemical actions, clinical applications, pharmacokinetics, methods of detection and potential for performance enhancement in athletes. PMID- 27465698 TI - Bringing complexity to sports injury prevention research: from simplification to explanation. PMID- 27465699 TI - Laser irradiation-induced Au-ZnO nanospheres with enhanced sensitivity and stability for ethanol sensing. AB - Incorporating noble metal nanoparticles on the surface or the inner side of semiconductors to form a hybrid nanostructure is an effective route for improving the gas sensing performance of the semiconductors. In this study, we present novel Au-decorated ZnO nanospheres (Au-ZnO NSs) obtained by the laser irradiation of liquids. Structural characterization indicated that the Au-ZnO NSs consisted of single crystalline ZnO NSs with a few Au nanoparticles decorated on their surfaces and abundant encapsulated Au nanoparticles with relatively small sizes. Laser irradiation-induced heating-melting-evaporating processes are responsible for the formation of unique Au-ZnO NSs. The gas sensing properties of the Au-ZnO NSs, as gas sensing materials, were investigated and compared with those of pure ZnO NSs. The former showed a lower working temperature, higher sensitivity, better selectivity, and good reproducibility. The response values of the Au-ZnO NS and pure ZnO NS sensors to ethanol of 100 ppm were 252 and 75 at a working temperature of 320 degrees C and 360 degrees C, respectively. Significant enhancements in gas sensing performance should be attributed to the electronic sensitization induced by the depleted layers between the encapsulated Au nanoparticles and ZnO and chemical sensitization originating from the catalytic effects of Au nanoparticles decorated on the surfaces that dissociated molecular oxygen. PMID- 27465700 TI - A high-performance dual-function material: self-assembled super long alpha-Fe2O3 hollow tubes with multiple heteroatom (C-, N- and S-) doping. AB - Novel heteroatom self-doped super long alpha-Fe2O3 hollow tubes have been synthesized by the combination of hydrothermal and calcination techniques using the chicken eggshell membrane as a template and a dopant. The obtained alpha Fe2O3 super long hollow tubes are composed of closely arranged building blocks (alpha-Fe2O3 nanorods), which are connected to each other and provide a lot of grain boundaries. Scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Raman spectroscopy and nitrogen adsorption-desorption analysis were used to characterize the structure of the synthesized products. To demonstrate their potential applications, the as-synthesized samples were applied to ethanol (C2H5OH) gas sensors and supercapacitors. When applied as a gas sensor, the alpha-Fe2O3 material exhibits a high gas sensitivity, excellent recovery properties (9 s at 100 ppm C2H5OH concentration) and perfect selectivity to ethanol. As an electrode in a supercapacitor, alpha-Fe2O3 shows a high specific capacitance (330 F g(-1) at a current density of 0.5 A g(-1)) with good cycling stability (64% maintained over after 2000 cycles). The excellent sensing and supercapacitor performances could be attributed to the unique super long hollow tubes combined with the abundant pore volume and the small amount of heteroatom doping. PMID- 27465702 TI - Validation of an obstetric fistula screening questionnaire in rural Nepal: a community-based cross-sectional and nested case-control study with clinical examination. AB - OBJECTIVE: To validate a symptom-based fistula screening questionnaire and estimate obstetric fistula (OF) prevalence in rural Nepal. DESIGN: Cross sectional and nested case-control study. SETTING: Sarlahi District, Nepal. POPULATION: Parous, reproductive age women. METHODS: The questionnaire assessed symptoms of vesicovaginal and rectovaginal fistula (VVF and RVF, respectively), stress and urge urinary incontinence (SUI and UUI, respectively), fecal incontinence (FI), and included interviewer observations on the smell and presence of urine and/or stool. All women who screened positive for OF and a randomly selected group of women who screened negative for OF were included in a nested case-control study (one case, four normal controls, and four incontinent controls) and underwent confirmatory clinical examinations. MAIN OUTCOME MEASURES: Clinically confirmed OF, and questionnaire sensitivity (Se) and specificity (Sp). RESULTS: Of the 16 893 women who completed cross-sectional screening, 68 were screened-positive cases. Fifty-five (82%) screened-positive cases, 203 screened-negative normal controls, and 203 screened-incontinent controls participated in the case-control study, which confirmed one case of VVF and one case of both VVF and RVF without any false-negative cases. For VVF, the screening tool demonstrated Se 100% (95% CI 34.2-100.0%), Sp 86.9% (95% CI 83.3 89.9%), and estimated VVF prevalence as 12 per 100 000 (95% CI 3-43); for RVF, it demonstrated Se 100% (95% CI 20.7-100.0), Sp 99.8% (95% CI 98.6-100.0), and estimated RVF prevalence as 6 per 100 000 (95% CI 1-34). CONCLUSIONS: The OF screening questionnaire demonstrated high sensitivity and specificity in this low prevalence setting. TWEETABLE ABSTRACT: Community-based obstetric fistula screening tool validation study, Nepal, n = 16 893: High Se, Sp & feasibility. PMID- 27465703 TI - Generation of Silicone Poly-HIPEs with Controlled Pore Sizes via Reactive Emulsion Stabilization. AB - Macrocellular silicone polymers are obtained after solidification of the continuous phase of a poly(dimethylsiloxane) emulsion, which contains poly(ethylene glycol) drops of sub-millimetric dimensions. Coalescence of the liquid template emulsion is prohibited by a reactive blending approach. The relationship is investigated in detail between the interfacial properties and the emulsion stability, and micro- and millifluidic techniques are used to generate macrocellular polymers with controlled structural properties over a wider range of cell sizes (0.2-2 mm) and volume fractions of the continuous phase (0.1%-40%). This approach could easily be transferred to a wide range of polymeric systems. PMID- 27465701 TI - A Mobile Ecological Momentary Assessment Tool (devilSPARC) for Nutrition and Physical Activity Behaviors in College Students: A Validation Study. AB - BACKGROUND: The majority of nutrition and physical activity assessments methods commonly used in scientific research are subject to recall and social desirability biases, which result in over- or under-reporting of behaviors. Real time mobile-based ecological momentary assessments (mEMAs) may result in decreased measurement biases and minimize participant burden. OBJECTIVE: The aim was to examine the validity of a mEMA methodology to assess dietary and physical activity levels compared to 24-hour dietary recalls and accelerometers. METHODS: This study was a pilot test of the SPARC (Social impact of Physical Activity and nutRition in College) study, which aimed to determine the mechanism by which friendship networks impact weight-related behaviors among young people. An mEMA app, devilSPARC, was developed to assess weight-related behaviors in real time. A diverse sample of 109 freshmen and community mentors attending a large southwestern university downloaded the devilSPARC mEMA app onto their personal mobile phones. Participants were prompted randomly eight times per day over the course of 4 days to complete mEMAs. During the same 4-day period, participants completed up to three 24-hour dietary recalls and/or 4 days of accelerometry. Self-reported mEMA responses were compared to 24-hour dietary recalls and accelerometry measures using comparison statistics, such as match rate, sensitivity and specificity, and mixed model odds ratios, adjusted for within person correlation among repeated measurements. RESULTS: At the day level, total dietary intake data reported through the mEMA app reflected eating choices also captured by the 24-hour recall. Entrees had the lowest match rate, and fruits and vegetables had the highest match rate. Widening the window of aggregation of 24 hour dietary recall data on either side of the mEMA response resulted in increased specificity and decreased sensitivity. For physical activity behaviors, levels of activity reported through mEMA differed for sedentary versus non sedentary activity at the day level as measured by accelerometers. CONCLUSIONS: The devilSPARC mEMA app is valid for assessing eating behaviors and the presence of sedentary activity at the day level. This mEMA may be useful in studies examining real-time weight-related behaviors. PMID- 27465704 TI - Surface ultrastructure of gills in relation to the feeding ecology of an angler catfish Chaca chaca (Siluriformes, Chacidae). AB - Surface ultrastructure of the gills of the angler catfish Chaca chaca was investigated to unravel the adaptive modifications associated with the feeding ecology of the fish. The fish is often found in mud or in soft substrates where they remain buried both for protection and to feed. Gill rakers present on the gill arch in most fish species are absent in this fish. The absence of gill rakers are associated with the feeding habit of the fish and is considered to facilitate the swallowing of captured prey smoothly without any hindrance. Highly corrugated surface of the gill arch and gill filaments could be associated to retain water/mucus to prevent dessicassion of the fish. Papillae like epithelial protuberances each bearing a taste bud at its summit toward the pharyngeal side of the gill arch is associated with the sorting of the food. Large number of mucous goblet cells on the gill arch epithelium are considered to secret copious mucus to lubricate the prey for easy swallowing. In C. chaca the gill septa between gill filaments are reduced. This could enhance the flexibility and permit the free movement of the gill filaments. Extensive secondary lamellae and infrequent mucous goblet cells on secondary lamellae are associated to increase the surface area to enhance efficiency of gaseous exchange. PMID- 27465705 TI - Scalable metagenomics alignment research tool (SMART): a scalable, rapid, and complete search heuristic for the classification of metagenomic sequences from complex sequence populations. AB - BACKGROUND: Next generation sequencing technology has enabled characterization of metagenomics through massively parallel genomic DNA sequencing. The complexity and diversity of environmental samples such as the human gut microflora, combined with the sustained exponential growth in sequencing capacity, has led to the challenge of identifying microbial organisms by DNA sequence. We sought to validate a Scalable Metagenomics Alignment Research Tool (SMART), a novel searching heuristic for shotgun metagenomics sequencing results. RESULTS: After retrieving all genomic DNA sequences from the NCBI GenBank, over 1 * 10(11) base pairs of 3.3 * 10(6) sequences from 9.25 * 10(5) species were indexed using 4 base pair hashtable shards. A MapReduce searching strategy was used to distribute the search workload in a computing cluster environment. In addition, a one base pair permutation algorithm was used to account for single nucleotide polymorphisms and sequencing errors. Simulated datasets used to evaluate Kraken, a similar metagenomics classification tool, were used to measure and compare precision and accuracy. Finally using a same set of training sequences we compared Kraken, CLARK, and SMART within the same computing environment. Utilizing 12 computational nodes, we completed the classification of all datasets in under 10 min each using exact matching with an average throughput of over 1.95 * 10(6) reads classified per minute. With permutation matching, we achieved sensitivity greater than 83 % and precision greater than 94 % with simulated datasets at the species classification level. We demonstrated the application of this technique applied to conjunctival and gut microbiome metagenomics sequencing results. In our head to head comparison, SMART and CLARK had similar accuracy gains over Kraken at the species classification level, but SMART required approximately half the amount of RAM of CLARK. CONCLUSIONS: SMART is the first scalable, efficient, and rapid metagenomics classification algorithm capable of matching against all the species and sequences present in the NCBI GenBank and allows for a single step classification of microorganisms as well as large plant, mammalian, or invertebrate genomes from which the metagenomic sample may have been derived. PMID- 27465706 TI - Spectral and Lensing Characteristics of Gel-Derived Strontium Tartrate Single Crystals Using Dual-Beam Thermal Lens Technique. AB - The Dual Beam mode-matched thermal lens spectrometry is a sensible technique for direct measurements of the thermal properties of tartrate crystalline materials. Here we report the measurement of thermal diffusivity of Strontium Tartrate single crystals incorporated with Rhodamine 6G using the thermal lens experiment. The respective crystals were prepared by solution-gel method at room temperature. The absorption characteristics of three different Strontium Tartrate crystals viz. pure, electric field applied and magnetic field applied were also carried out. PMID- 27465707 TI - Fluorescent Sensing of both Fe(III) and pH Based on 4-Phenyl-2-(2 Pyridyl)Thiazole and Construction of OR Logic Function. AB - In the presented paper we investigated a 2-pyridylthiazole derivative, 4-phenyl-2 (2-pyridyl)thiazole (2-PTP), as the molecular fluorescent switches. It was firstly found that 2-PTP could perform a "turn-on" fluorescent sensing for Fe(III) with selectivity and reversibility. A 2:1 stoichiometry between 2-PTP and Fe(III) was determined according to the molar ratio method. The binding constant was evaluated as (1.90 +/- 0.05) * 10(5) (L/mol)(2). The detection limit was found as 2.2 * 10(-7) M (S/N = 3). Secondly, 2-PTP also exhibited a pH-dependent dual-emission. The pK a(2-PTP-H(+)/2-PTP) value was then estimated as 2.0. To explain the identical emission at 479 nm of both the Fe(III) coordinated form and the protonated form of the ligand, we proposed a "locked" conformation. Finally, combining the two external stimuli as inputs, an OR logic gate was constructed using the fluorescent emission at 479 nm as the output channel. PMID- 27465708 TI - Observation of compositional domains within individual copper indium sulfide quantum dots. AB - The origin of photoluminescence in copper indium sulfide (CIS) quantum dots (Qdots) has previously been ascribed to a donor-acceptor pair (DAP) recombination, with a crystal lattice defect implicated as the origin of the donor state. In this study, electron energy-loss spectroscopy (EELS) was used to observe defect-rich compositional domains within individual CIS Qdots, supporting a model of defect-state-mediated photoluminescence for these particles, and identifying them as an ideal model system for future study of lattice defects on Qdot properties. PMID- 27465709 TI - From Treatment to Empowerment: New Approaches to Youth Mentoring. AB - Traditional approaches to formal youth mentoring have focused primarily on improving the lives of "at-risk" youth through the assignment of individual mentors who are typically disconnected from youth's communities. Similarly, research in the field of formal mentoring has emphasized the dyadic relationship between the mentor and the mentee, with less attention paid to the broader relational contexts in which such relationships unfold. The current paper proposes a new framework that expands the scope of mentoring interventions to include approaches that build on and cultivate informal supports and empower youth to identify and reach out to networks of potential supportive adults, thus increasing the reach of youth mentoring. PMID- 27465710 TI - Are nappers unhealthy? PMID- 27465711 TI - In-hospital complications of vaginal versus laparoscopic-assisted benign hysterectomy among older women: a propensity score-matched cohort study. AB - OBJECTIVE: This investigation compared the outcomes of vaginal and laparoscopic hysterectomies for nonprolapsed benign indications in older women. METHODS: We conducted a population-based, retrospective propensity score-matched cohort study using data from the Taiwan's National Health Insurance program. Women who were aged 65 years or older with vaginal hysterectomy (n = 290) were compared with women who had laparoscopic hysterectomy for nonprolapsed benign indications (n = 290). Propensity score was calculated based on both patient- (age, socioeconomic status, residential urbanicity, comorbidity, status of any prior catastrophic illness, surgical diagnosis, and year of hysterectomy) and provider-related characteristics (physician's age and sex, hospital accreditation level, and ownership type). RESULTS: Women undergoing laparoscopic hysterectomy were not associated with increased risk of inpatient readmission within 30 days, in hospital mortality, and in-hospital (including intraoperative) complications when compared with those who had vaginal hysterectomy. Women in the laparoscopic group had significantly shorter hospital stays than those in the vaginal group. The bleeding complications were mostly due to blood transfusion (2.1% in vaginal and 0.7% in laparoscopic hysterectomy groups) and urinary tract infection (1.0% in vaginal and 1.7% in laparoscopic hysterectomy groups). The surgical injury (intraoperative) complications included mostly surgical laceration of the urinary tract (0.7% in vaginal and 0.3% in laparoscopic hysterectomy groups). CONCLUSIONS: Advanced age alone should not be the limiting factor for surgical referral of laparoscopic hysterectomy. The shorter hospital stay and low in hospital complications associated with laparoscopic, as opposed to vaginal hysterectomies, are important attributes of a surgical procedure essential to the postoperative care in older women aged 65 years or more. PMID- 27465712 TI - Somatic, more than affective, anxiety increases the risk for menopausal hot flashes. PMID- 27465713 TI - Ages at menarche and menopause and reproductive lifespan as predictors of exceptional longevity in women: the Women's Health Initiative. AB - OBJECTIVE: The aim of the present study was to investigate associations between reproductive factors and survival to age 90 years. METHODS: This was a prospective study of postmenopausal women from the Women's Health Initiative recruited from 1993 to 1998 and followed until the last outcomes evaluation on August 29, 2014. Participants included 16,251 women born on or before August 29, 1924 for whom survival to age 90 during follow-up was ascertained. Women were classified as having survived to age 90 (exceptional longevity) or died before age 90. Multivariable logistic regression models were used to evaluate associations of ages at menarche and menopause (natural or surgical) and reproductive lifespan with longevity, adjusting for demographic, lifestyle, and reproductive characteristics. RESULTS: Participants were on average aged 74.7 years (range, 69-81 y) at baseline. Of 16,251 women, 8,892 (55%) survived to age 90. Women aged at least 12 years at menarche had modestly increased odds of longevity (odds ratio [OR], 1.09; 95% CI, 1.00-1.19). There was a significant trend toward increased longevity for later age at menopause (natural or surgical; Ptrend = 0.01), with ORs (95% CIs) of 1.19 (1.04-1.36) and 1.18 (1.02-1.36) for 50 to 54 and at least 55 compared with less than 40 years, respectively. Later age at natural menopause as a separate exposure was also significantly associated with increased longevity (Ptrend = 0.02). Longer reproductive lifespan was significantly associated with increased longevity (Ptrend = 0.008). The odds of longevity were 13% (OR 1.13; 95% CI, 1.03-1.25) higher in women with more than 40 compared with less than 33 reproductive years. CONCLUSIONS: Reproductive characteristics were associated with late-age survival in older women. PMID- 27465714 TI - Reproductive history and risk of type 2 diabetes mellitus in postmenopausal women: findings from the Women's Health Initiative. AB - OBJECTIVE: The aim of the study was to understand the association between women's reproductive history and their risk of developing type 2 diabetes. We hypothesized that characteristics signifying lower cumulative endogenous estrogen exposure would be associated with increased risk. METHODS: Prospective cohort analysis of 124,379 postmenopausal women aged 50 to 79 years from the Women's Health Initiative (WHI). We determined age of menarche and final menstrual period, and history of irregular menses from questionnaires at baseline, and calculated reproductive length from age of menarche and final menstrual period. Presence of new onset type 2 diabetes was from self-report. Using multivariable Cox proportional hazards models, we assessed associations between reproductive variables and incidence of type 2 diabetes. RESULTS: In age-adjusted models, women with the shortest (<30 y) reproductive periods had a 37% (95% CI, 30-45) greater risk of developing type 2 diabetes than women with medium-length reproductive periods (36-40 y). Women with the longest (45+ y) reproductive periods had a 23% (95% CI, 12-37) higher risk than women with medium-length periods. These associations were attenuated after full adjustment (HR 1.07 [1.01, 1.14] for shortest and HR 1.09 [0.99, 1.22] for longest, compared with medium duration). Those with a final menstrual period before age 45 and after age 55 had an increased risk of diabetes (HR 1.04; 95% CI, 0.99-1.09 and HR 1.08; 95% CI, 1.01-1.14, respectively) compared to those with age of final menstrual period between 46 and 55 years. Timing of menarche and cycle regularity was not associated with risk after full adjustment. CONCLUSIONS: Reproductive history may be associated with type 2 diabetes risk. Women with shorter and longer reproductive periods may benefit from lifestyle counseling to prevent type 2 diabetes. PMID- 27465715 TI - Cardiovascular, hemodynamic, neuroendocrine, and inflammatory markers in women with and without vasomotor symptoms. AB - OBJECTIVE: Vasomotor symptoms (VMS) may be associated with an increased risk of cardiovascular disease. One candidate mechanism may involve alterations in physiological responses to stress. The current study therefore examined the relationship between self-reported VMS bother and cardiovascular, hemodynamic, neuroendocrine, and inflammatory responses to an acute psychosocial stress protocol. METHODS: One hundred eighty-six women in the menopausal transition or early postmenopausal stage (age 45-60 y) provided the data for this article. Subjective hot flash and night sweat bother were assessed using the Greene Climacteric Scale. Women also underwent a stressor battery involving a speech and a mental arithmetic task while cardiovascular, hemodynamic, neuroendocrine, and inflammatory responses were assessed. Repeated measures regression analyses were used to examine the relationship between self-reported VMS and physiologic responses to the stressor. RESULTS: In multivariate analyses adjusting for potential confounders, self-reported hot flash bother was associated with lower overall cardiac index and stroke volume index and higher overall vascular resistance index and levels of the inflammatory cytokine interleukin-6. Hot flash bother also tended to be associated with higher overall cortisol levels and higher baseline levels of plasma norepinephrine. Night sweat bother, on the other hand, was associated with higher overall cortisol levels and tended to be associated with higher interleukin-6. CONCLUSIONS: Self-reported VMS bother is associated with an unfavorable hemodynamic and neuroendocrine profile characterized by increased hypothalamic-pituitary-adrenal axis and central sympathetic activation, inflammation, and vasoconstriction. Further research investigating this profile in relation to VMS, and the potential health implications of this association, is warranted. PMID- 27465716 TI - Low AMH levels as a marker of reduced ovarian reserve in young women affected by Down's syndrome. AB - OBJECTIVE: Women with Down's syndrome (DS) experience menopause earlier than healthy women and are twice as likely to undergo premature ovarian insufficiency. Menopause accelerates cognitive decline and is associated with a twofold increased mortality risk in DS women. Nonetheless, no previous studies investigated the ovarian reserve in this population. The aim of the present study was to evaluate the circulating antimullerian hormone (AMH) levels in DS women with regular menstrual cycles, in comparison with those observed in an age matched group of healthy women. METHODS: Fourteen women with DS and 20 normo ovulatory volunteers were enrolled in this study. A general physical examination was performed. Hormonal assays, including AMH, fasting insulin levels, and homeostatic model assessment-insulin resistance, were investigated in all participants. RESULTS: AMH levels were significantly lower in DS women compared with controls (1.34 +/- 1.11 vs 3.01 +/- 1.65 ng/mL, P < 0.01). Prolactin concentrations were in the normal range, although higher in DS women compared with controls (P < 0.01). After dividing the participants according to age, AMH was significantly lower in the DS group compared with controls, both below and above 30 years of age (1.77 vs 3.73 ng/mL, P < 0.01; 0.28 vs 2.20 ng/mL, P < 0.01, respectively). AMH was inversely correlated with age in both groups, and directly correlated with testosterone and dehydroepiandrosterone sulfate only in DS women. In the same participants, AMH showed a tendency toward a direct correlation with insulin levels (P = 0.055). CONCLUSIONS: AMH levels were significantly lower in DS women compared with age-matched controls. A subanalysis of data in DS participants under 30 years of age suggested an early follicular depletion related to trisomy 21. PMID- 27465718 TI - Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study. AB - OBJECTIVE: Data are controversial on the impact of postmenopausal hormone therapy (HT) on breast cancer mortality. We analyzed nationwide Finnish data on breast cancer mortality risk in women using HT consisting of estradiol-only therapy (ET) or estrogen-progestogen therapy (EPT). METHODS: In total, 489,105 women using HT in 1994 to 2009, traced from the nationwide reimbursement register, were followed from the HT initiation (3.3 million cumulative exposure years) to breast cancer death (n = 1,578 women). The observed deaths were compared with those in the age standardized background population. RESULTS: The breast cancer mortality risk was reduced in all HT users with exposure for at most 5 years (standardized mortality ratio 0.56; CI 0.52-0.60), more than 5 to 10 years (0.46; 0.41-0.51), or more than 10 years (0.62; 0.56-0.68). A significantly larger risk reduction was detected in the 50 to 59 years age group (0.33; 0.29-0.37) compared with 60 to 69 (0.64; 0.59-0.70) or 70 to 79 (0.78; 0.69-0.87) years age groups. The death risk reductions in ET users tended to be larger in all age groups compared with EPT users, with a significant difference only in the 70 to 79 years age group (0.66; 0.57-0.76 vs 0.88; 0.77-1.00). The age at HT initiation, regardless whether ET or EPT, showed no association with breast cancer mortality. CONCLUSIONS: In the Finnish unselected population, breast cancer is fatal in 1 of 10 patients. Our data imply that this risk is prevalent in 1 of 20 patients with history of HT use. This is an important message for women considering or already using HT. PMID- 27465717 TI - Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women. AB - OBJECTIVE: As longitudinal studies determined that anxiety is a strong risk factor for hot flashes, we hypothesized that an anxiogenic stimulus that signals air hunger (hypercapnic, normoxic gas) would trigger an exacerbated hot flash associated increase in tail skin temperature (TST) in a rat ovariectomy (OVEX) model of surgical menopause and hot flashes in symptomatic postmenopausal women. We also assessed TST responses in OVEX serotonin transporter (SERT) rats that models a common polymorphism that is associated with increased climacteric symptoms in postmenopausal women and increases in anxiety traits. METHODS: OVEX and sham-OVEX rats (initial experiment) and wildtype and SERT OVEX rats (subsequent experiment) were exposed to a 5-minute infusion of 20% carbon dioxide (CO2) normoxic gas while measuring TST. Postmenopausal women were given brief 20% and 35% CO2 challenges, and hot flashes were self-reported and objectively verified. RESULTS: Compared to controls, OVEX rats had exacerbated increases in TST, and SERT OVEX rats had prolonged TST increases following CO2. Most women reported mild/moderate hot flashes after CO2 challenges, and the hot flash severity to CO2 was positively correlated with daily hot flash frequency. CONCLUSIONS: The studies demonstrate that this anxiogenic stimulus is capable of inducing cutaneous vasomotor responses in OVEX rats, and eliciting hot flashes in postmenopausal women. In rats, the severity of the response was mediated by loss of ovarian function and increased anxiety traits (SERT), and, in women, by daily hot flash frequency. These findings may provide insights into anxiety-related triggers and genetic risk factors for hot flashes in thermoneutral environments. PMID- 27465720 TI - Dynamic Measures to Determine Volume Responsiveness: Logical, Biologically Plausible, and Unproven. PMID- 27465719 TI - Cell-free methods to produce structurally intact mammalian membrane proteins. AB - The crystal structures of four membrane proteins, from bacteria or a unicellular alga, have been solved with samples produced by cell-free protein synthesis. In this study, for mammalian membrane protein production, we established the precipitating and soluble membrane fragment methods: membrane proteins are synthesized with the Escherichia coli cell-free system in the presence of large and small membrane fragments, respectively, and are simultaneously integrated into the lipid environments. We applied the precipitating membrane fragment method to produce various mammalian membrane proteins, including human claudins, glucosylceramide synthase, and the gamma-secretase subunits. These proteins were produced at levels of about 0.1-1.0 mg per ml cell-free reaction under the initial conditions, and were obtained as precipitates by ultracentrifugation. Larger amounts of membrane proteins were produced by the soluble membrane fragment method, collected in the ultracentrifugation supernatants, and purified directly by column chromatography. For several proteins, the conditions of the membrane fragment methods were further optimized, such as by the addition of specific lipids/detergents. The functional and structural integrities of the purified proteins were confirmed by analyses of their ligand binding activities, size-exclusion chromatography profiles, and/or thermal stabilities. We successfully obtained high-quality crystals of the complex of human claudin-4 with an enterotoxin. PMID- 27465721 TI - Nutrition Supplements to Stimulate Lipolysis: A Review in Relation to Endurance Exercise Capacity. AB - Athletes make great efforts to increase their endurance capacity in many ways. Using nutrition supplements for stimulating lipolysis is one such strategy to improve endurance performance. These supplements contain certain ingredients that affect fat metabolism; furthermore, in combination with endurance training, they tend to have additive effects. A large body of scientific evidence shows that nutrition supplements increase fat metabolism; however, the usefulness of lipolytic supplements as ergogenic functional foods remains controversial. The present review will describe the effectiveness of lipolytic supplements in fat metabolism and as an ergogenic aid for increasing endurance exercise capacity. There are a number of lipolytic supplements available on the market, but this review focuses on natural ingredients such as caffeine, green tea extract, L carnitine, Garcinia cambogia (hydroxycitric acid), capsaicin, ginseng, taurine, silk peptides and octacosanol, all of which have shown scientific evidence of enhancing fat metabolism associated with improving endurance performance. We excluded some other supplements owing to lack of data on fat metabolism or endurance capacity. Based on the data in this review, we suggest that a caffeine and green tea extract improves endurance performance and enhances fat oxidation. Regarding other supplements, the data on their practical implications needs to be gathered, especially for athletes. PMID- 27465722 TI - Okara, a By-Product of Tofu Manufacturing, Modifies Triglyceride Metabolism at the Intestinal and Hepatic Levels. AB - Irrespective of a well-known hypocholesterolemic action, a few studies have shown a hypotriglyceridemic potential of okara, a by-product of tofu manufacturing. Okara was fed to rats at the level of 2.5 and 5.0% as dietary protein for 4 wk, and serum and hepatic lipid levels were determined. In addition, soy flour, which has a well-known hypolipidemic action, was used to compare effects on lipid metabolism. Mechanisms of action were further evaluated by measuring hepatic enzyme activity, gene expression of lipid metabolism-related proteins and fecal excretion of lipids. Feeding the okara diets resulted in a significantly lower weight of the liver and adipose tissue in a dose-dependent manner. Serum triglyceride levels were more than 50% lower in rats fed the okara diets compared to those fed the control diet. Enzyme activities of fatty acid synthesis were significantly lowered by the okara diet. Fecal weight was significantly higher in the okara group than in the control group, and fecal excretion of steroids tended to be higher. Therefore, a relatively low amount of okara may exert hypotriglyceridemic action in rats in part through decreased hepatic triglyceride synthesis. The present study also suggests an involvement of intestinal events in altered lipid metabolism in rats fed the okara diets. PMID- 27465723 TI - Sea Cucumber Saponin Echinoside A (EA) Stimulates Hepatic Fatty Acid beta Oxidation and Suppresses Fatty Acid Biosynthesis Coupling in a Diurnal Pattern. AB - Circadian rhythms control aspects of physiological events, including lipid metabolism, showing rhythmic fluctuation over 24 h. Therefore, it is not sufficient to evaluate thoroughly how dietary components regulate lipid metabolism with a single time-point assay. In the present study, a time-course study was performed to analyze the effect of sea cucumber saponin echinoside A (EA) on lipid metabolism over 24 h. Results showed that EA lowered the levels of TC and TG in both serum and liver at most time-points during the 24 h. Activities of hepatic lipogenic enzymes and lipolytic enzymes were inhibited and elevated respectively by EA to varied degrees at different time-points. Meanwhile, parallel variation trends of gene expression involved in fatty acid synthesis and beta-oxidation were observed accordingly. The interaction between EA and lipid metabolism showed a time-dependent effect. Overall, EA impaired fatty acid synthesis and enhanced mitochondrial fatty acid beta-oxidation in ad libitum feeding over 24 h. PMID- 27465725 TI - High Vitamin C Intake with High Serum beta-Cryptoxanthin Associated with Lower Risk for Osteoporosis in Post-Menopausal Japanese Female Subjects: Mikkabi Cohort Study. AB - Recent epidemiological studies show that antioxidant vitamins and carotenoids might be beneficial to the maintenance of bone health. Recently, we found that serum carotenoids were inversely associated with the risk of developing osteoporosis in post-menopausal Japanese female subjects. However, little is known about the vitamin alone and/or the combination of the vitamin and carotenoid with the risk of osteoporosis. The objective of this study was to investigate longitudinally whether antioxidant vitamins and their combination with carotenoids are associated with the risk of developing of osteoporosis. We conducted a follow-up study on 187 post-menopausal female subjects from the Mikkabi prospective cohort study. Those who participated in previous bone mineral density (BMD) surveys and completed four years of follow-up were examined longitudinally. During a four-year follow-up, fifteen of the post-menopausal female subjects developed new-onset osteoporosis. After adjustment for confounders, the odds ratios (OR) for osteoporosis in the highest tertiles of vitamins C and E and retinol intakes against the lowest tertiles were 0.15 (95% confidence interval (CI): 0.02-0.99), 0.50 (CI: 0.08-3.23), and 1.49 (CI: 0.36 6.22), respectively. Furthermore, a significantly lower odds ratio was observed in the higher vitamin C intake group (169-625 mg/d) with higher serum beta cryptoxanthin (1.88-10.53 MUM) against the lower vitamin C intake group (47-168 mg/d) with lower serum beta-cryptoxanthin (0.24-1.84 MUM) used for the reference group (p<0.05). The combination of beta-cryptoxanthin and vitamin C is inversely associated with the risk of developing osteoporosis in post-menopausal Japanese female subjects. PMID- 27465724 TI - Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice. AB - Proinflammatory cytokines contribute to the progression of muscle wasting caused by ubiquitin-proteasome-dependent proteolysis. We have previously demonstrated that isoflavones, such as genistein and daidzein, prevent TNF-alpha-induced muscle atrophy in C2C12 myotubes. In this study, we examined the effect of dietary flavonoids on the wasting of muscle. Mice were divided into the following four groups: vehicle-injected (control) mice fed the normal diet (CN); tumor bearing mice fed the normal diet (TN); control mice fed the isoflavone diet (CI); and tumor-bearing mice fed the isoflavone diet (TI). There were no significant differences in the intake of food or body weight gain among these four groups. The wet weight and myofiber size of gastrocnemius muscle in TN significantly decreased, compared with those in CN. Interestingly, the wet weight and myofiber size of gastrocnemius muscle in TI were nearly the same as those in CN and CI, although isoflavone supplementation did not affect the increased tumor mass or concentrations of proinflammatory cytokines, such as TNF-alpha and IL-6, in the blood. Moreover, increased expression of muscle-specific ubiquitin ligase genes encoding MAFbx/Atrogin-1 and MuRF1 in the skeletal muscle of TN was significantly inhibited by the supplementation of isoflavones. In parallel with the expression of muscle-specific ubiquitin ligases, dietary isoflavones significantly suppressed phosphorylation of ERK in tumor-bearing mice. These results suggest that dietary isoflavones improve muscle wasting in tumor-bearing mice via the ERK signaling pathway mediated-suppression of ubiquitin ligases in muscle cells. PMID- 27465726 TI - Persimmon-Tannin, an alpha-Amylase Inhibitor, Retards Carbohydrate Absorption in Rats. AB - Inhibitors of carbohydrate-hydrolyzing enzymes play an important role in controlling postprandial blood glucose levels. Thus the effect of persimmon tannin on pancreatic alpha-amylase and intestinal alpha-glucosidase has been investigated. Persimmon tannin inhibits pancreatic alpha-amylase and intestinal alpha-glucosidase in a concentration-dependent manner with the 50% inhibition concentration (IC50) for amylase, maltase and sucrase being 1.7 MUg/mL, 632 MUg/mL and 308 MUg/mL, respectively. The effect of persimmon-tannin extract on carbohydrate absorption in rats has also been investigated. Oral administration of persimmon tannin to normal rats fed cornstarch (2 g/kg body weight) significantly suppressed the increase in blood glucose levels and the area under the curve (AUC) after starch loading in a dose-dependent manner. The effective dose of persimmon tannin required to achieve 50% suppression of the rise in blood glucose level was estimated to be 300 mg/kg body weight. Administration of persimmon tannin to rats fed maltose or sucrose delayed the increase of blood glucose level and slightly suppressed AUC, but not significantly. These results suggest that persimmon tannin retards absorption of carbohydrate and reduces post prandial hyperglycemia mainly through inhibition of alpha-amylase. PMID- 27465727 TI - Effect of Enzyme-Treated Asparagus Extract (ETAS) on Psychological Stress in Healthy Individuals. AB - The aim of this study was to examine the effectiveness of Enzyme-Treated Asparagus Extract (ETAS) on improving stress response. A randomized, double blind, placebo-controlled cross-over trial was undertaken in healthy volunteers. ETAS (150 mg/d) or a placebo was consumed for 28 d, with a washout period. Psychological parameters were examined using a self-report scale questionnaire and psychological stress was applied using the Uchida-Kraepelin (U-K) test. During the stress load, autonomic nervous function was analyzed. After the stress load, a profile of mood states (POMS) psychological rating was performed, and serum cortisol, plasma catecholamine, salivary secretory immunoglobulin A (sIgA), and salivary cortisol were analyzed. ETAS intake improved the self-reported rating for the items "Feel tired," "Hard to get up," and "Feel heavy" in the psychological questionnaire; ameliorated the self-reported rating for the items "Depression-Dejection" and "Fatigue" in the POMS questionnaire; and increased salivary sIgA levels after the U-K test. In contrast, serum and salivary cortisol levels, and plasma catecholamine did not change. During the U-K test, ETAS significantly upregulated the sympathetic nerve activity. Furthermore, ETAS intake significantly increased the number of answers and the number of correct answers in the U-K test, suggesting that it might improve office work performance with swiftness and accuracy under stressful conditions. In conclusion, ETAS supplementation reduced feelings of dysphoria and fatigue, ameliorated quality of sleep, and enhanced stress-load performance as well as promoted stress response by increasing salivary sIgA levels. These data suggest ETAS intake may exert beneficial effects, resulting from well-controlled stress management, in healthy individuals. PMID- 27465728 TI - Protective Effect of Dietary Lily Bulb on Dextran Sulfate Sodium-Induced Colitis in Rats Fed a High-Fat Diet. AB - Lily bulb is traditionally consumed in East Asia and contains high amounts of glucomannan. This study investigated the effect of dietary lily bulb on dextran sulfate sodium (DSS)-induced colitis in rats fed a high-fat (HF) diet. Male Sprague-Dawley rats were fed a diet containing 30% beef tallow with or without 7% steamed lily bulb powder for 17 d. Experimental colitis was induced by replacing drinking water with DSS during the last 7 d. The disease activity index (DAI) was significantly lower in the lily bulb+DSS group than in the DSS group on day 17. The fecal abundance of Bifidobacterium was significantly reduced in the DSS group compared with that in the control group, but it was recovered by lily bulb intake. Cecal butyrate, fecal mucins, and alkaline phosphatase (ALP) activity were significantly higher in the DSS group than in the control group. Dietary lily bulb potentiated the increase in cecal butyrate, fecal mucins, and the ALP activity caused by DSS treatment. These results indicate that lily bulb attenuates DSS-induced colitis by modulating colonic microflora, organic acids, mucins, and ALP activity in HF diet-fed rats. PMID- 27465730 TI - Size and dose dependent effects of silver nanoparticle exposure on intestinal permeability in an in vitro model of the human gut epithelium. AB - BACKGROUND: The antimicrobial activity of silver nanoparticles (AgNP) has led to interest in their use in consumer products such as food contact materials, utensils, and storage containers. Incorporation of these materials into items intended for food processing and storage suggests that consumer use of these products could result in gastrointestinal exposure to AgNP, should the nanoparticles migrate from the product. The health impact of AgNP exposure is unknown, especially effects related to intestinal epithelial permeability and barrier function. This study examined the effects of AgNP exposure of different sizes (10, 20, 75 and 110 nm) and doses (20 and 100 ug/mL) on the permeability of T84 human colonic epithelial cells, which serve as an in vitro model of the human gut epithelium. RESULTS: Results showed that effects of AgNP on the T84 epithelial cells were size- and dose-dependent, with the 10 nm AgNP causing the most significant changes. Changes in permeability of the epithelial cell monolayer, as measured by transepithelial electrical resistance, after exposure to 10 nm AgNP were most dramatic at the highest dose (100 ug/mL), but also observed at the lower dose (20 ug/mL). AgNP could be visualized inside cells using transmission electron microscopy and silver was detected in basal wells using inductively coupled plasma-mass spectrometry. Exposure to AgNP significantly affected the expression of genes involved in anchoring tight junctions, cellular proliferation and signaling, endocytosis, and cell-cell adhesion, with the 10 nm AgNP having the greatest effect. CONCLUSIONS: The results of this study show that small-size AgNP have significant effects on intestinal permeability in an in vitro model of the human gastrointestinal epithelium. Such effects have the potential to compromise the integrity of the intestinal epithelium and this disruption of barrier function could have health consequences for the gastrointestinal tract. PMID- 27465731 TI - Developmental cardiorespiratory physiology of the air-breathing tropical gar, Atractosteus tropicus. AB - The physiological transition to aerial breathing in larval air-breathing fishes is poorly understood. We investigated gill ventilation frequency (fG), heart rate (fH), and air breathing frequency (fAB) as a function of development, activity, hypoxia, and temperature in embryos/larvae from day (D) 2.5 to D30 posthatch of the tropical gar, Atractosteus tropicus, an obligate air breather. Gill ventilation at 28 degrees C began at approximately D2, peaking at ~75 beats/min on D5, before declining to ~55 beats/min at D30. Heart beat began ~36-48 h postfertilization and ~1 day before hatching. fH peaked between D3 and D10 at ~140 beats/min, remaining at this level through D30. Air breathing started very early at D2.5 to D3.5 at 1-2 breaths/h, increasing to ~30 breaths/h at D15 and D30. Forced activity at all stages resulted in a rapid but brief increase in both fG and fH, (but not fAB), indicating that even in these early larval stages, reflex control existed over both ventilation and circulation prior to its increasing importance in older fishes. Acute progressive hypoxia increased fG in D2.5-D10 larvae, but decreased fG in older larvae (>=D15), possibly to prevent branchial O2 loss into surrounding water. Temperature sensitivity of fG and fH measured at 20 degrees C, 25 degrees C, 28 degrees C and 38 degrees C was largely independent of development, with a Q10 between 20 degrees C and 38 degrees C of ~2.4 and ~1.5 for fG and fH, respectively. The rapid onset of air breathing, coupled with both respiratory and cardiovascular reflexes as early as D2.5, indicates that larval A. tropicus develops "in the fast lane." PMID- 27465732 TI - Nocturnal sleep uniformly reduces numbers of different T-cell subsets in the blood of healthy men. AB - In humans, numbers of circulating T cells show a circadian rhythm with peak counts during the night and a steep decline in the morning. Sleep per se appears to counter this rhythm by acutely reducing the total number of T cells. The T cell population, however, is rather heterogeneous, comprising various subpopulations with different features and functions and also different circadian rhythms. Therefore, we examined here whether sleep likewise differentially affects these subsets. We measured eight different T-cell subsets (naive, central memory, effector memory, and effector CD4+ and CD8+ T cells) over a 24-h period under conditions of sustained wakefulness compared with a regular sleep-wake cycle in 14 healthy young men. Sleep reduced the number of all T-cell subsets during nighttime with this effect reaching the P < 0.05 level of significance in all but one subpopulation, i.e., effector CD4+ T cells, where it only approached significance. Furthermore, sleep was associated with an increase in growth hormone, prolactin, and aldosterone levels, whereas concentrations of catecholamines tended to be lower than during nocturnal wakefulness. The effect of sleep uniformly decreasing the different T-cell subsets is surprising considering their differential function and circadian rhythms, and even more so, since the sleep-induced decreases in these subsets are probably conveyed by different hormonal mediators. Although the reductions in cell numbers are rather small, they are comparable to changes seen, for example, after vaccination and are, therefore, likely to be of physiological relevance. PMID- 27465729 TI - The Integrin Receptor in Biologically Relevant Bilayers: Insights from Molecular Dynamics Simulations. AB - Integrins are heterodimeric (alphabeta) cell surface receptors that are potential therapeutic targets for a number of diseases. Despite the existence of structural data for all parts of integrins, the structure of the complete integrin receptor is still not available. We have used available structural data to construct a model of the complete integrin receptor in complex with talin F2-F3 domain. It has been shown that the interactions of integrins with their lipid environment are crucial for their function but details of the integrin/lipid interactions remain elusive. In this study an integrin/talin complex was inserted in biologically relevant bilayers that resemble the cell plasma membrane containing zwitterionic and charged phospholipids, cholesterol and sphingolipids to study the dynamics of the integrin receptor and its effect on bilayer structure and dynamics. The results of this study demonstrate the dynamic nature of the integrin receptor and suggest that the presence of the integrin receptor alters the lipid organization between the two leaflets of the bilayer. In particular, our results suggest elevated density of cholesterol and of phosphatidylserine lipids around the integrin/talin complex and a slowing down of lipids in an annulus of ~30 A around the protein due to interactions between the lipids and the integrin/talin F2-F3 complex. This may in part regulate the interactions of integrins with other related proteins or integrin clustering thus facilitating signal transduction across cell membranes. PMID- 27465733 TI - Effects of aerobic exercise under different thermal conditions on human somatosensory processing. AB - The present study aimed to investigate the effects of aerobic exercise on human somatosensory processing recorded by somatosensory evoked potentials (SEPs) under temperate [TEMP, 20 degrees C and 40% relative humidity (RH)] and hot (HOT, 35 degrees C and 30% RH) environments. Fifteen healthy subjects performed 4 * 15-min bouts of a moderate cycling exercise [mean power output: 156.5 +/- 7.7 (SE) W], with a 10-min rest period and received a posterior tibial nerve stimulation at the left ankle before and after each exercise bout; SEPs were recorded in five sessions; 1st (pre), 2nd (post-1st exercise bout), 3rd (post-2nd exercise bout), 4th (post-3rd exercise bout), and 5th (post-4th exercise bout). The peak latencies and amplitudes of the P37, N50, P60, and N70 components at Cz were evaluated. The latencies of P37, N50, P60, and N70 were significantly shorter with the repetition of aerobic exercise, and these shortened latencies were significantly greater in the HOT condition than in the TEMP condition (P37: 3rd, P < 0.05, and 5th, P < 0.01; P60: 4th, P < 0.05, and 5th, P < 0.01; N70: 4th, P < 0.05, and 5th, P < 0.001). No significant differences were observed in the amplitudes of any SEP component under either thermal condition. These results suggest that the conduction velocity of the ascending somatosensory input was accelerated by increases in body temperature, and aerobic exercise did not alter the strength of neural activity in cortical somatosensory processing. PMID- 27465734 TI - Loss of REDD1 augments the rate of the overload-induced increase in muscle mass. AB - The overload-induced increase in muscle mass is accompanied by protein accretion; however, the initiating events are poorly understood. Regulated in Development and DNA Damage 1 (REDD1), a repressor of the mechanistic target of rapamycin in complex 1 (mTORC1), blunts the elevation in protein synthesis induced by acute muscle contractions. Therefore, this study was designed to determine whether REDD1 alters the rate of the overload-induced increase in muscle mass. Wild-type (WT) and REDD1-null mice underwent unilateral functional overload (OV) of the plantaris, while the contralateral sham leg served as a control. After 3 and 5 days of OV, puromycin incorporation was used as a measurement of protein synthesis. The percent increase in plantaris wet weight and protein content was greater in REDD1-null mice after 3, 5, and 10 days OV. The overload-stimulated rate of protein synthesis in the plantaris was similar between genotypes after 3 days OV, but translational capacity was lower in REDD1-null mice, indicating elevated translational efficiency. This was likely due to elevated absolute mTORC1 signaling [phosphorylation of p70S6K1 (Thr-389) and 4E-BP1 (Ser-65)]. By 5 days of OV, the rate of protein synthesis in REDD1-null mice was lower than WT mice with no difference in absolute mTORC1 signaling. Additionally, markers of autophagy (LC3II/I ratio and p62 protein) were decreased to a greater absolute extent after 3 days OV in REDD1-null mice. These data suggest that loss of REDD1 augments the rate of the OV-induced increase in muscle mass by altering multiple protein balance pathways. PMID- 27465735 TI - Peripheral circadian misalignment: contributor to systemic insulin resistance and potential intervention to improve bariatric surgical outcomes. AB - Thirteen percent of the world's population suffers from obesity and 39% from being overweight, which correlates with an increase in numerous secondary metabolic complications, such as Type 2 diabetes mellitus. Bariatric surgery is the most effective treatment for severe obesity and results in significant weight loss and the amelioration of obesity-related comorbidities through changes in enteroendocrine activity, caloric intake, and alterations in gut microbiota composition. The circadian system has recently been found to be a critical regulatory component in the control of metabolism and, thus, may potentially play an important role in inappropriate weight gain. Indeed, some behaviors and lifestyle factors associated with an increased risk of obesity are also risk factors for misalignment in the circadian clock system and for the metabolic syndrome. It is thus possible that alterations in peripheral circadian clocks in metabolically relevant tissues are a contributor to the current obesity epidemic. As such, it is plausible that postsurgical alterations in central circadian alignment, as well as peripheral gene expression in metabolic tissues may represent another mechanism for the beneficial effects of bariatric surgery. Bariatric surgery may represent an opportunity to identify changes in the circadian expression of clock genes that have been altered by environmental factors, allowing for a better understanding of the mechanism of action of surgery. These studies could also reveal an overlooked target for behavioral intervention to improve metabolic outcomes following bariatric surgery. PMID- 27465736 TI - Expansion of capacities for iron transport and sequestration reflects plasma volumes and heart mass among white-blooded notothenioid fishes. AB - The family Channichthyidae or "icefishes" (suborder Notothenioidei) represents the only vertebrates lacking hemoglobin (Hb) as adults. Several icefish species also do not express cardiac myoglobin (Mb). We address how levels of proteins involved in iron (Fe) processing (transport, sequestration, and export) vary among white- and red-blooded notothenioids, and whether absence of Hb and/or Mb in channichthyids is accompanied by expansion of contents of Fe-binding proteins to protect against unchaperoned Fe. Levels of transferrin (Tf), ferritin (Ft), ceruloplasmin (Cp), and non-heme Fe were quantified in plasma, serum, and/or nonhematopoietic tissues (cardiac ventricle, skeletal muscle, and liver) from species of white-blooded (Chaenocephalus aceratus, Champsocephalus gunnari, Chionodraco rastrospinosus, Pseudochaenichthys georgianus) (the first two species not expressing Mb) and red-blooded (Notothenia coriiceps, Gobionotothen gibberifrons) notothenioids. We also measured levels of ascorbate (Asc), a mediator of Fe uptake. While plasma concentrations of Tf and tissue levels of Asc are similar among species, concentrations of plasma Asc are lower in white blooded species. Concentrations of Ft and non-heme Fe and activities of Cp are also generally reduced in icefishes compared with red-blooded notothenioids. The presence of cardiac Mb in some icefish species does not appear to influence levels of proteins involved in Fe processing. To address further the question of Fe sequestration within a physiological context, we account for well characterized differences in blood volume and heart mass among white- and red blooded notothenioids. We report that total contents of plasma Tf are greater, while ventricle non-heme Fe is at least at parity in white- vs. red-blooded species. PMID- 27465737 TI - Ceramides are involved in the regulation of food intake in rainbow trout (Oncorhynchus mykiss). AB - We hypothesize that ceramides are involved in the regulation of food intake in fish. Therefore, we assessed in rainbow trout (Oncorhynchus mykiss) the effects of intracerebroventricular treatment with C6:0 ceramide on food intake. In a second experiment, we assessed the effects in brain areas of ceramide treatment on neuropeptide expression, fatty acid-sensing systems, and cellular signaling pathways. Ceramide treatment induced a decrease in food intake, a response opposed to the orexigenic effect described in mammals, which can be related to enhanced mRNA abundance of cocaine and amphetamine-related transcript and proopiomelanocortin and decreased mRNA abundance of Agouti-related protein and neuropeptide Y. Fatty acid-sensing systems appear to be inactivated by ceramide treatment. The mRNA abundance of integrative sensors AMPK and sirtuin 1, and the phosphorylation status of cellular signaling pathways dependent on protein kinase B, AMPK, mammalian target of rapamycin (mTOR), and forkhead box protein O1 (FoxO1) are generally activated by ceramide treatment. However, there are differences between hypothalamus and hindbrain in the phosphorylation status of AMPK (decreased in hypothalamus and increased in hindbrain), mTOR (decreased in hypothalamus and increased in hindbrain), and FoxO1 (increased in hypothalamus and decreased in hindbrain) to ceramide treatment. The results suggest that ceramides are involved in the regulation of food intake in rainbow trout through mechanisms comparable to those characterized previously in mammals in some cases. PMID- 27465738 TI - Salt control. Focus on "High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ETB receptor expression". PMID- 27465739 TI - Characterization of the T-cell receptor beta chain repertoire in tumor infiltrating lymphocytes. AB - Tumor-infiltrating lymphocytes (TILs) are direct effectors of tumor immunity, and their characterization is important for further development of immunotherapy. Recent advances in high-throughput sequencing technologies have enabled a comprehensive analysis of T-cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, which may provide information of therapeutic importance. We developed a high-fidelity target sequencing method with the ability for absolute quantitation, and performed large-scale sequencing of TCR beta chain (TCRB) CDR3 regions in TILs and peripheral blood lymphocytes (PBLs). The estimated TCRB repertoire sizes of PBLs from four healthy individuals and TILs from four colorectal cancer tissue samples were 608,664-1,003,098 and 90,228 223,757, respectively. The usage of J- and V-regions was similar in PBLs and TILs. Proportions of CDR3 amino acid (aa) sequences occupying more than 0.01% of the total molecular population were 0.33-0.43% in PBLs and 1.3-3.6% in TILs. Additional low coverage sequencing of 15 samples identified five CDR3 aa sequences that were shared by nine patients, one sequence shared by 10 patients, and one sequence shared by 12 patients. The estimated size of the TCRB repertoire in TILs was significantly smaller than that in PBLs. The proportion of abundant species (>0.01%) in TILs was larger than that in PBLs. Shared CDR3 aa sequences represent a response to common antigens, and the identification of such CDR3 sequences may be beneficial in developing clinical biomarkers. PMID- 27465740 TI - The experience of adolescents participating in a randomised clinical trial in the field of mental health: a qualitative study. AB - BACKGROUND: This descriptive study aimed to investigate adolescents' motivations for participating in a randomised controlled trial (RCT), to explore the understanding that the young people had regarding a number of aspects of the trial design, to examine whether or not they found participation in the trial to be acceptable and what affected this, and to identify whether and how the young people felt that their participation in the RCT impacted on their experience of therapy and on therapeutic change. METHODS: Seventy-six adolescents who were taking part in a large-scale RCT to evaluate the clinical and cost effectiveness of psychological therapies for depression were interviewed at two time-points after completing therapy. The semi-structured interviews, which included a focus on the young people's experience of the research study, were analysed using framework analysis. RESULTS: The vast majority of adolescents found it acceptable to participate in the clinical trial, and many agreed to participate for reasons of 'conditional altruism'. However consent was often given without great understanding of the key elements of the trial, including the difference between treatment arms and the randomisation process. Although the adolescents were largely positive about their experiences from taking part, the study raises questions about whether clinical outcomes may be influenced by participation in the research elements of the trial. CONCLUSIONS: Although adolescents are under represented in clinical trials, those who do participate are generally positive about the experience; however, careful thought needs to be given to key elements of the trial design and the potential impact of the research participation on clinical outcomes. TRIAL REGISTRATION: ISRCTN registry, ISRCTN83033550 . Registered on 15 October 2009. PMID- 27465741 TI - Reduced LINE-1 methylation is associated with arsenic-induced genotoxic stress in children. AB - Early life exposure to arsenic has profound effect towards development of arsenic induced toxic outcomes. Some districts in the state of West Bengal, India are highly affected by arsenic, mainly through ground water. In children, not much of the toxic outcomes like dermatological lesions are observed but it is thought that the exposure leads to transient alteration in their biological processes that leads to various deleterious health effects later on. We evaluated the global methylation status by analyzing the LINE-1 methylation profile in children from arsenic exposed region between the age group 5-15 years along with the cytogenetic stress induced by arsenic as measured by lymphocyte micronucleus (MN) frequency. A total of 52 arsenic exposed and 32 unexposed children were analyzed. Whole blood DNA was used to measure the LINE-1 methylation by qRT-MSP. We found a significant association of MN-frequency in exposed individuals with highly depleted LINE-1 methylation compared to the exposed individuals with near baseline (which was comparable to unexposed control) methylation index as well as with those with the hypermethylated LINE-1 promoters. From our results, we interpret that LINE-1 methylation index may serve as a potent global epigenetic mark to detect the degree of arsenic genotoxicity at a very early age. We propose that this may be utilized to determine the extent of toxic influence exerted by arsenic, from a very early age. PMID- 27465743 TI - Help Us Remember Our History. PMID- 27465742 TI - Ratio abstraction over discrete magnitudes by newly hatched domestic chicks (Gallus gallus). AB - A large body of literature shows that non-human animals master a variety of numerical tasks, but studies involving proportional discrimination are sparse and primarily done with mature animals. Here we trained 4-day-old domestic chicks (Gallus gallus) to respond to stimuli depicting multiple examples of the proportion 4:1 when compared with the proportion 2:1. Stimuli were composed of green and red dot arrays; for the rewarded 4:1 proportion, 4 green dots for every red dot (e.g. ratios: 32:8, 12:3, and 44:11). The birds continued to discriminate when presented with new ratios at test (such as 20:5), characterized by new numbers of dots and new spatial configurations (Experiment 1). This indicates that chicks can extract the common proportional value shared by different ratios and apply it to new ones. In Experiment 2, chicks identified a specific proportion (2:1) from either a smaller (4:1) or a larger one (1:1), demonstrating an ability to represent the specific, and not relative, value of a particular proportion. Again, at test, chicks selectively responded to the previously reinforced proportion from new ratios. These findings provide strong evidence for very young animals' ability to extract, identify, and productively use proportion information across a range of different amounts. PMID- 27465744 TI - The Matter of Disability. AB - By ruling out questions of impairment from the social critique of disability, Disability Studies (DS) analyses establish a limit point in the field. Of course the setting of "limits" enables possibilities in multiple directions as well as fortifies boundaries of refusal. For instance, impairment (the biological conditions of an organism's inefficient attachment to the world) becomes in DS simultaneously a productive refusal to interpret disabled bodies as inferior to non-disabled bodies (i.e. pathologized) and a bar to thinking through more active engagements with disability as materiality. Disability materiality such as conditions produced by ecological toxicities serve as active switch-points for creative corporeal navigations of the interaction between bodies and environments.In fact in this paper we want to propose a more "lively" definition of disability materiality to existing definitions of impairment as limiting expressions of non-normative bodies. We have no useful ways of explaining disability as adaptation and it's time we begin the process of theorizing more active ideas of materiality that extend existing ideas of disability beyond simplistic conceptions of socially rejected biologies made available by social constructivist thought. PMID- 27465746 TI - Designing a Healthy Food Partnership: lessons from the Australian Food and Health Dialogue. AB - BACKGROUND: Poor diets are a leading cause of disease burden worldwide. In Australia, the Federal Government established the Food and Health Dialogue (the Dialogue) in 2009 to address this issue, primarily through food reformulation. We evaluated the Dialogue's performance over its 6 years of operation and used these findings to develop recommendations for the success of the new Healthy Food Partnership. METHODS: We used information from the Dialogue website, media releases, communiques, e-newsletters, materials released under freedom-of information, and Parliamentary Hansard to evaluate the Dialogue's achievements from October 2013 to November 2015, using the RE-AIM (reach, efficacy, adoption, implementation and maintenance) framework. We also engaged closely with two former Dialogue members. Our findings update a prior assessment done in October 2013. RESULTS: Little data is available to evaluate the Dialogue's recent achievements, with no information about progress against milestones released since October 2013. In the last 2 years, only one additional set of sodium reduction targets (cheese) was agreed and Quick Service Restaurant foods were added as an area for action. Some activity was identified in 12 of a possible 137 (9 %) areas of action within the Dialogue's mandate. Independent evaluation found targets were partially achieved in some food categories, with substantial variation in success between companies. No effects on the knowledge, behaviours or nutrient intake of the Australian population or evidence of impact on diet related disease could be identified. CONCLUSIONS: The new Healthy Food Partnership has similar goals to the Dialogue. While highly laudable and recognised globally as cost-effective, the mechanism for delivery in Australia has been woefully inadequate. Strong government leadership, adequate funding, clear targets and timelines, management of conflict of interest, comprehensive monitoring and evaluation, and a plan for responsive regulation in the event of missed milestones will be required if the new Healthy Food Partnership is to achieve its urgent public health goals. PMID- 27465745 TI - Effects of induction and inhibition of matrix cross-linking on remodeling of the aqueous outflow resistance by ocular trabecular meshwork cells. AB - The trabecular meshwork (TM) tissue controls drainage of aqueous humor from the anterior chamber of the eye primarily by regulating extracellular matrix (ECM) remodeling by matrix metalloproteinases (MMPs). Glaucomatous TM tissue is stiffer than age-matched controls, which may be due to alterations in ECM cross-linking. In this study, we used genipin or beta-aminopropionitrile (BAPN) agents to induce or inhibit matrix cross-linking, respectively, to investigate the effects on outflow resistance and ECM remodeling. Treatment with BAPN increased outflow rates in perfused human and porcine anterior segments, whereas genipin reduced outflow. Using a fluorogenic peptide assay, MMP activity was increased with BAPN treatment, but reduced with genipin treatment. In genipin-treated TM cells, Western immunoblotting showed a reduction of active MMP2 and MMP14 species and the presence of TIMP2-MMP14 higher molecular weight complexes. BAPN treatment increased collagen type I mRNA and protein levels, but genipin reduced the levels of collagen type I, tenascin C, elastin and versican. CD44 and fibronectin levels were unaffected by either treatment. Collectively, our results show that matrix cross-linking has profound effects on outflow resistance and ECM composition and are consistent with the emerging paradigm that the stiffer the ECM, the lower the aqueous outflow facility through the TM. PMID- 27465747 TI - Dabigatran in real-world atrial fibrillation. Meta-analysis of observational comparison studies with vitamin K antagonists. AB - In the RE-LY clinical trial, dabigatran presented a better effectiveness/safety profile when compared to warfarin. However, clinical trials are not very representative of the real-world setting. We aimed to assess the performance of dabigatran in real-world patients with atrial fibrillation (AF) by means of a systematic review and meta-analysis of observational comparison studies with vitamin K antagonists (VKA). We searched PubMed, Embase and Scopus databases until November 2015 and selected studies according to the following criteria: observational study performed with nonvalvular AF patients; reporting adjusted hazard ratios (HR) of clinical events in a follow-up period; for dabigatran 75 mg, 110 mg or 150 mg versus VKA. Twenty studies were selected which included 711,298 patients, 210,279 of which were treated with dabigatran and the remaining 501,019 with VKA. Ischaemic stroke incidence was of 1.65 /100 patient-years for dabigatran and 2.85/100 patient-years for VKA (HR 0.86, 95 % confidence interval of 0.74-0.99). Major bleeding rate was 3.93/100 patient-years for dabigatran and 5.61/100 patient-years for VKA (0.79, 0.69-0.89). Risk of mortality (0.73, 0.61 0.87) and intracranial bleeding (0.45, 0.38-0.52) were significantly lower in patients treated with dabigatran when compared to patients on VKA. Risk of gastrointestinal (GI) bleeding was significantly higher in patients treated with dabigatran (1.13, 1.00-1.28). No significant difference was observed in risk of myocardial infarction (0.99, 0.89-1.11). In this combined analysis of real-world observational comparison studies with VKA, dabigatran was associated with a lower risk of ischaemic stroke, major bleeding, intracranial bleeding and mortality, higher risk of GI bleeding and a similar risk of myocardial infarction. PMID- 27465748 TI - Application of Rasch analysis to the parent adherence report questionnaire in juvenile idiopathic arthritis. AB - BACKGROUND: Adherence to treatment in children with juvenile idiopathic arthritis (JIA) is associated with better outcomes. Assessing patient adherence in JIA, as well as attitudes and beliefs about prescribed treatments, is important for the clinician in order to optimize patient management. The objective of the current study was to evaluate the psychometric properties of the Parent (proxy-report) Adherence Report Questionnaires (PARQ), which assesses beliefs and behaviors related to adherence to treatments prescribed for JIA. METHODS: A Rasch analysis was conducted on data collected with parents of children with JIA from two studies in which the PARQ was used as a measure of adherence. RESULTS: The PARQ showed preliminary evidence of multidimensionality with two factors, accounting for 38 % and 27 % of the variance respectively. The PARQ in its original version does not adhere to expectations of the Rasch model. A transformed version of the PARQ obtained by deletion of the general adherence scale and modification of visual analog scales into 5-point likert scales improved fit to the model and showed preliminary evidence of unidimensionality. CONCLUSIONS: The PARQ was transformed based on the results of the Rasch analysis. The transformed version of the PARQ shows preliminary evidence of unidimensionality and may allow computation of a total score, although further testing is needed to verify these findings. PMID- 27465750 TI - Objectively measured physical activity predicts subsequent energy intake in 300 women. AB - OBJECTIVE: To determine if 7 d physical activity (PA) predicts energy intake over the same days and if PA on a given day predicts energy intake on the same day, the next day or subsequent days. DESIGN: A 7 d prospective investigation. PA was measured using accelerometers worn for seven consecutive days. During the same week, total energy intake (including alcohol) was assessed using weighed food records. SETTING: Twenty cities in the USA. SUBJECTS: Three hundred middle-aged women. RESULTS: After controlling for the covariates, energy intake was 36 (se 8) kJ higher for each additional 100000 activity counts (F=19.0, P<0.0001), based on the entire week of monitoring. Women with Low PA (n 75) had a mean energy intake of 8364 (sd 1235) kJ/d (1998 (sd 295) kcal/d), those with Moderate PA (n 150) consumed 8523 (sd 1264) kJ/d (2036 (sd 302) kcal/d) and those with High PA (n 75) consumed 9079 (sd 1473) kJ/d (2169 (sd 352) kcal/d; F=6.4, P=0.0019), a 5023 kJ/d (1200 kcal/d) difference between the High and Low PA groups. PA on a given day was predictive of energy consumption on the same day on four of the seven monitored days, and was predictive of energy intake the next day, with five of six associations significant. PA was not consistently predictive of energy intake on days beyond the next day. CONCLUSIONS: Over 7 d, PA and energy consumption tend to be positively related. Considered day to day, increased PA is weakly associated with increased energy intake the following day and, to a lesser extent, the same day. Therefore, managing weight by increasing PA may not result in the energy deficit expected. PMID- 27465749 TI - Signaling network map of the aryl hydrocarbon receptor. PMID- 27465751 TI - Intrarater and Interrater Reliability of the Hierarchical Balance Short Forms in Patients With Stroke. AB - OBJECTIVE: To examine the intrarater and interrater reliability of a quick balance measure, the Hierarchical Balance Short Forms (HBSF), in outpatients with stroke receiving rehabilitation. DESIGN: A repeated-assessments design (1wk apart) was used to examine the intrarater and interrater reliability of the HBSF. The HBSF was administered by a single rater in the intrarater reliability study and by 2 raters in the interrater reliability study. The raters had sufficient working experience in stroke rehabilitation. SETTING: Seven teaching hospitals. PARTICIPANTS: Two independent groups of outpatients (N=106; each group, n=53) with stroke in chronic stages and in stable medical condition were recruited. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: HBSF. RESULTS: For the intrarater reliability study, the values of the intraclass correlation coefficient (ICC), minimal detectable change (MDC), and percentage of minimal detectable change (MDC%) were .95, 1.02, and 16.3%, respectively, for the HBSF. The 95% limits of agreement (LOA) of the HBSF ranged from -.69 to 1.19. For the interrater reliability study, the values of the ICC, MDC, and MDC% were .91, 1.22, and 18.3%, respectively, for the HBSF. The 95% LOA of the HBSF ranged from 1.01 to 1.35. CONCLUSIONS: Our results suggest that the HBSF has satisfactory intrarater and interrater reliability for assessing balance function in outpatients with stroke. The MDC values of the HBSF are useful for both researchers and clinicians to determine whether the change in balance function of an individual patient is real when administered by an individual rater or by different raters. PMID- 27465752 TI - Cardiometabolic Syndrome in People With Spinal Cord Injury/Disease: Guideline Derived and Nonguideline Risk Components in a Pooled Sample. AB - OBJECTIVE: To assess cardiometabolic syndrome (CMS) risk definitions in spinal cord injury/disease (SCI/D). DESIGN: Cross-sectional analysis of a pooled sample. SETTING: Two SCI/D academic medical and rehabilitation centers. PARTICIPANTS: Baseline data from subjects in 7 clinical studies were pooled; not all variables were collected in all studies; therefore, participant numbers varied from 119 to 389. The pooled sample included men (79%) and women (21%) with SCI/D >1 year at spinal cord levels spanning C3-T2 (American Spinal Injury Association Impairment Scale [AIS] grades A-D). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We computed the prevalence of CMS using the American Heart Association/National Heart, Lung, and Blood Institute guideline (CMS diagnosis as sum of risks >=3 method) for the following risk components: overweight/obesity, insulin resistance, hypertension, and dyslipidemia. We compared this prevalence with the risk calculated from 2 routinely used nonguideline CMS risk assessments: (1) key cut scores identifying insulin resistance derived from the homeostatic model 2 (HOMA2) method or quantitative insulin sensitivity check index (QUICKI), and (2) a cardioendocrine risk ratio based on an inflammation (C-reactive protein [CRP]) adjusted total cholesterol/high-density lipoprotein cholesterol ratio. RESULTS: After adjustment for multiple comparisons, injury level and AIS grade were unrelated to CMS or risk factors. Of the participants, 13% and 32.1% had CMS when using the sum of risks or HOMA2/QUICKI model, respectively. Overweight/obesity and (pre)hypertension were highly prevalent (83% and 62.1%, respectively), with risk for overweight/obesity being significantly associated with CMS diagnosis (sum of risks, chi(2)=10.105; adjusted P=.008). Insulin resistance was significantly associated with CMS when using the HOMA2/QUICKI model (chi(2)2=21.23, adjusted P<.001). Of the subjects, 76.4% were at moderate to high risk from elevated CRP, which was significantly associated with CMS determination (both methods; sum of risks, chi(2)2=10.198; adjusted P=.048 and HOMA2/QUICKI, chi(2)2=10.532; adjusted P=.04). CONCLUSIONS: As expected, guideline-derived CMS risk factors were prevalent in individuals with SCI/D. Overweight/obesity, hypertension, and elevated CRP were common in SCI/D and, because they may compound risks associated with CMS, should be considered population-specific risk determinants. Heightened surveillance for risk, and adoption of healthy living recommendations specifically directed toward weight reduction, hypertension management, and inflammation control, should be incorporated as a priority for disease prevention and management. PMID- 27465753 TI - Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion. AB - Epidermal growth factor (EGF) is a cytoprotective protein that improves survival in preclinical models of sepsis through its beneficial effects on intestinal integrity. Alcohol use disorder worsens intestinal integrity and is associated with increased morbidity and mortality in critical illness. We sought to determine whether chronic alcohol ingestion alters the host response to systemic administration of EGF in sepsis. Six-week-old FVB/N mice were randomized to receive 20% alcohol or water for 12 weeks. All mice then underwent cecal ligation and puncture to induce polymicrobial sepsis. Mice were then randomized to receive either intraperitoneal injection of EGF (150 MUg/kg/day) or normal saline. Water fed mice given EGF had decreased 7-day mortality compared with water-fed mice (18% vs. 55%). Alcohol-fed mice given EGF also had decreased 7-day mortality compared with alcohol-fed mice (48% vs. 79%). Notably, while systemic EGF improved absolute survival to a similar degree in both water-fed and alcohol-fed mice, mortality was significantly higher in alcohol+EGF mice compared with water+EGF mice. Compared with water-fed septic mice, alcohol-fed septic mice had worsened intestinal integrity with intestinal hyperpermeability, increased intestinal epithelial apoptosis, decreased proliferation and shorter villus length. Systemic administration of EGF to septic alcohol-fed mice decreased intestinal permeability compared with septic alcohol-fed mice given vehicle, with increased levels of the tight junction mediators claudin-5 and JAM-A. Systemic administration of EGF to septic alcohol-fed mice also decreased intestinal apoptosis with an improvement in the Bax/Bcl-2 ratio. EGF also improved both crypt proliferation and villus length in septic alcohol-fed mice. EGF administration resulted in lower levels of both pro- and anti-inflammatory cytokines monocyte chemoattractant protein-1, tumor necrosis factor, and interleukin 10 in alcohol-fed mice. EGF is therefore effective at improving both intestinal integrity and mortality following sepsis in mice with chronic alcohol ingestion. However, the efficacy of EGF in sepsis is blunted in the setting of chronic alcohol ingestion, as intestinal integrity and mortality in alcohol-fed mice given EGF improves animals to levels seen in water-fed mice given vehicle but does not approach levels seen in water-fed mice given EGF. PMID- 27465755 TI - Searching For the Optimal Fluid to Restore Microcirculatory Flow Dynamics After Haemorrhagic Shock: A Systematic Review of Preclinical Studies. AB - BACKGROUND: Increased microcirculatory flow and perfusion has been reported to improve clinical outcomes following shock. The optimal resuscitation fluid to restore the flow dynamics of the microcirculation is unknown. This review summarizes the preclinical literature to inform the direction and most important hypotheses for future clinical interventional studies. METHODS: Standard systematic review methodology was utilized, and registered with the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES). Medline and Embase (via OVID SP) and SCOPUS were searched for all preclinical studies of haemorrhagic shock that compared fluid resuscitation of any kind (e.g., blood products, crystalloids, colloids, or haemoglobin based oxygen carriers) to another fluid or haemorrhage only, and reported at least one microcirculatory physical endpoint (such as flow rate, velocity, vessel diameter, functional capillary density, or glycocalyx thickness). Risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. Translatability was also assessed for each study based on the most common recommendations. RESULTS: There were 3,103 potential studies of interest, of which 71 studies fulfilled all eligibility criteria. There were 62 rodent, 5 canine, and 4 porcine studies. Flow rate, velocity, and vessel diameter were the most commonly reported endpoints. Studies reported the importance of the presence of haemoglobin, as well as osmotic potential and viscosity in providing optimal restoration of microcirculatory flow dynamics. Others reported the restoration of the endothelial glycocalyx and attenuation of inflammation as important properties for the choice of fluid. All studies were at potential risk of bias due to unclear randomization, concealment, and blinding. There were important threats to translatability for all studies. CONCLUSION: The ideal resuscitation fluid for restoration of the microcirculation following haemorrhagic shock is likely to contain a preparation of haemoglobin, favor higher oncotic potential, and viscosity, protect and reconstitute the endothelium, and attenuate inflammation. These hypotheses that are derived from preclinical research warrant further exploration in the clinical context. PMID- 27465757 TI - Move more, sit less! Time for a national physical activity action plan. PMID- 27465759 TI - Time to bury "hypertension". PMID- 27465756 TI - Changes in regional body composition over 8 years in a randomized lifestyle trial: The look AHEAD study. AB - OBJECTIVE: To test the hypothesis that an 8-year intensive lifestyle intervention (ILI) suppresses aging-dependent changes in regional lean mass (LM) and fat mass (FM) among people with overweight/obesity and type 2 diabetes. METHODS: Regional body composition was measured by dual-energy X-ray absorptiometry within a subset of 1,019 volunteers (45-75 years old) in the Look AHEAD study randomized to ILI or diabetes support and education (DSE). The ILI goal was to achieve and maintain >=7% weight loss through increased physical activity and reduced caloric intake. RESULTS: Over 8 years, the DSE group exhibited a linear loss of LM and FM. During year 1, the ILI group lost LM and FM. Between years 1 and 8, the ILI group regained most FM in all regions; regional LM converged with that of the DSE group; the percent of LM loss was greater for the leg than for the trunk. Among both groups, regional LM and FM change was proportional to the size of the region, trunk > leg > arm. CONCLUSIONS: Aging-dependent LM losses, particularly in the leg region, were not suppressed by ILI. The long-term consequences of rapid LM and FM loss and subsequent regain mostly as fat are unknown. PMID- 27465760 TI - "Congenital heart health": how psychological care can make a difference. PMID- 27465761 TI - How health technology helps promote cardiovascular health outcomes. PMID- 27465762 TI - Cardiac tamponade in undiagnosed systemic lupus erythematosus. PMID- 27465763 TI - Caritas Christi. PMID- 27465764 TI - Improving outcomes in coronary artery disease. PMID- 27465765 TI - Ensuring access to invasive care for all patients with acute coronary syndromes: beyond our reach? PMID- 27465766 TI - Variation in coronary angiography rates in Australia: correlations with socio demographic, health service and disease burden indices. AB - BACKGROUND: Variation in the provision of coronary angiography is associated with health care inefficiency and inequity. We explored geographic, socio-economic, health service and disease indicators associated with variation in angiography rates across Australia. METHODS: Australian census and National Health Survey data were used to determine socio-economic, health workforce and service indicators. Hospital separations and coronary deaths during 2011 were identified in the National Hospital Morbidity and Mortality databases. All 61 Medicare Locals responsible for primary care were included, and age- and sex-standardised rates of acute coronary syndrome (ACS) incidence, coronary angiography, revascularisation and mortality were tested for correlations, and adjusted by Bayesian regression. RESULTS: There were 3.7-fold and 2.3-fold differences between individual Medicare Locals in the lowest and highest ACS and coronary artery disease mortality rates respectively, whereas angiography rates varied 5.3 fold. ACS and death rates within Medicare Locals were correlated (partial correlation coefficient [CC], 0.52; P < 0.001). There was modest correlation between ACS and angiography rates (CC, 0.31; P = 0.018). The proportion of patients undergoing angiography who proceeded to revascularisation was inversely correlated with the total angiogram rate (CC, -0.71; P < 0.001). Socio-economic disadvantage and remoteness were correlated with disease burden, ACS incidence and mortality, but not with angiography rate. In the adjusted analysis, the strongest association with local angiography rates was with admissions to private hospitals (71 additional angiograms [95% CI, 47-93] for every 1000 admissions). CONCLUSION: Variation in rates of coronary angiography, not related to clinical need, occurs across Australia. A greater focus on clinical care standards and better distribution of health services will be required if these variations are to be attenuated. PMID- 27465767 TI - Pre-hospital thrombolysis in ST-segment elevation myocardial infarction: a regional Australian experience. AB - OBJECTIVE: The system of care in the Hunter New England Local Health District for patients with ST-segment elevation myocardial infarction (STEMI) foresees pre hospital thrombolysis (PHT) administered by paramedics to patients more than 60 minutes from the cardiac catheterisation laboratory (CCL), and primary percutaneous coronary intervention (PCI) at the CCL for others. We assessed the safety and effectiveness of the pre-hospital diagnosis strategy, which allocates patients to PHT or primary PCI according to travel time to the CCL. DESIGN, SETTING AND PARTICIPANTS: Prospective, non-randomised, consecutive, single-centre case series of STEMI patients diagnosed on the basis of a pre-hospital electrocardiogram (ECG), from August 2008 to August 2013. All patients were treated at the tertiary referral hospital (John Hunter Hospital, Newcastle). MAIN OUTCOME MEASURES: The primary efficacy endpoint was all-cause mortality at 12 months; the primary safety endpoint was bleeding. RESULTS: STEMI was diagnosed in 484 patients on the basis of pre-hospital ECG; 150 were administered PHT and 334 underwent primary PCI. The median time from first medical contact (FMC) to PHT was 35 minutes (IQR, 28-43 min) and to balloon inflation 130 minutes (IQR, 100 150 min). In the PHT group, 37 patients (27%) needed rescue PCI (median time, 4 h; IQR, 3-5 h). The 12-month all-cause mortality rate was 7.0% (PHT, 6.7%; PCI, 7.2%). The incidence of major bleeding (TIMI criteria) in the PHT group was 1.3%; no patients in the primary PCI group experienced major bleeding. CONCLUSION: PHT can be delivered safely by paramedical staff in regional and rural Australia with good clinical outcomes. PMID- 27465768 TI - The uptake of coronary fractional flow reserve in Australia in the past decade. PMID- 27465770 TI - The clinical utility of new cardiac imaging modalities in Australasian clinical practice. AB - Cardiac imaging is a rapidly evolving field, with improvements in the diagnostic capabilities of non-invasive cardiac assessment. We review the two main emerging technologies in cardiac imaging: computed tomography coronary angiography (CTCA) to evaluate chest symptoms and to exclude coronary artery disease; and cardiovascular magnetic resonance (CMR) for evaluating cardiac morphology, function and presence of scar. CTCA is an excellent "rule out" test, with a negative predictive value approaching 100%. Radiation exposure is no longer a concern for CTCA, with doses routinely < 5 mSv, and as low as < 1 mSv in selected patients. CTCA is useful for excluding coronary artery disease, investigating the anatomy of coronary anomalies or fistulae, and for the patency of coronary bypass grafts. CMR is the reference test for the accurate quantitation of left ventricular and right ventricular size and function. CMR has no ionising radiation, making it particularly suitable for patients with heart failure or congenital heart disease who require longitudinal follow-up. Evaluation of cardiomyopathies (hypertrophic, ischaemic, infiltrative, myocarditis, iron overload or idiopathic) is a unique strength of CMR. Stress perfusion CMR has a strong evidence base and improved spatial and temporal resolution compared with nuclear single-photon emission computed tomography. PMID- 27465769 TI - National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of acute coronary syndromes 2016. AB - INTRODUCTION: The modern care of suspected and confirmed acute coronary syndrome (ACS) is informed by an extensive and evolving evidence base. This clinical practice guideline focuses on key components of management associated with improved clinical outcomes for patients with chest pain or ACS. These are presented as recommendations that have been graded on both the strength of evidence and the likely absolute benefit versus harm. Additional considerations influencing the delivery of specific therapies and management strategies are presented as practice points. MAIN RECOMMENDATIONS: This guideline provides advice on the standardised assessment and management of patients with suspected ACS, including the implementation of clinical assessment pathways and subsequent functional and anatomical testing. It provides guidance on the: diagnosis and risk stratification of ACS; provision of acute reperfusion therapy and immediate post-fibrinolysis care for patients with ST segment elevation myocardial infarction; risk stratification informing the use of routine versus selective invasive management for patients with non-ST segment elevation ACS; administration of antithrombotic therapies in the acute setting and considerations affecting their long term use; and implementation of an individualised secondary prevention plan that includes both pharmacotherapies and cardiac rehabilitation. Changes in management as a result of the guideline: This guideline has been designed to facilitate the systematic integration of the recommendations into a standardised approach to ACS care, while also allowing for contextual adaptation of the recommendations in response to the individual's needs and preferences. The provision of ACS care should be subject to continuous monitoring, feedback and improvement of quality and patient outcomes. PMID- 27465771 TI - English as a second language and outcomes of patients presenting with acute coronary syndromes: results from the CONCORDANCE registry. PMID- 27465772 TI - English as a second language and outcomes of patients presenting with acute coronary syndromes: results from the CONCORDANCE registry. PMID- 27465773 TI - Are Indirect Benefits Relevant to Health Care Allocation Decisions? AB - When allocating scarce healthcare resources, the expected benefits of alternative allocations matter. But, there are different kinds of benefits. Some are direct benefits to the recipient of the resource such as the health improvements of receiving treatment. Others are indirect benefits to third parties such as the economic gains from having a healthier workforce. This article considers whether only the direct benefits of alternative healthcare resource allocations are relevant to allocation decisions, or whether indirect benefits are relevant too. First, we distinguish different conceptions of direct and indirect benefits and argue that only a recipient conception could be morally relevant. We analyze four arguments for thinking that indirect benefits should not count and argue that none is successful in showing that the indirectness of a benefit is a good reason not to count it. We conclude that direct and indirect benefits should be evaluated in the same way. PMID- 27465774 TI - Autonomy and the Moral Authority of Advance Directives. AB - Although advance directives are widely believed to be a key way to safeguard the autonomy of incompetent medical patients, significant questions exist about their moral authority. The main philosophical concern involves cases in which an incompetent patient no longer possesses the desires on which her advance directive was based (e.g., in cases of severe dementia). The question is, does that entail that prior expressions of medical choices are no longer morally binding? I believe that the answer is "yes." I argue that a patient's autonomy is not respected by honoring the desires she used to have but no longer does. I also consider and reject the view that honoring an advance directive that reflects the patient's previous values must be in that patient's best interests. If that is correct, then advance directives in the kind of case at issue are not morally binding. PMID- 27465775 TI - Substantial Life Extension and the Fair Distribution of Healthspans. AB - One of the strongest objections to the development and use of substantially life extending interventions is that they would exacerbate existing unjust disparities of healthy lifespans between rich and poor members of society. In both popular opinion and ethical theory, this consequence is sometimes thought to justify a ban on life-prolonging technologies. However, the practical and ethical drawbacks of banning receive little attention, and the viability of alternative policies is seldom considered. Moreover, where ethicists do propose alternatives, there is scant effort to consider their merits in light of developing world priorities. In response to these shortcomings, I distinguish four policy options and, on the basis of a plausible intuition about fairness, evaluate their implications for a fair distribution of healthy lifespans. I claim that even in developing nations it would be fairest to favor policies that promote equal access to at least one promising category of substantially life-extending intervention: calorie restriction mimetics. PMID- 27465776 TI - Synergistic effect of honokiol and 5-fluorouracil on apoptosis of oral squamous cell carcinoma cells. AB - BACKGROUND: 5-Fluorouracil (5-FU) is an essential chemotherapeutic agent for oral squamous cell carcinoma (OSCC). However, toxic side effects have limited its role in OSCC therapy. The aim of this study was to explore whether combination therapy with 5-FU and honokiol (HNK), a small natural organic molecule shown to induce apoptosis in OSCC cells, could enhance the anticancer activity of 5-FU without notably increasing its toxicity. METHODS: 5-FU and/or HNK were used to treat OSCC cells both in vitro and in vivo. The therapeutic effect and underlying mechanisms were evaluated by cell viability assay, flow cytometry, OSCC xenograft mouse model, and Western blot. Tumor tissue apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Toxicity was assessed following hematoxylin and eosin staining. RESULTS: Exposure to HNK + 5 FU produced a synergistic cytotoxic effect on OSCC cells. Both HNK and 5-FU could induce apoptosis through the mitochondria-mediated intrinsic pathway, and their specific signaling pathways were different. In the mouse OSCC xenograft model, treatment with 5-FU + HNK substantively retarded tumor growth, as compared to treatment with either drug individually. TUNEL analysis further confirmed that the superior in vivo antitumor efficacy of 5-FU + HNK was associated with enhanced stimulation of cell apoptosis. Notably, HNK did not increase the toxicity of 5-FU. CONCLUSION: These findings suggest that HNK and 5-FU exert a synergistic therapeutic effect on OSCC by inducing apoptosis. HNK might thus enhance the clinical therapeutic efficacy of 5-FU without increasing its toxicity. PMID- 27465777 TI - How Can We Address the Publication Bias Against Negative Scientific Study Data? PMID- 27465778 TI - Usnic Acid and Its Evolving Role as a Potent Antineoplastic Agent. PMID- 27465779 TI - Antiproliferative activity of Juglone derivatives on rat glioma. AB - Malignant gliomas are aggressive and life-threatening tumours that still show a poor prognosis: the current therapeutic approach based on surgical resection and chemotherapy combined with radiotherapy does not provide a satisfactory chance of long-term survival to patients. Natural bioactive compounds represent a precious source of molecules with antiproliferative activity, potentially effective also against glioma cells. Among these, Juglone is a known allelopathic compound extracted from the eastern black walnut (Juglans nigra) whose antimitotic effect has been extensively described in mammalian cells. We investigated the antiproliferative effect of a synthetic derivative of this natural compound, 2 (2,4-dihydroxyphenyl)-8-hydroxy-1,4-naphthoquinone (DiNAF), in rat glioma cells. We compared this molecule and its effect with the natural reference compound and with newly synthesised derivatives to build a preliminar structure-activity relationship. Biological assays and NMR-based redox experiments confirmed that DiNAF is a promising lead and supported the hypothesis of a redox mechanism underlying its cytotoxic activity. PMID- 27465780 TI - Desiccation of sediments affects assimilate transport within aquatic plants and carbon transfer to microorganisms. AB - With the projected increase in drought duration and intensity in future, small water bodies, and especially the terrestrial-aquatic interfaces, will be subjected to longer dry periods with desiccation of the sediment. Drought effects on the plant-sediment microorganism carbon continuum may disrupt the tight linkage between plants and microbes which governs sediment carbon and nutrient cycling, thus having a potential negative impact on carbon sequestration of small freshwater ecosystems. However, research on drought effects on the plant-sediment carbon transfer in aquatic ecosystems is scarce. We therefore exposed two emergent aquatic macrophytes, Phragmites australis and Typha latifolia, to a month-long summer drought in a mesocosm experiment. We followed the fate of carbon from leaves to sediment microbial communities with 13 CO2 pulse labelling and microbial phospholipid-derived fatty acid (PLFA) analysis. We found that drought reduced the total amount of carbon allocated to stem tissues but did not delay the transport. We also observed an increase in accumulation of 13 C labelled sugars in roots and found a reduced incorporation of 13 C into the PLFAs of sediment microorganisms. Drought induced a switch in plant carbon allocation priorities, where stems received less new assimilates leading to reduced starch reserves whilst roots were prioritised with new assimilates, suggesting their use for osmoregulation. There were indications that the reduced carbon transfer from roots to microorganisms was due to the reduction of microbial activity via direct drought effects rather than to a decrease in root exudation or exudate availability. PMID- 27465781 TI - Lipoplex-Mediated Deintercalation of Doxorubicin from Calf Thymus DNA-Doxorubicin Complex. AB - In this paper, we report the lipoplex-mediated deintercalation of anticancer drug doxorubicin (DOX) from the DOX-DNA complex under controlled experimental conditions. We used three zwitterionic liposomes, namely, 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC), which are widely different in their phase transition temperatures to form a lipoplex with calf thymus DNA in the presence of Ca(2+) ions. The study revealed that DPPC being in sol-gel phase was more effective in releasing the drug from the DOX-DNA complex compared with liposomes that remain in liquid crystalline phase (DMPC and POPC). The higher extent of drug release in the case of DPPC liposomes was attributed to the stronger lipoplex formation with DNA as compared with that of other liposomes. Owing to the relatively smaller head group area, the DPPC liposomes in their sol-gel phase can absorb a larger number of Ca(2+) ions and hence offer a strong electrostatic interaction with DNA. This interaction was confirmed by time-resolved anisotropy and circular dichroism spectroscopy. Apart from the electrostatic interaction, the possible hydrophobic interaction between the liposomes and DNA was also taken into account for the observed deintercalation. The successful uptake of drug molecules by liposomes from the drug-DNA complex in the post-release period was also confirmed using confocal laser scanning microscopy (CLSM). PMID- 27465782 TI - Long-term sexual outcomes after holmium laser enucleation of the prostate: which patients could benefit the most? AB - Assess rate and predictors of erectile function (EF) outcomes at long-term follow up (FU) after holmium laser enucleation of the prostate (HoLEP). Cross-sectional analyses were performed on 135 patients with a mean FU of 12 years post HoLEP. Patients completed both a baseline and a FU International Index of Erectile Function (IIEF)-EF domain and the International Prostatic Symptoms Score (IPSS). Postoperative EF outcomes, including rate and predictors of EF improvement considering minimal clinically important differences (MCIDs) criteria, were assessed. Logistic regression models tested the association between predictors and EF. At a mean (median) FU of 152.1 (163) months, patients showed a significant decrease in the IIEF-EF score P<0.01) and significant IPSS improvement (P<0.01). Overall, 50 (37%) patients worsened by at least one IIEF-EF category. Conversel, 23 (17%) patients reported an improvement in postoperative IIEF-EF score; 75 (55.6%) and 10 (7.4%) patients maintained and eventually improved their IIEF-EF category, respectively. Patients reporting a decrease in the postoperative IIEF-EF score were significantly older (P=0.03) and showed a significantly longer mean FU (P<0.01) than those reporting postoperative improvements of IIEF-EF. Nine (6.7%) patients showed significant EF improvement according to MCIDs criteria. Both higher IPSS scores (odds ratio (OR): 1.12; P=0.02) and lower IIEF-EF (OR: 0.88; P<0.01) at baseline, emerged as independent predictors of postoperative EF improvement. HoLEP was associated with a decrease in EF and a persistent amelioration of BPH-related urinary symptoms at long-term FU. Almost one third of patients worsened by at least one IIEF-EF category. However, a clinically meaningful EF improvement was observed in roughly 7% of the individuals. Patients with more severe preoperative urinary symptoms and ED benefited more from HoLEP in terms of EF. PMID- 27465783 TI - Where there is hope: a qualitative study examining patients' adherence to multi drug resistant tuberculosis treatment in Karakalpakstan, Uzbekistan. AB - BACKGROUND: Treatment for multi-drug resistant tuberculosis (MDR-TB) is lengthy, has severe side effects, and raises adherence challenges. In the Medecins Sans Frontieres (MSF) and Ministry of Health (MoH) programme in Karakalpakstan, Uzbekistan, a region with a high burden of MDR-TB, patient loss from treatment (LFT) remains high despite adherence support strategies. While certain factors associated with LFT have been identified, there is limited understanding of why some patients are able to adhere to treatment while others are not. We conducted a qualitative study to explore patients' experiences with MDR-TB treatment, with the aim of providing insight into the barriers and enablers to treatment-taking to inform future strategies of adherence support. METHODS: Participants were purposively selected. Programme data were analysed to enable stratification of patients by adherence category, gender, and age. 52 in-depth interviews were conducted with MDR-TB patients (n = 35) and health practitioners (n = 12; MSF and MoH doctors, nurses, and counsellors), including five follow-up interviews. Interview notes, then transcripts, were analysed using coding to identify emerging patterns and themes. Manual analysis drew upon principles of grounded theory with constant comparison of codes and categories within and between cases to actively seek discrepancies and generate concepts from participant accounts. Ethics approval was received from the MoH of the Republic of Uzbekistan Ethics Committee and MSF Ethics Review Board. RESULTS: Several factors influenced adherence. Hope and high quality knowledge supported adherence; autonomy and control enabled optimal engagement with treatment-taking; and perceptions of the body, self, treatment, and disease influenced drug tolerance. As far as we are aware, the influence of patient autonomy and control on MDR-TB treatment-taking has not previously been described. In particular, the autonomy of married women around treatment-taking was potentially undermined through their societal position as daughter-in-law, compromising their ability to adhere to treatment. Patients' engagement with and adherence to treatment could be hindered by hierarchical practitioner-patient relationships that displaced authority, ownership, and responsibility from the patient. CONCLUSIONS: Our findings reinforce the need for an individualised and holistic approach to adherence support with engagement of patients as active participants in their care who feel ownership and responsibility for their treatment. PMID- 27465784 TI - Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold. AB - The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1-C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum-deprived conditions and enhancement of nerve growth factor (NGF)-induced neurite outgrowth in PC12 neuronal cells. p-Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25 MUm. Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF-induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5 MUm led to 25- and 22-fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases. PMID- 27465785 TI - Fingolimod hydrochloride gel shows promising therapeutic effects in a mouse model of atopic dermatitis. AB - OBJECTIVES: To assess the efficacy of topically applied 2% hydroxypropyl cellulose gels containing 0.5% fingolimod hydrochloride (FNGL) with or without 6% colloidal oatmeal in an in vivo model of atopic dermatitis (AD). METHODS: AD-like lesions were induced in SKH1/Hr hairless mice and were treated with FNGL gels, non-medicated base gels and Elidel((r)) cream for 6 weeks. The severity/improvement of the lesions was assessed regularly using the Eczema Area and Severity Index (EASI), pH of the skin, transepidermal water loss, g/m(2) /h (TEWL), humidity and temperature. At the end of the experiments, the plasma levels of cytokines, FNGL and white blood cells were determined. KEY FINDINGS: The EASI score was almost unchanged for the vehicle-only groups compared to before the treatments, whereas the medicated groups showed a significant decrease in the overall EASI score (P < 0.01), although there was non-significant differences among them (P > 0.081). Both the FNGL groups also showed a significant (P ? 0.05) reduction in blood WBC. CONCLUSION: This study shows that the gels containing 0.50% FNGL and FNGL 0.50% plus 6% colloidal oatmeal have potential for the treatment of AD. The presence of colloidal oatmeal may provide additional benefits. PMID- 27465786 TI - Programmed Death-Ligand 1 Expression Is Common in Gastric Cancer Associated With Epstein-Barr Virus or Microsatellite Instability. AB - Blockade of the programmed death 1 (PD-1) pathway has emerged as a novel therapy for cancer. Therefore, development of biomarkers for response prediction, such as PD-ligand 1 (PD-L1) expression by immunohistochemistry, may help to stratify patients. Solid tumors with CD8 T-cell rich tumor microenvironment have been implicated to be associated with increased PD-L1 expression. We hypothesized that gastric cancers associated with Epstein-Barr virus infection (EBV+) or microsatellite instability (MSI), both of which are known to harbor such tumor microenvironment, are associated with increased PD-L1 expression. Forty-four resected gastric cancers including 7 EBV+, 16 MSI, and 21 microsatellite stable cancers without EBV (EBV-/MSS) were studied for PD-L1 expression and T-cell subpopulations by immunohistochemistry. Positive PD-L1 expression (PD-L1+), defined as membranous staining in either tumor cells or tumor immune infiltrates, was seen in 32 (72%) gastric cancers. EBV+ or MSI cancers showed significantly higher rates of PD-L1+ compared with EBV-/MSS cancers (7/7, 100%; 14/16, 87%; 11/21, 52%; P=0.013). PD-L1+/EBV+ and PD-L1+/MSI cancers had significantly more CD8 T cells at tumor invasive front than PD-L1+/EBV-/MSS cancers (P<0.001). PD L1+ was not associated with the depth of invasion or nodal metastasis (P=0.534, 0.288). Multivariate analysis showed PD-L1+ was not an independent predictor of disease-free survival while MSI was (P=0.548, 0.043). In summary, EBV+ or MSI gastric cancers are more likely to express PD-L1 and have increased CD8 T cells at tumor invasive front than EBV-/MSS cancers. Our results suggest EBV infection and MSI should be investigated for predicting response to PD-1 blockade. PMID- 27465787 TI - Enantiomers of tetrahedral metal-organic cages: a new class of highly efficient G quadruplex ligands with potential anticancer activities. AB - Four pairs of enantiomers of water-stable tetrahedral metal-organic cages [Ni4L6](8+) were facilely synthesized. They efficiently stabilized antiparallel G quadruplex DNA with moderate enantioselectivity, and displayed promising cytotoxicity against the human cancer cell lines HCT116, HepG2 and MCF-7. These results provide a new insight into the rational design of chiral G-quadruplex based anticancer agents. PMID- 27465788 TI - Correspondence on: A Hyaluronic Acid-Rich Node and Duct System in Which Pluripotent Adult Stem Cells Circulate. AB - The origin of the wide spread node and duct system described by Rai et al. remains a mystery. The explanation came when another study on yolk sack hemopoiesis was compared with the "primo vascular system". It came out that the yolk sack hematogenic tissue, introduced to the embryo by the vitelline veins, does not disappear in adults, but continues to exist in form of nods and ducts along blood vessels and different organs. PMID- 27465789 TI - In vitro characterization of acelluar porcine adipose tissue matrix for use as a tissue regenerative scaffold. AB - This study evaluated a novel approach to decellularizing porcine adipose tissue while preserving its 3-D architecture. An ethanol-water mixture was used as a solvent to remove lipids and the number of freeze-thaw cycles (1-7), ethanol concentration, and tissue thickness were tested. Trypsin incubation time (1-3 h) and xylene immersion time were investigated separately. Processed sample microarchitecture was analyzed via scanning electron microscope, cellular content was analyzed via hematoxylin and eosin (H&E) staining, and DNA content was analyzed using gel electrophoresis. Tensile testing and five-stage incremental stress-relaxation testing was performed in phosphate-buffered saline at 37 degrees C. Human neuroblasts were seeded and evaluated for infiltration and attachment over 8 days. Four cycles of freeze-thaw in 50% ethanol-water mixture removed one-third of the lipids. Microarchitecture showed the presence of pores, capillary channels, and lack of sidedness; H&E micrographs confirmed unaltered morphology and absence of cells. Incubation for 1.5 h in trypsin removed 99.5% DNA from delipidized samples. An average of 40% rehydration swelling, an elastic modulus of 324(+/-141) kPa, and an ultimate tensile strength of 87.4(+/-23.1) kPa were observed. The matrix exhibited strain hardening behavior similar to small intestinal submucosa. Cells successfully infiltrated and spread in the decellularized scaffold. Removal of lipids significantly reduced incubation in trypsin EDTA. In summary, the acellular matrix shows significant potential as a new template for tissue regeneration. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3127-3136, 2016. PMID- 27465790 TI - Antral bony wall erosion, trigeminal nerve injury, and enophthalmos after root canal surgery. AB - INTRODUCTION: The frequently used irrigant in dental surgery, sodium hypochlorite, is occasionally the cause of minor, usually circumscribed, adverse effects. Severe, extensive complications, with lasting sequelae, however, also can occur, as in the case we report herein. CASE REPORT: A 55-year-old woman underwent an endodontic procedure on a maxillary molar, whose roots, unknown to the surgeon, were protruding into the maxillary sinus. After sodium hypochlorite root canal irrigation, the patient immediately developed intense facial pain, facial edema, and periorbital cellulitis. An emergency department evaluation diagnosed an intense inflammatory disease of the maxillary sinus, with significant destruction of its bony walls, accompanied by midface paraesthesia due to infraorbital nerve injury. In the following weeks, the patient slowly developed enophthalmos due to bone erosion of the orbit floor. Treatment, besides prolonged oral steroids, required the endoscopic endonasal opening of the maxillary sinus for profuse irrigation. Two years later, the patient maintained a complete loss of function of the maxillary sinus, anesthesia-paraesthesia of the midface, and inferior dystonia of the eye with an enophthalmos. CONCLUSION: Dentists, maxillofacial surgeons, and otorhinolaryngologists should all be aware of the whole spectrum of complications of even the simplest dental work. Sodium hypochlorite irrigations should be used cautiously in root canal surgery, with the full awareness of its potential for causing soft-tissue damage. PMID- 27465791 TI - alpha1-Antitrypsin deficiency. AB - alpha1-Antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in SERPINA1, leading to liver and lung disease. It is not a rare disorder but frequently goes underdiagnosed or misdiagnosed as asthma, chronic obstructive pulmonary disease (COPD) or cryptogenic liver disease. The most frequent disease-associated mutations include the S allele and the Z allele of SERPINA1, which lead to the accumulation of misfolded alpha1-antitrypsin in hepatocytes, endoplasmic reticulum stress, low circulating levels of alpha1 antitrypsin and liver disease. Currently, there is no cure for severe liver disease and the only management option is liver transplantation when liver failure is life-threatening. A1ATD-associated lung disease predominately occurs in adults and is caused principally by inadequate protease inhibition. Treatment of A1ATD-associated lung disease includes standard therapies that are also used for the treatment of COPD, in addition to the use of augmentation therapy (that is, infusions of human plasma-derived, purified alpha1-antitrypsin). New therapies that target the misfolded alpha1-antitrypsin or attempt to correct the underlying genetic mutation are currently under development. PMID- 27465792 TI - BODIPY-Appended 2-(2-Pyridyl)benzimidazole Platinum(II) Catecholates for Mitochondria-Targeted Photocytotoxicity. AB - Platinum(II) complexes of the type [Pt(L)(cat)] (1 and 2), in which H2 cat is catechol and L represents two 2-(2-pyridyl)benzimidazole ligands with 4,4 difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) pendants, were synthesized to achieve mitochondria-targeted photocytotoxicity. The complexes showed strong absorptions in the range lambda=510-540 nm. Complex 1 exhibited intense emission at lambda=525 nm in 1 % DMSO/water solution (fluorescence quantum yield of 0.06). Nanosecond transient absorption spectral features indicated an enhanced population of the triplet excited state in di-iodinated complex 2. The generation of singlet oxygen by complex 2 upon exposure to visible light, as evidenced from experiments with 1,3-diphenylisobenzofuran, is suitable for photodynamic therapy because of the remarkable photosensitizing ability. The complexes resulted in excellent photocytotoxicity in HaCaT cells (half maximal inhibitory concentration IC50 ~3 MUm, lambda=400-700 nm, light dose=10 J cm(-2) ), but they remained non toxic in the dark (IC50 >100 MUm). Confocal microscopy images of 1 and Pt estimation from isolated mitochondria showed colocalization of the complexes in the mitochondria. Complex 2 displayed generation of reactive oxygen species induced by visible light, disruption of the mitochondrial membrane potential, and apoptosis. PMID- 27465793 TI - Vascular access registry of Serbia: a 4-year experience. AB - PURPOSE: Adequate and functional long-term vascular access (VA) is pivotal for the efficient hemodialysis (HD). It has been shown that the most reliable VA is autogenous arteriovenous fistulas (AVFs) as compared with arteriovenous grafts (AVGs) and vascular catheters (VCs). The vascular access register (VAR) has been established since 2010, and the 4-year trend of VA in Serbia is presented in this paper. METHODS: All HD centers in Serbia provided their data by fulfilling the questionnaire that included prevalent and incident HD patients on December 31, 2010-1013. RESULTS: AVF is the most frequent prevalent VA (89.5-93.1 %) and also the most frequent newly created VA (87-89 %) during the observational period. The number of preemptive AVF is increasing, but it is still low (7.8 % in 2010 and 14.6 % in 2013). The percentage of incident AVG is constant (~3.4 %) as well as the number of permanent VC (8.2 % in 2010 and 7.8 % in 2013). The number of incident patients who started HD with AVF is decreasing (from 37 to 27 %), and the number of urgent start with VC is on the increase (from 63 to 73 %). In almost all relevant dialysis centers, vascular access is created by surgeons. Temporal VCs are placed by anesthesiologists (all centers), nephrologists (up to 25 % of centers) and vascular surgeons (up to 20 %). VCs are located mainly in jugular vein, but the number of femoral catheters remains high (up to 69 %). CONCLUSION: Although we have favorable data, the VAR is of a great importance and ensures continuous quality improvement. PMID- 27465794 TI - Sclerostin as a new key factor in vascular calcification in chronic kidney disease stages 3 and 4. AB - BACKGROUND: Sclerostin is an osteocyte-derived inhibitor of the Wnt pathway and has been shown to play a key role in chronic kidney disease-mineral and bone disorder (CKD-MBD). The present study aimed to validate its potential as a predictor of vascular calcification in patients with CKD stages 3-4. METHODS: A total of 97 patients with CKD stages 3-4 were enrolled in this cross-sectional study. Routine clinical biochemistry tests and assays for sclerostin and mineral metabolism markers were performed. Additionally, vascular calcification was assessed by multislice spiral computed tomography. Logistic regression analyses were used to study the relationships between sclerostin and vascular calcification. RESULTS: Serum sclerostin levels (30.8 +/- 6.4 vs. 41.7 +/- 12.6 pmol/L, P < 0.05) were significantly elevated in patients with CKD stage 3a compared to in controls and increased with the decline in glomerular filtration rates. Furthermore, patients with vascular calcification had higher serum sclerostin levels. Patients with sclerostin levels above the median value had increased the prevalence of vascular calcification. Multivariate analysis revealed that sclerostin levels were positively associated with vascular calcification. CONCLUSION: Our data indicate that sclerostin levels are elevated in patients with CKD and are associated with vascular calcification. Therefore, sclerostin may be used as a predictor of vascular calcification in the clinical setting. PMID- 27465795 TI - Potential diagnostic biomarkers for IgA nephropathy: a comparative study pre- and post-tonsillectomy. AB - OBJECTIVE: The proteins BAFF, ST6GALNAC2, C1GALT1, and COSMC in peripheral blood mononuclear cells (PBMCs) and plasma levels of IgA1 and galactose-deficient IgA1 (Gd-IgA1) are potential biomarkers for IgAN nephropathy. In this study, we comparatively studied the changes of those biomarkers before and after tonsillectomy. METHODS: Peripheral blood samples were obtained from 16 IgAN patients with pre- and post-tonsillectomy. IgAN was diagnosed based on results from analysis of percutaneous renal biopsy tissue. Peripheral blood samples from three patients without renal diseases (non-IgAN), before and after tonsillectomy, and 16 healthy controls were also examined. BAFF, ST6GALNAC2, C1GALT1, and COSMC mRNA levels in PBMCs were detected using real-time PCR. Plasma IgA1 content was measured by ELISA. Gd-IgA1 levels were determined using the VV lectin-ELISA method. RESULTS: BAFF, ST6GALNAC2, C1GALT1, and COSMC mRNA levels and the plasma concentrations of IgA1 and Gd-IgA1 in IgAN patients before tonsillectomy were significantly higher than those in healthy controls (P < 0.05). Tonsillectomy significantly increased the expression of BAFF and ST6GALNAC2, and plasma IgA1 level, while it downregulated that of C1GALT1 and COSMC (P < 0.05). However, in non-IgAN patients, tonsillectomy did not affect the mRNA levels of BAFF, ST6GALNAC2, C1GALT1, and COSMC, plasma IgA1 content and Gd-IgA1 level. Positive correlations were established between BAFF and IgA1 (r = 0.604, P < 0.01) and between ST6GALNAC2 and Gd-IgA1 (r = 0.623, P < 0.01). CONCLUSIONS: Tonsillectomy changes the mRNA levels of BAFF, ST6GALNAC2, C1GALT1, and COSMC in PBMCs, as well as the plasma IgA1 level in IgAN patients. BAFF and ST6GALNAC2 might regulate IgA1 secretion and O-glycosylation. PMID- 27465796 TI - The renal mitochondrial dysfunction in patients with vascular calcification is prevented by sodium thiosulfate. AB - PURPOSE: Vascular calcification (VC) is an impact of calcium accumulation in end stage renal diseases, normally initiated in the mitochondria. Sodium thiosulfate (STS) is effective in rescuing mitochondrial function in the neurovascular complications associated with VC, but has limitation in protecting the cardiac mitochondria. However, the STS efficacy in restoring the renal mitochondrial function has not been studied, which is the primary focus of this study. METHODS: Wistar rats (n = 6/group) were administered 0.75 % adenine in the diet for 28 days to induce renal failure. STS (400 mg/kg) was given in two regimens STS_Pre (preventive: along with adenine for 28 days) and STS_Cur (curative: 29th to 49th day). Renal failure was assessed by plasma and urinary markers. The effectiveness of treatment was assessed from oxidative stress, DNA damage, mitochondrial physiology and enzymology in the renal tissue. RESULTS: 0.75 % adenine diet caused renal medullary swelling, tubular interstitial nephropathy and impaired renal function (creatinine, urea, uric acid and ALP), which were recovered after STS treatment. The renal failure was due to oxidative stress as measured by elevated malondialdehyde (29 %) and lowered reduced glutathione (27 %) levels. STS reduced the lipid peroxidation and significantly (p < 0.05) elevated the antioxidant enzymes. Further, it improved renal mitochondrial respiratory capacity by maintaining the hyperpolarized membrane potential and restored the complex enzyme activities. Absence of renal DNA fragmentation supports the above findings. CONCLUSION: STS protects the kidney by preserving renal mitochondria, in experimental adenine-induced vascular calcified rats. The efficacy was prominent when given after induction, i.e., in STS_Cur group. PMID- 27465798 TI - Irreversible morphological changes of a graphite negative-electrode at high potentials in LiPF6-based electrolyte solution. AB - The degradation mechanism of a graphite negative-electrode in LiPF6-based electrolyte solution was investigated using the basal plane of highly oriented pyrolytic graphite (HOPG) as a model electrode. Changes in the surface morphology were observed by in situ atomic force microscopy. In the initial cathodic scan, a number of pits appeared at around 1.75 V vs. Li(+)/Li, and fine particles formed on the terrace of the HOPG basal plane at about 1.5 V vs. Li(+)/Li. The fine particles were characterized by spectroscopic analysis, such as X-ray photoelectron spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy. We added one of the components to LiClO4-based electrolyte solution, and successfully reproduced the formation of pits and fine particles on the basal plane of HOPG. Based on these results, the formation mechanisms of pits and fine particle layers were proposed. PMID- 27465797 TI - Activation of general control nonderepressible 2 kinase protects human glomerular endothelial cells from harmful high-glucose-induced molecular pathways. AB - PURPOSE: Considering the referred beneficial effects of protein restriction on diabetic nephropathy (DN) and the role of renal endothelium in its pathogenesis, we evaluated the effect of general control nonderepressible 2 (GCN2) kinase activation, a sensor of amino acid deprivation, on known detrimental molecular pathways in primary human glomerular endothelial cells (GEnC). METHODS: GEnC were cultured under normal or high-glucose conditions in the presence or not of the GCN2 kinase activator, tryptophanol. Glucose transporter 1 (GLUT1) expression was assessed by western blotting and reactive oxygen species (ROS) using a fluorogenic probe. Activities of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and protein kinase C (PKC) were assessed by commercial activity assays, sorbitol colorimetrically, methylglyoxal by ELISA and O-linked beta-N-acetyl glucosamine (O-GlcNAc)-modified proteins by western blotting. RESULTS: High glucose induced GLUT1 expression, increased ROS and inhibited GAPDH. Also it increased the polyol pathway product sorbitol, PKC activity, the level of the O-GlcNAc-modified proteins that produced by the hexosamine pathway and the advanced glycation endproducts' precursor methylglyoxal. Co-treatment of GEnC with tryptophanol restored the above high-glucose-induced alterations. CONCLUSIONS: Activation of GCN2 kinase protects GEnC from high-glucose-induced harmful molecular pathways. By inhibiting concurrently many pathways involved in DN pathogenesis, GCN2 kinase may serve as a pharmaceutical target for the treatment of DN. PMID- 27465799 TI - Negative prognostic impact of low absolute CD4+ T cell counts in peripheral blood in mantle cell lymphoma. AB - Tumor microenvironment and host immunity are closely related to outcome in patients with mantle cell lymphoma (MCL). However, few researchers have focused on the prognostic value of peripheral blood lymphocyte subsets counts. The purpose of this study was to investigate the prognostic value of lymphocyte subsets and absolute monocyte counts. Sixty-eight patients were analyzed retrospectively. Absolute CD4+ T cell counts (ACD4C), CD8+ T cell counts, nature killer cell counts, and CD4/CD8 ratios were assessed by peripheral blood flow cytometry and correlated with clinical parameters and long-term outcomes. The median follow-up for all patients was 21 months and the median survival time was 44 months. The overall survival (OS) rate at 1, 3, and 5 years was 80%, 51%, and 41%, respectively. In our cohort, high absolute monocyte count, and low ACD4C and CD4/CD8 ratio were associated with unfavorable OS (P = 0.029, P = 0.027, and P = 0.045, respectively) by univariate analysis. Multivariate analysis indicated that low ACD4C was a significant predictor of unfavorable OS (P = 0.004) independent of the simplified MCL International Prognostic Index (P = 0.048) in patients treated with or without rituximab (P = 0.011). Low CD4+ T cell counts proved to be a significant predictor of unfavorable OS in patients with MCL. PMID- 27465800 TI - Growth of epitaxial silicon nanowires on a Si substrate by a metal-catalyst-free process. AB - The growth of epitaxial Si nanowires by a metal-catalyst-free process has been investigated as an alternative to the more common metal-catalyzed vapor-liquid solid process. The well-aligned Si nanowires are successfully grown on a (111) oriented Si substrate without any metal catalysts by a thermal treatment using silicon sulfide as a Si source at approximately 1200 degrees C. The needle shaped Si nanowires, which have a core-shell structure that consists of a single crystalline Si core along the <111> direction consistent with the substrate direction and a surface coating of silicon oxide, are grown by a metal-catalyst free process. In this process, the silicon sulfide in the liquid phase facilitates the nucleation and nanowire growth. In contrast, oxygen-rich nanowires that consist of crystalline Si at the tip and lumpy silicon oxide on the body are observed in a sample grown at 1300 degrees C, which disturbs the epitaxial growth of Si nanowires. PMID- 27465801 TI - Biological optimization, the Goldilocks principle, and how much is lagom in the preimplantation embryo. AB - The quiet embryo hypothesis postulates that early embryo viability is associated with a relatively low metabolism (Leese, 2002 BioEssays 24: 845-849). This proposal is re-visited here using retrospective and prospective data on the metabolic activity and kinetics of preimplantation development alongside the concept that an optimal range of such indices and of energetic efficiency influences embryogenesis. It is concluded that these considerations may be rationalized by proposing the existence of a "Goldilocks zone," or as it is known in Sweden, of lagom-meaning "just the right amount"-within which embryos with maximum developmental potential can be categorized. Mol. Reprod. Dev. 83: 748 754, 2016 (c) 2016 Wiley Periodicals, Inc. PMID- 27465802 TI - Ontogeny reveals function and evolution of the hadrosaurid dinosaur dental battery. AB - BACKGROUND: Hadrosaurid dinosaurs, dominant Late Cretaceous herbivores, possessed complex dental batteries with up to 300 teeth in each jaw ramus. Despite extensive interest in the adaptive significance of the dental battery, surprisingly little is known about how the battery evolved from the ancestral dinosaurian dentition, or how it functioned in the living organism. We undertook the first comprehensive, tissue-level study of dental ontogeny in hadrosaurids using several intact maxillary and dentary batteries and compared them to sections of other archosaurs and mammals. We used these comparisons to pinpoint shifts in the ancestral reptilian pattern of tooth ontogeny that allowed hadrosaurids to form complex dental batteries. RESULTS: Comparisons of hadrosaurid dental ontogeny with that of other amniotes reveals that the ability to halt normal tooth replacement and functionalize the tooth root into the occlusal surface was key to the evolution of dental batteries. The retention of older generations of teeth was driven by acceleration in the timing and rate of dental tissue formation. The hadrosaurid dental battery is a highly modified form of the typical dinosaurian gomphosis with a unique tooth-to-tooth attachment that permitted constant and perfectly timed tooth eruption along the whole battery. CONCLUSIONS: We demonstrate that each battery was a highly dynamic, integrated matrix of living replacement and, remarkably, dead grinding teeth connected by a network of ligaments that permitted fine scale flexibility within the battery. The hadrosaurid dental battery, the most complex in vertebrate evolution, conforms to a surprisingly simple evolutionary model in which ancestral reptilian tissue types were redeployed in a unique manner. The hadrosaurid dental battery thus allows us to follow in great detail the development and extended life history of a particularly complex food processing system, providing novel insights into how tooth development can be altered to produce complex dentitions, the likes of which do not exist in any living vertebrate. PMID- 27465803 TI - mHealth for Schizophrenia: Patient Engagement With a Mobile Phone Intervention Following Hospital Discharge. AB - BACKGROUND: mHealth interventions that use mobile phones as instruments for illness management are gaining popularity. Research examining mobile phone-based mHealth programs for people with psychosis has shown that these approaches are feasible, acceptable, and clinically promising. However, most mHealth initiatives involving people with schizophrenia have spanned periods ranging from a few days to several weeks and have typically involved participants who were clinically stable. OBJECTIVE: Our aim was to evaluate the viability of extended mHealth interventions for people with schizophrenia-spectrum disorders following hospital discharge. Specifically, we set out to examine the following: (1) Can individuals be engaged with a mobile phone intervention program during this high-risk period?, (2) Are age, gender, racial background, or hospitalization history associated with their engagement or persistence in using a mobile phone intervention over time?, and (3) Does engagement differ by characteristics of the mHealth intervention itself (ie, pre-programmed vs on-demand functions)? METHODS: We examined mHealth intervention use and demographic and clinical predictors of engagement in 342 individuals with schizophrenia-spectrum disorders who were given the FOCUS mobile phone intervention as part of a technology-assisted relapse prevention program during the 6-month high-risk period following hospitalization. RESULTS: On average, participants engaged with FOCUS for 82% of the weeks they had the mobile phone. People who used FOCUS more often continued using it over longer periods: 44% used the intervention over 5-6 months, on average 4.3 days a week. Gender, race, age, and number of past psychiatric hospitalizations were associated with engagement. Females used FOCUS on average 0.4 more days a week than males. White participants engaged on average 0.7 days more a week than African-Americans and responded to prompts on 0.7 days more a week than Hispanic participants. Younger participants (age 18-29) had 0.4 fewer days of on-demand use a week than individuals who were 30-45 years old and 0.5 fewer days a week than older participants (age 46-60). Participants with fewer past hospitalizations (1-6) engaged on average 0.2 more days a week than those with seven or more. mHealth program functions were associated with engagement. Participants responded to prompts more often than they self-initiated on-demand tools, but both FOCUS functions were used regularly. Both types of intervention use declined over time (on-demand use had a steeper decline). Although mHealth use declined, the majority of individuals used both on-demand and system-prompted functions regularly throughout their participation. Therefore, neither function is extraneous. CONCLUSIONS: The findings demonstrated that individuals with schizophrenia-spectrum disorders can actively engage with a clinically supported mobile phone intervention for up to 6 months following hospital discharge. mHealth may be useful in reaching a clinical population that is typically difficult to engage during high-risk periods. PMID- 27465804 TI - Steroidal estrogen sources in a sewage-impacted coastal ocean. AB - Estrogens are known to be potent endocrine disrupting chemicals that are commonly found in wastewater effluents at ng L(-1) levels. Yet, we know very little about the distribution and fate of estrogens in coastal oceans that receive wastewater inputs. This study measured a wide range of steroidal estrogens in sewage impacted seawater using ultra high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) together with the method of standard addition. In Massachusetts Bay, we find conjugated, free, and halogenated estrogens at concentrations that are consistent with dilution at sites close to the sewage source. At a site 6 miles down current of the sewage source, we observe estrone (E1) concentrations (520 +/- 180 pg L(-1)) that are nearly double the nearfield concentrations (320 +/- 60 pg L(-1)) despite 9-fold dilution of carbamazepine, which was used as a conservative sewage tracer. Our results suggest that background E1 concentrations in Massachusetts Bay (~270 +/- 50 pg L(-1)) are derived largely from sources unrelated to wastewater effluent such as marine vertebrates. PMID- 27465805 TI - A novel strategy towards designing a CdSe quantum dot-metallohydrogel composite material. AB - We have described here an efficient method to disperse hydrophobic CdSe quantum dots (QDs) in an aqueous phase using cetyltrimethylammonium bromide (CTAB) micelles without any surface ligand exchange. The water soluble QDs were then embedded in 3D self assembled fibrillar networks (SAFINs) of a hydrogel showing homogeneous dispersibility as evidenced from optical and electron microscopic techniques. The photophysical studies of the hydrogel-QD composite are reported for the first time. These composite materials may have potential applications in biology, optoelectronics, sensors, non-linear optics and materials science. PMID- 27465806 TI - Constructing representations of spatial location from briefly presented displays. AB - Spatial memory and reasoning rely heavily on allocentric (often map-like) representations of spatial knowledge. While research has documented many ways in which spatial information can be represented in allocentric form, less is known about how such representations are constructed. For example: Are the very early, pre-attentive parts of the process hard-wired, or can they be altered by experience? We addressed this issue by presenting sub-saccadic (53 ms) masked stimuli consisting of a target among one to three reference features. We then shifted the location of the feature array, and asked participants to identify the target's new relative location. Experience altered feature processing even when the display duration was too short to allow attention re-allocation. The results demonstrate the importance of early perceptual processes in the creation of representations of spatial location, and the malleability of those processes based on experience and expectations. PMID- 27465807 TI - Impact of cytomegalovirus reactivation on clinical outcomes in immunocompetent critically ill patients: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Cytomegalovirus (CMV) reactivation in critically ill patients is a well-recognized phenomenon with an incidence as high as 71 %. A number of studies have investigated the association between CMV reactivation and outcomes in critically ill patients with conflicting results. We propose to conduct a systematic review and meta-analysis to determine the impact of CMV reactivation on patient-centered outcomes and measures of health resource utilization in immunocompetent critically ill patients. METHODS: In consultation with a research librarian, a search strategy will be developed and electronic databases (i.e., Ovid MEDLINE, Ovid EMBASE, and the Cochrane Library including the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials (CENTRAL)) will be searched for original studies. Selected grey literature sources will be hand-searched. Search themes will include cytomegalovirus, intensive care unit, and sepsis. Citation screening, selection, quality assessment, and data abstraction will be performed in duplicate. Pooled effect estimates of the impact of CMV reactivation on selected patient-centered outcomes and measures of health resource utilization will be described. DISCUSSION: This systematic review aims to explore the impact of CMV reactivation on patient centered outcomes and health resource utilization in immunocompetent critically ill patients. Our results will help to better define the burden of disease associated with CMV reactivation. Indeed, evidence to date suggests increased mortality in this patient population. However, the relationship between CMV reactivation and health resource utilization remains less clear. Based on our results, future study on the impact of CMV treatment or prophylaxis on outcomes (including those other than mortality) may be warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016035446. PMID- 27465808 TI - Identifying Needs: a Qualitative Study of women's Experiences Regarding Rapid Genetic Testing for Hereditary Breast and Ovarian Cancer in the DNA BONus Study. AB - Genetic testing for hereditary breast and ovarian cancer is increasingly being offered in newly diagnosed breast and ovarian cancer patients. This genetic information may influence treatment decisions. However, there are some concerns that genetic testing offered in an already vulnerable situation might be an extra burden to these women. The aim of this study was to explore the experiences of women who had been offered and accepted genetic testing when newly diagnosed with breast or ovarian cancer. Four semi-structured focus-group interviews were conducted with 17 women recruited from a Norwegian multicenter study. The material was condensed, and conventional qualitative analysis was used to identify patterns in the participants' descriptions. Three core themes were identified: 1) being "beside oneself" 2) altruism and ethical dilemmas 3) the need for support and counselling to assist the decision process. The present study indicates that women who are offered genetic testing when newly diagnosed with breast or ovarian cancer want a consultation with a health professional. Personalized support and counselling might empower women to improve their ability to manage and comprehend this overwhelming situation, and find meaning in this experience. PMID- 27465809 TI - A Qualitative Study of Anticipated Decision Making around Type 2 Diabetes Genetic Testing: the Role of Scientifically Concordant and Discordant Expectations. AB - Type 2 diabetes mellitus (T2DM) genetic testing is undergoing clinical trials to measure the efficacy of genetic counseling for behavior-based risk reduction. The expectations patients bring to the testing process may play an important role in individual outcomes. We conducted a qualitative exploration of anticipated decision-making and expectations around T2DM genetic testing. Semi-structured interviews were completed with Mexican Americans (n = 34), non-Hispanic Black Americans (n = 39), and non-Hispanic White Americans (n = 39) at risk for T2DM. Transcripts were analyzed for themes. Most participants would accept T2DM genetic testing in order to motivate risk-reducing behaviors or apprise family members of their risk. Participants who would decline testing wished to avoid emotional distress or believed the test would not reveal new risk information. Non-Hispanic Whites and those with college education declined genetic testing more often than other groups. Those without college education were more likely to have testing expectations that were discordant with current science, such as conflating genetic testing with common 'blood tests.' Understanding expectations and decision-making factors around T2DM genetic testing will better prepare healthcare professionals to counsel their patients. This may lead to a higher efficacy of T2DM genetic testing and counseling. PMID- 27465810 TI - Mechanical Failure of Endocrowns Manufactured with Different Ceramic Materials: An In Vitro Biomechanical Study. AB - PURPOSE: To evaluate the effect of different silica-based ceramic materials on the mechanical failure behavior of endocrowns used in the restoration of endodontically treated mandibular molar teeth. MATERIALS AND METHODS: Thirty-six intact mandibular molar teeth extracted because of a loss of periodontal support received root canal treatment. The teeth were prepared with a central cavity to support the endocrowns, replacing the occlusal surface with mesial-lingual-distal walls. Data acquisition of the prepared tooth surfaces was carried out digitally with a powder-free intraoral scanner. Restoration designs were completed on manufactured restorations from three silicate ceramics: alumina-silicate (control), zirconia-reinforced (Zr-R), and polymer-infiltrated (P-I). Following adhesive cementation, endocrowns were subjected to thermal aging, and then, each specimen was obliquely loaded to record the fracture strength and define the mechanical failure. For the failure definition, the fracture type characteristics were identified, and further analytic measurements were made on the fractured tooth and ceramic structure. RESULTS: Load-to-fracture failure did not differ significantly, and the calculated mean values were 1035.08 N, 1058.33 N, and 1025.00 N for control, Zr-R, and P-I groups, respectively; however, the stiffness of the restoration-tooth complex was significantly higher than that in both test groups. No statistically significant correlation was established in paired comparisons of the failure strength, restorative stiffness, and fractured tooth distance parameters. The failure mode for teeth restored with zirconia-reinforced glass ceramics was identified as non-restorable. The resin interface in the control and P-I groups presented similar adhesive failure behavior. CONCLUSION: Mechanical failure of endocrown restorations does not significantly differ for silica-based ceramics modified either with zirconia or polymer. PMID- 27465812 TI - Construct and Predictive Validity of a Cystoscopic Checklist to Evaluate Surgical Competency in the Operating Room. AB - PURPOSE: The aim of this study was to demonstrate the construct and predictive validity of a task-specific checklist for cystoscopy in the operating room. METHODS: This study is a prospective observational study evaluating the validity of a task-specific checklist for cystoscopic proficiency on residents performing cystoscopy in the operating room over a 4-year period. Residents were scored on 2 task-specific checklists: (1) assembly and (2) performance of a diagnostic cystoscopy. Construct validity was evaluated by comparing absolute checklist scores based on resident year with a Kruskal-Wallis and chi test, respectively. Paired analysis was performed with Wilcoxon sign rank and McNemar tests to assess differences between initial and final observations. Predictive validity was evaluated by determining the percent of competently performed task-specific checklists subsequent to 1 competent task-specific checklist completion. RESULTS: One hundred fifty-three evaluations were performed on 30 residents from all 4 levels of training. The median task-specific checklist scores for both (1) assembly and (2) performance of a diagnostic cystoscopy demonstrated construct validity with statistically significant trends demonstrating improved scores as resident year increased from intern to chief, P values of <0.001 and <0.0001, respectively. Once competency was obtained for 1 cystoscope assembly checklist, 92% of future assembly checklists were competently competent. For diagnostic cystoscopy once checklist competency was obtained, 69% of future checklists were completed competently. All scores and competencies were significantly improved from the initial to the final observation. DISCUSSION: The task-specific checklists for (1) assembly and (2) performance of a diagnostic cystoscopy demonstrated construct validity. Predicative validity for assembly of a cystoscope is high but less so for performance of a diagnostic cystoscope. PMID- 27465813 TI - Subjective and Objective Outcomes of Robotic and Vaginal High Uterosacral Ligament Suspension. AB - OBJECTIVES: This study was designed to assess the short-term outcomes in patients undergoing robotic or transvaginal high uterosacral ligament suspension for symptomatic apical prolapse at the time of hysterectomy. METHODS: This retrospective study used hospital and office electronic medical records to identify patients with symptomatic stage 2 to 4 prolapse, who had undergone either a robotic or transvaginal high uterosacral ligament suspension from July 2010 to January 2014. The database was searched using procedural codes for uterosacral ligament suspension. Each patient was contacted 1 year postoperatively to answer the pelvic floor distress inventory-20 via telephone, and this was compared to their initial preprocedural baseline questionnaire. RESULTS: Our primary outcome included the fulfillment of 3 criteria: (1) Prolapse leading edge of 0 or less and apex of 1/2 total vaginal length or less; (2) the absence of pelvic organ prolapse symptoms as reported on the pelvic floor distress inventory-20 question No. 3; and (3) no prolapse reoperations or pessary use during the study period. Ninety-two percent (24/26) in the robotic group and 85% (36/42) in the vaginal group (P = 0.46) successfully fulfilled these outcome criteria. There was no significant difference in the operative data between the 2 groups. There were no intraoperative complications in either group. CONCLUSIONS: These short-term outcomes are promising and show a high success rate for the uterosacral ligament suspension at the time of a hysterectomy regardless of whether it was performed vaginally or robotically. PMID- 27465811 TI - Associations between male testosterone and immune function in a pathogenically stressed forager-horticultural population. AB - OBJECTIVES: Despite well-known fitness advantages to males who produce and maintain high endogenous testosterone levels, such phenotypes may be costly if testosterone-mediated investment in reproductive effort trade-off against investment in somatic maintenance. Previous studies of androgen-mediated trade offs in human immune function find mixed results, in part because most studies either focus on a few indicators of immunity, are confounded by phenotypic correlation, or are observational. Here the association between male endogenous testosterone and 13 circulating cytokines are examined before and after ex vivo antigen stimulation with phytohemagglutinin (PHA) and lipopolysaccharides (LPS) in a high pathogen population of Bolivian forager-horticulturalists. MATERIALS AND METHODS: A Milliplex 13-plex cytokine panel measured cytokine concentration in whole blood samples from 109 Tsimane men aged 40-89 (median = 50 years) before and after antigen stimulation with PHA and LPS. Urinary testosterone was measured via enzyme immunoassay, demographic, and anthropometric data were collected as part of the Tsimane Health and Life History Project. RESULTS: Higher endogenous testosterone was associated with down-regulated responses in all cytokines after PHA stimulation (but significantly in only 2/13 cytokines), controlling for age and body mass index. In contrast, testosterone was not significantly associated with down-regulation of cytokines after LPS stimulation. MANOVAs indicate that men with higher testosterone showed reduced cytokine responses to PHA compared with LPS (p = 0.0098). DISCUSSION: Endogenous testosterone appears to be immunomodulatory rather than immunosuppressive. Potentially costlier forms of immune activation like those induced by PHA (largely T-cell biased immune activation) are down-regulated in men with higher testosterone, but testosterone has less impact on potentially less costly immune activation following LPS stimulation (largely B-cell mediated immunity). PMID- 27465814 TI - Recurrent Urinary Tract Infection After Midurethral Sling: A Retrospective Study. AB - OBJECTIVES: Our primary objective was to estimate the proportion of patients with culture-proven urinary tract infection (UTI) and recurrent UTI after midurethral sling (MUS), as well as to evaluate their risk factors. Our secondary objective was to characterize the difference in the proportion of patients with recurrent UTI before and after MUS. METHODS: We conducted a retrospective study of patients who underwent MUS from 2009 to 2012 within a large health maintenance organization and subsequently had documentation of at least 1 positive urine culture (>100 K CFU/mL) within 1 year. Validated procedural and diagnostic codes were used to identify patients undergoing MUS and the diagnosis of UTI, respectively. RESULTS: Of the 7461 MUS performed, 883 (12%) patients had at least 1 culture-proven UTI and 258 (3.5%) patients met the definition of recurrent UTI postoperatively. Of those 883 patients, 89 (10%) patients met the definition of recurrent UTI before, and 258 (29%) patients after, MUS. McNemar chi test revealed that patients were more likely to have recurrent UTI after MUS compared with before (P < 0.0001). In multivariate logistic regression, Caucasian (odds ratio [OR], 1.60, 95% confidence interval [95% CI], 1.12-2.29; P = 0.01) and African-American (OR, 3.42; 95% CI, 1.42-8.29; P = 0.01) ethnicity, older age (OR, 1.02; 95% CI, 1.00-1.04; P = 0.03), and a history of recurrent UTI (OR 3.79, 95% CI 1.88-7.93, P = 0.0003) were risk factors for postoperative recurrent UTI. CONCLUSIONS: In this population, preoperative recurrent UTI was the only modifiable risk factor associated with an increased risk of postoperative recurrent UTI. PMID- 27465815 TI - The Association Between Levator-Urethra Gap Measurements and Symptoms and Signs of Female Pelvic Organ Prolapse. AB - OBJECTIVES: Levator avulsion is associated with pelvic organ prolapse in women. It is diagnosed clinically by a widened gap on palpation between the insertion of the puborectalis muscle on the inferior pubic ramus and the urethra. This gap can also be assessed on imaging. This study aimed to determine the association between sonographically determined levator-urethral gap (LUG) measurements and symptoms and signs of prolapse. METHODS: This is a retrospective study on 450 women seen in a tertiary urogynecological center for symptoms of pelvic floor dysfunction between January 2013 and February 2014. All had a standardized interview, International Continence Society Pelvic Organ Prolapse Quantification assessment and 4-dimensional translabial ultrasound. Post-imaging analysis of archived ultrasound volumes for LUG measurement was undertaken on tomographic slices at the plane of minimal hiatal dimensions and within 5-mm cranial to this plane, bilaterally at an interslice interval of 2.5 mm, blinded against all clinical data. A LUG of 25 mm or greater was considered abnormal. RESULTS: Mean LUG and maximum LUG in individuals were 22.5 mm (SD, 4.6) and 26.4 mm (SD, 6.0), respectively, with at least 1 abnormal LUG in 51% (n = 222). An abnormal LUG in all 3 slices involving the plane of minimal hiatal dimensions and within 5 mm cranial to this plane on at least 1 side was fulfilled in 24% (n = 103). The LUG measurements were strongly associated with bother, symptoms and signs of prolapse (P < 0.001 to 0.002). This remained significant on multivariate analysis controlling for potential confounding factors. CONCLUSIONS: Sonographically determined LUG is strongly associated with symptoms, symptom bother, and pelvic organ prolapse on clinical examination and imaging. PMID- 27465816 TI - A 2-Year Evaluation of Quality of Life Outcomes of Patients With Pelvic Organ Prolapse Treated With an Elevate Prolapse Repair System. AB - OBJECTIVES: To evaluate 2-year quality of life of women with pelvic organ prolapse submitted to prosthetic correction with Elevate. METHODS: We enrolled 116 consecutive patients with a stage >= to 2 prolapse. The Prolapse Quality of Life questionnaire was administered in the preoperative time and after 2 years of follow-up. The statistical results were obtained by using the SPSS Advanced StatisticalTM 11.0 Software. RESULTS: Patient's quality of life improved substantially following prosthetic vaginal surgery. In particular, a clear improvement in the "general state of patients health" (P < 0.05), and a reduction in the daily physical, social, and psychological quality of life (P < 0.05) connected to the prolapse of pelvic organ were observed. Furthermore, a significant reduction in the percentage of patients with urinal disturbances (86.2% preoperative vs 20.7% postoperative; P < 0.05), and an improvement in patient's relations with their partners with 12 patients resuming sexual activity were found. CONCLUSIONS: This study demonstrates that prosthetic vaginal correction represents a long-term efficient clinical instrument for women with symptomatic pelvic organ prolapse. It also achieves a resolution for urinary symptomatology and embarrassment, social limitation, physical and psychological difficulties of women, which, in great part, resulted in many overcoming surgical therapy, worried about fixed outcomes. PMID- 27465817 TI - The Incidence of Perioperative Adverse Events in the Very Elderly Undergoing Urogynecologic Surgery. AB - OBJECTIVES: To determine the incidence of perioperative adverse events in very elderly women (age >= 80 years) undergoing urogynecologic procedures and to examine the effect of preoperative functional status/capacity on these outcomes. METHODS: This is a retrospective analysis of all women aged 80 years or older who underwent a urogynecologic procedure at a tertiary care specialty practice between 2006 and 2014. Subjects were identified by their Current Procedural Terminology codes and the electronic medical record was queried for demographic and perioperative data. Functional status was recorded using data from the preoperative anesthesia assessment, and included the functional status score (range, 1-4) and a functional capacity evaluation (metabolic equivalents [METs, range, 1 to 8+]). RESULTS: One hundred sixty-four women aged 80 years or older underwent a urogynecologic procedure during the study period. Mean age was 83 years (+/-3; range, 80-95 years). The median functional status was 2 (1-4) and median functional capacity was 5.5 METs (1.75-8.0). The overall postoperative adverse event rate was 18.3%; the incidence of serious events was 7.8%. Most serious events were associated with preexisting medical conditions. Presence of 3 or more comorbid conditions was associated with a higher risk of postoperative readmission, need for transfusion and deep vein thrombosis/pulmonary embolism. Preoperative functional status and functional capacity were not associated with postoperative adverse events. Patients with METs scores of 4.5 or less were more likely to need home services or a skilled nursing facility (SNF) postoperatively compared with patients with higher scores (28.9% vs 6.7%, P < 0.0001; odds ratio, 4.3; 95% confidence interval, 1.6-11.9). Dementia was also associated with SNF admission (36.3% vs 10%; P = 0.01; odds ratio, 3.6; 95% confidence interval, 1.1 12.8). CONCLUSIONS: The incidence of serious postoperative adverse events is low in very elderly patients undergoing urogynecologic procedures. Dementia and poor functional capacity appear to be associated with a higher need for postoperative home services or SNF admission. PMID- 27465819 TI - A Modular Class of Fluorescent Difluoroboranes: Synthesis, Structure, Optical Properties, Theoretical Calculations and Applications for Biological Imaging. AB - Ten borylated bipyridines (BOBIPYs) have been synthesized and selected structural modifications have been made that allow useful structure-optical property relationships to be gathered. These systems have been further investigated using DFT calculations and spectroscopic measurements, showing blue to green fluorescence with quantum yields up to 41 %. They allow full mapping of the structure to determine where selected functionalities can be implemented, to tune the optical properties or to incorporate linking groups. The best derivative was thus functionalised with an alkyne linker, which would enable further applications through click chemistry and in this optic, the stability of the fluorophores has been evaluated. PMID- 27465818 TI - A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Tong Luo Hua Shi capsule, a modernized Tibetan medicine, in patients with rheumatoid arthritis. AB - BACKGROUND: Tong Luo Hua Shi (TLHS) is a new formulation of the traditional Tibetan medicine Wu-wei-gan-lu that has been used for the treatment of rheumatoid arthritis (RA) for hundreds of years in China. This study aimed to evaluate the efficacy and safety of TLHS in patients with RA. METHODS: This was a randomized, double-blind, placebo-controlled, dose-finding study performed in patients with active RA from five medical centers. Patients received three doses (4.8, 3.6, or 2.4 g/day po) of TLHS or placebo (tid po) for 8 weeks. Blood sampling, physical examination, and assessment of the American College of Rheumatology (ACR) 20 % improvement (ACR20) criteria were performed before and every 2 weeks after starting treatment. The primary endpoint was the ACR20. The secondary endpoints included safety. RESULTS: A total of 240 participants were screened and 236 patients were randomized (n = 59/group); 20 dropped out. After 8 weeks, ACR20 improvements in the TLHS 4.8 g and 3.6 g groups were significantly higher than in the placebo group (P < 0.01 and P < 0.05, respectively). ACR50 improvement in the TLHS 4.8 g group was significantly higher compared with the placebo group (P < 0.01). Symptoms of RA were significantly relieved in the TLHS groups. In the TLHS groups, insomnia (n = 1), gastroenteric reactions (n = 2), arrhythmia (n = 1), and minor hepatic lesion (n = 1) were reported; in the placebo group, hepatic dysfunction (n = 1) was reported (P = 0.878). CONCLUSIONS: TLHS improved the symptoms of patients with RA according to the ACR20. Moreover, TLHS was safe. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-12003871 . Registered on 1 January 2012. PMID- 27465820 TI - Clinical Features and Peripheral Blood T Lymphocyte Subsets in Hand, Foot, and Mouth Disease According to Different Pathogens. AB - OBJECTIVE: To investigate the changes in lymphocyte subsets that are caused by infection with different pathogens in children with hand, foot, and mouth disease. METHODS: T lymphocyte subsets were measured in the patients' peripheral blood, and serum, throat swab, and fecal samples were tested for enterovirus. RESULTS: Fecal and throat swab samples exhibited similar positive detection rates, and were significantly more likely to be positive, compared to serum samples (P < 0.01). The EV71-positive group exhibited significantly lower CD4 + TM cell counts (QR: 1.058), compared to the CD4 + TM cell counts in the CoxA16 positive group (QR: 1.391; P < 0.05). CONCLUSIONS: Throat swab and fecal samples exhibited significantly higher positive detection rates, compared to serum samples. In addition, EV71-infected children exhibited significantly lower CD4+ T cell counts, compared to CoxA16-infected children, which suggests that EV71 infection may be associated with a poorer prognosis. PMID- 27465821 TI - Precise estimation of genomic regions controlling lodging resistance using a set of reciprocal chromosome segment substitution lines in rice. AB - Severe lodging has occurred in many improved rice varieties after the recent strong typhoons in East and Southeast Asian countries. The indica variety Takanari possesses strong culm characteristics due to its large section modulus, which indicates culm thickness, whereas the japonica variety Koshihikari is subject to substantial bending stress due to its thick cortical fibre tissue. To detect quantitative trait loci (QTLs) for lodging resistance and to eliminate the effects of genetic background, we used reciprocal chromosome segment substitution lines (CSSLs) derived from a cross between Koshihikari and Takanari. The oppositional effects of QTLs for section modulus were confirmed in both genetic backgrounds on chromosomes 1, 5 and 6, suggesting that these QTLs are not affected by the genetic background and are controlled independently by a single factor. The candidate region of a QTL for section modulus included SD1. The section modulus of NIL-sd1 was lower than that of Koshihikari, whereas the section modulus of NIL-SD1 was higher than that of Takanari. This result indicated that those regions regulate the culm thickness. The reciprocal effects of the QTLs for cortical fibre tissue thickness were confirmed in both genetic backgrounds on chromosome 9 using CSSLs. PMID- 27465822 TI - Rubinstein-Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum. AB - Rubinstein-Taybi syndrome (RTS) is an autosomal dominant neurodevelopmental disorder characterized by growth deficiency, broad thumbs and great toes, intellectual disability and characteristic craniofacial appearance. Mutations in CREBBP account for around 55% of cases, with a further 8% attributed to the paralogous gene EP300. Comparatively few reports exist describing the phenotype of Rubinstein-Taybi because of EP300 mutations. Clinical and genetic data were obtained from nine patients from the UK and Ireland with pathogenic EP300 mutations, identified either by targeted testing or by exome sequencing. All patients had mild or moderate intellectual impairment. Behavioural or social difficulties were noted in eight patients, including three with autistic spectrum disorders. Typical dysmorphic features of Rubinstein-Taybi were only variably present. Additional observations include maternal pre-eclampsia (2/9), syndactyly (3/9), feeding or swallowing issues (3/9), delayed bone age (2/9) and scoliosis (2/9). Six patients had truncating mutations in EP300, with pathogenic missense mutations identified in the remaining three. The findings support previous observations that microcephaly, maternal pre-eclampsia, mild growth restriction and a mild to moderate intellectual disability are key pointers to the diagnosis of EP300-related RTS. Variability in the presence of typical facial features of Rubinstein-Taybi further highlights clinical heterogeneity, particularly among patients identified by exome sequencing. Features that overlap with Floating Harbor syndrome, including craniofacial dysmorphism and delayed osseous maturation, were observed in three patients. Previous reports have only described mutations predicted to cause haploinsufficiency of EP300, whereas this cohort includes the first described pathogenic missense mutations in EP300. PMID- 27465824 TI - Corrigendum. AB - Jung KJ, Chung CY, Park MS, Chung MK, Lee DY, Koo S, Lee KM. Concomitant ankle injuries associated with tibial shaft fractures. Foot Ankle Int. 2015;36(10):1209 1214. (Original DOI: 10.1177/1071100715588381). PMID- 27465823 TI - Adding corticosteroids to the pudendal nerve block for pudendal neuralgia: a randomised, double-blind, controlled trial. AB - OBJECTIVE: To compare the effect of corticosteroids combined with local anaesthetic versus local anaesthetic alone during infiltrations of the pudendal nerve for pudendal nerve entrapment. DESIGN: Randomised, double-blind, controlled trial. SETTING: Multicentre study. POPULATION: 201 patients were included in the study, with a subgroup of 122 women. METHODS: CT-guided pudendal nerve infiltrations were performed in the sacrospinous ligament and Alcock's canal. There were three study arms: patients in Arm A (n = 68) had local anaesthetic alone, those in Arm B (n = 66) had local anaesthetic plus corticosteroid and those in Arm C (n = 67) local anaesthetic plus corticosteroid with a large volume of normal saline. MAIN OUTCOME MEASURES: The primary end-point was the pain intensity score at 3 months. Patients were regarded as responders (at least a 30 point improvement on a 100-point visual analogue scale of mean maximum pain over a 2-week period) or nonresponders. RESULTS: Three months' postinfiltration, 11.8% of patients in the local anaesthetic only arm (Arm A) were responders versus 14.3% in the local anaesthetic plus corticosteroid arms (Arms B and C). This difference was not statistically significant (P = 0.62). No statistically significant difference was observed in the female subgroup between Arm A and Arms B and C (P = 0.09). No significant difference was detected for the various pain assessment procedures, functional criteria or quality-of-life criteria. CONCLUSIONS: Corticosteroids provide no additional therapeutic benefits compared with local anaesthetic and should therefore no longer be used. TWEETABLE ABSTRACT: Steroid infiltrations do not improve the results of local anaesthetic infiltrations in pudendal neuralgia. PMID- 27465826 TI - Spatiotemporal expression of Ezh2 in the developing mouse cochlear sensory epithelium. AB - The enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) is a histone lysine Nmethyltransferase enzyme that participates in DNA methylation. Ezh2 has also been reported to play crucial roles in stem cell proliferation and differentiation. However, the detailed expression profile of Ezh2 during mouse cochlear development has not been investigated. Here, we examined the spatiotemporal expression of Ezh2 in the cochlea during embryonic and postnatal development. Ezh2 expression began to be observed in the whole otocyst nuclei at embryonic day 9.5 (E9.5). At E12.5, Ezh2 was expressed in the nuclei of the cochlear prosensory epithelium. At E13.5 and E15.5, Ezh2 was expressed from the apical to the basal turns in the nuclei of the differentiating cochlear epithelium. At postnatal day (P) 0 and 7, the Ezh2 expression was located in the nuclei of the cochlear epithelium in all three turns and could be clearly seen in outer and inner hair cells, supporting cells, the stria vascularis, and spiral ganglion cells. Ezh2 continued to be expressed in the cochlear epithelium of adult mice. Our results provide the basic Ezh2 expression pattern and might be useful for further investigating the detailed role of Ezh2 during cochlear development. PMID- 27465827 TI - Barriers and countermeasures in developing traditional Chinese medicine in Europe. AB - Traditional Chinese medicine (TCM) is one of the unique cultural treasures of Chinese; it represents a significant feature and prominent advantage of the healthcare cause in China. Data in this paper were fromWorld Health Organization, Chinese Bureau of Statistics, China National Knowledge Infrastructure, and PubMed. In recent years, TCM has established a solid foundation in Europe, which made great strides in legislation, education, research, and international exchange, and has enjoyed a vast development space in the continent. Now, TCM is embracing unprecedented development opportunities in Europe. At the same time, the stiff international competition poses a grave threat to China's TCM industry. With multiple cultural, legal, and institutional challenges, as well as talent shortages in the way, TCM is now facing many difficulties in Europe. To fully prepare and enact active and vigorous steps to seize opportunities, we should have a clear picture about the serious challenges hampering TCM development in Europe. The TCM development at overseas markets has shifted from a spontaneous trade activity into a national strategy spearheaded by the government and participated in by multiple stakeholders. We should make a systematic, comprehensive, and sustainable push in fields such as TCM therapy, healthcare, education, research, culture, and industry development. The ultimate goal is to bring TCMs to the global market and allow them to play a role in safeguarding public health along with modern medicines. PMID- 27465828 TI - Strength and Water Interactions of Cellulose I Filaments Wet-Spun from Cellulose Nanofibril Hydrogels. AB - Hydrogels comprising cellulose nanofibrils (CNF) were used in the synthesis of continuous filaments via wet-spinning. Hydrogel viscosity and spinnability, as well as orientation and strength of the spun filaments, were found to be strongly affected by the osmotic pressure as determined by CNF surface charge and solid fraction in the spinning dope. The tensile strength, Young's modulus and degree of orientation (wide-angle X-ray scattering, WAXS) of filaments produced without drawing were 297 MPa, 21 GPa and 83%, respectively, which are remarkable values. A thorough investigation of the interactions with water using dynamic vapour sorption (DVS) experiments revealed the role of sorption sites in the stability of the filaments in wet conditions. DVS analysis during cycles of relative humidity (RH) between 0 and 95% revealed major differences in water uptake by the filaments spun from hydrogels of different charge density (CNF and TEMPO-oxidised CNF). It is concluded that the mechanical performance of filaments in the presence of water deteriorates drastically by the same factors that facilitate fibril alignment and, consequently, enhance dry strength. For the most oriented filaments, the maximum water vapour sorption at 95% RH was 39% based on dry weight. PMID- 27465829 TI - Endogenous inhibins regulate steroidogenesis in mouse TM3 Leydig cells by altering SMAD2 signalling. AB - This study tested the hypothesis that inhibins act in an autocrine manner on Leydig cells using a pre-pubertal Leydig cell line, TM3, as a model of immature Leydig cells. The expression of Inha, Inhba, and Inhbb in TM3 cells was determined by RT-PCR and the production of the inhibin-alpha subunit was confirmed by western blot. Knockdown of Inha expression resulted in significant decreases in the expression of Leydig cell markers Cyp17a1, Cyp11a1, Nr5a1, and Insl3. Western blot showed that activin A, TGFbeta1 and TGFbeta2 activated SMAD2, and that knockdown of Inha expression in TM3 cells enhanced both activin A- and TGFbeta-induced SMAD2 activation. SB431542, a chemical inhibitor of the TGFbeta/activin type I receptors, blocked ligand-induced SMAD2 activation and the downregulation of Cyp17a1 expression. Our findings demonstrate that TGFbetas and activin A negatively regulate steroidogenic gene expression in TM3 cells via ALK4/5 and SMAD2 and endogenous inhibins can counter this regulation. PMID- 27465832 TI - alpha1-Antitrypsin deficiency. PMID- 27465831 TI - Integrative proteomics and transcriptomics revealed that activation of the IL 6R/JAK2/STAT3/MMP9 signaling pathway is correlated with invasion of pituitary null cell adenomas. AB - Non-functioning pituitary adenomas (NFPAs) are a highly heterogeneous group, but few studies have explored the invasion mechanism of specific subtypes of NFPAs. The objective of this study was to investigate the differential molecular expression patterns and the critical biological signaling pathways involved in the invasion of pituitary null cell adenomas (PNCAs) through integrative proteomics and transcriptomics. A total of 1160 genes and 283 proteins were found to be differentially expressed in invasive and non-invasive PNCAs. The differentially expressed molecules related to invasion were enriched in 15 canonical signaling pathways, 15 clusters of diseases or biological functions and 5 upstream molecules. Among them, the majority of the differentially expressed molecules were found to be involved in transport of molecule, migration of cells and cell movement. Notably, IL-6 was a significantly activated upstream regulator, and the IL6R/JAK2/STAT3 cascade was found to play a critical role in acute phase response signaling, which was the most significant canonical signaling pathway. Furthermore, we validated the overexpression of IL-6R, JAK2, STAT3, p-STAT3 and MMP9 in invasive PNCAs. Our data suggest that overactivation of the IL-6R/JAK2/STAT3/MMP9 pathway is critical for the invasion of PNCAs. PMID- 27465830 TI - Islet distribution of Peptide YY and its regulatory role in primary mouse islets and immortalised rodent and human beta-cell function and survival. AB - Recent evidence suggests that the classic gut peptide, Peptide YY (PYY), could play a fundamental role in endocrine pancreatic function. In the present study expression of PYY and its NPY receptors on mouse islets and immortalised rodent and human beta-cells was examined together with the effects of both major circulating forms of PYY, namely PYY(1-36) and PYY(3-36), on beta-cell function, murine islet adaptions to insulin deficiency/resistance, as well as direct effects on cultured beta-cell proliferation and apoptosis. In vivo administration of PYY(3-36), but not PYY(1-36), markedly (p < 0.05) decreased food intake in overnight fasted mice. Neither form of PYY affected glucose disposal or insulin secretion following an i.p. glucose challenge. However, in vitro, PYY(1-36) and PYY(3-36) inhibited (p < 0.05 to p < 0.001) glucose, alanine and GLP-1 stimulated insulin secretion from immortalised rodent and human beta-cells, as well as isolated mouse islets, by impeding alterations in membrane potential, [Ca(2+)]i and elevations of cAMP. Mice treated with multiple low dose streptozotocin presented with severe (p < 0.01) loss of beta-cell mass accompanied by notable increases (p < 0.001) in alpha and PP cell numbers. In contrast, hydrocortisone induced insulin resistance increased islet number (p < 0.01) and beta-cell mass (p < 0.001). PYY expression was consistently observed in alpha-, PP- and delta-, but not beta-cells. Streptozotocin decreased islet PYY co-localisation with PP (p < 0.05) and somatostatin (p < 0.001), whilst hydrocortisone increased PYY co localisation with glucagon (p < 0.05) in mice. More detailed in vitro investigations revealed that both forms of PYY augmented (p < 0.05 to p < 0.01) immortalised human and rodent beta-cell proliferation and protected against streptozotocin-induced cytotoxicity, to a similar or superior extent as the well characterised beta-cell proliferative and anti-apoptotic agent GLP-1. Taken together, these data highlight the significance and potential offered by modulation of pancreatic islet NPY receptor signalling pathways for preservation of beta-cell mass in diabetes. PMID- 27465833 TI - Evaluation of in vivo antitumor effects of low-frequency ultrasound-mediated miRNA-133a microbubble delivery in breast cancer. AB - MicroRNAs (miRNAs), as a novel class of small noncoding RNAs, have been identified as important transcriptional and posttranscriptional inhibitors of gene expression. Ultrasound-targeted microbubble destruction (UTMD) is a noninvasive method for microRNA delivery. We aimed to investigate the effect of UTMD of miR-133a on breast cancer treatment. It has been reported that miRNA-133a is involved in various cancers. miR-133a was lowly expressed in breast cancer tissues and breast cancer cell lines MCF-7 and MDA-MB-231. The miR-133a expression was significantly upregulated under exogenous miRNA-133a treatment in MCF-7 and MDA-MB-231 cells analyzed by qRT-PCR. Exogenous miR-133a promoted the cell proliferation as determined by diphenyl tetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. Epidermal growth factor receptor (EGFR) expression and Akt phosphorylation were significantly suppressed after miR-133a transfection by western blot detection. We prepared the miR-133a-microbubble and injected it into breast cancer xenografts. The miR-133a-microbubble injection prolonged miR-133a circulatory time by detecting the amount of miRNA-133a in the plasma. No significant toxicity was observed on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at liver and albumin, blood urea nitrogen, or creatine kinase levels at kidney after miR-133a-microbubble injection. The tumor size of miR-133a-microbubble-injected mice was smaller than that of the control group. Furthermore, the delivery efficiency of miR-133a with low frequency was higher than that with common frequency. miR-133a suppressed cell proliferation by suppressing the expression of EGFR and the phosphorylation of Akt. UTMD of miR-133a inhibited the tumor growth and improved the survival rate in breast cancer mice. Our study provides new evidence that UTMD of miRNA is a promising platform for breast cancer therapy. PMID- 27465834 TI - Cervical polyps: Is histologic evaluation necessary? AB - OBJECTIVE: The aim of this study was to examine a series of clinically identified cervical polyps and determine the incidence of significant histologic and concurrent cytologic findings. METHODS: Consecutive cervical polyps from January 2000 through September 2012 were retrieved from the hospital laboratory information system. Histologic evaluation of these polyps was performed, followed by a chart review of clinical findings and correlation with the immediately prior or concurrently collected cervical Papanicolaou (Pap) test results, when available. RESULTS: A total of 369 cervical polyps were identified and reviewed. The patient ages ranged from 18 to 87 years (mean 46.5years). Eight polyps demonstrated squamous dysplasia (6 Cervical Intraepithelial Neoplasia/CIN I, and 2 CIN II/III), while 6 had malignant or atypical/potentially malignant features (2 adenosarcoma, 2 atypical polyps concerning for Mullerian adenosarcoma, 1 endometrioid endometrial adenocarcinoma and 1 adenocarcinoma in-situ). An increased incidence of atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells not otherwise specified (AGC NOS) Pap diagnoses (12.7% and 6.1%, respectively) was found in women with benign polyps on biopsy. DISCUSSION: We demonstrated a higher rate of clinically significant histologic findings in cervical polyps (14 of 369 cases, 3.7%) compared to previously reported studies. The increase in ASCUS and AGC Pap results was most likely related to reactive and inflammatory changes present in benign polyps. Our results suggest that removal of all cervical polyps with subsequent histologic review is warranted. PMID- 27465835 TI - The utility of SATB2 immunohistochemical expression in distinguishing between osteosarcomas and their malignant bone tumor mimickers, such as Ewing sarcomas and chondrosarcomas. AB - SATB2 is commonly expressed in osteosarcomas. Although apparently being a valuable diagnostic marker for differentiating between small cell osteosarcoma (SCO) and other small round cell tumors of bone, for instance Ewing sarcoma family of tumors (ESFT), it has not been tested in a large series of ESFT and chondrosarcomas so far. We studied the immunohistochemical expression of SATB2 in 42 osteosarcomas, 31 chondrosarcomas, and 371 genetically confirmed ESFT. SATB2 positivity was detected in 90.4% of osteosarcomas, 87.5% of SCO, 91.3% of osteoblastic osteosarcomas, and in all chondroblastic and parosteal osteosarcomas. The osteoblastic and SCO subtypes expressed SATB2 more intensely than other histological types. SATB2 was expressed in 46.6% of chondrosarcomas, and in 1.3% of ESFT. Sensitivity and specificity of SATB2 immunoexpression were 90.4% and 95.3%, respectively. The positive and negative predictive values in osteosarcoma diagnosis were 66.6% and 98.9%, respectively. In chondrosarcoma, SATB2 immunoexpression was more frequent and intense in high-grade chondrosarcoma (Grade III) and uncommon in chondrosarcoma grade I. SATB2 positivity was detected in 55.6% of chondrosarcomas grade II. SATB2 apparently cannot distinguish between chondroblastic osteosarcoma and high-grade chondrosarcoma. Nevertheless, SATB2 is frequently expressed in osteogenic tumors, but is rarely positive in ESFT, and with the support of CD99 expression and specific molecular studies, it is very useful for distinguishing between these two lesions. Although SATB2 immunoexpression helps to distinguish osteosarcoma from their mimickers, the identification of malignant osteoid matrix formation and the integration of clinical and radiological data remain the corner stone of osteosarcoma diagnosis and as yet no antibody has equalled the diagnostic value of this important morphologic hallmark. PMID- 27465836 TI - Primary enteric-type mucinous adenocarcinoma of the renal pelvis masquerading as cystic renal cell carcinoma: A case report and review of the literature. AB - Primary mucinous adenocarcinoma of the renal pelvis is easily misdiagnosed and it was rarely reported in the literature. We describe in this study a case of 40 year-old male patient presented with right lumbar pain of one year duration and elevated level of carcinoembryonic antigen (CEA). After a series of imaging examinations, the initial impression was a cystic renal cell carcinoma. Right radical nephrectomy was performed on the patient. The postoperative pathological examination indicated a primary mucinous adenocarcinoma of enteric type of the renal pelvis. After surgical removal of the tumor, an immunotherapy was administrated to prevent recurrence. The patient survives upon this report. A review of pertinent literature is also presented. PMID- 27465837 TI - Clinicopathological significance and concordance analysis of c-MET immunohistochemistry in non-small cell lung cancers: A meta-analysis. AB - OBJECTIVE: The aim of this study was to investigate the clinicopathological significance and concordance rate of c-MET immunohistochemistry (IHC) in non small cell lung cancer (NSCLC) through meta-analysis and diagnostic test accuracy review. METHODS: The current study included 4454 NSCLC cases of 22 eligible studies. The meta-analysis examined the correlation between c-MET IHC expression and clinicopathological parameters. We investigated concordance rate between c MET IHC and genetic alteration and performed subgroup analysis based on c-MET IHC cut-off value. RESULTS: The estimated positive rate of c-MET IHC was 0.440 (95% confidence interval [CI] 0.355-0.529). The positive rate of c-MET IHC was significantly high in non-squamous cell carcinomas and tumors with stage III-IV. However, there was no significant difference between c-MET IHC positivity and sex, smoking, and lymph node metastasis. The c-MET IHC positivity was significantly correlated with poor overall survival (hazard ratio 1.551, 95% CI 1.101-2.184). In c-MET IHC-positive and negative groups, the concordance rate was 0.941 (95% CI 0.885-0.971) and 0.300 (95% CI 0.196-0.429), respectively. The pooled sensitivity and specificity of the high cut-off subgroup for c-MET IHC was 1.00 (95% CI 0.92-1.00) and 0.78 (95% CI 0.75-0.81), respectively. The diagnostic odds ratio and the area under curve on summary receiver operating characteristic curve were 76.56 (95% CI 8.23-712.41) and 0.9949, respectively. CONCLUSION: The c MET IHC could be useful for screening of c-MET genetic alteration in NSCLC patients. Detailed criteria for c-MET IHC evaluation are necessary to determine how to best apply this approach in daily practice. PMID- 27465839 TI - Reporting Guidelines for Health Care Simulation Research: Extensions to the CONSORT and STROBE Statements. AB - INTRODUCTION: Simulation-based research (SBR) is rapidly expanding but the quality of reporting needs improvement. For a reader to critically assess a study, the elements of the study need to be clearly reported. Our objective was to develop reporting guidelines for SBR by creating extensions to the Consolidated Standards of Reporting Trials (CONSORT) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statements. METHODS: An iterative multistep consensus-building process was used on the basis of the recommended steps for developing reporting guidelines. The consensus process involved the following: (1) developing a steering committee, (2) defining the scope of the reporting guidelines, (3) identifying a consensus panel, (4) generating a list of items for discussion via online premeeting survey, (5) conducting a consensus meeting, and (6) drafting reporting guidelines with an explanation and elaboration document. RESULTS: The following 11 extensions were recommended for CONSORT: item 1 (title/abstract), item 2 (background), item 5 (interventions), item 6 (outcomes), item 11 (blinding), item 12 (statistical methods), item 15 (baseline data), item 17 (outcomes/estimation), item 20 (limitations), item 21 (generalizability), and item 25 (funding). The following 10 extensions were recommended for STROBE: item 1 (title/abstract), item 2 (background/rationale), item 7 (variables), item 8 (data sources/measurement), item 12 (statistical methods), item 14 (descriptive data), item 16 (main results), item 19 (limitations), item 21 (generalizability), and item 22 (funding). An elaboration document was created to provide examples and explanation for each extension. CONCLUSIONS: We have developed extensions for the CONSORT and STROBE Statements that can help improve the quality of reporting for SBR. PMID- 27465838 TI - Two IIIf Clade-bHLHs from Freesia hybrida Play Divergent Roles in Flavonoid Biosynthesis and Trichome Formation when Ectopically Expressed in Arabidopsis. AB - The MBW complex, comprised by R2R3-MYB, basic helix-loop-helix (bHLH) and WD40, is a single regulatory protein complex that drives the evolution of multiple traits such as flavonoid biosynthesis and epidermal cell differentiation in plants. In this study, two IIIf Clade-bHLH regulator genes, FhGL3L and FhTT8L, were isolated and functionally characterized from Freesia hybrida. Different spatio-temporal transcription patterns were observed showing diverse correlation with anthocyanin and proanthocyanidin accumulation. When overexpressed in Arabidopsis, FhGL3L could enhance the anthocyanin accumulation through up regulating endogenous regulators and late structural genes. Unexpectedly, trichome formation was inhibited associating with the down-regulation of AtGL2. Comparably, only the accumulation of anthocyanins and proanthocyanidins was strengthened in FhTT8L transgenic lines. Furthermore, transient expression assays demonstrated that FhGL3L interacted with AtPAP1, AtTT2 and AtGL1, while FhTT8L only showed interaction with AtPAP1 and AtTT2. In addition, similar activation of the AtDFR promoter was found between AtPAP1-FhGL3L/FhTT8L and AtPAP1- AtGL3/AtTT8 combinations. When FhGL3L was fused with a strong activation domain VP16, it could activate the AtGL2 promoter when co-transfected with AtGL1. Therefore, it can be concluded that the functionality of bHLH factors may have diverged, and a sophisticated interaction and hierarchical network might exist in the regulation of flavonoid biosynthesis and trichome formation. PMID- 27465840 TI - Interfacial Adsorption of Silk Fibroin Peptides and Their Interaction with Surfactants at the Solid-Water Interface. AB - Regenerated silk fibroin (RSF) is a Food and Drug Administration-approved material and has been widely used in many biomedical and cosmetic applications. Because of the amphiphilic nature of the primary repeat amino acid sequence (e.g., AGAGAS), RSF peptides can significantly reduce the water surface tension and therefore have the potential to be used as a surface active component for many applications, particularly in the biomedical, cosmetic, pharmaceutical, and food industries. In this paper, the adsorption of RSF peptides separated into molecular fractions of 5-30, 30-300, and >300 kDa has been studied at the solid water interface by neutron reflection and spectroscopic ellipsometry to assess its surface active behavior. A stable layer of RSF was found to be irreversibly adsorbed at the hydrophilic SiO2-water interface. Changes in solution concentration, pH, and ionic strength all had an impact on the final adsorbed amount found at the interface. There were no significant differences between the final adsorbed amounts or layer structure among the three RSF molecular fractions studied; however, >300 kDa RSF was more stable to changes in solution ionic strength. Adsorption of conventional anionic and cationic surfactants, sodium dodecyl sulfate (SDS) and dodecyl trimethylammonium bromide (C12TAB), to the preadsorbed 5-30 kDa RSF revealed penetration of the surfactant into the RSF layer, at concentrations below the critical micellar concentration (CMC). SDS was found in the preadsorbed RSF layer and gradually removed RSF from the surface with an increase in SDS concentration. At concentrations above the CMC, there is near complete removal of RSF by SDS at the interface. C12TAB adsorbed into the preadsorbed RSF layer with considerably less removal of RSF from the interface compared to SDS. At concentrations above the CMC, both C12Tab and RSF were found to coexist at the interface, forming a less thick layer but with a considerable amount of RSF still present. PMID- 27465841 TI - Landfill mining: Developing a comprehensive assessment method. AB - In Austria, the first basic technological and economic examinations of mass-waste landfills with the purpose to recover secondary raw materials have been carried out by the 'LAMIS - Landfill Mining Osterreich' pilot project. A main focus of its research, and the subject of this article, is the first conceptual design of a comprehensive assessment method for landfill mining plans, including not only monetary factors (like costs and proceeds) but also non-monetary ones, such as the concerns of adjoining owners or the environmental impact. Detailed reviews of references, the identification of influences and system boundaries to be included in planning landfill mining, several expert workshops and talks with landfill operators have been performed followed by a division of the whole assessment method into preliminary and main assessment. Preliminary assessment is carried out with a questionnaire to rate juridical feasibility, the risk and the expenditure of a landfill mining project. The results of this questionnaire are compiled in a portfolio chart that is used to recommend, or not, further assessment. If a detailed main assessment is recommended, defined economic criteria are rated by net present value calculations, while ecological and socio economic criteria are examined in a utility analysis and then transferred into a utility-net present value chart. If this chart does not support making a definite statement on the feasibility of the project, the results must be further examined in a cost-effectiveness analysis. Here, the benefit of the particular landfill mining project per capital unit (utility-net present value ratio) is determined to make a final distinct statement on the general benefit of a landfill mining project. PMID- 27465843 TI - Clinical Significance of Invasive Motor Cortex Stimulation for Trigeminal Facial Neuropathic Pain Syndromes. AB - BACKGROUND: Invasive neuromodulation of the cortical surface for various chronic pain syndromes has been performed for >20 years. The significance of motor cortex stimulation (MCS) in chronic trigeminal neuropathic pain (TNP) syndromes remains unclear. Different techniques are performed worldwide in regard to operative procedure, stimulation parameters, test trials, and implanted materials. OBJECTIVE: To present the clinical experiences of a single center with MCS, surgical approach, complications, and follow-up as a prospective, noncontrolled clinical trial. METHODS: The implantation of epidural leads over the motor cortex was performed via a burr hole technique with neuronavigation and intraoperative neurostimulation. Special focus was placed on a standardized test trial with an external stimulation device and the implementation of a double-blinded or placebo test phase to identify false-positive responders. RESULTS: A total of 36 patients with TNP were operated on, and MCS was performed. In 26 of the 36 patients (72%), a significant pain reduction from a mean of 8.11 to 4.58 (on the visual analog scale) during the test trial was achieved (P < .05). Six patients were identified as false-positive responders (17%). At the last available follow-up of 26 patients (mean, 5.6 years), active MCS led to a significant pain reduction compared with the preoperative pain ratings (mean visual analog scale score, 5.01; P < .05). CONCLUSION: MCS is an additional therapeutic option for patients with refractory chronic TNP, and significant long-term pain suppression can be achieved. Placebo or double-blinded testing is mandatory. ABBREVIATIONS: MCS, motor cortex stimulationNRS, numeric pain rating scaleTNP, trigeminal neuropathic or deafferentation painVAS, visual analog scale. PMID- 27465842 TI - CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angiogenesis by Inhibiting miR-126 Expression in Rheumatoid Arthritis. AB - Angiogenesis is the formation of new capillaries from preexisting vasculature. The perpetuation of angiogenesis plays a critical role in the pathogenesis of various disease states including rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61 or CCN1) is an important proinflammatory cytokine in RA. Here, we investigated the role of CCN1 in angiogenesis associated with vascular endothelial growth factor (VEGF) production and osteoblasts. We found higher expression of CCN1 and VEGF in synovial fluid from RA patients compared with healthy controls. CCN1 induced VEGF expression in osteoblasts and increased endothelial progenitor cells (EPCs) angiogenesis by inhibiting miR-126 via the protein kinase C-alpha (PKC-alpha) signaling pathway. CCN1 knockdown inhibited angiogenesis in both in vitro and in vivo models. Inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA (shRNA) ameliorated articular swelling, cartilage erosion, and angiogenesis in the ankle joint of mice with collagen-induced arthritis (CIA). Our study is the first to describe how CCN1 promotes VEGF expression in osteoblasts and increased EPCs angiogenesis in RA disease. CCN1 may serve as a potential target for RA treatment. (c) 2016 American Society for Bone and Mineral Research. PMID- 27465844 TI - The Impact of Age on Long-Term Quality of Life After Endonasal Endoscopic Resection of Skull Base Meningiomas. AB - BACKGROUND: Midline ventral skull base meningiomas may be amenable to an endonasal endoscopic approach, which has theoretical advantages and may help preserve quality of life (QOL) when compared with transcranial approaches. OBJECTIVE: To investigate the effect of age on QOL following endonasal endoscopic surgery, given the documented impact of age on QOL outcomes following transcranial resection of midline ventral skull base meningiomas. METHODS: We reviewed a prospectively acquired database of endonasal endoscopic surgery for meningiomas. Inclusion criteria included patients who had completed long-term postoperative (>=6 months follow-up) QOL questionnaires (Anterior Skull Base Questionnaire [ASBQ] and Sino-Nasal Outcome Test [SNOT-22]). Postoperative QOL scores were also compared with preoperative QOL in a patient subset. RESULTS: Long-term QOL data were available in 34 patients. Average postoperative ASBQ and SNOT-22 scores were 3.39 and 23.0, respectively. Better QOL was statistically associated with age <55 (P = .02). In a subset of patients, preoperative and postoperative ASBQ and SNOT-22 scores were compared. Only SNOT-22 scores significantly increased from 15.9 + 20.8 to 25.9 + 19.5 (P = .04). CONCLUSION: We report the first study specifically evaluating long-term QOL after endonasal endoscopic resection of skull base meningiomas. QOL was decreased postoperatively in patients aged >=55. ABBREVIATIONS: ASBQ, Anterior Skull Base QuestionnaireGTR, gross total resectionQOL, quality of lifeSNOT-22, 22-item Sino-Nasal Outcome Test. PMID- 27465845 TI - Can Combined Bypass Surgery at Middle Cerebral Artery Territory Save Anterior Cerebral Artery Territory in Adult Moyamoya Disease? AB - Background: Patients with moyamoya disease are frequently encountered with improved symptoms related to anterior cerebral artery territory (ACAt) and middle cerebral artery territory (MCAt) after bypass surgery at MCAt. Objective: To evaluate hemodynamic changes in MCAt and ACAt after bypass surgery in adult moyamoya disease. Methods: Combined bypass surgery was performed on 140 hemispheres in 126 patients with MCAt symptoms. Among them, 87 hemispheres (62.1%) accompanied preoperative ACAt symptoms. Clinical, hemodynamic, and angiographic states were evaluated preoperatively and approximately 6 months after surgery. Results: Preoperative symptoms resolved in 127 MCAt (90.7%) and 82 ACAt (94.3%). Hemodynamic analysis of total patients showed a significant improvement in MCAt basal perfusion and reservoir capacity ( P < .001 and P = .002, respectively) and ACAt basal perfusion ( P = .001). In a subgroup analysis, 82 hemispheres that completely recovered from preoperative ACAt symptoms showed a significant improvement in MCAt basal perfusion and reservoir capacity ( P < .001 and P = .05, respectively) and ACAt basal perfusion ( P = .04). Meanwhile, 53 hemispheres that had never experienced ACAt symptoms significantly improved MCAt basal perfusion and reservoir capacity ( P < .001 and P = .05, respectively); however, no ACAt changes were observed. A qualitative angiographic analysis demonstrated a higher trend of leptomeningeal formation from MCAt to ACAt in the former subgroup ( P = .05). During follow-up, no ACAt infarctions were observed. Conclusion: Combined bypass surgery at MCAt resulted in hemodynamic improvements in ACAt and MCAt, especially in patients with preoperative ACAt symptoms. PMID- 27465846 TI - The Association Between Operating Room Personnel and Turnover With Surgical Site Infection in More Than 12 000 Neurosurgical Cases. AB - BACKGROUND: Surgical site infection (SSI) contributes significantly to postoperative morbidity and mortality and greatly increases the cost of care. OBJECTIVE: To identify the impact of workflow and personnel-related risk factors contributing to the incidence of SSIs in a large sample of neurological surgeries. METHODS: Data were obtained using an enterprisewide electronic health record system, operating room, and anesthesia records for neurological procedures conducted between January 1, 2009, and November 30, 2012. SSI data were obtained from prospective surveillance by infection preventionists using Centers for Disease Control and Prevention definitions. A multivariate model was constructed and refined using backward elimination logistic regression methods. RESULTS: The analysis included 12 528 procedures. Most cases were elective (94.5%), and the average procedure length was 4.8 hours. The average number of people present in the operating room at any time during the procedure was 10.0. The overall infection rate was 2.3%. Patient body mass index (odds ratio, 1.03; 95% confidence interval [CI], 1.01-1.04) and sex (odds ratio, 1.36; 95% CI, 1.07 1.72) as well as procedure length (odds ratio, 1.19 per additional hour; 95% CI, 1.15-1.23) and nursing staff turnovers (odds ratio, 1.095 per additional turnover; 95% CI, 1.02-1.21) were significantly correlated with the risk of SSI. CONCLUSION: This study found that patient body mass index and male sex were associated with an increased risk of SSI. Operating room personnel turnover, a modifiable, work flow-related factor, was an independent variable positively correlated with SSI. This study suggests that efforts to reduce operating room turnover may be effective in preventing SSI. ABBREVIATIONS: OR, operating roomSSI, surgical site infection. PMID- 27465847 TI - Incorporation of a Physical Education and Nutrition Program Into Neurosurgery: A Proof of Concept Pilot Program. AB - BACKGROUND: Balancing the demands of a busy medical career with personal wellness can be daunting, and there is little education on these principles available to physicians in training. OBJECTIVE: To implement a voluntary wellness initiative in our neurosurgery department to promote healthy lifestyle choices. This report details the baseline data collected as part of this quality improvement initiative. METHODS: The wellness initiative was implemented in July 2015 and available to all faculty and resident physicians in the Department of Neurological Surgery in collaboration with the Medical University of South Carolina Wellness Center. All participants were provided a Fitbit Surge HR wrist monitor (Fitbit, Boston, Massachusetts) and underwent baseline physical and psychological testing. RESULTS: Six faculty physicians and 9 residents participated. Overall physical fitness levels varied widely between subjects. Health screening demonstrated abnormalities in 80% of participants (elevated systolic blood pressure in 60%, elevated diastolic in 47%, elevated serum low density lipoprotein in 53%). Body composition analysis demonstrated body weight higher than ideal in 69% (47% overweight; 13% obese). Recommended average body fat mass reduction was 25.4 pounds. Seventy-nine percent reported below-average quality of life compared with the average healthy adult. All subjects reported wanting more time for personal health. CONCLUSION: Baseline health and psychological screenings in our department demonstrated alarmingly prevalent, previously undiagnosed abnormalities on cardiovascular and body weight screenings. Obstacles to leading a healthier lifestyle have been identified and solutions have been incorporated into the program. This quality improvement initiative may serve as a template for other programs seeking to improve physician physical and mental well-being. ABBREVIATIONS: BMI, body mass indexESS, Epworth Sleepiness ScaleHR, heart rate. PMID- 27465849 TI - In Reply: The History of the Kernohan Notch Revisited. PMID- 27465848 TI - Treatment Practices and Outcomes After Blunt Cerebrovascular Injury in Children. AB - BACKGROUND: Pediatric blunt cerebrovascular injury (BCVI) lacks accepted treatment algorithms, and postinjury outcomes are ill defined. OBJECTIVE: To compare treatment practices among pediatric trauma centers and to describe outcomes for available treatment modalities. METHODS: Clinical and radiographic data were collected from a patient cohort with BCVI between 2003 and 2013 at 4 academic pediatric trauma centers. RESULTS: Among 645 pediatric patients evaluated with computed tomography angiography for BCVI, 57 vascular injuries (82% carotid artery, 18% vertebral artery) were diagnosed in 52 patients. Grade I (58%) and II (23%) injuries accounted for most lesions. Severe intracranial or intra-abdominal hemorrhage precluded antithrombotic therapy in 10 patients. Among the remaining patients, primary therapy was an antiplatelet agent in 14 (33%), anticoagulation in 8 (19%), endovascular intervention in 3 (7%), open surgery in 1 (2%), and no treatment in 16 (38%). Among 27 eligible grade I injuries, 16 (59%) were not treated, and the choice to not treat varied significantly among centers (P < .001). There were no complications from medical management. Glasgow Coma Scale (GCS) score <8 and increasing injury grade were predictors of injury progression (P = .001 and .004, respectively). Poor GCS score (P = .02), increasing injury grade (P = .03), and concomitant intracranial injury (P = .02) correlated with increased risk of mortality. Treatment modality did not correlate with progression of vascular injury or mortality. CONCLUSION: Treatment of BCVI with antiplatelet or anticoagulant therapy is safe and may confer modest benefit. Nonmodifiable factors, including presenting GCS score, vascular injury grade, and additional intracranial injury, remain the most important predictors of poor outcome. ABBREVIATIONS: ATT, antithrombotic therapyBCVI, blunt cerebrovascular injuryCTA, computed tomography angiographyGCS, Glasgow Coma Scale. PMID- 27465850 TI - Lichen secondary metabolite evernic acid as potential quorum sensing inhibitor against Pseudomonas aeruginosa. AB - Cystic Fibrosis is a genetic disease and it affects the respiratory and digestive systems. Pseudomonas aeruginosa infections in Cystic Fibrosis are presented as the main cause for high mortality and morbidity rates. Pseudomonas aeruginosa populations can regulate their virulence gene expressions via the bacterial communication system: quorum sensing. Inhibition of quorum sensing by employing quorum sensing inhibitors can leave the bacteria vulnerable. Therefore, determining natural sources to obtain potential quorum sensing inhibitors is essential. Lichens have ethnobotanical value for their medicinal properties and it is possible that their secondary metabolites have quorum sensing inhibitor properties. This study aims to investigate an alternative treatment approach by utilizing lichen secondary metabolite evernic acid to reduce the expressions of Pseudomonas aeruginosa virulence factors by inhibiting quorum sensing. For this purpose, fluorescent monitor strains were utilized for quorum sensing inhibitor screens and quantitative reverse-transcriptase PCR analyses were conducted for comparison. Results indicate that evernic acid is capable of inhibiting Pseudomonas aeruginosa quorum sensing systems. PMID- 27465851 TI - Cultivation and utility of Piptoporus betulinus fruiting bodies as a source of anticancer agents. AB - Piptoporus betulinus is a wood-rotting basidiomycete used in medicine and biotechnology. However, to date, no indoor method for cultivation of this mushroom fruiting bodies has been developed. Here we present the first report of successful production of P. betulinus mature fruiting bodies in artificial conditions. Four P. betulinus strains were isolated from natural habitats and their mycelia were inoculated into birch sawdust substrate supplemented with organic additives. All the strains effectively colonized the medium but only one of them produced fruiting bodies. Moisture and organic supplementation of the substrate significantly determined the fruiting process. The biological efficiency of the P. betulinus PB01 strain cultivated on optimal substrate (moisture and organic substance content of 55 and 65 and 25 or 35 %, respectively) ranged from 12 to 16 %. The mature fruiting bodies reached weight in the range from 50 to 120 g. Anticancer properties of water and ethanol extracts isolated from both cultured and nature-derived fruiting bodies of P. betulinus were examined in human colon adenocarcinoma, human lung carcinoma and human breast cancer cell lines. The studies revealed antiproliferative and antimigrative properties of all the investigated extracts. Nevertheless the most pronounced effects demonstrated the ethanol extracts, obtained from fruiting bodies of cultured P. betulinus. Summarizing, our studies proved that P. betulinus can be induced to fruit in indoor artificial culture and the cultured fruiting bodies can be used as a source of potential anticancer agents. In this respect, they are at least as valuable as those sourced from nature. PMID- 27465852 TI - Microbial production of fatty alcohols. AB - Fatty alcohols have numerous commercial applications, including their use as lubricants, surfactants, solvents, emulsifiers, plasticizers, emollients, thickeners, and even fuels. Fatty alcohols are currently produced by catalytic hydrogenation of fatty acids from plant oils or animal fats. Microbial production of fatty alcohols may be a more direct and environmentally-friendly strategy since production is carried out by heterologous enzymes, called fatty acyl-CoA reductases, able to reduce different acyl-CoA molecules to their corresponding primary alcohols. Successful examples of metabolic engineering have been reported in Saccharomyces cerevisiae and Escherichia coli in which the production of fatty alcohols ranged from 1.2 to 1.9 g/L, respectively. Due to their metabolic advantages, oleaginous yeasts are considered the best hosts for production of fatty acid-derived chemicals. Some of these species can naturally produce, under specific growth conditions, lipids at high titers (>50 g/L) and therefore provide large amounts of fatty acyl-CoAs or fatty acids as precursors. Very recently, taking advantage of such features, over 8 g/L of C16-C18 fatty alcohols have been produced in Rhodosporidium toruloides. In this review we summarize the different metabolic engineering strategies, hosts and cultivation conditions used to date. We also point out some future trends and challenges for the microbial production of fatty alcohols. PMID- 27465853 TI - Progress in the microbial production of S-adenosyl-L-methionine. AB - S-Adenosyl-L-methionine (SAM), which exists in all living organisms, serves as an activated group donor in a range of metabolic reactions, including trans methylation, trans-sulfuration and trans-propylamine. Compared with its chemical synthesis and enzyme catalysis production, the microbial production of SAM is feasible for industrial applications. The current clinical demand for SAM is constantly increasing. Therefore, vast interest exists in engineering the SAM metabolism in cells for increasing product titers. Here, we provided an overview of updates on SAM microbial productivity improvements with an emphasis on various strategies that have been used to enhance SAM production based on increasing the precursor and co-factor availabilities in microbes. These strategies included the sections of SAM-producing microbes and their mutant screening, optimization of the fermentation process, and the metabolic engineering. The SAM-producing strains that were used extensively were Saccharomyces cerevisiae, Pichia pastoris, Candida utilis, Scheffersomyces stipitis, Kluyveromyces lactis, Kluyveromyces marxianus, Corynebacterium glutamicum, and Escherichia coli, in addition to others. The optimization of the fermentation process mainly focused on the enhancement of the methionine, ATP, and other co-factor levels through pulsed feeding as well as the optimization of nitrogen and carbon sources. Various metabolic engineering strategies using precise control of gene expression in engineered strains were also highlighted in the present review. In addition, some prospects on SAM microbial production were discussed. PMID- 27465854 TI - Recent advances on prebiotic lactulose production. AB - Lactulose, a synthetic disaccharide, has received increasing interest due to its role as a prebiotic. The production of lactulose is important in the dairy industry, as it is regarded as a high value-added derivative of whey or lactose. The industrial production of lactulose is still mainly done by chemical isomerization. Due to concerns on the environmental and tedious separation processes, the enzymatic-based lactulose synthesis has been regarded as an interesting alternative. This work aims at comparing chemical and enzyme catalyzed lactulose synthesis. With an emphasis on the latter one, this review discusses the influences of the critical operating conditions and the suited operation mode on the transgalactosylation of lactulose using microbial enzymes. As an update and supplement to other previous reviews, this work also summarizes the recent reports that highlighted the enzymatic isomerization of lactose using cellobiose 2-epimerase to produce lactulose at elevated yields. PMID- 27465855 TI - Secretome, surfome and immunome: emerging approaches for the discovery of new vaccine candidates against bacterial infections. AB - Functional genomics has made possible advanced structure-to-function investigation of pathogens and helped characterize virulence mechanisms. Proteomics has been become a tool for large-scale identification of proteins involved during invasion and infection by the pathogens. Bacterial surface and secreted proteins play key role in the interaction between the bacterial cell and the host environment. Thus exoproteome and surface proteome of a microorganism are hypothesized to contain components of effective vaccines. Surfome and exoproteome analysis strategy facilitates identification of novel vaccine antigen and overall helps in progress of discovery of vaccine. The study of the antibody response can advance how proteomics is used, because it investigates antibody antigen interactions and also unravel the relationship of antibody responses to pathogen and host characteristics. System immunology integrating with proteome i.e. immunoproteomics is applicable to those infections that are having tendency of diverse antibody target recognition and thus accurately reflects progression of the infection. PMID- 27465856 TI - Extremophiles as sources of inorganic bio-nanoparticles. AB - Industrial use of nanotechnology in daily life has produced an emphasis on the safe and efficient production of nanoparticles (NPs). Traditional chemical oxidation and reduction methods are seen as inefficient, environmentally unsound, and often dangerous to those exposed and involved in NP manufacturing. However, utilizing microorganisms for biosynthesis of NPs allows efficient green production of a range of inorganic NPs, while maintaining specific size, shape, stability, and dispersity. Microorganisms living under harsh environmental conditions, called "Extremophiles," are one group of microorganisms being utilized for this biosynthesis. Extremophiles' unique living conditions have endowed them with various processes that enable NP biosynthesis. This includes a range of extremophiles: thermophiles, acidophilus, halophiles, psychrophiles, anaerobes, and some others. Fungi, bacteria, yeasts, and archaea, i.e. Ureibacillus thermosphaericus, and Geobacillus stearothermophilus, among others, have been established for NP biosynthesis. This article highlights the extremophiles and methods found to be viable candidates for the production of varying types of NPs, as well as interpreting selective methods used by the organisms to synthesize NPs. PMID- 27465857 TI - Interaction between the photosensitizer lumichrome and human serum albumin: effect of excipients. AB - Lumichrome (Lc) is a photodegradation product of riboflavin that can be used as a photosensitizer (PS) in antibacterial photodynamic therapy (aPDT). The binding of Lc with plasma proteins such as human serum albumin (HSA) could affect its efficiency as PS. Excipients are necessary to prepare stable formulations to be used in aPDT and they may affect the PS-HSA binding. Hydroxypropyl (HP)-alpha, beta, gamma-cyclodextrin (CD), polyethylene glycol 400 (PEG400) and Pluronic(r) F 127 (PF127) were selected as model excipients in this study. The intrinsic HSA fluorescence quenching and absorption and fluorescence spectroscopy were used to evaluate the Lc-HSA interaction in the absence and presence of excipients. Nano differential scanning calorimetry (DSC) was used to determine the effect of excipients on HSA. The photostability of the samples was also evaluated. The combined results showed a modest interaction between Lc and HSA which was reduced mainly by HPbetaCD. No major alterations of the HSA nano-DSC thermogram were observed after addition of excipients. HSA did enhance Lc photodegradation. The presence of PF127 did also induce photochemical destabilization of Lc independent of HSA. In conclusion, HPalphaCD, HPgammaCD and PEG400 seemed to be the excipients more suitable for use in topical preparations containing Lc. PMID- 27465858 TI - Using diffusion tensor imaging to identify corticospinal tract projection patterns in children with unilateral spastic cerebral palsy. AB - AIM: To determine whether diffusion tensor imaging (DTI) can be an independent assessment for identifying the corticospinal tract (CST) projecting from the more affected motor cortex in children with unilateral spastic cerebral palsy (CP). METHOD: Twenty children with unilateral spastic CP participated in this study (16 males, four females; mean age 9y 2mo [standard deviation (SD) 3y 2mo], Manual Ability Classification System [MACS] level I-III). We used DTI tractography to reconstruct the CST projecting from the more-affected motor cortex. We mapped the motor representation of the more-affected hand by stimulating the more- and the less-affected motor cortex measured with single-pulse transcranial magnetic stimulation (TMS). We then verified the presence or absence of the contralateral CST by comparing the TMS map and DTI tractography. Fisher's exact test was used to determine the association between findings of TMS and DTI. RESULTS: DTI tractography successfully identified the CST controlling the more-affected hand (sensitivity=82%, specificity=78%). INTERPRETATION: Contralateral CST projecting from the lesioned motor cortex assessed by DTI is consistent with findings of TMS mapping. Since CST connectivity may be predictive of response to certain upper extremity treatments, DTI-identified CST connectivity may potentially be valuable for determining such connectivity where TMS is unavailable or inadvisable for children with seizures. PMID- 27465859 TI - Aspirin use and bleeding volume in skin cancer patients undergoing surgery: a randomized controlled trial. AB - ?: We investigated the occurrence of bleeding complications in patients who underwent skin tumor surgery and compared it between Aspirin users and a placebo control group. In this double blind randomized controlled trial, 32 patients who continued taking aspirin (intervention group) and 38 patients who stopped taking Aspirin (placebo group) before surgery were compared in terms of intraoprative and postoperative bleeding problems, hematoma and local signs of coagulopathy. There was no statistically significant difference in intraoprative bleeding between the study groups (P = 0.107). We concluded that continuation of Aspirin therapy had no significant effect on bleeding complications in patients who underwent skin tumor surgery. TRIAL REGISTRATION: IRCT201602049768N5 Flow chart of the study process and its final finding. PMID- 27465861 TI - The Era of Smartphones: Back to Our Biological Makeup? PMID- 27465860 TI - Engineering complex tissue-like microgel arrays for evaluating stem cell differentiation. AB - Development of tissue engineering scaffolds with native-like biology and microarchitectures is a prerequisite for stem cell mediated generation of off-the shelf-tissues. So far, the field of tissue engineering has not full-filled its grand potential of engineering such combinatorial scaffolds for engineering functional tissues. This is primarily due to the many challenges associated with finding the right microarchitectures and ECM compositions for optimal tissue regeneration. Here, we have developed a new microgel array to address this grand challenge through robotic printing of complex stem cell-laden microgel arrays. The developed microgel array platform consisted of various microgel environments that where composed of native-like cellular microarchitectures resembling vascularized and bone marrow tissue architectures. The feasibility of our array system was demonstrated through localized cell spreading and osteogenic differentiation of human mesenchymal stem cells (hMSCs) into complex tissue-like structures. In summary, we have developed a tissue-like microgel array for evaluating stem cell differentiation within complex and heterogeneous cell microenvironments. We anticipate that the developed platform will be used for high-throughput identification of combinatorial and native-like scaffolds for tissue engineering of functional organs. PMID- 27465862 TI - Spatial negative priming: Location or response? AB - In tasks requiring a response to the location of a target stimulus (for example, reaching), responses often are slower to a location that was recently occupied by an irrelevant distractor stimulus. In most demonstrations of this "spatial negative priming" (SNP), there is a 1-to-1 correspondence between possible stimulus locations and possible responses. As such, it is ambiguous whether the effect is due to a location-specific processing delay or to inhibition of a response. In the present experiment, subjects were required to press a key corresponding to the ordinal position of a target O in one of four locations, ignoring a distractor X appearing in another location. Location markers were widely or narrowly spaced, such that the inner two locations of wide displays corresponded to the outer two locations of narrow displays (hence, requiring different responses). SNP occurred when a target appeared at the location of a recent distractor, regardless of whether the response was associated with the distractor. In contrast, no SNP occurred for a target sharing the same response as a distractor, but in a different location. The results strongly support a location-specific, rather than response-specific, locus of SNP. PMID- 27465863 TI - Molecular dynamics simulation studies of hyperbranched polyglycerols and their encapsulation behaviors of small drug molecules. AB - Hyperbranched polyglycerol (HPG) is one of the most important hyperbranched polymers (HBPs) due to its interesting properties and applications. Herein, the conformation of HPGs depending on the degree of polymerization (DP) and the degree of branching (DB) is investigated explicitly by molecular dynamics simulations. This study shows that the radius of gyration (Rg) scales as Rg ~ DP(1/3), which is in close agreement with the result of the SANS experiment. For HPGs with the same DP, the radius of gyration, asphericities and solvent accessible surface area all monotonically decrease with the increase of DB; while for HPGs with the same DB, the molecular anisotropy decreases with the increase of DP. The radial density investigation discloses that the cavities are randomly distributed in the interior of the HPG core to support the "dendritic box effect", which can be used to encapsulate the guest molecules. Interestingly, the terminal groups of HPGs with a high Wiener index (WI) are more favorable to fold back into the interiors than those with the low WI when in water. For the hyperbranched multi-arm copolymer with a HPG core and many polyethylene glycol (PEG) arms, drug encapsulation studies show that the PEG caps can not only effectively prevent tamoxifen from leaving the HPG core, but also encapsulate tamoxifen inside the PEG chains. These simulation results have provided more details for understanding the structure-property relationships of HPGs in water. PMID- 27465865 TI - [Chinese consensus on progestogen related to maintaining early pregnancy and preventing miscarriage]. PMID- 27465866 TI - [Application of chromosomal microarray analysis for fetuses with talipes equinovarus]. AB - OBJECTIVE: To investigate the application of fetuses with talipes equinovarus(TE)using chromosomal microarray analysis(CMA)technology. METHODS: From May 2012 to June 2015, 54 fetuses were found with TE and with or without other structural anomalies by prenatal ultrasound. Karyotyping was taking for them all, and the fetuses with normal karyotypes took another CMA test. The data were analyzed with CHAS software. Finally all the cases were followed up to know about their pregnancy outcomes. RESULTS: One of the 54 cases was detected with abnormal karyotype which was trisomy 18(2%, 1/54). CMA was undertaken to the remaining fetuses, they were divided into 2 groups, including isolated TE group(n= 38)and complex TE group(n=15). The detection rate of clinical significant copy number variations(CNV)by CMA was 11%(6/53), while isolated and complex TE group were 5%(2/38)and 4/15, respectively(P= 0.047). Of the 53 cases, 51 cases were successfully followed up. Eleven cases were found without TE after birth, and the false positive rate(FPR)of TE was 22%(11/51). CONCLUSIONS: Whole genome high-resolution CMA increased the detection rate by 11% in fetuses with TE. With the FPR and the detection rate of the clinical significant CNV of 2 groups, whole-genome CMA could be recommended to the fetuses with complex TE group but normal karyotypes. A series of ultrasonic tests should be suggested to the isolate TE group, while with the abnormal ultrasound, fetuses would be suggested to have CMA test for decreasing the rates of invasive prenatal diagnosis and FPR. PMID- 27465864 TI - Assessment of antigenic difference of equine influenza virus strains by challenge study in horses. AB - We previously reported that horse antiserum against the Japanese equine influenza vaccine virus, A/equine/La Plata/1993 (LP93) exhibited reduced cross neutralization against some Florida sublineage Clade (Fc) 2 viruses, for example, A/equine/Carlow/2011 (CL11). As a result, Japanese vaccine manufacturers will replace LP93 with A/equine/Yokohama/aq13/2010 (Y10, Fc2). To assess the benefit of updating the vaccine, five horses vaccinated with inactivated Y10 vaccine and five vaccinated with inactivated LP93 were challenged by exposure to a nebulized aerosol of CL11. The durations of pyrexia (>=38.5 degrees C) and other adverse clinical symptoms experienced by the Y10 group were significantly shorter than those of the LP93 group. PMID- 27465867 TI - [Clinical analysis of preimplantation genetic diagnosis with HLA matching for beta-thalassemia]. AB - OBJECTIVE: To investigate the efficacy and feasibility of preimplantation genetic diagnosis(PGD)with human leukocyte antigen(HLA)matching for beta-thalassemia. METHODS: A total of 43 referred beta-thalassemia couples, with at least on child in need of hematopoietic stem cell transplantation(HSCT), underwent PGD for HLA matching at the First Affiliated Hospital of Sun Yat-sen University from 2010 to 2015. PGD cycles of these couples were retrospectively analyzed, and 15 infants born from PGD-HLA were followed up. RESULTS: A total of 84 oocyte retrieval cycles were performed, providing 14+/-7 oocytes per cycle. Fifty nine embryos biopsied cycles were done, including 24 cleavage stage and 35 blastocyst stage biopsy cycles. In cleavage stage, 259 embryos were biopsied, 93.4%(242/259)of them with conclusive molecular diagnosis, and the percentage of unaffected embryos(normo-homozygote and heterozygote)was 71.4%(185/259). The percentage of HLA matched unaffected embryos was 9.3%(24/259). In blastocyst stage, 306 embryos were biopsied, while 93.8%(287/306)of them were conclusive, and the percentage of unaffected embryos was 70.6%(216/306). The percentage of HLA matched unaffected embryos in blastocyst stage biopsy was 14.4%(44/306), which was higher than in cleavage stage biopsy(P< 0.05). Forty three female carriers underwent 48 embryo transfer cycles including 3 fresh and 45 frozen-thawed embryo transfer cycles. Three fresh embryo transfer cycles were done after cleavage stage biopsy, resulted in a birth of healthy twins born at 36 weeks' gestation. All the embryos were frozen after blastocyst biopsied. Totally, 54 frozen-thawed embryos that were transferred in 45 frozen-thawed embryo transfer cycles included 25 embryo from cleavage stage biopsy and 29 embryo from blastocyst stage biopsy, and 42 of them were HLA matched. Clinical pregnancy rate and implantation rate per cycle in frozen-thawed embryo transfer were 38%(17/45)and 37%(20/54)respectively. A total of 15 infants were born, 2 were from a fresh embryo transfer cycle, and 13 were from frozen-thawed embryo transfer cycles. RESULTS of prenatal diagnosis from delivered cases were matched to that of PGD. Four sick children have been cured by HSCT from these HLA matched born siblings. CONCLUSION: PGD with HLA matching is an established method for conceiving a child who may donate hematopoietic stem cells to save an ill sibling. PMID- 27465868 TI - [Risk factors of peripartum hysterectomy in placenta previa: a retrospective study of 3 840 cases]. AB - OBJECTIVE: To investigate the risk factors of peripartum hysterectomy in placenta previa through retrospective study of 3 840 placenta previa cases. METHODS: The clinical data of 3 840 patients with placenta previa who delivered in West China Second University Hospital between Jan 2005 and June 2014 were analyzed retrospectively. The relationship of certain factors and peripartum hysterectomy was analyzed, including maternal age, residence place, parity, prior curettage, prior cesarean section, twin or multiple pregnancy, antenatal vaginal bleeding, type of placenta previa, suspected placenta accreta, antenatal level of hemoglobin and gestational age at delivery. RESULTS: The prevalence of placenta previa was 4.84%(3 840/79 304)in West China Second University Hospital during the study period, and the incidence of preipartum hysterectomy in patients with placenta previa was 2.76%(106/3 840). One-factor analysis demonstrated that residence place, parity, times of prior curettage, prior cesarean section, prenatal vaginal bleeding, anterior placenta, type of placenta previa, placenta accreta, antenatal anemia and gestational age at delivery were potential risk factors for peripartum hysterectomy(P<0.01). Variables with P<0.1 in one-factor analysis were introduced to multi-factor logistic regression analysis, which suggested that one prior cesarean section(OR=12.9,95% CI:6.3-26.3), two or more prior cesarean sections(OR=14.4, 95%CI:3.9-53.2), anterior placenta(OR=4.8, 95%CI:2.1-10.7), complete placenta previa(OR=5.9, 95%CI: 1.8-42.5), placenta accreta(OR=11.2, 95%CI:6.8-18.6), antenatal hemoglobin<100 g/L(OR=1.7, 95%CI: 1.0 2.8)and delivery before 34 gestational weeks(OR=3.2, 95%CI: 1.6-6.3)were independent risk factors of peripartum hysterectomy in patients with placenta previa(P<0.05). CONCLUSIONS: Prior cesarean section, anterior placenta, complete placenta previa, placenta accreta, antenatal anemia and delivery before 34 gestational weeks are high risk factors of peripartum hysterectomy in placenta previa patients. Perinatal care and risk evaluation before cesarean section are important to improve perinatal outcomes and reduce peripartum hysterectomy. PMID- 27465869 TI - [Clinical analysis of efficacy and quality of life of segmental bowel resection for bowel endometriosis]. AB - OBJECTIVE: To evaluate the efficacy and quality of life of segmental bowel resection for bowel endometriosis. METHODS: Totally 62 symptomatic patients with bowel endometriosis undergoing segmental bowel resection were recruited. A visual analogue scale(VAS)and the 36-item short form health survey(SF-36)questionnaire were administered before and at least 1 year after surgery, respectively. Pregnancy rates were also recorded. RESULTS: Sixty-two patients in total underwent follow-up ranging from 12 to 74 months. All patients complained of obvious pain symptoms, including dysmenorrhea, dyspareunia, pain on defecation and chronic pelvic pain. The relief of dysmenorrhea(2.9 +/- 2.2 versus 7.5 +/- 2.9), dyspareunia(0.7 +/- 0.5 versus 4.3 +/- 2.2)and pain on defecation(1.6 +/- 0.7 versus 7.3 +/- 1.9)after surgery was statistically significant(all P<0.01). The scores for all 8 domains of the SF-36 questionnaire were significant improved after segmental bowel resection(all P<0.01). The complication rate was 45%(28/62), including 18 cases of urinary retention, 4 rectovaginal fistulas, 2 cases of vaginal dehiscence, and 1 case each of thrombogenesis, pelvic abscess and general peritonitis. All of the patients with complications recovered well throughout follow-up. The postoperative pregnancy rate of the previous infertile patients was 6/10. Among the 6 gestational cases, 2 had labour, 2 underwent caesarean sections, one had a spontaneous natural abortion, and one underwent uterine curettage. CONCLUSION: Segmental bowel resection could significantly relieve pain and improve quality of life for patients with bowel endometriosis. PMID- 27465870 TI - [Utilize the simplified POP-Q system in the clinical practice of staging for pelvic organ prolapse: comparative analysis with standard POP-Q system]. AB - OBJECTIVE: To determine the association between simplified pelvic organ prolapse quantification system(S-POP-Q)and the standard pelvic organ prolapse quantification system(POP-Q)in describing pelvic organ prolapse. METHODS: This was an observational study. From Jan. 2010 to Jan. 2014, 256 subjects with pelvic floor disorder symptoms underwent two exams: a POP-Q exam and a S-POP-Q exam. For the S-POP-Q system, vaginal segments of the exam were defined using points Ba, Bp, C, and D. For the POP-Q system vaginal segments of the exam were defined using points Aa, Ba, Ap, Bp, C, and D. The inter-system consistency between the overall ordinal stages, the anterior vaginal wall stages, the posterior vaginal wall stages, the cervix stages, the posterior fornix or vaginal cuff stages from each two kind of exam were compared. RESULTS: The Kendall tau-b correlation coefficient for overall stage was 0.81, the Kendall tau-b correlation coefficients were 0.81, 0.81, 0.85, 0.88 for the anterior vaginal wall, for the posterior vaginal wall, for the cervix, for the posterior fornix or vaginal cuff, respectively. CONCLUSION: There is almost perfect association between S-POP-Q and POP-Q in describing pelvic organ prolapse. PMID- 27465871 TI - [Identification and prognostic value of differentially expressed proteins of patients with platinum resistance epithelial ovarian cancer in serum]. AB - OBJECTIVE: To identified differentially expressed proteins associated with platinum resistance in platinum resistance epithelial oarian cancer(EOC)patients in serum and investigate their clinical value. METHODS: A total of 106 patients withoverian tumor in affiliated tumor hospital of Guangxi Medical University from August 1998 to September 2013 were enrolled in this study, which include 52 cases od platinum-sensitive(PTS), 44 cases of platinum-resistant(PTR)and 10 cases of benign ovarian cyst(BOC). Thirty-three cases of normal women proceeded physical examination in our hospital in 2008 were chosen as control group(NC). Four groups of patients serum samples of 4 groups were collected and preserved.(1)Differentially express level of serum proteins of 10 cases of every group(PTS & PTR vs NC, PTS & PTR vs BOC, PTS vs PTR)were identified with isobaric tags for relative and absolute quantitative(iTRAQ)based quantitative proteomic approach and then was subjected to bioinformatics analysis.(2)Proteins that played a important role in multidrug resistance were validated by western blot(WB)and ELISA in 44 PTR patients, 52 PRS patients and 33 NC women.(3)Pearson correlation analysis was used to explain the relationship between proteins and clinical pathological parameters of PTR individuals. Kaplan-Meier method was supposed to explore serum biomarkers associated with clinical prognosis data. Receiver operating characteristic(ROC)curves were used to determine the diagnostic value of the markers. RESULTS: (1)Based on the result of bioinformatics analysis, 56 proteins, 39 proteins and 62 proteins were identified respectively among PTS & PTR vs NC, PTS & PTR vs BOC, PTS vs PTR. It showed that C6 and CNTN1 have a positive seletion effect among Asians and BCHE among Europeans through searching Haplotter database. CRP, FN1, S100A9, TF, ALB, VWF, APOC2, APOE, CD44, F2, GPX3 and ACTB proein were further verified related with platinum resistance by taking intersection analysis in the COREMINE database and TCGA.(2)The expression level of SERPINA1 protein in serum of PTR group, PTS group and NC groupwere 41.7+/-9.2, 32.8+/-6.6 and 14.2+/-3.6 respectively using WB assay, and(816+/-246),(686+/-205)and(756 +/- 244)MUg/MUl respectively using ELISA; the expression level of ORM1 protein in PTR, PTS and NC serum were 37.9+/ 7.0, 27.0+/-22.5 and 21.7+/-2.6 respectively using WB assay, and(221+/-35),(174+/ 23)and(157+/-18)MUg/MUl respectively using ELISA; the expression level of FN1 protein in PTR, PTS and NC serum were 30.3+/-11.4, 18.2+/-5.2, 23.7+/-3.9 respectively by WB assay, and(71+/-13),(62+/-13),(69+/-13)ng/MUl respectively by ELISA; the expression level of GPX3 protein in PTR, PTS and NC serum were 1.2+/ 0.3, 2.2+/- 0.3, 1.6+/-0.3 respectively WB assay. The expression of each protein by using western blot method and ELISA method had the same trend as that using iTRAQ technology.(3)Pearson correlation analysis showed, the expression of SERPINA1, FN1 and ORM1 had a positive correlation with recurrence and death of PTR patients(P <0.01, P <0.05), but was negatively correlated with progress free survival of PTR patients(P <0.05). Kaplan-Meier analysis indicated that clinical stage, initial treatment outcomes, the express level of SERPINA1, FN1 and ORM1 were significantly related with progression-free survival(P <0.05), the initial treatment outcomes was related with overall survival(P=0.027). The overall predictive accuracy of each protein was reflected by the area under the ROC curve(AUC), FN1 ORM1 and SERPINA with ROC areas of 0.679, 0.910 and 0.666 respectively. The diagnosis value of ORM1 protein in ovarian cancer patients with platinum resistance performance is significantly higher than that of FN1 and SERPINA1 protein(P=0.000) CONCLUSIONS: The differentially express level of FN1, SERPINA1 and ORM1 between PTS and PTR play a essential role in measuring subtle changes in response to platinum-based chemotherapy and may be involved in biological processes of platinum resistance. ORM1 has higher diagnostic efficiency of platinum resistance in ovarian cancer patients. It may be a promising candidate biomarker for screening and diagnosis of ovarian cancer patients with platinum resistance. PMID- 27465872 TI - [Comparison of the clinical efficacy of different treatments based on radical surgery in stage I b2 and IIa2 cervical cancer: a prospective randomized control study]. AB - OBJECTIVE: To compare the clinical efficacy of different treatments based on radical surgery in stage I b2 and II a2 cervical cancer through prospective randomized controlled study. METHODS: A total of 133 patients with stage I b2 and II a2 cervical cancer treated at Beijing Obstetrics and Gynecology Hospital of Capital Medical University during January 2009 to December 2012 were enrolled and randomly assigned to receive one of the following three treatments: preoperative intracavitary irradiation(PII)group, radical hysterectomy(RH)group, and neoadjuvant chemotherapy(NACT)group. Operation method included uterine extensive resection, pelvic lymph node excision, with or without para-aortic lymph node resection. The recent curative effect and side effect of preoperative treatment were observed. The operation time, intraoperative blood loss, surgical complications, postoperative pathological risk factors and postoperative adjuvant therapy and side effect, the survival situation were evaluated among the 3 groups. RESULTS: (1)The response rates were 88%(37/42)and 82%(37/45)respectively of the PII group and NACT group. The difference was insignificant(P=0.528). Side effects were less in the PII group. Only 5 patients(12% , 5/42)had slight gastrointestinal reaction. Myelosuppression and gastrointestinal reaction in NACT group were 76%(34/45)and 67%(30/45)respectively, which were more serious than that in group PII group(P<0.05).(2)Intraoperative blood loss and operation time in PII group [(678+/- 239)ml and(181+/-39)minutes]and NACT group [(625+/-137)ml and(168+/-25)minutes]had a decreasing trend compared with that in RH group [(711 +/- 319)ml and(202 +/- 64)minutes], but the differences were no significant(P >0.05). NACT group could shorten operation time compared with the RH group(P <0.05). The lymph node metastases rate were 30%(14/46), 29%(12/42)and 29%(13/45)and the deep stromal invasion rate were 22%(10/46), 31%(13/42)and 31%(14/45)in RH group, PII group and NACT group respectively(all P>0.05). The lymph-vascular space involvement(LVSI)in NACT group was significantly lower than that in RH group [31%(14/45)vs 57%(26/46), P=0.015]. The number of patients with histological risk factors in NACT group was higher thanthat in RH group [27%(12/45)vs 9%(4/46), P= 0.024]. All surgery were successfully completed and no treatment-related deaths occurred in three groups. The incidence of 3-4 grade adverse reactions evaluated by the common terminology criteria for adverse event(CTCAE)was 13%(6/46), 14%(6/42), 18%(8/45)in RH group, PII group and NACT group respectively(P=0.855). Three-year disease free survival(PFS)were 74.0%, 78.5% and 80.0%, and 3-year overall survival(OS)were 80.4%, 83.3% and 84.4% in RH group, PII group and NACT group respectively(all P>0.05). CONCLUSIONS: The recent curative effect of PII and NACT were similar. They couldn't improve 3-year of PFS and OS of the patients with Ib2 and IIa2 stage cervical cancer. But NACT can reduce the operation difficulty and can reduce the incidence of postoperative pathological risk factors, which could reduce postoperative adjuvant therapy. PMID- 27465873 TI - [Effects of antimicrobial peptide LL-37 expressed and purified from prokaryotes in the murine model of vaginal candidiasis]. AB - OBJECTIVE: To study the effects of antimicrobial peptide LL-37 expressed and purified from prokaryotes on candida albicans growth. METHODS: (1)Thirty female Kunming mice were treated with estrogen and white candida yeast suspension were poured into vagina to establish a vulvovaginal candidiasis(VVC)murine model. After successful establishing the VVC mouse model, mice were randomly sorted into test group(n=15)and control group(n=15). Suspension(30 MUl, 100 MUg/ml)of recombinant peptide LL-37 expressed and purified in Prokaryotes was given by intravaginal administration to the test group for 5 days, while the same amount of phosphate buffered saline(PBS)was given to the control group.(2)Tweenty-four hours after treatment, the fungal burden and colony-forming unit(CFU)of vaginal fluids were evaluated. All mice were subsequently sacrificed and vaginal tissues were harvested for tissue homogenate preparation. ELISA was used to determine the levels of nterleukin-10(IL-10)and interferon-gamma(IFN-gamma)in the isolated vaginal tissues. RESULTS: (1)VVC mouse model was established successfully in this study. Vaginal mucosa congestion, edema, vaginal plica disappearing were obviously observed in the control group. After treatment with recombinant protein LL-37 vaginal mucosa has no obvious change in the test group.(2)Fungal burden and CFU of vaginal fluids were significantly lower in the test group [(4.8+/ 1.0)*10(4) CFU/ml]than that in the control group [(8.5+/-2.1)*10(4) CFU/ml, P=0.017]. IFN-gamma level of the test group was increased [(257+/-11)vs(197+/ 4)pg/ml, P=0.000], while the level of IL-10 was reduced [(287 +/- 15)vs(379 +/- 17)pg/ml P=0.000] resulting in a the ratio of IFN-gamma/IL-10 was in significantly higher in test group(0.892+/-0.008 vs 0.496+/-0.013, P=0.000). CONCLUSION: Recombinant protein LL-37 expressed and purified from prokaryotes inhibits the growth candida albicans and improves vaginal immunity by adjusting IFN-gamma and IL-10 secretion in the VVC mouse model, highlighting the therapeutic potential of LL-37 for VVC. PMID- 27465874 TI - Mitochondrial haplogroup M9a1a1c1b is associated with hypoxic adaptation in the Tibetans. AB - While hypoxic environment at high altitude remains a major challenge for travelers from low-altitude areas, Tibetans have adapted to the high-altitude environment. Mitochondria are the energy conversion and supplement centers in eukaryotic cells. In recent years, studies have found that the diversity of the mitochondrial genome may have a role in the adaptation to hypoxia in Tibetans. In this study, mitochondrial haplogroup classification and variant genotyping were performed in Tibetan and Han Chinese populations living at different altitudes. The frequencies of mitochondrial haplogroups B and M7 in the high-altitude population were significantly lower compared with those in the low-altitude population (P=0.003 and 0.029, respectively), whereas the frequencies of haplogroups G and M9a1a1c1b in the high-altitude group were significantly higher compared with those in the low-altitude group (P=0.01 and 0.002, respectively). The frequencies of T3394C and G7697A, which are the definition sites of haplogroup M9a1a1c1b, were significantly higher in the high-altitude group compared with that in the low-altitude group (P=0.012 and 0.02, respectively). Our results suggest that mitochondrial haplogroups B and M7 are associated with inadaptability to hypoxic environments, whereas haplogroups G and M9a1a1c1b may be associated with hypoxic adaptation. In particular, the T3394C and G7697A variants on haplogroup M9a1a1c1b may be the primary cause of adaptation to hypoxia. PMID- 27465875 TI - Mesenchymal Stem Cells Derived from Human Bone Marrow and Adipose Tissue Maintain Their Immunosuppressive Properties After Chondrogenic Differentiation: Role of HLA-G. AB - Mesenchymal stem cells (MSC) have emerged as alternative sources of stem cells for regenerative medicine because of their multipotency and strong immune regulatory properties. Also, human leukocyte antigen G (HLA-G) is an important mediator of MSC-mediated immunomodulation. However, it is unclear whether MSC retain their immune-privileged potential after differentiation. As promising candidates for cartilage tissue engineering, the immunogenic and immunomodulatory properties of chondro-differentiated MSC (chondro-MSC) require in-depth exploration. In the present study, we used the alginate/hyaluronic acid (Alg/HA) hydrogel scaffold and induced both bone marrow- and adipose tissue-derived MSC into chondrocytes in three-dimensional condition. Then, MSC before and after chondrocyte differentiation were treated or not with interferon gamma and tumor necrosis factor alpha mimicking inflammatory conditions and were compared side by side using flow cytometry, mixed lymphocyte reaction, and immunostaining assays. Results showed that chondro-MSC were hypoimmunogenic and could exert immunosuppression on HLA-mismatched peripheral blood mononuclear cells as well as undifferentiated MSC did. This alloproliferation inhibition mediated by MSC or chondro-MSC was dose dependent. Meanwhile, chondro-MSC exerted inhibition on natural killer cell-mediated cytolysis. Also, we showed that HLA-G expression was upregulated in chondro-MSC under hypoxia context and could be boosted in allogenic settings. Besides, the Alg/HA hydrogel scaffold was hypoimmunogenic and its addition for supporting MSC chondrocyte differentiation did not modify the immune properties of MSC. Finally, considering their chondro-regenerative potential and their retained immunosuppressive capacity, MSC constitute promising allogenic sources of stem cells for cartilage repair. PMID- 27465876 TI - Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration as a New Diagnostic Tool for Invasive Pulmonary Mycoses. AB - Early diagnosis of invasive pulmonary mycoses in immunocompromised patients is a major determinant of effective treatment. However, making a reliable diagnosis is challenging and often requires transbronchial or even surgical lung biopsy. We provide evidence that endobronchial ultrasound-guided transbronchial needle aspiration may be an attractive, less invasive diagnostic method. Endobronchial ultrasound-guided transbronchial needle aspiration was not only a diagnostic clue in the presented kidney transplant recipient with invasive pulmonary mycosis but was useful in assessment of treatment efficacy. PMID- 27465877 TI - Release of transgenic progranulin from a living hyaline cartilage graft model: An in vitro evaluation on anti-inflammation. AB - Osteoarthritis (OA) is a prevalent condition that compromises and even jeopardizes the life quality of millions of people. Common symptoms in OA includes joint stiffness and soreness, and they are often associated with inflammations to various extend. Due to the avascular and aneural nature of articular hyaline cartilage, it has limited self-repair capabilities; especially under inflammatory conditions, damages inflicted on cartilage are often irreversible. Hence, treatment approaches focus on anti-inflammation or articular cartilage replacement. In this study, an engineered, dual-functional living hyaline cartilage graft (LhCG), capable of releasing transgenic anti-inflammatory cytokine-progranulin (PGRN) is developed and envisioned to simultaneously fulfil both requirements. The therapeutic functionality of PGRN releasing LhCG is evaluated by co-culturing the constructs with tumor necrosis factor-alpha (TNFalpha) secreting THP-1 cells to simulate the inflammatory condition in arthritis. Non-transgenic LhCG constructs and non-coculture sample groups were set up as controls. Gene expression and ECM composition changes across samples were assessed to understand the effects of PGRN as well as inflammatory environment on the cartilage graft. Collectively, the results in this study suggest that in situ release of transgenic recombinant PGRN protects LhCG from induced inflammation in vitro; contrastively, in the absence of PGRN, cartilage grafts are at risk of being degraded and mineralized under exposure to TNFalpha signaling. This shows that cartilage graft itself can be at risk of degradation or calcification when implanted in arthritic microenvironment. Hence, the inflammatory microenvironment has to be considered in cartilage replacement therapy to increase chances of successful joint mobility restoration. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2968-2977, 2016. PMID- 27465878 TI - How have guidelines on when to start antiretroviral therapy affected survival of people living with HIV infection? AB - PURPOSE OF REVIEW: Until recently, conflicting data led to discrepancies in guideline recommendation on 'when to start' antiretroviral therapy (ART) in asymptomatic HIV infection. This review focuses on evidence underpinning guidelines over the past decade and recent randomized clinical trial data in this area, which definitively informed the debate. RECENT FINDINGS: In 2015, the landmark START trial demonstrated clear clinical benefit in terms of a reduction in serious AIDS and non-AIDS-related events and death from any cause in HIV positive individuals randomized to start ART with a CD4 count more than 500 cells/MUl compared with deferring starting until CD4 count declined to 350 cells/MUl. Further, randomized clinical trial data were also available from the Temprano trial in Cote D'Ivoire which also demonstrated a reduced risk of death associated with earlier ART initiation. SUMMARY: Following the results of the START trial, guidelines that had previously set CD4 thresholds for treatment initiation were universally changed. This is likely to reduce mortality in people living with HIV who are diagnosed early and have immediate access to ART. However, unless HIV testing rates and ART coverage are increased globally, raising the threshold for initiation of ART in clinical guidelines may be of limited benefit in reducing mortality in HIV. PMID- 27465879 TI - Tenofovir Alafenamide. AB - OBJECTIVE: To review the pharmacology, efficacy, safety, and place in therapy for tenofovir alafenamide (TAF). DATA SOURCES: A search using PubMed was conducted (2004 to May 2016) using the following keywords: tenofovir alafenamide, TAF, and GS-7340. Articles were evaluated for content, and bibliographies were reviewed. Data available exclusively as abstracts from major infectious diseases and HIV conferences were also evaluated for inclusion. STUDY SELECTION AND DATA EXTRACTION: Studies included were in vitro investigations; phase I, II, and III clinical trials; and pharmacokinetic and pharmacodynamic evaluations. DATA SYNTHESIS: Similar to tenofovir disoproxil fumarate (TDF), TAF is a prodrug of tenofovir but results in significantly higher intracellular tenofovir concentrations and lower serum levels. As a result, TAF is expected to have efficacy similar to that of TDF while reducing tenofovir-associated nephrotoxicity and bone mineral density losses. Clinical trials evaluating the safety and efficacy of TAF-containing antiretroviral regimens have confirmed these expectations, consistently demonstrating similar virological suppression compared with TDF-containing regimens as well as significant improvements in markers of kidney function and bone health. Three combination products containing TAF were approved by the United States Food and Drug Administration for the management of HIV-1 infection. The first of these was a single tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF which is now a recommended regimen in clinical practice guidelines for initial treatment in antiretroviral-naive patients. CONCLUSIONS: TAF is a novel nucleotide reverse transcriptase inhibitor for the treatment of HIV-1 infection that has efficacy similar to that of TDF and improved safety compared with TDF. PMID- 27465880 TI - Evidence for the Use of Epoprostenol to Treat Raynaud's Phenomenon With or Without Digital Ulcers. AB - OBJECTIVE: To review the evidence for using intravenous (IV) epoprostenol to treat Raynaud's phenomenon (RP). DATA SOURCES: The databases MEDLINE (1946 to March 2016), PubMed, and International Pharmaceutical Abstracts were searched using the terms epoprostenol, Flolan, Raynaud's disease, and CREST syndrome. Further literature sources were identified by reviewing article citations. STUDY SELECTION AND DATA EXTRACTION: All English-language, clinical trials and case series evaluating IV epoprostenol for the management or treatment of RP were included. Lower-quality evidence were incorporated due to limited information. DATA SYNTHESIS: Seven small uncontrolled studies/case series, 1 small placebo controlled study, and 1 larger randomized trial were identified and included. There was no consistent measurement of efficacy utilized, but improvements in hand temperature, RP attack duration and frequency were commonly associated with IV epoprostenol treatment (5 trials). There were conflicting data regarding effect sustainability, with 5 trials showing long-term effects and 3 showing immediate effects. Fewer ischemic ulcers developed during treatment with IV epoprostenol in 1 trial compared to conventional treatment. Ulcer healing ocurred in 2 trials. Common adverse effects included hypotension, headache, flushing, gastrointestinal symptoms, and jaw pain. CONCLUSIONS: Available evidence supports the use of IV epoprostenol for treatment of severe RP in patients refractory or intolerant to standard therapies. The dose, titration schedule, and duration of IV epoprostenol utilized in studies varied, but a conservative approach to initiation should be considered. Patients who do not respond to intermittent infusions and have severe digital ischemia may require more aggressive regimens. PMID- 27465881 TI - Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin. AB - OBJECTIVE: New regimens to treat hepatitis C virus infection have expanded the eligible patient population to include more patients receiving concurrent warfarin. The primary objective of this study was to assess whether a drug interaction occurs when these regimens are added to warfarin therapy. METHODS: This was a retrospective cohort design using a nationwide database of the Veterans Affairs Health System. Patients on warfarin therapy treated with sofosbuvir or ombitasvir, paritaprevir-ritonavir, and dasabuvir (OBV-PTV/r-DSV) from March 2014 through October 2015 were identified. The warfarin dose response was calculated using a warfarin sensitivity index (WSI) defined as the steady state INR divided by the mean daily warfarin dose. The primary outcome was the change in WSI from hepatitis C treatment initiation to completion. RESULTS: The final sample consisted of 271 patients. The WSI decreased 23% from a mean baseline value of 0.53 to 0.39 (decrease of 0.14; 95% CI = 0.11 to 0.16; P < 0.001). OBV-PTV/r-DSV produced a significantly greater decrease than any sofosbuvir regimen. Concurrent ribavirin accounted for an additional decrease in warfarin sensitivity of -0.09 (95% CI = -0.06 to -0.12; P < 0.001). The percentage of subtherapeutic INR results increased from 26% prior to hepatitis C treatment to 58% during treatment. CONCLUSIONS: Results indicate a clinically significant reduction in warfarin dose-response when hepatitis C treatment regimens were added to warfarin. They were most profound with OBV-PTV/r-DSV. Ribavirin was associated with an additive effect. Clinicians should be aware of this potential drug interaction to closely monitor and minimize subtherapeutic levels of anticoagulation. PMID- 27465882 TI - Novel oral anticoagulant management issues for the stroke clinician. AB - BACKGROUND: Four nonvitamin K antagonist oral anticoagulants (NOACs) are approved for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). AIMS: In this review, we assemble available evidence for the best management of ischemic and hemorrhagic stroke patients in the context of NOAC use. SUMMARY OF REVIEW: NOACs provide predictable anticoagulation with fixed dosages. The direct thrombin inhibitor dabigatran and direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban are all noninferior to warfarin for the prevention of ischemic stroke and systemic embolism and are associated with reduced incidence of intracranial hemorrhage. While these agents offer treatment options for NVAF patients, they also present challenges specific to the clinician managing cerebrovascular disease patients. CONCLUSIONS: We summarize available evidence and current approaches to the initiation, dosing, monitoring and potential reversal of NOACs in stroke patients. PMID- 27465883 TI - Discussing Sexuality With Women Considering Risk-Reducing Salpingo-oophorectomy: An International Survey of Current Practice in Gynecologic Oncology. AB - OBJECTIVE: To determine how frequently gynecologic oncologists discuss sexuality with women considering risk-reducing salpingo-oophorectomy. Secondary objectives were to assess the availability of resources, and the barriers to discussing sexuality. METHODS: Members of the Australian Society of Gynaecologic Oncologists, International Gynecologic Cancer Society, and Society of Gynecologic Oncology were invited to complete an online survey. Questions addressed frequency of, and barriers to, discussing sexuality, and availability of resources related to sexual issues. RESULTS: Three hundred eighty-eight physicians in 43 countries responded from 4,006 email invitations (9.7%). Ninety-one percent reported discussing sexuality preoperatively, and 61% discuss it with every patient. Factors associated with higher rates of discussion were female sex (P = 0.020), higher level of training (P = 0.003), time in practice (P = 0.003), and consulting more risk-reducing salpingo-oophorectomy patients per month (P = 0.006). Commonly discussed issues were vasomotor menopausal symptoms (91%) and vaginal dryness (85%). Eighty-eight percent of respondents believed that sexuality should be discussed preoperatively, and most felt that it is their responsibility (82%). Fear of causing distress was the most common barrier to discussing sexuality (49%). Twenty-four percent felt that they did not have adequate training to discuss sexual function. CONCLUSIONS: Although most respondents believed that discussing sexuality should occur preoperatively, only 61% discuss this with every patient. Resources specifically relating to sexuality are limited. The most common barrier to discussing sexuality was fear of causing distress. Nearly one quarter of gynecologic oncologists felt inadequately trained to discuss sexual function. PMID- 27465884 TI - A Novel Genetic Mutation in a Patient With Recurrent Biparental Complete Hydatidiform Mole: A Brief Report. AB - Recurrent hydatidiform moles are defined by the occurrence of two or more molar pregnancies in the same patient. Familial recurrent hydatidiform moles (FRHM) is a rare autosomal recessive condition where women have an inherited predisposition to have molar pregnancies. Genotyping demonstrated that they are diploid and biparental. We report a case of FRHM from Egypt with a history of 6 recurrent complete moles. Sequencing of the NLPR7 gene revealed a deleterious homozygous base change in exon 2, c.197G>A, which would result in a truncated protein p.W66*. To the best of our knowledge, this mutation has not been described before. PMID- 27465885 TI - Patterns of Care and Outcome of Elderly Women Diagnosed With Cervical Cancer in the Developing World. AB - Scarce data exist about the impact of age in cervical cancer (CC) patients in the developing world. The objective of the current study was to examine the patterns of care and outcome of elderly patients treated in a developing country. Medical records of patients treated from 2006-2009 at the Brazilian National Cancer Institute were reviewed. Patients were divided between women 70 years or older and women younger than 70 years. The chi tests were used and odds ratios were calculated. Survival was examined using the Kaplan-Meier method. Single and multivariate Cox proportional hazards modeling were used. A total of 1482 patients were analyzed: 1339 patients younger than 70 years and 143 patients 70 years or older. A marked difference in treatment was noted, even after stratifying by disease stage. Only 21% of the older patients underwent surgical treatment compared with 27.6% of the younger. After adjusting for confounding variables, the hazard ratio for death from CC in the elderly was 1.05 (95% confidence interval, 0.81-1.36; P = 0.11). These results corroborate previous data from developed countries: elderly patients have more advanced disease at diagnosis, and age is an important factor in the allocation of treatment for patients with CC. Worse outcome seemed to be mainly the result of more advanced stage and treatment allocation rather than age itself. PMID- 27465886 TI - Tumor-Infiltrated Lymphocytes, Macrophages, and Dendritic Cells in Endometrioid Adenocarcinoma of Corpus Uteri as Potential Prognostic Factors: An Immunohistochemical Study. AB - AIM: In the present study, we aim to investigate the presence of inflammatory immune cells lymphocytes, macrophages, and dendritic cells as prognostic factors in the clinical outcome of endometrioid adenocarcinoma. MATERIALS AND METHODS: The study used data from the Belarus cancer registry and archival histological material of 82 patients with stage I to III (International Federation of Gynecology and Obstetrics, 2009) with retrospectively known good (survival) and poor (disease progression and death) outcomes. All cases were immunohistochemically stained for CD3, CD20, CD57, CD68, and S100. Two independent samples were compared for the characteristics of signs, and obtained results were analyzed by ROC analysis, Mantel-Cox tests. A P value of less than 0.05 was considered statistically significant. RESULTS: Expressions of CD3, CD57, and CD68 were significantly higher in the good outcome group (P < 0.001) compared with the poor outcome group. There was no significant difference between CD20 and S100 in the 2 groups. All criteria showed significant difference (P < 0.001) in survival of patients. CONCLUSIONS: In conclusion, our study showed for the first time that the low level of expression of markers for tumor-associated T lymphocytes (CD3), NK cells (CD57), macrophages (CD68), and an increased expression of markers for tumor-associated B lymphocytes (CD20) and dendritic cells (S100) in endometrioid adenocarcinoma progression lead to poor survival outcome. The associated criteria of these immune cells may be used as predictive factors in the diagnosis of tumor progression. Our study indicates that local antitumor immune response may be applied to define risk groups to predict clinical outcomes. PMID- 27465887 TI - Evaluation of a New Oncogynecologic Training Program. AB - OBJECTIVE: The first cohort of Turkish fellows has begun to graduate from a newly accredited training program on gynecologic oncology. This study aimed to investigate the value of experience on the confidence of these fellows to perform surgical procedures. METHODS: We assessed the characteristics of 32 fellows, including the perceived adequacy of their fellowship training, the facilities of the clinics at which they were trained, and their levels of exposure and confidence in performing a total of 44 procedures. Exposure levels were performing, assisting with, observing, or no exposure. Confidence was assessed by asking whether they could perform each procedure. Correlation analysis was used to determine the link between exposure levels and confidence. RESULTS: The confidence of fellows to perform a surgical procedure increased with exposure to that procedure (r = 0.820, P < 0.001). Performing, assisting with, and observing a procedure created a sense of confidence in 97.2%, 54.1%, and 31.1% of fellows. The majority of fellows (>75%) had performed type 2 hysterectomy, total omentectomy, and pelvic and para-aortic lymphadenectomy. None of the fellows had ever performed a trachelectomy. CONCLUSIONS: Efforts should be made in accredited systems for gynecologic oncology surgical training to provide more opportunities for trainees to perform surgical procedures, rather than assisting with and observing them. PMID- 27465888 TI - Modified Gluteal Fold V-Y Advancement Flap for Reconstruction After Radical Vulvectomy. AB - OBJECTIVE: To describe the surgical technique of the V-Y cutaneous supra-fascial (modified) gluteal advancement flaps for reconstruction after radical vulvectomy and to assess the outcome of patients according to their clinical characteristics. METHODS: Between January 2006 and July 2012, 36 V-Y flaps were performed in 21 patients to cover the defect after radical surgery of primary vulvar cancers. Surgery duration, blood loss, hospital stay, and wound healing were assessed according to patient age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, and the initial defect size. RESULTS: Median patient age, BMI, and ASA score were 80 (range, 31-91), 28 (range, 18-36), 3 (range, 1-3), respectively. Median surgery duration and blood loss were 180 minutes (range, 60-275) and 400 mL (range, 100-1000), respectively. Median operating time was higher in patients ASA3 than ASA less than 3, 200 versus 120 minutes (P = 0.038). Median initial defect size was higher in patients with BMI greater than 28 than 28 or less, 92 versus 55 cm (P = 0.004). Local scar defect was observed in 16 patients (76%), mild, less than 10 cm in 10 patients. Median wound healing duration was higher in patients with bilateral than unilateral flap, 16 versus 9.5 days (P = 0.034). CONCLUSIONS: The V-Y cutaneous suprafascial gluteal advancement flap for vulvar reconstruction after vulvectomy is an easy, safe, and reliable procedure. However, even mild local scar defect after bilateral flap may impact on wound healing and hospital stay, in elderly and ASA3 patients. PMID- 27465889 TI - Prognostic Factors of Recurrence and Survival in Vulvar Melanoma: Subgroup Analysis of the VULvar CANcer Study. AB - OBJECTIVE: The aim of this study was to analyze the prognostic factors related to the recurrence rate and overall survival of vulval melanoma patients by means of a subgroup analysis of the VULvar CANcer study. METHODS: The international multicenter VULvar CANcer study involved 100 international centers, which contributed 2453 vulvar cancer cases. Of the 1727 patients finally included in the study, 42 were suffering from vulvar melanoma (2.4%). RESULTS: The mean follow-up for vulval melanoma patients was 44.1+/-35.7 months. Recurrence rate was 50%, and the mean recurrence-free survival was 43.5+/-6.6 months. For local recurrences, the mean recurrence-free interval was 63.3+/-8.6 months; for metastasis, 33.5+/-3.5 months. The 5-year recurrence-free survival rate was 28.6%. The mean overall survival for vulvar melanomas was 45.9+/-4 months and the 5-year overall survival rate was 78.6%. The only factor with prognostic significance regarding local recurrence of vulvar melanoma was tumor size (P = 0.003). American Joint Committee on Cancer staging was the only prognostic factor associated with metastatic disease at recurrence (P < 0.001). Finally, age of patient was significantly associated with overall survival (P < 0.001). CONCLUSIONS: Tumor size and American Joint Committee on Cancer stage were independent prognostic factors associated with local and distant recurrence, respectively. Patients' age was the only independent prognostic factor associated with overall survival. PMID- 27465891 TI - Effects of a Small Interfering RNA Targeting YKL-40 Gene on the Proliferation and Invasion of Endometrial Cancer HEC-1A Cells. AB - OBJECTIVE: The purpose of this study was to explore the effects of a small interfering RNA (siRNA) targeting YKL-40 on the proliferation and invasion of endometrial cancer (EC) HEC-1A cells. METHODS: We used an siRNA targeting a sequence in YKL-40 (si-YKL-40) to transfect HEC-1A cells. Quantitative real-time polymerase chain reaction assay was performed to investigate the mRNA levels of YKL-40. MTT, migration, and invasion assays were performed to identify the effects of si-YKL-40 on the proliferation, migration, and invasive abilities of the HEC-1A cells. RESULTS: mRNA expression of YKL-40 was down-regulated in HEC-1A cells after transfection with si-YKL-40 (P < 0.05). The proliferation, migration, and invasive abilities of HEC-1A cells were inhibited by siRNA (P < 0.05). CONCLUSIONS: YKL-40 targeting siRNA specifically blocks the activity of YKL-40 in human EC HEC-1A cells, resulting in tumor suppression. This indicates that YKL-40 might serve as a potential small molecule target in the treatment of EC. PMID- 27465890 TI - Maximum Standardized Uptake Value of Pelvic Lymph Nodes in [18F] Fluorodeoxyglucose Positron Emission Tomography Is a Prognostic Factor for Para Aortic Lymph Node Recurrence in Pelvic Node-Positive Cervical Cancer Treated With Definitive Chemoradiotherapy. AB - OBJECTIVES: This study aimed to identify prognostic factors for para-aortic lymph node (PALN) recurrence and their effect on survival outcomes in patients with pelvic node-positive squamous cell carcinoma (SCC) of the cervix treated with definitive concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Of the 116 patients with biopsy-proven SCC of the uterine cervix who underwent primary CCRT from 2007 to 2012, 48 patients with pelvic LN metastasis detected by [F] fluorodeoxyglucose positron emission tomography (FDG PET) were retrospectively analyzed. Patients with evidence of para-aortic lymphadenopathy were excluded. The whole pelvis was the standard irradiation field for all patients. The associations of age, stage, serum SCC antigen (SCC-Ag) level, maximum standardized uptake value (SUVmax), hemoglobin level, overall treatment time, adjuvant chemotherapy, and pelvic LN status with PALN recurrence and survival outcomes were evaluated. RESULTS: At a median follow-up of 34.0 months (range, 8 73 months), 10 (20.8%) patients had developed PALN recurrences. The relationship between pelvic LN FDG uptake and PALN recurrence was evaluated by the cutoff value (SUVmax = 3.85) determined by receiver operating characteristic curve analysis. The independent risk factors for PALN recurrence were FDG-avid pelvic LN (SUVPLN) greater than 3.85 (hazard ratio, 13.12; P = 0.025) and posttreatment SCC-Ag level greater than 2.0 (ng/mL) (hazard ratio, 20.69; P = 0.019). Patients with an SUVPLN greater than 3.85 were found to have significantly worse 5-year distant metastasis-free (51.0% vs 79.0%, P = 0.016) and progression-free survival (38.7% vs 67.3%, P = 0.011) than those with an SUVPLN less than or equal to 3.85. CONCLUSIONS: SUVPLN is a statistically significant prognostic factor of PALN recurrence and survival after definitive CCRT for pelvic node-positive SCC of the uterine cervix. PMID- 27465892 TI - Long-term Pelvic Floor Function and Quality of Life After Radical Surgery for Cervical Cancer: A Multicenter Comparison Between Different Techniques for Radical Hysterectomy With Pelvic Lymphadenectomy. AB - OBJECTIVE: This study aimed to compare urinary and bowel symptoms and quality of life (QoL) among women treated with a Wertheim-Meigs (WM, type III) or Wertheim Okabayashi (WO, type IV) radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. METHODS: In this cross-sectional observational study, patients treated with a WO or a (nerve sparing) WM radical hysterectomy (with or without adjuvant radiotherapy) between January 2000 and December 2010 in the Center for Gynaecological Oncology Amsterdam or Leiden University Medical Center were included. To assess QoL, urinary and bowel symptoms we used the EORTC QLQ-C30, EORTC QLQ-CX24, and Leiden Questionnaire. We performed a multivariate analysis to identify factors associated with urinary symptoms. RESULTS: Two hundred sixty-eight women were included (152 WO and 116 WM). Quality of life was not significantly different in patients treated by WO or WM. Urinary symptoms were more often reported by patients in the WO group compared to the WM group: "feeling of urine retention" (53% vs 32%), "feeling less/no urge to void" (59% vs 14%), and "timed voiding" (49% vs 10%). With regard to bowel symptoms, there was no difference between both. Multivariate analysis showed that surgical technique was an independent factor for differences in urinary symptoms. CONCLUSIONS: Patients undergoing more radical surgery for early-stage cervical cancer report significantly more urinary dysfunction, whereas bowel function and health-related QoL are not decreased. PMID- 27465893 TI - Does the Robotic Platform Reduce Morbidity Associated With Combined Radical Surgery and Adjuvant Radiation for Early Cervical Cancers? AB - OBJECTIVE: Open radical hysterectomy followed by adjuvant radiation for cervical cancer has been associated with significant rates of morbidity. Radical hysterectomy is now often performed robotically. We sought to examine if the robotic platform decreased the morbidity associated with radical hysterectomy followed by adjuvant radiation. MATERIALS/METHODS: A retrospective cohort of patients with cervical cancer undergoing radical hysterectomy from 1995 to 2013 was evaluated. Complications were assessed using electronic record review and graded. chi tests and Student t tests were used for analysis. RESULTS: Overall, 243 patients underwent radical hysterectomy for cervical cancer. Surgical approach was 43% open and 57% robotic. Eighty-three patients (34.2%) required adjuvant radiation. Overall, radical hysterectomy plus adjuvant radiation was associated with increased risk of complication (29%) compared to radical hysterectomy alone (7%) (P < 0.001). Complications included lymphedema (n = 18), bowel-associated complications (n = 10), and urinary complications (n = 7). There was no difference in time to initiation of radiation between open and robotic surgery (43 vs 47 days; P = 0.33). There was no difference in grade 2/3 complications in patients receiving adjuvant radiation between open and robotic surgery (27.5% vs 27.9%; P = 0.97). Patients undergoing open surgery followed by radiation experienced a trend toward increased adhesion-related complications, such as bowel obstruction and ureteral stricture (10% vs 2.3%; P = 0.19); whereas patients undergoing robotic surgery followed by radiation experienced a trend toward increased lymphedema (19% vs 8%; P = 0.20). CONCLUSIONS: We found no difference in long-term complications between patients who underwent robotic surgery compared to open radical hysterectomy with adjuvant radiation. There may be fewer adhesion-related complications with robotic surgery. However, as many radiation-related complications occur at later time points, continued follow-up to evaluate for potential differences between the 2 groups is necessary. PMID- 27465894 TI - Testosterone Aromatization to Estradiol in Course of Ovarian Functioning Brenner Tumor Associated With Endometrial Carcinoma and Endometriosis (Roncati-Manenti Triad). AB - OBJECTIVE: Aromatization is the biochemical process in which aromatase catalyzes the conversion of testosterone into estradiol, the fundamental pathway for the synthesis of estrogens. When enhanced, it can lead to hyperestrogenism, a well known risk factor for gynecological cancers. METHODS: The surgical specimens, coming from 2 postmenopausal women with hyperestrogenism on pap smear and bioptic diagnosis of endometrial endometrioid carcinoma, were fixed in 10% neutral buffered formalin, paraffin embedded, and then submitted for routine hematoxylin/eosin staining and immunohistochemical characterization for antiestrogen, antiprogesterone, antitesterone, anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6. RESULTS: The presence of an undescribed triad represented by ovarian functioning Brenner tumor, endometrial carcinoma, and pelvic endometriosis has been ascertained. The immunohistochemical investigation proved a normal expression of the DNA mismatch repair proteins and revealed a bimodal hormonal status in the pathological tissues, that is, the Brenner tumor cells showed a high expression of testosterone, contrariwise endometrioid carcinoma and endometriosis a high estrogen and progesterone immunolabeling. CONCLUSIONS: This synchronous triad underlines the importance of aromatization and hyperestrogenism in the development of gynecological malignancies in which the immunohistochemical detection of an active source of hormone production - to always keep in consideration during synchronous diseases - can guide subsequent antihormone chemotherapy based on aromatase inhibitors. PMID- 27465895 TI - The Safety of Ovarian Preservation in Early-Stage Adenocarcinoma Compared With Squamous Cell Carcinoma of Uterine Cervix: A Systematic Review and Meta-Analysis of Observational Studies. AB - OBJECTIVE: The aim of this study was to compare the incidence of ovarian metastasis (OM) in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) in early-stage cervical cancer and evaluate the safety of ovarian preservation in early-stage ADC. METHODS: To perform a meta-analysis to compare the incidence of OM between early-stage ADC and SCC, we searched PubMed, EMBASE, and Cochrane for observational studies that compared it with pathological evidence after radical hysterectomy and oophorectomy. Odds ratios with 95% confidence intervals were calculated with a fixed effects model. We also found a few articles evaluating the oncological prognosis of patients with ovarian preservation to perform a systematic review. RESULTS: A total of 5 studies were included in the meta analyses. The incidence of OM of patients with early-stage ADC and SCC were 2% and 0.4%, respectively (odds ratio, 5.27; 95% confidence interval, 2.14-13.45). In 1427 patients with ADC or SCC of the cervix FIGO stage (CIS-IIA) who underwent hysterectomy, no ovarian recurrences were observed after unilateral or bilateral ovarian preservation in ADC patients in the follow-up (30-68 months); however, 15 patients with SCC developed pelvic recurrence. CONCLUSIONS: Although the incidence of OM was higher in early-stage ADC than SCC according to ovarian pathology, it might be relatively safe to perform ovarian preservation with early stage ADC because of low ovarian recurrence rate in short-term follow-ups. PMID- 27465896 TI - Omental Biopsy for Surgical Staging of Uterine Serous Carcinoma. AB - OBJECTIVES: The aims of this study were to determine the role of omental sampling in staging of uterine serous carcinoma (USC) and to evaluate its impact on patient outcomes. MATERIALS AND METHODS: A retrospective study of 106 women with USC who underwent primary surgery between 2005 and 2014 was done. Overall survival, disease-free survival, and progression and recurrence patterns were studied in 84 patients with follow-up over 1 year. Diagnostic characteristics were evaluated for preoperative imaging and operative findings. Univariate and multivariate analyses were performed to evaluate risk factors for omental metastasis. Survival curves were used to compare omental sampling status and the presence of omental metastasis. RESULTS: Of the 106 patients, 66 underwent surgical staging with omental biopsy (54; 82%) or omentectomy (12, 18%). Eight (12%) patients had metastatic disease in the omental samplings. All 6 patients with macrometastasis had visible lesions or palpable nodules and preoperative computed tomography (CT) was suspicious in 3. In 2 (3%) patients, omentum was not suspicious on CT or intraoperatively but had micrometastases. The negative predictive value regarding the staging CT scan was 92% and of the operative findings was 97%. On multivariate analysis, no variable was associated with omental involvement. Disease progressed or recurred in 40 (48%) patients. The most frequent sites of recurrence or progression were the omentum (23; 27%), peritoneum (26; 31%), pelvis (15, 18%), lung (15, 18%), and liver (12, 14%). Comparing the groups with or without omental assessment, no significant difference was found regarding progression and recurrence patterns, overall survival, and disease-free survival. CONCLUSIONS: Omental involvement in USC upstages patients to stage IV disease and traditional risk factors fail to predict extrauterine disease. Although omental sampling does not influence disease progression or survival, a comprehensive intraoperative evaluation of the omentum is advised as most cases have grossly visible lesions. PMID- 27465897 TI - Fertility Preservation Is Safe for Serous Borderline Ovarian Tumors. AB - OBJECTIVES: This study aimed to determine the overall survival (OS) and progression-free interval and the influence of fertility-preserving surgery (FPS) versus radical surgery (RS) in patients with serous borderline ovarian tumor (BOT). METHODS: Clinical parameters of patients with serous BOT treated between 1993 and 2013 in one institution were retrospectively investigated. All tumors were examined by one pathologist with experience in gynecological pathology. RESULTS: One hundred thirty-two patients with serous BOT (inclusive 16 microinvasive) were analyzed (45% were <=40 years), with a median follow-up of 6 years. Thirty-two percent (42/132) of the patients received FPS; 14% (18/132) relapsed (invasive or borderline). The 5-year progression-free survival was 89%. The risk of recurrence was higher in patients 40 years or younger (P = 0.019), after FPS (P = 0.002), in patients with a higher International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.016), for bilateral BOT (P = 0.0132), and for the micropapillary variant (P = 0.067). The OS at 5 years was 97%. There was no statistically significant difference in OS between FPS and RS [all (6 of 90) patients, except for 1, with RS died]. One patient died of relapsed BOT. Among the recurrences, low-grade invasive carcinoma was diagnosed in 4 patients. Three of these 4 patients were originally operated radically, 2 had a micropapillary variant FIGO stage III, and 1 had a papillary pattern FIGO stage II with microinvasion; all 3 had noninvasive implants and are alive. One patient with a micropapillary variant, FIGO stage IIIC with microinvasion and invasive implants, received FPS and died of disease. CONCLUSIONS: The risk of recurrence is higher after FPS compared with RS; however, no influence on OS was observed. This was because most of the patients relapsed as BOT. Fertility preservation is justified in young patients with serous borderline tumors. PMID- 27465898 TI - Enhancement of Ovarian Tumor Detection by DR6-Targeted Ultrasound Imaging Agents in Laying Hen Model of Spontaneous Ovarian Cancer. AB - OBJECTIVE: The lack of an effective early detection test leads to high case to death ratio of women with ovarian cancer (OVCA). To improve early detection, tumor-associated imaging targets need to be established and imaging agents to image these targets need to be developed. Targeted imaging agents offer potential for improvement of signal intensities from their targets. Expression of death receptor 6 (DR6) by ovarian malignant cells and tumor-associated microvessels increases during OVCA development and represents a novel target for ultrasound imaging. The goal of this study was to examine the feasibility of newly developed DR6-targeted ultrasound imaging agents in enhancing early detection of ovarian tumors in laying hen model of spontaneous OVCA. MATERIALS AND METHODS: The study was conducted in an exploratory cross-sectional design using 4-year-old laying hens (n = 130). DR6-targeted imaging agents were developed by conjugating microbubbles with rabbit anti-chicken DR6 antibodies. Changes in signal intensity of ultrasound imaging were determined before and after injection of targeted imaging agents in hens with or without spontaneous OVCA. Following targeted imaging, normal or tumor ovaries were processed for histopathological and immunohistochemical studies. RESULTS: DR6-targeted imaging agents bound with their targets expressed by malignant cells and tumor-associated microvessels in the ovary. Compared with pretargeted imaging, targeted imaging is enhanced by approximately 40% ultrasound echo signal intensity (P < 0.001) from early- and late-stage OVCA. Differences in signal enhancement were not observed among different histological subtypes of OVCA at early or late stages. Higher imaging signal intensities were associated with enhancement in DR6 expression by ovarian malignant cells and increase in the frequency of DR6-expressing microvessels during OVCA development. CONCLUSIONS: The results of this study suggest that DR6 targeted imaging agents enhance the visualization of ovarian tumors and tumor associated microvessels in hens with early-stage OVCA and will form a foundation for clinical studies. PMID- 27465899 TI - A Single-Institution Radical Surgery Results in Stage IB2/IIA2 (Bulky) Cervical Cancer. AB - OBJECTIVE: The aim of this study is to evaluate the results of radical surgery in patients with stage IB2 to IIA2 cervical cancer who were operated on at our center between 2002 and 2015. MATERIALS AND METHODS: Forty-seven cases of patients with stage IB2/IIA2 cervical cancer who underwent primary radical surgery between 2002 and 2015 were enrolled in this study. Patients' files and pathological reports were retrospectively reviewed. Surgical, pathological, and clinical variables were analyzed and their impact on survival period was researched. Disease-free survival and overall survival periods were determined using the Kaplan-Meier test. The P value was considered significant if less than 0.05. RESULTS: Type C2 radical hysterectomy with lymphadenectomy (5 pelvic, 42 pelvic and para-aortic) was performed for all of the 47 patients in accordance with the Querleu-Morrow classification. Thirty-three of the cases were stage Ib2 and 14 cases were IIa2. Five years of overall survival was 80%. Recurrence was noted in 10 (7 pelvic, 3 extrapelvic) patients. Adjuvant therapies were needed for 83% of the patients. A univariate analysis was made for all included variables in this research and, other than recurrence, none of them was found to be statistically significant on OS and DFS. CONCLUSIONS: Although adjuvant therapies are often resorted to, primary radical surgery is also a reasonable treatment option for stage IB2/IIA2 cervical cancer, especially in young premenopausal patients when preserving ovarian functions is desired. PMID- 27465900 TI - Incidence of Lymph Node Metastases in Apparent Early-Stage Low-Grade Epithelial Ovarian Cancer: A Comprehensive Review. AB - OBJECTIVES: This study aimed to determine the incidence of lymph node (LN) metastases in presumed stage I-II low-grade epithelial ovarian cancer (EOC). METHODS: Eligible studies were identified from MEDLINE and EMBASE (time frame, 2015-1975), that analyzed patients with clinical or radiologic presumed early stage EOC who underwent a complete pelvic and para-aortic lymphadenectomy as part of their surgical staging. The number and site of dissected and involved LNs and the correlation with overall outcome are analyzed. The term low grade and also the older term well differentiated were used. RESULTS: Thirteen of 978 identified studies were selected, and 13 of 75 studies were identified as eligible. A total of 1403 patients were analyzed in these 13 retrospective studies. The final International Federation of Gynecology and Obstetrics staging after completed surgical staging was I to II in 912 patients (65%). A total of 338 patients (24%) had grade 1 tumors whereas 473 patients (34%) had grade 2, and 502 patients (36%) had grade 3 tumors. Systematic lymphadenectomy was performed in 1159 patients (83%), whereof 1142 (82%) were pelvic and para-aortic LN dissections.In 185 patients (13%), an upstaging from an apparent clinical stage I-II to IIIC occurred because of LN involvement: 64 (35%) of the patients had only pelvic LNs metastases, 69 (37%) had only para-aortic LNs metastasis, and 51 (28%) had both a pelvic and para-aortic LN involvement. When analyzing only the patients with low grade (grade 1 as the old classification) presumed early-stage disease (n = 273), only 8 patients (2.9%; range, 0-6.2) were identified with LNs metastases present. CONCLUSIONS: The incidence of occult LN metastases in apparent early-stage low grade EOC is 2.9% in a metaanalysis of retrospective studies. Future larger-scale prospectively assessed studies with established surgical quality of the LN dissection are warranted to establish the true incidence of LN metastasis in presumed early low-grade disease. PMID- 27465901 TI - Diagnostic Accuracy of Serum Kallikrein-Related Peptidases for Ovarian Cancer: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: At present, considerable efforts have been made to identify new cancer specific markers for ovarian cancer (OC) diagnosis and the kallikrein-related peptidases (KLKs) family is one of the most studied candidates. This meta analysis aims to evaluate the pooled diagnostic value of serum KLK measurement for diagnosing OC. METHODS: The Cochrane Library, PubMed, Excerpt Medica Database were searched for all relevant literature. The Quality Assessment for Studies of Diagnostic Accuracy tool was applied to assess the quality of enrolled studies. Statistical analysis was conducted by using Stata 13.0 software and Meta-Disc. RESULTS: A total of 15 studies from 13 articles were considered eligible for inclusion in the present analysis. The following pooled parameters were calculated by using the bivariate model: sensitivity of 0.582 (95% confidence interval [CI], 0.517-0.644), specificity of 0.909 (95% CI, 0.833-0.952), positive likelihood ratios of 6.367 (95% CI, 3.330-12.172), negative likelihood ratios of 0.460 (95% CI, 0.388-0.546), diagnostic odds ratio of 13.831 (95% CI, 6.460 29.614), respectively. CONCLUSIONS: Kallikrein-related peptidase seems to be a promising candidate biomarker in diagnosing OC, but the associated poor sensitivity of KLK individually may limit its value in clinical application. To resolve this problem, the combination of KLK and other markers may offer improved performance than a single marker. PMID- 27465902 TI - Placental Site Trophoblastic Tumors: Analysis of the Clinicopathologic Characteristics of 20 Cases in Korea. AB - OBJECTIVES: The aim of this study was to evaluate the clinicopathologic features of placental site trophoblastic tumors (PSTTs) in Korea. METHODS/MATERIALS: Twenty patients given a diagnosis of PSTT in Korea (1990-2013) were evaluated retrospectively, including 14 patients identified through a literature review and 6 patients identified through a medical chart review of a single institution. The analysis included patient age, antecedent pregnancies, time since antecedent pregnancy, presenting symptoms, serum beta-human chorionic gonadotropin level, International Federation of Gynecology and Obstetrics stage, treatment, outcome, and follow-up. RESULTS: The mean age of the 20 patients was 32 years (range, 25 53 years). The antecedent pregnancies included 8 term pregnancies, 8 abortions, and 2 molar pregnancies. The time since the antecedent pregnancy was less than 1 year in 16 patients (80%). Nineteen patients (95%) presented with abnormal vaginal spotting or amenorrhea. Serum beta-human chorionic gonadotropin levels ranged from normal to 13,480 mIU/mL, although most patients (80%) had a level less than 1000 mIU/mL. Seventeen patients (85%) presented with stage I disease. Ten patients (50%) underwent hysterectomy, and 14 patients (70%) were treated with chemotherapy with or without hysterectomy. In 11 evaluated patients, the median mitotic count index was 3.4 (0.4-10) per 10 high-power fields. The median follow-up time was 17 months (range, 1-68 months). There was no recurrence or death from disease. CONCLUSIONS: Korean patients with PSTT often have early-stage disease, which has a favorable prognosis even with fertility-preserving therapy. However, international studies are necessary to determine the optimal treatment and prognostic factors. PMID- 27465903 TI - Detecting Asymptomatic Recurrence in Early-Stage Endometrial Cancer: The Value of Vaginal Cytology, Imaging Studies, and CA-125. AB - OBJECTIVE: The aim of this study was to evaluate the value of vaginal cytology, imaging modalities, and serum CA-125 in detecting asymptomatic recurrence during posttreatment surveillance for early-stage endometrial cancer. METHODS: A retrospective analysis was conducted on patients with stage I to II endometrial cancer who received primary surgical treatment at Seoul National University Hospital between 2000 and 2011. Clinicopathologic characteristics and surveillance test data were obtained from medical records. The total numbers of vaginal cytologies, imaging studies, and serum CA-125 levels performed during surveillance or until recurrence were evaluated, and the number of tests needed to detect each asymptomatic recurrence was calculated. RESULTS: A total of 389 patients were identified, together with a total of 3323 vaginal cytologies, 1025 chest x-rays, 1177 abdominal computed tomography (CT) scans, 98 magnetic resonance imaging scans, 163 positron emission tomography/CT scans, 298 ultrasonographies, and 3335 serum CA-125 results obtained during the surveillance period. Recurrence was detected in 14 patients (3.6%). Ten of these cases were asymptomatic, of which six were identified through CT scans and four were identified through elevated serum CA-125 levels. Most of the patients (7/10) with asymptomatic recurrences had localized recurrence patterns, five of whom underwent curative-intent resection and survived. The number of CA-125 tests needed to identify 1 asymptomatic recurrence was 839, whereas the number of CT scans needed to achieve the same result was 196. Other imaging modalities and vaginal cytology did not detect asymptomatic recurrence. CONCLUSIONS: For posttreatment surveillance in early-stage endometrial cancer, vaginal cytology and imaging modalities such as chest x-ray, magnetic resonance imaging, positron emission tomography/CT, and ultrasonography have low utility. Routine CT scans and serum CA-125 testing may be useful for detecting asymptomatic recurrence. PMID- 27465904 TI - Primacy of cardiac chymase over angiotensin converting enzyme as an angiotensin (1-12) metabolizing enzyme. AB - We showed previously that rat angiotensin-(1-12) [Ang-(1-12)] is metabolized by chymase and angiotensin converting enzyme (ACE) to generate Angiotensin II (Ang II). Here, we investigated the affinity of cardiac chymase and ACE enzymes for Ang-(1-12) and Angiotensin I (Ang I) substrates. Native plasma membranes (PMs) isolated from heart and lung tissues of adult spontaneously hypertensive rats (SHR) were incubated with radiolabeled (125)I-Ang-(1-12) or (125)I-Ang I, in the absence or presence of a chymase or ACE inhibitor (chymostatin and lisinopril, respectively). Products were quantitated by HPLC connected to an in-line flow through gamma detector. The rate of (125)I-Ang II formation from (125)I-Ang-(1 12) by chymase was significantly higher (heart: 7.0 +/- 0.6 fmol/min/mg; lung: 33 +/- 1.2 fmol/min/mg, P < 0.001) when compared to (125)I-Ang I substrate (heart: 0.8 +/- 0.1 fmol/min/mg; lung: 2.1 +/- 0.1 fmol/min/mg). Substrate affinity of (125)I-Ang-(1-12) for rat cardiac chymase was also confirmed using excess unlabeled Ang-(1-12) or Ang I (0-250 MUM). The rate of (125)I-Ang II formation was significantly lower using unlabeled Ang-(1-12) compared to unlabeled Ang I substrate. Kinetic data showed that rat chymase has a lower Km (64 +/- 6.3 MUM vs 142 +/- 17 MUM), higher Vmax (13.2 +/- 1.3 MUM/min/mg vs 1.9 +/- 0.2 MUM/min/mg) and more than 15-fold higher catalytic efficiency (ratio of Vmax/Km) for Ang-(1 12) compared to Ang I substrate, respectively. We also investigated ACE mediated hydrolysis of (125)I-Ang-(1-12) and (125)I-Ang I in solubilized membrane fractions of the SHR heart and lung. Interestingly, no significant difference in (125)I-Ang II formation by ACE was detected using either substrate, (125)I-Ang-(1 12) or (125)I-Ang I, both in the heart (1.8 +/- 0.2 fmol/min/mg and 1.8 +/- 0.3 fmol/min/mg, respectively) and in the lungs (239 +/- 25 fmol/min/mg and 248 +/- 34 fmol/min/mg, respectively). Compared to chymase, ACE-mediated Ang-(1-12) metabolism in the heart was several fold lower. Overall our findings suggest that Ang-(1-12), not Ang I, is the better substrate for Ang II formation by chymase in adult rats. In addition, this confirms our previous observation that chymase (rather than ACE) is the main hydrolyzing enzyme responsible for Ang II generation from Ang-(1-12) in the adult rat heart. PMID- 27465905 TI - Current incidence of venous thromboembolism and comparison with 1998: a community based study in Western France. AB - In 1998 we estimated the incidence of venous thromboembolism (VTE) to be 1.8/1,000 per year. The aim of this study was to compare current VTE incidence to that observed in 1998. We prospectively recorded all cases of symptomatic pulmonary embolism (PE) and deep vein thrombosis (DVT) of the lower limbs diagnosed between March 1, 2013 and February 28, 2014 in hospitals and in the community, using the same method and geographic area than in 1998. The 2013 incidence rates of VTE were computed and compared with those of 1998 using age- and sex-specific standardised incidence ratios (SIRs). In 2013, we recorded 576 VTE cases (279 isolated DVT and 297 PE +/- DVT). Among 367,911 inhabitants, the overall incidence of VTE was 1.57/1,000 (95 % CI 1.44-1.69). The overall VTE incidence was significantly lower in 2013 as compared with 1998: SIR 0.72 (95 % CI 0.67-0.79) as well as the incidence of isolated DVT: SIR 0.53 (95 % CI 0.47 0.60); conversely, the overall incidence of PE was unchanged: SIR 1.10 (95 % CI, 0.98-1.23) despite an increase in the incidence of isolated PE: SIR 1.29 (95 % CI, 1.10-1.52). In 1998, 4.4 % of PE cases were diagnosed using CTPA as compared with 73.7 % in 2013 (p < 0.001). In conclusion, between 1998 and 2013, the incidence of symptomatic DVT decreased. Conversely, we found no similar reduction in the incidence of symptomatic PE; whether this is due to changes in diagnostic tests and algorithms in the management of suspected PE requires further investigations. PMID- 27465906 TI - Is it possible to achieve bio-equivalence between an oral solid immediate-release and an analogue enteric-coated formulation? AB - OBJECTIVES: While bioequivalence between enteric-coated and immediate-release formulations can be achieved in terms of AUC, gastric emptying of enteric-coated dosage forms is a stochastic event, usually leading to lower Cmax values than those observed with the corresponding immediate release. This article examines challenges of developing enteric-coated dosage forms which are bioequivalent to the corresponding immediate-release formulations in terms of both AUC and Cmax using rasagiline as a model compound. METHODS: In vitro drug release profiles of enteric-coated formulations were obtained and compared to those of the immediate release formulation by dissolution testing. Pharmacokinetics was evaluated in bioequivalence studies in healthy human volunteers after single oral administration of enteric-coated and immediate-release formulations. KEY FINDINGS: The initial enteric-coated pellet formulation prototype was equivalent in terms of AUC, but differed in Cmax ; a second formulation prototype, consisting of a single-unit core and enteric-coating film, proved to be bioequivalent to immediate-release rasagiline tablets in terms of AUC and Cmax . In vitro, it released rasagiline rapidly at a pH of 6.8. CONCLUSIONS: Despite differences in gastric emptying between disintegrating immediate-release and enteric-coated solid dosage forms, bioequivalence in pharmacokinetic studies was achieved. PMID- 27465907 TI - Modular Synthesis of Arylacetic Acid Esters, Thioesters, and Amides from Aryl Ethers via Rh(II)-Catalyzed Diazo Arylation. AB - One-pot formation of arylacetic acid esters, thioesters, and amides via Rh(II) catalyzed arylation of a Meldrum's acid-derived diazo reagent with electron-rich arenes is described. The methodology was used to efficiently synthesize an anticancer compound. PMID- 27465908 TI - Allelic Variation of the Capsule Promoter Diversifies Encapsulation and Virulence In Streptococcus pneumoniae. AB - The polysaccharide capsule is the major virulence factor of Streptococcus pneumoniae (pneumococcus), a major human pathogen. The sequences in the promoter and coding regions of the capsule gene locus undergo extensive variations through the natural transformation-mediated horizontal gene transfer. The sequence variations in the coding region have led to at least 97 capsular serotypes. However, it remains unclear whether the sequence polymorphisms in the promoter region have any biological significance. In this study, we determined the sequences of the cps promoter region from 225 invasive pneumococcal isolates, and identified modular composition and remarkable inter-strain sequence variations in this region. The strain-to strain variations in the cps promoter are characterized by diversity in sequence and size, mosaic combinations of nucleotide polymorphisms and sequence modules, selective preservation of the sequence combinations, and promiscuous assortments of the sequences between the promoter and coding regions. Isogenic pneumococci carrying allelic variants of the cps promoter displayed significant differences in the transcription of the capsule genes, capsule production, adhesion to host epithelial cells, anti phagocytosis and virulence in mouse bacteremia model. This study has thus indicated that the sequence polymorphisms in the cps promoter represent a novel mechanism for fine-tuning the level of encapsulation and virulence among S. pneumoniae strains. PMID- 27465910 TI - Diameter-dependent multiferroic functionality in hybrid core/shell NWs. AB - A versatile approach towards nanofabrication of highly reproducible Co/BiCoO3 (Co/BCO) core/shell (CS) nanowires (NWs) with different diameters has been adopted by demonstrating easily available and low cost sol-gel and electrodeposition routes. X-ray diffraction (XRD) analysis confirmed the tetragonal system of the BCO nanoshells (NSs) with the space group P4mm. Scanning electron microscopy (SEM) clearly demonstrates the uniform morphology with well aligned CS NWs. The magnetization reversal processes (MRPs), experimentally and with analytical modelling, have been discussed for CS NWs with theta ranging from 0 degrees (in-plane magnetic easy axis) to 90 degrees (out-of-plane magnetic hard axis) with magnetic hysteresis loops and geometrical parameters. Crossover from the vortex to transverse reversal mode on increasing theta has been observed for all diameters. An exchange bias effect has been observed for smaller CS NWs diameters and it is attributed to the shell thickness of ~25 nm. Furthermore, the magnetic anisotropy effect has been discussed in some detail. PMID- 27465909 TI - Uptake of the centers for medicare and medicaid obesity benefit: 2012-2013. AB - OBJECTIVE: To assess the use of the Medicare Obesity Benefit (MOB) by a licensed physician or associate provider in an outpatient setting in older adults. METHODS: A serial cross-sectional analysis of fee-for-service Medicare claims (2012 and 2013) was used to assess the use of the MOB. Number and proportion of Medicare beneficiaries over age 65 using the benefit were assessed. Correlation between state-obesity rates and MOB uptake was determined based on state-specific obesity prevalence data from the Behavioral Risk Factor Surveillance System. Results There were 27,338 (0.10%) Medicare beneficiaries over age 65 in 2012 using the MOB and slightly more in 2013 (n = 46,821 [0.17%]). Mean age of MOB users in both years was 73 years, and 62% were females. Use declined with older age and was highest in the Northeast and lowest in the Midwest. High state obesity prevalence was not correlated with higher uptake of the MOB. Estimated proportion of persons with obesity using the MOB was 0.35% and 0.60% in successive years. A mean of 1.99 and 2.16 claims/MOB user was observed. CONCLUSIONS: While the rate of MOB use increased in the second full year of its implementation, few were availing themselves of this benefit. PMID- 27465911 TI - Soy Reduces Bone Turnover Markers in Women During Early Menopause: A Randomized Controlled Trial. AB - Menopausal estrogen loss leads to an increased bone loss. Soy isoflavones can act as selective estrogen receptor modulators, their role in bone turnover is unclear. The primary outcome was assessing changes in plasma bone turnover markers. The secondary outcomes were assessing changes in cardiovascular risk markers including insulin resistance, blood pressure, and lipid profile. We performed a double-blind randomized parallel study in which 200 women within 2 years after the onset of their menopause were randomized to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (SP), daily for 6 months. There was a significant reduction in type I collagen crosslinked beta C-telopeptide (betaCTX) (bone-resorption marker) with SPI supplementation (0.40 +/- 0.17 versus 0.15 +/- 0.09 MUg/L; p < 0.01) compared to SP supplementation (0.35 +/- 0.12 versus 0.35 +/- 0.13 MUg/L; p = 0.92) after 6 months. There was also a significant reduction in type I procollagen-N-propeptide (P1NP) (bone formation marker) with SPI supplementation (50.5 +/- 25.0 versus 34.3 +/- 17.6 MUg/L; p < 0.01), more marked between 3 and 6 months. Following SPI there was a significant reduction in fasting glucose, fasting insulin, insulin resistance, and systolic blood pressure whereas no significant changes in these parameters was observed with SP. There were no significant changes in fasting lipid profile and diastolic blood pressure with either preparation. There was a significant increase in TSH and reduction in free thyroxine (p < 0.01) with SPI supplementation though free tri-iodothyronine was unchanged. In conclusion, soy protein with isoflavones may confer a beneficial effect on bone health, analogous to the mode of action of antiresorptive agents, albeit to a less magnitude. There was a significant improvement of cardiovascular risk markers, but a significant increase in TSH and reduction in free thyroxine after SPI supplementation indicating a detrimental effect on thyroid function. (c) 2016 American Society for Bone and Mineral Research. PMID- 27465912 TI - Effect of elcatonin versus nonsteroidal anti-inflammatory medications for acute back pain in patients with osteoporotic vertebral fracture: a multiclinic randomized controlled trial. AB - The aim of this study was to compare the efficacy of elcatonin injections and oral nonsteroidal anti-inflammatory drugs (NSAIDs) for patients with osteoporosis who have acute lumbar pain after experiencing new vertebral compression fractures. Two hundred twenty-eight Japanese female patients (mean age 77.3 years) with acute lumbar pain from osteoporotic vertebral fractures were randomly divided into two groups. Patients in one group were given an NSAID (NSAIDs group) and patients in the other group were given weekly intramuscular injections of 20 units of elcatonin (elcatonin group). All patients underwent follow-up examinations up to 6 weeks from the start of the trial. Outcome measures were the level of functional impairment according to the Japan Questionnaire for Osteoporotic Pain (JQ22), the Roland-Morris Disability Questionnaire (RDQ), and a visual analog scale (VAS) of pain intensity. Statistical analyses focused on (1) the time course of pain and functional level using linear mixed effects models to analyze the longitudinal data and (2) the effectiveness of elcatonin injection with mean difference values and 95 % confidence intervals. Significant differences were seen over time between the initial values and the postintervention values (4 and 6 weeks) in JQ22, RDQ, and VAS scores (effect size d > 0.4) in each group. The mean differences between the elcatonin group and the NSAIDs group in each measure at 4 and 6 weeks were -4.8 and -8.3 for the JQ22, 1.3 and -2.6 for the RDQ, and -11.3 and -11.5 for the VAS, shifted to elcatonin. Once weekly elcatonin injection was more effective than NSAIDs for treating acute lumbar pain and improving mobility in Japanese women with osteoporotic vertebral fractures. PMID- 27465913 TI - Long-term outcome of cataract surgery in patients with idiopathic hypoparathyroidism and its relationship with their calcemic status. AB - Cataract is a cardinal manifestation of hypoparathyroidism. Although patients with hypoparathyroidism require cataract surgery at a younger age than individuals without hypoparathyroidism, there is limited information on the outcome of this surgery. We assessed long-term complications of cataract surgery in patients with idiopathic hypoparathyroidism (IH) and its relationship with their clinical and biochemical parameters. Twenty-seven patients with IH and 25 nonhypoparathyroid controls with a minimum follow-up of 2 years after cataract surgery were assessed for visual acuity, intraocular pressure, lens centricity, Nd:YAG laser capsulotomy, and the severity of posterior capsular opacification (PCO) and anterior capsular opacification. High-resolution optical slit-lamp images were analyzed by an ophthalmologist. Patients with IH had cataract surgery at a younger age than controls (34.0 +/- 16.4 years vs 58.0 +/- 11.2 years, P < 0.001). A higher proportion of IH patients had dense white PCO (75.0 % vs 39.4 %, P = 0.004), Nd:YAG laser capsulotomy (44.2 % vs 10.0 %, P = 0.001), anterior capsular opacification (97.7 % vs 84.2 %, P = 0.03), and a decentric lens (28.3% vs 2.6 %, P = 0.001) at a comparable time after surgery (8.6 +/- 6.1 years vs 8.7 +/- 6.8 years, P = 0.85). On regression analysis, the severity of PCO in IH correlated only with male sex and not with other factors, including serum total calcium and inorganic phosphorus levels at the baseline and during follow-up. To conclude, patients with IH are likelier than individuals without IH to develop PCO and to require Nd:YAG laser capsulotomy after cataract surgery. Proper precautions should be taken during surgery to minimize this complication in IH. PMID- 27465914 TI - Forearm bone mass predicts mortality in chronic hemodialysis patients. AB - We aim to determine the relationship between bone mineral density (BMD), measured by T- and Z-score, and mortality risk in hemodialysis (HD) patients. We also investigate which are the most suitable skeletal sites for predicting mortality rate. We analyzed the survival of 102 patients who had been treated with chronic HD according to BMD. Patients with a T-score <=2.5 at the middle, ultradistal and proximal part of the forearm had a higher mortality risk than those with a T score of -2.5 or higher. Furthermore, no statistically significant association was found between loss of bone mass at other measuring points-lumbar spine (anteroposterior orientation from L1-L4) and hip (neck, trochanter, intertrochanter, total and Ward's triangle)-and mortality risk. We were also interested in exploring the relationship between Z-score at different skeletal regions and mortality risk. We found that patients with a Z-score of -1 or lower at all three parts of the forearm had a greater mortality risk. It is also worth noting that the Z-score at all three parts of the forearm was a more apparent predictor of mortality, compared to the T-score at the same skeletal regions. This empirical analysis showed that BMD assessments should be obtained at the forearm, due to the good predictability of this skeletal site regarding mortality of HD patients. Moreover, data concerning bone density should be reported as Z scores. PMID- 27465915 TI - Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice. AB - The factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are also associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Here, we report a novel, N-ethyl-N nitrosourea-induced mutation that causes a gain of function in adenosine 5' monophosphate deaminase (AMPD3). Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. Mice were also found to be resistant to infection with the rodent malaria Plasmodium chabaudi. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection. PMID- 27465916 TI - Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. AB - New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available. PMID- 27465917 TI - IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells. AB - Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor postinfusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK-cell functions following cytokine withdrawal to model postinfusion performance. In contrast to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome associated messenger RNA (mRNA) revealed not only cytokine-dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15-stimulated NK cells was also observed using a clinically applicable protocol for NK-cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy. PMID- 27465920 TI - Linear assembly of patchy and non-patchy nanoparticles. AB - Linear assemblies of nanoparticles show promising applications due to their collective electronic, optical and magnetic properties. Rational design and controllable organization of nanoparticles in one-dimensional structures can strongly benefit from the marked similarity between conventional step-growth polymerization reactions and directional step-wise assembly of nanoparticles in linear chains. Here we show different aspects of the "polymerization" approach to the solution-based self-assembly of polymer-functionalized metal nanoparticles with different chemical compositions, shapes and dimensions. The self-assembly was triggered by inducing solvophobic attraction between polymer ligands, due to the change in solvent quality. We show that both anisotropic (patchy) nanoparticles and nanoparticles uniformly capped with polymer molecules can self assemble in linear chains. We explore the control of chain length, morphology, and composition, discuss the ability to form isotropic and hierarchical structures and show the properties and potential applications of linear assemblies of plasmonic nanoparticles. PMID- 27465919 TI - The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: Independent validation in a prospective cohort of early stage patients. AB - The chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) combines 5 parameters (age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], IGHV mutational status, serum beta2-microglobulin) to predict survival and time-to-first-treatment (TTFT) in CLL patients. We performed an observational study in 337 prospectively collected, Binet stage A patients to validate the ability of the CLL-IPI to predict TTFT in an independent cohort of early stage CLL patients. The CLL-IPI score stratified Binet stage A patients into three subgroups with different outcome. Since the CLL-IPI was originally developed to predict survival, we next investigated the optimal cut-off score to predict TTFT in Binet stage A patients. Recursive partitioning analysis identified three subsets with scores of 0 (n = 139), 1 (n = 90), and >= 2(n = 108). The probability of remaining free from therapy 5 years after diagnosis was 85%, 67% and 46% in these three categories (P < 0.0001.; C-statistic:c = 0.72; 95% CI:0.58-0.81). This optimized CLL-IPI scoring for TTFT was subsequently validated in an independent cohort of Binet A patients from the Mayo Clinic (n = 525). The ability of either original or optimized CLL-IPI to predict TTFT was equivalent to other prognostic models specifically designed for this endpoint (2011 MDACC score and O-CLL1 score). Although originally developed to predict suvival, the CLL-IPI is useful for predicting TTFT in early stage CLL patients. Am. J. Hematol. 91:1090-1095, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27465921 TI - Declines in traditional marine food intake and vitamin D levels from the 1960s to present in young Alaska Native women. AB - OBJECTIVE: To measure the trends in traditional marine food intake and serum vitamin D levels in Alaska Native women of childbearing age (20-29 years old) from the 1960s to the present. DESIGN: We measured a biomarker of traditional food intake, the delta15N value, and vitamin D level, as 25 hydroxycholecalciferol (25(OH)D3) concentration, in 100 serum samples from 20-29 year-old women archived in the Alaska Area Specimen Bank, selecting twenty-five per decade from the 1960s to the 1990s. We compared these with measurements of red-blood-cell delta15N values and serum 25(OH)D3 concentrations from 20-29-year old women from the same region collected during the 2000s and 2010s in a Center for Alaska Native Health Research study. SETTING: The Yukon Kuskokwim Delta region of south-west Alaska. SUBJECTS: Alaska Native women (n 319) aged 20-29 years at the time of specimen collection. RESULTS: Intake of traditional marine foods, as measured by serum delta15N values, decreased significantly each decade from the 1960s through the 1990s, then remained constant from the 1990s through the present (F 5,306=77.4, P<0.0001). Serum vitamin D concentrations also decreased from the 1960s to the present (F 4,162=26.1, P<0.0001). CONCLUSIONS: Consumption of traditional marine foods by young Alaska Native women dropped significantly between the 1960s and the 1990s and was associated with a significant decline in serum vitamin D concentrations. Studies are needed to evaluate the promotion of traditional marine foods and routine vitamin D supplementation during pregnancy for this population. PMID- 27465922 TI - Multiple siRNA delivery against cell cycle and anti-apoptosis proteins using lipid-substituted polyethylenimine in triple-negative breast cancer and nonmalignant cells. AB - Conventional breast cancer therapies have significant limitations that warrant a search for alternative therapies. Short-interfering RNA (siRNA), delivered by polymeric biomaterials and capable of silencing specific genes critical for growth of cancer cells, holds great promise as an effective, and more specific therapy. Here, we employed amphiphilic polymers and silenced the expression of two cell cycle proteins, TTK and CDC20, and the anti-apoptosis protein survivin to determine the efficacy of polymer-mediated siRNA treatment in breast cancer cells as well as side effects in nonmalignant cells in vitro. We first identified effective siRNA carriers by screening a library of lipid-substituted polyethylenimines (PEI), and PEI substituted with linoleic acid (LA) emerged as the most effective carrier for selected siRNAs. Combinations of TTK/CDC20 and CDC20/Survivin siRNAs decreased the growth of MDA-MB-231 cells significantly, while only TTK/CDC20 combination inhibited MCF7 cell growth. The effects of combinational siRNA therapy was higher when complexes were formulated at lower siRNA:polymer ratio (1:2) compared to higher ratio (1:8) in nonmalignant cells. The lead polymer (1.2PEI-LA6) showed differential transfection efficiency based on the cell-type transfected. We conclude that the lipid-substituted polymers could serve as a viable platform for delivery of multiple siRNAs against critical targets in breast cancer therapy. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3031-3044, 2016. PMID- 27465923 TI - Enhanced anticancer activity in vitro and in vivo of luteolin incorporated into long-circulating micelles based on DSPE-PEG2000 and TPGS. AB - OBJECTIVES: This study aimed to evaluate enhanced anticancer activity in vitro and in vivo of luteolin-loaded long-circulating micelles (DTLLMs) formulated. METHODS: DTLLM was the luteolin formulation prepared with 1,2-distearoyl-sn glycero-3-phosphoethanolamine-N-methoxy-poly (ethylene glycol 2000) (DSPE-PEG2000 ) and d-alpha-tocopheryl polyethylene glycol succinate (TPGS) in this study. We performed a systematic comparative evaluation of the antiproliferative effect, cellular uptake, antitumour efficacy and in vivo tumour targeting of these micelles using non-small cell lung cancer (NSCLC) A549 cells. KEY FINDINGS: Results showed that the obtained micelles have a mean particle size of around 42.34 nm, and the size of micelles was narrowly distributed. With the improved cellular uptake, DTLLM displayed a more potent antiproliferative action on A549 cell lines than luteolin; half-maximal inhibitory concentration (IC50 ) was 7.29 vs 19.14 MUg/ml, respectively. The antitumour efficacy test in nude mice showed that DTLLM exhibited significantly higher antitumour activity against NSCLC with lesser toxic effects on normal tissues. The imaging study for in vivo targeting demonstrated that the long-circulating micelles formulation achieved targeted drug delivery and make drug release slow to prolong the circulating time. CONCLUSION: DTLLM might be a potential antitumour formulation. PMID- 27465924 TI - Zn(2+) and Cd(2+) cationized serine complexes: infrared multiple photon dissociation spectroscopy and density functional theory investigations. AB - The gas-phase structures of zinc and cadmium dications bound to serine (Ser) are investigated by infrared multiple photon dissociation (IRMPD) action spectroscopy using the free electron laser FELIX, in combination with ab initio calculations. To identify the structures of the experimentally observed species, [Zn(Ser H)CH3CN](+) and CdCl(+)(Ser), the measured action spectra are compared to linear absorption spectra calculated at the B3LYP/6-311+G(d,p) level for Zn(2+) containing complexes and B3LYP/def2-TZVP levels for Cd(2+) containing complexes. Good agreement between the observed IRMPD spectra and the predicted spectra allows identification of the isomers present. The intact amino acid interacting with cadmium chloride adopts a tridentate chelation involving the amino acid backbone amine and carbonyl groups as well as the hydroxyl group of the side chain, [N,CO,OH]. The presence of two low-energy conformers is observed for the deprotonated serine-zinc complex, with the same tridentate coordination as for the cadmium complex but proton loss occurs at both the hydroxyl side-chain, [N,CO,O(-)], and the carboxylic acid of the amino acid backbone, [N,CO(-),OH]. These results are profitably compared with the analogous results previously obtained for comparable complexes with cysteine. PMID- 27465926 TI - Implementation of an education package on breast engorgement aimed at lactation consultants and midwives to prevent conflicting information for postnatal mothers. AB - AIM: The aim of this evidence-based practice project was to improve local practice in the treatment of breast engorgement in postnatal mothers and to ensure the treatment of engorgement in postnatal mothers is performed according to the best available evidence. METHODS: This evidence-based practice project took place in a 28-bed postnatal ward in a large metropolitan tertiary hospital. Twenty midwives and 20 in-patients were recruited for the project. The project utilized an audit and feedback design. Midwives were asked a series of questions to test their knowledge on engorgement, and mothers were asked questions relating to the breastfeeding and engorgement care they received. The project was conducted in three phases: preparation for quality audit, implementation of best practice and postimplementation audit. RESULTS: Comparison of Audit 1 (preimplementation) and Audit 2 (postimplementation) results shows significant improvements in all eight audit criteria. An increase of 80% was achieved for the criteria 'midwives received formal education on engorgement' on completion of the project. A 20% increase in 'consistency of education regarding latch' was reported by the mothers, and there was a 30% increase in 'information given to mothers on prevention and signs of engorgement'. Sixty-five percent of midwives were able to correctly identify and manage engorgement, a significant improvement from 5% at baseline. CONCLUSION: This evidence-based practice project successfully identified and utilized best practice in the management of breast engorgement care in mothers in our clinical setting. With effective breast engorgement interventions in place, mothers could continue to successfully breastfeed their babies. The major challenges identified during the conduct of the project included: time constraints on the midwives to attend education sessions and to educate mothers on prevention. At the completion of this project, a closer relationship was forged between the lactation consultant team and the midwives in the project setting. This increased the satisfaction and productivity of the midwives, and motivated them to deliver high-quality care, which contributed to an improvement in mother's confidence and reduction in conflicting information. PMID- 27465927 TI - Predicting a pathological complete response in rectal cancer. PMID- 27465925 TI - Directed Evolution of Scanning Unnatural-Protease-Resistant (SUPR) Peptides for in Vivo Applications. AB - Peptides typically have poor biostabilities, and natural sequences cannot easily be converted into drug-like molecules without extensive medicinal chemistry. We have adapted mRNA display to drive the evolution of highly stable cyclic peptides while preserving target affinity. To do this, we incorporated an unnatural amino acid in an mRNA display library that was subjected to proteolysis prior to selection for function. The resulting "SUPR (scanning unnatural protease resistant) peptide" showed ~500-fold improvement in serum stability (t1/2 =160 h) and up to 3700-fold improvement in protease resistance versus the parent sequence. We extended this approach by carrying out SUPR peptide selections against Her2-positive cells in culture. The resulting SUPR4 peptide showed low nanomolar affinity toward Her2, excellent specificity, and selective tumor uptake in vivo. These results argue that this is a general method to design potent and stable peptides for in vivo imaging and therapy. PMID- 27465928 TI - Surfactant-Triggered Fluorescence Turn "on/off" Behavior of a Polythiophene-graft Polyampholyte. AB - Polythiophene-graft-polyampholyte (PTP) is synthesized using N,N dimethylaminoethyl methacrylate and tert-butyl methacrylate monomers by grafting from polythiophene backbone, followed by hydrolysis. The resulting polymer exhibits aqueous solubility via formation of small-sized miceller aggregates with hydrophobic polythiophene at the center and radiating polyionic side chains (cationic or anionic depending on the pH of the medium) at the outer periphery. The critical micelle concentration of PTP in acidic solution (0.025 mg/mL, pH = 2.7) is determined from fluorescence spectroscopy. PTP exhibits reversible fluorescence on and off response in both acidic and basic medium with the sequential addition of differently charged ionic surfactants, repeatedly. The fluorescence intensity of PTP at pH 2.7 increases with the addition of an anionic surfactant, sodium dodecyl benzenesulfonate (SDBS), due to the self-aggregation forming compound micelles. The fluorescence intensity of these solutions again decreases on addition of a cationic surfactant, cetyltrimethylammonium bromide (CTAB), because of assembling of SDBS with CTAB, thus deassembling the PTP-SDBS aggregates. At pH 9.2, these turn on and turn off responses are also shown by PTP with the sequential addition of cationic surfactant (CTAB) and anionic surfactant (SDBS), respectively. This result shows that PTP has potential for surfactant induced reversible fluorescence turn on and off using ionic surfactant (SDBS and CTAB) through self-assembling and deassembling of the ionic aggregates. The reversible aggregation and disaggregation process of PTP with the surfactants at both acidic and basic pH is supported from dynamic light scattering and Fourier transform infrared spectroscopy. The morphology of the above systems studied by transmission and scanning electron microscopy also supports the above aggregation and disaggregation process. PMID- 27465929 TI - Heterogeneity of MYCN amplification in neuroblastoma at diagnosis, treatment, relapse, and metastasis. AB - Amplification of the MYCN gene in neuroblastoma is associated with a poor prognosis and is considered to remain unchanged in post-treatment specimens and metastases. While heterogeneity of MYCN copy number in tumor cells has been reported, serial samples have only been studied in a limited way, and the biologic relevance of this finding is not well understood. We used in situ hybridization on paraffin sections of 102 specimens from 30 patients with MYCN amplified neuroblastoma to determine MYCN copy number in the primary tumor, pre- and post-treatment, and in metastatic samples. Nineteen cases (63%) showed diffuse MYCN amplification in all samples tested. Nine cases (30%) showed a reduction in MYCN copy number: five cases with diffuse amplification subsequently showed focal amplification, one case with diffuse MYCN amplification showed MYCN gain after treatment, and three focally amplified cases were non-amplified in later specimens. In two cases (7%), focal amplification became diffuse in subsequent samples. Histology was not predictive of the temporal or spatial pattern of MYCN amplification for a particular tumor. If extent of amplification (focal vs. diffuse) is not considered, 26/30 (87%) of cases were consistently MYCN-amplified. However, our data suggest that MYCN status can be heterogeneous between tumor sites, during tumor progression or following treatment, challenging the notion that MYCN copy number does not change for a particular neuroblastoma. Assessing the biologic significance of MYCN heterogeneity will require larger studies of clinically annotated tumor samples, and will depend on interpreting heterogeneity in MYCN status in combination with other genetic changes. (c) 2016 Wiley Periodicals, Inc. PMID- 27465930 TI - Prefunctionalized Porous Organic Polymers: Effective Supports of Surface Palladium Nanoparticles for the Enhancement of Catalytic Performances in Dehalogenation. AB - Three porous organic polymers (POPs) containing H, COOMe, and COO(-) groups at 2,6-bis(1,2,3-triazol-4-yl)pyridyl (BTP) units (i.e., POP-1, POP-2, and POP-3, respectively) were prepared for the immobilization of metal nanoparticles (NPs). The ultrafine palladium NPs are uniformly encapsulated in the interior pores of POP-1, whereas uniform- and dual-distributed palladium NPs are located on the external surface of POP-2 and POP-3, respectively. The presence of carboxylate groups not only endows POP-3 an outstanding dispersibility in H2 O/EtOH, but also enables the palladium NPs at the surface to show the highest catalytic activity, stability, and recyclability in dehalogenation reactions of chlorobenzene at 25 degrees C. The palladium NPs on the external surface are effectively stabilized by the functionalized POPs containing BTP units and carboxylate groups, which provides a new insight for highly efficient catalytic systems based on surface metal NPs of porous materials. PMID- 27465931 TI - A Community Needs Assessment of the Physical Activity and Food Environment in a Predominantly Hispanic U.S. City. AB - INTRODUCTION: Hispanics suffer disproportionately compared with non-Hispanic Whites from health conditions that are affected by physical inactivity and poor dietary habits. METHOD: A needs assessment was conducted in Hialeah, Florida, the largest enclave of Cubans in the United States, to assess the perspectives of community stakeholders and members regarding the roles of physical activity and nutrition environments. Interviews were performed with community stakeholders (n = 21), and responses were grouped into major themes. Surveys were conducted with community members (n = 85). Descriptive analyses were used to categorize responses and potential differences across responses were explored. RESULTS: Both community members and stakeholders reported that the local park system was a major asset to healthy living in Hialeah and agreed that traffic issues and a lack of walkability were major barriers to being physically active; however, there was variability in the response to the quality of the food environment. CONCLUSION: The perspectives of the community members and stakeholders will be valuable in highlighting pathways to enhancing the health and wellness of the residents of Hialeah. PMID- 27465932 TI - Excessive Daytime Sleepiness as an Indicator of Depression in Hispanic Americans. AB - INTRODUCTION: Excessive daytime sleepiness (EDS) has been shown to be associated with depression; however, this relationship has not been confirmed among Hispanic Americans. METHOD: This study examined the link between EDS and depression among Hispanic Americans (N = 411) and explored the potential moderating roles of age, gender, income, education, health status, and acculturation. The Epworth Sleepiness Scale and Patient Health Questionnaire-9 measured EDS and depression, respectively. RESULTS: Hierarchical linear regression demonstrated that EDS was significantly related to depression. Receiver operating characteristic curve analysis suggested that the Epworth Sleepiness Scale discriminated with adequate sensitivity and specificity between participants with moderately severe depression and those with less severe symptoms. No sociodemographic variables moderated the EDS-depression relationship. CONCLUSION: These findings suggest that depression should be considered when Hispanic Americans present with EDS. PMID- 27465933 TI - Gingival Retraction Methods: A Systematic Review. AB - PURPOSE: The aim of this systematic review was to assess the gingival retraction methods in terms of the amount of gingival retraction achieved and changes observed in various clinical parameters: gingival index (GI), plaque index (PI), probing depth (PD), and attachment loss (AL). METHODS: Data sources included three major databases, PubMed, CINAHL plus (Ebsco), and Cochrane, along with hand search. Search was made using the key terms in different permutations of gingival retraction* AND displacement method* OR technique* OR agents OR material* OR medicament*. RESULTS: The initial search results yielded 145 articles which were narrowed down to 10 articles using a strict eligibility criteria of including clinical trials or experimental studies on gingival retraction methods with the amount of tooth structure gained and assessment of clinical parameters as the outcomes conducted on human permanent teeth only. Gingival retraction was measured in 6/10 studies whereas the clinical parameters were assessed in 5/10 studies. CONCLUSIONS: The total number of teeth assessed in the 10 included studies was 400. The most common method used for gingival retraction was chemomechanical. The results were heterogeneous with regards to the outcome variables. No method seemed to be significantly superior to the other in terms of gingival retraction achieved. Clinical parameters were not significantly affected by the gingival retraction method. PMID- 27465934 TI - Efficacy of system l amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma. AB - System l amino acid transporter 1 (LAT1) is highly expressed in various types of human cancer, and contributes to cancer growth and survival. Recently, we have shown that LAT1 expression is closely related to the growth and aggressiveness of esophageal cancer, and is an independent marker of poor prognosis. However, it remains unclear whether LAT1 inhibition could suppress esophageal cancer growth. In this study, we investigated the tumor-suppressive effects of the inhibition of LAT1. Both LAT1 and CD98, which covalently associates to LAT1 on the membrane, were expressed in human esophageal cancer cell lines KYSE30 and KYSE150. Quantitative PCR analysis showed that the expression of LAT1 was much higher than other subtypes of LAT. A selective inhibitor of LAT, 2-aminobicyclo-(2,2,1) heptane-2-carboxylic acid (BCH), suppressed cellular uptake of l-14 C-leucine and cell proliferation in a dose-dependent manner. It also suppressed phosphorylation of mammalian target of rapamycin, 4E-BP1, and p70S6K protein, and induced cell cycle arrest at G1 phase. These results suggest that suppression of both mammalian target of rapamycin signaling and cell cycle progression is involved in BCH-induced growth inhibition. In tumor-bearing mice, daily treatment with BCH significantly delayed tumor growth and decreased glucose metabolism, indicating that LAT1 inhibition potentially suppresses esophageal cancer growth in vivo. Thus, our results suggest that LAT1 inhibition could be a promising molecular target for the esophageal cancer therapy. PMID- 27465935 TI - Effect of Laparoscopic Sleeve Gastrectomy on Fasting Gastrointestinal, Pancreatic, and Adipose-Derived Hormones and on Non-Esterified Fatty Acids. AB - BACKGROUND: Alterations in gastrointestinal, pancreatic, and adipose hormone levels may have a greater role in weight loss than initially appreciated. The laparoscopic sleeve gastrectomy (LSG) operation is now the most frequently performed bariatric operation in many countries, but there are relatively few data regarding its molecular effects. We sought to characterize the effect of LSG on fasting plasma levels of selected hormones and on non-esterified fatty acids (NEFA), and to compare these to levels in non-obese control individuals. MATERIALS AND METHODS: The levels of nine plasma hormones were measured using a multiplex bead-based assay at baseline and at 3 months after operation in 11 obese patients undergoing LSG. NEFA levels were also measured. The levels were compared to those for 22 age- and sex-matched non-obese individuals. RESULTS: At baseline, obese patients showed significantly higher expression of C-peptide, insulin, and leptin and significantly lower ghrelin, glucose-dependent insulinotropic peptide (GIP), and resistin compared to non-obese controls (p < 0.05). LSG resulted in a reduction in BMI from 42.5 +/- 6.47 kg/m2 at operation to 35.2 +/- 5.14 kg/m2 at 3 months (42 % mean excess weight loss, p < 0.001). LSG led to a significant decrease in ghrelin, glucagon-like peptide-1 (GLP-1), glucagon, leptin, plasminogen activator inhibitor-1 (PAI-1), and NEFA. CONCLUSION: LSG induces marked early changes in the fasting levels of factors thought to be important regulators of obesity and metabolic health. These changes differ somewhat from the findings for operations with a malabsorptive component, suggesting that subtle differences exist in the mechanisms of weight loss between LSG and other bariatric operations. PMID- 27465936 TI - Efficacy of First-Time Intragastric Balloon in Weight Loss: a Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: The intragastric balloon (IGB) is an adjunctive treatment for obesity. This meta-analysis aimed to evaluate the efficacy and safety of IGB treatment by reviewing randomized controlled trials (RCTs). METHODS: A total of 20 RCTs involving 1195 patients were identified. Weight loss results before and after 3 months were analyzed separately. The weight loss results of patients with and without IGB treatment were compared. RESULTS: Our meta-analysis calculated the following significant effect sizes: 1.59 and 1.34 kg/m2 for overall and 3 month BMI loss, respectively; 14.25 and 11.16 % for overall and >3-month percentage of excess weight loss, respectively; 4.6 and 4.77 kg for overall and 3 month weight loss, respectively; and 2.81, 1.62, and 4.09 % for overall, 3-month, and >3-month percent of weight loss, respectively. A significant effect size was calculated that favored fluid-filled IGBs over air-filled IGBs. Flatulence (8.75 vs. 3.89 %, p = 0.0006), abdominal fullness (6.32 vs. 0.55 %, p = 0.001), abdominal pain (13.86 vs. 7.2 %, p = 0.0001), abdominal discomfort (4.37 vs. 0.55 %, p = 0.006), and gastric ulcer (12.5 vs. 1.2 %, p < 0.0001) were significantly more prevalent among IGB patients than among non-IGB control patients. No mortality was reported from IGB treatment. CONCLUSION: IGB treatment, in addition to lifestyle modification, is an effective short-term modality for weight loss. However, there is not sufficient evidence confirming its safety or long-term efficacy. PMID- 27465937 TI - The IGF-Axis and Diabetic Retinopathy Before and After Gastric Bypass Surgery. AB - BACKGROUND: Laparoscopic gastric bypass (LGB) abruptly causes remission of type 2 diabetes (T2D). Such dramatic metabolic changes have previously been found to cause worsening of diabetic retinopathy (DR) and circulating insulin-like growth factor I (IGF-I) has been suggested as a causal mediator. We aimed to evaluate baseline imbalances in the circulating IGF-system and changes after LGB in patients with T2D. METHODS: Prospective ocular examinations and measurement of the IGF-axis before and 3 and 12 months after LGB. IGF-bioactivity was measured by cell-based IGF-I receptor (IGF-IR) kinase activation assay (bioactive IGF). Total IGF-I, IGF-II and IGF binding protein (IGFBP) 1 and 3 were determined by immunoassays. RESULTS: At baseline, 18 of 36 patients presented with DR. These patients had higher levels of bioactive IGF (p = 0.03) than patients without DR and this association was strengthened in multivariate analysis (p = 0.006). Three patients had worsening of DR, unrelated to other markers. In univariate analysis, bioactive IGF increased at 3 months (p = 0.05) but this change became insignificant in multivariate analysis (p = 0.11). IGFBP-1 increased whereas IGFBP-3 and total IGF-II decreased at the two postoperative visits (p <= 0.001). Total IGF-I showed no significant changes. HbA1c, glucose, HOMA-IR and lipids improved after surgery. Two patients did not complete the 12-month visit. CONCLUSIONS: In obese T2D patients, bioactive IGF is a potential biomarker for DR and levels tended to increase 3 months after bariatric surgery. IGFBP-1 increased while IGFBP-3 and total IGF-II decreased postoperatively, but these changes were unassociated with the development of DR. Markers of the metabolic syndrome improved. PMID- 27465938 TI - The Phase Angle of the Bioelectrical Impedance Analysis as Predictor of Post Bariatric Weight Loss Outcome. AB - BACKGROUND: Bariatric surgery is proven to be the most effective therapy for obesity. However, the targeted weight reduction is not always achieved. Reliable predictors for postoperative success are rare. Also, most available predictors, such as gender and socioeconomic status, cannot be influenced. The aim of the study was to assess the reliability of the phase angle (PhA) as a predictor of weight reduction and body composition after bariatric surgery. METHODS: One hundred seventy-three patients (127 with Roux-en-Y gastric bypass and 46 with sleeve gastrectomy), treated between January 2004 and December 2012, were included into this prospective trial. Bioelectrical impedance analysis (BIA) was performed before and five times within the first year after the operation. Correlation between excess weight loss (EWL) was calculated using Pearson's correlation coefficient and a receiver operating characteristic (ROC) curve. RESULTS: The average weight loss was significant with a total weight loss of 30.1 %, while the PhA did not show any significant decrease during the first 12 months after surgery. The correlation between the preoperative PhA and the postoperative EWL was significant after 6 weeks and after 6, 9, and 12 months. The ROC curve has an area of 0.7. The best point of the curve is a PhA of 3.9 degrees with a sensitivity of 81 % and a specificity of 54 %. CONCLUSIONS: PhA may be a useful predictor of EWL after bariatric surgery, and a PhA of 3.9 degrees was calculated as the most suitable cut-off for a successful operation. PMID- 27465940 TI - [To improve the accessibility of hepatitis B treatment]. AB - The burden of chronic hepatitis B is substantial in China. An estimated 90 million people are living with chronic hepatitis B. About 7.4 million people are at high risk of advance stage liver disease and cancer due to chronic hepatitis B and who urgently require treatment. However, only 12.5% of chronic hepatitis B patients are receiving antiviral treatment at present. In order to improve the accessibility of antiviral treatment for chronic hepatitis B we should decrease the price of antiviral drugs; to bring antiviral drugs into the national essential drugs list; to include antiviral drugs in both inpatient and outpatient reimbursement category; to apply the mechanisms for drug price reduction such as rejecting the patent registration for drugs with public health risk and harm to welfare policy; initiating government unified price negotiations with drug companies. PMID- 27465939 TI - microRNA-145 Mediates the Inhibitory Effect of Adipose Tissue-Derived Stromal Cells on Prostate Cancer. AB - Adipose-derived stromal cell (ASC), known as one of the mesenchymal stem cells (MSCs), is a promising tool for regenerative medicine; however, the effect of ASCs on tumor growth has not been studied sufficiently. We investigated the hypothesis that ASCs have an inhibitory effect on metastatic tumor progression. To evaluate the in vitro inhibitory effect of ASCs on metastatic prostate cancer (PCa), direct coculture and indirect separate culture experiments with PC3M-luc2 cells and human ASCs were performed, and ASCs were administered to PC3M-luc2 cell derived tumor-bearing nude mice for in vivo experiment. We also performed exosome microRNA (miRNA) array analysis to explore a mechanistic insight into the effect of ASCs on PCa cell proliferation/apoptosis. Both in vitro and in vivo experiments exhibited the inhibitory effect of ASCs on PC3M-luc2 cell proliferation, inducing apoptosis and PCa growth, respectively. Among upregulated miRNAs in ASCs compared with fibroblasts, we focused on miR-145, which was known as a tumor suppressor. ASC-derived conditioned medium (CM) significantly inhibited PC3M-luc2 cell proliferation, inducing apoptosis, but the effect was canceled by miR-145 knockdown in ASCs. ASC miR-145 knockdown CM also reduced the expression of Caspase 3/7 with increased antiapoptotic protein, BclxL, expression in PC3M-luc2 cells. This study provides preclinical data that ASCs inhibit PCa growth, inducing PCa cell apoptosis with reduced activity of BclxL, at least in part, by miR-145, including exosomes released from ASCs, suggesting that ASC administration could be a novel and promising therapeutic strategy in patients with PCa. PMID- 27465941 TI - [An interpretation of European guidelines for the diagnosis and treatment of nonalcoholic fatty liver disease]. AB - Nonalcoholic fatty liver disease (NAFLD) is a pathological manifestation of obesity and metabolic syndrome involving the liver. It can cause disability and mortality related to liver disease, and it is closely associated with the high incidence rates of type 2 diabetes and cardiovascular diseases. At present, NAFLD has become the most common chronic liver disease worldwide, and the development and implementation of the clinical guideline for the diagnosis and treatment of NAFLD help to improve patients' prognosis. This article provides an interpretation of the latest Europeans guidelines through a comparative analysis of the previous and latest Europeans guidelines. PMID- 27465942 TI - [Loop-mediated isothermal amplification for visual detection of hepatitis B virus]. AB - OBJECTIVE: To investigate the method of loop-mediated isothermal amplification (LAMP) using boiled serum for visual detection of hepatitis B virus (HBV). METHODS: Specific LAMP primers were designed according to the conservative region compared with the sequence of S genes in GenBank, and DNA of the samples was extracted by kit and boiling methods. The reaction conditions of LAMP were optimized, and HBV standard strains and clinical samples were examined to evaluate the specificity, sensitivity, and anti-interference ability of LAMP. Visual detection was performed for the results of LAMP, and SPSS 17.0 was used for consistency test. RESULTS: The optimal reaction conditions of LAMP were established. LAMP had a high specificity, and there was no nonspecific amplification. The sensitivity of LAMP was 10 copies/tube, regardless of the method for nucleic acid extraction. Hydroxynaphthol blue (HNB) had a comparable sensitivity to electrophoresis and SYBR Green I, and, unlike SYBR Green I, did not cause aerosol pollution easily. In addition, with fluorescent quantitative PCR (FQ-PCR) as the gold standard, LAMP using the boiling method and FQ-PCR were in good consistency (Kappa = 0.762, P > 0.05). However, PCR using boiling method was not well consistent with FQ-PCR (Kappa = 0.186, P < 0.05). CONCLUSION: LAMP has certain advantages over PCR in detecting HBV infection, and LAMP can be used to detect HBV in the field or primary hospitals. PMID- 27465943 TI - [Clinicopathological features of early- and late-stage primary biliary cirrhosis: a comparative study]. AB - OBJECTIVE: To investigate the clinicopathological features of different stages of primary biliary cirrhosis (PBC), and to provide a basis of evidence-based medicine for early identification and effective treatment of this disease. METHODS: A total of 130 patients with pathologically confirmed PBC and complete clinical data were enrolled and divided into early-stage group and late-stage group based on pathological results. A retrospective analysis was performed for patients' general information, clinical manifestations, laboratory examinations, and pathological changes. RESULTS: The PBC patients had a mean age of 43.5+/-7.1 years, with middle-aged female patients accounting for 89%. The most common symptom was fatigue, followed by jaundice, pruritus, and abdominal distension in the late stage. Of all patients, 11.5% were complicated by autoimmune disease. The level of aminotransferases tended to decrease with the progression of PBC and showed no significant differences between the two groups (P > 0.05). Most patients showed an increase in serum bilirubin, mainly direct bilirubin; serum total bilirubin and direct bilirubin tended to increase with disease progression and showed significant differences between the two groups (P < 0.01). The patients showed increases in the serum levels of alkaline phosphatase (ALP) andgamma-glutamyl transpeptidase (GGT), but with the disease progression, the serum level of ALP increased and that of GGT decreased; the serum levels of ALP and GGT showed no significant differences between the early- and late-stage groups (P > 0.05). The positive rate of antimitochondrial antibody was 85%. The histopathological changes of PBC included severe lesions in the portal area and surrounding areas and slight lobular lesions. In the early stage, there were injuries of the interlobar bile ducts, proliferation of small bile ducts, aggregation and invasion of mononuclear cells in surrounding tissues, and the formation of lymphoid follicle-like structure; in the late stage, there were fibrotic expansion of the portal area, formation of fibrous septa and pseudolobuli, and even liver cirrhosis. CONCLUSION: PBC is commonly seen in middle-aged women and has an insidious onset. Early- and late-stage PBC have their own clinicopathological features. As for patients with no characteristic changes in serological test, liver biopsy should be performed to give a confirmed diagnosis and avoid missed diagnosis and misdiagnosis. PMID- 27465944 TI - [Expression profiles of long non-coding RNAs in human liver cell line LO2 with stable expression of hepatitis B x gene]. AB - OBJECTIVE: To investigate the differential expression profiles of long non-coding RNAs (lncRNAs) in human liver cell line LO2 with stable expression of hepatitis B x (HBx) gene, and to screen out the lncRNAs which play an important role in HBV related liver cancer. METHODS: The lncRNA microarray was used to establish the differential expression profiles of lncRNAs, and the methods such as scatter plots and cluster analysis were used to obtain the HBx-related lncRNAs with differential expression. The qRT-PCR was used to verify some lncRNAs with differential expression. The t-test was used to compare the expression of lncRNAs between the two microarray groups, and hierarchical cluster analysis was used for the original data of lncRNAs with differential expression. RESULTS: Compared with the control group transfected with blank plasmids (L02/pcDNA3.0), LO2/HBx cells had 323 lncRNAs with > 2-fold upregulation and 421 lncRNAs whose expression was reduced by more than 50% (P < 0.05). The results of qRT-PCR verified 4 upregulated lncRNAs (TCONS_00006195, ENST00000557524, NR_037597, and ENST00000539975) and 3 downregulated lncRNAs (ENST00000508424, ENST00000447433, and uc001lva.4), which were consistent with the results of microassay. CONCLUSION: HBx-related lncRNAs are successfully screened out, which lays a foundation for further investigation of the role of lncRNAs in the pathogenesis of liver cancer. PMID- 27465945 TI - [Clinical features and prognosis of patients with first-episode liver metastasis of different molecular subtypes of breast cancer]. AB - OBJECTIVE: To investigate the clinical features and prognosis of patients with first-episode liver metastasis of different molecular subtypes of breast cancer and risk factors for liver metastasis of breast cancer. METHODS: A retrospective analysis was performed for 122 breast cancer patients with first-episode liver metastasis from January 2009 to January 2014. According to the cell surface receptors of breast cancer, these patients were divided into the four molecular subtypes of Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2) overexpression, and triple-negative breast cancer (TNBC). The association of patients' age at initial diagnosis, body mass index (BMI), menstruation status, clinical TNM (cTNM) stage, levels of lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) at recurrence, liver metastasis, and treatment condition with the patients' prognosis were analyzed. The chi-square test and Fisher's exact test were used for categorical data, the Kaplan-Meier method was used for survival analysis, the log-rank test was used for univariate analysis of influencing factors, and the Cox regression model was used for multivariate analysis. RESULTS: Among the 122 patients, 12 had Luminal A subtype, 61 had Luminal B subtype, 30 had HER2 overexpression subtype, and 19 had TNBC subtype. In the patients with Luminal A, Luminal B, HER2 overexpression, and TNBC subtypes, the median disease-free survival (DFS) was 32, 23, 16, and 10 months, respectively (P = 0.001), the median overall survival (OS) was 54, 35, 26, and 13 months, respectively (P = 0.003), and the median OS after liver metastasis was 30, 16, 10, and 9 months, respectively (P = 0.019). In HER2-positive patients, the application of trastuzumab in the past significantly prolonged the patients' DFS by 11 months and OS by 18 months (P < 0.05). The results of the multivariate analysis showed that cTNM stage, molecular subtype, and targeted therapy were independent influencing factors for DFS of breast cancer patients with liver metastasis (P < 0.05), and that BMI, increased LDH at recurrence, cTNM stage, molecular subtype, salvage chemotherapy, radiotherapy, and targeted therapy were independent influencing factors for OS of breast cancer patients with liver metastasis (P < 0.05). The patients with TNBC, HER2 overexpression, and Luminal B subtypes exhibited worse prognosis and had a risk of recurrence 15.97, 8.81, and 4.76 times higher than those with Luminal A subtype. The risk of death in the patients with TNBC, HER2 overexpression, and Luminal B subtypes was 8.42, 6.02, and 3.86 times that in those with Luminal A subtype. CONCLUSION: The prognosis of breast cancer patients with first-episode liver metastasis is associated with the increase in LDH when liver metastasis occurs, BMI, cTNM stage, and molecular subtype. Compared with the patients with Luminal subtypes, those with HER2 overexpression and TNBC subtypes tend to develop liver metastasis in early stage and have a shorter OS. Salvage chemotherapy, targeted therapy, and radiotherapy can significantly improve the prognosis of patients with liver metastasis. PMID- 27465946 TI - [Value of a two-step approach with cytokeratin-18 and controlled attenuation parameter in noninvasive differential diagnosis of nonalcoholic steatohepatitis]. AB - OBJECTIVE: To investigate the value of a two-step approach with cytokeratin-18 (CK-18) and controlled attenuation parameter (CAP) in the noninvasive diagnosis of nonalcoholic steatohepatitis (NASH). METHODS: A total of 65 patients with biopsy-proven nonalcoholic fatty liver disease were enrolled, including 30 patients with NASH. The M30 and M65 enzyme-linked immunosorbent assay kits were used to measure serum CK-18, and FibroScan was used to measure CAP. The receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUROC) was used to determine the value of noninvasive diagnosis. The binary logistic regression model was used to calculate the predicted probability of combined diagnosis. The maximum Youden index, a sensitivity of >90%, and a specificity of > 90% were used to determine the optimal cut-off value, the low value, and the high value, respectively. RESULTS: The results of the multivariate analysis showed that M65 (OR = 1.004, 95% CI 1.002-1.007, P = 0.003) and CAP (OR = 1.017, 95% CI 1.001-1.033, P = 0.036) were independent predictors of NASH. The AUROC of M65+CAP was 0.851 (95% CI 0.761-0.942), higher than 0.808 (95% CI 0.702 0.913) of M65 and 0.677 (95% CI 0.545-0.808) of CAP alone. A two-step approach with high (820.8 U/L) and low (527.7 U/L) values for M65 and the optimal cut-off value (293.5 dB/m) for CAP was used for the differential diagnosis of NASH, with a positive predictive value of 85.7%, a negative predictive value of 100%, and a coincidence rate of 92.0%. CONCLUSION: A two-step approach with M65 and CAP can improve the value of noninvasive diagnosis of NASH, and a high negative predictive value can avoid unnecessary liver biopsy. PMID- 27465947 TI - [Investigation of metabolic disorders in patients with familial fatty liver disease and their first-degree relatives]. AB - OBJECTIVE: To investigate the metabolic disorders in patients of familial fatty liver disease and their first-degree relatives. METHODS: The probands with fatty liver disease and normal control probands were randomly selected from 2 000 persons who participated in the survey of"endocrine and metabolic diseases"conducted by Provincial Hospital Affiliated to Shandong University in Taian, Shandong Province, China, and their first-degree relatives were enrolled. A normal control group and a group of sporadic fatty liver disease were established in order to eliminate the influence of environment and diet. A total of 191 subjects were enrolled after being matched for sex and age, including 73 families, 73 probands, and 118 first-degree relatives. According to the presence or absence of fatty liver disease in probands and first-degree relatives, these subjects were divided into normal control group, familial fatty liver group, and sporadic fatty liver group. Clinical and laboratory markers were obtained from each group and statistical analyses were performed. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups or any two groups, the rank sum test was used for comparison of non-normally distributed continuous data, and the chi-square test was used for comparison of categorical data. RESULTS: The probands in the familial fatty liver group and sporadic fatty liver group had significantly higher abdominal obesity indices (body mass index, waist circumference, and hip circumference) than those in the normal control group (all P < 0.05). The first-degree relatives in the familial fatty liver group had significantly higher abdominal obesity indices (body mass index, waist circumference, and hip circumference), serum uric acid, and fasting blood glucose than those in the normal control group and sporadic fatty liver group (all P < 0.05), while these parameters showed no significant differences between the normal control group and sporadic fatty liver group (P > 0.05). The first-degree relatives in the familial fatty liver group had significantly higher incidence rates of overweight and/or obesity and a significantly higher prevalence rate of hyperglycemia compared with the normal control group(overweight and/or obestity:chi (2)= 12.83, P < 0.01; hyperglycemia:chi (2)= 6.96, P < 0.01) and sporadic fatty liver group (overweight and/or obesity: chi (2)= 12.63, P < 0.01; hyperglycemia:chi (2)= 12.22, P < 0.01). CONCLUSION: Persons with a family history of fatty liver disease tend to develop metabolic disorders (obesity and abnormal blood glucose), and early intervention may prevent or delay the development of metabolic syndrome. PMID- 27465948 TI - [Role of farnesoid X receptor in rats with acute cholestatic hepatitis]. AB - OBJECTIVE: To investigate the role of farnesoid X receptor (FXR) and its downstream molecules small heterodimer partner (SHP), UDP-glucuronosyltransferase 2B4 (UGT2B4), and bile salt export pump (BSEP) in rats with acute cholestatic hepatitis. METHODS: A total of 20 Sprague-Dawley rats were randomly divided into normal control group and model group, with 10 rats in each group. The rats in the model group were given a single dose (50 mg/kg) ofalpha-naphthyl isothiocyanate by gavage to establish the animal model of acute cholestatic hepatitis. Quantitative real-time PCR was used to measure the mRNA expression of FXR, UGT2B4, and BSEP in liver tissue at 48 hours after gavage. An automatic biochemical analyzer was used to measure the serum levels of total bilirubin, direct bilirubin, alanine aminotransferase, total bile acid, aspartate aminotransferase, alkaline phosphatase, andgamma-glutamyl transferase. The independent samples t-test was used for comparison of means between groups. RESULTS: The model group had significantly lower mRNA expression of FXR, SHP, UGT2B4, and BSEP in liver tissue than the normal control group (0.152+/ 0.088/0.559+/-0.194/0.177+/-0.039/0.561+/-0.123 vs 1.137+/-0.215/1.512+/ 0.309/2.394+/-0.462/1.631+/-0.376, t = 13.408, 8.260, 15.121, and 8.553, all P < 0.05). The model group had significantly higher liver function parameters than the normal control group (all P < 0.01). CONCLUSION: FXR, SHP, UGT2B4, and BSEP are involved in the development of acute cholestatic hepatitis. Reduced expression of FXR may cause reduced expression of downstream SHP, UGT2B4, and BSEP, increase the synthesis of bile acid, weaken detoxicating and transporting functions, and thus mediate the development of cholestatic hepatitis. PMID- 27465949 TI - [Association between interleukin-28B polymorphisms and antiviral effect in children with chronic hepatitis C]. PMID- 27465950 TI - [Influence of functional nutrients on serum growth hormone and human insulin-like growth factor-1 and their clinical effects in patients with liver cirrhosis]. PMID- 27465951 TI - [Effect of targeted interference of Golgi protein 73 gene on invasion and metastasis of liver cancer cells]. PMID- 27465952 TI - [One case of hereditary hemorrhagic telangiectasia complicated by liver cirrhosis]. PMID- 27465953 TI - [Sinusoidal obstruction syndrome caused by sorafenib administration after hepatectomy for liver cancer: a case report]. PMID- 27465954 TI - [Research advances in the impact of nonalcoholic fatty liver disease on cardiac structure and function]. AB - Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in developed and developing countries. NAFLD is considered to be the manifestation of metabolic syndrome in the liver and an important risk factor for cardiovascular diseases as well. Studies have shown that NAFLD patients have significantly increased the prevalence rates of the diseases including ischemic heart disease and heart failure. Therefore, whether the changes in cardiac structure and impaired cardiac function occur before the development of organic heart diseases in NAFLD patients has attracted scholars' attention. With reference to the published literature, this article reviews the research advances in the association between NAFLD and cardiac changes in adults, children, and patients with diabetes and hypertension. PMID- 27465955 TI - [Research advances in necessity of antiviral therapy for chronic hepatitis B virus carriers]. AB - Chronic hepatitis B virus (HBV) carriers are facing the risk of progression to liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. However, due to low risk, slow disease progression, and unsatisfactory short-term effect of antiviral treatment, controversy still exists over whether such patients should be given antiviral treatment. This article reviews the research advances in the necessity and feasibility of antiviral therapy for chronic hepatitis B virus carriers, so as to provide a reference for clinical practice. PMID- 27465956 TI - [Research advances in the role of interleukin-21 in chronic hepatitis B virus infection]. AB - Interleukin-21 (IL-21) is a cytokine mainly secreted by activated CD4+ T cells and natural killer T cells and has multiple effects. It is involved in innate and adaptive immune responses. Recent studies have shown that IL-21 can promote functional activation of various immune cells in the process of hepatitis B virus (HBV) infection, and the gene polymorphisms of IL-21 is associated with the susceptibility to HBV. In addition, the expression of IL-21 is closely associated with HV genotype, HBV clearance, HBeAg seroconversion, HBV-related liver cirrhosis, liver failure, liver cancer, and autoimmune disease. This article reviews the research advances in clinical trials with reference to the aspects above. PMID- 27465957 TI - [Association between chronicity of HBV infection and host immunity]. AB - The prognosis of hepatitis B virus (HBV) infection is determined by innate immunity, adaptive immunity, and a variety of regulatory factors in the host. Controversy still exists over the role of innate immunity in the progression of HBV infection. Adaptive immunity, especially the immune response mediated by CD8+ T cells, plays an important role in HBV clearance. However, in patients with chronic infection, such CD8+ T cells are often exhausted and associated with various regulatory factors including programmed cell death 1 and T-cell immunoglobulin mucin-3. This article elaborates on the association of chronicity of HBV infection with host immune system and various regulating factors. PMID- 27465958 TI - [Association between chronic urinary tract infection and primary biliary cirrhosis]. AB - The etiology of primary biliary cirrhosis (PBC) remains unclear, and at present, this disease is considered to be caused by the combined effect of genetic factors, infection, autoimmunity, and environmental factors. Since infection is the major cause for PBC, scholars have been focusing on the association between chronic microbial infection. Studies have shown that Escherichia coli is the most common bacterium for urinary tract infection (UTI), and recurrent UTI has been confirmed to be a risk factor for the development and progression of autoimmune liver diseases and is closely associated with PBC. This article investigates the association between UTI and PBC and possible mechanisms. PMID- 27465960 TI - It's all connected! Patient experience and healthy practice environments. PMID- 27465961 TI - Our role as legislative advocates. PMID- 27465959 TI - Clinical characteristics and factors associated with severe acute respiratory infection and influenza among children in Jingzhou, China. AB - BACKGROUND: Influenza is an important cause of respiratory illness in children, but data are limited on hospitalized children with laboratory-confirmed influenza in China. METHODS: We conducted active surveillance for severe acute respiratory infection (SARI; fever and at least one sign or symptom of acute respiratory illness) among hospitalized pediatric patients in Jingzhou, Hubei Province, from April 2010 to April 2012. Data were collected from enrolled SARI patients on demographics, underlying health conditions, clinical course of illness, and outcomes. Nasal swabs were collected and tested for influenza viruses by reverse transcription polymerase chain reaction. We described the clinical and epidemiological characteristics of children with influenza and analyzed the association between potential risk factors and SARI patients with influenza. RESULTS: During the study period, 15 354 children aged <15 years with signs and symptoms of SARI were enrolled at hospital admission. severe acute respiratory infection patients aged 5-15 years with confirmed influenza (H3N2) infection were more likely than children without influenza to have radiographic diagnosis of pneumonia (11/31, 36% vs 15/105, 14%. P<.05). Only 16% (1116/7145) of enrolled patients had received seasonal trivalent influenza vaccination within 12 months of hospital admission. Non-vaccinated influenza cases were more likely than vaccinated influenza cases to have pneumonia (31/133, 23% vs 37/256, 15%, P<.05). severe acute respiratory infection cases aged 5-15 years diagnosed with influenza were also more likely to have a household member who smoked cigarettes compared with SARI cases without a smoking household member (54/208, 26% vs 158/960, 16%, P<.05). CONCLUSIONS: Influenza A (H3N2) virus infection was an important contributor to pneumonia requiring hospitalization. Our results highlight the importance of surveillance in identifying factors for influenza hospitalization, monitoring adherence to influenza prevention and treatment strategies, and evaluating the disease burden among hospitalized pediatric SARI patients. Influenza vaccination promotion should target children. PMID- 27465962 TI - Mentoring to retain newly hired nurses. PMID- 27465964 TI - Healthcare in a virtual world. PMID- 27465963 TI - Meeting patients' behavioral health needs on medical-surgical units. PMID- 27465965 TI - Safe night-shift work. PMID- 27465966 TI - Strategies to influence RN specialty certification. PMID- 27465967 TI - Supporting LGBT nurses. AB - Find out how to respond appropriately when patients express bigotry at the bedside. PMID- 27465968 TI - Transform your leadership. PMID- 27465969 TI - Leadership Q&A. PMID- 27465970 TI - Stratifying delays for assessment by type of substance to improve the probability of attendance in outpatient services. AB - AIMS: 1) To confirm the association between delay for assessment (DFA) and probability of first-time attendance in outpatient substance use disorder (SUD) treatment. 2) To evaluate whether this association varies by the type of primary substance for which the assessment was requested. 3) To assess the possibility of estimating differential DFAs to conform to equal probabilities of attendance across various types of primary substance. METHODS: A prospective observational cohort of consecutive patients (N=1015) who requested a first-time assessment appointment at a publicly funded outpatient SUD treatment center in France between January 2014 and December 2015 was conducted. Logistic regression analyses were performed to evaluate associations between DFA (after log transformation) and attendance and to provide estimates of attendance probability over time by the type of primary substance. FINDINGS: After adjusting for gender, age and referral status, the attendance rate was observed to decrease significantly with longer DFA (OR=0.54; 95%CI: 0.44-0.66). The strength of this association differed across types of primary substance (p for heterogeneity <0.0001), with the strongest association being found for opioids (adjusted OR=0.21; 95%CI: 0.10-0.45). DFA was also associated with attendance for alcohol (OR=0.51; 95%CI: 0.37-0.71) and cannabis (OR=0.60; 95%CI: 0.37-0.96), but not for tobacco (OR=0.95; 95%CI: 0.60-1.50). Differential DFAs reflecting equal probabilities of attendance across types of substance could be estimated. CONCLUSION: Our study suggests that the approach of stratifying DFAs by the type of primary substance could be helpful to improve the probability of first-time attendance in outpatient SUD treatment services. PMID- 27465971 TI - Swarm dynamics may give rise to Levy flights. AB - "Continuous-time correlated random walks" are now gaining traction as models of scale-finite animal movement patterns because they overcome inherent shortcomings with the prevailing paradigm - discrete random walk models. Continuous-time correlated random walk models are founded on the classic Langevin equation that is driven by purely additive noise. The Langevin equation is, however, changed fundamentally by the smallest of multiplicative noises. The inclusion of such noises gives rise to Levy flights, a popular but controversial model of scale free movement patterns. Multiplicative noises have not featured prominently in the literature on biological Levy flights, being seen, perhaps, as no more than a mathematical contrivance. Here we show how Langevin equations driven by multiplicative noises and incumbent Levy flights arise naturally in the modelling of swarms. Model predictions find some support in three-dimensional, time resolved measurements of the positions of individual insects in laboratory swarms of the midge Chironomus riparius. We hereby provide a new window on Levy flights as models of movement pattern data, linking patterns to generative processes. PMID- 27465972 TI - The relationship between the vaginal microbiome and human health. PMID- 27465973 TI - Rac1 as a Potential Pharmacodynamic Biomarker for Thiopurine Therapy in Inflammatory Bowel Disease. AB - BACKGROUND: Azathioprine and mercaptopurine (MP) are effective in treating patients with inflammatory bowel disease (IBD). Immunosuppressive effects of thiopurines involve T-cell apoptosis after inhibition of GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1). This study aimed to assess whether expression and activity of Rac1 or phosphorylated ezrin-radixin-moesin (pERM) in patients with IBD could provide a useful biomarker for the pharmacodynamic thiopurine effect and might be related to clinical effectiveness. METHODS: This was a 2 stage study: stage 1 concerned a cross-sectional cohort of patients with IBD clinically in remission and treated with (n = 10) or without stable weight-based thiopurine therapy (n = 11) and healthy controls (n = 6); stage 2 concerned a prospective study regarding IBD patients with clinically active disease who initiated MP therapy (n = 11) compared with healthy controls (n = 11). Expression and activity of Rac1 and ERM and pERM were determined. RESULTS: The median Rac1 expression was statistically significantly reduced by thiopurine maintenance therapy {0.54 [interquartile range (IQR) 0.47-0.88] versus 0.80 arbitrary units [IQR 0.64-1.46]} compared with patients without immunosuppressive therapy (P = 0.042), but not Rac1 activity and pERM. In responders to MP therapy (n = 6), both median active Rac1 [93 (IQR 81-151) to 76 ng Rac1/mg protein (IQR 62-98)] and Rac1 expression [16.2 (8.8-29.4) to 1.5 arbitrary units (0.9-5.3)] decreased (P = 0.028). In nonresponders (n = 3), Rac1 expression and activity increased. CONCLUSIONS: IBD patients treated with thiopurines had a lower expression of Rac1 compared with those not treated with thiopurine. Effective MP therapy led to decreasing concentrations of Rac1-GTP and Rac1 expression. Therefore, Rac1-GTP and expression of Rac1, but not phosphorylation of ERM, form potentially pharmacodynamic markers of therapeutic thiopurine effectiveness in patients with IBD. PMID- 27465974 TI - Cannabis Use Surveillance by Sweat Analysis. AB - BACKGROUND: Sweat testing, an alternative matrix for establishing drug abuse, offers additional benefits to the more common biological samples. The authors developed a procedure using gas chromatography-mass spectrometry to test for Delta9-tetrahydrocannabinol, 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid, cannabinol (CBN), and cannabidiol (CBD) in a sweat patch. The results were compared with urine and hair sample results. METHODS: Urine, hair, and sweat samples were simultaneously collected from 12 patients who were involved, respectively, in forensic case and monitoring abuse. Selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), recovery, intraday and interday imprecision, and inaccuracy of the quantification procedure were validated. LODs in hair were 0.05 ng/mg for Delta9-tetrahydrocannabinol, CBN, and CBD, and 0.005 ng/mg for 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid. The LOD for sweat was 0.30 ng/patch for all substances. The LOQ in hair was 0.1 ng/mg for Delta9-tetrahydrocannabinol, CBN, and CBD, and 0.01 ng/mg for 11-nor Delta9-tetrahydrocannabinol-9-carboxylic acid. The LOQ was 0.4 ng/patch in sweat for each analyte. Cannabinoid in urine was determined by means of immunochemical screening (cutoff 11-nor-Delta-tetrahydrocannabinol-9-carboxylic acid 50 ng/mL). RESULTS: All subjects tested positive for 11-nor-Delta9-tetrahydrocannabinol-9 carboxylic acid and Delta9-tetrahydrocannabinol in urine and hair. In sweat samples, Delta9-tetrahydrocannabinol was found in all patches (0.4-2.0 ng/patch); 6 cases were positive for CBN (0.4-0.5 ng/patch) and 3 for CBD (0.4-0.6 ng/patch); 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid was never detected in patches. CONCLUSIONS: Present sweat analysis results integrated the information from hair and urine and showed that sweat analysis is a suitable, noninvasive method for monitoring compliance with rehabilitation therapy and for detecting recent cumulative use of cannabinoids. PMID- 27465975 TI - A Validated Fluorometric Method for the Rapid Determination of Pregabalin in Human Plasma Applied to Patients With Pain. AB - BACKGROUND: Pregabalin has been used for the treatment of pain. A clinically accepted method applied to patients with pain has not been published for the determination of pregabalin in human plasma. This study developed a fluorometric ultrahigh-performance liquid chromatography (UHPLC) method to measure pregabalin concentration in patients with pain. METHODS: After plasma pretreatment involving protein precipitation, pregabalin and gabapentin as an internal standard were derivatized with 4-fluoro-7-nitrobenzofurazan (NBD-F) under the following reaction conditions: 1 minute, pH 10, and 60 degrees C. The UHPLC separation was performed using a 2.3-MUm particle size octadecylsilyl column. The fluorescence detector was set at excitation and emission wavelengths of 470 and 530 nm, respectively. The predose blood samples were collected from 40 patients with pain who have been treated with 75 mg of pregabalin twice daily. RESULTS: The chromatographic run time was 1.25 minutes. No interfering peaks were observed in the blank plasma at the retention times of NBD derivatives. The calibration curve of pregabalin was linear at a range of 0.05-10 mcg/mL (r > 0.999). The lower limit of quantification was 0.05 mcg/mL. The intra-assay accuracy and precision were 98.3%-99.8% and within 4.3%, respectively. The inter-assay accuracy and precision were 103.2%-107.1% and within 4.1%, respectively. The predose plasma concentration of pregabalin in patients with pain ranged from 0.14 to 8.5 mcg/mL. CONCLUSIONS: This study provides a validated fluorometric UHPLC method with fast analytical performance for the determination of pregabalin in human plasma. The present method could be applied to patients with pain and be used for the clinical research or therapeutic drug monitoring of pregabalin. PMID- 27465976 TI - Maternal height and its relationship to offspring birth weight and adiposity in 6 to 10-year-old Maya children from poor neighborhoods in Merida, Yucatan. AB - OBJECTIVE: To analyze the relationship between maternal height, offspring birth weight, and adiposity at 6-10 years of age in a sample of 197 mother-child dyads from Merida, Mexico. MATERIALS AND METHODS: During 2008-2009 and 2011-2013, measurements were taken of maternal height and weight; and height, waist circumference (WC), and skinfolds (triceps, subscapular, and suprailiac) of their children. Participant body composition was estimated using a bioelectrical impedance analyzer. A questionnaire was applied to document household socioeconomic conditions. Multiple linear regression models were used to study the association between maternal height, offspring birth weight and fat mass index (FMI), WC, and sum of skinfolds (SumSkfZ) in boys and girls, separately. RESULTS: After adjusting for child age and household socioeconomic conditions, maternal height was identified to be significantly associated (p < .05) with FMI, WC, and SumSkf only in boys. In all models, child adiposity was inversely related to maternal height. Offspring birth weight was not associated with any adiposity parameter. DISCUSSION: The results suggest that maternal nutritional history as reflected in short maternal stature is associated with higher body fat in children, and that male offspring are more vulnerable to intergenerational influences. PMID- 27465977 TI - Syntheses, properties and bio-activities of water-soluble CO-releasing molecule based on manganese. AB - A series of water-soluble CO-releasing molecules, [Mn(CO)3NH2CHRCO2]2 (1-3), [M(CO)3Br[(Py-C = N)(Gly) n CO2] (M = Mn, Re, 4-7), Mn(CO)4[S2CNC m H n CO2] (8 12), were synthesized and characterized by (1)H NMR, IR and ESI-HRMS. The stability of all the complexes in solution was evaluated by means of UV, IR and (1)H NMR. Among all the complexes, complex 4 and complex 8 were stable in H2O, acidic aqueous solution and basic media; complex 1 was stable in acidic aqueous solution and weak basic media (pH < 9.4). The assays showed that each complex has CO-release ability; excess sodium dithionite can enhance CO release. Among them, complexes 8-12 were fast CO-releasers. In the test of the cell proliferation, all the complexes showed anti-proliferative activities for HeLa and HepG2. In particular, complex 8 displayed a 3.5-fold anti-proliferative activity on HeLa cells (IC50 23.13 MUM) and fivefold on HepG2 cells (34.00 MUM) compared with 5 FU. What is more, the complexes distinctly influenced cell cycle and promoted cell apoptosis; complex 1 arrested HeLa cells in S phase, whereas complex 4 and complex 8 arrested in G2/M phase; all the complexes induced HeLa cells "Early apoptosis". In addition, all complexes 1, 4 and 8 decreased intracellular nitrite levels, and complex 8 was stronger than both of the others. All these data demonstrate that complex 8 has potential to be a drug candidate. Three different categories of water-soluble CORMs 1-12 were synthesized, and their stability were evaluated. The biological activities were preliminarily evaluated. This includes anti-proliferation and anti-inflammatory properties. PMID- 27465978 TI - The role of compliance with PAP use on blood pressure in patients with obstructive sleep apnea: is longer use a key-factor? AB - Scientific data about the effects of positive airway pressure (PAP) treatment on blood pressure (BP) control are continuously increasing; however, they are controversial. We aimed to determine the long-term effects of compliance with PAP therapy on BP in both hypertensive and normotensive patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). One thousand one hundred sixty eight consecutive patients with newly diagnosed OSAHS, who had been recommended PAP therapy, were followed up for a minimum of 2 years. Patients with previous cardiovascular disease were excluded. BP was measured at baseline and after 2 years of PAP treatment. In addition, the correlation between the changes in BP with different levels of PAP compliance was assessed. At the end of the follow-up period, in the hypertensive group of patients (n=586), a significant decrease was shown in systolic (-11.2 mm Hg, P<0.001) and diastolic BP (-4.2 mm Hg, P<0.001). Furthermore, in the patients without hypertension (n=528), a significant decrease was noted both in systolic and diastolic BP (-3.6, P<0.001 and -2.4, P<0.001, respectively). A correlation between the magnitude of change in systolic and diastolic BP and hours of use of PAP (r=0.14, P=0.002 and r=0.1, P=0.025, respectively) was observed in all patients. Long-term use of PAP treatment, as well as increased hours of PAP in patients with OSAHS use showed significant reductions in BP not only in patients with hypertension, but also in normotensive patients. Therefore a significant potential reduction in cardiovascular mortality and morbidity should be expected in these patients. PMID- 27465979 TI - A prediction model for the response to oral labetalol for the treatment of antenatal hypertension. AB - This prospective observational study aimed to identify at presentation the maternal hemodynamic and demographic variables associated with a therapeutic response to oral labetalol and to use these variables to develop a prediction model to anticipate the response to labetalol monotherapy in women with hypertension. It was set at a maternity unit in a UK teaching hospital. Maternal demographic data from 50 pregnant women, presenting with hypertension between January and August 2013, was collected and blood pressure measured with a device validated for pregnancy and pre-eclampsia. Maternal haemodynamics were assessed with a bioreactance monitor. Participants were commenced on oral labetalol, and reviewed until delivery and discharge home. Logistic regression analysis was performed to assess the prediction of response to labetalol according to the maternal demographic and hemodynamic variables. Main outcome measures were the response to labetalol monotherapy up to delivery and discharge home, defined as sustained blood pressure control <140/90, and the rates of severe hypertension. Thirty-seven women (74%) had their blood pressure well controlled with labetalol monotherapy, 13 (26%) failed to achieve control with labetalol alone, of whom 9 developed severe hypertension. Multivariate logistic regression showed that heart rate, ethnicity and stroke volume index were independent predictors of the response to labetalol. The predictive accuracy of the model was 96% (95% confidence interval (CI) 86-99%). Maternal demographics and haemodynamics are potent predictors for the response to labetalol, and these parameters may guide therapy to enable effective blood pressure control and a lowering of severe hypertension rates. PMID- 27465980 TI - Consideration of hypertensive retinopathy as an important end-organ damage in patients with hypertension. AB - Longstanding and therapy-resistant hypertension may cause cerebral, renal, cardiac and retinal end-organ damage (EOD). Retinal hypertensive abnormalities are correlated with an increased risk of cardiovascular (CV) disease in general but are not included in CV risk assessment tools. Research into prevalence and determinants of retinal organ damage, such as hypertensive retinopathy (HR), is scarce. We evaluated the prevalence of HR and the association with other signs of EOD in patients with hypertension. A retrospective observational study was performed in all hypertensive patients referred by a general practitioner to the hypertension clinic at the Diakonessenhuis, Utrecht and Zeist, the Netherlands between 2011 and 2013. A screening of risk factors, albuminuria, left-ventricular hypertrophy (LVH) and retinal fundoscopy was performed. In all, 44% (123/280) of patients referred to the clinic were diagnosed with HR, while 15 and 11% were diagnosed with LVH and microalbuminuria, respectively. Patients with isolated HR consisted of 31% of all patients. When HR was added as a form of EOD, the percentage of patients with a treatment indication increased from 3 to 14%. Patients who were already on treatment goal exhibited a high prevalence of HR (28%), warranting treatment intensification. HR is prevalent in a third of hypertensive patients referred to our clinic, and isolated HR accounts for the majority of (end-) organ damages. Fundoscopy in the evaluation of hypertension might improve the indication for therapy. Furthermore, diagnosing HR could be helpful in selecting patients with hypertension on treatment goal in need of more aggressive treatment. PMID- 27465981 TI - Serum uric acid is an independent predictor for developing prehypertension: a population-based prospective cohort study. AB - Although the prevalence of prehypertension is rapidly increasing in China, the medical community has paid little attention to its prevention. Prior studies have demonstrated that uric acid directly contributes to vascular remodelling and endothelial dysfunction. However, few prospective studies have assessed the relationship between serum uric acid and prehypertension. We therefore designed a larger-scale cohort study to examine whether uric acid level is a predictive factor for developing prehypertension in adults. Participants were recruited from Tianjin Medical University General Hospital-Health Management Centre. A prospective assessment (n=15 143) was performed. Participants without a history of hypertension or prehypertension were followed up for 2 to 6 years with a median follow-up duration of 2.8 years. Serum uric acid levels and blood pressure were assessed yearly during the follow-up. Adjusted Cox proportional hazards regression models were used to assess relationships between the quintiles of uric acid levels and the incidence of prehypertension. The incidence of prehypertension was 191 per 1000 person-years. In the final multivariate models, the hazard ratios (95% confidence interval) for prehypertension across uric acid quintiles were 1.00 (reference), 0.98 (0.90-1.07), 1.01 (0.93-1.10), 1.09 (1.001 1.20) and 1.17 (1.06-1.29) (P for trend <0.001), respectively. This population based prospective cohort study has demonstrated that uric acid level is an independent predictor for developing prehypertension. PMID- 27465982 TI - Hypertension and aging in rural Haiti: results from a preliminary survey. AB - Cross-sectional studies in the developed countries document strong relationships among age, systolic blood pressure (SBP) and pulse pressure (PP). There is little information about these trends and their impact in underdeveloped countries with different socioeconomic and lifestyle characteristics. We studied a convenience sample of 572 residents of rural Fontaine, Haiti: 193 males and 379 females (mean, s.d.) age 40.2 (17.1) years and performed intake questionnaires and BP measurements in participants' homes. Income and educational achievement were very low but most-recommended lifestyle factors were very favorable: very high physical activity, low dietary fat, virtually no obesity (body mass index 21.8 (4.9)), and low smoking prevalence. Rough estimates of salt intake were high (~13 g per day) as was the overall prevalence of hypertension: 34.4% (23.4% in males, 40.2% in females). SBP and PP were related closely to age (r2=0.28, P<0.001 and r2=0.22, P<0.001); for each decade of age, SBP increased by 7.6 mm Hg. Diastolic BP peaked in the 6th decade (polynomial r2=0.22, P<0.001) and the nadir of PP occurred in the 3rd decade. We conclude that, despite a favorable profile of lifestyle characteristics and no obesity, the prevalence of hypertension and rate of increase in SBP and PP with age in Haiti are at least as high as those of developed countries. PMID- 27465983 TI - Phage Display Technique: A Novel Medicinal Approach to Overcome An tibiotic Resistance by Using Peptide-Based Inhibitors Against beta-Lactamases. AB - The emergence of antibiotic resistance in bacteria is a serious threat with enormous social and economic implications. The distribution of resistance genes/markers through horizontal gene transfer leads to the dissemination of resistant strains in different parts of the world. The resistant bacteria acquire the ability to overcome resistance by different modes amongst which the expression of beta-lactamases is a major factor. The beta-lactamase enzymes cleave the amide bond of the beta-lactam antibiotics, which constitute about one third of the antibiotics used all over the world. In a quest to control the spread of resistant bacteria, advanced generations of antibiotics are used either alone or in combination with inhibitors. However, these antibiotics and inhibitors also contain beta-lactam ring in their structure and hence are prone to be hydrolyzed by beta-lactamase enzymes in the near future. Thus, the severity of the problem is manifested due to the paucity of novel non-beta-lactam core containing antibiotics in the drug development stage. One approach to overcome these shortcomings is to use peptide-based inhibitors. Here, we describe the potential use of phage display technique to screen commercially available libraries to pan against beta-lactamase enzymes. The main advantage of using peptide-based inhibitors is that the bacteria will not be able to recruit pre existing defense mechanisms and it will take a long time to evolve a new mechanism in its defense against peptide-based inhibitors. PMID- 27465984 TI - Human exposures to pentobarbital-phenytoin combination veterinary drugs. AB - A combination of pentobarbital and phenytoin is used as a veterinary euthanasia drug. Because of its lethal effect, this study described pentobarbital-phenytoin combination veterinary drug human exposures reported to Texas poison centers during 2000-2015. Of 66 exposures, 73% involved female and 27% male patients. The distribution by patient age was 3% 0-5 years, 5% 6-19 years, 91% 20+ years, and 2% unknown. The most common routes were ocular (41%), ingestion (32%), injection (23%), and dermal (18%). The exposure reasons were unintentional (77%) and intentional (23%). The exposure site was the workplace (52%), patient's own residence (38%), health-care facility (2%), and other/unknown (9%). The management site was managed on site (48%), at/en route to health-care facility (45%), referred to health-care facility (5%), and other (2%). The medical outcomes were no effect (23%), minor effect (30%), moderate effect (8%), major effect (8%), not followed nontoxic (3%), not followed minimal effects (24%), unable to follow potentially toxic (2%), and unrelated (3%). The most common adverse effects were ocular irritation/pain (18%), drowsiness/lethargy (15%), and coma (9%). The most common treatments were dilution/irrigation (70%), intravenous fluids (21%), and oxygen (14%). This study found few pentobarbital-phenytoin combination veterinary drug exposures were reported to Texas poison centers during a 16-year period. Although meant to be administered intravenously, the most common exposure routes were ocular and ingestion. Many of the exposures appeared to be unintentional and occurred at the workplace. PMID- 27465985 TI - Development of carvedilol-cyclodextrin inclusion complexes using fluid-bed granulation: a novel solid-state complexation alternative with technological advantages. AB - OBJECTIVES: This study sought to evaluate the achievement of carvedilol (CARV) inclusion complexes with modified cyclodextrins (HPbetaCD and HPgammaCD) using fluid-bed granulation (FB). METHODS: The solid complexes were produced using FB and spray drying (SD) and were characterised by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction, SEM, flowability and particle size analyses and in vitro dissolution. KEY FINDINGS: The DSC, FTIR and powder X-ray diffraction findings suggested successful CARV inclusion in the modified beta- and gamma-cyclodextrins, which was more evident in acidic media. The CARV dissolution rate was ~7-fold higher for complexes with both cyclodextrins prepared using SD than for raw CARV. Complexes prepared with HPbetaCD using FB also resulted in a significant improvement in dissolution rate (~5-fold) and presented superior flowability and larger particle size. CONCLUSIONS: The findings suggested that FB is the best alternative for large-scale production of solid dosage forms containing CARV. Additionally, the results suggest that HPgammaCD could be considered as another option for CARV complexation because of its excellent performance in inclusion complex formation in the solid state. PMID- 27465987 TI - Relevance of adjacent joint imaging in the evaluation of ankle fractures. AB - BACKGROUND: Routinely obtaining adjacent joint radiographs when evaluating patients with ankle fractures may be of limited clinical utility and an unnecessary burden, particularly in the absence of clinical suspicion for concomitant injuries. METHODS: One thousand, three hundred and seventy patients who sustained ankle fractures over a 5-year period presenting to two level 1 trauma centers were identified. Medical records were retrospectively reviewed for demographics, physical examination findings, and radiographic information. Analyses included descriptive statistics along with sensitivity and predictive value calculations for the presence of adjacent joint fracture. RESULTS: Adjacent joint imaging (n=1045 radiographs) of either the knee or foot was obtained in 873 patients (63.7%). Of those, 75/761 patients (9.9%) demonstrated additional fractures proximal to the ankle joint, most commonly of the proximal fibula. Twenty-two of 284 (7.7%) demonstrated additional fractures distal to the ankle joint, most commonly of the metatarsals. Tenderness to palpation demonstrated sensitivities of 0.92 and 0.77 and positive predictive values of 0.94 and 0.89 for the presence of proximal and distal fractures, respectively. Additionally, 19/22 (86.4%) of patients sustaining foot fractures had their injury detectable on initial ankle X-rays. Overall, only 5.5% (75/1370) of patients sustained fractures proximal to the ankle and only 0.2% (3/1370) of patients had additional foot fractures not evident on initial ankle X-rays. CONCLUSION: The addition of adjacent joint imaging for the evaluation of patients sustaining ankle fractures is low yield. As such, patient history, physical examination, and clinical suspicion should direct the need for additional X-rays. LEVEL OF EVIDENCE: Level IV. PMID- 27465989 TI - Preparation and characterization of single and dual propylene oxide and octenyl succinic anhydride modified starch carriers for the microencapsulation of essential oils. AB - Hydroxypropylation with propylene oxide followed by esterification with octenyl succinic anhydride (OSA) was used to produce modified potato starch derivatives suitable for the encapsulation of essential oils. Caraway essential oil (EO) was encapsulated by spray-drying into enzymatically hydrolyzed dual/single modified and native starches. The EO microencapsulation efficiency in different modified starches, the retention of volatile aroma compounds, the emulsion particle size and the microstructure of the spray-dried encapsulated powdered products, as well as the compositional aroma changes taking place during the processing and storage for up to 8 months have been estimated. The increase of OSA content from 0.97 to 2.52% in the P-native structure and from 0.91% to 2.66% in P-HP resulted in the significant increase in the encapsulating capacity, evaluated as a percentage of the total EO retained, from 61.6 to 88.0% and 73.8% to 84.0%, respectively. However, the compositional changes of the microencapsulated caraway EO constituents were not remarkable. Additionally, the effect of pure and encapsulated caraway EO products on the oxidative stability of commercial rapeseed oil and mayonnaise was evaluated using the instrumental Oxipres method and it was shown that they were more effective in emulsion type products by the up to 1.8-fold increase in the oxidative stability of mayonnaise. PMID- 27465988 TI - Enhanced biglycan gene expression in the adipose tissues of obese women and its association with obesity-related genes and metabolic parameters. AB - Extracellular matrix (ECM) remodeling dynamically occurs to accommodate adipose tissue expansion during obesity. One non-fibrillar component of ECM, biglycan, is released from the matrix in response to tissue stress; the soluble form of biglycan binds to toll-like receptor 2/4 on macrophages, causing proinflammatory cytokine secretion. To investigate the pattern and regulatory properties of biglycan expression in human adipose tissues in the context of obesity and its related diseases, we recruited 21 non-diabetic obese women, 11 type 2 diabetic obese women, and 59 normal-weight women. Regardless of the presence of diabetes, obese patients had significantly higher biglycan mRNA in both visceral and subcutaneous adipose tissue. Biglycan mRNA was noticeably higher in non adipocytes than adipocytes and significantly decreased during adipogenesis. Adipose tissue biglycan mRNA positively correlated with adiposity indices and insulin resistance parameters; however, this relationship disappeared after adjusting for BMI. In both fat depots, biglycan mRNA strongly correlated with the expression of genes related to inflammation and endoplasmic reticulum stress. In addition, culture of human preadipocytes and differentiated adipocytes under conditions mimicking the local microenvironments of obese adipose tissues significantly increased biglycan mRNA expression. Our data indicate that biglycan gene expression is increased in obese adipose tissues by altered local conditions. PMID- 27465990 TI - Bench to bedside: the next steps for biomarkers in acute kidney injury. AB - No new biomarker of acute kidney injury (AKI) has entered routine clinical practice after a decade of promise, although liver-fatty acid binding protein (L FABP), neutrophil gelatinase-associated lipoprotein (NGAL), and the combination of tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) are approved for use in some jurisdictions. Acceptance of creatinine as a surrogate of not just glomerular filtration rate (GFR) but also renal injury, changes in nephrologist workloads, failure to establish the added value of each biomarker to current clinical variables across multiple clinical settings, the lack of treatment options, and simply an insufficient passage of time, have all contributed to the lack of progress. Future studies should establish reference intervals for biomarkers, associate biomarkers with meaningful clinical outcomes including mortality and development of chronic kidney disease, and assess the added value to clinical models. The real value of biomarkers will be determined with intervention trials that use an elevated biomarker to triage to treatment. Ideally, such treatments will be linked directly to the physiological processes, which the biomarker identifies. PMID- 27465991 TI - Aging-associated renal disease in mice is fructokinase dependent. AB - Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration. PMID- 27465992 TI - Urothelial purine release during filling of murine and primate bladders. AB - During urinary bladder filling the bladder urothelium releases chemical mediators that in turn transmit information to the nervous and muscular systems to regulate sensory sensation and detrusor muscle activity. Defects in release of urothelial mediators may cause bladder dysfunctions that are characterized with aberrant bladder sensation during bladder filling. Previous studies have demonstrated release of ATP from the bladder urothelium during bladder filling, and ATP remains the most studied purine mediator that is released from the urothelium. However, the micturition cycle is likely regulated by multiple purine mediators, since various purine receptors are found present in many cell types in the bladder wall, including urothelial cells, afferent nerves, interstitial cells in lamina propria, and detrusor smooth muscle cells. Information about the release of other biologically active purines during bladder filling is still lacking. Decentralized bladders from C57BL/6 mice and Cynomolgus monkeys (Macaca fascicularis) were filled with physiological solution at different rates. Intraluminal fluid was analyzed by high-performance liquid chromatography with fluorescence detection for simultaneous evaluation of ATP, ADP, AMP, adenosine, nicotinamide adenine dinucleotide (NAD+), ADP-ribose, and cADP-ribose content. We also measured ex vivo bladder filling pressures and performed cystometry in conscious unrestrained mice at different filling rates. ATP, ADP, AMP, NAD+, ADPR, cADPR, and adenosine were detected released intravesically at different ratios during bladder filling. Purine release increased with increased volumes and rates of filling. Our results support the concept that multiple urothelium derived purines likely contribute to the complex regulation of bladder sensation during bladder filling. PMID- 27465993 TI - The EP3 receptor regulates water excretion in response to high salt intake. AB - The mechanisms by which prostanoids contribute to the maintenance of whole body water homeostasis are complex and not fully understood. The present study demonstrates that an EP3-dependent feedback mechanism contributes to the regulation of water homeostasis under high-salt conditions. Rats on a normal diet and tap water were placed in metabolic cages and given either sulprostone (20 MUg.kg-1.day-1) or vehicle for 3 days to activate EP3 receptors in the thick ascending limb (TAL). Treatment was continued for another 3 days in rats given either 1% NaCl in the drinking water or tap water. Sulprostone decreased expression of cyclooxygenase 2 (COX-2) expression by ~75% in TAL tubules from rats given 1% NaCl concomitant with a ~60% inhibition of COX-2-dependent PGE2 levels in the kidney. Urine volume increased after ingestion of 1% NaCl but was reduced ~40% by sulprostone. In contrast, the highly selective EP3 receptor antagonist L-798106 (100 MUg.kg-1.day-1), which increased COX-2 expression and renal PGE2 production, increased urine volume in rats given 1% NaCl. Sulprostone increased expression of aquaporin-2 (AQP2) in the inner medullary collecting duct plasma membrane in association with an increase in phosphorylation at Ser269 and decrease in Ser261 phosphorylation; antagonism of EP3 with L-798106 reduced AQP2 expression. Thus, although acute activation of EP3 by PGE2 in the TAL and collecting duct inhibits the Na-K-2Cl cotransporter and AQP2 activity, respectively, chronic activation of EP3 in vivo limits the extent of COX-2 derived PGE2 synthesis, thereby mitigating the inhibitory effects of PGE2 on these transporters and decreasing urine volume. PMID- 27465995 TI - Delayed treatment with fenofibrate protects against high-fat diet-induced kidney injury in mice: the possible role of AMPK autophagy. AB - Fenofibrate activates not only peroxisome proliferator-activated receptor-alpha (PPARalpha) but also adenosine monophosphate-activated protein kinase (AMPK). AMPK-mediated cellular responses protect kidney from high-fat diet (HFD)-induced injury, and autophagy resulting from AMPK activation has been regarded as a stress-response mechanism. Thus the present study examined the role of AMPK and autophagy in the renotherapeutic effects of fenofibrate. C57BL/6J mice were divided into three groups: normal diet (ND), HFD, and HFD + fenofibrate (HFD + FF). Fenofibrate was administered 4 wk after the initiation of the HFD when renal injury was initiated. Mouse proximal tubule cells (mProx24) were used to clarify the role of AMPK. Feeding mice with HFD for 12 wk induced insulin resistance and kidney injury such as albuminuria, glomerulosclerosis, tubular injury, and inflammation, which were effectively inhibited by fenofibrate. In addition, fenofibrate treatment resulted in the activation of renal AMPK, upregulation of fatty acid oxidation (FAO) enzymes and antioxidants, and induction of autophagy in the HFD mice. In mProx24 cells, fenofibrate activated AMPK in a concentration dependent manner, upregulated FAO enzymes and antioxidants, and induced autophagy, all of which were inhibited by treatment of compound C, an AMPK inhibitor. Fenofibrate-induced autophagy was also significantly blocked by AMPKalpha1 siRNA but not by PPARalpha siRNA. Collectively, these results demonstrate that delayed treatment with fenofibrate has a therapeutic effect on HFD-induced kidney injury, at least in part, through the activation of AMPK and induction of subsequent downstream effectors: autophagy, FAO enzymes, and antioxidants. PMID- 27465996 TI - L'incidence de l'hypotension post-intubation endotracheale chez des patients en salle de reanimation: impact des definitions. AB - Objectif Notre objectif primaire est de mesurer l'incidence d'HPI selon quatre definitions differentes retrouvees dans la litterature. Notre principal objectif secondaire est d'evaluer l'impact de la presence d'instabilite hemodynamique avant l'intubation sur l'incidence d'HPI. Le deuxieme objectif secondaire consiste a determiner l'incidence de l'HPI en fonction de l'intervalle de temps durant lequel la premiere hypotension survient. Methode Une cohorte prospective a ete constituee par les patients intubes en salle de reanimation a l'hopital de l'Enfant-Jesus entre le 28/06/2011 et le 12/07/2012. L'HPI etait globalement definie comme >=1 mesure de tension arterielle systolique <90 mmHg suivant l'intubation. Les differentes definitions etudiees faisaient varier le temps de mesure de la tension arterielle (TA) apres l'intubation, soit 1) jusqu'a 5 minutes, 2) jusqu'a 15 minutes, 3) jusqu'a 30 minutes et 4) en tout temps lors du sejour en salle de reanimation. Resultat Au cours de la periode a l'etude, 155 patients ont ete intubes sur place dont 81 patients qui repondaient aux criteres d'inclusion. L'incidence de l'HPI pour chaque definition est respectivement de 9.9%, 18.5%, 24.7% et 28.4%. La comparaison entre chacune de ces incidences revele une difference statistiquement significative (p<0.05), a l'exception des deux dernieres. L'incidence cumulative d'HPI a tout moment suivant l'intubation chez les patients presentant une hypotension pre-intubation est de 62.5% (IC 95% 28.5-87.5) en opposition aux patients hemodynamiquement stables en pre-intubation qui presentaient une incidence d'HPI de 24.7% (IC 95% 16.1-35.8). CONCLUSION: L'hypotension post-intubation est un effet indesirable frequent chez les patients au departement d'urgence et son incidence varie de facon significative en fonction de la definition temporelle utilisee au sein d'une meme cohorte de patients. PMID- 27465994 TI - Early development of podocyte injury independently of hyperglycemia and elevations in arterial pressure in nondiabetic obese Dahl SS leptin receptor mutant rats. AB - The current study examined the effect of obesity on the development of renal injury within the genetic background of the Dahl salt-sensitive rat with a dysfunctional leptin receptor derived from zinc-finger nucleases (SSLepRmutant strain). At 6 wk of age, body weight was 35% higher in the SSLepRmutant strain compared with SSWT rats and remained elevated throughout the entire study. The SSLepRmutant strain exhibited impaired glucose tolerance and increased plasma insulin levels at 6 wk of age, suggesting insulin resistance while SSWT rats did not. However, blood glucose levels were normal throughout the course of the study. Systolic arterial pressure (SAP) was similar between the two strains from 6 to 10 wk of age. However, by 18 wk of age, the development of hypertension was more severe in the SSLepRmutant strain compared with SSWT rats (201 +/- 10 vs. 155 +/- 3 mmHg, respectively). Interestingly, proteinuria was substantially higher at 6 wk of age in the SSLepRmutant strain vs. SSWT rats (241 +/- 27 vs. 24 +/- 2 mg/day, respectively) and remained elevated until the end of the study. The kidneys from the SSLepRmutant strain displayed significant glomerular injury, including podocyte foot process effacement and lipid droplets compared with SSWT rats as early as 6 wk of age. By 18 wk of age, plasma creatinine levels were twofold higher in the SSLepRmutant strain vs. SSWT rats, suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SSLepRmutant strain develops podocyte injury and proteinuria independently of hyperglycemia and elevated arterial pressure that later progresses to CKD. PMID- 27465997 TI - Does the use of a semirigid stylet increase the efficacy of endotracheal intubation when using an ETView tube? PMID- 27465998 TI - Slow Relaxation of Magnetization in an Isostructural Series of Zinc-Lanthanide Complexes: An Integrated EPR and AC Susceptibility Study. AB - We report the synthesis, structure, and spectroscopic and dynamic magnetic properties of a series of heterodinuclear complexes, [ZnLn(LH4 )2 ](NO3 )3 ?6 H2 O (Ln=Nd, Tb, Dy, Ho, Er, and Yb), with the singly deprotonated form of a new compartmentalized Schiff-base ligand, LH5 . The Ln(III) ions in these systems show a distorted square-antiprism geometry with an LnO8 coordination sphere. EPR spectroscopy and DC magnetic studies have shown that the anisotropic nature of the complexes is far more complicated than predicted on the basis of a simple electrostatic model. Among the investigated systems, only the Dy(III) derivative showed single-ion magnet behavior, in zero and an applied magnetic field, both in pure polycrystalline samples and in a series of polycrystalline samples with different degrees of dilution at the single-crystal level in the isostructural Y(III) derivative. The rich dynamics observed as functions of frequency, field, and temperature reveals that multiple relaxation mechanisms are at play, resulting in a barrier of 189 cm(-1) , which is among the highest reported for a dinuclear Zn-Dy system. Analysis of the dynamic behavior as a function of dilution degree further evidenced the persistence of non-negligible intermolecular interactions, even at the lowest concentration of 1 %. PMID- 27465999 TI - A Prospective Biopsychosocial Investigation Into Head and Neck Cancer Caregiving. AB - PURPOSE: Head and neck cancer (HNC) patients suffer from significant morbidity, which may introduce challenging care demands and subsequent stress-induced mind body interactions for informal caregivers. This prospective study evaluated patient and caregiver predictors of diurnal cortisol rhythm among HNC caregivers during radiation treatment. METHOD: Patient-caregiver dyads completed measures at radiation treatment start (T1; n = 32) and 5 weeks into treatment (T2; n = 29). Measures included the Functional Assessment of Cancer Therapy-Head and Neck, the Caregiver Quality of Life (QOL) Index-Cancer, the Caregiver Reaction Assessment, the Medical Outcomes Social Support Survey, and the Eating Assessment tool. Patients also received a clinical swallowing evaluation using the Functional Assessment of Oral Intake Scale. Caregiver cortisol concentrations were assessed from salivary samples at T1 and T2. RESULTS: Caregiver cortisol slope became significantly flatter during radiation treatment. Greater caregiver schedule burden was associated with a flatter cortisol slope (beta = .35, p = .05) in caregivers at T1. Lower patient functional QOL (beta = -.41, p = .05) and lower overall caregiver QOL at T1 (beta = -.39, p = .04) were each separately associated with a flatter cortisol slope in caregivers over treatment. CONCLUSIONS: Results suggest the presence of a mind-body interaction in HNC caregivers. Dysregulation in diurnal cortisol rhythm in caregivers was significantly associated with increased caregiver schedule burden and lower patient and caregiver QOL. Targeted interventions developed for HNC caregivers may help to prevent negative health outcomes associated with dysregulated cortisol. PMID- 27466001 TI - Flexible in-plane microsupercapacitors with electrospun NiFe2O4 nanofibers for portable sensing applications. AB - The development of wearable electronic devices in recent decades has brought new opportunities in the exploration of micro-supercapacitors as energy storage units. In this work, we report the fabrication of flexible NiFe2O4 nanofiber based in-plane micro-supercapacitors (MSCs), which can serve as energy storage receptors to drive a portable graphene pressure sensor. The obtained NiFe2O4 nanofiber electrodes exhibited a specific capacitance of 2.23 F cm(-3) at the scan rate of 100 mV s(-1), and excellent rate capability and robust cycling stability with a capacitance retention of 93.6% after 10 000 charge/discharge cycles. Moreover, the in-plane MSCs have superior flexibility and outstanding stability even after repetition of charge/discharge cycles during the convex and concave bending states. The MSCs offered a high energy density of 0.197 mWh cm( 3) and power density up to 2.07 W cm(-3). We also coupled the MSCs with a graphene pressure sensor as a micro-integrated system to implement it's pressure response function and used MATLAB to simulate this system behavior as well. The performance of the designed systems exhibited a stable pressure response, and the simulated results coincide well with the experimental data, demonstrating its feasibility in wearable electronic devices. PMID- 27466000 TI - Clinical effectiveness and cost-effectiveness of foot orthoses for people with established rheumatoid arthritis: an exploratory clinical trial. AB - OBJECTIVES: Foot orthoses are commonly prescribed as an intervention for people with rheumatoid arthritis (RA). Data relating to the cost-effectiveness of foot orthoses in people with RA are limited. The aim was to evaluate the clinical and cost-effectiveness of two types of foot orthoses in people with established RA. METHOD: A single-blind randomized controlled trial was undertaken to compare custom-made foot orthoses (CMFOs) and simple insoles (SIs) in 41 people with established RA. The Foot Function Index (FFI) was used to measure foot pain, disability, and functional limitation. Costs were estimated from the perspective of the UK National Health Service (NHS), societal (patient and family) perspective, and secondary care resource use in terms of the intervention and staff time. Effects were assessed in terms of health gain expressed as quality adjusted life years (QALYs). RESULTS: At baseline, 20 participants received a CMFO and 21 participants received an SI. After 16 weeks foot pain improved in both the CMFOs (p = 0.000) and the SIs (p < 0.01). However, disability scores improved for CMFOs (p < 0.001) but not for SIs (p = 0.40). The cost-effectiveness results demonstrated no difference in cost between the arms (CMFOs: L159.10; SIs: L79.10; p = 0.35), with the CMFOs being less effective in terms of cost per QALY gain (p < 0.001). CONCLUSIONS: In people with established RA, semi-rigid customized foot orthoses can improve pain and disability scores in comparison to simple insoles. From a cost-effectiveness perspective, the customized foot orthoses were far more expensive to manufacture, with no significant cost per QALY gain. PMID- 27466002 TI - Reaction on Twitter to a Cluster of Perinatal Deaths: A Mixed Method Study. AB - BACKGROUND: Participation in social networking sites is commonplace and the micro blogging site Twitter can be considered a platform for the rapid broadcasting of news stories. OBJECTIVE: The aim of this study was to explore the Twitter status updates and subsequent responses relating to a number of perinatal deaths which occurred in a small maternity unit in Ireland. METHODS: An analysis of Twitter status updates, over a two month period from January to March 2014, was undertaken to identify the key themes arising in relation to the perinatal deaths. RESULTS: Our search identified 3577 tweets relating to the reported perinatal deaths. At the height of the controversy, Twitter updates generated skepticism in relation to the management of not only of the unit in question, which was branded as unsafe, but also the governance of the entire Irish maternity service. Themes of concern and uncertainty arose whereby the professional motives of the obstetric community and staffing levels in the maternity services were called into question. CONCLUSIONS: Twitter activity provides a useful insight into attitudes towards health-related events. The role of the media in influencing opinion is well-documented and this study underscores the challenges that clinicians face in light of an obstetric media scandal. Further study to identify how the obstetric community could develop tools to utilize Twitter to disseminate valid health information could be beneficial. PMID- 27466004 TI - Emerging ideas about sarcoidosis pathophysiology. PMID- 27466003 TI - Characterization of long non-coding RNA transcriptome in high-energy diet induced nonalcoholic steatohepatitis minipigs. AB - Today, obesity and nonalcoholic steatohepatitis are a worldwide epidemic, although how these syndromes are regulated with respect to lncRNAs remains largely unknown. Our previous studies have revealed important pathological features and molecular characteristics of nonalcoholic steatohepatitis in the minipig model, and in this study, we analyze the features of lncRNAs and their potential target genes. Minipig samples only from liver were analyzed using next generation deep sequencing. In total, we obtained 585 million raw reads approximately 70.4 Gb of high quality data. After a strict five-step filtering process, 1,179 lncRNAs were identified, including 89 differentially expressed lncRNAs (P < 0.05) in the experiment group relative to the control group. The cis and trans analysis identified target genes that were enriched for specific GO terms (P < 0.01), including immune processes, chemokine activity, cytokine activity, and G-protein coupled receptor binding, which are closely related to nonalcoholic steatohepatitis. The predicted protein-coding targets of the differentially expressed lncRNAs were further analyzed, such as PPAR, FADS2, DGAT2, ACAA2, CYP2E1, ADH4, and Fos. This study reveals a wealth of candidate lncRNAs involved in NASH and their regulated pathways, which should facilitate further research into the molecular mechanisms of this disorder. PMID- 27466006 TI - Unusual way of feeding by the deutonymph of Neottialges evansi (Actinotrichida, Astigmata, Hypoderatidae), a subcutaneous parasite of cormorants, revealed by fine structural analyses. AB - The parasitic deutonymphs of hypoderatid mites live within the subcutaneous layer of their avian hosts, where they become greatly engorged despite not having functional mouthparts. The method by which they take up nutrients has been mysterious up to now. Here, we report on the morphology of hypoderatid deutonymphs using scanning and transmission electron microscopy and describe structures that may resolve the mystery. The deutonymph of Neottialges evansi (Hypoderatidae) from the cormorant Phalacrocorax carbo is a simply organized stage lacking both mouthparts and a functional foregut. The structure of midgut and hindgut indicate that they are not capable of processing food. The midgut consists of highly branching flat cells and rarely shows a lumen. Almost the entire space between integument, gut remnants and other organs (synganglion, developing gonads) is filled by huge cells containing protein and glycogen granules and numerous lipid inclusions. The anal opening is minute. The structure of the cuticle and epidermis suggests that nutrients are not absorbed through the general integument. Thus the two main existing hypotheses about feeding modes in hypoderatid deutonymphs, anal vs. integumentary food absorbtion, are not supported. We suggest instead that two pairs of genital papillae showing peculiar microanatomical features are actively involved in movement of liquid materials between host and mite and most probably are the nutrient-intake organs. J. Morphol. 277:1368-1389, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27466007 TI - The influence of changes in expression of redox-sensitive genes on the development of retinopathy in rats. AB - Age-related macular degeneration (AMD) is a complex multifactorial disease of the elderly, with unclear pathogenesis; AMD is the leading cause of blindness. One of the destructive processes in AMD is oxidative stress, which leads to an imbalance in the processes responsible for production and detoxification of reactive oxygen species. The aryl hydrocarbon receptor (AhR) signaling pathway can participate in the development of oxidative stress, but the main regulator of antioxidant defense is nuclear factor, erythroid derived 2 (Nrf2). AhR-dependent oxidative stress can be attenuated by activation of Nrf2, and defects in the Nrf2 signaling pathway can increase sensitivity of the cell to oxidative stress. Our aim was to determine the role of the pro-oxidant (AhR-dependent) and antioxidant (Nrf2 dependent) systems in the pathogenesis of AMD using rats of OXYS strain and of OXYSb substrain with signs of AMD-like retinopathy of varying severity. We compared the retinal levels of mRNA expression of Nrf2- and AhR-dependent redox sensitive systems between 1-, 3-, and 12- month-old senescence-accelerated OXYS rats (have been shown to be a valid experimental model of AMD) and the rat substrain OXYSb, which shows low morbidity of AMD. We uncovered interstrain differences in the expression of Nrf2 and Nrf2-dependent genes (glutathione S reductase [Gsr] and heme oxygenase 1 [Hmox1]), in the expression of AhR-dependent genes (cytochrome P450 1A2 [Cyp1a2] and cytochrome P450 1B1 [Cyp1b1]), and in the NADPH-quinone oxidoreductase (Nqo1) expression, which is controlled by both AhR and Nrf2. Binding of AhR and Nrf2 proteins to the regulatory regions of AhR and Nrf2 genes, respectively, was detected by chromatin immunoprecipitation in the retina of 1-, 3-, and 12-month-old OXYS, OXYSb, and Wistar (control) rats. We compared the strength of DNA-protein interactions of AhR and Nrf2 with regulatory sequences and found that the level of autoupregulation of the AhR gene was higher in the retina of 1-month-old OXYSb rats in comparison with OXYS rats. An imbalance between pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems may play a crucial role in the onset and/or progression of AMD. PMID- 27466008 TI - Update in Pediatric Musculoskeletal Infections: When It Is, When It Isn't, and What to Do. AB - Musculoskeletal infections, including osteomyelitis, septic arthritis, and pyomyositis, are a substantial cause of morbidity in children and adolescents. The increased virulence of infectious agents and the increased prevalence of antimicrobial-resistant pathogens, particularly methicillin-resistant Staphylococcus aureus, have resulted in a more complicated clinical course for diagnosis and management, which is evidenced by an increased length of hospital stays, incidence of complications, and number of surgical interventions. Musculoskeletal infections are a challenge for surgeons because they vary substantially in their presentation and in their required treatment, which is based on the causative organism, the location of the infection, and the age of the patient. The necessity for a prompt diagnosis is complicated by several diseases that may mimic musculoskeletal infection, including transient synovitis, autoimmune arthritis, and tumors. Recent innovations in diagnosis and management have provided surgeons with new options to differentiate musculoskeletal infections from these rapidly evolving disease pathologies. As diagnostic and treatment modalities improve, collaboration among surgeons from multiple disciplines is required to develop evidence-based clinical practice guidelines that minimize the effect of musculoskeletal infection and optimize clinical outcomes for patients. PMID- 27466010 TI - Large area and deep sub-wavelength interference lithography employing odd surface plasmon modes. AB - In this paper, large area and deep sub-wavelength interference patterns are realized experimentally by using odd surface plasmon modes in the metal/insulator/metal structure. Theoretical investigation shows that the odd modes possesses much higher transversal wave vector and great inhibition of tangential electric field components, facilitating surface plasmon interference fringes with high resolution and contrast in the measure of electric field intensity. Interference resist patterns with 45 nm (~lambda/8) half-pitch, 50 nm depth, and area size up to 20 mm * 20 mm were obtained by using 20 nm Al/50 nm photo resist/50 nm Al films with greatly reduced surface roughness and 180 nm pitch exciting grating fabricated with conventional laser interference lithography. Much deeper resolution down to 19.5 nm is also feasible by decreasing the thickness of PR. Considering that no requirement of expensive EBL or FIB tools are employed, it provides a cost-effective way for large area and nano-scale fabrication. PMID- 27466012 TI - Fungal Isolate Optimized for Biogenesis of Silver Nanoparticles with Enhanced Colloidal Stability. AB - Understanding the synthesis and properties of nanomaterials is critical for reliable applications. Biological systems, such as fungi, have been described as a "green" alternative to synthesis, yet knowledge gaps exist in terms of production variability, comparison with commercial products, and identifying a clear biological advantage over other synthesis methods. In this study, we evaluated 12 fungal isolates of Fusarium oxysporum for Ag nanoparticle production and characterized the resultant biologically produced (biogenic) nanoparticles. We show evidence that isolate selection, temperature, and pH can influence the quantity, size, and shape of nanoparticles. All F. oxysporum isolates produced Ag nanoparticles, but in varied quantities. Increasing incubation temperature increased the quantity, yet nanoparticle diameter was inversely related to temperature. Variations in pH predominately influenced nanoparticle morphology. A direct comparison with commercial, chemically produced Ag nanoparticles yielded physical similarities; however, important differences in surface chemistry are observed. Biogenic nanoparticles show a greater degree of colloidal stability in high-ionic-strength solutions, pointing to a biological advantage associated with the fungal produced layer (corona) surrounding the nanoparticles. It is clear that understanding the organic layer and interfacial interactions will be beneficial in developing innovative applications, particularly in the field of biosensing. PMID- 27466013 TI - In Memoriam: Dr Graham Jackson, 1947-2016. PMID- 27466014 TI - More food for thought: preferred words. PMID- 27466015 TI - Re: Pregabalin prescriptions in the United Kingdom - a drug utilisation study of The Health Improvement Network (THIN) primary care database by Asomaning et al. PMID- 27466016 TI - Re: Letter written in reaction to "Pregabalin prescriptions in the United Kingdom: a drug utilisation study of The Health Improvement Network (THIN) primary care database", by Pottegard et al. - The authors (Asomaning et al.) respond. PMID- 27466017 TI - Plasma Levels of Biotin Metabolites Are Elevated in Hemodialysis Patients with Cramps. AB - Patients with renal failure undergoing hemodialysis (HD) are susceptible to muscle cramps during and after HD. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied by severe pain. Through HD, water-soluble vitamins are drawn out with water. Since biotin, a water soluble vitamin, plays an essential role as one of the coenzymes in producing energy, we have hypothesized that deficiency of biotin may be responsible for HD associated cramps. We previously reported that biotin administration ameliorated the muscle cramps, despite the elevated plasma biotin levels before HD and biotin administration, as judged by an enzyme-linked immunosorbent assay (ELISA). However, the ELISA measures not only biotin but also total avidin-binding substances (TABS) including biotin metabolites. In the present study, we determined biotin in HD patients as well as healthy controls, using a newly developed method with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The plasma samples were collected from 28 HD patients (16 patients with cramps and 12 patients without cramps) before HD and biotin administration and from 11 controls. The results showed that the accumulation of biotin and TABS in plasma of HD patients compared to controls. Importantly, the levels of biotin metabolites, i.e. TABS subtracted by biotin, increased significantly in patients with cramps over those without cramps. Moreover, the levels of biotin metabolites were significantly higher in patients with a poor response to administered biotin, compared to those with a good response. We propose that accumulated biotin metabolites impair biotin's functions as a coenzyme. PMID- 27466018 TI - Lifelong contribution to headache science: A tribute to Professor Jes Olesen. PMID- 27466019 TI - Diagnostic value of additional 18F-FDG PET/CT imaging using a vaginal catheter in patients with paravaginal malignant lesions. AB - BACKGROUND: In routine noncontrast-enhanced PET/computed tomography (CT) studies, the female pelvis is one of the most challenging anatomical regions to interpret. In surgically treated patients, it may be more difficult to determine the accurate location of paravaginal hypermetabolic lesions. In this study, the aim was to investigate the contribution of additional PET/CT imaging using a vaginal catheter in patients with pelvic malignant disease. METHODS: Forty-seven patients with pelvic malignancies were enrolled in this study. Following routine whole body fluorine-18 fluorodeoxyglucose (F-FDG) PET/CT scanning, an additional pelvic scan was obtained after placement of a plastic catheter in the vaginal lumen (v catheter). All suspected foci in vaginal and paravaginal areas were evaluated for both studies. The contribution of additional v-catheter imaging was determined visually by five experienced interpreters. RESULTS: Pathological F-FDG uptake in various vaginal and/or paravaginal locations was detected in 24 of 47 patients after conventional PET/CT imaging. In 10 of these 24 patients, anatomic relations within the uptake area could not be confidently described and v-catheter imaging provided a significant contribution in all 10 cases. In seven of these 10 sites examined, pathological F-FDG uptake was safely ruled out and three sites were confirmed to be malignant. In total, the final interpretation in 13 of 24 patients (54%) was modified by additional v-catheter imaging. The contribution rate of catheter imaging was 89% in treated patients and 33% in untreated patients with vaginal and/or paravaginal lesions on initial scans. CONCLUSIONS: Additional v-catheter imaging of pelvis may be of diagnostic value in the accurate anatomical definition of hypermetabolic lesions in the vaginal/paravaginal area on noncontrasted PET/CT studies. PMID- 27466020 TI - Sildenafil (Viagra((r))) prevents and restores LPS-induced inflammation in astrocytes. AB - Astrocytes are effectively involved in the pathophysiological processes in the central nervous system (CNS) and may contribute to or protect against development of inflammatory and degenerative diseases. Sildenafil is a potent and selective phosphodiesterase-5 (PDE-5) inhibitor, which induces cyclic GMP accumulation. However, the mechanisms of actions on glial cells are not clear. The aim of the present work is to evaluate the role of sildenafil in lipopolysaccharide (LPS) stimulated astrocytes. The cytoskeleton integrity and Ca(2+) waves were assessed as indicators of inflammatory state. Two main groups were done: (A) one prevention and (B) one restoration. Each of these groups: A1: control; A2: LPS for 24h; A3: sildenafil 1 or 10MUM for 4h and then sildenafil 1 or 10MUM+LPS for 24h. B1: control; B2: LPS for 24h; B3: LPS for 24h and then LPS+sildenafil 1 or 10MUM for 24h. Cytoskeleton integrity was analyzed through GFAP immunolabeling and actin labeling with an Alexa 488-conjugated phalloidin probe. Calcium responses were assessed through a Ca(2+)-sensitive fluorophore Fura-2/AM. The results show that both preventive and restorative treatments with sildenafil (in both concentrations) reduced the Ca(2+) responses in intensity and induced a more organized actin fiber pattern, compared to LPS treated cells. This work demonstrated for the first time that astrocytes are a key part of the sildenafil protective effects in the CNS. PMID- 27466021 TI - Event-related potentials reveal early activation of syntax information in Chinese verb processing. AB - By taking advantage of the semantic-syntactic characteristics of Chinese verbs, the current study examined the brain activity of automatic activation of syntactic features at the single word level. Both syntactic (transitivity) and semantic (integrity) features of the verb were manipulated. Event-related potentials were measured while subjects performed lexical decision tasks on visually presented verbs at the single word level. The results showed that there was a significant transitivity effect in both lateral and midline areas for the 150-200ms time window (N200 effect), indicating the retrieval of the syntactic feature. There was also a significant syntactic-semantic interaction at the late stage of verb processing (N400 effect) in the midline central-parietal region, reflecting syntactic influences on semantic processing. These findings suggest that transitivity is an integral part of the mental representation of Chinese verbs and such information can be retrieved at the early stage of single verb processing and can influence subsequent semantic integration. These results also reveal the special features of Chinese language processing. PMID- 27466023 TI - Sclareol isolated from Salvia officinalis improves facial wrinkles via an antiphotoaging mechanism. AB - BACKGROUND: Ultraviolet (UV) irradiation triggers skin photoaging processes, which disrupt the normal three-dimensional integrity of skin. UV-induced oxidative stress, both directly and indirectly, stimulates complex signaling pathways. UV radiation activates skin cell surface receptors on a molecular level and triggers severe changes in extracellular matrix (ECM) proteins, resulting in skin photoaging. AIMS: Sclareol isolated from Salvia officinalis is widely used as a fragrance material. Sclareol is known to exert various biological activities, but its antiphotoaging effect has not been elucidated to date. Therefore, we evaluated wrinkle improvement efficacy of sclareol. METHODS: Human dermal fibroblast cell line (Hs68) and a reconstructed human epidermis (RHE) model were used to evaluate the antiphotoaging effect of sclareol in vitro. A clinical study treated with 0.02% sclareol-containing cream was conducted to identify the ability of sclareol to improve wrinkles. RESULTS: First, sclareol enhanced cellular proliferation and blocked UVB-induced cell death. Sclareol inhibited the UVB-induced mRNA expression of matrix metalloproteinases (MMPs) by regulating the protein expression of AP-1 constituents. In RHE model, sclareol recovered the UVB-induced decrease in epidermal thickness and the expression of proliferating cell nuclear antigen (PCNA). In clinical trial, visually assessed changes and several wrinkle parameters were considered to be statistically different between the test and control groups at 12 weeks. CONCLUSIONS: In this study, sclareol inhibited various photoaging phenomena in human fibroblasts and RHE model. In addition, sclareol-containing cream improved wrinkles in a clinical trial. Taken together, sclareol alleviates facial wrinkle formation via an antiphotoaging mechanism and may be an effective candidate ingredient. PMID- 27466022 TI - Acute cognitive impact of antiseizure drugs in naive rodents and corneal-kindled mice. AB - OBJECTIVE: Some antiseizure drugs (ASDs) are associated with cognitive liability in patients with epilepsy, thus ASDs without this risk would be preferred. Little comparative pharmacology exists with ASDs in preclinical models of cognition. Few pharmacologic studies exist on the acute effects in rodents with chronic seizures. Predicting risk for cognitive impact with preclinical models may supply valuable ASD differentiation data. METHODS: ASDs (phenytoin [PHT]; carbamazepine [CBZ]; valproic acid [VPA]; lamotrigine [LTG]; phenobarbital [PB]; tiagabine [TGB]; retigabine [RTG]; topiramate [TPM]; and levetiracetam [LEV]) were administered equivalent to maximal electroshock median effective dose ([ED50]; mice, rats), or median dose necessary to elicit minimal motor impairment (median toxic dose [TD50]; rats). Cognition models with naive adult rodents were novel object/place recognition (NOPR) task with CF-1 mice, and Morris water maze (MWM) with Sprague-Dawley rats. Selected ASDs were also administered to rats prior to testing in an open field. The effect of chronic seizures and ASD administration on cognitive performance in NOPR was also determined with corneal-kindled mice. Mice that did not achieve kindling criterion (partially kindled) were included to examine the effect of electrical stimulation on cognitive performance. Sham kindled and age-matched mice were also tested. RESULTS: No ASD (ED50) affected latency to locate the MWM platform; TD50 of PB, RTG, TPM, and VPA reduced this latency. In naive mice, CBZ and VPA (ED50) reduced time with the novel object. Of interest, no ASD (ED50) affected performance of fully kindled mice in NOPR, whereas CBZ and LEV improved cognitive performance of partially kindled mice. SIGNIFICANCE: Standardized approaches to the preclinical evaluation of an ASD's potential cognitive impact are needed to inform drug development. This study demonstrated acute, dose- and model-dependent effects of therapeutically relevant doses of ASDs on cognitive performance of naive mice and rats, and corneal kindled mice. This study highlights the challenge of predicting clinical adverse effects with preclinical models. PMID- 27466024 TI - Symptom relief in patients with pneumonia and dementia: implementation of a practice guideline. AB - OBJECTIVE: This study aimed to assess the degree of implementation and barriers encountered in the use of a practice guideline for optimal symptom relief for patients with dementia and pneumonia in Dutch nursing homes. METHODS: A process evaluation included assessment of reach, fidelity, and dose delivered using researcher's observations, and dose received was addressed in a question "use of the practice guideline," which the physicians completed for each patient included in the study. Perceived barriers were assessed with a structured questionnaire (response 69%) and semi-structured interviews (n = 14), which were subject to qualitative content analysis. RESULTS: Of the 55 physicians involved in the intervention phase, 87% attended an implementation meeting; 20 physicians joined the study later (reach). The intervention was implemented as planned, and all intervention components were delivered by the researchers (fidelity and dose delivered). Thirty-six physicians included 109 patients. For 81% of the patients, the treating physician stated to have used the guideline (dose received). The guideline was perceived as providing a good overview of current practice, but some physicians had expected a more directive protocol or algorithm. Further, recommended regular observations of symptoms were rarely performed. Physician's often felt that "this is not different from what we usually do," and with the acute illness, there was not always enough time to (re)familiarize with the contents. CONCLUSIONS: The physicians used the practice guideline frequently despite important barriers. Future implementation may involve strategies such as multiple interactive meetings. Further, the greatest potential to alter usual practice should be emphasized, such as using observational instruments. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27466025 TI - Contributors to Enhanced CO2 Electroreduction Activity and Stability in a Nanostructured Au Electrocatalyst. AB - The formation of a nanostructure is a popular strategy for catalyst applications because it can generate new surfaces that can significantly improve the catalytic activity and durability of the catalysts. However, the increase in the surface area resulting from nanostructuring does not fully explain the substantial improvement in the catalytic properties of the CO2 electroreduction reaction, and the underlying mechanisms have not yet been fully understood. Here, based on a combination of extended X-ray absorption fine structure analysis, X-ray photoelectron spectroscopy, and Kelvin probe force microscopy, we observed a contracted Au-Au bond length and low work function with the nanostructured Au surface that had enhanced catalytic activity for electrochemical CO2 reduction. The results may improve the understanding of the enhanced stability of the nanostructured Au electrode based on the resistance of cation adhesion during the CO2 reduction reaction. PMID- 27466026 TI - Role of antioxidants on the clinical outcome of patients with perennial allergic rhinitis. AB - BACKGROUND: Antioxidants have a preventive or therapeutic role in oxygen free radical-mediated cell and tissue damage. The study aimed to investigate the therapeutic effects of antioxidants and intranasal steroid fluticasone furoate (FF) on the clinical outcome of patients with perennial allergic rhinitis. METHODS: Subjects with perennial allergic rhinitis (n = 61) were randomly divided into two groups, group A (n = 30) received FF and group B (n = 31) received FF with antioxidants for 6 weeks. Nasal and ocular symptoms were evaluated weekly by using a four-point categoric scale. The efficacy of the study drug was assessed based on the mean change from baseline of the total daytime nasal symptom scores, total nighttime nasal symptom scores, and the composite symptom scores. RESULTS: The combined therapy (FF with antioxidants) resulted in marked improvements (p less then or equal to 0.05) in the mean total daytime nasal symptom scores, total nighttime nasal symptom scores, and composite symptom scores of subjects compared with ones treated with intranasal steroid (FF) alone, which highlighted the therapeutic effect of antioxidants in allergic rhinitis. CONCLUSION: Significant improvement in clinical outcome was observed in subjects who received antioxidants along with FF. However, because this was an open-label study, the results must be interpreted with caution, and further double-blind, placebo controlled, dose-ranging trials supplemented with different antioxidants together with intranasal steroids are suggested. PMID- 27466027 TI - Reinforcement of integrin-mediated T-Lymphocyte adhesion by TNF-induced Inside out Signaling. AB - Integrin-mediated leukocyte adhesion to endothelial cells is a crucial step in immunity against pathogens. Whereas the outside-in signaling pathway in response to the pro-inflammatory cytokine tumour necrosis factor (TNF) has already been studied in detail, little knowledge exists about a supposed TNF-mediated inside out signaling pathway. In contrast to the outside-in signaling pathway, which relies on the TNF-induced upregulation of surface molecules on endothelium, inside-out signaling should also be present in an endothelium-free environment. Using single-cell force spectroscopy, we show here that stimulating Jurkat cells with TNF significantly reinforces their adhesion to fibronectin in a biomimetic in vitro assay for cell-surface contact times of about 1.5 seconds, whereas for larger contact times the effect disappears. Analysis of single-molecule ruptures further demonstrates that TNF strengthens sub-cellular single rupture events at short cell-surface contact times. Hence, our results provide quantitative evidence for the significant impact of TNF-induced inside-out signaling in the T lymphocyte initial adhesion machinery. PMID- 27466028 TI - Degradation prediction model and stem cell growth of gelatin-PEG composite hydrogel. AB - Gelatin hydrogel has great potential in regenerative medicine. The degradation of gelatin hydrogel is important to control the release profile of encapsulated biomolecules and regulate in vivo tissue repair process. As a plasticizer, PEG can significantly improve the mechanical property of gelatin hydrogel. However, how preparation parameters affect the degradation rate of gelatin-PEG composite hydrogel is still not clear. In this study, the significant effect factor, glutaraldehyde (GA) concentration, was confirmed by means of Plackett-Burman method. Then a mathematical model was built to predict the degradation rate of composite hydrogels under different preparation conditions using the response surface method (RSM), which was helpful to prepare the certain composite hydrogel with desired degradation rate. In addition, it was found that gelatin-PEG composite hydrogel surface well supported the adhesion and growth of human mesenchymal stem cells (MSCs). Moreover, PEG concentration not only could adjust hydrogel degradation more subtly, but also might increase the cross-linking degree and affect the cell migration. Therefore, these results would be useful to optimize the preparation of gelatin-PEG composite hydrogel for drug delivery or tissue engineering. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3149-3156, 2016. PMID- 27466029 TI - Resolving Fine Cardiac Structures in Rats with High-Resolution Diffusion Tensor Imaging. AB - Cardiac architecture is fundamental to cardiac function and can be assessed non invasively with diffusion tensor imaging (DTI). Here, we aimed to overcome technical challenges in ex vivo DTI in order to extract fine anatomical details and to provide novel insights in the 3D structure of the heart. An integrated set of methods was implemented in ex vivo rat hearts, including dynamic receiver gain adjustment, gradient system scaling calibration, prospective adjustment of diffusion gradients, and interleaving of diffusion-weighted and non-diffusion weighted scans. Together, these methods enhanced SNR and spatial resolution, minimised orientation bias in diffusion-weighting, and reduced temperature variation, enabling detection of tissue structures such as cell alignment in atria, valves and vessels at an unprecedented level of detail. Improved confidence in eigenvector reproducibility enabled tracking of myolaminar structures as a basis for segmentation of functional groups of cardiomyocytes. Ex vivo DTI facilitates acquisition of high quality structural data that complements readily available in vivo cardiac functional and anatomical MRI. The improvements presented here will facilitate next generation virtual models integrating micro structural and electro-mechanical properties of the heart. PMID- 27466030 TI - Anesthesia Technique and Mortality after Total Hip or Knee Arthroplasty: A Retrospective, Propensity Score-matched Cohort Study. AB - BACKGROUND: This propensity score-matched cohort study evaluates the effect of anesthetic technique on a 30-day mortality after total hip or knee arthroplasty. METHODS: All patients who had hip or knee arthroplasty between January 1, 2003, and December 31, 2014, were evaluated. The principal exposure was spinal versus general anesthesia. The primary outcome was 30-day mortality. Secondary outcomes were (1) perioperative myocardial infarction; (2) a composite of major adverse cardiac events that includes cardiac arrest, myocardial infarction, or newly diagnosed arrhythmia; (3) pulmonary embolism; (4) major blood loss; (5) hospital length of stay; and (6) operating room procedure time. A propensity score-matched pair analysis was performed using a nonparsimonious logistic regression model of regional anesthetic use. RESULTS: We identified 10,868 patients, of whom 8,553 had spinal anesthesia and 2,315 had general anesthesia. Ninety-two percent (n = 2,135) of the patients who had general anesthesia were matched to similar patients who did not have general anesthesia. In the matched cohort, the 30-day mortality rate was 0.19% (n = 4) in the spinal anesthesia group and 0.8% (n = 17) in the general anesthesia group (risk ratio, 0.42; 95% CI, 0.21 to 0.83; P = 0.0045). Spinal anesthesia was also associated with a shorter hospital length of stay (5.7 vs. 6.6 days; P < 0.001). CONCLUSIONS: The results of this observational, propensity score-matched cohort study suggest a strong association between spinal anesthesia and lower 30-day mortality, as well as a shorter hospital length of stay, after elective joint replacement surgery. PMID- 27466032 TI - Raman Spectroscopy Differentiates Each Tissue from the Skin to the Spinal Cord: A Novel Method for Epidural Needle Placement? AB - BACKGROUND: Neuraxial anesthesia and epidural steroid injection techniques require precise anatomical targeting to ensure successful and safe analgesia. Previous studies suggest that only some of the tissues encountered during these procedures can be identified by spectroscopic methods, and no previous study has investigated the use of Raman, diffuse reflectance, and fluorescence spectroscopies. The authors hypothesized that real-time needle-tip spectroscopy may aid epidural needle placement and tested the ability of spectroscopy to distinguish each of the tissues in the path of neuraxial needles. METHODS: For comparison of detection methods, the spectra of individual, dissected ex vivo paravertebral and neuraxial porcine tissues were collected using Raman spectroscopy (RS), diffuse reflectance spectroscopy, and fluorescence spectroscopy. Real-time spectral guidance was tested using a 2-mm inner-diameter fiber-optic probe-in-needle device. Raman spectra were collected during the needle's passage through intact paravertebral and neuraxial porcine tissue and analyzed afterward. The RS tissue signatures were verified as mapping to individual tissue layers using histochemical staining and widefield microscopy. RESULTS: RS revealed a unique spectrum for all ex vivo paravertebral and neuraxial tissue layers; diffuse reflectance spectroscopy and fluorescence spectroscopy were not distinct for all tissues. Moreover, when accounting for the expected order of tissues, real-time Raman spectra recorded during needle insertion also permitted identification of each paravertebral and neuraxial porcine tissue. CONCLUSIONS: This study demonstrates that RS can distinguish the tissues encountered during epidural needle insertion. This technology may prove useful during needle placement by providing evidence of its anatomical localization. PMID- 27466033 TI - Preclinical Pharmacology of CW002: A Nondepolarizing Neuromuscular Blocking Drug of Intermediate Duration, Degraded and Antagonized by l-cysteine-Additional Studies of Safety and Efficacy in the Anesthetized Rhesus Monkey and Cat. AB - BACKGROUND: CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by L-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous L-cysteine. Further, Institutional Animal Care and Use Committee-approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. METHODS: Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by L-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 * ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated. RESULTS: ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; L-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 * ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 * ED95. CONCLUSIONS: The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by L-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy. PMID- 27466034 TI - Intraoperative Care Transitions Are Not Associated with Postoperative Adverse Outcomes. AB - BACKGROUND: Whether anesthesia care transitions and provision of short breaks affect patient outcomes remains unclear. METHODS: The authors determined the number of anesthesia handovers and breaks during each case for adults admitted between 2005 and 2014, along with age, sex, race, American Society of Anesthesiologists physical status, start time and duration of surgery, and diagnosis and procedure codes. The authors defined a collapsed composite of in hospital mortality and major morbidities based on primary and secondary diagnoses. The relationship between the total number of anesthesia handovers during a case and the collapsed composite outcome was assessed with a multivariable logistic regression. The relationship between the total number of anesthesia handovers during a case and the components of the composite outcome was assessed using multivariate generalized estimating equation methods. Additionally, the authors analyzed major complications and/or death within 30 days of surgery based on the American College of Surgeons National Surgical Quality Improvement Program-defined events. RESULTS: A total of 140,754 anesthetics were identified for the primary analysis. The number of anesthesia handovers was not found to be associated (P = 0.19) with increased odds of postoperative mortality and serious complications, as measured by the collapsed composite, with odds ratio for a one unit increase in handovers of 0.957; 95% CI, 0.895 to 1.022, when controlled for potential confounding variables. A total of 8,404 anesthetics were identified for the NSQIP analysis (collapsed composite odds ratio, 0.868; 95% CI, 0.718 to 1.049 for handovers). CONCLUSIONS: In the analysis of intraoperative handovers, anesthesia care transitions were not associated with an increased risk of postoperative adverse outcomes. PMID- 27466035 TI - Intraoperative Transesophageal Echocardiography Alters Surgical Plan for Laser Lead Extraction. PMID- 27466036 TI - Neuropathic Pain: When Nerve Lesion Turns off Peripheral Analgesia. PMID- 27466038 TI - Clock drawing test in screening for Alzheimer's dementia and mild cognitive impairment in clinical practice. AB - OBJECTIVES: The clock drawing test (CDT) is a commonly used brief cognitive measure. We evaluated diagnostic accuracy of subjective ratings of CDT by physicians (with/without specialty in cognitive neurology) and neuropsychologists in discriminating amnestic mild cognitive impairment (aMCI), Alzheimer's dementia (AD) and cognitively healthy older adults. We further compared the diagnostic accuracy of subjective categorical ratings with complex scoring of CDT. METHODS: Three cognitive neurologists, three neuropsychologists and six neurology residents without experience in cognitive neurology blinded to the diagnosis rated 187 CDTs (50 mild AD, 49 aMCI and 88 cognitively healthy older adults) using a "yes" (abnormal) versus "suspected" versus "no" (normal) classification. The rating suspected was combined with yes or no to obtain two sets of sensitivity estimates. We also used a 17-point CDT rating system. RESULTS: When using the categorical rating, neuropsychologists had highest sensitivity (89%) in differentiating patients with mild AD (yes/suspected versus no), followed by neurologic residents (80%) and cognitive neurologists (79%). When differentiating patients with aMCI (yes/suspected versus no), the sensitivity was 84% for neuropsychologists, 64% for cognitive neurologists and 62% for residents. The sensitivity using the complex scoring system was 92% in patients with mild AD and 69% in patients with aMCI. CONCLUSIONS: A categorical rating of CDT shows high sensitivity for mild AD even in non-experienced raters. Neuropsychologists outperformed physicians in differentiating patients with aMCI from cognitively healthy older adults (specificity), which was counterbalanced by the lower specificity of their ratings. The diagnostic accuracy was not substantially improved by using complex scoring system. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27466037 TI - Prenatal genetic counselling for psychiatric disorders. AB - Psychiatric disorders like schizophrenia, bipolar disorder, depression, anxiety, and obsessive-compulsive disorder are common disorders with complex aetiology. They can exact a heavy toll on the individual with the condition and can have significant impact on family members too. Accordingly, psychiatric disorders can arise as a concern in the prenatal context - couples may be interested in learning about the chance for their child to develop the illness that manifests in the family and may be interested in discussing options for prenatal testing. However, the complex nature of these conditions can present challenges for clinicians who seek to help families with these issues. We established the world's first specialist genetic counselling service of its kind in Vancouver, Canada, in 2012, and to date, have provided counselling for ~500 families and have demonstrated increases in patients' empowerment and self efficacy after genetic counselling. We draw on our accumulated clinical experience to outline the process by which we approach prenatal genetic counselling for psychiatric disorders to assist other clinicians in providing thoughtful, comprehensive support to couples seeking out this service. (c) 2016 John Wiley & Sons, Ltd. PMID- 27466039 TI - Structured dietary intervention to facilitate weight loss after bariatric surgery: A randomized, controlled pilot study. AB - OBJECTIVE: To evaluate the potential utility of a structured dietary intervention to assist bariatric surgery patients with weight management. METHODS: Participants who underwent Roux-en-Y gastric bypass surgery 1 year previously were randomly assigned to a structured dietary intervention incorporating portion controlled foods (intervention, n = 20) or a comparison group (control, n = 20). Both groups received instruction in behavioral weight loss (one 60-min session) followed by four monthly coaching telephone calls. Assessments were conducted at baseline, 4 months (post-intervention), and 6 months. RESULTS: Participants were 85% female and 80% White. Average age was 46.9 (11.1) years, and body mass index was 31.3 (5.4) kg/m(2) at enrollment. Percent weight change from enrollment was significantly greater for intervention compared with control participants at 4 months [-4.56% vs. -0.13%, t(30) = -3.29, P = 0.003] and 6 months [-4.07% vs. 0.14%, t(31) = -2.03, P = 0.05]. Change in average daily calorie intake was greater among intervention compared with control [-108 vs. 116, t(30) = -2.01, P = 0.05] at 4 months only. CONCLUSIONS: A structured dietary intervention increased weight loss and reduced calorie intake when initiated 1 year following Roux-en-Y gastric bypass. This approach holds promise for optimizing postsurgery lifestyle change. PMID- 27466040 TI - Understanding and simulating the material behavior during multi-particle irradiations. AB - A number of studies have suggested that the irradiation behavior and damage processes occurring during sequential and simultaneous particle irradiations can significantly differ. Currently, there is no definite answer as to why and when such differences are seen. Additionally, the conventional multi-particle irradiation facilities cannot correctly reproduce the complex irradiation scenarios experienced in a number of environments like space and nuclear reactors. Therefore, a better understanding of multi-particle irradiation problems and possible alternatives are needed. This study shows ionization induced thermal spike and defect recovery during sequential and simultaneous ion irradiation of amorphous silica. The simultaneous irradiation scenario is shown to be equivalent to multiple small sequential irradiation scenarios containing latent damage formation and recovery mechanisms. The results highlight the absence of any new damage mechanism and time-space correlation between various damage events during simultaneous irradiation of amorphous silica. This offers a new and convenient way to simulate and understand complex multi-particle irradiation problems. PMID- 27466041 TI - Renal Drug Dosing. Effectiveness of Outpatient Pharmacist-Based vs. Prescriber Based Clinical Decision Support Systems. AB - OBJECTIVE: The purpose of this study was to compare the effectiveness of an outpatient renal dose adjustment alert via a computerized provider order entry (CPOE) clinical decision support system (CDSS) versus a CDSS with alerts made to dispensing pharmacists. METHODS: This was a retrospective analysis of patients with renal impairment and 30 medications that are contraindicated or require dose adjustment in such patients. The primary outcome was the rate of renal dosing errors for study medications that were dispensed between August and December 2013, when a pharmacist-based CDSS was in place, versus August through December 2014, when a prescriber-based CDSS was in place. A dosing error was defined as a prescription for one of the study medications dispensed to a patient where the medication was contraindicated or improperly dosed based on the patient's renal function. The denominator was all prescriptions for the study medications dispensed during each respective study period. RESULTS: During the pharmacist- and prescriber-based CDSS study periods, 49,054 and 50,678 prescriptions, respectively, were dispensed for one of the included medications. Of these, 878 (1.8%) and 758 (1.5%) prescriptions were dispensed to patients with renal impairment in the respective study periods. Patients in each group were similar with respect to age, sex, and renal function stage. Overall, the five-month error rate was 0.38%. Error rates were similar between the two groups: 0.36% and 0.40% in the pharmacist- and prescriber-based CDSS, respectively (p=0.523). The medication with the highest error rate was dofetilide (0.51% overall) while the medications with the lowest error rate were dabigatran, fondaparinux, and spironolactone (0.00% overall). CONCLUSIONS: Prescriber- and pharmacist-based CDSS provided comparable, low rates of potential medication errors. Future studies should be undertaken to examine patient benefits of the prescriber-based CDSS. PMID- 27466042 TI - A novel factor for primary arteriovenous fistula failure: hyperinsulinism. AB - INTRODUCTION: Dysfunction of vascular access is an important reason of morbidity for dialysis patients and it is a major factor affecting the economical burden of hemodialysis. The preferred type of vascular access is creation of an arteriovenous fistula (AVF). However, the problem of fistula maturation rate is still a challenge. Herein, we tried to search the role of hyperinsulinism and insulin resistance as a new predictor of primary AVF failure (pAVFF) that may be a cause of intimal damage. METHODS: We included 119 patients (73 male and 46 female) with a diagnosis of end-stage renal disease (ESRD) who had undergone an AVF operation by a vascular surgeon. The AVF was examined for presence of thrill on the first postoperative day. A successful cannulation with two fistula needles with a blood flow of 250 mL/min for at least one complete dialysis session, after 4 weeks of AVF surgery was defined as functioning access. Insulin resistance in our patients was determined by the standard homeostasis model assessment (homa IR). A logistic-regression analysis was performed to investigate the independent factors related with pAVFF. FINDINGS: Detection of pAVFF occurred in 27 (22.7%) patients. The presence of thrill, amount of daily proteinuria, insulin levels, homa-IR, and serum albumin levels were found to be significantly different between patients with fistula failure and those without pAVFF. The logistic regression analysis of preoperative factors revealed the following OR (odds ratio) and 95% CI values: homa-IR 1.205 (1.063-1.366) (p = 0.004), serum albumin 0.398 (0.178-0.892) (p = 0.025), and the amount of daily proteinuria 1.307 (1.012 1.688) (p = 0.041). Even after addition of the presence of postoperative thrill on AVF, which was a postoperative strong clinical factor to the analysis, mean homa-IR and mean serum albumin continued to be independent predictors of pAVFF. DISCUSSION: Insulin resistance or hyperinsulinism may be a significant cause of pAVFF, which emphasizes the role of endothelium in fistula dysfunction. PMID- 27466044 TI - Antimutagenic components in Glycyrrhiza against N-methyl-N-nitrosourea in the Ames assay. AB - Antimutagenesis against N-nitroso compounds contribute to prevention of human cancer. We have found that Glycyrrhiza aspera ethanolic extract exhibits antimutagenic activity against N-methyl-N-nitrosourea (MNU) using the Ames assay with Salmonella typhimurium TA1535. In the present study, eight purified components from Glycyrrhiza, namely glabridin, glycyrrhetinic acid, glycyrrhizin, licochalcone A, licoricesaponin H2, licoricesaponin G2, liquiritigenin and liquiritin were evaluated for their antimutagenicity against MNU in the Ames assay with S. typhimurium TA1535. Glycyrrhetinic acid, glycyrrhizin, licoricesaponin G2, licoricesaponin H2 and liquiritin did not show the antimutagenicity against MNU in S. typhimurium TA1535. Glabridin, licochalcone A and liquiritigenin reduced revertant colonies derived from MNU in S. typhimurium TA1535 without showing cytotoxic effects, indicating that these compounds possess antimutagenic activity against MNU. The inhibitory activity of glabridin and licochalcone A was more effective than that of liquiritigenin. Thus, Glycyrrhiza contains antimutagenic components against DNA alkylating, direct-acting carcinogens. PMID- 27466045 TI - Cooperative effect of silicon and other alloying elements on creep resistance of titanium alloys: insight from first-principles calculations. AB - Creep resistance is one of the key properties of titanium (Ti) alloys for high temperature applications such as in aero engines and gas turbines. It has been widely recognized that moderate addition of Si, especially when added together with some other elements (X), e.g., Mo, significantly improves the creep resistance of Ti alloys. To provide some fundamental understandings on such a cooperative effect, the interactions between Si and X in both hexagonal close packed alpha and body-centered cubic beta phases are systematically investigated by using a first-principles method. We show that the transition metal (TM) atoms with the number of d electrons (Nd) from 3 to 7 are attractive to Si in alpha phase whereas those with Nd > 8 and simple metal (SM) alloying atoms are repulsive to Si. All the alloying atoms repel Si in the beta phase except for the ones with fewer d electrons than Ti. The electronic structure origin underlying the Si-X interaction is discussed based on the calculated electronic density of states and Bader charge. Our calculations suggest that the beneficial X-Si cooperative effect on the creep resistance is attributable to the strong X-Si attraction. PMID- 27466043 TI - Impairment of a parieto-premotor network specialized for handwriting in writer's cramp. AB - Handwriting with the dominant hand is a highly skilled task singularly acquired in humans. This skill is the isolated deficit in patients with writer's cramp (WC), a form of dystonia with maladaptive plasticity, acquired through intensive and repetitive motor practice. When a skill is highly trained, a motor program is created in the brain to execute the same movement kinematics regardless of the effector used for the task. The task- and effector-specific symptoms in WC suggest that a problem particularly occurs in the brain when the writing motor program is carried out by the dominant hand. In this MRI study involving 12 WC patients (with symptoms only affecting the right dominant hand during writing) and 15 age matched unaffected controls we showed that: (1) the writing program recruited the same network regardless of the effector used to write in both groups; (2) dominant handwriting recruited a segregated parieto-premotor network only in the control group; (3) local structural alteration of the premotor area, the motor component of this network, predicted functional connectivity deficits during dominant handwriting and symptom duration in the patient group. Dysfunctions and structural abnormalities of a segregated parieto-premotor network in WC patients suggest that network specialization in focal brain areas is crucial for well-learned motor skill. Hum Brain Mapp 37:4363-4375, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27466046 TI - MHealth to Improve Measles Immunization in Guinea-Bissau: Study Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Recent studies have revealed a low measles vaccination (MV) rate in the Republic of Guinea-Bissau (West Africa) that has not increased in accordance with the increasing coverage of other vaccinations. Measles is the deadliest of all childhood rash/fever illnesses and spreads easily, implying that if the vaccination coverage is declining there is a significant risk of new measles outbreaks [27]. Meanwhile, mobile health (mHealth; the use of mobile phones for health interventions) has generated much enthusiasm, and shown potential in improving health service delivery in other contexts. OBJECTIVE: The aim of this study is to evaluate the efficiency of mHealth as a tool for improving MV coverage while contributing to the mHealth evidence base. METHODS: This study will take place at three health centers in different regions of Guinea-Bissau. Participants, defined as mothers of the children receiving the MV, will be enrolled when they arrive with their children at the health center to receive the Bacillus Calmette-Guerin vaccination, usually within one month of the child's birth. Enrolment will continue until a study population of 990 children has been reached. The participants will be randomly assigned to a control arm or one of two intervention arms. Each of the three groups will have 330 participants, distributed equally between health centers. Participants in the first intervention arm will receive a scheduled short message service (SMS) text message reminding them of the MV. Participants in the second intervention arm will receive a voice call in addition to the SMS message, while the control arm will receive no interventions. The MV is scheduled to be administered at 9 months of age. Although the vaccine would still be effective after 12 months, local policy in Guinea-Bissau prevents children aged >12 months from receiving the vaccination, and thus the study will follow-up with participants after the children reach 12 months of age. Children who have not yet received the MV will be offered vaccination by the project group. RESULTS: The study will analyze the efficiency of the intervention by determining its overall effect on MV coverage and timeliness when children reach 12 months of age. The main analysis will be stratified by intervention group, health center, level of education, ethnic group, and role of the person receiving the text messages (eg, mother, father, other family member). Secondary outcomes include the average number of health center visits (with intention to obtain the MV) required before successful administration. CONCLUSIONS: Despite the rapid proliferation of mHealth projects, only a small number have been evaluated in terms of direct links to health outcomes. This gap in knowledge requires solid evidence on which policy-makers can base decisions. This study aims to produce significant knowledge about mHealth implementation within a Sub-Saharan context while creating data-supported evidence. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02662595; https://clinicaltrials.gov/ct2/show/NCT02662595 (Archived by WebCite at http://www.webcitation.org/6jH8YiSjY). PMID- 27466047 TI - An index with improved diagnostic accuracy for the diagnosis of Crohn's disease derived from the Lennard-Jones criteria. AB - BACKGROUND: The Lennard-Jones criteria are considered the gold standard for diagnosing Crohn's disease (CD) and include the items granuloma, macroscopic discontinuity, transmural inflammation, fibrosis, lymphoid aggregates and discontinuous inflammation on histology. The criteria have never been subjected to a formal validation process. AIM: To develop a validated and improved diagnostic index based on the items of Lennard-Jones criteria. METHODS: Included were 328 adult patients with long-standing CD (median disease duration 10 years) from three centres and classified as 'established', 'probable' or 'non-CD' by Lennard-Jones criteria at time of diagnosis. Controls were patients with ulcerative colitis (n = 170). The performance of each of the six diagnostic items of Lennard-Jones criteria was modelled by logistic regression and a new index based on stepwise backward selection and cut-offs was developed. The diagnostic value of the new index was analysed by comparing sensitivity, specificity and accuracy vs. Lennard-Jones criteria. RESULTS: By Lennard-Jones criteria 49% (n = 162) of CD patients would have been diagnosed as 'non-CD' at time of diagnosis (sensitivity/specificity/accuracy, 'established' CD: 0.34/0.99/0.67; 'probable' CD: 0.51/0.95/0.73). A new index was derived from granuloma, fibrosis, transmural inflammation and macroscopic discontinuity, but excluded lymphoid aggregates and discontinuous inflammation on histology. Our index provided improved diagnostic accuracy for 'established' and 'probable' CD (sensitivity/specificity/accuracy, 'established' CD: 0.45/1/0.72; 'probable' CD: 0.8/0.85/0.82), including the subgroup isolated colonic CD ('probable' CD, new index: 0.73/0.85/0.79; Lennard Jones criteria: 0.43/0.95/0.69). CONCLUSION: We developed an index based on items of Lennard-Jones criteria providing improved diagnostic accuracy for the differential diagnosis between CD and UC. PMID- 27466048 TI - Synthesis of functionalized triple-doped zinc gallogermanate nanoparticles with superlong near-infrared persistent luminescence for long-term orally administrated bioimaging. AB - Near-infrared persistent luminescence nanoparticles (NIR-PLNPs) have great potential for bioimaging because of no need for in situ excitation, negligible autofluorescence background and deep tissue penetration in optical detection. However, it is challenging to synthesize monodispersed nanosize NIR-PLNPs along with high quantum yield and long afterglow. Here, we show a surfactant-aided hydrothermal method in combination with a short time calcination and a post hydrothermal procedure for the synthesis of ultra-bright monodispersed triple doped zinc gallogermanate nanostructures with super-long near-infrared persistent luminescence (ZGGO:Cr(3+),Yb(3+),Er(3+)). The ZGGO:Cr(3+),Yb(3+),Er(3+) exhibits NIR emission with high quantum yield (9.86%), superlong afterglow time (>20 days), monodispersed nanosize, red light renewability, excellent biocompatibility, and low toxicity. The effective red LED light activation of the persistent luminescence of ZGGO:Cr(3+),Yb(3+),Er(3+) with no need for UV pre irradiation permits the material for long-term in vivo bioimaging application. We also show for the first time the better targeting performance of the oral administration of folate acid functionalized ZGGO:Cr(3+),Yb(3+),Er(3+) for tumor targeting bioimaging than conventional intravenous injection. We believe that the ZGGO:Cr(3+),Yb(3+),Er(3+) will open new perspectives for orally administrated optical imaging and for diagnosis applications. PMID- 27466049 TI - Technique for 3-Dimesional (3D) Modeling of Osteoarticular Medial Femoral Condyle Vascularized Grafting to Replace the Proximal Pole of Unsalvagable Scaphoid Nonunions. AB - This study describes a novel technique for the preoperative surgical planning for an osteoarticular medial femoral condyle (MFC) graft to replace the proximal pole of a scaphoid. In cases of proximal pole scaphoid nonunion or in Preiser disease, fragmentation of the articular surface can occur, leading to significant pain and disability. Osteoarticular MFC bone grafting can be used to treat these injuries by providing a vascularized osteoarticular surface. Using 3-dimensional imaging and printing we are able to precisely model the injured scaphoid, and also accurately plan the harvest of MFC osteoarticular graft. This technique allows for accurate preoperative planning of a complex 3-dimensional bone, and has improved our execution of the plan intraoperatively. PMID- 27466051 TI - Editorial (Thematic Issue: The Biological Approach to Advanced Cancer: Are We in the Middle of the Road?). PMID- 27466053 TI - Visual Analytics for Pattern Discovery in Home Care. Clinical Relevance for Quality Improvement. AB - BACKGROUND: Visualization can reduce the cognitive load of information, allowing users to easily interpret and assess large amounts of data. The purpose of our study was to examine home health data using visual analysis techniques to discover clinically salient associations between patient characteristics with problem-oriented health outcomes of older adult home health patients during the home health service period. METHODS: Knowledge, Behavior and Status ratings at discharge as well as change from admission to discharge that was coded using the Omaha System was collected from a dataset on 988 de-identified patient data from 15 home health agencies. SPSS Visualization Designer v1.0 was used to visually analyze patterns between independent and outcome variables using heat maps and histograms. Visualizations suggesting clinical salience were tested for significance using correlation analysis. RESULTS: The mean age of the patients was 80 years, with the majority female (66%). Of the 150 visualizations, 69 potentially meaningful patterns were statistically evaluated through bivariate associations, revealing 21 significant associations. Further, 14 associations between episode length and Charlson co-morbidity index mainly with urinary related diagnoses and problems remained significant after adjustment analyses. Through visual analysis, the adverse association of the longer home health episode length and higher Charlson co-morbidity index with behavior or status outcomes for patients with impaired urinary function was revealed. CONCLUSIONS: We have demonstrated the use of visual analysis to discover novel patterns that described high-needs subgroups among the older home health patient population. The effective presentation of these data patterns can allow clinicians to identify areas of patient improvement, and time periods that are most effective for implementing home health interventions to improve patient outcomes. PMID- 27466052 TI - Cognitive differences between orang-utan species: a test of the cultural intelligence hypothesis. AB - Cultural species can - or even prefer to - learn their skills from conspecifics. According to the cultural intelligence hypothesis, selection on underlying mechanisms not only improves this social learning ability but also the asocial (individual) learning ability. Thus, species with systematically richer opportunities to socially acquire knowledge and skills should over time evolve to become more intelligent. We experimentally compared the problem-solving ability of Sumatran orang-utans (Pongo abelii), which are sociable in the wild, with that of the closely related, but more solitary Bornean orang-utans (P. pygmaeus), under the homogeneous environmental conditions provided by zoos. Our results revealed that Sumatrans showed superior innate problem-solving skills to Borneans, and also showed greater inhibition and a more cautious and less rough exploration style. This pattern is consistent with the cultural intelligence hypothesis, which predicts that the more sociable of two sister species experienced stronger selection on cognitive mechanisms underlying learning. PMID- 27466054 TI - Phylogenetic evidence for cladogenetic polyploidization in land plants. AB - PREMISE OF THE STUDY: Polyploidization is a common and recurring phenomenon in plants and is often thought to be a mechanism of "instant speciation". Whether polyploidization is associated with the formation of new species (cladogenesis) or simply occurs over time within a lineage (anagenesis), however, has never been assessed systematically. METHODS: We tested this hypothesis using phylogenetic and karyotypic information from 235 plant genera (mostly angiosperms). We first constructed a large database of combined sequence and chromosome number data sets using an automated procedure. We then applied likelihood models (ClaSSE) that estimate the degree of synchronization between polyploidization and speciation events in maximum likelihood and Bayesian frameworks. KEY RESULTS: Our maximum likelihood analysis indicated that 35 genera supported a model that includes cladogenetic transitions over a model with only anagenetic transitions, whereas three genera supported a model that incorporates anagenetic transitions over one with only cladogenetic transitions. Furthermore, the Bayesian analysis supported a preponderance of cladogenetic change in four genera but did not support a preponderance of anagenetic change in any genus. CONCLUSIONS: Overall, these phylogenetic analyses provide the first broad confirmation that polyploidization is temporally associated with speciation events, suggesting that it is indeed a major speciation mechanism in plants, at least in some genera. PMID- 27466055 TI - Single nucleotide polymorphism discovery via genotyping by sequencing to assess population genetic structure and recurrent polyploidization in Andropogon gerardii. AB - PREMISE OF THE STUDY: Autopolyploidy, genome duplication within a single lineage, can result in multiple cytotypes within a species. Geographic distributions of cytotypes may reflect the evolutionary history of autopolyploid formation and subsequent population dynamics including stochastic (drift) and deterministic (differential selection among cytotypes) processes. Here, we used a population genomic approach to investigate whether autopolyploidy occurred once or multiple times in Andropogon gerardii, a widespread, North American grass with two predominant cytotypes. METHODS: Genotyping by sequencing was used to identify single nucleotide polymorphisms (SNPs) in individuals collected from across the geographic range of A. gerardii. Two independent approaches to SNP calling were used: the reference-free UNEAK pipeline and a reference-guided approach based on the sequenced Sorghum bicolor genome. SNPs generated using these pipelines were analyzed independently with genetic distance and clustering. KEY RESULTS: Analyses of the two SNP data sets showed very similar patterns of population level clustering of A. gerardii individuals: a cluster of A. gerardii individuals from the southern Plains, a northern Plains cluster, and a western cluster. Groupings of individuals corresponded to geographic localities regardless of cytotype: 6x and 9x individuals from the same geographic area clustered together. CONCLUSIONS: SNPs generated using reference-guided and reference-free pipelines in A. gerardii yielded unique subsets of genomic data. Both data sets suggest that the 9x cytotype in A. gerardii likely evolved multiple times from 6x progenitors across the range of the species. Genomic approaches like GBS and diverse bioinformatics pipelines used here facilitate evolutionary analyses of complex systems with multiple ploidy levels. PMID- 27466056 TI - Mathematical modelling of microtumour infiltration based on in vitro experiments. AB - The present mathematical models of microtumours consider, in general, volumetric growth and spherical tumour invasion shapes. Nevertheless in many cases, such as in gliomas, a need for more accurate delineation of tumour infiltration areas in a patient-specific manner has arisen. The objective of this study was to build a mathematical model able to describe in a case-specific way as well as to predict in a probabilistic way the growth and the real invasion pattern of multicellular tumour spheroids (in vitro model of an avascular microtumour) immersed in a collagen matrix. The two-dimensional theoretical model was represented by a reaction-convection-diffusion equation that considers logistic proliferation, volumetric growth, a rim with proliferative cells at the tumour surface and invasion with diffusive and convective components. Population parameter values of the model were extracted from the experimental dataset and a shape function that describes the invasion area was derived from each experimental case by image processing. New possible and aleatory shape functions were generated by data mining and Monte Carlo tools by means of a satellite EGARCH model, which were fed with all the shape functions of the dataset. Then the main model is used in two different ways: to reproduce the growth and invasion of a given experimental tumour in a case-specific manner when fed with the corresponding shape function (descriptive simulations) or to generate new possible tumour cases that respond to the general population pattern when fed with an aleatory-generated shape function (predictive simulations). Both types of simulations are in good agreement with empirical data, as it was revealed by area quantification and Bland-Altman analysis. This kind of experimental-numerical interaction has wide application potential in designing new strategies able to predict as much as possible the invasive behaviour of a tumour based on its particular characteristics and microenvironment. PMID- 27466057 TI - Modulation of innate immune response by the vagus nerve in experimental hepatic amebiasis in rats. AB - The parasympathetic nervous system has a crucial role in immunomodulation of the vagus nerve, its structure provides a pathogen detection system, and a negative feedback to the immune system after the pathogenic agent has been eliminated. Amebiasis is a disease caused by the protozoan parasite Entamoeba histolytica, considered the third leading cause of death in the world. The rats are used as a natural resistance model to amoebic liver infection. The aim of this study is to analyze the interaction of Entamoeba histolytica with neutrophils, macrophages, and NK cells in livers of intact and vagotomized rats. Six groups were studied (n = 4): Intact (I), Intact + amoeba (IA), Sham (S), Sham + amoeba (SA), Vagotomized (V) and Vagotomized + amoeba (VA). Animals were sacrificed at 8 h post inoculation of E. histolytica. Then, livers were obtained and fixed in 4% paraformaldehyde. Tissue liver slides were stained with H-E, PAS and Masson. The best development time for E. histolytica infection was at 8 h. Amoeba was identified with a monoclonal anti-220 kDa E. histolytica lectin. Neutrophils (N) were identified with rabbit anti-human neutrophil myeloperoxidase, macrophages (Mphi) with anti-CD68 antibody and NK cells (NK) with anti-NK. Stomachs weight and liver glycogen were higher in V. Collagen increased in VA, whereas vascular and neutrophilic areas were decreased. There were fewer N, Mphi, NK around the amoeba in the following order IA > SA > VA (p < 0.05 between IA and VA). In conclusion, these results suggest that the absence of parasympathetic innervation affects the participation of neutrophils, macrophages and NK cells in the innate immune response, apparently by parasympathetic inhibition on the cellular functions and probably for participation in sympathetic activity. PMID- 27466058 TI - The inflammatory effect of infection with Hymenolepis diminuta via the increased expression and activity of COX-1 and COX-2 in the rat jejunum and colon. AB - The aim of this study was to determine whether Hymenolepis diminuta may affect the expression and activity of cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX 2), resulting in the altered levels of their main products - prostaglandins (PGE2) and thromboxane B2 (TXB2). The study used the same experimental model as in our previous studies in which we had observed changes in the transepithelial ion transport, tight junctions and in the indicators of oxidative stress, in both small and large intestines of rats infected with H. diminuta. In this paper, we investigated not only the site of immediate presence of the tapeworm (jejunum), but also a distant site (colon). Inflammation related to H. diminuta infection is associated with the increased expression and activation of cyclooxygenase (COX), enzyme responsible for the synthesis of PGE2 and TXB2, local hormones contributing to the enhanced inflammatory reaction in the jejunum and colon in the infected rats. The increased COX expression and activity is probably caused by the increased levels of free radicals and the weakening of the host's antioxidant defense induced by the presence of the parasite. Our immunohistochemical analysis showed that H. diminuta infection affected not only the intensity of the immunodetection of COX but also the enzyme protein localization within intestinal epithelial cells - from the entire cytoplasm to apical/basal regions of cells, or even to the nucleus. PMID- 27466059 TI - De novo bone formation underneath the sinus membrane supported by a bone patch: a pilot experiment in rabbit sinus model. AB - AIMS: The objectives of this study were to evaluate bone regeneration beneath a newly devised bone substitute combined with collagen membrane (called a bone patch) lying over a concomitantly placed mini-implant following sinus floor elevation and verify its usefulness as a carrier system for recombinant human bone morphogenetic protein-2 (rhBMP-2) in rabbits. MATERIALS AND METHODS: The sinus floor elevation procedure was performed bilaterally in five rabbits. Either a plain bone patch (control group) or an rhBMP-2-loaded patch (experimental group) was randomly placed beneath the elevated sinus membrane (SM) of both sinuses, where the mini-implants were concomitantly placed. Micro-computed tomographic and histologic analyses were performed at 4 weeks post-surgery. RESULTS: In micro-computed tomography, the median values of the total augmented volume and the mineralized bone volume were significantly higher in the experimental group than in the control group (161 vs. 122 mm3 [P < 0.01] and 48 vs. 42 mm3 [P < 0.05], respectively). Histometric analysis revealed the same outcomes, with new bone areas of 6.41 and 2.97 mm2 in the experimental and control groups, respectively (P < 0.001), and bone-to-implant contact ratios of 22.6% and 5.2%, respectively (P < 0.001). CONCLUSION: The newly devised bone patch in this study can support the elevated SM and facilitate bone regeneration from the basal bone with a reduced amount of biomaterial. The addition of rhBMP-2 may shorten the healing time for multidirectional bone regeneration toward the implant. PMID- 27466060 TI - Public perceptions of the tobacco-free generation in Tasmania: adults and adolescents. AB - BACKGROUND: The tobacco-free generation (TFG) proposal advocates prohibiting the sale of tobacco products to people born after the year 2000. In a world-first, the Tasmanian parliament is considering this proposed legislation. Levels of public support for the proposal among adults and adolescents were investigated. METHODS: Data were collected via 2 cross-sectional studies in 2014. 1 was a telephone survey of 600 randomly sampled Tasmanians aged 18 years or over, the other a pencil and paper survey of 1888 Tasmanian secondary school students aged 12-17 years.Regression models were used to examine characteristics associated with support for adults and adolescents, weighted to account for sampling and the Tasmanian population. RESULTS: Support for the TFG proposal was 75% among Tasmanian adults. Majority support extends across all sociodemographic subgroups, including 72% of current smokers. Support was higher among females and those educated up to year 12. Of those aged 12-17 years, 68% supported the TFG proposal, including 64% of those born after the year 2000, who would be directly affected by the TFG proposal. Support was higher among non-smokers and those born before the year 2000. CONCLUSIONS/IMPLICATIONS: There is strong public support for the TFG proposal in Tasmania, even among smokers and people born after the year 2000. PMID- 27466061 TI - Treating allergic conjunctivitis: A once-daily medication that provides 24-hour symptom relief. AB - BACKGROUND: Allergic conjunctivitis (AC) is a common ocular inflammatory manifestation of allergen exposure in sensitized individuals. Signs and symptoms of AC can decrease quality of life, interfere with productivity, and lead to considerable economic burden. Consistent suppression of conjunctival inflammation is necessary for managing AC, but currently available medications require frequent administration and exhibit limited duration of action. METHODS: In this review, we summarized AC pathogenesis, diagnosis, and current treatment options as well as their limitations. Findings from the literature were discussed in the context of the unmet need for a once-daily medication with sustained 24-hour effectiveness. RESULTS: Topical pharmacologic treatments are the most common approach for managing extant AC; however, most available medications require multiple daily instillations. Dual-acting antihistamine-mast cell stabilizing agents are currently considered first-line therapeutics for AC because they provide acute relief of signs and symptoms and block persistent inflammation to promote regression of AC. Recent studies of a newly-developed, higher concentration formulation of a dual-acting antihistamine-mast cell stabilizer have demonstrated that this formulation provides a 24-hour duration of action with once-daily dosing. CONCLUSIONS: Dual-acting AC medications exhibit a high degree of overall effectiveness and are well tolerated for chronic use. A newly available once-daily medication that manages signs and symptoms of AC for a full 24 hours may be considered a treatment of choice for patients experiencing seasonal or perennial AC. ClinicalTrials.gov NCT01743027 and NCT01479374. PMID- 27466062 TI - Surface Roughness Modulates Diffusion and Fibrillation of Amyloid-beta Peptide. AB - The presence of surfaces influences the kinetics of amyloid-beta (Abeta) peptide fibrillation. Although it has been generally recognized that the fibrillation process can be assisted or accelerated by surface chemistry, the impact of surface topography, i.e., roughness, on peptide fibrillation is relatively little understood. Here we study the role of surface roughness on surface-mediated fibrillation using polymer coatings of varying roughness as well as polymer microparticles. Using single-molecule tracking, atomic force microscopy, and the thioflavin T fluorescence technique, we show that a rough surface decelerates the two-dimensional (2D) diffusion of peptides and retards the surface-mediated fibrillation. A higher degree of roughness that presents an obstacle to peptide diffusion is found to inhibit the fibrillation process. PMID- 27466063 TI - Disrupted structural and functional rich club organization of the brain connectome in patients with generalized tonic-clonic seizure. AB - Network studies have demonstrated that a small set of highly connected regions may play a central role in global information integration, together forming a rich club organization. Given that generalized tonic-clonic seizure (GTCS) has been conceptualized as a network disorder, we hypothesized that the rich club disturbances may be related to the network abnormalities of GTCS. Here, we used graph theoretical analysis to investigate the rich club organization of both structural and functional connectome in patients with GTCS (n = 50) and healthy controls (n = 60). We further measured the level of global efficiency and clustering in rich club and non-rich club organization. We, respectively, identified a small number of highly connected hubs as rich club organization from structural and functional networks. Patients were found to exhibit significantly reduced rich club connectivity among the central hubs. Meanwhile, both structural and functional network showed changed levels of global efficiency and clustering of rich club organization in GTCS. Furthermore, in patients, lower levels of rich club connectivity were found to be correlated with longer duration of illness and seizure frequency. Together, these findings suggest that GTCS is characterized by a selective disruption of rich club organization due to the long-term injurious effects of epileptic actions on the central hub regions, which potentially contribute to a reduced level of brain integration capacity among different functional domains and an added effect of illness on a preexisting vulnerability. Our findings emphasize a central role for abnormal rich club organization in the pathophysiological mechanism underlying GTCS. Hum Brain Mapp 37:4487-4499, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27466065 TI - Methane Activation by 5 d Transition Metals: Energetics, Mechanisms, and Periodic Trends. AB - Although it has been known for almost three decades that several 5d transition metal cations will activate methane at room temperature, a more detailed examination of these reactions across the periodic table has only recently been completed. In this Minireview, we compare and contrast studies of the kinetic energy dependence of these reactions as studied using guided-ion-beam tandem mass spectrometry. Thermochemistry for the various products observed (MH+ , MH2+ , MC+ , MCH+ , MCH2+ , and MCH3+ ) are collected and periodic trends evaluated and discussed. The mechanisms for the reactions as elucidated by synergistic quantum chemical calculations are also reviewed. Recent spectroscopic evidence for the structures of the MCH2+ dehydrogenation products are discussed as well. PMID- 27466066 TI - All-optical switching in granular ferromagnets caused by magnetic circular dichroism. AB - Magnetic recording using circularly polarised femto-second laser pulses is an emerging technology that would allow write speeds much faster than existing field driven methods. However, the mechanism that drives the magnetisation switching in ferromagnets is unclear. Recent theories suggest that the interaction of the light with the magnetised media induces an opto-magnetic field within the media, known as the inverse Faraday effect. Here we show that an alternative mechanism, driven by thermal excitation over the anisotropy energy barrier and a difference in the energy absorption depending on polarisation, can create a net magnetisation over a series of laser pulses in an ensemble of single domain grains. Only a small difference in the absorption is required to reach magnetisation levels observed experimentally and the model does not preclude the role of the inverse Faraday effect but removes the necessity that the opto magnetic field is 10 s of Tesla in strength. PMID- 27466068 TI - Intragastric balloons for weight loss: Not just occupying space in the stomach. PMID- 27466067 TI - Immunosuppression, peripheral inflammation and invasive infection from endogenous gut microbiota activate retinal microglia in mouse models. AB - Although its actual role in the progression of degenerative processes is not fully known, the persistent activated state of retinal microglia and the concurrent secretion of inflammatory mediators may contribute to neuronal death and permanent vision loss. Our objective was to determine whether non-ocular conditions (immunosuppression and peripheral inflammation) could lead to activation of retinal microglia. Mouse models of immunosuppression induced by cyclophosphamide and/or peripheral inflammation by chemically induced sublethal colitis in C57BL/6J mice were used. Retinal microglia morphology, spatial distribution and complexity, as well as MHCII and CD11b expression levels were determined by flow cytometry and confocal immunofluorescence analysis with anti CD11b, anti-IBA1 and anti-MHCIIRT1B antibodies. Retinas of mice with double treatment showed changes in microglial morphology, spatial distribution and expression levels of CD11b and MHCII. These effects were higher than those observed with any treatment separately. In addition, we also observed in these mice: (i) translocation of endogenous bacteria from gut to liver, and (ii) upregulation of TLR2 expression in retinal microglia. Using a mouse model of immunosuppression and gut colonization by Candida albicans, translocation of fungal cells was confirmed to occur in wild type and, to a higher extent, in TLR2 KO mice, which are more susceptible to fungal invasion; interestingly microglial changes were also higher in TLR2 KO mice. Hence, non-ocular injuries (immunosuppression, peripheral inflammation and invasive infection from endogenous gut microbiota) can activate retinal microglia and therefore could affect the progression of neurodegenerative disorders and should be taken into account to improve therapeutic options. PMID- 27466069 TI - Assessing the Validity of Online Drug Forums as a Source for Estimating Demographic and Temporal Trends in Drug Use. AB - OBJECTIVES: Addiction researchers have begun monitoring online forums to uncover self-reported details about use and effects of emerging drugs. The use of such online data sources has not been validated against data from large epidemiological surveys. This study aimed to characterize and compare the demographic and temporal trends associated with drug use as reported in online forums and in a large epidemiological survey. METHODS: Data were collected from the Web site, drugs-forum.com, from January 2007 through August 2012 (143,416 messages posted by 8087 members) and from the US National Survey on Drug Use and Health (NSDUH) from 2007 to 2012. Measures of forum participation levels were compared with and validated against 2 measures from the NSDUH survey data: percentage of people using the drug in past 30 days and percentage using the drug more than 100 times in the past year. RESULTS: For established drugs (eg, cannabis), significant correlations were found across demographic groups between drugs-forum.com and the NSDUH survey data, whereas weaker, nonsignificant correlations were found with temporal trends. Emerging drugs (eg, Salvia divinorum) were strongly associated with male users in the forum, in agreement with survey-derived data, and had temporal patterns that increased in synchrony with poison control reports. CONCLUSIONS: These results offer the first assessment of online drug forums as a valid source for estimating demographic and temporal trends in drug use. The analyses suggest that online forums are a reliable source for estimation of demographic associations and early identification of emerging drugs, but a less reliable source for measurement of long-term temporal trends. PMID- 27466071 TI - Co-occurring Disordered Gambling Among Treatment-Seekers at a Community Outpatient Addiction Clinic. AB - BACKGROUND: Parallel to the ongoing expansion of legalized gambling activities is a growing concern about rising occurrence of uncontrollable gambling. People with preexisting gambling and/or chemical addictions may be particularly vulnerable, but the extent of such co-occurring conditions and their demographic and clinical characteristics have not been sufficiently elucidated. To that end, the present study attempted to both, quantify the presence and to characterize co-occurring pathological or problem gambling (ie, respectively, at least 1- or at least 5 pathological gambling criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) among treatment-seeking patients at a community outpatient addiction program. METHODS: The patients were assessed with the South Oaks Gambling Screen and their charts were reviewed for the extraction of demographic and clinical information according to a predetermined template. Data from 183 subjects withstood quality control procedures and were included. RESULTS: The prevalence rates of co-occurring problem- (18.6%) and pathological (10.9%) gambling were strikingly higher than those found in the general population (2% and 0.5%, respectively). No increase in the clinical severity indices was observed across the gambling groups. CONCLUSIONS: Our data replicate those of prior studies reporting heightened prevalence of problematic gambling in patients with substance use disorders and extend the prior findings by including a subject population of treatment-seekers. In the era of the gambling industry growth, these results call for creation and/or adjustment of clinical addiction services to meet emerging preventive and therapeutic needs. PMID- 27466070 TI - An Argument for Change in Tobacco Treatment Options Guided by the ASAM Criteria for Patient Placement. AB - Tobacco use is a major threat to public health in the United States, and the number one cause of preventable death. Although most smokers try to quit unaided, robust data indicate that pairing behavioral support to US Food Drug Administration-approved cessation medications significantly increase cessation rates. Those who do receive assistance in quitting usually receive very low intensity treatment, regardless of the severity of their dependence or their medical and environmental circumstances. This is in stark contrast to how other substance use disorders are treated, where there are varying levels of care depending on addiction severity and biopsychosocial circumstances. The American Society of Addiction Medicine (ASAM) developed a formal algorithm for assessing substance use disorders and determining the optimal level of care. The ASAM Patient Placement Criteria are regularly used to determine the appropriate level of care for all substance use disorders except tobacco. This paper will review key aspects of the ASAM dimensions of care and placement levels, with emphasis on how they apply to tobacco use and present case examples of typical smokers who would benefit from a higher intensity of tobacco dependence treatment. We also present current barriers to reimbursing healthcare providers for these services. We conclude with a commentary and discussion regarding recommendations for improvements in tobacco dependence treatment care. PMID- 27466072 TI - The neuron-astrocyte-microglia triad involvement in neuroinflammaging mechanisms in the CA3 hippocampus of memory-impaired aged rats. AB - We examined the effects of inflammaging on memory encoding, and qualitative and quantitative modifications on proinflammatory proteins, apoptosis, neurodegeneration and morphological changes of neuron-astrocyte-microglia triads in CA3 Stratum Pyramidale (SP), Stratum Lucidum (SL) and Stratum Radiatum (SR) of young (3months) and aged rats (20months). Aged rats showed short-term memory impairments in the inhibitory avoidance task, increased expression of iNOS and activation of p38MAPK in SP, increase of apoptotic neurons in SP and of ectopic neurons in SL, and decrease of CA3 pyramidal neurons. The number of astrocytes and their branches length decreased in the three CA3 subregions of aged rats, with morphological signs of clasmatodendrosis. Total and activated microglia increased in the three CA3 subregions of aged rats. In aged rats CA3, astrocytes surrounded ectopic degenerating neurons forming "micro scars" around them. Astrocyte branches infiltrated the neuronal cell body, and, together with activated microglia formed "triads". In the triads, significantly more numerous in CA3 SL and SR of aged rats, astrocytes and microglia cooperated in fragmentation and phagocytosis of ectopic neurons. Inflammaging-induced modifications of astrocytes and microglia in CA3 of aged rats may help clearing neuronal debris derived from low-grade inflammation and apoptosis. These events might be common mechanisms underlying many neurodegenerative processes. The frequency to which they appear might depend upon, or might be the cause of, the burden and severity of neurodegeneration. Targeting the triads may represent a therapeutic strategy which may control inflammatory processes and spread of further cellular damage to neighboring cells. PMID- 27466074 TI - Transdiagnostic versus diagnosis specific cognitive behavioural therapies for anxiety: A meta-analysis. AB - Research evaluating transdiagnostic CBT (tCBT) demonstrates its efficacy. Some evidence suggests equivalence between tCBT and diagnosis-specific CBT (dxCBT), however more investigations are necessary to clarify any difference in efficacy. This meta-analysis was conducted to compare tCBT and dxCBT, and to investigate the differential impact of comorbidity on effect sizes. Pre and post scores from primary anxiety measures in 83 treatment conditions, taken from studies primarily targeting anxiety disorders, were summarised and compared. Meta-regression analyses were then used to test the effects of comorbidity. DxCBT and tCBT meta effects were found to be large, where g=0.951, 95% CI: 0.874-1.027, and g=1.059, 95% CI: 0.876-1.242, respectively. While statistically different (p=0.008), overlap of confidence intervals indicated a lack of clinical significance. Furthermore, no relationship between comorbidity rate and tCBT outcome was observed. These results were discussed in the context of previous findings in the transdiagnostic CBT literature. PMID- 27466073 TI - Evidence-practice gap for dental sealant application: results from a dental practice-based research network in Japan. AB - PURPOSE: The study aims were: (i) to examine dentist practice patterns regarding treatment recommendations for dental sealants; and (ii) to identify characteristics associated with this recommendation. METHODS: The study was performed using a cross-sectional questionnaire survey (Clinicaltrials.gov registration number NCT01680848). Participants were Japanese dentists (n = 282) recruited from the Dental Practice-based Research Network Japan. Three clinical photographs of the occlusal surface of a mandibular first molar were presented, portraying increasing depths of cavitation in a 12-year-old patient with high caries risk. Sealants would be an appropriate treatment in all three scenarios. We asked about the treatment decision for each case. We then performed multiple logistic regression analyses to evaluate associations between the decision to recommend sealants, and dentist, patient and practice characteristics. RESULTS: Responses were obtained from 189 dentists (response rate = 67%). In the hypothetical scenarios, dentists' recommendations for sealants for the 12-year old patient varied from 16% to 26% across the three hypothetical clinical scenarios. Multiple logistic regression analysis indicated that dentist agreement with the efficacy of assessment for caries risk showed a significant association with the percentages of patients receiving sealants. CONCLUSIONS: Dentist practice patterns for sealant treatment recommendation show changes that are dependent on caries severity. The dentists' recommendations for sealants for the 12-year-old patient were low for all three selected scenarios, based on indications for sealants in the American Dental Association guidelines. Recommending a sealant showed a significant relationship with the dentist having a higher agreement with efficacy of caries risk assessment. PMID- 27466075 TI - Circulating Prolactin and Risk of Type 2 Diabetes: A Prospective Study. AB - Prolactin plays an important role in maintaining a normal glucose homeostasis during pregnancy and beyond. Studies investigating the association between prolactin and type 2 diabetes beyond pregnancy are rare and none is prospective. We aimed to examine whether prolactin associates with type 2 diabetes prospectively in a Chinese population. In 2009, 2,377 participants aged 40 years or older were enrolled from Shanghai, China. Among 1,596 diabetes-free participants at baseline, 1,510 completed the follow-up investigation in 2013. Participants who had a fasting plasma glucose >=126 mg/dL and/or a 2-hour plasma glucose >=200 mg/dL during a 75-g oral glucose tolerance test had a definite diagnosis of type 2 diabetes or received antidiabetic therapies during follow-up were classified as having type 2 diabetes. During a mean follow-up of 3.7 years, 189 new cases of type 2 diabetes were documented. After multivariate adjustment, women in the highest quartile of prolactin showed the lowest risk for diabetes compared with those in the lowest quartile (hazard ratio = 0.48, 95% confidence interval: 0.26, 0.90). However, such significant associations were not observed in men. Prolactin may be a mediator in the pathogenesis of type 2 diabetes in women; however, more studies are needed to elucidate the underlying sex-specific mechanism. PMID- 27466076 TI - Signaling Networks of Retinal Ganglion Cell Formation and the Potential Application of Stem Cell-Based Therapy in Retinal Degenerative Diseases. AB - Retinal degenerative diseases such as age-related macular degeneration, retinitis pigmentosa, and glaucoma result in permanent loss of retinal neurons and vision. Stem cell therapy could be a novel treatment strategy to restore visual function. In an ideal situation, a homogenous population of stem cell-derived retinal neurons with high purity is used for replacement therapy. Thus, it is crucial to elucidate the molecular mechanisms that regulate the development of retinal progenitor cells and subsequent generation of specific retinal neurons. Here, recent findings concerning the intrinsic and extrinsic factors that regulate retinal progenitor cell maintenance and differentiation are summarized, especially transcriptional factors and extrinsic signals. Understanding these mechanisms is indispensable because they have potential clinical applications, chiefly the generation of specific retinal cells such as retinal ganglion cells to treat glaucoma and other optic neuropathy diseases. PMID- 27466077 TI - A Toddler With Central Venous Catheter Develops Tachycardia. PMID- 27466078 TI - Expression of ADP-ribosyltransferase 1 Is Associated with Poor Prognosis of Glioma Patients. AB - Glioma has a poor prognosis due to its rapid overgrowth, diffuse invasion, and chemotherapy resistance. The improvements in clinical outcome are still limited and the identification of novel biomarkers involved in the progression of gliomas is still under critical demands. Amino acid ADP-ribosyltransferase 1 (ART1) is an enzyme that catalyzes the mono-ADP-ribosylation, a reversible post-translational modification. For example, the mono-ADP-ribosylation of transcription factors can affect their binding to target gene promoters. However, the functional significance of ART1 in glioma has not been reported. We collected 107 glioma cases from Qianfoshan Hospital and Yidu Central Hospital of Weifang between April 2008 and September 2015 to analyze the prognosis value of ART1 in gliomas. RT qPCR analysis showed that the expression level of ART1 mRNA in glioma tissues was 4-fold higher than that in normal brain tissues. According to the immunohistochemical staining results, 44 patients (41.1%) were categorized as ART1 positive (>= 20% of stained glioma cells), while the other 63 patients (58.9%) categorized as ART1 negative (< 20% of stained glioma cells). Moreover, the mean percentage of ART1-positive cells was 43.7%, 53.6% and 64.2% in WHO grade II, III and IV specimens, respectively. Through univariate and multivariate analyses, we identified ART1 as an independent prognostic factor. We also found that ART1 overexpression in U251 glioblastoma cells could significantly decrease the susceptibility to vincristine, one of tubulin-targeted drugs, which is widely used in clinical treatment for glioma. Taken together, we propose that up regulation of ART1 expression is associated with the aggressiveness of glioma. PMID- 27466079 TI - Bent bonds and the antiperiplanar hypothesis - a simple model to rationalize [1,3]-sigmatropic alkyl shifts. AB - The bent bond/antiperiplanar (BBA) hypothesis has been applied to the analysis of [1,3]-sigmatropic alkyl shifts. These thermal rearrangements, for which there is evidence that they proceed through diradical intermediates, can be interpreted by considering their transient allyl radical structures. For the thermolysis of cyclic molecules, the preferred generation of pyramidal allyl radicals in staggered conformations is postulated on the basis of the BBA hypothesis. This accounts for the preference of suprafacial rearrangement pathways as well as the extent of inversion or retention of configuration at the migrating carbons. PMID- 27466081 TI - Full-Thickness and Unstageable Pressure Injuries That Develop in Nursing Home Residents Despite Consistently Good Quality Care. AB - PURPOSE: The purpose of this study was to determine whether stage 3, 4, and unstageable pressure injuries develop despite consistently good quality care (CGQC); ascertain whether these wounds occur without prior recognition of a lower stage pressure injury; and to describe and analyze characteristics of nursing home residents and their higher-stage pressure injuries. DESIGN: Descriptive, nonexperimental, prospective analysis. SUBJECTS AND SETTING: A convenience sample of 20 residents from facilities participated in the study; research sites were located in 7 counties in Western Washington and Orange County, along with a single site in Wisconsin. METHODS: CGQC facilities were identified using a 3-step incremental approach. Research assistants verified CGQC at the facility level. After data collection was complete, a Longitudinal, Expert, All-Data Panel reviewed cases for a final resident-level validity check for CGQC. Remaining cases were submitted to analysis. RESULTS: Residents who developed advanced stage pressure injuries despite CGQC were older, had limited mobility, dementia, comorbid conditions, urinary or fecal incontinence, and infections. The pressure injuries were relatively small and had little-to-no undermining, exudate, or edema. CONCLUSIONS: Stage 3, 4, and unstageable pressure injuries were observed in nursing home residents despite CGQC. Results from this study may serve as a baseline for further research to evaluate characteristics of these wounds when they develop under settings of poor-quality care. Findings also may be useful in creating evidence-based practice guidelines to support decision making around mandatory reporting, diagnosis, and prosecution. PMID- 27466080 TI - Glomerular filtration rate in patients with atrial fibrillation and 1-year outcomes. AB - We assessed 1-year outcomes in patients with atrial fibrillation enrolled in the EurObservational Research Programme AF General Pilot Registry (EORP-AF), in relation to kidney function, as assessed by glomerular filtration rate (eGFR). In a cohort of 2398 patients (median age 69 years; 61% male), eGFR (ml/min/1.73 m(2)) calculated using the CKD-EPI formula was >=80 in 35.1%, 50-79 in 47.2%, 30 49 in 13.9% and <30 in 3.7% of patients. In a logistic regression analysis, eGFR category was an independent predictor of stroke/TIA or death, with elevated odds ratios associated with severe to mild renal impairment, ie. eGFR < 30 ml/min/1.73 m(2) [OR 3.641, 95% CI 1.572-8.433, p < 0.0001], 30-49 ml/min/1.73 m(2) [OR 3.303, 95% CI 1.740-6.270, p = 0.0026] or 50-79 ml/min/1.73 m2 [OR 2.094, 95% CI 1.194-3.672, p = 0.0003]. The discriminant capability for the risk of death was tested among various eGFR calculation algorithms: the best was the Cockcroft Gault equation adjusted for BSA, followed by Cockcroft-Gault equation, and CKD EPI equation, while the worst was the MDRD equation. In conclusion in this prospective observational registry, renal function was a major determinant of adverse outcomes at 1 year, and even mild or moderate renal impairments were associated with an increased risk of stroke/TIA/death. PMID- 27466082 TI - Surface chemistry regulates the sensitivity and tolerability of osteoblasts to various magnitudes of fluid shear stress. AB - Scaffolds provide a physical support for osteoblasts and act as the medium to transfer mechanical stimuli to cells. To verify our hypothesis that the surface chemistry of scaffolds regulates the perception of cells to mechanical stimuli, the sensitivity and tolerability of osteoblasts to fluid shear stress (FSS) of various magnitudes (5, 12, 20 dynes/cm2 ) were investigated on various surface chemistries (-OH, -CH3 , -NH2 ), and their follow-up effects on cell proliferation and differentiation were examined as well. The sensitivity was characterized by the release of adenosine triphosphate (ATP), nitric oxide (NO) and prostaglandin E2 (PGE2 ) while the tolerability was by cellular membrane integrity. The cell proliferation was characterized by S-phase cell fraction and the differentiation by ALP activity and ECM expression (fibronectin and type I collagen). As revealed, osteoblasts demonstrated higher sensitivity and lower tolerability on OH and CH3 surfaces, yet lower sensitivity and higher tolerability on NH2 surfaces. Observations on the focal adhesion formation, F actin organization and cellular orientation before and after FSS exposure suggest that the potential mechanism lies in the differential control of F-actin organization and focal adhesion formation by surface chemistry, which further divergently mediates the sensitivity and tolerability of ROBs to FSS and the follow-up cell proliferation and differentiation. These findings are essentially valuable for design/selection of desirable surface chemistry to orchestrate with FSS stimuli, inducing appropriate cell responses and promoting bone formation. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2978-2991, 2016. PMID- 27466083 TI - Experience of the Time to Change programme in England as predictor of mental health service users' stigma coping strategies. AB - AIMS: In the field of stigma research, an area of interest is the coping strategies that mental health service users can use in response to discriminatory experiences. As a part of the evaluation of the Time to Change (TTC) anti-stigma programme, the Viewpoint telephone survey was run annually in order to assess service users' reported levels of discrimination and selected coping strategies. The study aim is to test the extent to which experience of TTC programme is a positive predictor of selected coping strategies. METHODS: Telephone interview surveys carried out by peer interviewers were conducted annually. 'Educating others' and 'challenging' coping strategies were assessed alongside anticipated and experienced discrimination. RESULTS: During 2011-2014, 3903 mental health service users were interviewed. Participants more often adopted the 'educating others' strategy (2.31 +/- 0.01) than the 'challenging' strategy (2.15 +/- 0.02) (p < 0.001). On the other hand, those who participated in campaign activities endorsed 'challenging' more frequently than people who were not aware of TTC (2.78 +/- 1.23 v. 2.09 +/- 1.08, p < 0.001). According to the multi-variate linear regression model, we found that being actively involved in TTC activities (OR = 0.74, CI: 0.29-1.19; p < 0.05), having a diagnosis of a depressive disorder (OR = 0.20, CI: 0.04-0.36; p < 0.05) or personality disorder (OR = 0.23, CI: 0.04 0.43; p < 0.05) were good predictors of endorsing a 'challenging' strategy even after adjusted for confounding variables. CONCLUSIONS: A positive relationship between participating in the TTC programme and using the 'challenging' strategy was found. There is still a need to disentangle the complex association between these two coping strategies and the role of anti-stigma campaigns, promoting further local activities led by service users and carers' as well as all others stakeholders' associations. PMID- 27466084 TI - Three-Dimensional Polymeric Mechanical Metamaterials Fabricated by Multibeam Interference Lithography with the Assistance of Plasma Etching. AB - The pentamode structure is a type of mechanical metamaterial that displays dramatically different bulk and shear modulus responses. In this study, a face centered cubic (FCC) polymeric microstructure was fabricated by using SU8 negative-type photoresists and multibeam interference exposure. Isotropic plasma etching is used to control the solid-volume fraction; for the first time, we obtained a structure with the minimum solid-volume fraction as low as 15% that still exhibited high structural integrity. Using this method, we reduced the width of atom-to-atom connections by up to 40 nm. We characterize the effect of the connection area on the anisotropy of the mechanical properties using simulations. Nanoindentation measurements were also conducted to evaluate the energy dissipation by varying the connection area. The Young's/shear modulus ratio is 5 times higher for the etched microstructure than that of the bulk SU8 materials. The use of interference lithography may enable the properties of microscale materials to be engineered for various applications, such as MEMS. PMID- 27466085 TI - Is physical education an effective way to increase physical activity in children with lower cardiorespiratory fitness? AB - Several findings revealed the importance of accruing moderate and vigorous physical activity (MVPA) to improve health. Physical education (PE) may play an important role on promoting children's MVPA. However, it remains unknown whether PE might be effective when increasing physical activity (PA) levels in children with lower cardiorespiratory fitness (CRF). Therefore, the aim of this study was to assess children's PA during PE and during days with and without PE with a special focus on CRF status. One hundred and fifty Spanish children and adolescents from 3rd to 12th grade were recruited. PA levels were assessed with GT3X accelerometers. Peak oxygen uptake (VO2peak ) was estimated using a portable breath by breath Metamax 3B. Participants were classified as healthy aerobic fitness (HAF) and unhealthy aerobic fitness (UHAF) according to standardized cut off point criteria. During PE, students with HAF accrued more MVPA than those with UHAF (8.7 vs 5.7 min/session; P <= 0.001). MVPA was higher on PE days than days without for both UHAF (50.0 vs 42.7 min/day; P <= 0.05) and HAF students (56.9 vs 49.4 min/day; P <= 0.05). Although less active during PE, students with lower CRF accumulated more MVPA and total PA on PE days than days without PE. An increase in PE days might be a smart policy to raise the recommended PA levels, regardless of CRF status. PMID- 27466086 TI - Determination of ferroelectric contributions to electromechanical response by frequency dependent piezoresponse force microscopy. AB - Hysteresis loop analysis via piezoresponse force microscopy (PFM) is typically performed to probe the existence of ferroelectricity at the nanoscale. However, such an approach is rather complex in accurately determining the pure contribution of ferroelectricity to the PFM. Here, we suggest a facile method to discriminate the ferroelectric effect from the electromechanical (EM) response through the use of frequency dependent ac amplitude sweep with combination of hysteresis loops in PFM. Our combined study through experimental and theoretical approaches verifies that this method can be used as a new tool to differentiate the ferroelectric effect from the other factors that contribute to the EM response. PMID- 27466087 TI - More support for clinical trials in children. PMID- 27466088 TI - Agencies must show that basic research is worth the investment. PMID- 27466089 TI - Time to remodel the journal impact factor. PMID- 27466090 TI - Resilient British science will withstand Brexit. PMID- 27466102 TI - Trump vs Clinton: worlds apart on science. PMID- 27466103 TI - Planet hunters seek new ways to detect alien life. PMID- 27466104 TI - Brazil asks whether Zika acts alone to cause birth defects. PMID- 27466105 TI - Chinese scientists to pioneer first human CRISPR trial. PMID- 27466106 TI - Europe's premier funding agency measures its impact. PMID- 27466107 TI - Chinese satellite is one giant step for the quantum internet. PMID- 27466108 TI - Correction. PMID- 27466109 TI - 180,000 forgotten photos reveal the future of Greenland's ice. PMID- 27466110 TI - Tapping genetics for better beer. PMID- 27466111 TI - Lessons from Brexit. PMID- 27466112 TI - Science fiction: The science that fed Frankenstein. PMID- 27466114 TI - Sustainable Development Goals: diseases that neglect no goals. PMID- 27466115 TI - Great apes: Fresh strategies to save orangutans. PMID- 27466116 TI - Conservation practice: A very preventable mammal extinction. PMID- 27466117 TI - Preprint servers: Vet reproducibility of biology preprints. PMID- 27466118 TI - Sustainable Development Goals: create a coordinating body. PMID- 27466119 TI - Climate science: Unexpected fix for ocean models. PMID- 27466120 TI - Solar physics: Dynamo theory questioned. PMID- 27466121 TI - Microbiology: Antibiotics right under our nose. PMID- 27466122 TI - In retrospect: Thirty-five years of endless cell potential. PMID- 27466123 TI - Human commensals producing a novel antibiotic impair pathogen colonization. AB - The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics. PMID- 27466124 TI - Solar-type dynamo behaviour in fully convective stars without a tachocline. AB - In solar-type stars (with radiative cores and convective envelopes like our Sun), the magnetic field powers star spots, flares and other solar phenomena, as well as chromospheric and coronal emission at ultraviolet to X-ray wavelengths. The dynamo responsible for generating the field depends on the shearing of internal magnetic fields by differential rotation. The shearing has long been thought to take place in a boundary layer known as the tachocline between the radiative core and the convective envelope. Fully convective stars do not have a tachocline and their dynamo mechanism is expected to be very different, although its exact form and physical dependencies are not known. Here we report observations of four fully convective stars whose X-ray emission correlates with their rotation periods in the same way as in solar-type stars. As the X-ray activity-rotation relationship is a well-established proxy for the behaviour of the magnetic dynamo, these results imply that fully convective stars also operate a solar-type dynamo. The lack of a tachocline in fully convective stars therefore suggests that this is not a critical ingredient in the solar dynamo and supports models in which the dynamo originates throughout the convection zone. PMID- 27466125 TI - Combinatorial design of textured mechanical metamaterials. AB - The structural complexity of metamaterials is limitless, but, in practice, most designs comprise periodic architectures that lead to materials with spatially homogeneous features. More advanced applications in soft robotics, prosthetics and wearable technology involve spatially textured mechanical functionality, which requires aperiodic architectures. However, a naive implementation of such structural complexity invariably leads to geometrical frustration (whereby local constraints cannot be satisfied everywhere), which prevents coherent operation and impedes functionality. Here we introduce a combinatorial strategy for the design of aperiodic, yet frustration-free, mechanical metamaterials that exhibit spatially textured functionalities. We implement this strategy using cubic building blocks-voxels-that deform anisotropically, a local stacking rule that allows cooperative shape changes by guaranteeing that deformed building blocks fit together as in a three-dimensional jigsaw puzzle, and three-dimensional printing. These aperiodic metamaterials exhibit long-range holographic order, whereby the two-dimensional pixelated surface texture dictates the three dimensional interior voxel arrangement. They also act as programmable shape shifters, morphing into spatially complex, but predictable and designable, shapes when uniaxially compressed. Finally, their mechanical response to compression by a textured surface reveals their ability to perform sensing and pattern analysis. Combinatorial design thus opens up a new avenue towards mechanical metamaterials with unusual order and machine-like functionalities. PMID- 27466126 TI - Western boundary currents regulated by interaction between ocean eddies and the atmosphere. AB - Current climate models systematically underestimate the strength of oceanic fronts associated with strong western boundary currents, such as the Kuroshio and Gulf Stream Extensions, and have difficulty simulating their positions at the mid latitude ocean's western boundaries. Even with an enhanced grid resolution to resolve ocean mesoscale eddies-energetic circulations with horizontal scales of about a hundred kilometres that strongly interact with the fronts and currents the bias problem can still persist; to improve climate models we need a better understanding of the dynamics governing these oceanic frontal regimes. Yet prevailing theories about the western boundary fronts are based on ocean internal dynamics without taking into consideration the intense air-sea feedbacks in these oceanic frontal regions. Here, by focusing on the Kuroshio Extension Jet east of Japan as the direct continuation of the Kuroshio, we show that feedback between ocean mesoscale eddies and the atmosphere (OME-A) is fundamental to the dynamics and control of these energetic currents. Suppressing OME-A feedback in eddy resolving coupled climate model simulations results in a 20-40 per cent weakening in the Kuroshio Extension Jet. This is because OME-A feedback dominates eddy potential energy destruction, which dissipates more than 70 per cent of the eddy potential energy extracted from the Kuroshio Extension Jet. The absence of OME-A feedback inevitably leads to a reduction in eddy potential energy production in order to balance the energy budget, which results in a weakened mean current. The finding has important implications for improving climate models' representation of major oceanic fronts, which are essential components in the simulation and prediction of extratropical storms and other extreme events, as well as in the projection of the effect on these events of climate change. PMID- 27466127 TI - Transfer of mitochondria from astrocytes to neurons after stroke. AB - Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling. This ability to exchange mitochondria may represent a potential mode of cell-to-cell signalling in the central nervous system. Here we show that astrocytes in mice can also release functional mitochondria that enter neurons. Astrocytic release of extracellular mitochondrial particles was mediated by a calcium-dependent mechanism involving CD38 and cyclic ADP ribose signalling. Transient focal cerebral ischaemia in mice induced entry of astrocytic mitochondria into adjacent neurons, and this entry amplified cell survival signals. Suppression of CD38 signalling by short interfering RNA reduced extracellular mitochondria transfer and worsened neurological outcomes. These findings suggest a new mitochondrial mechanism of neuroglial crosstalk that may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke. PMID- 27466129 TI - Eye tracking a self-moved target with complex hand-target dynamics. AB - Previous work has shown that the ability to track with the eye a moving target is substantially improved when the target is self-moved by the subject's hand compared with when being externally moved. Here, we explored a situation in which the mapping between hand movement and target motion was perturbed by simulating an elastic relationship between the hand and target. Our objective was to determine whether the predictive mechanisms driving eye-hand coordination could be updated to accommodate this complex hand-target dynamics. To fully appreciate the behavioral effects of this perturbation, we compared eye tracking performance when self-moving a target with a rigid mapping (simple) and a spring mapping as well as when the subject tracked target trajectories that he/she had previously generated when using the rigid or spring mapping. Concerning the rigid mapping, our results confirmed that smooth pursuit was more accurate when the target was self-moved than externally moved. In contrast, with the spring mapping, eye tracking had initially similar low spatial accuracy (though shorter temporal lag) in the self versus externally moved conditions. However, within ~5 min of practice, smooth pursuit improved in the self-moved spring condition, up to a level similar to the self-moved rigid condition. Subsequently, when the mapping unexpectedly switched from spring to rigid, the eye initially followed the expected target trajectory and not the real one, thereby suggesting that subjects used an internal representation of the new hand-target dynamics. Overall, these results emphasize the stunning adaptability of smooth pursuit when self maneuvering objects with complex dynamics. PMID- 27466130 TI - Upslope treadmill exercise enhances motor axon regeneration but not functional recovery following peripheral nerve injury. AB - Following peripheral nerve injury, moderate daily exercise conducted on a level treadmill results in enhanced axon regeneration and modest improvements in functional recovery. If the exercise is conducted on an upwardly inclined treadmill, even more motor axons regenerate successfully and reinnervate muscle targets. Whether this increased motor axon regeneration also results in greater improvement in functional recovery from sciatic nerve injury was studied. Axon regeneration and muscle reinnervation were studied in Lewis rats over an 11 wk postinjury period using stimulus evoked electromyographic (EMG) responses in the soleus muscle of awake animals. Motor axon regeneration and muscle reinnervation were enhanced in slope-trained rats. Direct muscle (M) responses reappeared faster in slope-trained animals than in other groups and ultimately were larger than untreated animals. The amplitude of monosynaptic H reflexes recorded from slope-trained rats remained significantly smaller than all other groups of animals for the duration of the study. The restoration of the amplitude and pattern of locomotor EMG activity in soleus and tibialis anterior and of hindblimb kinematics was studied during treadmill walking on different slopes. Slope-trained rats did not recover the ability to modulate the intensity of locomotor EMG activity with slope. Patterned EMG activity in flexor and extensor muscles was not noted in slope-trained rats. Neither hindblimb length nor limb orientation during level, upslope, or downslope walking was restored in slope trained rats. Slope training enhanced motor axon regeneration but did not improve functional recovery following sciatic nerve transection and repair. PMID- 27466131 TI - Attenuation of visual reafferent signals in the parietal cortex during voluntary movement. AB - It is well established that the cortical processing of somatosensory and auditory signals is attenuated when they result from self-generated actions compared with external events. This phenomenon is thought to result from an efference copy of motor commands used to predict the sensory consequences of an action through a forward model. The present work examined whether attenuation also takes place for visual reafferent signals from the moving limb during voluntary reaching movements. To address this issue, EEG activity was recorded in a condition in which visual feedback of the hand was provided in real time and compared with a condition in which it was presented with a 150-ms delay, thus creating a mismatch between the predicted and actual visual consequences of the movement. Results revealed that the amplitude of the N1 component of the visual event-related potential evoked by hand visual feedback over the parietal cortex was significantly smaller when presented in real time compared with when it was delayed. These data suggest that the cortical processing of visual reafferent signals is attenuated when they are correctly predicted, likely as a result of a forward model. PMID- 27466132 TI - Functional versus effector-specific organization of the human posterior parietal cortex: revisited. AB - It has been proposed that the posterior parietal cortex (PPC) is characterized by an effector-specific organization. However, strikingly similar functional MRI (fMRI) activation patterns have been found in the PPC for hand and foot movements. Because the fMRI signal is related to average neuronal activity, similar activation levels may result either from effector-unspecific neurons or from intermingled subsets of effector-specific neurons within a voxel. We distinguished between these possibilities using fMRI repetition suppression (RS). Participants made delayed, goal-directed eye, hand, and foot movements to visual targets. In each trial, the instructed effector was identical or different to that of the previous trial. RS effects indicated an attenuation of the fMRI signal in repeat trials. The caudal PPC was active during the delay but did not show RS, suggesting that its planning activity was effector independent. Hand and foot-specific RS effects were evident in the anterior superior parietal lobule (SPL), extending to the premotor cortex, with limb overlap in the anterior SPL. Connectivity analysis suggested information flow between the caudal PPC to limb specific anterior SPL regions and between the limb-unspecific anterior SPL toward limb-specific motor regions. These results underline that both function and effector specificity should be integrated into a concept of PPC action representation not only on a regional but also on a fine-grained, subvoxel level. PMID- 27466133 TI - Dynamics of excitatory and inhibitory networks are differentially altered by selective attention. AB - Inhibition and excitation form two fundamental modes of neuronal interaction, yet we understand relatively little about their distinct roles in service of perceptual and cognitive processes. We developed a multidimensional waveform analysis to identify fast-spiking (putative inhibitory) and regular-spiking (putative excitatory) neurons in vivo and used this method to analyze how attention affects these two cell classes in visual area V4 of the extrastriate cortex of rhesus macaques. We found that putative inhibitory neurons had both greater increases in firing rate and decreases in correlated variability with attention compared with putative excitatory neurons. Moreover, the time course of attention effects for putative inhibitory neurons more closely tracked the temporal statistics of target probability in our task. Finally, the session-to session variability in a behavioral measure of attention covaried with the magnitude of this effect. Together, these results suggest that selective targeting of inhibitory neurons and networks is a critical mechanism for attentional modulation. PMID- 27466134 TI - Repetition priming of motor activity mediated by a central pattern generator: the importance of extrinsic vs. intrinsic program initiators. AB - Repetition priming is characterized by increased performance as a behavior is repeated. Although this phenomenon is ubiquitous, mediating mechanisms are poorly understood. We address this issue in a model system, the feeding network of Aplysia This network generates both ingestive and egestive motor programs. Previous data suggest a chemical coding model: ingestive and egestive inputs to the feeding central pattern generator (CPG) release different modulators, which act via different second messengers to prime motor activity in different ways. The ingestive input to the CPG (neuron CBI-2) releases the peptides feeding circuit activating peptide and cerebral peptide 2, which produce an ingestive pattern of activity. The egestive input to the CPG (the esophageal nerve) releases the peptide small cardioactive peptide. This model is based on research that focused on a single aspect of motor control (radula opening). Here we ask whether repetition priming is observed if activity is triggered with a neuron within the core CPG itself and demonstrate that it is not. Moreover, previous studies demonstrated that effects of modulatory neurotransmitters that induce repetition priming persist. This suggests that it should be possible to "prime" motor programs triggered from within the CPG by first stimulating extrinsic modulatory inputs. We demonstrate that programs triggered after ingestive input activation are ingestive and programs triggered after egestive input activation are egestive. We ask where this priming occurs and demonstrate modifications within the CPG itself. This arrangement is likely to have important consequences for "task" switching, i.e., the cessation of one type of motor activity and the initiation of another. PMID- 27466136 TI - Magnetoencephalography-based identification of functional connectivity network disruption following mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) leads to long-term cognitive sequelae in a significant portion of patients. Disruption of normal neural communication across functional brain networks may explain the deficits in memory and attention observed after mTBI. In this study, we used magnetoencephalography (MEG) to examine functional connectivity during a resting state in a group of mTBI subjects (n = 9) compared with age-matched control subjects (n = 15). We adopted a data-driven, exploratory analysis in source space using phase locking value across different frequency bands. We observed a significant reduction in functional connectivity in band-specific networks in mTBI compared with control subjects. These networks spanned multiple cortical regions involved in the default mode network (DMN). The DMN is thought to subserve memory and attention during periods when an individual is not engaged in a specific task, and its disruption may lead to cognitive deficits after mTBI. We further applied graph theoretical analysis on the functional connectivity matrices. Our data suggest reduced local efficiency in different brain regions in mTBI patients. In conclusion, MEG can be a potential tool to investigate and detect network alterations in patients with mTBI. The value of MEG to reveal potential neurophysiological biomarkers for mTBI patients warrants further exploration. PMID- 27466137 TI - Serum indoleamine 2,3 dioxygenase and tryptophan and kynurenine ratio using the UPLC-MS/MS method, in patients undergoing peritoneal dialysis, hemodialysis, and kidney transplantation. AB - BACKGROUND: The level and activity of indoleamine 2,3-dioxygenase (IDO) and the concentrations of L-tryptophan and its metabolite L-kynurenine were determined in association with various renal diseases. However, there have been no data regarding these parameters in patients on peritoneal dialysis compared to those undergoing hemodialysis or kidney transplantation. METHODS: This study investigated the level and activity of IDO and determined oxidative balance by calculating the total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI). We enrolled 60 kidney disease patients, including 20 on peritoneal dialysis (PD group), 19 on hemodialysis (HD group), and 21 with kidney transplantation (KT group), as well as 21 control group. RESULTS: IDO levels were increased in the PD, HD, and KT groups compared to the control group. The concentration of kynurenine was significantly increased in the PD group compared to the other groups (p < 0.01). The kynurenine/tryptophan ratio was increased in the PD group compared to the other groups (all p < 0.01). TAS levels in the PD and HD groups were significantly decreased compared to the control group (both p < 0.05). TAS levels in the PD group were significantly decreased compared to the KT group. TOS levels in the PD group were higher than in the HD and KT groups. CONCLUSION: The results showed that IDO levels were increased in peritoneal dialysis and hemodialysis patients and in renal transplant recipients, while oxidative stress was found to be related to IDO activity and was most increased in the patients on peritoneal dialysis. PMID- 27466138 TI - Normal lactate concentration range in the neonatal brain. AB - OBJECTIVE: Lactate peaks are occasionally observed during in vivo magnetic resonance spectroscopy (MRS) scans of the neonatal brain, even in healthy patients. The purpose of this study was to investigate the normal range of neonatal brain lactate concentration, as a definitive normal range would be clinically valuable. METHODS: Using a clinical 3T scanner (echo/repetition times, 30/5000ms), single-voxel MRS data were obtained from the basal ganglia (BG) and centrum semiovale (CS) in 48 healthy neonates (postconceptional age (PCA), 30 43weeks), nine infants (age, 1-12months old), and 20 children (age, 4-15years). Lactate concentrations were calculated using an MRS signal quantification program, LCModel. Correlations between regional lactate concentration and PCA (neonates), or age (all subjects) were investigated. RESULTS: Absolute lactate concentrations of the BG and CS were as follows: neonates, 0.77mM (0-2.02) [median (range)] and 0.77 (0-1.42), respectively; infants, 0.38 (0-0.79) and 0.49 (0.17-1.17); and children, 0.17 (0-0.76) and 0.22 (0-0.80). Overall, subjects' lactate concentrations decreased significantly with age (Spearman: BG, n=61, rho= 0.38, p=0.003; CS, n=68, rho=-0.57, p<0.001). However, during the neonatal period no correlations were detected between lactate concentration in either region and PCA. CONCLUSION: We determined normal ranges of neonatal lactate concentration, which may prove useful for diagnostic purposes. Further studies regarding changes in brain lactate concentration during development would help clarify the reasons for higher concentrations observed during the neonatal period, and contribute to improvements in diagnoses. PMID- 27466135 TI - Contrast response functions in the visual wulst of the alert burrowing owl: a single-unit study. AB - The neuronal representation of luminance contrast has not been thoroughly studied in birds. Here we present a detailed quantitative analysis of the contrast response of 120 individual neurons recorded from the visual wulst of awake burrowing owls (Athene cunicularia). Stimuli were sine-wave gratings presented within the cell classical receptive field and optimized in terms of eye preference, direction of drift, and spatiotemporal frequency. As contrast intensity was increased from zero to near 100%, most cells exhibited a monotonic response profile with a compressive, at times saturating, nonlinearity at higher contrasts. However, contrast response functions were found to have a highly variable shape across cells. With the view to capture a systematic trend in the data, we assessed the performance of four plausible models (linear, power, logarithmic, and hyperbolic ratio) using classical goodness-of-fit measures and more rigorous statistical tools for multimodel inferences based on the Akaike information criterion. From this analysis, we conclude that a high degree of model uncertainty is present in our data, meaning that no single descriptor is able on its own to capture the heterogeneous nature of single-unit contrast responses in the wulst. We further show that the generalizability of the hyperbolic ratio model established, for example, in the primary visual cortex of cats and monkeys is not tenable in the owl wulst mainly because most neurons in this area have a much wider dynamic range that starts at low contrast. The challenge for future research will be to understand the functional implications of these findings. PMID- 27466141 TI - Posterior and anterior cortex - where is the difference that makes the difference? PMID- 27466139 TI - Altered protein phosphorylation as a resource for potential AD biomarkers. AB - The amyloidogenic peptide, Abeta, provokes a series of events affecting distinct cellular pathways regulated by protein phosphorylation. Abeta inhibits protein phosphatases in a dose-dependent manner, thus it is expected that the phosphorylation state of specific proteins would be altered in response to Abeta. In fact several Alzheimer's disease related proteins, such as APP and TAU, exhibit pathology associated hyperphosphorylated states. A systems biology approach was adopted and the phosphoproteome, of primary cortical neuronal cells exposed to Abeta, was evaluated. Phosphorylated proteins were recovered and those whose recovery increased or decreased, upon Abeta exposure across experimental sets, were identified. Significant differences were evident for 141 proteins and investigation of their interactors revealed key protein clusters responsive to Abeta treatment. Of these, 73 phosphorylated proteins increased and 68 decreased upon Abeta addition. These phosphorylated proteins represent an important resource of potential AD phospho biomarkers that should be further pursued. PMID- 27466140 TI - Acoustofluidic actuation of in situ fabricated microrotors. AB - We have demonstrated in situ fabricated and acoustically actuated microrotors. A polymeric microrotor with predefined oscillating sharp-edge structures is fabricated in situ by applying a patterned UV light to polymerize a photocrosslinkable polyethylene glycol solution inside a microchannel around a polydimethylsiloxane axle. To actuate the microrotors by oscillating the sharp edge structures, we employed piezoelectric transducers which generate tunable acoustic waves. The resulting acoustic streaming flows rotate the microrotors. The rotation rate is tuned by controlling the peak-to-peak voltage applied to the transducer. A 6-arm microrotor can exceed 1200 revolutions per minute. Our technique is an integration of single-step microfabrication, instant assembly around the axle, and easy acoustic actuation for various applications in microfluidics and microelectromechanical systems (MEMS). PMID- 27466142 TI - Meanings of self-grooming depend on an inverted U-shaped function with aversiveness. PMID- 27466144 TI - Decision making: Making your mind up. PMID- 27466145 TI - Spatial processing: Location, location, location. PMID- 27466143 TI - The enigmatic mossy cell of the dentate gyrus. AB - Mossy cells comprise a large fraction of the cells in the hippocampal dentate gyrus, suggesting that their function in this region is important. They are vulnerable to ischaemia, traumatic brain injury and seizures, and their loss could contribute to dentate gyrus dysfunction in such conditions. Mossy cell function has been unclear because these cells innervate both glutamatergic and GABAergic neurons within the dentate gyrus, contributing to a complex circuitry. It has also been difficult to directly and selectively manipulate mossy cells to study their function. In light of the new data generated using methods to preferentially eliminate or activate mossy cells in mice, it is timely to ask whether mossy cells have become any less enigmatic than they were in the past. PMID- 27466146 TI - 'Stressing' rodent self-grooming for neuroscience research. PMID- 27466148 TI - Neuroimmunology: Immune to the placebo effect. PMID- 27466147 TI - Neurophysiology: Going with the flow. PMID- 27466149 TI - Future directions for identifying the neural correlates of consciousness. PMID- 27466151 TI - Nearly massless Dirac fermions hosted by Sb square net in BaMnSb2. AB - Layered compounds AMnBi2 (A = Ca, Sr, Ba, or rare earth element) have been established as Dirac materials. Dirac electrons generated by the two-dimensional (2D) Bi square net in these materials are normally massive due to the presence of a spin-orbital coupling (SOC) induced gap at Dirac nodes. Here we report that the Sb square net in an isostructural compound BaMnSb2 can host nearly massless Dirac fermions. We observed strong Shubnikov-de Haas (SdH) oscillations in this material. From the analyses of the SdH oscillations, we find key signatures of Dirac fermions, including light effective mass (~0.052m0; m0, mass of free electron), high quantum mobility (1280 cm(2)V(-1)S(-1)) and a pi Berry phase accumulated along cyclotron orbit. Compared with AMnBi2, BaMnSb2 also exhibits much more significant quasi two-dimensional (2D) electronic structure, with the out-of-plane transport showing nonmetallic conduction below 120 K and the ratio of the out-of-plane and in-plane resistivity reaching ~670. Additionally, BaMnSb2 also exhibits a G-type antiferromagnetic order below 283 K. The combination of nearly massless Dirac fermions on quasi-2D planes with a magnetic order makes BaMnSb2 an intriguing platform for seeking novel exotic phenomena of massless Dirac electrons. PMID- 27466152 TI - Isolation and Characterization, Including by X-ray Crystallography, of Contact and Solvent-Separated Ion Pairs of Silenyl Lithium Species. AB - Reaction of bromoacylsilane 1 (pink solution) with tBu2 MeSiLi (3.5 equiv) in a 4:1 hexane:THF solvent mixture at -78 degrees C to room temperature yields the solvent separated ion pair (SSIP) of silenyl lithium E-[(tBuMe2 Si)(tBu2 MeSi)C=Si(SiMetBu2 )](-) [Li?4THF](+) 2 a (green-blue solution). Removal of the solvent and addition of benzene converts 2 a into the corresponding contact ion pair (CIP) 2 b (violet-red solution) with two THF molecules bonded to the lithium atom. The 2 a?2 b interconversion is reversible upon THF? benzene solvent change. Both 2 a and 2 b were characterized by X-ray crystallography, NMR and UV/Vis spectroscopy, and theoretical calculations. The degree of dissociation of the Si Li bond has a large effect on the visible spectrum (and thus color) and on the silenylic (29) Si NMR chemical shift, but a small effect on the molecular structure. This is the first report of the X-ray molecular structure of both the SSIP and the CIP of any R2 E=E'RM species (E=C, Si; E'=C, Si; M=metal). PMID- 27466150 TI - Adhesion G protein-coupled receptors in nervous system development and disease. AB - Members of the adhesion G protein-coupled receptor (aGPCR) class have emerged as crucial regulators of nervous system development, with important implications for human health and disease. In this Review, we discuss the current understanding of aGPCR functions during key steps in neural development, including cortical patterning, dendrite and synapse formation, and myelination. We focus on aGPCR modulation of cell-cell and cell-matrix interactions and signalling to control these varied aspects of neural development, and we discuss how impaired aGPCR function leads to neurological disease. We further highlight the emerging hypothesis that aGPCRs can be mechanically activated and the implications of this property in the nervous system. PMID- 27466153 TI - Direct Measurement of Electron Transfer in Nanoscale Host-Guest Systems: Metallocenes in Carbon Nanotubes. AB - Electron-transfer processes play a significant role in host-guest interactions and determine physicochemical phenomena emerging at the nanoscale that can be harnessed in electronic or optical devices, as well as biochemical and catalytic systems. A novel method for qualifying and quantifying the electronic doping of single walled carbon nanotubes (SWNTs) using electrochemistry has been developed that establishes a direct link between these experimental measurements and ab initio DFT calculations. Metallocenes such as cobaltocene and methylated ferrocene derivatives were encapsulated inside SWNTs (1.4 nm diameter) and cyclic voltammetry (CV) was performed on the resultant host-guest systems. The electron transfer between the guest molecules and the host SWNTs is measured as a function of shift in the redox potential (E1/2 ) of Co(II) /Co(I) , Co(III) /Co(II) and Fe(III) /Fe(II) . Furthermore, the shift in E1/2 is inversely proportional to the nanotube diameter. To quantify the amount of electron transfer from the guest molecules to the SWNTs, a novel method using coulometry was developed, allowing the mapping of the density of states and the Fermi level of the SWNTs. Correlated with theoretical calculations, coulometry provides an accurate indication of n/p doping of the SWNTs. PMID- 27466154 TI - A procedure for comprehensive two-dimensional gas chromatography retention time locked dual detection. AB - In this paper, a novel, and easy to perform, retention time locking procedure for locking primary and secondary retention times of detector signals in comprehensive two-dimensional gas chromatography (GCxGC) dual-detection is proposed and its advantages are demonstrated and discussed. The dual detection retention time locking procedure is a 2-step process for a GCxGC system in which the effluent of the primary column is split, by using a pressure regulated splitter, towards the GCxGC modulator using two identical secondary GC columns of which one is installed in the main GC oven and the other is installed in a secondary GC oven. The first step of the locking procedure is to minimize the secondary retention time difference between both detectors of a compound, which has a retention factor (k) close to 0. This is done by stepwise altering the effective secondary column length, simply by sliding the secondary column, which is installed in the main oven, forwards or backwards through the modulator. The second step is to minimize the secondary retention time difference of a compound which has a significant retention in both dimensions. This is done by stepwise altering the secondary oven temperature rate. This locking procedure was successfully demonstrated for the analysis of a diesel sample by GCxGC coupled to a time of flight mass spectrometer (TOFMS) and a nitrogen chemiluminescence detector (NCD) and by GCxGC coupled to a TOFMS and a flame ionization detector (FID). For all compounds the average absolute secondary retention time differences between the NCD or the FID and the TOFMS detectors were 0.03, and 0.07s, respectively, which are significantly less than the average peak widths at half heights, which was 0.2s. PMID- 27466155 TI - Rapamycin increases RSV RNA levels and survival of RSV-infected dendritic cell depending on T cell contact. AB - The macrolide rapamycin inhibits mTOR (mechanist target of rapamycin) function and has been broadly used to unveil the role of mTOR in immune responses. Inhibition of mTOR on dendritic cells (DC) can influence cellular immune response and the survival of DC. RSV is the most common cause of hospitalization in infants and is a high priority candidate to vaccine development. In this study we showed that rapamycin treatment on RSV-infected murine bone marrow-derived DC (BMDC) decreases the frequency of CD8(+)CD44(high) T cells. However, inhibition of mTOR on RSV-infected BMDC did not modify the activation phenotype of these cells. RSV-RNA levels increase when infected BMDC were treated with rapamycin. Moreover, we observed that rapamycin diminishes apoptosis cell death of RSV infected BMDC co-culture with T cells and this effect was abolished when the cells were co-cultured in a transwell system that prevents cell-to-cell contact or migration. Taken together, these data indicate that rapamycin treatment present a toxic effect on RSV-infected BMDC increasing RSV-RNA levels, affecting partially CD8 T cell differentiation and also increasing BMDC survival in a mechanism dependent on T cell contact. PMID- 27466156 TI - Hospital closures and the current healthcare climate: the future of rural hospitals in the USA. AB - Hospital closures occur from time to time. These closures affect not only the patients that depend on the hospitals but also the economy in many rural areas. Many factors come into play when a hospital decides to shut off services. Although influencing reasons may vary, hospital closures are likely to be caused by financial shortfalls. In the USA recently, several rural hospitals have closed and many are on the verge of closing. The recent changes in the healthcare industry due to the new reforms are believed to have impacted certain small community and rural hospitals by putting them at risk of closure. In this article, we will discuss some of the highlights of the healthcare reforms and the events that followed, to relate how they may have affected the hospitals. We will also discuss what the future of these hospitals may look like and the necessary steps that the hospitals need to adopt to sustain themselves. PMID- 27466157 TI - Characterizing structural neural networks in de novo Parkinson disease patients using diffusion tensor imaging. AB - Parkinson disease (PD) can be considered as a brain multisystemic disease arising from dysfunction in several neural networks. The principal aim of this study was to assess whether large-scale structural topological network changes are detectable in PD patients who have not been exposed yet to dopaminergic therapy (de novo patients). Twenty-one drug-naive PD patients and thirty healthy controls underwent a 3T structural MRI. Next, Diffusion Tensor Imaging (DTI) and graph theoretic analyses to compute individual structural white-matter (WM) networks were combined. Centrality (degree, eigenvector centrality), segregation (clustering coefficient), and integration measures (efficiency, path length) were assessed in subject-specific structural networks. Moreover, Network-based statistic (NBS) was used to identify whether and which subnetworks were significantly different between PD and control participants. De novo PD patients showed decreased clustering coefficient and strength in specific brain regions such as putamen, pallidum, amygdala, and olfactory cortex compared with healthy controls. Moreover, NBS analyses demonstrated that two specific subnetworks of reduced connectivity characterized the WM structural organization of PD patients. In particular, several key pathways in the limbic system, basal ganglia, and sensorimotor circuits showed reduced patterns of communications when comparing PD patients to controls. This study shows that PD is characterized by a disruption in the structural connectivity of several motor and non-motor regions. These findings provide support to the presence of disconnectivity mechanisms in motor (basal ganglia) as well as in non-motor (e.g., limbic, olfactory) circuits at an early disease stage of PD. Hum Brain Mapp 37:4500-4510, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27466158 TI - Influence of False Lumen Status on the Prognosis of Acute Type A Aortic Dissection without Urgent Surgical Treatment. AB - AIM: Recently, much attention has been focused on partial thrombosis of the false lumen in patients with acute aortic dissection. However, its effect on clinical outcomes in these patients, especially in case of acute type A aortic dissection, has not been clearly elucidated. This study evaluated the influence of the false lumen status, including partial thrombosis, on short-term clinical outcomes in acute type A aortic dissection patients without urgent surgical treatment. METHODS: Sixty-two patients (29 males, mean age 73+/-13 years) with acute type A aortic dissection who did not receive urgent surgical treatment at four hospitals were enrolled. Patients were divided into three groups based on the false lumen status on enhanced computed tomography image (complete thrombosis, n=28; partial thrombosis, n=27; patent, n=7). Patients with partial thrombosis were further divided into two groups (thrombus-dominant, n=15; flow-dominant, n=12). RESULTS: The short-term mortality rate (in-hospital and 30-day) was significantly higher in patients with a patent false lumen, while no significant difference was seen between the other two groups. Patients with flow-dominant partial thrombosis had significantly higher short-term mortality rate than those with thrombus-dominant partial thrombosis (in-hospital, p=0.001 and 30-day, p<0.001). CONCLUSIONS: The short-term mortality rate in acute type A aortic dissection patients without urgent surgical treatment was lower in patients with partial thrombosis of the false lumen than in those with a patent false lumen. Furthermore, patients with flow-dominant partial thrombosis had higher mortality rate than those with thrombus-dominant partial thrombosis. PMID- 27466159 TI - Development of Antisense Drugs for Dyslipidemia. AB - Abnormal elevation of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins in plasma as well as dysfunction of anti-atherogenic high-density lipoprotein (HDL) have both been recognized as essential components of the pathogenesis of atherosclerosis and are classified as dyslipidemia. This review describes the arc of development of antisense oligonucleotides for the treatment of dyslipidemia. Chemically-armed antisense candidates can act on various kinds of transcripts, including mRNA and miRNA, via several different endogenous antisense mechanisms, and have exhibited potent systemic anti-dyslipidemic effects. Here, we present specific cutting-edge technologies have recently been brought into antisense strategies, and describe how they have improved the potency of antisense drugs in regard to pharmacokinetics and pharmacodynamics. In addition, we discuss perspectives for the use of armed antisense oligonucleotides as new clinical options for dyslipidemia, in the light of outcomes of recent clinical trials and safety concerns indicated by several clinical and preclinical studies. PMID- 27466160 TI - Transcription Factor Trps1 Promotes Tubular Cell Proliferation after Ischemia Reperfusion Injury through cAMP-Specific 3',5'-Cyclic Phosphodiesterase 4D and AKT. AB - Trichorhinophalangeal 1 (Trps1) is a transcription factor essential for epithelial cell morphogenesis during kidney development, but the role of Trps1 in AKI induced by ischemia-reperfusion (I/R) remains unclear. Our study investigated Trps1 expression during kidney repair after acute I/R in rats and explored the molecular mechanisms by which Trps1 promotes renal tubular epithelial cell proliferation. Trps1 expression positively associated with the extent of renal repair after I/R injury. Compared with wild-type rats, rats with knockdown of Trps1 exhibited significantly delayed renal repair in the moderate I/R model, with lower GFR levels and more severe morphologic injury, whereas rats overexpressing Trps1 exhibited significantly accelerated renal repair after severe I/R injury. Additionally, knockdown of Trps1 inhibited and overexpression of Trps1 enhanced the proliferation of renal tubular epithelial cells in rats. Chromatin immunoprecipitation sequencing assays and RT-PCR revealed that Trps1 regulated cAMP-specific 3',5'-cyclic phosphodiesterase 4D (Pde4d) expression. Knockdown of Trps1 decreased the renal protein expression of Pde4d and phosphorylated Akt in rats, and dual luciferase analysis showed that Trps1 directly activated Pde4d transcription. Furthermore, knockdown of Pde4d or treatment with the phosphatidylinositol 3 kinase inhibitor wortmannin significantly inhibited Trps1-induced tubular cell proliferation in vitro Trps1 may promote tubular cell proliferation through the Pde4d/phosphatidylinositol 3 kinase/AKT signaling pathway, suggesting Trps1 as a potential therapeutic target for kidney repair after I/R injury. PMID- 27466162 TI - Chronic Invasive Pulmonary Aspergillosis in Two Cats with Diabetes Mellitus. AB - Human patients with diabetes mellitus are at increased risk of fungal infections. Diabetes mellitus has also been implicated as a predisposing factor in the establishment of fungal lung infections in cats. Two diabetic cats of different origins presented with severe acute respiratory conditions that resulted in their death. At necropsy examination there was friable, black material in the main bronchi that obstructed the bronchial lumina. Microscopical examination of the lungs revealed the presence of pneumonia, calcium oxalate crystals and a large quantity of fungal hyphae and conidial heads. Fungal infection was confirmed with Grocott's methenamine silver stain. The results of the mycology analysis were compatible with Aspergillus section Nigri. PMID- 27466163 TI - Early Versus Delayed Colonoscopy in Hospitalized Patients With Lower Gastrointestinal Bleeding: A Meta-Analysis. AB - BACKGROUND: Early colonoscopy is recommended for patients with severe lower gastrointestinal bleeding (LGIB). There is limited data as to whether this is associated with improved outcomes. METHODS: We performed a meta-analysis of studies comparing early (<24 h) versus delayed colonoscopy (>24 h). PubMed, Embase, and Web of Science were searched for manuscripts using colonoscopy as a diagnostic/treatment modality for patients hospitalized with LGIB. Studies were included if data were available on outcomes comparing early and delayed colonoscopy. Articles were reviewed for time to colonoscopy, rebleeding, mortality, length of stay (LOS), surgery, interventions, localization of LGIB, and number of packed red blood cells. Pooled measures were reported using the Mantel-Haenszel method. RESULTS: A total of 8491 studies were assessed of which 6 were included. There were 422 patients in the early arm and 479 in the delayed arm. There were no differences in age (64.2 vs. 65.7, P=0.85), admission hemoglobin (10.3 vs. 10.3 g/dL, P=0.96), LOS (5.21 vs. 6.09, P=0.52), and packed red blood cells transfusion (2.37 vs. 2.35, P=0.92) between the groups. In hospital mortality [odds ratio (OR), 1.64; 95% confidence interval (CI), 0.51 5.32], rebleeding (OR, 1.38; 95% CI, 0.85-2.23) and need for surgery (OR, 0.89; 95% CI, 0.42-1.89) were not different in delayed versus early colonoscopy. Early colonoscopy was associated with a higher detection of bleeding source (OR, 2.97; 95% CI, 2.11-4.19) and endoscopic intervention (OR, 3.99; 95% CI, 2.59-6.13). CONCLUSIONS: Early colonoscopy is not associated with reduced rebleeding, LOS, or surgery but is associated with a higher rate of source localization and endoscopic intervention. PMID- 27466164 TI - Mechanism of Increased Intestinal Permeability in Acute Pancreatitis: Alteration in Tight Junction Proteins. AB - BACKGROUND AND AIMS: Intestinal permeability (IP) has been shown to be increased in acute pancreatitis (AP) and is considered to be responsible for development of septic complications. However, the mechanism of increase in IP is not well studied. We studied whether alteration in tight junction proteins (TJP) has any role in altered IP in patients with AP. MATERIALS AND METHODS: This is a prospective study conducted at a tertiary care referral center. Twenty consecutive moderate and severe AP patients fulfilling the study criteria were included along with 20 controls that underwent gastroduodenoscopy for dyspepsia. IP was measured with lactulose mannitol (LM) ratio and TJP were studied by measuring expression of claudin-2 and claudin-4 in duodenal biopsy samples. Statistical analysis was done with STATA 13.0. RESULTS: IP as depicted by LM ratio was significantly higher in AP patients as compared with controls (4.659+/ 10.4 vs. 0.101+/-0.297; P<0.001). Claudin-4 expression was reduced in duodenal biopsies in AP patients (P<0.001 for crypt intercellular junction and P=0.007 for crypt cytoplasm). However, LM ratio was not associated with either mortality (P=0.12) or development of infected pancreatic necrosis (P=0.3). CONCLUSIONS: IP is increased in AP. Alteration in TJP in the form of reduced claudin-4 expressions could be the possible mechanism for increased IP. PMID- 27466161 TI - Informing etiologic research priorities for squamous cell esophageal cancer in Africa: A review of setting-specific exposures to known and putative risk factors. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in most Eastern and Southern African countries, but its etiology has been understudied to date. To inform its research agenda, we undertook a review to identify, of the ESCC risk factors which have been established or strongly suggested worldwide, those with a high prevalence or high exposure levels in any ESCC-affected African setting and the sources thereof. We found that for almost all ESCC risk factors known to date, including tobacco, alcohol, hot beverage consumption, nitrosamines and both inhaled and ingested PAHs, there is evidence of population groups with raised exposures, the sources of which vary greatly between cultures across the ESCC corridor. Research encompassing these risk factors is warranted and is likely to identify primary prevention strategies. PMID- 27466165 TI - Sequential Crohn's Ileitis, Ileosigmoidal Fistula, Segmental Sigmoid Polyposis, and Sigmoid Stricture: The Natural History. AB - BACKGROUND: We have previously recognized segmental sigmoid polyps as an indicator of a fistula from Crohn's ileitis to the sigmoid or the proximal rectum. In the course of this study, we realized that many patients with this fistula had no sigmoid polyps, but the sigmoid was the site of marked inflammation and early or late stricture formation. Furthermore, in some patients with a stricture, the fistula was not recognized until the surgeon (or the pathologist) dissected an inflammatory peri-ileal and/or a perisigmoidal mass.In this study, we have sought to clarify the sequence of events by focusing on the segmental inflammation and the stricturing of the sigmoid so that its significance can be recognized as a local complication of the ileitis and the progression of its severity as opposed to arising sui generis. MATERIALS AND METHODS: From our database of >3000 patients with inflammatory bowel disease at Lenox Hill Hospital, we identified 45 patients with Crohn's ileitis and ileosigmoid fistula (ISF): 24 had segmental sigmoid polyps and 18 had segmental inflammatory sigmoid strictures. The fistula was first seen by imaging in 36 patients, but not until resection by the surgeon or dissection by the pathologist in 7 patients. RESULTS: The method of diagnosis for the initial recognition of the ISF and the sigmoid stricture is presented in Table 1. In 36 of the 45 cases, the ISF was recognized by radiologic imaging. In total, 31 of the 36 cases required surgical intervention, not because of the fistula, but because of small bowel obstruction due to the ileitis. In 7 of the 31 (22%) cases, the fistula was recognized only by dissection of the inflammatory ileosigmoid mass by the surgeon or examination of the surgical specimen by the pathologist. The sequence of events from the originating ileitis to the ISF to the segmental sigmoid polyposis and stricture, with the resulting sigmoid obstruction, is shown in Figures 1A-E. CONCLUSIONS: We emphasize the natural history of the ISF so that its recognition will lead to earlier medical management of the originating ileitis. Furthermore, it adds evidence of the recognition that the causative agent of Crohn's disease is carried by the fecal stream. PMID- 27466166 TI - A Systematic Review Assessing Medical Treatment for Rectovaginal and Enterovesical Fistulae in Crohn's Disease. AB - BACKGROUND: Rectovaginal and enterovesical fistulae are difficult to treat in patients with Crohn's disease. Currently, there is no consensus regarding their appropriate management. AIM OF THE STUDY: The aim of the study was to review the literature on the medical management of rectovaginal and enterovesical fistulae in Crohn's disease and to assess their response to treatment. METHOD: A literature search of MEDLINE, EMBASE, Science Citation Index Expanded, and Cochrane was performed. RESULTS: Twenty-three studies were identified, reporting on 137 rectovaginal and 44 enterovesical fistulae. The overall response rates of rectovaginal fistulae to medical therapy were: 38.3% complete response (fistula closure), 22.3% partial response, and 39.4% no response. For enterovesical fistulae the response rates to medical therapy were: 65.9% complete response, 20.5% partial response, and 13.6% no response. Specifically, response to anti tumor necrosis factor therapy of 78 rectovaginal fistulae was: 41.0% complete response, 21.8% partial response, and 37.2% no response. Response of 14 enterovesical fistulae to anti-tumor necrosis factor therapy was: 57.1% complete response, 35.7% partial response, and 7.1% no response. The response to a combination of medical and surgical therapy in 43 rectovaginal fistulae was: 44.2% complete response, 20.9% partial response, and 34.9% no response. CONCLUSIONS: Medical therapy, alone or in combination with surgery, appears to benefit some patients with rectovaginal or enterovesical fistula. However, given the small size and low quality of the published studies, it is still difficult to draw conclusions regarding treatment. Larger, better quality studies are required to assess response to medical treatment and evaluate indications for surgery. PMID- 27466167 TI - Diagnostic Accuracy of the Combination of Clinical Symptoms and CT or MR Angiography in Patients With Chronic Gastrointestinal Ischemia. AB - BACKGROUND: No golden diagnostic standard is available to diagnose chronic gastrointestinal ischemia (CGI). GOALS: We aimed to establish an accurate prediction model for CGI, based on clinical symptoms and radiologic evaluation of the amount of stenosis in the celiac artery (CA) and superior mesenteric artery (SMA) by means of computed tomography-angiography or magnetic resonance (MR) angiography. STUDY: We prospectively included 436 consecutive patients with clinical suspicion of CGI in a tertiary referral center. Predictors for CGI were obtained by comparing clinical parameters to the diagnosis of CGI. Multivariable logistic regression was used to combine the strongest predictors in a model. A score chart based on the prediction model was provided to calculate the risk of CGI. RESULTS: CGI was present in 171/436 (39%) patients (67 y; range, 54 to 74 y; 27% male). Strongest predictors for CGI were female gender [odds ratio (OR)=1.44; 95% confidence interval (CI), 0.85-2.43], weight loss (OR=1.63, 95% CI, 0.98 2.72), concomitant cardiovascular disease (OR=1.70, 95% CI, 1.04-2.78), duration of symptoms (OR=0.88, 95% CI, 0.79-0.99), and stenosis of CA and SMA (50% to 70% stenosis CA: OR=1.33, 95% CI, 0.56-3.19; >70% stenosis CA: OR=5.79, 95% CI, 3.42 9.81; 50% to 70% stenosis SMA: OR=3.21, 95% CI, 0.81-12.74; >70% stenosis SMA: OR=4.39, 95% CI, 2.30-8.41). A model based on clinical symptoms alone showed limited discriminative ability for diagnosing CGI (c-statistic 0.62). Adding radiologic imaging of the mesenteric arteries improved the discriminative ability (c-statistic 0.79). CONCLUSIONS: Clinical symptoms alone are insufficient to predict the risk of CGI. Radiologic evaluation of the mesenteric arteries is essential. This tool may be useful for clinicians to assess the risk of CGI and to decide whether further diagnostic work-up for CGI is needed. PMID- 27466168 TI - Stercoral Colitis With Silent Perforation in a Child. PMID- 27466169 TI - Severe Elevation of Liver Tests in Choledocholithiasis: An Uncommon Occurrence With Important Clinical Implications. AB - BACKGROUND AND AIMS: Choledocholithiasis is not commonly associated with dramatic elevations in aminotransferase or total serum bilirubin. Ours is the largest case series thus far studying the prevalence of dramatic elevations in liver tests associated with choledocholithiasis. MATERIALS AND METHODS: We performed a retrospective chart review of all patients with choledocholithiasis diagnosed on endoscopic retrograde pancreatocholangiogram at a tertiary referral hospital over 7 years. We identified 740 patients with available liver tests and determined the prevalence of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >1000 IU/L and of total serum bilirubin >10 mg/dL. We compared clinical characteristics of these 2 nonoverlapping groups. RESULTS: Of 740 patients, AST and/or ALT values >1000 IU/L were present in 45 (6.1%) patients. On average AST and ALT decreased 79% and 56%, respectively, at discharge 1 to 8 days later. Total serum bilirubin levels >10 mg/dL were present in 35 (4.7%) patients and decreased by an average of 64% at discharge 1 to 8 days later. When compared with the group with total serum bilirubin >10 mg/dL, the group with elevated aminotransferases had significantly more females (93% vs. 43%, P<0.001), had smaller common bile duct diameter (8.5 vs. 10.6 mm, P=0.04), and were more likely to have had a prior cholecystectomy (40% vs. 14%, P=0.01). These 80 patients had higher utilization of health resources: half had additional laboratory studies and one fourth had additional imaging studies performed. CONCLUSIONS: In patients with high AST and/or ALT and serum total bilirubin levels with known choledocholithiasis, elaborate work up to look for another etiology is not required. As long as the values decrease significantly, they do not need to be followed until they normalize in the same hospitalization. PMID- 27466170 TI - DNA-free two-gene knockout in Chlamydomonas reinhardtii via CRISPR-Cas9 ribonucleoproteins. AB - Microalgae are versatile organisms capable of converting CO2, H2O, and sunlight into fuel and chemicals for domestic and industrial consumption. Thus, genetic modifications of microalgae for enhancing photosynthetic productivity, and biomass and bio-products generation are crucial for both academic and industrial applications. However, targeted mutagenesis in microalgae with CRISPR-Cas9 is limited. Here we report, a one-step transformation of Chlamydomonas reinhardtii by the DNA-free CRISPR-Cas9 method rather than plasmids that encode Cas9 and guide RNAs. Outcome was the sequential CpFTSY and ZEP two-gene knockout and the generation of a strain constitutively producing zeaxanthin and showing improved photosynthetic productivity. PMID- 27466171 TI - Leucine-rich Alpha-2 Glycoprotein is a Serum Biomarker of Mucosal Healing in Ulcerative Colitis. AB - BACKGROUND AND AIMS: Although several noninvasive and easily accessible biomarkers for inflammatory bowel disease [IBD] are available, their sensitivity and specificity are not adequate to be used as single markers and do not overrule the need for endoscopic evaluation. We previously reported that serum leucine rich alpha-2 glycoprotein [LRG] was a novel biomarker for rheumatoid arthritis and IBD. We herein investigated whether LRG could indicate endoscopic activity in patients with ulcerative colitis [UC]. METHODS: Serum LRG concentrations were determined by enzyme-linked immunosorbent assay [ELISA] in consecutive 129 patients with UC in two tertiary care hospitals, and associations of LRG with clinical and endoscopic activities were evaluated. Clinical activity index [CAI] < 6 was defined as clinical remission, and mucosal healing [MH] and complete mucosal healing were defined as Matts' endoscopic grades of 1 or 2 and grade of 1, respectively. RESULTS: Serum LRG levels were significantly increased and correlated with clinical and endoscopic activities in patients with UC. LRG levels were associated with both clinical and endoscopic activities even in patients with normal serum C-reactive protein [CRP] levels. Furthermore, LRG levels were significantly lower in patients with complete MH and deep remission. Serial measurements of LRG levels in a subset of patients demonstrated that LRG was significantly elevated during the endoscopically active stage compared with that during the MH stage. CONCLUSIONS: Serum LRG is a novel biomarker for detecting MH during disease course in patients with UC and a surrogate marker of endoscopic inflammation in patients with normal CRP levels. PMID- 27466172 TI - Outcomes with Anti-Tumour Necrosis Factor-Alpha Therapy and Serology in Patients with Denovo Crohn's Disease After Ileal Pouch Anal Anastomosis. AB - BACKGROUND AND AIMS: A subset of patients who undergo ileal pouch-anal anastomosis [IPAA] for ulcerative colitis [UC] will later be diagnosed with denovo Crohn's disease [CD]. These patients have a higher risk of pouch failure. In this study we evaluated inflammatory bowel disease [IBD] serology in patients with denovo CD and examined the success of anti-tumour necrosis factor-alpha [anti-TNFalpha] therapy in preventing ileostomy in denovo CD patients who failed anti-TNFalpha therapy before IPAA. METHODS: A prospectively maintained database of patients undergoing IPAA was reviewed to identify patients who developed denovo CD [defined as small bowel inflammation above the pouch inlet or pouch fistula/perianal disease appearing more than 3 months after stoma closure]. Clinical characteristics and IBD serology were analysed. Treatment failure was defined as pouch failure requiring ileostomy or pouchectomy. RESULTS: Of 350 patients included in the study, 92 [26%] patients developed denovo CD. Significantly more denovo CD patients had anti-I2 positivity postoperatively versus preoperatively [p = 0.007]. Anti-TNFalpha therapy successfully treated denovo CD in 28 out of 38 [74%] patients. Out of 17 patients with denovo CD who had failed to respond to anti-TNFalpha agents before surgery and were treated with anti-TNFalpha therapy after surgery, 12 [71%] patients responded to treatment. CONCLUSIONS: I2 serology may possibly help identify patients who have developed or are at risk for developing denovo CD. Anti-TNFalpha therapy for denovo CD after IPAA can help prevent permanent ileostomy in almost 75% of cases, even in patients who previously failed anti-TNFalpha treatment before surgery. PMID- 27466173 TI - Submucosal Plexitis as a Predictive Factor for Postoperative Endoscopic Recurrence in Patients with Crohn's Disease Undergoing a Resection with Ileocolonic Anastomosis: Results from a Prospective Single-centre Study. AB - AIM: Ileocolonoscopy allows early detection of recurrence after surgical resection for Crohn's disease [CD]. Plexitis, defined as presence of inflammatory cells in or around enteric ganglia or nerve bundles, in the proximal surgical margin has been associated with an increased overall recurrence risk. We investigated prospectively whether plexitis can predict endoscopic recurrence [ER] in a consecutive cohort of CD patients undergoing ileocolonic resection. METHODS: All CD patients undergoing ileocolonic resection in our institution between October 2009 and December 2012 were eligible for this study. Clinical data were obtained prospectively from the patients' files, and biopsies from the proximal surgical margins were analysed immunohistochemically for inflammation at the myenteric and submucosal plexus [lymphocytes, mast cells, eosinophils]. The degree of plexitis was correlated with the presence of ER at 6 months, defined as a modified Rutgeerts' score of >= i2b. Multivariate models were developed and tested to predict posterior probability of ER. RESULTS: A total of 74 patients were included. Six months after ileocolonic resection, 50% showed ER. Known risk factors such as penetrating disease, previous resections, and active smoking, showed no relation with ER. On the other hand, submucosal lymphocytic plexitis was associated with ER [p = 0.020]. The predictive value of lymphocytic cell count increased with more extensive biopsy sampling and with application of immunohistochemistry. CONCLUSIONS: Submucosal lymphocytic plexitis in the proximal surgical margin was significantly related with a higher risk for ER after ileocolonic resection. These data support development of a postoperative prevention trial with vedolizumab, which may block lymphocytic trafficking in the postoperative bowel. PMID- 27466175 TI - The Proceedings of the 216th Kanto-Koshinetsu Regional Meeting of the Japanese Society of Neurology. PMID- 27466174 TI - Microbial Factors Associated with Postoperative Crohn's Disease Recurrence. AB - BACKGROUND AND AIMS: The intestinal microbiota is a key antigenic driver in Crohn's disease [CD]. We aimed to identify changes in the gut microbiome associated with, and predictive of, disease recurrence and remission. METHODS: A total of 141 mucosal biopsy samples from 34 CD patients were obtained at surgical resection and at colonoscopy 6 and/or 18 months postoperatively; 28 control samples were obtained: 12 from healthy patients [healthy controls] and 16 from hemicolectomy patients [surgical controls]. Bacterial 16S ribosomal profiling was performed using the Illumina MiSeq platform. RESULTS: CD was associated with reduced alpha diversity when compared with healthy controls but not surgical controls [p < 0.001 and p = 0.666, respectively]. Beta diversity [composition] differed significantly between CD and both healthy [p < 0.001] and surgical [p = 0.022] controls, but did not differ significantly between those with and without endoscopic recurrence. There were significant taxonomic differences between recurrence and remission. Patients experiencing recurrence demonstrated elevated Proteus genera [p = 0.008] and reduced Faecalibacterium [p< 0.001]. Active smoking was associated with elevated levels of Proteus [p = 0.013] postoperatively. Low abundance of Faecalibacterium [< 0.1%] and detectable Proteus in the postoperative ileal mucosa was associated with a higher risk of recurrence (odds ratio [OR] 14 [1.7-110], p = 0.013 and 13 [1.1-150], p = 0.039, respectively) when corrected for smoking. A model of recurrence comprising the presence of Proteus, abundance of Faecalibacterium, and smoking status showed moderate accuracy (area under the curve [AUC] 0.740, 95% confidence interval [CI] [0.69-0.79]). CONCLUSIONS: CD is associated with a microbial signature distinct from health. Microbial factors and smoking independently influence postoperative CD recurrence. The genus Proteus may play a role in the development of CD. PMID- 27466176 TI - The Proceedings of the 104th Kinki Regional Meeting of the Japanese Society of Neurology. PMID- 27466179 TI - Editor's Note. PMID- 27466180 TI - SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2. AB - Schwann cells are the myelinating glia of the peripheral nervous system and dysfunction of these cells causes motor and sensory peripheral neuropathy. The transcription factor SOX10 is critical for Schwann cell development and maintenance, and many SOX10 target genes encode proteins required for Schwann cell function. Loss-of-function mutations in the gene encoding myotubularin related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by myelin outfoldings along peripheral nerves. Previous reports indicate that MTMR2 is ubiquitously expressed making it unclear how loss of this gene causes a Schwann cell-specific phenotype. To address this, we performed computational and functional analyses at MTMR2 to identify transcriptional regulatory elements important for Schwann cell expression. Through these efforts, we identified an alternative, SOX10-responsive promoter at MTMR2 that displays strong regulatory activity in immortalized rat Schwann (S16) cells. This promoter directs transcription of a previously unidentified MTMR2 transcript that is enriched in mouse Schwann cells compared to immortalized mouse motor neurons (MN-1), and is predicted to encode an N terminally truncated protein isoform. The expression of the endogenous transcript is induced in a heterologous cell line by ectopically expressing SOX10, and is nearly ablated in Schwann cells by impairing SOX10 function. Intriguingly, overexpressing the two MTMR2 protein isoforms in HeLa cells revealed that both localize to nuclear puncta and the shorter isoform displays higher nuclear localization compared to the longer isoform. Combined, our data warrant further investigation of the truncated MTMR2 protein isoform in Schwann cells and in CMT4B1 pathogenesis. PMID- 27466181 TI - Huntingtin N17 domain is a reactive oxygen species sensor regulating huntingtin phosphorylation and localization. AB - The N17 domain of the huntingtin protein is post-translationally modified and is the master regulator of huntingtin intracellular localization. In Huntington's disease (HD), mutant huntingtin is hypo-phosphorylated at serines 13 and 16 within N17, and increasing N17 phosphorylation has been shown to be protective in HD mouse models. Thus, N17 phosphorylation is defined as a sub-target of huntingtin for potential therapeutic intervention. We have previously shown that cellular stress can affect huntingtin nuclear entry and phosphorylation. Here, we demonstrate that huntingtin localization can be specifically affected by reactive oxygen species (ROS) stress. We have located the sensor of this stress to the N17 domain, specifically to a highly conserved methionine at position 8. In vitro, we show by circular dichroism spectroscopy structural studies that the alpha-helical structure of N17 changes in response to redox conditions and show that the consequence of this change is enhanced N17 phosphorylation and nuclear targeting of endogenous huntingtin. Using N17 substitution point mutants, we demonstrate that N17 sulphoxidation enhances N17 dissociation from the endoplasmic reticulum (ER) membrane. This enhanced solubility makes N17 a better substrate for phosphorylation and subsequent nuclear retention. This ability of huntingtin to sense ROS levels at the ER, with phosphorylation and nuclear localization as a response, suggests that ROS stress due to aging could be a critical molecular trigger of huntingtin functions and dysfunctions in HD and may explain the age onset nature of the disorder. PMID- 27466182 TI - SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling. AB - SHOC2 is a scaffold protein composed almost entirely by leucine-rich repeats (LRRs) and having an N-terminal region enriched in alternating lysine and glutamate/aspartate residues (KEKE motifs). SHOC2 acts as a positive modulator of the RAS-RAF-MEK-ERK signalling cascade by favouring stable RAF1 interaction with RAS. We previously reported that the p.Ser2Gly substitution in SHOC2 underlies Mazzanti syndrome, a RASopathy clinically overlapping Noonan syndrome, promoting N-myristoylation and constitutive targeting of the mutant to the plasma membrane. We also documented transient nuclear translocation of wild-type SHOC2 upon EGF stimulation, suggesting a more complex function in signal transduction.Here, we characterized the domains controlling SHOC2 shuttling between the nucleus and cytoplasm, and those contributing to SHOC2S2G mistargeting to the plasma membrane, analysed the structural organization of SHOC2's LRR motifs, and determined the impact of SHOC2 mislocalization on ERK signalling. We show that LRRs 1 to 13 constitute a structurally recognizable domain required for SHOC2 import into the nucleus and constitutive targeting of SHOC2S2G to the plasma membrane, while the KEKE motif-rich region is necessary to achieve efficient SHOC2 export from the nucleus. We also document that SHOC2S2G localizes both in raft and non-raft domains, and that it translocates to the non-raft domains following stimulation. Finally, we demonstrate that SHOC2 trapping at different subcellular sites has a diverse impact on ERK signalling strength and dynamics, suggesting a dual counteracting modulatory role of SHOC2 in the control of ERK signalling exerted at different intracellular compartments. PMID- 27466183 TI - Lack of P4H-TM in mice results in age-related retinal and renal alterations. AB - Age-related macular degeneration (AMD), affecting the retinal pigment epithelium (RPE), is the leading cause of blindness in middle-aged and older people in developed countries. Genetic and environmental risk factors have been identified, but no effective cure exists. Using a mouse model we show that a transmembrane prolyl 4-hydroxylase (P4H-TM), which participates in the oxygen-dependent regulation of the hypoxia-inducible factor (HIF), is a potential novel candidate gene for AMD. We show that P4h-tm had its highest expression levels in the mouse RPE and brain, heart, lung, skeletal muscle and kidney. P4h-tm-/- mice were fertile and had a normal life span. Lack of P4h-tm stabilized HIF-1alpha in cortical neurons under normoxia, while in hypoxia it increased the expression of certain HIF target genes in tissues with high endogenous P4h-tm expression levels more than in wild-type mice. Renal erythropoietin levels increased in P4h-tm-/- mice with aging, but the resulting ~2-fold increase in erythropoietin serum levels did not lead to erythrocytosis. Instead, accumulation of lipid-containing lamellar bodies in renal tubuli was detected in P4h-tm-/- mice with aging, resulting in inflammation and fibrosis, and later glomerular sclerosis and albuminuria. Lack of P4h-tm was associated with retinal thinning, rosette-like infoldings and drusen-like structure accumulation in RPE with aging, as is characteristic of AMD. Photoreceptor recycling was compromised, and electroretinograms revealed functional impairment of the cone pathway in adult P4h-tm-/- mice and cone and rod deficiency in middle-aged mice. P4H-TM is therefore imperative for normal vision, and potentially a novel candidate for age induced diseases, such as AMD. PMID- 27466184 TI - A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging. AB - Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations. PMID- 27466185 TI - Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6. AB - The Acadian variant of Fanconi Syndrome refers to a specific condition characterized by generalized proximal tubular dysfunction from birth, slowly progressive chronic kidney disease and pulmonary interstitial fibrosis. This condition occurs only in Acadians, a founder population in Nova Scotia, Canada. The genetic and molecular basis of this disease is unknown. We carried out whole exome and genome sequencing and found that nine affected individuals were homozygous for the ultra-rare non-coding variant chr8:96046914 T > C; rs575462405, whereas 13 healthy siblings were either heterozygotes or lacked the mutant allele. This variant is located in intron 2 of NDUFAF6 (NM_152416.3; c.298 768 T > C), 37 base pairs upstream from an alternative splicing variant in NDUFAF6 chr8:96046951 A > G; rs74395342 (c.298-731 A > G). NDUFAF6 encodes NADH:ubiquinone oxidoreductase complex assembly factor 6, also known as C8ORF38. We found that rs575462405-either alone or in combination with rs74395342-affects splicing and synthesis of NDUFAF6 isoforms. Affected kidney and lung showed specific loss of the mitochondria-located NDUFAF6 isoform and ultrastructural characteristics of mitochondrial dysfunction. Accordingly, affected tissues had defects in mitochondrial respiration and complex I biogenesis that were corrected with NDUFAF6 cDNA transfection. Our results demonstrate that the Acadian variant of Fanconi Syndrome results from mitochondrial respiratory chain complex I deficiency. This information may be used in the diagnosis and prevention of this disease in individuals and families of Acadian descent and broadens the spectrum of the clinical presentation of mitochondrial diseases, respiratory chain defects and defects of complex I specifically. PMID- 27466186 TI - Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models. AB - The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1 phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signalling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbours, glycosylation losses, and differential changes in Wnt trans-synaptic signalling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signalling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology. PMID- 27466188 TI - Altered thalamocortical development in the SAP102 knockout model of intellectual disability. AB - Genetic mutations known to cause intellectual disabilities (IDs) are concentrated in specific sets of genes including both those encoding synaptic proteins and those expressed during early development. We have characterized the effect of genetic deletion of Dlg3, an ID-related gene encoding the synaptic NMDA-receptor interacting protein synapse-associated protein 102 (SAP102), on development of the mouse somatosensory cortex. SAP102 is the main representative of the PSD-95 family of postsynaptic MAGUK proteins during early development and is proposed to play a role in stabilizing receptors at immature synapses. Genetic deletion of SAP102 caused a reduction in the total number of thalamocortical (TC) axons innervating the somatosensory cortex, but did not affect the segregation of barrels. On a synaptic level SAP102 knockout mice display a transient speeding of NMDA receptor kinetics during the critical period for TC plasticity, despite no reduction in GluN2B-mediated component of synaptic transmission. These data indicated an interesting dissociation between receptor kinetics and NMDA subunit expression. Following the critical period NMDA receptor function was unaffected by loss of SAP102 but there was a reduction in the divergence of TC connectivity. These data suggest that changes in synaptic function early in development caused by mutations in SAP102 result in changes in network connectivity later in life. PMID- 27466187 TI - An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome. AB - The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis. PMID- 27466189 TI - HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder. AB - Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase predominantly expressed in the brain. Mutations of the CDKL5 gene lead to CDKL5 disorder, a neurodevelopmental pathology that shares several features with Rett Syndrome and is characterized by severe intellectual disability. The phosphorylation targets of CDKL5 are largely unknown, which hampers the discovery of therapeutic strategies for improving the neurological phenotype due to CDKL5 mutations. Here, we show that the histone deacetylase 4 (HDAC4) is a direct phosphorylation target of CDKL5 and that CDKL5-dependent phosphorylation promotes HDAC4 cytoplasmic retention. Nuclear HDAC4 binds to chromatin as well as to MEF2A transcription factor, leading to histone deacetylation and altered neuronal gene expression. By using a Cdkl5 knockout (Cdkl5 -/Y) mouse model, we found that hypophosphorylated HDAC4 translocates to the nucleus of neural precursor cells, thereby reducing histone 3 acetylation. This effect was reverted by re-expression of CDKL5 or by inhibition of HDAC4 activity through the HDAC4 inhibitor LMK235. In Cdkl5 -/Y mice treated with LMK235, defective survival and maturation of neuronal precursor cells and hippocampus-dependent memory were fully normalized. These results demonstrate a critical role of HDAC4 in the neurodevelopmental alterations due to CDKL5 mutations and suggest the possibility of HDAC4-targeted pharmacological interventions. PMID- 27466190 TI - IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome. AB - The short-rib polydactyly syndromes (SRPS) encompass a radiographically and genetically heterogeneous group of skeletal ciliopathies that are characterized by a long narrow chest, short extremities, and variable occurrence of polydactyly. Radiographic abnormalities include undermineralization of the calvarium, shortened and bowed appendicular bones, trident shaped acetabula and polydactyly. In a case of SRPS we identified compound heterozygosity for mutations in IFT52, which encodes a component of the anterograde intraflagellar transport complex. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. These data demonstrate that IFT52 is essential for anterograde complex integrity and for the biosynthesis and maintenance of cilia. The data identify a new locus for SRPS and show that IFT52 mutations result in a ciliopathy with primary effects on the skeleton. PMID- 27466191 TI - Neurodevelopmental alterations and seizures developed by mouse model of infantile hypophosphatasia are associated with purinergic signalling deregulation. AB - Hypomorphic mutations in the gene encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme, ALPL in human or Akp2 in mice, cause hypophosphatasia (HPP), an inherited metabolic bone disease also characterized by spontaneous seizures. Initially, these seizures were attributed to the impairment of GABAergic neurotransmission caused by altered vitamin B6 (vit-B6) metabolism. However, clinical cases in human newborns and adults whose convulsions are refractory to pro-GABAergic drugs but controlled by the vit-B6 administration, suggest that other factors are involved. Here, to evaluate whether neurodevelopmental alterations are underlying the seizures associated to HPP, we performed morphological and functional characterization of postnatal homozygous TNAP null mice, a model of HPP. These analyses revealed that TNAP deficient mice present an increased proliferation of neural precursors, an altered neuronal morphology, and an augmented neuronal activity. We found that these alterations were associated with a partial downregulation of the purinergic P2X7 receptor (P2X7R). Even though deficient P2X7R mice present similar neurodevelopmental alterations, they do not develop neonatal seizures. Accordingly, we found that the additional blockage of P2X7R prevent convulsions and extend the lifespan of mice lacking TNAP. In agreement with these findings, we also found that exogenous administration of ATP or TNAP antagonists induced seizures in adult wild-type mice by activating P2X7R. Finally, our results also indicate that the anticonvulsive effects attributed to vit-B6 may be due to its capacity to block P2X7R. Altogether, these findings suggest that the purinergic signalling regulates the neurodevelopmental alteration and the neonatal seizures associated to HPP. PMID- 27466193 TI - Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: a Mendelian randomization study. AB - Elevated gamma-glutamyl transferase (GGT) levels are associated with higher risk of type 2 diabetes in observational studies, but the underlying causal relationship is still unclear. Here, we tested a hypothesis that GGT levels have a causal effect on type 2 diabetes risk using Mendelian randomization. Data were collected from 7640 participants in a South Korean population. In a single instrumental variable (IV) analysis using two stage least squares regression with the rs4820599 in the GGT1 gene region as an instrument, one unit of GGT levels (IU/L) was associated with 11% higher risk of type 2 diabetes (odds ratio (OR) = 1.11, 95% confidence interval (CI): 1.04 to 1.19). In a multiple IV analysis using seven genetic variants that have previously been demonstrated to be associated with GGT at a genome-wide level of significance, the corresponding estimate suggested a 2.6% increase in risk (OR = 1.026, 95% CI: 1.001 to 1.052). In a two-sample Mendelian randomization analysis using genetic associations with type 2 diabetes taken from a trans-ethnic GWAS study of 110 452 independent samples, the single IV analysis confirmed an association between the rs4820599 and type 2 diabetes risk (P-value = 0.04); however, the estimate from the multiple IV analysis was compatible with the null (OR = 1.007, 95% CI: 0.993 to 1.022) with considerable heterogeneity between the causal effects estimated using different genetic variants. Overall, there is weak genetic evidence that GGT levels may have a causal role in the development of type 2 diabetes. PMID- 27466192 TI - The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity. AB - Aggregation of TAR-DNA-binding protein 43 (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in amyotrophic lateral sclerosis (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity. Thus, inhibition of TDP-25 and TDP-35 aggregation and promotion of their degradation may protect against cellular damage. Upregulation of HSPB8 is one possible approach for this purpose, since this chaperone promotes the clearance of an ALS associated fragments of TDP-43 and is upregulated in the surviving motor neurones of transgenic ALS mice and human patients. We report that overexpression of HSPB8 in immortalized motor neurones decreased the accumulation of TDP-25 and TDP-35 and that protection against mislocalized/truncated TDP-43 was observed for HSPB8 in Drosophila melanogaster Overexpression of HSP67Bc, the functional ortholog of human HSPB8, suppressed the eye degeneration caused by the cytoplasmic accumulation of a TDP-43 variant with a mutation in the nuclear localization signal (TDP-43-NLS). TDP-43-NLS accumulation in retinal cells was counteracted by HSP67Bc overexpression. According with this finding, downregulation of HSP67Bc increased eye degeneration, an effect that is consistent with the accumulation of high molecular weight TDP-43 species and ubiquitinated proteins. Moreover, we report a novel Drosophila model expressing TDP-35, and show that while TDP-43 and TDP-25 expression in the fly eyes causes a mild degeneration, TDP-35 expression leads to severe neurodegeneration as revealed by pupae lethality; the latter effect could be rescued by HSP67Bc overexpression. Collectively, our data demonstrate that HSPB8 upregulation mitigates TDP-43 fragment mediated toxicity, in mammalian neuronal cells and flies. PMID- 27466194 TI - The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface. AB - Dominant or recessive mutations in the progressive ankylosis gene ANKH have been linked to familial chondrocalcinosis (CCAL2), craniometaphyseal dysplasia (CMD), mental retardation, deafness and ankylosis syndrome (MRDA). The function of the encoded membrane protein ANK in cellular compartments other than the plasma membrane is unknown. Here, we show that ANK localizes to the trans-Golgi network (TGN), clathrin-coated vesicles and the plasma membrane. ANK functionally interacts with clathrin and clathrin associated adaptor protein (AP) complexes as loss of either protein causes ANK dispersion from the TGN to cytoplasmic endosome like puncta. Consistent with its subcellular localization, loss of ANK results in reduced formation of tubular membrane carriers from the TGN, perinuclear accumulation of early endosomes and impaired transferrin endocytosis. Our data indicate that clathrin/AP-mediated cycling of ANK between the TGN, endosomes, and the cell surface regulates membrane traffic at the TGN/endosomal interface. These findings suggest that dysfunction of Golgi-endosomal membrane traffic may contribute to ANKH-associated pathologies. PMID- 27466195 TI - Selective release of muscle-specific, extracellular microRNAs during myogenic differentiation. AB - MyomiRs are muscle-specific microRNAs (miRNAs) that regulate myoblast proliferation and differentiation. Extracellular myomiRs (ex-myomiRs) are highly enriched in the serum of Duchenne Muscular Dystrophy (DMD) patients and dystrophic mouse models and consequently have potential as disease biomarkers. The biological significance of miRNAs present in the extracellular space is not currently well understood. Here we demonstrate that ex-myomiR levels are elevated in perinatal muscle development, during the regenerative phase that follows exercise-induced myoinjury, and concomitant with myoblast differentiation in culture. Whereas ex-myomiRs are progressively and specifically released by differentiating human primary myoblasts and C2C12 cultures, chemical induction of apoptosis in C2C12 cells results in indiscriminate miRNA release. The selective release of myomiRs as a consequence of cellular differentiation argues against the idea that they are solely waste products of muscle breakdown, and suggests they may serve a biological function in specific physiological contexts. Ex myomiRs in culture supernatant and serum are predominantly non-vesicular, and their release is independent of ceramide-mediated vesicle secretion. Furthermore, ex-myomiRs levels are reduced in aged dystrophic mice, likely as a consequence of chronic muscle wasting. In conclusion, we show that myomiR release accompanies periods of myogenic differentiation in cell culture and in vivo. Serum myomiR abundance is therefore a function of the regenerative/degenerative status of the muscle, overall muscle mass, and tissue expression levels. These findings have implications for the use of ex-myomiRs as biomarkers for DMD disease progression and monitoring response to therapy. PMID- 27466196 TI - Partial loss of CALM function reduces Abeta42 production and amyloid deposition in vivo. AB - Aberrant production, clearance and deposition of amyloid-beta protein (Abeta) in the human brain have been implicated in the aetiology of Alzheimer disease (AD). gamma-Secretase is the enzyme responsible for generating various Abeta species, such as Abeta40 and toxic Abeta42. Recently, genome-wide association studies in late-onset AD patients have identified the endocytosis-related phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a genetic risk factor for AD. We previously found that the loss of expression of CALM protein encoded by PICALM affects the ratio of production of Abeta42, through the regulation of the clathrin-mediated endocytosis of gamma-secretase. Here, we show that the binding capacity of the assembly protein 180 N-terminal homology (ANTH) domain of CALM to phosphatidylinositol-4,5-biphosphate, as well as to nicastrin, is critical to the modulation of the internalization of gamma-secretase and to the Abeta42 production ratio. Moreover, reduction of CALM decreases Abeta deposition as well as brain levels of insoluble Abeta42 in vivo These results suggest that CALM expression modifies AD risk by regulating Abeta pathology. PMID- 27466197 TI - Pridopidine activates neuroprotective pathways impaired in Huntington Disease. AB - Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P = 1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7 < P < 0.04). In addition, pridopidine treatment upregulated the glucocorticoid receptor (GR) response, D1R-associated genes and the AKT/PI3K pathway (P = 1E-10, P = 0.001, P = 0.004, respectively). Pridopidine upregulates expression of BDNF, D1R, GR and AKT/PI3K pathways, known to promote neuronal plasticity and survival, as well as reported to demonstrate therapeutic benefit in HD animal models. Activation of S1R, necessary for its effect on the BDNF pathway, represents a core component of the mode of action of pridopidine. Since the newly identified pathways are downregulated in neurodegenerative diseases, including HD, these findings suggest that pridopidine may exert neuroprotective effects beyond its role in alleviating some symptoms of HD. PMID- 27466200 TI - Ataxin-1 regulates the cerebellar bioenergetics proteome through the GSK3beta mTOR pathway which is altered in Spinocerebellar ataxia type 1 (SCA1). AB - A polyglutamine expansion within the ataxin-1 protein (ATXN1) underlies spinocerebellar ataxia type-1 (SCA1), a neurological disorder mainly characterized by ataxia and cerebellar deficits. In SCA1, both loss and gain of ATXN1 biological functions contribute to cerebellar pathogenesis. However, the critical ATXN1 functions and pathways involved remain unclear. To further investigate the early signalling pathways regulated by ATXN1, we performed an unbiased proteomic study of the Atxn1-KO 5-week-old mice cerebellum. Here, we show that lack of ATXN1 expression induces early alterations in proteins involved in glycolysis [pyruvate kinase, muscle, isoform 1 protein (PKM-i1), citrate synthase (CS), glycerol-3-phosphate dehydrogenase 2 (GPD2), glucose-6-phosphate isomerase (GPI), alpha -: enolase (ENO1)], ATP synthesis [CS, Succinate dehydrogenase complex,subunit A (SDHA), ATP synthase subunit d, mitochondrial (ATP5H)] and oxidative stress [peroxiredoxin-6 (PRDX6), aldehyde dehydrogenase family 1, subfamily A1, 10-formyltetrahydrofolate dehydrogenase]. In the SCA1 mice, several of these proteins (PKM-i1, ATP5H, PRDX6, proteome subunit A6) were down-regulated and ATP levels decreased. The underlying mechanism does not involve modulation of mitochondrial biogenesis, but dysregulation of the activity of the metabolic regulators glycogen synthase kinase 3B (GSK3beta), decreased in Atxn1-KO and increased in SCA1 mice, and mechanistic target of rapamycin (serine/threonine kinase) (mTOR), unchanged in the Atxn1-KO and decreased in SCA1 mice cerebellum before the onset of ataxic symptoms. Pharmacological inhibition of GSK3beta and activation of mTOR in a SCA1 cell model ameliorated identified ATXN1-regulated metabolic proteome and ATP alterations. Taken together, these results point to an early role of ATXN1 in the regulation of bioenergetics homeostasis in the mouse cerebellum. Moreover, data suggest GSK3beta and mTOR pathways modulate this ATXN1 function in SCA1 pathogenesis that could be targeted therapeutically prior to the onset of disease symptoms in SCA1 and other pathologies involving dysregulation of ATXN1 functions. PMID- 27466199 TI - Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation. AB - Disrupted in Schizophrenia-1 (DISC1) has been associated with a broad spectrum of mental disorders. DISC1 is a multi-compartmentalized protein found in the cytoplasm, centrosome, nuclei and mostly enriched in mitochondria. In order to shed light on DISC1 mitochondrial function, we have studied its topology within the organelle. We show in here that in mammals DISC1 resides in the 'Mitochondrial contact site and Cristae Organizing system' (MICOS) complex, involved in cristae organization. DISC1 knockdown in SH-SY5Y cells causes MICOS disassembly and fragmentation of the mitochondrial morphology network. Moreover, DISC1 depleted cells have decreased mitochondrial DNA (mtDNA) content and steady state levels of oxidative phosphorylation (OXPHOS) subunits. As a consequence, OXPHOS complexes and supercomplexes are partially disassembled in DISC1 knockdown cells, which suffer severe bioenergetic defects, evidenced by impaired oxygen consumption, adenosine triphosphate synthesis and mitochondrial membrane potential. Transfection of recombinant full-length human DISC1 restores MICOS complex assembly and rescues OXPHOS function, meanwhile overexpression of the DISC1 truncated form Delta597-854, known to be pathogenic, fails to rescue the bioenergetic impairment caused by DISC1 knockdown. These results should contribute to reveal DISC1 physiological function and potential pathogenic role in severe mental illnesses. PMID- 27466198 TI - Analysis with the exome array identifies multiple new independent variants in lipid loci. AB - It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits. PMID- 27466202 TI - Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals. AB - For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified Cdca7 as the top down regulated gene in Zbtb24 homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the CDCA7 promoter suggesting that ZBTB24 can function as a transcription factor directly controlling Cdca7 expression. Finally, we show that this regulation is conserved between species and that CDCA7 levels are reduced in patients carrying ZBTB24 nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes ZBTB24 and CDCA7 at the level of transcription. PMID- 27466201 TI - A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity. AB - Genome-wide association studies have revealed a relationship between inter individual variation in blood pressure and the single nucleotide polymorphism rs13107325 in the SLC39A8 gene. This gene encodes the ZIP8 protein which co transports divalent metal cations, including heavy metal cadmium, the accumulation of which has been associated with increased blood pressure. The polymorphism results in two variants of ZIP8 with either an alanine (Ala) or a threonine (Thr) at residue 391. We investigated the functional impact of this variant on protein conformation, cadmium transport, activation of signalling pathways and cell viability in relation to blood pressure regulation. Following incubation with cadmium, higher intracellular cadmium was detected in cultured human embryonic kidney cells (HEK293) expressing heterologous ZIP8-Ala391, compared with HEK293 cells expressing heterologous ZIP8-Thr391. This Ala391 associated cadmium accumulation also increased the phosphorylation of the signal transduction molecule ERK2, activation of the transcription factor NFkappaB, and reduced cell viability. Similarly, vascular endothelial cells with the Ala/Ala genotype had higher intracellular cadmium concentration and lower cell viability than their Ala/Thr counterpart following cadmium exposure. These results indicate that the ZIP8 Ala391-to-Thr391 substitution has an effect on intracellular cadmium accumulation and cell toxicity, providing a potential mechanistic explanation for the association of this genetic variant with blood pressure. PMID- 27466203 TI - Zic2 mutation causes holoprosencephaly via disruption of NODAL signalling. AB - The ZIC2 transcription factor is one of the genes most commonly mutated in Holoprosencephaly (HPE) probands. Studies in cultured cell lines and mice have shown a loss of ZIC2 function is the pathogenic mechanism but the molecular details of this ZIC2 requirement remain elusive. HPE arises when signals that direct morphological and fate changes in the developing brain and facial primordia are not sent or received. One critical signal is sent from the prechordal plate (PrCP) which develops beneath the ventral forebrain. An intact NODAL signal transduction pathway and functional ZIC2 are both required for PrCP establishment. We now show that ZIC2 acts downstream of the NODAL signal during PrCP development. ZIC2 physically interacts with SMAD2 and SMAD3, the receptor activated proteins that control transcription in a NODAL dependent manner. Together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and Zic2 also controls the foxA2 expression during Xenopus development. Variant forms of the ZIC2 protein, associated with HPE in man or mouse, are deficient in their ability to influence SMAD-dependent transcription. These findings reveal a new mechanism of NODAL signal transduction in the mammalian node and provide the first molecular explanation of how ZIC2 loss-of-function precipitates HPE. PMID- 27466204 TI - Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice. AB - Defects in the RNA-binding proteins survival motor neuron (SMN) and TAR DNA binding protein 43 (TDP-43) cause progressive motor neuron degeneration in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. While low levels of SMN protein in motor neurons result in SMA, recent studies implicate abnormal SMN levels and function in ALS pathogenesis. Here, we determine that SMN protein is upregulated early and progressively in spinal and cortical motor neurons of male transgenic mutant TDP-43A315T mice. Cytoplasmic SMN aggregates that contain TDP-43 and HuR were identified in motor neurons of TDP-43A315T mice, consistent with the incorporation of SMN into stress granules. To test the impact of augmenting SMN levels in TDP-43 proteinopathy, we demonstrate that neuronal overexpression of human SMN in TDP-43A315T mice delayed symptom onset and prolonged survival. SMN upregulation also countered motor neuron degeneration, attenuated activation of astrocytes and microglia and restored AMP kinase activation in spinal cords of TDP-43A315T mice. We also reveal that expression of another factor conferring motor neuron vulnerability, androgen receptor (AR), is reduced in spinal cords of male TDP-43A315T mice. These results establish that SMN overexpression in motor neurons slows disease onset and outcome by ameliorating pathological signs in this model of mutant TDP 43-mediated ALS. Further approaches to augment SMN levels using pharmacological or gene therapy agents may therefore be warranted in ALS. Our data also reinforce a novel potential link between ALS and spinal bulbar muscular atrophy (SBMA), another motor neurodegenerative disease mediated by reduced AR function in motor neurons. PMID- 27466205 TI - Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy Resistant L858R/T790M/C797S Mutant. AB - The treatment of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third-generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR. PMID- 27466206 TI - Molecular developmental mechanism in polypterid fish provides insight into the origin of vertebrate lungs. AB - The lung is an important organ for air breathing in tetrapods and originated well before the terrestrialization of vertebrates. Therefore, to better understand lung evolution, we investigated lung development in the extant basal actinopterygian fish Senegal bichir (Polypterus senegalus). First, we histologically confirmed that lung development in this species is very similar to that of tetrapods. We also found that the mesenchymal expression patterns of three genes that are known to play important roles in early lung development in tetrapods (Fgf10, Tbx4, and Tbx5) were quite similar to those of tetrapods. Moreover, we found a Tbx4 core lung mesenchyme-specific enhancer (C-LME) in the genomes of bichir and coelacanth (Latimeria chalumnae) and experimentally confirmed that these were functional in tetrapods. These findings provide the first molecular evidence that the developmental program for lung was already established in the common ancestor of actinopterygians and sarcopterygians. PMID- 27466207 TI - Increased bottle size was associated with increased weight gain in infants. PMID- 27466208 TI - Public health for paediatricians: population screening. PMID- 27466210 TI - Boric Acid Is Reproductively Toxic to Adult Xenopus laevis, but Not Endocrine Active. AB - The potential reproductive and endocrine toxicity of boric acid (BA) in the African clawed frog, Xenopus laevis, was evaluated using a 30-day exposure of adult frogs. Adult female and male frogs established as breeders were exposed to a culture water control and 4 target (nominal) test concentrations [5.0, 7.5, 10.0, and 15 mg boron (B)/L, equivalent to 28.5, 42.8, 57.0, and 85.5 mg BA/L] using flow-through diluter exposure system. The primary endpoints measured were adult survival, growth (weight and snout-vent length [SVL]), necropsy data, reproductive fecundity, and development of progeny (F1) from the exposed frogs. Necropsy endpoints included gonad weight, gonado-somatic index (GSI), ovary profile (oocyte normalcy and stage distribution), sperm count, and dysmorphology. Endocrine endpoints included plasma estradiol (E2), testosterone (T), dihydrotestosteone (DHT), gonadal CYP 19 (aromatase), and gonadal 5alpha reductase (5-AR). BA exposure to adult female X. laevis increased the proportion of immature oocytes (< stage II) in the ovaries of females, reduced sperm counts and increased sperm cell dysmorphology frequency in male frogs exposed to 15 mg B/L. No effects on the other general, developmental (F1), or endocrine endpoints were observed. Based on the results of the present study, the no observed adverse effects concentration (NOAEC) for the reproductive endpoints was 10 mg B/L; and 15 mg B/L for reproductive fecundity, F1 embryo larval development, and endocrine function. These results confirmed that although BA is capable of inducing reproductive toxicity at high concentrations, it is not an endocrine disrupting agent. PMID- 27466212 TI - Effects of BMS-986094, a Guanosine Nucleotide Analogue, on Mitochondrial DNA Synthesis and Function. AB - BMS-986094, the prodrug of a guanosine nucleotide analogue (2'-C methylguanosine), was withdrawn from clinical trials due to serious safety issues. Nonclinical investigative studies were conducted as a follow up to evaluate the potential for BMS-986094-related mitochondrial-toxicity. In vitro, BMS-986094 was applied to human hepatoma cells (HepG2 and Huh-7) or cardiomyocytes (hiPSCM) up to 19 days to assess mitochondrial DNA content and specific gene expression. There were no mitochondrial DNA changes at concentrations <=10 uM. Transcriptional effects, such as reductions in Huh-7 MT ND1 and MT-ND5 mRNA content and hiPSCM MT-ND1, MT-COXII, and POLRMT protein expression levels, occurred only at cytotoxic concentrations (>=10 uM) suggesting these transcriptional effects were a consequence of the observed toxicity. Additionally, BMS-986094 has a selective weak affinity for inhibition of RNA polymerases as opposed to DNA polymerases. In vivo, BMS-986094 was given orally to cynomolgus monkeys for 3 weeks or 1 month at doses of 15 or 30 mg/kg/day. Samples of heart and kidney were collected for assessment of mitochondrial respiration, mitochondrial DNA content, and levels of high energy substrates. Although pronounced cardiac and renal toxicities were observed in some monkeys at 30 mg/kg/day treated for 3-4 weeks, there were no changes in mitochondrial DNA content or ATP/GTP levels. Collectively, these data suggest that BMS-986094 is not a direct mitochondrial toxicant. PMID- 27466211 TI - From the Cover: Sperm Molecular Biomarkers Are Sensitive Indicators of Testicular Injury following Subchronic Model Toxicant Exposure. AB - Traditional testis histopathology endpoints remain the gold standard for evaluating testicular insult and injury in a non-clinical setting, but are invasive and unfeasible for monitoring these effects clinically in humans. Assessing testicular injury in humans relies on semen and serum hormone analyses, both of which are insensitive and poor indicators of effect. Therefore, we hypothesized that sperm messenger RNA (mRNA) transcripts and DNA methylation marks can be used as translatable and sensitive indicators or testicular injury. Dose-response studies using adult male Fischer 344 rats subchronically exposed to model Sertoli cell toxicants (0.14, 0.21, and 0.33% 2,5-hexanedione, and 30, 50, and 70 mg/kg/day carbendazim), and a model germ cell toxicant (1.4, 3.4, and 5.1 mg/kg/day cyclophosphamide) for 3 months were evaluated for testicular injury by traditional histopathological endpoints, changes in sperm mRNA transcript levels using custom PCR arrays, and alterations in sperm DNA methylation via reduced representation bisulfite sequencing. Testis histopathological evaluation and PCR array analysis of the sperm transcriptome identified dose-dependent changes elicited by toxicant exposure (P < 0.05). Global sperm DNA methylation analysis of subchronic 0.33% 2,5-hexandione and 5.1 mg/kg/day cyclophosphamide exposure using a Monte Carlo approach did not identify differentially methylated regions (methylation difference > 10% and q < 0.05) with robust signatures. Overall, these results suggest that sperm mRNA transcripts are sensitive indicators of low dose toxicant-induced testicular injury in the rat, while sperm DNA methylation changes are not. Additionally, the Monte Carlo analysis is a powerful approach that can be used to assess the robustness of signals resulting from -omic studies. PMID- 27466213 TI - Dryad in the UK and USA-Prospective and Retrospective Data Publication. PMID- 27466209 TI - Uterine fibroid management: from the present to the future. AB - Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications.Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids.There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention.There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies.The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids. PMID- 27466216 TI - Local noise in a diffusive conductor. AB - The control and measurement of local non-equilibrium configurations is of utmost importance in applications on energy harvesting, thermoelectrics and heat management in nano-electronics. This challenging task can be achieved with the help of various local probes, prominent examples including superconducting or quantum dot based tunnel junctions, classical and quantum resistors, and Raman thermography. Beyond time-averaged properties, valuable information can also be gained from spontaneous fluctuations of current (noise). From these perspective, however, a fundamental constraint is set by current conservation, which makes noise a characteristic of the whole conductor, rather than some part of it. Here we demonstrate how to remove this obstacle and pick up a local noise temperature of a current biased diffusive conductor with the help of a miniature noise probe. This approach is virtually noninvasive for the electronic energy distributions and extends primary local measurements towards strongly non-equilibrium regimes. PMID- 27466215 TI - Calcium intake and colorectal cancer risk: Results from the nurses' health study and health professionals follow-up study. AB - The relationship between calcium intake and colorectal cancer (CRC) risk remains inconclusive. We conducted this study to evaluate whether the association between calcium intake and CRC risk differs by anatomic subsite and determine the dose response relationship for this association, as well as assess when in carcinogenesis calcium may play a role. We assessed calcium intake every 4 years and followed 88,509 women (1980-2012) in the Nurses' Health Study and 47,740 men (1986-2012) in the Health Professionals Follow-Up Study. We documented 3,078 incident CRC cases. Total calcium intake (>=1,400 vs. <600 mg/d) was associated with a statistically significant lower risk of colon cancer (multivariable relative risk: 0.78, 95%CI: 0.65-0.95). Similar results were observed by different sources of calcium (from all foods or dairy products only). The inverse association was linear and suggestively stronger for distal colon cancer (0.65, 0.43-0.99) than for proximal colon cancer (0.94, 0.72-1.22, p-common effects = 0.14). Additionally, when comparing different latencies, the overall pattern suggested that the inverse association appeared to be stronger with increasing latency and was strongest for intakes 12-16 years before diagnosis. Comparing total calcium intakes of >=1,400 vs. <600 mg/d for intake 12-16 y before diagnosis, the pooled RR (95% CIs) of CRC was 0.76 (0.64-0.91). Higher calcium intake was associated with a lower risk of developing colon cancer, especially for distal colon cancer. Overall inverse association was linear and did not differ by intake source. Additionally, calcium intake approximately 10 years before diagnosis appeared to be associated with a lower risk of CRC. PMID- 27466214 TI - Editor's Highlight: Lower Fractional Anisotropy in the Globus Pallidus of Asymptomatic Welders, a Marker for Long-Term Welding Exposure. AB - INTRODUCTION: Welding fumes contain several metals including manganese (Mn), iron (Fe), and copper (Cu) that at high exposure may co-influence welding-related neurotoxicity. The relationship between brain accumulation of these metals and neuropathology, especially in welders with subclinical exposure levels, is unclear. This study examined the microstructural integrity of basal ganglia (BG) regions in asymptomatic welders using diffusion tensor imaging (DTI). METHODS: Subjects with (n = 43) and without (age- and gender-matched controls; n = 31) history of welding were studied. Occupational questionnaires estimated short-term (HrsW; welding hours and E90; cumulative exposure, past 90 days) and long-term (YrsW; total years welding and ELT; cumulative exposure, lifetime) exposure. Whole blood metal levels (Mn, Fe, and Cu) were obtained. Brain MRI pallidal index (PI), R1 (1/T1), and R2* (1/T2*) were measured to estimate Mn and Fe accumulation in BG [caudate, putamen, and globus pallidus (GP)]. DTI was used to assess BG microstructural differences, and related with exposure measurements. RESULTS: When compared with controls, welders had significantly lower fractional anisotropy (FA) in the GP. In welders, GP FA values showed non-linear relationships to YrsW, blood Mn, and PI. GP FA decreased after a critical level of YrsW or Mn was reached, whereas it decreased with increasing PI values until plateauing at the highest PI values. GP FA, however, did not show any relationship with short-term exposure measurements (HrsW, E90), blood Cu and Fe, or R(2)* values. CONCLUSION: GP FA captured microstructural changes associated with chronic low-level Mn exposure, and may serve as a biomarker for neurotoxicity in asymptomatic welders. PMID- 27466217 TI - High energy X-ray phase and dark-field imaging using a random absorption mask. AB - High energy X-ray imaging has unique advantage over conventional X-ray imaging, since it enables higher penetration into materials with significantly reduced radiation damage. However, the absorption contrast in high energy region is considerably low due to the reduced X-ray absorption cross section for most materials. Even though the X-ray phase and dark-field imaging techniques can provide substantially increased contrast and complementary information, fabricating dedicated optics for high energies still remain a challenge. To address this issue, we present an alternative X-ray imaging approach to produce transmission, phase and scattering signals at high X-ray energies by using a random absorption mask. Importantly, in addition to the synchrotron radiation source, this approach has been demonstrated for practical imaging application with a laboratory-based microfocus X-ray source. This new imaging method could be potentially useful for studying thick samples or heavy materials for advanced research in materials science. PMID- 27466218 TI - Exenatide improves beta-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial. AB - OBJECTIVE: Glucagon-like peptide (GLP)-1 receptor agonist treatment improves beta cell function. In this study, we investigated whether the improvements are sustained during a 3-year treatment period. RESEARCH DESIGN AND METHODS: Sixty nine metformin-treated type 2 diabetes patients were randomised to the GLP1 receptor agonist, exenatide (EXE) twice daily (BID) or to insulin glargine (GLAR). beta-cell function parameters were derived using the Mari model from standardised breakfast and lunch meals that were administered before treatment, and after 1 and 3 years of treatment. EXE was administered before breakfast. RESULTS: Fifty-nine (EXE: n = 30; GLAR: n = 29) and thirty-six (EXE: n = 16; GLAR: n = 20) patients completed the meal at 1- and 3-year treatment respectively. After 3 years, groups had comparable glycaemic control (HbA1c: EXE 6.6 +/- 0.2% and GLAR 6.9 +/- 0.2%; P = 0.216). Compared with GLAR, at 1 and 3 years, EXE induced a stronger reduction in post-breakfast glucose concentrations (P < 0.001), with lower C-peptide levels (P < 0.001). Compared with GLAR, EXE increased insulin secretion at 8 mmol/L glucose throughout the study period (P < 0.01). Both treatments improved beta-cell glucose sensitivity after 1-year treatment. However, only EXE treatment sustained this improvement for 3 years. No consistent changes in other beta-cell parameters including rate sensitivity and potentiation were observed. CONCLUSIONS: Compared with GLAR, EXE improved the parameters of beta-cell function, especially insulin secretion at 8 mmol/L glucose and beta-cell glucose sensitivity, which was sustained during the 3-year treatment period. PMID- 27466219 TI - Promoting Worker Health on the Job and in the Community: A Vital Resource for Workers and Advocates Jailer Todd Lara-Meloy Miriam and Robbins Maggie . ( 2015 ). Workers' guide to health and safety . Berkeley, CA : Hesperian . 576 pages. $34.95 (paperback). ISBN: 978-0-942364-71-2 . PMID- 27466221 TI - T1rho Magnetic Resonance Imaging to Assess Cartilage Damage After Primary Shoulder Dislocation. AB - BACKGROUND: Patients who suffer anterior shoulder dislocations are at higher risk of developing glenohumeral arthropathy, but little is known about the initial cartilage damage after a primary shoulder dislocation. T1rho is a magnetic resonance imaging (MRI) technique that allows quantification of cartilage proteoglycan content and can detect physiologic changes in articular cartilage. PURPOSE: This study aimed to establish baseline T1rho MRI values for glenoid and humeral head cartilage, determine whether T1rho MRI can detect glenohumeral cartilage damage after traumatic primary shoulder dislocation, and assess for patterns in cartilage damage in anterior shoulder dislocation. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Nine male patients (mean age, 32.0 years; range, 20-59 years) who sustained first-time anterior shoulder dislocations underwent 3T T1rho MRI. Five healthy controls (mean age, 27.4 years; range, 24-30 years) without prior dislocation or glenohumeral arthritis also underwent 3T T1rho MRI. The T1rho relaxation constant was determined for the entire glenoid and humeral head for patients with a dislocation and for healthy controls. The glenoid and humeral head were divided into 9 zones, and T1rho values were determined for each zone in dislocated and control shoulders to identify patterns in cartilage damage in dislocated shoulders. RESULTS: Average overall T1rho values for humeral head cartilage in dislocated shoulders were significantly greater than in controls (41.7 +/- 3.9 ms vs 38.4 +/- 0.6 ms, respectively; P = .03). However, average overall T1rho values for glenoid cartilage were not significantly different in dislocated shoulders compared with controls (44.0 +/- 3.3 ms vs 44.6 +/- 2.4 ms, respectively; P = .40), suggesting worse damage to humeral head cartilage. T1rho values in the posterior-middle humeral head were higher in patients with a dislocation compared with controls (41.5 +/- 3.8 ms vs 38.2 +/- 2.2 ms, respectively; P = .021) and trended toward significance in the posterior-superior and middle-superior zones (35.2 +/- 4.9 ms vs 31.3 +/- 1.0 ms and 33.7 +/- 5.0 ms vs 30.5 +/- 1.3 ms, respectively; P = .056). These 3 humeral head zones are where Hill-Sachs lesions predominate. T1rho values in the anterior-inferior glenoid zone trended toward significance in patients with a dislocation compared with controls (47.4 +/- 5.0 ms vs 43.5 +/- 3.5 ms, respectively; P = .073). CONCLUSION: Humeral head cartilage sustained greater damage than glenoid cartilage in primary dislocation. T1rho values were higher in glenohumeral zones associated with Bankart and Hill-Sachs lesions. Widespread initial cartilage damage may predispose patients to glenohumeral arthropathy. PMID- 27466220 TI - Baseline Perfusion Alterations Due to Acute Application of Quetiapine and Pramipexole in Healthy Adults. AB - BACKGROUND: The dopaminergic system is implicated in many mental processes and neuropsychiatric disorders. Pharmacologically, drugs with dopamine receptor antagonistic and agonistic effects are used, but their effects on functional brain metabolism are not well known. METHODS: In this randomized crossover, placebo-controlled, and rater-blinded study, 25 healthy adults received an acute dose placebo substance (starch), quetiapine (dopamine receptor antagonist), or pramipexole (dopamine agonist of the nonergoline class) 1 hour before the experiment. Background-suppressed 2D pseudo-continuous arterial spin labeling was used to examine whole-brain baseline cerebral blood flow differences induced by the 3 substances. RESULTS: We found that quetiapine reduced perfusion in the occipital (early visual areas) and bilateral cerebellar cortex relative to placebo. In contrast, quetiapine enhanced cerebral blood flow (relative to placebo) in the striatal system (putamen and caudate nucleus) but also in the supplementary motor area, insular-, prefrontal- as well as in the pre- and postcentral cortex. Pramipexole increased cerebral blood flow compared with placebo in the caudate nucleus, putamen, middle frontal, supplementary motor area, and brainstem (substantia nigra), but reduced cerebral blood flow in the posterior thalamus, cerebellum, and visual areas. Pramipexole administration resulted in stronger cerebral blood flow relative to quetiapine in the hypothalamus, cerebellum, and substantia nigra. CONCLUSIONS: Our results indicate that quetiapine and pramipexole differentially modulate regional baseline cerebral blood flow. Both substances act on the dopaminergic system, although they affect distinct regions. Quetiapine altered dopaminergic function in frontal, striatal, and motor regions. In contrast, pramipexole affected cerebral blood flow of the nigrostriatal (striatum and substantia nigra) dopaminergic, but less the fronto-insular system. PMID- 27466222 TI - Irradiated Hamstring Tendon Allograft Versus Autograft for Anatomic Double-Bundle Anterior Cruciate Ligament Reconstruction: Midterm Clinical Outcomes. AB - BACKGROUND: Most studies on grafts for anterior cruciate ligament (ACL) reconstruction (ACLR) have been of autografts or nonirradiated allografts with a single-bundle (SB) technique. Outcome reports evaluating anatomic double-bundle (DB) ACLR with a hamstring tendon autograft versus irradiated allograft are rare. PURPOSE: To compare the clinical outcomes of arthroscopic anatomic DB ACLR with a hamstring tendon autograft versus irradiated allograft. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Between 2008 and 2009, a total of 107 patients undergoing arthroscopic DB ACLR were prospectively randomized consecutively into 1 of 2 groups (autograft [Auto] group and irradiated allograft [Ir-Allo] group). All the surgical procedures were performed by the same senior surgeon using the DB reconstruction technique. All irradiated hamstring tendon allografts were sterilized with 2.5 Mrad of irradiation before distribution and were obtained from a single certified tissue bank. Graft fixation on the femoral side was by an Endobutton, and on the tibial side by a bioabsorbable interference screw augmented with a staple. The same rehabilitation protocol was applied to all patients. Before surgery and at a mean of 6.9 years of follow-up, patients were evaluated by the same observer according to objective and subjective clinical evaluations including detailed history, physical examination, radiography, functional knee ligament testing, KT-2000 arthrometer testing, Harner vertical jump and Daniel 1-legged hop tests, Lysholm score, Tegner score, International Knee Documentation Committee (IKDC) standard evaluation form, and Cincinnati knee score. RESULTS: A total of 83 patients (Auto: n = 40 [mean age, 29.2 +/- 6.9 years]; Ir-Allo: n = 43 [mean age, 28.6 +/- 7.2 years]) fulfilled follow-up and clinical evaluations. No significant differences were found between the 2 groups according to the overall IKDC functional and subjective evaluations as well as testing of activity levels. Significant between-group differences were found when comparing the results at final follow-up according to the Lachman test, anterior drawer test, pivot-shift test, and KT-2000 arthrometer measurements (P < .001). Most importantly, 87.5% of patients in the Auto group and 34.9% in the Ir-Allo group had a side-to-side difference <3 mm. The rate of laxity (side-to-side difference >5 mm) with an irradiated allograft (30.2%) was higher than that with an autograft (7.5%) (P < .001). The failure rate in the Ir Allo group (30.2%) was higher than that in the Auto group (7.5%) (P < .001). Anterior and rotational stability decreased significantly in the Ir-Allo group; patients in the Ir-Allo group also had a shorter operation time. There were 10.0% (4/40) of patients in the Auto group and 32.6% (19/43) of patients in the Ir-Allo group who had arthritic progression (P < .05). CONCLUSION: There were no significant differences in postoperative activity levels and functional outcomes between the Auto and Ir-Allo groups. However, a significant increase in anterior and rotational laxity in the Ir-Allo group was found according to evaluations. We do not advocate an irradiated hamstring tendon allograft for DB ACLR. TRIAL REGISTRATION: Clinical Trial Register System of The Affiliated Hospital of Qingdao University (qdfy-ky2008-12). PMID- 27466223 TI - Analysis of the Current Indications for Microfracture of Chondral Lesions in the Hip Joint. AB - BACKGROUND: Data on the efficacy of microfracture for treatment of chondral defects in the hip are currently limited, and the recommended criteria for its use (minimal osteoarthritis; a focal, contained lesion <4 cm2 in size) have been taken from those that were established for the knee. PURPOSE: To determine if the current microfracture (ie, knee) criteria are appropriate for chondral lesions in the hip. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seventy patients who had hip arthroscopy and 2 years of follow-up after treatment of labral tears and cam and pincer bony deformities, as well as microfracture of full-thickness chondral defects, are the basis of this study. The size and location of the chondral defects were recorded on each patient's "hip sheet" and operative note at the time of hip arthroscopy and were confirmed from intraoperative photographs. The chondral defects were debrided and microfractured regardless of their size. All hips were assessed with the 100-point modified Harris Hip Score (mHHS) before arthroscopy and at 3, 6, 12, and 24 months after surgery. Patients who had a total hip arthroplasty or repeat arthroscopy during their 2-year follow-up period were assigned poor results. RESULTS: The average age of the 70 patients was 41 years, and the average size of the lesions microfractured was 143 mm2. Outcomes, based on patients' 2-year mHHS or being assigned a poor result for revision surgery, were as follows: 32 excellent, 11 good, 6 fair, and 21 poor; overall, 43 patients (61%) had good and excellent results, and 27 (39%) had fair and poor results. The revision surgery rate was 24%. Seven of the 70 patients had chondral lesions greater than the recommended size for microfracture in the hip (>400 mm) and ranged from 430 to 750 mm2. Their 2-year outcomes included 3 excellent, 1 good, 1 fair, and 1 poor result; the outcomes were the same as for the 8 patients with medium (200-400 mm2) and the 55 patients with smaller (<200 mm2) lesions (P = .25). There also was no difference in the 2-year outcomes of the older patients (age >=50 years; P = .91). CONCLUSION: Microfracture in the hip should not be limited to the criteria of knee lesions (<400 mm2) or to younger patients (age <50 years). However, the results also indicate that patients with full-thickness cartilage defects can anticipate a high rate of conversion to total hip arthroplasty within 2 years of their microfracture surgery and that only 60% of them will have good/excellent results over that time period. PMID- 27466224 TI - Early Viscosupplementation After Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Trial. AB - BACKGROUND: Hyaluronic acid (HA) has been widely used to treat osteoarthritis given its biological and mechanical properties. Because HA is an "intra articular" treatment approach that affects the joints, it could be used in the management of acute conditions, such as during the early postsurgical phase, to reduce inflammatory stress and improve articular function. PURPOSE: The aim of the present double-blind, randomized controlled trial was to evaluate pain control and functional recovery provided by a single injection of HA performed the day after anterior cruciate ligament (ACL) reconstruction. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: The study enrolled 60 patients affected by primary, chronic, and symptomatic ACL tear requiring surgical reconstruction. All patients were treated with the same reconstructive technique and rehabilitation protocol. Exclusion criteria were (1) concurrent articular lesion requiring surgical treatment, (2) axial malalignment in the index limb, and (3) functional limitation or pain in the contralateral knee. The day after the procedure, the patients were randomized to receive a single injection of 3 mL HA or 3 mL saline solution after surgical drains were removed. All patients were evaluated at baseline and at 15, 30, 60, and 180 days and 12 months after surgery by use of the following tools: Short Form-36 Health Survey (SF-36), International Knee Documentation Committee (IKDC) subjective score, visual analog scale (VAS) for pain, VAS for general health status, and Tegner score. At each follow-up evaluation, the transpatellar circumference and active and passive range of motion (ROM) of both knees were recorded. RESULTS: No severe adverse events were documented after early viscosupplementation. A significant improvement was documented in both treatment groups. Significant differences were documented in the transpatellar circumference at 60 days and in active ROM at 30 days postoperatively; patients who received HA had better values compared with the placebo group (P = .022 and .027, respectively). No statistically relevant intergroup differences were found in the clinical scores. CONCLUSION: The study documented no adverse events and had some positive findings in terms of active ROM recovery and transpatellar circumference reduction. However, the early postoperative application of viscosupplementation did not lead to significant improvement in clinical scores after ACL reconstruction. REGISTRATION: NCT02630407 (ClinicalTrials.gov identifier). PMID- 27466225 TI - Safe administration of docetaxel after weekly paclitaxel-induced acute pancreatitis. AB - Acute pancreatitis is an inflammatory process of the pancreas that can be mild to severe. It requires biochemical or radiologic evidence to establish the diagnosis. Only few chemotherapy agents are directly linked to acute pancreatitis. In this case report, we describe a patient who developed a mild acute pancreatitis on weekly paclitaxel with a positive dechallenge and rechallenge. A 57-year-old woman with advanced ovarian cancer started chemotherapy with carboplatin (AUC 5 every three weeks) and weekly paclitaxel (80 mg/m2 on days 1, 8, and 15). On day 13 of cycle 1, the patient presented with elevated lipase and mild epigastric pain with a suspicion of acute pancreatitis. Because the patient was asymptomatic and pancreatic enzymes decreased on day 16, the third paclitaxel dose was given on day 17 and was followed by another increase of these enzymes. She later received carboplatin and docetaxel without any perturbation of the amylase and lipase. Applying the Naranjo adverse drug reaction probability scale, a score of nine was obtained, indicating a definite association between the administration of paclitaxel and acute pancreatitis. This adverse event could be explained by paclitaxel itself or one of two diluents: cremophor or ethanol. Because paclitaxel is use in many chemotherapy protocols, pharmacists and physicians should be aware of this rare adverse event. Docetaxel administration proved to be safe in this patient without any appearance of pancreatitis signs or symptoms. PMID- 27466226 TI - Accurate Chromosome Segregation at First Meiotic Division Requires AGO4, a Protein Involved in RNA-Dependent DNA Methylation in Arabidopsis thaliana. AB - The RNA-directed DNA methylation (RdDM) pathway is important for the transcriptional repression of transposable elements and for heterochromatin formation. Small RNAs are key players in this process by regulating both DNA and histone methylation. Taking into account that methylation underlies gene silencing and that there are genes with meiosis-specific expression profiles, we have wondered whether genes involved in RdDM could play a role during this specialized cell division. To address this issue, we have characterized meiosis progression in pollen mother cells from Arabidopsis thaliana mutant plants defective for several proteins related to RdDM. The most relevant results were obtained for ago4-1 In this mutant, meiocytes display a slight reduction in chiasma frequency, alterations in chromatin conformation around centromeric regions, lagging chromosomes at anaphase I, and defects in spindle organization. These abnormalities lead to the formation of polyads instead of tetrads at the end of meiosis, and might be responsible for the fertility defects observed in this mutant. Findings reported here highlight an involvement of AGO4 during meiosis by ensuring accurate chromosome segregation at anaphase I. PMID- 27466227 TI - Maternal Gametophyte Effects on Seed Development in Maize. AB - Flowering plants, like placental mammals, have an extensive maternal contribution toward progeny development. Plants are distinguished from animals by a genetically active haploid phase of growth and development between meiosis and fertilization, called the gametophyte. Flowering plants are further distinguished by the process of double fertilization that produces sister progeny, the endosperm and the embryo, of the seed. Because of this, there is substantial gene expression in the female gametophyte that contributes to the regulation of growth and development of the seed. A primary function of the endosperm is to provide growth support to its sister embryo. Several mutations in Zea mays subsp. mays have been identified that affect the contribution of the mother gametophyte to the seed. The majority affect both the endosperm and the embryo, although some embryo-specific effects have been observed. Many alter the pattern of expression of a marker for the basal endosperm transfer layer, a tissue that transports nutrients from the mother plant to the developing seed. Many of them cause abnormal development of the female gametophyte prior to fertilization, revealing potential cellular mechanisms of maternal control of seed development. These effects include reduced central cell size, abnormal architecture of the central cell, abnormal numbers and morphology of the antipodal cells, and abnormal egg cell morphology. These mutants provide insight into the logic of seed development, including necessary features of the gametes and supporting cells prior to fertilization, and set up future studies on the mechanisms regulating maternal contributions to the seed. PMID- 27466228 TI - Biochemical Activities and Genetic Functions of the Drosophila melanogaster Fancm Helicase in DNA Repair. AB - Repair of DNA damage is essential to the preservation of genomic stability. During repair of double-strand breaks, several helicases function to promote accurate repair and prevent the formation of crossovers through homologous recombination. Among these helicases is the Fanconi anemia group M (FANCM) protein. FANCM is important in the response to various types of DNA damage and has been suggested to prevent mitotic crossovers during double-strand break repair. The helicase activity of FANCM is believed to be important in these functions, but no helicase activity has been detected in vitro We report here a genetic and biochemical study of Drosophila melanogaster Fancm. We show that purified Fancm is a 3' to 5' ATP-dependent helicase that can disassemble recombination intermediates, but only through limited lengths of duplex DNA. Using transgenic flies expressing full-length or truncated Fancm, each with either a wild-type or mutated helicase domain, we found that there are helicase independent and C-terminal-independent functions in responding to DNA damage and in preventing mitotic crossovers. PMID- 27466229 TI - Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson's Disease. AB - Understanding how genetic variation affects intermediate phenotypes, like DNA methylation or gene expression, and how these in turn vary with complex human disease provides valuable insight into disease etiology. However, intermediate phenotypes are typically tissue and developmental stage specific, making relevant phenotypes difficult to assay. Assembling large case-control cohorts, necessary to achieve sufficient statistical power to assess associations between complex traits and relevant intermediate phenotypes, has therefore remained challenging. Imputation of such intermediate phenotypes represents a practical alternative in this context. We used a mixed linear model to impute DNA methylation (DNAm) levels of four brain tissues at up to 1826 methylome-wide sites in 6259 patients with Parkinson's disease and 9452 controls from across five genome-wide association studies (GWAS). Six sites, in two regions, were found to associate with Parkinson's disease for at least one tissue. While a majority of identified sites were within an established risk region for Parkinson's disease, suggesting a role of DNAm in mediating previously observed genetic effects at this locus, we also identify an association with four CpG sites in chromosome 16p11.2. Direct measures of DNAm in the substantia nigra of 39 cases and 13 control samples were used to independently replicate these four associations. Only the association at cg10917602 replicated with a concordant direction of effect (P = 0.02). cg10917602 is 87 kb away from the closest reported GWAS hit. The employed imputation methodology implies that variation of DNAm levels at cg10917602 is predictive for Parkinson's disease risk, suggesting a possible causal role for methylation at this locus. More generally this study demonstrates the feasibility of identifying predictive epigenetic markers of disease risk from readily available data sets. PMID- 27466230 TI - A Fossilized Energy Distribution of Lightning. AB - When lightning strikes soil, it may generate a cylindrical tube of glass known as a fulgurite. The morphology of a fulgurite is ultimately a consequence of the energy of the lightning strike that formed it, and hence fulgurites may be useful in elucidating the energy distribution frequency of cloud-to-ground lightning. Fulgurites from sand mines in Polk County, Florida, USA were collected and analyzed to determine morphologic properties. Here we show that the energy per unit length of lightning strikes within quartz sand has a geometric mean of ~1.0 MJ/m, and that the distribution is lognormal with respect to energy per length and frequency. Energy per length is determined from fulgurites as a function of diameter, and frequency is determined both by cumulative number and by cumulative length. This distribution parallels those determined for a number of lightning parameters measured in actual atmospheric discharge events, such as charge transferred, voltage, and action integral. This methodology suggests a potential useful pathway for elucidating lightning energy and damage potential of strikes. PMID- 27466231 TI - A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab. AB - OBJECTIVE: To demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501. METHODS: Randomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (Cmax). Secondary end points included safety and immunogenicity. RESULTS: AUCinf and Cmax were similar across the three groups. Geometrical mean ratio (GMR) of AUCinf was 1.11 between ABP 501 and adalimumab (USA), and 1.04 between ABP 501 and adalimumab (EU). GMR of Cmax was 1.04 between ABP 501 and adalimumab (USA) and 0.96 between ABP 501 and adalimumab (EU). The 90% CIs for the GMRs of AUCinf and Cmax were within the prespecified standard PK equivalence criteria of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and were reported for 35.8%, 24.6% and 41.8% of subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) groups; incidence of antidrug antibodies (ADAbs) was similar among the study groups. CONCLUSIONS: Results of this study demonstrated PK similarity of ABP 501 with adalimumab (USA) and adalimumab (EU) after a single 40-mg subcutaneous injection. No new safety signals with ABP 501 were identified. The safety and tolerability of ABP 501 was similar to the reference products, and similar ADAb rates were observed across the three groups. TRIAL REGISTRATION NUMBER: EudraCT number 2012-000785-37; Results. PMID- 27466233 TI - A call to improve sampling methodology and reporting in young novice driver research. AB - Young drivers continue to be over-represented in road crash fatalities despite a multitude of research, communication and intervention. Evidence-based improvement depends to a great extent upon research methodology quality and its reporting, with known limitations in the peer-review process. The aim of the current research was to review the scope of research methodologies applied in 'young driver' and 'teen driver' research and their reporting in four peer-review journals in the field between January 2006 and December 2013. In total, 806 articles were identified and assessed. Reporting omissions included participant gender (11% of papers), response rates (49%), retention rates (39%) and information regarding incentives (44%). Greater breadth and specific improvements in study designs and reporting are thereby identified as a means to further advance the field. PMID- 27466232 TI - Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles. AB - Model-based analysis of regulation of gene expression (MARGE) is a framework for interpreting the relationship between the H3K27ac chromatin environment and differentially expressed gene sets. The framework has three main functions: MARGE potential, MARGE-express, and MARGE-cistrome. MARGE-potential defines a regulatory potential (RP) for each gene as the sum of H3K27ac ChIP-seq signals weighted by a function of genomic distance from the transcription start site. The MARGE framework includes a compendium of RPs derived from 365 human and 267 mouse H3K27ac ChIP-seq data sets. Relative RPs, scaled using this compendium, are superior to superenhancers in predicting BET (bromodomain and extraterminal domain) -inhibitor repressed genes. MARGE-express, which uses logistic regression to retrieve relevant H3K27ac profiles from the compendium to accurately model a query set of differentially expressed genes, was tested on 671 diverse gene sets from MSigDB. MARGE-cistrome adopts a novel semisupervised learning approach to identify cis-regulatory elements regulating a gene set. MARGE-cistrome exploits information from H3K27ac signal at DNase I hypersensitive sites identified from published human and mouse DNase-seq data. We tested the framework on newly generated RNA-seq and H3K27ac ChIP-seq profiles upon siRNA silencing of multiple transcriptional and epigenetic regulators in a prostate cancer cell line, LNCaP abl. MARGE-cistrome can predict the binding sites of silenced transcription factors without matched H3K27ac ChIP-seq data. Even when the matching H3K27ac ChIP-seq profiles are available, MARGE leverages public H3K27ac profiles to enhance these data. This study demonstrates the advantage of integrating a large compendium of historical epigenetic data for genomic studies of transcriptional regulation. PMID- 27466234 TI - Sex differences in the risk profile of hypertension: a cross-sectional study. AB - OBJECTIVE: To assess the socioeconomic and behavioural risk factors associated with hypertension among a sample male and female population in India. SETTING: Cross-sectional survey data from a Health and Demographic Surveillance System (HDSS) of rural West Bengal, India was used. PARTICIPANTS: 27 589 adult individuals (13 994 males and 13 595 females), aged >=18 years, were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Hypertension was defined as mean systolic blood pressure (SBP) >=140 mm Hg or diastolic blood pressure (DBP) >=90 mm Hg, or if the subject was undergoing regular antihypertensive therapy. Prehypertension was defined as SBP 120-139 mm Hg and DBP 80-89 mm Hg. Individuals were categorised as non-normotensives, which includes both the prehypertensives and hypertensives. Generalised ordered logit model (GOLM) was deployed to fulfil the study objective. RESULTS: Over 39% of the men and 25% of the women were prehypertensives. Almost 12.5% of the men and 11.3% of the women were diagnosed as hypertensives. Women were less likely to be non-normotensive compared to males. Odds ratios estimated from GOLM indicate that women were less likely to be hypertensive or prehypertensive, and age (OR 1.04, 95% CI 1.03 to 1.05; and OR 1.08, 95% CI 1.07 to 1.09 for males and females, respectively) and body mass index (OR 1.64, 95% CI 1.38 to 1.97 for males; and OR 1.32, 95% CI 1.08 to 1.60 for females) are associated with hypertension. CONCLUSIONS: An elevated level of hypertension exists among a select group of the rural Indian population. Focusing on men, an intervention could be designed for lifestyle modification to curb the prevalence of hypertension. PMID- 27466235 TI - Characteristics of patients with type 2 diabetes mellitus newly treated with GLP 1 receptor agonists (CHADIG Study): a cross-sectional multicentre study in Spain. AB - OBJECTIVE: Several glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1Ra) have been made recently available in Spain for type 2 diabetes mellitus (DM2) treatment. There are no published data on the clinical and sociodemographic profile of patients initiating treatment with GLP-1Ra in Spain. Our objective was to understand these patients' characteristics in a real-world clinical practice setting. DESIGN: Cross-sectional observational study. SETTING: Spanish specialist outpatient clinics. PARTICIPANTS: 403 adults with DM2 initiating GLP-1Ra treatment were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Sociodemographic and DM2-related clinical data, including treatment at and after GLP-1Ra initiation and comorbidities, were collected. RESULTS: Evaluable patients (n=403; 50.9% female) were included (July 2013 to March 2014) at 24 centres by 53 specialists (47 endocrinology, 6 internal medicine), with the following profile (value+/-SD): age (58.3+/-10.4 years), diabetes duration (9.9+/-7 years), body mass index (BMI; 36.2+/-5.5) and glycated haemoglobin (HbA1c; 8.4+/-1.4%); 14% had HbA1c<=7%. Previous antidiabetic treatment: 53.8% only oral antidiabetic drugs (OADs), 5.2% insulin and 40% insulin and OAD; of those receiving OAD, 35% single drug, 38.2% 2 drugs and 24% 3 drugs. Concomitant to GLP-1Ra, 55.3% were only on OAD, 36.2% on insulin and OAD, and 7.2% only on insulin. Of those receiving OAD, the GLP-1Ra was mainly associated with 1 drug (65%) or 2 drugs (31.8%). GLP-1Ra are frequently added to existing antidiabetic drugs, with dipeptidyl peptidase-4 inhibitors being the OAD most frequently switched (45% receiving 1 before starting GLP-1Ra, only 2.7% receiving it concomitantly). CONCLUSIONS: In Spain, GLP-1Ra therapy is usually started in combination with OADs or OADs and insulin. These drugs are used in relatively young patients often not reaching therapeutic goals with other treatment combinations, roughly a decade after diagnosis and with a relatively high BMI. The latter could be explained by Spanish regional payers limiting reimbursed prescription to patients with a minimum BMI threshold (>30 in most regions, >35 in some). PMID- 27466237 TI - Patterns of weight change after the diagnosis of type 2 diabetes in Scotland and their relationship with glycaemic control, mortality and cardiovascular outcomes: a retrospective cohort study. AB - OBJECTIVES: To determine weight change patterns in Scottish patients 2 years after diagnosis of type 2 diabetes and to examine these in association with medium-term glycaemic, mortality and cardiovascular outcomes. SETTING: Using a retrospective cohort design, ethical approval was obtained to link the Scottish diabetes care database to hospital admission and mortality records. PARTICIPANTS: 29 316 overweight/obese patients with incident diabetes diagnosed between 2002 and 2006 were identified with relevant information for >=2 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Weight records over time provided intrapatient weight change and variation and glycated haemoglobin (HbA1c) gave measures of glycaemic control. These characteristics and demographic variables at diagnosis were linked with notifications of death (2-5 years after diagnosis) and cardiovascular events (0-5 year after diagnosis). RESULTS: By 2 years, 36% of patients had lost >=2.5% of their weight. Increasing age, being female and a higher body mass index at diagnosis were associated with larger proportions of weight lost (p<0.001). Multivariable modelling showed that inadequate glycaemic control at 2 years was associated with being younger at baseline, being male, having lower levels of obesity at diagnosis, gaining weight or being weight stable with weight change variability, and starting antidiabetic medication. While weight change itself was not related to mortality or cardiovascular outcomes, major weight variability was independently associated with poorer survival and increased cardiovascular outcome risks, as was deprivation. CONCLUSIONS: Our results suggest that weight loss or being weight stable with little weight variability early after diabetes diagnosis, are associated with better glycaemic control and we identified groups less able to lose weight. With respect to mortality and cardiovascular outcomes, although weight change at 2 years was a weak predictor, major weight variability appeared to be the more relevant factor. PMID- 27466236 TI - SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol. AB - INTRODUCTION: The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, 'small molecule'-mediated Rho inhibition after acute SCI warrants clinical investigation. METHODS AND ANALYSIS: Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. ETHICS AND DISSEMINATION: The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02096913; Pre-results. PMID- 27466238 TI - Hundred top-cited articles focusing on acute kidney injury: a bibliometric analysis. AB - BACKGROUND: Acute kidney injury (AKI) is a major global health issue, associated with poor short-term and long-term outcomes. Research on AKI is increasing with numerous articles published. However, the quantity and quality of research production in the field of AKI is unclear. METHODS AND ANALYSIS: To analyse the characteristics of the most cited articles on AKI and to provide information about achievements and developments in AKI, we searched the Science Citation Index Expanded for citations of AKI articles. For the top 100 most frequently cited articles (T100), we evaluated the number of citations, publication time, province of origin, journal, impact factor, topic or subspecialty of the research, and publication type. RESULTS: The T100 articles ranged from a maximum of 1971 citations to a minimum of 215 citations (median 302 citations). T100 articles were published from 1951 to 2011, with most articles published in the 2000s (n=77), especially the 5-year period from 2002 to 2006 (n=51). The publications appeared in 30 journals, predominantly in the general medical journals, led by New England Journal of Medicine (n=17), followed by expert medical journals, led by the Journal of the American Society of Nephrology (n=16) and Kidney International (n=16). The majority (83.7%) of T100 articles were published by teams involving >=3 authors. T100 articles originated from 15 countries, led by the USA (n=81) followed by Italy (n=9). Among the T100 articles, 69 were clinical research, 25 were basic science, 21 were reviews, 5 were meta-analyses and 3 were clinical guidelines. Most clinical articles (55%) included patients with any cause of AKI, followed by the specific causes of contrast-induced AKI (25%) and cardiac surgery-induced AKI (15%). CONCLUSIONS: This study provides a historical perspective on the scientific progress on AKI, and highlights areas of research requiring further investigations and developments. PMID- 27466239 TI - Protocol for study of financial incentives for smoking cessation in pregnancy (FISCP): randomised, multicentre study. AB - INTRODUCTION: Maternal smoking during pregnancy is associated with adverse perinatal and postnatal health outcomes. The efficacy of nicotine replacement therapies in helping pregnant smokers to quit is not clearly demonstrated; therefore new interventions should be proposed and assessed. Financial incentives rewarding abstinence from tobacco smoking is one of the promising options. OBJECTIVE: To assess the efficacy of financial incentives on smoking abstinence among French pregnant smokers. METHODS AND ANALYSIS: PARTICIPANTS: pregnant smokers aged >=18 years, smoking at least five manufactured or three roll-your own cigarettes per day, and pregnant for <18 weeks of amenorrhoea (WA). SETTING: participants will be recruited, included and followed-up at monthly face-to-face visits in 16 maternity wards in France. INTERVENTIONS: participants will be randomised to a control or an intervention group. After a predefined quit date, participants in the control group will receive ?20 vouchers at the completion of each visit but no financial incentive for smoking abstinence. Participants in the intervention group will be rewarded for their abstinence by vouchers on top of the ?20 show-up fee. The amount of reward for abstinence will increase as a function of duration of abstinence to stimulate longer periods of abstinence. MAIN OUTCOME MEASURE: complete abstinence from quit date to the last predelivery visit. SECONDARY OUTCOME MEASURES: point prevalence abstinence, time to relapse to smoking, birth weight, fetal growth restriction, preterm birth. Main data analysis: outcomes will be analysed on an intention-to-treat (ITT) basis. The ITT population is defined as all randomised smoking pregnant women. ETHICS AND DISSEMINATION: The research protocol was approved by the ethics committee (Comite de Protection des Personnes, CPP) of the Pitie-Salpetriere Hospital on 15 May 2015, and Amendment No 1 was approved on 13 July 2015. Results will be presented at scientific meetings and published. TRIAL REGISTRATION NUMBER: NCT02606227; Pre results. PMID- 27466240 TI - Association of dental and periodontal disease with chronic kidney disease in patients of a single, tertiary care centre in Thailand. AB - BACKGROUND: Several studies have shown an association between oral diseases and chronic kidney disease (CKD), and regular oral care may be an important strategy for reducing the burden of CKD. The objective of this study was therefore to evaluate the association between dental and periodontal diseases in Thai patients with various stages of CKD. METHODS: This was designed as a cross-sectional study and was performed between 2011 and 2012. The inclusion criteria were age >20 years and a diagnosis of CKD for at least 90 days. Data from medical records were collected, clinical oral examination was performed, and data were statistically analysed. RESULTS: A total of 129 patients with different stages of CKD were included. Ninety-eight (76%) were men. The age range was 30-86 years. The Decay, Missing and Filling Tooth Index and the number of missing teeth were higher in the group with moderate CKD than in the control group (21 vs 17.5, p=0.045, 13 vs 8 p=0.01, respectively). Serum albumin levels decreased when estimated glomerular filtration rate (eGFR) was in decline (gamma=0.33; p=0.002). Severe periodontitis was significantly higher in the 'more severe CKD group' (eGFR <60 mL/min/1.73 m(2)) than in the 'less severe CKD group' (eGFR 60-90 mL/min/1.73 m(2); 24% vs 9%, p=0.03). Severe periodontitis, eGFR <30 mL/min/1.73 m(2) and brushing teeth more than once a day were associated with hypoalbuminaemia (defined as <3.8 g/dL) (OR (95% CI) 5.88 (1.64 to 21.11), 5.80 (1.58 to 21.35) and 0.16 (0.05 to 0.60), respectively). CONCLUSIONS: Severe periodontal diseases were more prevalent in patients with more severe CKD than in those with less severe CKD. The novel association of serum albumin levels with periodontal status was demonstrated in progressive stages of CKD. Dental intervention may be beneficial from the early stages of CKD. PMID- 27466241 TI - Study protocol for a randomised controlled trial to test the effectiveness of providing information on childbirth and postnatal period to partners of pregnant women. AB - INTRODUCTION: The objective of this study is to investigate the effect of the distribution of a booklet providing information to fathers during their partners' pregnancies on fathers' and mothers' postpartum mental health and quality of life (QOL), as well as on fathers' childcare participation and living situations. METHODS AND ANALYSIS: This randomised controlled trial will comprise 554 couples consisting of pregnant women due to give birth at an obstetric institution in Aichi Prefecture, Japan and their partners. Participants will be recruited during prenatal check-ups in the third trimester, and those who provide written consent will be allocated randomly to an intervention and a control group. The pregnant women's partners allocated to the intervention group will be given a booklet written for men containing information on childbirth and postnatal period. Its content will include matters such as what preparations the partner should make before birth and tips for housework and childcare as well as how to prevent unintentional injury to the baby. The control group will not receive any intervention. A baseline survey in the third trimester and follow-up surveys at 1 and 3 months post partum will be carried out using self-administered questionnaires. The primary outcome is the proportion of new mothers' partners at risk for paternal depression (Edinburgh Postnatal Depression Scale score >=8). Secondary outcomes include the risk of postnatal depression in new mothers, QOL of new mothers and their partners, partners' knowledge of and engagement in housework and childcare, marital relations and parenting stress on the part of new mothers. ETHICS AND DISSEMINATION: This study has been approved by the Ethical Committee at the National Center for Child Health and Development, Tokyo, Japan. The results of the study will be widely disseminated as peer-reviewed papers and at international conferences, with the aim of improving public health services in Japan. TRIAL REGISTRATION NUMBER: UMIN000021475; Pre-results. PMID- 27466242 TI - Hearing and vision screening tools for long-term care residents with dementia: protocol for a scoping review. AB - INTRODUCTION: Hearing and vision loss among long-term care (LTC) residents with dementia frequently goes unnoticed and untreated. Despite negative consequences for these residents, there is little information available about their sensory abilities and care assessments and practices seldom take these abilities or accessibility needs into account. Without adequate knowledge regarding such sensory loss, it is difficult for LTC staff to determine the level of an individual's residual basic competence for communication and independent functioning. We will conduct a scoping review to identify the screening measures used in research and clinical contexts that test hearing and vision in adults aged over 65 years with dementia, aiming to: (1) provide an overview of hearing and vision screening in older adults with dementia; and (2) evaluate the sensibility of the screening tools. METHODS AND ANALYSIS: This scoping review will be conducted using the framework by Arksey and O'Malley and furthered by methodological enhancements from cited researchers. We will conduct electronic database searches in CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We will also carry out a 'grey literature' search for studies or materials not formally published, both online and through interview discussions with healthcare professionals and research clinicians working in the field. Our aim is to find new and existing hearing and vision screening measures used in research and by clinical professionals of optometry and audiology. Abstracts will be independently reviewed twice for acceptance by a multidisciplinary team of researchers and research clinicians. ETHICS AND DISSEMINATION: This review will inform health professionals working with this growing population. With the review findings, we aim to develop a toolkit and an algorithmic process to select the most appropriate hearing and vision screening assessments for LTC residents with dementia that will facilitate accurate testing and can inform care planning, thereby improving residents' quality of life. PMID- 27466243 TI - Initial experience using a femtosecond laser cataract surgery system at a UK National Health Service cataract surgery day care centre. AB - OBJECTIVES: To describe the initial outcomes following installation of a cataract surgery laser system. SETTING: National Health Service cataract surgery day care unit in North London, UK. PARTICIPANTS: 158 eyes of 150 patients undergoing laser assisted cataract surgery. INTERVENTIONS: Laser cataract surgery using the AMO Catalys femtosecond laser platform. PRIMARY AND SECONDARY OUTCOME MEASURES: PRIMARY OUTCOME MEASURE: intraoperative complications including anterior and posterior capsule tears. SECONDARY OUTCOME MEASURES: docking to the laser platform, successful treatment delivery, postoperative visual acuities. RESULTS: Mean case age was 67.7+/-10.8 years (range 29-88 years). Docking was successful in 94% (148/158 cases), and in 4% (6/148 cases) of these, the laser delivery was aborted part way during delivery due to patient movement. A total of 32 surgeons, of grades from junior trainee to consultant, performed the surgeries. Median case number per surgeon was 3 (range from 1-20). The anterior capsulotomy was complete in 99.3% of cases, there were no anterior capsule tears (0%). There were 3 cases with posterior capsule rupture requiring anterior vitrectomy, and 1 with zonular dialysis requiring anterior vitrectomy (4/148 eyes, 2.7%). These 4 cases were performed by trainee surgeons, and were either their first laser cataract surgery (2 surgeons) or their first and second laser cataract surgeries (1 surgeon). CONCLUSIONS: Despite the learning curve, docking and laser delivery were successfully performed in almost all cases, and surgical complication rates and visual outcomes were similar to those expected based on national data. Complications were predominately confined to trainee surgeons, and with the exception of intraoperative pupil constriction appeared unrelated to the laser performed steps. PMID- 27466244 TI - 'My independent streak may get in the way': how older adults respond to falls prevention education in hospital. AB - OBJECTIVES: The aim of the study was to determine how providing individualised falls prevention education facilitated behaviour change from the perspective of older hospital patients on rehabilitation wards and what barriers they identified to engaging in preventive strategies. DESIGN: A prospective qualitative survey. METHODS: Older patients (n=757) who were eligible (mini-mental state examination score>23/30) received falls prevention education while admitted to eight rehabilitation hospital wards in Western Australia. Subsequently, 610 participants were surveyed using a semistructured questionnaire to gain their response to the in-hospital education and their identified barriers to engaging in falls prevention strategies. Deductive content analysis was used to map responses against conceptual frameworks of health behaviour change and risk taking. RESULTS: Participants who responded (n=473) stated that the education raised their awareness, knowledge and confidence to actively engage in falls prevention strategies, such as asking for assistance prior to mobilising. Participants' thoughts and feelings about their recovery were the main barriers they identified to engaging in safe strategies, including feeling overconfident or desiring to be independent and thinking that staff would be delayed in providing assistance. The most common task identified as potentially leading to risk-taking behaviour was needing to use the toilet. CONCLUSIONS: Individualised education assists older hospital rehabilitation patients with good levels of cognition to engage in suitable falls prevention strategies while on the ward. Staff should engage with patients to understand their perceptions about their recovery and support patients to take an active role in planning their rehabilitation. PMID- 27466246 TI - Erratum for Trinite et al., HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma Chain Cytokines. PMID- 27466245 TI - Impact of Potentially Inappropriate Prescribing on Adverse Drug Events, Health Related Quality of Life and Emergency Hospital Attendance in Older People Attending General Practice: A Prospective Cohort Study. AB - BACKGROUND: Potentially inappropriate prescribing (PIP) describes medications where risk generally outweighs benefit for older people. Cross-sectional studies suggest an association between PIP and poorer health outcomes but there is a paucity of prospective cohort studies. This study investigates the longitudinal association of PIP with adverse drug events (ADEs), health related quality of life, and accident & emergency visits. METHODS: Study design: Two-year (2010 2012) prospective cohort study (n = 904, >=70 years, community-dwelling) with linked pharmacy dispensing data. EXPOSURE: Baseline PIP: Screening Tool for Older Persons potentially Inappropriate Prescriptions (STOPP) and Beers 2012 applied 12 months prior. STUDY OUTCOMES: ADEs (patient interview), health related quality of life (EQ-5D-3L: patient questionnaire), and accident & emergency visits (general practice medical record review). STATISTICAL ANALYSIS: Descriptive statistics: Poisson (incidence rate ratio [95% confidence interval [CI]], linear regression models [regression coefficient [95% CI]], and logistic [odds ratio [OR] [95% CI]). RESULTS: Of 791 participants eligible for follow-up, 673 (85%) returned a questionnaire and 605 (77%) also completed an ADE interview. Baseline STOPP PIP prevalence was 40% and 445 (74%) patients reported >=1 ADE at follow-up. In multivariable analysis, >=2 STOPP PIP was associated with ADEs (adjusted incidence rate ratio: 1.29 [95% CI 1.03, 1.85; p = .03]; poorer health related quality of life [adjusted regression coefficient: -0.11 [95% CI -0.16, -0.06; p < .001]]; and, >=1 accident & emergency visit [adjusted OR: 1.85 [95% CI 1.06, 3.24; p = .03]]). Baseline Beers 2012 prevalence was 26% and there was no association with adverse health outcomes in multivariable analysis. CONCLUSIONS: Older community-dwelling people, prescribed >=2 STOPP PIP are more likely to report ADEs, poorer health related quality of life and attend the accident & emergency department over 2-year follow-up. PMID- 27466248 TI - Factors influencing trust and mistrust in health promotion partnerships. AB - Partnerships between sectors can achieve better outcomes than can be achieved by individual partners working alone. Trust is necessary for partnerships to function effectively. Mistrust makes partnership working difficult, if not impossible. There has been little research into partnership functioning factors that influence trust and mistrust. This study aimed to identify these factors in health promotion partnerships. Data were collected from 337 partners in 40 health promotion partnerships using a postal survey. The questionnaire incorporated multi-dimensional scales designed to assess the contribution of factors that influence partnership trust and mistrust. Newly validated scales were developed for trust, mistrust and power. Multiple regression analysis was used to identify the significance of each factor to partnership trust and mistrust. Power was found to be the only predictor of partnership trust. Power, leadership, and efficiency were the most important factors influencing partnership mistrust. Power in partnerships must be shared or partners will not trust each other. Power sharing and trust-building mechanisms need to be built into partnerships from the beginning and sustained throughout the collaborative process. PMID- 27466249 TI - Spaces of knowing: an Australian case study of capacity building across boundaries in a health promotion learning network. AB - This article explores the potential for health promotion capacity building across boundaries in a place-based health promotion learning network generated as part of a recent Australian Research Council-funded project in Queensland, Australia. We emphasise in particular the potential of creating new 'at the boundary' spaces of knowing that encourage and enable health promotion workers to work in interdisciplinary and intersectoral ways. The article discusses the way that diverse health promotion workers from different disciplines and government and non-government organisations came together to learn 'how to do' in new or re invigorated ways. For many network participants, this cross-boundary space of knowing and capacity building provided a welcome respite from their daily contexts of practice which may be limited by institutional, disciplinary or other boundaries. PMID- 27466250 TI - Development and validation of the Taiwan Children's Health Literacy Test. AB - BACKGROUND: Currently, health literacy (HL) worldwide is measured primarily among adults from a medical perspective. A children's HL test from a health promotion perspective is needed. This study develops the Taiwan Children's Health Literacy Test (TCHL) targeted at Taiwanese sixth-graders. METHODS: HL indicators were identified through interviews of sixth-grade teachers, primary caregivers, and sixth-graders. They were used to develop a 25-item online test, which was finalized after pretesting and administered to a stratified random sample of 671 students across 29 sixth-grade classes. RESULTS: The response rate was 87.2% (585 participants). Cronbach's alpha was 0.60-0.78 for the HL subtests and 0.79 for the overall HL test. Correlation coefficients among subtests ranged from 0.49 to 0.87. The average proportion correct was 0.80 for overall HL. In item response theory analysis, the difficulty level ranged from -2.77 to -0.40, while the degree of discrimination was 0.44-2.65. Item information peaked when the ability value was approximately -1.8. Furthermore, HL scores had a significant positive correlation with health behaviors. CONCLUSIONS: Overall, the test was found to be reliable and valid, with a low level of difficulty for basic HL ability. The present results can be used as a reference by government health education units to investigate national HL in children. PMID- 27466251 TI - Negative Aging Stereotypes Impair Performance on Brief Cognitive Tests Used to Screen for Predementia. AB - Objectives: There is today ample evidence that negative aging stereotypes impair healthy older adults' performance on cognitive tasks. Here, we tested whether these stereotypes also decrease performance during the screening for predementia on short cognitive tests widely used in primary care. Method: An experiment was conducted on 80 healthy older adults taking the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) under Threat or Reduced threat condition. Results: Stereotype threat significantly impaired older adults' performance on both tests, resulting in 40% of older adults meeting the screening criteria for predementia, compared with 10% in Reduced-threat condition (MMSE and MoCA averaged). Discussion: Our research highlights the influence of aging stereotypes on short cognitive tests used to screen for predementia. It is of critical importance that physicians provide a threat-free testing environment. Further research should clarify whether this socially induced bias may also operate in secondary care by generating false positives. PMID- 27466252 TI - Use of deep laryngeal oxygen insufflation during laryngoscopy in children: a randomized clinical trial. AB - BACKGROUND: Brief periods of haemoglobin oxygen desaturation are common in children during induction of general anaesthesia. We tested the hypothesis that oxygen insufflation during intubation slows desaturation. METHODS: Patients 1-17 yr old undergoing nasotracheal intubation were enrolled and randomly assigned to one of three groups: standard direct laryngoscopy (DL); laryngoscopy with Truview PCD videolaryngoscope (VLO2); or laryngoscopy with an oxygen cannula attached to the side of a standard laryngoscope (DLO2). The co-primary outcomes were time to 1% reduction in [Formula: see text] from baseline, and the slope of overall desaturation vs time. All three groups were compared against each other. RESULTS: Data from 457 patients were available for the final analysis: 159 (35%) DL; 145 (32%) DLO2; and 153 (33%) VLO2. Both VLO2 and DLO2 were superior to DL in both time to a 1% reduction in [Formula: see text] from baseline and the overall rate of desaturation (all P<0.001). The 25th percentile (95% confidence interval) of time to a 1% saturation decrease was 30 (24, 39) s for DL, 67 (35, 149) s for DLO2 and 75 (37, 122) s for VLO2. Mean desaturation slope was 0.13 (0.11, 0.15)% s(-1) for DL, 0.04 (0.02, 0.06)% s(-1) for DLO2 and 0.03 (0.004, 0.05)% s(-1) for VLO2. We did not find a correlation between decrease in [Formula: see text] percentage and BMI or age. CONCLUSIONS: Laryngeal oxygen insufflation increases the time to 1% desaturation and reduces the overall rate of desaturation during laryngoscopy in children. CLINICAL TRIAL REGISTRATION: NCT01886807. PMID- 27466254 TI - Nivolumab May Work as First-Line NSCLC Therapy. AB - The first trial of nivolumab as a first-line therapy for non-small cell lung cancer suggests that the drug can improve survival. Adding some platinum-doublet chemotherapy combinations did not further increase this effect, although the median overall survival wasn't reached for paclitaxel and carboplatin. Adding chemotherapy may increase the immunotherapy's toxicity. PMID- 27466253 TI - Fasciola hepatica Surface Tegument: Glycoproteins at the Interface of Parasite and Host. AB - Fasciola hepatica, commonly known as liver fluke, is a trematode that causes Fasciolosis in ruminants and humans. The outer tegumental coat of F. hepatica (FhTeg) is a complex metabolically active biological matrix that is continually exposed to the host immune system and therefore makes a good vaccine target. F. hepatica tegumental coat is highly glycosylated and helminth-derived immunogenic oligosaccharide motifs and glycoproteins are currently being investigated as novel vaccine candidates. This report presents the first systematic characterization of FhTeg glycosylation using lectin microarrays to characterize carbohydrates motifs present, and lectin histochemistry to localize these on the F. hepatica tegument. We discovered that FhTeg glycoproteins are predominantly oligomannose oligosaccharides that are expressed on the spines, suckers and tegumental coat of F. hepatica and lectin blot analysis confirmed the abundance of N- glycosylated proteins. Although some oligosaccharides are widely distributed on the fluke surface other subsets are restricted to distinct anatomical regions. We selectively enriched for FhTeg mannosylated glycoprotein subsets using lectin affinity chromatography and identified 369 proteins by mass spectrometric analysis. Among these proteins are a number of potential vaccine candidates with known immune modulatory properties including proteases, protease inhibitors, paramyosin, Venom Allergen-like II, Enolase and two proteins, nardilysin and TRIL, that have not been previously associated with F. hepatica Furthermore, we provide a comprehensive insight regarding the putative glycosylation of FhTeg components that could highlight the importance of further studies examining glycoconjugates in host-parasite interactions in the context of F. hepatica infection and the development of an effective vaccine. PMID- 27466255 TI - Medical performance and the 'inaccessible' experience of illness: an exploratory study. AB - We report a survey of audience members' responses (147 questionnaires collected at seven performances) and 10 in-depth interviews (five former patients and two family members, three medical practitioners) to bloodlines, a medical performance exploring the experience of haematopoietic stem-cell transplant as treatment for acute leukaemia. Performances took place in 2014 and 2015. The article argues that performances that are created through interdisciplinary collaboration can convey otherwise 'inaccessible' illness experiences in ways that audience members with personal experience recognise as familiar, and find emotionally affecting. In particular such performances are adept at interweaving 'objectivist' (objective, medical) and 'subjectivist' (subjective, emotional) perspectives of the illness experience, and indeed, at challenging such distinctions. We suggest that reflecting familiar yet hard-to-articulate experiences may be beneficial for the ongoing emotional recovery of people who have survived serious disease, particularly in relation to the isolation that they experience during and as a consequence of their treatment. PMID- 27466256 TI - Acquisition and Long-term Retention of Bedside Ultrasound Skills in First-Year Medical Students. AB - OBJECTIVES: The purpose of this study was to assess bedside ultrasound skill acquisition and retention in medical students after completion of the first year of a new undergraduate bedside ultrasound curriculum at McGill University. METHODS: Skill acquisition was assessed in first-year medical students (n = 195) on completion of their bedside ultrasound instruction. Instruction included 6 clinically based 60-minute practical teaching sessions evenly spaced throughout the academic year. Students' ability to meet course objectives was measured according to a 4-point Likert rating scale. Evaluations were performed by both instructors and the students themselves. Retention of skill acquisition was evaluated 8 months later on a year-end practical examination. RESULTS: The mean percentage +/- SD of students assigned a rating of "strongly agree" or "agree" by instructors was 98% +/- 0.4% for all 6 teaching sessions (strongly agree, 52% +/- 3%; agree, 46% +/- 3%). According to student self-evaluations, the mean percentage of students assigned a rating of strongly agree was significantly greater than the percentage assigned by instructors for all teaching sessions (86% +/- 2% versus 52% +/- 3%; P < .0005). Evaluation of skill retention on the year-end examination showed that 91% +/- 2% of students were assigned a rating of strongly agree or agree for their ability to demonstrate skills learned 8 months previously. Ninety-five percent of students reported that bedside ultrasound improved their understanding of anatomy for all 6 teaching sessions (mean, 95% +/ 0.01%). CONCLUSIONS: These results demonstrate that first-year medical students show acquisition and long-term retention of basic ultrasound skills on completion of newly implemented bedside ultrasound instruction. PMID- 27466257 TI - Three-Versus Two-Dimensional Sonographic Biometry for Predicting Birth Weight and Macrosomia in Diabetic Pregnancies. AB - OBJECTIVES: The purpose of this study was to test the hypothesis that a formula incorporating 3-dimensional (3D) fractional thigh volume would be superior to the conventional 2-dimensional (2D) formula of Hadlock et al (Am J Obstet Gynecol 1985; 151:333-337) for predicting birth weight and macrosomia. METHODS: We conducted a prospective cohort study of pregnancies complicated by pregestational or gestational diabetes and delivered after 38 weeks. Two-dimensional and 3D sonographic examinations were performed for fetal biometry and factional thigh volumes at 34 to 37 weeks. Fetal weight was estimated by Hadlock's 2D formula IV, which uses only 2D biometry, and formula 6 from Lee et al (Ultrasound Obstet Gynecol 2009; 34:556-565), which incorporates 3D fractional thigh volume and 2D biometry. The gestation-adjusted projection method was used to estimate predicted birth weights from 2D and 3D estimates. The primary outcome was fetal macrosomia, which was defined as birth weight of 4000 g or higher. RESULTS: A total of 115 women with diabetes met inclusion criteria, and 17 (14.8%) delivered macrosomic neonates. The mean percentage error was significantly lower for the 2D than the 3D projected estimate (1.0% versus 12.0%; P < .01). The standard deviation of the mean percentage error was also significantly lower for the 2D projected estimate (10.2% versus 17.2%; P< .01). Two-dimensional biometry was overall superior to 3D biometry for predicting macrosomia (area under the receiver operating characteristic curve, 0.88 versus 0.75; P = .03). Specificity was significantly higher for 2D biometry (85% versus 66%; P < .01), whereas the difference in sensitivity was not statistically significant (59% versus 71%; P = .22). CONCLUSIONS: In this study, the Hadlock 2D formula was superior to the 3D method for predicting birth weight and macrosomia in diabetic women when used approximately 2 weeks before delivery, based on the gestation-adjusted projection method. PMID- 27466258 TI - Multiterritory Atherosclerosis and Carotid Intima-Media Thickness as Cardiovascular Risk Predictors After Percutaneous Angioplasty of Symptomatic Subclavian Artery Stenosis. AB - OBJECTIVES: To identify independent predictors of cardiovascular events among patients with subclavian artery stenosis. METHODS: Two hundred eighteen consecutive patients with subclavian artery stenosis referred to angioplasty were examined for coexistent coronary, renal, or lower extremity artery stenosis of 50% or greater. Initial carotid intima-media thickness and internal carotid artery (ICA) stenosis were assessed. Intima-media thickness was reassessed in 108 randomly chosen patients to evaluate the change over time. The incidence of cardiovascular death, myocardial infarction (MI), ischemic stroke, and symptomatic lesion progression was recorded. RESULTS: The patients included 116 men and 102 women (mean age +/- SD, 62.1 +/- 8.4 years). Isolated subclavian artery stenosis and involvement of 1, 2, and 3 or 4 other territories with stenosis of 50% or greater were found in 46 (21.1%), 83 (38.1%), 55 (25.2%), and 34 (15.6%) patients, respectively. Internal carotid artery stenosis of 50% or greater (relative risk [RR], 1.54; 95% confidence interval [CI], 1.39-1.70; P < .001) and initial intima-media thickness (RR, 1.16; 95% CI, 1.05-1.28; P = .005) were identified as independent markers of multiterritory atherosclerosis. The optimal intima-media thickness cutoff for atherosclerosis extent was 1.3 mm (sensitivity, 75.6%; specificity, 76.1%). During follow-up of 57 +/- 35 months, cardiovascular death, MI, and ischemic stroke occurred in 29 patients (13.3%). Those patients had significantly higher intima-media thickness progression (+0.199 +/- 0.57 versus +0.008 +/- 0.26 mm; P = .039) and more widespread initial atherosclerosis (mean territories, 1.8 +/- 1.1 versus 1.3 +/- 1.1; P = .042). Independent predictors of cardiovascular death, MI, ischemic stroke, and lesion progression were coronary artery disease (RR, 1.32; 95% CI, 1.10-1.58; P = .003) and intima-media thickness progression (RR, 1.22; 95% CI, 1.02-1.46; P = .033; sensitivity, 75.0%; specificity, 61.8%). CONCLUSIONS: In patients with symptomatic subclavian artery stenosis, baseline carotid intima-media thickness and ICA stenosis of 50% or greater are associated with multiterritory atherosclerosis, whereas intima-media thickness progression is associated with the risk of cardiovascular events. PMID- 27466259 TI - Echocardiographic Parameters and Outcomes in Primary Fetal Cardiomyopathy. AB - OBJECTIVES: Primary fetal cardiomyopathy is a rare entity, with a poor prognosis. We sought to describe its echocardiographic characteristics and outcomes. METHODS: We performed a 12-year retrospective review of fetuses with primary cardiomyopathy. RESULTS: Of more than 6000 fetuses evaluated, 25 met criteria for primary cardiomyopathy, and 18 had sufficient echocardiographic and pregnancy outcome data for inclusion. At echocardiography, the median gestational age was 29.6 weeks (range, 21.0-36.4 weeks); median cardiovascular profile score was 6 (range, 1-9); median right ventricular Tei index was 0.52 (range, 0.32-0.94); and median left ventricular Tei index was 0.40 (range, 0.15-0.88). Two had fetal demise, and 16 survived to delivery. The median cardiovascular profile score in those with fetal demise was 3.0 and in those who survived to delivery was 6.5 (range, 3-9; P = .14). The median right ventricular Tei index in those with fetal demise was 0.39 and in those surviving to delivery was 0.53 (range, 0.38-0.94; P = .49). The median left ventricular Tei index in those with fetal demise was 0.29 and in those surviving to delivery was 0.42 (range, 0.15-0.88; P = .50). Sixty day survival was available in 11 of 16 fetuses. In addition to the 2 with fetal demise, 4 had postnatal demise, and 5 were alive at a median follow-up of 39 months. Hydrops (P = .01), skin edema (P = .01), and mild or greater mitral regurgitation (P = .02) were associated with fetal or postnatal demise, with a trend toward an association between moderate or greater tricuspid regurgitation (P = .07) and fetal or postnatal demise. CONCLUSIONS: Hydrops and atrioventricular valvar regurgitation are ominous signs in primary fetal cardiomyopathy. Although other commonly used methods for assessing cardiovascular performance may help in diagnosing primary cardiomyopathy, these data suggest limited predictive value. PMID- 27466260 TI - Doppler Sonography of Blood Flow Velocity in the Vertebral Arteries of Preterm and Term Neonates. AB - OBJECTIVES: This study aimed to evaluate normal blood flow in the vertebral arteries and the basilar artery of preterm and term neonates by Doppler sonography. METHODS: Blood flow in both vertebral arteries and the basilar artery was examined in 102 neonates between the biological ages of 28 and 41 weeks. Fifty-one boys and 51 girls underwent Doppler sonography. Measurements were usually undertaken at 6 days old. Systolic and diastolic flow velocities, including the resistive index, were measured and analyzed, taking into consideration biological age, weight, and sex. Anatomic aberrations of the vertebral arteries were recorded. RESULTS: Mean blood flow values +/- SD in the basilar artery were 35.2 +/- 7.4 cm/s (systolic velocity) and 10.9 +/- 3.5 cm/s (diastolic velocity). Mean blood flow values in the right vertebral artery were 26.8 +/- 9.3 cm/s (systolic velocity) and 8.0 +/- 3.7 cm/s (diastolic velocity). Mean blood flow values in the left vertebral artery were 28.6 +/- 8.3 cm/s (systolic velocity) and 8.7 +/- 3.3 cm/s (diastolic velocity). Systolic and diastolic blood flow in both vertebral arteries was significantly higher from 38 to 41 weeks compared with 28 to 32 and 33 to 37 weeks (P < .05). Regression analysis of systolic and diastolic blood flow velocities in the vertebral arteries versus biological age yielded significant results (P < .05). CONCLUSIONS: Sonography is an excellent tool for examining blood flow in the basilar and vertebral arteries of premature and term neonates. Mean systolic and diastolic blood flow velocities in the vertebral arteries increase significantly with age. PMID- 27466261 TI - Intersocietal Accreditation Commission Accreditation Status of Outpatient Cerebrovascular Testing Facilities Among Medicare Beneficiaries: The VALUE Study. AB - OBJECTIVES: Accreditation of cerebrovascular ultrasound laboratories by the Intersocietal Accreditation Commission (IAC) and equivalent organizations is supported by the Joint Commission certification of stroke centers. Limited information exists on the accreditation status and geographic distribution of cerebrovascular testing facilities in the United States. Our study objectives were to identify the proportion of IAC-accredited outpatient cerebrovascular testing facilities used by Medicare beneficiaries, describe their geographic distribution, and identify variations in cerebrovascular testing procedure types and volumes by accreditation status. METHODS: As part of the VALUE (Vascular Accreditation, Location, and Utilization Evaluation) Study, we examined the proportion of IAC-accredited facilities that conducted cerebrovascular testing in a 5% Centers for Medicare and Medicaid Services random Outpatient Limited Data Set in 2011 and investigated their geographic distribution using geocoding. RESULTS: Among 7327 outpatient facilities billing Medicare for cerebrovascular testing, only 22% (1640) were IAC accredited. The proportion of IAC-accredited cerebrovascular testing facilities varied by region (chi(2)[3] = 177.1; P < .0001), with 29%, 15%, 13%, and 10% located in the Northeast, South, Midwest, and West, respectively. However, of the total number of cerebrovascular outpatient procedures conducted in 2011 (38,555), 40% (15,410) were conducted in IAC accredited facilities. Most cerebrovascular testing procedures were carotid duplex, with 40% of them conducted in IAC-accredited facilities. CONCLUSIONS: The proportion of facilities conducting outpatient cerebrovascular testing accredited by the IAC is low and varies by region. The growing number of certified stroke centers should be accompanied by more accredited outpatient vascular testing facilities, which could potentially improve the quality of stroke care. PMID- 27466262 TI - Association Between Prenatal Sonographic Findings of Duodenal Obstruction and Adverse Outcomes. AB - OBJECTIVES: The purpose of this study was to evaluate the association of prenatal sonographic findings with adverse outcomes and the causes of duodenal obstruction. METHODS: A total of 59 cases of congenital duodenal obstruction were included in this study. The sonographic findings, including the degree of duodenal dilatation, polyhydramnios, and their change over gestation, were investigated. Adverse outcomes were defined as fetal death in utero, postnatal death, and gastrointestinal complications requiring readmission or reoperation during the follow-up period. The cause of duodenal obstruction was also assessed. RESULTS: Among the patients studied, 2 (3.4%) had fetal death in utero and 2 (3.5%) had postnatal death. Gastrointestinal complications requiring readmission or reoperation occurred in 10.9%. In the cases with or without adverse outcomes, no significant differences were observed in the prenatal sonographic findings: maximum duodenal dilatation, mean amniotic fluid index, and the changes in these parameters with advancing gestation. The cases with adverse outcomes were associated with a younger gestational age at delivery compared to the cases without adverse outcomes. Notably, the degree of duodenal dilatation and amniotic fluid volume were greater in duodenal atresia than in other causes of obstruction, including duodenal stenosis, a duodenal web, and an annular pancreas. In the study population, the overall postoperative survival rate was 98.2%. CONCLUSIONS: Prenatal sonographic findings of duodenal obstruction were not associated with adverse outcomes; however, they may be helpful for differentiating the cause of duodenal obstruction. PMID- 27466263 TI - Population Semiphysiologic Kinetic Modeling and Simulation of Plasma Triglyceride Levels After Soybean Oil-Based Intravenous Lipid Emulsion Administration in Rats. AB - BACKGROUND: Soybean oil-based intravenous lipid emulsion (SO-ILE) has clinical utility as an energy source and in lipid rescue therapy. However, an excessive infusion rate of SO-ILE in routine use and in lipid rescue therapy may cause serious side effects. There is little information about plasma triglyceride (TG) kinetics following SO-ILE administration. The present study aimed to develop a population semiphysiologic kinetic model of TG and to predict the TG kinetics even at extremely high concentrations in rats. MATERIALS AND METHODS: TG concentration profiles after intravenous bolus (0.1, 0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) or infusion (3.0 g/kg/h for 1 hour) of SO-ILE to rats were analyzed by a kinetic model constructed with 4 pathways: apolipoprotein acquisitions, zero order catabolism, first-order uptake to storage sites, and zero-order secretion from storage sites. The developed model was subjected to internal and external validation. RESULTS: Plasma TG concentrations appeared to decline in a biphasic manner with nonlinear TG kinetics. The developed kinetic model was well validated and found to accurately predict the external validation data. CONCLUSIONS: The proposed kinetic model accurately described TG concentrations after SO-ILE administration at various infusion rates, including a lipid rescue regimen. The maximum acceptable infusion rate of SO-ILE in routine use should correspond to the maximum velocity of the apolipoprotein acquisition: 0.619 g/kg/h in rats. The prediction of TG kinetics at extremely high concentrations will provide useful information for lipid rescue therapy. PMID- 27466264 TI - Abbreviated Steady State Intervals for Measuring Resting Energy Expenditure in Patients on Maintenance Hemodialysis. AB - BACKGROUND: Indirect calorimetry requires a steady state (SS) protocol to determine measured resting energy expenditure (mREE). Achieving stringent criteria for an SS interval may be difficult for patients on maintenance hemodialysis (MHD), as they may become uncomfortable because of the test itself or their health status. The study aim was to explore if a shortened SS interval was within acceptable limits for bias and precision. MATERIALS AND METHODS: For this cross-sectional secondary analysis, adults (N = 125) who received MHD thrice weekly were enrolled. The indirect calorimetry test was performed for a length of total time <=30 consecutive minutes. SS was evaluated in accordance with intervals of 10, 5, 4, 3, and 2 minutes. The mREE at the 10-minute SS was compared with the mREE at 5, 4, 3, and 2 minutes, via t tests and Bland-Altman analysis, to determine degree of bias and level of agreement. The a priori alpha level was set at <=0.5. RESULTS: The sample was primarily male, African American, and non-Hispanic, with a mean +/- SD age of 55.4 +/- 12.2 years, who reported being on MHD for an average of 62.4 +/- 74.3 months. None of the mREE measures were significantly different from that of the 10-minute SS interval. Seventy-two percent of the participants were able to achieve SS at the 10-minute interval, 83.2% at 5 minutes, 87.2% at 4 minutes, and 89.6% for both 3 and 2 minutes. CONCLUSION: For patients on MHD, an abbreviated SS interval of <10 minutes (eg, 5 minutes) yielded valid mREE measurements. PMID- 27466265 TI - Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma. AB - Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n = 82) or ipilimumab and additional LPT (n = 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P = 0.0028). Adverse immune related events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31-1.01, P = 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation. Cancer Immunol Res; 4(9); 744-54. (c)2016 AACR. PMID- 27466266 TI - A Qualitative Study of Participant Engagement With a Weight Loss Intervention. AB - BACKGROUND: Overweight and obesity are major public health problems and an increasing global challenge. In lieu of wider policy changes to tackle the obesogenic environment in which we presently reside, improving the design of individual-level weight loss interventions is important. AIM: To identify which aspects of the Camden Weight Loss randomized controlled trial weight loss intervention participants engaged with, with the aim of improving the design of future studies and maximizing retention. METHOD: A qualitative study comprising semistructured interviews ( n = 18) and a focus group ( n = 5) with intervention participants. RESULTS: Two important aspects of participant engagement with the intervention consistently emerged from interviews and focus group: the advisor participant relationship and the program structure. Some materials used during the program sessions were important in supporting the intervention; however, others were not well received by participants. CONCLUSION: An individual-level weight loss intervention should be acceptable from the patient perspective in order to ensure participants are engaged with the program for as long as possible to maximize favorable results. Providing ongoing support in a long-term program with a trained empathetic advisor may be effective at engaging with people trying to lose weight in a weight loss intervention. PMID- 27466267 TI - Smoking Education for Low-Educated Adolescents: Comparing Print and Audiovisual Messages. AB - This study aims to provide insight into which modality is most effective for educating low-educated adolescents about smoking. It compares the persuasive effects of print and audiovisual smoking education materials. We conducted a field experiment with two conditions (print vs. video) and three measurement times (Time 1, Time 2, and Time 3). A total of 221 high school students in the second year of the lowest levels of education in the Netherlands participated at all three time points of the study. Results showed that participants in both conditions had more negative beliefs about smoking after being exposed to the smoking education than before, but there were no differences between the print and video version in this effect. However, the video version did make the attitude toward smoking more negative at Time 3 compared to baseline, whereas the text version did not, which suggests that the video version was more effective for educating low-educated adolescents about smoking. PMID- 27466268 TI - Dream Teens: Adolescents-Led Participatory Project in Portugal in the Context of the Economic Recession. AB - This article describes the implementation process of a nationwide project to enhance young people's participation and active citizenship in the context of Portugal's economic recession. This project used an innovative Positive Youth Development approach that engaged Portuguese youth (aged 11-18 years) through social media tools to facilitate their civic engagement and development. Participants from all over the country were empowered (1) to design and conduct research activities on topics of their choice and about their life contexts and (2) to create ways to improve youth civic participation in their communities, while developing supportive interactions with adults and peers. Overall, youth were engaged in their activities, felt their voices were heard, and felt that they were viewed as experts of their own well-being and living contexts. Youth research actions and preliminary findings were then compiled in a set of recommendations that was formally received by a high commissioner of the Ministry of Health. The article concludes with a discussion of the next steps for the project and its limitations so far. PMID- 27466269 TI - Functional Interdependence Theory: An Evolutionary Account of Social Situations. AB - Social interactions are characterized by distinct forms of interdependence, each of which has unique effects on how behavior unfolds within the interaction. Despite this, little is known about the psychological mechanisms that allow people to detect and respond to the nature of interdependence in any given interaction. We propose that interdependence theory provides clues regarding the structure of interdependence in the human ancestral past. In turn, evolutionary psychology offers a framework for understanding the types of information processing mechanisms that could have been shaped under these recurring conditions. We synthesize and extend these two perspectives to introduce a new theory: functional interdependence theory (FIT). FIT can generate testable hypotheses about the function and structure of the psychological mechanisms for inferring interdependence. This new perspective offers insight into how people initiate and maintain cooperative relationships, select social partners and allies, and identify opportunities to signal social motives. PMID- 27466270 TI - Php4 Is a Key Player for Iron Economy in Meiotic and Sporulating Cells. AB - Meiosis is essential for sexually reproducing organisms, including the fission yeast Schizosaccharomyces pombe In meiosis, chromosomes replicate once in a diploid precursor cell (zygote), and then segregate twice to generate four haploid meiotic products, named spores in yeast. In S. pombe, Php4 is responsible for the transcriptional repression capability of the heteromeric CCAAT-binding factor to negatively regulate genes encoding iron-using proteins under low-iron conditions. Here, we show that the CCAAT-regulatory subunit Php4 is required for normal progression of meiosis under iron-limiting conditions. Cells lacking Php4 exhibit a meiotic arrest at metaphase I. Microscopic analyses of cells expressing functional GFP-Php4 show that it colocalizes with chromosomal material at every stage of meiosis under low concentrations of iron. In contrast, GFP-Php4 fluorescence signal is lost when cells undergo meiosis under iron-replete conditions. Global gene expression analysis of meiotic cells using DNA microarrays identified 137 genes that are regulated in an iron- and Php4 dependent manner. Among them, 18 genes are expressed exclusively during meiosis and constitute new putative Php4 target genes, which include hry1+ and mug14+ Further analysis validates that Php4 is required for maximal and timely repression of hry1+ and mug14+ genes. Using a chromatin immunoprecipitation approach, we show that Php4 specifically associates with hry1+ and mug14+ promoters in vivo Taken together, the results reveal that in iron-starved meiotic cells, Php4 is essential for completion of the meiotic program since it participates in global gene expression reprogramming to optimize the use of limited available iron. PMID- 27466271 TI - Genome-Wide Divergence in the West-African Malaria Vector Anopheles melas. AB - Anopheles melas is a member of the recently diverged An. gambiae species complex, a model for speciation studies, and is a locally important malaria vector along the West-African coast where it breeds in brackish water. A recent population genetic study of An. melas revealed species-level genetic differentiation between three population clusters. An. melas West extends from The Gambia to the village of Tiko, Cameroon. The other mainland cluster, An. melas South, extends from the southern Cameroonian village of Ipono to Angola. Bioko Island, Equatorial Guinea An. melas populations are genetically isolated from mainland populations. To examine how genetic differentiation between these An. melas forms is distributed across their genomes, we conducted a genome-wide analysis of genetic differentiation and selection using whole genome sequencing data of pooled individuals (Pool-seq) from a representative population of each cluster. The An. melas forms exhibit high levels of genetic differentiation throughout their genomes, including the presence of numerous fixed differences between clusters. Although the level of divergence between the clusters is on a par with that of other species within the An. gambiae complex, patterns of genome-wide divergence and diversity do not provide evidence for the presence of pre- and/or postmating isolating mechanisms in the form of speciation islands. These results are consistent with an allopatric divergence process with little or no introgression. PMID- 27466272 TI - A Genetic Screen for Fission Yeast Gene Deletion Mutants Exhibiting Hypersensitivity to Latrunculin A. AB - Fission yeast cells treated with low doses of the actin depolymerizing drug, latrunculin A (LatA), delay entry into mitosis via a mechanism that is dependent on both the Clp1p and Rad24p proteins. During this delay, cells remain in a cytokinesis-competent state that is characterized by continuous repair and/or reestablishment of the actomyosin ring. In this manner, cells ensure the faithful completion of the preceding cytokinesis in response to perturbation of the cell division machinery. To uncover other genes with a role in this response, or simply genes with roles in adapting to LatA-induced stress, we carried out a genome-wide screen and identified a group of 38 gene deletion mutants that are hyper-sensitive to the drug. As expected, we found genes affecting cytokinesis and/or the actin cytoskeleton within this set (ain1, acp2, imp2). We also identified genes with roles in histone modification (tra1, ngg1), intracellular transport (apl5, aps3), and glucose-mediated signaling (git3, git5, git11, pka1, cgs2). Importantly, while the identified gene deletion mutants are prone to cytokinesis failure in the presence of LatA, they are nevertheless fully capable of cell division in the absence of the drug. These results indicate that fission yeast cells make use of a diverse set of regulatory modules to counter abnormal cytoskeletal perturbations, and furthermore, that these modules act redundantly to ensure cell survival and proliferation. PMID- 27466273 TI - Adoption of Routine Ultrasound Guidance for Femoral Arterial Access for Cardiac Catheterization. AB - BACKGROUND: A randomized controlled trial published in 2010 demonstrated that ultrasound-guided femoral artery access for coronary angiography was faster and associated with fewer vascular complications than conventional fluoroscopic guided access. The landscape of ultrasound use among contemporary interventional cardiologists is unknown. METHODS: We sought to describe current knowledge, attitudes, and practices regarding ultrasound use among interventional cardiologists using an online survey. The questionnaire unfolded in phases, initially attempting to define current attitudes and then testing whether or not attitudes were adjustable after summarizing compelling research supporting the use of ultrasound-guided access. RESULTS: Sixty-eight responses were received (60.7%). Only 13.3% reported using ultrasound routinely despite widespread availability and technical expertise. The majority of respondents believed ultrasound use to be slower but safer than access by palpation alone. There was no significant association between age (P=.70) or annual case volume (P=.11) and baseline ultrasound use. After examining the results of a supporting clinical trial, 42.6% said ultrasound should be used routinely, but only 17.6% said they would adopt the technique. Younger operators tended to affirm routine ultrasound adoption after reading the trial summary more often than older respondents, although this did not reach statistical significance (relative risk = 1.8; P=.30). CONCLUSIONS: Routine ultrasound-guided femoral artery access and awareness of its validating evidence is uncommon among current interventional cardiologists; exposure to compelling data had minimal impact on respondents' willingness to change practice. PMID- 27466274 TI - Initial Experience Using the Gore Embolic Filter in Carotid Interventions. AB - BACKGROUND: This is the first clinical report on experience in the use of the Gore embolic filter in carotid interventions. It was designed as a guidewire and embolic protection system in carotid, peripheral, and coronary interventions. The ability to capture debris is driven by the frame of the filter, which is designed to improve vessel wall apposition and allows a short landing zone. METHODS: We report the results of the first 20 consecutive patients undergoing carotid artery stenting using the Gore embolic filter in our institution. We analyzed technical success as well as the occurrence of transient ischemic attack (TIA), stroke, or death periprocedurally and through 30 days of follow-up. Mean patient age was 72 years and 12 patients (60%) were male. Seven patients were symptomatic and 4 patients suffered recurrent neurological events. RESULTS: Technical success was achieved in all procedures. In 1 patient, the retrieval catheter was caught between the proximal struts of the stent and required further retrieval maneuvers. Within 30 days of follow-up, 1 patient had a TIA. No stroke, death, or myocardial infarction occurred. CONCLUSION: This initial experience suggests that the Gore embolic filter device can be used safely for distal embolic protection during carotid stenting procedures with high technical success. PMID- 27466275 TI - Balloon Aortic Valvuloplasty in the Transcatheter Aortic Valve Replacement Era. AB - BACKGROUND: The introduction of transcatheter aortic valve replacement (TAVR) has renewed interest in balloon aortic valvuloplasty (BAV) for severe aortic stenosis (AS). It is unclear whether technical advances and increased operator experience associated with TAVR development have resulted in improved BAV outcomes. We performed a systematic review encompassing all published BAV studies and examined the evolution in indications, outcomes, and complications of BAV procedures since its inception. METHODS: A literature search from 1986 through June 2013 was conducted for all studies reporting BAV outcomes. Studies with <50 BAV procedures were excluded. BAV outcomes and complications were compared in studies enrolling patients in the early/pre-TAVR and contemporary/TAVR periods (before vs after 2005). RESULTS: Twenty-seven studies representing 4123 patients were included. In the contemporary era, BAV was performed as a bridge to TAVR in 23.4% of patients. Significant and comparable improvement in transaortic valvular gradients, aortic valve area, and cardiac output following BAV were observed in both time periods. There was, however, a significant reduction in procedural death (1.5% vs 2.9%; P<.01), in-hospital mortality (4.6% vs 8.5%; P<.001), and major vascular complications (4.0% vs 10.2%; P<.001) associated with BAV procedures in the contemporary/TAVR era. CONCLUSION: BAV is increasingly used as a bridge to TAVR, continues to impart significant hemodynamic improvement in patients with severe AS, and has an improved safety profile in the contemporary era. PMID- 27466276 TI - The Balloon Aortic Valvuloplasty Makeover: From "Treatment" Procedure to "Bridge" Procedure. PMID- 27466277 TI - Late Right Coronary Ostium Occlusion After Percutaneous Aortic Paravalvular Leak Closure: Immediate Results Do Not Always Predict Long-Term Performance. AB - We present an 83-year-old woman with history of two aortic valve replacements; 2 years after the last replacement, she developed heart failure and severe paravalvular leak (PVL) was detected. Percutaneous PVL closure was completed with a single Amplatzer Vascular Plug III. Two months later, the patient presented with late coronary obstruction requiring emergent surgical revascularization. To the best of our knowledge, this is the first report of late coronary obstruction after percutaneous PVL closure. PMID- 27466278 TI - The Role of Multimodality Imaging in a Case of Traumatic Cardiac Pseudoaneurysm. AB - After a 40-foot fall from a balcony, a healthy 21-year-old sustained multiple injuries, including left ventricular pseudoaneurysm. This case demonstrates the critical necessity of the combination of a high index of suspicion and multimodality imaging for diagnosis and prompt intervention. PMID- 27466279 TI - Radial Artery Embolism: A Rare Complication of Angioplasty. AB - We present a 55-year-old man with multivessel coronary artery disease previously treated with stenting of the left main, left anterior descending, right coronary, circumflex, and first diagonal branch. He was diagnosed with in-stent restenosis of a diagonal branch, but treatment was complicated by radial artery coronary embolism, which is a rare complication of radial intervention. PMID- 27466280 TI - Lymphoid malignancies ARNT unstoppable. PMID- 27466281 TI - The Expanding Landscape of Moonlighting Proteins in Yeasts. AB - Moonlighting proteins are multifunctional proteins that participate in unrelated biological processes and that are not the result of gene fusion. A certain number of these proteins have been characterized in yeasts, and the easy genetic manipulation of these microorganisms has been useful for a thorough analysis of some cases of moonlighting. As the awareness of the moonlighting phenomenon has increased, a growing number of these proteins are being uncovered. In this review, we present a crop of newly identified moonlighting proteins from yeasts and discuss the experimental evidence that qualifies them to be classified as such. The variety of moonlighting functions encompassed by the proteins considered extends from control of transcription to DNA repair or binding to plasminogen. We also discuss several questions pertaining to the moonlighting condition in general. The cases presented show that yeasts are important organisms to be used as tools to understand different aspects of moonlighting proteins. PMID- 27466282 TI - The Cell Biology of Fission Yeast Septation. AB - In animal cells, cytokinesis requires the formation of a cleavage furrow that divides the cell into two daughter cells. Furrow formation is achieved by constriction of an actomyosin ring that invaginates the plasma membrane. However, fungal cells contain a rigid extracellular cell wall surrounding the plasma membrane; thus, fungal cytokinesis also requires the formation of a special septum wall structure between the dividing cells. The septum biosynthesis must be strictly coordinated with the deposition of new plasma membrane material and actomyosin ring closure and must occur in such a way that no breach in the cell wall occurs at any time. Because of the high turgor pressure in the fungal cell, even a minor local defect might lead to cell lysis and death. Here we review our knowledge of the septum structure in the fission yeast Schizosaccharomyces pombe and of the recent advances in our understanding of the relationship between septum biosynthesis and actomyosin ring constriction and how the two collaborate to build a cross-walled septum able to support the high turgor pressure of the cell. In addition, we discuss the importance of the septum biosynthesis for the steady ingression of the cleavage furrow. PMID- 27466285 TI - Lack of p53 Augments Antitumor Functions in Cytolytic T Cells. AB - Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and antitumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS-dependent JNK activation that leads to its activation-induced cell death. Because tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor-mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor-reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope-reactive T cells developed on p53 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNgamma secretion, cytolytic capacity, expression of stemness gene signature, and decreased TGF-beta signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR-transduced T cells using a combination of p53 inhibitors also potentiated the T-cell effector function and improved persistence. Thus, our data highlight the key role of p53 in regulating the tumor-reactive T-cell response and that targeting this pathway could have potential translational significance in adoptive T-cell therapy. Cancer Res; 76(18); 5229-40. (c)2016 AACR. PMID- 27466286 TI - Decoding Intratumoral Heterogeneity of Breast Cancer by Multiparametric In Vivo Imaging: A Translational Study. AB - Differential diagnosis and therapy of heterogeneous breast tumors poses a major clinical challenge. To address the need for a comprehensive, noninvasive strategy to define the molecular and functional profiles of tumors in vivo, we investigated a novel combination of metabolic PET and diffusion-weighted (DW)-MRI in the polyoma virus middle T antigen transgenic mouse model of breast cancer. The implementation of a voxelwise analysis for the clustering of intra- and intertumoral heterogeneity in this model resulted in a multiparametric profile based on [(18)F]Fluorodeoxyglucose ([(18)F]FDG)-PET and DW-MRI, which identified three distinct tumor phenotypes in vivo, including solid acinar, and solid nodular malignancies as well as cystic hyperplasia. To evaluate the feasibility of this approach for clinical use, we examined estrogen receptor-positive and progesterone receptor-positive breast tumors from five patient cases using DW-MRI and [(18)F]FDG-PET in a simultaneous PET/MRI system. The postsurgical in vivo PET/MRI data were correlated to whole-slide histology using the latter traditional diagnostic standard to define phenotype. By this approach, we showed how molecular, structural (microscopic, anatomic), and functional information could be simultaneously obtained noninvasively to identify precancerous and malignant subtypes within heterogeneous tumors. Combined with an automatized analysis, our results suggest that multiparametric molecular and functional imaging may be capable of providing comprehensive tumor profiling for noninvasive cancer diagnostics. Cancer Res; 76(18); 5512-22. (c)2016 AACR. PMID- 27466287 TI - Seventy two-hour glucose monitoring profiles in mild gestational diabetes mellitus: differences from healthy pregnancies and influence of diet counseling. AB - OBJECTIVE: To study glucose profiles of gestational diabetes (GDM) patients with 72 h of continuous glucose monitoring (CGM) either before (GDM1) or after (GDM2) dietary counseling, comparing them with nondiabetic (NDM) controls. DESIGN AND METHODS: We performed CGM on 22 GDM patients; 11 before and 11 after dietary counseling and compared them to 11 healthy controls. Several physiological and clinical characteristics of the glucose profiles were compared across the groups, including comparisons for pooled 24-h measures and hourly median values, summary measures representing glucose exposure (area under the median curves) and variability (amplitude, standard deviation, interquartile range), and time points related to meals. RESULTS: Most women (81.8%) in the GDM groups had fasting glucose <95mg/dL, suggesting mild GDM. Variability, glucose levels 1 and 2h after breakfast and dinner, peak values after dinner and glucose levels between breakfast and lunch, were all significantly higher in GDM1 than NDM (P<0.05 for all comparisons). The GDM2 results were similar to NDM in all aforementioned comparisons (P>0.05). Both GDM groups spent more time with glucose levels above 140mg/dL when compared with the NDM group. No differences among the groups were found for: pooled measurements and hourly comparisons, exposure, nocturnal, fasting, between lunch and dinner and before meals, as well as after lunch (P>0.05 for all). CONCLUSION: The main differences between the mild GDM1 group and healthy controls were related to glucose variability and excursions above 140mg/dL, while glucose exposure was similar. Glucose levels after breakfast and dinner also discerned the GDM1 group. Dietary counseling was able to keep glucose levels to those of healthy patients. PMID- 27466289 TI - Distress and quality of life in an ethnically diverse sample awaiting breast cancer surgery. AB - Poor breast cancer-related quality of life is associated with flattened cortisol rhythms and inflammation in breast cancer survivors and women with advanced disease. We explored the associations of cancer-specific distress (Impact of Events Scale), mood (Profile of Mood States), activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient) and cortisol (diurnal slope) circadian rhythms, and inflammation (interleukin-6) with quality of life (Functional Assessment of Cancer Therapy-Breast) among patients awaiting breast cancer surgery ( N = 57). Models were adjusted for differences in age and cancer stage. Distress and mood disturbance were significantly correlated with lower quality of life. Ethnic differences in the relationship between distress and mood disturbance with global quality of life and subscales of quality of life were observed. Actigraphic measures showed that in comparison with non-Hispanic patients, African Americans had significantly poorer activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient). Circadian disruption and inflammation were not associated with quality of life. Physiological dysregulation and associated comorbidities may take time to develop over the course of disease and treatment. PMID- 27466290 TI - Asthma and atopic diseases in adolescence and antidepressant medication in middle age. AB - This Swedish register-based cohort study examined whether asthma, hay fever and allergic dermatitis in late adolescence identified in the early 1970s are associated with antidepressant medication in middle age, between 2006 and 2009. After adjustment for childhood and adulthood sociodemographic characteristics, psychological, cognitive and physical function, and comorbidity, the magnitude of the associations diminished for asthma, while hay fever and atopic dermatitis retained associations. Hay fever and atopic dermatitis in adolescence have potentially important implications for future mental health, while asthma may already have influenced an individual's ability to cope with stress by late adolescence. PMID- 27466288 TI - Repeated Water Avoidance Stress Alters Mucosal Mast Cell Counts, Interleukin 1beta Levels with Sex Differences in the Distal Colon of Wistar Rats. AB - Background/Aims: This study was aimed at evaluating differences in the effects of repeated water avoidance stress (rWAS) on colonic movement, mucosal mast cell counts, cytokine levels, and visceromotor response (VMR) to colorectal distension (CRD) in rats of both sexes. Methods: Wistar rats were divided into stress and no stress groups. Rats in the stress group were exposed to rWAS (1 hr/day) for 10 days. Mucosal mast cells were immunohistochemically stained with anti-mast cell tryptase antibody and counted. The colonic mucosal cytokine levels were measured with enzyme-linked immunosorbent assay. The VMR to CRD (visceral analgesia) was assessed by using a barostat and noninvasive manometry. Results: The mean number of fecal pellets in the rWAS group increased significantly as compared with that in the no-stress group in both sexes. After adjustment for body weight, the female rats had a significantly higher pellet output than the male rats. The mucosal mast cell count of the female rWAS group was higher than that of the male rWAS group (13.0 +/- 0.9 vs 8.8 +/- 0.6; P < 0.001). The colonic mucosal interleukin-1beta level was also higher only in the female rats of the rWAS group than in those of the no-stress group. On days 10 and 11, a decrease in VMR to CRD was observed at 40 and 60 mmHg in both sexes of the rWAS group, without a sex based difference. Conclusions: The colonic response to stress appeared to be more sensitive in the female rats than in the male rats. However, stress-induced visceral analgesia had no sex-related difference and the underlying mechanism needs to be further evaluated. PMID- 27466291 TI - Adenosine Signaling Increases Proinflammatory and Profibrotic Mediators through Activation of a Functional Adenosine 2B Receptor in Renal Fibroblasts. AB - Interstitial renal fibrosis is a major pathophysiological manifestation of patients diagnosed with Chronic Kidney Disease (CKD), Diabetic Nephropathy (DN) and other inflammatory diseases. Adenosine signaling is an innate autocrine and paracrine cellular signaling pathway involving several key mediators that are elevated in the blood and kidneys of patients with DN. In these studies, we hypothesized that extracellular adenosine signals through one or more functional adenosine GPCRs on renal fibroblasts which increases profibrotic and proinflammatory mediators by inducing an activated fibroblast phenotype. Utilizing the renal fibroblast cell line NRK-49F, the presence and relative abundance of adenosine receptors (AR) A1, A2A, A2B, and A3 were quantified by RT PCR. Under normal homeostatic conditions, only AR1 and AR2B were detected. The functionality of each receptor was then assessed by receptor specific pharmacological agonism and antagonism and assessed for modulation of the GPCR associated secondary messenger molecule, cyclic adenosine monophosphate (cAMP). Agonism of the AR2B receptor resulted in increased intracellular cAMP while agonism of the AR1 receptor inhibited cAMP modulation. Upon direct agonism of the AR2B receptor, transcripts for profibrotic and inflammatory mediators including SMA-alpha, IL-6, TGF-beta, CTGF, and fibronectin were elevated between 2-4 fold. These data indicate that renal fibroblasts express a functional AR1 receptor that inhibits cAMP upon stimulation, leading to a functional AR2B receptor that increases cAMP upon stimulation and also induces an activated fibroblast phenotype resulting in increased fibrotic and inflammatory mediators. PMID- 27466292 TI - Biphasic Effects of Copper on Rat Learning and Memory in the Morris Water Maze. AB - Dysregulation of copper (Cu) metabolism interrupts neuron function, and subsequently results in neuron degeneration, necrosis, and gliocyte hyperplasia. To further explore the effects of hippocampal Cu concentration on learning and memory, Sprague-Dawley (SD) rats were given once-daily intraperitoneal injections of Copper(II) acetate (Cu(OAc)2) at doses of 0.2, 2, or 20mg/Kg over 5 days. Ultrasonic oscillation dialysis was used to determine the free Cu by graphite furnace atomic absorption spectrometry (GFAAS). Cu administration induced a dose dependent increase in total hippocampal Cu. However, free hippocampal Cu was found to increase only at the lower concentration of Cu(OAc)2 (0.2 mg/Kg) but decrease at higher concentrations of Cu(OAc)2 (2 and 20 mg/Kg). Higher doses of Cu(OAc)2 (2-20mg/Kg) decreased superoxide dismutase-1 (SOD1) activity, increased both malondialdehyde (MDA) levels and the glutamate/gamma-aminobutyric acid (Glu/GABA) ratio, and impaired spatial cognition. However, the lower dose of Cu(OAc)2 (0.2 mg/Kg) showed the opposite effects. This biphasic effect might be attributed to free hippocampal Cu levels and corresponding alterations of Glu/GABA ratio and SOD1 activity. PMID- 27466293 TI - Oleic/Palmitate Induces Apoptosis in Human Articular Chondrocytes via Upregulation of NOX4 Expression and ROS Production. AB - The association between obesity and reactive oxygen species (ROS) production in osteoarthritis (OA) patients has already been identified. However, the specific mechanism underlying ROS production and OA progression has never been elucidated. Osteoarthritic cartilage was obtained from patients undergoing total hip arthroplasty, and chondrocytes were isolated from these tissues. The cells were treated with varying concentrations (10,100,500 MUM, and 5 mM) of oleic/palmitate (O/P) mixture at different times, that is at 6, 24, and 48 h. Cell viability was determined using MTT assay. ROS production was detected using immunofluorescence and flow cytometry. The protein levels of NOX4 and cleaved-caspase3 were detected using Western blot assay. O/P significantly decreased cell viability at 10, 100, 500 MUM, and 5 mM in a dose-dependent manner. Furthermore, the cell viability was reduced by 500 MUM O/P mixture at 6, 24, and 48 h in a time-dependent manner. Pretreatment with 500 MUM O/P significantly enhanced ROS production and cell apoptosis in chondrocytes. Furthermore, treatment with O/P mixture significantly enhanced the expression of NOX4 and caspase3 activation in a dose- and time- dependent manner. More importantly, inhibition of NOX4 could partially eliminate O/P-induced chondrocytes apoptosis by reducing ROS production. To conclude, O/P treatment enhances ROS production and cell apoptosis mainly by upregulating the protein levels of NOX4 and caspase3 activation in chondrocytes, indicating a potential therapeutic target of OA in obesity patients. PMID- 27466294 TI - Novel and Recurrent ACADS Mutations and Clinical Manifestations Observed in Korean Patients with Short-chain Acyl-coenzyme a Dehydrogenase Deficiency. AB - Short-chain acyl-CoA dehydrogenase (SCAD) catalyzes the first step in mitochondrial short-chain beta-oxidation, and its deficiency is caused by mutations in the ACADS We sought to investigate the spectrum ACADS mutations and associated clinical manifestations in Korean patients with SCAD deficiency. The study included ten patients with SCAD deficiency from 8 unrelated families as diagnosed by biochemical profile and mutation analyses. Clinical features, biochemical data, growth, and neurodevelopmental state were reviewed retrospectively. Eight patients were found during newborn screening, and two were diagnosed by family screening. During follow-up ranging from 2 months to 4.5 years, no hypoglycemic event was noted, and the development and growth of the patients were normal, except in two siblings. One exhibited hypotonia and gross motor delay, while one girl showed cyclic vomiting until the age of two years. We identified seven different mutations of ACADS Of these, p.E344G was the most frequent mutation with an allele frequency of 50%, followed by p.P55L with 18.8%. p.G108D and four novel mutations were identified: p.L93I, p.E228K, p.P377L, and p.R386H. Korean patients with SCAD deficiency showed heterogenous clinical features and ACADS genotype. Our data contributes to a better understanding of the distinct molecular genetic characteristics and clinical manifestations of SCAD deficiency. PMID- 27466295 TI - High-resolution Melting PCR Analysis for Genotyping Lys109Arg and Gln223Arg in Patients with Renal Cell Carcinoma. AB - Although several studies have documented the role of leptin receptor gene polymorphisms in cancers, the association between leptin receptor gene polymorphisms and renal cell carcinoma (RCC) remains unknown. The aim of this study was to develop a high-resolution melting (HRM) approach for genotyping single nucleotide polymorphisms of leptin receptor gene on the LightCycler 480, and to explore the relation between polymorphisms of the leptin receptor gene and RCC. The study population consisted of 83 patients with renal cell carcinoma and 161 healthy control subjects. The Lys109Arg (A/G) and Gln223Arg (A/G) polymorphisms of leptin receptor gene were examined with HRM assay. Direct DNA sequencing and PCR-restriction fragment length polymorphisms were used as a reference method for genotyping Lys109Arg and Gln223Arg, respectively. Three genotypes of Lys109Arg or Gln223Arg were clearly distinguishable from the melting curve shapes with HRM assay. The data also showed the results of the direct DNA sequencing or PCR-restriction fragment length polymorphisms analysis were in complete concordance to genotyping results obtained by HRM (kappa=1.0). In addition, the data showed the G-G haplotype frequency was higher (p<0.05), and that the A-G (p<0.001) and G-A (p<0.01) haplotypes frequencies were lower in the RCC than controls. We developed a rapid, low cost, high-throughput and reliable single-tube technology for genotyping Lys109Arg and Gln223Arg polymorphisms. In addition, our data suggest that Lys109Arg and Gln223Arg gene polymorphisms are associated with RCC in Chinese Han studied population. PMID- 27466283 TI - JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. AB - The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states. PMID- 27466296 TI - Association of Polymorphisms in TRAIL and Chronic Hepatitis B in Chinese Han Populations from Shandong Province. AB - BACKGROUND: HBV is the most common and serious infectious disease in China. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) belongs to the TNF-super family and can induce apoptosis in addition to other biological effects. It has been found that the occurrence of chronic hepatitis B is related to polymorphisms of many apoptotic factors. This study therefore aims to investigate the association of TRAIL polymorphism with chronic hepatitis B by observing the polymorphism and gene frequency of the TRAIL gene at 1525G/A and 1595C/T of the 3'-UTR among people of the Chinese Han ethnicity. METHODS: This study followed a case-control design. Polymorphisms of the TRAIL gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods in 187 patients with chronic hepatitis B and 142 healthy controls. RESULTS: The alleles of TRAIL at 1525G/A and 1595C/T have achieved genetic equilibrium in normal individuals (P<0.05) and patients with chronic hepatitis B(P=0.547). The genotype frequencies of TRAIL at 1525GG/1595CC in female patients were significantly higher than those in male patients. The frequencies of the AA genotype at 1525G/A and the TT genotype at 1595C/T sites were significantly lower in patients with chronic hepatitis B with HBeAg positive than in healthy controls (10.5 vs 23.2%, P<0.05). The frequency of the AA genotype at 1525G/A and TT genotype at 1595C/T sites were significantly lower in the chronic hepatitis B individuals than in normal controls (12.3 vs 23.2%, P < 0.05). CONCLUSIONS: TRAIL may be related to susceptibility to hepatitis B. PMID- 27466297 TI - Usefulness of the Neutrophil-to-lymphocyte Ratio and Platelet Morphologic Parameters in Predicting Hepatic Fibrosis in Chronic Hepatitis C Patients. AB - BACKGROUND: Chronic hepatitis C (CHC) can progress to fibrosis and cirrhosis. The current gold standard for the diagnosis and staging of hepatic fibrosis is liver biopsy, but liver biopsies have various limitations. We evaluated the neutrophil to-lymphocyte ratio (NLR) and platelet morphologic parameters to determine fibrosis in CHC patients. METHODS: We retrospectively reviewed the data of 144 patients who were diagnosed with CHC by percutaneous liver biopsy. Patients' fibrosis scores and histological activity indices were calculated according to the Ishak scoring system. RESULTS: Eighty-six patients (60%) were female, and the mean age of the whole group was 53.7 years. The low fibrosis (F1-2) group included 56 patients, the high fibrosis group (F3-6) included 88 patients, and the cirrhosis group (F5-6) included 38 patients. There was no statistically significant difference between low and high fibrosis groups or cirrhotic and noncirrhotic groups in terms of NLR. However, plateletcrit (PCT) was significantly lower in patients with cirrhosis and high fibrosis. CONCLUSIONS: NLR is not associated with histological severity and is not an adequate test to determine either significant fibrosis or cirrhosis. For the first time in the literature, this study showed that PCT was significantly lower in patients with significant fibrosis and that NLR was positively correlated with cholestatic liver enzyme leves. PMID- 27466298 TI - Identification of the Presence of Variant Hemoglobin Using a Measurement of the Labile HbA1c (#C) Fraction. AB - Labile HbA1c migrates in the #C fraction together with modified hemoglobin (such as carbamylated hemoglobin, acetaldehyde hemoglobin, and acetylated hemoglobin) when HbA1c is measured by Arkray's high-performance liquid chromatography (HPLC). It is assumed that most of the labile glycation products of variant hemoglobin do not migrate in #C fraction; in addition, a part of the stable glycation products of variant hemoglobin migrates in #C fraction. We hypothesized that subjects with variant hemoglobin are likely to show abnormally low or high values of #C fraction. In this study, we investigated this hypothesis. Twenty-one non-diabetic subjects with nine types of variant hemoglobin, and 103 non-diabetic subjects without variant hemoglobin were used. HbA1c and #C fraction were measured by Arkray's HPLC (HA-8180) using standard mode. The values of #C fraction in the control group were 1.75 +/- 0.15% (range: 1.5-2.1%). The variant hemoglobin group reported #C fraction values of <=1.3% in twelve subjects, >=2.3% in five subjects, and within the reference range (1.4-2.2%) in three subjects. When the cutoff values of #C fraction were set at <=1.3% and >=2.3%, sensitivity and specificity were 86% and 100%, respectively. Most non-diabetic subjects with variant hemoglobin showed abnormal values of #C fraction. Measurement of #C fraction is a useful screening test for variant hemoglobin in non-diabetic subjects. PMID- 27466299 TI - Clinical and Laboratory Profile of Urinary Tract Infections Associated with Extended Spectrum beta-Lactamase Producing Escherichia coli and Klebsiella pneumoniae. AB - BACKGROUND: Urinary tract infection (UTI) is mainly due to invasion of the urethra, bladder or kidneys by pathogens. The emergence of extended spectrum beta lactamases (ESBL) is responsible for frequently observed empirical therapy failures. OBJECTIVES: To study the clinical and laboratory characteristics of UTIs caused by ESBL producing Escherichia coli (E. coli) and Klebsiella pneumonia (K. pneumonia). METHODS: A cross-sectional clinical and laboratory study was performed at King Khalid Hospital, Hafr Al Batin, Saudi Arabia between March 2014 to October 2015. A total of 908 urine samples from suspected UTI patients was collected. Samples were isolated on Cysteine Electrolyte-Deficient (CLED) agar. Positive cultures were identified and tested for antimicrobial susceptibility by MicroScan((r)) WalkAway-96 SI System, and then ESBL was confirmed by double disc synergy test (DDST) and phenotypic confirmatory disc diffusion test (PCDDT). RESULTS: A total of 680 samples (288 males and 392 females) were culture positive. 520 samples (76.5%) of E. Coli were found and 160 samples of K. pneumonia were identified (23.5%). ESBL testing showed 296 (218 E. coli and 78 K. pneumonia) samples of positive isolates. Non-ESBL isolates showed highest resistance to ampicillin followed by Mezocillin and Trimethoprim Sulphamethoxazole-which are usually recommended as the initial treatment of UTI while ESBL isolates showed resistance to third generation cephalosporin along with Ampicillin and Trimethoprim-Sulphamethoxazole. In this study, four significant risk factors for ESBL infection such as diabetes, recurrent UTI, previous use of antibiotics and previous hospitalization were found. CONCLUSION: Identifying the risk factors and antibiotic susceptibility patterns associated with ESBL producing E. coli and K. pneumonia is a useful guide for treatment strategy and control of ESBL UTI. PMID- 27466300 TI - Transforming Growth Factor Beta 1 (TGF-beta1) in Thyroid Cancer Patients: a View from the Peripheral Blood. AB - Transforming growth factor beta (TGF-beta) plays an important role in many pathophysiological conditions, including cancer. The level of TGF-beta in patients with differentiated thyroid cancer (DTC) has not been examined so far. The aim of this study was to measure TGF-beta concentration in serum samples and in PHA-stimulated whole blood culture in vitro and to analyze possible associations of TGF-beta1 levels with leukocyte, lymphocyte and platelets counts, the histological type of thyroid cancer, and stage of disease. TGF-beta1 was measured in 22 DTC patients and 20 healthy controls using the duoSet ELISA Development kit for human TGF-beta1. The concentration of TGF-beta1 in serum samples from both groups correlated positively with the platelet counts. There was no statistically significant difference in the serum concentrations of TGF beta1 between DTC patients and control subjects, but PHA stimulated whole blood cultures of DTC patients produced less TGF-beta1 than those from controls. Additional studies are needed to determine the significance of these in vitro findings. PMID- 27466301 TI - Application of SPR Imaging Biosensor for the Measurement of 20S Proteasomes in Blood Plasma of Children with Thermal Injury. AB - BACKGROUND: Determination of proteasome concentration in blood plasma in children with burns, with the Surface Plasmon Resonance Imaging biosensor. MATERIAL AND METHODS: 35 children scalded by hot water, with burns in 4-20% TBSA were included into the study (age 9 months up to 14 years, mean age 2,5+1 years). Blood plasma 20S proteasome concentration was assessed in 2-6h, 12-16h, 3d, 5d, and 7d after injury using Surface Plasmon Resonance Imaging biosensor. RESULTS: Statistically significant elevation of circulating 20S proteasome concentration was noted in all groups 12-16 hours after the injury; however, differences were more evident in children with the more severe burns. Circulating 20S proteasome concentration in the plasma was increased until day 7 in the group with severe burns, until day 5 in the group with moderate burns and until day 3 in the group with minor burns. Circulating 20S proteasome concentration in the plasma was highly correlated with burn severity. CONCLUSIONS: The SPR imaging biosensor can be used for determination of 20S proteasome in plasma of patients with burns. Circulating 20S proteasomes are elevated after burn injury and slowly reach the normal range during the wound healing process. Increase in circulating 20S proteasome concentration is proportional to the severity of the burn injury and do not correlate with age or sex. PMID- 27466284 TI - Stress Physiology of Lactic Acid Bacteria. AB - Lactic acid bacteria (LAB) are important starter, commensal, or pathogenic microorganisms. The stress physiology of LAB has been studied in depth for over 2 decades, fueled mostly by the technological implications of LAB robustness in the food industry. Survival of probiotic LAB in the host and the potential relatedness of LAB virulence to their stress resilience have intensified interest in the field. Thus, a wealth of information concerning stress responses exists today for strains as diverse as starter (e.g., Lactococcus lactis), probiotic (e.g., several Lactobacillus spp.), and pathogenic (e.g., Enterococcus and Streptococcus spp.) LAB. Here we present the state of the art for LAB stress behavior. We describe the multitude of stresses that LAB are confronted with, and we present the experimental context used to study the stress responses of LAB, focusing on adaptation, habituation, and cross-protection as well as on self induced multistress resistance in stationary phase, biofilms, and dormancy. We also consider stress responses at the population and single-cell levels. Subsequently, we concentrate on the stress defense mechanisms that have been reported to date, grouping them according to their direct participation in preserving cell energy, defending macromolecules, and protecting the cell envelope. Stress-induced responses of probiotic LAB and commensal/pathogenic LAB are highlighted separately due to the complexity of the peculiar multistress conditions to which these bacteria are subjected in their hosts. Induction of prophages under environmental stresses is then discussed. Finally, we present systems-based strategies to characterize the "stressome" of LAB and to engineer new food-related and probiotic LAB with improved stress tolerance. PMID- 27466302 TI - Detection of Mycobacterium tuberculosis Complex in Paraffin-Embedded Tissues by the New Automated Abbott RealTime MTB Assay. AB - OBJECTIVE: The Abbott RealTime MTB assay, launched in June 2014, has been shown to have a competitive performance in the detection of the Mycobacterium tuberculosis (MTB) complex in respiratory specimens. The present study was conducted to investigate the usefulness of the Abbott MTB Realtime assay in the detection of MTB in formalin-fixed paraffin-embedded (FFPE) tissues. METHODS: A total of 96 FFPE specimens obtained from microbiologically proven MTB cases (N=60) and nontuberculous Mycobacterium cases (N=36) were analyzed. The performance of the Abbott MTB Realtime assay was compared with that of the Roche Cobas TaqMan MTB assay. RESULTS: The overall sensitivity and specificity of the Abbott assay were 63.3% and 97.2%, respectively, compared with 11.7% and 100% for the Cobas assay. The detection rate of the Abbott assay was much higher among 37 acid-fast-positive specimens than among 23 acid-fast-negative specimens (89.3% versus 21.7%, respectively). The detection rate of the assay was higher among 29 resection specimens than among 31 small biopsy specimens (86.2% versus 41.9%, respectively). CONCLUSION: Our results suggest that the Abbott RealTime MTB assay can be used to differentiate MTB from nontuberculous mycobacterial infections in acid-fast-positive FFPE tissues. PMID- 27466303 TI - Clinical Significance of Long Non-coding RNA MALAT1 Expression in Tissue and Serum of Breast Cancer. AB - Long non-coding RNAs (lncRNAs) have been proven to serve a critical role in cancer development and progression. The aim of this study was to elucidate clinical significance of lncRNA MALAT1 expression in breast cancer (BC). A total of 78 BC patients treated with radical resection were enrolled in this study. Quantitative reverse transcription-polymerase chain reaction was used to detect MALAT1 expression in tissues and serum samples. The receiver operating characteristics (ROC) curve was constructed to describe diagnostic specificity and sensitivity. Lentivirus-mediated RNA interference was used to knockdown MALAT1 in the MDA-MB-231 cell line, and then cell proliferation and invasion were explored. Results showed that MALAT1 expression was significantly up-regulated in 85.9% (67/78) of cancerous tissues compared with normal counterparts (P<0.01). Further, an elevated MALAT1 expression in BC tissue was significantly associated with lymph metastasis (P=0.037) and adverse 5-year disease-free survival (mean 48.5 months vs 62.7 months, P=0.012). Suppression of lncRNA MALAT1 significantly inhibited BC cells proliferation, migration and invasion, induced apoptosis and cell cycle G1 arrest. In addition, serum MALAT1 levels in BC patients were much higher than levels in patients with benign breast disease (P<0.001), its diagnostic efficacy was satisfactory, area under the curve (AUC) was 0.833. In conclusion, MALAT1 upregulation plays an important rolein BC development, and serum MALAT1 level may be a potential tumor marker for BC diagnosis. PMID- 27466304 TI - Prostate Adenocarcinoma Metastasis to the Bilateral Ureters: a Rare but Potentially Important Finding. AB - The ureter is an extremely rare location for metastasis from prostate carcinoma. Here we present an autopsy case of an 82-year-old gentleman with history of prostate carcinoma who exhibited bilateral urinary tract obstruction secondary to metastatic prostate carcinoma. Our extensive literature search revealed only 44 cases of prostate carcinoma with ureteral metastasis worldwide that had been reported in the last century. Though it is an unusual pattern, ureteral metastasis should always be considered for a patient with urinary obstruction in the setting of prostate adenocarcinoma. PMID- 27466305 TI - A Rare Colon Cancer with Ossification: Pathogenetic Analysis of Bone Formation. AB - Heterotopic ossification occurring in colon cancer is an exceedingly rare event. The pathogenetic mechanism of tumor-related heterotopic bone formation remains unclear. Herein, we describe a rare case of colon cancer with ossification in a 76-year-old woman. We also highlight the etiology of heterotopic ossification by immunohistochemical evaluation of novel markers such as bone morphogenetic protein 9 (BMP9), osteocalcin, osteopontin, and beta-catenin. BMP9 is one of the most potent osteogenetic BMPs. However, no previous research has been performed concerning BMP9 in heterotopic ossification arising in colon cancer. Subsequently, we suggest a hypothesis of tumor-associated heterotopic bone formation through this case. When osteoblastic indicators including BMP9, osteocalcin, and osteopontin are upregulated in tumor cells, osteoblast-like transformation of such tumor cells occurs. These tumor cells augment the release of interactive osteogenetic factors (BMP9, osteocalcin, and osteopontin) and stimulate uncommitted mesenchymal stromal cells into specific osteoblastic differentiation, contributing to heterotopic bone formation. This transformation of tumor cells is considered a type of epithelial-mesenchymal transition (EMT) because of overexpression of BMP9 and beta-catenin. Patients should be followed closely because EMT has a tendency toward local recurrence. Our findings provide insight into the pathogenetic etiology of heterotopic ossification in colon cancer. PMID- 27466306 TI - Plasmodium Falciparum Recurrence Two Years after Exposure in Endemic Country: A Case Report. AB - Plasmodium falciparum typically manifests as a severe, symptomatic infection due to the high parasitemia and increased adherence of infected cells to blood vessel endothelium. However, there have been previous reports of P. falciparum recrudescence months to years after exposure. We report the case of a 56 year old woman who presented with malarial symptoms after recent travel to New York and previous travel to Liberia. PMID- 27466307 TI - First Case of Biphenotypic/bilineal (B/myeloid, B/monocytic) Mixed Phenotype Acute Leukemia with t(9;22)(q34;q11.2);BCR-ABL1. AB - Mixed phenotype acute leukemia (MPAL) includes biphenotypic leukemia, bilineal leukemia, or its combination by the 2008 WHO classification. A few cases of combined biphenotypic/bilineal MPAL have been reported so far; they all had biphenotypic expressions in only one of the two distinct leukemic populations. A 43-year-old female presented with leukocytosis and bicytopenia. Her complete blood counts were: hemoglobin, 6.9 g/dL; white blood cells, 62.8*10(9)/L; and platelets, 83*10(9)/L. Neither lymphadenopathy nor organomegaly was observed. Blasts and promonocytes/monoblasts were increased in her peripheral blood (42%) and bone marrow (60.1%). Flow cytometric analysis revealed two distinct populations of leukemic cells, which expressed CD11c, CD19, and cytoplasmic CD79a in common. Additionally, the first population expressed CD10 and CD117 (B/myeloid), and the second one expressed CD14 and CD20 (B/monocytic). She had a karyotype of 46,XX,inv(9)(p12q13),t(9;22)(q34;q11.2)[20] and BCR/ABL1 rearrangement. To the best of our knowledge, this is the first reported case of biphenotypic/bilineal MPAL with B/myeloid and B/monocytic expressions. PMID- 27466308 TI - Disseminated Phaeohyphomycosis with Brain Abscess and Biliary Invasion Due to Bipolaris spp. in an Immunocompetent Patient. AB - Bipolaris is a dematiaceous fungus seen in the skin, nasal sinuses, and occasionally in the central nervous system. We present an immunocompetent female with bilateral dural-based abscesses caused by a Bipolaris species. The patient had no involvement of the sinuses with the fungus but was later found to have a significant Bipolaris infection of her biliary tree. PMID- 27466309 TI - Letter to Editor: Cytokeratin 5/6 Expression in Adenoid Cystic Carcinoma. PMID- 27466310 TI - Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice. AB - Deficits in glucose, impaired insulin signalling and brain insulin resistance are common in the pathogenesis of Alzheimer's disease (AD); therefore, some scholars even called AD type 3 diabetes mellitus. Curcumin can reduce the amyloid pathology in AD. Moreover, it is a well-known fact that curcumin has anti-oxidant and anti-inflammatory properties. However, whether or not curcumin could regulate the insulin signal transduction pathway in AD remains unclear. In this study, we used APPswe/PS1dE9 double transgenic mice as the AD model to investigate the mechanisms and the effects of curcumin on AD. Immunohistochemical (IHC) staining and a western blot analysis were used to test the major proteins in the insulin signal transduction pathway. After the administration of curcumin for 6 months, the results showed that the expression of an insulin receptor (InR) and insulin receptor substrate (IRS)-1 decreased in the hippocampal CA1 area of the APPswe/PS1dE9 double transgenic mice, while the expression of phosphatidylinositol-3 kinase (PI3K), phosphorylated PI3K (p-PI3K), serine threonine kinase (AKT) and phosphorylated AKT (p-AKT) increased. Among the curcumin groups, the medium-dose group was the most effective one. Thus, we believe that curcumin may be a potential therapeutic agent that can regulate the critical molecules in brain insulin signalling pathways. Furthermore, curcumin could be adopted as one of the AD treatments to improve a patient's learning and memory ability. PMID- 27466311 TI - Using Super-Imposition by Translation And Rotation (SITAR) to relate pubertal growth to bone health in later life: the Medical Research Council (MRC) National Survey of Health and Development. AB - BACKGROUND: To explore associations between pubertal growth and later bone health in a cohort with infrequent measurements, using another cohort with more frequent measurements to support the modelling, data from the Medical Research Council (MRC) National Survey of Health and Development (2-26 years, 4901/30 004 subjects/measurements) and the Avon Longitudinal Study of Parents And Children (ALSPAC) (5-20 years) (10 896/74 120) were related to National Survey of Health and Development (NSHD) bone health outcomes at 60-64 years. METHODS: NSHD data were analysed using Super-Imposition by Translation And Rotation (SITAR) growth curve analysis, either alone or jointly with ALSPAC data. Improved estimation of pubertal growth parameters of size, tempo and velocity was assessed by changes in model fit and correlations with contemporary measures of pubertal timing. Bone outcomes of radius [trabecular volumetric bone mineral density (vBMD) and diaphysis cross-sectional area (CSA)] were regressed on the SITAR parameters, adjusted for current body size. RESULTS: The NSHD SITAR parameters were better estimated in conjunction with ALSPAC, i.e. more strongly correlated with pubertal timing. Trabecular vBMD was associated with early height tempo, whereas diaphysis CSA was related to weight size, early tempo and slow velocity, the bone outcomes being around 15% higher for the better vs worse growth pattern. CONCLUSIONS: By pooling NSHD and ALSPAC data, SITAR more accurately summarized pubertal growth and weight gain in NSHD, and in turn demonstrated notable associations between pubertal timing and later bone outcomes. These associations give insight into the importance of the pubertal period for future skeletal health and osteoporosis risk. PMID- 27466313 TI - Broad Screening and Identification of Novel Psychoactive Substances in Plasma by High-Performance Liquid Chromatography-High-Resolution Mass Spectrometry and Post run Library Matching. AB - Drug abuse is today a growing global problem. Often the consumers are not aware about the type of substances they are using and the correlated risks. In recent years, new psychoactive substances (NPS) appeared in the illicit market. The presence of NPS, such as synthetic cathinones, cannabinoids and phenethylamines, which are known to be pharmacologically and toxicologically hazardous, has been frequently reported. The aim of this study was the development of a liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method for a broad screening of NPS in plasma. Data acquisition was in MS/MS and full-scan modes and the method was validated for 25 NPS belonging to different chemical classes. Quantitative results have been obtained for these analytes with limits of quantification ranging from 0.03 to 0.4 ng/mL. The method was proven to be suitable for the screening of additional substances; to this aim, a post-run library matching was conducted for every sample with an in-house database containing over 300 NPS and known metabolites. The library may be constantly expanded with new drugs, in order to obtain a broad screening of NPS in biological matrices. PMID- 27466312 TI - Body fatness throughout the life course and the incidence of premenopausal breast cancer. AB - BACKGROUND: The role of body fatness in the aetiology of breast cancer is complex. We evaluated the independent and synergistic effects of body fatness, at different stages throughout a woman's life course, on premenopausal breast cancer risk. METHODS: Premenopausal participants of the Nurses' Health Study II (NHSII) were followed from 1991 up to 2009. Body fatness factors including birthweight, somatotype (a 9-level pictogram with level 1 being the leanest) at ages 5 and 10 years and body mass index (BMI) at age 18 were collected at baseline. Current BMI was updated biennially. Multivariate Cox regression models were used to evaluate the association between each body fatness factor as well as cross-classification of all factors and the incidence of breast cancer. RESULTS: Based on 1574 incident premenopausal breast cancer cases and 1 133 893 person-years of follow up, a lower incidence was associated with lower birthweight: hazard ratio (HR) [95% confidence interval (CI)] = 0.74 (0.58-0.95) for <2.5kg vs 3.9+kg, P for trend < 0.001; higher somatotype at age 5: HR=0.57 (95% CI 0.44-0.73) for 5-9 vs 1, P fortrend < 0.0001]; and at age 10: HR=0.61 (95% CI 0.49-0.75) for 5-9 vs 1, P for trend < 0.0001]; and BMI at age 18: HR=0.67 (95% 0.47-0.95) for >= 27.5 kg/m2 vs < 18.5 kg/m2, P for trend = 0.009], after adjusting for age and body fatness measures earlier in life and other risk factors, respectively. No significant interaction between body fatness measures was found. Women with the lowest birthweight, the highest somatotype at ages 5 and 10 and the highest BMI at age 18 and currently had a 72% (95% CI 54%-83%) lower incidence of invasive premenopausal breast cancer than women with the opposite extreme of each body fatness indicator. CONCLUSION: The lowest incidence of premenopausal breast cancer was associated with the lowest birthweight and the highest childhood, adolescent and early adult body fatness. PMID- 27466314 TI - Ebstein's anomaly with recurrent massive pericardial effusion: a rare presentation. AB - Ebstein's anomaly is known for its varied presentations and exceptionally long survival in some cases. Here the authors describe a case of previously undiagnosed Ebstein's anomaly in a patient who presented with massive pericardial effusion. Over the next 6 months, the patient was hospitalised twice for pericardiocentesis. To the best of our knowledge, a case of Ebstein's anomaly with recurrent massive pericardial effusion has not been described previously. PMID- 27466315 TI - Discordant relationship between Essure microinsert position and tubal occlusion. AB - Hysteroscopic sterilisation with Essure requires confirmation of tubal occlusion by hysterosalpingogram or microinsert position by transvaginal sonography 3 months after placement before women can rely on the method for pregnancy prevention. A 39-year-old woman underwent hysteroscopic sterilisation via Essure, with successful bilateral tubal occlusion documented on hysterosalpingogram. She had a subsequent unintended pregnancy and termination, and presented with persistent pelvic pain and other non-specific symptoms. She underwent a laparoscopic-assisted vaginal hysterectomy with bilateral salpingectomy, with complete resolution of her symptoms. Pathological evaluation demonstrated a perforated Essure microinsert and ipsilateral tubal occlusion, and a correctly placed Essure microinsert with ipsilateral tubal patency. Clinicians should be cautious about the assumption that correctly placed microinserts based on ultrasonography, hysterosalpingogram or laparoscopic evaluation assures occlusion success. PMID- 27466316 TI - Model-independent counting of molecules in single-molecule localization microscopy. AB - Most biomolecular processes rely on tightly controlled stoichiometries, from the formation of molecular assemblies to cellular signaling. Single-molecule localization micro-scopy studies of fluorophore blinking offer a promising route to probe oligomeric states. Here we show that the distribution of the number of blinking events assumes a universal functional form, independent of photophysics, under relatively mild assumptions. The number of photophysical states, the kinetics of interconversion, and the fraction of active fluorophores enter as two or three constants. This essentially model-independent formulation allows us to determine molecule counts from fluorophore blinking statistics. The formulas hold even if the fluorophores have many different yet unresolved dark states, as long as there is only a single fluorescent state, or if there are different yet unresolvable fluorescent states, as long as there is only a single dark state. We demonstrate the practical applicability of this approach by quantifying the oligomerization states of membrane proteins tagged with the mEos2 fluorescent protein. We find that the model parameters, obtained by likelihood maximization, are transferable. With the counting statistics being independent of the detailed photophysics and its parameters being transferable, the method should be robust and broadly applicable to counting colocalized molecules in vivo and in vitro. PMID- 27466317 TI - VE-cadherin interacts with cell polarity protein Pals1 to regulate vascular lumen formation. AB - Blood vessel tubulogenesis requires the formation of stable cell-to-cell contacts and the establishment of apicobasal polarity of vascular endothelial cells. Cell polarity is regulated by highly conserved cell polarity protein complexes such as the Par3-aPKC-Par6 complex and the CRB3-Pals1-PATJ complex, which are expressed by many different cell types and regulate various aspects of cell polarity. Here we describe a functional interaction of VE-cadherin with the cell polarity protein Pals1. Pals1 directly interacts with VE-cadherin through a membrane proximal motif in the cytoplasmic domain of VE-cadherin. VE-cadherin clusters Pals1 at cell-cell junctions. Mutating the Pals1-binding motif in VE-cadherin abrogates the ability of VE-cadherin to regulate apicobasal polarity and vascular lumen formation. In a similar way, deletion of the Par3-binding motif at the C terminus of VE-cadherin impairs apicobasal polarity and vascular lumen formation. Our findings indicate that the biological activity of VE-cadherin in regulating endothelial polarity and vascular lumen formation is mediated through its interaction with the two cell polarity proteins Pals1 and Par3. PMID- 27466318 TI - Sir protein-independent repair of dicentric chromosomes in Saccharomyces cerevisiae. AB - Sir2 protein has been reported to be recruited to dicentric chromosomes under tension, and such chromosomes are reported to be especially vulnerable to breakage in sir2Delta mutants. We found that the loss of viability in such mutants was an indirect effect of the repression of nonhomologous end joining in Sir(-) mutants and that the apparent recruitment of Sir2 protein to chromosomes under tension was likely due to methodological weakness in early chromatin immunoprecipitation studies. PMID- 27466321 TI - Primary Extramedullary Plasmacytoma in the Gastroduodenal Canal Associated With Epstein-Barr Virus-Associated Adenocarcinoma of the Stomach: A Case Report. AB - The coexistent occurrence of a lymphoid neoplasm with adenocarcinoma of the stomach is rare. We report herein a case of gastroduodenal extramedullary plasmacytoma simultaneously complicated by multiple gastric Epstein-Barr virus (EBV)-associated adenocarcinomas. The patient underwent distal gastrectomy to treat an adenocarcinoma occupying the gastric antrum. Histopathological examination revealed a massive submucosal plasma cell proliferation adjacent to the adenocarcinoma involving the pylorus to the duodenal bulb. Lambda immunoglobulin light chain restriction indicated that these plasma cells were monoclonal. Because the clinical investigation revealed no other lymphoid neoplasms, primary extramedullary plasmacytoma of the stomach was diagnosed. The histological examination of the resected stomach revealed 3 additional adenocarcinomas invading from the mucosa to the submucosa. A thorough histological examination of the remnant stomach resected 2 weeks after the first surgery revealed 2 additional adenocarcinomas in the remnant specimen, yielding a total of 6 carcinomas, all of which represented EBV-associated gastric carcinomas (EBV-GC). This is the second case report of gastric plasmacytoma concurrent with adenocarcinoma. Moreover, the plasmacytoma showed a conspicuous morphologic feature resembling Mott cells. Because Helicobacter pylori (HP) infection was also elucidated, this rare case may indicate a role of EBV or HP in carcinogenesis of both adenocarcinoma and lymphoplasmacytic neoplasms. PMID- 27466319 TI - Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylation-dependent mechanism. AB - Proper regulation of microtubule dynamics is essential for cell functions and involves various microtubule-associated proteins (MAPs). Among them, end-binding proteins (EBs) accumulate at microtubule plus ends, whereas structural MAPs bind along the microtubule lattice. Recent data indicate that the structural MAP tau modulates EB subcellular localization in neurons. However, the molecular determinants of EB/tau interaction remain unknown, as is the effect of this interplay on microtubule dynamics. Here we investigate the mechanisms governing EB/tau interaction in cell-free systems and cellular models. We find that tau inhibits EB tracking at microtubule ends. Tau and EBs form a complex via the C terminal region of EBs and the microtubule-binding sites of tau. These two domains are required for the inhibitory activity of tau on EB localization to microtubule ends. Moreover, the phosphomimetic mutation S262E within tau microtubule-binding sites impairs EB/tau interaction and prevents the inhibitory effect of tau on EB comets. We further show that microtubule dynamic parameters vary, depending on the combined activities of EBs and tau proteins. Overall our results demonstrate that tau directly antagonizes EB function through a phosphorylation-dependent mechanism. This study highlights a novel role for tau in EB regulation, which might be impaired in neurodegenerative disorders. PMID- 27466320 TI - Numb regulates the balance between Notch recycling and late-endosome targeting in Drosophila neural progenitor cells. AB - The Notch signaling pathway plays essential roles in both animal development and human disease. Regulation of Notch receptor levels in membrane compartments has been shown to affect signaling in a variety of contexts. Here we used steady state and pulse-labeling techniques to follow Notch receptors in sensory organ precursor cells in Drosophila. We find that the endosomal adaptor protein Numb regulates levels of Notch receptor trafficking to Rab7-labeled late endosomes but not early endosomes. Using an assay we developed that labels different pools of Notch receptors as they move through the endocytic system, we show that Numb specifically suppresses a recycled Notch receptor subpopulation and that excess Notch signaling in numb mutants requires the recycling endosome GTPase Rab11 activity. Our data therefore suggest that Numb controls the balance between Notch receptor recycling and receptor targeting to late endosomes to regulate signaling output after asymmetric cell division in Drosophila neural progenitors. PMID- 27466322 TI - Brexit and research: goodbye EU money and colleagues? PMID- 27466325 TI - The Neural Causes of Congenital Amusia. PMID- 27466323 TI - Dynamic cohesin-mediated chromatin architecture controls epithelial-mesenchymal plasticity in cancer. AB - Epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) are important interconnected events in tumorigenesis controlled by complex genetic networks. However, the cues that activate EMT-initiating factors and the mechanisms that reversibly connect EMT/MET are not well understood. Here, we show that cohesin-mediated chromatin organization coordinates EMT/MET by regulating mesenchymal genes. We report that RAD21, a subunit of the cohesin complex, is expressed in epithelial breast cancer cells, whereas its expression is decreased in mesenchymal cancer. Depletion of RAD21 in epithelial cancer cells causes transcriptional activation of TGFB1 and ITGA5, inducing EMT. Reduced binding of RAD21 changes intrachromosomal chromatin interactions within the TGFB1 and ITGA5 loci, creating an active transcriptional environment. Similarly, stem cell-like cancer cells also show an open chromatin structure at both genes, which correlates with high expression levels and mesenchymal fate characteristics. Conversely, overexpression of RAD21 in mesenchymal cancer cells induces MET-specific expression patterns. These findings indicate that dynamic cohesin-mediated chromatin structures are responsible for the initiation and regulation of essential EMT-related cell fate changes in cancer. PMID- 27466324 TI - Ubiquitously expressed genes participate in cell-specific functions via alternative promoter usage. AB - How do different cell types acquire their specific identities and functions is a fundamental question of biology. Previously significant efforts have been devoted to search for cell-type-specifically expressed genes, especially transcription factors, yet how do ubiquitously expressed genes participate in the formation or maintenance of cell-type-specific features remains largely unknown. Here, we have identified 110 mouse embryonic stem cell (mESC) specifically expressed transcripts with cell-stage-specific alternative transcription start sites (SATS isoforms) from 104 ubiquitously expressed genes, majority of which have active epigenetic modification- or stem cell-related functions. These SATS isoforms are specifically expressed in mESCs, and tend to be transcriptionally regulated by key pluripotency factors through direct promoter binding. Knocking down the SATS isoforms of Nmnat2 or Usp7 leads to differentiation-related phenotype in mESCs. These results demonstrate that cell-type-specific transcription factors are capable to produce cell-type-specific transcripts with alternative transcription start sites from ubiquitously expressed genes, which confer ubiquitously expressed genes novel functions involved in the establishment or maintenance of cell-type-specific features. PMID- 27466326 TI - Training Working Memory: Anatomy Matters. PMID- 27466327 TI - Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine. AB - Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine's effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a "primed" state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse. SIGNIFICANCE STATEMENT: Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action, the dopamine transporter (DAT). Preclinical literature has shown that reduced cocaine potency at the DAT increases cocaine taking, highlighting the key role of tolerance in addiction. Addiction is characterized by cycles of abstinence, often for many months, followed by relapse, making it important to determine possible interactions between abstinence and subsequent drug re-exposure. Using a rodent model of cocaine abuse, we found long-lasting, possibly permanent, cocaine-induced alterations to the DAT, whereby cocaine tolerance is reinstated by minimal drug exposure, even after recovery of DAT function over prolonged abstinence periods. PMID- 27466328 TI - A Probability Distribution over Latent Causes, in the Orbitofrontal Cortex. AB - The orbitofrontal cortex (OFC) has been implicated in both the representation of "state," in studies of reinforcement learning and decision making, and also in the representation of "schemas," in studies of episodic memory. Both of these cognitive constructs require a similar inference about the underlying situation or "latent cause" that generates our observations at any given time. The statistically optimal solution to this inference problem is to use Bayes' rule to compute a posterior probability distribution over latent causes. To test whether such a posterior probability distribution is represented in the OFC, we tasked human participants with inferring a probability distribution over four possible latent causes, based on their observations. Using fMRI pattern similarity analyses, we found that BOLD activity in the OFC is best explained as representing the (log-transformed) posterior distribution over latent causes. Furthermore, this pattern explained OFC activity better than other task-relevant alternatives, such as the most probable latent cause, the most recent observation, or the uncertainty over latent causes. SIGNIFICANCE STATEMENT: Our world is governed by hidden (latent) causes that we cannot observe, but which generate the observations we see. A range of high-level cognitive processes require inference of a probability distribution (or "belief distribution") over the possible latent causes that might be generating our current observations. This is true for reinforcement learning and decision making (where the latent cause comprises the true "state" of the task), and for episodic memory (where memories are believed to be organized by the inferred situation or "schema"). Using fMRI, we show that this belief distribution over latent causes is encoded in patterns of brain activity in the orbitofrontal cortex, an area that has been separately implicated in the representations of both states and schemas. PMID- 27466329 TI - Neural Responses to Heartbeats in the Default Network Encode the Self in Spontaneous Thoughts. AB - The default network (DN) has been consistently associated with self-related cognition, but also to bodily state monitoring and autonomic regulation. We hypothesized that these two seemingly disparate functional roles of the DN are functionally coupled, in line with theories proposing that selfhood is grounded in the neural monitoring of internal organs, such as the heart. We measured with magnetoencephalograhy neural responses evoked by heartbeats while human participants freely mind-wandered. When interrupted by a visual stimulus at random intervals, participants scored the self-relatedness of the interrupted thought. They evaluated their involvement as the first-person perspective subject or agent in the thought ("I"), and on another scale to what degree they were thinking about themselves ("Me"). During the interrupted thought, neural responses to heartbeats in two regions of the DN, the ventral precuneus and the ventromedial prefrontal cortex, covaried, respectively, with the "I" and the "Me" dimensions of the self, even at the single-trial level. No covariation between self-relatedness and peripheral autonomic measures (heart rate, heart rate variability, pupil diameter, electrodermal activity, respiration rate, and phase) or alpha power was observed. Our results reveal a direct link between selfhood and neural responses to heartbeats in the DN and thus directly support theories grounding selfhood in the neural monitoring of visceral inputs. More generally, the tight functional coupling between self-related processing and cardiac monitoring observed here implies that, even in the absence of measured changes in peripheral bodily measures, physiological and cognitive functions have to be considered jointly in the DN. SIGNIFICANCE STATEMENT: The default network (DN) has been consistently associated with self-processing but also with autonomic regulation. We hypothesized that these two functions could be functionally coupled in the DN, inspired by theories according to which selfhood is grounded in the neural monitoring of internal organs. Using magnetoencephalography, we show that heartbeat-evoked responses (HERs) in the DN covary with the self relatedness of ongoing spontaneous thoughts. HER amplitude in the ventral precuneus covaried with the "I" self-dimension, whereas HER amplitude in the ventromedial prefrontal cortex encoded the "Me" self-dimension. Our experimental results directly support theories rooting selfhood in the neural monitoring of internal organs. We propose a novel functional framework for the DN, where self processing is coupled with physiological monitoring. PMID- 27466331 TI - Multiple Mechanisms for Processing Reward Uncertainty in the Primate Basal Forebrain. AB - The ability to use information about the uncertainty of future outcomes is critical for adaptive behavior in an uncertain world. We show that the basal forebrain (BF) contains at least two distinct neural-coding strategies to support this capacity. The dorsal-lateral BF, including the ventral pallidum (VP), contains reward-sensitive neurons, some of which are selectively suppressed by uncertain-reward predictions (U(-)). In contrast, the medial BF (mBF) contains reward-sensitive neurons, some of which are selectively enhanced (U(+)) by uncertain-reward predictions. In a two-alternative choice-task, U(-) neurons were selectively suppressed while monkeys chose uncertain options over certain options. During the same choice-epoch, U(+) neurons signaled the subjective reward value of the choice options. Additionally, after the choice was reported, U(+) neurons signaled reward uncertainty until the choice outcome. We suggest that uncertainty-related suppression of VP may participate in the mediation of uncertainty-seeking actions, whereas uncertainty-related enhancement of the mBF may direct cognitive resources to monitor and learn from uncertain-outcomes. SIGNIFICANCE STATEMENT: To survive in an uncertain world, we must approach uncertainty and learn from it. Here we provide evidence for two mostly distinct mechanisms for processing uncertainty about rewards within different subregions of the primate basal forebrain (BF). We found that uncertainty suppressed the representation of certain (or safe) reward values by some neurons in the dorsal lateral BF, in regions occupied by the ventral pallidum. This uncertainty-related suppression was evident as monkeys made risky choices. We also found that uncertainty-enhanced the activity of many medial BF neurons, most prominently after the monkeys' choices were completed (as they awaited uncertain outcomes). Based on these findings, we propose that different subregions of the BF could support action and learning under uncertainty in distinct but complimentary manners. PMID- 27466330 TI - Transmission of Predictable Sensory Signals to the Cerebellum via Climbing Fiber Pathways Is Gated during Exploratory Behavior. AB - Pathways arising from the periphery that target the inferior olive [spino olivocerebellar pathways (SOCPs)] are a vital source of information to the cerebellum and are modulated (gated) during active movements. This limits their ability to forward signals to climbing fibers in the cerebellar cortex. We tested the hypothesis that the temporal pattern of gating is related to the predictability of a sensory signal. Low-intensity electrical stimulation of the ipsilateral hindlimb in awake rats evoked field potentials in the C1 zone in the copula pyramidis of the cerebellar cortex. Responses had an onset latency of 12.5 +/- 0.3 ms and were either short or long duration (8.7 +/- 0.1 vs 31.2 +/- 0.3 ms, respectively). Both types of response were shown to be mainly climbing fiber in origin and therefore evoked by transmission in hindlimb SOCPs. Changes in response size (area of field, millivolts per millisecond) were used to monitor differences in transmission during rest and three phases of rearing: phase 1, rearing up; phase 2, upright; and phase 3, rearing down. Responses evoked during phase 2 were similar in size to rest but were smaller during phases 1 and 3, i.e., transmission was reduced during active movement when self-generated (predictable) sensory signals from the hindlimbs are likely to occur. To test whether the pattern of gating was related to the predictability of the sensory signal, some animals received the hindlimb stimulation only during phase 2. Over ~10 d, the responses became progressively smaller in size, consistent with gating out transmission of predictable sensory signals relayed via SOCPs. SIGNIFICANCE STATEMENT: A major route for peripheral information to gain access to the cerebellum is via ascending climbing fiber pathways. During active movements, gating of transmission in these pathways controls when climbing fiber signals can modify cerebellar activity. We investigated this phenomenon in rats during their exploratory behavior of rearing. During rearing up and down, transmission was reduced at a time when self-generated, behaviorally irrelevant (predictable) signals occur. However, during the upright phase of rearing, transmission was increased when behaviorally relevant (unpredictable) signals may occur. When the peripheral stimulation was delivered only during the upright phase, so its occurrence became predictable over time, transmission was reduced. Therefore, the results indicate that the gating is related to the level of predictability of a sensory signal. PMID- 27466332 TI - Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain. AB - The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity. SIGNIFICANCE STATEMENT: The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system. PMID- 27466334 TI - mGluR1 and mGluR5 Synergistically Control Cholinergic Synaptic Transmission in the Thalamic Reticular Nucleus. AB - Acetylcholine (ACh) signaling is involved in a wide range of processes, including arousal, attention, and learning. An increasing number of studies indicate that cholinergic control of these functions is highly deterministic, mediated by synaptic afferents that generate reliable and precise responses in postsynaptic neurons. However, mechanisms that govern plastic changes of cholinergic synaptic strength are poorly understood, even though they are likely critical in shaping the impact of cholinergic inputs on neuronal networks. We have recently shown that in the thalamic reticular nucleus (TRN), synaptic release of ACh generates excitatory-inhibitory biphasic postsynaptic responses, mediated by the activation of alpha4beta2 nicotinic (nAChRs) and M2 muscarinic receptors (mAChRs), respectively. Here, using voltage-clamp recordings from TRN neurons in thalamocortical slices of mice, we demonstrate that the activation of Group I metabotropic glutamate receptors (mGluRs) by ambient or synaptically released glutamate evokes transient increases of nicotinic EPSCs. Additionally, we find that the selective Group I mGluR agonist DHPG [(S)-3,5-dihydroxyphenylglycine] evokes long-term potentiation of nicotinic EPSCs (mGluR-nLTP), dependent on increases in postsynaptic Ca(2+) concentration and the activation of phospholipase C. Both the induction and the maintenance of mGluR-nLTP require synergistic activation of mGluR1 and mGluR5. Together, our results show that postsynaptic Group I mGluRs are critically involved in the regulation of cholinergic synaptic strength on different time scales, suggesting that cholinergic control of local thalamic circuits is highly context-dependent and regulated by the overall levels of glutamatergic afferent activity. SIGNIFICANCE STATEMENT: Cholinergic signaling controls information processing and plasticity in neuronal circuits, but the mechanisms underlying the regulation of cholinergic synaptic strength on different time scales are unknown. Here we identify mGluR1 and mGluR5 as key elements in the dynamic regulation of cholinergic synaptic inputs onto neurons of the TRN. Our findings highlight potential mechanisms that regulate cholinergic signaling in the mammalian brain. PMID- 27466333 TI - Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor Facilitation. AB - Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a form of spinal motor plasticity. Competing mechanisms give rise to phrenic motor facilitation (pMF; a general term including pLTF) depending on the severity of hypoxia within episodes. In contrast, moderate acute sustained hypoxia (mASH) does not elicit pMF. By varying the severity of ASH and targeting competing mechanisms of pMF, we sought to illustrate why moderate AIH (mAIH) elicits pMF but mASH does not. Although mAIH elicits serotonin-dependent pLTF, mASH does not; thus, mAIH-induced pLTF is pattern sensitive. In contrast, severe AIH (sAIH) elicits pLTF through adenosine-dependent mechanisms, likely from greater extracellular adenosine accumulation. Because serotonin- and adenosine-dependent pMF interact via cross talk inhibition, we hypothesized that pMF is obscured because the competing mechanisms of pMF are balanced and offsetting during mASH. Here, we demonstrate the following: (1) blocking spinal A2A receptors with MSX-3 reveals mASH-induced pMF; and (2) sASH elicits A2A-dependent pMF. In anesthetized rats pretreated with intrathecal A2A receptor antagonist injections before mASH (PaO2 = 40-54 mmHg) or sASH (PaO2 = 25-36 mmHg), (1) mASH induced a serotonin dependent pMF and (2) sASH induced an adenosine-dependent pMF, which was enhanced by spinal serotonin receptor inhibition. Thus, competing adenosine- and serotonin dependent mechanisms contribute differentially to pMF depending on the pattern/severity of hypoxia. Understanding interactions between these mechanisms has clinical relevance as we develop therapies to treat severe neuromuscular disorders that compromise somatic motor behaviors, including breathing. Moreover, these results demonstrate how competing mechanisms of plasticity can give rise to pattern sensitivity in pLTF. SIGNIFICANCE STATEMENT: Intermittent hypoxia elicits pattern-sensitive spinal plasticity and improves motor function after spinal injury or during neuromuscular disease. Specific mechanisms of pattern sensitivity in this form of plasticity are unknown. We provide evidence that competing mechanisms of phrenic motor facilitation mediated by adenosine 2A and serotonin 2 receptors are differentially expressed, depending on the pattern/severity of hypoxia. Understanding how these distinct mechanisms interact during hypoxic exposures differing in severity and duration will help explain interesting properties of plasticity, such as pattern sensitivity, and may help optimize therapies to restore motor function in patients with neuromuscular disorders that compromise movement. PMID- 27466335 TI - Prefrontal Cortex to Accumbens Projections in Sleep Regulation of Reward. AB - Sleep profoundly affects the emotional and motivational state. In humans and animals, loss of sleep often results in enhanced motivation for reward, which has direct implications for health risks as well as potential benefits. Current study aims at understanding the mechanisms underlying sleep deprivation (SDe)-induced enhancement of reward seeking. We found that after acute SDe, mice had an increase in sucrose seeking and consumption but not food intake, suggesting a selective enhancement of motivation for reward. In the nucleus accumbens (NAc), a key brain region regulating emotional and motivational responses, we observed a decrease in the ratio of the overall excitatory over inhibitory synaptic inputs onto NAc principle neurons after SDe. The shift was partly mediated by reduced glutamatergic transmission of presynaptic origin. Further analysis revealed that there was selective reduction of the glutamate release probability at the medial prefrontal cortex (mPFC)-to-NAc synapses, but not those from the hippocampus, thalamus, or the basal lateral amygdala. To reverse this SDe-induced synaptic alteration, we expressed the stabilized step function opsin (SSFO) in the mPFC; optogenetic stimulation of SSFO at mPFC-to-NAc projection terminals persistently enhanced the action potential-dependent glutamate release. Intra-NAc optogenetic stimulation of SSFO selectively at mPFC-to-NAc terminals restored normal sucrose seeking in mice after SDe without affecting food intake. These results highlight the mPFC-to-NAc projection as a key circuit-based target for sleep to regulate reward-motivated behaviors. SIGNIFICANCE STATEMENT: Sleep loss, a costly challenge of modern society, has profound physiological and psychological consequences, including altered reward processing of the brain. The current study aims at understanding the mechanisms underlying sleep deprivation-induced enhancement of reward seeking. We identify that the medial prefrontal cortex (mPFC)-to-nucleus accumbens (NAc) glutamatergic transmission is selectively weakened following acute sleep deprivation, whose restoration normalizes reward seeking in sleep-deprived mice. These results suggest a possibility of normalizing sleep deprivation-induced abnormal reward seeking by targeting specific neural projections, and they demonstrate the mPFC-to-NAc glutamatergic projection as a key circuit-based target for sleep to regulate reward-motivated behaviors. PMID- 27466336 TI - Distinct Functions of Syntaxin-1 in Neuronal Maintenance, Synaptic Vesicle Docking, and Fusion in Mouse Neurons. AB - Neurotransmitter release requires the formation of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complexes by SNARE proteins syntaxin-1 (Stx1), synaptosomal-associated protein 25 (SNAP-25), and synaptobrevin-2 (Syb2). In mammalian systems, loss of SNAP-25 or Syb2 severely impairs neurotransmitter release; however, complete loss of function studies for Stx1 have been elusive due to the functional redundancy between Stx1 isoforms Stx1A and Stx1B and the embryonic lethality of Stx1A/1B double knock-out (DKO) mice. Here, we studied the roles of Stx1 in neuronal maintenance and neurotransmitter release in mice with constitutive or conditional deletion of Stx1B on an Stx1A-null background. Both constitutive and postnatal loss of Stx1 severely compromised neuronal viability in vivo and in vitro, indicating an obligatory role of Stx1 for maintenance of developing and mature neurons. Loss of Munc18-1, a high-affinity binding partner of Stx1, also showed severely impaired neuronal viability, but with a slower time course compared with Stx1A/1B DKO neurons, and exogenous Stx1A or Stx1B expression significantly delayed Munc18-1 dependent lethality. In addition, loss of Stx1 completely abolished fusion competent vesicles and severely impaired vesicle docking, demonstrating its essential roles in neurotransmission. Putative partial SNARE complex assembly with the SNARE motif mutant Stx1A(AV) (A240V, V244A) was not sufficient to rescue neurotransmission despite full recovery of vesicle docking and neuronal survival. Together, these data suggest that Stx1 has independent functions in neuronal maintenance and neurotransmitter release and complete SNARE complex formation is required for vesicle fusion and priming, whereas partial SNARE complex formation is sufficient for vesicle docking and neuronal maintenance. SIGNIFICANCE STATEMENT: Syntaxin-1 (Stx1) is a component of the synaptic vesicle soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex and is essential for neurotransmission. We present the first detailed loss-of function characterization of the two Stx1 isoforms in central mammalian neurons. We show that Stx1 is fundamental for maintenance of developing and mature neurons and also for vesicle docking and neurotransmission. We also demonstrate that neuronal maintenance and neurotransmitter release are regulated by Stx1 through independent functions. Furthermore, we show that SNARE complex formation is required for vesicle fusion, whereas partial SNARE complex formation is sufficient for vesicle docking and neuronal maintenance. Therefore, our work provides insights into differential functions of Stx1 in neuronal maintenance and neurotransmission, with the latter explored further into its functions in vesicle docking and fusion. PMID- 27466338 TI - Circuit Analysis of a Drosophila Dopamine Type 2 Receptor That Supports Anesthesia-Resistant Memory. AB - Dopamine is central to reinforcement processing and exerts this function in species ranging from humans to fruit flies. It can do so via two different types of receptors (i.e., D1 or D2) that mediate either augmentation or abatement of cellular cAMP levels. Whereas D1 receptors are known to contribute to Drosophila aversive odor learning per se, we here show that D2 receptors are specific for support of a consolidated form of odor memory known as anesthesia-resistant memory. By means of genetic mosaicism, we localize this function to Kenyon cells, the mushroom body intrinsic neurons, as well as GABAergic APL neurons and local interneurons of the antennal lobes, suggesting that consolidated anesthesia resistant memory requires widespread dopaminergic modulation within the olfactory circuit. Additionally, dopaminergic neurons themselves require D2R, suggesting a critical role in dopamine release via its recognized autoreceptor function. Considering the dual role of dopamine in balancing memory acquisition (proactive function of dopamine) and its "forgetting" (retroactive function of dopamine), our analysis suggests D2R as central player of either process. SIGNIFICANCE STATEMENT: Dopamine provides different information; while it mediates reinforcement during the learning act (proactive function), it balances memory performance between two antithetic processes thereafter (retroactive function) (i.e., forgetting and augmentation). Such bidirectional design can also be found at level of dopamine receptors, where augmenting D1 and abating D2 receptors are engaged to balance cellular cAMP levels. Here, we report that consolidated anesthesia-resistant memory (ARM), but not other concomitant memory phases, are sensitive to bidirectional dopaminergic signals. By means of genetic mosaicism, we identified widespread dopaminergic modulation within the olfactory circuit that suggests nonredundant and reiterating functions of D2R in support of ARM. Our results oppose ARM to its concomitant memory phases that localize to mushroom bodies and propose a decentralized organization of consolidated ARM. PMID- 27466337 TI - Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination. AB - Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need. Upon screening a G-protein-coupled receptor small-molecule library, we report the identification of a cluster of kappa-opioid receptor (KOR) agonists that significantly promotes oligodendrocyte differentiation and myelination. KOR agonists were validated in purified rat oligodendroglial cultures, and the (+/-)U-50488 compound proved to be most effective for differentiation. (+/-)U-50488 treatment significantly enhances differentiation and myelination in purified oligodendroglial cocultures and greatly accelerates the kinetics of remyelination in vivo after focal demyelination with lysolecithin. The effect of (+/-)U-50488 is attenuated by KOR antagonists and completely abolished in KOR-null oligodendroglia. Conditional deletion of KOR in murine oligodendrocyte precursor cells (OPCs) greatly inhibits remyelination after focal demyelination lacking any response to (+/-)U-50488 treatment. To determine whether agonism of KOR represents a feasible therapeutic approach, human induced pluripotent stem cell-derived OPCs were treated with (+/ )U-50488. Consistent with findings, differentiation of human OPCs into mature oligodendrocytes was significantly enhanced. Together, KOR is a therapeutic target to consider for future remyelination therapy. SIGNIFICANCE STATEMENT: Remyelination represents a promising strategy to achieve functional recovery in demyelinating diseases, like MS. Thus, identification of potent compounds and targets that promote remyelination represents a critically unmet need. This study reports a cluster of compounds that are highly effective in enhancing remyelination and identifies kappa-opioid receptor (KOR) as a positive regulator for oligodendroglial differentiation, implicating KOR agonism as a potential strategy to accelerate remyelination. PMID- 27466339 TI - The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming. AB - Amplified neuroinflammatory responses following an immune challenge occur with normal aging and can elicit or exacerbate neuropathology. The mechanisms mediating this sensitized or "primed" immune response in the aged brain are not fully understood. The alarmin high mobility group box 1 (HMGB1) can be released under chronic pathological conditions and initiate inflammatory cascades. This led us to investigate whether HMGB1 regulates age-related priming of the neuroinflammatory response. Here, we show that HMGB1 protein and mRNA were elevated in the hippocampus of unmanipulated aged rats (24-month-old F344XBN rats). Furthermore, aged rats had increased HMGB1 in the CSF, suggesting increased HMGB1 release. We demonstrate that blocking HMGB1 signaling with an intracisterna magna (ICM) injection of the competitive antagonist to HMGB1, Box A, downregulates basal expression of several inflammatory pathway genes in the hippocampus of aged rats. This indicates that blocking the actions of HMGB1 might reduce age-associated inflammatory priming. To test this hypothesis, we evaluated whether HMGB1 antagonism blocks the protracted neuroinflammatory and sickness response to peripheral Escherichia coli (E. coli) infection in aged rats. ICM pretreatment of aged rats with Box-A 24 h before E. coli infection prevented the extended hippocampal cytokine response and associated cognitive and affective behavioral changes. ICM pretreatment with Box-A also inhibited aging-induced potentiation of the microglial proinflammatory response to lipopolysaccharide ex vivo Together, these results suggest that HMGB1 mediates neuroinflammatory priming in the aged brain. Blocking the actions of HMGB1 appears to "desensitize" aged microglia to an immune challenge, thereby preventing exaggerated behavioral and neuroinflammatory responses following infection. SIGNIFICANCE STATEMENT: The world's population is aging, highlighting a need to develop treatments that promote quality of life in aged individuals. Normal aging is associated with precipitous drops in cognition, typically following events that induce peripheral inflammation (e.g., infection, surgery, heart attack). Peripheral immune stimuli cause exaggerated immune responses in the aged brain, which likely underlie these behavioral deficits. Here, we investigated whether the alarmin high mobility group box 1 (HMGB1) mediates age-associated "priming" of the neuroinflammatory response. HMGB1 is elevated in aged rodent brain and CSF. Blocking HMGB1 signaling downregulated expression of inflammatory pathway genes in aged rat brain. Further, HMGB1 antagonism prevented prolonged infection-induced neuroinflammatory and sickness responses in aged rats. Overall, blocking HMGB1 "desensitized" microglia in the aged brain, thereby preventing pathological infection-elicited neuroinflammatory responses. PMID- 27466340 TI - Neural Activity in the Ventral Pallidum Encodes Variation in the Incentive Value of a Reward Cue. AB - There is considerable individual variation in the extent to which reward cues are attributed with incentive salience. For example, a food-predictive conditioned stimulus (CS; an illuminated lever) becomes attractive, eliciting approach toward it only in some rats ("sign trackers," STs), whereas others ("goal trackers," GTs) approach the food cup during the CS period. The purpose of this study was to determine how individual differences in Pavlovian approach responses are represented in neural firing patterns in the major output structure of the mesolimbic system, the ventral pallidum (VP). Single-unit in vivo electrophysiology was used to record neural activity in the caudal VP during the performance of ST and GT conditioned responses. All rats showed neural responses to both cue onset and reward delivery but, during the CS period, STs showed greater neural activity than GTs both in terms of the percentage of responsive neurons and the magnitude of the change in neural activity. Furthermore, neural activity was positively correlated with the degree of attraction to the cue. Given that the CS had equal predictive value in STs and GTs, we conclude that neural activity in the VP largely reflects the degree to which the CS was attributed with incentive salience. SIGNIFICANCE STATEMENT: Cues associated with reward can acquire motivational properties (i.e., incentive salience) that cause them to have a powerful influence on desire and motivated behavior. There are individual differences in sensitivity to reward-paired cues, with some individuals attaching greater motivational value to cues than others. Here, we investigated the neural activity associated with these individual differences in incentive salience. We found that cue-evoked neural firing in the ventral pallidum (VP) reflected the strength of incentive motivation, with the greatest neural responses occurring in individuals that demonstrated the strongest attraction to the cue. This suggests that the VP plays an important role in the process by which cues gain control over motivation and behavior. PMID- 27466342 TI - Parallel Engagement of Regions Associated with Encoding and Later Retrieval Forms Durable Memories. AB - The fate of a memory is partly determined at initial encoding. However, the behavioral consequences of memory formation are often tested only once and shortly after learning, which leaves the neuronal predictors for the formation of durable memories largely unknown. Here, we hypothesized that durable memory formation (as opposed to weak or no memory formation) is reflected through increased activation in the medial temporal lobes and prefrontal cortex, and more consistent processing (i.e., stronger pattern similarity) across encoding material. Thirty-four human subjects studied unique picture-location associations while undergoing fMRI and performed a cued recall test immediately after study as well as 48 h later. Associative memories were defined as "weak" if they were retrieved during the immediate test only. Conversely, "durable" memories persisted also after 48 h. The posterior cingulate cortex showed increased pattern similarity during successful memory formation, independent of the eventual durability. For durable memory encoding, we found increased activation in medial and inferior temporal, prefrontal, and parietal regions. This was accompanied by stronger pattern similarity in lateral prefrontal and parietal regions, as well as in anterior and posterior midline structures that were also engaged during later memory retrieval. Thus, we show that pattern similarity, or consistent processing, in the posterior cingulate cortex predicts associative memory formation at encoding. If this is paralleled by additional activation increases in regions typically related to encoding, and by consistent processing in regions involved in later retrieval, formed memories appear durable for at least 48 h. SIGNIFICANCE STATEMENT: Successful memory formation is typically associated with increased neuronal activation in medial temporal and prefrontal regions at encoding, but memory is often assessed only once and shortly after study. Here, we addressed memory durability, and investigated the neuronal underpinnings of encoding for associations remembered over a longer period of time, less long, or immediately forgotten. We showed that durable memory formation is dependent on increased activation in the hippocampus and neocortical regions related to encoding, and on consistent processing of associative memory traces in midline structures that are involved in later memory retrieval. These findings highlight how durable memories are formed. PMID- 27466344 TI - Reversal of Pathologic Lipid Accumulation in NPC1-Deficient Neurons by Drug Promoted Release of LAMP1-Coated Lamellar Inclusions. AB - Aging and pathologic conditions cause intracellular aggregation of macromolecules and the dysfunction and degeneration of neurons, but the mechanisms are largely unknown. Prime examples are lysosomal storage disorders such as Niemann-Pick type C (NPC) disease, where defects in the endosomal-lysosomal protein NPC1 or NPC2 cause intracellular accumulation of unesterified cholesterol and other lipids leading to neurodegeneration and fatal neurovisceral symptoms. Here, we investigated the impact of NPC1 deficiency on rodent neurons using pharmacologic and genetic models of the disease. Improved ultrastructural detection of lipids and correlative light and electron microscopy identified lamellar inclusions as the subcellular site of cholesterol accumulation in neurons with impaired NPC1 activity. Immunogold labeling combined with transmission electron microscopy revealed the presence of CD63 on internal lamellae and of LAMP1 on the membrane surrounding the inclusions, indicating their origins from intraluminal vesicles of late endosomes and of a lysosomal compartment, respectively. Lamellar inclusions contained cell-intrinsic cholesterol and surface-labeled GM1, indicating the incorporation of plasma membrane components. Scanning electron microscopy revealed that the therapeutic drug candidate beta-cyclodextrin induces the subplasmalemmal location of lamellar inclusions and their subsequent release to the extracellular space. In parallel, beta-cyclodextrin mediated the NPC1 independent redistribution of cholesterol within neurons and thereby abolished a deleterious cycle of enhanced cholesterol synthesis and its intracellular accumulation, which was indicated by neuron-specific transcript analysis. Our study provides new mechanistic insight into the pathologic aggregation of macromolecules in neurons and suggests exocytosis as cellular target for its therapeutic reversal. SIGNIFICANCE STATEMENT: Many neurodegenerative diseases involve pathologic accumulation of molecules within neurons, but the subcellular location and the cellular impact are often unknown and therapeutic approaches lacking. We investigated these questions in the lysosomal storage disorder Niemann-Pick type C (NPC), where a defect in intracellular cholesterol transport causes loss of neurons and fatal neurovisceral symptoms. Here, we identify lamellar inclusions as the subcellular site of lipid accumulation in neurons, we uncover a vicious cycle of cholesterol synthesis and accretion, which may cause gradual neurodegeneration, and we reveal how beta-cyclodextrin, a potential therapeutic drug, reverts these changes. Our study provides new mechanistic insight in NPC disease and uncovers new targets for therapeutic approaches. PMID- 27466343 TI - SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein. AB - Proteolytic generation of amyloidogenic amyloid beta (Abeta) fragments from the amyloid precursor protein (APP) significantly contributes to Alzheimer's disease (AD). Although amyloidogenic APP proteolysis can be affected by trafficking through genetically associated AD components such as SORLA, how SORLA functionally interacts with other trafficking components is yet unclear. Here, we report that SNX27, an endosomal trafficking/recycling factor and a negative regulator of the gamma-secretase complex, binds to the SORLA cytosolic tail to form a ternary complex with APP. SNX27 enhances cell surface SORLA and APP levels in human cell lines and mouse primary neurons, and depletion of SNX27 or SORLA reduces APP endosome-to-cell surface recycling kinetics. SNX27 overexpression enhances the generation of cell surface APP cleavage products such as soluble alpha-APP C-terminal fragment (CTFalpha) in a SORLA-dependent manner. SORLA mediated Abeta reduction is attenuated by downregulation of SNX27. This indicates that an SNX27/SORLA complex functionally interacts to limit APP distribution to amyloidogenic compartments, forming a non-amyloidogenic shunt to promote APP recycling to the cell surface. SIGNIFICANCE STATEMENT: Many genes have been identified as risk factors for Alzheimer's disease (AD), and a large proportion of these genes function to limit production or toxicity of the AD-associated amyloid beta (Abeta) peptide. Whether and how these genes precisely operate to limit AD onset remains an important question. We identify binding and trafficking interactions between two of these factors, SORLA and SNX27, and demonstrate that SNX27 can direct trafficking of SORLA and the Abeta precursor APP to the cell surface to limit the production of Abeta. Diversion APP to the cell surface through modulation of this molecular complex may represent a complimentary strategy for future development in AD treatment. PMID- 27466346 TI - Antiproliferative Effect of Synadenium grantii Hook f. stems (Euphorbiaceae) and a Rare Phorbol Diterpene Ester. AB - Synadenium grantii is frequently used for the treatment of various diseases such as allergies, gastric disorders, and especially cancer. The aim of this study was to evaluate the possible antiproliferative potential of the methanol extract, fractions, and pure compounds from the stems of S grantii Phytochemical analysis was carried out by conventional chromatographic techniques, and the antiproliferative activity was analyzed using the sulforhodamine B assay and an MTT-based assay. Nonpolar fraction and its subfractions from the stems of S grantii exhibited promising cytostatic effect against several human tumor cell lines (glioma, breast, kidney, and lung), with total grown inhibition values ranging from 0.37 to 2.9 MUg/mL. One of the active principles of this plant was identified as a rare phorbol diterpene ester, denoted as 3,4,12,13 tetraacetylphorbol-20-phenylacetate. This compound demonstrated antiproliferative activity against glioma, kidney, lung, and triple-negative breast cancer cell lines. These results demonstrate that S grantii stems produce active principles with relevant antiproliferative potential. PMID- 27466341 TI - Reducing Endogenous alpha-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. AB - Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid beta (Abeta) and microtubule associate protein tau, leading to the selective degeneration of neurons in the neocortex, limbic system, and nucleus basalis, among others. Recent studies have shown that alpha-synuclein (alpha-syn) also accumulates in the brains of patients with AD and interacts with Abeta and tau, forming toxic hetero-oligomers. Although the involvement of alpha-syn has been investigated extensively in Lewy body disease, less is known about the role of this synaptic protein in AD. Here, we found that reducing endogenous alpha-syn in an APP transgenic mouse model of AD prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. Together, these results suggest that alpha-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing alpha-syn might be a potential approach to protecting these populations from the toxic effects of Abeta. SIGNIFICANCE STATEMENT: Reducing endogenous alpha-synuclein (alpha-syn) in an APP transgenic mouse model of Alzheimer's disease (AD) prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. These results suggest that alpha-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing alpha-syn might be a potential approach to protecting these populations from the toxic effects of amyloid beta. PMID- 27466345 TI - Increased Amplitude of Thalamocortical Low-Frequency Oscillations in Patients with Migraine. AB - For many years, neurobiological theories have emphasized the importance of neuronal oscillations in the emergence of brain function. At the same time, clinical studies have shown that disturbances or irregularities in brain rhythms may relate to various common neurological conditions, including migraine. Increasing evidence suggests that the CNS plays a fundamental role in the predisposition to develop different forms of headache. Here, we present human imaging data that strongly support the presence of abnormal low-frequency oscillations (LFOs) in thalamocortical networks of patients in the interictal phase of migraine. Our results show that the main source of arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus. In addition, spontaneous LFOs in the thalamus were selectively associated with the headache attack frequency, meaning that the varying amplitude of dysrhythmia could predispose patients to recurrent attacks. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability. We further speculate that the intrinsic dynamics of thalamocortical network oscillations are crucial for early sensory processing and therefore could underlie important pathophysiological processes involved in multisensory integration. SIGNIFICANCE STATEMENT: In many cases, migraine attacks are thought to begin centrally. A major obstacle to studying intrinsic brain activity has been the identification of the precise anatomical structures and functional networks that are involved in migraine. Here, we present imaging data that strongly support the presence of abnormal low-frequency oscillations in thalamocortical networks of patients in the interictal phase of migraine. This arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus and was selectively associated with headache attack frequency. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability and higher level processes involved in multisensory integration. PMID- 27466348 TI - Does elevated urinary 5-hydroxyindole acetic acid level predict acute appendicitis in children? AB - BACKGROUND: Acute appendicitis is the most common abdominal surgical emergency in children, and appendectomy is the most frequent acute abdominal operation. Prompt diagnosis and surgical treatment are required to reduce the risk of perforation and prevent complications, especially in small children. Enterochromaffin cells that contain large amounts of serotonin are mostly located in the distal appendix. Serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) could therefore be a marker for acute appendicitis. OBJECTIVE: We tested urinary 5-HIAA concentrations in spot urine samples from children with acute appendicitis. METHODS: We enrolled 93 patients who underwent surgery for suspicion of acute appendicitis. The diagnosis was made intraoperatively and confirmed histopathologically. Additionally, urine samples from 102 healthy children were collected as controls. Their 5-HIAA was measured using high-performance liquid chromatography. RESULTS: Acute appendicitis was diagnosed in 81 patients, whereas there were other explanations for abdominal pain in the remaining 12 patients in the non-appendicitis group. The control group comprised 102 healthy children. Considering the median of all measured 5-HIAA values as the cut-off, we analysed the proportions of patients with elevated values in all the groups. Our analysis showed that statistically there was no significant difference in the distribution of percentages among the groups. The area under the curve for 5-HIAA was 0.55 (95% CI 0.47 to 0.62) with sensitivity and specificity 60.4% and 48.9%, respectively. CONCLUSIONS: Urine 5-HIAA concentration measured in spot samples is not a reliable method for diagnosing acute appendicitis in children. PMID- 27466347 TI - One-two-triage: validation and reliability of a novel triage system for low resource settings. AB - OBJECTIVES: To validate and assess reliability of a novel triage system, one-two triage (OTT), that can be applied by inexperienced providers in low-resource settings. METHODS: This study was a two-phase prospective, comparative study conducted at three hospitals. Phase I assessed criterion validity of OTT on all patients arriving at an American university hospital by comparing agreement among three methods of triage: OTT, Emergency Severity Index (ESI) and physician defined acuity (the gold standard). Agreement was reported in normalised and raw weighted Cohen kappa using two different scales for weighting, Expert-weighted and triage-weighted kappa. Phase II tested reliability, reported in Fleiss kappa, of OTT using standardised cases among three groups of providers at an urban and rural Cambodian hospital and the American university hospital. RESULTS: Normalised for prevalence of patients in each category, OTT and ESI performed similarly well for expert-weighted kappa (OTT kappa=0.58, 95% CI 0.52 to 0.65; ESI kappa=0.47, 95% CI 0.40 to 0.53) and triage-weighted kappa (kappa=0.54, 95% CI 0.48 to 0.61; ESI kappa=0.57, 95% CI 0.51 to 0.64). Without normalising, agreement with gold standard was less for both systems but performance of OTT and ESI remained similar, expert-weighted (OTT kappa=0.57, 95% CI 0.52 to 0.62; ESI kappa=0.6, 95% CI 0.58 to 0.66) and triage-weighted (OTT kappa=0.31, 95% CI 0.25 to 0.38; ESI kappa=0.41, 95% CI 0.35 to 0.4). In the reliability phase, all triagers showed fair inter-rater agreement, Fleiss kappa (kappa=0.308). CONCLUSIONS: OTT can be reliably applied and performs as well as ESI compared with gold standard, but requires fewer resources and less experience. PMID- 27466349 TI - A systematic review of patients', parents' and healthcare professionals' adrenaline auto-injector administration techniques. AB - INTRODUCTION: In order to enable fast treatment response to anaphylactic reactions, adrenaline auto-injectors (AAI) have been developed and manufactured. It has been reported in several studies that administration technique is suboptimal. The primary purpose of this study was to review the nature and extent of the deficiencies in administration technique among patients, parents/caregivers and healthcare professionals. METHODS: Relevant publications were identified between 1998 and 2015 using two search methods: a keyword search in Embase, PubMed, British Nursing Index and Cumulative Index to Nursing and Allied Health Literature and a search of reference lists of relevant articles. RESULTS: Twenty-three studies met the inclusion criteria. Overall, 37% of patients, 32% of parents/caregivers and 21% of healthcare professionals demonstrated correct administration technique. For studies which employed a before-and-after training study design, correct technique was achieved in 77% of patients, 79% of caregivers and 65% of healthcare professionals. The most consistently observed error was the failure to hold the device in place for the recommended time. For patients, factors associated with good technique were being aged over 18 years, trained in AAI administration by an allergist, prescribed an AAI for more than 30 months, having a history of severe anaphylaxis and membership of a support group. For parents/caregivers in addition to those mentioned, being given a training device with which to practice, improved technique. DISCUSSION: There was wide variation in administration techniques reported. However, studies designed using before-and-after training show that even a brief demonstration and educational intervention can improve technique. Further studies are required to design and pilot acceptable and cost-effective educational materials. PMID- 27466350 TI - Optimizing Immunization Strategies for the Induction of Antigen-Specific CD4 and CD8 T Cell Responses for Protection against Intracellular Parasites. AB - Immunization strategies that generate either CD4 or CD8 T cell responses are relatively well described, but less is known with regard to optimizing regimens to induce both CD4 and CD8 memory T cells. Considering the importance of both CD4 and CD8 T cells in the control of intracellular pathogens such as Leishmania donovani, we wanted to identify vaccines that could raise both CD4 and CD8 T cell responses and determine how to configure immunization strategies to generate the best combined protective T cell response. We examined responses generated against the Leishmania vaccine antigen F3 following its administration in either recombinant form with the Toll-like receptor 4 (TLR4) agonist-containing adjuvant formulation GLA-SE (F3+GLA-SE) or as a gene product delivered in an adenoviral vector (Ad5-F3). Homologous immunization strategies using only F3+GLA-SE or Ad5 F3 preferentially generated either CD4 or CD8 T cells, respectively. In contrast, heterologous strategies generated both antigen-specific CD4 and CD8 T cells. Administration of F3+GLA-SE before Ad5-F3 generated the greatest combined CD4 and CD8 responses. Cytotoxic CD8 T cell responses were highest when Th1 cells were generated prior to their induction by Ad5-F3. Finally, a single immunization with a combination of F3+GLA-SE mixed with Ad5-F3 was found to be sufficient to provide protection against experimental L. donovani infection. Taken together, our data delineate immunization regimens that induce antigen-specific CD4 and CD8 T cell memory responses, and identify a single immunization strategy that could be used to rapidly provide protection against intracellular pathogens in regions where access to health care is limited or sporadic. PMID- 27466351 TI - Humanized Monoclonal Antibody That Passively Protects Mice against Systemic and Intranasal Ricin Toxin Challenge. AB - PB10 is a murine monoclonal antibody against an immunodominant epitope on ricin toxin's enzymatic subunit. Here, we characterize a fully humanized version of PB10 IgG1 (hPB10) and demonstrate that it has potent in vitro and in vivo toxin neutralizing activities. We also report the minimum serum concentrations of hPB10 required to protect mice against 10 times the 50% lethal dose of ricin when delivered by injection and inhalation. PMID- 27466352 TI - Seasonal Time Keeping in a Long-Distance Migrating Shorebird. AB - Because of the complications in achieving the necessary long-term observations and experiments, the nature and adaptive value of seasonal time-keeping mechanisms in long-lived organisms remain understudied. Here we present the results of a 20-year-long study of the repeated seasonal changes in body mass, plumage state, and primary molt of 45 captive red knots Calidris canutus islandica, a High Arctic breeding shorebird that spends the nonbreeding season in temperate coastal areas. Birds kept outdoors and experiencing the natural photoperiod of the nonbreeding area maintained sequences of life-cycle stages, roughly following the timing in nature. For 6 to 8 years, 14 of these birds were exposed to unvarying ambient temperature (12 degrees C) and photoperiodic conditions (12:12 LD). Under these conditions, for at least 5 years they expressed free-running circannual cycles of body mass, plumage state, and wing molt. The circannual cycles of the free-running traits gradually became longer than 12 months, but at different rates. The prebreeding events (onset and offset of prealternate molt and the onset of spring body mass increase) occurred at the same time of the year as in the wild population for 1 or several cycles. As a result, after 4 years in 12:12 LD, the circannual cycles of prealternate plumage state had drifted less than the cycles of prebasic plumage state and wing molt. As the onset of body mass gain drifted less than the offset, the period of high body mass became longer under unvarying conditions. We see these differences between the prebreeding and postbreeding life-cycle stages as evidence for adaptive seasonal time keeping in red knots: the life-cycle stages linked to the initiation of reproduction rely mostly on endogenous oscillators, whereas the later stages rather respond to environmental conditions. Postbreeding stages are also prone to carryover effects from the earlier stages. PMID- 27466353 TI - Biodistribution and Targeting of Anti-5T4 Antibody-Drug Conjugate Using Fluorescence Molecular Tomography. AB - Understanding a drug's whole-body biodistribution and tumor targeting can provide important information regarding efficacy, safety, and dosing parameters. Current methods to evaluate biodistribution include in vivo imaging technologies like positron electron tomography and single-photon emission computed tomography or ex vivo quantitation of drug concentrations in tissues using autoradiography and standard biochemical assays. These methods use radioactive compounds or are cumbersome and do not give whole-body information. Here, for the first time, we show the utility of fluorescence molecular tomography (FMT) imaging to determine the biodistribution and targeting of an antibody-drug conjugate (ADC). An anti 5T4-antibody (5T4-Ab) and 5T4-ADC were conjugated with a near-infrared (NIR) fluorophore VivoTag 680XL (VT680). Both conjugated compounds were stable as determined by SEC-HPLC and plasma stability studies. Flow cytometry and fluorescence microscopy studies showed that VT680-conjugated 5T4-ADC specifically bound 5T4-expressing cells in vitro and also exhibited a similar cytotoxicity profile as the unconjugated 5T4-ADC. In vivo biodistribution and tumor targeting in an H1975 subcutaneous xenograft model demonstrated no significant differences between accumulation of VT680-conjugated 5T4-Ab or 5T4-ADC in either normal tissues or tumor. In addition, quantitation of heart signal from FMT imaging showed good correlation with the plasma pharmacokinetic profile suggesting that it (heart FMT imaging) may be a surrogate for plasma drug clearance. These results demonstrate that conjugation of VT680 to 5T4-Ab or 5T4-ADC does not change the behavior of native biologic, and FMT imaging can be a useful tool to understand biodistribution and tumor-targeting kinetics of antibodies, ADCs, and other biologics. Mol Cancer Ther; 15(10); 2530-40. (c)2016 AACR. PMID- 27466354 TI - Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin Resistant Osteosarcoma. AB - Doxorubicin is one of the leading drugs for osteosarcoma standard chemotherapy. A total of 40% to 45% of high-grade osteosarcoma patients are unresponsive, or only partially responsive, to doxorubicin (Dox), due to the overexpression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). The aim of this work is to improve Dox-based regimens in resistant osteosarcomas. We used a chemically modified mitochondria-targeted Dox (mtDox) against Pgp-overexpressing osteosarcomas with increased resistance to Dox. Unlike Dox, mtDox accumulated at significant levels intracellularly, exerted cytotoxic activity, and induced necrotic and immunogenic cell death in Dox-resistant/Pgp-overexpressing cells, fully reproducing the activities exerted by anthracyclines in drug-sensitive tumors. mtDox reduced tumor growth and cell proliferation, increased apoptosis, primed tumor cells for recognition by the host immune system, and was less cardiotoxic than Dox in preclinical models of drug-resistant osteosarcoma. The increase in Dox resistance was paralleled by a progressive upregulation of mitochondrial metabolism. By widely modulating the expression of mitochondria-related genes, mtDox decreased mitochondrial biogenesis, the import of proteins and metabolites within mitochondria, mitochondrial metabolism, and the synthesis of ATP. These events were paralleled by increased reactive oxygen species production, mitochondrial depolarization, and mitochondria-dependent apoptosis in resistant osteosarcoma cells, where Dox was completely ineffective. We propose mtDox as a new effective agent with a safer toxicity profile compared with Dox that may be effective for the treatment of Dox-resistant/Pgp-positive osteosarcoma patients, who strongly need alternative and innovative treatment strategies. Mol Cancer Ther; 15(11); 2640-52. (c)2016 AACR. PMID- 27466356 TI - TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics. AB - TP53 tumor-suppressor gene mutations are among the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of VEGFR or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. Although only a subset of patients benefit from these antiangiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations upregulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next-generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%; with >=1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters [rate of stable disease (SD) >=6 months/partial and complete remission (PR/CR); (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure, and overall survival (multivariate analysis: all P <= 0.01)] for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with antiangiogenesis agents, a finding of seminal importance across the cancer field. Mol Cancer Ther; 15(10); 2475-85. (c)2016 AACR. PMID- 27466355 TI - Reversal of Chemoresistance in Ovarian Cancer by Co-Delivery of a P-Glycoprotein Inhibitor and Paclitaxel in a Liposomal Platform. AB - The overexpression of permeability-glycoprotein (P-gp), an ABC transporter involved in the cellular exclusion of chemotherapeutic drugs, is a major factor in paclitaxel-resistant ovarian cancer. However, in clinical trials, co administration of P-gp inhibitors and anticancer drugs has not resulted in the efficient reversal of drug resistance. To improve administration, we encapsulated the third-generation P-gp inhibitor tariquidar (XR-9576, XR), alone or in combination with paclitaxel (PCT) in liposomes (LP). After optimization, the liposomes demonstrated favorable physicochemical properties and the ability to reverse chemoresistance in experiments using chemosensitive/chemoresistant ovarian cancer cell line pairs. Analyzing publicly available datasets, we found that overexpression of P-gp in ovarian cancer is associated with a shorter progression-free and overall survival. In vitro, LP(XR) significantly increased the cellular retention of rhodamine 123, a P-gp substrate. LP(XR,PCT) synergistically inhibited cell viability, blocked proliferation, and caused G2-M arrest in paclitaxel-resistant SKOV3-TR and HeyA8-MDR cell lines overexpressing P gp. Holographic imaging cytometry revealed that LP(XR,PCT) treatment of SKOV3-TR cells induced almost complete mitotic arrest, whereas laser scanning cytometry showed that the treatment induced apoptosis. In proof-of-concept preclinical studies, LP(XR,PCT), when compared with LP(PCT), significantly reduced tumor weight (43.2% vs. 16.9%, P = 0.0007) and number of metastases (44.4% vs. 2.8%, P = 0.012) in mice bearing orthotopic HeyA8-MDR ovarian tumors. In the xenografts, LP(XR,PCT) efficiently induced apoptosis and impaired proliferation. Our findings suggest that co-delivery of a P-gp inhibitor and paclitaxel using a liposomal platform can sensitize paclitaxel-resistant ovarian cancer cells to paclitaxel. LP(XR,PCT) should be considered for clinical testing in patients with P-gp overexpressing tumors. Mol Cancer Ther; 15(10); 2282-93. (c)2016 AACR. PMID- 27466357 TI - Inhibition of Breast Cancer Metastasis by Presurgical Treatment with an Oral Matrix Metalloproteinase Inhibitor: A Preclinical Proof-of-Principle Study. AB - Breast cancer has the second highest death toll in women worldwide, despite significant progress in early diagnosis and treatments. The main cause of death is metastatic disease. Matrix metalloproteinases (MMP) are required for the initial steps of metastasis, and have therefore been considered as ideal pharmacologic targets for antimetastatic therapy. However, clinical trials of MMP inhibitors were unsuccessful. These trials were conducted in patients with advanced disease, beyond the stage when these compounds could have been effective. We hypothesized that early treatment with a selective MMP inhibitor between the time of diagnosis and definitive surgery, the so-called "window-of opportunity," can inhibit metastasis and thereby improve survival. To investigate our hypothesis, we used the 4T1 mouse model of aggressive mammary carcinoma. We treated the animals with SD-7300, an oral inhibitor of MMP-2, -9, and -13, starting after the initial detection of the primary tumor. Seven days later, the primary tumors were excised and analyzed for MMP activity, and the SD-7300 treatment was discontinued. After 4 weeks, the animals were sacrificed and their lungs analyzed histologically for number of metastases and metastatic burden (metastases' area/lung section area). SD-7300 treatment inhibited 70% to 80% of tumor-associated MMP activity (P = 0.0003), reduced metastasis number and metastatic burden by 50% to 60% (P = 0.002 and P = 0.0082, respectively), and increased survival (92% vs. 66.7%; P = 0.0409), relative to control vehicle. These results show that treatment of early invasive breast cancer with selective MMP inhibitors can lower the risk of recurrence and increase long-term disease free survival. Mol Cancer Ther; 15(10); 2370-7. (c)2016 AACR. PMID- 27466358 TI - Assessing the dysexecutive syndrome in dementia. AB - OBJECTIVE: We compared performance on tests of dysexecutive behaviour (DB) and executive function (EF) in patients with behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and corticobasal syndrome (CBS). METHODS: Patients diagnosed with bvFTD (n=124), PPA (n=34) and CBS (n=85) were recruited. EF was measured with the Delis-Kaplan Executive Function System (DKEFS: performance based), and DB was measured with the Frontal Systems Behavior Scale (FrSBe: caregiver-report based). Confirmatory factor analysis characterised the relationship between EF and DB, binary logistic regression evaluated the incremental diagnostic utility of the measures and neuroimaging data from 110 patients identified neural correlates. RESULTS: EF was lowest and DB was highest in bvFTD participants. EF and DB were distinct but related (r=-0.48). Measures correctly classified 89% of bvFTD from CBS patients and 93% of bvFTD from PPA patients-30% and 13% above base rates (59%, 80%), respectively. All modalities were useful in identifying CBS and PPA, whereas DB alone was useful for identifying bvFTD. EF was uniquely associated with caudal left dorsolateral prefrontal and lateral temporo-parietal cortices. DB was uniquely associated with the cingulate (R>L), right subcallosal and right anterior frontal cortex. EF and DB were associated with the rostral dorsolateral prefrontal cortex bilaterally. CONCLUSIONS: EF and DB measures displayed criterion and construct validity, had incremental utility at low DB levels (CBS and PPA) and were associated with overlapping and distinct neural correlates. EF and DB procedures can conjointly provide useful diagnostic and descriptive information in identifying and ruling out the dysexecutive syndrome. PMID- 27466359 TI - Misinterpretation of ischaemic infarct location in relationship to the cerebrovascular territories. AB - PURPOSE: Cerebral perfusion territories are known to vary widely among individuals. This may lead to misinterpretation of the symptomatic artery in patients with ischaemic stroke to a wrong assumption of the underlying aetiology being thromboembolic or hypoperfusion. The aim of the present study was to investigate such potential misinterpretation with territorial arterial spin labelling (T-ASL) by correlating infarct location with imaging of the perfusion territory of the carotid arteries or basilar artery. MATERIALS AND METHODS: 223 patients with subacute stroke underwent MRI including structural imaging scans to determine infarct location, time-of-flight MR angiography (MRA) to determine the morphology of the circle of Willis and T-ASL to identify the perfusion territories of the internal carotid arteries, and basilar artery. Infarct location and the perfusion territory of its feeding artery were classified with standard MRI and MRA according to a perfusion atlas, and were compared to the classification made according to T-ASL. RESULTS: A total of 149 infarctions were detected in 87 of 223 patients. 15 out of 149 (10%) infarcts were erroneously attributed to a single perfusion territory; these infarcts were partly located in the originally determined perfusion territory but proved to be localised in the border zone with the adjacent perfusion territory instead. 12 out of 149 (8%) infarcts were misclassified with standard assessments and were not located in the original perfusion territory. CONCLUSIONS: T-ASL with territorial perfusion imaging may provide important additional information for classifying the symptomatic brain-feeding artery when compared to expert evaluation with MRI and MRA. PMID- 27466360 TI - Rate of perihaematomal oedema expansion is associated with poor clinical outcomes in intracerebral haemorrhage. AB - BACKGROUND: Perihaematomal edema (PHE) expansion rate may be a predictor of outcome after intracerebral haemorrhage (ICH). We determined whether PHE expansion rate in the first 72 hours after ICH predicts outcome, and how it compares against other PHE measures. METHODS: We included patients from the Virtual International Stroke Trials Archive. We calculated PHE expansion rate using the equation: (PHE at 72 hours PHE at baseline)/(time to 72-hour CT scan time to baseline CT scan). Outcomes of interest were mortality and poor 90-day outcome (modified Rankin Scale score of >=3). Logistic regression was used to assess relationships with outcome. RESULTS: A total of 596 patients with ICH were included. At baseline, median haematoma volume was 15.0 mL (IQR 7.9-29.2) with median PHE volume of 8.7 mL (IQR 4.5-15.5). Median PHE expansion rate was 0.31 mL/hour (IQR 0.12-0.55). The odds of mortality were greater with increasing PHE expansion rate (OR 2.63, CI 1.10 to 6.25), while the odds of poor outcome also increased with greater PHE growth (OR 1.67, CI 1.28 to 2.39). Female sex had an inverse relationship with PHE growth, but baseline haematoma volume had a direct correlation. Among other PHE measures, only interval increase in PHE correlated with poor outcome. There was no significant difference between the 2 measures of PHE volume expansion. CONCLUSIONS: Rate of PHE growth over 72 hours was an independent predictor of mortality and poor functional outcomes following ICH. Baseline haematoma volume and gender appear to influence PHE growth. PMID- 27466361 TI - Secretion of the Intimin Passenger Domain Is Driven by Protein Folding. AB - Intimin is an essential adhesin of attaching and effacing organisms such as entropathogenic Escherichia coli It is also the prototype of type Ve secretion or inverse autotransport, where the extracellular C-terminal region or passenger is exported with the help of an N-terminal transmembrane beta-barrel domain. We recently reported a stalled secretion intermediate of intimin, where the passenger is located in the periplasm but the beta-barrel is already inserted into the membrane. Stalling of this mutant is due to the insertion of an epitope tag at the very N terminus of the passenger. Here, we examined how this insertion disrupts autotransport and found that it causes misfolding of the N-terminal immunoglobulin (Ig)-like domain D00. We could also stall the secretion by making an internal deletion in D00, and introducing the epitope tag into the second Ig like domain, D0, also resulted in reduced passenger secretion. In contrast to many classical autotransporters, where a proximal folding core in the passenger is required for secretion, the D00 domain is dispensable, as the passenger of an intimin mutant lacking D00 entirely is efficiently exported. Furthermore, the D00 domain is slightly less stable than the D0 and D1 domains, unfolding at ~200 piconewtons (pN) compared with ~250 pN for D0 and D1 domains as measured by atomic force microscopy. Our results support a model where the secretion of the passenger is driven by sequential folding of the extracellular Ig-like domains, leading to vectorial transport of the passenger domain across the outer membrane in an N to C direction. PMID- 27466362 TI - Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival. AB - Protein synthesis inhibition is an immediate response during stress to switch the composition of protein pool in order to adapt to the new environment. It was reported that this response could be either protective or deleterious. However, how cells choose to live or die upon protein synthesis inhibition is largely unknown. Previously, we have shown that elongation factor-2 kinase (eEF2K), a protein kinase that suppresses protein synthesis during elongation phase, is a positive regulator of apoptosis both in vivo and in vitro Consistently, here we report that knock-out of eEF2K protects mice from a lethal dose of whole-body ionizing radiation at 8 Gy by reducing apoptosis levels in both bone marrow and gastrointestinal tracts. Surprisingly, similar to the loss of p53, eEF2K deficiency results in more severe damage to the gastrointestinal tract at 20 Gy with the increased mitotic cell death in small intestinal stem cells. Furthermore, using epithelial cell lines, we showed that eEF2K is required for G2/M arrest induced by radiation to prevent mitotic catastrophe in a p53 independent manner. Specifically, we observed the elevation of Akt/ERK activity as well as the reduction of p21 expression in Eef2k(-/-) cells. Therefore, eEF2K also provides a protective strategy to maintain genomic integrity by arresting cell cycle in response to stress. Our results suggest that protective versus pro apoptotic roles of eEF2K depend on the type of cells: eEF2K is protective in highly proliferative cells, such as small intestinal stem cells and cancer cells, which are more susceptible to mitotic catastrophe. PMID- 27466363 TI - The Crystal Structures of the N-terminal Photosensory Core Module of Agrobacterium Phytochrome Agp1 as Parallel and Anti-parallel Dimers. AB - Agp1 is a canonical biliverdin-binding bacteriophytochrome from the soil bacterium Agrobacterium fabrum that acts as a light-regulated histidine kinase. Crystal structures of the photosensory core modules (PCMs) of homologous phytochromes have provided a consistent picture of the structural changes that these proteins undergo during photoconversion between the parent red light absorbing state (Pr) and the far-red light-absorbing state (Pfr). These changes include secondary structure rearrangements in the so-called tongue of the phytochrome-specific (PHY) domain and structural rearrangements within the long alpha-helix that connects the cGMP-specific phosphodiesterase, adenylyl cyclase, and FhlA (GAF) and the PHY domains. We present the crystal structures of the PCM of Agp1 at 2.70 A resolution and of a surface-engineered mutant of this PCM at 1.85 A resolution in the dark-adapted Pr states. Whereas in the mutant structure the dimer subunits are in anti-parallel orientation, the wild-type structure contains parallel subunits. The relative orientations between the PAS-GAF bidomain and the PHY domain are different in the two structures, due to movement involving two hinge regions in the GAF-PHY connecting alpha-helix and the tongue, indicating pronounced structural flexibility that may give rise to a dynamic Pr state. The resolution of the mutant structure enabled us to detect a sterically strained conformation of the chromophore at ring A that we attribute to the tight interaction with Pro-461 of the conserved PRXSF motif in the tongue. Based on this observation and on data from mutants where residues in the tongue region were replaced by alanine, we discuss the crucial roles of those residues in Pr-to Pfr photoconversion. PMID- 27466364 TI - Epsin N-terminal Homology Domain (ENTH) Activity as a Function of Membrane Tension. AB - The epsin N-terminal homology domain (ENTH) is a major player in clathrin mediated endocytosis. To investigate the influence of initial membrane tension on ENTH binding and activity, we established a bilayer system based on adhered giant unilamellar vesicles (GUVs) to be able to control and adjust the membrane tension sigma covering a broad regime. The shape of each individual adhered GUV as well as its adhesion area was monitored by spinning disc confocal laser microscopy. Control of sigma in a range of 0.08-1.02 mN/m was achieved by altering the Mg(2+) concentration in solution, which changes the surface adhesion energy per unit area of the GUVs. Specific binding of ENTH to phosphatidylinositol 4,5 bisphosphate leads to a substantial increase in adhesion area of the sessile GUV. At low tension (<0.1 mN/m) binding of ENTH can induce tubular structures, whereas at higher membrane tension the ENTH interaction deflates the sessile GUV and thereby increases the adhesion area. The increase in adhesion area is mainly attributed to a decrease in the area compressibility modulus KA We propose that the insertion of the ENTH helix-0 into the membrane is largely responsible for the observed decrease in KA, which is supported by the observation that the mutant ENTH L6E shows a reduced increase in adhesion area. These results demonstrate that even in the absence of tubule formation, the area compressibility modulus and, as such, the bending rigidity of the membrane is considerably reduced upon ENTH binding. This renders membrane bending and tubule formation energetically less costly. PMID- 27466365 TI - Sucrose Production Mediated by Lipid Metabolism Suppresses the Physical Interaction of Peroxisomes and Oil Bodies during Germination of Arabidopsis thaliana. AB - Physical interaction between organelles is a flexible event and essential for cells to adapt rapidly to environmental stimuli. Germinating plants utilize oil bodies and peroxisomes to mobilize storage lipids for the generation of sucrose as the main energy source. Although membrane interaction between oil bodies and peroxisomes has been widely observed, its underlying molecular mechanism is largely unknown. Here we present genetic evidence for control of the physical interaction between oil bodies and peroxisomes. We identified alleles of the sdp1 mutant altered in oil body morphology. This mutant accumulates bigger and more oil body aggregates compared with the wild type and showed defects in lipid mobilization during germination. SUGAR DEPENDENT 1 (SDP1) encodes major triacylglycerol lipase in Arabidopsis Interestingly, sdp1 seedlings show enhanced physical interaction between oil bodies and peroxisomes compared with the wild type, whereas exogenous sucrose supplementation greatly suppresses the interaction. The same phenomenon occurs in the peroxisomal defective 1 (ped1) mutant, defective in lipid mobilization because of impaired peroxisomal beta oxidation, indicating that sucrose production is a key factor for oil body peroxisomal dissociation. Peroxisomal dissociation and subsequent release from oil bodies is dependent on actin filaments. We also show that a peroxisomal ATP binding cassette transporter, PED3, is the potential anchor protein to the membranes of these organelles. Our results provide novel components linking lipid metabolism and oil body-peroxisome interaction whereby sucrose may act as a negative signal for the interaction of oil bodies and peroxisomes to fine-tune lipolysis. PMID- 27466366 TI - Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression. AB - Reproductive function is controlled by the pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates the expression of the gonadotropins luteinizing hormone and FSH in pituitary gonadotropes. Paradoxically, Fshb gene expression is maximally induced at lower frequency GnRH pulses, which provide a very low average concentration of GnRH stimulation. We studied the role of secreted factors in modulating gonadotropin gene expression. Inhibition of secretion specifically disrupted gonadotropin subunit gene regulation but left early gene induction intact. We characterized the gonadotrope secretoproteome and global mRNA expression at baseline and after Galphas knockdown, which has been found to increase Fshb gene expression (1). We identified 1077 secreted proteins or peptides, 19 of which showed mRNA regulation by GnRH or/and Galphas knockdown. Among several novel secreted factors implicated in Fshb gene regulation, we focused on the neurosecretory protein VGF. Vgf mRNA, whose gene has been implicated in fertility (2), exhibited high induction by GnRH and depended on Galphas In contrast with Fshb induction, Vgf induction occurred preferentially at high GnRH pulse frequency. We hypothesized that a VGF-derived peptide might regulate Fshb gene induction. siRNA knockdown or extracellular immunoneutralization of VGF augmented Fshb mRNA induction by GnRH. GnRH stimulated the secretion of the VGF-derived peptide NERP1. NERP1 caused a concentration-dependent decrease in Fshb gene induction. These findings implicate a VGF-derived peptide in selective regulation of the Fshb gene. Our results support the concept that signaling specificity from the cell membrane GnRH receptor to the nuclear Fshb gene involves integration of intracellular signaling and exosignaling regulatory motifs. PMID- 27466367 TI - Biosynthesis of Violacein, Structure and Function of l-Tryptophan Oxidase VioA from Chromobacterium violaceum. AB - Violacein is a natural purple pigment of Chromobacterium violaceum with potential medical applications as antimicrobial, antiviral, and anticancer drugs. The initial step of violacein biosynthesis is the oxidative conversion of l tryptophan into the corresponding alpha-imine catalyzed by the flavoenzyme l tryptophan oxidase (VioA). A substrate-related (3-(1H-indol-3-yl)-2 methylpropanoic acid) and a product-related (2-(1H-indol-3-ylmethyl)prop-2-enoic acid) competitive VioA inhibitor was synthesized for subsequent kinetic and x-ray crystallographic investigations. Structures of the binary VioA.FADH2 and of the ternary VioA.FADH2.2-(1H-indol-3-ylmethyl)prop-2-enoic acid complex were resolved. VioA forms a "loosely associated" homodimer as indicated by small-angle x-ray scattering experiments. VioA belongs to the glutathione reductase family 2 of FAD-dependent oxidoreductases according to the structurally conserved cofactor binding domain. The substrate-binding domain of VioA is mainly responsible for the specific recognition of l-tryptophan. Other canonical amino acids were efficiently discriminated with a minor conversion of l-phenylalanine. Furthermore, 7-aza-tryptophan, 1-methyl-tryptophan, 5-methyl-tryptophan, and 5 fluoro-tryptophan were efficient substrates of VioA. The ternary product-related VioA structure indicated involvement of protein domain movement during enzyme catalysis. Extensive structure-based mutagenesis in combination with enzyme kinetics (using l-tryptophan and substrate analogs) identified Arg(64), Lys(269), and Tyr(309) as key catalytic residues of VioA. An increased enzyme activity of protein variant H163A in the presence of l-phenylalanine indicated a functional role of His(163) in substrate binding. The combined structural and mutational analyses lead to the detailed understanding of VioA substrate recognition. Related strategies for the in vivo synthesis of novel violacein derivatives are discussed. PMID- 27466368 TI - Aldosterone Upregulates Transient Receptor Potential Melastatin 7 (TRPM7). AB - Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed Mg(2+)-permeable ion channel fused to a C-terminal alpha-kinase domain. Recently, aldosterone was shown to increase intracellular Mg(2+) levels and alter inflammatory signaling in TRPM7-expressing HEK293 cells. This study was undertaken to assess whether these effects were related to an aldosterone mediated increase of TRPM7 current and/or plasma membrane localization. Using HEK293 cells stably expressing WT-TRPM7, we found that 18-h application of aldosterone significantly increased TRPM7 current and TRPM7 plasma membrane protein expression by 48% and 34%, respectively. The aldosterone-mediated increase of TRPM7 current was inhibited by eplerenone, a mineralocorticoid receptor (MR) blocker, and GSK-650394, an inhibitor of the serum- and glucocorticoid-regulated kinase 1 (SGK1). SGK1 blockade also prevented the aldosterone-induced increase of TRPM7 plasma membrane protein. It was further determined that K1648R-TRPM7, the phosphotransferase-inactive TRPM7 mutant, was unresponsive to aldosterone. Therefore, chronic aldosterone treatment increases the plasma membrane expression of TRPM7, which is associated with an increase of TRPM7 current. This process occurs via an MR-dependent, genomic signaling cascade involving SGK1 and a functioning TRPM7 alpha-kinase domain. We suggest that this mechanism may be of general relevance when interpreting the effects of aldosterone because the MR receptor is found in multiple tissues, and TRPM7 and SGK1 are ubiquitously expressed. PMID- 27466371 TI - Characterization and redox regulation of Plasmodium falciparum methionine adenosyltransferase. AB - As a methyl group donor for biochemical reactions, S-adenosylmethionine plays a central metabolic role in most organisms. Depletion of S-adenosylmethionine has downstream effects on polyamine metabolism and methylation reactions, and is an effective way to combat pathogenic microorganisms such as malaria parasites. Inhibition of both the methylation cycle and polyamine synthesis strongly affects Plasmodium falciparum growth. Despite its central position in the methylation cycle, not much is currently known about P. falciparum methionine adenosyltransferase (PfalMAT). Notably, however, PfalMAT has been discussed as a target of different redox regulatory modifications. Modulating the redox state of critical cysteine residues is a way to regulate enzyme activity in different pathways in response to changes in the cellular redox state. In the present study, we optimized an assay for detailed characterization of enzymatic activity and redox regulation of PfalMAT. While the presence of reduced thioredoxin increases the activity of the enzyme, it was found to be inhibited upon S glutathionylation and S-nitrosylation. A homology model and site-directed mutagenesis studies revealed a contribution of the residues Cys52, Cys113 and Cys187 to redox regulation of PfalMAT by influencing its structure and activity. This phenomenon connects cellular S-adenosylmethionine synthesis to the redox state of PfalMAT and therefore to the cellular redox homeostasis. PMID- 27466369 TI - Structure of the Single-lobe Myosin Light Chain C in Complex with the Light Chain binding Domains of Myosin-1C Provides Insights into Divergent IQ Motif Recognition. AB - Myosin light chains are key regulators of class 1 myosins and typically comprise two domains, with calmodulin being the archetypal example. They bind IQ motifs within the myosin neck region and amplify conformational changes in the motor domain. A single lobe light chain, myosin light chain C (MlcC), was recently identified and shown to specifically bind to two sequentially divergent IQ motifs of the Dictyostelium myosin-1C. To provide a molecular basis of this interaction, the structures of apo-MlcC and a 2:1 MlcC.myosin-1C neck complex were determined. The two non-functional EF-hand motifs of MlcC pack together to form a globular four-helix bundle that opens up to expose a central hydrophobic groove, which interacts with the N-terminal portion of the divergent IQ1 and IQ2 motifs. The N- and C-terminal regions of MlcC make critical contacts that contribute to its specific interactions with the myosin-1C divergent IQ motifs, which are contacts that deviate from the traditional mode of calmodulin-IQ recognition. PMID- 27466370 TI - Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction. AB - TRAF3IP2 (TRAF3 interacting protein 2; previously known as CIKS or Act1) is a key intermediate in the normal inflammatory response and the pathogenesis of various autoimmune and inflammatory diseases. Induction of TRAF3IP2 activates IkappaB kinase (IKK)/NF-kappaB, JNK/AP-1, and c/EBPbeta and stimulates the expression of various inflammatory mediators with negative myocardial inotropic effects. To investigate the role of TRAF3IP2 in heart disease, we generated a transgenic mouse model with cardiomyocyte-specific TRAF3IP2 overexpression (TRAF3IP2-Tg). Echocardiography, magnetic resonance imaging, and pressure-volume conductance catheterization revealed impaired cardiac function in 2-month-old male transgenic (Tg) mice as evidenced by decreased ejection fraction, stroke volume, cardiac output, and peak ejection rate. Moreover, the male Tg mice spontaneously developed myocardial hypertrophy (increased heart/body weight ratio, cardiomyocyte cross-sectional area, GATA4 induction, and fetal gene re expression). Furthermore, TRAF3IP2 overexpression resulted in the activation of IKK/NF-kappaB, JNK/AP-1, c/EBPbeta, and p38 MAPK and induction of proinflammatory cytokines, chemokines, and extracellular matrix proteins in the heart. Although myocardial hypertrophy decreased with age, cardiac fibrosis (increased number of myofibroblasts and enhanced expression and deposition of fibrillar collagens) increased progressively. Despite these adverse changes, TRAF3IP2 overexpression did not result in cell death at any time period. Interestingly, despite increased mRNA expression, TRAF3IP2 protein levels and activation of its downstream signaling intermediates remained unchanged in the hearts of female Tg mice. The female Tg mice also failed to develop myocardial hypertrophy. In summary, these results demonstrate that overexpression of TRAF3IP2 in male mice is sufficient to induce myocardial hypertrophy, cardiac fibrosis, and contractile dysfunction. PMID- 27466372 TI - Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI. AB - High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available. PMID- 27466373 TI - Multiparametric magnetic resonance imaging including oxygenation mapping of experimental ischaemic stroke. AB - Recent advances in MRI methodology, such as microvascular and brain oxygenation (StO2) imaging, may prove useful in obtaining information about the severity of the acute stroke. We assessed the potential of StO2 to detect the ischaemic core in the acute phase compared to apparent diffusion coefficient and to predict the final necrosis. Sprague-Dawley rats (n = 38) were imaged during acute stroke (D0) and 21 days after (D21). A multiparametric MRI protocol was performed at 4.7T to characterize brain damage within three region of interest: 'LesionD0' (diffusion), 'Mismatch' representing penumbra (perfusion/diffusion) and 'Hypoxia' (voxels < 40% of StO2 within the region of interest LesionD0). Voxel-based analysis of stroke revealed heterogeneity of the region of interest LesionD0, which included voxels with different degrees of oxygenation decrease. This finding was supported by a dramatic decrease of vascular and perfusion parameters within the region of interest hypoxia. This zone presented the lowest values of almost all parameters analysed, indicating a higher severity. Our study demonstrates the potential of StO2 magnetic resonance imaging to more accurately detect the ischaemic core without the inclusion of any reversible ischaemic damage. Our follow-up study indicates that apparent diffusion coefficient imaging overestimated the final necrosis while StO2 imaging did not. PMID- 27466374 TI - P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain. AB - P-glycoprotein (PgP), a drug efflux pump in blood-brain barrier endothelial cells, is a major clinical obstacle for effective central nervous system drug delivery. Identifying PgP regulatory pathways that can be exploited clinically is critical for improving central nervous system drug delivery. We previously found that PgP activity increases in rat brain microvessels concomitant with decreased central nervous system drug delivery in response to acute peripheral inflammatory pain. In the current study, we tested the hypothesis that PgP traffics to the luminal plasma membrane of the microvessel endothelial cells from intracellular stores during peripheral inflammatory pain. Using immunofluorescence microscopy, we detected PgP in endothelial cell nuclei and in the luminal plasma membrane in control animals. Following peripheral inflammatory pain, luminal PgP staining increased while staining in the nucleus decreased. Biochemical analysis of nuclear PgP content confirmed our visual observations. Peripheral inflammatory pain also increased endothelial cell luminal staining of polymerase 1 and transcript release factor/cavin1 and serum deprivation response protein/cavin2, two caveolar scaffold proteins, without changing caveolin1 or protein kinase C delta binding protein/cavin3 location. Our data (a) indicate that PgP traffics from stores in the nucleus to the endothelial cell luminal membrane in response to peripheral inflammatory pain; (b) provide an explanation for our previous observation that peripheral inflammatory pain inhibits central nervous system drug uptake; and (c) suggest a novel regulatory mechanism for PgP activity in rat brain. PMID- 27466375 TI - KIR channels tune electrical communication in cerebral arteries. AB - The conducted vasomotor response reflects electrical communication in the arterial wall and the distance signals spread is regulated by three factors including resident ion channels. This study defined the role of inward-rectifying K+ channels (KIR) in governing electrical communication along hamster cerebral arteries. Focal KCl application induced a vasoconstriction that conducted robustly, indicative of electrical communication among cells. Inhibiting dominant K+ conductances had no attenuating effect, the exception being Ba2+ blockade of KIR. Electrophysiology and Q-PCR analysis of smooth muscle cells revealed a Ba2+ sensitive KIR current comprised of KIR2.1/2.2 subunits. This current was surprisingly small and when incorporated into a model, failed to account for the observed changes in conduction. We theorized a second population of KIR channels exist and consistent with this idea, a robust Ba2+-sensitive KIR2.1/2.2 current was observed in endothelial cells. When both KIR currents were incorporated into, and then inhibited in our model, conduction decay was substantive, aligning with experiments. Enhanced decay was ascribed to the rightward shift in membrane potential and the increased feedback arising from voltage-dependent-K+ channels. In summary, this study shows that two KIR populations work collaboratively to govern electrical communication and the spread of vasomotor responses along cerebral arteries. PMID- 27466377 TI - 'Festival in a Box': Development and qualitative evaluation of an outreach programme to engage socially isolated people with dementia. AB - We co-designed and piloted 'Festival in a Box', an outreach programme to enable socially isolated people with dementia to engage with and enjoy cultural activities in their homes. It comprised 3-4 weekly home visits, each led by a professional artist to create art works using materials brought in 'the box'. Activities included music, poetry, pottery, crafts and photography. We qualitatively interviewed 13 participants (6 people with dementia, 4 artists, 3 befrienders). Six participants with dementia completed, enjoyed and engaged with the planned visits. Main themes were: engagement, reflection on value of previous cultural activities, precariousness and isolation in current neighbourhood and the importance of a voice and being heard. Befrienders reported their preconceptions of what participants could do were challenged. Artists reported shifts in their preconceptions about dementia and the influence of the project on their professional practice. We propose that the 'Festival in a Box' pilot study suggests a means through which community arts festivals could work with socially isolated people with dementia to contribute to the creation of 'Dementia Friendly Communities'. A larger-scale pilot study is now needed to develop this hypothesis. PMID- 27466376 TI - Quantification of [11C]Ro15-4513 GABAAalpha5 specific binding and regional selectivity in humans. AB - [11C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAalpha5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAalpha5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABAAalpha5 selectivity of [11C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [11C]Ro15-4513 has high but not complete selectivity for GABAAalpha5, with alpha5 representing around 60-70% of the specific binding in alpha5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of alpha5 signal and might be used as reference regions under certain conditions. Off-target non-selective binding to other GABAA subtypes means that the choice of analysis method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both VT and VS, band pass spectral analysis for estimation of [Formula: see text] and the simplified reference tissue model for estimation of [Formula: see text]. PMID- 27466380 TI - Trafficking of MHC molecules to the cell surface creates dynamic protein patches. AB - Major histocompatibility complex class I (MHC-I) molecules signal infection or transformation by engaging receptors on T lymphocytes. The spatial organization of MHC-I on the plasma membranes is important for this engagement. We and others have shown that MHC-I molecules, like other membrane proteins, are not uniformly distributed, but occur in patches in the plasma membrane. Here, we describe the temporal details of MHC-I patch formation and combine them with the spatial details, which we have described earlier, to yield a comprehensive quantitative description of patch formation. MHC-I is delivered to the plasma membrane in clathrin-coated vesicles, arriving at a rate of ~2.5*10(-3) MUm(-1) min(-1) (or about two arrivals per minute over the whole cell). The vesicles dock and fuse at non-random, apparently targeted, locations on the membrane and the newly delivered MHC-I molecules form patches that are a few hundred nanometers in diameter. The patches are maintained at steady state by a dynamic equilibrium between the rate of delivery and the rate of hindered diffusion of MHC-I molecules out of the patches (caused by components of the actin cytoskeleton). PMID- 27466379 TI - The role of Sema3-Npn-1 signaling during diaphragm innervation and muscle development. AB - Correct innervation of the main respiratory muscle in mammals, namely the thoracic diaphragm, is a crucial pre-requisite for the functionality of this muscle and the viability of the entire organism. Systemic impairment of Sema3A Npn-1 (Npn-1 is also known as NRP1) signaling causes excessive branching of phrenic nerves in the diaphragm and into the central tendon region, where the majority of misguided axons innervate ectopic musculature. To elucidate whether these ectopic muscles are a result of misguidance of myoblast precursors due to the loss of Sema3A-Npn-1 signaling, we conditionally ablated Npn-1 in somatic motor neurons, which led to a similar phenotype of phrenic nerve defasciculation and, intriguingly, also formation of innervated ectopic muscles. We therefore hypothesize that ectopic myocyte fusion is caused by additional factors released by misprojecting growth cones. Slit2 and its Robo receptors are expressed by phrenic motor axons and migrating myoblasts, respectively, during innervation of the diaphragm. In vitro analyses revealed a chemoattractant effect of Slit2 on primary diaphragm myoblasts. Thus, we postulate that factors released by motor neuron growth cones have an influence on the migration properties of myoblasts during establishment of the diaphragm. PMID- 27466378 TI - A role for the yeast CLIP170 ortholog, the plus-end-tracking protein Bik1, and the Rho1 GTPase in Snc1 trafficking. AB - The diversity of microtubule functions is dependent on the status of tubulin C termini. To address the physiological role of the C-terminal aromatic residue of alpha-tubulin, a tub1-Glu yeast strain expressing an alpha-tubulin devoid of its C-terminal amino acid was used to perform a genome-wide-lethality screen. The identified synthetic lethal genes suggested links with endocytosis and related processes. In the tub1-Glu strain, the routing of the v-SNARE Snc1 was strongly impaired, with a loss of its polarized distribution in the bud, and Abp1, an actin patch or endocytic marker, developed comet-tail structures. Snc1 trafficking required dynamic microtubules but not dynein and kinesin motors. Interestingly, deletion of the microtubule plus-end-tracking protein Bik1 (a CLIP170 ortholog), which is preferentially recruited to the C-terminal residue of alpha-tubulin, similarly resulted in Snc1 trafficking defects. Finally, constitutively active Rho1 rescued both Bik1 localization at the microtubule plus ends in tub1-Glu strain and a correct Snc1 trafficking in a Bik1-dependent manner. Our results provide the first evidence for a role of microtubule plus ends in membrane cargo trafficking in yeast, through Rho1- and Bik1-dependent mechanisms, and highlight the importance of the C-terminal alpha-tubulin amino acid in this process. PMID- 27466381 TI - Cadherin 5 expression correlates with poor survival in human gastric cancer. AB - AIMS: Although expressed in tumour cells of various malignancies, cadherin 5 (CDH5), also known as vascular endothelial cadherin, plays an important role in homotypic cell-cell adhesion among epithelial cells. However, the clinical significance of CDH5 expression in gastric cancer has not been sufficiently demonstrated. In this study, CDH5 expression in gastric cancer was evaluated and the correlations between CDH5 expression and the clinicopathological features and outcomes of the disease were examined. METHODS: Differentiated-type gastric adenocarcinomas obtained from 102 patients who underwent gastrectomy were analysed. CDH5 expression was assessed by immunohistochemical staining of the membranes of the cancer cells. RESULTS: High CDH5 expression was significantly associated with the following clinicopathological variables related to tumour progression: depth of invasion (p=0.012), venous invasion (p=0.013), lymphatic invasion (p=0.001), metastatic lymph nodes (p=0.009), pathological stage (p=0.008) and distant metastasis or recurrent disease (p=0.009). Patients with high CDH5 expression had significantly poorer disease-specific survival (p=0.021), although CDH5 was not determined to be an independent prognostic factor by multivariate analysis. CONCLUSIONS: CDH5 may play a key role in the progression or metastasis of differentiated-type gastric cancer and serve as a target for its treatment. PMID- 27466382 TI - Novel germline mutations in the calreticulin gene: implications for the diagnosis of myeloproliferative neoplasms. AB - Mutations in the calreticulin (CALR) gene are found in the majority of Janus kinase 2-negative myeloproliferative neoplasms MPN and, thus far, have exclusively been reported as acquired, somatic mutations. We assessed the mutational status of exon 9 of the CALR gene in 2000 blood samples submitted to our centre and identified 12 subjects (0.6%) harbouring distinctive CALR mutations, all with an allelic frequency of 50% and all involving indels occurring as multiples of 3 bp. Buccal cell samples obtained from these patients confirmed the germline nature of the mutations. Importantly, these germline mutations were not diagnostic of MPN. We thus report for the first time the identification and confirmation of germline mutations in CALR distinct from those somatic mutations that define classical MPN. The finding of a non-standard CALR mutation with an allelic frequency of 50% should raise suspicion of the possibility of a germline CALR mutation and these cases investigated further. PMID- 27466383 TI - Validation of the Singapore nomogram for outcome prediction in breast phyllodes tumours: an Australian cohort. AB - AIM: To validate the utility of the Singapore nomogram for outcome prediction in breast phyllodes tumours. METHODS: Histological parameters, surgical margin status and clinical follow-up data of 34 women diagnosed with phyllodes tumours were analysed. Biostatistics modelling was performed, and the concordance between predicted and observed survivals was calculated. RESULTS: Women with a high nomogram score had an increased risk of developing relapse, which was predicted using the parameters defined by the Singapore nomogram. CONCLUSIONS: The Singapore nomogram is useful in predicting outcome in breast phyllodes tumours when applied to an Australian cohort of 34 women. PMID- 27466385 TI - Rapid Bedside Inactivation of Ebola Virus for Safe Nucleic Acid Tests. AB - Rapid bedside inactivation of Ebola virus would be a solution for the safety of medical and technical staff, risk containment, sample transport, and high throughput or rapid diagnostic testing during an outbreak. We show that the commercially available Magna Pure lysis/binding buffer used for nucleic acid extraction inactivates Ebola virus. A rapid bedside inactivation method for nucleic acid tests is obtained by simply adding Magna Pure lysis/binding buffer directly into vacuum blood collection EDTA tubes using a thin needle and syringe prior to sampling. The ready-to-use inactivation vacuum tubes are stable for more than 4 months, and Ebola virus RNA is preserved in the Magna Pure lysis/binding buffer for at least 5 weeks independent of the storage temperature. We also show that Ebola virus RNA can be manually extracted from Magna Pure lysis/binding buffer-inactivated samples using the QIAamp viral RNA minikit. We present an easy and convenient method for bedside inactivation using available blood collection vacuum tubes and reagents. We propose to use this simple method for fast, safe, and easy bedside inactivation of Ebola virus for safe transport and routine nucleic acid detection. PMID- 27466384 TI - Equine 5alpha-reductase activity and expression in epididymis. AB - The 5alpha-reductase enzymes play an important role during male sexual differentiation, and in pregnant females, especially equine species where maintenance relies on 5alpha-reduced progesterone, 5alpha-dihydroprogesterone (DHP). Epididymis expresses 5alpha-reductases but was not studied elaborately in horses. Epididymis from younger and older postpubertal stallions was divided into caput, corpus and cauda and examined for 5alpha-reductase activity and expression of type 1 and 2 isoforms by quantitative real-time polymerase chain reaction (qPCR). Metabolism of progesterone and testosterone to DHP and dihydrotestosterone (DHT), respectively, by epididymal microsomal protein was examined by thin-layer chromatography and verified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Relative inhibitory potencies of finasteride and dutasteride toward equine 5alpha-reductase activity were investigated. Pregnenolone was investigated as an additional potential substrate for 5alpha reductase, suggested previously from in vivo studies in mares but never directly examined. No regional gradient of 5alpha-reductase expression was observed by either enzyme activity or transcript analysis. Results of PCR experiments suggested that type 1 isoform predominates in equine epididymis. Primers for the type 2 isoform were unable to amplify product from any samples examined. Progesterone and testosterone were readily reduced to DHP and DHT, and activity was effectively inhibited by both inhibitors. Using epididymis as an enzyme source, no experimental evidence was obtained supporting the notion that pregnenolone could be directly metabolized by equine 5alpha-reductases as has been suggested by previous investigators speculating on alternative metabolic pathways leading to DHP synthesis in placenta during equine pregnancies. PMID- 27466386 TI - Panmixia in a Critically Endangered Fish: The Totoaba (Totoaba macdonaldi) in the Gulf of California. AB - Conservation of the evolutionary legacy of endangered species is a key component for long-term persistence. Totoaba is a long-lived fish endemic to the Gulf of California and is considered critically endangered. There is currently a debate concerning its conservation status and whether it can be used as a fishery resource. Unfortunately, basic information on biological and genetic population structure of the species is lacking. We sampled 313 individuals and employed 16 microsatellite loci and 3 mitochondrial DNA markers (16S, 547 pb; COI, 619 pb; control region, 650 pb) to assess population structure and demography of totoaba in the Gulf of California, with samples from locations that encompass nearly all of its recognized geographic distribution. We could not reject a hypothesis of panmixia for totoaba, using nuclear or mitochondrial markers. Demographic analysis of mtDNA suggests a sudden population expansion model. The results have important implications for totoaba conservation because poaching is a significant conservation challenge and could have additive negative effects over the single population of totoaba in the Gulf of California. PMID- 27466387 TI - Poly(ADP-ribose) polymers regulate DNA topoisomerase I (Top1) nuclear dynamics and camptothecin sensitivity in living cells. AB - Topoisomerase 1 (Top1) is essential for removing the DNA supercoiling generated during replication and transcription. Anticancer drugs like camptothecin (CPT) and its clinical derivatives exert their cytotoxicity by reversibly trapping Top1 in covalent complexes on the DNA (Top1cc). Poly(ADP-ribose) polymerase (PARP) catalyses the addition of ADP-ribose polymers (PAR) onto itself and Top1. PARP inhibitors enhance the cytotoxicity of CPT in the clinical trials. However, the molecular mechanism by which PARylation regulates Top1 nuclear dynamics is not fully understood. Using live-cell imaging of enhanced green fluorescence tagged human Top1, we show that PARP inhibitors (Veliparib, ABT-888) delocalize Top1 from the nucleolus to the nucleoplasm, which is independent of Top1-PARP1 interaction. Using fluorescence recovery after photobleaching and subsequent fitting of the data employing kinetic modelling we demonstrate that ABT-888 markedly increase CPT-induced bound/immobile fraction of Top1 (Top1cc) across the nuclear genome, suggesting Top1-PARylation counteracts CPT-induced stabilization of Top1cc. We further show Trp205 and Asn722 of Top1 are critical for subnuclear dynamics. Top1 mutant (N722S) was restricted to the nucleolus in the presence of CPT due to its deficiency in the accumulation of CPT-induced Top1-PARylation and Top1cc formation. This work identifies ADP-ribose polymers as key determinant for regulating Top1 subnuclear dynamics. PMID- 27466389 TI - Disclosing early steps of protein-primed genome replication of the Gram-positive tectivirus Bam35. AB - Protein-primed replication constitutes a generalized mechanism to initiate DNA or RNA synthesis in a number of linear genomes of viruses, linear plasmids and mobile elements. By this mechanism, a so-called terminal protein (TP) primes replication and becomes covalently linked to the genome ends. Bam35 belongs to a group of temperate tectiviruses infecting Gram-positive bacteria, predicted to replicate their genomes by a protein-primed mechanism. Here, we characterize Bam35 replication as an alternative model of protein-priming DNA replication. First, we analyze the role of the protein encoded by the ORF4 as the TP and characterize the replication mechanism of the viral genome (TP-DNA). Indeed, full length Bam35 TP-DNA can be replicated using only the viral TP and DNA polymerase. We also show that DNA replication priming entails the TP deoxythymidylation at conserved tyrosine 194 and that this reaction is directed by the third base of the template strand. We have also identified the TP tyrosine 172 as an essential residue for the interaction with the viral DNA polymerase. Furthermore, the genetic information of the first nucleotides of the genome can be recovered by a novel single-nucleotide jumping-back mechanism. Given the similarities between genome inverted terminal repeats and the genes encoding the replication proteins, we propose that related tectivirus genomes can be replicated by a similar mechanism. PMID- 27466388 TI - Role of mRNA structure in the control of protein folding. AB - Specific structures in mRNA modulate translation rate and thus can affect protein folding. Using the protein structures from two eukaryotes and three prokaryotes, we explore the connections between the protein compactness, inferred from solvent accessibility, and mRNA structure, inferred from mRNA folding energy (DeltaG). In both prokaryotes and eukaryotes, the DeltaG value of the most stable 30 nucleotide segment of the mRNA (DeltaGmin) strongly, positively correlates with protein solvent accessibility. Thus, mRNAs containing exceptionally stable secondary structure elements typically encode compact proteins. The correlations between DeltaG and protein compactness are much more pronounced in predicted ordered parts of proteins compared to the predicted disordered parts, indicative of an important role of mRNA secondary structure elements in the control of protein folding. Additionally, DeltaG correlates with the mRNA length and the evolutionary rate of synonymous positions. The correlations are partially independent and were used to construct multiple regression models which explain about half of the variance of protein solvent accessibility. These findings suggest a model in which the mRNA structure, particularly exceptionally stable RNA structural elements, act as gauges of protein co-translational folding by reducing ribosome speed when the nascent peptide needs time to form and optimize the core structure. PMID- 27466390 TI - Cyclic mismatch binding ligand CMBL4 binds to the 5'-T-3'/5'-GG-3' site by inducing the flipping out of thymine base. AB - A newly designed cyclic bis-naphthyridine carbamate dimer CMBL4: with a limited conformational flexibility was synthesized and characterized. Absorption spectra revealed that two naphthyridines in CMBL4: were stacked on each other in aqueous solutions. The most efficient binding of CMBL4: to DNA was observed for the sequence 5'-T-3'/5'-GG-3' (T/GG) with the formation of a 1:1 complex, which is one of possible structural elements involved in the higher order structures of (TGG)n repeat DNA triggering the genome microdeletion. Surface plasmon resonance assay also showed the binding of CMBL4: with TGG repeat DNA. Potassium permanganate oxidation studies of CMBL4: -bound duplex containing the T/GG site showed that the CMBL4: -binding accelerated the oxidation of thymine at that site, which suggests the flipping out of the thymine base from a pi-stack. Preferential binding was observed for CMBL4: compared with its acyclic variants, which suggests the marked significance of the macrocyclic structure for the recognition of the T/GG site. PMID- 27466391 TI - Trans-acting GC-rich non-coding RNA at var expression site modulates gene counting in malaria parasite. AB - Monoallelic expression of the var multigene family enables immune evasion of the malaria parasite Plasmodium falciparum in its human host. At a given time only a single member of the 60-member var gene family is expressed at a discrete perinuclear region called the 'var expression site'. However, the mechanism of var gene counting remains ill-defined. We hypothesize that activation factors associating specifically with the expression site play a key role in this process. Here, we investigate the role of a GC-rich non-coding RNA (ncRNA) gene family composed of 15 highly homologous members. GC-rich genes are positioned adjacent to var genes in chromosome-central gene clusters but are absent near subtelomeric var genes. Fluorescence in situ hybridization demonstrates that GC rich ncRNA localizes to the perinuclear expression site of central and subtelomeric var genes in trans. Importantly, overexpression of distinct GC-rich ncRNA members disrupts the gene counting process at the single cell level and results in activation of a specific subset of var genes in distinct clones. We identify the first trans-acting factor targeted to the elusive perinuclear var expression site and open up new avenues to investigate ncRNA function in antigenic variation of malaria and other protozoan pathogens. PMID- 27466394 TI - Translesion synthesis of O4-alkylthymidine lesions in human cells. AB - Environmental exposure, endogenous metabolism and cancer chemotherapy can give rise to alkylation of DNA, and the resulting alkylated thymidine (alkyldT) lesions were found to be poorly repaired and persistent in mammalian tissues. Unrepaired DNA lesions may compromise genomic integrity by inhibiting DNA replication and inducing mutations in these processes. In this study, we explored how eight O4-alkyldT lesions, with the alkyl group being a Me, Et, nPr, iPr, nBu, iBu, (R)-sBu and (S)-sBu, are recognized by DNA replication machinery in HEK293T human embryonic kidney cells. We found that the O4-alkyldT lesions are moderately blocking to DNA replication, with the bypass efficiencies ranging from 20 to 33% in HEK293T cells, and these lesions induced substantial frequencies T->C transition mutation. We also conducted the replication experiments in the isogenic cells where individual translesion synthesis (TLS) DNA polymerases were depleted by the CRISPR/Cas9 genome editing method. Our results showed that deficiency in Pol eta or Pol zeta, but not Pol kappa or Pol iota, led to pronounced drops in bypass efficiencies for all the O4-alkyldT lesions except O4 MedT. In addition, depletion of Pol zeta resulted in significant decreases in T >C mutation frequencies for all the O4-alkyldT lesions except O4-MedT and O4 nBudT. Thus, our study provided important new knowledge about the cytotoxic and mutagenic properties of the O4-alkyldT lesions and defined the roles of TLS polymerases in bypassing these lesions in human cells. PMID- 27466392 TI - Near-complete elimination of mutant mtDNA by iterative or dynamic dose-controlled treatment with mtZFNs. AB - Mitochondrial diseases are frequently associated with mutations in mitochondrial DNA (mtDNA). In most cases, mutant and wild-type mtDNAs coexist, resulting in heteroplasmy. The selective elimination of mutant mtDNA, and consequent enrichment of wild-type mtDNA, can rescue pathological phenotypes in heteroplasmic cells. Use of the mitochondrially targeted zinc finger-nuclease (mtZFN) results in degradation of mutant mtDNA through site-specific DNA cleavage. Here, we describe a substantial enhancement of our previous mtZFN-based approaches to targeting mtDNA, allowing near-complete directional shifts of mtDNA heteroplasmy, either by iterative treatment or through finely controlled expression of mtZFN, which limits off-target catalysis and undesired mtDNA copy number depletion. To demonstrate the utility of this improved approach, we generated an isogenic distribution of heteroplasmic cells with variable mtDNA mutant level from the same parental source without clonal selection. Analysis of these populations demonstrated an altered metabolic signature in cells harbouring decreased levels of mutant m.8993T>G mtDNA, associated with neuropathy, ataxia, and retinitis pigmentosa (NARP). We conclude that mtZFN-based approaches offer means for mtDNA heteroplasmy manipulation in basic research, and may provide a strategy for therapeutic intervention in selected mitochondrial diseases. PMID- 27466393 TI - Single strand transposition at the host replication fork. AB - Members of the IS200/IS605 insertion sequence family differ fundamentally from classical IS essentially by their specific single-strand (ss) transposition mechanism, orchestrated by the Y1 transposase, TnpA, a small HuH enzyme which recognizes and processes ss DNA substrates. Transposition occurs by the 'peel and paste' pathway composed of two steps: precise excision of the top strand as a circular ss DNA intermediate; and subsequent integration into a specific ssDNA target. Transposition of family members was experimentally shown or suggested by in silico high-throughput analysis to be intimately coupled to the lagging strand template of the replication fork. In this study, we investigated factors involved in replication fork targeting and analysed DNA-binding properties of the transposase which can assist localization of ss DNA substrates on the replication fork. We showed that TnpA interacts with the beta sliding clamp, DnaN and recognizes DNA which mimics replication fork structures. We also showed that dsDNA can facilitate TnpA targeting ssDNA substrates. We analysed the effect of Ssb and RecA proteins on TnpA activity in vitro and showed that while RecA does not show a notable effect, Ssb inhibits integration. Finally we discuss the way(s) in which integration may be directed into ssDNA at the replication fork. PMID- 27466395 TI - Understanding age and race disparities in the application of sentinel lymph node biopsy in breast cancer. AB - Sentinel lymph node biopsy (SLNB) is the standard of care for surgical evaluation of early-stage breast cancer and is being employed as a quality metric for accreditation of breast centers. Previous studies report disparities in SLNB receipt. The goal of this study is to determine SLNB rates and explore rationale for non-receipt of SLNB. Patients with early-stage breast cancer diagnosed between 2010 and 2011 were identified from the University Hospitals Case Medical Center tumor registry. Multivariable logistic models were used to identify clinical and demographic risk factors for patients who did not receive SLNB. We performed chart reviews to elucidate reasons for the lack of SLNB. Our total sample was 479 patients; of them 432 (90.2%) received SLNB. On average, patients who received SLNB were younger than those who did not receive SLNB (61 compared to 79 years, respectively). Patients >=80 years were 96% less likely to receive SLNB compared to patients <65 years (OR 0.04; 95% CI 0.00 to 0.14). There were no differences in SLNB by race, between patients undergoing Medicare or Medicaid and managed care, by surgeon specialty, or across medical centers. Chart review determined that 45/47 patients did not have SLNB, because it was a clinical decision-making; advanced age (>80 years) was cited in 27/47 women. Older women had much lower odds of receiving SLNB; however, non-receipt of SLNB was often due to a clinical reasoning. Our study highlights the importance of clinical reasoning in receiving SLNB, whereas other studies solely employing administrative databases do not. PMID- 27466396 TI - Retention of Teeth and Oral Health-Related Quality of Life. AB - The authors aimed to critically review the literature regarding the relationship between retention of teeth and oral health-related quality of life (OHRQoL) and the extent to which tooth retention can ensure OHRQoL among adults. The authors investigated studies that assessed the relationship between number of teeth and OHRQoL and how the position, type, and/or pattern of the teeth is related to OHRQoL. Relevant papers published in English from January 2004 to September 2015 were searched via PubMed and EMBASE. Twenty-nine papers-including cross sectional, longitudinal, clinical trial, and case-control studies-were included and categorized according to 4 subthemes to achieve the stated aim: 1) number of teeth or missing teeth and OHRQoL, 2) occluding pairs or functional units and OHRQoL, 3) position of remaining or missing teeth and OHRQoL, and 4) shortened dental arches (SDAs) and OHRQoL. The main findings for each subtheme were as follows: 1) A significant association between number of teeth and OHRQoL was shown in most studies; however, those studies found different cutoff points regarding the number of teeth that affect OHRQoL, after adjusting for other factors in the analyses (e.g., age, sex, cultural background, and study locations). 2) The number of occluding pairs and the location of remaining teeth have great impacts on OHRQoL. 3) Having fewer anterior occluding pairs had a greater negative impact on aesthetics and thus affected OHRQoL. 4) Two randomized clinical trials on SDAs indicated that people with SDAs do not show worse OHRQoL than do those with removable dentures. The only 2 population-based studies on SDAs showed that adults with SDAs have no impaired OHRQoL when compared with those having more natural teeth. To conclude, this review found evidence that retention of teeth is associated with better OHRQoL. The number of occluding pairs and the location of remaining teeth have great impacts on OHRQoL. People with SDAs maintain an acceptable level of OHRQoL. PMID- 27466397 TI - Association of Endodontic Lesions with Coronary Artery Disease. AB - An endodontic lesion (EL) is a common manifestation of endodontic infection where Porphyromonas endodontalis is frequently encountered. EL may associate with increased risk for coronary artery disease (CAD) via similar pathways as marginal periodontitis. The aim of this cross-sectional study was to delineate the associations between EL and CAD. Subgingival P. endodontalis, its immune response, and serum lipopolysaccharide were examined as potential mediators between these 2 diseases. The Finnish Parogene study consists of 508 patients (mean age, 62 y) who underwent coronary angiography and extensive clinical and radiographic oral examination. The cardiovascular outcomes included no significant CAD ( n = 123), stable CAD ( n = 184), and acute coronary syndrome (ACS; n = 169). EL was determined from a panoramic tomography. We combined data of widened periapical spaces (WPSs) and apical rarefactions to a score of EL: 1, no EL ( n = 210); 2, >=1 WPS per 1 apical rarefaction ( n = 222); 3, >=2 apical rarefactions ( n = 76). Subgingival P. endodontalis was defined by checkerboard DNA-DNA hybridization analysis, and corresponding serum antibodies were determined by ELISA. In our population, 50.4% had WPSs, and 22.8% apical rarefactions. A total of 51.2% of all teeth with apical rarefactions had received endodontic procedures. Subgingival P. endodontalis levels and serum immunoglobulin G were associated with a higher EL score. In the multiadjusted model (age, sex, smoking, diabetes, body mass index, alveolar bone loss, and number of teeth), having WPSs associated with stable CAD (odds ratio [OR] = 1.94, 95% confidence interval [95% CI] = 1.13 to 3.32, P = 0.016) and highest EL score were associated with ACS (OR = 2.46, 95% CI = 1.09 to 5.54, P = 0.030). This association was especially notable in subjects with untreated teeth with apical rarefactions ( n = 59, OR = 2.72, 95% CI = 1.16 to 6.40, P = 0.022). Our findings support the hypothesis that ELs are independently associated with CAD and in particular with ACS. This is of high interest from a public health perspective, considering the high prevalence of ELs and CAD. PMID- 27466398 TI - Diagnosis and Treatment of Congenital Chagas Disease in a Premature Infant. PMID- 27466401 TI - Opinion: NIH must support broadly focused basic research. PMID- 27466399 TI - Chronic exposure of adult, postnatal and in utero rat models to low-dose 137Cesium: impact on circulating biomarkers. AB - The presence of 137Cesium (137Cs) in the environment after nuclear accidents at Chernobyl and more recently Fukushima Daiichi raises many health issues for the surrounding populations chronically exposed through the food chain. To mimic different exposure situations, we set up a male rat model of exposure by chronic ingestion of a 137Cs concentration likely to be ingested daily by residents of contaminated areas (6500 Bq.l-1) and tested contaminations lasting 9 months for adult, neonatal and fetal rats. We tested plasma and serum biochemistry to identify disturbances in general indicators (lipids, proteins, carbohydrates and electrolytes) and in biomarkers of thyroid, heart, brain, bone, kidney, liver and testis functions. Analysis of the general indicators showed increased levels of cholesterol (+26%), HDL cholesterol (+31%), phospholipids B (+15%) and phosphorus (+100%) in the postnatal group only. Thyroid, heart, brain, bone and kidney functions showed no blood changes in any model. The liver function evaluation showed changes in total bilirubin (+67%) and alkaline phosphatase (-11%) levels, but only for the rats exposed to 137Cs intake in adulthood. Large changes in 17beta-estradiol (-69%) and corticosterone (+36%) levels affected steroidogenesis, but only in the adult model. This study showed that response profiles differed according to age at exposure: lipid metabolism was most radiosensitive in the postnatal model, and steroid hormone metabolism was most radiosensitive in rats exposed in adulthood. There was no evidence of deleterious effects suggesting a potential impact on fertility or procreation. PMID- 27466403 TI - Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling. AB - Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial-mesenchymal transition (EMT), TGF-beta1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin deficient (VIM(-/-)) wounds. Correspondingly, VIM(-/-) wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM(-/-) wounds. Vimentin reconstitution in VIM(-/-) fibroblasts restored both their proliferation and TGF-beta1 production. Similarly, restoring paracrine TGF-beta-Slug-EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-beta1-Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation. PMID- 27466404 TI - Structural and functional basis of protein phosphatase 5 substrate specificity. AB - The serine/threonine phosphatase protein phosphatase 5 (PP5) regulates hormone- and stress-induced cellular signaling by association with the molecular chaperone heat shock protein 90 (Hsp90). PP5-mediated dephosphorylation of the cochaperone Cdc37 is essential for activation of Hsp90-dependent kinases. However, the details of this mechanism remain unknown. We determined the crystal structure of a Cdc37 phosphomimetic peptide bound to the catalytic domain of PP5. The structure reveals PP5 utilization of conserved elements of phosphoprotein phosphatase (PPP) structure to bind substrate and provides a template for many PPP-substrate interactions. Our data show that, despite a highly conserved structure, elements of substrate specificity are determined within the phosphatase catalytic domain itself. Structure-based mutations in vivo reveal that PP5-mediated dephosphorylation is required for kinase and steroid hormone receptor release from the chaperone complex. Finally, our data show that hyper- or hypoactivity of PP5 mutants increases Hsp90 binding to its inhibitor, suggesting a mechanism to enhance the efficacy of Hsp90 inhibitors by regulation of PP5 activity in tumors. PMID- 27466405 TI - Loss of function at RAE2, a previously unidentified EPFL, is required for awnlessness in cultivated Asian rice. AB - Domestication of crops based on artificial selection has contributed numerous beneficial traits for agriculture. Wild characteristics such as red pericarp and seed shattering were lost in both Asian (Oryza sativa) and African (Oryza glaberrima) cultivated rice species as a result of human selection on common genes. Awnedness, in contrast, is a trait that has been lost in both cultivated species due to selection on different sets of genes. In a previous report, we revealed that at least three loci regulate awn development in rice; however, the molecular mechanism underlying awnlessness remains unknown. Here we isolate and characterize a previously unidentified EPIDERMAL PATTERNING FACTOR-LIKE (EPFL) family member named REGULATOR OF AWN ELONGATION 2 (RAE2) and identify one of its requisite processing enzymes, SUBTILISIN-LIKE PROTEASE 1 (SLP1). The RAE2 precursor is specifically cleaved by SLP1 in the rice spikelet, where the mature RAE2 peptide subsequently induces awn elongation. Analysis of RAE2 sequence diversity identified a highly variable GC-rich region harboring multiple independent mutations underlying protein-length variation that disrupt the function of the RAE2 protein and condition the awnless phenotype in Asian rice. Cultivated African rice, on the other hand, retained the functional RAE2 allele despite its awnless phenotype. Our findings illuminate the molecular function of RAE2 in awn development and shed light on the independent domestication histories of Asian and African cultivated rice. PMID- 27466406 TI - Chemical shift imprint of intersubunit communication in a symmetric homodimer. AB - Allosteric communication is critical for protein function and cellular homeostasis, and it can be exploited as a strategy for drug design. However, unlike many protein-ligand interactions, the structural basis for the long-range communication that underlies allostery is not well understood. This lack of understanding is most evident in the case of classical allostery, in which a binding event in one protomer is sensed by a second symmetric protomer. A primary reason why study of interdomain signaling is challenging in oligomeric proteins is the difficulty in characterizing intermediate, singly bound species. Here, we use an NMR approach to isolate and characterize a singly ligated state ("lig1") of a homodimeric enzyme that is otherwise obscured by rapid exchange with apo and saturated forms. Mixed labeled dimers were prepared that simultaneously permit full population of the lig1 state and isotopic labeling of either protomer. Direct visualization of peaks from lig1 yielded site-specific ligand-state multiplets that provide a convenient format for assessing mechanisms of intersubunit communication from a variety of NMR measurements. We demonstrate this approach on thymidylate synthase from Escherichia coli, a homodimeric enzyme known to be half-the-sites reactive. Resolving the dUMP1 state shows that active site communication occurs not upon the first dUMP binding, but upon the second. Surprisingly, for many sites, dUMP1 peaks are found beyond the limits set by apo and dUMP2 peaks, indicating that binding the first dUMP pushes the enzyme ensemble to further conformational extremes than the apo or saturated forms. The approach used here should be generally applicable to homodimers. PMID- 27466407 TI - Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90beta. AB - Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90beta and stress-induced Hsp90alpha, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90beta, identifying GBA as an Hsp90beta-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90beta. Because of its unprecedented selectivity for Hsp90beta among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease. PMID- 27466408 TI - Size-dependent forced PEG partitioning into channels: VDAC, OmpC, and alpha hemolysin. AB - Nonideal polymer mixtures of PEGs of different molecular weights partition differently into nanosize protein channels. Here, we assess the validity of the recently proposed theoretical approach of forced partitioning for three structurally different beta-barrel channels: voltage-dependent anion channel from outer mitochondrial membrane VDAC, bacterial porin OmpC (outer membrane protein C), and bacterial channel-forming toxin alpha-hemolysin. Our interpretation is based on the idea that relatively less-penetrating polymers push the more easily penetrating ones into nanosize channels in excess of their bath concentration. Comparison of the theory with experiments is excellent for VDAC. Polymer partitioning data for the other two channels are consistent with theory if additional assumptions regarding the energy penalty of pore penetration are included. The obtained results demonstrate that the general concept of "polymers pushing polymers" is helpful in understanding and quantification of concrete examples of size-dependent forced partitioning of polymers into protein nanopores. PMID- 27466409 TI - Phosphorylation of an HP1-like protein is a prerequisite for heterochromatin body formation in Tetrahymena DNA elimination. AB - Multiple heterochromatic loci are often clustered into a higher order nuclear architecture called a heterochromatin body in diverse eukaryotes. Although phosphorylation of Heterochromatin Protein 1 (HP1) family proteins regulates heterochromatin dynamics, its role in heterochromatin bodies remains unknown. We previously reported that dephosphorylation of the HP1-like protein Pdd1p is required for the formation of heterochromatin bodies during the process of programmed DNA elimination in the ciliated protozoan Tetrahymena Here, we show that the heterochromatin body component Jub4p is required for Pdd1p phosphorylation, heterochromatin body formation, and DNA elimination. Moreover, our analyses of unphosphorylatable Pdd1p mutants demonstrate that Pdd1p phosphorylation is required for heterochromatin body formation and DNA elimination, whereas it is dispensable for local heterochromatin assembly. Therefore, both phosphorylation and the following dephosphorylation of Pdd1p are necessary to facilitate the formation of heterochromatin bodies. We suggest that Jub4p-mediated phosphorylation of Pdd1p creates a chromatin environment that is a prerequisite for subsequent heterochromatin body assembly and DNA elimination. PMID- 27466410 TI - 'Bolam' to 'Montgomery' is result of evolutionary change of medical practice towards 'patient-centred care'. AB - The Supreme Court judgement in 'Montgomery v Lanarkshire Health Board' has caused a change in the law concerning the duty of doctors on disclosure of information to patients regarding risks. The law now requires a doctor to take reasonable care to ensure that the patient is aware of any material risks involved in any recommended treatment, and of any reasonable alternative or variant treatments. Are doctors totally removed from the protective shield even if the practice is accepted by a reasonable body of medical opinion previously laid down by 'Bolam' with the recent Supreme Court decision in the 'Montgomery' case? This paper questions whether the 'Bolam' principle needs to be discarded or re-interpreted in the modern context of health care. Adopting 'patient-centred' care to unfold the 'significant risks' attached to patients would align with the evolving changes in medical law. It should be the changing context of health care driving the evolving change of law. PMID- 27466411 TI - Influenza follicles and their buds as early diagnostic markers of influenza: typical images. PMID- 27466412 TI - A tale of two hearts. PMID- 27466413 TI - Retrograde Transport from Early Endosomes to the trans-Golgi Network Enables Membrane Wrapping and Egress of Vaccinia Virus Virions. AB - The anterograde pathway, from the endoplasmic reticulum through the trans-Golgi network to the cell surface, is utilized by trans-membrane and secretory proteins. The retrograde pathway, which directs traffic in the opposite direction, is used following endocytosis of exogenous molecules and recycling of membrane proteins. Microbes exploit both routes: viruses typically use the anterograde pathway for envelope formation prior to exiting the cell, whereas ricin and Shiga-like toxins and some nonenveloped viruses use the retrograde pathway for cell entry. Mining a human genome-wide RNA interference (RNAi) screen revealed a need for multiple retrograde pathway components for cell-to-cell spread of vaccinia virus. We confirmed and extended these results while discovering that retrograde trafficking was required for virus egress rather than entry. Retro-2, a specific retrograde trafficking inhibitor of protein toxins, potently prevented spread of vaccinia virus as well as monkeypox virus, a human pathogen. Electron and confocal microscopy studies revealed that Retro-2 prevented wrapping of virions with an additional double-membrane envelope that enables microtubular transport, exocytosis, and actin polymerization. The viral B5 and F13 protein components of this membrane, which are required for wrapping, normally colocalize in the trans-Golgi network. However, only B5 traffics through the secretory pathway, suggesting that F13 uses another route to the trans-Golgi network. The retrograde route was demonstrated by finding that F13 was largely confined to early endosomes and failed to colocalize with B5 in the presence of Retro-2. Thus, vaccinia virus makes novel use of the retrograde transport system for formation of the viral wrapping membrane. IMPORTANCE: Efficient cell-to-cell spread of vaccinia virus and other orthopoxviruses depends on the wrapping of infectious particles with a double membrane that enables microtubular transport, exocytosis, and actin polymerization. Interference with wrapping or subsequent steps results in severe attenuation of the virus. Some previous studies had suggested that the wrapping membrane arises from the trans-Golgi network, whereas others suggested an origin from early endosomes. Some nonenveloped viruses use retrograde trafficking for entry into the cell. In contrast, we provided evidence that retrograde transport from early endosomes to the trans-Golgi network is required for the membrane-wrapping step in morphogenesis of vaccinia virus and egress from the cell. The potent in vitro inhibition of this step by the drug Retro-2 suggests that derivatives with enhanced pharmacological properties might serve as useful antipoxviral agents. PMID- 27466414 TI - Virus-Like Particles Displaying Trimeric Simian Immunodeficiency Virus (SIV) Envelope gp160 Enhance the Breadth of DNA/Modified Vaccinia Virus Ankara SIV Vaccine-Induced Antibody Responses in Rhesus Macaques. AB - The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations with DNA (D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the second MVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of seven DNA/MVA and VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control. IMPORTANCE: The development of an effective HIV vaccine remains a global necessity for preventing HIV infection and reducing the burden of AIDS. While this goal represents a formidable challenge, the modest efficacy of the RV144 trial indicates that multicomponent vaccination regimens that elicit both cellular and humoral immune responses can prevent HIV infection in humans. However, whether protein immunizations synergize with DNA prime-viral vector boosts to enhance cellular and humoral immune responses remains poorly understood. We addressed this question in a nonhuman primate model, and our findings show benefit for sequential protein immunization combined with a potent adjuvant in boosting antibody titers induced by a preceding DNA/MVA immunization. This promising strategy can be further developed to enhance neutralizing antibody responses and boost CD8 T cells to provide robust protection and viral control. PMID- 27466415 TI - Characterization of Simian Immunodeficiency Virus Variants Anatomically Compartmentalized in Plasma and Milk in Chronically Infected African Green Monkeys. AB - Unlike human immunodeficiency virus type 1 (HIV-1)-infected humans, African origin, natural simian immunodeficiency virus (SIV) hosts, such as African green monkeys (AGMs), sustain nonpathogenic SIV infections and rarely vertically transmit SIV to their infants. Interestingly, chronically SIV-infected AGMs have anatomically compartmentalized SIV variants in plasma and milk, whereas humans and SIV-infected rhesus monkeys (RMs), Asian-origin nonnatural SIV hosts, do not exhibit this compartmentalization. Thus, it is possible that AGM SIV populations in milk have unique phenotypic features that contribute to the low postnatal transmission rates observed in this natural host species. In this study, we explored this possibility by characterizing the infectivity, tropism, and neutralization susceptibility of plasma and milk SIVsab env variants isolated from chronically SIVsab92018ivTF-infected AGMs. AGM plasma and milk SIVsab env pseudovirus variants exhibited similar infectivities, neutralization susceptibilities to autologous and heterologous plasma, and chemokine coreceptor usages for cell entry, suggesting similar abilities to initiate infection in a new host. We also assessed the cytokine milieu in SIV-infected AGM milk and compared it to that of SIV-infected RMs. MIP-1beta, granulocyte colony stimulating factor (G-CSF), interleukin-12/23 (IL-12/23), and IL-13 trended significantly higher in SIV-infected AGM milk than in that of RMs, while IL-18 and IL-6 trended significantly higher in SIV-infected RM milk than in that of AGMs. Taken together, our findings imply that nonviral maternal factors, such as the cytokine milieu, rather than unique characteristics of SIV populations in the milk contribute to the low postnatal transmission rates observed in AGMs. IMPORTANCE: Due to the ongoing global incidence of pediatric HIV-1 infections, including many that occur via breastfeeding, development of effective vaccine strategies capable of preventing vertical HIV transmission through breastfeeding remains an important goal. Unlike HIV-1-infected humans, African green monkeys (AGMs), the natural SIV host species, sustain nonpathogenic SIV infections, rarely transmit the virus postnatally to their infants, and exhibit anatomically compartmentalized SIV populations in milk and plasma. Identifying unique features of the anatomically compartmentalized milk SIV populations could enhance our understanding of how AGMs may have evolved to avoid transmission through breastfeeding. While this study identified limited phenotypic distinctions between AGM plasma and milk SIV populations, potential differences in milk cytokine profiles of natural and nonnatural SIV hosts were observed. These findings imply the potential importance of nonviral factors in natural SIV host species, such as innate SIV/HIV immune factors in milk, as a means of naturally preventing vertical transmission. PMID- 27466416 TI - Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency. AB - IFI16 (interferon gamma-inducible protein 16) recognizes nuclear episomal herpesvirus (Kaposi's sarcoma-associated herpesvirus [KSHV], Epstein-Barr virus [EBV], and herpes simplex virus 1 [HSV-1]) genomes and induces the inflammasome and interferon beta responses. It also acts as a lytic replication restriction factor and inhibits viral DNA replication (human cytomegalovirus [HCMV] and human papillomavirus [HPV]) and transcription (HSV-1, HCMV, and HPV) through epigenetic modifications of the viral genomes. To date, the role of IFI16 in the biology of latent viruses is not known. Here, we demonstrate that knockdown of IFI16 in the latently KSHV-infected B-lymphoma BCBL-1 and BC-3 cell lines results in lytic reactivation and increases in levels of KSHV lytic transcripts, proteins, and viral genome replication. Similar results were also observed during KSHV lytic cycle induction in TREX-BCBL-1 cells with the doxycycline-inducible lytic cycle switch replication and transcription activator (RTA) gene. Overexpression of IFI16 reduced lytic gene induction by the chemical agent 12-O-tetradecoylphorbol 13-acetate (TPA). IFI16 protein levels were significantly reduced or absent in TPA- or doxycycline-induced cells expressing lytic KSHV proteins. IFI16 is polyubiquitinated and degraded via the proteasomal pathway. The degradation of IFI16 was absent in phosphonoacetic acid-treated cells, which blocks KSHV DNA replication and, consequently, late lytic gene expression. Chromatin immunoprecipitation assays of BCBL-1 and BC-3 cells demonstrated that IFI16 binds to KSHV gene promoters. Uninfected epithelial SLK and osteosarcoma U2OS cells transfected with KSHV luciferase promoter constructs confirmed that IFI16 functions as a transcriptional repressor. These results reveal that KSHV utilizes the innate immune nuclear DNA sensor IFI16 to maintain its latency and repression of lytic transcripts, and a late lytic KSHV gene product(s) targets IFI16 for degradation during lytic reactivation. IMPORTANCE: Like all herpesviruses, latency is an integral part of the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), an etiological agent for many human cancers. Herpesviruses utilize viral and host factors to successfully evade the host immune system to maintain latency. Reactivation is a complex event where the latent episomal viral genome springs back to active transcription of lytic cycle genes. Our studies reveal that KSHV has evolved to utilize the innate immune sensor IFI16 to keep lytic cycle transcription in dormancy. We demonstrate that IFI16 binds to the lytic gene promoter, acts as a transcriptional repressor, and thereby helps to maintain latency. We also discovered that during the late stage of lytic replication, KSHV selectively degrades IFI16, thus relieving transcriptional repression. This is the first report to demonstrate the role of IFI16 in latency maintenance of a herpesvirus, and further understanding will lead to the development of strategies to eliminate latent infection. PMID- 27466417 TI - Multiple Transcripts Encode Full-Length Human Cytomegalovirus IE1 and IE2 Proteins during Lytic Infection. AB - Expression of the human cytomegalovirus (HCMV) IE1 and IE2 proteins is critical for the establishment of lytic infection and reactivation from viral latency. Defining the mechanisms controlling IE1 and IE2 expression is therefore important for understanding how HCMV regulates its replicative cycle. Here we identify several novel transcripts encoding full-length IE1 and IE2 proteins during HCMV lytic replication. Two of the alternative major immediate early (MIE) transcripts initiate in the first intron, intron A, of the previously defined MIE transcript, while others extend the 5' untranslated region. Each of the MIE transcripts associates with polyribosomes in infected cells and therefore contributes to IE1 and IE2 protein levels. Surprisingly, deletion of the core promoter region of the major immediate early promoter (MIEP) from a plasmid containing the MIE genomic locus did not completely abrogate IE1 and IE2 expression. Instead, deletion of the MIEP core promoter resulted in increased expression of alternative MIE transcripts, suggesting that the MIEP suppresses the activity of the alternative MIE promoters. While the canonical MIE mRNA was the most abundant transcript at immediate early times, the novel MIE transcripts accumulated to levels equivalent to that of the known MIE transcript later in infection. Using two HCMV recombinants, we found that sequences in intron A of the previously defined MIE transcript are required for efficient IE1 and IE2 expression and viral replication. Together, our results identify new regulatory sequences controlling IE1 and IE2 expression and suggest that multiple transcription units act in concert to regulate IE1 and IE2 expression during lytic infection. IMPORTANCE: The HCMV IE1 and IE2 proteins are critical regulators of HCMV replication, both during primary infection and reactivation from viral latency. This study expands our understanding of the sequences controlling IE1 and IE2 expression by defining novel transcriptional units controlling the expression of full-length IE1 and IE2 proteins. Our results suggest that alternative promoters may allow for IE1 and IE2 expression when MIEP activity is limiting, as occurs in latently infected cells. PMID- 27466418 TI - Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion. AB - The highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) cause significant morbidity and morality. There is currently no approved therapeutic for highly pathogenic coronaviruses, even as MERS-CoV is spreading throughout the Middle East. We previously screened a library of FDA-approved drugs for inhibitors of coronavirus replication in which we identified Abelson (Abl) kinase inhibitors, including the anticancer drug imatinib, as inhibitors of both SARS-CoV and MERS CoV in vitro Here we show that the anti-CoV activity of imatinib occurs at the early stages of infection, after internalization and endosomal trafficking, by inhibiting fusion of the virions at the endosomal membrane. We specifically identified the imatinib target, Abelson tyrosine-protein kinase 2 (Abl2), as required for efficient SARS-CoV and MERS-CoV replication in vitro These data demonstrate that specific approved drugs can be characterized in vitro for their anticoronavirus activity and used to identify host proteins required for coronavirus replication. This type of study is an important step in the repurposing of approved drugs for treatment of emerging coronaviruses. IMPORTANCE: Both SARS-CoV and MERS-CoV are zoonotic infections, with bats as the primary source. The 2003 SARS-CoV outbreak began in Guangdong Province in China and spread to humans via civet cats and raccoon dogs in the wet markets before spreading to 37 countries. The virus caused 8,096 confirmed cases of SARS and 774 deaths (a case fatality rate of ~10%). The MERS-CoV outbreak began in Saudi Arabia and has spread to 27 countries. MERS-CoV is believed to have emerged from bats and passed into humans via camels. The ongoing outbreak of MERS-CoV has resulted in 1,791 cases of MERS and 640 deaths (a case fatality rate of 36%). The emergence of SARS-CoV and MERS-CoV provides evidence that coronaviruses are currently spreading from zoonotic sources and can be highly pathogenic, causing serious morbidity and mortality in humans. Treatment of SARS-CoV and MERS-CoV infection is limited to providing supportive therapy consistent with any serious lung disease, as no specific drugs have been approved as therapeutics. Highly pathogenic coronaviruses are rare and appear to emerge and disappear within just a few years. Currently, MERS-CoV is still spreading, as new infections continue to be reported. The outbreaks of SARS-CoV and MERS-CoV and the continuing diagnosis of new MERS cases highlight the need for finding therapeutics for these diseases and potential future coronavirus outbreaks. Screening FDA-approved drugs streamlines the pipeline for this process, as these drugs have already been tested for safety in humans. PMID- 27466419 TI - Generation of Long-Lived Bone Marrow Plasma Cells Secreting Antibodies Specific for the HIV-1 gp41 Membrane-Proximal External Region in the Absence of Polyreactivity. AB - An effective preventive vaccine is highly sought after in order to stem the current HIV-1 pandemic. Both conservation of contiguous gp41 membrane-proximal external region (MPER) amino acid sequences across HIV-1 clades and the ability of anti-MPER broadly neutralizing antibodies (BNAbs) to block viral hemifusion/fusion establish the MPER as a prime vaccination target. In earlier studies, we described the development of an MPER vaccine formulation that takes advantage of liposomes to array the MPER on a lipid bilayer surface, paralleling its native configuration on the virus membrane while also incorporating molecular adjuvant and CD4 T cell epitope cargo. Here we demonstrate that several immunizations with MPER/liposomes induce high levels of bone marrow long-lived plasma cell (LLPC) antibody production. Single-cell immunoglobulin gene retrieval analysis shows that these plasma cells are derived from a germ line repertoire of B cells with a diverse representation of immunoglobulin genes, exhibiting antigen driven positive selection. Characterization of LLPC recombinant monoclonal antibodies (rMAbs) indicates that antigen recognition is achieved through convergence on a common epitopic focus by utilizing various complementarity determining region H3 (CDRH3) lengths. Importantly, the vast majority of rMAbs produced from these cells lack polyreactivity yet manifest antigen specificity in the context of lipids, shaping MPER-specific paratopes through selective pressure. Taken together, these findings demonstrate that the MPER is a vaccine target with minimal risk of generating off-target autoimmunity. IMPORTANCE: A useful vaccine must generate desired long-term, antigen-specific antibody responses devoid of polyreactivity or autoreactivity. The common polyreactive features of some HIV-1 BNAbs have raised concern about elicitation of anti-MPER antibodies. Utilizing single-LLPC repertoire analysis and biophysical characterization of anti-MPER rMAbs, we show that their fine specificities require a structural fitness of the antibody combining site involving heavy and light chain variable domains shaped by somatic hypermutation and affinity maturation of B cells in the germinal center. Perhaps more importantly, our results demonstrate that the majority of MPER-specific antibodies are not inherently polyspecific and/or autoreactive, suggesting that polyreactivity of MPER-specific antibodies is separable from their antigen specificity. PMID- 27466420 TI - Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion. AB - PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13 into recipient mice that had cleared an acute infection. We observed that LCMV specific CD8 T cells from chronically infected mice maintained their surface expression of PD-1 even after transfer into acute immune mice until day 45 posttransfer. Interestingly, the PD-1 transcriptional regulatory region continued to remain unmethylated in these donor CD8 T cells generated from a chronic infection. The observed maintenance of PD-1 surface expression and the demethylated PD-1 promoter were not a result of residual antigen in the recipient mice, because similar results were seen when chronic infection-induced effector cells were transferred into mice infected with a variant strain of LCMV (LCMV V35A) bearing a mutation in the cognate major histocompatibility complex class I (MHC-I) epitope that is recognized by the donor CD8 T cells. Importantly, the maintenance of PD-1 promoter demethylation in memory CD8 T cells was coupled with impaired clonal expansion and higher PD-1 re-expression upon secondary challenge. These data show that the imprinting of the epigenetic program of the inhibitory receptor PD-1 occurs during the effector phase of chronic viral infection. IMPORTANCE: Since PD-1 is a major inhibitory receptor regulating T cell dysfunction during chronic viral infection and cancers, a better understanding of the mechanisms that regulate PD-1 expression is important. In this work, we demonstrate that the PD-1 epigenetic program in antigen-specific CD8 T cells is fixed during the priming phase of chronic infection. PMID- 27466421 TI - Constitutively Active IRF7/IRF3 Fusion Protein Completely Protects Swine against Foot-and-Mouth Disease. AB - Foot-and-mouth disease (FMD) remains one of the most devastating livestock diseases around the world. Several serotype-specific vaccine formulations exist, but they require about 5 to 7 days to induce protective immunity. Our previous studies have shown that a constitutively active fusion protein of porcine interferon (IFN) regulatory factors (IRF) 7 and 3 [IRF7/3(5D)] strongly induced type I IFN and antiviral genes in vitro and prevented mortality in an FMD mouse model when delivered with a replication-defective adenoviral vector [Ad5 poIRF7/3(5D)]. Here, we demonstrate that pigs treated with 10(8), 10(9), or 10(10) PFU of Ad5-poIRF7/3(5D) 24 h before FMDV challenge were fully protected from FMD clinical signs and did not develop viremia, virus shedding or antibodies against FMDV nonstructural proteins. Pigs treated with Ad5-poIRF7/3(5D) had higher levels of IFN and antiviral activity in serum, and upregulated expression of several IFN-stimulated genes in peripheral blood mononuclear cells, compared to pigs treated with Ad5-Blue vector control. Importantly, treatment of porcine cultured cells with Ad5-poIRF7/3(5D) inhibited the replication of all 7 FMDV serotypes. In vitro experiments using cultured embryonic fibroblasts derived from IFN receptor knockout mice suggested that the antiviral response induced by Ad5 poIRF7/3(5D) was dependent on type I and III IFN pathways; however, experiments with mice demonstrated that a functional type I IFN pathway mediates Ad5 poIRF7/3(5D) protection conferred in vivo Our studies demonstrate that inoculation with Ad5-poIRF7/3(5D) completely protects swine against FMD by inducing a strong type I IFN response and highlights its potential application to rapidly and effectively prevent FMDV replication and dissemination. IMPORTANCE: Foot-and-mouth disease virus (FMDV) causes a fast-spreading disease that affects farm animals, with economically and socially devastating consequences. Our study shows that inoculation with a constitutively active transcription factor, namely, a fusion protein of porcine interferon (IFN) regulatory factors (IRF) 7 and 3 delivered by an adenovirus vector [Ad5-poIRF7/3(5D)], is a new effective treatment to prevent FMD in swine. Animals pretreated with Ad5-poIRF7/3(5D) 1 day before being exposed to FMDV were completely protected from viral replication and clinical disease. It is noteworthy that the doses of Ad5-poIRF7/3(5D) required for protection are lower than those previously reported for similar approaches using Ad5 vectors delivering type I, II, or III IFN, suggesting that this novel strategy would be economically appealing to counteract FMD. Our results also indicate that a dynamic interplay among different components of pigs' innate immune defenses allows potent antiviral effects after Ad5-poIF7/3(5D) administration. PMID- 27466422 TI - Replication of Human Norovirus RNA in Mammalian Cells Reveals Lack of Interferon Response. AB - Human noroviruses (HuNoVs), named after the prototype strain Norwalk virus (NV), are a leading cause of acute gastroenteritis outbreaks worldwide. Studies on the related murine norovirus (MNV) have demonstrated the importance of an interferon (IFN) response in host control of virus replication, but this remains unclear for HuNoVs. Despite the lack of an efficient cell culture infection system, transfection of stool-isolated NV RNA into mammalian cells leads to viral RNA replication and virus production. Using this system, we show here that NV RNA replication is sensitive to type I (alpha/beta) and III (interleukin-29 [IL-29]) IFN treatment. However, in cells capable of a strong IFN response to Sendai virus (SeV) and poly(I.C), NV RNA replicates efficiently and generates double-stranded RNA without inducing a detectable IFN response. Replication of HuNoV genogroup GII.3 strain U201 RNA, generated from a reverse genetics system, also does not induce an IFN response. Consistent with a lack of IFN induction, NV RNA replication is enhanced neither by neutralization of type I/III IFNs through neutralizing antibodies or the soluble IFN decoy receptor B18R nor by short hairpin RNA (shRNA) knockdown of mitochondrial antiviral signaling protein (MAVS) or interferon regulatory factor 3 (IRF3) in the IFN induction pathways. In contrast to other positive-strand RNA viruses that block IFN induction by targeting MAVS for degradation, MAVS is not degraded in NV RNA-replicating cells, and an SeV-induced IFN response is not blocked. Together, these results indicate that HuNoV RNA replication in mammalian cells does not induce an IFN response, suggesting that the epithelial IFN response may play a limited role in host restriction of HuNoV replication. IMPORTANCE: Human noroviruses (HuNoVs) are a leading cause of epidemic gastroenteritis worldwide. Due to lack of an efficient cell culture system and robust small-animal model, little is known about the innate host defense to these viruses. Studies on murine norovirus (MNV) have shown the importance of an interferon (IFN) response in host control of MNV replication, but this remains unclear for HuNoVs. Here, we investigated the IFN response to HuNoV RNA replication in mammalian cells using Norwalk virus stool RNA transfection, a reverse genetics system, IFN neutralization reagents, and shRNA knockdown methods. Our results show that HuNoV RNA replication in mammalian epithelial cells does not induce an IFN response, nor can it be enhanced by blocking the IFN response. These results suggest a limited role of the epithelial IFN response in host control of HuNoV RNA replication, providing important insights into our understanding of the host defense to HuNoVs that differs from that to MNV. PMID- 27466423 TI - Modification of Three Amino Acids in Sodium Taurocholate Cotransporting Polypeptide Renders Mice Susceptible to Infection with Hepatitis D Virus In Vivo. AB - Sodium taurocholate cotransporting polypeptide (NTCP) was identified as a functional receptor for hepatitis D virus (HDV) and its helper hepatitis B virus (HBV). In cultured cell lines, HDV infection through mouse NTCP is restricted by residues 84 to 87 of the receptor. This study shows that mice with these three amino acids altered their corresponding human residues (H84R, T86K, and S87N) in endogenous mouse NTCP support de novo HDV infection in vivo HDV infection was documented by the presence of replicative forms of HDV RNA and HDV proteins in liver cells at day 6 after viral inoculation. Monoclonal antibody specifically binding to the motif centered on K86 in NTCP partially inhibited HDV infection. These studies demonstrated specific interaction between the receptor and the viral envelopes in vivo and established a novel mouse model with minimal genetic manipulation for studying HDV infection. The model will also be useful for evaluating entry inhibitors against HDV and its helper HBV. IMPORTANCE: NTCP was identified as a functional receptor for both HDV and HBV in cell cultures. We recently showed that neonatal C57BL/6 transgenic (Tg) mice exogenously expressing human NTCP (hNTCP-Tg) in liver support transient HDV infection. In this study, we introduced alterations of three amino acids in the endogenous NTCP of FVB mice through genome editing. The mice with the humanized NTCP residues (H84R, T86K, and S87N) are susceptible to HDV infection, and the infection can be established in both neonatal and adult mice with this editing. We also developed a monoclonal antibody specifically targeting the region of NTCP centered on lysine residue 86, and it can differentiate the modified mouse NTCP from that of the wild type and partially inhibited HDV infection. These studies shed new light on NTCP-mediated HDV infection in vivo, and the NTCP-modified mice provide a useful animal model for studying HDV infection and evaluating antivirals against the infection. PMID- 27466424 TI - Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique. AB - HIV-1 establishes a pool of latently infected cells early following infection. New therapeutic approaches aiming at diminishing this persisting reservoir by reactivation of latently infected cells are currently being developed and tested. However, the reactivation kinetics of viral mRNA and viral protein production, and their respective consequences for phenotypical changes in infected cells that might enable immune recognition, remain poorly understood. We adapted a novel approach to assess the dynamics of HIV-1 mRNA and protein expression in latently and newly infected cells on the single-cell level by flow cytometry. This technique allowed the simultaneous detection of gagpol mRNA, intracellular p24 Gag protein, and cell surface markers. Following stimulation of latently HIV-1 infected J89 cells with human tumor necrosis factor alpha (hTNF-alpha)/romidepsin (RMD) or HIV-1 infection of primary CD4(+) T cells, four cell populations were detected according to their expression levels of viral mRNA and protein. gagpol mRNA in J89 cells was quantifiable for the first time 3 h after stimulation with hTNF-alpha and 12 h after stimulation with RMD, while p24 Gag protein was detected for the first time after 18 h poststimulation. HIV-1-infected primary CD4(+) T cells downregulated CD4, BST-2, and HLA class I expression at early stages of infection, proceeding Gag protein detection. In conclusion, here we describe a novel approach allowing quantification of the kinetics of HIV-1 mRNA and protein synthesis on the single-cell level and phenotypic characterization of HIV-1-infected cells at different stages of the viral life cycle. IMPORTANCE: Early after infection, HIV-1 establishes a pool of latently infected cells, which hide from the immune system. Latency reversal and immune-mediated elimination of these latently infected cells are some of the goals of current HIV-1 cure approaches; however, little is known about the HIV-1 reactivation kinetics following stimulation with latency-reversing agents. Here we describe a novel approach allowing for the first time quantification of the kinetics of HIV-1 mRNA and protein synthesis after latency reactivation or de novo infection on the single-cell level using flow cytometry. This new technique furthermore enabled the phenotypic characterization of latently infected and de novo-infected cells dependent on the presence of viral RNA or protein. PMID- 27466425 TI - HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer. AB - While combined antiretroviral therapy (cART) can result in undetectable plasma viral loads, it does not eradicate HIV infection. Furthermore, HIV-infected individuals while on cART remain at an increased risk of developing serious comorbidities, such as cancer, neurological disease, and atherosclerosis, suggesting that during cART, tissue-based HIV may contribute to such pathologies. We obtained DNA and RNA env, nef, and pol sequences using single-genome sequencing from postmortem tissues of three HIV(+) cART-treated (cART(+)) individuals with undetectable viral load and metastatic cancer at death and performed time-scaled Bayesian evolutionary analyses. We used a sensitive in situ hybridization technique to visualize HIV gag-pol mRNA transcripts in cerebellum and lymph node tissues from one patient. Tissue-associated virus evolved at similar rates in cART(+) and cART-naive (cART(-)) patients. Phylogenetic trees were characterized by two distinct features: (i) branching patterns consistent with constant viral evolution and dispersal among tissues and (ii) very recently derived clades containing both DNA and RNA sequences from multiple tissues. Rapid expansion of virus near death corresponded to wide-spread metastasis. HIV RNA(+) cells clustered in cerebellum tissue but were dispersed in lymph node tissue, mirroring the evolutionary patterns observed for that patient. Activated, infiltrating macrophages were associated with HIV RNA. Our data provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread. IMPORTANCE: Combined antiretroviral therapy (cART) reduces plasma HIV to undetectable levels; however, removal of cART results in plasma HIV rebound, thus highlighting its inability to entirely rid the body of infection. Additionally, HIV-infected individuals on cART remain at high risk of serious diseases, which suggests a contribution from residual HIV. In this study, we isolated and sequenced HIV from postmortem tissues from three HIV(+) cART(+) individuals who died with metastatic cancer and had no detectable plasma viral load. Using high resolution evolutionary analyses, we found that tissue-based HIV continues to replicate, evolve, and migrate among tissues during cART. Furthermore, cancer onset and metastasis coincided with increased HIV expansion, suggesting a linked mechanism. HIV-expressing cells were associated with tissue macrophages, a target of HIV infection. Our results suggest the importance of tissues, and macrophages in particular, as a target for novel anti-HIV therapies. PMID- 27466426 TI - HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads. AB - HIV infection treatment strategies have historically defined effectiveness through measuring patient plasma HIV RNA. While combined antiretroviral therapy (cART) can reduce plasma viral load (pVL) to undetectable levels, the degree that HIV is eliminated from other anatomical sites remains unclear. We investigated the HIV DNA levels in 229 varied autopsy tissues from 20 HIV-positive (HIV(+)) cART-treated study participants with low or undetectable plasma VL and cerebrospinal fluid (CSF) VL prior to death who were enrolled in the National Neurological AIDS Bank (NNAB) longitudinal study and autopsy cohort. Extensive medical histories were obtained for each participant. Autopsy specimens, including at least six brain and nonbrain tissues per participant, were reviewed by study pathologists. HIV DNA, measured in tissues by quantitative and droplet digital PCR, was identified in 48/87 brain tissues and 82/142 nonbrain tissues at levels >200 HIV copies/million cell equivalents. No participant was found to be completely free of tissue HIV. Parallel sequencing studies from some tissues recovered intact HIV DNA and RNA. Abnormal histological findings were identified in all participants, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. All brain tissues demonstrated some degree of pathology. Ninety-five percent of participants had some degree of atherosclerosis, and 75% of participants died with cancer. This study assists in characterizing the anatomical locations of HIV, in particular, macrophage-rich tissues, such as the central nervous system (CNS) and testis. Additional studies are needed to determine if the HIV recovered from tissues promotes the pathogenesis of inflammatory diseases, such as HIV-associated neurocognitive disorders, cancer, and atherosclerosis. IMPORTANCE: It is well-known that combined antiretroviral therapy (cART) can reduce plasma HIV to undetectable levels; however, cART cannot completely clear HIV infection. An ongoing question is, "Where is HIV hiding?" A well-studied HIV reservoir is "resting" T cells, which can be isolated from blood products and succumb to cART once activated. Less-studied reservoirs are anatomical tissue samples, which have unknown cART penetration, contain a comparably diverse spectrum of potentially HIV-infected immune cells, and are important since <2% of body lymphocytes actually reside in blood. We examined 229 varied autopsy specimens from 20 HIV(+) participants who died while on cART and identified that >50% of tissues were HIV infected. Additionally, we identified considerable pathology in participants' tissues, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. This study substantiates that tissue associated HIV is present despite cART and can inform future studies into HIV persistence. PMID- 27466427 TI - The Ubiquitin Ligase Itch and Ubiquitination Regulate BFRF1-Mediated Nuclear Envelope Modification for Epstein-Barr Virus Maturation. AB - The cellular endosomal sorting complex required for transport (ESCRT) was recently found to mediate important morphogenesis processes at the nuclear envelope (NE). We previously showed that the Epstein-Barr virus (EBV) BFRF1 protein recruits the ESCRT-associated protein Alix to modulate NE structure and promote EBV nuclear egress. Here, we uncover new cellular factors and mechanisms involved in this process. BFRF1-induced NE vesicles are similar to those observed following EBV reactivation. BFRF1 is ubiquitinated, and elimination of possible ubiquitination by either lysine mutations or fusion of a deubiquitinase hampers NE-derived vesicle formation and virus maturation. While it interacts with multiple Nedd4-like ubiquitin ligases, BFRF1 preferentially binds Itch ligase. We show that Itch associates with Alix and BFRF1 and is required for BFRF1-induced NE vesicle formation. Our data demonstrate that Itch, ubiquitin, and Alix control the BFRF1-mediated modulation of the NE and EBV maturation, uncovering novel regulatory mechanisms of nuclear egress of viral nucleocapsids. IMPORTANCE: The nuclear envelope (NE) of eukaryotic cells not only serves as a transverse scaffold for cellular processes, but also as a natural barrier for most DNA viruses that assemble their nucleocapsids in the nucleus. Previously, we showed that the cellular endosomal sorting complex required for transport (ESCRT) machinery is required for the nuclear egress of EBV. Here, we further report the molecular interplay among viral BFRF1, the ESCRT adaptor Alix, and the ubiquitin ligase Itch. We found that BFRF1-induced NE vesicles are similar to those observed following EBV reactivation. The lysine residues and the ubiquitination of BFRF1 regulate the formation of BFRF1-induced NE-derived vesicles and EBV maturation. During the process, a ubiquitin ligase, Itch, preferably associates with BFRF1 and is required for BFRF1-induced NE vesicle formation. Therefore, our data indicate that Itch, ubiquitin, and Alix control the BFRF1-mediated modulation of the NE, suggesting novel regulatory mechanisms for ESCRT-mediated NE modulation. PMID- 27466428 TI - Existence of Two Distinct Infectious Endogenous Retroviruses in Domestic Cats and Their Different Strategies for Adaptation to Transcriptional Regulation. AB - Endogenous retroviruses (ERVs) are the remnants of ancient retroviral infections of germ cells. Previous work identified one of the youngest feline ERV groups, ERV-DC, and reported that two ERV-DC loci, ERV-DC10 and ERV-DC18 (ERV-DC10/DC18), can replicate in cultured cells. Here, we identified another replication competent provirus, ERV-DC14, on chromosome C1q32. ERV-DC14 differs from ERV DC10/DC18 in its phylogeny, receptor usage, and, most notably, transcriptional activities; although ERV-DC14 can replicate in cultured cells, it cannot establish a persistent infection owing to its low transcriptional activity. Furthermore, we examined ERV-DC transcription and its regulation in feline tissues. Quantitative reverse transcription-PCR (RT-PCR) detected extremely low ERV-DC10 expression levels in feline tissues, and bisulfite sequencing showed that 5' long terminal repeats (LTRs) of ERV-DC10/DC18 are significantly hypermethylated in feline blood cells. Reporter assays found that the 5'-LTR promoter activities of ERV-DC10/DC18 are high, whereas that of ERV-DC14 is low. This difference in promoter activity is due to a single substitution from A to T in the LTR, and reverse mutation at this nucleotide in ERV-DC14 enhanced its replication and enabled it to persistently infect cultured cells. Therefore, ERV DC LTRs can be divided into two types based on this nucleotide, the A type or T type, which have strong or attenuated promoter activity, respectively. Notably, ERV-DCs with T-type LTRs, such as ERV-DC14, have expanded in the cat genome significantly more than A-type ERV-DCs, despite their low promoter activities. Our results provide insights into how the host controls potentially infectious ERVs and, conversely, how ERVs adapt to and invade the host genome. IMPORTANCE: The domestic cat genome contains many endogenous retroviruses, including ERV-DCs. These ERV-DCs have been acquired through germ cell infections with exogenous retroviruses. Some of these ERV-DCs are still capable of producing infectious virions. Hosts must tightly control these ERVs because replication-competent viruses in the genome pose a risk to the host. Here, we investigated how ERV-DCs are adapted by their hosts. Replication-competent viruses with strong promoter activity, such as ERV-DC10 and ERV-DC18, were suppressed by promoter methylation in LTRs. On the other hand, replication-competent viruses with weak promoter activity, such as ERV-DC14, seemed to escape strict control via promoter methylation by the host. Interestingly, ERV-DCs with weak promoter activity, such as ERV-DC14, have expanded in the cat genome significantly more than ERV-DCs with strong promoter activity. Our results improve the understanding of the host-virus conflict and how ERVs adapt in their hosts over time. PMID- 27466429 TI - Crystal Structure of the Human Astrovirus Capsid Protein. AB - Human astrovirus (HAstV) is a leading cause of viral diarrhea in infants and young children worldwide. HAstV is a nonenveloped virus with a T=3 capsid and a positive-sense RNA genome. The capsid protein (CP) of HAstV is synthesized as a 90-kDa precursor (VP90) that can be divided into three linear domains: a conserved N-terminal domain, a hypervariable domain, and an acidic C-terminal domain. Maturation of HAstV requires proteolytic processing of the astrovirus CP both inside and outside the host cell, resulting in the removal of the C-terminal domain and the breakdown of the rest of the CP into three predominant protein species with molecular masses of ~34, 27/29, and 25/26 kDa, respectively. We have now solved the crystal structure of VP90(71-415) (amino acids [aa] 71 to 415 of VP90) of human astrovirus serotype 8 at a 2.15-A resolution. VP90(71-415) encompasses the conserved N-terminal domain of VP90 but lacks the hypervariable domain, which forms the capsid surface spikes. The structure of VP90(71-415) is comprised of two domains: an S domain, which adopts the typical jelly-roll beta barrel fold, and a P1 domain, which forms a squashed beta-barrel consisting of six antiparallel beta-strands similar to what was observed in the hepatitis E virus (HEV) capsid structure. Fitting of the VP90(71-415) structure into the cryo electron microscopy (EM) maps of HAstV produced an atomic model for a continuous, T=3 icosahedral capsid shell. Our pseudoatomic model of the human HAstV capsid shell provides valuable insights into intermolecular interactions required for capsid assembly and trypsin-mediated proteolytic maturation needed for virus infectivity. Such information has potential applications in the development of a virus-like particle (VLP) vaccine as well as small-molecule drugs targeting astrovirus assembly/maturation. IMPORTANCE: Human astrovirus (HAstV) is a leading cause of viral diarrhea in infants and young children worldwide. As a nonenveloped virus, HAstV exhibits an intriguing feature in that its maturation requires extensive proteolytic processing of the astrovirus capsid protein (CP) both inside and outside the host cell. Mature HAstV contains three predominant protein species, but the mechanism for acquired infectivity upon maturation is unclear. We have solved the crystal structure of VP90(71-415) of human astrovirus serotype 8. VP90(71-415) encompasses the conserved N-terminal domain of the viral CP. Fitting of the VP90(71-415) structure into the cryo-EM maps of HAstV produced an atomic model for the T=3 icosahedral capsid. Our model of the HAstV capsid provides valuable insights into intermolecular interactions required for capsid assembly and trypsin-mediated proteolytic maturation. Such information has potential applications in the development of a VLP vaccine as well as small molecule drugs targeting astrovirus assembly/maturation. PMID- 27466430 TI - Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection. AB - Gammaherpesviruses establish persistent, systemic infections and cause cancers. Murid herpesvirus 4 (MuHV-4) provides a unique window into the early events of host colonization. It spreads via lymph nodes. While dendritic cells (DC) pass MuHV-4 to lymph node B cells, subcapsular sinus macrophages (SSM), which capture virions from the afferent lymph, restrict its spread. Understanding how this restriction works offers potential clues to a more comprehensive defense. Type I interferon (IFN-I) blocked SSM lytic infection and reduced lytic cycle independent viral reporter gene expression. Plasmacytoid DC were not required, but neither were SSM the only source of IFN-I, as IFN-I blockade increased infection in both intact and SSM-depleted mice. NK cells restricted lytic SSM infection independently of IFN-I, and SSM-derived virions spread to the spleen only when both IFN-I responses and NK cells were lacking. Thus, multiple innate defenses allowed SSM to adsorb virions from the afferent lymph with relative impunity. Enhancing IFN-I and NK cell recruitment could potentially also restrict DC infection and thus improve infection control. IMPORTANCE: Human gammaherpesviruses cause cancers by infecting B cells. However, vaccines designed to block virus binding to B cells have not stopped infection. Using a related gammaherpesvirus of mice, we have shown that B cells are infected not via cell free virus but via infected myeloid cells. This suggests a different strategy to stop B cell infection: stop virus production by myeloid cells. Not all myeloid infection is productive. We show that subcapsular sinus macrophages, which do not pass infection to B cells, restrict gammaherpesvirus production by recruiting type I interferons and natural killer cells. Therefore, a vaccine that speeds the recruitment of these defenses might stop B cell infection. PMID- 27466432 TI - Predicting Salmonella Typhimurium reductions in poultry ground carcasses. AB - To improve understanding of Salmonella Typhimurium LT2 inactivation in ground poultry carcasses, a series of experiments were carried out at multiple temperatures. Subsequently, a non-linear model was developed to predict Salmonella inactivation at composting and low rendering temperatures. The Salmonella inactivation study was conducted using bench-top experiments at 38, 48, 55, 62.5, 70, and 78 degrees C in mixed and non-mixed reactors using ground poultry carcasses as a feedstock. Subsequently, these observations were used for developing a non-linear model. The model predictions were compared with the observations of a different set of experiments. The comparisons among predictions and observations showed that the model predictions are reasonable and can be useful to determine the time required for Salmonella inactivation in poultry carcasses at multiple temperatures. Results showed that at composting conditions, when temperature varies between 48 and 62.5 degrees C, Salmonella survival can prolong between 10,000 and 25,000 min (7 to 17 d). If ambient temperature is maintained at low temperature rendering range (70 to 78 degrees C), then Salmonella survival can last for 90 to 120 minutes. We anticipate that this study will help in improving the existing understanding of Salmonella survival in poultry carcasses. PMID- 27466431 TI - Molecular cloning of chicken IL-7 and characterization of its antiviral activity against IBDV in vivo. AB - Mammalian interleukin-7 (IL-7) is able to stimulate lymphocyte proliferation and maturation, and reverse immunosuppression. However, whether poultry IL-7 has similar functions remains unclear. Chicken infectious bursal disease virus (IBDV) causes serious immunosuppression in chicken due to virus-induced immune disorder. Whether chicken IL-7 (chIL-7) has the ability to restore the immunity during IBDV induced immunosuppression is not clear. To test this, we amplified chIL-7 gene by RT-PCR, prepared recombinant chIL-7 using HEK293T cells and treated the chicken with the chIL-7 prior to IBDV infection. Our results indicate that chIL-7 promoted mouse B cell proliferation in vitro, and significantly reduced virus titer in bursal tissue and chicken morbidity of IBDV-infected chicken. Mechanically, chIL-7 induced chicken lymphocyte proliferation and interferon gamma production, but down-regulated TGF-beta expression, suggesting that chIL-7 has the ability to reverse IBDV-induced immunosuppression and might be a potential therapeutic agent for prevention and treatment of infectious bursal disease. PMID- 27466433 TI - Molecular cloning, characterization, and expression analysis of ghrelin and cholecystokinin in the pigeon (Columba livia). AB - Ghrelin and cholecystokinin (CCK) are multifunctional peptides. In the current study, complete sequences of ghrelin (800 bp) and CCK (739 bp) were firstly cloned in Columba livia by using rapid amplification of cDNA ends (RACE) method. The open reading frames of ghrelin (351bp) and CCK (393bp) encoded 116 amino acids and 130 amino acids, respectively. Sequence comparison indicated that pigeon ghrelin and CCK shared high identity with those reported in other avian species. Quantitative real-time PCR analysis found that ghrelin and CCK mRNAs expressed in three intestinal segments of pigeon during development. Both ghrelin and CCK showed generally higher expressions at days posthatch than embryonic periods regardless of intestinal segments. In duodenum and ileum, the expressions of ghrelin and CCK mRNA reached the peak values at 8 d posthatch. Jejunum CCK mRNA level increased linearly after hatching, and reached the highest point at posthatch 28 d. Based on documented effects of long chain fatty acids (LCFAs) on pigeon ghrelin and CCK expression were also investigated in vitro. Higher concentrations (50 MUM or 250 MUM) of linoleic acid, alpha-linolenic acid or arachidonic acid can significantly increase ghrelin mRNA level in pigeon jejunum. However, for oleic acid, the induction of ghrelin gene expressions needed a lower concentration (5 MUM). 5 MUM of linoleic acid, alpha-linolenic acid or arachidonic acid and 250 MUM palmitic acid repressed CCK expression significantly. A higher concentration (250 MUM) of oleic acid or alpha-linolenic acid can up-regulate CCK mRNA level significantly. Our results indicated that ghrelin and CCK may act key functions in pigeon intestine development and their expressions could be regulated by LCFAs. PMID- 27466435 TI - Six ways not to improve patient flow: a qualitative study. AB - BACKGROUND: Although well-established principles exist for improving the timeliness and efficiency of care, many organisations struggle to achieve more than small-scale, localised gains. Where care processes are complex and include segments under different groups' control, the elegant solutions promised by improvement methodologies remain elusive. This study sought to identify common design flaws that limit the impact of flow initiatives. METHODS: This qualitative study was conducted within an explanatory case study of a Canadian regional health system in which multitudinous flow initiatives had yielded no overall improvement in system performance. Interviews with 62 senior, middle and departmental managers, supplemented by ~700 documents on flow initiatives, were analysed using the constant comparative method. RESULTS: Findings suggested that smooth flow depends on linking a defined population to appropriate capacity by means of an efficient process; flawed initiatives reflected failure to consider one or more of these essential elements. Many initiatives focused narrowly on process, failing to consider that the intended population was poorly defined or the needed capacity inaccessible; some introduced capacity for an intended population, but offered no process to link the two. Moreover, interveners were unable to respond effectively when a bottleneck moved to another part of the system. Errors of population, capacity and process, in different combinations, generated six 'formulae for failure'. CONCLUSIONS: Typically, flawed initiatives focused on too small a segment of the patient journey to properly address the impediments to flow. The proliferation of narrowly focused initiatives, in turn, reflected a decentralised system in which responsibility for flow improvement was fragmented. Thus, initiatives' specific design flaws may have their roots in a deeper problem: the lack of a coherent system-level strategy. PMID- 27466434 TI - Thymus transcriptome reveals novel pathways in response to avian pathogenic Escherichia coli infection. AB - Avian pathogenic Escherichia coli (APEC) can cause significant morbidity in chickens. The thymus provides the essential environment for T cell development; however, the thymus transcriptome has not been examined for gene expression in response to APEC infection. An improved understanding of the host genomic response to APEC infection could inform future breeding programs for disease resistance and APEC control. We therefore analyzed the transcriptome of the thymus of birds challenged with APEC, contrasting susceptible and resistant phenotypes. Thousands of genes were differentially expressed in birds of the 5 day post infection (dpi) challenged-susceptible group vs. 5 dpi non-challenged, in 5 dpi challenged-susceptible vs. 5 dpi challenged-resistant birds, as well as in 5 dpi vs. one dpi challenged-susceptible birds. The Toll-like receptor signaling pathway was the major innate immune response for birds to respond to APEC infection. Moreover, lysosome and cell adhesion molecules pathways were common mechanisms for chicken response to APEC infection. The T-cell receptor signaling pathway, cell cycle, and p53 signaling pathways were significantly activated in resistant birds to resist APEC infection. These results provide a comprehensive assessment of global gene networks and biological functionalities of differentially expressed genes in the thymus under APEC infection. These findings provide novel insights into key molecular genetic mechanisms that differentiate host resistance from susceptibility in this primary lymphoid tissue, the thymus. PMID- 27466436 TI - The power of data mining in diagnosis of childhood pneumonia. AB - Childhood pneumonia is the leading cause of death of children under the age of 5 years globally. Diagnostic information on the presence of infection, severity and aetiology (bacterial versus viral) is crucial for appropriate treatment. However, the derivation of such information requires advanced equipment (such as X-rays) and clinical expertise to correctly assess observational clinical signs (such as chest indrawing); both of these are often unavailable in resource-constrained settings. In this study, these challenges were addressed through the development of a suite of data mining tools, facilitating automated diagnosis through quantifiable features. Findings were validated on a large dataset comprising 780 children diagnosed with pneumonia and 801 age-matched healthy controls. Pneumonia was identified via four quantifiable vital signs (98.2% sensitivity and 97.6% specificity). Moreover, it was shown that severity can be determined through a combination of three vital signs and two lung sounds (72.4% sensitivity and 82.2% specificity); addition of a conventional biomarker (C-reactive protein) further improved severity predictions (89.1% sensitivity and 81.3% specificity). Finally, we demonstrated that aetiology can be determined using three vital signs and a newly proposed biomarker (lipocalin-2) (81.8% sensitivity and 90.6% specificity). These results suggest that a suite of carefully designed machine learning tools can be used to support multi-faceted diagnosis of childhood pneumonia in resource constrained settings, compensating for the shortage of expensive equipment and highly trained clinicians. PMID- 27466437 TI - Evolving synergetic interactions. AB - Cooperators forgo their own interests to benefit others. This reduces their fitness and thus cooperators are not likely to spread based on natural selection. Nonetheless, cooperation is widespread on every level of biological organization ranging from bacterial communities to human society. Mathematical models can help to explain under which circumstances cooperation evolves. Evolutionary game theory is a powerful mathematical tool to depict the interactions between cooperators and defectors. Classical models typically involve either pairwise interactions between individuals or a linear superposition of these interactions. For interactions within groups, however, synergetic effects may arise: their outcome is not just the sum of its parts. This is because the payoffs via a single group interaction can be different from the sum of any collection of two player interactions. Assuming that all interactions start from pairs, how can such synergetic multiplayer games emerge from simpler pairwise interactions? Here, we present a mathematical model that captures the transition from pairwise interactions to synergetic multiplayer ones. We assume that different social groups have different breaking rates. We show that non-uniform breaking rates do foster the emergence of synergy, even though individuals always interact in pairs. Our work sheds new light on the mechanisms underlying such synergetic interactions. PMID- 27466439 TI - Structural features of reconstituted wheat wax films. AB - Cuticular waxes are essential for the well-being of all plants, from controlling the transport of water and nutrients across the plant surface to protecting them against external environmental attacks. Despite their significance, our current understanding regarding the structure and function of the wax film is limited. In this work, we have formed representative reconstituted wax film models of controlled thicknesses that facilitated an ex vivo study of plant cuticular wax film properties by neutron reflection (NR). Triticum aestivum L. (wheat) waxes were extracted from two different wheat straw samples, using two distinct extraction methods. Waxes extracted from harvested field-grown wheat straw using supercritical CO2 are compared with waxes extracted from laboratory-grown wheat straw via wax dissolution by chloroform rinsing. Wax films were produced by spin coating the two extracts onto silicon substrates. Atomic force microscopy and cryo-scanning electron microscopy imaging revealed that the two reconstituted wax film models are ultrathin and porous with characteristic nanoscale extrusions on the outer surface, mimicking the structure of epicuticular waxes found upon adaxial wheat leaf surfaces. On the basis of solid-liquid and solid-air NR and ellipsometric measurements, these wax films could be modelled into two representative layers, with the diffuse underlying layer fitted with thicknesses ranging from approximately 65 to 70 A, whereas the surface extrusion region reached heights exceeding 200 A. Moisture-controlled NR measurements indicated that water penetrated extensively into the wax films measured under saturated humidity and under water, causing them to hydrate and swell significantly. These studies have thus provided a useful structural basis that underlies the function of the epicuticular waxes in controlling the water transport of crops. PMID- 27466438 TI - In vitro response of macrophages to ceramic scaffolds used for bone regeneration. AB - Macrophages, the primary cells of the inflammatory response, are major regulators of healing, and mediate both bone fracture healing and the inflammatory response to implanted biomaterials. However, their phenotypic contributions to biomaterial mediated bone repair are incompletely understood. Therefore, we used gene expression and protein secretion analysis to investigate the interactions in vitro between primary human monocyte-derived macrophages and ceramic scaffolds that have been shown to have varying degrees of success in promoting bone regeneration in vivo Specifically, baghdadite (Ca3ZrSi2O9) and strontium hardystonite-gahnite (Sr-Ca2ZnSi2O7-ZnAl2O4) scaffolds were chosen as two materials that enhanced bone regeneration in vivo in large defects under load compared with clinically used tricalcium phosphate-hydroxyapatite (TCP-HA). Principal component analysis revealed that the scaffolds differentially regulated macrophage phenotype. Temporal changes in gene expression included shifts in markers of pro-inflammatory M1, anti-inflammatory M2a and pro-remodelling M2c macrophage phenotypes. Of note, TCP-HA scaffolds promoted upregulation of many M1 related genes and downregulation of many M2a- and M2c-related genes. Effects of the scaffolds on macrophages were attributed primarily to direct cell-scaffold interactions because of only minor changes observed in transwell culture. Ultimately, elucidating macrophage-biomaterial interactions will facilitate the design of immunomodulatory biomaterials for bone repair. PMID- 27466440 TI - Humanoid infers Archimedes' principle: understanding physical relations and object affordances through cumulative learning experiences. AB - Emerging studies indicate that several species such as corvids, apes and children solve 'The Crow and the Pitcher' task (from Aesop's Fables) in diverse conditions. Hidden beneath this fascinating paradigm is a fundamental question: by cumulatively interacting with different objects, how can an agent abstract the underlying cause-effect relations to predict and creatively exploit potential affordances of novel objects in the context of sought goals? Re-enacting this Aesop's Fable task on a humanoid within an open-ended 'learning-prediction abstraction' loop, we address this problem and (i) present a brain-guided neural framework that emulates rapid one-shot encoding of ongoing experiences into a long-term memory and (ii) propose four task-agnostic learning rules (elimination, growth, uncertainty and status quo) that correlate predictions from remembered past experiences with the unfolding present situation to gradually abstract the underlying causal relations. Driven by the proposed architecture, the ensuing robot behaviours illustrated causal learning and anticipation similar to natural agents. Results further demonstrate that by cumulatively interacting with few objects, the predictions of the robot in case of novel objects converge close to the physical law, i.e. the Archimedes principle: this being independent of both the objects explored during learning and the order of their cumulative exploration. PMID- 27466441 TI - Odorant receptors can mediate axonal identity and gene choice via cAMP independent mechanisms. AB - Odorant receptors (ORs) control several aspects of cell fate in olfactory sensory neurons (OSNs), including singular gene choice and axonal identity. The mechanisms of OR-induced axon guidance have been suggested to principally rely on G-protein signalling. Here, we report that for a subset of OSNs, deleting G proteins or altering their levels of signalling does not affect axonal identity. Signalling-deficient ORs or surrogate receptors that are unable to couple to Gs/Golf still provide axons with distinct identities and the anterior-posterior targeting of axons does not correlate with the levels of cAMP produced by genetic modifications. In addition, we refine the models of negative feedback by showing that ectopic ORs can be robustly expressed without suppressing endogenous gene choice. In conclusion, our results uncover a new feature of ORs, showing that they can instruct axonal identity and regulate olfactory map formation independent of canonical G-protein signalling and cAMP production. PMID- 27466443 TI - Characterization of DicB by partially masking its potent inhibitory activity of cell division. AB - DicB, a protein encoded by the Kim (Qin) prophage in Escherichia coli, inhibits cell division through interaction with MinC. Thus far, characterization of DicB has been severely hampered owing to its potent activity which ceases cell division and leads to cell death. In this work, through fusing maltose-binding protein to the N-terminus of DicB (MBP-DicB), we successfully expressed and purified recombinant DicB that enabled in vitro analysis for the first time. More importantly, taking advantage of the reduced inhibitory activity of MBP-DicB, we were able to study its effects on cell growth and morphology. Inhibition of cell growth by MBP-DicB was systematically evaluated using various DicB constructs, and their corresponding effects on cell morphology were also investigated. Our results revealed that the N-terminal segment of DicB plays an essential functional role, in contrast to its C-terminal tail. The N-terminus of DicB is of critical importance as even the first amino acid (following the initial Met) could not be removed, although it could be mutated. This study provides the first glimpse of the molecular determinants underlying DicB's function. PMID- 27466442 TI - Dynamic phosphorylation of RelA on Ser42 and Ser45 in response to TNFalpha stimulation regulates DNA binding and transcription. AB - The NF-kappaB signalling module controls transcription through a network of protein kinases such as the IKKs, as well as inhibitory proteins (IkappaBs) and transcription factors including RelA/p65. Phosphorylation of the NF-kappaB subunits is critical for dictating system dynamics. Using both non-targeted discovery and quantitative selected reaction monitoring-targeted proteomics, we show that the cytokine TNFalpha induces dynamic multisite phosphorylation of RelA at a number of previously unidentified residues. Putative roles for many of these phosphorylation sites on RelA were predicted by modelling of various crystal structures. Stoichiometry of phosphorylation determination of Ser45 and Ser42 revealed preferential early phosphorylation of Ser45 in response to TNFalpha. Quantitative analyses subsequently confirmed differential roles for pSer42 and pSer45 in promoter-specific DNA binding and a role for both of these phosphosites in regulating transcription from the IL-6 promoter. These temporal dynamics suggest that RelA-mediated transcription is likely to be controlled by functionally distinct NF-kappaB proteoforms carrying different combinations of modifications, rather than a simple 'one modification, one effect' system. PMID- 27466445 TI - The impact of seasonality on niche breadth, distribution range and species richness: a theoretical exploration of Janzen's hypothesis. AB - Being invoked as one of the candidate mechanisms for the latitudinal patterns in biodiversity, Janzen's hypothesis states that the limited seasonal temperature variation in the tropics generates greater temperature stratification across elevations, which makes tropical species adapted to narrower ranges of temperatures and have lower effective dispersal across elevations than species in temperate regions. Numerous empirical studies have documented latitudinal patterns in species elevational ranges and thermal niche breadths that are consistent with the hypothesis, but the theoretical underpinnings remain unclear. This study presents the first mathematical model to examine the evolutionary processes that could back up Janzen's hypothesis and assess the effectiveness of limited seasonal temperature variation to promote speciation along elevation in the tropics. Results suggest that trade-offs in thermal tolerances provide a mechanism for Janzen's hypothesis. Limited seasonal temperature variation promotes gradient speciation not due to the reduction in gene flow that is associated with narrow thermal niche, but due to the pleiotropic effects of more stable divergent selection of thermal tolerance on the evolution of reproductive incompatibility. The proposed modelling approach also provides a potential way to test a speciation model against genetic data. PMID- 27466444 TI - Structural dissection of a complex Bacteroides ovatus gene locus conferring xyloglucan metabolism in the human gut. AB - The human gastrointestinal tract harbours myriad bacterial species, collectively termed the microbiota, that strongly influence human health. Symbiotic members of our microbiota play a pivotal role in the digestion of complex carbohydrates that are otherwise recalcitrant to assimilation. Indeed, the intrinsic human polysaccharide-degrading enzyme repertoire is limited to various starch-based substrates; more complex polysaccharides demand microbial degradation. Select Bacteroidetes are responsible for the degradation of the ubiquitous vegetable xyloglucans (XyGs), through the concerted action of cohorts of enzymes and glycan binding proteins encoded by specific xyloglucan utilization loci (XyGULs). Extending recent (meta)genomic, transcriptomic and biochemical analyses, significant questions remain regarding the structural biology of the molecular machinery required for XyG saccharification. Here, we reveal the three dimensional structures of an alpha-xylosidase, a beta-glucosidase, and two alpha l-arabinofuranosidases from the Bacteroides ovatus XyGUL. Aided by bespoke ligand synthesis, our analyses highlight key adaptations in these enzymes that confer individual specificity for xyloglucan side chains and dictate concerted, stepwise disassembly of xyloglucan oligosaccharides. In harness with our recent structural characterization of the vanguard endo-xyloglucanse and cell-surface glycan binding proteins, the present analysis provides a near-complete structural view of xyloglucan recognition and catalysis by XyGUL proteins. PMID- 27466447 TI - The price of being seen to be just: an intention signalling strategy for indirect reciprocity. AB - Cooperation among strangers is a marked characteristic of human sociality. One prominent evolutionary explanation for this form of human cooperation is indirect reciprocity, whereby each individual selectively helps people with a 'good' reputation, but not those with a 'bad' reputation. Some evolutionary analyses have underscored the importance of second-order reputation information (the reputation of a current partner's previous partner) for indirect reciprocity as it allows players to discriminate justified 'good' defectors, who selectively deny giving help to 'bad' partners, from unjustified 'bad' defectors. Nevertheless, it is not clear whether people in fact make use of second-order information in indirect reciprocity settings. As an alternative, we propose the intention signalling strategy, whereby defectors are given the option to abandon a resource as a means of expunging their 'bad' reputation. Our model deviates from traditional modelling approaches in the indirect reciprocity literature in a crucial way-we show that first-order information is sufficient to maintain cooperation if players are given an option to signal their intention. Importantly, our model is robust against invasion by both unconditionally cooperative and uncooperative strategies, a first step towards demonstrating its viability as an evolutionarily stable strategy. Furthermore, in two behavioural experiments, when participants were given the option to abandon a resource so as to mend a tarnished reputation, participants not only spontaneously began to use this option, they also interpreted others' use of this option as a signal of cooperative intent. PMID- 27466448 TI - Plant-soil feedbacks promote negative frequency dependence in the coexistence of two aridland grasses. AB - Understanding the mechanisms of species coexistence is key to predicting patterns of species diversity. Historically, the ecological paradigm has been that species coexist by partitioning resources: as a species increases in abundance, self limitation kicks in, because species-specific resources decline. However, determining coexistence mechanisms has been a particular puzzle for sedentary organisms with high overlap in their resource requirements, such as plants. Recent evidence suggests that plant-associated microbes could generate the stabilizing self-limitation (negative frequency dependence) that is required for species coexistence. Here, we test the key assumption that plant-microbe feedbacks cause such self-limitation. We used competition experiments and modelling to evaluate how two common groups of soil microbes (rhizospheric microbes and biological soil crusts) influenced the self-limitation of two competing desert grass species. Negative feedbacks between the dominant plant competitor and its rhizospheric microbes magnified self-limitation, whereas beneficial interactions between both plant species and biological soil crusts partly counteracted this stabilizing effect. Plant-microbe interactions have received relatively little attention as drivers of vegetation dynamics in dry land ecosystems. Our results suggest that microbial mechanisms can contribute to patterns of plant coexistence in arid grasslands. PMID- 27466446 TI - Neonicotinoid insecticides can serve as inadvertent insect contraceptives. AB - There is clear evidence for sublethal effects of neonicotinoid insecticides on non-target ecosystem service-providing insects. However, their possible impact on male insect reproduction is currently unknown, despite the key role of sex. Here, we show that two neonicotinoids (4.5 ppb thiamethoxam and 1.5 ppb clothianidin) significantly reduce the reproductive capacity of male honeybees (drones), Apis mellifera Drones were obtained from colonies exposed to the neonicotinoid insecticides or controls, and subsequently maintained in laboratory cages until they reached sexual maturity. While no significant effects were observed for male teneral (newly emerged adult) body mass and sperm quantity, the data clearly showed reduced drone lifespan, as well as reduced sperm viability (percentage living versus dead) and living sperm quantity by 39%. Our results demonstrate for the first time that neonicotinoid insecticides can negatively affect male insect reproductive capacity, and provide a possible mechanistic explanation for managed honeybee queen failure and wild insect pollinator decline. The widespread prophylactic use of neonicotinoids may have previously overlooked inadvertent contraceptive effects on non-target insects, thereby limiting conservation efforts. PMID- 27466449 TI - Divergent evolution peaks under intermediate population bottlenecks during bacterial experimental evolution. AB - There is growing evidence that parallel molecular evolution is common, but its causes remain poorly understood. Demographic parameters such as population bottlenecks are predicted to be major determinants of parallelism. Here, we test the hypothesis that bottleneck intensity shapes parallel evolution by elucidating the genomic basis of adaptation to antibiotic-supplemented media in hundreds of populations of the bacterium Pseudomonas fluorescens Pf0-1. As expected, bottlenecking decreased the rate of phenotypic and molecular adaptation. Surprisingly, bottlenecking had no impact on the likelihood of parallel adaptive molecular evolution at a genome-wide scale. However, bottlenecking had a profound impact on the genes involved in antibiotic resistance. Specifically, under either intense or weak bottlenecking, resistance predominantly evolved by strongly beneficial mutations which provide high levels of antibiotic resistance. In contrast with intermediate bottlenecking regimes, resistance evolved by a greater diversity of genetic mechanisms, significantly reducing the observed levels of parallel genetic evolution. Our results demonstrate that population bottlenecking can be a major predictor of parallel evolution, but precisely how may be more complex than many simple theoretical predictions. PMID- 27466450 TI - The Ditylenchus destructor genome provides new insights into the evolution of plant parasitic nematodes. AB - Plant-parasitic nematodes were found in 4 of the 12 clades of phylum Nematoda. These nematodes in different clades may have originated independently from their free-living fungivorous ancestors. However, the exact evolutionary process of these parasites is unclear. Here, we sequenced the genome sequence of a migratory plant nematode, Ditylenchus destructor We performed comparative genomics among the free-living nematode, Caenorhabditis elegans and all the plant nematodes with genome sequences available. We found that, compared with C. elegans, the core developmental control processes underwent heavy reduction, though most signal transduction pathways were conserved. We also found D. destructor contained more homologies of the key genes in the above processes than the other plant nematodes. We suggest that Ditylenchus spp. may be an intermediate evolutionary history stage from free-living nematodes that feed on fungi to obligate plant parasitic nematodes. Based on the facts that D. destructor can feed on fungi and has a relatively short life cycle, and that it has similar features to both C. elegans and sedentary plant-parasitic nematodes from clade 12, we propose it as a new model to study the biology, biocontrol of plant nematodes and the interaction between nematodes and plants. PMID- 27466451 TI - Ocean acidification affects fish spawning but not paternity at CO2 seeps. AB - Fish exhibit impaired sensory function and altered behaviour at levels of ocean acidification expected to occur owing to anthropogenic carbon dioxide emissions during this century. We provide the first evidence of the effects of ocean acidification on reproductive behaviour of fish in the wild. Satellite and sneaker male ocellated wrasse (Symphodus ocellatus) compete to fertilize eggs guarded by dominant nesting males. Key mating behaviours such as dominant male courtship and nest defence did not differ between sites with ambient versus elevated CO2 concentrations. Dominant males did, however, experience significantly lower rates of pair spawning at elevated CO2 levels. Despite the higher risk of sperm competition found at elevated CO2, we also found a trend of lower satellite and sneaker male paternity at elevated CO2 Given the importance of fish for food security and ecosystem stability, this study highlights the need for targeted research into the effects of rising CO2 levels on patterns of reproduction in wild fish. PMID- 27466453 TI - 'Out of tune': consequences of inbreeding on bird song. AB - The expression of bird song is expected to signal male quality to females. 'Quality' is determined by genetic and environmental factors, but, surprisingly, there is very limited evidence if and how genetic aspects of male quality are reflected in song. Here, we manipulated the genetic make-up of canaries (Serinus canaria) via inbreeding, and studied its effects upon song output, complexity, phonetics and, for the first time, song learning. To this end, we created weight matched inbred and outbred pairs of male fledglings, which were subsequently exposed to the same tutor male during song learning. Inbreeding strongly affected syllable phonetics, but there were little or no effects on other song features. Nonetheless, females discriminated among inbred and outbred males, as they produced heavier clutches when mated with an outbred male. Our study highlights the importance of song phonetics, which has hitherto often been overlooked. PMID- 27466452 TI - Object size determines the spatial spread of visual time. AB - A key question for temporal processing research is how the nervous system extracts event duration, despite a notable lack of neural structures dedicated to duration encoding. This is in stark contrast with the orderly arrangement of neurons tasked with spatial processing. In this study, we examine the linkage between the spatial and temporal domains. We use sensory adaptation techniques to generate after-effects where perceived duration is either compressed or expanded in the opposite direction to the adapting stimulus' duration. Our results indicate that these after-effects are broadly tuned, extending over an area approximately five times the size of the stimulus. This region is directly related to the size of the adapting stimulus-the larger the adapting stimulus the greater the spatial spread of the after-effect. We construct a simple model to test predictions based on overlapping adapted versus non-adapted neuronal populations and show that our effects cannot be explained by any single, fixed scale neural filtering. Rather, our effects are best explained by a self-scaled mechanism underpinned by duration selective neurons that also pool spatial information across earlier stages of visual processing. PMID- 27466455 TI - Mapping the spatio-temporal risk of lead exposure in apex species for more effective mitigation. AB - Effective mitigation of the risks posed by environmental contaminants for ecosystem integrity and human health requires knowing their sources and spatio temporal distribution. We analysed the exposure to lead (Pb) in griffon vulture Gyps fulvus-an apex species valuable as biomonitoring sentinel. We determined vultures' lead exposure and its main sources by combining isotope signatures and modelling analyses of 691 bird blood samples collected over 5 years. We made yearlong spatially explicit predictions of the species risk of lead exposure. Our results highlight elevated lead exposure of griffon vultures (i.e. 44.9% of the studied population, approximately 15% of the European, showed lead blood levels more than 200 ng ml(-1)) partly owing to environmental lead (e.g. geological sources). These exposures to environmental lead of geological sources increased in those vultures exposed to point sources (e.g. lead-based ammunition). These spatial models and pollutant risk maps are powerful tools that identify areas of wildlife exposure to potentially harmful sources of lead that could affect ecosystem and human health. PMID- 27466454 TI - Changes in physiological stress and behaviour in semi-free-ranging red-capped mangabeys (Cercocebus torquatus) following antiparasitic treatment. AB - Parasites are ubiquitous in wildlife populations, but physiological and behavioural responses of hosts to infection are difficult to measure. We experimentally treated semi-free-ranging red-capped mangabeys (Cercocebus torquatus) in Nigeria with antiparasitic drugs and examined subsequent changes in glucocorticoid production and individual behaviour. Because both parasites and stress impact energy balance and health, we measured (i) behavioural time re allocation via activity budgets, (ii) social relationships (e.g. social connectivity and dominance hierarchy stability) and (iii) body condition. We collected triplicate faecal samples (n = 441) from 49 individuals prior to and following treatment. Cortisol levels fluctuated in parallel with parasite abundance. Elevations in cortisol, but not parasitism, were related to reduced body condition. Behaviour also shifted according to infection status, with uninfected individuals spending more time foraging and less time resting and vigilant compared with when they were infected. Time spent feeding, travelling or socializing did not differ between pre- and post-treatment time periods. Group cohesion, but not dominance stability, changed following treatment, suggesting parasite-induced social avoidance. Together, these findings show a coordinated response to infection that promotes host tolerance through stress and energy conservation, reduces transmission risk and increases protection when infected hosts are vulnerable. PMID- 27466456 TI - Joint effects of habitat, zooplankton, host stage structure and diversity on amphibian chytrid. AB - Why does the severity of parasite infection differ dramatically across habitats? This question remains challenging to answer because multiple correlated pathways drive disease. Here, we examined habitat-disease links through direct effects on parasites and indirect effects on parasite predators (zooplankton), host diversity and key life stages of hosts. We used a case study of amphibian hosts and the chytrid fungus, Batrachochytrium dendrobatidis, in a set of permanent and ephemeral alpine ponds. A field experiment showed that ultraviolet radiation (UVR) killed the free-living infectious stage of the parasite. Yet, permanent ponds with more UVR exposure had higher infection prevalence. Two habitat-related indirect effects worked together to counteract parasite losses from UVR: (i) UVR reduced the density of parasite predators and (ii) permanent sites fostered multi season host larvae that fuelled parasite production. Host diversity was unlinked to hydroperiod or UVR but counteracted parasite gains; sites with higher diversity of host species had lower prevalence of infection. Thus, while habitat structure explained considerable variation in infection prevalence through two indirect pathways, it could not account for everything. This study demonstrates the importance of creating mechanistic, food web-based links between multiple habitat dimensions and disease. PMID- 27466457 TI - Lessons Learned from the Accident at the Fukushima Dai-ichi Nuclear Power Plant More than Basic Knowledge: Education and its Effects Improve the Preparedness and Response to Radiation Emergency. AB - A huge earthquake struck the northeast coast of the main island of Japan on 11 March 2011 triggering an extremely large tsunami to hit the area. The earthquake and tsunami caused serious damage to the Fukushima nuclear power plants (NPPs) of Tokyo Electric Power Company (TEPCO), resulting in large amounts of radioactive materials being released into the environment. The major nuclides released were (131)I, (134)Cs and (137)Cs. The deposition of these radioactive materials on land resulted in a high ambient dose of radiation around the NPPs, especially within a 20-km radius. Dose assessments based on behavior survey and ambient dose rates revealed that external doses to most residents were lower than 5 mSv, with the maximum dose being 25 mSv. It was fortunate that no workers from the NPPs required treatment from the viewpoint of deterministic effects of radiation. However, a lack of exact knowledge of radiation and its effects prevented the system for medical care and transportation of contaminated personnel from functioning. After the accident, demands or requests for training courses have been increasing. We have learned from the response to this disaster that basic knowledge of radiation and its effects is extremely important for not only professionals such as health care providers but also for other professionals including teachers. PMID- 27466458 TI - MODELING H-ARS USING HEMATOLOGICAL PARAMETERS: A COMPARISON BETWEEN THE NON-HUMAN PRIMATE AND MINIPIG. AB - Multiple hematological biomarkers (i.e. complete blood counts and serum chemistry parameters) were used in a multivariate linear-regression fit to create predictive algorithms for estimating the severity of hematopoietic acute radiation syndrome (H-ARS) using two different species (i.e. Gottingen Minipig and non-human primate (NHP) (Macacca mulatta)). Biomarker data were analyzed prior to irradiation and between 1-60 days (minipig) and 1-30 days (NHP) after irradiation exposures of 1.6-3.5 Gy (minipig) and 6.5 Gy (NHP) 60Co gamma ray doses at 0.5-0.6 Gy min-1 and 0.4 Gy min-1, respectively. Fitted radiation risk and injury categorization (RRIC) values and RRIC prediction percent accuracies were compared between the two models. Both models estimated H-ARS severity with over 80% overall predictive power and with receiver operating characteristic curve area values of 0.884 and 0.825. These results based on two animal radiation models support the concept for the use of a hematopoietic-based algorithm for predicting the risk of H-ARS in humans. PMID- 27466463 TI - Separate origins of the left internal and external carotid arteries from the aortic arch and cervical internal carotid artery aneurysm in a patient with Noonan syndrome. AB - Distinct origins of the external carotid artery and the internal carotid artery (ICA) from the aortic arch have been rarely described, and represent an aberrant development of the aortic arches during fetal life. This anatomical variation is usually discovered incidentally; infrequently, an aneurysm of the cervical ICA might accompany this rare configuration. We describe one such case in a patient with Noonan syndrome who presented with pulsatile neck mass. The diagnostic features and management of the aneurysm and a review of the literature are presented. PMID- 27466462 TI - Body mass index trend in haemodialysis patients: the shift of nutritional disorders in two Italian regions. AB - BACKGROUND: In the USA, the increase in the prevalence of obesity in the general population has been accompanied by a marked increase in the prevalence and incidence of obesity in the dialysis population. However, secular trends of body mass index (BMI) have not been investigated in European renal registries. METHODS: We investigated the secular trend of BMI across 18 years (1994-2011) in two haemodialysis (HD) registries (Calabria in southern Italy and Emilia in northern Italy) on a total of 16 201 prevalent HD patients and in a series of 3559 incident HD patients. We compared trends in BMI for HD patients with those in the background general population of the same regions. RESULTS: The average BMI rose from 23.5 kg/m(2) in 1994 to 25.5 (+8.5%) in 2011 in the Calabria registry and from 23.7 in 1998 to 25.4 (+7.1%) in 2011 in the Emilia registry (P < 0.001). The proportion of obese patients (i.e. with BMI >30 kg/m(2)) rose from 6 to 14% in Calabria and from 6 to 16% in Emilia (P < 0.001). These patterns were fully confirmed in incident patients and were mirrored by a substantial decline in the prevalence of underweight-normal and underweight (P < 0.001) patients. Of note, the steepness of the increase in BMI in haemodialysis patients was 3.7 times more pronounced than that in the coeval, age- and sex-matched general population of Calabria and Emilia. CONCLUSIONS: In two regional haemodialysis registries in Italy a steady increase in overweight and obese patients is observed. These patterns are more pronounced than those found in the general population. If further confirmed in other European haemodialysis cohorts, these findings may have relevant public health implications. PMID- 27466464 TI - Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter): Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To update the 2004 American Academy of Neurology guideline for patients with stroke and patent foramen ovale (PFO) by addressing whether (1) percutaneous closure of PFO is superior to medical therapy alone and (2) anticoagulation is superior to antiplatelet therapy for the prevention of recurrent stroke. METHODS: Systematic review of the literature and structured formulation of recommendations. CONCLUSIONS: Percutaneous PFO closure with the STARFlex device possibly does not provide a benefit in preventing stroke vs medical therapy alone (risk difference [RD] 0.13%, 95% confidence interval [CI] 2.2% to 2.0%). Percutaneous PFO closure with the AMPLATZER PFO Occluder possibly decreases the risk of recurrent stroke (RD -1.68%, 95% CI -3.18% to -0.19%), possibly increases the risk of new-onset atrial fibrillation (AF) (RD 1.64%, 95% CI 0.07%-3.2%), and is highly likely to be associated with a procedural complication risk of 3.4% (95% CI 2.3%-5%). There is insufficient evidence to determine the efficacy of anticoagulation compared with antiplatelet therapy in preventing recurrent stroke (RD 2%, 95% CI -21% to 25%). RECOMMENDATIONS: Clinicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic stroke outside of a research setting (Level R). In rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified, clinicians may offer the AMPLATZER PFO Occluder if it is available (Level C). In the absence of another indication for anticoagulation, clinicians may routinely offer antiplatelet medications instead of anticoagulation to patients with cryptogenic stroke and PFO (Level C). PMID- 27466465 TI - Cerebral amyloid angiopathy in posttransplant patients with hereditary ATTR amyloidosis. AB - OBJECTIVE: To investigate the prevalence and clinical features of posttransplant CNS symptoms in patients with hereditary ATTR amyloidosis and their Pittsburgh compound B (PiB)-PET imaging correlates. METHODS: We monitored prevalence and type of CNS symptoms in 53 consecutive posttransplant patients with hereditary ATTR amyloidosis. (11)C-PiB-PET was performed in 15 patients with various disease durations. We also analyzed pathologic and biochemical characteristics of ATTR amyloid deposition in the brain of a posttransplant patient. RESULTS: Transient focal neurologic episodes (TFNEs) attributed to ATTR-type cerebral amyloid angiopathy (CAA) were found in 11.3% of posttransplant hereditary ATTR amyloidosis patients. TFNE occurred on average 16.8 years after onset of the disease. Patients with longer duration of illness (>=10 years) showed increased (11)C-PiB retention in the brain. The (11)C-PiB accumulation pattern in hereditary ATTR amyloidosis was unique and different from those in Alzheimer disease or Abeta-type CAA. In the autopsy case, ATTR amyloid deposition was mainly localized to leptomeningeal vessels and leptomeninges of the brain. Amyloid fibrils in the brain were almost completely composed of variant transthyretin (TTR). CONCLUSIONS: TFNE due to ATTR-type CAA occurred frequently in posttransplant patients with long disease durations. (11)C-PiB-PET is a useful diagnostic tool for ATTR-type CAA. ATTR amyloid deposition in the CNS, as measured by PiB-PET, was detected approximately 10 years before onset of TFNE. PMID- 27466466 TI - Genes cut across systems: Neurologists should think "heart" and cardiologists "brain". PMID- 27466468 TI - Acute Zika infection with concurrent onset of Guillain-Barre Syndrome. PMID- 27466469 TI - Successive pregnancies in multiple sclerosis. PMID- 27466467 TI - Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome. AB - OBJECTIVE: We investigated a series of patients with LGI1 antibody (Ab)-related cognitive deterioration to determine the clinical presentation, long-term outcome, and LGI1 Ab evolution. METHODS: We retrospectively analyzed the clinical information of 76 patients with LGI1 Ab-related cognitive deterioration. Presenting syndromes were classified as limbic encephalitis (LE), non-LE, or encephalopathy (normal MRI and no CSF pleocytosis). Frequency of relapses and clinical outcome were assessed in 48 patients with prolonged follow-up (median 39 months, range 18-200). RESULTS: Sixty-three patients (83%) developed LE, 3 (4%) non-LE, and 10 (13%) encephalopathy. All patients received steroids, IV immunoglobulins (Ig), or both. At 2 years, 17 (35%; 95% CI 21%-49%) fully recovered, 17 (35%) became functionally independent but not at baseline or were unable to return to work, 11 (23%) required assistance because of moderate or severe cognitive deficits, and 3 (6%) died. Predictors of bad outcome included no response to initial immunotherapy (odds ratio 23.0, 95% CI 2.4-215.6, p = 0.006) and clinical relapses (odds ratio 10.2, 95% CI 1.0-100.1, p = 0.047) that occurred in 13 patients (27%). In all patients, the LGI1 Abs were IgG4 and usually detectable in both serum and CSF (only CSF, 8%). Abs remained positive in serum of 4 of 16 patients with long-term follow-up; 3 of these 4 patients fully recovered and none showed class switch to IgG1. CONCLUSIONS: Up to 13% of patients with LGI1 Abs develop cognitive impairment without criteria of encephalitis. After immunotherapy, only 35% of patients return to their baseline cognitive function. Serum LGI1 Abs may remain detectable after full clinical recovery. PMID- 27466470 TI - History of multiple sclerosis in 2 successive pregnancies: A French and Italian cohort. AB - OBJECTIVE: To evaluate the risk of relapses during pregnancy and in the first 3 months after delivery in 2 successive pregnancies in a cohort of French and Italian women with multiple sclerosis (MS). METHODS: A total of 93 women were included if they had had 2 pregnancies followed prospectively after MS onset between January 1993 and 2013. The association of a relapse during pregnancy or the first postpartum trimester in pregnancy 1 and pregnancy 2 was evaluated by univariate logistic regression. RESULTS: A majority of women did not experience any exacerbation in the 3 months after delivery (31.2% and 23.7%, respectively, relapsed after pregnancy 1 and 2; p = 0.32). A total of 7.6% had a relapse after both pregnancies. The risk of relapse after pregnancy 2 was not associated with the number of relapses in the prepregnancy year (odds ratio [OR] 1.52 [0.57 4.05]) or during pregnancy (OR 1.57 [0.52-4.79]) or with the occurrence of a relapse after pregnancy 1 (OR 0.86 [0.29-2.50]). CONCLUSIONS: Our work provides original data on the evolution of successive pregnancies in MS, showing a similar (and even lower) disease activity in the second pregnancy. There was no correlation of activity in successive pregnancies. Therefore, counseling of women with MS who consider having a second baby should be the same as for the first one. PMID- 27466471 TI - Genetic biomarkers for the risk of seizures in long QT syndrome. AB - OBJECTIVES: The coprevalence, severity, and biomarkers for seizures and arrhythmias in long QT syndrome (LQTS) remain incompletely understood. METHODS: Using the Rochester-based LQTS Registry, this study included large cohorts of LQTS1-3 participants (LQTS+, n = 965) and those without a LQTS mutation (LQTS-, n = 936). RESULTS: Compared to LQTS- participants, there was a higher prevalence of LQTS1, LQTS2, and LQTS+ participants classified as having seizures (p < 0.001, i.e., history of seizures/epilepsy or antiseizure medication). LQTS+ participants with longer corrected QT interval (QTc) durations were more likely to have seizures. LQTS2 mutations in the KCNH2 pore domain were positive predictors for both arrhythmias and seizures. In contrast, mutations in the cyclic nucleotide binding domain (cNBD) of KCNH2 conferred a negative risk of seizures, but not arrhythmias. LQTS2, KCNH2-pore, KCNH2-cNBD, QTc duration, and sex were independent predictors of seizures. LQTS+ participants with seizures had significantly longer QTc durations, and a history of seizures was the strongest independent predictor of arrhythmias (hazard ratio 4.09, 95% confidence interval 2.63-6.36, p < 0.001). CONCLUSIONS: This study highlights potential biomarkers for neurocardiac electrical abnormalities in LQTS. PMID- 27466473 TI - Eosinophilic gastroenteritis in a woman with multiple sclerosis on dimethyl fumarate. PMID- 27466472 TI - Seizures in dominantly inherited Alzheimer disease. AB - OBJECTIVE: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. METHODS: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. RESULTS: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005). CONCLUSIONS: Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures. PMID- 27466475 TI - Surgical treatment of pediatric focal cortical dysplasia: Clinical spectrum and surgical outcome. AB - OBJECTIVE: To analyze the clinical presentation and outcomes of surgically treated focal cortical dysplasia (FCD) in children. METHODS: We reviewed 75 cases of confirmed FCD by pathology after resective surgery. We used the pathologic classification proposed by the International League Against Epilepsy and included clinical profile and seizure and neurodevelopmental outcomes in analyses. RESULTS: There were 11 cases of FCD type I, 34 of type IIa, 19 of type IIb, and 11 of type III. Fifty-one cases (68.0%) presented clinically as focal epilepsy (FE) and 24 (32.0%) as epileptic encephalopathy (EE), including 16 with Lennox Gastaut syndrome and 8 with West syndrome. We observed EE in 7 cases (63.6%) in FCD type I, 14 (41.2%) in type IIa, 2 (10.5%) in type IIb, and 1 (9.1%) in type III. We found the following more frequently in EE: seizure onset occurring at younger than 2 years (EE: 20 [83.3%], FE: 19 [37.3%]; p < 0.001), presence of intellectual disability before surgery (EE: 22 [91.7%], FE: 29 [56.9%]; p = 0.003), and multilobar resections (EE: 19 [79.2%], FE: 15 [29.4%]; p < 0.001). Forty-eight cases (64.0%) were seizure-free; 66.7% (34/51) in FE, 58.3% (14/24) in EE. Neurodevelopmental level showed more improvement (11/48 vs 0/27, p = 0.011) and less deterioration (2/48 vs 9/27, p = 0.001) in the seizure-free group compared to the non-seizure-free group. CONCLUSIONS: FCD can cause FE and EE in pediatric age, and resective surgery should be considered as a treatment option for both types of epilepsy. PMID- 27466476 TI - PiB-PET detects transthyretin-related cerebral amyloid angiopathy. PMID- 27466474 TI - Sensitivity of quantitative EEG for seizure identification in the intensive care unit. AB - OBJECTIVE: To evaluate the sensitivity of quantitative EEG (QEEG) for electrographic seizure identification in the intensive care unit (ICU). METHODS: Six-hour EEG epochs chosen from 15 patients underwent transformation into QEEG displays. Each epoch was reviewed in 3 formats: raw EEG, QEEG + raw, and QEEG only. Epochs were also analyzed by a proprietary seizure detection algorithm. Nine neurophysiologists reviewed raw EEGs to identify seizures to serve as the gold standard. Nine other neurophysiologists with experience in QEEG evaluated the epochs in QEEG formats, with and without concomitant raw EEG. Sensitivity and false-positive rates (FPRs) for seizure identification were calculated and median review time assessed. RESULTS: Mean sensitivity for seizure identification ranged from 51% to 67% for QEEG-only and 63%-68% for QEEG + raw. FPRs averaged 1/h for QEEG-only and 0.5/h for QEEG + raw. Mean sensitivity of seizure probability software was 26.2%-26.7%, with FPR of 0.07/h. Epochs with the highest sensitivities contained frequent, intermittent seizures. Lower sensitivities were seen with slow-frequency, low-amplitude seizures and epochs with rhythmic or periodic patterns. Median review times were shorter for QEEG (6 minutes) and QEEG + raw analysis (14.5 minutes) vs raw EEG (19 minutes; p = 0.00003). CONCLUSIONS: A panel of QEEG trends can be used by experts to shorten EEG review time for seizure identification with reasonable sensitivity and low FPRs. The prevalence of false detections confirms that raw EEG review must be used in conjunction with QEEG. Studies are needed to identify optimal QEEG trend configurations and the utility of QEEG as a screening tool for non-EEG personnel. CLASSIFICATION OF EVIDENCE REVIEW: This study provides Class II evidence that QEEG + raw interpreted by experts identifies seizures in patients in the ICU with a sensitivity of 63%-68% and FPR of 0.5 seizures per hour. PMID- 27466477 TI - The neurologist's role in supporting transition to adult health care: A consensus statement. AB - The child neurologist has a critical role in planning and coordinating the successful transition from the pediatric to adult health care system for youth with neurologic conditions. Leadership in appropriately planning a youth's transition and in care coordination among health care, educational, vocational, and community services providers may assist in preventing gaps in care, delayed entry into the adult care system, and/or health crises for their adolescent patients. Youth whose neurologic conditions result in cognitive or physical disability and their families may need additional support during this transition, given the legal and financial considerations that may be required. Eight common principles that define the child neurologist's role in a successful transition process have been outlined by a multidisciplinary panel convened by the Child Neurology Foundation are introduced and described. The authors of this consensus statement recognize the current paucity of evidence for successful transition models and outline areas for future consideration. PMID- 27466478 TI - The Role of FOXP3 in Human Cancers. AB - FOXP3 transcription factor can be observed as the main component of the immune system expressed in regulatory T (Treg) cells that regulate hemostasis and self tolerance. Moreover, the altered expression of FOXP3 was found in autoimmune diseases, benign tumors and carcinomas. Latest reports indicate that the FOXP3 gene mutation can contribute to carcinogenesis, which can be associated with immune response abnormalities. Infiltration of the Treg cells into tumor cells can be associated with prognosis. Understanding the biology of the FOXP3 gene may be crucial in developing new immunotherapeutics. PMID- 27466480 TI - Procalcitonin: A New Biomarker for Medullary Thyroid Cancer? A Systematic Review. AB - Medullary thyroid cancer (MTC) is a rare but aggressive thyroid malignancy. The gold-standard biomarker for its diagnosis and follow-up is calcitonin (CT); however, it has a variable half-life dependent on its circadian variability. It has been suggested that a more stable hormone, procalcitonin (PCT), may overcome these problems and its introduction to routine practice may give more accurate results in the diagnosis and follow-up of MTC. We systematically reviewed Pubmed, Scopus, Biosis Previews and Embase databases up to March 2016. A total of 15 out of 184 articles were retrieved and analyzed. Of these 15 studies, 3 were case reports. In these 15 studies, the values of CT and PCT were assessed in both patients with MTC and patients that were either healthy volunteers or with benign/malignant thyroid nodular disease or with bacterial infection. Our search suggests that PCT seems to be a useful biomarker for the diagnosis and follow-up of MTC when used in conjunction with CT, particularly in a small proportion of tumors that are CT-negative or secrete low levels of CT. So far, there has not been enough data to suggest a specific threshold for normal PCT. However, most studies indicate a value of 0.1 ng/ml as an acceptable cut-off in everyday clinical practice. At present, CT should continue to be the primary biomarker in MTC with the addition of PCT in some patient groups. Nevertheless, larger patient series need to be conducted in order to provide safer and more accurate results. PMID- 27466479 TI - Immunotherapy in Acute Leukemias: Implications and Perspectives Using Wt1 Antigen. AB - The WT1 gene encodes a transcription factor involved in regulation of many cellular processes, including proliferation, differentiation, mRNA processing and apoptosis, besides acting as a transcription repressor of growth factors and their receptors' genes. This gene is expressed at high levels in several types of cancers, including acute leukemias. In this regard, many studies have identified WT1 protein as a tumor antigen, considered a target molecule for clinical application in human acute leukemias. Immunotherapy using WT1 antigen has been effective in stimulating immune responses against leukemic cells. Regarding adoptive immunotherapy, the use of dendritic cells (DCs) for the WT1-specific cytotoxic T cells generation proved to be efficient in the development and maintenance of immunologic cells. Therefore, these therapeutic methods, that provided enthusiasm for moving ahead, highlight several opportunities and challenges to be used in clinical practice for managing acute leukemias. PMID- 27466481 TI - Use of alphav Integrin Linked to Green Fluorescent Protein in Osteosarcoma Cells and Confocal Microscopy to Image Molecular Dynamics During Lung Metastasis in Nude Mice. AB - BACKGROUND: We report here imaging of the behavior of alphav integrin linked to green fluorescent protein (GFP) in human osteosarcoma cells colonizing the lung of nude mice. MATERIALS AND METHODS: 143B osteosarcoma cells expressing alphav integrin-GFP were generated by transfection of an alphav integrin-GFP fusion-gene vector pCMV-AC- ITGAV-GFP. In order to generate experimental lung metastases, 143B osteosarcoma cells (1*10(6)), stably expressing alphav integrin-GFP, were injected intravenously via the tail vein. The osteosarcoma cells were transplanted orthotopically in the tibia of nude mice in order to generate spontaneous metastases. Lungs were harvested and imaged by confocal microscopy within 1 hour. RESULTS: In the experimental lung-metastasis model, extravasating and deformed osteosarcoma cells expressing alphav integrin-GFP were observed. Pseudopodia of the osteosarcoma cells contained small puncta of alphav integrin GFP. In early-stage spontaneous lung metastasis, tumor emboli were observed in pulmonary vessels. At high magnification, small alphav integrin-GFP puncta were observed in the tumor embolus. In late-stage spontaneous metastasis, tumor emboli were also observed in pulmonary vessels. Invading cancer cells with strong expression of alphav integrin-GFP were observed at the margin of the tumor emboli. CONCLUSION: The results of this study demonstrate that molecular dynamics of alphav integrin-GFP can be imaged in lung metastasis, which will allow further understanding of the role of alphav integrin in this process. The results also suggest a general concept for imaging molecular behavior in vivo. PMID- 27466482 TI - In Vivo Isolation of a Highly-aggressive Variant of Triple-negative Human Breast Cancer MDA-MB-231 Using Serial Orthotopic Transplantation. AB - AIM: We describe the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. MATERIALS AND METHODS: MDA-MB-231 cells expressing red fluorescent protein (RFP) (1*10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation in the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for two cycles and then isolated. RESULTS: The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. CONCLUSION: The availability of a highly invasive variant of TNBC targeting lymph nodes will be very useful for drug discovery of TNBC, a recalcitrant cancer and for mechanistic studies of its aggressiveness. PMID- 27466483 TI - Efficacy of the Combination of a PARP Inhibitor and UVC on Cancer Cells as Imaged by Focus Formation by the DNA Repair-related Protein 53BP1 Linked to Green Fluorescent Protein. AB - BACKGROUND: The ability to image DNA repair in cancer cells after irradiation, as well as its inhibition by potential therapeutic agents, is important for the further development of effective cancer therapy. 53BP1 is a DNA repair protein that is overexpressed and forms foci when double-stranded DNA breaks occur in DNA. MATERIALS AND METHODS: The re-localization of green fluorescent protein (GFP) fused to the chromatin-binding domain of 53BP1 to form foci was imaged after UVC irradiation of breast and pancreatic cancer cells expressing 53BP1-GFP using confocal microscopy. RESULTS: During live-cell imaging, 53BP1-GFP focus formation was observed within 10 minutes after UVC irradiation. Most 53BP1 foci resolved by 100 minutes. To block UVC-induced double-strand break repair in cancer cells, poly(ADP-ribose) polymerase (PARP) was targeted with ABT-888 (veliparib). PARP inhibition markedly enhanced UVC-irradiation-induced persistence of 53BP1-foci, even beyond 100 minutes after UVC irradiation, and reduced proliferation of breast and pancreatic cancer cells. CONCLUSION: Confocal microscopy of 53BP1-GFP is a powerful method for imaging UVC-induced DNA damage and repair, as well as inhibition of repair. PMID- 27466484 TI - Color-coded Live Imaging of Heterokaryon Formation and Nuclear Fusion of Hybridizing Cancer Cells. AB - BACKGROUND/AIM: Fusion of cancer cells has been studied for over half a century. However, the steps involved after initial fusion between cells, such as heterokaryon formation and nuclear fusion, have been difficult to observe in real time. In order to be able to visualize these steps, we have established cancer cell sublines from the human HT-1080 fibrosarcoma, one expressing green fluorescent protein (GFP) linked to histone H2B in the nucleus and a red fluorescent protein (RFP) in the cytoplasm and the other subline expressing RFP in the nucleus (mCherry) linked to histone H2B and GFP in the cytoplasm. MATERIALS AND METHODS: The two reciprocal color-coded sublines of HT-1080 cells were fused using the Sendai virus. The fused cells were cultured on plastic and observed using an Olympus FV1000 confocal microscope. RESULTS: Multi-nucleate (heterokaryotic) cancer cells, in addition to hybrid cancer cells with single-or multiple-fused nuclei, including fused mitotic nuclei, were observed among the fused cells. Heterokaryons with red, green, orange and yellow nuclei were observed by confocal imaging, even in single hybrid cells. The orange and yellow nuclei indicate nuclear fusion. Red and green nuclei remained unfused. Cell fusion with heterokaryon formation and subsequent nuclear fusion resulting in hybridization may be an important natural phenomenon between cancer cells that may make them more malignant. CONCLUSION: The ability to image the complex processes following cell fusion using reciprocal color-coded cancer cells will allow greater understanding of the genetic basis of malignancy. PMID- 27466485 TI - Regulation of Multicellular Spheroids by MAPK and FYN Kinase. AB - Understanding of the biology of oral squamous cell carcinoma (SCC) has not progressed significantly in the past 60 years, with 5-year survival remaining at approximately 50%. The epidemic of Human Papilloma Virus and its associated SCC warrants a renewed emphasis on fully understanding this disease. We previously used the 3-dimensional multicellular spheroid (MCS) model system to evaluate SCC behavior more accurately. In this study, we determined that SCC growth in MCS approximates epithelial to mesenchymal transition. Organization of an MCS requires the full-length beta6 integrin subunit and its maintenance requires mitogen-activated protein kinase (MAPK). Limiting FYN kinase activation results in the down-regulation of E-cadherin, beta-catenin and an increase in expression of N-cadherin and SNAIL. These results indicate that the microenvironment and growth patterns in an MCS are complex and require MAPK and FYN kinase. PMID- 27466486 TI - Concurrent Androgen and Estrogen Ablation and Inhibition of Steroid Biosynthetic Enzyme Treatment for Castration-resistant Prostate Cancer. AB - BACKGROUND/AIM: About 80 to 90% of prostate cancer (PCa) is androgen-dependent at diagnosis, but patients ultimately develop castration-resistant prostate cancer (CRPC), which is usually not amenable to androgen deprivation (ablation) therapy (ADT). Patients with CRPC usually succumb to death in less than 5 years and there is no cure. Here, we investigated reasons for ADT failure. MATERIALS AND METHODS: Biopsy specimens from untreated and diethylstilbestrol (DES)-treated patients were assessed for localization of antibody IgGs against androgen (AR) and estrogen (ER) receptors. RESULTS: In untreated and DES-treated sections, methylene blue stained basic proteins in dark basal (undifferentiated) PCa cells, whereas light basal cells were not stained. AR localized to light basal cells which showed widespread degeneration in sections from DES-treated patients, indicating their dependence on androgen. In contrast, dark basal cells did not show widespread degeneration in DES-treated patients; ER was usually localized in dark cells. The number of dark cells progressively increased in DES-treated patients indicating their androgen-independence. The localization of AR and ER in some light and dark basal cells indicated that the supply of androgen/estrogen was not inhibited during ADT. Dark basal cells had emerged prior to treatment and proliferated during DES treatment, that also indicated their androgen independence. CONCLUSION: PCa has at least two populations of cells: androgen dependent light basal and estrogen-dependent dark basal cells. ADT did not destroy estrogen-dependent cells which may have given rise to CRPC tumors. Therefore, ADT is an incomplete treatment. For a more complete treatment of PCa, we recommend concurrent androgen and estrogen ablation, together with the inhibition of selected steroid biosynthetic enzymes. PMID- 27466487 TI - Improved Risk Stratification for Breast Cancer Samples Based on the Expression Ratio of the Estrogen and Progesterone Receptor. AB - BACKGROUND: The receptors for estrogen (ESR1) and progesterone (PGR) are both part of the same signaling pathway and routinely used for breast cancer stratification. We tested the hypothesis if a coordinated analysis could add extra information for prognostic stratification. MATERIALS AND METHODS: ESR1 and PGR gene expression was first investigated by quantitative reverse transcription polymerase chain reaction in fresh-frozen invasive ductal breast cancer samples (Hamburg collective, case-control, n=317). Our results were then tested using two datasets generated by different technical approaches: i) a public DNA-chip data set (GSE3494, n=251) and ii) semiquantitative protein expression data based on immunohistochemistry (Stuttgart collective, n=18,528). RESULTS: The PGR/ESR1 gene expression ratio was a prognostic indicator in those with ESR1/PGR-positive breast cancer (Hamburg collective), with a high PGR/ESR1 expression ratio indicating a favorable outcome. In all three collectives, the PGR/ESR1 mRNA ratio or its protein equivalent was a univariate prognostic factor and also a multivariate prognostic factor in the Hamburg and Stuttgart collectives. CONCLUSION: Calculation of the PGR/ESR1 gene-expression ratio and its immunohistochemical surrogate could be a useful and simple addition to routine breast cancer diagnostics. A high PGR/ESR1 ratio could be indicative of a favorable clinical outcome. PMID- 27466488 TI - ID1 Controls Aggressiveness of Salivary Gland Cancer Cells via Crosstalk of IGF and AKT Pathways. AB - BACKGROUND: Inhibitor of differentiation or DNA binding 1 (ID1) is overexpressed in human salivary gland cancer (SGC). The insulin growth factor (IGF) system is an attractive target in cancer control because it is associated with various cancer progressions. MATERIALS AND METHODS: The human SGC cell line HSY with abundant ID1 was used. ID1 knockdown and its effect on the IGF system were investigated. Cell proliferation and invasion, as well as associated protein expression, were analyzed. Phospho-AKT was also evaluated. RESULTS: ID1 knockdown reduced cell proliferation and invasion, while the expression of proteins associated with malignant phenotypes was altered. IGF-II expression was suppressed, suggesting that this system is one of the mechanisms underlying effects of ID1 in SGC cells. c-Myc was up-regulated, whereas p21 and p27 were down-regulated. Moreover, phospho-AKT was reduced in ID1-knockeddown cells. CONCLUSION: ID1 down-regulation induced parallel changes in the IGF and AKT pathways. The crosstalk of these pathways may enhance malignant phenotypes in SGCs. PMID- 27466489 TI - Obesity and Intestinal Tumorigenesis in Adult Min/+ Mice from Early-life High-fat Diet Exposure Were Not Inherited Transgenerationally. AB - BACKGROUND/AIM: Exposure to 45% fat diet in utero and during nursing increased body weight and small intestinal tumor numbers in adult F1 multiple intestinal neoplasia (Min/+) mice, implicating that early-life obesogenic conditions predispose for obesity and intestinal tumorigenesis later in life. In this study, it was examined whether these effects were transferred to the next two generations. RESULTS: In F2 mice, exposed to the obesogenic diet as germ cells within the embryonic F1 mice, there were no consistent differences in body weight, blood glucose levels or small intestinal tumor numbers whether their mother or father, both, or no parents were exposed to 45% vs. 10% fat diet. In F3 mice, never exposed to obesogenic diet, no differences were found in any end points, whether both grandparents were exposed to 45% or 10% fat, or not. CONCLUSION: The effects of early-life high-fat diet on adult obesity and intestinal tumorigenesis were not inherited transgenera-tionally. PMID- 27466490 TI - Preclinical Evaluation of Combined Targeted Approaches in Malignant Rhabdoid Tumors. AB - BACKGROUND/AIM: Rhabdoid tumors (RT) are aggressive pediatric tumors, which show poor prognosis despite use of multimodal intensive therapy. In these tumors, several different oncogenic pathways and epigenetic regulators (like CDK4/6 cyclinD-Rb-signaling, EZH2, histone deacetylases) are contemporaneously deregulated as a consequence of biallelic SMARCB1/SNF5/INI1 alterations. Since these tumors are highly resistant to current therapies, alternative treatment strategies are urgently required. MATERIALS AND METHODS: In this study, we evaluated cytotoxic effects (by MTT tests) of small molecular compounds, which specifically target these deregulated pathways, using either single-drug or combined approaches. Half-maximal inhibitory concentration (IC50) and combined index (CI) were calculated. RESULTS: All target-directed inhibitors blocked cell growth of three different rhabdoid tumor cell lines in vitro. Several combinations of those target-specific drugs synergistically inhibited cell proliferation of rhabdoid tumors. CONCLUSION: Supporting earlier reports, combined target-directed approaches are a promising tool for the therapy of malignant rhabdoid tumors. PMID- 27466491 TI - Metabolism of Flavone-8-acetic Acid in Mice. AB - Flavone-8-acetic acid (FAA) is a potent antivascular agent in mice but not in humans. Assuming that FAA was bioactivated in mice, we previously demonstrated that 6-OH-FAA was formed from FAA by mouse microsomes but not by human microsomes; its antivascular activity was 2.1- to 15.9-fold stronger than that of FAA, and its antivascular activity was mediated through the Ras homolog gene family (Rho) protein kinase A (RhoA) pathway. The present work aimed to study FAA metabolism in order to verify if 6-OH-FAA is formed in mice. Using synthesized standards and high-performance liquid chromatography (HPLC) coupled with ultraviolet (UV) detection and mass spectrometry (MS) analysis, we herein demonstrated, for the first time, that in vitro FAA and its monohydroxylated derivatives could directly undergo phase II metabolism forming glucuronides, and two FAA epoxides were mostly scavenged by NAC and GSH forming corresponding adducts. FAA was metabolized in mice. Several metabolites were formed, in particular 6-OHFAA. The antitumor activity of 6-OH-FAA in vivo is worthy of investigation. PMID- 27466492 TI - Relationship Between Urinary 8-hydroxydeoxyguanine (8-OHdG) Levels and Clinicopathological Findings in Hepatobiliary Malignancies. AB - BACKGROUND/AIM: Oxidative stress is defined as an imbalance between the pro oxidant and antioxidant potential of cells leading to intracellular DNA damage. To clarify the oxidative stress response as a tumor marker, we investigated measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in hepatobiliary diseases. MATERIALS AND METHODS: Relationships between urinary 8-OHdG levels and clinicopathological factors were analyzed in 101 patients, including 84 with hepatobiliary malignancies, and 18 healthy volunteers. Co-existing biliary inflammation was detected in 8 patients. RESULTS: Urinary 8-OHdG levels did not correlate with any clinical or liver functional parameters. The existence of inflammation and any tumor-related factor did not correlate with urinary 8-OHdG levels either. Urinary 8-OHdG levels were significantly higher in patients with benign and malignant diseases than in healthy volunteers (p<0.05), but not significantly different between benign and malignant diseases. Among patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, urinary 8-OHdG levels tended to be higher in patients with lymph node metastasis-positive than in those with lymph node-negative disease (p=0.057). CONCLUSION: The clinical significance of oxidative DNA damage and increases in its urinary metabolites in patients with hepatobiliary malignancies or inflammatory diseases remain unknown. Further studies are necessary to clarify the relationship between node metastasis and oxidative stress as a prognostic marker. PMID- 27466493 TI - Glutathione-S-transferases and Chemotherapy Resistance of Hodgkin's Lymphoma Cell Lines. AB - BACKGROUND: Glutathione-S-transferases (GSTs) are associated with multidrug resistance of tumor cells and are involved in drug detoxification and control of apoptosis. We analyzed the impact of GSTs on apoptosis of Hodgkin's lymphoma (HL) cells. MATERIALS AND METHODS: Expression of GST isoforms in HL cell lines was assessed by analysis of DNA microarray data and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The impact of the GST inhibitor ethacrynic acid (EA) on HL cell survival was analyzed in vitro. RESULTS: DNA microarray analysis and qRT-PCR analysis demonstrated higher expression of GST isoforms in chemoresistant HL cells. Therefore, GSTs may contribute to chemoresistance of HL cells. Incubation of GST-expressing chemoresistant L-1236 HL cells with EA significantly enhanced the activity of cisplatin against these cells. CONCLUSION: Our data suggest that the combined treatment with chemotherapy and GST inhibitors such as EA might be an interesting option for patients with chemoresistant HL. PMID- 27466494 TI - Expression of Cell Cycle-Related Proteins p16, p27, p53 and Ki-67 in HPV-positive and -negative Samples of Papillomas of the Upper Respiratory Tract. AB - BACKGROUND: The role of human papillomavirus (HPV) infection as an etiological factor of respiratory tract papillomas has been described in numerous studies, however its role in malignant transformation has not been clearly defined. Depending on their oncogenic potential they have been classified as low- and high risk HPVs. We analyzed the expression of four cell cycle-related proteins in order to understand the processes leading to malignant transformation. MATERIALS AND METHODS: Fifty-six cases of pharyngeal and laryngeal papillomas were analyzed. Nested multiplex polymerase chain reactions to detect the presence of the HPV types, as well as immunohistochemical reactions were performed for the detection of cell cycle-related proteins p16, p27, p53 and Ki-67. RESULTS: The presence of HPVs 6/11 and 16 was confirmed in 10/56 cases. The expression of all analyzed cell cycle-related proteins was increased in HPV-infected papillomas. CONCLUSION: HPV infection of the upper respiratory tract may influence the expression of cell cycle-related proteins, that could indicate its possible role in the process of malignant transformation. PMID- 27466495 TI - Integrated Endoscopic System Based on Optical Imaging and Hyperspectral Data Analysis for Colorectal Cancer Detection. AB - BACKGROUND/AIM: Two-dimensional hyperspectral data systems with enhanced area detection and diagnostic abilities are now available in gastrointestinal endoscopy for colorectal cancer. We evaluated a new hyperspectral system for diagnosis of colorectal cancer. PATIENTS AND METHODS: A resected-specimen spectrum observation module (stereoscopic macroscope, hyperspectral camera, and xenon lamp) was used to evaluate 21 resected colorectal cancer specimens (ex vivo experiment). A colonoscopy spectrum observation module (imaging fiberscope and hyperspectral camera) was used to perform 24 colonoscopic spectroscopy evaluations (in vivo experiment). RESULTS: An approximately 525-nm increase in spectral absorption occurred between normal mucosa and adenoma, with a tendency toward decreased absorption rates with aggravation of other tumor types. In vivo discrimination between tumorous and non-tumorous tissues showed 72.5% sensitivity and 82.1% specificity. CONCLUSION: This in vivo hyperspectral diagnostic system showed that reflectance spectra intensity may discriminate between normal and abnormal colonic mucosa. PMID- 27466496 TI - Chemotherapeutic Vulnerability of Triple-negative Breast Cancer Cell-derived Tumors to Pretreatment with Vernonia amygdalina Aqueous Extracts. AB - BACKGROUND: Unresponsive to most clinical therapies, triple-negative breast cancer (TNBC) is the dominant biological cause of population-based racioethnic disparities in breast cancer mortality in the United States. We report the chemotherapeutic vulnerability of TNBC cells and stem cell-derived tumors to Vernonia amygdalina aqueous leaf extracts (VA extracts). VA extracts arrest cell proliferation and induce apoptosis in vitro and inhibit growth of implanted tumors and show chemo-preventive efficacy in vivo. MATERIALS AND METHODS: H(RAS) cells and MDA-MB-468 cells were subcutaneously implanted into nude mice with or without pretreatment with VA extracts before chemotherapeutic treatment with VA extracts and/or paclitaxel to evaluate their ability to inhibit tumor growth. RESULTS: The most significant reduction in tumor volume was observed in the MDA MB-468 cell-induced tumors following VA extract pre-treatment compared to those from HRAS cell implantation. CONCLUSION: VA extracts induce apoptosis, exhibit additive effects, inhibit tumor growth and display chemo-preventive actions against TNBCs. PMID- 27466497 TI - Expression Profile of MicroRNA-203 and its DeltaNp63 Target in Cervical Carcinogenesis: Prospects for Cervical Cancer Screening. AB - BACKGROUND/AIM: Host molecules disturbed by human papillomavirus (HPV) oncoproteins have been shown to be potential biomarkers of cervical carcinogenesis and represent an alternative or supplementary aid to cytological testing and HPV detection. The miR-203 and one of its targets, DeltaNp63, are known to be host molecules that interact with each other to control the proliferation and differentiation of keratinocytes; both have been found to be dysregulated in many cancers. As the role of p63 and miR-203 in cervical carcinogenesis is not yet well-understood, we have, thus, decided to evaluate the changes of expression of both in cervical carcinogenesis. MATERIALS AND METHODS: This study was carried out by obtaining quantitative polymerase chain reaction (qPCR) data from cervical biopsies. RESULTS: miR-203 and DeltaNp63 displayed a similar expression pattern across cervical tissues and both targets showed statistically significant differences between low-grade squamous intraepithelial lesion (LSIL) x high-grade squamous intraepithelial lesion (HSIL); HSIL x Cancer. Additionally, we did not observe an inverse correlation between DeltaNp63 mRNA and miR-203 levels as expected but, rather, a positive correlation between cervical tissues. CONCLUSION: Although preliminary, the expression levels of DeltaNp63 mRNA and miR-203 seem to be promising for cervical cancer screening. In addition, positive correlation between miR-203 and DeltaNp63 expression suggests the possible existence of some indirect pathways. However, further studies are needed to clarify the role of DeltaNp63 and miR-203 in cervical carcinogenesis and, thus, determine how they can be applied in new strategies for diagnosis. PMID- 27466498 TI - Protein-bound Polysaccharide-K Inhibits Hedgehog Signaling Through Down regulation of MAML3 and RBPJ Transcription Under Hypoxia, Suppressing the Malignant Phenotype in Pancreatic Cancer. AB - Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor. PMID- 27466499 TI - Expression of Endoglin and Vascular Endothelial Growth Factor as Prognostic Markers in Experimental Colorectal Cancer. AB - BACKGROUND/AIM: Endoglin (CD105) is a receptor for the transforming growth factor beta 1 (TGFbeta1) with crucial role in vascular development and angiogenesis. Additionally, vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival for several cancer types. These molecules have been shown to be useful markers for identifying proliferating endothelium involved in tumor angiogenesis, especially in patients with cancer at risk of developing metastases. The aim of this study was to evaluate the relationship between VEGF and endoglin expression in an experimental model of colorectal cancer, as well as to investigate the effect of cyclooxygenase-2 (COX2) inhibitors on tumor development incidence. MATERIALS AND METHODS: Colon cancer was induced with 1,2-dimethylhydrazine dihydrochloride (DMH). Celecoxib and diclofenac treatment was started simultaneously with DMH induction. Endoglin protein expression was performed using western blot analysis. VEGF plasma concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: In histopathological evaluations, no pathological change was observed in control rats, while adenocarcinoma (62.5%), dysplasia (31.25%) and inflammation (6.25%) were detected in the group given DMH. In treatment groups, a marked decrease was observed in adenocarcinoma rate. Expression of endoglin protein was significantly elevated in the DMH group compared to controls (p<0.001). No statistically significant difference was noted between treatment groups and DMH group regarding endoglin expression but a decrease was detected in the celecoxib-treated groups. CONCLUSION: It was confirmed by histopathology and western blotting that COX2 inhibitors, particularly celecoxib, decrease the rate of disease and slow-down progression of existing CRC. These data show that endoglin expression may have an important role in tumor angiogenesis and predict of tumor invasion. PMID- 27466500 TI - Evaluation of Global Histone Acetylation Levels in Bladder Cancer Patients. AB - BACKGROUND/AIM: Alterations of global histone modification levels have been identified in various tumor entities, including bladder cancer (BCA). Our study was designed to investigate the value of global histone acetylation levels as diagnostic and prognostic biomarker for BCA patients. MATERIALS AND METHODS: A tissue microarray with formalin-fixed paraffin-embedded tissues (271 BCA and 29 normal urothelial samples) was used to determine global histone acetylation levels (histone H3 acetylation (H3Ac); histone H3 lysine 18 acetylation (H3K18Ac); histone H4 acetylation (H4Ac)). RESULTS: Global H3Ac levels were decreased in BCA patients, whereas H3K18Ac and H4Ac levels were similar in both groups. All studied histone acetylation markers were lower in muscle-invasive BCA compared to non-muscle invasive BCA and normal urothelial tissue, thereby indicating a possible prognostic relevance. CONCLUSION: Global histone acetylation levels undergo quantitative alterations during bladder cancer progression and could be helpful to identify patients at risk for early cancer recurrence. PMID- 27466501 TI - Proliferation Index Evaluation in Breast Cancer Using ImageJ and ImmunoRatio Applications. AB - BACKGROUND: Proliferation index (PI) plays a critical role in distinguishing surrogate biological subtypes of breast cancer and, thus, determining the optimal therapeutic scheme. The commonly applied method of determining PI is visual semiquantitative scoring. The most precise way of PI evaluation is formal counting of nuclei on a digital picture using software equipped with a pointer function. The less time-consuming solution may be using image analysis software enabling automatic counting of nuclei, such as the free web application ImmunoRatio. MATERIALS AND METHODS: We analyzed a group of 98 patients diagnosed with invasive breast carcinoma. A digital image of the hot-spot was taken from each case. Cell Counter plug-in of ImageJ platform was employed to precisely count brown- and blue-stained nuclei. The same images were analyzed using ImmunoRatio. The results were compared using Pearson's and Spearman's coefficients. The agreement was assessed with Cohen's kappa. RESULTS: Pearson's correlation coefficient was 0.84 (p<0.05), Spearman's correlation coefficient was 0.83 (p<0.05). Moderate agreement was shown by Cohen's kappa calculation (K= 0.47; p<0.05). CONCLUSION: As many as 26 cases were classified to different biological subtypes depending on the method of PI assessment. Thus, ImmunoRatio needs further improvement to be a reliable diagnostic tool. PMID- 27466502 TI - Influence of Photodynamic Therapy on the Expression of Cancer/Testis Antigens in Squamous Cell Carcinoma of the Head and Neck. AB - BACKGROUND: Photodynamic therapy (PDT) represents a palliative treatment resulting in induction of inflammatory reactions with importance for the development of an antitumor immunity. Cancer/testis antigens (CTAs) have been associated with poor prognosis in different types of cancer, including head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Tumor tissue samples before and after PDT were evaluated for the expression of four different CTAs by immunohistochemistry. Expression intensity and subcellular expression pattern were assessed. RESULTS: Before PDT, expression of any CTA was detectable in 91%. Comparing the overall expression of CTAs, a decreased expression of all melanoma associated antigens (MAGEs) post-treatment and a slightly increased expression of New York esophageal squamous cell carcinoma 1 (NY-ESO-1) was visible. The simultaneous cytoplasmic and nuclear expression of pan-MAGE or MAGE-A3/A4 correlated with reduced treatment-failure-free-survival (TFFS). CONCLUSION: This study investigated the impact of PDT on CTA expression in HNSCC, detecting modified expression patterns after PDT. These changes may have been caused by immunological pressure or epigenetic regulation of CTA expression. PMID- 27466503 TI - Isocitrate Dehydrogenase 2 Dysfunction Contributes to 5-hydroxymethylcytosine Depletion in Gastric Cancer Cells. AB - The isocitrate dehydrogenase (IDH) family of enzymes comprises of the key functional metabolic enzymes in the Krebs cycle that catalyze the conversion of isocitrate to alpha-ketoglutarate (alpha-KG). alpha-KG acts as a cofactor in the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). However, the relationship between 5hmC and IDH in gastric cancer remains unclear. Our study revealed that the 5hmC level was substantially lower and 5mC level was slightly higher in gastric cancer tissues; however, 5-formylcytosine (5fC) and 5 carboxylcytosine (5caC) levels did not change significantly in these tissues. We further examined the expression levels of IDH1 and IDH2 in gastric cancer tissues and observed that IDH2 levels were significantly lower in gastric cancer tissues than in the adjacent normal tissues. The ectopic expression of IDH2 can increase 5hmC levels in gastric cancer cells. In conclusion, our results suggested that IDH2 dysfunction is involved in 5hmC depletion during gastric cancer progression. PMID- 27466504 TI - Prognostic Impact of Activated Leucocyte Cell Adhesion Molecule (ALCAM/CD166) in Infantile Neuroblastoma. AB - BACKGROUND/AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166) as a member of the 'immunoglobulin superfamily' is known to be involved in cancer cell proliferation and migration. The aim of this study was to investigate the expression of ALCAM in neuroblastoma tissues. MATERIALS AND METHODS: ALCAM expression was analyzed in primary neuroblastoma specimens by immunohistochemistry on microarray sections. Histopathological and clinical data were correlated with ALCAM expression and survival analysis was performed. RESULTS: Sixty-six children were included in the study. Strong expression of ALCAM was detected in 52 (79%) of the samples. Weak expression was significantly correlated with the International Neuroblastoma Staging System (INSS) stage (p=0.024) and positive n-MYC amplification (p=0.019). Recurrence-free survival (RFS) and overall survival (OS) were significantly shorter if ALCAM was expressed weakly (p=0.032 and p=0.001). CONCLUSION: Weak ALCAM expression was significantly correlated with established markers for poor prognosis, as well as shorter RFS and OS. ALCAM might be considered as a prognostic marker for infantile neuroblastoma. PMID- 27466506 TI - Gene Variability Between Perineural-positive and Perineural-negative Squamous Cell Skin Cancers. AB - AIM: To identify differentially expressed genes (DEGs) between perineural invasion-positive (PP) and -negative (PN) cutaneous squamous cell cancers (CSCC). MATERIALS/METHODS: Forty CSCC samples with and without perineural invasion were processed for RNA isolation and hybridization to Affymetrix-U219 DNA microarrays. Raw gene expression data were normalized by Robust Multi-array Averaging (RMA) and log2 transformed. Gene expression-based classification models were created and accuracies evaluated using leave-one-out cross-validation. RESULTS: At a stringent limma p-value (p<0.001), 24 genes were differentially expressed between PP and PN samples. The cross-validated performance of the eight classification models exhibited a mean accuracy of 85-95%. Diagonal linear discriminant was most accurate at 95%, followed by Bayesian compound covariate at 94%. The poorest accuracy (85%) was observed for 1-Nearest neighbor and Support vector machines. CONCLUSION: Gene expression may distinguish between PP and PN CSCC. Understanding these gene patterns may potentiate more timely diagnosis of perineural invasion and guide comprehensive therapies. PMID- 27466505 TI - PTEN Insufficiency Increases Breast Cancer Cell Metastasis In Vitro and In Vivo in a Xenograft Zebrafish Model. AB - BACKGROUND/AIM: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) insufficiency is commonly found in breast cancer patients with metastasis. We investigated the mechanisms by which PTEN affects breast cancer metastatic behavior. MATERIALS AND METHODS: Migration and invasion assay, western blot, immunofluorescent staining and zebrafish animal model were applied. RESULTS: We showed that PTEN insufficiency induced an increase in MCF-7 cell migration and invasion through induction of epithelial-mesenchymal transition (EMT), which was triggered by up-regulation of the EMT-inducing transcriptional factors Zeb1, Zeb2, Snail, Slug and Twist. Simultaneously, E-cadherin expression was inhibited and P-cadherin was up-regulated. Further, WNT1 inducible signaling pathway protein 1 (WISP1) and lipocalin-2 (LCN2) expressions were increased after PTEN knockdown in MCF-7 cells, which also exhibited increased filamentous actin (F actin) synthesis and extracellular matrix metalloproteinase-2 (MMP-2) and MMP-9 expression. We further showed that PTEN knockdown in MCF-7 cells could increase cell migration in the xenograft zebrafish model. CONCLUSION: Our findings reveal new therapeutic targets for breast cancer patients with PTEN insufficiency. PMID- 27466507 TI - Chemokine and Chemokine Receptor Profiles in Metastatic Salivary Adenoid Cystic Carcinoma. AB - AIM: To characterize the chemokine pattern in metastatic salivary adenoid cystic carcinoma (SACC). MATERIALS AND METHODS: Real-time polymerase chain reaction (RT PCR) was used to compare chemokine and chemokine receptor gene expression in two SACC cell lines: SACC-83 and SACC-LM (lung metastasis). Chemokines and receptor genes were then screened and their expression pattern characterized in human tissue samples of non-recurrent SACC and recurrent SACC with perineural invasion. RESULTS: Expression of chemokine receptors C5AR1, CCR1, CCR3, CCR6, CCR7, CCR9, CCR10, CXCR4, CXCR6, CXCR7, CCRL1 and CCRL2 were higher in SACC-83 compared to SACC-LM. CCRL1, CCBP2, CMKLR1, XCR1 and CXCR2 and 6 chemokine genes (CCL13, CCL27, CXCL14, CMTM1, CMTM2, CKLF) were more highly expressed in tissues of patients without tumor recurrence/perineural invasion compared to those with tumor recurrence. CCRL1 (receptor), CCL27, CMTM1, CMTM2, and CKLF (chemokine) genes were more highly expressed in SACC-83 and human tissues of patients without tumor recurrence/perineural invasion. CONCLUSION: CCRL1, CCL27, CMTM1, CMTM2 and CKLF may play important roles in the development of tumor metastases in SACC. PMID- 27466508 TI - Enoxaparin Attenuates Mouse Colon Cancer Liver Metastases by Inhibiting Heparanase and Interferon-gamma-inducible Chemokines. AB - BACKGROUND/AIM: Low-molecular-weight heparin (LMWH) has been suggested to reduce the risk of cancer progression in both preclinical and clinical studies but the underlying mechanisms remain poorly explored. The aim of the study was to investigate the anti-metastatic role of enoxaparin, a clinically-used LMWH, in a murine model of colon cancer and to explore its underlying mechanisms. MATERIALS AND METHODS: Using a reproducible mouse model of colon carcinomas, we assessed the capacity of enoxaparin, a LMWH, to affect tumor metastasis of colon carcinoma cell lines in mice. RESULTS: The hepatic growth of colon carcinoma metastases was strongly inhibited by enoxaparin compared to (Ctrl) group (p=0.001). This effect was associated to an inhibition of heparanase mRNA expression and protein production both in vivo and in vitro. In addition, enoxaparin inhibited the liver and serum production of interferon gamma (Ifngamma)-inducible chemokine receptor ligands. Overexpression of heparanase prompted proliferation, migration and growth of colon carcinoma in vitro and in vivo to a point that was not affected by enoxaparin in vivo anymore. CONCLUSION: Enoxaparin decreased liver metastases in a mouse model of colon carcinoma. These results suggest that enoxaparin may benefit patients with cancer and deserves further laboratory and clinical investigations. PMID- 27466509 TI - Role of Genomic Instability in Immunotherapy with Checkpoint Inhibitors. AB - AIM: We evaluated whether tumor genome sequencing to detect the number and type of alterations could be used as a valuable biomarker for judging the potential utility of immune checkpoint inhibitors in patients with advanced cancers. MATERIALS AND METHODS: We identified patients with solid tumors who were treated with checkpoint inibitors and had received commercially available next generation sequencing (NGS). Tumors profiled by Caris Life Sciences, Foundation Medicine and Guardant360 between 2013 and 2015. Patients were divided into 5 quintiles based on mutational load (pathogenic mutations plus variants of undetermined significance). RESULTS: Fifty patients with solid tumors on immunotherapy that had NGS reports available were identified. Top quintile patients had more genomic alterations (median=16.5) than the others (median=2) and had more pathogenic mutations in cell-cycle regulatory genes (100% versus 48%). The overall survival (OS) was significantly superior for patients in the top quintile (722 days) versus the others (432 days). We found no significant difference in progression free survival (PFS) between the two groups. The objective response rate was numerically higher for the top quintile (50%) vs. others (20%). Programmed cell death protein 1 (PD1) and programmed death-ligand 1 (PDL1) status by immunohistochemistry was not associated with outcomes. CONCLUSION: The use of immune checkpoint blockade in tumors with higher mutational load was associated with improved OS. Our results suggest that the evaluation of tumor genomes may be predictive of immunotherapy benefit. PMID- 27466510 TI - DNA Repair Gene Expression Levels as Indicators of Breast Cancer in the Breast Cancer Family Registry. AB - AIM: The expression level of DNA repair-related genes and their association with breast cancer status among participants of the New York site of the Breast Cancer Family Registry was investigated. MATERIALS AND METHODS: RNA from mononuclear cells in 194 sister sets (n=475 women) were assayed for ATM, BRCA1, MSH2, MUTYH and XPC gene expression levels and analyzed using generalized estimating equations (GEE). RESULTS: Individuals with decreased ATM and MSH2 expression had significantly higher odds for breast cancer compared to individuals with higher levels of expression (odds ratio (OR)=1.1, 95% confidence interval (CI)=1.02, 1.18) and (OR=1.90, 95% CI=1.21, 2.97), respectively. Upon stratifying the GEE model, reductions in ATM and MSH2 expression levels was heightened among women with an extended family history (FH) of breast cancer. CONCLUSION: Reduced expression of ATM and MSH2 compromises DNA repair capacity and, thereby, increases breast cancer prevalence. PMID- 27466511 TI - Conversion to Neuroendocrine Carcinoma from Squamous Cell Carcinoma of the Esophagus After Definitive Chemoradiotherapy. AB - BACKGROUND/AIM: Neuroendocrine carcinoma (NEC) of the esophagus is rare and aggressive. We herein report a case of a patient who showed NEC conversion from squamous cell carcinoma (SCC) of the esophagus in the recurrent lesion after definitive chemoradiotherapy. CASE REPORT: The patient was a 57-year-old Japanese male with mid-thoracic esophageal carcinoma diagnosed as SCC with invasion of the submucosal layer. After definitive chemoradiotherapy, the esophageal tumor completely disappeared. Two months later, local recurrence was recognized at the same location and salvage surgery was performed. An immunohistochemical examination of the resected specimen revealed that most of the recurrent tumor had neuroendocrine (NE) differentiation, although a retrospective review of the initial biopsy specimen showed no involvement of NE differentiation. CONCLUSION: This case is significant not only in bringing attention to the possibility of NEC conversion from SCC after chemoradiotherapy, but also in discussing tumors originating in the esophagus. PMID- 27466512 TI - Effect of Adjuvant Radiotherapy on Survival in Patients with Locoregional Urothelial Malignancies of the Upper Urinary Tract. AB - BACKGROUND: While radical nephroureterectomy is the treatment of choice for localized or regional urothelial carcinoma of the upper urinary tract (UTUC), the role of adjuvant radiotherapy is unclear, with conflicting data from various small studies. PATIENTS AND METHODS: We sought to study the impact of adjuvant radiotherapy on UTUC by utilizing the Survelliance, Epidemiolgy, and End Results (SEER) 9 database from 1998-2011. RESULTS: Of 2,572 identified cases, 113 patients (4.4%) received adjuvant radiotherapy, with a median age of 74 years (range=22-100 years). In univariate analysis, patients treated with adjuvant radiation therapy seemed to have a lower survival time than those without radiation therapy (19 months versus 31 months, p<0.05). However, after adjusting for covariates, including age at diagnosis, gender, race, year of diagnosis, stage, histological grade and surgery, radiation therapy did not seem to influence survival (hazard ratio=0.68; 95% confidence interval=0.68-1.06, p=0.85). CONCLUSION: This hypothesis-generating, population-based analysis shows that adjuvant radiotherapy may not influence survival among patients with locoregional UTUC. PMID- 27466513 TI - Cyclin D1 Co-localizes with Beclin-1 in Glioblastoma Recurrences: A Clue to a Therapy-induced, Autophagy-mediated Degradative Mechanism? AB - BACKGROUND: Glioblastoma (GB) recurrences are rarely removed, therefore, tissue modifications induced by radiotherapy, and temozolomide chemotherapy are scarcely known. Nuclear cyclin D1 is associated with GB progression and resistance to therapy. We previously found that the expression of autophagic protein beclin-1 is a major determinant of prognosis in GB. PATIENTS AND METHODS: In 31 patients with primary GB and their recurrences, we investigated the protein expression of cyclin D1 and beclin-1, before and after radiotherapy-temozolomide therapy by immunohistochemistry. RESULTS: Most (20/31) primary GBs were negative for nuclear cyclin D1, and highly expressed beclin-1. In their recurrences, cytoplasmic cyclin D1 positivity was observable, which co-localized with beclin-1. Eleven primary GBs instead exhibited low beclin-1 expression and were positive for nuclear cyclin D1; three of their recurrences exhibited an increase of beclin-1, which co-localized with cyclin D1 in the cytoplasm. CONCLUSION: Our results suggest therapy-induced degradation of cyclin D1 via autophagy. PMID- 27466514 TI - Postoperative Closed-loop Glycemic Control Using an Artificial Pancreas in Patients After Esophagectomy. AB - AIM: This study investigated the efficacy of an artificial pancreas in managing postoperative glycemic levels for patients after esophagectomy. PATIENTS AND METHODS: We reviewed 107 patients with esophageal cancer who underwent esophagectomy, and had postoperative glucose management using the artificial pancreas. The target blood glucose level (TBGL) range was 90-140 mg/dl. Achievement rate of TBGL, total insulin use, number of severe hypoglycemic (<40 mg/dl) events, surgical complications and length of hospitalization (LOH) were evaluated. RESULTS: Mean achievement rate of TBGL was 78.2%. Mean total insulin use was 47.9 units. Mean blood glucose level was 136.3 mg/dl (mean SD=20.7). The incidences of pneumonia, anastomotic leak, and surgical site infection were 11.2%, 12.1%, 23.4%, respectively. The mean LOH was 29.6 days. No patient developed severe hypoglycemia. CONCLUSION: Artificial pancreatic systems could minimize blood glucose variability and prevent severe hypoglycemic events for patients after esophagectomy. PMID- 27466515 TI - Identification of SATB1 as a Specific Biomarker for Lymph Node Metastasis in Colorectal Cancer. AB - BACKGROUND/AIM: The integration of gene expression analysis and genomic profiling represents an efficient approach to the discovery of cancer-related genes. Lymph node metastasis (LNM) is a significant prognostic factor in colorectal cancer (CRC). Detection and analysis of factors related to LNM will help develop new diagnostic methods or therapies. In this study, we aimed to identify genes that are significantly related to LNM in CRC through integrated copy number analysis (CNA) and gene expression analysis. MATERIALS AND METHODS: Genes showing both up regulated expression and copy number gains in cases involving CRC with LNM were extracted as candidate biomarkers. Expression of the mRNA of the final candidate was validated in 124 patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Expression of the protein encoded by this candidate gene was assessed using immunohistochemical (IHC) staining of tissuesigma from 328 patients. The association between protein expression and clinicopathological features was also examined. RESULTS: Special AT-rich sequence binding protein 1 (SATB1) was extracted from integrated microarray analysis. SATB1 mRNA expression in cancer tissue was significantly higher in patients with LNM than without LNM. SATB1 protein overexpression was significantly associated with LNM. Moreover, overexpression of SATB1 was an independent poor prognostic factor in stage I-III, especially in stage II CRC. CONCLUSION: SATB1 may play an important role in LNM of CRC. SATB1 may be a biomarker of LNM and of recurrence after surgery for CRC. PMID- 27466516 TI - Bite Force and Masticatory Performance Using Implant-supported Overdentures After Treatment of Mandibular Cancer. AB - AIM: To evaluate overdentures with regard to artificial restoration of oral function following mandibular cancer. MATERIALS AND METHODS: We examined 32 patients who had undergone mandibular bone resection as treatment for malignancy and were using implant-supported overdentures. The patients were aged 55-87 years (mean=68.6) with a male to female ratio of 23:9. Marginal resection was performed in 29 patients and segmentectomy in 3. RESULTS: Before and after using the attachment for overdenture, oral function differed significantly. After the setting of implant-retained overdentures, maximum bite force increased on average by 362% (average, from 16.2 N to 58.8 N; p<0.01). Xylitol gum examination showed a 363% increase in masticatory performance (average, 3.1 to 8.0 points; p<0.01). CONCLUSION: Implant-retained overdenture resulted in improved oral function, that was lost after treatment for mandibular cancer. PMID- 27466517 TI - Concurrent Chemoradiation with Concomitant Boost in Locally Advanced Rectal Cancer: A Phase II Study. AB - AIM: The aim of this study was to evaluate the pathological response of locally advanced rectal cancer after preoperative concurrent two-drug chemotherapy and intensified radiation therapy (RT) with concomitant boost. PATIENTS AND METHODS: Patients with T4 tumor or local recurrence were included. A trial based on two stage Simon's design was planned. RT was performed with 3D-conformal technique. The dose to the mesorectum and pelvic lymph nodes was 45 Gy (1.8 Gy/fraction). A concomitant boost was delivered to Gross Tumor Volume (GTV) 2 cm margin to a total dose of 55 Gy (2.2 Gy/fraction). The following concurrent chemotherapy was administered: Raltitrexed (3 mg/m(2)) and oxaliplatin (130 mg/m(2)) on days 1, 17, and 35 of RT. Pathological response was evaluated according to the Mandard classification. Toxicities were scored according to the Common Terminology Criteria for Adverse Events v3.0 scale. RESULTS: Eighteen patients (median age=64.5 years) were enrolled. The median follow-up was 22 months (range=2-36 months). After chemoradiation treatment, 16 patients underwent surgical resection (seven anterior resections and nine abdominal-perineal amputation); two patients did not undergo surgery due to early metastatic progression or refusal. R0 resection was achieved in all patients who underwent surgery. Five patients had pathological complete response [27.7%; 95% confidence interval (CI)=9.7-53.5%] and two patients showed only microscopic residual disease (11.1%; 95% CI=0.1 34.7%). Mandard grades 1 and 2 were detected in seven patients (38.9%; 95% CI=17.3-64.3%). Acute grade 3 or more toxicity was found in eight patients (44.4%; 95% CI=21.5-69.2%): one leucopenia-neutropenia, one liver, one skin and five cases of gastrointestinal toxicities. No patient had local tumor recurrence. One-, 2- and 3-year cumulative disease-free survival were 93.8%. One-, 2- and 3 year cumulative overall survival were 92.3%. CONCLUSION: Concurrent chemoradiation with concomitant boost in patients with advanced rectal cancer allows complete or near-complete pathological response in more than 38% of patients. However, severe acute toxicity was reported in more than one-third of patients. PMID- 27466519 TI - Optic Pathway Glioma and Cerebral Focal Abnormal Signal Intensity in Patients with Neurofibromatosis Type 1: Characteristics, Treatment Choices and Follow-up in 134 Affected Individuals and a Brief Review of the Literature. AB - Optic pathway glioma (OPG) is a rare neoplasm and a defining feature of neurofibromatosis type 1 (NF1), a tumor suppressor genetic disorder. OPG predominantly arises during childhood. In contrast to sporadic OPG, this neoplasm frequently appears to show a more favorable course. Outcome appears to depend on localization of tumor; however, the correlation of imaging findings and visual acuity is in general low. Treatment for symptomatic OPG is not well standardized. Furthermore, determination of visual acuity as the most important parameter of follow-up control is often difficult to determine, particularly in children. Focal abnormal signal intensity (FASI) is a characteristic finding on magnetic resonance imaging (MRI) of NF1 patients. The aim of this study was to evaluate clinical and imaging findings of NF1 patients affected with OPG. PATIENTS AND METHODS: Data of 925 NF1 patients with appropriate MRI cranial sectional images (N=1,948) were evaluated. A further 50 patients with cranial computed tomograms were included in the study. We compared imaging and clinical findings with respect to localization of OPG. Furthermore, we compared follow-up in treated individuals to those who were only regularly re-examined. The presence of FASI on MRI was determined and correlated to the occurrence of OPG. Dodge classification was applied to categorize OPG location. RESULTS: OPG was diagnosed in 134 patients. The mean age of patients with symptomatic OPG was 7.6 years (n=57, 42.5%) and 11.6 years (n=77, 57.5%) in asymptomatic patients. The female to male ratio was about 1.1:1. In 48 symptomatic patients, the findings of initial ophthalmological investigations were available. In symptomatic patients, reduced visual acuity was the predominant finding. Strabismus (25%), exophthalmos (22.9%) and amblyopia (20.8%) were most frequently noticed, followed by endrocrinological abnormalities (14.6%). However, these findings did not differ between patients who were treated or who were subjected to a 'wait-and-see' policy. We could not verify an effect of therapy on vision in patients treated for OPG compared to symptomatic patients without treatment. OPG affecting the total optic pathway was more frequently diagnosed in symptomatic patients. FASI did not correlate with functional OPG status. CONCLUSION: OPG in NF1 is symptomatic in slightly less than 50% of affected individuals. This neurological finding may show a wide range of symptoms. At present, no established treatment protocol emerges from the history of the patients of this study and also from the literature. Although the onset of symptomatic OPG is strongly associated with early childhood, late onset of symptomatic OPG is a feature of adult NF1. Research for association of FASI to neurological findings in these patients should be based on other issues than association with OPG. PMID- 27466518 TI - Influence of Chemotherapy on the Antioxidant Status of Human Skin. AB - BACKGROUND: Palmoplantar erythrodysesthesia is a frequent dermal side-effect during chemotherapy. Previous investigations showed radical formation subsequent to doxorubicin infusion and preventative and therapeutic effects of an antioxidant-containing ointment. PATIENTS AND METHODS: Using a non-invasive vivomeasuring system (Biozoom(r); Biozoom Services GmbH, Kassel, Germany) changes in the antioxidant status (as measured by relative carotenoid concentration) of the skin prior to and after intravenous administration of paclitaxel, docetaxel and 5-fluorouracil were investigated in 42 patients with cancer. RESULTS: A significant decrease of antioxidant concentration subsequent to intravenous administration was found for all investigated chemotherapeutic agents. The mean concentration of carotenoids decreased from 3.59+/-1.26 arbitrary units (a.u.) to 3.41+/-1.28 a.u. (p<0.001) after paclitaxel administration, from 6.33+/-2.43 to 5.63+/-2.29 a.u. after docetaxel (p=0.027) and from 4.26+/-1.81 to 3.98+/-1.53 a.u. (p=0.042) after 5-fluorouracil infusion. CONCLUSION: Oxidative stress might play a significant role in the pathomechanism of palmoplantar erythrodysesthesia associated with paclitaxel, docetaxel and 5-fluorouracil. Therefore, an antioxidant-containing ointment might serve as preventative and therapeutic option. PMID- 27466520 TI - Symptom Assessment for Patients with Non-small Cell Lung Cancer Scheduled for Chemotherapy. AB - AIM: This study assessed the symptoms and health-related quality of life (HRQOL) of patients with advanced non-small cell lung cancer (NSCLC) and examined the symptom-associated characteristics. PATIENTS AND METHODS: The symptoms of 122 patients with NSCLC scheduled for chemotherapy before starting treatment were surveyed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and Edmonton Symptom Assessment Scale (ESAS). RESULTS: The most prevalent symptoms were coughing (EORTC score 41.7), dyspnea (33.9), fatigue (31.9), insomnia (30.3) and pain (21.8). The mean EORTC score for global QoL was 56.9 (SD=23.5). Physical, cognitive and emotional functioning, insomnia, diarrhea, and dyspnea had a significant influence on the HRQOL (p<0.05). ESAS assessment correlated with these results and thus was an easy-to-use tool for symptom assessment (correlation coefficient range=0.546 0.865, p<0.0001 for all symptoms). CONCLUSION: Patients with advanced NSCLC suffer from multiple symptoms influencing HRQOL. ESAS provides a symptom assessment tool that is as reliable as but simpler to use than the EORTC questionnaire. PMID- 27466521 TI - Prevalence of H. pylori Infection and Atrophic Gastritis in a Population-based Screening with Serum Biomarker Panel (GastroPanel(r)) in St. Petersburg. AB - BACKGROUND/AIM: Russian Federation is among the high-incidence countries for gastric cancer (GC), with the incidence being projected to continue increasing. Using a non-invasive blood test with four stomach-specific biomarkers (pepsinogen I (PG-I) and -II (PG-II), amidated gastrin-17 (G-17) and Helicobacter pylori (HP) IgG antibodies) in a hospital-based screening setting, we aimed to determine the prevalence of GC risk conditions: HP-infection and atrophic gastritis (AG). PATIENTS AND METHODS: A population-derived cohort of 918 asymptomatic subjects (646 women and 272 men) with a mean age of 51.8 years (range=26-83) was examined with the GastroPanel(r) (GP) test. GP results were verified by gastroscopy and biopsies (the Updated Sydney System (USS) classification for all test-positive AG cases and for random 5% test-negatives (n=263) to correct for the verification bias. RESULTS: Of the 918 subjects, only 199 (21.7%) tested completely normal, while 76.7% (704/918) had HP-infection. Altogether, in 99 subjects (10.8%), GP suggested AG: atrophic gastritis in the antrum (AGA) (n=21), atrophic gastritis in the corpus (AGC) (n=69) or atrophic pangastritis (AGpan) (n=9). The overall concordance between GP and USS classification was 82.5% (217/263) with weighted kappa intra-class correlation coefficient (ICC)=0.875 (95% confidence interval (CI)=0.840-0.901). The sensitivity/specificity balance in receiver operating characteristic (ROC) analysis for PG-I as a marker of moderate/severe AGC (AGC2+) had area under the curve (AUC)=0.895 (95%CI=0.837-0.953). Using the AGC2+ end point, verification bias-corrected specificity of PGI reached 96.4% (95%CI=94.7 97.9) and that of PGI/PGII ratio 94.6% (95%CI=92.6-96.3), with inevitable erosion in sensitivities. CONCLUSION: While capable of detecting the subjects at risk for GC (HP and/or AG), GP should be the cost-effective means to break the current ominous trend in GC incidence in Russian Federation. PMID- 27466522 TI - Comparison of Transumbilical and Conventional Defunctioning Ileostomy in Laparoscopic Anterior Resections for Rectal Cancer. AB - BACKGROUND/AIM: Laparoscopic surgery has made possible anterior resections with small incisions suitable for creating stomas. We retrospectively compared surgical results and stomal complications between transumbilical defunctioning ileostomy (TDI) and conventional defunctioning ileostomy (CDI) in laparoscopic anterior resections for rectal cancer. PATIENTS AND METHODS: We compared patients who underwent laparoscopic anterior resection with TDI (n=47) with those undergoing CDI (n=27) for rectal cancer between February 2011 and January 2015. RESULTS: For the initial operations, the TDI group had significantly less intraoperative blood loss (30.3 ml vs. 117.0 ml; p=0.014). For stomal closure, the TDI group experienced significantly fewer wound infections (2 vs. 8 cases; p=0.002) and bowel obstructions (none vs. 3 cases; p=0.039). No significant differences in stomal complication rates were observed. CONCLUSION: TDI is associated with better surgical results and fewer complications than CDI after laparoscopic anterior resection for rectal cancer. PMID- 27466523 TI - Bone Marrow Metastases from a 1p/19q Co-deleted Oligodendroglioma - A Case Report. AB - BACKGROUND: Metastasis of oligodendroglioma outside of the central nervous system (CNS) is a very rare event. CASE: We describe in detail the clinical story of a 50-year-old woman diagnosed with profound pancytopenia and signs of extramedullary hematopoiesis caused by diffuse bone marrow replacement by a metastatic oligodendroglioma. RESULTS: Upon development of pancytopenia, a diagnostic bone marrow examination revealed the presence of metastatic oligodendroglial cells. No others sites of malignant dissemination were found outside the CNS. Despite best supportive care, the patient died three weeks after diagnosis of myelophthisis. CONCLUSION: Extracranial metastases from CNS oligodendroglioma are a very rare event but can be the cause of bone marrow failure. PMID- 27466524 TI - Benign and Malignant Salivary Gland Tumors - Clinical and Demographic Characteristics. AB - AIM: To examine the demographic, ethnic, and clinical characteristics of salivary benign and malignant tumors for better etiological understanding. PATIENTS AND METHODS: We examined medical records of 287 primary salivary gland tumor patients. RESULTS: Overall, 216 tumors were benign and 71 malignant. The mean age at diagnosis was 56.4 years for those with malignant tumors and 48.5 years for those with benign, a highly significant difference (p=0.001). Females had 45% of malignant tumors and 59% of benign, a significant difference (p=0.037). Ethnic origin, alcohol consumption and cigarette smoking rates were not significantly different (p>0.05) between groups. A total of 87% of benign and 55% of malignant tumors were in the parotid glands, a highly significant predilection (p<0.0001), sublocated mostly in the superfacial lobe; 36.6% of malignant tumors and 4.7% of benign (p<0.0001) were in the minor salivary glands, mostly in the hard palate. CONCLUSION: Baseline clinical, demographic and locational aspects of benign and malignant tumors are substantiated. PMID- 27466525 TI - Computational and Immunohistochemical Analyses Highlight AXL as a Potential Prognostic Marker for Ovarian Cancer Patients. AB - BACKGROUND/AIM: The activation of the membrane tyrosine kinase AXL is implicated in the migration and invasion in several carcinomas, including ovarian cancer. Herein, we investigated the association of the expression of AXL transcript and protein to the aggressiveness of ovarian cancer, as well as to patient outcome. MATERIALS AND METHODS: Overall and relapse-free survival were determined with respect to AXL transcript levels by computational analysis on two publicly available datasets containing data of gene expression from high-grade ovarian cancers (n=776). Immunohistochemical evaluation of AXL protein expression was then performed using a proprietary tissue microarray consisting of 62 ovarian cancers of different histology, grading and staging. Expression was analyzed for association with clinicopathological parameters, including survival. RESULTS: In both analyzed datasets, AXL transcript expression was significantly associated to both overall and relapse-free survival in high-grade ovarian cancers. Membrane expression of AXL protein was observed in 89% of the analyzed ovarian cancers. A significant correlation was found between AXL expression and serous histologic subtype, higher tumor grade and type II tumors. No significant association between AXL protein expression and patient survival was found in our cohort. AXL is frequently expressed in high-grade serous ovarian cancers and its expression is significantly associated to tumors displaying poor prognosis. CONCLUSION: AXL is a potential prognostic marker for the most aggressive ovarian carcinomas. PMID- 27466526 TI - Adjuvant Therapy for Salivary Gland Carcinomas. AB - AIM: We compared the clinical outcomes and toxicity profile among a retrospective cohort of patients with primary major salivary gland carcinomas (SGCs) treated with surgery followed by adjuvant radiation therapy (S+RT) versus surgery and adjuvant chemoradiotherapy (S+CRT). PATIENTS AND METHODS: Twenty patients (71%) underwent S+RT and eight (29%) S+CRT at our Institution between 2006 and 2015. Microscopic positive margins were present in 54% of the patients. RESULTS: The 3 year overall survival (OS) was 100% with S+RT and 87.5% with S+CRT (p=0.141) and locoregional control (LRC) was 95% with S+RT and 87.5% with S+CRT (p=0.383). There were no significant differences in the rate of acute (p=0.801) and late (p=0.714) toxicities. CONCLUSION: While we await randomized data, adjuvant CRT may be considered as a viable therapeutic option for patients at high-risk of local or regional recurrence, especially in those with a positive microscopic margin where further surgery may result in functional cranial neuropathies. PMID- 27466527 TI - Clinical Value of Serum p53 Antibody in the Diagnosis and Prognosis of Colorectal Cancer. AB - BACKGROUND: Serum p53 antibody (s-p53Ab), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were investigated to evaluate the significance of these singly and combined tumor markers in the diagnosis and prognosis of colorectal cancer (CRC). PATIENTS AND METHODS: Preoperative serum samples were obtained from 170 patients with histologically confirmed CRC, including 28 (16%) with stage I. s-p53Ab was assessed using the MESACUP Kit II, that is a new and highly specific version of a quantitative p53-Abs enzyme-linked immunosorbent assay. RESULTS: s-p53Ab was detected in 30.6% (52 out of 170) of patients with CRC, including 31.9% (29/91) of patients with early-stage CRC. The positive rates for CEA and CA19-9 of patients with CRC were 28.8% (49/170) and 22.9% (39/170), respectively. Combining use of s-p53-Ab with CEA increased the positive rate of a diagnosis of CRC to 48.8%. Positivity for s-p53Ab in CRC did not correlate with overall survival. On the other hand, Cox regression analysis of this series revealed that high levels of CEA served as an independent prognostic factor for CRC. Kaplan-Meier analysis revealed significant differences between patients with elevated s-p53Ab and CEA and those with elevated levels of either one or neither of these factors (p<0.001). CONCLUSION: The diagnostic rate of s-p53Ab was better than that of CEA and CA19-9 in patients with early-stage CRC. Combined detection of s-p53Ab and CEA can improve diagnostic sensitivity and may permit more accurate stratification of patients with CRC. PMID- 27466528 TI - Karnofsky Performance Score, Radiation Dose and Nodal Status Predict Survival of Elderly Patients Irradiated for Limited-disease Small-cell Lung Cancer. AB - AIM: Elderly patients require special consideration in oncology treatment. Small cell lung cancer (SCLC) is a highly aggressive tumour with dismal prognosis. The present study focused on prognostic factors in elderly patients irradiated for limited-disease SCLC. PATIENTS AND METHODS: In 36 patients aged >=65 years, 11 factors were evaluated for the impact on survival, namely gender, Karnofsky performance score, body mass index, T-category, N-category, tobacco consumption, time from SCLC diagnosis to irradiation, smoking during irradiation, simultaneous chemotherapy, radiation dose and prophylactic cranial irradiation. RESULTS: On multivariate analysis, Karnofsky performance score of >70 (p<0.001), N-category 0 2 (p<=0.001) and total radiation dose of >52 Gy (p=0.011) were significantly associated with better survival. CONCLUSION: Significant predictors of survival in elderly patients irradiated for limited-disease SCLC were identified. A radiation dose of >52 Gy resulted in improved survival when compared to lower doses. PMID- 27466529 TI - Target Volume Delineation Based on Diffusion-weighted magnetic Resonance Imaging for Locally Advanced Head and Neck Cancer. AB - AIM: To compare gross tumor volume (GTV) definition in locally advanced head and neck squamous cell carcinoma (LAHNSCC) using diffusion-weighted magnetic resonance imaging (DW-MRI) and computed tomography (CT) with intravenous contrast. PATIENTS AND METHODS: Patients with LAHNSCC were imaged with CT and DW MRI before treatment. GTV was delineated in both CT and DW-MRI images by two investigators. CT and MRI images were co-registered and volume data were extracted for statistical analysis. RESULTS: In general, DW-MRI volumes [based on the apparent diffusion coefficient (ADC)] were smaller than CT-based volumes. For all patients, GTV delineation based on pre-treatment DW-MRI was significantly smaller than that based on CT scan (CT-GTV) (p=0.0078). The mean difference (95% limits of agreement) between the two investigators was -0.37 cm(3) for CT-GTV and 0.17 cm(3) for ADC-GTV measurements, respectively. CONCLUSION: DW-MRI radiotherapy GTVs are smaller than CT-based targets with less interobserver variability. Further validation of these preliminary results is necessary in a much larger patient group. PMID- 27466530 TI - Clinical Value of 18F-fluorodihydroxyphenylalanine Positron Emission Tomography/Contrast-enhanced Computed Tomography (18F-DOPA PET/CT) in Patients with Suspected Paraganglioma. AB - AIM: To evaluate (18)F-fluorodihydroxyphenylalanine-positron emission tomography/ contrast-enhanced computed tomography ((18)F-DOPA PET/CT) for the detection of paragangliomas (PARA) without any patient selection, such as genetic predisposition for the development of these tumors, history of metastatic PARA or hormonal status. PATIENTS AND METHODS: In this retrospective study, 28 consecutive patients (15 women, 13 men; mean age=46.4 years; age range=19-73 years), who were referred to our PET/CT center for the detection of clinically suspected PARA, were included. Final diagnosis was confirmed by histological reports of surgically proven lesions and/or clinical follow-up (including laboratory results and/or PET/CT follow-up). RESULTS: On a per-lesion basis (45 lesions) analysis, there was a sensitivity of 64.3% for CT, 73.8% for PET, 100% for PET/CT and a positive predictive value (PPV) of 93.1% for CT, 96.9% for PET and 100% for PET/CT. On a per-patient basis analysis, the sensitivity, specificity and accuracy for CT was 86.7%, 84.6% and 85.7%, respectively, and, for PET 80%, 100% and 89.3%, respectively, and, for PET/CT 100%. CONCLUSION: Based on our data, (18)F-DOPA PET/CT is a "one-stop diagnostic modality" for the assessment of patients with suspected PARA. PMID- 27466531 TI - Ovarian Metastases from Breast Cancer: A Series of 28 Cases. AB - BACKGROUND/AIM: Ovarian metastases from breast cancer present diagnostic and therapeutic challenges. We conducted a two-center retrospective study to analyze the characteristics and evolution of patients with histologically proven ovarian metastases from breast cancer. PATIENTS AND METHODS: The records of 28 patients were analyzed, taking into consideration clinical and biological characteristics of primary breast tumors and ovarian metastases. Moreover, the outcomes of patients after diagnosis of metastases were analyzed by comparing two patient groups defined by whether the surgical treatment of ovarian metastases was optimal (residual tumor <2 cm) or not (residual tumor >2 cm). RESULTS: Ovarian metastases are largely found in primary breast cancer patients with poor prognostic factors (large tumor size, positive lymph nodes, high-grade) and lobular histology, occurring on average 5 years after the diagnosis of breast cancer. Their symptoms are mild and measurement of serum markers cancer antigen (CA) 125 and CA 15-3 is useful. Their prognosis is bleak due to frequent co existence with other metastatic sites. Lobular histology of the initial breast tumor is the only significant poor prognostic factor in our study. CONCLUSION: Women with lobular carcinoma of the breast and poor prognostic factors may benefit from ovarian surveillance based on CA 125. Following the discovery of ovarian metastases from breast cancer, further investigations are warranted to determine the extent of disease, specifically whether multiple metastases are present. Treatment of a solitary ovarian metastasis is based on surgery leaving no residual disease and adjuvant systemic treatment. PMID- 27466532 TI - Safety and Efficacy of Robot-assisted Radical Prostatectomy in a Low-volume Center: A 6-year Single-surgeon Experience. AB - AIM: To analyze safety and efficacy of robot-assisted radical prostatectomy (RARP) in a low-volume centre. PATIENTS AND METHODS: From 2008 to 2015, 400 consecutive patients undergoing RARP were prospectively enrolled. Complications were classified according to the Modified Clavien System. Biochemical recurrence (BCR) was defined as two consecutive prostate-specific antigen (PSA) values >=0.2 ng/ml. Functional outcomess were assessed using validated, self-administered questionnaires. RESULTS: Median patient age was 64.5 years. Mean standard deviation (SD) preoperative PSA level was 11.3 (11.7) ng/ml. Median interquartile range (IQR) follow-up was 36 (12-48) months. Overall complication rate was 27.7% (minor complications rate 16.2%). Overall 1-, 3- and 6-year BCR-free survival rates were 85.7%, 77.5% and 53.9%, respectively; these rates were 94.1%, 86.2% and 70.1% in pT2 diseases. At follow-up, 98.4% of patients were fully continent (median (IQR) time to continence was 2 (1-3) months) and 68.2% were potent (median (IQR) time to potency of 3 (3-4) months). CONCLUSION: RARP appears to be a valuable option for treating clinically localised prostate cancer also in a low volume institution. PMID- 27466534 TI - Cronkhite-Canada syndrome - A Case report. AB - BACKGROUND/AIM: Cronkhite-Canada syndrome (CCS) is a non-inherited, sporadic disorder characterized by generalized gastrointestinal polyps (hamartomas), cutaneous pigmentation, alopecia and onychodystrophy. More than 500 CCS patients have been reported, mostly from Asian countries. Patients with CCS have a propensity to develop colonic traditional serrated adenomas (TSA). Some authors found increased frequency of colonic carcinomas in CCS patients. In the present communication, we report a patient with CCS in whom a colonoscopic examination failed to disclose a coexistent TSA. CASE REPORT: A 73-year-old female had a history of alopecia and nail atrophy. Because of iron deficiency anemia and occult gastrointestinal bleeding, she underwent a colonoscopic examination. RESULTS: Colonoscopy revealed multiple broad-based polyps. Due to continuous bleedings, a coloproctectomy was performed four months after colonoscopy. Pathology disclosed 50 hamartomas and, unexpectedly, a TSA with high-grade dysplasia in the cecum. CONCLUSION: The TSA was either overlooked at colonoscopy or not interpreted as different from the other colonic polyps by the endoscopist. CCS cases are very rare in Western countries. Given this circumstance, it is suggested that, when confronting the next CCS case, endoscopists should perform a comprehensive colonoscopic examination, including chromoscopy and directed biopsies from irregular polyps, to rule out a TSA, an adenoma prone to evolve into invasive carcinoma. PMID- 27466533 TI - Circulating Growth and Angiogenic Factors and Lymph Node Status in Early-stage Breast Cancer - A Pilot Study. AB - AIM: To evaluate the possibility of selected biomarkers for breast cancer diagnostics and/or treatment monitoring, lymph node (LN) status determination and clinical decision regarding axillary node dissection. PATIENTS AND METHODS: Two hundred and eleven patients with malignant breast cancer and 42 age-matched healthy controls were enrolled. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and plasma epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), osteoprotegerin (OPG) and osteopontin (OPN) were measured. We compared patients versus controls, patients with negative versus positive lymph node and patients with and without axillary lymph node dissection (ALND). RESULTS: We found elevated IGF1 and VEGF levels in patients with lymph node metastases compared to controls (p=0.0179 and p=0.0091, respectively) and in patients with ALND (p=0.0337 and p=0.0438, respectively). CONCLUSION: Circulating IGF1 and VEGF levels may predict the presence of lymph node metastases and help in the decision to avoid ALND in patients with early-stage breast cancer. PMID- 27466535 TI - Risk Factors of Lymph Nodes Metastases by Endometrial Cancer: A Retrospective One center Study. AB - BACKGROUND/AIM: We aimed to identify the surgical-pathological risk factors separately for pelvic and para-aortic lymph nodes (LN) metastases in endometrial cancer (EC). PATIENTS AND METHODS: The study cohort consisted of 179 patients with first diagnosis of EC, who were operated in our Institution between 2007 and 2014. RESULTS: Pelvic and para-aortic LN dissection was performed in 115 patients (64.2%). The positive pelvic and para-aortic LN were diagnosed in 11.3% and 16.1% of cases, respectively. Patients with bad differentiated tumors (G3) showed about 5-times more risk to have affected LN. Deep infiltration of myometrium elevated the risk of pelvic LN infiltration 5 times and of para-aortic LN infiltration 14 times. G3, myometrial infiltration >50% and type II endometrial cancer correlated with a worse progression free survival (PFS) and overall survival (OS). CONCLUSION: Tumor grade and deep myometrial invasion were the only significant predictors of pelvic and para-aortic lymph node metastases. PMID- 27466536 TI - Implementation of Enhanced Recovery After Surgery (ERAS) Pathways in Gynecologic Oncology. A NOGGO-AGO* survey of 144 Gynecological Departments in Germany. AB - AIM: To gather standardized information of current perioperative management of gynecological oncology patients and to evaluate up to what extent the Enhanced Recovery after Surgery (ERAS) elements are established in the clinical routine of gynecologic oncology units in Germany. MATERIALS AND METHODS: We performed a multi-centric nationwide survey among 654 primary, secondary and maximal health care gynecological departments in Germany. A multiple-choice questionnaire based on the principles of ERAS was developed to gather information about perioperative management of two fictional cases in gynecological oncology. RESULTS: One hundred four units (22%) have been taken the survey. Only 49.5% of surveyed hospitals claimed to be adherent to more than 70% of ERAS elements in managing perioperative period of primary cytoreductive surgery in ovarian cancer patients. 21% of these hospitals implemented more than 80% and only 8.4% implemented more than 90%. The results in border-line tumors operations did not differ from those of ovarian cancer operations. CONCLUSION: The implementation of ERAS elements in gynecologic oncology in Germany is still not satisfying as only half of the departments will now be able to apply 70% of these principles. Therefore, we plan the second step of this survey in order to be able to build a consistent structured reporting platform between gynecological oncology units in Germany to facilitate the wide implementation and standardization of ERAS protocol. PMID- 27466537 TI - Lack of Relationship Between Clinical Features and KRAS Mutations in Patients with Metastatic Colorectal Cancer. AB - BACKGROUND/AIM: We previously identified three clinical predictive factors of efficacy of cetuximab-irinotecan. Here, we analyzed the clinical characteristics of patients with metastatic colorectal cancer (CRC) in order to detect potent correlations with KRAS mutations. PATIENTS AND METHODS: We conducted a retrospective, multicenter study between 2008 and 2012. We included patients with metastatic colorectal adenocarcinomas, previously treated by irinotecan, and with an available KRAS mutation test. RESULTS: We included 299 patients. The median age was 60 years; the median number of metastatic sites was 2. One hundred and eight patients (36.1%) had a previous objective response to irinotecan. The median interval between diagnosis and irinotecan discontinuation was 1.94 years. A KRAS mutation was detected in 133 patients (44.5%). In univariate and multivariate analyses, none of the assessed factors was associated with the presence of a KRAS mutation. CONCLUSION: No easily clinically assessable parameter was significantly associated with KRAS mutations in patients with colorectal cancer. PMID- 27466538 TI - Improved Efficacy by Addition of Protein-bound Polysaccharide K to Adjuvant Chemotherapy for Advanced Gastric Cancer. AB - AIM: To evaluate the efficacy of protein-bound polysaccharide K (PSK) added to S 1 adjuvant chemotherapy for treatment of advanced gastric cancer. PATIENTS AND METHODS: We retrospectively examined clinicopathological and recurrence-free survival (RFS) data for 136 patients with stage II or III advanced gastric cancer who underwent S-1 adjuvant chemotherapy with or without PSK. RESULTS: Among 13 clinicopathological factors, non-T4 stage (odds ratio (OR)=0.61; 95% confidence interval (CI)=0.41-0.89; p<0.01), N0-1 (OR=0.65; 95% CI=0.43-0.95; p=0.03) and number of treatment cycles >=7 (OR=0.37; 95% CI=0.20-0.67; p<0.01) were significant independent factors for better RFS. The number of treatment cycles of S-1 plus PSK was significantly higher than that of S-1 alone (p<0.01). CONCLUSION: S-1 adjuvant chemotherapy combined with PSK may reduce recurrence by prolonging the treatment cycles in patients with advanced non-T4 or N0-1 gastric cancer. PMID- 27466539 TI - Equivalent Outcome of Patients with Locally Advanced NSCLC Treated with Salvage Surgery Compared to Induction Chemotherapy Followed by Surgical Resection. AB - BACKGROUND: There have, so far, been few previous reports concerning the use of salvage surgery in small number of patients with primary lung cancer and there are no reports currently available regarding salvage surgery compared to other treatments. PATIENTS AND METHODS: The postoperative complications and long-term survival of patients with non-small cell lung cancer (NSCLC) who received salvage surgery compared to induction chemotherapy followed by surgery from 2000 and 2013, were evaluated. RESULTS: During the study period, 1,847 consecutive patients with lung cancer underwent pulmonary resection at our Institution. Salvage operations were performed in 16 (0.9%) patients. The clinical stages were diagnosed as stage IIB in 1, IIIA in 8, IIIB in 6 and stage IV in 1 patient. The mean interval between initial treatment and surgery was 31.4 months. The surgical procedures were lobectomy in 9, pneumonectomy in 4 and partial resection in 3 patients. The operation was performed during a mean of 303 min; no case required blood transfusion. Complete resection was performed in 81% of the patients. Thus, the morbidity was 31.3% and the mortality rate was 0%. The five-year overall survival (OS) rates in the patients with induction chemotherapy followed by surgery and salvage surgery were 65.2 and 62.2%, respectively, (p=0.460) when OS was calculated from the date of registration to the date of initial treatment. The median survival for patients receiving salvage surgery was 64.4 months at any rate when OS was calculated from the date of registration for initial treatment or surgery. CONCLUSION: Salvage surgery can be performed safely with no mortality and is associated with a reasonable long-term survival, equivalent to the outcome of induction chemotherapy followed by surgical resection. PMID- 27466540 TI - A Prognostic Nomogram for Overall Survival of Patients After Hepatectomy for Intrahepatic Cholangiocarcinoma. AB - AIM: We hypothesized that a nomogram can accurately predict overall survival (OS) for patients with intrahepatic cholangiocarcinoma (ICC) after hepatectomy. MATERIALS AND METHODS: A nomogram to predict OS based was developed using data from 185 ICC patients who had undergone hepatectomy. The nomogram was evaluated by concordance index (C-index), as well as testing calibration of predicted OS with observed OS for both internal and external cohorts. RESULTS: Ten clinicopathological independent factors for OS prediction were selected for use in the nomogram. For internal validation, the calibration curve for probability of OS showed good agreement between prediction by the nomogram and actual observation. In three external validation cohorts, the nomogram discrimination was also superior to two other staging systems. CONCLUSION: A nomogram integrating ten clinicopathological variables was developed that may assist in individual prognostic prediction of ICC after hepatectomy. PMID- 27466541 TI - Progression-free Survival as a Surrogate End-point in Advanced Colorectal Cancer Treated with Antiangiogenic Therapies. AB - BACKGROUND: It is not clear if progression-free survival (PFS) is a good surrogate end-point for overall survival (OS) for metastatic colorectal cancer if antiangiogenic therapies are used. MATERIALS AND METHODS: We investigated randomized controlled trials testing antiangiogenic agents against chemotherapy. Log hazard ratios (HR) for PFS and OS were used to construct linear regression models. The surrogate threshold effect (STE) was calculated. RESULTS: Thirteen studies and 24 comparison arms were available, including 7,179 patients. This model returned a significant correlation between PFS and OS (R(2)=0.68, p<0.001) with an STE of 0.83. Analysis restricted to first-line gave similar results (R(2)=0.68, p<0.001, STE=0.75). CONCLUSION: There is a significant correlation between the effect of treatment on PFS and OS. PFS remains a good surrogate end point for OS even if anti-angiogenic agents are used. PMID- 27466542 TI - Non-small Cell Lung Cancer in South Wales: Are Exon 19 Deletions and L858R Different? AB - BACKGROUND/AIM: In advanced non-small cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) mutations L858R and exon 19 deletion (del19) predict response to EGFR tyrosine kinase inhibitors (TKIs). Trials have suggested a differential response to the second-generation EGFR TKI afatinib in favour of del19. We investigated whether this differential response is observed in clinical practice. MATERIALS AND METHODS: Retrospective demographic, treatment and outcome data were collected on patients with: stage III/IV NSCLC and either del19 or L858R, receiving an EGFR TKI as first-line treatment. RESULTS: There was no significant difference in overall survival (OS) between del19 (648 days, 95% confidence interval (CI)=461-835) and L858R (813 days, 95%CI=387-1,238), (p=0.616), or in duration of therapy between del19 (365 days, 95% CI=192-538) and L858 (428 days, 95% CI=263-593), (p=0.928). CONCLUSION: Patients with exon del19 did not have a significantly longer OS with first-generation TKIs. PMID- 27466543 TI - Long-term Survival After Surgical Treatment of Renal Cell Carcinoma Metastasis Within the Pancreas. AB - BACKGROUND: The role of radical pancreatic surgery for metastatic lesions of renal cell carcinoma (RCC) remains unclear. PATIENTS AND METHODS: In this analysis, 19 patients underwent pancreatic resections for metastases of RCC between 2000 and 2014. RESULTS: Pancreatic metastases were diagnosed 10.2+/-27.1 years after primary diagnosis of RCC. Surgical approaches included pylorus preserving pancreatoduodenectomy (PPPD) (n=10, 55.6%), followed by distal pancreatectomy (n=5, 27.8%) and total pancreatectomy (n=4, 22.2%). The survival after 1, 3 and 5 years was 88.9%, 80% and 71.4%, respectively. Patients after PPPD procedure had a significant worse survival (p=0.030). RCC stage VI tumors seem to be associated with decreased short- and long-term survival rates (p=0.03). Additional metastatic lesions in the further postoperative course had no impact on outcome. CONCLUSION: The results of our analysis demonstrate promising long-term results with regard to disease-free and overall survival after surgical therapy for pancreatic metastases of renal cell carcinoma. PMID- 27466544 TI - The Value of Endorectal Magnetic Resonance Imaging of the Prostate in Improving the Detection of Anterior Prostate Cancer. AB - BACKGROUND/AIM: The diagnosis of anterior prostate cancer (APC) is troublesome due to its anatomical location. Patients with an APC often require multiple sets of biopsies until diagnosis is made. The objective of this study is to examine if endorectal magnetic resonance imaging (e-MRI) of the prostate could improve the detection of APC. PATIENTS AND METHODS: A retrospective review of 412 patients records with a clinical suspicion of prostate cancer (PCa) (prostate-specific antigen (PSA) levels >4 ng/ml or a suspicious finding on digital rectal examination (DRE)) who underwent conventional e-MRI (e-cMRI) and functional e-MRI (e-fMRI) of the prostate and subsequent prostate biopsy from April 2004 to July 2010 was conducted. All patients had a history of at least one prior negative set of prostate biopsy. Sixty-five percent (N=268) of patients' images were considered suspicious for PCa of which 53 (12.8%) cases were considered to be suspicious for APC (defined as the presence of PCa anterior to the urethra). All patients underwent an 18-core transrectal ultrasonography (TRUS)-guided biopsy of the peripheral zone and an additional 3-core TRUS-targeted biopsy anterior to the urethra. RESULTS: The median age and median PSA levels of the patients was 68.9 (range=56-72) years and 12.7 ng/ml (range=6.4-21.3), respectively. DRE was only positive in 6 patients (11.4%). The overall PCa detection rate was 90.5%. APC was detected through the targeted cores in 48 patients (90.5%). Seven patients (13.2%) exhibited a PCa of the peripheral zone as well. e-MRI-positive predictive value was 90.5%. CONCLUSION: e-MRI of the prostate has a high predictive value in detecting APC. Patients with a constant increase of PSA levels, negative DRE findings and prior negative sets of prostate biopsy are ideal candidates for e MRI of the prostate and subsequent TRUS-targeted biopsies of possible suspicious anterior gland sites. PMID- 27466545 TI - Is an Extended Prostate Biopsy Scheme Associated with an Improvement in the Accuracy Between the Biopsy Gleason Score and Radical Prostatectomy Pathology? A Multivariate Analysis. AB - AIM: To examine whether an extended prostate biopsy (PB) scheme is associated with an improvement in the accuracy between the PB Gleason score (GS) and radical prostatectomy (RP) pathology and to identify probable preoperative variables that stratified patients likely to harbor significant upgrading (SU). PATIENTS AND METHODS: A retrospective review of 538 patients' records diagnosed with prostate cancer (PCa) who underwent RP and exhibited a SU, at two tertiary medical centers, was conducted. The patients were divided into 3 groups: 194 who underwent a 6-core PB (36%), 156 who underwent a 12-core PB (28.9%) and 188 (34.9%) who underwent an 18-core PB. A multivariate analysis was conducted, including prostate-specific antigen (PSA) level, clinical stage, prostate size and duration from PB to RP. RESULTS: The 6-core group exhibited a 42.7% SU, the 12-core group exhibited a 38.8% SU and the 18-core group exhibited a 14.1% SU. There was a highly significant lower rate of SU in the 18-core than that in the 6 core (p<0.001) and 12-core PB group (p<0.001) but no significant difference in the rate of SU was noted between the 6- and 12-core group (p=0.913). According to the multivariate analysis, only a prostate size of >35 g significantly elevated the probability of SU in the 6-core (p<0.025) and 12-core PB groups (p<0.025), respectively. CONCLUSION: An extended PB scheme is associated with a significant improvement in the accuracy between the PB GS and RP pathology. Prostate size >35 g in patients who undergo a 6- or 12-core PB is the only preoperative variable that stratifies patients likely to harbor SU. PMID- 27466546 TI - Validity of Hepatic or Pancreatic Resection for Elderly Patients Aged 85 Years or Older at a Single Community Hospital in Japan. AB - AIM: To evaluate the efficacy of age on the surgical outcomes in hepatic or pancreatic resection. PATIENTS AND METHODS: We performed 50 hepatic or pancreatic resections in our community hospital and divided them into 2 groups based on age: patients aged >=85 years old and patients aged <85 years old. We calculated the Estimation of Physiologic Ability and Surgical Stress (E-PASS) score and the Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) system and compared the surgical outcome between the two groups. RESULTS: There was no significant difference between the two groups with regard to E-PASS and POSSUM scores. Patients aged >=85 years had a significantly higher frequency of anti-platelet agents. The incidence of postoperative complications and mortality in patients >=85 years old were comparable to those in patients aged <85 years old. CONCLUSION: Hepatic or pancreatic resection for elderly patients aged 85 years or older can be safely performed under a given careful patient selection. PMID- 27466547 TI - Investigating Urinary Conditions Prior to Robot-assisted Radical Prostatectomy in Search of a Desirable Method for Evaluating Post-prostatectomy Incontinence. AB - The aims of the study were to investigate desirable evaluation methods for post prostatectomy incontinence (PPI) by analyzing the urinary status before robot assisted radical prostatectomy (RARP).Questionnaires were evaluated from 155 patients prior to operation. The 24-h pad test before RARP revealed a weight of 1.1 g. The mean scores were as follows: total International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score, 1.2; total International Prostate Symptom Score (IPSS), 10.0; IPSS quality of life, 2.7; Overactive Bladder Symptom Score (OABSS), 2.9; and Expanded Prostate Cancer Index Composite urinary summary, 92.8. The abdominal leak point pressure test in 111 patients before RARP was negative in all cases. Desirable evaluation methods for PPI should be based on a combination of subjective and objective evaluations and comparisons between pre- and post-RP. ICIQ-SF is considerably convenient for evaluating incontinence, and the 24-h pad test enables evaluation of the incontinence volume in a highly objective manner. PMID- 27466548 TI - Efficacy and Safety of Regorafenib or TAS-102 in Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies. AB - BACKGROUND: Regorafenib and TAS-102 are novel antitumor agents for patients with metastatic colorectal cancer (mCRC) whose disease has progressed after standard therapies. In randomized trials, regorafenib and TAS-102 prolonged survival in patients with mCRC. However, the appropriate selection of regorafenib or TAS-102 in treatment strategy has not yet been established. PATIENTS AND METHODS: We performed a retrospective analysis, between March 2013 and July 2015, on the efficacy and safety of regorafenib or TAS-102. RESULTS: Thirty-seven patients with mCRC treated with regorafenib or TAS-102 were included. Of these 37 patients, 23 first received regorafenib and 14 received TAS-102. The median progression-free survival and overall survival were 3.0 and 5.8 months, respectively, in the regorafenib group and 2.1 and 6.3 months, respectively, in the TAS-102 group. Drug-related adverse events (AEs) and grade >=3 AEs were 23 (100%) and 10 (43.5%), respectively, in the regorafenib group and 13 (92.9%) and 2 (14.3%), respectively, in the TAS-102 group. The most frequent grade >=3 AEs were hepatotoxicity (17.4%) and hand-foot syndrome (13.0%) in the regorafenib group, and neutropenia (14.3%) in the TAS-102 group. In subgroup analysis, the median overall survival was 11.5 months in patients receiving crossover treatment with regorafenib to TAS-102, and 7.6 months in those receiving crossover treatment with TAS-102 to regorafenib. CONCLUSION: Our results showed that regorafenib and TAS-102 have comparable efficacy but different toxicity profiles in patients with mCRC. Both are considered new salvage treatment options. Differences in the toxicity profiles between the two treatments will help in choosing regorafenib or TAS-102. PMID- 27466549 TI - Synchronous Quadruple Primary Neoplasms: Colon Adenocarcinoma, Collision Tumor of Neuroendocrine Tumor and Schwann Cell Hamartoma and Sessile Serrated Adenoma of the Appendix. AB - Quadruple synchronous primary neoplasms are very rare with only three cases reported in the English-speaking literature to date. Collision tumors are also rare entities, especially of the appendix. We herein report a case of synchronous quadruple primary neoplasm in a 95-year-old female. She was diagnosed with colon adenocarcinoma, sessile serrated adenoma of the appendix and a collision tumor composed of a well-differentiated neuroendocrine tumor and Schwann cell hamartoma. Histological examination and immunohistochemistry supported these four lesions as separate entities. This case is unique because we report the diagnosis of quadruple synchronous primary, an extremely rare occurrence, in addition to a collision tumor of the appendix. We also provide a review of the literature for synchronous neoplasms and collision tumors. PMID- 27466551 TI - Primary and Secondary Soft Tissue Angiosarcomas: Prognostic Significance of Surgical Margins in 43 Patients. AB - BACKGROUND: Angiosarcomas are aggressive soft tissue sarcomas. Due to their rarity there is a paucity of data regarding the clinical outcome of patients with non-visceral angiosarcomas of the soft tissues. In particular, the prognostic significance of surgical margins remains controversial. PATIENTS AND METHODS: We retrospectively assessed the outcome of 43 patients with localised disease suitable for surgical treatment with curative intent. The median follow-up was 7.5 years. RESULTS: The 5-year overall survival (OS) rate was 46.2%. Sixteen patients (37.2%) were diagnosed with secondary, radiation-induced angiosarcomas. Twenty-four patients (55.8%) developed local recurrences and 15 patients (34.9%) distant metastases. Negative surgical margin emerged as the only statistically significant prognostic factor (5-year OS: R0 51.8% vs. R1/R2 17.1%, p=0.036). As indicated in the regression analysis, close and wide negative margins within the R0 subgroup led to similar outcomes. CONCLUSION: Angiosarcomas have a high risk of local recurrence and metastasis. Surgical resection with negative margins improves the outcome. PMID- 27466550 TI - Fluorodeoxyglucose Uptake in Advanced Non-small Cell Lung Cancer With and Without Pulmonary Lymphangitic Carcinomatosis. AB - AIM: To assess the correlation between advanced non-small cell lung cancer (NSCLC) with or without pulmonary lymphangitic carcinomatosis (PLC) and fluorodeoxyglucose (FDG) uptake and its effect on survival outcomes. PATIENTS AND METHODS: We retrospectively reviewed 157 patients with NSCLC. The mean and maximum standardized uptake values (SUVmean and SUVmax, respectively), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were evaluated for their effect on overall survival (OS) and progression-free survival (PFS). RESULTS: The PLC group included 55 patients and the non-PLC group included 102 patients. The SUVmean, SUVmax, MTV and TLG values were lower in the non-PLC group. In the PLC group, primary lung tumor TLG was a significant predictor of PFS, while whole body TLG was found to be a significant predictor in non-PLC patients. CONCLUSION: Primary lung tumor TLG was a good predictor in PLC patients. Whole-body TLG could be a useful predictor only in patients without PLC. PMID- 27466552 TI - Favorable Disease-free Survival Associated with Programmed Death Ligand 1 Expression in Patients with Surgically Resected Small-cell Lung Cancer. AB - BACKGROUND: The prognostic significance of programmed death ligand 1 (PD-L1) has been reported in non-small cell lung cancer; however, the significance of PD-L1 expression in patients with resected small-cell lung cancer (SCLC) remains to be clarified. MATERIALS AND METHODS: Forty patients with SCLC whose resected specimens were available for immunohistochemistry for PD-L1 were evaluated to determine the association between its expression and the clinicopathological factors and prognosis. RESULTS: Among 40 patients, PD-L1 was expressed in tumor cells (TCs) of six (15%), tumor-infiltrating cells (ICs) of 16 (40%), and TCs and/or ICs cells of 18 (45%) patients. Patients with PD-L1-positve ICs and TCs and/or ICs exhibited significantly longer disease-free survival than those without PD-L1-expression (hazard ratio (HR)=0.268; 95% confidence interval (CI)=0.100-0.645; p=0.003 and HR=0.301; 95% CI=0.118-0.702; p=0.005, respectively). CONCLUSION: This study provides important evidence on the prognostic value of the PD-L1 expression in resected SCLC patients. PMID- 27466553 TI - Implications of Long-term Indwelling of Tissue Expander in Breast Reconstruction: Risk of Expander Rupturing. AB - BACKGROUND/AIM: Breast reconstruction with a tissue expander (TE) is associated with postoperative complications, including rupturing of the TE. Any device can have a mechanical failure, and a TE may rupture over time. Although an interval of around one year from initial TE insertion to the second stage of two-stage surgery is historically considered the standard, the optimal interval has not yet been determined. Furthermore, the durability of a TE and the influence of long term indwelling on TE rupture are uncertain. In this study, we retrospectively investigated the effects of long-term indwelling on TE durability and rupturability. PATIENTS AND METHODS: We analyzed 24 patients and 25 breasts with breast cancer that had undergone breast reconstruction with an expander that was indwelling for more than a year. The resected margins were all clear, and none of the patients required postoperative radiotherapy. RESULTS: From a total of 25 reconstructed breast mounds, the TE ruptured in 4 cases. None of the clinicopathological features, including primary tumor progression, method of operation, presence of adjuvant chemotherapy, was significantly associated with TE rupture. Rupture was observed beginning at 1.5 years after the initial TE insertion. The rupture rate was 32.6% by the third year and 55.1% by five years. There were no ruptures among cases with TE exchange within a year. CONCLUSION: Long-term indwelling of TE is associated with TE rupture. We recommend that the appropriate interval between the first and second stages of breast reconstructive surgery is aproximatelly one year. PMID- 27466554 TI - Outcome and Follow-up of Patients with Endometrial Carcinoma Diagnosed on Operative Hysteroscopic Resection Specimens. AB - AIM: To study outcomes of patients diagnosed with endometrial carcinoma (EC) after histological analysis of endometrial resections retrieved during operative hysteroscopy performed for a presumed benign lesion. PATIENTS AND METHODS: A retrospective study was conducted using medical records of patients who underwent operative hysteroscopy for a presumed benign lesion with a final diagnosis of EC between January 1994 and April 2014 in two tertiary academic centers. RESULTS: A total of 29 patients were selected. International federation of gynecology and obstetrics (FIGO) classification was distributed as follows: 16 stages IA, 7 stages IB, 4 stages II and 2 stages III. Peritoneal cytology was positive in one case (stage IIIA). Median follow-up was 4.2 years (range=0.3-20.51). Two deaths were observed and were attributed to endometrial cancer. CONCLUSION: Operative hysteroscopy does not appear to influence stage of EC nor cause retrograde seeding of EC for 27/29 (93%) patients. For 2 patients, the impact of operative hysteroscopy remains uncertain. PMID- 27466555 TI - The Diagnostic and Prognostic Value of sIL-2R as an Immune Biomarker in Head and Neck Cancers. AB - BACKGROUND/AIM: Head and neck cancer (HNC) patients are usually diagnosed with advanced disease and multimodality therapies are required, as well as prognostic biomarkers to predict their response and assess survival. In this study, we aimed to evaluate the ability and clinical significance of the immune biomarker sIL-2R in HNC patients, to assess therapy response and prognosis. MATERIALS AND METHODS: We evaluated 328 blood samples from 145 head and neck cancer patients (HNC) from several subgroups: 84 larynx carcinomas pre- and 39 post-therapy, 46 oral cavity carcinomas pre- and 29 post-therapy, 12 nasopharynx carcinomas, 16 parotid and other salivary gland carcinoma patients. The control group included 45 healthy subjects. Serum sIL-2R levels were evaluated by ELISA assays and correlated to disease stage, lymph nodes, response to therapy, survival and cancer differentiation. RESULTS: Significantly higher sIL-2R levels were recorded in all HNC patients, as opposed to controls, in advanced versus early-stage disease that decreased following therapy. sIL-2R distinguished best, in comparison to other tumor markers, between HNC patients and controls. Survival was strongly associated to lower sIL-2R levels in patients entering the study. CONCLUSION: sIL 2R is a sensitive immune marker for HNC patients. Its levels correlate to disease stage, assess response to therapy and are predictive of recurrence or better survival. We suggest, therefore, using sIL-2R as a reliable prognostic marker in HNC patients as a single marker, or in a combined panel of biomarkers. PMID- 27466558 TI - Erratum. PMID- 27466556 TI - Semi-automatic Volumetric Measurement of Treatment Response in Hepatocellular Carcinoma After Trans-arterial Chemoembolization. AB - AIM: To perform a quantitative, volumetric analysis of therapeutic effects of trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients. PATIENTS AND METHODS: Entire tumor volume and a subset of hypervascular tumor portions were analyzed pre- and post-TACE in magnetic resonance imaging datasets of 22 HCC patients using a semi-automated segmentation and evaluation tool from the Medical Imaging Interaction Toolkit. Results were compared to mRECIST measurements and inter-reader variability was assessed. RESULTS: Mean total tumor volume increased statistical significantly after TACE (84.6 ml pre- vs. 97.1 ml post-TACE, p=0.03) while hypervascular tumor volume decreased from 9.1 ml pre- to 3.7 ml post-TACE (p=0.0001). Likewise, mRECIST diameters decreased significantly after therapy (44.2 vs. 15.4 mm). In the inter-reader assessment, overlap errors were 12.3-17.7% for entire and 36.3-64.2% for the enhancing tumor volume. CONCLUSION: Quantification of therapeutic changes after TACE therapy is feasible using a semi-automated segmentation and evaluation tool. Following TACE, hypervascular tumor volume decreases significantly. PMID- 27466557 TI - Comparison of the Mammography, Contrast-Enhanced Spectral Mammography and Ultrasonography in a Group of 116 patients. AB - Mammography (MG) is the gold-standard in breast cancer detection - the only method documented to reduce breast cancer mortality. Breast ultrasound (US) has been shown to increase sensitivity to breast cancers in screening women with dense breasts. Contrast-enhanced spectral mammography (CESM) is a novel technique intensively developed in the last few years. The goal of this study was to compare the sensitivity, specificity and accuracy of MG, US and CESM in detecting malignant breast lesions. The study included 116 patients. All patients were symptomatic and underwent MG, US and CESM. A radiologist with 20 years of experience in US and MG breast imaging and 1 year of experience in CESM reviewed images acquired in each of the three modalities separately, within an interval of 14-30 days. All identified lesions were confirmed at core biopsy. BI-RADS classifications on US, MG and CESM were compared to histopathology. MG, CESM and US were compared among 116 patients with 137 lesions encountered. Sensitivity of CESM was 100%, significantly higher than that of MG (90%, p<0.004) or US (92%, p<0.01). CESM accuracy was 78%, also higher than MG (69%, p<0.004) and US (70%, p=0.03). There was no statistically significant difference between AUCs for CESM and US (both 0.83). The AUCs of both US and CESM, however, were significantly larger than that of MG (p<0.0004 for each). CESM permitted better detection of malignant lesions than both MG and US, read individually. CESM found lesion enhancement in some benign lesions, as well, yielding a rate of false-positive diagnoses similar to that of MG and US. PMID- 27466560 TI - The Surgery of Childhood Tumors. Third Edition. PMID- 27466561 TI - Oxford Textbook of Oncology. Third Edition. PMID- 27466562 TI - The Nuclear Envelope. Methods and Protocols. PMID- 27466563 TI - The Mitotic Spindle. Methods and Protocols. PMID- 27466564 TI - Synthetic mRNA. Production, Introduction Into Cells, and Physiological Consequences. PMID- 27466565 TI - Angiogenesis Protocols. Third Edition. PMID- 27466566 TI - Dendritic Cell Protocols. Third Edition. PMID- 27466568 TI - Mesenchymal Stem Cells. Methods and Protocols. PMID- 27466567 TI - Natural Killer Cells. Methods and Protocols. PMID- 27466569 TI - Mouse Models for Drug Discovery. Methods and Protocols. Second Edition. PMID- 27466570 TI - Atlas of Animal Anatomy and Histology. PMID- 27466571 TI - Induction Chemotherapy. Systemic and Locoregional. Second Edition. PMID- 27466572 TI - Oncologic Emergency Medicine. Principles and Practice. PMID- 27466573 TI - Head and Neck Pathology. PMID- 27466574 TI - Dermatopathology. PMID- 27466575 TI - Salivary Gland Neoplasms. PMID- 27466577 TI - Surgical Oncology Manual. Second Edition. PMID- 27466576 TI - Ocular Tumors. PMID- 27466578 TI - Nanomedicine. PMID- 27466579 TI - Pharmaceutical Nanotechnology. Fundamentals and Practical Applications. PMID- 27466580 TI - Perspectives in Translational Research in Life Sciences and Biomedicine. PMID- 27466582 TI - System Engineering Approach to Planning Anticancer Therapies. PMID- 27466581 TI - Protein Targeting Compounds. Prediction, Selection and Activity of Specific Inhibitors. PMID- 27466583 TI - Epigenetic Advancements in Cancer. PMID- 27466584 TI - Genetics of Melanoma. PMID- 27466585 TI - Fetal Stem Cells in Regenerative Medicine. Principles and Translational Strategies. PMID- 27466586 TI - Host Defense Peptides and Their Potential as Therapeutic Agents. PMID- 27466587 TI - Advanced Technologies for Protein Complex Production and Characterization. PMID- 27466588 TI - Cellular Ageing and Replicative Senescence. PMID- 27466589 TI - High-Risk Cutaneous Squamous Cell Carcinoma. A Practical Guide for Patient Management. PMID- 27466590 TI - PET/CT in Neuroendocrine Tumors. PMID- 27466591 TI - Advances in Respiratory Cancerogenesis. PMID- 27466592 TI - Breast Disease. Management and Therapies. PMID- 27466593 TI - Analytical Ultracentrifugation. Instrumentation, Software, and Applications. PMID- 27466594 TI - Ethics and Governance of Biomedical Research. Theory and Practice. PMID- 27466595 TI - Melanoma. PMID- 27466596 TI - An Intraoperative Beta-Probe for Cancer Surgery. PMID- 27466597 TI - Handbook of HER2-Targeted Agents in Breast Cancer. PMID- 27466598 TI - Interleukin-27: Biological Properties and Clinical Application. PMID- 27466600 TI - Shared Decision-Making and Liability in Aesthetic Surgery. PMID- 27466601 TI - PPARalpha Downregulates Hepatic Glutaminase Expression in Mice Fed Diets with Different Protein:Carbohydrate Ratios. AB - BACKGROUND: Glutamine is catabolized in the liver by glutaminase 2 (GLS2). Evidence suggests that peroxisome proliferator-activated receptor alpha (PPARalpha) represses the expression of several amino acid-catabolizing enzymes, but for Gls2 this is unknown. OBJECTIVE: The aim of the study was to assess whether PPARalpha regulates Gls2 expression. METHODS: For 8 d, 7-9-wk-old male C57BL/6 wild-type (WT) and Ppara-null mice weighing 23.4 +/- 0.5 g were fed diets with different dietary protein:carbohydrate (DP:DCH) ratios (6%:77%, 20%:63%, or 50%:33%). Liver samples were obtained after 16 h of feed deprivation or 3 h of refeeding, and microarrays were performed. Hepatic glutaminase expression was measured by quantitative polymerase chain reaction and Western blotting. Cotransfection analyses in hepatocellular carcinoma cell line (HepG2) cells with PPARalpha and hepatocyte nuclear factor 4alpha (HNF4alpha) expression vectors were performed. RESULTS: The microarray results showed that Gls2 was the only upregulated gene in WT mice, but not in the Ppara-null mice. In the feed-deprived WT mice, the Gls2 mRNA and protein abundances in the 50%:33% group were 2.5- and 1.1-fold greater (P < 0.05), respectively, than those in the 20%:63% group, which were 2.3- and 0.4-fold greater than those in the 6%:77% group (P < 0.01). Gls2 mRNA expression in the 6%:77% group of feed-deprived Ppara-null mice was 33-fold greater than that in the same group of WT mice (P < 0.0001). GLS2 protein abundance in HepG2 cells was 78% greater than that in the controls (P < 0.0001) after HNF4alpha overexpression, and it was 99% greater after transfection with a short hairpin targeting PPARalpha. CONCLUSIONS: In Ppara-null mice, Gls2 mRNA expression was greater than in WT mice, regardless of the DP:DCH ratio. In HepG2 cells overexpressing HNF4alpha, Gls2 expression increased, an effect repressed by overexpression of PPARalpha. This suggests that Gls2 depends on the PPARalpha/HNF4alpha counterregulatory transcriptional control. PMID- 27466602 TI - Protein Supplementation Has Minimal Effects on Muscle Adaptations during Resistance Exercise Training in Young Men: A Double-Blind Randomized Clinical Trial. AB - BACKGROUND: To our knowledge the efficacy of soy-dairy protein blend (PB) supplementation with resistance exercise training (RET) has not been evaluated in a longitudinal study. OBJECTIVE: Our aim was to determine the effect of PB supplementation during RET on muscle adaptation. METHODS: In this double-blind randomized clinical trial, healthy young men [18-30 y; BMI (in kg/m(2)): 25 +/- 0.5] participated in supervised whole-body RET at 60-80% 1-repetition maximum (1 RM) for 3 d/wk for 12 wk with random assignment to daily receive 22 g PB (n = 23), whey protein (WP) isolate (n = 22), or an isocaloric maltodextrin (carbohydrate) placebo [(MDP) n = 23]. Serum testosterone, muscle strength, thigh muscle thickness (MT), myofiber cross-sectional area (mCSA), and lean body mass (LBM) were assessed before and after 6 and 12 wk of RET. RESULTS: All treatments increased LBM (P < 0.001). ANCOVA did not identify an overall treatment effect at 12 wk (P = 0.11). There tended to be a greater change in LBM from baseline to 12 wk in the PB group than in the MDP group (0.92 kg; 95% CI: -0.12, 1.95 kg; P = 0.09); however, changes in the WP and MDP groups did not differ. Pooling data from combined PB and WP treatments showed a trend for greater change in LBM from baseline to 12 wk compared with MDP treatment (0.69 kg; 95% CI: -0.08, 1.46 kg; P = 0.08). Muscle strength, mCSA, and MT increased (P < 0.05) similarly for all treatments and were not different (P > 0.10) between treatments. Testosterone was not altered. CONCLUSIONS: PB supplementation during 3 mo of RET tended to slightly enhance gains in whole-body and arm LBM, but not leg muscle mass, compared with RET without protein supplementation. Although protein supplementation minimally enhanced gains in LBM of healthy young men, there was no enhancement of gains in strength. This trial was registered at clinicaltrials.gov as NCT01749189. PMID- 27466603 TI - Food Insecurity Is Associated with Subsequent Cognitive Decline in the Boston Puerto Rican Health Study. AB - BACKGROUND: Living with hunger and fear of not having enough food is a growing worldwide concern. In our previous cross-sectional study, we found that food insecurity was associated with poor cognitive function, but the direction of this relation remains unclear. OBJECTIVE: We investigated whether food insecurity is associated with subsequent cognitive decline. METHODS: This was a longitudinal study of 597 participants aged 40-75 y from the Boston Puerto Rican Health Study cohort, with a Mini-Mental State Examination score of >=24 at baseline. Food security was assessed at baseline with the US Household Food Security Scale. Participants completed cognitive batteries, which included 7 cognitive tests, twice-at baseline and again at a 2-y follow-up. The primary outcome was the change in global cognitive function over 2 y. Multiple linear regression was used to obtain adjusted mean differences and 95% CIs in cognitive decline across baseline food security status. RESULTS: Food insecurity at baseline was associated with a 2-y decline in global cognitive function (P-trend = 0.03) after adjusting for relevant potential confounders, including age, sex, baseline cognitive score, body mass index, education, poverty, acculturation score, depression score, smoking status, use of alcohol, physical activity score, presence of diabetes and hypertension, apolipoprotein E status, plasma homocysteine, healthy eating index, and time between baseline and follow-up measures. Compared with the food-secure group, the decline in the very low food security group was greater [mean difference: -0.26 (95% CI: -0.41, -0.10)]. Baseline food insecurity was significantly associated with a faster decline in executive function (P-trend = 0.02) but not memory function (P-trend = 0.66). CONCLUSIONS: Food insecurity was associated with faster cognitive decline in this cohort of Puerto Rican adults. Our study emphasizes the importance of developing interventions for food insecurity that take into account the impact of food insecurity on cognition. PMID- 27466604 TI - High Dietary Selenium Intake Alters Lipid Metabolism and Protein Synthesis in Liver and Muscle of Pigs. AB - BACKGROUND: Prolonged high intakes of dietary selenium have been shown to induce gestational diabetes in rats and hyperinsulinemia in pigs. OBJECTIVE: Two experiments were conducted to explore metabolic and molecular mechanisms for the diabetogenic potential of high dietary selenium intakes in pigs. METHODS: In Expt. 1, 16 Yorkshire-Landrace-Hampshire crossbred pigs (3 wk old, body weight = 7.5 +/- 0.81 kg, 50% males and 50% females) were fed a corn-soybean meal basal diet supplemented with 0.3 or 1.0 mg Se/kg (as selenium-enriched yeast for 6 wk). In Expt. 2, 12 pigs of the same crossbreed (6 wk old, body weight = 16.0 +/- 1.8 kg) were fed a similar basal diet supplemented with 0.3 or 3.0 mg Se/kg for 11 wk. Biochemical and gene and protein expression profiles of lipid and protein metabolism and selenoproteins in plasma, liver, muscle, and adipose tissues were analyzed. RESULTS: In Expt. 1, the 1-mg-Se/kg diet did not affect body weight or plasma concentrations of glucose and nonesterified fatty acids. In Expt. 2, the 3 mg-Se/kg diet, compared with the 0.3-mg-Se/kg diet, increased (P < 0.05) concentrations of plasma insulin (0.2 compared with 0.4 ng/mL), liver and adipose lipids (41% to 2.4-fold), and liver and muscle protein (10-14%). In liver, the 3 mg-Se/kg diet upregulated (P < 0.05) the expression, activity, or both of key factors related to gluconeogenesis [phosphoenolpyruvate carboxykinase (PEPCK); 13%], lipogenesis [sterol regulatory element binding protein 1 (SREBP1), acetyl coenzyme A carboxylase (ACC), and fatty acid synthase (FASN); 46-90%], protein synthesis [insulin receptor (INSR), P70 ribosomal protein S6 kinase (P70), and phosphorylated ribosomal protein S6 (P-S6); 88-105%], energy metabolism [AMP activated protein kinase (AMPK); up to 2.8-fold], and selenoprotein glutathione peroxidase 3 (GPX3; 1.4-fold) and suppressed (P < 0.05) mRNA levels of lipolysis gene cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1; 88%) and selenoprotein gene selenoprotein W1 (SEPW1; 46%). In muscle, the 3-mg-Se/kg diet exerted no effect on the lipid profiles but enhanced (P < 0.05) expression of P S6 and mammalian target of rapamycin (mTOR; 42-176%; protein synthesis); selenoprotein P (SELP; 40-fold); and tumor suppressor protein 53 (P53) and peroxisome proliferator-activated receptor gamma (PPARG; 52-58%; lipogenesis) and suppressed (P < 0.05) expression of INSR (59%; insulin signaling); selenoprotein S (SELS); deiodinases, iodothyronine, type I (DIO1); and thioredoxin reductase 1 (TXNRD1; 50%; selenoproteins); and ACC1 and FASN (35-51%; lipogenesis). CONCLUSION: Our research showed novel roles, to our best knowledge, and mechanisms of high selenium intakes in regulating the metabolism of protein, along with that of lipid, in a tissue-specific fashion in pigs. PMID- 27466606 TI - Intake of High-Fat Yogurt, but Not of Low-Fat Yogurt or Prebiotics, Is Related to Lower Risk of Depression in Women of the SUN Cohort Study. AB - BACKGROUND: Yogurt and prebiotic consumption has been linked to better health. However, to our knowledge, no longitudinal study has assessed the association of yogurt and prebiotic consumption with depression risk. OBJECTIVE: We longitudinally evaluated the association of yogurt and prebiotic consumption with depression risk in a Mediterranean cohort. METHODS: The SUN (Seguimiento Universidad de Navarra) Project is a dynamic, prospective cohort of Spanish university graduates. A total of 14,539 men and women (mean age: 37 y) initially free of depression were assessed during a median follow-up period of 9.3 y. Validated food-frequency questionnaires at baseline and after a 10-y follow-up were used to assess prebiotic (fructans and galacto-oligosaccharide) intake and yogurt consumption (<0.5, >=0.5 to <3, >=3 to <7, and >=7 servings/wk). Participants were classified as incident cases of depression when they reported a new clinical diagnosis of depression by a physician (previously validated). Multivariable Cox proportional hazards models were used to calculate HRs and 95% CIs. RESULTS: We identified 727 incident cases of depression during follow-up. Whole-fat yogurt intake was associated with reduced depression risk: HR for the highest [>=7 servings/wk (1 serving = 125 g)] compared with the lowest (<0.5 servings/wk) consumption: 0.78 (95% CI: 0.63, 0.98; P-trend = 0.020). When stratified by sex, this association was significant only in women (HR: 0.66; 95% CI: 0.50, 0.87; P-trend = 0.004). Low-fat yogurt consumption was associated with a higher incidence of depression (HR: 1.32; 95% CI: 1.06, 1.65; P-trend = 0.001), although this association lost significance after the exclusion of early incident cases, suggesting possible reverse causation bias. Prebiotic consumption was not significantly associated with depression risk. CONCLUSIONS: Our study suggests that high consumption of whole-fat yogurt was related to a lower risk of depression in women of the SUN cohort. No association was observed for prebiotics. Further studies are needed to clarify why the yogurt-depression association may differ by fat content of the yogurt. PMID- 27466607 TI - Gut Microbiota Richness and Composition and Dietary Intake of Overweight Pregnant Women Are Related to Serum Zonulin Concentration, a Marker for Intestinal Permeability. AB - BACKGROUND: Increased intestinal permeability may precede adverse metabolic conditions. The extent to which the composition of the gut microbiota and diet contribute to intestinal permeability during pregnancy is unknown. OBJECTIVE: The aim was to investigate whether the gut microbiota and diet differ according to serum zonulin concentration, a marker of intestinal permeability, in overweight pregnant women. METHODS: This cross-sectional study included 100 overweight women [mean age: 29 y; median body mass index (in kg/m(2)): 30] in early pregnancy (<17 wk of gestation; median: 13 wk). Serum zonulin (primary outcome) was determined by using ELISA, gut microbiota by 16S ribosomal RNA sequencing, and dietary intake of macro- and micronutrients from 3-d food diaries. The Mann-Whitney U test was used for pairwise comparisons and linear regression and Spearman's nonparametric correlations for relations between serum zonulin and other outcome variables. RESULTS: Women were divided into "low" (<46.4 ng/mL) and "high" (>=46.4 ng/mL) serum zonulin groups on the basis of the median concentration of zonulin (46.4 ng/mL). The richness of the gut microbiota (Chao 1, observed species and phylogenetic diversity) was higher in the low zonulin group than in the high zonulin group (P = 0.01). The abundances of Bacteroidaceae and Veillonellaceae, Bacteroides and Blautia, and Blautia sp. were lower and of Faecalibacterium and Faecalibacterium prausnitzii higher (P < 0.05) in the low zonulin group than in the high zonulin group. Dietary quantitative intakes of n-3 (omega-3) polyunsaturated fatty acids (PUFAs), fiber, and a range of vitamins and minerals were higher (P < 0.05) in women in the low zonulin group than those in the high zonulin group. CONCLUSIONS: The richness and composition of the gut microbiota and the intake of n-3 PUFAs, fiber, and a range of vitamins and minerals in overweight pregnant women are associated with serum zonulin concentration. Modification of the gut microbiota and diet may beneficially affect intestinal permeability, leading to improved metabolic health of both the mother and fetus. This trial was registered at clinicaltrials.gov as NCT01922791. PMID- 27466605 TI - Highly Processed and Ready-to-Eat Packaged Food and Beverage Purchases Differ by Race/Ethnicity among US Households. AB - BACKGROUND: Racial/ethnic disparities in dietary quality persist among Americans, but it is unclear whether highly processed foods or convenience foods contribute to these inequalities. OBJECTIVE: We examined the independent associations of race/ethnicity with highly processed and ready-to-eat (RTE) food purchases among US households. We determined whether controlling for between-group differences in purchases of these products attenuated associations between race/ethnicity and the nutritional quality of purchases. METHODS: The 2000-2012 Homescan Panel followed US households (n = 157,142) that scanned their consumer packaged goods (CPG) food and beverage purchases. By using repeated-measures regression models adjusted for sociodemographic characteristics, we examined time-varying associations of race/ethnicity with processed and convenience food purchases, expressed as a percentage of calories purchased. We estimated associations between race/ethnicity and saturated fat, sugar, or energy density of total purchases with and without adjustment for processed and convenience food purchases. RESULTS: Compared with white households, black households had significantly lower purchases of highly processed foods (-4.1% kcal) and RTE convenience foods (-4.9% kcal) and had higher purchases of basic processed foods, particularly cooking oils and sugar (+5.4% kcal), foods requiring cooking/preparation (+4.5% kcal), and highly processed beverages (+7.1% kcal). Hispanics also had lower purchases of highly processed and RTE foods than whites. Blacks had CPG purchases with significantly higher median sugar (+2.2% kcal) and energy density (+72 kcal/1000 g), whereas Hispanics had purchases with lower saturated fat (-0.6% kcal) and energy density (-25 kcal/1000 g) than whites. Racial/ethnic differences remained significant after adjustment for processed and convenience food purchases. CONCLUSIONS: In our study, compared with white households, both black and Hispanic households had lower purchases of highly processed and RTE foods, yet had total CPG purchases with differing nutritional quality. Our findings suggest that highly processed convenience foods are associated with, but cannot fully explain, racial/ethnic disparities in the nutritional quality of CPG purchases. PMID- 27466608 TI - Short-Term Daily Consumption of Provitamin A Carotenoid-Biofortified Maize Has Limited Impact on Breast Milk Retinol Concentrations in Zambian Women Enrolled in a Randomized Controlled Feeding Trial. AB - BACKGROUND: Provitamin A carotenoid-biofortified maize is a conventionally bred staple crop designed to help prevent vitamin A deficiency. Lactating women are a potential target group, because regularly eating biofortified maize may increase vitamin A in breast milk-a critical source of vitamin A for breastfeeding infants. OBJECTIVE: We assessed whether daily consumption of biofortified orange maize would increase the retinol concentration in the breast milk of Zambian women. METHODS: Lactating women (n = 149) were randomly assigned to receive orange maize delivering 600 MUg retinol equivalents (REs)/d as carotenoid plus placebo (OM), low-carotenoid white maize plus 600 MUg REs/d as retinyl palmitate (VA), or white maize plus placebo (WM). Boiled maize (287 g dry weight/d) was served as 2 meals/d, 6 d/wk for 3 wk. We measured initial and final breast milk plasma retinol and beta-carotene concentrations, and plasma inflammatory protein concentrations. RESULTS: Groups were comparable at enrollment, with an overall geometric mean milk retinol concentration of 0.95 MUmol/L (95% CI: 0.86, 1.05 MUmol/L); 56% of samples had milk retinol <1.05 MUmol/L. Median capsule and maize intake was 97% and 258 g dry weight/d, respectively. Final milk beta-carotene did not vary across groups (P = 0.76). Geometric mean (95% CI) milk retinol concentration tended to be higher in the OM [1.15 MUmol/L (0.96, 1.39 MUmol/L)] and VA [1.17 MUmol/L (0.99, 1.38 MUmol/L)] groups than in the WM group [0.91 MUmol/L (0.72, 1.14 MUmol/L); P = 0.13], and the proportion of women with milk retinol <1.05 MUmol/L was 52.1%, 42.9%, and 36.7% in the WM, OM, and VA groups, respectively (P-trend = 0.16). CONCLUSIONS: Daily biofortified maize consumption did not increase mean milk retinol concentration in lactating Zambian women; however, there was a plausible downward trend in the risk of low milk retinol across intervention groups. This trial was registered at clinicaltrials.gov as NCT01922713. PMID- 27466609 TI - Serum Zinc Is a Major Predictor of Anemia and Mediates the Effect of Selenium on Hemoglobin in School-Aged Children in a Nationally Representative Survey in New Zealand. AB - BACKGROUND: Zinc, selenium, and vitamin D status of New Zealand (NZ) school-aged children was examined in a national survey in 2002. To our knowledge, however, the role of these micronutrients as predictors of hemoglobin has not been explored despite plausible mechanisms for such relations. OBJECTIVE: We examined the relations of iron, zinc, selenium, and vitamin D status with hemoglobin and anemia in children of New Zealand European and other (NZEO) ethnicity enrolled in the 2002 Children's Nutrition Survey and explored whether zinc mediated the relation between selenium and hemoglobin. METHODS: Multivariate regression was performed to examine the relations of serum micronutrient biomarkers, acute inflammation, socioeconomic status, and body mass index (BMI) with hemoglobin and anemia of NZEO children aged 5-15 y (n = 503). A mediation analysis also investigated direct and indirect (through zinc) relations between selenium and hemoglobin. RESULTS: In total, 4.6% of the children were anemic, 3.2% had depleted iron stores, and none had iron deficiency anemia. The prevalence of low serum zinc (<8.7-10.1 MUmol/L depending on age and sex), selenium (<0.82 MUmol/L), and 25-hydroxyvitamin D (<50 nmol/L) was 14.1%, 22.9%, and 48.5%, respectively. Major predictors of hemoglobin were serum zinc, age, and BMI-for age z score (P < 0.001); log ferritin and being female were also statistically significant (P < 0.05). Selenium had an indirect effect that was mediated by zinc, with a significant effect of selenium on zinc (P = 0.002) and zinc on hemoglobin (P < 0.001). Zinc was the only variable associated with anemia risk (OR: 5.49; 95% CI: 1.95, 15.46). CONCLUSIONS: Low serum zinc was an independent risk factor for anemia in NZEO school-aged children and mediated the effect of low selenium on hemoglobin. These findings emphasize the importance of considering multiple micronutrient deficiencies in addition to iron when interpreting anemia and of appreciating the mechanistic interactions that underlie these associations. PMID- 27466610 TI - A Conditional Cash Transfer Program in the Philippines Reduces Severe Stunting. AB - BACKGROUND: Pantawid, a conditional cash transfer (CCT) program in the Philippines, provided grants conditioned on health-related behaviors for children aged 0-5 y and schooling for those aged 10-14 y. OBJECTIVE: We investigated whether Pantawid improved anthropometric measurements in children aged 6-36 mo. METHODS: We estimated cross-sectional intention-to-treat effects using a 2011 cluster-randomized trial across 130 villages-65 treated and 65 control-with data collected after 31 mo of implementation. Anthropometry characteristics were measured for 241 children in treated areas and 244 children in control areas. Health service use for children aged 6-36 mo and dietary intake for those aged 6 60 mo also were measured. Outcome variables were height-for-age z scores (HAZs) and weight-for-age z scores (WAZs), stunting, severe stunting, underweight, and severely underweight. Impact also was assessed on perinatal care, institutional delivery, presence of skilled birth attendant, breastfeeding practices, immunization, growth monitoring and deworming, care-seeking, and children's intake of protein-rich foods. RESULTS: Pantawid was associated with a significant reduction in severe stunting [<-3 SD from WHO standards for healthy children; beta = -10.2 percentage points (95% CI -18.8, -1.6 percentage points); P = 0.020] as well as a marginally significant increase in HAZs [beta = 0.284 SDs (95% CI 0.033, 0.602 SDs); P = 0.08]. WAZs, stunting, underweight, and severely underweight status did not change. Concomitantly, several measures of health seeking behavior increased significantly. CONCLUSIONS: To our knowledge, Pantawid is one of few CCT programs worldwide that significantly reduced severe stunting in children aged 6-36 mo; changes in key parenting practices, including children's intake of protein-rich foods and care-seeking behavior, were concurrent. PMID- 27466611 TI - Consecutive results of blood cell count and retrospective biodosimetry: useful tools of health protection regulation for radiation workers. AB - BACKGROUND: Industrial radiography is known to be one of the most vulnerable lines of work among the range of different radiation work. According to the relevant law in Korea, every worker registered in this work should check their blood cell counts every year in addition to their thermoluminescent dosimeter (TLD) doses. Since the law was enacted, however, few follow-up studies have been carried out based on the obtained results. OBJECTIVES: To ascertain the clinical usefulness of complete blood cell count (CBC) results and suggest a proper protocol of health protection for radiation workers. METHODS: After reviewing all the consecutive results of CBC and TLD doses from radiation workers registered nationwide, we selected two groups of high-risk radiation workers, CBC-high risk (CBC-HR) and TLD-high risk (TLD-HR) groups. A control group of unexposed healthy adults was also included. We compared the absorbed doses calculated by cytogenetic biodosimetry among those three groups, and examined possible confounding factors for each group. RESULTS: Both groups of high-risk radiation workers, CBC-HR and TLD-HR, showed higher chromosome aberrations than the control group. In the control group, previous medical history of a CT scan increased the frequency of chromosome aberrations. In contrast, the frequency of chromosome aberrations in the high-risk radiation workers was affected not by the previous CT history but only by the duration of their work. CONCLUSIONS: We ascertain that reviewing consecutive results of blood cell counts and cytogenetic biodosimetry are useful complementary tools to TLD doses for health protection regulation. Several confounding factors including work duration and previous medical history need to be considered for the interpretation of biodosimetry results. PMID- 27466612 TI - Unreliable proposed 'new standard' for assessing asbestos exposure. PMID- 27466613 TI - Authors' reply to letters from Egilman et al and Oliver et al. PMID- 27466614 TI - New standard for assessing asbestos exposure and its consequences? PMID- 27466615 TI - Occupational exposure to chemicals drives the increased risk of asthma and rhinitis observed for exposure to vapours, gas, dust and fumes: a cross-sectional population-based study. AB - OBJECTIVES: Occupational exposure to the composite measure vapours, gases, dusts and fumes (VGDF), contribute to the burden of asthma and rhinitis. The objective was to evaluate occupational exposure to VGDF, which is further divided into the components chemicals, organic and inorganic dust in relation to asthma and rhinitis. METHODS: Previously examined participants from three population-based cohorts in the Obstructive Lung disease In Northern Sweden (OLIN) studies were re examined during 2002-2004. In total, 4036 participated in a structured interview and answered a questionnaire on occupational exposures. RESULTS: Occupational exposure to VGDF increased the risk of asthma, and concomitant asthma and rhinitis. Exposure to chemicals, but not dust, showed a similar pattern. Exposure to chemicals increased the risks (OR, 95% CI) of rhinitis without asthma (1.29, 1.10 to 1.52), asthma without rhinitis (1.42, 1.15 to 1.77) and concomitant asthma and rhinitis (1.60, 1.31 to 1.96) when adjusted for confounders such as age, smoking habits, body mass index and sex. The association between exposure to chemicals and asthma and rhinitis remained independent of exposure to dust and was also so when excluding exposure to isocyanates and welding fumes. The results were similar for women and men, as well as for never-smokers and participants without a history of allergy. CONCLUSIONS: In this cross-sectional population based study, occupational exposure to chemicals contributed substantially to the increased risk of asthma and rhinitis observed for occupational exposure to VGDF. PMID- 27466616 TI - Biomechanical and psychosocial exposures are independent risk factors for carpal tunnel syndrome: assessment of confounding using causal diagrams. AB - BACKGROUND: Between 2001 and 2010, six research groups conducted coordinated prospective studies of carpal tunnel syndrome (CTS) incidence among US workers from various industries to estimate exposure-response relationships. OBJECTIVE: This analysis examined the presence and magnitude of confounding between biomechanical and workplace psychosocial factors and incidence of dominant-hand CTS. METHODS: 1605 participants, without CTS at enrolment, were followed for up to 3.5 years (2471 person-years). Demographic information, medical history and workplace psychosocial stress measures were collected at baseline. Individual workplace biomechanical exposures were collected for each task and combined across the workweek using time-weighted averaging (TWA). CTS case criteria were based on symptoms and results of electrophysiological testing. HRs were estimated with Cox proportional hazard models. Confounding was assessed using causal diagrams and an empirical criterion of 10% or greater change in effect estimate magnitude. RESULTS: There were 109 incident CTS cases (IR=4.41/100 person-years; 6.7% cumulative incidence). The relationships between CTS and forceful repetition rate, % time forceful hand exertion and the Threshold Limit Value for Hand Activity Level (TLV-HAL) were slightly confounded by decision latitude with effect estimates being attenuated towards the null (10-14% change) after adjustment. The risk of CTS among participants reporting high job strain was attenuated towards the null by 14% after adjusting for the HAL Scale or the % time forceful hand exertions. CONCLUSIONS: Although attenuation of the relationships between CTS and some biomechanical and work psychosocial exposures was observed after adjusting for confounding, the magnitudes were small and confirmed biomechanical and work psychosocial exposures as independent risk factors for incident CTS. PMID- 27466617 TI - Occupational exposure to solar ultraviolet radiation and the risk of prostate cancer. AB - OBJECTIVES: Preventable risk factors for prostate cancer are poorly understood; sun exposure is a possible protective factor. The goal of this study was to investigate prostate cancer risk in outdoor workers, a population with high sun exposure. METHODS: Prostate cancer cases and controls from a large study (conducted between 1994 and 1997) were used for this analysis. A job exposure matrix (JEM) was used to assign solar ultraviolet radiation (UVR) at work as moderate (2 to <6 hours outside/day) or high (>=6 hours). Average daily satellite UV-B measures were linked to the latitude/longitude of the residences of each participant. Several other exposure metrics were also examined, including ever/never exposed and standard erythemal dose by years (SED*years). Logistic regression was used to evaluate the association between solar UVR exposure and the odds of prostate cancer. RESULTS: A total of 1638 cases and 1697 controls were included. Men of Indian and Asian descent had reduced odds of prostate cancer (ORs 0.17 (0.08 to 0.35) and 0.25 (0.15 to 0.41), respectively) compared with Caucasian men, as did single men (OR 0.76 (0.58 to 0.98)) compared with married men. Overall, no statistically significant associations were observed between sun exposure and prostate cancer with 1 exception. In the satellite enhanced JEM that considered exposure in high category jobs only, prostate cancer odds in the highest quartile of cumulative exposure was decreased compared with unexposed men (OR 0.68 (0.51 to 0.92)). CONCLUSIONS: This study found limited evidence for an association with prostate cancer, with the exception of 1 statistically significant finding of a decreased risk among workers with the longest term and highest sun exposure. PMID- 27466618 TI - Standards of Evidence and Mechanistic Inference in Autosomal Recessive Hypercholesterolemia. PMID- 27466619 TI - Atherosclerotic Plaque Rupture: Identifying the Straw That Breaks the Camel's Back. PMID- 27466620 TI - plasmidSPAdes: assembling plasmids from whole genome sequencing data. AB - MOTIVATION: Plasmids are stably maintained extra-chromosomal genetic elements that replicate independently from the host cell's chromosomes. Although plasmids harbor biomedically important genes, (such as genes involved in virulence and antibiotics resistance), there is a shortage of specialized software tools for extracting and assembling plasmid data from whole genome sequencing projects. RESULTS: We present the plasmidSPAdes algorithm and software tool for assembling plasmids from whole genome sequencing data and benchmark its performance on a diverse set of bacterial genomes. AVAILABILITY AND IMPLEMENTATION: plasmidSPAdes is publicly available at http://spades.bioinf.spbau.ru/plasmidSPAdes/ CONTACT: d.antipov@spbu.ruSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27466621 TI - Simultaneous gene finding in multiple genomes. AB - MOTIVATION: As the tree of life is populated with sequenced genomes ever more densely, the new challenge is the accurate and consistent annotation of entire clades of genomes. We address this problem with a new approach to comparative gene finding that takes a multiple genome alignment of closely related species and simultaneously predicts the location and structure of protein-coding genes in all input genomes, thereby exploiting negative selection and sequence conservation. The model prefers potential gene structures in the different genomes that are in agreement with each other, or-if not-where the exon gains and losses are plausible given the species tree. We formulate the multi-species gene finding problem as a binary labeling problem on a graph. The resulting optimization problem is NP hard, but can be efficiently approximated using a subgradient-based dual decomposition approach. RESULTS: The proposed method was tested on whole-genome alignments of 12 vertebrate and 12 Drosophila species. The accuracy was evaluated for human, mouse and Drosophila melanogaster and compared to competing methods. Results suggest that our method is well-suited for annotation of (a large number of) genomes of closely related species within a clade, in particular, when RNA-Seq data are available for many of the genomes. The transfer of existing annotations from one genome to another via the genome alignment is more accurate than previous approaches that are based on protein spliced alignments, when the genomes are at close to medium distances. AVAILABILITY AND IMPLEMENTATION: The method is implemented in C ++ as part of Augustus and available open source at http://bioinf.uni-greifswald.de/augustus/ CONTACT: stefaniekoenig@ymail.com or mario.stanke@uni-greifswald.deSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27466623 TI - NCMine: Core-peripheral based functional module detection using near-clique mining. AB - MOTIVATION: The identification of functional modules from protein-protein interaction (PPI) networks is an important step toward understanding the biological features of PPI networks. The detection of functional modules in PPI networks is often performed by identifying internally densely connected subnetworks, and often produces modules with "core" and "peripheral" proteins. The core proteins are the ones having dense connections to each other in a module. The difference between core and peripheral proteins is important to understand the functional roles of proteins in modules, but there are few methods to explicitly elucidate the internal structure of functional modules at gene level. RESULTS: We propose NCMine, which is a novel network clustering method and visualization tool for the core-peripheral structure of functional modules. It extracts near-complete subgraphs from networks based on a node-weighting scheme using degree centrality, and reports subgroups as functional modules. We implemented this method as a plugin of Cytoscape, which is widely used to visualize and analyze biological networks. The plugin allows users to extract functional modules from PPI networks and interactively filter modules of interest. We applied the method to human PPI networks, and found several examples with the core-peripheral structure of modules that may be related to cancer development. AVAILABILITY AND IMPLEMENTATION: The Cytoscape plugin and tutorial are available at Cytoscape AppStore. (http://apps.cytoscape.org/apps/ncmine). CONTACT: kengo@ecei.tohoku.ac.jpSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27466622 TI - Excess positional mutual information predicts both local and allosteric mutations affecting beta lactamase drug resistance. AB - MOTIVATION: Bacterial resistance to antibiotics, particularly plasmid-encoded resistance to beta lactam drugs, poses an increasing threat to human health. Point mutations to beta-lactamase enzymes can greatly alter the level of resistance conferred, but predicting the effects of such mutations has been challenging due to the large combinatorial space involved and the subtle relationships of distant residues to catalytic function. Therefore we desire an information-theoretic metric to sensitively and robustly detect both local and distant residues that affect substrate conformation and catalytic activity. RESULTS: Here, we report the use of positional mutual information in multiple microsecond-length molecular dynamics (MD) simulations to predict residues linked to catalytic activity of the CTX-M9 beta lactamase. We find that motions of the bound drug are relatively isolated from motions of the protein as a whole, which we interpret in the context of prior theories of catalysis. In order to robustly identify residues that are weakly coupled to drug motions but nonetheless affect catalysis, we utilize an excess mutual information metric. We predict 31 such residues for the cephalosporin antibiotic cefotaxime. Nine of these have previously been tested experimentally, and all decrease both enzyme rate constants and empirical drug resistance. We prospectively validate our method by testing eight high-scoring mutations and eight low-scoring controls in bacteria. Six of eight predicted mutations decrease cefotaxime resistance greater than 2 fold, while only one control shows such an effect. The ability to prospectively predict new variants affecting bacterial drug resistance is of great interest to clinical and epidemiological surveillance. AVAILABILITY AND IMPLEMENTATION: Excess mutual information code is available at https://github.com/kassonlab/positionalmi CONTACT: kasson@virginia.edu. PMID- 27466624 TI - WALT: fast and accurate read mapping for bisulfite sequencing. AB - : Whole-genome bisulfite sequencing (WGBS) has emerged as the gold-standard technique in genome-scale studies of DNA methylation. Mapping reads from WGBS requires unique considerations that make the process more time-consuming than in other sequencing applications. Typical WGBS data sets contain several hundred million reads, adding to this analysis challenge. We present the WALT tool for mapping WGBS reads. WALT uses a strategy of hashing periodic spaced seeds, which leads to significant speedup compared with the most efficient methods currently available. Although many existing WGBS mappers slow down with read length, WALT improves in speed. Importantly, these speed gains do not sacrifice accuracy. AVAILABILITY AND IMPLEMENTATION: WALT is available under the GPL v3 license, and downloadable from https://github.com/smithlabcode/walt. CONTACT: andrewds@usc.edu or tingchen@usc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 27466626 TI - Drug drug interaction extraction from biomedical literature using syntax convolutional neural network. AB - MOTIVATION: Detecting drug-drug interaction (DDI) has become a vital part of public health safety. Therefore, using text mining techniques to extract DDIs from biomedical literature has received great attentions. However, this research is still at an early stage and its performance has much room to improve. RESULTS: In this article, we present a syntax convolutional neural network (SCNN) based DDI extraction method. In this method, a novel word embedding, syntax word embedding, is proposed to employ the syntactic information of a sentence. Then the position and part of speech features are introduced to extend the embedding of each word. Later, auto-encoder is introduced to encode the traditional bag-of words feature (sparse 0-1 vector) as the dense real value vector. Finally, a combination of embedding-based convolutional features and traditional features are fed to the softmax classifier to extract DDIs from biomedical literature. Experimental results on the DDIExtraction 2013 corpus show that SCNN obtains a better performance (an F-score of 0.686) than other state-of-the-art methods. AVAILABILITY AND IMPLEMENTATION: The source code is available for academic use at http://202.118.75.18:8080/DDI/SCNN-DDI.zip CONTACT: yangzh@dlut.edu.cnSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27466625 TI - Joint sparse canonical correlation analysis for detecting differential imaging genetics modules. AB - MOTIVATION: Imaging genetics combines brain imaging and genetic information to identify the relationships between genetic variants and brain activities. When the data samples belong to different classes (e.g. disease status), the relationships may exhibit class-specific patterns that can be used to facilitate the understanding of a disease. Conventional approaches often perform separate analysis on each class and report the differences, but ignore important shared patterns. RESULTS: In this paper, we develop a multivariate method to analyze the differential dependency across multiple classes. We propose a joint sparse canonical correlation analysis method, which uses a generalized fused lasso penalty to jointly estimate multiple pairs of canonical vectors with both shared and class-specific patterns. Using a data fusion approach, the method is able to detect differentially correlated modules effectively and efficiently. The results from simulation studies demonstrate its higher accuracy in discovering both common and differential canonical correlations compared to conventional sparse CCA. Using a schizophrenia dataset with 92 cases and 116 controls including a single nucleotide polymorphism (SNP) array and functional magnetic resonance imaging data, the proposed method reveals a set of distinct SNP-voxel interaction modules for the schizophrenia patients, which are verified to be both statistically and biologically significant. AVAILABILITY AND IMPLEMENTATION: The Matlab code is available at https://sites.google.com/site/jianfang86/JSCCA CONTACT: wyp@tulane.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27466627 TI - Motif comparison based on similarity of binding affinity profiles. AB - : Measuring motif similarity is essential for identifying functionally related transcription factors (TFs) and RNA-binding proteins, and for annotating de novo motifs. Here, we describe Motif Similarity Based on Affinity of Targets (MoSBAT), an approach for measuring the similarity of motifs by computing their affinity profiles across a large number of random sequences. We show that MoSBAT successfully associates de novo ChIP-seq motifs with their respective TFs, accurately identifies motifs that are obtained from the same TF in different in vitro assays, and quantitatively reflects the similarity of in vitro binding preferences for pairs of TFs. AVAILABILITY AND IMPLEMENTATION: MoSBAT is available as a webserver at mosbat.ccbr.utoronto.ca, and for download at github.com/csglab/MoSBAT. CONTACT: t.hughes@utoronto.ca or hamed.najafabadi@mcgill.caSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27466630 TI - This volume constitutes the Proceedings of the 17th International Symposium. PMID- 27466628 TI - Identification of polymer surface adsorbed proteins implicated in pluripotent human embryonic stem cell expansion. AB - Improved biomaterials are required for application in regenerative medicine, biosensing, and as medical devices. The response of cells to the chemistry of polymers cultured in media is generally regarded as being dominated by proteins adsorbed to the surface. Here we use mass spectrometry to identify proteins adsorbed from a complex mouse embryonic fibroblast (MEF) conditioned medium found to support pluripotent human embryonic stem cell (hESC) expansion on a plasma etched tissue culture polystyrene surface. A total of 71 proteins were identified, of which 14 uniquely correlated with the surface on which pluripotent stem cell expansion was achieved. We have developed a microarray combinatorial protein spotting approach to test the potential of these 14 proteins to support expansion of a hESC cell line (HUES-7) and a human induced pluripotent stem cell line (ReBl-PAT) on a novel polymer (N-(4-Hydroxyphenyl) methacrylamide). These proteins were spotted to form a primary array yielding several protein mixture 'hits' that enhanced cell attachment to the polymer. A second array was generated to test the function of a refined set of protein mixtures. We found that a combination of heat shock protein 90 and heat shock protein-1 encourage elevated adherence of pluripotent stem cells at a level comparable to fibronectin pre treatment. PMID- 27466631 TI - Skeletal muscle is a highly dynamic and adaptive tissue, constantly changing. Introduction. PMID- 27466629 TI - First Multicenter, Randomized Phase 3 Study in Patients (Pts) With Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL): Alisertib (MLN8237) Versus Investigator's Choice (LUMIERE trial; NCT01482962). PMID- 27466632 TI - The book series Neuroscience and Respiration presents contributions by expert researchers and clinicians. Introduction. PMID- 27466633 TI - Neural correlates of second-language communication and the effect of language anxiety. AB - Communicative speech is a type of language use that involves goal-directed action targeted at another person based on social interactive knowledge. Previous studies regarding one's first language (L1) have treated the theory of mind system, which is associated with understanding others, and the sensorimotor system, which is associated with action simulation, as important contributors to communication. However, little is known about the neural basis of communication in a second language (L2), which is limited in terms of its use as a communication tool. In this fMRI study, we manipulated the type of speech (i.e., communication vs. description) and the type of language (L1 vs. L2) to identify the specific brain areas involved in L2 communication. We also attempted to examine how the cortical mechanisms underlying L2 speech production are influenced by oral proficiency and anxiety regarding L2. Thirty native Japanese speakers who had learned English as an L2, performed communicative and descriptive speech-production tasks in both L1 and L2 while undergoing fMRI scanning. We found that the only the L2 communication task recruited the left posterior supramarginal gyrus (pSMG), which may be associated with the action simulation or prediction involved in generating goal-directed actions. Furthermore, the neural mechanisms underlying L2 communication, but not L2 description, were sensitive to both oral proficiency and anxiety levels; a) activation in the left middle temporal gyrus (MTG) increased as oral proficiency levels increased, and b) activation in the orbitofrontal cortex (OFC), including the left insula, decreased as L2 anxiety levels increased. These results reflect the successful retrieval of lexical information in a pragmatic context and an inability to monitor social behaviors due to anxiety. Taken together, the present results suggest that L2 communication relies on social skills and is mediated by anxiety and oral proficiency. PMID- 27466634 TI - Authors' response. PMID- 27466635 TI - Reply. PMID- 27466637 TI - Reply. PMID- 27466636 TI - Reply. PMID- 27466638 TI - Is GOP Idea Deja vu All Over Again? PMID- 27466639 TI - Telemedicine Start-ups Promise To Transform Health Care. PMID- 27466640 TI - Intermountain Health Plan Promises Price Cap To Employers Willing to Make a Commitment. PMID- 27466692 TI - Pilot study of intensive exercise on endurance, advanced mobility and gait speed in adults with chronic severe acquired brain injury. AB - BACKGROUND AND PURPOSE: Effects of high-intensity exercise on endurance, mobility and gait speed of adults with chronic moderate-to-severe acquired brain injury (ABI) were investigated. It was hypothesized that intensive exercise would be associated with improvements in impairment and activity limitation measures. PARTICIPANTS: Fourteen adults with chronic ABI in supported independent living who could stand with minimal or no assist and walk with or without ambulation device were studied. Eight presented with low ambulatory status. METHODS: This was a single group pre- and post-intervention study. Participants received a 6 week exercise intervention for 60-90 minutes, 3 days/week assisted by personal trainers under physical therapist supervision. Measures (6MWT, HiMAT and 10MWT) were collected at baseline, post-intervention and 6 weeks later. Repeated measures T-test and Wilcoxon Signed Ranks test were used. RESULTS: Post intervention improvements were achieved on average on all three measures, greater than minimal detectable change (MDC) for this population. Three participants transitioned from low-to-high ambulatory status and maintained the change 6 weeks later. DISCUSSION AND CONCLUSION: People with chronic ABI can improve endurance, demonstrate the ability to do advanced gait and improve ambulatory status with 6 weeks of intensive exercise. Challenges to sustainability of exercise programmes for this population remain. PMID- 27466693 TI - Believing in Expertise: How Authors' Credentials and Language Use Influence the Credibility of Online Health Information. AB - Today, many people use the Internet to seek health advice. This study examines how an author's expertise is established and how this affects the credibility of his or her online health information. In a 2 (authors' credentials: medical vs. nonmedical) * 2 (authors' language use: technical vs. every day) within-subjects design, 127 study participants, or "seekers," judged authors' expertise, benevolence, and integrity as well as the credibility of their medical statements. In addition, we assessed seekers' awareness of their own knowledge and behavior. Results revealed that users consciously rewarded authors' credentials and subconsciously punished technical language. Seekers were keenly aware of authors' credentials and perceived authors with medical credentials to have a higher level of expertise and their information to be more credible. Technical language use negatively affected authors' integrity and the credibility of their health information, despite seekers being unaware of it. Practical implications for health communication and implications for future research are outlined. PMID- 27466694 TI - Single-Cell RNAseq Reveals That Pancreatic beta-Cells From Very Old Male Mice Have a Young Gene Signature. AB - Aging improves pancreatic beta-cell function in mice. This is a surprising finding because aging is typically associated with functional decline. We performed single-cell RNA sequencing of beta-cells from 3- and 26-month-old mice to explore how changes in gene expression contribute to improved function with age. The old mice were healthy and had reduced blood glucose levels and increased beta-cell mass, which correlated to their body weight. beta-Cells from young and old mice had similar transcriptome profiles. In fact, only 193 genes (0.89% of all detected genes) were significantly regulated (>=2-fold; false discovery rate < 0.01; normalized counts > 5). Of these, 183 were down-regulated and mainly associated with pathways regulating gene expression, cell cycle, cell death, and survival as well as cellular movement, function, and maintenance. Collectively our data show that beta-cells from very old mice have transcriptome profiles similar to those of young mice. These data support previous findings that aging is not associated with reduced beta-cell mass or functional beta-cell decline in mice. PMID- 27466695 TI - Investigating Water Splitting with CaFe2O4 Photocathodes by Electrochemical Impedance Spectroscopy. AB - Artificial photosynthesis constitutes one of the most promising alternatives for harvesting solar energy in the form of fuels, such as hydrogen. Among the different devices that could be developed to achieve efficient water photosplitting, tandem photoelectrochemical cells show more flexibility and offer high theoretical conversion efficiency. The development of these cells depends on finding efficient and stable photoanodes and, particularly, photocathodes, which requires having reliable information on the mechanism of charge transfer at the semiconductor/solution interface. In this context, this work deals with the preparation of thin film calcium ferrite electrodes and their photoelectrochemical characterization for hydrogen generation by means of electrochemical impedance spectroscopy (EIS). A fully theoretical model that includes elementary steps for electron transfer to the electrolyte and surface recombination with photogenerated holes is presented. The model also takes into account the complexity of the semiconductor/solution interface by including the capacitances of the space charge region, the surface states and the Helmholtz layer (as a constant phase element). After illustrating the predicted Nyquist plots in a general manner, the experimental results for calcium ferrite electrodes at different applied potentials and under different illumination intensities are fitted to the model. The excellent agreement between the model and the experimental results is illustrated by the simultaneous fit of both Nyquist and Bode plots. The concordance between both theory and experiments allows us to conclude that a direct transfer of electrons from the conduction band to water prevails for hydrogen photogeneration on calcium ferrite electrodes and that most of the carrier recombination occurs in the material bulk. In more general vein, this study illustrates how the use of EIS may provide important clues about the behavior of photoelectrodes and the main strategies for their improvement. PMID- 27466697 TI - High-k Dielectric Passivation: Novel Considerations Enabling Cell Specific Lysis Induced by Electric Fields. AB - A better understanding of the electrodynamic behavior of cells interacting with electric fields would allow for novel scientific insights and would lead to the next generation of cell manipulation, diagnostics, and treatment. Here, we introduce a promising electrode design by using metal oxide high-k dielectric passivation. The thermally generated dielectric passivation layer enables efficient electric field coupling to the fluid sample comprising cells while simultaneously decoupling the electrode ohmically from the electrolyte, allowing for better control and adjustability of electric field effects due to reduced electrochemical reactions at the electrode surface. This approach demonstrates cell-size specific lysis with electric fields in a microfluidic flow-through design resulting in 99.8% blood cell lysis at 6 s exposure without affecting the viability of Gram-positive and Gram-negative bacterial spike-ins. The advantages of this new approach can support next-generation investigations of electrodynamics in biological systems and their exploitation for cell manipulation in multiple fields of medicine, life science, and industry. PMID- 27466696 TI - Regiospecific Prenylation of Hydroxyxanthones by a Plant Flavonoid Prenyltransferase. AB - C-Prenylated xanthones are pharmacologically attractive specialized metabolites that are distributed in plants and microorganisms. The prenylation of xanthones often contributes to the structural diversity and biological activities of these compounds. However, efficient regiospecific prenylation of xanthones is still challenging. In this study, the regiospecific prenylation of a number of structurally different hydroxyxanthones (3-10) by MaIDT, a plant flavonoid prenyltransferase with substrate flexibility from Morus alba, is demonstrated. Among the enzymatic products, 2-dimethylallyl-1,3,7-trihydroxyxanthone (3a) effectively attenuated glutamate-induced injury in SK-N-SH neuroblastoma cells. These results suggest a potential approach for the synthesis of bioactive prenylated xanthones by a substrate-relaxed flavonoid prenyltransferase. PMID- 27466698 TI - U.S. Mortality Due to Carbon Monoxide Poisoning, 1999-2014. Accidental and Intentional Deaths. AB - RATIONALE: Carbon monoxide (CO) poisoning accounts for hundreds of deaths and thousands of emergency department visits in the United States annually. Development of initiatives to reduce CO mortality through poisoning prevention requires a comprehensive understanding of the condition. OBJECTIVES: To describe U.S. mortality from 1999 to 2014 due to CO poisoning from all sources except fires, to examine the epidemiology of accidental and intentional exposures, and to identify trends. METHODS: The CDC WONDER database was used to extract and analyze data from the CDC's Multiple Cause of Death 1999-2014 file. The file contains mortality data derived from all death certificates filed in the United States. MEASUREMENTS AND MAIN RESULTS: Information on deaths, crude death rate, age-adjusted death rate, intent of exposure, and characteristics of exposures from CO poisoning was extracted. Total deaths by CO poisoning decreased from 1,967 in 1999 to 1,319 in 2014 (P < 0.001). Crude and adjusted death rates fell accordingly. Accidental poisoning accounted for 13% fewer deaths per year in 2014 than in 1999 (P < 0.001). The number of intentional deaths by CO poisoning decreased by 47% over the same period (P < 0.001). The rate of decline in combined adjusted death rates from 1999 to 2014 in the 19 states that required residential CO alarms by 2010 was not different from that for the 31 states that did not require residential alarms (P = 0.982). CONCLUSIONS: Numbers of deaths and death rates, both accidental and intentional, due to CO poisoning significantly declined in the United States from 1999 to 2014. Continued public education about CO toxicity should be emphasized. Additional study is needed to demonstrate the efficacy of residential CO alarms. PMID- 27466699 TI - Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment. AB - CONTEXT: Somatostatin analogs (SAs) used in acromegaly to suppress GH secretion and tumor growth also suppress insulin secretion and may impact GH signaling. OBJECTIVE: To compare GH and insulin signaling after iv GH exposure in acromegalic patients controlled by surgery (n = 9) or SA (n = 9). DESIGN: Each patient was studied for 3 hours after an overnight fast (t = -60 to 120 minutes). GH was administered at t = 0 minutes; muscle and fat biopsies were obtained at t = 0 minutes and at t = 30 minutes (muscle) and t = 120 minutes (fat). Interstitial fluid was obtained from skin suction blisters (t = 0 minutes). MAIN OUTCOME MEASURES: GH and insulin signalling in muscle and fat. GH and IGF-1 in serum and interstitial fluid; insulin and free fatty acids in serum. RESULTS: The groups were comparable as regards GH and IGF-1. The SA group exhibited higher free fatty acid and glucose levels; basal suppressor of cytokine signaling protein 1 (SOCS1) mRNA in fat was increased in the SA group and correlated positively with SA dose (r2 = 0.54; P = .04). GH-induced GH signalling (pSTAT5b) in muscle occurred in both groups together with increased expression of SOCS and CISH genes. GH-induced pAKTthr308 was observed in SA patients. In both groups, mRNA expression of phosphatase and tensin homolog, a suppressor of insulin signaling, increased in fat after GH. CONCLUSION: 1) Signatures of GH and insulin signaling differ as a function of acromegaly treatment modality. 2) Extra pituitary effects of SA may account for this. 3) The clinical implications remain to be investigated. PMID- 27466700 TI - Self-Assembly of Janus Oligomers into Onion-like Vesicles with Layer-by-Layer Water Discharging Capability: A Minimalist Model. AB - A vesicle in a cell is an enclosed structure in which the interior fluid is encompassed by a lipid bilayer. Synthetic vesicles are known as the liposomes. Liposomes with a single phospholipid bilayer are called unilamellar liposomes; otherwise, they are called multilamellar liposomes or onion-like liposomes (vesicles). One prototype synthetic onion-like vesicle, namely, onion-like dendrimersomes, have been recently produced via the self-assembly of amphiphilic Janus dendrimers (Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 1162). Herein, we show computer simulation evidence of another type of onion-like vesicle, namely, onion like oligomersomes, via the self-assembly of amphiphilic Janus oligomers in water. Specifically, we investigate the minimum-sized oligomers (or minimalist model) that can give rise to the onion-like oligomersomes as well as the composition-dependent phase diagrams. Insights into the formation condition and formation process of the onion-like oligomersomes are obtained. We demonstrate that the discharge of the in-vesicle water is through the remarkable "peeling-one onion-layer-at-a-time" fashion, a feature that can be utilized for a clinical dosing regimen. The ability to control the formation of onion-like oligomersomes by design can be exploited for applications in drug and gene delivery. PMID- 27466701 TI - Glacier Melting Increases the Solute Concentrations of Himalayan Glacial Lakes. AB - Over the past two decades, we observed a substantial rise in ionic content that was mainly determined by the sulfate concentration at 20 remote high elevation lakes located in central southern Himalaya. At LCN9, which was monitored on an annual basis for the last 20 years, the sulfate concentrations increased over 4 fold. Among the main causes, we exclude a change in the composition of wet atmospheric deposition, as well as a possible influence of decrease in seasonal snow cover duration, which could have exposed larger basin surfaces to alteration processes. Glacier retreat likely was the main factor responsible for the observed increase of sulfate concentrations. We attribute this chemical changes mainly to the sulfide oxidation processes that occur in subglacial environments. Moreover, we observe that the weakened monsoon of the past two decades has only partially contributed to the lakes enrichment through runoff waters that are more concentrated in solutes or lowering the water table, resulting in more rock exposed to air and enhanced mineral oxidation. PMID- 27466702 TI - Recent Advances in the Theory and Simulation of Model Colloidal Microphase Formers. AB - This mini-review synthesizes our understanding of the equilibrium behavior of particle-based models with short-range attractive and long-range repulsive (SALR) interactions. These models, which can form stable periodic microphases, aim to reproduce the essence of colloidal suspensions with competing interparticle interactions. Ordered structures, however, have yet to be obtained in experiments. In order to better understand the hurdles to periodic microphase assembly, marked theoretical and simulation advances have been made over the past few years. Here, we present recent progress in the study of microphases in models with SALR interactions using liquid-state theory and density-functional theory as well as numerical simulations. Combining these various approaches provides a description of periodic microphases, and gives insights into the rich phenomenology of the surrounding disordered regime. Ongoing research directions in the thermodynamics of models with SALR interactions are also presented. PMID- 27466703 TI - Omarigliptin for the treatment of type 2 diabetes mellitus. AB - INTRODUCTION: The estimated global prevalence of diabetes mellitus for adults aged 20-70 in 2015 was 415 million with approximately 90% of diagnosed cases being Type 2 diabetes mellitus (T2DM). Improvements in lifestyle and effective therapies are key to management but due to the progressive nature of T2DM, pharmacotherapy is typically required. Whilst the initial therapy will usually be with metformin, thereafter treatment should be individualised, with consideration of several different second line options. These include the dipeptidyl peptidase 4 (DPP-4) inhibitors, of which omarigliptin is the second once weekly version. AREAS COVERED: The paper summarises key pharmoacodynamic and pharmacokinetic features and reviews the efficacy and safety trial data of omarigliptin, a once weekly DPP-4 inhibitor. EXPERT OPINION: Omarigliptin results in a significant improvement in glycaemia with an effective once weekly pharmacokinetic profile and low risk of drug-drug interactions. It has equivalent efficacy to existing once daily DPP-4 inhibitors and shares a similar side effect profile. It is weight neutral with a significantly lower risk of hypoglycaemia compared with sulphonylureas. Adherence to prescribed medication is poor in patients with T2DM. Once weekly omarigliptin is a welcomed addition to the therapeutic armoury but whether it will improve compliance remains to be seen. PMID- 27466705 TI - Hydrogen-Bonded Liquid Crystal Nanocomposites. AB - Nanoparticle-liquid crystal (NP-LC) composites based on hydrogen bonding were explored using a model system. The ligand shells of 3 nm diameter zirconium dioxide nanoparticles (ZrO2 NPs) were varied to control their interaction with 4 n-hexylbenzoic acid (6BA). The miscibility and effect of the NPs on the nematic order as a function of particle concentration was characterized by polarized optical microscopy (POM), fluorescence microscopy and (2)H NMR spectroscopy. Nonfunctionalized ZrO2 NPs have the lowest miscibility and strongest effect on the LC matrix due to irreversible binding of 6BA to the NPs via a strong zirconium carboxylate bond. The ZrO2 NPs were functionalized with 6 phosphonohexanoic acid (6PHA) or 4-(6-phosphonohexyloxy)benzoic acid (6BPHA) which selectively bind to the ZrO2 NP surface via the phosphonic acid groups. The miscibility was increased by controlling the concentration of the pendant CO2H groups by adding hexylphosphonic acid (HPA) to act as a spacer group. Fluorescence microscopy of lanthanide doped ZrO2 NPs showed no aggregates in the nematic phase below the NP concentration where aggregates are observed in the isotropic phase. The functionalized NPs preferably concentrate into LC defects and any remaining isotropic liquid but are still present throughout the nematic liquid at a lower concentration. PMID- 27466704 TI - Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression. AB - KCNQ channels are critical determinants of neuronal excitability, thus emerging as a novel target of anti-epileptic drugs. To date, the mechanisms of KCNQ channel modulation have been mostly characterized to be inhibitory via Gq-coupled receptors, Ca(2+)/CaM, and protein kinase C. Here we demonstrate that methylation of KCNQ by protein arginine methyltransferase 1 (Prmt1) positively regulates KCNQ channel activity, thereby preventing neuronal hyperexcitability. Prmt1+/- mice exhibit epileptic seizures. Methylation of KCNQ2 channels at 4 arginine residues by Prmt1 enhances PIP2 binding, and Prmt1 depletion lowers PIP2 affinity of KCNQ2 channels and thereby the channel activities. Consistently, exogenous PIP2 addition to Prmt1+/- neurons restores KCNQ currents and neuronal excitability to the WT level. Collectively, we propose that Prmt1-dependent facilitation of KCNQ PIP2 interaction underlies the positive regulation of KCNQ activity by arginine methylation, which may serve as a key target for prevention of neuronal hyperexcitability and seizures. PMID- 27466707 TI - Identification of a novel metabolic-related mutation (IDH1) in metastatic pancreatic cancer. AB - Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme implicated in cancer cell metabolic reprogramming. This is underscored by the detection of functional, somatic IDH1 mutations frequently found in secondary glioblastoma. To our knowledge, there has never been a reported, validated case of an IDH1 mutation in a pancreatic ductal adenocarcinoma (PDA). Herein, we present a case of a patient with metastatic PDA that harbored a potentially actionable, albeit rare, IDH1 mutation. As part of the Know Your Tumor project (Pancreatic Cancer Action Network), a 48-year-old female was diagnosed with metastatic PDA and subsequently started on standard of care chemotherapy, during which her hepatic lesions progressed. Detailed molecular profiling was performed on a biopsy from a liver lesion that demonstrated an IDH1 mutation, R132H. This mutation was confirmed by an independent sequencing reaction from the tumor sample, and by immunohistochemistry using an antibody specific for the IDH1 R132H mutation. The patient subsequently received a mutant IDH1 inhibitor (AG-120, Agios Pharmaceuticals, Cambridge, MA), but with no response. IDH1 mutations are common in certain cancer types, but have not been reported in PDA. We report the first case of an IDH1 mutation in this tumor type, perhaps providing a rare opportunity for a targeted therapy as a treatment option for PDA. PMID- 27466708 TI - Extended use of systemic steroid is beneficial in preserving hearing in guinea pigs after cochlear implant. AB - CONCLUSION: Seven-day administration of systemic steroids was more effective in preserving hearing for 12 weeks after cochlear implantation (CI) than a 3-day delivery. OBJECTIVES: To determine the effectiveness of extended delivery of systemic steroids to preserve hearing in guinea pigs after CI. METHODS: Dexamethasone (4 mg/ml) was delivered parenterally via a mini-osmotic pump for either 3 or 7 days. A dummy CI electrode was inserted via cochleostomy approach in 8-week-old guinea pigs. Auditory thresholds were assessed from tone burst auditory brainstem responses (2, 8, 16, 24, and 32 kHz) at 1 day prior to CI, and 1, 4, and 12 weeks after implantation. Histologic evaluation of the cochleae was carried out. RESULTS: No differences were observed in hearing thresholds among groups before CI. Significant hearing preservation was achieved at 8, 16, 24, and 32 kHz only in the 7-day infusion group compared with the control group at 1 week after CI. The same trend was maintained at 4 weeks (16, 24 kHz) and 12 weeks (16, 24, and 32 kHz). Histologic review of the 7-day infusion group revealed less fibrosis and ossification in the scala tympani and the preservation of more spiral ganglion cells, compared with the control group. PMID- 27466706 TI - Paradigm shift in bacteriophage-mediated delivery of anticancer drugs: from targeted 'magic bullets' to self-navigated 'magic missiles'. AB - INTRODUCTION: New phage-directed nanomedicines have emerged recently as a result of the in-depth study of the genetics and structure of filamentous phage and evolution of phage display and phage nanobiotechnology. This review focuses on the progress made in the development of the cancer-targeted nanomaterials and discusses the trends in using phage as a bioselectable molecular navigation system. Areas covered: The merging of phage display technologies with nanotechnology in recent years has proved promising in different areas of medicine and technology, such as medical diagnostics, molecular imaging, vaccine development and targeted drug/gene delivery, which is the focus of this review. The authors used data obtained from their research group and sourced using Science Citation Index (Web of Science) and NCBI PubMed search resources. Expert opinion: First attempts of adapting traditional concepts of direct targeting of tumor using phage-targeted nanomedicines has shown minimal improvements. With discovery and study of biological and technical barriers that prevent anti-tumor drug delivery, a paradigm shift from traditional drug targeting to nanomedicine navigation systems is required. The advanced bacteriophage-driven self-navigation systems are thought to overcome those barriers using more precise, localized phage selection methods, multi-targeting 'promiscuous' ligands and advanced multifunctional nanomedicine platforms. PMID- 27466709 TI - Findings From the National Machine Guarding Program-A Small Business Intervention: Machine Safety. AB - OBJECTIVES: The purpose of this nationwide intervention was to improve machine safety in small metal fabrication businesses (3 to 150 employees). The failure to implement machine safety programs related to guarding and lockout/tagout (LOTO) are frequent causes of Occupational Safety and Health Administration (OSHA) citations and may result in serious traumatic injury. METHODS: Insurance safety consultants conducted a standardized evaluation of machine guarding, safety programs, and LOTO. Businesses received a baseline evaluation, two intervention visits, and a 12-month follow-up evaluation. RESULTS: The intervention was completed by 160 businesses. Adding a safety committee was associated with a 10% point increase in business-level machine scores (P < 0.0001) and a 33% point increase in LOTO program scores (P < 0.0001). CONCLUSIONS: Insurance safety consultants proved effective at disseminating a machine safety and LOTO intervention via management-employee safety committees. PMID- 27466711 TI - Single cell-resolution western blotting. AB - This protocol describes how to perform western blotting on individual cells to measure cell-to-cell variation in protein expression levels and protein state. Like conventional western blotting, single-cell western blotting (scWB) is particularly useful for protein targets that lack selective antibodies (e.g., isoforms) and in cases in which background signal from intact cells is confounding. scWB is performed on a microdevice that comprises an array of microwells molded in a thin layer of a polyacrylamide gel (PAG). The gel layer functions as both a molecular sieving matrix during PAGE and a blotting scaffold during immunoprobing. scWB involves five main stages: (i) gravity settling of cells into microwells; (ii) chemical lysis of cells in each microwell; (iii) PAGE of each single-cell lysate; (iv) exposure of the gel to UV light to blot (immobilize) proteins to the gel matrix; and (v) in-gel immunoprobing of immobilized proteins. Multiplexing can be achieved by probing with antibody cocktails and using antibody stripping/reprobing techniques, enabling detection of 10+ proteins in each cell. We also describe microdevice fabrication for both uniform and pore-gradient microgels. To extend in-gel immunoprobing to gels of small pore size, we describe an optional gel de-cross-linking protocol for more effective introduction of antibodies into the gel layer. Once the microdevice has been fabricated, the assay can be completed in 4-6 h by microfluidic novices and it generates high-selectivity, multiplexed data from single cells. The technique is relevant when direct measurement of proteins in single cells is needed, with applications spanning the fundamental biosciences to applied biomedicine. PMID- 27466710 TI - A strategy for co-translational folding studies of ribosome-bound nascent chain complexes using NMR spectroscopy. AB - During biosynthesis on the ribosome, an elongating nascent polypeptide chain can begin to fold, in a process that is central to all living systems. Detailed structural studies of co-translational protein folding are now beginning to emerge; such studies were previously limited, at least in part, by the inherently dynamic nature of emerging nascent chains, which precluded most structural techniques. NMR spectroscopy is able to provide atomic-resolution information for ribosome-nascent chain complexes (RNCs), but it requires large quantities (>=10 mg) of homogeneous, isotopically labeled RNCs. Further challenges include limited sample working concentration and stability of the RNC sample (which contribute to weak NMR signals) and resonance broadening caused by attachment to the large (2.4 MDa) ribosomal complex. Here, we present a strategy to generate isotopically labeled RNCs in Escherichia coli that are suitable for NMR studies. Uniform translational arrest of the nascent chains is achieved using a stalling motif, and isotopically labeled RNCs are produced at high yield using high-cell-density E. coli growth conditions. Homogeneous RNCs are isolated by combining metal affinity chromatography (to isolate ribosome-bound species) with sucrose density centrifugation (to recover intact 70S monosomes). Sensitivity-optimized NMR spectroscopy is then applied to the RNCs, combined with a suite of parallel NMR and biochemical analyses to cross-validate their integrity, including RNC optimized NMR diffusion measurements to report on ribosome attachment in situ. Comparative NMR studies of RNCs with the analogous isolated proteins permit a high-resolution description of the structure and dynamics of a nascent chain during its progressive biosynthesis on the ribosome. PMID- 27466712 TI - Analysis of bacterial-surface-specific antibodies in body fluids using bacterial flow cytometry. AB - Antibacterial antibody responses that target surfaces of live bacteria or secreted toxins are likely to be relevant in controlling bacterial pathogenesis. The ability to specifically quantify bacterial-surface-binding antibodies is therefore highly attractive as a quantitative correlate of immune protection. Here, binding of antibodies from various body fluids to pure-cultured live bacteria is made visible with fluorophore-conjugated secondary antibodies and measured by flow cytometry. We indicate the necessary controls for excluding nonspecific binding and also demonstrate a cross-adsorption technique for determining the extent of cross-reactivity. This technique has numerous advantages over standard ELISA and western blotting techniques because of its independence from scaffold binding, exclusion of cross-reactive elements from lysed bacteria and ability to visualize bacterial subpopulations. In addition, less than 10(5) bacteria and less than 10 MUg of antibody are required per sample. The technique requires 3-4 h of hands-on experimentation and analysis. Moreover, it can be combined with automation and mutliplexing for high-throughput applications. PMID- 27466714 TI - Leaders with style. PMID- 27466715 TI - It's all connected! Patient experience and healthy practice environments. PMID- 27466713 TI - A mutagenesis and screening strategy to generate optimally thermostabilized membrane proteins for structural studies. AB - The thermostability of an integral membrane protein (MP) in detergent solution is a key parameter that dictates the likelihood of obtaining well-diffracting crystals that are suitable for structure determination. However, many mammalian MPs are too unstable for crystallization. We developed a thermostabilization strategy based on systematic mutagenesis coupled to a radioligand-binding thermostability assay that can be applied to receptors, ion channels and transporters. It takes ~6-12 months to thermostabilize a G-protein-coupled receptor (GPCR) containing 300 amino acid (aa) residues. The resulting thermostabilized MPs are more easily crystallized and result in high-quality structures. This methodology has facilitated structure-based drug design applied to GPCRs because it is possible to determine multiple structures of the thermostabilized receptors bound to low-affinity ligands. Protocols and advice are given on how to develop thermostability assays for MPs and how to combine mutations to make an optimally stable mutant suitable for structural studies. The steps in the procedure include the generation of ~300 site-directed mutants by Ala/Leu scanning mutagenesis, the expression of each mutant in mammalian cells by transient transfection and the identification of thermostable mutants using a thermostability assay that is based on binding of an (125)I-labeled radioligand to the unpurified, detergent-solubilized MP. Individual thermostabilizing point mutations are then combined to make an optimally stable MP that is suitable for structural biology and other biophysical studies. PMID- 27466716 TI - Osmotic stress alters UV-based oxidative damage tolerance in a heterocyst forming cyanobacterium. AB - Cyanobacteria are successful in diverse habitats due to their adaptation strategies. Their mechanisms to cope with individual stresses have been studied. However, the response to combined stress conditions as found in nature remains unclear. With this aim, we studied the dual effect of 24h-osmotic and 3h-UV irradiation on the cyanobacterium Calothrix BI22. Our approach included the study of redox homeostasis, oxidative damage, reactive oxygen species production consumption processes and photosynthetic activity. Superoxide in vivo determination with confocal image processing showed the highest accumulation under UV. However, no lipoperoxidation occurred due to a high SOD activity. This cyanobacterium was less prepared to cope with the osmotic stress assayed. Under this condition, O2 photoevolution decreased abruptly and oxidative damage was produced by reactive species other than superoxide. In this situation the cellular control of the amount of ROS failed to prevent oxidative damage and photosynthesis was seriously disturbed in spite of maximum quantum photosynthetic efficiency remained unchanged. Calothrix BI22 presented the more severe oxidative damage when both stressors were applied. The osmotic stress disentangled the mechanisms developed by this cyanobacterium to deal with 3h-UV irradiation alone. PMID- 27466717 TI - Serratia liquefaciens Causing Severe Ocular Damage in Noncontact Lens Wearer. AB - Serratia liquefaciens is a rarely encountered gram-negative organism in ophthalmology practice. The only reported ocular infections are from contamination of contact lenses. The authors report the first case of a patient who developed orbital cellulitis secondary to severe S. liquefaciens microbial keratitis. PMID- 27466718 TI - Multicenter Study of a Novel Topical Interleukin-1 Receptor Inhibitor, Isunakinra, in Subjects With Moderate to Severe Dry Eye Disease. AB - OBJECTIVES: Isunakinra, formerly known as EBI-005, is a novel interleukin (IL)-1 receptor inhibitor developed for topical treatment of patients with dry eye disease (DED). This phase 1b/2a multicenter, double-masked, randomized, vehicle controlled environmental trial assessed the safety and biological activity of isunakinra in patients with moderate to severe DED. METHODS: Subjects (N=74) were randomized to vehicle (placebo) or isunakinra (5 or 20 mg/mL) 3*/daily for 6 weeks. Evaluations included safety, tolerability, biological activity for signs (corneal fluorescein staining [CFS]), symptoms (pain or sore eyes and total Ocular Surface Disease Index [OSDI]), and reduction in rescue artificial tear use. RESULTS: Topical administration of isunakinra (5 and 20 mg/mL) was safe and well tolerated and resulted in clinically relevant improvements in symptoms (OSDI score, painful/sore eye component of OSDI) and signs (total CFS) compared with baseline with no dose response. OSDI scores improved from baseline by 38% (18.9 points) at 6 weeks and CFS scores improved by 33% (3 points) in the isunakinra groups. These changes were not statistically significant compared with the vehicle. Use of artificial rescue tears was significantly reduced in the isunakinra treatment groups (mean=9 vials) compared with vehicle (mean=31 vials). The differences between isunakinra and vehicle treatments were more pronounced in subjects with OSDI scores less than 50 at baseline. CONCLUSIONS: Isunakinra was safe, well tolerated and showed clinically meaningful improvements in signs and symptoms of DED. These results encouraged the design of an adequately powered study to characterize the safety and efficacy of isunakinra in ocular surface diseases. PMID- 27466720 TI - Development of a Meibomian Gland Dysfunction-Specific Symptom Questionnaire. AB - OBJECTIVES: The aim of this study was to develop and evaluate, using psychometric approaches, a meibomian gland dysfunction (MGD)-specific questionnaire in noncontact lens wearers. METHODS: The MGD subjects were recruited and classified as the MGD dry eye subtype based on accepted tests (e.g., Schein symptom survey, tear breakup time, corneal and conjunctival staining, abnormal meibum or meibomian gland atrophy, and a normal Schirmer test). The MGD questionnaire items were drawn from published and anecdotal sources. The preliminary instrument contained 24 items targeting the frequency and intensity of 12 symptoms. Rasch analysis was used for psychometric evaluation of the survey items. RESULTS: Sixty nine MGD subjects completed the survey and clinical testing. Sample severity levels were as follows: none subclinical, 10 minimal, 43 mild, 16 moderate, and none severe. Three iterations of analysis, eliminating INFIT and OUTFIT scores <, and >3.0, and using subject responses reduced the final questionnaire to seven question pairs. Final analysis for the remaining 14 items demonstrated an excellent fit to the Rasch model (e.g., for persons, INFIT MNSQ=0.97; ZSTD=-0.2; OUTFIT MNSQ=0.96; ZSTD=-0.2; item fit statistics were similar). Construct validity also seems good (e.g., correlation to Schein and change with treatment). CONCLUSIONS: The MGD-specific instrument is a valid quantitative measure of the symptoms stemming from MGD sufferers. Further research is necessary to determine whether diagnostic efficacy is sufficient to differentiate the MGD dry eye subtype in an independent sample of normals and both major dry eye subtypes exhibiting a broad severity range. PMID- 27466719 TI - The Infant Aphakia Treatment Study Contact Lens Experience to Age 5 Years. AB - PURPOSE: To describe our experience treating a cohort of unilateral aphakic infants with contact lenses in the Infant Aphakia Treatment Study (IATS). MATERIALS AND METHODS: Fifty-seven of the 114 infants in the IATS were randomized to contact lens wear; all were followed until age 5 years, although a few had lapses in care. An examination under anesthesia, including keratometry, was performed at the time of enrollment and at approximately 1 year of age; keratometry was performed again at 5 years of age. A traveling examiner assessed visual acuity at approximately 1 year of age and again at 4.5 years of age. RESULTS: Twenty-four treated eyes (46%) wore silicone elastomer (SE) contact lenses, 11 eyes (19%) rigid gas permeable (GP) contact lenses and 17 eyes (29%) wore both lens types at various points of time. Median logMAR visual acuity was +0.70 (interquartile range (IQR), +0.30 to 1.20) in the SE group and 2.03 (IQR, +0.20 to 2.28) in the GP group at age 4.5 years. The mean (+/-SD) keratometric power of the treated eyes was 46.3+/-2.8 diopter (D) at baseline, 44.6+/-2.3 D at 1 year of age, and 44.3+/-1.7 D at 5 years of age. Keratometric astigmatism of treated eyes was 1.98+/-1.37 D at baseline, 1.62+/-0.98 D at 1 year of age, and 2.00+/-1.00 D at 5 years of age. Thirteen contact lens-related adverse events occurred among 7 patients after age 1 year. CONCLUSIONS: A cohort of infants with unilateral aphakia successfully wore contact lenses with relatively few adverse events. PMID- 27466721 TI - Interexaminer Reliability of Meibography: Upper or Lower Eyelid? AB - OBJECTIVES: To investigate the interexaminer reliability of meibography evaluation and the impact of eyelid selection for the procedure. METHODS: Meibography images of 30 subjects' right eye, including both lids, were evaluated by three clinicians. Meibomian gland (MG) dropout was noted with respect to both percentage and grading (0-4). The examiners' (E1, E2, and E3) consistency was assessed by the intraclass correlation coefficient for MG loss percent and weighted kappa for grading. Correlations between the meibography findings and the fluorescein tear break-up time (FBUT), ocular surface disease index (OSDI) questionnaire, and noninvasive tear break-up time (NIBUT) data were also analyzed. RESULTS: The patients' mean age was 49.2+/-13.4 years, and the male/female ratio distribution was 15/15. Mean FBUT was 9.6+/-3.1 sec. OSDI and NIBUT were not correlated with meibography findings. FBUT measurements were correlated with the MG loss assessments of all examiners for the upper lid (Spearman correlation test, E1: r=-0.617, P<0.001; E2: r=-0.428, P<0.018; E3: r= 0.429, P=0.018) but not for the lower lid. Weighted kappa statistics based on MG dropout grading revealed moderate-to-good agreement for the upper lid (E1-E2: kappa=0.516, P<0.001; E1-E3: kappa=0.621, P<0.001; E2-E3: kappa=0.650, P<0.001) and fair-to-moderate agreement for the lower lid (E1-E2: kappa=0.212; E1-E3: kappa=0.272; E2-E3: kappa=0.530). CONCLUSIONS: Meibography is an objective tool for the detection of MG loss. Because of the correlation with FBUT and better interexaminer agreement on dropout by grading, the upper lid might be the preferred lid to make an evaluation. PMID- 27466722 TI - Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) Treatment for Complications After LASIK. AB - OBJECTIVES: To report experience with Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) treatment for complications after laser in situ keratomileuisis (LASIK). METHODS: Retrospective review of clinical and manufacturing records. A database of patients who underwent PROSE treatment from 1992 to 2007 was searched to yield all patients with history of LASIK. Primary indication for PROSE treatment and year of LASIK is reported as well as history of contact lens intolerance and pretreatment and posttreatment best-corrected visual acuity (BCVA). RESULTS: From 1992 to 2007, 44 patients (75 eyes) with history of LASIK underwent PROSE treatment. Patients with corneal ectasia (n=23, 52%) comprise the largest group of patients, followed by those with other optical aberrations (n = 14.32%), dry eye (n = 4.9%), and corneal neuralgia (n=3.7%). Thirteen patients (30%) had more than one indication for PROSE treatment. The majority (71%) of patients referred for PROSE treatment had LASIK between 1998 and 2000, including every patient with aberrations as primary indication. Eighty six percent of all patients had history of contact lens intolerance. Eighty-four percent of eyes showed improvement in BCVA after PROSE treatment, mean 0.3LogMAR, (P < 0.0001, 2-tailed paired t test, n = 75). CONCLUSIONS: PROSE treatment is an effective option for management of ectasia, cornea first surface aberrations, dry eye, and corneal neuralgia after LASIK, even in patients who are contact lens intolerant. PMID- 27466724 TI - A Case of Disulfiram-Induced Psychosis in a Previously Asymptomatic Patient Maintained on Mixed Amphetamine Salts: A Review of the Literature and Possible Pathophysiological Explanations. AB - Although perhaps better known as an irreversible aldehyde dehydrogenase inhibitor causing increased acetaldehyde levels after concomitant intake of ethanol, disulfiram or one of its metabolites (diethyldithiocarbamate) also inhibit dopamine beta-hydroxylase, an enzyme that converts dopamine to norepinephrine. This mechanism has been advanced as a possible explanation for the development of psychosis, during disulfiram treatment, either in monotherapy or in combination therapy, when interaction-emergent psychosis could be causal. We present a young woman who was taking mixed amphetamine salts for treatment of attention deficit/hyperactivity disorder and developed a short-lived psychosis after introduction of disulfiram. The psychotic symptoms resolved after discontinuation of both medications, without the use of antipsychotic drugs. We proceed with a review of the literature of disulfiram-induced psychosis and discuss pathophysiological theories that possibly were involved in our patient's phenomenology. PMID- 27466725 TI - Intestinal dysbiosis in systemic lupus erythematosus: cause or consequence? AB - PURPOSE OF REVIEW: Recent discoveries relay commensal gut microbiota as a relevant factor in the maintenance of intestinal homeostasis. RECENT FINDINGS: Alterations in the composition of the intestinal microbiota have been reported in patients with systemic lupus erythematosus and many other inflammatory and autoimmune conditions. However, the mechanisms by which the intestinal microbiota can influence systemic immunity in these situations remain to be elucidated. The inappropriate immune responses of patients with systemic lupus erythematosus could originate a breakdown of tolerance towards the microbiota, leading to the expansion and/or contraction of specific bacterial groups that may culminate in a dysbiotic state. Conversely, an altered composition of the intestinal microbiome in genetically predisposed individuals could influence systemic immunity by several mechanisms, leading to a breakdown of tolerance to self-antigens. Moreover, humoral immune responses can be affected by specific bacterial groups in these individuals. SUMMARY: Recent findings support an important role for the crosstalk between bacteria and immune cells to maintain an intestinal homeostasis crucial to sustain tolerance toward self-antigens and intestinal microbiota. PMID- 27466726 TI - Update on enthesitis-related arthritis. AB - PURPOSE OF REVIEW: This review provides a detailed update regarding the genetics, pathogenesis, disease phenotype evaluation, therapies and expected outcomes for children with enthesitis-related arthritis (ERA). RECENT FINDINGS: Recent studies evaluated human leukocyte antigen (HLA)-B27 subtypes and non-major histocompatibility complex genes including toll like receptor 4, NLRP3, CXCR4 and PTPN12 in children with ERA. The microbiome and gammadelta-T cells have also been an area of active investigation. Several studies focus on the imaging phenotype of children with ERA, including the use of ultrasonography and MRI. MRI techniques studied in this population include dedicated MRI, whole-body MRI and diffusion-weighted imaging. Conventional and biologic disease-modifying agents continue to be the mainstay of therapy, though the past 2 years have witnessed several greatly needed randomized controlled trials to study the efficacy of these medications in ERA. Finally, long-term effectiveness studies of biologics in children with ERA have helped inform provider and patient expectations of disease response and prognosis. SUMMARY: Further evaluation of the role of the microbiome and the interleukin 17/interleukin 23 axis, techniques to optimize evaluation of disease features, and efficacy and effectiveness of newer medications are greatly needed in this understudied population of children. PMID- 27466727 TI - Long-Lived Hole Spin/Valley Polarization Probed by Kerr Rotation in Monolayer WSe2. AB - Time-resolved Kerr rotation and photoluminescence measurements are performed on MOCVD-grown monolayer tungsten diselenide (WSe2). We observe a surprisingly long lived Kerr rotation signal (~80 ns) at 10 K, which is attributed to spin/valley polarization of the resident holes. This polarization is robust to transverse magnetic field (up to 0.3 T). Wavelength-dependent measurements reveal that only excitation near the free exciton energy generates this long-lived spin/valley polarization. PMID- 27466738 TI - Characterization of polyphenols in apricot and peach purees by UHPLC coupled to HRMS Q-Exactive(TM) mass spectrometer: an approach in the identification of adulterations. AB - The genuineness of fruit juices and purees is regulated by guidelines of European Fruit Juice Association. Nevertheless, the addition of peach puree to apricot puree is considered the most common adulteration, very difficult to discover. In this study, the composition in free and conjugated polyphenols of apricot and peach purees was performed by target and untarget approaches with Q-Exactive(TM) quadrupole-Orbitrap mass spectrometer. Apricot purees showed a higher polyphenol content than those of peaches. Between target coumpounds, chlorogenic acid, rutin, catechin and smaller quantities of hyperoside and kaempferol-3-rutinoside were found in both purees. Apricot puree was also found to contain epicatechin and procianidin B2, absent in peach puree. Peach puree was found to contain small amounts of kaempferol-3-glucoside, absent in apricot. In order to identify untarget polyphenols, data obtained by ultra-high pressure liquid chromatography tandem mass spectrometry analysis were processed with Thermo Scientific automated label-free differential expression software (sieve(TM) 2.1 software). Three hydroxycinnamic acid conjugates and a procyanidin were identified and confirmed by tandem mass spectrometry spectra. Some compounds of interest found from differential analysis had a putative identification, while others remained unidentified. The high-resolution mass spectrometry approach using Q-Exactive(TM) quadrupole-Orbitrap mass spectrometer could be an important and powerful tool for determination of new biomarkers in fruits and vegetables. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27466739 TI - The Molecular Mechanism of Iron(III) Oxide Nucleation. AB - A molecular understanding of the formation of solid phases from solution would be beneficial for various scientific fields. However, nucleation pathways are still not fully understood, whereby the case of iron (oxyhydr)oxides poses a prime example. We show that in the prenucleation regime, thermodynamically stable solute species up to a few nanometers in size are observed, which meet the definition of prenucleation clusters. Nucleation then is not governed by a critical size, but rather by the dynamics of the clusters that are forming at the distinct nucleation stages, based on the chemistry of the linkages within the clusters. This resolves a longstanding debate in the field of iron oxide nucleation, and the results may generally apply to oxides forming via hydrolysis and condensation. The (molecular) understanding of the chemical basis of phase separation is paramount for, e.g., tailoring size, shape and structure of novel nanocrystalline materials. PMID- 27466741 TI - Risk of incident cardiovascular events amongst individuals with anxiety and depression: A prospective cohort study in the east London primary care database. AB - BACKGROUND: It is unknown how risk of myocardial infarction and stroke differ for patients with and without anxiety or depression, and whether this risk can be explained by demographics, medication use, cardiovascular risk factors. The aim of this study is to quantify differences in risk of non-fatal MI or stroke among patients with anxiety or depression. METHODS: Prospective cohort study examining risk of incident MI and stroke between March 2005 and March 2015 for 524,952 patients aged 30 and over from the east London primary care database for patients with anxiety or depression. RESULTS: Amongst 21,811 individuals with depression at baseline, 1.2% had MI and 0.4% had stroke. Of 22,128 individuals with anxiety at baseline, 1.1% had MI and 0.3% had stroke. Depression was independently associated with both MI and stroke, whereas anxiety was associated with MI only before adjustment for cardiovascular risk factors. Antidepressant use increased risk for MI but not stroke. Mean age at first MI was lower in those with anxiety, while mean age at first stroke was lower in those with depression. LIMITATIONS: The study was limited to patients currently registered in the database and thus we did not have any patients that died during the course of follow-up. CONCLUSIONS: Patients with depression have increased risk of cardiovascular events. The finding of no increased cardiovascular risk in those with anxiety after adjusting for cardiovascular risk factors is of clinical importance and highlights that the adequate control of traditional risk factors is the cornerstone of cardiovascular disease prevention. Targeting management of classical cardiovascular risk factors and evaluating the risks of antidepressant prescribing should be prioritized. PMID- 27466740 TI - Megaloblastic Anemia with Ring Sideroblasts is not Always Myelodysplastic Syndrome. PMID- 27466742 TI - When social anxiety and depression go together: A population study of comorbidity and associated consequences. AB - BACKGROUND: Despite several studies suggesting higher depression severity and dysfunction occurring in individuals with major depressive disorder (MDD) comorbid with social anxiety disorder (SAD), a clear understanding of the specific risks associated with this comorbidity is lacking. In this study we compared the disease characteristics and level of disability of individuals with MDD-SAD with other comorbidities between depression and anxiety. METHODS: Data from the Collaborative Psychiatric Epidemiology Surveys (CPES) (N=20,013) were used. Individuals were divided in four groups comparing MDD-SAD with MDD alone, as well as other comorbidities between MDD and one anxiety (MDD-1ANX) or more than two anxiety disorders (MDD>=2ANX), with respect to several clinical, demographic, and functional characteristics. RESULTS: MDD-SAD comorbidity in the general population occurred in younger people, particularly men, and seemed to have an earlier onset of MDD. Occupational and social dysfunction was similar between individuals with MDD-SAD and those with MDD-1ANX. However, individuals with MDD>=2ANX had significantly higher severity as measured by suicidality as well as substance abuse and social and occupational dysfunction. SAD was the most prevalent comorbid anxiety in this group. LIMITATIONS: The findings of this study were derived from the cross-sectional data. CONCLUSION: Our results suggest that the particular risks associated with MDD-SAD are the early onset and likelihood of additional anxiety, leading to higher severity and disability levels. Clinicians should increase the screening and treatment of SAD and other anxiety disorders in individuals with MDD given the higher associated health risk and functional impairment. PMID- 27466744 TI - Self-help strategies for sub-threshold anxiety: A Delphi consensus study to find messages suitable for population-wide promotion. AB - BACKGROUND: Many self-help strategies have been recommended for anxiety, but it is not clear which strategies are most effective and could be encouraged as part of an early intervention approach. This study used the Delphi expert consensus method to identify which strategies for mild (sub-threshold) anxiety are thought to be helpful and feasible to implement for individuals without professional assistance. METHODS: Participants were an international sample of 51 clinicians/researchers and 32 consumer advocates with expertise in anxiety. The scientific and lay literature was systematically searched for strategies claimed to be effective for anxiety. Participants rated the likely helpfulness of each strategy in reducing sub-threshold anxiety (related to generalised anxiety, social anxiety, or non-specific anxiety symptoms) and the feasibility of implementation in an iterative process across three questionnaire rounds. RESULTS: 66 out of 324 candidate strategies were endorsed by at least 80% of both consumers and clinicians/researchers as likely to be helpful, and 18 were judged as feasible to carry out. Endorsed strategies were most frequently related to cognitive strategies and other psychological methods, interpersonal strategies, reducing physical tension, and lifestyle strategies. Few strategies were endorsed that were related to diet, supplements, or complementary medicine. LIMITATIONS: Findings may not apply to other forms of mild anxiety related to panic attacks or specific phobias. CONCLUSIONS: This study contributes to the evidence-base on strategies that individuals can use to improve mild anxiety symptoms. Research is now required to evaluate whether promoting the strategies can help reduce the overall community burden from anxiety disorders. PMID- 27466743 TI - Depression and serum low-density lipoprotein: A systematic review and meta analysis. AB - BACKGROUND: A cross-sectional association between depression and serum low density lipoprotein (LDL) has been noted in the literature. This study aims to employ meta-analytic techniques to clarify the relationship between depression and serum LDL. METHODS: Published articles through April 2015 were identified through systematic query of PubMed with follow-up manual searches. Data from 36 studies reporting mean difference and 7 studies reporting odds ratios were analyzed separately. RESULTS: Meta-analysis of studies modeling serum LDL as a continuous measure demonstrates overall significantly lower serum LDL in depression (Mean difference=-4.29, 95% CI=-8.19, -0.40, p=0.03). Meta-analysis of studies modeling serum LDL as a categorical measure demonstrates a marginally significant lower odds of depression in the presence of low serum LDL relative to high serum LDL (OR=0.90, 95% CI=0.80, 1.01, p=0.08). LIMITATIONS: High heterogeneity was noted across sampled studies, which may be a function of variations in study design, participants sampled, or other factors. The potential for publication bias was also assessed. CONCLUSIONS: This meta-analysis demonstrates a cross-sectional link between depression and low serum LDL. PMID- 27466745 TI - Effective self-management strategies for bipolar disorder: A community-engaged Delphi Consensus Consultation study. AB - BACKGROUND: Self-management represents an important complement to psychosocial treatments for bipolar disorder (BD), but research is limited. Specifically, little is known about self-management approaches for elevated mood states; this study investigated self-management strategies for: (1) maintaining balance in mood, and (2) stopping progression into hypomania/mania. METHODS: To identify the common components of BD self-management, Delphi Consensus Consultation methods were combined with a Community-Based Participatory Research (CBPR) approach across five study phases: (1) Qualitative dataset content analysis; (2) Academic/grey literature reviews; (3) Content analysis; (4) Two Delphi rounds (rating strategies on a 5-point Likert scale, Very Unhelpful-Very Helpful), and; (5) Quantitative analysis and interpretation. Participants were people with BD and healthcare providers. RESULTS: Phases 1 and 2 identified 262 and 3940 candidate strategies, respectively; 3709 were discarded as duplicates/unintelligible. The remaining 493 were assessed via Delphi methods in Phase 4: 101 people with BD and 52 healthcare providers participated in Round 1; 83 of the BD panel (82%) and 43 of the healthcare provider panel (83%) participated in Round 2-exploratory factor analysis (EFA) was conducted on Round 2 results. LIMITATIONS: EFA was underpowered and sample was not ethnically diverse, limiting generalizability. DISCUSSION: High concordance was observed in ratings of strategy effectiveness between the two panels. Future research could usefully investigate the provisional discovery here of underlying factors which link individual strategies. For example, 'maintaining hope' underpinned strategies for maintaining balance, and 'decreasing use of stimulants' underpinned strategies to interrupt hypo/manic ascent. There is merit in combining CBPR and Delphi methods. PMID- 27466746 TI - Sexual orientation and treatment-seeking for depression in a multilingual worldwide sample. AB - BACKGROUND: Prior research has found higher rates of mental health problems among sexual minority individuals. We examine treatment-seeking for depression, as well as its relationship with sexual orientation, in a large, multilingual, international sample. METHOD: Participants in an automated, quintilingual internet-based depression screening tool were screened for depression, and completed several background measures, including sexual orientation (with an option to decline to state) and past and current depression treatment seeking. RESULTS: 3695 participants screened positive for current or past depression and responded to the sexual orientation question. Those who declined to state their sexual orientation were far less likely to seek any treatment than individuals endorsing any orientation; they were especially unlikely to seek psychotherapy. Individuals identifying as bisexual sought both psychotherapy and alternative treatments at a higher rate than other groups. An interaction was observed between sexual orientation and gender, such that lesbian women were especially likely to have used psychotherapy. Other variables that emerged as significant predictors of treatment-seeking for depression included age and participant's language. LIMITATIONS: Limitations include possible misinterpretation of translated terms due to regional differences, and possible limits to generalizability due to this study being conducted on the internet. CONCLUSIONS: Our results suggest that individuals who decline to state their sexual orientation may be more likely to forgo effective treatments for depression. Further studies of depression service utilization should focus on developing treatment modalities that could better engage sexual minority individuals, especially those who are reluctant to disclose their orientation. PMID- 27466748 TI - Cannabis and cannabinoids. PMID- 27466749 TI - Jentadueto XR for type 2 diabetes. PMID- 27466747 TI - Developmental risk factors in generalized anxiety disorder and panic disorder. AB - BACKGROUND: There is a lack of clarity regarding specific risk factors discriminating generalized anxiety disorder (GAD) from panic disorder (PD). GOAL: This study investigated whether GAD and PD could be discriminated through differences in developmental etiological factors including childhood parental loss/separation, psychological disorders, and maternal and paternal attachment. METHOD: Twenty people with adult generalized anxiety disorder (GAD), 20 with adult panic disorder (PD), 11 with adult comorbid GAD and PD, and 21 adult non anxious controls completed diagnostic interviews to assess symptoms of mental disorders in adulthood and childhood. Participants also reported on parental attachment, loss and separation. RESULTS: Childhood diagnoses of GAD and PD differentiated clinical groups from controls as well as from each other, suggesting greater likelihood for homotypic over heterotypic continuity. Compared to controls, specific phobia was associated with all three clinical groups, and childhood depression, social phobia, and PTSD were uniquely associated with adult GAD. Both maternal and paternal attachment also differentiated clinical groups from controls. However, higher levels of subscales reflecting maternal insecure avoidant attachment (e.g., no memory of early childhood experiences and balancing/forgiving current state of mind) emerged as more predictive of GAD relative to PD. There were no group differences in parental loss or separation. CONCLUSIONS: These results support differentiation of GAD and PD based on developmental risk factors. Recommendations for future research and implications of the findings for understanding the etiology and symptomatology of GAD and PD are discussed. PMID- 27466750 TI - Emtricitabine/tenofovir alafenamide (Descovy) for HIV. PMID- 27466751 TI - Venetoclax (Venclexta) for chronic lymphocytic leukemia. PMID- 27466752 TI - Addendum: Depression and suicidality with isotretinoin. PMID- 27466753 TI - Multiparticle collision dynamics for diffusion-influenced signaling pathways. AB - An efficient yet accurate simulation method for modeling diffusion-influenced reaction networks is presented. The method extends existing reactive multiparticle collision dynamics by incorporating species-dependent diffusion coefficients, and developing theoretical expressions for the reactant-dependent diffusion control. This off-lattice particle-based mesoscopic simulation tool is particularly suited for problems in which detailed descriptions of particle trajectories and local reactions are required. Numerical simulations of an intracellular signaling pathway for bacterial chemotaxis are carried out to validate our approach, and to demonstrate its efficiency. PMID- 27466754 TI - Evaluation of exposure to phthalate esters and DINCH in urine and nails from a Norwegian study population. AB - Phthalate esters (PEs) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) used as additives in numerous consumer products are continuously released into the environment, leading to subsequent human exposure which might cause adverse health effects. The human biomonitoring approach allows the detection of PEs and DINCH in specific populations, by taking into account all possible routes of exposure (e.g. inhalation, transdermal and oral) and all relevant sources (e.g. air, dust, personal care products, diet). We have investigated the presence of nine PE and two DINCH metabolites and their exposure determinants in 61 adult residents of the Oslo area (Norway). Three urine spots and fingernails were collected from each participant according to established sampling protocols. Metabolite analysis was performed by LC-MS/MS. Metabolite levels in urine were used to back-calculate the total exposure to their corresponding parent compound. The primary monoesters, such as monomethyl phthalate (MMP, geometric mean 89.7ng/g), monoethyl phthalate (MEP, 104.8ng/g) and mono-n-butyl phthalate (MnBP, 89.3ng/g) were observed in higher levels in nails, whereas the secondary bis(2 ethylhexyl) phthalate (DEHP) and DINCH oxidative metabolites were more abundant in urine (detection frequency 84-100%). The estimated daily intakes of PEs and DINCH for this Norwegian population did not exceed the established tolerable daily intake and reference doses, and the cumulative risk assessment for combined exposure to plasticizers with similar toxic endpoints indicated no health concerns for the selected population. We found a moderate positive correlation between MEP levels in 3 urine spots and nails (range: 0.56-0.68). Higher frequency of personal care products use was associated with greater MEP concentrations in both urine and nail samples. Increased age, smoking, wearing plastic gloves during house cleaning, consuming food with plastic packaging and eating with hands were associated with higher levels in urine and nails for some of the metabolites. In contrast, frequent hair and hand washing was associated with lower urinary levels of monoisobutyl phthalate (MiBP) and mono(2-ethyl-5 hydroxyhexyl) phthalate (5-OH-MEHP), respectively. PMID- 27466756 TI - Intended Target of the Centers for Disease Control and Prevention Opioid Guidelines-Reply. PMID- 27466755 TI - Novel application of statistical methods for analysis of multiple toxicants identifies DDT as a risk factor for early child behavioral problems. AB - BACKGROUND: The aim of this study was to assess the association between postnatal exposure to multiple persistent organic pollutants (POPs) measured in breast milk samples and early behavioral problems using statistical methods to deal with correlated exposure data. METHODS: We used data from the Norwegian HUMIS study. We measured concentrations of 24 different POPs in human milk from 612 mothers (median collection time: 32 days after delivery), including 13 polychlorinated biphenyls (PCB) congeners, 6 polybrominated diphenyl ethers (PBDE) congeners and five organochlorine compounds. We assessed child behavioral problems at 12 and 24 months using the infant toddler symptom checklist (ITSC). Higher score in ITSC corresponds to more behavioral problems. First we performed principal component analysis (PCA). Then two variable selection methods, elastic net (ENET) and Bayesian model averaging (BMA), were applied to select any toxicants associated with behavioral problems. Finally, the effect size of the selected toxicants was estimated using multivariate linear regression analyses. RESULTS: p,p'-DDT was associated with behavioral problems at 12 months in all the applied models. Specifically, the principal component composed of organochlorine pesticides was significantly associated with behavioral problems and both ENET and BMA identified p,p'-DDT as associated with behavioral problems. Using a multiple linear regression model an interquartile increase in p,p'-DDT was associated with a 0.62 unit increase in ITSC score (95% CI 0.45, 0.79) at 12 months, corresponding to more behavioral problems. The association was modified by maternal education: the effect of p,p'-DDT was strongest in women with lower education (beta=0.59; 95%CI: 0.38, 0.81) compared to the mother with higher education (beta=0.14; 95%CI: -0.05, 0.34) (p-value for interaction=0.089). At 24 months, neither selection method consistently identified any toxicant associated with behavioral problems. CONCLUSION: Within a mixture of 24 toxicants measured in breast milk, p,p'-DDT was the single toxicant associated with behavioral problems at 12 months using different methods for handling numerous correlated exposures. PMID- 27466758 TI - Update: Interim Guidance for Prevention of Sexual Transmission of Zika Virus - United States, July 2016. AB - Zika virus has been identified as a cause of congenital microcephaly and other serious brain defects (1). CDC issued interim guidance for the prevention of sexual transmission of Zika virus on February 5, 2016, with an initial update on April 1, 2016 (2). The following recommendations apply to all men and women who have traveled to or reside in areas with active Zika virus transmission* and their sex partners. The recommendations in this report replace those previously issued and are now updated to reduce the risk for sexual transmission of Zika virus from both men and women to their sex partners. This guidance defines potential sexual exposure to Zika virus as having had sex with a person who has traveled to or lives in an area with active Zika virus transmission when the sexual contact did not include a barrier to protect against infection. Such barriers include male or female condoms for vaginal or anal sex and other barriers for oral sex.(?) Sexual exposure includes vaginal sex, anal sex, oral sex, or other activities that might expose a sex partner to genital secretions.(S) This guidance will be updated as more information becomes available. PMID- 27466759 TI - Facial Reconstruction-Judging Our Results. PMID- 27466760 TI - 18(th) EuroQSAR: Perspectives on QSAR, Molecular Informatics and Drug Design. PMID- 27466761 TI - Next-generation QSAR. PMID- 27466762 TI - Computational-Regulatory Developments in the Prediction of Oral Drug Absorption. AB - Early prediction of human intestinal absorption is important in selection of potential orally administered drugs. Various computational models for prediction of the fraction of dose absorbed, Fa, have been developed. In 1989, a sigmoidal relationship between Fa and drug absorption potential was shown. Since then various physicochemical descriptors of molecules (lipophilicity, polar surface area, hydrogen bond descriptors) have been found to correlate with human intestinal absorption and various attempts in estimating Fa have been reported. Most studies rely on the presupposition that Fa is mainly dependent on drug's solubility, which drives the dissolution rate in the gastrointestinal (GI) fluids, and the rate of passive drug transport across the intestinal membrane. In the same vein, the biopharmaceutics classification system (BCS) and the relevant FDA guideline classify drugs in four categories according to their aqueous solubility and permeability. However, the biopharmaceutics drug disposition classification system (BDDCS) revealed the poor predictability of permeability estimates for Fa and the major role of transporters for GI uptake of drugs. The role of solubility in the reaction limited model of dissolution and the ubiquitous presence of supersaturated solubility-dissolution phenomena in the GI lumen, call for a more physiologically relevant consideration of GI absorption. PMID- 27466763 TI - Ligand Efficiency Indices (LEIs): More than a Simple Efficiency Yardstick. AB - The concept of ligand efficiency and the usage of ligand efficiency values to assess the quality of fragments and compounds is becoming more accepted in the practice of medicinal chemistry. This is particularly true as it refers to the efficiency of ligands per unit size (i.e., binding affinity/number of non hydrogen atoms or binding affinity/MW). The use of the Ligand Efficiency Indices (LEIs) as variables for a Cartesian mapping of chemico-biological space, the concept of AtlasCBS, has been presented in a recent publication with some initial drug-discovery applications. In this communication, we present additional applications of the concept in three domains of drug discovery: i) analyze and compare the content of databases: inhibitors vs. drugs; ii) polypharmacology; and iii) applications to Fragment-Based strategies. We suggest that the combined use of LEIs in a Cartesian representation of Chemico-Biological Space (AtlasCBS) could be a useful tool in various aspects of drug-discovery in the future. PMID- 27466764 TI - Discovery of a Potent and Selective Hetero-Bivalent AChE Inhibitor via Bioisosteric Replacement. PMID- 27466765 TI - Time-Trajectories in Efficiency Maps as Effective Guides for Drug Discovery Efforts. PMID- 27466766 TI - Correction: Time-Trajectories in Efficiency Maps as Effective Guides for Drug Discovery Efforts. PMID- 27466767 TI - Correction: Time-Trajectories in Efficiency Maps as Effective Guides for Drug Discovery Efforts. PMID- 27466768 TI - Identification of Inhibitors of the Tyrosine Kinase c-Met by Structure-Based Virtual Screening. PMID- 27466769 TI - Using Spherical Harmonic Surface Property Representations for Ligand-Based Virtual Screening. AB - Ligand-based virtual screening (VS) techniques have become well established in the drug discovery process. However, despite their relative success, there still exists the problem of how to define the initial query compounds and which of their conformations should be used. Here, we propose a novel shape plus surface property approach using multiple local spherical harmonic (SH) functions. We also investigate the use of shape-based and shape plus property-based consensus SH queries calculated in several different ways. The utility of these approaches is compared using the 40 pharmaceutically relevant targets of the DUD database. Our results show that using a combination of SH-based properties often gives better VS performance than using simple shape-based queries. Shape-based consensus queries also perform well, but we find that explicit 3D shape-property conformations should be retained for highly flexible ligands. PMID- 27466770 TI - Retrospective Mapping of SAR Data for TTR Protein in Chemico-Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies. AB - We have previously reported the design and synthesis of ligands that stabilize Transthyretin protein (TTR) in order to obtain therapeutically active compounds for Familial Amyloid Polyneuropathy (FAP). We are hereby reporting a drug design strategy to optimize these ligands and map them in Chemico-Biological Space (CBS) using Ligand Efficiency Indices (LEIs). We use a binding efficiency index (BEI) based on the measured binding affinity related to the molecular weight (MW) of the compound combined with surface-binding efficiency index (SEI) based on Polar Surface Area (PSA). We will illustrate the use of these indices, combining three crucial variables (potency, MW and PSA) in a 2D graphical representation of chemical space, to perform a retrospective mapping of SAR data for a current TTR inhibitors database, and we propose prospective strategies to use these efficiency indices and chemico-biological space maps for optimization and drug design efforts for TTR ligands. PMID- 27466771 TI - General Purpose Electronegativity Relaxation Charge Models Applied to CoMFA and CoMSIA Study of GSK-3 Inhibitors. AB - Two fast empirical charge models, Kirchhoff Charge Model (KCM) and Dynamic Electronegativity Relaxation (DENR), had been developed in our laboratory previously for widespread use in drug design research. Both models are based on the electronegativity relaxation principle (Adv. Quantum Chem. 2006, 51, 139-156) and parameterized against ab initio dipole/quadrupole moments and molecular electrostatic potentials, respectively. As 3D QSAR studies comprise one of the most important fields of applied molecular modeling, they naturally have become the first topic to test our charges and thus, indirectly, the assumptions laid down to the charge model theories in a case study. Here these charge models are used in CoMFA and CoMSIA methods and tested on five glycogen synthase kinase 3 (GSK-3) inhibitor datasets, relevant to our current studies, and one steroid dataset. For comparison, eight other different charge models, ab initio through semiempirical and empirical, were tested on the same datasets. The complex analysis including correlation and cross-validation, charges robustness and predictability, as well as visual interpretability of 3D contour maps generated was carried out. As a result, our new electronegativity relaxation-based models both have shown stable results, which in conjunction with other benefits discussed render them suitable for building reliable 3D QSAR models. PMID- 27466772 TI - Back to the Roots: Prediction of Biologically Active Natural Products from Ayurveda Traditional Medicine. AB - Ayurveda, the traditional Indian medicine is one of the most ancient, yet living medicinal traditions. In the present work, we developed an in silico library of natural products from Ayurveda medicine, coupled with structural information, plant origin and traditional therapeutic use. Following this, we compared their structures with those of drugs from DrugBank and we constructed a structural similarity network. Information on the traditional therapeutic use of the plants was integrated in the network in order to provide further evidence for the predicted biologically active natural compounds. We hereby present a number of examples where the traditional medicinal use of the plant matches with the medicinal use of the drug that is structurally similar to a plant component. With this approach, we have brought to light a number of obscure compounds of natural origin (e.g. kanugin, norruffscine, isoazadirolide) that could provide the basis and inspiration for further lead development. Apart from the identification of novel natural leads in drug discovery, we envisage that this integrated in silico ethnopharmacology approach could find applications in the elucidation of the molecular basis of Ayurveda medicine and in drug repurposing. PMID- 27466774 TI - Using Local Models to Improve (Q)SAR Predictivity. AB - We present a novel (Q)SAR approach that detects groups of structures for local (Q)SAR modeling. The algorithm combines clustering and classification or regression for making predictions on chemical structure data. A clustering procedure producing clusters with shared structural scaffolds is applied as a preprocessing step, before a (local) model is learned for each relevant cluster. Instead of using only one global model (classical approach), we use weighted local models for predictions of query compounds dependent on cluster memberships. The approach is evaluated and compared against standard statistical (Q)SAR algorithms on various datasets. The results show that in many cases the application of local models significantly improves the predictive power of the derived (Q)SAR models compared to the classical approach, to models that are induced by a fingerprint-based or a hierarchical clustering approach and to locally weighted learning. PMID- 27466775 TI - Structural Bioinformatics Approach of Cyclin-Dependent Kinases 1 and 3 Complexed with Inhibitors. AB - The cyclin-dependent kinases or CDKs participate in the regulation of both the cell progression cycle and the RNA polymerase-II transcription cycle. In several human tumours deregulation of CDK-related mechanisms have been detected, e.g., overexpression of cyclins or deletion of genes encoding for CKIs. Regarding these observations, CDKs came up to be interesting targets for elaboration of novel antitumour drugs. Based on the importance of the CDKs, this research aimed to describe, to characterize and to compare the molecular models of CDK1 and CDK3. Since the structures of human CDK1 and CDK3 are unavailable in the Protein Data Bank -PDB, homology models were created based on the CDK2 as the template, once they share a substantial identity. The structural studies of the CDK1 and CDK3 biding sites were conducted by molecular docking with 15 different CDK inhibitors previously identified to CDK2. This study allowed the understanding of the structure of the complexes between CDK1/ CDK3 with inhibitors. The knowledge of their structural features mainly the biding sites might be useful to discovery and rationalization of drug design process. PMID- 27466773 TI - CADASTER QSPR Models for Predictions of Melting and Boiling Points of Perfluorinated Chemicals. AB - Quantitative structure property relationship (QSPR) studies on per- and polyfluorinated chemicals (PFCs) on melting point (MP) and boiling point (BP) are presented. The training and prediction chemicals used for developing and validating the models were selected from Syracuse PhysProp database and literatures. The available experimental data sets were split in two different ways: a) random selection on response value, and b) structural similarity verified by self-organizing-map (SOM), in order to propose reliable predictive models, developed only on the training sets and externally verified on the prediction sets. Individual linear and non-linear approaches based models developed by different CADASTER partners on 0D-2D Dragon descriptors, E-state descriptors and fragment based descriptors as well as consensus model and their predictions are presented. In addition, the predictive performance of the developed models was verified on a blind external validation set (EV-set) prepared using PERFORCE database on 15 MP and 25 BP data respectively. This database contains only long chain perfluoro-alkylated chemicals, particularly monitored by regulatory agencies like US-EPA and EU-REACH. QSPR models with internal and external validation on two different external prediction/validation sets and study of applicability-domain highlighting the robustness and high accuracy of the models are discussed. Finally, MPs for additional 303 PFCs and BPs for 271 PFCs were predicted for which experimental measurements are unknown. PMID- 27466776 TI - On the Use of Local and Global QSPRs for the Prediction of Physico-chemical Properties of Polybrominated Diphenyl Ethers. AB - Polybrominated diphenyl ethers (PBDEs) are persistent chemicals that have been among the most marketed flame retardants used all over the world in the last decades. PBDEs have been detected in all environmental compartments, as well as in humans and wildlife, where they are able to accumulate and exert their toxic effects. At present only a limited amount of experimental data is available to characterize the physico-chemical and toxicological behavior of PBDEs and similar brominated flame retardants. QSA(P)R approaches are very useful tools to predict missing data starting from the chemical structure of compounds. In this study several local QSPR models, developed specifically for the prediction of logKoa, logKow and melting point of PBDEs, were compared with predictions by global QSPR models, such as KoaWIN, KowWIN and MPBPWIN from the EPI Suite package, and AlogP and MlogP from DRAGON software, which were trained on heterogeneous and large datasets. The analysis addressed in the paper supported the identification of points of strength and weaknesses of both local models, and global models. The results are relevant to support decisions made by general QSAR users and regulators, when they have to select and apply one of the analyzed models to predict properties for PBDEs. PMID- 27466777 TI - QSAR Modelling of Rat Acute Toxicity on the Basis of PASS Prediction. AB - The method for QSAR modelling of rat acute toxicity based on the combination of QNA (Quantitative Neighbourhoods of Atoms) descriptors, PASS (Prediction of Activity Spectra for Substances) predictions and self-consistent regression (SCR) is presented. PASS predicted biological activity profiles are used as independent input variables for QSAR modelling with SCR. QSAR models were developed using LD50 values for compounds tested on rats with four types of administration (oral, intravenous, intraperitoneal, subcutaneous). The proposed method was evaluated on the set of compounds tested for acute rat toxicity with oral administration (7286 compounds) used for testing the known QSAR methods in T.E.S.T. 3.0 program (U.S. EPA). The several other sets of compounds tested for acute rat toxicity by different routes of administration selected from SYMYX MDL Toxicity Database were used too. The method was compared with the results of prediction of acute rodent toxicity for noncongeneric sets obtained by ACD/Labs Inc. The test sets were predicted with regards to the applicability domain. Comparison of accuracy for QSAR models obtained separately using QNA descriptors, PASS predictions, nearest neighbours' assessment with consensus models clearly demonstrated the benefits of consensus prediction. Free available web-service for prediction of LD50 values of rat acute toxicity was developed: http://www.pharmaexpert.ru/GUSAR/AcuToxPredict/. PMID- 27466778 TI - Multi-pH QSAR: II. Regression Analysis Sensitive Enough to Determine the Transition-State pKa of Human Buccal Absorption. AB - An analysis of published human buccal absorption data of an acid and a base at six pH values extends multi-pH QSAR to an extreme: QSAR on a single compound. The compounds analyzed are 4-n-hexylphenylacetic acid and propranolol. This analysis might be considered as much an analysis of the model as the compound, itself. Ionizable compounds undergo a pKa change in the process of absorption. Multi-pH QSAR allows determination of the pKa of the presumed rate-limiting step for absorption, which we label the transition-state pKa (pKa (TS) ). Comparison of the pKa (TS) with the corresponding aqueous and membrane pKa values provides the extent of molecular penetration at the transition state. It is 49 % of the path length for the arylacetic acid and 73 % for propranolol. PMID- 27466779 TI - Predictivity of Simulated ADME AutoQSAR Models over Time. AB - The automation of model building and model updating (autoQSAR) is an important step forward towards real-time small molecule drug discovery project support using the latest experimental data. We present here a simulation study using real company data of the behaviour of QSAR models over time. Three different global QSAR models, namely, human plasma protein binding, aqueous solubility and log D7.4 , are updated on a monthly basis over a period of three years. The effect of updating the models on their predictivity is studied using a series of monthly temporal test sets in addition to a final terminal temporal test set. Partial Least Squares (PLS), Random Forest (RF) and Bayesian Neural Networks (BNN) models are examined, covering three distinctly different approaches to QSAR modelling. It is demonstrated that the models are able to predict forward in time, but that updating models on a regular basis increases their ability to make predictions for current compounds. The degree of the improvement depends on the property studied and the model building technique used. These results demonstrate the importance of updating models on a regular basis. For both static models predicting forward in time, and regularly updating models it is shown that RF models are the most predictive for these data sets. PMID- 27466780 TI - Prediction of Acute Rodent Toxicity on the Basis of Chemical Structure and Physicochemical Similarity. AB - A development of the Arithmetic Mean Toxicity (AMT) approach is presented in this article. Twenty six physicochemical descriptors, calculated by using the HYBOT program, along with molecular weight and lipophilicity were included in the selection of structural and physicochemical neighbours (analogues). Toxicity predictions of 906 chemicals from the REACH Pre-Registration Substance (PRS) list were carried out with the application of six nearest structural neighbours and three pairs of structural/physicochemical neighbours on the basis of molecular polarizability, the sum of negative atomic charges in a molecule, the sum of H bond acceptor and donor factors and the octanol-water partition coefficient. The best prediction results were obtained three pair structural neighbours were applied (each pair contains one chemical with a higher and one chemical with a lower descriptor value). The prediction of toxicity as the mean arithmetic toxicity value of the nearest structural and physicochemical neighbours can be considered a robust approach for the read-across of properties (toxicity data) between analogues. Traditionally, analogues would be selected by expert judgement, but increasingly the availability of large databases and the application of nearest neighbour approaches such as the AMT approach provide a means of automating such assessments. PMID- 27466781 TI - Growth Response of Trichoderma Species to Organic Solvents. AB - The growth response of 25 Trichoderma strains to 26 alkanols and 7 other organic solvents was examined in vitro. The sensitivity of strains considerably varied depending on their taxonomic position, thus the strains of Longibrachiatum section proved to be more tolerant than those of Pachybasium and Trichoderma sections. Significant relationship was revealed between structure of C1 -C24 alkanols and their growth inhibitory effect to Trichodermas, both efficacy and selectivity of C1 -C3 and C14 -C24 alkanols failed off the C9 -C11 alkanols. The non-alkanol solvents tested were non-toxic. The C8 -C11 alkanols used in agricultural practices exhibited noticeable toxicity to all Trichoderma strains, therefore pesticidal preparations containing these alkanols cannot be used simultaneously with Trichoderma based biopreparations. PMID- 27466782 TI - The control of the electronic structure of dinuclear copper complexes of redox active tetrakisguanidine ligands by the environment. AB - The electronic structures of dinuclear copper complexes of the general formula [GFA(CuX2)2], where X = Br or Cl and GFA denotes a redox-active bridging Guanidino-Functionalized Aromatic ligand, were analysed and compared. The diamagnetic complexes [GFA(CuBr2)2] can all be described as dinuclear CuI complexes with bridging GFA2+ dicationic ligand units exhibiting a [CuI-GFA2+ CuI] electronic structure. The electronic structure prevails in the solid state and in all applicable organic solvents. The situation changes completely for the [GFA(CuCl2)2] complexes. They are paramagnetic in the solid state, where they are adequately described as dinuclear CuII complexes with neutral bridging GFA ligand units ([CuII-GFA-CuII]). In solution, they exist either as [CuII-GFA-CuII] or as valence-tautomeric [CuI-GFA2+-CuI] complexes, depending on the polarity of the solvent. Only in the case of GFA = 2,3,5,6-tetrakis(tetramethylguanidino)pyridine and in acetone as solvent, the two valence tautomers are in a temperature dependent equilibrium. Quantum chemical computations show that the structural difference between the two valence tautomeric forms is smaller for this complex than for the others, explaining the low energy barrier for the intramolecular electron transfer in accordance with Marcus theory. PMID- 27466783 TI - Conjugated linoleic acid rat pretreatment reduces renal damage in ischemia/reperfusion injury: Unraveling antiapoptotic mechanisms and regulation of phosphorylated mammalian target of rapamycin. AB - SCOPE: Conjugated linoleic acids (CLAs) are dietary components with beneficial effects on human health. The aim of this study was to evaluate the potential benefits of CLA pretreatment in a rat model of renal ischemia/reperfusion injury (IRI). METHODS AND RESULTS: Animals were treated with CLAs (200 mg/kg/day) or water for two weeks prior to sham surgery or to surgery to induce IRI. Renal function, oxidative stress, apoptosis, and cell proliferation markers, were evaluated. Moreover, kidney sections were submitted to histological evaluation. IRI induced increased serum creatinine, blood urea nitrogen, fractional sodium excretion, malondialdehyde, Bax, and phosphorylated mammalian target of rapamycin (P-mTOR), and decreased clearance of creatine, superoxide dismutase and catalase activities, and Bax in comparison with control groups. CLA prefeeding restored, at least in part, the above reported markers to normal levels, increased the anti apoptotic protein, B-cell lymphoma 2 (Bcl-2), and reduce the histological damage. CONCLUSION: The results suggest that the decreased renal tissue damage and improved renal function and oxidative stress, in rats pretreated with CLAs before renal IRI induction, could be associated with downregulation of Bax and P-mTOR, and upregulation of Bcl-2. CLAs pretreatment resulted to protect against IRI through the regulation of signaling pathways involved in apoptosis. PMID- 27466784 TI - Septicemia in an Indian Rhesus Macaque (Macaca mulatta) associated with Providencia stuartii. AB - Providencia stuartii (P. stuartii) is an opportunistic pathogen and major concern in urinary catheter-related infections in human medicine. Here we report P. stuartii-induced septicemia in an eighteen-year-old, female India-origin Rhesus macaque with multiple traumatic wounds. The animal had neutrophilic leukocytosis, necrosuppurative meningoencephalitis, hypophysitis and bronchopneumonia with vasculitis, thrombosis, and clusters of extracellular Gram-negative bacilli. P. stuartii was isolated from the lesions of the brain and lung and confirmed by PCR and sequencing. To the authors' knowledge, this is the first case of septicemia associated with P. stuartii in a non-human primate. PMID- 27466785 TI - Development of safety performance functions for Spanish two-lane rural highways on flat terrain. AB - Over decades safety performance functions (SPF) have been developed as a tool for traffic safety in order to estimate the number of crashes in a specific road section. Despite the steady progression of methodological innovations in the crash analysis field, many fundamental issues have not been completely addressed. For instance: Is it better to use parsimonious or fully specified models? How should the goodness-of-fit of the models be assessed? Is it better to use a general model for the entire sample or specific models based on sample stratifications? This paper investigates the above issues by means of several SPFs developed using negative binomial regression models for two-lane rural highways in Spain. The models were based on crash data gathered over a 5-year period, using a broad number of explanatory variables related to exposure, geometry, design consistency and roadside features. Results show that the principle of parsimony could be too restrictive and that it provided simplistic models. Most previous studies apply conventional measurements (i.e., R(2), BIC, AIC, etc.) to assess the goodness-of-fit of models. Seldom do studies apply cumulative residual (CURE) analysis as a tool for model evaluation. This paper shows that CURE plots are essential tools for calibrating SPF, while also providing information for possible sample stratification. Previous authors suggest that sample segmentation increases the model accuracy. The results presented here confirm that finding, and show that the number of significant variables in the final models increases with sample stratification. This paper point out that fully models based on sample segmentation and on CURE may provide more useful insights about traffic crashes than general parsimonious models when developing SPF. PMID- 27466786 TI - Spike timing in auditory-nerve fibers during spontaneous activity and phase locking. AB - In vertebrates, all acoustic information transmitted from the inner ear to the central auditory system is relayed by primary auditory afferents (auditory-nerve fibers; ANFs). These neurons are also the most peripheral elements to use action potentials (spikes) to encode the acoustic information. Here, we review what is known about the spiking of ANFs during spontaneous activity, when spike timing might be regarded as largely random, and during stimulation by low-frequency sounds, when spikes are phase locked to the stimulus waveform, a phenomenon generally considered a hallmark of temporal precision and speed in the auditory system. We focus on mammals, in which each ANF is driven by a single ribbon synapse in a single receptor cell, but also cover relevant research on ANFs of vertebrates from other classes. For spontaneous activity, we highlight several spike-history effects in interspike interval distributions, hazard-rate functions, serial interval correlations, and spike-count statistics. We also review models that have attempted to account for these properties. For phase locking, we focus on the responses to low-frequency tones, rather than to low frequency components of broadband signals such as noise or clicks. We critically review the measures commonly used to quantify phase locking and urge caution when interpreting such measures with respect to spike-timing precision. We also review the dependence of phase locking on stimulus amplitude and frequency. Finally, we identify some open questions. PMID- 27466787 TI - Gliomatosis cerebri: A consensus summary report from the First International Gliomatosis cerebri Group Meeting, March 26-27, 2015, Paris, France. AB - Gliomatosis cerebri (GC) is a universally fatal extensive and diffuse infiltration of brain parenchyma by a glial tumor. Many aspects of this phenomenon remain unknown. The First International Gliomatosis cerebri Group Meeting had the following goals: refine the clinical and radiologic diagnostic criteria for GC, suggest appropriate diagnostic procedures, standardize tissue manipulation for histologic and molecular characterization, and prioritize relevant preclinical projects. Also, general treatment recommendations were outlined for the pediatric population. Importantly, this meeting was the starting point for meaningful collaborative international research projects. This review is a consensus summary of discussions shared and conclusions derived from this meeting. PMID- 27466788 TI - A Mesoporous Superlattice Consisting of Alternately Stacking Interstitial Nanospace within Binary Silica Colloidal Crystals. AB - A novel class of nonclassical structures of mesoporous silica, namely a binary nanoparticle mesoporous superlattice (BNMS), is obtained by the assembly of silica nanospheres of different sizes into a binary colloidal crystal. The colloidal crystal has a CrB-type structure and consists of alternate stacks of unary fcc and binary AlB2 -type structures along the b axis and has four types of interstitial mesopores. The BNMS can be deposited on a substrate by dip coating to form an oriented thin film in which the direction of the superstructure (b axis) is perpendicular to the substrate. PMID- 27466790 TI - The Geoepidemiology and Clinical Aspects of IgG4-Related Disease. AB - Immunoglobulin G4-related disease (IgG4-RD) is a recently described systemic inflammatory disease characterized by increased serum IgG4 concentrations, lymphoplasmacytic infiltrations, storiform fibrosis, and obliterative phlebitis. However, although IgG4-RD has become increasingly recognized, the number of patients with IgG4-RD remains unclear. Data from several studies indicate that patients who have a T-helper type 2 (Th2-) dominant immune response, which leads to the hyperproduction of Th2 cytokines, then progress to IgG4-RD. Glucocorticoids are the most common treatment for IgG4-RD and generally, patients have a good response-a characteristic of IgG4-RD. However, relapses during the tapering of glucocorticoid therapy are common. Second-line therapy after glucocorticoids includes immunosuppressant agents. Although the long-term outcome still remains unclear, there is increased interest in the relationships between IgG-RD and malignancies. In this review, the authors provide a detailed overview of the geoepidemiology, pathogenesis, diagnostic features, treatment, and prognosis of IgG4-RD. PMID- 27466791 TI - The Immunobiology of Immunoglobulin G4. AB - Human immunoglobulin G4 (IgG4) antibodies are in many ways unusual. In this review, an overview is given of the structural and functional aspects of IgG4 antibodies, the consequences of IgG4 antibody formation in various disease settings, and the factors involved in the regulation of IgG4 responses. Unlike most IgG antibodies, IgG4 antibodies exist in a dynamic equilibrium with other IgG4 antibodies, continuously exchanging half-molecules resulting in effectively monovalent antibodies that cannot cross-link. Together with the low affinities to C1q and most Fc receptors, and a generally high affinity for antigen, IgG4 antibodies appear to be nature's way of producing "blocking antibodies." On the one hand, IgG4 may contribute to tolerance to allergens, presumably via competition with IgE. Also, IgG4 immune responses to filarial parasites might prevent excessive immune reactions during such infections. On the other hand, IgG4 autoantibodies may be pathogenic, simply because they inhibit the function of their target molecules. Furthermore, IgG4 antibodies to biologicals may result in secondary loss of response. In addition, IgG4 has been implicated to impair humoral immunity to tumors. The role of high IgG4 serum levels in IgG4-related disease has not yet been established. Regulation of IgG4 responses is most likely a multifactorial process, which in vivo requires prolonged or repeated challenge with antigen, and is associated with regulatory T cells, T helper 2 cells, interleukin- (IL-) 4, and IL-10. In vitro, cytokines like IL-4, IL-13, IL-10, and IL-21 have been shown to differentially influence IgG4 production. The properties of IgG4 B cells have now started to be elucidated, and may provide additional clues to explain the unusual dynamics of IgG4-antibody responses. PMID- 27466789 TI - Long-term outcomes after multidisciplinary management of T3 laryngeal squamous cell carcinomas: Improved functional outcomes and survival with modern therapeutic approaches. AB - BACKGROUND: The purpose of this study was to evaluate the long-term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers. METHODS: We reviewed 412 patients treated for T3 laryngeal squamous cell cancer from 1985 to 2011. RESULTS: The 10-year overall survival (OS) was 35%; disease specific-survival (DSS) was 61%; locoregional control was 76%; and freedom from distant metastasis was 83%. Chemotherapy, age, performance status <2, node negative status, and glottic subsite were associated with improved survival (all p < .03). Larynx preservation with induction and/or concurrent chemoradiotherapy (LP-CRT) had better laryngectomy-free survival than RT alone (LP-RT; hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.47-0.81; p = .0005); 10-year laryngectomy-free survival rates of the LP-CRT cohort (37%) were higher than those of the LP-RT cohort (18%). The 5-year DSS and OS rates of the LP-CRT cohort (79% and 67%) were better after total laryngectomy with postoperative RT (TL PORT; 61% and 50%) and LP-RT (64% and 46%; p < .006 for all). CONCLUSION: In patients with T3 laryngeal cancers, LP-CRT provides better functional, oncologic, and survival outcomes than historical TL-PORT or LP-RT does. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1739-1751, 2016. PMID- 27466792 TI - IgG4-Related Sclerosing Cholangitis. AB - More men than women develop immunoglobulin G4-related sclerosing cholangitis (IgG4-SC). Age at clinical onset is significantly older in patients with IgG4-SC. Patients with IgG4-SC appear similar to those with cholangiocarcinoma and primary sclerosing cholangitis (PSC). The association between IgG4-SC and autoimmune pancreatitis (AIP) is useful for the diagnosis of IgG4-SC. However, some IgG4-SC cases are isolated from AIP and are difficult to diagnose. The authors focus on three distinct features of IgG4-SC. First, diffuse inflammation induces a longer stenosis on cholangiography in contrast to the short stenosis of patients with PSC. Second, fibroinflammatory involvement is observed mainly in the stroma of the bile duct wall, whereas the bile duct epithelium is intact. Third, steroid therapy results in remarkable improvement. Although the prognosis of patients with IgG4-SC is good, some cases have developed portal hypertension and liver cirrhosis during their clinical course. Further study is needed to elucidate the long-term outcomes and mechanism of IgG4-SC. PMID- 27466793 TI - Histopathology of IgG4-Related Autoimmune Hepatitis and IgG4-Related Hepatopathy in IgG4-Related Disease. AB - Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease involving many organs; it includes IgG4-related sclerosing cholangitis and inflammatory pseudotumor in the hepatobiliary system. Two types of hepatic parenchymal involvement have been reported in IgG4-RD: IgG4-related autoimmune hepatitis (AIH) and IgG4-hepatopathy. Moreover, only three cases of IgG4-related AIH have been reported. Immunoglobulin G4-related AIH is clinicopathologically similar to AIH, except for an elevated serum IgG4 level and heavy infiltration of IgG4 positive plasma cells in the liver tissue. Interestingly, IgG4-related AIH can be complicated by well-known IgG4-RD(s). Immunoglobulin G4-hepatopathy, which includes various histopathological lesions encountered in the liver of patients with type I autoimmune pancreatitis, is classified into five histological categories: portal inflammation, large bile duct damage, portal sclerosis, lobular hepatitis, and cholestasis. Immunoglobulin G4-hepatopathy is currently a collective term covering hepatic lesions primarily or secondarily related to IgG4 related sclerosing cholangitis and type 1 autoimmune pancreatitis. In conclusion, the liver is not immune to IgG4-RD, and at least two types of hepatic involvement in IgG4-RD have been reported: IgG4-related AIH and IgG4-hepatopathy. Additional studies are required to clarify their precise clinical significance with respect to IgG4-RD and inherent liver diseases. PMID- 27466794 TI - The Pathology of IgG4-Related Disease in the Bile Duct and Pancreas. AB - Immunoglobulin G4-related disease (IgG4-RD) in the pancreatobiliary system manifests as sclerosing cholangitis (SC), hepatic inflammatory pseudotumors, and type 1 autoimmune pancreatitis (AIP). The pathology of IgG4-RD involves an inflammatory process and fibrogenic pathway, the combination of which damages the affected organs. Fibroinflammatory injury is characterized by three microscopic findings: a diffuse lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, obliterative phlebitis, and storiform fibrosis. Although the diagnosis of IgG4-related pancreatocholangitis is relatively straightforward in surgical specimens, the current clinical requirement is to diagnose patients using biopsy samples, which remains challenging. Histological differential diagnoses include primary SC, follicular cholangitis/pancreatitis, SC with granulocytic epithelial lesions, and type 2 AIP. Although the massive infiltration of IgG4-positive plasma cells is a histological hallmark of IgG4-RD, many other immune cells (e.g., Th2 lymphocytes, regulatory T cells, and M2 macrophages) appear to be strongly involved in orchestral immune reactions. PMID- 27466795 TI - Current Concepts and Diagnosis of IgG4-Related Pancreatitis (Type 1 AIP). AB - Although now considered to be a member of the systemic entity of immunoglobulin G4- (IgG4-) related disease, IgG4-related pancreatitis is generally referred to as type 1 autoimmune pancreatitis (AIP). Type 1 AIP was established based on a pathological background of lymphoplasmacytic sclerosing pancreatitis, high serum IgG4 concentration, and abundant IgG4-bearing plasma cell infiltration. The characteristic clinical features of type 1 AIP, such as elderly male preponderance, obstructive jaundice, and mass-forming lesions in the pancreas, often mimic those of pancreatic cancer. However, because AIP responds favorably to corticosteroid treatment, careful differentiation from pancreatic cancer is required. An AIP diagnosis is currently based on the 2011 International Consensus Diagnostic Criteria for AIP, which are based on high sensitivity, selectivity, and accuracy. Over the long term, AIP can progress to a chronic condition, with pancreatic stone formation and atrophy resembling that of chronic pancreatitis. Although AIP has been linked to the complication of malignancies, it remains controversial whether an association exists between the disease and tumor formation. PMID- 27466796 TI - IgG4-Related Disease in Organs Other than the Hepatobiliary-Pancreatic System. AB - Immunoglobulin G4-related disease (IgG4-RD) is a new disease entity that was established in this century. It is a systemic and chronic inflammatory disorder. Autoimmune pancreatitis is a representative condition, but there is clearly involvement from other organs, including the kidneys, the retroperitoneal cavity, the lungs, and the thyroid, lacrimal, salivary, pituitary, and prostate glands. To aid in the resolution of the numerous issues related to IgG4-RD, the authors established a registry system of patients in multicenter institutes with IgG4-RD the SMART registry. Using SMART registry data, they provide an overview of the involvement of organs other than the hepatobiliary-pancreatic system in IgG4-RD and emphasize the importance of consultation and cooperation with other specialists in the diagnosis, treatment, and management of patients with IgG4-RD. PMID- 27466797 TI - IgG4-Related Kidney Disease and IgG4-Related Retroperitoneal Fibrosis. AB - Immunoglobulin G4-related kidney disease (IgG4-RKD) is the collective name encompassing renal parenchymal and renal pelvic lesions. The hallmark of renal parenchymal lesions of IgG4-related disease is plasma cell-rich tubulointerstitial nephritis with numerous IgG4-positive plasma cells and characteristic fibrosis. In addition, glomerular lesions are sometimes present, with membranous glomerulonephritis being the most common. Although IgG4-RKD shows good responsiveness to corticosteroid therapy, follow-up imaging studies have revealed that partial cortical scars persist when the start of therapy is delayed. In this review, the authors provide an overview of the latest knowledge of IgG4-RKD, focusing in particular on its pathological and imaging characteristic features. PMID- 27466798 TI - The Treatment of IgG4-Related Diseases in the Hepatobiliary-Pancreatic System. AB - An accurate diagnosis should be made before treatment of autoimmune pancreatitis and immunoglobulin G4-related sclerosing cholangitis. Once a diagnosis has been established, steroids are the standard therapy and symptoms are the major indications. Before steroid therapy, obstructive jaundice and hyperglycemia should be controlled. An initial dose of 0.6 mg/kg/d of oral prednisolone is administered for 2 to 4 weeks, and is gradually tapered over 2 to 3 months. After steroid therapy has begun, blood and imaging tests are performed periodically. Patients with a poor response to steroids should be reevaluated on suspicion of malignancy. To prevent relapse, maintenance therapy using low-dose prednisolone (2.5-5 mg/d) for 1 to 3 years is recommended in Japan. Proximal biliary stricture is reported to be a predictor of relapse. Readministration and dose-up of steroids are effective for relapses. In Western countries, immunosuppressive drugs and rituximab have also been shown to be effective. The optimal treatment regimen should be addressed in future randomized, controlled clinical trials. PMID- 27466799 TI - Patterns of opioid use in sickle cell disease. AB - Pain, the hallmark complication of sickle cell disease (SCD), is largely managed with opioid analgesics in the United States, but comprehensive data regarding the long-term use of opioids in this patient population is lacking. The pain medication prescription records from a cohort of 203 SCD patients were analyzed. Twenty-five percent were not prescribed opioid medications while 47% took only short-acting opioids, 1% took only long-acting opioids, and 27% took a combination of short-acting and long-acting opioids. The median (interquartile range) daily opioid dose was 6.1 mg (1.7-26.3 mg) of oral morphine equivalents, which is lower than the published opioid use among patients with other pain syndromes. The dose of opioids correlated with the number of admissions due to vaso-occlusive crisis (VOC) (r = 0.53, P < 0.001). When the patients were grouped into quartiles based on daily dose opioid use, a logistic regression model showed that history of avascular necrosis (AVN) (OR: 2.87, 95% CI: 1.37-6.02, P = 0.005), 25-OHD levels (OR: 0.59, 95% CI: 0.38-0.93, P = 0.024) and total bilirubin concentration (OR: 0.64, 95% CI: 0.42-0.99, P = 0.043) were independently associated with opioid use quartiles. In conclusion, doses and types of opioid medications used by adult SCD patients vary widely. Our findings implicate AVN and lower vitamin D levels as factors associated with higher opioid use. They also suggest an association of higher bilirubin levels, possibly suggesting higher hemolytic rate, with lower opioid use. Am. J. Hematol. 91:1102 1106, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27466801 TI - A Gerontological Perspective on Visual Impairment and Mobility. PMID- 27466800 TI - Structural identification of the lipopolysaccharide-binding capability of a cupin family protein from Helicobacter pylori. AB - We solved the crystal structure of a functionally uncharacterized protein, HP0902, from Helicobacter pylori. Its structure demonstrated an all-beta cupin fold that cannot bind metal ions due to the absence of a metal-binding histidine that is conserved in many metallo-cupins. In contrast, isothermal titration calorimetry and NMR titration demonstrated that HP0902 is able to bind bacterial endotoxin lipopolysaccharides (LPS) through its surface-exposed loops, where metal-binding sites are usually found in other metallo-cupins. This report constitutes the first identification of an LPS-interacting protein, both in the cupin family and in H. pylori. Furthermore, identification of the ability of HP0902 to bind LPS uncovers a putative role for this protein in H. pylori pathogenicity. PMID- 27466802 TI - Muscle MRI of the Upper Extremity in the Myotonic Dystrophy Type 1. AB - BACKGROUND: The purpose of this study was to explore the relation between muscle MRI findings and weakness of the upper extremity muscles in patients with myotonic dystrophy type 1 (DM1). METHODS: Nineteen DM1 patients from 15 families were enrolled in this study. Muscle weakness was evaluated using the modified Medical Research Council scale. Subjects also underwent a genetic study and muscle MRI of the upper extremities. RESULTS: In patients with DM1, the flexor digitorum profundus (FDP), flexor pollicis longus, flexor digitorum superficialis (FDS), extensor pollicis, abductor pollicis longus (APL), lateral head of triceps brachii and infraspinatus (INF) muscles were frequently and severely affected. Muscle strength was significantly correlated with the severity of muscle MRI findings in the FDP, short head of biceps brachii (SBB), and medial head of triceps brachii muscles. Disease duration was correlated significantly with MRI findings in the FDP, FDS, long head of biceps brachii, INF, APL, and SBB muscles. Unexpectedly, the degree of trinucleotide expansion of myotonin protein kinase was not correlated with muscle MRI findings. CONCLUSION: Muscle MRI of the upper extremity is useful to detect affected muscles in DM1 patients. PMID- 27466803 TI - Correction: Time Trends in Ischemic Stroke among Type 2 Diabetic and Non-Diabetic Patients: Analysis of the Spanish National Hospital Discharge Data (2003-2012). AB - [This corrects the article DOI: 10.1371/journal.pone.0145535.]. PMID- 27466804 TI - Phylogenomics and Divergence Dating of Fungus-Farming Ants (Hymenoptera: Formicidae) of the Genera Sericomyrmex and Apterostigma. AB - Fungus-farming ("attine") ants are model systems for studies of symbiosis, coevolution, and advanced eusociality. A New World clade of nearly 300 species in 15 genera, all attine ants cultivate fungal symbionts for food. In order to better understand the evolution of ant agriculture, we sequenced, assembled, and analyzed transcriptomes of four different attine ant species in two genera: three species in the higher-attine genus Sericomyrmex and a single lower-attine ant species, Apterostigma megacephala, representing the first genomic data for either genus. These data were combined with published genomes of nine other ant species and the honey bee Apis mellifera for phylogenomic and divergence-dating analyses. The resulting phylogeny confirms relationships inferred in previous studies of fungus-farming ants. Divergence-dating analyses recovered slightly older dates than most prior analyses, estimating that attine ants originated 53.6-66.7 million of years ago, and recovered a very long branch subtending a very recent, rapid radiation of the genus Sericomyrmex. This result is further confirmed by a separate analysis of the three Sericomyrmex species, which reveals that 92.71% of orthologs have 99% - 100% pairwise-identical nucleotide sequences. We searched the transcriptomes for genes of interest, most importantly argininosuccinate synthase and argininosuccinate lyase, which are functional in other ants but which are known to have been lost in seven previously studied attine ant species. Loss of the ability to produce the amino acid arginine has been hypothesized to contribute to the obligate dependence of attine ants upon their cultivated fungi, but the point in fungus-farming ant evolution at which these losses occurred has remained unknown. We did not find these genes in any of the sequenced transcriptomes. Although expected for Sericomyrmex species, the absence of arginine anabolic genes in the lower-attine ant Apterostigma megacephala strongly suggests that the loss coincided with the origin of attine ants. PMID- 27466805 TI - Identification of Known and Novel microRNAs and Their Targets in Peach (Prunus persica) Fruit by High-Throughput Sequencing. AB - MicroRNAs (miRNAs) are a group of non-coding RNAs that have functions in post transcriptional gene regulation in plants. Although the most important economic component of peach trees (Prunus persica) is the fruit, not much is known about miRNAs in this organ. In this study, miRNAs and their targets were identified and characterized from libraries of small RNAs of peach fruit through Solexa based sequencing and bioinformatics approaches. A total of 557 known peach miRNAs belonging to 34 miRNA families were identified, and some of these miRNAs were found to be highly conserved in at least four other plant species. Using the most current criteria for miRNA annotation, 275 putative novel miRNAs were predicted, and the sequencing frequencies of these novel miRNAs were less than those of the conserved miRNAs. In total, 3959 and 1614 target genes for 349 known and 193 novel miRNAs, respectively, were predicted with the criteria that a single target gene can be targeted by different miRNAs and that a single miRNA can also have a large number of target genes. Three targets were even found to be targeted by 13 novel miRNAs that contained the same complete miRNA sequence at different locations and had different scaffolds. The proteins predicted to be targeted by the miRNAs identified in this study encompass a wide range of transcription factors and are involved in many biological processes and pathways, including development, metabolism, stress responses and signal transduction. A total of 115 and 101 target genes were identified to be cleaved by 60 known miRNAs and 27 novel miRNAs through degradome sequencing, respectively. These miRNAs induce cleavage of their targets precisely at the position between nucleotides 10 and 11 of the miRNA sequences from the 5' to the 3' end. Thirty conserved miRNAs and 19 novel miRNAs exhibited differential expression profiles in the peach, and the expression patterns of some miRNAs appeared to be tissue- or developmental stage specific. The findings of this study provide an important basis for the analysis of miRNAs, their targets and the functions of these targets in peach fruit. PMID- 27466806 TI - Social Learning in the Real-World: 'Over-Imitation' Occurs in Both Children and Adults Unaware of Participation in an Experiment and Independently of Social Interaction. AB - The current study avoided the typical laboratory context to determine instead whether over-imitation-the disposition to copy even visibly, causally unnecessary actions-occurs in a real-world context in which participants are unaware of being in an experiment. We disguised a puzzle-box task as an interactive item available to the public within a science engagement zone of Edinburgh Zoo. As a member of the public approached, a confederate acting as a zoo visitor retrieved a reward from the box using a sequence of actions containing both causally relevant and irrelevant elements. Despite the absence of intentional demonstration, or social pressure to copy, a majority of both child and even adult observers included all causally irrelevant actions in their reproduction. This occurred even though causal irrelevance appeared manifest because of the transparency of the puzzle box. That over-imitation occurred so readily in a naturalistic context, devoid of social interaction and pressure, suggests that humans are opportunistic social learners throughout the lifespan, copying the actions of other individuals even when these actions are not intentionally demonstrated, and their causal significance is not readily apparent. The disposition to copy comprehensively, even when a mere onlooker, likely provides humans, irrespective of their age, with a powerful mechanism to extract maximal information from the social environment. PMID- 27466807 TI - Formation of a Polycomb-Domain in the Absence of Strong Polycomb Response Elements. AB - Polycomb group response elements (PREs) in Drosophila are DNA-elements that recruit Polycomb proteins (PcG) to chromatin and regulate gene expression. PREs are easily recognizable in the Drosophila genome as strong peaks of PcG-protein binding over discrete DNA fragments; many small but statistically significant PcG peaks are also observed in PcG domains. Surprisingly, in vivo deletion of the four characterized strong PREs from the PcG regulated invected-engrailed (inv-en) gene complex did not disrupt the formation of the H3K27me3 domain and did not affect inv-en expression in embryos or larvae suggesting the presence of redundant PcG recruitment mechanism. Further, the 3D-structure of the inv-en domain was only minimally altered by the deletion of the strong PREs. A reporter construct containing a 7.5kb en fragment that contains three weak peaks but no large PcG peaks forms an H3K27me3 domain and is PcG-regulated. Our data suggests a model for the recruitment of PcG-complexes to Drosophila genes via interactions with multiple, weak PREs spread throughout an H3K27me3 domain. PMID- 27466808 TI - High Throughput Method for Analysis of Repeat Number for 28 Phase Variable Loci of Campylobacter jejuni Strain NCTC11168. AB - Mutations in simple sequence repeat tracts are a major mechanism of phase variation in several bacterial species including Campylobacter jejuni. Changes in repeat number of tracts located within the reading frame can produce a high frequency of reversible switches in gene expression between ON and OFF states. The genome of C. jejuni strain NCTC11168 contains 29 loci with polyG/polyC tracts of seven or more repeats. This protocol outlines a method-the 28-locus-CJ11168 PV analysis assay-for rapidly determining ON/OFF states of 28 of these phase variable loci in a large number of individual colonies from C. jejuni strain NCTC11168. The method combines a series of multiplex PCR assays with a fragment analysis assay and automated extraction of fragment length, repeat number and expression state. This high throughput, multiplex assay has utility for detecting shifts in phase variation states within and between populations over time and for exploring the effects of phase variation on adaptation to differing selective pressures. Application of this method to analysis of the 28 polyG/polyC tracts in 90 C. jejuni colonies detected a 2.5-fold increase in slippage products as tracts lengthened from G8 to G11 but no difference between tracts of similar length indicating that flanking sequence does not influence slippage rates. Comparison of this observed slippage to previously measured mutation rates for G8 and G11 tracts in C. jejuni indicates that PCR amplification of a DNA sample will over estimate phase variation frequencies by 20-35-fold. An important output of the 28 locus-CJ11168 PV-analysis assay is combinatorial expression states that cannot be determined by other methods. This method can be adapted to analysis of phase variation in other C. jejuni strains and in a diverse range of bacterial species. PMID- 27466809 TI - Prevalence and Genetic Diversity of Giardia duodenalis and Cryptosporidium spp. among School Children in a Rural Area of the Amhara Region, North-West Ethiopia. AB - BACKGROUD: Giardia duodenalis and Cryptosporidium spp. are enteric protozoan causing gastrointestinal illness in humans and animals. Giardiasis and cryptosporidiosis are not formally considered as neglected tropical diseases, but belong to the group of poverty-related infectious diseases that impair the development and socio-economic potential of infected individuals in developing countries. METHODS: We report here the prevalence and genetic diversity of G. duodenalis and Cryptosporidium spp. in children attending rural primary schools in the Bahir Dar district of the Amhara Region, Ethiopia. Stool samples were collected from 393 children and analysed by molecular methods. G. duodenalis was detected by real-time PCR, and the assemblages and sub-assemblages were determined by multilocus sequence-based genotyping of the glutamate dehydrogenase and beta-giardin genes of the parasite. Detection and identification of Cryptosporidium species was carried out by sequencing of a partial fragment of the small-subunit ribosomal RNA gene. PRINCIPAL FINDINGS: The PCR-based prevalences of G. duodenalis and Cryptosporidium spp. were 55.0% (216/393) and 4.6% (18/393), respectively. A total of 78 G. duodenalis isolates were successfully characterized, revealing the presence of sub-assemblages AII (10.3%), BIII (28.2%), and BIV (32.0%). Discordant typing results AII/AIII and BIII/BIV were identified in 7.7% and 15.4% of the isolates, respectively. An additional five (6.4%) isolates were assigned to assemblage B. No mixed infections of assemblages A+B were found. Extensive genetic variation at the nucleotide level was observed within assemblage B (but no within assemblage A), resulting in the identification of a large number of sub-types. Cryptosporidium diversity was demonstrated by the occurrence of C. hominis, C. parvum, and C. viatorum in the population under study. CONCLUSIONS: Our data suggest an epidemiological scenario with an elevated transmission intensity of a wide range of G. duodenalis genetic variants. Importantly, the elevated degree of genetic diversity observed within assemblage B is consistent with the occurrence of intra assemblage recombination in G. duodenalis. PMID- 27466810 TI - Comparative Methods to Improve the Detection of BRAF V600 Mutations in Highly Pigmented Melanoma Specimens. AB - Genotyping BRAF in melanoma samples is often challenging. The presence of melanin greatly interferes with thermostable DNA polymerases and/or nucleic acids in traditional polymerase chain reaction (PCR)-based methods. In the present work, we evaluated three easy-to-use strategies to improve the detection of pigmented DNA refractory to PCR amplification. These pre-PCR processing methods include the addition of bovine serum albumin (BSA), the dilution of DNA, and the purification of DNA using the NucleoSpin(r) gDNA Clean-up XS Kit. We found that BRAF genotyping in weakly and moderately pigmented samples was more efficient when the sample was processed with BSA or purified with a NucleoSpin(r) gDNA Clean-up XS Kit prior to PCR amplification. In addition, the combination of both methods resulted in successful detection of BRAF mutation in pigmented specimens, including highly pigmented samples, thereby increasing the chance of patients being elicited for anti-BRAF treatment. These solutions to overcome melanin induced PCR inhibition are of tremendous value and provide a simple solution for clinical chemistry and routine laboratory medicine. PMID- 27466811 TI - Reporting Crime Victimizations to the Police and the Incidence of Future Victimizations: A Longitudinal Study. AB - BACKGROUND: Law enforcement depends on cooperation from the public and crime victims to protect citizens and maintain public safety; however, many crimes are not reported to police because of fear of repercussions or because the crime is considered trivial. It is unclear how police reporting affects the incidence of future victimization. OBJECTIVE: To evaluate the association between reporting victimization to police and incident future victimization. METHODS: We conducted a retrospective cohort study using National Crime Victimization Survey 2008-2012 data. Participants were 12+ years old household members who may or may not be victimized, were followed biannually for 3 years, and who completed at least one follow-up survey after their first reported victimization between 2008 and 2012. Crude and adjusted generalized linear mixed regression for survey data with Poisson link were used to compare rates of future victimization. RESULTS: Out of 18,657 eligible participants, 41% participants reported to their initial victimization to police and had a future victimization rate of 42.8/100 person years (PY) (95% CI: 40.7, 44.8). The future victimization rate of those who did not report to the police (59%) was 55.0/100 PY (95% CI: 53.0, 57.0). The adjusted rate ratio comparing police reporting to not reporting was 0.78 (95%CI: 0.72, 0.84) for all future victimizations, 0.80 (95% CI: 0.72, 0.90) for interpersonal violence, 0.73 (95% CI: 0.68, 0.78) for thefts, and 0.95 (95% CI: 0.84, 1.07) for burglaries. CONCLUSIONS: Reporting victimization to police is associated with fewer future victimization, underscoring the importance of police reporting in crime prevention. This association may be attributed to police action and victim services provisions resulting from reporting. PMID- 27466812 TI - Changes in the Lodging-Related Traits along with Rice Genetic Improvement in China. AB - Rice yield potential was greatly improved since the green revolution, but the occurrence of lodging often restricts the achievement of potential yield. Currently, it is still obscure about how the lodging-related traits change along with the genetic improvement in yield potential of rice, although much efforts have been devoted to study the trend of and physiological mechanisms underlying changes in grain yield. Therefore, fourteen rice mega-varieties that were released and disseminated from 1930s to 2005 in China were investigated through a two-year experiment in the field condition. The results showed that large genotypic differences in lodging-related morphological traits were observed among these varieties. Lodging index (LI) of semi-dwarf varieties was significantly lower compared with that of SLX(Shenglixian). There were significant differences in LI among the semi-dwarf varieties, but no relationship between LI and the release year was found. Bending moment (BM) of semi-dwarf varieties released in 1940s-1980s was significantly lower than that of SLX. However, varieties released after 1980s had similar bending moment with SLX, but significantly higher breaking resistance (BR). The increase in both BM and BR after 1980s was related with the increase in internode diameter (ND) and stem fresh weight. Overall, this study disclosed the changing pattern of lodging-related traits in the genetic improvement of rice, and suggested that further increase in ND, internode dry weight (NDW) and dry weight per unit length (DWUL) of lower internode in modern super rice variety could effectively enhance lodging resistance and bring down LI. PMID- 27466813 TI - Competitive Fitness of Influenza B Viruses Possessing E119A and H274Y Neuraminidase Inhibitor Resistance-Associated Substitutions in Ferrets. AB - Neuraminidase (NA) inhibitors (NAIs) are the only antiviral drugs recommended for influenza treatment and prophylaxis. Although NAI-resistant influenza B viruses that could pose a threat to public health have been reported in the field, their fitness is poorly understood. We evaluated in ferrets the pathogenicity and relative fitness of reverse genetics (rg)-generated influenza B/Yamanashi/166/1998-like viruses containing E119A or H274Y NA substitutions (N2 numbering). Ferrets inoculated with NAI-susceptible rg-wild-type (rg-WT) or NAI resistant (rg-E119A or rg-H274Y) viruses developed mild infections. Growth of rg E119A virus in the nasal cavities was delayed, but the high titers at 3 days post inoculation (dpi) were comparable to those of the rg-WT and rg-H274Y viruses (3.6 4.1 log10TCID50/mL). No virus persisted beyond 5 dpi and replication did not extend to the trachea or lungs. Positive virus antigen-staining of the nasal turbinate epithelium was intermittent with the rg-WT and rg-H274Y viruses; whereas antigen-staining for the rg-E119A virus was more diffuse. Virus populations in ferrets coinoculated with NAI-susceptible and -resistant viruses (1:1 mixture) remained heterogeneous at 5 dpi but were predominantly rg-WT (>70%). Although the E119A substitution was associated with delayed replication in ferrets, the H274Y substitution did not measurably affect viral growth properties. These data suggest that rg-H274Y has undiminished fitness in single virus inoculations, but neither rg-E119A nor rg-H274Y gained a fitness advantage over rg-WT in direct competition experiments without antiviral drug pressure. Taken together, our data suggest the following order of relative fitness in a ferret animal model: rg-WT > rg-H274Y > rg-E119A. PMID- 27466814 TI - 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice. AB - 3D volume imaging using iDISCO+ was applied to observe the spatial and temporal progression of tau pathology in deep structures of the brain of a mouse model that recapitulates the earliest stages of Alzheimer's disease (AD). Tau pathology was compared at four timepoints, up to 34 months as it spread through the hippocampal formation and out into the neocortex along an anatomically connected route. Tau pathology was associated with significant gliosis. No evidence for uptake and accumulation of tau by glia was observed. Neuronal cells did appear to have internalized tau, including in extrahippocampal areas as a small proportion of cells that had accumulated human tau protein did not express detectible levels of human tau mRNA. At the oldest timepoint, mature tau pathology in the entorhinal cortex (EC) was associated with significant cell loss. As in human AD, mature tau pathology in the EC and the presence of tau pathology in the neocortex correlated with cognitive impairment. 3D volume imaging is an ideal technique to easily monitor the spread of pathology over time in models of disease progression. PMID- 27466815 TI - Multiscale Mechano-Biological Finite Element Modelling of Oncoplastic Breast Surgery-Numerical Study towards Surgical Planning and Cosmetic Outcome Prediction. AB - Surgical treatment for early-stage breast carcinoma primarily necessitates breast conserving therapy (BCT), where the tumour is removed while preserving the breast shape. To date, there have been very few attempts to develop accurate and efficient computational tools that could be used in the clinical environment for pre-operative planning and oncoplastic breast surgery assessment. Moreover, from the breast cancer research perspective, there has been very little effort to model complex mechano-biological processes involved in wound healing. We address this by providing an integrated numerical framework that can simulate the therapeutic effects of BCT over the extended period of treatment and recovery. A validated, three-dimensional, multiscale finite element procedure that simulates breast tissue deformations and physiological wound healing is presented. In the proposed methodology, a partitioned, continuum-based mathematical model for tissue recovery and angiogenesis, and breast tissue deformation is considered. The effectiveness and accuracy of the proposed numerical scheme is illustrated through patient-specific representative examples. Wound repair and contraction numerical analyses of real MRI-derived breast geometries are investigated, and the final predictions of the breast shape are validated against post-operative follow-up optical surface scans from four patients. Mean (standard deviation) breast surface distance errors in millimetres of 3.1 (+/-3.1), 3.2 (+/-2.4), 2.8 (+/-2.7) and 4.1 (+/-3.3) were obtained, demonstrating the ability of the surgical simulation tool to predict, pre-operatively, the outcome of BCT to clinically useful accuracy. PMID- 27466817 TI - Engineered Production of Short Chain Fatty Acid in Escherichia coli Using Fatty Acid Synthesis Pathway. AB - Short-chain fatty acids (SCFAs), such as butyric acid, have a broad range of applications in chemical and fuel industries. Worldwide demand of sustainable fuels and chemicals has encouraged researchers for microbial synthesis of SCFAs. In this study we compared three thioesterases, i.e., TesAT from Anaerococcus tetradius, TesBF from Bryantella formatexigens and TesBT from Bacteroides thetaiotaomicron, for production of SCFAs in Escherichia coli utilizing native fatty acid synthesis (FASII) pathway and modulated the genetic and bioprocess parameters to improve its yield and productivity. E. coli strain expressing tesBT gene yielded maximum butyric acid titer at 1.46 g L-1, followed by tesBF at 0.85 g L-1 and tesAT at 0.12 g L-1. The titer of butyric acid varied significantly depending upon the plasmid copy number and strain genotype. The modulation of genetic factors that are known to influence long chain fatty acid production, such as deletion of the fadD and fadE that initiates the fatty acid degradation cycle and overexpression of fadR that is a global transcriptional activator of fatty acid biosynthesis and repressor of degradation cycle, did not improve the butyric acid titer significantly. Use of chemical inhibitor cerulenin, which restricts the fatty acid elongation cycle, increased the butyric acid titer by 1.7-fold in case of TesBF, while it had adverse impact in case of TesBT. In vitro enzyme assay indicated that cerulenin also inhibited short chain specific thioesterase, though inhibitory concentration varied according to the type of thioesterase used. Further process optimization followed by fed-batch cultivation under phosphorous limited condition led to production of 14.3 g L-1 butyric acid and 17.5 g L-1 total free fatty acid at 28% of theoretical yield. This study expands our understanding of SCFAs production in E. coli through FASII pathway and highlights role of genetic and process optimization to enhance the desired product. PMID- 27466816 TI - Immune Recognition of Citrullinated Proteoglycan Aggrecan Epitopes in Mice with Proteoglycan-Induced Arthritis and in Patients with Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. METHODS: We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)-containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. RESULTS: Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. CONCLUSIONS: We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitope-induced T-cell activation or antibody deposition may occur in the joints of RA patients. PMID- 27466818 TI - Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach. AB - SESN3 has been implicated in multiple biological processes including protection against oxidative stress, regulation of glucose and lipid metabolism. However, little is known about the factors and mechanisms controlling its gene expression at the transcriptional level. We performed in silico phylogenetic footprinting analysis of 5 kb upstream regions of a diverse set of human SESN3 orthologs for the identification of high confidence conserved binding motifs (BMo). We further analyzed the predicted BMo by a motif comparison tool to identify the TFs likely to bind these discovered motifs. Predicted TFs were then integrated with experimentally known protein-protein interactions and experimentally validated to delineate the important transcriptional regulators of SESN3. Our study revealed high confidence set of BMos (integrated with DNase I hypersensitivity sites) in the upstream regulatory regions of SESN3 that could be bound by transcription factors from multiple families including FOXOs, SMADs, SOXs, TCFs and HNF4A. TF TF network analysis established hubs of interaction that include SMAD3, TCF3, SMAD2, HDAC2, SOX2, TAL1 and TCF12 as well as the likely protein complexes formed between them. We show using ChIP-PCR as well as over-expression and knock out studies that FOXO3 and SOX2 transcriptionally regulate the expression of SESN3 gene. Our findings provide an important roadmap to further our understanding on the regulation of SESN3. PMID- 27466820 TI - The 3Ts of the new millennium neurorehabilitation gym: therapy, technology, translationality. PMID- 27466819 TI - Inhibition of Vascular Endothelial Growth Factor Receptor 2 Exacerbates Loss of Lower Motor Neurons and Axons during Experimental Autoimmune Encephalomyelitis. AB - Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are inflammatory demyelinating and neurodegenerative diseases in the central nervous system (CNS). It is believed that MS and EAE are initiated by autoreactive T lymphocytes that recognize myelin antigens; however, the mechanisms responsible for neurodegeneration in these diseases remain elusive. Data indicate that vascular endothelial growth factor A (VEGF-A) plays a role in the development of MS and EAE. Interestingly, VEGF-A is regarded as a neurotrophic factor in the CNS that promotes neuron survival and neurogenesis in various neurodegenerative diseases by activating VEGF receptor 2 (VEGFR2). In this study, we sought to explore the role of the VEGF-A/VEGFR2 signaling in neurodegeneration in MS and EAE. We showed that the expression of VEGF-A was decreased in the spinal cord during EAE and that VEGFR2 was activated in lower motor neurons in the spinal cord of EAE mice. Interestingly, we found that treatment with SU5416, a selective VEGFR2 inhibitor, starting after the onset of EAE clinical symptoms exacerbated lower motor neuron loss and axon loss in the lumbar spinal cord of mice undergoing EAE, but did not alter Purkinje neuron loss in the cerebellum or upper motor neuron loss in the cerebral cortex. Moreover, SU5416 treatment had a minimal effect on EAE clinical symptoms as well as inflammation, demyelination, and oligodendrocyte loss in the lumbar spinal cord. These results imply the protective effects of the VEGF-A/VEGFR2 signaling on lower motor neurons and axons in the spinal cord in MS and EAE. PMID- 27466822 TI - Notes from the Field: Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers - United States, 2010-2015. AB - Kratom (Mitragyna speciosa) is a plant consumed throughout the world for its stimulant effects and as an opioid substitute (1). It is typically brewed into a tea, chewed, smoked, or ingested in capsules (2). It is also known as Thang, Kakuam, Thom, Ketum, and Biak (3). The Drug Enforcement Administration includes kratom on its Drugs of Concern list (substances that are not currently regulated by the Controlled Substances Act, but that pose risks to persons who abuse them), and the National Institute of Drug Abuse has identified kratom as an emerging drug of abuse (3,4). Published case reports have associated kratom exposure with psychosis, seizures, and deaths (5,6). Because deaths have been attributed to kratom in the United States (7), some jurisdictions have passed or are considering legislation to make kratom use a felony (8). CDC characterized kratom exposures that were reported to poison centers and uploaded to the National Poison Data System (NPDS) during January 2010-December 2015. The NPDS is a national database of information logged by the country's regional poison centers serving all 50 United States, the District of Columbia, and Puerto Rico and is maintained by the American Association of Poison Control Centers. NPDS case records are the result of call reports made by the public and health care providers. PMID- 27466823 TI - Intrinsic Charge Trapping Observed as Surface Potential Variations in diF-TES-ADT Films. AB - Spatial variations in surface potential are measured with Kelvin probe force microscopy for thin films of 2,8-difluoro-5,11 bis(triethylsilylethynyl)anthradithiophenes (diF-TES-ADT) grown on SiO2 and silane-treated SiO2 substrates by organic molecular beam deposition. The variations are observed both between and within grains of the polycrystalline organic film and are quantitatively different than electrostatic variations on the substrate surfaces. The skewness of surface potential distributions is larger on SiO2 than on HMDS-treated substrates. This observation is attributed to the impact of substrate functionalization on minimizing intrinsic crystallographic defects in the organic film that can trap charge. PMID- 27466824 TI - T7 Peptide-Functionalized PEG-PLGA Micelles Loaded with Carmustine for Targeting Therapy of Glioma. AB - Glioma is regarded as the deadliest and most common brain tumor because of the extremely difficult surgical excision ascribed from its invasive nature. In addition, the natural blood-brain barrier (BBB) greatly restricts the therapeutics' penetration into the central nervous system. Carmustine (BCNU) is a widely used antiglioma drug in clinical applications. However, its serious complications prevent it from being applied in a clinical setting to some extent. Thus, it is urgent to explore novel BCNU delivery systems specially designed for glioma. Development of polymeric nanoparticles offers a favorable alternative to serve this purpose. Particularly, use of poly(lactic-co-glycolic acid) (PLGA) has been shown to be advantageous for its favorable biodegradability and biocompatibility, which ensure safe therapies. In this study, T7 peptide conjugated, BCNU-loaded micelles were constructed successfully via the emulsion solvent evaporation method. The micelles were characterized by transmission electron microscopy and dynamic light scattering in detail, and the capacity of BBB crossing was studied. The in vivo detecting results of the targeting effect using the BODIPY probe evidenced that T7-modified micelles showed a more pronounced accumulation and accumulated in the tumor more efficiently than in the unconjugated probe. Meanwhile, the targeting group exhibited the best curative effect accompanied with the lowest loss in body weight, the smallest tumor size, and an obviously prolonged survival time among the groups. In the near future, we believe the targeted delivery system specially designed for BCNU is expected to provide sufficient evidence to proceed to clinical trials. PMID- 27466825 TI - A Stannyl-Decorated Zintl Ion [Ge18Pd3(Sn(i)Pr3)6](2-): Twinned Icosahedron with a Common Pd3-Face or 18-Vertex Hypho-Deltahedron with a Pd3-Triangle Inside. AB - We report the synthesis and characterization of the title anion which has a germanium/palladium cluster core of [Ge18Pd3] and six tri-isopropyl tin substituents. Its two Ge9-halves are the first examples of germanium deltahedra with three nonsilyl substituents, tri-isopropyl tin in this case. The new cluster is made by a reaction of an acetonitrile suspension of K4Ge9 with (i)Pr3SnCl that generates primarily tristannylated 9-atom clusters [Ge9{Sn(i)Pr3}3](-), followed by addition of Pd(PPh3)4 to the reaction mixture. It was structurally characterized by single-crystal X-ray diffraction in [K(222crypt)]2[Ge18Pd3{Sn(i)Pr3}6].(i)Pr2O and was also confirmed in solution by ESI-MS and NMR. The new anion can be viewed both as a dimer of face-fused icosahedra (twinned icosahedron) with a common Pd3-face, i.e., [((i)Pr3Sn)3Ge9Pd3Ge9(Sn(i)Pr3)3](2-) that resembles but is not isoelectronic with the known borane version B21H18(-) or as a large hypho-deltahedron of 18 Ge atoms with a triangle of Pd3 inside, i.e., [Pd3@Ge18(Sn(i)Pr3)6](2-). DFT calculations show a very large HOMO-LUMO gap of 2.42 eV. PMID- 27466826 TI - Autologous Minced Muscle Grafts Improve Muscle Strength in a Porcine Model of Volumetric Muscle Loss Injury. AB - OBJECTIVES: The traumatic loss of muscle tissue, defined as volumetric muscle loss (VML) injury, has no definitive therapy. The purposes of this study were: (1) to develop a porcine model of VML and (2) to investigate autologous minced muscle grafts (1-mm pieces of muscle) as a potential therapeutic. Minced grafts were evaluated because they have promoted fiber regeneration and functional recovery in rat VML models and do not require US Food and Drug Administration approval for clinical use. METHODS: In 5 female Yorkshire-cross pigs, ~5 g (~20%) of tissue was excised from the peroneous tertius muscle (~3 * 3 * 1.5-cm defect) of each leg. The defect in one leg was treated with autologous minced grafts derived from the contralateral leg. Maximal isometric tetanic strength assessments of the dorsiflexor muscles (ie, the peroneous tertius muscle) were performed before and biweekly up to 12 weeks postinjury. RESULTS: VML injury resulted in a -43.5% +/- 7.2% strength deficit 12 weeks postinjury in nonrepaired legs. Autologous minced muscle graft repair significantly improved strength over 12 weeks (32% strength increase 12 weeks postinjury vs. nonrepaired muscles with a remaining -27.8% +/- 7.0% strength deficit; P < 0.001). Nonrepaired muscles developed extensive fibrosis and presented no evidence of muscle fiber regeneration within the defect area. Minced graft-treated muscles presented areas of putative de novo muscle fiber regeneration within the defect area, although extensive fibrotic tissue deposition was also present. CONCLUSION: Autologous minced muscle grafts partially restored neuromuscular strength in a novel porcine model of VML. PMID- 27466827 TI - Scombroid syndrome: it seems to be fish allergy but... it isn't. AB - PURPOSE OF REVIEW: Scombroid poisoning is a frequent cause of admission in emergency department. In everyday clinical practice, it can be difficult to discriminate between scombroid syndrome and fish allergy. The aim of this review is to provide the clinician some instruments to make a correct differential diagnosis. RECENT FINDINGS: In the last few years, a better characterization of scombroid syndrome occurred, in particular regarding its possible severe presentations. Two cases of Kounis syndrome secondary to scombroid syndrome have been described and in these cases a differential diagnosis in patients with this clinical presentation can be even more difficult. Finally, in term of diagnosis, the useful role of serum tryptase was recently consolidated. SUMMARY: Scombroid syndrome is a histamine-induced reaction because of the ingestion of histamine contaminated fish, whereas fish allergy is an IgE-mediated reaction. Clinical presentation can be similar and for this reason scombroid syndrome is often misdiagnosed. The differences lie in pathogenic mechanisms, possible outcome, therapy, and prevention measures. Moreover, some laboratory tests are helpful to discriminate between the two diseases. PMID- 27466829 TI - Conversational topics discussed by individuals with severe traumatic brain injury and their communication partners during sub-acute recovery. AB - PRIMARY OBJECTIVE: To investigate the nature and patterns of conversational topics discussed by individuals with severe TBI and familiar communication partners at 3 and 6 months post-injury, and to examine changes occurring in conversational topics during sub-acute recovery. RESEARCH DESIGN: Qualitative content analysis was used to explore the nature of topics and generate conversational themes. Topic analysis provided an understanding of conversational topic management by identifying patterns of topic initiation and maintenance. METHODS: Twenty-two people with severe TBI and a familiar communication partner engaged in a 10-minute casual conversation on self-selected topics at 3 and 6 months post-injury. MAIN OUTCOMES AND RESULTS: Three main conversational themes were identified: connecting; re-engaging; and impacts of injury. The nature of topics related to these themes changed over time to reflect participants' sub acute rehabilitation experiences. Most conversational dyads maintained similar conversational and topic patterns during sub-acute recovery. CONCLUSIONS: Qualitative analysis provides a new insight into the conversational topics of individuals with severe TBI. Many participants engaged in appropriate conversations and discussed mutually important topics with familiar communication partners. Findings may inform speech-language pathology intervention in sub-acute recovery to improve conversational discourse abilities of individuals with severe TBI and support their communication partners. PMID- 27466840 TI - CORT, Cort, B, Corticosterone, and now Cortistatin: Enough Already! PMID- 27466828 TI - Cancer Information Seeking and Cancer-Related Health Outcomes: A Scoping Review of the Health Information National Trends Survey Literature. AB - Cancer is a leading cause of death among adults in the United States. Only 54% of U.S. adults reported seeking cancer information in 2014. Cancer information seeking has been positively associated with cancer-related health outcomes such as screening adherence. We conducted a scoping review of studies that used data from the Health Information National Trends Survey (HINTS) in order to examine cancer information seeking in depth and the relationship between cancer information seeking and cancer-related health outcomes. We searched five databases and the HINTS website. The search yielded a total of 274 article titles. After review of 114 de-duplicated titles, 66 abstracts, and 50 articles, 22 studies met inclusion criteria. Cancer information seeking was the outcome in only four studies. The other 18 studies focused on a cancer-related health outcome. Cancer beliefs, health knowledge, and information seeking experience were positive predictors of cancer information seeking. Cancer-related awareness, knowledge, beliefs, preventive behaviors, and screening adherence were higher among cancer information seekers. Results from this review can inform other research study designs and primary data collection focused on specific cancer sites or aimed at populations not represented or underrepresented in the HINTS data (e.g., minority populations, those with lower socioeconomic status). PMID- 27466841 TI - Differential Diagnosis of Chronic Rhinosinusitis with Nasal Polyps. AB - Nasal polyps are semi-translucent mucosal outgrowths of the paranasal sinuses which typically arise in the setting of chronic rhinosinusitis (CRS). Nasal polyps are also associated with asthma, aspirin sensitivity, cystic fibrosis and allergic fungal rhinosinusitis (AFS). The majority of nasal polyps are bilateral and characterized by tissue edema and eosinophil infiltration. Patients with nasal polyps often present with complaints including nasal obstruction, congestion, rhinorrhea or altered sense of smell. The differential diagnosis ranges from benign masses such as schneiderian papilloma, antrochoanal polyp, angiofibroma and encephalocele to malignant neoplasms such as squamous cell carcinoma (SCC), esthesioneuroblastoma, nasal lymphoma and rhabdomyosarcoma. These lesions may have a similar appearance as nasal polyps and particular attention to an alternative diagnosis for nasal polyps should be entertained if the mass is unilateral or congenital in nature. Workup for patients with a unilateral mass should include radiographic imaging, possible biopsy and careful follow-up when appropriate. Here, we review the disease etiology of nasal polyps and describe the approach to the patient with nasal polyps with emphasis on differential diagnosis and workup. PMID- 27466842 TI - Allergic Fungal Rhinosinusitis: The Latest in Diagnosis and Management. AB - Allergic fungal rhinosinusitis (AFRS) is the most common form of fungal sinusitis in the United States. Its pathophysiological basis is associated with a predisposed person's type I IgE-mediated allergic response to inhaled mold spores that are ubiquitous in the environment. AFRS is a well-recognized type of chronic, recurrent, and non-invasive hypertrophic sinus disease that affects immunocompetent hosts, most commonly young African American males. There are 5 main criteria used for the diagnosis of AFRS, one being the presence of nasal polyposis. A review of the current literature was performed in order to provide the most up-to-date knowledge regarding the background, diagnosis, management, recent research, and controversies surrounding AFRS. Although much is known about the pathophysiology and etiology of this disease, controversy exists regarding the importance of type I hypersensitivity in AFRS, as humoral immunity and immunoglobulin-independent pathways may also contribute. The potential role of local sinonasal IgE production in the pathophysiology of AFRS is an area of discussion, as is the role of preoperative antifungal medication in improving postoperative patient outcomes. Recent advancements in the diagnosis of AFRS include identification of genes and proteins unique to or over-expressed in AFRS patients. Although AFRS is a well-known and well-described cause of nasal polyposis, controversy still exists regarding this diagnosis. Advances in research may eventually resolve any diagnostic controversies in AFRS. PMID- 27466843 TI - Aspirin Exacerbated Respiratory Disease. AB - Aspirin exacerbated respiratory disease (AERD) has been defined as a non steroidal anti-inflammatory drug (NSAID)-triggered hypersensitivity, non-allergic bronchial asthma and chronic rhinosinusitis (CRS) with nasal polyps. The underlying pathophysiology of AERD is not completely understood so far. An altered arachidonic acid metabolism and dysregulated enzyme activity are regarded to be causal. AERD is characterized by recalcitrant CRS with recurrent nasal polyps after sinus surgery, accompanied by difficult to treat bronchial asthma and adverse reaction after NSAID ingestion such as nasal blockage, itching, laryngospasm and severe asthma attacks. Affected individuals suffer from poor quality of life. Besides functional endoscopic sinus surgery, the application of topical and systemic steroids and symptomatic therapy, aspirin desensitization is the only causative treatment option. The diagnostic approach to AERD, the ideal desensitization protocol and especially the following daily maintenance dose is part of an ongoing debate. This article summarizes the current knowledge about the pathophysiology, focuses on modern diagnostic approaches of AERD and discusses various aspirin desensitization protocols with respect to efficacy as well as to undesirable side effects. PMID- 27466844 TI - Cystic Fibrosis Sinusitis. AB - Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF transmembrane conductance regulator gene(CFTR) resulting in impaired ion transport. Nearly all people with CF will develop chronic rhino sinusitis (CRS) and present with the characteristic viscous mucus, impaired mucociliary clearance and chronic inflammation/infection of the sinonasal cavity. While some individuals with CF can appear relatively asymptomatic in terms of their sinus disease, commonly reported symptoms include anosmia, headache, facial pain, nasal obstruction, chronic congestion and nasal discharge. Nasal endoscopy typically reveals mucosal edema, purulent discharge and nasal polyposis. Computed tomography (CT) imaging classically demonstrates the distinguishing findings of sinus hypoplasia or aplasia with generalized opacification, medial bulging of the lateral sinonasal sidewall and a demineralized uncinate process. Current treatment for CF sinusitis includes the use of hypertonic saline, topical and systemic steroids, antibiotics and endoscopic surgery. Research investigating novel therapies designed at targeting the primary defect of CF is showing promise for reversal of CF sinus disease, in addition to potential for disease prevention. PMID- 27466845 TI - Influence of P-Glycoprotein Function on Chronic Rhinosinusitis/Nasal Polyps Pathophysiology. AB - Permeability glycoprotein (P-gp) is an active efflux membrane transporter that has been researched extensively due to its ability to confer multidrug resistance in a wide range of cancers. P-gp has an impressively broad substrate specificity and is known to interact with hundreds of compounds, including drugs and toxins. This substrate promiscuity is the key to its physiological role, and P-gp is thought to be responsible for extruding xenobiotics and cellular metabolites, as well as maintaining tissue barriers at the blood-brain interface and gastrointestinal epithelium. In addition, P-gp is thought to be involved in regulating immune responses and is able to influence the secretion of cytokines and chemokines. This role as an immunomodulator links P-gp activity in the sinonasal epithelium with chronic rhinosinusitis (CRS), and a series of studies have provided evidence suggesting that P-gp may be a potential therapeutic target for treating CRS. Here, we highlight key knowledge about this intriguing protein, which may offer an important advancement in our understanding of CRS pathogenesis. PMID- 27466846 TI - B-Cells and Antibody-Mediated Pathogenesis in Chronic Rhinosinusitis with Nasal Polyps. AB - The sinonasal mucosa forms a dynamic immune barrier where epithelial cells and the immune system interact with the inhaled environment and nasal microbiome. Recent studies suggest that B-cells, plasma cells and antibody production are highly activated locally within the nasal mucosa of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Findings additionally suggest that polyp tissue contains elevated levels of cytokines, chemokines and complement that may drive this profound B-cell response. Currently, the data are conflicting on whether the B-cell response found in the CRSwNP nasal mucosa is antigen specific, a superantigen response or an expansion of natural antibody responses. Indeed, investigations into the specificity of the mucosal antibody responses find increased production of class-switched antibodies that bind to aeroallergens, staphylococcus aureus as well as autoantigens. A continuation of these studies is needed to elucidate whether extrinsic factors, like the inhaled environment, or intrinsic factors, like the mucosal microbiome and host inflammatory response, are key to the pathogenesis of CRSwNP. This chapter will cover the current evidence regarding local B-cell responses in CRSwNP. PMID- 27466847 TI - Innate Lymphoid Cells: The Innate Counterpart to T Helper Cells. AB - Innate lymphoid cells (ILCs) are a recently discovered subset of innate immune cells that are capable of secreting great amounts of cytokines that have been found to influence effector cell activity. Chronic rhinosinusitis (CRS) in the absence (CRSsNP) or presence (CRSwNP) of nasal polyps has been characterized as type 1- and type 2-skewed, respectively, based on the presence of cytokines characteristic of type 1 and 2 immune responses. Based on the ability of type 1 ILCs to secrete interferon-x03B3;, a type 1 cytokine found elevated in CRSsNP and type 2 ILCs to secrete IL-5 and IL-13, type 2 cytokines found elevated in CRSwNP, it is essential to examine the role that ILCs may play in the pathogenesis of CRS. This chapter introduces each subset of ILC (type 1-3) and the non-CRS pathologies they have been associated with in both mouse and human models. It will discuss the current research into ILCs in CRS, particularly ILC2s and NK cells in CRSwNP. Finally, the chapter will consider the therapeutic implications of ILC involvement in CRS and highlight the needs for future research into the role that ILCs play in CRS. PMID- 27466849 TI - Acquired Cystic Fibrosis Transmembrane Conductance Regulator Deficiency. AB - In the genetic airway disease cystic fibrosis (CF), deficiency or dysfunction of the cystic fibrosis membrane conductance regulator (CFTR) alters anion transport in respiratory epithelium and consequently disrupts mucociliary clearance. An enriched understanding of the role of CFTR in the maintenance of normal epithelial function has revealed that mild and variable CFTR mutations play a causative role in a number of diseases not classically associated with CF. Furthermore, recent evidence indicates that acquired defects in wild-type CFTR protein processing, endocytic recycling and function can contribute to the pathogenesis of airway diseases, such as chronic obstructive pulmonary disease. In this chapter, we discuss emerging findings implicating acquired CFTR dysfunction in the pathogenesis of chronic rhinosinusitis and propose a new and leading edge approach to future CRS therapy using CFTR potentiators. PMID- 27466848 TI - The Role of Innate Immunity and Aeroallergens in Chronic Rhinosinusitis. AB - Allergy has been inferred to contribute to the pathophysiology of chronic rhinosinusitis (CRS) although this role is controversial and the mechanism is debated. Furthermore, the role of aeroallergens in CRS is poorly defined and has been postulated to contribute to CRS through direct penetration in the sinuses or downstream systemic consequences. Common aeroallergens implicated in chronic rhinosinusitis include air pollution/second hand smoke, dust mite and pollen [1,2,3]. One emerging potential mechanism whereby aeroallergens contribute to CRS is through sinonasal epithelial barrier disruption (fig. 1). Characterization of cytokine disruption of sinonasal epithelial cell barrier has been described including interleukin (IL)-4 and IL-13, as well as aeroallergens such as house dust mite and cigarette smoke. Recent results have demonstrated severe barrier disruption in response to direct application of either particulate matter (PM) or house dust mite (HDM) to sinonasal epithelial cells. Sinonasal epithelial barrier disruption may contribute to CRS by enabling the perpetual and chronic exposure of inflammatory allergens and stimuli. The sinonasal epithelial barrier plays a significant role in innate immune host defense. Mechanisms of innate immune defense include pattern recognition receptors (PRRs), secreted endogenous antimicrobials and inflammatory cytokines that aid in repair mechanisms including IL-33. Here we discuss recent evidence implicating aeroallergens and dysregulated host innate immune responses in the development of CRS.
1Fig. 1. Aeroallergens and inflammatory stimuli disrupt sinonasal epithelial barrier function. These agents act to destabilize the barrier through stimulating endocytosis and destruction of cell junction proteins via oxidative stress and MyD88-dependent mechanisms. Furthermore, aeroallergens and inflammatory stimuli induce secretion of IL-25, IL-33, and TSLP from sinonasal epithelial cells.F01
. PMID- 27466850 TI - Role of Vitamin D in Pathogenesis of Chronic Sinusitis with Nasal Polyposis. AB - Vitamin D3 (VD3) is a potent immunomodulatory steroid hormone involved in the regulation of numerous host immune cells. Additionally, it may have an important role in host immunity against chronic bacterial infections, as well as in chronic rhinosinusitis. Many factors modulate expression of various enzymes important for production of VD3, local concentration of which may be important for its complex and diverse functions. Here, we explore some of the contributions of VD3 to chronic rhinosinusitis with nasal polyposis and its role as a disease-modifying agent. PMID- 27466851 TI - Taste Receptors in Upper Airway Immunity. AB - Taste receptors are well known for their role in communicating information from the tongue to the brain about nutritional value or potential toxicity of ingested substances. More recently, it has been shown that taste receptors are expressed in other locations throughout the body, including the airway, gastrointestinal tract, brain and pancreas. The roles of some 'extraoral' taste receptors are largely unknown, but emerging research suggests that bitter and sweet taste receptors in the airway are capable of sensing bacteria and modulating innate immunity. This chapter focuses on the role of bitter and sweet taste receptors in human airway innate immunity and their clinical relevance to rhinosinusitis. The bitter taste receptor T2R38 expressed in sinonasal cilia detects bitter bacterial quorum-sensing molecules and activates a nitric oxide-dependent innate immune response; moreover, there are polymorphisms in T2R38 that underlie susceptibility to chronic rhinosinusitis (CRS). Bitter and sweet receptors in sinonasal solitary chemosensory cells control secretion of antimicrobial peptides in the upper airway and may have a profound impact on airway infections in patients with CRS and diabetes. Future research on taste receptors in the airway has enormous potential to expand our understanding of host-pathogen immune interactions and provide novel therapeutic targets. PMID- 27466852 TI - Immunomodulators in the Treatment of Nasal Polyposis. AB - The inflammatory mechanisms that contribute to chronic rhinosinusitis with nasal polyps (CRSwNP) are complex. In the past, medical options for treating CRSwNP have been limited. Emerging classes of immunomodulators such as omalizumab, anti leukotrienes, anti-IL-4, anti-IL-5, and recognition of the modulating effects of macrolides have shown promising results in the treatment of CRSwNP. Ultimately, large randomized controlled trials are necessary to establish the efficacy of these medications but for now, the area of medical immunomodulators remains an exciting frontier. PMID- 27466853 TI - Delivery of Topical Therapies. AB - Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory disease of the sinonasal passages. Similar to other chronic inflammatory diseases, an essential component of the long-term control is prolonged medical therapy. To minimize the risk of adverse effects and cumulative complications of systemic medications, topical sinonasal therapy has become the primary strategy for prolonged medical therapy. The objective of this review article is to describe the evidence for the most common topical sinonasal delivery techniques. Evidence supports that high-volume irrigations provide the most reliable delivery of medical therapy to the paranasal sinuses. Low-volume nasal sprays and drops provide reliable delivery to the nasal cavity and a degree of penetration into the middle meatus and olfactory cleft; however, they do not reliably penetrate the paranasal sinuses. Sinus surgery and the head down-forward position optimize the delivery of high-volume irrigations into the paranasal sinuses. Additionally, high-volume irrigations assist in overcoming unfavorable nasal anatomy such as septal deviation and turbinate hypertrophy. PMID- 27466854 TI - Topical Steroids. AB - Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory condition with heterogeneous pathophysiology. A cornerstone of the management of this condition is the use of anti-inflammatory agents. Corticosteroids are very effective and the most commonly used, but other drugs with immunodulatory activity such as anti-IL5, doxycycline (Th2), and macrolides (anti neutrophilic/IL8) have been shown to have efficacy. Although systemic corticosteroids have shown benefit in managing this condition, the frequency of use often required in this condition is associated with significant adverse effects. Topical corticosteroids, particularly when utilized after endoscopic sinus surgery and delivered in a high volume, high pressure manner, provide the desired anti-inflammatory effects with nearly negligible systemic absorption. Studies assessing the long-term use of second generation topical corticosteroids have demonstrated no significant effects on cortisol levels, growth rate, intraocular pressures or lens opacification, or local mucosal atrophy. Patients who often respond most favorably to corticosteroid treatment are those with a Th2 mediated, highly eosinophilic CRSwNP. However, there is a subset of patients who are steroid resistant. In the case of a predominantly neutrophilic CRSwNP, it is important to be aware that patients may respond well to the use of macrolide therapy. Additionally, the use of verapamil has shown promise in increasing steroid responsiveness in a difficult to treat group of patients with steroid resistance. Topical corticosteroids play a key role in the long term management of this complicated inflammatory condition by providing the much needed pharmacologic local control with minimal systemic adverse effects. PMID- 27466855 TI - Implantable Devices/Drugs in the Management of Nasal Polyps. AB - The use of biomaterials, which include nasal packing and sinus stents, has an evolving role in the postoperative management of patients with chronic rhinosinusitis with polyps. Some of these biomaterials include drug-eluting properties. The usage of biomaterials postoperatively is both surgeon and patient specific. The published literature supports the use of these products and demonstrates the ability to limit swelling, lateralization and reduce polyp regrowth postoperatively. However, there are heterogeneity in both available materials and results that the otolaryngologist must factor in to the decision making algorithm. PMID- 27466856 TI - Oral Therapeutics for Rhinosinusitis with Nasal Polyposis. AB - Oral therapeutics for chronic rhinosinusitis with nasal polyps (CRSwNP) include oral corticosteroids (OCS), antibiotics, antifungals and anti-leukotrienes. Of these treatments, the strongest evidence exists to support the use of a short course of OCS for treatment of CRSwNP, and OCS are the most consistently recommended oral therapy in practice guidelines. Antibiotics have demonstrated some utility, which appears more likely related to an anti-inflammatory rather than antimicrobial effect. The non-macrolide antibiotics lack sufficient evidence to support their use, though among this class doxycycline has some limited evidence of benefit in CRSwNP. Greater evidence exists for the use of macrolide antibiotics which have shown reduction of subjective and objective measures of CRSwNP severity. A short course of a macrolide should be considered as an option. Oral antifungals are not recommended in the treatment of CRSwNP given disappointing results and known potential adverse effects, except in allergic fungal rhinosinusitis where they may play a role. Leukotriene antagonists have demonstrated some promise in the treatment of CRSwNP, though studies are limited, but should be considered a potentially useful oral therapeutic. The current level of evidence for these oral therapeutic options for CRSwNP is reviewed in this chapter. PMID- 27466857 TI - Advances in Surgery: Extended Procedures for Sinonasal Polyp Disease. AB - In the standard functional endoscopic sinus surgery (FESS) procedure, the amount of dissection is often determined by the extent of disease with the goal to preserve as much normal mucosa as possible while restoring ventilation and reestablishing mucociliary clearance. A subset of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP), however, may continue to have persistent mucosal inflammatory and aggressive polyp regrowth despite standard FESS and maximal pharmacology therapy, leading to recurrent and recalcitrant disease. Advanced endoscopic surgery techniques such as the modified endoscopic medial maxillectomy, endoscopic modified Lothrop procedure, otherwise known as a Draf 3 frontal sinusotomy, and nasalisation or radical ethmoidectomy are extensive surgical procedures to maximize disease clearance while providing sizeable drainage pathways for effective postoperative surveillance and topical delivery of medications. Studies have shown a decreased risk of revision surgery as well as a longer time interval for revision surgery in patients with refractory CRSwNP who have undergone extensive sinus surgery for polyps. PMID- 27466858 TI - Outcomes in Medical and Surgical Treatment of Nasal Polyps. AB - Chronic rhinosinusitis with nasal polyps is a heterogeneous disease with a variety of medical and surgical options available to the patient and provider. Consensus statements and recent trends in outcomes research advocate that treatment be driven by patient-reported outcome measures. To this end, there has been increasing sophistication and nuance in both the outcome instruments themselves, as well as the method in which they are collected and interpreted. This is reflected in concepts such as the minimally clinically important difference and domain stratification, which have helped clinicians understand patient motivations and response to treatment. Medical management with topical and possibly systemic corticosteroids is considered the initial treatment strategy of choice, with endoscopic sinus surgery (ESS) reserved for patients who fail to improve. While there is strong evidence for surgical intervention over continued medical therapy in recalcitrant patients, a variety of additional targeted medical treatments and refinements to the nature and extent of ESS have been proposed to further maximize outcomes. Here, with the understanding that limitations continue to exist in our ability to fully answer many treatment related questions, we present the current cumulative evidence for a patient centered and outcomes-focused approach to manage this uniquely challenging disease. PMID- 27466859 TI - Candidate Evaluation Using Targeted Construct Assessment in the Multiple Mini Interview: A Multifaceted Rasch Model Analysis. AB - : Construct: A 7-station multiple mini-interview (MMI) circuit was implemented and assessed for 214 candidates rated by 37 interviewers (N = 1,498 ratings). The MMI stations were designed to assess 6 specific constructs (adaptability, empathy, integrity, critical thinking, teamwork [receiving instruction], teamwork [giving instruction]) and one open station about the candidate's interest in the school. BACKGROUND: Despite the apparent benefits of the MMI, construct irrelevant variance continues to be a topic of study. Refining the MMI to more effectively measure candidate ability is critical to improving our ability to identify and select candidates that are equipped for success within health professions education and the workforce. APPROACH: Each station assessed a single construct and was rated by a single interviewer who was provided only the name of the candidate and no additional information about the candidate's background, application, or prior academic performance. All interviewers received online and in-person training in the fall prior to the MMI and the morning of the MMI. A 3 facet multifaceted Rasch measurement analysis was completed to determine interviewer severity, candidate ability, and MMI station difficulty and examine how the model performed overall (e.g., rating scale). RESULTS: Altogether, the Rasch measures explained 62.84% of the variance in the ratings. Differences in candidate ability explained 45.28% of the variance in the data, whereas differences in interviewer severity explained 16.09% of the variance in the data. None of the interviewers had Infit or Outfit mean-square scores greater than 1.7, and only 2 (5.4%) had mean-square scores less than 0.5. CONCLUSIONS: The data demonstrated acceptable fit to the multifaceted Rasch measurement model. This work is the first of its kind in pharmacy and provides insight into the development of an MMI that provides useful and meaningful candidate assessment ratings for institutional decision making. PMID- 27466860 TI - Complete, bilateral hippocampal ischemia: a case series. AB - Acute and complete ischemia of the hippocampi represents a rare cause of amnesia. This paper describes the features of four such cases presenting to a single tertiary care center over a 3-year period. Interestingly, in three instances, toxicology screening was positive for opioids at the time of presentation, while in the fourth, there was a known, reportedly remote, history of heroin use. Taken together with the known literature on the topic, complete hippocampal ischemia appears at least highly suggestive of a toxic exposure. Further case finding is necessary to better understand the etiology, nature, and prevalence of this unusual clinico-radiologic entity. PMID- 27466861 TI - Trends and predicted trends in presentations of older people to Australian emergency departments: effects of demand growth, population aging and climate change. AB - Objectives The aim of the present study was to describe trends in and age and gender distributions of presentations of older people to Australian emergency departments (EDs) from July 2006 to June 2011, and to develop ED utilisation projections to 2050. Methods A retrospective analysis of data collected in the National Non-admitted Patient Emergency Department Care Database was undertaken to assess trends in ED presentations. Three standard Australian Bureau of Statistics population growth models, with and without adjustment for current trends in ED presentation growth and effects of climate change, were examined with projections of ED presentations across three age groups (0-64, 65-84 and >=85 years) to 2050. Results From 2006-07 to 2010-11, ED presentations increased by 12.63%, whereas the Australian population over this time increased by only 7.26%. Rates of presentation per head of population were greatest among those aged >=85 years. Projections of ED presentations to 2050 revealed that overall ED presentations are forecast to increase markedly, with the rate of increase being most marked for older people. Conclusion Growth in Australian ED presentations from 2006-07 to 2010-11 was greater than that expected from population growth alone. The predicted changes in demand for ED care will only be able to be optimally managed if Australian health policy, ED funding instruments and ED models of care are adjusted to take into account the specific care and resource needs of older people. What is known about the topic? Rapid population aging is anticipated over coming decades. International studies and specific local-level Australian studies have demonstrated significant growth in ED presentations. There have been no prior national-level Australian studies of ED presentation trends by age group. What does this paper add? The present study examined national ED presentation trends from July 2006 to June 2011, with specific emphasis on trends in presentation by age group. ED presentation growth was found to exceed population growth in all age groups. The rate of ED presentations per head of population was highest among those aged >=85 years. ED utilisation projections to 2050, using standard Australian Bureau of Statistics population modelling, with and without adjustment for current ED growth, were developed. The projections demonstrated linear growth in ED presentation for those aged 0-84 years, with growth in ED presentations of the >=85 year age group demonstrating marked acceleration after 2030. What are the implications for practitioners? Growth in ED presentations exceeding population growth suggests that current models of acute health care delivery require review to ensure that optimal care is delivered in the most fiscally efficient manner. Trends in presentation of older people emphasise the imperative for ED workforce planning and education in care of this complex patient cohort, and the requirement to review funding models to incentivise investment in ED avoidance and substitutive care models targeting older people. PMID- 27466862 TI - Copper Nanoparticle Induced Cytotoxicity to Nitrifying Bacteria in Wastewater Treatment: A Mechanistic Copper Speciation Study by X-ray Absorption Spectroscopy. AB - With the inclusion of engineered nanomaterials in industrial processes and consumer products, wastewater treatment plants (WWTPs) could serve as a major sink for these emerging contaminants. Previous research has demonstrated that nanomaterials are potentially toxic to microbial communities utilized in biological wastewater treatment (BWT). Copper-based nanoparticles (CuNPs) are of particular interest based on their increasing use in wood treatment, paints, household products, coatings, and byproducts of semiconductor manufacturing. A critical step in BWT is nutrient removal through nitrification. This study examined the potential toxicity of uncoated and polyvinylpyrrolidone (PVP)-coated CuO, and Cu2O nanoparticles, as well as Cu ions to microbial communities responsible for nitrification in BWT. Inhibition was inferred from changes to the specific oxygen uptake rate (sOUR) in the absence and presence of Cu ions and CuNPs. X-ray absorption fine structure spectroscopy, with linear combination fitting (LCF), was utilized to track changes to Cu speciation throughout exposure. Results indicate that the dissolution of Cu ions from CuNPs drive microbial inhibition. The presence of a PVP coating on CuNPs has little effect on inhibition. LCF analysis of the biomass combined with metal partitioning analysis supports the current hypothesis that Cu-induced cytotoxicity is primarily caused by reactive oxygen species formed from ionic Cu in solution via catalytic reaction intermediated by reduced Cu(I) species. PMID- 27466863 TI - Evaluation of the Efficacy and Safety of Short-Course Deep Sedation Therapy for the Treatment of Intracerebral Hemorrhage After Surgery: A Non-Randomized Control Study. AB - BACKGROUND While mild and moderate sedation have been widely used to reduce sudden agitation in intracerebral hemorrhage (ICH) patients after surgery, agitation is still a frequent problem, which may cause postoperative blood pressure fluctuation. The present study aimed to evaluate the efficacy and safety of short-course deep sedation for the treatment of ICH after surgery. MATERIAL AND METHODS A total of 41 ICH patients who received surgery, including traditional craniotomy hematoma removal and decompressive craniectomy, were including in this non-randomized control study. Patients in the deep sedation group received continuous postoperative sedation with a target course for <=12 hours and reached SAS scores of 1~2. Patients in the traditional sedition group received continuous light sedation and reached SAS scores of 3~4. Additional therapeutic interventions included antihypertensive treatment, mechanical ventilation, tracheotomy, and re-operation. RESULTS Patients in the deep sedation group had deeper sedation degree, and lower systolic blood pressure (SBP) and diastolic blood pressure (DBP). Residual hematoma after surgery in patients in the deep sedation group were smaller on the second, seventh, and fourteenth day after surgery (p=0.023, 0.003, 0.004, respectively). The 3-month mortality and quality of life of patients in the deep sedation group were lower and better than that of patients in the traditional sedation group, respectively (p=0.044, p<0.01). No significant difference in the incidence of ventilator-associated pneumonia (VAP) and ICU days were observed between the two groups. CONCLUSIONS Short-course deep sedation therapy in ICH patients after surgery is efficient in controlling postoperative blood pressure, reducing re-bleeding, and improving clinical prognosis. PMID- 27466864 TI - Stem Cells in Spine Surgery. AB - INTRODUCTION: Spine surgeons are embracing advanced biologic technologies in an attempt to help millions of people achieve a better outcome in spine surgery. These new technologies may be complicated to understand, partly because the contribution of different types of cells has not been definitively identified. This paper describes the characteristics of the stem cells used in spine surgery, including their actions and possible complications. The description necessitates an overview of all studies to date on the use of stem cells in spine surgery, as well as other cells used in cellular therapy. MATERIALS AND METHODS: The paper summarizes the results of major studies to date on the use of stem cells in spine surgery. Cells were harvested from the posterior superior iliac spine, vertebral bodies in surgery, fat tissue, or from the posterior spine of cadavers. RESULTS: This paper reports on three studies involving 37 patients treated with stem cells for regenerative spine surgery, 14 studies involving 533 patients treated with stem cells in spinal fusion surgery, and one study in which stem cells were used for the treatment of anterior cervical discectomy and fusion. DISCUSSION: Indications, techniques, and calibration of results were different in each study. Results are available for cellular augmentation of demineralized bone sponges, OsteoSponge(r) (Bacterin, Belgrade, Montana) and concentrated bone marrow (Terumo BCT(r), Lakewood, CO); cancellous allograft bone and BMA; mineralized collagen and BMA; Osteocel(r) Plus (OC+) (Nuvasive(r), San Diego, California); b Tricalcium phosphate (b-TCP) (SYNTHES(r) Dento, West Chester, Pennsylvania; a silicate-substituted calcium phosphate (Si-CaP) with bone marrow aspirate (BMA), and HEALOS(r) graft carrier (DePuy Synthes, West Chester, Pennsylvania) with bone marrow aspirate. CONCLUSION: Stem cell augmentation of spinal fusion surgery is equivalent to the gold standard for iliac crest bone graft in posterolateral fusion models. There is evidence of safety and feasibility in the injectable treatment of DDD with autologous BMC that indicates a favorable outcome of mesenchymal cell concentration on discogenic pain reduction. The use of adult stem cells is an innovation that promises fewer complications and improved function in patients who are demographically suitable for stem cell therapy. PMID- 27466865 TI - Accuracy of Intravascular Ultrasound Evaluation for the Assessment of Native Valve Measures in Patients Undergoing TAVI: Preliminary Results. AB - INTRODUCTION: Transcatheter aortic valve implantation (TAVI) technique represents a real revolution in the field of interventional cardiology and medicine, in particular for the treatment of severe aortic valve stenosis in elderly patients or in patients when the periprocedural risk for the traditional surgical option is considered too high, as an alternative to the traditional aortic valve replacement. Although experience on the valves of the last generation is still limited in terms of time, the data currently available are definitely moving in the direction of a minimum hospital mortality (1%) as well as a drastic reduction in the incidence of complications when compared to the devices of the previous generation. Finally, the evolution of specified materials of the newest generation have greatly enhanced safety and efficacy of TAVI procedures in the last years. In order to ensure the selection of the most appropriate valve and the success of the procedure, the role of cardiac imaging (computed tomography scan evaluation and angiography) is crucial. These examinations require the use of contrast medium in patients suffering from renal dysfunction at the baseline. The need for fluoroscopy and angiography using contrast agents to aid positioning of the valve may lead to contrast-induced nephropathy (CIN) as one form or one etiology of acute kidney injury (AKI), which is associated with increased morbidity and mortality. The aim of our study is to investigate the accuracy of intravascular ultrasound (IVUS-a technique which does not need contrast) for the assessment of native valve measures in patients undergoing TAVI by comparing values obtained with IVUS to those ones previously obtained in the same patients with computed tomography (CT) scans. MATERIAL AND METHODS: We enrolled 25 consecutive patients (10 males, average age 81.3+/-5,1 years) who underwent TAVI with femoral access in our Cardiac Surgery Cath-Lab (University of Bari) from January to October 2015 (Logistic EuroSCORE 21.6+/-15.4%; STS score mortality 20.9+/-14.9%). Each patient scheduled for TAVI underwent coronary angiography and high resolution angio-CT in order to obtain a complete evaluation (diameters, perimeters, and areas at annulus level, -3mm level, +15mm level, height of coronary ostia, shape, and conformation of left ventricle outflow tract, conformation, and calcifications of aortic and ileo-femoral axis) to choose the most suitable prosthetic aortic valve for each patient. In all patients, during the procedure (before the prosthetic valve implantation), we executed a manual IVUS pullback (from left ventricle outflow tract to ascending aorta) by using a 7F IVUS probe (Volcano Corporation, San Diego, CA). On the recorded IVUS pullback, a second operator (who did not know the values obtained by CT measurements) identified the aortic annulus and, at this level, measured: minimum and maximum diameter; perimeter; derived perimeter, and area. The t-student test has been used to compare the averages of these IVUS values to the CT ones. A p value< 0.05 was considered as statistically significant. RESULTS: Independently from the kind and size of implanted prosthetic valve, no statistical differences were found when the averages of all considered parameters (obtained both with CT and IVUS) were compared. The following are the results obtained: minimum diameter (CT: 19,62mm+/-1,10 vs. IVUS: 19,55mm+/-1,40; p=0.41); maximum diameter (CT: 24,73mm+/-2,42 vs. IVUS: 25,9mm+/-1,80; p=0.08); perimeter (CT: 72,05mm+/-4,36 vs. IVUS: 73,32mm+/-6,09; p=0.164); derived perimeter (CT: 22,94mm+/-1,40 vs. IVUS: 23,32mm +/- 1,95; p=0,198); and area (CT: 3,99cm2 +/-0,97 vs. IVUS: 4,06 cm2 +/- 0,47; p=0,073) (Figs. 1-3). CONCLUSIONS: These preliminary data suggest accurate IVUS measures when compared to CT in the evaluation of valve parameters considered (minimum and maximum diameters, area, perimeter, and derived perimeter at the annulus level). In order to confirm these findings and to give them statistical significance, it will be necessary to increase the sample size. PMID- 27466866 TI - Outpatient Robotic-Arm Total Hip Arthroplasty Surgical Technique. AB - Outpatient total hip arthroplasty (THA) has remained controversial and challenging. Traditional hospital stays following total joint arthroplasty were substantial and resulted in increased rates of morbidity, significant pain, and severe restriction in mobility. Advancements in the surgical approach, anesthetic regimens, and the initiation of rapid rehabilitation protocols have had an impact on the length of recovery following elective THA. Still, very few studies have specifically outlined outpatient hip arthroplasty and, thus far, none have addressed the use of robotic-arm navigation in outpatient THA. This article describes in detail the technique used to perform outpatient THA with the use of robotic-arm assistance. We believe that outpatient THA using robotic-arm assistance in combination with tissue-preserving surgery, multi-modal pain and nausea management, early rehabilitation, and stringent patient selection yields a suitable alternative to inpatient joint replacement . PMID- 27466867 TI - Aneuploidy and Tetraploidy as Distinct Patterns During Melanomagenesis. AB - Melanoma is characterized by a high degree of chromosome instability (CIN), the loss or gain of entire chromosomes or pieces of chromosomes. Also, CIN is likely to drive the progression of benign melanocytic lesions to malignant tumors, although very little is known about the acquisition of the mechanisms that promote CIN along this progression. Here, we describe the development of a model system to study the progression of melanomagenesis starting with normal human melanocytes followed by inactivation of the p53 and pRb tumor suppressors by addition of the E6/E7 proteins. The cells were then transduced with a growth promoting, constitutionally-active mutant NRAS. The addition of E6/E7 and E6/E7 NRAS was found to give a growth advantage to the cells compared to normal melanocytes and a statistically significant gain of aneuploidy; aneuploidy was 24.7% in primary melanocytes, 33.8% in E6/E7 melanocytes, and 70.5% in E6/E7 NRAS melanocytes. Further, we found an increase in tetraploid cells in the cell model which was statistically significant between primary melanocytes and E6/E7, NRAS melanocytes. We also observed an increase in aneuploid cells between three population doublings in primary melanocytes, whereas this increase was not seen in the E6/E7 melanocytes. Together, these data demonstrate that this model system utilizing stepwise addition of genetic mutations driving melanomagenesis is a useful tool to study CIN and could even be used to study the mechanisms responsible for these alterations in genetic makeup. PMID- 27466868 TI - Thickness of Cadaveric Human Lung Tissue. AB - BACKGROUND: Choosing the correct surgical staple height is dependent on knowledge of specific tissue thickness and compressibility. The purpose of this study was to measure the thickness of cadaveric human lung tissue. MATERIALS AND METHODS: Between December 2012 and February 2013, whole lungs were procured from 12 donors. Inclusion criteria included negative serology, no prior thoracic surgery, and completion of measurements within 72 hours of death. Tissue thickness was measured in the anterior-to-posterior direction using a tissue measuring device (TMD) at 41 lung locations. The tissue measuring device applied a constant pressure (8 g/mm2) via a plunger for 15 seconds before reading the thickness. RESULTS: Cadaveric lung tissue thickness displayed a large variation by location and within each location. Mean thickness in the anterior-to-posterior direction ranged from 1.5 mm (right middle lobe [inferior peripheral] location) to 9.0 mm (right inferior lobe [mid-central] location). In general, the periphery of the lung lobes was thinner than the central locations (e.g., mean peripheral location thickness: 4.1 mm; mean central location thickness: 5.9 mm). The thinnest tissues among the 12 donor cadaveric lung specimens were found in the one donor with a history of severe emphysema/chronic bronchitis. Height (P = 0.012) and weight (P = 0.036) were positively correlated with tissue thickness. Additionally, after adjusting for height, cadaveric lung tissue was 3.0 mm thicker for females than males. CONCLUSIONS: Large variations of lung tissue thickness were demonstrated throughout the lung as well as within each measured location across different cadaveric specimens. Generally, peripheral locations were thinner than the central locations of the lobes. There was a strong positive correlation between thickness and height, and females had slightly thicker lung tissue than males of the same height. PMID- 27466869 TI - Next Generation Mesh Fixation Technology for Hernia Repair. AB - Laparoscopic ventral hernia repair (LVHR) remains a safe, reproducible, and popular method employed by surgeons to repair abdominal wall hernias. Patient selection, operative technique, instrumentation, and implant choice all remain surgeon dependent. Inherent in the technique is the option of using mesh. The decision of where to place the mesh and how to optimally fixate the mesh in the onlay, sublay, or intraabdominal positions also remain surgeon dependent and has been the subject of ongoing debates for the past two decades. In an ongoing effort to develop new methods for securing mesh to minimize pain without increased recurrence rates, novel mesh fasteners and mesh textiles have been developed. With increasing surgeon responsibility to improve value, surgeons should concentrate more on choosing the novel options that not only improve outcomes, but also reduce overall costs. This chapter reviews some of the emerging markets for these technologies. PMID- 27466870 TI - The Science Behind Mini-Laparoscopic Cholecystectomy. AB - BACKGROUND: Mini-laparoscopy (Mini) was pioneered more than 20 years ago. Newer generation mini instruments have recently become available with improved effector tips, a choice of shaft diameters and lengths, better shaft insulation and electrosurgery capability, improved shaft strength and rotation, more ergonomic handles, low-friction trocar options, and improved instrument durability. Whether the use of mini instruments, particularly newer generation instruments, offers advantages for laparoscopic cholecystectomy is the subject of this review. MATERIALS AND METHODS: The literature was searched for level I data comparing mini-laparoscopic cholecystectomy (Mini LC) to standard laparoscopic cholecystectomy (Std LC). Three systematic reviews and 19 randomized clinical trials were identified and these were studied to evaluate the science behind Mini LC. RESULTS: Mini LC requires conversion to Std LC in 12.3% of patients. Mini LC and Std LC require conversion to open cholecystectomy at the same rate (2-3%). As compared to Std LC, Mini LC: (1) takes 3.4-4.9 minutes longer to perform; (2) has the same rate of intraoperative and postoperative complications; (3) may result in slightly less pain in the first 24 hours after surgery; (4) has the same duration of hospital stay, pain scores 1-28 days after surgery, time to return to activity, time to return to work, and postoperative quality of life 10 days after surgery; (5) provides a better early cosmetic result (as graded by patients and by blinded observers); and (6) provides no apparent difference in late cosmesis (as evaluated 6-12 months postop). There are minimal level I data published on the effects of newer mini instruments for laparoscopic cholecystectomy. CONCLUSION: When applied to elective laparoscopic cholecystectomy, the use of mini-laparoscopic instruments results in a slightly longer operative procedure (3 5 minutes), slightly less immediate postoperative pain (in the first 24 hours), and a better early cosmetic result, with no other apparent significant differences. Additional data are needed from large, well-conducted studies of Mini LC to resolve several unanswered questions, including the role of newer mini instruments. PMID- 27466871 TI - 3D HD Endoscopy in Skull Base Surgery: From Darkness to Light. AB - The introduction of modern endoscopy in neurosurgery brought light to one of the darkest areas: the skull base. In particular, the trans-nasal route allowed skull base surgeons to visualize and dominate the entire midline skull base. We analyzed our surgical series of 199 patients that were affected by several pathologies (pituitary adenomas, clivalchordomas, craniopharyngioma, Rathke's cleft cysts, tuberculum sellaemeningiomas, and craniovertebral junction pathologies with bulbar compression) and treated each by using a 3D-HD endoscope between December 2012 and December 2015 and reviewed the literature. We present our results in terms of tumor resections and decompression inpatients affected by craniovertebral junction pathologies. Analyzing our direct experience, as well as the literature, we can assert that the amount and accuracy of necessary movements in order to achieve a determined target are affected by the screen clarity and image resolution of the device. Additionally, the experience of the surgeon has an important role in the surgical outcome. Moreover, depth perception is critical in order to obtain precise and accurate movements. Our observations and the experts' opinion indicate that this modality provides improved surgical dexterity by affording the surgeon with depth perception while manipulating tissue and maneuvering the endoscope in the endonasal corridor, which is especially crucial in reducing the learning curve of young neurosurgeons. PMID- 27466872 TI - Multiple Small Diameter Drillings Increase Femoral Neck Stability Compared with Single Large Diameter Femoral Head Core Decompression Technique for Avascular Necrosis of the Femoral Head. AB - Femoral head core decompression is an efficacious joint-preserving procedure for treatment of early stage avascular necrosis. However, postoperative fractures have been described which may be related to the decompression technique used. Femoral head decompressions were performed on 12 matched human cadaveric femora comparing large 8mm single bore versus multiple 3mm small drilling techniques. Ultimate failure strength of the femora was tested using a servo-hydraulic material testing system. Ultimate load to failure was compared between the different decompression techniques using two paired ANCOVA linear regression models. Prior to biomechanical testing and after the intervention, volumetric bone mineral density was determined using quantitative computed tomography to account for variation between cadaveric samples and to assess the amount of bone disruption by the core decompression. Core decompression, using the small diameter bore and multiple drilling technique, withstood significantly greater load prior to failure compared with the single large bore technique after adjustment for bone mineral density (p< 0.05). The 8mm single bore technique removed a significantly larger volume of bone compared to the 3mm multiple drilling technique (p< 0.001). However, total fracture energy was similar between the two core decompression techniques. When considering core decompression for the treatment of early stage avascular necrosis, the multiple small bore technique removed less bone volume, thereby potentially leading to higher load to failure. PMID- 27466873 TI - Autologous Adipose Derived Regenerative Cells: A Platform for Therapeutic Applications. AB - Adipose derived regenerative cells (ADRCs) are a heterogeneous population of cells including multipotent adipose derived stems cells, other progenitor cells, fibroblasts, T-regulatory cells, and macrophages. Preclinical data exist supporting benefits that are predominantly through angiogenesis, modulation of inflammation, and wound remodeling. Such effects are likely paracrine in nature. The application of autologous ADRCs has been investigated across multiple therapeutic areas. While there are numerous publications, there is a relative lack of double-blind, well-controlled, randomized clinical trials in the literature. Nevertheless, a consistency in outcomes and a consistency with preclinical and laboratory studies suggests a true positive effect. The therapeutic areas reported include orthopedics, autoimmune disease, wounds and reconstruction, cardiology, peripheral vascular disease, genitourinary disorders, gastrointestinal fistulas, and neurology. Case reports have documented wound healing in otherwise intractable wounds such as ischemic- and radiation-related cutaneous ulcers and enterocutaneous fistulas. An open label, 12-patient-study indicated substantial improvement in hand manifestations of scleroderma across multiple endpoints. Post-radical prostatectomy urinary incontinence improved in a study of 11 patients with local delivery of ADRCs. Small studies of intramyocardial delivery have been associated with trends towards benefit. The studies also indicate that same day fat harvest through liposuction, cell processing, and cell delivery is feasible and can be performed with an acceptable safety profile. The objective of this review is to highlight the interest, potential, and trends that support the need to continue evaluation and exploration for the role of ADRCs as a therapeutic agent. PMID- 27466874 TI - Single-Port Totally Extraperitoneal Preperitoneal Hernia Repair: Procedure, Tips, and Our Experience. AB - Single-port laparoscopic surgery is gaining increased attention because of its superiority in terms of cosmesis. A 1.5 cm vertical transumbilical incision is used for the single port, which is created by the glove method. We began applying single-port surgery to hernia repair in 2010, at which time we used the transabdominal preperitoneal (TAPP) approach. We began applying the totally extraperitoneal peritoneal (TEP) approach in 2013. Single-port TEP repair is now our standard procedure for inguinal hernia repair, and we consider it to be indicated for all cases of inguinal hernia unless the hernia has occurred during pregnancy, the patient is assigned to American Society of Anesthesiologists (ASA) class 3/4, or ascites due to liver cirrhosis is present. Provided herein is a step-by-step description of our single glove-port TEP hernia repair procedure, tips that facilitate the procedure, and a brief summary of the 102 cases in which we have performed TEP repair. PMID- 27466875 TI - Traumatic Diastasis of the Pubic Symphysis-A Review of Fixation Method Outcomes. AB - Traumatic pubic symphysis diastases (PSD) are life-threatening injuries that often require operative fixation. The purpose of this review is to evaluate the outcomes of patients following various operative fixation techniques of these particular pelvic ring injuries. Specifically, we will analyze the role of: (1) surgical approach; (2) implant failure; and (3) fixation methods in treating traumatic PSD. They are typically fixed using the Pfannestiel approach, but a midline approach may be used in cases where this is not ideal. These fractures often have implant failure; however, studies have shown this does not impact clinical outcomes. Currently, the gold standard of fixation is multiple-hole plate fixation. There are a number of other surgical fixation methods such as two hole plating or percutaneous fixation that may be considered as well. Future studies should focus on the long-term outcomes and efficacy of these new innovative techniques for fixation of traumatic PSD. PMID- 27466876 TI - Ochronosis as Etiology of Requiring Total Knee Arthroplasty-A Case Series. AB - Alkaptonuria is a rare hereditary metabolic disorder that leads to the accumulation of homogentisic acid accumulation and weakens the collagen, creating fissuring and articular cartilage degeneration. Therefore, we are reporting a multicenter case series of three patients (four arthroplasties) who presented with signs and symptoms of ochronotic arthropathy-and eventually underwent total knee arthroplasty (TKA)-and provide a review of the current literature on total joint arthroplasty in ochronotic osteoarthritis. Each patient achieved excellent Knee Society Scores (KSS) after at least a five-year follow-up-regardless of receiving cemented or cementless prostheses-and suffered no complications. There have been a number of case reports published on patients who had TKA and were found to have a diagnosis of ochronosis. We believe that surgery for symptomatic patients who are surgical candidates for TKA should not be delayed for concerns of complications. However, future studies should compare outcomes to those who undergo TKA without ochronotic arthropathy. PMID- 27466877 TI - Laparoscopic Hemi-hysterectomy and Trachelectomy in a Case of Herlyn-Werner Wunderlich Syndrome. AB - BACKGROUND: Herlyn-Werner-Wunderlich Syndrome (HWWS) is a rare Mullerian anomaly characterized by uterus didelphys coexisting with an obstructed hemivagina and ipsilateral renal agenesis. CASE: A 13-year-old female presented one-year after menarche with severe dysmenorrhea and a right-sided pelvic mass. Imaging identified a right uterus with hematometra, hematocolpos, absent right kidney, normal left kidney, ureter, left uterus, and vagina compressed to the left by right hematocolpos. We performed laparoscopic hemi-hysterectomy of the non communicating hemi-uterus, and laparoscopic trachelectomy. CONCLUSION: Laparoscopic hemi-hysterectomy and trachelecotmy is a minimally invasive surgical option for patients with Herlyn-Werner-Wunderlich Syndrome. PMID- 27466878 TI - Prospective Randomized Clinical Trial of HEMOPATCH Topical Sealant in Cardiac Surgery. AB - OBJECTIVE: Hemostasis is a critical component of all surgical procedures and especially cardiac surgery. In addition to traditional means, topical hemostatic agents have been reported to be extremely effective in terminating bleeding during cardiac procedures. We compared a hemostatic matrix sealant agent (HEMOPATCH Baxter Healthcare Corporation, Deerfield, IL) with alternative topical hemostatic treatment in patients undergoing ascending aorta surgery with moderate bleeding. MATERIALS AND METHODS: Following sample size calculation, in a prospective randomized study design, 85 patients were treated with HEMOPATCH matrix sealant and 85 patients received alternative treatment (dry or wet gauze compression or similar [control group]). The primary outcome measure was the percentage of patients with successful hemostasis within three minutes of HEMOPATCH or traditional treatment application. Other study outcome measures were postoperative blood loss and the rate of transfusion of blood products. RESULTS: A statistically higher rate of successful hemostasis within three minutes was observed in the HEMOPATCH group (97.6% [83/85] vs. 65.8% [56/85] in the control group; p< 0.001). The percentages of patients with postoperative bleeding and the rate of transfusion were lower in the HEMOPATCH group than in the control group. CONCLUSIONS: The use of HEMOPATCH is effective in terminating bleeding in patients undergoing ascending aorta cardiac procedures. Fewer patients treated with HEMOPATCH required blood transfusion. The cost-utility profile of HEMOPATCH should be addressed in dedicated trials. PMID- 27466879 TI - Pressure Pain Threshold as a Predictor of Acute Postoperative Pain Following Total Joint Arthroplasty. AB - OBJECTIVES: Acute pain in the postoperative period after total joint arthroplasty (TJA) has a significant effect on early rehabilitation, hospital length of stay, and the development of chronic pain. Consequently, efforts have been made to predict the occurrence of postoperative pain using preoperative and intraoperative factors. In this study, we tested the usefulness of preoperative pressure pain threshold (PPT) values in the prediction of three outcomes for patients who underwent TJA: visual analog scale pain scores, hospital length of stay, and opioid consumption. MATERIALS AND METHODS: Using a digital pressure algometer, we measured the preoperative PPT in 41 patients expected to undergo TJA at three different body sites: the first web space of the hand, the operative joint, and the contralateral joint. We correlated each PPT separately with postoperative visual analog scale pain scores, hospital length of stay, and opioid consumption. RESULTS: No significant correlation was found between preoperative PPT and the three postoperative outcomes. This finding held true when patients were subdivided by surgery type (total knee arthroplasty vs. total hip arthroplasty). There was no significant difference in PPT between the three body testing sites. DISCUSSION: This study failed to prove the usefulness of PPT in the prediction of acute postoperative pain, pain medication consumption, and length of stay. The pressure algometer has previously found a place in the assessment of pain in a variety of clinical settings, but its utility has not yet been demonstrated in patients undergoing TJA. PMID- 27466880 TI - Hydrophobic polymers for orodispersible films: a quality by design approach. AB - OBJECTIVES: To develop orodispersible films (ODF) based on hydrophobic polymers with higher stability to ordinary environmental humidity conditions without compromising their fast disintegration time. METHODS: A quality by design approach was applied to screen three different formulations each one based on a different hydrophobic polymer: polyvinyl acetate, methacrylate-based copolymer and shellac. The screening formulations were characterized regarding their mechanical properties, residual water content, disintegration time and appearance, in order to find a suitable ODF formulation according to established critical quality attributes. The selected critical process parameters for the selection of appropriate ODF formulations were the percentage of the different excipients and the plasticizer type. RESULTS: Three hydrophobic-based matrices with fast disintegration were developed. These were generically composed by a hydrophobic polymer, a stabilizer, a disintegrant and a plasticizer. It verified that the common components within the three different formulations behave differently depending on the system/chemical environment that they were included. CONCLUSIONS: It was shown that it is possible to develop oral films based on hydrophobic polymers with fast disintegration time, good texture and appearance, breaking a paradigm of the ODF research field. PMID- 27466881 TI - Electrostatically Confined Monolayer Graphene Quantum Dots with Orbital and Valley Splittings. AB - The electrostatic confinement of massless charge carriers is hampered by Klein tunneling. Circumventing this problem in graphene mainly relies on carving out nanostructures or applying electric displacement fields to open a band gap in bilayer graphene. So far, these approaches suffer from edge disorder or insufficiently controlled localization of electrons. Here we realize an alternative strategy in monolayer graphene, by combining a homogeneous magnetic field and electrostatic confinement. Using the tip of a scanning tunneling microscope, we induce a confining potential in the Landau gaps of bulk graphene without the need for physical edges. Gating the localized states toward the Fermi energy leads to regular charging sequences with more than 40 Coulomb peaks exhibiting typical addition energies of 7-20 meV. Orbital splittings of 4-10 meV and a valley splitting of about 3 meV for the first orbital state can be deduced. These experimental observations are quantitatively reproduced by tight binding calculations, which include the interactions of the graphene with the aligned hexagonal boron nitride substrate. The demonstrated confinement approach appears suitable to create quantum dots with well-defined wave function properties beyond the reach of traditional techniques. PMID- 27466882 TI - Chemical Constituents of Mangifera indica and Their Antiausterity Activity against the PANC-1 Human Pancreatic Cancer Cell Line. AB - Human pancreatic cancer cell lines such as PANC-1 have an altered metabolism, enabiling them to tolerate and survive under extreme conditions of nutrient starvation. The search for candidates that inhibit their viability during nutrition starvation represents a novel antiausterity strategy in anticancer drug discovery. A methanol extract of the bark of Mangifera indica was found to inhibit the survival of PANC-1 human pancreatic cancer cells preferentially under nutrient-deprived conditions with a PC50 value of 15.5 MUg/mL, without apparent toxicity, in normal nutrient-rich conditions. Chemical investigation on this bioactive extract led to the isolation of 19 compounds (1-19), including two new cycloartane-type triterpenes, mangiferolate A (1) and mangiferolate B (2). The structures of 1 and 2 were determined by NMR spectroscopic analysis. Among the isolated compounds, mangiferolate B (2) and isoambolic acid (12) exhibited potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under the nutrition-deprived condition with PC50 values of 11.0 and 4.8 MUM, respectively. PMID- 27466883 TI - Thermoreversible Gels Composed of Colloidal Silica Rods with Short-Range Attractions. AB - Dynamic arrest transitions of colloidal suspensions containing nonspherical particles are of interest for the design and processing of various particle technologies. To better understand the effects of particle shape anisotropy and attraction strength on gel and glass formation, we present a colloidal model system of octadecyl-coated silica rods, termed as adhesive hard rods (AHR), which enables control of rod aspect ratio and temperature-dependent interactions. The aspect ratios of silica rods were controlled by varying the initial TEOS concentration following the work of Kuijk et al. (J. Am. Chem. Soc., 2011, 133, 2346-2349) and temperature-dependent attractions were introduced by coating the calcined silica rods with an octadecyl-brush and suspending in tetradecane. The rod length and aspect ratio were found to increase with TEOS concentration as expected, while other properties such as the rod diameter, coating coverage, density, and surface roughness were nearly independent of the aspect ratio. Ultrasmall angle X-ray scattering measurements revealed temperature-dependent attractions between octadecyl-coated silica rods in tetradecane, as characterized by a low-q upturn in the scattered intensity upon thermal quenching. Lastly, the rheology of a concentrated AHR suspension in tetradecane demonstrated thermoreversible gelation behavior, displaying a nearly 5 orders of magnitude change in the dynamic moduli as the temperature was cycled between 15 and 40 degrees C. The adhesive hard rod model system serves as a tunable platform to explore the combined influence of particle shape anisotropy and attraction strength on the dynamic arrest transitions in colloidal suspensions with thermoreversible, short-range attractions. PMID- 27466885 TI - The Role of Bacteriologic Studies in Predicting Recurrent Mastoiditis in 456 Patients. AB - OBJECTIVES: To evaluate the effect of microbiologic growth on the recurrence rate of mastoiditis. MATERIALS AND METHODS: A historical prospective study on all cases of children with acute mastoiditis (AM) admitted between 2000 and 2015, was performed. The following data were collected in the recurrent AM (rAM) group: age, sex, and medical history, antibiotic therapy before hospitalization, clinical presentation at admission including symptoms and signs, blood test results, computed tomography (CT) imaging, microbiological findings, treatment, complications, outcome, and follow-up duration. RESULTS: Four hundred fifty six consecutive hospitalizations because of mastoiditis were identified; 22 patients were found to have rAM. The median age at first episode in the rAM group was 1 year (range, 1-11 years), and the median period from one episode to the next was 2 months. There were 15 men and 7 women. The right ear was involved in 11 cases in the first and in the second episode. The rate of Pseudomonas aeruginosa growth in the rAM group was significantly higher compared with the AM group (40.9 and 8.9%, respectively) (p = 0.001) as was found in anerobic growth (15 vs. no growth) (p < 0.001) and in polymicrobial growth (59% vs. 3.6%) (p < 0.001). CONCLUSION: Patients with P. aeruginosa growth, anaerobic bacteria, and polymicrobia infection cultured in an AM infection, are prone to have rAM, and therefore antibiotic adjustments according to their bacteriologic studies should be considered even if clinical improvement is encountered, or surgical intervention during the first AM episode, and closer follow up with proper antibiotic treatment when signs of recurrent ear infection are encountered. PMID- 27466884 TI - Plasma Taurine, Diabetes Genetic Predisposition, and Changes of Insulin Sensitivity in Response to Weight-Loss Diets. AB - CONTEXT: Taurine metabolism disturbance is closely linked to obesity, insulin resistance, and diabetes. Previous evidence suggested that the preventative effects of taurine on diabetes might be through regulating the expression levels of diabetes-related genes. OBJECTIVE: We estimated whether blood taurine levels modified the overall genetic susceptibility to diabetes on improvement of insulin sensitivity in a randomized dietary trial. DESIGN AND SETTING: We genotyped 31 diabetes-associated variants to calculate a genetic risk score (GRS) and measured plasma taurine levels and glycemic traits among participants from the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial. PARTICIPANTS: Seven-hundred eleven overweight or obese participants (age 30-70 y; 60% females) had genetic variants genotyped and blood taurine levels measured. INTERVENTION: Participants went on 2-year weight-loss diets, which were different in macronutrient composition. MAIN OUTCOME MEASURE: Improvements in glycemic traits were measured. RESULTS: We found that baseline taurine levels significantly modified the effects of diabetes GRS on changes in fasting glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) during the 2-year diet intervention (P-interaction = .04, .01, .002, respectively), regardless of weight loss. High baseline taurine levels were associated with a less reduction in both glucose and HOMA-IR among the participants with the lowest tertile of diabetes GRS (both P = .02), and with a greater reduction in both insulin and HOMA-IR among those with the highest tertile of diabetes GRS (both P = .04). CONCLUSIONS: Our data suggest that blood taurine levels might differentially modulate the effects of diabetes-related genes on improvement of insulin sensitivity among overweight/obese patients on weight-loss diets. PMID- 27466886 TI - Taste Disturbance Due to Cochlear Implant Stimulation. AB - OBJECTIVE: To characterize stimulation of taste fibers in the facial nerve following cochlear implantation. PATIENT: A 34-year old presented with reversible dysgeusia following activation of a cochlear implant. INTERVENTION: Reprogramming targeted to specific offending electrodes reduced symptom intensity. Computed tomography demonstrated dehiscence of the bone separating the labyrinthine segment of the facial nerve and the basal turn of the cochlea in proximity to the electrode array. RESULTS: Dysgeusia was attributed to stimulation of taste fibers in the facial nerve by electrodes 13 to 16 of the cochlear implant array located in the superior-most portion of the basal turn. CONCLUSIONS: Dysgeusia following cochlear implant activation has not previously been reported. This likely results from stimulation of taste fibers through dehiscence of the bone separating the labyrinthine segment of the Fallopian canal and the basal turn of the cochlea. While in some cases of apparent dehiscence there may be thin bone present, recognition of this potential anatomic feature may influence the choice of which ear and which electrode design to implant. PMID- 27466887 TI - The Outcomes of Surgery and Chemoradiotherapy for Temporal Bone Cancer. AB - OBJECTIVE: We aimed to evaluate the prognostic factors and efficacy of treatment modalities for patients with temporal bone cancer, and to determine if definitive chemoradiotherapy (CRT) for advanced-stage disease can provide a substitute for highly invasive surgeries. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Sixty-six patients with previously untreated squamous cell carcinoma of the temporal bone treated with curative intent between April 1997 and March 2015. INTERVENTION: Surgery alone, radiotherapy (RT) alone, surgery followed by RT or definitive CRT. MAIN OUTCOME MEASURE: The overall survival (OS) rate. RESULTS: The 5-year OS rate for each T classification was 100% for T1, 76.2% for T2, 55.6% for T3, and 36.7% for T4. Univariable and multivariable analysis showed that T classification was an independent predictor of the OS rate (hazard ratio 5.66; 95% confidence interval 1.51-27.0; p = 0.015). Analysis by treatment modality revealed that the 5-year OS rate for patients with T1-2 was 100% for surgery and 81.3% for RT alone. The rate for patients with T3-4 was 52.1% for definitive CRT and 55.6% for surgery followed by RT with or without chemotherapy. CONCLUSIONS: Patients with T1-2 benefited from surgical intervention without significant morbidity or mortality. Our findings also suggested that definitive CRT might be appropriate as the first-line treatment for T3-4, especially in cases with unresectable tumors. PMID- 27466888 TI - Vestibular Schwannomas: Do Linear and Volumetric Parameters on MRI Correlate With Hearing Loss? AB - PURPOSE: To determine if two-dimensional and volumetric imaging parameters in vestibular schwannomas (VS) correlate with hearing loss at presentation. STUDY DESIGN: Retrospective. METHODS: Forty-one cases of pathologically confirmed sporadic VS were analyzed. Maximal tumor dimensions in anteroposterior (AP), coronal (ML), and craniocaudal (CC) dimensions were obtained along with tumor fundus distance and internal auditory canal (IAC) porus diameters. Volumetric analysis was done on 37 cases. Tumors volumes were calculated through both 3-D volumetric and ABC/2 [AP * ML * CC/2] methodology. With the 3-D method, total tumor volume (TTV), and cerebellopontine angle (CPA) tumor volume were separately calculated and IAC volumes obtained by subtracting CPA tumor volumes from TTV. Pure tone average (PTA) and speech discrimination scores (SDS) were correlated with tumor dimensions. RESULTS: Non-volumetric analysis was performed on 41 tumors. The AP and ML dimensions correlated with both PTA and SDS (p < 0.05). No significant correlations were seen between hearing loss and tumor-fundus distance or porus diameters. The tumor volume calculated through ABC/2 methodology correlated with PTA and SDS (p < 0.05). The 3-D TTV and CPA volumes only correlated with PTA. IAC tumor volumes did not correlate with hearing loss. CONCLUSION: Maximal AP and ML dimensions are the only non-volumetric variables, which significantly correlate with hearing loss. Tumor volume calculated through ABC/2 method significantly correlates with hearing impairment while the 3-D TTV and CPA tumor volumes only correlated significantly with PTA scores but not SDS scores. PMID- 27466889 TI - The Yield of Multigene Testing in the Management of Pediatric Unilateral Sensorineural Hearing Loss. AB - OBJECTIVE: To explore the role and yield of multigene evaluation in children recently diagnosed with unilateral sensori-neural hearing loss (SNHL). STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary level pediatric institution. PATIENTS: Sixty children diagnosed with unilateral SNHL between January 2005 and December 2015. INTERVENTION: Targeted mutation analysis was performed in 51 children using DNA microarray for genotyping 11 different genes known to be correlated with nonsyndromic SNHL. MAIN OUTCOME MEASURE: Multigene testing results. RESULTS: Average age at diagnosis was 4.3 years. All children appeared to have nonsyndromic hearing loss (HL). HL was categorized as mild (17 children), moderate (17 children), severe (7 children), or profound (19 children). Genetic testing was performed in 51 (85%) children. Sixteen children (31.3%) were tested positive to connexin 26 (GJB2). One patient (2%) from this subgroup was homozygous and 15 were heterozygous. The average age of GJB2 positive children was 6 years and their average pure tone audiometry (PTA) was 75 dB. Computed tomography (CT) and/or magnetic resonance imaging (MRI) scans were performed in 43 children (71.66%). Out of the children who had a scan, 27 patients (62.8%) had negative findings on either CT or MRI scans. Sixteen (37.2%) patients had positive scan finding/s. CONCLUSIONS: Significant proportion of children with unilateral SNHL may have positive genetic testing while the vast majority of these children present with heterozygous mutations of connexin 26 (GJB2). Findings suggest that genetic evaluation has a role as a complementary modality in HL evaluation for pediatric unilateral SNHL although it may not be necessary to analyze for various abnormalities other than connexin 26 when practising in a limited resources environment. PMID- 27466891 TI - Response to "Drug Diffusion to the Apex of the Human Cochlea?". PMID- 27466890 TI - Vestibular Impairment in Dementia. AB - OBJECTIVE: Recent studies suggest an association between vestibular and cognitive function. The goal of the study was to investigate whether vestibular function was impaired in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared with cognitively normal individuals. STUDY DESIGN: Cross sectional study. SETTING: Outpatient memory clinic and longitudinal observational study unit. PATIENTS: Older individuals >=55 years with MCI or AD. Age, sex, and education-matched normal controls were drawn from the Baltimore Longitudinal Study of Aging (BLSA). INTERVENTION: Saccular and utricular function was assessed with cervical and ocular vestibular-evoked myogenic potentials (c- and oVEMPs) respectively, and horizontal semicircular canal function was assessed with video head impulse testing. MAIN OUTCOME MEASURES: Presence or absence of VEMP responses, VEMP amplitude, and vestibular ocular reflex (VOR) gain were measured. RESULTS: Forty-seven individuals with cognitive impairment (MCI N = 15 and AD N = 32) underwent testing and were matched with 94 controls. In adjusted analyses, bilaterally absent cVEMPs were associated with an over three-fold odds of AD (OR 3.42, 95% CI 1.33-8.91, p = 0.011). One microvolt increases in both cVEMP and oVEMP amplitudes were associated with decreased odds of AD (OR 0.28, 95% CI 0.09 0.93, p = 0.038 and OR 0.92, 95% CI 0.85-0.99, p = 0.036, respectively). There was no significant difference in VOR gain between the groups. CONCLUSIONS: These findings confirm and extend emerging evidence of an association between vestibular dysfunction and cognitive impairment. Further investigation is needed to determine the causal direction for the link between peripheral vestibular loss and cognitive impairment. PMID- 27466892 TI - Treatment Outcomes for Single Modality Management of Glomus Jugulare Tumors With Stereotactic Radiosurgery. AB - OBJECTIVES: The objectives were to evaluate the audiological outcomes, response of symptoms, and response of tumor volume in patients with glomus jugulare tumors treated solely with single fraction gamma knife radiosurgery. STUDY DESIGN: Single institution retrospective review. SETTING: Academic, tertiary referral center. PATIENTS: The diagnosis code for glomus jugulare was used to identify patients. Only those who underwent gamma knife radiosurgery were included. Those previously treated with any modality were excluded. A total of 12 patients were included for the tumor response and symptom response data and 7 of those were included in the audiometric analysis. MAIN OUTCOMES MEASURES: Audiometric data at most recent follow-up compared with presentation, subjective improvement in pulsatile tinnitus, and change in tumor volume at most recent follow-up compared with pretreatment. RESULTS: The average time to most recent follow-up was 27.6 months. There was no significant change in pure-tone average or word recognition. Pulsatile tinnitus completely resolved or improved in 80% of patients. Cranial neuropathies were stable or improved. A single patient experienced facial nerve paresis 2 years after treatment, which resolved with steroid treatment. Tumor control was 100% and the average change in tumor volume was a decrease of 37%. CONCLUSION: Single modality gamma knife radiosurgery treatment of glomus jugulare tumors seems to be safe. Treatment results in decreased tumor volume and improved pulsatile tinnitus in most patients. There was no significant progression of hearing loss after treatment. Lower cranial nerve function remains stable in all patients. PMID- 27466893 TI - Music-induced Hearing Loss in Children, Adolescents, and Young Adults: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Exposure to loud music has increased significantly because of the current development of personal music players and mobile phones. The aim of this study was to provide an overview of music-induced hearing loss and its symptoms in children. DATA SOURCES: The search was performed in the databases Embase, Medline (OvidSP), Web-of-science, Scopus, Cinahl, Cochrane, PubMed publisher, and Google Scholar. Only articles written in English were included. STUDY SELECTION: Articles describing hearing levels and music exposure in children were used, published from 1990 until April 2015. DATA EXTRACTION: The quality of the studies was assessed on reporting, validity, power, and the quality of audiometric testing. DATA SYNTHESIS: Data of each publication was extracted into spreadsheet software and analyzed using best evidence synthesis. CONCLUSION: The prevalence of increased hearing levels (>15 dB HL) was 9.6%, and high-frequency hearing loss was found in 9.3%. The average hearing thresholds were 4.79 dB HL at low frequencies (0.5, 1, and 2 kHz) and 9.54 dB HL at high frequencies (3, 4, and 6 kHz). Most studies reported no significant association between pure-tone air thresholds and exposure to loud music. However, significant changes in hearing thresholds and otoacoustic emissions, and a high tinnitus prevalence suggest an association between music exposure and hearing loss in children. PMID- 27466894 TI - Cochlear Implants in Adults: Effects of Age and Duration of Deafness on Speech Recognition. AB - OBJECTIVE: Unexplained outcome variability exists among adults with cochlear implants (CIs). Two significant predictors are age and duration of deafness, with older patients and those with longer durations of deafness generally demonstrating poorer speech recognition. However, these factors are often highly correlated. Thus, it is unclear whether poorer outcomes should be attributed primarily to age-related declines or to the experience of auditory deprivation. Our aim was to examine the effects of aging and duration of hearing loss on outcomes for postlingually deaf adults with CIs. STUDY DESIGN: Retrospective review of adults who received CIs from 1983 to 2014. SETTING: Tertiary adult CI program. PATIENTS: Sixty-four adult patients with postlingual hearing loss beginning after age 12 years, full electrode insertion, normal cochlear anatomy, and availability of postoperative outcome measures. INTERVENTION: Cochlear implantation with 12 months or greater of device use. MAIN OUTCOME MEASURES: Postoperative pure-tone averages (0.5, 1, 2, and 3 kHz) and recognition of words in sentences (Hearing in Noise Test and AzBio). RESULTS: Age at postoperative testing had a negative partial correlation with AzBio scores, when controlling for duration of deafness, whereas duration of deafness had a positive partial correlation with AzBio scores, when controlling for age. No other effects were identified. CONCLUSION: Older age at testing was associated with poorer recognition of words in difficult sentences, suggesting that cognitive aging may negatively impact CI outcomes. Further studies are needed to examine how a long duration of auditory deprivation affects CI outcomes. PMID- 27466895 TI - A Review of Temporal Bone CT Imaging With Respect to Pediatric Bone-anchored Hearing Aid Placement. AB - OBJECTIVE: Bone-anchored hearing aid has been shown to be effective in hearing rehabilitation for conductive loss or single-sided deafness. Current FDA guidelines allow implantation in patients over 5 years old. This guideline is at least partially due to concern for thickness of bone stock at the implant site. We aim to investigate whether temporal bone thickness should be a deterrent to implantation in those younger than five. STUDY DESIGN: A retrospective review of high-resolution temporal bone computed tomographies (CTs) comparing measurements between ears with chronic disease and controls. SETTING: Single institution tertiary care center. PATIENTS: One hundred patients between 1 and 5.99 years had temporal bone CTs performed between 2000 and 2009. Patients with chronic ear disease were identified by ICD-9 code, as well as confirmation by review of the imaging. INTERVENTION(S): None. MAIN OUTCOME MEASURES: Temporal bone thickness was measured on axial CT slices at a point 1 cm posterior to the sigmoid sinus, at the superior margin of the bony canal. RESULTS: Average thickness was greater than 3 mm in all age groups. No significant difference was found between age groups, or between normal ears and ears with chronic disease (3.5 mm versus 3.3 mm, p = 0.21) when compared individually. CONCLUSION: This data shows pediatric temporal bone thickness is frequently greater than the recommended 3 mm, even in patients as young as one. Anatomically, concerns regarding temporal bone thickness in patients younger than five could be reliably addressed with imaging typically obtained in workup of hearing loss. PMID- 27466896 TI - The Use of an Ultrasonic Serrated Knife in Transcanal Excision of Exostoses. AB - OBJECTIVE: To describe a novel approach for excision of exostoses and evaluate the outcomes of transcanal excision of exostoses using ultrasonic serrated knife assistance versus microosteotomes only. STUDY DESIGN: Retrospective analysis. SETTING: Academic Tertiary Care Center. PATIENTS/INTERVENTIONS: Patients receiving a transcanal excision of exostoses between 2007 and 2016. MAIN OUTCOME MEASURES: The outcomes and postoperative complications of 138 patients who received transcanal microosteotome only technique were compared to 10 patients who received transcanal excision of exostoses using ultrasonic serrated knife assistance (Stryker Corporation, Kalamazoo, MI). RESULTS: A total of 175 ears in 128 patients underwent a transcanal microosteotome only technique. Of these, 11 (6.3%) developed an intraoperative tympanic membrane perforation. One developed anterior canal mobilization requiring prolonged (3 wk) packing. One hundred thirty-five ears (77%) were well healed by the 3-week postoperative visit. All but one ear was well healed by the 6-week visit. In comparison, 11 ears in 10 patients were treated for exostoses using a transcanal approach with the use of ultrasonic serrated knife and microosteotomes. One ear canal (the first in the series) was not well healed by the 3-week postoperative visit due to suspected thermal injury. All patients had well-healed ear canals by 6 weeks, and there were no complications. CONCLUSION: This is the first series to report the use of an ultrasonic serrated knife in the transcanal excision of exostoses. When compared with a transcanal microosteotome only excision of exostoses, the addition of the Sonopet seems to result in a similarly low complication rate. Sonopet can allow for more controlled transcanal excision of broad-based exostoses in patients with severe obstruction. PMID- 27466898 TI - Maternal creatine supplementation during pregnancy prevents acute and long-term deficits in skeletal muscle after birth asphyxia: a study of structure and function of hind limb muscle in the spiny mouse. AB - BACKGROUND: Maternal antenatal creatine supplementation protects the brain, kidney, and diaphragm against the effects of birth asphyxia in the spiny mouse. In this study, we examined creatine's potential to prevent damage to axial skeletal muscles. METHODS: Pregnant spiny mice were fed a control or creatine supplemented diet from mid-pregnancy, and 1 d before term (39 d), fetuses were delivered by c-section with or without 7.5 min of birth asphyxia. At 24 h or 33 +/- 2 d after birth, gastrocnemius muscles were obtained for ex-vivo study of twitch-tension, muscle fatigue, and structural and histochemical analysis. RESULTS: Birth asphyxia significantly reduced cross-sectional area of all muscle fiber types (P < 0.05), and increased fatigue caused by repeated tetanic contractions at 24 h of age (P < 0.05). There were fewer (P < 0.05) Type I and IIa fibers and more (P < 0.05) Type IIb fibers in male gastrocnemius at 33 d of age. Muscle oxidative capacity was reduced (P < 0.05) in males at 24 h and 33 d and in females at 24 h only. Maternal creatine treatment prevented all asphyxia induced changes in the gastrocnemius, improved motor performance. CONCLUSION: This study demonstrates that creatine loading before birth protects the muscle from asphyxia-induced damage at birth. PMID- 27466897 TI - Structural and genomic variation in preterm birth. AB - BACKGROUND: Runs of homozygosity (ROH) are consecutive homozygous genotypes, which may result from population inbreeding or consanguineous marriages. ROH enhance the expression of recessive traits. METHODS: We mapped ROH in a case control study of women delivering at term compared with women delivering at or before 34 wk gestation. Gene sets known to be important in risk of preterm birth were examined for their overlap with identified ROH segments. RESULTS: While we found no evidence of increased burden of ROH or copy number variations in mothers delivering at or before 34 wk compared with term, we identified 424 genome-wide 50 kb segments with significant difference in abundance of overlapping ROH segments in cases vs. controls, P < 0.05. These regions overlap 199 known genes. We found preterm birth associated genes (CXCR4, MYLK, PAK1) and genes shown to have an evolutionary link to preterm (CXCR4, PPP3CB, C6orf57, DUSP13, and SLC25A45) with significant differences in abundance of overlapping ROH blocks in cases vs. controls, P < 0.001. CONCLUSION: We conclude, while we found no significant burden of ROH, we did identify genomic regions with significantly greater abundance of ROH blocks in women delivering preterm that overlapped genes known to be involved in preterm birth. PMID- 27466899 TI - Diagnostic Yield and Complications of Transbronchial Lung Cryobiopsy for Interstitial Lung Disease. A Systematic Review and Metaanalysis. AB - RATIONALE: The diagnostic usefulness and safety of transbronchial lung cryobiopsy for the evaluation of interstitial lung disease remain unclear. OBJECTIVES: This systematic review and metaanalysis aims to establish the diagnostic accuracy and yield of transbronchial cryobiopsy for interstitial lung diseases. METHODS: We searched MedLine, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings to identify studies assessing the diagnostic accuracy (compared with surgical biopsy) or yield of transbronchial lung cryobiopsy for interstitial lung disease (from database inception to January 2016). The diagnostic accuracy and yield were quantified and stratified by the method of diagnosis determination (histologic interpretation in isolation vs. incorporation within a multidisciplinary discussion). The frequency of procedure-related complications was also assessed from these reports. For full-text studies, random effects models were used to calculate pooled estimates of diagnostic accuracy, yield, and complication frequency. MEASUREMENTS AND MAIN RESULTS: Of 900 citations, 11 studies were selected for inclusion in this systematic review (7 full text, 4 abstracts). The selected studies reported on a total of 731 patients. No studies reported the diagnostic accuracy of transbronchial cryobiopsy. Diagnostic yield ranged from 74 to 98% when transbronchial cryobiopsy findings were interpreted in isolation, with a pooled estimate of 83% (95% confidence interval [CI], 73-94). Diagnostic yield ranged from 51 to 98% when transbronchial cryobiopsy was reviewed within a multidisciplinary discussion, with a pooled estimate of 79% (95% CI, 65-93). Pooled estimates for pneumothorax and moderate/severe bleeding were 12% (95% CI, 3-21) and 39% (95% CI, 3-76), respectively. CONCLUSIONS: The diagnostic accuracy of transbronchial lung cryobiopsy cannot be determined given the absence of studies directly comparing cryobiopsy diagnoses with diagnoses derived from surgical lung biopsies interpreted within multidisciplinary discussions. The histopathological and multidisciplinary discussion-based diagnostic yield of transbronchial cryobiopsy appears high, but with variable frequencies of complications dominated by pneumothorax and moderate-to-severe hemorrhage. PMID- 27466900 TI - In Setting Global Policy, Nursing's Voice Is Needed. AB - It's time to reach beyond the bedside. PMID- 27466902 TI - Napping on the Night Shift. PMID- 27466901 TI - When Families Ask About an Autopsy. AB - It's time to say 'yes' to this valuable teaching tool and source of information. PMID- 27466903 TI - Napping on the Night Shift. PMID- 27466904 TI - Napping on the Night Shift. PMID- 27466906 TI - Practice What You Preach. PMID- 27466905 TI - Simulation for Home Care Settings. PMID- 27466907 TI - Transgender Rights in Health Care. AB - Regulations are raising awareness of the needs of gender-nonconforming patients. PMID- 27466908 TI - Toxic Exposures of Young Children to E-Cigarettes Are on the Rise. AB - The increasing popularity of e-cigarettes has led to severe outcomes in young children. PMID- 27466910 TI - Arsenic Levels in Drinking Water Linked to Bladder Cancer in New England. AB - Arsenic exposure may be responsible for elevated rates of bladder cancer in three states. PMID- 27466912 TI - A Snapshot of the 2015 National Nursing Workforce. AB - RNs today are younger, more diverse, and more highly educated than before. PMID- 27466917 TI - Community College Baccalaureate Nursing Programs Are Growing Nationwide. AB - Innovative RN-to-BSN programs allow students in rural communities to study where they live and work. PMID- 27466920 TI - The FDA Reevaluates Oral Fluconazole Use in Pregnancy. PMID- 27466921 TI - The FDA Revises Restrictions on Metformin Use in Kidney Impairment. PMID- 27466922 TI - Increased Risk of Heart Failure with Two Diabetes Drugs. PMID- 27466926 TI - A Clinical Nurse Specialist-Directed Initiative to Reduce Postoperative Urinary Retention in Spinal Surgery Patients. AB - : Postoperative urinary retention (POUR) is the inability to void when the bladder is full after surgery. It is a common complication in postoperative patients, especially in patients undergoing spinal surgery. At our institution, patients who were discharged from the postanesthesia care unit (PACU) to the inpatient surgical unit typically had bladder distention and a bladder volume of more than 450 mL. In an effort to address this situation, an interprofessional group of advanced practice RNs and physicians formed a team, reviewed the existing literature, examined the PACU nursing practice guideline for evaluating and managing POUR, and devised a quality improvement (QI) project to raise the PACU nursing staff's awareness of the potential for POUR among postoperative patients and to develop an updated nursing practice algorithm for the evaluation and management of POUR in spinal surgery patients. A description of the QI process, including the revised algorithm and pre- and postintervention results, is reported here. In the preintervention group (n = 42), 19 indwelling urinary catheterizations were documented in patient records; no use of intermittent catheterization was documented. In the postintervention group (n = 43), seven indwelling urinary catheterizations were documented in patient records; the use of intermittent catheterization was documented in 11. As a result of our intervention, we decreased the number of indwelling urinary catheters inserted in the PACU, and supported the PACU nursing staff in more frequent and appropriate use of intermittent catheterization in patients undergoing spinal surgery. PMID- 27466927 TI - NP-Led Clinic Reduces 30-Day Stroke Readmissions. PMID- 27466928 TI - Rate and Rhythm Control are Equally Effective in Treating Postoperative Atrial Fibrillation. PMID- 27466929 TI - Endometriosis is Associated with Higher CHD Risk. PMID- 27466930 TI - ED Screening May Detect Patients at Risk for Suicide. PMID- 27466931 TI - Peace and Reconciliation. AB - Susan Schnall speaks about the lingering effects of Agent Orange-and what remains to be done about them. PMID- 27466932 TI - Health Care Worker Fatigue. AB - The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, birthing centers, and abortion facilities must file information on incidents and serious events.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu. PMID- 27466933 TI - Constraint-Induced Movement Therapy for Hemiparesis Following Stroke. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. PMID- 27466934 TI - If She Yells 'Help Me'-Poster Therapy to Convey the Needs, Identity of an Ailing Parent. AB - Updated several times a week with posts by a wide variety of authors, AJN's blog, Off the Charts, allows us to provide more timely-and often more personal perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to bring AJN readers recent posts that we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com. PMID- 27466935 TI - Fatigue as it Affects Nursing. AB - : Editor's note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but they also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives highlights articles selected to fit today's topics and times.In this month's article from the January 1935 issue, Lillian M. Gilbreth, a highly respected psychologist and industrial engineer, examines the problem of fatigue in nursing. A nonnurse expert, Gilbreth notes the negative effects of fatigue on skills, a problem "enormously more serious when the product of the work is human comfort and sometimes even human life, as it often is with the work of the nurse." In their article in this issue, "Health Care Worker Fatigue," Lea Anne Gardner and Deborah Dubeck of the Pennsylvania Patient Safety Authority share examples of fatigue-related adverse events and discuss the need for both personal and institutional fatigue risk management strategies. PMID- 27466936 TI - A Measure of Contentment. AB - In a long-term care facility, a nurse takes note of one patient's ritual. PMID- 27466937 TI - New developments in genetics of myositis. AB - PURPOSE OF REVIEW: This article reviews the advances that have been made in our understanding of the genetics of the idiopathic inflammatory myopathies (IIM) in the past 2 years, with a particular focus on polymyositis, dermatomyositis and inclusion body myositis. RECENT FINDINGS: Two large human leukocyte antigen (HLA) imputation studies have confirmed a strong association with the 8.1 ancestral haplotype in clinical subgroups of myositis and suggest multiple independent associations on this haplotype. Risk in these genes may be due to specific amino acid positions within the peptide-binding grooves of HLA molecules. A large genetic study in 2566 IIM patients revealed associations such as PTPN22, STAT4, UBE2L3 and BLK, which overlap with risk variants reported in other seropositive autoimmune diseases. There is also evidence of different genetic architectures in clinical subgroups of IIM. Candidate gene studies in the Japanese and Chinese populations have replicated previous IIM associations which suggest common aetiology between ethnicities. SUMMARY: International collaborations have facilitated large genetic studies in IIM that have revealed much about the genetics of this rare complex disease both within the HLA region and genome-wide. Future approaches, such as sequencing and trans-ethnic meta-analyses, will advance our knowledge of IIM genetics. PMID- 27466941 TI - QuickStats: Percentage* of Adults Aged 18-64 Years Who Had Visited or Talked to a Health Care Professional in the Past 12 Months,? by Race/EthnicityS - National Health Interview Survey, 2010 and 2015 . AB - From 2010 to 2015, there was an increase in the percentage of non-Hispanic white adults (82.5% to 84.0%) and non-Hispanic black adults (80.5% to 83.5%) aged 18-64 years who had seen or talked to a health care professional in the past 12 months. In 2010, non-Hispanic white adults aged 18-64 years were the most likely to have seen or talked to a health professional in the past 12 months, but there was no significant difference between non-Hispanic white and non-Hispanic black adults in 2015. In both 2010 and 2015, Hispanic adults aged 18-64 years were the least likely to have seen or talked to a health care professional in the past 12 months. PMID- 27466938 TI - Gonadotoxic Effects of Nilotinib in Chronic Myeloid Leukemia Treatment Dose in a Mouse Model. AB - OBJECTIVE: Tyrosine kinase inhibitors may have deleterious effects on spermatogenesis or folliculogenesis, resulting in male or female subfertility. The aim of this study is to determine the effect of nilotinib, which is used routinely to treat chronic myeloid leukemia, on spermatogenesis and folliculogenesis by using histopathological parameters. MATERIALS AND METHODS: Ten male and ten female mice were orally treated with nilotinib at 20 mg/kg body weight dissolved in drinking water daily for 2 months. RESULTS: When compared with the control group, a statistically significant decrease was demonstrated in the total follicle numbers of the female mice in the nilotinib group (268+/-110 vs. 170+/-60; p=0.03). Active spermatogenesis was observed in each tubule sample taken from the mice in the control and nilotinib groups. Spermatogenic activity was similar in the two groups. CONCLUSION: We have demonstrated that even though spermatogenesis is preserved, folliculogenesis is inhibited by the usage of a continuous nilotinib treatment dose in chronic myeloid leukemia. PMID- 27466942 TI - Method to evaluate the abilities of scores in predicting mortality: not only receiver operating characteristic curves. PMID- 27466944 TI - Push-Pull Stabilization of Parent Monochlorosilylenes. AB - While reaction of carbene-stabilized disilicon L:Si?Si:L (L: = C{N(2,6 (i)Pr2C6H3)CH}2) (8) with HCl.NC5H5 results in carbene-stabilized Si2Cl2 (2) and substituted 1H-imidazole (9), combination of the corresponding Fe(CO)4-modified disilicon carbene complex L:Si?Si[Fe(CO)4]:L (6) with pyridine hydrochloride gives a species containing two push-pull-stabilized parent monochlorosilylenes that are bridged by an Fe(CO)3 unit (7). The nature of 7 was further elucidated by spectroscopic, crystallographic, and computational methods. Spectroscopic data suggest that 7 exists as two diastereoisomers. PMID- 27466943 TI - The Effect of Glatiramer Acetate on Spinal Cord Volume in Relapsing-Remitting Multiple Sclerosis. AB - BACKGROUND: Spinal cord atrophy occurs early in the multiple sclerosis (MS) disease course, is closely related to physical disability, and is a putative neuroprotective therapeutic outcome measure. OBJECTIVE: This pilot study explored glatiramer acetate (GA)'s effect on spinal cord volume in patients with relapsing remitting MS (RRMS). METHODS: Fifteen patients receiving daily subcutaneous GA were prospectively followed. At baseline, age was 43.6 +/- 7.4 years, Expanded Disability Status Scale (EDSS) score was 1.4 +/- 1.5, timed 25-foot walk (T25FW) was 4.7 +/- 1.1 seconds, and time on GA was 2.1 +/- 3.1 years. Healthy controls (n = 10) with similar age and sex to the patients were also enrolled. The spinal cord was imaged at baseline and one year later with 3T magnetic resonance imaging. An active surface method measured the C1-C7 spinal cord volume from which we calculated the normalized area. RESULTS: The spinal cord area showed no significant change in the MS group over one year (P = .19). Furthermore, the change in the spinal cord area did not differ significantly between the MS and control groups over one year (P = .26). In the MS group, the EDSS score (P = .44) and T25FW (P = .92) did not change significantly on-study. CONCLUSION: In this pilot study of RRMS, GA therapy was not associated with any ongoing spinal cord atrophy or any difference in the one-year rate of spinal cord area change versus healthy controls. These results paralleled the lack of clinical worsening and may reflect a treatment effect of GA. Further studies are needed to confirm these preliminary findings. PMID- 27466945 TI - A Bispidine Iron(IV)-Oxo Complex in the Entatic State. AB - For a series of Fe(IV) =O complexes with tetra- and pentadentate bispidine ligands, the correlation of their redox potentials with reactivity, involving a variety of substrates for alkane hydroxylation (HAT), alkene epoxidation, and phosphine and thioether oxidation (OAT) are reported. The redox potentials span approximately 350 mV and the reaction rates over 8 orders of magnitude. From the experimental data and in comparison with published studies it emerges that electron transfer and the driving force are of major importance, and this is also supported by the DFT-based computational analysis. The striking difference of reactivity of two isomeric systems with pentadentate bispidines is found to be due to a destabilization of the S=1 ground state of one of the ferryl isomers, and this is supported by the experimentally determined redox potentials and published stability constants with a series of first-row transition metal ions with these two isomeric ligands. PMID- 27466946 TI - Horizontal Flow Models That Are Not. PMID- 27466947 TI - Compound Design by Fragment-Linking. AB - The linking together of two fragment compounds that bind to distinct protein sub sites can lead to a superadditivity of binding affinities, in which the binding free energy of the linked fragments exceeds the simple sum of the binding energies of individual fragments (linking coefficient E<1). However, a review of the literature shows that such events are relatively rare and, in the majority of the cases, linking coefficients are far from optimal being much greater than 1. It is critical to design a linker that does not disturb the original binding poses of each fragment in order to achieve successful linking. However, such an ideal linker is often difficult to design and even more difficult to actually synthesize. We suggest that the chance of achieving successful fragment linking can be significantly improved by choosing a fragment pair that consists of one fragment that binds by strong H-bonds (or non-classical equivalents) and a second fragment that is more tolerant of changes in binding mode (hydrophobic or vdW binders). We also propose that the fragment molecular orbital (FMO) calculations can be used to analyse the nature of the binding interactions of the fragment hits for the selection of fragments for evolution, merging and linking in order to optimize the chance of success. PMID- 27466948 TI - Boltzmann-Enhanced Flexible Atom-Pair Kernel with Dynamic Dimension Reduction. PMID- 27466949 TI - Addressing the Conformational Flexibility of Serine Racemase by Combining Targeted Molecular Dynamics, Conformational Sampling and Docking Studies. AB - Serine racemase (SR) is a PLP-dependent enzyme catalyzing the racemization of L Ser into D-Ser, which is now recognized as an endogenous co-agonist at the NMDA receptor complex. As indicated by available X-ray structures, SR undergoes significant conformational changes during ligand recognition, and it is conceivable that, in addition to the reported X-ray structures, other intermediate conformational states may have relevance in drug discovery studies. Targeted molecular dynamics (TMD) simulations are an effective tools to follow the conformational transition of a protein under the constrain of reaching a known target states. In this study we use TMD to simulate the transition between the open and closed form of SR in the presence of the endogenous substrate or an orthosteric inhibitor. The trajectories thus obtained are then clustered to collect an ensemble of intermediate conformational states. Docking of a small library of known SR inhibitors or closely related inactive analogs demonstrates that ensemble docking performs better than docking on available crystal structures, thus indicating that inclusion of conformational flexibility into ligand design strategies will be crucial for the development of new classes of SR inhibitors. PMID- 27466950 TI - Targeting PKC-beta II and PKB Connection: Design of Dual Inhibitors. AB - Protein kinase C (PKC) has been the center of many cell signaling pathways. PKC isoforms, specifically PKC-beta II is linked to both diabetic complications as well as in promotion of angiogenesis and regulation of cancers. PKC-beta II activates the PKB/Akt pathway. Enzastaurin, a selective PKC-beta II inhibitor has been found to inhibit PKB/Akt by suppressing the regulation of various cancerous pathways. In the present work, we carried out an in depth study on the binding mode of inhibitors of PKC-beta II, enzastaurin and ruboxistaurin with the active site residues of PKB and PKC-beta II. A ligand based approach has been further used to determine the pharmacophoric features and spatial arrangement of molecules, having common properties necessary for appropriate binding to the active site of both targets. Virtual screening of the respective pharmacophores of both proteins led to identification of hits which may be useful for treatment of diabetic complications and cancer. The study has highlighted important features that may be considered in the future for designing novel inhibitors. PMID- 27466951 TI - Differential Virtual Screening (DVS) with Active and Inactive Molecular Models for Finding and Profiling GPCR Modulators: Case of the CCK1 Receptor. AB - We discovered a constitutively activating mutation (CAM) V308E for the neurotensin NT1 receptor. Molecular dynamics (MD) performed for the CAM NT1-V308E exhibiting a high spontaneous activity, and for the wild-type NT1 without basal activity, show dramatic conformational changes for the CAM. To test if the two MD models could be valuable active and inactive templates for building molecular models for other class-A GPCR, supposed active and inactive models were built by homology for the cholecystokinin CCK1 receptor. Virtual screening of a corporate library with 250 000 compounds was performed with the two CCK1 models, and a differential virtual screening analysis (DVS), led us to isolate 250 predicted agonists and 250 predicted antagonists. The two sets were merged and the compounds were tested in CCK1 agonist and antagonist cellular assays. An excellent correlation was obtained between predictions and biological results. The effective profiling provided by DVS with active and inactive molecular models, opens new perspectives for finding agonists and antagonists for other class-A GPCR, notably for orphan GPCRs for which no ligands are known. PMID- 27466952 TI - A Combination of Computational and Experimental Approaches to Investigate the Binding Behavior of B.sub Lipase A Mutants with Substrate pNPP. AB - The formation of so-called enzyme-substrate complex is the key step for a successful enzyme-catalysis reaction. Enzymes use substrate-binding energy both to promote ground-state association and to stabilize the reaction transition state selectively. Some residues besides the catalytic triads play important roles toward the substrate binding process. In this study, we employed ONIOM methodology and docking to explore the influence of individual amino acids of Bacillus subtilis (B.sub) lipase A on the hydrolysis reaction, with the aim to guide mutagenesis experiments on the basis of computational framework. Subsequently, the B.sub lipase A is modified experimentally with different non polar residues at the position 12, which is spatially adjacent to the active site, by using site-directed mutagenesis. We obtain a good correlation model between the computationally predicted binding energies and the experimental measured affinities, with a correlation coefficient r=0.78. It is largely unexplored that the combination of docking and quantum mechanical/molecular mechanical (QM/MM) analyses is used in conjunction with experimental procedure to investigate the enzyme catalysis process. We therefore expect that this work could provide a new pathway for exploring the molecular mechanism of enzyme substrate recognition and interaction. PMID- 27466953 TI - MHC Class II Binding Prediction by Molecular Docking. AB - Proteins of the Major Histocompatibility Complex (MHC) bind self and nonself peptide antigens or epitopes within the cell and present them at the cell surface for recognition by T cells. All T-cell epitopes are MHC binders but not all MCH binders are T-cell epitopes. The MHC class II proteins are extremely polymorphic. Polymorphic residues cluster in the peptide-binding region and largely determine the MHC's peptide selectivity. The peptide binding site on MHC class II proteins consist of five binding pockets. Using molecular docking, we have modelled the interactions between peptide and MHC class II proteins from locus DRB1. A combinatorial peptide library was generated by mutation of residues at peptide positions which correspond to binding pockets (so called anchor positions). The binding affinities were assessed using different scoring functions. The normalized scoring functions for each amino acid at each anchor position were used to construct quantitative matrices (QM) for MHC class II binding prediction. Models were validated by external test sets comprising 4540 known binders. Eighty percent of the known binders are identified in the best predicted 15 % of all overlapping peptides, originating from one protein. PMID- 27466954 TI - In Silico Prediction of Caco-2 Cell Permeability by a Classification QSAR Approach. AB - In the present study, 21 validated QSAR models that discriminate compounds with high Caco-2 permeability (Papp >=8*10(-6) cm/s) from those with moderate-poor permeability (Papp <8*10(-6) cm/s) were developed on a novel large dataset of 674 compounds. 20 DRAGON descriptor families were used. The global accuracies of obtained models were ranking between 78-82 %. A general model combining all types of molecular descriptors was developed and it classified correctly 81.56 % and 83.94 % for training and test sets, respectively. An external set of 10 compounds was predicted and 80 % was correctly assessed by in vitro Caco-2 assays. The potential use of the final model was evaluated by a virtual screening of a human intestinal absorption database of 269 compounds. The model predicted 121 compounds with high Caco-2 permeability and the 90 % of them had high values of human intestinal absorption (HIA>=80). This study provides the most comprehensive database of Caco-2 permeability and evidenced the utility of the combined methodology (in silico+in vitro) in the prediction of Caco-2 permeability. It suggests that the present methodology can be used in the design of large libraries of compounds with appropriate values of permeability and to perform virtual screening in the early stages of drug development. PMID- 27466955 TI - Erratum: Multi-pH QSAR: A Method to Differentiate the Activity of Neutral and Ionized Species and Obtain True Correlations when Both Species are Involved. AB - The inhibition of monoamine oxidase (MAO) by n-alkylamines was incorrectly analyzed because datasets containing both pH adjusted and unadjusted rate constants were combined. The correct analysis supports the findings of the original McEwen paper that inhibition is due to the neutral species and a hydrophobic binding site is evident for chain lengths greater than C4 . Contrary to our original paper, no significant role was found for the protonated amine. PMID- 27466966 TI - Differing cytotoxicity and bioavailability of selenite, methylselenocysteine, selenomethionine, selenosugar 1 and trimethylselenonium ion and their underlying metabolic transformations in human cells. AB - SCOPE: The trace element selenium (Se) is an integral component of our diet. However, its metabolism and toxicity following elevated uptake are not fully understood. Since the either adverse or beneficial health effects strongly depend on the ingested Se species, five low molecular weight species were investigated regarding their toxicological effects, cellular bioavailability and species specific metabolism in human cells. METHODS AND RESULTS: For the first time, the urinary metabolites methyl-2-acetamido-2-deoxy-1-seleno-beta-D-galactopyranoside (selenosugar 1) and trimethylselenonium ion (TMSe) were toxicologically characterised in comparison to the food relevant species methylselenocysteine (MeSeCys), selenomethionine (SeMet) and selenite in human urothelial, astrocytoma and hepatoma cells. In all cell lines selenosugar 1 and TMSe showed no cytotoxicity. Selenite, MeSeCys and SeMet exerted substantial cytotoxicity, which was strongest in the urothelial cells. There was no correlation between the potencies of the respective toxic effects and the measured cellular Se concentrations. Se speciation indicated that metabolism of the respective species is likely to affect cellular toxicity. CONCLUSION: Despite being taken up, selenosugar 1 and TMSe are non-cytotoxic to urothelial cells, most likely because they are not metabolically activated. The absent cytotoxicity of selenosugar 1 and TMSe up to supra-physiological concentrations, support their importance as metabolites for Se detoxification. PMID- 27466967 TI - Traumatic brain injury: It is all about definition. AB - BACKGROUND: TBI may be defined by different methods. Some may be most useful for immediate clinical purposes, however less optimal for epidemiologic research. Other methods, such as the Abbreviated Injury Score (AIS), may prove more beneficial for this task, if the cut-off-points for their categories are defined correctly. OBJECTIVE: To reveal the optimal cut-off-points for AIS in definition of severity of TBI in order to ensure uniformity between future studies of TBI. RESULTS: Mortality of patients with TBI AIS 3, 4 was 1.9% and 2.9% respectively, comparing with 31.1% among TBI AIS 5+. Predictive discrimination ability of the model with cut-off-points of 5+ for TBI AIS (in comparison with other cut-off points) was better. Patients with missing Glasgow Coma Scale (GCS) in the ED had an in-hospital mortality rate of 11.5%. In this group, 25% had critical TBI according to AIS. Normal GCS didn't indicate an absence of head injury, as, among patients with GCS 15 in the ED, 26% had serious/critical TBI injury. Moreover, 7% of patients with multiple injury and GCS 3-8 had another reason than head injury for unconsciousness. CONCLUSIONS: This study recommends the adoption of an AIS cut-off >= 5 as a valid definition of severe TBI in epidemiological studies, while AIS 3-4 may be defined as 'moderate' TBI and AIS 1-2 as 'mild'. PMID- 27466968 TI - Synthesis of Yolk-Shell Structured Fe3O4@void@CdS Nanoparticles: A General and Effective Structure Design for Photo-Fenton Reaction. AB - Yolk-shell (Y-S) structured Fe3O4@void@CdS nanoparticles (NPs) are synthesized through a one-pot coating-etching process with Fe3O4@SiO2 as the core, where the coating of an outer CdS shell from a chemical bath deposition (CBD) process is simultaneously accompanied by the gradual etching of an inner SiO2 shell. The as prepared Fe3O4@void@CdS NPs (ca. 200 nm) possess good monodispersity and a uniform CdS shell of ca.15 nm. This composite exhibits excellent photo-Fenton (ph F) activity toward the degradation of methylene blue (MB) in a wide pH working range of 4.5-11 under the visible light irradiation. A series of control experiments demonstrate the unique Y-S structure contributes to the enhanced activity, where the separation of hole-electron pair from CdS and the reduction of Fe(2+) from Fe(3+) are mutually promoted. The similar efficiency can also be achieved when the shell component changes to TiO2 or CeO2, demonstrating a general strategy for the design of robust ph-F agent. PMID- 27466969 TI - Long-term follow-up in dogs with idiopathic eosinophilic bronchopneumopathy treated with inhaled steroid therapy. AB - BACKGROUND: Treatment of canine idiopathic eosinophilic bronchopneumopathy mainly consists of long-term oral corticosteroid therapy. To avoid side effects, inhaled steroid therapy has been increasingly used but long-term clinical response and potential side effects are sparsely described. OBJECTIVES: Description of clinical response and side effects with long-term fluticasone in dogs with eosinophilic bronchopneumopathy. METHODS: Case series of dogs with eosinophilic bronchopneumopathy and treated with fluticasone monotherapy for at least 6 months. Clinical response and side effects assessed by physical examination, standardised questionnaire and ACTH (corticotropin) stimulation test. RESULTS: Eight dogs were treated for between 6 months and 5 years. Cough initially improved in all dogs; two dogs remained free of clinical signs, three were well controlled, but three showed severe relapse. Pituitary-adrenal axis inhibition occurred in two dogs treated with fluticasone monotherapy for more than 2 years; only one dog had clinical signs of iatrogenic hyperadrenocorticism. CLINICAL SIGNIFICANCE: Fluticasone monotherapy allows initial improvement or remission in the majority of dogs but long-term treatment fails to resolve the cough in some individuals. In addition, such therapy may induce pituitary-adrenal axis inhibition. Prospective larger and randomised studies including both fluticasone and orally-treated dogs are needed to define the optimal treatment. PMID- 27466970 TI - Health and Health Care Access of Rural Women Veterans: Findings From the National Survey of Women Veterans. AB - PURPOSE: Disparities in health and health care access between rural and urban Americans are well documented. There is evidence that these disparities are mirrored within the US veteran population. However, there are few studies assessing this issue among women veterans (WVs). METHODS: Using the 2008-2009 National Survey of Women Veterans, a population-based cross-sectional national telephone survey, we examined rural WVs' health and health care access compared to urban WVs. We measured health using the Medical Outcomes Study Short-Form (SF 12); access using measures of regular source of care (RSOC), health care utilization, and unmet needs; and barriers to getting needed care. FINDINGS: Rural WVs have significantly worse physical health functioning compared to urban WVs (mean physical component score of 43.6 for rural WVs versus 47.2 for urban WVs; P = .007). Rural WVs were more likely to have a VA RSOC (16.4% versus 10.6%; P = .009) and use VA health care (21.7% versus 12.9%; P < .001), and had fewer non-VA health care visits compared with urban WVs (mean 4.2 versus 5.9; P = .021). They had similar overall numbers of health care visits (mean 5.8 versus 7.1; P = .11 ). Access barriers were affordability for rural WVs and work release time for urban WVs. Rural WVs additionally reported that transportation was a major factor affecting health care decisions. CONCLUSIONS: Our findings demonstrate VA's crucial role in addressing disparities in health and health care access for rural WVs. As VA continues to strive to optimally meet the needs of all WVs, innovative care models need to account for their high health care needs and persistent barriers to care. PMID- 27466971 TI - Mitigating Chinese-Indian rhesus macaque (Macaca mulatta) hybridity at the California National Primate Research Center (CNPRC). AB - The effectiveness of abating hybridity in a rhesus breeding colony was evaluated. STR data from the 2006 to 2015 newborns were analyzed. Hybridity decreased over successive years. Birth cohorts retained high genetic variability without signs of inbreeding and differentiation. Hybridity was minimized without compromising overall genetic variability. PMID- 27466972 TI - Posttraumatic stress disorder after cancer diagnosis in adults: A meta-analysis. AB - BACKGROUND: Since the introduction of serious illness as a potential traumatic stressor in the fourth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), research on the prevalence and predictors of posttraumatic stress disorder (PTSD) after cancer diagnosis has proliferated. Studies have reported widely varying estimates of the number of people with PTSD after cancer. The aim of this review is to synthesize quantitative data from studies reporting the proportion of people with PTSD among groups of cancer survivors. METHODS: We undertook a diversified literature search strategy and identified 120 samples from 110 sources reporting a proportion of cancer survivors with PTSD. Of these, 11 studies, containing 12 samples, reported estimates of PTSD in cancer survivors compared to matched controls. RESULTS: A random effects meta-analysis estimated the odds ratio as 1.66 (95% confidence interval (CI): 1.09-2.53) for PTSD in cancer survivors compared to controls, although some of this apparent increase may have arisen from publication bias. Factors influencing the reported proportion of a postcancer sample with PTSD included measurement type (clinical interview vs. self-report instrument), type of cancer, type of treatment, geographic region, whether the term "posttraumatic stress" was in the title or abstract, prior trauma, age, and time since diagnosis. CONCLUSIONS: PTSD, diagnosed according to DSM-IV criteria, is more common in survivors of cancer than it is in the general population. Estimates of the occurrence of PTSD in patients with a history of cancer depend upon clinical and demographic factors, as well as upon study design. PMID- 27466973 TI - Effects of carbon dioxide on juveniles of the freshwater mussel (Lampsilis siliquoidea [Unionidae]). AB - Carbon dioxide (CO2 ) has shown promise as a tool to control movements of invasive Asian carp, but its effects on native freshwater biota have not been well studied. The authors evaluated lethal and sublethal responses of juvenile fatmucket (Lampsilis siliquoidea) mussels to CO2 at levels (43-269 mg/L, mean concentration) that bracket concentrations effective for deterring carp movement. The 28-d lethal concentration to 50% of the mussels was 87.0 mg/L (95% confidence interval [CI] 78.4-95.9) and at 16-d postexposure, 76.0 mg/L (95% CI 62.9-90.3). A proportional hazards regression model predicted that juveniles could not survive CO2 concentrations >160 mg/L for more than 2 wk or >100 mg/L CO2 for more than 30 d. Mean shell growth was significantly lower for mussels that survived CO2 treatments. Growth during the postexposure period did not differ among treatments, indicating recovery of the mussels. Also, CO2 caused shell pitting and erosion. Behavioral effects of CO2 included movement of mussels to the substrate surface and narcotization at the highest concentrations. Mussels in the 110 mg/L mean CO2 treatment had the most movements in the first 3 d of exposure. If CO2 is infused continuously as a fish deterrent, concentrations <76 mg/L are recommended to prevent juvenile mussel mortality and shell damage. Mussels may survive and recover from brief exposure to higher concentrations. Environ Toxicol Chem 2017;36:671-681. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 27466974 TI - Kinetics of bread crumb hydration as related to porous microstructure. AB - During oral processing and throughout the digestion process, hydration mechanisms have a key influence on the functional properties of food. This is the case with bread, for which hydration may affect the kinetics of starch hydrolysis as well as taste, aroma and texture perceptions. In this context, the aim of the present study is to understand how crumb porous micro-architecture impacts hydration kinetics. Four types of French baguettes were considered, varying in structure and/or compositions. An experimental set-up was developed for the real-time measurement of water uptake in crumb samples. Mathematical models were then fitted to extract quantitative parameters of use for the description and the understanding of experimental observations. Finally, bread crumb samples were analyzed before and after hydration through X-ray micro-computed tomography for the assessment of crumb micro-architectural properties. Distinct hydration behaviors were observed for the four types of bread. Higher hydration rates and capacities were reported for industrial baguettes (highest porosity) compared to denser semi-industrial, whole wheat and traditional baguettes. However, crumb porosity alone is not sufficient to predict hydration behavior. This study made it possible to point out the importance of capillary action in crumb hydration mechanisms, with a strong role of cells with diameters of 2 mm and below. The high density of these small cells generates high interconnection probabilities that may have an impact both on crumb hydration duration and capacity. As a consequence, accounting for microstructural features resulting from bread formulation may provide useful leverages for the control of functional properties. PMID- 27466975 TI - Teaching concepts in ultrasound-guided regional anesthesia. AB - PURPOSE OF REVIEW: Ultrasound-guided regional anesthesia is a challenging, complex skill and requires competence in teaching. The aim of this study was to review current literature on identification of education and learning of ultrasound-guided regional anesthesia and to summarize recent findings on teaching concepts. RECENT FINDINGS: Several teaching programs have been described and implemented into daily routine. Factors relevant to current practice are the knowledge of sonoanatomy, the acquisition of manual skills, the teaching ability, and the feedback given to the trainee. Simulation is a rapidly growing field and is supported by the development of phantoms. Needle visualization is one of the core competencies that is necessary for successful ultrasound-guided procedures and could be supported by technical developments in the future to improve teaching concepts. SUMMARY: Although a lot of key questions cannot be answered by the latest study results, some interesting findings were able to improve existing education programs. These results should be tailored to the individual need of a trainee, and the effects of improved training programs on patient safety and quality of care have to be investigated. The see one, do one, teach one approach is obsolete and should be abandoned. PMID- 27466976 TI - Measuring perioperative outcome. AB - PURPOSE OF REVIEW: Measuring clinically relevant and patient-centered perioperative outcomes provides the knowledge that enables clinicians to optimize their practice and guide shared decision-making, researchers to set a future agenda and policymakers to prioritize healthcare spending. RECENT FINDINGS: A large international collaboration is currently working to define a set of core outcomes for use in perioperative medicine research. Standardizing which outcomes are measured and how they are defined will help ensure that perioperative research output is meaningful and practice changing. The ability to pool nonheterogeneous data from multiple clinical trials will also improve ability of research to provide definitive answers and improve the cost-effectiveness of research spending. SUMMARY: Future clinical trials in perioperative medicine should utilize clearly defined, validated and standardized patient-centered outcome measures. PMID- 27466977 TI - Project on the Good Physician: A Proposal for a Moral Intuitionist Model of Virtuous Caring. AB - THEORY: In the Project on the Good Physician, the authors endeavor to advance medical character education by proposing and testing a moral intuitionist model of virtuous caring that may be applicable to physician training. This model proposes that the moral intuition to care/harm motivates students to extend care to those in need. HYPOTHESES: Hypothesis 1: Medical students will report stronger preferences for the intuition to Care/harm over other moral intuitions in clinical decision making. Hypothesis 2: Care/harm will have the strongest correlation with Generosity than the other moral intuitions. Hypothesis 3: There will be positive associations between Care/harm and the caring virtues (Mindfulness, Empathic Compassion, and Generosity). Hypotheses 4-5: The virtue of Empathic Compassion (or Mindfulness) will moderate the relationship between Care/harm and Generosity. Hypotheses 6-7: Neuroticism (or Burnout) will negatively moderate the association between Care/harm and Generosity (or between Empathic Compassion and Generosity). METHOD: The authors used data from a 2011 nationally representative sample of U.S. medical students (N = 500) to test the relationship between the moral intuition to Care/harm and physician caring virtues. Moral intuitions were assessed using the Moral Foundations Questionnaire, whereas physician virtues were measured using scales adapted from validated constructs. RESULTS: The authors found that students reported stronger preferences for the intuition to Care/harm over the four other moral intuitions. Each moral foundation was weakly but significantly correlated with Generosity, yet Care/harm had the strongest correlation among them. Neuroticism and Burnout did not weaken the link between Care/harm and the virtues. CONCLUSIONS: Data from the descriptive-correlational study reported here offer preliminary support for the construct validity of an educational model that targets the moral intuitions. The article concludes with a discussion of the implications of a moral intuitionist approach for medical character education and offers three hypotheses for future empirical research. PMID- 27466978 TI - Uncomfortably numb: new evidence for suppressed emotional reactivity in response to body-threats in those predisposed to sub-clinical dissociative experiences. AB - INTRODUCTION: Depersonalisation and derealisation disorders refer to feelings of detachment and dissociation from one's "self" or surroundings. A reduced sense of self (or "presence") and emotional "numbness" is thought to be mediated by aberrant emotional processing due to biases in self-referent multi-sensory integration. This emotional "numbing" is often accompanied by suppressed autonomic arousal to emotionally salient stimuli. METHODS: 118 participants completed the Cambridge Depersonalisation scale [Sierra, & Berrios, 2000. The Cambridge Depersonalisation Scale: A new instrument for the measurement of depersonalisation. Psychiatry Research, 93, 153-164)] as an index of dissociative anomalous experience. Participants took part in a novel "Implied Body-Threat Illusion" task; a pantomimed injection procedure conducted directly onto their real body (hand). Objective psychophysiological data were recorded via standardised threat-related skin conductance responses and finger temperature measures. RESULTS: Individuals predisposed to depersonalisation/derealisation revealed suppressed skin conductance responses towards the pantomimed body threat. Although the task revealed a reliable reduction in finger temperature as a fear response, this reduction was not reliably associated with measures of dissociative experience. CONCLUSIONS: The present findings significantly extend previous research by revealing emotional suppression via a more direct body threat task, even for sub-clinical groups. The findings are discussed within probabilistic and predictive coding frameworks of multi-sensory integration underlying a coherent sense of self. PMID- 27466979 TI - Chemical Characterization of Secondary Organic Aerosol from Oxidation of Isoprene Hydroxyhydroperoxides. AB - Atmospheric oxidation of isoprene under low-NOx conditions leads to the formation of isoprene hydroxyhydroperoxides (ISOPOOH). Subsequent oxidation of ISOPOOH largely produces isoprene epoxydiols (IEPOX), which are known secondary organic aerosol (SOA) precursors. Although SOA from IEPOX has been previously examined, systematic studies of SOA characterization through a non-IEPOX route from 1,2 ISOPOOH oxidation are lacking. In the present work, SOA formation from the oxidation of authentic 1,2-ISOPOOH under low-NOx conditions was systematically examined with varying aerosol compositions and relative humidity. High yields of highly oxidized compounds, including multifunctional organosulfates (OSs) and hydroperoxides, were chemically characterized in both laboratory-generated SOA and fine aerosol samples collected from the southeastern U.S. IEPOX-derived SOA constituents were observed in all experiments, but their concentrations were only enhanced in the presence of acidified sulfate aerosol, consistent with prior work. High-resolution aerosol mass spectrometry (HR-AMS) reveals that 1,2-ISOPOOH derived SOA formed through non-IEPOX routes exhibits a notable mass spectrum with a characteristic fragment ion at m/z 91. This laboratory-generated mass spectrum is strongly correlated with a factor recently resolved by positive matrix factorization (PMF) of aerosol mass spectrometer data collected in areas dominated by isoprene emissions, suggesting that the non-IEPOX pathway could contribute to ambient SOA measured in the Southeastern United States. PMID- 27466980 TI - Personalized and Conscientious Medical Imaging: To Image or Not to Image. PMID- 27466981 TI - Measurement of the Quality of Facial Lesion Reconstruction With Observer-Graded Affect Display. AB - Importance: The impact of facial reconstructive surgery on improving affect display for patients with facial lesions is incompletely understood. Objectives: To measure the impact of surgically reconstructing facial lesions on observer graded affect display. Design, Setting, and Participants: This was a prospective randomized controlled experiment at an academic tertiary referral center; 120 naive observers completed one of 4 surveys of 20 images of faces. Main Outcomes and Measures: A total of 80 different images of faces were used: 32 faces with lesions preoperatively and postoperatively, and 16 normal faces. The 32 lesion faces were categorized into 4 categories of lesion with 8 faces in each category: small peripheral, small central, large peripheral, and large central. Participants viewed 20 images of faces: 8 preoperative, 8 postoperative, and 4 normal. Observers rated faces by selecting all terms that applied from 8 affects of the Derogatis Affects Balance Scale (DABS), the Ekman scale's 6 basic emotions, and a neutral term. Latent class analysis and regression were used to determine number and characteristics of affect classes and significance of covariates: operation status, size, and location. Postoperative faces were compared with normal faces via bootstrap analysis to determine statistically significant differences in affect display. Analysis took place in August 2014 and was verified in December 2015. Results: A total of 120 observers rated 80 facial images via 4 surveys. The mean (SD) age of the observers was 32.2 (13.5) years (range, 18-72 years). Both scales collapsed into 3 latent classes: positive, neutral, and negative for normal faces and faces with lesions. Using the DABS, faces with lesions preoperatively were more likely to be in the negative affect class (small peripheral [SP]: mean, 0.384; 95 % CI, 0.325-0.444; small central [SC]: mean, 0.505; 95% CI, 0.433-0.577; large peripheral [LP]: mean, 0.583; 95% CI, 0.519-0.647; large central [LC]: mean, 0.475; 95% CI, 0.412-0.539) than normal faces (mean, 0.235; 95% CI, 0.190-0.281) or postoperatively (SP: mean, 0.141; 95% CI, 0.106-0.176; SC: mean, 0.207; 95% CI, 0.160-0.254; LP: mean, 0.272; 95% CI, 0.219-0.325; LC: mean, 0.189; 95% CI, 0.149-0.228) and less likely to be in the positive affect class (SP: mean, 0.213; 95% CI, 0.168-0.257; SC: mean, 0.204; 95% CI, 0.164-0.243; LP: 0.130; 95% CI, 0.096-0.164; LC: mean, 0.213; 95% CI, 0.172-0.254) than normal faces (mean, 0.459; 95% CI, 0.399-0.519) or postoperatively (SP: mean, 0.384; 95% CI, 0.323-0.445; SC: mean, 0.410; 95% CI, 0.350-0.469; LP, 0.298; 95% CI, 0.243-0.354; LC: mean, 0.415; 95% CI, 0.358 0.472). Postoperatively, faces with SP, SC, and LC lesions were restored to similar or improved levels of positive and negative affect as normal faces. Faces with LP lesions were improved in positive and negative affect from preoperatively, and restored to similar levels of negative affect as normal faces, but still had lower levels of positive affect compared with normal faces. Results using the Ekman scale were similar. Conclusions and Relevance: Facial reconstructive surgery was effective in restoring affect display in patients with facial lesions. This provides new data supporting the positive impact of reconstructive surgery on patients' quality of life. Level of Evidence: NA. PMID- 27466982 TI - Addressing cost of unwarranted medical care in the medical curriculum. AB - Within the past decade, there has been a significant increase in Australia's health expenditure, with a concurrent rise in overdiagnosis. Australia has introduced the Choosing Wisely campaign in a bid to identify and reduce commonly used investigations, treatments and procedures that add little benefit to patient care. By catalysing a discussion regarding evidence-based use of medications and medical testing, the Choosing Wisely campaign can minimise risk of harm to patients, as well as reduce expenditure. Internationally, several institutions are considering introducing training regarding cost-effective medical investigations into medical school curricula. The American College of Radiology has found positive results when conducting small-group teaching sessions with medical students regarding appropriate imaging modalities. These results are reflected in a US study that used an educational intervention to improve students' understanding of investigation costs. In addition, the Academy of Clinical Laboratory Physicians and Scientists has developed a proposed curriculum to further medical students' training in appropriate ordering of laboratory investigations. Australian medical educators must consider whether introducing evidence-based testing into Australian medical curricula should be part of a wider strategy to prevent unnecessary testing and health expenditure now and into the future. PMID- 27466983 TI - Visual Function, Social Position, and Health and Life Chances: The UK Biobank Study. AB - IMPORTANCE: The adverse impact of visual impairment and blindness and correlations with socioeconomic position are known. Understanding of the effect of the substantially more common near-normal vision (mild impairment) and associations with social position as well as health and life chances is limited. OBJECTIVE: To investigate the association of visual health (across the full acuity spectrum) with social determinants of general health and the association between visual health and health and social outcomes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional epidemiologic study was conducted using UK Biobank data from 6 regional centers in England and Wales. A total of 112 314 volunteers (aged 40-73 years) were assessed in June 2009 and July 2010. Data analysis was performed from May 20, 2013, to November 19, 2014. MAIN OUTCOMES AND MEASURES: Habitual (correction if prescribed) distance visual acuity was used to assign participants to 1 of 8 categories from bilateral normal visual acuity (logMAR, 0.2 or better; Snellen equivalent, 6/9.5 or better) to visual impairment or blindness (logMAR, 0.5 or worse; Snellen equivalent, 6/19 or worse) using World Health Organization and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision taxonomy. Relationships between vision, key social determinants and health and social outcomes (including the main factors that define an individual's life-the social, economic, educational, and employment opportunities and outcomes experienced by individuals during their life course) were examined using multivariable regression. RESULTS: Of the of 112 314 participants, 61 169 were female (54.5%); mean (SD) age was 56.8 (8.1) years. A total of 759 (0.7%) of the participants had visual impairment or blindness, and an additional 25 678 (22.9%) had reduced vision in 1 or both eyes. Key markers of social position were independently associated with vision in a gradient across acuity categories; in a gradient of increasing severity, all cause impaired visual function was associated with adverse social outcomes and impaired general and mental health. These factors, including having no educational qualifications (risk ratio [RR], 1.86 [95% CI, 1.69-2.04]), having a higher deprivation score (RR, 1.08 [95% CI, 1.07-1.09]), and being in a minority ethnic group (eg, Asian) (RR, 2.05 [95% CI, 1.83-2.30]), were independently associated with being in the midrange vision category (at legal threshold for driving). This level of vision was associated with an increased risk of being unemployed (RR, 1.55 [95% CI, 1.31-1.84]), having a lower-status job (RR, 1.24 [95% CI, 1.09-1.41]), living alone (RR, 1.24 [95% CI, 1.10-1.39]), and having mental health problems (RR, 1.12 [95% CI, 1.04-1.20]). CONCLUSIONS AND RELEVANCE: Impaired vision in adults is common, and even near-normal vision, potentially unrecognized without assessment, has a tangible influence on quality of life. Because inequalities in visual health by social position mirror other health domains, inclusion of vision in generic initiatives addressing health inequalities could address the existing significant burden of underrecognized and/or latent visual disability. Longitudinal investigations are needed to elucidate pathophysiologic pathways and target modifiable mechanisms. PMID- 27466984 TI - "Vehicular homicide", a new Italian offence: law provisions and comparison with some other European countries. AB - According to the most recent World Health Organization report, road accidents represent a very serious public health issue, claiming each year more than 1.2 million lives worldwide and being the leading cause of death among young people aged between 15 and 29 years. Up to now, the policies to reduce this issue are different, unbalanced and often inadequate not only in Italy, but also in the other European Countries. Specifically, the Italian Parliament has recently introduced a new law (n. 41 of March 23rd, 2016), making vehicular homicide together with road traffic injuries a criminal offense, both to be punished as a result of negligence. The measure came into force on March 25th, 2016. In this paper, the provisions of the above-reported law have been assessed, taking into account the modifications introduced in the Penal Code by this law and the impact it is having and will have on drivers on a day-to-day basis. Similarities and differences with legislative framework of some other European countries were also examined. Finally, some open questions to be solved are named as an open eye for future considerations. PMID- 27466985 TI - Expression of autophagy-related protein LC3B, p62, and cytoplasmic p53 in human retinoblastoma tissues. AB - OBJECTIVE: Dysfunction of autophagy has been implicated in development and progression of diverse human cancers. However, the exact role and mechanism of autophagy have not been fully understood in human cancers, especially in retinoblastoma (Rb). PATIENTS AND METHODS: We determined the autophagy activity in human Rb tissues by assessing the autophagy markers microtubule-associated protein light chain 3B (LC3) and p62 (SQSTM1) in formalin fixed and paraffin embedded human tissue by immunohistochemistry and then associated their expression with patient clinicopathological features. We further explored the correlation between the expression of LC3B and p62 and the expression of cytoplasmic p53, a newly identified autophagy suppressor, in Rb tissues. RESULTS: Our data revealed that the expression of LC3B and p62, was significantly associated with disease progression and tumor invasion of Rb. Furthermore, we also revealed that cytoplasmic expression of p53 was inversely associated with the behavior of tumor invasion. Finally, Spearman correlation analysis demonstrated that cytoplasmic expression of p53 was significantly and inversely correlated to the expression of both LC3B and p62. CONCLUSIONS: Autophagy might play an important role in human Rb progression, and LC3B and p62 may be useful predictors of disease progression in patients with Rb. PMID- 27466986 TI - Clinical efficacy of one stage posterior debridement joint graft fixation for lumbar vertebral fractures in spinal tuberculosis patients with compression. AB - OBJECTIVE: Spinal tuberculosis, though destructive, can be cured in many patients by chemotherapy, though surgery is often necessary for decompression and deformity correction. Our aim of this study was to investigate the clinical efficacy of posterior debridement joint graft fixation therapy for lumbar vertebral fractures in patients with spinal tuberculosis with a compression fracture. PATIENTS AND METHODS: We prospectively included 48 patients diagnosed with spinal tuberculosis and lumbar compression fracture in our hospital from June 2010 to June 2013. The patients were randomly divided into observation group (n = 27) and control group (n = 21). The patients in the control group underwent an anterior debridement joint bone fixation therapy, whereas, the patients in the observation group underwent one stage posterior debridement joint bone fixation therapy. The patients in the both groups were followed-up for about 2 years and the postoperative complications were recorded and analyzed. RESULTS: Incision length, operative time and blood loss in patients of the observation group were significantly lower than the control group (p < 0.05). The kyphosis Cobb's angle was found to be reduced in a time-dependent manner in both groups, however, patients in the observation group achieved a significant reduction than the control (p < 0.05). The ASIA grade of few patients in the observation group significantly (p < 0.05) improved to class E from D at the time of the end of follow-up. The patients under the class 'excellent' and 'good' of Kirkaldy-Willis criteria were significantly (p < 05) higher in the observation group (92.6%) than the control group (85.7%). Also, the patients in the Bridwell grade I and II in the observation group (88.9%) were significantly (p < 0.05) higher in comparison with control group (81%). The prevalence of postoperative complications was significantly lower in the observation group (18.5%) when compared with the control group (28.6%). CONCLUSIONS: Our results indicate that one-stage posterior debridement joint bone fixation therapy is an effective and safe procedure for patients with spinal tuberculosis and lumbar compression; this method is worthy of clinical application. PMID- 27466987 TI - Kinetic and kinematic analysis of gait pattern of 13 year old children with unilateral genu valgum. AB - OBJECTIVE: Genu valgum is a common knee deformity in growing children. It alters the alignment of the lower extremity, body posture, and gait pattern of the children. Understanding of kinematic and kinetic parameters of gait in genu valgum is essential for planning and implementing the intervention to correcting the valgus deformity. The aim of this paper is to investigate the kinetic and kinematic gait differences in children with genu valgum. PATIENTS AND METHODS: A 13-year old girl with left side unilateral genu valgum and a closely matched healthy counterpart were recruited to compare the kinetic and kinematic parameters of their gait performances, and they were captured by The VICON motion analysis system. RESULTS: The results showed that the child with genu valgum had lower left and right knee angles (39.6; 30.2) and higher ankle angles (35.6; 28.4) than the healthy subject (64.2, 60.2). In addition, the child with genu valgum had lower moments on the left side of the knee (42.1 mm.N) than unaffected right knee (73.9 mm.N). Also, the ground reaction force was (0.7 N) lower in the affected knee of the child with genu valgum than the normal subject. CONCLUSIONS: This study revealed that there were decreased knee and ankle moments and lower knee and ankle ground reaction forces in the affected genu valgum extremity when compared with the healthy counterpart. These changes might be responsible for the altering gait pattern of the child with genu valgum. PMID- 27466988 TI - Anaesthesiological strategies to improve outcome in liver transplantation recipients. AB - Graft and patients survival are the main goal of anesthesiological management in patients undergoing liver transplantation (LT). Even if anesthesiological practice sustained major developments over time, some evidence-based intraoperative strategies have not yet been widely applied. The aim of this review was to summarize intraoperative anesthesiological strategies which could have the potential to improve LT graft and/or recipient survival. Monitoring must be as accurate as possible in order to manage intraoperative hemodynamic changes. The pulmonary artery catheter still represents the more reliable method to monitor cardiac output by using the intermittent bolus thermodilution technique. Minimally invasive hemodynamic monitoring devices may be considered only in stable cirrhotic patients. Goal-directed fluid-therapy has not yet defined for LT, but it could have a role in optimizing the long-term sequelae associated with volume depletion or overload. The use of vasopressor may affect LT recipient's outcome, by preventing prolonged hypotension, decreasing blood products transfusion and counteracting hepato-renal syndrome. The use of viscoelastic point of care is also warranted in order to reduce blood products requirements. Decreasing mechanical ventilation time, when it is feasible, may considerably improve survival. Finally, monitoring the depth of anesthesia when integrated into an early extubation protocol might have a positive effect on graft function. PMID- 27466990 TI - The effect of sequential transcatheter arterial chemoembolization (TACE) and portal venous embolizations (PVE) vs. TACE or PVE alone on rabbit VX2 liver carcinoma and on liver regeneration. AB - OBJECTIVE: This study aimed to build VX2 liver tumor model in rabbits and to investigate the sequential transcatheter arterial chemoembolization (TACE) and portal vein embolizations (PVE) vs. TACE or PVE alone on rabbit VX2 liver carcinoma and liver regeneration. MATERIALS AND METHODS: VX2 liver tumor models were built in the rabbit. Rabbits carrying VX2 liver tumors were divided into four groups, including TACE+PVE, TACE, PVE and Sham groups respectively. Hematoxylin and eosin (HE) staining was performed to visualize the structures of tumor tissues. The volume data of caudal liver on day 3 and day 7 was measured by CT. Western blot analysis of active caspase-3 was performed to examine cell apoptosis. Immunohistochemical (IHC) staining of Ki-67 was performed to visualize hepatocyte regeneration. Serum IL-6, TNF-alpha, HGF and TGF-beta1 on 6th h, 24th h, day 3 and day 7 were measured by ELISA assay. RESULTS: The TACE+PVE group had the strongest suppressive effect on tumor growth and induced the highest level of tumor cell apoptosis. TACE+PVE can induce evident liver regeneration, which is reflected by the largest caudal liver volume increase and the highest ratio of Ki 67 positive cells. ELISA assay showed that during the first 7 days since day 0, TACE+PVE group had the highest level of HGF, IL-6 and TNF-alpha. CONCLUSIONS: TACE+PVE can significantly inhibit VX2 tumor growth, induce tumor cell apoptosis and liver regeneration, the effects of which are stronger than TACE or PVE alone. In the first 7 days since day 0, TACE+PVE group had the highest level of IL-6, TNF-alpha and HGF. This might be the reason why TACE+PVE induced the strongest liver regeneration. PMID- 27466989 TI - The expression of inhibitor of growth 4 is reduced in cervical cancer tissues. AB - OBJECTIVE: Inhibitor of growth 4 (ING4) is a candidate tumor suppressor which plays an important role in multiple processes including DNA repair, apoptosis, cell cycle control, tumor metastasis and angiogenesis. However, clinical data about the role of ING4 in the development and progression of cervical cancer are still limited. This study aimed to examine ING4 expression in cervical cancer and analyze its correlation with the progression of the malignancy. PATIENTS AND METHODS: RT-PCR, Western blot and immunohistochemistry analysis were performed to determine ING4 expression in 18 clinical specimens from cervical cancer patients. The correlation of ING4 expression with the clinical-pathological features of the patients was analyzed. Moreover, the correlation between ING4 and HPV E6/E7 transcription level in SiHa cells was analyzed. RESULTS: ING4 expression was decreased significantly at mRNA and protein levels in the tissues of cervical cancer compared with paracarcinoma tissues. Analysis of the subcellular localization of ING4 showed that ING4 expression was decreased in the nucleus of cervical cancer tissues. Ectopic expression of ING4 reduced the proliferation of SiHa cells, accompanied by decreased HPV E6/E7 transcription. CONCLUSIONS: ING4 expression is decreased in human cervical cancer tissues. Reconstitution of ING4 expression in cervical cancer cells is correlated with decreased HPV E6/E7 transcription. These data suggest that ING4 expression has diagnostic and prognostic significance for cervical cancer. PMID- 27466991 TI - Upregulation of miR-522 is associated with poor outcome of hepatocellular carcinoma. AB - OBJECTIVE: The aim of our study was to explore the clinicopathologic and prognostic significance of miR-522 expression in human hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The expression of miR-522 in 161 HCC tissues and adjacent non-tumor tissues was examined using quantitative real-time-PCR. The association of miR-522 expression with clinicopathological features and the prognosis of HCC patients were also analyzed. The overall survival (OS) was analyzed by log-rank test. Cox regression models were fitted to analyze the effect of prognostic factors on OS. RESULTS: The relative level of miR-522 was significantly higher in HCC tissues compared to the adjacent normal liver tissues. In addition, miR-522 upregulation more frequently occurred in HCC specimens with lymph node metastasis (p = 0.000), and tumor grade (p = 0.002). Moreover, the level of miR-522 expression was markedly correlated with the HCC patients' overall survival (p < 0.000). In the Cox proportional hazard model, the results showed that miR-522 overexpression was an independent prognostic factor for OS CONCLUSIONS: Overexpression of miR-522 functions as an unfavorable prognostic biomarker in HCC patients. PMID- 27466992 TI - GAS5 is downregulated in gastric cancer cells by promoter hypermethylation and regulates adriamycin sensitivity. AB - OBJECTIVE: GAS5 is a tumor suppressive lncRNA that is downregulated in gastric cancer. In this study, we firstly investigated whether epigenetic regulation contributed to GAS5 downregulation and further investigated the role of GAS5 in Adriamycin (ADM) sensitivity in gastric cancer cells. MATERIALS AND METHODS: GAS5 expression in 15 paired gastric cancer tissues and adjacent normal tissues and in gastric cancer cells were detected using qRT-PCR. Methylation-Specific PCR (MSP) was performed with the use of 5-AZA-dC to detect the methylation status of GAS5 promoter. SGC-7901 and SGC-7901/ADM cells were transfected for GAS5 overexpression and were further used for analysis of ADM sensitivity. RESULTS: GAS5 expression was significantly downregulated in gastric cancer tissues and cancer cell lines and was further downregulated in ADM resistant cells. SGC 7901/ADM cells had significantly higher level of promoter methylation than SGC 7901 cells. 5-AZA-dC treatment significantly reduced the level of methylation and restored GAS5 expression in both SGC-7901 and SGC-7901/ADM cells. SGC-7901/ADM cells with enforced GAS5 expression had significantly decreased the growth rate and increased the ratio of apoptosis after ADM treatment, suggesting that GAS5 can sensitize gastric cancer cells to ADM. CONCLUSIONS: GAS5 is significantly downregulated in gastric cancer cells and further decreased in ADM resistant cancer cells at least partly due to promoter hypermethylation. The enforced GAS5 expression can sensitize gastric cancer cells to ADM. PMID- 27466993 TI - Application value of stomach filling ultrasonography and intravenous contrast agents in diagnosis of advanced gastric cancer. AB - OBJECTIVE: To explore the imaging characteristics and clinical application value of gastric filling ultrasound combined with an intravenous contrast agent (double contrast ultrasonography, DCUS) in the diagnosis of advanced gastric carcinoma. PATIENTS AND METHODS: Totally 48 patients with advanced gastric carcinoma were confirmed by endoscopic biopsy and then administrated with DCUS and enhanced magnetic resonance examination before treatment. Retrospective analysis was conducted based on the characteristics of their ultrasonic images, and the results of diagnosis were compared and analyzed between the DCUS technology and the enhanced magnetic resonance examination. RESULTS: The DCUS technology showed rapid positive development in the arterial phase and rapid negative development in the portal phase at all foci of advanced gastric carcinomas. The initiation time in the arterial phase was (19.35+/-4.82) s, the peak value was (31.41+/ 4.23) dB, and the expurgation time was (41.71+/-7.03) s. The accuracy rates of the DCUS diagnosis and the enhanced magnetic resonance diagnosis of advanced gastric cancer were 87.5% and 66.7% respectively, with statistical differences (p<0.05). CONCLUSIONS: DCUS had specific fast-in and fast-out characteristics and high accuracy in diagnosing the advanced gastric cancer and so could be used as an effective means to the diagnosis of the disease in clinic. PMID- 27466994 TI - Study on 256-slice spiral CT bronchial artery imaging of common pathological types of central-type lung cancer. AB - OBJECTIVE: In this study, we analyzed features of 256-slice spiral CT bronchial artery imaging in common pathological types of central-type lung cancer to provide a reference for clinical diagnosis. PATIENTS AND METHODS: 74 patients diagnosed as central-type lung cancer were selected. They included 34 cases of squamous carcinoma and 40 cases of non-squamous carcinoma. 256-slice spiral CT bronchial artery imaging examination was performed for patients in the two groups. The 3D reconstruction technique was used in a stand-alone workstation, using different rotation axis to observe space anatomical details of the bronchial artery and to compare development ratio of the bronchial artery, artery diameter, diameter of tumor and developing condition of the pulmonary artery. RESULTS: It was found that left side, right side and both sides developing ratios of a bronchial artery in the squamous carcinoma group were higher than the other group. Moreover, the average diameter of the artery and diameter of the tumor was significantly higher than non-squamous carcinoma group. The occurrence rates of compression and narrowing on the pulmonary arterial branch at tumor side were significantly increased (p<0.05). CONCLUSIONS: There were different 256-slice spiral CT bronchial artery imaging results for different pathological types of central-type lung cancer, which has a certain reference value for clinical diagnosis. PMID- 27466995 TI - Role of radiation therapy in lung cancer management - a review. AB - Lung cancer is the leading cause of cancer death worldwide. Furthermore, more than 50% of lung cancer patients are found affected by distant metastases at the time of diagnosis. On the other hand, 20% of these patients are without regional spread and are good candidates for surgical operation. The remaining 30% represent an intermediate group whose tumors have metastasized up to regional lymph nodes. These remain 30% are the most appropriate candidates for radiation therapy. These patients are also called as "locally advanced lung cancer" or stage III lung cancer patients. In these patients strategy of combination therapy viz. radiation therapy in combination with chemotherapy is also tried by various groups in the recent past for this better management. However, long-term survival is still poor with a 5-year survival in 5-25% of patients. During the last decades, there has been a development in radiation strategies. The present review article focuses on different approaches to optimize radiotherapy for these patients. PMID- 27466996 TI - MiR-375 is epigenetically downregulated due to promoter methylation and modulates multi-drug resistance in breast cancer cells via targeting YBX1. AB - OBJECTIVE: In this study, we firstly verified how miR-375 is downregulated in breast cancer cells with multi-drug resistance (MDR) and further investigated the regulative effect of miR-375 on Ybx1 expression. MATERIALS AND METHODS: MiR-375 expression and promoter methylation status were studied by retrieving data in NCBI GEO Datasets, qRT-PCR and Methylation-Specific PCR (MSP) assay. Drug sensitivity of the cancer cells was assessed using MTT assay. The binding between miR-375 and YBX1 gene was predicted using Targetscan 7.1 and verified using western blot and dual luciferase assay. RESULTS: MiR-375 is significantly downregulated in both MCF-7/ADM and MCF-7/PTX cells than in MCF-7 cells. MCF 7/ADM and MCF-7/PTX cells had significantly higher level of promoter methylation than MCF-7 cells. 5-AZA-dC treatment significantly reduced the methylation in MCF 7/ADM and MCF-7/PTX cells and increased miR-375 expression. MiR-375 can directly target 3'UTR of YBX1 and thereby decrease its expression in MCF-7/ADM and MCF 7/PTX cells. Both miR-375 overexpression and YBX1 knockdown significantly decreased P-gp expression and increased chemosensitivity of the cancer cells. CONCLUSIONS: MiR-375 is downregulated in MCF-7/ADM and MCF-7/PTX cells, and its downregulation is a result of promoter methylation. MiR-375 can directly target 3'UTR of YBX1 and thereby decrease its expression, which might be an important mechanism of MDR in breast cancer cells. PMID- 27466997 TI - Soluble Klotho levels in diabetic nephropathy: relationship with arterial stiffness. AB - OBJECTIVE: In this cross-sectional study, we investigate the relationship between soluble Klotho (s-Klotho) levels, markers of bone mineral metabolism and arterial stiffness in 109 diabetic nephropathy patients (median age 61.00+/- 9.77 years) and 32 healthy controls (median age 49.23 +/- 7.32 years). PATIENTS AND METHODS: Blood samples were collected to measure the levels of s-Klotho, and FGF23, serum creatinine, Calcium (Ca), Phosphorus (P), 25-hydroxyvitamin D3 (25hD) and parathyroid hormone (PTH). Pulse wave velocity (PWV) and blood pressure were also measured using a combined monitor. RESULTS: s-Klotho, FGF23 and PTH levels were significantly higher and 25hD was significantly lower in the patients than in controls (p < 0.001). Systolic blood pressure, pulse pressure and PWV were also significantly higher in the patients (p < 0.001). s-Klotho, FGF23 and 25hD levels significantly varied between sub-groups according to CKD stages, defined according to the CKD epidemiology collaboration equation. A strong positive correlation was found between s-Klotho and FGF23 (r = 0.768, p = 0.001) levels, but not with other bone mineral metabolism, blood pressure or arterial stiffness parameters. Creatinine levels significantly differed (p = 0.009) between three s Klotho-level sub-groups, with the high creatinine levels in the sub-group with the lowest s-Klotho levels and estimated glomerular filtration rate (eGFR). CONCLUSIONS: There was no correlation between eGFR and s-Klotho levels. Arterial stiffness increased in CKD but was not related to s-Klotho or FGF23 levels. Among all parameters, FGF23 levels had the greatest effect on s-Klotho levels. PMID- 27466998 TI - Racial differences of endothelial function and plasma endothelin 1 level in preclinical Tibetan and Han male population. AB - OBJECTIVE: The differences in endothelial function between Tibetan and Han nationality population have not been fully investigated. The aim of this work is to investigate the differences in endothelial function and plasma endothelin 1 (ET-1) concentration between Tibetan and Han male population. PATIENTS AND METHODS: Totally 272 Tibetan male subjects aged 42.9 +/- 9.4 years were enrolled in this study to stand for Tibetan population. All of them were native residents in Lhasa City. And 580 Qinghai-Tibet Railway constructors with Han nationality aged 41.8 +/- 11.1 years were enrolled in this study to stand for Han nationality population. All of them were male subjects and lived in Lhasa City for at least 1 year. All subjects lived in the same high-altitude area (the altitude of Lhasa is 3658 m). Height, weight, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure were evaluated. Body mass index (BMI) was calculated. Brachial artery flow-mediated dilation (FMD) was measured in the fasting state using high-resolution B-mode ultrasound. Computer-assisted analysis software was used to calculate brachial artery diameters. Venous blood was sampled for the measurement of total cholesterol (CH), triglyceride (TG), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and HbA1c. Plasma ET-1 was quantitated using a commercially available ELISA kits. RESULTS: Totally 272 Tibetan subjects and 580 Han nationality subjects were enrolled in this study. BMI and waist-hip ratio in Tibetan subjects were much higher than those in Han subjects (p < 0.01). LDL cholesterol level and plasma ET 1 concentration in Tibetan subjects were significantly higher than Han subjects (p < 0.01). The baseline brachial artery diameter in Tibetan group was much higher than that of Han group (p < 0.01). The absolute and percent changes in brachial artery diameter were lower in Tibetan population compared with Han population (p < 0.01). The linear regression analysis showed that LDL cholesterol, and plasma ET-1 were correlated with FMD (p < 0.01). CONCLUSIONS: Endothelial function and plasma ET-1 concentration were different between Tibetan and Han male populations. PMID- 27466999 TI - The relation of calcium-phosphorus metabolism-related indexes with cardiac damages. AB - OBJECTIVE: To observe and analyze the relation of calcium-phosphorus metabolism related indexes with cardiac damage-related indexes in patients with chronic kidney disease (CKD) and to explore the roles of calcic and phosphor metabolization in cardiac damage and provide references for prevention of cardiovascular events in CKD patients. PATIENTS AND METHODS: A total of 98 inpatients, from Urology Department, who were not undergoing dialysis treatment and diagnosed with stages 3, 4, and 5 CKD according to K/DOQI guide were recruited. We measured the calcium-phosphorus metabolism-related indexes (including serum calcium (Ca), the serum phosphate (Pi), the intact parathyroid hormone (iPTH), the beta-collagen-specific sequences (beta-CTX), the total N terminal propeptide of type I procollagen (TPINP), the N-terminal-mid fragment of osteocalcin (N-MID), the cardiac damage-related indexes (including left ventricular end diastolic diameter (LVEDD), the interventricular septal thickness (IVST), the left ventricular posterior wall thickness (LVPWT), the ejection fraction (EF), the blood flow velocity at mitral diastolic late phase (A) and mitral diastolic early phase (E) via echocardiography. Then, we conducted a correlation analysis employing these two types of indexes. RESULTS: We found an escalating trend in the level of calcium-phosphorus metabolism-related indexes from stage 3 to stage 5 CKD. The difference between stage 3 and 5 is statistically significant (p < 0.05) while that between stage 3 and 4 is not (p > 0.05). Among 98 CKD patients, the myocardial hypertrophy accounted for 35.9% (n = 36), the diastolic dysfunction accounted for 72.1% (n = 70), and systolic dysfunction accounted for 27.5% (n = 27). Levels of beta-CTX, N-MID, TP1NP, Pi, and iPTH are positively associated with the myocardial hypertrophy and yet negatively associated with cardiac systolic (EF) and diastolic function (A/E value). CONCLUSIONS: Calcium-phosphorus metabolism disorder in the context of kidney dysfunction may contribute to the damages of cardiac structure and functions. PMID- 27467000 TI - Two-dimensional speckle tracking echocardiography is useful in early detection of left ventricular impairment in patients with Crohn's disease. AB - OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract. Cardiac involvement is considered very rare. Pericarditis, myocarditis, endocarditis, cardiomyopathy and complete heart block are some of the cardiac extraintestinal manifestations of CD. The aim of this study was to explore the left ventricular (LV) functions with two dimensional (2D) speckle tracking echocardiography (STE) in patients with CD with normal cardiac functions. PATIENTS AND METHODS: We enrolled 50 consecutive patients with CD and 50 age and sex matched healthy controls. All patients underwent a transthoracic echocardiogram with evaluation of LV functions with 2D STE. RESULTS: Baseline characteristics were similar between patients with CD (24 male, mean age: 41.0 +/- 13.9 years) and controls (24 male, mean age: 40.1 +/- 7.3 years). Although conventional echocardiographic parameters were similar between two groups, global longitudinal strain was significantly lower in patients with CD compared to controls (19.6 +/- 3.3 versus 21.2 +/- 2.9, p = 0.014). Correlation analysis revealed that Crohn's Disease Activity Index is inversely correlated with LV global longitudinal strain (r = -0.703, p < 0.001) in patients with CD. We also evaluated inflammatory parameters such as CRP, erythrocyte sedimentation rate, and complete blood counts in patients with CD. Correlation analysis revealed that only platelet value is weakly correlated with Crohn's Disease Activity Index (r = 0.311, p = 0.083). CONCLUSIONS: Crohn's disease is associated with impairment in LV global longitudinal myocardial function. Crohn's Disease Activity Index is also strongly correlated with LV global longitudinal strain. 2D-STE may be an useful method for early detection of LV impairment in patients with CD. PMID- 27467001 TI - MEFV gene variation R202Q is associated with metabolic syndrome. AB - OBJECTIVE: MEFV (Mediterranean fever) gene encoding pyrin regulates inflammatory responses. It has been shown that MEFV gene variations are associated with higher acute phase responses and altered course in the different inflammatory diseases. MEFV gene variations may affect the course of metabolic syndrome components. PATIENTS AND METHODS: This study included 50 patients with metabolic syndrome and 50 unrelated healthy controls. Genomic DNAs were isolated from patients and healthy controls with standard methods and analysis of exon 2 and 10 of MEFV gene was performed by using Sanger sequencing method. RESULTS: The MEFV gene variations were detected in 21 patients with metabolic syndrome (42%) and 12 healthy controls (24%) (p=0.55). The frequency of MEFV gene variations with high penetrance (i.e. M694V, M680I, V726A) was similar between patients and healthy controls (p>0.05). We found that R202Q was more frequent in the patient group (n=11 [22%] vs. n=3 [6%]) and associated with metabolic syndrome (p: 0.021; OR: 4.42; CI95%: 1.15-16.97). When patients with and without MEFV gene variations were compared, no significant difference was found in laboratory and clinical parameters. CONCLUSIONS: To best of our knowledge, this is the first study indicating an association between MeS and R202Q mutation of MEFV gene. Familial Mediterranean fever (FMF) related MEFV gene variations may contribute to the pathogenesis of metabolic syndrome. PMID- 27467002 TI - The prebiotic inulin as a functional food - a review. AB - The newborn digestive tract is rapidly colonized right after birth. The type of feeding could significantly influence this colonization process. Infant formulas like inulin try to mimic the bifidogenic effects of human milk by addition of prebiotics. Moreover, studies in the recent past have evidenced important effects of inulin during early infant life. The present review article will highlight recent updates about the use of inulin in the pediatric clinical setting. PMID- 27467003 TI - Black hood assisted colonoscopy for detection of colorectal polyps: a prospective randomized controlled study. AB - OBJECTIVE: Colonoscopy is considered as a standard method for detecting various kinds of colorectal polyps. However, conventional colonoscopy (CC) still has chances to miss some lesions. Some scholars have already reported that transparent hood assisted colonoscopy (THAC) can improve the detection rate of colorectal polyps. However, the efficacy of detection of colorectal polyps with black hood assisted colonoscopy (BHAC) is still unclear. In this study, BHAC was compared with CC for evaluating the efficacy of detection of colorectal polyps. PATIENTS AND METHODS: Between Sep 2014 and Apr 2015, 542 patients underwent CC and meanwhile 534 patients underwent BHAC were enrolled into this prospective randomized controlled study. Comparison of baseline characteristics, cecal intubation time, withdrawal time, total number of detected polyps, detection rate of polyps, location, size, morphology and pathological diagnosis of polyps between these two groups was performed. RESULTS: Cecal intubation time was significantly shorter in BHAC group than in CC group (6.31 +/- 3.51 min vs. 7.05 +/- 4.15 min, p = 0.002). The total number of detected polyps and detection rate of polyps were significantly higher in BHAC group than in CC group (349/65.36% vs. 264/48.71%, p = 0.004). CONCLUSIONS: Compared with CC, BHAC could significantly improve the detection rate of colorectal polyps, and cecal intubation time was significantly reduced by BHAC. PMID- 27467004 TI - Budd-Chiari syndrome: current perspectives and controversies. AB - Budd-Chiari syndrome (BCS) is a rare disorder caused by hepatic venous outflow obstruction with a wide spectrum of etiologies. Clinical manifestations are so heterogeneous that the diagnosis should be considered in any patients with acute or chronic liver disease. Therapeutic modalities for BCS have improved dramatically during the last few years. The concept of a step-wise treatment strategy has been established, including anticoagulation, thrombolysis, percutaneous recanalization, transjugular intrahepatic portosystemic shunt, surgery and liver transplantation. However, this strategy is primarily based on experts' opinions and retrospective case series, rather than prospective randomized trials. Furthermore, an earlier use of TIPS has been proposed in selected cases because of a relatively high mortality from BCS patients who underwent medical therapy alone. Herein, we review the advances in the classification, etiology, clinical presentation, diagnosis and treatment of BCS. PMID- 27467005 TI - Induction of cell cycle arrest and apoptosis by grape seed procyanidin extract in human bladder cancer BIU87 cells. AB - OBJECTIVE: The aim of this study was to evaluate the effects of grape seed procyanidin extract (GSPE) on cell proliferation and apoptosis in human bladder cancer BIU87 cells and to investigate its molecular mechanism in vitro. MATERIALS AND METHODS: BIU87 cells were treated with different concentrations of GSPE for 24h in vitro while an untreated group was taken as control. MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, Hoechst 33258 staining, flow cytometry, RT-PCR and Western blot were used to detect the anti proliferation and apoptotic induction effects of GSPE on BIU87 cells. RESULTS: It was found that GSPE inhibited the cell growth through cell cycle arrest at G1 phase and induced cell apoptosis in BIU87 cells in a dose-dependent manner. Semi quantitated RT-PCR and Western blot analyses indicated that GSPE increased caspase-3 (p<0.01), but decreased the expression of cyclinD1, CDK4 and survivin (p<0.01). CONCLUSIONS: GSPE inhibits cell proliferation by inducing cell cycle arrest and apoptosis in BIU87 cells, and the effect may be related with its down regulation of cyclinD1, CDK4 and survivin. PMID- 27467006 TI - Genistein-induced apoptosis is mediated by endoplasmic reticulum stress in cervical cancer cells. AB - OBJECTIVE: Genistein, a major isoflavone found in soybeans, exhibits anti-cancer activity. Endoplasmic reticulum (ER) stress is known to be implicated in apoptosis induced by anti-cancer drugs. This study aimed to characterize the role of ER stress in genistein-induced apoptosis in cervical cancer. MATERIALS AND METHODS: HeLa cells were treated with genistein or/and 4-phenylbutyric acid. Cell viability and apoptosis were evaluated by MTT assay and flow cytometry. Protein levels were detected by Western blot analysis. RESULTS: Genistein suppressed the viability of HeLa cells in a dose dependent manner. In addition, genistein caused apoptosis in HeLa cells in a dose dependent manner. Genistein triggered ER stress in HeLa cells, as indicated by the upregulation of glucose-regulated protein 78 (GRP78) and CHOP expression. Furthermore, ER stress inhibitor 4-phenylbutyric acid alleviated genistein-induced apoptosis and ER stress in HeLa cells. CONCLUSIONS: Our results suggest that ER stress contributes to genistein-induced apoptosis in cervical cancer cells, and genistein is a promising agent for cervical cancer therapy. PMID- 27467007 TI - Insulin in combination with selenium inhibits HG/Pal-induced cardiomyocyte apoptosis by Cbl-b regulating p38MAPK/CBP/Ku70 pathway. AB - OBJECTIVE: In this study, we investigated whether insulin and selenium in combination (In/Se) suppresses cardiomyocyte apoptosis and whether this protection is mediated by Cbl-b regulating p38MAPK/CBP/Ku70 pathway. MATERIALS AND METHODS: Firstly, H9c2 cardiomyocytes were treatment with high glucose (25 mmol/L) and palmitate (600 MUmol/L) (HG/Pal). Next, H9c2 cardiomyocytes were treatment with HG/Pal+In/Se (10 nmol/L Insulin in combination with 10 nmol/L selenium). Finally, cells were treated with siRNA against Cbl-b, followed by HG/Pal and HG/Pal+In/Se treatment. Then, Cell apoptosis was observed by flow cytometry (FCM). The levels of Cbl-b, p-p38MAPK, CBP and Bax were examined by Western blotting. The acetylated Ku70 was detected by immunoprecipitation. RESULTS: Insulin and selenium in combination reduced cell apoptosis, up-regulated Cbl-b expression, down-regulated p38MAPK, CBP and acetylated Ku70 expressions and prevented Bax translocation, whereas Cbl-b knockdown strongly suppressed In/Se induced these effects in HG/Pal-treated cardiomyocytes. CONCLUSIONS: Insulin and selenium synergistically suppressed cardiomyocyte apoptosis by Cbl-b regulating p38MAPK/CBP/Ku70 pathway. PMID- 27467008 TI - Fasudil alleviated hypoxia-induced pulmonary hypertension by stabilizing the expression of angiotensin-(1-7) in rats. AB - OBJECTIVE: The aim of this study was to investigate the mechanism of fasudil alleviating hypoxic pulmonary hypertension (HPH). MATERIALS AND METHODS: A total of 50 Sprague-Dawley rats were randomized into control, model and fasudil intervention groups. Hemodynamic and pulmonary pathomorphology data were collected using Powerlab system and hematoxylin and eosin staining. The protein expression of Ang-(1-7) was detected by immunohistochemical staining and ELISA assay in vivo or in vitro. Western blot was utilized to observe the protein expression of ACE2 and HIF-1alpha in vitro. RESULTS: Fasudil treatment repressed the elevation of RVSP, RV/(LV+S), attenuated the pulmonary vascular structure remodeling (PVSR) of pulmonary arterioles induced by chronic hypoxia, and stabilized the expression of Ang-(1-7) in vivo and in vitro. In addition, experiments consistently indicated an escalation of ACE2 and a reduction of HIF 1alpha. CONCLUSIONS: Our results suggest that fasudil can effectively attenuate PVSR and PH. The underlying mechanism may partially up-regulated Ang-(1-7) and ACE2, and lessened HIF-1alpha. PMID- 27467009 TI - Combination high-dose omega-3 fatty acids and high-dose cholecalciferol in new onset type 1 diabetes: a potential role in preservation of beta-cell mass. AB - Several studies have evaluated the role of inflammation in type 1 diabetes (T1D). The safety profile and anti-inflammatory properties of high dose omega-3 fatty acids combined with Vitamin D supplementation make this therapy a possible candidate for T1D intervention trials. Herein, we describe the case of a 14-year old boy with new onset T1D treated with high dose Omega-3 and vitamin D3. By 12 months, peak C-peptide increased to 0.55 nmol/L (1.66 ng/mL) corresponding to a 20% increment from baseline and AUC C-peptide was slightly higher compared to 9 months (0.33 vs. 0.30 nmol/L/min) although remaining slightly lower than baseline. Combination high-dose Omega-3 fatty acids and high-dose vitamin D3 therapy was well tolerated and may have beneficial effects on beta-cell function. Randomized controlled trials could be of assistance to determine whether this therapy may result in the preservation of beta-cell function in patients with new onset T1D. PMID- 27467010 TI - Mitochondria and neurodegenerative diseases: the promising role of nanotechnology in targeted drug delivery. AB - INTRODUCTION: Neurodegenerative diseases (NDs) represent a group of different clinical entities that, despite the specific primary etiologies, share a common signature in terms of a general mitochondrial dysfunction with consequent oxidative stress accumulation. As these two events occur early during neurodegenerative process, they could be considered ideal therapeutic targets. Areas covered: This review describes the nanotechnologies explored for the specific targeted delivery of drugs, in order to precisely direct molecules into the intended site, where they can practice their therapeutic effects. Expert opinion: Conventional drug delivery systems cannot provide adequate restoration and connection patterns that are essential for a functional recovery in NDs. Since orally delivered antioxidants are easily destroyed by acids and enzymes, only a small portion of consumed antioxidants gets absorbed, leading to low bioavailability and low concentration at the target site. In this scenario, the identification of new proenergetic drugs, in combination with the development of methods for selectively delivering biologically active molecules into mitochondria, will potentially launch new therapeutic approaches for the treatment of NDs, where energetic imbalance plays a central role. PMID- 27467011 TI - Bandgap Energy of Wurtzite InAs Nanowires. AB - InAs nanowires (NWs) have been grown on semi-insulating InAs (111)B substrates by metal-organic chemical vapor deposition catalyzed by 50, 100, and 150 nm-sized Au particles. The pure wurtzite (WZ) phase of these NWs has been attested by high resolution transmission electron microscopy and selected area diffraction pattern measurements. Low temperature photoluminescence measurements have provided unambiguous and robust evidence of a well resolved, isolated peak at 0.477 eV, namely 59 meV higher than the band gap of ZB InAs. The WZ nature of this energy band has been demonstrated by high values of the polarization degree, measured in ensembles of NWs both as-grown and mechanically transferred onto Si and GaAs substrates, in agreement with the polarization selection rules for WZ crystals. The value of 0.477 eV found here for the bandgap energy of WZ InAs agrees well with theoretical calculations. PMID- 27467012 TI - Survey of Sedation and Analgesia Practice Among Canadian Pediatric Critical Care Physicians. AB - BACKGROUND: Despite the fact that almost all critically ill children experience some degree of pain or anxiety, there is a lack of high-quality evidence to inform preferred approaches to sedation, analgesia, and comfort measures in this environment. We conducted this survey to better understand current comfort and sedation practices among Canadian pediatric intensivists. METHODS: The survey was conducted after a literature review and initial focus groups. The survey was then pretested and validated. The final survey was distributed by email to 134 intensivists from 17 PICUs across Canada using the Research Electronic Data Capture system. RESULTS: The response rate was 73% (98/134). The most commonly used sedation scores are Face, Legs, Activity, Cry, and Consolability (42%) and COMFORT (41%). Withdrawal scores are commonly used (65%). In contrast, delirium scores are used by only 16% of the respondents. Only 36% of respondents have routinely used sedation protocols. The majority (66%) do not use noise reduction methods, whereas only 23% of respondents have a protocol to promote day/night cycles. Comfort measures including music, swaddling, soother, television, and sucrose solutions are frequently used. The drugs most commonly used to provide analgesia are morphine and acetaminophen. Midazolam and chloral hydrate were the most frequent sedatives. CONCLUSION: Our survey demonstrates great variation in practice in the management of pain and anxiety in Canadian PICUs. Standardized strategies for sedation, delirium and withdrawal, and sleep promotion are lacking. There is a need for research in this field and the development of evidence-based, pediatric sedation and analgesia guidelines. PMID- 27467013 TI - Nanostructure of Poly(N-isopropylacrylamide) Brush at the Air/Water Interface and Its Responsivity to Temperature and Salt. AB - Nanostructure and transition of the poly(N-isopropylacrylamide (PNIPAm) brush at the air/water interface were investigated by pi-A isotherm and X-ray reflectivity, and an interesting behavior was observed with the change in temperature and salt. The polymer monolayer of poly(n-butyl acrylate)(PnBA)-b PNIPAm on the water surface showed a transition between carpet-only/carpet+brush structures as a function of brush density, which was controlled by compression/expansion, as was the case for ionic brush systems. The brush stretching factor was about 50%, which was slightly less than that for a strongly ionic brush. The number of water molecules inside the brush layer was estimated to be 11-13 per repeating unit of PNIPAm chain. This value is very close to the number of hydrated water molecules reported, which means that all the water molecules inside the brush layer were hydrated water. With elevating temperature, the PNIPAm brush shrank, and the number of water molecules in the brush layer was reduced to 3. These observations certainly indicated a dehydration process. Interestingly, a part of the PNIAPm chain formed a "hydrophobic PNIPAm layer" on the carpet layer under the PnBA hydrophobic layer. A similar transition was observed also by the addition of salt to the water subphase. Although the formation of "hydrophobic PNIPAm layer" was not observed in this case, shrinking of the brush was observed with increasing salt concentration, and finally it became a carpet-only structure, which contained no water molecules. This salt effect was found to be ion specific, and its effectiveness was in the order of F( ) > Cl(-) > Br(-), which is in agreement with the Hofmeister series. PMID- 27467014 TI - Stable isotope biomarker breath tests for human metabolic and infectious diseases: a review of recent patent literature. AB - INTRODUCTION: Stable isotope breath tests can rapidly and quantitatively report metabolic phenotypes and disease in both humans and microbes in situ. The labelled compound is administered and acted upon by human or microbial metabolism, producing a labelled gas that is detected in exhaled breath. Areas covered: This review details the unique advantages (and disadvantages) of phenotypic stable isotope based breath tests. A review of recent US patent applications and prosecutions since 2010 is conducted. Finally, current clinical trials, product pipelines and approved products are discussed. Expert opinion: Stable isotope breath tests offer new approaches for rapid and minimally invasive detection and study of metabolic phenotypes, both human and microbial. The patent literature has developed considerably in the last 6 years, with over 30 patent applications made. Rates of issuance remain high, although rejections citing 35 U.S.C. S101(subject matter eligibility), S102 (novelty), S103 (obviousness) and S112 (description, enablement and best mode) have occurred. The prior art is significantly greater for human metabolism than microbial, and may drive differing rates of future issuance. These biomarker and diagnostic tools can enable optimization of drug doses, diagnosis of metabolic disease and its progression, and detection of infectious disease and optimize its treatment. PMID- 27467015 TI - Sulforaphene-Carboplatin Combination Synergistically Enhances Apoptosis by Disruption of Mitochondrial Membrane Potential and Cell Cycle Arrest in Human Non Small Cell Lung Carcinoma. AB - Worldwide non-small cell lung cancer (NSCLC) causes substantial morbidity and mortality among human populations. Due to the severe side effects and low survival rate of patients with the conventional drugs, implementation of new combination therapies is much needed. The aim of this study was to evaluate the efficacy of a combination therapy with a conventional drug and a natural medicine. We compared the combination of chemotherapy drug carboplatin and the radish-derived isothiocyanate compound sulforaphene, which synergistically induces higher apoptosis and growth inhibition in A549, to the drug alone in human NSCLC cells. We found that this combination group significantly induced higher depolarization of mitochondrial membrane potential (MMP) and intracellular reactive oxygen species generation than the single drug dose, followed by cell cycle arrest at the G0/G1 phase after 24 h of incubation. In addition to that, the Western blot assays showed that combination treatment inhibited the expression of Bcl-2 and successively upregulated the expression of Bax, cytochrome C, apoptosis-inducing factor, caspase-9 and -3, and cleaved poly ADP ribose polymerase. It also modulated the expression of PI3K, p-extracellular signal-regulated kinase (1/2), and p-c-Jun N-terminal kinase indicating the involvement of antiproliferative properties. Further pretreatment with pan caspase inhibitor Z-VAD-fmk was carried out to confirm the effect of caspases in the combination therapy-induced apoptosis. To summarize, this is the first report that sulforaphene-carboplatin combination treatment synergistically promotes enhanced apoptosis and antiproliferative effect over single drug treatment against A549, human NSCLC cells through caspase activation, MMP disruption, and cell cycle arrest. This study demonstrates that the duel character of this combination therapy may be an effective replacement for conventional therapy alone against NSCLC. PMID- 27467016 TI - Nation-wide measure of variability in HCMV, EBV and BKV DNA quantification among centers involved in monitoring transplanted patients. AB - BACKGROUND: Inter-laboratory variability in quantifying pathogens involved in viral disease following transplantation may have a great impact on patient care, especially when pre-emptive strategies are used for prevention. OBJECTIVES: The aim of this study was to analyze the variability in quantifying CMV, EBV and BKV DNA from 15 virology laboratories of the Italian Infections in Transplant Working Group (GLaIT) involved in monitoring transplanted patients. STUDY DESIGN: Panels from international Quality Control programs for Molecular Diagnostics (QCMD, year 2012), specific for the detection of CMV in plasma, CMV in whole blood (WB), EBV and BKV were used. Intra- and inter-laboratory variability, as well as, deviations from QCMD consensus values were measured. RESULTS: 100% specificity was obtained with all panels. A sensitivity of 100% was achieved for EBV and BKV evaluations. Three CMV samples, with concentrations below 3 log10 copies/ml, were not detected by a few centers. Mean intra-laboratory variability (% CV) was 1.6 for CMV plasma and 3.0 for CMV WB. Mean inter-laboratory variability (% CV) was below 15% for all of the tested panels. Inter-laboratory variability was higher for CMV in WB with respect to the CMV plasma panel (3.0 vs 1.6% CV). The percentiles 87.7%, 58.6%, 89.6% and 74.7% fell within+/-0.5 log10 difference of the consensus values for CMV plasma, CMV WB, EBV and BKV panels, respectively. CONCLUSIONS: An acceptable intra- and inter-laboratory variability, in comparison with international standards was observed in this study. However, further harmonization in viral genome quantification is a reasonable goal for the future. PMID- 27467017 TI - Incidence and seroprevalence of hepatitis E virus infection in pregnant women infected with hepatitis B virus and antibody placental transfer in infants. AB - BACKGROUND: Hepatitis E has poor outcomes in pregnant women. Superinfection of hepatitis E virus (HEV) in patients infected with hepatitis B virus (HBV) may worsen liver disease. OBJECTIVES: To estimate the incidence and seroprevalence of HEV infection among HBV-infected pregnant women, to investigate the transplacental transfer of maternal anti-HEV IgG, and to compare the maternal and neonatal outcomes in anti-HEV positive and negative pregnant women. STUDY DESIGN: Totally 391 HBV-infected pregnant women were recruited from April 2012 to October 2014. Paired mothers and infants were followed up at an average 9.8 months postpartum. Anti-HEV IgG and IgM were tested by ELISA. RESULTS: Of the pregnant women, none was anti-HEV IgM positive and 42 (10.7%) were IgG positive. At the follow-up, 3 seronegative women converted to anti-HEV IgG positive, with an estimated incidence of 17 per 1000 person-years. No significant differences of gestational age, preterm birth rate, Apgar score and birthweight were observed between newborns of anti-HEV IgG positive and negative mothers. Of the 42 neonates born to anti-HEV IgG positive mothers, 38 (90.5%) had anti-HEV IgG in their cord blood. The neonatal and maternal anti-HEV IgG levels were positively correlated (r=0.827, p<0.05). All infants were negative for both anti-HEV IgM and IgG at the follow-up. CONCLUSIONS: HBV-infected pregnant women rarely have novel HEV infection during late pregnancy in Jiangsu, China. Maternal anti-HEV IgG efficiently transfers into the fetuses, and disappears in infants before 10 months old. PMID- 27467018 TI - Monitoring of human cytomegalovirus DNAemia during primary infection in transmitter and non-transmitter mothers. AB - BACKGROUND AND OBJECTIVES: It has been reported that maternal DNAemia is detectable in three quarters of pregnant women with acute/recent primary HCMV infections, with a higher median number of HCMV DNA copies/ml blood in transmitter as compared with non-transmitter mothers. STUDY DESIGN: The kinetics of HCMV DNA in blood of transmitter vs non-transmitter pregnant women with primary HCMV infection was retrospectively analyzed from their first blood sampling at referral up to amniocentesis strictly performed at 19-21 weeks' gestation. Monthly monitoring of maternal HCMV DNAemia was performed up to prenatal diagnosis. RESULTS: HCMV DNAemia was determined in 154 pregnant women. At amniocentesis, HCMV DNA in blood was positive in 42/50 (84.0%) amniotic fluid (AF) -positive and 21/104 (20.2%) AF-negative mothers (p<0.0001). The number of HCMV DNA copies/ml blood was not significantly different in AF-positive as compared with AF-negative mothers in the interval 0-30days post-infection (p=0.14). On the contrary, HCMV DNA load at 30-60days (p=0.03) and at 60-90days (p<0.001) after onset of infection was significantly different, as observed at amniocentesis (p<0.001). Three patterns (clearance, delayed decrease, and increasing) in both transmitter and non-transmitter mothers were observed. However, 79.8% AF- negative mothers cleared HCMV DNA in blood, while in AF positive mothers increasing (44.0%) or persisting (40.0%) levels of DNAemia were observed. CONCLUSIONS: The presence of viral DNA in maternal blood at amniocentesis is statistically associated with fetal HCMV infection. Increasing or persisting levels of maternal DNAemia during primary HCMV infection in pregnancy correlate with HCMV transmission to the fetus. PMID- 27467020 TI - Celebrating Two Centuries since the Invention of the Stethoscope. Rene Theophile Hyacinthe Laennec (1781-1826). AB - Rene Theophile Hyacinthe Laennec (1781-1826), a French physician, is considered one of the pioneers of respiratory medicine. His contribution to the invention of the stethoscope and to the development of clinical auscultation played a key role in the progress of the diagnosis of chest diseases. Almost two centuries after his invention of the stethoscope, his achievements continue to be widely appreciated and used by modern physicians in current pulmonology. PMID- 27467019 TI - Apollo Lunar Astronauts Show Higher Cardiovascular Disease Mortality: Possible Deep Space Radiation Effects on the Vascular Endothelium. AB - As multiple spacefaring nations contemplate extended manned missions to Mars and the Moon, health risks could be elevated as travel goes beyond the Earth's protective magnetosphere into the more intense deep space radiation environment. The primary purpose of this study was to determine whether mortality rates due to cardiovascular disease (CVD), cancer, accidents and all other causes of death differ in (1) astronauts who never flew orbital missions in space, (2) astronauts who flew only in low Earth orbit (LEO), and (3) Apollo lunar astronauts, the only humans to have traveled beyond Earth's magnetosphere. Results show there were no differences in CVD mortality rate between non-flight (9%) and LEO (11%) astronauts. However, the CVD mortality rate among Apollo lunar astronauts (43%) was 4-5 times higher than in non-flight and LEO astronauts. To test a possible mechanistic basis for these findings, a secondary purpose was to determine the long-term effects of simulated weightlessness and space-relevant total-body irradiation on vascular responsiveness in mice. The results demonstrate that space-relevant irradiation induces a sustained vascular endothelial cell dysfunction. Such impairment is known to lead to occlusive artery disease, and may be an important risk factor for CVD among astronauts exposed to deep space radiation. PMID- 27467021 TI - Carbon and Metal Quantum Dots toxicity on the microalgae Chlorella pyrenoidosa. AB - In this report, we investigated the cytotoxicity of two types of quantum dots(QDs) (carbon quantum dots(CQDs): N, S doped CQDs, N doped CQDs, no doped CQDs; metal QDs(MQDs): CdTe QDs, CdS QDs, CuInS2/ZnS QDs) on Chlorella pyrenoidosa(C. Pyrenoidosa) at different concentrations. We compared the toxicity of different QDs on C. Pyrenoidosa through determination of the algal growth inhibition, acute toxicity tests (EC50), Chlorophyll a(Chla) contents, protein contents, the activity of enzymatic and metabolites contents. When C. Pyrenoidosa was treated by various concentrations of QDs, the Chla contents were consistent to the number of algae cells, showing a good dose-response relationship. At the 96h, the EC50 of N, S doped CQDs, N doped CQDs, no doped CQDs and CdTe QDs, CdS QDs, CuInS2/ZnS QDs were 38.56, 185.83, 232.47, 0.015, 4.88, 459.5mg/l, respectively. The toxicity order of them was: CuInS2/ZnS QDshexa-PCB>tetra-PCB>tri PCB>Pb(2+)>DEHP>Cu(2+)>DBP>BDE209>Zn(2+)>DMP>DEP, where B[a]P is benzo(a)pyrene, PCB is polychlorinated biphenyl, DEHP is diethylhexyl phthalate, DBP is dibutyl phthalate, BDE209 is decabromodiphenyl ether, DMP is dimethyl phthalate, and DEP is diethyl phthalate. All the PM2.5 samples analyzed proved to be weak toxic for PPT3. The toxicity of PM2.5 was assessed by the dose-addition of organic species and heavy metallic elements existing in PM2.5 with PPT3. The bioluminescence test showed that the metals and organics detected in PM2.5 promoted PM2.5 toxicity. The total detectable organics (denoted by SigmaOrs) exhibited slightly higher toxicity than the total metals (denoted by SigmaMs). In contrast, the sum of water-soluble ions (denoted by SigmaIons) was beneficial to PPT3. The PM2.5 toxicity increased as the PM2.5 trapped more organics or metallic elements from the industrial or densely populated urban areas, where the PM2.5 had a high inhibition rate of bioluminescence for PPT3 in contrast to the residential PM2.5 samples, where the minimum inhibition rate was observed. The toxicity of PM2.5 samples varied with the mass concentrations, chemical constituents, and sampling locations. The chemicals in PM2.5, especially organic species and metallic elements, affected its eco-toxicity. These data provided good understanding of the atmospheric PM2.5 pollution in the large portion of the East China. PMID- 27467022 TI - Contrasting effects of biochar, compost and farm manure on alleviation of nickel toxicity in maize (Zea mays L.) in relation to plant growth, photosynthesis and metal uptake. AB - Nickel (Ni) toxicity in agricultural crops is a widespread problem while little is known about the role of biochar (BC) and other organic amendments like farm manure (FM) from cattle farm and compost (Cmp) on its alleviation. A greenhouse experiment was conducted to evaluate the effects of BC, Cmp and FM on physiological and biochemical characteristics of maize (Zea mays L.) under Ni stress. Maize was grown in Ni spiked soil without and with two rates of the amendments (equivalent to 1% and 2% organic carbon, OC) applied separately to the soil. After harvest, plant height, root length, dry weight, chlorophyll contents, gas exchange characteristics and trace elements in plants were determined. In addition, post-harvest soil characteristics like pHs, ECe and bioavailable Ni were also determined. Compared to the control, all of the amendments increased plant height, root length, shoot and root dry weight with the maximum increase in all parameters by FM (2% OC) treatment. Similarly, total chlorophyll contents and gas exchange characteristics significantly increased with the application of amendments being maximum with FM (2% OC) application. Amendments significantly increased copper, zinc, manganese and iron concentrations and decreased Ni concentrations in the plants. The highest reduction in shoot Ni concentration was recorded with FM (2% OC) followed by BC (2% OC) being 73.2% and 61.1% lower compared to the control, respectively. The maximum increase in soil pH and decrease in AB-DTPA extractable Ni was recorded with BC (2% OC) followed by FM (2% OC). It is concluded that FM (2% OC) was the most effective in reducing Ni toxicity to plants by reducing Ni uptake while BC (2% OC) was the most effective in decreasing bioavailable Ni in the soil through increasing soil pH. However, long-term field studies are needed to evaluate the effects of these amendments in reducing Ni toxicity in plants. PMID- 27467024 TI - Trauma memory characteristics and the development of acute stress disorder and post-traumatic stress disorder in youth. AB - BACKGROUND & OBJECTIVES: The present study addresses gaps in knowledge regarding the association between trauma memory processes and posttraumatic stress responses in youth. Our primary goal was to explore the relative contribution of perceptions of trauma memory quality versus narrative trauma memory characteristics to explain overall adjustment. METHODS: Children (N = 67) were interviewed within four weeks (T1) of an injury leading to hospital treatment and then again eight weeks later (T2). In each interview, the child told a trauma narrative (which were later coded), and answered the Trauma Memory Quality Questionnaire (Meiser-Stedman, Smith, Yule, & Dalgleish, 2007a), a self-report measure indexing the sensory, fragmented, and disorganised characteristics of trauma memory. They then completed measures of Acute Stress Disorder (ASD) symptoms and associated psychopathology at T1 and measures of Posttraumatic Stress (PTS) symptoms and associated psychopathology at T2. RESULTS: Self reported trauma memory characteristics predicted ASD symptoms cross-sectionally at T1 and PTS symptoms prospectively over time. At both time points, self reported trauma memory characteristics accounted for all of the unique variance in symptoms initially explained by narrative characteristics. A reduction in self report ratings, but not the hypothesised narrative features (e.g., disorganised or lexical elements of the narrative), significantly predicted a reduction in PTS symptoms over time. LIMITATIONS: The small sample size and the absence of a within-subjects narrative control were the main limitations of the study. CONCLUSIONS: These findings underscore the importance of self-reported trauma memory characteristics to the aetiology of PTSD. PMID- 27467025 TI - Visuospatial context learning and configuration learning is associated with analogue traumatic intrusions. AB - BACKGROUND AND OBJECTIVES: Cognitive and information processing theories of Post Traumatic Stress Disorder (PTSD) assert that trauma intrusions are characterized by poor contextual embedding of visuospatial memories. Therefore, efficient encoding of visuospatial contextual information might protect against intrusions. We tested this idea using indices of visuospatial memory embedding along with the trauma film paradigm. METHODS: Individual differences in spatial configuration learning, as well as the degree to which visual recognition memory depends on its visual encoding context (i.e., memory contextualization), were assessed in 81 healthy participants. Next, participants viewed a distressing film. Intrusions and other PTSD analogue symptoms were assessed subsequently. RESULTS: Participants displaying stronger memory contextualization developed fewer intrusions and PTSD analogue symptoms. Spatial configuration learning was unrelated to memory contextualization and, contrary to prior findings, predicted higher levels of intrusions. LIMITATIONS: Due to the analogue design, our findings may not translate directly to clinical populations. Furthermore, due to the correlational design of the study, causal relations remain to be tested. CONCLUSIONS: Our results suggest a protective role for the ability to integrate memories in their original visual learning context against the development of PTSD symptoms. PMID- 27467026 TI - MRI Markers Predict Cognitive Decline Assessed by Telephone Interview: The Northern Manhattan Study. AB - BACKGROUND: Brain magnetic resonance imaging (MRI) allows researchers to observe structural pathology that may predict cognitive decline. Some populations are less accessible through traditional in-person visits, and may be under represented in the literature. METHODS: We examined white matter hyperintensity volume (WMHV) and cerebral parenchymal fraction (CPF) as predictors of cognitive decline measured by a modified Telephone Interview for Cognitive Status (TICS-m) in the Northern Manhattan Stroke Study, a racially and ethnically diverse cohort study. Participants were stroke-free, above 50 years old, and had no contraindications to MRI. A total of 1143 participants had MRI and TICS-m data available [mean age 70 (SD=9), 61% women, 66% Hispanic, 17% Black, 15% white]. RESULTS: Those in the third and fourth quartiles of WMHV had significantly greater decline in TICS-m over time as compared with those in the first quartile (Q3: -0.17 points/year, Q4: -0.30 points/year). Those in the bottom 2 quartiles of CPF had significantly greater decline in TICS-m than those in the top quartile (Q1: -0.3 points/year, Q2: -0.2 points/year). Apolipoprotein E (APOE) e4 allele carriers had greater cognitive decline per unit of CPF. Those with greater CPF preserve TICS-m performance better despite greater WMHV. CONCLUSIONS: Telephone cognitive assessments can detect decline due to white matter lesions and smaller brain volumes. PMID- 27467027 TI - Improvements in emotion regulation following repetitive transcranial magnetic stimulation for generalized anxiety disorder. AB - Generalized anxiety disorder (GAD) is characterized by emotion regulation difficulties, which are associated with abnormalities in neural circuits encompassing fronto-limbic regions including the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to determine whether DLPFC neuromodulation improves emotion regulation in patients with GAD. This is a secondary analysis from a randomized-controlled trial comparing 30 sessions of low-frequency right sided active (n=13) versus sham (n=12, sham coil) repetitive transcranial magnetic stimulation (rTMS) at the right DLPFC in patients with GAD. Results indicated statistically significant improvements in self-reported emotion regulation difficulties at posttreatment and 3-month follow-up in the active group only. Improvements were found primarily in the domains of goal-directed behaviors and impulse control and were significantly associated with a global clinician rating of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change. PMID- 27467028 TI - Initial data on a 5-item measure of OCD symptom severity and change: The obsessive compulsive session change index (OCSCI). AB - Repeated measurement of symptoms throughout treatment allows providers to assess individual patterns of symptom change. However, outside of a clinical trial, administration of lengthy measures at each session is unlikely. Therefore, in order to bridge the gap between clinical research and actual clinical practice we developed a brief self-report measure of obsessive compulsive symptoms that can be used at each session, the Obsessive Compulsive Session Change Index (OCSCI). The OCSCI assesses time spent on obsessions, time spent on compulsions, interference and distress related to obsessions and compulsions, and relative change in symptoms from the beginning of treatment. This paper reports initial psychometric properties of the OCSCI. Twenty-seven adults receiving exposure and ritual prevention for obsessive compulsive disorder (OCD) completed the OCSCI at each session. Results showed that the OCSCI had good internal consistency, and convergent and divergent validity. Specifically, the OCSCI had moderate to strong correlations with both self-reported and clinician rated OCD. Finally, the OCSCI was not as strongly correlated with depressive symptoms as it was with OCD symptoms. The findings presented herein suggest that the OCSCI can be useful as a measure of client progress throughout treatment. PMID- 27467029 TI - [Compassion as a mediator between stressful events and perceived stress in Greek students]. AB - Compassion is closely related with human's survival as a mammal and has been developed through evolution for pain reduction, for forming affiliative bonds and alliances with non kin in order to increase protection and cope with external threats. Compassion seems to influence people's ability to deal with life's adverse situations such as stress and it is linked with lower psychopathology and greater wellbeing. Compassion is closely related to empathy and altruism and it is defined as the recognition of the pain of the self or others' that is accompanied with the will to take action in order to relieve the person from pain. Its main features are kindness instead of self-judgment and indifference, the recognition of common humanity instead of the feeling of separation and mindfulness when facing adverse conditions instead of over-identification with one's pain or disengagement with the pain of others. According to the biopsychosocial approach, stress can be defined by three dimensions such as the cause or stressful factors that can be major life events or daily hassles, the perception of stress that is manifested through cognitive, emotional and behavioural reactions and the physiological response for achieving homeostasis. The purpose of the present study was to investigate the role of compassion for self and others in the occurrence of stressful events and levels of perceived stress in students. Participants were 280 undergraduate students from two Greek universities. Results indicated that students who had experienced a greater amount of stressful events during the past year reported having higher levels of perceived stress and that higher self-compassion was correlated with less perceived stress. Moreover, the adverse effect of stressful events on perceived stress was partially explained by the mediating role of self-compassion. Students who reported more stressful events showed higher compassion for others in opposition to compassion towards themselves but compassion for others was not significantly correlated with perceived stress. Since compassion is not considered being a fixed personality trait but it is seen as a capacity that can be developed by appropriate training it was suggested that enhancing self compassion's stress buffering properties can be useful for dealing with stressful events and reducing stress responses. Moeover, it was suggested that it is interesting to explore the relationship between compassion for others and positive characteristics such as sense of coherence, quality of life and social support that may enhance stress resilience indirectly. The above findings imply that it is important to investigate further the role of compassion in coping with stress in qualitative, longitudinal studies as well as randomized control trials. Compassion may be an alternative mechanism for coping with stressful events and stress, other than fight or flight that has been shaped by evolution. PMID- 27467030 TI - [Greek students' attitudes towards mental disorders]. AB - Attitudes and beliefs of the population regarding the mentally ill have been universally subject of many researches. Research of different groups' opinion for mental disorders has given remarkable findings that assist in the right design of psychiatric services. Objective of this thesis is to study the attitude of students towards mental illness. In particular, it intends to study the differences derived from the age, gender, place of birth, kind of studies, year of study, duration of stay at the place of studies and the existence of mental disorders in the student's family. Data were collected from 536 students randomly selected from Universities and Technological Institutions both in Athens and Thessaloniki. In general, the participants are being divided based on the subject of their studies in undergraduates of human sciences, exact sciences, social and health sciences. The short version of the scale "Community Attitudes Toward the Mentality III" (CAMI) was used, which consists of 26 questions sorted to four subscales (domination scale, humanism scale, social exclusion scale and the scale measuring the community beliefs regarding the care of mentally ill), along with a special questionnaire in order to collect social and demographic data. Students' attitudes towards mental illness are influenced by demographic factors, the department they are studying at and the year of study. Female gender (p=0.000), personal contact with mentally ill (p=0.012), studying in Universities (p=0.031) and especially social sciences (p=0.009) are associated with positive attitudes. On the contrary, less years of studying are associated with negative attitudes whereas older students appear to score less in the Domination Scale (p=0.000). It is significant that the place of birth (p=0,335) and the duration of stay at the place of studies (r=0.735) did not show any association with the variables studied in this research. However these results cannot be compared with older researches since there are not sufficient findings. Women tend to show more humanitarian attitude towards the mentally ill in comparison to men, emphasizing the role the community plays in their support reinforcing their reintegration in the community verifying the results of research conducted in Greece and other countries. Furthermore, students who have previously been in contact with mentally ill tend to have more favorable attitude and understanding towards them. The findings concerning the age and the years of studying highlight the imperative need of exploring thoroughly the knowledge regarding the attitudes towards mental illness. PMID- 27467031 TI - [Alphanti-Inflammatory medication as adjunctive antidepressive treatment]. AB - Mounting data of evidence that have emerged during the last twenty years, point towards the existence of an inflammatory mechanism underlying the pathophysiology of depressive disorder. These data have inspired a number of clinical studies characterized by the administration of inflammatory response altering medication in addition to conventional medication in depressive disorder patients. The drugs were either Non Steroid Anti-inflammatory Drugs (NSAIDs) or Tumor Necrosis Factor alpha (TNFa) inhibitors and were selected among those that are already in use for various diseases related to the immune system. The choice of these specific immunomodulatory agents for the co-administration with conventional antidepressive medication was based on a number of laboratory data and clinical evidence. A total of seven relevant clinical trials have been conducted, all of them with promising results that have been published between 2006 and 2013. However, only four out of them were eligibly designed regarding the homogeneity of the study groups, randomization, double-blinding and placebo controlling. These three studies showed clinical advantages of the adjunctive medication as estimated by significant drops in Hamilton scores. Of interest are the findings of the most recent and largest clinical trial of the TNF-a antagonist infliximab which show that treatment with anti-inflammatory agents may be beneficial only in depressive patients with raised levels of baseline inflammatory markers. A limitation of the studies was that, since no guidelines currently exist for anti inflammatory agents and depression, adjunctive medication could have been under or overdosed. Other limitations were the follow-up period that was rather small and the number of the participants that was also small. Recently, a lot of progress has been made in identifying therapeutic targets along metabolic pathways in the brain relevant to depression, which could be manipulated by immune mediators. In fact, tryptophan -the precursor of serotonin- metabolism appears as an important field of cross reactions between immune and neurochemical mediators and, elucidating it might contribute in new therapeutic strategies. Future clinical trials, eligibly designed, should include the use of biomarkers that reflect inflammatory status or/and metabolic activity in order to identify patients who may be uniquely responsive to immune-targeted therapies. These biomarkers could also serve to objectively monitor therapeutic responses and to determine the appropriate, for each patient, dosage of the new medicine. It is possible that relevant findings can benefit the great population of depression disorder patients that fail to achieve remission and also contribute in the personalization of the treatment of depression. PMID- 27467032 TI - [Pharmacokinetic and pharmacodynamic effects of psychotropic medications: Differences between sexes]. AB - The gender based or gender sensitive pharmacology is a new research area. Differences among sexes are observed in several parameters of their pharmacokinetic which may relate to alteration of their pharmacodynamic as well. Most psychotropics are given per os, and the greater part of their absorption takes place in the small intestine. Premenopausal women have slower gastric emptying times and lower gastrointestinal blood flow which probably reduces the extent of drug absorption. The distribution of drugs is influenced by the relative lower body mass index, the lower blood volume and flow and the greater percentage of body fat of women. Further, the elimination and renal clearance is reduced in women and the hepatic metabolism differ between sexes. Besides, women differ from men in physiological conditions which may have an impact on the psychotropic medication and dosage required for efficacy and response. Women are exposed to monthly hormonal fluctuations (menstruation), pregnancy, puerperium, menopause and use of contraceptives or synthetic hormonal replacement therapies. Throughout of these conditions changes may occur in total body water, in renal clearance, cardiovascular and autoimmune system, which may cause fluctuations in the activity of the psychotropics, changes in the central neurotransmitters, in the number and sensitivity of the receptors, and the general metabolism as well. Despite the fact that women are the primer consumers of psychotropic medication, taking more psychotropics as well as more multiple medications than men, little attention has been paid to sex differences in psychopharmacology. Till recently women were under-represented or excluded from most of the pharmacological clinical trials. The treatment guidelines for psychotropic medication are based on studies verified and investigated almost exclusively in men. Results from such studies were generalized and recommended for use in the clinical practice without any critique and justification between the sexes. In conclusion, women compared to men, tend to have a greater bioavailability and slower elimination of drugs leading to higher concentrations of free circulating drugs in serum and causing more side effects and adverse reactions to the psychotropic medication than men do. In general, women require lower doses of antidepressants, antipsychotics and benzodiazepines than men. For safety and efficacy reasons and despite the fact that research is still being carried out to determine the exact differences in pharmacodynamic of several psychotropics between genders, the clinician must be aware of the reported effect of the recommended medications on serum levels and organ tissues both for men and women. PMID- 27467033 TI - [Online Counselling: The prospect of a therapeutic connection]. AB - Over the last few years, Internet has become an integral part of daily life. An abundant source of information and a principal gateway of communication between individuals, Internet has been continuously gaining considerable ground as a tool of awareness and intervention in the area of public health. With regard to the field of mental health, Internet exhibits a credible potential in facilitating dialogue not only between experts and their beneficiaries but also between stakeholders. Moreover and with regard to various aspects of public concern, it can serve as a circulation portal of educational material between students and teachers. The advent of remote support services dates back in the decade of 1970 1980. In the present time, they consist of informative guides and self-help groups or online counselling. The latter is defined as the process in which both parties, namely the therapist and the client, are involved in an oral or written conciliation through means of an internet connection, videoconferencing, live chat or e-mail exchange. The benefits of this practice - accessibility, relocation, convenience, anonymity, facilitation of face-to-face psychotherapy and low cost - could make online counseling, in specific cases, the treatment of choice. While the usage of the World Wide Web seems promising for the rectification of mental health disorders, there is some debate among experts regarding the ethical aspect of practicing psychotherapy in an interactive digital environment. Issues such as technical expertise and the tackling of related problems, difficulties in the diagnostic process, interchange of verbal and nonverbal cues, crisis management, safeguarding the therapeutic alliance, protection of personal data, age restriction, keeping boundaries in relation to the setting, the time and the dynamics of the therapeutic relationship and, finally, training and supervisory process of online therapist, are some subjects of disagreement. Relevant research reveals the effectiveness of online counseling in decreasing the magnitude of reported symptoms, with a direct positive impact on the improvement of daily functioning and on future relapses. However, the usefulness of developing a therapeutic relationship through internet connection is being criticized by a group of clinicians, with their main arguments revolving around spatiotemporal issues and the reliability of incoming information. Some other researchers correlate the therapeutic alliance concluded in the context of electronic communication with a positive therapeutic effect. The data on the effectiveness of online practice are not sufficient to draw a definite conclusion. In an era of direct and rapid communication, it is imperative to encourage further research, for the determination of optimal conditions with respect to the practice of internet-delivered psychotherapy and the patients' well being as a result of treatment. PMID- 27467034 TI - [Eating disorders and sexual function]. AB - Women suffering from eating disorders, present considerable retardation and difficulties in their psychosexual development during adolescence. This leads to primary or secondary insufficiencies in their adult sexual life. The cause of these difficulties seems to be a series of biological, family and psychosocial factors. The majority of the research findings indicate that eating disorders have a negative impact on the patient's sexual function. The factors related to eating disorders symptomatology that influence sexuality are various and differ among each eating disorder diagnostic categories. Considering anorexia nervosa, it has been reported that women have negative attitudes to sexual issues and their body. Their sexual motivation increases when they engage in psychotherapy and their body weight is gradually restored. Starvation and its consequences on the human physiology and especially on the brain function seem to be the main factor that leads to reduced sexual desire and scarce sexual activity. Moreover, personality traits that are common in patients suffering from anorexia nervosa such as compulsivity and rigidity are also related with difficulties initiating and retaining romantic and sexual relationships. Usually patients suffering from anorexia nervosa report impaired sexual behavior and lack of interest to engage in a sexual relationship. Considering Bulimia Nervosa, impulsivity and difficulties in emotion regulation that are common features of the individuals that suffer from bulimia nervosa are also related to impulsive and sometimes self harming sexual behaviors. Moreover women sufferers often report repulsion, anger and shame towards their body and weight, mainly due to the distorted perception that they are fat and ugly. It is interesting that a number of research findings indicate that although patients suffering from bulimia nervosa are more sexually active and have more sexual experiences than patients suffering from anorexia nervosa, both groups of patients report more often than general population a lack of satisfaction from their sexual experiences. Other factors that are common to eating disorders and sexual dysfunction are personality traits, negative body image, adverse childhood experiences, negative family climate and especially early traumatic experiences such as sexual abuse. Furthermore, comorbidity of eating disorders with depression may have a negative impact on the patient's sexual function. The treatment and improvement of sexual behavior is quite problematic when the patient is also suffering from an eating disorder. Eating Disorder patients are often very reluctant to discuss their sexual life with the therapist and to engage in any kind of therapeutic intervention. Comorbidity with a number of other disorders makes psychotherapy even more difficult for those patients. Furthermore, a considerable percentage of Anorexia Nervosa patients do not have any kind of sexual activity, at least until nutrition and weight are restored. PMID- 27467036 TI - The psychosocial repercussions of domestic violence in battered women. AB - This study is trying to record the consequences of domestic violence to the mental health of abused women. The tools that were used were the following: PCL-S and GHQ. The research was conducted by B?Psychiatric Clinic of Attica General Hospital in collaboration with the National Centre of Social Solidarity and the WIN HELLAS (NGO). The victims did not have any diagnosed mental disorder before the present study. Concerning the form of violence that they had gone through, 33% of the victims had suffered psychological abuse, 30% has suffered physical abuse and the 16% sexual abuse, while 20% of the victims has suffered all the above forms of violence. As arises from the preliminary results of our research, 60% of the victims presented symptoms of post-traumatic stress disorder while 46% from the above percentage presented chronic PTSD. Regarding to the state of their psychosomatic health, 40% of victims has declared that during the last two weeks they felt worse than usual. More specifically, 60% feels a physical discomfort, 73% of victims presents reduction in functionalism while 56% seems to have stress symptoms. Finally 53% of victims show symptoms of depressions. By referring to the duration of abuse, 72% of total victims declared that had suffered violence during the last months; while 13% of total declared that they were being abused for more than five years.1,2. PMID- 27467035 TI - [Psychotic episode due to Hashimoto's thyroiditis]. AB - Thyroid hormones are crucial in adult brain metabolic activity. As a result, abnormal thyroid gland function and in particular hypofunction, might cause principally depression and neurocognitive dysfunction. Psychosis, presented mainly with thought disorders and perceptual disturbances, is a much rarer manifestation of hypothyreoidism. A correlation between hypothyreoidism and psychosis has been described since 1888, especially in cases of advanced hypothyreoidism. A few years later (1949), Asher first added the terminology "myxedema madness" to the literature. Psychotic symptoms typically appear after the onset of physical symptoms, usually with a delay of months or years. The case of a female patient who presented a psychotic episode as a first manifestation of hypothyroidism will be described. NE, a 48 yearold female patient, was admitted for the first time to an inpatient mental health care unit due to delusions of persecution and reference, as well as auditory hallucinations that appeared a few weeks ago. After the patient admission, routine laboratory examination was conducted. In order to relieve the patient from her sense of discomfort and while awaiting laboratory results, olanzapine, 5 mg/day, was administered. Neurological examination and cranial computed tomography scan were unremarkable. Hormonal laboratory tests though revealed severe low thyroid hormone levels. Thyroid antibody testing certified Hashimoto's thyroiditis. Olanzapine was discontinued and the patient received thyroid hormone substitution, levothyroxine 75 MUg/day, instead. The patient was discharged showing a significant improvement of psychotic symptoms after a 12-day hospitalization. A month later the patient was reevaluated. She had fully recovered from the psychotic episode. A year later, the patient continues to remain free from psychiatric symptoms, while thyroid hormone levels have been restored within normal range. The patient continues receiving only thyroid hormone substitution therapy with levothyroxine. Cases of acute psychosis associated with low levels of thyroid hormones in the context of primary hypothyreoidism have been repeatedly reported. The present case report emphasizes the importance of hypothyroidism exclusion as a secondary cause of psychosis. Thyroid disease treatment ameliorates psychotic disorder symptoms and recovers patients' mental condition. PMID- 27467037 TI - Scheimpflug and Optical Coherence Tomography Analysis of Posterior Keratoconus. AB - PURPOSE: To report a case series of 7 eyes of 6 patients with posterior keratoconus, evaluating corneal Scheimpflug tomographic changes and anterior segment optical coherence tomography (OCT). METHODS: In our descriptive study, 6 patients were diagnosed with posterior keratoconus: 5 unilateral (7-, 33-, and 42 year-old males and 64- and 60-year-old female) and 1 bilateral (45-year-old female). Patients were diagnosed with slit-lamp examination, which revealed corneal opacity with an underlying posterior corneal depression. Additional analysis with anterior-segment OCT and Scheimpflug tomography evaluation was performed. RESULTS: Localized paracentral posterior keratoconus was diagnosed in 7 eyes. Scheimpflug images demonstrated posterior corneal depression. Clinical findings were examined by OCT. Genetic analysis revealed no alterations or associated syndromes. All patients were amblyopic in the affected eye, and no surgery was offered to improve their visual acuity. CONCLUSIONS: Posterior keratoconus is a rare noninflammatory condition usually present at birth and sometimes related to developmental abnormalities. Posterior keratoconus is usually unilateral and can present as a generalized or localized change in posterior corneal curvature. PMID- 27467038 TI - Comparison of 120- and 140-MUm SMILE Cap Thickness Results in Eyes With Thick Corneas. AB - PURPOSE: To evaluate clinical outcomes after small incision lenticule extraction (SMILE) with different cap thicknesses in thick corneas. METHODS: Forty patients with central corneal thickness of more than 560 MUm were recruited in this prospective, randomized, masked, paired-eye study. Patients were randomized to receive SMILE with a 120-MUm cap thickness in 1 eye and 140-MUm cap thickness in the other. Uncorrected and corrected distance visual acuity (CDVA), contrast sensitivity (CS), higher-order aberrations (HOAs), and morphologic modifications of corneal architecture were measured during the 3-month follow-up period. RESULTS: Postoperative refractive outcomes, visual outcomes, CS, and the changes in HOAs were similar between both groups. The persistence of brightly reflective particles in the corneal interface layer was 1388.6 +/- 219.5/mm in eyes with 120 MUm cap thickness and 54.7 +/- 8.6/mm in eyes with 140-MUm cap thickness (P < 0.001). The hyperreflectivity line at the interface layer almost disappeared in all eyes with 140-MUm cap thickness, and it still persisted in 43% of the fellow eyes at 3 months postoperatively. The anterior surfaces of lenticules in the 140 MUm cap thickness group exhibited more smoothness than in the 120-MUm cap thickness group. CONCLUSIONS: There was a lower level corneal wound-healing response after SMILE with a 140-MUm cap thickness than with a 120-MUm cap thickness, although the thickness of cap creation did not affect visual outcomes by 3 months postoperatively. PMID- 27467039 TI - Precisely Controlled Side Cut in Femtosecond Laser-Assisted Deep Lamellar Keratoplasty for Advanced Keratoconus. AB - PURPOSE: To evaluate the outcomes of femtosecond laser-assisted deep lamellar keratoplasty (FDLK) in treating advanced keratoconus. METHODS: In the management of keratoconus in advanced stages, 89 patients (94 eyes) received FDLK, and 100 patients (100 eyes) underwent vacuum trephine-assisted deep anterior lamellar keratoplasty (DALK). Visual acuity, corneal curvature, and central corneal thickness were measured. The follow-up duration was 1 year. RESULTS: The best corrected visual acuity (logMAR) was 0.23 +/- 0.15 at 6 months and 0.08 +/- 0.07 at 1 year in the FDLK group, which was significantly better than that in the vacuum trephination group (0.30 +/- 0.10 and 0.13 +/- 0.08, respectively). The mean curvature was 43.24 +/- 5.25 D in the eyes treated by FDLK and 48.31 +/- 3.68 D in the eyes treated by vacuum trephine-assisted DALK at 1 year. The mean astigmatism in the FDLK group was lower as compared with the vacuum trephination group. In the FDLK group, the graft adhered well with the recipient, which was 72 +/- 17 MUm in thickness. In the vacuum trephination group, the remaining peripheral corneal thickness was 153 +/- 25 MUm. The epithelium healed at 3 +/- 2 days and 6 +/- 2 days in both groups, respectively. CONCLUSIONS: The vacuum trephine remains as a major surgical tool for deep lamellar keratoplasty. The precise control of side cut in the diameter and depth in the FDLK procedure can help to accelerate the healing of epithelium and the improvement of visual acuity early after surgery for advanced keratoconus, compared with vacuum trephine assisted DALK. PMID- 27467040 TI - Confocal Microscopy and Anterior Segment Optical Coherence Tomography Findings After Chemical Alkali Corneal Burn. PMID- 27467041 TI - Orbital Involvement and Ocular Surface Changes in IgG4-Related Systemic Disease. AB - PURPOSE: To evaluate ophthalmic involvement of systemic immunoglobulin-G4-related disease (IgG4-RD) and describe the changes in both ocular surface parameters and corneal subbasal nerve plexus. MATERIALS AND METHODS: Twenty eyes of 10 patients with systemic IgG4-RD and 20 eyes of 10 control subjects were enrolled in this study. Demographic information, medical history, serum IgG4 levels, orbital imaging, and follow-up data of subjects were recorded. Ocular surface tests were carried out in the order of tear break-up time (BUT), lissamine green (LG) staining, Schirmer I test with anesthesia, and ocular surface disease index (OSDI) questionnaire for all participants. Corneal subbasal nerves and basal epithelial cell layer were evaluated using in vivo confocal microscopy. RESULTS: Among the 10 patients with IgG4-RD, 11 eyes of 7 patients had orbital involvement. Among these 7 patients with IgG4-related ophthalmic disease, 4 presented with painless eyelid or periorbital swelling, 2 with diplopia and restricted ocular motility, and 1 with proptosis. Patients with IgG4-RD had higher OSDI (5.9 +/- 6.6 vs. 1.7 +/- 2.4, P < 0.001) and LG staining scores (0.7 +/- 1.0 vs. 0.0 +/- 0.0, P = 0.011) and lower BUT (5.6 +/- 1.4 vs. 10.2 +/- 1.0, P < 0.001) and Schirmer values (11.9 +/- 10.3 vs. 18.3 +/- 4.4, P = 0.021) as compared with those of control subjects. Total nerve density and nerve fiber length were found to be significantly lower in patients with IgG4-RD. CONCLUSIONS: The orbit is frequently involved during the course of IgG4-RD. These patients should be evaluated in terms of ocular surface disease and dry eye, which may be associated with lacrimal gland and/or orbital nerve involvement. PMID- 27467042 TI - Effect of Anisometropia on the Predictability and Accuracy of Refractive Surgery. AB - PURPOSE: To evaluate the predictability and accuracy of refractive surgery among adults with myopic anisometropia. METHODS: Consecutive cases of myopic eyes that underwent bilateral laser-assisted in situ keratomileusis (LASIK) or bilateral photorefractive keratectomy (PRK) during a 12-year period in a single center were included. Myopic anisometropia was defined as a difference greater than 1.5 D in spherical equivalent between eyes preoperative. RESULTS: A total of 10,046 paired, operated nonamblyopic eyes of 5023 patients were analyzed. Of these, 472 eyes of 236 (4.7%) patients had myopic anisometropia without amblyopia, and 9574 eyes of 4787 patients served as isometropic controls. After refractive surgery, in the anisometropic group the more myopic eye was corrected by +0.47 +/- 0.78 (D) more than the contralateral eye (P < 0.0001). Relative to the target refraction, the more myopic eye was overcorrected by 0.21 +/- 0.79 D compared with an undercorrection of 0.16 +/- 0.60 D in the less myopic contralateral eye (P < 0.0001) and compared with an undercorrection of 0.15 +/- 0.62 D in the isometropic controls (P < 0.0001). Additionally, the variability in the correction of the more myopic eyes was significantly higher compared with the less myopic contralateral eyes and isometropic controls (P < 0.0001). These trends were evident both in PRK and LASIK treatments. The effect of anisometropia was found to be independent of the magnitude of preoperative myopia or surgeon identity. CONCLUSIONS: The more myopic eye of anisometropes undergoing refractive surgery has lower predictability and accuracy and tends to be overcorrected, whereas the less myopic eye has outcome similar to isometropic controls. These results suggest that refractive surgery nomograms should take into account anisometropia. PMID- 27467043 TI - Microwave Irradiation as a Promising Method of Sterilization for Acanthamoeba polyphaga in Cultures. AB - PURPOSE: To determine the killing effect of microwave irradiation on Acanthamoeba polyphaga. METHODS: The trophozoites and cysts of A. polyphaga both in water and on agar were exposed to microwave irradiation with a capacity of 750 W for 0, 1, 3, 5, and 10 minutes, respectively. Furthermore, the trophozoites and cysts of A. polyphaga in water were exposed to microwave irradiation with a capacity of 100, 300, and 500 W for 1 minute, respectively. RESULTS: The trophozoites and cysts of A. polyphaga on agar were completely killed by 3 minutes of microwave irradiation with a capacity of 750 W. The trophozoites and cysts of A. polyphaga in water were completely killed by microwave irradiation with a capacity of 300 W for 1 minute. CONCLUSIONS: We demonstrate that microwave treatment is effective in killing A. polyphaga both in water and on agar and may be a helpful modality to prevent Acanthamoeba keratitis. PMID- 27467044 TI - Microsporidial Stromal Keratitis: Clinical Features, Unique Diagnostic Criteria, and Treatment Outcomes in a Large Case Series. AB - PURPOSE: To describe the history, clinical features, and outcomes of a large case series of microsporidial stromal keratitis with emphasis on probable predictors of the etiology in this rare and unspecified form of keratitis. METHODS: Retrospective analysis of cases seen between January, 2002, and December, 2013, diagnosed at LV Prasad Eye Institute as having microsporidial stromal keratitis based on clinical, microbiology, and histopathology examination. Outcomes of medical and surgical management with visual recovery were documented. RESULTS: There were 34 cases of microsporidial stromal keratitis with a mean age of 43.3 years (range 2-77 years) and male preponderance. The duration of symptoms was chronic in most cases (mean duration of 288 days). Nearly half of the cases had a history of trauma, in the age group of 20 to 50 years. The most common clinical misdiagnosis was herpes simplex virus keratitis (26.5%) followed by fungal keratitis (17.6%). This could be attributed to the nonspecific clinical picture of diffuse multifocal stromal lesions in 82.4% of cases. The organisms were detected in microbiological evaluation of corneal scrapings in 47% cases, and histopathological detection of the organisms showed a positivity rate of 92.3%. Surgical management was necessary in the majority of the cases (73.5% of patients). CONCLUSIONS: The typical history of trauma with a smoldering, diffuse form of keratitis refractory to conventional medical therapy, responding to surgical removal for recovery is clearly demonstrated as a recurring feature in the majority of the cases. Patients presenting with this characteristic clinical picture should be suspected to harbor this rare pathogen, and early surgical interventions should be considered. PMID- 27467045 TI - Attitudes and Knowledge Concerning Corneal Donation in a Population-Based Sample of Urban Chinese Adults. AB - PURPOSE: To better understand knowledge and attitudes concerning corneal donation among Chinese adults. METHODS: Randomly selected residents in predetermined age strata 20 to 60+ years completed home-based questionnaires in each of 12 randomly chosen communities in Guangzhou, southern China. RESULTS: Among 1217 selected persons, 430 (35.3%) completed the questionnaires (mean age 40.4 yrs, 57.9% female). Refusers were older (44.8 yrs, P < 0.001), but sex did not differ (52.2% female, P = 0.07). Among participants, 175 (40.7%) were willing to donate their corneas (WTD). Differences between WTD and not WTD included donation knowledge score (range, 1-12) [WTD (SD) 6.91 +/- 2.21, not WTD 5.62 +/- 2.43, P < 0.001]; having discussed donation (WTD 26.3%, not WTD 8.63%, P < 0.001); viewing donation as unpopular (WTD 88.0%, not WTD 96.5%, P = 0.001); and feeling donation "damages the body" (WTD 15.4%, not WTD 25.7%, P = 0.013). Associated significantly with WTD in multiple regression models were higher knowledge score [odds ratio (OR) = 1.18, 95% confidence interval (CI), 1.04-1.32, P = 0.008]; not feeling donation "damages the body" (OR = 1.91, 95% CI, 1.07-3.43, P = 0.030); and willingness to discuss donation (OR = 10.6, 95% CI, 3.35-33.9, P < 0.001). WTD did not differ by age (>60 yrs: 22/51, 43.1%; <=60 yrs: 153/379, 40.4%, P = 0.706). Assuming all those refusing the survey would not donate, 14.4% (175/1217) were WTD for themselves, though only 7.1% (86/1217) would do so on behalf of a family member if they did not know the deceased's preference. CONCLUSIONS: Interventions to increase knowledge and promote discussions about donation, and policies allowing widespread expression of donation preference, are needed in this setting. PMID- 27467046 TI - Globe Rupture of a Post-LASIK Keratectasia Eye From Blunt Trauma. AB - PURPOSE: To report a case of globe rupture in a patient with post-laser in situ keratomileusis (LASIK) ectasia after blunt trauma. METHODS: Observational case report. RESULTS: A 42-year-old man with a history of post-LASIK ectasia sustained paracentral corneal rupture secondary to blunt trauma from a fist to his left eye (OS). Slit-lamp examination revealed rupture in the posterior stroma (inferior paracentral) of the OS with an overlying intact LASIK flap; however, the inferior edges of the LASIK flap were Seidel positive. The anterior chamber was flat. Although he was initially managed with cyanoacrylate glue and a bandage contact lens, the patient eventually required tectonic penetrating keratoplasty. The postoperative course was unremarkable, and over 1 year later, the visual acuity OS was 20/25 with -7.50 + 2.00 * 0.50. CONCLUSIONS: Globe rupture from blunt trauma has not been shown to be more common in patients with a history of LASIK. Although blunt trauma to the post-LASIK globe would generally incur a similar risk of rupture to that of the normal eye, keratectasia after LASIK may predispose the globe to rupture. PMID- 27467047 TI - Late Acute Rejection After Allograft Limbal Stem Cell Transplantation: Evidence for Long-Term Donor Survival. AB - PURPOSE: To describe the clinical presentation and management of late (>3.0 years) acute graft rejection in keratolimbal allograft (KLAL) recipients. METHODS: This was a multicenter, retrospective observational case series. Six eyes of 6 patients with ocular surface transplant at a mean age of 36.2 years were seen at 3 tertiary referral centers for acute graft rejection between 2007 and 2013. Main outcome measures included strength of systemic immunosuppression (SI) at the time of rejection, time to rejection, and clinical presentation of rejection. RESULTS: Preoperative diagnoses included total limbal stem cell deficiency because of aniridia (n = 2) or chemical injury (n = 4). After an initially successful outcome, patients experienced late acute graft rejection at a mean time of 67.8 +/- 24.1 months (range: 41-98) after KLAL while receiving suboptimal levels of SI because of medication taper (n = 5) or noncompliance (n = 1). Objective findings included an epithelial rejection line (n = 6), edema (n = 2), corneal epithelial irregularities (n = 2), and neovascularization (n = 1). Antirejection management consisted of topical corticosteroids (n = 6) and augmentation of SI therapy (n = 5). CONCLUSIONS: These cases of late acute graft rejection in KLAL patients support the notion that allodonor cells can persist over the long run and remain at risk for immunologic rejection. It further underscores the fact that long-term success with KLAL may require extension of SI beyond the first few years, albeit at lower levels individualized to each patient. PMID- 27467048 TI - Characteristics of a new meningococcal serogroup B vaccine, bivalent rLP2086 (MenB-FHbp; Trumenba(r)). AB - Neisseria meningitidis is a common cause of bacterial meningitis, often leading to permanent sequelae or death. N. meningitidis is classified into serogroups based on the composition of the bacterial capsular polysaccharide; the 6 major disease-causing serogroups are designated A, B, C, W, X, and Y. Four of the 6 disease-causing serogroups (A, C, Y, and W) can be effectively prevented with available quadrivalent capsular polysaccharide protein conjugate vaccines; however, capsular polysaccharide conjugate vaccines are not effective against meningococcal serogroup B (MnB). There is no vaccine available for serogroup X. The public health need for an effective serogroup B vaccine is evident, as MnB is the most common cause of meningococcal disease in the United States and is responsible for almost half of all cases in persons aged 17 to 22 years. In fact, serogroup B meningococci were responsible for the recent meningococcal disease outbreaks on college campuses. However, development of a suitable serogroup B vaccine has been challenging, as serogroup B polysaccharide-based vaccines were found to be poorly immunogenic. Vaccine development for MnB focused on identifying potential outer membrane protein targets that elicit broadly protective immune responses across strains from the vast number of proteins that exist on the bacterial surface. Human factor H binding protein (fHBP; also known as LP2086), a conserved surface-exposed bacterial lipoprotein, was identified as a promising vaccine candidate. Two recombinant protein-based serogroup B vaccines that contain fHBP have been successfully developed and licensed in the United States under an accelerated approval process: bivalent rLP2086 (MenB-FHbp; Trumenba(r)) and 4CMenB (MenB-4 C; Bexsero(r)). This review will focus on bivalent rLP2086 only, including vaccine components, mechanism of action, and potential coverage across serogroup B strains in the United States. PMID- 27467053 TI - An investigation of the association of genetic susceptibility risk with somatic mutation burden in breast cancer. AB - BACKGROUND: Genome-wide association studies have reported nearly 100 common germline susceptibility loci associated with the risk for breast cancer. Tumour sequencing studies have characterised somatic mutation profiles in breast cancer patients. The relationship between breast cancer susceptibility loci and somatic mutation patterns in breast cancer remains largely unexplored. METHODS: We used single-nucleotide polymorphism (SNP) genotyping array data and tumour exome sequencing data available from 638 breast cancer patients of European ancestry from The Cancer Genome Atlas (TCGA) project. We analysed both genotype data and, when necessary, imputed genotypes for 90 known breast cancer susceptibility loci. We performed linear regression models to investigate possible associations between germline risk variants with total somatic mutation count (TSMC), as well as specific mutation types. We examined individual SNP genotypes, as well as a multi-SNP polygenic risk score (PRS). Models were statistically adjusted for age at diagnosis, stage, oestrogen-receptor (ER) and progesterone-receptor (PR) status of breast cancer. We also performed stratified analyses by ER and PR status. RESULTS: We observed a significant inverse association (P=8.75 * 10(-6); FDR=0.001) between the risk allele in rs2588809 of the gene RAD51B and TSMC across all breast cancer patients, for both ER(+) and ER(-) tumours. This association was also evident for different types of mutations. The PRS analysis for all patients, with or without rs2588809, showed a significant inverse association (P=0.01 and 0.04, respectively) with TSMC. This inverse association was significant in ER(+) patients with the ER(+)-specific PRS (P=0.02), but not among ER(-) patients for the ER(-)-specific PRS (P=0.39). CONCLUSIONS: We observed an inverse association between common germline risk variants and TSMC, which, if confirmed, could provide new insights into how germline variation informs our understanding of somatic mutation patterns in breast cancer. PMID- 27467054 TI - FOLFIRINOX for advanced pancreatic cancer: the Princess Margaret Cancer Centre experience. AB - BACKGROUND: FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre. METHODS: This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. RESULTS: One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3-16.1) months with full dose and 12.9 (10.3-30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1-not reached) months with full dose and 23 (not reached-not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9-15.2) months with full dose and 8.7 (5.7-12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1-not reached) months with full dose and 10.4 (6.8-not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002). CONCLUSIONS: Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction. PMID- 27467055 TI - Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? AB - BACKGROUND: Menopausal hormone therapy (MHT) increases breast cancer risk; however, most cohort studies omit MHT use after enrolment and many infer menopausal age. METHODS: We used information from serial questionnaires from the UK Generations Study cohort to estimate hazard ratios (HRs) for breast cancer among post-menopausal women with known menopausal age, and examined biases induced when not updating data on MHT use and including women with inferred menopausal age. RESULTS: Among women recruited in 2003-2009, at 6 years of follow up, 58 148 had reached menopause and 96% had completed a follow-up questionnaire. Among 39 183 women with known menopausal age, 775 developed breast cancer, and the HR in relation to current oestrogen plus progestogen MHT use (based on 52 current oestrogen plus progestogen MHT users in breast cancer cases) relative to those with no previous MHT use was 2.74 (95% confidence interval (CI): 2.05-3.65) for a median duration of 5.4 years of current use, reaching 3.27 (95% CI: 1.53 6.99) at 15+ years of use. The excess HR was underestimated by 53% if oestrogen plus progestogen MHT use was not updated after recruitment, 13% if women with uncertain menopausal age were included, and 59% if both applied. The HR for oestrogen-only MHT was not increased (HR=1.00; 95% CI: 0.66-1.54). CONCLUSIONS: Lack of updating MHT status through follow-up and inclusion of women with inferred menopausal age is likely to result in substantial underestimation of the excess relative risks for oestrogen plus progestogen MHT use in studies with long follow-up, limited updating of exposures, and changing or short durations of use. PMID- 27467057 TI - TAKING THE LEAD IN COLORECTAL CANCER PREVENTION. PMID- 27467056 TI - Development of an Optical Zn2+ Probe Based on a Single Fluorescent Protein. AB - Various fluorescent probes have been developed to reveal the biological functions of intracellular labile Zn2+. Here, we present Green Zinc Probe (GZnP), a novel genetically encoded Zn2+ sensor design based on a single fluorescent protein (single-FP). The GZnP sensor is generated by attaching two zinc fingers (ZF) of the transcription factor Zap1 (ZF1 and ZF2) to the two ends of a circularly permuted green fluorescent protein (cpGFP). Formation of ZF folds induces interaction between the two ZFs, which induces a change in the cpGFP conformation, leading to an increase in fluorescence. A small sensor library is created to include mutations in the ZFs, cpGFP and linkers between ZF and cpGFP to improve signal stability, sensor brightness and dynamic range based on rational protein engineering, and computational design by Rosetta. Using a cell based library screen, we identify sensor GZnP1, which demonstrates a stable maximum signal, decent brightness (QY = 0.42 at apo state), as well as specific and sensitive response to Zn2+ in HeLa cells (Fmax/Fmin = 2.6, Kd = 58 pM, pH 7.4). The subcellular localizing sensors mito-GZnP1 (in mitochondria matrix) and Lck-GZnP1 (on plasma membrane) display sensitivity to Zn2+ (Fmax/Fmin = 2.2). This sensor design provides freedom to be used in combination with other optical indicators and optogenetic tools for simultaneous imaging and advancing our understanding of cellular Zn2+ function. PMID- 27467058 TI - Foley Catheters as Temporary Gastrostomy Tubes: Experience of a Nurse-Led Service. AB - Percutaneous endoscopic gastrostomy tube is the modality of choice for long-term enteral nutrition. In the event that replacement tubes are not available, urinary catheters can be used to maintain patency of the gastrostomy tract. This study reports our experience in a nurse-led service using Foley catheters as temporary gastrostomy tubes and the associated complications. Patients who had used Foley catheter as gastrostomy tube over a 2-year period (Jan 2011 to December 2012) were studied. Twenty-one patients had used Foley catheters as a temporary gastrostomy tube, and 12 (57.4%) did not experience any complications, including three patients who were still using Foley catheters at a median of 15 months (range 3-18). Two patients preferred the Foley catheter as feeding tubes. Six patients had replacements with formal balloon replacement tubes, and two patients did not require replacement. Complications occurred in nine (42.6%) patients: repeated burst Foley catheter balloon with peristomal leakage (n = 4), lumen blockage (n = 1), and catheter migration resulting in small bowel obstruction (n = 4). All complications were successfully managed with tube replacements. We showed that in a nurse-led service, using a Foley catheter as a temporary feeding gastrostomy tube is safe, but requires monitoring for complications. PMID- 27467059 TI - Risk Factors for Cholelithiasis. AB - Gallstone disease is one of the most common public health problems in the United States. Approximately 10%-20% of the national adult populations currently carry gallstones, and gallstone prevalence is rising. In addition, nearly 750,000 cholecystectomies are performed annually in the United States; direct and indirect costs of gallbladder surgery are estimated to be $6.5 billion. Cholelithiasis is also strongly associated with gallbladder, pancreatic, and colorectal cancer occurrence. Moreover, the National Institutes of Health estimates that almost 3,000 deaths (0.12% of all deaths) per year are attributed to complications of cholelithiasis and gallbladder disease. Although extensive research has tried to identify risk factors for cholelithiasis, several studies indicate that definitive findings still remain elusive. In this review, predisposing factors for cholelithiasis are identified, the pathophysiology of gallstone disease is described, and nonsurgical preventive options are discussed. Understanding the risk factors for cholelithiasis may not only be useful in assisting nurses to provide resources and education for patients who are diagnosed with gallstones, but also in developing novel preventive measures for the disease. PMID- 27467060 TI - Effects of Health Insurance Among Patients on Hepatitis C Treatment Along the Texas-Mexico Border. AB - The incidence and prevalence of hepatitis C virus (HCV) is steadily increasing across the world. Increasing morbidity and mortality rates associated with HCV are influencing research on treatment outcomes. The purpose of this project was to examine the effect of health insurance status and office visit compliance on sustained virologic response (SVR) in adult patients living along the Texas Mexico border treated for HCV and who received dual or triple medication therapy between January 2010 and August 2013. The objective of this project was to determine whether there is an association between health insurance status, and/or office visit compliance, and SVR. We conducted a longitudinal retrospective chart review pilot study of patients who underwent treatment with dual and triple therapy in a border community in Texas. Results revealed that lack of insurance did not affect SVR in the Texas Tech University Health Sciences Center El Paso based clinic setting due to enrollment into a managed healthcare program. Providing a financial benefit may improve treatment compliance of HCV-infected individuals, reduce overall cost, and improve the patient's quality of life. PMID- 27467061 TI - AN UNUSUAL CAUSE OF ANEMIA IN AN ELDER: ISOLATED SPLENIC HEMANGIOMATOSIS AND HEMORRHAGIC TELANGIECTASIA. PMID- 27467062 TI - CONSERVATIVE MANAGEMENT FOR PERSISTED LEAK AFTER THE OPERATIVE REPAIR OF AN ABDOMINAL ESOPHAGEAL PERFORATION: A CASE REPORT. PMID- 27467063 TI - "Skin Ditty": My Personal Poetry. PMID- 27467064 TI - Evaluating Prostate Cancer Using Fractional Tissue Composition of Radical Prostatectomy Specimens and Pre-Operative Diffusional Kurtosis Magnetic Resonance Imaging. AB - BACKGROUND: Evaluating tissue heterogeneity using non-invasive imaging could potentially improve prostate cancer assessment and treatment. METHODS: 20 patients with intermediate/high-risk prostate cancer underwent diffusion kurtosis imaging, including calculation of apparent diffusion (Dapp) and kurtosis (Kapp), prior to radical prostatectomy. Whole-mount tissue composition was quantified into: cellularity, luminal space, and fibromuscular stroma. Peripheral zone tumors were subdivided according to Gleason score. RESULTS: Peripheral zone tumors had increased cellularity (p<0.0001), decreased fibromuscular stroma (p<0.05) and decreased luminal space (p<0.0001). Gleason score >=4+3 tumors had significantly increased cellularity and decreased fibromuscular stroma compared to Gleason score <=3+4 (p<0.05). In tumors, there was a significant positive correlation between median Kapp and cellularity (rho = 0.50; p<0.05), and a negative correlation with fibromuscular stroma (rho = -0.45; p<0.05). In normal tissue, median Dapp had a significant positive correlation with luminal space (rho = 0.65; p<0.05) and a negative correlation with cellularity (rho = -0.49; p<0.05). Median Kapp and Dapp varied significantly between tumor and normal tissue (p<0.0001), but only median Kapp was significantly different between Gleason score >=4+3 and <=3+4 (p<0.05). CONCLUSIONS: Peripheral zone tumors have increased cellular heterogeneity which is reflected in mean Kapp, while normal prostate has a more homogeneous luminal space and cellularity better represented by Dapp. PMID- 27467065 TI - Comparison of Standing Posture Bioelectrical Impedance Analysis with DXA for Body Composition in a Large, Healthy Chinese Population. AB - Bioelectrical impedance analysis (BIA) is a common method for assessing body composition in research and clinical trials. BIA is convenient but when compared with other reference methods, the results have been inconclusive. The level of obesity degree in subjects is considered to be an important factor affecting the accuracy of the measurements. A total of 711 participants were recruited in Taiwan and were sub-grouped by gender and levels of adiposity. Regression analysis and Bland-Altman analysis were used to evaluate the agreement of the measured body fat percentage (BF%) between BIA and DXA. The BF% measured by the DXA and BIA methods (Tanita BC-418) were expressed as BF%DXA and BF%BIA8, respectively. A one-way ANOVA was used to test the differences in BF% measurements by gender and levels of adiposity. The estimated BF%BIA8 and BF%DXA in the all subjects, male and female groups were all highly correlated (r = 0.934, 0.901, 0.916, all P< 0.001). The average estimated BF%BIA8 (22.54 +/- 9.48%) was significantly lower than the average BF%DXA (26.26 +/- 11.18%). The BF%BIA8 was overestimated in the male subgroup (BF%DXA< 15%), compared to BF%DXA by 0.45%, respectively. In the other subgroups, the BF%BIA8 values were all underestimated. Standing BIA estimating body fat percentage in Chinese participants have a high correlation, but underestimated on normal and high obesity degree in both male and female subjects. PMID- 27467066 TI - A Validation Study of a Smartphone-Based Finger Tapping Application for Quantitative Assessment of Bradykinesia in Parkinson's Disease. AB - BACKGROUND: Most studies of smartphone-based assessments of motor symptoms in Parkinson's disease (PD) focused on gait, tremor or speech. Studies evaluating bradykinesia using wearable sensors are limited by a small cohort size and study design. We developed an application named smartphone tapper (SmT) to determine its applicability for clinical purposes and compared SmT parameters to current standard methods in a larger cohort. METHODS: A total of 57 PD patients and 87 controls examined with motor UPDRS underwent timed tapping tests (TT) using SmT and mechanical tappers (MeT) according to CAPSIT-PD. Subjects were asked to alternately tap each side of two rectangles with an index finger at maximum speed for ten seconds. Kinematic measurements were compared between the two groups. RESULTS: The mean number of correct tapping (MCoT), mean total distance of finger movement (T-Dist), mean inter-tap distance, and mean inter-tap dwelling time (IT DwT) were significantly different between PD patients and controls. MCoT, as assessed using SmT, significantly correlated with motor UPDRS scores, bradykinesia subscores and MCoT using MeT. Multivariate analysis using the SmT parameters, such as T-Dist or IT-DwT, as predictive variables and age and gender as covariates demonstrated that PD patients were discriminated from controls. ROC curve analysis of a regression model demonstrated that the AUC for T-Dist was 0.92 (95% CI 0.88-0.96). CONCLUSION: Our results suggest that a smartphone tapping application is comparable to conventional methods for the assessment of motor dysfunction in PD and may be useful in clinical practice. PMID- 27467067 TI - Correction: Predictors of Adherence to Multiple Clinical Preventive Recommendations among Adults with Diabetes in Spain. AB - [This corrects the article DOI: 10.1371/journal.pone.0131844.]. PMID- 27467068 TI - Safety Assessment of Two New Lactobacillus Strains as Probiotic for Human Using a Rat Model. AB - Two previously isolated Lactobacillus strains (L. fermentum HM3 from human milk and L. buchneri FD2 from fermented dates), intended as probiotic for human, were assessed for their safety using acute and subacute oral toxicity tests in rats. In addition, their effects on cecal microflora and harmful bacterial enzymes (beta-glucuronidase and beta-glucosidase) of the tested animals were also determined. The results showed that L. buchneri FD2, L. fermentum HM3, or a mixture of them were safe up to a level of 1010 CFU/kg BW/day in a 14-day or 28 day treatment period. Both strains were well tolerated and there were no observed adverse effects on growth, feed consumption, cellular blood components and vital organs of the treated animals. The Lactobacillus strains were also able to reduce harmful intestinal bacterial enzymes, and decrease pathogenic bacterial populations while increasing beneficial bacterial populations. These results suggest that the two Lactobacillus strains are safe and could be potential probiotic for human. PMID- 27467069 TI - Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia. AB - Leptomeningeal anastomoses play a critical role in regulating vascular re perfusion following obstruction, however, the mechanisms regulating their development remains under investingation. Our current findings indicate that EphA4 receptor is a novel negative regulator of collaterogenesis. We demonstrate that EphA4 is highly expressed on pial arteriole collaterals at post-natal day (P) 1 and 7, then significantly reduced by P21. Endothelial cell (EC)-specific loss of EphA4, EphA4f/f/Tie2::Cre (KO), resulted in an increase in the density but not diameter of pial collaterals compared to WT mice. ECs isolated from KO mice displayed a 3-fold increase in proliferation, enhanced migration, tube formation and elevated levels of phospho(p)-Akt compared to WT ECs. Attenuating p Akt, using LY294002, reduced the proliferative and migration effects in the KO ECs. RNAseq analysis also revealed altered expression patterns for genes that regulate cell proliferation, vascular development, extracellular matrix and immune-mediate responses, namely MCP-1, MMP2 and angiopoietin-1. Lastly, we show that induction of hindlimb ischemia resulted in accelerated re-perfusion, collateral remodeling and reduced tissue necrosis in the absence of EC-specific EphA4 compared to WT mice. These findings demonstrate a novel role for EphA4 in the early development of the pial collateral network and suggests a role in regulating vascular remodeling after obstruction. PMID- 27467070 TI - Selection on a Subunit of the NURF Chromatin Remodeler Modifies Life History Traits in a Domesticated Strain of Caenorhabditis elegans. AB - Evolutionary life history theory seeks to explain how reproductive and survival traits are shaped by selection through allocations of an individual's resources to competing life functions. Although life-history traits evolve rapidly, little is known about the genetic and cellular mechanisms that control and couple these tradeoffs. Here, we find that two laboratory-adapted strains of C. elegans descended from a single common ancestor that lived in the 1950s have differences in a number of life-history traits, including reproductive timing, lifespan, dauer formation, growth rate, and offspring number. We identified a quantitative trait locus (QTL) of large effect that controls 24%-75% of the total trait variance in reproductive timing at various timepoints. Using CRISPR/Cas9-induced genome editing, we show this QTL is due in part to a 60 bp deletion in the 3' end of the nurf-1 gene, which is orthologous to the human gene encoding the BPTF component of the NURF chromatin remodeling complex. Besides reproduction, nurf-1 also regulates growth rate, lifespan, and dauer formation. The fitness consequences of this deletion are environment specific-it increases fitness in the growth conditions where it was fixed but decreases fitness in alternative laboratory growth conditions. We propose that chromatin remodeling, acting through nurf-1, is a pleiotropic regulator of life history trade-offs underlying the evolution of multiple traits across different species. PMID- 27467071 TI - DNA-Dye-Conjugates: Conformations and Spectra of Fluorescence Probes. AB - Extensive molecular-dynamics (MD) simulations have been used to investigate DNA dye and DNA-photosensitizer conjugates, which act as reactants in templated reactions leading to the generation of fluorescent products in the presence of specific desoxyribonucleic acid sequences (targets). Such reactions are potentially suitable for detecting target nucleic acids in live cells by fluorescence microscopy or flow cytometry. The simulations show how the attached dyes/photosensitizers influence DNA structure and reveal the relative orientations of the chromophores with respect to each other. Our results will help to optimize the reactants for the templated reactions, especially length and structure of the spacers used to link reporter dyes or photosensitizers to the oligonucleotides responsible for target recognition. Furthermore, we demonstrate that the structural ensembles obtained from the simulations can be used to calculate steady-state UV-vis absorption and emission spectra. We also show how important quantities describing the quenching of the reporter dye via fluorescence resonance energy transfer (FRET) can be calculated from the simulation data, and we compare these for different relative chromophore geometries. PMID- 27467072 TI - pH-Responsive Polyethylene Glycol Monomethyl Ether-epsilon-Polylysine-G-Poly (Lactic Acid)-Based Nanoparticles as Protein Delivery Systems. AB - The application of poly(lactic acid) for sustained protein delivery is restricted by the harsh pH inside carriers. In this study, we synthesized a pH-responsive comb-shaped block copolymer, polyethylene glycol monomethyl ether-epsilon polylysine-g-poly (lactic acid) (PEP)to deliver protein (bovine serum albumin (BSA)). The PEP nanoparticles could automatically adjust the internal pH to a milder level, as shown by the quantitative ratio metric results. The circular dichroism spectra showed that proteins from the PEP nanoparticles were more stable than those from poly(lactic acid) nanoparticles. PEP nanoparticles could achieve sustained BSA release in both in vitro and in vivo experiments. Cytotoxicity results in HL-7702 cells suggested good cell compatibility of PEP carriers. Acute toxicity results showed that the PEP nanoparticles induced no toxic response in Kunming mice. Thus, PEP nanoparticles hold potential as efficient carriers for sustained protein release. PMID- 27467073 TI - Models to identify treatments for the acute and persistent effects of seizure inducing chemical threat agents. AB - Exposures to seizure-inducing chemical threat agents are a major public health concern. Of particular need is improved treatment to terminate convulsions and to prevent the long-term neurological sequelae in survivors. We are studying the organophosphorus cholinesterase inhibitor diisopropyl fluorophosphate (DFP) and the GABA receptor inhibitor tetramethylenedisulfotetramine (TETS), which arguably encompass the mechanistic spectrum of seizure-inducing chemical threats, with the goal of identifying therapeutic approaches with broad-spectrum efficacy. Research efforts have focused on developing translational models and translational diagnostic approaches, including (1) in vivo models of DFP- and TETS-induced seizures for studying neuropathological mechanisms and identifying treatment approaches; (2) in vivo imaging modalities for noninvasive longitudinal monitoring of neurological damage and response to therapeutic candidates; and (3) higher-throughput in vitro platforms for rapid screening of compounds to identify potential antiseizure and neuroprotective agents, as well as mechanistically relevant novel drug targets. This review summarizes our progress toward realizing these goals and discusses best practices and mechanistic insights derived from our modeling efforts. PMID- 27467074 TI - Molecular Scanning and Morpho-Physiological Dissection of Component Mechanism in Lens Species in Response to Aluminium Stress. AB - Aluminium (Al) stress was imposed on 285 lentil genotypes at seedling stage under hydroponics to study its effects on morpho-physiological traits where resistant cultigens and wilds showed minimum reduction in root and shoot length and maximum root re-growth (RRG) after staining. Molecular assortment based on 46 simple sequence repeat (SSR) markers clustered the genotypes into 11 groups, where wilds were separated from the cultigens. Genetic diversity and polymorphism information content (PIC) varied between 0.148-0.775 and 0.140-0.739, respectively. Breeding lines which were found to be most resistant (L-7903, L-4602); sensitive cultivars (BM-4, L-4147) and wilds ILWL-185 (resistant), ILWL-436 (sensitive) were grouped into different clusters. These genotypes were also separated on the basis of population structure and Jaccard's similarity index and analysed to study Al resistance mechanism through determination of different attributes like localization of Al and callose, lipid peroxidation, secretion of organic acids and production of antioxidant enzymes. In contrast to sensitive genotypes, in resistant ones most of the Al was localized in the epidermal cells, where its movement to apoplastic region was restricted due to release of citrate and malate. Under acidic field conditions, resistant genotypes produced maximum seed yield/plant as compared to sensitive genotypes at two different locations i.e. Imphal, Manipur, India and Basar, Arunanchal Pradesh, India during 2012-13, 2013 14 and 2014-15. These findings suggest that Al stress adaptation in lentil is through exclusion mechanism and hybridization between the contrasting genotypes from distinct clusters can help in development of resistant varieties. PMID- 27467075 TI - Toxicity of individual pharmaceuticals and their mixtures to Aliivibrio fischeri: Experimental results for single compounds and considerations of their mechanisms of action and potential acute effects on aquatic organisms. AB - In the first part of a broader study on the effects of individual and multicomponent mixtures of pharmaceutical active compounds, the authors used the Microtox(r) test system to analyze in detail the effects of 10 widely used human and veterinary pharmaceutical active compounds toward the bioluminescent bacterium Aliivibrio fischeri. The experimental results indicated moderate toxicity for the majority of the tested compounds. Comparison between experimental 50% inhibitory concentrations and those predicted from the quantitative structure-activity relationship models indicated that most of the tested pharmaceutical active compounds behave as polar narcotic compounds toward A. fischeri (only the antibiotic chlortetracycline seemed to have a specific mechanism of action). A comparison between the experimental results and a collection of acute toxicity data on other nontarget organisms indicated that in general A. fischeri has a comparable sensitivity to other aquatic species. However, according to the Globally Harmonized System of Classification and Labelling of Chemicals, the majority of the investigated chemicals can be classified as harmful or nontoxic for aquatic ecosystems. Finally, based on comparisons among the 95th percentile of measured environmental concentrations found in European Union water bodies and acute toxicity data on various aquatic organisms, no risk to aquatic life exists when the tested pharmaceutical active compounds are assessed as individual chemicals. Environ Toxicol Chem 2017;36:807 814. (c) 2016 SETAC. PMID- 27467076 TI - Diterpenoids of terrestrial origin. AB - Covering January to December 2015. Previous review; Nat. Prod. Rep., 2015, 32, 1654-1663.This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 214 references. PMID- 27467077 TI - Smoking Is Associated with an Increased Risk for Surgery in Diverticulitis: A Case Control Study. AB - IMPORTANCE: Cigarette smoking increases the risk of surgery in Crohn's disease. However, the effect of smoking on the need for surgery for diverticulitis is unknown. OBJECTIVE: We evaluated whether smoking was a risk factor for surgery among patients admitted to hospital with acute diverticulitis. DESIGN: We conducted a population-based comparative cohort study of patients admitted to hospital for diverticulitis who were treated with medical versus surgical management. SETTING & PARTICIPANTS: We used the population-based Discharge Abstract Database to identify 176 adults admitted emergently with a diagnosis of diverticulitis between 2009 and 2010 in Calgary. INTERVENTION & MAIN OUTCOME: We performed a medical chart review to confirm the diagnosis of diverticulitis and to extract clinical data. The primary outcome was a partial colectomy during hospitalization. Logistic regression evaluated the association between smoking and surgery after adjusting for potential confounders, including age, sex, comorbidity, and disease severity. RESULTS: A partial colectomy was performed on 35.6% of patients with diverticulitis and 1.3% died. Among diverticulitis patients, 26.8% were current smokers, 31.5% were ex-smokers, and 41.6% never smoked. Compared to non-smokers, current smokers (adjusted odds ratio [OR] 9.02; 95% confidence interval [CI]: 2.47-32.97) and former smokers (adjusted OR 5.41; 95% CI: 1.54-18.96) had increased odds of surgery. CONCLUSION AND RELEVANCE: Smoking is associated with the need for surgical management of diverticulitis. PMID- 27467078 TI - Up-Regulation of CYP2C19 Expression by BuChang NaoXinTong via PXR Activation in HepG2 Cells. AB - BACKGROUND: Cytochrome P450 2C19 (CYP2C19) is an important drug-metabolizing enzyme (DME), which is responsible for the biotransformation of several kinds of drugs such as proton pump inhibitors, platelet aggregation inhibitors and antidepressants. Previous studies showed that Buchang NaoXinTong capsules (NXT) increased the CYP2C19 metabolic activity in vitro and enhanced the antiplatelet effect of clopidogrel in vivo. However, the underlying molecular mechanism remained unclear. In the present study, we examined whether Pregnane X receptor (PXR) plays a role in NXT-mediated regulation of CYP2C19 expression. METHODS: We applied luciferase assays, real-time quantitative PCR (qPCR), Western blotting and cell-based analysis of metabolic activity experiments to investigate the NXT regulatory effects on the CYP2C19 promoter activity, the mRNA/ protein expression and the metabolic activity. RESULTS: Our results demonstrated that NXT significantly increased the CYP2C19 promoter activity when co-transfected with PXR in HepG2 cells. Mutations in PXR responsive element abolished the NXT inductive effects on the CYP2C19 promoter transcription. Additionally, NXT incubation (150 and 250MUg/mL) also markedly up-regulated endogenous CYP2C19 mRNA and protein levels in PXR-transfected HepG2 cells. Correspondingly, NXT leaded to a significant enhancement of the CYP2C19 catalytic activity in PXR-transfected HepG2 cells. CONCLUSION: In summary, this is the first study to suggest that NXT could induce CYP2C19 expression via PXR activation. PMID- 27467079 TI - Genetic Screen in Drosophila Larvae Links ird1 Function to Toll Signaling in the Fat Body and Hemocyte Motility. AB - To understand how Toll signaling controls the activation of a cellular immune response in Drosophila blood cells (hemocytes), we carried out a genetic modifier screen, looking for deletions that suppress or enhance the mobilization of sessile hemocytes by the gain-of-function mutation Toll10b (Tl10b). Here we describe the results from chromosome arm 3R, where five regions strongly suppressed this phenotype. We identified the specific genes immune response deficient 1 (ird1), headcase (hdc) and possibly Rab23 as suppressors, and we studied the role of ird1 in more detail. An ird1 null mutant and a mutant that truncates the N-terminal kinase domain of the encoded Ird1 protein affected the Tl10b phenotype, unlike mutations that affect the C-terminal part of the protein. The ird1 null mutant suppressed mobilization of sessile hemocytes, but enhanced other Tl10b hemocyte phenotypes, like the formation of melanotic nodules and the increased number of circulating hemocytes. ird1 mutants also had blood cell phenotypes on their own. They lacked crystal cells and showed aberrant formation of lamellocytes. ird1 mutant plasmatocytes had a reduced ability to spread on an artificial substrate by forming protrusions, which may explain why they did not go into circulation in response to Toll signaling. The effect of the ird1 mutation depended mainly on ird1 expression in hemocytes, but ird1-dependent effects in other tissues may contribute. Specifically, the Toll receptor was translocated from the cell membrane to intracellular vesicles in the fat body of the ird1 mutant, and Toll signaling was activated in that tissue, partially explaining the Tl10b-like phenotype. As ird1 is otherwise known to control vesicular transport, we conclude that the vesicular transport system may be of particular importance during an immune response. PMID- 27467080 TI - Insight on Mutation-Induced Resistance from Molecular Dynamics Simulations of the Native and Mutated CSF-1R and KIT. AB - The receptors tyrosine kinases (RTKs) for the colony stimulating factor-1, CSF 1R, and for the stem cell factor, SCFR or KIT, are important mediators of signal transduction. The abnormal function of these receptors, promoted by gain-of function mutations, leads to their constitutive activation, associated with cancer or other proliferative diseases. A secondary effect of the mutations is the alteration of receptors' sensitivity to tyrosine kinase inhibitors, compromising effectiveness of these molecules in clinical treatment. In particular, the mutation V560G in KIT increases its sensitivity to Imatinib, while the D816V in KIT, and D802V in CSF-1R, triggers resistance to the drug. We analyzed the Imatinib binding affinity to the native and mutated KIT (mutations V560G, S628N and D816V) and CSF-1R (mutation D802V) by using molecular dynamics simulations and energy calculations of Imatinib*target complexes. Further, we evaluated the sensitivity of the studied KIT receptors to Imatinib by measuring the inhibition of KIT phosphorylation. Our study showed that (i) the binding free energy of Imatinib to the targets is highly correlated with their experimentally measured sensitivity; (ii) the electrostatic interactions are a decisive factor affecting the binding energy; (iii) the most deleterious impact to the Imatinib sensitivity is promoted by D802V (CSF-1R) and D816V (KIT) mutations; (iv) the role of the juxtamembrane region, JMR, in the imatinib binding is accessory. These findings contribute to a better description of the mutation-induced effects alternating the targets sensitivity to Imatinib. PMID- 27467082 TI - A Library of Fluorinated Electrophiles for Chemical Tagging and Materials Synthesis. AB - Various applications could benefit from new fluorinated molecules that offer chemical handles for quickly functionalizing reactive surfaces and molecules. Herein, we report the synthesis of a library of fluorinated molecules that contain nonafluoro-tert-butyl groups and electrophilic handles, mostly acrylates and acrylamides. Featuring a variety of hydrophobic and hydrophilic linkers, these molecules could find use in polymer chemistry, biomaterials, biomedical imaging, and protein tagging. PMID- 27467081 TI - The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia. AB - The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5' [1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS 933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc) and set shift performance in rats (1-10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po). BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc) and mismatch negativity (0.03-3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans. PMID- 27467083 TI - Influence of Immunology Knowledge on Healthcare and Healthy Lifestyle. AB - Completing a course in Immunology is expected to improve health care knowledge (HCK), which in turn is anticipated to influence a healthy lifestyle (HLS), controlled use of health care services (HCS) and an awareness of emerging health care concerns (HCC). This cross-sectional study was designed to determine whether these interrelationships are empirically supported. Participants involved in this study were government servants from two ministries in Malaysia (n = 356) and university students from a local university (n = 147). Participants were selected using the non-random purposive sampling method. Data were collected using a self developed questionnaire, which had been validated in a pilot study involving similar subjects. The questionnaire items were analyzed using Rasch analysis, SPSS version 21 and AMOS version 22. Results have shown that participants who followed a course in Immunology (CoI) had a higher primary HCK (Mean = 0.69 logit, SD = 1.29 logits) compared with those who had not (Mean = -0.27logit, SD = 1.26 logits). Overall, there were significant correlations among the HLS, the awareness of emerging HCC, and the controlled use of HCS (p <0.001). However, no significant correlations were observed between primary HCK and the other variables. However, significant positive correlation was observed between primary HCK and controlled use of HCS for the group without CoI. Path analysis showed that the awareness of emerging HCC exerted a positive influence on controlled use of HCS (beta = 0.156, p < .001) and on HLS (beta = 0.224, p < .001). These findings suggest that having CoI helps increase primary HCK which influences controlled use of HCS but does not necessarily influence HLS. Hence, introducing Immunology at various levels of education and increasing the public awareness of emerging HCC might help to improve population health en masse. In addition, further investigations on the factors affecting HLS is required to provide a better understanding on the relationship between primary HCK and HLS. PMID- 27467084 TI - Career Coaches as a Source of Vicarious Learning for Racial and Ethnic Minority PhD Students in the Biomedical Sciences: A Qualitative Study. AB - INTRODUCTION: Many recent mentoring initiatives have sought to help improve the proportion of underrepresented racial and ethnic minorities (URMs) in academic positions across the biomedical sciences. However, the intractable nature of the problem of underrepresentation suggests that many young scientists may require supplemental career development beyond what many mentors are able to offer. As an adjunct to traditional scientific mentoring, we created a novel academic career "coaching" intervention for PhD students in the biomedical sciences. OBJECTIVE: To determine whether and how academic career coaches can provide effective career development-related learning experiences for URM PhD students in the biomedical sciences. We focus specifically on vicarious learning experiences, where individuals learn indirectly through the experiences of others. METHOD: The intervention is being tested as part of a longitudinal randomized control trial (RCT). Here, we describe a nested qualitative study, using a framework approach to analyze data from a total of 48 semi-structured interviews from 24 URM PhD students (2 interviews per participant, 1 at baseline, 1 at 12-month follow-up) (16 female, 8 male; 11 Black, 12 Hispanic, 1 Native-American). We explored the role of the coach as a source of vicarious learning, in relation to the students' goal of being future biomedical science faculty. RESULTS: Coaches were resources through which most students in the study were able to learn vicariously about how to pursue, and succeed within, an academic career. Coaches were particularly useful in instances where students' research mentors are unable to provide such vicarious learning opportunities, for example because the mentor is too busy to have career-related discussions with a student, or because they have, or value, a different type of academic career to the type the student hopes to achieve. IMPLICATIONS: Coaching can be an important way to address the lack of structured career development that students receive in their home training environment. PMID- 27467085 TI - Structure-Based Pharmacophores for Virtual Screening. AB - Pharmacophores describe the spatial arrangement of essential interactions in a receptor-ligand complex. Although highly established in ligand-based virtual screening, the application of pharmacophores for in absence of a ligand is more sophisticated. This article summarizes the recent approaches to derive and evaluate pharmacophore models using only limited information (e.g. a homology model of the binding site). A range of different methodologies including geometrical and/or potential-based methods and successes in the application to virtual screening problems are described. Advantages and current limitations of the state-of-the-art methods and future perspectives for development are discussed in this publication. PMID- 27467086 TI - In Silico Target Profiling of One Billion Molecules. PMID- 27467087 TI - Molecular Features Underlying the Perception of Astringency as Probed by Molecular Modeling. PMID- 27467088 TI - In Silico Studies of the Relationship Between Chemical Structure and Drug Induced Phospholipidosis. AB - Drug-induced phospholipidosis (PLD) is a side effect of the administration of cationic amphiphilic drugs (CADs). It is desirable to identify and screen compounds with the potential to induce PLD as early as possible in drug development. Recently, a number of in silico methods have been developed to predict PLD. These models are low-cost and high-throughput strategies; however, they produce a high number of false positive predictions. The aim of this study was to assess the predictive performance of existing in silico approaches and to develop new strategies for the rapid identification of the potential PLD inducers. Studies on 450 chemicals confirmed the high false positive rate of prediction of models based only on log P and pKa values. Modification of the methods by incorporating structural information gave moderate improvements in the prediction performance. Therefore, a new strategy, based on molecular fragments captured by SMARTS strings was developed. These structural fragments were able to identify potential PLD-inducers and achieved a high sensitivity of 85 %. The results showed that the phospholipidosis is linked directly to the molecular structure of chemical; therefore the SMARTS pattern methodology could be used as a first line of screening of PLD potential during the drug discovery process. PMID- 27467089 TI - Contribution of Non-Canonical Interactions to the Stability of Sm/LSm Oligomeric Assemblies. AB - The distinguishing property of Sm/LSm protein assemblies is their high stability. In order to better understand the nature of Sm/LSm protein oligomers in this study we have analyzed the contribution of non-canonical interactions to the stability of assemblies. The predominant types of non-canonical interactions at Sm/LSm protein interfaces are CH???O, and CH???N interactions represented at interfaces. Our results show low percentages of XH-pi and non-canonical interactions involving sulfur atoms, while the backbone groups were less frequently involved. The data show a high percentage of non-canonical interactions in interfaces formed by charged residues with Lys and Arg, these being the major charged donors. The main chain non-canonical interactions might be slightly more linear than the side chain interactions, and they have somewhat shorter median distances. Comparing the stabilizing amino acid residues with amino acids which build non-canonical interactions at interfaces shows that certain amino acids like Phe, Pro, His and Tyr are involved with a high percentage. The high conservation score of amino acids that are involved in non canonical interactions in protein interfaces is an additional strong argument for their importance in the stabilization of Sm/LSm protein assemblies. PMID- 27467090 TI - Development and Comparison of hERG Blocker Classifiers: Assessment on Different Datasets Yields Markedly Different Results. AB - In recent years, considerable effort has been invested in the development of classification models for prospective hERG inhibitors, due to the implications of hERG blockade for cardiotoxicity and the low throughput of functional hERG assays. We present novel approaches for binary classification which seek to separate strong inhibitors (IC50 <1 uM) from 'non-blockers' exhibiting moderate (1-10 uM) or weak (IC50 >=10 uM) inhibition, as required by the pharmaceutical industry. Our approaches are based on (discretized) 2D descriptors, selected using Winnow, with additional models generated using Random Forest (RF) and Support Vector Machines (SVMs). We compare our models to those previously developed by Thai and Ecker and by Dubus et al. The purpose of this paper is twofold: 1. To propose that our approaches (with Matthews Correlation Coefficients from 0.40 to 0.87 on truly external test sets, when extrapolation beyond the applicability domain was not evident and sufficient quantities of data were available for training) are competitive with those currently proposed in the literature. 2. To highlight key issues associated with building and assessing truly predictive models, in particular the considerable variation in model performance when training and testing on different datasets. PMID- 27467091 TI - Docking and Molecular Dynamics Calculations of Pyrrolidinone Analog MMK16 Bound to COX and LOX Enzymes. AB - The new molecule 4-[(2S)-2-(1H-imidazol-1-ylmethyl)-5-oxotetrahydro-1H-pyrrol-1 yl]methylbenzenecarboxylic acid (MMK16) was found to have promising anti inflammatory activity. This biological behavior of MMK16 triggered our interest to study its binding affinity using NMR spectroscopy in LOX and its docking and molecular dynamics (MD) properties in LOX and COX enzymes. The present NMR and docking binding studies not only rationalize the obtained biological results since in all three receptors MMK16 shows high affinity and scoring but also make it a potential dual LOX-5/COX-2 inhibitor. Thus, this class of molecules must be further investigated for discovering compounds possessing better biological activity and more lasting biological effect. PMID- 27467092 TI - Outcome after carpal tunnel release: impact of factors related to metabolic syndrome. AB - OBJECTIVE: The standard surgical treatment of carpal tunnel syndrome (CTS), with an open carpal tunnel release, is reported to relieve symptoms in most patients. In a retrospective observational study, outcome after open carpal tunnel release was evaluated, focusing on factors related to the metabolic syndrome: diabetes, hypertension, obesity (BMI >=30) and statin treatment. METHODS: Results from 493 out of 962 patients (531/1044 hands) operated for CTS during 18 months that had filled in QuickDASH questionnaires before and 1-year after surgery were included in the study. RESULTS: Patients with diabetes (n = 76) had higher QuickDASH scores pre- (56 [36-77]; i.e. median [interquartile range]) and postoperatively (31 [9-61]) compared to patients without diabetes (48 [32-66]; p < 0.05 and 16 [5 43]; p < 0.001), but the change in total score was equal. A higher proportion of patients with diabetes had a postoperative score of >10 (74% vs 61%; p < 0.05). The odds of having a change in QuickDASH score <8 was 2.6-times higher in patients with polyneuropathy than in patients without polyneuropathy. Patients with hypertension, obesity, or statin treatment had a similar improvement after surgery as patients without these factors. CONCLUSIONS: Patients with diabetes without neuropathy, as well as patients with hypertension, obesity or statin treatment, and CTS can expect the same effects of open carpal tunnel release as otherwise healthy patients. Patients with diabetic neuropathy and CTS did not experience the same improvement as otherwise healthy patients and should be informed about the risk of an unsatisfactory outcome. PMID- 27467093 TI - Role of Regulatory T Cells in Tubercular Uveitis. AB - PURPOSE: To study the role of regulatory T cells (Tregs) in patients with tubercular uveitis. METHODS: Frequencies of peripheral Tregs, Th1, Th17 cells, and intracellular cytokines were determined in 17 tubercular uveitis patients and 18 disease controls. Function of Tregs, Th1, and Th17 cells was assessed in vitro. Simultaneously, ocular levels of IFN-gamma, IL-17A, IL-4, and IL-10 were also measured. RESULTS: Frequencies of peripheral Tregs in tubercular uveitis subjects were significantly lower compared with disease controls. Furthermore, expression of TGF-beta and IL-2Ralpha, but not CTLA4, was reduced in Tregs of the tubercular uveitis group. The tubercular uveitis group demonstrated heightened Th1, Th17 responses following in vitro stimulation with phorbol myristate acetate (PMA)/ionomycin. Interestingly, Treg suppression assay did not show a significant difference between the two groups. Ocular levels of IFN-gamma, IL-17A, and IL-10 were also elevated in tubercular uveitis group. CONCLUSIONS: Low Treg frequency and hyporesponsive function contribute to proinflammatory responses manifesting at ocular level in tubercular uveitis. PMID- 27467094 TI - Recent Trends in Primary Care Interest and Career Choices Among Medical Students at an Academic Medical Institution. AB - : Phenomenon: As an impending shortage of primary care physicians is expected, understanding career trajectories of medical students will be useful in supporting interest in primary care fields and careers. The authors sought to characterize recent trends in primary care interest and career trajectories among medical students at an academic medical institution that did not have a family medicine department. APPROACH: Match data for 2,477 graduates who matched into resident training programs between 1989 and 2014 were analyzed to determine the proportion entering primary care residency programs. An online search and confirmatory phone call methodology was used to determine primary care career trajectories for the 795 graduates who matched into primary care residency programs between 1989 to 2010. Subanalyses were performed to characterize primary care career entrance among graduates who matched into the three primary care residency programs: Family Medicine, Categorical and Primary Care Internal Medicine, and Categorical and Primary Care Pediatrics. FINDINGS: Between 1989 and 2014, 911 (37%) of all matched graduates matched into primary care residency programs. Of the 795 graduates who matched into these programs between 1989 and 2010, less than half (245; 31%) entered primary care careers. Of the graduates who ultimately entered primary care careers, 82% matched into either internal medicine or pediatrics residency programs and 18% matched into family medicine programs. Although there have been fluctuations in primary care interest that seem to parallel health care trends over the 26-year period, the overall percentage of graduates entering primary care residency programs and careers has remained fairly stable. Between 2006 and 2010, entrance into both primary care residency programs and primary care careers steadily increased. Despite this, the overall percentage of matched graduates who entered primary care careers over the 22-year study period (12%) was less than the national average (16%-18%). Insights: In the 26-year period between 1989 and 2014, primary care career interest increased slightly among medical students at this academic medical institution, with fluctuations that seem to coincide with national health care trends. Year-to-year fluctuations appear to be driven by rising numbers of Categorical Pediatrics and Categorical Internal Medicine matchers pursuing careers in primary care. There may be a need for specialized curricula and strategies to promote and retain interest in primary care at academic medical institutions, especially at institutions without family medicine training programs. PMID- 27467095 TI - Ewing Sarcoma and Atypical Teratoid Rhabdoid Tumor: A FISH and Immunohistochemical Comparison. AB - Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) and atypical teratoid rhabdoid tumor (ATRT) are high-grade malignancies of childhood, each of which is associated with genetic abnormalities on chromosome 22. ES is typically characterized by rearrangement of the EWSR1 locus and ATRT by deletion of SMARCB1. We report a case with an unusual FISH signal pattern consistent with EWSR1 rearrangement that was shown to have loss of INI1 expression by immunohistochemistry due to deletion in the long arm of one chromosome 22. In light of the unusual findings in this case as well as the proximity of the EWSR1 locus and SMARCB1 locus on chromosome 22 and frequent CD99 staining in both tumors, we examined 16 ES cases and 17 ATRT, renal rhabdoid tumor (RRT), and extrarenal rhabdoid tumor (ERRT) cases for CD99 and INI1 staining and for EWSR1 rearrangement. Staining with INI1 was negative in ATRT, RRT, and ERRT and positive in ES cases; CD99 was positive in ES cases and variable in ATRT cases. All but 2 cases of ES, and no cases of ATRT, showed rearrangement of EWSR1. The present case appears to be best classified as a unique variant of ATRT based on immunohistochemistry, EWSR1 FISH and RT-PCR, and SMARCB1 gene sequencing. PMID- 27467096 TI - What is your diagnosis? Subcutaneous mass from a dog. PMID- 27467097 TI - Testing the Ability of the NSQIP Risk Calculator to Predict Laryngectomy Complications. PMID- 27467098 TI - What Happens When Underperforming Big Ideas in Research Become Entrenched? PMID- 27467099 TI - Polymer Encapsulation of an Amorphous Pharmaceutical by initiated Chemical Vapor Deposition for Enhanced Stability. AB - The usage of amorphous solids in practical applications, such as in medication, is commonly limited by the poor long-term stability of this state, because unwanted crystalline transitions occur. In this study, three different polymeric coatings are investigated for their ability to stabilize amorphous films of the model drug clotrimazole and to protect against thermally induced transitions. For this, drop cast films of clotrimazole are encapsulated by initiated chemical vapor deposition (iCVD), using perfluorodecyl acrylate (PFDA), hydroxyethyl methacrylate (HEMA), and methacrylic acid (MAA). The iCVD technique operates under solvent-free conditions at low temperatures, thus leaving the solid state of the encapsulated layer unaffected. Optical microscopy and X-ray diffraction data reveal that at ambient conditions of about 22 degrees C, any of these iCVD layers extends the lifetime of the amorphous state significantly. At higher temperatures (50 or 70 degrees C), the p-PFDA coating is unable to provide protection, while the p-HEMA and p-MAA strongly reduce the crystallization rate. Furthermore, p-HEMA and p-MAA selectively facilitate a preferential alignment of clotrimazole and, interestingly, even suppress crystallization upon a temporary, rapid temperature increase (3 degrees C/min, up to 150 degrees C). The results of this study demonstrate how a polymeric coating, synthesized directly on top of an amorphous phase, can act as a stabilizing agent against crystalline transitions, which makes this approach interesting for a variety of applications. PMID- 27467100 TI - Supporting continuity of care between prison and the community for women in prison: a medical record review. AB - Objectives The aim of the present study was to examine health information transfer and continuity of care arrangements between prison and community health care providers (HCPs) for women in prison. Methods Medical records of women released from New South Wales prisons in 2013-14 were reviewed. Variables included health status, health care in prison and documented continuity of care arrangements, including information transfer between prison and community. Associations were measured by adjusted odds ratios (AORs) using a logistic regression model. Text from the records was collected as qualitative data and analysed to provide explanatory detail. Results In all, 212 medical records were systematically sampled and reviewed. On prison entry, information was requested from community HCPs in 53% of cases, mainly from general practitioners (GPs, 39%), and was more likely to have occurred for those on medication (AOR 7.08; 95% confidence interval (CI) 3.71, 13.50) or with schizophrenia or other psychotic disorders (AOR 4.20; 95% CI 1.46, 12.11). At release, continuity of care arrangements and health information transfer to GPs were usually linked to formal pre-release healthcare linkage programs. Outside these programs, only 20% of records had evidence of such continuity of care at release, with the odds higher for those on medication (AOR 8.28; 95% CI 1.85, 37.04) and lower for women with problematic substance misuse (AOR 0.32; 95% CI 0.14, 0.72). Few requests for information were received after individuals had been released from custody (5/212; two from GPs). Conclusion Increased health information transfer to community HCPs is needed to improve continuity of care between prison and community. What is known about the topic? Many women in prison have high health needs. Health and well being are at further risk at the time of transition between prison and community. What does this paper add? This study provides evidence that outside formal programs, which are currently available only for a minority of women, continuity of care arrangements and transfer of health information do not usually occur when women leave prison. Pragmatic choices about continuity of care at the interface between prison and community may have been made, particularly focusing on medication continuity. Barriers to continuity of care and ways forward are suggested. What are the implications for practitioners? Siloing of health care delivered within prison health services through lack of continuity of care at release is wasteful, both in terms of healthcare costs and lost opportunities to achieve health outcomes in a vulnerable population with high health needs. There is need for an increased focus on continuity of care between prison and community health services, HCP support and training and expansion of pre-release planning and healthcare linkage programs to assist larger numbers of women in prison. PMID- 27467101 TI - A Unique Case of Bilateral Hurthle Cell Adenoma in an Adolescent. AB - BACKGROUND: Hurthle cell (HC) neoplasms are rare among pediatric thyroid cancers. HC adenomas (HCA) are typically benign and localized unilaterally without recurrence, and they are thus treated by hemithyroidectomy. HC carcinomas (HCC) can be bilateral and are more aggressive, necessitating total thyroidectomy. Diagnosis relies upon surgical histopathology demonstrating invasion for classification as HCC or lack of invasion in HCA, since fine needle aspiration fails to differentiate between the two. METHODS: We report a case of a 14-year old adolescent female with bilateral HCA. She had an initial left hemithyroidectomy for a large nodule measuring 2 * 1.5 * 1.2 cm3 in the left lobe, while smaller subcentimeter nodules remained under surveillance in the right. One year later, a nodule in the right lobe doubled in size, necessitating a right hemithyroidectomy which also revealed HCA. CONCLUSION: To our knowledge, this is the first reported case of bilateral HCA in pediatrics. It highlights the importance of close surveillance of persistent small nodules, even in patients with previously documented benign lesions such as HCA, which are typically thought to be unilateral and localized. Both HCA and HCC remain unpredictable in behavior, and treatment of HCA should be individualized. PMID- 27467102 TI - NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model. AB - BACKGROUND/AIMS: Type 1 diabetes (T1D) is characterized by absolute insulin deficiency due to destruction of pancreatic beta-cells by cytokines (e.g., interleukin-1beta; IL-1beta) released by invading immune cells. The mechanisms by which these cytokines induce beta-cell dysfunction remain poorly understood. Recent evidence suggests that excessive generation of reactive oxygen species (ROS) by the phagocyte-like NADPH oxidase2 (Nox2), along with significantly low levels of antioxidants in beta-cells, drive them toward oxidative damage. Rac1, a small G-protein, is one of the members of Nox2 holoenzyme. We recently reported that NSC23766, a known inhibitor of Rac1, significantly attenuated cytokine induced Nox2 activation and ROS generation in pancreatic islet beta-cells in vitro. Herein, we determined the effects of NSC23766 (2.5 mg/kg/day, i.p/daily) on the development of diabetes in the NOD mouse, a model for T1D. METHODS: Two groups of experimental animals (Balb/c and NOD mice) received NSC23766, while the two control groups received equal volume of saline. Body weights and blood glucose were measured every week for 34 weeks. Rac1 activation in pancreatic islets was measured by GLISA activation assay. Rac1 and CHOP expression was determined by Western Blotting. RESULTS: Our findings indicate that administration of NSC23766 significantly prevented the development of spontaneous diabetes in the NOD mice. Furthermore, NSC23766 markedly suppressed Rac1 expression and activity and the endoplasmic reticulum stress (CHOP expression) in NOD islets. CONCLUSIONS: Our findings provide the first evidence implicating the role of Tiam1-Rac1-Nox2 signaling pathway in the onset of spontaneous diabetes in the NOD mouse model. PMID- 27467103 TI - Dialytic dose in pediatric continuous renal replacement therapy patients. AB - Although universally recognized as a crucial component of renal replacement therapy (RRT), dialytic dose has not been investigated in children with renal failure, differently from the adult population. Consequently, clear indications on the adequacy of continuous RRT in pediatric population is currently missing and wide variations in clinical practice exist worldwide. Fluid balance has been identified as a key factor in affecting outcomes these patients. Nonetheless, the concept and the precise evaluation of the dialytic dose for continuous pediatric RRT seems crucial, especially in light of the small body surface area of neonates and infants that might result into a difficult dose calculation. The present review clearly demonstrates that dialytic dose in pediatric RRT has been underestimated by scientific literature. Nowadays, the absence of any specific dedicated prospective study and the tendency to overlook theoretical basis of pediatric dialytic dose have led to the absence of a standard prescription: worldwide clinical practice ranges from very high doses to lower ones, also depending on different ways of estimating patients' sizes and solutes' volume of distribution. Large structured studies are warranted in order to define a reference dialytic dose for critically ill children, capable to cope an adequate solute control to gentle and safe treatments. PMID- 27467104 TI - A rare case of hypomelanosis of Ito presenting with generalized alopecia. PMID- 27467105 TI - A case of iatrogenic acute hypermagnesemia mimicking sepsis. PMID- 27467106 TI - Unexpected urothelial tumor in a young boy with asymptomatic hematuria. PMID- 27467107 TI - Acute rotavirus-associated encephalopathy and cerebellitis. PMID- 27467108 TI - Massive subcutaneous emphysema and pneumomediastinum, an underestimated clinical sign of child abuse. PMID- 27467110 TI - Pediatric-onset Chronic Nonspecific Multiple Ulcers of Small Intestine: A Nationwide Survey and Genetic Study in Japan. AB - We performed a Japanese nationwide survey of pediatric-onset chronic nonspecific multiple ulcers of the small intestine between January 2000 and July 2013 in 176 institutions of pediatric surgery or pediatric gastroenterology and clarified the clinical features associated with genetic abnormalities in the Solute Carrier Organic Anion Transporter Family, Member 2A1 (SLCO2A1) gene. A total of 4 cases (3 girls and 1 boy) were diagnosed in this series, which had to be differentiated from Crohn disease, Behcet disease, tuberculosis, or drug-induced enteropathy. Clinical symptoms appeared in infants and accurate diagnosis required several years. Medical therapies for inflammatory bowel disease were administered in all patients; however, 2 of the 4 patients had mutation in the SLCO2A1 gene which are responsible for primary hypertrophic osteoarthopathy, and underwent strictureplasty or ileal resection after long-term follow-up. Pediatric gastroenterologists should include this new entity in the differential diagnosis of small intestinal ulcers and inflammatory bowel disease. PMID- 27467111 TI - Splanchnic Oxygenation at First Enteral Feeding in Preterm Infants: Correlation With Feeding Intolerance. AB - Preterm infants are at risk of developing gastrointestinal complications such as feeding intolerance and necrotizing enterocolitis. Near-infrared spectroscopy (NIRS) provides continuous monitoring of abdominal oxygenation (ArSO2) and could help to predict gastrointestinal complications in preterm neonates. In this prospective observational study, ArSO2 patterns at first enteral feed were evaluated by NIRS in 61 clinically stable preterm infants. Splanchnic-cerebral oxygenation ratio, which is a marker of gut hypoxia, was also calculated. ArSO2 and splanchnic-cerebral oxygenation ratio were significantly lower both at baseline and after feeding administration in infants who later developed feeding intolerance (n = 23). NIRS could help the early prediction of gastrointestinal complications in high-risk preterm infants. PMID- 27467112 TI - Iron Status at Age 6 Months in Colombian Infants Exclusively Breast-fed for 4 to 5 Versus 6 Months. AB - OBJECTIVES: The optimal age for introducing complementary feeding to breast-fed infants may differ depending on the setting. Prolonged exclusive breast-feeding (EBF) protects against infection but may increase the risk of iron deficiency (ID)/anaemia (IDA) in vulnerable infants. The aim of the present study was to compare haemoglobin (Hb), serum ferritin (SF), anaemia (Hb < 11 g/L), ID (SF < 12 MUg/L) and IDA (Hb < 10.5 g/dL + Hct < 33% + ID) using observational analyses in 6-month old infants from Bogota, Colombia who were EBF for 4 to 5 versus 6 months or older, and examine predictors. METHODS: Infant feeding was recorded, anthropometry performed, and blood obtained for Hb and SF at 6 months in healthy term infants (birth weight > 2500 g), all EBF for >=4 months. RESULTS: One hundred eight infants (54% boys) were recruited; 46% EBF for 4 to 5 months, 54% EBF at 6 months. Prevalence of anaemia, ID, and IDA was 20%, 10%, and 5%, with no significant difference between EBF4-5 and EBF6 groups. In multivariate models, anaemia/ID were predicted by greater weight gain from 0 to 6 months, and anaemia also by caesarean delivery; Hb was lower in infants with higher intake of cows' milk; SF was lower in boys and those with greater weight gain. EBF4-5 versus EBF6 was not a significant predictor of any outcome. CONCLUSIONS: Anaemia and ID were common at 6 months but were not affected by EBF for 4 to 5 versus 6 months, suggesting 6 months EBF is safe in this population. Further research is, however, required to examine effects on later iron status. The findings highlight the need to emphasise avoidance of cow's milk before 12 months. PMID- 27467113 TI - Context matters: The importance of dimerization-induced conformation of the LukGH leukocidin of Staphylococcus aureus for the generation of neutralizing antibodies. AB - LukGH (LukAB) is a potent leukocidin of Staphylococcus aureus that lyses human phagocytic cells and is thought to contribute to immune evasion. Unlike the other bi-component leukocidins of S. aureus, LukGH forms a heterodimer before binding to its receptor, CD11b expressed on professional phagocytic cells, and displays significant sequence variation. We employed a high diversity human IgG1 library presented on yeast cells to discover monoclonal antibodies (mAbs) neutralizing the cytolytic activity of LukGH. Recombinant LukG and LukH monomers or a LukGH dimer were used as capture antigens in the library selections. We found that mAbs identified with LukG or LukH as bait had no or very low toxin neutralization potency. In contrast, LukGH dimer-selected antibodies proved to be highly potent, and several mAbs were able to neutralize even the most divergent LukGH variants. Based on biolayer interferometry and mesoscale discovery, the high affinity antibody binding site on the LukGH complex was absent on the individual monomers, suggesting that it was generated upon formation of the LukG-LukH dimer. X-ray crystallography analysis of the complex between the LukGH dimer and the antigen binding fragment of a very potent mAb (PDB code 5K59) indicated that the epitope is located in the predicted cell binding region (rim domain) of LukGH. The corresponding IgG inhibited the binding of LukGH dimer to target cells. Our data suggest that knowledge of the native conformation of target molecules is essential to generate high affinity and functional mAbs. PMID- 27467115 TI - Photocatalytic Hydrogen-Evolution Cross-Couplings: Benzene C-H Amination and Hydroxylation. AB - We present a blueprint for aromatic C-H functionalization via a combination of photocatalysis and cobalt catalysis and describe the utility of this strategy for benzene amination and hydroxylation. Without any sacrificial oxidant, we could use the dual catalyst system to produce aniline directly from benzene and ammonia, and phenol from benzene and water, both with evolution of hydrogen gas under unusually mild conditions in excellent yields and selectivities. PMID- 27467114 TI - Abnormal structural and functional hypothalamic connectivity in mild traumatic brain injury. AB - PURPOSE: To investigate whether there is imaging evidence of hypothalamic injury in patients with mild traumatic brain injury (MTBI), which is a major public health problem due to the high prevalence and difficulty in diagnosis and treatment. MATERIALS AND METHODS: Twenty-four patients (mean age 34.2, range, 18 56 years) with symptomatic MTBI and 22 age-matched healthy controls (mean age 37.0, range 20-61 years) participated in the study. Diffusion kurtosis imaging was performed with diffusion-weighted images acquired along 30 gradient directions and three b-values (b = 0, 1000, 2000 s/mm2 ) based on a twice refocused spin-echo sequence with a 3T magnetic resonance imaging (MRI) scanner. Resting-state functional (f)MRI with standard echo planar imaging (EPI) were performed to localize the resting-state networks (RSN) and hypothalamic functional connectivity. RESULTS: There were significantly reduced mean kurtosis (P = 0.0092) and radial kurtosis (P = 0.0078) in patients as compared to controls in the hypothalamus. Furthermore, there was a significant negative correlation (r = -0.675, P = 0.0007) between radial kurtosis in the hypothalamus and fatigue severity scale in patients. The MTBI group also showed disrupted hypothalamic RSNs, with significantly decreased positive connectivity in medial prefrontal cortex, inferior posterior parietal, and cingulate regions but increased connectivity in the peri-hypothalamic regions and cerebellum, together with significantly decreased negative RSNs in visual and bilateral premotor areas (cluster corrected P < 0.05). CONCLUSION: Our results show disruption of functional and structural hypothalamic connectivity in patients with MTBI, and might further the understanding of an array of clinical symptoms in MTBI such as sleep disturbance and fatigue. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:1105-1112. PMID- 27467116 TI - Local anaesthetic sympathetic blockade for complex regional pain syndrome. AB - BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews, 2005, Issue 4 (and last updated in the Cochrane Database of Systematic Reviews, 2013 issue 8), on local anaesthetic blockade (LASB) of the sympathetic chain to treat people with complex regional pain syndrome (CRPS). OBJECTIVES: To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure. SEARCH METHODS: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (Ovid), EMBASE (Ovid), LILACS (Birme), conference abstracts of the World Congresses of the International Association for the Study of Pain, and various clinical trial registers up to September 2015. We also searched bibliographies from retrieved articles for additional studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that evaluated the effect of sympathetic blockade with local anaesthetics in children or adults with CRPS compared to placebo, no treatment, or alternative treatments. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The outcomes of interest were reduction in pain intensity, the proportion who achieved moderate or substantial pain relief, the duration of pain relief, and the presence of adverse effects in each treatment arm. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table. MAIN RESULTS: We included an additional four studies (N = 154) in this update. For this update, we excluded studies that did not follow up patients for more than 48 hours. As a result, we excluded four studies from the previous review in this update. Overall we included 12 studies (N = 461), all of which we judged to be at high or unclear risk of bias. Overall, the quality of evidence was low to very low, downgraded due to limitations, inconsistency, imprecision, indirectness, or a combination of these.Two small studies compared LASB to placebo/sham (N = 32). They did not demonstrate significant short-term benefit for LASB for pain intensity (moderate quality evidence).One small study (N = 36) at high risk of bias compared thoracic sympathetic block with corticosteroid and local anaesthetic versus injection of the same agents into the subcutaneous space, reporting statistically significant and clinically important differences in pain intensity at one-year follow-up but not at short term follow up (very low quality evidence).Of two studies that investigated LASB as an addition to rehabilitation treatment, the only study that reported pain outcomes demonstrated no additional benefit from LASB (very low quality evidence).Eight small randomised studies compared sympathetic blockade to various other active interventions. Most studies found no difference in pain outcomes between sympathetic block versus other active treatments (low to very low quality evidence).One small study compared ultrasound-guided LASB with non-guided LASB and found no clinically important difference in pain outcomes (very low quality evidence).Six studies reported adverse events, all with minor effects reported. AUTHORS' CONCLUSIONS: This update's results are similar to the previous versions of this systematic review, and the main conclusions are unchanged. There remains a scarcity of published evidence and a lack of high quality evidence to support or refute the use of local anaesthetic sympathetic blockade for CRPS. From the existing evidence, it is not possible to draw firm conclusions regarding the efficacy or safety of this intervention, but the limited data available do not suggest that LASB is effective for reducing pain in CRPS. PMID- 27467117 TI - Deterred drug abuse using superabsorbent polymers. AB - OBJECTIVE: This study aimed to determine whether selected superabsorbent polymers (SAPs) could be used as a suitable alternative to thwart extraction, filtration, and syringeability attempts for abuse. Many abuse-deterrent formulations (ADFs) rely on high molecular weight polymers such as poly(ethylene oxide) to provide crush and extraction resistance. However, these polymers suffer from slow dissolution kinetics, and are susceptible to a variety of abuse conditions. METHODS: Several commercially available SAPs were evaluated for swelling behavior in extraction solvents, and tableting properties. Post-compaction abuse properties were evaluated by recoverable volume and syringeability after solvent extraction. Drug release and percent drug extraction were conducted using tramadol HCl as a model drug. RESULTS: Certain SAPs had the ability to rapidly imbibe solvent and effectively stop extraction processes in a variety of solvents, including water and water/alcohol mixtures. Tablets containing SAP and drug showed no effect on drug release in vitro. CONCLUSIONS: SAPs possess adequate properties for tableting, and maintain their high and fast swelling properties after compaction. The fast and extensive interactions of SAPs with aqueous medium are a major advantage over non-crosslinked high molecular weight viscosifying agents such as poly(ethylene oxide). PMID- 27467118 TI - Total Synthesis and Stereochemical Revision of the Anti-Tuberculosis Peptaibol Trichoderin A. AB - The first total synthesis of the postulated structure of the aminolipopeptide trichoderin A and its epimer are reported. A late-stage solution phase C-terminal coupling was employed to introduce the C-terminal aminoalcohol moiety. This methodology provides a foundation to prepare analogues of trichoderin A to establish a structure-activity relationship. NMR spectroscopic analysis established that the C-6 position of the 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue in trichoderin A possesses an (R)-configuration as opposed to the originally proposed (S)-configuration. PMID- 27467119 TI - A Facebook Follow-Up Strategy for Rural Drug-Using Women. AB - PURPOSE: Facebook (FB) use has grown exponentially over the past decade, including in rural areas. Despite its popularity, FB has been underutilized as a research follow-up approach to maintain contact with research participants and may have advantages in less densely populated areas and among more hard-to-reach, at-risk groups. The overall goal of this study was to examine FB as a supplemental follow-up approach to other follow-up strategies with rural drug using women. METHODS: Face-to-face interviews were conducted with randomly selected women who completed baseline interviews in 3 rural jails in 1 state. Analyses focus on participants who were released from jail and were eligible for 3-month follow-up (n = 284). Bivariate analyses were used to examine differences between FB users and nonusers, and multivariate logistic regression models examined predictors of 3-month follow-up participation and being located for follow-up using FB. FINDINGS: About two-thirds (64.4%) of participants were regular FB users. Bivariate analyses indicated that FB users were younger, more educated, and more likely to have used alcohol in the 30 days before incarceration but less likely to have a chronic health problem. Regression analyses indicated that rural FB users had more than 5 times the odds of being located for the 3-month follow-up interview, even after controlling for other variables. There were no significant predictors of being followed up using FB. CONCLUSIONS: Findings suggest that FB is widely used and well accepted among rural drug-using women. Among hard-to-reach populations, including those in rural, geographically isolated regions, FB serves as a method to improve participant follow-up. PMID- 27467120 TI - Categorization of dynamic realistic motion events: Infants form categories of path before manner. AB - Acquiring verbs and prepositions requires categorization of spatial relations. This study examined whether a ground object differentially influences 13- to 15 month-old English-learning infants' categorization of a figure's path (e.g., around; Experiment 1) and manner (e.g., hopping; Experiment 2) of motion in non linguistic dynamic realistic events. Furthermore, we tested whether categorizing path is "easier" than categorizing manner. Results revealed that infants categorized path only in the presence of a ground object, validating Talmy's definition of path. In contrast, infants categorized manner only in the absence of a ground object. Finally, infants categorizing path showed stronger novelty preferences than those categorizing manner, supporting a primacy of path. Infants showed sensitivity to event components lexicalized in relational terms. PMID- 27467122 TI - Adsorption of Hydrogen Molecules on Carbon Nanotubes Using Quantum Chemistry and Molecular Dynamics. AB - Physisorption and storage of molecular hydrogen on single-walled carbon nanotube (SWCNT) of various diameters and chiralities are studied by means of classical molecular dynamics (MD) simulations and a force field validated using DFT-D2 and CCSD(T) calculations. A nonrigid carbon nanotube model is implemented with stretching (C-C) and valence angle potentials (C-C-C) formulated as Morse and Harmonic cosine potentials, respectively. Our results evidence that the standard Lennard-Jones potential fails to describe the H2-H2 binding energies. Therefore, our simulations make use of a potential that contains two-body term with parameters obtained from fitting CCSD(T)/CBS binding energies. From our MD simulations, we have analyzed the interaction energies, radial distribution functions, gravimetric densities (% wt), and the distances of the adsorbed H2 layers to the three zigzag type of nanotubes (5,0), (10,0), and (15,0) at 100 and 300 K. PMID- 27467121 TI - Phase I, multicenter, open-label, dose-escalation study of sonidegib in Asian patients with advanced solid tumors. AB - Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov: NCT01208831.). PMID- 27467123 TI - Impact of exercise selection on hamstring muscle activation. AB - OBJECTIVE: To determine which strength training exercises selectively activate the biceps femoris long head (BFLongHead) muscle. METHODS: We recruited 24 recreationally active men for this two-part observational study. Part 1: We explored the amplitudes and the ratios of lateral (BF) to medial hamstring (MH) normalised electromyography (nEMG) during the concentric and eccentric phases of 10 common strength training exercises. Part 2: We used functional MRI (fMRI) to determine the spatial patterns of hamstring activation during two exercises which (1) most selectively and (2) least selectively activated the BF in part 1. RESULTS: Eccentrically, the largest BF/MH nEMG ratio occurred in the 45 degrees hip-extension exercise; the lowest was in the Nordic hamstring (Nordic) and bent knee bridge exercises. Concentrically, the highest BF/MH nEMG ratio occurred during the lunge and 45 degrees hip extension; the lowest was during the leg curl and bent-knee bridge. fMRI revealed a greater BF(LongHead) to semitendinosus activation ratio in the 45 degrees hip extension than the Nordic (p<0.001). The T2 increase after hip extension for BFLongHead, semitendinosus and semimembranosus muscles was greater than that for BFShortHead (p<0.001). During the Nordic, the T2 increase was greater for the semitendinosus than for the other hamstring muscles (p<=0.002). SUMMARY: We highlight the heterogeneity of hamstring activation patterns in different tasks. Hip-extension exercise selectively activates the long hamstrings, and the Nordic exercise preferentially recruits the semitendinosus. These findings have implications for strategies to prevent hamstring injury as well as potentially for clinicians targeting specific hamstring components for treatment (mechanotherapy). PMID- 27467124 TI - Assessing the Impact of Peer Educator Outreach on the Likelihood and Acceleration of Clinic Utilization among Sex Workers. AB - OBJECTIVE: Peer-led outreach is a critical element of HIV and STI-reduction interventions aimed at sex workers. We study the association between peer-led outreach to sex workers and the time to utilize health facilities for timely STI syndromic-detection and treatment. Using data on the timing of peer-outreach interventions and clinic visits, we utilize an Extended Cox model to assess whether peer educator outreach intensity is associated with accelerated clinic utilization among sex workers. METHODS: Our data comes from 2705 female sex workers registered into Pragati, a women-in-sex-work outreach program, and followed from 2008 through 2012. We analyze this data using an Extended Cox model with the density of peer educator visits in a 30-day rolling window as the key predictor, while controlling for the sex workers' age, client volume, location of sex work, and education level. The principal outcome of interest is the timing of the first voluntary clinic utilization. RESULTS: More frequent peer visit is associated with earlier first clinic visit (HR: 1.83, 95% CI, 1.75-1.91, p < .001). In addition, 18% of all syndrome-based STI detected come from clinic visits in which the sex worker reports no symptoms, underscoring the importance of inducing clinic visits in the detection of STI. Additional models to test the robustness of these findings indicate consistent beneficial effect of peer educator outreach. CONCLUSIONS: Peer outreach density is associated with increased likelihood of-and shortened duration to-clinic utilization among female sex workers, suggesting potential staff resourcing implications. Given the observational nature of our study, however, these findings should be interpreted as an association rather than as a causal relationship. PMID- 27467125 TI - A Method to Calculate Adherence to Inhaled Therapy that Reflects the Changes in Clinical Features of Asthma. AB - RATIONALE: Currently, studies on adherence to inhaled medications report average adherence over time. This measure does not account for variations in the interval between doses, nor for errors in inhaler use. OBJECTIVES: To investigate whether adherence calculated as a single area under the (concentration-time) curve (AUC) measure, incorporating the interval between doses and inhaler technique, was more reflective of patient outcomes than were current methods of assessing adherence. METHODS: We attached a digital audio device (INhaler Compliance Assessment) to a dry powder inhaler. This recorded when the inhaler was used, and analysis of the audio data indicated if the inhaler had been used correctly. These aspects of inhaler use were combined to calculate adherence over time, as an AUC measure. Over a 3-month period, a cohort of patients with asthma was studied. Adherence to a twice-daily inhaler preventer therapy using this device and clinical measures were assessed. MEASUREMENTS AND MAIN RESULTS: Recordings from 239 patients with severe asthma were analyzed. Average adherence that was based on the dose counter was 84.4%, whereas the ratio of expected to observed accumulated AUC, actual adherence, was 61.8% (P < 0.01). Of all the adherence measures, only adherence calculated as AUC reflected changes in asthma quality of life, beta-agonist reliever use, and peak expiratory flow over the 3 months (P < 0.05 compared with other measures of adherence). CONCLUSIONS: Adherence that incorporates the interval between doses and inhaler technique, and calculated as AUC, is more reflective of changes in quality of life and lung function than are the currently used measures of adherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01529697). PMID- 27467126 TI - Correction: Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury. AB - [This corrects the article DOI: 10.1371/journal.pone.0158810.]. PMID- 27467127 TI - Evaluating the Operational Features of an Unconventional Dual-Bay U-Turn Design for Intersections. AB - Median U-turn intersection treatment (MUTIT) has been considered an alternative measure to reduce congestion and traffic conflict at intersection areas. The MUTIT is sometimes difficult to implement in the field because it requires wide median on arterials for U-turn vehicles. The objective of this study is to introduce an unconventional U-turn treatment (UUT) for intersections which requires less median space but is also effective. The UUT has a dual-bay design with different turning radiuses for small and large vehicles. The VISSIM simulation model was developed to evaluate the operational features of the UUT. The model was calibrated using data collected from intersections in China. The capacity, delay and number of stops were evaluated and compared with the direct left-turn (DLT) for the same intersections. The results showed that the UUT significantly improved the operations at intersection areas, especially when volume/capacity ratio is small, and ratio of left-turn to through traffic is small. With the UUT, the capacity is increased by 9.81% to 10.38%, vehicle delay is decreased by 18.5% to 40.1%, and number of stops is decreased by 23.19% to 36.62%, when volume/capacity ratio is less than 0.50. The study also found that traffic efficiency could be further improved when the UUT is designed in conjunction with signal control. In the case, the UUT plus signalized control increases the capacity by 25% to 26.02%, decreases vehicle delay by 50.5% to 55.8%, and reduces number of stops by 69.5%, compared with the traditional DLT. PMID- 27467128 TI - Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window? AB - LARGE is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (alpha-DG). Absence of this protein in the LARGEmyd mouse results in alpha-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of alpha-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores alpha-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20-100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window. PMID- 27467130 TI - Thirty Years of Compositional Change in an Old-Growth Temperate Forest: The Role of Topographic Gradients in Oak-Maple Dynamics. AB - Ecological communities are structured in response to spatial and temporal variation of numerous factors, including edaphic conditions, biotic interactions, climatic patterns and disturbance regimes. Widespread anthropogenic factors such as timber harvesting can create long-lasting impacts, obscuring the relationship between community structure and environmental conditions. Minimally impacted systems such as old-growth forests can serve as a useful ecological baseline for predicting long-term compositional shifts. We utilized decadal tree species sampling data (1979-2010) divided into three strata (understory, midstory, overstory) to examine temporal changes in relative abundances and spatial distributions of dominant taxa, as well as overall shifts in community composition, in a relatively pristine Appalachian old-growth forest in eastern Kentucky, USA. Quercus and Carya species persisted mainly as mature canopy trees with decreasing juvenile recruitment, especially in mesic areas. In contrast, Acer, Fagus, and other mesophytic species were abundant and spatially widespread in subcanopy layers suggesting these species are more likely to recruit in gap scale canopy openings. In the overstory, mesophytic species were spatially restricted to lower and mid-slope mesic habitats. Temporal changes in community composition were most evident in the understory and tended to be greater in mesic areas, a trend seemingly driven by recruitment failure among xerophytic species. In subcanopy vegetation we discovered a loss of distinction through time among the ecological community designations established following the 1979 survey (Chestnut oak, Mixed mesophytic, and Beech). The overstory was more stable through time, suggesting a storage effect where long-lived trees have maintained a particular community composition through time in areas where regeneration opportunities are minimal under current environmental conditions. Overall, sitewide canopy succession is occurring slowly in the absence of major disturbance, and topography-driven environmental variation appears to have an important local-scale filtering effect on communities. PMID- 27467129 TI - FACT Assists Base Excision Repair by Boosting the Remodeling Activity of RSC. AB - FACT, in addition to its role in transcription, is likely implicated in both transcription-coupled nucleotide excision repair and DNA double strand break repair. Here, we present evidence that FACT could be directly involved in Base Excision Repair and elucidate the chromatin remodeling mechanisms of FACT during BER. We found that, upon oxidative stress, FACT is released from transcription related protein complexes to get associated with repair proteins and chromatin remodelers from the SWI/SNF family. We also showed the rapid recruitment of FACT to the site of damage, coincident with the glycosylase OGG1, upon the local generation of oxidized DNA. Interestingly, FACT facilitates uracil-DNA glycosylase in the removal of uracil from nucleosomal DNA thanks to an enhancement in the remodeling activity of RSC. This discloses a novel property of FACT wherein it has a co-remodeling activity and strongly enhances the remodeling capacity of the chromatin remodelers. Altogether, our data suggest that FACT may acts in concert with RSC to facilitate excision of DNA lesions during the initial step of BER. PMID- 27467132 TI - Mechanism of Alcohol-Water Dehydrogenative Coupling into Carboxylic Acid Using Milstein's Catalyst: A Detailed Investigation of the Outer-Sphere PES in the Reaction of Aldehydes with an Octahedral Ruthenium Hydroxide. AB - In aqueous basic media, the square-pyramidal complex [Ru(PNN)(CO)(H)] (1-Ru, where PNN is a dearomatized bipyridyl-CH-P(t)Bu2 pincer ligand) catalyzes the transformation of alcohols and water into carboxylates and H2. A previous theoretical investigation reported the following mechanism for the reaction: (i) metal-catalyzed dehydrogenation of the alcohol into an aldehyde, (ii) metal ligand cooperation (MLC) addition of water to 1-Ru to give an octahedral ruthenium hydroxide (2-Ru-OH), (iii) concerted MLC hydration of the aldehyde by 2 Ru-OH to give separated 1-Ru and a gem-diol, and (iv) concerted MLC dehydrogenation of the gem-diol by 1-Ru into an octahedral ruthenium dihydride (2 Ru-H) and a carboxylic acid. We calculate the outer-sphere PES in the reaction between the aldehyde and 2-Ru-OH to start with a localized coupling step yielding an ion-pair minimum (7-ip-OH) in which the hydroxyl group of an alpha-hydroxyl alkoxide (gem-diolate) is coordinated to the metal of a cationic square-pyramidal complex. From 7-ip-OH, we identify a route to carboxylic acid that circumvents ligand deprotonation involving (i) 1,1-rearrangement of the gem-diolate within the contact ion pair through an alpha-OH/O(-) slippage TS into the octahedral 2 Ru-OCH(OH)R and (ii) a second 1,1-rearrangement through an alpha-O(-)/H slippage TS that gives a new ion-pair minimum in which the alpha-hydrogen of the anion is coordinated to the metal, followed by a localized hydride-transfer TS that gives a carboxylic acid and the octahedral hydride complex (2-Ru-H). The net transformation from 2-Ru-OH and the aldehyde to the carboxylic acid and 2-Ru-H can be viewed as a H/OH metathesis in which a hydride and a hydroxide are exchanged between the acyl group of the aldehyde and the metal center of 2-Ru-OH. The MLC mechanism gives the same metathesis products through the intermediacy of a gem-diol. When the SMD solvent continuum model is applied during geometry optimization with water as the solvent, the Gibbs free energy profile of the slippage pathway is predicted to be much lower than that predicted for MLC. The possibility of dissociation of the ion pair 7-ip-OH into free ions and reassociation is also briefly addressed. Some calculations are also performed to address why no esters are observed in the given system. PMID- 27467131 TI - Production of Acetoin through Simultaneous Utilization of Glucose, Xylose, and Arabinose by Engineered Bacillus subtilis. AB - Glucose, xylose and arabinose are the three most abundant monosaccharide found in lignocellulosic biomass. Effectively and simultaneously utilization of these sugars by microorganisms for production of the biofuels and bio-chemicals is essential toward directly fermentation of the lignocellulosic biomass. In our previous study, the recombinant Bacillus subtilis 168ARSRCPDeltaacoADeltabdhA strain was already shown to efficiently utilize xylose for production of acetoin, with a yield of 0.36 g/g xylose. In the current study, the Bacillus subtilis168ARSRCPDeltaacoADeltabdhA strain was further engineered to produce acetoin from a glucose, xylose, and arabinose mixtures. To accomplish this, the endogenous xylose transport protein AraE, the exogenous xylose isomerase gene xylA and the xylulokinase gene xylB from E. coli were co-overexpressed in the Bacillus subtilis 168ARSRCPDeltaacoADeltabdhA strain, which enabled the resulting strain, denoted ZB02, to simultaneously utilize glucose and xylose. Unexpectedly, the ZB02 strain could simultaneously utilize glucose and arabinose also. Further results indicated that the transcriptional inhibition of the arabinose transport protein gene araE was the main limiting factor for arabinose utilization in the presence of glucose. Additionally, the arabinose operon in B. subtilis could be activated by the addition of arabinose, even in the presence of glucose. Through fed-batch fermentation, strain ZB02 could simultaneously utilize glucose, xylose, and arabinose, with an average sugar consumption rate of 3.00 g/l/h and an average production of 62.2 g/l acetoin at a rate of 0.864 g/l/h. Finally, the strain produced 11.2 g/l acetoin from lignocellulosic hydrolysate (containing 20.6g/l glucose, 12.1 g/l xylose and 0.45 g/l arabinose) in flask cultivation, with an acetoin yield of 0.34 g/g total sugar. The result demonstrates that this strain has good potential for the utilization of lignocellulosic hydrolysate for production of acetoin. PMID- 27467134 TI - Molecular profiling of renal cell carcinoma: building a bridge toward clinical impact. AB - PURPOSE OF REVIEW: The daunting task of identifying key molecular drivers of renal cell carcinoma (RCC) has begun to reveal significant insights into tumor biology. This review provides an update on recent discoveries in this field and their possible clinical implications. RECENT FINDINGS: Molecular profiles within the classic RCC histologic subtypes present distinctive appreciation of tumor biology and also allow for exploitation of targeted treatment regimens for patients with metastatic disease. Prognostic signatures have demonstrated the ability to accurately predict many clinical outcomes. SUMMARY: The molecular and genomic profiling of RCC subtypes has identified a unique and diverse spectrum of alterations. Utilization of these characteristics to improve our prognostic and therapeutic outcomes in the clinical realm remains in its infancy but is rapidly advancing. PMID- 27467135 TI - Surveillance following surgery for nonmetastatic renal cell carcinoma. AB - PURPOSE OF REVEIW: Approximately one in three patients with nonmetastatic renal cell carcinoma (RCC) at the time of surgery will subsequently develop local or metastatic recurrence. The purpose of this review is to examine the current rationale for surveillance, describe sites of RCC metastasis, evaluate the existing guidelines for postsurgical follow-up studies, and analyze the risk stratification systems following RCC surgery. RECENT FINDINGS: Although 75% of recurrences will be identified during the first 5 years following surgery, late recurrences are not uncommon. The risk of recurrence can be predicted from the tumor stage, grade, and other pathologic features. Advanced risk stratification will likely be possible in the future with increased use of molecular classification and serum biomarkers. Patient comorbidities, age, and individual recurrence risk should also be considered when designing individualized surveillance protocols. SUMMARY: Follow-up after surgery for RCC should focus on imaging of the chest and abdomen to detect common sites of recurrence. Patients should be stratified for risk, and surveillance imaging should be more frequent and intensive in healthy patients with higher risk. Future research is needed to define an optimal individualized surveillance strategy that balances the potential benefits of early cancer detection with the risks and cost of surveillance. PMID- 27467133 TI - Polymorphisms in stearoyl coa desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people. AB - SCOPE: n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity; however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin-sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes. MATERIALS AND METHODS: Anthropometric variables and metabolic phenotypes were measured in a cross sectional sample of Yup'ik individuals (n = 1135) and 33 polymorphisms were tested for main effects and interactions using linear models that account for familial correlations. n-3 PUFA intake was estimated using red blood cell nitrogen stable isotope ratios. SCD polymorphisms were associated with ApoA1 concentration and n-3 PUFA interactions with SCD polymorphisms were associated with reduced fasting cholesterol levels and waist-to-hip ratio. SLC2A4 polymorphisms were associated with hip circumference, high-density lipoprotein and ApoA1 concentrations. SREBF1 polymorphisms were associated with low-density lipoprotein and HOMA-IR and n-3 PUFA interactions were associated with reduced fasting insulin and HOMA-IR levels. CONCLUSION: The results suggest that an individual's genotype may interact with dietary n-3 PUFAs in ways that are associated with protection from obesity-related diseases in Yup'ik people. PMID- 27467136 TI - Advances in treatment of metastatic renal cell carcinoma. AB - PURPOSE OF REVIEW: Multiple agents, including vascular endothelial growth factor (VEGF) inhibitors and mammalian target of rapamycin inhibitors have been approved over the past decade for the treatment of metastatic renal cell carcinoma (mRCC). Here, we focus on nivolumab, cabozantinib, and lenvatinib plus everolimus, agents that have recently emerged with positive clinical data leading to 'Food and Drug Administration approval or pending approval in mRCC. We also review the development of novel agents of interest showing promise in mRCC as part of combination therapy'. RECENT FINDINGS: Nivolumab and cabozantinib both offer improved survival over everolimus in the second-line treatment of mRCC. Lenvatinib plus everolimus has similarly shown encouraging survival benefits in a phase II trial for the second-line setting. Novel combinations in mRCC, including dual immune checkpoint blockade, VEGF and programmed death 1 inhibition, VEGF and vaccine therapy, dual angiogenic blockade, and VEGF-directed therapy with nanoparticle-containing camptothecin have shown promising activity in early-phase trials. SUMMARY: Multiple promising agents are available in the treatment of mRCC. The appropriate sequencing of agents in the treatment of mRCC may become further elucidated by future studies that prospectively analyze potential biomarkers to identify patients who will derive the greatest benefit from VEGF, mammalian target of rapamycin, or checkpoint inhibitors. PMID- 27467137 TI - Rapidly changing landscape of PET/CT imaging in prostate cancer. AB - PURPOSE OF REVIEW: PET/CT imaging in men with prostate cancer (PCa) is rapidly growing as clinicians are becoming aware of its possible fundamental role in the diagnostic flow chart of these patients. As this technology becomes more available worldwide, a considerable number of scientific studies are focusing on specific clinical scenarios and novel PET radiopharmaceuticals that might assist improving early diagnosis and shifting to a truly tailored treatment for PCa. This review focuses on the most recent and important publications in PET/CT imaging of PCa. RECENT FINDINGS: Choline, radiolabelled with either 11-C or 18-F, is now widely used and has shown good performance in detecting sites of disease compared with conventional imaging, especially in biochemical recurrence. However, its sensitivity and specificity when PSA values are low, and especially below 1.0 ng/ml, is insufficient. More recently, a number of new tracers have been proposed for clinical practice. Among them, 68-Ga Prostate-specific membrane antigen have shown so far the most promising results and is replacing choline PET in centres where it is available. It is particularly useful for detecting PCa relapse at low PSA values but may also be useful for staging of patients with intermediate or high risk prostate cancer. 18-F fluorodeoxyglucose PET/CT remains useful for a limited number of patients with PCa and may provide useful prognostic information. SUMMARY: PET/CT is a reliable technique in the diagnostic work-up of patients with PCa, particularly in the setting of biochemical recurrence following previous definitive treatment. The landscape of available radiotracers is changing rapidly and includes fluorodeoxyglucose, sodium fluoride, choline, anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid, and prostate-specific membrane antigen. Of these, prostate-specific membrane antigen PET/CT appears the most likely to represent a new gold standard with evidence of clinical utility emerging in a variety of scenarios, including staging and biochemical recurrence. PMID- 27467138 TI - Benzo- and Naphthopentalenes: Syntheses, Structures, and Properties. AB - Benzo- and naphthopentalene derivatives were synthesized, and the effects of structural variations on their antiaromaticity and optoelectronic and electrochemical properties were examined experimentally and theoretically in detail. The results unveiled that with increasing the bond order of the carbon carbon bond ([5,6] junction) shared by the pentalene and aromatic moieties, the 8pi antiaromatic character of pentalene is enhanced and the HOMO-LUMO gap is decreased, which accompanies both the elevation of the HOMO level and the lowering of the LUMO level. The ethynylene units between the pentalene skeleton and the phenyl groups proved to extend pi-conjugation sufficiently. PMID- 27467139 TI - Safety and efficacy considerations due to misuse of extended-release formulations of stimulant medications. AB - Amphetamine or methylphenidate are first-line options for treating attention deficit/hyperactivity disorder (ADHD). Deviations from suggested routes of administration such as crushing, chewing, intravenous administration, or snorting stimulant medication may alter the release rate, absorption, and bioavailability of the active drug. Additionally, the pharmacokinetic (PK) profiles of extended release formulations of certain medications (e.g., some opioids) are known to be dangerously altered when consumed with alcohol; specifically, there is an unintended, rapid release of a significant portion of the drug (dose dumping). In vitro data suggest some extended-release stimulants dose dump in the presence of alcohol, which is of concern because the ADHD patient population is at risk for alcohol abuse. This article reviews the available scientific literature concerning modifications to routes of administration that may alter PK properties of stimulant-based medication for treating ADHD. These modifications are of clinical interest because they may pose safety hazards and affect efficacy. Electronic databases were searched for appropriate studies using relevant search terms. The misuse and abuse potential for stimulants and the efforts to prevent misuse are also discussed. Future research should be focused on determining the PK ramifications of stimulant misuse, along with developing new formulations with abuse-deterrent properties. PMID- 27467140 TI - Association of Vision Impairment and Major Eye Diseases With Mobility and Independence in a Chinese Population. AB - Importance: Mobility limitations arising from vision impairment (VI) can result in loss of independence and reduced quality of life. However, few data are available on the association between VI and mobility limitations at a population based level, particularly in Asian populations. Objective: To assess the association of VI and major eye diseases with mobility and independence (M&I) in a Chinese population. Design, Setting, and Participants: The Singapore Chinese Eye Study (February 9, 2009, to December 19, 2011) was a population-based, cross sectional study of 3353 persons aged 40 to 80 years of Chinese ethnicity. Patients underwent visual acuity testing, and sociodemographic and medical data were collected from standardized questionnaires. Data analysis for this study was performed October 2015 to April 2016. Exposures: Presenting bilateral visual acuity (categorized as none, moderate, or severe VI) and major eye diseases (cataract, uncorrected refractive error, glaucoma, age-related macular degeneration, and diabetic retinopathy). Main Outcomes and Measures: Patients answered questions on the M&I scale of the Impact of Vision Impairment questionnaire, validated using Rasch analysis. The composite M&I score (score range, -4.47 to 7.48 logits; higher scores indicate better M&I) and 11 individual item scores were the main outcomes. The association between bilateral VI and eye conditions and the composite and individual M&I item scores was assessed using linear regression models. Results: Of the 3353 patients, the mean (SD) age was 59.7 (9.9) years, and 1662 (49.6%) were male. The mean (SD) presenting visual acuity values in the better and worse eyes were 0.20 (0.21) and 0.39 (0.42) logMAR, respectively. A total of 1432 patients (42.7%) and 114 patients (3.4%) had moderate and severe bilateral VI, respectively. Mobility and independence systematically worsened as the severity of bilateral VI increased. There was a clinically meaningful reduction in M&I (20%; beta, -1.44; 95% CI, -1.75 to -1.13) and all 11 M&I tasks in patients with severe bilateral VI compared with no VI. Glaucoma (13%; beta, -0.94; 95% CI, -1.82 to -0.06) and cataract (6%; beta, 0.43; 95% CI, -0.65 to -0.22) were independently associated with worse M&I, with patients with glaucoma particularly concerned about avoiding falling or tripping. Conclusions and Relevance: Bilateral VI in this population was associated with substantial decrements in M&I, with glaucoma and cataract independently associated with worse M&I. Although these associations do not prove that preventing bilateral VI will improve M&I in this population, the results suggest that such interventions could be of tremendous value from this perspective. PMID- 27467141 TI - alpha-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase Activating Protein TBC1D1 Independently of AMPK. AB - The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis. In this study, we examined the molecular signaling pathway involved in alpha-MSH stimulated glucose uptake in differentiated L6 myotubes and mouse muscle explants. In order to examine the involvement of AMPK, we investigate -MSH stimulation in both wild type and AMPK deficient mice. We found that -MSH significantly induces phosphorylation of TBC1 domain (TBC1D) family member 1 (S237 and T596), which is independent of upstream PKA and AMPK. We find no evidence to support that -MSH-stimulated glucose uptake involves TBC1D4 phosphorylation (T642 and S704) or GLUT4 translocation. PMID- 27467142 TI - Crimean-Congo Hemorrhagic Fever Virus in Bulgaria and Turkey. AB - Infections of humans with the tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) can cause a severe hemorrhagic fever with case fatality rates of up to 80%. Most humans are infected by tick bite, crushing infected ticks by hand or by unprotected contact with blood of viremic mammals. Next to the notified human CCHF cases, the real distribution and the situation in animals in Southeastern Europe are nearly unknown. Since domestic ruminants play a crucial role in the life cycle of the vector ticks and the transmission and amplification of the virus, the antibody prevalence in those animals is a good indicator for the presence of CCHFV in a region. Therefore, the prevalence of CCHFV-specific antibodies was investigated in domestic ruminants of different regions of Bulgaria and Turkey. Sera of 1165 ruminants were tested and a prevalence of up to 90% was identified. The overall prevalence for Bulgaria was 26% and for Turkey 57%. The results highlight the risk of human infections in those regions and the importance of the investigation of the prevalence in animals for identification of risk areas. This article provides a unique overview about published CCHFV antibody prevalence in animals in comparison to human incidences in different areas of Bulgaria and Turkey. Although it will help to complete the understanding of the CCHFV situation in these countries, it also demonstrates the lack of unpublished and published data even in these highly endemic areas. PMID- 27467143 TI - Thymic Stromal Lymphopoietin Neutralization Inhibits the Immune Adjuvant Effect of Di-(2-Ethylhexyl) Phthalate in Balb/c Mouse Asthma Model. AB - Di-(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer, has an adjuvant effect in combination with ovalbumin (OVA). The adjuvant effect of DEHP has already been verified in our previous studies. In this study, to further investigate whether thymic stromal lymphopoietin (TSLP) was involved in the DEHP adjuvant effect, DEHP was administered through a daily gavage exposure route. Mice were sensitized with ovalbumin (OVA) to trigger allergic responses, and an anti-TSLP monoclonal antibody was used to neutralize the effect of TSLP. Biomarkers including cytokines in bronchoalveolar lavage fluid (BALF), serum total IgE and TSLP content in the lung were detected. In addition, airway hyperreactivity and lung sections were examined. Collectively, these data indicated a salient Th2 response which was characterized by the upregulation of Th2-type cytokines, such as interleukin 4 (IL-4), IL-5 and IL-13. Moreover, the eosinophil number in BALF and the eosinophil cationic protein (ECP) in the lung were seen to have increased significantly. However, neutralization of TSLP with an anti-TSLP mAb reversed the adjuvant effect of DEHP on airway inflammation, structural alterations in the airway wall and increased airway hyperresponsiveness (AHR) to methacholine induced by the OVA allergen, suggesting that TSLP was an effective target site for suppressing the adjuvant effect of DEHP co-exposure. PMID- 27467144 TI - T Helper Cell Activation and Expansion Is Sensitive to Glutaminase Inhibition under Both Hypoxic and Normoxic Conditions. AB - Immune responses often take place where nutrients and O2 availability are limited. This has an impact on T cell metabolism and influences activation and effector functions. T cell proliferation and expansion are associated with increased consumption of glutamine which is needed in a number of metabolic pathways and regulate various physiological processes. The first step in endogenous glutamine metabolism is reversible and is regulated by glutaminase (GLS1 and GLS2) and glutamine synthase (GLUL). There are two isoforms of GLS1, Kidney type glutaminase (KGA) and Glutaminase C (GAC). The aim of this study is to investigate the expression, localization and role of GLS1 and GLUL in naive and activated human CD4+ T cells stimulated through the CD3 and CD28 receptors under normoxia and hypoxia. In proliferating cells, GAC was upregulated and KGA was downregulated, and both enzymes were located to the mitochondria irrespective of O2 levels. By contrast GLUL is localized to the cytoplasm and was upregulated under hypoxia. Proliferation was dependent on glutamine consumption, as glutamine deprivation and GLS1 inhibition decreased proliferation and expression of CD25 and CD226, regardless of O2 availability. Again irrespective of O2, GLS1 inhibition decreased the proportion of CCR6 and CXCR3 expressing CD4+ T cells as well as cytokine production. We propose that systemic Th cell activation and expansion might be dependent on glutamine but not O2 availability. PMID- 27467145 TI - Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses. AB - Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of vivax relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to vivax recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy. PMID- 27467146 TI - Quadruplex-Flanking Stem Structures Modulate the Stability and Metal Ion Preferences of RNA Mimics of GFP. AB - The spinach family of RNA aptamers are RNA mimics of green fluorescent protein (GFP) that have previously been designed to address the challenges of imaging RNA inside living cells. However, relatively low levels of free intracellular magnesium limited the practical use of these aptamers. Recent cell-based selections identified the broccoli RNA aptamer, which requires less magnesium for fluorescence, but the basis for magnesium preference remained unclear. Here, we find that the broccoli RNA structure is very similar to that of baby spinach, a truncated version of the spinach aptamer. Differences in stability and metal ion preferences between these two aptamers, and among broccoli mutants, are primarily associated with the sequence and structure of predicted quadruplex-flanking stem structures. Mutation of purine-purine pairs in broccoli at the terminal stem quadruplex transition caused reversion of broccoli to a higher magnesium dependence. Unique duplex-to-quadruplex transitions in GFP-mimic RNAs likely explain their sensitivity to magnesium for stability and fluorescence. Thus, optimizations designed to improve aptamers should take into consideration the role of metal ions in stabilizing the transitions and interactions between independently folding RNA structural motifs. PMID- 27467147 TI - Gene Expression Profile in the Liver of Sheep Infected with Cystic Echinococcosis. AB - BACKGROUND: Cystic Echinococcosis (CE), caused by infection with the Echinococcus granulosus (E. granulosus), represents considerable health problems in both humans and livestock. Nevertheless, the genetic program that regulates the host response to E. granulosus infection is largely unknown. Previously, using microarray analysis, we found that the innate immunity played a vital role in the E. granulosus defense of the intestine tissue where E. granulosus first invaded. Subsequently, we turned our attention to investigating the molecular immune mechanism in its organ target, the liver, which is where the E. granulosus metacestodes are established and live for very long periods. In this work, the microarray-based methodology was used to study gene expression profiles in the liver of sheep infected with E. granulosus at 8 weeks post infection, corresponding to the early cystic established phase. METHODS: A total of 6 female 1-year-old healthy Kazakh sheep were used for the experiments. Three Kazakh sheep were orally infected with E. granulosus eggs, and the others remained untreated and served as controls. Sheep were humanely euthanized and necropsized at 8 weeks post-infection (the early stage of cyst established). The microarray was used to detect differential hepatic gene expression between CE infection sheep and healthy controls at this time point. Real-time PCR was used to validate the microarray data. RESULTS: We found that E. granulosus infection induces 153 differentially expressed genes in the livers of infected sheep compared with healthy controls. Among them, 87 genes were up-regulated, and 66 genes were notably down-regulated. Functional analysis showed that these genes were associated with three major functional categories: (a) metabolism, (b) the immune system and (c) signaling and transport. Deeper analysis indicated that complement together with other genes associated with metabolism, played important roles in the defense of E. granulosus infection. CONCLUSION: The present study identified genes profiling in the liver tissue of E. granulosus infection in sheep. The expression pattern obtained here could be helpful for understanding the molecular immunity mechanisms of host responses to E. granulosus infection. However, it is necessary to carry out further studies to evalute the role of these genes. PMID- 27467151 TI - Molecular Dynamics Simulations Using Graphics Processing Units. AB - It is increasingly easy to develop software that exploits Graphics Processing Units (GPUs). The molecular dynamics simulation community has embraced this recent opportunity. Herein, we outline the current approaches that exploit this technology. In the context of biomolecular simulations, we discuss some of the algorithms that have been implemented and some of the aspects that distinguish the GPU from previous parallel environments. The ubiquity of GPUs and the ingenuity of the simulation community augur well for the scale and scope of future computational studies of biomolecules. PMID- 27467152 TI - Text Mining for Drugs and Chemical Compounds: Methods, Tools and Applications. AB - Providing prior knowledge about biological properties of chemicals, such as kinetic values, protein targets, or toxic effects, can facilitate many aspects of drug development. Chemical information is rapidly accumulating in all sorts of free text documents like patents, industry reports, or scientific articles, which has motivated the development of specifically tailored text mining applications. Despite the potential gains, chemical text mining still faces significant challenges. One of the most salient is the recognition of chemical entities mentioned in text. To help practitioners contribute to this area, a good portion of this review is devoted to this issue, and presents the basic concepts and principles underlying the main strategies. The technical details are introduced and accompanied by relevant bibliographic references. Other tasks discussed are retrieving relevant articles, identifying relationships between chemicals and other entities, or determining the chemical structures of chemicals mentioned in text. This review also introduces a number of published applications that can be used to build pipelines in topics like drug side effects, toxicity, and protein disease-compound network analysis. We conclude the review with an outlook on how we expect the field to evolve, discussing its possibilities and its current limitations. PMID- 27467153 TI - Identification of Nonpeptide Oxytocin Receptor Ligands by Receptor-Ligand Fingerprint Similarity Search. PMID- 27467154 TI - A Comparative Study of Nonlinear Machine Learning for the "In Silico" Depiction of Tyrosinase Inhibitory Activity from Molecular Structure. AB - In the preset report, for the first time, support vector machine (SVM), artificial neural network (ANN), Bayesian networks (BNs), k-nearest neighbor (k NN) are applied and compared on two "in-house" datasets to describe the tyrosinase inhibitory activity from the molecular structure. The data set Data I is used for the identification of tyrosinase inhibitors (TIs) including 701 active and 728 inactive compounds. Data II consists of active chemicals for potency estimation of TIs. The 2D TOMOCOMD-CARDD atom-based quadratic indices are used as molecular descriptors. The derived models show rather encouraging results with the areas under the Receiver Operating Characteristic (AURC) curve in the test set above 0.943 and 0.846 for the Data I and Data II, respectively. Multiple comparison tests are carried out to compare the performance of the models and reveal the improvement of machine learning (ML) techniques with respect to statistical ones (see Chemometr. Intell. Lab. Syst. 2010, 104, 249). In some cases, these ameliorations are statistically significant. The tests also demostrate that k-NN, despite being a rather simple approach, presents the best behavior in both data. The obtained results suggest that the ML-based models could help to improve the virtual screening procedures and the confluence of these different techniques can increase the practicality of data mining procedures of chemical databases for the discovery of novel TIs as possible depigmenting agents. PMID- 27467156 TI - A Risk Assessment Perspective of Current Practice in Characterizing Uncertainties in QSAR Regression Predictions. AB - The European REACH legislation accepts the use of non-testing methods, such as QSARs, to inform chemical risk assessment. In this paper, we aim to initiate a discussion on the characterization of predictive uncertainty from QSAR regressions. For the purpose of decision making, we discuss applications from the perspective of applying QSARs to support probabilistic risk assessment. Predictive uncertainty is characterized by a wide variety of methods, ranging from pure expert judgement based on variability in experimental data, through data-driven statistical inference, to the use of probabilistic QSAR models. Model uncertainty is dealt with by assessing confidence in predictions and by building consensus models. The characterization of predictive uncertainty would benefit from a probabilistic formulation of QSAR models (e.g. generalized linear models, conditional density estimators or Bayesian models). This would allow predictive uncertainty to be quantified as probability distributions, such as Bayesian predictive posteriors, and likelihood-based methods to address model uncertainty. QSAR regression models with point estimates as output may be turned into a probabilistic framework without any loss of validity from a chemical point of view. A QSAR model for use in probabilistic risk assessment needs to be validated for its ability to make reliable predictions and to quantify associated uncertainty. PMID- 27467155 TI - Computational Insights into Ligand Selectivity of Estrogen Receptors from Pharmacophore Modeling. AB - Estrogen receptors (ERs) belong to the nuclear receptor superfamily, which play crucial roles in the human body. To date, two subtypes, ERalpha and ERbeta, have been identified. The function and expression of both subtypes are various, stimulating the interest for discovering subtype selective ligands. However, ERalpha and ERbeta are highly homologous. They share 56 % sequence identity in the ligand binding domain and only two pairs of residues differ in the ligand binding pocket. In this study, pharmacophore models were built for both subtypes based on 23 ERalpha and 24 ERbeta selective ligands, respectively. It was found from these pharmacophore models that hydrophobic and hydrogen bonding interactions were essential for the subtype selectivity. The hydrogen bond donor feature in the phenol part was a favorable contribution to ERbeta selectivity, whereas the one in the benzopyran part of the ligand was important for ERalpha selectivity. Furthermore, simulated virtual screening was performed with both subtype specific pharmacophore models. The results confirmed the reliability and discrimination ability of both models. These findings could not only be helpful for the understanding of a possible mechanism underlying ligand selectivity of ERs, but could also pave a new avenue for the discovery of novel selective ER ligands. PMID- 27467157 TI - Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors. AB - A myriad of methods are available for virtual screening of small organic compound databases. In this study we have successfully applied a quantitative model of consensus measurements, using a combination of 3D similarity searches (ROCS and EON), Hologram Quantitative Structure Activity Relationships (HQSAR) and docking (FRED, FlexX, Glide and AutoDock Vina), to retrieve cruzain inhibitors from collected databases. All methods were assessed individually and then combined in a Ligand-Based Virtual Screening (LBVS) and Target-Based Virtual Screening (TBVS) consensus scoring, using Receiving Operating Characteristic (ROC) curves to evaluate their performance. Three consensus strategies were used: scaled-rank-by number, rank-by-rank and rank-by-vote, with the most thriving the scaled-rank-by number strategy, considering that the stiff ROC curve appeared to be satisfactory in every way to indicate a higher enrichment power at early retrieval of active compounds from the database. The ligand-based method provided access to a robust and predictive HQSAR model that was developed to show superior discrimination between active and inactive compounds, which was also better than ROCS and EON procedures. Overall, the integration of fast computational techniques based on ligand and target structures resulted in a more efficient retrieval of cruzain inhibitors with desired pharmacological profiles that may be useful to advance the discovery of new trypanocidal agents. PMID- 27467158 TI - Structure-Based Pharmacophore Modeling from Multicomplex: a Comprehensive Pharmacophore Generation of Protein Kinase CK2 and Virtual Screening Based on it for Novel Inhibitors. AB - Protein kinase CK2, a member of the serine/threonine kinase family, is an attractive therapeutic target for anticancer combination therapy. A multiple structure-based modeling approach complemented with shape components was taken to build a reliable pharmacophore model for ATP-competitive CK2 inhibitors. The final model consisted of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), two hydrophobic (HY) features, several excluded volumes and shape constraints. In the validation study, this model yielded an enrichment factor of 10.22 and performed fairly well in distinguishing active compounds. SPECS database was searched based on this query and sixteen compounds were retained after multiple filtrations for biological test. 4 compounds with IC50 values less than 10 uM were disclosed, providing 2 new chemical scaffolds as CK2 inhibitors. It is expected that the information provided here is helpful for discovering more potential CK2 inhibitors. PMID- 27467159 TI - Interpretation of QSAR Models Based on Random Forest Methods. AB - A new algorithm for the interpretation of Random Forest models has been developed. It allows to calculate the contribution of each descriptor to the calculated property value. In case of the simplex representation of a molecular structure, contributions of individual atoms can be calculated, and thus it becomes possible to estimate the influence of separate molecular fragments on the investigated property. Such information can be used for the design of new compounds with a predefined property value. The proposed measure of descriptor contributions is not an alternative to the importance of Breiman's variable, but it characterizes the contribution of a particular explanatory variable to the calculated response value. PMID- 27467160 TI - MPO Inhibitors Selected by Virtual Screening. AB - The hemeprotein myeloperoxidase (MPO) participates in innate immune defense through its ability to generate potent microbicidal oxidants. However, these oxidants are also key mediators of the tissue damage associated with many inflammatory diseases. Thus, there is considerable interest in developing therapeutically useful MPO inhibitors. Here, we used structure-based drug design (SBDD) and ligand-based drug design (LBDD) to select for potentially new and selective MPO inhibitors. A pharmacophore model was developed based on the crystal structure of human MPO in complex with salicylhydroxamic acid (SHA), a known inhibitor of the enzyme. The pharmacophore model was used to screen the ZINC database for potential ligands, which were further filtered on the basis of their physical-chemical properties and docking score. The filtered compounds were visually inspected, and nine were purchased for experimental studies. Surprisingly, almost all of the selected compounds belonged to the aromatic hydrazide class, which had been previously described as MPO inhibitors. The compounds selected by virtual screening were shown to inhibit the chlorinating activity of MPO; the top four compounds displayed IC50 values ranging from 1.0 to 2.8 uM. MPO inactivation by the most effective compound was shown to be irreversible. Overall, our results show that SBDD and LBDD may be useful for the rational development of new MPO inhibitors. PMID- 27467161 TI - A Comparative Study on the Constitutive Properties of Marketed Pesticides. AB - The concept of drug-likeness has been established in the field of drug discovery. Pesticide discovery is also a complicated and rigorous filtering process compared with drug discovery. This study involved investigation of the constitutive properties of 788 marketed pesticides, including 341 herbicides, 182 fungicides, and 265 insecticides. In a comparison of the constitutive properties of different kinds of pesticides and of pesticides from different periods of registration, ClogP, the number of H-bond donors (HBD), and the number of aromatic bonds (ARB) were identified as the most important factors that distinguish herbicides, fungicides, and insecticides. In addition, the reduction in pesticide toxicity with revolution time was found to have some relationship with an increase in values of the six constitutive properties. Finally, we established some rules for pesticide-likeness, including molecular weight<=435 Da, ClogP<=6, number of H bond acceptors (HBA)<=6, HBD<=2, number of rotatable bonds (ROB)<=9, and ARB<=17. The constitutive property-related novel findings in this study will promote the structure-based optimization of pesticide candidates. PMID- 27467162 TI - Predicting the Thermal Stability of Nitroaromatic Compounds Using Chemoinformatic Tools. AB - In the framework of the European REACH regulation major attention was recently devoted to toxicological and ecotoxicological problems while little attention has been dedicated to other important applications concerning chemical hazards, for instance, explosive properties. In this work different chemoinformatic tools such as partial least squares, multilinear regressions, and decision trees have been used for the development of a novel quantitative structure-property relationships to predict the heat of decomposition of a series of nitroaromatic compounds. Models were conceived in order to follow the regulatory requirements according to OECD principles for the validation of QSAR methods. Three models derived with MLR, PLS and decision tree techniques were developed, validated (internally and externally) and their applicability domains have been defined and analyzed. All models proved to be reliable with remarkable robustness in terms of full cross validation scheme and showed good predictive power toward the external validation set. These models also present a large applicability domain within nitrobenzene derivatives and are easy to implement and interpret in terms of subjacent mechanisms. PMID- 27467163 TI - Copper-Catalyzed Enantioselective Allyl-Allyl Coupling between Allylic Boronates and Phosphates with a Phenol/N-Heterocyclic Carbene Chiral Ligand. AB - Copper-catalyzed enantioselective allyl-allyl coupling between allylboronates and either Z-acyclic or cyclic allylic phosphates using a new chiral N-heterocyclic carbene ligand, bearing a phenolic hydroxy, is reported. This reaction occurs with exceptional SN 2'-type regioselectivities and high enantioselectivities to deliver chiral 1,5-diene derivatives with a tertiary stereogenic center at the allylic/homoallylic position. PMID- 27467164 TI - High Resistance to Azithromycin in Clinical Samples from Patients with Sexually Transmitted Diseases in Guangxi Zhuang Autonomous Region, China. AB - Azithromycin is used as an alternative medicine in patients with syphilis who are intolerant to penicillin. Nevertheless, the report of treatment failure of azithromycin for patients with syphilis has raised concerns in China in the past years. In this study, 178 patients with early syphilis, who were treated in sexually transmitted infections clinics in four cities in Guangxi Zhuang Autonomous Region were enrolled to investigate the regional prevalence of Treponema pallidum strain resistant to azithromycin. Nested PCR was performed to amplify the 23S ribosomal RNA (23SrRNA) gene. The point mutation of A2058G in 23SrRNA, which confers Treponema pallidum resistance to azithromycin, was measured by endonuclease digestion of PCR amplification products using MboII. A2058G point mutation was detected in 91.0% (162/178; 95% CI, 86.8%, 95.2%) of the specimens, but no difference in prevalence of azithromycin resistance was found between the patients who had taken antibiotics before enrollment and the patients who had not (91.8% vs. 89.4%), nor between the patients with and without past sexually transmitted infections (87.1% vs. 93.1%). We concluded that azithromycin may not be suitable for syphilis as a treatment option in Guangxi Zhuang Autonomous Region because of the extremely high prevalence of resistance in the general syphilis population. PMID- 27467165 TI - Association of Long Non-Coding RNA HOTAIR Polymorphisms with Cervical Cancer Risk in a Chinese Population. AB - Long non-coding RNAs (lncRNAs), HOTAIR has been reported to be upregulated in cervical cancer development and progression. However, SNPs (single nucleotide polymorphisms) in the lncRNAs and their associations with cervical cancer susceptibility have not been reported. In the current study, we hypothesized that SNPs within the lncRNA HOTAIR may influence the risk of cervical cancer. We performed a case-control study including 510 cervical cancer patients (cases) and 713 cancer-free individuals (controls) to investigate the association between three haplotype-tagging SNPs (rs920778, rs1899663 and rs4759314) in the lncRNA HOTAIR and the risk of cervical cancer. We found a strong association between the SNP rs920778 in the intronic enhancer of the HOTAIR and cervical cancer (P<10-4). Moreover, the cervical cancer patients with homozygous TT genotype were significantly associated with tumor-node-metastasis (TNM) stage. In vitro assays with allele-specific reporter constructs indicated that the reporter constructs bearing rs920778T allele conferred elevated reporter gene transcriptional activity when compared to the reporter constructs containing rs920778C allele. Furthermore, HOTAIR expression was higher in cervical cancer tissues than that in corresponding normal tissues, and the high expression was associated with the risk-associated allele T. In summary, our studies provide strong functional evidence that functional SNP rs920778 regulates HOTAIR expression, and may ultimately influence the predisposition for cervical cancer. PMID- 27467167 TI - Importance of Glutamate Dehydrogenase (GDH) in Clostridium difficile Colonization In Vivo. AB - Clostridium difficile is the principal cause of antibiotic-associated diarrhea. Major metabolic requirements for colonization and expansion of C. difficile after microbiota disturbance have not been fully determined. In this study, we show that glutamate utilization is important for C. difficile to establish itself in the animal gut. When the gluD gene, which codes for glutamate dehydrogenase (GDH), was disrupted, the mutant C. difficile was unable to colonize and cause disease in a hamster model. Further, from the complementation experiment it appears that extracellular GDH may be playing a role in promoting C. difficile colonization and disease progression. Quantification of free amino acids in the hamster gut during C. difficile infection showed that glutamate is among preferred amino acids utilized by C. difficile during its expansion. This study provides evidence of the importance of glutamate metabolism for C. difficile pathogenesis. PMID- 27467168 TI - Leading on the edge: The nature of paramedic leadership at the front line of care. AB - BACKGROUND: Health care organizations are considered complex systems that represent both formal leadership as well as more informal and shared leadership models. Implementing these models is essential for optimizing care and patient outcomes. The paramedic profession specifically, although considered informally, leads out of hospital patient care. PURPOSE: To date, few empirical studies investigate shared leadership in health care settings. In paramedicine specifically, studies of leadership are scarce, despite paramedics' essential role in leading on the front lines of care. Using an exemplar of paramedics, we examine what it means to informally lead on the front lines of patient care with the emphasis on paramedics responding out of hospital. METHODOLOGY: We employed a qualitative, semistructured interview methodology with 29 paramedics from a group of companies in central/eastern Canada to explore the conditions and practices surrounding shared leadership. FINDINGS: Paramedics argue that, despite their job title, they classify themselves as informal leaders who share the leadership role. More specifically, the paramedics discuss the precursors, practices, and structural conditions surrounding shared leadership within the realm of emergency medical services. They note that they often face out-of-hospital care without a formal manager, requiring them to collectively lead. The leader will shift in times of urgency, and this is contingent on their skills and competence. Furthermore, managers routinely called upon paramedics to lead in their absence. PRACTICE IMPLICATIONS: It is shown here that, although informally enacted, paramedics view leadership as a necessary competency for clinical practice. We argue that leadership development of paramedics must begin during their formal education and training as part of the core curriculum. As well, direct managers can promote an environment of shared leadership and encourage paramedics to practice leadership with quality of patient service in mind. PMID- 27467169 TI - Longitudinal analysis of high-technology medical services and hospital financial performance. AB - BACKGROUND: U.S. hospitals have been investing in high-technology medical services as a strategy to improve financial performance. Despite the interest in high-tech medical services, there is not much information available about the impact of high-tech services on financial performance. PURPOSE: The aim of this study was to examine the impact of high-tech medical services on financial performance of U.S. hospitals by using the resource-based view of the firm as a conceptual framework. METHODOLOGY/APPROACH: Fixed-effects regressions with 2 years lagged independent variables using a longitudinal panel sample of 3,268 hospitals (2005-2010). It was hypothesized that hospitals with rare or large numbers (breadth) of high-tech medical services will experience better financial performance. FINDINGS: Fixed effects regression results supported the link between a larger breadth of high-tech services and total margin, but only among not-for-profit hospitals. Both breadth and rareness of high-tech services were associated with high total margin among not-for-profit hospitals. Neither breadth nor rareness of high-tech services was associated with operating margin. Although breadth and rareness of high-tech services resulted in lower expenses per inpatient day among not-for-profit hospitals, these lower costs were offset by lower revenues per inpatient day. PRACTICE IMPLICATIONS: Enhancing the breadth of high-tech services may be a legitimate organizational strategy to improve financial performance, especially among not-for-profit hospitals. Hospitals may experience increased productivity and efficiency, and therefore lower inpatient operating costs, as a result of newer technologies. However, the negative impact on operating revenue should caution hospital administrators about revenue reducing features of these technologies, which may be related to the payer mix that these technologies may attract. Therefore, managers should consider both the cost and revenue implications of these technologies. PMID- 27467170 TI - Associations between respiratory signs and abnormalities reported in thoracic CT scans of cats. AB - OBJECTIVES: To estimate the prevalence of subclinical abnormalities reported in thoracic (CT) scans of cats and to investigate associations between respiratory signs and CT signs. METHODS: Retrospective review of signalment, indications, respiratory signs and reported CT findings in a series of cats. Associations between patient variables, respiratory signs and CT signs were analysed using multi-variable regression methods. RESULTS: Records of 352 consecutive cats were reviewed. Abnormalities affecting thoracic structures were reported in CT scans of 138/179 (77%) cats that did not have respiratory signs; the most prevalent CT findings were pulmonary collapse (41%), evidence of bronchial disease (24%) and space-occupying lesions (21%). Dyspnoea, cough and tachypnoea were associated with space-occupying lesions. Dyspnoea was also associated with pulmonary consolidation and atelectasis. Increasing body weight was associated with pulmonary atelectasis and increasing age was associated with evidence of bronchial disease. CLINICAL SIGNIFICANCE: Abnormalities were commonly detected in thoracic CT scans of cats that did not show respiratory signs. The most prevalent abnormality - pulmonary atelectasis - is probably a temporary effect of sedation or anaesthesia. A high prevalence of subclinical abnormalities and limited correlations between clinical signs and CT findings will complicate diagnosis. PMID- 27467171 TI - The Effects of Supplementary Food on the Breeding Performance of Eurasian Reed Warblers Acrocephalus scirpaceus; Implications for Climate Change Impacts. AB - Understanding the mechanisms by which climate variation can drive population changes requires information linking climate, local conditions, trophic resources, behaviour and demography. Climate change alters the seasonal pattern of emergence and abundance of invertebrate populations, which may have important consequences for the breeding performance and population change of insectivorous birds. In this study, we examine the role of food availability in driving behavioural changes in an insectivorous migratory songbird; the Eurasian reed warbler Acrocephalus scirpaceus. We use a feeding experiment to examine the effect of increased food supply on different components of breeding behaviour and first-brood productivity, over three breeding seasons (2012-2014). Reed warblers respond to food-supplementation by advancing their laying date by up to 5.6 days. Incubation periods are shorter in supplemented groups during the warmest mean spring temperatures. Nestling growth rates are increased in nests provisioned by supplemented parents. In addition, nest predation is reduced, possibly because supplemented adults spend more time at the nest and faster nestling growth reduces the period of vulnerability of eggs and nestlings to predators (and brood parasites). The net effect of these changes is to advance the fledging completion date and to increase the overall productivity of the first brood for supplemented birds. European populations of reed warblers are currently increasing; our results suggest that advancing spring phenology, leading to increased food availability early in the breeding season, could account for this change by facilitating higher productivity. Furthermore, the earlier brood completion potentially allows multiple breeding attempts. This study identifies the likely trophic and behavioural mechanisms by which climate-driven changes in invertebrate phenology and abundance may lead to changes in breeding phenology, nest survival and net reproductive performance of insectivorous birds. PMID- 27467172 TI - Heparanase: A Potential New Factor Involved in the Renal Epithelial Mesenchymal Transition (EMT) Induced by Ischemia/Reperfusion (I/R) Injury. AB - BACKGROUND: Ischemia/reperfusion (I/R) is an important cause of acute renal failure and delayed graft function, and it may induce chronic renal damage by activating epithelial to mesenchymal transition (EMT) of renal tubular cells. Heparanase (HPSE), an endoglycosidase that regulates FGF-2 and TGFbeta-induced EMT, may have an important role. Therefore, aim of this study was to evaluate its role in the I/R-induced renal pro-fibrotic machinery by employing in vitro and in vivo models. METHODS: Wild type (WT) and HPSE-silenced renal tubular cells were subjected to hypoxia and reoxygenation in the presence or absence of SST0001, an inhibitor of HPSE. In vivo, I/R injury was induced by bilateral clamping of renal arteries for 30 min in transgenic mice over-expressing HPSE (HPA-tg) and in their WT littermates. Mice were sacrificed 48 and 72 h after I/R. Gene and protein EMT markers (alpha-SMA, VIM and FN) were evaluated by bio-molecular and histological methodologies. RESULTS: In vitro: hypoxia/reoxygenation (H/R) significantly increased the expression of EMT-markers in WT, but not in HPSE-silenced tubular cells. Notably, EMT was prevented in WT cells by SST0001 treatment. In vivo: I/R induced a remarkable up-regulation of EMT markers in HPA-tg mice after 48-72 h. Noteworthy, these effects were absent in WT animals. CONCLUSIONS: In conclusion, our results add new insights towards understanding the renal biological mechanisms activated by I/R and they demonstrate, for the first time, that HPSE is a pivotal factor involved in the onset and development of I/R-induced EMT. It is plausible that in future the inhibition of this endoglycosidase may represent a new therapeutic approach to minimize/prevent fibrosis and slow down chronic renal disease progression in native and transplanted kidneys. PMID- 27467174 TI - Functional mitral regurgitation in patients with heart failure and depressed ejection fraction. AB - PURPOSE OF REVIEW: Functional mitral regurgitation (FMR) is a common complication of left ventricular dysfunction. It is now recognized as an important clinical entity and an independent predictor of poor prognosis in cardiomyopathy patients. In this review, we provide a comprehensive summary of the pathophysiology, latest imaging modalities, and diagnostic criteria for FMR. Additionally, we discuss the recent literature on the continuously evolving surgical and percutaneous treatment options. RECENT FINDINGS: The criteria for quantification of FMR on echocardiography were updated and are distinct from organic mitral regurgitation in the most recent American College of Cardiology/American Heart Association 2014 valve guidelines. Furthermore, the evolving role of MitraClip for potential treatment of FMR offers exciting prospects to treat high-risk symptomatic patients. SUMMARY: Our review serves to consolidate the current diagnostic and treatment modalities for FMR and provide a contemporary resource for clinicians while treating patients. Additionally, we identify the gaps present in our knowledge of FMR to guide further clinical investigation. PMID- 27467175 TI - Is there a need to assess myocardial viability in patients presenting with heart failure? AB - PURPOSE OF REVIEW: Cardiac MRI is unique amongst the cardiac imaging modalities in its ability to directly image myocardial fibrosis using late gadolinium enhancement techniques. The ability to identify not only the presence of fibrosis but also its pattern of distribution within the myocardium can aid in distinguishing between ischemic and nonischemic causes of left ventricular dysfunction, as well as provide valuable prognostic information for patients with various etiologies of heart failure. RECENT FINDINGS: Amongst patients with ischemic cardiomyopathy, the Surgical Treatment for Ischemic Heart Failure (STICH) trial was attempted to assess the value of coronary artery bypass surgery. Although the early results were disappointing as to the overall utility of surgical revascularization, the recently published 10-year follow-up now demonstrates improved survival amongst patients undergoing surgical revascularization when compared with medical therapy alone. Although a substudy of STICH failed to demonstrate utility of preprocedural viability assessment with dobutamine echocardiography or single-photon-emission computed tomography, other studies support the identification of myocardial fibrosis as carrying important prognostic information. The ongoing development of new techniques, particularly T1 mapping of extracellular volume fraction, holds promise for the future as early studies suggest complementary prognostic value and perhaps the ability to avoid contrast administration. SUMMARY: Cardiac MRI use for viability assessment demonstrates important utility amongst patients with heart failure, regardless of its cause. PMID- 27467173 TI - Right heart imaging in patients with heart failure: a tale of two ventricles. AB - PURPOSE OF REVIEW: The purpose is to describe the recent advances made in imaging of the right heart, including deformation imaging, tissue, and flow characterization by MRI, and molecular imaging. RECENT FINDINGS: Recent developments have been made in the field of deformation imaging of the right heart, which may improve risk stratification of patients with heart failure and pulmonary hypertension. In addition, more attention has been given to load adaptability metrics of the right heart; these simplified indices, however, still face challenges from a conceptual point of view. The emergence of novel MRI sequences, such as native T1 mapping, allows better detection and quantification of myocardial fibrosis and could allow better prediction of postsurgical recovery of the right heart. Other advances in MRI include four-dimensional flow imaging, which may be particularly useful in congenital heart disease or for the detection of early stages of pulmonary vascular disease. SUMMARY: The review will place the recent developments in right heart imaging in the context of clinical care and research. PMID- 27467176 TI - Role of multimodality imaging in patients with left ventricular assist device. AB - PURPOSE OF REVIEW: The article provides an overview of recent advances in imaging patients with a left ventricular assist device (LVAD). RECENT FINDINGS: There is a growing population of patients with LVADs. LVADs improve survival in patients with end-stage heart failure, but are also associated with significant adverse outcomes. Imaging, particularly echocardiography, plays a critical role in patient selection and in predicting and detecting complications. SUMMARY: Recent studies have illustrated links between imaging parameters with adverse outcomes, such as pump thrombosis, right ventricular failure, and continuous aortic regurgitation. Novel parameters and imaging techniques have been developed. PMID- 27467178 TI - Ototoxicity of 12 mg/kg cisplatin in the Fischer 344/NHsd rat using multiple dosing strategies. AB - Ototoxicity continues to be a major dose-limiting side effect of cis diamminedichloroplatinum(II) (cisplatin). With an ongoing need to develop pharmaceutical protection strategies for cisplatin's ototoxicity, there is also a need to develop stable in-vivo mammalian models of cisplatin ototoxicity. The current study examined the difference in ototoxicity of a cumulative 12 mg/kg dose of cisplatin in the Fischer 344/NHsd rat when administered over four different dosing protocols. Hearing sensitivity was measured using free-field auditory brainstem response thresholds under anesthesia. Rats were divided into four groups. The first group was administered 12 mg/kg of cisplatin in a single bolus infusion. The second group was administered two 6 mg/kg infusions separated by 7 days. The third group was administered 3 mg/kg injections once per day for 4 consecutive days. The fourth group was administered 3 mg/kg injections in four injections separated by 3 days each. Hearing thresholds and body weights were measured at 3 and 7 days after the final cisplatin exposure. Postmortem sensory cell counts were used to confirm injury to the auditory system. The 4 consecutive days of 3 mg/kg induced a greater mortality rate and greater hearing loss at day 3 than the other experimental protocols. The 3 mg/kg administered every 3 days induced less sensory cell loss than the other conditions. The findings indicate that 4 consecutive days of 3 mg/kg cisplatin is not a viable ototoxicity model in the Fischer 344/NHsd rat, but that the other models are all effective in inducing comparable cochlear injuries. PMID- 27467179 TI - Investigating the effect of emotional intelligence education on baccalaureate nursing students' emotional intelligence scores. AB - Nursing students, particularly at the time of entering clinical education, experience a great deal of stress and emotion typically related to their educational and clinical competence. Emotional intelligence is known to be one of the required skills to effectively cope with such feelings. The aim of this study was to investigate the effect of training on first-year nursing students' levels of emotional intelligence. This was a quasi-experiment study in which 69 first year nursing students affiliated with Tehran University of Medical Sciences were assigned to either the control or the experimental groups. The study intervention included of an emotional intelligence educational program offered in eight two hour sessions for eight subsequent weeks. In total, 66 students completed the study. The study groups did not differ significantly in terms of emotional intelligence scores before and after educational program. Although the educational program did not have an effect on students' emotional intelligence scores, this study finding can be explained. Limited time for exercising the acquired knowledge and skills may explain the non-significant findings. Moreover, our participants were exclusively first-year students who had no clinical experience and hence, might have felt no real need to learn emotional intelligence skills. PMID- 27467180 TI - A Focus on the Epidemiology of Uveitis. AB - PURPOSE: Uveitis is a common, sight-threatening inflammatory ocular disease and includes multiple heterogeneous clinical entities. The prevalence of various types of uveitis depends upon multiple factors, such as age, sex, race, geographic distribution, environmental influence, genetics, and social habits. Epidemiologic research of uveitis is necessary to understand the etiology and immunopathogenesis of this group of diseases. The present study attempts to concentrate on the most recent information on the epidemiology of uveitis and compare it with previous knowledge. METHODS: An extensive literature search was performed in the Medline database (PubMed) and included surveys completed until 2015. Articles that reported prevalence and incidence were studied. References cited in the articles were also studied. RESULTS: The incidence and prevalence of uveitis differs based on age, anatomic location of the inflammatory process (anterior, intermediate, posterior uveitis, panuveitis), gender, histopathology (granulomatous, non-granulomatous), type of inflammatory process (acute, chronic, recurrent), and etiology (infectious, non-infectious). Prevalence differs by geographic location. Idiopathic anterior uveitis is the most common form of uveitis in the community. Infectious causes are common (30-60%) in the developing countries. Herpes and toxoplasmosis are the leading infectious causes of uveitis. Non-infectious uveitic conditions are generally more common in the developed world. An increase in the prevalence of infectious etiologies, including tuberculosis and syphilis, has been seen in developed countries. Introduction of new treatment options has also changed patterns of disease. CONCLUSIONS: Introduction of new uveitis entities, changes in the incidence of already known disease and increased availability of diagnostic testing have all altered the epidemiology of uveitis in recent years. Knowledge of regional patterns of disease is essential. A more detailed classification of uveitis with the establishment of uniform diagnostic criteria and prospective population based studies would certainly benefit epidemiologic research and clinical practice. PMID- 27467181 TI - The prevalences of and association between nonmedical prescription opioid use and poor sleep among Chinese high school students. AB - The purpose of this study was to investigate the prevalences of and association between nonmedical prescription opioid use (NMPOU) and sleep quality among Chinese high school students. A cross-sectional study was conducted in Chongqing high school students in 2012, and questionnaires from 18,686 students were completed and eligible for this study. Demographic and NMPOU information was collected using a self-administered questionnaire. The Chinese Pittsburgh Sleep Quality index (CPSQI) was used to assess the occurrence of poor sleep. Among the total sample, 18.0% were classified as poor sleepers (27.4% of the subjects with past-month NMPOU), and the prevalences of lifetime, past-year and past-month NMPOU were 14.6, 4.6 and 2.8% across the entire sample, respectively. The most commonly used medicine was licorice tablets with morphine (9.1, 2.5 and 1.5% for lifetime, past-year and past-month, respectively), followed by cough syrup with codeine, Percocet, diphenoxylate and tramadol. After adjustment for potential confounders, the association between past-month NMPOU and poor sleep remained significant (AOR = 1.47, 95% CI 1.17 to 1.85). Programs aimed at decreasing NMPOU should also pay attention to sleep quality among adolescents. PMID- 27467182 TI - Tissue-based quantitative proteome analysis of human hepatocellular carcinoma using tandem mass tags. AB - CONTEXT AND OBJECTIVE: Human hepatocellular carcinoma (HCC) is a severe malignant disease, and accurate and reliable diagnostic markers are still needed. This study was aimed for the discovery of novel marker candidates by quantitative proteomics. METHODS AND RESULTS: Proteomic differences between HCC and nontumorous liver tissue were studied by mass spectrometry. Among several significantly upregulated proteins, translocator protein 18 (TSPO) and Ras related protein Rab-1A (RAB1A) were selected for verification by immunohistochemistry in an independent cohort. For RAB1A, a high accuracy for the discrimination of HCC and nontumorous liver tissue was observed. CONCLUSION: RAB1A was verified to be a potent biomarker candidate for HCC. PMID- 27467177 TI - Sleep: important considerations for the prevention of cardiovascular disease. AB - PURPOSE OF REVIEW: Sleep plays many roles in maintenance of cardiovascular health. This review summarizes the literature across several areas of sleep and sleep disorders in relation to cardiometabolic disease risk factors. RECENT FINDINGS: Insufficient sleep duration is prevalent in the population and is associated with weight gain and obesity, inflammation, cardiovascular disease, diabetes, and mortality. Insomnia is also highly present and represents an important risk factor for cardiovascular disease, especially when accompanied by short sleep duration. Sleep apnea is a well-characterized risk factor for cardiometabolic disease and cardiovascular mortality. Other issues are relevant as well. For example, sleep disorders in pediatric populations may convey cardiovascular risks. Also, sleep may play an important role in cardiovascular health disparities. SUMMARY: Sleep and sleep disorders are implicated in cardiometabolic disease risk. This review addresses these and other issues, concluding with recommendations for research and clinical practice. PMID- 27467184 TI - Do women with smaller breasts perform better in long-distance running? AB - Literature has established that a range of physiological, biomechanical, and training variables influence marathon performance. The influence of anthropometric characteristics has also received attention. However, despite major marathons exceeding 40,000 participants and approximately a third of these runners being female, no data exist on the influence of the breast on running performance. This cross-sectional study aimed to explore the impact of breast mass on marathon finish time. One hundred and sixty-eight of 321 female marathon runners contacted completed an on-line survey focusing on marathon performance during the 2012 London marathon. Participants were categorised as smaller (<500 g, 54%) or larger breasted (>500 g, 46%). Regression analysis identified that 24% of marathon performance variance could be explained by body mass index (BMI), but breast mass improved the model to explain 28% of performance variation. The model determined that for women with 32/34 or 36/38 underband each increase in cup size equates to a performance decrement of 4.6 min or 8.6 min, equivalent to 34.4 min difference between a woman with 36A compared to 36DD breast size. Larger breasted runners had greater BMIs, completed less marathons and had slower marathon finish times (316 +/- 48 min) compared to smaller breasted runners (281 +/- 51 min). Twenty-five per cent less larger breasted women finished in the fastest quartile. These results suggest that differences in breast mass are an important factor for female athletes and should be considered in future research in this area. PMID- 27467183 TI - Colorectal Cancer in African Americans: An Update. AB - This review is an update to the American College of Gastroenterology (ACG) Committee on Minority Affairs and Cultural Diversity's paper on colorectal cancer (CRC) in African Americans published in 2005. Over the past 10 years, the incidence and mortality rates of CRC in the United States has steadily declined. However, reductions have been strikingly much slower among African Americans who continue to have the highest rate of mortality and lowest survival when compared with all other racial groups. The reasons for the health disparities are multifactorial and encompass physician and patient barriers. Patient factors that contribute to disparities include poor knowledge of benefits of CRC screening, limited access to health care, insurance status along with fear and anxiety. Physician factors include lack of knowledge of screening guidelines along with disparate recommendations for screening. Earlier screening has been recommended as an effective strategy to decrease observed disparities; currently the ACG and American Society of Gastrointestinal Endoscopists recommend CRC screening in African Americans to begin at age 45. Despite the decline in CRC deaths in all racial and ethnic groups, there still exists a significant burden of CRC in African Americans, thus other strategies including educational outreach for health care providers and patients and the utilization of patient navigation systems emphasizing the importance of screening are necessary. These strategies have been piloted in both local communities and Statewide resulting in notable significant decreases in observed disparities. PMID- 27467185 TI - Eosinophilic esophagitis: current perspectives from diagnosis to management. AB - Eosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disease of the esophagus characterized by symptoms related to esophageal dysfunction, as well as significant esophageal eosinophilia. Although dense eosinophilia is the hallmark of EoE, other characteristic histologic features have been described that may help distinguish EoE from other competing diagnoses, although none are specific to EoE. One or more foods and, at times, environmental allergens trigger EoE. Left untreated, esophageal inflammation in EoE may lead to esophageal remodeling and stricture formation. Symptoms in EoE vary with age, as they relate to the progression of the disease from an inflammatory to a fibrostenotic phenotype over time. There are currently no U.S. Food and Drug Administration approved therapies for EoE. Current options include various dietary-restriction therapies, topical corticosteroids, and esophageal dilations. Several emerging therapies aiming at restoring the esophageal barrier function or targeting various inflammatory cells or their mediators are under investigation. PMID- 27467186 TI - Negative association of pretreatment cigarette use with smoking-induced striatal dopamine release in smokers receiving bupropion treatment. AB - BACKGROUND AND OBJECTIVES: In an effort to help identify factors that maintain heavy smoking, this study tested the association of pretreatment cigarette use (cigarettes per day) with striatal dopamine release during smoking-cessation treatment. METHODS: Thirteen regular smokers (>=10 cigarettes per day) were evaluated on parameters of smoking behavior, and they entered a smoking cessation treatment protocol, including bupropion administration and individual counseling for 2 months. On week 7 of treatment, 10 of the participants underwent brain scans using [(11) C]raclopride with positron emission tomography to assess smoking-induced dopamine release in the caudate nucleus and putamen, inferred from changes in dopamine D2 -type receptor availability. RESULTS: Receptor availability, measured as binding potential referred to non-displaceable uptake (BPND ) in both striatal regions re-demonstrated a significant decrease after smoking a cigarette; and pre-treatment cigarette use significantly negatively correlated with smoking-induced dopamine release in the caudate. CONCLUSIONS AND SIGNIFICANCE: The negative association of cigarette use with dopamine release suggests tolerance or down-regulation of the dopamine system by chronic smoking, or a pre-existing condition that promotes more frequent smoking. This association should be regarded as preliminary evidence that warrants verification. (Am J Addict 2016;25:486-492). PMID- 27467187 TI - NEDD4 Depletion Inhibits Hepatocellular Carcinoma Growth via Targeting PTEN. AB - BACKGROUND/AIMS: Neural precursor cell-expressed developmentally down-regulated gene 4 (NEDD4) plays an important role in tumor cell growth, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study is to establish NEDD4 as a prognostic biomarker by which the survival of HCC patients can be predicted and to reveal the role of NEDD4 in hepatocellular carcinoma cell growth. METHODS: The expression of NEDD4 in 219 HCC specimens was assessed by immunohistochemistry. Postoperative overall survival and time to recurrence were evaluated by univariate and multivariate analyses. The roles of NEDD4 in hepatocellular carcinoma cell proliferation and invasion were determined. RESULTS: The patients with low NEDD4 expression tumors had an average cumulative survival of 64.9 +/- 6.5 months during follow-up while the patients with high NEDD4 expression tumors had an average cumulative survival of 20.3 +/- 15.8 months. NEDD4 silencing inhibited Huh7 cell proliferation and altered cell cytoskeletal assembly, and NEDD4 depletion furthermore seemed to suppress cell migration and invasion. A possible molecular mechanism for the observed effects might be that NEDD4 silence led to an increase in PTEN (phosphatase and tensin homologue) expression, which in turn resulted in the inactivation of STAT3, AKT, and ERK1/2. CONCLUSION: Our findings indicate that NEDD4 may participate in the HCC progression and may therefore be a potential target for HCC therapy. PMID- 27467188 TI - Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. AB - CONTEXT/OBJECTIVE: Testosterone treatment for pubertal induction in boys with hypogonadotropic hypogonadism (HH) provides virilization, but does not induce testicular growth or fertility. Larger studies evaluating the outcomes of gonadotropin replacement during adolescence have not been reported to date; whether previous testosterone substitution affects testicular responses is unresolved. We aimed to assess the effects of human chorionic gonadotropin (hCG) and recombinant FSH (rFSH) in boys and adolescents with HH with respect to a) testicular growth, b) spermatogenesis, c) quality of life (QoL) and to identify factors influencing therapeutic success. DESIGN/SETTING: A prospective case study was conducted in 26 paediatric endocrine centres PATIENTS/INTERVENTIONS: HCG and rFSH were administered until cessation of testicular growth and plateauing of spermatogenesis to (1) prepubertal HH boys with absent or early arrested puberty (group A) and to (2) HH adolescents who had previously received full testosterone replacement (group B). OUTCOME MEASURES: Bi-testicular volumes (BTVs), sperm concentrations and QoL. RESULTS: Sixty (34 A/26 B) HH patients aged 14-22 years were enrolled. BTVs rose from 5 +/- 5 to 34 +/- 3 ml in group A vs 5 +/- 3 to 32 +/- 3 ml in group B, with normal final BTVs (>=24 ml) attained in 74%/70% after 25/23 months in A/B, respectively. Sperm in the ejaculate were found in 21/23(91%)/18/19(95%), with plateauing concentrations after 31/30 months of hCG and 25/25 months of combined treatment in A/B. Sperm concentrations were normal (>=15 mill/ml) in 61%/32%, with mean concentrations of 40 +/- 73 vs 19 +/- 38 mill/ml in A/B (n.s.). Outcomes were better in patients without bilateral cryptorchidism, with non-congenital HH causes, higher baseline BTVs, and higher baseline inhibin B and AMH levels. QoL increased in both groups. CONCLUSIONS: HCG/rFSH replacement during adolescence successfully induces testicular growth and spermatogenesis, irrespective of previous testosterone replacement, and enhances QoL. PMID- 27467189 TI - Fractionating negative and positive affectivity in handedness: Insights from the Reinforcement Sensitivity Theory of personality. AB - The Annett Hand Preference Questionnaire (AHPQ), as modified by Briggs and Nebes [(1975). Patterns of hand preference in a student population. Cortex, 11(3), 230 238. doi: 10.1016/s0010-9452(75)80005-0] , was administered to a sample of 177 participants alongside the Reinforcement Sensitivity Theory of Personality Questionnaire [RST-PQ; Corr, P. J., & Cooper, A. (2016). The Reinforcement Sensitivity Theory of Personality Questionnaire (RST-PQ): Development and validation. Psychological Assessment. doi: 10.1037/pas000 ], which measures two factors of defensive negative emotion, motivation and affectivity-the Behavioural Inhibition System (BIS) and the Fight-Flight-Freeze System (FFFS)-and one positive-approach dimension related to reward sensitivity, persistence and reactivity-the Behavioural Approach System. We sought to clarify the nature of negative, and positive, affectivity in relation to handedness. ANOVAs and multiple regression analyses converged on the following conclusions: left-handers were higher on the BIS, not the FFFS, than right-handers; in right-handers only, strength of hand preference was positively correlated with the FFFS, not the BIS. The original assessment method proposed by Annett was also used to assess handedness, but associations with RST-PQ factors were not found. These findings help us to clarify existing issues in the literature and raise new ones for future research. PMID- 27467190 TI - Ambulatory diffuse optical tomography and multimodality physiological monitoring system for muscle and exercise applications. AB - Ambulatory diffuse optical tomography (aDOT) is based on near-infrared spectroscopy (NIRS) and enables three-dimensional imaging of regional hemodynamics and oxygen consumption during a person's normal activities. Although NIRS has been previously used for muscle assessment, it has been notably limited in terms of the number of channels measured, the extent to which subjects can be ambulatory, and/or the ability to simultaneously acquire synchronized auxiliary data such as electromyography (EMG) or electrocardiography (ECG). We describe the development of a prototype aDOT system, called NINscan-M, capable of ambulatory tomographic imaging as well as simultaneous auxiliary multimodal physiological monitoring. Powered by four AA size batteries and weighing 577 g, the NINscan-M prototype can synchronously record 64-channel NIRS imaging data, eight channels of EMG, ECG, or other analog signals, plus force, acceleration, rotation, and temperature for 24+ h at up to 250 Hz. We describe the system's design, characterization, and performance characteristics. We also describe examples of isometric, cycle ergometer, and free-running ambulatory exercise to demonstrate tomographic imaging at 25 Hz. NINscan-M represents a multiuse tool for muscle physiology studies as well as clinical muscle assessment. PMID- 27467191 TI - Cervical Osteomyelitis After Pharyngeal Surgical Manipulation. PMID- 27467192 TI - 3-Hydroxy-4-nitrobenzoic Acid as a MALDI Matrix for In-Source Decay. AB - In-source decay (ISD) in matrix-assisted laser desorption/ionization (MALDI) is a rapid sequencing method for peptides. 1,5-Diaminonaphthalene (1,5-DAN) is a most frequently used matrix for ISD. However, using 1,5-DAN generates mainly c- and z series ions by N-Calpha bond cleavage, which makes it difficult to distinguish leucine (Leu) and isoleucine (Ile), and frequently lacks c(n-1)-series ions owing to proline (Pro) at residues n. Several oxidizing matrices generating a- and x series ions accompanied by d-series ions by Calpha-C bond cleavage have been reported, but an issue remained concerning their sensitivity. 3-Hydroxy-4 nitrobenzoic acid (3H4NBA) has been reported as a matrix for 2 nitrobenzenesulfenyl-labeled peptides by Matsuo et al. (Proteomics 2006, 6, 2042 2049). Here, we used 3H4NBA as an oxidizing matrix for ISD. As a result, numerous a- and d-series ions for amyloid beta 1-40 were generated with high sensitivity using 3H4NBA. Each of the two Leu and two Ile was identified by the d-series ions. The sensitivity of the a-series ions using 3H4NBA was a little lower than that of c-series ions using 1,5-DAN. The same tendency was observed for N-acetyl renin substrate and ACTH 18-39. The a-series ions were detected, even at the left side of Pro. The sensitivity of the a-series ions using 3H4NBA was higher than with other existing oxidizing matrices, such as 5-nitrosalicylic acid and 5 formyl salycilic acid. The ions were detected over the entire area of the matrix analyte spot using 3H4NBA. 3H4NBA was confirmed to be a useful oxidizing matrix for ISD, leading to higher sequence coverage of peptides. PMID- 27467193 TI - Construction of the 1,5-Benzodiazepine Skeleton from o-Phenylendiamine and Propargylic Alcohols via a Domino Gold-Catalyzed Hydroamination/Cyclization Process. AB - The gold-catalyzed reaction of o-phenylendiamine with propargylic alcohols affords 1,5-benzodiazepines bearing different substituents on the 2 and 4 positions. The method allows even for the selective preparation of 4-substituted 1,5-benzodiazepine derivatives. PMID- 27467194 TI - Infrared Spectroscopic Investigation of the Acidic CH Bonds in Cationic n Alkanes: Pentane, Hexane, and Heptane. AB - Radical cations of n-alkanes (pentane, hexane, and heptane) in the gas phase are investigated by infrared predissociation spectroscopy with the argon or nitrogen tagging. All-trans and gauche-involving conformers are identified for these cations by comparisons of observed infrared spectra and vibrational simulations. Intense CH stretch bands are observed in the frequency region lower than the normal alkyl CH stretch frequency. These low frequencies and high intensities of the CH stretch bands are caused by the CH bond weakening and the enhanced positive charge of the hydrogen atoms through the delocalization of the sigma electron in the CH bonds. These effects of the delocalization of the sigma electron result in the enhanced acidity of the CH bonds. The conformation as well as alkyl chain length dependence of the acidity of the CH bonds is demonstrated by the CH stretch frequency shift trend. PMID- 27467195 TI - Comparative study of CD4 and CD45RO T cells and CD20 B cells in cerebrospinal fluid of syphilitic meningitis and tuberculous meningitis patients. AB - This study was to investigate the differences of lymphocyte in the cerebrospinal fluid (CSF) of patients with syphilis meningitis (SM) and tuberculous meningitis (TBM) for new diagnostic insights. Totally, 79 cases of SM and 45 cases of TBM were enrolled. In the CSF, the CD4, CD45RO or CD20 positive lymphocytes were detected by immunohistochemistry. The proportion of CD4 T cells in the CSF lymphocytes in patients with SM was significantly higher than that in patients with TBM (p < 0.05). After medical therapy, there was a significantly decline trend of the CD4 T-cell proportion in both groups (p < 0.05). The proportion of CD45RO T cells in CSF lymphocytes of patients with SM was less than that of patients with TBM (p < 0.05). After medical therapy, the positive ratio of CD45RO T cells was increased in the CSF of both group patients (p < 0.05). The proportion of CD20B cells in the CSF lymphocytes was not obviously different between the two groups during every stage. In conclusion, there are strong differences of CD4 and CD45RO T-cell ratio, but not the CD20 B cells in the meningitis. CD4 and CD45RO T cells in CSF are a useful complement in differentially diagnosing SM and TBM; it contributes to further understand the pathogenesis and prognosis of SM and TBM. PMID- 27467196 TI - U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. AB - The 2016 U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) comprises recommendations for the use of specific contraceptive methods by women and men who have certain characteristics or medical conditions. These recommendations for health care providers were updated by CDC after review of the scientific evidence and consultation with national experts who met in Atlanta, Georgia, during August 26-28, 2015. The information in this report updates the 2010 U.S. MEC (CDC. U.S. medical eligibility criteria for contraceptive use, 2010. MMWR 2010:59 [No. RR-4]). Notable updates include the addition of recommendations for women with cystic fibrosis, women with multiple sclerosis, and women receiving certain psychotropic drugs or St. John's wort; revisions to the recommendations for emergency contraception, including the addition of ulipristal acetate; and revisions to the recommendations for postpartum women; women who are breastfeeding; women with known dyslipidemias, migraine headaches, superficial venous disease, gestational trophoblastic disease, sexually transmitted diseases, and human immunodeficiency virus; and women who are receiving antiretroviral therapy. The recommendations in this report are intended to assist health care providers when they counsel women, men, and couples about contraceptive method choice. Although these recommendations are meant to serve as a source of clinical guidance, health care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients. Persons should seek advice from their health care providers when considering family planning options. PMID- 27467197 TI - Risk assessment from exposure to arsenic, antimony, and selenium in urban gardens (Madrid, Spain). AB - The authors discuss the geochemical behavior of arsenic (As), antimony (Sb), and selenium (Se) in urban gardens and the human health implications associated with urban agriculture. A total of 42 samples from 7 urban gardens in Madrid, Spain, were collected from the top 20 cm of soil. Concentrations of As, Sb, and Se and the main soil properties (i.e., total iron, pH, texture, calcium carbonate, and organic matter) were determined. A significant correlation was found between As and Sb and calcium carbonate, indicating the possibility of surface adsorption or ligand exchange with the carbonate group. Also, Sb seemed to form stable chelates with soil organic matter. On the other hand, Se showed a significant association with clay and iron content. The concentration of Sb in soil exceeded the recommended value for agricultural use in 70% of the urban gardens. A human health risk assessment resulted in acceptable levels of both noncarcinogenic and carcinogenic risks (although with elevated values of the latter), with As as the main risk driver and soil and food ingestion as the main exposure pathways. The numerical results of the risk assessment should be interpreted with caution given the considerable uncertainties in some exposure variables and the lack of quantitative values for the suspected carcinogenicity of Sb and Se. Environ Toxicol Chem 2017;36:544-550. (c) 2016 SETAC. PMID- 27467199 TI - Fabrication of Highly Stable and Efficient PtCu Alloy Nanoparticles on Highly Porous Carbon for Direct Methanol Fuel Cells. AB - Boosting the durability of Pt nanoparticles by controlling the composition and morphology is extremely important for fuel cells commercialization. We deposit the Pt-Cu alloy nanoparticles over high surface area carbon in different metallic molar ratios and optimize the conditions to achieve desired material. The novel bimetallic electro-catalyst {Pt-Cu/PC-950 (15:15%)} offers exceptional electrocatalytic activity when tested for both oxygen reduction reaction and methanol oxidation reactions. A high mass activity of 0.043 mA/MUgPt (based on Pt mass) is recorded for ORR. An outstanding longevity of this electro-catalyst is noticed when compared to 20 wt % Pt loaded either on PC-950 or commercial carbon. The high surface area carbon support offers enhanced activity and prevents the nanoparticles from agglomeration, migration, and dissolution as evident by TEM analysis. PMID- 27467200 TI - Hydrothermal Gelation of Aqueous Cellulose Nanocrystal Suspensions. AB - We report the facile preparation of gels from the hydrothermal treatment of suspensions of cellulose nanocrystals (CNCs). The properties of the hydrogels have been investigated by rheology, electron microscopy, and spectroscopy with respect to variation in the temperature, time, and CNC concentration used in preparation. Desulfation of the CNCs at high temperature appears to be responsible for the gelation of the CNCs, giving highly porous networks. The viscosity and storage modulus of the gels was shown to increase when samples were prepared at higher treatment temperature. Considering the wide natural abundance and biocompatibility of CNCs, this simple, green approach to CNC-based hydrogels is attractive for producing materials that can be used in drug delivery, insulation, and as tissue scaffolds. PMID- 27467198 TI - Rice root curling, a response to mechanosensing, is modulated by the rice E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE1 (OsHOS1). AB - Plant development depends on the perception of external cues, such as light, gravity, touch, wind or nutrients, among others. Nevertheless, little is known regarding signal transduction pathways integrating these stimuli. Recently, we have reported the involvement of a rice E3-ubiquitin ligase (OsHOS1, HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE1), previously associated with abiotic stress response, in root responses to mechanical stimuli. We showed that OsHOS1 is involved in the regulation of root curling after mechanosensing and that RNAi::OsHOS1 plants failed to exhibit the root curling phenotype observed in WT. Interestingly, the straight root phenotype of these transgenics correlated with the up-regulation of rice ROOT MEANDER CURLING (OsRMC, a negative regulator of rice root curling) and was reverted by the exogenous application of jasmonic acid. Altogether, our results highlight the role of the proteasome modulating plant responses to mechanical stimuli and suggest that OsHOS1 is a hub integrating environmental and hormonal signaling into plant growth and development. PMID- 27467201 TI - A Clinical and Molecular Genetic Study in 11 Chinese Children With Peutz-Jeghers Syndrome. AB - OBJECTIVES: Peutz-Jeghers syndrome (PJS) is caused by the germline mutations in serine/threonine kinase 11 (STK11) gene. The aim of the present study was to investigate the spectrum of STK11 gene mutations using multiplex ligation dependent probe amplification (MLPA) assay in combination with direct sequencing in Chinese children with PJS. METHODS: Nine children who met the clinical criteria for PJS and 2 presumed patients with PJS were enrolled in the present study. Patients' clinical information on polyp characteristics, polyp-related complications, family histories, and so on were reviewed and analyzed. After obtaining informed consent, we performed a mutation analysis of STK11 gene in 11 Chinese patients using MLPA assay and direct sequencing. RESULTS: By means of MLPA method, we detected exonic deletions in 5 patients. In details, 1 patient had the complete deletion of all 10 exons, 3 patients showed deletions of promoter region and exon 1, and 1 patient had exon deletions from 1 to 9. By direct sequencing of the coding region of STK11 gene, we identified point mutations in 4 patients at c.548T>G/p.Leu183Arg, c.580G>T/p.Asp194Tyr, c.152_153insGG/Asp53GlyfsX12, and c.631delC/Arg211GlyfsX76, respectively, and 3 of them are novel mutations. We failed to find any mutation in left 2 patients who met the clinical criteria of PJS. CONCLUSIONS: MLPA plus direct sequencing revealed large genomic deletions of STK11 gene in Chinese children with PJS and increased the detecting rate of STK11 gene mutations in Chinese patients with PJS. MLPA combined with direct sequencing could serve as a better strategy for the genetic diagnosis of PJS in Chinese population. PMID- 27467202 TI - Efficacy and Safety of Povidone-Iodine Irrigation in Reducing the Risk of Capsular Contracture in Aesthetic Breast Augmentation: A Systematic Review and Meta-Analysis. PMID- 27467204 TI - Testing the usefulness of the number needed to treat to be harmed (NNTH) in benefit-risk evaluations: case study with medicines withdrawn from the European market due to safety reasons. AB - OBJECTIVE: To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessments, by studying the agreement between NNTH values and withdrawals of medicines from European market due to safety reasons. METHODS: Medicines with data from longitudinal studies were included. Studies were identified from European Medicines Agency's Reports. Meta-analyses were performed to pool odds ratios (OR) with 95% confidence-intervals (CI). Published control event rates were applied to ORs to calculate NNTHs (95%CI) for selected adverse events. RESULTS: NNTH (95%CI) decreased from pre- to post-marketing for the eight medicines included: peripheral neuropathy (infinity vs. 12[non significant; NS] with almitrine; heart valve disease with benfluorex (infinity vs. NNTH ranging from 7[4-13] to 7[5-9]); myopathy (-4096[NS] vs. 797[421-1690]), new-onset diabetes (113[NS] vs. 390[425-778]), bleeding (infinity vs. 517[317 1153]), and infection (infinity vs. 253[164-463]) with niacin-laropiprant; psychiatric disorders (12[7-34] vs. 9[5-24]) with rimonabant; myocardial infarction (MI) [-1305 vs. 270[89-4362]) with rofecoxib; MI (-510 vs. NNTH ranging from 152[55-4003] to 568[344-1350]) with rosiglitazone; cardiovascular events (infinity vs. 245[129-1318]) with sibutramine; and liver injury (infinity vs. 5957[NS]) with ximelagatran. CONCLUSION: NNTH have potential of use as a supportive tool in benefit-risk re-evaluations of medicines and may help regulators to making decisions on drug safety. PMID- 27467203 TI - Inclusion of populations at risk of advanced melanoma in an opportunistic targeted screening project involving general practitioners. AB - OBJECTIVE: The study objective was to measure the rates of inclusion of populations at risk of advanced melanoma in a pilot targeted screening project involving general practitioners. DESIGN: This cross-sectional database study compared the inclusion rates of patients who signed inclusion in a targeted screening project with those of patients who did not, during a period in which both groups of patients consulted investigators. SETTING: Data were extracted from the national healthcare insurance records in western France from 11 April to 30 October 2011. PATIENTS: Patients, older than 18, considered for the data extraction had consulted one of the 78 participating GPs during the study period, and were affiliated with the national healthcare insurance. MAIN OUTCOME MEASURES: Inclusion in the screening was the main outcome measure. Patients at risk of advanced melanoma were characterized by male gender, age over 50, low income, rural residence, farmer, and presence of chronic disease. RESULTS: A total of 57,279 patients consulted GPs during the inclusion period and 2711 (4.73%) were included in the targeted screening. Populations at risk of advanced melanoma were less included: men (OR = 0.67; 95%CI [0.61-0.73]; p < 0.001), older than 50 (OR = 0.67; 95%CI [0.60-0.74]; p < 0.001), low income (OR = 0.65; 95%CI [0.55-0.77]; p < 0.001), farmer (OR = 0.23; 95%CI [0.17-0.30]; p < 0.001) and presence of a chronic disease (OR = 0.87; 95%CI [0.77-0.98]; p < 0.028). CONCLUSION: This study demonstrated inequalities in the inclusion of patients in a melanoma screening. Patients at risk of advanced cancer were screened less often. Further studies should focus on GPs ability to identify and screen these patients. KEY POINTS Advanced melanoma is more frequently diagnosed in men, older patients and socioeconomically disadvantaged populations, which leads to survival inequalities. * Despite the involvement of general practitioners, the implementation of targeted melanoma screening did not avoid inclusion inequalities. * Men, older patients, patients suffering from chronic diseases, and low-income patients were less likely to benefit from screening. * The display of a conventional or an alarmist poster in the waiting room did not statistically reduce these inclusion inequalities. PMID- 27467205 TI - Thrombomodulin Attenuates Inflammatory Damage Due to Liver Ischemia and Reperfusion Injury in Mice in Toll-Like Receptor 4-Dependent Manner. AB - Liver ischemia reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit an anti-inflammatory effect through binding to the high-mobility group box 1 protein (HMGB-1) known as a proinflammatory mediator. We examined the effect of recombinant human TM (rTM) on a partial warm hepatic IRI model in wild-type (WT) and toll-like receptor 4 (TLR 4) KO mice focusing on the HMGB-1/TLR-4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB-1 protein. The rTM showed a protective effect on liver IRI. The rTM diminished the downstream signals of TLR 4 and also HMGB-1 expression in liver cells, as well as release of HMGB-1 from the liver. Interestingly, neither rTM treatment in vivo nor HMGB-1 treatment in vitro showed any effect on TLR-4 KO mice. Parallel in vitro studies have confirmed that rTM interfered with the interaction between HMGB-1 and TLR-4. Furthermore, the recombinant N-terminal lectin-like domain 1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in a TLR-4 pathway-dependent manner. PMID- 27467206 TI - Householders' Mental Models of Domestic Energy Consumption: Using a Sort-And Cluster Method to Identify Shared Concepts of Appliance Similarity. AB - If in-home displays and other interventions are to successfully influence people's energy consumption, they need to communicate about energy in terms that make sense to users. Here we explore householders' perceptions of energy consumption, using a novel combination of card-sorting and clustering to reveal shared patterns in the way people think about domestic energy consumption. The data suggest that, when participants were asked to group appliances which they felt naturally 'went together', there are relatively few shared ideas about which appliances are conceptually related. To the extent participants agreed on which appliances belonged together, these groupings were based on activities (e.g., entertainment) and location within the home (e.g., kitchen); energy consumption was not an important factor in people's categorisations. This suggests messages about behaviour change aimed at reducing energy consumption might better be tied to social practices than to consumption itself. PMID- 27467207 TI - Hidradenitis suppurativa: haploinsufficiency of gamma-secretase components does not affect gamma-secretase enzyme activity in vitro. PMID- 27467208 TI - Measuring Drug Metabolism Kinetics and Drug-Drug Interactions Using Self Assembled Monolayers for Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry. AB - The competition of two drugs for the same metabolizing enzyme is a common mechanism for drug-drug interactions that can lead to altered kinetics in drug metabolism and altered elimination rates in vivo. With the prevalence of multidrug therapy, there is great potential for serious drug-drug interactions and adverse drug reactions. In an effort to prevent adverse drug reactions, the FDA mandates the evaluation of the potential for metabolic inhibition by every new chemical entity. Conventional methods for assaying drug metabolism (e.g., those based on HPLC) have been established for measuring drug-drug interactions; however, they are low-throughput. Here we describe an approach to measure the catalytic activity of CYP2C9 using the high-throughput technique self-assembled monolayers for matrix-assisted laser desorption-ionization (SAMDI) mass spectrometry. We measured the kinetics of CYP450 metabolism of the substrate, screened a set of drugs for inhibition of CYP2C9 and determined the Ki values for inhibitors. The throughput of this platform may enable drug metabolism and drug drug interactions to be interrogated at a scale that cannot be achieved with current methods. PMID- 27467209 TI - Environmental Screening for the Scedosporium apiospermum Species Complex in Public Parks in Bangkok, Thailand. AB - The Scedosporium apiospermum species complex, comprising filamentous fungal species S. apiospermum sensu stricto, S. boydii, S. aurantiacum, S. dehoogii and S. minutispora, are important pathogens that cause a wide variety of infections. Although some species (S. boydii and S. apiospermum) have been isolated from patients in Thailand, no environmental surveys of these fungi have been performed in Thailand or surrounding countries. In this study, we isolated and identified species of these fungi from 68 soil and 16 water samples randomly collected from 10 parks in Bangkok. After filtration and subsequent inoculation of samples on Scedo-Select III medium, colony morphological examinations and microscopic observations were performed. Scedosporium species were isolated from soil in 8 of the 10 parks, but were only detected in one water sample. Colony morphologies of isolates from 41 of 68 soil samples (60.29%) and 1 of 15 water samples (6.67%) were consistent with that of the S. apiospermum species complex. Each morphological type was selected for species identification based on DNA sequencing and phylogenetic analysis of the beta-tubulin gene. Three species of the S. apiospermum species complex were identified: S. apiospermum (71 isolates), S. aurantiacum (6 isolates) and S. dehoogii (5 isolates). In addition, 16 sequences could not be assigned to an exact Scedosporium species. According to our environmental survey, the S. apiospermum species complex is widespread in soil in Bangkok, Thailand. PMID- 27467210 TI - Selumetinib in the treatment of non-small-cell lung cancer. AB - The RAS-RAF-MEK-ERK pathway regulates processes involved in the proliferation and survival of cells. KRAS mutations, prevalent in approximately 30% of patients with non-small-cell lung cancer (NSCLC), result in constitutive activation of the pathway. Selumetinib (AZD6244, ARRY-142886) is a potent and selective inhibitor of MEK1/2 which has demonstrated significant efficacy in combination with docetaxel in patients with KRAS mutant pretreated advanced NSCLC. Several trials in combination with other chemotherapy and targeted therapy regimens in lung cancer are ongoing. We review the development of selumetinib in patients with NSCLC, summarize the pharmacodynamic, pharmacokinetic and tolerability characteristics, and the available clinical trial data to understand the role of selumetinib in the treatment of NSCLC. PMID- 27467211 TI - Corrigendum: An Unusually Small Singlet-Triplet Gap in a Quinoidal 1,6 Methano[10]annulene Resulting from Baird's 4n pi-Electron Triplet Stabilization. PMID- 27467213 TI - The World's Great Religions and Their Neglected Tropical Diseases. PMID- 27467219 TI - Practical applications of rapid review methods in the development of Australian health policy. AB - Rapid reviews (RRs) are a method of evidence synthesis that can provide robust evidence to support policy decisions in a timely manner. Herein we describe the methods used to conduct RRs and present an illustrative case study to describe how RRs can be used to inform contemporary Australian health policy. The aim of the present study was to explore several important aspects of how RRs can inform decision makers. RRs are conducted within limited time frames of as little as 4 weeks. Policy questions may focus on issues of efficacy, service delivery and service organisation rather than reimbursement of new services, which is better answered by a more comprehensive assessment. RRs use flexible and pragmatic methods, which aim to balance the objectivity and rigour required of the reviews within limited time frames. This flexibility allows for great variation across products with regard to length, depth of analysis and methods used. As a result, RRs can be specifically tailored to address targeted policy questions and are a useful tool in the development of Australian health policy. PMID- 27467215 TI - Direct Copper(III) Formation from O2 and Copper(I) with Histamine Ligation. AB - Histamine chelation of copper(I) by a terminal histidine residue in copper hydroxylating enzymes activates dioxygen to form unknown oxidants, generally assumed as copper(II) species. The direct formation of copper(III)-containing products from the oxygenation of histamine-ligated copper(I) complexes is demonstrated here, indicating that copper(III) is a viable oxidation state in such products from both kinetic and thermodynamic perspectives. At low temperatures, both trinuclear Cu(II)2Cu(III)O2 and dinuclear Cu(III)2O2 predominate, with the distribution dependent on the histamine ligand structure and oxygenation conditions. Kinetics studies suggest the bifurcation point to these two products is an unobserved peroxide-level dimer intermediate. The hydrogen atom reactivity difference between the trinuclear and binuclear complexes at parity of histamine ligand is striking. This behavior is best attributed to the accessibility of the bridging oxide ligands to exogenous substrates rather than a difference in oxidizing abilities of the clusters. PMID- 27467216 TI - Local versus whole-body sweating adaptations following 14 days of traditional heat acclimation. AB - The purpose of this study was to examine if local changes in sweat rate following 14 days of heat acclimation reflect those that occur at the whole-body level. Both prior to and following a 14-day traditional heat acclimation protocol, 10 males exercised in the heat (35 degrees C, ~20% relative humidity) at increasing rates of heat production equal to 300 (Ex1), 350 (Ex2), and 400 (Ex3) W.m(-2). A 10-min recovery period followed Ex1, while a 20-min recovery period separated Ex2 and Ex3. The exercise protocol was performed in a direct calorimeter to measure whole-body sweat rate and, on a separate day, in a thermal chamber to measure local sweat rate (LSR), sweat gland activation (SGA), and sweat gland output (SGO) on the upper back, chest, and mid-anterior forearm. Post-acclimation, whole body sweat rate was greater during each exercise bout (Ex1: 14.3 +/- 0.9; Ex2: 17.3 +/- 1.2; Ex3: 19.4 +/- 1.3 g.min(-1), all p <= 0.05) relative to pre acclimation (Ex1: 13.1 +/- 0.6; Ex2: 15.4 +/- 0.8; Ex3: 16.5 +/- 1.3 g.min(-1)). In contrast, only LSR on the forearm increased with acclimation, and this increase was only observed during Ex2 (Post: 1.32 +/- 0.33 vs. Pre: 1.06 +/- 0.22 mg.min(-1).cm(-2), p = 0.03) and Ex3 (Post: 1.47 +/- 0.41 vs. Pre: 1.17 +/- 0.23 mg.min(-1).cm(-2), p = 0.05). The greater forearm LSR post-acclimation was due to an increase in SGO, as no changes in SGA were observed. Overall, these data demonstrate marked regional variability in the effect of heat acclimation on LSR, such that not all local measurements of sweat rate reflect the improvements observed at the whole-body level. PMID- 27467218 TI - Metabolic consequences of beta-alanine supplementation during exhaustive supramaximal cycling and 4000-m time-trial performance. AB - The present study investigated the effects of beta-alanine supplementation on the resultant blood acidosis, lactate accumulation, and energy provision during supramaximal-intensity cycling, as well as the aerobic and anaerobic contribution to power output during a 4000-m cycling time trial (TT). Seventeen trained cyclists (maximal oxygen uptake = 4.47 +/- 0.55 L.min(-1)) were administered 6.4 g of beta-alanine (n = 9) or placebo (n = 8) daily for 4 weeks. Participants performed a supramaximal cycling test to exhaustion (equivalent to 120% maximal oxygen uptake) before (PreExh) and after (PostExh) the 4-week supplementation period, as well as an additional postsupplementation supramaximal cycling test identical in duration and power output to PreExh (PostMatch). Anaerobic capacity was quantified and blood pH, lactate, and bicarbonate concentrations were measured pre-, immediately post-, and 5 min postexercise. Subjects also performed a 4000-m cycling TT before and after supplementation while the aerobic and anaerobic contributions to power output were quantified. beta-Alanine supplementation increased time to exhaustion (+12.8 +/- 8.2 s; P = 0.041) and anaerobic capacity (+1.1 +/- 0.7 kJ; P = 0.048) in PostExh compared with PreExh. Performance time in the 4000-m TT was reduced following beta-alanine supplementation (-6.3 +/- 4.6 s; P = 0.034) and the mean anaerobic power output was likely to be greater (+6.2 +/- 4.5 W; P = 0.035). beta-Alanine supplementation increased time to exhaustion concomitant with an augmented anaerobic capacity during supramaximal intensity cycling, which was also mirrored by a meaningful increase in the anaerobic contribution to power output during a 4000-m cycling TT, resulting in an enhanced overall performance. PMID- 27467217 TI - Effect of resistance exercise intensity on the expression of PGC-1alpha isoforms and the anabolic and catabolic signaling mediators, IGF-1 and myostatin, in human skeletal muscle. AB - The purpose of this study was to investigate the acute messenger (mRNA) expression of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) isoforms, insulin-like growth factor-1Ea (IGF-1Ea), and myostatin in response to 2 resistance exercise intensities. In a uniform balanced, crossover design, 10 participants performed 2 separate testing sessions involving a lower body resistance exercise component consisting of a lower intensity (50% of 1-repetition maximum; 1RM) protocol and a higher intensity (80% of 1RM) protocol of equal volumes. Muscle samples were obtained at before exercise, 45 min, 3 h, 24 h, and 48 h postexercise. Resistance exercise did not alter total PGC-1alpha mRNA expression; however, distinct responses of each PGC 1alpha isoform were observed. The response of each isoform was consistent between sessions, suggesting no effect of resistance exercise intensity on the complex transcriptional expression of the PGC-1alpha gene. IGF-1Ea mRNA expression significantly increased following the higher intensity session compared with pre exercise and the lower intensity session. Myostatin mRNA expression was significantly reduced compared with pre-exercise values at all time points with no difference between exercise intensity. Further research is needed to determine the effects of the various isoforms of PGC-1alpha in human skeletal muscle on the translational level as well as their relation to the expression of IGF-1 and myostatin. PMID- 27467220 TI - Disulfide-Trapping Identifies a New, Effective Chemical Probe for Activating the Nuclear Receptor Human LRH-1 (NR5A2). AB - Conventional efforts relying on high-throughput physical and virtual screening of large compound libraries have failed to yield high-efficiency chemical probes for many of the 48 human nuclear receptors. Here, we investigated whether disulfide trapping, an approach new to nuclear receptors, would provide effective lead compounds targeting human liver receptor homolog 1 (hLRH-1, NR5A2). Despite the fact that hLRH-1 contains a large ligand binding pocket and binds phospholipids with high affinity, existing synthetic hLRH-1 ligands are of limited utility due to poor solubility, low efficacy or significant off-target effects. Using disulfide-trapping, we identified a lead compound that conjugates with remarkably high-efficiency to a native cysteine residue (Cys346) lining the hydrophobic cavity in the ligand binding domain of hLRH-1. Guided by computational modeling and cellular assays, the lead compound was elaborated into ligands PME8 and PME9 that bind hLRH-1 reversibly (no cysteine reactivity) and increase hLRH-1 activity in cells. When compared with the existing hLRH-1 synthetic agonist RJW100, both PME8 and PME9 showed comparable induction of the LRH-1 dependent target gene CYP24A1 in human HepG2 cells, beginning as early as 3 h after drug treatment. The induction is specific as siRNA-mediated knock-down of hLRH-1 renders both PME8 and PME9 ineffective. These data show that PME8 and PME9 are potent activators of hLRH-1 and suggest that with further development this lead series may yield useful chemical probes for manipulating LRH-1 activity in vivo. PMID- 27467222 TI - Correction: Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0150623.]. PMID- 27467214 TI - Acute Exercise Improves Insulin Clearance and Increases the Expression of Insulin Degrading Enzyme in the Liver and Skeletal Muscle of Swiss Mice. AB - The effects of exercise on insulin clearance and IDE expression are not yet fully elucidated. Here, we have explored the effect of acute exercise on insulin clearance and IDE expression in lean mice. Male Swiss mice were subjected to a single bout of exercise on a speed/angle controlled treadmill for 3-h at approximately 60-70% of maximum oxygen consumption. As expected, acute exercise reduced glycemia and insulinemia, and increased insulin tolerance. The activity of AMPK-ACC, but not of IR-Akt, pathway was increased in the liver and skeletal muscle of trained mice. In an apparent contrast to the reduced insulinemia, glucose-stimulated insulin secretion was increased in isolated islets of these mice. However, insulin clearance was increased after acute exercise and was accompanied by increased expression of the insulin-degrading enzyme (IDE), in the liver and skeletal muscle. Finally, C2C12, but not HEPG2 cells, incubated at different concentrations of 5-aminoimidazole-4-carboxamide-1-beta-d ribofuranoside (AICAR) for 3-h, showed increased expression of IDE. In conclusion, acute exercise increases insulin clearance, probably due to an augmentation of IDE expression in the liver and skeletal muscle. The elevated IDE expression, in the skeletal muscle, seems to be mediated by activation of AMPK ACC pathway, in response to exercise. We believe that the increase in the IDE expression, comprise a safety measure to maintain glycemia at or close to physiological levels, turning physical exercise more effective and safe. PMID- 27467221 TI - Impacts of Grazing Intensity and Plant Community Composition on Soil Bacterial Community Diversity in a Steppe Grassland. AB - Soil bacteria play a key role in the ecological and evolutionary responses of agricultural ecosystems. Domestic herbivore grazing is known to influence soil bacterial community. However, the effects of grazing and its major driving factors on soil bacterial community remain unknown for different plant community compositions under increasing grazing intensity. Thus, to investigate soil bacterial community diversity under five plant community compositions (Grass; Leymus chinensis; Forb; L. chinensis & Forb; and Legume), we performed a four year field experiment with different grazing intensity treatments (no grazing; light grazing, 4 sheep.ha-1; and heavy grazing, 6 sheep.ha-1) in a grassland in China. Total DNA was obtained from soil samples collected from the plots in August, and polymerase chain reaction (PCR) analysis and denaturing gradient gel electrophoresis (DGGE) fingerprinting were used to investigate soil bacterial community. The results showed that light grazing significantly increased indices of soil bacterial community diversity for the Forb and Legume groups but not the Grass and L. chinensis groups. Heavy grazing significantly reduced these soil bacterial diversity indices, except for the Pielou evenness index in the Legume group. Further analyses revealed that the soil N/P ratio, electrical conductivity (EC), total nitrogen (TN) and pH were the major environmental factors affecting the soil bacterial community. Our study suggests that the soil bacterial community diversity was influenced by grazing intensity and plant community composition in a meadow steppe. The present study provides a baseline assessment of the soil bacterial community diversity in a temperate meadow steppe. PMID- 27467223 TI - Legislative provisions related to marriage and divorce of persons with mental health problems: a global review. PMID- 27467224 TI - Unveiling ubiquitinome rearrangements induced by Salmonella infection. AB - Ubiquitination plays a critical role in the activation of host immune responses to infection and serves as a signal for pathogen delivery to phagophores along the xenophagy pathway. We recently performed systematic ubiquitination site profiling of epithelial cells infected with Salmonella Typhimurium. Our findings specifically highlight components of the NFKB, membrane trafficking pathways and RHO GTPase systems as ubiquitination hubs during infection. In addition, a broad spectrum of bacterial effectors and several outer membrane proteins are ubiquitinated in infected cells. This comprehensive resource of ubiquitinome dynamics during Salmonella infection enables further understanding of the complex host-pathogen interplay and may reveal novel targets for the inhibition of Salmonella invasion and inflammation. PMID- 27467225 TI - Celery root extract as an inducer of mania induction in a patient on venlafaxine and St John's Wort. AB - Celery root belongs to a group of plants classified as the umbelliferous family, which contains phytoestrogens. Phytoestrogens are structurally similar to estrogen as they share a pair of hydroxyl groups and phenolic ring, which enables them to bind to estrogen receptors directly, making them a herbal remedy for low estrogen states such as menopause. We present a case of a female patient with depression who was stabilized on venlafaxine and St John's Wort, and who developed a manic episode due to elevated serum venlafaxine levels after she started taking celery extracts for menopausal related issues. We proffer a hypothesis for this unusual occurrence. PMID- 27467226 TI - Metastatic Cutaneous Squamous Cell Carcinoma: The Importance of T2 Stratification and Hematologic Malignancy in Prognostication. AB - BACKGROUND: While infrequent, nodal metastases in cutaneous squamous cell carcinoma (cSCC) can result in death from disease. Identification of those at risk for metastases is key to improved prognostication and treatment. OBJECTIVE: To review metastatic cSCC at the study institution. METHODS AND MATERIALS: Sixteen patients with metastatic cSCC were identified at the New York University Dermatologic Associates and Cancer Associates from 1998 to 2013. Patients were staged with American Joint Committee on Cancer (AJCC) and modified Brigham and Women's Hospital (BWH) criteria and compared to 32 control subjects. RESULTS: Seven of 16 patients were identified as Stage T2 by AJCC criteria and Stage T2b by BWH criteria; two patients were on Stage T1, three patients were on more advanced T stages, and four patients lacked primary tumor data. Five patients had hematologic malignancy, and one patient had a solid-organ transplant. CONCLUSION: The modified BWH criteria aims to better prognosticate the large group of T2 AJCC tumors, resulting in the majority of mortality. In the experience of the authors, the majority of patients with metastatic disease were on T2, stratifying to stage T2b by BWH criteria, or more advanced T stages. The findings of this study support BWH stratification of T2 tumors and also indicate that hematologic malignancy is a significant comorbidity associated with a poor outcome. PMID- 27467227 TI - Penile Squamous Cell Carcinoma: Penis-Preserving Treatment With Mohs Micrographic Surgery. AB - BACKGROUND: There have been few published case series of penile squamous cell carcinoma (SCC) removed with Mohs micrographic surgery (MMS). Of these case series, the published cure rates are between 68% and 74%. OBJECTIVE: To report 30 years of experience removing penile SCCs with MMS. METHODS AND MATERIALS: Retrospective record review of 42 patients with 44 penile SCCs. RESULTS: There was one recurrence of the 19 primary SCCs in situ, resulting in a cure rate of 94.7%. There were no recurrences among the 10 primary invasive SCC. Of the 6 recurrent invasive SCCs, 2 recurred, resulting in an initial cure rate of 66.7%. These 2 recurrences were re-treated with MMS with no evidence of recurrence at 5 years. There were 4 patients with SCC in situ of the glans with extension down the urethra. While all 4 patients required urethral dilation postoperatively secondary to urethral stricture, none of these tumors recurred and normal function was restored in each case. CONCLUSION: In conclusion, MMS may be preferred for patients with penile carcinoma by providing a high cure rate and tissue conservative alternative to partial or total penectomy and does not need to be limited to low-grade, small, superficial tumors. PMID- 27467228 TI - Mohs Micrographic Surgery for the Treatment of Merkel Cell Carcinoma. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive malignant neoplasm. Traditionally, wide local excision has been used for local control. However, the tissue-sparing capability of Mohs micrographic surgery (MMS) and the greater certainty of complete tumor removal offer a potential advantage over wide local excision if MMS offers acceptable cure rates. OBJECTIVE: This study aims to help elucidate management of MCC and includes one of the largest groups of patients from a single institution. MATERIALS AND METHODS: This study is a retrospective chart review of 22 patients with cutaneous MCC treated with MMS at our practice over 20 years. Clinical characteristics and outcomes were examined. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in the approval by our institution's human research review committee. RESULTS: The overall local recurrence rate was 5% (1/22). The overall rate of biopsy-proven metastasis to regional lymph nodes was 14% (3/22). No cases of distant metastases were documented. CONCLUSION: To our knowledge, this is the largest group of patients with MCC treated with MMS from a single institution and indicates that MMS may be a useful treatment modality for this rare aggressive disease. PMID- 27467229 TI - A Retrospective Analysis of the Treatment of Melasma Using a Fractional Long Pulsed Alexandrite Laser in Korean Patients. AB - BACKGROUND: Long-pulsed, 755-nm, alexandrite lasers have been shown to be effective and safe in the treatment of pigmentary lesions. OBJECTIVE: Clinical outcomes and side effects in the treatment of melasma using a fractional, long pulsed, alexandrite laser were assessed. MATERIALS AND METHODS: Forty-eight patients with melasma received 2 to 4 treatment sessions of fractional, long pulsed, alexandrite laser at 2 to 3 weeks intervals. The parameter of treatment was 60 to 80 J/cm without dynamic cooling device using 15-mm spot size of fractional hand piece, with a 0.5- to 1-millisecond pulse width. RESULTS: The mean modified melasma area and severity index score decreased significantly 2 months after the final treatment compared with baseline (16.5 +/- 8.2 vs 11.5 +/- 7.0; p = .002). The patients with epidermal type melasma were more effective compared to dermal type (p < .001). CONCLUSION: Long-pulsed alexandrite lasers using a fractional hand piece are moderately effective in the treatment of melasma with low risk of adverse effects, and it is suggested that fractional, long-pulsed, alexandrite laser with combination of other modalities can be an additional therapeutic option in patients with melasma. PMID- 27467231 TI - Fluorouracil-Induced Reactive Follicular Squamous Cell Carcinoma. PMID- 27467230 TI - Successful Treatment of Chronic Venous Ulcers With a 1,320-nm Endovenous Laser Combined With Other Minimally Invasive Venous Procedures. AB - BACKGROUND: Venous ulcers are very common with few curative treatment options. OBJECTIVE: To report the closure rate and clinical characteristics of active venous ulcers in a vein clinic using endovenous laser ablation (EVLA) with a 1,320-nm laser. METHODS AND MATERIALS: A prospective database was kept consisting of patients with an active venous ulcer at the time of consultation in a single practitioner academic vein clinic from March 2007 to May 2014. A database was maintained and charts were reviewed with attention to the length of time the patient reported having the ulcer, procedures performed, and time to ulcer healing. RESULTS: Thirty-one patients were identified at consultation with venous ulceration. One patient's ulcer was healed with conservative medical management before receiving treatment. The remaining 30 patients were treated with a combination of EVLA of the great and/or short saphenous veins, foam sclerotherapy of insufficient varicose and reticular veins, and phlebectomy as appropriate. Two patients were lost to follow up after partial treatment. Ulcer healing occurred in more than 93% (27/29) of patients with a median healing time of 55 days from the time of first treatment. The median follow-up time after treatment was 448 days. CONCLUSION: Endovenous laser ablation with a 1,320-nm laser in combination with foam sclerotherapy and phlebectomy as appropriate is effective treatment of chronic venous ulcers and should be considered as a treatment option for patients with C6 venous insufficiency. To the authors' knowledge, this is the largest, prospective series of chronic venous ulcers treated with EVLA. Further randomized controlled studies are needed to confirm these findings. PMID- 27467232 TI - Mohs Micrographic Surgery for the Treatment of Superficial Angiomyxoma. PMID- 27467233 TI - Comparison of Outcomes of Laser Trabeculoplasty Performed by Optometrists vs Ophthalmologists in Oklahoma. AB - Importance: Oklahoma is one of the few states where optometrists have surgical privileges to perform laser trabeculoplasty (LTP). Optometrists in other states are lobbying to obtain privileges to perform LTP and other laser procedures. Little is known whether outcomes of patients undergoing this procedure by optometrists are similar to those undergoing LTP by ophthalmologists. Objective: To compare outcomes of LTPs performed by ophthalmologists with those performed by optometrists to determine whether differences exist in the need for additional LTPs. Design, Setting, and Participants: This retrospective longitudinal cohort study used a health care claims database containing more than 1000 eyes of Medicare enrollees with glaucoma who underwent LTP in Oklahoma from January 1, 2008, through December 31, 2013. For each procedure, the data specify the type of eye care professional who performed the LTP. The rate of LTPs performed by ophthalmologists that required 1 or more additional LTPs in the same eye was compared with the rate of LTPs performed by optometrists. Regression models determined factors affecting risk of undergoing more than 1 LTP in the same eye. Main Outcomes and Measures: Proportion of enrollees requiring additional LTPs, hazard ratio with 95% CIs of undergoing additional LTPs. Results: A total of 1384 eyes of 891 eligible patients underwent LTP from January 1, 2008, through December 31, 2013. There were 1150 eyes that received LTP (83.1%) by an ophthalmologist and 234 eyes (16.9%) that had the procedure performed by an optometrist. The mean (SD) age at the initial LTP was 77.7 (7.5) years for enrollees with ophthalmologist-performed LTP and 77.6 (8.0) years for those with optometrist-performed LTP (P = .89). Among the 1384 eyes receiving LTP, 258 (18.6%) underwent more than 1 LTP in the same eye. The proportion of eyes undergoing LTP by an optometrist requiring 1 or more subsequent LTP session (35.9%) was more than double the proportion of eyes that received this procedure by an ophthalmologist (15.1%). Medicare beneficiaries undergoing LTP by optometrists had a 189% increased hazard of requiring additional LTPs in the same eye compared with those receiving LTP by ophthalmologists (hazard ratio, 2.89; 95% CI, 2.00-4.17; P < .001) after adjusting for potential confounders. Conclusions and Relevance: Considerable differences exist among the proportions of patients requiring additional LTPs comparing those who were initially treated by ophthalmologists with those initially treated by optometrists. Health policy makers should be cautious about approving laser privileges for optometrists practicing in other states until the reasons for these differences are better understood. PMID- 27467234 TI - Conjugate Addition of 3-Buytn-2-one to Anilines in Ethanol: Alkene Geometric Insights through In Situ FTIR Monitoring. AB - A convenient, mild and effective conjugate addition of 3-butyn-2-one to a variety of anilines in ethanol is reported. The reaction was monitored and characterized through in situ FTIR, and the dynamics of the facile E/Z alkene geometry interconversion of the resultant aniline-derived enaminones was explored through NMR, FTIR and X-ray crystallography. A straightforward purification protocol that employs direct Kugelrohr distillation was identified, and the method was further extended to other amines and ynones, allowing rapid access to these interesting compounds. PMID- 27467235 TI - Mediationg Role of Mindfulness as a Trait Between Attachment Styles and Depressive Symptoms. AB - Attachment styles and dysfunctional symptoms have been associated. This relationship could be affected by metacognitive capacity. The aim of this study is to clarify the relationship between depressive symptoms, attachment styles, and metacognitive capacity. In addition, the mediating role of metacognition between attachment and depressive symptoms has been studied. A total of 505 participants recruited from the general population of the province of Bizkaia (Spain) completed questionnaires regarding depression, anxiety, mindfulness, decentering, and attachment. Results showed positive and significant relations between (a) dysfunctional symptoms and insecure attachment styles and (b) metacognitive capacity and secure attachment style. Additionally, the mediating role of metacognition between attachment and depressive symptoms was confirmed. Intervention in metacognitive abilities such as mindfulness could be a useful therapeutic tool for depressive symptoms. PMID- 27467236 TI - Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities. AB - Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration. PMID- 27467240 TI - Credit for Computation. PMID- 27467241 TI - Principles of Systems Biology, No. 7. AB - With applications of CRISPR-Cas proteins for probing chromatin dynamics and recording information in a genome, this month's Cell Systems call (Cell Systems 1, 307) highlights a plethora of new techniques. PMID- 27467242 TI - What Is the Key Best Practice for Collaborating with a Computational Biologist? PMID- 27467239 TI - Meta-Analysis of Genome-Wide Association Studies and Network Analysis-Based Integration with Gene Expression Data Identify New Suggestive Loci and Unravel a Wnt-Centric Network Associated with Dupuytren's Disease. AB - Dupuytren's disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren's disease, much of the inherited risk in Dupuytren's disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren's disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10-5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole transcriptome data between patient- and control-derived tissue samples and found the Wnt/beta-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren's disease. PMID- 27467243 TI - Inferring Tumor Phylogenies from Multi-region Sequencing. AB - A new computational method illuminates the heterogeneity and evolutionary histories of cells within a tumor. PMID- 27467244 TI - Time is Money: Designing Cost-Effective Time Series Experiments. AB - A new theoretical model helps to evaluate the tradeoffs between running technical replicates in high-throughput experiments and sampling at more time points. PMID- 27467245 TI - On the Evaluation of Module Preservation. AB - The ability to compare the modular structure of gene expression networks requires fast and accurate statistical tools. NetRep software provides a permutation approach which validates seven measures used to contrast the preservation of co expression across diverse datasets. PMID- 27467246 TI - Inferring the Mutational History of a Tumor Using Multi-state Perfect Phylogeny Mixtures. AB - Phylogenetic techniques are increasingly applied to infer the somatic mutational history of a tumor from DNA sequencing data. However, standard phylogenetic tree reconstruction techniques do not account for the fact that bulk sequencing data measures mutations in a population of cells. We formulate and solve the multi state perfect phylogeny mixture deconvolution problem of reconstructing a phylogenetic tree given mixtures of its leaves, under the multi-state perfect phylogeny, or infinite alleles model. Our somatic phylogeny reconstruction using combinatorial enumeration (SPRUCE) algorithm uses this model to construct phylogenetic trees jointly from single-nucleotide variants (SNVs) and copy-number aberrations (CNAs). We show that SPRUCE addresses complexities in simultaneous analysis of SNVs and CNAs. In particular, there are often many possible phylogenetic trees consistent with the data, but the ambiguity decreases considerably with an increasing number of samples. These findings have implications for tumor sequencing strategies, suggest caution in drawing strong conclusions based on a single tree reconstruction, and explain difficulties faced by applying existing phylogenetic techniques to tumor sequencing data. PMID- 27467247 TI - AptaTRACE Elucidates RNA Sequence-Structure Motifs from Selection Trends in HT SELEX Experiments. AB - Aptamers, short RNA or DNA molecules that bind distinct targets with high affinity and specificity, can be identified using high-throughput systematic evolution of ligands by exponential enrichment (HT-SELEX), but scalable analytic tools for understanding sequence-function relationships from diverse HT-SELEX data are not available. Here we present AptaTRACE, a computational approach that leverages the experimental design of the HT-SELEX protocol, RNA secondary structure, and the potential presence of many secondary motifs to identify sequence-structure motifs that show a signature of selection. We apply AptaTRACE to identify nine motifs in C-C chemokine receptor type 7 targeted by aptamers in an in vitro cell-SELEX experiment. We experimentally validate two aptamers whose binding required both sequence and structural features. AptaTRACE can identify low-abundance motifs, and we show through simulations that, because of this, it could lower HT-SELEX cost and time by reducing the number of selection cycles required. PMID- 27467248 TI - A Scalable Permutation Approach Reveals Replication and Preservation Patterns of Network Modules in Large Datasets. AB - Network modules-topologically distinct groups of edges and nodes-that are preserved across datasets can reveal common features of organisms, tissues, cell types, and molecules. Many statistics to identify such modules have been developed, but testing their significance requires heuristics. Here, we demonstrate that current methods for assessing module preservation are systematically biased and produce skewed p values. We introduce NetRep, a rapid and computationally efficient method that uses a permutation approach to score module preservation without assuming data are normally distributed. NetRep produces unbiased p values and can distinguish between true and false positives during multiple hypothesis testing. We use NetRep to quantify preservation of gene coexpression modules across murine brain, liver, adipose, and muscle tissues. Complex patterns of multi-tissue preservation were revealed, including a liver-derived housekeeping module that displayed adipose- and muscle-specific association with body weight. Finally, we demonstrate the broader applicability of NetRep by quantifying preservation of bacterial networks in gut microbiota between men and women. PMID- 27467249 TI - Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. AB - Hi-C experiments explore the 3D structure of the genome, generating terabases of data to create high-resolution contact maps. Here, we introduce Juicer, an open source tool for analyzing terabase-scale Hi-C datasets. Juicer allows users without a computational background to transform raw sequence data into normalized contact maps with one click. Juicer produces a hic file containing compressed contact matrices at many resolutions, facilitating visualization and analysis at multiple scales. Structural features, such as loops and domains, are automatically annotated. Juicer is available as open source software at http://aidenlab.org/juicer/. PMID- 27467250 TI - Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom. AB - Hi-C experiments study how genomes fold in 3D, generating contact maps containing features as small as 20 bp and as large as 200 Mb. Here we introduce Juicebox, a tool for exploring Hi-C and other contact map data. Juicebox allows users to zoom in and out of Hi-C maps interactively, just as a user of Google Earth might zoom in and out of a geographic map. Maps can be compared to one another, or to 1D tracks or 2D feature sets. PMID- 27467251 TI - An Encapsulation of Gene Signatures for Hepatocellular Carcinoma, MicroRNA-132 Predicted Target Genes and the Corresponding Overlaps. AB - OBJECTIVES: Previous studies have demonstrated that microRNA-132 plays a vital part in and is actively associated with several cancers, with its tumor suppressive role in hepatocellular carcinoma confirmed. The current study employed multiple bioinformatics techniques to establish gene signatures for hepatocellular carcinoma, microRNA-132 predicted target genes and the corresponding overlaps. METHODS: Various assays were performed to explore the role and cellular functions of miR-132 in HCC and a successive panel of tasks was completed, including NLP analysis, miR-132 target genes prediction, comprehensive analyses (gene ontology analysis, pathway analysis, network analysis and connectivity analysis), and analytical integration. Later, HCC-related and miR 132-related potential targets, pathways, networks and highlighted hub genes were revealed as well as those of the overlapped section. RESULTS: MiR-132 was effective in both impeding cell growth and boosting apoptosis in HCC cell lines. A total of fifty-nine genes were obtained from the analytical integration, which were considered to be both HCC- and miR-132-related. Moreover, four specific pathways were unveiled in the network analysis of the overlaps, i.e. adherens junction, VEGF signaling pathway, neurotrophin signaling pathway, and MAPK signaling pathway. CONCLUSIONS: The tumor-suppressive role of miR-132 in HCC has been further confirmed by in vitro experiments. Gene signatures in the study identified the potential molecular mechanisms of HCC, miR-132 and their established associations, which might be effective for diagnosis, individualized treatments and prognosis of HCC patients. However, combined detections of miR-132 with other bio-indicators in clinical practice and further in vitro experiments are needed. PMID- 27467253 TI - Resistance training for people with Parkinson's disease (PEDro synthesis). PMID- 27467252 TI - Functional Authentication of a Novel Gastropod Gonadotropin-Releasing Hormone Receptor Reveals Unusual Features and Evolutionary Insight. AB - A gonadotropin-releasing hormone (GnRH)-like molecule was previously identified in a gastropod, Aplysia californica, and named ap-GnRH. In this study, we cloned the full-length cDNA of a putative ap-GnRH receptor (ap-GnRHR) and functionally authenticated this receptor as a bona fide ap-GnRHR. This receptor contains two potential translation start sites, each accompanied by a Kozak sequence, suggesting the translation of a long and a short form of the receptor is possible. The putative ap-GnRHR maintains the conserved structural motifs of GnRHR-like receptors and shares 45% sequence identity with the octopus GnRHR. The expression of the putative ap-GnRHR short form is ubiquitous in all tissues examined, whereas the long form is only expressed in parts of the central nervous system, osphradium, small hermaphroditic duct, and ovotestis. The cDNA encoding the long or the short receptor was transfected into the Drosophila S2 cell line and subject to a radioreceptor assay using 125I-labeled ap-GnRH as the radioligand. Further, the transfected cells were treated with various concentrations of ap-GnRH and measured for the accumulation of cAMP and inositol monophosphate (IP1). Radioreceptor assay revealed that only the long receptor bound specifically to the radioligand. Further, only the long receptor responded to ap-GnRH with an increased accumulation of IP1, but not cAMP. Our studies show that despite the more prevalent expression of the short receptor, only the long receptor is the functional ap-GnRHR. Importantly, this is only the second report on the authentication of a protostome GnRHR, and based on the function and the phylogenetic grouping of ap-GnRHR, we suggest that this receptor is more similar to protostome corazonin receptors than chordate GnRHRs. PMID- 27467255 TI - Graphitic Carbon Nitride/Nitrogen-Rich Carbon Nanofibers: Highly Efficient Photocatalytic Hydrogen Evolution without Cocatalysts. AB - An interconnected framework of mesoporous graphitic-C3 N4 nanofibers merged with in situ incorporated nitrogen-rich carbon has been prepared. The unique composition and structure of the nanofibers as well as strong coupling between the components endow them with efficient light-harvesting properties, improved charged separation, and a multidimensional electron transport path that enhance the performance of hydrogen production. The as-obtained catalyst exhibits an extremely high hydrogen-evolution rate of 16885 MUmol h(-1) g(-1) , and a remarkable apparent quantum efficiency of 14.3 % at 420 nm without any cocatalysts, which is much higher than most reported g-C3 N4 -based photocatalysts even in the presence of Pt-based cocatalysts. PMID- 27467254 TI - Psychometric Assessment of the Japanese Version of the Zurich Claudication Questionnaire (ZCQ): Reliability and Validity. AB - PURPOSE: The Zurich Claudication Questionnaire (ZCQ) is a self-administered measure to evaluate symptom severity, physical function, and surgery satisfaction in lumbar spinal stenosis (LSS). The purpose of this study is to assess the psychometric properties of the Japanese ZCQ in LSS patients. METHODS: LSS patients who are scheduled to undergo surgery were recruited from 12 facilities. Responses to several questionnaires, including the Japanese ZCQ; the visual analogue scale (VAS) to evaluate the degree of pain in the buttocks/legs, numbness in the buttocks/legs, and low back pain; the Oswestry Disability Index (ODI); and the SF-36v2, were collected before surgery and again 3 months after surgery (the post-surgery ZCQ was administered twice for test-retest reliability). For reliability, test-retest reliability was evaluated using the intra-class coefficient (ICC) and internal consistency was evaluated using Cronbach's alpha coefficient. Concurrent validity was assessed using Spearman's correlation coefficients between the Japanese ZCQ and other questionnaires. Effect size (ES) and standard response mean were calculated for responsiveness. All analyses were performed individually for the Japanese ZCQ symptom, function, and satisfaction domains. RESULTS: Data from 180 LSS patients were used in this analysis. The ICCs were 0.81, 0.89, and 0.88 and Cronbach's alpha coefficients were 0.78, 0.84, and 0.92 for the Japanese ZCQ symptom, function, and satisfaction domains, respectively. Regarding the concurrent validity, strong correlations (+/-0.5) were demonstrated between the Japanese ZCQ domains and the VAS leg pain, ODI, and SF-36v2 physical functioning or bodily pain, whereas correlations were approximately 0.3 in scales measuring other symptoms that are less related to symptom, function, or satisfaction domains. ESs showed high values for the ZCQ symptom and function domains (-1.73 for both). CONCLUSIONS: These psychometric assessments demonstrate that the Japanese ZCQ is a psychometrically reliable and valid measure in LSS. The Japanese ZCQ can evaluate both multi-dimensional aspects and the level of surgery satisfaction. PMID- 27467257 TI - Rule-Based Classification of Chemical Structures by Scaffold. AB - Databases for small organic chemical molecules usually contain millions of structures. The screening decks of pharmaceutical companies contain more than a million of structures. Nevertheless chemical substructure searching in these databases can be performed interactively in seconds. Because of this nobody has really missed structural classification of these databases for the purpose of finding data for individual chemical substructures. However, a full deck high throughput screen produces also activity data for more than a million of substances. How can this amount of data be analyzed? Which are the active scaffolds identified by an assays? To answer such questions systematic classifications of molecules by scaffolds are needed. In this review it is described how molecules can be hierarchically classified by their scaffolds. It is explained how such classifications can be used to identify active scaffolds in an HTS data set. Once active classes are identified, they need to be visualized in the context of related scaffolds in order to understand SAR. Consequently such visualizations are another topic of this review. In addition scaffold based diversity measures are discussed and an outlook is given about the potential impact of structural classifications on a chemically aware semantic web. PMID- 27467256 TI - Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer. AB - Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up regulated MHC-I and MHC-II proteins on IFNgamma treated keratinocytes but abrogated IFNgamma-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up regulated in response to IFNgamma more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNgamma signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation. PMID- 27467258 TI - Mapping Chemical Structures to Markush Structures Using SMIRKS. PMID- 27467259 TI - Classification of the Toxicity of Some Organic Compounds to Tadpoles (Rana Temporaria) Through Integrating Multiple Classifiers. PMID- 27467260 TI - Bioactive Molecules: Perfectly Shaped for Their Target? AB - In this study, we examined target subsets extracted from the MDL Drug Data Report (MDDR)1 to identify specific molecular shape profiles that are representative for compounds active on those targets. Normalized Principal Moments of Inertia Ratios (NPRs)2 have been used to describe molecular shape of small molecules in a finite triangular descriptor space. The clustering behavior of the MDDR target subsets in a cell-based triangular system shows a significant difference compared to randomly sampled datasets and proves the capability of the NPR descriptor to provide information. For some of the target subsets, certain parts of the descriptor space are unlikely to be occupied by bioactive compounds. All analyzed datasets show a generally biased distribution of molecular shapes: the majority of their compounds exhibit a rod-like character. The influence of the employed 3D conformer generators on this distribution has been assessed as well as the capability of multiple conformations of compounds to increase the shape space covered. PMID- 27467261 TI - Molecular Docking Guided Comparative GFA, G/PLS, SVM and ANN Models of Structurally Diverse Dual Binding Site Acetylcholinesterase Inhibitors. AB - Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were identified on the basis of molecular docking approach, and its comparative quantitative structure-activity relationship (QSAR) models were developed. These structurally diverse inhibitors were obtained by our previously reported high-throughput in vitro screening technique using 384-well plate's assay based on colorimetric method of Ellman. QSAR models were developed using (i) genetic function algorithm, (ii) genetic partial least squares, (iii) support vector machine and (iv) artificial neural network techniques. The QSAR model robustness and significance was critically assessed using different cross validation techniques on test data set. The generated QSAR models using thermodynamic, electrotopological and electronic descriptors showed that nonlinear methods are more robust than linear methods, and provide insight into the structural features of compounds that are important for AChE inhibition. PMID- 27467262 TI - AMBIT-SMARTS: Efficient Searching of Chemical Structures and Fragments. AB - We present new developments in the AMBIT open source software package for efficient searching of chemical structures and structural fragments. AMBIT-SMARTS is a Java based software built on top of The Chemistry Development Kit. The AMBIT SMARTS parser implements the entire SMARTS language specification with several syntax extensions that enable support for custom modifications introduced by third party software packages such as OpenEye, MOE and OpenBabel. The goal of yet another open-source SMARTS parser implementation is to achieve better performance and compatibility with multiple existing flavours of the SMARTS language, as well as to provide utilities for running efficient SMARTS queries in large structural databases. We describe a combination of approaches towards lowering the computational cost and improving the response time of substructure queries. An exhaustive comparison of the AMBIT algorithm with several subgraph isomorphism implementations is performed. To demonstrate the performance of the entire system from an end-user point of view, response time statistics for Web service substructure search queries against a database of 4.5 M structures are also reported. The package has wide applicability in the implementation of various chemoinformatics tasks. It has already been used in several projects dealing with descriptor calculation and predictive algorithms, database queries, web applications and web services. PMID- 27467263 TI - The Importance of Descriptor-Based Clusterization in QSAR Models Development: Tyrosine Kinases Inhibitors as a Key Study. AB - Quantitative Structure Activity Relationship (QSAR) is a well known cheminformatic tool for the discovery of novel biologically active compounds. However, when large and heterogeneous datasets are mined, it is not possible to derive a QSAR equation able to predict in a satisfactory manner the activity of the compounds. Thus, QSAR models are often inadequate for virtual screening purpose. Herein we present a novel approach to multitarget classification QSAR models, useful to assess the selectivity profile of the tyrosine kinases inhibitors. A descriptor-based clusterization process was employed, that allowed the generation of models with high accuracies and independent from the chemical classification of the compounds (i.e. from the scaffold type). The herein proposed methodology can lead to QSAR models useful for virtual screening processes. PMID- 27467264 TI - Electrostatic Similarity Determination Using Multiresolution Analysis. AB - Molecular similarity is an important tool in protein and drug design for analyzing the quantitative relationships between physicochemical properties of two molecules. We present a family of similarity measures which exploits the ability of wavelet transformation to analyze the spectral components of physicochemical properties and suggests a sensitive way for measuring similarities of biological molecules. In order to investigate how effective wavelet-based similarity measures were against conventional measures, we defined several patterns which involve scalar or topological changes in the distribution of electrostatic properties. The wavelet-based measures were more successful in discriminating these patterns in contrast to the current state-of-art similarity measures. We also present the validity of wavelet-based similarity measures through the hierarchical clustering of two protein datasets consisting of families of homologous domains and alanine scan mutants. This type of similarity analysis is useful for protein structure-function studies and protein design. PMID- 27467265 TI - The Risk of Chronic Pancreatitis in Patients with Psoriasis: A Population-Based Cohort Study. AB - BACKGROUND: Psoriasis is a chronic systemic inflammatory disorder, and studies have revealed its association with a variety of comorbidities. However, the risk of chronic pancreatitis (CP) in psoriasis has not been studied. This study aimed to investigate the risk of CP among patients with psoriasis. METHODS: Using the Taiwan National Health Insurance Research Database, this population-based cohort study enrolled 48430 patients with psoriasis and 193720 subjects without psoriasis. Stratified Cox proportional hazards models were used to compare the risks of CP between the patients with and without psoriasis. RESULTS: The incidence of CP was 0.61 per 1000 person-years in patients with psoriasis and 0.34 per 1000 person-years in controls during a mean 6.6-year follow-up period. Before adjustment, patients with psoriasis had a significantly higher risk of CP (crude hazard ratio (HR) = 1.81; 95% confidence interval (CI) = 1.53-2.15), and the risk remained significantly higher after adjustments for gender, age group, medications, and comorbidities (adjusted HR (aHR) = 1.76; 95% CI = 1.47-2.10). All psoriasis patient subgroups other than those with arthritis, including those with mild and severe psoriasis and those without arthritis, had significantly increased aHRs for CP, and the risk increased with increasing psoriasis severity. Psoriasis patients taking nonsteroidal anti-inflammatory drugs (aHR = 0.33; 95% CI = 0.22-0.49) and methotrexate (aHR = 0.28; 95% CI = 0.12-0.64) had a lower risk of developing CP after adjustments. CONCLUSIONS: Psoriasis is associated with a significantly increased risk of CP. The results of our study call for more research to provide additional insight into the relationship between psoriasis and CP. PMID- 27467267 TI - Proximity under Threat: The Role of Physical Distance in Intergroup Relations. AB - Throughout human history, social groups have invested immense amounts of wealth and time to keep threatening out-groups at a distance. In the current research, we explored the relationship between intergroup threat, physical distance, and discrimination. Specifically, we examined how intergroup threat alters estimates of physical distance to out-groups and how physical proximity affects intergroup relations. Previous research has found that people judge threatening out-groups as physically close. In Studies 1 and 2, we examined ways to attenuate this bias. In Study 1 a secure (vs. permeable) US-Mexico border reduced the estimated proximity to Mexico City among Americans who felt threatened by Mexican immigration. In Study 2, intergroup apologies reduced estimates of physical proximity to a threatening cross-town rival university, but only among participants with cross-group friendships. In Study 3, New York Yankees fans who received an experimental induction of physical proximity to a threatening out group (Boston Red Sox) had a stronger relationship between their collective identification with the New York Yankees and support for discriminatory policies toward members of the out-group (Red Sox fans) as well as how far they chose to sit from out-group members (Red Sox fans). Together, these studies suggest that intergroup threat alters judgment of physical properties, which has important implications for intergroup relations. PMID- 27467266 TI - Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3. AB - One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD. PMID- 27467268 TI - The Aminopeptidase CD13 Induces Homotypic Aggregation in Neutrophils and Impairs Collagen Invasion. AB - Aminopeptidase N (CD13) is a widely expressed cell surface metallopeptidase involved in the migration of cancer and endothelial cells. Apart from our demonstration that CD13 modulates the efficacy of tumor necrosis factor-alpha induced apoptosis in neutrophils, no other function for CD13 has been ascribed in this cell. We hypothesized that CD13 may be involved in neutrophil migration and/or homotypic aggregation. Using purified human blood neutrophils we confirmed the expression of CD13 on neutrophils and its up-regulation by pro-inflammatory agonists. However, using the anti-CD13 monoclonal antibody WM-15 and the aminopeptidase enzymatic inhibitor bestatin we were unable to demonstrate any direct involvement of CD13 in neutrophil polarisation or chemotaxis. In contrast, IL-8-mediated neutrophil migration in type I collagen gels was significantly impaired by the anti-CD13 monoclonal antibodies WM-15 and MY7. Notably, these antibodies also induced significant homotypic aggregation of neutrophils, which was dependent on CD13 cross-linking and was attenuated by phosphoinositide 3 kinase and extracellular signal-related kinase 1/2 inhibition. Live imaging demonstrated that in WM-15-treated neutrophils, where homotypic aggregation was evident, the number of cells entering IL-8 impregnated collagen I gels was significantly reduced. These data reveal a novel role for CD13 in inducing homotypic aggregation in neutrophils, which results in a transmigration deficiency; this mechanism may be relevant to neutrophil micro-aggregation in vivo. PMID- 27467269 TI - Can Recent Global Changes Explain the Dramatic Range Contraction of an Endangered Semi-Aquatic Mammal Species in the French Pyrenees? AB - Species distribution models (SDMs) are the main tool to predict global change impacts on species ranges. Climate change alone is frequently considered, but in freshwater ecosystems, hydrology is a key driver of the ecology of aquatic species. At large scale, hydrology is however rarely accounted for, owing to the lack of detailed stream flow data. In this study, we developed an integrated modelling approach to simulate stream flow using the hydrological Soil and Water Assessment Tool (SWAT). Simulated stream flow was subsequently included as an input variable in SDMs along with topographic, hydrographic, climatic and land cover descriptors. SDMs were applied to two temporally-distinct surveys of the distribution of the endangered Pyrenean desman (Galemys pyrenaicus) in the French Pyrenees: a historical one conducted from 1985 to 1992 and a current one carried out between 2011 and 2013. The model calibrated on historical data was also forecasted onto the current period to assess its ability to describe the distributional change of the Pyrenean desman that has been modelled in the recent years. First, we found that hydrological and climatic variables were the ones influencing the most the distribution of this species for both periods, emphasizing the importance of taking into account hydrology when SDMs are applied to aquatic species. Secondly, our results highlighted a strong range contraction of the Pyrenean desman in the French Pyrenees over the last 25 years. Given that this range contraction was under-estimated when the historical model was forecasted onto current conditions, this finding suggests that other drivers may be interacting with climate, hydrology and land-use changes. Our results imply major concerns for the conservation of this endemic semi-aquatic mammal since changes in climate and hydrology are expected to become more intense in the future. PMID- 27467270 TI - Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer. AB - Dickkopf 3 (DKK3) has been associated with tumor suppression of various tumor entities including breast cancer. However, the functional impact of DKK3 on the tumorigenesis of distinct molecular breast cancer subtypes has not been considered so far. Therefore, we initiated a study analyzing the subtype-specific DKK3 expression pattern as well as its prognostic and functional impact with respect to breast cancer subtypes. Based on three independent tissue cohorts including one in silico dataset (n = 30, n = 463 and n = 791) we observed a clear down-regulation of DKK3 expression in breast cancer samples compared to healthy breast tissue controls on mRNA and protein level. Interestingly, most abundant reduction of DKK3 expression was detected in the highly aggressive basal breast cancer subtype. Analyzing a large in silico dataset comprising 3,554 cases showed that low DKK3 mRNA expression was significantly associated with reduced recurrence free survival (RFS) of luminal and basal-like breast cancer cases. Functionally, DKK3 re-expression in human breast cancer cell lines led to suppression of cell growth possibly mediated by up-regulation of apoptosis in basal-like but not in luminal-like breast cancer cell lines. Moreover, ectopic DKK3 expression in mesenchymal basal breast cancer cells resulted in partial restoration of epithelial cell morphology which was molecularly supported by higher expression of epithelial markers like E-Cadherin and down-regulation of mesenchymal markers such as Snail 1. Hence, we provide evidence that down regulation of DKK3 especially promotes tumorigenesis of the aggressive basal breast cancer subtype. Further studies decoding the underlying molecular mechanisms of DKK3-mediated effects may help to identify novel targeted therapies for this clinically highly relevant breast cancer subtype. PMID- 27467271 TI - Preventing Zika Virus Infection during Pregnancy Using a Seasonal Window of Opportunity for Conception. AB - It has come to light that Zika virus (ZIKV) infection during pregnancy can result in trans-placental transmission to the fetus along with fetal death, congenital microcephaly, and/or Central Nervous System (CNS) malformations. There are projected to be >9,200,000 births annually in countries with ongoing ZIKV transmission. In response to the ZIKV threat, the World Health Organization (WHO) is strategically targeting prevention of infection in pregnant women and funding contraception in epidemic regions. I propose that the damaging effects of ZIKV can be reduced using a seasonal window of opportunity for conception that may minimize maternal exposure. Like other acute viral infections-including the related flavivirus, dengue virus (DENV)-the transmission of ZIKV is anticipated to be seasonal. By seasonally planning pregnancy, this aspect of pathogen ecology can be leveraged to align sensitive periods of gestation with the low transmission season. PMID- 27467272 TI - Assessment of the adequacy of oxygen delivery. AB - PURPOSE OF REVIEW: This article reviews the recent literature pertaining to assessment of the adequacy of oxygen delivery in critically ill patients with circulatory shock. RECENT FINDINGS: The assessment of the adequacy of oxygen delivery has traditionally involved measurement of lactate, central (or mixed) venous oxygen saturation (ScvO2), and global hemodynamic markers such as mean arterial pressure and cardiac index. The search for noninvasive, reliable, and sensitive methods to detect derangements in oxygen delivery and utilization continues. Recent studies focus on near-infrared spectroscopy (NIRS) to assess regional tissue oxygenation, as well as bedside ultrasound techniques to assess the macrovascular hemodynamic factors in oxygen delivery. SUMMARY: In this article, we review physiologic principles of global oxygen delivery, and discuss the bedside approach to assessing the adequacy of oxygen delivery in critically ill patients. Although there have been technological advances in the assessment of oxygen delivery, we revisit and emphasize the importance of a 'tried and true' method - the physical examination. Also potentially important in the evaluation of oxygen delivery is the utilization of biomarkers (e.g., lactate, ScvO2, NIRS). In complementary fashion, bedside ultrasound for hemodynamic assessment may augment the physical examination and biomarkers, and represents a potentially important adjunct for assessing the adequacy of oxygen delivery. PMID- 27467273 TI - Role of albumin, starches and gelatins versus crystalloids in volume resuscitation of critically ill patients. AB - PURPOSE OF REVIEW: The review focuses on fluid resuscitation of critically ill patients with either colloid or crystalloid solutions. RECENT FINDINGS: In healthy patients, the volume expanding effect of colloids is greater than that of crystalloids. However, in critically ill patients, a similar amount of crystalloids and colloids is required for fluid resuscitation, suggesting a lower efficiency of colloids when capillary permeability is increased, and endothelial glycocalyx disrupted. Recent studies on synthetic colloids in surgical patients confirmed the increased risk of renal failure reported in large clinical trials performed in critically ill patients. Experimental studies suggest that albumin maintains plasma volume expansion efficiency even when the capillary permeability is impaired, and that extravasation of albumin to the interstitium is lower than that of hydroxyethyl starch. SUMMARY: Fluid administration should be tailored to patient characteristics. Synthetic colloids should be avoided when possible, especially in patients at risk for kidney injury. In critically ill patients with suspected increased permeability, colloids may not be superior to crystalloids in expanding plasma volume. Albumin appears to be less harmful than synthetic colloids, although its beneficial effects need to be further investigated. The endothelial glycocalyx layer is the key structure finely regulating intravascular fluid distribution. PMID- 27467274 TI - Examining misses in reading aloud repeated words. AB - This study examined a novel task in which participants read aloud passages shown two words per line on a computer screen. There were four different passages, all of which included unrelated sentences, with each sentence containing one test word. The passages differed only in the text type (prose, scrambled) and in the identity of the test word (the, one). The word the is a common function word, whereas one is a less common content word. The test word was repeated in half of the sentences at the end of one line and at the start of the following line. Many more misses in reading aloud occurred on the than on one, especially for prose passages; almost all misses involved repeated words. These results were interpreted in terms of hypotheses and models that have been proposed for the letter-detection task. Specifically, it is concluded that reading aloud is influenced by structural processes that differentiate between function and content words. PMID- 27467275 TI - Bursts of high-frequency repetitive transcranial magnetic stimulation (rTMS), together with lorazepam, suppress seizures in a rat kainate status epilepticus model. AB - BACKGROUND: Status epilepticus (SE) is a condition of prolonged or recurrent and often drug-resistant seizures where nonsedating SE therapy remains an important unmet need. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a means to suppress seizures but has not been extensively studied in models. OBJECTIVES: We aimed to test the antiepileptic potential of high-frequency rTMS in SE. As a step toward eventual coupling of rTMS with antiepileptic pharmacotherapy, we also tested whether high-frequency rTMS in combination with a low (ineffective but less likely to cause a side effect) lorazepam dose is as effective as a full lorazepam dose in suppressing seizures in a rat SE model. METHODS: EEG was recorded to measure epileptic spike frequency in the rat kainate SE model. Epileptic spikes were counted before, during, and after either high frequency rTMS treatment alone or high-frequency rTMS treatment in combination with lorazepam, a firstline SE treatment. RESULTS: We found that rTMS alone decreases epileptic spike frequency only acutely. However, combinatory treatment with half-dose lorazepam together with rTMS was as effective as a full lorazepam dose. CONCLUSION: We report that high-frequency rTMS has modest antiepileptic potential alone but acts in complement with lorazepam to suppress seizures. PMID- 27467276 TI - Renal Function Predicts Outcomes in Patients with Ischaemic Stroke and Haemorrhagic Stroke. AB - BACKGROUND/AIMS: We evaluated renal function and the impact of renal function on in-hospital outcomes in patients with ischaemic and haemorrhagic stroke. METHODS: We collected data from 766 patients with stroke; 637 (83.2 %) with ischaemic and 129 with haemorrhagic one. RESULTS: The mean serum creatinine on admission in patients with both types of stroke, who died, was significantly higher than in those who survived. Multivariate analysis showed that independent predictors of mortality in patients with ischaemic stroke were: ischemic heart disease or prior myocardial infarction, diabetes, admission glucose and eGFR on admission. Also, multivariate analysis showed that independent predictors of mortality in patients with haemorrhagic stroke were: age and admission glucose. CONCLUSIONS: Patients with haemorrhagic stroke, in particular with acute kidney injury during hospitalisation had significantly worse outcomes than patients with ischaemic stroke. Assessment of kidney function is prerequisite to employ the necessary measures to decrease the risk of in-hospital mortality among patients with acute stroke. Appropriate approach to patients with renal dysfunction (adequate hydration, avoidance of nephrotoxic drugs, drug dose adjustment etc) should be considered as preventive and therapeutic strategies in the management of acute stroke. PMID- 27467278 TI - Serum Alkaline Phosphatase Levels are Not Associated with Increased Death Risk in Prevalent Hemodialysis Patients: 5-Year Experience in a Single Hemodialysis Center. AB - BACKGROUND/AIMS: Although high serum alkaline phosphatase (ALP) levels were reported as predictive factors for death risk in dialysis patients on the basis of large databank analyses, the real scenario in a single hemodialysis (HD) center is unknown. METHODS: In this study, a 5-year cohort of 1126 prevalent HD patients in the largest HD center in Taiwan was studied. The associations of ALP levels expressed as baseline, time-average, and time-dependent with all-cause mortality and cardiovascular mortality were evaluated by using adjusted Cox regression models. RESULTS: At baseline, levels of serum parathyroid hormone, calcium, and liver enzymes are increased in parallel with ALP quartiles. The hazard ratio (HR) for all-cause mortality was significantly increased in time average and time-dependent ALP quartile in the unadjusted Cox analysis. The significance disappeared when multivariate adjusted Cox analysis was used. Similarly, HR was not significantly increased for cardiovascular mortality with ALP quartile expressed as baseline, time-average, and time-dependent in three models of Cox analyses. CONCLUSION: Our study demonstrated that serum ALP levels were not associated with increased death risk in prevalent HD patients over a 5 year interval. PMID- 27467277 TI - Urotensin II Induces ER Stress and EMT and Increase Extracellular Matrix Production in Renal Tubular Epithelial Cell in Early Diabetic Mice. AB - BACKGROUND/AIMS: Urotensin II (UII) and its receptor are highly expressed in the kidney tissue of patients with diabetic nephropathy (DN). The aim of this study is to examine the roles of UII in the induction of endoplasmic reticulum stress (ER stress) and Epithelial-mesenchymal transition (EMT) in DN in vivo and in vitro. METHODS: Kidney tissues were collected from patients with DN. C57BL/6 mice and mice with UII receptor knock out were injected with two consecutive doses of streptozotocin to induce diabetes and were sacrificed at 3th week for in vivo study. HK-2 cells in vitro were cultured and treated with UII. Markers of ER stress and EMT, fibronectin and type IV collagen were detected by immunohistochemistry, real time PCR and western blot. RESULTS: We found that the expressions of protein of UII, GRP78, CHOP, ALPHA-SMA, fibronectin and type IV collagen were upregulated while E-cadherin protein was downregulated as shown by immunohistochemistry or western blot analysis in kidney of diabetic mice in comparison to normal control; moreover expressions of GRP78, CHOP, ALPHA-SMA, fibronectin and type IV collagen were inhibited while E-caherin expression was enhanced in kidney in diabetic mice with UII receptor knock out in comparison to C57BL/6 diabetic mice. In HK-2 cells, UII induced upregulation of GRP78, CHOP, ALPHA-SMA, fibroblast-specifc protein 1(FSP-1), fibronectin and type collagen and downregulation of E-cadherin. UII receptor antagonist can block UII-induced ER stress and EMT; moreover, 4-PBA can inhibit the mRNA expression of ALPHA-SMA and FSP1 induced by UII in HK-2 cells. CONCLUSIONS: We are the first to verify UII induces ER stress and EMT and increase extracellular matrix production in renal tubular epithelial cell in early diabetic mice. Moreover, UII may induce renal tubular epithelial EMT via triggering ER stress pathway in vitro, which might be the new pathogenic pathway for the development of renal fibrosis in DN. PMID- 27467279 TI - Inhibition of Cardiomyocytes Hypertrophy by Resveratrol Is Associated with Amelioration of Endoplasmic Reticulum Stress. AB - BACKGROUND/AIMS: Resveratrol (Res), a polyphenol antioxidant found in red wine, has been shown to play a cardioprotective role. This study was undertaken to investigate whether Res can protect the heart suffering from hypertrophy injuries induced by isoproterenol (ISO), and whether the protective effect is mediated by endoplasmic reticulum (ER) stress. METHODS: Cardiomyocytes were randomly assigned to the control group, ISO group (100 nM ISO for 48 h), Res + ISO group (50 MUM Res and 100 nM ISO for 48 h) and Res group (50 MUM Res for 48h only). Hypertrophy was estimated by measuring the cell surface area and the atrial natriuretic peptide (ANP) gene expression. Apoptosis was measured using Hoechst 33258 staining and transmission electron microscopy. Protein expression of ER stress and apoptosis factors was analyzed using Western Blot analysis. RESULTS: Res effectively suppress the cardiomyocytes hypertrophy and apoptosis induced by ISO, characterized by the reduction of the myocardial cell surface area, the ANP gene expression, the LDH and MDA leakage amount and the rate of cell apoptosis, while decrease of the protein expression of GRP78, GRP94 and CHOP, and reverse the expression of Bcl-2 and Bax. CONCLUSION: In summary, Res treatment effectively suppressed myocardial hypertrophy and apoptosis at least partially via inhibiting ER stress. PMID- 27467281 TI - Plate failure by bending following tibial fracture stabilisation in 10 cats. AB - OBJECTIVE: To describe the clinical findings and management of tibial fractures in cats in which osteosynthesis failed due to plate bending. METHODS: Case records and radiographs of cat tibial fracture repairs from five referral centres were reviewed for signalment and to assess incidence of plate failure by bending. Cats that sustained plate bending following plate or plate-rod fixation were reviewed for fracture configuration, repair method, initial postoperative and postfailure tibial alignment, revision treatment and outcome. RESULTS: The incidence of plate bending in cat fractures managed with plate and plate-rod fixation in the four referral centres where the overall number could be established was 13% (8/60). In the 10 cats in which plates bent, initial fractures were generally oblique or spiral with mild comminution and located in the middle or distal third of the tibia. Mean time to implant failure was 24 days (range 2 to 56 days). Mean tibial valgus angle increased from 12.9 degrees to 30.9 degrees following bending of the plate. Short-term outcome following revision surgery using orthogonal plating or stacked medial plates was favourable with improvement in tibial valgus in all five fractures with follow-up data. CLINICAL SIGNIFICANCE: Plate bending following tibial fracture stabilisation in these 10 cats resulted in tibial valgus deformation. Consideration of plate and/or intramedullary rod selection and application should be given to avoid a plate strain environment that exceeds the yield point of the plate. PMID- 27467282 TI - Analysis of Ly49 gene transcripts in mature NK cells supports a role for the Pro1 element in gene activation, not gene expression. AB - The variegated expression of murine Ly49 loci has been associated with the probabilistic behavior of an upstream promoter active in immature cells, the Pro1 element. However, recent data suggest that Pro1 may be active in mature natural killer (NK) cells and function as an enhancer element. To assess directly if Pro1 transcripts are present in mature Ly49-expressing NK cells, RNA-sequencing of the total transcript pool was performed on freshly isolated splenic NK cells sorted for expression of either Ly49G or Ly49I. No Pro1 transcripts were detected from the Ly49a, Ly49c or Ly49i genes in mature Ly49(+) NK cells that contained high levels of Pro2 transcripts. Low levels of Ly49g Pro1 transcripts were found in both Ly49G(+) and Ly49G(-) populations, consistent with the presence of a small population of mature NK cells undergoing Ly49g gene activation, as previously demonstrated by culture of splenic NK cells in interleukin-2. Ly49 gene reporter constructs containing Pro1 failed to show any enhancer activity of Pro1 on Pro2 in a mature Ly49-expressing cell line. Taken together, the results are consistent with Pro1 transcription having a role in gene activation in developing NK, and argue against a role for Pro1 in Ly49 gene transcription by mature NK cells. PMID- 27467284 TI - Specific HLA genotypes confer susceptibility to acute necrotizing encephalopathy. AB - Acute necrotizing encephalopathy (ANE) is a rare and severe syndrome of acute encephalopathy triggered by viral infections. Cytokine storm is considered as the main pathogenetic mechanism of ANE. ANE is prevalent in East Asia, suggesting the association of host genetic factors. To elucidate the genetic background of Japanese ANE, we examined genotypes of human leukocyte antigen (HLA)-A, C, B, DRB1, DQB1 and DPB1 in 31 patients. Significant positive association was observed in both the allele frequency and positivity of DRB1*09:01 (P=0.043 and 0.025, respectively), as well as those of DQB1*03:03 (P=0.034 and 0.026, respectively). The carrier frequency of DRB1*09:01 and DQB1*03:03 alleles was higher in the patients (45.16%) than in controls (28.57%). These alleles are more common in East Asian than in European populations, and are reportedly associated with various autoimmune diseases in Japanese patients. Our data provide further evidence that altered immune response based on individual HLA genotypes may contribute to ANE pathogenesis. PMID- 27467283 TI - Genetic risk and longitudinal disease activity in systemic lupus erythematosus using targeted maximum likelihood estimation. AB - Systemic lupus erythematous (SLE) is a chronic autoimmune disease associated with genetic and environmental risk factors. However, the extent to which genetic risk is causally associated with disease activity is unknown. We utilized longitudinal targeted maximum likelihood estimation to estimate the causal association between a genetic risk score (GRS) comprising 41 established SLE variants and clinically important disease activity as measured by the validated Systemic Lupus Activity Questionnaire (SLAQ) in a multiethnic cohort of 942 individuals with SLE. We did not find evidence of a clinically important SLAQ score difference (>4.0) for individuals with a high GRS compared with those with a low GRS across nine time points after controlling for sex, ancestry, renal status, dialysis, disease duration, treatment, depression, smoking and education, as well as time-dependent confounding of missing visits. Individual single-nucleotide polymorphism (SNP) analyses revealed that 12 of the 41 variants were significantly associated with clinically relevant changes in SLAQ scores across time points eight and nine after controlling for multiple testing. Results based on sophisticated causal modeling of longitudinal data in a large patient cohort suggest that individual SLE risk variants may influence disease activity over time. Our findings also emphasize a role for other biological or environmental factors. PMID- 27467286 TI - Dual effects of testosterone in Behcet's disease: implications for a role in disease pathogenesis. AB - Behcet's disease (BD) exhibits more severe disease course and higher mortality among male patients. However, underlying mechanisms of gender differences in clinical manifestations and disease severity are unclear. The aim of this study was to determine whether testosterone (T) has any role on BD pathogenesis. We studied peripheral blood mononuclear cells (PBMC) and neutrophils of BD patients and controls. Functional assay of neutrophils, cytokine measurements of culture supernatants and gene expressions on both cells were analyzed before and after T incubation. Neutrophils were significantly activated after incubation with T in only BD patients. Incubation with T caused significantly elevated interleukin (IL)-12 and IL-2 in BD. Gene expression of IL-10 was significantly downregulated after incubation with T in BD, especially in male patients. The same difference was observed in IL-10 levels in culture supernatant after T. Baseline TLR4 expression was significantly higher in BD patients compared to healthy donors (HC). Toll-like receptor (TLR) 4 expression on PBMC was significantly elevated in female BD patients. ERAP1 expressions of all patients and controls were decreased under the T effect but it differed significantly between BD vs HC. Baseline IL23R expression was higher in BD males compared with females but the difference disappeared after T. When BD patients were analyzed separately, baseline C-C motif chemokine receptor1 (CCR1), STAT4, TLR4 and KLRC4 expressions were lower in males. Despite immunosuppressive behavior in healthy subjects, T causes neutrophil hyperactivation and TH1 type immune alterations in BD patients. Our results suggest that T may have a role in BD pathogenesis by altering the expression level of IL-10, TLR4, ERAP1, CCR1. PMID- 27467285 TI - Survival of autoreactive T lymphocytes by microRNA-mediated regulation of apoptosis through TRAIL and Fas in type 1 diabetes. AB - Autoreactive CD8(+) T cells recognizing autoantigens expressed by pancreatic islets lead to the destruction of insulin-producing beta cells in type 1 diabetes (T1D), but these T cells also occur in healthy subjects. We tested the hypothesis that uncontrolled expansion of diabetogenic T cells in patients occurs, resulting from failure to activate apoptosis. We compared function, transcriptome and epigenetic regulation thereof in relation with fate upon repeated exposure to islet-autoantigen of islet autoreactive T cells from healthy and type 1 diabetic donors with identical islet epitope specificity and HLA-A2 restriction. Patient's T cells proliferated exponentially, whereas those of non-diabetic origin succumbed to cell death. Transcriptome analysis revealed reduced expression of TRAIL, TRAIL-R2, FAS and FASLG (members of the extrinsic apoptosis pathway) in patient-derived compared with healthy donor-derived T cells. This was mirrored by increased expression of microRNAs predicted to regulate these particular genes, namely miR-98, miR-23b and miR-590-5p. Gene-specific targeting by these microRNAs was confirmed using dual-luciferase reporter assays. Finally, transfection of these microRNAs into primary T cells reduced FAS and TRAIL mRNA underscoring their functional relevance. We propose that repression of pro-apoptotic pathways by microRNAs contributes to unrestricted expansion of diabetogenic cytotoxic T cells, implicating microRNA-mediated gene silencing in islet autoimmunity in T1D. PMID- 27467287 TI - CD58 mutations are common in Hodgkin lymphoma cell lines and loss of CD58 expression in tumor cells occurs in Hodgkin lymphoma patients who relapse. AB - CD58 is involved in immune recognition of tumor cells via binding of the CD2 receptor expressed on cytotoxic T cells. In diffuse large B-cell lymphoma, mutations of the CD58 gene are reported to contribute to immune evasion of the tumor cells. We previously showed CD58 mutations in three Hodgkin lymphoma (HL) cell lines by whole-exome sequencing. In this study, we confirmed the mutations by Sanger sequencing at the DNA and RNA level and showed low levels or total loss of CD58 mRNA expression in two of the three cell lines. CD58 protein expression as determined by flow cytometry, western blotting and immunohistochemistry was absent in all three mutated HL cell lines. In primary tissue samples, loss of CD58 expression was observed in 11% of the patients who relapse. These data suggest that loss of CD58 is a potential immune escape mechanism of HL tumor cells, especially in clinically aggressive disease. PMID- 27467288 TI - Mycobacterium Chelonae Sinusitis in an Immunocompetent Adult. PMID- 27467289 TI - Native DIGE proteomic analysis of mitochondria from substantia nigra and striatum during neuronal degeneration and its compensation in an animal model of early Parkinson's disease. AB - Cause of Parkinson's disease (PD) is still not understood. Motor symptoms are not observed at early stages of disease due to compensatory processes. Dysfunction of mitochondria was indicated already at preclinical PD. Selective toxin 6-OHDA was applied to kill dopaminergic neurons in substantia nigra and disturb neuronal transmission in striatum. Early phase of active degeneration and later stage, when surviving cells adapted to function normally, were analysed. 2D BN/SDS difference gel electrophoresis (DIGE) of mitochondrial proteome enabled to point out crucial processes involved at both time-points in dopaminergic structures. Marker proteins such as DPYSL2, HSP60, ATP1A3, EAAT2 indicated structural remodelling, cytoskeleton rearrangement, organelle trafficking, axon outgrowth and regeneration. Adaptations in dopaminergic and glutamatergic neurotransmission, recycling of synaptic vesicles, along with enlargement of mitochondria mass were proposed as causative for compensation. Changed expression of carbohydrates metabolism and oxidative phosphorylation proteins were described, including their protein-protein interactions and supercomplex assembly. PMID- 27467292 TI - Staying true to your purpose. PMID- 27467290 TI - A Practical Training Program for Peripheral Radial Artery Catheterization in Adult Patients: A Prospective, Randomized Controlled Trial. AB - BACKGROUND: The main cause of unsuccessful peripheral radial artery catheterization using traditional palpation is imprecisely locating the arterial center. The authors evaluated factors causing disparities between the arterial centers determined by palpation versus ultrasound. The authors applied them to create and test a novel catheterization training program. METHODS: The arterial central axis was determined by ultrasound and palpation in 350 adults. Potential independent predictors of disparity included sex, body mass index, pulse pressure, transverse arterial diameter, subcutaneous arterial depth, chronic hypertension, and experience as an anesthesiologist (less than 3 vs. greater than or equal to 3 yr). Using the results, the authors developed a radial artery catheterization training program. It was tested by enrolling 20 first-year interns, randomized to a training or control group. The time to successful insertion was the primary outcome measure. The success rate and time required for catheterization by palpation were evaluated in 100 adult patients per group. RESULTS: Independent predictors of central axis disparity were pulse pressure, subcutaneous radial artery depth, years of experience, and chronic hypertension. Training improved the catheterization time (training group 56 +/- 2 s vs. control group 109 +/- 2 s; difference -53 +/- 3 s; 95% CI, -70 to -36 s; P < 0.0001) and total success rate (training group 83 of 100 attempts, 83%; 95% CI, 75 to 90 vs. control group 57 of 100, 57%; 95% CI, 47 to 66; odds ratio, 3.7; 95% CI, 2.7 to 5.1). CONCLUSIONS: Misjudging the central axis position of the radial artery is common with a weak pulse and/or deep artery. The authors' program, which focused on both these issues, shortened the time for palpation-guided catheterization and improved success. PMID- 27467293 TI - A man with worsening gastrointestinal and neurologic symptoms. AB - A Coast Guardsman deployed to a remote island in the Bahamas contacted his primary care office about worsening gastrointestinal and neurologic complaints. This article describes the telemedicine consultation to determine the cause of his symptoms, whether he needed emergency evacuation, and how treatment was handled. PMID- 27467294 TI - Pediatric temporal bone rhabdomyosarcoma. AB - Rhabdomyosarcoma is one of the most common soft-tissue sarcomas in children. Prompt diagnosis and treatment significantly improve survival; however, misdiagnosis is common because of this aggressive temporal bone lesion's similarity to more common benign diseases. Clinicians should maintain a high index of suspicion for rhabdomyosarcoma in patients with a presumed otologic infection not responsive to medical therapy. PMID- 27467296 TI - An unusual cause of hoarseness and recurrent laryngeal nerve palsy. AB - Recurrent laryngeal nerve palsy and thyroid disease suggest locally invasive thyroid malignancy. In contrast, recurrent laryngeal nerve palsy caused by benign multinodular goiters or ectopic thyroid tissue accounts for only 1% of cases. This article describes an unusual case of recurrent laryngeal nerve palsy secondary to a benign ectopic retrosternal thyroid tissue mass. Recurrent laryngeal nerve palsy should be considered in the differential diagnosis of patients presenting with progressive voice weakness and hoarseness. PMID- 27467297 TI - Transfusion-free treatment strategies for acute anemia in critical care. AB - Acute anemia is a frequently encountered diagnosis in critically ill patients, and can be a challenge if blood products are not readily available or if patients refuse these products on the basis of their religious beliefs. This article discusses the goals of anemia management and summarizes several alternatives to blood transfusions that can be used to prevent and treat acute anemia. PMID- 27467298 TI - HIV testing at a community health center before and after implementing universal screening. AB - This study analyzed the quality of HIV screening at one of the largest community health centers in Connecticut. The data indicated that implementing universal HIV screening increased the proportion of underrepresented minorities and women tested, reducing the HIV testing disparities that previously existed at this center. PMID- 27467299 TI - Hepatitis B virus. PMID- 27467300 TI - What is causing this man's seizures? PMID- 27467301 TI - Update on pediatric oral healthcare. AB - As part of the patient-centered medical home, clinicians are being asked to apply fluoride varnish and perform oral examinations in children. This article reviews the latest national recommendations for fluoride varnish use to prevent dental caries. PMID- 27467302 TI - A mysterious case of abdominal pain. PMID- 27467303 TI - Moments without an ICD-10 code. PMID- 27467305 TI - Trust in Our Colleagues. PMID- 27467304 TI - Intraplant communication in maize contributes to defense against insects. AB - The vasculature of plants act as a channel for transport of signal(s) that facilitate long-distance intraplant communication. In maize, Maize insect resistance1-Cysteine Protease (Mir1-CP), which has homology to papain-like proteases, provides defense to different feeding guilds of insect pests. Furthermore, accumulation of Mir1-CP in the vasculature suggests that Mir1-CP can potentially function as a phloem-mobile protein. In a recent study, we provided evidence that Mir1-CP can curtail the growth of phloem-sap sucking insect, corn leaf aphid (CLA; Rhopalosiphum maidis). Our current study further examined whether aboveground feeding by CLA can induce resistance to subsequent herbivory by belowground feeding western corn rootworm (WCR; Diabrotica virgifera virgifera). Aboveground feeding by CLA systemically induced the accumulation of Mir1-CP in the roots. Furthermore, foliage feeding by CLA provided enhanced resistance to subsequent herbivory by belowground feeding of WCR. Taken together, our previous findings and results presented here indicate that long-distance transport of Mir1-CP is critical for providing enhanced resistance to insect attack in maize. PMID- 27467306 TI - Speed Posters: An Alternative to Traditional Poster and Podium Sessions. AB - Speed posters were used as an alternative concurrent session option during a national nursing education conference. The session format was received positively by both participants and presenters, and, as a result, recommendations for use were developed by the conference planners. J Contin Educ Nurs. 2016;47(8):344 346. PMID- 27467307 TI - Cybersecurity in the Clinical Setting: Nurses' Role in the Expanding "Internet of Things". AB - Nurses face growing complexity in their work. The expanding "Internet of Things" with "smart" technologies can reduce the burden. However, equipment and devices that connect to patients, the network, or to the Internet can be exploited by hackers. Nurses should be able to identify, understand, and protect against cybersecurity risks to safeguard patients. J Contin Educ Nurs. 2016;47(8):347 349. PMID- 27467308 TI - Think Competencies, Not Hours, When Planning Your Next Education Initiative. AB - As the focus of health care is shifting from organization-centered to patient centered care, education is also adjusting to new models that are more learner centered. Nursing professional development experts can benefit from the work that has been conducted in higher education and in professional development in teaching and medicine, where using competency based education is increasingly the norm. J Contin Educ Nurs. 2016;47(8):350-352. PMID- 27467309 TI - Tips for Conducting the Pre-Brief for a Simulation. AB - The pre-brief is an important part of a simulation. It offers participants an orientation to the simulation environment and enables them to reach the intended goals and objectives of the learning activity. This article describes the components of the pre-brief and provides practical tips on how to conduct this step using a simulation. These teaching strategies will help provide a positive learning experience for participants. J Contin Educ Nurs. 2016;47(8):353-355. PMID- 27467310 TI - It Could Never Happen Here: Promoting Violence Prevention Education for Emergency Department Nurses. AB - HOW TO OBTAIN CONTACT HOURS BY READING THIS ISSUE Instructions: 1.1 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded after you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. In order to obtain contact hours you must: 1. Read the article, "It Could Never Happen Here: Promoting Violence Prevention Education for Emergency Department Nurses," found on pages 356-360, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website to register for contact hour credit. You will be asked to provide your name, contact information, and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until July 31, 2019. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. OBJECTIVES Suggest strategies targeted for emergency department nurses to prevent or mitigate their exposure to workplace violence. Describe specific patient behaviors that will help emergency nurses in identifying potentially violent patients. Review the importance of following written facility violence prevention policies, as well as reporting all violent events. DISCLOSURE STATEMENT Neither the planners nor the author have any conflicts of interest to disclose. This article describes the necessity for emergency department nurses to receive violence prevention training to identify and mitigate violent events before they occur. In the emergency department setting, violence is a frequent occurrence and continues to be a growing concern. Despite the growing numbers, focus on training of staff in violence minimization and prevention has decreased. This article outlines three important safety topics and interventions that can be used to assist nurses when managing potentially violent patients: creating a safe emergency department environment, recognizing and evaluating the behaviors of a potentially violent patient, and identifying nurses' behaviors that may trigger patient violence. Nurses educated in violence prevention will be better prepared to recognize potentially violent patients, use specific strategies to prevent violence, and manage a violent event in a safe, professional manner. J Contin Educ Nurs. 2016;47(8):356-360. PMID- 27467312 TI - Effects of Education Programs on Evidence-Based Practice Implementation for Clinical Nurses. AB - This study was conducted to identify the effectiveness of an education program for evidence-based practice (EBP) implementation of clinical nursing. EBP knowledge/skill, attitude, and belief; information search ability; and EBP implementation were significantly higher in the experimental group than in the control group. Furthermore, the effect on implementation was maintained at week 4 and week 8, indicating that the education program practically promotes the EBP implementation of nurses. Results confirm that the education program for EBP implementation is critical and the continuous education program is an essential part of EBP implementation. Also, to promote EBP implementation and disseminate it to nursing organizations, an immediate concern should be the cultivation of mentors for EBP and fortification of the belief and ability regarding EBP implementation. J Contin Educ Nurs. 2016;47(8):363-371. PMID- 27467313 TI - Importance of Gamification in Increasing Learning. AB - Gamification is being used in the business industry as a way to engage employees into achieving organizational goals, as well as incentivize customers to use their products. More recently, gamification has become a powerful instructional method in K-12 education, as well as top colleges and universities. Health care is still in the early stages of embracing gamification in education; however, some of this may be due to a knowledge deficit related to what gamification is and how it could be applied in the health care setting. This article describes the theory, components, applications, and benefits of gamification for educators who are interested in embarking on a new and innovative way of teaching. J Contin Educ Nurs. 2016;47(8):372-375. PMID- 27467314 TI - Nurse Perspectives on Referrals for Oncology Patients to Reproductive Endocrinologists: Results of a Learning Activity. AB - BACKGROUND: Although concern about future fertility for adolescents and young adults (AYAs) with cancer is high, referrals to reproductive endocrinologists (REI) are low. Oncology nurses are well positioned to facilitate these referrals but may lack the knowledge and training. This report describes a learning activity in the Educating Nurses about Reproductive Issues in Cancer Healthcare (ENRICH) program whereby oncology nurses interviewed REIs. METHOD: Participants were instructed to conduct an interview with an REI using a semistructured guide and provided a written report of the discussion. We examined responses to each question using qualitative content analysis. RESULTS: Seventy-seven participants across 15 states provided a summary. Learner summaries highlighted four themes related to FP, including Cost, Time, Lack of Information or Referrals, and Learning About Available Options. CONCLUSION: Oncology nurses have an opportunity for a partnership to ensure that concerns about fertility among AYA patients are addressed. J Contin Educ Nurs. 2016;47(8):376-384. PMID- 27467315 TI - Searching the right coronary artery we found a rare anomaly documented by 3 dimensional volume rendering. PMID- 27467316 TI - Usefulness of microvolt T-wave alternans for predicting outcome in patients with Chagas disease with implantable cardioverter defibrillators. AB - BACKGROUND: Chagas disease (ChD) may lead to life-threatening heart disease, including malignant ventricular arrhythmias. The use of implantable cardioverter defibrillators (ICDs) has become the main therapeutic strategy for secondary prevention of SCD in Chagas disease (ChD). Microvolt T-wave alternans (MTWA) is a direct measure of ventricular repolarization instability and has emerged as a potentially useful way of determining arrhythmia vulnerability. However, this methodology has not been evaluated in patients with ChD. OBJECTIVE: To evaluate the predictive value of MTWA testing for appropriate therapy or death in ChD patients with ICDs. METHODS: This prospective study included consecutive patients who received ICD implantations in a Brazilian tertiary referral center. RESULTS: Seventy-two patients were followed for a median time of 422 (range 294-642) days. Thirty-three patients had ChD. The MTWA was non-negative (positive or indeterminate) in 27 (81.8%) of ChD patients. The combined primary outcome (appropriate ICD therapy or death) occurred in 29 patients (40.3%); 17 out 33 ChD patients presented the primary outcome. There was a statistically significant difference in event-free survival between ChD patients with negative and non negative MTWA results (p=0.02). Non-negative MTWA tests nearly triple the risk of appropriate ICD therapy or death (HR=2.7, 95% CI: 1.7-4.4, p=0.01) in patients with ChD and was the only variable associated with outcomes. The sensitivity and the negative predictive value was 100% in ChD patients. CONCLUSIONS: MTWA may be useful in recognizing high-risk ICD patients who may require adjunctive therapies with antiarrhythmic drugs or catheter ablation. PMID- 27467317 TI - The relationship between the proportion of admitted high risk ACS patients and hospital delivery of evidence based care. AB - AIMS: Variations in the delivery of evidence based care to high risk patients with Acute Coronary Syndromes (ACS) exist between hospitals. We hypothesised that the relative proportion of admitted high risk patients contributes to variation in care and outcomes. METHODS: Receipt of evidence based therapies (EBT) according to patient risk was documented in the Australian Co-operative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events (CONCORDANCE). Hospitals were stratified into quartiles (Q) by fraction of high risk patients according to: GRACE Risk Score (GRS), chronic kidney disease (CKD), age, Killip class, and myocardial infarction (MI). For each category, EBT and mortality were compared between hospital groups. RESULTS: This study included 8390 ACS patients from 39 hospitals. Patients with GRS>130, CKD, and >80years, were less likely to receive EBT at high proportion hospitals (p<0.0001 for all). After adjustment, proportion of patients with CKD negatively predicted coronary angiography (CA) (Q4 vs Q1: OR 0.21, 95%CI 0.10-0.45). Adjusted 6month mortality was greater in CKD and trended greater in >80years in hospitals treating the highest proportions of these patients (Q4 vs Q1 OR 3.80, 95%CI 1.85-7.83, and OR 3.10, 95%CI 0.99-9.70 respectively). CONCLUSION: Elderly ACS patients and those with CKD are less likely to receive EBT at hospitals seeing high proportions of these patients. Failure to provide EBT to these high risk populations may contribute to avoidable mortality in these institutions. PMID- 27467318 TI - The significance of unrecognized histological high-risk features on response to therapy in papillary thyroid carcinoma measuring 1-4 cm: implications for completion thyroidectomy following lobectomy. AB - BACKGROUND: Although lobectomy is an alternative to total thyroidectomy (TT) for 1-4 cm papillary thyroid carcinoma (PTC) without high-risk features (HRFs) such as aggressive histology, vascular invasion, lymphovascular invasion (LVI), microscopic extrathyroidal extension, positive margin, nodal metastasis >5 mm and multifocality, these HRFs are not recognized until after surgery. Therefore, the chance of completion TT being required following lobectomy might be high. We evaluated the frequency of unrecognized HRFs and how they affected the response to therapy following TT and radioiodine (RAI). METHODS: Altogether, 1513 patients were analysed. Only 1-4 cm PTCs without recognizable HRFs were included. For response-to-therapy evaluation, only patients who had TT and post-RAI-stimulated thyroglobulin were analysed. Patients without an excellent response were defined as having 'incomplete response'. A multivariate analysis for incomplete response was performed. RESULTS: Of the 600 patients eligible for lobectomy, 257 (42.8%) had >=1 unrecognized histological HRF before surgery. The prevalence of unrecognized HRFs was similar between 1-2 cm and >2-4 cm PTCs (P = 0.393). Of the 330 patients eligible for response-to-therapy evaluation, 260 (78.8%) had an excellent response while 70 (21.2%) had an incomplete response. LVI was the only independent unrecognized HRF for incomplete response (P = 0.021). CONCLUSIONS: The prevalence of unrecognized histological HRFs under the current recommendations is relatively high among 1-4 cm PTCs. Among the unrecognized histological HRFs, LVI was the only one which independently associated with an incomplete response (i.e. posing an increased risk of persistent/recurrent disease after curative surgery). These findings may have implications for patients who undergo lobectomy for 1-4 cm PTCs with no clinically recognizable HRFs under the current recommendations. PMID- 27467319 TI - U.S. Selected Practice Recommendations for Contraceptive Use, 2016. AB - The 2016 U.S. Selected Practice Recommendations for Contraceptive Use (U.S. SPR) addresses a select group of common, yet sometimes controversial or complex, issues regarding initiation and use of specific contraceptive methods. These recommendations for health care providers were updated by CDC after review of the scientific evidence and consultation with national experts who met in Atlanta, Georgia, during August 26-28, 2015. The information in this report updates the 2013 U.S. SPR (CDC. U.S. selected practice recommendations for contraceptive use, 2013. MMWR 2013;62[No. RR-5]). Major updates include 1) revised recommendations for starting regular contraception after the use of emergency contraceptive pills and 2) new recommendations for the use of medications to ease insertion of intrauterine devices. The recommendations in this report are intended to serve as a source of clinical guidance for health care providers and provide evidence based guidance to reduce medical barriers to contraception access and use. Health care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients. Persons should seek advice from their health care providers when considering family planning options. PMID- 27467320 TI - A survey of bonobo (Pan paniscus) oral contraceptive pill use in North American zoos. AB - Contraception is an essential tool in reproductive management of captive species. The Association of Zoos and Aquariums (AZA) Reproductive Management Center (RMC) gathers data on contraception use and provides recommendations. Although apes have been given oral contraceptive pills (OCPs) for at least 30 years, there have been no published reports with basic information on why the pill is administered, formulations and brands used, and effects on physiology and behavior. Here, we report survey results characterizing OCP use in bonobos (Pan paniscus) housed in North American zoos, as well as information accumulated in the RMC's Contraception Database. Of 26 females treated, there have been no failures and nine reversals. The most commonly administered OCP formulation in bonobos contained ethinyl estradiol (EE) 35 MUg/norethindrone 1 mg. Few females on combined oral contraceptives (COCs) were given a continuous active pill regimen; a hormone-free interval of at least 5 days was allowed in most. Crushing the pill and mixing with juice or food was common. Females on COCs seldom experienced breakthrough estrus or bleeding, while these conditions were sometimes observed for females on continuous COCs. All females on COCs exhibited some degree of perineal swelling, with a mean score of 3 or 3+ most commonly reported. Behavioral changes included less sexual behavior, dominant females becoming subordinate, and a negative effect on mood. No appreciable change in weight was noted. Taken together, these results indicate that OCPs are an effective and reversible contraceptive option for bonobos that can be used by zoos and sanctuaries to limit reproduction. Zoo Biol. 35:444-453, 2016. (c) Wiley Periodicals, Inc. PMID- 27467321 TI - Normal and abnormal physiology, pharmacology, and anatomy of the gastroesophageal junction high-pressure zone. AB - The high-pressure zone of the gastroesophageal junction acts as a multifunctional valve that comprises different groups of smooth muscles located in the distal esophagus and the proximal stomach, in addition to the extrinsic crural diaphragm, composed of skeletal muscle. In this review article, we evaluate the current literature with respect to human subjects, discussing the anatomic locations and physiologic and pharmacologic processes controlling these muscles. These muscles work individually and as a group to prevent reflux of gastric contents while allowing anterograde passage of food and liquid and retrograde passage of gas. We also reviewed new findings with respect to abnormalities that are permissive of reflux of gastric contents into the esophagus, which may lead to gastroesophageal reflux disease. PMID- 27467322 TI - [Novel approaches to control the rise in pertussis cases]. AB - Pertussis is a respiratory disease caused by the Gram-negative encapsulated bacterium Bordetella pertussis. Despite the high vaccination coverage rate and addition of new booster doses to the immunisation scheme (in response to the epidemiological situation), pertussis is on the rise not only in the Czech Republic but also in many other countries. The age groups at highest risk are infants and, to a lower extent, newborns who can get infected before receiving the first dose of vaccine and develop a severe course of the disease, often requiring admission to hospital. The most common source of infection are adults or adolescents from the childs close environment who experience a mild course of the disease because of the previous vaccination. The immune response induced by the currently available acellular vaccines does not last. It can be reasonably assumed that pertussis has been underreported. Multiple studies have shown mutations in the causative bacterium that confer higher pathogenicity to it, either as a result of enhanced production of pertussis toxin or loss of some antigens. Possible strategies to control these negative trends are to develop novel more effective vaccines using new adjuvants or to use whole-cell vaccines. Maternal vaccination in pregnancy trimester 3 also turned out to be effective. KEY WORDS: pertussis - vaccination - epidemiology - diagnosis - newborns. PMID- 27467323 TI - [Pandemic of hepatitis C virus infection]. AB - Hepatitis C virus (HCV) is an important human pathogen that causes hepatitis, advanced liver fibrosis, cirrhosis (CIH), and hepatocellular carcinoma (HCC). Especially the chronic form of hepatitis C (HC), with 55-85% of acute cases progressing to it, is a serious problem worldwide. HCV is a cause of the significant morbidity and mortality that are only expected to peak. An ongoing research of new therapeutic molecules for the treatment of HCV infection is a promise for a better future. The costs incurred are, however, high. KEY WORDS: hepatitis C - genotypes - prevalence - risk groups - HCV-associated diseases. PMID- 27467324 TI - [Some aspects of the immune system in the pathogenesis of Alzehimers disease]. AB - Alzheimers disease is a severe neurodegenerative disorder and the most common cause of dementia in the population above 60 years of age. Beta-amyloid accumulation and neurofibrillary tangles formation in the brain precedes the development of Alzheimer's dementia by many years. As beta-amyloid accumulation inhibition failed as a treatment option, the theories on the Alzheimers disease pathophysio-lo-gy are being revised. In this context, research targets the role of inflammation as the possible trigger mechanism and accompanying process of neurodegeneration. This article summarizes some knowledge of the immune function of brain cells and its potential relation to Alzheimers disease progression in the light of the immune reaction hypothesis. PMID- 27467325 TI - [Detection of cell death markers as a tool for bacterial antimicrobial susceptibility testing]. AB - Antimicrobial resistance among nosocomial pathogens has emerged as one of the most important health care problems in the new millennium. In this review, we present new methods for bacterial antimicrobial susceptibility testing, based on the detection of antibiotic-mediated cell death markers that could provide valuable alternatives to existing phenotypic approaches in the very near future. PMID- 27467326 TI - Molecular and antigenic characterization of the H3 hemagglutinin of H3N2 influenza A virus strains collected in the Czech Republic during the 2014/2015 epidemic season. AB - The 2014/2015 influenza epidemic season was characterized by the predominance of the H3N2 subtype. The presented study investigated the genetic and antigenic heterogeneity of the H3N2 strains collected in the Czech Republic from November 2014 to March 2015. Phylogenetic analysis of the representative H3 hemagglutinin sequences was performed and the glycosylation status and crucial antigenic mutations were compared relative to the 2014 and 2015 vaccine strains (A/Texas/50/2012 and A/Switzerland/9715293/2013) and visualized in the H3 crystal structure. The molecular data were further supplemented by hemagglutination inhibition test (HIT) results on fifteen H3N2 2014/2015 strains by using the A/Texas/50/2012 (H3N2) and A/Switzerland/9715293/13 (H3N2) antisera. Our data on the Czech H3N2 viruses from the 2014/2015 epidemic season could supplement the reports of official authorities with data from a particular geographi-cal area. PMID- 27467327 TI - [Multiple-locus variable number tandem repeat analysis of Bordetella pertussis strains collected in the Czech Republic in 1967-2015: spread of a variant adapted to the population with a high vaccination coverage]. AB - AIM: To perform multiple-locus variable number tandem repeat analysis (MLVA) of B. pertussis strains from the collection of the National Reference Laboratory for Diphtheria and Pertussis (NRL/DIPE), National Institute of Public Health (NIPH), Prague. The study strains were isolated from clinical specimens collected mostly in the Czech Republic over a nearly 50-year period from 1967 to 2015 (June). The isolates from three periods characterized by different vaccination strategies and trends in pertussis are compared for genetic diversity and distribution of MLVA types (MT). Based on the results obtained, the suitability for use of MLVA in the analysis of epidemic outbreaks of B. pertussis in the Czech Republic is considered. MATERIAL AND METHODS: DNA samples extracted from B. pertussis strains included in the present study were examined by MLVA using the standard protocol. Data were processed by means of the eBURST algorithm and the calculation of the Simpson diversity index (DI) was used for the statistical analysis. Data were analyzed as a whole and also separately for strains from the three periods: 1967 1980, 1990-2007, and 2008-2015 (June). RESULTS: Fourteen different MT were detected in the study strains, with three of them not being reported before. The most common MTs were MT27 and MT29. MT29 was predominant in 1967-1980 while MT27 was the most prevalent in 1990-2007 and 2008-2015 (June). The DI was the lowest (0.49) in 2008-2015 (June), and comparably higher DIs were calculated for the two previous periods (i.e. 0.667 for 1967-1980 and 0.654 for 1990-2007). CONCLUSION: MLVA revealed a decrease in genetic diversity and shifts in MT distribution of B. pertussis strains isolated from clinical specimens in the Czech Republic from 1967 to 2015 (June). These shifts in the Czech Republic can be characterized as a progressive increase in global MTs at the expense of the locally unique ones. The most common MT, similarly to other geographical areas with long-term high vaccination coverage, is MT27. The results of MLVA of 136 B. pertussis strains can provide a background for using this method in molecular epidemiological analysis of smaller groups of strains. PMID- 27467328 TI - Improvement of diagnostic approach to Lyme neuroborreliosis in children by using recombinant antigens in detection of intrathecally produced IgM/IgG. AB - BACKGROUND: The purpose of the study was to evaluate new 3rd-generation test kits, EIA Borrelia recombinant IgM and IgG (TestLine, Brno, Czech Republic), in serum and cerebrospinal fluid (CSF) of children with Lyme neuroborreliosis. METHODS: Comparison of three tests was used: the whole-cell EIA from Borrelia garinii (EIA 1) was compared with the EIA using recombinant antigens (EIA 2) and immunoblot. In total, 364 samples of serum and CSF were examined. Eighty-six paired sera and CSF samples were evaluated in the first group of children with Lyme neuroborreliosis. The second group consisted of 30 children with probable Lyme neuroborreliosis. Sixty-six samples from children with neuroinfections other than borrelial etiology were used as controls. RESULTS: In the first group of children with proven LNB, EIA 2 gave significantly more positive results for IgG in serum (P = 0.006; OR = 7.5) as in CSF (P < 0.001; OR = 4.5). There was no statistically significant difference in the IgM positivity of serum (P = 0.54; OR = 0.71). EIA 2 determined significantly (P = 0.001; OR = 0.06) less positive results of IgM in CSF in the LNB patients. IgG antibody index (AI) assessed by both methods revealed similar results (P = 0.646; OR = 1.38). Both methods are comparable, but IgM AI assessed by EIA 2 showed significantly less positive results (P < 0.001; OR = 0.04).The differences in the detection of positive IgM/IgG antibodies in serum and CSF did not reach statistical significance either in the groups of children with excluded LNB or in controls. CONCLUSIONS: EIA 2 showed better results than EIA 1 and western blot for the detection of positive IgG antibodies in serum and CSF. The difference in the calculation of AI IgG by EIA 1 and EIA 2 was not noticeable in the group of LNB patients. Comparing IgG and IgM AIs calculated from both tests, the sensitivity for EIA 2 was 68% for IgG and 26% for IgM. The specificity is 100% for both tests. PMID- 27467329 TI - The occurrence of Ixodes ricinus ticks and important tick-borne pathogens in areas with high tick-borne encephalitis prevalence in different altitudinal levels of the Czech Republic Part I. Ixodes ricinus ticks and tick-borne encephalitis virus. AB - STUDY OBJECTIVE: The aim of the three-year study (2011-2013) was to monitor population density of Ixodes ricinus ticks and its infection rate with the tick borne encephalitis virus in areas with a high incidence of tick-borne encephalitis as reported in the previous decade 2001-2010. Such a comprehensive and long-term study based on existing epidemiolo-gical findings has not previously been conducted in Europe. MATERIAL AND METHODS: In the areas of the Usti nad Labem Region, Olomouc Region, South Bohemian Region, and Highlands Region, 600 m2 plots were selected in the local optimal I. ricinus habitats where tick flagging was performed every year in the spring-summer and autumn seasons of the questing activity. In total, 18,721 I. ricinus ticks (1448 females, 1425 males, and 15,848 nymphs) were collected and investigated. RESULTS AND CONCLUSION: The results have shown that the differences in the infection rate of I. ricinus observed between regions are driven by variation in the density of the local I. ricinus populations which is influenced by the characteris-tics of the whole local biocenosis. The overall prevalence estimate of TBE virus in Ixodes ricinus ticks at the altitudes below 600 m a.s.l. was 0.096 % (95% CI 0.055 0.156) for nymphs, and 0.477 % (95% CI 0.272-0.773) for adults. The dynamics of the seasonal variation in I. ricinus populations, depending primarily on the climatic factors, are behind the interyear differences in the infection rate of ticks and, consequently, in the epidemiological situation of tick-borne encephalitis. The nymph to adult ratio was 5.5 on average but showed great interregional variability (from 10.3 in the Usti nad Labem Region to 1.8 in the Highlands Region). It might be used in the future as one of the indicators of the composition of the local I. ricinus population and of the level of the circulation of tick-borne pathogens in zoonotic sphere and also for use in the health risk assessment in a given area. Despite the permanent expansion of ticks and tick-borne pathogens in higher altitudes the high risk limit for human infection with tick-borne encephalitis is 600 m a.s.l. in the Czech Republic. PMID- 27467330 TI - [The effect of oxygen on endotoxin production in bacteria of the Bacteroides fragilis group isolated from patients with colorectal carcinoma]. AB - OBJECTIVE: The aim of the study was to draw attention to the risk posed by anaerobic bacteria of the Bacteroides fragilis (BAFR) group, isolated particularly from abdominal lesions, and to assess the possible role of these species in colorectal cancer. A correlation has previously been suggested between the detection of the bacteria of the genus Bacteroides in patients on a meat based diet and intestinal and, in particular, colorectal cancer. Given that the species of the BAFR group are major producers of endotoxins, measurements and statistical analysis of endotoxin production were used to compare the Bacteroides strains isolated from clinical specimens of patients with colon cancer, rectal cancer, and other abdominal lesions. MATERIALS AND METHODS: Endotoxin production was detected in bacterial strains of the BAFR group (B. fragilis, B. thetaiotaomicron, B. distasonis, and B. vulgatus) isolated from clinical specimens of patients with rectal cancer, colon cancer, and intestinal cancer and was compared with that in strains from samples of patients with inflammatory conditions (anal abscess, appendicitis, skin abscess, etc.) under anaerobic and microaerophilic (with 5% of oxygen) culture conditions. The production of endotoxins was detected quantitatively using the Pyrosate LAL assay kit (Limulus Amoebocyte Lysate Test, BIOGENIX, CR) in four species of the BAFR group after anaerobic and microaerophilic culture. Five strains of each isolated Bacteroides species from each type of specimens were tested (in total 140 BAFR strains). The amount of endotoxin was given in endotoxin units per ml (EU/ml). RESULTS: Endotoxin production by bacteria under microaerophilic culture conditions was several times higher in comparison with strictly anaerobic culture.The difference was statistically significant (F1.269 = 160, p <0.0001). As regards the effect of oxygen on endotoxin production, the amount of endotoxins produced under microaerophilic culture conditions (average 889.1 EU/ml) was 2.5 times as high as that observed under anaerobic culture conditions (358.2 EU/ml), regardless of the bacteroides species and diagnosis. These results suggest that the amount of free oxygen in the environment affects the amount of endotoxin generated by the Bacteroides strains. CONCLUSION: The results show that endotoxin production by the Bacteroides strains under microaerophilic culture conditions is several times as high as that under strictly anaerobic culture conditions. PMID- 27467331 TI - Differential Phosphorylation of Akt and signaling in CD4+ T Cells in Pathogenic and Apathogenic SIV Infection. AB - Increased CD4+ T cell apoptosis and activation induced cell death (AICD) as a result of HIV infection in humans and SIV infection in Rhesus macaques (RM) is indicative of disease. Some non-human primate species naturally infected by SIV, such as African sooty mangabeys (SM), do not succumb to SIV despite high viral loads. Previously, we showed that mRNA levels of GSK-3beta a kinase involved in T cell signaling, are significantly decreased in SIV+ RM compared to SIV+ SM. The current study confirms that expression of GSK-3beta is decreased at the protein level in SIV+ RM. In addition, CD4+ T cells from SIV+ RM, but not other animals show an increase in both total Akt, a kinase directly interacting with GSK-3beta and p-AktThr308 in response to stimulation via CD3/CD28, which is associated with an increase in apoptosis. Furthermore, the differences between the uninfected and pathogenically or non-pathogenically infected animals are not only species specific, but also T cell subset specific and that these trends correlate with AICD. This is one of few studies indicating the activity of Akt can be specific to only one phosphorylation site and may be linked to the differences in AICD and resistance to the lentivirus induced disease. PMID- 27467332 TI - [A report of 10 cases of familial Creutzfeld-Jakob disease]. AB - AIM: The analysis of the available reported data and epidemiological investigation data on the cases of Creutzfeld-Jakob disease (CJD) that emerged in the Novy Jicin district in 2001-2011, with a focus on the familial form of the disease. MATERIAL AND METHODS: Data from the Regional Public Health Service of the Moravian-Silesian Region, local Public Health Centre Novy Jicin, were used for the analysis. RESULTS: This is a retrospective report of 10 cases of familial Creutzfeld-Jakob disease (CJD) in the Novy Jicin district in 2001-2011, based on the data from the public health service. Overall eight cases were notified and seven suspected cases were identified retrospectively. Out of these 15 cases, five were concluded to be sporadic CJD and 10 to be familial CJD. The PRNP D178N mutation was found in two fatal cases from 2002 and 2003. Genetic investigation of their relatives was not performed for ethical reasons. CONCLUSION: The high incidence of familial CJD in the Novy Jicin district in 2001-2011 is surprising, but the retrospective investigation failed to provide further evidence to understand this outbreak. PMID- 27467333 TI - Quantitation of alpha-hydroxy acids in complex prebiotic mixtures via liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Spark discharge experiments, like those performed by Stanley Miller in the 1950s, generate complex, analytically challenging mixtures that contain biopolymer building blocks. Recently, alpha-amino acids and alpha-hydroxy acids (AHAs) were subjected to environmental cycling to form simple depsipeptides (peptides with both amide and ester linkages). The synthesis of AHAs under possible primordial environments must be examined to better understand this chemistry. METHODS: We report a direct, quantitative method for AHAs using ultrahigh-performance liquid chromatography and triple quadrupole mass spectrometry. Hexylamine ion-pairing chromatography and selected reaction monitoring detection were combined for the rapid analysis of ten AHAs in a single run. Additionally, prebiotic simulation experiments, including the first-ever reproduction of Miller's 1958 cyanamide spark discharge experiment, were performed to evaluate AHA synthesis over a wide range of possible primitive terrestrial environments. RESULTS: The quantitating transition for each of the AHAs targeted in this study produced a limit of detection in the nanomolar concentration range. For most species, a linear response over a range spanning two orders of magnitude was found. The AHAs glycolic acid, lactic acid, malic acid, and alpha-hydroxyglutaric acid were detected in electric discharge experiments in the low micromolar concentration range. CONCLUSIONS: The results of this work suggest that the most abundant building blocks available for prebiotic depsipeptide synthesis would have been glycolic, lactic, malic, and alpha-hydroxyglutaric acids, and their corresponding amino acids, glycine, alanine, and aspartic and glutamic acids. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27467334 TI - Coming in sportsmedicine. PMID- 27467335 TI - Hurry Up and Slow Down. PMID- 27467338 TI - Brief reports. PMID- 27467336 TI - Letters. PMID- 27467339 TI - Scanning sports. PMID- 27467340 TI - Progress in US Olympie Sports Medicine. PMID- 27467341 TI - A Case of Mumpsimus. PMID- 27467342 TI - Preparing Alberto Salazar for the Heat of the 1984 Olympic Marathon. AB - In brief: Observations were made on US marathon record holder Alberto Salazar during a climatic chamber trial, heat acclimatization training, and the 1984 Olympic Marathon. The purpose was to evaluate his physiological responses to heat tolerance testing and to advise him regarding heat acclimatization, thermoregulation, and fluid discipline. Salazar was advised to avoid the showers along the race course during the marathon. Although fine-mist sprays, showers, and other skin-wetting techniques may make runners feel good, they have little effect on rectal temperature or sweat rate during a race. This applies to casual joggers as well as elite competitors. PMID- 27467343 TI - Ocular Trauma in War Games. AB - In brief: War games-a new and increasingly popular form of recreation that combines sports and military activity-are resulting in serious eye injuries. The 13 cases discussed in this paper represent 6% of all sports-related eye injuries reported in Quebec in 1984. None of the victims was wearing goggles or other facial protection when the injury occurred. Types of injuries include hyphema, vitreous hemorrhage, and cataract. Better ocular protection is essential for preventing injuries in those who participate in these games. In addition, more effort should be made to educate the players on the importance of using ocular protection. PMID- 27467344 TI - Survey of Bicycling Accidents in Boulder, Colorado. AB - In brief: To determine what public and individual efforts might reduce bicycling accidents and injuries, a survey was conducted during the primary cycling months (April through September) in Boulder, Colorado. Of 253 patients (87 women, 166 men, average age 22) treated for injuries in bicycling accidents, almost 30% of the accidents were caused by gravel, and nearly half involved a motor vehicle. The most frequent types of injury were abrasions, contusions, lacerations, and fractures. The survey results confirm the need for adequate head protection, satisfactory lighting, and increased awareness on the bicyclist's part. In addition, improved street maintenance will drastically reduce the number of cycling injuries and accidents. PMID- 27467345 TI - How I Manage Exercise-Related Menstrual Disturbances. AB - In brief: All women who stop menstruating or menstruate irregularly should be examined. Amenorrhea and oligomenorrhea are often related to heavy exercise, but in athletes as well as nonathletes these conditions can signal a serious pathologic condition. Even athletes with regular periods can experience hormone alterations, short luteal phase, or anovulation. Anovulation and hypoestrogenism are the two major conditions experienced by women with oligomenorrhea and amenorrhea. Anovulation may lead to endometrial pathology and an increased risk of breast cancer, while hypoestrogenism increases the risk of developing osteoporosis. Tests to pinpoint the causes of menstrual dysfunctions and measure estrogen levels are listed, and treatments to establish a proper balance of estrogen and progesterone are described. PMID- 27467346 TI - Ratings of Perceived Exertion, Heart Rate, and Power Output in Predicting Maximal Oxygen Uptake During Submaximal Cycle Ergometry. AB - In brief: Sixty-two subjects completed a four- stage submaximal cycle ergometer test to volitional fatigue. The purpose was to determine if estimates of V O2 max could be improved by using ratings of perceived exertion singly or in combination with easily obtainable physiological measures during submaximal cycle ergometry. While these procedures may not be acceptable for scientific purposes, clinicians could use them to estimate the aerobic power of their patients and athletes. PMID- 27467347 TI - Body Composition. AB - In brief: Athletes at many levels undergo body composition assessments to learn how much fat they have. Yet the subject of body composition remains fraught with confusion and unanswered questions. How accurate are the present methods for assessing body composition? Of what use is body composition assessment in preventive health care? How much do primary care physicians need to know about body composition? What are the optimal proportions of body fat for athletic performance and for health? How much is known about the measurement of muscle and bone as body components? Four panelists with long experience in body composition research address these and other questions. PMID- 27467348 TI - HDL-C Concentrations in Weight-Trained, Endurance-Trained, and Sedentary Females. AB - In brief: Serum high-density lipoprotein cholesterol (HDL-C) levels and percent HDL-C were significantly higher in nine female endurance runners than in equal groups of female weight trainers and sedentary female controls. Weight trainers and controls showed no significant differences in HDL-C and percent HDL-C. Subjects who had higher HDL-C levels were more likely to be non-smokers who consumed little alcohol and did not use oral contraceptives. No significant dose response relationships were found for either runners or weight trainers when daily training duration, weekly training frequency, and weekly mileage were correlated with HDL-C. It was concluded that HDL-C levels in females are associated with specific training methods. PMID- 27467349 TI - The Effect of Cycle Phase on the Adolescent Swimmers. AB - In brief: Performance times of six postmen-archeal adolescents who competed on junior and senior national levels were recorded during a 12-week period. The fastest times for the 100-yd freestyle and 100-yd best event occurred during the menstrual phase and the slowest times during the premenstruum. Symptoms were rated biweekly with the Moos Menstrual Distress Questionnaire. Subjects reported feeling better during menstruation than premenstruation, and none reported dysmenorrhea. Based on basal body temperature, five of ten cycles were clearly biphasic, two were monophasic, and three were possibly biphasic with very short luteal phases. These results, albeit from a small sample, suggest that menstrual cycle phase may affect athletic performance as measured by practice times. PMID- 27467351 TI - Vitamins and Minerais as Ergogenic Aids. PMID- 27467350 TI - Decompression Sickness: An Update. AB - In brief: Until 20 years ago, the physical phenomenon of bubbling was the primary consideration in decompression sickness (DCS). Now the physiological aspects of DCS and the physiochemical states that lead to bubbling are better understood. This paper discusses four important developments in the study of DCS: (1) the recognition of the importance of hydration states and flow in the microcirculation, (2) the documentation of intravascular bubble formation during asymptomatic decompressions, (3) the recognition of pharmacological substances that influence DCS, and (4) the development of an animal model to understand spinal cord bends. More attention will probably be given to the use of pharmacological agents in treating DCS in the future. PMID- 27467352 TI - Aerobic Dance for Children: Resources and Recommendations. AB - Aerobic dance classes for children are the latest trend in this exercise field. They may be safe for older children, but programs for younger age-groups should emphasize creativity within the limits of organized play. PMID- 27467353 TI - Mountain Nutrition: Common Sense May Prevent Cachexia. AB - High altitude cachexia-a general physical wasting and malnutrition that is one of the dangers of mountain climbing-may be prevented by a few simple dietary changes. But then again, it may not be all that simple. PMID- 27467355 TI - Can Exercise Make Us Immune to Disease? AB - Some people believe that exercise is a panacea; they're convinced it can even strengthen their immune system. But immunologists caution that while that belief remains plausible, there is evidence that excessive physical activity might invite infection. PMID- 27467354 TI - Infant Swimming Classes: Immersed in Controversy. AB - Swimming classes that use forced infant submersion are popular among parents who want to give their children a head start. But these classes may pose health hazards. PMID- 27467357 TI - Are Physician Credentials in Sports Medicine Needed Now? AB - The need for a procedure to determine who is qualified to practice sports medicine is becoming more apparent as the field expands. Physicians agree that credentials are a problem, but because of the many specialties involved in sports medicine, they don't see any simple answers. PMID- 27467356 TI - HMOs: Directing the Future of Sports Medicine? AB - Health maintenance organizations may be the best thing to happen to sports medicine since the fitness boom. Or they may hinder patient care and frustrate physicians. It depends on who is asked. PMID- 27467358 TI - Terrestrial Rowing. AB - The rowing machine is widely touted as the home fitness equipment that confers the most all-around benefits, but it has its drawbacks. PMID- 27467359 TI - Four-Square Ankle Rehabilitation Exercises. PMID- 27467361 TI - Abstracts at a glance. PMID- 27467362 TI - Noteworthy. PMID- 27467364 TI - To Walk Rather Than Run. PMID- 27467365 TI - Death in Community Australian Football: A Ten Year National Insurance Claims Report. AB - While deaths are thought to be rare in community Australian sport, there is no systematic reporting so the frequency and leading causes of death is unknown. The aim of this study was to describe the frequency and cause of deaths associated with community-level Australian Football (AF), based on insurance-claims records. Retrospective review of prospectively collected insurance-claims for death in relation to community-level AF activities Australia-wide from 2004 to 2013. Eligible participants were aged 15+ years, involved in an Australian football club as players, coaches, umpires or supporting roles. Details were extracted for: year of death, level of play, age, sex, anatomical location of injury, and a descriptive narrative of the event. Descriptive data are presented for frequency of cases by subgroups. From 26,749 insurance-claims relating to AF, 31 cases were in relation to a death. All fatalities were in males. The initial event occurred during on-field activities of players (football matches or training) in 16 cases. The remainder occurred to people outside of on-field football activity (n = 8), or non-players (n = 7). Road trauma (n = 8) and cardiac conditions (n = 7) were the leading identifiable causes, with unconfirmed and other causes (including collapsed or not yet determined) comprising 16 cases. Although rare, fatalities do occur in community AF to both players and people in supporting roles, averaging 3 per year in this setting alone. A systematic, comprehensive approach to data collection is urgently required to better understand the risk and causes of death in participants of AF and other sports. PMID- 27467366 TI - Safety and Benefits of Bronchoalveolar Lavage and Lung Biopsy in the Management of Pulmonary Infiltrates in Children With Leukemia. AB - BACKGROUND: Children with leukemia are at risk of developing life-threatening opportunistic pulmonary infections. The role of bronchoalveolar lavage (BAL) and lung biopsy (BX) in the management of these patients is controversial. In this study, we evaluate the yield and safety of BAL and BX in children with leukemia. PROCEDURE: We reviewed the records of all children with leukemia who underwent either BAL or BX between 1997 and 2007 at the St Jude Children's Research Hospital. RESULTS: A total of 64 patients were included, of whom 35 (55%) had BX and 29 (45%) had BAL. Positive results were obtained in 69% of BAL cohort and in 46% of BX cohort. Both procedures resulted in change in antimicrobial coverage (77% in BX, 83% in BAL). Pulmonary hemorrhage occurred in 2 patients, and transient hypoxia was the most frequent complication. All resolved without negatively impacting the clinical course. CONCLUSIONS: Both BAL and BX are safe and useful in the management of children with leukemia and pulmonary disease. PMID- 27467368 TI - Alternative Donor Hematopoietic Cell Transplantation Conditioned With Myeloablative Busulfan, Fludarabine, and Melphalan is Well Tolerated and Effective Against High-risk Myeloid Malignancies. AB - Busulfan, fludarabine, and melphalan as hematopoietic cell transplant conditioning, was used in 6 patients aged 1 to 19 years with very high-risk myeloid malignancies. This dose regimen had an acceptable toxicity profile resulting in complete donor engraftment even following transplantation of small 2/6 antigen disparate umbilical cord blood grafts. It provided excellent disease control as all patients had high-risk features in terms of cytogenetics, therapy related leukemia, and/or significant measurable disease before transplant. All patients remain in remission, without acute or chronic graft-versus-host disease with a median follow-up of 24 months. A larger study is indicated to confirm the efficacy and safety of this regimen. PMID- 27467367 TI - High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia. AB - OBJECTIVE: Use of high-dose cyclophosphamide without hematopoietic stem cell transplant to treat severe aplastic anemia (SAA) has been controversial due to concern for increased infectious toxicity as compared with antithymocyte globulin and cyclosporine A. As children often tolerate dose-intensive therapy better than adults, we sought to perform a detailed retrospective analysis of both treatment response and toxicity in 28 patients younger than 22 years of age treated with 29 courses of high-dose cyclophosphamide as the sole form of immunosuppression. STUDY DESIGN: Children and adolescents with SAA who lacked an human leukocyte antigen-matched sibling donor were treated with cyclophosphamide 50 mg/kg/d for 4 consecutive days then received daily granulocyte colony stimulating factor until neutrophil recovery, transfusion support, and antimicrobial prophylaxis. RESULTS: Overall survival was 85%, with hematologic response of 79% and complete response of 66%. Cumulative incidences of bacterial infection (86%) and fungal infection (62%) were high but deaths due to infection were rare, as were clonal evolution (1/28), clinically relevant paroxysmal nocturnal (1/28), and relapse (2/28). CONCLUSIONS: Response rates and survival following high-dose cyclophosphamide in pediatric patients with SAA exceed those seen in adults and compare favorably to antithymocyte globulin/cyclosporine A with manageable infectious toxicity. PMID- 27467369 TI - Hepatoblastoma and Abernethy Malformation Type I: Case Report. AB - A 2-year-old boy presented with pneumonia and an abdominal mass was noted incidentally. A right lobe hepatic mass classified as PRETEXT III and congenital absence of the portal vein with drainage of the superior mesenteric vein to the inferior vena cava (Abernethy malformation type I) were confirmed by computed tomography and angiography. After a clinical diagnosis of hepatoblastoma had been made, he was treated with 4 cycles of doxorubicin and cisplatin and hepatic arterial chemoembolization with doxorubicin, after which the tumor was classified as POSTEXT III. He underwent a right extended hepatic lobectomy with resection of the caudate lobe but died on postoperative day 4 due to hepatic failure. The Abernethy malformation type I is associated with the development of hepatic tumors, and the abnormal blood flow might predispose to hepatic failure after liver resection. Extensive study of the hepatic vasculature is warranted in patients with suspected malformations. Liver transplant could be considered in patients with congenital portosystemic shunt and malignant liver tumors. PMID- 27467370 TI - The Association Between Plasma Ferritin Level and Simple Febrile Seizures in Children. AB - INTRODUCTION: We conducted this study to determine the role of iron deficiency (ID) as a risk factor for simple febrile seizure (SFS) in 6- to 60-month-old children. MATERIALS AND METHODS: In this case-control study 100 children aged 6 to 60 months with febrile seizure (FS) (study group) and 100 febrile children without seizures (control group) admitted to Pediatric Departments of Kecioren Training and Research Hospital in between June 2014 and March 2015 were evaluated. Complete blood count, serum iron, plasma ferritin, and total iron binding capacity analyses were performed in children with FS and were compared with controls. RESULTS: Ferritin level was significantly lower in the study group than controls (P<0.05). Compared with the onset of the study (first day), ferritin levels of the study group significantly decreased at the 10th day (P<0.05). At the onset, we were not able to determine ID in 18% of children because of fever. CONCLUSIONS: There was a relationship between low plasma ferritin level and SFS. Low plasma ferritin level may be a risk factor for the development of SFS. For preventing the FS attacks, treatment of present ID and oral supplementary iron therapy should be initiated for children with SFS who have a low plasma ferritin. PMID- 27467371 TI - Autoimmune Hepatitis and Seronegative Hepatitis Associated With Myelodysplastic Syndrome in Children. AB - An association between hepatitis and aplastic anemia (AA) is known as hepatitis associated AA, and is characterized by an acute attack of hepatitis followed by the development of AA. We report 2 clinical cases of acute seronegative hepatitis in which pancytopenia with mild dysplasia developed after 3 months; however, neither of our cases fulfilled the histological criteria of AA, but rather myelodysplastic syndrome. This novel association bears considerable resemblance to hepatitis-associated AA, and raises the question of whether hepatitis associated dysmyelopoiesis should be included in the spectrum of hypocellular myelodysplastic syndrome. PMID- 27467372 TI - Delayed Measurement of Eosin-5'-Maleimide Binding May Affect the Test Results of Highly Hemolyzed Samples In Vivo and In Vitro-A Case Study. AB - Diagnosis of hereditary spherocytosis (HS) is based on clinical evaluation and eosin-5'-maleimide (EMA) test. A decrease in EMA fluorescence compared with healthy individuals is typical for HS and serves as a basis for HS diagnosis. Sensitivity and specificity of the test is high and false-positive results rarely occur. Studies have shown that anticoagulated blood sample when stored at 4 degrees C for 7 days do not affect the test results. This case study is about an autoimmune hemolytic anemia patient who showed a primary positive result for EMA test (decrease in EMA fluorescence-47% compared with 100% for samples of healthy individual), when the test was performed in the sample stored for 48 hours after venipuncture and before staining. An irrelevant decrease (92.5% compared with 100% for samples of healthy individual) was found when freshly collected sample was analyzed. On the basis of the results obtained, it is recommended that EMA staining should be performed on the same day of blood collection for patients with significant hemolysis. PMID- 27467373 TI - Development of Quality Metrics to Evaluate Pediatric Hematologic Oncology Care in the Outpatient Setting. AB - There are currently no clinic-level quality of care metrics for outpatient pediatric oncology. We sought to develop a list of quality of care metrics for a leukemia-lymphoma (LL) clinic using a consensus process that can be adapted to other clinic settings. Medline-Ovid was searched for quality indicators relevant to pediatric oncology. A provisional list of 27 metrics spanning 7 categories was generated and circulated to a Consensus Group (CG) of LL clinic medical and nursing staff. A Delphi process comprising 2 rounds of ranking generated consensus on a final list of metrics. Consensus was defined as >=70% of CG members ranking a metric within 2 consecutive scores. In round 1, 19 of 27 (70%) metrics reached consensus. CG members' comments resulted in 4 new metrics and revision of 8 original metrics. All 31 metrics were included in round 2. Twenty four of 31 (77%) metrics reached consensus after round 2. Thirteen were chosen for the final list based on highest scores and eliminating redundancy. These included: patient communication/education; pain management; delay in access to clinical psychology, documentation of chemotherapy, of diagnosis/extent of disease, of treatment plan and of follow-up scheme; referral to transplant; radiation exposure during follow-up; delay until chemotherapy; clinic cancellations; and school attendance. This study provides a model of quality metric development that other clinics may use for local use. The final metrics will be used for ongoing quality improvement in the LL clinic. PMID- 27467374 TI - Primary Orbital Histiocytic Sarcoma in a Child Successfully Treated With Multiagent Chemotherapy. AB - Histiocytic sarcoma (HS), a malignant proliferation of mature tissue histiocytes presenting with single or multifocal extranodal tumors, is rarely seen in children. Primary orbital HS has never been reported in a child. Disseminated disease to the bone marrow typically has an aggressive course and poor prognosis. There is no consensus currently on the optimal therapeutic approach for HS. We present the case of a 2-year-old girl with orbital HS with likely bone marrow involvement treated successfully with multiagent chemotherapy, now in complete remission and disease free 3.5 years from end of therapy. PMID- 27467375 TI - The Impact of Socioeconomic Factors on the Outcome of Childhood Acute Lymphoblastic Leukemia (ALL) Treatment in a Low/Middle Income Country (LMIC). AB - Survival for childhood acute lymphoblastic leukemia (ALL) has improved significantly, but these benefits may not be available to many children from low and middle income countries, where reasons for treatment failure may be unique to their environment. We retrospectively reviewed data on pediatric (1 to 18 y or younger) patients with newly diagnosed ALL treated over 5 years at a children's cancer hospital in Pakistan. Patients were treated with modified Berlin-Frankfurt Muenster -based therapy without risk stratification. There were 255 children with a median age of 7 years (mean, 7.65 y) and a male preponderance (M:F=1.6:1). 20% had T-ALL, one-third had white blood cells >50*10/L and 13.7% central nervous system disease. A majority (56.5%) was malnourished. In total, 49 (19.2%) died before the end of induction and 21 died in complete remission. Most deaths were infection-related. A total of 50 patients relapsed and 19 abandoned therapy after complete remission. Five-year overall survival is 52.9% with abandonment censored and 45.8% with abandonment as an event. Overall survival was related to socioeconomic status but not to known risk factors. The outcome of ALL at our center is suboptimal and associated with factors not commonly seen in developed countries. Special attention to early diagnosis, infection control, and parental educational are needed to improve the survival. PMID- 27467376 TI - Collecting Duct Renin Does Not Mediate DOCA-Salt Hypertension or Renal Injury. AB - Collecting duct (CD)-derived renin is involved in the hypertensive response to chronic angiotensin-II (Ang-II) administration. However, whether CD renin is involved in Ang-II independent hypertension is currently unknown. To begin to examine this, 12 week old male and female CD-specific renin knock out (KO) mice and their littermate controls were subjected to uni-nephrectomy followed by 2 weeks of deoxycorticosterone acetate (DOCA) infusion combined with a high salt diet. Radiotelemetric blood pressure (BP) was similar between KO and control mice at baseline; BP increased in both groups to a similar degree throughout the 2 weeks of DOCA-salt treatment. Urinary albumin excretion and plasma blood urea nitrogen were comparable between the two groups after DOCA-salt treatment. Fibrosis as assessed by Masson's Trichrome stain/Sirius Red stain and collagen-1 mRNA expression was similar between control and KO mice. Compared to baseline, DOCA-salt treatment decreased plasma renin concentration (PRC), urinary renin excretion and medullary renin mRNA expression in both floxed and CD renin KO mice with no detectable differences between the two groups. Further, in primary culture of rat inner medullary CD, aldosterone treatment did not change renin activity or total renin content. Taken together, these data suggest that CD derived renin does not play a role in DOCA-salt hypertension. PMID- 27467377 TI - SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR AFTER BEVACIZUMAB OR RANIBIZUMAB TREATMENT FOR RETINOPATHY OF PREMATURITY. AB - PURPOSE: To investigate vascular endothelial growth factor (VEGF) levels in the systemic circulation after intravitreal injections of bevacizumab (IVB) or ranibizumab (IVR) in patients with Type 1 retinopathy of prematurity (ROP). METHODS: Patients who had Type 1 ROP and received IVB or IVR were enrolled. Serum samples were collected before and up to 12 weeks after IVB or IVR treatment. The main outcome measurements were serum levels of VEGF up to 12 weeks after anti VEGF treatment. RESULTS: In total, 10 patients with Type 1 ROP were enrolled in this study. All the eyes had complete resolution of abnormal neovascularization of ROP after IVB or IVR. In the direct comparison of IVB with IVR, serum VEGF was found to be suppressed more in patients with Type 1 ROP who received IVB treatment, compared with those who received IVR treatment (P = 0.01, P = 0.03, and P = 0.03, respectively, 2, 4, and 8 weeks after intravitreal injection). CONCLUSION: Serum VEGF levels in patients with Type 1 ROP were suppressed for 2 months after treatment with IVB, and VEGF levels were less affected after IVR treatment. Further studies are warranted to investigate the long-term effects of VEGF changes in ROP patients. PMID- 27467378 TI - Diagnostic and Therapeutic Challenges. PMID- 27467379 TI - PHOTORECEPTOR INNER SEGMENT MORPHOLOGY IN BEST VITELLIFORM MACULAR DYSTROPHY. AB - PURPOSE: To characterize outer retina structure in best vitelliform macular dystrophy (BVMD) and to determine the effect of macular lesions on overlying and adjacent photoreceptors. METHODS: Five individuals with BVMD were followed prospectively with spectral domain optical coherence tomography and confocal and nonconfocal split-detector adaptive optics scanning light ophthalmoscopy (AOSLO). The AOSLO cone photoreceptor mosaic images were obtained within and around retinal lesions. Cone density was measured inside and outside lesions. In 2 subjects, densities were compared with published measurements acquired ~2.5 years before. One subject was imaged 3 times over a 5-month period. RESULTS: The AOSLO imaging demonstrated that photoreceptor morphology within BVMD retinal lesions was highly variable depending on the disease stage, with photoreceptor structure present even in advanced disease. The AOSLO imaging was repeatable even in severe disease over short-time and long-time intervals. Photoreceptor density was normal in retinal areas immediately adjacent to lesions and stable over ~2.5 years. Mobile disk-like structures possibly representing subretinal macrophages were also observed. CONCLUSION: Combined confocal and nonconfocal split-detector AOSLO imaging reveals substantial variability within clinical lesions in all stages of BVMD. Longitudinal cellular photoreceptor imaging could prove a powerful tool for understanding disease progression and monitoring emerging therapeutic treatment response in inherited degenerations such as BVMD. PMID- 27467380 TI - SYSTEMIC BETA-BLOCKERS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To evaluate whether oral beta-blockers (BBs) are associated with a decreased number of intravitreal injections in patients with incident neovascular age-related macular degeneration. METHODS: A retrospective cohort study of subjects with a new diagnosis of neovascular age-related macular degeneration was conducted using a medical claims database from a large national US insurer. Two cohorts were created for comparison consisting of patients with regular use of BBs or calcium channel blockers. The main outcome measured was the difference in the mean number of intravitreal injections administered between the two cohorts. RESULTS: After inclusion and exclusion criteria, 239 BB and 155 calcium channel blocker subjects remained for analysis. Univariate analysis revealed that the mean number of injections in the BB cohort was 6.43 (95% confidence interval [CI] 5.90-6.95) versus 6.55 (95% CI 5.85-7.25) in the calcium channel blocker cohort (P = 0.78). After multivariate adjustment, the mean number of injections in the BB group was 6.32 (95% CI 5.77-6.87) versus 6.71 (95% CI 6.02-7.40) in the calcium channel blocker group. The overall difference between the 2 groups was 0.39 (95% CI difference -1.29 to 0.51; P = 0.40). CONCLUSION: The use of oral BBs is not associated with a decreased number of intravitreal injections in incident neovascular age-related macular degeneration patients. PMID- 27467381 TI - Human Rabies Survivors in India: An Emerging Paradox? PMID- 27467383 TI - Ultrathin ZnS and ZnO Interfacial Passivation Layers for Atomic-Layer-Deposited HfO2 Films on InP Substrates. AB - Ultrathin ZnS and ZnO films grown by atomic layer deposition (ALD) were employed as interfacial passivation layers (IPLs) for HfO2 films on InP substrates. The interfacial layer growth during the ALD of the HfO2 film was effectively suppressed by the IPLs, resulting in the decrease of electrical thickness, hysteresis, and interface state density. Compared with the ZnO IPL, the ZnS IPL was more effective in reducing the interface state density near the valence band edge. The leakage current density through the film was considerably lowered by the IPLs because the film crystallization was suppressed. Especially for the film with the ZnS IPL, the leakage current density in the low-voltage region was significantly lower than that observed for the film with the ZnO IPL, because the direct tunneling current was suppressed by the higher conduction band offset of ZnS with the InP substrate. PMID- 27467382 TI - Olive Oil Consumption and Age-Related Macular Degeneration: The Alienor Study. AB - BACKGROUND: Olive oil provides a mixture of lipids and antioxidant nutrients which may help preventing age-related diseases such as age-related macular degeneration (AMD). However, little is known about the associations between olive oil consumption and the risk of AMD. OBJECTIVE: To examine associations between olive oil use and AMD prevalence in elderly subjects. METHODS: Alienor (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) is a population-based study on eye diseases performed in elderly residents of Bordeaux (France). In 1999-2000, frequencies of consumption of main categories of dietary fats used were collected. In 2006-2088, AMD was graded from non mydriatic retinal photographs into three exclusive stages: no AMD, early AMD, and late AMD. Two categories of preferred dietary fat used (olive oil, n-3 rich oils, n-6 rich oils, mixed oils, butter and margarine) were defined: "no use" and "regular use" (using fat for spreading and/or cooking and/or dressing). Associations of AMD with each fat use were estimated using Generalized Estimating Equation logistic regressions models. RESULTS: Our study included 654 subjects (1269 eyes) with complete data (n = 268 eyes with early AMD and n = 56 with late AMD). After adjustment for potential confounders, regular use of olive oil was significantly associated with a decreased risk of late AMD (odds ratio [OR] = 0.44, 95% confidence interval [CI]: 0.21;0.91). In contrast, regular use of olive oil was not significantly associated with early AMD (OR = 0.84, 95%CI: 0.59;1.21). No associations were found between regular consumption of n-3 rich oils, n-6 rich oils, mixed oils, butter and margarine and AMD, whatever the stage. CONCLUSIONS: This study suggests a protective effect of olive oil consumption for late AMD in this elderly community-dwelling population. Characterization of the mediating nutrients deserves further research. PMID- 27467384 TI - Transcriptional Bursting Explains the Noise-Versus-Mean Relationship in mRNA and Protein Levels. AB - Recent analysis demonstrates that the HIV-1 Long Terminal Repeat (HIV LTR) promoter exhibits a range of possible transcriptional burst sizes and frequencies for any mean-expression level. However, these results have also been interpreted as demonstrating that cell-to-cell expression variability (noise) and mean are uncorrelated, a significant deviation from previous results. Here, we re-examine the available mRNA and protein abundance data for the HIV LTR and find that noise in mRNA and protein expression scales inversely with the mean along analytically predicted transcriptional burst-size manifolds. We then experimentally perturb transcriptional activity to test a prediction of the multiple burst-size model: that increasing burst frequency will cause mRNA noise to decrease along given burst-size lines as mRNA levels increase. The data show that mRNA and protein noise decrease as mean expression increases, supporting the canonical inverse correlation between noise and mean. PMID- 27467385 TI - Cross-Reactivity between Schistosoma mansoni Antigens and the Latex Allergen Hev b 7: Putative Implication of Cross-Reactive Carbohydrate Determinants (CCDs). AB - IgG antibodies produced by rabbits immunized against S. mansoni antigens cross reacted with aqueous soluble constituents of a variety of allergens. The antibody cross-reactivity was largely sensitive to degradation by treatment of the target antigens with sodium meta-periodate, suggesting the cross-reactivity was due to carbohydrate determinants that were common to both the schistosome and the allergens (CCDs). The reaction between the rabbit antibodies and a 43 kDa molecule in a rubber latex extract was analysed further: tandem mass spectrometry identified the latex molecule as allergen Hev b 7. Rabbit anti-schistosome IgG antibodies purified by acid-elution from solid-phase latex Hev b 7 reacted with the S. mansoni egg antigens IPSE/alpha-1 and kappa-5 and cercarial antigens SPO-1 and a fatty acid-binding protein. Moreover, purified anti-S. mansoni egg, latex cross-reactive antibodies reacted with antigenic constituents of some fruits, a result of potential relevance to the latex-fruit syndrome of allergic reactions. We propose that IgG anti-schistosome antibodies that cross-react with allergens may be able to block IgE-induced allergic reactions and thus provide a possible explanation for the hygiene hypothesis. PMID- 27467387 TI - On the Existence of Step-To-Step Breakpoint Transitions in Accelerated Sprinting. AB - Accelerated running is characterised by a continuous change of kinematics from one step to the next. It has been argued that breakpoints in the step-to-step transitions may occur, and that these breakpoints are an essential characteristic of dynamics during accelerated running. We examined this notion by comparing a continuous exponential curve fit (indicating continuity, i.e., smooth transitions) with linear piecewise fitting (indicating breakpoint). We recorded the kinematics of 24 well trained sprinters during a 25 m sprint run with start from competition starting blocks. Kinematic data were collected for 24 anatomical landmarks in 3D, and the location of centre of mass (CoM) was calculated from this data set. The step-to-step development of seven variables (four related to CoM position, and ground contact time, aerial time and step length) were analysed by curve fitting. In most individual sprints (in total, 41 sprints were successfully recorded) no breakpoints were identified for the variables investigated. However, for the mean results (i.e., the mean curve for all athletes) breakpoints were identified for the development of vertical CoM position, angle of acceleration and distance between support surface and CoM. It must be noted that for these variables the exponential fit showed high correlations (r2>0.99). No relationship was found between the occurrences of breakpoints for different variables as investigated using odds ratios (Mantel Haenszel Chi-square statistic). It is concluded that although breakpoints regularly appear during accelerated running, these are not the rule and thereby unlikely a fundamental characteristic, but more likely an expression of imperfection of performance. PMID- 27467386 TI - Functional Balance and Its Determinants in Older People with Diabetes. AB - OBJECTIVE: To determine functional balance abilities of older adults with diabetes, and identify determinants of these abilities. METHODS: Eighty diabetic and 67 healthy non-diabetic community-dwelling older adults completed the Mini Mental Status Examination (MMSE) and questionnaires about their medical and fall histories. Participants were also assessed for vision, plantar sensitivity, muscle strength, and functional balance, including Functional Reach (FR), Five Times Sit-to-Stand (FTSTS), and 180 degrees turn (TURN). In addition to between group comparisons, hierarchical regression analysis was conducted to identify the independent determinants for each of the individual balance tasks for the diabetes and control group separately. RESULTS: The diabetes group had significantly greater body mass index, higher rate of cardiac disease, and poorer plantar sensitivity, mental status, grip and lower limb strength. The diabetes group performed significantly poorer in FTSTS and TURN (both p<0.001), but not FR (p = 0.108). The significant determinants for the balance tasks varied substantially between tasks and groups. For the diabetes group, they included visual and plantar sensitivity and MMSE for FR (R2 = 0.39), ankle dorsiflexion strength for FTSTS (R2 = 0.377), and plantar sensitivity, knee extension strength and MMSE for TURN (R2 = 0.391). For the control group, knee extension strength emerged as the common and only significant determinant and only explained approximately 10% of the variance for FR and TURN. CONCLUSIONS: Impairments in functional balance abilities were evident for older adults with diabetes. Their underpinning functional limitations were different for different tasks and were also different from those of the control group. Screening of functional balance and mental status, lower limb strength and sensory function, and interventions to address these impairments may be important to maintain function, independence and safety for older clients with diabetes. PMID- 27467388 TI - Prevalence and Associated Clinical Characteristics of Exercise-Induced ST-Segment Elevation in Lead aVR. AB - BACKGROUND: Exercise-induced ST-segment elevation (STE) in lead aVR may be an important indicator of prognostically important coronary artery disease (CAD). However, the prevalence and associated clinical features of exercise-induced STE in lead aVR among consecutive patients referred for exercise stress electrocardiography (ExECG) is unknown. METHODS: All consecutive patients receiving a Bruce protocol ExECG for the diagnosis of CAD at a tertiary care academic center were included over a two-year period. Clinical characteristics, including results of coronary angiography, were compared between patients with and without exercise-induced STE in lead aVR. RESULTS: Among 2227 patients undergoing ExECG, exercise-induced STE >=1.0mm in lead aVR occurred in 3.4% of patients. Patients with STE in lead aVR had significantly lower Duke Treadmill Scores (DTS) (-0.5 vs. 7.0, p<0.01) and a higher frequency of positive test results (60.2% vs. 7.3%, p<0.01). Furthermore, patients with STE in lead aVR were more likely to undergo subsequent cardiac catheterization than those without STE in lead aVR (p<0.01, odds ratio = 4.2). CONCLUSIONS: Among patients referred for ExECG for suspected CAD, exercise-induced STE in lead aVR was associated with a higher risk DTS, an increased likelihood of a positive ExECG, and referral for subsequent coronary angiography. These results suggest that exercise-induced STE in lead aVR may represent a useful ECG feature among patients undergoing ExECG in the risk stratification of patients. PMID- 27467389 TI - Conquering Neutrophils. PMID- 27467390 TI - Rapid Extraction and Identification of Maitotoxin and Ciguatoxin-Like Toxins from Caribbean and Pacific Gambierdiscus Using a New Functional Bioassay. AB - BACKGROUND: Ciguatera is a circumtropical disease produced by polyether sodium channel toxins (ciguatoxins) that enter the marine food chain and accumulate in otherwise edible fish. Ciguatoxins, as well as potent water-soluble polyethers known as maitotoxins, are produced by certain dinoflagellate species in the genus Gambierdiscus and Fukuyoa spp. in the Pacific but little is known of the potential of related Caribbean species to produce these toxins. METHODS: We established a simplified procedure for extracting polyether toxins from Gambierdiscus and Fukuyoa spp. based on the ciguatoxin rapid extraction method (CREM). Fractionated extracts from identified Pacific and Caribbean isolates were analysed using a functional bioassay that recorded intracellular calcium changes (Ca2+) in response to sample addition in SH-SY5Y cells. Maitotoxin directly elevated Ca2+i, while low levels of ciguatoxin-like toxins were detected using veratridine to enhance responses. RESULTS: We identified significant maitotoxin production in 11 of 12 isolates analysed, with 6 of 12 producing at least two forms of maitotoxin. In contrast, only 2 Caribbean isolates produced detectable levels of ciguatoxin-like activity despite a detection limit of >30 pM. Significant strain-dependent differences in the levels and types of ciguatoxins and maitotoxins produced by the same Gambierdiscus spp. were also identified. CONCLUSIONS: The ability to rapidly identify polyether toxins produced by Gambierdiscus spp. in culture has the potential to distinguish ciguatoxin producing species prior to large-scale culture and in naturally occurring blooms of Gambierdiscus and Fukuyoa spp. Our results have implications for the evaluation of ciguatera risk associated with Gambierdiscus and related species. PMID- 27467391 TI - Proteomic Analysis of the Excretory and Secretory Proteins of Haemonchus contortus (HcESP) Binding to Goat PBMCs In Vivo Revealed Stage-Specific Binding Profiles. AB - Haemonchus contortus is a parasitic gastrointestinal nematode, and its excretory and secretory products (HcESPs) interact extensively with the host cells. In this study, we report the interaction of proteins from HcESPs at different developmental stages to goat peripheral blood mononuclear cells (PBMCs) in vivo using liquid chromatography-tandem mass spectrometry. A total of 407 HcESPs that interacted with goat PBMCs at different time points were identified from a H. contortus protein database using SEQUEST searches. The L4 and L5 stages of H. contortus represented a higher proportion of the identified proteins compared with the early and late adult stages. Both stage-specific interacting proteins and proteins that were common to multiple stages were identified. Forty-seven interacting proteins were shared among all stages. The gene ontology (GO) distributions of the identified goat PBMC-interacting proteins were nearly identical among all developmental stages, with high representation of binding and catalytic activity. Cellular, metabolic and single-organism processes were also annotated as major biological processes, but interestingly, more proteins were annotated as localization processes at the L5 stage than at the L4 and adult stages. Based on the clustering of homologous proteins, we improved the functional annotations of un-annotated proteins identified at different developmental stages. Some unnamed H. contortus ATP-binding cassette proteins, including ADP-ribosylation factor and P-glycoprotein-9, were identified by STRING protein clustering analysis. PMID- 27467393 TI - Does Facial Amimia Impact the Recognition of Facial Emotions? An EMG Study in Parkinson's Disease. AB - According to embodied simulation theory, understanding other people's emotions is fostered by facial mimicry. However, studies assessing the effect of facial mimicry on the recognition of emotion are still controversial. In Parkinson's disease (PD), one of the most distinctive clinical features is facial amimia, a reduction in facial expressiveness, but patients also show emotional disturbances. The present study used the pathological model of PD to examine the role of facial mimicry on emotion recognition by investigating EMG responses in PD patients during a facial emotion recognition task (anger, joy, neutral). Our results evidenced a significant decrease in facial mimicry for joy in PD, essentially linked to the absence of reaction of the zygomaticus major and the orbicularis oculi muscles in response to happy avatars, whereas facial mimicry for expressions of anger was relatively preserved. We also confirmed that PD patients were less accurate in recognizing positive and neutral facial expressions and highlighted a beneficial effect of facial mimicry on the recognition of emotion. We thus provide additional arguments for embodied simulation theory suggesting that facial mimicry is a potential lever for therapeutic actions in PD even if it seems not to be necessarily required in recognizing emotion as such. PMID- 27467392 TI - Heterologous Infection of Pregnant Mice Induces Low Birth Weight and Modifies Offspring Susceptibility to Malaria. AB - Pregnancy malaria (PM) is associated with poor pregnancy outcomes, and can arise due to relapse, recrudescence or a re-infection with heterologous parasites. We have used the Plasmodium chabaudi model of pregnancy malaria in C57BL/6 mice to examine recrudescence and heterologous infection using CB and AS parasite strains. After an initial course of patent parasitemia and first recrudescence, CB but not AS parasites were observed to recrudesce again in most animals that became pregnant. Pregnancy exacerbated heterologous CB infection of AS experienced mice, leading to mortality and impaired post-natal growth of pups. Parasites were detected in placental blood without evidence of sequestration, unlike P. falciparum but similar to other malaria species that infect pregnant women. Inflammatory cytokine levels were elevated in pregnant females during malaria, and associated with intensity of infection and with poor outcomes. Pups born to dams during heterologous infection were more resistant to malaria infections at 6-7 weeks of age, compared to pups born to malaria-experienced but uninfected dams or to malaria-naive dams. In summary, our mouse model reproduces several features of human PM, including recrudescences, heterologous infections, poor pregnancy outcomes associated with inflammatory cytokines, and modulation of offspring susceptibility to malaria. This model should be further studied to explore mechanisms underlying PM pathogenesis. PMID- 27467394 TI - Increased Hepatitis E Virus Seroprevalence Correlates with Lower CD4+ Cell Counts in HIV-Infected Persons in Argentina. AB - Hepatitis E virus (HEV) is a single-stranded RNA virus that can cause hepatitis in an epidemic fashion. HEV usually causes asymptomatic or limited acute infections in immunocompetent individuals, whereas in immunosuppressed individuals such as transplant recipients, HEV can cause chronic infections. The risks and outcomes of HEV co-infection in patients infected with human immunodeficiency virus (HIV) are poorly characterized. We used a third generation immunoassay to measure serum IgG antibodies specific for HEV in 204 HIV-infected individuals from Argentina and a control group of 433 HIV-negative individuals. We found 15 of 204 (7.3%, 95%CI 3.74-10.96%) individuals in the HIV-positive group to have positive HEV IgG levels suggestive of previous infection, compared to 19 of 433 (4.4%, 95% CI 2.5-6.3%) individuals in the HIV-negative control group (p = 0.12). Among HIV-positive individuals, those with HEV seropositivity had lower CD4 counts compared to those that were HEV seronegative (average CD4 count of 234 vs 422 mm3, p = 0.01), indicating that patients with lower CD4 counts were more likely to be HEV IgG positive. Moreover, HEV seropositivity in patients with CD4 counts <200 mm3 was 16%, compared to 4.5% in those with CD4 counts >200 mm3 (p = 0.012). We found a positive PCR result for HEV in one individual. Our study found that increased seroprevalence of HEV IgG correlated with lower CD4 counts in HIV-infected patients in Argentina. PMID- 27467395 TI - Domesticated Animal Biobanking: Land of Opportunity. AB - In the past decade, biobanking has fuelled great scientific advances in the human medical sector. Well-established domesticated animal biobanks and integrated networks likewise harbour immense potential for great scientific advances with broad societal impacts, which are currently not being fully realised. Political and scientific leaders as well as journals and ethics committees should help to ensure that we are well equipped to meet future demands in livestock production, animal models, and veterinary care of companion animals. PMID- 27467396 TI - Home-based rehabilitation improves exercise capacity and reduces respiratory symptoms in people with COPD (PEDro synthesis). PMID- 27467398 TI - Addressing psychosocial issues in cancer survivorship: past, present and future. AB - With a burgeoning population of cancer survivors, organizations in the USA and around the world are considering how to address the many long-term and late psychosocial effects of cancer and cancer treatment. This article reviews the changing landscape of survivorship care over the past 50 years, from the time when there were relatively few survivors to the future, when the number of cancer survivors in the USA alone is expected to reach close to 20 million. Institute of Medicine Reports, intra-organizational summits and accrediting standards that have influenced the development of survivorship care plans and programs and the roles of the Internet and smartphone applications along with oncology specialist and primary care providers are discussed. PMID- 27467397 TI - Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates. AB - Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with beta-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance. PMID- 27467400 TI - Survey of parent and carer experiences and expectations of paediatric rheumatology care in New South Wales. AB - Objective The aim of the present survey of parent and carers was to document the level of care and services currently provided to children diagnosed with rheumatic diseases (RD) in New South Wales (NSW), Australia. Methods The survey included parents and carers of children presenting to paediatric rheumatology (PR) services in NSW. Subjects attending PR clinics in both public and private settings were invited to participate in an online or paper survey. Results Overall, 148 surveys were completed. The process of obtaining the diagnosis of RD was described as being 'difficult' or 'very difficult' by 56.1% (n=83) of the surveyed cohort, and 41.2% (n=61) saw four or more different clinicians before diagnosis. Between symptom onset and final diagnosis, 42.6% (n=63) of participants reported a delay of 5 months or more, and 16.9% (n=25) waited longer than 12 months. Eventually, 91% (n=134) were referred to a paediatric rheumatologist and 63.5% (n=94) were seen within 4 weeks from initial referral. More than half the respondents felt that general practitioners (GPs) and general paediatricians were not aware of RD. Overall, respondents felt that improved knowledge of PR diseases among GPs, improved access to PR clinics, improved educational materials for patients and families, access to speciality rheumatology nurses and coordinated rheumatology teams would have significantly improved the experience of their child's disease. Conclusions Children with RD in NSW still experience significant delays from symptom onset to final diagnosis through consultations with multiple healthcare professionals. Multidisciplinary team care was not the norm for this patient group, despite established national and international management standards. What is known about the topic? Early diagnosis and management by a multidisciplinary team is the gold standard in PR management. Delays in diagnosis may significantly impair the outcomes of children diagnosed with RD, with reduced quality of life, increased pain level and worse long-term prognosis. What does this paper add? Children diagnosed with RD in NSW endure significant delays from symptom onset until a final diagnosis is made, with multiple consultations with different healthcare professionals. When the referral to PR services in NSW is made, RD children are mostly seen within 4 weeks, faster than other international standards. GPs and paediatric rheumatologists in NSW helped improve the children's and their family's experience of the diagnosis and treatment of a rheumatic condition and better informed them using appropriate educational materials. What are the implications for practitioners? This paper provides new evidence to practitioners to increase their knowledge of the current experiences and expectation of the paediatric rheumatology care in NSW. PMID- 27467399 TI - Autophagy regulates cytoplasmic remodeling during cell reprogramming in a zebrafish model of muscle regeneration. AB - Cell identity involves both selective gene activity and specialization of cytoplasmic architecture and protein machinery. Similarly, reprogramming differentiated cells requires both genetic program alterations and remodeling of the cellular architecture. While changes in genetic and epigenetic programs have been well documented in dedifferentiating cells, the pathways responsible for remodeling the cellular architecture and eliminating specialized protein complexes are not as well understood. Here, we utilize a zebrafish model of adult muscle regeneration to study cytoplasmic remodeling during cell dedifferentiation. We describe activation of autophagy early in the regenerative response to muscle injury, while blocking autophagy using chloroquine or Atg5 and Becn1 knockdown reduced the rate of regeneration with accumulation of sarcomeric and nuclear debris. We further identify Casp3/caspase 3 as a candidate mediator of cellular reprogramming and Fgf signaling as an important activator of autophagy in dedifferentiating myocytes. We conclude that autophagy plays a critical role in cell reprogramming by regulating cytoplasmic remodeling, facilitating the transition to a less differentiated cell identity. PMID- 27467402 TI - Allocation Based on Virtual Crossmatch Alone: Not Yet Ready for Primetime. PMID- 27467401 TI - Therapeutic Efficacy and Cost Effectiveness of High Cut-Off Dialyzers Compared to Conventional Dialysis in Patients with Cast Nephropathy. AB - BACKGROUND: High Cut-Off (HCO) dialysis membranes efficiently reduce serum free light chain (FLC) concentrations and may improve renal recovery and survival from multiple myeloma (MM) associated renal failure with cast nephropathy. However, clinical trials comparing dialysis with HCO versus conventional filters are lacking. The aim of this study was to assess clinical outcomes and economic impact of HCO dialyzers compared to conventional hemodialysis membranes in cast nephropathy. METHODS: Multicenter retrospective analysis of 19 patients treated for renal failure from FLC associated cast nephropathy with standard induction chemotherapy (bortezomib/dexamethasone). We compared hemodialysis treatment with High Cut-Off (n = 12) versus conventional dialyzers (n = 7). Primary endpoint was survival; secondary endpoints were renal recovery, renal function and treatment costs. RESULTS: At 12 months, patient survival was 25% in the HCO group versus 0% in controls (p = NS). A tendency towards faster renal recovery (p = 0.066) and better renal function at 3, 6 and 12 months (p = 0.109) after diagnosis of MM was noted in the HCO group. Complete renal response rate was achieved in 10.5 and 0% of HCO and control patients, respectively, partial renal response in 15.8 and 5.3%, and minor renal response in 26.3 and 15.8%, respectively. Both patient survival and renal recovery were significantly correlated with the extent of free light chain (FLC) reduction in serum. Median treatment costs were CHF 230'000 and 223'000 (p = NS) in the HCO and control group, respectively. CONCLUSIONS: Hemodialysis treatment with HCO membranes for cast nephropathy tended towards better survival as well as faster and better recovery of renal function versus conventional dialyzers. Moreover, total medical costs were comparable between groups. In the absence of results from randomized prospective trials on this topic, the use of HCO dialyzers in patients with renal failure from cast nephropathy may be recommended. Prospective randomized trials are required. PMID- 27467403 TI - International Academy of Cardiology Annual Scientific Sessions 2016 21st World Congress on Heart Disease, Boston, Mass., USA, July 30-August 1, 2016: Abstracts. PMID- 27467404 TI - Ficolins Promote Fungal Clearance in vivo and Modulate the Inflammatory Cytokine Response in Host Defense against Aspergillus fumigatus. AB - Aspergillus fumigatus is an opportunistic fungal pathogen that causes severe invasive infections in immunocompromised patients. Innate immunity plays a major role in protection against A. fumigatus. The ficolins are a family of soluble pattern recognition receptors that are capable of activating the lectin pathway of complement. Previous in vitro studies reported that ficolins bind to A. fumigatus, but their part in host defense against fungal infections in vivo is unknown. In this study, we used ficolin-deficient mice to investigate the role of ficolins during lung infection with A. fumigatus. Ficolin knockout mice showed significantly higher fungal loads in the lungs 24 h postinfection compared to wild-type mice. The delayed clearance of A. fumigatus in ficolin knockout mice could not be attributed to a compromised recruitment of inflammatory cells. However, it was revealed that ficolin knockout mice exhibited a decreased production of proinflammatory cytokines in the lungs compared to wild-type mice following A. fumigatus infection. The impaired clearance and cytokine production in ficolin knockout mice was independent of complement, as shown by equivalent levels of A. fumigatus-mediated complement activation in ficolin knockout mice and wild-type mice. In conclusion, this study demonstrates that ficolins are important in initial innate host defense against A. fumigatus infections in vivo. PMID- 27467405 TI - Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to alpha-Synuclein. AB - The intrinsically disordered and amyloidogenic protein alpha-synuclein (AS) has been linked to several neurodegenerative states, including Parkinson's disease. Here, nanoelectrospray-ionization mass spectrometry (nano-ESI-MS), ion mobility (IM), and native top-down electron transfer dissociation (ETD) techniques are employed to study AS interaction with small molecules known to modulate its aggregation, such as epigallocatechin-3-gallate (EGCG) and dopamine (DA). The complexes formed by the two ligands under identical conditions reveal peculiar differences. While EGCG engages AS in compact conformations, DA preferentially binds to the protein in partially extended conformations. The two ligands also have different effects on AS structure as assessed by IM, with EGCG leading to protein compaction and DA to its extension. Native top-down ETD on the protein ligand complexes shows how the different observed modes of binding of the two ligands could be related to their known opposite effects on AS aggregation. The results also show that the protein can bind either ligand in the absence of any covalent modifications, such as oxidation. PMID- 27467406 TI - Effect of Elevated Intracranial Pressure on Amplitudes and Frequency Tuning of Ocular Vestibular Evoked Myogenic Potentials Elicited by Bone-Conducted Vibration. AB - OBJECTIVE: Recently, it could be demonstrated that an increased intracranial pressure causes a modulation of the air conducted sound evoked ocular vestibular evoked myogenic potential (oVEMP). The mechanism for this modulation is not resolved and may depend on a change of either receptor excitability or sound energy transmission. DESIGN: oVEMPs were elicited in 18 healthy subjects with a minishaker delivering 500 and 1000 Hz tone bursts, in supine and tilted positions. RESULTS: The study could confirm the frequency tuning of oVEMP. However, at neither stimulus frequency could a modulating effect of increased intracranial pressure be observed. CONCLUSION: These data suggest that the observed modulation of the oVEMP response by an increased intracranial pressure is primarily due to the effect of an increased intralabyrinthine pressure onto the stiffness of the inner ear contents and the middle ear-inner ear junction. Future studies on the effect of intracranial pressure on oVEMP should use air conducted sound and not bone-conducted vibration. PMID- 27467407 TI - Editorial: Charting Chemical Space: Challenges and Opportunities for Artificial Intelligence and Machine Learning. PMID- 27467408 TI - From Hits to Leads: Challenges for the Next Phase of Machine Learning in Medicinal Chemistry. PMID- 27467410 TI - Target-Driven Subspace Mapping Methods and Their Applicability Domain Estimation. AB - This work describes a methodology for assisting virtual screening of drugs during the early stages of the drug development process. This methodology is proposed to improve the reliability of in silico property prediction and it is structured in two steps. Firstly, a transformation is sought for mapping a high-dimensional space defined by potentially redundant or irrelevant molecular descriptors into a low-dimensional application-related space. For this task we evaluate three different target-driven subspace mapping methods, out of which we highlight the recent Correlative Matrix Mapping (CMM) as the most stable. Secondly, we apply an applicability domain model on the low-dimensional space for assessing confidentiality of compound classification. By a probabilistic framework the applicability domain approach identifies poorly represented compounds in the training set (extrapolation problems) and regions in the space where the uncertainty about the correct class is higher than normal (interpolation problems). This two-step approach represents an important contribution to the development of confident prediction tools in the chemoinformatics area, where the field is in need of both interpretable models and methods that estimate the confidence of predictions. PMID- 27467409 TI - Modeling Choices for Virtual Screening Hit Identification. AB - Making suitable modeling choices is crucial for successful in silico drug design, and one of the most important of these is the proper extraction and curation of data from qHTS screens, and the use of optimized statistical learning methods to obtain valid models. More specifically, we aim to learn the top-1 % most potent compounds against a variety of targets in a procedure we call virtual screening hit identification (VISHID). To do so, we exploit quantitative high-throughput screens (qHTS) obtained from PubChem, descriptors derived from molecular structures, and support vector machines (SVM) for model generation. Our results illustrate how an appreciation of subtle issues underlying qHTS data extraction and the resulting SVM models created using these data can enhance the effectiveness of solutions and, in doing so, accelerate drug discovery. PMID- 27467411 TI - Tree and Hashing Data Structures to Speed up Chemical Searches: Analysis and Experiments. AB - In many large chemoinformatics database systems, molecules are represented by long binary fingerprint vectors whose components record the presence or absence of particular functional groups or combinatorial features. For a given query molecule, one is interested in retrieving all the molecules in the database with a similarity to the query above a certain threshold. Here we describe a method for speeding up chemical searches in these large databases of small molecules by combining previously developed tree and hashing data structures to prune the search space without any false negatives. More importantly, we provide a mathematical analysis that allows one to predict the level of pruning, and validate the quality of the predictions of the method through simulation experiments. PMID- 27467412 TI - SketchSort: Fast All Pairs Similarity Search for Large Databases of Molecular Fingerprints. AB - Similarity networks of ligands are often reported useful in predicting chemical activities and target proteins. However, the naive method of computing all pairwise similarities of chemical fingerprints takes quadratic time, which is prohibitive for large scale databases with millions of ligands. We propose a fast all pairs similarity search method, called SketchSort, that maps chemical fingerprints to symbol strings with random projections, and finds similar strings by multiple masked sorting. Due to random projection, SketchSort misses a certain fraction of neighbors (i.e., false negatives). Nevertheless, the expected fraction of false negatives is theoretically derived and can be kept under a very small value. Experiments show that SketchSort is much faster than other similarity search methods and enables us to obtain a PubChem-scale similarity network quickly. PMID- 27467413 TI - Probabilistic Substructure Mining From Small-Molecule Screens. AB - Identifying the overrepresented substructures from a set of molecules with similar activity is a common task in chemical informatics. Existing substructure miners are deterministic, requiring the activity of all mined molecules to be known with high confidence. In contrast, we introduce pGraphSig, a probabilistic structure miner, which effectively mines structures from noisy data, where many molecules are labeled with their probability of being active. We benchmark pGraphSig on data from several small-molecule high throughput screens, finding that it can more effectively identify overrepresented structures than a deterministic structure miner. PMID- 27467414 TI - Visual Interpretation of Kernel-Based Prediction Models. AB - Statistical models are frequently used to estimate molecular properties, e.g., to establish quantitative structure-activity and structure-property relationships. For such models, interpretability, knowledge of the domain of applicability, and an estimate of confidence in the predictions are essential. We develop and validate a method for the interpretation of kernel-based prediction models. As a consequence of interpretability, the method helps to assess the domain of applicability of a model, to judge the reliability of a prediction, and to determine relevant molecular features. Increased interpretability also facilitates the acceptance of such models. Our method is based on visualization: For each prediction, the most contributing training samples are computed and visualized. We quantitatively show the effectiveness of our approach by conducting a questionnaire study with 71 participants, resulting in significant improvements of the participants' ability to distinguish between correct and incorrect predictions of a Gaussian process model for Ames mutagenicity. PMID- 27467415 TI - A Cyclized Helix-Loop-Helix Peptide as a Molecular Scaffold for the Design of Inhibitors of Intracellular Protein-Protein Interactions by Epitope and Arginine Grafting. AB - The design of inhibitors of intracellular protein-protein interactions (PPIs) remains a challenge in chemical biology and drug discovery. We propose a cyclized helix-loop-helix (cHLH) peptide as a scaffold for generating cell-permeable PPI inhibitors through bifunctional grafting: epitope grafting to provide binding activity, and arginine grafting to endow cell-permeability. To inhibit p53-HDM2 interactions, the p53 epitope was grafted onto the C-terminal helix and six Arg residues were grafted onto another helix. The designed peptide cHLHp53-R showed high inhibitory activity for this interaction, and computational analysis suggested a binding mode for HDM2. Confocal microscopy of cells treated with fluorescently labeled cHLHp53-R revealed cell membrane penetration and cytosolic localization. The peptide inhibited the growth of HCT116 and LnCap cancer cells. This strategy of bifunctional grafting onto a well-structured peptide scaffold could facilitate the generation of inhibitors for intracellular PPIs. PMID- 27467416 TI - Use of boron cluster-containing redox nanoparticles with ROS scavenging ability in boron neutron capture therapy to achieve high therapeutic efficiency and low adverse effects. AB - A boron delivery system with high therapeutic efficiency and low adverse effects is crucial for a successful boron neutron capture therapy (BNCT). In this study, we developed boron cluster-containing redox nanoparticles (BNPs) via polyion complex (PIC) formation, using a newly synthesized poly(ethylene glycol) polyanion (PEG-polyanion, possessing a (10)B-enriched boron cluster as a side chain of one of its segments) and PEG-polycation (possessing a reactive oxygen species (ROS) scavenger as a side chain of one of its segments). The BNPs exhibited high colloidal stability, selective uptake in tumor cells, specific accumulation, and long retention in tumor tissue and ROS scavenging ability. After thermal neutron irradiation, significant suppression of tumor growth was observed in the BNP-treated group, with only 5-ppm (10)B in tumor tissues, whereas at least 20-ppm (10)B is generally required for low molecular weight (LMW) (10)B agents. In addition, increased leukocyte levels were observed in the LMW (10)B agent-treated group after thermal neutron irradiation, and not in BNP treated group, which might be attributed to its ROS scavenging ability. No visual metastasis of tumor cells to other organs was observed 1 month after irradiation in the BNP-treated group. These results suggest that BNPs are promising for enhancing the BNCT performance. PMID- 27467417 TI - Cu(II) doped polyaniline nanoshuttles for multimodal tumor diagnosis and therapy. AB - Nanodevices for multimodal tumor theranostics have shown great potentials for noninvasive tumor diagnosis and therapy, but the libraries of multimodal theranostic building blocks should be further stretched. In this work, Cu(II) ions are doped into polyaniline (Pani) nanoshuttles (NSs) to produce Cu-doped Pani (CuPani) NSs, which are demonstrated as new multimodal building blocks to perform tumor theranostics. The CuPani NSs are capable of shortening the longitudinal relaxation (T1) of protons under magnetic fields and can help light up tumors in T1-weighted magnetic resonance imaging. In addition, the released Cu(II) ions from CuPani NSs lead to cytotoxicity, showing the behavior of chemotherapeutic agent. The good photothermal performance of CuPani NSs also makes them as photothermal agents to perform thermochemotherapy. By combining near-infrared laser irradiation, a complete tumor ablation is achieved and no tumor recurrence is observed. PMID- 27467418 TI - Non-viral gene activated matrices for mesenchymal stem cells based tissue engineering of bone and cartilage. AB - Recent regenerative medicine and tissue engineering strategies for bone and cartilage repair have led to fascinating progress of translation from basic research to clinical applications. In this context, the use of gene therapy is increasingly being considered as an important therapeutic modality and regenerative technique. Indeed, in the last 20 years, nucleic acids (plasmid DNA, interferent RNA) have emerged as credible alternative or complement to proteins, which exhibited major issues including short half-life, loss of bioactivity in pathologic environment leading to high dose requirement and therefore high production costs. The relevance of gene therapy strategies in combination with a scaffold, following a so-called "Gene-Activated Matrix (GAM)" approach, is to achieve a direct, local and sustained delivery of nucleic acids from a scaffold to ensure efficient and durable cell transfection. Among interesting cells sources, Mesenchymal Stem Cells (MSC) are promising for a rational use in gene/cell therapy with more than 1700 clinical trials approved during the last decade. The aim of the present review article is to provide a comprehensive overview of recent and ongoing work in non-viral genetic engineering of MSC combined with scaffolds. More specifically, we will show how this inductive strategy can be applied to orient stem cells fate for bone and cartilage repair. PMID- 27467420 TI - Pilot study measuring the effects of bandaging and cold compression therapy following tibial plateau levelling osteotomy. AB - OBJECTIVES: To compare cold compression therapy, modified Robert-Jones bandage or the combination of cold compression therapy plus modified Robert-Jones bandage on operated limbs following tibial plateau levelling osteotomy in dogs. METHODS: Twenty-one client-owned dogs with cranial cruciate ligament disease were prospectively enrolled. Dogs were randomly assigned to one of three postoperative treatment groups: cold compression therapy, modified Robert-Jones bandage or a combination of both. Patients were evaluated preoperatively and at 12, 24 and 36 hours following tibial plateau levelling osteotomy. Measurements included weight bearing on the operated limb, stifle flexion and extension angles and circumference of the operated limb at four levels. RESULTS: There was no significant difference in weight-bearing, range of motion or limb swelling between groups. There was a trend for dogs in the cold compression therapy and cold compression therapy with a bandage groups to have a greater increase in weight-bearing after surgery compared with the bandage-only group. CLINICAL RELEVANCE: Cold compression therapy is a safe modality following tibial plateau levelling osteotomy surgery. The trend towards improved use of the operated limb in the groups receiving cold compression therapy compared with those treated with only a bandage may be an indication that these patients are more comfortable in the postoperative period. The small sample size limits interpretation of the data but this pilot study provides data to guide future investigation. PMID- 27467421 TI - Down's Syndrome-Transient Abnormal Myelopoiesis and Acute Leukaemia. AB - Subjects with Down's syndrome have an increased risk, particularly during childhood, of developing acute leukaemia. There is an increased incidence both of acute lymphoblastic leukaemia and of acute myeloid leukaemia (AML), particularly acute megakaryoblastic leukaemia, often presenting with the clinical features of acute myelofibrosis. In addition neomates with Down's syndrome show a high incidence of polycythaemia and may also develope a syndrome simulating acute leukaemia, commonly designated transient abnormal myelopoiesis (TAM). Although TAM closely resembles acute leukaemia there are some subtle differences and infants who survive four to eight weeks usually show a complete remission. Subsequently a significant proportion of these infants develop AML usually around the age of 2 to 3 years. Cytogenetic evidence indicates that in at least some neonates with TAM the abnormal cells are monoclonal. The presence of a cytogenetically abnormal clone is not incompatible with subsequent complete remission with loss of the abnormal close and long survival. For these reasons it may be justifiable to regard TAM as transient acute myeloid leukaemia. Although other lineages are also involved in TAM the blast cells are usually predominantly megakaryoblasts. This, together with the predominance of megakaryoblastic leukaemia among cases of AML in Down's syndrome, suggests that abnormal proliferation of megakaryoblasts in specifically linked to the presence of a supernumerary chromosome 21. Further support for this hypothesis is provided by cases of TAM in subjects with mosaicism for trisomy 21 or for a related abnormality of chromosome 21; the abnormal proliferating cells are derived from the cytogenetically abnormal population. Additional factors are clearly necessary for the occurrence of TAM or AML in subjects with Down's syndrome but their nature is as yet unknown. PMID- 27467422 TI - T-Cell Blast Crisis in Chronic Myeloid Leukemia. AB - Involvement of T cells in chronic myeloid leukemia is a rare event. Twenty-one cases of T-cell lymphoid blast crisis of chronic myeloid leukemia reported in the literature are reviewed, and evidence for T-lineage involvement is evaluated. Patients present with a distinctive clinical phenotype. Most frequently they are young males with extensive extramedullary deposits of blast cells, rapidly progressive lymphadenopathy, organomegaly and pleural involvement. Clonal cytogenetic evolution is common and survival short. The identification of this phenotype may be of clinical and prognostic significance. PMID- 27467423 TI - Use of cDNA Probes for Typing Cells of B Lymphoid Lineage: Application of Early Response Genes to the Analysis of Mature B Cell Malignancies. AB - In vitro phorbol ester-induced plasmacytoid differentiation of primary B chronic lymphocytic leukaemia (BCLL) cells is accompanied by the rapid, transient increased expression of a large number of early response genes (ERGs) whose expression is highly cell type specific. We have examined phorbol ester responsive expression of a panel of 13 ERGs in a series of B cell lines representing different stages of differentiation and in primary malignant cells from patients with hairy cell leukaemia and with centroblastic-centrocytic non Hodgkin's lymphoma. The results revealed a spectrum of ERG expression which appeared to be correlated with stage of differentiation relative to BCLL cells, where no two cell types gave an identical ERG response. These results, while preliminary, suggest that panels of ERG probes provide a useful approach for analysis of cell type which may help in mapping stages of differentiation arrest and defining cell lineage relationships amongst mature B cell malignancies. PMID- 27467424 TI - A 20 Year Clinical and Laboratory Study of Familial B-Chronic Lymphocytic Leukemia in a Single Kindred. AB - Four siblings and a parent in a single kindred had documented blood and marrow lymphocytosis during the past 18 to 20 years consistent with chronic lymphocytic leukemia (CLL). Of the four siblings, one developed a spontaneous remission; one died secondary to subepiglotitis with sepsis; one died with prolymphocytoid transformation and one remains alive with splenomegalic CLL. Lymphadenopathy and splenomegaly were variable as was the clinical response to chemotherapy. Bone marrow morphology was initially nodular but progessed to diffuse patterns in both deceased siblings. Blood lymphocyte morphology was extremely variable as were cell doubling times and cytogenetic studies. ABO and HLA typing revealed no evidence of linkage. Immunophenotypic analysis of the B lymphocytes demonstrated a CD19 +, CD20-, CD5 +, Leu8-, Kappa + and a CD19 +, CD20 +, CD5 +, Leu8 +, Kappa + monoclonal lymphocytosis in two affected members. An unaffected sibling showed a CD4 lymphocytosis. VHV and VHII gene sequences were previously described in this kindred (PNAS 84: 8563, '87). We speculate that a CD5 B cell and CD4 T cell lymphocytosis may arise early in this disease followed by the development of a pleomorphic, monoclonal lymphocytosis. The subsequent oligomorphic, monoclonal lymphocytosis shows genotypic, immunophenotypic and some morphological heterogeneity consistent with ongoing differentiation. The longitudinal investigation of familial CLL offers a unique opportunity to study the sequence of events related to the natural history of B-CLL. PMID- 27467425 TI - Esterase Isoenzyme Profiles in Acute and Chronic Leukemias. AB - Using isoelectric focusing (IEF) a number of carboxylic esterase isoenzymes (EC 3.1.1.1) with isoelectric points between pH 4.5-8.0 can be separated. One particular isoenzyme with an isoelectric point at about pH 6.0, the Mono-band, can be selectively and completely inhibited by sodium fluoride; this isoenzyme comprises a number of closely related subcomponents and may appear in more than one band on the gel. We analyzed the expression of typical esterase isoenzyme patterns in cells from a large panel of leukemias which were tested under identical conditions by IEF on horizontal thin-layer polyacrylamide gels with an ampholyte of pH 2-11. The 442 cases of acute and chronic myeloid and lymphoid leukemia (AML/AMMoL, CML/CMML, ALL, CLL) were classified according to clinical, morpho-cytochemical and immunophenotyping criteria. While bands between pH 4.5 5.5 appeared not to be specific for lineage or stage of differentiation, isoenzymes between pH 6.6-7.7 provided information on the type of leukemia involved. Seven typical isoenzyme patterns termed Mono1/Mono2 (fo monocyte associated), My1/My2 (myeloid), Lym1/Lym2 (lymphoid) and Und (undifferentiated) could be discerned. Lym and Und patterns are characterized by fewer bands with a weaker staining intensity than Mono and My patterns. Nearly all cases of lymphoid leukemias (acute and chronic) expressed only Lym or Und esterase isoenzyme patterns, but no Mono or My patterns. Cases of acute or chronic myeloid and (myelo)monocytic leukemia showed strong isoenzyme staining displaying predominantly Mono or My isoenzyme patterns. The isoenzyme patterns found in CML in lymphoid or myeloid blast crisis corresponded to those seen in the respective acute leukemias, ALL or AML. The Mono-band was found in most cases of leukemias with monocytic elements (AMMoL 80%, CML 44%, CMML 100%), in the occasional case of CML-myeloid blast crisis or AML, but in none of the cases of ALL or CLL. This isoenzyme is a distinctive, specific marker for leukemias of monocytic origin and is of discriminatory value for the differentiation of monocytic from non monocytic leukemia variants. Esterase isoenzyme profiles can give additional evidence on the origin and stage of differentiation of leukemic cells. PMID- 27467426 TI - A Randomized Comparison of Doxorubicin and Doxorubicin-DNA in the Treatment of Acute NonLymphoblastic Leukemia. AB - In the light of previous findings that treatment of leukemia patients with DNA linked doxorubicin gave higher doxorubicin concentrations in leukemic cells than treatment with doxorubicin alone, the Leukemia Group of Middle Sweden performed a randomized clinical trial to compare the effects of doxorubicin and doxorubicin DNA in patients with acute non-lymphoblastic leukemia. One hundred and twenty consecutive patients within the age range 15 to 60 years were randomized to one of three treatment groups. In two of these, remission induction treatment was performed with prednisolone, vincristine, ara-C and thioguanine combined with either doxorubicin or doxorubicin-DNA. Patients entering a complete remission received intensive consolidation during 16 months with 4 courses each of doxorubicin (+/ - DNA)/ara-C, doxorubicin (+/ - DNA)/azacytidine, ara-C and amsacrine. The third treatment group followed a protocol from a previous study with daunorubicin and ara-C for induction therapy and a less intensive maintenance therapy. No further patients were assigned to this "control" group after 3 years or to the two other groups after 6 years. This report is based on a follow-up 31 months thereafter. The overall rate of complete remission was 67% and the mean time to complete remission was 71 days, with no differences between the treatment groups. Patients treated with the doxorubicin-DNA conjugate had a significantly longer survival [median for all patients 27.2 months (p < 0.01) and for patients in CR 47.0 months (p < 0.025)] and longer duration of first remission (median 23.6 months, p < 0.025) than the other groups. There were significantly fewer reports of cardiotoxicity (p < 0.05) and severe intestinal toxicity (p < 0.02) in patients treated with the doxorubicin-DNA conjugate and there was a tendency towards less hepatic (p < 0.08) and renal toxicity (p < 0.08). The frequency of myelosuppression, fever and infectious complications was similar in all three groups. Complex binding to DNA appears to increase the therapeutic effects and reduce some toxic effects of doxorubicin in patients with ANLL. PMID- 27467427 TI - Acute Myeloid Leukemia in Children Less Than Two Years Old: Clinical, Cytologic and Cytogenetic Correlations Comparison with other age categories. A clinical survey of 39 cases. AB - Thirty-nine children under two years of age with newly diagnosed Acute Myeloid Leukemia (AML) were consecutively admitted to the Hopital Saint-Louis (Paris) over a ten-year period (1978-1987). Nineteen were under one year of age at diagnosis and 3 had congenital leukemia. Comparison of FAB sub-classes among the different age categories showed that AML with a monocytic component (M4 and M5) (44%), and AML with megakaryocytic elements (M7) (21%), were much more frequent in children before the age of two years. This comparison was made on a series of 1409 AML and 859 ALL diagnosed in the same hospital during a twelve years period of time. During this period of observation, the compared incidence of ALL and AML showed 50% for each category for children under 2 years, 73% ALL versus 27% AML for children under 15 years, and 18% ALL versus 82% AML for adults. Of the 29 cases subjected to cytogenetic study, 62% had clonal chromosomal abnormalities, the most frequent being a translocation involving the long arm of chromosome 11. With a 72 months median follow-up for patients who are still alive, the 6-year actuarial survival was 23%, while the event free interval for Complete Remission (CR) patients was 35%. For the M4-M5 subgroup, these results were 37% and 50% respectively with a plateau reached at 27 months. M4-M5 FAB types represented the most common leukemia at this age, and these usually correlated with translocation of the long arm of chromosome 11. We obtained an unexpectedly high rate of survival, with acceptable sequellae, for children treated with intensive chemotherapy. PMID- 27467429 TI - Measurement of Soluble Interleukin 2 Receptor in Sera of Adult Patients with Hematological or Solid Malignancies. AB - Interleukin 2 (IL-2) exerts its biological activity through a specific membrane receptor. Using specific monoclonal antibodies directed against the IL-2 receptor, a soluble form of this receptor can be detected in the serum. This soluble part of the human IL-2 receptor (sIL-2R) is released by T and B lymphocytes and plays a role in lymphoid cell growth regulation. We have measured the sIL-2R by ELISA in the serum of patients with solid tumors and with hematological malignancies (44 chronic lymphocytic leukemias (CLL), 5 hairy cell leukemias (HCL), 14 Hodgkin's diseases (HKD), 34 non-Hodgkin's lymphomas (NHL) and 19 acute lymphoblastic leukemias (ALL). The mean sIL-2R level in 40 normal subjects was 173 + 168 U/ml (mean {pminus} SD). It was considerably increased in HCL: 17938 {pminus} 23748 (P < 0.0003). In CLL, a significant increase was found which was particularly pronounced at clinical stage III and IV with a mean level of 1299 {pminus} 1127 U/ml. In HKD, sIL-2R was slightly but significantly increased 519 + 524 U/ml (P < 0.0004). In NHL, the sIL-2R level was 1015 {pminus} 1022 U/ml, but this increase did not correlate with the clinical stage or the histological grade of the disease. In ALL, sIL-2R levels were also significantly increased 1633 + 1046 U/ml (P < 0.00001). In 69 patients with solid tumors (including lung carcinomas, gynecological and digestive malignancies), 39% of the patients tested had slightly increased sIL-2R levels. However, this increase, when present, could not be related to the tumor histology. These results suggest that sIL-2R measurement is a poor diagnostic marker for solid tumors and some lymphoproliferative disorders. However, in patients with hematological malignancies, it could be a useful tool to monitor lymphoid neoplasias. PMID- 27467430 TI - Primary Non-Hodgkin's Lymphomas of the Nasal and Mouth Cavity and the Waldeyer's Ring: A morphological and immunohistochemical study. AB - Twenty-six non-Hodgkin's malignant lymphomas (ML) of the Waldeyer's ring, the mouth and nasal cavities were studied morphologically and immunohistochemically on paraffin and frozen sections. A B-cell origin was shown in all 14 cases of Waldeyer's ring M.L., while 5 of 7 nasal and 3 of 5 buccal cases were of T-cell nature. Seventy-nine per cent of all the above ML were high-grade malignancies. Combined morphological and immunohistochemical studies of such malignant lymphomas in Western populations have been reported rarely and are rather limited. The documentation of the first nasal and buccal cases of anaplastic Ki-1 positive peripheral T-cell ML is emphasised in conjunction with the more frequent carcinomas of the same anatomical areas under consideration. PMID- 27467428 TI - Hodgkin's Disease in 50 Intravenous Drug Users with HIV-Infection. AB - Fifty cases of Hodgkin's disease in intravenous drug users (IVDU) have been collected by the Italian Cooperative Group on AIDS-Related Tumors (G.I.C.A.T.). Ninety-two per cent of the patients were males; the median age was 26 years. Persistent generalized lymphadenopathy (PGL) at onset was present in 54% of patients, AIDS in 9%, ARC in 9% while 28% were simply HIV-positive. The initial median absolute number of CD4 lymphocytes was 264/mmc. Opportunistic infections were diagnosed in 20% of patients. In most patients the histological pattern was that of mixed cellularity and lymphocytic depletion (76%). In almost half the initial symptom was a persistent lymph node enlargement due to PGL. In the majority of patients (58%) only a clinical staging and bone marrow biopsy could be performed due to the presence of opportunistic infections, rapid disease progression or refusal of pathologic staging procedures. One patient presented with a Waldeyer's ring involvement, but no other unusual presentations were observed. After MOPP alternated or followed by ABVD or MOPP alone, 15/29 CR (52%) and 14/29 PR (48%) were observed. The median duration of CR was 14 months, while the median survival of CR has not been reached; the median survival of patients treated with chemotherapy with CD4 values at presentation {geq}400/mmc was significantly superior to that in those with CD4 < 400/mmc. The overall median survival was 16 months. Twenty-eight per cent of patients receiving chemotherapy + radiotherapy developed opportunistic as well as non-opportunistic infections (21%). Lethal hepatic toxicity was observed in 2 patients. In conclusion, Hodgkin's disease in IVDU was not found to be associated with unusual presentations, as previously reported for homosexuals. Complete remissions could be achieved in over 50% of patients, but in IVDU non-opportunistic infections in addition to opportunistic infections may also limit treatment administration. The presence of parenchymal functional impairment due to drug abuse, or drug abuse related infections, such as pneumonia, endocarditis and hepatitis, should lead to the choice of antitumour agents with no or only minor potential liver, lung and cardiac toxicity. PMID- 27467431 TI - Survival of T- and B-Phenotype Diffuse Aggressive Non-Hodgkin's Lymphomas. AB - Survival of immunophenotyped non-Hodgkin's lymphomas (NHLs) diagnosed as diffuse mixed, diffuse large and large cell immunoblastic by the working formulation was evaluated based on phenotypic categories. These subtypes were grouped as diffuse aggressive NHLs due to their similarities, and categorized into T- and B phenotype NHLs. There were 45 (57.7%) cases of T-NHL and 33 (42.3%) B-NHL. Major clinical factors such as sex, age, stage, B-symptoms and site of disease, as well as performance status (PS), LDH, primary site and number of extra-nodal sites involved showed equal distributions between T- and B-NHLs. Combination chemotherapeutic regimens based on doxorubicin were used in 84% of these cases. Complete remission was achieved in 73.6% of T-NHL and 74.1% of B-NHL. Median survival for the T- and B-NHL was the same over 30 months. Projected survival at 5 years was also similar, T-NHL (35%) and B-NHL (38%). Unilaterally, survival was adversely affected in stage III/IV of T-NHL and for age over 65 years for B-NHL. Survival was unfavorable for the B-NHL without B-symptoms when compared to T NHLs. Multivariately, only sex, B-symptoms and PS significantly (P < 0.05) affected the survival of T-NHL. Although the overall results indicate that the response and survival of T- and B-NHL are similar, the differences observed on the effect of sex, age, stage, B-symptoms and PS on survival of T- and B-NHLs imply that, their influence on T-NHLs was different from that for B-NHLs. Therefore we suggest that separate prognostic models are needed for the T- and B phenotype NHLs. PMID- 27467432 TI - Does the Therapy According to Stage Improve Response and Survival in Multiple Myeloma Patients? AB - The records of 104 patients (1972-80) with Multiple Myeloma (MM) were reviewed and a staging system was used dividing patients into Low Risk (LR) and High Risk (HR) groups, according to individual factors. Serum-calcium and serum creatinine, haemoglobin and the percentage of bone marrow plasma cells (BMPC), at the time of diagnosis, had predictive value on survival. This group of patients had already received treatment independent of these risk categories. Subsequently during 1980 to 1988, 114 evaluable patients with MM entered a prospective study using two treatment regimens according to that same staging system: LR patients were treated with Melphalan + Prednisone (MP) and HR patients with Vincristine, Melphalan, Cyclophosphamide and Prednisone (VMCP) for a minimum of six cycles. In the event of no response to the initial therapy given, a more aggressive regimen was then used: VMCP for LR patients and VAP or BAP (Vincristine or BCNU, Adriamycin, Prednisone) for the HR group for six to twelve cycles. The rate of response for Low and High Risk category was 42% and 73%, respectively. The median duration of response to initial therapy was 19 months for LR and 11 months for HR patients. Furthermore therapy chosen according to stage resulted in an improvement in survival compared to the earlier 1972-80 series. This was particularly significant for HR patients who benefited by an obvious decrease in the number of early deaths, due to progression of disease, when the combined regimens were used. The study indicates that therapy according to risk categories seems to be a worthwhile approach, MP being an appropriate initial treatment for LR while combination chemotherapy may be better for HR patients. PMID- 27467433 TI - Dysmyelopoietic Features and Bone Marrow Histology in 30 Cases of Primary Myelodysplastic Syndromes. AB - Thirty cases of primary myelodysplastic syndromes (MDS) were diagnosed according to the FAB criteria. The age ranged between 5-78 years, the median age being 38 years. Twelve (40%) patients were younger than 30 years of age. Male female ratio was 2:1. Nine cases each were diagnosed as refractory anaemia (RA) and refractory anaemia with excess of blasts (RAEB) whereas 12 were diagnosed as RAEB in transformation (RAEB-T). Significantly more RA and RAEB-T cases showed dyserythropoietic features when compared to RAEB. The frequency of dysgranulopoiesis and dysmegakaryopoiesis was similar in all 3 FAB subgroups. Abnormal localisation of immature precursors (ALIP) was present in only 36.6% of the patients and was seen in 58.3% of RAEB-T. When present it appeared to indicate a worse prognosis. Six of the 12 cases showing this finding progressed either to acute myeloblastic leukemia or from RA to RAEB or RAEB-T. PMID- 27467434 TI - Cytogenetic Studies in Patients with Acute Myeloid Leukemia Following a Myelodysplastic Syndrome. AB - Between 1981 and 1988, thirty-nine patients with acute myeloid leukemia (AML) following a de novo myelodysplastic syndrome (n-MDS) were studied cytogenetically. The chromosomal aberration rate was 59%. The anomalies most often found were: complex (four or more) aberrations (n = 6), a 5q- chromosome (n = 6), monosomy 7 or a 7q- chromosome and trisomy 8 as the sole defect (n = 3). Incidence and types of chromosomal aberrations were approximately the same as in myelodysplastic syndromes and in 191 patients with de novo AML studied in our laboratory during the same period. But the cytogenetic pattern in AML post de novo MDS also shared certain similarities with chromosomal findings in 35 patients with secondary, therapy-induced (t) AML/MDS. In both these types of acute leukemia primary changes such as t(8;21), t(15;17) and inv (16) were not found; the frequency of AA-Karyotypes was high (70 and 66%) and the incidence of 5,5q- in AML post de novo MDS was more comparable with that found in t-AML/MDS than in de novo AML. Thus the chromosomal patterns seen in AML post de novo MDS indicate that these leukemias share similarities with both de novo and t-AML not only clinically but also cytogenetically. PMID- 27467435 TI - Plasma Lactoferrin Concentration in Acute Non-Lymphocytic Leukaemia (ANLL). AB - Plasma lactoferrin concentration was measured in 46 patients with acute non lymphoblastic leukaemia. In 8/46 (17%) elevated lactoferrin concentrations, above the upper limit of normal (450 {mu}g/1), were found. Elevated plasma lactoferrin concentrations were associated with a significantly reduced chance of achieving CR (1/8; 12.5%) as compared to those with normal (100-450 {mu}g/1) or low (<100 {mu}g/1) lactoferrin concentrations (CR rate 27/38; 71%). Elevated plasma lactoferrin concentrations were associated with higher peripheral blast cell counts but with low polymorph counts suggesting origin of the lactoferrin from partially differentiated cells originating from the leukaemic clone. The failure to achieve CR among patients with high lactoferrin values was associated with death in aplasia suggesting further that elevated plasma lactoferrin may define a group of patients with little residual normal heamopoetic reserve. PMID- 27467436 TI - Co-infection with HIV-I and HTLV-I/II In Intravenous Drug Users in Suburban New York City, With Comparison to Other Geographic Areas. AB - Co-infection with human T-lymphotropic virus types I or II (HTLV-I or -II) may be a cofactor in the progression of human immunodeficiency virus (HIV) infection. We assessed the frequency of simultaneous infection with these retroviruses among intravenous drug users from Westchester County, N.Y., a suburb of New York City. Comparison was made with similar studies in the United States and Europe. PMID- 27467437 TI - Recombinant Interferon Alpha-2b in Patients with Progressive and/or Recurrent Hodgkin's Disease. AB - Six patients were included in a trial involving the SC administration of rIFN{alfa)-2b (Schering Plough) at a dose of 5 {multi} 10(6) IU daily, 5 days a week and continued while a clinical response was observed. All patients had previously received between 3 to 5 salvage chemotherapy programs without a disease free interval prior to the administration of rIFN{ALFA}-2b. Two patients had extranodal disease (lung, bone) and all 6 patients had "B" symptoms. Five of the patients showed stable disease, for a period of 3 to 12 months. One patient with recurrent HD obtained partial remission which lasted 26 months, at which time he developed autoimmune hemolytic anemia. Toxicities observed were mild and consisted of a flulike syndrome, supraventricular tachycardia and mild increase in transaminases. The quality of life improved while on rIFN{ALFA}-2b therapy, contrasting with the toxicity of the aggressive chemotherapy regimens previously administered which required frequent hospitalizations. This preliminary experience suggests that the role of rIFN{ALFA}-2b in the treatment of HD requires more study. PMID- 27467438 TI - Pre-B Acute Lymphoblastic Leukemia During a Complete Remission in T-Acute Lymphoblastic Leukemia. AB - This case provides evidence for a phenotypic switch from a characteristic T-ALL into a typical pre-B ALL. A 17 years old boy presented with massive hepatosplenomegaly and a mediastinal mass. The blasts were characterized as L2 type according to the French, American and British (FAB) classification and the staining with acid phosphatase was positive. The immunophenotype was CD2 +, CD5 +, CD7 + and CD10 -. The patient achieved a complete remission but relapsed 4 years later. At relapse, a striking immunological shift was apparent. The blast cells were now morphologically LI subtype and displayed the CD10 +. C{mew} + phenotype but were CD2 -, CD5 -, CD7 -. These findings are consistent with a transformation of the initial clone although the development of a second leukemia in the same patient could not be excluded with complete certainty. PMID- 27467439 TI - Chromosome 14 Abnormality with a Breakpoint of p12 in Adult T-cell Leukemia. AB - We describe a patient with adult T-cell leukemia (ATL) with a 14p chromosomal abnormality. Cytogenetic study revealed two clonal populations of leukemic cells in the peripheral blood sample. Both clones were karyotypically related to each other. One of them showed rearrangement of chromosome 14 at break band p 12 (14p12) in addition to + 3, + 7, -X and del(6) (q14q21). The nucleolar organizer region (NOR) is assigned to the band 14p12 and the role of the rearrangement of chromosome 14p12 in the pathogenesis of ATL is discussed. PMID- 27467441 TI - A systematic review on the impact of psychotropic drugs on electroencephalogram waveforms in psychiatry. AB - OBJECTIVES: It is known that psychotropic medications have an impact on the readings found in Electroencephalogram (EEG). In the field of psychiatry, there are several psychotropics utilized by clinicians. This review seeks to investigate all the available data for psychotropic drugs and their impact on EEG changes. METHODS: A systematic review of all the published and ongoing literature was conducted via PubMed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was used for each search. Key words for searches include 'EEG and Psychotropics', 'EEG and Mood Stabilizers', 'EEG and Clozapine', 'EEG and Bupropion', 'EEG and SSRI', 'EEG and Lamotrigine', 'EEG and Carbamazepine', 'EEG and Lithium' and 'EEG and Valproate', 'EEG and Haloperidol', 'EEG and Aripiprazole', 'EEG and Methylphenidate', 'EEG and Topiramate', 'EEG and Gabapentin' and 'EEG and Oxcarbamazepine'. After applying the inclusion criteria, 201 articles were eligible and reviewed. RESULTS: Following an extensive review of selected studies from the 201 articles, the studies indicate that each of the psychotropic medications reviewed impact alpha, beta, delta and theta waves independently and differently from each other. Additionally, certain medications, particularly haloperidol and valproic acid, have dissimilar results exemplified in all waveforms. CONCLUSIONS: This PRISMA systematic review illustrates that while there is available data on psychotropic medications and their proposed effect on EEG activity, further research is needed to confirm these findings to help allow clinical correlations to be made between the patient's response and the psychotropic agent. PMID- 27467440 TI - Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia. AB - Importance: Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment. Objective: To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family. Design, Setting, and Participants: We performed whole exome sequencing (WES) from peripheral lymphocyte DNA on 4 distant relatives from our multiplex, multigenerational familial Barrett esophagus family to identify candidate disease susceptibility variants. Gene variants were filtered, verified, and segregation analysis performed to identify a single candidate variant. Gene expression analysis was done with both quantitative real-time polymerase chain reaction and in situ RNA hybridization. A 3-dimensional organotypic cell culture model of esophageal maturation was utilized to determine the phenotypic effects of our gene variant. We used electron microscopy on esophageal mucosa from an affected family member carrying the gene variant to assess ultrastructural changes. Main Outcomes and Measures: Identification of a novel, germline disease susceptibility variant in a previously uncharacterized gene. Results: A multiplex, multigenerational family with 14 members affected (3 members with esophageal adenocarcinoma and 11 with Barrett esophagus) was identified, and whole-exome sequencing identified a germline mutation (S631G) at a highly conserved serine residue in the uncharacterized gene VSIG10L that segregated in affected members. Transfection of S631G variant into a 3-dimensional organotypic culture model of normal esophageal squamous cells dramatically inhibited epithelial maturation compared with the wild-type. VSIG10L exhibited high expression in normal squamous esophagus with marked loss of expression in Barrett-associated lesions. Electron microscopy of squamous esophageal mucosa harboring the S631G variant revealed dilated intercellular spaces and reduced desmosomes. Conclusions and Relevance: This study presents VSIG10L as a candidate familial Barrett esophagus susceptibility gene, with a putative role in maintaining normal esophageal homeostasis. Further research assessing VSIG10L function may reveal pathways important for esophageal maturation and the pathogenesis of Barrett esophagus and esophageal adenocarcinoma. PMID- 27467442 TI - New advances in analytical methods and assessment tools to identify deficiency and metabolic risk. PMID- 27467443 TI - Construction of Hexahydrophenanthrenes By Rhodium(I)-Catalyzed Cycloisomerization of Benzylallene-Substituted Internal Alkynes through C-H Activation. AB - The treatment of benzylallene-substituted internal alkynes with [RhCl(CO)2 ]2 effects a novel cycloisomerization by C(sp(2) )-H bond activation to produce hexahydrophenanthrene derivatives. The reaction likely proceeds through consecutive formation of a rhodabicyclo[4.3.0] intermediate, sigma-bond metathesis between the C(sp(2) )-H bond on the benzene ring and the C(sp(2) ) Rh(III) bond, and isomerization between three sigma-, pi-, and sigma allylrhodium(III) species, which was proposed based on experiments with deuterated substrates. PMID- 27467444 TI - Impact of Extent of Lymphadenectomy on Survival, Post Neoadjuvant Chemotherapy and Transthoracic Esophagectomy. AB - OBJECTIVE: The aim of this study was to evaluate the influence of lymph node yield and the location of nodes on prognosis in patients with distal esophageal or gastroesophageal junction adenocarcinoma who have received neoadjuvant chemotherapy followed by transthoracic esophagectomy. BACKGROUND: Debate continues regarding the extent of lymphadenectomy required when carrying out an esophagectomy. Lymph node yield has been used as a surrogate for extent of lymphadenectomy. Node location must, however, be reviewed to determine the true extent of lymphadenectomy. METHODS: Data from consecutive patients with potentially curable adenocarcinoma of the lower esophagus or gastroesophageal junction were reviewed. Patients were treated with neoadjuvant chemotherapy, transthoracic esophagectomy, and 2-field lymphadenectomy. Outcomes according to lymph node yield were determined. Projected prognosis of carrying out less radical lymphadenectomies was calculated according to 3 groups: group 1-exclusion of proximal thoracic nodes, group 2-a minimal abdominal lymphadenectomy, and group 3-a minimal abdominal and thoracic lymphadenectomy. RESULTS: Three hundred five patients were included. Median cancer-related survival was 37.7 months (confidence interval 29-46 mo). Absolute lymph node retrieval was not related to survival (P = 0.520). An estimated additional 4 (2-6) cancer-related deaths were projected if group 1 nodes were omitted, 2 (1-4) additional deaths if group 2 nodes were omitted, and 9 (6-12) extra deaths if group 3 nodes were omitted. A minimal lymphadenectomy (groups 1, 2, and 3) was projected to lead to a 23% reduction in survival in patients with N1 or N2. CONCLUSIONS: The present study demonstrates high lymph node yields are possible after transthoracic esophagectomy with en bloc 2-field lymphadenectomy in patients post neoadjuvant chemotherapy. This allows excellent postoperative staging. Furthermore, the extent of lymphadenectomy must be correlated with node location, which may have important implications in patients who have a less extensive lymphadenectomy. PMID- 27467445 TI - Supercapacitor Electrodes Based on High-Purity Electrospun Polyaniline and Polyaniline-Carbon Nanotube Nanofibers. AB - Freestanding, binder-free supercapacitor electrodes based on high-purity polyaniline (PANI) nanofibers were fabricated via a single step electrospinning process. The successful electrospinning of nanofibers with an unprecedentedly high composition of PANI (93 wt %) was made possible due to blending ultrahigh molecular weight poly(ethylene oxide) (PEO) with PANI in solution to impart adequate chain entanglements, a critical requirement for electrospinning. To further enhance the conductivity and stability of the electrodes, a small concentration of carbon nanotubes (CNTs) was added to the PANI/PEO solution prior to electrospinning to generate PANI/CNT/PEO nanofibers (12 wt % CNTs). Scanning electron microscopy (SEM) and Brunauer-Emmett-Teller (BET) porosimetry were conducted to characterize the external morphology of the nanofibers. The electrospun nanofibers were further probed by transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT IR). The electroactivity of the freestanding PANI and PANI/CNT nanofiber electrodes was examined using cyclic voltammetry, galvanostatic charge-discharge, and electrochemical impedance spectroscopy. Competitive specific capacitances of 308 and 385 F g(-1) were achieved for PANI and PANI-CNT based electrodes, respectively, at a current density of 0.5 A g(-1). Moreover, specific capacitance retentions of 70 and 81.4% were observed for PANI and PANI-CNT based electrodes, respectively, after 1000 cycles. The promising electrochemical performance of the fabricated electrodes, we believe, stems from the porous 3-D electrode structure characteristic of the nonwoven interconnected nanostructures. The interconnected nanofiber network facilitates efficient electron conduction while the inter- and intrafiber porosity enable excellent electrolyte penetration within the polymer matrix, allowing fast ion transport to the active sites. PMID- 27467446 TI - Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating alpha4beta7 Integrin CD4+ T Cells: Implications for HIV Microbicides. AB - CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for antiretroviral (ARV) based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating alpha4beta7+CD4+ T cells, which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing alpha4beta7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, and BCRP and uptake transporter CNT2 were significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p = 0.01-0.03). Conversely, circulating alpha4beta7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p = 0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral alpha4beta7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between alpha4beta7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs. PMID- 27467447 TI - Development of a Protocol for Simultaneous Assessment of Cognitive Functioning Under Psychosocial Stress. AB - This study presents a protocol for induction of moderate psychosocial stress and investigates its impact on psychological and physiological responses. The proposed procedure was designed to enable researchers to assess cognitive performance under effect of various classes of stressors. The protocol's structure contains three main periods: baseline, assessment, and recovery. The assessment stage starts with task anticipation, during which audience (three member commission) is introduced and apparatus (cameras, microphones, lights, and physiological measuring devices) stationed. Subsequently, cognitive performance was tested. The protocol was evaluated on 56 university students that were randomly assigned to control or stress (protocol) treatment and administered three cognitive tests (working memory operation span, remote associates test, and semantic fluency). Compared to control sessions, protocol induced state anxiety, interfering worry thoughts, and disturbance during recovery period. In addition, the stress group also showed elevated levels of skin conductance, higher average heart rates, and larger drops in peripheral temperature. Even though more research is needed, these results suggest that the protocol effectively induces both psychological and physiological stress responses and therefore encourages utilization in cognitive-affective and cognitive-biological fields of research. PMID- 27467449 TI - Corrections. PMID- 27467448 TI - A C-F Bond Directed Diels-Alder Reaction. AB - We demonstrate a C-F bond driven Diels-Alder reaction of a fluorinated dienophile and a borole that shows remarkable diastereoselectivity. The product's structure was confirmed by X-ray crystallography, revealing an unusual conformation featuring a hypercoordinate boron. Calculations suggest that a B...F interaction instigates the reaction chemistry, the magnitude of which is maximized in the transition state-in essence, the B...F distance "yo-yos" from long to short in the transition state and back again to long in the product. PMID- 27467451 TI - How various aspects of motion parallax influence distance judgments, even when we think we are standing still. AB - It is well known that when we intentionally make large head movements, the resulting motion parallax helps us judge objects' distances. The information about distance could be obtained in various ways: from the changes in the object's position with respect to ourselves, from the changes in its orientation relative to the line of sight, and from the relative retinal motion between the target's image and that of the background. We explore here whether these motion parallax cues are used when we think we are standing still. To answer this question we asked subjects to indicate the position of a virtual target with their unseen finger. The position and the size of the target changed across trials. There were pairs of trials in which the same target was presented at the same location, except that one or more of the three motion parallax cues indicated that the target was either 10 cm closer or 10 cm farther away than the 'true' distance. Any systematic difference between the positions indicated for the closer and further targets of such pairs indicates that the cues in question influence subjects' judgments. The results show that motion parallax cues have a detectable influence on our judgments, even when the head only moves a few millimeters. Relative retinal image motion has the clearest effect. Subjects did not move their head differently when we presented the targets to only one eye in order to increase the benefit of considering motion parallax. PMID- 27467450 TI - Global attention facilitates the planning, but not execution of goal-directed reaches. AB - In daily life, humans interact with multiple objects in complex environments. A large body of literature demonstrates that target selection is biased toward recently attended features, such that reaches are faster and trajectory curvature is reduced when target features (i.e., color) are repeated (priming of pop-out). In the real world, however, objects are comprised of several features-some of which may be more suitable for action than others. When fetching a mug from the cupboard, for example, attention not only has to be allocated to the object, but also the handle. To date, no study has investigated the impact of hierarchical feature organization on target selection for action. Here, we employed a color oddity search task in which targets were Pac-men (i.e., a circle with a triangle cut out) oriented to be either consistent or inconsistent with the percept of a global Kanizsa triangle. We found that reaches were initiated faster when a task irrelevant illusory figure was present independent of color repetition. Additionally, consistent with priming of pop-out, both reach planning and execution were facilitated when local target colors were repeated, regardless of whether a global figure was present. We also demonstrated that figures defined by illusory, but not real contours, afforded an early target selection benefit. In sum, these findings suggest that when local targets are perceptually grouped to form an illusory surface, attention quickly spreads across the global figure and facilitates the early stage of reach planning, but not execution. In contrast, local color priming is evident throughout goal-directed reaching. PMID- 27467452 TI - Service utilisation and costs of language impairment in children: The early language in Victoria Australian population-based study. AB - PURPOSE: To examine (1) the patterns of service use and costs associated with language impairment in a community cohort of children from ages 4-9 years and (2) the relationship between language impairment and health service utilisation. METHOD: Participants were children and caregivers of six local government areas in Melbourne participating in the community-based Early Language in Victoria Study (ELVS). Health service use was reported by parents. Costs were valued in Australian dollars in 2014, from the government and family perspectives. Depending on age, the Australian adapted Clinical Evaluation of Language Fundamentals - Pre-school, 2nd Edition (CELF-P2) or the CELF, 4th Edition (CELF4) was used to assess expressive and receptive language. RESULT: At 5, 7 and 9 years respectively 21%, 11% and 8% of families reported using services for speech and/or language concerns. The annual costs associated with using services averaged A$612 (A$255 to government, A$357 to family) at 5 years and A$992 (A$317 to government, A$675 to family) at 7 years. Children with persistent language impairment had significantly higher service costs than those with typical language. CONCLUSION: Language impairment in 4-9-year-old children is associated with higher use of services and costs to both families and government compared to typical language. PMID- 27467455 TI - 2016 ACMG Annual Meeting presidential address: the practice of medical genetics: myths and realities. PMID- 27467453 TI - EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality. AB - PURPOSE: EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. METHODS: We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. RESULTS: Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. CONCLUSIONS: NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156. PMID- 27467454 TI - Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. AB - DISCLAIMER: This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9-10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are no other screening options to identify these conditions. Providers should have a more thorough understanding of patient preferences and be able to educate about the current drawbacks of NIPS across the prenatal screening spectrum. Laboratories are encouraged to meet the needs of providers and their patients by delivering meaningful screening reports and to engage in education. With health-care-provider guidance, the patient should be able to make an educated decision about the current use of NIPS and the ramifications of a positive, negative, or no-call result.Genet Med 18 10, 1056 1065. PMID- 27467456 TI - The significant impact of education, poverty, and race on Internet-based research participant engagement. AB - PURPOSE: Internet-based technologies are increasingly being used for research studies. However, it is not known whether Internet-based approaches will effectively engage participants from diverse racial and socioeconomic backgrounds. METHODS: A total of 967 participants were recruited and offered genetic ancestry results. We evaluated viewing Internet-based genetic ancestry results among participants who expressed high interest in obtaining the results. RESULTS: Of the participants, 64% stated that they were very or extremely interested in their genetic ancestry results. Among interested participants, individuals with a high school diploma (n = 473) viewed their results 19% of the time relative to 4% of the 145 participants without a diploma (P < 0.0001). Similarly, 22% of participants with household income above the federal poverty level (n = 286) viewed their results relative to 10% of the 314 participants living below the federal poverty level (P < 0.0001). Among interested participants both with a high school degree and living above the poverty level, self-identified Caucasians were more likely to view results than self-identified African Americans (P < 0.0001), and females were more likely to view results than males (P = 0.0007). CONCLUSION: In an underserved population, engagement in Internet-based research was low despite high reported interest. This suggests that explicit strategies should be developed to increase diversity in Internet based research.Genet Med 19 2, 240-243. PMID- 27467458 TI - Impact of oral P2Y12 inhibitors on residual thrombus burden and reperfusion indexes in patients with ST-segment elevation myocardial infarction. AB - AIMS: We sought to assess the impact of different oral P2Y12 receptor inhibitors on residual thrombus and reperfusion indexes in ST-segment elevation myocardial infarction patients enrolled in the COCTAIL II trial, which included 128 primary percutaneous coronary interventions randomized to intracoronary vs. intralesion abciximab bolus with or without thrombectomy. METHODS: Patients were divided into three groups: clopidogrel (n = 44), prasugrel (n = 45) and ticagrelor (n = 39). Residual intra-stent thrombus was quantified by optical coherence tomography using both the number of cross-sections with thrombus area more than 10% and thrombus volume. Reperfusion indexes included thrombolysis in myocardial infarction (TIMI) flow, corrected TIMI frame count, myocardial blush grade (MBG) and complete ST-segment resolution (>=70%). RESULTS: In the prasugrel group, optical coherence tomography depicted a lower percentage of cross-sections with residual thrombus area more than 10% [4.0 (1.0-8.5)], as compared with clopidogrel [8.0 (1.0-15.0), P = 0.011] and ticagrelor [7.0 (3.0-13.5), P = 0.026].A higher thrombus volume was found in the clopidogrel group 4.0 mm(2.7 6.2) as compared with the prasugrel group [2.8 mm(1.8-4.4), P = 0.023], whereas the other between-group comparisons yield no significant differences. The frequency of MBG 3 was higher in the prasugrel group (73.3%) as compared with clopidogrel (45.5%) and ticagrelor [(56.4%), P = 0.027]. Final TIMI flow, TIMI frame count and ST resolution were not significantly different across the three groups (P = 0.423, 0.179 and 0.848, respectively). At multivariate analysis, pretreatment with prasugrel was independently associated with MBG 3 (odds ratio = 3.93; 95% confidence interval = 1.01-15.39). CONCLUSION: Prasugrel loading dose was associated with a lower percentage of cross-sections with residual thrombus area more than 10% as compared with both clopidogrel and ticagrelor, although intrastent thrombus volume was not significantly different between prasugrel and ticagrelor.The frequency of MBG 3 was the only reperfusion index that was significantly more prevalent in prasugrel treated group as compared with clopidogrel and ticagrelor groups. PMID- 27467459 TI - Recurrent pericarditis in children and adolescents: a multicentre cohort study. AB - OBJECTIVE: Limited data are available about recurrent pericarditis in children. We sought to explore contemporary causes, characteristics, therapies and outcomes of recurrent pericarditis in paediatric patients. METHODS: A multicentre (eight sites) cohort study of 110 consecutive cases of paediatric patients with at least two recurrences of pericarditis over an 11-year period (2000-2010) [median 13 years, interquartile range (IQR) 5, 69 boys]. RESULTS: Recurrences were idiopathic or viral in 89.1% of cases, followed by postpericardiotomy syndrome (9.1%) and familial Mediterranean fever (0.9%). Recurrent pericarditis was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) in 80.9% of cases, corticosteroids in 64.8% and colchicine was added in 61.8%. Immunosuppressive therapies were administered in 15.5% of patients after subsequent recurrences. After a median follow-up of 60th months, 528 subsequent recurrences were recorded (median 3, range 2-25). Corticosteroid-treated patients experienced more recurrences (standardized risk of recurrence per 100 person-years was 93.2 for patients treated with corticosteroids and 45.2 for those without), side effects and disease-related hospitalizations (for all P < 0.05). Adjuvant therapy with colchicine was associated with a decrease in the risk of recurrence from 3.74 per year before initiation of colchicine to 1.37 per year after (P < 0.05). Anakinra therapy (n = 12) was associated with a drop in the number of recurrences from 4.29 per year before to 0.14 per year after (P < 0.05). Transient constrictive pericarditis developed in 2.7% of patients. CONCLUSION: Recurrent pericarditis has an overall favourable prognosis in children, although it may require frequent readmissions and seriously affect the quality of life, especially in patients treated with corticosteroids. Colchicine or anakinra therapies were associated with significant decrease in the risk of recurrence. PMID- 27467460 TI - Comparative effectiveness of water and salt community-based fluoridation methods in preventing dental caries among schoolchildren. AB - OBJECTIVE: To compare the effectiveness of water and salt community-based fluoridation methods on caries experience among schoolchildren. METHODS: Data derived from two population-based oral health surveys of 12-year-old schoolchildren exposed to different community-based fluoridation methods were compared: artificially fluoridated water in Porto Alegre, South Brazil and artificially fluoridated salt in Montevideo, Uruguay. Data on socio-demographic characteristics, maternal education and oral hygiene were collected. Dental caries was defined according to the WHO criteria (cavitated lesions) and to the modified WHO criteria (active noncavitated lesions and cavitated ones). The association between community-based fluoridation methods and dental caries was modelled using logistic (caries prevalence) and Poisson regression (DMFT). Odds ratios (OR), rate ratios (RR), and the 95% confidence intervals (CI) were estimated. RESULTS: A total of 1528 in Porto Alegre and 1154 in Montevideo were examined (response rates: 83.2% and 69.6%, respectively). Adjusted estimates for caries prevalence and DMFT showed that schoolchildren from Porto Alegre were less affected by dental caries than their counterparts from Montevideo, irrespective of the criteria used. After adjusting for important characteristics, schoolchildren exposed to fluoridated salt had significantly higher likelihood of having caries (WHO criteria) than those exposed to fluoridated water (OR for prevalence=1.61, 95% CI=1.26-2.07; RR for DMFT=1.32, 95% CI=1.16-1.51). Similar differences were observed using the modified WHO criteria. CONCLUSION: Fluoridated water appears to provide a better protective effect against dental caries than fluoridated household salt among schoolchildren from developing countries. PMID- 27467461 TI - Graduated Driver Licensing Night Driving Restrictions and Drivers Aged 16 or 17 Years Involved in Fatal Night Crashes - United States, 2009-2014. AB - Fatal crash risk is higher at night for all drivers, but especially for young, inexperienced drivers (1). To help address the increased crash risk for beginner teen drivers, 49 states and the District of Columbia include a night driving restriction (NDR) in their Graduated Driver Licensing (GDL) system. NDRs have been shown to reduce crashes among newly licensed teens, with higher reductions associated with NDRs starting at 10:00 p.m. or earlier (2-3). However, in 23 states and the District of Columbia, NDRs begin at 12:00 a.m. or later, times when most teen drivers subject to GDL are not driving. CDC analyzed 2009-2014 national and state-level data from the Fatality Analysis Reporting System (FARS) to determine the proportion of drivers aged 16 or 17 years involved in fatal crashes who crashed at night (9:00 p.m.-5:59 a.m.) and the proportion of these drivers who crashed before 12:00 a.m. Nationwide, among 6,104 drivers aged 16 or 17 years involved in fatal crashes during 2009-2014, 1,865 (31%) were involved in night crashes. Among drivers involved in night crashes, 1,054 (57%) crashed before 12:00 a.m. State-level analyses revealed an approximately twofold variation among states in both the proportions of drivers aged 16 or 17 years involved in fatal crashes that occurred at night and the proportions of night fatal crash involvements that occurred before 12:00 a.m. Because nearly all of the night driving trips taken by drivers aged 16 or 17 years end before 12:00 a.m., NDRs beginning at 12:00 a.m. or later provide minimal protection. States could consider updating their NDR coverage to include earlier nighttime hours. This descriptive report summarizes the characteristics of NDRs, estimates the extent to which drivers aged 16 or 17 years drive at night, and describes their involvement in fatal nighttime crashes during 2009-2014. The effects of NDRs on crashes were not evaluated because of the small state-level sample sizes during the 6-year study period. PMID- 27467457 TI - Intratumoral genetic heterogeneity and number of cytogenetic aberrations provide additional prognostic significance in chronic lymphocytic leukemia. AB - PURPOSE: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with cytogenetic aberrations that are still considered the gold standard of prognostic factors. However, heterogeneity remains within each cytogenetic group, especially in patients with concomitant cytogenetic aberrations. METHODS: A panel of DNA probes was used to detect cytogenetic aberrations, including RB1/D13S25 at 13q14, ATM at 11q22, TP53 at 17p13, CEP12 and IGH translocation at 14q32, by fluorescence in situ hybridization. A comprehensive method integrating the number of cytogenetic aberrations and intratumoral genetic heterogeneity was used to analyze the prognosis for patients with concomitant aberrations. RESULTS: Within the conventional favorable or neutral prognostic groups (i.e., with del 13q, trisomy 12, and/or t(14q32)), the coincidence of these three aberrations worsened survival in terms of time to first therapy, progression-free survival, and overall survival. However, within the conventional unfavorable prognostic group (i.e., del 11q or del 17p), patients with a minor unfavorable clone had an unexpected survival advantage compared with patients with a major unfavorable clone. A new cytogenetic prognostic system that integrates the number of cytogenetic aberrations and intratumoral genetic subclones was more precise than the conventional system. CONCLUSION: The number of cytogenetic aberrations and the size of intratumoral genetic subclones should be comprehensively considered to determine the prognosis for CLL.Genet Med 19 2, 182-191. PMID- 27467462 TI - Photodegradation of cyprodinil under UV-visible irradiation - chemical and toxicological approaches. AB - RATIONALE: Cyprodinil is a fungicide active on grapes, strawberries, tomatoes, and many other fruits. Under UV-visible irradiation, it undergoes photodegradation through various processes to form transformation products (TPs) whose structures and potential toxicities are unknown. The structures of the TPs were elucidated by comparing the photodegradation of cyprodinil and cyprodinil-D5 . The potential toxicities of these compounds were compared with that of cyprodinil. METHODS: Aqueous solutions of cyprodinil were irradiated in a reactor equipped with a mercury vapor lamp. Analyses were carried out using high performance liquid chromatography coupled to a quadrupole time-of-flight (QTOF) mass spectrometer or to a SolarixXR 9.4 Tesla Fourier transform (FT) mass spectrometer. High-resolution mass measurements, MS/MS and isotopic labeling experiments allowed structural elucidation of the cyprodinil TPs. The toxicities were estimated by three tests in silico using the TEST software and in vitro bioassays using Vibrio fischeri bacteria. These bioassays were carried out on irradiated solution for several exposure times and non-irradiated solutions. RESULTS: The structures of 19 photoproducts were characterized by LC/HRMS/MS after 4 h of irradiation of a cyprodinil aqueous solution. The use of cyprodinil D5 allowed the TPs to be characterized with more confidence. Knowing the structure of the TPs allows the estimation of their potential toxicities by in silico tests. Most of the photoproducts are potentially more toxic than the parent compound, based on the oral rat LD50 values, and most of them might induce more developmental and mutagenic toxicities. In vitro assays on Vibrio fischeri bacteria showed that the global ecotoxicity of the cyprodinil solution significantly increases with irradiation time. CONCLUSIONS: Structures of photoproducts were characterized after irradiation of a cyprodinil aqueous solution combining LC/HRMS, LC/HRMS/MS and the use of a labeled compound. Their formations imply several photodegradation reactions, namely direct bond cleavages, cyclization, isomerization and hydroxylation. Most of the TPs exhibit a toxicity significantly higher than that of the parent molecule. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27467463 TI - Vacuolar SPX-MFS transporters are essential for phosphate adaptation in plants. AB - To survive in most soils in which inorganic phosphate (Pi) levels are limited and constantly changing, plants universally use the vacuoles as cellular Pi "sink" and "source" to maintain Pi homeostasis. However, the transporters that mediate Pi sequestration into the vacuoles remain unknown. Recently, we and other 2 groups independently identified the members of SPS-MSF family as the candidates for tonoplast Pi transporters in Arabidopsis thaliana and Oryza sativa. We and Liu et al. demonstrated that one of SPS-MSF member, VPT1 (Vacuolar Phosphate Transporter 1), also named as PHT5;1 (Phosphate Transporter 5;1), plays a predominant role in Pi sequestration of vacuoles in Arabidopsis. Here we show that vpt1 mutants and VPT1-GFP overexpressing lines displayed sensitive to Pi stress under the hydroponic system containing the medium with low iron, supporting that VPT1 is essential for Arabidopsis to adapt phosphate stress. PMID- 27467464 TI - Weight loss advice and prospective weight change among overweight firefighters. AB - BACKGROUND: Obesity compromises firefighter safety, yet more than 70% of firefighters are overweight. Though healthcare professionals are encouraged to counsel overweight patients, the effectiveness of weight counseling is not consistent across studies. OBJECTIVE: Examine longitudinal changes in cardiovascular risk factors and determine the role of healthcare professional weight loss advice on six-month weight changes among a national sample of male, overweight and obese firefighters. METHODS: This study included baseline and six month assessments of 757 firefighters. Medical and demographic data were collected using questionnaires. Investigators collected height, weight, percent body fat, waist circumference, blood pressure, and fasting serum samples (total cholesterol, high-density lipoprotein, low-density lipoprotein, glucose). Multilevel linear regression assessed the association between weight advice and outcomes. RESULTS: Participants lost an average of 0.55 kg (95%CI: 0.17-0.93), and experienced significant improvements in systolic blood pressure (mean: 3.75 mm Hg; 95% CI: 2.35-5.14) and non-significant improvements in other clinical outcomes. Healthcare professional weight advice was not significantly associated with weight loss or other outcomes. CONCLUSION: Similar to other studies, results show little benefit of low intensity weight loss counseling. Additional research is needed to identify effective and feasible weight management strategies to address firefighter obesity. PMID- 27467465 TI - Resting-State Functional MR Imaging for Determining Language Laterality in Intractable Epilepsy. AB - Purpose To measure the accuracy of resting-state functional magnetic resonance (MR) imaging in determining hemispheric language dominance in patients with medically intractable focal epilepsies against the results of an intracarotid amobarbital procedure (IAP). Materials and Methods This study was approved by the institutional review board, and all subjects gave signed informed consent. Data in 23 patients with medically intractable focal epilepsy were retrospectively analyzed. All 23 patients were candidates for epilepsy surgery and underwent both IAP and resting-state functional MR imaging as part of presurgical evaluation. Language dominance was determined from functional MR imaging data by calculating a laterality index (LI) after using independent component analysis. The accuracy of this method was assessed against that of IAP by using a variety of thresholds. Sensitivity and specificity were calculated by using leave-one-out cross validation. Spatial maps of language components were qualitatively compared among each hemispheric language dominance group. Results Measurement of hemispheric language dominance with resting-state functional MR imaging was highly concordant with IAP results, with up to 96% (22 of 23) accuracy, 96% (22 of 23) sensitivity, and 96% (22 of 23) specificity. Composite language component maps in patients with typical language laterality consistently included classic language areas such as the inferior frontal gyrus, the posterior superior temporal gyrus, and the inferior parietal lobule, while those of patients with atypical language laterality also included non-classical language areas such as the superior and middle frontal gyri, the insula, and the occipital cortex. Conclusion Resting state functional MR imaging can be used to measure language laterality in patients with medically intractable focal epilepsy. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 27467466 TI - Benign Prostatic Hyperplasia: Cone-Beam CT in Conjunction with DSA for Identifying Prostatic Arterial Anatomy. AB - Purpose To describe findings in prostatic arteries (PAs) at digital subtraction angiography (DSA) and cone-beam computed tomography (CT) that allow identification of benign prostatic hyperplasia and to determine the value added with the use of cone-beam CT. Materials and Methods This retrospective single institution study was approved by the institutional review board, and the requirement for written informed consent was waived. From February 2009 to December 2014, a total of 148 patients (mean age +/- standard deviation, 70.5 years +/- 14.5) underwent DSA of the internal iliac arteries and cone-beam CT with a flat-detector angiographic system before they underwent prostate artery embolization. Both the DSA and cone-beam CT images were evaluated by two interventional radiologists to determine the number of independent PAs and their origins and anastomoses with adjacent arteries. The exact McNemar test was used to compare the detection rate of the PAs and the anastomoses with DSA and with cone-beam CT. Results The PA anatomy was evaluated successfully by means of cone beam CT in conjunction with DSA in all patients. Of the 296 pelvic sides, 274 (92.6%) had only one PA. The most frequent PA origin was the common gluteal pudendal trunk with the superior vesicular artery in 118 (37.1%), followed by the anterior division of the internal iliac artery in 99 (31.1%), and the internal pudendal artery in 77 (24.2%) pelvic sides. In 67 (22.6%) pelvic sides, anastomoses to adjacent arteries were documented. The numbers of PA origins and anastomoses, respectively, that could be identified were significantly higher with cone-beam CT (301 of 318 [94.7%] and 65 of 67 [97.0%]) than with DSA (237 [74.5%] and 39 [58.2%], P < .05). Cone-beam CT provided essential information that was not available with DSA in 90 of 148 (60.8%) patients. Conclusion Cone beam CT is a useful adjunctive technique to DSA for identification of the PA anatomy and provides information to help treatment planning during prostatic arterial embolization. (c) RSNA, 2016. PMID- 27467467 TI - Pediatric Brain: Repeated Exposure to Linear Gadolinium-based Contrast Material Is Associated with Increased Signal Intensity at Unenhanced T1-weighted MR Imaging. AB - Purpose To determine whether repeated exposure of the pediatric brain to a linear gadolinium-based contrast agent (GBCA) is associated with an increase in signal intensity (SI) relative to that in GBCA-naive control subjects at unenhanced T1 weighted magnetic resonance (MR) imaging. Materials and Methods This single center, retrospective study was approved by the institutional review board and compliant with HIPAA. The authors evaluated 46 pediatric patients who had undergone at least three GBCA-enhanced MR examinations (30 patients for two-group analysis and 16 for pre- and post-GBCA exposure comparisons) and 57 age-matched GBCA-naive control subjects. The SI in the globus pallidus, thalamus, dentate nucleus, and pons was measured at unenhanced T1-weighted MR imaging. Globus pallidus-thalamus and dentate nucleus-pons SI ratios were calculated and compared between groups and relative to total cumulative gadolinium dose, age, sex, and number of and mean time between GBCA-enhanced examinations. Analysis included the Wilcoxon signed rank test, Wilcoxon rank sum test, and Spearman correlation coefficient. Results Patients who underwent multiple GBCA-enhanced examinations had increased SI ratios within the dentate nucleus (mean SI ratio +/- standard error of the mean for two-group comparison: 1.007 +/- 0.0058 for GBCA-naive group and 1.046 +/- 0.0060 for GBCA-exposed group [P < .001]; mean SI ratio for pre- and post-GBCA comparison: 0.995 +/- 0.0062 for pre-GBCA group and 1.035 +/- 0.0063 for post-GBCA group [P < .001]) but not the globus pallidus (mean SI ratio for two-group comparison: 1.131 +/- 0.0070 for GBCA-naive group and 1.014 +/- 0.0091 for GBCA-exposed group [P = .21]; mean SI ratio for pre- and post-GBCA comparison: 1.068 +/- 0.0094 for pre-GBCA group and 1.093 +/- 0.0134 for post GBCA group [P = .12]). There was a significant correlation between dentate nucleus SI and total cumulative gadolinium dose (r = 0.4; 95% confidence interval [CI]: 0.03, 0.67; P = .03), but not between dentate nucleus SI and patient age (r = 0.23; 95% CI: -0.15, 0.56; P = .22), sex (mean SI ratio: 1.046 +/- 0.0072 for boys and 1.045 +/- 0.0110 for girls; P = .88), number of contrast-enhanced examinations (r = 0.13; 95% CI: -0.25, 0.48; P = .49), or time between contrast enhanced examinations (r = -0.06; 95% CI: -0.42, 0.32; P = .75). Conclusion SI in the pediatric brain increases on unenhanced T1-weighted MR images with repeated exposure to a linear GBCA. (c) RSNA, 2016. PMID- 27467469 TI - Cervical Osteomyelitis After Pharyngeal Surgical Manipulation-Reply. PMID- 27467468 TI - Implementation of Synthesized Two-dimensional Mammography in a Population-based Digital Breast Tomosynthesis Screening Program. AB - Purpose To evaluate the early implementation of synthesized two-dimensional (s2D) mammography in a population screened entirely with s2D and digital breast tomosynthesis (DBT) (referred to as s2D/DBT) and compare recall rates and cancer detection rates to historic outcomes of digital mammography combined with DBT (referred to as digital mammography/DBT) screening. Materials and Methods This was an institutional review board-approved and HIPAA-compliant retrospective interpretation of prospectively acquired data with waiver of informed consent. Compared were recall rates, biopsy rates, cancer detection rates, and radiation dose for 15 571 women screened with digital mammography/DBT from October 1, 2011, to February 28, 2013, and 5366 women screened with s2D/DBT from January 7, 2015, to June 30, 2015. Two-sample z tests of equal proportions were used to determine statistical significance. Results Recall rate for s2D/DBT versus digital mammography/DBT was 7.1% versus 8.8%, respectively (P < .001). Biopsy rate for s2D/DBT versus digital mammography/DBT decreased (1.3% vs 2.0%, respectively; P = .001). There was no significant difference in cancer detection rate for s2D/DBT versus digital mammography/DBT (5.03 of 1000 vs 5.45 of 1000, respectively; P = .72). The average glandular dose was 39% lower in s2D/DBT versus digital mammography/DBT (4.88 mGy vs 7.97 mGy, respectively; P < .001). Conclusion Screening with s2D/DBT in a large urban practice resulted in similar outcomes compared with digital mammography/DBT imaging. Screening with s2D/DBT allowed for the benefits of DBT with a decrease in radiation dose compared with digital mammography/DBT. (c) RSNA, 2016 An earlier incorrect version of this article appeared online. This article was corrected on August 11, 2016. PMID- 27467470 TI - Cardiac Rehabilitation Series. PMID- 27467471 TI - Coming in sportsmedicine. PMID- 27467472 TI - Scanning sports. PMID- 27467473 TI - Brief reports. PMID- 27467475 TI - Sportsmedicine forum. PMID- 27467476 TI - Abstracts at a glance. PMID- 27467477 TI - Sports Sickness. PMID- 27467478 TI - 1986 Annual Meeting of the American College of Sports Medicine. PMID- 27467479 TI - A Fight to the Finish. PMID- 27467480 TI - Drug Testing in a University Athletic Program: Protocol and Implementation. AB - In brief: Much attention is being focused on drug abuse by athletes. As sports medicine physicians become increasingly involved in the drug abuse issue, they are called upon not only to educate and counsel athletes but also to test them for drugs. This paper discusses an athletic drug education/counseling screening program at Wake Forest University. Such a program requires practical decisions regarding which athletes to test under informed consent, which drugs to test for and how to test for them, in what way and how often to collect urine samples for testing, and what measures to take when an athlete has a positive test result. Constant feedback from everyone involved allows for modification of the program as needed to make it more confidential, acceptable, and beneficial. PMID- 27467481 TI - Open Fracture Dislocation of the Ankle With Loss of the Medial Malleolus in a College Tennis Player. AB - In brief: A 20-year-old college tennis player suffered a severe open fracture dislocation of her left ankle and a cervical spine fracture in an auto accident. This type of ankle injury often results in severe contamination and a poorly functioning joint. The patient underwent ankle surgery as well as treatment for her cervical spine fracture. By following a diligent rehabilitation program, she was subsequently able to return to her college tennis team and perform at a high level. The case Remonstrates the effectiveness of meticulous treatment and a good rehabilitation program. PMID- 27467482 TI - Cardiac Rehabilitation in the Mid-1980s. AB - In brief: The cardiac rehabilitation program al Georgia Baptist Medical Center in Atlanta, one of more than 700 such programs in the United States, gives an idea of the state of the art. The program consists of training and supervision in exercise, nutrition, and stress management. Inpatient care involves aggressive treatment, early mobilization, and predischarge treadmill testing. Immediately after discharge, patients follow either a prescribed norne exercise regimen or a telemetry-monitored program in the hospital gymnasium. Late-postdischarge patients perform various aerobic exercise routines at least three times a week. Home exercise programs clearly improve cardiorespiratory fitness and save money. Although it is not" yet clear that such Programs reduce mortality, the evidence Joints in that direction. PMID- 27467483 TI - Body Fat Assessment: A Comparison of Visual Estimation and Skinfold Techniques. AB - In brief: The purpose of this study was to compare skinfold measurement and visual estimation as methods of measuring percent body fat by testing them against densitometry. Seventy-one male volunteers underwent skinfold measurements and underwater weighing and were photographed from the front, side, and rear. The skinfold measurements and underwater weighing were used to determine percent fat by accepted mathematical methods. Two experts then visually estimated the subjects' percent fat by comparing the photographs with five sets of reference photographs The results suggest that some individuals can visually estimate percent fat about as accurately as it can be calculated from skinfold measurements. PMID- 27467484 TI - Knee Braces to Prevent Injuries in Football. AB - In brief: Knee braces are used widely by linemen in professional and college football, and many coaches and team physicians believe the braces have reduced the number and severity of knee injuries. But questions remain about the strength of the braces, whether they prestress the knee in some cases, and, above all, whether they actually reduce injuries. This panel of team physicians says that most evidence of reduced injuries is anecdotal and that some limited evidence suggests that the braces actually increase injuries. While most of the panelists favor continued use of knee braces, they believe that more clinical and biomechanical research is necessary to establish their value. PMID- 27467485 TI - Acute Quadriplegia Following the Use of Progressive Resistance Exercise Machinery. AB - In brief: This case report describes a 26-year-old female fitness instructor in excellent health who suffered the acute onset of permanent quadriplegia only a few minutes after using progressive resistance exercise devices. She began her workday as she usually did-with a light workout of low-resistance exercise that lasted about 20 minutes. The onset of quadriplegia may have been a tragic coincidence or may have been related to her workout in a way that remains unexplained. Several possible causes of her condition, which was diagnosed as spinal apoplexy of an unknown cause, are discussed. PMID- 27467486 TI - How I Manage Testicular Injury. AB - In brief: The pain and swelling that often follow testicular injuries can make it difficult to distinguish a contusion from a severe injury. An accurate diagnosis is imperative because in cases of testicular rupture or intrascrotal bleeding, surgery may be necessary to save the testicle. If scrotal swelling makes examination of the testis difficult, transillumination or ultrasound may help. Aspiration of the scrotum is rarely indicated for diagnostic reasons. A contusion generally can be treated with bed rest and oral analgesics, but a spermatic cord block may be used if the pain is very severe. If testicular rupture cannot be ruled out, prompt urological referral is appropriate. PMID- 27467487 TI - Stress and the Athlete: Coping With Exercise. AB - Stress is not unique to athletes, but the ability to cope with stress may determine whether a race is won or whether a person sticks with an exercise program. PMID- 27467488 TI - Sports Activity and Arthritis: Individually Determined or Preplanned? AB - Why are some athletes more prone toward injury and subsequent arthritis than others? How does exercise affect the onset of the degenerative process? Robert P. Nirschl, MD, answers these questions, analyzes the role of heredity in sport selection, and gives tips on preventing injury and treating inflammatory disorders. PMID- 27467489 TI - Guidelines for Exercise During Pregnancy: Too Little or Too Much? AB - Since the ACOG guidelines for exercise and pregnancy were released almost one year ago, they have been the subject of some controversy. Some critics contend that the guidelines are too general, others think they're too specific. ACOG stands behind the guidelines. PMID- 27467490 TI - Judo: A Sport Fit for Everybody? AB - After a century-long tradition as an Eastern sport, judo has begun to attract some nontraditional Western fitness buffs. The reason: Judo may offer certain fitness benefits and present a low risk of serious injury compared with other contact sports. PMID- 27467491 TI - Cardiac Rehabilitation: It's More Than Exercise. PMID- 27467492 TI - The Marathon: Is More Less? AB - The marathon, a legendary race and a supreme challenge, lures many to attempt it. The level of exercise required to prepare for and run in repeated marathons, however, may be injurious to middle-aged men and is in fact unnecessary for providing protection from heart attack among such men. PMID- 27467494 TI - Noteworthy. PMID- 27467495 TI - How Does Exercise Affect Blood Pressure. PMID- 27467497 TI - Periprosthetic cortical bone remodeling in patients with an osseointegrated leg prosthesis. AB - Qualitative studies have shown that the periprosthetic cortical bone may decrease in the first years after the implantation of an osseointegrated leg prosthesis (OILP) in patients with a transfemoral amputation. The resorption of periprosthetic cortical bone may endanger implant survival because of outbreak fractures and aseptic loosening. A decrease in periprosthetic bone quality may also lead to insufficient bone stock for potential revision surgery. This study quantified the periprosthetic bone changes and skeletal remineralization in 27 patients with an ILP (Integrated Leg Prosthesis)-type transfemoral OILP. Periprosthetic cortical thickness was analyzed from standard anteroposterior (AP) radiographs that were taken immediately postoperatively and at both 12 and 24 months post-implantation. The bone mineral density of the femoral hip neck on both sides was measured pre-operatively with Dual X-ray absorptiometry (DXA) and at 12 and 24 months post-implantation. Compared to that immediately post operative, the periprosthetic cortical thickness increased significantly by 9.6% (p = 0.020) and 8.9% (p < 0.001) at 12 and 24 months, respectively. The change in bone mineral density of the hip neck on both sides was not significant. In contrast to previous observations, this study reports increased periprosthetic cortical thickness around the OILP implant in the first 2 years after implantation. These data indicate good prospects for implant survival and possibilities for revision surgery. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1237-1241, 2017. PMID- 27467498 TI - The prognostic significance of serum TGF-beta1 levels in patients with Crimean Congo hemorrhagic fever. AB - Crimean-Congo Hemorrhagic Fever (CCHF) may exhibit a mild clinical course or a severe profile like mortal bleeding. The pathogenesis of the illness and reason of bleeding are unclear. However, endothelial injury is a key factor in the pathogenesis of the illness. Transforming growth factor beta (TGF-beta) is one of the materials involved in repairing injured endothelium. This is a significant polypeptide released in pretty much all cells and important for the regulation of cellular events, epithelium formation, inflammation, blood coagulation, and collagen synthesis. This study aimed to determine the prognostic significance of serum TGF-beta1 levels in CCHF patients. We examined 120 patients hospitalized with CCHF diagnosis and their serum TGF-beta1 was investigated, retrospectively. Patients were put into two groups according to the existence of hemorrhage. Forty four (36.7%) patients had hemorrhage. TGF-beta1 levels in patients with bleeding were 5.2 +/- 1.8, and 7.1 +/- 2.2 for non-bleeding (P < 0.0001). When ROC analysis was performed in patients with CCHF alone in order to identify patients with bleeding, at a TGF-beta1 cut-off point of 4.9, AUC was 0.762 (0.675-0.835), sensitivity 59.1%, specificity 85.5%, PPV 70.3%, and NPV 78.3%. We summarize that TGF-beta1 level and endothelial dysfunction can be related. A decreased TGF-beta1 level is a likely prognostic and diagnostic factor for bleeding in CCHF patients. Therefore, this marker should be considered in the treatment strategy for these patients. J. Med. Virol. 89:413-416, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27467499 TI - Associations Between Posttraumatic Stress Disorder, Emotion Dysregulation, and Alcohol Dependence Symptoms Among Inner City Females. AB - OBJECTIVE: The purpose of this study was to examine how emotion dysregulation (ED) might help explain the relationship between posttraumatic stress disorder (PTSD) and alcohol dependence (AD) symptoms in females. METHOD: Participants included 260 women from primary, diabetes, and gynecological clinics of an urban public hospital. This is a primarily African American sample (96.9%), including individuals reporting exposure to at least 1 traumatic event. We examined the associations and predictability patterns between severity of PTSD symptoms, ED, and AD symptoms. RESULTS: Using linear regression analyses, PTSD avoidance and numbing symptoms and ED were significant predictors of AD symptoms. When looking at specific dimensions of ED, one's inability to engage in goal-directed behavior under strong emotional influences showed a full indirect effect on the relationship between PTSD avoidance and numbing symptoms and AD symptoms. CONCLUSION: Our findings suggest that having poor emotion regulation skills may help explain why females with PTSD become dependent on alcohol. PMID- 27467500 TI - Demographic and Clinical Characteristics of Uveitis in Turkey: The First National Registry Report. AB - PURPOSE: To describe the demographic and clinical profiles of uveitis patients seen at secondary and tertiary care centers in Turkey. METHODS: A nationwide web based registry of patients with uveitis was initiated in November 2008. We analyzed data from a single baseline registry-enrollment visit. RESULTS: In 33 centers, 6967 eyes of 4863 consecutive patients were registered. The mean age at presentation was 36.6 +/- 15.7 (1-92) years; 51.3% were male. Behcet disease was the leading diagnosis (24.9%), followed by ankylosing spondylitis and/or HLA-B27 associated anterior uveitis (9.7%), toxoplasmosis (7.1%), Fuchs uveitis (6.3%), and presumed herpetic anterior uveitis (6.0%). Visual acuity was 0.1 or worse in 22% of eyes. The most common ocular complications were posterior synechiae (16.2%) and cataract formation (16.2%). CONCLUSIONS: Behcet disease is still the most common non-infectious etiology in Turkish uveitis patients, while ocular toxoplasmosis and herpetic anterior uveitis are the most common infectious uveitic entities. PMID- 27467501 TI - Evaluation of antimicrobial resistance and virulence of enterococci from equipment surfaces, raw materials, and traditional cheeses. AB - Forty enterococci isolated along the production chains of three traditional cheeses (PDO Pecorino Siciliano, PDO Vastedda della Valle del Belice, and Caciocavallo Palermitano) made in Sicily (southern Italy) were studied for the assessment of their antibiotic resistance and virulence by a combined phenotypic/genotypic approach. A total of 31 Enterococcus displayed resistance to at least one or more of the antimicrobials tested. The strains exhibited high percentages of resistance to erythromycin (52.5%), ciprofloxacin (35.0%), quinupristin-dalfopristin (20.0%), tetracycline (17.5%), and high-level streptomycin (5.0%). The presence of tet(M), cat(pC221), and aadE genes for resistance to tetracycline, chloramphenicol, and streptomycin, respectively, was registered in all strains with resistance phenotype. The erm(B) gene was not detected in any erythromycin-resistant strain. The Enterococcus strains were further tested by PCR for the presence of virulence genes, namely, gelE, asa1, efaA, ace, and esp. Twenty strains were positive for all virulence genes tested. Among the enterococci isolated from final cheeses, three strains (representing 33.3% of total cheese strains) were sensible to all antimicrobials tested and did not carry any virulence factor. Although this study confirmed that the majority of dairy enterococci are vectors for the dissemination of antimicrobial resistance and virulence genes, only two strains showed a high resistance to aminoglycosides, commonly administered to combat enterococci responsible for human infections. Furthermore, the presence of the strains E. casseliflavus FMAC163, E. durans FMAC134B, and E. faecium PON94 without risk determinants, found at dominating levels over the Enterococcus populations in the processed products, stimulates further investigations for their future applications in cheese making. All strains devoid of the undesired traits were isolated from stretched cheeses. Thus, this cheese typology represents an interesting environment to deepen the studies on the risk/benefit role of enterococci in fermented foods for their qualified presumption of safety (QPS) assessment. PMID- 27467503 TI - Uncovering Spatial Variation in Acoustic Environments Using Sound Mapping. AB - Animals select and use habitats based on environmental features relevant to their ecology and behavior. For animals that use acoustic communication, the sound environment itself may be a critical feature, yet acoustic characteristics are not commonly measured when describing habitats and as a result, how habitats vary acoustically over space and time is poorly known. Such considerations are timely, given worldwide increases in anthropogenic noise combined with rapidly accumulating evidence that noise hampers the ability of animals to detect and interpret natural sounds. Here, we used microphone arrays to record the sound environment in three terrestrial habitats (forest, prairie, and urban) under ambient conditions and during experimental noise introductions. We mapped sound pressure levels (SPLs) over spatial scales relevant to diverse taxa to explore spatial variation in acoustic habitats and to evaluate the number of microphones needed within arrays to capture this variation under both ambient and noisy conditions. Even at small spatial scales and over relatively short time spans, SPLs varied considerably, especially in forest and urban habitats, suggesting that quantifying and mapping acoustic features could improve habitat descriptions. Subset maps based on input from 4, 8, 12 and 16 microphones differed slightly (< 2 dBA/pixel) from those based on full arrays of 24 microphones under ambient conditions across habitats. Map differences were more pronounced with noise introductions, particularly in forests; maps made from only 4-microphones differed more (> 4 dBA/pixel) from full maps than the remaining subset maps, but maps with input from eight microphones resulted in smaller differences. Thus, acoustic environments varied over small spatial scales and variation could be mapped with input from 4-8 microphones. Mapping sound in different environments will improve understanding of acoustic environments and allow us to explore the influence of spatial variation in sound on animal ecology and behavior. PMID- 27467502 TI - Regulation of Cell Proliferation and Migration by miR-203 via GAS41/miR-10b Axis in Human Glioblastoma Cells. AB - Glioma amplified sequence 41(GAS41) is a potent transcription factor that play a crucial role in cell proliferation and survival. In glioblastoma, the expression of GAS41 at both transcriptional and post transcriptional level needs to be tightly maintained in response to cellular signals. Micro RNAs (miRNA) are small non coding RNA that act as important regulators for modulating the expression of various target genes. Studies have shown that several miRNAs play role in the post-transcriptional regulation of GAS41. Here we identified GAS41 as a novel target for endogenous miR-203 and demonstrate an inverse correlation of miR-203 expression with GAS41 in glioma cell lines (HNGC2 and U87). Over expression of miR-203 negatively regulates GAS41 expression in U87 and HNGC2 cell lines. Moreover, miR-203 restrained miR-10b action by suppressing GAS41. GAS41 is essential for repressing p53 in tumor suppressor pathway during cell proliferation. Enforced expression of GAS41 produced contradictory effect on miR 203 but was able to enhance p53 tumor suppressor pathway associated protein. It was also found that miR-203 maintains the stability of p53 as knock down of p53 expression using siRNA resulted in down regulation of pri-miR and mature miR-203 expression. Conversely reconstitution of miR-203 expression induced apoptosis and inhibited migratory property of glioma cells. Taken together, we show that miR 203 is a key negative regulator of GAS41 and acts as tumor suppressor microRNA in glioma. PMID- 27467504 TI - Risk prediction in Barrett's esophagus - aspects of a combination of molecular and epidemiologic biomarkers reflecting alterations of the microenvironment. AB - Barrett's esophagus (BE) is a chronic, metaplastic lesion of the esophagus and the only known precursor of esophageal adenocarcinoma. The identification of risk factors to assess the risk for BE and their correspondence with hallmarks of malignant progression for early stratification purposes is critically needed. Data legitimate the assumption that aside of reflux symptoms and related conditions, also demographic and environmental factors are thought to be associated with the risk for BE and its progression to esophageal adenocarcinoma. Molecular biomarkers and inflammatory mechanisms are subjects of intensive research and dispone of promising features regarding risk assessment especially for progressive BE. The amount of investigated epidemiologic factors, as well as discovered biomarkers gets confusingly large. Despite the recognized potential relevance of environmental and molecular factors, the efforts to date have resulted in moderately applicable risk estimates. More prospective data is needed to allow an imputation of the mostly retrospectively assessed factors to reappraise their meaningfulness in risk prediction approaches. PMID- 27467506 TI - Acupuncture-Related Quality of Life Changes Using PROMIS Computer Adaptive Tests in a Pragmatic Trial with Oncology and General Integrative Medicine Patients: The Role of Baseline Acupuncture Expectations. AB - INTRODUCTION: Acupuncture has been shown to alleviate symptoms and increase general well-being in different medical patient samples. A major challenge in acupuncture clinical research is the availability of comparable and standardized patient-reported outcome measurement (PRO) tools. OBJECTIVES: This study used a pragmatic design to examine longitudinal changes in quality of life (QOL) in a medical patient sample following acupuncture using PROs from the National Institutes of Health's Patient Reported Outcomes Measurement Information System (PROMIS) initiative. It also examined the role of acupuncture expectancies, as well as patient and provider perceptions of acupuncture benefit. DESIGN: Following informed consent, patients completed baseline QOL measures (T1) prior to their first acupuncture session. Subsequent assessments (up to 20) were completed immediately following ensuing acupuncture sessions. Patients completed assessments either on a touch-screen computer at the clinic or from their home computer. RESULTS: Compared with acupuncture-naive participants, those who received prior acupuncture treatment reported significantly higher anxiety, fatigue, sleep disturbance, and lower positive affect at baseline. By the second assessment, however, these differences became nonexistent. Participants who held greater baseline acupuncture expectations (e.g., their situation would improve a lot, they would have improved coping skills, their symptoms would disappear, their energy would increase) reported significantly higher fatigue, pain interference, and problems with physical functioning. Between T1 and T2, all participants reported significant improvements in anxiety, depression, and fatigue. Exploratory longitudinal models demonstrated significant linear improvements over time in anxiety (p = 0.006), depression (p = 0.007), pain interference (p < 0.001), and sleep disturbance (p = 0.004). No linear reduction over time was found with fatigue (p = 0.587), physical function (p = 0.654), or positive affect (p = 0.247). CONCLUSIONS: Overall, PROMIS computer adaptive tests were able to assess domains of QOL briefly. Although pretreatment acupuncture expectations highlighted subgroup differences in outcomes at baseline, linear growth models demonstrated the positive effects of acupuncture over time on anxiety, depression, pain interference, and sleep disturbance. PMID- 27467505 TI - Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model. AB - Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNgamma, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children. PMID- 27467508 TI - Tuning the Voices of a Choir: Detecting Ecological Gradients in Time-Series Populations. AB - This paper introduces a new approach-the Principal Component Gradient Analysis (PCGA)-to detect ecological gradients in time-series populations, i.e. several time-series originating from different individuals of a population. Detection of ecological gradients is of particular importance when dealing with time-series from heterogeneous populations which express differing trends. PCGA makes use of polar coordinates of loadings from the first two axes obtained by principal component analysis (PCA) to define groups of similar trends. Based on the mean inter-series correlation (rbar) the gain of increasing a common underlying signal by PCGA groups is quantified using Monte Carlo Simulations. In terms of validation PCGA is compared to three other existing approaches. Focusing on dendrochronological examples, PCGA is shown to correctly determine population gradients and in particular cases to be advantageous over other considered methods. Furthermore, PCGA groups in each example allowed for enhancing the strength of a common underlying signal and comparably well as hierarchical cluster analysis. Our results indicate that PCGA potentially allows for a better understanding of mechanisms causing time-series population gradients as well as objectively enhancing the performance of climate transfer functions in dendroclimatology. While our examples highlight the relevance of PCGA to the field of dendrochronology, we believe that also other disciplines working with data of comparable structure may benefit from PCGA. PMID- 27467507 TI - Modulation of Pathways Underlying Distinct Cell Death Mechanisms in Two Human Lung Cancer Cell Lines in Response to SN1 Methylating Agents Treatment. PMID- 27467509 TI - Control of Cutaneous Leishmaniasis Using Geographic Information Systems from 2010 to 2014 in Khuzestan Province, Iran. AB - BACKGROUND: Cutaneous leishmanisis (CL) is found worldwide and is considered to be endemic in 88 countries such as Iran. Geographic information system (GIS) is a method that can create, archive, analyze traditional map and place data of the disease distribution. The aim of this study was to produce distributional maps of CL over five years and evaluate the role of GIS in control of CL in Khuzestan province where an endemic area of CL in Iran is. METHODS: CL epidemiological data on the District and village levels for the period 2010-2013 were provided as census by health surveillance system in all counties and in control diseases center (CDC) of Khuzestan province. After collection of CL data, the collected data of CL from 2010 to 2013 were analyzed using GIS. The collected data of CL from 2010 to 2013 was analyzed using GIS. The endemic areas of CL during 2010 2013 were recognized using GIS maps and the control programs of CL were done in these regions based on epidemiological situation and the stratification of risk areas. RESULTS: During the study period, there were 4672 recorded cases of clinical cases of CL by Khuzestan Health Center. Data of GIS referring to CL patients showed that center and eastern districts of Khuzestan had a significant number of cases. In 2014 that control program was done, ten distinct of Khuzestan Province didn't show any cases of the disease. CONCLUSION: In conclusion, analyses of data distributed in the geographic spaces are increasingly appreciated in leishmaniasis control management. GIS tools promoted greater efficiency in making decisions and planning activities in the control of vector born disease such as leishmaniasis. PMID- 27467510 TI - Silencing the Transcriptional Repressor, ZCT1, Illustrates the Tight Regulation of Terpenoid Indole Alkaloid Biosynthesis in Catharanthus roseus Hairy Roots. AB - The Catharanthus roseus plant is the source of many valuable terpenoid indole alkaloids (TIAs), including the anticancer compounds vinblastine and vincristine. Transcription factors (TFs) are promising metabolic engineering targets due to their ability to regulate multiple biosynthetic pathway genes. To increase TIA biosynthesis, we elicited the TIA transcriptional activators (ORCAs and other unidentified TFs) with the plant hormone, methyl jasmonate (MJ), while simultaneously silencing the expression of the transcriptional repressor ZCT1. To silence ZCT1, we developed transgenic hairy root cultures of C. roseus that expressed an estrogen-inducible Zct1 hairpin for activating RNA interference. The presence of 17beta-estradiol (5MUM) effectively depleted Zct1 in hairy root cultures elicited with MJ dosages that either optimize or inhibit TIA production (250 or 1000MUM). However, silencing Zct1 was not sufficient to increase TIA production or the expression of the TIA biosynthetic genes (G10h, Tdc, and Str), illustrating the tight regulation of TIA biosynthesis. The repression of the TIA biosynthetic genes at the inhibitory MJ dosage does not appear to be solely regulated by ZCT1. For instance, while Zct1 and Zct2 levels decreased through activating the Zct1 hairpin, Zct3 levels remained elevated. Since ZCT repressors have redundant yet distinct functions, silencing all three ZCTs may be necessary to relieve their repression of alkaloid biosynthesis. PMID- 27467511 TI - Allosteric Inhibition of Factor XIIIa. Non-Saccharide Glycosaminoglycan Mimetics, but Not Glycosaminoglycans, Exhibit Promising Inhibition Profile. AB - Factor XIIIa (FXIIIa) is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa's active site by using sulfated glycosaminoglycans (GAGs) or non-saccharide GAG mimetics (NSGMs) would lead to the discovery of the first allosteric FXIIIa inhibitors. We tested a library of 22 variably sulfated GAGs and NSGMs against human FXIIIa to discover promising hits. Interestingly, although some GAGs bound to FXIIIa better than NSGMs, no GAG displayed any inhibition. An undecasulfated quercetin analog was found to inhibit FXIIIa with reasonable potency (efficacy of 98%). Michaelis-Menten kinetic studies revealed an allosteric mechanism of inhibition. Fluorescence studies confirmed close correspondence between binding affinity and inhibition potency, as expected for an allosteric process. The inhibitor was reversible and at least 9-fold- and 26 fold selective over two GAG-binding proteins factor Xa (efficacy of 71%) and thrombin, respectively, and at least 27-fold selective over a cysteine protease papain. The inhibitor also inhibited the FXIIIa-mediated polymerization of fibrin in vitro. Overall, our work presents the proof-of-principle that FXIIIa can be allosterically modulated by sulfated non-saccharide agents much smaller than GAGs, which should enable the design of selective and safe anticoagulants. PMID- 27467512 TI - Major Sensing Proteins in Pathogenic Fungi: The Hybrid Histidine Kinase Family. PMID- 27467513 TI - Reliability and Validity of Cervical Range of Motion and Muscle Strength Testing. AB - Kubas, C, Chen, Y-W, Echeverri, S, McCann, S, Denhoed, M, Walker, C, Kennedy, C, and Reid, WD. Reliability and validity of cervical range of motion and muscle strength testing. J Strength Cond Res 31(4): 1087-1096, 2017-Cervical range of motion (ROM) and strength are fundamental measures to assess treatment effectiveness. The JTECH wireless devices provide versatile means of quantifying these measurements. The purpose of this study was to determine intrarater and interrater reliabilities and concurrent validity of the JTECH wireless dual inclinometer and handheld dynamometer. This study included 20 healthy subjects (mean age = 28.7 +/- 7.8 years). The directions of ROM movement measured were cervical flexion, extension, lateral flexion, and rotation. Isometric strength was measured for flexion, extension, and lateral flexion. Two testers measured cervical ROM and isometric strength for each subject using the JTECH devices during 2 or 3 sessions to determine reliability. The same ROM and muscle strength movements were measured using the CROM3 and MicroFET2, respectively, to assess concurrent validity. Reliability and validity were analyzed using intraclass correlation coefficient (ICC), along with SEM and minimal detectable change. The results of this study showed that the intrarater reliability of the JTECH inclinometer and dynamometer was moderate to excellent (ICCs (3,1) = 0.53-0.90 and 0.74-0.91, respectively). The interrater reliability of the JTECH inclinometer was moderate to excellent (ICCs (2,3) = 0.69-0.89), whereas the JTECH dynamometer showed excellent interrater reliability (ICCs (2,3) = 0.84 0.88). The JTECH inclinometer and dynamometer showed moderate to excellent concurrent validity (ICCs (3,2) = 0.65-0.91 and 0.91-0.96, respectively). With the ease of use, portability, and ability to record multiple measurements without stopping, these devices can be applied to clinical and research settings. PMID- 27467514 TI - Match Physical Performance of Elite Female Soccer Players During International Competition. AB - Datson, N, Drust, B, Weston, M, Jarman, IH, Lisboa, P, and Gregson, W. Match physical performance of elite female soccer players during international competition. J Strength Cond Res 31(9): 2379-2387, 2017-The purpose of this study was to provide a detailed analysis of the physical demands of competitive international female soccer match play. A total of 148 individual match observations were undertaken on 107 outfield players competing in competitive international matches during the 2011-2012 and 2012-2013 seasons, using a computerized tracking system (Prozone Sports Ltd., Leeds, England). Total distance and total high-speed running distances were influenced by playing position, with central midfielders completing the highest (10,985 +/- 706 m and 2,882 +/- 500 m) and central defenders the lowest (9,489 +/- 562 m and 1,901 +/- 268 m) distances, respectively. Greater total very high-speed running distances were completed when a team was without (399 +/- 143 m) compared to with (313 +/- 210 m) possession of the ball. Most sprints were over short distances with 76% and 95% being less than 5 and 10 m, respectively. Between half reductions in physical performance were present for all variables, independent of playing position. This study provides novel findings regarding the physical demands of different playing positions in competitive international female match play and provides important insights for physical coaches preparing elite female players for competition. PMID- 27467515 TI - Proof of Concept of Automated Collision Detection Technology in Rugby Sevens. AB - Clarke, AC, Anson, JM, and Pyne, DB. Proof of concept of automated collision detection technology in rugby sevens. J Strength Cond Res 31(4): 1116-1120, 2017 Developments in microsensor technology allow for automated detection of collisions in various codes of football, removing the need for time-consuming postprocessing of video footage. However, little research is available on the ability of microsensor technology to be used across various sports or genders. Game video footage was matched with microsensor-detected collisions (GPSports) in one men's (n = 12 players) and one women's (n = 12) rugby sevens match. True positive, false-positive, and false-negative events between video and microsensor detected collisions were used to calculate recall (ability to detect a collision) and precision (accurately identify a collision). The precision was similar between the men's and women's rugby sevens game (~0.72; scale 0.00-1.00); however, the recall in the women's game (0.45) was less than that for the men's game (0.69). This resulted in 45% of collisions for men and 62% of collisions for women being incorrectly labeled. Currently, the automated collision detection system in GPSports microtechnology units has only modest utility in rugby sevens, and it seems that a rugby sevens-specific algorithm is needed. Differences in measures between the men's and women's game may be a result of physical size, and strength, and physicality, as well as technical and tactical factors. PMID- 27467516 TI - Physical and Physiological Demands of Experienced Male Basketball Players During a Competitive Game. AB - Puente, C, Abian-Vicen, J, Areces, F, Lopez, R, and Del Coso, J. Physical and physiological demands of experienced male basketball players during a competitive game. J Strength Cond Res 31(4): 956-962, 2017-The aim of this investigation was to analyze the physical and physiological demands of experienced basketball players during a real and competitive game. Twenty-five well-trained basketball players (8 guards, 8 forwards, and 9 centers) played a competitive game on an outdoor court. Instantaneous running speeds, the number of body impacts above 5 g, and the number of accelerations and decelerations were assessed by means of a 15-Hz global Positioning System accelerometer unit. Individual heart rate was also recorded using heart rate monitors. As a group mean, the basketball players covered 82.6 +/- 7.8 m.min during the game with a mean heart rate of 89.8 +/- 4.4% of maximal heart rate. Players covered 3 +/- 3% of the total distance running at above 18 km.h and performed 0.17 +/- 0.13 sprints per minute. The number of body impacts was 8.2 +/- 1.8 per minute of play. The running pace of forwards was higher than that of centers (86.8 +/- 6.2 vs. 76.6 +/- 6.0 m.min; p <= 0.05). The maximal speed obtained during the game was significantly higher for guards than that for centers (24.0 +/- 1.6 km.h vs. 21.3 +/- 1.6 km.h; p <= 0.05). Centers performed a lower number of accelerations/decelerations than guards and forwards (p <= 0.05). In conclusion, the extraordinary rates of specific movements performed by these experienced basketball players indicate the high physiological demands necessary to be able to compete in this sport. The centers were the basketball players who showed lower physiological demands during a game, whereas there were no differences between guards and forwards. These results can be used by coaches to adapt basketball training programs to the specific demands of each playing position. PMID- 27467517 TI - Effects of a 10-Week Nordic Hamstring Exercise and Russian Belt Training on Posterior Lower-Limb Muscle Strength in Elite Junior Soccer Players. AB - Rey, E, Paz-Dominguez, A, Porcel-Almendral, D, Paredes-Hernandez, V, Barcala Furelos, R, and Abelairas-Gomez, C. Effects of a 10-week Nordic hamstring exercise and Russian belt training on posterior lower-limb muscle strength in elite junior soccer players. J Strength Cond Res 31(5): 1198-1205, 2017-The purpose of this study was to assess the effect of 2 eccentric hamstring training exercises, Nordic hamstring exercise (NHE) and Russian belt (RB), on lower-limb strength and bilateral asymmetry using the single-leg hamstring bridge (SLHB) test. Forty-seven elite junior soccer players (age 17.7 +/- 0.5 years, height 175.3 +/- 3.6 cm, body mass 68.1 +/- 7.4 kg) were randomized into 1 of 3 groups, the NHE group (n = 16), RB group (n = 15), or the control group (CG) (n = 16). The eccentric training intervention consisted of 27 supervised training sessions over 10 weeks. Within-group analysis showed significant improvements (p < 0.001) in right SLHB (+25.52% for NHE and +18.33% for RB) and left SLHB (+28.92% for NHE and +20.08% for RB) from pretest to posttest in NHE and RB. However, no significant pre-post changes were observed for the CG in any variable. In addition, a significant time effect (p = 0.028) was also observed for NHE in bilateral asymmetry decreasing from pre- to posttest. In the between-groups analysis, significant better results were found in right SLHB and left SLHB, in the NHE group and RB group in comparison with CG. However, there were no differences between the eccentric training groups (NHE vs. RB). The RB seems to be a viable alternative to the NHE to developing posterior lower-limb muscle strength based on SLHB. PMID- 27467518 TI - The Hog Cycle of Law Professors: An Econometric Time Series Analysis of the Entry Level Job Market in Legal Academia. AB - The (German) market for law professors fulfils the conditions for a hog cycle: In the short run, supply cannot be extended or limited; future law professors must be hired soon after they first present themselves, or leave the market; demand is inelastic. Using a comprehensive German dataset, we show that the number of market entries today is negatively correlated with the number of market entries eight years ago. This suggests short-sighted behavior of young scholars at the time when they decide to prepare for the market. Using our statistical model, we make out-of-sample predictions for the German academic market in law until 2020. PMID- 27467519 TI - Detection of Successful and Unsuccessful Pregnancies in Mice within Hours of Pairing through Frequency Analysis of High Temporal Resolution Core Body Temperature Data. AB - Many controllable factors negatively impact fetal development, underscoring the importance of early pregnancy detection and identification of events that reliably predict potential complications. Clinically, core body temperature (CBT) is used to aid family planning and pregnancy detection. However, such temperature data typically are gathered in single, daily measurements. In animal studies, interventions or cell/tissue harvesting at defined stages of fetal development are arduous, requiring timed mating by trained observers. The value of continuous temperature measurements remains largely unexplored, but the advent of small, inexpensive, and increasingly ubiquitous, accurate sensor devices makes continuous measures feasible. Here, using a mouse model, we show that continuous, 1-min resolution CBT measurements reliably allow for the earliest and most accurate detection of pregnancy (100%, within 14 h of initial pairing), without requiring interaction with the animal for data collection. This method also reveals a subset of females that exhibit a pregnancy-like response following pairing that persists for a variable number of days. Application of wavelet analysis that permits frequency analysis while preserving temporal resolution, uncovers significant differences in ultradian frequencies of CBT; these rhythms are significantly increased in the 12 h after the day of pairing for pregnancies carried to term compared to apparent pregnancies that failed. High temporal resolution CBT and wavelet analysis permit strikingly early detection and separation of successful pregnancies and pregnancy-like events. PMID- 27467520 TI - Effect of Chronic Kidney Diseases on Mortality among Digoxin Users Treated for Non-Valvular Atrial Fibrillation: A Nationwide Register-Based Retrospective Cohort Study. AB - PURPOSE: This study investigated the impact of chronic kidney disease on all causes and cardiovascular mortality in patients with atrial fibrillation treated with digoxin. METHODS: All patients with non-valvular atrial fibrillation and/or atrial flutter as hospitalization diagnosis from January 1, 1997 to December 31, 2012 were identified in Danish nationwide administrative registries. Cox proportional hazard model was used to compare the adjusted risk of all-causes and cardiovascular mortality among patients with and without chronic kidney disease and among patients with different chronic kidney disease stages within 180 days and 2 years from the first digoxin prescription. RESULTS: We identified 37,981 patients receiving digoxin; 1884 patients had the diagnosis of chronic kidney disease. Cox regression analysis showed no statistically significant differences in all-causes (Hazard Ratio, HR 0.89; 95% confident interval, CI 0.78-1.03) and cardiovascular mortality (HR 0.88; 95%CI 0.74-1.05) among patients with and without chronic kidney disease within 180 days of follow-up period. No statistically significant differences was found using a 2 years follow-up period neither for all causes mortality (HR 0.90; 95%CI 0.79-1.03), nor for cardiovascular mortality (HR 0.87; 95%CI 0.74-1.02). No statistically significant differences was found comparing patients with and without estimated Glomerular Filtration Rate <30ml/min/1.73m2 and patients with different stages of chronic kidney disease, for all-causes and cardiovascular mortality within 180 days and 2 years from the first digoxin prescription. CONCLUSIONS: This study suggest no direct effect of chronic kidney disease and chronic kidney disease stages on all causes and cardiovascular mortality within both 180 days and 2 years from the first digoxin prescription in patients treatment-naive with digoxin for non valvular atrial fibrillation. PMID- 27467521 TI - Crucial Role of Elovl6 in Chondrocyte Growth and Differentiation during Growth Plate Development in Mice. AB - ELOVL family member 6, elongation of very long chain fatty acids (Elovl6) is a microsomal enzyme, which regulates the elongation of C12-16 saturated and monounsaturated fatty acids. Elovl6 has been shown to be associated with various pathophysiologies including insulin resistance, atherosclerosis, and non alcoholic steatohepatitis. To investigate a potential role of Elovl6 during bone development, we here examined a skeletal phenotype of Elovl6 knockout (Elovl6-/-) mice. The Elovl6-/- skeleton was smaller than that of controls, but exhibited no obvious patterning defects. Histological analysis revealed a reduced length of proliferating and an elongated length of hypertrophic chondrocyte layer, and decreased trabecular bone in Elovl6-/- mice compared with controls. These results were presumably due to a modest decrease in chondrocyte proliferation and accelerated differentiation of cells of the chondrocyte lineage. Consistent with the increased length of the hypertrophic chondrocyte layer in Elovl6-/- mice, Collagen10alpha1 was identified as one of the most affected genes by ablation of Elovl6 in chondrocytes. Furthermore, this elevated expression of Collagen10alpha1 of Elovl6-null chondrocytes was likely associated with increased levels of Foxa2/a3 and Mef2c mRNA expression. Relative increases in protein levels of nuclear Foxa2 and cytoplasmic histone deacethylase 4/5/7 were also observed in Elovl6 knockdown cells of the chondrocyte lineage. Collectively, our data suggest that Elovl6 plays a critical role for proper development of embryonic growth plate. PMID- 27467522 TI - Association of Fluid Accumulation with Clinical Outcomes in Critically Ill Children with Severe Sepsis. AB - OBJECTIVE: To evaluate whether early and acquired daily fluid overload (FO), as well as fluctuations in fluid accumulation, were associated with adverse outcomes in critically ill children with severe sepsis. METHODS: This study enrolled 202 children in a pediatric intensive care unit (PICU) with severe sepsis. Early fluid overload was defined as >=5% fluid accumulation occurring in the first 24 hours of PICU admission. The maximum daily fluid accumulation >=5% occurring during the next 6 days in patients with at least 48 hours of PICU stay was defined as PICU-acquired daily fluid overload. The fluctuation in fluid accumulation was calculated as the difference between the maximum and the minimum daily fluid accumulation obtained during the first 7 days after admission. RESULTS: Of the 202 patients, 61 (30.2%) died during PICU stay. Among all patients, 41 (20.3%) experienced early fluid overload, including 9 with a FO >=10%. Among patients with at least 48 hours of PICU stay (n = 154), 36 (23.4%) developed PICU-acquired daily fluid overload, including 2 with a FO >=10%. Both early fluid overload (AOR = 1.20; 95% CI 1.08-1.33; P = 0.001; n = 202) and PICU acquired daily fluid overload (AOR = 5.47 per log increase; 95% CI 1.15-25.96; P = 0.032; n = 154) were independent risk factors associated with mortality after adjusting for age, illness severity, etc. However, fluctuations in fluid accumulation were not associated with mortality after adjustment. Length of PICU stay increased with greater fluctuations in fluid accumulation in all patients with at least 48 hours of PICU stay (FO <5%, 5%-10% vs. >=10%: 4 [3-8], 7 [4-11] vs. 10 [6-16] days; P <0.001; n = 154) and in survivors (4 [3-8], 7 [5-11] vs. 10 [5-15] days; P <0.001; n = 121). Early fluid overload achieved an area under-the receiver-operating-characteristic curve of 0.74 (95% CI 0.65-0.82; P <0.001; n = 202) for predicting mortality in patients with severe sepsis, with a sensitivity of 67.2% and a specificity of 80.1% at the optimal cut-off value of 2.65%. CONCLUSIONS: Both early and acquired daily fluid overload were independently associated with PICU mortality in children with severe sepsis. PMID- 27467523 TI - The Glutathione-S-Transferase, Cytochrome P450 and Carboxyl/Cholinesterase Gene Superfamilies in Predatory Mite Metaseiulus occidentalis. AB - Pesticide-resistant populations of the predatory mite Metaseiulus (= Typhlodromus or Galendromus) occidentalis (Arthropoda: Chelicerata: Acari: Phytoseiidae) have been used in the biological control of pest mites such as phytophagous Tetranychus urticae. However, the pesticide resistance mechanisms in M. occidentalis remain largely unknown. In other arthropods, members of the glutathione-S-transferase (GST), cytochrome P450 (CYP) and carboxyl/cholinesterase (CCE) gene superfamilies are involved in the diverse biological pathways such as the metabolism of xenobiotics (e.g. pesticides) in addition to hormonal and chemosensory processes. In the current study, we report the identification and initial characterization of 123 genes in the GST, CYP and CCE superfamilies in the recently sequenced M. occidentalis genome. The gene count represents a reduction of 35% compared to T. urticae. The distribution of genes in the GST and CCE superfamilies in M. occidentalis differs significantly from those of insects and resembles that of T. urticae. Specifically, we report the presence of the Mu class GSTs, and the J' and J" clade CCEs that, within the Arthropoda, appear unique to Acari. Interestingly, the majority of CCEs in the J' and J" clades contain a catalytic triad, suggesting that they are catalytically active. They likely represent two Acari-specific CCE clades that may participate in detoxification of xenobiotics. The current study of genes in these superfamilies provides preliminary insights into the potential molecular components that may be involved in pesticide metabolism as well as hormonal/chemosensory processes in the agriculturally important M. occidentalis. PMID- 27467524 TI - An Immunohistochemical Study on the Role of Oxidative and Nitrosative Stress in Irradiated Skin. AB - BACKGROUND/AIM: The effects of ionizing radiation through the generation of free radicals, reactive aldehydes, and other oxidative and nitrosative by-products account for skin injuries as side effects of radiation therapy (RT). This study aims to identify cellular pathways in oxidative and nitrosative stress in irradiated skin using well-established marker proteins in an immunohistochemical analysis. MATERIALS AND METHODS: Tissue specimens of 51 patients were obtained during operative access to the neck. Twenty patients (39.2%) received RT prior to the surgical intervention. Immunohistochemical analysis of stable degradation products of reactive oxygen and nitrogen species (RONS), 3-nitrotyrosine, 8 isoprostane, phosphorylated AKT (p-AKT), and phosphorylated extracellular signal regulated kinase (p-ERK) was performed in specimens which were exposed to RT and those without a history of RT. RESULTS: Immunohistochemical staining showed a significantly increased expression of nitrotyrosine in superficial and basal epidermal regions of interest (ROI), p-AKT in all epidermal ROI, and p-ERK in all the investigated epidermal and dermal ROI, as well as in an overall analysis. No significance could be detected in immunostaining against isoprostane. DISCUSSION: This study summarizes the influence of RONS in RT. Moreover, a detailed histological analysis was able to identify epidermal ROI as a main starting point of RONS in irradiated skin. Even though the role of RONS in high-dose therapeutic radiation remains a subject for further research, these data underlines the crucial role of RONS in high-dose radiation. PMID- 27467525 TI - Moving towards Specific Nutrigenetic Recommendation Algorithms: Caffeine, Genetic Variation and Cardiovascular Risk. AB - Recent research has indicated that part of the interindividual variability in cardiovascular responses to caffeine has a genetic basis. Therefore, knowledge of the individual's genetic constitution may allow an individual tailoring of dietary advice for the use of caffeine-containing beverages, yielding an example of the potential of practical translation of nutrigenetic information. This paper reviews the basis for possible nutrigenetic recommendations on the consumption of caffeine, discussing the current gaps in knowledge but also proposing a mode of action in this research area, which may be transposed to other types of similar recommendations. PMID- 27467527 TI - D-Allulose Production from D-Fructose by Permeabilized Recombinant Cells of Corynebacterium glutamicum Cells Expressing D-Allulose 3-Epimerase Flavonifractor plautii. AB - A d-allulose 3-epimerase from Flavonifractor plautii was cloned and expressed in Escherichia coli and Corynebacterium glutamicum. The maximum activity of the enzyme purified from recombinant E. coli cells was observed at pH 7.0, 65 degrees C, and 1 mM Co2+ with a half-life of 40 min at 65 degrees C, Km of 162 mM, and kcat of 25280 1/s. For increased d-allulose production, recombinant C. glutamicum cells were permeabilized via combined treatments with 20 mg/L penicillin and 10% (v/v) toluene. Under optimized conditions, 10 g/L permeabilized cells produced 235 g/L d-allulose from 750 g/L d-fructose after 40 min, with a conversion rate of 31% (w/w) and volumetric productivity of 353 g/L/h, which were 1.4- and 2.1 fold higher than those obtained for nonpermeabilized cells, respectively. PMID- 27467526 TI - Context Specific and Differential Gene Co-expression Networks via Bayesian Biclustering. AB - Identifying latent structure in high-dimensional genomic data is essential for exploring biological processes. Here, we consider recovering gene co-expression networks from gene expression data, where each network encodes relationships between genes that are co-regulated by shared biological mechanisms. To do this, we develop a Bayesian statistical model for biclustering to infer subsets of co regulated genes that covary in all of the samples or in only a subset of the samples. Our biclustering method, BicMix, allows overcomplete representations of the data, computational tractability, and joint modeling of unknown confounders and biological signals. Compared with related biclustering methods, BicMix recovers latent structure with higher precision across diverse simulation scenarios as compared to state-of-the-art biclustering methods. Further, we develop a principled method to recover context specific gene co-expression networks from the estimated sparse biclustering matrices. We apply BicMix to breast cancer gene expression data and to gene expression data from a cardiovascular study cohort, and we recover gene co-expression networks that are differential across ER+ and ER- samples and across male and female samples. We apply BicMix to the Genotype-Tissue Expression (GTEx) pilot data, and we find tissue specific gene networks. We validate these findings by using our tissue specific networks to identify trans-eQTLs specific to one of four primary tissues. PMID- 27467528 TI - Real-Time Subject-Independent Pattern Classification of Overt and Covert Movements from fNIRS Signals. AB - Recently, studies have reported the use of Near Infrared Spectroscopy (NIRS) for developing Brain-Computer Interface (BCI) by applying online pattern classification of brain states from subject-specific fNIRS signals. The purpose of the present study was to develop and test a real-time method for subject specific and subject-independent classification of multi-channel fNIRS signals using support-vector machines (SVM), so as to determine its feasibility as an online neurofeedback system. Towards this goal, we used left versus right hand movement execution and movement imagery as study paradigms in a series of experiments. In the first two experiments, activations in the motor cortex during movement execution and movement imagery were used to develop subject-dependent models that obtained high classification accuracies thereby indicating the robustness of our classification method. In the third experiment, a generalized classifier-model was developed from the first two experimental data, which was then applied for subject-independent neurofeedback training. Application of this method in new participants showed mean classification accuracy of 63% for movement imagery tasks and 80% for movement execution tasks. These results, and their corresponding offline analysis reported in this study demonstrate that SVM based real-time subject-independent classification of fNIRS signals is feasible. This method has important applications in the field of hemodynamic BCIs, and neuro-rehabilitation where patients can be trained to learn spatio-temporal patterns of healthy brain activity. PMID- 27467529 TI - Resting-state functional MRI of abnormal baseline brain activity in young depressed patients with and without suicidal behavior. AB - BACKGROUND: Suicide among youth is a major public health challenge, attracting increasing attention. However, the neurobiological mechanisms and the pathophysiology underlying suicidal behavior in depressed youths are still unclear. The fMRI enables a better understanding of functional changes in the brains of young suicide attempters with depressive disorder through detecting spontaneous neural activity. The purpose of this study was to identify the relationship between abnormalities involving local brain function and suicidal attempts in depressed youths using resting-state fMRI (RS-fMRI). METHOD: Thirty five depressed youths aged between 15 and 29 years with a history of suicidal attempts (SU group), 18 patients without suicidal attempts (NSU group) and 47 gender-, age- and education-matched healthy controls (HC) underwent psychological assessment and R-fMRI. The differences in fractional amplitude of low-frequency fluctuation (ALFF) among the three groups were compared. The clinical factors correlated with z-score ALFF in the regions displaying significant group differences were investigated. The ROC method was used to evaluate these clusters as markers to screen patients with suicidal behavior. RESULTS: Compared with the NSU and HC groups, the SU group showed increased zALFF in the right superior temporal gyrus (r-STG), left middle temporal gyrus (L-MTG) and left middle occipital gyrus (L-MOG). Additionally, significantly decreased zALFF values in the L-SFG and L-MFG were found in the SU group compared with the NSU group, which were negatively correlated with BIS scores in the SU group. Further ROC analysis revealed that the mean zALFF values in these two regions (sensitivity=83.3% and specificity=71.4%) served as markers to differentiate the two patient subtypes. CONCLUSION: The SU group had abnormal spontaneous neural activity during the resting state, and decreased activity in L-SFG and L-MFG was associated with increased impulsivity in SU group. Our results suggested that abnormal neural activity in these brain regions may represent a potential neurobiological diathesis or predisposition to suicidal behavior in youth depression. PMID- 27467531 TI - Power Failure: The Battered Legacy of Leaded Batteries. PMID- 27467532 TI - Decreased Circulating Sclerostin Levels in Renal Transplant Recipients With Persistent Hyperparathyroidism: Who's Conducting the Orchestra? PMID- 27467530 TI - Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells. AB - Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure. PMID- 27467533 TI - Bone Density, Microarchitecture, and Tissue Quality Long-term After Kidney Transplant. AB - BACKGROUND: Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry is used to assess bone health in kidney transplant recipients (KTR). Trabecular bone score and in vivo microindentation are novel techniques that directly measure trabecular microarchitecture and mechanical properties of bone at a tissue level and independently predict fracture risk. We tested the bone status of long-term KTR using all 3 techniques. METHODS: Cross-sectional study including 40 KTR with more than 10 years of follow-up and 94 healthy nontransplanted subjects as controls. Bone mineral density was measured at lumbar spine and the hip. Trabecular bone score was measured by specific software on the dual-energy x-ray absorptiometry scans of lumbar spine in 39 KTR and 77 controls. Microindentation was performed at the anterior tibial face with a reference-point indenter device. Bone measurements were standardized as percentage of a reference value, expressed as bone material strength index (BMSi) units. Multivariable (age, sex, and body mass index-adjusted) linear regression models were fitted to study the association between KTR and BMD/BMSi/trabecular bone score. RESULTS: Bone mineral density was lower at lumbar spine (0.925 +/- 0.15 vs 0.982 +/- 0.14; P = 0.025), total hip (0.792 +/- 0.14 vs 0.902 +/- 0.13; P < 0.001), and femoral neck (0.667 +/- 0.13 vs 0.775 +/- 0.12; P < 0.001) in KTR than in controls. BMSi was also lower in KTR (79.1 +/- 7.7 vs 82.9 +/- 7.8; P = 0.012) although this difference disappeared after adjusted model (P = 0.145). Trabecular bone score was borderline lower (1.21 +/- 0.14 vs 1.3 +/- 0.15; adjusted P = 0.072) in KTR. CONCLUSIONS: Despite persistent decrease in BMD, trabecular microarchitecture and tissue quality remain normal in long-term KTR, suggesting important recovery of bone health. PMID- 27467534 TI - Successful Posttransplant Treatment of Hepatitis C With Ledipasvir-Sofosbuvir in HIV+ Kidney Transplant Recipients. AB - BACKGROUND: Ledipasvir-sofosbuvir is effective at eradicating hepatitis C virus (HCV) infection in the general population and in HCV-monoinfected kidney transplant recipients, but there are no data to guide its use in human immunodeficiency virus/HCV coinfected kidney transplant patients. METHODS: We treated 6 human immunodeficiency virus/HCV coinfected kidney transplant recipients with ledipasvir-sofosbuvir at our 2 centers. All were infected with genotype 1 and 66% had received kidneys from HCV+ donors. RESULTS: All patients cleared the virus while on therapy and 100% have achieved a sustained virologic response at 12 weeks after completion of ledipasvir-sofosbuvir. Tacrolimus dosing required adjustment during and after ledipasvir-sofosbuvir therapy but antiretroviral regimens did not. CONCLUSIONS: Ledipasvir-sofosbuvir was well tolerated. Although all patients in our series were treated posttransplant, the ideal timing of HCV therapy in this population is unknown, and the impact of HCV clearance on posttransplant outcomes is yet to be determined. PMID- 27467535 TI - Recurrence of CMV Infection and the Effect of Prolonged Antivirals in Organ Transplant Recipients. AB - BACKGROUND: Although initial therapy for cytomegalovirus (CMV) is usually successful, a significant subset of patients may have recurrent viremia. However, the epidemiology and risk factors for recurrence have not been fully defined, as well as the utility of prolonged antivirals after initial clearance. METHODS: Solid organ transplant patients with first episode of CMV disease or asymptomatic viremia (>=1000 IU/mL) requiring treatment were identified by chart review. Clinical and virologic data were collected. The primary outcome was recurrence of CMV viremia or disease within 6 months of treatment discontinuation. RESULTS: The first episode of CMV viremia requiring antiviral therapy was assessed in 282 patients (147 CMV disease and 135 asymptomatic viremia). Cytomegalovirus occurred at 5.6 (0.63-27.7) months posttransplant. Recurrent CMV occurred in 30.5% patients at a median of 51 (0-160) days after discontinuation of therapy. Factors predictive of recurrence were treatment phase viral kinetics (P = 0.005), lung transplant (P = 0.002), CMV donor (D)+/recipient (R)- serostatus(P = 0.04) and recent acute rejection(P = 0.02). Prolonged antiviral therapy was given to 226 (80.1%) of 282 patients. Recurrence occurred in 73 (32.3%) of 226 patients that received prolonged antivirals versus 13 (23.2%) of 56 in those with no prolonged antivirals (P = 0.19). CONCLUSIONS: Recurrent CMV occurs in a significant percentage of patients after treatment of the first episode of CMV viremia/disease. CMV D+/R- serostatus, lung transplant, and treatment phase viral kinetics were significant predictors of recurrence. Continuation of prolonged antivirals beyond initial clearance was not associated with a reduced risk of recurrence. PMID- 27467536 TI - Effect of Paricalcitol on FGF-23 and Klotho in Kidney Transplant Recipients. AB - BACKGROUND: Paricalcitol decreases intact parathyroid hormone and the frequency of secondary hyperparathyroidism after kidney transplantation. This proof-of concept study aimed to assess the effect of paricalcitol on fibroblast growth factor-23/KLOTHO axis in renal transplants. METHODS: Twenty-nine subjects with secondary hyperparathyroidism received oral paricalcitol 1 MUg/d for 3 months, and 8 patients matched by age, sex, and creatinine clearance, but with intact parathyroid hormone less than 100 pg/mL, were included as controls. RESULTS: Intact parathyroid hormone decreased in paricalcitol-treated patients (P < 0.0001). Serum fibroblast growth factor-23 enhanced (P < 0.01), whereas KLOTHO concentrations showed a trend to increase (P = 0.067). KLOTHO gene expression in peripheral blood mononuclear cells increased by 45.7% in paricalcitol-treated patients (P < 0.01), without change in controls. Paricalcitol administration resulted in a median percent decrease of 56% in methylated DNA levels of KLOTHO promoter (P < 0.001). The ratio of the unmethylated/methylated KLOTHO promoter DNA did not change in controls, but it increased by 177% in paricalcitol-treated subjects (P < 0.0001). The increase in this ratio was independently associated with the change in serum KLOTHO (r = 0.55, P < 0.01) and messenger RNA expression levels (r = 0.40, P < 0.05). CONCLUSIONS: Paricalcitol administration to renal transplant patients significantly reduced intact parathyroid hormone and increased fibroblast growth factor-23, with a trend to increase in serum KLOTHO. Paricalcitol-treated patients showed a decrease in the methylation of the KLOTHO promoter with an increment in the ratio of un-methyated/methylated DNA, which was associated with an increase of KLOTHO gene expression levels and serum KLOTHO concentrations. Long-term studies are needed to assess whether paricalcitol induced increase in KLOTHO gene expression and serum concentrations may translate into beneficial clinical effects. PMID- 27467537 TI - Continuous Normothermic Ex Vivo Kidney Perfusion Improves Graft Function in Donation After Circulatory Death Pig Kidney Transplantation. AB - BACKGROUND: Donation after circulatory death (DCD) is current clinical practice to increase the donor pool. Deleterious effects on renal graft function are described for hypothermic preservation. Therefore, current research focuses on investigating alternative preservation techniques, such as normothermic perfusion. METHODS: We compared continuous pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) with static cold storage (SCS) in a porcine model of DCD autotransplantation. After 30 minutes of warm ischemia, right kidneys were removed from 30-kg Yorkshire pigs and preserved with 8-hour NEVKP or in 4 degrees C histidine-tryptophan-ketoglutarate solution (SCS), followed by kidney autotransplantation. RESULTS: Throughout NEVKP, electrolytes and pH values were maintained. Intrarenal resistance decreased over the course of perfusion (0 hour, 1.6 +/- 0.51 mm per minute vs 7 hours, 0.34 +/- 0.05 mm Hg/mL per minute, P = 0.005). Perfusate lactate concentration also decreased (0 hour, 10.5 +/- 0.8 vs 7 hours, 1.4 +/- 0.3 mmol/L, P < 0.001). Cellular injury markers lactate dehydrogenase and aspartate aminotransferase were persistently low (lactate dehydrogenase < 100 U/L, below analyzer range; aspartate aminotransferase 0 hour, 15.6 +/- 9.3 U/L vs 7 hours, 24.8 +/- 14.6 U/L, P = 0.298). After autotransplantation, renal grafts preserved with NEVKP demonstrated lower serum creatinine on days 1 to 7 (P < 0.05) and lower peak values (NEVKP, 5.5 +/- 1.7 mg/dL vs SCS, 11.1 +/- 2.1 mg/dL, P = 0.002). The creatinine clearance on day 4 was increased in NEVKP-preserved kidneys (NEVKP, 39 +/- 6.4 vs SCS, 18 +/- 10.6 mL/min; P = 0.012). Serum neutrophil gelatinase-associated lipocalin at day 3 was lower in the NEVKP group (1267 +/- 372 vs 2697 +/- 1145 ng/mL, P = 0.029). CONCLUSIONS: Continuous pressure-controlled NEVKP improves renal function in DCD kidney transplantation. Normothermic ex vivo kidney perfusion might help to decrease posttransplant delayed graft function rates and to increase the donor pool. PMID- 27467538 TI - Graft Loss and CLAD-Onset Is Hastened by Viral Pneumonia After Lung Transplantation. AB - BACKGROUND: Community-acquired respiratory virus (CARV) infections occur frequently after lung transplantation and may adversely impact outcomes. We hypothesized that while asymptomatic carriage would not increase the risk of chronic lung allograft dysfunction (CLAD) and graft loss, severe infection would. METHODS: All lung transplant cases between January 2000 and July 2013 performed at our center were reviewed for respiratory viral samples. Each isolation of virus was classified according to clinical level of severity: asymptomatic, symptomatic without pneumonia, and viral pneumonia. Multivariate Cox modeling was used to assess the impact of CARV isolation on progression to CLAD and graft loss. RESULTS: Four thousand four hundred eight specimens were collected from 563 total patients, with 139 patients producing 324 virus-positive specimens in 245 episodes of CARV infection. Overall, the risk of CLAD was elevated by viral infection (hazard ratio [HR], 1.64; P < 0.01). This risk, however, was due to viral pneumonia alone (HR, 3.94; P < 0.01), without significant impact from symptomatic viral infection (HR, 0.97; P = 0.94) nor from asymptomatic viral infection (HR, 0.99; P = 0.98). The risk of graft loss was not increased by asymptomatic CARV infection (HR, 0.74; P = 0.37) nor symptomatic CARV infection (HR, 1.39; P = 0.41). Viral pneumonia did, however, significantly increase the risk of graft loss (HR, 2.78; P < 0.01). CONCLUSIONS: With respect to CARV, only viral pneumonia increased the risk of both CLAD and graft loss after lung transplantation. In the absence of pneumonia, respiratory viruses had no impact on measured outcomes. PMID- 27467539 TI - National Assessment of Hospitalization Rates for Incident End-Stage Renal Disease After Liver Transplantation. AB - BACKGROUND: We examined the association of incident end-stage renal disease (ESRD) after liver transplantation (LT) and resource utilization using a data linkage between the Scientific Registry of Transplant Recipients and claims data from the Centers for Medicare and Medicaid Services. METHODS: The study cohort consisted of patients aged >=18 years who underwent deceased donor LT between January 1, 2003, and December 31, 2010, with Medicare as primary or secondary insurance and were discharged alive from the index LT hospitalization (n = 7019). The association of ESRD and post-LT hospitalization was assessed by sequential stratification, which entailed prognostic score matching of ESRD-free patients to each LT recipient at ESRD onset. The prognostic score was developed from a model of time to hospitalization and included baseline factors and hospitalization history as predictors. RESULTS: The overall hospitalization rates for LT recipients with and without ESRD were 2.7 and 1.1 per patient-year at risk, respectively. The total number of days hospitalized patient per year was 23 in ESRD and 7 in non-ESRD LT recipients. The adjusted post-LT hospitalization rate was 97% higher after reaching ESRD compared to non-ESRD (hazard ratio, 1.97; P < 0.0001). CONCLUSIONS: Hospitalization rates increased significantly for LT recipients after ESRD onset. Early risk factor modification efforts targeting patients who are at high ESRD risk may reduce post-LT ESRD incidence and hence decrease morbidity and cost among LT recipients. PMID- 27467540 TI - The Sum of the Parts: Understanding How Skin Allografts Are Rejected. PMID- 27467542 TI - Sustainable Antibiofouling Properties of Thin Film Composite Forward Osmosis Membrane with Rechargeable Silver Nanoparticles Loading. AB - Microbial attachment and biofilm formation on filtration membrane can greatly compromise its flux and separation efficiency. Here, a simple and facile approach has been developed to in situ generate silver nanoparticles (Ag NPs) on the thin film composite forward osmosis (TFC FO) membrane for sustainable antibiofouling performances. Mussel-inspired dopamine chemistry was applied to grow polydopamine coating on both surfaces of FO membranes, followed by the generation of Ag NPs upon a simple dip coating in silver nitrate aqueous solution. Furthermore, the Ag NPs deposited membranes had a long-term silver release profile with rechargability for multiple times upon their depletion, and exhibited strong sustainable bactericidal efficacy against Gram-negative bacteria and Gram positive bacteria. The Ag NPs had a controllable effect on the membrane performances including the water flux and reverse salt flux in the FO test mode. Our practicable antibacterial strategy may apply to other types of filtration membranes with diverse material surfaces and may pave a new way to achieve the sustainable membrane antibiofouling performance on a large scale. PMID- 27467541 TI - Mental Health and Behavioral Barriers in Access to Kidney Transplantation: A Canadian Cohort Study. AB - BACKGROUND: A history of mental health (MH) disorders or nonadherence (NA) may be barriers to completing the work-up (WU) and/or undergoing kidney transplantation (KT) but this has not been well documented. In this work, we analyzed the relationship between a history of MH disorders or NA and the likelihood of completing the WU or undergoing KT. METHODS: Patients referred for KT to the Toronto General Hospital from January 1, 2003, to December 31, 2012, and who completed a social work assessment, were included (n = 1769). The association between the history of MH disorders or NA and the time from referral to WU completion or KT were examined using Cox proportional hazards models. RESULTS: A history of MH disorders or NA was present in 24% and 18%, respectively. Patients with MH disorders had a 17% lower adjusted hazard of completing the WU within 2 years of referral (HR 0.83; 95% confidence interval [95% CI], 0.71-0.97). Similarly, patients with a history of NA had a 21% lower hazard of completing the WU (hazard ratio [HR], 0.79; 95% CI, 0.66-0.94). The adjusted HR for KT was 0.88 (95% CI, 0.74-1.05) and 0.79 (95% CI, 0.64-0.97) for MH disorders and NA, respectively. CONCLUSIONS: These findings suggest that a history of MH disorders or NA is a potential barrier to KT. Whether targeted psychosocial support can improve access to KT for these patients requires further study. PMID- 27467543 TI - The role of local ablative therapy in oligometastatic non-small-cell lung cancer: hype or hope. AB - In recent years, the emergence of the oligometastatic state has called into question whether patients found to have a limited or low metastatic tumor burden may benefit from locally ablative therapy (LAT). In the past two decades, stereotactic body radiation therapy has been increasingly used to safely deliver LAT and provide high local control in nonoperable non-small-cell lung cancer patients. Mostly retrospective analyses suggest that using LAT for oligometastatic disease in non-small-cell lung cancer offers excellent local control and may provide an improvement in progression-free survival. Any meaningful improvement in cancer-specific survival remains debatable. We examine the role of integrating LAT in this patient population and the rationale behind its use in combination with targeted therapy and immunotherapy. PMID- 27467544 TI - Novel organic NLO material bis(N-phenylbiguanidium(1+)) oxalate - A combined X ray diffraction, DSC and vibrational spectroscopic study of its unique polymorphism. AB - Three polymorphic modifications of bis(N-phenylbiguanidium(1+)) oxalate are reported, and their characterization is discussed in this paper. The non centrosymmetric bis(N-phenylbiguanidium(1+)) oxalate (I), which was obtained from an aqueous solution at 313K, belongs to the monoclinic space group Cc (a=6.2560(2)A, b=18.6920(3)A, c=18.2980(5)A, beta=96.249(1) degrees , V=2127.0(1)A(3), Z=4, R=0.0314 for 4738 observed reflections). The centrosymmetric bis(N-phenylbiguanidium(1+)) oxalate (II) was obtained from an aqueous solution at 298K and belongs to the monoclinic space group P21/n (a=6.1335(3)A, b=11.7862(6)A, c=14.5962(8)A, beta=95.728(2) degrees , V=1049.90(9)A(3), Z=4, R=0.0420 for 2396 observed reflections). The cooling of the centrosymmetric phase (II) leads to the formation of bis(N phenylbiguanidium(1+)) oxalate (III) (a=6.1083(2)A, b=11.3178(5)A, c=14.9947(5)A, beta=93.151(2) degrees , V=1035.05(8)A(3), Z=4, R=0.0345 for 2367 observed reflections and a temperature of 110K), which also belongs to the monoclinic space group P21/n. The crystal structures of the three characterized phases are generally based on layers of isolated N-phenylbiguanidium(1+) cations separated by oxalate anions and interconnected with them by several types of N-H(...)O hydrogen bonds. The observed phases generally differ not only in their crystal packing but also in the lengths and characteristics of their hydrogen bonds. The thermal behaviour of the prepared compounds was studied using the DSC method in the temperature range from 90K up to a temperature near the melting point of each crystal. The bis(N-phenylbiguanidium(1+)) oxalate (II) crystals exhibit weak reversible thermal effects on the DSC curve at 147K (heating run). Further investigation of this effect, which was assigned to the isostructural phase transformation, was performed using FTIR, Raman spectroscopy and X-ray diffraction analysis in a wide temperature range. PMID- 27467545 TI - Adipophilin expression in lung adenocarcinoma is associated with apocrine-like features and poor clinical prognosis: an immunohistochemical study of 328 cases. AB - AIMS: The lipogenic pathway is up-regulated in proliferating cells. However, the clinical impact of neoplastic steatogenesis in lung cancer is unclear. The aim of the present study was to evaluate the association of intracytoplasmic lipids with the clinicopathological features of lung adenocarcinoma (ADC), by immunohistochemical analysis of adipophilin (ADP), a coating protein found on intracytoplasmic lipid droplets. METHODS AND RESULTS: Tissue microarrays consisting of 328 primary lung ADCs surgically resected at Kyoto University Hospital were immunostained for ADP. Subsequently, correlations between ADP expression and clinical, molecular and survival data were performed. Fifty-one (15.5%) cases were ADP-positive. The presence of vascular invasion (P = 0.003), predominantly solid histology (P < 0.001), poorly differentiated type (P < 0.001), wild-type EGFR (P = 0.002), ALK fusion (P < 0.001), strong/diffuse mitochondrial staining (P < 0.001), a lack of surfactant protein B expression (P = 0.014) and a high Ki67 index (P < 0.001) were significantly correlated with ADP positive ADC. In contrast, there were no correlations between ADP-positive ADC and sex, age, smoking history, tumour stage, thyroid transcription factor-1 expression, or KRAS mutational status. ADP-positive ADCs had apocrine-like features (P < 0.001). Patients with ADP-positive ADC had worse disease-free and overall survival (P = 0.047 and P = 0.013, respectively) than those with ADP negative ADC. CONCLUSIONS: ADP was expressed in a small proportion of lung ADCs. ADP-positive lung ADC was significantly associated with apocrine-like features, wild-type EGFR, and poor prognosis, suggesting that ADP-positive lung ADC could be a distinct subtype of lung adenocarcinoma, induced by up-regulation of the lipogenic pathway. PMID- 27467546 TI - Beyond the cardiovascular risk charts: the new way of hybrid profiles. PMID- 27467547 TI - Active implanted cardiac devices and magnetic resonance: results of a survey among cardiologists of Piedmont. AB - The recent introduction of Magnetic Resonance-conditional implantable cardiac device has abolished the previous absolute or relative contraindications to magnetic resonance scan also in patients implanted with such devices. The present survey aimed at investigating the level of knowledge of terms and conditions for a well-tolerated use of Magnetic Resonance-conditional devices prior, during and after magnetic resonance scan among cardiologists in Piedmont (Italy). A questionnaire consisting of 32 questions was distributed to 256 cardiologists and 73 responded to the survey. The interviewed considered loop recorders (18%), pacemakers (13%), implantable cardiac defibrillators (23%), and joint prostheses (20%) as an absolute contraindication to magnetic resonance. For pacemakers and implantable cardiac defibrillators, 87-77% of the respondents respectively indicated that the specific type of device may allow magnetic resonance, regardless the type of device. Ninety-three percent of the cardiologists did not perfectly recognize the meaning of the term 'Magnetic Resonance-conditional.' Half of respondents did not recognize the preliminary check to be performed on implanted electronic device before Magnetic Resonance. About 35% of the cardiologists replied that a magnetic resonance could not be prescribed in patients with implanted electronic devices because of a specific prohibition by Italian law. The results of the present survey highlight the need to fill knowledge gaps among cardiology specialists on this topic. PMID- 27467548 TI - Total pericardial agenesis mimicking arrhythmogenic right ventricular dysplasia. AB - : We report the incidental finding of pericardial agenesis in a patient with electrocardiographic and echocardiographic abnormalities mimicking arrhythmogenic right ventricular dysplasia. The anatomic findings were clearly depicted by cardiac magnetic resonance. The patient was asymptomatic and the clinical relevance of this finding would be raised in case a possible differential diagnosis of right heart overload should be necessary. Diagnosis may be easily suspected from the ECG and echocardiography; MRI will provide definite diagnosis. PMID- 27467549 TI - In response to: Pay attention to EBSLN in anatomical classification of the superior pole in thyroid surgery. PMID- 27467551 TI - Synthetic Approaches to Trifluoromethoxy-Substituted Compounds. AB - Because of the unique properties of the trifluoromethoxy group, molecules bearing this moiety will find applications in various fields, particularly in the life sciences. However, despite the great interest in this functional group, only a small number of trifluoromethoxylated molecules are currently synthetically accessible. Over the last few years, several innovative and promising strategies for the synthesis of trifluoromethoxylated compounds have been described. This Minireview discusses these existing methods with a particular focus on more recent advances. PMID- 27467550 TI - Novel Anthropometry Based on 3D-Bodyscans Applied to a Large Population Based Cohort. AB - Three-dimensional (3D) whole body scanners are increasingly used as precise measuring tools for the rapid quantification of anthropometric measures in epidemiological studies. We analyzed 3D whole body scanning data of nearly 10,000 participants of a cohort collected from the adult population of Leipzig, one of the largest cities in Eastern Germany. We present a novel approach for the systematic analysis of this data which aims at identifying distinguishable clusters of body shapes called body types. In the first step, our method aggregates body measures provided by the scanner into meta-measures, each representing one relevant dimension of the body shape. In a next step, we stratified the cohort into body types and assessed their stability and dependence on the size of the underlying cohort. Using self-organizing maps (SOM) we identified thirteen robust meta-measures and fifteen body types comprising between 1 and 18 percent of the total cohort size. Thirteen of them are virtually gender specific (six for women and seven for men) and thus reflect most abundant body shapes of women and men. Two body types include both women and men, and describe androgynous body shapes that lack typical gender specific features. The body types disentangle a large variability of body shapes enabling distinctions which go beyond the traditional indices such as body mass index, the waist-to height ratio, the waist-to-hip ratio and the mortality-hazard ABSI-index. In a next step, we will link the identified body types with disease predispositions to study how size and shape of the human body impact health and disease. PMID- 27467552 TI - The response of contrasting tomato genotypes to combined heat and drought stress. AB - Efforts to maximize yields of food crops can be undermined by abiotic stress factors, particularly those related to climate change. Here, we use a range of physiological methods to detect the individual and combined effects of heat and drought stress on three contrasting varieties of tomato: Hybrid 61, Moskvich, and Nagcarlang. Seedlings were acclimated under the following treatment regimes: CONTROL (25-36 degrees C; well-watered), DRY (25-36 degrees C; 20% field capacity), HOT (25-42 degrees C; well-watered) and HOT+DRY (25-42 degrees C; 20% field capacity). In each treatment, stomatal conductance, leaf temperature, chlorophyll content, and several chlorophyll fluorescence variables (both in situ and in vitro following a heat shock treatment) were measured. Plants from the HOT treatment remained statistically similar to the CONTROL plants in most of the measured parameters, while those from the DRY treatment and especially the HOT+DRY treatment showed clear effects of abiotic stress. Hybrid 61 showed considerable resilience to heat and drought stress compared to the other varieties, with significantly cooler leaves (one day after treatments imposed) and significantly higher Fv/Fm values both in situ and in vitro. The genotypic differences in resilience to heat stress were only apparent under water-limited conditions, highlighting the need to consider leaf temperature rather than air temperature when testing for tolerance to heat stress. The most effective parameters for discriminating genotypic variation in heat and drought stress were in vitro Fv/Fm and chlorophyll content. PMID- 27467553 TI - Expression of specific genes involved in Cd uptake, translocation, vacuolar compartmentalisation and recycling in Populus alba Villafranca clone. AB - Cadmium (Cd) is a heavy metal toxic to humans and its occurrence in soils represents a significant environmental problem. Poplar trees may provide one possible option to help remove Cd contamination from soil. However, before this is practicable, the ability of poplar to accumulate Cd needs to be enhanced. A better understanding of the genes involved in Cd accumulation in poplar would help to achieve this goal. Here, we monitored the expression of genes known to be involved in Cd uptake, accumulation and translocation from other species, in order to provide information on their potential role in Cd accumulation in poplar. Cd concentration in poplar was significantly higher in roots than in stem and leaves in Cd treated plants. Expression of the poplar homologues of IRT1, NRAMP and OPT3 was initially increased after exposure to Cd but reduced after longer term Cd exposure. Exposure to Cd also influenced the accumulation of Fe, Ca, Cu, Mg and Mn in poplar. In particular, Cd treated plants had a higher concentration of Fe, Ca, Cu, and Mg in leaves and stem compared to control plants after one day and one week of experiment; while in roots after one month Cd treated plants had a lower concentration of Mn, Fe, Cu, Co, and Mg. PMID- 27467554 TI - Signatures of Tolerance or Immunosuppression? PMID- 27467555 TI - Rosa canina Extracts Have Antiproliferative and Antioxidant Effects on Caco-2 Human Colon Cancer. AB - The in vitro antiproliferative and antioxidant effects of different fractions of Rosa canina hips on human colon cancer cell lines (Caco-2) was studied. The compounds tested were total extract (fraction 1), vitamin C (fraction 2), neutral polyphenols (fraction 3) and acidic polyphenols (fraction 4). All the extracts showed high cytotoxicity after 72 h, both low and high concentrations. The flow cytometric analysis revealed that all the fractions produce disturbances in the cell cycle resulting in a concomitant cell death by an apoptotic pathway. Changes in the redox status of Caco-2 cells in response to Rosa canina hips were determined. Cells were exposed to hydrogen peroxide in presence of plant fractions and the production of Reactive Oxygen Species (ROS) was significantly decreased. Therefore, our data demonstrate that rosehip extracts are a powerful antioxidant that produces an antiproliferative effect in Caco-2 cells. Therefore, these results predict a promising future for Rosa canina as a therapeutic agent. Thus, this natural plant could be an effective component of functional foods addressed towards colorectal carcinoma. PMID- 27467558 TI - Emergency department-based interventions for women suffering domestic abuse: a critical literature review. AB - Domestic abuse represents a serious public health and human rights concern. Interventions to reduce the risk of abuse include staff training and standardized documentation improving detection and adherence to referral pathways. Interventional studies have been conducted in primary care, maternity and outpatient settings. Women disclosing abuse in emergency departments differ from women attending other healthcare settings, and it is unclear whether these interventions can be transferred to the emergency care setting. This review examines interventional studies to evaluate the effectiveness of emergency department-based interventions in reducing domestic abuse-related morbidity. Medline, EMBASE, CINAHL, PsycINFO and Cochrane Library were searched, according to prespecified selection criteria. Study quality was assessed using the Jadad scale. Of 273 search results, nine were eligible for review. Interventions involving staff training demonstrated benefits in subjective measures, such as staff knowledge regarding abuse, but no changes in clinical practice, based on detection and referral rates. When staff training was implemented in conjunction with supporting system changes - for example, standardized documentation for assessment and referral - clinically relevant improvements were noted. Interventions centred around staff training are insufficient to bring about improvements in the management and, thus, outcome of patients suffering abuse. Instead, system changes, such as standardized documentation and referral pathways, supported by training, may bring about beneficial changes. It remains uncertain whether surrogate outcomes employed by most studies translate to changes in abuse-related morbidity: the ultimate goal. PMID- 27467556 TI - Prevalence and Hospital Management of Amphotericin B Deoxycholate-Related Toxicities during Treatment of HIV-Associated Cryptococcal Meningitis in South Africa. AB - BACKGROUND: We aimed to establish the prevalence of amphotericin B deoxycholate (AmBd)-related toxicities among South African patients with cryptococcosis and determine adherence to international recommendations to prevent, monitor and manage AmBd-related toxicities. METHODS: Clinical data were collected from cases of laboratory-confirmed cryptococcosis at 25 hospitals, October 2012 -February 2013. Anemia was defined as hemoglobin (Hb) concentration <10 g/dl, hypokalemia as serum potassium (K) <3.4 mEq/L and nephrotoxicity as an increase in serum creatinine (Cr) to >1.1 times the upper limit of normal. To determine adherence to toxicity prevention recommendations, we documented whether baseline Hb, K and Cr tests were performed, whether pre-emptive hydration and IV potassium chloride (KCl) was administered prior to 80% and 60% of AmBd doses and whether daily oral KCl supplementation was given >=60% of the time. To determine adherence to monitoring recommendations, we ascertained whether a daily fluid chart was completed, Hb was monitored weekly and K or Cr were monitored bi-weekly. RESULTS: Of 846 patients, clinical data were available for 76% (642/846), 82% (524/642) of whom received AmBd. Sixty-four per cent (n = 333) had documented baseline laboratory tests, 40% (n = 211) were given pre-emptive hydration and 14% (n = 72) and 19% (n = 101) received intravenous and oral KCl. While on AmBd, 88% (n = 452) had fluid monitoring; 27% (n = 142), 45% (n = 235) and 44% (n = 232) had Hb, K and Cr levels monitored. Toxicities developed frequently during treatment: anemia, 16% (86/524); hypokalemia, 43% (226/524) and nephrotoxicity, 32% (169/524). CONCLUSION: AmBd-related toxicities occurred frequently but were potentially preventable with adequate monitoring, supplemental fluid and electrolyte therapies. PMID- 27467557 TI - Automatic Analysis of Cellularity in Glioblastoma and Correlation with ADC Using Trajectory Analysis and Automatic Nuclei Counting. AB - OBJECTIVE: Several studies have analyzed a correlation between the apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI and the tumor cellularity of corresponding histopathological specimens in brain tumors with inconclusive findings. Here, we compared a large dataset of ADC and cellularity values of stereotactic biopsies of glioblastoma patients using a new postprocessing approach including trajectory analysis and automatic nuclei counting. MATERIALS AND METHODS: Thirty-seven patients with newly diagnosed glioblastomas were enrolled in this study. ADC maps were acquired preoperatively at 3T and coregistered to the intraoperative MRI that contained the coordinates of the biopsy trajectory. 561 biopsy specimens were obtained; corresponding cellularity was calculated by semi-automatic nuclei counting and correlated to the respective preoperative ADC values along the stereotactic biopsy trajectory which included areas of T1-contrast-enhancement and necrosis. RESULTS: There was a weak to moderate inverse correlation between ADC and cellularity in glioblastomas that varied depending on the approach towards statistical analysis: for mean values per patient, Spearman's rho = -0.48 (p = 0.002), for all trajectory values in one joint analysis Spearman's rho = -0.32 (p < 0.001). The inverse correlation was additionally verified by a linear mixed model. CONCLUSIONS: Our data confirms a previously reported inverse correlation between ADC and tumor cellularity. However, the correlation in the current article is weaker than the pooled correlation of comparable previous studies. Hence, besides cell density, other factors, such as necrosis and edema might influence ADC values in glioblastomas. PMID- 27467559 TI - The Effect of Dietary Replacement of Ordinary Rice with Red Yeast Rice on Nutrient Utilization, Enteric Methane Emission and Rumen Archaeal Diversity in Goats. AB - Twenty castrated Boer crossbred goats were used in the present study with two treatments to examine the effect of dietary replacement of ordinary rice with red yeast rice on nutrient utilization, enteric methane emission and ruminal archaea structure and composition. Two treatment diets contained (DM basis) 70.0% of forage, 21.8% of concentrates and 8.2% of either ordinary rice (control) or red yeast rice (RYR). Nutrient utilization was measured and enteric methane emissions were determined in respiration chambers. Results showed that RYR had significantly lower digestibility of N and organic matter compared to control group. However, feeding red yeast rice did not affect N retention as g/d or a proportion of N intake, and reduced heat production as MJ/d or as a proportion of metabolizable energy intake, thus leading to a higher proportion of metabolizable energy intake to be retained in body tissue. RYR also had significantly lower methane emissions either as g/d, or as a proportion of feed intake. Although feeding red yeast rice had no negative effect on any rumen fermentation variables, it decreased serum contents of total cholesterol, triglycerides, HDL cholesterol and LDL-cholesterol. In the present study, 75616 archaeal sequences were generated and clustered into 2364 Operational Taxonomic Units. At the genus level, the predominant archaea in the rumen of goats was Methanobrevibacter, which was significantly inhibited with the supplementation of red yeast rice. In conclusion, red yeast rice is a potential feed ingredient for mitigation of enteric methane emissions of goats. However, caution should be taken when it is used because it may inhibit the digestibility of some nutrients. Further studies are required to evaluate its potential with different diets and animal species, as well as its effects on animal health and food safety. PMID- 27467560 TI - Effects of Multidrug Resistant Tuberculosis Treatment on Patients' Health Related Quality of Life: Results from a Follow Up Study. AB - BACKGROUND: At present, within the management of multidrug resistant tuberculosis (MDR-TB) much attention is being paid to the traditional microbiological and clinical indicators. Evaluation of the impact of MDR-TB treatment on patients' Health Related Quality of Life (HRQoL) has remained a neglected area. OBJECTIVE: To evaluate the impact of MDR-TB treatment on patients HRQoL, and determine the predictors of variability in HRQoL along the course of treatment. METHODS: A prospective follow up study was conducted at the programmatic management unit for drug resistant TB of Lady Reading Hospital Peshawar. Culture confirmed eligible MDR-TB patients were asked to self complete SF-36v2 at the baseline visit, and subsequently after the completion of 12 months of treatment and at the end of treatment. A score of <47 norm-based scoring (NBS) points on component summary measures and health domain scales was considered indicative of function impairment. General linear model repeated measures ANOVA was used examine the change and predictors of change in physical component summary (PCS) and mental component summary (MCS) scores over the time. RESULTS: A total of 68 out of enrolled 81 eligible MDR-TB patients completed SF-36v2 questionnaire at the three time points. Patients' mean PCS scores at the three time points were, 38.2+/-4.7, 38.6+/-4.4 and 42.2+/-5.2 respectively, and mean MCS were 33.7+/-7.0, 35.5+/-6.9 and 40.0+/-6.9 respectively. Length of sickness prior to the diagnosis of MDR-TB was predictive of difference in PCS scores (F = 4.988, Df = 1, 66), whereas patients' gender (F = 5.638, Df = 1, 66) and length of sickness prior to the diagnosis of MDR-TB (F = 4.400, Df = 1, 66) were predictive of difference in MCS scores. CONCLUSION: Despite the positive impact of MDR-TB treatment on patients' HRQoL, the scores on component summary measures suggested compromised physical and mental health even at the end of treatment. A large multicenter study is suggested to confirm the present findings. PMID- 27467561 TI - Cost consciousness among physicians in the neonatal intensive care unit. AB - OBJECTIVE: The objectives of this study were (1) to describe the prevalence and correlates of cost consciousness among physician providers in neonatology and (2) to describe knowledge of cost of common medications, laboratory/imaging evaluations, hospitalization costs and reimbursements. STUDY DESIGN: A 54-item survey was administered to members of the Section on Neonatal-Perinatal Medicine of the American Academy of Pediatrics. RESULTS: Of the 602 participants, 37% reported cost consciousness in decision making. Adjusting for years in practice, gender, training level, type of practice setting and region of practice, formalized education about costs was associated with increased cost consciousness in practice (adjusted odds ratio (AOR): 3.4; 95% confidence interval (CI): 1.2 to 9.8). Working in a private practice setting was also associated with increased cost consciousness when ordering laboratory (AOR: 3.0; (95% CI: 1.2 to 7.6)) or imaging tests (AOR: 2.0; 95% CI: 1.0 to 4.8). CONCLUSIONS: We found variation in knowledge of cost. Formal education about costs and working in a private practice setting were associated with increased cost consciousness. PMID- 27467562 TI - Vitamin D and bronchopulmonary dysplasia in preterm infants. AB - OBJECTIVE: Vitamin D deficiency is associated with asthma and reactive airway disease in childhood but its potential contribution to bronchopulmonary dysplasia (BPD) in preterm infants is unknown. Preterm infants have lower levels of 25 hydroxyvitamin D (25(OH)D) at birth and are at risk for nutritional deficiencies after birth. The objective of the study was to evaluate the association of 25(OH)D concentrations at birth and at 36 weeks' corrected gestational age with BPD in preterm infants born before 29 completed weeks of gestation. STUDY DESIGN: We collected umbilical cord blood samples from 44 preterm infants (gestational age <29 weeks) delivered at Brigham and Women's Hospital in Boston. In addition, with parental consent we collected venous samples at 36 weeks' corrected age from 20 preterm infants born before 29 weeks' gestation (including 6 infants with previously collected cord blood). Samples were frozen at -80 degrees C until subsequent measurement of 25(OH)D levels by chemiluminescence. We used multivariable logistic models to adjust for gestational age and considered other confounding variables, including maternal race, age, mode of delivery and infant sex. RESULTS: Among 44 infants, 41 (93.2%) survived and 3 (6.8%) died before 36 weeks' corrected age. Median 25(OH)D levels at birth were 30.4 ng ml(-1) in preterm infants who subsequently died or developed BPD and 33.8 ng ml(-1) in infants who survived without BPD (P=0.6). Median 25(OH)D levels at corrected age of 36 weeks were 59.0 ng ml(-1) among survivors without BPD and 64.2 ng ml(-1) among survivors with BPD (P=0.9). Neither cord blood nor 36 weeks' corrected 25(OH)D levels were associated with odds of death or BPD (adjusted odds ratio (OR) 1.00, 95% confidence interval (CI): 0.73 to 1.37; and OR 0.93, 95% CI: 0.61 to 1.43, respectively). CONCLUSIONS: Among this population of extremely preterm infants neither cord blood nor the 36 weeks' corrected age 25(OH)D levels were associated with development of BPD. Notably, at the current level of supplementation, all extremely preterm infants in our cohort had achieved 25(OH)D levels >30 ng ml(-1) by 36 weeks' corrected age, which is thought to represent sufficiency in adult and pediatric populations. PMID- 27467563 TI - A population study of first and subsequent pregnancy smoking behaviors in Ohio. AB - OBJECTIVE: The objective of this study is to identify maternal characteristics associated with non-smoking during a subsequent pregnancy after first pregnancy smoking. STUDY DESIGN: We conducted a retrospective population-based analysis of Ohio vital birth records from 2007 to 2013. We used logistic regression to calculate adjusted odds ratios with 95% confidence intervals for detection of characteristics associated with non-smoking during a subsequent pregnancy after first pregnancy smoking. RESULTS: Among 75 190 mothers, 75.6% were non-smokers and 13.7% were smokers during both pregnancies. During their first pregnancy, 49.7% of 15 075 smokers quit. Of them, 50.1% remained non-smokers during their subsequent pregnancy. Women who reduced, but continued smoking during their first pregnancy, were more than five times as likely to smoke during their subsequent pregnancy than women who quit (odds ratio (95% confidence interval): 2.85 (2.43 to 3.35) vs 0.55 (0.45 to 0.67)). CONCLUSION: Interventions targeting complete cessation, rather than reduction in smoking among first-time mothers, may be the most effective at optimizing long-term health benefits. PMID- 27467564 TI - Severe congenital anomalies of the kidney and urinary tract: epidemiology can inform ethical decision-making. AB - OBJECTIVE: Decision-making for pregnancies complicated by severe congenital anomalies of the kidneys and urinary tract (CAKUT) are ethically challenging, partly because the outcomes are not well studied. STUDY DESIGN: Retrospective cohort study of severe cases of CAKUT over 14 years. RESULTS: Seventy-one of the 108 cases could be completely analyzed. Forty-six percent (n=33) infants were live-born; one-third (n=11) survived to 12 months. Twice as many non-surviving infants received a trial of therapy vs comfort care only. Two-thirds of non survivors who received a trial of therapy died within the first 9 h of life. Live born infants faced morbidities such as pneumothorax and neonatal dialysis. CONCLUSIONS: Over half of pregnancies complicated by severe CAKUT ended in termination or stillbirth, but one-third of live-born infants survived to 12 months and the majority of non-survivors died within hours. This may allay concerns about prolonged and futile intensive care for parents considering a trial of therapy. PMID- 27467565 TI - Clinical impact of term-equivalent magnetic resonance imaging in extremely low birth-weight infants at a regional NICU. AB - OBJECTIVE: To evaluate the clinical impact of routine term-equivalent magnetic resonance imaging (TE-MRI) for extremely low-birth-weight infants at a regional neonatal intensive care unit. STUDY DESIGN: This is a single-center retrospective study evaluating preterm survivors who underwent TE-MRI. MRI abnormalities were compared between infants with and without cranial ultrasonography (CUS) abnormalities. Cost analysis comparing imaging modalities was also performed. RESULTS: TE-MRI use increased from 17% in 2006 to 76% in 2010. MRI detected new findings in nearly half of infants, whether or not they had known ultrasound abnormalities. MRI detected more cerebellar (18% vs 6%, P=0.04) and moderate white matter injury (12% vs 7%, P<0.001), and altered simulated neurological prognosis across developmental domains. The cost of TE-MRI was $1600, which was comparable to serial CUSs. CONCLUSION: TE-MRI detects new abnormalities and impacts developmental prognosis in the extremely low birth weight, which supports its use despite the added financial cost. PMID- 27467566 TI - Population-based risks of mortality and preterm morbidity by gestational age and birth weight. AB - OBJECTIVE: The objective of this study is to examine the effect of small or large for gestational age (SGA/LGA) status on mortality and morbidity by gestational age. STUDY DESIGN: Logistic binomial regression was used to calculate relative risks (RRs) and 95% confidence intervals for infant mortality and preterm morbidities for SGA or LGA compared with appropriately grown (AGA) deliveries stratified by gestational age group. RESULTS: Compared with AGA infants of similar gestational age, SGA infants were at increased risk for infant mortality. Mortality risk was decreased for LGA infants born between 25 and 27 weeks (RR: 0.6) but increased for LGA infants born between 28 and 31 weeks (RR: 1.9). Risk of preterm morbidity was increased for SGA infants born between 28 and 38 weeks, but decreased for LGA infants born before 37 weeks. CONCLUSION: This study demonstrates the importance of considering birth weight for gestational age when evaluating morbidity and mortality risks. PMID- 27467567 TI - Ag-Promoted ZrBEA Zeolites Obtained by Post-Synthetic Modification for Conversion of Ethanol to Butadiene. AB - 1,3-Butadiene was synthesized from ethanol using zirconium-containing zeolite beta (ZrBEA) catalysts doped with 1 wt % silver. The Zr was planted using post synthesis modification by dealumination of the parent zeolite followed by treatment with ZrOCl2 in a DMSO solution. FTIR and NMR spectroscopy were used to investigate the planting process by preparing materials with different Si/Al ratios and crystal sizes. The results showed preferential grafting of Zr to the terminal silanols present on the external surface of the zeolite crystals instead of incorporation of Zr into silanol nests. The grafting yielded highly accessible Zr(OSi)3 OH open sites with high Lewis acidity, as confirmed by FTIR spectroscopy of adsorbed CO. These sites are shown to be extremely active for the conversion of ethanol to butadiene. Ag/ZrBEA catalysts prepared using the post-synthesis method showed significant advantages compared with Ag/ZrBEA catalysts synthesized using a conventional hydrothermal procedure. The best catalyst performance in terms of butadiene formation rate (3 MUmol g(-1) s(-1) ) was observed over Ag/Zr(3.5)BEA(75) (containing 3.5 wt % Zr), which had the smallest crystal size and the highest content of Zr open sites of the prepared catalysts. PMID- 27467568 TI - What qualities of long-acting reversible contraception do women perceive as desirable or undesirable? A systematic review. AB - Little research examining qualities of contraception that make them attractive or unattractive to users, particularly young women, exists. The aim of this study is to systemically review the evidence regarding desirable and undesirable qualities of long-acting reversible contraception (LARC), including intrauterine devices, the implant and the injection, as perceived by women. Five electronic databases were searched in May 2015 using terms related to LARC and method preference or decision-making. Studies were included if they concerned women aged 18-23 years from developed countries and reported on perceived positive or negative qualities of LARC. Thirty articles were deemed relevant. Five key themes emerged under which qualities were categorised; including: (1) impact on bleeding; (2) impact on the body; (3) device-specific characteristics; (4) general characteristics; and (5) perceptions and misbeliefs. Fit and forget, high efficacy and long-term protection were considered the top desirable qualities of LARC. Undesirable qualities varied among the LARC methods; however, irregular bleeding, painful insertion and removal procedure, weight gain and location in the body were among those most commonly reported. The contraceptive benefits of LARC, including their high efficacy and longevity, are generally considered to be positive qualities by women, while the potential impact of side-effects on the body are considered as negative qualities. This information is crucial in the clinical setting as it provides practitioners with a greater understanding of the qualities women do and do not like about LARC methods. Discussion about these qualities, positive and negative, during consultations about contraception may increase rates of uptake. PMID- 27467569 TI - Pharmacokinetic evaluation of fixed-ratio combination of insulin degludec and liraglutide in the treatment of type 2 diabetes. AB - INTRODUCTION: Type 2 diabetes is a complex disease requiring individualized and often multi-faceted treatment plans. Balancing glycemic control with adverse medication side effects can be challenging. Combination therapy of basal insulin and GLP-1 receptor agonist therapy appears to provide a balance between glycemic efficacy, hypoglycemia and weight gain. AREAS COVERED: Available pharmacokinetic data, clinical trials and abstracts regarding fixed-ratio combination of insulin degludec and liraglutide were reviewed. Literature was searched from PubMed and available abstracts using the search term IDegLira up to June 2016. EXPERT OPINION: Fixed-ratio combination of insulin degludec and liraglutide is associated with sustained glucose-lowering effects as assessed by HbA1c reduction. Overall, hypoglycemia is reduced and weight loss is observed compared to basal insulin alone. There is no significant increase in gastrointestinal side effects, including nausea compared to non-glucagon-like peptide-1 receptor agonists. Pen injector delivery and dose-step titration allow for individualized therapy intensification. Combined treatment for type 2 diabetes with degludec and liraglutide therapy provides complementary therapeutic efficacy in the treatment of individuals with type 2 diabetes. PMID- 27467570 TI - Elevated Colonization of Microborers at a Volcanically Acidified Coral Reef. AB - Experiments have demonstrated that ocean acidification (OA) conditions projected to occur by the end of the century will slow the calcification of numerous coral species and accelerate the biological erosion of reef habitats (bioerosion). Microborers, which bore holes less than 100 MUm diameter, are one of the most pervasive agents of bioerosion and are present throughout all calcium carbonate substrates within the reef environment. The response of diverse reef functional groups to OA is known from real-world ecosystems, but to date our understanding of the relationship between ocean pH and carbonate dissolution by microborers is limited to controlled laboratory experiments. Here we examine the settlement of microborers to pure mineral calcium carbonate substrates (calcite) along a natural pH gradient at a volcanically acidified reef at Maug, Commonwealth of the Northern Mariana Islands (CNMI). Colonization of pioneer microborers was higher in the lower pH waters near the vent field. Depth of microborer penetration was highly variable both among and within sites (4.2-195.5 MUm) over the short duration of the study (3 mo.) and no clear relationship to increasing CO2 was observed. Calculated rates of biogenic dissolution, however, were highest at the two sites closer to the vent and were not significantly different from each other. These data represent the first evidence of OA-enhancement of microboring flora colonization in newly available substrates and provide further evidence that microborers, especially bioeroding chlorophytes, respond positively to low pH. The accelerated breakdown and dissolution of reef framework structures with OA will likely lead to declines in structural complexity and integrity, as well as possible loss of essential habitat. PMID- 27467572 TI - Mumps Outbreak at a University and Recommendation for a Third Dose of Measles Mumps-Rubella Vaccine - Illinois, 2015-2016. AB - Mumps is an acute viral disease characterized by fever and swelling of the parotid or other salivary glands. On May 1, 2015, the Illinois Department of Public Health (IDPH) confirmed a mumps outbreak at the University of Illinois at Urbana-Champaign. IDPH and the Champaign-Urbana Public Health District (C-UPHD) conducted an investigation and identified 317 cases of mumps during April 2015 May 2016. Because of sustained transmission in a population with high 2-dose coverage with measles-mumps-rubella (MMR) vaccine, a third MMR dose was recommended by IDPH, C-UPHD, and the university's McKinley Health Center. No formal recommendation for or against the use of a third MMR dose has been issued by the Advisory Committee on Immunization Practices (ACIP) (1). However, CDC has provided guidelines for use of a third dose as a control measure during mumps outbreaks in settings in which persons are in close contact with one another, where transmission is sustained despite high 2-dose MMR coverage, and when traditional control measures fail to slow transmission (2). PMID- 27467571 TI - Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons. AB - Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson's Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin's neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD. PMID- 27467573 TI - The Circulation of Scientific Articles in the Sphere of Web-Based Media: Citation Practices, Communities of Interests and Local Ties. AB - On 5th December 2012, a scientific article reviewing a change in the feeding behaviour of the European catfish, one of the largest freshwater fish, was published in the American scientific journal, PLOS ONE, an open access journal, which also allows the mass publication of pictures and videos. Within a few days following the publication of this article, it was relayed by numerous web sites and generated a media craze. In this paper, we analyse the circulation of this scientific information in the sphere of Web-based media during the two months following its publication, by revealing the citation mechanisms of the original article and the logic of the Internet users participating in its diffusion. In addition, since the circulation of its informational content travelled beyond linguistic and geographical boundaries, we chose to compare the citation modalities and intertextual relationships of documents in the three countries where the article spread the most widely, namely: France, the United States and Great Britain. Even though our study shows that the media circulation of scientific papers operates in a traditional way, the intertextual analysis underlines the grand variety of participants (such as journalists, non scientists, fishermen, technology enthusiasts and Internet users) involved in the diffusion of this information, each of them mobilizing different intertextual strategies, according to their various targets. They all transformed, reformulated and appropriated the scientific information according to their own, unique interests. This study also emphasizes the importance of journalistic websites as opinion relays. They were the first diffusers involved in spreading the information but this role was rarely acknowledged by the Internet users - through citations, for example. In contrast, we observed that amateurs' communities (communities of practices and communities of interest of fishermen or of buzz fans), which only became involved in a second temporal phase of the spreading, preferred to build up their credibility through citations of the original article. Finally, this research helps to rethink the mechanisms of the circulation of scientific information in the Web-based media, highlighting both the variety and the inventiveness of the interactions between the academic and public spheres. PMID- 27467574 TI - Neuron-Specific Deletion of the Nf2 Tumor Suppressor Impairs Functional Nerve Regeneration. AB - In contrast to axons of the central nervous system (CNS), axons of the peripheral nervous system (PNS) show better, but still incomplete and often slow regeneration following injury. The tumor suppressor protein merlin, mutated in the hereditary tumor syndrome Neurofibromatosis type 2 (NF2), has recently been shown to have RhoA regulatory functions in PNS neurons-in addition to its well characterized, growth-inhibitory activity in Schwann cells. Here we report that the conditional knockout of merlin in PNS neurons leads to impaired functional recovery of mice following sciatic nerve crush injury, in a gene-dosage dependent manner. Gross anatomical or electrophysiological alterations of sciatic nerves could not be detected. However, correlating with attenuated RhoA activation due to merlin deletion, ultrastructural analysis of nerve samples indicated enhanced sprouting of axons with reduced caliber size and increased myelination compared to wildtype animals. We conclude that deletion of the tumor suppressor merlin in the neuronal compartment of peripheral nerves results in compromised functional regeneration after injury. This mechanism could explain the clinical observation that NF2 patients suffer from higher incidences of slowly recovering facial nerve paralysis after vestibular schwannoma surgery. PMID- 27467576 TI - Modulation of Phosphopeptide Fragmentation via Dual Spray Ion/Ion Reactions Using a Sulfonate-Incorporating Reagent. AB - The labile nature of phosphoryl groups has presented a long-standing challenge for the characterization of protein phosphorylation via conventional mass spectrometry-based bottom-up proteomics methods. Collision-induced dissociation (CID) causes preferential cleavage of the phospho-ester bond of peptides, particularly under conditions of low proton mobility, and results in the suppression of sequence-informative fragmentation that often prohibits phosphosite determination. In the present study, the fragmentation patterns of phosphopeptides are improved through ion/ion-mediated peptide derivatization with 4-formyl-1,3-benezenedisulfonic acid (FBDSA) anions using a dual spray reactor. This approach exploits the strong electrostatic interactions between the sulfonate moieties of FBDSA and basic sites to facilitate gas-phase bioconjugation and to reduce charge sequestration and increase the yield of phosphate-retaining sequence ions upon CID. Moreover, comparative CID fragmentation analysis between unmodified phosphopeptides and those modified online with FBDSA or in solution via carbamylation and 4-sulfophenyl isothiocyanate (SPITC) provided evidence for sulfonate interference with charge directed mechanisms that result in preferential phosphate elimination. Our results indicate the prominence of charge-directed neighboring group participation reactions involved in phosphate neutral loss, and the implementation of ion/ion reactions in a dual spray reactor setup provides a means to disrupt the interactions by competing hydrogen-bonding interactions between sulfonate groups and the side chains of basic residues. PMID- 27467578 TI - Monkeypox virus induces the synthesis of less dsRNA than vaccinia virus, and is more resistant to the anti-poxvirus drug, IBT, than vaccinia virus. AB - Monkeypox virus (MPXV) infection fails to activate the host anti-viral protein, PKR, despite lacking a full-length homologue of the vaccinia virus (VACV) PKR inhibitor, E3. Since PKR can be activated by dsRNA produced during a viral infection, we have analyzed the accumulation of dsRNA in MPXV-infected cells. MPXV infection led to less accumulation of dsRNA than VACV infection. Because in VACV infections accumulation of abnormally low amounts of dsRNA is associated with mutations that lead to resistance to the anti-poxvirus drug isatin beta thiosemicarbazone (IBT), we investigated the effects of treatment of MPXV infected cells with IBT. MPXV infection was eight-fold more resistant to IBT than wild-type vaccinia virus (wtVACV). These results demonstrate that MPXV infection leads to the accumulation of less dsRNA than wtVACV, which in turn likely leads to a decreased capacity for activation of the dsRNA-dependent host enzyme, PKR. PMID- 27467577 TI - Cobalt Alloy Implant Debris Induces Inflammation and Bone Loss Primarily through Danger Signaling, Not TLR4 Activation: Implications for DAMP-ening Implant Related Inflammation. AB - Cobalt alloy debris has been implicated as causative in the early failure of some designs of current total joint implants. The ability of implant debris to cause excessive inflammation via danger signaling (NLRP3 inflammasome) vs. pathogen associated pattern recognition receptors (e.g. Toll-like receptors; TLRs) remains controversial. Recently, specific non-conserved histidines on human TLR4 have been shown activated by cobalt and nickel ions in solution. However, whether this TLR activation is directly or indirectly an effect of metals or secondary endogenous alarmins (danger-associated molecular patterns, DAMPs) elicited by danger signaling, remains unknown and contentious. Our study indicates that in both a human macrophage cell line (THP-1) and primary human macrophages, as well as an in vivo murine model of inflammatory osteolysis, that Cobalt-alloy particle induced NLRP3 inflammasome danger signaling inflammatory responses were highly dominant relative to TLR4 activation, as measured respectively by IL-1beta or TNF alpha, IL-6, IL-10, tissue histology and quantitative bone loss measurement. Despite the lack of metal binding histidines H456 and H458 in murine TLR4, murine calvaria challenge with Cobalt alloy particles induced significant macrophage driven in vivo inflammation and bone loss inflammatory osteolysis, whereas LPS calvaria challenge alone did not. Additionally, no significant increase (p<0.05) in inflammation and inflammatory bone loss by LPS co-challenge with Cobalt vs. Cobalt alone was evident, even at high levels of LPS (i.e. levels commiserate with hematogenous levels in fatal sepsis, >500pg/mL). Therefore, not only do the results of this investigation support Cobalt alloy danger signaling induced inflammation, but under normal homeostasis low levels of hematogenous PAMPs (<2pg/mL) from Gram-negative bacteria, seem to have negligible contribution to the danger signaling responses elicited by Cobalt alloy metal implant debris. This suggests the unique nature of Cobalt alloy particle bioreactivity is strong enough to illicit danger signaling that secondarily activate concomitant TLR activation, and may in part explain Cobalt particulate associated inflammatory and toxicity-like reactions of specific orthopedic implants. PMID- 27467580 TI - Not "Pulling up the Ladder": Women Who Organize Conference Symposia Provide Greater Opportunities for Women to Speak at Conservation Conferences. AB - The scientific community faces numerous challenges in achieving gender equality among its participants. One method of highlighting the contributions made by female scientists is through their selection as featured speakers in symposia held at the conferences of professional societies. Because they are specially invited, symposia speakers obtain a prestigious platform from which to display their scientific research, which can elevate the recognition of female scientists. We investigated the number of female symposium speakers in two professional societies (the Society of Conservation Biology (SCB) from 1999 to 2015, and the American Society of Ichthyologists and Herpetologists (ASIH) from 2005 to 2015), in relation to the number of female symposium organizers. Overall, we found that 36.4% of symposia organizers and 31.7% of symposia speakers were women at the Society of Conservation Biology conferences, while 19.1% of organizers and 28% of speakers were women at the American Society of Ichthyologists and Herpetologists conferences. For each additional female organizer at the SCB and ASIH conferences, there was an average increase of 95% and 70% female speakers, respectively. As such, we found a significant positive relationship between the number of women organizing a symposium and the number of women speaking in that symposium. We did not, however, find a significant increase in the number of women speakers or organizers per symposium over time at either conference, suggesting a need for revitalized efforts to diversify our scientific societies. To further those ends, we suggest facilitating gender equality in professional societies by removing barriers to participation, including assisting with travel, making conferences child-friendly, and developing thorough, mandatory Codes of Conduct for all conferences. PMID- 27467579 TI - B cells naturally induced during dengue virus infection release soluble CD27, the plasma level of which is associated with severe forms of pediatric dengue. AB - The CD27 and CD38 antigens are highly expressed on the plasmablast surface, and a massive plasmablast response has been described for dengue virus infection. Soluble CD27 and CD38 forms (sCD27 and sCD38, respectively) increase after immune activation. Here, we show increased sCD27 release in cultures of purified polyclonally stimulated B cells. T and B cells isolated from children with dengue spontaneously produced higher levels of sCD27 but not sCD38, compared with healthy children (P=0.03), and sCD27 levels positively correlated with plasmablast frequency in the cultures (rho=0.58, P=0.01). Children with dengue had higher plasma levels of sCD27 and sCD38 than healthy children, which decreased during convalescence. Plasma sCD27 was higher in severe than with mild dengue, but the opposite was observed for sCD38. These findings support a potential new role for B cells in dengue pathogenesis, and sCD27 and sCD38 are novel biomarkers associated with clinical outcome during dengue virus infection. PMID- 27467581 TI - Mild Cognitive Impairment in Patients with Early-Onset Parkinson's Disease. AB - BACKGROUND/AIMS: Few studies have described mild cognitive impairment (MCI) and cognitive characteristics in early-onset Parkinson's disease (EOPD). This study describes attention/working memory, language, memory, visuospatial abilities, executive function, and frequency of MCI and dementia in EOPD. METHODS: Eighty one EOPD patients were administered neuropsychological tests and the Beck Depression Inventory. Scores were compared with age/education-appropriate norms and were correlated to years of disease progression and severity of motor symptoms. The frequency of MCI and dementia was determined by the Movement Disorder Society criteria. RESULTS: Thirty-one percent of patients met the MCI criteria, but none had dementia. Commonly affected domains were memory, visuospatial, and executive function. Cognitive dysfunction was not explained by depression or severity of motor symptoms. CONCLUSION: One third of EOPD patients presented with MCI, which was not associated with the same risk factors as reported in late-onset Parkinson's disease. MCI could have a different prognostic value in EOPD. PMID- 27467575 TI - Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. AB - A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts. PMID- 27467582 TI - Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells. AB - Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells. Inhibition of Hsp90 ATPase suppressed aromatase expression. Silencing Aha1 (activator of Hsp90 ATPase 1), a co-chaperone of Hsp90 required for its ATPase activity, led to both inhibition of Hsp90 ATPase activity and reduced aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client proteins, HIF-1alpha, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1alpha and PKM2 was recruited to the aromatase promoter II in LFS stromal cells. Silencing either HIF-1alpha or PKM2 suppressed aromatase expression in LFS stromal cells. CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90 ATPase activity, levels of PKM2 and HIF-1alpha, and aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90 ATPase activity, Aha1, HIF-1alpha, PKM2, and aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1alpha were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/HIF 1alpha axis mediates the induction of aromatase in LFS. PMID- 27467584 TI - Higher Fruit Intake Is Related to TNF-alpha Hypomethylation and Better Glucose Tolerance in Healthy Subjects. AB - BACKGROUND/AIM: This study hypothesized an association between healthy dietary patterns, hypermethylation of the tumor necrosis factor-alpha (TNF-alpha) promoter and decreased risk of metabolic changes. METHODS: Forty normal-weight young women were involved in this cross-sectional study. DNA was isolated from white blood cells, and CpG site methylation in TNF-alpha was analyzed by Sequenom EpiTyper. The quality of the diet was assessed by Healthy Eating Index (HEI 2005). RESULTS: Contradicting our hypothesis, HEI-2005 score was negatively associated with CpG5 (r = -0.460, p = 0.003) and TNF-alpha total methylation (r = -0.355, p = 0.026). A higher intake of fruits was related to lower insulin, HOMA IR, and TNF-alpha methylation. No other dietary pattern was related to TNF-alpha methylation. TNF-alpha total methylation correlated positively with systolic blood pressure (r = 0.323; p = 0.042) and CpG5 methylation with body mass index (r = 0.333, p = 0.036). Furthermore, fiber intake was negatively associated with the CpG5 (r = -0.324, p = 0.041) and TNF-alpha total methylation (r = -0.434, p = 0.005), whereas vitamin C intake was negatively associated with TNF-alpha total methylation (r = -0.411, p = 0.009). Intakes of apples and citrus fruits were negatively associated with TNF-alpha total methylation. CONCLUSION: A healthy dietary pattern and higher fruit intake (particularly apples and citrus fruits) were related to better glucose tolerance in healthy subjects, which could be mediated by lower TNF-alpha methylation. PMID- 27467583 TI - A Multi-scale Computational Platform to Mechanistically Assess the Effect of Genetic Variation on Drug Responses in Human Erythrocyte Metabolism. AB - Progress in systems medicine brings promise to addressing patient heterogeneity and individualized therapies. Recently, genome-scale models of metabolism have been shown to provide insight into the mechanistic link between drug therapies and systems-level off-target effects while being expanded to explicitly include the three-dimensional structure of proteins. The integration of these molecular level details, such as the physical, structural, and dynamical properties of proteins, notably expands the computational description of biochemical network level properties and the possibility of understanding and predicting whole cell phenotypes. In this study, we present a multi-scale modeling framework that describes biological processes which range in scale from atomistic details to an entire metabolic network. Using this approach, we can understand how genetic variation, which impacts the structure and reactivity of a protein, influences both native and drug-induced metabolic states. As a proof-of-concept, we study three enzymes (catechol-O-methyltransferase, glucose-6-phosphate dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase) and their respective genetic variants which have clinically relevant associations. Using all-atom molecular dynamic simulations enables the sampling of long timescale conformational dynamics of the proteins (and their mutant variants) in complex with their respective native metabolites or drug molecules. We find that changes in a protein's structure due to a mutation influences protein binding affinity to metabolites and/or drug molecules, and inflicts large-scale changes in metabolism. PMID- 27467585 TI - MRI as a Novel In Vivo Approach for Assessing Structural Changes of Chlamydia Pathology in a Mouse Model. AB - Chlamydia trachomatis is among the most prevalent of sexually transmitted diseases. While Chlamydia infection is a reportable event and screening has increased over time, enhanced surveillance has not resulted in a reduction in the rate of infections, and Chlamydia infections frequently recur. The development of a preventative vaccine for Chlamydia may be the only effective approach for reducing infection and the frequency of pathological outcomes. Current vaccine research efforts involve time consuming and/or invasive approaches for assessment of disease state, and MRI presents a clinically translatable method for assessing infection and related pathology both quickly and non-invasively. Longitudinal T2 weighted MRI was performed over 63 days on both control or Chlamydia muridarum challenged mice, either with or without elementary body (EB) immunization, and gross necropsy was performed on day 65. A scoring system was developed to assess the number of regions affected by Chlamydia pathology and was used to document pathology over time and at necropsy. The scoring system documented increasing incidence of pathology in the unimmunized and challenged mice (significantly greater compared to the control and EB immunized-challenged groups) by 21 days post-challenge. No differences between the unchallenged and EB immunized challenged mice were observed. MRI scores at Day 63 were consistently higher than gross necropsy scores at Day 65, although two of the three groups of mice showed no significant differences between the two techniques. In this work we describe the application of MRI in mice for the potential evaluation of disease pathology and sequelae caused by C. muridarum infection and this technique's potential for evaluation of vaccines for Chlamydia. PMID- 27467586 TI - Threshold Levels of Gfi1 Maintain E2A Activity for B Cell Commitment via Repression of Id1. AB - A regulatory circuit that controls myeloid versus B lymphoid cell fate in hematopoietic progenitors has been proposed, in which a network of the transcription factors Egr1/2, Nab, Gfi1 and PU.1 forms the core element. Here we show that a direct link between Gfi1, the transcription factor E2A and its inhibitor Id1 is a critical element of this regulatory circuit. Our data suggest that a certain threshold of Gfi1 is required to gauge E2A activity by adjusting levels of Id1 in multipotent progenitors, which are the first bipotential myeloid/lymphoid-restricted progeny of hematopoietic stem cells. If Gfi1 levels are high, Id1 is repressed enabling E2A to activate a specific set of B lineage genes by binding to regulatory elements for example the IL7 receptor gene. If Gfi1 levels fall below a threshold, Id1 expression increases and renders E2A unable to function, which prevents hematopoietic progenitors from engaging along the B lymphoid lineage. PMID- 27467587 TI - High Plasmodium malariae Prevalence in an Endemic Area of the Colombian Amazon Region. AB - Malaria is a worldwide public health problem; parasites from the genus Plasmodium are the aetiological agent for this disease. The parasites are mostly diagnosed by conventional microscopy-based techniques; however, their limitations have led to under-registering the reported prevalence of Plasmodium species. This study has thus been aimed at evaluating the infection and coinfection prevalence of 3 species of Plasmodium spp., in an area of the Colombian Amazon region. Blood samples were taken from 671 symptomatic patients by skin puncture; a nested PCR amplifying the 18S ssRNA region was used on all samples to determine the presence of P. vivax, P. malariae and P. falciparum. Statistical analysis determined infection and coinfection frequency; the association between infection and different factors was established. The results showed that P. vivax was the species having the greatest frequency in the study population (61.4%), followed by P. malariae (43.8%) and P. falciparum (11.8%). The study revealed that 35.8% of the population had coinfection, the P. vivax/P. malariae combination occurring most frequently (28.3%); factors such as age, geographical origin and clinical manifestations were found to be associated with triple-infection. The prevalence reported in this study differed from previous studies in Colombia; the results suggest that diagnosis using conventional techniques could be giving rise to underestimating some Plasmodium spp. species having high circulation rates in Colombia (particularly in the Colombian Amazon region). The present study's results revealed a high prevalence of P. malariae and mixed infections in the population being studied. The results provide relevant information which should facilitate updating the epidemiological panorama and species' distribution so as to include control, prevention and follow-up measures. PMID- 27467588 TI - Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells. AB - Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure) or metronomic (7-day continuous exposure) treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50) was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks) and metronomic (5 days a week for 2 weeks) topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3-23) was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p<0.05). Metronomic topotecan or melphalan significantly inhibited in vitro tube formation in HUVEC and EPC compared to vehicle-treated cells (p<0.05). Both treatment schemes induced apoptosis and/or necrosis in all cell models. No significant difference was observed in the expression of ABCB1, ABCC1 or ABCG2 when comparing cells treated with melphalan or topotecan between treatment schedules at the IC50 or with control cells (p>0.05). In mice, continuous topotecan lead to significantly lower tumor volumes compared to conventional treatment after 14 days of treatment (p<0.05). Continuous exposure to melphalan or topotecan increased the chemosensitivity of retinoblastoma and endothelial cells to both chemotherapy agents with lower IC50 values compared to short-term treatment. These findings were validated in an in vivo model. None of the dosing modalities induced multidrug resistance mechanisms while apoptosis was the mechanism of cell death after both treatment schedules. Metronomic chemotherapy may be a valid option for retinoblastoma treatment allowing reductions of the daily dose. PMID- 27467590 TI - Validation of data quality in the Swedish National Register for Oesophageal and Gastric Cancer. AB - BACKGROUND: The Swedish National Register for Oesophageal and Gastric Cancer (NREV) was launched in 2006. Data are reported at diagnosis (diagnostic survey), at the time of surgery (surgical survey) and at first outpatient follow-up (follow-up survey). The aim of this study was to evaluate data originating from NREV in terms of comparability, completeness, accuracy and timeliness. METHODS: Coding routines were compared with international standards and completeness was evaluated by means of a 5-year (2009-2013) comparison with mandatory national registers. Validity was tested by comparison with reabstracted data from source medical records in 400 patients chosen randomly with stratification for hospital size and catchment area population. Timeliness of registration was described. RESULTS: Coding routines followed national and international guidelines. Compared with the Swedish Cancer Registry from 2009 to 2013, 6069 (95.5 per cent) of 6354 patients were registered in NREV at the time of data extraction. Of 60 variables investigated, 10 966 of 12 035 original entries were correct in the reabstraction, resulting in an exact agreement of 91.1 per cent in the register. There were 782 (6.5 per cent) incorrect and 287 (2.4 per cent) missing entries. Median time to registration was 3.9, 3.4 and 4.1 months for diagnostic, surgical and follow-up surveys respectively. CONCLUSION: NREV has reached a position with good coverage of those with the relevant diagnoses, and contains comparable and valid data. Quality data on each variable are available. Timeliness is an area with potential for improvement. PMID- 27467589 TI - Randomized controlled trial of the Valencia model of waking hypnosis plus CBT for pain, fatigue, and sleep management in patients with cancer and cancer survivors. AB - BACKGROUND: This study evaluated the efficacy of an intervention combining the Valencia model of waking hypnosis with cognitive-behavioral therapy (VMWH-CBT) in managing cancer-related pain, fatigue, and sleep problems in individuals with active cancer or who were post-treatment survivors. We hypothesized that four sessions of VMWH-CBT would result in greater improvement in participants' symptoms than four sessions of an education control intervention. Additionally, we examined the effects on several secondary outcome domains that are associated with increases in these symptoms (depression, pain interference, pain catastrophizing, and cancer treatment distress). METHODS: The study design was a randomized controlled crossover clinical trial comparing the VMWH-CBT intervention with education control. Participants (N = 44) received four sessions of both treatments, in a counterbalanced order (n = 22 per order condition). RESULTS: Participants were 89% female (N = 39) with mean age of 61 years (SD = 12.2). They reported significantly greater improvement after receiving the active treatment relative to the control condition in all the outcome measures. Treatment gains were maintained at 3-month follow-up. CONCLUSIONS: This study supports the beneficial effects of the VMWH-CBT intervention relative to a control condition and that treatment gains remain stable. VMWH-CBT-trained clinicians should be accessible for managing symptoms both during and after cancer treatment, though the findings need to be replicated in larger samples of cancer survivors. PMID- 27467591 TI - [Will 68Ga-PSMA PET become the New Imaging Standard for Prostate Cancer?]. AB - This article describes the current knowledge in prostate cancer imaging with (68)Ga-PSMA PET, which achieves excellent specificities and higher sensitivities compared with standard imaging for local tumour detection as well as primary and recurrence staging. Therefore, (68)Ga-PSMA PET will probably play an increasing role for the diagnostic investigation of prostate cancer and will be more widely used in the future. PMID- 27467593 TI - Engineering the Membrane/Electrode Interface To Improve the Performance of Solid State Supercapacitors. AB - This paper investigates the effect of adding a 450 nm layer based on porous TiO2 at the interface between a 4.5 MUm carbon/TiO2 nanoparticle-based electrode and a polymer electrolyte membrane as a route to improve energy storage performance in solid-state supercapacitors. Electrochemical characterization showed that adding the interface layer reduced charge transfer resistance, promoted more efficient ion transfer across the interface, and significantly improved charge/discharge dynamics in a solid-state supercapacitor, resulting in an increased areal capacitance from 45.3 to 111.1 mF cm(-2) per electrode at 0.4 mA cm(-2). PMID- 27467592 TI - Cell Killing Mechanisms and Impact on Gene Expression by Gemcitabine and 212Pb Trastuzumab Treatment in a Disseminated i.p. Tumor Model. AB - In pre-clinical studies, combination therapy with gemcitabine and targeted radioimmunotherapy (RIT) using 212Pb-trastuzumab showed tremendous therapeutic potential in the LS-174T tumor xenograft model of disseminated intraperitoneal disease. To better understand the underlying molecular basis for the observed cell killing efficacy, gene expression profiling was performed after a 24 h exposure to 212Pb-trastuzumab upon gemcitabine (Gem) pre-treatment in this model. DNA damage response genes in tumors were quantified using a real time quantitative PCR array (qRT-PCR array) covering 84 genes. The combination of Gem with alpha-radiation resulted in the differential expression of apoptotic genes (BRCA1, CIDEA, GADD45alpha, GADD45gamma, IP6K3, PCBP4, RAD21, and p73), cell cycle regulatory genes (BRCA1, CHK1, CHK2, FANCG, GADD45alpha, GTSE1, PCBP4, MAP2K6, NBN, PCBP4, and SESN1), and damaged DNA binding and repair genes (BRCA1, BTG2, DMC1, ERCC1, EXO1, FANCG, FEN1, MSH2, MSH3, NBN, NTHL1, OGG1, PRKDC, RAD18, RAD21, RAD51B, SEMA4G, p73, UNG, XPC, and XRCC2). Of these genes, the expression of CHK1, GTSE1, EXO1, FANCG, RAD18, UNG and XRCC2 were specific to Gem/212Pb trastuzumab administration. In addition, the present study demonstrates that increased stressful growth arrest conditions induced by Gem/212Pb-trastuzumab could suppress cell proliferation possibly by up-regulating genes involved in apoptosis such as p73, by down-regulating genes involved in cell cycle check point such as CHK1, and in damaged DNA repair such as RAD51 paralogs. These events may be mediated by genes such as BRCA1/MSH2, a member of BARC (BRCA associated genome surveillance complex). The data suggest that up-regulation of genes involved in apoptosis, perturbation of checkpoint genes, and a failure to correctly perform HR-mediated DSB repair and mismatch-mediated SSB repair may correlate with the previously observed inability to maintain the G2/M arrest, leading to cell death. PMID- 27467594 TI - Transferring Patients with Intracerebral Hemorrhage Does Not Increase In-Hospital Mortality. AB - INTRODUCTION: Comprehensive stroke centers (CSCs) accept transferred patients from referring hospitals in a given regional area. The transfer process itself has not been studied as a potential factor that may impact outcome. We compared in-hospital mortality and severe disability or death at CSCs between transferred and directly admitted intracerebral hemorrhage (ICH) patients of matched severity. MATERIALS AND METHODS: We retrospectively reviewed all primary ICH patients from a prospectively-collected stroke registry and electronic medical records, at two tertiary care sites. Patients meeting inclusion criteria were divided into two groups: patients transferred in for a higher level of care and direct presenters. We used propensity scores (PS) to match 175 transfer patients to 175 direct presenters. These patients were taken from a pool of 530 eligible patients, 291 (54.9%) of whom were transferred in for a higher level of care. Severe disability or death was defined as a modified Rankin Scale (mRS) sore of 4 6. Mortality and morbidity were compared between the 2 groups using Pearson chi squared test and Student t test. We fit logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between transfer status and in-hospital mortality and severe disability or death in full and PS-matched patients. RESULTS: There were no significant differences in the PS matched transfer and direct presentation groups. Patients transferred to a regional center were not at higher odds of in-hospital mortality (OR: 0.93, 95% CI: 0.50-1.71) and severe disability or death (OR: 0.77, 95% CI: 0.39-1.50), than direct presenters, even after adjustment for PS, age, baseline NIHSS score, and glucose on admission. CONCLUSION: Our observation suggests that transfer patients of similar disease burden are not at higher risk of in-hospital mortality than direct presenters. PMID- 27467596 TI - Adapting to Life after Hurricane Katrina and the Deepwater Horizon Oil Spill: An Examination of Psychological Resilience and Depression on the Mississippi Gulf Coast. AB - The purpose of this study was to examine relationships among depression, psychological resilience, and other sociodemographic factors of individuals who were highly exposed to Hurricane Katrina in 2005 and the Deepwater Horizon Oil Spill in 2010. A spatially stratified random sample of 294 Mississippi Gulf Coast residents living in close proximity to the Gulf of Mexico were surveyed. Findings indicated that low education attainment, financial hardship, and disaster-related damages increased the likelihood of depression, whereas psychological resilience and having health insurance reduced the odds of depression. Implications for enhancing psychological resilience and increasing access to health insurance are discussed. PMID- 27467595 TI - Characterization of Venom and Oviduct Components of Parasitoid Wasp Asobara japonica. AB - During natural parasitization, Asobara japonica wasps introduce lateral oviduct (LO) components into their Drosophila hosts soon after the venom injection to neutralize its strong toxicity; otherwise, the host will die. Although the orchestrated relationship between the venom and LO components necessary for successful parasitism has attracted the attention of many researchers in this field, the molecular natures of both factors remain ambiguous. We here showed that precipitation of the venom components by ultracentrifugation yielded a toxic fraction that was inactivated by ultraviolet light irradiation, boiling, and sonication, suggesting that it is a virus-like entity. Morphological observation of the precipitate after ultracentrifugation showed small spherical heterogeneous virus-like particles 20-40 nm in diameter. The venom's detrimental effect on D. melanogaster larvae was not directly neutralized by the LO components but blocked by a hemolymphal neutralizing factor activated by the LO factor. Furthermore, we found that A. japonica venom and LO components acted similarly on the larvae of the common cutworm Spodoptera litura: the venom injection caused mortality but coinjection of the LO factor protected S. litura larvae from the venom's toxicity. In contrast, D. ficusphila and D. bipectinata, which are closely related to D. melanogaster but non-habitual host species of A. japonica, were not negatively affected by A. japonica venom due to an intrinsic neutralizing activity in their hemolymph, indicating that these species must have acquired a neutralizer of A. japonica venom during evolution. These results give new insights into the characteristics of both the venom and LO components: A. japonica females have utilized the virus-like toxic venom factor to exploit a wider range of host species after the evolutionary process enabled them to use the LO factor for activation of the host hemolymph neutralizer precursor, although the non-habitual host Drosophila species possess an active intrinsic neutralizer in their hemolymph. PMID- 27467598 TI - Soil Aggregate Stability and Grassland Productivity Associations in a Northern Mixed-Grass Prairie. AB - Soil aggregate stability data are often predicted to be positively associated with measures of plant productivity, rangeland health, and ecosystem functioning. Here we revisit the hypothesis that soil aggregate stability is positively associated with plant productivity. We measured local (plot-to-plot) variation in grassland community composition, plant (aboveground) biomass, root biomass, % water-stable soil aggregates, and topography. After accounting for spatial autocorrelation, we observed a negative association between % water-stable soil aggregates (0.25-1 and 1-2 mm size classes of macroaggregates) and dominant graminoid biomass, and negative associations between the % water-stable aggregates and the root biomass of a dominant sedge (Carex filifolia). However, variation in total root biomass (0-10 or 0-30 cm depths) was either negatively or not appreciably associated with soil aggregate stabilities. Overall, regression slope coefficients were consistently negative thereby indicating the general absence of a positive association between measures of plant productivity and soil aggregate stability for the study area. The predicted positive association between factors was likely confounded by variation in plant species composition. Specifically, sampling spanned a local gradient in plant community composition which was likely driven by niche partitioning along a subtle gradient in elevation. Our results suggest an apparent trade-off between some measures of plant biomass production and soil aggregate stability, both known to affect the land's capacity to resist erosion. These findings further highlight the uncertainty of plant biomass-soil stability associations. PMID- 27467597 TI - Differential Frequency of CD8+ T Cell Subsets in Multiple Sclerosis Patients with Various Clinical Patterns. AB - Recent evidence points to a pathogenic role for CD8+ cytotoxic T (Tc) cells in Multiple sclerosis (MS). Based on cytokine profile, Tc cells can be divided into different subsets: IFN-gamma (Tc1), IL-4 (Tc2), IL-10 (Tc10), IL-17 (Tc17), IL-21 (Tc21), IL-22 (Tc22) and TNF-alpha producing cells. In this study we evaluated the frequency of Tc cell subsets and the serum level of Tc17 differentiation cytokines in MS patients with different clinical patterns. We analyzed Tc cell subsets percentage in peripheral blood of relapsing-remitting (RRMS) (n = 28), secondary-progressive (SPMS) (n = 10) and primary-progressive (PPMS) (n = 4) MS patients in comparison to healthy controls (n = 15) using flow cytometry. Serum level of TGF-beta, IL-6 and IL-23 were measured by ELISA. We showed elevated levels of Tc1 and Tc17 cells in SPMS and RRMS patients in relapse phase, respectively (P = 0.04). Interestingly, the percentage of TNF-alpha producing CD8+ T cells in relapse and remission phase of RRMS and SPMS patients were higher than controls (P = 0.01, P = 0.004, P = 0.01, respectively) and Tc21 increased in remission phase of RRMS compared to SPMS (P = 0.03). We also found higher frequency of CD8+ IFN-gamma+ TNF-alpha+ IL-17+ T cells in relapse phase of RRMS compared to remission phase, SPMS patients and controls (P = 0.01, P = 0.004 and P = 0.02, respectively). TGF- beta increased in sera of RRMS patients in remission phase (P = 0.03) and SPMS (P = 0.05) compared to healthy subjects. Increased level of Tc17 and CD8+ IFN-gamma+ TNF-alpha+ IL-17+ T cells in relapse phase highlights the critical role of IL-17 in RRMS pathogenesis. PMID- 27467599 TI - [4 + 3] Cycloaddition of Phthalazinium Dicyanomethanides with Azoalkenes Formed in Situ: Synthesis of Triazepine Derivatives. AB - [4 + 3] cycloaddition of phthalazinium dicyanomethanides with in situ formed azoalkenes was achieved, providing an access to various 1,2,4-triazepine derivatives in moderate to excellent yields. PMID- 27467602 TI - Coming in Sportsmedicine. PMID- 27467604 TI - Scanning Sports. PMID- 27467603 TI - Noteworthy. PMID- 27467605 TI - Brief Reports. PMID- 27467600 TI - Fulminant Amebic Colitis after Corticosteroid Therapy: A Systematic Review. AB - BACKGROUND: Amebic colitis, caused by intestinal infection with the parasite, Entamoeba histolytica, is a common cause of diarrhea worldwide. Fulminant amebic colitis is the most devastating complication of this infection, associated with both high mortality and morbidity. We conducted a review of the English literature to describe cases of fulminant amebic colitis associated with exposure to corticosteroid medications in order to identify the risk factors for poor outcome and determine difficulties in diagnosis and treatment. METHODOLOGY AND PRINCIPAL FINDINGS: Articles reporting severe and fulminant forms of amebic colitis between 1991 and 2016 were collected. 525 records were screened to identify 24 cases for qualitative analysis associated with corticosteroid use. Cases arose from areas of high endemicity or travel to such areas. Most cases (14 of 24, 58%) were given corticosteroids for initially misdiagnosed colitis, mainly inflammatory bowel, resulting in rapid progression of disease. Nearly half of all cases underwent surgical intervention, and 25% of cases died, despite all patients eventually receiving treatment with metronidazole. The odds of death did not differ significantly by prior misdiagnosis, co-morbidities, bowel perforation or need for surgery. CONCLUSIONS AND SIGNIFICANCE: Infection with E. histolytica should be considered prior to the administration of corticosteroids, in particular for patients residing in endemic areas or those with appropriate travel history, especially prior to the diagnosis of inflammatory bowel disease. The development of preventative and treatment interventions are needed to improve outcomes of fulminant disease. PMID- 27467606 TI - Sportsmedicine Forum. AB - A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to sir your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondence to Sportsmedicine Forum, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis 55435. PMID- 27467607 TI - abstracts at a glance. PMID- 27467608 TI - Guest Editorial. PMID- 27467610 TI - Exercise Fatigue in Adolescents: Diagnosis of Athlete Burnout. AB - In brief: When a young athlete complains of chronic fatigue, declining performance, and dental lassitude-symptoms of burnout syndrome-a comprehensive diagnostic approach is required. Identification of anthropometric, physiological, or psychological abnormalities that interfere with normal exercise capacity usually can be made by means of a complete medical history and physical lamination along with limited laboratory testing. In most situations, proper therapeutic intervention will reverse exercise impairment and restore the patient's normal ability to tolerate physical activity. PMID- 27467611 TI - Boxing Injuries From an Instructional Program. AB - In brief: Boxing is a controversial sport, and numerous reports have been published about injuries in professional and amateur bouts. No reports have been made, however, about injuries sustained when boxing is part of an educational program. At the US Military Academy in West Point, New York, boxing is an integral part of the physical development and sports program for male cadets. However, because of the program's safeguards, few serious injuries occur. This paper describes the safeguards as well as the injury pattern at the academy over a two-year period (1983-84 and 1984-85). About 2,100 cadets received boxing instruction during that time, with an injury rate of less than 4%. PMID- 27467612 TI - Injuries to Athletes with Physical Disabilities: Prevention Implications. AB - In brief: While athletes with disabilities may not be injured any more often than the able-bodied, the types of injuries they sustain are specific to their disabilities and sports. Wheelchair athletes, for example, are especially susceptible to hypothermia and hyperthermia due to their inactive leg muscles, vasomotor paralysis, and reduced evaporative heat loss and cooling. This review of current literature reveals that high-risk sports are track and field, basketball, and road racing, with soft-tissue injuries the most common among wheelchair athletes. Carpal tunnel syndrome is also a characteristic injury. Many preventive measures are suggested, including prescription of sport chairs tailored to an athlete's body type, disability, and sport. PMID- 27467613 TI - Endurance Exercise: Normal Physiology and Limitations Imposed by Pathological Processes (Part 2). AB - In brief: Endurance exercise causes rapid changes in physiological and metabolic functions, involving not only the body's oxygen transport system (discussed in part 1 of this article, August 1986, page 94) but also the fuel supply and endocrine systems. The hormonal changes increase glucose delivery by stimulating glycogenolysis and gluconeogenesis in the liver and glycogen utilization in muscles, and also increase free fatty acid delivery by stimulating lipolysis in fat cells. Patients with disorders of muscle energy metabolism may have difficulty performing either brief, intense exercise or prolonged exercise, depending on the disorder. Diseases that cause abnormal hormonal and autonomic responses to exercise include autonomic neuropathy, central Cushing's disease, and diabetes mellitus. PMID- 27467614 TI - The Anemias of Athletes. AB - In brief: Diagnosing anemia in athletes is complicated, because athletes normally have lower hemoglobin and serum ferritin concentrations than nonathletes. This dilutional pseudoanemia-a beneficial adaptation that enhances athletic performance-needs no treatment. Athletes can also develop true anemia from iron deficiency and/or footstrike hemolysis. True anemia can be treated with iron supplements and diet modification to increase absorbable iron; footstrike hemolysis can be minimized by paying attention to body weight, gait, shoes, and terrain. The widespread notion that depletion of iron stores without anemia limits performance is probably wrong, but even very mild iron deficiency anemia impairs maximal performance. The physician who recognizes and manages the diverse anemias of athletes performs a vital service. PMID- 27467615 TI - Effects of Strength Training on Muscle Development in Prepubescent, Pubescent, and Postpubescent Males. AB - In brief: Thirty-three prepubescent, pubescent, and postpubescent males participated in a nine-week resistive exercise program to test the hypothesis that pubescent males respond better to strength training than older and younger groups do. Before and after the program, the subjects' strength in elbow and knee flexion and extension was tested bilaterally on a dynamometer at two velocities. The posttest showed that all of the subjects gained strength in elbow flexion and extension and knee extension but not in knee flexion. The prepubescent group showed significantly greater gains than the others on three of the 16 tests, but in no case did the pubescent group show significantly greater gains. PMID- 27467616 TI - Primary Causes of Drowning and Near Drowning in Scuba Diving. AB - In brief: Two scuba divers who were semiconscious when retrieved from the water of a training pool were found to have different primary injuries that required distinctly different treatments. Near drowning in a swimmer or scuba diver should alert a physician to look beyond the simple immersion accident to discover if an underlying disorder may have been the cause. In a scuba diver, the differential diagnosis must be extended to include decompression sickness, cerebral air embolism, pneumothorax, and carbon monoxide poisoning. Assessment and treatment perhaps with hyperbaric oxygen therapy-must be carried out at once, both to resuscitate the diver and maximize the chances for a complete recovery. PMID- 27467617 TI - Back to School for Youth Fitness Tests. AB - What fitness test should US schoolchildren take this year? The question may be answered by next year. PMID- 27467618 TI - Exercise Training for Heart Transplant Patients. AB - An exercise program for cardiac transplant patients in England has convinced at least one researcher that exercise for these patients is both feasible and beneficial. PMID- 27467619 TI - Hotels Make Room for Fitness. AB - Hotels are trying to prove they understand what the fitness boom means to many travelers-but do they understand safety? PMID- 27467620 TI - Should Epileptics Exercise? AB - While common sense rules out epileptics' participation in sports like high diving and gymnastics, those with medically controlled seizures should be encouraged to Participate in carefully supervised exercise programs. PMID- 27467621 TI - Exercise and Depression: Swapping Sweat for Serenity? AB - Many physicians now prescribe exercise as a safe and effective treatment for depression-though researchers are hard-pressed to explain why it seems to help. PMID- 27467622 TI - Sports Medicine Directory 1986. AB - This is the seventh edition of the annual list of sports medicine treatment centers that was published originally in September 1980. We have added information about a number of centers not previously listed and have also rechecked the listings for accuracy. We have not tried to verify the information supplied, nor do we recommend or endorse any of the clinics listed. Those using this list as a guide for referral should check the codes carefully to ascertain whether a particular clinic will fit their needs. We anticipate that the directory will continue to be updated annually. Centers that are not listed but wish to be added next year should contact: THE PHYSICIAN AND SPORTSMEDICINE, Centers Project, 4530 W 77th St, Minneapolis 55435. Centers are listed alphabetically by state and by zip code within the states. If a director is listed, the name follows the zip code. The following key summarizes available information about the centers. PMID- 27467623 TI - Nutrition and fitness. PMID- 27467625 TI - Cardiac Rehabilitation. PMID- 27467624 TI - a need to know. PMID- 27467626 TI - Sportsmedicine Adviser. PMID- 27467640 TI - Tales of blood, sweat and tears. PMID- 27467641 TI - Safer care event: promoting learning across an institution. PMID- 27467642 TI - Evaluating the effectiveness of smoking cessation in the management of COPD. AB - The aim of this literature review is to assess the effectiveness of smoking cessation in managing patients with chronic obstructive pulmonary disease (COPD). COPD is the fifth leading cause of death in the world and smoking leads to COPD in more than 80% of cases. Smoking cessation aids are considered the most effective intervention to improve quality of life and prevent further deterioration in COPD. Evidence based on the use of pharmacotherapies, patient support and motivation as part of smoking cessation strategies were evaluated and discussed. The findings demonstrate that pharmacotherapies, support and counselling in smoking cessation help reduce hospital stay and hospitalisation and improve symptoms and quality of life. In addition, nurses need more education on how to use open-ended questions and motivation when giving advice on smoking cessation to patients with COPD. PMID- 27467643 TI - Integration of leadership competencies in a community health simulation. AB - AIM: The purpose of this article is to address ways in which a nursing faculty can build nursing leadership competencies into a nursing programme. This article describes the use of simulation as a compelling learning strategy. BACKGROUND: Nurses need to be prepared to meet the demands of mass casualty events. With the growing need for major incident training, leadership competency development is a critical gap in the literature. EVALUATION: A collaborative simulation was used to help students apply classroom knowledge. In this simulation, students participated in major incident triage and the application of leadership competencies to appropriately manage victims' care. CONCLUSION: Collaboration among faculty members when designing simulation scenarios is a powerful approach to nursing education. Students were able to engage in necessary skills for their future nursing practice. PMID- 27467644 TI - Providing choice for ostomates. PMID- 27467645 TI - Preoperative fasting for elective surgery in a regional hospital in Oman. AB - BACKGROUND: A fasting period before anesthesia is necessary to avoid the aspiration of stomach contents, which can be threatening to the patient's life. Guidelines from professional societies in the USA and UK recommend that healthy patients fast for 6 hours from solid food and 2 hours from liquids. Despite this, many institutions still practice nil-by-mouth after midnight. This can affect the patient's recovery after surgery, and increase the length of stay in hospital. The aim of this study was to assess the duration of fasting before elective surgery on the part of adult patients. METHODS: A prospective study was conducted to identify the fasting time and complications among surgical patients undergoing elective surgery over a 4-month period. The patients were asked for preoperative fasting times, and the complication. The demographic data were taken from the patients' files. RESULT: A total of 169 patients were included in the study, 88 male and 81 female. The minimum and maximum fasting hours with regard to food were 7 hours and 19 hours, respectively; all the patients fasted from food for longer than the recommended time. The minimum and maximum fasting hours for fluids were 4 hours and 19 hours, respectively; all the patients fasted from fluid for longer than the recommended time. CONCLUSION: Most of the patients fasted from food and fluids for more than the time recommended by the American Society of Anaesthesiologists, the Royal College of Nursing, the Association of Anaesthetists of Great Britain and Ireland and the Royal College of Anaesthetists. Excessive fasting could lead to discomfort and possible morbidity in surgical patients. The surgical team needs to collaborate to reduce the fasting time by revising the operative list. PMID- 27467646 TI - Nursing research ethics, guidance and application in practice. AB - Ethics is fundamental to good research practice and the protection of society. From a historical point of view, research ethics has had a chequered past and without due cognisance there is always the potential for research to do harm. Research ethics is fundamental to research practice, nurse education and the development of evidence. In conducting research, it is important to plan for and anticipate any potential or actual risks. To engage in research, researchers need to develop an understanding and knowledge of research ethics and carefully plan how to address ethics within their research. This article aims to enhance students' and novice researchers' research ethics understanding and its application to nursing research. PMID- 27467647 TI - Eat more fat? The controversial new dietary advice for the UK population. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses the looming crisis caused by rising levels of obesity among the population-and the controversy surrounding the advice to tackle it. PMID- 27467648 TI - Ensuring the safe discharge of older patients from hospital. AB - John Tingle, Reader in Health Law at Nottingham Trent University, discusses two reports that consider hospital discharge, the failures that they highlight and recommendations to improve care for older patients. PMID- 27467649 TI - Brexit: what does it mean for the future of UK nursing? AB - Following the result of the UK referendum on membership of the European Union, Jennifer Hurlow, a Nurse Practitioner from the USA, considers how this may shape nursing in the coming years. PMID- 27467650 TI - Good practice for one-to-one care. AB - Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, reflects on the patient and carer experience of one-to-one care. PMID- 27467651 TI - Clinical evaluation of a securement device used on midline catheters. AB - Since the introduction of sutureless securement products for vascular access devices (VADs), there has been a great deal of discussion of their advantages and disadvantages in comparison with sutures. This includes questions related to VAD securement, patients' comfort, infection control, user-friendliness and potential complications of using the device. The literature review of the available evidence indicates the superiority of the novel sutureless devices in the aforementioned aspects. The authors collected data to further contribute in the analysis of the attributes of these products, namely StatlockTM and Grip-LokTM (current devices). The authors then trialled, collected and analysed data from relevant healthcare practitioners on their perception of a novel sutureless 3MTM TegadermTM PICC/CVC Securement Device + TegadermTM I.V. Advanced Securement Dressing (trialled device) for midline VADs. Evaluation forms have been provided and filled in by the practitioners. The results showed that the trialled product is perceived as user-and patient-friendly, resulting in increased security of VAD and easier handling compared to the current devices. Overall, 70% of the evaluators stated that the trialled product has better or much better overall performance. The remaining 30% characterised the overall performance comparable with the current devices. PMID- 27467652 TI - Therapeutic opportunities when using vapocoolants for cannulation in children. AB - How nurses make a difference and influence outcome has been the subject of much debate over many years and is perhaps more relevant now owing to healthcare funding being a scarce commodity. Nurses need justification and validation of what they do. Nursing therapeutics is a relatively new term that can help nurses and others to appreciate the multifariousness, complexity and value of what they do. It encapsulates the means by which a nurse delivers care that is both evidence based and beneficial to his or her patients. This article highlights how nurses can make use of common nursing interventions to ensure that the full impact of their skills is embedded in their care-using the administration of vapocoolants as the focus of the discussion. It will be illustrated that through each patient contact, a nurse can establish therapeutic principles that can positively influence health outcomes. PMID- 27467653 TI - Selection of case studies describing PICC tip malposition. AB - This article presents a number of case studies, spanning a 12-month period, associated with peripherally inserted central catheter (PICC) tip location. The aim is to generate debate around the journey PICC tips may take; it is not the purpose of this article to debate technological solutions to the issue of PICC tip location. The discussion of each case illustrates a wide range of potential aberrant PICC tip locations and offers an insight into how the abberant tip location was resolved in each case. PMID- 27467654 TI - Welcoming global perspectives. PMID- 27467655 TI - BJN Awards 2016: IV therapy. AB - Claire Rickard Professor of Nursing, National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Nursing, Griffith University, was awarded second place in the BJN Awards 2016 for IV Therapy Nurse of the Year. Here she talks about the she has done to be recognised in this field. PMID- 27467656 TI - Keeping up to date with catheter securement: an overview. PMID- 27467657 TI - Structured learning in paediatric vascular access: effects on clinical practice. AB - Vascular access is an essential skill requirement for many health professionals. Traditionally, in-house medical and nurse training has revealed limited paediatric vascular access experience. AIM: To critically evaluate the effectiveness of the implementation of a structured learning and assessment framework for paediatric vascular access and its impact on improving the learning experience, skill acquisition and retention of health professionals. METHODS: A two-part retrospective (group 1) and prospective (group 2) study involving 49 health professionals was undertaken. Purposive sampling was used with the study method of survey to evaluate learning experience and assess if learning had been transferred into practitioner clinical practice. RESULTS: Overall 61% of participants in group 1 were competent 12 months post training. In comparison, 57% in group 2 were competent 10 weeks post training. CONCLUSION: Findings highlight encouraging results with improvement in practitioner learning experience, skill acquisition and retention post framework implementation. RECOMMENDATIONS: A structured programme incorporating assessment is required with the use of multi-evaluation methods to evaluate education effectiveness. PMID- 27467659 TI - Matrix Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Aqueous Humor of Diabetic Macular Edema Patients. AB - PURPOSE: To assess the concentrations of matrix metalloproteinase (MMP)-1 and MMP 9 in the aqueous humor of diabetic macular edema (DME) patients. METHOD: The concentrations of MMP-1 and MMP-9 in the aqueous humors of 15 cataract patients and 25 DME patients were compared. DME patients were analyzed according to the diabetic retinopathy (DR) stage, diabetes mellitus (DM) duration, pan-retinal photocoagulation (PRP) treatment, recurrence within 3 months, HbA1C (glycated hemoglobin) level, and axial length. RESULTS: The concentrations of MMP-1 and MMP 9 of the DME groups were higher than those of the control group (p = 0.005 and p = 0.002, respectively). There was a significant difference in MMP-1 concentration between the mild non-proliferative diabetic retinopathy (NPDR) group and the proliferative diabetic retinopathy (PDR) group (p = 0.012). MMP-1 concentrations were elevated in PRP-treated patients (p = 0.005). There was a significant difference in MMP-9 concentrations between the mild NPDR group and the PDR group (p < 0.001), and between the moderate and severe NPDR group and the PDR group (p < 0.001). The MMP-9 concentrations in PRP treated patients, DM patients with diabetes >= 10 years and recurrent DME within 3months were elevated (p = 0.023, p = 0.011, and p = 0.027, respectively). In correlation analyses, the MMP-1 level showed a significant correlation with age (r = -0.48, p = 0.01,), and the MMP-9 level showed significant correlations with axial length (r = -0.59, p < 0.01) and DM duration (r = 049, p = 0.01). CONCLUSIONS: Concentrations of MMP-1 and MMP-9 were higher in the DME groups than in the control group. MMP-9 concentrations also differed depending on DR staging, DM duration, PRP treatment, and degree of axial myopia. MMP-9 may be more important than MMP-1 in the induction of DM complications in eyes. PMID- 27467658 TI - Shikonin Suppresses NLRP3 and AIM2 Inflammasomes by Direct Inhibition of Caspase 1. AB - Shikonin is a highly lipophilic naphtoquinone found in the roots of Lithospermum erythrorhizon used for its pleiotropic effects in traditional Chinese medicine. Based on its reported antipyretic and anti-inflammatory properties, we investigated whether shikonin suppresses the activation of NLRP3 inflammasome. Inflammasomes are cytosolic protein complexes that serve as scaffolds for recruitment and activation of caspase-1, which, in turn, results in cleavage and secretion of proinflammatory cytokines IL-1beta and IL-18. NLRP3 inflammasome activation involves two steps: priming, i.e. the activation of NF-kappaB pathway, and inflammasome assembly. While shikonin has previously been reported to suppress the priming step, we demonstrated that shikonin also inhibits the second step of inflammasome activation induced by soluble and particulate NLRP3 instigators in primed immortalized murine bone marrow-derived macrophages. Shikonin decreased NLRP3 inflammasome activation in response to nigericin more potently than acetylshikonin. Our results showed that shikonin also inhibits AIM2 inflammasome activation by double stranded DNA. Shikonin inhibited ASC speck formation and caspase-1 activation in murine macrophages and suppressed the activity of isolated caspase-1, demonstrating that it directly targets caspase-1. Complexing shikonin with beta-lactoglobulin reduced its toxicity while preserving the inhibitory effect on NLRP3 inflammasome activation, suggesting that shikonin with improved bioavailability might be interesting for therapeutic applications in inflammasome-mediated conditions. PMID- 27467661 TI - Lineage-Specific Monocytic Esterase, a Distinct Marker for Leukemias of Monocytic Origin: Cytochemical, Isoenzymatic and Biochemical Features. AB - Cytochemical staining of "non-specific esterases" is commonly used in the classification of acute leukemias. In the biochemical nomenclature these enzymes represent the "carboxylesterases (EC 3.1.1.1)" and are mostly visualized by a substrate-diazonium dye reaction using alpha-naphthyl acetate which led to the term "alpha-naphthyl acetate esterases (ANAE)". Separation of cell extracts by polyacrylamide gel electrophoresis (PAGE) or isoelectric focusing (IEF) have demonstrated that the carboxylic esterase (system) comprises a number of distinct isoenzymes. Included among these is a distinct isoenzyme (group), defined by IEF with acidic isoelectric points (pI) of approximately 6.0, that is characterized by its strong staining intensity and inhibition by sodium fluoride (NaF). Due to its selective expression in normal and malignant monocytes and its unique plasmalemmal location as an ectoenzyme on monocytes, this isoenzyme (the "monocyte esterase") appears to be specific for cells of monocytic origin. While a number of studies have analyzed the biochemical features of the monocyte esterase, little is known about its physiological function. Examining purified normal cell populations and fresh or cultured leukemia cells, it was found that the expression of the monocyte esterase is, indeed, restricted to cells of monocytoid/macrophage differentiation. Expression of this protein can be induced in-vitro by physiological or pharmacological agents in responsive cell populations which can be triggered to differentiate along the monocyte/macrophage cell axis. Compared with the level of enzymatic activity in normal monocytes, there seems to be an overexpression of monocyte esterase in some leukemic cells. Molecular cloning of the gene encoding this protein, an emphasis on studies of function and further detailed characterization of the biochemistry are future avenues of research. PMID- 27467660 TI - An exploratory investigation of the daily talk time of people with non-fluent aphasia and non-aphasic peers. AB - PURPOSE: This paper presents an exploratory investigation of the talk time of people with non-fluent aphasia, as measured by the CommFitTM app. Aims were to compare the talk time of people with aphasia with non-aphasic peers and measures of impairment, activity and participation. The variability of talk time over weeks and days of the week was also investigated. METHOD: Twelve people with post stroke, non-fluent aphasia and seven non-aphasic controls measured their talk time using the CommFitTM app for 6 h/day for 14 days. RESULT: People with aphasia talked for a mean of 4.5 min/h and non-aphasic controls 7.2 min/h, which was not a significant difference (p = 0.056). Talk time of people with aphasia was not significantly correlated with WAB-R AQ or CADL-2 scores, but a moderate-high positive relationship between talk time and SIPSO scores was found (r = 0.648, p = 0.015). Talk time was not significantly different between the first and second weeks of recording for either group, and days of the week were not significantly different except for Saturdays, in which talk time was higher. CONCLUSION: This study provides some preliminary data on talk time in people with aphasia, suggesting that talk time is an indicator of participation. PMID- 27467662 TI - Gene Rearrangement Studies in the Assessment of Lymphoid Neoplasias. PMID- 27467663 TI - Treatment Results in Adolescent and Adult Acute Lymphoblastic Leukaemia Using a Uniform Chemotherapy Protocol. AB - Fifty-four adolescent and adult patients with newly-diagnosed acute lymphoblastic leukaemia (ALL) were treated with combination chemotherapy at three Australian hospitals. The protocol consisted of one month of induction therapy with five cytotoxic agents, followed by consolidation therapy and prophylactic treatment to the central nervous system, then maintenance chemotherapy for 30 months on an outpatient basis. Complete remission was achieved in 47 (87%) patients, with 5 deaths due to treatment-related toxicity. Two patients had drug-resistant disease. Twenty-two patients subsequently relapsed in the bone marrow (18) or in the central nervous system (4). The median survival for all 54 patients is 45.6 months, while the median duration of remission for the 47 complete responders is 39.0 months, with 38.1% projected to be disease-free at 5 years. Age at diagnosis was found to be the only parameter at presentation with a significant predictive effect on outcome. Patients between 10 and 20 years of age had a median survival of 120.6 months, with the median duration of remission not yet reached. In contrast, patients aged 20 years or more had a significantly poorer outcome, with median survival and remission of 25.8 and 20.8 months respectively. These results would support the use of intensive chemotherapy for adolescent patients with ALL. The poor results in adults however justify the use of alternative approaches such as bone marrow transplantation. PMID- 27467664 TI - Monocytes/Macrophages Stimulate Hairy-Cell Proliferation. AB - During a study of the effect of B-cell growth factors on the growth of hairy cells (HCs), proliferation of a sub-population of HCs was observed in the absence of added growth factors in 1 (WB) of 9 patients with hairy-cell leukaemia (HCL). Double staining analysis using monoclonal antibodies detecting the Ki-67 nuclear proliferation antigen and a range of surface/cytoplasmic antigens, confirmed that the HCs were proliferating and that these cells broadly resembled the majority non-proliferative population. The HC proliferation of patient WB was shown to be dependent on the presence of autologous monocytes, but not of T cells. Investigation of other cases of HCL showed that allogeneic monocytes/macrophages from various sources stimulated HC proliferation in 3/4 cases. Neither supernatants from HC-monocyte/macrophage cultures nor tumour necrosis factor (TNF alpha) could replace the proliferative effect induced by monocytes/macrophages. The proliferative effect was dependent on monocyte viability and on cell contact between monocytes/macrophages and HCs. This proliferation was markedly inhibited by alpha interferon (alpha-IFN). In view of the known tissue association in the bone marrow between HCs and macrophages, it is suggested that these observations are of pathophysiological significance in vivo. PMID- 27467665 TI - Abnormal Neutrophil Chemotaxis after Successful Bone Marrow Transplantation. AB - Twenty patients with self-sustaining hematopoiesis were evaluated for neutrophil functions and bone marrow histology 7 to 34 months after bone marrow transplantation (BMT) (7 allogeneic, 13 autologous) performed for acute leukemia in complete remission (11 patients), Hodgkin's lymphoma (2 patients), chronic myeloid leukemia (6 patients) or severe aplastic anemia (1 patient). The chemotactic response toward zymosan-treated serum was severely depressed (<35% of normal) in peripheral neutrophils of 11 patients (2 allogeneic and 9 autologous BMT) and moderately defective (35-70% of normal) in 5 others (2 allogeneic and 3 autologous BMT). On the other hand, phagocytic activity, activation of the metabolic burst and surface expression of CD11/CD18 molecules were within normal limits or moderately increased. The chemotactic defect was independent of age, sex, conditioning regimen and the time period after marrow infusion. The incidence of defective chemotaxis was much greater in patients receiving an autologous BMT (92% of the patients) than in those who had an allogeneic BMT (57% of the patients). Simultaneous bone marrow biopsy studies showed significant stromal alterations in most of our patients; since the bone marrow microenvironment plays an essential role in the process of blood cell formation and release, these observations suggest that defective neutrophil chemotaxis may well serve as a marker of abnormal post-transplant hematopoiesis. PMID- 27467666 TI - Effect of Radiotherapy on Natural Killer Activity in Childhood Acute Lymphoblastic Leukemia and Lymphoma. AB - Natural killer (NK) activity was increased after 24 Gy prophylactic cranial irradiation in childhood acute lymphoblastic leukemia (ALL), although there was no change in the percentage and the number of CD16 (Leu 11)(+) cells. NK activity as well as the percentage and the number of CD16(+) cells was not decreased in malignant lymphoma children treated with high doses of cervical irradiation (20 Gy <). A single dose of 20 Gy irradiation to lymphocytes augmented NK activity 1.4-fold in vitro in healthy individuals. Radiosensitive concanavalin A-induced suppressor T cells did not play a role in the suppression of NK activity, indicating that the enhanced NK activity induced by irradiation was not due to irradiation-induced impairments of suppressor T cells. The supernatants from irradiated lymphocytes slightly enhanced NK activity. In conclusion, the augmentation of NK activity by irradiation seems to be due to its direct effect on NK cells, not via NK suppressor cells but perhaps humoral factors play some role in this respect. PMID- 27467667 TI - Interferon alpha-2b for Essential Thrombocythaemia: Results in 13 Previously Untreated Patients. AB - Interferon alpha-2b (alphaIF) was administered to 13 previously untreated patients with essential thrombocythaemia (ET). Pretreatment median platelet count was 1.178 (range, 662 to 1,700) x 10(9)/L, with ten patients showing values above 1,000 * 10(9)/L. Six patients had vascular symptoms attributable to ET, whereas in the remaining cases treatment was instituted due to either an increased vascular risk or platelet counts higher than 1,000 * 10(9)/L. With an induction regimen of alphaIF 3 MU/day, given subcutaneously, a rapid decrease in the platelet counts was observed in all cases. Two patients did not complete the induction therapy because of unacceptable toxic side-effects at the time their platelet counts approached normal values. In the remaining 11 patients a complete haematologic response (platelets below 400 * 10(9)/L) was observed, after a median of 9.5 (range, 2.6 to 36) weeks from the start of therapy. In only 3 patients was dose escalation of interferon to 5 MU/day required. Eleven patients experienced flu-like symptoms, that could be well controlled by oral paracetamol in 7 cases. After discontinuing therapy a rise in the platelet counts was observed in all patients, after a median of 5 (range, 2 to 35) weeks. Two patients subsequently refused to continue on interferon therapy, whereas in the remainder a dose of 3 MU 2 to 4 times weekly maintained normal platelet counts. PMID- 27467668 TI - Involvement of the BCL2 Gene in 131 Cases of Non-Hodgkin's B Lymphomas: Analysis of Correlations with Immunological Findings and Cell Cycle. AB - The t(14;18) chromosomal translocation is widely recognized as a cytogenetic abnormality associated with follicular lymphomas, but estimates of its frequency in this type of lymphoma vary from less than 40% to almost 90% according to the geographic origin of the patients. Using two human genomic probes for major and minor breakpoint cluster regions mapping at chromosome 18q21, we have analysed 131 cases of B non-Hodgkin's lymphomas obtained from France, by the Southern blot technique. The genotypic study was complemented in most cases by immunophenotypic and cell kinetic analyses. The BCL2 gene located at 18q21 band was rearranged in 39 of 56 (70%) follicular lymphomas and in 9 of 74 (12%) diffuse lymphomas; probes for major and minor breakpoint regions detected two thirds and one third of the rearrangements respectively. Regarding the morphologic subtypes of follicular and diffuse lymphomas, no significant differences were observed irrespective of the probe used. Review of the literature showed that comparable results have been obtained previously using both cytogenetic and molecular approaches and our results support the view that the global incidence of the t(14;18)(q32;q21) translocation in follicular lymphomas is about 70% with wide geographic variations. The immunological study provides evidence for a significant correlation of BCL2 rearrangement with surface immunoglobulin gamma isotype expression and with the lack of reactivity of the malignant cells with an antibody against the CD5 cluster. In the cases where cell kinetics was analysed, we did not find any significant difference between the rate of proliferation and BCL2 rearrangement. These data should be compared with previously reported observations made in humans or in transgenic mice and enable us to propose a model accounting for the role of BCL2 in B cell tumorigenesis. PMID- 27467669 TI - Late Relapses in Hodgkin's Disease: Are They a Distinct Entity? AB - It is claimed that late relapses of Hodgkin's disease have a good prognosis when retreated. A number of unfavourable outcomes led us to review our experience of 72 consecutive cases of Hodgkin's disease diagnosed and treated in a combined clinical haematology and radiation oncology unit between 1968 and 1984. 62 of 72 patients (86%) achieved a complete remission and of these, 35 patients (56%) relapsed, 18 occurring more than three years after diagnosis. Thus, 4 patient groups were identified: 10 patients with refractory disease, 27 patients who went into complete remission and have not relapsed, 17 patients who relapsed within 3 years of diagnosis (early relapse) and 18 patients who relapsed more than 3 years from diagnosis (late relapse). Patients who relapsed were retreated with well accepted protocols of chemotherapy and/or radiotherapy with surprisingly poor results. There was no significant difference between the survival from relapse of patients who relapsed early compared to those who relapsed late. Late relapses are not uncommon in Hodgkin's disease and the prognosis may be less favourable than generally perceived. The risk of relapse was almost constant with time and brings into question the concept of early and late relapse. PMID- 27467670 TI - Analysis of HTLV-I in Hodgkin's Disease. AB - Both Epstein-Barr virus (EBV) and the human T-cell leukemia virus I (HTLV-I) have been implicated in the generation of human lymphoproliferative disorders such as Burkitt's lymphoma, Hodgkin's disease (HD) and acute T-cell leukemia (ATL). In Hodgkin's disease EBV has been recently detected in Hodgkin's and Sternberg-Reed cells in about 20% of the cases. We analysed if HTLV-I is also involved in Hodgkin's disease by using Northern Blot analysis and the polymerase chain reaction (PCR). In our experiments we did not detect HTLV-I specific sequences in HD derived cell lines or in primary specimens. PMID- 27467671 TI - Serum Antibodies to Cytoskeletal Systems in Patients with Adult T-Cell Leukemia and Healthy HTLV-1 Carriers. AB - Serum antibodies to cytoskeletal systems were detected, using indirect immunofluorescence in patients with adult T-cell leukemia (ATL), healthy carriers of human T cell lymphotropic virus 1 (HTLV-1), patients with infectious mononucleosis and healthy adults. Healthy carriers of HTLV-1 had IgG antibodies to cytoskeletal systems as evidenced by an increased incidence of IgG antibodies to actin and vimentin. Decreased IgG antibody levels to Epstein-Barr virus nucleic acid (EBNA) were also evident. In patients with ATL, the titers of IgM antibodies to vimentin and cytokeratin showed a positive correlation with decreased serum levels of IgM, despite the fact that serum concentrations of IgM were significantly decreased in patients with ATL. The IgM antibody titer divided by the IgM concentration (the antibody ratio) was nigher than that of healthy carriers and healthy adults, suggesting that the IgM antibody response to cytoskeletal systems was preferentially preserved in these cases. There was also a suggestion of the presence of polyclonal as well as specific antibody responses to cytoskeletal systems in patients with infectious mononucleosis. As a result of these findings we suggest that there is some difference in the mechanisms responsible for the production of autoantibodies to cytoskeletal systems following HTLV-1 infection and Epstein-Barr virus infection. PMID- 27467673 TI - Detection of Interleukin-1beta and Interleukin-6 in Human Multiple Myeloma by Fluorescent in situ Hybridization. AB - Using fluorescent in situ hybridization together with cell surface marker staining, we studied the expression of mRNA of IL-6 and mRNA of IL-1beta in bone marrow samples from human multiple myeloma patients. It is known that IL-6 can stimulate B cell growth and differentiation and recently it has been suggested that IL-6 is responsible for autocrine growth stimulation of myeloma cells and that IL-1 may play a role in bone resorption. These interleukins have previously been detected in the supernatants of cultured myeloma cells. Here we report the expression of IL-1beta mRNA by plasma cells, T cells and macrophages according to morphology and immunologic marker analysis, suggesting that not only myeloma cells but other cell types can also contribute to the production of IL-1beta and thus to bone-resorption. IL-6 mRNA could not be detected in plasma cells from bone marrow aspirates but were present in monocytes and T cells, suggesting that in vivo IL-6 stimulates the growth of myeloma cells in a paracrine instead of an autocrine way. PMID- 27467672 TI - Immunophenotypic and Gene Rearrangement Analysis in Null- or T-Cell Neoplasias: Study of 16 Cases. AB - Immunophenotypic and molecular studies were performed in sixteen cases of T-cell lymphoproliferative disorders. These included eleven patients with peripheral T cell lymphoma, two thymic lymphomas and three patients with T-gamma lymphocytosis. Peripheral T-cell lymphomas were of both low and high grades. There was one case of Sezary's syndrome, two of small T-cell pleomorphic type, two medium sized T-cell pleomorphic lymphomas, two large T-cell pleomorphic type and four large cell anaplastic T cell lymphomas with activated T cell markers. Two patients had lymphoblastic lymphoma of thymic origin. In this report we attempted to correlate immunophenotypic and molecular characteristics. Rearrangements of the T-cell receptor (TCR) genes were observed in all cases, including those lacking any immunophenotypic markers, and unusual rearrangements of both the TCR and Ig genes were evident in thymic and peripheral T-cell lymphomas. In the cases of T-gamma lymphocytosis, a lymphoproliferative disorder that is not always clearly defined monoclonality was seen in one. The use of the genotypic approach for refining the characterization and diagnosis of some T-cell neoplasias is emphasized. The problems and pitfalls arising from the application of these methods are also discussed. PMID- 27467674 TI - An Early B Cell Line with a Variant 11;19 Translocation. AB - A cell line (BS) carrying a variant 11;19 translocation was established following exposure to Epstein-Barr virus (EBV) of the blast cells from an infant with null (B precursor) acute lymphoblastic leukaemia (ALL). Morphology, cytochemistry and immunophenotype were identical to those of the original leukaemic blasts and characteristic of an early B cell neoplasm. Both the cell line and the patient's blasts had an identical karyotype, 46.XY, t(11;19) (q23;p13), t(11;19)(q13;q13). Immunoglobulin heavy chains were rearranged without concomitant light chain rearrangement. No rearrangements of the beta, gamma or delta chain of the T cell receptor, the proto-oncogene c-ets 1 or the insulin receptor gene which maps to 19p13 were detected. Exposure of the BS line to phorbol ester (PMA) induced a myelomonocytic phenotype with coexpression of B and myeloid cell surface antigens and myeloid cytochemistry. No EBV nuclear antigens (EBNA 1,2) were detectable in the cell line using either immunocytochemical or molecular analyses and the mechanism of "immortalization" by EBV remains unknown. With its unique karyotype, BS provides a useful cell line to study the four translocation breakpoints which occur frequently in both acute lymphoblastic and acute myeloid leukaemias. PMID- 27467675 TI - Acute Monoblastic Leukemia with t(9;11) in a Patient Receiving Chemotherapy for Ovarian Cancer: Secondary Leukemia or Fortuitous Association of Two Neoplasias? AB - We describe the clinical course of a 61 years old patient who developed fulminant acute monoblastic leukemia (MSA, FAB) while still on systemic chemotherapy for an advanced adenocarcinoma of the ovary. The leukemia developed following chemotherapy with Cyclophosphamide and Cisplatin (9 cycles), and then Cyclophosphamide and Carboplatin (6 cycles) resulting in a partial remission of the ovarian tumor. Survival from the onset of acute leukemia was extremely short and the cause of death was intracerebral bleeding. Cytogenetic analysis of the leukemic cells revealed a 9:11 translocation, a pattern usually occurring in de novo leukemias. The literature on the association of solid tumors, particularly ovarian cancer, with acute leukemia is reviewed; while systemic chemotherapy for ovarian cancer definitely increases the risk of secondary leukemia, especially if alkylating agents are administered, the occurrence of leukemia during the administration of chemotherapy for the solid tumor is distinctly unusual. Our patient seems to be an additional example of a recently described therapy-related variant of acute leukemia developing shortly after the onset of chemotherapy and characterized by a rapidly downhill clinical course, a monocytic lineage and a cytogenetic rearrangement t(9;11)(p22;q23). While the number of these newly described cases is still small, this additional example should increase the awareness of this potential association in Cisplatin-treated patients. PMID- 27467676 TI - Interdigitating Reticulum Cell Sarcoma Positive immunohistochemistry for HLA-DR and two other activation antigens, CD30(Ki-1) and CD25(IL2R). AB - This communication reports a case of the rare interdigitating reticulum cell (IDRC) sarcoma of lymph nodes in a 46-year-old man. Extensive immunophenotypic analysis on paraffin and frozen sections revealed positivity on the neoplastic cells for protein S-100 as well as for antigens CD1, HLA-DR, CD4, CD25 (IL2R) and CD30 (Ki-1). The simultaneous positivity for the three activation antigens CD30, HLA-DR, and IL2R, a phenomenon mostly described in H and S-R cells of Hodgkin's disease, is discussed in particular. PMID- 27467677 TI - Aggressive Diffuse Lymphoma Coexpressing NRAS p21 and C-erbB-2 (neu) Oncogene Products, and CALL A (CD 10). AB - We describe here a case of malignant lymphoma (ML) which coexpressed common acute lymphoblastic leukemia antigen (CALLA:CD10) and NRAS p21 and c-erbB-2 (neu) oncogene products. The patient, an 83 year-old man, had massive generalized lymphadenopathy and pleural effusions. Serum LDH levels were elevated to 801 IU/L. Surface phenotypes were analysed by a fluorescent-activated cell sorter with a panel of monoclonal antibodies (MAbs). The ML cells coexpressed antigens detected by MAbs CD10, CD19, CD20, CD22, CD24, CD38, Ia (HLA-DR), c-neu and surface immunoglobulin (Ig) G, Kappa. Gene rearrangements for the Ig JH and JK were found. Overexpression of NRAS p21 was shown by gene amplification using Southern blot analysis, while gene amplification of c-erbB-2 oncogene was also demonstrated. To our knowledge, this is the first report to demonstrate an overexpression of p185 c-neu on ML cells. These findings suggest that the p185 neu may be a prognostic indicator not only for breast adenocarcinomas but also for lymphoproliferative disorders, and that the transforming p185 protein may be involved in the mechanisms of aggressive expansion of lymphoid neoplasias. PMID- 27467678 TI - Highlights of the Fifth International Symposium on Autologous Bone Marrow Transplantation Omaha, Nebraska, August 23-25, 1990. PMID- 27467679 TI - Highlights of the 19th Annual Meeting of the International Society for Experimental Hematology (ISEH) Held in Seattle, Washington, USA, August 26-30, 1990. PMID- 27467680 TI - Teaching Cases from the Royal Marsden Hospital Case 1: a young man with petechiae and splenomegaly. PMID- 27467681 TI - Perception of risk and shared decision making process in multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) treatment has changed considerably in recent years thanks to the introduction of ever-more-powerful drugs. Unfortunately, the higher efficacies of these therapies are associated with increased risks of severe adverse events. In this scenario, neurologists and persons with MS (pwMSs) must now balance benefits and risks when making decisions regarding MS management. Areas covered: This review highlights the importance of the risk perception of pwMSs and their neurologists in the shared decision-making process in MS management, taking into account different ways improve the empowerment and engagement of pwMSs. Expert commentary: The shared decision making process in MS is strongly influenced by an individual's risk perception, which is dynamic and influenced by the personal, emotional, social, and experiential factors of both the pwMSs and neurologists. PMID- 27467682 TI - Reconstruction of a postraumatic radial club hand with a free fibular osteoseptocutaneous flap and Sauve-Kapandji procedure-A case report. AB - Radial club hand may be congenital or acquired; radial deviation of the hand is usually found, associated with palmar flexion-pronation and treatment of severe forms of radial club hand is often difficult. Here we present a case of reconstruction of a severe postraumatic radial club hand with a free fibular osteoseptocutaneous flap and Sauve-Kapandji procedure in a 28-year-old man. The patient had a radial deviation of the wrist and right upper limb shortening as a result of an infected pseudarthrosis of the radius. This deformity was reconstructed with a free fibular osteoseptocutaneous flap associated to arthrodesis of the distal radioulnar joint and an ulnar resection osteotomy proximal to the arthrodesis in order to restore rotation of the forearm (Sauve Kapandji procedure). The flap fully survived and no complications were seen in the early postoperative period at both recipient and donor sites. Radius alignment was restored. At 5-month follow-up, the skeleton was healed. There was minimal osteopenia at the distal radial segment. Wrist extension was 48 degrees, flexion 24 degrees, and pronation-supination was 58-0-48 degrees, with full finger flexion. The patient could hold a 4 kg dumbbell with the elbow flexed without discomfort. His DASH score-Disabilities of the Arm, Shoulder, and Hand Questionnaire was 15.83. Combined free fibular osteoseptocutaneous flap and Sauve Kapandji procedure may be considered in severe forms of postraumatic radial club hand, however, further data are necessary. (c) 2016 Wiley Periodicals, Inc. Microsurgery 36:593-597, 2016. PMID- 27467683 TI - Impact of the Daily Use of a Microcrystal Hydroxyapatite Dentifrice on De Novo Plaque Formation and Clinical/Microbiological Parameters of Periodontal Health. A Randomized Trial. AB - AIM: This 12-week prospective, randomized, double-blind, two-center trial evaluated the impact of a microcrystalline zinc hydroxyapatite (mHA) dentifrice on plaque formation rate (PFR) in chronic periodontitis patients. We hypothesized that mHA precipitates cause delayed plaque development when compared to a fluoridated control (AmF/SnF2), and therefore would improve periodontal health. MATERIAL & METHODS: At baseline and after 4 and 12 weeks, PFR and other clinical and microbiological parameters were recorded. Seventy periodontitis patients received a mHA or AmF/SnF2 dentifrice as daily oral care without hygiene instructions. Four weeks after baseline, participants received full mouth debridement and continued using the dentifrices for another 8 weeks. RESULTS: Primary outcome PFR did not change statistically significantly from baseline to weeks 4 and 12, neither in mHA (n = 33; 51.7+/-17.2% vs. 48.5+/-16.65% vs. 48.4+/ 19.9%) nor in AmF/SnF2-group (n = 34; 52.3+/-17.5% vs. 52.5+/-21.3% vs. 46.1+/ 21.8%). Secondary clinical parameters such as plaque control record, gingival index, bleeding on probing, and pocket probing depth improved, but between-group differences were not statistically significant. Microbiological analyses showed similar slight decreases in colony-forming units in both groups. CONCLUSION: In patients with mild-to-moderate periodontitis, periodontal therapy and use of a mHA-or AmF/SnF2 dentifrice without instructions induced comparable improvements in periodontal health but did not significantly reduce the PFR. TRIAL REGISTRATION: ClincalTrials.gov NCT02697539. PMID- 27467685 TI - Missing Heroes of Pancreatic Surgery. PMID- 27467684 TI - Ochratoxin A Detection on Antibody- Immobilized on BSA-Functionalized Gold Electrodes. AB - Ochratoxin A (OTA)-a toxin produced by Aspergillus carbonarius, Aspergillus ochraceus, and Penicillium verrucosum-is one of the most-abundant food contaminating mycotoxins. To avoid the risk of OTA consumption for humans and animals, the rapid detection and quantitation of OTA level in different commodities are of great importance. In this work, an impedimetric immunosensor for ochratoxin A (OTA) detection, a common toxic botanical contaminant, was developed via the immobilization of anti-OTA antibody on bovine serum albumin modified gold electrodes. A four-step reaction protocol was tested to modify the gold electrode and obtain the sensing substrate. All the steps of the immunosensor elaboration and also the immunochemical reaction between surface bound antibody and ochratoxin A were analyzed using cyclic voltammetry and electrochemical impedance spectroscopy. Modification of the impedance due to the specific antigen-antibody reaction at immunosensor surface, was used in order to detect ochratoxin A. Linear proportionality of the charge transfer resistance to the concentration of OTA allows ochratoxin A detection in the range of 2.5-100 ng/mL. PMID- 27467686 TI - Preventing Complications of Pediatric Tracheostomy Through Standardized Wound Care and Parent Education. AB - Importance: Pediatric tracheostomy is commonly performed for upper airway obstruction and prolonged mechanical ventilation. Children undergoing tracheostomy typically have multiple chronic medical problems that place them at high risk for readmission and additional complications. Objective: To determine whether the institution of a postoperative protocol for parent education and wound care with a nurse trained in tracheostomy care decreases the rate of readmission and other complications. Design, Setting, and Participants: A case series and medical record review was conducted of children 18 years and younger who underwent tracheostomy at a tertiary pediatric medical center between January 1, 2009, and December 31, 2014. Intervention: A postoperative tracheostomy care and education protocol. Main Outcomes and Measures: Overall 30-day readmission rate, 30-day tracheostomy-related readmission rate, tracheostomy wound complications, and additional factors that may have affected readmission rates and wound complications (age at the time of tracheostomy, discharge location, indication for tracheostomy). Results: A total of 191 children (118 boys and 73 girls) were included; of these, 112 participated in the education protocol and 79 children did not. Following institution of the education protocol, there was no decrease in the overall readmission rate (26.8% before the protocol vs 26.6% after the protocol; difference, 0.2%; 95% CI, -12.5% to 13.0%) or in the tracheostomy-related readmission rate (10.1% before the protocol vs 7.1% after the protocol; difference, 3.0%; 95% CI, -5.0% to 11.0%). Overall, 68.6% of readmissions were associated with medical comorbidities (95% CI, 55.9% to 81.3%). There was a significant decrease in tracheostomy-related wound complications after institution of the protocol (31.6% to 17.9%; difference, 13.7%; 95% CI, 1.6% to 26.0%). Multiple logistic regression analysis showed that children who were discharged home were significantly more likely to be readmitted for a tracheostomy-related complication than were patients discharged to an advanced care facility (odds ratio, 14.47; 95% CI, 3.08 to 67.92). Conclusions and Relevance: Tracheostomy care requires expertise for all caregivers and is challenging for people without specialized training. Specialized nursing and education protocols are associated with decreased complications of tracheostomy wounds. Children who are discharged directly to home are at higher risk for readmission compared with children discharged to advanced care facilities. Further development of caregiver education protocols is necessary to continue to reduce readmissions and tracheostomy-related complications. PMID- 27467687 TI - Cardiac Assessment of Patients With Type 1 Diabetes Median 10 Years After Successful Simultaneous Pancreas and Kidney Transplantation Compared With Living Donor Kidney Transplantation. AB - BACKGROUND: In recipients with type 1 diabetes, we aimed to determine whether long-term normoglycemia achieved by successful simultaneous pancreas and kidney (SPK) transplantation could beneficially affect progression of coronary artery disease (CAD) when compared with transplantation of a kidney-alone from a living donor (LDK). METHODS: In 42 kidney transplant recipients with functioning grafts who had received either SPK (n = 25) or LDK (n = 17), we studied angiographic progression of CAD between baseline (pretransplant) and follow-up at 7 years or older. In addition, computed tomography scans for measures of coronary artery calcification and echocardiographic assessment of left ventricular systolic function were addressed at follow-up. RESULTS: During a median follow-up time of 10.1 years (interquartile range [IQR], 9.1-11.5) progression of CAD occurred at similar rates (10 of 21 cases in the SPK and 5 of 14 cases in the LDK group; P = 0.49). Median coronary artery calcification scores were high in both groups (1767 [IQR, 321-4035] for SPK and 1045 [IQR, 807-2643] for LDK patients; P = 0.59). Left ventricular systolic function did not differ between the 2 groups. The SPK and LDK recipients were similar in age (41.2 +/- 6.9 years vs 40.5 +/- 10.3 years; P = 0.80) and diabetes duration at engraftment but with significant different mean HbA1c levels of 5.5 +/- 0.4% for SPK and 8.3 +/- 1.5% for LDK patients (P < 0.001) during follow-up. CONCLUSIONS: In patients with both type 1 diabetes and end-stage renal disease, SPK recipients had similar progression of CAD long-term compared with LDK recipients. Calcification of coronary arteries is a prominent feature in both groups long-term posttransplant. PMID- 27467688 TI - WNK3 Kinase Enhances the Sodium Chloride Cotransporter Expression via an ERK 1/2 Signaling Pathway. AB - BACKGROUND: WNK kinase is a serine/threonine kinase that plays an important role in normal blood pressure homeostasis. WNK3 was previously found to enhance the activity of sodium chloride cotransporter (NCC) in Xenopus oocyte. However, the mechanism through which it works remains unclear. METHODS: Using overexpression and siRNA knock-down techniques, the effects of WNK3 on NCC in both Cos-7 and mouse distal convoluted cells were analyzed by Western blot. RESULTS: We found that WNK3 significantly increased NCC protein expression in a dose-dependent manner. NCC protein expression in Cos-7 cells was markedly decreased after 2 h treatment with protease inhibitor, cycloheximide (CHX) in the NCC alone group, but was significantly decreased after 8 h treatment of CHX in the WNK3 + NCC group. WNK3 significantly increased NCC protein expression in both NCC alone and WNK3 + NCC groups regardless the overnight treatments of bafilomycin A1, a proton pump inhibitor, suggesting that WNK3-mediated increased NCC expression is not dependent on the lysosomal pathway. We further found that WNK3 group had a quicker NCC recovery than the control group using CHX pulse assay, suggesting that WNK3 increases NCC protein synthesis. WNK3 enhanced NCC protein level while reducing ERK 1/2 phosphorylation. In addition, knock-down of ERK 1/2 expression reversed WNK3-mediated increase of NCC expression. CONCLUSION: These results suggest that WNK3 enhances NCC protein expression by increasing NCC synthesis via an ERK 1/2-dependent signaling pathway. PMID- 27467690 TI - "You Pulled Me out of a Dark Well": A Case Study of a Colombian Displaced Woman Empowered Through Interpersonal Counseling (IPC). AB - Interpersonal counseling (IPC), a briefer and simplified adaptation of interpersonal psychotherapy (IPT), was used with internally displaced women (IDW) in Bogota, Colombia, an implementation study of a mental health care pathway funded by Grand Challenges Canada. Preliminary evidence suggests that IPC led to positive outcomes for IDW and may be a feasible first line treatment for displaced women with elevated symptoms of common mental disorders. The case study demonstrates the use of IPC as an intervention to treat depression, anxiety, and posttraumatic stress symptoms in one participant across 11 sessions, from the case formulation through the termination phase. PMID- 27467689 TI - The Landscape of A-to-I RNA Editome Is Shaped by Both Positive and Purifying Selection. AB - The hydrolytic deamination of adenosine to inosine (A-to-I editing) in precursor mRNA induces variable gene products at the post-transcription level. How and to what extent A-to-I RNA editing diversifies transcriptome is not fully characterized in the evolution, and very little is known about the selective constraints that drive the evolution of RNA editing events. Here we present a study on A-to-I RNA editing, by generating a global profile of A-to-I editing for a phylogeny of seven Drosophila species, a model system spanning an evolutionary timeframe of approximately 45 million years. Of totally 9281 editing events identified, 5150 (55.5%) are located in the coding sequences (CDS) of 2734 genes. Phylogenetic analysis places these genes into 1,526 homologous families, about 5% of total gene families in the fly lineages. Based on conservation of the editing sites, the editing events in CDS are categorized into three distinct types, representing events on singleton genes (type I), and events not conserved (type II) or conserved (type III) within multi-gene families. While both type I and II events are subject to purifying selection, notably type III events are positively selected, and highly enriched in the components and functions of the nervous system. The tissue profiles are documented for three editing types, and their critical roles are further implicated by their shifting patterns during holometabolous development and in post-mating response. In conclusion, three A-to I RNA editing types are found to have distinct evolutionary dynamics. It appears that nervous system functions are mainly tested to determine if an A-to-I editing is beneficial for an organism. The coding plasticity enabled by A-to-I editing creates a new class of binary variations, which is a superior alternative to maintain heterozygosity of expressed genes in a diploid mating system. PMID- 27467691 TI - Street vending and waste picking in developing countries: a long-standing hazardous occupational activity of the urban poor. AB - Uncontrolled urbanization in developing countries has led to widespread urban poverty and increased susceptibility to environmental exposures owing to the hazardous occupational activities of the urban poor. Street vending and waste picking are the dominant works undertaken by the urban poor, and besides the physical hazards, it also exposes them to several pathogens and high levels of air pollutants present in the outdoor environment. The situation has severe consequences for the health of the workers. Eliminating these occupational activities from the urban landscape of developing countries should therefore receive urgent attention from the global health community and governments. In this article, we provide evidence to support this policy recommendation by documenting exposure experiences of the workers, the associated adverse health effects, whilst also outlining measures for addressing the problem sustainably. We conclude that with the adoption of the sustainable development goals (SDG), governments now have a commitment to address poverty and the associated occupational health hazards experienced by the poor through their choices to help achieve the health-related SDG target (3.9) of substantially reducing the number of deaths and illnesses from hazardous chemicals and air, water, and soil pollution and contamination by 2030. PMID- 27467693 TI - Peptides from Tetraspanin CD9 Are Potent Inhibitors of Staphylococcus Aureus Adherence to Keratinocytes. AB - Staphylococcus aureus is one of the primary causative agents of skin and wound infections. As bacterial adherence is essential for infection, blocking this step can reduce invasion of host tissues by pathogens. An anti-adhesion therapy, based on a host membrane protein family, the tetraspanins, has been developed that can inhibit the adhesion of S. aureus to human cells. Synthetic peptides derived from a keratinocyte-expressed tetraspanin, CD9, were tested for anti-adhesive properties and at low nanomolar concentrations were shown to inhibit bacterial adhesion to cultured keratinocytes and to be effective in a tissue engineered model of human skin infection. These potential therapeutics had no effect on keratinocyte viability, migration or proliferation, indicating that they could be a valuable addition to current treatments for skin infection. PMID- 27467692 TI - Differences in Facial Emotion Recognition between First Episode Psychosis, Borderline Personality Disorder and Healthy Controls. AB - BACKGROUND: Facial emotion recognition (FER) is essential to guide social functioning and behaviour for interpersonal communication. FER may be altered in severe mental illness such as in psychosis and in borderline personality disorder patients. However, it is unclear if these FER alterations are specifically related to psychosis. Awareness of FER alterations may be useful in clinical settings to improve treatment strategies. The aim of our study was to examine FER in patients with severe mental disorder and their relation with psychotic symptomatology. MATERIALS AND METHODS: Socio-demographic and clinical variables were collected. Alterations on emotion recognition were assessed in 3 groups: patients with first episode psychosis (FEP) (n = 64), borderline personality patients (BPD) (n = 37) and healthy controls (n = 137), using the Degraded Facial Affect Recognition Task. The Positive and Negative Syndrome Scale, Structured Interview for Schizotypy Revised and Community Assessment of Psychic Experiences scales were used to assess positive psychotic symptoms. WAIS III subtests were used to assess IQ. RESULTS: Kruskal-Wallis analysis showed a significant difference between groups on the FER of neutral faces score between FEP, BPD patients and controls and between FEP patients and controls in angry face recognition. No significant differences were found between groups in the fear or happy conditions. There was a significant difference between groups in the attribution of negative emotion to happy faces. BPD and FEP groups had a much higher tendency to recognize happy faces as negatives. There was no association with the different symptom domains in either group. CONCLUSIONS: FEP and BPD patients have problems in recognizing neutral faces more frequently than controls. Moreover, patients tend to over-report negative emotions in recognition of happy faces. Although no relation between psychotic symptoms and FER alterations was found, these deficits could contribute to a patient's misinterpretations in daily life. PMID- 27467694 TI - Alcohol and substance abuse, depression and suicide attempts after Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Small studies suggest that subjects who have undergone bariatric surgery are at increased risk of suicide, alcohol and substance use disorders. This population-based cohort study aimed to assess the incidence of treatment for alcohol and substance use disorders, depression and attempted suicide after primary Roux-en-Y gastric bypass (RYGB). METHODS: All patients who underwent primary RYGB in Sweden between 2001 and 2010 were included. Incidence of hospital admission for alcohol and substance use disorders, depression and suicide attempt was measured, along with the number of drugs prescribed. This cohort was compared with a large age-matched, non-obese reference cohort based on the Swedish population. Inpatient care and prescribed drugs registers were used. RESULTS: Before RYGB surgery, women, but not men, were at higher risk of being diagnosed with alcohol and substance use disorder compared with the reference cohort. After surgery, this was the case for both sexes. The risk of being diagnosed and treated for depression remained raised after surgery. Suicide attempts were significantly increased after RYGB. The adjusted hazard ratio for attempted suicide in the RYGB cohort after surgery compared with the general non-obese population was 2.85 (95 per cent c.i. 2.40 to 3.39). CONCLUSION: Patients who have undergone RYGB are at an increased risk of being diagnosed with alcohol and substance use, with an increased rate of attempted suicide compared with a non obese general population cohort. PMID- 27467695 TI - Obesity and government. AB - PURPOSE OF REVIEW: Despite much effort, obesity prevalence and disease severity continues to worsen. The purpose of this review is to describe the leading government supported food and nutrition interventions and policies to prevent and address obesity in the USA. The review also summarizes obesity interventions and policies that the government plays a role in, but further development is warranted. RECENT FINDINGS: The government's role in obesity has largely focused on interventions and policies such as national surveillance, obesity education and awareness, grant-based food subsidy programs, zoning for food access, school based nutrition programs, dietary guidelines, nutrition labeling, and food marketing and pricing policies. The government has played a lesser role in obesity interventions and policies that provide access to evidence-based obesity care to people affected by the disease. SUMMARY: Given the magnitude of the obesity epidemic, the government should explore multiple evidence-based interventions and policies across prevention and clinical care. PMID- 27467696 TI - Perinatal Mortality Magnitude, Determinants and Causes in West Gojam: Population Based Nested Case-Control Study. AB - INTRODUCTION: In Ethiopia, even if a significant reduction in child mortality is recorded recently, perinatal mortality rate is still very high. This study assessed the magnitude, determinants and causes of perinatal death in West Gojam zone, Ethiopia. METHODS AND MATERIALS: A nested case control study was conducted on 102 cases (mothers who lost their newborns for perinatal death) and 204 controls (mothers who had live infants in the same year) among a cohort of 4097 pregnant mothers in three districts of the West Gojam zone, from Feb 2011 to Mar 2012. Logistic regression models were used to identify the independent determinant factors for perinatal mortality. The World Health Organization verbal autopsy instrument for neonatal death was used to collect mortality data and cause of death was assigned by a pediatrician and a neonatologist. RESULT: Perinatal mortality rate was 25.1(95% CI 20.3, 29.9) per 1000 live and stillbirths. Primiparous mothers had a higher risk of losing their newborn babies for perinatal death than mothers who gave birth to five or more children (AOR = 3.15, 95% CI 1.03-9.60). Babies who were born to women who had a previous history of losing their baby to perinatal death during their last pregnancy showed higher odds of perinatal death than their counterparts (AOR = 9.55, 95% CI 4.67-19.54). Preterm newborns were more at risk for perinatal death (AOR = 9.44, 95%CI 1.81 49.22) than term babies. Newborns who were born among a household of more than two had a lesser risk of dying during the perinatal period as compared to those who were born among a member of only two. Paradoxically, home delivery was found to protect against perinatal death (AOR = 0.07 95% CI, 0.02-0.24) in comparison to institutional delivery. Bacterial sepsis, birth asphyxia and obstructed labour were among the leading causes of perinatal death. CONCLUSION: Perinatal mortality rate remains considerably high, but proper maternal and child health care services can significantly decrease the burden. PMID- 27467697 TI - Dual Antiplatelet Therapy (DAPT) versus No Antiplatelet Therapy and Incidence of Major Bleeding in Patients on Venoarterial Extracorporeal Membrane Oxygenation. AB - AIMS: Bleeding is a frequent complication in patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO). An indication for dual antiplatelet therapy due to coronary stent implantation is present in a considerable number of these patients. The objective of this retrospective study was to evaluate if dual antiplatelet therapy (DAPT) significantly increases the high intrinsic bleeding risk in patients on VA-ECMO. METHODS AND RESULTS: A total of 93 patients were treated with VA-ECMO between October 2010 and October 2013. Average time on VA-ECMO was 58.9 +/- 1.7 hours. Dual antiplatelet therapy was given to 51.6% of all patients. Any bleeding was recorded in 60.2% of all patients. There was no difference in bleeding incidence in patients on DAPT when compared to those without any antiplatelet therapy including any bleeding (66.7% vs. 57.1%, p = 0.35), BARC3 bleeding (43.8% vs. 33.3%, p = 0.31) or pulmonary bleeding (16.7% vs. 19.0%, p = 0.77). This holds true after adjustment for confounders. Rate of transfusion of red blood cells were similar in patients with or without DAPT (35.4% vs. 28.6%, p = 0.488). CONCLUSIONS: Bleeding on VA-ECMO is frequent. This registry recorded no statistical difference in bleeding in patients on dual antiplatelet therapy when compared to no antiplatelet therapy. When indicated, DAPT should not be withheld from VA ECMO patients. PMID- 27467699 TI - Didehydroaspartate Modification in Methyl-Coenzyme M Reductase Catalyzing Methane Formation. AB - All methanogenic and methanotrophic archaea known to date contain methyl-coenzyme M reductase (MCR) that catalyzes the reversible reduction of methyl-coenzyme M to methane. This enzyme contains the nickel porphinoid F430 as a prosthetic group and, highly conserved, a thioglycine and four methylated amino acid residues near the active site. We describe herein the presence of a novel post-translationally modified amino acid, didehydroaspartate, adjacent to the thioglycine as revealed by mass spectrometry and high-resolution X-ray crystallography. Upon chemical reduction, the didehydroaspartate residue was converted into aspartate. Didehydroaspartate was found in MCR I and II from Methanothermobacter marburgensis and in MCR of phylogenetically distantly related Methanosarcina barkeri but not in MCR I and II of Methanothermobacter wolfeii, which indicates that didehydroaspartate is dispensable but might have a role in fine-tuning the active site to increase the catalytic efficiency. PMID- 27467698 TI - Complex Assembly of Polymer Conjugated Mesoporous Silica Nanoparticles for Intracellular pH-Responsive Drug Delivery. AB - There is a great challenge in constructing pH-responsive drug delivery systems in biomedical application research. Many nanocomposites are intended to be pH responsive as drug carriers because of a tumorous or intracellular mildly acidic environment. However, it is always difficult to find an appropriate system for quick response and release before the carrier is excreted from the living system. In this work, hyperbranched polymer, hyperbranched polyglycerol (hPG), and conjugated mesoporous silica nanoparticles (MSNs) were assembled as complexes to serve as drug carriers. Herein, the conjugated polymer-MSNs interacted through the Schiff base bond, which possessed a mildly acidic responsive property. Interestingly, the assembled system could rapidly respond and release guest molecules inside cancer cells. This would make the entrapped drug released before the carriers escape from the endosome counterpart. The results show that the assembled composite complexes can be considered to be a drug delivery system for cancer therapy. PMID- 27467700 TI - Predictors of outcomes in outpatients with anorexia nervosa - Results from the ANTOP study. AB - This study aimed to determine predictors of BMI and recovery for outpatients with anorexia nervosa (AN). Patients were participants of the ANTOP (Anorexia Nervosa Treatment of Out-Patients) trial and randomized to focal psychodynamic therapy (FPT), enhanced cognitive behavior therapy (CBT-E), or optimized treatment as usual (TAU-O). N=169 patients participated in the one-year follow-up (T4). Outcomes were the BMI and global outcome (recovery/partial syndrome/full syndrome) at T4. We examined the following baseline variables as possible predictors: age, BMI, duration of illness, subtype of AN, various axis I diagnoses, quality of life, self-esteem, and psychological characteristics relevant to AN. Linear and logistic regression analyses were conducted to identify the predictors of the BMI and global outcome. The strongest positive predictor for BMI and recovery at T4 was a higher baseline BMI of the patients. Negative predictors for BMI and recovery were a duration of illness >6 years and a lifetime depression diagnosis at baseline. Additionally, higher bodily pain was significantly associated with a lower BMI and self-esteem was a positive predictor for recovery at T4. A higher baseline BMI and shorter illness duration led to a better outcome. Further research is necessary to investigate whether or not AN patients with lifetime depression, higher bodily pain, and lower self esteem may benefit from specific treatment approaches. PMID- 27467701 TI - The effect of exposure to missile attacks on posttraumatic stress disorder symptoms as a function of perceived media control and locus of control. AB - Exposure is one of the most robust predictors of post-traumatic stress disorder (PTSD) symptoms in warfare situations. Yet, while many are sensitive to exposure, others do not develop PTSD. In the current study, we address how perceived media control along with external locus of control moderate effects of exposure on PTSD symptoms among 1268 individuals exposed to missile attacks (mean age=36.97). We expected that the coupling of low perceived media control, whereby one feels poor control over media consumption (an inability to stop), especially when irrelevant and non-informative (e.g., involuntarily viewing the same terror incident shown repeatedly in a looped fashion) along with a self-perception of external locus of control, will render participants highly vulnerable to exposure. As expected, results suggest that effects of exposure on PTSD are not automatic, rather, the coupling of both low media control along with believing that life event are controlled by external factors exacerbates effects of exposure. These findings bear practical implications, as both media control and locus of control can be modified by therapeutic interventions, rendering one less vulnerable to the detrimental effects of traumatic exposure. PMID- 27467702 TI - Experimental modification of perspective on thoughts and metacognitive beliefs in alcohol use disorder. AB - Metacognitive therapy is designed to impact directly on cognitive monitoring and control processes such that individuals can develop alternative ways of experiencing and regulating thoughts. One technique used for this purpose is 'detached mindfulness' which promotes a decentred perspective to thoughts and decouples repetitive thinking and coping from their occurrence. This study set out to test the effects of detached mindfulness against a control condition, a brief exposure to alcohol-related thoughts. Eight patients diagnosed with alcohol use disorder in an abstinence regime were exposed to detached mindfulness versus brief exposure in a counterbalanced repeated-measures design. Results showed that detached mindfulness led to significantly greater decreases in meta-appraisal and metacognitive beliefs about alcohol-related thoughts compared to a brief exposure. Significantly greater decreases in distress and urge to use alcohol were also observed in detached mindfulness. The clinical implications are discussed. PMID- 27467703 TI - Unscented Kalman Filter-Trained Neural Networks for Slip Model Prediction. AB - The purpose of this work is to investigate the accurate trajectory tracking control of a wheeled mobile robot (WMR) based on the slip model prediction. Generally, a nonholonomic WMR may increase the slippage risk, when traveling on outdoor unstructured terrain (such as longitudinal and lateral slippage of wheels). In order to control a WMR stably and accurately under the effect of slippage, an unscented Kalman filter and neural networks (NNs) are applied to estimate the slip model in real time. This method exploits the model approximating capabilities of nonlinear state-space NN, and the unscented Kalman filter is used to train NN's weights online. The slip parameters can be estimated and used to predict the time series of deviation velocity, which can be used to compensate control inputs of a WMR. The results of numerical simulation show that the desired trajectory tracking control can be performed by predicting the nonlinear slip model. PMID- 27467706 TI - Waxing and Waning Pruritic Cutaneous Lesions Refractory to Antibiotic Treatment. PMID- 27467707 TI - State and Regional Prevalence of Diagnosed Multiple Chronic Conditions Among Adults Aged >=18 Years - United States, 2014. AB - The prevalence and care management of multiple (two or more) chronic conditions (MCC) are important public health concerns (1). Approximately 25% of U.S. adults have diagnoses of MCC (2). Care management of MCC presents a challenge to both patients and providers because of the substantial costs associated with treating more than one condition and the traditional care strategies that focus on single conditions as opposed to enhanced care coordination (3,4). Maintaining surveillance, targeting service delivery, and projecting resources are all important to meet this challenge, and these actions can be informed by identifying state and other regional variations in MCC prevalence (5,6). Data from the 2014 National Health Interview Survey (NHIS) were used to estimate prevalence of MCC (defined as two or more of 10 diagnosed chronic conditions) for each U.S. state and region by age and sex. Significant state and regional variation in MCC prevalence was found, with state-level estimates ranging from 19.0% in Colorado to 38.2% in Kentucky. MCC prevalence also varied by region, ranging from 21.4% in the Pacific region to 34.5% in the East South Central region. The prevalence of MCC was higher among women than among men within certain U.S. regions, and was higher in older persons in all regions. Such findings further the research and surveillance objectives stated in the U.S. Department of Health and Human Services (HHS) publication, Multiple Chronic Conditions: A Strategic Framework (1). Furthermore, geographic disparities in MCC prevalence can inform state-level surveillance programs and groups targeting service delivery or allocating resources for MCC prevention activities. PMID- 27467705 TI - CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection. AB - Mycobacterium tuberculosis (Mtb), possesses at least three type VII secretion systems, ESX-1, -3 and -5 that are actively involved in pathogenesis and host pathogen interaction. We recently showed that an attenuated Mtb vaccine candidate (Mtb Deltappe25-pe19), which lacks the characteristic ESX-5-associated pe/ppe genes, but harbors all other components of the ESX-5 system, induces CD4+ T-cell immune responses against non-esx-5-associated PE/PPE protein homologs. These T cells strongly cross-recognize the missing esx-5-associated PE/PPE proteins. Here, we characterized the fine composition of the functional cross-reactive Th1 effector subsets specific to the shared PE/PPE epitopes in mice immunized with the Mtb Deltappe25-pe19 vaccine candidate. We provide evidence that the Mtb Deltappe25-pe19 strain, despite its significant attenuation, is comparable to the WT Mtb strain with regard to: (i) its antigenic repertoire related to the different ESX systems, (ii) the induced Th1 effector subset composition, (iii) the differentiation status of the Th1 cells induced, and (iv) its particular features at stimulating the innate immune response. Indeed, we found significant contribution of PE/PPE-specific Th1 effector cells in the protective immunity against pulmonary Mtb infection. These results offer detailed insights into the immune mechanisms underlying the remarkable protective efficacy of the live attenuated Mtb Deltappe25-pe19 vaccine candidate, as well as the specific potential of PE/PPE proteins as protective immunogens. PMID- 27467709 TI - Acute Charles Bonnet Syndrome following Hughes procedure. AB - A 69-year-old male experienced monocular formed visual hallucinations after occlusion of the right eye following resection of eyelid basal cell carcinoma and reconstruction with a Hughes procedure (tarsoconjunctival flap). His symptoms included recurrent, well-defined, organized, complex, formed images of small children playing in the snow. These visual phenomena occurred only in the occluded eye, began several hours after surgery, and recurred intermittently several times daily for 4 days, lasting several minutes with each occurrence. The patient retained insight into the false nature of the images throughout the duration of his symptoms, and the hallucinations resolved spontaneously while the flap was still in place. To our knowledge, this is the first reported case of Charles Bonnet Syndrome (CBS) following a Hughes procedure in a patient with normal visual acuity in the non-occluded fellow eye. Unlike other reported cases of acute onset CBS following transient monocular occlusion, hallucinations in the occluded eye remitted prior to restoration of vision in the occluded eye. Ophthalmologists should be aware of the potential for CBS following even transient monocular occlusion and should consider warning patients about its potential to occur. PMID- 27467708 TI - Cognitive dysfunction after withdrawal of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia. PMID- 27467710 TI - Evaluation of LIAISON(r) XL system for HBsAg, and anti-HCV and anti-HIV/Ag p24. AB - The aim of this study was to compare the data obtained using the new LIAISON(r) XL chemiluminescence system to search for HBsAg, anti-HCV, and anti-HIV1-2/p24 Ag with those obtained using the VITROS system currently adopted by the Microbiology Unit of the Hospital of Legnano. Routine samples of patients who were referred by practitioners for the determination of HBsAg (1,000 samples) and/or anti-HCV (1,002 samples) and/or anti-HIV1-2 (995 samples) were simultaneously analyzed using both systems. The concordant positive and discordant samples were re examined for confirmation by means of an HBsAg neutralization assay, anti-HCV immunoblot, or anti-HIV1-2 Western blot; HBV-DNA, or HCV-RNA or HIV-RNA was also sought in the discordant samples. Samples of patients known to be positive were tested (100 HBsAg positive, 100 anti-HCV positive, and 100 HIV 1-2 positive) as well throughout treatment, with viremia levels becoming undetectable after treatment. The HBsAg, anti-HCV, and anti-HIV1-2 concordance between the two systems in routine series was respectively 99.8%, 98.5% and 99.7%, and 100% for all markers in samples known positive. The various molecular biology and confirmatory tests of the discordant samples were all negative (except for one anti-HCV positive sample). Measure of Cohen's kappa coefficient for HBsAg, anti HCV, and anti-HIV gave K values of respectively 0.992, 0.946, and 0.980. In conclusion, the performance of the LIAISON(r) XL system in the routine laboratory determination for all three markers was comparable with that of the VITROS system. J. Med. Virol. 89:489-496, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27467711 TI - Cognitive, physical and physiological responses of school boy cricketers to a 30 over batting simulation. AB - The purpose of this study was to assess how cognitive and physical performance are affected during a prolonged, fatigue-inducing cricket-batting simulation. Fifteen amateur batters from three Eastern Cape schools in South Africa were recruited (mean +/- SD: age 17 +/- 0.92 years; stature 1.75 +/- 0.07 m; body mass 78.3 +/- 13.2 kg). Participants completed a 6-stage, 30-over batting simulation (BATEX(c)). During the protocol, there were five periods of cognitive assessment (CogState brief test battery, Melbourne, Australia). The primary outcome measures from each cognitive task were speed and accuracy/error rates. Physiological (heart rate) and physical (sprint times) responses were also recorded. Sprint times deteriorated (d = 0.84; P < 0.01) while physiological responses increased (d = 0.91; P < 0.01) as batting duration increased, with longest times and highest responses occurring in the final stage. Prolonged batting had a large effect on executive task performance (d = 0.85; P = 0.03), and moderate effects on visual attention and vigilance (d = 0.56; P = 0.21) and attention and working memory (d = 0.61; P = 0.11), reducing task performance after 30 overs. Therefore, prolonged batting with repeated shuttle running fatigues amateur batters and adversely affects higher-order cognitive function. This will affect decision making, response selection, response execution and other batting-related executive processes. We recommend that training should incorporate greater proportions of centre-wicket batting with repeated, high-intensity shuttle running. This will improve batting-related skills and information processing when fatigued, making practice more representative of competition. PMID- 27467713 TI - Phytochemical Study of Juglans regia L. Pericarps from Greece with a Chemotaxonomic Approach. AB - Phytochemical research of different polarity extracts from green Juglans regia L. pericarps from Greece afforded 32 compounds: four pentacyclic triterpenes (1 - 4), three sesquiterpenes (5 - 7), four tetralones (8 - 11), two naphthoquinones (12 and 13), seven phenolic acids (14 - 20), one diarylheptanoid (21), one neo lignan (22), seven flavonoids (23 - 29), two phenylethanoids (30 and 31) and one hydrolysed tannin (32). Compounds 4 and 29 are isolated for the first time from the species, while compounds 3, 7, 20, 22, 23, 24, 25, 26, 28, 30 are reported for the first time in Juglandaceae. Chemotaxonomic significance of isolated compounds into Junglandaceae family is thoroughly discussed. PMID- 27467714 TI - Randomized placebo-controlled study of baclofen in the treatment of muscle cramps in patients with liver cirrhosis. AB - BACKGROUND AND AIMS: Muscle cramps adversely influence the quality of life of patients with liver cirrhosis. Indeed, to date, a well-established therapy for this complication is still lacking. This is the first randomized placebo controlled trial of baclofen in the treatment of muscle cramps in patients with liver cirrhosis. PATIENTS AND METHODS: A total of 100 patients with liver cirrhosis and muscle cramps signed an informed consent to participate in this study. They were recruited from the Department of Tropical Medicine-Tanta University Hospital. They were randomized to receive either baclofen or placebo for 3 months. Patients were followed monthly and 1 month after withdrawal. At each visit, the clinicoepidemiological data were recorded, the muscle cramp questionnaire was filled, and any drug-related side effects were reported. RESULTS: In the baclofen group, the frequency of muscle cramps decreased significantly after 1 and 3 months of treatment (P<0.005), with a significant relapse after withdrawal (P<0.001). Patients receiving baclofen showed a significant decrease in the severity and duration of muscle cramps (P<0.001). After 3 months of baclofen therapy at a dose of 30 mg/day, muscle cramps disappeared completely in 72%, reduced in 20%, and led to no change in 8% of patients. No significant changes in the frequency, severity, and duration of muscle cramps were noted in the placebo group. There were few but nonsignificant side effects in the baclofen group compared with the placebo group. CONCLUSION: Baclofen was well tolerated, safe, and effective in the treatment of muscle cramps in patients with liver cirrhosis. PMID- 27467715 TI - Netherlands: Health System Review. AB - This analysis of the Dutch health system reviews recent developments in organization and governance, health financing, healthcare provision, health reforms and health system performance. Without doubt, two major reforms implemented since the mid-2000s are among the main issues today. The newly implemented long-term care reform will have to realize a transition from publicly provided care to more self-reliance on the part of the citizens and a larger role for municipalities in its organization. A particular point of attention is how the new governance arrangements and responsibilities in long-term care will work together. The 2006 reform replaced the division between public and private insurance by one universal social health insurance and introduced managed competition as a driving mechanism in the healthcare system. Although the reform was initiated almost a decade ago, its stepwise implementation continues to bring changes in the healthcare system in general and in the role of actors in particular. In terms of performance, essential healthcare services are within easy reach and waiting times have been decreasing. The basic health insurance package and compensations for lower incomes protect citizens against catastrophic spending. Out-of-pocket payments are low from an international perspective. Moreover, the Dutch rate the quality of the health system and their health as good. International comparisons show that the Netherlands has low antibiotic use, a low number of avoidable hospitalizations and a relatively low avoidable mortality. National studies show that healthcare has made major contributions to the health of the Dutch population as reflected in increasing life expectancy. Furthermore, some indicators such as the prescription of generics and length of stay reveal improvements in efficiency over the past years. Nevertheless, the Netherlands still has one of the highest per capita health expenditures in Europe, although growth has slowed considerably after reverting to more traditional sector agreements on spending. PMID- 27467712 TI - Measuring Oxytocin and Vasopressin: Bioassays, Immunoassays and Random Numbers. AB - In this review, we consider the ways in which vasopressin and oxytocin have been measured since their first discovery. Two different ways of measuring oxytocin in widespread use currently give values in human plasma that differ by two orders of magnitude, and the values measured by these two methods in the same samples show no correlation. The notion that we should accept this seems absurd. Either one (or both) methods is not measuring oxytocin, or, by 'oxytocin', the scientists that use these different methods mean something very different. If these communities are to talk to each other, it is important to validate one method and invalidate the other, or else to establish exactly what each community understands by 'oxytocin'. A similar issue concerns vasopressin: again, different ways of measuring vasopressin give values in human plasma that differ by two orders of magnitude, and it appears that the same explanation for discrepant oxytocin measurements applies to discrepant vasopressin measurements. The first assays for oxytocin and vasopressin measured biological activity directly. When immunoassays were introduced, they encountered problems: high molecular weight factors in raw plasma interfered with the binding of antibodies to the hormones, leading to high and erroneous readings. When these interfering factors were removed by extraction of plasma samples, immunoassays gave measurements consistent with bioassays, with measures of turnover and with the sensitivity of target tissues to exogenous hormone. However, many recent papers use an enzyme linked immunoassay to measure plasma levels without extracting the samples. Like the first radioimmunassays of unextracted plasma, this generates impossibly high and wholly erroneous measurements. PMID- 27467718 TI - Hydrophilic MoSe2 Nanosheets as Effective Photothermal Therapy Agents and Their Application in Smart Devices. AB - A facile poly(vinylpyrrolidone) (PVP)-assisted exfoliation method is utilized to simultaneously exfoliate and noncovalently modify MoSe2 nanosheets. The resultant hydrophilic nanosheets are shown to be promising candidates for biocompatible photothermal therapy (PTT) agents, and they could also be encapsulated into a hydrogel matrix for some intelligent devices. This work not only provides novel insights into exfoliation and modification of transition metal dichalcogenide (TMD) nanosheets but also might spark more research into engineering multifunctional TMD-related nanocomposites, which is in favor of further exploiting the attractive properties of these emerging layered two-dimensional (2D) nanomaterials. PMID- 27467716 TI - Comparison of 18F-FES, 18F-FDG, and 18F-FMISO PET Imaging Probes for Early Prediction and Monitoring of Response to Endocrine Therapy in a Mouse Xenograft Model of ER-Positive Breast Cancer. AB - BACKGROUND: There is an increasing need to characterize biological processes for early prediction and monitoring of response to endocrine therapy in breast cancer using multiple positron emission tomography (PET) imaging probes. However, use of more than two PET tracers in a single clinical trial is quite challenging. In this study we carried out a longitudinal investigation of 18F-FES, 18F-FDG, and 18F-FMISO PET imaging probes for early prediction and monitoring of response to endocrine therapy in a mouse xenograft model of estrogen receptor (ER)-positive breast cancer. METHOD: ER+ human breast cancer ZR-75-1 models were established in female mice that were then randomly assigned to a treatment (fulvestrant, 5.0 mg/week for 21 days) or vehicle group. Micro-PET/CT imaging with 18F-FES, 18F FDG, and 18F-FMISO was performed on days 0, 3, 14, and 21 after treatment. The uptake value (percentage injected dose per gram, %ID/g) for each probe in tumor (T) tissue and contralateral muscle (M) was measured for quantitative analysis and T/M calculation. Tumor volume was measured to record tumor growth at each time point. Tumor tissues were sampled for immunohistochemical staining of ER expression. Correlations for tumor volume and ERalpha levels with uptake data for the probe were tested. RESULTS: Uptake data for 18F-FES in ZR-75-1 tumor tissues corresponded well with tumor response to endocrine therapy, but not for 18F-FDG and 18F-FMISO, according to longitudinal micro-PET/CT imaging and quantitative correlation analysis. There was a significant positive correlation between 18F FES uptake and ER levels (%ID/gmax r2 = 0.76, P< 0.05; T/M r2 = 0.82, P<0.05). Notably, 18F-FES uptake on day 3 was significantly correlated with the day 21/baseline tumor volume ratio (%ID/gmax r2 = 0.74, P < 0.05; T/M r2 = 0.78, P < 0.05). CONCLUSIONS: Comparison of 18F-FES, 18F-FDG, and 18F-FMISO probes revealed that 18F-FES PET/CT molecular imaging can provide a precise early prediction of tumor response to endocrine therapy in ER+ breast cancer in a ZR-75-1 xenograft model. This molecular imaging strategy with 18F-FES PET/CT will be useful in evaluating the efficacy of endocrine therapies and in developing new endocrine drugs. PMID- 27467719 TI - Confidence intervals are no salvation from the alleged fickleness of the P value. PMID- 27467720 TI - Response to "Confidence intervals are no salvation from the alleged fickleness of the P value". PMID- 27467721 TI - The democratization of cryo-EM. PMID- 27467722 TI - A clash of cultures in discussions of the P value. PMID- 27467723 TI - Stem cells: a dish of neurons. PMID- 27467724 TI - The quest for multiplexed spatially resolved transcriptional profiling. PMID- 27467725 TI - A glance at N(6)-methyladenosine in transcript isoforms. PMID- 27467727 TI - Contrast agents for molecular photoacoustic imaging. AB - Photoacoustic imaging (PAI) is an emerging tool that bridges the traditional depth limits of ballistic optical imaging and the resolution limits of diffuse optical imaging. Using the acoustic waves generated in response to the absorption of pulsed laser light, it provides noninvasive images of absorbed optical energy density at depths of several centimeters with a resolution of ~100 MUm. This versatile and scalable imaging modality has now shown potential for molecular imaging, which enables visualization of biological processes with systemically introduced contrast agents. Understanding the relative merits of the vast range of contrast agents available, from small-molecule dyes to gold and carbon nanostructures to liposome encapsulations, is a considerable challenge. Here we critically review the physical, chemical and biochemical characteristics of the existing photoacoustic contrast agents, highlighting key applications and present challenges for molecular PAI. PMID- 27467726 TI - A practical guide to photoacoustic tomography in the life sciences. AB - The life sciences can benefit greatly from imaging technologies that connect microscopic discoveries with macroscopic observations. One technology uniquely positioned to provide such benefits is photoacoustic tomography (PAT), a sensitive modality for imaging optical absorption contrast over a range of spatial scales at high speed. In PAT, endogenous contrast reveals a tissue's anatomical, functional, metabolic, and histologic properties, and exogenous contrast provides molecular and cellular specificity. The spatial scale of PAT covers organelles, cells, tissues, organs, and small animals. Consequently, PAT is complementary to other imaging modalities in contrast mechanism, penetration, spatial resolution, and temporal resolution. We review the fundamentals of PAT and provide practical guidelines for matching PAT systems with research needs. We also summarize the most promising biomedical applications of PAT, discuss related challenges, and envision PAT's potential to lead to further breakthroughs. PMID- 27467728 TI - Biomarkers in melanoma. AB - Malignant melanoma remains the skin cancer with the highest number of mortalities worldwide. While early diagnosis and complete surgical excision remain the best possibility for curing disease, prognosis at the stage of metastasis is still poor. Recent years have brought about considerable advances in terms of understanding the pathogenesis of melanoma and treating advanced disease. The discovery of activating BRAF mutations in around 50% of tumors has led to the introduction of targeted therapies downregulating BRAF signaling output. These have been further refined as combination therapies, which by targeting multiple targets have further improved the clinical outcome. A comparable, potentially even superior therapeutic alternative has been the introduction of immunotherapeutic approaches, including PD-1 and CTLA-4 checkpoint blockade therapies. Despite all genetic knowledge acquired in recent years, a clearly applicable prognostic signature of clinical value has not been established. General prognostic assessment of cutaneous melanoma remains based on clinical and pathological criteria (most importantly tumor thickness). The main challenges lying ahead are to establish a reliable prognostic test effectively determining which tumors will metastasize. Additionally establishing biomarkers which will allow patients to be stratified according to the most promising systemic therapy (immunotherapies and/or BRAF inhibitor therapies) is of utmost importance for patients with metastasized disease. Identifying serum biomarkers enabling disease to be monitored as well as determining tumor properties (i.e. resistance) would also be of great value. While initial results have proven promising, there remains much work to be done. PMID- 27467729 TI - Pay attention to EBSLN in anatomical classification of the superior pole in thyroid surgery. PMID- 27467730 TI - Haemodynamic assessment of human coronary arteries is affected by degree of freedom of artery movement. AB - : Abnormal haemodynamic parameters are associated with atheroma plaque progression and instability in coronary arteries. Flow recirculation, shear stress and pressure gradient are understood to be important pathogenic mediators in coronary disease. The effect of freedom of coronary artery movement on these parameters is still unknown. Fluid-structure interaction (FSI) simulations were carried out in 25 coronary artery models derived from authentic human coronaries in order to investigate the effect of degree of freedom of movement of the coronary arteries on flow recirculation, wall shear stress (WSS) and wall pressure gradient (WPG). Each FSI model had distinctive supports placed upon it. The quantitative and qualitative differences in flow recirculation, maximum wall shear stress (MWSS), areas of low wall shear stress (ALWSS) and maximum wall pressure gradient (MWPG) for each model were determined. The results showed that greater freedom of movement was associated with lower MWSS, smaller ALWSS, smaller flow recirculation zones and lower MWPG. With increasing percentage diameter stenosis (%DS), the effect of degree of freedom on flow recirculation and WSS diminished. Freedom of movement is an important variable to be considered for computational modelling of human coronary arteries, especially in the setting of mild to moderate stenosis. ABBREVIATIONS: 3D: Three-dimensional; 3DR: Three dimensional Reconstruction; 3D-QCA: Three-dimensional quantitative coronary angiography; ALWSS: Areas of low wall shear stress; CAD: Coronary artery disease; CFD: Computational fluid dynamics; %DS: Diameter stenosis percentage; EPCS: End point of counter-rotating streamlines; FSI: Fluid-structure interaction; IVUS: Intravascular ultrasound; LAD: Left anterior descending; MWSS: Maximum wall shear stress; SST: Shear stress transport; TAWSS: Time-averaged wall shear stress; WSS: wall shear stress; WPG: Wall pressure gradient; MWPG: Maximum wall pressure gradient; FFR: Fractional flow reserve; iFR: Instantaneous wave-free ratio. PMID- 27467731 TI - PROMISE, OASIS, and SWAT: Evaluating the Future of Sepsis Care. PMID- 27467732 TI - Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD. AB - NMDA receptors have been widely reported to be involved in the regulation of synaptic plasticity through effects on long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD have been implicated in learning and memory processes. Besides synaptic plasticity, it is known that the phenomenon of gamma oscillations is critical in cognitive functions. Synaptic plasticity has been widely studied, however it is still not clear, to what degree synaptic plasticity regulates the oscillations of neuronal networks. Two NMDA receptor antagonists, ketamine and memantine, have been shown to regulate LTP and LTD, to promote cognitive functions, and have even been reported to bring therapeutic effects in major depression and Alzheimer's disease respectively. These compounds allow us to investigate the putative interrelationship between network oscillations and synaptic plasticity and to learn more about the mechanisms of their therapeutic effects. In the present study, we have identified that ketamine and memantine could inhibit LTD, without impairing LTP in the CA1 region of mouse hippocampus, which may underlie the mechanism of these drugs' therapeutic effects. Our results suggest that NMDA-induced LTD caused a marked loss in the gamma power, and pretreatment with 10 MUM ketamine prevented the oscillatory loss via its inhibitory effect on LTD. Our study provides a new understanding of the role of NMDA receptors on hippocampal plasticity and oscillations. PMID- 27467744 TI - The Restoration of Passive Rotational Tibio-Femoral Laxity after Anterior Cruciate Ligament Reconstruction. AB - While the anterior cruciate ligament (ACL) is considered one of the most important ligaments for providing knee joint stability, its influence on rotational laxity is not fully understood and its role in resisting rotation at different flexion angles in vivo remains unknown. In this prospective study, we investigated the relationship between in vivo passive axial rotational laxity and knee flexion angle, as well as how they were altered with ACL injury and reconstruction. A rotometer device was developed to assess knee joint rotational laxity under controlled passive testing. An axial torque of +/-2.5Nm was applied to the knee while synchronised fluoroscopic images of the tibia and femur allowed axial rotation of the bones to be accurately determined. Passive rotational laxity tests were completed in 9 patients with an untreated ACL injury and compared to measurements at 3 and 12 months after anatomical single bundle ACL reconstruction, as well as to the contralateral controls. Significant differences in rotational laxity were found between the injured and the healthy contralateral knees with internal rotation values of 8.7 degrees +/-4.0 degrees and 3.7 degrees +/-1.4 degrees (p = 0.003) at 30 degrees of flexion and 9.3 degrees +/ 2.6 degrees and 4.0 degrees +/-2.0 degrees (p = 0.001) at 90 degrees respectively. After 3 months, the rotational laxity remained similar to the injured condition, and significantly different to the healthy knees. However, after 12 months, a considerable reduction of rotational laxity was observed towards the levels of the contralateral controls. The significantly greater laxity observed at both knee flexion angles after 3 months (but not at 12 months), suggests an initial lack of post-operative rotational stability, possibly due to reduced mechanical properties or fixation stability of the graft tissue. After 12 months, reduced levels of rotational laxity compared with the injured and 3 month conditions, both internally and externally, suggests progressive rotational stability of the reconstruction with time. PMID- 27467733 TI - Genotype-Phenotype Associations of the CD-Associated Single Nucleotide Polymorphism within the Gene Locus Encoding Protein Tyrosine Phosphatase Non Receptor Type 22 in Patients of the Swiss IBD Cohort. AB - BACKGROUND: Protein tyrosine phosphatase non-receptor type 22 (PTPN22) plays an important role in immune cell function and intestinal homeostasis. The single nucleotide polymorphism (SNP) rs2476601 within the PTPN22 gene locus results in aberrant function of PTPN22 protein and protects from Crohn's disease (CD). Here, we investigated associations of PTPN22 SNP rs2476601 in inflammatory bowel disease (IBD) patients in the Swiss IBD Cohort Study (SIBDCS). METHODS: 2'028 SIBDCS patients (1173 CD and 855 ulcerative colitis (UC) patients) were included. The clinical characteristics were analysed for an association with the presence of the PTPN22 SNP rs2476601 genotypes 'homozygous variant' (AA), 'heterozygous' (GA) and 'homozygous wild-type' (GG). RESULTS: 13 patients (0.6%) were homozygous variant (AA) for the PTPN22 polymorphism, 269 (13.3%) heterozygous variant (GA) and 1'746 (86.1%) homozygous wild-type (GG). In CD, AA and GA genotypes were associated with less use of steroids and antibiotics, and reduced prevalence of vitamin D and calcium deficiency. In UC the AA and GA genotype was associated with increased use of azathioprine and anti-TNF antibodies, but significantly less patients with the PTPN22 variant featured malabsorption syndrome (p = 0.026). CONCLUSION: Our study for the first time addressed how presence of SNP rs2476601 within the PTPN22 gene affects clinical characteristics in IBD patients. Several factors that correlate with more severe disease were found to be less common in CD patients carrying the A-allele, pointing towards a protective role for this variant in affected CD patients. In UC patients however, we found the opposite trend, suggesting a disease-promoting effect of the A allele. PMID- 27467745 TI - Anterior Overgrowth in Primary Curves, Compensatory Curves and Junctional Segments in Adolescent Idiopathic Scoliosis. AB - INTRODUCTION: Although much attention has been given to the global three dimensional aspect of adolescent idiopathic scoliosis (AIS), the accurate three dimensional morphology of the primary and compensatory curves, as well as the intervening junctional segments, in the scoliotic spine has not been described before. METHODS: A unique series of 77 AIS patients with high-resolution CT scans of the spine, acquired for surgical planning purposes, were included and compared to 22 healthy controls. Non-idiopathic curves were excluded. Endplate segmentation and local longitudinal axis in endplate plane enabled semi-automatic geometric analysis of the complete three-dimensional morphology of the spine, taking inter-vertebral rotation, intra-vertebral torsion and coronal and sagittal tilt into account. Intraclass correlation coefficients for interobserver reliability were 0.98-1.00. Coronal deviation, axial rotation and the exact length discrepancies in the reconstructed sagittal plane, as defined per vertebra and disc, were analyzed for each primary and compensatory curve as well as for the junctional segments in-between. RESULTS: The anterior-posterior difference of spinal length, based on "true" anterior and posterior points on endplates, was +3.8% for thoracic and +9.4% for (thoraco)lumbar curves, while the junctional segments were almost straight. This differed significantly from control group thoracic kyphosis (-4.1%; P<0.001) and lumbar lordosis (+7.8%; P<0.001). For all primary as well as compensatory curves, we observed linear correlations between the coronal Cobb angle, axial rotation and the anterior-posterior length difference (r>=0.729 for thoracic curves; r>=0.485 for (thoraco)lumbar curves). CONCLUSIONS: Excess anterior length of the spine in AIS has been described as a generalized growth disturbance, causing relative anterior spinal overgrowth. This study is the first to demonstrate that this anterior overgrowth is not a generalized phenomenon. It is confined to the primary as well as the compensatory curves, the junctional zones do not exhibit this growth discrepancy, however, they are straight. PMID- 27467746 TI - Re-Evaluation of Reportedly Metal Tolerant Arabidopsis thaliana Accessions. AB - Santa Clara, Limeport, and Berkeley are Arabidopsis thaliana accessions previously identified as diversely metal resistant. Yet these same accessions were determined to be genetically indistinguishable from the metal sensitive Col 0. We robustly tested tolerance for Zn, Ni and Cu, and genetic relatedness by growing these accessions under a range of Ni, Zn and Cu concentrations for three durations in multiple replicates. Neither metal resistance nor variance in growth were detected between them and Col-0. We re-sequenced the genomes of these accessions and all stocks available for each accession. In all cases they were nearly indistinguishable from the standard laboratory accession Col-0. As Santa Clara was allegedly collected from the Jasper Ridge serpentine outcrop in California, USA we investigated the possibility of extant A. thaliana populations adapted to serpentine soils. Botanically vouchered Arabidopsis accessions in the Jepson database were overlaid with soil maps of California. This provided no evidence of A. thaliana collections from serpentine sites in California. Thus, our work demonstrates that the Santa Clara, Berkeley and Limeport accessions are not metal tolerant, not genetically distinct from Col-0, and that there are no known serpentine adapted populations or accessions of A. thaliana. PMID- 27467747 TI - Laparoscopic Partial Splenectomy: A Preferred Method for Select Patients. AB - BACKGROUND: The purpose of this study was to explore the feasibility and safety of laparoscopic partial splenectomy (LPS) using a harmonic scalpel (HS) combined with bipolar coagulation. MATERIALS AND METHODS: Using HS and bipolar coagulation technology, 18 patients suffering from splenic cystic neoplasm were treated with LPS between January 2010 and December 2014, and their clinical data were analyzed retrospectively. RESULTS: LPS was performed successfully without conversion to open surgery in all cases. The mean intra-operative blood loss was 75.8 +/- 33.5 mL, and the mean operation time was 54.3 +/- 16.6 minutes (range, 48-82 minutes). No cases of postoperative bleeding, infection, or pancreatic fistula occurred. No patient required total splenectomy. The mean hospital stay was 6.6 +/- 3.2 days, and the median postoperative follow-up was 19.8 months (range, 5-60 months). All patients recovered successfully, with normal complete blood counts and without any recurrence on follow-up. CONCLUSIONS: LPS is a safe and feasible operation for selected patients. Combined use of an HS and bipolar coagulation can shorten the operation time, reduce blood loss, and improve the safety of the operation. PMID- 27467749 TI - Retraction of: Characteristics of sleep habits among adolescents living in the city of Ribeirao Preto (SP). PMID- 27467748 TI - Ultrasound Induced Fluorescence of Nanoscale Liposome Contrast Agents. AB - A new imaging contrast agent is reported that provides an increased fluorescent signal upon application of ultrasound (US). Liposomes containing lipids labelled with pyrene were optically excited and the excimer fluorescence emission intensity was detected in the absence and presence of an ultrasound field using an acousto-fluorescence setup. The acousto-fluorescence dynamics of liposomes containing lipids with pyrene labelled on the fatty acid tail group (PyPC) and the head group (PyPE) were compared. An increase in excimer emission intensity following exposure to US was observed for both cases studied. The increased intensity and time constants were found to be different for the PyPC and PyPE systems, and dependent on the applied US pressure and exposure time. The greatest change in fluorescence intensity (130%) and smallest rise time constant (0.33 s) are achieved through the use of PyPC labelled liposomes. The mechanism underlying the observed increase of the excimer emission intensity in PyPC labelled liposomes is proposed to arise from the "wagging" of acyl chains which involves fast response and requires lower US pressure. This is accompanied by increased lipid lateral diffusivity at higher ultrasound pressures, a mechanism that is also active in the PyPE labelled liposomes. PMID- 27467750 TI - Heteroplasmy and atrazine resistance in Chenopodium album and Senecio vulgaris. AB - Atrazine-resistant weeds are well known, and the resistance is primarily caused by a point mutation in the psbA chloroplast gene encoding the photosystem II D1 protein. Heteroplasmy, the presence of different types of chloroplasts in an individual plant, is also very common. Thus, atrazine-resistant weeds may also partly possess the atrazine-binding sequence and vice versa. The region of the psbA gene containing the mutation was sequenced from atrazine-resistant and atrazine-sensitive Chenopodium album and Senecio vulgaris plants. In atrazine sensitive C. album plants, the expected AGT triplet was found. The atrazine resistant plants contained the expected base substitution (AGT to GGT); however, in addition the AGT triplet was found. The atrazine-resistant S. vulgaris plants contained the expected GGT sequence, whereas the atrazine-sensitive plants contained both the AGT and GGT sequences. This clearly indicates that in addition to Gly264 also Ser264 is present in atrazine-resistant plants, and vice versa in atrazine-sensitive plants, indicating heteroplasmy in these weeds. PMID- 27467751 TI - A novel plant enzyme with dual activity: an atypical Nudix hydrolase and a dipeptidyl peptidase III. AB - In a search for plant homologues of dipeptidyl peptidase III (DPP III) family, we found a predicted protein from the moss Physcomitrella patens (UniProt entry: A9TLP4), which shared 61% sequence identity with the Arabidopsis thaliana uncharacterized protein, designated Nudix hydrolase 3. Both proteins contained all conserved regions of the DPP III family, but instead of the characteristic hexapeptide HEXXGH zinc-binding motif, they possessed a pentapeptide HEXXH, and at the N-terminus, a Nudix box, a hallmark of Nudix hydrolases, known to act upon a variety of nucleoside diphosphate derivatives. To investigate their biochemical properties, we expressed heterologously and purified Physcomitrella (PpND) and Arabidopsis (AtND) protein. Both hydrolyzed, with comparable catalytic efficiency, the isopentenyl diphosphate (IPP), a universal precursor for the biosynthesis of isoprenoid compounds. In addition, PpND dephosphorylated four purine nucleotides (ADP, dGDP, dGTP, and 8-oxo-dATP) with strong preference for oxidized dATP. Furthermore, PpND and AtND showed DPP III activity against dipeptidyl-2-arylamide substrates, which they cleaved with different specificity. This is the first report of a dual activity enzyme, highly conserved in land plants, which catalyzes the hydrolysis of a peptide bond and of a phosphate bond, acting both as a dipeptidyl peptidase III and an atypical Nudix hydrolase. PMID- 27467752 TI - Structural analysis and interaction studies of acyl-carrier protein (acpP) of Staphylococcus aureus, an extraordinarily thermally stable protein. AB - : Acyl-carrier-protein (acpP) is an essential protein in fatty acid biosynthesis of Staphylococcus aureus [Cronan, J.E. and Thomas, J. (2009). Complex enzymes in microbial natural product biosynthesis, part B: polyketides, aminocoumarins and carbohydrates. METHOD: Enzymol. 459, 395-433; Halavaty, A.S., Kim, Y., Minasov, G., Shuvalova, L., Dubrovska, I., Winsor, J., Zhou, M., Onopriyenko, O., Skarina, T., Papazisi, L., et al. (2012). Structural characterization and comparison of three acyl-carrier-protein synthases from pathogenic bacteria. Acta Crystallogr. Sect. D Biol. Crystallogr. 68, 1359-1370]. The inactive apo-form is converted to the active holo-enzyme by acyl-carrier protein synthase (acpS) through addition of a 4'-phosphopantetheine group from coenzyme A to a conserved serine residue of acpP [Flugel, R.S., Hwangbo, Y., Lambalot, R.H., Cronan, J.E., and Walsh, C.T. (2000). Holo-(acyl-carrier protein) synthase and phosphopantetheinyl transfer in Escherichia coli. J. Biol. Chem. 275, 959-968; Lambalot, R.H. and Walsh, C.T. (1995). Cloning, overproduction, and characterization of the Escherichia coli holo-acyl-carrier protein synthase. J. Biol. Chem. 270, 24658-24661]. Once activated, acpP acts as an anchor for the growing fatty acid chain. Structural data from X-ray crystallographic analysis reveals that, despite its small size (8 kDa), acpP adopts a distinct, mostly alpha-helical structure when complexed with acpS [Halavaty, A.S., Kim, Y., Minasov, G., Shuvalova, L., Dubrovska, I., Winsor, J., Zhou, M., Onopriyenko, O., Skarina, T., Papazisi, L., et al. (2012). Structural characterization and comparison of three acyl-carrier-protein synthases from pathogenic bacteria. Acta Crystallogr. Sect. D Biol. Crystallogr. 68, 1359-1370; Byers, D.M. and Gong, H. (2007). Acyl carrier protein: structure function relationships in a conserved multifunctional protein family. Biochem. Cell Biol. 85, 649-662]. We expressed and purified recombinant, active S. aureus acpP from Escherichia coli and mimicked the beginning of fatty acid biosynthesis by employing an [14C]-acp loading assay. Surprisingly, acpP remained functional even after heat treatment at 95 degrees C for up to 10 min. NMR data from 2D-HSQC experiments as well as interaction studies with acpS confirmed that acpP is structured and active both before and after heat treatment, with no significant differences between the two. Thus, our data suggest that S. aureus acpP is a highly stable protein capable of maintaining its structure at high temperatures. PMID- 27467753 TI - More than just innate affairs - on the role of annexins in adaptive immunity. AB - In more than 30 years of research annexins have been demonstrated to regulate immune responses. The prototype member of this family, annexin (Anx) A1, has been widely recognized as an anti-inflammatory mediator affecting migration and cellular responses of various cell types of the innate immune system. Evidently, effects on innate immune cells also impact on the course of adaptive immune responses. Innate immune cells provide a distinct cytokine milieu during initiation of adaptive immunity which regulates the development of T cell responses. Moreover, innate immune cells such as monocytes can differentiate into dendritic cells and take an active part in T cell stimulation. Accumulating evidence shows a direct role for annexins in adaptive immunity. Anx A1, the annexin protein studied in most detail, has been shown to influence antigen presentation as well as T cells directly. Moreover, immune modulatory roles have been described for several other annexins such as Anx A2, Anx A4, Anx A5 and Anx A13. This review will focus on the involvement of Anx A1 and other annexins in central aspects of adaptive immunity, such as recruitment and activation of antigen presenting cells, T cell differentiation and the anti-inflammatory removal of apoptotic cells. PMID- 27467754 TI - Letter in response to: Identifying risk in the use of tumor markers to improve patient safety. PMID- 27467755 TI - Interplay of Proximal Flow Confluence and Distal Flow Divergence in Patient Specific Vertebrobasilar System. AB - Approximately one-quarter of ischemic strokes involve the vertebrobasilar arterial system that includes the upstream flow confluence and downstream flow divergence. A patient-specific hemodynamic analysis is needed to understand the posterior circulation. The objective of this study is to determine the distribution of hemodynamic parameters in the vertebrobasilar system, based on computer tomography angiography images. Here, the interplay of upstream flow confluence and downstream flow divergence was hypothesized to be a determinant factor for the hemodynamic distribution in the vertebrobasilar system. A computational fluid dynamics model was used to compute the flow fields in patient specific vertebrobasilar models (n = 6). The inlet and outlet boundary conditions were the aortic pressure waveform and flow resistances, respectively. A 50% reduction of total outlet area was found to induce a ten-fold increase in surface area ratio of low time-averaged wall shear stress (i.e., TAWSS <= 4 dynes/cm2). This study enhances our understanding of the posterior circulation associated with the incidence of atherosclerotic plaques. PMID- 27467756 TI - Complete response to high-dose IL-2 and enhanced IFNgamma+Th17 : TREG ratio in a melanoma patient. AB - High-dose IL-2 (HDIL-2) is associated with complete and durable responses in only 5-10% of patients with stage intravenous melanoma and the toxicity profile is significant. In-vivo human models have recently shown a stimulatory effect of exogenous IL-2 on both the Th17 and regulatory T-cell (TREG) compartments. We investigated and compared the effect of HDIL-2 on the Th17 and TREG compartments in HDIL-2 responders versus nonresponders. HDIL-2 was administered at a dose of 720 000 IU/kg to patients with melanoma (n=6) and peripheral blood was collected at baseline and at 24, 48, 72, and 96 h during treatment. Peripheral blood mononuclear cells were isolated and subjected to intracellular cytokine and extracellular receptor staining for flow cytometry. Five of six patients progressed clinically on HDIL-2 therapy, and these patients showed an increase in the frequency of TREGs on day 4 of treatment. A single patient responded to HDIL 2 therapy and showed a decrease in the frequency of TREG cells on day 4 of treatment. We found that HDIL-2 resulted in a larger increase in the frequency and total numbers of IFNgammaTh17 cells in the complete responder compared with all nonresponders. As such, the complete responder showed a high IFNgammaTh17 : TREG ratio. Our results suggest that a distinct immunophenotype may be associated with response to HDIL-2. The peripheral IFNgammaTh17 : TREG ratio may serve as an early biomarker in the setting of HDIL-2 to help identify those patients who would benefit from subsequent cycles. PMID- 27467757 TI - Temporal Shift of Circadian-Mediated Gene Expression and Carbon Fixation Contributes to Biomass Heterosis in Maize Hybrids. AB - Heterosis has been widely used in agriculture, but the molecular mechanism for this remains largely elusive. In Arabidopsis hybrids and allopolyploids, increased photosynthetic and metabolic activities are linked to altered expression of circadian clock regulators, including CIRCADIAN CLOCK ASSOCIATED1 (CCA1). It is unknown whether a similar mechanism mediates heterosis in maize hybrids. Here we report that higher levels of carbon fixation and starch accumulation in the maize hybrids are associated with altered temporal gene expression. Two maize CCA1 homologs, ZmCCA1a and ZmCCA1b, are diurnally up regulated in the hybrids. Expressing ZmCCA1 complements the cca1 mutant phenotype in Arabidopsis, and overexpressing ZmCCA1b disrupts circadian rhythms and biomass heterosis. Furthermore, overexpressing ZmCCA1b in maize reduced chlorophyll content and plant height. Reduced height stems from reduced node elongation but not total node number in both greenhouse and field conditions. Phenotypes are less severe in the field than in the greenhouse, suggesting that enhanced light and/or metabolic activities in the field can compensate for altered circadian regulation in growth vigor. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveals a temporal shift of ZmCCA1-binding targets to the early morning in the hybrids, suggesting that activation of morning-phased genes in the hybrids promotes photosynthesis and growth vigor. This temporal shift of ZmCCA1-binding targets correlated with nonadditive and additive gene expression in early and late stages of seedling development. These results could guide breeding better hybrid crops to meet the growing demand in food and bioenergy. PMID- 27467758 TI - 5'-Terminal AUGs in Escherichia coli mRNAs with Shine-Dalgarno Sequences: Identification and Analysis of Their Roles in Non-Canonical Translation Initiation. AB - Analysis of the Escherichia coli transcriptome identified a unique subset of messenger RNAs (mRNAs) that contain a conventional untranslated leader and Shine Dalgarno (SD) sequence upstream of the gene's start codon while also containing an AUG triplet at the mRNA's 5'- terminus (5'-uAUG). Fusion of the coding sequence specified by the 5'-terminal putative AUG start codon to a lacZ reporter gene, as well as primer extension inhibition assays, reveal that the majority of the 5'-terminal upstream open reading frames (5'-uORFs) tested support some level of lacZ translation, indicating that these mRNAs can function both as leaderless and canonical SD-leadered mRNAs. Although some of the uORFs were expressed at low levels, others were expressed at levels close to that of the respective downstream genes and as high as the naturally leaderless cI mRNA of bacteriophage lambda. These 5'-terminal uORFs potentially encode peptides of varying lengths, but their functions, if any, are unknown. In an effort to determine whether expression from the 5'-terminal uORFs impact expression of the immediately downstream cistron, we examined expression from the downstream coding sequence after mutations were introduced that inhibit efficient 5'-uORF translation. These mutations were found to affect expression from the downstream cistrons to varying degrees, suggesting that some 5'-uORFs may play roles in downstream regulation. Since the 5'-uAUGs found on these conventionally leadered mRNAs can function to bind ribosomes and initiate translation, this indicates that canonical mRNAs containing 5'-uAUGs should be examined for their potential to function also as leaderless mRNAs. PMID- 27467759 TI - Influence of Repressive Histone and DNA Methylation upon D4Z4 Transcription in Non-Myogenic Cells. AB - We looked at a disease-associated macrosatellite array D4Z4 and focused on epigenetic factors influencing its chromatin state outside of the disease context. We used the HCT116 cell line that contains the non-canonical polyadenylation (poly-A) signal required to stabilize somatic transcripts of the human double homeobox gene DUX4, encoded from D4Z4. In HCT116, D4Z4 is packaged into constitutive heterochromatin, characterized by DNA methylation and histone H3 tri-methylation at lysine 9 (H3K9me3), resulting in low basal levels of D4Z4 derived transcripts. However, a double knockout (DKO) of DNA methyltransferase genes, DNMT1 and DNMT3B, but not either alone, results in significant loss of DNA and H3K9 methylation. This is coupled with upregulation of transcript levels from the array, including DUX4 isoforms (DUX4-fl) that are abnormally expressed in somatic muscle in the disease Facioscapulohumeral muscular dystrophy (FSHD) along with DUX4 protein, as indicated indirectly by upregulation of bondafide targets of DUX4 in DKO but not HCT116 cells. Results from treatment with a chemical inhibitor of histone methylation in HCT116 suggest that in the absence of DNA hypomethylation, H3K9me3 loss alone is sufficient to facilitate DUX4-fl transcription. Additionally, characterization of a cell line from a patient with Immunodeficiency, Centromeric instability and Facial anomalies syndrome 1 (ICF1) possessing a non-canonical poly-A signal and DNA hypomethylation at D4Z4 showed DUX4 target gene upregulation in the patient when compared to controls in spite of retention of H3K9me3. Taken together, these data suggest that both DNA methylation and H3K9me3 are determinants of D4Z4 silencing. Moreover, we show that in addition to testis, there is appreciable expression of spliced and polyadenylated D4Z4 derived transcripts that contain the complete DUX4 open reading frame (ORF) along with DUX4 target gene expression in the thymus, suggesting that DUX4 may provide normal function in this somatic tissue. PMID- 27467760 TI - The Effect of an Altitude Training Camp on Swimming Start Time and Loaded Squat Jump Performance. AB - This study evaluated the influence of an altitude training (AT) camp on swimming start time and loaded squat jump performance. To accomplish this goal, 13 international swimmers (8 women, 5 men) were allocated to both the control (Sea Level Training, SLT) and experimental conditions (AT, 2320 m above sea level) that were separated by a one year period. All tests (15 m freestyle swimming start and loaded squat jumps with additional loads of 25%, 50%, 75%, and 100% of swimmers' body weight) were performed before and after a concurrent 3-week strength and endurance training program prescribed by the national coach. Following the SLT camp, significant impairments in swimming start times to 10 (+3.1%) and 15 m (+4.0%) were observed (P < 0.05), whereas no significant changes for the same distances were detected following the AT camp (-0.89%; P > 0.05). Trivial changes in peak velocity were obtained during the loaded squat jump after both training periods (effect sizes: < 0.20). Based on these results we can conclude that a traditional training high-living high strategy concurrent training of 3 weeks does not adversely affect swimming start time and loaded squat jump performance in high level swimmers, but further studies are necessary to assess the effectiveness of power-oriented resistance training in the development of explosive actions. PMID- 27467761 TI - Missing Heroes of Pancreatic Surgery: Reply to Professor Kelemen. PMID- 27467763 TI - Association of a Common Oxytocin Receptor Gene Polymorphism with Self-Reported 'Empathic Concern' in a Large Population of Healthy Volunteers. AB - BACKGROUND: Previous research has linked genomic variations of the oxytocin receptor (OXTR) gene with individual differences in empathy. The impact of these variations on specific cognitive and emotional aspects of empathy, however, remains to be clarified. METHODS: We analysed associations of a common OXTR polymorphism (rs53576) with trait empathy in a sample of 421 blood donors (231 M, 190 F; age 18-74) using the Interpersonal Reactivity Index (IRI) as an established multidimensional self-report measure of empathy. RESULTS: Female sex was significantly associated with higher empathy scores in all IRI scales (p<0.001) with the exception of the cognitive perspective taking scale (p = 0.09). The overall trait empathy score was significantly associated with rs53576 (p = 0.01), with mean scores increasing from AA to GG genotypes. An analysis of the IRI subscores revealed that the polymorphism was especially associated with the emotional empathic concern scale (p = 0.02). Separate analysis of the male and female subgroup revealed a significant association of the polymorphism with female (p = 0.04), but not with male (p = 0.20) empathic concern. A comparison of effect sizes between the groups showed greater effects for women compared to men although effect size differences did not become significant in our sample. CONCLUSIONS: Our findings suggest a significant association of the rs53576 OXTR gene polymorphism with trait empathy and especially with emotional aspects of empathy. This association is possibly weaker or absent in men compared to women. PMID- 27467762 TI - Attentional Mechanisms during the Performance of a Subsecond Timing Task. AB - There is evidence that timing processes in the suprasecond scale are modulated by attentional mechanisms; in addition, some studies have shown that attentional mechanisms also affect timing in the subsecond scale. Our aim was to study eye movements and pupil diameter during a temporal bisection task in the subsecond range. Subjects were trained to discriminate anchor intervals of 200 or 800 msec, and were then confronted with intermediate durations. Eye movements revealed that subjects used different cognitive strategies during the bisection timing task. When the stimulus to be timed appeared randomly at a central or 4 peripheral positions on a screen, some subjects choose to maintain their gaze toward the central area while other followed the peripheral placement of the stimulus; some others subjects used both strategies. The time of subjective equality did not differ between subjects who employed different attentional mechanisms. However, differences emerged in the timing variance and attentional indexes (time taken to initial fixation, latency to respond, pupil dilatation and duration and number of fixations to stimulus areas). Timing in the subsecond range seems invariant despite the use of different attentional strategies. Future research should determine whether the selection of attentional mechanisms is related to particular timing tasks or instructions or whether it represents idiosyncratic cognitive "styles". PMID- 27467765 TI - Noninvasive measurement of regional pulse wave velocity in human ascending aorta with ultrasound imaging: an in-vivo feasibility study. AB - OBJECTIVES: Accurate and noninvasive techniques for measurement of local/regional pulse wave velocity (PWV), instead of global PWV, is desired for quantifying localized arterial stiffness and improving cardiovascular disease assessment. This study aimed at investigating the feasibility of regional PWV measurement in human ascending aorta in vivo using an ultrasound-based technique. METHODS: Proximal ascending aortas of 76 healthy patients (23-71 years) were scanned with transthoracic echocardiography in parasternal long-axis view, and ultrasound radiofrequency data were acquired in a high temporal resolution (~404 Hz). The PWV was derived from the determination of arrival times and identification of travel distances. Both PWVs in early systolic phase (PWVsf; pulse wave velocity measured using the systolic foot as characteristic time point) and late systolic phase (PWVdn; pulse wave velocity measured using the dicrotic notch as characteristic time point) were obtained. RESULTS: The PWVsf and PWVdn were 4.58 +/- 1.38 and 6.51 +/- 1.90 m/s, respectively, and both were correlated with age (r = 0.30, P = 0.02 and r = 0.71, P < 0.0001). The measurements were reproducible, and PWVdn showed significant correlation with aortic diameter (r = 0.53, P < 0.0001), relative distension (r = -0.44, P = 0.0002), and local PWV derived from Bramwell-Hill equation (r = 35, P = 0.004). The PWV difference (PWVdn - PWVsf) reflected aortic stiffness change within cardiac cycle from early systole to late systole and was also correlated with age (r = 0.50, P < 0.0001). CONCLUSION: The feasibility of ascending aortic PWV measurement using ultrasound imaging was illustrated in vivo, suggesting the potential of the technique in characterization of regional aortic stiffness and assessment of aortic diseases. PMID- 27467764 TI - Differential body weight, blood pressure and placental inflammatory responses to normal versus high-fat diet in melanocortin-4 receptor-deficient pregnant rats. AB - OBJECTIVES: Although obesity increases the risk for hypertensive disorders of pregnancy, the mechanisms remain unclear. Neural melanocortin-4 receptor (MC4R) deficiency causes hyperphagia and obesity. Effects of MC4R deficiency on body weight, blood pressure (BP) and placental inflammatory responses to high-fat diet (HFD) are unknown. We tested two hypotheses: MC4R deficiency results in higher body weight, BP and placental inflammation under normal-fat diet (NFD) conditions and HFD exaggerates these responses in MC4R-deficient pregnant rats. METHODS: MC4R and MC4R rats were maintained on NFD (13% kcal fat) or HFD (40% kcal fat) for ~15 weeks, then measurements made on gestational day 19. RESULTS: MC4R pregnant rats had greater body mass and total body fat and visceral adipose tissue weights along with greater circulating total cholesterol (TC) and leptin levels than MC4R rats regardless of diet. On NFD, circulating adiponectin levels were lower and placental TNFalpha levels and BP (conscious with carotid catheter) were higher in these heavier rats. Circulating adiponectin levels were lower and placental TNFalpha levels and BP were higher in MC4R rats compared with NFD controls. These parameters were not affected by HFD in the already heavier and hypertensive MC4R pregnant rats. CONCLUSION: Obesity in MC4R deficiency and HFD in MC4R rats result in higher BP and placental inflammation during pregnancy. However, HFD did not exaggerate these responses in already obese MC4R pregnant rats. These data suggest that obesity and HFD are independently related to hypertension and placental inflammation in pregnancy. PMID- 27467766 TI - Recent blood pressure trends in adolescents from China, Korea, Seychelles and the United States of America, 1997-2012. AB - OBJECTIVE: Although the prevalence of obesity is increasing worldwide, secular trends in elevated blood pressure (BP) differ across populations. We aimed to compare recent BP and obesity trends in adolescents aged 10-19 years in China, Korea, Seychelles and the United States of America. METHODS: Data in adolescents aged 10-19 years came from China (1997-2011, n = 8025), Korea (1998-2012, n = 10 119), Seychelles (1998-2012, n = 27 569) and the United States of America (1999 2012, n = 14 580). Elevated BP was defined as SBP or DBP equal to or above the referent sex, age and height-specific 95th percentile of the US Fourth Report. Overweight and obesity were defined using criteria of the International Obesity Task Force. RESULTS: Between 1997-2000 and 2011-2012, the prevalence of elevated BP decreased in Korea and did not change substantially in China and in the United States of America. The prevalence of elevated BP increased in Seychelles. In 2011 2012, the prevalence of elevated BP was 1.7% in the United States of America, 3.8% in China, 3.7% in Korea and 14.3% in Seychelles. The prevalence of overweight and obesity increased over time and reached in 2011-2012 41.2% in the United States of America, 18.6% in China, 25.2% in Korea and 27.4% in Seychelles. Elevated BP was strongly associated with obesity in all countries. CONCLUSION: Although the prevalence of obesity increased markedly in the four countries, secular BP trends in adolescents differed in countries of different regions. PMID- 27467767 TI - 12 min/week of high-intensity interval training reduces aortic reservoir pressure in individuals with metabolic syndrome: a randomized trial. AB - OBJECTIVE: Decreased aortic reservoir function leads to a rise in aortic reservoir pressure that is an independent predictor of cardiovascular events. Although there is evidence that high-intensity interval training (HIIT) would be useful to improve aortic reservoir pressure, the optimal dose of high-intensity exercise to improve aortic reservoir function has yet to be investigated. Therefore, this study compared the effect of different volumes of HIIT and moderate-intensity continuous training (MICT) on aortic reservoir pressure in participants with the metabolic syndrome (MetS). METHODS: Fifty individuals with MetS were randomized into one of the following 16-week training programs: MICT [n = 17, 30 min at 60-70% peak heart rate (HRpeak), five times/week]; 4 * 4-min high intensity interval training (4HIIT) (n = 15, 4 * 4 min bouts at 85-95% HRpeak, interspersed with 3 min of active recovery at 50-70% HRpeak, three times/week); and 1 * 4-min high-intensity interval training (1HIIT) (n = 18, 1 * 4 min bout at 85-95% HRpeak, three times/week). Aortic reservoir pressure was calculated from radial applanation tonometry. RESULTS: Although not statistically significant, there was a trend for a small-to-medium group * time interaction effect on aortic reservoir pressure, indicating a positive adaptation following 1HIIT compared with 4HIIT and MICT [F (2,46) = 2.9, P = 0.07, eta = 0.06]. This is supported by our within-group analysis wherein only 1HIIT significantly decreased aortic reservoir pressure from pre to postintervention (pre-post: 1HIIT 33 +/- 16 to 31 +/- 13, P = 0.03; MICT 29 +/- 9-28 +/- 8, P = 0.78; 4HIIT 28 +/- 10-30 +/- 9 mmHg, P = 0.10). CONCLUSION: Three sessions of 4 min of high-intensity exercise per week (12 min/week) was sufficient to improve aortic reservoir pressure, and thus may be a time-efficient exercise modality for reducing cardiovascular risk in individuals with MetS. PMID- 27467769 TI - Report of the International Society of Hypertension Teaching Seminar organized by the International Society of Hypertension Africa Regional Advisory Group: Maputo, Mozambique, 2016. AB - The International Society of Hypertension (ISH), in fulfilment of its mission of promoting hypertension control and prevention and also of advancing knowledge globally, organizes hypertension teaching seminars or 'summer schools' worldwide through the ISH Regional Advisory Groups. In Africa, seven of such seminars have been organized. This is a report of the eighth seminar held in Maputo, Mozambique, April, 2016. The seminar was attended by over 65 participants from 11 African countries. The Faculty consisted of 11 international hypertension experts. The eighth African hypertension seminar was a great success as confirmed by a pre- and post-test questionnaire. PMID- 27467770 TI - The approach to hypertension: from childhood to old age. PMID- 27467768 TI - 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. AB - Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, as they call attention to the burden of HTN in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents. PMID- 27467771 TI - Slower Decline in C-Reactive Protein after an Inflammatory Insult Is Associated with Longer Survival in Older Hospitalised Patients. AB - BACKGROUND: Enhancing biological resilience may offer a novel way to prevent and ameliorate disease in older patients. We investigated whether changes in C reactive protein (CRP), as a dynamic marker of the acute inflammatory response to diverse stressors, may provide a way to operationalize the concept of resilience in older adults. We tested this hypothesis by examining whether such changes could predict prognosis by identifying which individuals are at greater risk of 6 month mortality. METHODS: Analysis of prospective, routinely collected datasets containing data on hospitalization, clinical chemistry and rehabilitation outcomes for rehabilitation inpatients between 1999 and 2011. Maximum CRP response during acute illness and CRP recovery indices (time and slope of CRP decay to half maximum, and to <50mg/L if peak values were greater than 50mg/L) was derived from biochemistry data. 6-month survival plots were conducted on quartiles of CRP recovery indices. Cox proportional hazards models were used to test univariate and multivariate predictors of 6-month mortality. Covariates included age, sex, number of medications, serum calcium, haemoglobin level, renal function, and the presence of previous myocardial infarction, stroke, chronic heart failure, COPD and diabetes. RESULTS: 3723 patients, mean age 84 years, were included. 1535 (41%) were male and 733 (20%) died during six-month follow-up. The lower an individual's peak CRP reading, and the longer the time taken for their CRP to fall, the better their 6-month survival. The time for CRP to reach half of its maximum value was the best dynamic CRP index of survival (HR 0.93 per week, 95% CI 0.89 to 0.98; p = 0.004); this remained significant even after adjustment for maximum CRP level and covariates listed above. CONCLUSION: CRP recovery indices are associated with survival in older people; further work is required to explain differences in physiology between patients with a fast and slow CRP recovery. PMID- 27467772 TI - Outcomes and Costs of Treating Hepatitis C Patients in the Era of First Generation Protease Inhibitors - Results from the PAN Study. AB - 1 OBJECTIVE: Chronic hepatitis C virus infections (HCV) cause a significant public health burden. Introduction of telaprevir (TVR) and boceprevir (BOC) has increased sustained virologic response rates (SVR) in genotype 1 patients but were accompanied by higher treatment costs and more side effects. Aim of the study was to assess outcomes and costs of treating HCV with TVR or BOC in routine care. 2 MATERIAL AND METHODS: Data was obtained from a non-interventional study. This analysis relates on a subset of 1,786 patients for whom resource utilisation was documented. Sociodemografic and clinical parameters as well as resource utilisation were collected using a web-based data recording system. Costs were calculated using official remuneration schemes. 3 RESULTS: Mean age of patients was 49.2 years, 58.6% were male. In treatment-naive patients SVR-rates of 62.2% and 55.7% for TVR and BOC were observed (prior relapser: 68.5% for TVR and 63.5% for BOC; prior non-responder: 45.6% for TVR and 39.1% for BOC). Treatment costs are dominated by costs for pharmaceuticals and range between ?39,081 and ?53,491. We calculated average costs per SVR of ?81,347 (TVR) and ?70,163 (BOC) in treatment-naive patients (prior relapser: 78,089 ?/SVR for TVR and 82,077 ?/SVR for BOC; prior non-responder: 116,509 ?/SVR for TVR and 110,156 ?/SVR for BOC). Quality of life data showed a considerable decrease during treatment. 4 CONCLUSION: Our study is one of few investigating both, outcomes and costs, of treating HCV in a real-life setting. Data can serve as a reference in the discussion of increasing costs in recently introduced agents. PMID- 27467773 TI - Ligand Similarity Complements Sequence, Physical Interaction, and Co-Expression for Gene Function Prediction. AB - The expansion of protein-ligand annotation databases has enabled large-scale networking of proteins by ligand similarity. These ligand-based protein networks, which implicitly predict the ability of neighboring proteins to bind related ligands, may complement biologically-oriented gene networks, which are used to predict functional or disease relevance. To quantify the degree to which such ligand-based protein associations might complement functional genomic associations, including sequence similarity, physical protein-protein interactions, co-expression, and disease gene annotations, we calculated a network based on the Similarity Ensemble Approach (SEA: sea.docking.org), where protein neighbors reflect the similarity of their ligands. We also measured the similarity with functional genomic networks over a common set of 1,131 genes, and found that the networks had only small overlaps, which were significant only due to the large scale of the data. Consistent with the view that the networks contain different information, combining them substantially improved Molecular Function prediction within GO (from AUROC~0.63-0.75 for the individual data modalities to AUROC~0.8 in the aggregate). We investigated the boost in guilt-by association gene function prediction when the networks are combined and describe underlying properties that can be further exploited. PMID- 27467774 TI - An Interprofessional Approach to Reducing the Risk of Falls Through Enhanced Collaborative Practice. AB - Falls are the leading cause of accidental deaths in older adults and are a growing public health concern. The American Geriatrics Society (AGS) and British Geriatrics Society (BGS) published guidelines for falls screening and risk reduction, yet few primary care providers report following any guidelines for falls prevention. This article describes a project that engaged an interprofessional teaching team to support interprofessional clinical teams to reduce fall risk in older adults by implementing the AGS/BGS guidelines. Twenty five interprofessional clinical teams with representatives from medicine, nursing, pharmacy, and social work were recruited from ambulatory, long-term care, hospital, and home health settings for a structured intervention: a 4-hour training workshop plus coaching for implementation for 1 year. The workshop focused on evidence-based strategies to decrease the risk of falls, including screening for falls; assessing gait, balance, orthostatic blood pressure, and other medical conditions; exercise including tai chi; vitamin D supplementation; medication review and reduction; and environmental assessment. Quantitative and qualitative data were collected using chart reviews, coaching plans and field notes, and postintervention structured interviews of participants. Site visits and coaching field notes confirmed uptake of the strategies. Chart reviews showed significant improvement in adoption of all falls prevention strategies except vitamin D supplementation. Long-term care facilities were more likely to address environmental concerns and add tai chi classes, and ambulatory settings were more likely to initiate falls screening. The intervention demonstrated that interprofessional practice change to target falls prevention can be incorporated into primary care and long-term care settings. PMID- 27467775 TI - Changes in the Metabolome in Response to Low-Dose Exposure to Environmental Chemicals Used in Personal Care Products during Different Windows of Susceptibility. AB - The consequences of ubiquitous exposure to environmental chemicals remain poorly defined. Non-targeted metabolomic profiling is an emerging method to identify biomarkers of the physiological response to such exposures. We investigated the effect of three commonly used ingredients in personal care products, diethyl phthalate (DEP), methylparaben (MPB) and triclosan (TCS), on the blood metabolome of female Sprague-Dawley rats. Animals were treated with low levels of these chemicals comparable to human exposures during prepubertal and pubertal windows as well as chronically from birth to adulthood. Non-targeted metabolomic profiling revealed that most of the variation in the metabolites was associated with developmental stage. The low-dose exposure to DEP, MPB and TCS had a relatively small, but detectable impact on the metabolome. Multiple metabolites that were affected by chemical exposure belonged to the same biochemical pathways including phenol sulfonation and metabolism of pyruvate, lyso-plasmalogens, unsaturated fatty acids and serotonin. Changes in phenol sulfonation and pyruvate metabolism were most pronounced in rats exposed to DEP during the prepubertal period. Our metabolomics analysis demonstrates that human level exposure to personal care product ingredients has detectable effects on the rat metabolome. We highlight specific pathways such as sulfonation that warrant further study. PMID- 27467776 TI - Effect of ultrasonic and microwave disintegration on physico-chemical and biodegradation characteristics of waste-activated sludge. AB - The purpose of this study was to investigate the effect of ultrasonic and microwave disintegration on physico-chemical and biodegradability properties of waste-activated sludge (WAS) from a municipal wastewater treatment plant. Another aim was to carry out particle size distribution (PSD) analysis as an integral component of sludge characterization to highlight the transformation mechanisms involved in pretreatment processes and better understand the biodegradation patterns of sonicated and irradiated WAS liquids examined by means of respirometric measurements. Various combinations of sonication and microwave irradiation parameters were applied to optimize operating conditions. The optimum ultrasonic density was determined as 1.5 W/mL, and energy dosages lower than 30,000 kJ/kg TS resulted in a fairly linear increase in the soluble chemical oxygen demand (SCOD) release. An irradiation time of 10 min and a temperature of 175 degrees C were selected as the optimum microwave pretreatment conditions for sludge liquefaction. The most apparent impact of ultrasonication on the PSD of COD was the shifting of the peak at the particulate fraction (>1600 nm) toward the lowest size range (<2 nm). Microwave heating at the selected experimental conditions and ultrasonic pretreatment at 30,000 kJ/kg TS exhibited comparable size distribution and biodegradation characteristics to those of domestic sewage. PMID- 27467778 TI - Forecasts of 21st Century Snowpack and Implications for Snowmobile and Snowcoach Use in Yellowstone National Park. AB - Climate models project a general decline in western US snowpack throughout the 21st century, but long-term, spatially fine-grained, management-relevant projections of snowpack are not available for Yellowstone National Park. We focus on the implications that future snow declines may have for oversnow vehicle (snowmobile and snowcoach) use because oversnow tourism is critical to the local economy and has been a contentious issue in the park for more than 30 years. Using temperature-indexed snow melt and accumulation equations with temperature and precipitation data from downscaled global climate models, we forecast the number of days that will be suitable for oversnow travel on each Yellowstone road segment during the mid- and late-21st century. The west entrance road was forecast to be the least suitable for oversnow use in the future while the south entrance road was forecast to remain at near historical levels of driveability. The greatest snow losses were forecast for the west entrance road where as little as 29% of the December-March oversnow season was forecast to be driveable by late century. The climatic conditions that allow oversnow vehicle use in Yellowstone are forecast by our methods to deteriorate significantly in the future. At some point it may be prudent to consider plowing the roads that experience the greatest snow losses. PMID- 27467777 TI - SPHK1/sphingosine kinase 1-mediated autophagy differs between neurons and SH-SY5Y neuroblastoma cells. AB - Although implicated in neurodegeneration, autophagy has been characterized mostly in yeast and mammalian non-neuronal cells. In a recent study, we sought to determine if SPHK1 (sphingosine kinase 1), implicated previously in macroautophagy/autophagy in cancer cells, regulates autophagy in neurons. SPHK1 synthesizes sphingosine-1-phosphate (S1P), a bioactive lipid involved in cell survival. In our study, we discovered that, when neuronal autophagy is pharmacologically stimulated, SPHK1 relocalizes to the endocytic and autophagic organelles. Interestingly, in non-neuronal cells stimulated with growth factors, SPHK1 translocates to the plasma membrane, where it phosphorylates sphingosine to produce S1P. Whether SPHK1 also binds to the endocytic and autophagic organelles in non-neuronal cells upon induction of autophagy has not been demonstrated. Here, we determined if the effect in neurons is operant in the SH-SY5Y neuroblastoma cell line. In both non-differentiated and differentiated SH-SY5Y cells, a short incubation of cells in amino acid-free medium stimulated the formation of SPHK1-positive puncta, as in neurons. We also found that, unlike neurons in which these puncta represent endosomes, autophagosomes, and amphisomes, in SH-SY5Y cells SPHK1 is bound only to the endosomes. In addition, a dominant negative form of SPHK1 was very toxic to SH-SY5Y cells, but cultured primary cortical neurons tolerated it significantly better. These results suggest that autophagy in neurons is regulated by mechanisms that differ, at least in part, from those in SH-SY5Y cells. PMID- 27467779 TI - Urea- and Thiourea-Catalyzed Aminolysis of Carbonates. AB - The aminolysis of (poly)carbonates by (poly)amines provides access to non isocyanate polyurethanes (NIPUs) that are toxic-reagent-free analogues of polyurethanes (PUs). Owing to their low reactivity, the ring opening of cyclic carbonates requires the use of a catalyst. Herein, we report that the more available and cheaper ureas could advantageously be used for catalyzing the formation of NIPUs at the expense of the thiourea analogues. In addition, we demonstrate a medium-range pKa of the (thio)urea and an unqeual substitution pattern is critical for controlling the efficiency of the carbonate opening. PMID- 27467780 TI - Genome-Wide Prediction and Analysis of 3D-Domain Swapped Proteins in the Human Genome from Sequence Information. AB - 3D-domain swapping is one of the mechanisms of protein oligomerization and the proteins exhibiting this phenomenon have many biological functions. These proteins, which undergo domain swapping, have acquired much attention owing to their involvement in human diseases, such as conformational diseases, amyloidosis, serpinopathies, proteionopathies etc. Early realisation of proteins in the whole human genome that retain tendency to domain swap will enable many aspects of disease control management. Predictive models were developed by using machine learning approaches with an average accuracy of 78% (85.6% of sensitivity, 87.5% of specificity and an MCC value of 0.72) to predict putative domain swapping in protein sequences. These models were applied to many complete genomes with special emphasis on the human genome. Nearly 44% of the protein sequences in the human genome were predicted positive for domain swapping. Enrichment analysis was performed on the positively predicted sequences from human genome for their domain distribution, disease association and functional importance based on Gene Ontology (GO). Enrichment analysis was also performed to infer a better understanding of the functional importance of these sequences. Finally, we developed hinge region prediction, in the given putative domain swapped sequence, by using important physicochemical properties of amino acids. PMID- 27467781 TI - Synthesis of Functionalized gem-Difluoroalkenes via a Photocatalytic Decarboxylative/Defluorinative Reaction. AB - A photocatalytic decarboxylative/defluorinative reaction of alpha-trifluoromethyl alkenes with alpha-keto acids and alpha-amino acids has been developed. The reaction occurs at room temperature under visible light irradiation, affording various gamma,gamma-difluoroallylic ketones and 1,1-difluorohomoallyl amines in good yields. The synthetic applications of the resulting functionalized gem difluoroalkenes were also described. PMID- 27467782 TI - Direct Synthesis of Few-Layer F-Doped Graphene Foam and Its Lithium/Potassium Storage Properties. AB - Heteroatom-doped graphene is considered a potential electrode materials for lithium-ion batteries (LIBs). However, potassium-ion batteries (PIBs) systems are possible alternatives due to the comparatively higher abundance. Here, a practical solid-state method is described for the preparation of few-layer F doped graphene foam (FFGF) with thickness of about 4 nm and high surface area (874 m(2)g(-1)). As anode material for LIBs, FFGF exhibits 800 mAh.g(-1) after 50 cycles at a current density of 100 mA.g(-1) and 555 mAh.g(-1) after 100 cycles at 200 mA.g(-1) as well as remarkable rate capability. FFGF also shows 165.9 mAh.g( 1) at 500 mA.g(-1) for 200 cycles for PIBs. Research suggests that the multiple synergistic effects of the F-modification, high surface area, and mesoporous membrane structures endow the ions and electrons throughout the electrode matrix with fast transportation as well as offering sufficient active sites for lithium and potassium storage, resulting in excellent electrochemical performance. Furthermore, the insights obtained will be of benefit to the design of reasonable electrode materials for alkali metal ion batteries. PMID- 27467783 TI - Eruption of Eyelid Target Lesions. PMID- 27467785 TI - Introducing a New Board Member. PMID- 27467784 TI - Tidal Marshes across a Chesapeake Bay Subestuary Are Not Keeping up with Sea Level Rise. AB - Sea-level rise is a major factor in wetland loss worldwide, and in much of Chesapeake Bay (USA) the rate of sea-level rise is higher than the current global rate of 3.2 mm yr-1 due to regional subsidence. Marshes along estuarine salinity gradients differ in vegetation composition, productivity, decomposition pathways, and sediment dynamics, and may exhibit different responses to sea-level rise. Coastal marshes persist by building vertically at rates at or exceeding regional sea-level rise. In one of the first studies to examine elevation dynamics across an estuarine salinity gradient, we installed 15 surface elevation tables (SET) and accretion marker-horizon plots (MH) in tidal freshwater, oligohaline, and brackish marshes across a Chesapeake Bay subestuary. Over the course of four years, wetlands across the subestuary decreased 1.8 +/- 2.7 mm yr-1 in elevation on average, at least 5 mm yr-1 below that needed to keep pace with global sea level rise. Elevation change rates did not significantly differ among the marshes studied, and ranged from -9.8 +/- 6.9 to 4.5 +/- 4.3 mm yr-1. Surface accretion of deposited mineral and organic matter was uniformly high across the estuary (~9 15 mm yr-1), indicating that elevation loss was not due to lack of accretionary input. Position in the estuary and associated salinity regime were not related to elevation change or surface matter accretion. Previous studies have focused on surface elevation change in marshes of uniform salinity (e.g., salt marshes); however, our findings highlight the need for elevation studies in marshes of all salinity regimes and different geomorphic positions, and warn that brackish, oligohaline, and freshwater tidal wetlands may be at similarly high risk of submergence in some estuaries. PMID- 27467786 TI - Scanning sports. PMID- 27467790 TI - Sportsmedicine forum. PMID- 27467792 TI - Sunset on Sandy Hook. PMID- 27467791 TI - The One-Eyed Athlete. PMID- 27467793 TI - Noteworthy. PMID- 27467794 TI - Coming in sportsmedicine. PMID- 27467795 TI - Fitness, Heart Disease, and High-Density Lipoproteins: A Look at the Relationships. AB - In brief: Coronary heart disease (CHD) causes over 500,000 deaths per year in the United States, although this rate is declining. Preventive strategies have focused on reducing modifiable risk factors such as hypertension, cigarette smoking, and serum cholesterol levels. However, physical activity can exert a preventive effect as well. High-density lipoprotein cholesterol (HDL-C), which seems to be the most critical determinant of risk of CHD, increases with greater fitness levels. On the basis of this literature review, the author recommends that future research programs include more precise measurements of fitness as well as determination of certain parameters of lipid metabolism, such as HDL-C, apolipoproteins, and lipoprotein lipase. PMID- 27467796 TI - How I Manage Heel Spur Syndrome. AB - In brief: Plantar fasciitis and heel spurs are two contributing causes of heel spur syndrome and sometimes cannot be differentiated from one another. In any case, the syndrome is caused by trauma to the heel and is often accompanied by severe pain. Treatment methods include rest, anti-inflammatory medication, and various types of shoe padding. Cortisone may be injected into the heel if symptoms continue, and surgery may be necessary if conservative treatment is unsuccessful. PMID- 27467797 TI - Eating Disorders Among Female Athletes. AB - In brief: Research has indicated that 4% to 19% of female college students have eating disorders such as anorexia nervosa, anorexia athletica, or bulimia. To determine the extent to which preoccupation with weight and tendencies toward eating disorders are problems among female athletes, we analyzed the responses to a questionnaire completed by 168 college women-101 nonathletes, 35 athletes whose sports emphasize leanness, and 32 athletes whose sports do not emphasize leanness. The results showed that 6% of the nonathletes, 20% of the athletes in sports that emphasize leanness, and 10% of all the athletes were either exceptionally preoccupied with weight or had tendencies toward eating disorders. PMID- 27467798 TI - Unresolved Osgood-Schlatter Disease. AB - In brief: Osgood-Schlatter disease is usually characterized by a finite clinical course with no sequelae. Occasionally, however, a patient will have continuing problems and may require surgery. The college skier described here did not respond to conservative therapy (nonsteroidal anti-inflammatory medication, muscle-strengthening exercises, and immobilization), and surgery was deemed appropriate. PMID- 27467799 TI - Injuries in Professional Rodeo: An Update. AB - In brief: A medical team kept records for four years on all injuries that occurred during an annual state championship rodeo. Fifty-five (19.7%) of the 278 competitors and rodeo clowns who participated sustained a total of 61 injuries. Bull riding was the most dangerous event, accounting for 20 injuries to 18 competitors; saddle bronc riding and bareback riding followed with 13 injuries each. Barrel racing was the safest, with no injuries. The most common injuries were contusions, sprains, and strains, and the elbow was injured more often than any other part of the body. Protective equipment and physical conditioning could reduce rodeo injuries. PMID- 27467800 TI - Is Fast Walking an Adequate Aerobic Training Stimulus for 30- to 69-Year-Old Men and Women? AB - In brief: Two related studies were conducted to determine whether fast walking is intense enough to elicit a training heart rate (THR), which is defined as >= 70% of maximal heart rate. In one study, 343 subjects (165 men, 178 women) walked a mile as fast as possible. Ninety-one percent of all the women and 83% of men aged 50 and older reached a THR. In the second study, ten men with high V o2 max values were instructed to achieve and maintain a THR and were provided with visual feedback of their heart rate (HR) during a 30-minute walk. These subjects maintained a THR for an average of 25 minutes during the walk. Thus, it seems that fast walking may indeed offer an adequate aerobic training stimulus for most adults. PMID- 27467801 TI - Hyperventilation Syndrome in Adolescent Athletes. AB - In brief: Ten high school students (three males, seven females) hyperventilated 12 times during athletic events over a two-year period. Symptoms associated with hyperventilation syndrome include an inability to catch one's breath, rapid deep respirations, anxiety (often associated with losing among athletes), tetany, numbness of lips and hands, chest pain, and even loss of consciousness. Treatment may consist of rebreathing into a paper bag, which is embarrassing in front of observers, or slowly inhaling through the nose and exhaling through the mouth. PMID- 27467802 TI - Diet Patterns of Elite Australian Male Triathletes. AB - In brief: The triathlon makes heavy demands on the body and especially on glycogen supply. This article describes the self-reported diet practices of 25 elite Australian male triathletes during training and racing. They consumed a mean of 4,095 kcal/day, 59.5% of which was carbohydrate, 13% protein, 27% fat, and 0.5% alcohol; glycogen and protein intakes met or surpassed recommended levels. Intakes of five vitamins and two minerals also exceeded recommendations, and iron status was satisfactory. The athletes ate carbohydrate mostly in complex form, snacking frequently to get enough for energy needs. Few subjects trained deliberately to build up a tolerance for consuming food and fluids during competition. PMID- 27467803 TI - Carbohydrate, Muscle Glycogen, and Improved Performance. AB - In brief: Muscle glycogen is the body's chief source of energy for prolonged exercse at moderately high intensity (65% to 85% of Vo2 max); glyocgen reserves therefore limit endurance at this pace. Endurance athletes who train daily must maintain normal glycogen stores to support their training and thereby improve performance. Glycogen synthesis after prolonged exercise is directly related to the amount of dietary carbohydrate; accordingly, athletes who engage in intense daily training should consume 70% of their calories as carbohydrate. Further, athletes can increase their endurance by overloading their glycogen stores. This is done by tapering training the week before a competition and increasing carbohydrate intake the last three days before the event. PMID- 27467804 TI - Can Fitness Be Found at the Top of the Stairs? AB - It's tempting to bypass the stairs for the elevator, but research suggests that making a little extra effort every day may help increase longevity. Making a big effort may result in an aerobic workout. PMID- 27467805 TI - Treating the Wounded and the Weary at a Large Cross-Country Ski Marathon. AB - The medical team at the American Birkebeiner, the largest cross-country ski marathon in North America, has formed a health care system that is considered by many medical professionals and ski enthusiasts to be a model for other ski marathons. PMID- 27467807 TI - Abstracts at a glance. PMID- 27467806 TI - Why Do Some Athletes Choose High-Risk Sports? AB - Physicians who treat sky divers or mountain climbers may wonder what drives these athletes to risk injury-or even death-in the pursuit of sport. Psychologists have proposed a variety of explanations. PMID- 27467808 TI - Exercise and the Common Cold. PMID- 27467810 TI - The Mayo Portland Adaptability Inventory-4 outcome measure is superior to UK FIM+FAM in a British military population. AB - OBJECTIVE: The aim of this study was to identify the most appropriate rehabilitation outcome measure for use in a young adult population with acquired brain injury. METHODS: A 2-year prospective study of patients admitted to a UK military neuro-rehabilitation unit with acquired brain injury to compare the appropriateness of the Functional Independence Measure/Functional Assessment Measure (FIM+FAM) vs the Mayo-Portland Adaptability Inventory Version 4 (MPAI-4) in assessing outcomes. Patients were assessed at admission, discharge and at 4 month follow-up using FIM+FAM and MPAI-4. RESULTS: The FIM+FAM total motor score showed a marked ceiling affect, 42% of patients scored the maximum on admission rising to 80% at discharge. The MPAI-4 did not show significant ceiling effects. The other sub-scales of FIM+FAM and MPAI-4 were generally comparable, no more than 17% achieved ceiling at follow-up. CONCLUSIONS: This is the first comparative study of FIM+FAM and MPAI-4 in a young adult military population following acquired brain injury. All patients showed improvements in both outcome measures following intensive inpatient rehabilitation. However, the MPAI-4 did not show ceiling effects in motor scores. This measure was, therefore, found to be more appropriate in the cohort. PMID- 27467811 TI - Novel Approach of Using Nutraceutic-Directed Caloric Antioxidant Density and Ion Ratio for Evaluating Fruit's Health Quality. AB - Seven kinds of indigenous fruits and five imported fruits were compared for their "health quality." Methods including the calorific, antioxidant, and ion ratios were carried out. Results indicated the order of content (in mg/100g) was: Ca(2+) , Murcott orange (218.2) > Kiwifruit (200.0) > pineapple (138.5) > Golden kiwi (117.6); Mg(2+) , Pitaya (192.2), banana (88.0), Kiwifruit (63.4), and Golden kiwi (58.4); Zn(2+) , Pitaya (19.53) > pear (10.8) > Kiwifruit (6.09) > Irwin mango (4.58). Cu(2+) , Kiwifruit (0.70) > Red globe grape (0.67) > Golden kiwi (0.65) > Irwin mango (0.42) ~ Pitaya (0.40). In terms of ion ratio, Pitaya showed Zn(2+) /Cu(2+) (48.8), Mg(2+) /Ca(2+) (6.7) and uniquely possessed selenium 0.002 mg/100 g; for pear, Zn(2+) /Cu(2+) = 37.2, while Kyoho grape, Red globe grape, and Golden kiwi revealed extremely high Fe(2+) /(Co(2+) +Ni(2+) ) ratios. On the other hands, Irwin mango and Pitaya astonishingly contained huge amount of inositol, reaching 3523.2 mg/100 g and 1998.7 mg/100 g, respectively. To evaluate the "health quality" of fruits, an overall ranking method by combining (a) the Function-directed Caloric Antioxidant Density (CAD) and (b) the ion ratio was developed. The finalized ranking of these selected fruits was: Pitaya > cherry > Irwin mango > Murcott orange = pineapple > banana > Golden kiwi > pear > Kiwifruit > Red globe grape > apple > Kyoho grape. Conclusively, this evaluation method is novel, contemporary and scientific, which could more clearly assess the "health quality" of fruits in view of nutritional, calorific, and antioxidant balance. PMID- 27467812 TI - Correction to Doping-Induced Tunable Wettability and Adhesion of Graphene. PMID- 27467813 TI - Slovenia: Health System Review. AB - This analysis of the Slovene health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. The health of the population has improved over the last few decades. While life expectancy for both men and women is similar to EU averages, morbidity and mortality data show persistent disparities between regions, and mortality from external causes is particularly high. Satisfaction with health care delivery is high, but recently waiting times for some outpatient specialist services have increased. Greater focus on preventive measures is also needed as well as better care coordination, particularly for those with chronic conditions. Despite having relatively high levels of co payments for many services covered by the universal compulsory health insurance system, these expenses are counterbalanced by voluntary health insurance, which covers 95% of the population liable for co-payments. However, Slovenia is somewhat unique among social health insurance countries in that it relies almost exclusively on payroll contributions to fund its compulsory health insurance system. This makes health sector revenues very susceptible to economic and labour market fluctuations. A future challenge will be to diversify the resource base for health system funding and thus bolster sustainability in the longer term, while preserving service delivery and quality of care. Given changing demographics and morbidity patterns, further challenges include restructuring the funding and provision of long-term care and enhancing health system efficiency through reform of purchasing and provider-payment systems. PMID- 27467814 TI - Ab Initio Atom-Atom Potentials Using CamCASP: Theory and Application to Many-Body Models for the Pyridine Dimer. AB - Creating accurate, analytic atom-atom potentials for small organic molecules from first principles can be a time-consuming and computationally intensive task, particularly if we also require them to include explicit polarization terms, which are essential in many systems. We describe how the CamCASP suite of programs can be used to generate such potentials using some of the most accurate electronic structure methods currently applicable. We derive the long-range terms from monomer properties and determine the short-range anisotropy parameters by a novel and robust method based on the iterated stockholder atom approach. Using these techniques, we develop distributed multipole models for the electrostatic, polarization, and dispersion interactions in the pyridine dimer and develop a series of many-body potentials for the pyridine system. Even the simplest of these potentials exhibits root mean square errors of only about 0.6 kJ mol(-1) for the low-energy pyridine dimers, significantly surpassing the best empirical potentials. Our best model is shown to support eight stable minima, four of which have not been reported before in the literature. Further, the functional form can be made systematically more elaborate so as to improve the accuracy without a significant increase in the human-time spent in their generation. We investigate the effects of anisotropy, rank of multipoles, and choice of polarizability and dispersion models. PMID- 27467815 TI - Endoscopic submucosal dissection of cecal lesions in proximity to the appendiceal orifice. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is performed for treatment of various gastrointestinal lesions; however, the cecum in proximity to the appendiceal orifice remains a challenging area. We reviewed our experience with cecal ESD near the appendiceal orifice in order to clarify whether this procedure is a safe and effective therapeutic option. PATIENTS AND METHODS: We retrospectively reviewed ESD for lesions within approximately 12 mm of the appendiceal orifice at Kobe University Hospital and an affiliated hospital between January 2003 and December 2014. Lesions were classified as: Type 0, proximity to the appendiceal orifice but does not reach it; Type 1, reaches border of the appendix, but does not enter orifice; Type 2, enters orifice, and transition to normal appendiceal mucosa is discernible on inspection of the appendiceal lumen; and Type 3, enters orifice deeply and tumor edge cannot be observed. ESD was not performed for Type 3 lesions unless appendectomy was performed prior to ESD. RESULTS: A total of 76 lesions satisfied the inclusion criteria (47 Type 0 lesions, 20 Type 1, 6 Type 2, and 3 Type 3). En bloc resection was achieved in 72 lesions (94.7 %). Median specimen size was 49 mm (range 15 - 114 mm), and median tumor size was 35.5 mm (10 - 110 mm). One patient experienced postoperative bleeding, which was treated by endoscopic hemostasis. Another patient who experienced intraoperative perforation and was treated by clip closure later developed appendicitis; he underwent emergency ileocecal surgical resection. Another patient experienced postoperative appendicitis and recovered with antibiotic treatment. CONCLUSIONS: ESD in close proximity to the appendiceal orifice seems safe and effective. PMID- 27467816 TI - The biomechanical effect of clavicular shortening on shoulder muscle function, a simulation study. AB - BACKGROUND: Malunion of the clavicle with shortening after mid shaft fractures can give rise to long-term residual complaints. The cause of these complaints is as yet unclear. METHODS: In this study we analysed data of an earlier experimental cadaveric study on changes of shoulder biomechanics with progressive shortening of the clavicle. The data was used in a musculoskeletal computer model to examine the effect of clavicle shortening on muscle function, expressed as maximal muscle moments for abduction and internal rotation. FINDINGS: Clavicle shortening results in changes of maximal muscle moments around the shoulder girdle. The mean values at 3.6cm of shortening of maximal muscle moment changes are 16% decreased around the sterno-clavicular joint decreased for both ab- and adduction, 37% increased around the acromion-clavicular joint for adduction and 32% decrease for internal rotation around the gleno-humeral joint in resting position. INTERPRETATION: Shortening of the clavicle affects muscle function in the shoulder in a computer model. This may explain for the residual complaints after short malunion with shortening. LEVEL OF EVIDENCE: Basic Science Study. Biomechanics. Cadaveric data and computer model. PMID- 27467817 TI - Targeting Tumor Necrosis Factor-alpha with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion. AB - OBJECTIVE: It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-alpha is known as a crucial mediator of early pro atherosclerotic events. Epidemiologic data suggest that blockade of TNF-alpha has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-alpha blockade by adalimumab-which is approved for several inflammatory disorders-on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. METHODS AND RESULTS: Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-alpha. The TNF-alpha rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-alpha inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice. CONCLUSION: Our results show that adalimumab prevents major inflammatory effects of TNF-alpha on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation. PMID- 27467818 TI - G6PD Deficiency Does Not Enhance Susceptibility for Acquiring Helicobacter pylori Infection in Sardinian Patients. AB - BACKGROUND: Subjects with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be more susceptible to infections due to impaired leukocyte bactericidal activity. The disorder is common in the Mediterranean area. The aim of this study was to investigate whether G6PD deficiency may be a risk factor for acquiring H. pylori infection. METHODS: We performed a retrospective study. Data from clinical records of 6565 patients (2278 men and 4287 women, median age 51, range 7-94) who underwent upper endoscopy between 2002 and 2014 were collected. H. pylori status, assessed by histology plus rapid urease test or 13C-urea breath test, and G6PD status were also reported. A multiple logistic regression model was used to investigate the association between G6PD deficiency and H. pylori infection. RESULTS: Enzyme deficiency was detected in 12% (789/6565) of the entire cohort, and more specifically in 8.3% of men and in 14.0% of women. Overall, the proportion of patients positive for H. pylori was 50.6% and 51.5% among G6PD deficient and non-deficient patients (chi2 = 0.271; p = 0.315). Moreover, among G6PD-deficient and normal patients the frequency of previous H. pylori infection was similar. After adjustment for age and gender the risk for acquiring H. pylori infection was similar in G6PD-deficient and normal patients. Only age was a strong statistically significant risk predictor. CONCLUSIONS: These results demonstrate for the first time that G6PD deficiency does not enhance patients' susceptibility to acquire H. pylori infection in Sardinia. PMID- 27467819 TI - Prevalence of Central Obesity among Adults with Normal BMI and Its Association with Metabolic Diseases in Northeast China. AB - OBJECTIVES: The present study aimed to investigate the prevalence of central obesity among adults with normal BMI and its association with metabolic diseases in Jilin Province, China. METHODS: A population-based cross-sectional study was conducted in 2012 in Jilin Province of China. Information was collected by face to face interview. Descriptive data analysis and 95% confidence intervals (CI) of prevalence/frequency were conducted. Log-binomial regression analyses were used to find the independent factors associated with central obesity and to explore the adjusted association between central obesity and metabolic diseases among adults with normal BMI. RESULTS: Among the adult residents with normal BMI in Jilin Province, 55.6% of participants with central obesity self-assessed as normal weight and 27.0% thought their body weight were above normal. 12.7% of central obesity people took methods to lose weight, while 85.3% didn't. Female, older people and non-manual worker had higher risk to be central obesity among adults with normal BMI. Hypertension, diabetes and hyperlipidemia were significantly associated with central obesity among adults with normal BMI, the PRs were 1.337 (1.224-1.461), 1.323 (1.193-1.456) and 1.261 (1.152-1.381) separately when adjusted for gender, age and BMI. CONCLUSIONS: Hypertension, diabetes and hyperlipidemia were significantly associated with central obesity among adults with normal BMI in Jilin Province, China. The low rates of awareness and control of central obesity among adults with normal BMI should be improved by government and health department. PMID- 27467820 TI - Update: Interim Guidance for Health Care Providers Caring for Pregnant Women with Possible Zika Virus Exposure - United States, July 2016. AB - CDC has updated its interim guidance for U.S. health care providers caring for pregnant women with possible Zika virus exposure, to include the emerging data indicating that Zika virus RNA can be detected for prolonged periods in some pregnant women. To increase the proportion of pregnant women with Zika virus infection who receive a definitive diagnosis, CDC recommends expanding real-time reverse transcription-polymerase chain reaction (rRT-PCR) testing. Possible exposures to Zika virus include travel to or residence in an area with active Zika virus transmission, or sex* with a partner who has traveled to or resides in an area with active Zika virus transmission without using condoms or other barrier methods to prevent infection.(?) Testing recommendations for pregnant women with possible Zika virus exposure who report clinical illness consistent with Zika virus disease(S) (symptomatic pregnant women) are the same, regardless of their level of exposure (i.e., women with ongoing risk for possible exposure, including residence in or frequent travel to an area with active Zika virus transmission, as well as women living in areas without Zika virus transmission who travel to an area with active Zika virus transmission, or have unprotected sex with a partner who traveled to or resides in an area with active Zika virus transmission). Symptomatic pregnant women who are evaluated <2 weeks after symptom onset should receive serum and urine Zika virus rRT-PCR testing. Symptomatic pregnant women who are evaluated 2-12 weeks after symptom onset should first receive a Zika virus immunoglobulin (IgM) antibody test; if the IgM antibody test result is positive or equivocal, serum and urine rRT-PCR testing should be performed. Testing recommendations for pregnant women with possible Zika virus exposure who do not report clinical illness consistent with Zika virus disease (asymptomatic pregnant women) differ based on the circumstances of possible exposure. For asymptomatic pregnant women who live in areas without active Zika virus transmission and who are evaluated <2 weeks after last possible exposure, rRT-PCR testing should be performed. If the rRT-PCR result is negative, a Zika virus IgM antibody test should be performed 2-12 weeks after the exposure. Asymptomatic pregnant women who do not live in an area with active Zika virus transmission, who are first evaluated 2-12 weeks after their last possible exposure should first receive a Zika virus IgM antibody test; if the IgM antibody test result is positive or equivocal, serum and urine rRT-PCR should be performed. Asymptomatic pregnant women with ongoing risk for exposure to Zika virus should receive Zika virus IgM antibody testing as part of routine obstetric care during the first and second trimesters; immediate rRT-PCR testing should be performed when IgM antibody test results are positive or equivocal. This guidance also provides updated recommendations for the clinical management of pregnant women with confirmed or possible Zika virus infection. These recommendations will be updated when additional data become available. PMID- 27467822 TI - Ingestion of an orthodontic archwire resulting in a perforated bowel: A case report. AB - Accidentally, ingesting components of an orthodontic appliance can result in serious consequences for the patient. This paper presents one such complication, not previously reported, where the patient needed emergency surgery to retrieve part of an orthodontic appliance. This case report highlights the consequences of and possible solutions to prevent patients inhaling or ingesting parts of their appliance. PMID- 27467821 TI - Tissue-Engineered Small Diameter Arterial Vascular Grafts from Cell-Free Nanofiber PCL/Chitosan Scaffolds in a Sheep Model. AB - Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient's own cells can engraft and form functional neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 +/- 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and neotissue formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive neotissue formation and stenosis. PMID- 27467823 TI - Does the uterus need to be removed to correct uterovaginal prolapse? AB - PURPOSE OF REVIEW: Owing to growing interest in uterine preservation, this evidence-based review compares hysteropexy with hysterectomy during surgery for uterovaginal prolapse. RECENT FINDINGS: LeFort colpocleisis is preferred over vaginal hysterectomy and total colpocleisis. The majority of studies show no differences in outcomes comparing sacrospinous hysteropexy with vaginal hysterectomy native tissue prolapse repair except for a single randomized controlled trial showing increased apical recurrences with advanced prolapse. Results comparing uterosacral hysteropexy and sacral hysteropexy with hysterectomy native tissue repairs are inconclusive. Potentially better outcomes are reported when laparoscopic hysterectomy (total or supracervical) is performed with sacral colpopexy compared with laparoscopic sacral hysteropexy, but mesh and morcellation risks should be considered. Data comparing vaginal mesh hysteropexy with currently available products with hysterectomy prolapse repairs are lacking but a high-quality study is underway. SUMMARY: High satisfaction and low reoperation rates can be accomplished using a variety of hysteropexy techniques. The advantages and disadvantages of uterine conservation must be considered when planning uterovaginal prolapse surgery. The type of hysteropexy and possible graft configuration may impact reoperation rates for recurrent prolapse. Vaginal mesh risks must be considered and laparoscopic mesh risks must be balanced with potential difficulty of future hysterectomy if needed. PMID- 27467824 TI - Prevalence of Primary HPV in Djibouti: Feasibility of Screening for Early Diagnosis of Squamous Intraepithelial Lesions. AB - OBJECTIVE: In many African Sub-Saharan countries, human papilloma virus (HPV) prevalence data are not available. The current study estimated the prevalence of HPV virus in the female population of Djibouti. METHODS: Approximately 1000 asymptomatic women 16 to 64 years old were enrolled from 3 of the main health structures of Djibouti in 2014 and 2015; 998 cervical samples were tested for HPV DNA of high risk types, 499 during the first year, and 499 during the second. Positive samples were typed with an HPV genotyping kit. RESULTS: The women were an average age of 38.8 years (SD, 10.2); 54 women tested positive for HPV (prevalence rate, 5.4% [95% confidence interval, 4.0-6.8]). The highest prevalence was observed among the women younger than 35 years. HPV66 was the most prevalent (15.4% of the infections), followed by HPV31 and HPV52 (10.8% both) and HPV16 (9.2%). All 54 women who tested HPV-positive underwent a Pap test, which was positive in 8 cases (14.8%): 2 high-grade squamous intraepithelial lesion (HSIL) and 6 low-grade (LSIL). CONCLUSIONS: The HPV prevalence shows a curve by age similar to that of other African countries. The proportion of HPV16 is among the lowest ever seen in similar studies. The findings suggest to Djibouti the choice of a strategy of screening that includes forms of cytological triage, thus limiting recourse to colposcopy. PMID- 27467825 TI - Amicrobial Pustulosis of the Folds and Autoimmunity. PMID- 27467826 TI - Outcome of Persistent Low-Grade Cervical Intraepithelial Neoplasia Treated With Loop Electrosurgical Excision Procedure. AB - OBJECTIVE: The aim of the study was to evaluate the outcome of persistent (>=2 years) low-grade cervical intraepithelial neoplasia (CIN 1) treated with loop electrosurgical excision procedure (LEEP). MATERIALS AND METHODS: A study of 252 subjects with persistent biopsy-confirmed CIN 1 diagnosed after low-grade squamous intraepithelial lesions or atypical squamous lesions of undetermined significance on Papanicolaou test and treated with LEEP. Post-LEEP follow-up cytological, colposcopic, and molecular diagnostic examinations were scheduled at 6 months, 1 year, and yearly thereafter. RESULTS: The 252 subjects enrolled had a total number of 1,008 visits per colposcopies (median = 3, range = 1-7) during a median post-LEEP follow-up of 25 months (range = 12-121). The cumulative incidence of CIN 2+ at 2 years and at 3 years of follow-up was 2.3% (4/176) and 5.5% (7/128), respectively, or 1.7 cases (95% CI = 1-2.8) per 100 woman-years. Low-grade cervical lesions during post-LEEP follow-up were diagnosed in 70 subjects (27.8%) or 10 cases (95% CI = 7.9-12.6) per 100 woman-years. Overall, persistent and multiple high-risk HPV infections during follow-up were associated with increased rates of CIN persistence or progression. CONCLUSIONS: Women with persistent CIN 1 after atypical squamous lesions of undetermined significance/low grade squamous intraepithelial lesion treated with LEEP had a low rate of progression to CIN 2+ but remained at a high risk of low-grade cervical abnormalities during follow-up. This information should be taken into account when deciding on the treatment strategy and counseling women with persistent CIN 1. PMID- 27467827 TI - Henoch-Schonlein Purpura During Treatment with Fluoxetine. PMID- 27467828 TI - Frailty is Highly Prevalent and Associated with Vitamin D Deficiency in Male Nursing Home Residents. PMID- 27467829 TI - High-Resolution Diffusion Tensor Spinal Cord MRI Measures as Biomarkers of Disability Progression in a Rodent Model of Progressive Multiple Sclerosis. AB - Disease in the spinal cord is a major component of disability in multiple sclerosis, yet current techniques of imaging spinal cord injury are insensitive and nonspecific. This study seeks to remove this major impediment to research in multiple sclerosis and other spinal cord diseases by identifying reliable biomarkers of disability progression using diffusion tensor imaging (DTI), a magnetic resonance imaging technique, to evaluate the spinal cord in a model of multiple sclerosis, i.e. the Theiler's Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD). Mice with TMEV-IDD with varying levels of clinical disease were imaged using a 9.4T small animal MRI scanner. Axial diffusivity, radial diffusivity, and fractional anisotropy were calculated. Disability was assessed periodically using Rotarod assay and data were expressed as a neurological function index. Correlation was performed between DTI measurements and disability scores. TMEV-IDD mice displayed significant increased neurological deficits over time when compared with controls (p<0.0001). Concurrently, the values of fractional anisotropy and axial diffusivity were both decreased compared to controls (both p<0.0001), while radial diffusivity was increased (p<0.0001). Overall, fractional anisotropy changes were larger in white matter than in grey matter and differences were more pronounced in the ventral region. Lower disability scores were associated with decreased fractional anisotropy values measured in the ventral (r = 0.68; p<0.0001) and ventral lateral (r = 0.70; p<0.0001) regions of the white matter. These data demonstrate that DTI measures of the spinal cord contribute to strengthening the association between neuroradiological markers and clinical disability, and support the use of DTI measures in spinal cord imaging in MS patients. PMID- 27467830 TI - An abbreviated Faecal Incontinence Quality of Life Scale for Chinese-speaking population with colorectal cancer after surgery: cultural adaptation and item reduction. AB - No instrument is available to assess the impact of faecal incontinence (FI) of quality of life for Chinese-speaking population. The purpose of the study was to adapt the Faecal Incontinence Quality of Life Scale (FIQL) for patients with colorectal cancer, assess the factor structure and reduce the items for brevity. A sample of 120 participants were enrolled. Internal consistency, test-retest reliability, and convergent and contrasted-groups validity were assessed. Construct validity was analysed using an exploratory and confirmatory factor analyses (CFA). The internal consistency (Cronbach's alpha of the total scale and four subscales = 0.98 and 0.97, 0.96, 0.92, 0.82 respectively), test-retest reliability (intraclass correlation coefficients >=.98 for all scales with p < .001) and significant correlations of all scales with selected subscales of the Medical Outcomes Study 36-Item Short-Form Health Survey and the Wexner scale suggested satisfactory reliability and validity. The severe FI group (with a Wexner score >=9) scored significantly lower on the scale than the less severe FI group (with a Wexner score <9) did (p < .001). The CFA supported a two-factor structure and demonstrated an excellent model fit of the 15-item abbreviated version of the FIQL-Chinese. The FIQL-Chinese has satisfactory validity and reliability and the abbreviated version may be more practical and applicable. PMID- 27467843 TI - Granulocyte-monocyte and Granulocyte-Colony Stimulating Factors in Myelodysplastic Syndromes. AB - Myelodysplastic syndromes (MDS) are a heterogenous group of clonal disorders of hemopoiesis entailing hypoproliferative and ineffective hematopoiesis. The biology of MDS may relate to uncoupling of hemopoietic cellular differentiative and proliferative programs. The MDS provide a clinical setting for evaluating the evolution of relative benign hematologic disorders into frankly malignant diseases similar to acute myelogenous leukemia (AML). In vitro marrow hemopoietic cultures were utilized to evaluate the effect of granulocyte-monocyte colony stimulating factor (GM-CSF) and granulocyte-colony stimulating factors (G-CSF) on proliferating differentiative and regenerative responsiveness of marrow cells from MDS patients. We determined possible differing effects of G-CSF and GM-CSF in morphological and cytogenetical subgroups of MDS patients. G-CSF was able to induce granulocytic differentiation of enriched hemopoietic precursors from MDS patients, generally without increased clonal self-generation. G-CSF has greater granulocytic differentiative and less proliferative activity for MDS marrow cells than GM-CSF in vitro, particularly for patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T) and those with normal cytogenetics. These findings provided a biologic rationale for in vivo clinical trials using G-CSF in MDS patients. Prospective investigations will be necessary to determine the possible utility of such in vitro studies for designing future in vivo clinical trials with these colony stimulating factors. PMID- 27467844 TI - Interleukin-7 and its Effects on Leukemia and Lymphoma Cells. PMID- 27467845 TI - Percutaneous Fine Needle Aspiration Cytology and Biopsy in the Diagnosis and Classification of Lymphoma: Clinical Evaluation. AB - In some patients with suspected de novo or recurrent lymphoma, the absence of a palpable mass or peripheral lymph node enlargement can be a diagnostic challenge. We report our experience of fine needle aspiration (FNA) and biopsy in the management of 47 consecutive patients investigated in our institution over a period of 4 years. Lymphoma was suspected in 32 cases, and recurrent disease in 15 cases. Cytology was performed in all patients and biopsy in 16 patients, when a safe approach was possible. The specimens were obtained with computed tomography guidance and were diagnostic by cytology in 85% of cases: 28 patients had a newly diagnosed lymphoma and 3 had recurrent disease; residual fibrosis was diagnosed in 2 cases. Five patients with a previously diagnosed lymphoma had a new neoplasm: lung carcinoma: 3, renal adenocarcinoma: 1, metastatic lymph nodes: 1. One patient had non-neoplastic intercurrent disease (pulmonary nocardiosis). In 7 patients, no conclusive tissue was obtained (acellular: 1, blood: 3, necrosis: 3). In one case of suspected recurrent disease, a false-positive result was obtained. Cytology always allowed distinction between non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD), with attempts to subclassify NHL according to the International Working Formulation. In 12 patients, immunochemical studies could be performed for immunologic subclassification of lymphoma on the basis of cytology (n = 6) and biopsy (n = 6). Our results show that percutaneous fine needle aspiration cytology is a reliable method for the diagnosis and classification of lymphoma, and immunologic studies can be performed on cytology alone if biopsy is unsafe. PMID- 27467846 TI - Autologous Bone Marrow Transplantation Followed by Involved Field Radiotherapy in Patients with Relapsed or Refractory Hodgkin's Disease. AB - Twenty-six patients with refractory or relapsed Hodgkin's disease were treated with high dose cyclophosphamide, BCNU, etoposide, and thiotepa followed by autologous hematopoietic stem cell rescue. Involved field radiotherapy was given following hematologic recovery in selected patients. The overall response rate to the high dose chemotherapy was 69% with 34% complete responses. Following radiotherapy, the complete response rate increased to 50%. The predicted disease free survival at two years is 22%. Toxicity with this regimen was significant, with five patients dying as a result of transplant related complications. We conclude that the addition of thiotepa to the standard CBV regimen did not result in improved therapeutic efficacy and possibly contributed significantly to the toxicity of the treatment. PMID- 27467847 TI - Late Relapse in Hodgkin's Disease: Report of Five Cases and a Review of the Literature. AB - During the past 15 years the treatment of Hodgkin's disease (HD) with chemo/radiotherapy has been shown to appreciably improve the long-term prognosis of patients, even those with more advanced disease. In the past it was accepted that the probability of primary relapse 5 years after achieving complete remission (CR) was small and a 5-year disease-free period was sufficient to be considered as a cure. During the past 15 years, however, more data has been published relating to late relapses in these patients after an initial "cure" has been achieved. This report briefly examines our own experience with five patients initially "cured" who relapsed 5 to 11 years after achieving CR and also reviews recent literature on the subject. The phenomenon of late relapse has thus become a more important issue in the management of patients with HD. PMID- 27467848 TI - Monoclonal and/or Oligoclonal Immunoglobulins in Sera of Patients with Non Hodgkin's Lymphomas, Determined by Iso-Electric Focusing and Immunoblotting. AB - Sera from 60 patients with non-Hodgkin's lymphomas (NHL) were tested by isoelectric focusing (IEF) and immunoblotting (IB) techniques for the presence of monoclonal or oligoclonal immunoglobulins (Ig). Of the 60 NHL patients, 18 were newly diagnosed and had not received any treatment while the rest had received some chemotherapy in the past. Two serum samples were obtained from 27 patients over the treatment period. Oligoclonal Ig patterns were detected in 34 of the 60 (56.6%) sera, and were further identified by IB as IgG of mixed kappa (K) and lambda (lambda) types. Seven of the 18 (38.8%) newly diagnosed NHL patients had these oligoclonal bands, compared with 27 of the 42 (69%) who had received chemotherapy in the past. In 11 of these 27 (40.7%) patients, follow-up studies revealed the appearance of new Ig bands (9 cases) with the disappearance of preexisting ones (2 cases). After treatment of sera with 2-mercaptoethanol, monoclonal IgM was detected in 39 of the 60 (65%) NHL patients. These monoclonal Ig spikes occurred together with oligoclonal IgG (20/60 cases) or appeared in the absence of oligoclonal IgG (19/60 cases), while oligoclonal IgG could also appear as the sole serum finding (14/60 cases). There was a higher prevalence of monoclonal IgM among patients with stage IV disease and of oligoclonal IgG among patients with high grade of malignancy NHL. Our results demonstrate that among patients with NHL there is a high prevalence of monoclonal or oligoclonal Ig bands detected by highly sensitive methods such as IEF and IB. PMID- 27467849 TI - Augmentation of the Susceptibility of Human Leukemia to Lymphokine-Activated Killer (LAK) Cells by Exposure of the Leukemic Target Cells to Cytotoxic Drugs in Vitro and in Vivo. AB - Experimental studies have shown that interleukin-2-induced lymphokine-activated killer (LAK) cells are able to lyse fresh noncultured leukemia cells and that human leukemia cells have a distinct susceptibility to LAK-cell-mediated cytolysis. Cytolysis is considerably lower with fresh noncultured leukemia cells than with the leukemia cell lines K562 and Daudi. For therapeutic considerations it would be desirable to achieve as much cytolysis as possible. The current study revealed that incubating leukemia cells with cytotoxic drugs in vitro significantly augments their susceptibility to the lytic effect of LAK cells and, more importantly that exposing leukemia cells to anticancer agents in vivo during induction chemotherapy also increases their sensitivity to LAK-cell-mediated cytolysis. These results support a possible benefit from combining chemotherapy with immunotherapeutic approaches in leukemia treatment. PMID- 27467850 TI - Nuclear Topoisomerase II Activity Changes During HL-60 Leukemic Cell Differentiation: Alterations in Drug Sensitivity and pH Dependency. AB - We have studied the effect of dimethyl-sulfoxide(DMSO)-induced granulocytic differentiation on the sensitivity of HL-60 cells to various cytotoxic topoisomerase II inhibitors: (i) undifferentiated HL-60 cells are highly sensitive to etoposide, while differentiated HL-60 cells are 700-1000 fold resistant to etoposide, (ii) undifferentiated HL-60 are 50-100 fold resistant against 4-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA) when compared to the differentiated HL-60 cells, (iii) the addition of mAMSA to the medium inhibits granulocytic differentiation of HL-60 cells. This change in resistance pattern is probably due to an alteration of topoisomerases since distinctive iso activites of topoisomerase can be discriminated on the basis of the pH profile, which alters markedly during differentiation. In an etoposide-resistant HL-60 cell line we found a reduced topoisomerase activity at pH 7.8/7.9. This topoisomerase iso-activity is obviously involved in etoposide cytotoxicity. PMID- 27467851 TI - Translocation (14;19)(q32;q13.1) in a Young Patient who Developed a Large Cell Lymphoma after an Initial Diagnosis of CLL. AB - A translocation (14;19)(q32;q13.1) was found in a 31 year old man with a large cell lymphoma which had evolved from chronic lymphocytic leukaemia (CLL). Molecular analysis showed a monoclonal proliferation of B cells with rearrangement of the immunoglobulin (Ig) heavy and kappa light chain genes, and of the bcl-3 gene on chromosome 19q. Nine cases with t(14;19) from the literature were reviewed; B cell lymphoma had been diagnosed in eight and acute biphenotypic leukaemia in one of these cases. Four had transformed from CLL to a more aggressive disease, as in the present case. Two out of seven patients as well as the present one, with t(14;19) and CLL were young (less than 40). The t(14;19) is usually associated with other cytogenetic abnormalities; in our case a (15;16)(q15;p13) translocation was found and appears to be an additional nonrandom aberration in t(14;19) disorders. PMID- 27467852 TI - Chronic Myelogenous Leukemia Associated with Extranodal B-Cell Lymphoma. AB - A 75-year-old man is reported with a 10 year-history of villous adenoma of the colon and carcinoma in situ treated by hemicolectomy. Seven years later, he developed chronic myelogenous leukemia (CML). After a 3-month course of busulfan he was kept off chemotherapy for a one year period. Two years after the diagnosis of CML, an extranodal B-cell lymphoma developed in the left ankle region. A clonal pericentric inversion of chromosome 20 was shown in the lymphoma cells, but without Philadelphia (Ph') chromosome. The possible relation between the two malignant disorders is discussed in the light of current knowledge on the clonal origin of CML. PMID- 27467853 TI - Effect of dietary acids on the formation of aflatoxin B2a as a means to detoxify aflatoxin B1. AB - Aflatoxin B1 (AFB1) is a class 1 carcinogen and a common food contaminant worldwide with widely uncontrolled human exposure. The ability of organic acids to transform AFB1 into a known detoxified form, aflatoxin B2a (AFB2a), was investigated using high performance liquid chromatography-electrospray ionisation time of flight mass spectrometry (HPLC/ESI/TOF/MS). The identity of the transformation product was confirmed by accurate mass measurement, chromatographic separation from other aflatoxins, H(1)-nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. Of the weak acids tested, citric acid was found to be the most effective for AFB2a formation. At room temperature, 1 M citric acid was able to convert > 97% of AFB1 to AFB2a over 96 h of treatment. Up to 98% transformation was achieved by boiling AFB1 in the presence of citric acid for 20 min. AFB1 hydration after ingestion was explored by spiking AFB1 into simulated gastric fluid containing citric acid. Under these conditions, > 71% of AFB1 was hydrated to AFB2a and did not show any reversion to the parent compound after being transferred to a neutral solution. These results provide a basis for a practical and effective method for detoxification of AFB1 in contaminated foods. PMID- 27467854 TI - Tuning Surface Properties of Poly(methyl methacrylate) Film Using Poly(perfluoromethyl methacrylate)s with Short Perfluorinated Side Chains. AB - To control the surface properties of a commonly used polymer, poly(methyl methacrylate) (PMMA), poly(perfluoromethyl methacrylate)s (PFMMAs) with short perfluorinated side groups (i.e., -CF3, -CF2CF3, -(CF3)2, -CF2CF2CF3) were used as blend components because of their good solubility in organic solvents, low surface energies, and high optical transmittance. The surface energies of the blend films of PFMMA with the -CF3 group and PMMA increased continuously with increasing PMMA contents from 17.6 to 26.0 mN/m, whereas those of the other polymer blend films remained at very low levels (10.2-12.6 mN/m), similar to those of pure PFMMAs, even when the blends contained 90 wt %PMMA. Surface morphology and composition measurements revealed that this result originated from the different blend structures, such as lateral and vertical phase separations. We expect that these PFMMAs will be useful in widening the applicable window of PMMA. PMID- 27467855 TI - Transglycosylation, a new role for multifunctional cellulase in overcoming product inhibition during the cellulose hydrolysis. AB - Cellulase mainly consisting of exo-glucanase, endo-glucanase and beta glucosidase, was considered as the most important biocatalyst for bioconversion of ethanol and other biofuels, feedstuffs and pharmaceuticals. Hydrolysis product inhibition, especially of glucose inhibition, is one of the critical difficulty awaiting to be overcome during cellulose bioconversion. Recently, several studies showed that some multifunctional cellulases (e.g., Umcel9y-1, Td2F2 and CoGH1A) could eliminate or relieve the product inhibition through transglycosylation actions during the cellulose hydrolysis. Transglycosylation confers multifunctional cellulases insensitive character to the end products (glucose and/or cellobiose), and provides a potential access in overcoming the inhibition of biofuels conversion. Moreover, transglycosylation harboring cellulases are also attracted as substitute of glycosyltransferase in synthesis of functional foods, nutraceuticals, or pharmaceuticals. Here, several interested transglycosylation harboring cellulases were summarized and assessed for the potential values in bioengineering application. PMID- 27467856 TI - Laparoscopy in the Surgical Treatment of Disorders of Sexual Development. AB - INTRODUCTION: Disorder of sexual development (DSD) is a rare condition. The surgical treatment of these patients includes investigation of the internal genitalia, evaluation of the gonads, and if necessary gonadectomy. The prevention of germ cell tumors is the most important issue in the surgical treatment of this varied and special group of patients. This study aimed to evaluate the role of laparoscopy in the surgical treatment of patients with DSD. MATERIALS AND METHODS: Over a 4-year-period, all patients presenting with DSD who underwent laparoscopic surgery at our institution were retrospectively reviewed. Operative procedure, age at the time of surgery, and histopathological results were evaluated. In addition, karyotypes and phenotypes were investigated. RESULTS: Altogether, 12 patients undergoing 14 laparoscopic procedures were included. Median age at the time of surgery was 6 years with a range from 9 months to 17 years. Explorative laparoscopy was performed in all patients. In seven children, laparoscopic gonadectomy was necessary. Histopathologic examination revealed germ cell tumors in four children. In two patients, a gonadoblastoma was identified; in two patients, a dysgerminoma was found. Inguinal exploration was performed in four patients and led to removal of gonadal remnants in one case and gonadopexy in three cases. In two patients presenting with repeated urinary tract infections, laparoscopic removal of an utriculus was performed. CONCLUSIONS: Laparoscopic gonadal biopsy, gonadopexy, and gonadectomy can be performed successfully, even in patients with germ cell tumors. To define guidelines for the surgical treatment of patients with DSD, further prospective and multicenter studies are necessary. PMID- 27467857 TI - Dynamics of Protonated Peptide Ion Collisions with Organic Surfaces: Consonance of Simulation and Experiment. AB - In this Perspective, mass spectrometry experiments and chemical dynamics simulations are described that have explored the atomistic dynamics of protonated peptide ions, peptide-H(+), colliding with organic surfaces. These studies have investigated the energy transfer and fragmentation dynamics for peptide-H(+) surface-induced dissociation (SID), peptide-H(+) physisorption on the surface, soft landing (SL), and peptide-H(+) reaction with the surface, reactive landing (RL). SID provides primary structures of biological ions and information regarding their fragmentation pathways and energetics. Two SID mechanisms are found for peptide-H(+) fragmentation. A traditional mechanism in which peptide H(+) is vibrationally excited by its collision with the surface, rebounds off the surface and then dissociates in accord with the statistical, RRKM unimolecular rate theory. The other, shattering, is a nonstatistical mechanism in which peptide-H(+) fragments as it collides with the surface, dissociating via many pathways and forming many product ions. Shattering is important for collisions with diamond and perfluorinated self-assembled monolayer (F-SAM) surfaces, increasing in importance with the peptide-H(+) collision energy. Chemical dynamics simulations also provide important mechanistic insights on SL and RL of biological ions on surfaces. The simulations indicate that SL occurs via multiple mechanisms consisting of sequences of peptide-H(+) physisorption on and penetration in the surface. SL and RL have a broad range of important applications including preparation of protein or peptide microarrays, development of biocompatible substrates and biosensors, and preparation of novel synthetic materials, including nanomaterials. An important RL mechanism is intact deposition of peptide-H(+) on the surface. PMID- 27467858 TI - Effects of Different Variants in the ENPP1 Gene on the Functional Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family Member 1. AB - Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (E-NPP1), encoded by ENPP1, is a plasma membrane protein that generates inorganic pyrophosphate (PPi ), a physiologic inhibitor of hydroxyapatite formation. In humans, variants in ENPP1 are associated with generalized arterial calcification of infancy, an autosomal-recessive condition causing premature onset of arterial calcification and intimal proliferation resulting in stenoses. ENPP1 variants also cause pseudoxanthoma elasticum characterized by ectopic calcification of soft connective tissues. To determine the functional impact of ENPP1 missense variants, we analyzed 13 putative pathogenic variants in vitro regarding their functional properties, that is, activity, localization, and PPi generation. Transfection of eight of the 13 variants led to complete loss of NPP activity, whereas four mutants (c.1412A > G, p.Tyr471Cys; c.1510A > C, p.Ser504Arg; c.1976A > G, p.Tyr659Cys; c.2330A > G, p.His777Arg) showed residual activity compared with wild-type E-NPP1. One putative pathologic variant (c.2462 G > A, p.Arg821His) showed normal activity. The five mutants with normal or residual E NPP1 enzyme activity were still able to generate PPi and localized in the plasma membrane. In this study, we identified a functional ENPP1 polymorphism, which was expected to be pathogenic till now. Furthermore, we identified four mutants (p.Tyr471Cys, p.Ser504Arg, p.Tyr659Cys, p.His777Arg) with residual E-NPP1 function, which would be potential therapeutical targets for conformational stabilizing agents. PMID- 27467859 TI - An alpha-Helix-Mimicking 12,13-Helix: Designed alpha/beta/gamma-Foldamers as Selective Inhibitors of Protein-Protein Interactions. AB - A major current challenge in bioorganic chemistry is the identification of effective mimics of protein secondary structures that act as inhibitors of protein-protein interactions (PPIs). In this work, trans-2 aminocyclobutanecarboxylic acid (tACBC) was used as the key beta-amino acid component in the design of alpha/beta/gamma-peptides to structurally mimic a native alpha-helix. Suitably functionalized alpha/beta/gamma-peptides assume an alpha-helix-mimicking 12,13-helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild-type alpha-peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction. PMID- 27467860 TI - Granular Activated Carbon Treatment May Result in Higher Predicted Genotoxicity in the Presence of Bromide. AB - Certain unregulated disinfection byproducts (DBPs) are more of a health concern than regulated DBPs. Brominated species are typically more cytotoxic and genotoxic than their chlorinated analogs. The impact of granular activated carbon (GAC) on controlling the formation of regulated and selected unregulated DBPs following chlorine disinfection was evaluated. The predicted cyto- and genotoxicity of DBPs was calculated using published potencies based on the comet assay for Chinese hamster ovary cells (assesses the level of DNA strand breaks). Additionally, genotoxicity was measured using the SOS-Chromotest (detects DNA damaging agents). The class sum concentrations of trihalomethanes, haloacetic acids, and unregulated DBPs, and the SOS genotoxicity followed the breakthrough of dissolved organic carbon (DOC), however the formation of brominated species did not. The bromide/DOC ratio was higher than the influent through much of the breakthrough curve (GAC does not remove bromide), which resulted in elevated brominated DBP concentrations in the effluent. Based on the potency of the haloacetonitriles and halonitromethanes, these nitrogen-containing DBPs were the driving agents of the predicted genotoxicity. GAC treatment of drinking or reclaimed waters with appreciable levels of bromide and dissolved organic nitrogen may not control the formation of unregulated DBPs with higher genotoxicity potencies. PMID- 27467861 TI - Imaging of osteonecrosis of the femoral head. AB - Osteonecrosis of the femoral head is a common disease affecting both children and adults causing acute hip pain and functional impairment. Among the various techniques allowing a correct diagnosis, MRI represents the gold standard for an early detection, the latter being useful for a positive outcome. The purpose of this review is to describe the imaging findings of the osteonecrosis of the femoral head. PMID- 27467862 TI - MRI in acute ligamentous injuries of the ankle. AB - Ankle sprains are the most common lower limb injuries and affect more frequently young athletes; imaging is needed for an accurate diagnosis of such traumatic injuries. The purpose of this review is to analyse the magnetic resonance (MR) findings of both normal and pathological ankle's ligaments; indeed, MRI is the gold standard for the diagnosis of acute traumatic injuries and is useful for differentiation of the causes of ankle instability as well as for pre-operative planning. PMID- 27467863 TI - Use of DWI in identification of small solid pancreatic focalities (<= 2 cm). AB - Incidental finding of pancreatic focalities has increased thanks to a larger use of radiological examinations (Ultrasound, CT). The differential diagnosis between focal inflammatory and heteroplastic disease is frequently complicated by the wide spectrum of lesions and by the aspecificity of clinical and medical history, as well as of imaging findings. MRI is the second level choice of examination thanks to its higher intrinsic contrast resolution and parametric capability (1); furthermore, the use of Diffusion Weighted Imaging (DWI) sequences provides additional diagnostic informations. PMID- 27467864 TI - MRI findings of intraductal papillary mucinous neoplasms (IPMNs). AB - Cystic lesions of the pancreas are relatively frequent imaging findings due to the improvement of imaging technologies. They may be secondary to both benign and malignant disease processes and their prevalence increases with age. In most cases, these lesions are detected incidentally by computed tomography and magnetic resonance imaging (MRI) performed for other reasons. Intraductal papillary mucinous neoplasms (IPMNs) represent 25% of the cystic neoplasms, morphologically classified into "main pancreatic duct IPMN" (MPD-IPMN), "side branches IPMN" (SB-IPMN) and mixed forms. Magnetic Resonance Cholangiopancreatography (MRCP) is a multiparametricity not invasive radiological technique that doesn't use ionizing radiation or organ iodinized contrast agents; it allows an accurate characterization of the lesions (number and size of cystic lesions, internal features of a cyst, ducts dilation, communication with main pancreatic duct) that is important to guide the differential diagnosis and establish a correct follow-up. International guidelines consider IPMN of MPD and mixed forms to be an indication for surgery, while clinical and radiological follow-up is indicated in asymptomatic patients with SB-IPMN, especially when lesions are < 2,5-3 cm in diameter and there are no mural nodules or dilation of MPD. PMID- 27467865 TI - Defecography: a still needful exam for evaluation of pelvic floor diseases. AB - The aim of this discussion is to describe what is a defecography, how we have to perform it, what can we see and to present the main physio-pathological illnesses of pelvic floor and anorectal region that can be studied with this method and its advantages over other screening techniques. Defecography is a contrastographic radiological examination that highlights structural and functional pelvic floor diseases. Upon preliminary ileum-colic opacification giving to patient radiopaque contrast, are first acquired static images (at rest, in maximum voluntary contraction of the pelvic muscles, while straining) and secondarily dynamic sequences (during evacuation), allowing a complete evaluation of the functionality of the anorectal region and the pelvic floor. Defecography is an easy procedure to perform widely available, and economic, carried out in conditions where the patient experiences symptoms, the most realistic possible. It can be still considered reliable technology and first choice in many patients in whom the clinic alone is not sufficient and it is not possible or necessary to perform a study with MRI. PMID- 27467866 TI - Gallstone ileus: literature review. AB - Gallstone ileus is a rare case of mechanical intestinal obstruction observed in patients with history of cholelithiasis or cholecystitis. Its diagnosis is difficult and it is characterized by high mortality rate. Diagnostic Imaging plays an important role in the management of patients with suspected gallstone ileus because an early diagnosis could reduce the mortality. Abdominal Computed Tomography (CT) is the preferred modality because of its rapid diagnosis. Surgery remains the gold standard treatment. PMID- 27467867 TI - Imaging of congenital pulmonary malformations. AB - Congenital pulmonary malformations represent a broad spectrum of anomalies that may result in varied clinical and pathologic pictures, ranging from recurrent pulmonary infections and acute respiratory distress syndrome, which require timely drug therapy, up to large space-occupying lesions needing surgical treatment. This classification includes three distinct anatomical and pathological entities, represented by Congenital Cystic Adenomatoid Malformation, Bronchopulmonary Sequestration and Congenital Lobar Emphysema. The final result in terms of embryological and fetal development of these alterations is a Congenital Lung Hypoplasia. Since even Bronchial Atresia, Pulmonary Bronchogenic Cysts and Congenital Diaphragmatic Hernias are due to Pulmonary Hypoplasia, these diseases will be discussed in this review (1, 2). PMID- 27467868 TI - CT arthrography for evaluation of autologous chondrocyte and chondral-inductor scaffold implantation in the osteochondral lesions of the talus. AB - PURPOSE: to analyse the findings of CT arthrography of the ankle, one year after the transplant of autologous chondrocytes in solution (ACI technique) and the covering with the only scaffold implantation of the osteochondral lesions of the talus, in comparison with the clinical evaluation of the ankle. METHODS: This retrospective study includes 10 patients (6 male, 4 female, mean age 49.4, range 25-74 years) with an osteochondral lesion of the medial side of the talus, 4 pure chondrals, 6 osteochondrals, painful and limiting the articulation, who underwent ACI using autologous chondrocyte (5 cases) and a covering with the only scaffold implantation (5 cases), in patients who underwent multi-detector CT arthrography between April 2006 and December 2013, at least 12 months after the surgery. RESULTS: Grade 0 was presented in 5 cases (50%), grade 1 in 2 cases (20%), grade 3 in 2 cases (20%) and grade 4 in 1 case (10%). Among the 5 cases even to 0 according to ICRS classification, the patient presented no symptoms in 4 out of 5 cases (80%); in 1 case, the patient presented post-operation pain of moderate entity due to the onset of adhesive capsulitis (20%). The 2 grade 1 patients, according to the ICRS classification, did not report any post-operation pain (0%). The 2 grade 3 patients, according to the ICRS classification, reported a light pain in 1 case (50%). The grade 4 patient, according to the ICRS classification, reported moderate pain (100%). CONCLUSIONS: The CT arthrography, for the elevate spatial and contrast resolution, is a very accurate exam in detecting irregularities in the chondral-inductor scaffold implantation, and in correlating the clinical presentation. PMID- 27467869 TI - CT-guided fine-needle aspiration of abdominal and retroperitoneal small lesions with the coaxial technique using MPR images. AB - PURPOSE: To demonstrate the advantages of CT-guided fine-needle aspiration (FNA) of abdominal and retroperitoneal small lesions with the coaxial technique using MPR images. MATERIALS AND METHODS: The study included retrospectively 50 patients who underwent CT-guided FNA of abdominal and/or retroperitoneal small lesion (<30 mm). Patients with suspected lymphomas or sarcomas were excluded. Cytology reports were the reference standard. RESULTS: The cytology was diagnostic in 48/50 biopsies (96%): out of 41 neoplastic lesions (85%), 37 were malignant (90.2%) and 4 were benign (9.8%); 7 out of 48 were non-neoplastic (14.6%). No procedural complications were observed (0%). CONCLUSION: By using MPR images there is an effective improvement in coaxial CT-guided FNA of abdominal and retroperitoneal small lesions. PMID- 27467870 TI - Gynecomastia: a common indication for mammography in men of all age. AB - BACKGROUND AND AIM: Gynecomastia (GM) is the most frequent cause of male breast related signs and symptoms and represents also the most common indication for mammography (MX) in men. In this article, our 7-year long experience with MX in men suffering from GM is reviewed, and the mammographic features of GM are presented. METHODS: MXs performed in male patients at our institution from January 2009 to January 2016 were retrospectively reviewed and patients with mammographic features of GM were selected. Informed consent was waived by the local institutional review board given the retrospective nature of the study. Mammograms were performed in both cranio-caudal (CC) and medio-lateral-oblique (MLO) views according to diagnostic needs. Clinical and pathologic data were obtained by review of patient charts. RESULTS: 37 males (aged between 13-79 years, mean 59 years) referred for MX at our institution because of palpable lump (31/37; 83.8%), breast enlargement (33/37; 89.2%), tenderness or pain (25/37; 67.6%). Of the 37 patients evaluated, 32 (86.5%) had true GM while 5 (13.5%) had pseudoGM. CONCLUSIONS: The evaluation of GM can be complex but a stepwise approach that starts with careful history taking and physical examination may obviate the need for extensive work-up. In this context, MX has been shown to be an accurate diagnostic tool for detecting GM and should be the first imaging examination to be performed in all clinically suspicious lesions referred for imaging. PMID- 27467871 TI - Texture analysis in a rare case of tibial intraosseous lipoma. AB - Intraosseous lipoma is a very rare lesion, accounting for only 0.1% of all primary osseous tumors (1), first described in 1980 (2). This lesion is considered the rarest of benign bone tumors (3); probably it is not the actual incidence because these lesions are frequently asymptomatic and the introduction of cross-sectional imaging, especially MRI, seems to have increased the detection (4). The majority of intraosseus lipomas are in the lower limbs (70%) and the os calcis being the most frequently involved (32%). Most cases reported in literature have an age of 40 years (5). Tumor texture could be measured from medical images that provide a non-invasive method of capturing intratumoral heterogeneity and could potentially enable a prior assessment of a patient. Some Authors recently proposed Texture analysis to characterize musculoskeletal lesions (6). For the first time we measured the tumoral texture from Magnetic Resonance images in tibial intraosseous lipoma in a 29-years-old female. PMID- 27467872 TI - Introduction. AB - This special issue covers important and controversial topics in radiology. Each topic addressed presents important viewpoints from leading radiologists. High quality reproductions of radiographs, CT scans, MR images, and sonograms clearly depict what is being described in each article. This articles offer an outstanding, time-saving investigation into some current topics most relevant to radiologists. PMID- 27467873 TI - Molecular Informatics - The First Year. PMID- 27467874 TI - Flat and Easy: 2D Depiction of Protein-Ligand Complexes. AB - Visualization of molecular complexes is commonly used to support the investigation of interaction patterns formed between the members of a molecular complex ensemble. Similar to the representation of single small molecules as structure diagrams, a schematic two-dimensional design of molecular complexes features several advantages. This visualization mode enables the peer to scan large numbers of complexes in short time, originating for example from a virtual screening or de novo design campaign, and to get an impression of their quality. In addition, the diagrams can be printed on hardcopies without information loss and are therefore well suited for publications and talks. We will give an overview of the existing algorithms for the automatic generation of two dimensional complex diagrams. The reduction of dimensions from three to two is a quite difficult task since the resulting layout has to be more or less free of overlaps and has to follow esthetical guidelines. All programs proceed on input being composed of the three-dimensional ligand and receptor coordinates. Due to the lack of guiding principles, the algorithms and resulting diagrams of the different available tools substantially differ in graphical styles, level of detail, and information content. PMID- 27467875 TI - Chemoinformatics as a Theoretical Chemistry Discipline. AB - Here, chemoinformatics is considered as a theoretical chemistry discipline complementary to quantum chemistry and force-field molecular modeling. These three fields are compared with respect to molecular representation, inference mechanisms, basic concepts and application areas. A chemical space, a fundamental concept of chemoinformatics, is considered with respect to complex relations between chemical objects (graphs or descriptor vectors). Statistical Learning Theory, one of the main mathematical approaches in structure-property modeling, is briefly reviewed. Links between chemoinformatics and its "sister" fields - machine learning, chemometrics and bioinformatics are discussed. PMID- 27467876 TI - Classification of Aurora-A Kinase Inhibitors Using Self-Organizing Map (SOM) and Support Vector Machine (SVM). AB - Two classification models of 148 Aurora-A kinase inhibitors were developed to separate active and weakly potent active inhibitors of Aurora-A kinase. Each molecule was represented by 12 selected molecular descriptors calculated by the ADRIANA.Code. Then the classification models were built using a Kohonen's Self Organizing Map (SOM) and a Support Vector Machine (SVM) method, respectively, which could be used for virtual screening an existing database to find possible new lead compounds with higher activity. The prediction accuracy of the models for the training and test sets are 96.6 % and 90.0 % for SOM, 93.2 % and 93.3 % for SVM. PMID- 27467877 TI - Targeting PKC-beta II by Peptides and Peptidomimetics Derived from RACK 1: An In Silico Approach. AB - Diabetes causes contractile myocardial dysfunction through accelerated atherosclerosis and hypertension, termed Diabetic Cardiomyopathy. Experimental results reveals liaison between cardiovascular disease and diabetic complications. Protein kinase C (PKC), a heterogeneous family of phospholipid dependent kinases was found to be specifically involved in diabetic complications, of which PKC-beta II isoform played a significant role in induction of this fatal disease. Members of PKC family share high degree of similarity in both structure and functions, which has given rise to specificity related issues. In the present study, we have designed peptides and peptidomimetics based on RACK 1 (Receptor for Activated C Kinases) region, as this protein increases the substrate phosphorylation and stabilizes the activated form of PKC-beta II. RACK 1 being specific for PKC-beta II could resolve the specificity issue and also peptides and peptidomimetics, being conformationally restrained structures offers potential advantages of being used as drug molecules over organic molecules. This study has provided useful insights that may contribute to the development of molecules which may be useful in the treatment of diabetic complications. PMID- 27467878 TI - BIBuilder: Exhaustive Searching for De Novo Ligands. AB - The de novo design program BIBuilder has been developed for structure-based as well as ligand-based design. Incremental growth allows for the de novo design of novel molecules with putative bioactivity. In addition, linking between existing fragments enables scaffold hopping tasks. A RECAP-based retrosynthetic fragment connection protocol yields ligands that are synthesizable. An exhaustive fragment search protocol assures that known ligands are always found if all necessary fragments exist in the database of building blocks. To make an exhaustive search possible, a strategy of connecting tens of thousands of unique fragments with only three growth or linking steps is adopted resulting in the generation of up to 10(16) possible compounds with up to 10(21) conformations. Ligands are scored by shape and pharmacophore matches that can be individually weighted. Final hits are evaluated through customizable scoring functions. Estrogen receptor, COX-2, renin, and NNRTI examples illustrate the performance of BIBuilder in different tasks such as structure-based or ligand-based growing and linking. Not only are known ligands reproduced in all test cases but a number of interesting alternative scaffolds and ligands have been found. PMID- 27467879 TI - Age-Dependent Morphologic Alterations in the Outer Retinal and Choroidal Thicknesses Using Swept Source Optical Coherence Tomography. AB - PURPOSE: To evaluate the age-dependent morphologic alterations in the outer retina and choroid at the macula using swept-source optical coherence tomography (OCT). METHODS: Thirty eyes (30 normal subjects; average age, 49 years) were examined; five (age range, third-eighth decades of life) had refractive errors of +/-2 diopters or less and no fundus abnormalities. An Early Treatment Diabetic Retinopathy Study (ETDRS) map of the outer retinal and choroidal thickness was constructed using swept-source OCT. The outer retinal and choroidal segmentation lines were drawn automatically, partially manually, within 6 millimeters of the macula. RESULTS: The mean outer retinal and choroidal thicknesses in the 6 millimeter-diameter circle were 145+/-13 and 236+/-68 microns, respectively. The choroidal thickness and age were negatively (r = -0.66, P<0.01) correlated; the outer retinal thickness and age were not correlated (r = -0.16, P = 0.39). The outer retinal and choroidal thicknesses in the ETDRS map were not correlated (r = -0.13, P = 0.49) within 1 millimeter but correlated (r = 0.32, P<0.01) within 6 millimeters. CONCLUSIONS: The choroid thins with aging. The outer retina remains stable. Outer retina and choroid are correlated in the entire macula except for the center. ETDRS map can be useful for evaluation of the morphologic relationship between the outer retina and choroid. PMID- 27467880 TI - Silk Sericin-Functionalized Bacterial Cellulose as a Potential Wound-Healing Biomaterial. AB - Bacterial cellulose (BC) is a polysaccharide known as a suitable matrix for proper wound healing. To improve this ability, BC was functionalized with silk sericin (SS) that has cytoprotective and mitogenic effects. The composites obtained by solution impregnation were stabilized by hydrogen bonds, and SS could be released in a controlled manner. The constructs were highly porous with interconnected pores allowing for high water uptake that varied with the SS concentration used for sample preparation. While SS did not disrupt the stability of the BC network, soluble SS diffusing from the composites did not influence keratinocyte growth but enhanced fibroblast proliferation, which would further optimize the wound healing process and improve extracellular matrix production, accelerating healing. Further, improved cell viability was observed upon the composites. Because of their attractive structure and properties, these BC-SS biomaterials represent potential candidates not only for wound dressing applications but also for tissue engineering. PMID- 27467881 TI - The use of non-economic criteria in pricing and reimbursement decisions in Central and Eastern Europe: issues, trends and recommendations. AB - INTRODUCTION: According to some experts, there is still room for improvement with regard to the inclusion of ethical considerations in Health Technology Assessment (HTA). AREAS COVERED: The pros and cons of the introduction of non-economic criteria in the HTA process in Central and Eastern Europe (CEE) are discussed. In comparison to Western Europe, financial considerations are even more important in CEE settings; however, it could also be said that attachment to equity and justice is part of CEE's heritage. Therefore, the trade-off between conflicting principles is evaluated. Expert commentary: To ensure the right balance between equity and efficiency in decision making, the current HTA framework has to be further augmented to allow all conflicting criteria to be addressed to a satisfactory degree. Following other examples, the applicability of multi criteria decision analysis technique to CEE settings should be further investigated. PMID- 27467882 TI - Revisiting the Robustness of PET-Based Textural Features in the Context of Multi Centric Trials. AB - PURPOSE: This study aimed to investigate the variability of textural features (TF) as a function of acquisition and reconstruction parameters within the context of multi-centric trials. METHODS: The robustness of 15 selected TFs were studied as a function of the number of iterations, the post-filtering level, input data noise, the reconstruction algorithm and the matrix size. A combination of several reconstruction and acquisition settings was devised to mimic multi centric conditions. We retrospectively studied data from 26 patients enrolled in a diagnostic study that aimed to evaluate the performance of PET/CT 68Ga-DOTANOC in gastro-entero-pancreatic neuroendocrine tumors. Forty-one tumors were extracted and served as the database. The coefficient of variation (COV) or the absolute deviation (for the noise study) was derived and compared statistically with SUVmax and SUVmean results. RESULTS: The majority of investigated TFs can be used in a multi-centric context when each parameter is considered individually. The impact of voxel size and noise in the input data were predominant as only 4 TFs presented a high/intermediate robustness against SUV-based metrics (Entropy, Homogeneity, RP and ZP). When combining several reconstruction settings to mimic multi-centric conditions, most of the investigated TFs were robust enough against SUVmax except Correlation, Contrast, LGRE, LGZE and LZLGE. CONCLUSION: Considering previously published results on either reproducibility or sensitivity against delineation approach and our findings, it is feasible to consider Homogeneity, Entropy, Dissimilarity, HGRE, HGZE and ZP as relevant for being used in multi-centric trials. PMID- 27467883 TI - Selexipag for the treatment of pulmonary arterial hypertension. AB - INTRODUCTION: Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe. AREAS COVERED: We review the discovery and development of drugs targeting IP receptors in PAH and describe preclinical and phase I studies of selexipag. Furthermore, we review important phase II and III selexipag studies and place them into the clinical context of previously approved prostanoids. EXPERT OPINION: Oral selexipag offers a promising therapeutic option within the class of available drugs targeting IP receptors. However, its role as first-line therapy based on its efficacy/side effect profile in current studies is questionable. Most likely, selexipag will be used in combination with other PAH-specific oral drugs. The potential of selexipag to replace or postpone the use of inhaled or parenteral prostanoids needs to be investigated in future trials. PMID- 27467884 TI - Improvement of Functional Properties of Wheat Gluten Using Acid Protease from Aspergillus usamii. AB - Hydrolysis parameters (temperature, E/S ratio, pH, and time) for acid protease (from Aspergillus usamii) hydrolysis of wheat gluten were optimized by response surface methodology (RSM) using emulsifying activity index (EAI) as the response factor. A temperature of 48.9 degrees C, E/S ratio of 1.60%, pH 3.0, hydrolysis time of 2.5 h was found to be the optimum condition to obtain wheat gluten hydrolysate with higher EAI. The solubility of wheat gluten was greatly improved by hydrolysis and became independent of pH over the studied range. Enzymatic hydrolysis resulted in dramatically increase in EAI, water and oil holding capacity. Molecular weight distribution results showed that most of the peptides above 10 kDa have been hydrolyzed into smaller peptides. The results of FTIR spectra and disulfide bond (SS) and sulfhydryl (SH) content suggested that a more extensional conformation was formed after hydrolysis, which could account for the improved functional properties. PMID- 27467885 TI - Correction: Turing Patterning Using Gene Circuits with Gas-Induced Degradation of Quorum Sensing Molecules. AB - [This corrects the article DOI: 10.1371/journal.pone.0153679.]. PMID- 27467886 TI - Estimation of Tumor Interstitial Fluid Pressure (TIFP) Noninvasively. AB - Tumor interstitial fluid pressure (TIFP), is a physiological parameter with demonstrated predictive value for a tumor's aggressiveness, drug delivery, as well as response to treatments such as radiotherapy and chemotherapy. Despite its utility, measurement of TIFP has been limited by the need for invasive procedures. In this work, the theoretical basis for approaching the absolute value of TIFP and the experimental method for noninvasively measuring TIFP are presented. Given specific boundary and continuity conditions, we convert theoretical variables into measurable variables by applying MRI technology. The work shows that TIFP in the central region of the tumor can be estimated by an analysis of the variation of tissue fluid motion in the tumor rim and surrounding tissue. It is determined from three noninvasive measurable parameters: i) an estimate of the velocity of the tumor interstitial fluid at the tumor surface, which is maximal, ii) a measurement of the distance from the tumor surface to where the tumor exudates are absorbed (or normalized), and iii) an estimate of the hydraulic conductivity of the interstitium through which the tumor exudate travels. We experimentally show that the fluid flow within the tumor rim is not uniform, even for a round shaped tumor, and demonstrate the procedures for the noninvasive measurement of TIFP. PMID- 27467887 TI - CoP Nanoparticles in Situ Grown in Three-Dimensional Hierarchical Nanoporous Carbons as Superior Electrocatalysts for Hydrogen Evolution. AB - The development of efficient and low-cost hydrogen evolution reaction (HER) catalysts is critical for storing energy in hydrogen via water splitting but still presents great challenges. Herein, we report synthesis of three-dimensional (3-D) hierarchical nanoporous carbon (HNC) supported transition metal phosphides (TMPs) for the first time by in situ growth of CoP nanoparticles (NPs) in CaCO3 NP-templated Cinnamomum platyphyllum leaf extract-derived carbon. They were subsequently employed as a HER catalyst, showing an onset potential of 7 mV and an overpotential of 95.8 mV to achieve 10 mA cm(-2), a Tafel plot of 33 mV dec( 1), and an exchange current density of 0.1182 mA cm(-2), of which the onset overpotential and the Tafel plot are the lowest reported for non-noble-metal HER catalysts, and the overpotential to achieve 10 mA cm(-2) and the exchange current density also compare favorably to most reported HER catalysts. In addition, this catalyst exhibits excellent durability with negligible loss in current density after 2000 CV cycles ranging from +0.01 to -0.17 V vs RHE at a scan rate of 100 mV s(-1) or 22 h of chronoamperometric measurement at an overpotential of 96 mV and a high Faraday efficiency of close to 100%. This work not only creates a novel high-performance non-noble-metal HER electrocatalyst and demonstrates the great advantages of the in situ grown 3-D HNC supported TMP NPs for the electrocatalysis of HER but also offers scientific insight into the mechanism for the in situ growth of TMP and their precursor NPs, in which an ultralow reactant concentration and rich functional groups on the 3-D HNC support play critical roles. PMID- 27467889 TI - Laser Trabeculoplasty Use Patterns Among Optometrists and Ophthalmologists in Oklahoma. PMID- 27467888 TI - Referrals for Services Prohibited In Catholic Health Care Facilities. AB - CONTEXT: Catholic hospitals control a growing share of health care in the United States and prohibit many common reproductive services, including ones related to sterilization, contraception, abortion and fertility. Professional ethics guidelines recommend that clinicians who deny patients reproductive services for moral or religious reasons provide a timely referral to prevent patient harm. Referral practices in Catholic hospitals, however, have not been explored. METHODS: Twenty-seven obstetrician-gynecologists who were currently working or had worked in Catholic facilities participated in semistructured interviews in 2011-2012. Interviews explored their experiences with and perspectives on referral practices at Catholic hospitals. The sample was religiously and geographically diverse. Referral-related themes were identified in interview transcripts using qualitative analysis. RESULTS: Obstetrician-gynecologists reported a range of practices and attitudes in regard to referrals for prohibited services. In some Catholic hospitals, physicians reported that administrators and ethicists encouraged or tolerated the provision of referrals. In others, hospital authorities actively discouraged referrals, or physicians kept referrals hidden. Patients in need of referrals for abortion were given less support than those seeking referrals for other prohibited services. Physicians received mixed messages when hospital leaders wished to retain services for financial reasons, rather than have staff refer patients elsewhere. Respondents felt referrals were not always sufficient to meet the needs of low-income patients or those with urgent medical conditions. CONCLUSIONS: Some Catholic hospitals make it difficult for obstetrician-gynecologists to provide referrals for comprehensive reproductive services. PMID- 27467890 TI - Depression following traumatic brain injury: A functional connectivity perspective. AB - INTRODUCTION: Despite the mounting evidence that depression is one of the most common psychiatric sequelae in survivors of traumatic brain injury (TBI), no studies so far have attempted to provide an explanation in terms of functional network integrity. This proof of concept study investigated the association between the severity of depressive symptoms and resting network integrity in a sample of patients with TBI and a group of healthy controls. METHODS: We first examined the association between depression symptomatology and global functional connectivity and then attempted to characterize the extent of differences in functional network integrity. RESULTS: The severity of depressive symptoms in patients with TBI was associated with neuroadaptations within the insula, the thalamus and the subgenual anterior cingulate cortex (ACC). Specifically, patients with TBI displayed increased connectivity between the insula and a region encompassing the rolandic operculum and the superior temporal cortex and reduced connectivity between the thalamus and the dorsolateral prefrontal cortex. CONCLUSIONS: These findings show the network level involvement of the insula, the thalamus and the subgenual ACC in the depressive symptomatology of patients with TBI and tentatively propose that TBI-induced depression may result from altered functional connectivity of a set of networks associated with emotional regulation. However, other factors including a number of adjustment issues and challenges may also lead to depression in this population. PMID- 27467891 TI - Prisms to travel in time: Investigation of time-space association through prismatic adaptation effect on mental time travel. AB - Accumulating evidence suggests that humans process time and space in similar veins. Humans represent time along a spatial continuum, and perception of temporal durations can be altered through manipulations of spatial attention by prismatic adaptation (PA). Here, we investigated whether PA-induced manipulations of spatial attention can also influence more conceptual aspects of time, such as humans' ability to travel mentally back and forward in time (mental time travel, MTT). Before and after leftward- and rightward-PA, participants projected themselves in the past, present or future time (i.e., self-projection), and, for each condition, determined whether a series of events were located in the past or the future with respect to that specific self-location in time (i.e., self reference). The results demonstrated that leftward and rightward shifts of spatial attention facilitated recognition of past and future events, respectively. These findings suggest that spatial attention affects the temporal processing of the human self. PMID- 27467892 TI - The impact of subliminal effect images in voluntary vs. stimulus-driven actions. AB - According to the ideomotor theory, actions are represented in terms of their sensory effects. In the current study we tested whether subliminal effect images influence action control (1) at early and/or late preparatory stages of (2) voluntary actions or stimulus-driven actions (3) with or without Stimulus Response (S-R) compatibility. In Experiment 1, participants were presented at random with 50% of S-R compatible stimulus-driven action trials and 50% of voluntary action trials. The actions' effects (i.e. up- or down-pointing arrows) were presented subliminally before each action (i.e. a keypress). In voluntary actions, participants selected more often the action congruent with the prime when it was presented at long intervals before the action. Moreover they responded faster in prime-congruent than in prime-incongruent trials when primes were presented at short intervals before the action. In Experiment 2, participants were only presented with stimulus-driven action trials, with or without S-R compatibility. In stimulus-driven action trials with S-R compatibility (e.g., left-pointing arrow signaling a left keypress), subliminal action-effects did not generate any significant effect on RTs or error rates. On the other hand, in stimulus-driven action trials without S-R compatibility (e.g., letter "H" signaling a left keypress), participants were significantly faster in prime-congruent trials when primes were presented at the shortest time interval before the action. These results suggest that subliminal effect images facilitate voluntary action preparation on an early and a late level. Stimulus-driven action preparation is influenced on a late level only, and only if there is no compatibility between the stimulus and the motor response, that is when the response is not automatically triggered by the common properties existing between the stimulus and the required action. PMID- 27467894 TI - Current multiple sclerosis treatments have improved our understanding of MS autoimmune pathogenesis. AB - Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults. When MS is not treated, it leads to irreversible and severe disability. The etiology of MS and its pathogenesis are not fully understood. The recent discovery that MS-associated genetic variants code for molecules related to the function of specific immune cell subsets is consistent with the concept of MS as a prototypic, T-cell-mediated autoimmune disease targeting the CNS. While the therapeutic efficacy of the currently available immunomodulatory therapies further strengthen this concept, differences observed in responses to MS treatment as well as additional clinical and imaging observations have also shown that the autoimmune pathogenesis underlying MS is much more complex than previously thought. There is therefore an unmet need for continued detailed phenotypic and functional analysis of disease-relevant adaptive immune cells and tissues directly derived from MS patients to unravel the immune etiology of MS in its entire complexity. In this review, we will discuss the currently available MS treatment options and approved drugs, including how they have contributed to the understanding of the immune pathology of this autoimmune disease. PMID- 27467895 TI - Optimization of Organotin Polymers for Dielectric Applications. AB - Recently, there has been a growing interest in developing wide band gap dielectric materials as the next generation insulators for capacitors, photovoltaic devices, and transistors. Organotin polyesters have shown promise as high dielectric constant, low loss, and high band gap materials. Guided by first principles calculations from density functional theory (DFT), in line with the emerging codesign concept, the polymer poly(dimethyltin 3,3-dimethylglutarate), p(DMTDMG), was identified as a promising candidate for dielectric applications. Blends and copolymers of poly(dimethyltin suberate), p(DMTSub), and p(DMTDMG) were compared using increasing amounts of p(DMTSub) from 10% to 50% to find a balance between electronic properties and film morphology. DFT calculations were used to gain further insight into the structural and electronic differences between p(DMTSub) and p(DMTDMG). Both blend and copolymer systems showed improved results over the homopolymers with the films having dielectric constants of 6.8 and 6.7 at 10 kHz with losses of 1% and 2% for the blend and copolymer systems, respectively. The energy density of the film measured as a D-E hysteresis loop was 6 J/cc for the copolymer, showing an improvement compared to 4 J/cc for the blend. This improvement is hypothesized to come from a more uniform distribution of diacid repeat units in the copolymer compared to the blend, leading toward improved film quality and subsequently higher energy density. PMID- 27467896 TI - Pseudohypoparathyroidism Type 1A-Subclinical Hypothyroidism and Rapid Weight Gain as Early Clinical Signs: A Clinical Review of 10 Cases. AB - OBJECTIVE: To evaluate the clinical signs and symptoms that would help clinicians to consider pseudohypoparathyroidism (PHP) type 1A as a diagnosis in a child. METHODS: A retrospective review of the medical records of children diagnosed by erythrocyte Gsalpha activity and/or GNAS1 gene study and followed-up for PHP type 1A. Clinical and biochemical parameters along with epidemiological data were extracted and analyzed. Weight gain during infancy and early childhood was calculated as change in weight standard deviation score (SDS), using the French growth reference values. An upward gain in weight >=0.67 SDS during these periods was considered indicative of overweight and/or obesity. RESULTS: Ten cases of PHP type 1A were identified (mean age 41.1 months, range from 4 to 156 months). In children aged <=2 years, the commonest clinical features were round lunar face, obesity (70%), and subcutaneous ossifications (60%). In older children, brachydactyly was present in 60% of cases. Seizures occurred in older children (3 cases). Short stature was common at all ages. Subclinical hypothyroidism was present in 70%, increased parathormone (PTH) in 83%, and hyperphosphatemia in 50%. Only one case presented with hypocalcemia. Erythrocyte Gsalpha activity tested in seven children was reduced; GNAS1 gene testing was performed in 9 children. Maternal transmission was the most common (six patients). In three other cases, the mutations were de novo, c.585delGACT in exon 8 (case 2) and c.344C>TP115L in exon 5 (cases 6&7). CONCLUSION: Based on our results, PHP type 1A should be considered in toddlers presenting with round face, rapid weight gain, subcutaneous ossifications, and subclinical hypothyroidism. In older children, moderate mental retardation, brachydactyly, afebrile seizures, short stature, and thyroid-stimulating hormone resistance are the most suggestive features. PMID- 27467898 TI - Error in Figure 2 Axis Labels. PMID- 27467897 TI - Serum-free light-chain analysis in diagnosis and management of multiple myeloma and related conditions. AB - The introduction of the serum-free light-chain (S-FLC) assay has been a breakthrough in the diagnosis and management of plasma cell dyscrasias, particularly monoclonal light-chain diseases. The first method, proposed in 2001, quantifies serum-free light-chains using polyclonal antibodies. More recently, assays based on monoclonal antibodies have entered into clinical practice. S-FLC measurement plays a central role in the screening for multiple myeloma and related conditions, in association with electrophoretic techniques. Analysis of S FLC is essential in assessing the risk of progression of precursor diseases to overt plasma cell dyscrasias. It is also useful for risk stratification in solitary plasmacytoma and AL amyloidosis. The S-FLC measurement is part of the new diagnostic criteria for multiple myeloma, and provides a marker to follow changes in clonal substructure over time. Finally, the evaluation of S-FLC is fundamental for assessing the response to treatment in monoclonal light chain diseases. PMID- 27467899 TI - Characterization of Salt-Induced Oligomerization of Human beta2-Microglobulin at Low pH. AB - Misfolding and amyloid aggregation of human beta2-microglobulin (beta2m) have been linked to dialysis-related amyloidosis. Previous studies have shown that in the presence of different salt concentrations and at pH 2.5, beta2m assembles into aggregates with distinct morphologies. However, the structural and mechanistic details of the aggregation of beta2m, giving rise to different morphologies, are poorly understood. In this work, we have extensively characterized the salt-induced oligomers of the acid-unfolded state of beta2m using an array of biophysical tools including steady-state and time-resolved fluorescence, circular dichroism, dynamic light scattering, and atomic force microscopy imaging. Fluorescence studies using the oligomer-sensitive molecular rotor, 4-(dicyanovinyl)-julolidine, in conjunction with the light scattering and cross-linking assay indicated that at low salt (NaCl) concentrations beta2m exists as a disordered monomer, capable of transforming into ordered amyloid. In the presence of higher concentrations of salt, beta2m aggregates into a larger oligomeric species that does not appear to transform into amyloid fibrils. Site specific fluorescence experiments using single Trp variants of beta2m revealed that the middle region of the protein is incorporated into these oligomers, whereas the C-terminal segment is highly exposed to bulk water. Additionally, stopped-flow kinetic experiments indicated that the formation of hydrophobic core and oligomerization occur concomitantly. Our results revealed the distinct pathways by which beta2m assembles into oligomers and fibrils. PMID- 27467900 TI - Effect of Complex-Valued Optimal Orbitals on Atomization Energies with the Perdew Zunger Self-Interaction Correction to Density Functional Theory. AB - The spurious interaction of an electron with itself-self-interaction error-is one of the biggest problems in modern density-functional theory. Some of its most glaring effects, such as qualitatively incorrect charge separation upon dissociation, can be removed by an approximate self-interaction correction due to Perdew and Zunger (PZ) (Perdew, J.; Zunger, A. Phys. Rev. B 1981, 23, 5048). However, the correction introduces an explicit dependence on the occupied orbital densities, which makes proper minimization of the functional difficult. Previous work (Vydrov et al., J. Chem. Phys. 2006, 124, 094108) has suggested that the application of the PZ correction results in worse atomization energies than those obtained with the uncorrected parent functional. But, it has only recently been found that the correct minimization of the PZ energy functional requires complex valued orbitals, which have not been used in previous work on atomization energies. Here, we study the effect of the proper use of complex-valued orbitals on the atomization energies of molecules in the W4-11 data set (Karton, A.; Daon, S.; Martin, J. M. Chem. Phys. Lett. 2001, 510, 165). We find that the correction has a tendency to weaken the binding of molecules. The correction using complex valued orbitals is invariably found to yield better atomization energies than the correction with real-valued orbitals. The correction applied to the PBEsol exchange-correlation functional results in a functional that is more accurate than the (uncorrected) PBE functional. PMID- 27467901 TI - Household Food Insecurity May Predict Underweightand Wasting among Children Aged 24-59 Months. AB - The aim of this study was to examine the association between household food insecurity and nutritional status among children aged 24-59 months in Haromaya District. Children (N = 453) aged 24-59 months were recruited in a community based cross-sectional survey with a representative sample of households selected by a multistage sampling procedure in Haromaya District. Household Food Insecurity Access Scale and anthropometry were administered. Multinomial logistic regression models were applied to select variables that are candidate for multivariable model. The prevalences of stunting, underweight, and wasting among children aged 24-59 months were 61.1%, 28.1%, and 11.8%, respectively. The mean household food insecurity access scale score was 3.34, and 39.7% of households experienced some degree of food insecurity. By logistic regression analysis and after adjusting for the confounding factors, household food insecurity was significantly predictive of underweight (AOR = 2.48, CI = 1.17-5.24, p = .05) and chronic energy deficiency (AOR = 0.47, CI = 0.23-0.97, p = .04) and marginally significant for wasting (AOR = 0.53, CI = 0.27-1.03, p = .06). It is concluded that household food security improves child growth and nutritional status. PMID- 27467902 TI - Esophageal Submucosal Hematoma Possibly Caused by Gastric Tube Insertion Under General Anesthesia. AB - We present a case of an esophageal submucosal hematoma that developed after endovascular treatment for coil embolization for an unruptured cerebral aneurysm. The patient had received antiplatelet therapy before surgery and anticoagulation therapy during surgery. The orogastric tube was removed at case end with sustained negative pressure. After surgery, the patient reported chest and back pain and was diagnosed with an esophageal submucosal hematoma. The hematoma might have been related to the gastric tube insertion or removal. Providers should keep in mind the possibility of this complication when a patient who was given antithrombotic therapy reports chest or back pain after surgery. PMID- 27467903 TI - A Case of Pseudocholinesterase Deficiency Resulting From Malnutrition. AB - Pseudocholinesterase deficiencies occur because of both genetic and acquired factors. We present the case of a patient with a history of bariatric surgery and severe malnutrition who subsequently developed prolonged neuromuscular blockade after succinylcholine administration. She had markedly decreased pseudocholinesterase levels at the time of the incident, but her motor function returned to normal with supportive care. After aggressive nutritional support over multiple weeks, her pseudocholinesterase levels drastically improved. For those patients in a poor nutritional state who experience an unexpected episode of apnea or prolonged neuromuscular blockade, practitioners must always consider malnutrition-induced pseudocholinesterase deficiency as a possible etiology. PMID- 27467904 TI - Do Not Burn Your Airway Bridge: A Technique to Safely Exchange a Tracheostomy Tube for a Tracheal Tube. AB - Tracheostomy is one of the most ancient and commonly performed surgical procedures. When tracheostomized patients require a subsequent intervention, it is usually necessary to exchange the tracheostomy tube for a tracheal tube, which can be dangerous. These potential complications may be overlooked or underestimated by the anesthesia providers. An inability to ventilate the patient and replace the tube after removal of a fresh tracheostomy tube can escalate rapidly to a life-threatening crisis. We present a case in which an airway exchange catheter was used to safely replace a tracheostomy tube with a tracheal tube in a patient with a fresh tracheostomy. PMID- 27467906 TI - Injury Patterns among Elite Football Players: A Media-based Analysis over 6 Seasons with Emphasis on Playing Position. AB - The study objective was to describe the types, localizations and severity of injuries among first division Bundesliga football players, and to study the effect of playing position on match and training injury incidence and severity, based on information from the public media. Exposure and injuries data from 1 448 players over 6 consecutive seasons were collected from a media-based register. In total, 3 358 injuries were documented. The incidence rate for match and training injuries was 11.5 per 1 000 match-hours (95% confidence interval [CI]: 10.9 12.2), and 61.4 per 100 player-seasons (95% CI: 58.8-64.1), respectively. Strains (30.3%) and sprains (16.7%) were the major injury types, with the latter causing significantly longer lay-off times than the former. Significant differences between the playing positions were found regarding injury incidence and injury burden (lay-off time per incidence-rate), with wing-defenders sustaining significantly lower incidence-rates of groin injuries compared to forwards (rate ratio: 0.43, 95% CI: 0.17-0.96). Wing-midfielders had the highest incidence-rate and injury burden from match injuries, whereas central-defenders sustained the highest incidence-rate and injury burden from training injuries. There were also significant differences in match availability due to an injury across the playing positions, with midfielders sustaining the highest unavailability rates from a match and training injury. Injury-risk and patterns seem to vary substantially between different playing positions. Identifying positional differences in injury risk may be of major importance to medical practitioners when considering preventive measures. PMID- 27467905 TI - Importance of propionate for the repression of hepatic lipogenesis and improvement of insulin sensitivity in high-fat diet-induced obesity. AB - SCOPE: The SCFA acetate (Ac) and propionate (Pr) are major fermentation products of dietary fibers and provide additional energy to the host. We investigated short- and long-term effects of dietary Ac and Pr supplementation on diet-induced obesity and hepatic lipid metabolism. METHODS AND RESULTS: C3H/HeOuJ mice received high-fat (HF) diets supplemented with 5% SCFA in different Ac:Pr ratios, a high acetate (HF-HAc; 2.5:1 Ac:Pr) or high Pr ratio (HF-HPr; 1:2.5 Ac:Pr) for 6 or 22 weeks. Control diets (low-fat (LF), HF) contained no SCFA. SCFA did not affect body composition but reduced hepatic gene and protein expression of lipogenic enzymes leading to a reduced hepatic triglyceride concentration after 22 weeks in HF-HPr mice. Analysis of long-chain fatty acid composition (liver and plasma phospholipids) showed that supplementation of both ratios led to a lower omega6:omega3 ratio. Pr directly led to increased odd-chain fatty acid (C15:0, C17:0) formation as confirmed in vitro using HepG2 cells. Remarkably, plasma C15:0 was correlated with the attenuation of HF diet-induced insulin resistance. CONCLUSION: Dependent on the Ac:Pr ratio, especially odd-chain fatty acid formation and insulin sensitivity are differentially affected, indicating the importance of Pr. PMID- 27467907 TI - Incidence, Predictors, and Outcomes of New-Onset Atrial Fibrillation in Critically Ill Patients with Sepsis. A Cohort Study. AB - RATIONALE: Patients admitted to intensive care units with sepsis are prone to developing cardiac dysrhythmias, most commonly atrial fibrillation. OBJECTIVES: To determine the incidence, risk factors, and outcomes of atrial fibrillation in a cohort of critically ill patients with sepsis. METHODS: We assessed the association between atrial fibrillation and mortality using time-dependent competing risks survival analysis. Subsequently, for development of a risk score estimating the probability of a first occurrence of atrial fibrillation within the following 24 hours, we performed logistic regression analysis. MEASUREMENTS AND MAIN RESULTS: Among 1,782 patients with sepsis admitted to two tertiary intensive care units in the Netherlands between January 2011 and June 2013, a total of 1,087 episodes of atrial fibrillation occurred in 418 (23%) individuals. The cumulative risk of new-onset atrial fibrillation was 10% (95% confidence interval [CI], 8-12), 22% (95% CI, 18-25), and 40% (95% CI, 36-44) in patients with sepsis, severe sepsis, and septic shock, respectively. New-onset atrial fibrillation was associated with a longer stay (hazard ratio [HR], 0.55; 95% CI, 0.48-0.64), an increased death rate (HR, 1.52; 95% CI, 1.16-2.00), and an overall increased mortality risk (subdistribution HR, 2.10; 95% CI, 1.61-2.73) when considering discharge as a competing event. A simple risk score for daily prediction of atrial fibrillation occurrence yielded good discrimination (C statistic, 0.81; 95% CI, 0.79-0.84) and calibration (chi-square, 9.38; P = 0.31), with similar performance in an independent validation cohort (C statistic, 0.80; 95% CI, 0.76-0.85). CONCLUSIONS: Atrial fibrillation is a common complication of sepsis and independently associated with excess mortality. A simple risk score may identify patients at high risk of this complication. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033). PMID- 27467909 TI - Ovarian cancer chemokines may not be a significant barrier during whole tumor antigen dendritic-cell vaccine and adoptive T-cell immunotherapy. AB - Tumor barriers preventing T-cell homing and engraftment should be neutralized during cancer immunotherapy. We recently discovered that ovarian cancer expresses quasi-universal chemokines that can support T-cell homing. Furthermore, T cells elicited by whole tumor antigen dendritic-cell vaccines express cognate chemokine receptors which are upregulated by CD3/CD28 costimulation. PMID- 27467908 TI - Analysis and Visualization Tool for Targeted Amplicon Bisulfite Sequencing on Ion Torrent Sequencers. AB - Targeted sequencing of PCR amplicons generated from bisulfite deaminated DNA is a flexible, cost-effective way to study methylation of a sample at single CpG resolution and perform subsequent multi-target, multi-sample comparisons. Currently, no platform specific protocol, support, or analysis solution is provided to perform targeted bisulfite sequencing on a Personal Genome Machine (PGM). Here, we present a novel tool, called TABSAT, for analyzing targeted bisulfite sequencing data generated on Ion Torrent sequencers. The workflow starts with raw sequencing data, performs quality assessment, and uses a tailored version of Bismark to map the reads to a reference genome. The pipeline visualizes results as lollipop plots and is able to deduce specific methylation patterns present in a sample. The obtained profiles are then summarized and compared between samples. In order to assess the performance of the targeted bisulfite sequencing workflow, 48 samples were used to generate 53 different Bisulfite-Sequencing PCR amplicons from each sample, resulting in 2,544 amplicon targets. We obtained a mean coverage of 282X using 1,196,822 aligned reads. Next, we compared the sequencing results of these targets to the methylation level of the corresponding sites on an Illumina 450k methylation chip. The calculated average Pearson correlation coefficient of 0.91 confirms the sequencing results with one of the industry-leading CpG methylation platforms and shows that targeted amplicon bisulfite sequencing provides an accurate and cost-efficient method for DNA methylation studies, e.g., to provide platform-independent confirmation of Illumina Infinium 450k methylation data. TABSAT offers a novel way to analyze data generated by Ion Torrent instruments and can also be used with data from the Illumina MiSeq platform. It can be easily accessed via the Platomics platform, which offers a web-based graphical user interface along with sample and parameter storage. TABSAT is freely available under a GNU General Public License version 3.0 (GPLv3) at https://github.com/tadkeys/tabsat/ and http://demo.platomics.com/. PMID- 27467910 TI - HLA ligandomics identifies histone deacetylase 1 as target for ovarian cancer immunotherapy. AB - The recent approval of clincially effective immune checkpoint inhibitors illustrates the potential of cancer immunotherapy. A challenging task remains the identification of specific targets guiding immunotherapy. Facilitated by technical advances, the direct identification of physiologically relevant targets is enabled by analyzing the HLA ligandome of cancer cells. Since recent publications demonstrate the immunogenicity of ovarian cancer (OvCa), immunotherapies, including peptide-based cancer vaccines, represent a promising treatment approach. To identify vaccine peptides, we employed a combined strategy of HLA ligandomics in high-grade serous OvCa samples and immunogenicity analysis. Only few proteins were naturally presented as HLA ligands on all samples analyzed, including histone deacetylase (HDAC) 1 and 2. In vitro priming of CD8(+) T cells demonstrated that two HDAC1/2-derived HLA ligands can induce T cell responses, capable of killing HLA-matched tumor cells. High HDAC1 expression shown by immunohistochemistry in 136 high-grade serous OvCa patients associated with significantly reduced overall survival (OS), whereas patients with high numbers of CD3(+) tumor-infiltrating lymphocytes (TILs) in the tumor epithelium and CD8(+) TILs in the tumor stroma showed improved OS. However, correlating HDAC1 expression with TILs, high levels of TILs abrogated the impact of HDAC1 on OS. This study strengthens the role of HDAC1/2 as an important tumor antigen in OvCa, demonstrating its impact on OS in a large cohort of OvCa patients. We further identified two immunogenic HDAC1-derived peptides, which frequently induce multi-functional T-cell responses in many donors, suitable for future multi-peptide vaccine trials in OvCa patients. PMID- 27467911 TI - Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma. AB - Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment. PMID- 27467912 TI - Rapid dissemination of RET-transgene-driven melanoma in the presence of non-obese diabetic alleles: Critical roles of Dectin-1 and Nitric-oxide synthase type 2. AB - Mice transgenic for the RET oncogene provide a remarkable model for investigating the mechanisms underlying the promotion and the development of melanoma. This model was established on the C57BL/6 genetic background. In the present study, we investigated an effect of the strongly proinflammatory and autoimmune genetic makeup of the non-obese diabetic (NOD) strain. We bred (NODxB6)F1 mice and backcrossed them with NOD mice. F1 mice and mice at subsequent generations of backcrossing showed marked acceleration of tumor development, in particular with a more frequent and earlier extension of the primary uveal melanoma. In close relation with this severe evolution, we observed a profound drop in Dectin-1 expression on CD11b(+)Ly6G(+) granulocytic myeloid cells correlating with an expansion of CD4(+)Foxp3(+) T regulatory cell and of interferon(IFN)gamma producing CD8(+) T cell subsets in tumors. IFNgamma is a major inducer of the type 2 nitric-oxide synthase (Nos2) gene whose products are known to be tumorigenic. Germline inactivation of the Nos2 gene was associated with a dramatically improved tumor prognosis and a restoration of Dectin-1 expression on myeloid cells. Moreover, in vivo treatment of (NODxB6)F1.RET(+) mice with curdlan, a glucose polymer that binds Dectin-1, prevented tumor extension and was associated with marked reduction of the CD4(+)Foxp3(+) T cell subset. These observations highlight the (NODxB6)F1.RET(+) mice as a new model to investigate the role of the immune system in the host-tumor relationship and point to Dectin 1 and Nos2 as potentially promising therapeutic targets. PMID- 27467913 TI - Long-term survival correlates with immunological responses in renal cell carcinoma patients treated with mRNA-based immunotherapy. AB - Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003-2005, we performed a phase I/II trial testing an mRNA-based vaccine formulation consisting of a mixture of in vitro transcribed RNA coding for six different TAAs (MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1) in 30 metastatic RCC (mRCC) patients. In the first 14 patients, vaccinations were applied i.d. on days 0, 14, 28, and 42. In the consecutive 16 patients, an intensified protocol consisting of i.d. injections (daily on days 0-3, 7-10, 28, and 42) was used. After the respective induction periods, patients in both cohorts were vaccinated monthly until tumor progression. At survival update performed in July 2015, one of the 30 patients was still alive. One patient was lost to follow-up. Median survival of 24.5 mo (all patients) and 89 mo (favorable risk patients) exceeded predicted survival according to Memorial Sloan Kettering Cancer Center (MSKCC) risk score. Impressively, long-term survivors displayed immunological responses to the applied antigens while vice versa no patient without detectable immune response had survived more than 33 mo. The current survival update shows a clear correlation between survival and immunological responses to TAAs encoded by the naked mRNA vaccine. This is one of the first vaccination studies and the only RNA trial that reports on safety and efficacy after a follow-up of more than 10 y. PMID- 27467914 TI - The multidrug-resistance transporter Abcc3 protects NK cells from chemotherapy in a murine model of malignant glioma. AB - Abcc3, a member of the ATP-binding cassette transporter superfamily, plays a role in multidrug resistance. Here, we found that Abcc3 is highly expressed in blood derived NK cells but not in CD8(+) T cells. In GL261 glioma-bearing mice treated with the alkylating agent temozolomide (TMZ) for 5 d, an early increased frequency of NK cells was observed. We also found that Abcc3 is strongly upregulated and functionally active in NK cells from mice treated with TMZ compared to controls. We demonstrate that Abcc3 is critical for NK cell survival during TMZ administration; more importantly, Akt, involved in lymphocyte survival, is phosphorylated only in NK cells expressing Abcc3. The resistance of NK cells to chemotherapy was accompanied by increased migration and homing in the brain at early time points. Cytotoxicity, evaluated by IFNgamma production and specific lytic activity against GL261 cells, increased peripherally in the later phases, after conclusion of TMZ treatment. Intra-tumor increase of the NK effector subset as well as in IFNgamma, granzymes and perforin-1 expression, were found early and persisted over time, correlating with a profound modulation on glioma microenvironment induced by TMZ. Our findings reveal an important involvement of Abcc3 in NK cell resistance to chemotherapy and have important clinical implications for patients treated with chemo-immunotherapy. PMID- 27467915 TI - Anti-alpha-enolase antibody limits the invasion of myeloid-derived suppressor cells and attenuates their restraining effector T cell response. AB - Pancreatic Ductal Adenocarcinoma (PDA) is a very aggressive tumor for which effective therapeutical strategies are still lacking. Globally, the 5 y survival rate is 5-7% and surgery is the only potentially curative treatment. Immunotherapy represents a novel possibility for treating PDA, and myeloid derived suppressor cells (MDSC), which are increased in cancer patients and correlate with metastatic burden and cancer stage, offer a new target in cancer therapy. We have previously shown that antibodies against the PDA-associated antigen alpha-enolase (ENO1) are detected in more than 60% of PDA patients and correlate with a better prognosis. Furthermore, ENO1-DNA vaccination in mice induced anti-ENO1 antibodies that mediated antitumor activity. In this study, the effects of anti-ENO1 binding on MDSC functions and on the T cell response were evaluated. Here, we show that MDSC express ENO1 on their surface, which increased after LPS stimulation. Moreover, anti-ENO1 mAb inhibited adhesion to endothelial cells, as well as in vitro and in vivo migration. Similarly, after ENO1 mAb treatment of MDSC, arginase activity decreased, while the secretion of pro inflammatory cytokines (particularly IL-6) increased, and co-stimulatory molecule expression and suppression functions were only partially affected. Finally, we found that activated T cells in the presence of anti-ENO1 mAb-treated MDSC increased IFNgamma and IL-17 secretion and decreased IL-10 and TGFbeta secretion compared to control MDSC. In conclusion, anti-ENO1 antibodies may inhibit in vivo the infiltration into the tumor microenvironment of MDSC, and attenuate their restraining of effector T cell response, opening a new perspective to render PDA immunotherapy more effective. PMID- 27467916 TI - Frameshift mutations, neoantigens and tumor-specific CD8(+) T cells in microsatellite unstable colorectal cancers. AB - Microsatellite unstable colorectal cancers (CRC) express frameshift mutation derived tumor-specific neoantigens. We recently showed that: (i) frameshift mutations were correlated with tumor-infiltrating CD8(+) T cell density, (ii) neoantigen-specific cytotoxic T cells could be obtained in patients whose tumors harbored these mutations, underlining the interest of developing personalized immunotherapy strategies in these cancers. PMID- 27467917 TI - Tipping a favorable CNS intratumoral immune response using immune stimulation combined with inhibition of tumor-mediated immune suppression. AB - High-grade gliomas are notoriously heterogeneous regarding antigen expression, effector responses, and immunosuppressive mechanisms. Therefore, combinational immune therapeutic approaches are more likely to impact a greater number of patients and result in longer, durable responses. We have previously demonstrated the monotherapeutic effects of miR-124, which inhibits the signal transducer and activator of transcription 3 (STAT3) immune suppressive pathway, and immune stimulatory 4-1BB aptamers against a variety of malignancies, including genetically engineered immune competent high-grade gliomas. To evaluate potential synergy, we tested an immune stimulatory aptamer together with microRNA-124 (miRNA-124), which blocks tumor-mediated immune suppression, and found survival to be markedly enhanced, including beyond that produced by monotherapy. The synergistic activity appeared to be not only secondary to enhanced CD3(+) cell numbers but also to reduced macrophage immune tumor trafficking, indicating that a greater therapeutic benefit can be achieved with approaches that both induce immune activation and inhibit tumor-mediated immune suppression within the central nervous system (CNS) tumors. PMID- 27467918 TI - Tetraspanin CD81, a modulator of immune suppression in cancer and metastasis. AB - Cancer cells can escape the antitumor immune response by recruiting immune suppressor cells. However, although innate myeloid-derived suppressor cells (MDSCs) and T regulatory (Treg) cells accumulate normally in tumor-bearing CD81 deficient mice, both populations are impaired in their ability to suppress the antitumor immune response. PMID- 27467919 TI - Unraveling the molecular pathways of DNA-methylation inhibitors: human endogenous retroviruses induce the innate immune response in tumors. AB - Loss of DNA methylation can activate endogenous retroviral expression and dsRNA in cancer cells. This leads to induction of toll-like receptor signaling stimulating an antiviral interferon response. Recent findings provide a therapeutic rationale for combining DNA methylation inhibitors with blockage of immune checkpoint proteins to fight cancer. PMID- 27467920 TI - Tumor evasion of humoral immunity mediated by proteolytic impairment of antibody triggered immune effector function. AB - Immune suppression is recognized as a hallmark of cancer and this notion is largely based on studies on cellular immunity. Our recent studies have demonstrated a potential new mechanism of cancer suppression of immunity by impairment of antibody effector function mediated by proteolytic enzymes in the tumor microenvironment. PMID- 27467921 TI - GITR drives TH9-mediated antitumor immunity. AB - TH9 cells have been implicated in triggering antitumor immunity. We have identified that GITR co-stimulation inhibits iTreg cell generation but drives TH9 cell differentiation, thereby suppressing tumor growth via enhancing the function of DCs and CTLs in vivo. Our findings provide novel mechanisms by which GITR agonists exert antitumor activity. PMID- 27467923 TI - ADAM10 new selective inhibitors reduce NKG2D ligand release sensitizing Hodgkin lymphoma cells to NKG2D-mediated killing. AB - Hodgkin lymphoma (HL) resistant to conventional therapies is increasing, making of interest the search for new schemes of treatment. Members of the "A Disintegrin And Metalloproteases" (ADAMs) family, mainly ADAM10 or ADAM17, have been proposed as therapeutic targets in solid tumors and some ADAMs inhibitors have been shown to exert antitumor effects. We have previously described an overexpression of ADAM10 in HL, together with increased release of NKG2D ligands (NKG2D-L) and reduced activation of effector T lymphocytes with anti-lymphoma capacity. Aim of the present work was to verify whether inhibition of ADAM10 in HL cells could restore the triggering of NKG2D-dependent anti-lymphoma T cell response. As no selective ADAM10 blockers have been reported so far, we synthesized the two hydroxamate compounds LT4 and MN8 with selectivity for ADAM10 over metalloproteases (MMPs), LT4 showing higher specificity for ADAM10 over ADAM17. We show that (i) HL lymph nodes (LN) and cultured HL cells express high levels of the mature active membrane form of ADAM10; (ii) ADAM10 is the major sheddase for the NKG2D-L in HL cells; (iii) the new LT4 and MN8 compounds strongly reduce the shedding of NKG2D-L by HL cell lines and enhance the binding of NKG2D receptor; (iv) of note, these new ADAM10 inhibitors increase the sensitivity of HL cell lines to NKG2D-dependent cell killing exerted by natural killer and gammadelta T cells. Overall, the biologic activity of LT4 and MN8 appears to be more potent than that of the commercial inhibitor GI254023X. PMID- 27467922 TI - Combined inhibition of TGFbeta and PDGF signaling attenuates radiation-induced pulmonary fibrosis. AB - Background : Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods : C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFbeta receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFbeta inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFbeta-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFbeta pathways. Conclusion : Combined small-molecule inhibition of PDGF and TGFbeta signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFbeta and PDGF play a key role. Here, we show that a combined inhibition of TGFbeta and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the TGFbeta-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of TGFbeta and PDGF signaling and the attenuation of SPP1 (Osteopontin) expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis (IPF), our study suggests that the combined application of small molecule inhibitors of TGFbeta and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer. PMID- 27467924 TI - TLR4/IFNgamma pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models. AB - Toll-like receptor (TLR) 4 agonists have emerged as a new group of molecules used for cancer therapy. They have been exploited to enhance the immunogenicity of current chemotherapeutic regimens. However, their effects on cancer cells remain elusive. Here, we showed that a TLR4 agonist, namely a synthetic lipid A analog (ALA), OM-174, exhibits antitumor effects in several mammary tumor mouse models. We also showed that immune components are involved in such effects, as attested to by the failure of ALA to induce tumor regression or an increase of animal survival in mice knocked-out for interferon gamma (IFNgamma) or TLR4. TLR4 and IFNgamma receptor (INFR2) expressed by cancer cells are involved in the antitumor efficacy of ALA since this last did not inhibit tumor growth in mice bearing a tumor but lacking TLR4 or IFNgamma receptor 2 (IFNR2). Mechanistic investigations revealed that nitric oxide (NO), superoxide and peroxynitrite produced by uncoupling of inducible NO synthase (NOS II) in cancer cells are key mediators of ALA and IFNgamma-mediated tumor growth inhibition. We present here a comprehensive picture of tumor cell death induction, in vivo and in vitro, by immunotherapy and for the first time the involvement of the TLR4/IFNgamma/NOS II pathway in immunotherapy was investigated. PMID- 27467925 TI - Melanoma driver mutations and immune therapy. AB - Melanoma harbors recurrent oncogenic driver mutations in BRAF and NRAS, but these mutations' impact on immunotherapy outcomes is unclear. We assessed 229 patients treated with immunotherapy, and found that clinical outcomes were largely superior in those with NRAS mutations. Herein, we discuss our findings and their implications for melanoma therapeutics. PMID- 27467928 TI - Unlocking tumor vascular barriers with CXCR3: Implications for cancer immunotherapy. AB - Promising cancer immunotherapeutics depend on mobilization of cytotoxic T cells across tumor vascular barriers through mechanisms that are poorly understood. Recently, we discovered that the CXCR3 chemokine receptor uniquely functions as the master-regulator of cytotoxic CD8(+) T cell extravasation and tumor control despite the multiplicity of chemokines available in the tumor landscape. PMID- 27467926 TI - Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis. AB - OBJECTIVE: In tumor patients, IL-6 appears to be one component of a consistent cancer-associated cytokine network resulting in both a systemic immune stimulation and a microenvironment of cancer-induced immune suppression that ultimately protects the cancer cells. IL-6 has been associated with prognosis in cancer patients, but so far a systemical analysis has not been carried out. METHODS: The present meta-analysis studies the relation between IL-6 serum levels and the prognosis of cancer patients in the available clinical literature of 100 articles published between 1993 and 2013 comprising 11,583 patients. RESULTS: The IL-6 serum level was described as significantly correlating with survival in 82/101 series comprising 85.6% of patients (9917/11,583) with 23 different cancer types. A total of 64 studies dichotomized patient cohorts according to various cut-off IL-6 serum levels: in 59/64 of these series corresponding to 94.5% of the reported patients (7694/8142) significant correlations between IL-6 serum level and survival were seen. The median survival of cancer patients had been determined above various cut-off levels of serum IL-6 in 24 dichotomized studies (26 cohorts). There was a highly significant inverse correlation between median survival of the cohorts with IL-6 serum level above cut-off (1272 patients) and their corresponding IL-6 cut-off values (Spearman R -0,48 p= < 0.001) following a linear regression when both parameters were log-transformed (p < 0.001). A significant correlation between increasing serum IL-6 and tumor stage or metastases was described in 39/44 studies and 91% of published patients (4221/4636) where clinical parameters had been specified. CONCLUSIONS: Closely associated with the patient's clinical condition and independent of the cancer histology, the increased IL-6 serum level uniformly appears to correlate with survival as paraneoplastic condition in later cancer stages independent of the cancer type. Modifications of this paraneoplastic immune reaction may offer new therapeutic options in cancer. PMID- 27467929 TI - Yet another pattern recognition receptor involved in the chemotherapy-induced anticancer immune response: Formyl peptide receptor-1. AB - Several pattern recognition receptors including toll-like receptors and purinergic receptors are implicated in the anticancer immune response elicited by anthracyclines or oxaliplatin. Recently, formyl peptide receptor-1 (FPR1) has been involved in this response as well. FPR1 is required for the correct positioning of dendritic cells (DC) close to dying cancer cells. A genetic defect in FPR1 abrogates cross-presentation of tumor antigens by DC, thereby compromising therapy-elicited immunosurveillance. PMID- 27467927 TI - Polyfunctional Melan-A-specific tumor-reactive CD8(+) T cells elicited by dacarbazine treatment before peptide-vaccination depends on AKT activation sustained by ICOS. AB - The identification of activation pathways linked to antitumor T-cell polyfunctionality in long surviving patients is of great relevance in the new era of immunotherapy. We have recently reported that dacarbazine (DTIC) injected one day before peptide-vaccination plus IFN-alpha improves the antitumor lytic activity and enlarges the repertoire of Melan-A-specific T-cell clones, as compared with vaccination alone, impacting the overall survival of melanoma patients. To identify the mechanisms responsible for this improvement of the immune response, we have analyzed the endogenous and treatment-induced antigen (Ag)-specific response in a panel of Melan-A-specific CD8(+) T-cell clones in terms of differentiation phenotype, inhibitory receptor profile, polyfunctionality and AKT activation. Here, we show that Melan-A-specific CD8(+) T cells isolated from patients treated with chemoimmunotherapy possess a late differentiated phenotype as defined by the absence of CD28 and CD27 co stimulatory molecules and high levels of LAG-3, TIM-3 and PD-1 inhibitory receptors. Nevertheless, they show higher proliferative potential and an improved antitumor polyfunctional effector profile in terms of co-production of TNF-alpha, IFNgamma and Granzyme-B (GrB) compared with cells derived from patients treated with vaccination alone. Polyfunctionality is dependent on an active AKT signaling related to the engagement of the co-stimulatory molecule ICOS. We suggest that this phenotypic and functional signature is dictated by a fine-tuned balance between TCR triggering, AKT activation, co-stimulatory and inhibitory signals induced by chemoimmunotherapy and may be associated with antitumor T cells able to protect patients from tumor recurrence. PMID- 27467931 TI - BCR-ABL transcript variations in chronic phase chronic myelogenous leukemia patients on imatinib first-line: Possible role of the autologous immune system. AB - Many chronic myelogenous leukemia (CML) patients in chronic phase who respond well to imatinib therapy show fluctuations in their leukemic loads in the long term. We developed a mathematical model of CML that incorporates the intervention of an autologous immune response. Our results suggest that the patient's immune system plays a crucial role in imatinib therapy in maintaining disease control over time. The observed BCR-ABL/ABL oscillations in such patients provide a signature of the autologous immune response. PMID- 27467930 TI - Producer T cells: Using genetically engineered T cells as vehicles to generate and deliver therapeutics to tumors. AB - Adoptive cell transfer (ACT) is an emerging anticancer therapy that has shown promise in various malignancies. Redirecting antigen specificity by genetically engineering T cells to stably express receptors has become an effective variant of ACT. A novel extension of this approach is to utilize engineered T cells to produce and deliver anticancer therapeutics that enhance cytotoxic T cell function and simultaneously inhibit immunosuppressive processes. Here, we review the potential of using T cells as therapeutic-secreting vehicles for immunotherapies and present theoretical and established arguments in support of further development of this unique cell-based immunotherapy. PMID- 27467933 TI - Size matters: Survival benefit conferred by intratumoral T cells is dependent on surgical outcome, treatment sequence and T cell differentiation. AB - Outcome of cytoreductive surgery, treatment sequence and the differentiation status of T cells are key factors to take into account when studying the prognostic value of tumor-infiltrating lymphocytes (TIL) in high grade serous ovarian cancer. PMID- 27467932 TI - Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis. AB - The factors that determine whether disseminated transformed cells in vivo yield neoplastic lesions have only been partially identified. We established an ad hoc model of peritoneal carcinomatosis by injecting colon carcinoma cells in mice. Tumor cells recruit inflammatory leukocytes, mostly macrophages, and generate neoplastic peritoneal lesions. Phagocyte depletion via clodronate treatment reduces neoplastic growth. Colon carcinoma cells release a prototypic damage associated molecular pattern (DAMP)/alarmin, High Mobility Group Box1 (HMGB1), which attracts leukocytes. Exogenous HMGB1 accelerates leukocyte recruitment, macrophage infiltration, tumor growth and vascularization. Lentiviral-based HMGB1 knockdown or pharmacological interference with its extracellular impair macrophage recruitment and tumor growth. Our findings provide a preclinical proof of principle that strategies based on preventing HMGB1-driven recruitment of leukocytes could be used for treating peritoneal carcinomatosis. PMID- 27467934 TI - Notching tumor: Signaling through Notch receptors improves antitumor T cell immunity. AB - Notch signaling is crucial for lymphocyte effector and memory differentiation. While tumor suppress Notch signaling in antitumor lymphocytes, recent studies show that the pharmacological Delta-like ligand-1 multivalent cluster or proteasome inhibitor bortezomib can restore Notch-NF-kappaB signaling in T cells of tumor-bearing hosts with a potential to overcome cancer cell resistance to therapy. PMID- 27467935 TI - Harnessing the IL-7/IL-7Ralpha axis to improve tumor immunotherapy. AB - IL-7 and IL-15 are critical for supporting T cells transferred into a lymphopenic environment. As activated CD8(+) T cells downregulate IL-7Ralpha, it is thought IL-15 is more important. However, we find that CD8(+) T cells activated with IL 12 have elevated IL-7Ralpha and rely on IL-7 for persistence and antitumor immunity. PMID- 27467936 TI - Reducing prostaglandin E2 production to raise cancer immunogenicity. AB - Cyclooxygenases (COX), commonly upregulated in numerous cancers, generate prostaglandin E2 (PGE2), which has been implicated in key aspects of malignant growth including proliferation, invasion and angiogenesis. Recently, we showed that production of PGE2 by cancer cells dominantly enables progressive tumor growth via immune escape and that cyclooxygenase inhibitors synergize with immunotherapy to enhance tumor eradication. PMID- 27467937 TI - Motolimod effectively drives immune activation in advanced cancer patients. AB - A novel approach to immunotherapy is the activation of toll-like receptor 8 (TLR8). Motolimod, a selective TLR8 agonist can act in concert with approved immunotherapies to sensitize T cells and augment natural killer (NK) cell function. Despite treatment with chemotherapeutic agents and advance disease, cancer patients remain sensitive to motolimod. PMID- 27467938 TI - STAT3 inhibition for cancer therapy: Cell-autonomous effects only? AB - A paper recently published in Science Translational Medicine describes a next generation antisense oligonucleotide that specifically downregulates the expression of human signal transducer and activator of transcription 3 (STAT3). Such an oligonucleotide, AZD9150, exerts antineoplastic effects on a selected panel of STAT3-dependent human cancer cells growing in vitro and in vivo (as xenografts in immunodeficient mice). Moreover, preliminary data from a Phase I clinical trial indicate that AZD9150 may cause partial tumor regression in patients with chemorefractory lymphoma and non-small cell lung carcinoma. STAT3 not only participates in cell-autonomous processes that are required for the survival and growth of malignant cells, but also limits their ability to elicit anticancer immune responses. Moreover, STAT3 contribute to the establishment of an immunosuppressive tumor microenvironment. Thus, the inhibition of STAT3 may promote immunosurveillance by a dual mechanism: (1) it may increase the immunogenicity of cancer cells via cell-autonomous pathways; and (2) it may favor the reprogramming of the tumor microenvironment toward an immunostimulatory state. It will therefore be important to explore whether immunological biomarkers predict the efficacy of AZD9150 in the clinic. This may ameliorate patient stratification and it may pave the way for rational combination therapies involving classical chemotherapeutics with immunostimulatory effects, AZD9150 and immunotherapeutic agents such as checkpoint blockers. PMID- 27467939 TI - Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes. AB - CD245 is a human surface antigen expressed on peripheral blood lymphocytes, initially delineated by two monoclonal antibodies DY12 and DY35. Until now, CD245 molecular and functional characteristics remained largely unknown. We combined immunological and proteomic approaches and identified CD245 as the unconventional myosin 18A, a highly conserved motor enzyme reported as a receptor for the surfactant protein A (SP-A), that plays a critical role in cytoskeleton organization and Golgi budding. We report that the recruitment of CD245 strongly enhanced NK cell cytotoxicity. Further, we show that the enhancement of the NK lymphocytes killing ability toward CD137-ligand expressing target cells could result from the induction of CD137 expression following CD245 engagement. The SP A receptor could therefore represent a novel and promising target in cancer immunotherapy. PMID- 27467940 TI - Cell-to-cell distances between tumor-infiltrating inflammatory cells have the potential to distinguish functionally active from suppressed inflammatory cells. AB - Beyond their mere presence, the distribution pattern of inflammatory cells is of special interest. Our hypothesis was that random distribution may be a clear indicator of being non-functional as a consequence of lack of interaction. Here, we have assessed the implication of cell-to-cell distances among inflammatory cells in anal squamous cell carcinoma and a possible association with survival data. Thirty-eight patients suffering from anal carcinoma were studied using tissue microarrays, double staining immunohistochemistry, whole slide scanning and image analysis software. Therapy consisted of concurrent radiochemotherapy. Numbers of stromal and intraepithelial tumor-infiltrating inflammatory cells (TIC) and the distances between cells were quantified. Double-staining of FoxP3(+) cells with either CD8(+), CD1a(+) or CD20(+) cells was performed. Measured cell-to-cell distances were compared to computer simulated cell-to-cell distances leading to the assumption of non-randomly distributed and therefore functional immune cells. Intraepithelial CD1a(+) and CD20(+) cells were randomly distributed and therefore regarded as non-functional. In contrary, stromal CD20(+) cells had a non-random distribution pattern. A non-random distance between CD20(+) and FoxP3(+) cells was associated with a clearly unfavorable outcome. Measured distances between FoxP3(+) cells were distinctly shorter than expected and indicate a functional active state of the regulatory T cells (Treg). Analysis of cell-to-cell distances between TIC has the potential to distinguish between suppressed non-functional and functionally active inflammatory cells. We conclude that in this tumor model most of the CD1a(+) cells are non-functional as are the intraepithelial CD20(+) cells, while stromal CD20(+) cells and FoxP3(+) cells are functional cells. PMID- 27467941 TI - Nucleic acid-sensing toll-like receptors 3, 7 and 8 in esophageal epithelium, barrett's esophagus, dysplasia and adenocarcinoma. AB - Toll-like receptors (TLRs) are immunological receptors recognizing various microbial and endogenous ligands, such as DNA, RNA, and other microbial and host components thus activating immunological responses. The expression of TLRs in esophageal adenocarcinoma is not well known. The aim of this study was to evaluate expression patterns of those TLRs that sense nucleic acids in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinoma. TLRs 3, 7 and 8 were stained immunohistochemically and evaluated in a cohort of patients with esophageal adenocarcinoma or dysplasia. Specimens with normal esophagus (n = 88), gastric (n = 67) or intestinal metaplasia (n = 51) without dysplasia, and low-grade (n = 42) or high-grade dysplasia (n = 37) and esophageal adenocarcinoma (n = 99) were studied. We used immunofluorescence to confirm the subcellular localization of TLRs. We found abundant expression of TLR3, 7 and 8 in esophageal squamous epithelium, columnar metaplasia, dysplasia and adenocarcinoma. Cytoplasmic expression of TLR3, TLR7 or TLR8 did not associate to clinicopathological parameters or prognosis in esophageal cancer. High nuclear expression of TLR8, confirmed with immunofluorescence, in cancer cells was observed in tumors of high T-stage (p < 0.01) and in tumors with organ metastasis (p < 0.001). High nuclear TLR8 expression was associated with poor prognosis (p < 0.001). The expression of TLR3, TLR7 and TLR8 increased toward dysplasia and adenocarcinoma. We demonstrated nuclear localization of TLR8, which associates with metastasis and poor prognosis. TLR3 and TLR7 do not seem to have prognostic significance in esophageal adenocarcinoma. PMID- 27467942 TI - CD73-adenosine reduces immune responses and survival in ovarian cancer patients. AB - Multiple non-redundant immunosuppressive pathways are active within the microenvironment of cancers to avoid tumor eradication by the immune system. Our results demonstrate that the CD73-adenosine pathway is a major immunosuppressive mechanism co-opted by ovarian tumors to escape antitumor immunity. In ovarian cancer patients, high CD73 expression correlates with poor outcome and impaired CD8(+) T cell immunosurveillance. PMID- 27467943 TI - High-risk oncogenic HPV genotype infection associates with increased immune activation and T cell exhaustion in ART-suppressed HIV-1-infected women. AB - Persistence of human papillomavirus (HPV) and cervical disease in the context of HIV co-infection can be influenced by introduction of antiretroviral therapy (ART) and sustained immune activation despite ART. We conducted a cross-sectional study in order to evaluate immune activation/exhaustion in ART-suppressed HIV(+) women with or without high-risk (HR) HPV-related cervical intraepithelial neoplasia (CIN). 55 South African women were recruited in three groups: HR (-) (n = 16) and HR (+) (n = 15) HPV with negative cervical histopathology, and HR (+) HPV with CIN grade 1/2/3 (n = 24). Sampling included endocervical brushing (HPV DNA genotyping), Pap smear (cytology), colposcopic punch biopsy (histopathology, histochemical evaluation of immune cells), and peripheral blood (clinical assessment, flow cytometry-based immune subset characterization). Statistics were done using R2.5.1. Irrespective of the presence of CIN, HR (+) HPV women had higher circulating levels of T cells expressing markers of activation/exhaustion (CD38, PD1, CTLA-4, BTLA, CD160), Tregs, and myeloid subsets expressing corresponding ligands (PDL1, PDL2, CD86, CD40, HVEM) than HR (-) HPV women. A decrease in circulating NK cells was associated with CIN grade. CD4(+) T cell count associated negatively with T cell exhaustion and expression of negative regulators on myeloid cells. Women with CIN when compared to HR (-) HPV women, had higher cervical cell density in stroma and epithelium for CD4(+), CD68(+), and CD11c(+) cells, and only in stroma for CD8(+) cells. We conclude that in ART suppressed HIV-infected women with HPV co-infection the levels of T and myeloid cell activation/exhaustion are associated with the presence of HR HPV genotypes. PMID- 27467944 TI - Cripto-1 vaccination elicits protective immunity against metastatic melanoma. AB - Metastatic melanoma is a fatal disease that responds poorly to classical treatments but can be targeted by T cell-based immunotherapy. Cancer vaccines have the potential to generate long-lasting cytotoxic CD8(+) T cell responses able to eradicate established and disseminated tumors. Vaccination against antigens expressed by tumor cells with enhanced metastatic potential represents a highly attractive strategy to efficiently target deadly metastatic disease. Cripto-1 is frequently over-expressed in human carcinomas and melanomas, but is expressed only at low levels on normal differentiated tissues. Cripto-1 is particularly upregulated in cancer-initiating cells and is involved in cellular processes such as cell migration, invasion and epithelial-mesenchymal transition, which are hallmarks of aggressive cancer cells able to initiate metastatic disease. Here, we explored the potential of Cripto-1 vaccination to target metastatic melanoma in a preclinical model. Cripto-1 was overexpressed in highly metastatic B16F10 cells as compared to poorly metastatic B16F1 cells. Moreover, B16F10 cells grown in sphere conditions to enrich for cancer stem cells (CSC) progressively upregulated cripto1 expression. Vaccination of C57Bl/6 mice with a DNA vaccine encoding mouse Cripto-1 elicited a readily detectable/strong cytotoxic CD8(+) T cell response specific for a H-2 Kb-restricted epitope identified based on its ability to bind H-2(b) molecules. Remarkably, Cripto-1 vaccination elicited a protective response against lung metastasis and subcutaneous challenges with highly metastatic B16F10 melanoma cells. Our data indicate that vaccination against Cripto-1 represents a novel strategy to be tested in the clinic. PMID- 27467946 TI - Linking cancer-induced Nlrp3 inflammasome activation to efficient NK cell mediated immunosurveillance. AB - We have recently demonstrated that the Nlrp3 inflammasome can detect the presence of colorectal cancer (CRC) metastatic growth in the liver and limit its growth. Inflammasome signaling primed natural killer (NK) cells through Interleukin (IL) 18 and activated their ability to trigger FasL-induced apoptosis of the tumor. PMID- 27467945 TI - Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. AB - The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3 derived peptide vaccine. PMID- 27467947 TI - Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma. AB - Cumulative evidence suggests that constitutively activated signal transducer and activator of transcription (STAT3) may contribute to sustaining immunosuppressive status, and that inhibiting STAT3 signaling represents a potential strategy to improve antitumor immunity. In the present study, we observed that high levels phosphorylated of STAT3 are significantly associated with the markers for both myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in human head and neck squamous cell carcinoma (HNSCC). Additionally, we showed that targeting STAT3 signaling with a tolerable selective inhibitor S3I-201 significantly decreased immature myeloid cells such as MDSCs, TAMs and iDCs in genetically defined mice HNSCC model. These findings highlight that targeting STAT3 signaling may be effective to enhance antitumor immunity via myeloid suppressor cells in HNSCC. PMID- 27467948 TI - Immune response modulation by Galectin-1 in a transgenic model of neuroblastoma. AB - Galectin-1 (Gal-1) has been described to promote tumor growth by inducing angiogenesis and to contribute to tumor immune escape by promoting apoptosis of activated T cells. We had previously identified upregulation of Gal-1 in preclinical models of aggressive neuroblastoma (NB), a solid tumor of childhood. However, the clinical and biological relevance of Gal-1 in this tumor entity is unclear. Here, the effect of Gal-1 on the immune system and tumorigenesis was assessed using modulation of Gal-1 expression in immune effector cells and in a transgenic NB model, designated TH-MYCN. The fraction of CD4(+) T cells was decreased in tumor-bearing TH-MYCN mice compared to tumor-free littermates, while both CD4(+) T cells as well as CD8(+) T cells were less activated, compatible with a reduced immune response in tumor-bearing mice. Tumor incidence was not significantly altered by decreasing Gal-1/LGALS1 gene dosage in TH-MYCN mice, but TH-MYCN/Gal-1(-/-) double transgenic mice displayed impaired tumor angiogenesis, splenomegaly, and impaired T cell tumor-infiltration with no differences in T cell activation and apoptosis rate. Additionally, a lower migratory capacity of Gal-1 deficient CD4(+) T cells toward tumor cells was observed in vitro. Transplantation of TH-MYCN-derived tumor cells into syngeneic mice resulted in significantly reduced tumor growth and elevated immune cell infiltration when Gal 1 was downregulated by shRNA. We therefore conclude that T cell-derived Gal-1 mediates T cell tumor-infiltration, whereas NB-derived Gal-1 promotes tumor growth. This opposing effect of Gal-1 in NB should be considered in therapeutic targeting strategies, as currently being developed for other tumor entities. PMID- 27467949 TI - PD-L1 expression in non-small cell lung cancer: Correlations with genetic alterations. AB - Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Two PD-L1 immunohistochemistry (IHC) assays have been approved as companion diagnostic tests for therapeutic anti-PD-1 antibodies. However, many aspects of PD-L1 prevalence and association with genetically defined subtypes have not been addressed systematically. Here, we analyzed PD-L1 expression in 436 genetically annotated NSCLC specimens enriched for early stages using PD-L1 antibody 5H1. Expression of PD-L1 was detected in the tumor cells (TC) (34% of cases) and in associated immune cells (IC) (49%) across all stages of NSCLC, either alone or in combination. PD-L1 IHC-positive TC, but not IC showed significantly higher PD-L1 RNA expression levels. Expression in TC was associated with TP53, KRAS and STK11 mutational status in adenocarcinomas (AD) and with NFE2L2 mutations in squamous cell carcinomas (SQ). No correlations with histological subtype, clinical characteristics and overall survival were found. The presence of PD-L1-positive IC was significantly associated with patients' smoking status in AD. The findings are in agreement with the emerging concept that tumors with high mutational burden are more likely to benefit from immunotherapy, since TP53 and KRAS mutations are linked to smoking, increased numbers of somatic mutations and expression of neoantigens. Current clinical studies focus on stage IIIB and IV NSCLC; however, PD-L1 expression occurs in earlier stages and might be a predictive biomarker in clinical trials testing (neo-) adjuvant strategies. PMID- 27467950 TI - TRAIL-receptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo. AB - Agonistic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor-specific antibodies are attractive antitumor therapeutics. Recently, our group has generated several human monoclonal antibodies (mAbs) to TRAIL-receptor 1 (TRAIL-R1) (TR1-IgGs) using ISAAC technology. However, these TR1-IgGs did not demonstrate ideal apoptosis-inducing capacity in the absence of additional antibodies. To overcome this limitation, we class-switched the TR1-IgGs to TRAIL R1 IgM antibodies (TR1-IgMs); TR1-IgMs might possess high valency and facilitate the crosslinking of the cell surface receptors. We showed that the TR1-IgMs bound TRAIL-R1, activated the caspase signal, and induced strong apoptosis (100-fold higher compared with the IgG form in one case) in human tumor cell lines without any additional crosslinking in vitro. We further demonstrated that these TR1-IgMs dramatically inhibited tumor growth in a xenograft model through the caspase activation cascade. These data suggest that TR1-IgMs may become potential immunotherapeutic agents for cancer therapy. PMID- 27467951 TI - Regulatory B lymphocyte functions should be considered in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is characterized by an abnormal expansion of mature B cells in the bone marrow and their accumulation in blood and secondary lymphoid organs. Tumor CLL cells share expression of various surface molecules with many subsets of B cells and have several common characteristics with regulatory B cells (B regs). However, the identification of B regs and their role in CLL remain elusive. The aim of this review is to summarize recent works regarding the regulatory and phenotypic characteristic of B regs and their associated effects on the immune system. It is also meant to highlight their potential importance with regards to the immunotherapeutic response. PMID- 27467952 TI - Priming of neutrophils toward NETosis promotes tumor growth. AB - Neutrophils play a major role in cancer biology and both pro- and antitumoral functions of tumor-infiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer. PMID- 27467953 TI - The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. AB - INTRODUCTION: Randomized controlled trials of platinum-based neoadjuvant chemotherapy (NAC) for bladder cancer have shown that patients who achieve a pathologic response to NAC exhibit 5 y survival rates of approximately 80-90% while NAC resistant (NR) cases exhibit 5 y survival rates of approximately 30 40%. These findings highlight the need to predict who will benefit from conventional NAC and the need for plausible alternatives. METHODS: The pre treatment biopsy tissues from a cohort of 41 patients with muscle invasive bladder who were treated with NAC were incorporated in tissue microarray and immunohistochemistry for PD-L1, CD8, and FOXP3 was performed. Percentage of PD-L1 positive tumor cells was measured. Tumor-infiltrating lymphocytes (TIL) densities, along with CD8 and Treg-specific TILs, were measured. RESULTS: TIL density was strongly correlated with tumor PD-L1 expression, consistent with the mechanism of adaptive immune resistance in bladder cancer. Tumor cell PD-L1 expression was not a significant predictor of response. Neither was the CD8 nor Treg TIL density associated with response. Intriguingly though, the ratio of CD8 to Treg TIL densities was strongly associated with response (p = 0.0003), supporting the hypothesis that the immune system plays a role in the response of bladder cancer to chemotherapy. DISCUSSION: To our knowledge, this is the first report in bladder cancer showing that the CD8 to Treg TIL density in the pre treatment tissues is predictive for conventional NAC response. These findings warrant further investigations to both better characterize this association in larger cohorts and begin to elucidate the underlying mechanism(s) of this phenomenon. PMID- 27467954 TI - Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting. AB - Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8(+) T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors. PMID- 27467956 TI - Thymic hyperplasia after chemotherapy in adults with mature B cell lymphoma and its influence on thymic output and CD4(+) T cells repopulation. AB - To investigate the thymic regenerative potential in adults accepting chemotherapy for lymphoma. The dynamics of thymic activity in 54 adults from baseline to 12 mo post-chemotherapy was analyzed by assessing thymic structural changes with serial computed tomography (CT) scans, and correlating these with measurements of thymic output by concurrent analysis of single-joint (sj) T-cell receptor excision circles (sjTREC) and CD31(+) recent thymic emigrants (RTE) in peripheral blood. Furthermore, the consequence of thymic renewal on peripheral CD4(+) T cell recovery after chemotherapy was evaluated. Time-dependent changes of thymic size and thymic output assessed by both sjTREC levels and CD31(+) RTE counts in peripheral blood were observed during and after chemotherapy. Enlargement of thymus over baseline following chemotherapy regarded as rebound thymic hyperplasia (TH) was identified in 20 patients aged 18-53 y (median 33 y). By general linear models repeated measure analysis, it was found that, patients with TH (n = 20) had a faster recovery of sjTREC levels and CD31(+) RTE counts after chemotherapy than patients with comparable age, gender, diagnosis, disease stage, thymic volume and output function at baseline but without TH (n = 18) (p = 0.035, 0.047); besides, patients with TH had a faster repopulation of both naive CD4(+) T cell and natural regulatory CD4(+) T cell subsets than those without TH (p = 0.042, 0.038). These data suggested that adult thymus retains the capacity of regeneration after chemotherapy, especially in young adults. The presence of TH could contribute to the renewal of thymopoiesis and the replenishment of peripheral CD4(+) T cell pool following chemotherapy in adults. PMID- 27467955 TI - Immunoprevalence and magnitude of HLA-DP4 versus HLA-DR-restricted spontaneous CD4(+) Th1 responses against telomerase in cancer patients. AB - Cumulative evidence supports that CD4(+) Th1 cells play a key role in antitumor immunity. We previously reported the presence of spontaneous HLA-DR-restricted CD4(+) Th1 responses against telomerase reverse transcriptase (TERT) in various cancers by using promiscuous HLA-DR epitopes. Here, we described novel highly immunogenic HLA-DP4-binding epitopes from TERT named TERT541-555, TERT573-587, TERT613-627 and TERT911-925 and addressed the question about the immunoprevalence and magnitude of the naturally occurring antitumor CD4(+) T cell responses restricted by HLA-DP4 or HLA-DR, the two most common HLA class II. Direct comparative study of spontaneous anti-TERT CD4(+) T cell responses in a cohort of 87 lung cancer patients showed that HLA-DP4 and HLA-DR sustained specific Th1 responses in 10.1% and 25.2% of cancer patients respectively (p = 0.01). The magnitude of the HLA-DR-restricted responses was two to three times significantly higher than HLA-DP one (p = 0.005). Similar results were found in other cancers such as melanoma, breast cancer, renal cell carcinoma and colon cancer. Thus, our results describe for the first time in a large cohort of cancer patients a high immunoprevalence of HLA-DR-restricted spontaneous anti-TERT Th1 immunity compared to HLA-DP restriction. These results provide a new tool for comprehensive monitoring of antitumor CD4(+) Th1 response in various cancers. PMID- 27467957 TI - Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA. AB - T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs. T cells re-directed with the A23 and A94 TCR constructs efficiently recognized malignant HLA-A2(pos) B cells endogenously expressing CD20, including patient-derived follicular lymphoma and chronic lymphocytic leukemia (CLL) cells. In contrast, a wide range of HLA A2(pos)CD20(neg) cells representing different tissue origins, and HLA A2(neg)CD20(pos) cells, were not recognized. Cytotoxic T cells re-directed with CD20p/HLA-A2-specific TCRs or CD19 CARs responded with similar potencies to cells endogenously expressing comparable levels of CD20 and CD19. The CD20p/HLA-A2 specific TCRs recognized CD20p bound to HLA-A2 with high functional avidity. The results show that T cells expressing CD20p/HLA-A2-specific TCRs efficiently and specifically target B cells. When used in context of an HLA-haploidentical allogeneic stem cell transplantation where the donor is HLA-A2(neg) and the patient HLA-A2(pos), these T cells would selectively kill patient-derived B cells and allow reconstitution of the B-cell compartment with HLA-A2(neg) donor cells. These results should pave the way for clinical testing of T cells genetically engineered to target malignant B cells without permanent depletion of normal B cells. PMID- 27467958 TI - Serum anti-MDM2 and anti-c-Myc autoantibodies as biomarkers in the early detection of lung cancer. AB - This study aims to investigate the clinical significance of serum autoantibodies against MDM2 and c-Myc and evaluate their feasibility in the immunodiagnosis of lung cancer. 50 sera samples with 43 available paired lung cancer tissue and adjacent normal tissue slides with follow up information and 44 sera from normal human controls (NHC) were used in the research group. Another 62 lung cancer sera and 43 NHC sera were used in the validation group. The results of IHC showed that MDM2 and c-Myc protein were overexpressed in lung cancer tissues compared to adjacent normal tissues (p < 0.001). Likewise, significantly higher levels of serum autoantibodies against MDM2 and c-Myc were found in lung cancer compared to NHC both in research and validation groups. Further analysis on IHC and ELISA results showed that serum level of autoantibodies against these two TAAs were positively associated with tissue staining scores (both p < 0.05). The area under curve (AUC) values of anti-MDM2 and anti-cMyc autoantibodies for discriminating lung cancers from NHC were 0.698 and 0.636 in research group, 0.777 and 0.815 in the validation group, respectively. Both anti-MDM2 and anti-c-Myc autoantibodies can discriminate stage I lung cancer patients from NHC with AUC values of 0.703 and 0.662. Kaplan-Meier analysis showed that higher level of serum anti-c-Myc autoantibodies was significantly related to shortened disease-free survival (DFS) (p = 0.041). In conclusion, our finding suggested that serum MDM2 and c-Myc autoantibodies may have the potential to serve as non-invasive diagnostic biomarkers in patients with lung cancer. PMID- 27467959 TI - Rituximab-based treatments followed by adoptive cellular immunotherapy for biopsy proven EBV-associated post-transplant lymphoproliferative disease in recipients of allogeneic hematopoietic stem cell transplantation. AB - To improve prognosis of post-transplant lymphoproliferative disease (PTLD), a sequential therapeutic strategy that rituximab-based treatments followed by donor lymphocyte infusion (DLI) or autologous EBV-specific cytotoxic T lymphocytes (EBV CTL) for biopsy-proven EBV-associated PTLD in recipients of allogeneic hematopoietic stem cell transplantation was designed. 84 patients with EBV-PTLD were enrolled in this prospective study. After two cycles of the rituximab-based treatments, 68 of 84 patients (81% [95% CI 71-88]) responded and 52 (62% [51-72]) had CRs. This increased to 73 of 77 patients (95% [87-98]) with completion of sequential cell infusions, and 70 of 77 (91% [82-96]) achieved CRs after DLI or autologous EBV-CTL infusion. 22 patients experienced acute GVHD (aGVHD) (grade I in 5 and grade II in 13, grade III in 4) and 13 chronic GVHD (limited cGVHD in 7 and extensive cGVHD in 6) in 62 patients undergoing a median of three doses of DLI. The incidences of GVHD were similar between DLI and EBV-CTL group (aGVHD 35% vs. 33%, p = 0.876; cGVHD 21% vs. 13%; p = 0.503). EBV-CTL activity after the rituximab-based treatments did not change, while increased after cell infusions and reached its maximum in the 3rd or 6th month after EBV-CTL or DLI treatment, respectively. The 5-y cumulative incidence of PTLD relapse was 4.5% +/- 3.3%. The 5-y overall survival (OS) and progression-free survival (PFS) after PTLD were 70.7% +/- 5.2% and 68.9% +/- 5.3%, respectively. Rituximab-based treatments combined with adoptive cellular immunotherapy might elevate CR rates and reduce relapse of PTLD after allo-HSCT. PMID- 27467960 TI - Lenalidomide enhances myeloma-specific T-cell responses in vivo and in vitro. AB - Immunomodulation is an important part of lenalidomide's mode of action. We analyzed the impact of lenalidomide on T cells from patients with multiple myeloma during lenalidomide therapy in vivo and in patients with lenalidomide refractory disease in vitro Patients enrolled in the German Speaking Myeloma Multicenter Group (GMMG) MM5 trial received a consolidation therapy with two cycles of lenalidomide after autologous stem cell transplantation (ASCT). Half of the study population continued treatment with lenalidomide maintenance therapy for 2 y, while the other patients received lenalidomide maintenance therapy until complete remission. We analyzed 58 patients with (n = 30) or without (n = 28) lenalidomide therapy and 12 patients refractory to lenalidomide with regards to their anti-myeloma-specific T-cell responses displayed by IFNgamma, Granzyme B, and Perforin secretion. The immunophenotype of T-cells was investigated by flow cytometry. Significantly, more myeloma-specific T-cell responses were observed in patients during lenalidomide therapy, compared to patients without treatment. Furthermore, we found on T-cells from patients treated with lenalidomide a decreased CD45RA expression, indicating a maturated immunophenotype and a decreased expression of CD57, indicating functional T cells. An improved myeloma specific T-cell response was observed in 6 out of 12 heavily pretreated patients (refractory to lenalidomide) after in vitro incubation with lenalidomide. Complementary to the results in vivo, lenalidomide decreased CD45RA expression on T cells in vitro. PMID- 27467961 TI - The clinical impact of ICOS signal in colorectal cancer patients. AB - The inducible T-cell co-stimulator (ICOS) belongs to the B7-CD28 immunoglobulin superfamily, which is currently the subject of intense study due to great successes gained in treatment of different malignancies by disrupting their family members. However, the role of ICOS played in colorectal cancer (CRC) remains poorly understood. A tissue microarray (n = 310) was stained with the ICOS specific antibody and ICOS expression is decreased in patients with either lymphatic or distant metastasis and inversely associated with CEA level and TNM stage of CRC patients. Importantly, high ICOS expression is significantly correlated with overall survival (OS) of CRC patients (n = 230, p < 0.001), and ICOS expression is also proved to be an independent prognostic factor by multivariate analysis. Surgical excised CRC specimens (n = 26) were enzymatically digested to get the tumor-infiltrating leukocytes and ICOS is mainly expressed on CD4(+) T cells and its ligand ICOSL is detected on macrophages and tumor cells. ICOS expression level is associated with increased cytotoxic T lymphocyte antigen (CTLA)-4 (p < 0.001) and programmed death (PD-1) (p = 0.005) expression on T cells and more infiltrated CD8(+) T cells (p < 0.001). Interestingly, ICOS(+)CD4(+) cells isolated from tumor tissues have high T-bet and interferon (IFN)gamma expression, the characteristics of Th1 cells, compared to ICOS( )CD4(+) cells. In addition, the correlation between the percentage of ICOS(+)CD4(+) T cells in tumor tissue and peripheral blood was detected. Conclusively, expression of ICOS is associated with improved survival in CRC and percentage of ICOS(+)CD4(+) cells acting as Th1 cells in either primary tumor tissue or peripheral blood may be a clinical biomarker for good prognosis of CRC patients. PMID- 27467962 TI - Combating rituximab resistance by inducing ceramide/lysosome-involved cell death through initiation of CD20-TNFR1 co-localization. AB - Despite the success of CD20 antibody rituximab in immunotherapy, acquired resistance is one of the prime obstacles for the successful treatment of B-cell malignancies. There is an urgent need to intensify efforts against resistance in cancer treatment. Growing evidence indicated that lysosomes may form an "Achilles heel" for cancer cells by sensitizing them to death pathways. Here, we uncover an important role of CD20 in initiation of ceramide/lysosomal membrane permeabilization (LMP)-mediated cell death, showing that colocalization of CD20 TNFR1 after type II CD20 antibody ligation can stimulate de novo ceramide synthesis by ceramide synthase and consequently induce remarkable lysosomal permeabilization (LMP) and lysosome-mediated cell death. Further studies show that the potent lysosome-mediated cell death induced by CD20 antibodies exhibits a profound killing effect against both rituximab-sensitive and -resistant (RR) lymphoma. Furthermore, engineering of rituximab by introducing a point mutation endows it with the ability to induce potent ceramide/LMP-mediated cell death in both RR lymphoma and primary B-cell malignancies from patients with rituximab refractory, suggesting the potential clinical application to combat rituximab resistance. PMID- 27467963 TI - (19)F-MRI for monitoring human NK cells in vivo. AB - The availability of clinical-grade cytokines and artificial antigen-presenting cells has accelerated interest in using natural killer (NK) cells as adoptive cellular therapy (ACT) for cancer. One of the technological shortcomings of translating therapies from animal models to clinical application is the inability to effectively and non-invasively track these cells after infusion in patients. We have optimized the nonradioactive isotope fluorine-19 ((19)F) as a means to label and track NK cells in preclinical models using magnetic resonance imaging (MRI). Human NK cells were expanded with interleukin (IL)-2 and labeled in vitro with increasing concentrations of (19)F. Doses as low as 2 mg/mL (19)F were detected by MRI. NK cell viability was only decreased at 8 mg/mL (19)F. No effects on NK cell cytotoxicity against K562 leukemia cells were observed with 2, 4 or 8 mg/mL (19)F. Higher doses of (19)F, 4 mg/mL and 8 mg/mL, led to an improved (19)F signal by MRI with 3 * 10(11) (19)F atoms per NK cell. The 4 mg/mL (19)F labeling had no effect on NK cell function via secretion of granzyme B or interferon gamma (IFNgamma), compared to NK cells exposed to vehicle alone. (19)F labeled NK cells were detectable immediately by MRI after intratumoral injection in NSG mice and up to day 8. When (19)F-labeled NK cells were injected subcutaneously, we observed a loss of signal through time at the site of injection suggesting NK cell migration to distant organs. The (19)F perfluorocarbon is a safe and effective reagent for monitoring the persistence and trafficking of NK cell infusions in vivo, and may have potential for developing novel imaging techniques to monitor ACT for cancer. PMID- 27467965 TI - Editorial retraction. AB - [This retracts the article DOI: 10.4161/onci.1.2.18241.]. PMID- 27467964 TI - Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma. AB - BACKGROUND: Untreated metastatic uveal melanoma (UM) carries a grave prognosis. Unlike cutaneous melanoma (CM), there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1-PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab. METHODS: To assess the efficacy and safety of pembrolizumab, we retrospectively analyzed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access program (EAP) who received pembrolizumab at 2 mg/kg 3 weekly. Tumor assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (irRC) by CT scanning. Toxicity was recorded utilizing Common Terminology Criteria for Adverse Events ("CTCAE") v4.03. RESULTS: Twenty-five patients were identified receiving a median of six cycles of treatment. Two patients achieved a partial response and six patients stable disease. After a median follow-up of 225 d median progression free survival (PFS) was 91 d and overall survival (OS) was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. Five patients experienced grade 3 or 4 adverse events (AEs); there were no treatment related deaths. CONCLUSIONS: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities. PMID- 27467967 TI - Ability of the National Surgical Quality Improvement Program Risk Calculator to Predict Complications Following Total Laryngectomy. AB - Importance: The accuracy of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) risk calculator has been assessed in multiple surgical subspecialties; however, there have been no publications doing the same in the head and neck surgery literature. Objective: To evaluate the accuracy of the calculator's predictions in a single institution's total laryngectomy (TL) population. Design, Setting, and Participants: Total laryngectomies performed between 2013 and 2014 at a tertiary referral academic center were evaluated using the risk calculator. Predicted 30-day outcomes were compared with observed outcomes for return to operating room, surgical site infection, postoperative pneumonia, length of stay, and venous thromboembolism. Main Outcomes and Measures: Comparison of the NSQIP risk calculator's predicted postoperative complication rates and length of stay to what occurred in this patient cohort using percent error, Brier scores, area under the receiver operating characteristic curve, and Pearson correlation analysis. Results: Of 49 patients undergoing TL, the mean (SD) age at operation was 59 (9.3) years, with 67% male. The risk calculator had limited efficacy predicting perioperative complications in this group of patients undergoing TL with or without free tissue reconstruction or preoperative chemoradiation or radiation therapy with a few exceptions. The calculator overestimated the occurrence of pneumonia by 165%, but underestimated surgical site infection by 7%, return to operating room by 24%, and length of stay by 13%. The calculator had good sensitivity and specificity of predicting surgical site infection for patients undergoing TL with free flap reconstruction (area under the curve, 0.83). For all other subgroups, however, the calculator had poor sensitivity and specificity for predicting complications. Conclusions and Relevance: The risk calculator has limited utility for predicting perioperative complications in patients undergoing TL. This is likely due to the complexity of the treatment of patients with head and neck cancer and factors not taken into account when calculating a patient's risk. PMID- 27467966 TI - Subcritical Water Induced Complexation of Soy Protein and Rutin: Improved Interfacial Properties and Emulsion Stability. AB - Rutin is a common dietary flavonoid with important antioxidant and pharmacological activities. However, its application in the food industry is limited mainly because of its poor water solubility. The subcritical water (SW) treatment provides an efficient technique to solubilize and achieve the enrichment of rutin in soy protein isolate (SPI) by inducing their complexation. The physicochemical, interfacial, and emulsifying properties of the complex were investigated and compared to the mixtures. SW treatment had much enhanced rutin combined capacity of SPI than that of conventional method, ascribing to the well contacted for higher water solubility of rutin with stronger collision-induced hydrophobic interactions. Compared to the mixtures of rutin with proteins, the complex exhibited an excellent surface activity and improved the physical and oxidative stability of its stabilized emulsions. This improving effect could be attributed to the targeted accumulation of rutin at the oil-water interface accompanied by the adsorption of SPI resulting in the thicker interfacial layer, as evidenced by higher interfacial protein and rutin concentrations. This study provides a novel strategy for the design and enrichment of nanovehicle providing water-insoluble hydrophobic polyphenols for interfacial delivery in food emulsified systems. PMID- 27467968 TI - Combined effect of sex and age in response to antiretroviral therapy in HIV infected patients. AB - BACKGROUND: Gender-specific data on the management of HIV infection are scarce. Further, an increase in the proportion of new HIV diagnoses in older persons has been observed. Using data from the CoRIS cohort, we compared immunovirological responses and survival in HIV-infected men and women who started their first combination antiretroviral therapy (cART) when aged < />=50 years. METHODS: We used multivariable logistic, linear and Cox regression, adjusting for potential confounders and including an interaction between age and sex, to assess differences in immunovirological responses and mortality, respectively. RESULTS: At 96 weeks, among subjects <50 years, women were less likely than men to achieve virological response (VR; adjusted OR [aOR] 0.77, 95% CI 0.60, 0.99) and among women, older individuals were more likely to achieve VR than the younger ones (aOR 1.96; 95% CI 1.15, 3.34). Initiating cART at >=50 years was associated with lower increases in CD4+ T-cell count both in men (-65.8; 95% CI -91.3, -40.3) and women (-37.7; 95% CI -79.7, 4.4) and women showed higher increases than men in both subjects aged <50 (21.8; 95% CI -1.9, 45.5) and >=50 years at cART initiation (49.9; 95% CI 19.9, 79.9). A higher risk of death in men >=50 was observed (adjusted hazard ratio [aHR] 2.69; 95% CI 1.73, 4.21), but not in women (aHR 1.49; 95% CI 0.70, 1.14). Women experienced lower mortality than men <50 (0.66; 95% CI 0.41, 1.07) and in those >=50 (0.37; 95% CI 0.14, 0.93). CONCLUSIONS: Sex and age at cART initiation have a noticeable association with both virological and immunological responses and mortality. Age >=50 is associated with poorer immunological response and higher mortality but this effect is less pronounced in women than in men. PMID- 27467969 TI - Discharge BNP is a stronger predictor of 6-month mortality in acute heart failure compared with baseline BNP and admission-to-discharge percentage BNP reduction. AB - INTRODUCTION: Prior studies found a significant relationship between admission B type natriuretic peptide (BNP), discharge BNP and admission-to-discharge percentage BNP reduction and post-discharge mortality in acute heart failure (HF). METHODS: The ESCAPE trial data was utilized to identify which of these BNP parameters best predicts 6-month all-cause mortality. RESULTS: 433 patients (mean age 56years, 74% men) included in our analysis had an admission BNP, discharge BNP and admission-to-discharge percentage BNP reduction of 1009pg/mL, 743pg/mL and -70%, respectively. There were significant differences between survivors and nonsurvivors with regards to admission BNP (P=0.001), discharge BNP (P=0.0001) and admission-to-discharge percentage BNP reduction (P=0.01). Discharge BNP had the highest area under the curve (AUC) for predicting mortality (AUC=0.702, P<0.001) followed by admission BNP (AUC=0.633, P=0.0006) then percentage BNP reduction (AUC=0.620, P=0.008). Comparison of AUC revealed a significant difference between discharge BNP and admission BNP (difference between areas 0.087, P=0.0223) and a trend towards significance when comparing AUC of discharge BNP with percentage BNP reduction (P=0.0637). Kaplan-Meier analysis showed a significant difference in survival according to optimum cutoff values of discharge BNP of 319pg/mL (log-rank P<0.001), admission BNP of 912pg/mL (P<0.001) and percentage BNP reduction of 7.71% (P=0.008). Cox-proportional-hazard-analysis revealed that discharge BNP is an independent predictor of 6-month mortality (hazard ratio=1.063, 95% CI=1.037-1.089, P<0.001). The combination of a discharge BNP <=319pg/mL and percentage BNP reduction >=7.71% was associated with significantly lower mortality (4.8% versus 27.2%, relative risk=0.134, 95% CI=0.046-0.387, P<0.001). CONCLUSION: The absolute BNP value at discharge is a more accurate predictor of 6-month mortality than the magnitude of percentage in hospital BNP reduction and baseline BNP. PMID- 27467970 TI - Neuroendocrine tumours of the gynecological tract. AB - PURPOSE OF REVIEW: The purpose of this article will be to review neuroendocrine tumours (NETs) of the gynaecological tract. NETs are generally considered to be uncommon and primary tumours in the gynaecological tract on arrival rare or very rare. It is important to distinguish true primary tumours from metastatic as the management is very different. These tumours ranged from highly aggressive small cell carcinomas (SCCs) sometimes associated with secretion of neuropeptides that may be functional and cause distinctive syndromes. On the other hand, the well differentiated low-grade NETs generally behave in a very indolent manner with an excellent prognosis. Very recent new data have identified a molecular marker for small cell carcinomas of the ovary although as yet there is no associated candidate drug. RECENT FINDINGS: Recent developments include the identification of a molecular marker for small cell carcinomas of the ovary of hypercalcaemic type; this will help to identify these tumours more confidently. New therapeutic developments for well differentiated NETs include mammalian target of rapamycin pathway inhibitors and peptide receptor radionuclide therapy. SUMMARY: In summary, these are rare tumours with a low incidence although higher prevalence. They require a multidisciplinary approach to management and should be supervised by specialist teams familiar with NETs. PMID- 27467971 TI - Risk-adapted transplant strategies for high-risk Hodgkin lymphoma: are we there? AB - PURPOSE OF REVIEW: The treatment of high-risk classic Hodgkin lymphoma (cHL) patients remains challenging, especially after autologous stem cell transplant (ASCT) failure. Moreover, the outcome of chemorefractory patients is still poor. RECENT FINDINGS: The development of novel targeted therapies has changed the therapeutic options for high-risk patients. To improve outcome, treatment algorithms should integrate up-front, newly established prognostic markers. Tandem ASCT instead of single ASCT has been proposed as an option to improve outcome for high-risk patients. Availability of less toxic reduced intensity conditioning regimens and recent development in haploidentical transplantation have widened applicability and improved outcomes of allo-hematopoietic cell transplantation. Their exact role in cHL is still controversial and there is no consensus on the optimal transplantation strategy. In this context, results of tandem ASCT should also be compared with those of the autologous/reduced intensity conditioning-allo tandem approach. In this review, we discuss how transplantation strategies (auto and allo) can fit into the salvage treatment plan for patients with relapsed/refractory cHL, taking into account the new drugs available and integrating modern risk assessment. SUMMARY: We speculated that improvements could be achieved by transplanting patients in earlier phases of their disease, if necessary after 'bridging' using the new drugs, and we propose an algorithm integrating the different treatment options. PMID- 27467972 TI - Monitoring of Pentoxifylline Thermal Behavior by Novel Simultaneous Laboratory Small and Wide X-Ray Scattering (SWAXS) and Differential Scanning Calorimetry (DSC). AB - The thermal and structural evolutions associated to active pharmaceutical ingredient (API) purity are monitored using a laboratory instrument (S3 MicroCaliX) allowing simultaneous time-resolved X-ray scattering at both wide and small angles (SWAXS) as a function of temperature. This is performed simultaneously with differential scanning calorimetric (DSC) that is carried out in the same apparatus at scanning rate of 2 K/min on the same sample in the range from 20 degrees to 200 degrees C. We have studied simultaneous thermal and structural properties of pentoxifylline, as an active pharmaceutical ingredient (API), for its purity quality control. We have found a satisfying API purity, due to obtained melting temperature and enthalpy values, which are in a well agreement with literature. We have also found that the combination of these techniques allows the thermal monitoring of scanning rates of 2 K/min, continuously without the need for static thermal equilibration, particularly for X-ray spectra. Hence, DSC and SWAXS allowing better identification of the structural thermal events recorded by following of the phase transitions simultaneously. This interpretation is much better possible when X-ray scattering at small and wide angles is coupled with DSC from the same sample. Hence, as a laboratory tool, the method presents a reproducible thermal and crystallographic API purity quality control of non-complex samples, as crucial information for pharmaceutical technology. PMID- 27467973 TI - In memory of Professor Jack Pearce, BSc PhD CChem FRSC FIFST. PMID- 27467974 TI - Biotechnology and Bioengineering: Volume 113, Number 9, September 2016. PMID- 27467975 TI - Cancer metastasis on a chip. PMID- 27467977 TI - Sticky peptides for better gene delivery. PMID- 27467976 TI - Scale-down model development for disk-stack centrifugation. PMID- 27467978 TI - Development of wall-immobilized enzyme microreactors for O2 -dependent bioprocesses. PMID- 27467980 TI - Intrasexual selection favours an immune-correlated colour ornament in a dragonfly. AB - Sexual signalling is predicted to shape the evolution of sex-specific ornamentation, and establishing the costs and benefits of ornamentation and the information that ornamentation provides to receivers is necessary to evaluating this adaptive function. Here, we assessed the adaptive function of a common colour ornament in insects, melanin wing ornamentation, using the dragonfly Pachydiplax longipennis. We hypothesized that greater ornamentation would improve territory-holding success by decreasing aggression that males receive from territorial rivals, but that more ornamented males may have shorter lifespans. Using mark-recapture field observations, we found that more ornamented males had greater territory-holding success and that viability selection did not act on wing melanization. We then compared the aggression of territorial rivals to decoy males before and after experimentally augmenting wing melanization, finding that males significantly reduced aggression following the manipulation. We next hypothesized that wing melanization would signal fighting ability to territorial rivals by reflecting condition via investment in the costly melanin synthesis pathway. We observed a positive relationship between ornamentation and the likelihood of winning territorial disputes, suggesting that wing melanization provides information about fighting ability to rivals. We also found a positive relationship between melanin-based immune defence and ornamentation, supporting a link between the signal and condition. We conclude that wing melanization is a condition-related signal of fighting ability and suggest that this may be a common mechanism promoting the evolution of melanin ornamentation. PMID- 27467981 TI - Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry. AB - The Hemostasis and Thrombosis Research Society (HTRS) Registry was used to monitor the postapproval use of recombinant factor VIIa. The objective of this manuscript is to provide key insights on the demographics of patients with acquired hemophilia in the HTRS Registry. Acquired hemophilia patient registration in HTRS captured age; sex; comorbidities and predisposing conditions; first bleeding location; laboratory parameters; exposure to blood products, factor, and bypassing agents; and initiation of immune suppression/tolerance therapy. Overall, 166 patients with acquired hemophilia were registered in HTRS (83 women, 73 men, median age 70 years); the majority were non-Hispanic whites (61.4%). The most common comorbidities were autoimmune disease (28.4%) and malignancy (14.5%). The most common first site of bleeding was subcutaneous (27.1%); this was more common in whites (29.1%) than blacks (12.5%) and in non-Hispanics (26.4%) than Hispanics (11.8%). Blood product exposure was reported for 33.1% of patients; the most commonly reported product was packed red blood cells (28%). Of the 57 patients with outcome data available for immune tolerance therapy, 26 patients (46%) reported successful treatment, 13 reported unsuccessful treatment (23%), and 18 (32%) were receiving active treatment at the time of registration. The HTRS Registry final analysis provides the only current comprehensive look at acquired hemophilia in the US population, including details on underlying autoimmune diseases and malignancies. Pertinent to recognition and diagnosis of the disease, subcutaneous bleeding as a presenting bleeding symptom was more common in white and non-Hispanic individuals. PMID- 27467982 TI - Impact of shear stress on Src and focal adhesion kinase phosphorylation in fibrinogen-adherent platelets. AB - : Shear stress alone can activate platelets resulting in a subsequent platelet aggregation, so-called 'shear-induced platelet aggregation'. In our work, we analyzed how differently elevated shear stress impacts the Src and focal adhesion kinase (FAK) activation in fibrinogen-adherent human platelets. We detected the extents of Src pY418 and FAK pY397 activations in platelets on immobilized fibrinogen and over BSA under shear conditions. Moreover, we analyzed the role of alphaIIbbeta3 in the shear-induced platelet signaling by performing our experiments in the presence of the alphaIIbbeta3-antagonist Abciximab. Abnormally high shear rates (5000 s) significantly increased the extent of phosphorylation of both tyrosine kinases after short (2 min) incubation time independently of the presence or absence of the integrin alphaIIbbeta3 ligand, fibrinogen. We could see considerably greater Src activation on immobilized fibrinogen than on BSA, but the extent of FAK Y397 phosphorylation was independent on the matrix. Abciximab not only reduced the Src and FAK signaling in platelets exposed to 5000 s on immobilized fibrinogen, but in platelets exposed to 5000 s over BSA as well. Our data indicate that whereas Src activation under shear stress is dominantly ligand-dependent, FAK signaling seems to be mostly shear induced. PMID- 27467983 TI - Does whole blood coagulation analysis reflect developmental haemostasis? AB - : Developmental haemostasis has been well documented over the last 3 decades and age-dependent reference ranges have been reported for a number of plasmatic coagulation parameters. With the increasing use of whole blood point-of-care tests like rotational thromboelastometry (ROTEM) and platelet function tests, an evaluation of age-dependent changes is warranted for these tests as well. We obtained blood samples from 149 children, aged 1 day to 5.9 years, and analysed conventional plasmatic coagulation tests, including activated partial prothrombin time, prothrombin time, and fibrinogen (functional). Whole blood samples were analysed using ROTEM to assess overall coagulation capacity and Multiplate analyzer to evaluate platelet aggregation. Age-dependent changes were analysed for all variables. We found age-dependent differences in all conventional coagulation tests (all P values < 0.05), but there was no sign of developmental changes in whole blood coagulation assessment when applying ROTEM, apart from clotting time in the EXTEM assay (P < 0.03). Despite marked differences in mean platelet aggregation between age groups, data did not reach statistical significance. Citrate-anticoagulated blood showed significantly reduced platelet aggregation compared with blood anticoagulated with heparin or hirudin (all P values < 0.003). We confirmed previous developmental changes in conventional plasmatic coagulation test. However, these age-dependent changes were not displayed in whole blood monitoring using ROTEM or Multiplate analyzer. Type of anticoagulant had a significant influence on platelet aggregation across all age groups. PMID- 27468003 TI - Medical Teacher in Ten Minutes. PMID- 27468002 TI - Hand anthropometric study in northern Colombia. AB - The main purpose of this study is to gather information about the dimensions of the northern Colombian (Caribbean region) population, focusing on the dimensions of the hand and comparing them with measurements from other regions. Thirty-two hand dimensions were chosen and 120 males and 86 females were measured. Results indicated that there were differences between the dimensions of the hand for men and women, showing that men are larger. Also, there was a comparison made between some measurements of other studies in different regions of Colombia, the USA, Chile, Jordan, Korea and Japan. The results indicated important physiological differences between regions in Colombia and across countries. It was therefore concluded that differences in anthropometric measurements must be included in the design and procurement of machinery and apparatus in order to avoid productivity loss, occupational injuries or illness. PMID- 27468005 TI - A GIS-based Matched Case-control Study of Road Characteristics in Farm Vehicle Crashes. AB - BACKGROUND: Farm vehicle-related crashes (crashes) are hazardous for farm and non farm vehicle users; however, most studies examine risk factors of injury given a crash, and shed little light on risk factors of crashes. We evaluated the association of road sinuosity and gradient with crashes in nine Midwestern States from 2005 to 2010. METHODS: We collected crash data from the state departments of transportation, and road segment data from the Environmental Sciences Research Institute. We measured gradient and sinuosity of road segments using ArcGIS. A road segment with a crash was defined as a case (n = 6,848), and that without a crash was defined as a control. Controls were matched to cases by ZIP code, road type, and length in 1:1 (controls = 6,808) matching scheme. In addition, a 1:many control matched scheme was employed such that all road segments adjacent to the case would serve as controls (n = 24,390). We computed odds ratios (OR) and 95% confidence intervals (CIs) using multivariable conditional logistic regression. RESULTS: The adjusted OR of a crash on a road segment with 6%-10% gradient was 0.60 (95% CI: 0.49, 0.75) as compared with a leveled (<1% gradient) road segment. Compared with a straight (<1% sinuosity) road segment, the adjusted OR of a crash on a road segment with 6%-10% sinuosity was 0.38 (95% CI: 0.29, 0.52). CONCLUSIONS: Roads with increased gradient and sinuosity had fewer farm crashes. These associations may be due to cautious driving behaviors on curvy or steep roads and road side signage alerting drivers of impending curve or grade. PMID- 27468004 TI - Ambient Air Pollution-related Mortality in Dairy Cattle: Does It Corroborate Human Findings? AB - BACKGROUND: Despite insights for humans, short-term associations of air pollution with mortality to our knowledge have never been studied in animals. We investigated the association between ambient air pollution and risk of mortality in dairy cows and assessed effect modification by season. METHODS: We collected ozone (O3), particulate matter (PM10), and nitrogen dioxide (NO2) concentrations at the municipality level for 87,108 dairy cow deaths in Belgium from 2006 to 2009. We combined a case-crossover design with time-varying distributed lag models. RESULTS: We found acute and delayed associations between air pollution and dairy cattle mortality during the warm season. The increase in mortality for a 10 MUg/m increase in 2-day (lag 0-1) O3 was 1.2% (95% confidence interval [CI] = 0.3%, 2.1%), and the corresponding estimates for a 10 MUg/m increase in same day (lag 0) PM10 and NO2 were 1.6% (95% CI = 0.0%, 3.1%) and 9.2% (95% CI = 6.3%, 12%), respectively. Compared with the acute increases, the cumulative 26-day (lag 0-25) estimates were considerably larger for O3 (3.0%; 95% CI = 0.2%, 6.0%) and PM10 (3.2%; 95% CI = -0.6%, 7.2%), but not for NO2 (1.4%; 95% CI = -4.9%, 8.2%). In the cold season, we only observed increased mortality risks associated with same-day (lag 0) exposure to NO2 (1.4%; 95% CI = -0.1%, 3.1%) and with 26-day (lag 0-25) exposure to O3 (4.6%; 95% CI = 2.2%, 7.0%). CONCLUSIONS: Our study adds to the epidemiologic findings in humans and reinforces the evidence on the plausibility of causal effects. Furthermore, our results indicate that air pollution associations go beyond short-term mortality displacement. (See video abstract at http://links.lww.com/EDE/B105.). PMID- 27468006 TI - Drinking Water Disinfection By-products, Genetic Polymorphisms, and Birth Outcomes in a European Mother-Child Cohort Study. AB - BACKGROUND: We examined the association between exposure during pregnancy to trihalomethanes, the most common water disinfection by-products, and birth outcomes in a European cohort study (Health Impacts of Long-Term Exposure to Disinfection By-Products in Drinking Water). We took into account exposure through different water uses, measures of water toxicity, and genetic susceptibility. METHODS: We enrolled 14,005 mothers (2002-2010) and their children from France, Greece, Lithuania, Spain, and the UK. Information on lifestyle- and water-related activities was recorded. We ascertained residential concentrations of trihalomethanes through regulatory records and ad hoc sampling campaigns and estimated route-specific trihalomethane uptake by trimester and for whole pregnancy. We examined single nucleotide polymorphisms and copy number variants in disinfection by-product metabolizing genes in nested case-control studies. RESULTS: Average levels of trihalomethanes ranged from around 10 MUg/L to above the regulatory limits in the EU of 100 MUg/L between centers. There was no association between birth weight and total trihalomethane exposure during pregnancy (beta = 2.2 g in birth weight per 10 MUg/L of trihalomethane, 95% confidence interval = 3.3, 7.6). Birth weight was not associated with exposure through different routes or with specific trihalomethane species. Exposure to trihalomethanes was not associated with low birth weight (odds ratio [OR] per 10 MUg/L = 1.02, 95% confidence interval = 0.95, 1.10), small-for-gestational age (OR = 0.99, 0.94, 1.03) and preterm births (OR = 0.98, 0.9, 1.05). We found no gene-environment interactions for mother or child polymorphisms in relation to preterm birth or small-for-gestational age. CONCLUSIONS: In this large European study, we found no association between birth outcomes and trihalomethane exposures during pregnancy in the total population or in potentially genetically susceptible subgroups. (See video abstract at http://links.lww.com/EDE/B104.). PMID- 27468007 TI - Photon Antibunching in Complex Intermolecular Fluorescence Quenching Kinetics. AB - We present a novel fluorescence spectroscopic method, which combines fluorescence antibunching, time-correlated single-photon counting (TCSPC), and steady-state emission spectroscopy, to study chemical reactions at the single molecule level. We exemplify our method on investigating intermolecular fluorescence quenching of Rhodamine110 by aniline. We demonstrate that the combination of measurements of fluorescence antibunching, fluorescence lifetime, and fluorescence steady state intensity, captures the full picture of the complex quenching kinetics, which involves static and dynamics quenching, and which cannot be seen by steady-state or lifetime measurements alone. PMID- 27468008 TI - KOALA RETROVIRUS: A REVIEW. AB - Koala retrovirus (KoRV) is a gammaretrovirus that has been identified in both captive and free-ranging koalas ( Phascolarctos cinereus ) with variable geographic distribution in Australia. KoRV is capable of both exogenous and endogenous transmission, which provides an interesting research platform for scientists to study active retrovirus endogenization into a host genome and offers veterinary scientists an opportunity to examine the clinical consequences of KoRV infection in koalas. Causation between KoRV and frequently recognized clinical conditions associated with immune suppression and neoplasia in koalas has not been definitively established, however research continues to evaluate a potential association. Three KoRV variants, KoRV-A, KoRV-B, and KoRV-J, have been the most thoroughly described and preliminary evidence suggests KoRV variability may be fundamental in host pathogenicity. In addition to reviewing what is currently known about KoRV, this article discusses treatment, management, and future research directions. PMID- 27468009 TI - EFFECT OF epsilon-AMINOCAPROIC ACID ON FIBRINOLYSIS IN PLASMA OF ASIAN ELEPHANTS (ELEPHAS MAXIMUS). AB - epsilon-Aminocaproic acid (EACA) is a lysine analogue antifibrinolytic drug used to treat bleeding disorders in humans and domestic animals. Use in zoological medicine is rare and dose recommendations are anecdotal, but EACA may be a valuable therapeutic option for bleeding disorders in exotic species, including Asian elephants ( Elephas maximus ). This study used an in vitro model of hyperfibrinolysis and a thromboelastograph-based assay to estimate the therapeutic plasma concentration of EACA in Asian elephants (61.5 MUg/ml, 95% CI = 34.6-88.5 MUg/ml). Substantial but incomplete inhibition of lysis was seen at relatively low concentrations of EACA (40 MUg/ml). Asian elephants appear sensitive to EACA-mediated inhibition of hyperfibrinolysis. Doses published for domestic animals, targeting higher plasma concentrations, may be inappropriate in this species. PMID- 27468010 TI - THE IMPACT OF ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS ON THE CAPTIVE ASIAN ELEPHANT (ELEPHAS MAXIMUS) POPULATION OF THE UNITED KINGDOM AND IRELAND (1995-2013). AB - Elephant endotheliotropic herpesvirus (EEHV) is one of the most devastating infections and causes of mortality in captive Asian elephant ( Elephas maximus ) populations. Eight confirmed fatal EEHV cases have occurred since 1995 within the captive Asian elephant population of the United Kingdom and Ireland. This report aims to review the impact of EEHV on the captive Asian elephant population in the United Kingdom and Ireland, document and compare fatal cases, and recommend a framework of monitoring within the United Kingdom and Ireland to increase the success of treatment of EEHV hemorrhagic disease (EEHV HD) in the future. Six zoologic institutions (which include zoos, safari parks, and wildlife parks) that currently house or have previously housed a captive Asian elephant group were included in this report. Medical records and postmortem results were collected from four of these institutions for each confirmed fatal case. EEHV HD was found to be responsible for 29.6% of fatalities in Asian elephants born in captivity in the United Kingdom and Ireland between 1995 and 2013. Following a review of all the cases, it is shown that although clinical signs may be associated with specific EEHV species, the swiftness of disease progression means that most body tissues are impacted 1-6 days following the presentation of visible clinical signs and treatment is less likely to succeed. Therefore, EEHV monitoring should consist of conducting regular polymerase chain reaction analysis of whole blood samples from at-risk, young Asian elephants aged 1-8 yr in order for subclinical viremia to be identified early and treatment to be started before the appearance of visible clinical signs. PMID- 27468011 TI - IMMUNOLOCALIZATION OF INHIBIN/ACTIVIN SUBUNITS AND STEROIDOGENIC ENZYMES IN THE TESTES OF AN ADULT AFRICAN ELEPHANT (LOXODONTA AFRICANA). AB - In this case report, the authors investigated immunolocalization of inhibin alpha and inhibin/activin betaA and betaB subunits, as well as steroidogenic enzymes, in the testes of an African elephant. Testes were collected from a reproductively active male African elephant (24 yr old) at autopsy. Histologically, all types of spermatogenic cells including mature-phase spermatozoa were found in the seminiferous tubules. Positive immunostaining for inhibin alpha and inhibin/activin betaA and betaB subunits was observed in Sertoli and Leydig cells. In addition, P450scc, 3betaHSD, P450c17, and P450arom were also detected in the cytoplasm of Leydig cells. These results suggested that Leydig cells of adult African elephant testes have the ability to synthesize progestin, androgen, and estrogen, whereas both Sertoli and Leydig cells appear as a major source of inhibin secretion in the male African elephant. PMID- 27468012 TI - SEROPREVALENCE OF TOXOPLASMA GONDII IN CAPTIVE ANTILLEAN MANATEE (TRICHECHUS MANATUS MANATUS) IN BRAZIL. AB - Antillean manatees ( Trichechus manatus manatus) are aquatic mammals that inhabit marine waters from Central America to the northeastern region of Brazil, and they are an endangered species. Infection with Toxoplasma gondii through intake of water or food contaminated with oocysts has been reported among marine mammals. The present study aimed to evaluate the prevalence of antibodies to T. gondii in West Indian manatees living in captivity in northeastern Brazil. Serum samples from 55 West Indian manatees from three different captive groups were tested for T. gondii antibodies by means of the modified agglutination test using a cutoff of 1:25. The samples were screened at dilutions of 1:25, 1:50, and 1:500, and positive samples were end-titrated using twofold serial dilutions; antibodies were found in six Antillean manatees (10.9%) with titers of 1:50 in three, 1:500 in one, 1:3,200 in one, and 1:51,200 in one manatee. This study is the first report of T. gondii antibodies in captive Antillean manatees in Brazil. PMID- 27468013 TI - COINFECTION OF CALIFORNIA SEA LION ADENOVIRUS 1 AND A NOVEL POLYOMAVIRUS IN A HAWAIIAN MONK SEAL (NEOMONACHUS SCHAUINSLANDI). AB - The Hawaiian monk seal (Neomonachus schauinslandi) is an endangered species. Here, we present a clinical case of a 26-yr-old male Hawaiian monk seal (HMS) kept in an aquarium with a history of intermittent anorexia and evidence of renal disease. Histologic examination revealed eosinophilic intranuclear inclusions in the liver. Conventional nested PCR protocols were used to test for viruses, and it tested positive for adenovirus and polyomavirus, and negative for herpesvirus. The adenovirus partial polymerase gene is 100% homologous to that of California sea lion adenovirus 1 (CSLAdV-1). CSLAdV-1 causes viral hepatitis in CSL, and has recently been reported in different species of otariids in an aquarium in Japan ( Otaria flavescens and Arctocephalus pusillus ) and a sequence from Spain has been submitted in NCBI as Otaria flavescens adenovirus-1. The polyomavirus in this animal is a novel virus, and is the first polyomavirus discovered in Hawaiian monk seals. This new virus is designated Hawaiian monk seal polyomavirus (HMSPyV 1), and is 83% homologous to California sea lion Polyomavirus-1 (CSLPyV-1). This is the first report of viral coinfection in a HMS and clinical significance in this case remains unclear but may be associated with advanced age. PMID- 27468014 TI - PHARMACOKINETIC STUDY OF ORAL epsilon-AMINOCAPROIC ACID IN THE NORTHERN ELEPHANT SEAL (MIROUNGA ANGUSTIROSTRIS). AB - epsilon-Aminocaproic acid (EACA) is a lysine analogue antifibrinolytic drug used to treat bleeding disorders in humans and domestic animals. Its use in zoological medicine is rare, and dosage is anecdotal. One possible application of EACA is to treat bleeding associated with prepatent Otostrongylus arteritis in Northern elephant seals ( Mirounga angustirostris ) presenting to wildlife rehabilitation centers. This study used an in vitro model of hyperfibrinolysis and a thromboelastograph-based assay to estimate the therapeutic plasma concentration of EACA in elephant seals (85 MUg/ml, 95% confidence interval = 73.8-96.8 MUg/ml). A concurrent pharmacokinetic study of orally administered, single-dose EACA found that doses of 75 and 100 mg/kg achieved therapeutic plasma concentrations (>85 MUg/ml), but the drug was rapidly eliminated and remained in the therapeutic range for only 0.4 and 1.5 hr, respectively. Models of repeated oral dosing at 100 mg/kg every 6 hr predict that therapeutic plasma concentration will be maintained for 31.7% (7.6 hr) of a 24-hr period. More frequent dosing would be required to maintain continuous therapeutic concentrations but would be impractical in a wildlife rehabilitation setting. Further pharmacodynamic studies to evaluate the duration of action of EACA in elephant seals and a prospective, placebo-controlled study are needed to determine if EACA is effective in decreasing bleeding associated with prepatent Otostrongylus arteritis and other bleeding disorders in this species. PMID- 27468015 TI - THE EFFECT OF UVB RADIATION ON SERUM VITAMIN D AND IONIZED CALCIUM IN THE AFRICAN SPOONBILL (PLATALEA ALBA). AB - Metabolic bone disease (MBD) was diagnosed in two chicks produced by a captive breeding colony of African spoonbills (Platalea alba). The birds were housed indoor during the winter breeding season and had no access to natural sunlight. When the index cases occurred, the nesting birds and chicks had a mean 25 hydroxyvitamin D (25-OHD) concentration of 9.9 +/- 2.7 nmol/L and a mean ionized calcium (iCa) concentration of 0.98 +/- 0.12 mmol/L (winter pretreatment). For comparison purposes, serum was collected the following summer; mean 25-OHD was 20.8 +/- 3.9 nmol/L and mean iCa was 1.32 +/- 0.05 mmol/L (summer). During the following breeding season, ultraviolet B (UVB) lighting was provided to the flock, resulting in a mean 25-OHD of 19.0 +/- 5.6 nmol/L and mean iCa of 1.23 +/- 0.06 mmol/L (winter treatment 1). Both 25-OHD and iCa were significantly higher compared with winter pretreatment, and 25-OHD was not significantly different from summer, indicating that treatment during the winter months succeeded in increasing 25-OHD levels to summer levels. However, winter treatment 1 and summer iCa were significantly different. During the next breeding season (winter treatment 2), the birds were exposed to a light with higher UVB output. The mean 25-OHD of the flock was 16.5 +/- 7.2 nmol/L, and the mean iCa increased to 1.34 +/- 0.04 mmol/L. Both were comparable to summer values. Healthy chicks were hatched during both breeding seasons, and no further cases of MBD occurred during the course of the study. Provision of a UVB light source to captive African spoonbills maintained indoors during the winter months can increase 25-OHD and iCa to levels equivalent to those seen in the summer months, when birds have unrestricted access to natural sunlight. UVB lighting is recommended for all breeding spoonbills that do not have access to natural sunlight. PMID- 27468016 TI - PHARMACOKINETICS OF CEFTIOFUR CRYSTALLINE FREE ACID, A LONG-ACTING CEPHALOSPORIN, IN AMERICAN FLAMINGOS (PHOENICOPTERUS RUBER). AB - Antibiotic usage is a vital component of veterinary medicine but the unique anatomy of some species can make administration difficult. The objective of this study was to determine the pharmacokinetic parameters of ceftiofur crystalline free acid (CCFA), a long-acting cephalosporin antibiotic, after parenteral administration in American flamingos ( Phoenicopterus ruber ). A dose of 10 mg/kg of CCFA was administered intramuscularly to 11 birds and blood was collected at various time points from 0 to 192 hr. Pharmacokinetic parameters for ceftiofur equivalents were determined and reached levels above minimum inhibitory concentrations of various bacterial organisms in other avian species through 96 hr in 9/11 birds. Based on these findings and comparison to other avian studies, ceftiofur crystalline free acid appears to be a long-acting antibiotic option for American flamingos. Administration of this antibiotic should be utilized in conjunction with culture and sensitivity of suspected pathogens. PMID- 27468017 TI - COAGULATION PARAMETERS IN THE AMERICAN FLAMINGO (PHOENICOPTERUS RUBER). AB - American flamingos ( Phoenicopterus ruber ) are commonly kept in zoologic collections. When presented to veterinarians in states of health and illness, evaluation of selected coagulation parameters can aid in assessment of various coagulopathies, as well as other disease processes such as septicemia, vasculitis, and hepatic disease. Sixteen American flamingos (eight males, eight females) were presented for annual health evaluations. A blood sample was collected from the medial metatarsal vein, and prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, and fibrin degradation products (FDPs) were evaluated using an automated hemostasis analyzer. Results were reported as median and range (minimum-maximum): PT = 72.7 (39 to >100 sec), APTT = 97.5 (6.1 to >200 sec), fibrinogen = 184 (138-364 mg/dl), and FDPs = <5 (<5 to >20 MUg/ml). To the authors' knowledge, this is the first report of coagulation parameters in American flamingos. Knowledge of coagulation parameters will allow for better clinical assessment and management of American flamingos. PMID- 27468018 TI - PHARMACOKINETIC EVALUATION OF A LONG-ACTING FENTANYL SOLUTION AFTER TRANSDERMAL ADMINISTRATION IN HELMETED GUINEAFOWL (NUMIDA MELEAGRIS). AB - The objective of this study was to investigate the pharmacokinetics of a long acting fentanyl solution in helmeted guineafowl ( Numida meleagris ) after transdermal administration. Twenty-one guineafowl received a single administration of 5 mg/kg of fentanyl transdermal solution. No adverse effects on behavior were appreciated. Plasma fentanyl concentrations were determined by liquid chromatography-mass spectrometry analysis of protein-precipitated samples. Mean maximum plasma concentration was 228.8 ng/ml at 4 hr. The mean plasma terminal half-life was 33.2 hr. At 168 hr the mean plasma concentration was 1.3 ng/ml. A single topical dose of 5 mg/kg appears to be safe for use in this species and maintained plasma concentrations above those reported to be analgesic in dogs for at least 7 days. PMID- 27468019 TI - AN EVALUATION OF INFRARED THERMOGRAPHY FOR DETECTION OF BUMBLEFOOT (PODODERMATITIS) IN PENGUINS. AB - The objective of this study was to evaluate infrared thermography as a noninvasive screening tool for detection of pododermatitis during the developing and active stages of disease in three species of penguins: king penguin (Aptenodytes patagonicus) , macaroni penguin (Eudyptes chrysolophus), and rockhopper penguin (Eudyptes chrysocome). In total, 67 penguins were examined every 3 mo over a 15-mo period. At each exam, bumblefoot lesions were characterized and measured, and a timed series of thermal images were collected over a 4-min period. Three different methods were compared for analysis of thermograms. Feet with active lesions that compromise the surface of the foot were compared to feet with inactive lesions and no lesions. The hypothesis was that feet with active lesions would have warmer surface temperatures than the other conditions. Analysis of the data showed that although feet with active bumblefoot lesions are warmer than feet with inactive or no lesions, the variability seen in each individual penguin from one exam day to the next and the overlap seen between temperatures from each condition made thermal imaging an unreliable tool for detection of bumblefoot in the species studied. PMID- 27468020 TI - EXPLORATORY PLASMA BIOCHEMISTRY REFERENCE INTERVALS FOR URAL OWLS (STRIX URALENSIS, PALLAS 1771) FROM THE AUSTRIAN REINTRODUCTION PROJECT. AB - The Ural owl (Strix uralensis) is the biggest forest-living owl in Austria; however, it became extinct in Austria through poaching and habitat loss more than half a century ago. The birds examined in the present study were breeding pairs from the reintroduction project with the aim of determining exploratory plasma biochemistry reference intervals in Ural owls and evaluating the amount of biological variation between seasons, sexes, and ages. A total of 45 birds were sampled, including 13 adult males, 14 adult females, and 18 juvenile birds. Remarkably, almost all of the analytes showed significant differences between the subgroups, primarily between seasons, followed by age and sex. Only creatinkinase, glucose, lactatdehydrogenase, and triglycerides did not show any significant variations. Despite partitioning of reference values into subgroups according to biological variation diminishing the number of reference individuals in the respective groups, the resulting smaller reference intervals will improve medical assessment. The results of the present study once again demonstrate that significant seasonal fluctuations must be expected and considered in the interpretation. It can be assumed that these differences are probably even greater in free-range birds with considerable changes in food quantity and quality during and between years. PMID- 27468021 TI - COMPARISON OF PRE- AND POSTQUARANTINE BLOOD CHEMISTRY AND HEMATOLOGY VALUES FROM WILD-CAUGHT COWNOSE RAYS (RHINOPTERA BONASUS). AB - Though one of the most widely kept elasmobranchs in human care, the cownose ray (CNR; Rhinoptera bonasus ), remains a species with minimal published information on hematologic reference intervals. As part of a larger study investigating the health and nutrition of the CNR, this study established a preliminary data set of plasma chemistry and hematology values specific to animals recently caught from the wild and compared this data set (intake sample) to values obtained following a period of quarantine (27-40 days) in an aquarium (exit sample). Blood samples were collected from 47 wild female (n = 46) and male (n = 1) CNR caught in pound nets off the coast of North Carolina and South Carolina. Differences between intake and exit values were analyzed. Due to the preponderance of female animals, data were not analyzed for sex differences. Plasma biochemical profiles were performed and analyzed. A select number of complete blood cell counts were performed (n = 24 from 12 animals). Statistically significant differences (P < 0.05) specific to time of sampling were determined for packed cell volume, total solids, blood urea nitrogen, sodium, chloride, potassium, phosphorus, cholesterol, glucose, and aspartate aminotransferase. Values reported are a significant expansion on the existing limited data for CNRs and will serve as a reference for health assessment of individuals both in the wild and in exhibit populations. PMID- 27468022 TI - EPINEPHRINE OR GV-26 ELECTRICAL STIMULATION REDUCES INHALANT ANESTHESTIC RECOVERY TIME IN COMMON SNAPPING TURTLES (CHELYDRA SERPENTINA). AB - Prolonged anesthetic recovery times are a common clinical problem in reptiles following inhalant anesthesia. Diving reptiles have numerous adaptations that allow them to submerge and remain apneic for extended periods. An ability to shunt blood away from pulmonary circulation, possibly due to changes in adrenergic tone, may contribute to their unpredictable inhalant anesthetic recovery times. Therefore, the use of epinephrine could antagonize this response and reduce recovery time. GV-26, an acupuncture point with reported beta adrenergic and respiratory effects, has reduced anesthetic recovery times in other species. In this prospective randomized crossover study, six common snapping turtles (Chelydra serpentina) were anesthetized with inhalant isoflurane for 90 min. Turtles were assigned one of three treatments, given immediately following discontinuation of isoflurane: a control treatment (0.9% saline, at 0.1 ml/kg i.m.), epinephrine (0.1 mg/kg i.m.), or acupuncture with electrical stimulation at GV-26. Each turtle received all treatments, and treatments were separated by 48 hr. Return of spontaneous ventilation was 55% faster in turtles given epinephrine and 58% faster in the GV-26 group versus saline (P < 0.001). The times to movement and to complete recovery were also significantly faster for both treatments than for saline (P < 0.02). Treated turtles displayed increases in temperature not documented in the control (P < 0.001). Turtles administered epinephrine showed significantly increased heart rates and end-tidal CO(2) (P < 0.001). No adverse effects were noted in the study animals. The mechanisms of action were not elucidated in the present investigation. Nevertheless, the use of parenteral epinephrine or GV-26 stimulation in the immediate postanesthetic period produces clinically relevant reductions in anesthetic recovery time in common snapping turtle. Further research is necessary to evaluate the effects of concurrent GV-26 and epinephrine administration and to assess responses in other reptilian species. PMID- 27468023 TI - PRELIMINARY EVALUATION OF SPIROTOME(r) DEVICE FOR LIVER BIOPSY IN GREEN IGUANAS (IGUANA IGUANA): A PILOT STUDY. AB - The aim of this study was to evaluate a large-core manual biopsy device (Spirotome((r)), Medinvents, 3500 Hasselt, Belgium) for liver sampling and histologic diagnosis in green iguanas (Iguana iguana). The study included eight green iguanas, and two ultrasound-guided biopsies were collected for each lizard, for 16 biopsies in total. The procedure was carried out under general anesthesia induced by intravenous injection of propofol (10 mg/kg) maintained with a mixture of 2.0% isoflurane and 0.8-1.2 L/min oxygen after tracheal intubation. Fourteen (87.5%) of the 16 biopsies were considered diagnostic. Liver biopsy quality was assessed according to sample size and tissue preservation. In particular, mean length (16.2 +/- 4.5 mm), width (2.2 +/- 0.5 mm), area (34.8 +/- 6.9 mm(2)), and number of portal areas (9.4 +/- 3.9) of each biopsy were recorded for all green iguanas. The total available surface of the sections obtained from the biopsies and their grade of preservation enabled a satisfactory evaluation of the parenchymal architecture. One of the green iguanas in the study died the day after the procedure due to severe hemocoeloma. Risk assessment evaluation suggested that small green iguanas may not be suitable for this biopsy procedure. PMID- 27468024 TI - THE EFFECT OF A SLOW-RELEASE FORMULATION OF ZUCLOPENTHIXOL ACETATE (ACUNIL(r)) ON CAPTIVE BLUE WILDEBEEST (CONNOCHAETES TAURINUS) BEHAVIOR AND PHYSIOLOGICAL RESPONSE. AB - The study investigated the effect of a slow-release formulation of zuclopenthixol acetate (Acunil(r)) on blue wildebeest ( Connochaetes taurinus ) in captivity. Two groups of trials were conducted using either Acunil or a placebo (control). Animals (Acunil: n = 17; placebo: n = 12) were observed for a 12-hr period before the administration of Acunil or the placebo (pretreatment). After 24 hr, animals were administered Acunil (1.5 mg/kg) or a placebo (1.0-3.0 ml of sterile water) and observed again for 12 hr (posttreatment). During both treatments, animals were stimulated every 2 hr for 1 min by a person entering the enclosure (referred to as periods of stimulation). Behavioral observations and continuous heart rate, respiration rate, and motion measurements were taken throughout. Animals treated with Acunil spent more time lying with their heads folded back, eating and standing with their heads down, and less time being vigilant and exploring while walking around. Animals treated with the placebo also spent less time being vigilant and more time lying with heads up. Animals treated with Acunil groomed less while standing and performed less head shaking; no such changes were observed in the control group. Neither Acunil nor the placebo had any effect (P > 0.05) on heart rate. However, overall mean respiration rate was lowered (P = 0.02) when animals were treated with Acunil (pretreatment: 14.5 +/- 0.82 breaths/min; posttreatment: 12.5 +/- 0.83 breaths/min). Acunil also caused a lowered (P < 0.05) respiration rate during periods when animals were stimulated (pretreatment: 16.2 +/- 0.87 breaths/min; posttreatment: 13.7 +/- 0.87 breaths/min) and when animals were trotting and being vigilant. No such changes were observed with the placebo. Both placebo- and Acunil-treated animals spent more time being stationary during periods of stimulation. However, Acunil-treated animals also spent less time moving fast when they were stimulated. PMID- 27468025 TI - BILIRUBIN CONCENTRATIONS IN CLINICALLY HEALTHY AND DISEASED CAPTIVE WATERBUCK (KOBUS ELLIPSIPRYMNUS) AT THE SAN DIEGO ZOO SAFARI PARK. AB - Captive waterbuck ( Kobus ellipsiprymnus ) that appear clinically healthy have been noted to have high serum bilirubin concentrations compared with other ruminants; however, questions remain about the physiologic factors affecting bilirubin concentration and its potential association with underlying disease and icteric serum or mucous membranes. Serum bilirubin concentrations of healthy and diseased waterbuck housed at the San Diego Zoo Safari Park from 1989 to 2012 were retrospectively analyzed to determine any link between icteric serum, total bilirubin concentration (tBili), and disease entities in this species. Total bilirubin and direct (dBili) bilirubin concentrations and the prevalence of icteric serum were compared by subspecies, age group, and health status; associations with complete blood count and biochemical results and clinical diagnosis were assessed. No significant differences were found in tBili or dBili between Ellipsen (n = 32) and Defassa (n = 29) subspecies or in juveniles (n = 22) versus adults (n = 39). Clinically healthy waterbuck (n = 40) had significantly higher tBili (mean +/- 2SD, 7.9 +/- 1.2 mg/dl; P < 0.001) and dBili (3.7 +/- 1.0 mg/dl; P < 0.001) than did diseased waterbuck (n = 21; tBili: 4.9 +/ 2.56 mg/dl; dBili: 2.2 +/- 0.8 mg/dl). No waterbuck had icteric tissues on physical examination. Twelve (19.7%) waterbuck (six healthy, six diseased) had icteric serum. Few minor correlations were seen between tBili or dBili and clinical, laboratory, or necropsy evidence of disease, though an inverse correlation between dBili and blood glucose was noted. Of the 40 healthy animals, reference intervals were calculated for tBili (5.5-10.3 mg/dl), dBili (1.7-5.7 mg/dl), and indirect bilirubin (2.2-6.2 mg/dl). These results suggest healthy waterbuck have relatively high tBili and dBili compared with related species. Icteric serum may be seen in up to 15% of healthy animals in the absence of icteric tissues. PMID- 27468026 TI - GREATER KUDU (TRAGELAPHUS STREPSICEROS) MORTALITY IN EUROPEAN ZOOLOGICAL INSTITUTIONS: A RETROSPECTIVE STUDY. AB - A questionnaire was sent to 39 European institutions holding greater kudus (Tragelaphus strepsiceros), in order to determine the causes of captive greater kudu mortality. All reported macroscopic lesions and histopathologic observations, as well as other information regarding individuals that died, were analyzed to determine the most affected body systems and causes of death. Overall response rate was 31%, and 131 individuals were included in the study. The most frequently affected body systems were the digestive system (47%), respiratory system (38%), musculoskeletal system (37%), and cardiovascular system (32%). Most frequent causes of death were infectious diseases (27%) and trauma/accidents (18%); the cause was undetermined in 28% of cases. Nutrition-related disorders were difficult to assess, but results highlight possible nutritional imbalances. This retrospective study represents the first overview of greater kudu mortality in a captive population. PMID- 27468027 TI - CHARACTERIZATION OF VIRULENCE GENES AND ANTIMICROBIAL RESISTANCE OF LUNG PATHOGENIC ESCHERICHIA COLI ISOLATES IN FOREST MUSK DEER (MOSCHUS BEREZOVSKII). AB - This study investigated genotypic diversity, 26 virulence genes, and antimicrobial susceptibility of lung pathogenic Escherichia coli (LPEC) isolated from forest musk deer. Associations between virulence factors (VFs) and phylogenetic group, between antimicrobial resistance (AMR) and phylogenetic group, and between AMR and VFs were subsequently assessed. The results showed 30 LPEC isolated were grouped into seven different clusters (A, B, C, D, E, F, and G). The detection rates of crl (90%), kpsMT II (76.67%), mat (76.67%), and ompA (80%) were over 75%. The most frequent types of resistance were to amoxicillin (100%), sulfafurazole (100%), ampicillin (96.67%), and tetracycline (96.67%), with 93.33% (n = 28) of isolates resistant to more than eight types of drugs. There were significant relationships between resistance to cefalotin and the presence of iucD(a) (P < 0.001), papC (P = 0.032), and kpsMT II (P = 0.028); between resistance to chloromycetin and the presence of irp2 (P = 0.004) and vat (P = 0.047); between resistance to nalidixic acid and the presence of crl (P = 0.002) and iucD(a) (P = 0.004); and between resistance to ampicillin/sulbactam and the presence of vat (P = 0.013). These results indicated there could be some association between resistance and VFs, and there is a great need for the prudent use of antimicrobial agents in LPEC. PMID- 27468028 TI - CANINE DISTEMPER VIRUS ANTIBODY TITERS IN DOMESTIC CATS AFTER DELIVERY OF A LIVE ATTENUATED VIRUS VACCINE. AB - Three methods for delivering a live attenuated canine distemper virus (CDV) vaccine to domestic cats ( Felis catus ) were investigated, as models for developing vaccination protocols for tigers (Panthera tigris). Twenty domestic cats were randomly divided into four treatment groups: saline injection (negative controls); and oral, intranasal, and subcutaneous vaccinates. Cats were injected with saline or a CDV vaccine (Nobivac DP, Merck) at wk 0 and 4. Blood and nasal swabs were collected at wk 0 (prior to the initial vaccination) and weekly thereafter for 9 wk. Urine samples were collected on wk 1 to 9 after initial vaccination. Forty-nine weeks following the initial vaccination series, three cats from the subcutaneous group and three cats from the intranasal group were revaccinated. Blood was collected immediately prior, and 7 and 21 days subsequent to revaccination. Nasal swabs and urine samples were collected from each cat prior to wk 49 revaccination and daily for 7 days thereafter. Nasal swabs and urine were analyzed by quantitative PCR for vaccine virus presence. Sera were tested for CDV antibodies by virus neutralization. All cats were sero-negative for CDV antibodies at the beginning of the study, and saline-injected cats remained sero-negative throughout the study. A dramatic anamnestic response was seen following wk 4 subcutaneous vaccinations, with titers peaking at wk 6 (geometric mean = 2,435.5). Following wk 49 revaccination, subcutaneous vaccinates again mounted impressive titers (wk 52 geometric mean = 2,048). Revaccination of the intranasal group cats at wk 49 produced a small increase in titers (wk 52 geometric mean = 203). CDV viral RNA was detected in six nasal swabs but no urine samples, demonstrating low viral shedding postvaccination. The strong antibody response to subcutaneous vaccination and the lack of adverse effects suggest this vaccine is safe and potentially protective against CDV infection in domestic cats. PMID- 27468029 TI - EVALUATION OF TWO CANINE DISTEMPER VIRUS VACCINES IN CAPTIVE TIGERS (PANTHERA TIGRIS). AB - Canine distemper virus (CDV) has caused clinical disease and death in nondomestic felids in both captive settings and in the wild. Outbreaks resulting in high mortality rates in tigers (Panthera tigris) have prompted some zoos to vaccinate tigers for CDV. In this study, six tigers received a recombinant canarypox vectored CDV vaccine (1 ml s.c.) and were revaccinated with 3 ml s.c. (mean) 39 days later. Blood collection for CDV antibody detection via serum neutralization was performed on (mean) days 0, 26, and 66 post-initial vaccination. No tigers had detectable antibodies at days 0 or 26, and only two tigers had low (16 and 32) antibody titers at day 66. Eight additional tigers received a live, attenuated CDV vaccine (1 ml s.c.) on day 0 and were revaccinated with 1 ml s.c. (mean) 171 days later. Blood collection for CDV antibody detection via serum neutralization was performed on (mean) days 0, 26, 171, and 196. Seven of eight tigers receiving the live, attenuated vaccine had no detectable titers prior to vaccination, but all animals had titers of >128 (range 128-1,024) at day 26. At 171 days, all tigers still had detectable titers (geometric mean 69.8, range 16 256), and at 196 days (2 wk post-revaccination) all but two showed an increase to >128 (range 32-512). To determine safety, an additional 41 tigers were vaccinated with 2 ml of a recombinant vaccine containing only CDV components, and an additional 38 tigers received 1 ml of the live, attenuated vaccine, administered either subcutaneously or intramuscularly; no serious adverse effects were noted. Although both vaccines appear safe, the live, attenuated vaccine produced a stronger and more consistent serologic response in tigers. PMID- 27468030 TI - HEMATOLOGICAL AND SERUM BIOCHEMICAL VALUES IN ANESTHETIZED CAPTIVE TASMANIAN DEVILS (SARCOPHILUS HARRISII). AB - The Tasmanian devil (Sarcophilus harrisii) population has decreased by estimates of 80% in the past 20 yr due to the effects of devil facial tumor disease (DFTD). In the process of creating a DFTD-free insurance population, the captive population and the number of institutions housing devils worldwide has increased tremendously. In order to provide the best husbandry and veterinary care for these captive animals, it is essential to know normal hematology and biochemistry values for the species. Baseline reference intervals (RIs) were determined for hematology and biochemistry variables for 170 healthy anesthetized captive Tasmanian devils and significant sex and age differences were determined. Higher relative neutrophil counts, hemoglobin, mean corpuscular hemoglobin (MCH), creatinine, creatine phosphokinase, and cholesterol were seen in males compared to females, whereas higher white cell counts (WBC) and lymphocyte counts (absolute and relative) were seen in females. Subadults have higher red blood cell counts, WBC, lymphocytes (absolute and relative), calcium and phosphorus, alkaline phosphatase, glutamate dehydrogenase, glucose, and albumin than adults; whereas, adults have higher relative neutrophils, relative eosinophils, mean corpuscular volume, MCH, platelets, total solids, total plasma proteins, globulins, and chloride than subadults. This study provides a comprehensive report of hematology and serum biochemistry RIs for healthy captive anesthetized Tasmanian devils and offers invaluable diagnostic information to care for the growing captive population of this endangered marsupial. PMID- 27468031 TI - RADIOGRAPHIC AND ULTRASONOGRAPHIC ABDOMINAL ANATOMY IN CAPTIVE RING-TAILED LEMURS (LEMUR CATTA). AB - The ring-tailed lemur (Lemur catta) is primarily distributed in south and southwestern Madagascar. It is classified as an endangered species by the International Union for Conservation of Nature. Various abdominal diseases, such as hepatic lipidosis, intestinal ulcers, cystitis, urinary tract obstruction, and neoplasia (e.g., colonic adenocarcinoma and cholangiocarcinoma), have been reported in this species. The aim of this study was to describe the normal radiographic and ultrasonographic abdominal anatomy in captive ring-tailed lemurs to provide guidance for clinical use. Radiography of the abdomen and ultrasonography of the liver, spleen, kidneys, and urinary bladder were performed in 13 and 9 healthy captive ring-tailed lemurs, respectively, during their annual health examinations. Normal radiographic and ultrasonographic reference ranges for abdominal organs were established and ratios were calculated. The majority (12/13) of animals had seven lumbar vertebrae. The sacrum had mainly (12/13) three segments. Abdominal serosal detail was excellent in all animals, and hypaxial muscles were conspicuous in the majority (11/13) of animals. The spleen was frequently (12/13) seen on the ventrodorsal (VD) view and rarely (3/13) on the right lateral (RL) view. The liver was less prominent and well contained within the ribcage. The pylorus was mostly (11/13) located to the right of the midline. The right and left kidneys were visible on the RL and VD views, with the right kidney positioned more cranial and dorsal to the left kidney. On ultrasonography, the kidneys appeared ovoid on transverse and longitudinal views. The medulla was hypoechoic to the renal cortex. The renal cortex was frequently (8/9) isoechoic and rarely (1/9) hyperechoic to the splenic parenchyma. The liver parenchyma was hypoechoic (5/5) to the renal cortex. Knowledge of the normal radiographic and ultrasonographic abdominal anatomy of ring-tailed lemurs may be useful in the diagnosis of diseases and in routine health examinations. PMID- 27468032 TI - LEISHMANIA INFANTUM INFECTION IN BENNETT'S WALLABIES (MACROPUS RUFOGRISEUS RUFOGRISEUS) IN A SPANISH WILDLIFE PARK. AB - Although dogs are the main reservoir for human Leishmania infantum infection, the disease has also been reported in other domestic and wild mammals. In 2011, a fatal case of naturally acquired leishmaniosis was described for the first time in a Bennett's wallaby (Macropus rufogriseus rufogriseus) kept in a wildlife park in Madrid (Spain). This study was designed to assess the infection status of twelve Bennett's wallabies in the same park one year after this incident. Phlebotomus perniciosus, the main vector of L. infantum in Spain, was screened for using sticky and Centers for Disease Control miniature light traps. L. infantum infection was confirmed by molecular diagnosis in four animals, but only one wallaby returned a positive serology result. The presence of the sand fly vector was also confirmed in this habitat. These results suggest that the first case of L. infantum in a wallaby in this park was not an isolated incident and stress the need for further work to determine the role of this parasite in the morbidity and mortality of these macropods. Madrid was recently the scene of an outbreak of human cutaneous and visceral leishmaniosis. Epidemiological studies have so far revealed the widespread presence of L. infantum infection in animals other than the dog. Our ongoing work suggests a risk of L. infantum infection not only among captive animals in Madrid, but also among threatened species or even species that are already extinct in the wild. PMID- 27468033 TI - BODY DISTRIBUTION OF HANNEMANIA SP. (ACARI: LEEUWENHOEKIIDAE) IN RHINELLA SPINULOSA, PLEURODEMA BUFONINA, AND PLEURODEMA THAUL FROM CHILE. AB - Hannemania larvae are parasites of amphibians in North and South America. In Chile, only one species of Hannemania has been reported from Batrachyla taeniata (banded wood frog). The objective of the study was to determine the abundance and body distribution of Hannemania among three amphibians from Antuco (Biobio Region, Chile): Pleurodema thaul (13 adults; Chile four-eyed frog), Pleurodema bufonina (5 adults; large four-eyed frog), and Rhinella spinulosa (15 adults and 16 juveniles; warty toad). Amphibians (82.75 %; n = 49) were infested with Hannemania. The infestation rate in R. spinulosa juveniles was lower than in adults (68 versus 100%, respectively; mean larval intensity: juvenile = 3.2 +/- 2.5 and adult = 17.3 +/- 16.3). Mean intensity of larval infestation in P. bufonina (63.2 +/- 47.9) was higher than in the other two species of amphibians (R. spinulosa adult: 17.3 +/- 16.3; R. spinulosa juvenile: 3.2 +/- 2.5; P. thaul: 11.62 +/- 7.8). There was no significant association between body size and mean intensity of infestation. The inguinal region, ventrum, and dorsal forearm region were the most parasitized. These body zones would be in direct contact with the substrate making the infestation easier for the larvae. This study represents the first record of Hannemania sp. in P. bufonina, R. spinulosa, and P. thaul in Chile. PMID- 27468034 TI - VITAMIN B6 (PYRIDOXINE HYDROCHLORIDE) TOXICOSIS IN FALCONS. AB - This manuscript reports three independent accidental cases of vitamin (Vit) B6 toxicosis in gyrfalcons (Falco rusticolus) and peregrine falcons (Falco peregrinus) and a toxicology study that was conducted to characterize the clinical responses of gyrfalcons and gyrfalcon * peregrine falcons to a range of single intramuscular (IM) and oral (PO) doses of Vit B6. Both lethal and nonlethal doses were determined. Twelve female gyrfalcons died following IM injection of 1 ml of a vitamin B preparation. Within 30 min of injection, the birds passed pistachio green-colored urates and progressed to vomiting, anorexia, cessation of normal activity, ptosis, collapse, and death, occurring 24-36 hr post injections. Three individuals vomited frothy, partially digested blood and had clonic spasms and convulsions. Postmortem and histopathology revealed multifocal severe hepatic necrosis, splenic lymphoid tissue depletion and hemorrhages with arterial necrosis, and acute renal tubular necrosis. Following administration of a different, oral, mineral-vitamin supplement, a total of 21 peregrine falcons in two separate European facilities died suddenly. Histology of the liver showed diffuse congestion and multifocal coagulative necrosis with mild infiltration of heterophils. The particular nutritional supplement, used by both breeders, was analyzed and found to contain 5-9.7% Vit B6. Other randomly selected lots of the product contained 0.007-0.27% Vit B6. According to the product label, Vit B6 should have been present at 0.004%. To confirm the hypothesis that Vit B6 was responsible for the deaths of the falcons in Abu Dhabi, Vit B6 (British Pharmacopoeia [BP] grade) in powder form was diluted in water for injection and administered IM to four groups of falcons. Groups of four gyrfalcon * peregrine hybrid falcons or gyrfalcons (or both) were given a single IM dose of 5, 10, 15, or 20 mg/kg of Vit B6 or received an oral dose of 25, 50, or 75 mg of Vit B6. Only birds in the lowest-dose groups survived. The maximum nonlethal single doses of Vit B6 in falcons were 5 mg/kg i.m. and 25 mg/kg p.o. PMID- 27468035 TI - DIAGNOSIS AND MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA IN A PIED TAMARIN (SAGUINUS BICOLOR). AB - An intact male pied tamarin (Saguinus bicolor) presented with a hunched posture while moving, dysuria, pollakiuria, and hematuria. After diagnostic imaging assessment and prostate biopsy, benign prostatic hyperplasia was diagnosed. Treatments with delmadinone acetate and osaterone caused clinical signs and hematuria to resolve temporarily for a variable period of time. Because of frequent recurrence, elective surgical castration was performed, leading to resolution of the clinical signs. PMID- 27468036 TI - MANAGEMENT OF ENDOMETRIOSIS IN TWO CAPTIVE MANDRILLS (MANDRILLUS SPHINX). AB - Endometriosis has been reported in humans, great apes, and Old World monkeys. Although cases are noted anecdotally in Mandrillus spp., and a previously reported case was noted on postmortem examination, to the authors' knowledge, no previous reports of case management have been published in the peer-reviewed literature. This paper describes the medical and surgical management of endometriosis in two mandrills (Mandrillus sphinx). PMID- 27468037 TI - INTRAOCULAR SILICONE BALL IMPLANTATION AFTER EVISCERATION IN A SLOW LORIS (NYCTICEBUS COUCANG). AB - A slow loris, Nycticebus coucang , was brought to Ji Dong Beom Animal Hospital from the National Institute of Ecology due to globe enlargement and frequent blepharospasm of the right eye. Ophthalmic diagnoses included glaucoma with posterior lens luxation and cataract. Because this animal was on exhibition at the National Institute of Ecology, preservation of the eyeball by intraocular silicone implantation following evisceration rather than enucleation was selected. Before the surgery, examination of the normal left eye was performed using Retcam and spectral domain optical coherence tomography. Three months later, the globe size was almost the same as the left eye; however, corneal edema remained. PMID- 27468038 TI - KLOSSIELLA DULCIS N. SP. (APICOMPLEXA: KLOSSIELLIDAE) IN THE KIDNEYS OF PETAURUS BREVICEPS (MARSUPIALIA: PETAURIDAE). AB - Two cases of renal klossiellosis were diagnosed by histopathology in pet sugar gliders (Petaurus breviceps). In both cases, parasites were associated with tubular dilation and mild interstitial nephritis. Rare schizonts were seen in the proximal convoluted renal tubular epithelium, whereas all other life cycle stages were found within distal convoluted tubule cells or the urinary space of the structures distal to the loop of Henle. Conventional optical and transmission electron microscopies were used to assess the life stages of the parasite. The morphologic characteristics and measurements observed differ from those of previously described species of Klossiella infecting marsupial hosts, and the name Klossiella dulcis n. sp. is hereby proposed. This is the first report of a Klossiella sp. infection in Petaurus breviceps . PMID- 27468040 TI - HYDROCEPHALUS IN THREE JUVENILE NORTH AMERICAN BLACK BEARS (URSUS AMERICANUS). AB - Hydrocephalus has been reported in a variety of species, including the North American black bear ( Ursus americanus ). This report describes three cases of hydrocephalus in this species from wild bears aged 3-4 mo considered retrospectively from necropsy records of one institution. Clinical signs included cortical blindness and ataxia. Primary gross findings were doming of the skull, gyri compression and flattening, and lateral ventricle dilation. Two cases had severe bilateral ventricular dilation with loss of the septum pellucidum; atrophy of the surrounding corpus callosum; and bilateral periventricular tears involving the caudate nuclei, internal capsule, and adjacent cerebrum. Histologically, the cases with periventricular tearing had severe axonal loss and degeneration, malacia, hemorrhage, and variable periventricular astrocytosis. All cases were likely congenital, given the bears' age and lack of an apparent acquired obstruction. PMID- 27468039 TI - HYPOALDOSTERONISM IN A MATSCHIE'S TREE KANGAROO (DENDROLAGUS MATSCHIEI). AB - A 20-yr-old female Matschie's tree kangaroo (Dendrolagus matschiei) was diagnosed with hypoaldosteronism, a rare condition in which the body fails to produce normal amounts of the mineralocorticoid aldosterone. Aldosterone plays a key role in body salt homeostasis, increasing sodium reabsorption and promoting excretion of potassium. Hypoaldosteronism resulted in decreased appetite, lethargy, and weight loss in conjunction with hyponatremia, hyperkalemia, and hypercalcemia in this tree kangaroo. The animal was successfully managed with mineralocorticoid replacement using desoxycorticosterone pivalate. To the authors' knowledge this is the first report of hypoaldosteronism in a tree kangaroo and one of the few reports in the veterinary literature in any species. PMID- 27468041 TI - EAR AND TAIL LESIONS ON CAPTIVE WHITE-TAILED DEER FAWNS (ODOCOILEUS VIRGINIANUS): A CASE STUDY. AB - During the 2008-2011 time period, undiagnosed lesions were observed in 21 of 150 white-tailed deer fawns (Odocoileus virginianus) that were part of a captive deer herd at Mississippi State University. Clinical findings in healthy and diseased fawns from 0 to 90 days of age included bite and scratch marks followed by moderate to severe ear and tail necrosis. Gross necropsy findings of necrotizing ulcerative dermatitis correlated with histopathologic findings that included focally severe multifocal vasculitis, vascular necrosis, and thrombosis. This article is a clinical description of these previously unreported lesions associated with tissue necrosis in young captive white-tailed deer. PMID- 27468042 TI - BLASTOCYSTIS SP. AND BLASTOCYSTIS RATTI IN A BRAZILIAN PORCUPINE (COENDOU PREHENSILIS) WITH DIARRHEA. AB - A hand-raised, 5-mo-old, intact male Brazilian porcupine (Coendou prehensilis) was evaluated for chronic diarrhea, failure to thrive, and anorexia. On presentation the porcupette was dull, dehydrated, and passing yellow, malodourous, watery diarrhea. Cytologic examination of feces revealed a large number of organisms, morphologically consistent with Blastocystis. Blastocystis polymerase chain reaction (PCR) performed on feces was positive. Direct sequencing on two sequential samples confirmed the presence of Blastocystis ratti and a novel Blastocystis sequence. The porcupette was treated supportively, which included a 4-wk metronidazole course. Diarrhea resolved within 2 wk of treatment, and the animal's growth rate dramatically improved. Recheck PCR was negative for Blastocystis. Although an important and controversial cause of diarrhea in immunocompromised humans, this organism is not well recognized as a potential pathogen and zoonosis in zoo animals. Clinicians should be aware of the potential for disease associated with this organism, especially in immunocompromised animals. PMID- 27468043 TI - CLINICAL MANAGEMENT OF BILATERAL CUTANEOUS SQUAMOUS CELL CARCINOMA OF THE HIND FEET PADS IN A SOUTHERN WHITE RHINOCEROS (CERATOTHERIUM SIMUM SIMUM). AB - The current report describes the temporary regression, due to intensive symptomatic treatment, of ulcerative skin lesions caused by squamous cell carcinoma in a white rhinoceros. A captive, 40-yr-old southern white rhinoceros (Ceratotherium simum simum) developed profound, ulcerative skin lesions on the pads of both hind feet. At the peak of the disease, at least one quarter of the pads was affected. A diagnosis of squamous cell carcinoma was made via biopsy. Treatment included anti-inflammatory drugs, antibiotics, and local care. The lesions regressed on both feet until they seemed clinically healed. It was presumed that long-term, anti-inflammatory treatment and local bandaging had induced the temporary regression of the lesions. Two years later, however, a small ulcerative lesion reappeared on one pad and post mortem examination confirmed that the carcinoma was also histologically present in the clinically intact tissue. No metastasis was found and computed tomography showed normal digital bones. PMID- 27468044 TI - SYSTEMIC HISTIOCYTIC SARCOMA IN A COMMON HIPPOPOTAMUS (HIPPOPOTAMUS AMPHIBIUS). AB - A 37-yr-old captive common hippopotamus (Hippopotamus amphibius) developed lethargy and decline in mobility that progressed to death, despite supportive therapy. Histopathologic examination revealed severe, diffuse, intravascular and interstitial infiltration of neoplastic histiocytes in the spleen, liver, lymph nodes, lungs, large intestine, kidneys, and thyroid gland. Neoplastic cells were pleomorphic with marked anisocytosis and anisokaryosis, scattered multinucleated giant cells, numerous bizarre mitotic figures, and marked erythrophagocytosis. Immunohistochemistry demonstrated that neoplastic cells were positive for ionized calcium-binding adapter molecule 1 (a histiocytic marker) and negative for CD3 (a T-cell marker) and myeloperoxidase, confirming the diagnosis of systemic histiocytic sarcoma. PMID- 27468045 TI - ACUTE PHASE PROTEINS AS A MARKER OF RESPIRATORY INFLAMMATION IN PRZEWALSKI'S HORSE (EQUUS FERUS PRZEWALSKII). AB - Acute phase proteins are sensitive markers of inflammation, which are highly conserved across taxa. Although the utility of these proteins are becoming well defined in human and domestic animal medical fields, their role in nondomestic species remains unclear. In this communication, a 20-yr-old Przewalski's horse was presented for unresolving aspiration pneumonia, which cultured a unique Actinomyces-like bacteria. Despite waxing and waning clinical signs and minimal changes on baseline hematologic analysis, protein electrophoresis, serum amyloid A, and surfactant protein D serum concentrations showed changes that more accurately reflected the clinical severity of this case. PMID- 27468046 TI - REFERENCE AND BASELINE HEMATOCRIT MEASURES FOR THE THREATENED NEW ENGLAND COTTONTAIL (SYLVILAGUS TRANSITIONALIS) AND COMPARISON WITH SYMPATRIC EASTERN COTTONTAIL (SYLVILAGUS FLORIDANUS) RABBITS. AB - From June 2014 to June 2015, capillary tube collections of blood were obtained concurrently with ear clips of trapped free-ranging, globally vulnerable New England cottontails (NEC; Sylvilagus transitionalis) and eastern cottontail rabbits (EC; Sylvilagus floridanus) in the Hudson Valley region of New York, United States. Species identification (NEC, EC) and sex (NEC) were determined genetically using a mitochondrial DNA assay and Y chromosome marker, respectively. Hematocrit values were obtained using a microhematocrit centrifuge. We provide the reference values 35.15-49.55 (2.5 and 97.5 percentiles) and 90% confidence intervals (CI) [lower: 33.00, 36.08; upper: 46.95, 51.00], for hematocrit of NEC. The mean hematocrit for NEC was 42.35% (SE = 0.58, n = 47) and a comparative contemporaneous mean in the same area for EC [39.96 (SE = 0.81, n = 26)], which was significantly different from NEC (P = 0.02). There was a significant sex difference for NEC [male: 43.99 (SE = 1.02, n = 28); female: 39.92 (SE = 0.78, n = 19), P < 0.0001], though not for EC. PMID- 27468047 TI - SPONTANEOUS LIPOPROTEIN GLOMERULOPATHY-LIKE NEPHROPATHY IN A SQUIRREL (SCIURUS VULGARIS). AB - Lipoprotein glomerulopathy (LPG) is a rare human glomerular disease caused by abnormal lipid metabolism. Naturally occurring LPG has not been reported in animals. We describe the histopathological characterization of spontaneous LPG like nephropathy in a captive squirrel ( Sciurus vulgaris ). Macroscopically, swollen glomeruli were distinctively identified as fine white granules in the renal cortex. Histologically, most glomeruli were markedly enlarged with distended capillaries containing faintly eosinophilic and amorphous materials. The amorphous material was negative using the periodic acid-Schiff reaction, periodic acid-methenamine silver stain, or Masson's trichrome stain. Sudan III staining revealed lipid in the materials, and immunohistochemistry demonstrated that the material additionally contained apolipoprotein E. Electron microscopy showed numerous lipid granules and vacuoles of various sizes in the capillary lumina associated with foot process effacement of podocytes. These pathological characteristics bear some resemblance to those of human LPG. PMID- 27468048 TI - VENTRICULAR SEPTAL DEFECT IN A CRAB-EATING FOX (CERDOCYON THOUS). AB - Congenital heart diseases are not commonly diagnosed in wild animals. It is not surprising that few reports exist in the literature, so that prevalence of these anomalies is unknown in wild species. We report a case of a ventricular septal defect documented in a free-ranging crab-eating fox (Cerdocyon thous). This animal presented with rapid, labored breathing, and on physical examination, pulmonary crackles and a holosystolic murmur were auscultated. The echocardiogram with Doppler showed discontinuity of the dorsal section of the ventricular septum, which allowed a turbulent systolic flow to move from the left to the right ventricle. The postmortem examination confirmed the absence of a dorsal connection between the septum and the atrioventricular junction, and pronounced left ventricular myocardial dilation was observed on histopathology. To the authors' knowledge, this is the first report of a perimembranous ventricular septal defect in a crab-eating fox. PMID- 27468049 TI - NORMAL VAGINAL BACTERIAL FLORA OF GIANT PANDAS (AILUROPODA MELANOLEUCA) AND THE ANTIMICROBIAL SUSCEPTIBILITY PATTERNS OF THE ISOLATES. AB - To study the typical vaginal bacterial flora of giant pandas (Ailuropoda melanoleuca), we took vaginal swabs for the sake of bacterial isolation, from 24 healthy female giant pandas. A total of 203 isolates were identified, representing a total of 17 bacterial species. The most common bacteria isolated were Lactobacillus spp. (54.2%, 13/24), followed by Staphylococcus epidermidis (41.7%, 10/24) and Escherichia coli (33.3%, 8/24). Some opportunistic pathogenic bacteria, such as Peptostreptococcus spp., Klebsiella pneumoniae , and Proteus mirabilis , were also isolated but showed no pathology. Antimicrobial susceptibility testing of aerobic bacterial isolates was performed with the disk diffusion method. Of the 152 isolates, resistance was most frequently observed with chloramphenicol (17.8%), followed by tetracycline (14.5%), ciprofloxacin (12.5%), streptomycin (11.8%), and florfenicol (11.8%), whereas 7.2% were multidrug resistant. This is the first report of the normal culturable vaginal bacterial flora of giant pandas and the antimicrobial susceptibility patterns of the isolates. PMID- 27468050 TI - A PUFFERFISH (TETRADON NIGROVIRIDIS) AVAILABLE IN THE COMMON PET TRADE HARBORS LETHAL CONCENTRATIONS OF TETRODOTOXIN: A CASE STUDY OF POISONING IN A CUVIER'S DWARF CAIMAN (PALEOSUCHUS PALPEBROSUS). AB - Many pufferfish possess tetrodotoxin (TTX). Unaware of this fact, the owner of a 3-mo-old pet Cuvier's dwarf caiman ( Paleosuchus palpebrosus ) fed the caiman a green spotted pufferfish ( Tetraodon nigroviridis ), acquired from a local discount department store. The caiman was nonresponsive within an hour of consumption of the fish. The caiman was presented for veterinary evaluation but died despite intensive medical care. High-performance liquid chromatography and a competitive inhibition enzyme immunoassay were used to determine whether the pufferfish was tetrodotoxic and whether the deceased caiman had TTX in its system. Skin and liver of the pufferfish harbored high concentrations of TTX, and the caiman had TTX in the blood, liver, and kidney. The clinical signs and presence of TTX in the caiman suggest that the caiman succumbed to tetrodotoxicosis. The implication is that lethally poisonous species are available commercially and pose a danger to other pets and possibly small children. PMID- 27468051 TI - SUSPECTED FENBENDAZOLE TOXICITY IN AN AMERICAN WHITE PELICAN (PELECANUS ERYTHRORHYNCHOS). AB - A wild-raised, 5.0-kg male American white pelican ( Pelecanus erythrorhynchos ) of unknown age presented for routine examination at both the start and completion of a 30-day quarantine period at a zoological park. Upon physical examination, the pelican was bright, alert, and responsive and in good body condition. Two complete blood counts and a plasma biochemistry did not reveal any clinically significant abnormalities. Whole-body radiographs were unremarkable. Two fecal flotations (28 days apart) confirmed the presence of ascarid-type eggs. Fenbendazole anthelmintic was prescribed (50 mg/kg p.o. s.i.d. for 5 days). The pelican became lethargic and inappetent on day 3 of fenbendazole treatment and was found dead on day 7. Postmortem examination and histopathology revealed intestinal crypt cell necrosis, stomatitis, and splenic lymphoid depletion consistent with fenbendazole toxicity. To the authors' knowledge, this is the first report to describe fenbendazole toxicity in an American white pelican. PMID- 27468052 TI - IATROGENIC MICROCHIP ARTERIAL EMBOLISM IN A CHILEAN FLAMINGO (PHOENICOPTERUS CHILENSIS). AB - Aberrant microchip migration has been reported in domestic animal species, but in most cases, this migration is atraumatic to the patient. Reports of microchip associated trauma and sarcoma development also have been reported in a variety of mammal species. This report describes accidental arterial microchip insertion causing obstruction of the iliac artery in a Chilean flamingo (Phoenicopterus chilensis). Diagnostic imaging included digital radiography and pre- and post contrast computed tomography to determine the location of the microchip. Surgical removal of the microchip was attempted; however, the flamingo died intraoperatively. Postmortem evaluation found trauma to the epicardium, without penetration of the ventricle. The descending aorta was found traumatized and identified as the most likely insertion point leading to the embolism. PMID- 27468053 TI - MANAGEMENT OF OSTEOMYELITIS CAUSED BY SALMONELLA ENTERICA SUBSP. HOUTENAE IN A TAYLOR'S CANTIL (AGKISTRODON BILINEATUS TAYLORI) USING AMIKACIN DELIVERED VIA OSMOTIC PUMP. AB - An adult female Taylor's cantil (Agkistrodon bilineatus taylori) presented with marked spinal and mandibular osteomyelitis that cultured positive for Salmonella enterica subsp. houtenae, serovar IV 43:z4,z32:-. Progression of osteomyelitis was arrested by treatment using amikacin (0.026 mg/kg per hour) delivered via subcutaneous osmotic pump for 10 mo, replacing the pump every 4 wk. No adverse effects on renal function were appreciated throughout the course of therapy. Amikacin therapy was discontinued after improvement with treatment, but 5 mo later, bony lesions worsened, and an additional abscess formed at the previous pump site. The animal's condition declined and euthanasia was elected. Postmortem examination confirmed marked osteomyelitis with Salmonella infection of same serovar as the initial biopsy. This report highlights the pathogenicity of the S. enterica subsp. houtenae serovar and the ability to deliver effective amikacin dosage via osmotic pump to arrest osteomyelitis due to salmonellosis in a venomous snake. PMID- 27468056 TI - Obamacare's Skyrocketing Premiums? Why the Sky Isn't Falling. PMID- 27468057 TI - Donabedian's Lasting Framework for Health Care Quality. PMID- 27468058 TI - Immunogenicity of a Meningococcal B Vaccine during a University Outbreak. AB - BACKROUND: In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitidis B at a U.S. university. Data suggested that vaccination would control the outbreak because isolates expressed antigens that were closely related to the vaccine antigens (factor H-binding protein [fHbp] and neisserial heparin-binding antigen). We quantified the immune responses induced by 4CMenB during the outbreak. METHODS: We conducted a seroprevalence survey among students to assess vaccination status and collect serum specimens to quantify titers of serum bactericidal antibodies (SBA) with an assay that included human complement (hSBA). We compared the proportion of vaccinated and unvaccinated participants who were seropositive for the outbreak strain and for one closely related reference strain (44/76-SL, which included fHbp) and one mismatched reference strain (5/99, which included neisserial adhesin A), both of which were used in vaccine development. Seropositivity was defined as an hSBA titer of 4 or higher. RESULTS: Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearson's correlation,0.64; P<0.001) but not with the response to the 5/99 strain (Pearson's correlation,-0.06; P=0.43). CONCLUSIONS: Eight weeks after the second dose of the 4CMenB vaccine was administered, there was no evidence of an hSBA response against the outbreak strain in 33.9% of vaccinees, although no cases of meningococcal disease caused by N. meningitidis B were reported among vaccinated students. (Funded by Princeton University and others.). PMID- 27468060 TI - Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. AB - Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2). PMID- 27468062 TI - IMAGES IN CLINICAL MEDICINE. Thyroid Ophthalmopathy, Dermopathy, and Acropachy. PMID- 27468061 TI - Medical Considerations before International Travel. PMID- 27468059 TI - HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014-2015. AB - BACKGROUND: In January 2015, a total of 11 new diagnoses of human immunodeficiency virus (HIV) infection were reported in a small community in Indiana. We investigated the extent and cause of the outbreak and implemented control measures. METHODS: We identified an outbreak-related case as laboratory confirmed HIV infection newly diagnosed after October 1, 2014, in a person who either resided in Scott County, Indiana, or was named by another case patient as a syringe-sharing or sexual partner. HIV polymerase (pol) sequences from case patients were phylogenetically analyzed, and potential risk factors associated with HIV infection were ascertained. RESULTS: From November 18, 2014, to November 1, 2015, HIV infection was diagnosed in 181 case patients. Most of these patients (87.8%) reported having injected the extended-release formulation of the prescription opioid oxymorphone, and 92.3% were coinfected with hepatitis C virus. Among 159 case patients who had an HIV type 1 pol gene sequence, 157 (98.7%) had sequences that were highly related, as determined by phylogenetic analyses. Contact tracing investigations led to the identification of 536 persons who were named as contacts of case patients; 468 of these contacts (87.3%) were located, assessed for risk, tested for HIV, and, if infected, linked to care. The number of times a contact was named as a syringe-sharing partner by a case patient was significantly associated with the risk of HIV infection (adjusted risk ratio for each time named, 1.9; P<0.001). In response to this outbreak, a public health emergency was declared on March 26, 2015, and a syringe-service program in Indiana was established for the first time. CONCLUSIONS: Injection drug use of extended-release oxymorphone within a network of persons who inject drugs in Indiana led to the introduction and rapid transmission of HIV. (Funded by the state government of Indiana and others.). PMID- 27468063 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 22-2016. A 65-Year-Old Man with Syncope, Dyspnea, and Leg Edema. PMID- 27468064 TI - A Challenge in Vaccine Development--Neisseria meningitidis Serogroup B. PMID- 27468065 TI - Hormone-Replacement Therapy for Melanocyte-Stimulating Hormone Deficiency. PMID- 27468066 TI - Defining Metastatic Cell Latency. PMID- 27468067 TI - Artemisinin-Based Treatments in Pregnant Women with Malaria. PMID- 27468068 TI - Artemisinin-Based Treatments in Pregnant Women with Malaria. PMID- 27468069 TI - Trimethoprim-Sulfamethoxazole for Uncomplicated Skin Abscess. PMID- 27468070 TI - Trimethoprim-Sulfamethoxazole for Uncomplicated Skin Abscess. PMID- 27468071 TI - Trimethoprim-Sulfamethoxazole for Uncomplicated Skin Abscess. PMID- 27468072 TI - Trimethoprim-Sulfamethoxazole for Uncomplicated Skin Abscess. PMID- 27468073 TI - Kidney Transplants from HLA-Incompatible Live Donors and Survival. PMID- 27468074 TI - Kidney Transplants from HLA-Incompatible Live Donors and Survival. PMID- 27468075 TI - Kidney Transplants from HLA-Incompatible Live Donors and Survival. PMID- 27468076 TI - Kidney Transplants from HLA-Incompatible Live Donors and Survival. PMID- 27468077 TI - Reduction in Late Mortality after Childhood Cancer. PMID- 27468078 TI - Reduction in Late Mortality after Childhood Cancer. PMID- 27468079 TI - Chronic Stable Angina. PMID- 27468080 TI - Chronic Stable Angina. PMID- 27468081 TI - Chronic Stable Angina. PMID- 27468082 TI - Interference of New Drugs with Compatibility Testing for Blood Transfusion. PMID- 27468083 TI - Pembrolizumab-Induced Demyelinating Polyradiculoneuropathy. PMID- 27468084 TI - IMAGES IN CLINICAL MEDICINE. Nodular Lymphoid Hyperplasia. PMID- 27468085 TI - B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy. AB - BACKGROUND: B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease. OBJECTIVE: To elucidate the involvement of B cells in Crohn's disease, we here performed an 'in depth' analysis of intestinal and blood B-cells in this chronic inflammatory disease. METHODS: Patients with Crohn's disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients. RESULTS: Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab. CONCLUSIONS: B cells in patients with Crohn's disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFalpha-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn's disease, which could be targeted with new therapeutics that specifically regulate B-cell function. PMID- 27468086 TI - Dual Antiplatelet Therapy and Outcomes in Patients With Atrial Fibrillation and Acute Coronary Syndromes Managed Medically Without Revascularization: Insights From the TRILOGY ACS Trial. AB - Associations between atrial fibrillation (AF), outcomes, and response to antiplatelet therapies in patients with acute coronary syndrome (ACS) managed medically without revascularization remain uncertain. We examined these associations for medically managed ACS patients randomized to dual antiplatelet therapy (DAPT) using patient data from the TRILOGY ACS trial. DAPT included aspirin plus clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d for those <60 kg or age >=75 years). Patients receiving oral anticoagulants were excluded. Cox proportional hazards regression modeling was used to characterize associations between patients with AF (AF+) vs those without (AF-) and risk of ischemic and bleeding events, and to explore effects of randomized treatment on outcomes. Among 9101 patients with baseline AF status, 710 (7.8%) had AF. AF+ patients were older and had more comorbidities. Unadjusted associations of the composite of cardiovascular death/myocardial infarction/stroke were significantly higher among AF patients at 30 months (31.1% vs 18.4%; HR: 1.61, 95% CI: 1.35-1.92, P < 0.001), but differences did not persist after adjustment (HR: 1.16, 95% CI: 0.97 1.39, P = 0.11). When individual components of the composite endpoint were evaluated, 30-month risk of events in AF+ patients was significantly higher. Thirty-month risk of all-cause death was significantly higher in AF+ patients: 18.1% vs 11.1% (HR: 1.62, 95% CI: 1.30-2.02, P < 0.001). There was no significant interaction with randomized treatment and AF for the primary endpoint. Among medically managed high-risk ACS patients receiving DAPT, AF was associated with higher unadjusted risks of ischemic and bleeding outcomes that were similar by treatment group. PMID- 27468087 TI - Clinical and molecular characteristics of XPO1 mutations in patients with chronic lymphocytic leukemia. PMID- 27468088 TI - Respiratory epithelial cysts of the orbit. AB - To describe post-traumatic and congenital respiratory epithelial cysts in the orbit, which are rare lesions with only 5 and 13 published cases, respectively. We reviewed all cases of respiratory epithelial cysts diagnosed at three institutions (two tertiary referral hospitals, one private clinic) between 1995 and 2015. We describe 10 cases of post-traumatic respiratory epithelial cyst (age range 23 - 82), presenting a mean of 17.4 years after their original trauma; and 3 congenital cases (age range 17-34). All but one case underwent surgical excision of the cyst and its lining, along with any surgical implant within the cyst. Two were recurrent after incomplete excision. Three presented with acute infection within the cyst. Respiratory epithelial orbital cysts are probably commoner than the paucity of published reports would suggest. Post-traumatic cysts often present many years after trauma, and may become secondarily infected. Complete surgical removal is recommended to prevent future recurrence. PMID- 27468089 TI - Understanding the Role of Particulate Iron in Lead Release to Drinking Water. AB - Lead service lines (LSLs) are a major source of drinking water lead, and high iron levels are frequently observed along with elevated lead release. A model distribution system, dosed with orthophosphate, was used to evaluate the effect of corroded iron distribution mains on lead release from recovered LSLs. Lead release was higher by 96 MUg L(-1), on average, from LSLs supplied by corroded iron compared to the inert reference material (PVC). This effect may be explained by deposition of semiconducting iron oxide particles within LSLs. When galvanic cells with lead and magnetite (Fe3O4) electrodes were short-circuited, lead release increased 8-fold and a current averaging 26 MUA was observed. In effluent from LSLs with an upstream iron main, colloidal lead and iron occurred in the same size fraction-possibly due to release of colloidal particles from LSL corrosion scale enriched with iron. Under these circumstances, high molecular weight (>669 kDa) (208)Pb and (56)Fe elution profiles, observed via size exclusion chromatography, were highly correlated (average R(2) = 0.97). Increasing orthophosphate from 0.5 to 1.0 mg L(-1) (as PO4(3-)) accompanied an average reduction in lead release of 6 MUg L(-1) month(-1) but did not significantly reduce the effect of an upstream iron main. PMID- 27468090 TI - [Not Available]. AB - INTRODUCTION: The incidence of mesothelioma in Italy shows wide geographical variation, with the highest incidence rates in Genoa and Friuli Venezia Giulia (FVG). For mesothelioma, national standard incidence rates are not available prior to the calendar year 2006. OBJECTIVES: To estimate the Standardized Incidence rate Ratio (SIR) of mesothelioma in a cohort of former workers undergoing health surveillance because of previous asbestos exposure, when sex-, age-, and calendar year-specific rates of the national standard are not available and the number of expected cases calculated from the regional rates is biased by the size of the study cohort. METHODS: We conducted a sensitivity analysis in a cohort of 2,488 men. We considered every Italian cancer registry available with complete data in the period 1995-2007 (N=14). We calculated, for each year and age group, the corresponding weighted mean rate of 10 registries of North-Italy (Mean W10), the weighted mean rate of all 14 registries available (Mean W14) and considered FVG standard rate. RESULTS: During the period 1995-2007, we observed 25 incident cases of mesothelioma with expected cases that varied between 2.00 (Mean W14) and 2.56 (FVG standard rate), with a SIR of 12.49 (CI95% 8.08-18.48) and 9.76 (CI95% 6.32-14.45) respectively. CONCLUSIONS: Our results show that the use of FVG rates as standard does not lead to significant distortions in the calculation of the expected cases. However, distortion is remarkable in the SIRs estimation. Using a weighted mean standard incidence rate may be a valid alternative for SIR estimate when national standard rates are not available. PMID- 27468092 TI - Co3 O4 Nanoparticles Supported on Mesoporous Carbon for Selective Transfer Hydrogenation of alpha,beta-Unsaturated Aldehydes. AB - A simple and scalable method for synthesizing Co3 O4 nanoparticles supported on the framework of mesoporous carbon (MC) was developed. Benefiting from an ion exchange process during the preparation, the cobalt precursor is introduced into a mesostructured polymer framework that results in Co3 O4 nanoparticles (ca. 3 nm) supported on MC (Co3 O4 /MC) with narrow particle size distribution and homogeneous dispersion after simple reduction/pyrolysis and mild oxidation steps. The as-obtained Co3 O4 /MC is a highly efficient catalyst for transfer hydrogenation of alpha,beta-unsaturated aldehydes. Selectivities towards unsaturated alcohols are always higher than 95 % at full conversion. In addition, the Co3 O4 /MC shows high stability under the reaction conditions, it can be recycled at least six times without loss of activity. PMID- 27468091 TI - Rye B chromosomes encode a functional Argonaute-like protein with in vitro slicer activities similar to its A chromosome paralog. AB - B chromosomes (Bs) are supernumerary, dispensable parts of the nuclear genome, which appear in many different species of eukaryote. So far, Bs have been considered to be genetically inert elements without any functional genes. Our comparative transcriptome analysis and the detection of active RNA polymerase II (RNAPII) in the proximity of B chromatin demonstrate that the Bs of rye (Secale cereale) contribute to the transcriptome. In total, 1954 and 1218 B-derived transcripts with an open reading frame were expressed in generative and vegetative tissues, respectively. In addition to B-derived transposable element transcripts, a high percentage of short transcripts without detectable similarity to known proteins and gene fragments from A chromosomes (As) were found, suggesting an ongoing gene erosion process. In vitro analysis of the A- and B encoded AGO4B protein variants demonstrated that both possess RNA slicer activity. These data demonstrate unambiguously the presence of a functional AGO4B gene on Bs and that these Bs carry both functional protein coding genes and pseudogene copies. Thus, B-encoded genes may provide an additional level of gene control and complexity in combination with their related A-located genes. Hence, physiological effects, associated with the presence of Bs, may partly be explained by the activity of B-located (pseudo)genes. PMID- 27468093 TI - Obeticholic acid for the treatment of primary biliary cholangitis. AB - INTRODUCTION: Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo. AREAS COVERED: This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database. EXPERT OPINION: If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA. PMID- 27468094 TI - Public Health Policy Lessons From Oklahoma. PMID- 27468095 TI - [Editorial]. PMID- 27468096 TI - [Keratitis - Infectious or Autoimmune?]. AB - Histopathological evaluation of ocular tissues is important in differentiating between infectious and autoimmune disease. Inflammation, necrosis and keratolysis are common to most forms of keratitis. Histopathology can be of great help in identifying the causative organism, establishing a final diagnosis and/or managing the patient with herpes simplex virus keratitis, mycotic keratitis, acanthamoeba keratitis or microsporidia keratoconjunctivitis. Important pathogenetic knowledge with therapeutic relevance has been gained from histopathological studies in nummular keratitis after epidemic keratoconjunctivitis and atopic keratoconjunctivitis. PMID- 27468097 TI - [Blepharitis - When to Perform Surgery?]. AB - AIM: Meibomian gland dysfunction/blepharitis is usually a harmless inflammatory process of the lid margin. However, it can be the first sign of a malignant lesion. Patients/Results: Clinical and histological findings are illustrated for 8 patients with changes in the lid margin and with the differential diagnosis of blepharitis. CONCLUSION: Tumours of the lid margin can mimic blepharitis or induce meibomian gland dysfunction. Conversely, blepharitis can present in a nodular form, which is highly indicative of a neoplasm. In these cases, surgical excision with ophthalmopathological evaluation of the tissue is mandatory, in order to reach the correct diagnosis and to treat the patient appropriately. PMID- 27468098 TI - [Intraocular Inflammation: Autoimmune or Infectious?]. AB - Presentation of 3 cases of intraocular inflammation: 1. 47-year old female patient with severe necrotising scleritis and uveitis with underlying granulomatous polyangiitis (formerly known as Wegener granulomatosis, in honour of the German pathologist Friedrich Wegener), known for 10 years. 2. 48-year old male patient with longstanding bilateral uveitis and granulomatous polyangiitis for 2 years. In the histopathological examination of the enucleation specimen, a retrolental tumour turned out to be a granuloma. 3. 57-year old male patient in status post renal transplantation with intraocular cellular infiltration suspicious for lymphoma, which surprisingly proved to be Toxoplasma gondii associated uveitis. The clinical course and characteristic histological signs and therapeutic options are discussed. PMID- 27468099 TI - [Lymphoma of Ocular and Periocular Tissues - Clinicopathological Correlations]. AB - Lymphomas of the ocular adnexa and intraocular tissue include a wide range of lymphoproliferative neoplastic disorders. They are predominantly extranodal non Hodgkin lymphomas (NHL). The World Health Organization (WHO) classification of lymphoid neoplasm and individual morphological, immunophenotypical, and molecular genetic features, indicate that they may be divided into B-cell (approximately 80 % of all NHL) and T-cell lymphomas (approximately 10-20 % of all NHL). The most common forms of ocular NHL are extranodal marginal zone lymphoma (EMZL) of the mucosa-associated lymphoid tissue (MALT-type), follicular lymphoma (FL), diffuse large B-cell lymphoma, and mantel cell lymphoma. The clinical signs and symptoms are usually very unspecific and depend on the location, size, and extent of the underlying lymphoma subtype. Typical low grade lymphomas have an indolent clinical course and often remain unrecognized for many years. On the other hand, high grade NHLs, such as DLBCL or MCL, are frequently aggressive, with rapid tumour growth and poor prognosis, despite early detection. Histopathology is still the gold standard in the diagnosis of ocular lymphomas. Basic understanding of the principal pathophysiological and clinical aspects of the development and progression of orbital and ocular lymphomas seems to be mandatory for optimal diagnosis and treatment and for improving survival and prognosis. Both residents in training and board certified ophthalmologists should be aware of these problems. PMID- 27468100 TI - Dopamine D2 receptor suppresses gastric cancer cell invasion and migration via inhibition of EGFR/AKT/MMP-13 pathway. AB - Dopamine (DA), an important neurotransmitter, has been reported to play a negative role in tumor progression. DA acts its role via dopamine receptors (DRs), which can be divided into five receptor subtypes (D1R-D5R). Among these receptor subtypes, D2R has been found to inhibit IGF-I-induced gastric cancer cell growth. However, the functions of D2R in gastric cancer cell invasion remain elusive. Here, we found that D2R expression was decreased in gastric cancer cells. DA treatment dose-dependently inhibited EGF-mediated gastric cancer cell invasion and migration via D2R. Furthermore, D2R decreased EGF-mediated MMP-13 production, and attenuated EGFR and AKT activation. Together with the results that EGF promoted gastric cancer cell invasion and migration via EGFR/AKT pathway, these data indicate that DA treatment, acting via D2R, suppresses gastric cancer cell invasion and migration via inhibition of EGFR/AKT/MMP-13 pathway. Thus, our findings suggest that use of D2R agonist may have a potential therapeutic effect on gastric cancer. PMID- 27468101 TI - alpha1 -antitrypsin Pittsburgh and plasmin-mediated proteolysis. AB - : Essentials Patients with alpha-1-antitrypsin (alpha1-AT) Pittsburgh exhibit a mild bleeding tendency. A new case of alpha1-AT Pittsburgh with suspected high antifibrinolytic potential was studied. We showed that alpha1-AT Pittsburgh inhibits tissue plasminogen activator and plasmin. The antifibrinolytic potential of the variant contributes to explaining the mild bleeding phenotype. SUMMARY: alpha1 -Antitrypsin (alpha1 -AT) Pittsburgh has a Met358 to Arg substitution at the reactive Met-Ser site of alpha1 -AT, which enables the protein to act as a potent thrombin inhibitor. Four patients with alpha1 -AT Pittsburgh have been described to date. An additional young girl was recently diagnosed with alpha1 AT Pittsburgh in our center after presenting with a large hematoma in the forearm. Interestingly, all of these patients showed a potent thrombin inhibitor in the plasma and a mild bleeding phenotype. This observation suggests that the in vivo consequences of the mutation may contribute to the maintenance of normal hemostatic balance. We assessed inhibition of the fibrinolytic system by the variant protein by evaluating the fibrinolysis inhibitory potential of the patient's plasma, purified wild-type alpha1 -AT and purified Pittsburgh alpha1 AT with an electrophoretic zymography system, western blotting, and clot fibrinolysis. Our results indicate that the patient's plasma and purified alpha1 AT Pittsburgh have strong potential to inhibit tissue-type plasminogen activator and plasmin. PMID- 27468102 TI - Efficient halal bleeding, animal handling, and welfare: A holistic approach for meat quality. AB - Traditional halal slaughter and other forms of religious slaughter are still an issue of debate. Opposing arguments related to pre-slaughter handling, stress and pain associated with restraint, whether the incision is painful or not, and the onset of unconsciousness have been put forward, but no consensus has been achieved. There is a need to strike a balance between halal bleeding in the light of science and animal welfare. There is a paucity of scientific data with respect to animal welfare, particularly the use of restraining devices, animal handling, and efficient halal bleeding. However, this review found that competent handling of animals, proper use of restraining devices, and the efficient bleeding process that follows halal slaughter maintains meat eating quality. In conclusion, halal bleeding, when carried out in accordance with recommended animal welfare procedures, will not only maintain the quality and wholesomeness of meat but could also potentially reduce suffering and pain. Maintained meat quality increases consumer satisfaction and food safety. PMID- 27468103 TI - Self-Organizing Maps for In Silico Screening and Data Visualization. AB - Self-organizing maps, which are unsupervised artificial neural networks, have become a very useful tool in a wide area of disciplines, including medicinal chemistry. Here, we will focus on two applications of self-organizing maps: the use of self-organizing maps for in silico screening and for clustering and visualisation of large datasets. Additionally, the importance of parameter selection is discussed and some modifications to the original algorithm are summarised. PMID- 27468104 TI - KNIME Workflow to Assess PAINS Filters in SMARTS Format. Comparison of RDKit and Indigo Cheminformatics Libraries. PMID- 27468105 TI - Optimization of Structure Based Virtual Screening Protocols Against Thymidine Monophosphate Kinase Inhibitors as Antitubercular Agents. AB - Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKMtub ) is an established drug target against tuberculosis. The enzyme TMPKMtub is responsible for the survival of bacterium MTB and required to synthesize an essential building block of the bacterial DNA which is thymidine triphosphate (TTP). There are several potent inhibitors available against the target enzyme but the majority are substrate analogues. Recently, three dimensional structures of the enzyme TMPKMtub inhibitor complexes were resolved using X-ray crystallography. These available crystal structures were the basis of initiating a structure based lead identification campaign against TMPKMtub . The available information was utilized to perform structure-based virtual screening against TMPKMtub with the hope to diversify the structures of the current inhibitors. In order to setup the protocol, 10 000 out of 45 000 drug-like molecules were randomly selected from National Cancer Institute's (NCI) database. Additionally 105 known inhibitors along with 11 natural substrates were mixed with the 10 000 selected compounds. For the current study, a rigid based docking algorithm, i.e., FRED has been utilized to set up an efficient docking and scoring protocol. The methods including enrichment curves, consensus scoring and ROC curves are providing useful insights into the setting up of a suitable structure-based docking protocol against TMPKMtub . As a result, an optimum docking and scoring function has been identified for future large scale virtual screening. In the present work, we have demonstrated a rational choice of protocol for structure based virtual screening of chemical libraries and help to understand the influence of receptor flexibility by using multiple geometries. PMID- 27468106 TI - Deciphering the Structural Requirements of Nucleoside Bisubstrate Analogues for Inhibition of MbtA in Mycobacterium tuberculosis: A FB-QSAR Study and Combinatorial Library Generation for Identifying Potential Hits. AB - The re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade. Inhibitors of aryl acid adenylating enzyme known as MbtA, involved in siderophore biosynthesis in Mycobacterium tuberculosis, are being explored as potential antitubercular agents. The ability to identify fragments that interact with a biological target is a key step in fragment based drug design (FBDD). To expand the boundaries of quantitative structure activity relationship (QSAR) paradigm, we have proposed a Fragment Based QSAR methodology, referred here in as FB-QSAR, for deciphering the structural requirements of a series of nucleoside bisubstrate analogs for inhibition of MbtA, a key enzyme involved in siderophore biosynthetic pathway. For the development of FB-QSAR models, statistical techniques such as stepwise multiple linear regression (SMLR), genetic function approximation (GFA) and GFAspline were used. The predictive ability of the generated models was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. To aid the creation of novel antituberculosis compounds, a bioisosteric database was enumerated using the combichem approach endorsed mining in a lead-like chemical space. The generated library was screened using an integrated in-silico approach and potential hits identified. PMID- 27468107 TI - Identification of Novel Inhibitors of UDP-Galactopyranose Mutase by Structure Based Virtual Screening. AB - UDP-galactopyranose mutase (UGM) is a flavo-enzyme involved in the bacterial cell wall biosynthesis. UGM catalyzes the reversible isomerization of UDP galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). UDP-Galf is the activated precursor of galactofuranose (Galf) residues that are essential components of the cell wall of certain pathogenic bacteria such as Klebsiella pneumoniae and Mycobacterium tuberculosis. Neither UGM nor Galf residues are found in humans, making Galf biosynthesis a potential drug target for developing antibacterial agents. We report the identification of novel inhibitors of UGM by in silico docking of the LeadQuest compound database against UGM from Escherichia coli. The 13 most promising inhibitors were then evaluated against K. pneumonia and M. tuberculosis UGMs by enzyme inhibition studies. Two inhibitors were identified with IC50 values of ~1 uM and subsequently these compounds were docked into the recently solved X-ray structure of Deinococcus radiodurans UGM. The structure-activity relationships of the initial 13 compounds evaluated as inhibitors are discussed. PMID- 27468108 TI - Selecting Relevant Descriptors for Classification by Bayesian Estimates: A Comparison with Decision Trees and Support Vector Machines Approaches for Disparate Data Sets. AB - Classification algorithms suffer from the curse of dimensionality, which leads to overfitting, particularly if the problem is over-determined. Therefore it is of particular interest to identify the most relevant descriptors to reduce the complexity. We applied Bayesian estimates to model the probability distribution of descriptors values used for binary classification using n-fold cross validation. As a measure for the discriminative power of the classifiers, the symmetric form of the Kullback-Leibler divergence of their probability distributions was computed. We found that the most relevant descriptors possess a Gaussian-like distribution of their values, show the largest divergences, and therefore appear most often in the cross-validation scenario. The results were compared to those of the LASSO feature selection method applied to multiple decision trees and support vector machine approaches for data sets of substrates and nonsubstrates of three Cytochrome P450 isoenzymes, which comprise strongly unbalanced compound distributions. In contrast to decision trees and support vector machines, the performance of Bayesian estimates is less affected by unbalanced data sets. This strategy reveals those descriptors that allow a simple linear separation of the classes, whereas the superior accuracy of decision trees and support vector machines can be attributed to nonlinear separation, which are in turn more prone to overfitting. PMID- 27468109 TI - A Mechanism for Evolving Novel Plant Sesquiterpene Synthase Function. AB - Plant sesquiterpene synthases, a subset of the terpene synthase superfamily, are a mechanistically diverse family of enzymes capable of synthesizing hundreds of complex compounds with high regio- and stereospecificity and are of biological importance due to their role in plant defense mechanisms. In the current report we describe a large-scale, high-resolution phylogenetic analysis of ~200 plant sesquiterpene synthases integrated with structural and experimental data that address these issues. We observe that all sequences that cluster together on the phylogenetic tree into well-defined groups share at least the first reaction in the catalytic mechanism subsequent to the initial ionization step and many share steps beyond this down to proton transfers between the enzyme and substrate. Most significant is the previously unreported high conservation of an Asp-Tyr-Asp triad. Due to its high conservation, patterns in the phylogenetic tree as well as experimental and modeling results, we suggest that this Asp-Tyr-Asp triad is an important functional element responsible for many proton transfers to and from the substrate and intermediates along the plant sesquiterpene synthase catalytic cycle and whose position can be tuned by residues outside the active site that can lead to the evolution of novel enzyme function. PMID- 27468110 TI - Spectroscopy and Tautomerization Studies of Porphycenes. AB - Tautomerization in porphycenes, constitutional isomers of porphyrins, is strongly entangled with spectral and photophysical parameters. The intramolecular double hydrogen transfer occurring in the ground and electronically excited states leads to uncommon spectroscopic characteristics, such as depolarized emission, viscosity-dependent radiationless depopulation, and vibrational-mode-specific tunneling splittings. This review starts with documentation of the electronic spectra of porphycenes: Absorption and magnetic circular dichroism are discussed, together with their analysis based on the perimeter model. Next, photophysical characteristics are presented, setting the stage for the final part, which discusses the developments in research on tautomerism. Porphycenes have been studied in different experimental regimes: molecules in condensed phases, isolated in supersonic jets and helium nanodroplets, and, recently also on the level of single molecules investigated by optical and scanning probe microscopies. Because of the rich and detailed information obtained from these diverse investigations, porphycenes emerge as very good models for studying the complex, multidimensional phenomena involved in the process of intramolecular double hydrogen transfer. PMID- 27468111 TI - Structure-guided wavelength tuning in far-red fluorescent proteins. AB - In recent years, protein engineers have succeeded in tuning the excitation spectra of natural fluorescent proteins from green wavelengths into orange and red wavelengths, resulting in the creation of a series of fluorescent proteins with emission in the far-red portions of the optical spectrum. These results have arisen from the synergistic combination of structural knowledge of fluorescent proteins, chemical intuition, and high-throughput screening methods. Here we review structural features found in autocatalytic far-red fluorescent proteins, and discuss how they add to our understanding of the biophysical mechanisms of wavelength tuning in biological chromophores. PMID- 27468113 TI - Multifunctional Hyaluronic Acid and Chondroitin Sulfate Nanoparticles: Impact of Glycosaminoglycan Presentation on Receptor Mediated Cellular Uptake and Immune Activation. AB - Hyaluronic acid (HA) and chondroitin sulfate (CS) polymers are extensively used for various biomedical applications, such as for tissue engineering, drug delivery, and gene delivery. Although both these biopolymers are known to target cell surface CD44 receptors, their relative cellular targeting properties and immune activation potential have never been evaluated. In this article, we present the synthesis and characterization of novel self-assembled supramolecular HA and CS nanoparticles (NPs). These NPs were developed using fluorescein as a hydrophobic component that induced amphiphilicity in biopolymers and also efficiently stabilized anticancer drug doxorubicin (DOX) promoting a near zero order drug release. The cellular uptake and cytotoxicity studies of these NPs in different human cancer lines, namely, human colorectal carcinoma cell line HCT116 and human breast cancer cell line MCF-7 demonstrated dose dependent cytotoxicity. Interestingly, both NPs showed CD44 dependent cellular uptake with the CS-DOX NP displaying higher dose-dependent cytotoxicity than the HA-DOX NP in different mammalian cells tested. Immunological evaluation of these nanocarriers in an ex vivo human whole blood model revealed that unlike unmodified polymers, the HA NP and CS NP surprisingly showed platelet aggregation and thrombin-antithrombin complex formation at high concentrations (0.8 mg/mL). We also observed a clear difference in early- and late-stage complement activation (C3a and sC5b-9) with CS and CS NP triggering significant complement activation at high concentrations (0.08-0.8 mg/mL), unlike HA and HA NP. These results offer new insight into designing glycosaminoglycan-based NPs and understanding their hematological responses and targeting ability. PMID- 27468112 TI - Magnetoencephalography shows atypical sensitivity to linguistic sound sequences in autism spectrum disorder. AB - Neuroscientific evidence points toward atypical auditory processing in individuals with autism spectrum disorders (ASD), and yet, the consequences of this for receptive language remain unclear. Using magnetoencephalography and a passive listening task, we test for cascading effects on speech sound processing. Children with ASD and age-matched control participants (8-12 years old) listened to nonce linguistic stimuli that either did or did not conform to the phonological rules that govern consonant sequences in English (e.g. legal 'vimp' vs. illegal 'vimk'). Beamformer source analysis was used to isolate evoked responses (0.1-30 Hz) to these stimuli in the left and the right auditory cortex. Right auditory responses from participants with ASD, but not control participants, showed an attenuated response to illegal sequences relative to legal sequences that emerged around 330 ms after the onset of the critical phoneme. These results suggest that phonological processing is impacted in ASD, perhaps because of cascading effects from disrupted initial acoustic processing. PMID- 27468114 TI - Slow pupillary light responses in infants at high risk of cerebral palsy were associated with periventricular leukomalacia and neurological outcome. AB - AIM: Having observed slow pupillary light responses (PLRs) in infants at high risk of cerebral palsy, we retrospectively evaluated whether these were associated with specific brain lesions or unfavourable outcomes. METHODS: We carried out neurological examinations on 30 infants at very high risk of cerebral palsy five times until the corrected age of 21 months, classifying each PLR assessment as normal or slow. The predominant reaction during development was determined for each infant. Neonatal brain scans were classified based on the type of brain lesion. Developmental outcome was evaluated at 21 months of corrected age with a neurological examination, the Bayley Scales of Infant Development Second Edition and the Infant Motor Profile. RESULTS: Of the 30 infants, 16 developed cerebral palsy. Predominantly slow PLRs were observed in eight infants and were associated with periventricular leukomalacia (p = 0.007), cerebral palsy (p = 0.039), bilateral cerebral palsy (p = 0.001), poorer quality of motor behaviour (p < 0.0005) and poorer cognitive outcome (p = 0.045). CONCLUSION: This explorative study suggested that predominantly slow PLR in infants at high risk of cerebral palsy were associated with periventricular leukomalacia and poorer developmental outcome. Slow PLR might be an expression of white matter damage, resulting in dysfunction of the complex cortico-subcortical circuitries. PMID- 27468115 TI - A Cost-effectiveness Analysis of Early vs Late Tracheostomy. AB - Importance: The timing of tracheostomy in critically ill patients requiring mechanical ventilation is controversial. An important consideration that is currently missing in the literature is an evaluation of the economic impact of an early tracheostomy strategy vs a late tracheostomy strategy. Objective: To evaluate the cost-effectiveness of the early tracheostomy strategy vs the late tracheostomy strategy. Evidence Acquisition: This economic analysis was performed using a decision tree model with a 90-day time horizon. The economic perspective was that of the US health care third-party payer. The primary outcome was the incremental cost per tracheostomy avoided. Probabilities were obtained from meta analyses of randomized clinical trials. Costs were obtained from the published literature and the Healthcare Cost and Utilization Project database. A multivariate probabilistic sensitivity analysis was performed to account for uncertainty surrounding mean values used in the reference case. Results: The reference case demonstrated that the cost of the late tracheostomy strategy was $45 943.81 for 0.36 of effectiveness. The cost of the early tracheostomy strategy was $31 979.12 for 0.19 of effectiveness. The incremental cost-effectiveness ratio for the late tracheostomy strategy compared with the early tracheostomy strategy was $82 145.24 per tracheostomy avoided. With a willingness-to-pay threshold of $50 000, the early tracheostomy strategy is cost-effective with 56% certainty. Conclusions and Relevance: The adaptation of an early vs a late tracheostomy strategy depends on the priorities of the decision-maker. Up to a willingness-to-pay threshold of $80 000 per tracheostomy avoided, the early tracheostomy strategy has a higher probability of being the more cost-effective intervention. PMID- 27468116 TI - The influence of work characteristics, emotional display rules and affectivity on burnout and job satisfaction: A survey among geriatric care workers. AB - BACKGROUND: Previous studies have demonstrated that geriatric care employees are exposed to a large number of factors that can affect their levels of job satisfaction and occupational stress. Although working with elderly people is emotionally demanding, little research has been done on the role played by perceptions of emotional display rules, alongside more traditional work characteristics and individual factors, in the prediction of geriatric care employees' wellbeing. OBJECTIVES: The aim of the present study was to examine the role played by work characteristics (job demands, job control, emotional display rules) and individual (affectivity) factors to predict job satisfaction and burnout among French geriatric care nurses. METHOD AND PARTICIPANTS: Questionnaires were sent to 891 employees working in 32 geriatric care centers in France. A total of 371 valid questionnaires (response rate: 41.60%) were analyzed using structural equation modeling techniques. RESULTS: Results revealed two main processes of burnout and job satisfaction among women geriatric care workers, namely a salutogenic process and a pathogenic process. As expected, negative affectivity, low job status, perceived negative display rules and job demands are involved in the pathogenic process; while positive affectivity, perceived positive display rules and job control are implied in the salutogenic one. More specifically, as expected, negative affectivity is a positive predictor of burnout, both directly and indirectly through its impact on perceived negative display rules and job demands. Moreover, negative affectivity was negatively related to job satisfaction. Simultaneously, positive affectivity can predict job satisfaction, both directly and indirectly through its impact on perceived positive display rules and job control. Positive affectivity is also a negative predictor of burnout. CONCLUSIONS: Practical implications are discussed to support intervention programs that develop healthy workplaces, and also to inform nurses about how to manage emotional display rules in retirement homes. PMID- 27468118 TI - Erythrocyte Sedimentation Rate in Chronic Mountain Sickness. PMID- 27468117 TI - Usefulness, feasibility and face validity of the interRAI Palliative Care instrument according to care professionals in nursing homes: A qualitative study. AB - BACKGROUND: Nursing homes are important locations for palliative care. High quality palliative care requires an evaluation of the different care needs of the nursing home residents. The interRAI Palliative Care instrument is a comprehensive assessment that evaluates the needs and preferences of adults receiving palliative care. OBJECTIVES: This study aims to evaluate the usefulness, feasibility and face validity of the interRAI Palliative Care instrument. DESIGN: A qualitative study was conducted, based on the abductive reasoning approach. SETTING: Fifteen nursing homes in Flanders (Belgium). PARTICIPANTS: Calls for participation were sent out by four umbrella organizations of Flemish nursing homes (Belgium) and at a national conference for nursing home staff. Nineteen care professionals (nurses, certified nursing assistants, psychologists, physiotherapists, quality coordinators and directors) of 15 nursing homes voluntarily agreed to participate in the study. METHODS: During one year, care professionals evaluated the needs and preferences of all nursing home residents receiving palliative care by means of the interRAI Palliative Care instrument. Data on the usefulness, feasibility and face validity of the interRAI Palliative Care instrument were derived from notes, semi structured interviews and focus groups with participating care professionals and were thematically analyzed and synthesized. Data were gathered between December 2013 and March 2015. RESULTS: In general, the interRAI Palliative Care (interRAI PC instrument) is a useful instrument according to care professionals in nursing homes. However, care professionals made a series of recommendations in order to optimize the usefulness of the instrument. The interRAI PC instrument is not always feasible to complete because of organizational reasons. Furthermore, the face validity of the instrument could be improved since certain items are incomplete, lacking, redundant or too complex. CONCLUSIONS: Findings highlight the importance of adapting the content of the interRAI Palliative Care instrument for use in nursing homes. Furthermore, the use of the instrument should be integrated in the organization of daily care routines in the nursing homes. Tackling the critical remarks of care professionals will help to optimize the interRAI Palliative Care instrument and hence support palliative care of high quality in nursing homes. PMID- 27468119 TI - Optic Disc Metastasis as the Presenting Sign of Lung Adenocarcinoma. AB - A 67-year-old woman noticed vision loss in her right eye and was found to have an elevated, well-circumscribed white mass within the right optic disc. The patient underwent an evaluation which revealed 4 brain metastases and a large left hilar mass that proved to be adenocarcinoma of the lung. Because she continued to lose vision, the optic disc metastasis was treated with stereotactic radiotherapy. Although she reported vision improvement, she died soon afterward. There are 9 previous reports in the English literature of isolated optic disc metastasis as the presenting sign of cancer. Familiarity with the features of optic disc metastasis can lead to earlier recognition and treatment of the underlying malignant neoplasm. PMID- 27468120 TI - Nonglaucomatous Cupping: Fundus Photography and Spectral Domain Optical Coherence Tomography Imaging Features. AB - Nonglaucomatous cupping is commonly encountered in neuro-ophthalmic practice. However, the progression of clinical and imaging findings over time has not been well described. We present serial fundus photographs and spectral domain optical coherence tomography from a pediatric patient with neuromyelitis optic spectrum disorder, which demonstrated progression of both cupping and optic atrophy in the setting of normal intraocular pressure. PMID- 27468121 TI - Clinical and Molecular Genetic Analysis in Three Children with Wolfram Syndrome: A Novel WFS1 Mutation (c.2534T>A). AB - Wolfram syndrome (WS) is an autosomal recessive disorder caused by mutations in WFS1 gene. The clinical features include diabetes insipidus, diabetes mellitus (DM), optic atrophy, deafness, and other variable clinical manifestations. In this paper, we present the clinical and genetic characteristics of 3 WS patients from 3 unrelated Turkish families. Clinical characteristics of the patients and the age of onset of symptoms were quite different in each pedigree. The first two cases developed all symptoms of the disease in their first decade of life. The heterozygous father of case 2 was symptomatic with bilateral deafness. The first ocular finding of one patient (patient 3) was bilateral cataract which was accompanying DM as a first feature of the syndrome. In this patient's family, there were two members with features suggestive of WS. Previously known homozygous mutations, c.460+1G>A in intron 4 and c.1885C>T in exon 8, were identified in these cases. A novel homozygous c.2534T>A mutation was also detected in the exon 8 of WFS1 gene. Because of the rarity and heterogeneity of WS, detection of specific and nonspecific clinical signs including ocular findings and family history in non-autoimmune, insulinopenic diabetes cases should lead to a tentative diagnosis of WS. Genetic testing is required to confirm the diagnosis. PMID- 27468122 TI - The tale of the shrinking weapon: seasonal changes in nutrition affect weapon size and sexual dimorphism, but not contemporary evolution. AB - Sexually selected traits are often highly variable in size within populations due to their close link with the physical condition of individuals. Nutrition has a large impact on physical condition, and thus, any seasonal changes in nutritional quality are predicted to alter the average size of sexually selected traits as well as the degree of sexual dimorphism in populations. However, although traits affected by mate choice are well studied, we have a surprising lack of knowledge of how natural variation in nutrition affects the expression of sexually selected weapons and sexual dimorphism. Further, few studies explicitly test for differences in the heritability and mean-scaled evolvability of sexually selected traits across conditions. We studied Narnia femorata (Hemiptera: Coreidae), an insect where males use their hind legs as weapons and the femurs are enlarged, to understand the extent to which weapon expression, sexual dimorphism and evolvability change across the actual range of nutrition available in the wild. We found that insects raised on a poor diet (cactus without fruit) are nearly monomorphic, whereas those raised on a high-quality diet (cactus with ripe fruit) are distinctly sexually dimorphic via the expression of large hind leg weapons in males. Contrary to our expectations, we found little evidence of a potential for evolutionary change for any trait measured. Thus, although we show weapons are highly condition dependent, and changes in weapon expression and dimorphism could alter evolutionary dynamics, our populations are unlikely to experience further evolutionary changes under current conditions. PMID- 27468123 TI - Chemotherapy for Advanced Non-Small-Cell Lung Cancer in Elderly Patients. AB - Clinical Question: Do patients above 70 years of age with newly diagnosed advanced non-small-cell lung cancer benefit from platinum-based combination or should they receive non-platinum agents either as single-agent or in combination? Bottom Line: For fit elderly patients platinum-based combination is associated with better overall survival, progression-free survival, and objective response rate, however this improvement should be counter balanced against the higher risk of major adverse events (AE). PMID- 27468124 TI - Loss of mtch2 function impairs early development of liver, intestine and visceral adipocytes in zebrafish larvae. AB - The mitochondrial carrier homologue 2 (MTCH2) has been shown to be essential for embryogenesis in mice, and variants in the MTCH2 locus have been linked to obesity in humans. Here, we investigated the importance of mtch2 for embryogenesis and adipocyte formation in zebrafish in vivo. We show that mtch2 is conserved in zebrafish and broadly expressed during embryogenesis. Knock-down of mtch2 results in impaired development of liver and intestine, and is associated with a reduced number of adipocytes and impaired postembryonic growth. The findings indicate an essential role for mtch2 during organ development and adipogenesis in vivo. PMID- 27468125 TI - Diffusion of Fluorescently Labeled Bacteriocin from Edible Nanomaterials and Embedded Nano-Bioactive Coatings. AB - Application of nano-biotechnology to improve the controlled release of drugs or functional agents is widely anticipated to transform the biomedical, pharmaceutical, and food safety trends. The purpose of the current study was to assess and compare the release rates of fluorescently labeled antimicrobial peptide nisin (lantibiotic/biopreservative) from liposomal nanocarriers. The elevated temperature, high electrostatic attraction between anionic bilayers and cationic nisin, larger size, and higher encapsulation efficiency resulted in rapid and elevated release through pore formation. However, acidic pH and optimal ethanol concentration in food simulating liquid (FSL) improved the stability and retention capacity of loaded drug. Thus, controlling various factors had provided partition coefficient K values from 0.23 to 8.78 indicating variation in nisin affinity toward encapsulating macromolecule or FSL. Interaction between nisin and nanoscale bilayer systems by atomic force (AFM) and transmission electron microscopy demonstrated membrane activity of nisin from adsorption and aggregation to pore formation. Novel nanoactive films with preloaded nanoliposomes embedded in biodegradable polymer revealed improved morphological, topographic, and roughness parameters studied by confocal microscopy and AFM. Pre encapsulated nanoactive biopolymer demonstrated excellent retention capacity as drug carriers by decreasing the partition coefficient value from 1.8 to 0.66 (~30%) due to improved stability of nanoliposomes embedded in biopolymer network. PMID- 27468126 TI - Structure-Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors. AB - EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure-activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity. PMID- 27468128 TI - Fructose overfeeding in first-degree relatives of type 2 diabetic patients impacts energy metabolism and mitochondrial functions in skeletal muscle. AB - SCOPE: The aim of the study was to assess the effects of a high-fructose diet (HFrD) on skeletal muscle transcriptomic response in healthy offspring of patients with type 2 diabetes, a subgroup of individuals prone to metabolic disorders. METHODS AND RESULTS: Ten healthy normal weight first-degree relatives of type 2 diabetic patients were submitted to a HFrD (+3.5 g fructose/kg fat-free mass per day) during 7 days. A global transcriptomic analysis was performed on skeletal muscle biopsies combined with in vitro experiments using primary myotubes. Transcriptomic analysis highlighted profound effects on fatty acid oxidation and mitochondrial pathways supporting the whole-body metabolic shift with the preferential use of carbohydrates instead of lipids. Bioinformatics tools pointed out possible transcription factors orchestrating this genomic regulation, such as PPARalpha and NR4A2. In vitro experiments in human myotubes suggested an indirect action of fructose in skeletal muscle, which seemed to be independent from lactate, uric acid, or nitric oxide. CONCLUSION: This study shows therefore that a large cluster of genes related to energy metabolism, mitochondrial function, and lipid oxidation was downregulated after 7 days of HFrD, thus supporting the concept that overconsumption of fructose-containing foods could contribute to metabolic deterioration in humans. PMID- 27468129 TI - Dispositional Affect Moderates the Stress-Buffering Effect of Social Support on Risk for Developing the Common Cold. AB - OBJECTIVE: The aim was to examine whether trait positive and negative affect (PA, NA) moderate the stress-buffering effect of perceived social support on risk for developing a cold subsequent to being exposed to a virus that causes mild upper respiratory illness. METHOD: Analyses were based on archival data from 694 healthy adults (Mage = 31.0 years, SD = 10.7 years; 49.0% female; 64.6% Caucasian). Perceived social support and perceived stress were assessed by self report questionnaire and trait affect by aggregating responses to daily mood items administered by telephone interview across several days. Subsequently, participants were exposed to a virus that causes the common cold and monitored for 5 days for clinical illness (infection + objective signs of illness). RESULTS: Two 3-way interactions emerged-Support * Stress * PA and Support * Stress * NA. The nature of these effects was such that among persons with high trait PA or low trait NA, greater social support attenuated the risk of developing a cold when under high but not low perceived stress; this stress buffering effect did not emerge among persons with low trait PA or high trait NA. CONCLUSIONS: Dispositional affect might be used to identify individuals who may be most responsive to social support and support-based interventions. PMID- 27468130 TI - Loperamide Restricts Intracellular Growth of Mycobacterium tuberculosis in Lung Macrophages. AB - New approaches for improving tuberculosis (TB) control using adjunct host directed cellular and repurposed drug therapies are needed. Autophagy plays a crucial role in the response to TB, and a variety of autophagy-inducing drugs that are currently available for various medical conditions may serve as an adjunct treatment in pulmonary TB. Here, we evaluated the potential of loperamide, carbamazepine, valproic acid, verapamil, and rapamycin to enhance the antimicrobial immune response to Mycobacterium tuberculosis (Mtb). Human monocyte derived macrophages (MDMs) and murine alveolar cells (MACs) were infected with Mtb and treated with loperamide, carbamazepine, valproic acid, verapamil, and rapamycin in vitro. Balb/c mice were intraperitoneally administered loperamide, valproic acid, and verapamil, and MACs were infected in vitro with Mtb. The induction of autophagy, the containment of Mtb within autophagosomes and the intracellular Mtb burden were determined. Autophagy was induced by all of the drugs in human and mouse macrophages, and loperamide significantly increased the colocalization of microtubule-associated protein 1 light chain 3 with Mtb in MDMs. Carbamazepine, loperamide, and valproic acid induced microtubule-associated protein 1 light chain 3 and autophagy related 16- like protein 1 gene expression in MDMs and in MACs. Loperamide also induced a reduction in TNF-alpha production. Loperamide and verapamil induced autophagy, which was associated with a significant reduction in the intracellular growth of Mtb in MACs and alveolar macrophages. The intraperitoneal administration of loperamide and valproic acid induced autophagy in freshly isolated MACs. The antimycobacterial activity in MACs was higher after loperamide treatment and was associated with the degradation of p62. In conclusion, loperamide shows potential as an adjunctive therapy for the treatment of TB. PMID- 27468131 TI - Lifestyle behavior interventions delivered using technology in childhood, adolescent, and young adult cancer survivors: A systematic review. AB - Childhood, adolescent, and young adult cancer survivors demonstrate increased cardio-metabolic risk factors, which are amenable to lifestyle changes. The use of technology to impact lifestyle change expands previously limited intervention access, yet little is known about its use. We summarized lifestyle interventions for survivors delivered using technology, finding six studies, primarily targeting physical activity. Study samples were small and durations ranged from 5 to 16 weeks and outcomes modest. Participants were older, white, survivors of leukemia or brain tumors, and the majority received Web-based interventions. Study quality was moderate. Few technology-based interventions have been developed, suggesting an area of opportunity for survivors. PMID- 27468132 TI - N-Iodosuccinimide-Initiated Spirocyclopropanation of Styrenes with 1,3-Dicarbonyl Compound for the Synthesis of Spirocyclopropanes. AB - Herein is reported an N-iodosuccinimide-initiated spirocyclopropanation reaction of styrenes with 1,3-dicarbonyl compounds in the presence of white LED light. The reaction proceeds via two C-H and two C-I bond cleavage event, along with two C-C bond formation event, and formation of quaternary centers. These reactions could be carried out at room temperature and tolerated a wide range of substrates, resulting in good to excellent chemical yields. This developed radical reaction provides easy and practical access to spiro[2.4]heptane-4,7-dione derivatives. PMID- 27468133 TI - DNA authentication of animal-derived concentrated Chinese medicine granules. AB - Concentrated Chinese medicine granules (CCMG) offer patients a convenient option for traditional therapy. However with morphological and microscopic characteristics lost, it is difficult to authenticate and control the quality of these medicinal products. This study is the first to examine the feasibility of using DNA techniques to authenticate animal-derived CCMG, which has so far lacking of effective means for authentication. Primers targeting amplicons of different sizes were designed to determine the presence of PCR-amplifiable DNA fragments in two types of CCMG, namely Zaocys and Scorpio. Species-specific primers were designed to differentiate the genuine drugs from their adulterants. The specificity of the designed primers was evaluated in crude drugs (including genuine and adulterant) and CCMG. Results showed that by using species-specific primers, DNA fragments of less than 200bp could be isolated from the CCMG and the concerned source materials. This study demonstrated the presence of small size DNA in animal-derived CCMG and the DNA is effective in species identification. The work has extended the application of DNA techniques in herbal medicine and this approach may be further developed for quality control and regulatory compliance in the CCMG industry. PMID- 27468134 TI - In-silico modeling of granulomatous diseases. AB - PURPOSE OF REVIEW: The pathogenesis of genetically complex granulomatous diseases, such as sarcoidosis and latent tuberculosis, remains largely unknown. With the recent advent of more powerful research tools, such as genome-wide expression platforms, comes the challenge of making sense of the enormous data sets so generated. This manuscript will provide demonstrations of how in-silico (computer) analysis of large research data sets can lead to novel discoveries in the field of granulomatous lung disease. RECENT FINDINGS: The application of in silico research tools has led to novel discoveries in the fields of noninfectious (e.g., sarcoidosis) and infectious granulomatous diseases. Computer models have identified novel disease mechanisms and can be used to perform 'virtual' experiments rapidly and at low cost compared with conventional laboratory techniques. SUMMARY: Granulomatous lung diseases are extremely complex, involving dynamic interactions between multiple genes, cells, and molecules. In-silico interpretation of large data sets generated from new research platforms that are capable of comprehensively characterizing and quantifying pools of biological molecules promises to rapidly accelerate the rate of scientific discovery in the field of granulomatous lung disorders. PMID- 27468135 TI - 4-Chloro-alpha-cyanocinnamic acid is an efficient soft matrix for cyanocobalamin detection in foodstuffs by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). AB - 4-Chloro-alpha-cyanocinnamic acid (ClCCA) is a very useful matrix able to give the protonated adduct [M+H](+) of intact cyanocobalamin (CNCbl) as the base peak (m/z 1355.58) in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The only fragment observed is [M-CN + H](+*) formed through the facile (*) CN neutral loss reflecting the fairly low Co-C bond energy. All other investigated proton transfer matrices, including alpha-cyano-4 hydroxycinnamic acid, para-nitroaniline and 2,5-dihydroxybenzoic acid, give rise to a complete decyanation of CNCbl with concomitant formation of [M-CN + H](+*) , [M-CN + Na](+*) and [M-CN + K](+*) adducts at m/z 1329.57, 1351.55 and 1367.51, respectively. Depending on the matrix used, a variable degree of fragmentation involving the alpha-side axial ligand was observed. A plausible explanation of the specific behaviour of 4-chloro-alpha-cyanocinnamic acid as a soft matrix is discussed. Tandem mass spectra of both [M + H](+) and [M-CN + H](+*) ions were obtained and product ions successfully assigned. The possibility of detecting the protonated adduct of intact CNCbl was exploited in foodstuff samples such as cow milk and hen egg yolk by MALDI tandem MS upon sample extraction. We believe that our data provide strong basis for the application of MALDI tandem MS in the qualitative analysis of natural CNCbl, including fish, liver and meat samples. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27468136 TI - Recombinant human hyaluronidase facilitated subcutaneous immunoglobulin treatment in pediatric patients with primary immunodeficiencies: long-term efficacy, safety and tolerability. AB - AIM: To assess the long-term efficacy, safety and tolerability of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulin (Ig) (fSCIG; HYQVIA((r)); IGHy) in children aged <18 years. PATIENTS & METHODS: Patients with primary immunodeficiency diseases were included in the studies. IGHy was administered every 3 or 4 weeks. RESULTS: Validated acute serious bacterial infections were reported at 0.08/patient-year (four pneumonia episodes in three patients). No serious adverse drug reaction (ADR) was reported, and rates of local and systemic ADRs were low (0.09/infusion and 0.1/infusion). Infection rates were low (3.02/patient-year) with sustained Ig trough levels (median: 1009 mg/dl). Of 674 IGHy infusions, 97.2% required no change of administration due to ADR, in most (82.5%) with one infusion site. No patient developed neutralizing anti-rHuPH20 antibodies. Postpivotal study, 100% of patients aged <14 years or their caregivers and 85.7% of patients aged 14 to <18 years expressed preference for IGHy compared with Ig administered intravenously or Ig administered subcutaneously. CONCLUSION: These studies, with the longest (maximum: 3.3 years) duration of any reported Ig replacement trials in children with primary immunodeficiency diseases, showed low infection, local and systemic reaction rates along with well-tolerated infusions given in a single site. PMID- 27468138 TI - Effects of dietary natural and fermented herb combination on growth performance, carcass traits and meat quality in grower-finisher pigs. AB - The effects of an herb combination (pomegranate, Ginkgo biloba, licorice) in natural (NPGL) or fermented (FPGL) form administered as 0.4% of the basal diet on the performance and meat quality of grower-finisher pigs were evaluated. Dietary supplementation with NPGL or FPGL reduced the feed intake and back fat thickness of pigs, while increasing lean production. Serum IgG was higher in the FPGL supplemented group. Remarkably, ingestion of NPGL and FPGL reduced the ether extract in the longissimus dorsi muscle (LDM) with increased moisture, whereas the cholesterol was lower in the NPGL group. Dietary supplementation of NPGL and FPGL increased the n-3 fatty acid in LDM with a reduced ratio of n-6/n-3. Both NPGL and FPGL significantly reduced the TBARS value of pig meat when fresh and after 2 and 3weeks of storage. Overall, dietary NPGL and FPGL improved the quality of pig meat by increasing the n-3 fatty acid levels while reducing the ether extract and TBARS value. PMID- 27468139 TI - Identification and control of moulds responsible for black spot spoilage in dry cured ham. AB - The aims of this work were to identify moulds responsible for black spot spoilage in the drying and cellar stages of dry-cured ham processing and evaluate the effectiveness of preventive actions for controlling this alteration. Four mould strains isolated from spoiled hams were identified by morphological characteristics and the ITS and beta-tubulin sequencing. Two of them were Cladosporium oxysporum, one was C. cladosporioides and the remaining one was C. herbarum. These spoiling strains reproduced the black spots on dry-cured ham based media and ham slices. Additionally, the effect of water activity (aw) conditions reached throughout dry-cured ham ripening and the activity of the protective culture Penicillium chrysogenum CECT 20922 against the spoiling moulds were evaluated. In the dry-cured ham model system the growth of the Cladosporium strains was minimised when the aw approaches 0.84 or in P. chrysogenum CECT 20922 inoculated dry-cured ham slices. Therefore such combination could be used to avoid the black spot formation in dry-cured ham. PMID- 27468137 TI - Delays in postremission chemotherapy for Philadelphia chromosome negative acute lymphoblastic leukemia are associated with inferior outcomes in patients who undergo allogeneic transplant: An analysis from ECOG 2993/MRC UK ALLXII. AB - Adults with acute lymphoblastic leukemia (ALL) have a poorer prognosis than children due to a high risk of relapse. One explanation may be variable adherence to dose-intense chemotherapy. However, little is known about risk factors for delays in therapy and their impact on survival. We conducted an analysis of ECOG 2993/UKALLXII trial to study delays in postremission chemotherapy in adults with newly diagnosed ALL. Logistic regression was used to identify risk factors for a very long delay (VLD, >4 weeks) in start of intensification therapy. Cox regression was used to evaluate the impact of delays on overall survival (OS) and event-free survival (EFS). We evaluated 1076 Philadelphia chromosome negative (Ph ) patients who completed induction chemotherapy, achieved complete remission, and started intensification. Factors independently associated with VLD included duration of hospitalization (odds ratio [OR] = 1.2, P < 0.001) during Phase I; thrombocytopenia during Phase I (OR = 1.16, P = 0.004) or Phase II (OR 1.13, P = 0.001); chemotherapy dose reductions during Induction Phase I (OR = 1.72, P < 0.014); female sex (OR = 1.53, P = 0.010); Black (OR = 3.24, P = 0.003) and Asian (OR = 2.26, P = 0.021) race; and increasing age (OR = 1.31, P < 0.001). In multivariate Cox regression, patients who underwent allogeneic stem cell transplant (alloHCT) had significantly worse OS (HR 1.4, P = 0.03) and EFS (HR 1.4, P = 0.02) after experiencing a VLD compared to alloHCT patients who experienced <=4 weeks delay. Specific populations (female, older, Black, and Asian patients) were more likely to experience delays in chemotherapy, as were those with significant toxicity during induction. VLDs in therapy negatively affected outcomes in patients undergoing allografting. Am. J. Hematol. 91:1107 1112, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27468140 TI - Changes in coronary plaque morphology in patients with acute coronary syndrome versus stable angina pectoris after initiation of statin therapy. AB - OBJECTIVES: The aim of this study was to examine coronary plaque morphology after initiation of statins and compare changes in plaque morphology in patients presenting with acute coronary syndrome (ACS) versus stable angina pectoris (SAP). BACKGROUND: ACS is associated with a pan-inflammatory state, and intraplaque features of inflammation correlate with coronary plaque progression. Statins have known anti-inflammatory properties that may contribute toward their beneficial cardiovascular effects. METHODS: Sixty-nine statin-naive patients (ACS, n=55; SAP, n=14) underwent baseline imaging with optical coherence tomography and intravascular ultrasound. Repeat imaging was performed at 6 and 12 months. A total of 97 nonculprit plaques were analyzed (ACS, n=74; SAP, n=23). RESULTS: Fibrous cap thickness increased in both ACS and SAP patients (all P<0.001 compared with the baseline); the ACS group showed greater percent change in fibrous cap thickness at 12 months (192.8+/-148.9% in ACS vs. 128.2+/-88.7% in SAP, P=0.018). The ACS group also showed a significant decrease in plaque microvessels (44.6% at baseline vs. 26.6% at 12 months, P=0.0386). CONCLUSION: Compared with patients with SAP, patients presenting with ACS show more favorable changes in plaque morphology after starting statin treatment. This supports a potential additive benefit of statins in the inflammatory state of ACS and reaffirms the clinical importance of statin therapy for coronary atherosclerosis. PMID- 27468141 TI - Coronary artery thrombus in patients with ST-segment elevation myocardial infarction: bad to have it, bad to remove it and a case for glycoprotein IIb/IIIa inhibitors? PMID- 27468142 TI - Race and Sex Differences in Management and Outcomes of Patients After ST Elevation and Non-ST-Elevation Myocardial Infarct: Results From the NCDR. AB - BACKGROUND: Race and sex have been shown to affect management of myocardial infarction (MI); however, it is unclear if such disparities exist in contemporary care of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). HYPOTHESIS: Disparities in care will be less prevalent in more heavily protocol-driven management of STEMI than the less algorithmic care of NSTEMI. METHODS: Data were collected from the ACTION Registry GWTG database to assess care differences related to race and sex of patients presenting with NSTEMI or STEMI. For key treatments and outcomes, adjustments were made including patient demographics, baseline comorbidities, and markers of socioeconomic status. RESULTS: Key demographic variables demonstrate significant differences in baseline comorbidities; black patients had higher incidences of hypertension and diabetes, and women more frequently had diabetes. With few exceptions, rates of acute and discharge medical therapy were similar by race in any sex category in both STEMI and NSTEMI populations. Rates of catheterization were similar by race for STEMI but not for NSTEMI, where both black men and women had lower rates of invasive therapy. Rates of revascularization were significantly lower for black patients in both the STEMI and NSTEMI groups regardless of sex. Rates of adverse events differed by sex, with disparities for death and major bleeding; after adjustment, rates were similar by race within sex comparisons. CONCLUSIONS: In this contemporary cohort, although there are differences by race in presentation and management of MI, heavily protocol-driven processes seem to show fewer racial disparities. PMID- 27468143 TI - Twice-daily application of topical corticosteroids with a squirt system for patients with steroid-responsive olfactory impairment. AB - CONCLUSION: Twice-daily topical corticosteroid treatment using a squirt system was beneficial in maintaining improvements in olfactory dysfunction which had been achieved by oral steroid treatment. OBJECTIVES: Some patients suffering from olfactory dysfunction respond well to corticosteroids. However, maintaining these improvements is challenging. The aim of this study was to evaluate the maintenance effect of twice-daily topical steroid treatment using a squirt system. METHODS: Twenty-two anosmic patients with an increase in odor threshold, discrimination, and identification (TDI) scores in Sniffin' Sticks tests by more than six points after 1-week of oral steroid treatment were enrolled. All the patients used a squirt system to apply topical corticosteroids and were followed up at 1, 3, and 6 months. RESULTS: Nineteen, 16, and 10 patients were followed-up at 1, 3, and 6 months after treatment, respectively. All the patients had significant visual analog scale scores improvements compared to pre-treatment. The mean improvements in TDI scores were 9.80 (p < 0.001), 11.58 (p = 0.001), and 13.87 (p = 0.005) after 1, 3, and 6 months of treatment, respectively. The self rated and objective olfactory function scores were maintained with steroid squirt therapy without significant decline, even in the patients who were followed up for 6 months. PMID- 27468144 TI - Range, Magnitude, and Ultrafast Dynamics of Electric Fields at the Hydrated DNA Surface. AB - Range and magnitude of electric fields at biomolecular interfaces and their fluctuations in a time window down to the subpicosecond regime have remained controversial, calling for electric-field mapping in space and time. Here, we trace fluctuating electric fields at the surface of native salmon DNA via their interactions with backbone vibrations in a wide range of hydration levels by building the water shell layer by layer. Femtosecond two-dimensional infrared spectroscopy and ab initio based theory establish water molecules in the first two layers as the predominant source of interfacial electric fields, which fluctuate on a 300 fs time scale with an amplitude of 25 MV/cm due to thermally excited water motions. The observed subnanometer range of these electric interactions is decisive for biochemical structure and function. PMID- 27468146 TI - A Microarray Tool Provides Pathway and GO Term Analysis. AB - Analysis of gene expression profiles is no longer exclusively a task for bioinformatic experts. However, gaining statistically significant results is challenging and requires both biological knowledge and computational know-how. Here we present a novel, user-friendly microarray reporting tool called maRt. The software provides access to bioinformatic resources, like gene ontology terms and biological pathways by use of the DAVID and the BioMart web-service. Results are summarized in structured HTML reports, each presenting a different layer of information. In these report, contents of diverse sources are integrated and interlinked. To speed up processing, maRt takes advantage of the multi-core technology of modern desktop computers by using parallel processing. Since the software is built upon a RCP infrastructure it might be an outset for developers aiming to integrate novel R based applications. AVAILABILITY: Installer, documentation and various kinds of tutorials are available under LGPL license at the website of our institute http://www.pharma.uni-bonn.de/www/mart. This software is free for academic use. PMID- 27468147 TI - Large-Scale Evaluation of CavBase for Analyzing the Polypharmacology of Kinase Inhibitors. PMID- 27468145 TI - PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis. AB - BACKGROUND: The influence of neoadjuvant radiochemotherapy (RCT) on programmed death-ligand 1 (PD-L1) expression, a predictive marker for programmed cell death protein 1 (PD-1) inhibitor therapy, was studied on tumour and inflammatory cells in rectal adenocarcinoma patients along with its prognostic value. METHODS: PD-L1 immunohistochemistry was performed on tissue microarrays of 103 pre-RCT biopsies and 159 post-RCT surgical specimens (central tumour, invasive front and normal tissue) of 199 patients. In 63 patients, both samples were available. Proportion and maximum intensity of PD-L1-positive (PD-L1+) cells were evaluated. RESULTS: RCT increased the proportion of PD-L1-expressing cancer cells from 2.1% to 7.8% in the central tumour (p < 0.001) or 9.3% in the invasive front (p < 0.001). Cancer cell PD-L1 on its own could not predict prognosis. High PD-L1 expression on pre-RCT inflammatory cells (maximum intensity: p = 0.048) and post-RCT invasive front inflammatory cells (p = 0.010) correlated with improved no evidence of disease survival. In multivariate analysis, the combination of low PD L1 in cancer and inflammatory cells was an independent negative prognostic marker for overall survival (OS) pre-RCT (Cox's proportional hazard ratio 0.438, p = 0.045) and in the invasive front post-RCT (Cox's proportional hazard ratio 0.257, p = 0.030). CONCLUSION: Neoadjuvant RCT is associated with an increased PD-L1 expression in rectal adenocarcinoma patients, which should prompt clinical trials combining radiotherapy and PD-1/PD-L1 pathway blockade. Combined low PD-L1 expression on tumour and inflammatory cells is an independent negative prognostic marker for OS in RCT of rectal adenocarcinoma. PMID- 27468148 TI - A Novel Generalized 3D-QSAR Model of Camptothecin Analogs. AB - In the present paper, we are interested to explore if the application of docking driven conformational analysis could increase the goodness of 3D-QSAR statistical models, as alternative approach to a conventional ligand-based conformer generation. In particular, we have selected as peculiar key-study an ensemble of Camptothecin (CPT) analogs classified as human DNA Topoisomerase I (Top1) selective inhibitors. The CPT analogs dataset has been recently analyzed by Hansch and Verma using a classical 2D-QSAR study. PMID- 27468149 TI - Toward an Optimal Approach for Variable Selection in Counter-Propagation Neural Networks: Modeling Protein-Tyrosine Kinase Inhibitory of Flavanoids Using Substituent Electronic Descriptors. AB - Counter propagation neural network (CPNN) is one of the attractive tools of classification in QSAR studies. A major obstacle in classification by CPNN is finding the best subset of variables. In this study, the performance of some different feature selection algorithms including F score-based ranking, eigenvalue ranking of PCs obtained from data set, Non-Error-Rate (NER) ranking of both descriptors and PCs, and 3-way handling of data, Parallel Factor Analysis (PARAFAC), was evaluated in order to find the best classification model. The methods were applied for modeling protein-tyrosine kinase inhibitory of some flavonoid derivatives using substituent electronic descriptors (SED) as novel source of electronic descriptors. The results showed that the best performance was achieved by F-score ranking while the NER ranking of principal components (PCs) showed very fluctuate results and the worst performance was belonging to PARAFAC-CPNN. Furthermore, comparison of results of these nonlinear algorithms with linear discriminate analysis method revealed better predictions by the former. PMID- 27468150 TI - A Role for Hydration in Interleukin-2 Inducible T Cell Kinase (Itk) Selectivity. AB - The selectivity profile of kinase inhibitors is commonly explained in terms of favourable or unfavourable interactions between the inhibitor and active site residues. In practice residue sequence differences have not always been sufficient to explain observed selectivity profiles. A series of interleukin-2 inducible T cell kinase (Itk, EC 2.7.10.2) inhibitors that achieve selectivity through the introduction of a single nitrogen atom in an aromatic ring has recently been discovered. Structures of these inhibitors bound to Itk showed this nitrogen to be solvent exposed and not involved in any direct interactions with the enzyme. By analysing active site hydration, using the molecular dynamics tool WaterMap, the observed selectivity profile can be explained in terms of the replacement of a thermodynamically unfavourable water molecule by the inhibitor and improved hydration of the bound ligand. The location of this hydration site was successfully used to enrich virtual screening results in their content of selective Itk inhibitors. PMID- 27468151 TI - Automated QSAR with a Hierarchy of Global and Local Models. AB - We present an automated QSAR procedure that is used in AstraZeneca's AutoQSAR system. The approach involves automatically selecting the most predictive models from pools of both global and local models. The effectiveness of this QSAR modelling strategy is demonstrated with a retrospective study that uses a diverse selection of 9 early stage AstraZeneca drug discovery projects and 3 physicochemical endpoints: LogD; solubility and human plasma protein binding. We show that the strategy makes a statistically significant improvement to the accuracy of predictions when compared to an updating global strategy, and that the systematic biases inherent in the global model predictions are almost completely removed. This improvement is attributed to the model selection aspect of the strategy. PMID- 27468152 TI - Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site. AB - Aliskiren is the first orally active, direct renin inhibitor to be approved for the treatment of hypertension. Its structure elucidation and conformational analysis were explored using 1D and 2D NMR spectroscopy, as well as random search and molecular dynamics (MD) simulations. For the first time, MD calculations have also been performed for aliskiren at the receptor site, in order to reveal its molecular basis of action. It is suggested that aliskiren binds in an extended conformation and is involved in several stabilizing hydrogen bonding interactions with binding cavity (Asp32/255, Gly34) and other binding-cavity (Arg74, Ser76, Tyr14) residues. Of paramount importance is the finding of a loop consisting of residues around Ser76 that determines the entrapping of aliskiren into the active site of renin. The details of this mechanism will be the subject of a subsequent study. Additionally molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations for the aliskiren-renin complex provided insight into the binding mode of aliskiren by identifying van der Waals and nonpolar contribution to solvation as the main components of favorable binding interactions. PMID- 27468153 TI - Blind Dockings of Benzothiazoles to Multiple Receptor Conformations of Triosephosphate Isomerase from Trypanosoma cruzi and Human. AB - We aim to uncover the binding modes of benzothiazoles, which have been reported as specific inhibitors of triosephosphate isomerase from the parasite Trypanosoma cruzi (TcTIM), by performing blind dockings on both TcTIM and human TIM (hTIM). Detailed analysis of binding sites and specific interactions are carried out based on ensemble dockings to multiple receptor conformers obtained from molecular dynamics simulations. In TcTIM dimer dockings, the inhibitors preferentially bind to the tunnel-shaped cavity formed at the interface of the subunits, whereas non-inhibitors mostly choose other sites. In contrast, TcTIM monomer binding interface and hTIM dimer interface do not present a specific binding site for the inhibitors. These findings point to the importance of the tunnel and of the dimeric form for inhibition of TcTIM. Specific interactions of the inhibitors and their sulfonate-free derivatives with the receptor residues indicate the significance of sulfonate group for binding affinity and positioning on the TcTIM dimer interface. One of the inhibitors also binds to the active site, which may explain its relatively higher inhibition effect on hTIM. PMID- 27468154 TI - Identification and Application of Antitarget Activity Hotspots to Guide Compound Optimization. AB - The optimization of a lead structure to a development candidate often requires removal of undesirable antitarget activities. To this end, we have developed an approach to extract antitarget activity hotspots from larger databases and to transfer this knowledge onto novel chemical series. These antitarget activity hotspots will be captured as pairs of informative molecules, which are chemically closely related, but differ significantly in biological activity. We illustrate the application of antitarget activity hotspots as informative compound pairs for the optimization of side effects in lead structures for relevant antitargets in pharmaceutical research. The use for prospective design requires establishing a structural link between known antitarget hotspot pairs and a new lead structure: we employ 3D-based similarity comparison for this task. The entire workflow serves as idea generator in early optimization. The feasibility of this approach is demonstrated in several optimization problems related to hERG inhibition, and CYP3A4 inhibition. Several structural examples demonstrate the ability of the 3D shape searching to identify related scaffolds and the usefulness of the antitarget hotspot information to guide optimization by modulating the undesirable antitarget activity. Such a concept based on the analysis of local similarities and the transfer to 3D-related series is especially promising in those cases, where the construction of antitarget QSAR models fails to detect local SAR trends for guiding the next optimization cycle. PMID- 27468155 TI - Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis. AB - Autosomal recessive osteopetroses (AROs) are rare, genetically heterogeneous skeletal diseases with increased bone density that are often lethal if left untreated. A precise molecular classification is relevant for the patient's management, because in some subgroups hematopoietic stem cell transplantation (HSCT), which is the only curative therapy, is contraindicated. In two unrelated ARO patients, the molecular analysis revealed the presence of a synonymous variant in known ARO genes, namely in the TCIRG1 gene in one patient and in the CLCN7 in the other patient, predicted to impact on the splicing process. In the latter case, sequencing of the transcript confirmed the splicing defect, whereas in the former, for whom an RNA sample was not available, the defect was reconstructed in vitro by the minigene technology. These results strongly suggest that these synonymous changes were responsible for the disease in our patients. Our findings are novel with respect to ARO and add to the few reports in literature dealing with different diseases, underlining the importance of cDNA analysis for the correct assessment of exonic changes, even when exome sequencing is performed. In particular, we highlight the possibility that at least in some cases ARO is due to synonymous changes, erroneously considered clinically silent, in the genes already described in literature, and suggest carefully reevaluating the sequencing results of these genes when mutations are not found at a first analysis. In addition, with respect to the CLCN7 gene, we suggest that synonymous variants might also contribute to the large spectrum of severity typical of CLCN7 dependent osteopetrosis through more subtle, but not negligible, effects on protein availability and functionality. (c) 2016 American Society for Bone and Mineral Research. PMID- 27468156 TI - US States' Childhood Obesity Surveillance Practices and Recommendations for Improving Them, 2014-2015. AB - INTRODUCTION: Routine collection, analysis, and reporting of data on child height, weight, and body mass index (BMI), particularly at the state and local levels, are needed to monitor the childhood obesity epidemic, plan intervention strategies, and evaluate the impact of interventions. Child BMI surveillance systems operated by the US government do not provide state or local data on children across a range of ages. The objective of this study was to describe the extent to which state governments conduct child BMI surveillance. METHODS: From August through December 2014, we conducted a structured telephone survey with state government administrators to learn about state surveillance of child BMI. We also searched websites of state health and education agencies for information about state surveillance. RESULTS: State agency administrators in 48 states and Washington, DC, completed telephone interviews (96% response rate). Based on our interviews and Internet research, we determined that 14 states collect child BMI data in a manner consistent with standard definitions of public health surveillance. CONCLUSION: The absence of child BMI surveillance systems in most states limits the ability of public health practitioners and policymakers to develop and evaluate responses to the childhood obesity epidemic. Greater investment in surveillance is needed to identify the most effective and cost effective childhood obesity interventions. PMID- 27468157 TI - Intervention Costs From Communities Putting Prevention to Work. AB - INTRODUCTION: In 2010, the Centers for Disease Control and Prevention funded 50 communities to participate in the Communities Putting Prevention to Work (CPPW) program. CPPW supported community-based approaches to prevent or delay chronic disease and promote wellness by reducing tobacco use and obesity. We collected the direct costs of CPPW for the 44 communities funded through the American Recovery and Reinvestment Act (ARRA) and analyzed costs per person reached for all CPPW interventions and by intervention category. METHODS: From 2011 through 2013, we collected quarterly data on costs from the 44 CPPW ARRA-funded communities. We estimated CPPW program costs as spending on labor; consultants; materials, travel, and services; overhead activities; and partners plus the value of in-kind donations. We estimated communities' costs per person reached for each intervention implemented and compared cost allocations across communities that focused on reducing tobacco use, or obesity, or both. Analyses were conducted in 2014; costs are reported in 2012 dollars. RESULTS: The largest share of CPPW total costs of $363 million supported interventions in communities that focused on obesity ($228 million). Average costs per person reached were less than $5 for 84% of tobacco-related interventions, 88% of nutrition interventions, and 89% of physical activity interventions. Costs per person reached were highest for social support and services interventions, almost $3 for tobacco-use interventions and $1 for obesity prevention interventions. CONCLUSIONS: CPPW cost estimates are useful for comparing intervention cost per person reached with health outcomes and for addressing how community health intervention costs vary by type of intervention and by community size. PMID- 27468158 TI - Associations Between Cardiovascular Health and Health-Related Quality of Life, Behavioral Risk Factor Surveillance System, 2013. AB - INTRODUCTION: The American Heart Association established 7 cardiovascular health metrics as targets for promoting healthier lives. Cardiovascular health has been hypothesized to play a role in individuals' perception of quality of life; however, previous studies have mostly assessed the effect of cardiovascular risk factors on quality of life. METHODS: Data were from the 2013 Behavioral Risk Factor Surveillance System, a state-based telephone survey of adults 18 years or older (N = 347,073). All measures of cardiovascular health and health-related quality of life were self-reported. The 7 ideal cardiovascular health metrics were normal blood pressure, cholesterol, body mass index, not having diabetes, not smoking, being physically active, and having adequate fruit or vegetable intake. Cardiovascular health was categorized into meeting 0-2, 3-5, or 6-7 ideal cardiovascular health metrics. Logistic regression models examined the association between cardiovascular health, general health status, and 3 measures of unhealthy days per month, adjusting for age, sex, race/ethnicity, education, and annual income. RESULTS: Meeting 3 to 5 or 6 to 7 ideal cardiovascular health metrics was associated with a 51% and 79% lower adjusted prevalence ratio (aPR) of fair/poor health, respectively (aPR = 0.49, 95% confidence interval [CI] [0.47 0.50], aPR = 0.21, 95% CI [0.19-0.23]); a 47% and 72% lower prevalence of >=14 physically unhealthy days (aPR = 0.53, 95% CI [0.51-0.55], aPR = 0.28, 95% CI [0.26-0.20]); a 43% and 66% lower prevalence of >=14 mentally unhealthy days (aPR = 0.57, 95% CI [0.55-0.60], aPR = 0.34, 95% CI [0.31-0.37]); and a 50% and 74% lower prevalence of >=14 activity limitation days (aPR = 0.50, 95% CI [0.48 0.53], aPR = 0.26, 95% CI [0.23-0.29]) in the past 30 days. CONCLUSION: Achieving a greater number of ideal cardiovascular health metrics may be associated with less impairment in health-related quality of life. PMID- 27468159 TI - Engineering of CH3 NH3 PbI3 Perovskite Crystals by Alloying Large Organic Cations for Enhanced Thermal Stability and Transport Properties. AB - The number of studies on organic-inorganic hybrid perovskites has soared in recent years. However, the majority of hybrid perovskites under investigation are based on a limited number of organic cations of suitable sizes, such as methylammonium and formamidinium. These small cations easily fit into the perovskite's three-dimensional (3D) lead halide framework to produce semiconductors with excellent charge transport properties. Until now, larger cations, such as ethylammonium, have been found to form 2D crystals with lead halide. Here we show for the first time that ethylammonium can in fact be incorporated coordinately with methylammonium in the lattice of a 3D perovskite thanks to a balance of opposite lattice distortion strains. This inclusion results in higher crystal symmetry, improved material stability, and markedly enhanced charge carrier lifetime. This crystal engineering strategy of balancing opposite lattice distortion effects vastly increases the number of potential choices of organic cations for 3D perovskites, opening up new degrees of freedom to tailor their optoelectronic and environmental properties. PMID- 27468161 TI - Use of Online Communication by Patients With Newly Diagnosed Breast Cancer During the Treatment Decision Process. PMID- 27468160 TI - Green tea (-)-epigallocatechin-3-gallate counteracts daytime overeating induced by high-fat diet in mice. AB - SCOPE: High-fat diet (HFD) induces overeating and obesity. Green tea (-) epigallocatechin-3-gallate (EGCG) reduces HFD-induced body weight and body fat gain mainly through increased lipid metabolism and fat oxidation. However, little is known about its effect on HFD-induced alterations in feeding behavior. METHODS AND RESULTS: Three diet groups of wildtype C57B/6j male mice at 5 months old were fed on normal chow diet, 1 week of HFD (60% of energy) and 3 months of HFD (diet induced obesity (DIO)) prior to EGCG supplement in respective diet. EGCG had no effect on feeding behavior in normal chow diet group. Increased daytime feeding induced by HFD was selectively corrected by EGCG treatment in HFD groups, including reversed food intake, feeding frequency and meal size in HFD + EGCG group, and reduced food intake and feeding frequency in DIO + EGCG group. Moreover, EGCG treatment altered diurnally oscillating expression pattern of key appetite-regulating genes, including AGRP, POMC, and CART, and key circadian genes Clock and Bmal1 in hypothalamus of DIO mice, indicating its central effect on feeding regulation. CONCLUSION: Our study demonstrates that EGCG supplement specifically counteracts daytime overeating induced by HFD in mice, suggesting its central role in regulating feeding behavior and energy homeostasis. PMID- 27468162 TI - Removing the Taboo on the Surgical Violation (Cut-Through) of Cancer. AB - Importance: The surgical dictum of en bloc resection without violating cancer tissue has been challenged by novel treatments in head and neck cancer. Observations: An analysis of treatment outcomes involving piecemeal removal of sinonasal, laryngeal, oropharyngeal, and hypopharyngeal cancer shows that it did not compromise tumor control. The rationale for the evolution toward use of this technique is outlined. Conclusions and Relevance: While complete resection with clear margins remains a key end point in surgical oncology, we believe it is time to acknowledge that this time-honored dictum of avoiding tumor violation is no longer valid in selected situations. PMID- 27468163 TI - Letter to the editor: Sleep as a contributing factor in the relationship between depression and cell aging. PMID- 27468164 TI - Involvement of PI3K/Akt/GSK-3beta and mTOR in the antidepressant-like effect of atorvastatin in mice. AB - Atorvastatin is a cholesterol-lowering statin that has been shown to exert several pleiotropic effects in the nervous system as a neuroprotective and antidepressant-like agent. Antidepressant-like effect of atorvastatin in mice is mediated by glutamatergic and serotoninergic receptors, although the precise intracellular signaling pathways involved are unknown. PI3K/Akt/GSK-3beta/mTOR signaling pathway has been associated to neurobiology of depression and seems to be modulated by some pharmacological antidepressant strategies. The present study investigated the participation of the PI3K/Akt/GSK-3beta/mTOR signaling pathway in the antidepressant-like effect of an acute atorvastatin treatment in mice. Atorvastatin sub-effective (0.01 mg/kg) or effective (0.1 mg/kg) doses in the tail suspension test (TST) was administered orally alone or in combination with PI3K, GSK-3beta or mTOR inhibitors. The administration of PI3K inhibitor, LY294002 (10 nmol/site, i.c.v) completely prevented the antidepressant-like effect of atorvastatin (0.1 mg/kg, p.o.). The participation of GSK-3beta in the antidepressant-like effect of atorvastatin was demonstrated by co-administration of a sub-effective dose of atorvastatin (0.01 mg/kg, p.o.) with AR-A014418 (0.01 MUg/site, i.c.v., a selective GSK-3beta inhibitor) or with lithium chloride (10 mg/kg, p.o., a non-selective GSK-3beta inhibitor). The mTOR inhibitor, rapamycin (0.2 nmol/site, i.c.v.) was also able to prevent atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. These behavioral findings were supported by neurochemical observations, as atorvastatin treatment increased the immunocontent of the phosphorylated isoforms of Akt, GSK-3beta and mTOR in the hippocampus of mice. Taken together, our results suggest an involvement of the PI3K/Akt/GSK 3beta/mTOR signaling pathway in the antidepressant-like effect of atorvastatin in mice. PMID- 27468166 TI - Risk, coping and PTSD symptom trajectories in World Trade Center responders. AB - Trajectories of disaster-related posttraumatic stress disorder (PTSD) symptoms are often heterogeneous, and associated with common and unique risk factors, yet little is known about potentially modifiable psychosocial characteristics associated with low-symptom and recovering trajectories in disaster responders. A total of 4487 rescue and recovery workers (1874 police and 2613 non-traditional responders) involved during and in the aftermath of the unprecedented World Trade Center (WTC) attacks, were assessed an average of 3, 6, 8, and 12 years post 9/11/2001. Among police responders, WTC-related PTSD symptoms were characterized by four trajectories, including no/low-symptom (76.1%), worsening (12.1%), improving (7.5%), and chronic (4.4%) trajectories. In non-traditional responders, a five-trajectory solution was optimal, with fewer responders in a no/low-symptom trajectory (55.5%), and the remainder in subtly worsening (19.3%), chronic (10.8%), improving (8.5%), and steeply worsening (5.9%) trajectories. Consistent factors associated with symptomatic PTSD trajectories across responder groups included Hispanic ethnicity, pre-9/11 psychiatric history, greater WTC exposure, greater medical illness burden, life stressors and post-9/11 traumas, and maladaptive coping (e.g., substance use, avoidance coping). Higher perceived preparedness, greater sense of purpose in life, and positive emotion-focused coping (e.g., positive reframing, acceptance) were negatively associated with symptomatic trajectories. Findings in this unique cohort indicate considerable heterogeneity in WTC-related PTSD symptom trajectories over 12 years post 9/11/2001, with lower rates of elevated PTSD symptoms in police than in non traditional responders. They further provide a comprehensive risk prediction model of PTSD symptom trajectories, which can inform prevention, monitoring, and treatment efforts in WTC and other disaster responders. PMID- 27468167 TI - Management of type 2b von Willebrand disease in the neonatal period. AB - Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting one in 1,000 people. Type 2b VWD is a less common subtype caused by a gain-of-function mutation in von Willebrand factor (VWF) that leads to the formation of large, ineffective VWF-platelet multimers in circulation. This unique pathophysiology creates diagnostic and treatment dilemmas. There is limited information on the management of type 2b VWD in the neonatal period. This report describes the management of a neonate with type 2b VWD with an emphasis on the added benefit of concomitant platelet transfusion and factor replacement therapy over factor replacement therapy alone. PMID- 27468165 TI - The microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression. AB - MicroRNAs (miRNAs) are small, non-coding RNAs acting as post-transcriptional regulators of gene expression. Though implicated in multiple CNS disorders, miRNAs have not been examined in any psychiatric disease state in anterior cingulate cortex (AnCg), a brain region centrally involved in regulating mood. We performed qPCR analyses of 29 miRNAs previously implicated in psychiatric illness (major depressive disorder (MDD), bipolar disorder (BP) and/or schizophrenia (SZ)) in AnCg of patients with MDD and BP versus controls. miR-132, miR-133a and miR-212 were initially identified as differentially expressed in BP, miR-184 in MDD and miR-34a in both MDD and BP (although none survived multiple correction testing and must be considered preliminary). In silico target prediction algorithms identified putative targets of differentially expressed miRNAs. Nuclear Co-Activator 1 (NCOA1), Nuclear Co-Repressor 2 (NCOR2) and Phosphodiesterase 4B (PDE4B) were selected based upon predicted targeting by miR 34a (with NCOR2 and PDE4B both targeted by miR-184) and published relevance to psychiatric illness. Luciferase assays identified PDE4B as a target of miR-34a and miR-184, while NCOA1 and NCOR2 were targeted by miR-34a and 184, respectively. qPCR analyses were performed to determine whether changes in miRNA levels correlated with mRNA levels of validated targets. NCOA1 showed an inverse correlation with miR-34a in BP, while NCOR2 demonstrated a positive correlation. In sum, this is the first study to demonstrate miRNA changes in AnCg in psychiatric illness and validate miR-34a as differentially expressed in CNS in MDD. These findings support a mechanistic role for miRNAs in the regulation of stress-responsive genes disrupted in psychiatric illness. PMID- 27468168 TI - DNA G-quadruplexes show strong interaction with DNA methyltransferases in vitro. AB - The DNA methyltransferase enzymes (DNMTs) catalyzing cytosine methylation do so at specific locations of the genome, although with some level of redundancy. The de novo methyltransferases DNMT3A and 3B play a vital role in methylating the genome of the developing embryo in regions devoid of methylation marks. The ability of DNMTs to colocalize at sites of DNA damage is suggestive that recognition of mispaired bases and unusual structures is inherent to the function of these proteins. We provide evidence for G-quadruplex formation within imprinted gene promoters, and report high-affinity binding of recombinant human DNMTs to such DNA G-quadruplexes in vitro. These observations suggest a potential interaction of G-quadruplexes with the DNA methylation machinery, which may be of epigenetic and biological significance. PMID- 27468170 TI - Cancerome: A hidden informative subnetwork of the diseasome. AB - Neoplastic disorders are a leading cause of mortality and morbidity worldwide. Studying the relationships between different cancers using high throughput generated data may elucidate undisclosed aspects of cancer etiology, diagnosis, and treatment. Several studies have described relationships between different diseases based on genes, proteins, pathways, gene ontology, comorbidity, symptoms, and other features. In this study, we first constructed an integrated human disease network based on nine different biological aspects, including molecular, functional, and clinical features. Next, we extracted the cancerome as a cancer-related subnetwork. Further investigation of cancerome could reveal hidden mechanisms of cancer and could be useful in developing new diagnostic tests and effective new drugs. PMID- 27468169 TI - Automatic counting of fungiform papillae by shape using cross-correlation. AB - The determination of the number of fungiform papillae (FP) on the human tongue is important for taste sensitivity studies. Most of the time, the counting of the FP is done manually. In this paper we propose a novel algorithm to count the FP using shape characteristics measured by cross-correlation. The accuracy of the algorithm is evaluated by counting the FP manually on the same images and then doing a statistical analysis. A Poisson regression model is fitted using maximum likelihood. The result is that the algorithm counts are very similar to the human experts. Another advantage of the algorithm is its facility of use, velocity and that it can work on a plain tongue image, without the need to stain the tongue as is usual in manual counting. PMID- 27468171 TI - Facile pretreatment of lignocellulosic biomass using deep eutectic solvents. AB - In this work, three kinds of deep eutectic solvents (DESs) were facilely prepared and used in the pretreatment of corncob, including monocarboxylic acid/choline chloride, dicarboxylic acid/choline chloride and polyalcohol/choline chloride. The enhanced delignification and subsequent enzymatic hydrolysis efficiency were found to be related to the acid amount, acid strength and the nature of hydrogen bond acceptors. The XRD, SEM and FT-IR results consistently indicated that the structures of corncob were disrupted by the removal of lignin and hemicellulose in the pretreatment process. In addition, the optimal pretreatment temperature and time were 90 degrees C and 24h, respectively. This study explored the roles of various DESs combinations, pretreatment temperature and time to better utilize the DESs in the pretreatment of lignocellulosic biomass. PMID- 27468172 TI - Intended Target of the Centers for Disease Control and Prevention Opioid Guidelines. PMID- 27468174 TI - Nursing Students on the Unit: Staff Nurses' Role in the Clinical Practice Setting. PMID- 27468173 TI - Prognostic Role of Right Ventricular Function in Patients With Heart Failure Undergoing Cardiac Resynchronization Therapy. AB - BACKGROUND: Because 20% to 40% of patients undergoing cardiac resynchronization therapy (CRT) do not respond to it, identification of potential factors predicting response is a relevant research topic. HYPOTHESIS: There is a possible association between right ventricular function and response to CRT. METHODS: We analyzed 227 patients from the Cardiac Resynchronization Therapy Modular Registry (CRT-MORE) who received CRT according to current guidelines from March to December 2013. Response to therapy was defined as a decrease of >=15% in left ventricular end-systolic volume (LVESV) at 6 months. RESULTS: The tricuspid annular plane systolic excursion (TAPSE) value that best predicted improvement in LVESV (sensitivity 68%, specificity 54%) was 17 mm. Stratifying patients according to TAPSE, LVESV decreased >=15% in 78% of patients with TAPSE >17 mm (vs 59% in patients with TAPSE <=17 mm; P = 0.006). At multivariate analysis, TAPSE >17 mm was independently associated with LVESV improvement (odds ratio: 1.97, 95% confidence interval: 1.03-3.80, P < 0.05), together with ischemic etiology (odds ratio: 0.39, 95% confidence interval: 0.20-0.75, P < 0.01). These results were confirmed for New York Heart Association class III to IV patients (79% echocardiographic response rate in patients with TAPSE >17 mm vs 55% in patients with TAPSE <17 mm; P = 0.012). CONCLUSIONS: Baseline signs of right ventricular dysfunction suggest possible remodeling after CRT. A TAPSE value of 17 mm was identified as a good cutoff for predicting a better response to CRT in patients with both mildly symptomatic and severe heart failure. PMID- 27468178 TI - Potential Explosion Hazard of Carbonaceous Nanoparticles: Screening of Allotropes. AB - There is a concern that engineered carbon nanoparticles, when manufactured on an industrial scale, will pose an explosion hazard. Explosion testing has been performed on 20 codes of carbonaceous powders. These include several different codes of SWCNTs (single-walled carbon nanotubes), MWCNTs (multi-walled carbon nanotubes) and CNFs (carbon nanofibers), graphene, diamond, fullerene, as well as several different control carbon blacks and graphites. Explosion screening was performed in a 20 L explosion chamber (ASTM E1226 protocol), at a concentration of 500 g/m3, using a 5 kJ ignition source. Time traces of overpressure were recorded. Samples typically exhibited overpressures of 5-7 bar, and deflagration index KSt = V1/3 (dP/dt)max ~ 10 - 80 bar-m/s, which places these materials in European Dust Explosion Class St-1. There is minimal variation between these different materials. The explosive characteristics of these carbonaceous powders are uncorrelated with primary particle size (BET specific surface area). PMID- 27468179 TI - Transpiration and canopy conductance in an inner alpine Scots pine (Pinus sylvestris L.) forest. AB - Canopy transpiration (Ec) of a 150-year old Pinus sylvestris L. stand in an inner alpine dry valley, Tyrol, Austria was estimated throughout two growing seasons 2011 and 2012 by means of xylem sap flow measurements. Although there were prolonged periods of limited soil water availability Ec did not show a clear trend with respect to soil water availability and averaged 0.4 +/- 0.19 mm day-1 under conditions of non-limiting soil water availability and 0.37 +/- 0.17 mm day 1 when soil water availability was limited. This is because canopy conductance declined significantly with increasing evaporative demand and thus significantly reduced tree water loss. The growing season total of Ec was 74 mm and 88 mm in 2011 and 2012, respectively, which is significantly below the values estimated for other P. sylvestris forest ecosystems in Central Europe, and thus reflecting a strong adaptation to soil drought during periods of high evaporative. PMID- 27468180 TI - Impacts of chemical modification on the toxicity of diverse nanocellulose materials to developing zebrafish. AB - Cellulose is an abundant and renewable resource currently being investigated for utility in nanomaterial form for various promising applications ranging from medical and pharmaceutical uses to mechanical reinforcement and biofuels. The utility of nanocellulose and wide implementation ensures increasing exposure to humans and the environment as nanocellulose-based technologies advance. Here, we investigate how differences in aspect ratio and changes to surface chemistry, as well as synthesis methods, influence the biocompatibility of nanocellulose materials using the embryonic zebrafish. Investigations into the toxicity of neutral, cationic and anionic surface functionalities revealed that surface chemistry had a minimal influence on the overall toxicity of nanocellulose materials. Higher aspect ratio cellulose nanofibers produced by mechanical homogenization were, in some cases, more toxic than other cellulose-based nanofibers or nanocrystals produced by chemical synthesis methods. Using fluorescently labeled nanocellulose we were able to show that nanocellulose uptake did occur in embryonic zebrafish during development. We conclude that the benign nature of nanocellulose materials makes them an ideal platform to systematically investigate the inherent surface features driving nanomaterial toxicity in order to create safer design principles for engineered nanoparticles. PMID- 27468181 TI - Anorectal emergencies. AB - Anorectal emergencies refer to anorectal disorders presenting with some alarming symptoms such as acute anal pain and bleeding which might require an immediate management. This article deals with the diagnosis and management of common anorectal emergencies such as acutely thrombosed external hemorrhoid, thrombosed or strangulated internal hemorrhoid, bleeding hemorrhoid, bleeding anorectal varices, anal fissure, irreducible or strangulated rectal prolapse, anorectal abscess, perineal necrotizing fasciitis (Fournier gangrene), retained anorectal foreign bodies and obstructing rectal cancer. Sexually transmitted diseases as anorectal non-surgical emergencies and some anorectal emergencies in neonates are also discussed. The last part of this review dedicates to the management of early complications following common anorectal procedures that may present as an emergency including acute urinary retention, bleeding, fecal impaction and anorectal sepsis. Although many of anorectal disorders presenting in an emergency setting are not life-threatening and may be successfully treated in an outpatient clinic, an accurate diagnosis and proper management remains a challenging problem for clinicians. A detailed history taking and a careful physical examination, including digital rectal examination and anoscopy, is essential for correct diagnosis and plan of treatment. In some cases, some imaging examinations, such as endoanal ultrasonography and computerized tomography scan of whole abdomen, are required. If in doubt, the attending physicians should not hesitate to consult an expert e.g., colorectal surgeon about the diagnosis, proper management and appropriate follow-up. PMID- 27468183 TI - Function-preserving gastrectomy for gastric cancer in Japan. AB - Surgery used to be the only therapy for gastric cancer, and since its ability to cure gastric cancer was the focus of attention, less attention was paid to function-preserving surgery in gastric cancer, though it was studied for gastroduodenal ulcer. Maki et al developed pylorus-preserving gastrectomy for gastric ulcer in 1967. At the same time, the definition of early gastric cancer (EGC) was being considered, histopathological investigations of EGC were carried out, and the validity of modified surgery was sustained. After the development of H2-blockers, the number of operations for gastroduodenal ulcers decreased, and the number of EGC patients increased simultaneously. As a result, the indications for pylorus-preserving gastrectomy for EGC in the middle third of the stomach extended, and various alterations were added. Since then, many kinds of function preserving gastrectomies have been performed and studied in other fields of gastric cancer, and proximal gastrectomy, jejunal pouch interposition, segmental gastrectomy, and local resection have been performed. On the other hand, from the overall perspective, it can be said that endoscopic resection, which was launched at almost the same time, is the ultimate function-preserving surgery under the current circumstances. The current function-preserving gastrectomies that are often performed and studied are pylorus-preserving gastrectomy and proximal gastrectomy. The reasons for this are that these procedures that can be performed with systemic lymph node dissection, and they include three important elements: (1) reduction of the extent of gastrectomy; (2) preservation of the pylorus; and (3) preservation of the vagal nerve. In addition, these operations are more likely to be performed with a laparoscopic approach as minimally invasive surgery. Of the above-mentioned three elements, reduction of the extent of gastrectomy is the most important in our view. Therefore, we should try to reduce the extent of gastrectomy if curability of the gastric cancer can still be achieved. However, if we preserve a wider residual stomach in function-preserving gastrectomy, we should pay attention to the development of metachronous gastric cancer. PMID- 27468182 TI - HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice. AB - HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are: (1) the choice of sample with regards to cancer morphology - intestinal vs diffuse areas; (2) the choice of scoring criteria - use of HER2 scoring criteria specific for gastric cancer; and (3) the choice of HER2 evaluation methods - use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include: (1) pre-analytic variables with particular emphasis on fixation; (2) recommended methodology for HER2 assessment (immunohistochemistry vs in situ hybridization); (3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases; (4) reliability of biopsies in HER 2 evaluation; and (5) quantity of sample (FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment. PMID- 27468185 TI - Is endoscopic papillary balloon dilatation really a risk factor for post-ERCP pancreatitis? AB - Endoscopic papillary balloon dilatation (EPBD) is useful for decreasing early complications of endoscopic retrograde cholangio-pancreatography (ERCP), including bleeding, biliary infection, and perforation, but it is generally avoided in Western countries because of a relatively high reported incidence of post-ERCP pancreatitis (PEP). However, as the efficacy of endoscopic papillary large-balloon dilatation (EPLBD) becomes widely recognized, EPBD is attracting attention. Here we investigate whether EPBD is truly a risk factor for PEP, and seek safer and more effective EPBD procedures by reviewing past studies. We reviewed thirteen randomised control trials comparing EPBD and endoscopic sphincterotomy (EST) and ten studies comparing direct EPLBD and EST. Three randomized controlled trials of EPBD showed significantly higher incidence of PEP than EST, but no study of EPLBD did. Careful analysis of these studies suggested that longer and higher-pressure inflation of balloons might decrease PEP incidence. The paradoxical result that EPBD with small-calibre balloons increases PEP incidence while EPLBD does not may be due to insufficient papillary dilatation in the former. Insufficient dilatation could cause the high incidence of PEP through the use of mechanical lithotripsy and stress on the papilla at the time of stone removal. Sufficient dilation of the papilla may be useful in preventing PEP. PMID- 27468184 TI - Exploring the role of molecular biomarkers as a potential weapon against gastric cancer: A review of the literature. AB - Gastric cancer (GC) is a global health problem and a major cause of cancer related death with high recurrence rates ranging from 25% to 40% for GC patients staging II-IV. Unfortunately, while the majority of GC patients usually present with advanced tumor stage; there is still limited evidence-based therapeutic options. Current approach to GC management consists mainly of; endoscopy followed by, gastrectomy and chemotherapy or chemo-radiotherapy. Recent studies in GC have confirmed that it is a heterogeneous disease. Many molecular characterization studies have been performed in GC. Recent discoveries of the molecular pathways underlying the disease have opened the door to more personalized treatment and better predictable outcome. The identification of molecular markers is a useful tool for clinical managementin GC patients, assisting in diagnosis, evaluation of response to treatment and development of novel therapeutic modalities. While chemotherapeutic agents have certain physiological effects on the tumor cells, the prediction of the response is different from one type of tumor to the other. The specificity of molecular biomarkers is a principal feature driving their application in anticancer therapies. Here we are trying to focus on the role of molecular pathways of GC and well-established molecular markers that can guide the therapeutic management. PMID- 27468186 TI - Recent traction methods for endoscopic submucosal dissection. AB - Endoscopic mucosal resection (EMR) is problematic with regard to en bloc and curable resection rates. Advancements in endoscopic techniques have enabled novel endoscopic approaches such as endoscopic submucosal dissection (ESD), which has overcome some EMR problems, and has become the standard treatment for gastrointestinal tumors. However, ESD is technically difficult. Procedure time is longer and complications such as intraoperative perforation and bleeding occur more frequently than in EMR. Recently various traction methods have been introduced to facilitate ESD procedures, such as clip with line, external forceps, clip and snare, internal traction, double scope, and magnetic anchor. Each method must be used appropriately according to the anatomical characteristics. In this review we discuss recently proposed traction methods for ESD based on the characteristics of various anatomical sites. PMID- 27468187 TI - Bleeding after endoscopic submucosal dissection: Risk factors and preventive methods. AB - Endoscopic submucosal dissection (ESD) has become widely accepted as a standard method of treatment for superficial gastrointestinal neoplasms because it enables en block resection even for large lesions or fibrotic lesions with minimal invasiveness, and decreases the local recurrence rate. Moreover, specimens resected in an en block fashion enable accurate histological assessment. Taking these factors into consideration, ESD seems to be more advantageous than conventional endoscopic mucosal resection (EMR), but the associated risks of perioperative adverse events are higher than in EMR. Bleeding after ESD is the most frequent among these adverse events. Although post-ESD bleeding can be controlled by endoscopic hemostasis in most cases, it may lead to serious conditions including hemorrhagic shock. Even with preventive methods including administration of acid secretion inhibitors and preventive hemostasis, post-ESD bleeding cannot be completely prevented. In addition high-risk cases for post-ESD bleeding, which include cases with the use of antithrombotic agents or which require large resection, are increasing. Although there have been many reports about associated risk factors and methods of preventing post-ESD bleeding, many issues remain unsolved. Therefore, in this review, we have overviewed risk factors and methods of preventing post-ESD bleeding from previous studies. Endoscopists should have sufficient knowledge of these risk factors and preventive methods when performing ESD. PMID- 27468189 TI - Selective intestinal decontamination for the prevention of early bacterial infections after liver transplantation. AB - Bacterial infection in the first month after liver transplantation is a frequent complication that poses a serious risk for liver transplant recipients as contributes substantially to increased length of hospitalization and hospital costs being a leading cause of death in this period. Most of these infections are caused by gram-negative bacilli, although gram-positive infections, especially Enterococcus sp. constitute an emerging infectious problem. This high rate of early postoperative infections after liver transplant has generated interest in exploring various prophylactic approaches to surmount this problem. One of these approaches is selective intestinal decontamination (SID). SID is a prophylactic strategy that consists of the administration of antimicrobials with limited anaerobicidal activity in order to reduce the burden of aerobic gram-negative bacteria and/or yeast in the intestinal tract and so prevent infections caused by these organisms. The majority of studies carried out to date have found SID to be effective in the reduction of gram-negative infection, but the effect on overall infection is limited due to a higher number of infection episodes by pathogenic enterococci and coagulase-negative staphylococci. However, difficulties in general extrapolation of the favorable results obtained in specific studies together with the potential risk of selection of multirresistant microorganisms has conditioned controversy about the routinely application of these strategies in liver transplant recipients. PMID- 27468188 TI - Predictive factors of short term outcome after liver transplantation: A review. AB - Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1(th) and the 5(th) day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function. PMID- 27468190 TI - Role of inflammation and infection in the pathogenesis of human acute liver failure: Clinical implications for monitoring and therapy. AB - Acute liver failure is a rare and devastating clinical condition. At present, emergency liver transplantation is the only life-saving therapy in advanced cases, yet the feasibility of transplantation is affected by the presence of systemic inflammation, infection and resultant multi-organ failure. The importance of immune dysregulation and acquisition of infection in the pathogenesis of acute liver failure and its associated complications is now recognised. In this review we discuss current thinking regarding the role of infection and inflammation in the pathogenesis of and outcome in human acute liver failure, the implications for the management of such patients and suggest directions for future research. PMID- 27468192 TI - Pulmonary complications of hepatic diseases. AB - Severe chronic liver disease (CLD) may result from portal hypertension, hepatocellular failure or the combination of both. Some of these patients may develop pulmonary complications independent from any pulmonary pathology that they may have. Among them the hepatopulmonary syndrome (HPS), portopulmonary hypertension (PPH) and hepatic hydrothorax (HH) are described in detail in this literature review. HPS is encountered in approximately 15% to 30% of the patients and its presence is associated with increase in mortality and also requires liver transplantation in many cases. PPH has been reported among 4%-8% of the patient with CLD who have undergone liver transplantation. The HH is another entity, which has the prevalence rate of 5% to 6% and is associated in the absence of cardiopulmonary disease. These clinical syndromes occur in similar pathophysiologic environments. Most treatment modalities work as temporizing measures. The ultimate treatment of choice is liver transplant. This clinical review provides basic concepts; pathophysiology and clinical presentation that will allow the clinician to better understand these potentially life-threatening complications. This article will review up-to-date information on the pathophysiology, clinical features and the treatment of the pulmonary complications among liver disease patients. PMID- 27468193 TI - Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells. AB - AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis. METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 MUmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays. RESULTS: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-kappaB). Incubation of steatotic cells with silybin 50 MUmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT 1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-kappaB activation. CONCLUSION: We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies. PMID- 27468194 TI - Increased duodenal expression of miR-146a and -155 in pediatric Crohn's disease. AB - AIM: To evaluate the role of microRNA (miR)-146a, -155 and -122 in the duodenal mucosa of pediatric patients with Crohn's disease (CD) and the effect of transforming growth factor-beta (TGF-beta) on these miRs in duodenal epithelial and fibroblast cells. METHODS: Formalin-fixed, paraffin-embedded biopsies derived from the macroscopically inflamed (CD inflamed: n = 10) and intact (CD intact: n = 10) duodenal mucosa of pediatric CD patients and control children (C: n = 10) were examined. Expression of miR-146a, -155 and -122 was determined by real-time polymerase-chain reaction (PCR). The expression of the above miRs was investigated in recombinant human TGF-beta (1 nmol/L, 24 h) or vehicle treated small intestinal epithelial cells (CCL-241) and primary duodenal fibroblast cells derived from healthy children as well. RESULTS: Expression of miR-146a was significantly higher in the inflamed duodenal mucosa compared to the intact duodenal mucosa of children with CD (CD inflamed: 3.21 +/- 0.50 vs CD intact: 0.62 +/- 0.26, P <= 0.01) and to the control group (CD inflamed: 3.21 +/- 0.50 vs C: 1.00 +/- 0.33, P <= 0.05). The expression of miR-155 was significantly increased in the inflamed region of the duodenum compared to the control group (CD inflamed: 4.87 +/- 1.02 vs CONTROL: 1.00 +/- 0.40, P <= 0.001). The expression of miR-122 was unchanged in the inflamed or intact mucosa of CD patients compared to controls. TGF-beta treatment significantly decreased the expression of miR-155 in small intestinal epithelial cells (TGF-beta: 0.7 +/- 0.083 vs CONTROL: 1 +/- 0.09, P <= 0.05) and also the expression of miR-146a (TGF beta: 0.67 +/- 0.04 vs CONTROL: 1 +/- 0.15, P <= 0.01) and miR-155 (TGF-beta: 0.72 +/- 0.09 vs CONTROL: 1 +/- 0.06, P <= 0.05) in primary duodenal fibroblasts compared to corresponding vehicle treated controls. TGF-beta treatment did not influence the expression of miR-122. CONCLUSION: The elevated expression of miR 146a and -155 in the inflamed duodenal mucosa of CD patients suggests the role of these miRs in the pathomechanism of inflammatory bowel disease. Anti-inflammatory TGF-beta plays an important role in the regulation of the expression of these miRs. PMID- 27468195 TI - Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats. AB - AIM: To evaluate the efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation in the treatment of liver fibrosis. METHODS: Cultured human UC-MSCs were isolated and transfused into rats with liver fibrosis induced by dimethylnitrosamine (DMN). The effects of UC-MSCs transfusion on liver fibrosis were then evaluated by histopathology; serum interleukin (IL)-4 and IL 10 levels were also measured. Furthermore, Kupffer cells (KCs) in fibrotic livers were isolated and cultured to analyze their phenotype. Moreover, UC-MSCs were co cultured with KCs in vitro to assess the effects of UC-MSCs on KCs' phenotype, and IL-4 and IL-10 levels were measured in cell culture supernatants. Finally, UC MSCs and KCs were cultured in the presence of IL-4 antibodies to block the effects of this cytokine, followed by phenotypical analysis of KCs. RESULTS: UC MSCs transfused into rats were recruited by the injured liver and alleviated liver fibrosis, increasing serum IL-4 and IL-10 levels. Interestingly, UC-MSCs promoted mobilization of KCs not only in fibrotic livers, but also in vitro. Co culture of UC-MSCs with KCs resulted in increased production of IL-4 and IL-10. The addition of IL-4 antibodies into the co-culture system resulted in decreased KC mobilization. CONCLUSION: UC-MSCs could increase IL-4 and promote mobilization of KCs both in vitro and in vivo, subsequently alleviating the liver fibrosis induced by DMN. PMID- 27468196 TI - Development and validation of a risk score for advanced colorectal adenoma recurrence after endoscopic resection. AB - AIM: To develop and validate a risk score for advanced colorectal adenoma (ACA) recurrence after endoscopic polypectomy. METHODS: Out of 3360 patients who underwent colon polypectomy at University of Foggia between 2004 and 2008, data of 843 patients with 1155 ACAs was retrospectively reviewed. Surveillance intervals were scheduled by guidelines at 3 years and primary endpoint was considered 3-year ACA recurrence. Baseline clinical parameters and the main features of ACAs were entered into a Cox regression analysis and variables with P < 0.05 in the univariate analysis were then tested as candidate variables into a stepwise Cox regression model (conditional backward selection). The regression coefficients of the Cox regression model were multiplied by 2 and rounded in order to obtain easy to use point numbers facilitating the calculation of the score. To avoid overoptimistic results due to model fitting and evaluation in the same dataset, we performed an internal 10-fold cross-validation by means of bootstrap sampling. RESULTS: Median lesion size was 16 mm (12-23) while median number of adenomas was 2.5 (1-3), whereof the number of ACAs was 1.5 (1-2). At 3 years after polypectomy, recurrence was observed in 229 ACAs (19.8%), of which 157 (13.5%) were metachronous neoplasms and 72 (6.2%) local recurrences. Multivariate analysis, after exclusion of the variable "type of resection" due to its collinearity with other predictive factors, confirmed lesion size, number of ACAs and grade of dysplasia as significantly associated to the primary outcome. The score was then built by multiplying the regression coefficients times 2 and the cut-off point 5 was selected by means of a Receiver Operating Characteristic curve analysis. In particular, 248 patients with 365 ACAs fell in the higher-risk group (score >= 5) where 3-year recurrence was detected in 174 ACAs (47.6%) whereas the remaining 595 patients with 690 ACAs were included in the low-risk group (score < 5) where 3-year recurrence rate was 7.9% (55/690 ACAs). Area under the curve of the model was 0.81 (0.72-0.86) with an overall classification error rate of 0.09. The model was finally validated by means of 10-fold cross validation. CONCLUSION: Our study provides support for the use of a novel risk score as a clinical predictor of ACA recurrence after colon polypectomy. PMID- 27468198 TI - Impact of biliary stent-related events in patients diagnosed with advanced pancreatobiliary tumours receiving palliative chemotherapy. AB - AIM: To determine the impact (morbidity/mortality) of biliary stent-related events (SRE) (cholangitis or stent obstruction) in chemotherapy-treated pancreatico-biliary patients. METHODS: All consecutive patients with advanced pancreatobiliary cancer and a biliary stent in-situ prior to starting palliative chemotherapy were identified retrospectively from local electronic case-note records (Jan 13 to Jan 15). The primary end-point was SRE rate and the time-to SRE (defined as time from first stenting before chemotherapy to date of SRE). Progression-free survival and overall survival were measured from the time of starting chemotherapy. Kaplan-Meier, Cox and Fine-Gray regression (univariate and multivariable) analyses were employed, as appropriate. For the analysis of time to-SRE, death was considered as a competing event. RESULTS: Ninety-six out of 693 screened patients were eligible; 89% had a metal stent (the remainder were plastic). The median time of follow-up was 9.6 mo (range 2.2 to 26.4). Forty-one patients (43%) developed a SRE during follow-up [cholangitis (39%), stent obstruction (29%), both (32%)]. There were no significant differences in baseline characteristics between the SRE group and no-SRE groups. Recorded SRE consequences were: none (37%), chemotherapy delay (24%), discontinuation (17%) and death (22%). The median time-to-SRE was 4.4 mo (95%CI: 3.6-5.5). Patients with severe comorbidities (P < 0.001) and patients with >= 2 baseline stents/biliary procedures [HR = 2.3 (95%CI: 1.2-4.44), P = 0.010] had a shorter time-to-SRE on multivariable analysis. Stage was an independent prognostic factor for overall survival (P = 0.029) in the multivariable analysis adjusted for primary tumour site, performance status and development of SRE (SRE group vs no SRE group). CONCLUSION: SREs are common and impact on patient's morbidity. Our results highlight the need for prospective studies exploring the role of prophylactic strategies to prevent/delay SREs. PMID- 27468199 TI - Preoperative defining system for pancreatic head cancer considering surgical resection. AB - AIM: To provide appropriate treatment, it is crucial to share the clinical status of pancreas head cancer among multidisciplinary treatment members. METHODS: A retrospective analysis of the medical records of 113 patients who underwent surgery for pancreas head cancer from January 2008 to December 2012 was performed. We developed preoperative defining system of pancreatic head cancer by describing "resectability - tumor location - vascular relationship - adjacent organ involvement - preoperative CA19-9 (initial bilirubin level) - vascular anomaly". The oncologic correlations with this reporting system were evaluated. RESULTS: Among 113 patients, there were 75 patients (66.4%) with resectable, 34 patients (30.1%) with borderline resectable, and 4 patients (3.5%) with locally advanced pancreatic cancer. Mean disease-free survival was 24.8 mo (95%CI: 19.6 30.1) with a 5-year disease-free survival rate of 13.5%. Pretreatment tumor size >= 2.4 cm [Exp(B) = 3.608, 95%CI: 1.512-8.609, P = 0.044] and radiologic vascular invasion [Exp(B) = 5.553, 95%CI: 2.269-14.589, P = 0.002] were independent predictive factors for neoadjuvant treatment. Borderline resectability [Exp(B) = 0.222, P = 0.008], pancreatic head cancer involving the pancreatic neck [Exp(B) = 9.461, P = 0.001] and arterial invasion [Exp(B) = 6.208, P = 0.010], and adjusted CA19-9 >= 50 [Exp(B) = 1.972 P = 0.019] were identified as prognostic clinical factors to predict tumor recurrence. CONCLUSION: The suggested preoperative defining system can help with designing treatment plans and also predict oncologic outcomes. PMID- 27468197 TI - Visualizing the hepatic vascular architecture using superb microvascular imaging in patients with hepatitis C virus: A novel technique. AB - AIM: To identify the hepatic vascular architecture of patients with hepatitis C virus (HCV) using superb microvascular imaging (SMI) and investigate the use of SMI in the evaluation of liver fibrosis. METHODS: SMI was performed in 100 HCV patients. SMI images were classified into five types according to the vascular pattern, and these patterns were compared with the fibrosis stage. Moreover, the images were analyzed to examine vascularity by integrating the number of SMI signals in the region of interest ROI [number of vascular trees (VT)]. The number of VT, fibrosis stage, serum parameters of liver function, and CD34 expression were investigated. RESULTS: There was a significant difference between SMI distribution pattern and fibrosis stage (P < 0.001). The mean VT values in each of the fibrosis stages were as follows: 26.69 +/- 7.08 in F0, 27.72 +/- 9.32 in F1, 36.74 +/- 9.23 in F2, 37.36 +/- 5.32 in F3, and 58.14 +/- 14.08 in F4. The VT showed excellent diagnostic ability for F4 [area under the receiver operator characteristic (AUROC): 0.911]. The VT was significantly correlated with the CD34 labeling index (r = 0.617, P < 0.0001). CONCLUSION: SMI permitted the detailed delineation of the vascular architecture in chronic liver disease. SMI appears to be a reliable tool for noninvasively detecting significant fibrosis or cirrhosis in HCV patients. PMID- 27468200 TI - High circulating tumor cell concentrations in a specific subtype of gastric cancer with diffuse bone metastasis at diagnosis. AB - AIM: To clarify the biological feature contributing to gastric cancer with diffuse bone metastases at diagnosis. METHODS: The participants visited the Department of Clinical Oncology, Akita University Hospital, from January 2014 to August 2015. The selection criterion for gastric cancer with diffuse bone metastases at diagnosis includes over 29 hot spots of bone scintigraphy. Circulating tumor cell were collected from 20 mL of peripheral venous blood drawn using a CellSearch kit and a CellTracks AutoPrep system by SRL, a clinical laboratory. The endpoints of this study were correlations between circulating tumor cells (CTC) count and therapeutic outcomes. RESULTS: Among 39 patients with gastric cancer, 5 patients met the criterion. The incidence of this subtype was 12.8%. CTC counts ranged from 235 to 6440 cells/7.5 mL of peripheral blood (median of 1724). These values were much higher than common gastric cancers (2 cells). In chemo-sensitive cases, CTC counts decreased within 14 d (median) from 275, 235 and 1724 to 2, 7 and 66, respectively. On the other hand, CTC counts increased after treatment failure or insensitive case from 2, 7 and 6440 to 787, 513 and 7885, respectively. The correlation between CTC count and survival time showed a trend, but did not reach significance (Y = 234.6 - 0.03X, P = 0.085). CONCLUSION: High CTC count is a biological hallmark of this subtype, and can be used as a direct and definitive indicator of therapeutic outcome. PMID- 27468191 TI - Pancreatic cancer stem cell markers and exosomes - the incentive push. AB - Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC TEX. PMID- 27468201 TI - Henoch-Schonlein purpura from vasculitis to intestinal perforation: A case report and literature review. AB - Henoch-Schonlein purpura (HSP) is generally a self-limited vasculitis disease and has a good prognosis. We report a 4-year-old Thai boy who presented with palpable purpura, abdominal colicky pain, seizure, and eventually developed intestinal ischemia and perforation despite adequate treatment, including corticosteroid and intravenous immunoglobulin therapy. Imaging modalities, including ultrasonography and contrast-enhanced computed tomography, could not detect intestinal ischemia prior to perforation. In this patient, we also postulated that vasculitis-induced mucosal ischemia was a cause of the ulcer, leading to intestinal perforation, and high-dose corticosteroid could have been a contributing factor since the histopathology revealed depletion of lymphoid follicles. Intestinal perforation in HSP is rare, but life-threatening. Close monitoring and thorough clinical evaluation are essential to detect bowel ischemia before perforation, particularly in HSP patients who have hematochezia, persistent localized abdominal tenderness and guarding. In highly suspicious cases, exploratory laparotomy may be needed for the definite diagnosis and prevention of further complications. PMID- 27468202 TI - Hepatitis C virus genotypes in Myanmar. AB - Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis C virus (HCV) infection is 2%, and HCV infection accounts for 25% of hepatocellular carcinoma. In this study, we reviewed the prevalence of HCV genotypes in Myanmar. HCV genotypes 1, 3 and 6 were observed in volunteer blood donors in and around the Myanmar city of Yangon. Although there are several reports of HCV genotype 6 and its variants in Myanmar, the distribution of the HCV genotypes has not been well documented in areas other than Yangon. Previous studies showed that treatment with peginterferon and a weight-based dose of ribavirin for 24 or 48 wk could lead to an 80%-100% sustained virological response (SVR) rates in Myanmar. Current interferon-free treatments could lead to higher SVR rates (90%-95%) in patients infected with almost all HCV genotypes other than HCV genotype 3. In an era of heavy reliance on direct-acting antivirals against HCV, there is an increasing need to measure HCV genotypes, and this need will also increase specifically in Myanmar. Current available information of HCV genotypes were mostly from Yangon and other countries than Myanmar. The prevalence of HCV genotypes in Myanmar should be determined. PMID- 27468204 TI - Hepatocellular carcinoma: Will novel targeted drugs really impact the next future? AB - Cancer treatment has been revolutionized by the advent of new molecular targeted and immunotherapeutic agents. Identification of the role of tumor angiogenesis changed the understanding of many tumors. After the unsuccessful results with chemotherapy, sorafenib, by interfering with angiogenic pathways, has become pivotal in the treatment of hepatocellular carcinoma. Sorafenib is the only systemic treatment to show a modest but statistically significant survival benefit. All novel drugs and strategies for treatment of advanced hepatocellular carcinoma must be compared with the results obtained with sorafenib, but no new drug or drug combination has yet achieved better results. In our opinion, the efforts to impact the natural history of the disease will be directed not only to drug development but also to understanding the underlying liver disease (usually hepatitis B virus- or hepatitis C virus-related) and to interrupting the progression of cirrhosis. It will be important to define the role and amount of mutations in the complex pathogenesis of hepatocellular carcinoma and to better integrate locoregional and systemic therapies. It will be important also to optimize the therapeutic strategies with existing chemotherapeutic drugs and new targeted agents. PMID- 27468203 TI - Diabetes mellitus and metformin in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments. PMID- 27468205 TI - Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene's expression driven by tumor specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment. PMID- 27468206 TI - Role of NK, NKT cells and macrophages in liver transplantation. AB - Liver transplantation has become the treatment of choice for acute or chronic liver disease. Because the liver acts as an innate immunity-dominant organ, there are immunological differences between the liver and other organs. The specific features of hepatic natural killer (NK), NKT and Kupffer cells and their role in the mechanism of liver transplant rejection, tolerance and hepatic ischemia reperfusion injury are discussed in this review. PMID- 27468207 TI - Doppler ultrasonography in living donor liver transplantation recipients: Intra- and post-operative vascular complications. AB - Living-donor liver transplantation has provided a solution to the severe lack of cadaver grafts for the replacement of liver afflicted with end-stage cirrhosis, fulminant disease, or inborn errors of metabolism. Vascular complications remain the most serious complications and a common cause for graft failure after hepatic transplantation. Doppler ultrasound remains the primary radiological imaging modality for the diagnosis of such complications. This article presents a brief review of intra- and post-operative living donor liver transplantation anatomy and a synopsis of the role of ultrasonography and color Doppler in evaluating the graft vascular haemodynamics both during surgery and post-operatively in accurately defining the early vascular complications. Intra-operative ultrasonography of the liver graft provides the surgeon with useful real-time diagnostic and staging information that may result in an alteration in the planned surgical approach and corrections of surgical complications during the procedure of vascular anastomoses. The relevant intra-operative anatomy and the spectrum of normal and abnormal findings are described. Ultrasonography and color Doppler also provides the clinicians and surgeons early post-operative potential developmental complications that may occur during hospital stay. Early detection and thus early problem solving can make the difference between graft survival and failure. PMID- 27468208 TI - Advances in endoscopic management of biliary complications after living donor liver transplantation: Comprehensive review of the literature. AB - Apart from noticeable improvements in surgical techniques and immunosuppressive agents, biliary complications remain the major causes of morbidity and mortality after living donor liver transplantation (LDLT). Bile leakage and stricture are the predominant complications. The reported incidence of biliary complications is 15%-40%, and these are known to occur more frequently in living donors than in deceased donors. Despite the absence of a confirmed therapeutic algorithm, many approaches have been used for treatment, including surgical, endoscopic, and percutaneous transhepatic techniques. In recent years, nonsurgical approaches have largely replaced reoperation. Among these, the endoscopic approach is currently the preferred initial treatment for patients who undergo duct-to-duct biliary reconstruction. Previously, endoscopic management was achieved most optimally through balloon dilatation and single or multiple stents placement. Recently, there have been significant developments in endoscopic devices, such as novel biliary stents, as well as advances in endoscopic technologies, including deep enteroscopy, the rendezvous technique, magnetic compression anastomosis, and direct cholangioscopy. These developments have resulted in almost all patients being managed by the endoscopic approach. Multiple recent publications suggest superior long-term results, with overall success rates ranging from 58% to 75%. This article summarizes the advances in endoscopic management of patients with biliary complications after LDLT. PMID- 27468209 TI - Aberrant post-translational protein modifications in the pathogenesis of alcohol induced liver injury. AB - It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain. PMID- 27468210 TI - Pleiotropic effects of statins in the diseases of the liver. AB - Statins are a class of molecules that inhibit HMG CoA reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma (HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies. PMID- 27468211 TI - Hepatitis C virus - associated B cell non-Hodgkin's lymphoma. AB - The hepatitis C virus (HCV) infected patients are prone to develop bone marrow or various tissue infiltrates with monoclonal B cells, monoclonal B lymphocytosis or different types of B cell non-Hodgkin's lymphoma (BCNHL), of which the most common are splenic marginal zone BCNHL, diffuse large BCNHL and follicular lymphoma. The association between chronic HCV infection and non Hodgkin's lymphoma has been observed especially in areas with high prevalence of this viral infection. Outside the limitations of some studies that have been conducted, there are also geographic, environmental, and genetic factors that contribute to the epidemiological differences. Various microenvironmental signals, such as cytokines, viral antigenic external stimulation of lymphocyte receptors by HCV antigens, and intercellular interactions contribute to B cell proliferation. HCV lymphotropism and chronic antigenic stimulation are involved in B-lymphocyte expansion, as mixted cryoglobulinemia or monoclonal gammopathy of undetermined significance, which can progress to BCNHL. HCV replication in B lymphocytes has oncogenic effect mediated by intracellular HCV proteins. It is also involved in an important induction of reactive oxygen species that can lead to permanent B lymphocyte damage, as DNA mutations, after binding to surface B-cell receptors. Post-transplant lymphoproliferative disorder could appear and it has a multiclonal potentiality that may develop into different types of lymphomas. The hematopoietic stem cell transplant made for lymphoma in HCV-infected patients can increase the risk of earlier progression to liver fibrosis and cirrhosis. HCV infected patients with indolent BCNHL who receive antiviral therapy can be potentially cured. Viral clearance was related to lymphoma response, fact that highlights the probable involvement of HCV in lymphomagenesis. Direct acting antiviral drugs could be a solution for the patients who did not tolerate or respond to interferon, as they seem to be safe and highly effective. The use of chemotherapy in combination with rituximab for the treatment of BCNHL in patients infected with HCV can produce liver dysfunction. The addition of immunotherapy with rituximab can increase the viral replication, and severe complications can occure especially in patients co-infected with hepatitis B virus or immune immunodeficiency virus, in those with hepatocarcinoma, cirrhosis, or liver cytolysis. But the final result of standard immunochemotherapy applied to diffuse large BCNHL patients with HCV infection is not notably worse than in those without this viral infection. The treatment of patients chronically infected with HCV and having BCNHL is complex and requires a multidisciplinary approach and the risk / benefit ratio of rituximab treatment must be evaluated especially in those with liver cytolysis. PMID- 27468213 TI - Glucose deprivation induces chemoresistance in colorectal cancer cells by increasing ATF4 expression. AB - AIM: To investigate the role of activating transcription factor 4 (ATF4) in glucose deprivation (GD) induced colorectal cancer (CRC) drug resistance and the mechanism involved. METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RT-PCR and Western blot were used to detect the mRNA and protein expression of drug resistance gene 1 (MDR1), respectively. RESULTS: GD protected CRC cells from drug induced apoptosis (oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug re-sensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells. CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression. PMID- 27468212 TI - Serum metabolome profiles characterized by patients with hepatocellular carcinoma associated with hepatitis B and C. AB - AIM: To clarify the characteristics of metabolite profiles in virus-related hepatocellular carcinoma (HCC) patients using serum metabolome analysis. METHODS: The serum levels of low-molecular-weight metabolites in 68 patients with HCC were quantified using capillary electrophoresis chromatography and mass spectrometry. Thirty and 38 of the patients suffered from hepatitis B virus-related HCC (HCC-B) and hepatitis C virus-related HCC (HCC-C), respectively. RESULTS: The main metabolites characteristic of HCC were those associated with glutathione metabolism, notably 13 gamma-glutamyl peptides, which are by-products of glutathione induction. Two major profiles, i.e., concentration patterns, of metabolites were identified in HCC patients, and these were classified into two groups: an HCC-B group and an HCC-C group including some of the HCC-B cases. The receiver operating characteristic curve for the multiple logistic regression model discriminating HCC-B from HCC-C incorporating the concentrations of glutamic acid, methionine and gamma-glutamyl-glycine-glycine showed a highly significant area under the curve value of 0.94 (95%CI: 0.89-1.0, P < 0.0001). CONCLUSION: The serum levels of gamma-glutamyl peptides, as well as their concentration patterns, contribute to the development of potential biomarkers for virus-related HCC. The difference in metabolite profiles between HCC-B and HCC-C may reflect the respective metabolic reactions that underlie the different pathogeneses of these two types of HCC. PMID- 27468214 TI - Immunohistochemistry panel segregates molecular types of hepatocellular carcinoma in Brazilian autopsy cases. AB - AIM: To assess the distribution of proteins coded by genes reported as relevant for the molecular classification of hepatocellular carcinoma (HCC). METHODS: In this retrospective cross-sectional study, the following clinicopathological data were analyzed in 80 autopsied HCC patients: sex, age, ethnicity, alcohol intake, infection with hepatitis B and/or C virus, infection with human immunodeficiency virus, prior treatment, basic and immediate causes of death, liver weight, presence of cirrhosis, number and size of nodules, gross pattern, histological grade and variants, architectural pattern, invasion of large veins, and presence and location of extrahepatic metastases. The protein products of genes known to be involved in molecular pathogenesis of HCC, including epidermal growth factor receptor (EGFR), MET, keratin 19 (K19), vimentin, beta-catenin, mechanistic target of rapamycin (mTOR), extracellular signaling-related kinase (ERK)1, ERK2, Ki67, cyclin D1, caspase 3 and p53, were detected by immunohistochemistry on tissue microarrays. The expression levels were scored and statistically assessed for correlation with HCC parameters. RESULTS: Infection with hepatitis C virus was identified in 49% of the 80 autopsy patients, cirrhosis in 90%, advanced tumors in 95%, and extrahepatic metastases in 38%. Expression of K19, p53 and ERK1 correlated to high-grade lesions. Expression of ERK1, nuclear beta-catenin, cyclin D1 and ERK2 correlated to higher rates of cell proliferation as determined by Ki67. Expression of MET, EGFR (> 0) and caspase 3 correlated with lower histological grades. Expression of EGFR correlated to that of caspase 3, and overexpression of EGFR (>= 200/300) was observed in low-grade tumors more frequently (grades 1 and 2: 67% vs grade 3: 27% and grade 4: 30%). Expression of ERK1 was associated with that of K19 and vimentin, whereas expression of ERK2 was associated with that of cyclin D1, MET and membrane beta-catenin. Expression of vimentin was strongly correlated with that of K19. CONCLUSION: Expression of K19, p53, ERK1, ERK2, vimentin and nuclear beta-catenin was related to higher-grade markers, as opposed to expression/overexpression of EGFR, MET and caspase 3. PMID- 27468215 TI - Effect of dietary vitamin C on gastric cancer risk in the Korean population. AB - AIM: To investigate the effects of dietary vitamin C and foods containing vitamin C on gastric cancer risk. METHODS: Our study included 830 control subjects and 415 patients. Data regarding demographics, medical history, and lifestyle, including dietary and nutrient intake, were collected using reliable self administered questionnaires. Dietary intake information was collected from the participants using a food frequency questionnaire that has been previously reported as reliable and valid. A rapid urease test and a histological evaluation were used to determine the presence of Helicobacter pylori (H. pylori) infection. Twenty-three vitamin C-contributing foods were selected, representing over 80% of the cumulative vitamin C contribution. RESULTS: In analyses adjusted for first degree family history of gastric cancer, education level, job, household income, smoking status, and regular exercise, an inverse association between vitamin C intake and gastric cancer risk was observed for the highest (>= 120.67 mg/d) vs the lowest (< 80.14 mg/d) intake category [OR (95%CI): 0.64 (0.46-0.88)], with a significant trend across the three intake categories (P = 0.007). No protective effect of vitamin C was detected after stratification by gender. No effect of vitamin C intake on the gastric cancer incidence was found in either men or women infected with H. pylori. Vitamin C-contributing foods, including cabbage [0.45 (0.32-0.63), 0.50 (0.34-0.75), 0.45 (0.25-0.81)], strawberries [0.56 (0.40-0.78), 0.49 (0.32-0.74), 0.52 (0.29-0.93)], and bananas [0.40 (0.29-0.57), 0.41 (0.27 0.62), 0.34 (0.19-0.63)], were protective factors against the risk of gastric cancer based on the results of the overall adjusted analyses and the results for men and women, respectively. CONCLUSION: A protective effect of vitamin C and vitamin C-contributing foods against gastric cancer was observed. Further studies using larger sample sizes are required to replicate our results. PMID- 27468216 TI - Feasibility and safety of endoscopic submucosal dissection for lower rectal tumors with hemorrhoids. AB - AIM: To evaluate the feasibility and safety of endoscopic submucosal dissection (ESD) for lower rectal lesions with hemorrhoids. METHODS: The outcome of ESD for 23 lesions with hemorrhoids (hemorrhoid group) was compared with that of 48 lesions without hemorrhoids extending to the dentate line (non-hemorrhoid group) during the same study period. RESULTS: Median operation times (ranges) in the hemorrhoid and non-hemorrhoid groups were 121 (51-390) and 130 (28-540) min. The en bloc resection rate and the curative resection rate in the hemorrhoid group were 96% and 83%, and they were 100% and 90% in the non-hemorrhoid group, respectively. In terms of adverse events, perforation and postoperative bleeding did not occur in both groups. In terms of the clinical course of hemorrhoids after ESD, the rate of complete recovery of hemorrhoids after ESD in lesions with resection of more than 90% was significantly higher than that in lesions with resection of less than 90%. CONCLUSION: ESD on lower rectal lesions with hemorrhoids could be performed safely, similarly to that on rectal lesions extending to the dentate line without hemorrhoids. In addition, all hemorrhoids after ESD improved to various degrees, depending on the resection range. PMID- 27468217 TI - Favorable lifestyle before diagnosis associated with lower risk of screen detected advanced colorectal neoplasia. AB - AIM: To investigate the association between adherence to health recommendations and detection of advanced colorectal neoplasia (ACN) in colorectal cancer (CRC) screening. METHODS: A total of 14832 women and men were invited to CRC screening, 6959 in the fecal immunochemical test arm and 7873 in the flexible sigmoidoscopy arm. These were also sent a self-reported lifestyle questionnaire to be completed prior to their first CRC screening. A lifestyle score was created to reflect current adherence to healthy behaviors in regard to smoking, body mass index, physical activity, alcohol consumption and food consumption, and ranged from zero (poorest) to six (best). Odds ratios (ORs) and 95%CIs were calculated using multivariable logistic regression to evaluate the association between the single lifestyle variables and the lifestyle score and the probability of detecting ACN. RESULTS: In all 6315 women and men completed the lifestyle questionnaire, 3323 (53%) in the FIT arm and 2992 (47%) in the FS arm. This was 89% of those who participated in screening. ACN was diagnosed in 311 (5%) participants of which 25 (8%) were diagnosed with CRC. For individuals with a lifestyle score of two, three, four, and five-six, the ORs (95%CI) for the probability of ACN detection were 0.82 (0.45-1.16), 0.43 (0.28-0.73), 0.41 (0.23-0.64), and 0.41 (0.22-0.73), respectively compared to individuals with a lifestyle score of zero-one. Of the single lifestyle factors, adherence to non-smoking and moderate alcohol intake were associated with a decreased probability of ACN detection compared to being a smoker or having a high alcohol intake 0.53 (0.42-0.68) and 0.63 (0.43-0.93) respectively. CONCLUSION: Adopted healthy behaviors were inversely associated with the probability of ACN detection. Lifestyle assessment might be useful for risk stratification in CRC screening. PMID- 27468218 TI - Total and not bevacizumab-bound vascular endothelial growth factor as potential predictive factors to bevacizumab-based chemotherapy in colorectal cancer. AB - AIM: To identify suitable biomarkers of response to bevacizumab (BV) - it remains an open question. The measurement of serum vascular endothelial growth factor (VEGF) has been proposed as a predictive factor for this drug, even if literature data are contradictory. METHODS: We prospectively evaluated the role of BV, total and not BV-bound VEGF and angiopoietin-2 (Ang-2) serum levels as potential predictive factors of response for BV in combination with an oxaliplatin-based chemotherapy. BV, Ang-2, total and not BV-bound VEGF levels were measured at baseline, before 2(nd) and 5(th) cycle of oxaliplatin-based chemotherapy in 20 consecutive metastatic colorectal cancer patients. RESULTS: Results were correlated to response to treatment. Variability in BV levels have been found, with decreased level in less responding patients. In particular, the concentration of BV increased of 3.96 +/- 0.69 folds in serum of responsive patients after 3 more cycles of therapy compared to those with stable or progressive disease with a 0.72 +/- 0.25 and 2.10 +/- 0.13 fold increase, respectively. The determination of free and total VEGF demonstrated that the ratio between the two values, evaluated immediately before the 2(nd) and the 5(th) cycle of therapy, decreased from 26.65% +/- 1.33% to 15.50% +/- 3.47% in responsive patients and from 53.41% +/- 4.75 to 34.95% +/- 2.88% in those with stable disease. Conversely, in those with progression of disease, the ratio showed the opposite behavior coming up from 25.99% +/- 5.23% to 51.71% +/- 5.28%. The Ang-2 levels did not show any relationship. CONCLUSION: Our data show that the ratio of not BV-bound VEGF to total VEGF serum and BV plasma concentrations for predicting the response to BV plus oxaliplatin-based chemotherapy could be a promising biomarker of response to BV. PMID- 27468220 TI - Effectiveness of exercise in hepatic fat mobilization in non-alcoholic fatty liver disease: Systematic review. AB - AIM: To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease (NAFLD) patients. METHODS: Ovid Medline, PubMed, EMBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged >= 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: "NASH", "NAFLD", "non-alcoholic steatohepatitis", "non-alcoholic fatty liver disease", "fat", "steatosis", "diet", "exercise", "MR spectroscopy" and "liver biopsy". NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy (H-MRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. RESULTS: Eight studies met selection criteria (6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-MRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared the two interventions. The beneficial effects of exercise on intrahepatic triglyceride (IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid contents. CONCLUSION: Prescribed exercise in subjects with NAFLD reduces IHTG independent of dietary intervention. Diet and exercise was more effective than exercise alone in reducing IHTG. PMID- 27468222 TI - Efficacy and safety of sustained-delivery fluocinolone acetonide intravitreal implant in patients with chronic diabetic macular edema insufficiently responsive to available therapies: a real-life study. AB - PURPOSE: To evaluate the efficacy and safety of sustained-delivery fluocinolone acetonide (FAc) intravitreal implant for diabetic macular edema (DME). PATIENTS AND METHODS: Prospective study in patients with DME insufficiently responsive to laser and anti-vascular endothelial growth factor (anti-VEGF). Patients with history of rise of intraocular pressure after intravitreal corticosteroids were excluded. RESULTS: The macular edema rapidly decreased both in group 1 (prior laser only; n=7 eyes) and group 2 (prior laser and >=3 monthly anti-VEGF therapy; n=10 eyes) and central subfield thickness was reduced by -299 MUm (P=0.008) and 251 MUm (P=0.016) at 12 months, respectively. Mean area under the curve from baseline to last value for pseudophakic eyes was +4.2 letters in group 1 and +9.5 letters in group 2. Overall, the FAc implant was well tolerated. CONCLUSION: This prospective study confirms the efficacy of the FAc implant in DME patients insufficiently responsive to laser and anti-VEGF. Moreover, with a careful patient selection, our safety results would support an earlier use of FAc in the DME treatment pathway. PMID- 27468221 TI - Bile cast nephropathy: A case report and review of the literature. AB - Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well. We report our case of bile cast nephropathy and the therapeutic measures undertaken in a middle-aged male with chronic renal insufficiency that developed hyperbilirubinemia and drug induced liver injury secondary to antibiotic use. He developed acute renal injury in the setting of rising bilirubin. He subsequently had a progressive decline in renal and hepatic function, requiring dialysis and plasmapheresis with some improvement, ultimately requiring transplantation. PMID- 27468219 TI - Environmental risk factors for inflammatory bowel diseases: Evidence based literature review. AB - AIM: Advances in genetics and immunology have contributed to the current understanding of the pathogenesis of inflammatory bowel diseases (IBD). METHODS: The current opinion on the pathogenesis of IBD suggests that genetically susceptible individuals develop intolerance to dysregulated gut microflora (dysbiosis) and chronic inflammation develops as a result of environmental insults. Environmental exposures are innumerable with varying effects during the life course of individuals with IBD. Studying the relationship between environmental factors and IBD may provide the missing link to increasing our understanding of the etiology and increased incidence of IBD in recent years with implications for prevention, diagnosis, and treatment. Environmental factors are heterogeneous and genetic predisposition, immune dysregulation, or dysbiosis do not lead to the development of IBD in isolation. RESULTS: Current challenges in the study of environmental factors and IBD are how to effectively translate promising results from experimental studies to humans in order to develop models that incorporate the complex interactions between the environment, genetics, immunology, and gut microbiota, and limited high quality interventional studies assessing the effect of modifying environmental factors on the natural history and patient outcomes in IBD. CONCLUSION: This article critically reviews the current evidence on environmental risk factors for IBD and proposes directions for future research. PMID- 27468223 TI - History of falling and visual ability among independently living elderly in Sweden. AB - PURPOSE: The aim of this study was to assess the performance-based visual ability among independently living elderly subjects and to investigate whether there was any association between visual ability and falls. SUBJECTS AND METHODS: A total of 298 randomly selected subjects aged 70-85 years were invited for an examination including monocular and binocular visual acuity (VA), contrast sensitivity (CS), stereoscopic vision, and monocular visual fields (VFs), which were integrated to estimate the binocular VFs. Type of lenses used in their habitual correction was noted. RESULTS: Out of the 212 subjects who were examined, 38% reported at least one fall and 48% of these reported at least two falls during the last 2 years. Most subjects had normal results; 90% had normal binocular VA, 85% had normal binocular CS, and ~80% had positive stereopsis. Twenty-nine subjects had VF defects in the lower quadrants of the binocular VF, and 14 of these reported at least one fall. A significant association was seen between one fall or more and VA better eye, the odds ratio (OR) was 2.26, P=0.013, and between recurrent falls and lack of stereoscopic vision, the OR was 3.23, P=0.002; no other functional test showed any significant association with recurrent falls. The ORs were 1.58 for worse binocular VA, 0.60 for worse binocular CS, and 0.71 for non-normal stereoscopic vision for at least one fall, but wide confidence intervals made it difficult to draw firm conclusions about any association. Bifocal or progressive spectacles were worn by 71% with no significant difference between fallers and nonfallers (P=0.078). CONCLUSION: Even though ~40% of the total sample had experienced one or more falls, the only visual function test significantly associated with falls were VA better eye, lack of stereoscopic vision, and recurrent falls. Our results suggest that there may be more powerful predictors of falling than decreased visual ability. PMID- 27468224 TI - Acyl lipidation of a peptide: effects on activity and epidermal permeability in vitro. AB - Short-chain lipid conjugates can increase permeability of a small peptide across human epidermis; however, the emerging lipoaminoacid (LAA) conjugation technique is costly and can deliver mixed synthetic products of varied biological potential. LAA conjugation using a racemic mixture produces a mixture of D- and L stereoisomers. Individual enantiomers can be produced at an extra cost. We investigated an affordable technique that produces only one synthetic product: short-chain (C7-C8) acyl lipidation. Acyl lipidation of Ala-Ala-Pro-Val, an inhibitor of human neutrophil elastase (HNE; believed to lead to abnormal tissue destruction and disease development), was investigated as an alternative to LAA conjugation. The current study aimed to assess the effects of acyl lipidation (either at the N-terminal or at the C-terminal) on neutrophil elastase activity in vitro and on transdermal delivery ex vivo. The inhibitory capacity of the acyl conjugates was compared to LAA conjugates (conjugated at the N-terminal) of the same peptide. The L-stereoisomer appears to rapidly degrade, but it represents a significantly (P<0.05) better inhibitor of HNE than the parent peptide (Ala-Ala Pro-Val). Although the D-stereoisomer appears to permeate human epidermal skin sections in a better fashion than the L-stereoisomer, it is not a significantly better inhibitor of HNE than the parent peptide. Acyl lipidation (with a C7 lipid chain) at either end of the peptide substantially enhances the permeability of the peptide across human skin epidermis as well as significantly (P<0.005) increases its elastase inhibitory potential. Therefore, our current study indicates that acyl lipidation of a peptide is a more economical and effective alternative to LAA conjugation. PMID- 27468225 TI - Pharmacogenetic analysis of cinacalcet response in secondary hyperparathyroidism patients. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT) is one of the major risk factors of morbidity and mortality in end-stage renal disease. Cinacalcet effectively controls SHPT without causing hypercalcemia and hyperphosphatemia. However, there is significant inter-individual response variance to cinacalcet treatment. Therefore, we aimed to evaluate the genetic effects related with parathyroid hormone regulation as factors for cinacalcet response variance. METHODS: Patients with a diagnosis of SHPT based on intact parathyroid hormone (iPTH) >300 pg/mL on dialysis were included in this study. They were over 18 years and have been treated by cinacalcet for more than 3 months. Responders and nonresponders were grouped by the serum iPTH changes. Twenty-four single nucleotide polymorphisms of CASR, VDR, FGFR1, KL, ALPL, RGS14, NR4A2, and PTHLH genes were selected for the pharmacogenetic analysis. RESULTS: After adjusting for age, sex, and calcium level, CASR rs1042636 (odds ratio [OR]: 0.066, P=0.027) and rs1802757 (OR: 10.532, P=0.042) were associated with cinacalcet response. The association of haplotypes of CASR rs1042636, rs10190, and rs1802757; GCC (OR: 0.355, P=0.015); and ATT (OR: 2.769, P=0.014) with cinacalcet response was also significant. CONCLUSION: We obtained supporting information of the associations between cinacalcet response and CASR polymorphisms. CASR single nucleotide polymorphisms (SNPs) rs1802757, rs1042636, and haplotypes of rs1042636, rs10190, and rs1802757 were significantly associated with cinacalcet response variance. PMID- 27468226 TI - Puerarin transport across a Calu-3 cell monolayer - an in vitro model of nasal mucosa permeability and the influence of paeoniflorin and menthol. AB - Nasal administration is a high-potential delivery system, particularly because it can provide a pathway from the nose to the brain. The objective of this research is to characterize puerarin transport across a Calu-3 cell monolayer used as a model of the nasal mucosa and to evaluate the influence of puerarin in combination with paeoniflorin and menthol to explore the enhanced mechanism of the permeability at the cell level. The apparent permeability coefficients (P app) of puerarin bidirectional transport were both <1.5*10(-6) cm/s, and the efflux ratio was <1.5, indicating that puerarin alone exhibited poor absorption and that its transport primarily occurred by passive diffusion through the cell monolayer. When puerarin was coad ministered with paeoniflorin, the P app was not changed (P>0.05). However, the addition of menthol significantly (P<0.05) improved the P app of puerarin in both directions. Moreover, based on immunofluorescence experiments and transepithelial electrical resistance measurements, the data indicated that the drug compatibility opened tight junctions and weakened the barrier capabilities of epithelial cells, thereby promoting the permeability of puerarin. PMID- 27468227 TI - Thymoquinone subdues tumor growth and potentiates the chemopreventive effect of 5 fluorouracil on the early stages of colorectal carcinogenesis in rats. AB - Colorectal cancer (CRC) is one of the most prevalent cancers and has a high mortality rate. Insensitivity and the limited therapeutic efficacy of its standard chemotherapeutic drug, 5-fluorouracil (5-FU), represents an important challenge in CRC treatment. The robust antitumor properties of thymoquinone (TQ), the main bioactive constituent of Nigella sativa, have recently been demonstrated on different cancers. We investigated whether TQ could potentiate the chemopreventive effect of 5-FU to eradicate the early stages of CRC and elucidated its underlying mechanisms. An intermediate-term (15 weeks) model of colorectal tumorigenesis was induced in male Wistar rats by azoxymethane (AOM), and the animals were randomly and equally divided into five groups: control, AOM, AOM/5-FU, AOM/TQ, and AOM/5-FU/TQ. TQ (35 mg/kg/d; 3 d/wk) was given during the seventh and 15th weeks post-AOM injection, while 5-FU was given during the ninth and tenth weeks (12 mg/kg/d for 4 days; then 6 mg/kg every other day for another four doses). At week 15, the resected colons were subjected to macroscopic, histopathological, molecular, and immunohistochemical examinations. Interestingly, 5-FU/TQ combination therapy resulted in a more significant reduction on AOM-induced colorectal tumors and large aberrant crypts foci than treatment with the individual drugs. Mechanistically, 5-FU and TQ remarkably cooperated to repress the expression of procancerous Wnt, beta-catenin, NF kappaB, COX-2, iNOS, VEGF, and TBRAS and upregulate the expression of anti tumorigenesis DKK-1, CDNK-1A, TGF-beta1, TGF-betaRII, Smad4, and GPx. Overall, our findings present the first report describing the in vivo enhancement effect of combined TQ and 5-FU against early stages of CRC; however, further studies are required to determine the value of this combination therapy in an advanced long term model of CRC and also to realize its clinical potential. PMID- 27468228 TI - An appraisal of golimumab in the treatment of severe, active nonradiographic axial spondyloarthritis. AB - Golimumab (Simponi((r))) is a fully human tumor necrosis factor alpha inhibitor (TNFi) antibody administered subcutaneously. In the European Union, golimumab is indicated for the treatment of adults with severe, active axial spondyloarthritis (axSpA), which includes both ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA). In the US, it is indicated for the treatment of adults with active AS only. This article reviews the efficacy and tolerability of golimumab in nr-axSpA patients compared to other TNFi agents (adalimumab, infliximab, etanercept, and certolizumab pegol). In one ongoing, well-designed controlled study (GO-AHEAD), data at 16 weeks showed that treatment with golimumab (50 mg every 4 weeks) was effective in improving the clinical signs and symptoms of disease in nr-axSpA patients. In addition, 16 weeks of treatment with golimumab reduced inflammation in the sacroiliac joints and spine in patients with nr axSpA. Moreover, objective evidence of active inflammation at baseline, such as a positive magnetic resonance imaging scan and/or an elevated CRP level, was a good predictor of treatment response to golimumab. Golimumab was generally well tolerated in this study, with a tolerability profile consistent with that seen in previous clinical trials for other indications. Although additional long-term data are needed, current evidence indicates that golimumab is an effective option for the treatment of nr-axSpA. However, in the absence of comparative head-to head trials, there is no recommended hierarchy for the first prescription of a TNFi agent for the treatment of either nr-axSpA or AS. PMID- 27468229 TI - The impact of pharmacist-managed clinic on medication adherence and health related quality of life in patients with COPD: a randomized controlled study. AB - INTRODUCTION: COPD is rapidly becoming one of the most challenging health problems worldwide, which is characterized by not fully reversible airflow limitation. Although a lot of treatment medications have been delivered, the treatment goals of COPD are often not achieved. Furthermore, few well-designed randomized controlled trials in the People's Republic of China have been reported to evaluate the impact of pharmacist-managed clinic (PMC) on medication adherence and health-related quality of life in patients with COPD. METHODS: A prospective randomized controlled study (on a PMC group and a control group) was conducted between January 2015 and December 2015. A structured education about COPD was provided by a clinical pharmacist to the PMC group. Primary outcomes were medication adherence (assessed by medication refill adherence scores) and health related quality of life (assessed by St George's Respiratory Questionnaire). Secondary outcomes were exacerbation rate, hospitalization rate, and smoking behavior. RESULTS: A total of 244 patients were enrolled for our study. The PMC group showed a significantly greater improvement in medication adherence compared with the baseline (93.1+/-14.2 vs 78.8+/-12.3, P<0.01). When compared with the control group, there were more patients whose medication refill adherence score was >=80 in the PMC group (83.3% vs 51.3%, P<0.01). The total St George's Respiratory Questionnaire scores was found to be improved significantly in the PMC group (42.7+/-3.2 vs 52.4+/-5.2, P<0.05). There was a lower hospitalization rate in the PMC group, and more patients in the PMC group quit smoking (71.0% vs 52.2%, P<0.05). CONCLUSION: The PMC may result in improvement of medication adherence and the health-related quality of life in patients with COPD. In the PMC group, a significant reduction in exacerbation rate, hospitalization rate, and smoking behavior was observed; therefore, our study provides support for a greater involvement of PMC in the care of patients with COPD. PMID- 27468230 TI - Brazilian studies on pulmonary function in COPD patients: what are the gaps? AB - BACKGROUND: COPD is a major cause of death and morbidity worldwide, and is characterized by persistent airflow obstruction. The evaluation of obstruction is critically dependent on sensitive methods for lung-function testing. A wide body of knowledge has been accumulated in recent years showing that these methods have been significantly refined and seems promising for detection of early disease. OBJECTIVES: This review focuses on research on pulmonary function analysis in COPD performed in Brazil during this century. MATERIALS AND METHODS: The literature was searched using a systematic search strategy limited to English language studies that were carried out in Brazil from the year 2000 onward, with study objectives that included a focus on lung function. RESULTS: After we applied our inclusion and exclusion criteria, 94 articles addressed our stated objectives. Among the new methods reviewed are the forced-oscillation technique and the nitrogen-washout test, which may provide information on small-airway abnormalities. Studies investigating the respiratory muscles and thoracoabdominal motion are also discussed, as well as studies on automatic clinical decision support systems and complexity measurements. We also examined important gaps in the present knowledge and suggested future directions for the cited research fields. CONCLUSION: There is clear evidence that improvements in lung-function methods allowed us to obtain new pathophysiological information, contributing to improvement in our understanding of COPD. In addition, they may also assist in the diagnosis and prevention of COPD. Further investigations using prospective and longitudinal design may be of interest to elucidate the use of these new methods in the diagnosis and prevention of COPD. PMID- 27468232 TI - Green synthesis of multifunctional silver and gold nanoparticles from the oriental herbal adaptogen: Siberian ginseng. AB - Pharmacologically active stem of the oriental herbal adaptogen, Siberian ginseng, was employed for the ecofriendly synthesis of Siberian ginseng silver nanoparticles (Sg-AgNPs) and Siberian ginseng gold nanoparticles (Sg-AuNPs). First, for metabolic characterization of the sample, liquid chromatography-tandem mass spectrometry analysis (indicated the presence of eleutherosides A and E), total phenol content, and total reducing sugar were analyzed. Second, the water extract of the sample mediated the biological synthesis of both Sg-AgNPs and Sg AuNPs that were crystalline face-centered cubical structures with a Z-average hydrodynamic diameter of 126 and 189 nm, respectively. Moreover, Fourier transform infrared analysis indicated that proteins and aromatic hydrocarbons play a key role in the formation and stabilization of Sg-AgNPs, whereas phenolic compounds accounted for the synthesis and stability of Sg-AuNPs. 3-(4,5-Dimethyl 2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay determined that Sg AgNPs conferred strong cytotoxicity against MCF7 (human breast cancer cell line) and was only slightly toxic to HaCaT (human keratinocyte cell line) at 10 ug?mL( 1). However, Sg-AuNPs did not display cytotoxic effects against both of the cell lines. The disc diffusion assay indicated a dose-dependent increase in the zone of inhibition of Staphylococcus aureus (ATCC 6538), Bacillus anthracis (NCTC 10340), Vibrio parahaemolyticus (ATCC 33844), and Escherichia coli (BL21) treated with Sg-AgNPs, whereas Sg-AuNPs did not show inhibitory activity. In addition, the 2,2-diphenyl-1-picrylhydrazyl assay demonstrated that both Sg-AgNPs and Sg AuNPs possess strong antioxidant activity. To the best of our knowledge, this is the first report unraveling the potential of Eleutherococcus senticosus for silver and gold nanoparticle synthesis along with its biological applications, which in turn would promote widespread usage of the endemic Siberian ginseng. PMID- 27468231 TI - Associations of autophagy with lung diffusion capacity and oxygen saturation in severe COPD: effects of particulate air pollution. AB - Although traffic exposure has been associated with the development of COPD, the role of particulate matter <10 MUm in aerodynamic diameter (PM10) in the pathogenesis of COPD is not yet fully understood. We assessed the 1-year effect of exposure to PM10 on the pathogenesis of COPD in a retrospective cohort study. We recruited 53 subjects with COPD stages III and IV and 15 healthy controls in a hospital in Taiwan. We estimated the 1-year annual mean levels of PM10 at all residential addresses of the cohort participants. Changes in PM10 for the 1-year averages in quintiles were related to diffusion capacity of the lung for carbon monoxide levels (r=-0.914, P=0.029), changes in the pulse oxygen saturation (DeltaSaO2; r=-0.973, P=0.005), receptor for advanced glycation end-products (r= 0.881, P=0.048), interleukin-6 (r=0.986, P=0.002), ubiquitin (r=0.940, P=0.017), and beclin 1 (r=0.923, P=0.025) in COPD. Next, we observed that ubiquitin was correlated with DeltaSaO2 (r=-0.374, P=0.019). Beclin 1 was associated with diffusion capacity of the lung for carbon monoxide (r=-0.362, P=0.028), DeltaSaO2 (r=-0.354, P=0.032), and receptor for advanced glycation end-products (r=-0.471, P=0.004). Autophagy may be an important regulator of the PM10-related pathogenesis of COPD, which could cause deterioration in the lung diffusion capacity and oxygen saturation. PMID- 27468234 TI - Cortical spreading depression produces a neuroprotective effect activating mitochondrial uncoupling protein-5. AB - Depression of electrocorticogram propagating over the cortex surface results in cortical spreading depression (CSD), which is probably related to the pathophysiology of stroke, epilepsy, and migraine. However, preconditioning with CSD produces neuroprotection to subsequent ischemic episodes. Such effects require the expression or activation of several genes, including neuroprotective ones. Recently, it has been demonstrated that the expression of the uncoupling proteins (UCPs) 2 and 5 is amplified during brain ischemia and their expression exerts a long-term effect upon neuron protection. To evaluate the neuroprotective consequence of CSD, the expression of UCP-5 in the brain cortex was measured following CSD induction. CSD was evoked in four samples of rats, which were sacrificed after 2 hours, 4 hours, 6 hours, and 24 hours. Western blot analyses were carried out to measure UCP-5 concentrations in the prefrontal cortices of both hemispheres, and immunohistochemistry was performed to determine the localization of UCP-5 in the brain cortex. The results showed a significant elevation in UCP-5 expression at 24 hours in all cortical strata. Moreover, UCP-5 was triggered by CSD, indicating that UCP-5 production can have a neuroprotective effect. PMID- 27468235 TI - Risk factors for suicide among patients with schizophrenia: a cohort study focused on cerebrospinal fluid levels of homovanillic acid and 5 hydroxyindoleacetic acid. AB - BACKGROUND: The objective of this study was to investigate the association between 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF), bullying, and later suicide among patients with schizophrenia. METHODS: Ninety-nine patients with schizophrenia were included. Correlations of clinical factors, 5-HIAA and HVA, and later suicide were investigated. RESULTS: Twelve patients committed suicide (12%) during a 28-year follow-up period. Later suicide was correlated to bullying in childhood (P=0.02) and a lower quotient of HVA/5-HIAA in CSF (P<0.05). CONCLUSION: Suicide in schizophrenia is related to childhood exposedness and CSF neurotransmitter levels. PMID- 27468236 TI - A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults. AB - OBJECTIVE: The aim of the study was to investigate the efficacy and safety of St John's wort extract and selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. METHODS: Databases were searched for studies comparing efficacy and/or safety of St John's wort extract with SSRIs in depression from 1966 to April 2015. Stata software was used for statistical analysis. RESULTS: Twenty-seven studies met the study entry criteria. A total of 3,126 patients with depression were included. St John's wort extract did not differ from SSRIs in clinical response, remission, and mean reduction in Hamilton Rating Scale for Depression score. St John's wort extract had a significantly lower rate of adverse events compared to SSRIs (summary relative risk: 0.77; 95% confidence interval: 0.70, 0.84, P=0.00) and had fewer withdrawals due to adverse events. St John's wort extract had superior safety in the management of patients with depression. CONCLUSION: Both St John's wort extract and SSRIs are effective in treating mild-to-moderate depression. St John's wort extract is safer than SSRIs. PMID- 27468237 TI - Correlation between obesity and chronic kidney disease: is obstructive sleep apnea an interfering factor? PMID- 27468238 TI - Observational cohort study focused on treatment continuity of patients administered XELOX plus bevacizumab for previously untreated metastatic colorectal cancer. AB - BACKGROUND: There has been remarkable progress in systemic chemotherapy for metastatic colorectal cancer due to the widespread use of irinotecan, oxaliplatin, anti-vascular endothelial growth factor antibody, and anti-epidermal growth factor receptor antibody. It is important to continue treatment with the optimal combination of these drugs and prolong progression-free survival (PFS) to improve overall survival (OS). We conducted a prospective observational cohort study of 40 patients treated with XELOX plus bevacizumab for previously untreated metastatic colorectal cancer to investigate treatment continuity. PATIENTS AND METHODS: Eligibility criteria were as follows: 1) histologically confirmed metastatic colorectal cancer; 2) lesions evaluable by imaging; 3) previously untreated; 4) suitable condition to receive XELOX plus bevacizumab; and 5) written informed consent. Outcomes were treatment continuity, overall response rate, resection rate, liver resection rate, time to treatment failure, PFS, and OS. Forty patients were enrolled and followed up for 2 years. RESULTS: Between July 2010 and June 2012, 40 patients were enrolled. The median number of treatment cycles was 7.5, and the reasons for discontinuation of treatment were as follows: complete response (five patients), resection (ten patients), progression (15 patients), adverse events (seven patients), and patient refusal (three patients). The overall response rate was 57.5%, resection rate was 25%, and liver resection rate was 15%. After a median follow-up of 31.4 months, the median time to treatment failure, PFS, and OS were 5.3, 13.3, and 38.9 months, respectively. CONCLUSION: Although the median time to treatment failure was 5.3 months, the median PFS and OS were prolonged to 13.3 and 38.9 months, respectively. This may have resulted from the chemotherapy-free interval due to complete response in five patients and resection in ten patients. PMID- 27468233 TI - A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. AB - Increasing evidence highlights bipolar disorder as being associated with impaired neurogenesis, cellular plasticity, and resiliency, as well as with cell atrophy or loss in specific brain regions. This has led most recent research to focus on the possible neuroprotective effects of medications, and particularly interesting findings have emerged for lithium. A growing body of evidence from preclinical in vitro and in vivo studies has in fact documented its neuroprotective effects from different insults acting on cellular signaling pathways, both preventing apoptosis and increasing neurotrophins and cell-survival molecules. Furthermore, positive effects of lithium on neurogenesis, brain remodeling, angiogenesis, mesenchymal stem cells functioning, and inflammation have been revealed, with a key role played through the inhibition of the glycogen synthase kinase-3, a serine/threonine kinase implicated in the pathogenesis of many neuropsychiatric disorders. These recent evidences suggest the potential utility of lithium in the treatment of neurodegenerative diseases, neurodevelopmental disorders, and hypoxic-ischemic/traumatic brain injury, with positive results at even lower lithium doses than those traditionally considered to be antimanic. The aim of this review is to briefly summarize the potential benefits of lithium salts on neuroprotection and neuroregeneration, emphasizing preclinical and clinical evidence suggesting new therapeutic potentials of this drug beyond its mood stabilizing properties. PMID- 27468240 TI - Clinical efficacy of first-generation EGFR-TKIs in patients with advanced non small-cell lung cancer harboring EGFR exon 20 mutations. AB - PURPOSE: Subsets of non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations carry uncommon subtypes. We evaluated the efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib, and icotinib) in patients with non-small-cell lung cancer carrying insertions and T790M and S768I mutations in EGFR exon 20. PATIENTS AND METHODS: Patients carrying EGFR exon 20 insertion/T790M/S768I mutations and treated with EGFR-TKIs were evaluated from 2005 to 2014 in Zhejiang Cancer Hospital. The efficacy was evaluated using the Kaplan-Meier method and compared with the log rank test. RESULTS: Sixty-two patients with exon 20 insertion/T790M/S768I mutations were enrolled. Mutations including exon 20 insertions and T790M and S768I mutations were observed in 29, 23, and ten patients, respectively. In total, the response rate and median progression-free survival (PFS) were 8.1% and 2.1 months, respectively. Patients with S768I mutation manifested the longest median PFS (2.7 months), followed by those with T790M (2.4 months) and exon 20 insertions (1.9 months; P=0.022). Patients with complex mutations show a better PFS than those with single mutations (2.7 months vs 1.9 months; P=0.034). CONCLUSION: First-generation EGFR-TKIs are less effective in patients with exon 20 uncommon mutations than in those with common mutations. Patients with complex mutations benefited more from first-generation EGFR-TKIs than those with single mutations. PMID- 27468239 TI - Intravenous pamidronate versus oral and intravenous clodronate in bone metastatic breast cancer: a randomized, open-label, non-inferiority Phase III trial. AB - PURPOSE: Patients with metastasized breast cancer often suffer from discomfort caused by metastatic bone disease. Thus, osteoprotection is an important part of therapy in breast cancer metastasized to bone, and bisphosphonates (BPs) are a major therapeutic option. In this study, our objectives were to compare the side effects of oral versus intravenous BP treatment and to assess their clinical effectiveness. PATIENTS AND METHODS: In this prospective randomized, open-label, non-inferiority trial, we enrolled breast cancer patients with at least one bone metastasis and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned to one of the three treatment groups: A, 60 mg pamidronate intravenously q3w; B-iv, 900 mg clodronate intravenously q3w; and B o, 2,400 mg oral clodronate daily. Assessments were performed at baseline and every 3 months thereafter. RESULTS: Between 1995 and 1999, 321 patients with confirmed bone metastases from breast cancer were included in the study. At first follow-up, gastrointestinal (GI) tract side effects were most common, and adverse effects on the GI tract were more frequent in the oral treatment group (P=0.002 and P<0.001, respectively). There were no statistically significant differences among the treatment cohorts for other documented side effects (skin, serum electrolytes, urinary tract, immune system, and others). No significant differences in clinical effectiveness of BP treatment, as assessed by pain score, were detected among the groups; however, pathologic fractures were more effectively prevented by intravenous than oral BP administration (P=0.03). Noncompliance rates were similar among the study cohorts. CONCLUSION: We conclude that oral BP treatment is significantly associated with higher rates of adverse GI side effects. Additionally, our data indicate that intravenous BP administration is more effective than oral treatment in prevention of pathologic fractures; hence, oral administration should be considered with caution. PMID- 27468241 TI - A review of the clinical efficacy and safety of MP-AzeFlu, a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate, in clinical studies conducted during different allergy seasons in the US. AB - A novel intranasal formulation of azelastine HCl (AZE, an antihistamine) and fluticasone propionate (FP, a corticosteroid) in a single spray (MP-AzeFlu [Dymista(r)]) was studied in four randomized, double-blind, placebo-controlled trials of patients with seasonal allergic rhinitis conducted in the US. Study sites were distributed so that all major US geographic regions and the prevalent pollens within these regions were represented. Spring and summer studies included patients aged 12 years and older with allergy to grass and tree pollens. Fall studies enrolled patients with allergy to weeds, in particular ragweed. In addition, a study was conducted during the winter months in patients with allergy to mountain cedar pollen in TX, USA. Regardless of allergy season or prevalent pollen, MP-AzeFlu improved nasal symptoms of allergic rhinitis (AR) to a significantly greater degree than AZE or FP, two treatments that currently are recommended as the first-line AR therapy. MP-AzeFlu improved all individual AR symptoms and was significantly better than FP and AZE for nasal congestion relief, which is generally accepted as the most bothersome symptom for AR patients. The onset of action was within 30 minutes. MP-AzeFlu also provided clinically important improvement in the overall Rhinoconjunctivitis Quality of Life Questionnaire score and significantly improved ocular symptoms of rhinitis compared to placebo. Favorable characteristics of the MP-AzeFlu formulation as well as superior clinical efficacy make it an ideal intranasal therapy for AR. PMID- 27468242 TI - Strategies for prevention of ultrasound-guided prostate biopsy infections. AB - Prostate cancer is the most common cancer in male patients and the second leading cause of cancer-related mortality in males. To confirm the diagnosis of prostate cancer, an ultrasound-guided needle biopsy is necessary to obtain prostate tissue sufficient for histologic analysis by pathologists. Ultrasound-guided prostate needle biopsy can be accomplished via a transperineal or transrectal approach. The latter biopsy technique involves placing an ultrasound probe into the rectum, visualizing the prostate located just anterior to it, and then obtaining 12-14 biopsies. Each biopsy core requires piercing of the rectal mucosa which can inherently contribute to infection. The increasing infectious risk of prostate needle biopsy requires refinement and re-evaluation of the process in which the technique is performed. Such processes include (but are not limited to) prebiopsy risk stratification, antibiotic prophylaxis, use of rectal preparations, and equipment processing. In the subsequent review, we highlight the current available information on different strategies to reduce the risk of infection following prostate needle biopsy. PMID- 27468244 TI - The relationship between the presence of lower urinary tract symptoms and waist circumference. AB - PURPOSE: The aim of the study is to evaluate the pressure of the pelvic floor muscles (PFM) according to waist circumference (WC) and correlate the presence of urinary tract symptoms (UTS) with WC. PATIENTS AND METHODS: The study was observational and cross-sectional. One-hundred and sixty-four females between 45 and 65 years of age were evaluated. The sample was divided into two groups, according to WC: Group <=80 (G<=80) was composed of females in whom WC was up to 80 cm; and Group >80 (G>80) was composed of females with WC above 80 cm. The subjects were assessed in terms of sociodemographic data, pre-existing conditions, urogynecological and obstetric history, and the presence of lower UTS (LUTS), as well as physical examination, measurement of WC, height, and weight. The PFM assessment was made by perineometry. To compare the mean between groups, the independent samples t-test was applied, and to correlate the WC with perineometry and LUTS, the Pearson's correlation test was used. RESULTS: The final sample was composed of 156 patients. The average age of participants was 55.21 (+/-24.5) years in G<=80 and 57.23 (+/-6.12) years in G>80. There were significant differences regarding the presence of LUTS between the groups (P<0.05); as to the perineometry, there was a significant difference (P=0.03) between the groups: 38.68+/-13.63 cmH2O for G<=80 and 30.11+/-11.20 cmH2O for G>80. There was a correlation between the presence of urinary urgency (r=0.7; P=0.00), nocturia (r=0.7; P=0.00), and urinary incontinence (r=0.9; P=0.00) with WC. CONCLUSION: Females with larger abdominal diameter have a higher prevalence of LUTS such as urinary incontinence, nocturia, and urinary urgency, as well as a lower PFM pressure. Furthermore, a relationship between LUTS with WC was also observed. PMID- 27468243 TI - Early detection of neonatal group B streptococcus sepsis and the possible diagnostic utility of IL-6, IL-8, and CD11b in a human umbilical cord blood in vitro model. AB - BACKGROUND: Group B streptococcus (GBS) infection remains a major cause of neonatal morbidity and mortality, and GBS III is the predominant strain in early onset GBS neonatal sepsis. To avoid both over- and undertreatment of infants with nonspecific signs of infection, early diagnostic tools are warranted. The aim of this study was to identify biomarkers with high sensitivity and specificity in an early stage of GBS infection. A secondary aim was to assess the utility of a human umbilical cord blood (HUCB) model system of early-onset neonatal sepsis. METHODS: Umbilical cord blood samples from 20 healthy term pregnancies were stimulated for 2 hours with a GBS III isolate from a patient and a commercially available GBS Ia strain. Nonstimulated samples served as controls. Leukocyte surface markers (CD11b, CD64, toll-like receptor [TLR] 2, TLR4, and TLR6) were analyzed by flow cytometry and soluble biomarkers by enzyme-linked immunosorbent assay (interleukin [IL]-6 and -8; interferon-gamma-inducing protein [IP]-10; and S100b). The area under the receiver operating characteristic curve (AUC) was calculated for the markers. RESULTS: GBS III gave the highest responses and AUC values for all biomarkers. Only IL-6 and IL-8 displayed an AUC approaching 0.8 for both GBS serotypes (P<0.001). IL-8 >5,292 pg/mL had both a sensitivity and a specificity of 1.00. IL-6 >197 pg/mL had both a sensitivity and a specificity of 0.95 for GBS III stimulation. CD11b on granulocytes and monocytes was the leukocyte surface marker with the highest AUC values for both GBS serotypes. CONCLUSION: In agreement with previous studies, IL-6, IL-8, and potentially CD11b could be useful in diagnosing neonatal GBS infection in an early stage. Our HUCB early-onset neonatal sepsis model may be useful for evaluating biomarkers of neonatal sepsis. The HUCB of neonates with risk factors for sepsis might even be used for diagnostic purposes, but requires further study. PMID- 27468245 TI - Ferumoxytol versus placebo in iron deficiency anemia: efficacy, safety, and quality of life in patients with gastrointestinal disorders. AB - INTRODUCTION: Iron deficiency anemia (IDA) is common in patients with gastrointestinal (GI) disorders and can adversely affect quality of life. Oral iron is poorly tolerated in many patients with GI disorders. Ferumoxytol is approved for the intravenous treatment of IDA in patients with chronic kidney disease. This study aimed to evaluate the efficacy and safety of ferumoxytol in patients with IDA and concomitant GI disorders. PATIENTS AND METHODS: This analysis included 231 patients with IDA and GI disorders from a Phase III, randomized, double-blind, placebo-controlled trial evaluating ferumoxytol (510 mg *2) versus placebo in patients who had failed or were intolerant of oral iron therapy. The primary study end point was the proportion of patients achieving a >=20 g/L increase in hemoglobin (Hgb) from baseline to Week 5. Other end points included mean change in Hgb, proportion of patients achieving Hgb >=120 g/L, mean change in transferrin saturation, and patient-reported outcomes (PROs). RESULTS: Significantly more patients with IDA receiving ferumoxytol achieved a >=20 g/L increase in Hgb versus placebo (82.1% vs 1.7%, respectively; P<0.001). Mean increase in Hgb (28.0 g/L vs -1.0 g/L, respectively; P<0.001) significantly favored ferumoxytol treatment. Ferumoxytol-treated patients demonstrated significantly greater improvements than placebo-treated patients relative to their very poor baseline PRO scores posttreatment, including improvements in the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and various domains of the 36-Item Short-Form Health Survey. Ferumoxytol-treated patients had a low rate of adverse events. CONCLUSION: In this study, ferumoxytol was shown to be an efficacious and generally well-tolerated treatment option for patients with IDA and underlying GI disorders who were unable to use or had a history of unsatisfactory oral iron therapy. PMID- 27468246 TI - Significance of mast cell distribution in placental tissue and membranes in spontaneous preterm birth. AB - BACKGROUND: Preterm birth is a common cause of adverse neonatal and childhood outcomes, in both the short and long term. Preterm labor is commonly associated with inflammation at the maternal-fetal interface. There is some indirect evidence that mast cells (MCs) might represent a link between hormonal influences and local reactions leading to the onset of labor. PATIENTS AND METHODS: The placentas and membranes of 51 uncomplicated spontaneous term births were compared to those from 50 spontaneous preterm births. Immunohistochemical staining for MC tryptase was undertaken allowing MC concentration, location, and degranulation status to be determined. Regression modeling was used to compare results. RESULTS: There were no significant differences in the demographic characteristics of the two cohorts. There were significantly more MCs in the decidua for term births than preterm births (P=0.03). The presence of histological chorioamnionitis did not affect MC concentrations. CONCLUSION: Despite evidence suggesting a possible role for MCs in spontaneous preterm birth, this study found that the concentration of decidual MCs was in fact significantly lower in preterm compared to term birth. PMID- 27468247 TI - Utilization of genetic testing among children with developmental disabilities in the United States. AB - PURPOSE: Several professional societies recommend that genetic testing be routinely included in the etiologic workup of children with developmental disabilities. The aim of this study was to determine the rate at which genetic testing is performed in this population, based on data from a nationally representative survey. METHODS: Data were analyzed from the Survey of Pathways to Diagnosis and Services, a telephone-based survey of parents and guardians of US school-age children with current or past developmental conditions. This study included 3,371 respondents who indicated that their child had an autism spectrum disorder (ASD), intellectual disability (ID), and/or developmental delay (DD) at the time of survey administration. History of genetic testing was assessed based on report by the parent/s. Children were divided into the following five mutually exclusive condition groups: ASD with ID; ASD with DD, without ID; ASD only, without ID or DD; ID without ASD; and DD only, without ID or ASD. Logistic regression was used to assess the demographic correlates of genetic testing, to compare the rates of genetic testing across groups, and to examine associations between genetic testing and use of other health-care services. RESULTS: Overall, 32% of this sample had a history of genetic testing, including 34% of all children with ASD and 43% of those with ID. After adjusting for demographics, children with ASD + ID were more than seven times as likely as those with ASD only, and more than twice as likely as those who had ID without ASD, to have undergone genetic testing. Prior specialist care (developmental pediatrician or neurologist) and access to all needed providers within the previous year were associated with higher odds of genetic testing. CONCLUSION: The majority of children in this nationally representative sample did not undergo recommended genetic testing. Research is needed to identify barriers to the use of genetic testing in this population. PMID- 27468248 TI - Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. AB - Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed. PMID- 27468249 TI - Reporting quality of stepped wedge design randomized trials: a systematic review protocol. AB - BACKGROUND: Stepped wedge design (SWD) is a cluster randomized controlled trial (RCT) design that sequentially rolls out intervention to all clusters at varying time points. Being a relatively new design method, reporting quality has yet to be explored, and this review will seek to fill this gap in knowledge. OBJECTIVES: The objectives of this review are: 1) to assess the quality of SWD trial reports based on the CONSORT guidelines or CONSORT extension to cluster RCTs; 2) to assess the completeness of reporting of SWD trial abstracts using the CONSORT extension for abstracts; 3) to assess the reporting of sample size details in SWD trial reports or protocols; 4) to assess the completeness of reporting of SWD trial protocols according to SPIRIT guidelines; 5) to assess the consistency between the trial registration information and final SWD trial reports; and 6) to assess the consistency of what is reported in the abstracts and main text of the SWD trial reports. We will also explore factors that are associated with the completeness of reporting. METHODS: We will search MEDLINE, EMBASE, Web of Science, CINAHL, and PsycINFO for all randomized controlled trials utilizing SWD. Details from eligible papers will be extracted in duplicate. Demographic statistics obtained from the data extraction will be analyzed to answer the primary objectives pertaining to the reporting quality of several aspects of a published paper, as well as to explore possible temporal trends and consistency between abstracts, trial registration information, and final published articles. DISCUSSION: Findings from this review will establish the reporting quality of SWD trials and inform academics and clinicians on their completeness and consistency. Results of this review will influence future trials and improve the overall quality and reporting of SWD trials. PMID- 27468251 TI - Long-lasting corneal endothelial graft rejection successfully reversed after dexamethasone intravitreal implant. AB - Graft rejection is the most significant complication corneal transplantation and the leading indication for overall corneal transplantation. Corticosteroid therapy represents the mainstay of graft rejection treatment; however, the optimal route of administration of corticosteroid remains uncertain. We report herein for the first time the multimodal imaging of a case of long-lasting corneal endothelial graft rejection successfully reversed 3 months after dexamethasone intravitreal implant. A 29-year-old Asian female presented with a long-lasting corneal endothelial graft rejection in her left phakic eye. She underwent penetrating keratoplasty for advanced keratoconus 24 months before presentation. Hourly dexamethasone eyedrops, daily intravenous methylprednisolone, and one parabulbar injection of methylprednisolone acetate were administered during the 5 days of hospitalization. However, the clinical picture remained approximately unchanged despite therapy. By mutual agreement, we opted for the off-label injection of dexamethasone 0.7 mg intravitreal implant in order to provide therapeutic concentrations of steroid for a period of ~6 months. No other concomitant therapies were prescribed to the patient. Visual acuity measurement, slit lamp biomicroscopy, anterior segment photography, confocal microscopy, anterior segment optical coherence tomography, laser cell flare meter, intraocular pressure measurement, and ophthalmoscopy were performed monthly for the first postoperative 6 months. Three months after injection, both clinical and subclinical signs of rejection disappeared with a full recovery of visual acuity to 20/30 as before the episode. Currently, at the 12-month follow up visit, the clinical picture remains stable without any sign of rejection, recurrence, or graft failure. Dexamethasone intravitreal implant seems to be a new potential effective treatment for corneal graft rejection, particularly in case of poor compliance or lack of response to conventional treatment. In addition, it could be especially useful in diabetic patients unable to receive systemic steroids. PMID- 27468250 TI - Systemic lupus erythematosus: strategies to improve pregnancy outcomes. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with a high prevalence in females of childbearing age. Thus, reproduction in SLE patients is a major concern for clinicians. In the past, SLE patients were advised to defer pregnancy because of poor pregnancy outcomes and fear of SLE flares during pregnancy. Investigations to date show that maternal and fetal risks are higher in females with SLE than in the general population. However, with appropriate management of the disease, sufferers may have a relatively uncomplicated pregnancy course. Factors such as appropriate preconception counseling and medication adjustment, strict disease control prior to pregnancy, intensive surveillance during and after pregnancy by both the obstetrician and rheumatologist, and appropriate interventions when necessary play a key role. This review describes the strategies to improve pregnancy outcomes in SLE patients at different time points in the reproduction cycle (preconception, during pregnancy, and postpartum period) and also details the neonatal concerns. PMID- 27468252 TI - Bioresorbable vascular scaffolds technology: current use and future developments. AB - Coronary bioresorbable vascular scaffolds are a new appealing therapeutic option in interventional cardiology. The most used and studied is currently the Absorb BVSTM. Its backbone is made of poly-L-lactide and coated by a thin layer of poly D,L-lactide, it releases everolimus and is fully degraded to H2O and CO2 in 2-3 years. Absorb BVSTM seems to offer several theoretical advantages over metallic stent, as it gives temporary mechanical support to vessel wall without permanently caging it. Therefore, long-term endothelial function and structure are not affected. A possible future surgical revascularization is not compromised. Natural vasomotion in response to external stimuli is also recovered. Several observational and randomized trials have been published about BVS clinical outcomes. The main aim of this review is to carry out a systematic analysis about Absorb BVSTM studies, evaluating also the technical improvements of the Absorb GT1 BVSTM. PMID- 27468254 TI - Which oropharyngeal factors are significant risk factors for obstructive sleep apnea? An age-matched study and dentist perspectives. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is a common sleep breathing disorder. Untreated OSA may lead to a number of cardiovascular complications. Dentists may play an important role in OSA detection by conducting careful oral examinations. This study focused on the correlation of oral anatomical features in Thai patients who presented with OSA. METHODS: We conducted a prospective comparative study at a sleep/hypertension clinic and a dental clinic at Khon Kaen University in Thailand. Patients with OSA were enrolled in the study, along with age-matched patients with non-OSA (controls). Baseline characteristics, clinical data, and oropharyngeal data of all patients were compared between the two groups. Oropharyngeal measurements included tongue size, torus mandibularis, Mallampati classification, palatal space, and lateral pharyngeal wall area. Multivariate logistic regression analysis was used to identify the factors associated with OSA. RESULTS: During the study period, there were 156 patients who met the study criteria; 78 were patients with OSA and the other 78 were healthy control subjects. In the OSA group, there were 43 males with a mean age of 53 (standard deviation 12.29) years and a mean BMI of 30.86 kg/mm(2). There were 37 males in the control group with a mean age of 50 (standard deviation 12.04) years and a mean BMI of 24.03 kg/mm(2). According to multivariate logistic analysis, three factors were perfectly associated with OSA, including torus mandibularis class 6, narrow lateral pharyngeal wall, and Mallampati class 4. There were two other significant factors associated with having OSA, namely, BMI and Mallampati classification. The adjusted odds ratios (95% confidence interval) of these two factors were 1.445 (1.017, 2.052) and 5.040 (1.655, 15.358), respectively. CONCLUSION: Dentists may play an important role in the detection of OSA in patients with high BMI through careful oropharyngeal examination in routine dental treatment. A large torus mandibularis, Mallampati class 4, and a narrow lateral pharyngeal wall are important anatomical risk factors for OSA. PMID- 27468253 TI - Pulse oximetry screening: a review of diagnosing critical congenital heart disease in newborns. AB - Congenital heart disease (CHD) is one of the most common birth defects, with an incidence of nine out of every 1,000 live births. The mortality of infants with CHD has decreased over the past 3 decades, but significant morbidity and mortality continue to occur if not diagnosed shortly after birth. Pulse oximetry was recommended as a screening tool to detect critical CHD in 2011 by the American Academy of Pediatrics and the American Heart Association. Pulse oximetry is a tool to measure oxygen saturation, and based on the presence of hypoxemia, many cardiac lesions are detected. Due to its ease of application to the patient, providing results in a timely manner and without the need for calibrating the sensor probe, pulse oximetry offers many advantages as a screening tool. However, pulse oximetry has also important limitations of which physicians should be aware to be able to assess the significance of the pulse oximetry measurement for a given patient. This review aims to highlight the benefits and shortcomings of pulse oximetry within the context of screening for critical CHD and suggests future avenues to cover existing gaps in current practices. PMID- 27468255 TI - Good teacher, good tutor. PMID- 27468256 TI - Constrained Source Apportionment of Coarse Particulate Matter and Selected Trace Elements in Three Cities from the Multi-Ethnic Study of Atherosclerosis. AB - PM10-2.5 mass and trace element concentrations were measured in Winston-Salem, Chicago, and St. Paul at up to 60 sites per city during two different seasons in 2010. Positive Matrix Factorization (PMF) was used to explore the underlying sources of variability. Information on previously reported PM10-2.5 tire and brake wear profiles was used to constrain these features in PMF by prior specification of selected species ratios. We also modified PMF to allow for combining the measurements from all three cities into a single model while preserving city-specific soil features. Relatively minor differences were observed between model predictions with and without the prior ratio constraints, increasing confidence in our ability to identify separate brake wear and tire wear features. Brake wear, tire wear, fertilized soil, and re-suspended soil were found to be important sources of copper, zinc, phosphorus, and silicon respectively across all three urban areas. PMID- 27468257 TI - Extensive deep vein thrombosis treatment using fondaparinux and edoxaban: a case report. AB - BACKGROUND: Factor Xa inhibitor is a key drug in the coagulation cascade. Parenteral anticoagulation using low molecular weight heparin or fondaparinux is the recommended form of treatment for most patients presenting with venous thrombosis. Following the acute phase, edoxaban is recommended. We present a case of extensive deep vein thrombosis treated using fondaparinux and edoxaban. CASE PRESENTATION: A 63-year-old man with redness, pain, and swelling of the left leg lasting for more than 1 month was referred to our hospital. Ultrasonography revealed a thrombus in the left femoral vein. Computed tomographic angiography revealed clots in the distal right pulmonary artery. Thus, the anticoagulant treatment was initiated with subcutaneous injections of fondaparinux (7.5 mg) for 5 consecutive days, followed by once daily oral administration of edoxaban (60 mg). After 3 months of treatment, a regression of thrombotic clots was shown. Three months later, the remaining clots disappeared, leaving only mural thrombi; no bleeding complications were observed during the treatment period. CONCLUSION: The anticoagulant treatment with subcutaneous fondaparinux and subsequently with oral edoxaban was effective for treating extensive deep vein thrombosis. PMID- 27468259 TI - Editorial: Unraveling Neuroprotective and Neurodegenerative Signals in Neurodegeneration. PMID- 27468258 TI - Post-exercise branched chain amino acid supplementation does not affect recovery markers following three consecutive high intensity resistance training bouts compared to carbohydrate supplementation. AB - BACKGROUND: Amino acid supplementation has been shown to potentially reduced exercise-induced muscle soreness. Thus, the purpose of this study was to examine if branched chain amino acid and carbohydrate (BCAACHO) versus carbohydrate-only sports drink (CHO) supplementation attenuated markers of muscle damage while preserving performance markers following 3 days of intense weight training. METHODS: Healthy resistance-trained males (n = 30) performed preliminary testing (T1) whereby they: 1) donated a baseline blood draw, 2) performed knee extensor dynamometry to obtain peak quadriceps isometric and isokinetic torque as well as electromyography (EMG) activity at 60 degrees /s and 120 degrees /s, and 3) performed a one repetition maximum (1RM) barbell back squat. The following week participants performed 10 sets x 5 repetitions at 80 % of their 1RM barbell back squat for 3 consecutive days and 48 h following the third lifting bout participants returned for (T2) testing whereby they repeated the T1 battery. Immediately following and 24 h after the three lifting bouts, participants were randomly assigned to consume one of two commercial products in 600 mL of tap water: 1) BCAAs and CHO (3 g/d L-leucine, 1 g/d L-isoleucine and 2 g/d L-valine with 2 g of CHO; n = 15), or 2) 42 g of CHO only (n = 15). Additionally, venous blood was drawn 24 h following the first and second lifting bouts and 48 h following the third bout to assess serum myoglobin concentrations, and a visual analog scale was utilized prior, during, and after the 3-d protocol to measure subjective perceptions of muscular soreness. RESULTS: There were similar decrements in 1RM squat strength and isokinetic peak torque measures in the BCAA CHO and CHO groups. Serum myoglobin concentrations (p = 0.027) and perceived muscle soreness (p < 0.001) increased over the intervention regardless of supplementation. A group*time interaction was observed for monocyte percentages (p = 0.01) whereby BCAA-CHO supplementation attenuated increases in this variable over the duration of the protocol compared to CHO supplementation. CONCLUSION: BCAA-CHO supplementation did not reduce decrements in lower body strength or improve select markers of muscle damage/soreness compared to CHO supplementation over three consecutive days of intense lower-body training. PMID- 27468260 TI - APOE2 Is Associated with Spatial Navigational Strategies and Increased Gray Matter in the Hippocampus. AB - The Apolipoprotein E (APOE) gene has a strong association with Alzheimer's disease (AD). The epsilon4 allele is a well-documented genetic risk factor of AD. In contrast, the epsilon2 allele of the APOE gene is known to be protective against AD. Much of the focus on the APOE gene has been on the epsilon4 allele in both young and older adults and few studies have looked into the cognitive and brain structure correlates of the epsilon2 allele, especially in young adults. In the current study, we investigated the relationship between APOE genotype, navigation behavior, and hippocampal gray matter in healthy young adults. One hundred and twenty-four healthy young adults were genotyped and tested on the 4on8 virtual maze, a task that allows for the assessment of navigation strategy. The task assesses the spontaneous use of either a hippocampus-dependent spatial strategy or a caudate nucleus-dependent response strategy. Of the 124 participants, 37 underwent structural magnetic resonance imaging (MRI). We found that epsilon2 carriers use a hippocampus-dependent spatial strategy to a greater extent than epsilon3 homozygous individuals and epsilon4 carriers. We also found that APOE epsilon2 allele carriers have more gray matter in the hippocampus compared to epsilon3 homozygous individuals and epsilon4 carriers. Our findings suggest that the protective effects of the epsilon2 allele may, in part, be expressed through increased hippocampus gray matter and increased use of hippocampus-dependent spatial strategies. The current article demonstrates the relationship between brain structure, navigation behavior, and APOE genotypes in healthy young adults. PMID- 27468261 TI - Brain Decoding-Classification of Hand Written Digits from fMRI Data Employing Bayesian Networks. AB - We are frequently exposed to hand written digits 0-9 in today's modern life. Success in decoding-classification of hand written digits helps us understand the corresponding brain mechanisms and processes and assists seriously in designing more efficient brain-computer interfaces. However, all digits belong to the same semantic category and similarity in appearance of hand written digits makes this decoding-classification a challenging problem. In present study, for the first time, augmented naive Bayes classifier is used for classification of functional Magnetic Resonance Imaging (fMRI) measurements to decode the hand written digits which took advantage of brain connectivity information in decoding classification. fMRI was recorded from three healthy participants, with an age range of 25-30. Results in different brain lobes (frontal, occipital, parietal, and temporal) show that utilizing connectivity information significantly improves decoding-classification and capability of different brain lobes in decoding classification of hand written digits were compared to each other. In addition, in each lobe the most contributing areas and brain connectivities were determined and connectivities with short distances between their endpoints were recognized to be more efficient. Moreover, data driven method was applied to investigate the similarity of brain areas in responding to stimuli and this revealed both similarly active areas and active mechanisms during this experiment. Interesting finding was that during the experiment of watching hand written digits, there were some active networks (visual, working memory, motor, and language processing), but the most relevant one to the task was language processing network according to the voxel selection. PMID- 27468262 TI - Probabilistic Models and Generative Neural Networks: Towards an Unified Framework for Modeling Normal and Impaired Neurocognitive Functions. AB - Connectionist models can be characterized within the more general framework of probabilistic graphical models, which allow to efficiently describe complex statistical distributions involving a large number of interacting variables. This integration allows building more realistic computational models of cognitive functions, which more faithfully reflect the underlying neural mechanisms at the same time providing a useful bridge to higher-level descriptions in terms of Bayesian computations. Here we discuss a powerful class of graphical models that can be implemented as stochastic, generative neural networks. These models overcome many limitations associated with classic connectionist models, for example by exploiting unsupervised learning in hierarchical architectures (deep networks) and by taking into account top-down, predictive processing supported by feedback loops. We review some recent cognitive models based on generative networks, and we point out promising research directions to investigate neuropsychological disorders within this approach. Though further efforts are required in order to fill the gap between structured Bayesian models and more realistic, biophysical models of neuronal dynamics, we argue that generative neural networks have the potential to bridge these levels of analysis, thereby improving our understanding of the neural bases of cognition and of pathologies caused by brain damage. PMID- 27468263 TI - Embarrassingly Parallel Acceleration of Global Tractography via Dynamic Domain Partitioning. AB - Global tractography estimates brain connectivity by organizing signal-generating fiber segments in an optimal configuration that best describes the measured diffusion-weighted data, promising better stability than local greedy methods with respect to imaging noise. However, global tractography is computationally very demanding and requires computation times that are often prohibitive for clinical applications. We present here a reformulation of the global tractography algorithm for fast parallel implementation amendable to acceleration using multi core CPUs and general-purpose GPUs. Our method is motivated by the key observation that each fiber segment is affected by a limited spatial neighborhood. In other words, a fiber segment is influenced only by the fiber segments that are (or can potentially be) connected to its two ends and also by the diffusion-weighted signal in its proximity. This observation makes it possible to parallelize the Markov chain Monte Carlo (MCMC) algorithm used in the global tractography algorithm so that concurrent updating of independent fiber segments can be carried out. Experiments show that the proposed algorithm can significantly speed up global tractography, while at the same time maintain or even improve tractography performance. PMID- 27468265 TI - The Indirect Effect of Age Group on Switch Costs via Gray Matter Volume and Task Related Brain Activity. AB - Healthy aging simultaneously affects brain structure, brain function, and cognition. These effects are often investigated in isolation ignoring any relationships between them. It is plausible that age related declines in cognitive performance are the result of age-related structural and functional changes. This straightforward idea is tested in within a conceptual research model of cognitive aging. The current study tested whether age-related declines in task-performance were explained by age-related differences in brain structure and brain function using a task-switching paradigm in 175 participants. Sixty three young and 112 old participants underwent MRI scanning of brain structure and brain activation. The experimental task was an executive context dual task with switch costs in response time as the behavioral measure. A serial mediation model was applied voxel-wise throughout the brain testing all pathways between age group, gray matter volume, brain activation and increased switch costs, worsening performance. There were widespread age group differences in gray matter volume and brain activation. Switch costs also significantly differed by age group. There were brain regions demonstrating significant indirect effects of age group on switch costs via the pathway through gray matter volume and brain activation. These were in the bilateral precuneus, bilateral parietal cortex, the left precentral gyrus, cerebellum, fusiform, and occipital cortices. There were also significant indirect effects via the brain activation pathway after controlling for gray matter volume. These effects were in the cerebellum, occipital cortex, left precentral gyrus, bilateral supramarginal, bilateral parietal, precuneus, middle cingulate extending to medial superior frontal gyri and the left middle frontal gyri. There were no significant effects through the gray matter volume alone pathway. These results demonstrate that a large proportion of the age group effect on switch costs can be attributed to individual differences in gray matter volume and brain activation. Therefore, age related neural effects underlying cognitive control are a complex interaction between brain structure and function. Furthermore, the analyses demonstrate the feasibility of utilizing multiple neuroimaging modalities within a conceptual research model of cognitive aging. PMID- 27468267 TI - The Development and Validation of a Generic Instrument, QoDoS, for Assessing the Quality of Decision Making. AB - INTRODUCTION: The impact of decision-making during the development and the regulatory review of medicines greatly influences the delivery of new medicinal products. Currently, there is no generic instrument that can be used to assess the quality of decision-making. This study describes the development of the Quality of Decision-Making Orientation Scheme QoDoS((c)) instrument for appraising the quality of decision-making. METHODS: Semi-structured interviews about decision-making were carried out with 29 senior decision makers from the pharmaceutical industry (10), regulatory authorities (9) and contract research organizations (10). The interviews offered a qualified understanding of the subjective decision-making approach, influences, behaviors and other factors that impact such processes for individuals and organizations involved in the delivery of new medicines. Thematic analysis of the transcribed interviews was carried out using NVivo8(r) software. Content validity was carried out using qualitative and quantitative data by an expert panel, which led to the developmental version of the QoDoS. Further psychometric evaluations were performed, including factor analysis, item reduction, reliability testing and construct validation. RESULTS: The thematic analysis of the interviews yielded a 94-item initial version of the QoDoS((c)) with a 5-point Likert scale. The instrument was tested for content validity using a panel of experts for language clarity, completeness, relevance and scaling, resulting in a favorable agreement by panel members with an intra class correlation coefficient value of 0.89 (95% confidence interval = 0.56, 0.99). A 76-item QoDoS((c)) (version 2) emerged from content validation. Factor analysis produced a 47-item measure with four domains. The 47-item QoDoS((c)) (version 3) showed high internal consistency (n = 120, Cronbach's alpha = 0.89), high reproducibility (n = 20, intra-class correlation = 0.77) and a mean completion time of 10 min. Reliability testing and construct validation was successfully performed. CONCLUSION: The QoDoS((c)) is both reliable and valid for use. It has the potential for extensive use in medicines development by both the pharmaceutical industry and regulatory authorities. The QoDoS((c)) can be used to assess the quality of decision-making and to inform decision makers of the factors that influence decision-making. PMID- 27468266 TI - Older Age Results in Differential Gene Expression after Mild Traumatic Brain Injury and Is Linked to Imaging Differences at Acute Follow-up. AB - Older age consistently relates to a lesser ability to fully recover from a traumatic brain injury (TBI); however, there is limited data to explicate the nature of age-related risks. This study was undertaken to determine the relationship of age on gene-activity following a TBI, and how this biomarker relates to changes in neuroimaging findings. A young group (between the ages of 19 and 35 years), and an old group (between the ages of 60 and 89 years) were compared on global gene-activity within 48 h following a TBI, and then at follow up within 1-week. At each time-point, gene expression profiles, and imaging findings from both magnetic resonance imaging (MRI) and computed tomography were obtained and compared. The young group was found to have greater gene expression of inflammatory regulatory genes at 48 h and 1-week in genes such as basic leucine zipper transcription factor 2 (BACH2), leucine-rich repeat neuronal 3 (LRRN3), and lymphoid enhancer-binding factor 1 (LEF1) compared to the old group. In the old group, there was increased activity in genes within S100 family, including calcium binding protein P (S100P) and S100 calcium binding protein A8 (S100A8), which previous studies have linked to poor recovery from TBI. The old group also had reduced activity of the noggin (NOG) gene, which is a member of the transforming growth factor-beta superfamily and is linked to neurorecovery and neuroregeneration compared to the young group. We link these gene expression findings that were validated to neuroimaging, reporting that in the old group with a MRI finding of TBI-related damage, there was a lesser likelihood to then have a negative MRI finding at follow-up compared to the young group. Together, these data indicate that age impacts gene activity following a TBI, and suggest that this differential activity related to immune regulation and neurorecovery contributes to a lesser likelihood of neuronal recovery in older patients as indicated through neuroimaging. PMID- 27468264 TI - Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline. AB - Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline. PMID- 27468269 TI - The Systemic Changes to Improve Efficiency in Polish Primary Health Care. AB - Primary health care is an important part of any health care system. In highly developed countries it secures the population's most elementary health needs, with particular emphasis on preventive care and early intervention. Polish PHC model is currently undergoing a thorough transformation, associated with the need to adapt to standards designated based on the WHO's criteria, and with reference to the experience of other European countries. The paper describes the process of changes being carried out, in the context of previous experiences of reform relating to the sphere of organization, processes and efficiency. A review and systematization has been made, with regard to the undertaken activities in the field of deregulation and change of legal provisions, which are aimed at achieving the improvement of the efficiency of treatment and resource allocation. A set of recommendations based on expert's discourse have also been provided, with respect to future directions of Polish PHC transformation. PMID- 27468268 TI - Blood Biomarkers for Evaluation of Perinatal Encephalopathy. AB - Recent research in identification of brain injury after trauma shows many possible blood biomarkers that may help identify the fetus and neonate with encephalopathy. Traumatic brain injury shares many common features with perinatal hypoxic-ischemic encephalopathy. Trauma has a hypoxic component, and one of the 1st physiologic consequences of moderate-severe traumatic brain injury is apnea. Trauma and hypoxia-ischemia initiate an excitotoxic cascade and free radical injury followed by the inflammatory cascade, producing injury in neurons, glial cells and white matter. Increased excitatory amino acids, lipid peroxidation products, and alteration in microRNAs and inflammatory markers are common to both traumatic brain injury and perinatal encephalopathy. The blood-brain barrier is disrupted in both leading to egress of substances normally only found in the central nervous system. Brain exosomes may represent ideal biomarker containers, as RNA and protein transported within the vesicles are protected from enzymatic degradation. Evaluation of fetal or neonatal brain derived exosomes that cross the blood-brain barrier and circulate peripherally has been referred to as the "liquid brain biopsy." A multiplex of serum biomarkers could improve upon the current imprecise methods of identifying fetal and neonatal brain injury such as fetal heart rate abnormalities, meconium, cord gases at delivery, and Apgar scores. Quantitative biomarker measurements of perinatal brain injury and recovery could lead to operative delivery only in the presence of significant fetal risk, triage to appropriate therapy after birth and measure the effectiveness of treatment. PMID- 27468270 TI - Modeling Interactions among Individual P2 Receptors to Explain Complex Response Patterns over a Wide Range of ATP Concentrations. AB - Extracellular ATP acts on the P2X family of ligand-gated ion channels and several members of the P2Y family of G protein-coupled receptors to mediate intercellular communication among many cell types including bone-forming osteoblasts. It is known that multiple P2 receptors are expressed on osteoblasts (P2X2,5,6,7 and P2Y1,2,4,6). In the current study, we investigated complex interactions within the P2 receptor network using mathematical modeling. To characterize individual P2 receptors, we extracted data from published studies of overexpressed human and rodent (rat and mouse) receptors and fit their dependencies on ATP concentration using the Hill equation. Next, we examined responses induced by an ensemble of endogenously expressed P2 receptors. Murine osteoblastic cells (MC3T3-E1 cells) were loaded with fluo-4 and stimulated with varying concentrations of extracellular ATP. Elevations in the concentration of cytosolic free calcium ([Ca(2+)]i) were monitored by confocal microscopy. Dependence of the calcium response on ATP concentration exhibited a complex pattern that was not explained by the simple addition of individual receptor responses. Fitting the experimental data with a combination of Hill equations from individual receptors revealed that P2Y1 and P2X7 mediated the rise in [Ca(2+)]i at very low and high ATP concentrations, respectively. Interestingly, to describe responses at intermediate ATP concentrations, we had to assume that a receptor with a K 1/2 in that range (e.g. P2Y4 or P2X5) exerts an inhibitory effect. This study provides new insights into the interactions among individual P2 receptors in producing an ensemble response to extracellular ATP. PMID- 27468271 TI - Belief about Nicotine Modulates Subjective Craving and Insula Activity in Deprived Smokers. AB - Little is known about the specific neural mechanisms through which cognitive factors influence craving and associated brain responses, despite the initial success of cognitive therapies in treating drug addiction. In this study, we investigated how cognitive factors such as beliefs influence subjective craving and neural activities in nicotine-addicted individuals using model-based functional magnetic resonance imaging (fMRI) and neuropharmacology. Deprived smokers (N = 24) participated in a two-by-two balanced placebo design, which crossed beliefs about nicotine (told "nicotine" vs. told "no nicotine") with the nicotine content in a cigarette (nicotine vs. placebo) which participants smoked immediately before performing a fMRI task involving reward learning. Subjects' reported craving was measured both before smoking and after the fMRI session. We found that first, in the presence of nicotine, smokers demonstrated significantly reduced craving after smoking when told "nicotine in cigarette" but showed no change in craving when told "no nicotine." Second, neural activity in the insular cortex related to craving was only significant when smokers were told "nicotine" but not when told "no nicotine." Both effects were absent in the placebo condition. Third, insula activation related to computational learning signals was modulated by belief about nicotine regardless of nicotine's presence. These results suggest that belief about nicotine has a strong impact on subjective craving and insula responses related to both craving and learning in deprived smokers, providing insights into the complex nature of belief-drug interactions. PMID- 27468272 TI - Abstract Mindsets Increase Believability of Spatially Distant Online Messages. AB - Growing evidence from online credibility research reveals that online users rely on heuristic processes to evaluate the credibility of online information. The current paper, which is based on the construal level theory (CLT), proposes that congruency between the psychological distance of a stimulus and the way it is mentally construed can act as a heuristic for believability. According to CLT, psychologically close (e.g., spatially, temporally, socially) stimuli are represented concretely whereas psychologically distant stimuli are represented abstractly. The level of mental construals and the psychological distance of information have been shown to influence people's truth judgments in offline contexts. This study tests whether congruency between the construal level of people's mindsets (abstract vs. concrete) and the psychological distance implied in an online message (far vs. close) enhances message believability. By partially confirming CLT predictions, we found that believability of an online news item about a distant location increased when people maintained an abstract mindset rather than a concrete one. The effect of a concrete mindset on believability was not significant for the close psychological distance condition. Our findings provide initial evidence that congruency between the construal level of people's mindsets and psychological distance cues in online messages can act as a heuristic for believability. We discuss the potential of applying the CLT framework to the growing literature on online cognitive heuristics in the area of online information credibility. PMID- 27468273 TI - Blurred lines: Performance Enhancement, Common Mental Disorders and Referral in the U.K. Athletic Population. AB - Through the awareness-raising efforts of several high-profile current and former athletes, the issue of common mental disorders (CMD) in this population is gaining increasing attention from researchers and practitioners alike. Yet the prevalence is unclear and most likely, under-reported. Whilst the characteristics of the sporting environment may generate CMD within the athletic population, it also may exacerbate pre-existing conditions, and hence it is not surprising that sport psychology and sport science practitioners are anecdotally reporting increased incidences of athletes seeking support for CMD. In a population where there are many barriers to reporting and seeking help for CMD, due in part to the culture of the high performance sporting environment, anecdotal reports suggest that those athletes asking for help are approaching personnel who they are most comfortable talking to. In some cases, this may be a sport scientist, the sport psychologist or sport psychology consultant. Among personnel in the sporting domain, there is a perception that the sport psychologist or sport psychology consultant is best placed to assist athletes seeking assistance for CMD. However, sport psychology as a profession is split by two competing philosophical perspectives; one of which suggests that sport psychologists should work exclusively with athletes on performance enhancement, and the other views the athlete more holistically and accepts that their welfare may directly impact on their performance. To add further complication, the development of the profession of sport psychology varies widely between countries, meaning that practice in this field is not always clearly defined. This article examines case studies that illustrate the blurred lines in applied sport psychology practice, highlighting challenges with the process of referral in the U.K. athletic population. The article concludes with suggestions for ensuring the field of applied sport psychology is continually evolving and reconfiguring to ensure that it continues to meet the demands of its clients. PMID- 27468274 TI - State Anxiety Subjective Imbalance and Handicap in Vestibular Schwannoma. AB - INTRODUCTION: Evidence is emerging for a significant clinical and neuroanatomical relationship between balance and anxiety. Research has suggested a potentially priming effect with anxiety symptoms predicting a worsening of balance function in patients with underlying balance dysfunction. We propose to show that a vestibular stimulus is responsible for an increase in state anxiety, and there is a relationship between increased state anxiety and worsening balance function. AIMS: (1) To quantify state anxiety following a vestibular stimulus in patients with a chronic vestibular deficit. (2) To determine if state anxiety during a vestibular stimulus would correlate with the severity of chronic balance symptoms and handicap. METHODS: Two separate cohorts of vestibular schwannoma (VS) patients underwent vestibular tests (electronystagmography, cervical and ocular vestibular evoked myogenic potentials, and caloric responses) and questionnaire assessments [vertigo handicap questionnaire (VHQ), vertigo symptom scale (VSS), and state-trait anxiety inventory (STAIY)]. Fifteen post-resection VS patients, with complete unilateral vestibular deafferentation, were assessed at a minimum of 6 months after surgery in Experiment 1 (Aim 1). Forty-five patients with VS in situ formed the cohort for Experiment 2 (Aim 2). Experiment 1: VS subjects (N = 15) with a complete post-resection unilateral vestibular deafferentation completed a state anxiety questionnaire before caloric assessment and again afterward with the point of maximal vertigo as the reference (Aim 1). Experiment 2: state anxiety measured at the point of maximal vertigo following a caloric assessment was compared between two groups of patients with VS in situ presenting with balance symptoms (Group 1, N = 26) and without balance symptoms (Group 2, N = 11) (Aim 2). The presence of balance symptoms was defined as having a positive score on the VSS-VER. RESULTS: In Experiment 1, a significant difference (p < 0.01) was found when comparing STAIY at baseline and at the peak of the subjective vertiginous response in post-resection patients with a unilateral vestibular deafferentation. In Experiment 2, VS in situ patients with balance symptoms had significantly worse state anxiety at the peak vertiginous response than patients without balance symptoms (p < 0.001), as did patients with a balance-related handicap (p < 0.001). CONCLUSION: Anxiety symptoms during a vestibular stimulus may contribute to a priming effect that could explain worsening balance function. PMID- 27468275 TI - Distinguishing Radiculopathies from Mononeuropathies. AB - Identifying "where is the lesion" is particularly important in the approach to the patient with focal dysfunction where a peripheral localization is suspected. This article outlines a methodical approach to the neuromuscular patient in distinguishing focal neuropathies versus radiculopathies, both of which are common presentations to the neurology clinic. This approach begins with evaluation of the sensory examination to determine whether there are irritative or negative sensory signs in a peripheral nerve or dermatomal distribution. This is followed by evaluation of deep tendon reflexes to evaluate if differential hyporeflexia can assist in the two localizations. Finally, identification of weak muscle groups unique to a nerve or myotomal pattern in the proximal and distal extremities can most reliably assist in a precise localization. The article concludes with an application of the described method to the common scenario of distinguishing radial neuropathy versus C7 radiculopathy in the setting of a wrist drop and provides additional examples for self-evaluation and reference. PMID- 27468276 TI - Influence of Butylated Hydroxyanisole on the Growth, Hyphal Morphology, and the Biosynthesis of Fumonisins in Fusarium proliferatum. AB - Fusarium proliferatum as a common fungus pathogen in foods can produce toxic fumonisins, which can cause animal diseases and increase risks of human cancers. On contrary, butylated hydroxyanisole (BHA) as a synthetic antioxidant offers a clue for preventing growth of fungal species and inhibiting production of mycotoxins. Unfortunately, information of the inhibitory mechanism of BHA on Fusarium species is still limited. In this study, influence of BHA treatment on growth and inhibition of fumonisin production in relation to the expression of the fumonisin biosynthesis-related genes of the F. proliferatum ZYF was investigated, which revealed that BHA had a negative influence on growth and fumonisin production of F. proliferatum. To further elucidate the mechanism of BHA on the growth of F. proliferatum, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to examine the F. proliferatum hyphae. The BHA treatment induced the loss of cytoplasm and cellular constituents, as well as distortion of mycelia, but it did not directly degrade the fumonisin. Furthermore, the BHA treatment markedly inhibited the expressions of FUM1 (a polyketide synthase encoding gene) and FUM8 (an aminotransferase encoding gene) genes, which resulted in the depression of metabolic pathway of F. proliferatum. The transcriptional analyses of the FUM1 and FUM8 genes confirmed a correlation between the fumonisin production and its gene expression. This study provided some insights into mechanisms of production of fumonisin and feasible prevention to reduce fumonisin contamination in favor of human and animal health. PMID- 27468278 TI - Region 4 of Rhizobium etli Primary Sigma Factor (SigA) Confers Transcriptional Laxity in Escherichia coli. AB - Sigma factors are RNA polymerase subunits engaged in promoter recognition and DNA strand separation during transcription initiation in bacteria. Primary sigma factors are responsible for the expression of housekeeping genes and are essential for survival. RpoD, the primary sigma factor of Escherichia coli, a gamma-proteobacteria, recognizes consensus promoter sequences highly similar to those of some alpha-proteobacteria species. Despite this resemblance, RpoD is unable to sustain transcription from most of the alpha-proteobacterial promoters tested so far. In contrast, we have found that SigA, the primary sigma factor of Rhizobium etli, an alpha-proteobacteria, is able to transcribe E. coli promoters, although it exhibits only 48% identity (98% coverage) to RpoD. We have called this the transcriptional laxity phenomenon. Here, we show that SigA partially complements the thermo-sensitive deficiency of RpoD285 from E. coli strain UQ285 and that the SigA region sigma4 is responsible for this phenotype. Sixteen out of 74 residues (21.6%) within region sigma4 are variable between RpoD and SigA. Mutating these residues significantly improves SigA ability to complement E. coli UQ285. Only six of these residues fall into positions already known to interact with promoter DNA and to comprise a helix-turn-helix motif. The remaining variable positions are located on previously unexplored sites inside region sigma4, specifically into the first two alpha-helices of the region. Neither of the variable positions confined to these helices seem to interact directly with promoter sequence; instead, we adduce that these residues participate allosterically by contributing to correct region folding and/or positioning of the HTH motif. We propose that transcriptional laxity is a mechanism for ensuring transcription in spite of naturally occurring mutations from endogenous promoters and/or horizontally transferred DNA sequences, allowing survival and fast environmental adaptation of alpha-proteobacteria. PMID- 27468280 TI - A Novel Tightly Regulated Gene Expression System for the Human Intestinal Symbiont Bacteroides thetaiotaomicron. AB - There is considerable interest in studying the function of Bacteroides species resident in the human gastrointestinal (GI)-tract and the contribution they make to host health. Reverse genetics and protein expression techniques, such as those developed for well-characterized Escherichia coli cannot be applied to Bacteroides species as they and other members of the Bacteriodetes phylum have unique promoter structures. The availability of useful Bacteroides-specific genetic tools is therefore limited. Here we describe the development of an effective mannan-controlled gene expression system for Bacteroides thetaiotaomicron containing the mannan-inducible promoter-region of an alpha-1,2 mannosidase gene (BT_3784), a ribosomal binding site designed to modulate expression, a multiple cloning site to facilitate the cloning of genes of interest, and a transcriptional terminator. Using the Lactobacillus pepI as a reporter gene, mannan induction resulted in an increase of reporter activity in a time- and concentration-dependent manner with a wide range of activity. The endogenous BtcepA cephalosporinase gene was used to demonstrate the suitability of this novel expression system, enabling the isolation of a His-tagged version of BtCepA. We have also shown with experiments performed in mice that the system can be induced in vivo in the presence of an exogenous source of mannan. By enabling the controlled expression of endogenous and exogenous genes in B. thetaiotaomicron this novel inducer-dependent expression system will aid in defining the physiological role of individual genes and the functional analyses of their products. PMID- 27468279 TI - Controlling the Microbiome: Microhabitat Adjustments for Successful Biocontrol Strategies in Soil and Human Gut. PMID- 27468277 TI - Ecology of Nitrogen Fixing, Nitrifying, and Denitrifying Microorganisms in Tropical Forest Soils. AB - Soil microorganisms play important roles in nitrogen cycling within forest ecosystems. Current research has revealed that a wider variety of microorganisms, with unexpected diversity in their functions and phylogenies, are involved in the nitrogen cycle than previously thought, including nitrogen-fixing bacteria, ammonia-oxidizing bacteria and archaea, heterotrophic nitrifying microorganisms, and anammox bacteria, as well as denitrifying bacteria, archaea, and fungi. However, the vast majority of this research has been focused in temperate regions, and relatively little is known regarding the ecology of nitrogen-cycling microorganisms within tropical and subtropical ecosystems. Tropical forests are characterized by relatively high precipitation, low annual temperature fluctuation, high heterogeneity in plant diversity, large amounts of plant litter, and unique soil chemistry. For these reasons, regulation of the nitrogen cycle in tropical forests may be very different from that of temperate ecosystems. This is of great importance because of growing concerns regarding the effect of land use change and chronic-elevated nitrogen deposition on nitrogen cycling processes in tropical forests. In the context of global change, it is crucial to understand how environmental factors and land use changes in tropical ecosystems influence the composition, abundance and activity of key players in the nitrogen cycle. In this review, we synthesize the limited currently available information regarding the microbial communities involved in nitrogen fixation, nitrification and denitrification, to provide deeper insight into the mechanisms regulating nitrogen cycling in tropical forest ecosystems. We also highlight the large gaps in our understanding of microbially mediated nitrogen processes in tropical forest soils and identify important areas for future research. PMID- 27468281 TI - Dual Repression of the Multidrug Efflux Pump CmeABC by CosR and CmeR in Campylobacter jejuni. AB - During transmission and intestinal colonization, Campylobacter jejuni, a major foodborne human pathogen, experiences oxidative stress. CosR, a response regulator in C. jejuni, modulates the oxidative stress response and represses expression of the CmeABC multidrug efflux pump. CmeABC, a key component in resistance to toxic compounds including antimicrobials and bile salts, is also under negative regulation by CmeR, a TetR family transcriptional regulator. How CosR and CmeR interact in binding to the cmeABC promoter and how CosR senses oxidative stress are still unknown. To answer these questions, we conducted various experiments utilizing electrophoretic mobility shift assays and transcriptional fusion assays. CosR and CmeR bound independently to two separate sites of the cmeABC promoter, simultaneously repressing cmeABC expression. This dual binding of CosR and CmeR is optimal with a 17 base pair space between the two binding sites as mutations that shortened the distance between the binding sites decreased binding by CmeR and enhanced cmeABC expression. Additionally, the single cysteine residue (C218) of CosR was sensitive to oxidation, which altered the DNA-binding activity of CosR and dissociated CosR from the cmeABC promoter as determined by electrophoretic mobility shift assay. Replacement of C218 with serine rendered CosR insensitive to oxidation, suggesting a potential role of C218 in sensing oxidative stress and providing a possible mechanism for CosR mediated response to oxidative stress. These findings reveal a dual regulatory role of CosR and CmeR in modulating cmeABC expression and suggest a potential mechanism that may explain overexpression of cmeABC in response to oxidative stress. Differential expression of cmeABC mediated by CmeR and CosR in response to different signals may facilitate adaptation of Campylobacter to various environmental conditions. PMID- 27468283 TI - The Interaction of Immune Priming with Different Modes of Disease Transmission. PMID- 27468282 TI - Highly Effective Inhibition of Biofilm Formation by the First Metagenome-Derived AI-2 Quenching Enzyme. AB - Bacterial cell-cell communication (quorum sensing, QS) represents a fundamental process crucial for biofilm formation, pathogenicity, and virulence allowing coordinated, concerted actions of bacteria depending on their cell density. With the widespread appearance of antibiotic-resistance of biofilms, there is an increasing need for novel strategies to control harmful biofilms. One attractive and most likely effective approach is to target bacterial communication systems for novel drug design in biotechnological and medical applications. In this study, metagenomic large-insert libraries were constructed and screened for QS interfering activities (quorum quenching, QQ) using recently established reporter strains. Overall, 142 out of 46,400 metagenomic clones were identified to interfere with acyl-homoserine lactones (AHLs), 13 with autoinducer-2 (AI-2). Five cosmid clones with highest simultaneous interfering activities were further analyzed and the respective open reading frames conferring QQ activities identified. Those showed homologies to bacterial oxidoreductases, proteases, amidases and aminotransferases. Evaluating the ability of the respective purified QQ-proteins to prevent biofilm formation of several model systems demonstrated highest inhibitory effects of QQ-2 using the crystal violet biofilm assay. This was confirmed by heterologous expression of the respective QQ proteins in Klebsiella oxytoca M5a1 and monitoring biofilm formation in a continuous flow cell system. Moreover, QQ-2 chemically immobilized to the glass surface of the flow cell effectively inhibited biofilm formation of K. oxytoca as well as clinical K. pneumoniae isolates derived from patients with urinary tract infections. Indications were obtained by molecular and biochemical characterizations that QQ-2 represents an oxidoreductase most likely reducing the signaling molecules AHL and AI-2 to QS-inactive hydroxy-derivatives. Overall, we propose that the identified novel QQ-2 protein efficiently inhibits AI-2 modulated biofilm formation by modifying the signal molecule; and thus appears particularly attractive for medical and biotechnological applications. PMID- 27468284 TI - Endonuclease Restriction-Mediated Real-Time Polymerase Chain Reaction: A Novel Technique for Rapid, Sensitive and Quantitative Detection of Nucleic-Acid Sequence. AB - The article reported a novel methodology for real-time PCR analysis of nucleic acids, termed endonuclease restriction-mediated real-time polymerase chain reaction (ET-PCR). Just like PCR, ET-PCR only required one pair of primers. A short sequence, which was recognized by restriction enzyme BstUI, was attached to the 5' end of the forward (F) or reverse (R) PCR primer, and the new F or R primer was named EF or ER. EF/ER was labeled at the 5' end with a reporter dye and in the middle with a quenching dye. BstUI cleaves the newly synthesized double-stranded terminal sequences (5' end recognition sequences and their complementary sequences) during the extension phase, which separates the reporter molecule from the quenching dye, leading to a gain of fluorescence signal. This process is repeated in each amplification cycle and unaffected the exponential synthesis of the PCR amplification. ET-PCR allowed real-time analysis of single or multiple targets in a single vessel, and provided the reproducible quantitation of nucleic acids. The analytical sensitivity and specificity of ET PCR were successfully evaluated, detecting down to 250 fg of genomic DNA per tube of target pathogen DNA examined, and the positive results were generated in a relatively short period. Moreover, the practical application of ET-PCR for simultaneous detection of multiple target pathogens was also demonstrated in artificially contaminated blood samples. In conclusion, due to the technique's simplicity of design, reproducible data and low contamination risk, ET-PCR assay is an appealing alternative to conventional approaches currently used for real time nucleic acid analysis. PMID- 27468285 TI - Biogeographic Distribution Patterns of Bacteria in Typical Chinese Forest Soils. AB - Microbes are widely distributed in soils and play a very important role in nutrient cycling and ecosystem services. To understand the biogeographic distribution of forest soil bacteria, we collected 115 soil samples in typical forest ecosystems across eastern China to investigate their bacterial community compositions using Illumina MiSeq high throughput sequencing based on 16S rRNA. We obtained 4,667,656 sequences totally and more than 70% of these sequences were classified into five dominant groups, i.e., Actinobacteria, Acidobacteria, Alphaproteobacteria, Verrucomicrobia, and Planctomycetes (relative abundance >5%). The bacterial diversity showed a parabola shape along latitude and the maximum diversity appeared at latitudes between 33.50 degrees N and 40 degrees N, an area characterized by warm-temperate zones and moderate temperature, neutral soil pH and high substrate availability (soil C and N) from dominant deciduous broad-leaved forests. Pairwise dissimilarity matrix in bacterial community composition showed that bacterial community structure had regional similarity and the latitude of 30 degrees N could be used as the dividing line between southern and northern forest soils. Soil properties and climate conditions (MAT and MAP) greatly accounted for the differences in the soil bacterial structure. Among all soil parameters determined, soil pH predominantly affected the diversity and composition of the bacterial community, and soil pH = 5 probably could be used as a threshold below which soil bacterial diversity might decline and soil bacterial community structure might change significantly. Moreover, soil exchangeable cations, especially Ca(2+) (ECa(2+)) and some other soil variables were also closely related to bacterial community structure. The selected environmental variables (21.11%) explained more of the bacterial community variation than geographic distance (15.88%), indicating that the edaphic properties and environmental factors played a more important role than geographic dispersal limitation in determining the bacterial community structure in Chinese forest soils. PMID- 27468286 TI - Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens. AB - Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4(+) or CD8(+) T cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b(+) myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b(+) myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID- 27468287 TI - Glutamine synthetase in Durum Wheat: Genotypic Variation and Relationship with Grain Protein Content. AB - Grain protein content (GPC), is one of the most important trait in wheat and its characterized by a very complex genetic control. The identification of wheat varieties with high GPC (HGPC), as well as the characterization of central enzymes involved in these processes, are important for more sustainable agricultural practices. In this study, we focused on Glutamine synthetase (GS) as a candidate to study GPC in wheat. We analyzed GS expression and its enzymatic activity in different tissues and phenological stages in 10 durum wheat genotypes with different GPC. Although each genotype performed quite differently from the others, both because their genetic variability and their adaptability to specific environmental conditions, the highest GS activity and expression were found in genotypes with HGPC and vice versa the lowest ones in genotypes with low GPC (LGPC). Moreover, in genotypes contrasting in GPC bred at different nitrogen regimes (0, 60, 140 N Unit/ha) GS behaved differently in diverse organs. Nitrogen supplement increased GS expression and activity in roots of all genotypes, highlighting the key role of this enzyme in nitrogen assimilation and ammonium detoxification in roots. Otherwise, nitrogen treatments decreased GS expression and activity in the leaves of HGPC genotypes and did not affect GS in the leaves of LGPC genotypes. Finally, no changes in GS and soluble protein content occurred at the filling stage in the caryopses of all analyzed genotypes. PMID- 27468289 TI - Seasonal Shift in Climatic Limiting Factors on Tree Transpiration: Evidence from Sap Flow Observations at Alpine Treelines in Southeast Tibet. AB - Alpine and northern treelines are primarily controlled by low temperatures. However, little is known about the impact of low soil temperature on tree transpiration at treelines. We aim to test the hypothesis that in cold-limited forests, the main limiting factors for tree transpiration switch from low soil temperature before summer solstice to atmospheric evaporative demand after summer solstice, which generally results in low transpiration in the early growing season. Sap flow, meteorological factors and predawn needle water potential were continuously monitored throughout one growing season across Smith fir (Abies georgei var. smithii) and juniper (Juniperus saltuaria) treelines in southeast Tibet. Sap flow started in early May and corresponded to a threshold mean air temperature of 0 degrees C. Across tree species, transpiration was mainly limited by low soil temperature prior to the summer solstice but by vapor pressure deficit and solar radiation post-summer solstice, which was further confirmed on a daily scale. As a result, tree transpiration for both tree species was significantly reduced in the pre-summer solstice period as compared to post summer solstice, resulting in a lower predawn needle water potential for Smith fir trees in the early growing season. Our data supported the hypothesis, suggesting that tree transpiration mainly responds to soil temperature variations in the early growing season. The results are important for understanding the hydrological response of cold-limited forest ecosystems to climate change. PMID- 27468288 TI - Phenotypic and Marker-Assisted Genetic Enhancement of Parental Lines of Rajalaxmi, an Elite Rice Hybrid. AB - The cytoplasmic male sterile line system comprising CRMS 32A and its maintainer line CRMS 32B is a popular choice for the development of new hybrids in India as CRMS 32A, having Kalinga 1 cytoplasm (other than WA), is a viable alternative to WA cytoplasm. However, both lines are susceptible to bacterial blight (BB), a major disease on rice. As enhancement of host plant resistance is the most effective and economical strategy to control this disease, four resistance genes (Xa4, xa5, xa13, and Xa21) were transferred from a BB pyramid line of IR64, into the A and B lines using a marker-assisted backcrossing (MAB) breeding strategy. During the transfer of genes into CRMS 32B, foreground selection was applied using markers associated with the genes, and plants having resistance alleles of the donor, are selected. Selection for morphological and quality traits was practiced to select plants similar to the recurrent parent. The four gene and three gene pyramid lines exhibited high levels of resistance against the BB pathogen when challenged with eight virulent isolates. Using genome wide based SSR markers for background selection, pyramids having >95% of the recurrent parent genome were identified. With CRMS 32B gene pyramid as donor, the four resistance genes were transferred into the A line through repeated backcrosses and the A line pyramids also exhibited high level of resistance against BB. Through a combination of selection at phenotypic and molecular levels, four BB resistance genes were successfully introduced into two parental lines (CRMS 32 B and A) of Rajalaxmi, an elite popular hybrid. The pyramided B lines did exhibit high levels of resistance against BB. Selection for morphological and quality traits and background selection hastened the recovery of the recurrent parent genome in the recombinants. Through repeated backcrosses, all the four resistance genes were transferred to CRMS 32A and test crosses suggest that the maintenance ability of the improved CRMS 32B lines is intact. These improved maintainer and CMS lines can directly be used in hybrid rice breeding and the new hybrids can play an important role in sustainable rice production in India. PMID- 27468290 TI - Low Temperature and Short-Term High-CO2 Treatment in Postharvest Storage of Table Grapes at Two Maturity Stages: Effects on Transcriptome Profiling. AB - Table grapes (Vitis vinifera cv. Cardinal) are highly perishable and their quality deteriorates during postharvest storage at low temperature mainly because of sensitivity to fungal decay and senescence of rachis. The application of a 3 day CO2 treatment (20 kPa CO2 + 20 kPa O2 + 60 kPa N2) at 0 degrees C reduced total decay and retained fruit quality in early and late-harvested table grapes during postharvest storage. In order to study the transcriptional responsiveness of table grapes to low temperature and high CO2 levels in the first stage of storage and how the maturity stage affect these changes, we have performed a comparative large-scale transcriptional analysis using the custom-made GrapeGen GeneChip(r). In the first stage of storage, low temperature led to a significantly intense change in grape skin transcriptome irrespective of fruit maturity, although there were different changes within each stage. In the case of CO2 treated samples, in comparison to fruit at time zero, only slight differences were observed. Functional enrichment analysis revealed that major modifications in the transcriptome profile of early- and late-harvested grapes stored at 0 degrees C are linked to biotic and abiotic stress-responsive terms. However, in both cases there is a specific reprogramming of the transcriptome during the first stage of storage at 0 degrees C in order to withstand the cold stress. Thus, genes involved in gluconeogenesis, photosynthesis, mRNA translation and lipid transport were up-regulated in the case of early-harvested grapes, and genes related to protein folding stability and intracellular membrane trafficking in late-harvested grapes. The beneficial effect of high CO2 treatment maintaining table grape quality seems to be an active process requiring the induction of several transcription factors and kinases in early-harvested grapes, and the activation of processes associated to the maintenance of energy in late-harvested grapes. PMID- 27468291 TI - Ascorbate-Deficient vtc2 Mutants in Arabidopsis Do Not Exhibit Decreased Growth. AB - In higher plants the L-galactose pathway represents the major route for ascorbate biosynthesis. The first committed step of this pathway is catalyzed by the enzyme GDP-L-galactose phosphorylase and is encoded by two paralogs in Arabidopsis - VITAMIN C2 (VTC2) and VTC5. The first mutant of this enzyme, vtc2-1, isolated via an EMS mutagenesis screen, has approximately 20-30% of wildtype ascorbate levels and has been reported to have decreased growth under standard laboratory conditions. Here, we show that a T-DNA insertion into the VTC2 causes a similar reduction in ascorbate levels, but does not greatly affect plant growth. Subsequent segregation analysis revealed the growth defects of vtc2-1 mutants segregate independently of the vtc2-1 mutation. These observations suggest that it is the presence of an independent cryptic mutation that affects growth of vtc2 1 mutants, and not the 70-80% decrease in ascorbate levels that has been assumed in past studies. PMID- 27468293 TI - Trophic Relationships between the Parasitic Plant Species Phelipanche ramosa (L.) and Different Hosts Depending on Host Phenological Stage and Host Growth Rate. AB - Phelipanche ramosa (L.) Pomel (branched broomrape) is a holoparasitic plant that reproduces on crops and also on weeds, which contributes to increase the parasite seed bank in fields. This parasite extracts all its nutrients at the host's expense so that host-parasite trophic relationships are crucial to determine host and parasite growth. This study quantified the intensity with which P. ramosa draws assimilates from its host and analyzed whether it varied with host species, host phenological stage and host growth rate. A greenhouse experiment was conducted on three host species: the crop species Brassica napus (L.) (oilseed rape) and two weed species, Capsella bursa-pastoris (L.) Medik. and Geranium dissectum (L.). Plants were grown with or without P. ramosa and under three light levels to modulate host growth rate. The proportion of host biomass loss due to parasitism by P. ramosa differed between host species (at host fructification, biomass loss ranged from 34 to 84%). B. napus and C. bursa-pastoris displayed a similar response to P. ramosa, probably because they belong to the same botanical family. The sensitivity to P. ramosa in each host species could be related to the precocity of P. ramosa development on them. Host compartments could be ranked as a function of their sensitivity to parasitism, with the reproductive compartment being the most severely affected, followed by stems and roots. The proportion of biomass allocated to leaves was not reduced by parasitism. The proportion of pathosystem biomass allocated to the parasite depended on host species. It generally increased with host stage progression but was constant across light induced-host growth rate, showing that P. ramosa adapts its growth to host biomass production. The rank order of host species in terms of sink strength differed from that in terms of host sensitivity. Finally, for B. napus, the biomass of individual parasite shoots decreased with increasing their number per host plant, regardless of host growth rate. Results will be incorporated into a mechanistic model in order to analyze the effect of parasitic plant species on weed community assembly and to design new cropping systems for controlling P. ramosa. PMID- 27468292 TI - Biosynthesis and Metabolic Fate of Phenylalanine in Conifers. AB - The amino acid phenylalanine (Phe) is a critical metabolic node that plays an essential role in the interconnection between primary and secondary metabolism in plants. Phe is used as a protein building block but it is also as a precursor for numerous plant compounds that are crucial for plant reproduction, growth, development, and defense against different types of stresses. The metabolism of Phe plays a central role in the channeling of carbon from photosynthesis to the biosynthesis of phenylpropanoids. The study of this metabolic pathway is particularly relevant in trees, which divert large amounts of carbon into the biosynthesis of Phe-derived compounds, particularly lignin, an important constituent of wood. The trunks of trees are metabolic sinks that consume a considerable percentage of carbon and energy from photosynthesis, and carbon is finally immobilized in wood. This paper reviews recent advances in the biosynthesis and metabolic utilization of Phe in conifer trees. Two alternative routes have been identified: the ancient phenylpyruvate pathway that is present in microorganisms, and the arogenate pathway that possibly evolved later during plant evolution. Additionally, an efficient nitrogen recycling mechanism is required to maintain sustained growth during xylem formation. The relevance of phenylalanine metabolic pathways in wood formation, the biotic interactions, and ultraviolet protection is discussed. The genetic manipulation and transcriptional regulation of the pathways are also outlined. PMID- 27468294 TI - Comparative Transcriptome Reconstruction of Four Hypericum Species Focused on Hypericin Biosynthesis. AB - Next generation sequencing technology rapidly developed research applications in the field of plant functional genomics. Several Hypericum spp. with an aim to generate and enhance gene annotations especially for genes coding the enzymes supposedly included in biosynthesis of valuable bioactive compounds were analyzed. The first de novo transcriptome profiling of Hypericum annulatum Moris, H. tomentosum L., H. kalmianum L., and H. androsaemum L. leaves cultivated in vitro was accomplished. All four species with only limited genomic information were selected on the basis of differences in ability to synthesize hypericins and presence of dark nodules accumulating these metabolites with purpose to enrich genomic background of Hypericum spp. H. annulatum was chosen because of high number of the dark nodules and high content of hypericin. H. tomentosum leaves are typical for the presence of only 1-2 dark nodules localized in the apical part. Both H. kalmianum and H. androsaemum lack hypericin and have no dark nodules. Four separated datasets of the pair-end reads were gathered and used for de novo assembly by Trinity program. Assembled transcriptomes were annotated to the public databases Swiss-Prot and non-redundant protein database (NCBI-nr). Gene ontology analysis was performed. Differences of expression levels in the marginal tissues with dark nodules and inner part of leaves lacking these nodules indicate a potential genetic background for hypericin formation as the presumed site of hypericin biosynthesis is in the cells adjacent to these structures. Altogether 165 contigs in H. annulatum and 100 contigs in H. tomentosum were detected as significantly differentially expressed (P < 0.05) and upregulated in the leaf rim tissues containing the dark nodules. The new sequences homologous to octaketide synthase and enzymes catalyzing phenolic oxidative coupling reactions indispensable for hypericin biosynthesis were discovered. The presented transcriptomic sequence data will improve current knowledge about the selected Hypericum spp. with proposed relation to hypericin biosynthesis and will provide a useful resource of genomic information for consequential studies in the field of functional genomics, proteomics and metabolomics. PMID- 27468295 TI - Concanavalin A Disrupts the Release of Fibrous Material Necessary for Zygote Formation of a Unicellular Charophycean Alga, Closterium peracerosum-strigosum littorale Complex. AB - The Closterium peracerosum-strigosum-littorale (C. psl.) complex is the best characterized charophycean alga with respect to the processes of sexual reproduction. We examined the effect of concanavalin A (Con A) on physiological and ultrastructural changes during the conjugation of the C. psl. complex. Two heterothallic gametangial cells formed a sexual pair as usual; however, the release of gametes was completely blocked by the addition of Con A. Fluorescein isothiocyanate-labeled Con A bound to the outermost layer of the conjugation papillae of paired cells. In the absence of Con A, the disruption of outer cell walls on the conjugation papillae and the secretion of fibrous materials from the conjugation papillae were observed using a transmission electron microscope, but Con A-treated cells did not show these changes. Instead, a highly electron-dense layer was observed in the outermost papillae, and the excess fibrous materials remained at the inside of the layer. These results suggest that an unknown molecule(s) recognized by Con A is essential for the diffusion of fibrous materials at the conjugation papillae, which is an indispensable step for gamete release during conjugation of the C. psl. complex. PMID- 27468296 TI - Corrigendum: Overexpression of an Apocynum venetum DEAD-Box Helicase Gene (AvDH1) in Cotton Confers Salinity Tolerance and Increases Yield in a Saline Field. AB - [This corrects the article on p. 1227 in vol. 6, PMID: 26779246.]. PMID- 27468297 TI - Analysis of Variance Components for Genetic Markers with Unphased Genotypes. AB - An ANOVA type general multi-allele (GMA) model was proposed in Wang (2014) on analysis of variance components for quantitative trait loci or genetic markers with phased or unphased genotypes. In this study, by applying the GMA model, we further examine estimation of the genetic variance components for genetic markers with unphased genotypes based on a random sample from a study population. In one locus and two loci cases, we first derive the least square estimates (LSE) of model parameters in fitting the GMA model. Then we construct estimators of the genetic variance components for one marker locus in a Hardy-Weinberg disequilibrium population and two marker loci in an equilibrium population. Meanwhile, we explore the difference between the classical general linear model (GLM) and GMA based approaches in association analysis of genetic markers with quantitative traits. We show that the GMA model can retain the same partition on the genetic variance components as the traditional Fisher's ANOVA model, while the GLM cannot. We clarify that the standard F-statistics based on the partial reductions in sums of squares from GLM for testing the fixed allelic effects could be inadequate for testing the existence of the variance component when allelic interactions are present. We point out that the GMA model can reduce the confounding between the allelic effects and allelic interactions at least for independent alleles. As a result, the GMA model could be more beneficial than GLM for detecting allelic interactions. PMID- 27468298 TI - Using a community of practice model to create change for Northern homeless women. AB - This is a story about three virtual and face-to-face communities which met in the capitals of Canada's three Northern territorial cities over a two-year period to discuss and act on culturally safe and gender-specific services for Northern women (and their children) experiencing homelessness, mental health and substance use concerns. It is a story of how researchers and community-based advocates can work across distance and culture, using co-learning in virtual communities as a core strategy to create relational system change. The three communities of practice were linked through a pan-territorial action research project entitled Repairing the Holes in the Net, in which all participants: learned together, mapped available services, discussed the findings from interviews with northern women about their trajectories of homelessness, analyzed relevant policy, planned local service enhancements, and generally took inspiration from each other. PMID- 27468299 TI - Clinical Experience with Octagam(r) 10 %, a solvent detergent virus inactivated intravenous immunoglobulin: a Canadian retrospective review of utilization. AB - In Canada, intravenous immune globulin (IVIg) products are licensed for six disease indications, however it has been demonstrated that patients with a number of other conditions also benefit from IVIg. Here we report the routine clinical use of Octagam((r)) 10 % across three Canadian institutions. A total of 135 patients were treated with Octagam((r)), for conditions represented by five distinct indication groups. The results of this review indicate that Octagam((r)) has been well adopted and is prescribed to Canadian patients similar to other IVIg products. In alignment with current practices, 85 % of Octagam's utilization was classified as appropriate based on Canadian IVIg guidelines. PMID- 27468301 TI - When gene flow really matters: gene flow in applied evolutionary biology. PMID- 27468300 TI - Patterns and management of degloving injuries: a single national level 1 trauma center experience. AB - BACKGROUND: Degloving soft tissue injuries (DSTIs) are serious surgical conditions. We aimed to evaluate the pattern, management and outcome of DSTIs in a single institute. METHODS: A retrospective analysis was performed for patients admitted with DSTIs from 2011to 2013. Presentation, management and outcomes were analyzed according to the type of DSTI. RESULTS: Of 178 DSTI patients, 91 % were males with a mean age of 30.5 +/- 12.8. Three-quarter of cases was due to traffic related injuries. Eighty percent of open DSTI cases were identified. Primary debridement and closure (62.9 %) was the frequent intervention used. Intermediate closed drainage under ultrasound guidance was performed in 7 patients; however, recurrence occurred in 4 patients who underwent closed serial drainage for recollection and ended with a proper debridement with or without vacuum assisted closure (VAC). Closed DSTIs were mainly seen in the lower extremity and back region and initially treated with conservative management as compared to open DSTIs. Infection and skin necrosis were reported in 9 cases only. Open DSTIs were more likely involving head and neck region and being treated by primary debridement/suturing and serial debridement/washout with or without VAC. All cause DSTI mortality was 9 % that was higher in the closed DSTIs (19.4 vs 6.3 %; p = 0.01). CONCLUSION: The incidence of DSTIs is 4 % among trauma admissions over 3 years, with a greater predilection to males and young population. DSTIs are mostly underestimated particularly in the closed type that are usually missed at the initial presentation and associated with poor outcomes. Treatment guidelines are not well established and therefore further studies are warranted. PMID- 27468302 TI - Evolutionary and social consequences of introgression of nontransgenic herbicide resistance from rice to weedy rice in Brazil. AB - Several studies have expressed concerns about the effects of gene flow from transgenic herbicide-resistant crops to their wild relatives, but no major problems have been observed. This review describes a case study in which what has been feared in transgenics regarding gene flow has actually changed biodiversity and people's lives. Nontransgenic imidazolinone-resistant rice (IMI-rice) cultivars increased the rice grain yield by 50% in southern Brazil. This increase was beneficial for life quality of the farmers and also improved the regional economy. However, weedy rice resistant to imidazolinone herbicides started to evolve three years after the first use of IMI-rice cultivars. Population genetic studies indicate that the herbicide-resistant weedy rice was mainly originated from gene flow from resistant cultivars and distributed by seed migration. The problems related with herbicide-resistant weedy rice increased the production costs of rice that forced farmers to sell or rent their land. Gene flow from cultivated rice to weedy rice has proven to be a large agricultural, economic, and social constraint in the use of herbicide-resistant technologies in rice. This problem must be taken into account for the development of new transgenic or nontransgenic rice technologies. PMID- 27468303 TI - Ambient insect pressure and recipient genotypes determine fecundity of transgenic crop-weed rice hybrid progeny: Implications for environmental biosafety assessment. AB - Transgene introgression into crop weedy/wild relatives can provide natural selective advantages, probably causing undesirable environmental impact. The advantages are likely associated with factors such as transgenes, selective pressure, and genetic background of transgene recipients. To explore the role of the environment and background of transgene recipients in affecting the advantages, we estimated the fitness of crop-weed hybrid lineages derived from crosses between marker-free insect-resistant transgenic (Bt/CpTI) rice with five weedy rice populations under varied insect pressure. Multiway anova indicated the significant effect of both transgenes and weedy rice genotypes on the performance of crop-weed hybrid lineages in the high-insect environment. Increased fecundity was detected in most transgene-present F1 and F2 hybrid lineages under high insect pressure, but varied among crop-weed hybrid lineages with different weedy rice parents. Increased fecundity of transgenic crop-weed hybrid lineages was associated with the environmental insect pressure and genotypes of their weedy rice parents. The findings suggest that the fitness effects of an insect resistant transgene introgressed into weedy populations are not uniform across different environments and genotypes of the recipient plants that have acquired the transgene. Therefore, these factors should be considered when assessing the environmental impact of transgene flow to weedy or wild rice relatives. PMID- 27468304 TI - Fitness correlates of crop transgene flow into weedy populations: a case study of weedy rice in China and other examples. AB - Whether transgene flow from crops to cross-compatible weedy relatives will result in negative environmental consequences has been the topic of discussion for decades. An important component of environmental risk assessment depends on whether an introgressed transgene is associated with a fitness change in weedy populations. Several crop-weed pairs have received experimental attention. Perhaps, the most worrisome example is transgene flow from genetically engineered cultivated rice, a staple for billions globally, to its conspecific weed, weedy rice. China's cultivated/weedy rice system is one of the best experimentally studied systems under field conditions for assessing how the presence of transgenes alters the weed's fitness and the likely impacts of that fitness change. Here, we present the cultivated/weedy rice system as a case study on the consequences of introgressed transgenes in unmanaged populations. The experimental work on this system reveals considerable variation in fitness outcomes - increased, decreased, and none - based on the transgenic trait, its introgressed genomic background, and the environment. A review of similar research from a sample of other crop-wild pairs suggests such variation is the rule. We conclude such variation in fitness correlates supports the case-by-case method of biosafety regulation is sound. PMID- 27468305 TI - Genetic structure reveals a history of multiple independent origins followed by admixture in the allopolyploid weed Salsola ryanii. AB - It has recently become clear that many invasive species have evolved in situ via hybridization or polyploidy from progenitors which themselves are introduced species. For species formed by hybridization or polyploidy, genetic diversity within the newly formed species is influenced by the number of independent evolutionary origins of the species. For recently formed species, an analysis of genetic structure can provide insight into the number of independent origin events involved in the formation of the species. For a putative invasive allopolyploid species, the number of origins involved in the species formation, the genetic diversity present within these origins, and the level of gene flow between independent origins determines the genetic composition of the neospecies. Here we analyze the genetic structure of the newly formed allopolyploid species, Salsola ryanii, a tumbleweed which evolved within the last 20-100 years in California. We utilize the genetic structure analysis to determine that this new species is the result of at least three independent allopolyplodization events followed by gene flow between the descendants of independent origins. PMID- 27468306 TI - Gene flow from an adaptively divergent source causes rescue through genetic and demographic factors in two wild populations of Trinidadian guppies. AB - Genetic rescue, an increase in population growth owing to the infusion of new alleles, can aid the persistence of small populations. Its use as a management tool is limited by a lack of empirical data geared toward predicting effects of gene flow on local adaptation and demography. Experimental translocations provide an ideal opportunity to monitor the demographic consequences of gene flow. In this study we take advantage of two experimental introductions of Trinidadian guppies to test the effects of gene flow on downstream native populations. We individually marked guppies from the native populations to monitor population dynamics for 3 months before and 26 months after gene flow. We genotyped all individuals caught during the first 17 months at microsatellite loci to classify individuals by their genetic ancestry: native, immigrant, F1 hybrid, F2 hybrid, or backcross. Our study documents a combination of demographic and genetic rescue over multiple generations under fully natural conditions. Within both recipient populations, we found substantial and long-term increases in population size that could be attributed to high survival and recruitment caused by immigration and gene flow from the introduction sites. Our results suggest that low levels of gene flow, even from a divergent ecotype, can provide a substantial demographic boost to small populations, which may allow them to withstand environmental stochasticity. PMID- 27468307 TI - Hybridization and extinction. AB - Hybridization may drive rare taxa to extinction through genetic swamping, where the rare form is replaced by hybrids, or by demographic swamping, where population growth rates are reduced due to the wasteful production of maladaptive hybrids. Conversely, hybridization may rescue the viability of small, inbred populations. Understanding the factors that contribute to destructive versus constructive outcomes of hybridization is key to managing conservation concerns. Here, we survey the literature for studies of hybridization and extinction to identify the ecological, evolutionary, and genetic factors that critically affect extinction risk through hybridization. We find that while extinction risk is highly situation dependent, genetic swamping is much more frequent than demographic swamping. In addition, human involvement is associated with increased risk and high reproductive isolation with reduced risk. Although climate change is predicted to increase the risk of hybridization-induced extinction, we find little empirical support for this prediction. Similarly, theoretical and experimental studies imply that genetic rescue through hybridization may be equally or more probable than demographic swamping, but our literature survey failed to support this claim. We conclude that halting the introduction of hybridization-prone exotics and restoring mature and diverse habitats that are resistant to hybrid establishment should be management priorities. PMID- 27468308 TI - What, if anything, are hybrids: enduring truths and challenges associated with population structure and gene flow. AB - Hybridization is a potent evolutionary process that can affect the origin, maintenance, and loss of biodiversity. Because of its ecological and evolutionary consequences, an understanding of hybridization is important for basic and applied sciences, including conservation biology and agriculture. Herein, we review and discuss ideas that are relevant to the recognition of hybrids and hybridization. We supplement this discussion with simulations. The ideas we present have a long history, particularly in botany, and clarifying them should have practical consequences for managing hybridization and gene flow in plants. One of our primary goals is to illustrate what we can and cannot infer about hybrids and hybridization from molecular data; in other words, we ask when genetic analyses commonly used to study hybridization might mislead us about the history or nature of gene flow and selection. We focus on patterns of variation when hybridization is recent and populations are polymorphic, which are particularly informative for applied issues, such as contemporary hybridization following recent ecological change. We show that hybridization is not a singular process, but instead a collection of related processes with variable outcomes and consequences. Thus, it will often be inappropriate to generalize about the threats or benefits of hybridization from individual studies, and at minimum, it will be important to avoid categorical thinking about what hybridization and hybrids are. We recommend potential sampling and analytical approaches that should help us confront these complexities of hybridization. PMID- 27468309 TI - Applying gene flow science to environmental policy needs: a boundary work perspective. AB - One application of gene flow science is the policy arena. In this article, we describe two examples in which the topic of gene flow has entered into the U.S. national environmental policymaking process: regulation of genetically engineered crops and clarification of the jurisdictional scope of the Clean Water Act. We summarize both current scientific understanding and the legal context within which gene flow science has relevance. We also discuss the process by which scientific knowledge has been synthesized and communicated to decision-makers in these two contexts utilizing the concept of 'boundary work'. Boundary organizations, the work they engage in to bridge the worlds of science, policy, and practice, and the boundary objects they produce to translate scientific knowledge existed in both examples. However, the specific activities and attributes of the objects produced varied based on the needs of the decision makers. We close with suggestions for how scientists can contribute to or engage in boundary work with policymakers. PMID- 27468310 TI - Improving pentose fermentation by preventing ubiquitination of hexose transporters in Saccharomyces cerevisiae. AB - BACKGROUND: Engineering of the yeast Saccharomyces cerevisiae for improved utilization of pentose sugars is vital for cost-efficient cellulosic bioethanol production. Although endogenous hexose transporters (Hxt) can be engineered into specific pentose transporters, they remain subjected to glucose-regulated protein degradation. Therefore, in the absence of glucose or when the glucose is exhausted from the medium, some Hxt proteins with high xylose transport capacity are rapidly degraded and removed from the cytoplasmic membrane. Thus, turnover of such Hxt proteins may lead to poor growth on solely xylose. RESULTS: The low affinity hexose transporters Hxt1, Hxt36 (Hxt3 variant), and Hxt5 are subjected to catabolite degradation as evidenced by a loss of GFP fused hexose transporters from the membrane upon glucose depletion. Catabolite degradation occurs through ubiquitination, which is a major signaling pathway for turnover. Therefore, N terminal lysine residues of the aforementioned Hxt proteins predicted to be the target of ubiquitination, were replaced for arginine residues. The mutagenesis resulted in improved membrane localization when cells were grown on solely xylose concomitantly with markedly stimulated growth on xylose. The mutagenesis also improved the late stages of sugar fermentation when cells are grown on both glucose and xylose. CONCLUSIONS: Substitution of N-terminal lysine residues in the endogenous hexose transporters Hxt1 and Hxt36 that are subjected to catabolite degradation results in improved retention at the cytoplasmic membrane in the absence of glucose and causes improved xylose fermentation upon the depletion of glucose and when cells are grown in d-xylose alone. PMID- 27468311 TI - GAGA factor, a positive regulator of global gene expression, modulates transcriptional pausing and organization of upstream nucleosomes. AB - BACKGROUND: Genome-wide studies in higher eukaryotes have revealed the presence of paused RNA polymerase II (RNA-Pol) at about 30-50 bp downstream of the transcription start site of genes involved in developmental control, cell proliferation and intercellular signaling. Promoter-proximal pausing is believed to represent a critical step in transcriptional regulation. GAGA sequence motifs have frequently been found in the upstream region of paused genes in Drosophila, implicating a prevalent binding factor, GAF, in transcriptional pausing. RESULTS: Using newly isolated mutants that retain only ~3 % normal GAF level, we analyzed its impacts on transcriptional regulation in whole animals. We first examined the abundance of three major isoforms of RNA-Pol on Hsp70 during heat shock. By cytogenetic analyses on polytene chromosomes and chromatin immunoprecipitation (ChIP), we show that paused RNA-Pol of Hsp70 is substantially reduced in mutants. Conversely, a global increase in paused RNA-Pol is observed when GAF is over expressed. Coupled analyses of transcriptome and GAF genomic distribution show that 269 genes enriched for upstream GAF binding are down-regulated in mutants. Interestingly, ~15 % of them encode transcriptional factors, which might control ~2000 additional genes down-regulated in mutants. Further examination of RNA-Pol distribution in GAF targets reveals that a positive correlation exists between promoter-proximal RNA-Pol density and GAF occupancy in WT, but not in mutants. Comparison of nucleosome profiles indicates that nucleosome occupancy is preferentially attenuated by GAF in the upstream region that strongly favors nucleosome assembly. Using a dominant eye phenotype caused by GAF over expression, we detect significant genetic interactions between GAF and the nucleosome remodeler NURF, the pausing factor NELF, and BAB1 whose binding sites are enriched specifically in genes displaying GAF-dependent pausing. CONCLUSION: Our results provide direct evidence to support a critical role of GAF in global gene expression, transcriptional pausing and upstream nucleosome organization of a group of genes. By cooperating with factors acting at different levels, GAF orchestrates a series of events from local nucleosome displacement to paused transcription. The use of whole animals containing broad tissue types attests the physiological relevance of this regulatory network. PMID- 27468313 TI - Use of a real time continuous glucose monitoring system as an educational tool for patients with gestational diabetes. AB - BACKGROUND: Women with gestational diabetes mellitus (GDM) are required to control their blood glucose shortly after GDM diagnosis to minimize adverse pregnancy outcomes. A real time-continuous glucose monitoring system (RT-CGMS) provides the patient with continuous information about the alterations in levels of the blood glucose. This visibility may empower the patient to modify her lifestyle and engage in therapeutic management. The aim of this study was to determine whether a single application of RT-CGMS to pregnant women shortly after GDM diagnosis is useful as an educational and motivational tool. METHODS: This study was a prospective open label randomized controlled study conducted at Maternity and Children Hospital, Medina, Saudi Arabia. A total of 130 pregnant women with GDM were randomised to either blood glucose self-monitor alone (SMBG group) (n = 62) or in addition to SMBG, patients wore a Guardian((r)) REAL-Time Continuous Glucose Monitoring System (Medtronic MiniMed) once for 3-7 days, within 2 weeks of GDM diagnosis (RT-CGMS group) (n = 68). The primary outcomes were maternal glycemic control and pregnancy outcomes. Secondary outcomes were the changes in parameters of glucose variability, which includes mean sensor readings, standard deviation (SD) of blood glucose, and area under the curve for hyper and hypoglycaemia at the end of the RT-CGMS application. RESULTS: HbA1c, mean fasting and postprandial glucose levels were similar in both groups at the end of the pregnancy. Pregnancy outcomes were comparable. However, there was significant improvement in the parameters of glucose variability on the last day of sensor application; both mean glucose and the SD of mean glycaemia were reduced significantly; P = 0.016 and P = 0.034, respectively. The area under the curve for hyper and hypoglycaemia were improved, however, the results were not statistically significant. CONCLUSION: Although a single application of RT-CGMS shortly after GDM diagnosis is helpful as an educational tool, it was not associated with improvement in glycemic control or pregnancy outcomes. PMID- 27468312 TI - Establishing normative foot posture index values for the paediatric population: a cross-sectional study. AB - BACKGROUND: The Foot Posture Index (FPI) is an observational tool designed to measure the position of the foot. Its reliability is well established, and it provides normative reference values for the general population. However, this is not so for the paediatric population. The aim of this study is to determine FPI reference values in childhood, taking into account age and gender. METHODS: This cross-sectional study included 1,762 school children (863 boys and 899 girls) aged 6-11 years, from Malaga, Granada and Plasencia (Spain). In every case, FPI measurements were obtained for both feet by two experienced podiatrists. A descriptive analysis was then conducted and the percentiles of the variables determined, with a significance level of P < 0.05. RESULTS: The consolidated FPI results for the sample population produced mean values of 3.74 (SD 2.93) points for the right foot and 3.83 (SD 2.92) for the left. The 50th percentile was 4 points for both genders and for both feet, except for the right foot among the girls, which was slightly lower, at 3 points. The 85th percentile, which is considered to represent the boundary between the normal and the pronated foot among children, was 6 points, uniformly among the subjects. CONCLUSIONS: As a normative FPI value for the paediatric population, we recommend the 50th percentile, i.e. 4 points, for children, of both genders, aged 6 years. This value progressively falls with age, to 3 FPI points for children aged 11 years. The 85th percentile for the pronated foot and the 4th percentile for the supinated foot can be considered the pathological boundary. PMID- 27468314 TI - Impact of metabolic syndrome on lipid target achievements in the Arabian Gulf: findings from the CEPHEUS study. AB - BACKGROUND: The aim of this study was to determine the impact of metabolic syndrome (MetS) on lipid target achievements in the Arabian Gulf. METHODS: The centralized pan-middle east survey on the undertreatment of hypercholesterolemia (CEPHEUS) included 4171 high and very high atherosclerotic cardiovascular disease (ASCVD) risk patients from six Arabian Gulf countries. Analyses were performed using univariate statistics. RESULTS: The overall mean age was 57 +/- 11 years, 41 % were females and 71 % had MetS. MetS patients were less likely to attain their HDL-C (34 vs. 79 %; P < 0.001), LDL-C (27 vs. 37 %; P < 0.001), non HDL-C (35 vs. 55 %; P < 0.001) and Apo B (35 vs. 54 %; P < 0.001) compared to those without MetS. Within the MetS cohort, those with very high ASCVD risk were less likely to attain their lipid targets compared to those with high ASCVD risk [HDL C (32 vs. 41 %; P < 0.001), LDL-C (24 vs. 43 %; P < 0.001), non HDL-C (32 vs. 51 %; P < 0.001) and Apo B (33 vs. 40 %; P = 0.001)]. In those with MetS and very high ASCVD risk status, females were less likely to attain their HDL-C (27 vs. 36 %; P < 0.001), LDL-C (19 vs. 27 %; P < 0.001) and Apo B (30 vs. 35 %; P = 0.009) compared to males. CONCLUSIONS: MetS was associated with low lipid therapeutic targets. Women and those with very high ASCVD risk were also less likely to attain their lipid targets in the Arabian Gulf. PMID- 27468316 TI - Classifying four-category visual objects using multiple ERP components in single trial ERP. AB - Object categorization using single-trial electroencephalography (EEG) data measured while participants view images has been studied intensively. In previous studies, multiple event-related potential (ERP) components (e.g., P1, N1, P2, and P3) were used to improve the performance of object categorization of visual stimuli. In this study, we introduce a novel method that uses multiple-kernel support vector machine to fuse multiple ERP component features. We investigate whether fusing the potential complementary information of different ERP components (e.g., P1, N1, P2a, and P2b) can improve the performance of four category visual object classification in single-trial EEGs. We also compare the classification accuracy of different ERP component fusion methods. Our experimental results indicate that the classification accuracy increases through multiple ERP fusion. Additional comparative analyses indicate that the multiple kernel fusion method can achieve a mean classification accuracy higher than 72 %, which is substantially better than that achieved with any single ERP component feature (55.07 % for the best single ERP component, N1). We compare the classification results with those of other fusion methods and determine that the accuracy of the multiple-kernel fusion method is 5.47, 4.06, and 16.90 % higher than those of feature concatenation, feature extraction, and decision fusion, respectively. Our study shows that our multiple-kernel fusion method outperforms other fusion methods and thus provides a means to improve the classification performance of single-trial ERPs in brain-computer interface research. PMID- 27468315 TI - Cumulative life events, traumatic experiences, and psychiatric symptomatology in transition-aged youth with autism spectrum disorder. AB - BACKGROUND: Co-occurring mood and anxiety symptomatology is commonly observed among youth with autism spectrum disorders (ASD) during adolescence and adulthood. Yet, little is known about the factors that might predispose youth with ASD to mood and anxiety problems. In this study, we focus on the role of cumulative stressful life events and trauma in co-occurring psychopathology among youth with ASD who are preparing to exit high school. Specifically, we examined the distribution of cumulative life events and traumatic experiences and their relations with mood and anxiety symptomatology. METHODS: Participants included 36 youth with ASD, all of whom were in their last year of high school. Cumulative life events and trauma were assessed by parent report. Mood and anxiety symptomatology was determined using a variety of methods (structured interview, questionnaire, self- and informant report). Frequencies were used to examine the distributions of cumulative life events (count of total events) and trauma (coded into any trauma vs. no trauma), as well as mood and anxiety symptomatology (categorized into clinical-level, sub-threshold, or none for each). Bivariate relations between life events/trauma and mood/anxiety symptomatology were assessed using analysis of variance and chi-square. Ordinal logistic regression models were used to test whether significant bivariate relations remained after controlling for the sex of the youth with ASD and his/her IQ. RESULTS: Over 50 % of youth had experienced at least one trauma. Nearly one half had clinical-level mood or anxiety symptomatology. There was a statistically significant relation between absence/presence of trauma and mood symptomatology; nearly 90 % of the youth with clinical-level mood symptoms had at least one trauma, compared to 40 % of those with no mood symptomatology. CONCLUSIONS: Our findings suggest that contextual factors such as trauma might be important for the development of mood symptomatology in individuals with ASD. Although this idea is well-accepted in typically developing populations, contextual factors are rarely studied in investigations of psychopathology or transition outcomes in ASD. Given the high rates of psychiatric comorbidities in this population, future research should continue to identify the range of possible factors-both behavioral and contextual that might influence the emergence of these disorders. PMID- 27468317 TI - Selectivity of stimulus induced responses in cultured hippocampal networks on microelectrode arrays. AB - Sensory information can be encoded using the average firing rate and spike occurrence times in neuronal network responses to external stimuli. Decoding or retrieving stimulus characteristics from the response pattern generally implies that the corresponding neural network has a selective response to various input signals. The role of various spiking activity characteristics (e.g., spike rate and precise spike timing) for basic information processing was widely investigated on the level of neural populations but gave inconsistent evidence for particular mechanisms. Multisite electrophysiology of cultured neural networks grown on microelectrode arrays is a recently developed tool and currently an active research area. In this study, we analyzed the stimulus responses represented by network-wide bursts evoked from various spatial locations (electrodes). We found that the response characteristics, such as the burst initiation time and the spike rate, can be used to retrieve information about the stimulus location. The best selectivity in the response spiking pattern could be found for a small subpopulation of neurones (electrodes) at relatively short post-stimulus intervals. Such intervals were unique for each culture due to the non-uniform organization of the functional connectivity in the network during spontaneous development. PMID- 27468319 TI - A model of cooperative effect of AMPA and NMDA receptors in glutamatergic synapses. AB - Glutamatergic synapses play a pivotal role in brain excitation. The synaptic response is mediated by the activity of two receptor types (AMPA and NMDA). In the present paper we propose a model of glutamatergic synaptic activity where the fast current generated by the AMPA conductance produces a local depolarization which activates the voltage- and [Mg(2+)]-dependent NMDA conductance. This cooperative effect is dependent on the biophysical properties of the synaptic spine which can be considered a high input resistance specialized compartment. Herein we present results of simulations where different values of the spine resistance and of the Mg(2+) concentrations determine different levels of cooperativeness between AMPA and NMDA receptors in shaping the post-synaptic response. PMID- 27468318 TI - Direction and viewing area-sensitive influence of EOG artifacts revealed in the EEG topographic pattern analysis. AB - The influence of eye movement-related artifacts on electroencephalography (EEG) signals of human subjects, who were requested to perform a direction or viewing area dependent saccade task, was investigated by using a simultaneous recording with ocular potentials as electro-oculography (EOG). In the past, EOG artifact removals have been studied in tasks with a single fixation point in the screen center, with less attention to the sensitivity of cornea-retinal dipole orientations to the EEG head map. In the present study, we hypothesized the existence of a systematic EOG influence that differs according to coupling conditions of eye-movement directions with viewing areas including different fixation points. The effect was validated in the linear regression analysis by using 12 task conditions combining horizontal/vertical eye-movement direction and three segregated zones of gaze in the screen. In the first place, event-related potential topographic patterns were analyzed to compare the 12 conditions and propagation coefficients of the linear regression analysis were successively calculated in each condition. As a result, the EOG influences were significantly different in a large number of EEG channels, especially in the case of horizontal eye-movements. In the cross validation, the linear regression analysis using the appropriate dataset of the target direction/viewing area combination demonstrated an improved performance compared with the traditional methods using a single fixation at the center. This result may open a potential way to improve artifact correction methods by considering the systematic EOG influence that can be predicted according to the view angle such as using eye-tracker systems. PMID- 27468320 TI - Vibrotactile feedback for conveying object shape information as perceived by artificial sensing of robotic arm. AB - This work is a preliminary study towards developing an alternative communication channel for conveying shape information to aid in recognition of items when tactile perception is hindered. Tactile data, acquired during object exploration by sensor fitted robot arm, are processed to recognize four basic geometric shapes. Patterns representing each shape, classified from tactile data, are generated using micro-controller-driven vibration motors which vibrotactually stimulate users to convey the particular shape information. These motors are attached on the subject's arm and their psychological (verbal) responses are recorded to assess the competence of the system to convey shape information to the user in form of vibrotactile stimulations. Object shapes are classified from tactile data with an average accuracy of 95.21 %. Three successive sessions of shape recognition from vibrotactile pattern depicted learning of the stimulus from subjects' psychological response which increased from 75 to 95 %. This observation substantiates the learning of vibrotactile stimulation in user over the sessions which in turn increase the system efficacy. The tactile sensing module and vibrotactile pattern generating module are integrated to complete the system whose operation is analysed in real-time. Thus, the work demonstrates a successful implementation of the complete schema of artificial tactile sensing system for object-shape recognition through vibrotactile stimulations. PMID- 27468321 TI - Passivity of memristor-based BAM neural networks with different memductance and uncertain delays. AB - This paper addresses the passivity problem for a class of memristor-based bidirectional associate memory (BAM) neural networks with uncertain time-varying delays. In particular, the proposed memristive BAM neural networks is formulated with two different types of memductance functions. By constructing proper Lyapunov-Krasovskii functional and using differential inclusions theory, a new set of sufficient condition is obtained in terms of linear matrix inequalities which guarantee the passivity criteria for the considered neural networks. Finally, two numerical examples are given to illustrate the effectiveness of the proposed theoretical results. PMID- 27468322 TI - Locating and navigation mechanism based on place-cell and grid-cell models. AB - Extensive experiments on rats have shown that environmental cues play an important role in goal locating and navigation. Major studies about locating and navigation are carried out based only on place cells. Nevertheless, it is known that navigation may also rely on grid cells. Therefore, we model locating and navigation based on both, thus developing a novel grid-cell model, from which firing fields of grid cells can be obtained. We found a continuous-time dynamic system to describe learning and direction selection. In our simulation experiment, according to the results from physiology experiments, we successfully rebuild place fields of place cells and firing fields of grid cells. We analyzed the factors affecting the locating accuracy. Results show that the learning rate, firing threshold and cell number can influence the outcomes from various tasks. We used our system model to perform a goal navigation task and showed that paths that are changed for every run in one experiment converged to a stable one after several runs. PMID- 27468323 TI - Role of structural inhomogeneities in resting-state brain dynamics. AB - Brain imaging methods allow a non-invasive assessment of both structural and functional connectivity. However, the mechanism of how functional connectivity arises in a structured network of interacting neural populations is as yet poorly understood. Here we use a modeling approach to explore the way in which functional correlations arise from underlying structural connections taking into account inhomogeneities in the interactions between the brain regions of interest. The local dynamics of a neural population is assumed to be of phase oscillator type. The considered structural connectivity patterns describe long range anatomical connections between interacting neural elements. We find a dependence of the simulated functional connectivity patterns on the parameters governing the dynamics. We calculate graph-theoretic measures of the functional network topology obtained from numerical simulations. The effect of structural inhomogeneities in the coupling term on the observed network state is quantified by examining the relation between simulated and empirical functional connectivity. Importantly, we show that simulated and empirical functional connectivity agree for a narrow range of coupling strengths. We conclude that identification of functional connectivity during rest requires an analysis of the network dynamics. PMID- 27468324 TI - Composite Tissue Transplant of Hand or Arm: A Health Technology Assessment. AB - BACKGROUND: Injuries to arms and legs following severe trauma can result in the loss of large regions of tissue, disrupting healing and function and sometimes leading to amputation of the damaged limb. People experiencing amputations of the hand or arm could potentially benefit from composite tissue transplant, which is being performed in some countries. Currently, there are no composite tissue transplant programs in Canada. METHODS: We conducted a systematic review of the literature, with no restriction on study design, examining the effectiveness and cost-effectiveness of hand and arm transplant. We assessed the overall quality of the clinical evidence with GRADE. We developed a Markov decision analytic model to determine the cost-effectiveness of transplant versus standard care for a healthy adult with a hand amputation. Incremental cost-effectiveness ratios (ICERs) were calculated using a 30-year time horizon. We also estimated the impact on provincial health care costs if these transplants were publicly funded in Ontario. RESULTS: Compared to pre-transplant function, patients' post transplant function was significantly better. For various reasons, 17% of transplanted limbs were amputated, 6.4% of patients died within the first year after the transplant, and 10.6% of patients experienced chronic rejections. GRADE quality of evidence for all outcomes was very low. In the cost-effectiveness analysis, single-hand transplant was dominated by standard care, with increased costs ($735,647 CAD vs. $61,429) and reduced quality-adjusted life-years (QALYs) (10.96 vs. 11.82). Double-hand transplant also had higher costs compared with standard care ($633,780), but it had an increased effectiveness of 0.17 QALYs, translating to an ICER of $3.8 million per QALY gained. In most sensitivity analyses, ICERs for bilateral hand transplant were greater than $1 million per QALY gained. A hand transplant program would lead to an estimated annual budget impact of $0.9 million to $1.2 million in the next 3 years, 2016 to 2018, to treat 3 adults per year. CONCLUSIONS: Composite tissue transplant of the hand or arm may improve a patient's ability to function, but because the overall quality of evidence is of very low quality, there is considerable uncertainty as to whether benefits outweigh harms. Compared with standard care, both single- and double-hand transplants are not cost-effective. PMID- 27468325 TI - Retinal Prosthesis System for Advanced Retinitis Pigmentosa: A Health Technology Assessment. AB - BACKGROUND: Retinitis pigmentosa is a group of genetic disorders that involves the breakdown and loss of photoreceptors in the retina, resulting in progressive retinal degeneration and eventual blindness. The Argus II Retinal Prosthesis System is the only currently available surgical implantable device approved by Health Canada. It has been shown to improve visual function in patients with severe visual loss from advanced retinitis pigmentosa. The objective of this analysis was to examine the clinical effectiveness, cost-effectiveness, budget impact, and safety of the Argus II system in improving visual function, as well as exploring patient experiences with the system. METHODS: We performed a systematic search of the literature for studies examining the effects of the Argus II retinal prosthesis system in patients with advanced retinitis pigmentosa, and appraised the evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria, focusing on visual function, functional outcomes, quality of life, and adverse events. We developed a Markov decision-analytic model to assess the cost effectiveness of the Argus II system compared with standard care over a 10-year time horizon. We also conducted a 5-year budget impact analysis. We used a qualitative design and an interview methodology to examine patients' lived experience, and we used a modified grounded theory methodology to analyze information from interviews. Transcripts were coded, and themes were compared against one another. RESULTS: One multicentre international study and one single centre study were included in the clinical review. In both studies, patients showed improved visual function with the Argus II system. However, the sight threatening surgical complication rate was substantial. In the base-case analysis, the Argus II system was cost-effective compared with standard care only if willingness-to-pay was more than $207,616 per quality-adjusted life-year. The 5-year budget impact of funding the Argus II system ranged from $800,404 to $837,596. Retinitis pigmentosa significantly affects people's ability to navigate physical and virtual environments. Argus II was described as enabling the fundamental elements of sight. As such, it had a positive impact on quality of life for people with retinitis pigmentosa. CONCLUSIONS: Based on evidence of moderate quality, patients with advanced retinitis pigmentosa who were implanted with the Argus II retinal prosthesis system showed significant improvement in visual function, real-life functional outcomes, and quality of life, but there were complications associated with the surgery that could be managed through standard ophthalmologic treatments. The costs for the technology are high. PMID- 27468326 TI - Ultrasound as an Adjunct to Mammography for Breast Cancer Screening: A Health Technology Assessment. AB - BACKGROUND: Screening with mammography can detect breast cancer early, before clinical symptoms appear. Some cancers, however, are not captured with mammography screening alone. Ultrasound has been suggested as a safe adjunct screening tool that can detect breast cancers missed on mammography. We investigated the benefits, harms, cost-effectiveness, and cost burden of ultrasound as an adjunct to mammography compared with mammography alone for screening women at average risk and at high risk for breast cancer. METHODS: We searched Ovid MEDLINE, Ovid Embase, EBM Reviews, and the NHS Economic Evaluation Database, from January 1998 to June 2015, for evidence of effectiveness, harms, diagnostic accuracy, and cost-effectiveness. Only studies evaluating the use of ultrasound as an adjunct to mammography in the specified populations were included. We also conducted a cost analysis to estimate the costs in Ontario over the next 5 years to fund ultrasound as an adjunct to mammography in breast cancer screening for high-risk women who are contraindicated for MRI, the current standard of care to supplement mammography. RESULTS: No studies in average-risk women met the inclusion criteria of the clinical review. We included 5 prospective, paired cohort studies in high-risk women, 4 of which were relevant to the Ontario context. Adjunct ultrasound identified between 2.3 and 5.9 additional breast cancers per 1,000 screens. The average pooled sensitivity of mammography and ultrasound was 53%, a statistically significant increase relative to mammography alone (absolute increase 13%; P < .05). The average pooled specificity of the combined test was 96%, an absolute increase in the false positive rate of 2% relative to mammography screening alone. The GRADE for this body of evidence was low. Additional annual costs of using breast ultrasound as an adjunct to mammography for high-risk women in Ontario contraindicated for MRI would range from $15,500 to $30,250 in the next 5 years. CONCLUSIONS: We found no evidence that evaluated the comparative effectiveness or diagnostic accuracy of screening breast ultrasound as an adjunct to mammography among average-risk women aged 50 years and over. In women at high risk of developing breast cancer, there is low-quality evidence that screening with mammography and adjunct ultrasound detects additional cases of disease, with improved sensitivity compared to mammography alone. Screening with adjunct ultrasound also increases the number of false-positive findings and subsequent biopsy recommendations. It is unclear if the use of screening breast ultrasound as an adjunct to mammography will reduce breast cancer-related mortality among high-risk women. The annual cost burden of using adjunct ultrasound to screen high-risk women who cannot receive MRI in Ontario would be small. PMID- 27468327 TI - Women's Experiences of Inaccurate Breast Cancer Screening Results: A Systematic Review and Qualitative Meta-synthesis. AB - BACKGROUND: Adjunct screening with ultrasound has the potential to detect breast cancers that may not be visible on screening mammography. The use of adjunct ultrasonography is thought to be a safe and inexpensive approach to improving the sensitivity of screening with mammography alone, but potentially at the expense of increasing the rate of false-positive findings. The objective of this review was to examine women's experiences of inaccurate breast cancer screening results and how they affect perceptions of breast cancer screening technologies. METHODS: This report synthesizes 16 primary qualitative studies, which together involved 690 participating women, to examine women's experiences of inaccurate breast cancer screening results. Qualitative meta-synthesis was used to integrate findings across primary research studies. RESULTS: The experience of a false positive result caused short-term anxiety until the negative result was confirmed. It also led to reoccurring anxiety during future screening. The anxiety experienced in the face of a false-positive result was magnified in high risk women, who often reflected on the previous breast cancer experiences of family members while awaiting further results. Despite this increased anxiety, women who had experienced a false-positive result were generally not deterred from future screening. Rather, the experiences heightened their awareness of breast cancer and led to a desire for more examinations and more technologies. Women who had experienced false-negative results struggled to restore trust in screening but recognized that some breast cancers were identified through mammography. They were willing to see themselves as exceptions to an otherwise beneficial service. CONCLUSIONS: Qualitative studies provide some insight into how breast cancer screening inaccuracy affects women, including their faith in the screening technology. Although women suffered marked anxiety from experiencing false-positive mammography tests and loss of confidence from false negative results, these feelings generally did not diminish women's belief in the value of mammography screening. In many cases, the experiences reinforced the importance of risk reduction as well as screening. PMID- 27468328 TI - Space-Time Smoothing of Complex Survey Data: Small Area Estimation for Child Mortality. AB - Many people living in low and middle-income countries are not covered by civil registration and vital statistics systems. Consequently, a wide variety of other types of data including many household sample surveys are used to estimate health and population indicators. In this paper we combine data from sample surveys and demographic surveillance systems to produce small area estimates of child mortality through time. Small area estimates are necessary to understand geographical heterogeneity in health indicators when full-coverage vital statistics are not available. For this endeavor spatio-temporal smoothing is beneficial to alleviate problems of data sparsity. The use of conventional hierarchical models requires careful thought since the survey weights may need to be considered to alleviate bias due to non-random sampling and non-response. The application that motivated this work is estimation of child mortality rates in five-year time intervals in regions of Tanzania. Data come from Demographic and Health Surveys conducted over the period 1991-2010 and two demographic surveillance system sites. We derive a variance estimator of under five years child mortality that accounts for the complex survey weighting. For our application, the hierarchical models we consider include random effects for area, time and survey and we compare models using a variety of measures including the conditional predictive ordinate (CPO). The method we propose is implemented via the fast and accurate integrated nested Laplace approximation (INLA). PMID- 27468329 TI - Pediatric Flexor Pollicis Longus Injury: Practical Modifications of Assessment and Repair. PMID- 27468330 TI - Reconstruction of Moderately Constricted Ears by Combining V-Y Advancement of Helical Root, Conchal Cartilage Graft, and Mastoid Hitch. AB - OBJECTIVE: Despite the multitude of corrective procedures described in the literature, adequate surgical correction of the congenital constricted ear remains a challenge. The maintenance of the shape and size of the reconstructed upper neohelix poses a particular problem. METHODS: In the present study, a total of 12 cases of reconstruction were undertaken. All of them were moderate (type IIA Tanzer classification) deformities. A combined procedure was adopted using a V-Y advancement of the helical root, cartilage scoring, and cartilage grafting from the contralateral concha to reconstruct the upper helix. A mastoid hitch was used as an adjunct to these procedures to maintain helical elevation and prevent recurrence. Mean follow-up period was 6 months. RESULTS: RESULTS were excellent (n = 7), good (n = 4), and fair (n = 1). Paired t test showed a significant increase in the height of the constricted ear postoperatively (P < .001) and a nonsignificant difference between the height of the constricted and contralateral ears postoperatively (P > .05). Apart from dislodgment of the mastoid hitch suture in 1 patient, no complications were recorded. CONCLUSION: This combined technique is useful in correcting moderately constricted ear deformities. PMID- 27468331 TI - Therapeutic potential of human embryonic stem cells in type 2 diabetes mellitus. AB - AIM: To evaluate the safety and efficacy of human embryonic stem cells (hESCs) for the management of type 2 diabetes mellitus (T2DM). METHODS: Patients with a previous history of diabetes and its associated complications were enrolled and injected with hESC lines as per the defined protocol. The patients were assessed using Nutech functional score (NFS), a numeric scoring scale to evaluate the patients for 11 diagnostic parameters. Patients were evaluated at baseline and at the end of treatment period 1 (T1). All the parameters were graded on the NFS scale from 1 to 5. Highest possible grade (HPG) of 5 was considered as the grade of best improvement. RESULTS: Overall, 94.8% of the patients showed improvement by at least one grade of NFS at the end of T1. For all the 11 parameters evaluated, 54% of patients achieved HPG after treatment. The four essential parameters (improvement in glycated hemoglobin (HbA1c) and insulin level, and fall in number of other oral hypoglycemic drugs with and without insulin) are presented in detail. For HbA1c, 72.6% of patients at the end of T1 met the World Health Organization cut off value, i.e., 6.5% of HbA1c. For insulin level, 65.9% of patients at the end of T1 were able to achieve HPG. After treatment, the improvement was seen in 16.3% of patients who required no more than two medications along with insulin. Similarly, 21.5% of patients were improved as their dosage regimen for using oral drugs was reduced to 1-2 from 5. CONCLUSION: hESC therapy is beneficial in patients with diabetes and helps in reducing their dependence on insulin and other medicines. PMID- 27468332 TI - Transcranial Doppler ultrasonography: From methodology to major clinical applications. AB - Non-invasive Doppler ultrasonographic study of cerebral arteries [transcranial Doppler (TCD)] has been extensively applied on both outpatient and inpatient settings. It is performed placing a low-frequency (<= 2 MHz) transducer on the scalp of the patient over specific acoustic windows, in order to visualize the intracranial arterial vessels and to evaluate the cerebral blood flow velocity and its alteration in many different conditions. Nowadays the most widespread indication for TCD in outpatient setting is the research of right to left shunting, responsable of so called "paradoxical embolism", most often due to patency of foramen ovale which is responsable of the majority of cryptogenic strokes occuring in patients younger than 55 years old. TCD also allows to classify the grade of severity of such shunts using the so called "microembolic signal grading score". In addition TCD has found many useful applications in neurocritical care practice. It is useful on both adults and children for day-to day bedside assessment of critical conditions including vasospasm in subarachnoidal haemorrhage (caused by aneurysm rupture or traumatic injury), traumatic brain injury, brain stem death. It is used also to evaluate cerebral hemodynamic changes after stroke. It also allows to investigate cerebral pressure autoregulation and for the clinical evaluation of cerebral autoregulatory reserve. PMID- 27468333 TI - Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure. AB - In advanced heart failure (HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase III inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guideline-directed HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker (BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF. PMID- 27468336 TI - Rare presentation of intralobar pulmonary sequestration associated with repeated episodes of ventricular tachycardia. AB - Arterial supply of an intralobar pulmonary sequestration (IPS) from the coronary circulation is extremely rare. A significant coronary steal does not occur because of dual or triple sources of blood supply to sequestrated lung tissue. We present a 60-year-old woman who presented to us with repeated episodes of monomorphic ventricular tachycardia (VT) in last 3 mo. Radio frequency ablation was ineffective. On evaluation, she had right lower lobe IPS with dual arterial blood supply, i.e., right pulmonary artery and the systemic arterial supply from the right coronary artery (RCA). Stress myocardial perfusion scan revealed significant inducible ischemia in the RCA territory. Coronary angiogram revealed critical stenosis of proximal RCA just after the origin of the systemic artery supplying IPS. The critical stenosis in the RCA was stented. At 12 mo follow-up, she had no further episodes of VT or angina. PMID- 27468334 TI - Takotsubo syndrome: Advances in the understanding and management of an enigmatic stress cardiomyopathy. AB - Takotsubo cardiomyopathy is a syndrome mimicking an acute myocardial infarction in absence of obstructive epicardial coronary artery disease to explain the degree of the wall motion abnormalities. Typically more common in the elderly women, this condition is usually triggered by unexpected emotional or physical stress situations, and is associated with electrocardiogram abnormalities and slight elevation of cardiac biomarkers. The pathophysiological mechanism is not clear yet, but it is believed that a high circulating concentration of catecholamines causes an acute dysfunction of the coronary microcirculation and metabolism of cardiomyocytes, leading to a transient myocardial stunning. Typically, it presents with acute left ventricular systolic dysfunction that in most cases is completely resolved at short term. Recurrences are rare and it is thought that the long-term prognosis is good. We present here a review of the clinical features, pathophysiology and management of this enigmatic condition. PMID- 27468335 TI - Impact of clinical and procedural factors upon C reactive protein dynamics following transcatheter aortic valve implantation. AB - AIM: To determine the effect of procedural and clinical factors upon C reactive protein (CRP) dynamics following transcatheter aortic valve implantation (TAVI). METHODS: Two hundred and eight consecutive patients that underwent transfemoral TAVI at two hospitals (Imperial, College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom and San Raffaele Scientific Institute, Milan, Italy) were included. Daily venous plasma CRP levels were measured for up to 7 d following the procedure (or up to discharge). Procedural factors and 30-d safety outcomes according to the Valve Academic Research Consortium 2 definition were collected. RESULTS: Following TAVI, CRP significantly increased reaching a peak on day 3 of 87.6 +/- 5.5 mg/dL, P < 0.001. Patients who developed clinical signs and symptoms of sepsis had significantly increased levels of CRP (P < 0.001). The presence of diabetes mellitus was associated with a significantly higher peak CRP level at day 3 (78.4 +/- 3.2 vs 92.2 +/- 4.4, P < 0.001). There was no difference in peak CRP release following balloon-expandable or self-expandable TAVI implantation (94.8 +/- 9.1 vs 81.9 +/- 6.9, P = 0.34) or if post-dilatation was required (86.9 +/- 6.3 vs 96.6 +/- 5.3, P = 0.42), however, when pre-TAVI balloon aortic valvuloplasty was performed this resulted in a significant increase in the peak CRP (110.1 +/- 8.9 vs 51.6 +/- 3.7, P < 0.001). The development of a major vascular complication did result in a significantly increased maximal CRP release (153.7 +/- 11.9 vs 83.3 +/- 7.4, P = 0.02) and there was a trend toward a higher peak CRP following major/life-threatening bleeding (113.2 +/- 9.3 vs 82.7 +/- 7.5, P = 0.12) although this did not reach statistical significance. CRP was not found to be a predictor of 30-d mortality on univariate analysis. CONCLUSION: Careful attention should be paid to baseline clinical characteristics and procedural factors when interpreting CRP following TAVI to determine their future management. PMID- 27468337 TI - Vitamin D Studies: Mistaking Correlation for Causation. PMID- 27468339 TI - Usefulness of Heavy Drinking and Binge Drinking for the Diagnosis of Alcohol Use Disorder. AB - BACKGROUND: This research investigated the sensitivity and specificity of heavy and binge drinking for screening of alcohol use disorder. METHODS: This retrospective study was conducted with 976 adults who visited the Sun Health Screening Center for health screenings in 2015. Daily drinking amount, drinking frequency per week, and weekly drinking amount were investigated. Using criteria from the National Institute on Alcohol Abuse and Alcoholism, participants were classified as normal drinkers, heavy drinkers, or binge drinkers, and grouped by age and sex. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of heavy and binge drinking were compared for the diagnosis of alcohol abuse and alcohol dependence using the Diagnostic and Statistical Manual of Mental Disorders (DSM) 4th edition-text revision and alcohol use disorder using the DSM 5th edition. RESULTS: The sensitivity of heavy and binge drinking for the diagnosis of alcohol abuse, alcohol dependence, and alcohol use disorder were 51.7%, 43.8%, and 35.3%, and 69.0%, 62.5%, and 48.2%, respectively. The specificity of these were 90.1%, 91.7%, and 95.5%, and 84.3%, 86.8%, and 91.2%, respectively. The PPV of these were 24.8%, 40.5%, and 72.7%, and 21.7%, 38.0%, and 65.2%, respectively. The NPV of these were 96.7%, 92.6%, and 81.2%, and 97.8%, 94.7%, and 83.7%, respectively. CONCLUSION: Heavy and binge drinking did not show enough diagnostic power to screen DSM alcohol use disorder although they did show high specificity and NPV. PMID- 27468338 TI - Preventing a Mass Disease: The Case of Gallstones Disease: Role and Competence for Family Physicians. AB - Gallstone formation is the result of a complex interaction between genetic and nongenetic factors. We searched and reviewed the available literature to define how the primary prevention of gallstones (cholesterol gallstones in particular) could be applied in general practice. Electronic bibliographical databases were searched. Prospective and retrospective cohort studies and case-controlled studies were analyzed and graded for evidence quality. The epidemiological data confirmed that genetic factors are estimated to account for only approximately 25% of the overall risk of gallstones, while metabolic/environmental factors are at least partially modifiable in stone-free risk groups, and are thus modifiable by primary prevention measures related to diet, lifestyle, and environmental factors (i.e., rapid weight loss, bariatric surgery, somatostatin or analogues therapy, transient gallbladder stasis, and hormone therapy). There is no specific recommendation for the secondary prevention of recurrent gallstones. Family physicians can contribute to preventing gallstones due to their capability to identify and effectively manage several risk factors discussed in this study. Although further studies are needed to better elucidate the involvement of epigenetic factors that may regulate the effect of environment and lifestyle on gene expression in the primary prevention of gallstone formation, preventive interventions are feasible and advisable in the general practice setting. PMID- 27468340 TI - The Association between Vitamin D and Health-Related Quality of Life in Korean Adults. AB - BACKGROUND: We examined the relationship between vitamin D status and health related quality of life, and explored other related factors in the general Korean population. METHODS: We used data from the 2007-2012 Korea National Health and Nutrition Examination Survey on 14,104 adults, aged 20-49 years, who had consented to serum vitamin D measurement and answered health-related quality of life questions. EuroQol-5 was used for measurement. Serum vitamin D levels were measured at intervals of 0-9.99, 10-19.99, 20-29.99, and >=30 ng/mL. RESULTS: Participants with higher serum vitamin D (serum 25-hydroxyvitamin D) levels were significantly less likely to report problems with depression and anxiety. After adjustment for age, gender, income level, education level, marital status, alcohol consumption, smoking status, and the existence of depressive disorders, the odds ratio for reporting a problem with depression and anxiety was 0.60 (95% confidence interval [CI], 0.39-0.91). The odds ratio for the prevalence of any problem was 0.69 (95% CI, 0.53-0.89) before adjustment, but was not statistically significant after adjustment. No significant associations were observed for problems with mobility, self-care, usual activity, or pain and discomfort. CONCLUSION: This is the first study to examine the associations between vitamin D and health-related quality of life for the general Korean population. Vitamin D status was not significantly associated with the dimensions of EuroQol-5 except for depression and anxiety problems. PMID- 27468341 TI - Factors Associated with Depression Assessed by the Patient Health Questionnaire-2 in Long-Term Cancer Survivors. AB - BACKGROUND: This cross-sectional study aimed to evaluate the prevalence of depressive disorders and factors associated in long-term cancer survivors. METHODS: A total of 702 long-term cancer survivors over 5-years in remission were recruited in a university-affiliated tertiary hospital in Korea. Self-report using the Patient Health Questionnaire-2 and the Fatigue Severity Scale assessed depression and fatigue, respectively. Demographic characteristics, cancer-related clinical characteristics, comorbidity, health behaviors, and physical symptoms were assessed through the review of medical records or a structured self administered questionnaire. RESULTS: We identified 26.1% of patients who had a depressed mood or displayed a loss of interest. The most prevalent primary site of cancer was the stomach (65.2%), followed by lung, breast, colorectal, and thyroid cancer. We also found that 5.7% of subjects experienced double or triple primary cancers. Larger proportion among depressive group (89.1%) complained at least one physical problem than among non-depressive group (53.2%). Physical symptoms including sleep problems, dry mouth, indigestion, pain, decreased appetite, and febrile sense were more frequent in the depressive group than in the non-depressive group. The Fatigue Severity Scale scores were higher in the depressive group than in the non-depressive group (P<0.001). Multiple logistic regression analysis showed that the highest tertile level of fatigue (odds ratio, 7.31; 95% confidence interval, 3.81-14.02) was associated with the increased risk of depression. CONCLUSION: These findings suggest that careful concern about depression is necessary in long-term cancer survivors. Fatigue may be a surrogate sign for depression, and warrants further evaluation. PMID- 27468342 TI - Risk of Cardiovascular Disease Using Framingham Risk Score in Korean Cancer Survivors. AB - BACKGROUND: Cardiovascular disease is an important cause of morbidity and mortality in cancer survivors. The aim of this study was to investigate the modifiable cardiovascular disease risk factors and 10-year probability of the disease based on the Framingham risk score in cancer survivors, compared with the general population. METHODS: A total of 1,225 cancer survivors and 5,196 non cancer controls who participated in the 2007-2013 Korea National Health and Nutrition Examination Surveys were enrolled. We assessed modifiable cardiovascular disease risk factors including smoking, body mass index, physical inactivity, high blood pressure, high cholesterol, and elevated blood glucose level. The 10-year probability of cardiovascular disease was determined by applying the Framingham cardiovascular disease risk equation among cancer survivors and non-cancer controls, ranging from 30 to 74 years old who had no overt cardiovascular diseases. RESULTS: The proportion of subjects who had higher fasting glucose levels, hemoglobin A1c levels, systolic blood pressure, and low density lipoprotein cholesterol levels, and those who had lower high density lipoprotein cholesterol levels was significantly higher in the cancer survivors than in the non-cancer controls. The average 10-year probability of cardiovascular disease among the cancer survivors was higher than that in the non cancer controls in both men and women. The average 10-year probability of cardiovascular disease in relation to the cancer type was significantly higher in patients with hepatic, colon, lung, breast, and gastric cancer. CONCLUSION: Cancer survivors have a higher cardiovascular disease risk and 10-year probability of cardiovascular disease than non-cancer controls. Control of cardiovascular disease risk factors and implementation of a well-defined cardiovascular disease prevention program are needed for treating cancer survivors. PMID- 27468343 TI - Sex Difference in the Association between Serum Homocysteine Level and Non Alcoholic Fatty Liver Disease. AB - BACKGROUND: The relationship between serum homocysteine levels and non-alcoholic fatty liver disease is poorly understood. This study aims to investigate the sex specific relationship between serum homocysteine level and non-alcoholic fatty liver disease in the Korean population. METHODS: This cross-sectional study included 150 men and 132 women who participated in medical examination programs in Korea from January 2014 to December 2014. Patients were screened for fatty liver by abdominal ultrasound and patient blood samples were collected to measure homocysteine levels. Patients that consumed more than 20 grams of alcohol per day were excluded from this study. RESULTS: The homocysteine level (11.56 vs. 8.05 nmol/L) and the proportion of non-alcoholic fatty liver disease (60.7% vs. 19.7%) were significantly higher in men than in women. In men, elevated serum homocysteine levels were associated with a greater prevalence of non-alcoholic fatty liver disease (quartile 1, 43.6%; quartile 4, 80.6%; P=0.01); however, in females, there was no significant association between serum homocysteine levels and the prevalence of non-alcoholic fatty liver disease. In the logistic regression model adjusted for age and potential confounding parameters, the odds ratio for men was significantly higher in the uppermost quartile (model 3, quartile 4: odds ratio, 6.78; 95% confidential interval, 1.67 to 27.56); however, serum homocysteine levels in women were not associated with non-alcoholic fatty liver disease in the crude model or in models adjusted for confounders. CONCLUSION: Serum homocysteine levels were associated with the prevalence of non alcoholic fatty liver disease in men. PMID- 27468344 TI - Multiple Cavitary Pulmonary Nodules Caused by Mycobacterium intracellulare. AB - Nontuberculous mycobacteria (NTM) have been increasingly recognized as an important cause of chronic pulmonary infections. The Mycobacterium avium complex (MAC), which is composed of two species, Mycobacterium avium and Mycobacterium intracelluare, is the most commonly encountered pathogen associated with NTM lung disease. MAC pulmonary infection typically presents in a fibrocavitary form or a nodular bronchiectatic form. However, there have been atypical presentations of MAC pulmonary infections, including solitary pulmonary nodules (SPN). There have been several previous reports of SPN due to MAC infection in the United States, Japan, and Korea. In 2009, Sekine and colleagues reported a case of MAC pulmonary infection presenting with multiple nodules. To date, however, there have been no cases of NTM lung infection with multiple cavitary pulmonary nodules, and neither a fibrotic change nor nodular bronchiectasis. The present case showed a multiple cavitating nodular lung infection due to MAC, which is very rare and different from the typical presentation of MAC pulmonary infections. We also showed that percutaneous transthoracic needle aspiration can be a useful diagnostic tool to evaluate a case of multiple cavitary nodules. PMID- 27468346 TI - Hyperamylasemia Related to Sertraline. PMID- 27468345 TI - Prevalence and Risk Factors of Domestic Violence against Iranian Women: A Cross Sectional Study. AB - BACKGROUND: Violence against women in families is the most common form of violence against them. The purpose of this study was to determine the prevalence of domestic violence and its effects on married women of Ilam. METHODS: In this descriptive-sectional research, 334 married women referred to medical health centers in Ilam were selected to participate using a random sampling method. After obtaining their consent to participate in the study, participants responded to a 46 items questionnaire and responses were analyzed using IBM SPSS for Windows ver. 20.0 (IBM Co., Armonk, NY, USA). RESULTS: The majority of the participants reported experiencing domestic violence and emotional violence was more prevalent than other kinds of violence. Logistic regression analysis showed that lower education level, marriage at a younger age, shorter duration of marriage, fewer children, being a housewife, and husband's unemployment had a significant relationship with domestic violence against women. CONCLUSION: The high prevalence of wife abuse in Ilam especially emotional violence due to lower education levels and marriage at younger age could be a serious threat for women's health as well as for other members of the family. This could be a grounding factor for other social harms such as suicide and this issue must be studied from legal, religious, and cultural standpoints. PMID- 27468347 TI - Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. AB - BACKGROUND: Not including female rats or mice in neuroscience research has been justified due to the variable nature of female data caused by hormonal fluctuations associated with the female reproductive cycle. In this study, we investigated whether female rats are more variable than male rats in scientific reports of neuroscience-related traits. METHODS: PubMed and Web of Science were searched for the period from August 1, 2010, to July 31, 2014, for articles that included both male and female rats and that measured diverse aspects of brain function. Only empirical articles using both male and female gonad-intact adult rats, written in English, and including the number of subjects (or a range) were included. This resulted in 311 articles for analysis. Data were extracted from digital images from article PDFs and from manuscript tables and text. The mean and standard deviation (SD) were determined for each data point and their quotient provided a coefficient of variation (CV) as a measure of trait-specific variability for each sex. Additionally, the results were coded for the type of research being measured (behavior, electrophysiology, histology, neurochemistry, and non-brain measures) and for the strain of rat. Over 6000 data points were extracted for both males and females. Subsets of the data were coded for whether male and female mean values differed significantly and whether animals were grouped or individually housed. RESULTS: Across all traits, there were no sex differences in trait variability, as indicated by the CV, and there were no sex differences in any of the four neuroscience categories, even in instances in which mean values for males and females were significantly different. Female rats were not more variable at any stage of the estrous cycle than male rats. There were no sex differences in the effect of housing conditions on CV. On one of four measures of non-brain function, females were more variable than males. CONCLUSIONS: We conclude that even when female rats are used in neuroscience experiments without regard to the estrous cycle stage, their data are not more variable than those of male rats. This is true for behavioral, electrophysiological, neurochemical, and histological measures. Thus, when designing neuroscience experiments to include both male and female rats, power analyses based on variance in male measures are sufficient to yield accurate numbers for females as well, even when the estrous cycle is not taken into consideration. PMID- 27429737 TI - DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations. AB - The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are no significant matches, the ligand cannot be docked in the protein. Otherwise, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. This provides the docked ligand in the target enzyme. Previously, CLASP was used to predict and validate (in vivo) the inhibition of phosphoinositide specific phospholipase C (PI-PLC) from Bacillus cereus by two dipeptidyl peptidase-IV (DPP4) inhibitors - vildagliptin and K-579. In the current work, vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. The docked ligand is free from steric clashes and interacts with the same side chain residues that bind myo-inositol, providing corroboration of the validity of the proposed methodology. PMID- 27429738 TI - regionReport: Interactive reports for region-level and feature-level genomic analyses. AB - regionReport is an R package for generating detailed interactive reports from region-level genomic analyses as well as feature-level RNA-seq. The report includes quality-control checks, an overview of the results, an interactive table of the genomic regions or features of interest and reproducibility information. regionReport provides specialised reports for exploring DESeq2, edgeR, or derfinder differential expression analyses results. regionReport is also flexible and can easily be expanded with report templates for other analysis pipelines. PMID- 27429737 TI - DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations. AB - The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already 'plastic' binding site. Thus, DOCLASP presents a method for 'soft docking' ligands to proteins with low computational requirements. PMID- 27468351 TI - Undernutrition and associated factors among adults living with Human Immune Deficiency Virus in Dembia District, northwest Ethiopia: an institution based cross-sectional study. AB - BACKGROUND: Appropriate dietary intake determines the disease progression and success of Anti-Retroviral Therapy (ART). Undernutrition unacceptably increases the risk of mortality among adults living with Human Immune Deficiency Virus (HIV). However in resource limited settings including Ethiopia, many of HIV positive clients lack access to sufficient quantities of nutritious food. There is limited evidences showing the magnitude of undernutrition in this segment of the community, particularly in the rural residents. Therefore, this study aimed to assess undernutrition and associated factors among HIV positive adults attending ART clinic in Dembia District. METHODS: An institution based cross sectional study was conducted in Dembia District from October 1 to 30, 2015. Systematic random sampling technique was used to recruit the study subjects. The anthropometric measurement, Body Mass Index, was computed to determine the nutritional status of the study participants. In order to identify factors associated with undernutrition a multivariable logistic regression analysis was employed. The Adjusted Odds Ratio (AOR) with 95 % Confidence Interval (CI) was calculated to show the strength of association. In multivariable analysis, variables with a P-value of <0.05 were considered as statistically significant. RESULTS: Of the study participants, about 23.2 % [95 % CI: 19.2, 27.2 %] were undernourished in Dembia District. The result of adjusted analysis revealed that, the odds of undernutrition was higher among adults whose age ranged between 18-29 years [AOR = 2.50, 95 % CI: 1.10, 5.69], who had a Cluster of Differentiation (CD)4 count less than 200 cells/mm(3) [AOR = 6.21, 95 % CI: 2.97, 12.98), were widowed [AOR = 2.18, 95 % CI: 1.08,4.40), and anemic [AOR = 3.17, 95 % CI: 1.70, 5.92]. CONCLUSIONS: The prevalence of undernutrition among HIV positive adults was higher in the study area. Furthermore, being in the age range of 18-29 years, widowed, anemic, and having a CD4 count of less than 200 cells/mm(3) were positively associated with undernutrition. Therefore, efforts should be strengthened to mitigate the higher burden of undernutrition by considering the identified determinants. PMID- 27468352 TI - The relation of weight suppression and BMIz to bulimic symptoms in youth with bulimia nervosa. AB - BACKGROUND: Weight suppression (WS), which is the difference between a patient's highest and current weight, has been associated with bulimic symptom severity in adults with bulimia nervosa (BN). However, the impact of WS on eating disorder psychopathology in youth with BN is unknown. METHODS: Participants included 85 youth with DSM-5 BN who presented for outpatient treatment. Current WS was calculated as the difference between highest and current body mass index z-score (BMIz), while greatest WS was the difference between highest and lowest BMIz, both assessed at participants' current height. Separate multivariable linear regressions were conducted to determine if current or greatest WS was significantly associated with frequency of binge eating, compensatory behaviors, or dietary restraint. A secondary analysis was conducted on youth ages 16 and older, given the limitation of assessing WS at current height in younger participants with greater height instability. RESULTS: Youth with higher levels of greatest WS (but not current WS) were older, had a longer duration of illness, and reported greater weight and shape concern. When adjusting for BMIz, neither current nor greatest WS was significantly associated with bulimic behaviors or dietary restraint in the full sample. However, in the subset of youth ages 16 and older, current WS moderated the effect of BMIz on binge eating and compensatory behaviors. For youth with high WS, those with a high current BMIz engaged in more frequent binge eating than those with low current BMIz, and the negative impact of BMIz on compensatory behaviors became weaker. CONCLUSIONS: Our findings suggest that WS is clinically relevant in the presentation of youth with BN, and that it may need to be addressed as one important factor in BN psychopathology. Future studies using growth charts to determine historically highest and lowest BMIz may help to further elucidate the link (or lack thereof) between WS and BN psychopathology in youth. PMID- 27468353 TI - Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori infection: a review of current diagnosis and management. AB - Helicobacter pylori (H. pylori)-associated gastritis is one of the most common infectious diseases in the United States, China and worldwide. Gastric mucosa associated tissue lymphoma (MALT lymphoma) is a rare mature B-cell neoplasm associated with H. pylori infection that is curable by antibiotics therapy alone. The pathological diagnosis of gastric MALT lymphoma can be reached by histological examination, immunohistochemical staining and B-cell clonality analysis. H. pylori eradication is the choice of therapy for early-stage gastric MALT lymphoma. High response rates and long-term survival have been reported in refractory and localized diseases treated with low-dose radiation therapy. Systemic chemotherapy is recommended for advanced-stage gastric MALT lymphoma and cases with large B-cell lymphoma transformation. Recent advances in the pathological diagnosis and management of gastric MALT lymphoma are reviewed in this article. PMID- 27468355 TI - Pancreatic developmental defect evaluated by celiac artery angiography in a patient with MODY5. AB - The hepatocyte nuclear factor 1beta gene (HNF1B) is responsible for maturity onset diabetes of the young type 5 (MODY5), which is characterized by early-onset diabetes mellitus and urogenital malformations. HNF1B is expressed during visceral endoderm formation. We identified a disruption of the great pancreatic artery in a patient with MODY5 with no pancreatic body or tail. Our finding supports the significance of HNF1B in the development of the pancreas. PMID- 27468354 TI - Fertility preservation in women with cervical, endometrial or ovarian cancers. AB - BACKGROUND: Although cancer in general affects an aged population, a significant number of women develop cancer at childbearing age. Long-term survival rates after gynecological cancer, especially in young patients are increasing and all quality-of-life aspects, including preservation of fertility have become of major relevance. OUTCOMES: Surgical techniques aimed at sparing reproductive organs and preserving fertility have been developed for women presenting with gynecological cancer found at early stages. Indications for fertility-sparing surgery are in general restricted to women presenting with a well-differentiated low-grade tumor in its early stages or with low malignant potential. Up to now, use of fertility sparing techniques in well-selected patients has not been shown to affect overall survival negatively and fertility outcomes reported have been favorable. Still larger amounts of data and longer follow-up periods are needed. Several current fertility-sparing cancer treatments may result in sub-fertility and in those cases assisted reproductive techniques are indicated. Overall quality of life has been satisfactory in cancer patients after fertility-sparing surgery. CONCLUSIONS: Fertility-sparing surgery is a viable tool to enable gynecological cancer patients of young age to fulfill their family building without impairment of oncological outcome. Cancer patients of reproductive age should undergo fertility counseling to analyze this sensitive subject. Further studies are needed to investigate the role of fertility-sparing treatment and combined adjuvant therapy in higher-grade cancers. PMID- 27468356 TI - Collagen-grafted porous HDPE/PEAA scaffolds for bone reconstruction. AB - After tumor resection, bone reconstruction such as skull base reconstruction using interconnected porous structure is absolutely necessary. In this study, porous scaffolds for bone reconstruction were prepared using heat-pressing and salt-leaching methods. High-density polyethylene (HDPE) and poly(ethylene-co acrylic acid) (PEAA) were chosen as the polymer composites for producing a porous scaffold of high mechanical strength and having high reactivity with biomaterials such as collagen, respectively. The porous structure was observed through surface images, and its intrusion volume and porosity were measured. Owing to the carboxylic acids on PEAA, collagen was successfully grafted onto the porous HDPE/PEAA scaffold, which was confirmed by FT-IR spectroscopy and electron spectroscopy for chemical analysis. Osteoblasts were cultured on the collagen grafted porous scaffold, and their adhesion, proliferation, and differentiation were investigated. The high viability and growth of the osteoblasts suggest that the collagen-grafted porous HDPE/PEAA is a promising scaffold material for bone generation. PMID- 27468357 TI - Hypertensive response to exercise: mechanisms and clinical implication. AB - A hypertensive response to exercise (HRE) is frequently observed in individuals without hypertension or other cardiovascular disease. However, mechanisms and clinical implication of HRE is not fully elucidated. Endothelial dysfunction and increased stiffness of large artery contribute to development of HRE. From neurohormonal aspects, excess stimulation of sympathetic nervous system and augmented rise of angiotensin II seems to be important mechanism in HRE. Increasing evidences indicates that a HRE is associated with functional and structural abnormalities of left ventricle, especially when accompanied by increased central blood pressure. A HRE harbors prognostic significance in future development of hypertension and increased cardiovascular events, particularly if a HRE is documented in moderate intensity of exercise. As supported by previous studies, a HRE is not a benign phenomenon, however, currently, whether to treat a HRE is controversial with uncertain treatment strategy. Considering underlying mechanisms, angiotensin receptor blockers and beta blockers can be suggested in individuals with HRE, however, evidences for efficacy and outcomes of treatment of HRE in individuals without hypertension is scarce and therefore warrants further studies. PMID- 27468358 TI - MicroRNA-26a inhibits osteosarcoma cell proliferation by targeting IGF-1. AB - There are still controversies about the roles of microRNA-26a (miR-26a) in human malignancies, as it is a tumor suppressor in breast cancer, gastric cancer, and hepatocellular carcinoma, but is an oncogene in glioma and cholangiocarcinoma. Until now, the function of miR-26a in osteosarcoma remains largely elusive. Here, we found that miR-26a was downregualted in osteosarcoma tissues. Using in vitro and in vivo assays, we confirmed that miR-26a could inhibit the abilities of in vitro proliferation and suppress in vivo tumor growth in mouse model. Furthermore, we identified insulin-like growth factor 1 (IGF-1) as a novel and direct target of miR-26a and revealed that miR-26a exerted its tumor-suppressor function, at least in part, by inhibiting IGF-1 expression. These findings contribute to our understanding of the functions of miR-26a in osteosarcoma. PMID- 27468359 TI - The hypoxia-inducible factor-1alpha activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. AB - Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-1alpha (HIF-1alpha) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1alpha mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-1alpha and FGF23 were co-localized in spindle-shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-1alpha protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1alpha expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1alpha inhibitors decreased HIF-1alpha and FGF23 protein accumulation and inhibited HIF 1alpha-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1alpha consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF 1alpha inhibitor. These results show for the first time that HIF-1alpha is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF 1alpha activity in TIO contributes to the aberrant FGF23 production in these patients. PMID- 27468362 TI - Synthesizing a Cellulase like Chimeric Protein by Recombinant Molecular Biology Techniques. AB - In order to meet the Renewable Fuels Standard demands for 30 billion gallons of biofuels by the end of 2020, new technologies for generation of cellulosic ethanol must be exploited. Breaking down cellulose by cellulase enzyme is very important for this purpose but this is not thermostable and degrades at higher temperatures in bioreactors. Towards creation of a more ecologically friendly method of rendering bioethanol from cellulosic waste, we attempted to produce recombinant higher temperature resistant cellulases for use in bioreactors. The project involved molecular cloning of genes for cellulose-degrading enzymes based on bacterial source, expressing the recombinant proteins in E. coli and optimizing enzymatic activity. We were able to generate in vitro bacterial expression systems to produce recombinant His-tag purified protein which showed cellulase like activity. PMID- 27468361 TI - Reducing HIV risk among Hispanic/Latino men who have sex with men: Qualitative analysis of behavior change intentions by participants in a small-group intervention. AB - OBJECTIVE: The southeastern United States has the fastest-growing Hispanic/Latino population in the country and carries a disproportionate HIV burden. Among Hispanics/Latinos, men, and men who have sex with men (MSM) in particular, are at elevated risk of HIV infection; however, very few efficacious behavioral HIV prevention interventions are available for use with this vulnerable population. To address this shortage of prevention resources, our community-based participatory research (CBPR) partnership developed and is currently evaluating the efficacy of the HOLA en Grupos intervention to increase condom use and HIV testing among Hispanic/Latino MSM. METHODS: We recruited 304 Hispanic/Latino MSM who were randomized to receive the small group HOLA en Grupos intervention that was implemented during four 4-hour long sessions over four consecutive Sundays, or a 4-session small group general health education comparison intervention. At the end of the fourth session of the HOLA en Grupos intervention, the intervention facilitators asked participants to write down the sexual health related behaviors they intended to change as a result of their participation. RESULTS: Qualitative analysis of the participants' responses identified six types of intended behavior changes: increasing and maintaining condom use; identifying strategies to support correct and consistent condom use; increasing communication and negotiation with sexual partners about condom use; getting tested for HIV and other sexually transmitted infections; applying other sexual health promotion strategies; and sharing newly learned sexual health information with their peers. CONCLUSION: Most risk-reduction intentions aligned with the intervention's key messages of using condoms consistently and getting tested for HIV. However, participants' stated intentions may have also depended on which behavior changes they perceived as most salient after participating in the intervention. Participants' intentions to share information with their peers may result in elements of the intervention content reaching others within their social networks, and potentially contributing to a broader community-level impact. PMID- 27468363 TI - Mode of Delivery in Premature Neonates: Does It Matter? AB - OBJECTIVE: Despite the current prevalence of preterm births, no clear guidelines exist on the optimal mode of delivery. Our objective was to investigate the effects of mode of delivery on neonatal outcomes among premature infants in a large cohort. STUDY DESIGN: We applied a retrospective cohort study design to a database of 6,408 births. Neonates were stratified by birth weight and a composite score was calculated to assess neonatal outcomes. The results were then further stratified by fetal exposure to antenatal steroids, birth weight, and mode of delivery. RESULTS: No improvement in neonatal outcome with cesarean delivery (CD) was noted when subjects were stratified by mode of delivery, both in the presence or absence of antenatal corticosteroid administration. In the 1,500 to 1,999 g subgroup, there appears to be an increased risk of respiratory distress syndromes in neonates born by CD. CONCLUSION: In our all-comers cohort, replicative of everyday obstetric practice, CD did not improve neonatal outcomes in preterm infants. PMID- 27468360 TI - A review of UHMWPE wear-induced osteolysis: the role for early detection of the immune response. AB - In a world where increasing joint arthroplasties are being performed on increasingly younger patients, osteolysis as the leading cause of failure after total joint arthroplasty (TJA) has gained considerable attention. Ultra-high molecular weight polyethylene wear-induced osteolysis is the process by which prosthetic debris mechanically released from the surface of prosthetic joints induces an immune response that favors bone catabolism, resulting in loosening of prostheses with eventual failure or fracture. The immune response initiated is innate in that it is nonspecific and self-propagating, with monocytic cells and osteoclasts being the main effectors. To date, detecting disease early enough to implement effective intervention without unwanted systemic side effects has been a major barrier. These barriers can be overcome using newer in vivo imaging techniques and modules linked with fluorescence and/or chemotherapies. We discuss the pathogenesis of osteolysis, and provide discussion of the challenges with imaging and therapeutics. We describe a positron emission tomography imaging cinnamoyl-Phe-(D)-Leu-Phe-(D)-Leu-Phe-Lys module, specific to macrophages, which holds promise in early detection of disease and localization of treatment. Further research and increased collaboration among therapeutic and three dimensional imaging researchers are essential in realizing a solution to clinical osteolysis in TJA. PMID- 27468364 TI - Infantile Hepatic Hemangioendothelioma: An Uncommon Cause of Persistent Pulmonary Hypertension in a Newborn Infant. AB - Multifocal and diffuse infantile hepatic hemangioendotheliomas commonly present with signs of high-output congestive heart failure. In addition, prolonged persistent pulmonary overcirculation eventually leads to the development of pulmonary hypertension at a later age. We report a 2-day old, full-term infant with multifocal, large infantile hepatic hemangioendothelioma, who presented with an early onset of pulmonary hypertension, managed successfully with supportive care and systemic therapy directed toward the involution of infantile hepatic hemangioendothelioma. PMID- 27468365 TI - Complete remission after single agent blinatumomab in a patient with pre-B acute lymphoid leukemia relapsed and refractory to three prior regimens: hyperCVAD, high dose cytarabine mitoxantrone and CLAG. AB - BACKGROUND: The current standard of care for relapsed and refractory acute lymphoblastic leukemia (ALL) is combination chemotherapy. CASE PRESENTATION: We report a case of highly refractory ALL who was treated with blinatumomab. The ALL in this patient relapsed within a month after completion of hyperCVAD regimen and was refractory to high dose mitoxantrone/cytarabine and CLAG regimens. CONCLUSION: This highly refractory pre-B Ph(-) ALL was induced to complete remission after one course of single agent blinatumomab. PMID- 27468366 TI - Management of the Essex-Lopresti Injury. AB - Essex-Lopresti injuries (ELIs) are characterized by fracture of the radial head, disruption of the forearm interosseous membrane, and dislocation of the distal radioulnar joint. This injury pattern results in axial and longitudinal instability of the forearm. Initial radiographs may fail to reveal the full extent of the injury, and therefore diagnosis in the acute setting requires a high index of suspicion. Early recognition and treatment are preferred as failure to fully treat the problem may result in chronic wrist pain from ulnar abutment or chronic elbow pain from radiocapitellar arthrosis. In this article the presentation, relevant anatomy, and management options for ELIs are overviewed, and a summary of outcomes reported in the literature is provided. Additionally, the preferred surgical technique of the senior author is presented, which involves reconstruction of the interosseous membrane with a local pronator rerouting autograft. PMID- 27468367 TI - Suture-Button Reconstruction of the Interosseous Membrane. AB - BACKGROUND: Reconstruction of the interosseous membrane (IOM) may play a role in the treatment of acute and chronic longitudinal forearm instability. Several reconstruction techniques have been proposed. Suture-button reconstruction is attractive because it obviates donor site morbidity and is relatively easy to perform. How this method compares to its alternatives, however, is unknown. MATERIALS AND METHODS: We review literature describing reconstruction of the forearm axis. We describe how we perform suture-button reconstruction of the IOM, summarize our previously published biomechanical data on the subject, and offer a case report. DESCRIPTION OF TECHNIQUE: A suture-button is implanted so as to approximate the course of the interosseous ligament. This may be accomplished percutaneously, or when grafting is desired, through an open approach. RESULTS: Data informing the choice of one reconstruction technique over another consist mostly of biomechanical studies and a small number of case reports. CONCLUSIONS: Suture-button reconstruction of the IOM may encourage anatomic healing of acute forearm axis injuries especially as an adjunct to radial head replacement or repair. Chronic injuries may benefit from a combination suture-button graft construct and ulnar shortening osteotomy. PMID- 27468368 TI - Central Band Interosseous Membrane Reconstruction For Forearm Longitudinal Instability. AB - BACKGROUND: The Essex-Lopresti injury results from injuries to the stabilizing structures of the forearm, the radial head, the interosseous membrane, and the triangular fibrocartilage complex. CASE DESCRIPTION/LITERATURE REVIEW: We describe principles in approaching the patient with an acute or chronic Essex Lopresti injury and describe surgical techniques to address these challenging cases both in the acute and chronic setting and describe outcomes of these techniques. CLINICAL RELEVANCE: Further research into the role of the interosseous ligament in providing longitudinal and transverse stability to the forearm is likely to change our understanding of the Essex-Lopresti injury and alter management strategies. PMID- 27468369 TI - Interosseous Membrane of the Forearm. AB - BACKGROUND: Injuries of the interosseous membrane (IOM) of the forearm are frequently unrecognized, difficult to treat, and can result in a devastating sequelae for the wrist and elbow. PURPOSE: The purpose of this review article is to evaluate the dignosis, biomechanics, clinical results, and propose a treatment approach to this rare complex entity. METHODS: The biomechanical and clinical literature is reviewed. A treatment approach is described based on the known biomechanics and clinical experience of the senior author (T. W. W.). RESULTS: Multiple different reconstructive methods have been proposed for the treatment of both acute and chronic IOM injuries. The results of the published series are reviewed. IOM injuries can have reasonable outcomes particularly if diagnosed and treated early. CONCLUSION: There are multiple methods for treating patients with IOM injuries. Physicians should be highly suspicious about this injury when a patient presents with a highly displaced radial head fracture associated with wrist pain. Treatment with reconstruction of the cerebral band of the IOM with radial head replacement (do not overstuff) and temporary uploading the construct with K-wires from the ulna to the radius will give the most predictable results. PMID- 27468370 TI - Dorsal or Volar Plate Fixation of the Distal Radius: Does the Complication Rate Help Us to Choose? AB - BACKGROUND: Internal fixation with plates is a reliable fixation technique for the treatment of distal radius fractures. An ongoing discussion exists whether volar or dorsal plating is the appropriate technique. In clinical practice, volar plate fixation is usually preferred because of the assumed lower complication frequency. However, recent studies with the newer generation low-profile dorsal plates reported lower complication rates. PURPOSE: The aim of our study was to evaluate the differences in complication rates between volar and dorsal plate for the treatment of distal radius fractures in adult patients. PATIENTS AND METHODS: A total of 214 patients with acute distal radius fractures were included in this retrospective study with a minimum 2 years of follow-up. In total, 123 patients were treated with dorsal plate fixation and 91 patients with volar plate fixation. Our primary study outcome was complication rate. RESULTS: The overall risk for complications was 15.4% in the dorsal group and 14.3% in the volar group (p = 0.81). A total of 19 patients had implant removal due to complications: 11 patients in the dorsal group and 8 patients in the volar group (p = 0.97). CONCLUSION: There is no preferred plate fixation technique based on these study results. In our opinion, decision for type of plate fixation should be based on fracture type and surgeon's experience with the specific approach and plate types. LEVEL OF EVIDENCE: Therapeutic level III. PMID- 27468371 TI - Trends in the Utilization of Total Wrist Arthroplasty versus Wrist Fusion for Treatment of Advanced Wrist Arthritis. AB - BACKGROUND: Total wrist arthroplasty (TWA) provides the requisite range of motion to accomplish activities of daily living, especially for low-demand patients with bilateral wrist arthritis. However, there are no large epidemiologic studies to evaluate nationwide trends of TWA and wrist fusion (WF). QUESTIONS/PURPOSES: To analyze data collected from the National Inpatient Sample (NIS) to compare utilization, demographic, and outcome data among patients undergoing TWA versus total WF. We hypothesized that utilization rates of TWA have significantly increased over the prior decade in the United States. METHODS: NIS data from 2001 to 2010 were reviewed. Procedures were identified by ICD-9-CM codes 81.73 (TWA) and 81.25 (WF). Utilization rates, primary treatment diagnoses, patient demographic and medical comorbidity data, and procedure costs were compared between TWA and WF. RESULTS: There was a decrease in the number of procedures per year for TWA, while the number of WF remained relatively unchanged. There was, however, a transient increase in the frequency of TWA procedures performed from 2005 to 2008, following a decline in 2005. Patients with traumatic arthritis were more likely to receive WF. Rheumatoid patients were more likely to receive TWA. Patients receiving TWA tended to be older, female, be insured by Medicare, have a greater comorbidity burden, and have rheumatologic disease. CONCLUSION: WF was performed nearly four times more frequently than TWA. A trend was demonstrated toward a decreasing number of TWA being implanted, and in patients with more underlying comorbidities. TWA was associated with a higher hospitalization charge, which may be expected given the higher implant costs associated with arthroplasty. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 27468372 TI - Distal Radius Hemiarthroplasty. AB - INTRODUCTION: Due to a higher risk for implant loosening, particularly of the distal component, patients with physically demanding lifestyles are infrequently considered for total wrist arthroplasty (TWA). A distal radius hemiarthroplasty may obviate the need for the strict restrictions recommended for patients treated by TWA, thus providing another surgical option for active patients with severe wrist arthritis, especially those with articular degeneration of the lunate facet of the radius, capitate head, or combination of both, who are not typically candidates for traditional motion-preserving procedures. MATERIALS AND METHODS: Eight fresh-frozen cadaver limbs (age range, 43-82 years) with no history of rheumatoid arthritis or upper extremity trauma were used. Radiodense markers were inserted in the radius and hand. Posteroanterior (PA) fluoroscopic images with the wrist in neutral, radial deviation, and ulnar deviation, and lateral images with the wrist in neutral, flexion, and extension were obtained for each specimen before implantation, after distal radius hemiarthroplasty, and after combined hemiarthroplasty and PRC. RESULTS: On the PA images, the capitate remained within 1.42 and 2.21 mm of its native radial-ulnar position following hemiarthroplasty and hemiarthroplasty with PRC, respectively. Lateral images showed the capitate remained within 1.06 mm of its native dorsal-volar position following hemiarthroplasty and within 4.69 mm following hemiarthroplasty with PRC. Following hemiarthroplasty, capitate alignment changed 2.33 and 2.59 mm compared with its native longitudinal alignment on PA and lateral films, respectively. These changes did not reach statistical significance. As expected, significant shortening in longitudinal alignment was seen on both PA and lateral films for hemiarthroplasty with PRC. CONCLUSION: A distal radius implant hemiarthroplasty with or without a PRC provides good static alignment of the wrist in a cadaver model and thus supports the concept as potential treatment alternatives for advanced wrist arthritis; however, combined hemiarthroplasty with a PRC has more clinical relevance because it avoids the risk of proximal carpal row instability and eliminates the commonly arthritic radioscaphoid joint. PMID- 27468373 TI - Three-Dimensional Carpal Kinematics after Carpal Tunnel Release. AB - BACKGROUND: Carpal tunnel release (CTR) has been shown to change carpal arch morphology. However, the effect of CTR on the three-dimensional kinematics of the carpal bones has not been demonstrated. PURPOSE: This study examined whether release of the transverse carpal ligament (TCL) would alter the three-dimensional kinematics of the carpus, specifically the bony attachments of the TCL. METHODS: The in vitro kinematics of the carpus was studied in five fresh-frozen cadaveric wrists before and after CTR using three-dimensional computed tomography. The specimens were evaluated in three positions: neutral, 60 degrees of flexion, and 60 degrees of extension. RESULTS: The data indicate that carpal arch width increases significantly in all positions after CTR as measured between the trapezium and hamate. Second, the trapezium-hamate distance increases in both a translational and rotational component after CTR. Additionally, the pisiform rotates away from the triquetrum after CTR. CONCLUSIONS: Carpal kinematics is significantly altered with a CTR, especially on the ulnar side of the wrist. CLINICAL RELEVANCE: Although the kinematic changes are small, they may be clinically significant and potentially responsible for pillar pain or postoperative loss of grip strength. PMID- 27468374 TI - Arthroscopic Resection of Distal Pole of the Scaphoid for Scaphotrapeziotrapezoid Joint Arthritis: Comparison between Simple Resection and Implant Interposition. AB - BACKGROUND: Isolated scaphotrapeziotrapezoid is a relatively rare condition, and there is still not complete consensus on the treatment of this pathology. PURPOSE: The aim of the present study is to assess the utility of implant interposition after arthroscopic scaphoid distal pole resection for scaphotrapeziotrapezoid arthritis. MATERIAL AND METHODS: The authors present a prospective study after the arthroscopic resection of the distal pole of the scaphoid in 24 patients. In a group of 11 patients, the simple resection was performed while in the other 13 patients the scaphoid resection and pyrocarbone implant interposition. RESULTS: All patients were clinically evaluated with disability of arm, shoulder, hand score. Dorsal intercalated segment instability deformity was also measured from X-ray analysis. Grip and pinch strength were measured too, and patients were also given a visual analog scale questionnaire. Both clinical and radiographic assessments were done at 24 months postoperatively. CONCLUSIONS: The study showed comparable results with both the techniques. LEVEL OF EVIDENCE II: A prospective comparative study. PMID- 27468375 TI - Bilateral Complete Osseous Coalition of the Capitate and Trapezoid. AB - BACKGROUND: Isolated capitate-trapezoid coalition is a rare form of carpal coalition with few cases described in the literature and a little insight as to how it should be addressed clinically. CASE DESCRIPTION: We present a case of bilateral, a complete osseous carpal coalition between capitate and trapezoid discovered in the setting of atraumatic, symptomatic scapholunate dissociation in a 59-year-old, right-handed mechanic. LITERATURE REVIEW: Published reports of capitate-trapezoid coalition are rare, and there is no consensus as to whether this abnormality is a symptomatic pathology or incidental finding. Most reports describe the finding, but do not recommend a course of treatment; several recommend surgery, but the patient declined or it was not mentioned whether it was performed. CLINICAL RELEVANCE: Capitate-trapezoid coalition is a rare condition that may present symptomatically or may be found incidentally. Reports are scant, and there are no guidelines for how to address these clinically. We present the first bilateral case report of capitate-trapezoid coalition confirmed with cross-sectional imaging and present a treatment algorithm. PMID- 27468376 TI - Multiple Volar Carpometacarpal Dislocations: Case Report/Review of the Literature. AB - Simultaneous volar dislocations of the second through fifth carpometacarpal joints are rare injuries, usually a result of high-energy trauma to the hand. The literature regarding this topic is sparse and consists primarily of case reports. We present a case associated with median nerve contusion that was treated with open reduction and pin fixation. The median nerve injury resolved without incident, and the pins were removed at 10 weeks without loss of reduction. Three years postoperatively, the patient was without pain and had excellent use of his hand without strength or motion deficit. PMID- 27468377 TI - Single-Incision Carpal Tunnel Release and Distal Radius Open Reduction and Internal Fixation: A Cadaveric Study. AB - BACKGROUND: The safety of surgical approaches for single- versus double-incision carpal tunnel release in association with distal radius open reduction and internal fixation remains controversial. PURPOSE: The purpose of this study was to identify critical structures to determine if a single-incision extension of the standard flexor carpi radialis (FCR) approach can be performed safely. METHODS: Nine cadaveric arms with were dissected under loupe magnification, utilizing a standard FCR approach. After the distal radius exposure was complete, the distal portion of the FCR incision was extended to allow release of the carpal tunnel. Dissection of critical structures was performed, including the recurrent thenar motor branch of the median nerve, the palmar cutaneous branch of the median nerve (PCBm), the palmar carpal and superficial palmar branches of the radial artery, and proximally the median nerve proper. The anatomic relationship of these structures relative to the surgical approach was recorded. RESULTS: Extension of the standard FCR approach as described in this study did not damage any critical structure in the specimens dissected. The PCBm was noted to arise from the radial side of the median nerve an average of 6.01cm proximal to the proximal edge of the transverse carpal ligament. The PCBm became enveloped in the layers of the antebrachial fascia and the transverse carpal ligament at the incision site, protecting it from injury. The recurrent motor branch of the median nerve, branches of the radial artery and the median nerve proper were not at risk during extension of the FCR approach to release the carpal tunnel. CONCLUSIONS: Extension of the standard FCR approach to include carpal tunnel release can be performed with minimal risk to the underlying structures. This exposure may offer benefits in both visualization and extent of carpal tunnel release. PMID- 27468378 TI - Gender based Dosing of Metoprolol in the Elderly using Population Pharmacokinetic Modeling and Simulations. AB - INTRODUCTION: This article seeks to clarify if gender-based differences occur in the pharmacokinetics of metoprolol in the elderly patients. There are a series of physiologic changes that occur in the elderly ranging from decreased hepatic blood flow to increased adiposity causing higher plasma concentrations at therapeutic doses as compared to the healthy young population. METHODS: Population pharmacokinetic modeling were performed using MONOLIX and Monte-Carlo simulations were conducted using MATLAB. The data was based from a previously published dataset where elderly patients, having multiple comorbidities, were administered a 50mg dose of metoprolol. RESULTS: Metoprolol was modeled using a one-compartment model and resulted in the following population pharmacokinetic parameters: volume of distribution, V=38L (CV=155%), clearance rates, CL Men=105L/hour and CL-Women=59.1L/hour (38%), time lag, Tlag=0.469 hour (CV=17%), and the absorption rate constant, Ka=0.235 hr-1 (CV=23%). CONCLUSION: Gender stratified doses resulting in an equivalent systemic metoprolol exposure in geriatric patients have been identified. Metoprolol doses resulting a similar AUC in a healthy young male administered 50mg tablet were 15mg for geriatric women and 25mg for geriatric men. Further, Metoprolol doses of 25mg for geriatric women and 50mg for geriatric men resulted in an equivalent AUC to a healthy young males dosed with a 100mg tablet. A 15mg Metoprolol tablet may need to be compounded to account for the gender differences in Metoprolol pharmacokinetics. PMID- 27468379 TI - Identifying Treatment Response of Sertraline in a Teenager with Selective Mutism using Electrophysiological Neuroimaging. AB - BACKGROUND: Selective Mutism is described as the inability to verbally express oneself in anxiety provoking social situations and may result in awkward social interactions in school-aged children. In this case-report we present the baseline electrophysiological neuroimaging results and after treatment with Sertraline for 6-weeks. METHODS: A 20-channel EEG event-related potential recording was acquired during an internal voice task at baseline prior to the initiation of 50mg of Sertraline and then repeated 6-weeks after treatment with Sertraline. EEG signals were processed for movement, eye-blink, and muscle artifacts and ERP signal averaging was completed. ERPs were analyzed using Standard Low Resolution Brain Electromagnetic Tomography (sLORETA). RESULTS: At baseline, Sertraline increased the neuronal activation in the middle temporal gyrus and the anterior cingulate gyrus from baseline in the patient following 6-weeks of treatment. CONCLUSION: Our findings suggest that electrophysiological neuroimaging may provide a creative approach for personalizing medicine by providing insight to the pharmacodynamics of antidepressants. PMID- 27468380 TI - Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A New Challenging Entity for Consultation-Liaison Psychiatrist. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a relatively newly identified autoimmune neuropsychiatric disorder that predominantly affects children and young adults. Although psychiatric symptoms are highly prevalent and frequently severe, it has mainly been reported in neurological, but not psychiatric, literature. Understanding this form of encephalitis, its quick diagnosis and which treatment to provide are of utmost importance for consultation-liaison (C-L) psychiatrists. The aim of this paper was to describe a case of anti-NMDAR encephalitis with severe psychiatric manifestations, who showed impressive recovery but required intensive involvement of the C-L psychiatry team. We emphasise the behavioural aspects, psychiatric symptoms and challenges faced by the CL consultant across the different phases of the treatment. METHODS: We report the different treatment phases for a young woman with anti-NMDAR encephalitis who developed severe neuropsychiatric symptoms, with a focus on the role and challenges faced by the C-L psychiatrist. The literature is reviewed for each of these challenges. RESULTS: This case illustrated that even extremely severely affected patients may show impressive recovery, but require long lasting psychiatric care. C-L psychiatrists are faced with numerous challenges where only little literature is available. CONCLUSION: C L psychiatrists play a pivotal role throughout the multidisciplinary care of patients with anti-NMDAR encephalitis and should be informed about this entity. PMID- 27468382 TI - Classification of different Hepatitis B infected individuals with saturated incidence rate. AB - The role of incidence rate is very important in the study of epidemiological models. In this article, the analysis of an epidemic problem for the transmission dynamic of HBV with saturated incidence rate is presented, which is more generalize than bilinear incidence rate. After formulating the new mathematical model, the threshold quantity reproduction number [Formula: see text] is investigated by using the well known approach i.e. next generation matrix and investigate the possible equilibriums such as disease free and endemic equilibria. Then for the local and global behavior of the proposed problem, the local asymptotic stability analysis as well as global asymptotic stability analysis are proved. To prove the global asymptotic stability at disease free equilibrium, the classic Lyapunov function theory is considered. Similarly to show global asymptotic stability at endemic equilibria, the geometrical approach is used, which is the generalization of Lyapunov theory. Finally, numeric of the proposed problem are carried out to show the feasibility of the obtained results and the role of saturated incidence rate. PMID- 27468381 TI - Realist theory construction for a mixed method multilevel study of neighbourhood context and postnatal depression. AB - BACKGROUND: We have recently described a protocol for a study that aims to build a theory of neighbourhood context and postnatal depression. That protocol proposed a critical realist Explanatory Theory Building Method comprising of an: (1) emergent phase, (2) construction phase, and (3) confirmatory phase. A concurrent triangulated mixed method multilevel cross-sectional study design was described. The protocol also described in detail the Theory Construction Phase which will be presented here. METHODS: The Theory Construction Phase will include: (1) defining stratified levels; (2) analytic resolution; (3) abductive reasoning; (4) comparative analysis (triangulation); (5) retroduction; (6) postulate and proposition development; (7) comparison and assessment of theories; and (8) conceptual frameworks and model development. THEORY CONSTRUCTION: The stratified levels of analysis in this study were predominantly social and psychological. The abductive analysis used the theoretical frames of: Stress Process; Social Isolation; Social Exclusion; Social Services; Social Capital, Acculturation Theory and Global-economic level mechanisms. Realist propositions are presented for each analysis of triangulated data. Inference to best explanation is used to assess and compare theories. A conceptual framework of maternal depression, stress and context is presented that includes examples of mechanisms at psychological, social, cultural and global-economic levels. Stress was identified as a necessary mechanism that has the tendency to cause several outcomes including depression, anxiety, and health harming behaviours. The conceptual framework subsequently included conditional mechanisms identified through the retroduction including the stressors of isolation and expectations and buffers of social support and trust. CONCLUSION: The meta-theory of critical realism is used here to generate and construct social epidemiological theory using stratified ontology and both abductive and retroductive analysis. The findings will be applied to the development of a middle range theory and subsequent programme theory for local perinatal child and family interventions. PMID- 27468383 TI - An emerging trend of equal authorship credit in major public health journals. AB - BACKGROUND: This study aimed to identify the longitudinal trends and characteristics of the practice of explicitly giving equal credit to multiple authors of publications in public health journals. Manual searches were conducted to identify original research articles, published in five public health journals with the highest IFs according to the "2012 JCR Science Edition" between January 1, 2004 and December 31, 2013, which awarded equal credit to multiple authors (Epidemiologic Reviews, Environmental Health Perspectives, the International Journal of Epidemiology, Epidemiology, and the Annual Review of Public Health). The Instructions to Authors in the five journals were also examined with regard to information about giving equal credit to multiple authors. FINDINGS: Statistically significant differences were noted in the annual prevalence in Environmental Health Perspectives, International Journal of Epidemiology, and Epidemiology (r = 0.753, P = 0.012; r = 0.894, P = 0.000; r = 0.522, P = 0.122, respectively). The first two authors listed in the by-line received equal credit in the majority of articles, but this practice was also extended to authors in nearly every position on the by-line in some publications. The authors given equal credit in articles appearing in Environmental Health Perspectives, International Journal of Epidemiology, and Epidemiology were primarily from European and North American countries. Finally, none of the journals provided specific guidance regarding this practice in their Instructions to Authors. CONCLUSIONS: An emerging trend of giving equal credit to multiple authors is observed in the public health journals. This practice should be better addressed in the guidance provided by journals to authors. PMID- 27468384 TI - The protective effect of hydrogen sulfide on systemic sclerosis associated skin and lung fibrosis in mice model. AB - BACKGROUD: Systemic sclerosis (SSc) caused fibrosis can be fatal and it still lack of effective treatment. Hydrogen sulfide (H2S) appears to be an attractive therapeutic candidates. This study aimed to investigate the protective effect of H2S on SSc-associated skin and lung fibrosis. METHODS: We developed a model of SSc by subcutaneous injecting BLM to female C3H mice. The mice received daily subcutaneous injections of NaHS (56 and 112 MUg/kg), an H2S donor. On days 7, 28, and 42, the mice were killed and blood samples were collected to measure the plasma H2S concentration, the skin and lung tissues was harvested for microscopic examination, immunohistochemistry and quantify biological parameters (hydroxyproline content, RT-qPCR and Western blot). RESULTS: In model group, the dermis of skin tissues at different time points gradually thickened, collagen deposition increased. The lung tissues presented pathological changes such as obvious inflammatory cell infiltration, increased collagen deposition and the plasma H2S concentrations points significantly decreased. Administration of NaHS markedly decreased the biomarkers of fibrosis such as alpha-smooth muscle actin, collagen-I, collagen-III, fibronectin, transforming growth factor-beta1, Smad2/3 phosphorylation and inflammation including the marker protein of monocyte/macrophage and monocyte chemoattractant protein-1 in the lung. Compared to the low dose group, the expression in the high dose group have decreased trend, but the difference was not significant. CONCLUSION: We demonstrate the beneficial effects of H2S on SSc-associated skin and lung fibrosis. H2S may be a potential therapy against this intractable disease. PMID- 27468385 TI - Bacteria of the genus Rhodopseudomonas (Bradyrhizobiaceae): obligate symbionts in mycelial cultures of the black truffles Tuber melanosporum and Tuber brumale. AB - BACKGROUND: This work aimed at characterizing 12 isolates of the genus Tuber including Tuber melanosporum (11 isolates) and Tuber brumale (one isolate). This was done using internal transcribed spacer (ITS) sequences, confirming their origin. RESULTS: Analysis of their mating type revealed that both MAT1-1 and MAT1 2 exist within these isolates (with 3 and 8 of each, respectively). We observed that each of these cultures was consistently associated with one bacterium that was intimately linked to fungal growth. These bacterial associates failed to grow in the absence of fungus. We extracted DNA from bacterial colonies in the margin of mycelium and sequenced a nearly complete 16S rDNA gene and a partial ITS fragment. We found they all belonged to the genus Rhodopseudomonas, fitting within different phylogenetic clusters. No relationships were evidenced between bacterial and fungal strains or mating types. Rhodopseudomonas being a sister genus to Bradyrhizobium, we tested the nodulation ability of these bacteria on a promiscuously nodulating legume (Acacia mangium), without success. We failed to identify any nifH genes among these isolates, using two different sets of primers. CONCLUSIONS: While the mechanisms of interaction between Tuber and Rhodopseudomonas remain to be elucidated, their interdependency for in vitro growth seems a novel feature of this fungus. PMID- 27468386 TI - Preliminary characterization of a novel beta-agarase from Thalassospira profundimonas. AB - BACKGROUND: The objective of this study was to characterize the agarase from a newly isolated agarolytic bacterium Thalassospira profundimaris fst-13007. RESULTS: Agarase-fst was purified to homogeneity which apparent molecular weight was 66.2 kDa. Its activity was optimal at 45 degrees C and pH 8 and was stable at pH 5-9 or 30-50 degrees C. Agarase-fst required Mn(2+) for agarase activity and inhibition by Cu(2+), Fe(3+) and EDTA. Tests of hydrolysis pattern and substrate specificity, TLC analysis and mass spectrometry of the hydrolysis products revealed that it is an endo-type beta-agarase hydrolyzing agarose into neoagarobiose, neoagarotetraose and neoagarohexaose. Results of MALDI-TOF-TOF/MS indicate that it lack of homology to previously identified proteins and present conserved domain of beta-agarase. CONCLUSION: Agarase-fst from T. profundimaris fst-13007 was confirmed to be a novel endo-type beta-agarase. PMID- 27468387 TI - Population genetic structure analysis and forensic evaluation of Xinjiang Uigur ethnic group on genomic deletion and insertion polymorphisms. AB - BACKGROUND: The Uigur ethnic minority is the largest ethnic group in the Xinjiang Uygur Autonomous Region of China, and valuable resource for the study of ethnogeny. The objective of this study was to estimate the genetic diversities and forensic parameters of 30 insertion-deletion loci in Uigur ethnic group from Xinjiang Uigur Autonomous Region of China and to analyze the genetic relationships between Xinjiang Uigur group and other previously published groups based on population data of these loci. RESULTS: All the tested loci were conformed to Hardy-Weinberg equilibrium after Bonferroni correction. The observed and expected heterozygosity ranged from 0.3750 to 0.5515; and 0.4057 to 0.5037, respectively. The combined power of discrimination and probability of exclusion in the group were 0.99999999999940 and 0.9963, respectively. We analyzed the D A distance, interpopulation differentiations and population structure, conducted principal component analysis and neighbor-joining tree based on our studied group and 21 reference groups. The present results indicated that the studied Xinjiang Uigur group (represented our samples from the whole territory of Xinjiang Uigur Autonomous Region) had a close relationships with Urumchi Uigur (represented previously reported samples from Urumchi of Xinjiang) and Kazak groups. CONCLUSIONS: The present study may provide novel biological information for the study of population genetics, and can also increase our understanding of the genetic relationships between Xinjiang Uigur group and other groups. PMID- 27468388 TI - Identification of differentially expressed genes implicated in peel color (red and green) of Dimocarpus confinis. AB - Nowadays, there are few reports about regulatory genes implicated in peel color of longan. The basic genetic research of longan has been in stagnation for a long time as a lack of transcriptomic and genetic information. To predict candidate genes associated with peel color, Gene Functional Annotation and Coding Sequence prediction were used to perform functional annotation for our assembled unigenes and investigate differentially expressed genes (DEGs) of fruitlet peels from Longli (Dimocarpus confinis). Finally, a total of 24,044 (44.19 %) unigenes were annotated at least in one database after BLAST search to NCBI non-redundant protein sequence, NCBI non-redundant nucleotide sequences, Kyoto Encyclopedia of Genes and Genomes (KEGG) Ortholog, manually annotated and reviewed protein sequence database (Swiss-Prot), Protein family, Gene Ontology, euKaryotic Ortholog Groups databases. After searching against the KEGG-GENE protein database, a result of 6228 (11.45 %) unigenes were assigned to 245 KEGG pathways. Via comparing the distributions of expression value of all corresponding unigenes from red peel and green peel fruit, it could be intuitively concluded that high similarity was existed in the two distributions; however, on the whole, between two distributions of log RPKM expression value, some differences indicated that expression level in green-peel fruit group is slightly higher than values in red peel fruit group. Finally, a total of 1349 unigenes were identified as DEGs after blasting the DEGs to public sequence databases, and 32 peel-color-related genes were identified in longan. Our results suggest that a number of unigenes involved in longan metabolic process, including anthocyanin biosynthesis. In addition, DRF, F3H, ANS, CYP75A1 and C1 may be the key ones. The study on key genes related to peel color will be contributed to revealing the molecular mechanisms of regulating peel color in woody plants. PMID- 27468389 TI - Juvenile psammomatoid ossifying fibroma of the posterior fossa: a case report and review. AB - BACKGROUND: Ossifying fibroma is a rare benign bone tumor that occurs mostly in the jaw, but also affects paranasal sinuses and fronto-ethmoidal complex. Occipital bone is an extremely rare location for these tumors; only two cases have been reported. METHODS: We present the first case reported as psammomatoid subtype of ossifying fibroma, according to the 2005 WHO classification. An 18 years old male patient with infratentorial tumor, in the occipital bone, that produces mass effect over the cerebellum. CONCLUSIONS: This case may provide a guide to consider these lesions for a more rapid and precise diagnostic in future cases. PMID- 27468390 TI - First detection of Paenibacillus larvae the causative agent of American Foulbrood in a Ugandan honeybee colony. AB - Paenibacillus larvae is a highly contagious and often lethal widely distributed pathogen of honeybees, Apis mellifera but has not been reported in eastern Africa to date. We investigated the presence of P. larvae in the eastern and western highland agro-ecological zones of Uganda by collecting brood and honey samples from 67 honeybee colonies in two sampling occasions and cultivated them for P. larvae. Also, 8 honeys imported and locally retailed in Uganda were sampled and cultivated for P. larvae. Our aim was to establish the presence and distribution of P. larvae in honeybee populations in the two highland agro-ecological zones of Uganda and to determine if honeys that were locally retailed contained this lethal pathogen. One honeybee colony without clinical symptoms for P. larvae in an apiary located in a protected area of the western highlands of Uganda was found positive for P. larvae. The strain of this P. larvae was genotyped and found to be ERIC I. In order to compare its virulence with P. larvae reference strains, in vitro infection experiments were conducted with carniolan honeybee larvae from the research laboratory at Ghent University, Belgium. The results show that the virulence of the P. larvae strain found in Uganda was at least equally high. The epidemiological implication of the presence of P. larvae in a protected area is discussed. PMID- 27468391 TI - A validation study regarding a generative approach in choosing appropriate colors for impaired users. AB - In many circumstances, concepts, ideas and emotions are mainly conveyed by colors. Color vision disorders can heavily limit the user experience in accessing Information Society. Therefore, color vision impairments should be taken into account in order to make information and services accessible to a broader audience. The task is not easy for designers that generally are not affected by any color vision disorder. In any case, the design of accessible user interfaces should not lead to to boring color schemes. The selection of appealing and harmonic color combinations should be preserved. In past research we investigated a generative approach led by evolutionary computing in supporting interface designers to make colors accessible to impaired users. This approach has also been followed by other authors. The contribution of this paper is to provide an experimental validation to the claim that this approach is actually beneficial to designers and users. PMID- 27468392 TI - A copyright protection scheme for digital images based on shuffled singular value decomposition and visual cryptography. AB - This paper proposes a new watermarking algorithm based on the shuffled singular value decomposition and the visual cryptography for copyright protection of digital images. It generates the ownership and identification shares of the image based on visual cryptography. It decomposes the image into low and high frequency sub-bands. The low frequency sub-band is further divided into blocks of same size after shuffling it and then the singular value decomposition is applied to each randomly selected block. Shares are generated by comparing one of the elements in the first column of the left orthogonal matrix with its corresponding element in the right orthogonal matrix of the singular value decomposition of the block of the low frequency sub-band. The experimental results show that the proposed scheme clearly verifies the copyright of the digital images, and is robust to withstand several image processing attacks. Comparison with the other related visual cryptography-based algorithms reveals that the proposed method gives better performance. The proposed method is especially resilient against the rotation attack. PMID- 27468393 TI - Extended inclusive fitness theory: synergy and assortment drives the evolutionary dynamics in biology and economics. AB - W.D. Hamilton's Inclusive Fitness Theory explains the conditions that favor the emergence and maintenance of social cooperation. Today we know that these include direct and indirect benefits an agent obtains by its actions, and through interactions with kin and with genetically unrelated individuals. That is, in addition to kin-selection, assortation or homophily, and social synergies drive the evolution of cooperation. An Extended Inclusive Fitness Theory (EIFT) synthesizes the natural selection forces acting on biological evolution and on human economic interactions by assuming that natural selection driven by inclusive fitness produces agents with utility functions that exploit assortation and synergistic opportunities. This formulation allows to estimate sustainable cost/benefit threshold ratios of cooperation among organisms and/or economic agents, using existent analytical tools, illuminating our understanding of the dynamic nature of society, the evolution of cooperation among kin and non-kin, inter-specific cooperation, co-evolution, symbioses, division of labor and social synergies. EIFT helps to promote an interdisciplinary cross fertilization of the understanding of synergy by, for example, allowing to describe the role for division of labor in the emergence of social synergies, providing an integrated framework for the study of both, biological evolution of social behavior and economic market dynamics. Another example is a bio-economic understanding of the motivations of terrorists, which identifies different forms of terrorism. PMID- 27468394 TI - The effect of injection speed and serial injection on propidium iodide entry into cultured HeLa and primary neonatal fibroblast cells using lance array nanoinjection. AB - BACKGROUND: Although site-directed genetic engineering has greatly improved in recent years, particularly with the implementation of CRISPR-Cas9, the ability to deliver these molecular constructs to a wide variety of cell types without adverse reaction is still a challenge. One non-viral transfection method designed to address this challenge is a MEMS based biotechnology described previously as lance array nanoinjection (LAN). LAN delivery of molecular loads is based upon the combinational use of electrical manipulation of loads of interest and physical penetration of target cell membranes. This work explores an original procedural element to nanoinjection by investigating the effects of the speed of injection and also the ability to serially inject the same sample. RESULTS: Initial LAN experimentation demonstrated that injecting at speeds of 0.08 mm/s resulted in 99.3 % of cultured HeLa 229 cells remaining adherent to the glass slide substrate used to stage the injection process. These results were then utilized to examine whether or not target cells could be injected multiple times (1, 2, and 3 times) since the injection process was not pulling the cells off of the glass slide. Using two different current control settings (1.5 and 3.0 mA) and two different cell types (HeLa 229 cells and primary neonatal fibroblasts [BJ(ATCC((r)) CRL-2522TM)], treatment samples were injected with propidium iodide (PI), a cell membrane impermeable nucleic acid dye, to assess the degree of molecular load delivery. Results from the serial injection work indicate that HeLa cells treated with 3.0 mA and injected twice (*2) had the greatest mean PI uptake of 60.47 % and that neonatal fibroblasts treated with the same protocol reached mean PI uptake rates of 20.97 %. CONCLUSIONS: Both experimental findings are particularly useful because it shows that greater molecular modification rates can be achieved by multiple, serial injections via a slower injection process. PMID- 27468396 TI - Bone Scan Index predicts skeletal-related events in patients with metastatic breast cancer. AB - BACKGROUND: Bone Scan Index (BSI) expresses tumor burden in bone as a percentage of total skeletal mass, but its significance for metastatic breast cancer patients is unknown. We investigated whether baseline BSI is associated with skeletal-related events (SREs) or survival and identified the cut-off BSI score for predicting SREs in metastatic breast cancer patients. METHODS: We retrospectively reviewed 144 patients with bone metastatic breast cancer. Bone scan examinations were performed and BSI was calculated using the Bonenavi((r)) automated method. All patients received standard medical treatment for metastatic breast cancer. For bone metastasis prophylaxis, bisphosphonates were infused initially with analgesics as needed. We defined SRE as either bony, requiring intervention (surgery and/or radiotherapy) for pain or prevention of fracture, or spinal cord compression. The rates of SRE and overall survival (OS) were evaluated according to baseline BSI, and the cut-off score of BSI for predicting SRE in metastatic breast cancer patients was identified. RESULTS: Thirty-three patients (25.6 %) had SREs. The median BSI was 1.08 % (inter-quartile range 0.50 3.23 %). To identify the cut-off BSI score for predicting SRE, we performed sensitivity analysis to check P-value at every 0.1 BSI interval (0.4-2.4) by multiple-variable proportional hazard analysis. A BSI cut-off point of 1.4 % showed the lowest P value. Patients with BSI scores >=1.4 had a significantly higher rate of SRE than those with lower BSI (P = 0.022). However there was no significant difference in OS. CONCLUSION: BSI may predict SRE in patients with metastatic breast cancer. A high BSI value (>=1.4) at diagnosis of bone metastasis may be a predictor of SREs in bone metastatic breast cancer patients. PMID- 27468397 TI - Existence and exponential stability of positive almost periodic solution for Nicholson's blowflies models on time scales. AB - In this paper, we first give a new definition of almost periodic time scales, two new definitions of almost periodic functions on time scales and investigate some basic properties of them. Then, as an application, by using a fixed point theorem in Banach space and the time scale calculus theory, we obtain some sufficient conditions for the existence and exponential stability of positive almost periodic solutions for a class of Nicholson's blowflies models on time scales. Finally, we present an illustrative example to show the effectiveness of obtained results. Our results show that under a simple condition the continuous-time Nicholson's blowflies model and its discrete-time analogue have the same dynamical behaviors. PMID- 27468395 TI - Research advances on structure and biological functions of integrins. AB - Integrins are an important family of adhesion molecules that were first discovered two decades ago. Integrins are transmembrane heterodimeric glycoprotein receptors consisting of alpha and beta subunits, and are comprised of an extracellular domain, a transmembrane domain, and a cytoplasmic tail. Therein, integrin cytoplasmic domains may associate directly with numerous cytoskeletal proteins and intracellular signaling molecules, which are crucial for modulating fundamental cell processes and functions including cell adhesion, proliferation, migration, and survival. The purpose of this review is to describe the unique structure of each integrin subunit, primary cytoplasmic association proteins, and transduction signaling pathway of integrins, with an emphasis on their biological functions. PMID- 27468398 TI - Automatic no-reference image quality assessment. AB - No-reference image quality assessment aims to predict the visual quality of distorted images without examining the original image as a reference. Most no reference image quality metrics which have been already proposed are designed for one or a set of predefined specific distortion types and are unlikely to generalize for evaluating images degraded with other types of distortion. There is a strong need of no-reference image quality assessment methods which are applicable to various distortions. In this paper, the authors proposed a no reference image quality assessment method based on a natural image statistic model in the wavelet transform domain. A generalized Gaussian density model is employed to summarize the marginal distribution of wavelet coefficients of the test images, so that correlative parameters are needed for the evaluation of image quality. The proposed algorithm is tested on three large-scale benchmark databases. Experimental results demonstrate that the proposed algorithm is easy to implement and computational efficient. Furthermore, our method can be applied to many well-known types of image distortions, and achieves a good quality of prediction performance. PMID- 27468399 TI - Moringa oleifera aqueous leaf extract inhibits reducing monosaccharide-induced protein glycation and oxidation of bovine serum albumin. AB - Advanced glycation end products (AGEs) play an important factor for pathophysiology of diabetes and its complications. Moringa oleifera is one of the medicinal plants that have anti-hyperglycemic activity. However, anti-glycation property of Moringa oleifera leaf extract on the different types of reducing monosaccharides-induced protein glycation has not been investigated. Therefore, the aim of this study was to examine the protective effect of Moringa oleifera aqueous leaf extract (MOE) on reducing sugars-induced protein glycation and protein oxidation. Total phenolic content of MOE was measured using the Folin Ciocalteu method. Bovine serum albumin was incubated with 0.5 M of reducing sugars (glucose or fructose) with or without MOE (0.5-2.0 mg/mL) for 1, 2, 3 and 4 weeks. The results found that total phenolic content was 38.56 +/- 1.50 mg gallic acid equivalents/g dry extract. The formation of fluorescent and non fluorescent AGEs [N (epsilon)-(carboxymethyl) lysine (CML)] and the level of fructosamine were determined to indicate protein glycation, whereas the level of protein carbonyl content and thiol group were examined for protein oxidation. MOE (0.5-2.0 mg/mL) significantly inhibited the formation of fluorescent, N (epsilon) CML and markedly decreased fructosamine level (P < 0.05). Moreover, MOE significantly prevented protein oxidation manifested by reducing protein carbonyl and the depletion of protein thiol in a dose-dependent manner (P < 0.05). Thus, the findings indicated that polyphenols containing in MOE have high potential for decreasing protein glycation and protein oxidation that may delay or prevent AGE related diabetic complications. PMID- 27468400 TI - Health behaviours, body weight and self-esteem among grade five students in Canada. AB - PURPOSE: This study sought to identify the principal components of self-esteem and the health behavioural determinants of these components among grade five students. METHODS: We analysed data from a population-based survey among 4918 grade five students, who are primarily 10 and 11 years of age, and their parents in the Canadian province of Nova Scotia. The survey comprised the Harvard Youth and Adolescent Questionnaire, parental reporting of students' physical activity (PA) and time spent watching television or using computer/video games. Students heights and weights were objectively measured. We applied principal component analysis (PCA) to derive the components of self-esteem, and multilevel, multivariable logistic regression to quantify associations of diet quality, PA, sedentary behaviour and body weight with these components of self-esteem. RESULTS: PCA identified four components for self-esteem: self-perception, externalizing problems, internalizing problems, social-perception. Influences of health behaviours and body weight on self-esteem varied across the components. Better diet quality was associated with higher self-perception and fewer externalizing problems. Less PA and more use of computer/video games were related to lower self-perception and social-perception. Excessive TV watching was associated with more internalizing problems. Students classified as obese were more likely to report low self- and social-perception, and to experience fewer externalizing problems relative to students classified as normal weight. CONCLUSION: This study demonstrates independent influences of diet quality, physical activity, sedentary behaviour and body weight on four aspects of self esteem among children. These findings suggest that school programs and health promotion strategies that target health behaviours may benefit self-esteem in childhood, and mental health and quality of life later in life. PMID- 27468401 TI - Screening of tropical isolates of Metarhizium anisopliae for virulence to the red palm weevil Rhynchophorus ferrugineus Olivier (Coleoptera: Curculionidae). AB - The red palm weevil, Rhynchophorus ferrugineus Olivier (Coleoptera: Curculionidae) is a serious pest of the palm tree in tropical regions of the world. One strain of Metarhizium sp. ZJ-1, isolated from Chinese soils, was evaluated for growth characteristics, and screened for its virulence to R. ferrugineus larvae in laboratory conditions. An approximately 685-bp fragment was amplified by ITS (ITS1-5.8S-ITS2) PCR from strain ZJ-1, further phylogenetic analysis revealed that 93 % similarity to Metarhizium anisopliae. Inoculation of 1 * 10(8) conidia/mL caused 100 % mortality of R. ferrugineus, LT50 levels of ZJ 1 were 1.66 days (1 * 10(8) conidia/mL), indicating that the conidia of strain ZJ 1 were highly virulent. These results suggest that M. anisopliae ZJ-1 has potential as an effective and persistent biological control agent for R. ferrugineus. PMID- 27468402 TI - Treatment outcomes of spontaneous rupture of hepatocellular carcinoma with hemorrhagic shock: a multicenter study. AB - BACKGROUND: Spontaneous rupture is one of the most fatal complications of HCC. The incidence of HCC still remains a significant health problem in Eastern Asia. Many studies have shown that the in-hospital or 30-day mortality rates are as high as 25-100 %. It is often difficult to stratify these patients based on clinical manifestations and biochemical data, for deciding on an appropriate treatment strategy, especially when the patient's hemodynamic status is unstable. This study aimed to explore the clinical outcomes of treatment of spontaneously ruptured hepatocellular carcinoma with hemorrhagic shock. METHODS: One hundred and sixty two patients with hemorrhagic shock secondary to spontaneous rupture of hepatocellular carcinoma were included in this retrospective study. The therapeutic methods included conservative treatment, transcatheter arterial embolization (TAE) and hepatectomy. The outcomes in terms of 30 day and 1 year survival were analyzed. RESULTS: Thirty five (21.6 %) received only conservative management, TAE was performed in 48 (29.6 %) and partial hepatectomy (emergency and staged) in 106 (65.4 %) patients. The 30-day survival rate was lower in patients receiving conservative treatment (8.6 %) than in those receiving either hepatectomy or TAE (88.2 %; P < 0.001). Conservative treatment was associated with poorer long-term survival (0 % at 1 year) when compared to those receiving either hepatectomy or TAE (54.3 % at 1 year; P < 0.001). The survival rates at 30 days and 1 year were 92.5 % and 59.4 % for the patients who underwent hepatectomy, which were significantly higher (66.7 and 28.6 % respectively) than those receiving TAE alone (P = 0.003 and P = 0.009, respectively). Multivariate Cox-regression analysis showed that hepatectomy and TAE were significant protective factors for survival as compared with conservative treatment (all P < 0.01). CONCLUSIONS: Partial hepatectomy, tended to provide better survival than transcatheter arterial embolization alone or conservative treatment in the management of patients with hemorrhagic shock secondary to spontaneous rupture of hepatocellular carcinoma. PMID- 27468403 TI - Case study on impact performance optimization of hydraulic breakers. AB - BACKGROUND: In order to expand the range of activities of an excavator, attachments, such as hydraulic breakers have been developed to be applied to buckets. However, it is very difficult to predict the dynamic behavior of hydraulic impact devices such as breakers because of high non-linearity. Thus, the purpose of this study is to optimize the impact performance of hydraulic breakers. The ultimate goal of the optimization is to increase the impact energy and impact frequency and to reduce the pressure pulsation of the supply and return lines. RESULTS: The optimization results indicated that the four parameters used to optimize the impact performance of the breaker showed considerable improvement over the results reported in the literature. A test was also conducted and the results were compared with those obtained through optimization in order to verify the optimization results. The comparison showed an average relative error of 8.24 %, which seems to be in good agreement. CONCLUSIONS: The results of this study can be used to optimize the impact performance of hydraulic impact devices such as breakers, thus facilitating its application to excavators and increasing the range of activities of an excavator. PMID- 27468405 TI - Development of a quadruplex loop-mediated isothermal amplification assay for field detection of four Vibrio species associated with fish disease. AB - A quadruplex loop-mediated isothermal amplification (LAMP) method was developed to detect four Vibrio species, including Vibrio ichthyoenteri, Vibrio parahaemolyticus, Vibrio scophthalmi, and Vibrio vulnificus, simultaneously. Four sets of species-specific primers were designed with different restriction sites contained in the inner primers. The quadruplex LAMP method could distinguish four Vibrio species via the subsequent restriction enzyme analysis. The sensitivity of the quadruplex LAMP method were 10(2)-10(3) times higher than the sensitivity of conventional PCR. V. scophthalmi, V. vulnificus, V. parahaemolyticus and V. ichthyoenteri could be detected in the different tissues of the infected fish by the quadruplex LAMP method simply and conveniently through using SYBR Green I to facilitate visual inspection of the LAMP products. The method we developed in this study could be a simple and convenient diagnostic tool for field detection of Vibrio infection in fish. PMID- 27468404 TI - Enhancement of arterial pulsation during flow-mediated dilation is impaired in the presence of ischemic heart disease. AB - PURPOSE: The aim of this study is to investigate the relationship between arterial pulse amplitude change under increased shear stress and the presence of ischemic heart disease (IHD). METHODS: This study comprised 31 subjects, including 14 subjects with IHD. We investigated the change in brachial artery pulse amplitude during flow-mediated dilation (FMD) using ultrasonography. RESULTS: The arterial pulse amplitude increased during FMD in 19 subjects, whereas it decreased in 12 subjects. There was a marked difference in the change in arterial pulse amplitude (the maximum amplitude of the arterial pulse amplitude during FMD/the arterial pulse amplitude at baseline) between subjects with and without IHD (0.98 +/- 0.53 and 1.37 +/- 0.53, p = 0.028). Furthermore, decreased arterial pulse amplitude during FMD was a significant predictor of IHD after adjustment of age, blood pressure, the presence of each type of coronary risks, the value of FMD and sex (p = 0.0001). CONCLUSIONS: The decrease of arterial pulsation amplitude during FMD was a useful predictive parameter for IHD. PMID- 27468406 TI - Ectopic Acromegaly Arising from a Pituitary Adenoma within the Bony Intersphenoid Septum of a Patient with Empty Sella Syndrome. AB - OBJECTIVE: To describe the work-up and treatment of rare ectopic acromegaly caused by a biopsy-proven somatotroph pituitary adenoma located within the bony intersphenoid septum of a patient with empty sella syndrome (ESS). METHODS: We report the presentation, clinical course, diagnostic work-up, and lesion localization and treatment challenges encountered in a 55-year-old patient, with a brief review of relevant literature. RESULTS: A 55-year-old African-American man presented with acromegaly and ESS. Attempts to definitively localize the causative tumor were unsuccessful, though petrosal sinus sampling supported central growth hormone production and imaging suggested bone-enclosed subsellar pituitary tissue. Endoscopic endonasal transphenoidal exploration was undertaken with resection of a somatotroph pituitary microadenoma, and subsequent clinical improvement and biochemical remission. Retrospective review revealed the patient's pituitary to have been located ectopically within a unique bony intersphenoid septum. CONCLUSION: This report describes the first known case of an ectopic pituitary adenoma located within the midline bony intersphenoid septum, which we postulate to have resulted from anomalous embryological pituitary migration. Intra-intersphenoid septal tumors should be considered in cases of apparent central acromegaly with ESS or absence of tumor tissue within the paranasal sinuses or other peripheral locations. INDEXING: Acromegaly, ESS, pituitary adenoma, sphenoid sinus septum. PMID- 27468407 TI - Management of Giant Cervical Teratoma with Intracranial Extension Diagnosed in Utero. AB - Cervical teratomas are rare germ cell tumors affecting the fetus that are associated with significant morbidity and mortality due to an increased risk of airway obstruction at delivery. These tumors can commonly produce polyhydramnios that results from the fetus' impaired ability to swallow amniotic fluid. Improved rates of prenatal diagnosis through comprehensive evaluations and imaging have dramatically impacted the perinatal management of infants with this condition. Here, we report a patient diagnosed with polyhydramnios whose fetus was discovered to have a giant cervical teratoma on imaging studies. The child underwent surgical resection after having the airway secured under the uteroplacental support as part of an ex utero intrapartum treatment procedure performed at 37 weeks. The following gross pathological and magnetic resonance images demonstrate this condition and its currently accepted treatment. PMID- 27468408 TI - Neisseria meningitides Can Survive in Corpses for At Least Eleven Days. PMID- 27468409 TI - Enteroaggregative Escherichia coli in Daycare-A 1-Year Dynamic Cohort Study. AB - Enteroaggregative Escherichia coli (EAEC) has been associated with persistent diarrhea, reduced growth acceleration, and failure to thrive in children living in developing countries and with childhood diarrhea in general in industrialized countries. The clinical implications of an EAEC carrier-status in children in industrialized countries warrants clarification. To investigate the pathological significance of an EAEC carrier-state in the industrialized countries, we designed a 1-year dynamic cohort study and performed follow-up every second month, where the study participants submitted a stool sample and answered a questionnaire regarding gastrointestinal symptoms and exposures. Exposures included foreign travel, consumption of antibiotics, and contact with a diseased animal. In the capital area of Denmark, a total of 179 children aged 0-6 years were followed in a cohort study, in the period between 2009 and 2013. This is the first investigation of the incidence and pathological significance of EAEC in Danish children attending daycare facilities. Conventional microbiological detection of enteric pathogens was performed at Statens Serum Institute, Copenhagen, Denmark, and at Hvidovre Hospital, Copenhagen, Denmark. Parents completed questionnaires regarding gastrointestinal symptoms. The EAEC strains were further characterized by serotyping, phylogenetic analysis, and susceptibility testing. EAEC was detected in 25 (14%) of the children during the observational period of 1 year. One or more gastrointestinal symptoms were reported from 56% of the EAEC-positive children. Diarrhea was reported in six (24%) of the EAEC positive children, but no cases of weight loss, and general failure to thrive were observed. The EAEC strains detected comprised a large number of different serotypes, confirming the genetic heterogeneity of this pathotype. EAEC was highly prevalent (n = 25, 14%) in Danish children in daycare centers and was accompanied by gastrointestinal symptoms in 56% of the infected children. No serotype or phylogenetic group was specifically linked to children with disease. PMID- 27468410 TI - Vitamin B12 deficiency among adult diabetic patients in Uganda: relation to glycaemic control and haemoglobin concentration. AB - BACKGROUND: Vitamin B12 deficiency is highly prevalent among adult individuals with diabetes yet screening is infrequent in Uganda. There are currently no published data regarding the prevalence of vitamin B12 deficiency and its associated factors among adult individuals with diabetes in sub-Saharan Africa. This study aimed at describing the prevalence and factors associated with vitamin B12 deficiency among this patient population in a resource constrained setting in sub-Saharan Africa. METHODS: In this cross-sectional study, 280 eligible study participants attending the outpatient diabetic clinic at Mulago national referral and teaching hospital in Kampala, Uganda were enrolled. Their socio-demographic, clinical and laboratory data was collected using a pre-tested questionnaire. RESULTS: The majority of the study participants were female (68.9 %), with a median age of 50 (IQR: 40-58) years. The mean (SD) serum vitamin B12 levels was 472.0 (16.4) pg/ml. The prevalence of vitamin B12 deficiency was 10.7 %. Hemoglobin level < 12 g/dl (AOR 3.38; 95 % CI 1.38-8.32, p value = 0.008) and glycated hemoglobin >= 7 % (AOR 3.29; 1.44-7.51, p value = 0.005) were associated with vitamin B12 deficiency. CONCLUSIONS: Vitamin B12 deficiency is prevalent in approximately 1 in 10 of adult individuals with diabetes in Uganda. We recommend screening for vitamin B12 deficiency among diabetic patients in Uganda especially those with low hemoglobin concentrations and glycated hemoglobin levels >= 7 %. PMID- 27468411 TI - Anatomic Relationships of the Distal and Proximal Radioulnar Joints Articulating Surface Areas and of the Radius and Ulna Bone Volumes - Implications for Biomechanical Studies of the Distal and Proximal Radioulnar Joints and Forearm Bones. AB - BACKGROUND: Previous work from this laboratory has evidenced the biomechanical role of forearm osseoligamentous structures in load transfer of applied forces. It has shown that forces transmitted across the distal radioulnar joint (DRUJ) and proximal radioulnar joint (PRUJ) are similar, though not identical, under axial loading conditions. The purpose of the study was to assess the articulating surface areas of the radioulnar joints and the volumes of the forearm bones addressing the hypothesis that there may be anatomic adaptations that reflect the biomechanical function of the integrated forearm unit. METHODS: The articulating surface areas of PRUJ and DRUJ were assessed using a laser scanner in 24 cadaver forearms. The articulating joint surfaces were additionally delineated from standardized photographs assessed by three observers. The surface areas of matched pairs of joints were compared on the null hypothesis that these were the same within a given forearm specimen. An additional 44 pairs of matched forearm bone volumes were measured using water displacement technique and again compared through statistical analysis (paired sample t-test and Bland-Altman analysis). RESULTS: The findings of this study are that the articulating surface areas of the DRUJ and PRUJ as well as the bone volumes are significantly different and, yet, strongly correlated. The paired sample t-test showed a significant difference between the surface areas of the DRUJ and PRUJ (p < 0.05). The PRUJ articulating surface area was marginally larger than the DRUJ with a PRUJ:DRUJ ratio of 1.02. Paired sample t-test showed a significant difference between the two bone volumes (p < 0.01) with a radius to ulna bone volume ratio of 0.81. When the olecranon was disregarded, radius volume was on average of 4% greater than ulna volume. CONCLUSION: This study demonstrates and defines the anatomical relationships between the two forearm bones and their articulating joints when matched for specimen. The data obtained are consistent with the theory of integrated forearm function generated from published biomechanical studies. PMID- 27468412 TI - Denosumab could be a Potential Inhibitor of Valvular Interstitial Cells Calcification in vitro. AB - OBJECTIVE: Denosumab is a fully human monoclonal antibody and novel antiresorptive agent that works by binding receptor activator of nuclear factor kappa-beta ligand (RANKL) and inhibiting the signaling cascade that causes osteoclast maturation, activity, and survival. We aimed to elucidate the effect of Denosumab in the process of spontaneous and induced calcification in an in vitro porcine valvular interstitial cells (VICs) model. MATERIALS AND METHODS: VICs were extracted from fresh porcine hearts by serial collagenase digestion. Spontaneous calcification of VICs was increased in vitro by adding Na3PO4 (3 mM, pH 7.4) and different concentrations (0.1, 1 and 10 ng/ml) of transforming growth factor beta (TGFbeta). The degree of calcification before and after treatment with Denosumab was estimated by Alizarin Red staining for calcium deposition, and Sirius Red staining for collagen. Colorimetric techniques were used to determine calcium and collagen deposition quantitatively. For statistical analysis we used SPSS and Microsoft Office Excel 2013. RESULTS: Porcine aortic VICs in vitro were induced to calcify by the addition of either 3 mM Na3PO4, showing a 5.2 fold increase by 14 days (P<0.001), or 3 mM Na3PO4 + 10 ng/ml of TGFbeta, showing a 7 fold increase by Day 14 (P<0.001). Denosumab inhibited induced calcification by 3 mM Na3PO4 and 3 mM Na3PO4 with the addition of TGFbeta at either 0.1, 1 or 10 ng/ml to basal levels only at a concentration of 50 MUg/ml (P<0.001). CONCLUSION: This study has proved that Denosumab could be a potential inhibitor of the calcification of VICs in vitro. A fuller understanding of the actions of Denosumab may identify a novel therapeutic strategy for clinical intervention against aortic valve calcification and aortic stenosis. PMID- 27468413 TI - Lessons learned from the search for genes responsible for rare Mendelian disorders. PMID- 27468414 TI - A view on clinical genetics and genomics in Spain: of challenges and opportunities. AB - A view on clinical genetics and genomics in Spain: of challenges and opportunities. PMID- 27468415 TI - A 2.5-year snapshot of Mendelian discovery. PMID- 27468416 TI - A novel approach for next-generation sequencing of circulating tumor cells. AB - BACKGROUND: Next-generation sequencing (NGS) of surgically resected solid tumor samples has become integral to personalized medicine approaches for cancer treatment and monitoring. Liquid biopsies, or the enrichment and characterization of circulating tumor cells (CTCs) from blood, can provide noninvasive detection of evolving tumor mutations to improve cancer patient care. However, the application of solid tumor NGS approaches to circulating tumor samples has been hampered by the low-input DNA available from rare CTCs. Moreover, whole genome amplification (WGA) approaches used to generate sufficient input DNA are often incompatible with blood collection tube preservatives used to facilitate clinical sample batching. METHODS: To address this, we have developed a novel approach combining tumor cell isolation from preserved blood with Repli-G WGA and Illumina TruSeq Amplicon Cancer Panel-based NGS. We purified cell pools ranging from 10 to 1000 cells from three different cell lines, and quantitatively demonstrate comparable quality of DNA extracted from preserved versus unpreserved samples. RESULTS: Preservation and WGA were compatible with the generation of high-quality libraries. Known point mutations and gene amplification were detected for libraries that had been prepared from amplified DNA from preserved blood. CONCLUSION: These spiking experiments provide proof of concept of a clinically applicable workflow for real-time monitoring of patient tumor using noninvasive liquid biopsies. PMID- 27468417 TI - Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas. AB - BACKGROUND: Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC). METHODS: We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model-based and model-free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model-based linkage analysis. Model-based and model-free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome-wide associations were also tested in these families. RESULTS: Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female-affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported. CONCLUSION: Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC. PMID- 27468418 TI - Importance of nonsynonymous OCA2 variants in human eye color prediction. AB - BACKGROUND: The color of the eyes is one of the most prominent phenotypes in humans and it is often used to describe the appearance of an individual. The intensity of pigmentation in the iris is strongly associated with one single nucleotide polymorphism (SNP), rs12913832:A>G that is located in the promotor region of OCA2 (OMIM #611409). Nevertheless, many eye colors cannot be explained by only considering rs12913832:A>G. METHODS: In this study, we searched for additional variants in OCA2 to explain human eye color by sequencing a 500 kbp region, encompassing OCA2 and its promotor region. RESULTS: We identified three nonsynonymous OCA2 variants as important for eye color, including rs1800407:G>A (p.Arg419Gln) and two variants, rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile), not previously described as important for eye color variation. It was shown that estimated haplotypes consisting of four variants (rs12913832:A>G, rs1800407:G>A (p.Arg419Gln), rs74653330:A>T (p.Ala481Thr), and rs121918166:G>A (p.Val443Ile)) explained 75.6% (adjusted R (2) = 0.76) of normal eye color variation, whereas rs12913832:A>G alone explained 68.8% (adjusted R (2) = 0.69). Moreover, rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile) had a measurable effect on quantitative skin color (P = 0.008). CONCLUSION: Our data showed that rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile) have a measurable effect on normal pigmentation variation. PMID- 27468419 TI - Computational assessment of feature combinations for pathogenic variant prediction. AB - BACKGROUND: Although several methods have been proposed for predicting the effects of genetic variants and their role in disease, it is still a challenge to identify and prioritize pathogenic variants within sequencing studies. METHODS: Here, we compare different variant and gene-specific features as well as existing methods and investigate their best combination to explore potential performance gains. RESULTS: We found that combining the number of "biological process" Gene Ontology annotations of a gene with the methods PON-P2, and PROVEAN significantly improves prediction of pathogenic variants, outperforming all individual methods. A comprehensive analysis of the Gene Ontology feature suggests that it is not a variant-dependent annotation bias but reflects the multifunctional nature of disease genes. Furthermore, we identified a set of difficult variants where different prediction methods fail. CONCLUSION: Existing pathogenicity prediction methods can be further improved. PMID- 27468420 TI - Identification of genetic variants of LGI1 and RTN4R (NgR1) linked to schizophrenia that are defective in NgR1-LGI1 signaling. AB - BACKGROUND: The protein NgR1 is encoded by RTN4R, a gene linked to schizophrenia. We previously reported NgR1 as receptor for the epilepsy-linked protein LGI1. NgR1 regulates synapse number and synaptic plasticity, whereas LGI1 antagonizes NgR1 signaling and promotes synapse formation. Impairments in synapse formation are common in neurological disease and we hypothesized that an LGI1-NgR1 signaling pathway may contribute to the development of schizophrenia. METHODS: We screened two unrelated schizophrenic populations for variants in RTN4R and LGI1 using whole exome sequencing and Sanger sequencing. We tested the ability of LGI1 to bind rare coding variants of NgR1 using a cell surface binding assays and the signaling ability of NgR1 using COS7 cell-spreading assays. RESULTS: We observed a previously reported rare coding variant in RTN4R (c.1195C>T, pR399W). We report the first LGI1 mutations to be identified in individuals with schizophrenia. Three different LGI1 mutations were found, two missense mutations (c.205G>A, p.V69I) and (c.313G>A, V105M), and an intronic variant (g.897T>C) that likely leads to a protein truncation. We found NgR1(R119W) and NgR1(277C) have a reduced ability to bind LGI1 in a cell surface binding assay. COS7 cell-spreading assays reveal that NgR1 mutants are impaired in their ability to mediate RhoA activation. CONCLUSION: Variants in NgR1 and LGI1 may be associated with schizophrenia and variants in NgR1 found in schizophrenic patients have impaired LGI1-NgR1 signaling. Impaired LGI1-NgR1 signaling may contribute to disease progression. PMID- 27468421 TI - The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita. AB - BACKGROUND: Telomere length <1st percentile-for-age in leukocyte subsets by flow cytometry with fluorescence in situ hybridization (flow FISH) is highly sensitive and specific in diagnosing patients with dyskeratosis congenita (DC), a telomere biology disorder. METHODS: We evaluated the clinical utility of the high throughput quantitative real-time PCR (qPCR) relative telomere length (RTL) measurement as a diagnostic test for DC in patients with a priori clinical and/or genetic DC diagnoses. We calculated the sensitivity and specificity of RTL at different age-specific percentile cutoffs in 31 patients with DC and 51 mutation negative relatives, and evaluated RTL difference by disease genotype. RESULTS: qPCR RTL <1st percentile-for-age failed to identify more than 60% of the patients already known to have DC (sensitivity = 39%, specificity = 98%). Three-quarters of DC patients had RTL below the 10th percentile-for-age (sensitivity = 74%), as did 12% of the unaffected relatives (specificity = 88%). CONCLUSIONS: Our findings suggest that the qPCR RTL method is not optimal for diagnosing DC. In light of these limitations, leukocyte flow FISH telomere length remains the recommended molecular test for diagnosing DC. PMID- 27468422 TI - The effect of parental age on the presence of de novo mutations - Lessons from neurofibromatosis type I. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous disease with a prevalence of 1:2500. Approximately, 50% of the cases are sporadic. Advanced paternal age is associated with germline mutations and autosomal diseases. We aimed to use NF1 as a paradigm to study the effect of parental age on sporadic mutation rates for both advanced and younger parental ages. METHODS: The medical charts of 118 NF1 pediatric patients followed in a specialized Israeli NF1 clinic were evaluated. Thirty-one cases were diagnosed by genetic tests and 87 by NIH clinical criteria. Sixty-four cases (54%) had a negative family history of NF1 (sporadic cases). Data on parental ages at the time of the children's birth were compared to the national population database. RESULTS: Parental age of children with sporadic NF1 was higher than the general population (32.7 years vs. 30.1 years, respectively, for the mothers and 36.5 years vs. 32.6 years, respectively, for the fathers; P < 0.0001 for both groups). In contrast, the age of the mothers and the fathers in the familial cases (30.3 and 33.9 years, respectively) did not differ from the general population. Significantly, fewer fathers of the sporadic group had been 25-29 years old at their child's birth compared with fathers in the general population (7.8% vs. 21%, respectively, P = 0.009), and significantly more fathers were >=40 years old (29.7% vs. 13.6%, respectively, P = 0.0002). Differences in maternal age between these two groups were less prominent. CONCLUSION: Parents of sporadic NF1 cases are older. The risk for sporadic NF1 was lower when the fathers were younger at the time of the affected child's birth, and gradually increased with paternal age. PMID- 27468425 TI - Measurement of Inositol Triphosphate Levels from Rat Hippocampal Slices. AB - Inositol triphosphate (IP3) is an important second messenger that participates in signal transduction pathways in diverse cell types including hippocampal neurons. Stimulation of phospholipase C in response to various stimuli (hormones, growth factors, neurotransmitters, neurotrophins, neuromodulators, odorants, light, etc) results in hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, and leads to the production of IP3 and diacylglycerol. Binding of IP3 to the IP3 receptor (IP3R) induces Ca2+ release from intracellular stores and enables the initiation of intracellular Ca2+-dependent signaling. Here we describe a procedure for the measurement of cellular IP3 levels in tissue homogenates prepared from rat hippocampal slices. PMID- 27468424 TI - Sweet-P inhibition of glucocorticoid receptor beta as a potential cancer therapy. AB - The need for the development of new cancer therapies and push for the design of new targeting techniques is on the rise, and would be useful for cancers that are resistant to current drug treatments. The understanding of the genome has significantly advanced cancer therapy, as well as prevention and earlier detection. This research highlight discusses a potential new type of cancer targeting molecule, Sweet-P, which is the first of its kind. Sweet-P specifically targets the microRNA-144 binding site in the 3' untranslated region (3' UTR) of the human glucocorticoid receptor beta (GRbeta), which has been demonstrated to increase expression. GRbeta has been shown to be highly expressed in cells from solid tumors of uroepithelial carcinomas, gliomas, osteosarcomas, and hepatocellular carcinomas, as well as in liquid tumor cells from leukemia patients. In non-cancerous diseases, GRbeta has been shown to be highly expressed in glucocorticoid-resistant asthma. These maladies brought the need for the development of the Sweet-P anti-GRbeta molecule. Sweet-P was shown to repress the migration of bladder cancer cells, and may serve as a new therapeutic for GRbeta related diseases. PMID- 27468423 TI - Cholinergic Circuit Control of Postnatal Neurogenesis. AB - New neuron addition via continued neurogenesis in the postnatal/adult mammalian brain presents a distinct form of nervous system plasticity. During embryonic development, precise temporal and spatial patterns of neurogenesis are necessary to create the nervous system architecture. Similar between embryonic and postnatal stages, neurogenic proliferation is regulated by neural stem cell (NSC) intrinsic mechanisms layered upon cues from their local microenvironmental niche. Following developmental assembly, it remains relatively unclear what may be the key driving forces that sustain continued production of neurons in the postnatal/adult brain. Recent experimental evidence suggests that patterned activity from specific neural circuits can also directly govern postnatal/adult neurogenesis. Here, we review experimental findings that revealed cholinergic modulation, and how patterns of neuronal activity and acetylcholine release may differentially or synergistically activate downstream signaling in NSCs. Higher order excitatory and inhibitory inputs regulating cholinergic neuron firing, and their implications in neurogenesis control are also considered. PMID- 27468426 TI - Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue. AB - We have previously identified prohibitin (PHB) and annexin A2 (ANX2) as proteins interacting on the surface of vascular endothelial cells in white adipose tissue (WAT) of humans and mice. Here, we demonstrate that ANX2 and PHB also interact in adipocytes. Mice lacking ANX2 have normal WAT vascularization, adipogenesis, and glucose metabolism but display WAT hypotrophy due to reduced fatty acid uptake by WAT endothelium and adipocytes. By using cell culture systems in which ANX2/PHB binding is disrupted either genetically or through treatment with a blocking peptide, we show that fatty acid transport efficiency relies on this protein complex. We also provide evidence that the interaction between ANX2 and PHB mediates fatty acid transport from the endothelium into adipocytes. Moreover, we demonstrate that ANX2 and PHB form a complex with the fatty acid transporter CD36. Finally, we show that the colocalization of PHB and CD36 on adipocyte surface is induced by extracellular fatty acids. Together, our results suggest that an unrecognized biochemical interaction between ANX2 and PHB regulates CD36 mediated fatty acid transport in WAT, thus revealing a new potential pathway for intervention in metabolic diseases. PMID- 27468427 TI - Vaccine-generated lung tissue-resident memory T cells provide heterosubtypic protection to influenza infection. AB - Tissue-resident memory T cells (TRM) are a recently defined, noncirculating subset with the potential for rapid in situ protective responses, although their generation and role in vaccine-mediated immune responses is unclear. Here, we assessed TRM generation and lung-localized protection following administration of currently licensed influenza vaccines, including injectable inactivated influenza virus (IIV, Fluzone) and i.n. administered live-attenuated influenza virus (LAIV, FluMist) vaccines. We found that, while IIV preferentially induced strain specific neutralizing antibodies, LAIV generated lung-localized, virus-specific T cell responses. Moreover, LAIV but not IIV generated lung CD4+ TRM and virus specific CD8+ TRM, similar in phenotype to those generated by influenza virus infection. Importantly, these vaccine-generated TRM mediated cross-strain protection, independent of circulating T cells and neutralizing antibodies, which persisted long-term after vaccination. Interestingly, intranasal administration of IIV or injection of LAIV failed to elicit T cell responses or provide protection against viral infection, demonstrating dual requirements for respiratory targeting and a live-attenuated strain to establish TRM. The ability of LAIV to generate lung TRM capable of providing long-term protection against nonvaccine viral strains, as demonstrated here, has important implications for protecting the population against emergent influenza pandemics by direct fortification of lung-specific immunity. PMID- 27468428 TI - Environmental Assessment for Sustainability and Resiliency for Ecological and Human Health. AB - Considerable attention has been devoted to environmental assessment and monitoring, primarily by physical and biological scientists, and more recently by social scientists. However, population growth and global change have resulted in an imperative to assess the resiliency of the environment to adapt to large scale changes and to continue to produce goods and services for future generations (sustainability). Changing land use needs or expectations may require the remediation and restoration of degraded or contaminated land. This paper provides an overview of monitoring types, and discusses how indicators for the different monitoring types can be developed to address questions of ecological health, human health, and whether restoration and remediation are effective. We suggest that along with more traditional types of monitoring, agencies should consider recovery indicators or metrics, as well as resiliency metrics. We suggest that one goal of assessment should be to determine if management, remediation, restoration, and mitigation reduce recovery time, thus reducing community vulnerability and enhancing resiliency to environmental stressors and disasters. PMID- 27468430 TI - AB-stacked square-like bilayer ice in graphene nanocapillaries. AB - Water, when constrained between two graphene sheets and under ultrahigh pressure, can manifest dramatic differences from its bulk counterparts such as the van der Waals pressure induced water-to-ice transformation, known as the metastability limit of two-dimensional (2D) liquid. Here, we present result of a new crystalline structure of bilayer ice with the AB-stacking order, observed from molecular dynamics simulations of constrained water. This AB-stacked bilayer ice (BL-ABI) is transformed from the puckered monolayer square-like ice (pMSI) under higher lateral pressure in the graphene nanocapillary at ambient temperature. BL ABI is a proton-ordered ice with square-like pattern. The transition from pMSI to BL-ABI is through crystal-to-amorphous-to-crystal pathway with notable hysteresis loop in the potential energy during the compression/decompression process, reflecting the compression/tensile limit of the 2D monolayer/bilayer ice. In a superheating process, the BL-ABI transforms into the AB-stacked bilayer amorphous ice with the square-like pattern. PMID- 27468429 TI - Can the Brain Benefits of Exercise Be Enhanced Without Additional Exercise? PMID- 27468431 TI - Competing processes of micellization and fibrillization in native and reduced casein proteins. AB - Kappa-casein (kappaCN) and beta-casein (betaCN) are disordered proteins present in mammalian milk. In vitro, betaCN self-assembles into core-shell micelles. kappaCN self assembles into similar micelles, as well as into amyloid-like fibrils. Recent studies indicate that fibrillization can be suppressed by mixing betaCN and kappaCN, but the mechanism of fibril inhibition has not been identified. Examining the interactions of native and reduced kappa-caseins (N kappaCN and R-kappaCN) with betaCN, we expose a competition between two different self-assembly processes: micellization and fibrillization. Quite surprisingly, however, we find significant qualitative and quantitative differences in the self assembly between the native and reduced kappaCN forms. Specifically, thermodynamic analysis reveals exothermic demicellization for betaCN and its mixtures with R-kappaCN, as opposed to endothermic demicellization of N-kappaCN and its mixtures with betaCN at the same temperature. Furthermore, with time, R kappaCN/betaCN mixtures undergo phase separation into pure betaCN micelles and R kappaCN fibrils, while in the N-kappaCN/betaCN mixtures fibril formation is considerably delayed and mixed micelles persist for longer periods of time. Fibrils formed in N-kappaCN/betaCN mixtures are shorter and more flexible than those formed in R-kappaCN/betaCN systems. Interestingly, in the N-kappaCN/betaCN mixtures, the sugar moieties of N-kappaCN oligomers seem to organize on the mixed micelles surface in a manner similar to the organization of kappaCN in milk casein micelles. PMID- 27468433 TI - Intramolecular mobility of eta(5)-ligands in chiral zirconocene complexes and the enantioselectivity of alkene functionalization by organoaluminum compounds. AB - The effect of solvent nature (CD2Cl2, d8-toluene, d8-THF) on the conformational behavior of neomenthyl-substituted zirconocenes CpInd*ZrCl2 (Cp = eta(5)-C5H5, Ind* = eta(5)-neomenthylindenyl), CpCp'ZrCl2 (Cp = eta(5)-C5H5, Cp' = eta(5) neomenthyl-4,5,6,7-tetrahydroindenyl), and Ind*2ZrCl2 (Ind* = eta(5) neomenthylindenyl) was shown by means of dynamic NMR spectroscopy, and the constants and thermodynamic parameters of conformer exchange were determined. The experimental conformational composition of the complexes was compared with structures obtained by quantum chemical modeling using the DFT methods PBE/3zeta and M06-2X/cc-pVDZ(H, C, Cl)/cc-pVDZ-PP(Zr), which predicted three rotamers in the case of both CpInd*ZrCl2 and CpCp'ZrCl2, and seven rotational isomers for Ind*2ZrCl2, three of these being C2-symmetric and the others being asymmetric. The enantioselectivity of the conformationally mobile complex Ind*2ZrCl2 in the reactions of terminal alkenes with AlR3 (R = Me, Et) was compared with that of rigid ansa-complexes, rac-p-S, p-S-[Y(eta(5)-C9H10)2]ZrX2 (Y = SiMe2, C2H4; X = S binaphtholate). Faster exchange between the conformers of Ind*2ZrCl2 in a chlorinated solvent gives the structural isomer of catalytically active sites, which affords higher substrate conversion and reaction enantioselectivity. Binding of the ligands to ansa-zirconocenes prevents the rotational isomerism of the complexes, providing the same configuration of the beta-stereogenic center in the methyl- and ethylalumination products (unlike the conformationally mobile complex Ind*2ZrCl2) with an enantiomeric purity of 50-65%. PMID- 27468432 TI - Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity. AB - For the first time, a series of 25 pseudo-octahedral pyridylphosphinate metal complexes (Ru, Os, Rh, Ir) has been synthesised and assessed in biological systems. Each metal complex incorporates a pyridylphosphinate ligand, a monodentate halide and a capping eta(6)-bound aromatic ligand. Solid- and solution-state analyses of two complexes reveal a structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1 : 1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R' group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 MUM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid l-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment. PMID- 27468435 TI - William Joseph Thompson, 1932-2015. PMID- 27468434 TI - Coupling molecular spin centers to microwave planar resonators: towards integration of molecular qubits in quantum circuits. AB - We present spectroscopic measurements looking for the coherent coupling between molecular magnetic centers and microwave photons. The aim is to find the optimal conditions and the best molecular features to achieve the quantum strong coupling regime, for which coherent dynamics of hybrid photon-spin states take place. To this end, we used a high critical temperature YBCO superconducting planar resonator working at 7.7 GHz and at low temperatures to investigate three molecular mononuclear coordination compounds, namely (PPh4)2[Cu(mnt)2] (where mnt2- = maleonitriledithiolate), [ErPc2]-TBA+ (where pc2- is the phtalocyaninato and TBA+ is the tetra-n-butylammonium cation) and Dy(trensal) (where H3trensal = 2,2',2''-tris(salicylideneimino)triethylamine). Although the strong coupling regime was not achieved in these preliminary experiments, the results provided several hints on how to design molecular magnetic centers to be integrated into hybrid quantum circuits. PMID- 27468436 TI - Watching our nursing and midwifery leader in action. PMID- 27468437 TI - Baby Asha unites community against refugee policy. PMID- 27468438 TI - Aged Care Senate Inquiry: The need to prioritise resident care over profits. PMID- 27468440 TI - Patients as partners: You can make it happen! PMID- 27468439 TI - Election issue 4. Healthy budgets are essential for safe quality care. PMID- 27468441 TI - Good delegation favours guidelines over guesswork. PMID- 27468443 TI - Rocky midwives take a stand on unsafe workloads. PMID- 27468442 TI - MORE LEADERSHIP, LESS PAPERWORK: IT'S TIME TO REFOCUS THE NUM/MUM ROLE. PMID- 27468444 TI - Do we seriously need a double dissolution election? PMID- 27468446 TI - CHOOSE WISELY. Which MACRA track makes sense? PMID- 27468445 TI - COSTLY CONDITION. Hospitals try new approaches to treating opioid-dependent babies. PMID- 27468447 TI - MOST WIRED. Leveraging data for bundled payments, orthopedics goes first. PMID- 27468448 TI - BY THE BOOK. Value being built into foundation of new medical school. PMID- 27468449 TI - CHICKPEA AND CHOCOLATE? From plow to plate ... to patient. PMID- 27468450 TI - FLYING DIRECT. Three questions with: Brent Estes. PMID- 27468451 TI - LET THEM LINGER. Kaiser reimagines primary care. PMID- 27468452 TI - MAKEUP DAY. Pomp and unusual circumstance. PMID- 27468453 TI - Changing the face of a troubled community. PMID- 27468454 TI - Clinical Integration Managing across the care continuum. AB - In the changing world of health care, the traditional boundaries are vanishing and hospitals and others must integrate care within their own organizations, as well as externally, across the care continuum. Here are three approaches to accomplishing just that. PMID- 27468455 TI - Advocating for Mental Health Parity. PMID- 27468456 TI - WOMEN'S HEALTH. Beyond OB-GYN: 3 ways to rethink women's services across the board. AB - Providers often thought of women's health services in terms of obstetrics and gynecology. But a better understanding of gender differences in disease and treatments has encouraged three health systems to broaden that view. PMID- 27468457 TI - A Nurse's Eye. Hospitals turning to clinicians for insights on facility design. AB - Nurses know a thing or two about how facility design can enhance or inhibit what they do. Now health care systems and design firms are bringing nurses into the discussion when planning new facilities or reconfiguring current spaces. PMID- 27468458 TI - Clinical and Business Analytics: Delivering Real-Time, Predictive Intelligence. PMID- 27468459 TI - NEW CONNECTIONS SPEED UP CARE. PMID- 27468460 TI - Arthritis: Listening Leads To Enhanced Outcomes. PMID- 27468461 TI - Reenergizing Research While Improving Patient Care. PMID- 27468462 TI - Captopril augments acetylcholine-induced bronchial smooth muscle contractions in vitro via kinin-dependent mechanisms. AB - Angiotensin converting enzyme (ACE) inhibitors therapy is aassociated with bothersome dry cough as an adverse effect. The mechanisms underlying this adverse effect are not clear. Therefore, influence of captopril (an ACE inhibitor) on acetylcholine (ACh)-induced bronchial smooth muscle contractions was investigated. Further, the mechanisms underlying the captopril-induced changes were also explored. In vitro contractions of rat bronchial smooth muscle to cumulative concentrations of ACh were recorded before and after exposure to captopril. Further, the involvement of kinin and inositol triphosphate (IP3) pathways for captopril-induced alterations were explored. ACh produced concentration-dependent (5-500 uM) increase in bronchial smooth muscle contractions. Pre-treatment with captopril augmented the ACh-induced contractions at each concentration significantly. Pre-treatment with aprotinin (kinin synthesis inhibitor) or heparin (inositol triphosphate, IP3-inhibitor), blocked the captopril-induced augmentation of bronchial smooth muscle contractions evoked by ACh. Further, captopril-induced augmentation was absent in calcium-free medium. These results suggest that captopril sensitizes bronchial smooth muscles to ACh-induced contractions. This sensitization may be responsible for dry cough associated with captopril therapy. PMID- 27468463 TI - Effect of hydroalcoholic fruit extract of Persea americana Mill. on high fat diet induced obesity: A dose response study in rats. AB - The fruits of Persea Americana Mill., commonly known as Avocado, are traditionally consumed for various health benefits including weight reduction. Here, we studied the effect of hydroalcoholic fruit extract of Persea americana (HAEPA) on high fat diet (HFD) induced obesity in rats. Obesity was induced in male Sprague Dawley rats by feeding HFD for 14 wk. The hypolipidemic effect was evaluated by co-administering 25, 50, 100 and 200 mg/kg body wt. of HAEPA. There was a significant increase in weight gain, body mass index (BMI), blood lipids, low density lipoproteins (LDL), lipid peroxides (LPO) and serum transaminases in HFD fed rats. HFD+HAEPA fed rats showed a significant decrease in blood lipids, LPO, liver lipids and increase in antioxidant status when compared to HFD control rats. The activity of lipid metabolic key enzymes such as fatty acid synthase and HMG CoA reductase in liver were also found to be decreased significantly in HAEPA co-administered rats. Lipoprotein lipase activity was found increased in HFD+HAEPA rats. Among the 4 doses studied, 100 mg of HAEPA/kg body wt. exhibited optimum hypolipidemic activity. Histopathological observations in liver and visceral adipose tissue added more evidence for the lipid lowering effect of HAEPA. It can be concluded that avocado fruit extract can act as hypolipidemic agent probably by modulating the activities of HMG CoA reductase and fatty acid synthase in liver. PMID- 27468464 TI - Cytotoxic and pro-apoptotic activities of leaf extract of Croton bonplandianus Baill. against lung cancer cell line A549. AB - The acetone extract (AcE) of the Croton bonplandianus Baill., an exotic weed of the Euphorbiaceae family was studied for cytotoxicity, apoptosis, cell cycle arrest in A549 cell line and antioxidant capacities using MTT assay, acridine orange/ethidium bromide (AO/EB staining), cell cycle analysis and DPPH radical scavenging assay respectively. Based on the cytotoxic activity, the extract was tested for the apoptotic effect using AO/EB and Hoechst 33258 staining. The apoptosis was characterized by chromatin condensation and DNA fragmentation. Further, to determine the stage of cell death, cell cycle analysis was performed by flow cytometry and AcE was found to arrest G2/M phase in a dose dependent manner. The number of cells in G2/M phase increases with concurrent accumulation of cells in sub G0/G1phase indicates the induction of apoptosis at G2M phase. The free radical scavenging activity of the AcE against DPPH was considerably significant. The cytotoxic, apoptotic and antioxidant effect of the AcE could be well correlated with the presence of potent free radical scavenging secondary metabolites such as phenols (43 +/- 0.05 ug/mL), flavonoids (3.5 +/- 0.07 ug/mL) and tannin (0.36 +/- 0.1 ug/mL). Our study has shown that A549 cells were more sensitive to AcE with an IC50 of 15.68 +/- 0.006 ug/mL compared to the standard drug 2.20 +/- 0.008 ug/mL (cisplatin). The results suggest that Croton bonplandianus could serve as a potential source of alternative therapeutic agent for treating cancer. Further research is required to isolate the active principle compound and determination of its anticancer property. PMID- 27468465 TI - Salicylic acid induces differential antioxidant response in spring maize under high temperature stress. AB - High temperature is one of the important stress factors that affect crops in tropical countries. Plants do evolve or adopt different mechanisms to overcome such stress for survival. It is an interesting subject and has attracted many researchers to work upon. Here, we studied the effect of salicylic acid (SA) on seedling growth and antioxidative defense system in two spring maize (Zea mays L.) genotypes viz., CML-32 (relatively heat tolerant) and LM-11 (relatively heat susceptible), under high temperature stress. High temperature induced greater reduction in dry biomass of LM-1 1 seedlings as compared to those of CML-32. There was a parallel increase in ascorbate peroxidase and glutathione reductase activities in the roots of CML-32 seedlings. However, the activities of catalase and superoxide dismutase decreased and the contents of H202, proline and malonaldialdehyde (MDA) increased in seedlings of both the genotypes. Application of SA (400 uM) led to increased dry biomass in heat stressed CML-32 seedlings. It improved the efficiency of Halliwell-Asada pathway in roots of CML-32 seedlings as was evidenced by the enhanced ascorbate peroxidase and glutathione reductase activities. The activities of catalase and superoxide dismutase increased in both the tissues of LM-11 seedlings, whereas in CML-32, it was only in shoots, after SA application. Peroxidase activity increased in SA treated seedlings of both the genotypes, though the increase was comparatively higher in CML-32. The contents of H2O2 and MDA decreased and that of proline increased in SA treated seedlings of both the genotypes, under stress conditions. It may be concluded that SA induced differential antioxidant response by upregulating Halliwell-Asada pathway in roots and attaining high POX activity in both the tissues of CML-32 seedlings, under high temperature stress. PMID- 27468466 TI - Tagging and mapping of SSR marker for rust resistance gene in lentil (Lens culinaris Medikus subsp. culinaris). AB - Lentil, as an economical source of protein, minerals and vitamins, plays important role in nutritional security of the common man. Grown mainly in West Asia, North Africa (WANA) region and South Asia, it suffers from several biotic stresses such as wilt, rust, blight and broomrape. Lentil rust caused by autoecious fungus Uromyces viciae fabae (Pers.) Schroet is a serious lentil disease in Algeria, Bangladesh, Ethiopia, India, Italy, Morocco, Pakistan and Nepal. The disease symptoms are observed during flowering and early podding stages. Rust causes severe yield losses in lentil. It can only be effectively controlled by identifying the resistant source, understanding its inheritance and breeding for host resistance. The obligate parasitic nature of pathogen makes it difficult to maintain the pathogen in culture and to apply it to screen segregating progenies under controlled growth conditions. Hence, the use of molecular markers will compliment in identification of resistant types in different breeding programs. Here, we studied the inheritance of resistance to rust in lentil using F1, F2 and F2:3 from cross PL 8 (susceptible) x L 4149 (resistant) varieties. The phenotyping of lentil population was carried out at Sirmour, India. The result of genetic analysis revealed that a single dominant gene controls rust resistance in lentil genotype L 4149. The F2 population from this cross was used to tag and map the rust resistance gene using SSR and SRAP markers. Markers such as 270 SRAP and 162 SSR were studied for polymorphism and 101 SRAP and 33 SSRs were found to be polymorphic between the parents. Two SRAP and two SSR markers differentiated the resistant and susceptible bulks. SSR marker Gllc 527 was estimated to be linked to rust resistant locus at a distance of 5.9 cM. The Gllc 527 marker can be used for marker assisted selection for rust resistance; however, additional markers closer to rust resistant locus are required. The markers linked to the rust resistance gene can serve as starting points for map-based cloning of the rust resistance gene. PMID- 27468467 TI - Identification of molecular markers to study the Garcinia spp. diversity. AB - The genus Garcinia shows a considerable variation in its morphological characters such as leaf, flower and fruit with taxonomic ambiguity. It is a potential under exploited multipurpose crop that gained considerable attention for the presence of (-) hydroxycitric acid, an anti-obesity compound, in its fruit rind and leaves. Here, we evaluated the genetic relationship through molecular markers among the selected 9 species commonly available in the Western Ghats and the Northeastern Himalayan foot hills of India. The nucleotide sequence data obtained from two prominent monomorphic bands generated in ISSR profiling of the species was utilized for the study. The selected bands were found to be of ITS region (700 bp) and partial region of KNOX-1 gene (600 bp). The evolutionary cluster was formed using MEGA5 software. The study indicated 2 major clusters, influenced by floral morphology of the species and availability of (-) hydroxycitric acid in their fruit rinds. In the subclusters, one species from the Western Ghats were paired with another from Northeastern Himalayas with relatively similar morphological traits. PMID- 27468468 TI - Leucaena leucocephala (Lam.) de Wit., "subabul" stem lignin: Isolation, structural characterization and thermal properties. AB - Lignin is the second most abundant renewable biopolymer on earth after cellulose. It is being used in many industrial applications due to its abundance. In the present study, lignin was isolated from the stems of Leucaena leucocephala (Lam.) de Wit., a high biomass yielding plant using acidic dioxane under N2 atmosphere. Structural characterization of isolated dioxane lignin (DL) was performed by analytical techniques: UV, FT-IR, 1H NMR and 13C NMR. Their monolignol content was determined by nitrobenzene oxidation followed by HPLC-MS/MS analysis. The data was compared with commercial alkali lignin (AL). The results showed that DL is of hardwood guaiacyl-syringyl (GS) type, whereas AL is softwood type with more guaiacyl units and trace amounts of p-hydroxyphenyl units (H). Thermogravimetric analysis (TGA) of DL showed two stage thermal degradation profile similar to AL. The DTGmax for DL and AL were found in the second major loss event of second stage of TGA at 424 degrees C and 404 degrees C, respectively. Differential scanning calorimetry (DSC) study exhibited the glass transition temperatures (Tg) at 132 degrees C and 122 degrees C for DL and AL, respectively. The results from thermal stability studies suggest that dioxane lignin isolated from the "miracle tree" (subabul) can be exploited in various thermoplastic industrial applications. PMID- 27468469 TI - Purification and characterization of buffalo liver L-arginase and its kinetic properties with dihydropyrimidine and metal ions. AB - Arginase (L-arginine amidinohydrolase, EC.3.5.3.1) from animal tissues such as, liver and kidney has been partially characterized by many researchers. In this study, we purified arginase to homogeneity from buffalo liver with about ~2857 purification fold and a 20% recovery by chromatographic and spectroscopic analysis were obtained. The molecular mass determined by gel filtration and SDS PAGE was found to be 118 kDa and 47 kDa, respectively. The optimal pH and temperature of the arginase was 9.5 and 40 degrees C, respectively. Kinetic parameters (Km and Vmax) showed activation of arginase in the reaction medium with decrease in Km (7.14, 5.26, 4.0 and control 3.22 mM) and Vmax (0.05, 0.035, 0.027 and control 0.021 mg/mL/min), while co-factor activity of arginase was optimized using metal ions like Mn2+ and Mg2+ at 2 mM, which revealed an increase in Vmax values (0.011, 0.013, 0.015 and control 0.010 mg/mL/min) and a decrease in Km values (2.22, 2.12, 1.88 and control 1.66 mM). The kinetic data suggested that the arginase activity is enhanced in the presence of dihydropyrimidine derivative and metal ions, indicating essential mode of activation. PMID- 27468470 TI - [Epigallocatechin-3-gallate Attenuates Myocardial Reperfusion Injury in Rats Through Activation of PI3K/Akt Signaling Pathway]. AB - OBJECTIVE: This study was designed to investigate whether epigallocatechin-3 gallate (EGCG) postconditioning protects the heart against ischemic-reperfusion injury (IRI), and to explore its potential mechanisms in a rat model. METHODS: Male Wistar rats were subjected to myocardial ischemia (30 min) and reperfusion (up to 2 h) and the rats were divided into sham group (SO) group, ischemia reperfusion (I/R) model group and EGCG group. EGCG group were treated with EGCG (10 mg/kg) via intravenous infusion 5 min before reperfusion. Electrocardiogram were applied to record ventricular arrhythmia frequency. The severity of myocardial injury [serum level of lactate dehydrogenase (LDH) and creatine kinase (CK), hematoxylineosin (HE) staining] and ventricular arrhythmia, and the serum levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6) and IL-8] were assessed with ELISA, electrocardiogram and Western blot respectively. RESULTS: EGCG given before reperfusion could effectively reduce the serum level of LDH and CK and the incidence of ventricular arrhythmia (P < 0.05, respectively), improved the pathological damage. Meanwhile, EGCG could down-regulate the expression levels of TNF-alpha, IL-6, IL-8 in the myocardial tissue after IRI (P < 0.05, repectively). The expression levels of p p85 and p-Akt in the EGCG group were significantly up-regulated compared to those in I/R group (P < 0.05, repectively). CONCLUSION: EGCG-related anti-inflammatory action could attenuate rat myocardial IRI and this cardioprotective effect might be activated through the PI3K/Akt pathway. PMID- 27468471 TI - [The Protective Effect of Target Temperature Management Combined with Prostaglandin E1 on Ischemia/Reperfusion Injury of Cerebral Micro-vascular Endothelium of ROSC Rat]. AB - OBJECTIVE: To investigate the protective effect of target temperature management (TTM) combined with prostaglandin E1 (PGE1) on ischemia/reperfusion (I/R) injury of cerebral micro-vascular endothelium cell (CMEC) in the return of spontaneous circulation (ROSC) rats with successful cardiopulmonary resuscitation. METHODS: Transoesophageal cardiac pacing with alternating current was used to induce ventricular fibrillation in rats. Five groups were set: Sham group (S group), ROSC group (R group), PGE1 group (P group), TTM group (T group) and PGE1/TTM group (PT group). Cell edema and micro-thrombus formation in cerebral tissue were evaluated through HE staining. I/R injury of CMEC was evaluated through CD34/TUNEL and vascular endothelial (VE)-cadherin/VE growth factor receptor double fluorescent immunohistochemistry staining. VE-cadherin mRNA and vascular cell adhesion molecule-1 (VCAM-1) mRNA expression in cerebral tissue lysate was analyzed by fluorescence quantitative PCR. RESULTS: TTM, PGE1 and PGE1/TTM could significantly improve cerebral interstitial edema, micro-thrombus, and inflammatory cells infiltration in the brain tissue, and reduce the apoptosis and VE-cadherin protein loss of CMEC. PGE1/TTM showed better protective effect. These 3 interventions also inhibited the rapid elevation of VE-cadherin mRNA (0. 5 h) and VCAM-1 mRNA (4 h and 8 h) expression (P < 0.05), which might indicate the less I/R injury of CMEC of ROSC rat. CONCLUSION: Both PGE1 and TTM could alleviate I/R injury of CMEC from ROSC rat after CPR separately, while PGE1/TTM combined intervention might have synergistic better effect. PMID- 27468472 TI - [Employing DNA Damage Response Inhibitors to Enhance Chemosensitivity of Ovarian Carcinoma Cells]. AB - OBJECTIVE: To assess the sensitisation effects of DDR inhibitors combined with conventional chemotherapeutics agents (cisplatin et al) in a drug-resistant ovarian cancer cell line(OVCAR-8). METHODS: Inhibitors of DDR regulators with cisplatin were applied to challenge OVCAR-8, and evaluated the DNA damage response (DDR) and cytotoxic effects of different combination of chemicals. Inhibition of proliferation to OVCAR-8 of different drugs was evaluated by MTT assay. The activation of phosphorylation of histone family 2A variant (yH2AX) and p53 binding protein 1 (53BP1) in OVCAR-8 were evaluated by immunofluorescence to observe their ability of recruitment and forming foci at DNA damage site. RESULTS: We observed that combined treatment of ataxia-telangiectasia mutated (ATM)/ATM and Rad 3-related (ATR) inhibitor and cisplatin can suppress the activation of damage repair mechanisms and weakened the proliferative activity of OVCAR-8 cells (P<0. 01) ; ATR pathway was suppressed and the signal of gammaH2AX weakened and cell survival rate significantly reduced when combination therapy of HU and Wortmannin (P < 0.05); poly ADP-ribose polymerase (PARP) inhibitor could not enhance chemosensitivity in OVCAR-8 cells when combined with cisplatin (P > 0.05). CONCLUSION: We substantiated that appropriate inhibitors of DNA damage response may have a potential to improve the anti-tumor effect of conventional chemotherapy drugs and prevent drug resistances. PMID- 27468473 TI - [The Expression of Pokemon in Endometrial Carcinoma Tissue and the Correlation with Mutant p53]. AB - OBJECTIVE: To detect the expression of Pokemon in endometrial carcinoma (EC), to provide preliminary theoretical basis for clarifying pathogenesis and searching for effective targets. METHODS: Ninety-eight cases of endometrial tissue paraffin specimens form July 2012 to July 2014 in West China Second University Hospital, Sichuan University, were collected, including: EC group, consisting of adenocarcinoma 23 cases, adenosquamous 12 cases, serous 3 cases, mucinous 11 cases and clear cell 9 cases, and control group, consisting of atypical hyperplasia endometrium 20 cases and normal endometrium 20 cases (secretory 10 cases, hyperplasia 10 cases). Immunohistochemistry was used to detect the expression of Pokemonin each section, analyzing the correlation of Pokemon expression with clinicopathologic characteristics and p53 expression. RESULTS: The positive rate of Pokemon in normal endometrium was 25% (5/20), significantly lower than that in atypical hyperplasia endometrium (60.0%, 12/20) and EC (93.1%, 54/58) (P < 0.05); the rate in type II was 97. 12% (34/35), significantly higher than that in type I (86.96%, 20/23) (P = 0.018). The positive rate of Pokemon in III-IV stage, type II and Ki-67 >= 50 EC tissue was much higher (P = 0.012, 0.023, 0.029). In type II EC tissue, the correlation index between Pokemon and p53 is 0.669 (P = 0.000). CONCLUSION: The over expression of Pokemon upregulates the expression of mutant p53, which may be one of the carcinogenesis modes in type II EC. PMID- 27468474 TI - [A Preliminary Study on Portal Vein Hemodynamic Changes and Liver Regeneration in Rats after 70% Partial Hepatectomy]. AB - OBJECTIVE: To explore portal vein hemodynamic changes and liver regeneration in rats after 70% partial hepatectomy (PH). METHODS: Rats were randomly subjected into sham operation group and 70% PH group. A 5-12 MHz high-frequency linear transducer was applied to measure the portal vein diameter (PVD) and the maximum portal vein velocity (PVV) before and after operation on day 1, 3, 7, 14. On the corresponding time, liver tissue morphological changes were observed, and the expression level of PCNA was measured, and the liver regeneration rate (LRR) was calculated. RESULTS: On day 1 after PH, PCNA began to increase, and hepatocyte vacuolated obviously which squeezed and narrowed the hepatic sinusoid. Meanwhile, PVD started to dilate and PVV decelerated. On day 3 after operation, PCNA peaked and active mitosis resulted in the disorders of hepatic structure. PVD peaked and PVV decelerated to the lowest. Until the 14 d after operation, the cell morphology, lobular structure and PCNA recovered gradually accompany by LRR above 90%. PVD and PVV also almost recovered to levels closed to sham group (P < 0.05). CONCLUSION: The hemodynamic parameters PVD, PVV correlated with hepatic pathology changes, mitosis status and regenerated liver volume after PH, which state the potential possibility for ultrasound image study in liver regeneration surveillance. PMID- 27468475 TI - [Inhibitory Effect of High Concentration Insulin on the Proliferation of Human Leukemia Cell Strain K562]. AB - OBJECTIVE: To study the impact of high concentration insulin on the proliferation and apoptosis of K562 cell strain. METHODS: K562 cells were treated with different concentrations of insulin. The proliferation activity was tested by CCK 8 assay, cytometry, and trypan blue exclusion. The alterations in glucose concentration of the culture media were monitored while the apoptosis of K562 cells was detected by flow cytometry. The effects of high concentration insulin on the proliferation of K562 cells were inhibited by varying concentrations of insulin-like growth factor-1 (IGF-1) and Suramin. RESULTS: Under the range of concentration (0.1-1 mU/mL), insulin facilitated the proliferation of K562 cells. In contrast, insulin at high concentrations (1.6-100 mU/mL) had the opposite effect, in a dose- and time-dependent manner. Different concentrations of glucose in the culture medium had no significant influence on the inhibitory effect of high concentration insulin on the proliferation of human leukemia cell strain K562. At low concentration insulin inhibited the apoptosis of K562 cells, in a dose-dependent manner. In contrast, insulin at high concentration had the opposite effect, in a dose-dependent manner. Furthermore, IGF-1 reversed the inhibitory effect of high concentration insulin on the proliferation of K562 cell in a dose- and time-dependent manner. Suramin, which is an IGF-1 receptor non specific blocker, had the opposite effect on K562 cells, also in a dose- and time dependent manner. CONCLUSION: These results indicate insulin has a dual effect on K562 cells. The dual effect is probably mediated by the binding of insulin and IGF-1R. Inhibitory effect of high concentration insulin on the proliferation of K562 cells is unrelated with the glucose metabolism in the culture media. PMID- 27468476 TI - [Effect of "Gubentongluo Formula" on the IgA Class Switch Recombination of B Lymohocytes in Peyer's Patches in Mice with IgA Nephropathy]. AB - OBJECTIVE: To explore the underlying mechanism of "Gubentongluo Formula" in treatment of IgA nephropathy (IgAN). METHODS: After the IgAN model was successfully induced at week 12, the Kunming mice were randomly divided into three groups: normal control group (n = 15), IgAN group (n = 15) and Traditional Chinese Medicine (TCM) group. The mice in normal control and IgAN group were intragastriclly administrated with normal saline for 8 weeks; meanwhile, the mice in TCM group were intragastriclly administrated with "Gubentongluo Formula" 1.35 mL/ (g . d). The levels of 24 h urine protein were determined at Week 0, 12 and 20. At week 20, the changes of renal pathology were detected; the mRNA expressions of transforming growth factor-beta (TGF-beta) and small mothers against decapentaplegic (Smad) 3 in Peyer's patches (PPs) were detected by fuorescent quantitative reverse transcription-polymerase chain reaction; the protein expressions of TGF-beta and Smad 3 in PPs were detected by immunohistochemistry technique; the levels of (IgA + B)/B lymphocytes in PPs were determined by flow cytometry. RESULTS: Compared with those results of normal control group, the levels of 24 h urine protein, IgA deposition in glomerular mesangial area, and expressions of protein and mRNA of TGF-beta and Smad3 in IgAN group were significantly increased (P < 0.01). Besides, the levels of (IgA+B)/B lymphocytes were significantly elevated in IgAN group (P < 0.01). All these indicators were improved in TCM group. Compared with IgAN group, the differences were statistically significant (P < 0.01). Compared with those results of control group, the levels of (IgA + B)/B lymphocytes showed no significant difference in TCM group (P > 0.05), but other indicators showed significant differences (P < 0.01). CONCLUSION: "Gubentongluo Formula" could effectively improve proteinuria and suppress IgA deposition in glomerular mesangial area in IgAN mice, due to affect IgA class switch recombination of B lymphocytes in PPs through regulating TGF-beta/Smad3 pathway. PMID- 27468477 TI - [Effect of Fushengong Decoction on the Expression of Nephrin mRNA in Kidney of Rats with Chronic Renal Failure]. AB - OBJECTIVE: To investigate the effect of Fushengong Decoction on the expression of nephrin mRNA in renal tissue of rats with chronic renal failure (CRF). METHODS: Fifty five male SD rats were randomly divided into five groups: control group, CRF model group, and low, medium and high Fushengong Decoction dose groups. Rats in control group were fed with standard chow, while the other four groups were fed with adenine to make CRF. The rats in control group received intra-gastric normal saline (NS) of 20 mL/(kg . d) for 30 d, while those in low, medium and high Fushengong Decoction dose groups received Fushengong Decoction at the dose of 4 g/kg, 8 g/kg and 16 g/kg respectively, once a day for 30 d. After that, 24 h urinary protein in urine was measured, blood urea nitrogen (BUN) and serum creatinine (SCr) were detected. Histomorphology of glomerulus were studied by HE staining, and the expression of nephrin were detected by immunohistochemistry and RT-PCR. RESULTS: Compared to the control group, the levels of 24 h urinary protein, BUN and SCr increased significantly (P < 0.05) and the expression of nephrin protein and mRNA decreased significantly (P < 0.05) in CRF model group. The renal interstitium showed fibrotic lesions in model group. The levels of 24 h urinary protein, BUN and SCr decreased significantly after the treatment of Fushengong Decoction (P < 0.05), while the expression of nephrin protein and mRNA increased significantly (P < 0.05). CONCLUSION: Fushengong Decoction could reduce urinary protein and relieve renal damage in rats with CRF by improving the expression of nephrin and reducing the injury of podocytes. PMID- 27468478 TI - [Effect of Brucea Javanica Oil Emulsion on the Invasiveness of Glioma Cells and Its Possible Mechanism]. AB - OBJECTIVE: To investigate the effect of brucea javanica oil emulsion on the invasiveness of glioma cells and hosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway. METHODS: C6 glioma cells were treated by brucea javanica oil emulsion. The inhibition rate of glioma cells was detected by MTT, Western blot was used to detect protein expression levels of PI3K, AKT, and nuclear factor (NF)-kappaB in glioma cells. The number of the glioma cells migrated through polycarbonate membrane was detected by crystal violet staining method. RESULTS: Brucea javanica oil emulsion inhibited PI3K, AKT, and NF-kappaB protein expression which reached the highest inhibition at 30 min, 60 min, and 120 min after brucea javanica oil emulsion, respectively. Maximum suppression on the proliferation of C6 glioma cells reached at 180 min after brucea javanica oil emulsion, while the number of glioma cells migrated through polycarbonate membrane was the least. CONCLUSION: Brucea javanica oil emulsion inhibit the proliferation and invasiveness of glioma cells, which may be related to the inhibition of PI3K/AKT signal pathway. PMID- 27468479 TI - [Senescence-associated Beta Galactosidase Expression in Rat Schwann Cells after Chronic Denervation]. AB - OBJECTIVE: To investigate the effect of prolonged axon depletion on senescence associated beta galactosidase (SA-beta-gal) expression in Schwann cells (SCs) of adult rats. METHODS: Male adult Sprague-Dawley (SD) rats were randomize grouped into sham-operated group and denervation groups for 1 week, 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks and 8 weeks. Rats were subjected to right sciatic nerve transection. After particular denervation duration for the distal stumps, animals were anesthetized and perfused. Proximal stumps of 5 mm and distal stumps of 10 mm from injured nerves, and the corresponding segments from the sham groups and contralateral nerves were harvested and prepared for SA-beta-gal staining to detect SA-beta-gal expression. Then, additional injured distal stumps denervated for 8 weeks were employed for determining cellular distribution of SA-beta-gal expression by co-labeling of SA-beta-gal and SC-specific protein (S100beta). RESULTS: SA-beta-gal expression transiently increased in distal tips of proximal stumps 2 weeks after adult rat sciatic nerve transection without suture. In contrast, in the distal stumps of transected adult rat sciatic nerves, axon depletion for 2 weeks increased SA-beta-gal expression, and the increased expression of SA-beta-gal remained constant after prolonged denervation durations. Furthermore, combination of SA-beta-gal staining with S100beta immunofluorescence staining showed that SA-beta-gal expression. was exclusively present in denervated SCs. CONCLUSION: Prolonged axon depletion increased SA-beta gal expression in adult rat SCs. PMID- 27468480 TI - [The Study of Lipofibroblasts Differentiation of CD90+ and CD90- Orbital Fibroblasts Subsets in Patients with TAO]. AB - OBJECTIVE: Divided orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) into CD90+ and CD90- subsets respect to surface CD90 expression, then determined whether CD90+ and/or CD90- fibroblasts were capable of differentiating into lipofibroblasts. METHODS: Fibroblasts subset separation into CD90+ and CD90- subsets was accomplished by three to four rounds of magnetic bead selection, then treated with 3-isobutyl-1-lmethylxanthine (IBMX), insulin and dexamethasone which was an known inducer of the lipofibroblastic phenotype, then the cells were observed every day to find Lipid droplets. Oil red O staining were conducted at 5 d, 10 d, 15 d, 20 d and 25 d after inducing. The percent of lipofibroblasts were calculated. RESULTS: The ratio in fibroblast derived from extraocular muscles of differentiating into lipofibroblast is less than from connective/adipose tissue (P < 0.05). The ratio of CD90+ fibroblast is less than CD90- fibroblast (P < 0.05). CD90+ cells derived from extraocular miscles could not be induced to differentiate into lipofibroblast. The ratio in CD90- fibroblast from connective/adipose tissue is highest (P < 0.05). CONCLUSION: Orbital fibroblast which has the function of differentiating into lipofibroblast is mainly CD90- connective/adipose tissue. PMID- 27468481 TI - [Effects of Gelatin on Performance of alpha-tricalcium Phosphate Bone Cement]. AB - OBJECTIVE: To determine the effects of gelatin on the performance of calcium phosphate cement (CPC). METHODS: alpha-tricalcium phosphate (alpha-TCP) bone cement was mixed with different concentrations of gelatin solutions. The CPC samples were soaked into simulated body fluid for one day before their compressive and bending strengths were measured. We also compared their waterproof performance, solidification time and surface topography. RESULTS: Gelatin solutions changed the performance of CPC. Optimal performance of CPC was achieved when the volume ratio of gelatin solution to CPC (Vgelatin solution:V(CPC liquid)) was set at 25:100, which increased compressive strength from (7.874 54 +/- 0.660 97) MPa to (9.936 52 +/- 0.433 17) MPa and bending strength from (5.157 06 +/- 0.298 30) MPa to (7.959 71 +/- 0.281 63) MPa. Gelatin solution also prolonged setting time of CPC, improved its waterproof performance, and promoted formulation of more dense and uniform hydroxyapatite crystals. CONCLUSION: Gelatin can improve the compressive and bending strengths of CPC, and make CPC more suitable for clinic use through improvements in setting time and waterproof performance. PMID- 27468482 TI - [Clinical Significance of Hip Rotation Center Location after Reconstruction with Modular Hemipelvic Prostheses for Pelvic Tumor]. AB - OBJECTIVE: To investigatethe clinical significance of hip rotation center location after reconstruction with modular hemipelvic prostheses for periacetabula tumors. METHODS: Forty-two patients who received periacetabular tumor resection and reconstruction with modular hemipelvic prosthesis between January 2004 and January 2014 in our institute were included. Postoperative complications, function (measured by MSTS score), survival rate and recurrence rate were analyzed. The position of prosthetic hip rotation center was measured. By its deviation angle from the ideal rotation center, the patients were divided into inward group, normal group and outward group in the horizontal level, and upward group, normal group and downward group in the vertical direction. And the relationship between positional difference of prosthetic hip rotation center and function at 1 month, 3 months, 6 months and 12 months after surgery was analyzed. RESULTS: Of forty-two cases in total, 25 patients were male and 17 patients were female. The age of the patients ranged from 12 and 69 years (median, 38 years). The minimal followup period was 12 months (mean,36 months; range,12-86 months). The complication rate was 31.0% and hip dislocation rate was 7.1%. The overall survival rate was 69.4% at 3 years and 43.7% at 5 years. After 1 month, 3 months, 6 months, the function of the reconstructed hip gradually improved, with MSTS score showing an increasing trend. The MSTS scores at these three time points were compared, the difference was statistically significant (P < 0.05). The improvement of function after 6 months and 12 months was not obvious, with the difference not being statistically significant (P > 0.05). The deviation of hip rotation center in the longitudinal direction and the horizontal direction did not affect the function of the hip (P > 0.05). CONCLUSION: It is safe and effective for patients with pelvic tumor to receive modular hemipelvic prosthesis reconstruction once the prosthesis is fixed in the most firmly position, where soft tissue fully covered, the muscles could be rebuilt more easily and where the eccentricity of the femoral got a certain degree of recovery. The relationship between the deviation of hip rotation center and postoperative function needs to be confirmed. PMID- 27468483 TI - [Immediate Inguinal Lymph Node Dissection Improves Survival in Patients of Penile Cancer]. AB - OBJECTIVE: To investigate the clinical outcome of immediate inguinal lymph node dissection on the survival of the patients with penile carcinoma. METHODS: A total of 67 patients of penile carcinoma whose inguinal lymph nodes (ILN) were initial clinically impalpable, received inguinal lymph node dissection (ILND) from Dec 2008 to April 2014. Among them, 33 patients received immediate ILND within 1 month after the resection of penile cancer, while 34 patients underwent delayed ILND which was performed when ILN was found clinically apparent during follow-up. The Kaplan-Meier survival analysis was performed. The prognostic factors was evaluated by log-rank test, including age, morphology, location, T stage, grade of primary tumor, clinical status of ILN before ILND, lymphatic pathology, time to ILND. Cox proportional hazard model was used to find the independent risk factors on survival. RESULTS: The median age was 50 year-old (range 26 to 84 year-old). The median follow-up time was 23 months (range 3-76 months). The 3-year and 5-year overall survival were 70.1% and 65.4%, respectively, The 5-year survival rate in immediate ILND and delayed ILND group were 93.1%, and 33.7% respectively. Positive ILN metastasis was found in 7 patients from immediate ILND group but 26 patients from delayed ILND group that the prognostic factors included T stage, tumor grade, clinical status of inguinal lymph nodes before ILND, and lymphatic pathology. Cox model found the status of inguinal lymph nodes was independent prognostic factor for the survival. CONCLUSION: Inguinal lymph node metastasis is the important prognostic indicator of the survival of penile cancer. Immediate ILND could improve survival for the patients with clinically impalpable lymph nodes. PMID- 27468484 TI - [The Iron Content of Hepatocellular Carcinoma Associated Nodules: Study of Histopathology and MR Imaging]. AB - OBJECTIVE: To explore the clinical value of MRI imaging of measuring the iron content for hepatocellular carcinoma (HCC) associated nodules. METHODS: 55 male Wistar rats were randomly allocated into a treatment and a control group, which were administered with diethyl nitrosamine (DEN) and the sterilized tap water. According to the macro pathology differences, the treatment groups were divided into three groups: cirrhotic nodules group, cirrhotic nodules with HCC group, and HCC group; According to the micro pathology differences, the treatment groups were divided into four groups: regenerative nodules (RN) group, low grade dysplastic nodules (LGDN) group, high grade dysplastic nodules (HGDN) group, and HCC group. After 13 weeks, the rats were scanned by MRI T2WI and T2 * WI. The next day all rats were sacrificed for histological tests and tissue iron level determination. The correlations were statically analyzed between the values of T2, T2 * and the grades of iron stain, the quantification of tissue iron. RESULTS: With macro pathology observation, the values of T2, T2 * among control group (normal rats) , cirrhotic nodules group, cirrhotic nodules with HCC group, HCC group were increased, while the quantification of tissue iron were decreased. Significant differences were found for T2, T2 * and quantification of tissue iron in three groups (P < 0.05). Low-grade negative correlations could be found between T2, T2 * and quantification of tissue iron in whole samples (r1 = -0.364, P1 = 0.000; r2 = -0.245, P2 = 0.018). With micro pathology observation, there were significant differences among the control (normal rats), RN, LGDN, HGDN, and HCC groups for the grades of iron stain both in the essence and the interstitial (P < 0.05). After comparison each two groups, significant differences were found among some groups for the grades of iron stain both in the essence and the interstitial (P < 0.05). Generally the grades of iron stain for HCCs were lower than non-HCC both in the essence and the interstitial. CONCLUSION: Negative correlation between T2, T2 * and iron content demonstrats that T2 and T2 * could roughly estimate the iron content in the cirrhotic nodules. T2 and T2 * measurements could contribute to differential diagnosis of HCC nodules. PMID- 27468485 TI - [Development of a Questionnaire Measuring Sexual Mental Health of Tibetan University Students]. AB - OBJECTIVE: To develop a questionnaire measuring sexual mental health of Tibetan university students. METHODS: A draft questionnaire was developed with reference to the Sexual Civilization Survey for University Students of New Century and other published literature, and in consultation with experts. The questionnaire was tested in 230 students. Exploratory factor analyses with principal component and varimax orthogonal rotation were performed. Common factors with a > 1 eigenvalues and >= 3 loaded items (factor loading >= 0.4) were retained. Items with a < 0.4 factor loading, < 0.2 commonality, or falling into a common factor with < 3 items were excluded. The revised questionnaire was administered in another sample of 481 university students. Cronbach's alpha and split-half reliabilities were estimated. Confirmatory factor analyses were performed to test the construct validity of the questionnaire. RESULTS: Four rounds of exploratory factor analyses reduced the draft questionnaire items from 39 to 34 with a 7 factor structure. The questionnaire had a Cronbach's alpha of 0.920, 0.898, 0.812, 0.844, 0.787, 0.684, 0.703, and 0.608, and a Spearman-Brown coefficient of 0.763, 0.867, 0.742, 0838, 0.746, 0.822, 0.677, and 0.564 for the overall questionnaire and its 7 domains, respectively, suggesting good internal reliability. The structural equation of confirmatory factor analysis fitted well with the raw data: fit index chi2/df 3.736; root mean square residual (RMR) 0.081; root mean square error of approximation (RMSEA = 0.076; goodness of fit index (GFI) 0.805; adjusted goodness of fit index (AGFI) 0.770; normed fit index (NFI) = 0.774; relative fit index (RFI) 0.749; incremental fit index (IFI) 0.824; non-normed fit index (NNFI) = 0.803; comparative fit index (CFI) = 0.823; parsimony goodness of fit index (PGFI) = 0.684; parsimony normed fit index (PNFI) = 0.698; parsimony comparative fit index (PCFI) = 0.742, suggesting good construct validity of the questionnaire. CONCLUSION: The Sexual Mental Health Questionnaire for Tibetan University Student has demonstrated good reliability and validity. PMID- 27468486 TI - [Prevalence of Cognitive Impairments and Its Determinants in Rural Elderly in Sichuan Province]. AB - OBJECTIVE: To determine the prevalence of cognitive impairment and its influencing factors in rural elderly in Sichuan Province. METHODS: A multi-stage random sampling method was adopted to select participants in six towns and eighteen administrative villages in Fushun and Lizhou. The cognitive functions of 1 065 rural elderly were assessed. Factors associated with cognitive impairments of the rural elderly were identified. RESULTS: About 39. 9% of the rural elderly had cognitive impairments. Gender, age, marital status, educational attainment, regular physical activities, quality of life and social support were associated with cognitive impairments. CONCLUSION: The prevalence of cognitive impairments in rural elderly in Sichuan is high in comparison with national and international averages. Targeted interventions are needed based on the identified influencing factors. PMID- 27468487 TI - [Comparison of Flu Outbreak Reporting Standards Based on Transmission Dynamics Model]. AB - OBJECTIVE: To compare the current two flu outbreak reporting standards for the purpose of better prevention and control of flu outbreaks. METHODS: A susceptible exposed-infectious/asymptomatic-removed (SEIAR) model without interventions was set up first, followed by a model with interventions based on real situation. Simulated interventions were developed based on the two reporting standards, and evaluated by estimated duration of outbreaks, cumulative new cases, cumulative morbidity rates, decline in percentage of morbidity rates, and cumulative secondary cases. RESULTS: The basic reproductive number of the outbreak was estimated as 8. 2. The simulation produced similar results as the real situation. The effect of interventions based on reporting standard one (10 accumulated new cases in a week) was better than that of interventions based on reporting standard two (30 accumulated new cases in a week). CONCLUSION: The reporting standard one (10 accumulated new cases in a week) is more effective for prevention and control of flu outbreaks. PMID- 27468489 TI - [Associations Between Stress Coping Strategies and Perceived Social Support in Young Patients with Gynecologic Cancers]. AB - OBJECTIVE: To determine the associations between stress coping strategies and perceived social support in young patients with gynecologic cancers. METHODS: The study was conducted in young patients with gynecologic cancers who were admitted to the West China Second University Hospital, Sichuan University from January 2014 to January 2015. Data were collected using three questionnaires, tapping into clinical features, multidimensional scales of perceived social support (MSPSS), and coping strategies with stress [including effective coping ways (ECW) and ineffective coping ways (ICW)]. RESULTS: A total of 236 patients completed the questionnaires. Those with a job, fare incomes, or higher levels of education were more likely to get higher total MSPSS scores and lower ICW scores compared with those unemployed, less than expenditures or primary school level (P < 0.05). ECW scores increased with increasing levels of total MSPSS scores (r = 0.247, P < 0.05) and support from family (r = 0.324, P < 0.05), friends (r = 0.172, P < 0.05), and significant others (r = 0.183, P < 0.05). CONCLUSION: Social support from family members is the main source of young women with gynecologic cancers in coping with stress. PMID- 27468488 TI - [Progressive Risks of Latent Keshan Disease: a Long Term Follow-up Study]. AB - OBJECTIVE: To observe ten-year prognosis of patients with latent Keshan disease (KD) and to determine its associated risk factors. METHODS: A total of 448 patients with newly diagnosed latent KD were monitored and followed up for 10 years. Their ECG abnormalities were classified as major or minor using the Minnesota Code. COX proportional hazards regression models were established to identify risk factors associated with the development of chronic KD. RESULTS: A final sample of 414 cases was included in analyses, with an average of (112.9 +/- 17.5) months of follow-up. At the end of follow-up, 92 (22. 2%) patients developed chronic KD. Older age (> 15 years), male, family history of KD, smoking, lower level of blood selenium (< 60 ug/L), major ECG abnormalities, and 18.5 kg/m2 <= body mass index (BMI) 23.9 kg/m2 were associated with higher cumulative incidence of chronic KD. The COX regression models showed that major ECG abnormalities, BMI, selenium deficiency, hypertension, and ventricular premature complex (VPC) abnormalities contributed to increased risk of chronic KD. A positive linear correlation (r = 0.719, P < 0.01) between GPx activity and blood selenium concentration was found. CONCLUSION: Major ECG abnormalities, BMI, selenium deficiency, hypertension and VPC abnormalities are associated with the development of chronic KD. PMID- 27468490 TI - [Predicting Incidence of Hepatitis E in Chinausing Fuzzy Time Series Based on Fuzzy C-Means Clustering Analysis]. AB - OBJECTIVE: To explore the application of fuzzy time series model based on fuzzy c means clustering in forecasting monthly incidence of Hepatitis E in mainland China. METHODS: Apredictive model (fuzzy time series method based on fuzzy c means clustering) was developed using Hepatitis E incidence data in mainland China between January 2004 and July 2014. The incidence datafrom August 2014 to November 2014 were used to test the fitness of the predictive model. The forecasting results were compared with those resulted from traditional fuzzy time series models. RESULTS: The fuzzy time series model based on fuzzy c-means clustering had 0.001 1 mean squared error (MSE) of fitting and 6.977 5 x 10-4 MSE of forecasting, compared with 0.0017 and 0.0014 from the traditional forecasting model. CONCLUSION: The results indicate that the fuzzy time series model based on fuzzy c-means clustering has a better performance in forecasting incidence of Hepatitis E. PMID- 27468491 TI - [Pharmacokinetics and Bioequiavailability of Asparaginase in Asparaginase Nanospheres]. AB - OBJECTIVE: To determine the pharmacokinetics and bioequivalence of self-assembled hyaluronic acid-graft-poly (ethylene glycol)/hydroxypropyl-beta-cyclodextrin hollow nanospheres loaded with asparaginase (AHHPs) in SD rats. METHODS: AHHPs were prepared and observed under transmission electron microscopy. Its size, Zeta potential and entrapment efficiency were detected. Asparaginase (AAS) activities were measured after intravenous injection of AHHPs or free AAS in rats. The pharmacokinetic parameters were calculated using software DAS 2.1.1 for bioequivalence assessment. RESULTS: The self-prepared AHHPs had an average particle size of (367.43 +/- 2.72) nm, Zeta potential of (-15. 70 +/- 1.25) mV, and average entrapment efficiency of (66.03 +/- 3.81)%. The intravenous injection of AHHPs and free AAS produced an area under concentration-time Curve (AUC)(0-48 h) of (162.06 +/- 4.01) U/mL . h and (46.38 +/- 1.98) U/mL . h, AUC(0-infinity) of (203.74 +/- 12.91) U/mL . h and (51.44 +/- 3.01) U/mL . h, mean residence time (MRT) (0-72h) of (4.35 +/- 0.06) h and (1.76 +/- 0.06) h, MRT(0-infinity) of (7.53 +/- 1.05) h and (2.44 +/- 0.29) h, peak concentration (Cmax) of (30.37 +/- 0.43) U/mL and (26.06 +/- 0.88) U/mL, and time to peak concentration (Tmax) of (0.75 +/- 0.00) h and (0.08 +/- 0.00) h, respectively. Compared with free AAS, the AUC(0-48 h), AUC(0-infinity), MRT(0-72 h), MRT(0-infinity),Cmax and Tmax of AHHPs increased by 3.5, 4.0, 2.5, 3.1, 1.2 and 9.4 times, respectively. The 90% confidential intervals of AUC(0-48 h), AUC(0.infinity) and Cmax of the tested formulation were 72.6%-74.0%, 72.3%-73.7%, 94.7%-96.3%, respectively. CONCLUSION: AHHPs can improve the bioavailability of AAS, extending its biological half-life in rats. AHHPs and free AAS are not bioequivalent. PMID- 27468492 TI - [Determination of Nicotine and Cotinine in Urine by Dispersive Liquid-Liquid Microextraction Combined with Gas Chromatography-Mass Spectrometry]. AB - OBJECTIVE: To develop a method for the determination of nicotine and cotinine in urine samples by dispersive liquid-liquid microextraction (DLLME) combined with gas chromatography-mass spectrometry (DLLME-GC/MS). METHODS: The experimental conditions for GC-MS and DLLME were investigated in detail. DLLME was performed with the following procedure: 5 mL of urine sample was adjusted to pH9. 0 with NaOH solution; NaCl was added to increase ionic strength; 100 uL chloroform (containing internal standard of quinolone) as extractant was mixed with 1 000 pL methanol as dispersant and then injected into the urine sample to make it emulsified and dispersed. The sample solution was centrifuged for 5 min at 4,000 r/min, and 1 uL of its extraction solvent was injected into the GC/MS system for analysis. GC separation was performed with DB-5 column under programmed temperature. Nicotine and cotinine were quantified using selected ion monitoring (SIM) mode of mass spectrum detection and internal standard working curve. RESULTS: Good linear relationship was obtained for detecting nicotine and cotinine ranging from 0. 2 ng/mL to 100 ng/mL, with a detection limit of 0. 010 ng/mL and 0. 022 ng/mL for nicotine and cotinine respectively. The relative standard derivation (RSD) for determination of nicotine and cotinine in urine samples were 8.2% and 9.6% respectively. The spiked recoveries ranged from 92.0% to 108.0% for nicotine, 83.0% to 110.0% for cotinine. CONCLUSION: The method is rapid, sensitive, accurate and simple, with little consumption of organic solvent. It is suitable for determination of nicotine and cotinine in urine, and can meet the requirements for evaluating human tobacco exposure. PMID- 27468493 TI - [Fast Removal of CT Ring Artifacts]. AB - OBJECTIVE: To explore how to remove CT ring-shaped artifact quickly and effectively, and to improve accuracy of CT reconstruction image. METHODS: CT graphics (including the ring-shaped artifacts) were used first in coordinate transformation with a new transformation method. A two-dimensional filter was designed to filter the image. Then, a one-dimensional filter was used to re filter the image. Finally, a new transform method was used to restore the image. RESULTS: The two-step coordinate transformation of ring-shaped artifact algorithm resulted in accurate restored original CT image, effectively reducing its interference on useful information. CONCLUSION: The method described in this study can overcome disadvantages of existing methods and obtain good results. PMID- 27468494 TI - [PREDICTING, POSSIBLE WAYS TO REDUCE AND CORRECTION OF MASSIVE INTRAOPERATIVE BLOOD LOSS IN SPINAL TUMOR SURGERY]. AB - The paper discusses the problem ofpredicting, prevention and therapy of massive intraoperative blood loss in patients with metastasis in spine and spinal cord. We analyze 60 surgical cases in last 14 years in our clinic. Amount of blood loss was more that 80% of total blood volume in each case (from 2.5 to 17 liters). Preoperative selective angiography data on intensity of tumor blood supply were essential for blood loss prediction. Simultaneous embolization oftumor during angiography dramatically reduced intraoperative blood loss. Combination of blood saving techniques (preoperative autodonation, acute normovolemic hemodilution and intraoperative cell salvage) led to effective compensation of blood volume deficit and minimizing of allogenic blood transfusion. Plasma-derived and recombinant factors were effective in management of hemostatic disorders associated with massive blood loss. PMID- 27468495 TI - [INFUSION THERAPY IN RECONSTRUCTIVE MAXILLOFACIAL SURGERY]. AB - Restricted infusion strategy in combination with antifibrinolytic agents such as aprotinin and tranexamic acid is effective for blood saving in maxillofacial surgery. But reduction of infusion volume can lead to intraoperative hypovolemia. The goal of this study was to assess compensative effect of different regimes of infusion therapy and antifibrinolytics on intraoperative volume status and electrolyte balance in reconstructive maxillofacial surgery. MATERIALS AND METHODS: 65 patients were included in the study. There were 4 groups: (1) Infusion rate 8-12 mg/kg/h and acute normo/hypervolemic hemodilution; (2) 4-6 mg/kg/h and aprotinin 500,000 - 100,000 IU/4 hours; 3.6-8 mg/kg/h and tranexamic acid 8-10 mg/kg every 4 hours; 4.6-8 mg/kg/h and tranexamic acid 8-10 mg/kg every 4 hours and regional analgesia offacial nerves. We assessed parameters of central hemodynamic, peripheral perfusion, water-electrolyte balance and acid-base status. RESULTS: Different infusion strategies were effective in maintaining positive volume balance despite intraoperative blood loss and continuous diuresis. Hypovolemia or peripheral perfusion insufficiency weren't mentioned in the study. Water-electrolyte and acid-base balance was also secured in every case. Nevertheless, CVP and diuresis in the group with infusion rate 4-6 ml/kg/h were near the critical threshold and could be dangerous in poorly controlled intraoperative bleeding. CONCLUSION: The optimal infusion rate for surgical interventions in reconstructive maxillofacial surgery is 6-8 ml/kg/h. Infusion rate 8-12 ml/kg/h can potentially lead to dilutional coagulopathy and thus to increase the volume of blood loss. Infusion rate 4-6 ml/kg/h is associated with relative risk of hypovolemia and can't be recommended. PMID- 27468496 TI - [ENTROPY MONITORING DURING LOW-FLOW INHALATION ANESTHESIA--A TRIBUTE TO FASHION OR NECESSITY?]. AB - OBJECTIVE: To compare anesthesia quality and sevoflurane consumption during standard and extended intraoperative monitoring. MATERIALS AND METHODS: 74 patients were included in prospective randomized study. Patients had spinal pathology of varying severity, extension and localization. A comparative evaluation of standard and extended (with entropy) monitoring was performed during low-flow inhalation anesthesia with the automated control of the anesthetic concentration and exhaled oxygen fraction (Et-control). RESULTS: Monitoring depth of anesthesia based on entropy enables more accurate dosing of inhaled anesthetics. CONCLUSIONS: The study revealed that the use of entropy monitoring in high-risk surgery alleviates providing the controlled anesthesia with the optimal inhalation anesthetic concentration and minimal hemodynamic reactions of the patient. PMID- 27468497 TI - [INHOSPITAL TRANSPORT OF PATIENTS IN ACUTE PERIOD OF SEVERE ISOLATED TRAUMATIC BRAIN INJURY WITH MULTIMODAL MONITORING]. AB - Transporting patients out of intensive care unit (ICU) in the acute period of TBI to perform diagnostic tests is an integral part of the treatment process and may be associated with the risk of secondary brain injury. Despite the large number of studies related to in-hospital transport ofpatients with TBI there are no clear recommendations on the required monitoring. OBJECTIVE: To provide safe transportation of the patient by multimodal monitoring in acute period of brain injury. MATERIALS AND METHODS: The study included 9 patients with severe TBI and loss of consciousness (Glasgow coma scale (GCS) 8 or less). The average GCS score was 5.5. The median age was 31 +/- 12 (21 to 54 years). There were 2 women and 7 men. Duration of the transportation was 52 +/- 7,4 min. Data collection was carried out every minute. All patients during transportation were monitoredfor the following parameters: HR, invasive ABP, ICE CPP EtCO2, SpO2. Before and immediately after the transportation sampling of arterial blood was performed for blood gas analysis. RESULTS: Statistically significant differences in ICP was noted in 5 main items (*p < 0.05). Mean ICP was mentioned in bed (12.5 +/- 5.3), on wheelchair (18.2 +/- 6.8*), in CT-scan (16.6 +/- 3.2**), on wheelchair after scan (18.4 +/- 4.1***), in bed again (15.8 +/- 2.9). Other parameters didn't differ significantly. CONCLUSIONS: Multimodal monitoring enables safe transportation ofpatients in acute period of TBI. There are 5 critical items associated with major complication during transportation (original ICE shifting patient from bed to transport wheelchair from wheelchair to CT-scanner table, from CT-scanner table to transport wheelchair from wheelchair to bed). The most unstable parameter is ICP PMID- 27468498 TI - [ROLE OF VAGOINSULAR AND ENTERIC ENDOCRINE SYSTEMS IN ACUTE GASTRODUODENAL EROSION AND ULCERS FORMATION IN SEVERE COMBINED TRAUMATIC BRAIN INJURY DEPENDING ON THE COMBINATION OF DAMAGE]. AB - 347 patients were analyzed and role of vagoinsular and enteric endocrine systems in acute gastroduodenal erosion and ulcers formation in severe traumatic brain injury were assessed depending on the combination of TBI with various organs and systems damage. It was revealed that activation ofvagoinsular and enteric endocrine systems due to microcirculatory disorders and hypoxia associated with severe TBI plays a crucial role in increasing the frequency of manifestations of erosions and ulcers in gastroduodenal mucosa. Identification of these complications on the early stages may lead to more effective management of acute erosions and ulcers. PMID- 27468499 TI - [BRAIN NATRIURETIC PEPTIDE AS A MARKER OF SEVERITY OF PATIENT'S CONDITION AFTER SEVERE TRAUMATIC BRAIN INJURY]. AB - The aim of the study was to assess the significance of NT-proBNP levels as a predictor of the severity of patients' condition after severe TBI and critical stress of the heart. In this prospective observational study 118 patients admitted on 1-4 day after severe TBI (GCS <8 points on admission) was supervised. The average age of patients was 32 +/- 16 years, 28 women and 90 men were in this group. 12 of the observed patients died within the first 10 days. NT-proBNP level was determined by immunochemiluminescent analyzer "Immulite 2000" (Siemens). Blood sampling was performed daily at 8:00 am during the acute period--an average for 7 days (5 to 10) from the date of admission. At the same time hemodynamic status was assessed by PiCCO. It has been shown that NT-proBNP level may be not only a marker of severity of condition and poor outcome in patients with severe TBI, but also can be used as a good predictor of exhaustion of compensatory myocardial capacity in these patients. PMID- 27468500 TI - [POLYNEUROPATHY IN CRITICALLY ILL CHILDREN WITH INFECTIOUS DISEASES]. AB - 14 pediatric critically ill patients with various infectious pathologies were assessed. Electroneuromyography was carried out in all patients. Polyneuropathy of critical states were revealed in 10 children. It is shown that the frequency of severeform of this state was 40%. Polyneuropathy mostly affects the peripheral nerves of the lower extremities. Polyneuropathy developed typically on 5-7 day from the start of mechanical ventilation. PMID- 27468501 TI - [POSITIVE END-EXPIRATORY PRESSURE (PEEP) INFLUENCES ON INTRACRANIAL PRESSURE, SYSTEMIC HEMODYNAMICS AND PULMONARY GAS EXCHANGE IN PATIENTS WITH INTRACRANIAl HEMORRHAGE IN CRITICAL STATE]. AB - Positive end-expiratory pressure is one of the main parameters of respiratory support influencing the gas exchange. However, despite the number ofpositive effects, PEEP can compromise venous outflow from the cranial cavity, increased intracranial pressure, decreased venous return and cardiac output and, consequently, reduced blood pressure and cerebral perfusion. The article presents the results of a survey of 39 patients with intracranial hemorrhage in critical state, undergoing respiratory support with different levels of positive end expiratory pressure. Increasing of PEEP to 15 cm H2O had no adverse effect on mean arterial pressure, heart rate and cerebral perfusion pressure and led only to an clinical insignificant increase (maximum on 2.4 +/- 5.1 mmHg) in intracranial pressure. The greatest hemodynamic changes were observed with increasing PEEP up to 20 cm H2O in patients with preserved compliance ofthe respiratory system. The instability of cerebral perfusion and intracranial pressure associated with a decrease in cardiac output and preload and the exhaustion of compensatory mechanism of peripheral vascular resistance. High levels of PEEP despite the trend towards Cstat reduction will not lead to an increase in the content of extravascular lung water Thus a gradual increase of PEEP to 15 cm H2O can be safe and effective method of improving pulmonary gas exchange in patients with intracranial hemorrhage in critical state. PMID- 27468502 TI - [BALANCED MULTIMODAL ANALGESIA IN GYNECOLOGIC ONCOLOGY]. AB - This article is about the issues of anesthesia during radical surgery in gynecologic oncology. MATERIALS AND METHODS: the study included 336 patients who underwent simple and extended hysterectomy for the period from 2014 to 2015. There were 3 groups where PCA was carried out in groups I and III. RESULTS AND DISCUSSION: found a significant difference between the groups in pain intensity before and after surgery, as well as the need for opioid analgesics in the surgical treatment stages. Also is reflected the comparative characteristic of analgesia during the operation with epidural analgesia and systemic analgesia. CONCLUSIONS: the study proves the effectiveness ofpatient-controlledepidural analgesia by calculating the sum ofpain intensity profile on the visual analogue scale in the postoperative period to 72 hours. It confirmed the needfor systemic analgesia in conjunction with epidural block in extensive gynecological cancer operations. PMID- 27468503 TI - [DIAGNOSTIC AND THERAPEUTIC BRONCHOSCOPY IN PATIENTS UNDERGOING CARDIAC SURGERY IN INTRA- AND POSTOPERATIVE PERIODS]. AB - The article presents research conducted to evaluate the use of diagnostic and therapeutic fiberoptic bronchoscopy in the treatment of ventilator-associated pneumonia (VAP) and tracheobronchitis in patients in cardiac ICU. The paper presents the results of the study and comparison of invasive techniques for sampling from the respiratory tract for bacteriological analysis. We studied the bacterial profile of ICU, original content of the respiratory tract of cardiac patients in the intraoperative period and possible ways for prevention of VAP and tracheobronchitis in the postoperative period using bronchoscopy. In addition data on the effect of bronchoscopy on the respiratory and cardiovascular systems in cardiac surgical patients undergoing mechanical ventilation presented. PMID- 27468504 TI - [ROLE OF ANESTHESIOLOGIST IN CHRONIC PAIN MANAGEMENT]. AB - About 23% of the population according to WHO data suffer from chronic pain. It significantly reduces the quality of life of this patients and lead to their disability. Physicians of any existing specialties in Russia are not trained properly to the treatment of chronic pain. Anesthesiologists have the best background for management chronic pain syndrome. PMID- 27468505 TI - [FAST TRACK CONCEPT IN MODERN NEUROANESTHESIOLOGY]. AB - The concept of fast-track is one of the most discussed trends in the development of modern surgery. According to supporters of this ideology, the use of fast track leads to the reduction ofhospital stay without increasing in readmission, reducing the frequency of postoperative complications, which is reflected in the decrease in the cost of the treatment and social expenses, due to earlier return of patients to normal life. The authors of this review discuss different anesthetic issues of fast-track approach (early awakening, postoperative analgesia, prevention of PONV; neuromuscular block reversion). The paper contains also valuable reasons for using fast-track in neurosurgery, as well as contraindications to the use of this approach. PMID- 27468506 TI - [AUTONOMIC NERVOUS SYSTEM AND ITS IMBALANCE IN NEURO INTENSIVE CARE UNIT]. AB - The autonomic nervous system (ANS) provides homeostasis due to the innervation of the secretory glands, smooth muscle and cardiac muscle. Higher centers of the ANS (primarily the hypothalamus, some centers of the brain stem and limbic system) form a integrative network, which plays a key role in coordinating the functioning of the endocrine, immune system and other parts of the central nervous system. Intracranial centers of the ANS are responsible for the consciousness, behavioral, emotional, and other components of the higher nervous activity. Thus, the significance of the ANS can't be overestimated. At the same time today in neurointensive care there are no clear criteria for ANS dysfunction, we don't have universally recognized monitoring facilities for ANS and approaches to targeted therapy of its disorders. This paradox is even more important as in the pathogenesis of some critical conditions such as neurogenic pulmonary edema, stunned myocardium, cardiomyopathy Takotsubo lies precisely ANS imbalance. This review devoted to the ANS and some problems associated with its imbalance. PMID- 27468507 TI - [NON-CONVULSIVE EPILEPTIC SEIZURE IN PATIENT WITH DELAYED AWAKENING AFTER SUPRATENTORIAL TUMOR REMOVAL]. AB - In some cases after elective neurosurgical procedures we use technique of delayed awakening of patients. Prolonged sedation however can hide the development of epileptic seizures and lead to the status epilepticus formation. This article is a demonstration and discussion of a clinical case of nonconvulsive status epilepticus during delayed awakening of the patient due to prolonged sedation after elective neurosurgical interventionsforsupratentorial brain tumor Presented case suggests the presence of significant risk of nonconvulsive status epilepticus during prolonged sedation. For early detection we advise to use continuous EEG monitoring during the entire period of sedation. PMID- 27468508 TI - [INTENSIVE THERAPY OF THE PATIENT WITH VIRAL-BACTERIAL PNEUMONIA, PROLONGED VENTILATION (137 DAYS) AND TRACHEOESOPHAGEAL FISTULA]. AB - A case of successful therapy of the patient with viral and bacterial pneumonia, prolonged ventilation (137 days) and tracheoesophagealfistula presented. The possibility of optimizing the gas exchange in the lungs by selecting appropriate modes of mechanical ventilation with the use ofproportional assist ventilation of the lungs (PVVL or PAV +), rather than suppressing patient's own attempts is shown. PMID- 27468509 TI - [MUSCLE WEAKNESS WITH NO SIGNS OF POLYNEUROPATHY IN PATIENTS WITH PROLONGED DISTURBANCE OF CONSCIOUSNESS. CASE REPORT]. AB - Paper present several clinical examples of prolonged tetraplegia, which could be outcome not only of polyneuromyopathy of critical states, but also of disturbances in hierarchical relationship in CNS. PMID- 27468510 TI - [HYPOTHERMIA INFLUENCES ON OXYGEN TENSION IN THE BRAIN PARENCHYMA IN PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE]. AB - Aneurysmal subarachnoid hemorrhage is a serious medical and social problem. The main physiological mechanisms that determine secondary brain damage in this patients are intracranial hypertension, cerebral vasospasm, dysfunction of autoregulation mechanisms, violation of liquorodynamics and delayed cerebral ischemia. The multimodal neuromonitoring for prevention and timely correction ofsecondary brain injury factors has become routine practice in neuroICU. Measurement of oxygen tension in the brain parenchyma is one of neuromonitoring options. During the years of intensive use of this method in clinical practice the reasons for reducing the oxygen tension in the brain parenchyma were revealed, as well as developed and clinically validated algorithms for correction of such conditions. However, there are clinical situations that are difficult to interpret and even more difficult to make the right tactical and therapeutic solutions. We present the clinical observation of the patient with aneurysmal subarachnoid hemorrhage, who had dramatically reduced brain intraparenchymal oxygen pressure although prolonged hypothermia were used. Despite this, the outcome was favorable. The analysis allowed to assume that the reason for this decrease in oxygen tension in the brain parenchyma could be hypothermia itself PMID- 27468511 TI - Heroin Addiction: Not a Laughing Matter. PMID- 27468512 TI - Depression, Anxiety, and Quality of Life In Children and Adolescents With Sickle Cell Disease. AB - The relationships among depression, anxiety, and quality of life were tested, as were the effects of age, gender, and pain frequency on these variables in children (n = 44) and adolescents (n = 31) with sickle cell disease. Participants completed the Revised Child Anxiety and Depression Scale (ROADS) and the Pediatric Quality of Life (PedQL Generic Model). The mean and standard deviation for summary RCADS scores for the majority of participants were below the clinical thresholds of T < 65, indicating low risk for depression (n = 65; 89.3%) and anxiety (n = 70; 93.3%). The subscale scores for the different dimensions of QOL health were a) psychosocial (73.3 +/- 15.9), b) emotional (75.0 +/- 20.7), c) social (80.8 +/- 19.1), d) school functioning (64.0 >= 19.8), and e) physical (77.4 +/- 17.4). Significant negative correlations were found between mean total quality of life scores and symptoms of a) general anxiety (r = -0.51, p < 0.0001), b) depression (r = -0.66, p < 0.0001), c) obsessive compulsive (r = 0.53, p < 0.0001), d) panic (r = -0.60, p < 0.0001), and e) social phobia (r = 0.57, p < 0.0001). Age and gender did not have significant effects on risk for depression and anxiety or poor QOL. Pain frequency also did not have significant effects on the risk for depression and anxiety. Findings suggest that health care providers need to screen for anxiety and depression, and make referrals for early interventions to improve quality of life and promote school function in youth with sickle cell disease. PMID- 27468513 TI - Online Focus Groups with Parents And Adolescents with Heart Transplants: Challenges and Opportunities. AB - Pediatric heart transplant recipients are scarce and widely dispersed. Previous studies of adolescents in this population were limited to small homogenous samples. Although online focus groups are an emerging data collection method, its use in pediatric populations has not been fully realized. The purpose of this study was to explore the feasibility of using online focus groups with pediatric populations. Adolescents (aged 13 to 21 years) at least 6 months post-heart transplant and their parents were recruited from two children's hospitals. An online discussion forum (iTracks) was used to conduct asynchronous focus groups with separate parent and adolescent groups. Six parents and four adolescents participated in the discussions. iTracks provided a framework for conducting focus groups in dispersed populations. Access to the discussion transcripts enhanced data analysis and eliminated transcription costs. Overall, online discussion forums were a feasible and cost-effective option to conduct online focus groups in this pediatric population. PMID- 27468514 TI - Effects of Vibration Therapy in Pediatric Immunizations. AB - A randomized clinical trial of 100 children (52 boys, 48 girls) ages 2 months to 7 years was conducted to evaluate the effect of vibration therapy without cold analgesia on pain. A convenience sample was recruited at two sites: a publicly funded, free immunization clinic and a private group pediatric practice. Participants were randomly assigned to receive vibration therapy via a specialized vibrating device or standard care. All children regardless of intervention group were allowed to be distracted and soothed by the parent. Pain was evaluated using the FLACC score, which two nurses assessed at three points in time: prior to, during, and after the injection(s). Data were analyzed using a two-independent samples-paired t-test. Results show that vibration therapy had no effect on pain scores in the younger age groups studied (2 months <= 1 year, > 1 year <= 4 years). In the oldest age group (> 4 to 7 years of age), a heightened pain reading was found in the period from preinjection to post-injection periods (p = 0.045). These results indicate that the addition of vibration therapy (without cold analgesia) to standard soothing techniques is no more effective in reducing immunization pain than standard soothing techniques alone, and thus, is not indicated for use with immunization pain. Recommendations include further evaluation of interventions. PMID- 27468516 TI - Taking It Home. PMID- 27468515 TI - Assessment of Home Safety in Children From Kentuckiana. AB - PURPOSE: To evaluate home safety of children in the Ohio Valley Region. DESIGN AND METHODS: Using a cross-sectional design, data were collected by baccalaureate nursing students enrolled in a pediatric nursing course. A standardized Home Safety Assessment Survey and a Rural or Urban Safety Assessment were used with 95 families. Participants included 15 families who lived in rural areas and 80 families who lived in urban areas. The surveys were conducted in the homes of families that nursing students selected. RESULTS: Families with children under the age of 1 year had lower safe practices, while those with older and more than one child demonstrated higher safe practices. PRACTICE IMPLICATIONS: Based on these findings, interventions could be developed that focus on child injury prevention within home settings. Families presenting with the greatest risk of unintentional injuries can be identified and given extra attention and education. PMID- 27468517 TI - Parents' Perception of Satisfaction With Pediatric Nurse Practitioners' Care And Parental Intent to Adhere To Recommended Health Care Regimen. AB - The purposes of this study were to explore parents' perceptions of satisfaction with care from primary care pediatric nurse practitioners (PNPs) and to explore the relationships of the four components of parental satisfaction with parents' intent to adhere to recommended health care regimen. The study used a descriptive correlational research design. A convenience sample of 91 participants was recruited from practices in southeastern Pennsylvania. The 28-item, Parents' Perceptions of Satisfaction with Care from Pediatric Nurse Practitioners (PPSC PNP) tool was developed to measure four components of satisfaction and overall satisfaction of parents with PNP care after the health visit. A 100 mm visual analog (VAS) scale measured parental intent to adhere to the care regimen recommended by the PNP. Parents' perceptions of overall satisfaction with care from PNPs and satisfaction with each of the four components (communication, clinical competence, caring behavior, and decisional control) were high as measured by the PPSC-PNP. Multiple regression analysis revealed that clinical competence had the strongest positive relationship with parental intent to adhere to PNP recommended health regimen and was the only variable to enter the regression equation. The findings of this study have implications for nursing practice. The PPSC-PNP instrument may be used with a variety of pediatric populations and settings as a benchmark for quality care. Clinical competence is important for the role of the PNP. Other variables of parental intent to adhere to the health regimen should be explored in future studies. PMID- 27468519 TI - Preparing Children and Families For Procedures or Surgery. PMID- 27468518 TI - Mentoring Practice and Mentoring Benefit 2: Mapping the Future and Career Optimism--An Overview and Application to Practice Using Mentoring Activities. PMID- 27468520 TI - Polytobacco Use Among Adolescents. PMID- 27468521 TI - How Many Embryos should be Transferred? The Relevance of Parity and Obstetric History. AB - BACKGROUND: Fertility treatments are responsible for the rise in high order pregnancies in recent decades and their associated complications. Reducing the number of embryos returned to the uterus will reduce the rate of high order pregnancies. OBJECTIVES: To explore whether obstetric history and parity have a role in the clinician's decision making regarding the number of embryos transferred to the uterus during in vitro fertilization (IVF). METHODS: In a retrospective study for the period August 2005 to March 2012, data of twin deliveries > 24 weeks were collected, including parity, mode of conception (IVF vs. spontaneous), gestational age at delivery, preeclampsia, birth weight, admission to the neonatal intensive care unit (NICU), and Apgar scores. RESULTS: A total of 1651 twin deliveries > 24 weeks were record- ed, of which 959 (58%) were at term (> 37 weeks). The early preterm delivery (PTD) rate (< 32 weeks) was significantly lower with increased parity (12.6%, 8.5%, and 5.6%, in women with 0, 1, and >= 2 previous term deliveries, respectively). Risks for PTD (< 37 weeks), preeclampsia and NICU admission were significantly higher in primiparous women compared to those who had one or more previous term deliveries. Primiparity and preeclampsia, but not IVF, were significant risk factors for PTD. CONCLUSIONS: The risk for PTD in twin pregnancies is significantly lower in women who had a previous term delivery and decreases further after two or more previous term deliveries. This finding should be considered when deciding on the number of embryos to be transferred in IV. PMID- 27468523 TI - Clinical Profile of Attention Deficit Hyperactivity Disorder: Impact of Ethnic and Social Diversities in Israel. AB - BACKGROUND: Despite the increased worldwide recognition of attention deficit/hyperactivity disorder (ADHD), there is a variability in the diagnostic rate of both ADHD and its co-morbidities. These diversities are probably related to the methodology and instruments used for the diagnosis of ADHD and to awareness and cultural interpretation of its existence. OBJECTIVES: To identify consistent differences in the clinical profile of Arab and Jewish children with ADHD in Israel who differ in cultural, ethnic and socioeconomic background. METHODS: We analyzed the data of 823 children and adolescents with ADHD (516 Jews and 307 Arabs) and compared the clinical characteristics between these two ethnic groups. All patients were evaluated in two neuropediatric and child development centers in northern Israel: one in Haifa and one in Hadera. Children with autism and intellectual disabilities were excluded. RESULTS: The distribution of ADHD subtypes was similar in both populations. However, learning disorders and psychiatric co-morbidities (behavioral difficulties and anxiety) were reported more frequently in the Jewish population. The most commonly reported adverse effects to psychostimulants were mood changes, anorexia, headache, insomnia and rebound effect, and were more frequently reported in the Jewish population (42.0% vs.18.0%, P < 0.05). CONCLUSIONS: We assume that these differences are related to cultural and socioeconomic factors. We suggest that the physician take cultural background into consideration when treating patients with ADHD. PMID- 27468522 TI - Syncope in Primary Prevention Implantable Cardioverter Defibrillator Patients. AB - BACKGROUND: Syncope is a common clinical condition spanning from benign to life threatening diseases. There is sparse information on the outcomes of syncopal patients who received an implantable cardiac defibrillator (lCD) for primary prevention of sudden cardiac death (SCD). OBJECTIVES: To assess the outcomes and prognosis of patients who underwent implantable cardiac defibrillator (ICD) implantation for primary prevention of SCD and compare them to patients who presented with or without prior syncope. METHODS: We compared the medical records of 75 patients who underwent ICD implantation for primary prevention of SCD and history of syncope to those of a similar group of 80 patients without prior syncope. We assessed the episodes of ventricular tachycardia (VT), ventricular fibrillation (VF), shock, anti-tachycardia pacing (ATP) and mortality in each group during follow-up. RESULTS: Mean follow-up was 893 days (810-976, 95% CI) (no difference between groups). There was no significant difference in gender or age. Patients with prior syncope had a higher ejection fraction rate (35.5 ? 12.6 vs. 31.4 8.76, P = 0.02), experienced more episodes of VT (21.3% vs. 3.8%, P = 0.001) and VF (8% vs. 0%, P = 0.01), and received more electric shocks (18.7% vs. 3.8%, P = 0.004) and ATP (17.3% vs. 6.2%, P = 0.031). There were no differences in inappropriate shocks (6.7% vs. 5%, P = 0.74), cardiovascular mortality (cumulative 5 year estimate 29.9% vs. 32.2%, P = 0.97) and any death (cumulative 5 year estimate 38.1% vs. 48.9%, P = 0.18). CONCLUSIONS: Patients presenting with syncope before ICD implantation seemed to have more episodes of VT/VF and shock or ATP. No differences in mortality were observed. PMID- 27468524 TI - Down-Regulation of Cardiac Erythropoietin Receptor and its Downstream Activated Signal Transducer Phospho-STAT-5 in a Rat Model of Chronic Kidney Disease. AB - BACKGROUND: Chronic kidney disease (CKD) is often accompanied by impairment of cardiac function that may lead to major cardiac events. Erythropoietin (EPO), a kidney-produced protein, was shown to be beneficial to heart function. It was suggested that reduced EPO secretion in CKD may play a role in the initiation of heart damage. OBJECTIVES: To investigate molecular changes in the EPO/ erythropoietin receptor (EPO-R) axis in rat cardiomyocytes using a rat model for CKD. METHODS: We established a rat model for CKD by kidney resection. Cardiac tissue sections were stained with Masson's trichrome to assess interstitial fibrosis indicating cardiac damage. To evaluate changes in the EPO/EPO-R signaling cascade in the myocardium we measured cardiac EPO and EPO-R as well as the phosphorylation levels of STAT-5, a downstream element in this cascade. RESULTS: At 11 weeks after resection, animals presented severe renal failure reflected by reduced creatinine clearance, elevated blood urea nitrogen and presence of anemia. Histological analysis revealed enhanced fibrosis in cardiac sections of CKD animals compared to the sham controls. Parallel to these changes, we found that although cardiac EPO levels were similar in both groups, the expression of EPO-R and the activated form of its downstream protein STAT-5 were significantly lower in CKD animals. CONCLUSIONS: CKD results in molecular changes in the EPO/EPO-R axis. These changes may play a role in early cardiac damage observed in the cardiorenal syndrome. PMID- 27468525 TI - Gastrostomy Tube Weaning and Treatment of Severe Selective Eating in Childhood: Experience in Israel Using an Intensive Three Week Program. AB - BACKGROUND: Children dependent on gastrostomy tube feeding and those with extremely selective eating comprise the most challenging groups of early childhood eating disorders. We established, for the first time in Israel, a 3 week intensive weaning and treatment program for these patients based on the "Graz model." OBJECTIVES: To investigate the Graz model for tube weaning and for treating severe selective eating disorders in one center in Israel. METHODS: Pre program assessment of patients' suitability to participate was performed 3 months prior to the study, and a treatment goal was set for each patient. The program included a multidisciplinary outpatient or inpatient 3 week treatment course. The major outcome measures were achievement of the target goal of complete or partial tube weaning for those with tube dependency, and expansion of the child's nutritional diversity for those with selective eating. RESULTS: Thirty-four children, 28 with tube dependency and 6 with selective eating, participated in four programs conducted over 24 months. Their mean age was 4.3 +/- 0.37 years. Of all patients, 29 (85%) achieved the target goal (24 who were tube-dependent and 5 selective eaters). One patient was excluded due to aspiration pneumonia. After 6 months follow-up, 24 of 26 available patients (92%) maintained their target or improved. CONCLUSIONS: This intensive 3 week program was highly effective in weaning children with gastrostomy tube dependency and ameliorating severe selective eating. Preliminary evaluation of the family is necessary for completion of the program and achieving the child's personal goal, as are an experienced multidisciplinary team and the appropriate hospital setup, i.e., inpatient or outpatient. PMID- 27468526 TI - Post-Infectious Glomerulonephritis in Pediatric Patients over Two Decades: Severity-Associated Features. AB - BACKGROUND: The incidence of post-infectious glomerulonephritis (PIGN) has decreased over the last decades. As a result, recent epidemiological data from industrialized countries are scarce. OBJECTIVES: To evaluate patterns of PIGN in children and detect possible predictors of disease severity. METHODS: We collected clinical and laboratory data of patients with PIGN admitted to Schneider Children's Medical Center during 1994-2011. Diagnostic criteria included presence of hematuria with/without other features of nephritic syndrome along with hypocomplementemia and/or microbiological/serological evidence of streptococcal infection. Patients with other diseases (systemic lupus erythematosus, vasculitis, etc.) were excluded from the study. RESULTS: A total of 125 patients with a mean age of 5.8 +/- 3.3 years (range 1.5-17.6), of whom 16% were < 3 years, matched the study criteria. Presenting features included hypertension in 103 (82.4%) patients, azotemia in 87 (70.2%), fever in 49 (40/6), and elevated C-reactive protein in 75 (81.5%). Isolated macrohematuria was found in 21 (16%). Full-blown nephritic syndrome was diagnosed in 51 patients (41.1%) and 28 (22.9%) had nephritic syndrome with nephrotic-range proteinuria. Depressed C3 complement levels were associated with the presence of nephritic syndrome (OR 0.73, 95% CI 0.60-0.88, P = 0.001) as well as older age (OR 1.24, Cl 1.08-1.43, P = 0.001). At last follow-up (mean 42 months) all examined patients (100 of 125) had normal renal function, 6 had hypertension, and 1 had proteinuria. CONCLUSIONS: PIGN remains an important cause of glomerular disease in children and may affect very young patients. Nephrotic-range proteinuria with hypoalbuminemia seems to be more frequent than previously reported. Hypocomplementemia is associated with a more severe disease course, namely, azotemia and nephritic syndrome. PMID- 27468527 TI - Using Advanced Imaging Methods to Study Neurolathyrism. AB - BACKGROUND: Neurolathyrism is a toxic nutritional disorder caused by consumption of the grass pea, Lathyrus sativus. The disease, which manifests as an acute or insidiously evolving spastic paraparesis, continues to occur throughout Africa and Asia. Research on this disease is limited, and to our knowledge no imaging studies of patients with neurolathyrism have been published. OBJECTIVES: To better localize the site of damage in neurolathyrism using advanced imaging methods. METHODS: Three male patients, immigrants from Ethiopia, were included in the study. All had a history of arrested spastic paraparesis that had evolved before their emigration from Ethiopia, and a past history of exposure to grass pea without any other cause. Functional magnetic resonance imaging (fMRI) included simple motor tasks to evaluate cortical motor areas. Anatomic scans included diffusion tensor imaging (DTI) to evaluate the corticospinal tracts. RESULTS: In all patients clear activation was found in motor regions, and the patients' activity pattern was qualitatively similar to that in control sublects. In one patient in whom clinical symptoms were asymmetric, an asymmetric activity pattern in Ml was identified. DTI analysis identified intact corticospinal tracts connecting the pons and the primary motor regions, similar to control subjects. CONCLUSIONS: Advanced neuroimaging clearly identified well-functioning motor regions and tracts in neurolathyrism patients, suggesting a spinal etiology. PMID- 27468528 TI - Estimating Risk of Venous-Thromboembolic Events in Hospitalized Medical Patients: Comparison between 2008 and 2012 Guidelines. AB - BACKGROUND: Prophylaxis for hospitalized venous-thromboembolic events (VTEs) is frequently underutilized, in part due to lack of a simple risk assessment model (RAM). OBJECTIVES: To compare patient selection and administration of VTE prophylaxis according to the American College of Chest Physicians (ACCP) 2008 guidelines versus the newer 2012 guidelines, and assess the feasibility of developing simpler local RAMs. METHODS: We conducted a prospective assessment of VTE risk among 300 unselected consecutive patients admitted to a medical hospital ward, using the 2008 and 2012 ACCP guidelines. The frequency and relative weight of each risk factor in the 2012 ACCP guidelines were used to develop a local VTE RAM. RESULTS: VTE prophylaxis was indicated by the 2008 and 2012 ACCP guidelines in 40% and 42% of the cohort respectively, and was administered in 28% and 26% of eligible patients, respectively. Contraindication to VTE prophylaxis was found in 29% of patients according to both guidelines. In comparison to the 2008 guidelines, sensitivity and specificity of the 2012 guidelines were 96% and 88%, respectively. A local RAM based on the following concise score, comprising age, malignancy and immobility, correctly identified 99% of at-risk patients based on the 2012 guidelines, with a sensitivity and specificity of 98% and 95%, respectively. CONCLUSIONS: Both guidelines performed to a similar degree and were poorly implemented in daily practice. A simplified RAM accurately identified the vast majority of these eligible patients. The development of local RAMs is feasible and may result in higher utilization rates. PMID- 27468529 TI - Learning Curve of Fine-Needle Aspiration Cytology of Head and Neck Masses. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) is used to provide rapid diagnostic information regarding masses of the head and neck. To achieve good results, adequate training is essential. OBJECTIVES: To evaluate the efficacy of FNAC in the diagnosis of head and neck masses performed by residents and attending physicians. METHODS: Palpable guided FNA biopsies from 166 consecutive patients with head and neck masses, excluding thyroid, who were treated in our department between 2008 and 2010 were retrospectively reviewed. Accuracy, sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: A total of 193 FNACs were performed in 161 patients (5 patients were excluded due to age under 18). Mean age was 57.3 years; female to male ratio was approximately 5:4. Most FNACs were performed in masses in the parotid gland (37.3%), 14.5% in the posterior neck, 19.1% in the lateral neck, 15% at level 1, and 9.3% at level 6. The median size of the masses aspirated was 2 cm. Most FNACs were performed by an experienced physician (2.5:1). About 25% of the patients required a second FNAC. Almost 70% of FNACs were diagnostic. Of these, 71.2% were of benign processes and 28.8% of malignancies. CONCLUSIONS: An FNAC of a palpable mass in all sites of the neck, excluding the thyroid, can be done as an office procedure with reasonable results without imaging guidance. About 25% of patients will require another biopsy. The procedure is not difficult to master, as evidenced by the fact that there were no differences in the results of FNACs performed by an attending otolaryngologist or a resident. PMID- 27468530 TI - Preoperative Planning of Orthopedic Procedures using Digitalized Software Systems. AB - The progression from standard celluloid films to digitalized technology led to the development of new software programs to fulfill the needs of preoperative planning. We describe here preoperative digitalized programs and the variety of conditions for which those programs can be used to facilitate preparation for surgery. A PubMed search using the keywords "digitalized software programs," "preoperative planning" and "total joint arthroplasty" was performed for all studies regarding preoperative planning of orthopedic procedures that were published from 1989 to 2014 in English. Digitalized software programs are enabled to import and export all picture archiving communication system (PACS) files (i.e., X-rays, computerized tomograms, magnetic resonance images) from either the local working station or from any remote PACS. Two-dimension (2D) and 3D CT scans were found to be reliable tools with a high preoperative predicting accuracy for implants. The short learning curve, user-friendly features, accurate prediction of implant size, decreased implant stocks and low-cost maintenance makes digitalized software programs an attractive tool in preoperative planning of total joint replacement, fracture fixation, limb deformity repair and pediatric skeletal disorders. PMID- 27468531 TI - Rare Diseases in Europe: from a Wide to a Local Perspective. AB - The European Union defines rare diseases (RDs) as life-threatening or chronically debilitating conditions whose prevalence is less than 5 per 10,000. Moreover, for many RDs, including those of genetic origin, combined efforts are required to reduce morbidity or perinatal and early mortality, and address the considerable decline in an individual's quality of life and socioeconomic potential. Their specificities, i.e., a limited number of patients and scarcity of relevant knowledge and expertise, make RDs a unique condition which requires wide cooperation at a supranational level. Many steps were therefore taken to develop a network of European Reference Centers and to improve RDs coding and classification. In Italy, the RDs issue was addressed in 2001 with the development of a national network and a national registry coordinated by the National Center for RDs of the Italian National Institute of Health. Registries are an important resource for the development of appropriate public health policies and research on specific RDs. Research on RDs is essential for the development of novel therapeutic approaches and requires the involvement of scientific societies and patient organizations. Nevertheless, the management of patients with a chronic-RD requires a qualified care network. The network for RDs of Piedmont and the Aosta Valley (northwest Italy) represents an example of health care organization based on the availability of advanced therapies close to the patient's home. PMID- 27468532 TI - How Many Embryos Should Be Transferred? The Relevance of Parity and Obstetric History. PMID- 27468533 TI - Advances in Digitalized Preoperative Templating in Orthopedic Surgery. PMID- 27468534 TI - A Rare Case of Caffeine Storm due to Excessive Coca-Cola Consumption. PMID- 27468535 TI - Breast MRI: Malignant Cystosarcoma Phyllodes Tumor Exhibits Unique Anisotropic Diffusion. PMID- 27468536 TI - Rare Myxoma Arising from Posterior Wall of Left Atrium. PMID- 27468538 TI - Goodbye, Botswana! PMID- 27468537 TI - Ex vivo Tumor Resection for Primary Cardiac Sarcoma. PMID- 27468539 TI - [Clinical value of Tongguanteng (Radix seu Herba Marsdeniae Tenacissimae) extract combined with chemotherapy in the treatment of advanced non-small cell lung cancer: a Meta-analysis]. AB - OBJECTIVE: To investigate the clinical efficacy and safety of Tongguanteng (Radix seu Herba Marsdeniae Tenacissimae) extract combined with chemotherapy in the treatment of advanced non-small cell lung cancer (NCSLC) compared with chemotherapy alone. METHODS: Databases including Chinese National Knowledge Infrastructure, China Biology Medicine Disc, Wanfang, and MEDLINE were searched until April 1, 2014. Two assessors independently reviewed each trial. The primary outcome was the effective rate (ER) of Tongguanteng (Radix seu Herba Marsdeniae Tenacissimae) extract combined with chemotherapy. The secondary outcomes included quality of life improvement rate (QOLIR) and adverse reactions. Statistical calculations were performed by using Cochrane Collaboration Review Manager 5.2. RESULTS: A total of 888 patients from 15 studies, 13 randomized controlled trials (RCT) and two controlled clinical trials, were included. Compared with chemotherapy alone, Tongguanteng (Radix seu Herba Marsdeniae Tenacissimae) extract plus chemotherapy significantly improved ER [Risk ratio (RR) = 1.32, 95% CI, (1.14, 1.54)] (based on 15 studies) and QOLIR [RR = 2.04, 95% CI, (1.69, 2.47)] (based on 13 studies). Compared with chemotherapy alone, Tongguanteng (Radix seu Herba Marsdeniae Tenacissimae) extract plus chemotherapy significantly inhibited chemotherapy-induced white blood cell decline [RR = 0.79, 95% CI, (0.70, 0.90) (based on 10 studies), chemotherapy-induced platelet decline [RR = 0.77, 95% CI, (0.60, 0.98)] (based on 8 studies), and significantly alleviated nausea and vomiting (NV) [RR = 0.83, 95% CI, (0.71, 0.97)] (based on 7 studies). There was no significant difference in hemoglobin decline between the two therapies [RR = 0.88, 95% CI, (0.70, 1.09)] (based on 6 studies). CONCLUSION: This Meta-analysis suggests that Tongguanteng (Radix seu Herba Marsdeniae Tenacissimae) extract combined with chemotherapy may be more efficacious in the treatment of advanced NSCLC than chemotherapy alone. This effect includes enhancing ER and QOLIR, and weakening chemotherapy toxicity. However, large-scale RCTs are required to further investigate the short- and long-term effects of Tongguanteng (Radix seu Herba Marsdeniae Tenacissimae) extract. PMID- 27468540 TI - [Effectiveness of acupuncture in postoperative ileus: a systematic review and Meta-analysis]. AB - OBJECTIVE: To conduct a systematic review and Meta-analysis of the effectiveness of acupuncture and common acupoint selection for postoperative ileus (POI). METHODS: Randomized controlled trials (RCTs) comparing acupuncture and non acupuncture treatment were identified from the databases PubMed, Cochrane, EBSCO (Academic Source Premier and MEDLINE), Ovid (including Evidence-Based Medicine Reviews), China National Knowledge Infrastructure, and Wanfang Data. The data from eligible studies were extracted and a Meta-analysis performed using a fixed effects model. Results were expressed as relative risk (RR) for dichotomous data, and 95% CI (confidence intervals) were calculated. Each trial was evaluated using the CONSORT (Consolidated Standards of Reporting Trials) and STRICTA (STandards for Reporting Interventions in Controlled Trials of Acupuncture) guideline . The quality of the study was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Of the 69 studies screened, eight RCTs were included for review. Among these, four RCTs (with a total of 123 patients in the intervention groups and 124 patients in the control groups) met the criteria for Meta-analysis. The Meta-analysis results indicated that acupuncture combined with usual care showed a significantly higher total effective rate than the control condition (usual care) (RR 1.09, 95% CI 1.01, 1.18; P = 0.02). Zusanli (ST 36) and Shangjuxu (ST 37) were the most common acupoints selected. However, the quality of the studies was generally low, as they did not emphasize the use of blinding. CONCLUSION: The results suggested that acupuncture might be effective in improving POI; however, a definite conclusion could not be drawn because of the low quality of trials. Further large scale, high-quality randomized clinical trials are needed to validate these findings and to develop a standardized method of treatment. We hope that the present results will lead to improved research, resulting in better patient care worldwide. PMID- 27468541 TI - [Multicenter clinical efficacy observation of integrated Traditional Chinese Medicine-Western Medicine treatment in acute onset period of pulmonary heart disease]. AB - OBJECTIVE: To evaluate the efficacy of integrated Traditional Chinese Medicine Western Medicine (TCM-WM) in the treatment of acute onset pulmonary heart disease (PHD). METHODS: A total of 240 patients met the inclusion criteria and were enrolled. These inpatients were divided into group A (treatment group) and B (control group) in order of admission according to the principles of randomization and control. The research was performed simultaneously in three hospitals. Two groups were given basic treatment that included: controlled oxygen therapy, active and effective anti-infection, maintaining airway patency, correcting O2 deficiency and CO2 retention, correcting acid-base imbalance and electrolyte disturbance, reducing pulmonary hypertension and treating right heart failure, nutritional support and treatment of.complications. Group A was given basic treatment and integrated Traditional Chinese Medicine (TCM) differentiating therapy; group B was given basic therapy and a placebo that was similar in appearance and taste to TCM medicinal broth of pharmaceutical preparations, provided by Yibin Pharmaceutical Company (Yibin, China, Wuliangye Group). RESULTS: The mortality in the treatment group decreased by 4.98% compared with the control group. The treatment group reported improved ventilation, corrected hypoxemia, improved nutritional status and promoted digestive functions. It also significantly improved the patient's self-life skills, improved the patient's quality of life and could shorten the length of hospital stay. CONCLUSION: Comprehensive integrated TCM-WM treatment showed good clinical efficacy toward the acute onset period of PHD patients. PMID- 27468542 TI - [Effect of Qingxue Dan on obesity and metabolic biomarker: a double-blind randomized-controlled pilot study]. AB - OBJECTIVE: To investigate the clinical effect of Qingxue Dan (QXD) on obesity and metabolic biomarker related to obesity. METHODS: A randomized, double blinded, placebo-controlled trial with a paralleled study design was conducted. Twenty-six obese volunteers aged between 30 and 60 with obesity and more than 2 metabolic risk factors were recruited at the department of oriental rehabilitation medicine, Kyunghee university oriental medical hospital, Seoul, Korea. Subjects were randomly assigned to an intervention (QXD) group or a placebo group, and treated with 900 mg/d of QXD or placebo medicine for 8 weeks. Primary endpoint was the change of body mass index (BMI) at 8 week from baseline. Secondary outcomes included the change of body composition, abdominal fat mass measured with Dual energy X-ray absorptiometry (DXA), blood pressure, lipid profiles and the homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: BMI was decreased in the QXD group significantly. Total body fat, abdominal fat mass measured with DXA Region of Interest and waist circumference (WC) showed a trend toward decreasing in the QXD group, but fat free mass was decreased in all groups. Triglyceride (TG) was decreased in QXD group significantly, but WC, total cholesterol and high-density lipoprotein cholesterol were increased in both group. BP didn't change during the study period. HOMA-IR is decreased in both groups without group effect. CONCLUSION: 8-weeks of oral administrations of QXD (900 mg/d) reduces BMI, with a tendency of lose of total body fat mass, especially abdominal fat. It also significantly reduced serum TG level. These results suggest QXD could be used to treat obesity and metabolic risk factors. Further study is needed to confirm our pilot findings. PMID- 27468543 TI - [Effect of Astragali and Angelica particle on proteinuria in Chinese patients with primary glomerulonephritis]. AB - OBJECTIVE: To investigate the effect of the traditional Chinese herbs Astragali and Angelicae Sinensis (A & As) particle [contains Huangqi (Radix Astragali Mongolica), Danggui (Radix Angelicae Sinensis), Huzhanggeng (Rhizoma Polygoni Cuspidati) and Danshen (Radix Salviae Miltiorrhizae)] on proteinuria in glomerulonephritis patients with stage 2 chronic kidney disease. METHODS: A prospective, multi-center, and randomized controlled clinical trial was performed for 24 weeks. From March 2011 to April 2012, 158 patients from nine hospitals in China participated. They were randomized into the A & As group (79 cases, A & As particle 15.2 g/day) and losartan group (79 cases, losartan 50 mg/day). At each follow-up visit, clinical data including blood pressure, urinalysis, 24-h-urinary protein excretion, serum albumin and serum creatinine were collected. RESULTS: All 158 patients completed the follow-up. Proteinuria in the losartan group exhibited a biphasic time-dependent decline with a significant steady reduction from baseline to week 12 (P = 0.0014), and a platform level during the remaining 12-week follow-up (P > 0.05). In contrast, there was a continual significant decrease of proteinuria in the A & As group (P < 0.001). When compared with the losartan results, proteinuria in the A & As group from week 16 to week 24 was significantly reduced (P < 0.001). Stable eGFRs and blood pressure were also observed in both groups. Medication side effects were minimal and non-fatal. CONCLUSION: For Chinese glomerulonephritis patients with stage 2 chronic kidney disease, therapy with A & As particles may provide effective anti-proteinuria treatment. PMID- 27468544 TI - [Retrospective study of Traditional Chinese Medicine treatment of type 2 diabetes mellitus]. AB - OBJECTIVE: To provide clinical evidence in support of Dahuang Huanglian Xiexin decoction (DHXD) to treat type 2 diabetes mellitus (T2DM) and to introduce a new treatment option for clinicians. METHODS: Retrospective analysis was used to evaluate DHXD for the treatment of T2DM by analyzing clinical records of 183 cases. Patients with T2DM who met the inclusion criteria between January 1, 2013 and January 1, 2014 were enrolled. The effects of the treatment were evaluated by the changes in fasting blood-glucose (FBG), postprandial blood sugar (PBG), hemoglobin A1c (HbA1c), blood lipid profiles and body mass index (BMI) at 1, 2, 3 and 6 months. The changes in main symptoms were also evaluated. The dosage of Huanglian (Rhizoma Coptidis) and related factors were analyzed. RESULTS: There was a significant improvement in mean HbA1C at 3 and 6 months after DHXD treatment compared with the baseline level (P < 0.01). There were also significant improvements in FBG, PBG, blood lipid series and BMI. DHXD also improved the main symptoms of stomach and intestine excessive heat syndrome in patients with obese T2DM. Huanglian (Rhizoma Coptidis) was the most frequently used in 678 clinical visits, the dosage of Huanglian (Rhizoma Coptidis) was related to age, BMI, DM duration, the level of blood glucose, and use of Western hypoglycemic drugs. CONCLUSION: This study suggests that DHXD could decrease blood glucose and improve T2DM symptoms and reduce body weight. The use of DHXD may indicate a new optional treatment for T2DM. PMID- 27468545 TI - [Effect of Chinese massage (Tui Na) on isokinetic muscle strength in patients with knee osteoarthritis]. AB - OBJECTIVE: Chinese massage (Tui Na) is one of the most popular Traditional Chinese Medicine remedies for knee osteoarthritis (OA). Several studies have subjectively evaluated the effect of Chinese massage on knee OA through self assessment questionnaires; however, very few studies have objectively assessed the effect by measuring knee muscle strength. The purpose of this study was to assess the efficacy of Chinese massage in improving knee extensor and flexor muscle strength in patients with knee OA. METHODS: Thirty patients with knee OA received Chinese massage therapy three times per week for 2 weeks. Patients completed pre- and post-treatment Visual Analogue Scale (VAS) pain questionnaires, and pre- and post-treatment knee muscle strength was evaluated using the Biodex Multi-Joint System 3. Isokinetic muscle strength measurements were performed at 60 degrees/s and 180 degrees/s. The peak torque (PT), peak torque/body weight(PT/BW), total work (TW), average power (AP), hamstring/quadriceps (H/Q), and range of motion (ROM) values were recorded separately for flexors and extensors. RESULTS: Chinese massage therapy significantly improved knee pain as assessed by the VAS in patients with knee OA (P < 0.05). Post-treatment values were significantly greater than pre-treatment values in the extensor muscles for PT (right P = 0.013, left P = 0.001), PT/BW (right P = 0.008, left P = 0.001) and TW (right P = 0.036, left P = 0.004) at 60 degrees/s. The AP increased significantly after treatment in the flexor muscles in the right knee (P = 0.009) and the extensor muscles in the left knee (P = 0.001). There were no significant differences in pre- and post-treatment ROM and H/Q at 60 degrees/s and 180 degrees/s. CONCLUSION: Chinese massage therapy decreased pain and may improve extensor muscle strength in patients with knee OA, but does not appear to improve ROM. PMID- 27468546 TI - [Purple-bluish tongue is associated with platelet counts, and the recurrence of epithelial ovarian cancer]. AB - OBJECTIVE: To evaluate the relationship between purple-bluish tongue and platelet counts, and further to examine their associations with the recurrence of epithelial ovarian cancer. METHODS: A total of 82 epithelial ovarian cancer patients were enrolled in this study. Cluster analysis was used for grouping patients' P(RGB) (Red-R; Green-G; Blue-B; Average percentage of RGB, P(RGB)) values. Receiver operating characteristic (ROC) curve was performed for detecting the diagnostic standard of purple-bluish tongue. Chi2 test was used to assess the relationship between purple-bluish tongue and platelet counts, and the recurrence of epithelial ovarian cancer. The perioperative (preoperative) platelet level was examined with tongue image and disease recurrence. RESULTS: Tongue images were classified into two groups basing on P(RGB) values of images by cluster analysis. The numbers of cases in cluster "1" (normal color tongue) was 16 and cluster "2" (purple-bluish tongue) was 66. Two groups of P(RGB) values, classified by cluster analysis, were significantly correlated with vision-based tongue color recognition (Kappa = 0.852, P < 0.001). ROC curve showed that the ratio of P(B) to P(R) had the highest diagnostic value. The sensitivity and the specificity of the ratio of P(B) to P(R) were 95.3% and 88.9% respectively and the optimal cut off point was 0.71. Purple-bluish tongue was significantly correlated with increased platelet counts (P < 0.001). Both the increased platelet counts (P = 0.01) and purple-bluish tongue were associated with recurrence of epithelial ovarian cancer (P < 0.001). CONCLUSION: The ratio of P(B) to P(R) greater than 0.71 could serve as an indicator for purple-bluish tongue diagnosing used in symptom pattern identification in Traditional Chinese Medicine. Purple-bluish tongue, associated with increased platelet counts, was also closely correlated with the recurrence of epithelial ovarian cancer. PMID- 27468547 TI - [Changes in symptom patterns and health-related quality of life of cancer patients before and after chemotherapy]. AB - OBJECTIVE: Symptom patterns are an important diagnostic concept in terms of Traditional Chinese Medicine. Although symptom patterns and health related quality of life (HRQOL) are common diagnostic measures for cancer patients, the association between them has not been studied. This study aimed to describe the changes in the pattern of symptoms of Yang-deficiency, Yin-deficiency, blood stasis, and HRQOL before and after chemotherapy, and to examine the association between the patterns and the cancer patients' HRQOL. METHODS: A panel study was undertaken with 123 cancer patients who were about to begin their first course of chemotherapy at four teaching hospitals in Taiwan. A structured questionnaire was used before and after chemotherapy. HRQOL was assessed using the Medical Outcomes Survey Short-Form 36. The Traditional Chinese Medical Constitutional Scale was used to measure Yang-deficiency, Yin-deficiency, and blood stasis patterns, with higher scores indicating a larger deficiency. RESULTS: The patients had significantly worse scores for Yang-deficient pattern, Yin-deficiency pattern, blood stasis pattern, and the physical components of HRQOL after chemotherapy compared with before chemotherapy. The HRQOL scores correlated significantly with Yang-deficiency, Yin-deficiency, and the blood stasis pattern scores. A generalized estimating equation model showed that the HRQOL scores were significantly worse after chemotherapy compared with before chemotherapy for the physical component, but not for the mental component. Blood stasis pattern was significantly associated with a decreased HRQOL in both the physical and mental components. A hemoglobin level < 12 g/dL was associated with a worse physical component of HRQOL. CONCLUSION: The Yang-deficiency, Yin-deficiency, and blood stasis patterns were all associated with lower HRQOL in cancer patients after chemotherapy. PMID- 27468548 TI - [Algal oligosaccharides ameliorate osteoporosis via up-regulation of parathyroid hormone 1-84 and vascular endothelial growth factor]. AB - OBJECTIVE: To determine whether algal oligosac- charide~ affects the levels of parathyroid hormone 1-84 (PTH1-84) and vascular endothelial growth fac- tor (VEGF). METHODS: An osteoporosis rat model was estab- lished via bilateral ovariectomy. The model rats were fed algal oligosaccharides (molecular weights: 600-1, 200 Da) for 4 months. Bone mineral density (BMD) was then measured. MG-63 human osteo- blastic cells were treated with algal oligosaccha- rides. The expression of PTH1-84 and VEGF was then examined. Oligosaccharide-treated cells were transfected with PTH1-84 short hairpin RNA (shR- NA), VEGF shRNA, and PTH1 84-VEGF small interfer- ing RNA (siRNA). The growth rates were then com- pared between transfected and non-transfected RESULTS: Algal oligosaccharides increased the BMD of the osteoporosis rat model compared with untreated controls (P < 0.05). When MG-63 cells were treated with algal oligosaccharides, the growth rate increased by 25% compared with the control group at day 3 (P < 0.05). In addition, the ex- pression of P.TH84 and VEGF was. enhanced. Con- versey w hen tecells were tranfected with PTH84 shRNA, VEGF shRNA, or PTH1-84-VEGF siR- NA, the growth rate was decreased by 17%, 35% and 70%, respectively, compared with controls at day 3 (P < 0.05). CONCLUSION: Algal oligosaccharides ameliorate osteoporosis via up-regulation of PTH1-84 and VEGF. Algal oligosaccharides should be developed as a potential drug for osteoporosis treatment. PMID- 27468549 TI - [Effect of moxa-burning heat stimulating Liangmen (ST 21) and Zusanli (ST 36) on proliferation and apoptosis signaling proteins in rats with stress-induced gastric ulcer]. AB - OBJECTIVE: To observe the effect of moxa-burning heat stimulating acupoints of Liangmen (ST 21) and Zusanli (ST 36) on the proliferation and apoptosis signaling proteins in rats with stress-induced gastric ulcer. METHODS: Forty rats were randomly divided into four groups: negative control (NC), ulcer control (UC), acupoints of stomach meridian (ASM), and acupoints control (AC). The acute gastric ulcer model was established by bound and water immersion. Rats in NC and UC groups didn't receive any moxa-burning heat stimulating treatment, while rats in ASM and AC groups were treated with buringmoxa heat stimulating the acupoints of Liangmen (ST 21) and Zusanli (ST 36) and their controlled points, respectively. Rats in all groups were sacrificed after 12 consecutive days treatment. The ulcer index was evaluated by using Guth's method. The expression of tumor necrosis factor-alpha (TNF-alpha), apoptotic protease activating facter 1 (Apaf-1), Caspase-3, p21 activated kinase 1 (PAK1), extracellular regulated protein kinases 2 (ERK2), phosphorylated ERK2 (pERK2), phosphoinositide 3-kinase (PI3K) and RAC-alpha serine/threonine-protein kinase (Akt) in gastric mucosa was detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with UC group, the ulcer index of ASM and AC groups decreased, and the injured gastric mucosa was improved, the expression of TNF-alpha, Apaf-1 and Caspase-3 in gastric mucosa was significantly reduced (P < 0.05), while the expression of PAK1, ERK2, pERK2, PI3K and Akt in gastric mucosa was significantly increased (P < 0.05). And ASM showed better effect than AC group (P < 0.05). CONCLUSION: Moxa-burning Heat stimulating of Liangmen (ST 21) and Zusanli (ST 36) could promote the recovery of gastric mucosal lesion probably by inhibiting cell apoptosis and promoting cell proliferation in stress-induced gastric ulcer. PMID- 27468550 TI - [Chinese herbal medicine enhances sexual function and c-Fos/nNOS expression in the nucleus accumbens of orchidectomized rats]. AB - RESULTS: There was a decrease in accessory genital organ weight, plasma testosterone, and sexual behavior, as well as a low number of c-Fos-positive cells and a large nNOS-positive cell area in orchidectomized rats. Administration of the herbal medicine increased accessory genital organ weight, testosterone level, mating behavior, and c-Fos-positive cell number, while it decreased the nNOS-positive cell area in orchidectomized rats. CONCLUSION: An increase of plasma testosterone after administration of "kidney-nourishing" herbal medicine might contribute to the elevated sexual function and activity in orchidectomized rats. In addition, a central nervous system mechanism, such as the functional alteration of NAc, might be involved. Abstract OBJECTIVE: To determine whether the central nervous system is involved in the effect of Chinese herbal medicine on sexual function recovery in orchidectomized rats. METHODS: Orchidectomized rats were administered intragastrically with a decoction of "kidney-nourishing" Chinese herbal medicine once per day for 28 days. Accessory genital organ weight, plasma testosterone, and mating behavior were investigated. The expression of c Fos and neuronal nitric oxide synthase (nNOS) in neuronal cells in the nucleus accumbens (NAc) was analyzed by immunohistochemistry. PMID- 27468551 TI - [Evodiamine induces extrinsic and intrinsic apoptosis of ovarian cancer cells via the mitogen-activated protein kinase/phosphatidylinositol-3-kinase/protein kinase B signaling pathways]. AB - OBJECTIVE: To explore the effects of evodiamine on ovarian cancer cells and the mechanisms underlying such effects. METHODS: Human. ovarian cancer cells HO 8910PM were treated with evodiamine at 0, 1.25, 2.5, and 5 MUM for 1-4 d. 3-(4,5 Dimethiylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect the growth inhibition rate of evodiamine-treated HO-8910PM cells. The cell cycle was observed via propidium iodide (PI) staining. Apoptosis induction was assessed via Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V FITC/PI) double staining assay. To verify the mechanism of apoptosis, caspase dependent apoptotic pathway-related protein was detected by Western blot analysis. The expression levels of mitogen-activated protein kinase (MAPK) and/or phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway-related proteins were also investigated. RESULTS: Evodiamine significantly inhibited the proliferation of HO-8910PM cells in a dose- and time-dependent manner. Evodiamine induced G2/M arrest with an increase of cyclin B1 level, and promoted cell apoptosis with a decrease of B cell lymphoma/lewkmia-2 (Bcl-2) and an increase of Bcl-2-associated X protein (Bax) level. In addition, evodiamine treatment led to the activation of caspase-8, caspase-9, and caspase-3 and the cleavage of poly (ADP-ribose)-polymerase (PARP). Evodiamine targeted the MAPK and/or PI3K/Akt pathways by reducing the expression and activity of PI3K, Akt, and extracellular signal-regulated kinase mitogen-activated protein kinase (ERK1/2 MAPK) and the activity of p38 MAPK. CONCLUSION: Evodiamine can inhibit the growth of ovarian cancer cells by G2/M arrest and intrinsic and extrinsic apoptosis. In addition, evodiamine-induced PI3K/Akt, ERK1/2 MAPK, and p38 MAPK signaling may be involved in cell death. PMID- 27468552 TI - [Wnt/beta-catenin signaling is involved in the Icariin induced proliferation of bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To investigate the effect of icariin on proliferation of bone marrow mesenchymal stem cells (BMSCs) in Sprague-Dawley (SD) rats. METHODS: BMSCs were obtained from SD rat bone marrow with differential time adherent method. Its characteristic was identified through differentiation cell surface antigens and the multi-lineage (osteo/adipo/chondo) differentiation potential. 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and 5-Bromo-2 Deoxyuridine (BrdU) incorporation were applied to detect the effect of icariin on BMSCs proliferation. Flow cytometry was used to detect proliferation index of BMSCs. The RNA level and the distribution of beta-catenin were evaluated by Real time Polymerase Chain Reaction (PCR) and Immunofluorescent staining respectively. Western blot was used to detect protein expression levels of beta-catenin, glycogen synthase kinase-3 beta (GSK-3beta), phospho-glycogen synthase kinase-3 beta (pGSK-3beta) and cyclinD1. RESULTS: Icariin promoted BMSCs proliferation at the concentration of 0.05-2.0 mg/L. The percentage of BrdU positive cells of BMSCs was increased from 40.98% to 70.42%, and the proliferation index value was increased from 8.9% to 17.5% with the treatment of 0.05 mg/L icariin, which significance values were both less than 0.05. Compared with the control group, total and nuclear beta-catenin proteins, as well as beta-catenin mRNA expression, were all increased with icariin treatment. Meanwhile, the phosphorylation level of GSK-3beta and cyclinD1 protein expressions were also increased in BMSCs with icariin treatment. CONCLUSION: The findings of the present study demonstrated that low dosage of icariin could promote BMSCs proliferation. The activation of Wnt/beta-catenin pathways was involved in this process. PMID- 27468553 TI - [Antiviral activities against influenza virus (FM1) of bioactive fractions and representative compounds extracted from Banlangen (Radix Isatidis)]. AB - OBJECTIVE: To study the antiviral activities of clemastanin B (CB), epigoitrin, phenylpropanoids portion (PEP) and the mixture of phenylpropanoids, alkaloids and organic acid fractions (PEP+ALK+OA) from Banlangen (Radix Isatidis). METHODS: The experiment consisted of four parts: therapeutic action, prophylaxsis action, inhibition of virus attachment, and direct virucidal action. Cytopathic effect (CPE) and 3-(4,5-Dimethylthiazol-2-yI)-2,5-diphenyltetrazolium (MTT) were used to assess antiviral activity. RESULTS: CB, epigoitrin, PEP and PEP + ALK +OA fractions from Banlangen (Radix Isatidis) extract significantly increased the viability of MDCK cells pre-infected with the virus compared with the virus control group in all the dilutions (P < 0.01). Pretreated with either pure compounds or chemical fractions of Banlangen (Radix Isatidis) extract in all the dilutions significantly improved the viability of MDCK cells (P < 0.01). The inhibition of virus absorption to the host cells by CB, epigoitrin and PEP was in a dose dependent manner. CONCLUSION: CB, epigoitrin, PEP and PEP+ ALK+ OA exert their anti-influenza activity by inhibiting the virus multiplication, prophylaxsis and blocking the virus attachment. The primary mode of action of PEP and PEP + ALK + OA is the inhibition of virus replication. The inhibitory effects on virus attachment and multiplication are the main modes for epigoitrin. PMID- 27468554 TI - [Acute toxicity study of Aspidopterys obcordata aqueous extract in Sprague-Dawley rats]. AB - OBJECTIVE: To examine the acute toxicity of an aqueous extract of Aspidopterys obcordata (A. obcordata) in Sprague Dawley rats. METHODS: The rats were orally administered a dose of 5000 mg/kg body weight and observed continuously for 6 h and then daily for 14 days. Control rats were administered distilled water. The effect of the extract on general behavior, body weight, and food and water intake were measured. After 14 days, the rats were sacrificed and their organs (liver, heart, spleen, lungs, kidney, adrenal glands, ovaries, and testes) were removed for macroscopic examination. The body and organ weights in addition to hematology (e.g., hemoglobin and white blood cell counts) and clinical blood biochemistry (e.g., albumin and bilirubin) were also examined. RESULTS: There were no deaths recorded, and the rats treated with A. obcordata showed no signs of toxicity. All measured parameters in rats treated with A. obcordata were unaffected when compared with those in control rats. The acute toxicity (LD50) was estimated to be > 5000 mg/kg body weight. CONCLUSION: Our results demonstrate the safety of an acute oral administration of an aqueous extract of A. obcordata in rats and indicate that future subacute and long-term toxicity testing of A. obcordata is warranted. PMID- 27468555 TI - [Reporting quality and effect size comparison in randomized controlled trials of bo's abdominal acupuncture using CONSORT statement and STRICTA]. AB - OBJECTIVE: To evaluate the reporting quality of randomized controlled trials (RCT) that compared Bo's abdominal acupuncture with conventional body acupuncture, and compare the efficacy and safety between them by performing a Meta-analysis. METHODS: All RCTs comparing Bo's abdominal acupuncture with conventional body acupuncture were included. English and Chinese databases were searched from their respective inceptions to March 2014. The reporting quality was assessed according to the "Consolidated Standards of Reporting Trials" (CONSORT) checklist for parallel RCTs and the revised "Standards for Reporting Interventions in Clinical Trials of Acupuncture" (STRICTA). A Meta-analysis was conducted to synthesize the effect sizes, and publication bias was evaluated by the Egger linear regression test using Stata. RESULTS: Ninety-seven studies were included, of which most lacked adequate reporting information, and 80.4% showed that the efficacy of abdominal acupuncture is superior to conventional body acupuncture, especially for the following diseases: lumbar disc herniation, cervical spondylosis, omarthritis and cervical vertigo, except simple obesity. Effect-sizes were controversial when evaluating different outcomes. CONCLUSION: The international standard CONORT statement and STRICTA guidelines should be strictly applied when reporting acupuncture RCTs in the future. Abdominal acupuncture appears to be more effective compared with conventional body acupuncture for some diseases. However, fur-her high quality blind RCTs using validated out-ome indexes and standard reporting are warranted. PMID- 27468556 TI - [Herb-drug enzyme-mediated interactions and the associated experimental methods: a review]. AB - OBJECTIVE: To review the interactions between herbs and widely used drugs and summarize the associated experimental methods. METHODS: Definite herb-drug interactions were obtained by searching PubMed, other large overseas databases and summarizing new researches from China. We summarize some methods to assess the interaction between herbs and drugs involving microsomal, cell culture and animal experiments, and clinical trials, classifying this method as single ingredient herbs, crude herb extracts, and herbal formulae. RESULTS: Many herbs interact with drugs through a complex cytochrome P450 and/or P-glycoprotein mechanism. Herb-induced enzyme inhibition and/or induction may result in enhanced and/or decreased plasma, tissue, urine and bile drug concentrations, leading to a change in a drug's pharmacokinetic parameters and resulting in the improper treatment of patients and potentially severe side effects. Use of an appropriate method for comprehensively assessing herb-drug interactions can minimize clinical risks. Different methods were used by researchers to assess the pharmacological changes of drugs in vivo and in vitro and the mechanisms of the interactions from microsomal, cell culture and animal experiments, and clinical trials are discussed in this review. CONCLUSION: Co-medication with herbs can result in changes in pharmacological effects of many drugs. This review describes the assessment of single-ingredient herbs, crude herb extracts, and herbal formulae. When choosing a research method to investigate herb-drug interactions, the properties of the drugs and herbs should be considered. PMID- 27468557 TI - [Comment on the intervention of Traditional Chinese Medicine on survival rates of patients living with human immunodeficiency virus and acquired immune deficiency syndrome]. AB - Despite many differences between Traditional Chinese Medicine (TCM) and conventional medicine, the use of TCM in the treatment of human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is increasingly recognized and accepted by patients. Recent research findings on the benefits of Chinese herbal medicine on long-term survival in patients with HIV/AIDS are encouraging and hopeful, but inconclusive. More research is needed. PMID- 27468558 TI - Advances in Biomarkers in Critical Ill Polytrauma Patients. AB - BACKGROUND: The complexity of the cases of critically ill polytrauma patients is given by both the primary, as well as the secondary, post-traumatic injuries. The severe injuries of organ systems, the major biochemical and physiological disequilibrium, and the molecular chaos lead to a high rate of morbidity and mortality in this type of patient. The 'gold goal' in the intensive therapy of such patients resides in the continuous evaluation and monitoring of their clinical status. Moreover, optimizing the therapy based on the expression of certain biomarkers with high specificity and sensitivity is extremely important because of the clinical course of the critically ill polytrauma patient. In this paper we wish to summarize the recent studies of biomarkers useful for the intensive care unit (ICU) physician. METHODS: For this study the available literature on specific databases such as PubMed and Scopus was thoroughly analyzed. Each article was carefully reviewed and useful information for this study extracted. The keywords used to select the relevant articles were "sepsis biomarker", "traumatic brain injury biomarker" "spinal cord injury biomarker", "inflammation biomarker", "microRNAs biomarker", "trauma biomarker", and "critically ill patients". RESULTS: For this study to be carried out 556 original type articles were analyzed, as well as case reports and reviews. For this review, 89 articles with relevant topics for the present paper were selected. The critically ill polytrauma patient, because of the clinical complexity the case presents with, needs a series of evaluations and specific monitoring. Recent studies show a series of either tissue-specific or circulating biomarkers that are useful in the clinical status evaluation of these patients. CONCLUSIONS: The biomarkers existing today, with regard to the critically ill polytrauma patient, can bring a significant contribution to increasing the survival rate, by adapting the therapy according to their expressions. Nevertheless, the necessity remains to research new non-invasive diagnostic methods that present with higher specificity and selectivity. PMID- 27468559 TI - Quality of Clotting Factor Activity in Fresh Frozen Plasma at Thaw with a Microwave System and after Storage at 4 degrees C for 48 Hours. AB - BACKGROUND: Uncontrolled hemorrhage in polytrauma patients usually results in rapid need of blood products. Despite the shorter thawing times of microwave devices for heating fresh frozen plasma (FFP), their use has remained controversial, and just a few laboratory analyses have been published on this topic. The aim of this study was to analyse the quality of clotting factors immediately after thawing FFP with a microwave device and after 48-hour post thaw storage at 4 degrees C. METHODS: 24 FFP units of all four ABO blood groups (six of each blood group) were thawed with a Transfusio-therm 2000 and later stored at 4 degrees C for 48 hours. Samples were drawn aseptically and investigated on various clotting factors and protein proteases (fibrinogen, antithrombin, FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, vWF antigen and activity, protein S, and protein C) using standard coagulation and chromogenic assays immediately after thawing and again after a 48-hour storage period at 4 degrees C. All units were tested for both anaerobic and aerobic microbial contamination using standard operating procedures immediately after thawing. RESULTS: After thawing, all coagulation factors and protein protease activities were within normal ranges. Blood group O individuals had approximately 25% lower plasma levels of vWF antigen and activity. After a 48-hour storage period at 4 degrees C, FVIII and FIX activities declined significantly in all blood groups, whereas the remaining clotting factors remained comparably stable. CONCLUSIONS: Immediately after rapid thawing using a microwave system, all FFP units contained adequate coagulation factor activities to maintain hemostatic activity at the time of product thaw. The post thaw refrigerated storage caused an anticipated decrease in factor VIII and IX activities, but retained normal coagulation factor levels of many plasma proteins. Therefore we conclude that the Transfusio-therm 2000 has no clinically significant influence on the activity of clotting factors and plasma proteases in FFP units. PMID- 27468560 TI - Increased Expression of 58-kDa Microspherule Protein (MSP58) in Human Gastric Cancer Promotes Cell Proliferation and Correlates with Poor Patient Survival. AB - BACKGROUND: Gastric cancer (GC) is one of the most frequently occurring malignancies with poor prognosis because of its huge heterogeneity and limited available therapeutic options. The nucleolar 58-kDa microspherule protein (MSP58) is involved in a variety of cellular processes. Though MSP58 was identified as a candidate oncogene in many cancer types, it has both oncogenic and tumor suppressive properties. The oncogenic effect of MSP58 in GC is currently unclear. The present study identified MSP58 expression in GCs and investigated its role in tumor proliferation and patient survival. METHODS: MSP58 expression in GCs was identified using western blotting and immunochemistry methods and correlations with clinicopathological features. Patient survival was calculated by multivariate survival analysis. Small interference RNA transfection, CCK8, and clonogenic assays were performed to investigate the roles of MSP58 in cell proliferation. RESULTS: MSP58 was highly expressed in MGC803, BGC823, and NCI-N87 cell lines compared with normal gastric mucosa cells. The study thus provided evidence that knockdown of MSP58 expression significantly suppressed cell proliferation and colony-forming ability. Immunohistochemical analysis showed MSP58 was highly expressed in 51.5% of GC tissues and in 11.9% of normal corresponding mucosal tissues. Significant positive correlations between MSP58 expression and differentiation grade, depth of invasion, and pathological tumor node metastasis (TNM) stage was further identified. The overall 5-year survival rate for the MSP58-positive group was lower than that of the MSP58-negative group. Depth of invasion, lymph node metastasis, and MSP58 expression were found to be independent prognostic factors. CONCLUSIONS: These findings suggested that MSP58 plays an important role in tumorigenesis and progression and may help predict the prognosis of GC patients. PMID- 27468561 TI - High Beclin-1 Expression in Human Alveolar Macrophage Significantly Correlate with the Bacteriologic Sterilization in Pulmonary Tuberculosis Patients. AB - BACKGROUND: Tuberculosis (TB) continues to be a major health problem, and there are few biomarkers for predicting TB progression and anti-TB outcome. Recently, studies suggested that autophagy may link the multistep process of intracellular MTB clearance. So we hypothesized that autophagy level might indicate anti-TB prognostic significance. METHODS: Sixty-five pulmonary tuberculosis (PTB) patients and 15 healthy controls were included in the study. Laboratory examinations were determined in all subjects. Beclin-1 level, which was highly related with autophagy process, was determined using RT-PCR and western blotting assay in human alveolar macrophages. We divided the patients into Beclin-1 high group and Beclin-1 low group and treated them with the same anti-TB regimens. The predictive ability of Beclin-1 on the treatment outcome was further studied. RESULTS: In this study, we found Beclin-1 was markedly increased in alveolar macrophages in PTB patients. Sterilization of the sputum culture was achieved faster in the Beclin-1 high group, as demonstrated either by the percentage of negative smear findings or by the colony-forming unit (CFU) assay. Furthermore, Beclin-1 high group demonstrated faster relief of respiratory symptoms. CONCLUSIONS: Our results suggested the expression of Beclin-1 could be a novel biomarker for predicting anti-TB outcomes. PMID- 27468562 TI - Association of XPC Gene Polymorphisms with Prostate Cancer Risk. AB - BACKGROUND: Defective DNA repair capacity caused by inherited polymorphisms could be associated with cancer susceptibility. One of the major repair pathways is Nucleotide Excision Repair (NER). We investigated Xeroderma Pigmentosum complementation group C (XPC) polymorphisms (Lys939Gln, PAT) with the risk of prostate cancer. METHODS: 154 confirmed prostate cancer patients and 205 Benign Prostate Hyperplasia (BPH) controls were recruited in this survey. The genotypes were determined by PCR-Restriction Fragment Length Polymorphism (RFLP) method. RESULTS: Our results indicated that there were no significant differences between the BPH group and patient group for the XPC Lys939Gln in this pathway. However, deletion/insertion (D/I) and insertion/insertion (I/I) of XPC PAT polymorphism in this pathway could decrease the risk of prostate cancer and act as a protective factor. CONCLUSIONS: In this study, XPC Lys939Gln gene polymorphism was not associated with the risk of developing prostate cancer in Iranian patients. There are no association between different alleles of this polymorphism and grades and stages of tumors, but our results indicated the significant association between XPC PAT and reduction of prostate cancer risk in this group of patients. For more significant results, further samples are required. PMID- 27468563 TI - Evaluation of High Performance Liquid Chromatography and Liquid Chromatography Tandem Mass Spectrometry Methods for 25 (OH) D3 Assay. AB - BACKGROUND: This study was designed to compare the performances of HPLC (High Performance Liquid Chromatography) and LC-MS/MS (Liquid Chromatography-Tandem Mass Spectrometry) methods in 25 (OH) D3 testing. METHODS: This study is comprised of 306 randomly chosen plasma samples from the subjects who applied for routine measurement of 25 (OH) D3. Plasma 25 (OH) D3 levels were quantified using HPLC and LC-MS/MS. The LC-MS/MS method was used as the reference method. The linearity, precision, carry-over, limit of blank, limit of detection (LoD), and comparison studies were done for method validation. Accuracy was tested using external quality assurance samples. RESULTS: Coefficients of variation for both methods were at around 10.0%. The HPLC and LC-MS/MS assays were linear over the working range from 5.0 to 100 ng/mL (r > 0.99). The HPLC assay showed a higher LoD compared to LC-MS/MS (5.1 vs. 1.6 ng/mL, respectively). Results from external quality assurance samples were within ? 1 SD range for both methods. The comparison study revealed good correlation between HPLC and LC-MS/MS methods (y = 1.054x - 1.981 with a small mean bias (-0.953) (r = 0.9752)), when all samples were included, regardless of their 25 (OH) D3 levels. However, the correlation was poor for samples with 25 (OH) D3 concentrations lower than 10 ng/mL. CONCLUSIONS: Both methods have acceptable performance characteristics for use in clinical diagnostic applications. A good comparability was obtained between HPLC and LC-MS/MS methods. However, LoD of HPLC assay was higher and there was a poor correlation between the two systems for samples with 25 (OH) D3 concentrations below 10 ng/mL, showing that LC-MS/MS system is more successful in measuring samples with low 25 (OH) D3 concentration. PMID- 27468564 TI - Application and Comparison of Laboratory Parameters for Forecasting Severe Hand Foot-Mouth Disease Using Logistic Regression, Discriminant Analysis and Decision Tree. AB - BACKGROUND: In recent years, the prevalence of hand-foot-mouth disease (HFMD) in China and some other countries has caused worldwide concern. Mild cases tend to recover within a week, while severe cases may progress rapidly and tend to have bad outcome. Since there is no vaccine for HFMD and anti-inflammatory treatment is not ideal. In this study, we aimed to establish a valid forecasting model for severe HFMD using common laboratory parameters. METHODS: Retrospectively, 77 severe HFMD cases from Zhengzhou Children's hospital in the peaking period between years 2013 to 2015 were collected, with 77 mild HFMD cases in the same area. The study recorded common laboratory parameters to assist in establishment of the severe HFMD model. After screening the important variables using Mann Whitney U test, the study also matched the logistic regression (LR), discriminant analysis (DA), and decision tree (DT) to make a comparison. RESULTS: Compared with that of the mild group, serum levels of WBC, PLT, PCT, MCV, MCH, LCR, SCR, LCC, GLO, CK-MB, K, S100, and B in the severe group were higher (p < 0.05), while MCR, EOR, BASOR, SCC, MCC, EO, BASO, NA, CL, T, Th, and Th/Ts were lower (p < 0.05). Five indicators including MCR, LCC, Th, CK-MB, and CL were screened out by LR and the same for DA, and five variables including EO, LCC, CL, GLO, and MCC screened out by DT. The area under the curve (AUC) of LR, DA, and DT was 0.805, 0.779 and 0.864, respectively. CONCLUSIONS: The findings were that common laboratory indexes were effectively used to distinguish the mild HFMD cases and severe HFMD cases by LR, DA, and DT, and DT had the best classification effect with an AUC of 0.864. PMID- 27468565 TI - Pre-Analytical Components of Risk in Four Branches of Clinical Laboratory in Romania--Prospective Study. AB - BACKGROUND: Development of quality measurement principles is a strategic point for each clinical laboratory. Preexamination process is the most critical and the most difficult to be managed. The aim of this study is to identify, quantify, and monitor the nonconformities of the pre-analytical process using quality indicators that can affect the patient's health safety in four different locations of a Romanian private clinical laboratory. METHODS: The study group consisted of all the analysis requests received by the departments of biochemistry, hematology, and coagulation from January through March 2015. In order to collect the pre-analytical nonconformities, we created a "Risk Budget", using the entries from the "Evidence notebook--non-conform samples" from the above mentioned departments. The laboratory established the quality indicators by means of the risk management technique in order to identify and control the sources of errors, FMEA (Failure Modes and Effects Analyses), which had been implemented and monitored for its purposes and special needs. For the assessment of the control level over the processes, the results were transformed on the Six Sigma scale, using the Westgard calculation method and being obtained in this way the frequency with which an error may occur. (https://www.westgard. com/six-sigma calculators.htm). RESULTS: The obtained results prove that the quantification and monitoring of the indicators can be a control instrument for the pre-analytic activities. The calculation of the Six Sigma value adds extra information to the study because it allows the detection of the processes which need improvement (Sigma value higher than 4 represents a well controlled process). The highest rates were observed for the hemolyzed and the lipemic samples, in the department of biochemistry and hemolyzed, insufficient sample volume, or clotted samples for the department of hematology and coagulation. Significant statistical differences between laboratories participating in the study have been recorded for these indicators. CONCLUSIONS: The elaborated study between the four branches of a Romanian private clinical laboratory was a challenge, and it helped in choosing strategic decisions regarding the improvement of the patient's health safety in the institution, corresponding to the accreditation requirements in accordance with ISO 15189:2013. PMID- 27468566 TI - Relationship between Smoking and Cardiometabolic Index in Middle-Aged Men. AB - BACKGROUND: Cardiometabolic index (CMI) is a new index for discriminating diabetes mellitus and has been demonstrated to be associated with the degree of atherosclerosis in patients with peripheral arterial disease. The purpose of this study was to clarify the relationship of CMI with smoking, a major risk factor for atherosclerotic disease. METHODS: The subjects included 31,742 Japanese men (35 - 60 years old) receiving health-checkup examinations at their workplaces. CMI was calculated as a product of waist-to-height ratio and triglycerides-to-HDL cholesterol ratio. Relationships between CMI and smoking were investigated by using analysis of covariance and logistic regression analysis after adjusting for age and histories of alcohol drinking and regular exercise. RESULTS: Odds ratios (with their confidence intervals) vs. nonsmokers for high CMI (> 1.748) were 1.16 (1.10 - 1.23, p < 0.01) in light smokers (< or = 20 cigarettes/day), 1.60 (1.49 - 1.70, p < 0.01) in heavy smokers (> 20 and 5 40 cigarettes/day), and 2.34 (1.77 - 3.09, p < 0.01) in very heavy smokers (> 40 cigarettes/day). CMI was significantly higher in each smoker group than in the nonsmoker group and tended to be higher with an increase in amount of smoking. The odds ratio (with its confidence interval) for diabetes of subjects with vs. those without high CMI was 2.27 (2.06 - 2.50, p < 0.01) in overall subjects and was not significantly different in each smoker group compared with the odds ratio in the nonsmoker group. CONCLUSIONS: There was a dose-dependent relationship between CMI and amount of smoking, while the association between CMI and diabetes was not different in smokers and nonsmokers. Thus, CMI was suggested to be useful for discriminating diabetes both in smokers and nonsmokers. PMID- 27468567 TI - Clinical Evaluation of the Newly Developed HISCL-5000 Analyzer on Detection of Hepatitis B Virus Markers in West China Hospital. AB - BACKGROUND: Detection of serum hepatitis B virus (HBV) markers is important for rapid screening and diagnosis of HBV infection. In this study, the newly launched HISCL-5000 analyzer (Sysmex Corporation, Kobe, Japan) was appraised in parallel with the MODULAR E170 (Roche Diagnostics, Penzberg, Germany), with regard to the detection of serological HBV markers in China for comparing and evaluating their results and capability. METHODS: In this study, a total of 5,662 clinical serum samples were tested with the two automated systems. Among them, 1,266 samples were assessed for HBsAg, 1,000 for anti-HBs, 1,301 for HBeAg, 1,007 for anti-HBe, and 1,088 for anti-HBc. Reproducibility performance of HISCL-5000 was assayed four times per day for five days consecutively. For qualitative results between the two analyzers, the concordance rates and kappa coefficients were calculated. Spearman's rank correlation analysis was performed for quantitative results. RESULTS: The HISCL-5000 detection mode showed excellent reproducibility with total CVs of less than 5.0%. Concordance between the two analyzers was 99.92% for HBsAg, 95.90% for anti-HBs, 100% for HBeAg, 99.30% for anti-HBe, and 98.62% for anti-HBc. Kappa values between the qualitative results of five HBV markers were 0.998, 0.906, 1.0, 0.983, and 0.969, respectively. For anti-HBs, linear regression analysis demonstrated a good correlation between HISCL-5000 and MODULAR E170 with an R2 value of 0.887. Spearman's correlation coefficients of 0.892, 0.644, -0.609, and -0.700 were observed for the other four markers, HBsAg, HBeAg, anti-H1Be, anti-HBc, respectively. CONCLUSIONS: The newly launched HISCL 5000 displayed high agreement with the more matured MODULAR E170 on screening and diagnosing HBV infection in a clinical laboratory of West China Hospital. PMID- 27468568 TI - Analysis of Ambient Influences Affecting Interleukin-6 Secretion in the Context of Clinical Trials of Stem Cell Therapy for Myocardial Infarction. AB - BACKGROUND: Contradictory results of large clinical trials of stem cell therapy in acute myocardial infarction (AMI) have impeded a wider clinical use. As signalling via paracrine factors in AMI has received more and more attention recently, we sought to compare processing protocols with special emphasis on interleukin-6 (IL-6), a factor of major relevance for triggering cardioprotective signals via STAT3 and PI3K. METHODS: Bone marrow and peripheral blood mononuclear cells were processed according to protocols used in the REPAIR-AMI and ASTAMI study. RESULTS: Keeping cells at higher temperatures significantly boosted secretion of IL-6. Moreover, the use of autologous serum and X-Vivo medium was superior over reagents used in the protocol of the ASTAMI study. CONCLUSIONS: External influencing factors (higher temperature, use of a modern cell culture medium supplemented with serum) led to higher concentrations of IL-6. These results could provide an explanation for the superior results found in the REPAIR AMI study. PMID- 27468569 TI - Serum Sialic Acid Concentration and Content in ApoB-Containing Lipoproteins in Liver Diseases. AB - BACKGROUND: The great significance for the metabolism of lipoproteins is the composition of carbohydrate chain of apolipoproteins, where sialic acid (SA) is located. In VILDL and LDL sialic acid is attached to apolipoprotein B. The sialylation of serum proteins including apolipoprotein B can be affected in the course of liver diseases. Therefore, the aim of this study was to assess the effect of liver diseases on the concentration and content of SA in ApoB containing lipoproteins. METHODS: The tested group consisted of 165 patients (118 males, 47 females) with liver diseases: alcoholic cirrhosis, non-alcoholic cirrhosis, chronic hepatitis, toxic hepatitis, chronic viral hepatitis, and liver cancer. ApoB-containing lipoproteins were isolated by a turbidimetric procedure and SA concentration was measured according to an enzymatic method. RESULTS: There was a significant increase in the serum concentration of SA in ApoB containing lipoproteins in viral hepatitis. Although the serum concentration of ApoB was not significantly different between specific liver diseases, the serum levels of SA in ApoB-containing lipoproteins appeared to be different. There is an association between SA concentration and triglycerides in alcoholic cirrhosis and viral hepatitis. Also, in viral hepatitis SA concentration correlated negatively with HDL-cholesterol. The content of SA in ApoB-containing lipoproteins in alcoholic cirrhosis and viral hepatitis was significantly higher than that in the control group, but did not differ between diseases. CONCLUSIONS: This study may explain the variations in serum lipids and lipoproteins in liver diseases. It seems that the reason for these abnormalities is the changes in the concentration of sialic acid in ApoB-containing lipoproteins. PMID- 27468570 TI - Establishment and Application of a Method for High-Risk Human Papillomavirus Genotyping in Cervical Cancer Tissue. AB - BACKGROUND: Persistent high-risk HPV infection is a major cause of cervical cancer and E6/E7 genes and the Li gene in the HPV genome are key targets to detect high-risk HPV. This study aims to explore the relationship between cervical lesions and E6/7 by establishing a polymerase chain reaction (PCR) to detect multiplex genes based on HPV EE7 genes. It is hoped that such methods will provide a more reliable method for clinical screening and the prevention of cervical cancer. METHODS: Based on alignment, specific primers were designed for HPV E6/E7 genes, the sequences of which came from five5 high-risk papillomaviruses that are common in China. This enabled an E6/E7 gene detection method based on multiplex PCR to be established. E6/E7 and Li gene testing were then performed on 65 cervical cancer tissue samples. The gene copy number of HPV E6/E7 genes and the Li gene were detected from different classifications by real time fluorescence quantitative PCR. RESULTS: Out of the 65 cervical cancer tissue samples, 47 (72.31%) showed positive results in E6/E7 multiplex PCR, 21 (32.31%) showed positive results in the Ll gene PCR, and out of the 219 cervical exfoliate cell samples, 56 (25.57%) showed positive results in E6/E7 multiplex PCR, 21 (13.24%) showed positive results in the L1 gene PCR. There were significant differences (p < 0.05) between these two test results. Fluorescent quantitative PCR showed that the ratio of gene copy number of L1 genes and E6/E7 genes was below 1 (p < 0.05) in cervical cancer tissue, in which both the Li and E6/E7 genes coexist. CONCLUSIONS: The established HPV multiplex PCR assay based on the design of E6/E7 gene is a specific and sensitive method for the detection and genotype of five high-risk HPVs. PMID- 27468571 TI - Low Serum-Butyrylcholinesterase Activity as a Prognostic Marker of Mortality Associates with Poor Cardiac Function in Acute Myocardial Infarction. AB - BACKGROUND: Recently, butyrylcholinesterase (BChE) activity seems to have an independent prognostic role in acute coronary syndrome (ACS). However, the underlying mechanisms remain unclear. A previous study showed that serum BChE activity had a diagnostic value for chronic heart failure. This raises a question: whether BChE activity is associated with cardiac function in ACS, and if so, is this association related to the predictive value of BChE? The aim of this study was to determine the association between BChE activity with cardiac function assessed by Killip class and left ventricular ejection fraction (LVEF) in acute myocardial infarction (AMI) and to evaluate the independent prognostic role of BChE with consideration of these two indicators. METHODS: A total of 350 consecutive patients with AMI were retrospectively included. Serum BChE activity was measured upon admission. All patients were divided into two groups according to median value of BChE activity. All-cause death was defined as endpoint. The prognostic value of mortality was assessed by using Cox regression analysis. RESULTS: BChE activity was higher in patients with low Killip class (I or II) than that in those with high Killip class (III and IV) (7.0 +/- 1.3 or 7.0 +/- 1.5 vs. 6.2 +/- 1.6, p < 0.01). BChE activity was positively correlated with LVEF (r = 0.24, p < 0.001). During a mean follow-up period of 29 +/- 7 months, 25 patients died. BChE activity was significantly higher in surviving patients compared with non-surviving ones (7.0 +/- 1.4 vs. 5.7 +/- 1.3, p < 0.001). The survival rates were 89% and 97%, respectively, in the low and high groups of BChE activity. In a multivariate Cox proportional hazards regression analysis, after adjusting for potential confounders, BChE activity was an independent predictor of mortality after myocardial infarction [Hazard Ratio (HR) 0.65, 95% CI 0.46 - 0.91; p = 0.0131. However, when introducing Killip class and LVEF into the model, BChE activity was not in the equation. CONCLUSIONS: Low BChE activity as a predictor of mortality in AMI might be related to its association with poor cardiac function. PMID- 27468572 TI - Antibodies of IgG, IgA and IgM against Human Bronchial Epithelial Cell in Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Recently, autoimmune mechanisms and pulmonary epithelial cells have attracted attention in chronic obstructive pulmonary disease (COPD). Circulating antibodies against human bronchial epithelial cells (anti-HBEC) bind to bronchial epithelial antigens and induce bronchial epithelial cell damage. This study aimed to detect the expression of IgG, IgM, and IgA anti-HBEC in patients with COPD. METHODS: The association of gender, age, body mass index (BMI), and pulmonary function with the presence of IgG, IgA, and IgM anti-HBEC in the plasma was determined in 170 patients with COPD and 150 age-matched healthy controls. Circulating IgG, IgA, and IgM anti-HBEC were detected by indirect immunofluorescence (IIF). RESULTS: Positive IgG anti-HBEC was seen in 34/170 (20.00%) COPD and 11/150 (7.33%) healthy controls (p < 0.001) (1:100 dilution); positive IgA anti-HBEC were presented in 50/170 (29.41%) COPD and 13/150 (8.67%) healthy controls (p < 0.0001) (1:40 dilution); 19/170 (11.19%) COPD and 10/150 (6.67%) healthy controls exhibited positive IgM anti-HBEC (p > 0.05) (1:40 dilution). The positive IgG and IgA anti-HBEC COPD patients were mostly classified as GOLD (Global Initiative for Chronic Obstructive Lung Disease) III and GOLD IV. The positive IgA anti-HBEC COPD patients had lower BMI than healthy controls (p < 0.05). CONCLUSIONS: Our results suggest that an autoimmune component associated with bronchial epithelial cell damage is possibly involved in COPD and the presence of IgG and IgA anti-HBEC correlated with the GOLD stage of COPD. Therefore, our studies indicate that IgG and IgA anti-HBEC may associate with the disease severity of COPD. PMID- 27468573 TI - Circulating Reticulocalbin 1 and Reticulocalbin 3 in Systemic Sclerosis Patients: Results of a Case Control Study. AB - BACKGROUND: Proteomic candidate biomarkers for systemic sclerosis (Ssc) useful for appropriate patient evaluation and follow-up were identified in mass spectrometry studies; however, most of these biomarkers were not evaluated and confirmed on independent patient samples. Up-regulation of reticulocalbin 1 (RCN1) and reticulocalbin 3 (RCN3) in the dermal fibroblast secretome originating from Ssc patients was previously described. The aim of the study was to evaluate circulating RCN1 and RCN3 as candidate biomarkers for Ssc clinical expression. METHODS: 40 consecutive Ssc patients and 20 gender and age matched controls were included. Serum RCN1 and RCN3 was evaluated using commercial ELISA kits. RESULTS: Serum RCN1 and RCN3 were not statistically significant different between Ssc patients and healthy controls. Serum RCN1 and RCN3 were correlated in both Ssc and healthy control groups (p < 0.001). Serum RCN1 was positively correlated with Ssc disease activity score (EUSTAR, p = 0.02) and remained associated with EUSTAR after adjusting for disease duration in multivariate analysis. 6 Ssc patients (15%) had elevated RCN1 values compared to reference values obtained from healthy control samples. These patients had higher prevalence of digital ulcers, higher disease activity scores, and tended to have esophageal hypomotility, calcinosis, telangiectasia, and diffuse Ssc subtype. CONCLUSIONS: RCN1 and RCN3 expression was not statistically significantly different to healthy controls. However, RCN1 was associated with disease activity score and could be used as a stratification biomarker for Ssc patients, as patients with high RCN1 shared a particular disease pattern. PMID- 27468575 TI - Comparison of AFP-L3 and p53 Antigen Concentration with Alpha-Fetoprotein as Serum Markers for Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) has the worst prognosis among all major cancers, largely due to the lack of sensitive diagnostic markers. We aimed to compare three HCC tumor markers, alpha-fetoprotein (AFP), p53, and AFP-L3%, to evaluate whether measuring serum p53 levels and AFP-L3% has an additive diagnostic value for detection of HCC. METHODS: A total of 86 patients with chronic liver diseases were included. HCC was detected in 68 (79.1%) patients. Twenty healthy age-matched volunteers served as healthy controls. Serum concentrations of AFP, AFP-L3, and p53 protein were measured. The correlations between the three markers with status of viral hepatitis, liver function tests, and Child-Pugh scores were determined. RESULTS: HCC patients showed significantly higher percentages of cirrhosis and Child-Pugh grade C (p < 0.001 and 0.05, respectively) compared with non-HCC group. AFP-L3% and p53 levels were significantly (p < 0.001, 0.0001, respectively) higher in HCC than non-HCC patients. AFP-L3% was found significantly correlated with Child-Pugh classification (p < 0.05) and alkaline phosphatase (p < 0.01). While, p53 significantly correlated with age and HCV positivity. ROC curve analysis showed that the highest specificity and sensitivity of the studied parameters are gained at cutoffs of 15%, 120.5 ng/mL, and 0.14 ng/mL for AFP-L3, AFP, and p53; respectively. Combining AFP-L3 and p53 improved sensitivity to 95.4% with a specificity of 85%. CONCLUSIONS: No significant correlation was found between AFP, AFP-L3%, and p53; however, the simultaneous determination of the three tumor markers yielded a better diagnostic accuracy and sensitivity in the detection of HCCs than each biomarker alone. PMID- 27468574 TI - Detecting of p16 Autoantibody as a Potential Early Diagnostic Serum Biomarker in Patients with Cervical Cancer. AB - BACKGROUND: Over-expression of tumor-associated antigens (TAAs) may trigger secretion of their auto-antibodies. The present work was designed to test whether circulating antibody to P16 protein-derived antigens was altered in cervical cancer. METHODS: 141 cases of cervical cancer patients, 133 cases of cervical benign tumor patients, and 153 healthy volunteers matched in age were recruited. The level of circulating P16 auto-antibody was tested using an ELISA developed in house with linear peptide antigens derived from the P16 protein. RESULTS: The P16 auto-antibody in the malignant tumor group had a significantly higher level than the healthy control group and the benign tumor group (t = 4.016, p < 0.001; t = 3.879, p < 0.001). Patients with stage I cervical cancer have the highest level of P16 autoantibody and the sensitivity against > 90% specificity was 20.3%. CONCLUSIONS: The circulating auto-antibody to P16 may be one of a series of potential biomarkers with early prognostic values for cervical cancer. PMID- 27468576 TI - Immunoglobulin G-Rheumatoid Factor Interferes Negatively with Serum Hepatitis B Envelope Antigen Chemiluminescent Microparticle Immunoassay. AB - BACKGROUND: Rheumatoid factor (RF) can interfere both positively and negatively in immunoassays. It remains unclear whether the negative interference is an exceptional phenomenon or a denominator of immunoassays and which RF subgroup plays a key role in its causation. METHODS: Serum models comprising hepatitis B envelope antigen (HBeAg) and RF were made by blending HBeAg-positive sera and RF positive sera at a ratio of 1:9. Paramagnetic microparticles coated with P human chorionic gonadotropin (betaHCG)-anti-betaHCG complexes were used to remove RFs from the models, and HBeAg was determined in models using the chemiluminescent microparticle immunoassay (CMIA). RESULTS: HBeAg sample/cutoff (S/CO) relative light units (RLUs) measured in 27.06% of the serum models were significantly lower than those in the control models with a maximum decline rate of > 70.00%. The discrepancies between the HBeAg S/CO RLUs measured in serum and control models were not associated with the serum RF levels when these ranged from 20 to 1510 IU/mL. Pretreatment of the serum models with the paramagnetic microparticles increased the HBeAg S/CO RLUs measured and decreased the immunoglobulin (Ig) A-RF and IgG-RF levels significantly. However, the discrepancies between the HBeAg S/CO RLUs measured in serum models before and after pretreatment were only associated inversely with the discrepancies in IgG-RF levels. CONCLUSIONS: Measurement of HBeAg by CMIA is susceptible to negative interference from RFs. The level of IgG-RF played a key role in interfering with HBeAg CIMA and predominantly caused falsely low results. The pretreatment of samples with blocking reagents is therefore advisable prior to the interpretation of test results. PMID- 27468577 TI - Decreased miR-124-3p Expression Prompted Breast Cancer Cell Progression Mainly by Targeting Beclin-1. AB - BACKGROUND: Recent findings have revealed that abnormal expression of microRNAs (miRNA, miR) contributes to the malignancies of various cancers. Here, we report a novel miRNA that regulates the expression of Beclin-1 in breast cancer cells. METHODS: The expression of miR-124-3p and Beclin-1 was identified in breast cancer tissues and breast cancer cell lines. To explore whether Beclin-1 was the target gene of miR-124-3p, luciferase reporter assay was applied. MIR-124-3p was overexpressed or inhibited with the corresponding mimics or inhibitors. The expression of autophagy-related proteins including Beclin-1 and LC3II were explored by western blot and quantitative real-time PCR. RESULTS: We first demonstrated that miR-124-3p was decreased in breast cancer tissues and breast cancer cells lines. Furthermore, we validated that miR-124-3p could negatively regulate the expression of Beclin-1. Increased miR-124-3p significantly decreased the expression of Beclin-1 and LC3I. Further study showed that overexpres- sion of miR-124-3p could partially reverse 4-hydroxytamoxifen (4-OHT)-induced autophagy in breast cancer cells. CONCLUSIONS: Decreased miR-124-3p expression prompted breast cancer cell progression mainly by enhancing the expression of autophagy related protein, Beclin-1. PMID- 27468578 TI - An Analysis of IL-10/IL-10R Genetic Factors Related to Risk of Colon Cancer and Inflammatory Bowel Disease in a Han Chinese Population. AB - BACKGROUND: Patients with chronic inflammatory bowel disease (IBD) are at high risk of developing colon cancer and represent a valuable patient cohort for studying the correlation between chronic inflammation and cancer formation. Cytokines play key roles in the regulation of systemic inflammation, local tissue damage, and immunomodulation involved in tumor development and progression. Therefore, functional polymorphisms in genes that encode cytokines and cytokine receptors represent potential candidate genes associated with carcinogenesis. The present study aimed to ascertain if any of the candidate single nucleotide polymorphisms (SNPs) in inflammation-related genes IL-10/IL-10R are associated with colon cancer or IBD in Han Chinese population. METHODS: A case-control study in a Chinese Han cohort was conducted and included 375 patients with colon cancer, 278 patients with IBD, and 382 age and gender matched healthy controls. Genotyping of four candidate SNPs (IL-10 rs1800896, rs1800872, rs3024505, and IL 10R rs9610) was performed and analysis was done using the MassARRAY system based on the MALDI-TOF MS platform. RESULTS: The C allele at rs1800872 may be a protective factor incolon cancer (OR = 0.770; 95% CI: 0.653 - 0.909; p = 0.002). A decreased risk of colon cancer in patients with rs1800872 AC genotype (OR = 0.794; 95% CI, 0.664 - 950; p = 0.011), CC genotype (OR = 0.589; 95% CI, 0.372 - 0.933; p = 0.022) or AC/CC genotype (OR = 792; 95% CI, 0.678 - 0.925; p = 0.003) was observed, compared with the common AA genotype. Conversely, carriers of the variant T allele of rs3024505 flanking the IL-10 gene were at increased risk of IBD (OR = 1.999; 95% CI: 1.174 - 3.401; p = 0.009). Compared with the common CC genotype, carrying heterozygous (OR = 1.762; 95% CI, 1.030 - 3.012; p = 0.036), or heterozygous and homozygous combined (OR = 1.874; 95% CI, 1.105 - 3.177; p = 0.018) at the IL-10 rs3024505, was associated with increased risk of IBD. Stratified analysis showed that a positive association was identified between the AC/CC genotype at IL-10 rs1800872 and tumor stage (p = 0.029). CONCLUSIONS: These data suggest that the variants in the IL-10 gene may change the risk of both colon cancer and IBD. The C allele at rs1800872 may be a protective factor in colon cancer and the T allele at rs3024505 may be a risk factor in IBD in a Han Chinese population. PMID- 27468579 TI - Diagnostic Value of Serum Epstein-Barr Virus Capsid Antigen-IgA for Nasopharyngeal Carcinoma: a Meta-Analysis Based on 21 Studies. AB - BACKGROUND: Epstein-Barr virus capsid antigen immunoglobulin A (EBV VCA-IgA) exerts an important role in the diagnosis of nasopharyngeal carcinoma (NPC). This meta-analysis aimed to evaluate the pooled diagnostic performance of VCA-IgA for NPC. METHODS: Literature fulfilling the criteria was searched in PubMed and Embase databases. The quality of the studies was assessed in terms of the Quality Assessment of Diagnosis Accuracy Studies (QUADAS) criteria. The pooled diagnostic parameters were generated using a bivariate meta-analysis model. Statistical analysis was performed based on the platforms of Meta-Disc 1.4 and Stata 12.0 software. The trim and fill adjustment method was applied to further assess the possible effects of publication bias. RESULT: Twenty one studies comprising 2986 NPC patients and 3507 controls were included in this meta-analysis. The overall pooled sensitivity and specificity of serum VCA-IgA for NPC were 0.83 (95%CI: 0.82 - 0.84) and 0.88 (95% CI: 0.87 - 0.89), respectively, accompanied by a pooled diagnostic odds ratio (DOR) of 49.87 and area under curve (AUC) of 0.9390. Moreover, our stratified analyses suggested that combinations of multiple EBV antigens (sensitivity, specificity, DOR, and AUC of 0.93, 0.95, 331.8, and 0.9850, respectively) yielded higher accuracy than single VCA-IgA test (sensitivity, specificity, DOR and AUC of 0.83, 0.88, 49.87, and 0.9393, respectively). Additionally, the immunoenzyme assay (IEA) seemed to be a better alternative for the analysis of serum VCA-IgA level, with a sensitivity of 0.92, specificity of 0.94, and AUC of 0.9644. CONCLUSIONS: Serum VCA-IgA hallmarks promising accuracy in the management of NPC and that parallel tests of multiple EBV antigens may be more suitable for NPC serodiagnosis than single VCA-IgA assay. .151122) PMID- 27468580 TI - Cost-Effectiveness of POC Coagulation Testing Using Multiple Electrode Aggregometry. AB - BACKGROUND: The economic effects of Point-of-Care (POC) coagulation testing including Multiple Electrode Aggregometry (MEA) with the Multiplate device have not been examined. METHODS: A health economic model with associated clinical endpoints was developed to calculate the effectiveness and estimated costs of coagulation analyses based on standard laboratory testing (SLT) or POC testing offering the possibility to assess platelet dysfunction using aggregometric measures. Cost estimates included pre- and perioperative costs of hemotherapy, intra- and post-operative coagulation testing costs, and hospitalization costs, including the costs of transfusion-related complications. RESULTS: Our model calculation using a simulated true-to-life cohort of 10,000 cardiac surgery patients assigned to each testing alternative demonstrated that there were 950 fewer patients in the POC branch who required any transfusion of red blood cells. The subsequent numbers of massive transfusions and patients with transfusion related complications were reduced with the POC testing by 284 and 126, respectively. The average expected total cost in the POC branch was 288 Euro lower for every treated patient than that in the SLT branch. CONCLUSIONS: Incorporating aggregometric analyses using MEA into hemotherapy algorithms improved medical outcomes in cardiac surgery patients in the presented health economic model. There was an overall better economic outcome associated with POC testing compared with SLT testing despite the higher costs of testing. PMID- 27468581 TI - An Improved PCR-RFLP Assay for the Detection of a Polymorphism of PLIN1 Gene. AB - BACKGROUND: In recent research, it has been shown that there have been variants of rs894160 within the PLINI gene which have been associated with obesity, type 2 diabetes, and other diseases. But the isoschizomers such as the Mn1I enzyme required for the detection of this polymorphism are expensive. METHODS: The study used an improved PCR-RFLP method with mismatched base for detection of the single nucleotide polymorphism rs894160. RESULTS: After detecting 550 Chinese Han individuals, the genotype frequencies were 26.0% for AA, 50.0% for AG, and 24.0% for GG. The allelic frequencies were 51.0% for A and 49.0% for G. The PCR results were confirmed by DNA sequencing. The chi2 test showed the genotype and allele frequencies of PLIN1 do not deviate from Hardy-Weinberg equilibrium, and the sequences of amplified products were consistent with the one published in Genbank with the exception of mismatched base. CONCLUSIONS: Based on the PCR with mismatched primers we designed, the PLIN1 polymorphisms could be identified effectively. PMID- 27468582 TI - Molecular Diagnostic of Prostate Cancer From Body Fluids Using Methylation Specific PCR (MS-PCR) Method. AB - BACKGROUND: Worldwide prostate cancer (PCa) represents the 2nd leading cause of cancer related deaths among men. Currently, the screening for early detection of PCa is based on determination of serum prostate-specific antigen (PSA) levels. But this biomarker presents some disadvantages related to its specificity and sensitivity. In our study, we want to determine if methylation levels of the glutathione S-transferase P1 (GSTP1) gene could be used as a new biomarker for the early detection of PCa and to distinguish between malignant and benign pros tatic lesions. METHODS: To determine the methylation levels of the GSTP1 gene, 31 men with histopathological diagnosis of prostate adenocarcinoma and 34 men with the histopathological diagnosis of benign prostatic hyperplasia (BPH) as controls were included in the study group. The genomic DNA was extracted from urine samples. We analyzed the methylation levels of the GSTP1 gene by methylation specific polymerase chain reaction (MS-PCR) method. RESULTS: In prostate cancer patients 27 of 31 (87%) presented hypermethylated levels of the GSTP1 gene, whereas 4 of 34 (11.8%) BPH patients had hypermethylated levels of the GSTP1 gene. Further, in the case of these four patients a second biopsy was done, which confirmed the diagnosis of prostate adenocarcinoma. Using the receiver operating curve (ROC), we obtained a specificity of 87% and a sensitivity of 98% for the GSTP1 gene. CONCLUSIONS: We can conclude that GSTP1 represents a new molecular biomarker which can aid in early detection of PCa and be used to discriminate between benign and malignant prostatic lesions from body fluids by noninvasive methods. PMID- 27468584 TI - Polypharmacy and Isolated Gama Glutamyl Transferase Elevation in the Elderly. PMID- 27468583 TI - A Case of Bloodstream Infection of Bacteroides pyogenes Identified by 16S rRNA, gyrB, and hsp60 Gene Sequencing. PMID- 27468585 TI - Rules for some? PMID- 27468586 TI - Three-dimensional computed tomographic assessment of mandibular muscles in growing subjects with different vertical facial patterns. AB - AIM: The present study was undertaken to assess the relationship between the mandibular muscles and dentofacial skeletal morphology in children with different underlying vertical facial patterns, using three-dimensional computed tomography (3D-CT). METHOD: Thirty children (mean age 12.24 +/- 1.57 years) underwent cranial CT examination for diagnostic purposes. 3D-CT images were reconstructed for the evaluation of the cross-sectional size, volume, and spatial orientation of the masseter and medial pterygoid muscles. These muscle parameters were also assessed in relation to the vertical facial pattern, gender and skeleto-dental form. RESULTS: Significant differences were found in muscular angulation for subjects with different underlying patterns. Greater masseter volumes were associated with increased facial width. Greater intermolar widths were found in brachyfacial subjects, with less acute muscular angulations in relation to horizontal reference lines, compared with dolichofacial subjects. This was also more obvious in the maxillary arch. CONCLUSION: Clinicians should note the likely differences in masseter and medial pterygoid orientation and volume in subjects with different underlying vertical facial patterns and that these differences may, in turn, be related to both facial skeletal width and naturally-occurring transverse dental arch dimensions. PMID- 27468587 TI - Porcelain surface conditioning protocols and shear bond strength of orthodontic brackets. AB - AIM: The objective of the present study was to determine which of six bonding protocols yielded a clinically acceptable shear bond strength (SBS) of metal orthodontic brackets to CAD/CAM lithium disilicate porcelain restorations. A secondary aim was to determine which bonding protocol produced the least surface damage at debond. METHODS: Sixty lithium disilicate samples were fabricated to replicate the facial surface of a mandibular first molar using a CEREC CAD/CAM machine. The samples were split into six test groups, each of which received different mechanical/chemical pretreatment protocols to roughen the porcelain surface prior to bonding a molar orthodontic attachment. Shear bond strength testing was conducted using an Instron machine. The mean, maximum, minimal, and standard deviation SBS values for each sample group including an enamel control were calculated. A t-test was used to evaluate the statistical significance between the groups. RESULTS: No significant differences were found in SBS values, with the exception of surface roughening with a green stone prior to HFA and silane treatment. This protocol yielded slightly higher bond strength which was statistically significant. CONCLUSION: Chemical treatment alone with HFA/silane yielded SBS values within an acceptable clinical range to withstand forces applied by orthodontic treatment and potentially eliminates the need to mechanically roughen the ceramic surface. PMID- 27468588 TI - Effect of bromelain and papain gel on enamel deproteinisation before orthodontic bracket bonding. AB - AIM: To test the hypothesis that enamel surface deproteinisation with different concentrations of bromelain in association with 10% papain increases the shear bond strength (SBS) of brackets bonded with orthodontic composite and resin modified glass ionomer cement (RMGIC). MATERIALS AND METHODS: Orthodontic brackets were attached according to the following protocols to 195 bovine incisors, which were acquired and divided into 13 groups: 1) Transbond XT (TXT) according to the manufacturer's recommendations; 2) Deproteinisation with 3% bromelain (BD) plus 10% papain and TXT; 3) 6% BD plus 10% Papain and TXT; 4) RMGIC, without enamel deproteinisation and without acid etching; 5) RMGIC, with 3% BD plus 10% papain and without acid etching; 6) RMGIC, with 6% BD plus 10% papain and without acid etching; 7) attachment using RMGIC following etching with polyacrylic acid; 8) 3% BD plus 10% papain, attachment using RMGIC and etching with polyacrylic acid; 9) 6% BD plus 10% papain, and attachment using RMGIC following etching with polyacrylic acid; 10) etching with 37% phosphoric acid and attachment using RMGIC; 11) 3% BD plus 10% papain, etching with 37% phosphoric acid and attachment using RMGIC; 12) 6% BD plus 10% papain, etching with 37% phosphoric acid and attachment using RMGIC; 13) deproteinisation with 2.5% sodium hypochlorite (NaOCl), etching with polyacrylic acid and RMGIC. After bonding, the brackets were removed by a universal mechanical testing machine, which recorded shear bond strength at failure. The material remaining on the tooth was assessed using the adhesive remnant index (ARI). RESULTS: Deproteinisation with 3% and 6% bromelain gel plus papain significantly increased the shear bond strength (p < 0.05), when acid etching was performed with phosphoric acid, followed by primer application and attachment using Transbond XT (Group 3) and when attached with RMGIC without etching. Deproteinisation with 6% bromelain gel plus papain significantly increased (p < 0.05) the ARI score only when attachment was performed using RMGIC, without etching (Group 6). CONCLUSIONS: Deproteinisation with bromelain associated with papain in a gel increased the shear bond strength and is recommended before orthodontic bracket attachment. PMID- 27468589 TI - A comparison of the sagittal and vertical dentofacial effects of maxillary expansion produced by a memory screw and a hyrax screw. AB - AIM: The aim of the present study was to investigate and compare the cephalometric effects of a conventional Hyrax expansion screw and a memory screw on the skeletal and dentoalveolar structures and soft tissues of the face. METHODS: Thirty-two patients with a maxillary transverse deficiency were divided into two groups. A memory-screw group included 17 patients (nine females and eight males), while a Hyrax-screw group was comprised of 15 patients (eight females and seven males). The mean ages of the subjects in the memory-screw and Hyrax-screw groups were 13.00 +/- 1.29 and 12.58 ? 1.50 years, respectively. Lateral cephalograms were taken of the patients at the beginning of the treatment (T1), at the end of expansion (T2) and retention periods (T3). The mean expansion period was 7.76 +/- 1.04 days in the memory-screw group and 35.46 +/- 9.39 days in the Hyrax-screw group. The Shapiro-Wilk Normality test was used to determine whether the investigated parameters were homogeneous. To determine the treatment changes within the groups, a paired test and Wilcoxon Signed Rank test were applied to the homogeneous and non-homogeneous parameters, respectively. A comparison between the groups was carried out using the Student's t-test for homogeneous parameters and the Mann-Whitney U test for all others. RESULTS: A results summary indicates that mid-palatal sutural opening and subsequent important skeletal and dental expansions were obtained in all patients. The maxilla moved anteriorly and inferiorly in both groups while the mandible rotated inferiorly and posteriorly but to a greater extent in the memory-screw group. CONCLUSION: The newly-developed memory expansion screw takes advantage of rapid and slow maxillary expansion protocols. The suture is opened and the maxilla expanded with relatively lighter forces over a shorter time. The RME using the memory screw resulted in similar sagittal and vertical changes to those produced by the Hyrax screw. PMID- 27468591 TI - Cephalometric assessment of soft tissue morphology of patients with acromegaly. AB - AIM: To assess the sagittal soft tissue morphology of patients with acromegaly in comparison with a healthy control group. METHODS: Twenty-seven patients with acromegaly (11 male, 16 female; mean age 47.3 +/- 11.5 years) and 30 healthy subjects (15 male, 15 female; mean age 42.2 +/- 17.4 years) were included in the study. Linear and angular measurements were made on lateral cephalograms to evaluate soft tissue and skeletal characteristics. The intergroup comparisons were analysed with the Student's t-test. RESULTS: Facial convexity (p < 0.01) and the nasolabial angle (p < 0.001) were reduced in patients with acromegaly, whereas nose prominence (p < 0.01), upper lip sulcus depth (p < 0.01), upper lip thickness (p < 0.01), basic upper lip thickness (p < 0.01), lower lip protrusion (p < 0.05), mentolabial sulcus depth (p < 0.05) and soft tissue chin thickness (p < 0.001) were increased. Anterior cranial base length (p < 0.05), the supraorbital ridge (p < 0.01), the length of the maxilla and mandible (p < 0.001, p < 0.01, respectively) were significantly increased, and mandibular prognathism was an acromegalic feature (p < 0.05). CONCLUSION: Acromegalic coarsening and thickening of the craniofacial soft tissues was identified from lateral cephalograms, which may therefore contribute to early diagnosis when evaluated together with other changes caused by the disease. PMID- 27468590 TI - Comparison of traditional orthodontic polishing systems with novel non orthodontic methods for residual adhesive removal. AB - BACKGROUND: Following the debonding of orthodontic brackets, the removal of residual adhesive from the enamel surface is required. Published adhesive removal protocols present conflicting advice. AIMS: The present study evaluated the surface roughness of enamel after debonding and instrumentation with non traditional orthodontic polishing systems. METHODS: The facial aspects of 35 extracted human incisor teeth were scanned with a surface profilometer for surface roughness prior to the bonding of orthodontic brackets. After debonding, residual adhesive was removed with a 12-fluted titanium carbide bur. The teeth were randomly divided into seven groups (N = 5 per group) and the enamel surface was polished with one of seven products. All samples were re-scanned for surface roughness and subjectively evaluated via SEM. RESULTS: There was no significant difference in enamel surface roughness between the groups when compared using surface profilometry. Visual observations from the SEM evaluations demonstrated differences in the enamel surface at the microscopic level that were not detected by profilometric analysis. CONCLUSIONS: The present study found no statistically significant difference in mean enamel smoothness change from pretreatment to post treatment between the seven polishing methods studied via profilometer surface reading measurements. An SEM analysis showed visual differences in enamel striations viewed at 1000x magnification in a comparison of traditional versus non- traditional polishing methods. PMID- 27468592 TI - Orthodontists' and laypeople's perception of smile height aesthetics in relation to varying degrees of transverse cant of anterior teeth. AB - AIMS: To determine the effect of varying the transverse cant of the anterior teeth on orthodontists' and laypeople's perceptions of smile aesthetics, and the influence that smile height has on this perception. MATERIALS AND METHODS: A 20 year-old Chinese female with an aesthetic smile and normal occlusion was chosen and agreed to participate. Digital pictures of her posed smile were taken and manipulated to create three smile height variations: low, medium, or high. Each variation was further manipulated to create varying degrees of transverse anterior tooth cant. Fifty-six laypeople and 40 orthodontists participated as raters of the dental and facial impact of the altered smile images. RESULTS: The orthodontists more commonly and precisely identified the transverse cants of the anterior teeth and the detracting influence on smile aesthetics compared with laypersons. The orthodontists accepted a lesser range of anterior transverse cant. Increased smile heights enhanced the capability of all raters to detect a transverse cant and reduced the acceptable cant range. In addition, an increased smile height worsened the detracting effects of the transverse anterior cant in all raters' perceptions of smile aesthetics. An increased display of teeth and angulation of an anterior cant increased the ability of raters in both groups to detect differences. CONCLUSION: Transverse cants of anterior teeth can affect orthodontists' and laypeople's perceptions of smile aesthetics. Smile height and incisor display were significant factors that affected the orthodontist's and layperson's perceptions of smile aesthetics, and suggested that a description of the detracting effect of an anterior transverse cant should also consider smile height. CLINICAL RELEVANCE: A transverse occlusal cant is an important aesthetic factor used by clinicians during orthodontic diagnosis and review. It is important to appreciate that there is a difference in perception between orthodontic professionals and patients (laypeople). The extent of this perceptual difference and influencing factors could help the clinician set more appropriate treatment goals. PMID- 27468593 TI - The effect of benzocaine and ketoprofen gels on pain during fixed orthodontic appliance treatment: a randomised, double-blind, crossover trial. AB - AIMS: To compare the analgesic effect of topical benzocaine (5%) and ketoprofen (1.60 mg/mL) after 2 mm activation of 7 mm long delta loops used for maxillary en masse orthodontic space closure. SUBJECTS AND METHODS: Twenty patients (seven males, 13 females, 15-25 years of age, mean age of 19.5 years) participated in a randomised crossover, double-blind trial. After appliance activation, participants were instructed to use analgesic gels and record pain perception at 2, 6, 24 hours and 2, 3 and 7 days (at 18.00 hrs), using a visual analogue scale ruler (VAS, 0-4). Each patient received all three gels (benzocaine, ketoprofen, and a control (placebo)) randomly, but at three different appliance activation visits following a wash-over gap of one month. After the first day, the patients were instructed to repeat gel application twice a day at 10:00 and 18:00 hrs for three days. The recorded pain scores were subjected to non-parametric analysis. RESULTS: The highest pain was recorded at 2 and 6 hours. Pain scores were significantly different between the three groups (Kruskal-Wallis test, p < 0.01). The overall mean (SD) pain scores for the benzocaine 5%, ketoprofen, and control (placebo) groups were 0.89 (0.41), 0.68 (0.34), and 1.15 (0.81), respectively. The pain scores were significantly different between the ketoprofen and control groups (mean difference = 0.47, p = 0.005). All groups demonstrated significant differences in pain scores at the six different time intervals (p < 0.05) and there was no gender difference (p > 0.05). CONCLUSION: A significant pain reduction was observed following the use of ketoprofen when tested against a control gel (placebo). The highest pain scores were experienced in patients administered the placebo and the lowest scores in patients who applied ketoprofen gel. Benzocaine had an effect mid-way between ketoprofen and the placebo. The highest pain scores were recorded 2 hours following force application, which decreased to the lowest scores after 7 days. PMID- 27468594 TI - Changes in mandibular position in treated Class II division 2 malocclusions in growing and non-growing subjects. AB - OBJECTIVE: To determine changes in mandibular position after the treatment of patients presenting with Class II division 2 malocclusions and to test the null hypothesis that there is posterior displacement of the mandible in these patients, in comparison with a control group of Class II division 1 subjects. MATERIALS AND METHODS: The assessed data consisted of pre- and post-treatment cephalometric radiographs of 77 subjects identified with Class II division 1 and Class II division 2 malocclusions matched according to age, gender and treatment duration. All completed fixed appliance orthodontic treatment. The changes in the position of point B, Pogonion and Articulare were determined at the end of treatment by superimposing the cephalometric radiographs on Sella-Nasion line at Sella. Thirteen cephalometric parameters including the distance between Basion and Articular (Ba-Art) were measured at each stage. RESULTS: In both groups, SNB angle, SNPog angle and Ba-Art distance showed no statistically significant changes. Pogonion was displaced significantly in a forward and downward direction in the growing group, with no significant differences identified between Class I division 1 and Class II division 2 subjects. CONCLUSION: The null hypothesis that there is posterior displacement of the mandible in Class II division 2 malocclusion is rejected. The growth pattern of the mandible in both divisions of a Class I malocclusion after orthodontic treatment was found to be similar PMID- 27468595 TI - Invisalign treatment of lower incisor extraction cases. AB - AIM: To demonstrate the use of the Invisalign appliance in lower incisor extraction cases. METHOD: Twelve patients, consecutively treated by the removal of a single lower incisor and Invisalign appliances, were selected from the author's private practice. Pretreatment, treatment and post-treatment photographic records were obtained and are presented. RESULTS: All cases completed treatment, with a mean treatment time of 42 weeks. Fifty percent of the cases required a brief period of refinement (average six weeks) at the end of the initial projected treatment period. CONCLUSION: The Invisalign appliance, in correctly diagnosed cases, with careful 'ClinCheck' set-ups and good clinical monitoring, can routinely produce satisfactory outcomes in patients who require the removal of a lower incisor. PMID- 27468596 TI - The efficacy of Hybrid Hyrax-Mentoplate combination in early Class III treatment: a novel approach and pilot study. AB - INTRODUCTION: The aim of the present study was to assess the skeletal, dental and soft tissue effects of a specific treatment protocol in consecutively treated patients who presented with a Class III malocclusion. Treatment involved the use of a Hybrid Hyrax (HH) in the maxilla, a Mentoplate in the mandible and the application of continuous intra-oral Class III elastics. METHOD: The treated group was comprised of seven males and seven females (mean pretreatment age 10.4 +/- 1.7 yr, range 7.8-12.9 yr). Treatment changes were analysed on lateral cephalograms taken 6-12 months prior to commencing treatment (T1) and at the finish of the orthopaedic phase (T2). Where a normality assumption was met, a parametric paired-sample t-test was used to assess the change differences at T1 and T2. For non-normal data, a non-parametric Wilcoxon sign rank test for related samples was used to assess T1 and T2 differences. The level of statistical significance was set at p < 0.05 (2-tailed). RESULTS: The average sagittal changes showed an improved SNA angle of 2.1 +/- 2 degrees (p = 0.002), an ANB angle of 1.9 +/- 1.8 degrees (p = 0.002), a Wits improvement of 3.4 +/- 2.7 mm (p < 0.001) and an overjet reduction of 2.0 +/- 2.2 mm (p = 0.005). There were no statistically significant correlations found between the age at T1, age at treatment start and age at T2 and the changes identified in the cephalometric variables (T2-T1). CONCLUSION: The HH-Mentoplate Class III treatment protocol induced a mean Wits improvement of 3.4 mm in the maxillary and mandibular sagittal base relationship at the functional occlusal level. This was primarily achieved by sagittal maxillary skeletal protraction with negligible effects on the mandible, facial vertical dimension and the incisor angulations. A controlled clinical study with larger sample sizes and longer follow-up times is needed. PMID- 27468597 TI - Long-term surgical-orthodontic management of hemimandibular hyperplasia. AB - BACKGROUND: Hemimandibular hyperplasia (HH), also known as hemimandibular hypertrophy, is characterised by excessive unilateral three-dimensional growth of the mandible after birth. Vertical unilateral elongation of the mandible becomes clinically evident as a rare form of vertical facial asymmetry. Aberrant growth of the facial skeleton affects the developing dentition and the dental compensatory mechanism is usually unable to maintain optimal occlusal relationships. The resulting malocclusion is effectively managed by combined surgical-orthodontic care to address the facial, skeletal and dental problems that confront clinicians. Orthodontists are advised to assess patients with HH during the post-treatment retention stage for continuing mandibular growth and assess the stability of treatment outcomes with long-term follow-up and records as required. AIM: To present a case of hemimandibular hyperplasia treated successfully by combined surgical-orthodontic care and evaluated for stability over a seven-year follow-up period. METHODS: Surgical-orthodontic management was accomplished in four stages: 1) pre-surgical orthodontic; 21 surgical; 3) post surgical orthodontic; and 4) post-treatment orthodontic retention. Complete orthodontic records, including extra- and intra-oral photographs, study models, and cephalograms plus panoramic radiographs were taken at the pretreatment, post treatment, and seven-year orthodontic retention time-points. RESULTS: Facial, skeletal and dental goals were achieved in the three planes of space and the long term stability of the treatment results was shown during a post-treatment orthodontic retention period of seven years. CONCLUSION: Hemimandibular hyperplasia is a true growth anomaly which may be managed effectively. Clinicians may expect successful long-term correction and stability by utilising a comprehensive surgical-orthodontic treatment approach. PMID- 27468598 TI - Fresh stirrings among statisticians: statistical commentary. AB - For some years there has been unrest in the statistical world regarding the use of the p-value. It has been indicated that the significance of p-values is open to question, which therefore reduces the ability to measure the strength of evidence. This paper examines the use and misuse of the p-value and recommends consideration in its application. PMID- 27468599 TI - The Stanley Wilkinson Oration. PMID- 27468600 TI - Critical ethnography: An under-used research methodology in neuroscience nursing. AB - Critical ethnography is a qualitative research method that endeavours to explore and understand dominant discourses that are seen as being the 'right' way to think, see, talk about or enact a particular 'action' or situation in society and recommend ways to re-dress social power inequities. In health care, vulnerable populations, including many individuals who have experienced neurological illnesses or injuries that leave them susceptible to the influence of others, would be suitable groups for study using critical ethnography methodology. Critical ethnography has also been used to study workplace culture. While ethnography has been effectively used to underpin other phenomena of interest to neuroscience nurses, only one example of the use of critical ethnography exists in the published literature related to neuroscience nursing. In our "Research Corner" in this issue of the Canadian Journal of Neuroscience Nursing (CJNN) our guest editors, Dr. Cheryl Ross and Dr. Cath Rogers will briefly highlight the origins of qualitative research, ethnography, and critical ethnography and describe how they are used and, as the third author, I will discuss the relevance of critical ethnography findings for neuroscience nurses. PMID- 27468601 TI - Understanding the challenges to improve transition to palliative care: An issue for the primary malignant brain tumour population. AB - Reports highlight the growing unmet need for palliative care as it applies to all cancers, yet the system and health care professionals (HCP) appear slow to respond. The following discussion paper highlights the current state of palliative care within the context of the primary malignant brain tumour (PMBT) population and argues for a shift in the current health care system's approach, which continues to place greater emphasis on cure over care. METHODS: An exploration of extant literature over the past 10 years. RESULTS: The current literature demonstrates that timely referrals to palliative care consult teams and access to community-based resources have been associated with fewer hospitalizations and visits to emergency departments and a decrease in the initiation of invasive, aggressive treatment at end of life. Timely referral to palliative care has also been shown to reduce distress, enhance quality of life and, in some cases, increase life expectancy. CONCLUSION: Earlier referral to palliative care has yet to become a reality for many patients diagnosed with life limiting illnesses and, in particular, those with a PMBT. More research is needed to uncover and challenge the barriers to early transition including communication issues among professionals, patients and families around palliative care. PMID- 27468602 TI - Hope, Coping, and Quality of Life in Adults with Myasthenia Gravis. AB - Myasthenia gravis significantly impacts quality of life. However, the relationship between hope, coping, and quality of life (QOL)in myasthenia patients has not been studied (Kulkantrakorn & Jarungkiatkul, 2009; Raggi et al., 2010). OBJECTIVE: The aim of this study was to explore the relationship between hope, coping, and quality of life in adults with myasthenia gravis. DATA COLLECTION: Subjects with MG (n = 100) completed six questionnaires, including a demographic profile, the Myasthenia Gravis Activities of Daily Living Scale (MG ADL), Herth Hope Index (HHI), Jalowiec Coping Scale (JCS), Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), and Short Form Health Survey (SF-36v2). RESULTS: Mean hope scores indicated a high level of hope. An optimistic coping style was the most common and effective coping strategy identified by subjects. Positive thinking and humour were also frequently used strategies. Participants identified quality of life as good tolerability, above general population mental well-being, and below general populationphysical well-being. Participants who identified good quality of life had low scores on the MG-QOL15 scale and high scores on the SF36v2. Hope and independence for activities of daily living were found to correlate with improved quality of life and mental well-being(p < 0.001). Age and length of illness were not significant factors. There was no mediation by well-being or quality of life in the relationship between hope and coping. Hope and coping were not important factors for well-being or quality of life. CONCLUSION: Nurses caring for adults with myasthenia gravis should use interventions that continue to support hope, quality of life, and coping throughout the unpredictable and chronic course of MG. PMID- 27468603 TI - [Making a safe transition home after a meningioma resection: The impact of nursing care]. AB - INTRODUCTION: This study originated from patients' demands that they be better informed and that their meningioma diagnosis be considered serious. Meningioma are brain tumours that represent about 30% of all primary brain tumours. In 90% of the cases, they are non-cancerous. The objective was to identify whether educational intervention by nurses would have a positive impact on transition. METHOD: The study lasted 12 months and included two groups: intervention and control. Intervention involved the verbal and written delivery of answers to frequently asked questions, as well as patient follow-up for six weeks post surgery. Nurses were available during the preparation for discharge, as well as the follow-up call 48-72 hours later. RESULTS: Educational nursing care had no demonstrable effect. DISCUSSION: Differences between the groups might have influenced the effect of educational intervention. Our results suggest certain lines of thought as to the doses of information that should be given based on stages of care and individual particularities. PMID- 27468604 TI - [NEW OPPORTUNITIES IN NEURO-REHABILITATION: ROBOT MEDIATED THERAPY IN CONDITONS POST CENTRAL NERVOUS SYSTEM IMPAIRMENTS]. AB - Decreasing the often-seen multiple disabilities as a consequence of central nervous system impairments requires broadening of the tools of rehabilitation. A promising opportunity for this purpose is the application of physiotherapy robots. The development of such devices goes back a quarter of century. Nowadays several robots are commercially available both for supporting upper and lower limb therapy. The aim is never to replace the therapists, but rather to support and supplement their work. It is worthwhile applying these devices for goal oriented exercises in high repetition, which one physically fatiguing for the therapist or for the correction of functional movement by various strategies. Robot mediated therapy is also useful for motivation of the patient and making the rehabilitation programme more versatile. Robots can be used for assessment of the neuromotor status as well. Several clinical studies have been executed in this field, all over the world. Meta-analyses based on randomized, controlled trials show that supplementing the traditional physiotherapy with a robot mediated component presents advantage for the patients. Further studies are necessary to clarify which modality and intensity of the exercises, in which group of patients, in which stage lead to the expected outcome. PMID- 27468605 TI - [GENETICALLY DETERMINED DISEASES ASSOCIATED WITH PATHOLOGICAL BRAIN IRON ACCUMULATION AND NEURODEGENERATION]. AB - The rare, genetically determined group of diseases characterized by pathological accumulation of iron in the central nervous system and progressive, typically movement disorder's symptoms are called NBIA (neurodegeneration with brain iron accumulation). By the rapid development of molecular genetics, it has become apparent that different mutations in numerous genes can lead to pathological cerebral iron accumulation. Simultaneously, it has also been recognized that the age of onset, the symptoms and the prognosis of NBIA disorders are much more diverse than it was previously perceived. To our knowledge, a review article on the most recent clinical data of NBIA has not been published in Hungarian. In the first part of this publication, we survey the general clinical characteristics and the diagnostic algorithm of NBIA diseases and address some considerations for differential diagnostics. In the second part of this review, the particular NBIA disorders are presented in details. The purpose of this article is to provide a clinical overview that may be useful for neurologists, pediatricians and any other medical practitioners interested in this field. PMID- 27468606 TI - [ELECTROPHYSIOLOGIC ANALYSIS OF MENTAL ARITHMETIC TASK BY THE "MINIMUM SPANNING TREE" METHOD]. AB - GOALS: In the present study basic arithmetic induced rearrangements in functional connections of the brain were investigated by using graph theoretical analysis what becomes increasingly important both in theoretical neuroscience and also in clinical investigations. RESEARCH QUESTIONS: During mental arithmetic operations (working) memory plays an important role, but there are only a few studies in which an attempt was made to separate this effect from the process of arithmetic operations themselves. The goal of our study was to separate the neural networks involved in cognitive functions. METHODS: As an attempt to clarify this issue the graph-theoretical "minimal spanning tree" method was used for the analysis of EEG recorded during task performance. The effects of passive viewing, number recognition and mental arithmetic on PLI based minimal spanning trees (MST) were investigated on the EEG in young adults (adding task: 17 subjects; passive viewing and number recognition: 16 subjects) in the theta (4-8 Hz) frequency band. RESULTS: Occipital task relevant synchronization was found by using the different methods, probably related to the effect of visual stimulation. With respect to diameter, eccentricity and fraction of leafs different task-related changes were found. DISCUSSION: It was shown that the task related changes of various graph indices are capable to identify networks behind the various relevant dominant functions. Thus the "minimal spanning tree" method is suitable for the analysis of the reorganization of the brain with respect to cognitive functions. PMID- 27468607 TI - THE RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND VERBAL MEMORY MAY BE INFLUENCED BY BODY MASS INDEX (BMI) IN YOUNG HEALTHY WOMEN. AB - The objective of this study was to examine the relationship between verbal memory and total cholesterol (TC) levels related to body mass index (BMI) in healthy young women. Verbal memory was assessed using the Rey Auditory-Verbal Learning Test (RAVLT) while total serum cholesterol was measured by enzymatic colorimetric test. In order to analyze the potential significance of BMI subjects were divided into three groups according to their calculated BMI percentile values. No significant correlation was found when assessing the group as a whole. However a remarkable pattern of correlation emerged when assessing the BMI groups separately: a close-to-significant positive correlation was found for total learning score and TC in the low BMI group, no correlation emerged in the medium BMI group while a strong inverse correlation was found in the high BMI group. These findings indicate that the relationship between verbal memory and serum TC level is also influenced by BMI. PMID- 27468608 TI - [DISEASE BURDEN OP DUCHENNE MUSCULAR DYSTROPHY PATIENTS AND THEIR CAREGIVERS]. AB - BACKGROUND AND PURPOSE: Data on the disease burden of Duchenne Muscular Dystrophy are scarce in Hungary. The aim of this study was to assess patients' and their caregivers' health related quality of life and healthcare utilisations. METHODS: A cross sectional survey was performed as part of the European BURQOL-RD project. The EQ-5D-5L and Barthel Index questionnaires were applied, health care utilisations and patients' informal carers were surveyed. RESULTS: One symptomatic female carer, 50 children (boys 94%) and six adult patients (five males) participated in the study, the latter two subgroups were included in the analysis. The average age was 9.7 (SD = 4.6) and 24.3 (SD = 9.8) years, respectively. Median age at time of diagnosis was three years. The average EQ-5D score among children and adults was 0.198 (SD = 0.417) and 0.244 (SD = 0.322), respectively, the Barthel Index was 57.6 (SD = 29.9) and 53.0 (SD = 36.5). Score of satisfaction with healthcare (10-point Likert-scale) was mean 5.3 (SD = 2.1) and 5.3 (SD = 2.9). 15 children were hospitalised in the past 12 months for mean 12.9 (SD = 24.5) days. Two patients received help from professional carer. 25 children (mean age 11.1, SD = 4.4 years) were helped/supervisied by principal informal carer (parent) for mean 90.1 (SD = 44.4) hours/week and further family members helped in 21 cases. Correlation between EQ-5D and Barthel Index was strong and significant (0.731; p < 0.01) as well as with informal care time ( 0.770; p < 0.01), but correlation with satisfaction with health care was not significant (EQ-5D: 0.241; Barthel Index: 0.219; informal care: -0.142). CONCLUSION: Duchenne muscular dystrophy leads to a significant deterioration in the quality of life of patients. Parents play outstanding role in the care of affected children. This study is the first in the Central and Eastern European region that provides quality of life data in this rare disease for further health economic studies. PMID- 27468609 TI - COMPARISON TACHOCOMB WITH SURGIWRAP, SURGICEL AND LYODURA IN EPIDURAL FIBROSIS: AN EXPERIMENTAL RAT MODEL. AB - OBJECTIVES: We designed this study to evaluate the effect of TachoComb and to compare it with SurgiWrap, Surgicel, and Lyodura in an experimental rat model for epidural fibrosis (EF). METHODS: This prospective and experimental rat model study was performed at Dicle University, School of Medicine, Department of Neurosurgery, in Diyarbakir, Turkey, between January 2005 and June 2005, using 50 Sprague Dawley rats (30 female and 20 male) with a mean weight of 290 g. The rats were divided into five groups: TachoComb, Surgicel, SurgiWrap, Lyodura, and control. RESULTS: Eight weeks after laminectomy, the rats were killed and EF was evaluated. EF was statistically different between the groups. The lowest EF score was in the TachoComb group (F = 6.915, p < 0.001). CONCLUSIONS: According to this study, TachoComb was found to be a more effective agent in decreasing EF than Surgicel, SurgiWrap, or Lyodura. PMID- 27468610 TI - [EFFECT OF INSTRUMENTAL SURGICAL FUSION ON THE QUALITY OF LIFE IN DEGENERATIVE SPONDYLOLISTHESIS]. AB - OBJECTIVE: There is no internationally accepted guideline for treatment of spondylolisthesis in the literature, otherwise this degenerative disease has great social and economical impact. There is no hungarian study examining the efficacy of instrumented fusion procedure in surgical treatment of spondylolisthesis. In current study we examined the effectiveness of fusion technique focusing on the impact of quality of life. METHODS: Between 1st January, 2011 and 30th June, 2012 we examined a group of patients--who were operated on by instrumented fusion technique because of spondylolisthesis--, in the National Institute of Clinical Neurosciences, using the Oswestry Low Back Disability Questionnaire. All patients were treated after ineffective conservative treatment. The question was wheather how has changed the patients' quality of life after the operation. Paired-sample t-test was used in this study. RESULTS: Eighty-eight of the 97 examined patients reported different levels of impovement in the postoperative period, two patient's condition has not changed in spite of the surgery, seven patient's condition showed progression in average one year after the surgery. The pain improved most significantly (55.5%) (p < 0.0001). Using the 16 point borderline according to the Questionnaire (over moderate disability), significant improvement was detected in 50 patients (51.5%). Succesful surgical result--according to the quality of life--was seen in 77.41% of male and in 50.98% of female patients. According to the different age groups, 72.72% of the younger (before retirement), and 53.06% of the retired patients belonged to this group. At least 15 point improvement was detected 35.05% of the patients, the overall improvement was 10.5 point. DISCUSSION: Our results proved effectiveness of instrumented surgical fusion procedure in the treatment of degenerative spondylolisthesis. According to our results the younger male population with significant symptoms is the group, where improvement in quality of life is more pronaunced after the surgical procedure. CONCLUSION: The instrumented fusion surgical technique provides successful clinical and surgical outcome in patients with degenerative spondylolisthesis. It could improve the quality of life. Althought multicentre follow-up studies are needed to determine the exact indication and optimal therapy. PMID- 27468611 TI - [CLOSURE OF NASOCRANIAL FISTULAS WITH "BATH-PLUG" TECHNIQUE AND MULTILAYER RECONSTRUCTION]. AB - BACKGROUND AND PURPOSE: In case of dehiscenses developing on the anterior scull base, complete closure resulting in the cessation of the communication between the nasal cavity and the intracranial space is mandatory as soon as possible, in order to prevent serious complications. With the development of the endoscopic techniques, the endonasal management for the reconstruction has become available in recent decades. METHODS: We aim to present the reconstruction techniques applied in our department in the cases of two patients recently operated at our institute. The choice of methods primarily depends on the size and the localization of the defect. Dehiscenses under 5 mm of diameter can be closed with the so called "bath-plug" technique, while bigger defects, where the required closure of the plug is not possible, can be solved with multilayer reconstruction. We use autogenous fascia, fat and muco-periosteum in both cases. RESULTS: Our patient, who underwent the aforementioned "bath-plug" procedure, could be discharged after a few days of uneventful postoperative period. During a ten-month follow-up period new fistula formation was not observed. In the case of a patient who underwent multilayer reconstruction, meningitis occurred postoperatively, which was resolved after antibiotic therapy. During a 17-month follow-up period recurrent liquorrhoea did not occur. CONCLUSION: With suitable technical background and appropriate endoscopic skills the surgeries of the anterior skull base cerebrospinal fluid fistulas can be performed efficiently and with low complication rate. These are minimally invasive procedures accompanied by less surgical trauma, morbidity and shorter hospitalization, hence these techniques are considered to be cost-effective and well-tolerated for the patients. PMID- 27468613 TI - [Attention to the role of mobile health in preventing stroke in patients with atrial fibrillation]. PMID- 27468612 TI - Mechanistic Studies on the Self-Assembly of PLGA Patchy Particles and Their Potential Applications in Biomedical Imaging. AB - Currently, several challenges prevent poly(lactic-co-glycolic acid) (PLGA) particles from reaching clinical settings. Among these is a lack of understanding of the molecular mechanisms involved in the formation of these particles. We have been studying in depth the formation of patchy polymeric particles. These particles are made of PLGA and lipid-polymer functional groups. They have unique patch-core-shell structural features: hollow or solid hydrophobic cores and a patchy surface. Previously, we identified the shear stress as the most important parameter in a patchy particle's formation. Here, we investigated in detail the role of shear stress in the patchy particle's internal and external structure using an integrative experimental and computational approach. By cross-sectioning the multipatch particles, we found lipid-based structures embedded in the entire PLGA matrix, which represents a unique finding in the PLGA field. By developing novel computational fluid dynamics and molecular dynamics simulations, we found that the shear stress determines the internal structure of the patchy particles. Equally important, we discovered that these particles emit a photoacoustic (PA) signal in the optical clinical imaging window. Our results show that particles with multiple patches emit a higher PA signal than single-patch particles. This phenomenon most likely is due to the fact that multipatchy particles absorb more heat than single-patchy particles as shown by differential scanning calorimetry analysis. Furthermore, we demonstrated the use of patchy polymeric particles as photoacoustic molecular probes both in vitro and in vivo studies. The fundamental studies described here will help us to design more effective PLGA carriers for a number of medical applications as well as to accelerate their medical translation. PMID- 27468614 TI - [Analysis of clinical characteristics and risk of stroke and death within 1 year of patients with nonvalvular atrial fibrillation combined with diabetes mellitus]. AB - OBJECTIVE: To explore the clinical characteristics and impact of diabetes mellitus (DM) on prognosis in patients with nonvalvular atrial fibrillation (AF). METHODS: Data of nonvalvular AF patients in the Chinese Emergency Atrial Fibrillation Registry Study were retrospectively analyzed. The eligible patients were divided into the DM group and the non-DM group. Uni- and multi-variate Cox regression analysis were used to explore risk factors of 1-year outcomes. RESULTS: A total of 1 644 patients were enrolled in the study with 227 patients combined with DM (16.8%). Compared with non-DM group, patients with DM were older and had higher body weight, had higher prevalence of myocardial infarction, coronary heart disease, hypertension and stroke, and were at higher risk of thromboembolism. The proportion of anticoagulant treatment was low in both groups (10.1% vs 7.4%, P=0.141). Compared with patients without DM, patients with DM had higher all-cause mortality (19.5% vs 12.7%, P=0.004), cardiovascular death (10.8% vs 7.02%, P=0.047) and combined end events (CEE, 26.4% vs 2.4%, P=0.023), while with comparable incidence of stroke (10.1% vs 7.4%, P=0.141). Multi-variate Cox regression analysis showed that DM was an independent risk factor for 1-year all cause mortality (HR=1.558, 95% CI 1.126-2.156), cardiovascular death (HR=1.615, 95% CI 1.052-2.479) and CEE (HR=1.523, 95% CI 1.098-2.112), while not for stroke (HR=1.523, 95% CI 1.098-2.112). CONCLUSION: DM is the independent risk factor for all-cause mortality, cardiovascular death and combined end events in patients with nonvalvular AF, while not a predictor for the occurrence of stroke. PMID- 27468615 TI - [Situation of long-term use of oral anticoagulation among atrial fibrillation patients with stroke in different level hospital]. AB - OBJECTIVE: To investigate the current situation, time trends and factors associated with long-term use of oral anticoagulation (OAC) among atrial fibrillation (AF) patients with ischemic stroke. METHODS: We used the dataset from the CAFR (Chinese Atrial Fibrillation Registry), a prospective, multicenter, hospital-based registry study involving 20 tertiary and 12 nontertiary hospitals in Beijing. In brief, 380 consecutive AF patients with following ischemic stroke were enrolled from 2003 to 2014.Patients with valvular AF, radiofrequency catheter ablation history or contraindications of OAC were excluded. We divided the patients into two groups according to hospital level, and investigated the rate of OAC use and its change over time in patients who had indication, the factors including patient characteristics and hospital level associated with OAC use were also analyzed. RESULTS: Overall oral anticoagulation use rate was 27.71%, which dropped to 22.11% and 15.26% at 6 months and 12 months, respectively.A total of 298 participates were enrolled from tertiary hospitals (78.42%), and 82 were enrolled from nontertiary hospitals. The status of OAC use in tertiary hospitals was better than nontertiary hospitals (32.66% vs 7.32%, P<0.001). Multivariable analysis showed better oral anticoagulation use was independently associated with higher-level hospitals (odds ratio 1.785, 95% confidence interval 1.026-3.106, P=0.040), and history of heart failure (odds ratio 2.247, 95% confidence interval 1.235-4.090, P=0.008). CONCLUSIONS: These data indicates oral anticoagulation use has improved in atrial fibrillation patients with stroke in Beijing. The use of anticoagulation among the patients from tertiary hospitals is significantly better than those from nontertiary hospitals, and the history of heart failure may have effect on the use of oral anticoagulation. PMID- 27468616 TI - [Effect of intravenous thrombolysis with recombinant tissue type plasminogen activator (rt-PA) in different time windows on acute cerebral infarction patients with atrial fibrillation]. AB - OBJECTIVES: To observe the intravenous thrombolysis effect of rt-PA in different time windows of acute cerebral infarction with atrial fibrillation(AF). METHODS: Acute cerebral infarction patients who accepted the intravenous thrombolysis treatment with AF from January 2012 to December 2015 were included.According to the time from onset to intravenous thrombolysis, patients were divided into two groups: thrombolysis within 3 h and thrombolysis between 3-4.5 h. The Nation Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to evaluate early and long-time therapeutic effects. The incidence of hemorrhagic infarction(HI), parenchymal hemorrhage(PH) and symptomatic intracranial hemorrhage(sICH) after thrombolysis within 24 hours were observed in the two groups. RESULTS: A total of 103 patients were included in the study, with 48 cases in thrombolysis within 3 h group and 55 cases in thrombolysis between 3 4.5 h group. After thrombolysis treatment, the 24-hour and 7-day NIHSS score of the two groups were significant lower than before treatment, and the difference was statistically significant(P<0.05). Compared between groups, 24-hour clinical efficacy of thrombolysis within 3 h group was better than that of thrombolysis between 3-4.5 h group, and the difference was statistically significant(P<0.05). There were no statistically significant differences between these two groups about 7-day and 90-day prognosis(P<0.05). The rate of PH in thrombolysis within 3 h group and thrombolysis between 3-4.5 h group is 6.3%(3/48) and 21.8%(12/55) individually, and the difference was statistically significant(P<0.05). While no statistically significant differences was found about the rate of HI(18.8% vs 32.7%, P>0.05) and sICH(8.3% vs 14.5%, P>0.05) between these two groups. CONCLUSIONS: For patients of acute cerebral infarction with AF, intravenous thrombolytic therapy by rt-PA within 3 h may contribute to a greatly improvement in a short time. Thrombolysis between 3-4.5 h increase the incidence of PH, but do not increase the incidence of sICH. There are no statistically significant differences between these two groups about 90-day favorable prognosis, indicating that thrombolysis between 3-4.5 h is safe and effective for acute cerebral infarction patients with AF. PMID- 27468617 TI - [Effect of asymmetrical dimethylarginine for predicting pro-thrombotic risk in atrial fibrillation]. AB - OBJECTIVE: Atrial fibrillation (AF) is responsible for some thromboembolic events. Asymmetrical dimethylarginine(ADMA) increases in atrial fibrillation(AF) animals with dysfunction of endothelium, but its role in pro-thrombotic state of AF was unknown. The aim of our study was to explore the role of ADMA in predicting the pro-thrombotic state in AF and to reveal its mechanism. METHODS: One hundred and thirty-eight patients in the First Affiliated Hospital, Sun Yat sen University, from 2010 to 2012, were enrolled (persistent atrial fibrillation group, PAF, n=80; paroxysmal atrial fibrillation group, Paf, n=30; sinus rhythm, SR, n=28). Plasma ADMA levels were detected by ELISA-kits. CHADS2 and CHA2DS2 VASc scores were estimated for each patient.14 Beagles (pacing group, n=8; sham group, n=6) were subjected to rapid atrial pacing (RAP). ADMA level was detected after 4 weeks of RAP. RESULTS: ADMA level was elevated significantly in patients with atrial fibrillation especially in patients with persistent atrial fibrillation, and showed a significant linear correlation to CHADS2 and CHA2DS2 VASc score. With ADMA, ROC area under the curve was 0.865 in CHADS2 score >=2 and was 0.959 in CHA2DS2-VASc score >=2 (P<0.001 respectively). After 4 weeks of RAP, ADMA level was elevated compared to sham group and before operation. ADMA showed a linear correlation with atrial fibrillation susceptibility(r=0.686, P=0.007). CONCLUSIONS: ADMA levels are elevated both in AF patients and RAP beagles. ADMA correlates with stroke risk concerning with CHADS2/CHA2DS2-VASc score. ADMA may become a new biomarker for predicting pro-thrombotic risk in AF. PMID- 27468618 TI - [Relationship between autophagy of melanocytes in patients with vitiligo and clinical types]. AB - OBJECTIVE: To evaluate autophagy of melanocytes and its mechanism in patients with vitiligo and to analyze its correlation with clinical types of vitiligo. METHODS: Nine cases of segmental vitiligo (SV) and 11 cases of generalized vitiligo (GV) were recruited in Hangzhou Third Hospital between May 2014 and June 2015. Six people with healthy skin were recruited as controls. Epidermal melanocytes were obtained from the normal colour skin around the white spot area in SV and GV patients and from foreskin in controls for culture in vitro. Cultures for each group contained negative control and rapamycin (30 nmol/L) sub groups. The autophagy was observed using transmission electron microscopy (TEM) and immunofluorescence laser scanning confocal microscope (LSCFM). Protein expressions of microtube-associated protein light chain 3 (LC3II) and microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase related protein (TYRP)1, and TYRP2 were detected by Western blot. RESULTS: (1)Autophagy of melanocytes was observed under TEM and LSCFM in both SV and control groups before rapamycin treatment, but not in GV patients. The expressions of autophagosome and LC3II protein were increased in melanocytes in SV, GV and control groups after autophagy induction(SV group 0.58+/-0.10 vs 0.37+/-0.06; GV group 0.57+/-0.16 vs 0.22+/-0.08; control group 0.67+/-0.09 vs 0.46+/-0.12), and the autophagy intensity was higher in the GV group compared to the SV group and the control group. (2)Before autophagy induction, the expressions of MITF, TYR, TYRP1, and TYRP2 protein were lower in the GV and SV patients compared with the control group; after autophagy induction, the expressions of MITF, TYR, and TYRP1 statistically significantly increased in melanocytes in all the three groups(all P<0.05), while TYRP2 protein expression was not significantly changed (all P>0.05). CONCLUSIONS: Autophagy of melanocytes may be present in vitiligo and affect the expression of functional molecules, and is related with clinical type of vitiligo. PMID- 27468619 TI - [MicroRNA-205 targeted Kruppel-like factor 12 and regulated MDA-MB-468 cells apoptosis in basal-like breast carcinoma]. AB - OBJECTIVE: To identify basal-like breast carcinoma (BLBC)-specific microRNA (miRs) and its target gene and to investigate the distinct biological function. METHOD: Kruppel-like factor 12 (KLF12) 3'-UTR was constructed and luciferase reporter assay was performed for target gene. Expression levels of miR including its target genes were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry (IHC). Further functional analyses were conducted which included apoptosis. RESULTS: Luciferase assay showed miR-205 directly targets KLF12 through binding its 3'-UTR (P=0.001 6). QRT-PCR revealed that miR-205 expression levels were exclusively lower in MDA MB-468 cell lines (P=0.00 7) and BLBC tumor tissues (P=0.007 4; n=3), but KLF12 were highly expressed in MDA-MB-468 cell lines (P=0.003 9); knock-up of miR-205 expression by transfection with its mimics in MDA-MB-468 cells substantially increased miR-205 expression level (P=0.000) and reduced KLF12 expression level (P=0.038). Western blot displayed that KLF12 expression levels were higher in tumor tissues when compared with normal breast tissues (P=0.008 3; n=9). Knock-up of miR-205 expression by transfection with its mimics promoted MDA-MB-468 cells apoptosis (P=0.006 1). CONCLUSIONS: Our results suggest that miR-205 is a miR specific for BLBC which exerts tumor suppression role through negative regulated proto-oncogene KLF12 and promote cell apoptosis. MiR-205 and KLF12 may provide potential diagnosis molecular biomarker and possible new approach for the treatment for BLBC. PMID- 27468620 TI - [Empirical therapy of bloodstream infections caused by extended-spectrum beta lactamase-producing Enterobacteriaceae]. AB - OBJECTIVE: To compare the clinical outcomes and costs associated with carbapenems and beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) for the empirical treatment of patients with extended-spectrum beta-lactamase (ESBL)-positive Enterobacteriaceae bloodstream infections (BSIs). METHODS: The medical records of individuals diagnosed with ESBL-producing Escherichia coli and Klebsiella pneumoniae BSIs between January 2014 and June 2015 at Changhai Hospital were reviewed. Patients were divided into two groups based on the empirical therapy (carbapenems group and BLBLIs group). Propensity score matching in a 1?1 ratio was used to match the patients from two groups. Clinical outcomes and costs were compared before and after matching. RESULTS: One hundred and fifty-eight patients were analyzed, 93 in the carbapenems group and 65 in the BLBLIs group. Before matching, the two groups were significantly different in department distribution, tumor rate, deep vein catheter rate, urinary catheter rate, nasogastric tube rate, and mechanical ventilation rate (all P<0.05), and the carbapenems group had longer total length of stay (LOS) and post-BSI LOS (26.0 vs 18.0 d, P=0.029 and 12.0 vs 10.0 d, P=0.044) , higher hospital cost and daily hospital cost (84 120 vs 39 000 ?, P<0.001 and 3 451 vs 2 574 ?, P=0.002). After matching, the two groups had no significant differences in covariates such as sex, age, department distribution, pathogens, comorbidities, invasive interventions, LOS before BSI, multiple admissions, surgical rate during hospitalization and delayed antimicrobial therapy (all P>0.05). Finally, there were no differences between two groups in mortality, post-BSI LOS, total LOS, hospital cost and antimicrobial cost (all P>0.05). CONCLUSION: BLBLIs may provide a reasonable carbapenem-sparing option for the empirical treatment of ESBL producers. PMID- 27468621 TI - [Expression of major histocompatibility complex class I chain-related protein A and B in operable lung adenocarcinoma and its clinical significance]. AB - OBJECTIVE: To explore the expression of major histocompatibility complex classIchain-related protein A and B (MICA/B) in operable lung adenocarcinoma and its clinical significance. METHODS: Between January 2002 and December 2003, 100 patients with operable lung adenocarcinoma in People's Hospital of Zhengzhou were collected. The expression of MICA/B was examined by immunohistochemistry staining.According to immunohistochemical staining, the cases with score >=5 points were high expression of MICA/B while <5 points were low expression of MICA/B.Chi-square test was utilized to analyze the relationship between MICA/B expression and clinicopathologic features. The association between MICA/B protein and overall survival in the patients with operable lung adenocarcinoma was analyzed by Kaplan-Meier survival curve, together with Log-Rank test. The COX regression model was established to analyze the single and combined effects of these covariants. RESULTS: The percentage with high expression of MICA/B protein in operable lung adenocarcinoma tissue was 38% (38/100). The over-expression rate of MICA/B protein in the group with mutant epidermal growth factor receptor (EGFR) gene was significantly higher than that in the group with wild EGFR gene (93.8% vs 11.8%, P<0.001). No statistical significance was observed between the expression of MICA/B protein and other clinicopathologic parameters, including age, sex, TNM stage, T- staging, histological grade and lymph node metastasis. Kaplan-Meier analysis showed that overexpression of MICA/B protein was closely associated with shorter survival time (10.4 vs 28.9 months, P=0.005). CONCLUSION: Overexpression of MICA/B in operable lung adenocarcinoma tissue is closely related to the mutations of EGFR and overall survival, which may be a poor prognosis indicator in patients with operable lung adenocarcinoma. PMID- 27468622 TI - [Interleukin-17 expression and clinical significance in the lung tissue of patients with stable chronic obstructive pulmonary disease]. AB - OBJECTIVE: To observe the interleukin-17 (IL-17) expression in lung tussiue of patients with stable chronic obstructive pulmonary disease (COPD) and investigate the clinical significance. METHODS: A total of 50 patients receiving lung resections in General Hospital, Tianjin Medical University for lung cancer from October 2010 to October 2011 were included and divided into non-smoking COPD group (NS group), smoking non-COPD group (S group), smoking COPD group (COPD group) according to smoking status and 2013 COPD diagnosis standard. The expression of IL-17 was detected by immumohistochemical staining. The volume of IL-17 in the airway and lung parenchyma was calculated by immumohistochemical staining scores which was product of dyeing cells positive rate and intensity. Pearson correlation analysis was used to analyze the relationships between expression of IL-17 in the airway and lung parenchyma and forced expiratory volume in 1 second/predicted value (FEV1%pred), carbon monoxide diffusion amount accounting for the percentage of the expected value (DLCO%pred), COPD assessment test (CAT) score, body mass index (BMI). RESULTS: The expressions of IL-17 in airway and lung parenchyma in S group (5.6+/-3.1, 6.4+/-2.5) were higher than those in NS group (1.6+/-1.4, 1.4+/-1.2) (both P<0.05), while expressions in COPD group (7.3+/-2.5, 7.8+/-2.1) were further higher than S group (both P<0.05). In the S group and COPD group, the expressions of IL-17 in the airway and lung parenchyma were positively correlated with smoking (r=0.453, P=0.007 and r=0.573, P<0.001); In the COPD group, the expressions of IL-17 in the airway and lung parenchyma were negatively correlated with FEV1%pred (r=-0.729, P=0.001 and r= 0.489, P=0.039), negatively related with DLCO%pred (r=-0.493, P=0.038 and r= 0.520, P=0.027), positively correlated with COPD CAT score (r=0.730, P=0.001 and r=0.644, P=0.004) and negatively related with BMI (r=-0.653, P=0.003 and r= 0.485, P=0.041). CONCLUSION: Smoking increases inflammation of lung tissue, increases IL-17 expression in airway and lung parenchyma; the expression of IL-17 is closely related to the severity of disease, the quality of life and prognosis in COPD patients. PMID- 27468623 TI - [Liver transplantation for benign liver tumor: six cases report and literature review]. AB - OBJECTIVE: To analyse and explore the indications and efficacy of liver transplantation for benign liver tumor. METHODS: From Jan.2001 to Dec.2014, 6 patients, incluing 3 males and 3 females, with benign liver tumor underwent liver transplantation in our department.There were 2 cases of hepatic epithelioid hemangioendothelioma, 1 case of hepatic cavernous hemangioma, 1 case of liver mesenchymal hamartoma, 1 case of hilar bile duct mucinous cystadenoma, and 1 case of hepatic adenoma. The data of surgical procedure, perioperative complications, postoperative management, and the outcome of follow-up were analyzed. RESULTS: Six orthotopic liver transplantation from one living donor and five cadaveric donors were performed. One patient died in the perioperative period, and other patients were discharged with normal liver and kidney function. Within the follow up time of 22 to 88 months, these patients could live the normal lives with stable graft function and nutritional status. CONCLUSIONS: Liver transplantation is the most efficient treatment for unresectable and symptomatic benign lesions, with the favourable outcome. PMID- 27468624 TI - [Mechanism of RhoA/Rho-kinase signal pathway-induced erectile dysfunction in hyperlipidemic rats]. AB - OBJECTIVE: To investigate the expression of RhoA/Rho-kinase (ROCK) in penile corpus cavernosum smooth muscles in rats of hyperlipidemia-induced erectile dysfunction and its molecular mechanism. METHODS: Forty male Sprague-Dawley rats were randomly divided into control and experimental groups using a random number table. Rats in the control group (n=20) were fed with regular diet for 24 weeks and those in the experimental group (n=20) with high-fat diet for the same period of time. The serum lipids profile was detected before and after the diet treatment. The ratio of intracavernosal pressure (DeltaICP)/mean arterial pressure (MAP) was measured, and Western blot was used to detect the expression of total RhoA, ROCK1, and ROCK2 in penile corpus cavernosum smooth muscles, and RhoA protein in cell membrane and cytoplasm of smooth muscles after 24 weeks. RESULTS: After 24 weeks, the levels of cholesterol, triglyceride, and low-density lipoprotein were significantly higher in the experimental group compared with those before diet treatment and the control group (all P<0.01). DeltaICP/MAP in the experimental group was greatly lower than in the control group (P<0.01). The protein expression of ROCK2 in penile corpus cavernosum smooth muscles was higher in the experimental group than in the control group (0.77+/-0.10 vs 0.27+/-0.08, P<0.01) after 24 weeks, while no statistically significant differences were observed in total RhoA and ROCK 1 protein expression between the two groups (both P>0.05). RhoA expression in cytoplasm was lower in the experimental than in the control group (1.66+/-0.09 vs 1.79+/-0.15, P<0.05). The ratio of RhoA expression in menmbrane/cytoplasm was higher in the experimental than in the control group (0.33+/-0.09 vs 0.26+/-0.07, P<0.05). CONCLUSION: Up-regulation of RhoA/ROCK may be involved in hyperlipidemia-induced erectile dysfunction in rats. PMID- 27468625 TI - Public participation in decision-making on the coverage of new antivirals for hepatitis C. AB - Purpose - New hepatitis C medicines such as sofosbuvir underline the need to balance considerations of innovation, clinical evidence, budget impact and equity in health priority-setting. The purpose of this paper is to examine the role of public participation in addressing these considerations. Design/methodology/approach - The paper employs a comparative case study approach. It explores the experience of four countries - Brazil, England, South Korea and the USA - in making coverage decisions about the antiviral sofosbuvir and involving the public and patients in these decision-making processes. Findings - Issues emerging from public participation ac tivities include the role of the universal right to health in Brazil, the balance between innovation and budget impact in England, the effect of unethical medical practices on public perception in South Korea and the legitimacy of priority-setting processes in the USA. Providing policymakers are receptive to these issues, public participation activities may be re-conceptualized as processes that illuminate policy problems relevant to a particular context, thereby promoting an agenda-setting role for the public. Originality/value - The paper offers an empirical analysis of public involvement in the case of sofosbuvir, where the relevant considerations that bear on priority-setting decisions have been particularly stark. The perspectives that emerge suggest that public participation contributes to raising attention to issues that need to be addressed by policymakers. Public participation activities can thus contribute to setting policy agendas, even if that is not their explicit purpose. However, the actualization of this contribution is contingent on the receptiveness of policymakers. PMID- 27468626 TI - Hydrothermal-Assisted Cold Sintering Process: A New Guidance for Low-Temperature Ceramic Sintering. AB - Sintering is a thermal treatment process that is generally applied to achieve dense bulk solids from particulate materials below the melting temperature. Conventional sintering of polycrystalline ceramics is prevalently performed at quite high temperatures, normally up to 1000 to 1200 degrees C for most ceramic materials, typically 50% to 75% of the melting temperatures. Here we present a new sintering route to achieve dense ceramics at extraordinarily low temperatures. This method is basically modified from the cold sintering process (CSP) we developed very recently by specifically incorporating the hydrothermal precursor solutions into the particles. BaTiO3 nano polycrystalline ceramics are exemplified for demonstration due to their technological importance and normally high processing temperature under conventional sintering routes. The presented technique could also be extended to a much broader range of material systems than previously demonstrated via a hydrothermal synthesis using water or volatile solutions. Such a methodology is of significant importance, because it provides a chemical roadmap for cost-effective inorganic processing that can enable broad practical applications. PMID- 27468627 TI - Insulin-like Growth Factor 1 for Healthy Spines and Healthy Minds? PMID- 27468628 TI - The Splice Is Right: ANK3 and the Control of Cortical Circuits. PMID- 27468629 TI - Lethal and sub-lethal effects of triclosan toxicity to the earthworm Eisenia fetida assessed through GC-MS metabolomics. AB - Triclosan (TCS) is a ubiquitous contaminant in municipal biosolids, which has also been detected in soils and earthworms sampled from agricultural fields amended with biosolids. The goal of this study was to evaluate the toxicity of TCS to earthworms using a metabolomics-based approach for an improved interpretation of toxicity. Toxicity of TCS was assessed using the OECD Method 207 filter paper contact test measuring the endpoints of weight loss, mortality, and ten metabolites determined by GC-MS. Eight earthworms were exposed as individual replicates to six concentrations of triclosan (0, 0.0001, 0.001, 0.01, 0.1, and 1mg TCS cm-2) on filter paper, with mortality assessed after 6, 24 and 48h. Mortalities were first observed at 24h, with 100% mortality in the 1 and 0.1mgcm-2 treatments. Worms at 1mgcm-2 lost most of their coelomic fluid before they could be sampled. The 48h LC50 for triclosan was estimated to be 0.006 and 0.008mgcm-2 by a linear and logistic model, respectively. Based on the LC50, triclosan is relatively more toxic to earthworms than a number of other emerging contaminants, but is less toxic than other chlorophenols and many pesticides. Alanine, valine, leucine, serine, phenylalanine, putrescine, spermidine, mannitol, and inositol were significantly different between treatments, although changes were most often associated with mortality rather than triclosan exposure. An increase in putrescine and decrease in amino acids, polyols, and spermidine were associated with mortality, suggesting decomposition had begun. Principal components analysis did not reveal evidence of metabolic impacts at sub-lethal concentrations. However, there were changes in the pattern of correlations between metabolite pairs in surviving worms at both 0.0001 and 0.001mgcm-2 exposure compared to the control. PMID- 27468631 TI - Delusional disorder and schizophrenia: a comparative study across multiple domains. AB - BACKGROUND: Delusional disorder (DD) is an under-researched condition and its relationship to schizophrenia (SZ) controversial. This study aimed to further characterize DD and to examine multi-domain evidence for the distinction between DD and SZ. METHOD: Using univariate analyses we examined 146 subjects with DD, 114 subjects with paranoid SZ and 244 subjects with non-paranoid SZ on 52 characteristics from several domains including demographics, risk factors, premorbid features, illness characteristics, index episode features, delusional related features, response to treatment and outcome. In a further step, we searched for independent associations of the examined characteristics with DD v. SZ. RESULTS: Univariate analyses showed that DD differed from either form of SZ in 40 characteristics, the pattern of findings indicated that paranoid SZ was much more similar to non-paranoid SZ than DD. Relative to subjects with SZ, those with DD were more likely to have drug abuse before illness onset, better premorbid sexual adjustment, later age at illness onset, higher levels of affective symptoms and lack of insight, poorer response to antipsychotic medication, better functioning in the domains of personal care, paid work and social functioning; last, subjects with DD had fewer but more severe delusions and higher ratings of conviction of delusional experience than those with SZ. Predominance of jealousy and somatic delusions was confined to subjects with DD. CONCLUSIONS: DD and SZ represent two distinct classes of disorders, the differential features of DD being of nosological, aetiological and therapeutic relevance. PMID- 27468630 TI - Validity of Adjuvant! Online in older patients with stage III colon cancer based on 2967 patients from the ACCENT database. AB - BACKGROUND: Adjuvant! Online is a tool used for clinical decision making in patients with early stage colon cancer. As details of the tool's construction are not published, the ability of Adjuvant! Online to accurately predict outcomes for older patients (age 70+) with node positive colon cancer receiving adjuvant chemotherapy is unclear. METHODS: Individual data from older patients with stage III colon cancer who enrolled into multiple trials within the ACCENT database were entered into the Adjuvant! Online program to obtain predicted probabilities of 5-year overall survival (OS) and recurrence-free survival (RFS). Median predictions were compared with known rates. As co-morbidities were not known for ACCENT patients, but required for calculator entry, patients were assumed to have either "minor" or "average for age" co-morbidities. RESULTS: 2967 older patients from 10 randomized studies were included. When "minor" co-morbidities were assumed, the median predicted 5-year OS rate of 64% nearly matched the actual rate of 65%; when "average for age" co-morbidities were assumed, the median prediction dropped to 58%, outside the CI for the actual rate. On the other hand, assuming "minor" co-morbidities gave a median 5-year RFS prediction of 62%, outside the 95% CI for the actual rate of 58%, while assuming "average for age" co-morbidities yielded a better median prediction of 57%. CONCLUSION: Adjuvant! Online is reasonably accurate overall for predicting outcomes in older trial patients with stage III colon cancer, though accuracy may differ between 5-year RFS and 5-year OS predictions when a fixed degree of co-morbidities is assumed. PMID- 27468632 TI - Eustachian Tube Function. AB - The fibrocartilaginous eustachian tube is part of a system of contiguous organs including the nose, palate, rhinopharynx, and middle ear cleft. The middle ear cleft consists of the tympanic cavity, which includes the bony eustachian tube (protympanum) and the mastoid gas cells system. The tympanic cavity and mastoid gas cells are interconnected and allow gaseous exchange and pressure regulation. The fibrocartilaginous eustachian tube is a complex organ consisting of a dynamic conduit with its mucosa, cartilage, surrounding soft tissue, peritubal muscles (ie, tensor and levator veli palatine, salpingopharyngeus and tensor tympani), and superior bony support (the sphenoid sulcus). PMID- 27468633 TI - Endoscopic Facial Nerve Surgery. AB - Tympanic facial nerve segment surgery has been traditionally performed using microscopic approaches, but currently, exclusive endoscopic approaches have been performed for traumatic, neoplastic, or inflammatory diseases, specially located at the geniculate ganglion, greater petrosal nerve, and second tract of the facial nerve, until the second genu. The tympanic segment of the facial nerve can be reached and visualized using an exclusive transcanal endoscopic approach, even in poorly accessible regions such as the second genu and geniculate ganglion, avoiding mastoidectomy, bony demolition, and meningeal or cerebral lobe tractions, with low complication rates using a minimally invasive surgical route. PMID- 27468634 TI - Anatomy of the Eustachian Tube. AB - The eustachian tube consists of 2 compartments: the Rudinger's safety canal and the auxiliary gap. It is surrounded by a cartilaginous wall on the craniomedial side and a membranous wall on the inferolateral side. The eustachian tube cartilage is firmly attached to the skull base by the lateral and the medial suspensory ligaments, which are separated by the medial Ostmann fat pad. The function of the isometric tensor veli palatini muscle is modulated by hypomochlia, which have an influence on the muscular force vectors. PMID- 27468635 TI - Preoperative and Intraoperative Evaluation of the Eustachian Tube in Chronic Ear Surgery. AB - This article discusses the authors' approach to the assessment of the eustachian tube using opening pressure measurement, endoscopic assessment of the protympanic segment of the eustachian tube, and Valsalva computed tomography. A possible algorithm for the evaluation of eustachian tube obstructive disorders is detailed both preoperatively and intraoperatively. PMID- 27468636 TI - Endoscopic Management of Middle Ear and Temporal Bone Lesions. AB - Tantamount to the management of temporal bone neoplasms is the ability to visualize the pathology and its relationship with the numerous critical structures housed therein. Transcanal endoscopic ear surgery provides the surgeon with an unparalleled view of the entire middle ear. This article presents the latest information on the usefulness of transcanal endoscopic ear surgery in the management of middle ear and temporal bone neoplasms. PMID- 27468637 TI - Transnasal Endoscopic Eustachian Tube Surgery. AB - The purpose of this article is to give a contemporary review of transnasal endoscopic surgery for Eustachian tube disorders. The authors' perspective of the relevant anatomy, pathophysiology, and evaluation of Eustachian tube disorders as related to surgical intervention also is provided. PMID- 27468638 TI - Ultrastructural immunogold localization of major sperm protein (MSP) in spermatogenic cells of the nematode Acrobeles complexus (Nematoda, Rhabditida). AB - The nematode spermatozoa represent a highly modified (aberrant) type of male gametes that lack a flagellum but for which the process of spermatogenesis culminates in the production of a crawling spermatozoon on the basis of the cytoskeletal component known as "major sperm protein", or MSP. MSP is also known as an important hormone triggering oocyte maturation and ovulation in the model nematode Caenorhabditis elegans, where this protein was first identified. However, direct evidence of MSP localization and of its fate in nematode spermatogenic cells is rare. In this study, the spermatogenesis and sperm structure in the rhabditid nematode Acrobeles complexus (Rhabditida: Tylenchina: Cephalobomorpha: Cephaloboidea: Cephalobidae) has been examined with electron microscopy. Morphological observations were followed by high-pressure freezing and freeze-substitution fixation which allows post-embedding immunogold localization of MSP in all stages of sperm development using antibodies raised for MSP of C. elegans. In spermatocytes, synthetic activity results in the development of specific cellular components, fibrous bodies (FB) and membranous organelles (MO), which appear as FB-MO complexes where the filamentous matter of FB has been MSP-labeled. The spermatids subdivide into a residual body with superfluous cytoplasm, and a main cell body which contains nucleus, mitochondria and FB-MO complexes. These complexes dissociate into individual components, MO and FB, with the MSP being localized in FB. Immature spermatozoa from testes are opaque cells where a centrally located nucleus is surrounded by mitochondria, MO and FB clustered together, the MSP still being localized only in FB. Cytoplasm of mature spermatozoa from spermatheca is segregated into external pseudopods lacking organelles and a central cluster of mitochondria with intact MO surrounding the central nucleus. The FB ultimately disappear, and the MSP labeling becomes concentrated in the filamentous content of pseudopods and cytoplasm of the main cell body. Although the spermatogenesis and sperm structure of A. complexus is similar to that of many other rhabditid nematodes, their intact MO makes the morphology of the mature spermatozoa distinct from the "rhabditid pattern" and may be considered as a synapomorphy. The MSP localization in spermatogenic cells of A. complexus also follows the "rhabditid pattern" described in C. elegans and Ascaris spp. Our results and techniques of MSP labeling of A. complexus spermatogeneous cells reveal new possibilities to elucidate different research questions on MSP localization in nematodes related to C. elegans. Furthermore, the laboratory-cultured A. complexus strains can be used as a new and fascinating model to study MO and MSP functions in nematode reproduction. PMID- 27468639 TI - Exploratory behaviour modulates the relationship between colony familiarity and helping in a cooperative bird. AB - Individuals within animal groups may differ in personality and degree of familiarity raising the question of how this influences their social interactions. In Iberian magpies Cyanopica cooki, a portion of first-year males engage in cooperative behaviours and dispersal, allowing addressing this question. In this study, we first investigate the relationship between colony familiarity (native versus foreign) and reproductive status (breeding versus helping) of males during 21 years. Secondly, we measure the exploratory behaviour and monitor reproductive status of a sample of individuals with different colony familiarity during 2 years. Long-term monitoring revealed that foreign individuals were more likely breeders. The analysis on the subset of individuals in which exploratory behaviour was measured revealed a mediatory effect of exploratory behaviour in the association between colony familiarity and helping behaviour. Specifically, among foreign individuals, higher explorative males were more frequently involved in helping behaviour than lower explorative ones. Conversely, among native males, breeders were more explorative than helpers. Our results suggest that aspects of personality may mediate the value of familiarity in reproductive tasks in social species. PMID- 27468640 TI - Corrigendum to "Borderline tumours of the ovary: A cohort study of the Arbeitsgemeinschaft Gynakologische Onkologie AGO Study Group" [Eur J Cancer 49 (2013) 1905-1914]. PMID- 27468641 TI - Flammulina velutipes: An option for "alperujo" use. AB - BACKGROUND: Two-phase olive-mill wastes (or "alperujo") exhibit highly phytotoxic properties, mainly due to phenols. A valuable option for alperujo is its agricultural use, provided that no phytotoxic effects occur. AIMS: The present investigation was aimed at evaluating the efficacy of two strains of the lignin degrading fungus Flammulina velutipes to colonize alperujo in order to produce edible mushrooms and to achieve its detoxification. METHODS: Some important cultural characters related to mushroom production (earliness, biological efficiency and quality of basidiomes) were estimated. The production of lignocellulolytic enzymes, phenol removal and detoxification of the substrate was evaluated. RESULTS: High biological efficiencies (70.8%) were obtained at 12 degrees C with F. velutipes strain BAFC 670/06 in a substrate containing poplar wood shavings and 90% of alperujo. The nature of the substrate did not seem to exert an important influence on pileus and stem morphology; nevertheless shortest stems were observed at higher temperatures. Endo-beta-1,4-glucanase, endo-beta 1,4-xylanase, laccase and Mn-peroxidase activities were detected in the extracts recovered from the solid-state cultures. Both F. velutipes strains were effective in removing the phenolic compounds. The initial concentration in the substrate with 90% alperujo was reduced in the case of F. velutipes BAFC 1763 by 84.31%, and 40.15% by F. velutipes BAFC 670/06. Germinability experiments on Raphanus sativus, showed that alperujo phytotoxicity was significantly reduced by F. velutipes cultures. CONCLUSIONS: The experimented changes by the spent mushroom substrate resulting from F. velutipes cultivation with high amount of alperujo would allow its reuse for agricultural purposes. PMID- 27468642 TI - Analysis of direct-to-consumer marketed Chlamydia trachomatis diagnostic tests in Norway. AB - Background In 2014, and for the first time in Norway, a pharmacy chain started selling home sampling kits for Chlamydia trachomatis (C. trachomatis) detection. Direct-to-consumer diagnostic kits for C. trachomatis have been available in Norway from an Internet company since 2005. There has been little assessment of persons who purchase direct-to-consumer diagnostic tests for sexually transmissible infections (STIs) detection and if low-risk populations are being unnecessarily encouraged to buy these tests. METHODS: The prevalence of C. trachomatis in customers who purchased home sampling kits from the pharmacy chain and from the commercial Internet Co. were compared to that of patients attending STI clinics and other free primary healthcare services. Prevalences of other STIs in pharmacy and Internet customers were also determined. RESULTS: The prevalence of C. trachomatis among pharmacy customers was 11%, almost identical to the prevalence among Internet customers (12%). In comparison, the prevalence among patients attending STI clinics in Oslo was 7.2%, which is similar to the prevalence among patients who have been tested through primary healthcare services. The prevalence of Mycoplasma genitalium was two-fold less than that of C. trachomatis in the STI and primary physician population, and significantly less in the Internet and the pharmacy population. Neisseria gonorrhoeae was not detected in urine samples from pharmacy customers or from Internet customers. CONCLUSIONS: Both pharmacy and Internet C. trachomatis home-sampling kits seem to be purchased by the right risk population. Marketing of direct-to-consumer N. gonorrhoeae tests and possibly M. genitalium tests cannot be justified in Norway. Direct-to-consumer diagnostic tests should be actively utilised as part of national programs in preventing the spread of C. trachomatis. PMID- 27468644 TI - Erratum. PMID- 27468645 TI - Intra-cellular immunosuppressive drugs monitoring: A step forward towards better therapeutic efficacy after organ transplantation? AB - Immunosuppressive drugs (IS) used in solid organ transplantation are critical dose drugs with high intra- and inter-subject variability. Therefore, IS therapeutic drug monitoring (TDM), mainly as trough levels analysis, is a major support to patient management, mandatory to optimize clinical outcome. Even though transplant patients undoubtedly benefited by this pre-dose (C0) monitoring, the relationship between these C0 concentrations and the incidence of graft rejections remains hardly predictable. Identification and validation of additional biomarkers of efficacy are therefore very much needed. As the main IS effects are mediated through the inhibition of lymphocyte proliferation pathways, direct drug quantification within this target compartment would appear meaningful, providing hopefully more consistent information on drug efficacy. Due to the analytical performances improvement, these intracellular concentrations became accessible for comprehensive studies regarding clinical benefit of intracellular IS TDM after solid organ transplantation. Over the last ten years, number of studies investigated the potential relationship between IS blood and intracellular pharmacokinetics, genetic variability, and clinical efficacy after solid organ transplantation. A recent literature review suggests that calcineurin inhibitors (tacrolimus and cyclosporine) intracellular concentrations appear more closely related to drug efficacy than blood levels. This closer association has however not been described for the m-TOR inhibitors (sirolimus, everolimus) and the antimetabolite (mycophenolic acid). Additional larger and multicenter clinical trials are needed to confirm these observations. PMID- 27468646 TI - Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3. AB - Macrolide antibiotics exert immunomodulatory activity by reducing pro inflammatory cytokine production by airway epithelial cells, fibroblasts, vascular endothelial cells, and immune cells. However, the underlying mechanism of action remains unclear. Here, we examined the effect of clarithromycin (CAM) on pro-inflammatory cytokine production, including interferons (IFNs), by primary human nasal epithelial cells and lung epithelial cell lines (A549 and BEAS-2B cells) after stimulation by Toll-like receptor (TLR) and RIG-I-like receptor (RLR) agonists and after infection by human respiratory syncytial virus (RSV). CAM treatment led to a significant reduction in poly I:C- and RSV-mediated IL-8, CCL5, IFN-beta and -lambda production. Furthermore, IFN-beta promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM. CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus. We conclude that CAM acts a crucial modulator of the innate immune response, particularly IFN production, by modulating IRF-3 dimerization and subsequent translocation to the nucleus of airway epithelial cells. This newly identified immunomodulatory action of CAM will facilitate the discovery of new macrolides with an anti-inflammatory role. PMID- 27468647 TI - Nitric oxide-induced oxidative stress impairs pacemaker function of murine interstitial cells of Cajal during inflammation. AB - The pacemaker function of interstitial cells of Cajal (ICC) is impaired during intestinal inflammation. The aim of this study is to clarify the pathophysiological mechanisms of ICC dysfunction during inflammatory condition by using intestinal cell clusters. Cell clusters were prepared from smooth muscle layer of murine jejunum and treated with interferon-gamma and lipopolysaccharide (IFN-gamma+LPS) for 24h to induce inflammation. Pacemaker function of ICC was monitored by measuring cytosolic Ca(2+) oscillation in the presence of nifedipine. Treatment with IFN-gamma+LPS impaired the pacemaker activity of ICC with increasing mRNA level of interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6 in cell clusters; however, treatment with these cytokines individually had little effect on pacemaker activity of ICC. Treatment with IFN gamma+LPS also induced the expression of inducible nitric oxide synthase (iNOS) in smooth muscle cells and resident macrophages, but not in ICC. Pretreatment with NOS inhibitor, L-NAME or iNOS inhibitor, 1400W ameliorated IFN-gamma+LPS induced pacemaker dysfunction of ICC. Pretreatment with guanylate cyclase inhibitor, ODQ did not, but antioxidant, apocynin, to suppress NO-induced oxidative stress, significantly suppressed the impairment of ICC function induced by IFN-gamma+LPS. Treatment with IFN-gamma+LPS also decreased c-Kit-positive ICC, which was prevented by pretreatment with L-NAME. However, apoptotic ICC were not detected in IFN-gamma+LPS-treated clusters, suggesting IFN-gamma+LPS stimulation just changed the phenotype of ICC but not induced cell death. Moreover, ultrastructure of ICC was not disturbed by IFN-gamma+LPS. In conclusion, ICC dysfunction during inflammation is induced by NO-induced oxidative stress rather than NO/cGMP signaling. NO-induced oxidative stress might be the main factor to induce phenotypic changes of ICC. PMID- 27468648 TI - H2S-induced thiol-based redox switches: Biochemistry and functional relevance for inflammatory diseases. AB - During the last decades, small inorganic molecules like reactive oxygen species (ROS), nitric oxide (NO), carbon monoxide (CO) and even the highly toxic hydrogen sulfide (H2S) have been evolved as important signaling molecules that trigger crucial cellular processes by regulating the activity of kinases, phosphatases and transcription factors. These redox molecules use similar target structures and therefore, the composition of the complex "redox environment" determines the final outcome of signaling processes and may subsequently also affect the behavior of a cell in an inflammatory environment. Here, we discuss the role of H2S in this complex interplay with a focus on the transcription factors Nrf2 and NFkappaB. PMID- 27468650 TI - Potassium lowering agents: Recommendations for physician and patient education, treatment reappraisal, and serial monitoring of potassium in patients with chronic hyperkalemia. PMID- 27468651 TI - Impact of statin therapy on plasma resistin and visfatin concentrations: A systematic review and meta-analysis of controlled clinical trials. AB - The beneficial effects of statin therapy in reducing cardiovascular morbidity and mortality is not merely explained by the lipid-modulating effects. Although adipokines levels have been associated with cardiometabolic disorders, a few studies have explored the effect of statin on resistin and visfatin. We aimed to evaluate the impact of statin therapy on levels of resistin and visfatin through a meta-analysis of published studies. A systematic literature search in Medline and SCOPUS databases was conducted up to January 2015 to identify controlled trials assessing changes in plasma concentrations of visfatin and resistin during treatment with statins. Quantitative data synthesis was performed using a random effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. 12 eligible studies with 14 treatment arms were included. Overall, 844 participants were studied. No significant change in plasma resistin concentrations was observed following statin therapy (WMD: -0.11ng/mL, CI: -1.94,1.73, p=0.909). This effect was robust and not affected by statin type, treatment duration and LDL-cholesterol concentrations. With respect to visfatin concentrations, there was a marginally significant reduction following statin therapy (WMD: -2.40ng/mL, CI: -4.79,-0.002, p=0.050). However, this effect size was weak and sensitive to three of the trials included in the analysis. This meta analysis did not suggest any effect of statin therapy on plasma resistin levels, while a slight reduction in visfatin levels was found. The effect of statins on visfatin levels may represent a novel pleiotropic characteristic of these drugs. PMID- 27468649 TI - Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression. AB - Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection (Third International Consensus definition for Sepsis and septic shock). Despite decades of research, sepsis remains the leading cause of death in intensive care units. More than 40 clinical trials, most of which have targeted the sepsis-associated pro-inflammatory response, have failed. Thus, antibiotics and fluid resuscitation remain the mainstays of supportive care and there is intense need to discover and develop novel, targeted therapies to treat sepsis. Both pre-clinical and clinical studies over the past decade demonstrate unequivocally that sepsis not only causes hyper-inflammation, but also leads to simultaneous adaptive immune system dysfunction and impaired antimicrobial immunity. Evidences for immunosuppression include immune cell depletion (T cells most affected), compromised T cell effector functions, T cell exhaustion, impaired antigen presentation, increased susceptibility to opportunistic nosocomial infections, dysregulated cytokine secretion, and reactivation of latent viruses. Therefore, targeting immunosuppression provides a logical approach to treat protracted sepsis. Numerous pre-clinical studies using immunomodulatory agents such as interleukin-7, anti-programmed cell death 1 antibody (anti-PD-1), anti-programmed cell death 1 ligand antibody (anti-PD-L1), and others have demonstrated reversal of T cell dysfunction and improved survival. Therefore, identifying immunosuppressed patients with the help of specific biomarkers and administering specific immunomodulators holds significant potential for sepsis therapy in the future. This review focusses on T cell dysfunction during sepsis and discusses the potential immunotherapeutic agents to boost T cell function during sepsis and improve host resistance to infection. PMID- 27468652 TI - BRET-based beta-arrestin2 recruitment to the histamine H1 receptor for investigating antihistamine binding kinetics. AB - Ligand residence time is thought to be a critical parameter for optimizing the in vivo efficacy of drug candidates. For the histamine H1 receptor (H1R) and other G protein-coupled receptors, the kinetics of ligand binding are typically measured by low throughput radioligand binding experiments using homogenized cell membranes expressing the target receptor. In this study, a real-time proximity assay between H1R and beta-arrestin2 in living cells was established to investigate the dynamics of antihistamine binding to the H1R. No receptor reserve was found for the histamine-induced recruitment of beta-arrestin2 to the H1R and the transiently recruited beta-arrestin2 therefore reflected occupancy of the receptor by histamine. Antihistamines displayed similar kinetic signatures on antagonizing histamine-induced beta-arrestin2 recruitment as compared to displacing radioligand binding from the H1R. This homogeneous functional method unambiguously determined the fifty-fold difference in the dissociation rate constant between mepyramine and the long residence time antihistamines levocetirizine and desloratadine. PMID- 27468653 TI - Usage and Dose Response of a Mobile Acceptance and Commitment Therapy App: Secondary Analysis of the Intervention Arm of a Randomized Controlled Trial. AB - BACKGROUND: Mobile phone apps offer a promising medium to deliver psychological interventions. A mobile app based on Acceptance and Commitment Therapy (ACT) was developed and studied in a randomized controlled trial (RCT). OBJECTIVE: To study usage metrics of a mobile ACT intervention and dose-response relationship between usage and improvement in psychological flexibility. METHODS: An RCT was conducted to investigate the effectiveness of different lifestyle interventions for overweight people with psychological stress. This paper presents a secondary analysis of the group that received an 8-week mobile ACT intervention. Most of the analyzed 74 participants were female (n=64, 86%). Their median age was 49.6 (interquartile range, IQR 45.4-55.3) years and their mean level of psychological flexibility, measured with the Acceptance and Action Questionnaire II, was 20.4 (95% confidence interval 18.3-22.5). Several usage metrics describing the intensity of use, usage of content, and ways of use were calculated. Linear regression analyses were performed to study the dose-response relationship between usage and the change in psychological flexibility and to identify the usage metrics with strongest association with improvement. Binary logistic regression analyses were further used to assess the role of usage metrics between those who showed improvement in psychological flexibility and those who did not. In addition, associations between usage and baseline participant characteristics were studied. RESULTS: The median number of usage sessions was 21 (IQR 11.8-35), the number of usage days was 15 (IQR 9.0-24), and the number of usage weeks was 7.0 (IQR 4.0-8.0). The participants used the mobile app for a median duration of 4.7 (IQR 3.2-7.2) hours and performed a median of 63 (IQR 46-98) exercises. There was a dose-response relationship between usage and the change in psychological flexibility. The strongest associations with psychological flexibility (results adjusted with gender, age, and baseline psychological variables) were found for lower usage of Self as context related exercises (B=0.22, P=.001) and higher intensity of use, described by the number of usage sessions (B=-0.10, P=.01), usage days (B=-0.17, P=.008), and usage weeks (B=-0.73, P=.02), the number of exercises performed (B=-0.02, P=.03), and the total duration of use (B=-0.30, P=.04). Also, higher usage of Acceptance related exercises (B=-0.18, P=.04) was associated with improvement. Active usage was associated with female gender, older age, and not owning a smart mobile phone before the study. CONCLUSIONS: The results indicated that active usage of a mobile ACT intervention was associated with improved psychological flexibility. Usage metrics describing intensity of use as well as two metrics related to the usage of content were found to be most strongly associated with improvement. TRIAL REGISTRATION: ClinicalTrials.gov NCT01738256; https://clinicaltrials.gov/ct2/show/NCT01738256 (Archived by WebCite at http://www.webcitation.org/6iTePjPLL). PMID- 27468654 TI - Feature-location binding in 3D: Feature judgments are biased by 2D location but not position-in-depth. AB - A fundamental aspect of human visual perception is the ability to recognize and locate objects in the environment. Importantly, our environment is predominantly three-dimensional (3D), but while there is considerable research exploring the binding of object features and location, it is unknown how depth information interacts with features in the object binding process. A recent paradigm called the spatial congruency bias demonstrated that 2D location is fundamentally bound to object features, such that irrelevant location information biases judgments of object features, but irrelevant feature information does not bias judgments of location or other features. Here, using the spatial congruency bias paradigm, we asked whether depth is processed as another type of location, or more like other features. We initially found that depth cued by binocular disparity biased judgments of object color. However, this result seemed to be driven more by the disparity differences than the depth percept: Depth cued by occlusion and size did not bias color judgments, whereas vertical disparity information (with no depth percept) did bias color judgments. Our results suggest that despite the 3D nature of our visual environment, only 2D location information - not position-in depth - seems to be automatically bound to object features, with depth information processed more similarly to other features than to 2D location. PMID- 27468655 TI - Trophoblastic debris modifies endothelial cell transcriptome in vitro: a mechanism by which fetal cells might control maternal responses to pregnancy. AB - The mechanisms by which the fetus induces maternal physiological adaptations to pregnancy are unclear. Cellular debris, shed from the placental syncytiotrophoblast into the maternal blood and phagocytosed by maternal endothelial and immune cells, may be one of these mechanisms. Here we show that trophoblastic debris from normal first trimester placentae induces changes in the transcriptome and proteome of endothelial cells in vitro, which might contribute to the adaptation of the maternal cardiovascular system to pregnancy. Trophoblastic debris also induced endothelial cells to transcribe placenta specific genes, including the vasodilator hormone CSH1, thereby expanding the effective functional size of the placenta. Our data suggest that the deportation of trophoblastic debris is an important part of the complex network of feto maternal communication. PMID- 27468656 TI - Effect of leptin combined with CoCl2 on healing in Sprague Dawley Rat fracture model. AB - To evaluate the effect of leptin combined with CoCl2 on rat femur fracture healing. 48 male Sprague Dawley rats were randomly divided into two main groups. Then standardized femur fractures were created to all rats. Control group rats were treated with 0.5 mL physiological saline, and experimental group rats were treated with 5 MUg/Kg.d leptin and 15 mg/Kg.d CoCl2 along with 0.5 mL physiological saline for 42 days intraperitoneally. Each main group was divided into three subgroups for each evaluation at second, fourth and sixth weeks, each subgroup included eight rats. The radiological evaluation showed that the fracture healing progress of experimental group was superior to control group from second week. At fourth week, experimental group had better fracture healing progress than control group significantly. Results of biomechanics show the ultimate load (N) and deflection ultimate load (mm) of experimental group was significantly increased than that in control group from fourth week. The present result demonstrated that leptin combined with CoCl2 significantly increased the mRNA expression levels of HIF1A, Vegfa, Runx2, Bmp2, Bglap and Alpl. It suggested that leptin combined with CoCl2 have a positive effect on rat femur fracture healing by activating the HIF1A pathway. PMID- 27468658 TI - Toward an operational neuroethical risk analysis and mitigation paradigm for emerging neuroscience and technology (neuroS/T). AB - Research in neuroscience and neurotechnology (neuroS/T) is progressing at a rapid pace with translational applications both in medicine, and more widely in the social milieu. Current and projected neuroS/T research and its applications evoke a number of neuroethicolegal and social issues (NELSI). This paper defines inherent and derivative NELSI of current and near-term neuroS/T development and engagement, and provides an overview of our group's ongoing work to develop a systematized approach to their address. Our proposed operational neuroethical risk assessment and mitigation paradigm (ONRAMP) is presented, which entails querying, framing, and modeling patterns and trajectories of neuroS/T research and translational uses, and the NELSI generated by such advancements and their applications. Extant ethical methods are addressed, with suggestion toward possible revision or re-formulation to meet the needs and exigencies fostered by neuroS/T and resultant NELSI in multi-cultural contexts. The relevance and importance of multi-disciplinary expertise in focusing upon NELSI is discussed, and the need for neuroethics education toward cultivating such a cadre of expertise is emphasized. PMID- 27468659 TI - Findings of Unknown Etiology but Doubtful Significance. PMID- 27468657 TI - Deficiency in matrix metalloproteinase-2 results in long-term vascular instability and regression in the injured mouse spinal cord. AB - Angiogenesis plays a critical role in wound healing after spinal cord injury. Therefore, understanding the events that regulate angiogenesis has considerable relevance from a therapeutic standpoint. We evaluated the contribution of matrix metalloproteinase (MMP)-2 to angiogenesis and vascular stability in spinal cord injured MMP-2 knockout and wildtype (WT) littermates. While MMP-2 deficiency resulted in reduced endothelial cell division within the lesioned epicenter, there were no genotypic differences in vascularity (vascular density, vascular area, and endothelial cell number) over the first two weeks post-injury. However, by 21days post-injury MMP-2 deficiency resulted in a sharp decline in vascularity, indicative of vascular regression. Complementary in vitro studies of brain capillary endothelial cells confirmed MMP-2 dependent proliferation and tube formation. As deficiency in MMP-2 led to prolonged MMP-9 expression in the injured spinal cord, we examined both short-term and long-term exposure to MMP-9 in vitro. While MMP-9 supported endothelial tube formation and proliferation, prolonged exposure resulted in loss of tubes, findings consistent with vascular regression. Vascular instability is frequently associated with pericyte dissociation and precedes vascular regression. Quantification of PDGFrbeta+ pericyte coverage of mature vessels within the glial scar (the reactive gliosis zone), a known source of MMP-9, revealed reduced coverage in MMP-2 deficient animals. These findings suggest that acting in the absence of MMP-2, MMP-9 transiently supports angiogenesis during the early phase of wound healing while its prolonged expression leads to vascular instability and regression. These findings should be considered while developing therapeutic interventions that block MMPs. PMID- 27468660 TI - Decompressive Craniectomy for Ischemic Stroke: Effect of Hemorrhagic Transformation on Outcome. AB - BACKGROUND: Decompressive hemicraniectomy (DhC) is a life-saving surgical procedure being increasingly employed for malignant middle cerebral artery strokes. We examined the incidence of hemorrhagic transformation following DhC. METHODS: We retrospectively reviewed the charts and radiological images of patients who underwent DhC for malignant middle cerebral artery strokes. We classified the hemorrhagic events and assessed the short-term 30-day outcome associated with these events. RESULTS: A total of 23 DhCs were performed for supratentorial ischemic strokes in 22 patients. There were 16 males and 6 females with an average age of 47 years (21-69 years). Of the 22 patients, 13 (59%) developed a new hemorrhage following DhC. There were 3 mortalities (14%). Of the survivors, 6 (27%) were discharged home with a modified Rankin Scale (mRS) score of 2. The remaining 13 patients (59%) recovered to a degree wherein they were discharged to a rehabilitation center (mRS score 3-4). No patient persisted in a vegetative or semivegetative state (mRS score 5). CONCLUSIONS: In this study, the rate of hemorrhagic transformation following DhC for ischemic stroke was 59%. This is much higher than that reported in the stroke thrombolysis literature. The presence of any type of new hemorrhagic transformation in this patient population does not appear to alter the natural history of their ischemic strokes in terms of Glasgow outcome scores or destination of disposition. PMID- 27468661 TI - Accuracy of National Institutes of Health Stroke Scale Score in Predicting the Site of Arterial Occlusion in Acute Stroke: A Transcranial Doppler Study. AB - BACKGROUND: In acute stroke, it is crucial to assess for intracranial large vessel occlusion and site of occlusion. The National Institutes of Health Stroke Scale score (NIHSSS) is the frequently used clinical tool to predict the site of arterial occlusion. In this study we aimed to determine the following: (1) if there is a correlation between the site of occlusion and the NIHSSS at presentation (bNIHSSS); and (2) if there is a bNIHSSS cutoff which can distinguish proximal occlusions (PO) from distal occlusions (DO). METHODS: Up to 313 patients from CLOTBUST data bank with demonstrable intracranial arterial occlusion and having received intravenous recombinant tissue plasminogen activator (rt-PA) were included. Occlusions were classified as PO (terminal internal carotid artery, M1 segment of middle cerebral artery [M1 MCA], and basilar artery) or DO (M2 MCA, anterior cerebral artery, posterior cerebral artery, and vertebral artery). RESULTS: By univariate analysis, bNIHSSS, thrombolysis in brain ischemia (TIBI) flow grade before rt-PA, degree of recanalization after rt-PA, and modified Rankin Scale score at 3 months were significantly different between various sites of occlusion. By univariate analysis, a higher bNIHSSS, lower TIBI flow grade, and lower ASPECTS (Alberta Stroke Program Early CT Score) differentiated PO from DO. Lower TIBI flow grade and higher bNIHSSS differentiated PO from DO by logistic regression analysis. No single NIHSSS cutoff with acceptable sensitivity and specificity could be derived to differentiate PO from DO. CONCLUSIONS: Although NIHSSS are higher in PO, there is no satisfactory NIHSSS cutoff which differentiates PO from DO. A vascular imaging or transcranial doppler should be obtained to determine the site of arterial occlusion in acute stroke. PMID- 27468662 TI - Aspirin and Clopidogrel Inhibit Aneurysm Healing after HydroCoil Implantation in External Carotid Artery Aneurysm Model. AB - PURPOSE: To understand whether the use of antiplatelet agents leads to less intra aneurismal tissue formation following coil implantation in a rat end-pouch external carotid artery (ECA) aneurysm model. METHODS: End-pouch ECA aneurysms were created in adult rats and were then embedded with either platinum or HydroCoils. Rats were treated either with aspirin, clopidogrel, aspirin + clopidogrel, or saline for 2 weeks after coil implantation. At 2 weeks after coil implantation, rats were sacrificed and the aneurysm pouch was removed for histological and immunohistochemical analysis. A blinded single observer calculated the percentage of the organized area and the residual length of elastic lamina within the aneurysm. Student's t-test was used to compare data from image analysis between the different groups. RESULTS: Within the platinum group, the organized tissue area was not affected by antiplatelet administration (aspirin versus saline, P = .83; clopidogrel versus saline, P = .46; aspirin + clopidogrel versus saline, P = .54). For the HydroCoil group, the organized tissue area was significantly reduced (aspirin versus saline, P = .02; clopidogrel versus saline, P = .04; aspirin + clopidogrel versus saline, P = .02) in rats treated with antiplatelet agents; however, no difference (aspirin versus clopidogrel, P = .8; aspirin versus aspirin + clopidogrel, P = .3; clopidogrel versus aspirin + clopidogrel, P = .5) was found among type or combination of antiplatelets administered. HydroCoil-treated aneurysms had a similar number of macrophages compared to the platinum group (P = .3819); however, the HydroCoil group had significant suppression of macrophages in the groups treated with combined antiplatelets (P = .02). CONCLUSION: Following HydroCoil implantation, the area of organized tissue is diminished significantly in a rat end-pouch ECA aneurysm model treated with antiplatelets. PMID- 27468663 TI - ACE Gene in Egyptian Ischemic Stroke Patients. AB - BACKGROUND: Angiotensin-1-converting enzyme (ACE) is a crucial player in vascular homeostasis and in the pathogenesis of atherosclerosis and hypertension. The present study was conducted to determine whether there is an association between the ACE insertion/deletion (I/D) polymorphism and ischemic stroke in Egyptian population. Also, we analyzed the ACE gene I/D polymorphism as a risk factor for small-vessel (SV) versus large-vessel (LV) disease. METHODS: Sixty patients with ischemic stroke were included: 30 with SV disease and 30 with LV disease. In addition, a control group of 30 apparent healthy subjects were studied. Clinical assessment, computed tomography, magnetic resonance imaging brain, and genetic study using the polymerase chain reaction of ACE gene were done for all subjects. RESULTS: We found that the distribution of ACE gene polymorphism frequency was significantly different between the 3 groups. The DD genotype was far more common in stroke patients compared to controls. It was also significantly more common in each of the patient groups compared to controls but rather similar in the 2 patient groups with SV and LV diseases. CONCLUSION: We found that the ACE gene deletion/deletion genotype is common in Egyptian patients with non-cardioembolic ischemic stroke but does not appear to be specific neither to SV nor to LV disease. PMID- 27468664 TI - Smoking relapse-prevention intervention for cancer patients: Study design and baseline data from the surviving SmokeFree randomized controlled trial. AB - Continued smoking after a cancer diagnosis contributes to several negative health outcomes. Although many cancer patients attempt to quit smoking, high smoking relapse rates have been observed. This highlights the need for a targeted, evidence-based smoking-relapse prevention intervention. The design, method, and baseline characteristics of a randomized controlled trial assessing the efficacy of a self-help smoking-relapse prevention intervention are presented. Cancer patients who had recently quit smoking were randomized to one of two conditions. The Usual Care (UC) group received the institution's standard of care. The smoking relapse-prevention intervention (SRP) group received standard of care, plus 8 relapse-prevention booklets mailed over a 3month period, and a targeted educational DVD developed specifically for cancer patients. Four hundred and fourteen participants were enrolled and completed a baseline survey. Primary outcomes will be self-reported smoking status at 6 and 12-months after baseline. Biochemical verification of smoking status was completed for a subsample. If found to be efficacious, this low-cost intervention could be easily disseminated with significant potential for reducing the risk of negative cancer outcomes associated with continued smoking. PMID- 27468665 TI - Fundamental Considerations for Ultrasound-Guided Musculoskeletal Interventions. AB - Ultrasound can be used to guide joint and soft tissue interventions to improve accuracy, efficacy, patient satisfaction, and to minimize complications. This article summarizes the rationale supporting ultrasound-guided injections and explains how to safely and effectively set up and perform these procedures. PMID- 27468666 TI - Ultrasound-Guided Interventional Procedures About the Shoulder: Anatomy, Indications, and Techniques. AB - Chronic and acute shoulder pain and dysfunction are common complaints among patients. Shoulder pain may be the result of abnormality involving the rotator cuff, subacromial-subdeltoid bursa, biceps tendon, glenoid labrum, glenohumeral joint, acromioclavicular joint, sternoclavicular joint, or glenohumeral joint capsule. Ultrasound-guided (USG) procedures of the shoulder are well established for interventional management. Ultrasound provides the advantages of excellent soft tissue resolution, injection accuracy, low cost, accessibility, portability, lack of ionizing radiation, and the ability to perform real-time image-guided procedures. The purpose of this article is to review common indications and effective techniques for USG injections about the shoulder. PMID- 27468667 TI - Ultrasound-Guided Elbow Procedures. AB - High-resolution ultrasonography can help clinicians visualize key anatomic structures of the elbow and guide periarticular and intra-articular injections. Historically, most procedures done around the elbow have been done using landmark guidance, and few studies have reported the accuracy of ultrasonography-guided injections in the elbow region. This article reviews common musculoskeletal disorders about the elbow that can be evaluated with ultrasonography, reviews the literature on ultrasonography-guided injections of the elbow region, and describes the senior author's preferred approach for the most commonly performed elbow region injections. PMID- 27468668 TI - Ultrasound-Guided Interventional Procedures of the Wrist and Hand: Anatomy, Indications, and Techniques. AB - Acute and chronic wrist and hand conditions are commonly seen by neuromuscular and musculoskeletal specialists. High-frequency diagnostic ultrasonography (US) has facilitated advances in the diagnosis and interventional management of wrist and hand disorders. US provides excellent soft tissue resolution, accessibility, portability, lack of ionizing radiation, and the ability to dynamically assess disorders and precisely guide interventional procedures. This article review the relevant anatomy, indications, and interventional techniques for common disorders of the wrist and hand, including radiocarpal joint arthritis, scaphotrapeziotrapezoidal joint arthritis, trapeziometacarpal joint arthritis, phalangeal joint arthritis, first dorsal compartment tenosynovitis, ganglion cysts, and stenosing tenosynovitis. PMID- 27468669 TI - Ultrasound-Guided Hip Procedures. AB - This article describes the techniques for performing ultrasound-guided procedures in the hip region, including intra-articular hip injection, iliopsoas bursa injection, greater trochanter bursa injection, ischial bursa injection, and piriformis muscle injection. The common indications, pitfalls, accuracy, and efficacy of these procedures are also addressed. PMID- 27468670 TI - Ultrasound-Guided Knee Procedures. AB - Most knee structures can be accurately targeted using ultrasound guidance. These structures are usually superficial, and the overlying soft tissues are mobile and compressible, facilitating excellent visualization with a high-frequency linear array transducer. The circumferential accessibility to the knee affords flexibility and often multiple procedural approach options. In most cases, an in plane approach is easily achieved. Studies of ultrasonography-guided knee procedures have consistently shown high accuracy, and its use is particularly beneficial for obese patients, diagnostic injection specificity, safety, and precise targeting of pathology. More studies are needed to assess the clinical efficacy and cost-effectiveness of ultrasonography-guided knee procedures. PMID- 27468671 TI - Ultrasound-Guided Foot and Ankle Procedures. AB - This article reviews commonly performed injections about the foot and ankle region. Although not exhaustive in its description of available techniques, general approaches to these procedures are applicable to any injection about the foot and ankle. As much as possible, the procedures described are based on commonly used or published techniques. An in-depth knowledge of the regional anatomy and understanding of different approaches when performing ultrasonography guided procedures allows clinicians to adapt to any clinical scenario. PMID- 27468672 TI - Ultrasound-Guided Spinal Procedures for Pain: A Review. AB - As the population ages, more patients are developing degenerative changes of the spine and associated pain. Although interventional procedures for axial and radicular spine pain have been available for decades, common imaging modalities have relied on ionizing radiation for guidance. Over the past decade, ultrasound has become increasingly popular to image both peripheral musculoskeletal and axial structures. This article reviews the use of ultrasound in the guidance of spine procedures, including cervical and lumbar facet injections and medial branch blocks, third occipital nerve blocks, thoracic facet and costotransverse joint injections, sacroiliac joint injections, and caudal and interlaminar epidural injections. PMID- 27468673 TI - Ultrasound-Guided Peripheral Nerve Procedures. AB - Ultrasound guidance allows real-time visualization of the needle in peripheral nerve procedures, improving accuracy and safety. Sonographic visualization of the peripheral nerve and surrounding anatomy can provide valuable information for diagnostic purposes and procedure enhancement. Common procedures discussed are the suprascapular nerve at the suprascapular notch, deep branch of the radial nerve at the supinator, median nerve at the pronator teres and carpal tunnel, lateral cutaneous nerve of the thigh, superficial fibular nerve at the leg, tibial nerve at the ankle, and interdigital neuroma. For each procedure, the indications, relevant anatomy, preprocedural scanning technique, and injection procedure itself are detailed. PMID- 27468675 TI - Advanced Ultrasound-Guided Interventions for Tendinopathy. AB - Tendinopathy is increasingly recognized as an important cause of musculoskeletal pain and disability. Tendinopathy is thought to be principally a degenerative process, rather than inflammatory as was traditionally believed. Consequently, traditional tendinopathy treatments focused solely on decreasing inflammation have often been ineffective or even harmful. The advancement of ultrasonography as for guidance of outpatient musculoskeletal procedures has facilitated the development of novel percutaneous procedures for the treatment of tendinopathy, mostly by using mechanical intervention to stimulate regeneration. Several of these techniques, including percutaneous needle tenotomy, percutaneous ultrasonic tenotomy, high-volume injection, and percutaneous needle scraping, are reviewed in this article. PMID- 27468674 TI - Orthobiologic Interventions Using Ultrasound Guidance. AB - The application of regenerative therapies for the treatment of musculoskeletal conditions has emerged over the last decade with recent acceleration. These include prolotherapy, platelet-rich plasma, and mesenchymal stem cell therapy. These strategies augment the body's innate physiology to heal pathologic processes. This article presents an overview of platelet-rich plasma and mesenchymal stem cell therapy for the treatment of musculoskeletal injuries. A brief literature review is included, as are techniques for the use of ultrasound guidance to assist with these procedures. PMID- 27468676 TI - Past, Present, and Future Considerations for Musculoskeletal Ultrasound. AB - Musculoskeletal ultrasound has a rich history originally rooted in nautical technology. In recent years, it has proliferated significantly for both diagnostic and interventional purposes in the point-of-care clinical setting by nonradiologist musculoskeletal clinicians. This article outlines the history of musculoskeletal ultrasound, examines present developments, and discusses its future outlook. PMID- 27468677 TI - A New Interventional Field? PMID- 27468678 TI - Outpatient Ultrasound-Guided Musculoskeletal Techniques. PMID- 27468679 TI - A multivariate method for estimating cross-frequency neuronal interactions and correcting linear mixing in MEG data, using canonical correlations. AB - BACKGROUND: Cross-frequency interactions between distinct brain areas have been observed in connection with a variety of cognitive tasks. With electro- and magnetoencephalography (EEG/MEG) data, typical connectivity measures between two brain regions analyze a single quantity from each region within a specific frequency band; given the wideband nature of EEG/MEG signals, many statistical tests may be required to identify true coupling. Furthermore, because of the poor spatial resolution of activity reconstructed from EEG/MEG, some interactions may actually be due to the linear mixing of brain sources. NEW METHOD: In the present work, a method for the detection of cross-frequency functional connectivity in MEG data using canonical correlation analysis (CCA) is described. We demonstrate that CCA identifies correlated signals and also the frequencies that cause the correlation. We also implement a procedure to deal with linear mixing based on symmetry properties of cross-covariance matrices. RESULTS: Our tests with both simulated and real MEG data demonstrate that CCA is able to detect interacting locations and the frequencies that cause them, while accurately discarding spurious coupling. COMPARISON WITH EXISTING METHODS: Recent techniques look at time delays in the activity between two locations to discard spurious interactions, while we propose a linear mixing model and demonstrate its relationship with symmetry aspects of cross-covariance matrices. CONCLUSIONS: Our tests indicate the benefits of the CCA approach in connectivity studies, as it allows the simultaneous evaluation of several possible combinations of cross frequency interactions in a single statistical test. PMID- 27468681 TI - Distal femoral osteotomy using a novel deformity reduction device. AB - Distal femoral osteotomy is a surgical procedure used to correct patellar luxation, secondary to a femoral deformity. A distal femoral osteotomy using the tibial plateau levelling osteotomy-jig to temporarily provide stability of the distal femoral osteotomy, maintaining limb alignment in the frontal and axial planes prior to internal plate fixation of the osteotomy, has been described. This report describes a novel jig named Deformity Reduction Device (DRD). This device was developed with the specific aim of increasing precision and predictability during corrective osteotomy execution in order to be consistent with the preoperative planning. The distal femoral osteotomy DRD-assisted procedure is described in detail, discussing the theoretical and practical principles of the application. PMID- 27468680 TI - Ultrasound-guided laryngeal air column width difference and the cuff leak volume in predicting the effectiveness of steroid therapy on postextubation stridor in adult. Are they useful? AB - OBJECTIVE: To evaluate the effectiveness of steroids therapy on postextubation stridor (PES) depending on the clinical response, the ultrasound guided laryngeal air column width difference (LACWD) and the cuff leak volume (CLV). DESIGN: Prospective, observer-blinded study. SETTING: Carried out in intensive care unit in Tanta university hospital. PATIENTS: 432 patients of both sexes received mechanical ventilation for more than 24 hours and met defined criteria for a weaning trial. MEASUREMENTS: Ultrasound guided LACWD and CLV were conducted before extubation. Patients developing postextubation stridor were intravenously given 8 mg of dexamethasone every 8 hours for 3 days. The clinical response, ultrasounds guided LACWD and CLV before and after steroid therapy were analyzed. Primary outcome and secondary outcomes of our study were reported. RESULTS: 387 patients (89.5%) had no PES and 45 patients (10.5%) had PES. Risk factors for PES were longer duration of intubation, younger age and female gender. Both CLV and LACWD showed significant decrease (P< .05) in patients with PES in comparison with no PES patients. 45 patients with PES received dexamethasone treatment; 18 were completely recovered while 27 patients needed reintubation after 1 h. of these 27 patients; 19 patients had successful extubation while 8 patients had tracheostomy. In patients with PES, CLV and LACWD showed significant increase (P< .05) in comparison with before administration. Level of CLV <200 ml and LACWD <0.9 mm carry high sensitivity with high positive predictive value and high accuracy for presence of PES. CONCLUSION: Steroids therapy improves postextubation stridor. Both LACWD and CLV are non-invasive and simple methods for monitoring of laryngeal edema regression after steroid therapy. We recommend administration of corticosteroids to patients with a lower level of leak volume and LACWD before extubation. PMID- 27468682 TI - Pain coping strategies: Neonatal intensive care unit survivors in adolescence. AB - BACKGROUND: Data on long-term consequences of preterm birth on pain coping later in life are limited. AIM: To assess whether gestational age, birth weight and neonatal disease severity have effect on pain coping style in adolescents born preterm or with low birth weight. STUDY DESIGN: Observational, longitudinal study (Project On Preterm and SGA-infants, POPS-19). SUBJECTS: We analyzed data of 537 adolescents at the age of 19 years, who were born at a gestational age <32 weeks or with a birth weight <1500g. OUTCOME MEASURES: Participants completed the pain coping questionnaire (PCQ) that assesses pain coping strategies in three higher order factors: approach ("to deal with pain"), problem-focused avoidance ("to disengage from pain") and emotion-focused avoidance ("expression of pain"). Furthermore, their pain coping effectiveness, pain controllability and emotional reactions to pain were assessed. All participants completed an IQ test. RESULTS: Univariate analysis showed no significant correlation between length of stay, sepsis and necrotizing enterocolitis and any of the higher-order factors. Approach was only correlated with IQ. Problem-focused avoidance was, in the multiple regression analysis (including gestational age, IVH and IQ), only correlated with IQ. For emotion-focused avoidance (including birth weight, SGA, IVH, respiratory support and IQ) three independent predictors remained: IVH was positively correlated, while respiratory support and IQ were negatively correlated with emotion-focused avoidance. CONCLUSIONS: Early neonatal characteristics and neonatal disease severity have limited effect on pain coping style in adolescence. Higher IQ was associated with the use of adaptive coping strategies, while maladaptive strategies were used less. PMID- 27468683 TI - Mammalian cell entry (Mce) protein of Leptospira interrogans binds extracellular matrix components, plasminogen and beta2 integrin. AB - A severe re-emergingzoonosis, leptospirosis, is caused by pathogenic spirochetes of the genus Leptospira. Several studies have identified leptospiral surface proteins with the ability to bind ECM and plasma components, which could mediate adhesion and invasion through the hosts. It has been shown that Mce of pathogenic Leptospira spp. is an RGD (Arg-Gly-Asp)-motif-dependent virulence factor, responsible for infection of cells and animals. In the present article, we decided to further study the repertoire of the Mce activities in leptospiral biological properties. We report that the recombinant Mce is a broad-spectrum ECM binding protein, capable of interacting with laminin, cellular and plasma fibronectin and collagen IV. Dose--r-esponse interaction was observed for all the components, fulfilling ligand--receptor requirements. Mce is a PLG binding protein capable to recruit this component from NHS, generating PLA in the presence of PLG activator. Binding of Mce was also observed with the leukocyte cell receptors alphaLbeta2 [(CD11a/CD18)-LFA-1] and alphaMbeta2 [(CD11b/CD18)-Mac 1], suggesting the involvement of this protein in the host immune response. Indeed, virulent Leptospira L1-130 was capable of binding both integrins, whereas culture-attenuated M-20 strain only bind to alphaMbeta2 [(CD11b/CD18)-Mac-1]. To the best of our knowledge, this is the first work to describe that Mce surface protein could mediate the attachment of Leptospira interrogans to human cell receptors alphaLbeta2(CD11a/CD18) and alphaMbeta2(CD11b/CD18). PMID- 27468684 TI - Deconvoluting hepatic processing of carbon nanotubes. AB - Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs. Here we provide the unexpected details of hepatic processing of covalently functionalized nanotubes including receptor-mediated endocytosis, cellular trafficking and biliary elimination. Ammonium-functionalized fibrillar nanocarbon is found to preferentially localize in the fenestrated sinusoidal endothelium of the liver but not resident macrophages. Stabilin receptors mediate the endocytic clearance of nanotubes. Biocompatibility is evidenced by the absence of cell death and no immune cell infiltration. Towards clinical application of this platform, nanotubes were evaluated for the first time in non-human primates. The pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans. PMID- 27468685 TI - PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL. AB - Proteins involved in DNA double-strand break (DSB) repair localize within the promyelocytic leukemia nuclear bodies (PML-NBs), whose disruption is at the root of the acute promyelocytic leukemia (APL) pathogenesis. All-trans-retinoic acid (RA) treatment induces PML-RARalpha degradation, restores PML-NB functions, and causes terminal cell differentiation of APL blasts. However, the precise role of the APL-associated PML-RARalpha oncoprotein and PML-NB integrity in the DSB response in APL leukemogenesis and tumor suppression is still lacking. Primary leukemia blasts isolated from APL patients showed high phosphorylation levels of H2AX (gamma-H2AX), an initial DSBs sensor. By addressing the consequences of ionizing radiation (IR)-induced DSB response in primary APL blasts and RA responsive and -resistant myeloid cell lines carrying endogenous or ectopically expressed PML-RARalpha, before and after treatment with RA, we found that the disruption of PML-NBs is associated with delayed DSB response, as revealed by the impaired kinetic of disappearance of gamma-H2AX and 53BP1 foci and activation of ATM and of its substrates H2AX, NBN, and CHK2. The disruption of PML-NB integrity by PML-RARalpha also affects the IR-induced DSB response in a preleukemic mouse model of APL in vivo. We propose the oncoprotein-dependent PML-NB disruption and DDR impairment as relevant early events in APL tumorigenesis. PMID- 27468686 TI - Mitochondrial dysfunction in an Opa1(Q285STOP) mouse model of dominant optic atrophy results from Opa1 haploinsufficiency. AB - Mutations in the opa1 (optic atrophy 1) gene lead to autosomal dominant optic atrophy (ADOA), a hereditary eye disease. This gene encodes the Opa1 protein, a mitochondrial dynamin-related GTPase required for mitochondrial fusion and the maintenance of normal crista structure. The majority of opa1 mutations encode truncated forms of the protein, lacking a complete GTPase domain. It is unclear whether the phenotype results from haploinsufficiency or rather a deleterious effect of truncated Opa1 protein. We studied a heterozygous Opa1 mutant mouse carrying a defective allele with a stop codon in the beginning of the GTPase domain at residue 285, a mutation that mimics human pathological mutations. Using an antibody raised against an N-terminal portion of Opa1, we found that the level of wild-type protein was decreased in the mutant mice, as predicted. However, no truncated Opa1 protein was expressed. In embryonic fibroblasts isolated from the mutant mice, this partial loss of Opa1 caused mitochondrial respiratory deficiency and a selective loss of respiratory Complex IV subunits. Furthermore, partial Opa1 deficiency resulted in a substantial resistance to endoplasmic reticulum stress-induced death. On the other hand, the enforced expression of truncated Opa1 protein in cells containing normal levels of wild-type protein did not cause mitochondrial defects. Moreover, cells expressing the truncated Opa1 protein showed reduced Bax activation in response to apoptotic stimuli. Taken together, our results exclude deleterious dominant-negative or gain-of-function mechanisms for this type of Opa1 mutation and affirm haploinsufficiency as the mechanism underlying mitochondrial dysfunction in ADOA. PMID- 27468687 TI - PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes. AB - The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment. PMID- 27468688 TI - Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts. AB - It is established that the interaction between microenvironment and cancer cells has a critical role in tumor development, given the dependence of neoplastic cells on stromal support. However, how this communication promotes the activation of normal (NFs) into cancer-associated fibroblasts (CAFs) is still not well understood. Most microRNA (miRNA) studies focused on tumor cell, but there is increasing evidence of their involvement in reprogramming NFs into CAFs. Here we show that miR-9, upregulated in various breast cancer cell lines and identified as pro-metastatic miRNA, affects the properties of human breast fibroblasts, enhancing the switch to CAF phenotype, thus contributing to tumor growth. Expressed at higher levels in primary triple-negative breast CAFs versus NFs isolated from patients, miR-9 improves indeed migration and invasion capabilities when transfected in immortalized NFs; viceversa, these properties are strongly impaired in CAFs upon miR-9 inhibition. We also demonstrate that tumor-secreted miR-9 can be transferred via exosomes to recipient NFs and this uptake results in enhanced cell motility. Moreover, we observed that this miRNA is also secreted by fibroblasts and in turn able to alter tumor cell behavior, by modulating its direct target E-cadherin, and NFs themselves. Consistently with the biological effects observed, gene expression profiles of NFs upon transient transfection with miR-9 show the modulation of genes mainly involved in cell motility and extracellular matrix remodeling pathways. Finally, we were able to confirm the capability of NFs transiently transfected with miR-9 to promote in vivo tumor growth. Taken together, these data provide new insights into the role of miR-9 as an important player in the cross-talk between cancer cells and stroma. PMID- 27468689 TI - Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6. AB - Cereblon (CRBN) is a substrate receptor protein for the CRL4A E3 ubiquitin ligase complex. In this study, we report on a new regulatory role of CRBN in TLR4 signaling. CRBN overexpression leads to suppression of NF-kappaB activation and production of pro-inflammatory cytokines including IL-6 and IL-1beta in response to TLR4 stimulation. Biochemical studies revealed interactions between CRBN and TAK1, and TRAF6 proteins. The interaction between CRBN and TAK1 did not affect the association of the TAB1 and TAB2 proteins, which have pivotal roles in the activation of TAK1, whereas the CRBN-TRAF6 interaction critically affected ubiquitination of TRAF6 and TAB2. Binding mapping results revealed that CRBN interacts with the Zinc finger domain of TRAF6, which contains the ubiquitination site of TRAF6, leading to attenuation of ubiquitination of TRAF6 and TAB2. Functional studies revealed that CRBN-knockdown THP-1 cells show enhanced NF kappaB activation and p65- or p50-DNA binding activities, leading to up regulation of NF-kappaB-dependent gene expression and increased pro-inflammatory cytokine levels in response to TLR4 stimulation. Furthermore, Crbn(-/-) mice exhibit decreased survival in response to LPS challenge, accompanied with marked enhancement of pro-inflammatory cytokines, such as TNF-alpha and IL-6. Taken together, our data demonstrate that CRBN negatively regulates TLR4 signaling via attenuation of TRAF6 and TAB2 ubiquitination. PMID- 27468690 TI - Tumorigenic potential is restored during differentiation in fusion-reprogrammed cancer cells. AB - Detailed understanding of the mechanistic steps underlying tumor initiation and malignant progression is critical for insights of potentially novel therapeutic modalities. Cellular reprogramming is an approach of particular interest because it can provide a means to reset the differentiation state of the cancer cells and to revert these cells to a state of non-malignancy. Here, we investigated the relationship between cellular differentiation and malignant progression by the fusion of four independent mouse cancer cell lines from different tissues, each with differing developmental potentials, to pluripotent mouse embryonic stem (ES) cells. Fusion was accompanied by loss of differentiated properties of the four parental cancer cell lines and concomitant emergence of pluripotency, demonstrating the feasibility to reprogram the malignant and differentiative properties of cancer cells. However, the original malignant and differentiative phenotypes re-emerge upon withdrawal of the fused cells from the embryonic environment in which they were maintained. cDNA array analysis of the malignant hepatoma progression implicated a role for Foxa1, and silencing Foxa1 prevented the re-emergence of malignant and differentiation-associated gene expression. Our findings support the hypothesis that tumor progression results from deregulation of stem cells, and our approach provides a strategy to analyze possible mechanisms in the cancer initiation. PMID- 27468691 TI - Egg antigen p40 of Schistosoma japonicum promotes senescence in activated hepatic stellate cells by activation of the STAT3/p53/p21 pathway. AB - Liver fibrosis is a serious disease that is characterized by the excess deposition of extracellular matrix (ECM) components. Activated hepatic stellate cells (HSCs) are a major source of ECM and serve as a key regulator in liver fibrogenesis. Inactivation of HSCs is essential for liver fibrotic regression. The present study explores the underlying mechanisms of Schistosoma japonicum egg antigen p40 (Sjp40) promoting senescence in HSCs and antifibrosis. For the first time we report that Sjp40 inhibits the activation and proliferation of an immortalized human HSC line (LX-2 cells) and promotes cellular senescence and cell cycle arrest. Sjp40 through action on the STAT3/p53/p21 pathway triggered cellular senescence, while knockdown of p53 or STAT3 partly restored cell senescence. In addition, Sjp40-induced cellular senescence caused LX-2 cells to be more sensitive to a human NK cell line (YT cells). Together these findings provide novel insights into the mechanism of antifibrosis and may have implications for the development of antifibrosis therapies. PMID- 27468692 TI - DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity. AB - EZH2 is a histone methyltransferase whose functions in stem cells and tumor cells are well established. Accumulating evidence shows that EZH2 has critical roles in T cells and could be a promising therapeutic target for several immune diseases. To further reveal the novel functions of EZH2 in human T cells, protein co immunoprecipitation combined mass spectrometry was conducted and several previous unknown EZH2-interacting proteins were identified. Of them, we focused on a DNA damage responsive protein, Ku80, because of the limited knowledge regarding EZH2 in the DNA damage response. Then, we demonstrated that instead of being methylated by EZH2, Ku80 bridges the interaction between the DNA-dependent protein kinase (DNA-PK) complex and EZH2, thus facilitating EZH2 phosphorylation. Moreover, EZH2 histone methyltransferase activity was enhanced when Ku80 was knocked down or DNA-PK activity was inhibited, suggesting DNA-PK-mediated EZH2 phosphorylation impairs EZH2 histone methyltransferase activity. On the other hand, EZH2 inhibition increased the DNA damage level at the late phase of T-cell activation, suggesting EZH2 involved in genomic integrity maintenance. In conclusion, our study is the first to demonstrate that EZH2 is phosphorylated by the DNA damage responsive complex DNA-PK and regulates DNA damage-mediated T-cell apoptosis, which reveals a novel functional crosstalk between epigenetic regulation and genomic integrity. PMID- 27468694 TI - Pro-death activity of a BH3 domain in an aquaporin from the protozoan parasite Leishmania. PMID- 27468693 TI - Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury. AB - The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c Kit(TgD814Y) receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-Kit(TgD814Y) mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit(+) cardiac cell number was not different compared with wt mice. However, when c-Kit(TgD814Y) mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit(+)CD31(+) endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45(-)c-Kit(+) cardiac stem cells isolated from transgenic c-Kit(TgD814Y) mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival. PMID- 27468696 TI - Predictors of anticoagulation quality in 15 834 patients performing patient self management of oral anticoagulation with vitamin K antagonists in real-life practice: a survey of the International Self-Monitoring Association of Orally Anticoagulated Patients. AB - Although patient self-management (PSM) of oral anticoagulation with vitamin K antagonists is recommended for patients requiring long-term anticoagulation, important aspects are still unclear. Using data from a large international survey (n = 15 834; median age 72 years; 30.1% female), we studied predictors of poor anticoagulation control (percentage of International Normalized Ratio values within therapeutic range below 75%) and developed a simple prediction model. The following variables were identified as risk factors for poor anticoagulation control and included in the final model: higher intensity of therapeutic range (odds ratio [OR] on every level 1.9; 95% confidence interval [CI] 1.8-2.0), long intervals between measurements (>14 d; 1.5; 95% CI 1.3-1.7), female sex (OR 1.3; 95% CI 1.2-1.4), and management other than PSM (OR 1.4; 95% CI 1.2-1.6). At a threshold of 0.2 (at least one variable present), the model predicted poor anticoagulation control with a sensitivity of 85.3% (95% CI: 84.0, 86.4) and a specificity of 28.5% (27.6, 29.5). The area under the receiver operated characteristic curve was 0.65. Using the proposed prediction model, physicians will be able to identify patients with a low chance of performing well, considering additional training, regular follow-up, or adjustment of therapeutic ranges. PMID- 27468695 TI - PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model. AB - Regulation of innate immune responses and activation of tissue regenerative processes are key elements in the pathophysiology of brain injuries. The promyelocytic leukemia (PML) gene was originally identified on a breakpoint of chromosomal translocation t(15;17) associated with acute PML. We have studied the role of PML protein during acute and regenerative phases after hypoxia-ischemia (HI) in brains of neonatal mice. We found that PML prevents tissue loss and apoptotic cell death selectively in subcortical regions of the brain at early stages after damage. In accordance with this, we revealed that PML is important for microglia activation and production of key inflammatory cytokines such as IL1alpha, IL1beta, IL1RN, CXCL10, CCL12 and TNFalpha. During the regenerative phase, PML-depleted mice were found to have impaired transformation of transit amplifying precursors into migratory progenitors. This was accompanied by increased ratios of symmetric versus asymmetric neural progenitor cell divisions during tissue repair and a specific defect in tissue restoration within the striatum 42 days after HI. The data demonstrate a dual role of PML in protection and recovery after brain injury. PMID- 27468697 TI - Retracted: FLT3: beyond good and evil. AB - The above article, published online on 29 July 2016 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the Journal Editor in Chief, Journal Production Manager, and John Wiley & Sons, Ltd. The retraction has been agreed due to 48% similar significant between this article and an article published in Nature Reviews Cancer journal. PMID- 27468698 TI - High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway. AB - Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-alpha, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2alpha and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation. PMID- 27468699 TI - Regulation of actin dynamics by WNT-5A: implications for human airway smooth muscle contraction. AB - A defining feature of asthma is airway hyperresponsiveness (AHR), which underlies the exaggerated bronchoconstriction response of asthmatics. The role of the airway smooth muscle (ASM) in AHR has garnered increasing interest over the years, but how asthmatic ASM differs from healthy ASM is still an active topic of debate. WNT-5A is increasingly expressed in asthmatic ASM and has been linked with Th2-high asthma. Due to its link with calcium and cytoskeletal remodelling, we propose that WNT-5A may modulate ASM contractility. We demonstrated that WNT 5A can increase maximum isometric tension in bovine tracheal smooth muscle strips. In addition, we show that WNT-5A is preferentially expressed in contractile human airway myocytes compared to proliferative cells, suggesting an active role in maintaining contractility. Furthermore, WNT-5A treatment drives actin polymerisation, but has no effect on intracellular calcium flux. Next, we demonstrated that WNT-5A directly regulates TGF-beta1-induced expression of alpha SMA via ROCK-mediated actin polymerization. These findings suggest that WNT-5A modulates fundamental mechanisms that affect ASM contraction and thus may be of relevance for AHR in asthma. PMID- 27468701 TI - Rapid detection of talcum powder in tea using FT-IR spectroscopy coupled with chemometrics. AB - This paper investigated the feasibility of Fourier transform infrared transmission (FT-IR) spectroscopy to detect talcum powder illegally added in tea based on chemometric methods. Firstly, 210 samples of tea powder with 13 dose levels of talcum powder were prepared for FT-IR spectra acquirement. In order to highlight the slight variations in FT-IR spectra, smoothing, normalize and standard normal variate (SNV) were employed to preprocess the raw spectra. Among them, SNV preprocessing had the best performance with high correlation of prediction (RP = 0.948) and low root mean square error of prediction (RMSEP = 0.108) of partial least squares (PLS) model. Then 18 characteristic wavenumbers were selected based on a hybrid of backward interval partial least squares (biPLS) regression, competitive adaptive reweighted sampling (CARS) algorithm and successive projections algorithm (SPA). These characteristic wavenumbers only accounted for 0.64% of the full wavenumbers. Following that, 18 characteristic wavenumbers were used to build linear and nonlinear determination models by PLS regression and extreme learning machine (ELM), respectively. The optimal model with RP = 0.963 and RMSEP = 0.137 was achieved by ELM algorithm. These results demonstrated that FT-IR spectroscopy with chemometrics could be used successfully to detect talcum powder in tea. PMID- 27468700 TI - Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis. AB - Previous studies have demonstrated that gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2D) share common genetic polymorphisms. We conducted meta-analysis and subgroup analysis of all available variants and determined the effects of confounding and experimental components on the genetic association of GDM. Any case-controlled or cohort studies with genotype distribution compared GDM cases with controls were included. In total, 28 articles including 8,204 cases and 15,221 controls for 6 polymorphisms were studied. rs10830963(MTNR1B), rs7903146(TCF7L2), and rs1801278(IRS1) were significantly associated with the increased GDM risk. The association of rs4402960(IGF2BP2) and rs1800629(TNF alpha) was significant only when the studies with control allele frequency deviation and publication bias were excluded. Further subgroup analysis showed the risk alleles of rs7903146(TCF7L2) and rs1801282(PPARG) were significantly associated with the GDM risk only in Asian, but not in Caucasian population. The OGTT test using 100 g, but not 75 g; and genotype detection by other assays, but not Taqman method, were also significantly associated with increased GDM risk in rs1801278(IRS1) and rs7903146(TCF7L2). Overall GDM was associated with rs10830963(MTNR1B), rs7903146(TCF7L2), and rs1801278(IRS1), but only rs7903146(TCF7L2) and rs1801282(PPARG) were significant in Asian populations. While rs1801278(IRS1) and rs7903146(TCF7L2) were significantly affected by OGTT protocol and genotyping methods. PMID- 27468702 TI - Interface-enhanced Li ion conduction in a LiBH4-SiO2 solid electrolyte. AB - We have developed a fast solid state Li ion conductor composed of LiBH4 and SiO2 by means of interface engineering. A composite of LiBH4-SiO2 was simply synthesized by high energy ball-milling, and two types of SiO2 (MCM-41 and fumed silica) having different specific surface areas were used to evaluate the effect of the LiBH4/SiO2 interface on the ionic conductivity enhancement. The ionic conductivity of the ball-milled LiBH4-MCM-41 and LiBH4-fumed silica mixture is as high as 10(-5) S cm(-1) and 10(-4) S cm(-1) at room temperature, respectively. In particular, the conductivity of the latter is comparable to the LiBH4 melt infiltrated into MCM-41. The conductivities of the LiBH4-fumed silica mixtures at different mixing ratios were analyzed employing a continuum percolation model, and the conductivity of the LiBH4/SiO2 interface layer is estimated to be 10(5) times higher than that of pure bulk LiBH4. The result highlights the importance of the interface and indicates that significant enhancement in ionic conductivity can be achieved via interface engineering. PMID- 27468703 TI - Proposal of Mucilaginibacter phyllosphaerae sp. nov. isolated from the phyllosphere of Galium album. AB - A pink-pigmented, Gram-stain-negative, rod-shaped, non-spore-forming bacterial strain, PP-F2F-G21T, was isolated from the phyllosphere of Galium album. Phylogenetic analysis of the nearly full-length 16S rRNA gene sequence of strain PP-F2F-G21T showed the closest relationship to type strains of the species Mucilaginibacter lutimaris (97.7 %), Mucilaginibacter soli (97.3 %) and Mucilaginibacter rigui (97.1 %). Sequence similarities to all other type strains were below 97 %. The predominant cellular fatty acids of strain PP-F2F-G21T are C16 : 1 omega7c/iso-C15 : 0 2-OH (measured as summed feature 3 fatty acids) and iso-C15 : 0 followed by iso-C17 : 0 3-OH, C16 : 1 omega5c and C16 : 0. The major compound in the polyamine pattern was sym-homospermidine and the diamino acid of the peptidoglycan was meso-diaminopimelic acid. The quinone system was exclusively composed of menaquinone MK-7. The polar lipid profile contained the major lipid phosphatidylethanolamine and in addition 18 unidentified lipids. Based on phylogenetic, chemotaxonomic and phenotypic analyses, we propose a novel species of the genus Mucilaginibacter named Mucilaginibacter phyllosphaeraesp. nov. The type strain is PP-F2F-G21T (=CCM 8625T=CIP 110921T=LMG 29118T). PMID- 27468704 TI - Attitudes toward driver's licenses for people with epilepsy: 2012 versus 2014. AB - BACKGROUND: We compared knowledge about and attitudes toward epilepsy and the issuing of driver's licenses to people with epilepsy among non-medical students before and after media controversies. METHODS: The survey was performed in 2012 and 2014 using a structured questionnaire. Participants were non-medical students who attended a lecture on neurological diseases in children. The proportion of positive answers to each question in 2012 was compared with that in 2014. In addition, questions regarding attitudes toward driver's licenses were compared according to knowledge about car accidents linked to people with epilepsy. RESULTS: More participants were familiar with epilepsy and had a favorable attitude toward epilepsy in 2014 than in 2012. In contrast, the proportion of participants who knew of car accidents linked to people with epilepsy was reduced in 2014 compared with 2012. The proportion of participants who did not think that severe punishment should be given to people with epilepsy if they caused a car accident decreased in 2014 among those without knowledge of car accidents. CONCLUSIONS: Familiarity with and attitudes toward epilepsy were improved in 2014, whereas the decrease in proportion of positive answers on punishment among participants unfamiliar with car accidents suggests a latent worsening of public attitudes. PMID- 27468705 TI - The impact of operator experience during institutional adoption of trans-radial cardiac catheterization. AB - OBJECTIVES: We studied the impact of operator experience on trans-radial (TR) cardiac catheterization performance in contemporary practice. BACKGROUND: TR cardiac catheterization offers advantages over trans-femoral (TF) cardiac catheterization, but the TR approach has been slowly adopted in the United States. METHODS: We reviewed all cases of attempted TR cardiac catheterization at a single tertiary care medical center from May 2008 until April 2015. We classified the attending operator TR case experience at the time of each case, and the control group constituted cases performed by operators with >300 TR cases. Study endpoints were TR cannulation failure, TF cross-over, contrast medium dose, and fluoroscopy time. RESULTS: Over the study period, 4177 attempted TR cardiac catheterization cases were performed. The percentage of TR cases performed with percutaneous coronary intervention (PCI) increased from 14.0% in 2009 to 30.2% in 2015 (P-trend <0.001). The rate of TR cannulation failure decreased from 4.3% in 2009 to 2.0% in 2015 (P-trend = 0.071), and the rate of TF cross-over decreased from 4.3% in 2009 to 3.2% in 2015 (P-trend = 0.034). Operators with over 100 cases had the lowest odds of TR cannulation failure, while operators with over 200 cases had the lowest odds of TF cross-over. Operators with over 200 cases used the lowest mean contrast medium dose and mean fluoroscopy time. CONCLUSIONS: Increasing operator TR experience is associated with lower odds of TR cannulation failure and TF cross-over, as well as lower contrast medium dose and fluoroscopy time. (c) 2016 Wiley Periodicals, Inc. PMID- 27468706 TI - Silibinin Inhibits Neutrophilic Inflammation and Mucus Secretion Induced by Cigarette Smoke via Suppression of ERK-SP1 Pathway. AB - Silibinin, the main ingredient of silymarin, has been used as a traditional drug for over 2000 years to treat a range of liver diseases. Recent studies have also demonstrated that silibinin possesses antiinflammatory and anticancer properties. In the study, we researched the efficacy of silibinin on the development of COPD using a cigarette smoke (CS)-induced and lipopolysaccharide (LPS)-induced COPD model mice and stimulation of NCI-H292 cells with CS condensate. Silibinin was administered to mice by oral gavage 1 h before CS exposure for 10 days. In in vitro experiment, we evaluated the effect of silibinin on the expression of MUC5AC in H292 cells stimulated with CS condensate. Furthermore, silibinin suppressed the CS and LPS treatment-induced extracellular signal-regulated kinase (ERK) phosphorylation and SP-1 expression. Silibinin also decreased airway inflammation and reduced the expression of MUC5AC and myeloperoxidase. Furthermore, co-treatment with silibinin and ERK inhibitors considerably decreased the levels of pro-inflammatory mediators, ERK phosphorylation, and SP-1 expression. Taken together, the results indicate that silibinin effectively suppressed the neutrophilic airway inflammation provoked by treatment with LPS and CS, which was closely associated with downregulation of ERK phosphorylation. Therefore, our searching offers that silibinin has a remedical probable for COPD disease. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27468707 TI - Reducing Readmissions among Heart Failure Patients Discharged to Home Health Care: Effectiveness of Early and Intensive Nursing Services and Early Physician Follow-Up. AB - OBJECTIVE: To compare the effectiveness of two "treatments"-early, intensive home health nursing and physician follow-up within a week-versus less intense and later postacute care in reducing readmissions among heart failure (HF) patients discharged to home health care. DATA SOURCES: National Medicare administrative, claims, and patient assessment data. STUDY DESIGN: Patients with a full week of potential exposure to the treatments were followed for 30 days to determine exposure status, 30-day all-cause hospital readmission, other health care use, and mortality. An extension of instrumental variables methods for nonlinear statistical models corrects for nonrandom selection of patients into treatment categories. Our instruments are the index hospital's rate of early aftercare for non-HF patients and hospital discharge day of the week. DATA EXTRACTION METHODS: All hospitalizations for a HF principal diagnosis with discharge to home health care between July 2009 and June 2010 were identified from source files. PRINCIPAL FINDINGS: Neither treatment by itself has a statistically significant effect on hospital readmission. In combination, however, they reduce the probability of readmission by roughly 8 percentage points (p < .001; confidence interval = 12.3, -4.1). Results are robust to changes in implementation of the nonlinear IV estimator, sample, outcome measure, and length of follow-up. CONCLUSIONS: Our results call for closer coordination between home health and medical providers in the clinical management of HF patients immediately after hospital discharge. PMID- 27468709 TI - Pseudomonas oceani sp. nov., isolated from deep seawater. AB - In this study, we identified a novel Gram-stain-negative, aerobic, motile, and rod-shaped bacterium, strain KX 20T, isolated from the deep seawater in Okinawa Trough, northwestern Pacific Ocean. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain KX 20T was related to members of the genus Pseudomonas and shares the highest sequence identities with Pseudomonas aestusnigri CECT 8317T (99.4 %) and Pseudomonas pachastrellae JCM 12285T (98.5 %). The 16S rRNA gene sequence identities between strain KX 20T and other members of the genus Pseudomonaswere below 96.6 %. The gyrB and rpoD genes of strain KX 20T shared 82.0 to 89.3 % sequence identity with the gyrB and rpoD genes of the closest phylogenetic neighbours of KX 20T. The predominant cellular fatty acids of strain KX 20T were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) (29.2 %), C16 : 0 (24.5 %), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) (21.5 %) and C12 : 0 (8.2 %). The major polar lipids of strain KX 20T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and unknown phospholipids. The genomic DNA G+C content of strain KX 20T was 62.9 mol%. On the basis of phylogenetic analysis and phenotypic characteristics, a novel species, Pseudomonas oceani sp. nov. is proposed. The type strain is KX 20T (=CGMCC 1.15195T=DSM 100277T). PMID- 27468710 TI - Use of Non-Selective Non-Steroidal Anti-Inflammatory Drugs in Relation to Cardiovascular Events. A Systematic Pharmacoepidemiological Review. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, having numerous indications. However, despite their therapeutic role, they are associated with serious cardiovascular (CV) adverse events. Objectives-Methods: This review comprising recent observational studies and metaanalyses over the past few years aims at updating the assessment of CV adverse events, namely stroke, myocardial infarction (MI), CV death, atrial fibrillation (AF), serious bleeding and heart failure related to the use of 4 of the most widely prescribed NSAIDs: ibuprofen, naproxen, diclofenac and mefenamic acid. RESULTS: The best safety profile related to MI was found for naproxen, while the worst safety profile, with excessively increased risk for stroke, MI and major bleeding, was for diclofenac. Naproxen showed higher risk for major bleeding than ibuprofen and the risk for stroke was slightly higher than ibuprofen. Regarding heart failure, ibuprofen presented the highest risk while the highest risk for AF was attributed to the current use of diclofenac. There are few data related to mefenamic acid, which showed a strong association with increased risk for stroke and a moderately increased risk for MI. CONCLUSION: Further research is needed in order to devise new guidelines for safer use of NSAIDs. PMID- 27468708 TI - Oral AGE restriction ameliorates insulin resistance in obese individuals with the metabolic syndrome: a randomised controlled trial. AB - AIMS/HYPOTHESIS: We previously reported that obese individuals with the metabolic syndrome (at risk), compared with obese individuals without the metabolic syndrome (healthy obese), have elevated serum AGEs that strongly correlate with insulin resistance, oxidative stress and inflammation. We hypothesised that a diet low in AGEs (L-AGE) would improve components of the metabolic syndrome in obese individuals, confirming high AGEs as a new risk factor for the metabolic syndrome. METHODS: A randomised 1 year trial was conducted in obese individuals with the metabolic syndrome in two parallel groups: L-AGE diet vs a regular diet, habitually high in AGEs (Reg-AGE). Participants were allocated to each group by randomisation using random permuted blocks. At baseline and at the end of the trial, we obtained anthropometric variables, blood and urine samples, and performed OGTTs and MRI measurements of visceral and subcutaneous abdominal tissue and carotid artery. Only investigators involved in laboratory determinations were blinded to dietary assignment. Effects on insulin resistance (HOMA-IR) were the primary outcome. RESULTS: Sixty-one individuals were randomised to a Reg-AGE diet and 77 to an L-AGE diet; the data of 49 and 51, respectively, were analysed at the study end in 2014. The L-AGE diet markedly improved insulin resistance; modestly decreased body weight; lowered AGEs, oxidative stress and inflammation; and enhanced the protective factors sirtuin 1, AGE receptor 1 and glyoxalase I. The Reg-AGE diet raised AGEs and markers of insulin resistance, oxidative stress and inflammation. There were no effects on MRI-assessed measurements. No side effects from the intervention were identified. HOMA-IR came down from 3.1 +/- 1.8 to 1.9 +/- 1.3 (p < 0.001) in the L-AGE group, while it increased from 2.9 +/- 1.2 to 3.6 +/- 1.7 (p < 0.002) in the Reg-AGE group. CONCLUSIONS/INTERPRETATION: L-AGE ameliorates insulin resistance in obese people with the metabolic syndrome, and may reduce the risk of type 2 diabetes, without necessitating a major reduction in adiposity. Elevated serum AGEs may be used to diagnose and treat 'at-risk' obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01363141 FUNDING: The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (DK091231). PMID- 27468711 TI - Rapid in situ growth of oriented titanium-nickel oxide composite nanotubes arrays coated on a nitinol wire as a solid-phase microextraction fiber coupled to HPLC UV. AB - An oriented titanium-nickel oxide composite nanotubes coating was in situ grown on a nitinol wire by direct electrochemical anodization in ethylene glycol with ammonium fluoride and water for the first time. The morphology and composition of the resulting coating showed that the anodized nitinol wire provided a titania rich coating. The titanium-nickel oxide composite nanotubes coated fiber was used for solid-phase microextraction of different aromatic compounds coupled to high performance liquid chromatography with UV detection. The titanium-nickel oxide composite nanotubes coating exhibited high extraction capability, good selectivity, and rapid mass transfer for weakly polar UV filters. Thereafter the important parameters affecting extraction efficiency were investigated for solid phase microextraction of UV filters. Under the optimized conditions, the calibration curves were linear in the range of 0.1-300 MUg/L for target UV filters with limits of detection of 0.019-0.082 MUg/L. The intraday and interday precision of the proposed method with the single fiber were 5.3-7.2 and 5.9-7.9%, respectively, and the fiber-to-fiber reproducibility ranged from 6.3 to 8.9% for four fibers fabricated in different batches. Finally, its applicability was evaluated by the extraction and determination of target UV filters in environmental water samples. PMID- 27468712 TI - Tendon pathology in trauma CT imaging: an under-recognized entity. AB - Computed tomography (CT) scans are increasingly ordered in the emergent setting, for diagnosis of occult fractures and treatment planning of known fractures or fracture dislocations. Although having inferior soft tissue contrast resolution compared to magnetic resonance imaging (MRI), CT may provide important information regarding tendon pathology that is often under-recognized but may better serve patient outcomes, whether in or out of the operative setting. In this pictorial essay, we present CT cases which demonstrate some of the more commonly encountered tendon abnormalities in patients with acute trauma. PMID- 27468713 TI - Determinants of peripapillary retinal nerve fiber layer thickness regarding ocular and systemic parameters - the MIPH Eye&Health Study. AB - BACKGROUND: Optical coherence tomography (OCT) allows quantitative image analysis of retinal tissue in vivo. Peripapillary retinal nerve fiber layer (pRNFL) thickness is widely used for evaluation of retinal nerve fiber rarefaction in several optic neuropathies. This study evaluates associations of pRNFL thickness in healthy adult subjects in order to evaluate influencing factors. METHODS: A cross-sectional study was performed in a working-age population. Only eyes without detectable ocular pathologies were included in the analysis. Among analyzed systemic cardiovascular parameters were age, gender, body-mass index, mean arterial blood pressure, HbA1c, high- and low-density-lipoproteins, and triglycerides. A comprehensive ophthalmological examination including refraction, tonometry, keratometry, and central corneal thickness measurmentwas performed. In addition, pRNFL thickness was imaged by spectral-domain OCT. Univariable and multivariable associations of pRNFL thickness in all four quadrants and on average with systemic and ocular parameters were calculated using a generalized estimating equation model. RESULTS: Three hundred and six subjects were included. pRNFL thickness measurements showed a significant association with spherical equivalent: pRNFL thickness decreased with increasing myopia in all quadrants (multivariable regression coefficients Beta: superior: 1.16, 95 % CI [0.62;1.71], p < 0.001; temporal: 0.87, [0.33;1.41], p = 0.001; inferior: 1.80, [1.18;2.42], p < 0.001; nasal: 2.60, [2.01;3.20], p < 0.001) and on average (1.51, [1.20;1.82], p < 0.001). A thicker central cornea thickness was related to lower pRNFL in the superior (-0.05, [-0.10; -0.01], p = 0.01), the inferior quadrant (-0.05, [ 0.10;0.00], p = 0.03) and on average (-0.04, [-0.07; -0.01], p = 0.02). All other parameters were not associated. CONCLUSION: Our findings highlight the importance of refraction when evaluating pRNFL thickness and its independence from other systemic parameters. PMID- 27468714 TI - P2RX7-V3 is a novel oncogene that promotes tumorigenesis in uveal melanoma. AB - Uveal melanoma (UM) has a high mortality rate for primary intraocular tumors. Approximately half of UM patients present with untreatable and fatal metastases. Long non-coding RNAs (lncRNAs) have emerged as potent regulatory RNAs that play key roles in various cellular processes and tumorigenesis. However, to date, their roles in UM are not well-known. Here, we identified a transcriptional variant transcribed from the P2RX7 gene locus, named P2RX7-V3 (P2RX7 variant 3), which was expressed at a high level in UM cells. P2RX7-V3 silencing revealed that this variant acts as a necessary UM oncoRNA. Knockdown of P2RX7-V3 expression significantly suppressed tumor growth in vitro and in vivo. A genome-wide cDNA array revealed that a variety of genes were dysregulated following P2RX7-V3 silencing. These observations identified P2RX7-V3 that plays a crucial role in UM tumorigenesis and may serve as a useful biomarker in the diagnosis and prognosis treatment of UM in the future. PMID- 27468715 TI - Investigation of N-cadherin/beta-catenin expression in adrenocortical tumors. AB - beta-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound beta-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). beta-catenin mutations were evaluated by sequencing, and beta-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in beta-catenin gene. qRT-PCR showed overexpression of beta-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear beta catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. beta-catenin overexpression together with the aberrant expression of N cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and beta-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools. PMID- 27468717 TI - miR-137 plays tumor suppressor roles in gastric cancer cell lines by targeting KLF12 and MYO1C. AB - Aberrant expression of miR-137 has been reported in many kinds of cancers, but its mechanisms seem to be diversely. In the present study, we compared the expression level of miR-137 in 18 paired gastric cancer (GC) samples and surgical margin (SM) samples by RNA extraction and quantitative real-time PCR (QRT-PCR). Then, we investigated the effects of miR-137 on cell proliferation, cell cycle, and cell migration separately by cell growth counting assay, cell cycle analysis, and transwell assay. Candidate targets of miR-137 were selected by biological information analysis from the intersection of miRDB, Pictar, and TarScan. Finally, mRNA and protein expression level of Kruppel-like factor 12 (KLF12) and Myosin 1C (MYO1C) were tested by QRT-PCR and western blotting assay, followed by the Luciferase reporter assay to investigate the direct interaction between them and miR-137. The results showed that miR-137 was down-regulated in GC samples than in SM samples. The expression level of miR-137 was significantly higher in patients without the vascular embolus than those with vascular embolus. And the overall survival time of patients with high miR-137 expression was longer than those with low miR-137 expression. Over expression of miR-137 could inhibit the cell migration, proliferation, and promote cell cycle arrest in G0/G1 stage in BGC-823 and SGC-7901 cell lines. KLF12 and MYO1C might be the candidate target genes of miR-137 with direct interactions between them and miR-137. In conclusion, miR-137 plays tumor suppressor roles in gastric cancer cell lines by targeting KLF12 and MYO1C. PMID- 27468716 TI - Molecular targets of curcumin for cancer therapy: an updated review. AB - In recent years, natural edible products have been found to be important therapeutic agents for the treatment of chronic human diseases including cancer, cardiovascular disease, and neurodegeneration. Curcumin is a well-known diarylheptanoid constituent of turmeric which possesses anticancer effects under both pre-clinical and clinical conditions. Moreover, it is well known that the anticancer effects of curcumin are primarily due to the activation of apoptotic pathways in the cancer cells as well as inhibition of tumor microenvironments like inflammation, angiogenesis, and tumor metastasis. In particular, extensive studies have demonstrated that curcumin targets numerous therapeutically important cancer signaling pathways such as p53, Ras, PI3K, AKT, Wnt-beta catenin, mTOR and so on. Clinical studies also suggested that either curcumin alone or as combination with other drugs possess promising anticancer effect in cancer patients without causing any adverse effects. In this article, we critically review the available scientific evidence on the molecular targets of curcumin for the treatment of different types of cancer. In addition, we also discuss its chemistry, sources, bioavailability, and future research directions. PMID- 27468718 TI - Identification of MGMT promoter methylation sites correlating with gene expression and IDH1 mutation in gliomas. AB - O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation was reported to be an independent prognostic and predictive factor in glioma patients who received temozolomide treatment. However, the predictive value of MGMT methylation was recently questioned by several large clinical studies. The purpose of this study is to identify MGMT gene promoter CpG sites or region whose methylation were closely correlated with its gene expression to elucidate this contradictory clinical observations. The methylation status for all CpG dinucleotides in MGMT promoter and first exon region were determined in 42 Chinese glioma patients, which were then correlated with MGMT gene expression, IDH1 mutation, and tumor grade. In whole 87 CpG dinucleotides analyzed, three distinct CpG regions covering 28 CpG dinucleotides were significantly correlated with MGMT gene expression; 10 CpG dinucleotides were significantly correlated with glioma classification (p < 0.05). Isocitrate dehydrogenase 1 (IDH1) mutation and MGMT gene hypermethylation significantly co-existed, but not for MGMT gene expression. The validation cohort of gliomas treated with standard of care and comparison of the CpGs we identified with the current CpGs used in clinical setting will be very important for gliomas individual medicine in the future. PMID- 27468719 TI - Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO/EPO-R system and hypoxia-related proteins. AB - Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas. There is great interest to know the molecular basis of the tumor biology of ccRCC that might contribute to a better understanding of the aggressive biological behavior of this cancer and to identify early biomarkers of disease. This study describes the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (hypoxia-inducible factor (HIF)-1alpha, erythropoietin (EPO), vascular endothelial growth factor (VEGF)), their receptors (EPO-R, VEGFR-2), and stearoyl desaturase-1 (SCD-1) in early stages of ccRCC. Tissue samples were obtained at the Urology Unit of the J.R. Vidal Hospital (Corrientes, Argentina), from patients who underwent radical nephrectomy for renal cancer between 2011 and 2014. Four experimental groups according to pathological stage and nuclear grade were organized: T1G1 (n = 6), T2G1 (n = 4), T1G2 (n = 7), and T2G2 (n = 7). The expression of HIF-1alpha, EPO, EPO-R, VEGF, VEGFR-2, Bcl-xL, and SCD-1 were evaluated by immunohistochemistry, Western blotting, and/or RT-PCR. Apoptosis was assessed by the TUNEL in situ assay, and tumor proliferation was determined by Ki 67 immunohistochemistry. Data revealed that HIF-1alpha, EPO, EPO-R, VEGF, and VEGF-R2 were overexpressed in most samples. The T1G1 group showed the highest EPO levels, approximately 200 % compared with distal renal tissue. Bcl-xL overexpression was concomitant with the enhancement of proliferative indexes. SCD 1 expression increased with the tumor size and nuclear grade. Moreover, the direct correlations observed between SCD-1/HIF-1alpha and SCD-1/Ki-67 increments suggest a link among these molecules, which would determine tumor progression in early stages of ccRCC. Our results demonstrate the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (HIF-1alpha, EPO, VEGF), their receptors (EPO-R, VEGFR 2), and SCD-1 in early stages of ccRCC. PMID- 27468720 TI - Biomarkers of genome instability and cancer epigenetics. AB - Tumorigenesis is a multistep process involving genetic and epigenetic alterations that drive somatic evolution from normal human cells to malignant derivatives. Collectively, genetic and epigenetic alterations might be combined into biomarkers for the assessment of risk, the detection of early stage tumors, and accurate tumor characterization before and after treatment. Recent efforts have provided systematic approaches to cancer genomics through the application of massive sequencing of specific tumor types. Here, we review biomarkers of genome instability and epigenetics. Cancer evolvability and adaptation emerge through genetic and epigenetic lesions of a variety of sizes and qualities-from point mutations and small insertions/deletions to large-scale chromosomal rearrangements, alterations in whole chromosome copy number, preferential allelic expression of cancer risk alleles, and mechanisms that increase tumor mutation rates. We also review specific epigenetic mechanisms that facilitate or hinder tumor adaptation, including DNA methylation, histone modification, nucleosome remodeling, transcription factor activity, and small non-coding RNAs. Given the complexity of the carcinogenic process, the challenge ahead will be to interpret disparate signals across hundreds of genes and summarize these signals into a single actionable diagnosis that translates into specific treatments. Another challenge is to refine preventive efforts through the identification of epigenetic processes that mediate increased cancer rates in individuals exposed to sources of toxic environmental stress and pollution, specially through development and early childhood. PMID- 27468721 TI - Identification of aldolase A as a potential diagnostic biomarker for colorectal cancer based on proteomic analysis using formalin-fixed paraffin-embedded tissue. AB - Colorectal cancer (CRC) is one of the most common cancers worldwide, and many patients are already at an advanced stage when they are diagnosed. Therefore, novel biomarkers for early detection of colorectal cancer are required. In this study, we performed a global shotgun proteomic analysis using formalin-fixed and paraffin-embedded (FFPE) CRC tissue. We identified 84 candidate proteins whose expression levels were differentially expressed in cancer and non-cancer regions. A label-free semiquantitative method based on spectral counting and gene ontology (GO) analysis led to a total of 21 candidate proteins that could potentially be detected in blood. Validation studies revealed cyclophilin A, annexin A2, and aldolase A mRNA and protein expression levels were significantly higher in cancer regions than in non-cancer regions. Moreover, an in vitro study showed that secretion of aldolase A into the culture medium was clearly suppressed in CRC cells compared to normal colon epithelium. These findings suggest that decreased aldolase A in blood may be a novel biomarker for the early detection of CRC. PMID- 27468722 TI - miRNA-regulated cancer stem cells: understanding the property and the role of miRNA in carcinogenesis. AB - Over the last few years, microRNAs (miRNA)-controlled cancer stem cells have drawn enormous attention. Cancer stem cells are a small population of tumor cells that possess the stem cell property of self-renewal. Recent data shows that miRNA regulates this small population of stem cells. In the present review, we explained different characteristics of cancer stem cells as well as miRNA regulation of self-renewal and differentiation in cancer stem cells. We also described the migration and tumor formation. Finally, we described the different miRNAs that regulate various types of cancer stem cells, such as prostate cancer stem cells, head and neck cancer stem cells, breast cancer stem cells, colorectal cancer stem cells, lung cancer stem cells, gastric cancer stem cells, pancreatic cancer stem cells, etc. Extensive research is needed in order to employ miRNA based therapeutics to control cancer stem cell population in various cancers in the future. PMID- 27468723 TI - Downregulated expression of DIXDC1 in hepatocellular carcinoma and its correlation with prognosis. AB - Dishevelled-Axin domain containing 1 (DIXDC1) is a DIX (Dishevelled-Axin) domain possessing protein that acts as a positive regulator of the Wnt pathway. Although DIXDC1 has been investigated in several cancers, it has not yet been studied in human hepatocellular carcinoma (HCC). The purpose of the current study was to investigate the expression pattern of DIXDC1 and assess the clinical significance of DIXDC1 expression in HCC patients. Data containing three independent investigations from Oncomine database demonstrated that DIXDC1 mRNA was downregulated in HCC compared with matched non-cancerous tissues. Similar results were also obtained in 25 paired HCC tissues and corresponding non-cancerous tissues by qPCR and Western blot analysis. Additionally, another independent set of 140 pairs of HCC specimens was evaluated for DIXDC1 expression by IHC and demonstrated that reduced expression of DIXDC1 in 50.7 % (71/140) of HCC tissues was significantly correlated with tumor size (p = 0.024), tumor differentiation (p < 0.001), tumor thrombi (p = 0.019), TNM stage (p = 0.019), and BCLC stage (p = 0.008). Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC patients and found that DIXDC1 protein expression was one of the independent prognostic factors for overall survival of HCC patients. PMID- 27468724 TI - Association of variants in BAFF (rs9514828 and rs1041569) and BAFF-R (rs61756766) genes with the risk of chronic lymphocytic leukemia. AB - The B-cell activator factor (BAFF)/BAFF receptor (BAFF-R) axis seems to play an important role in the development and progression of chronic lymphocytic leukemia (CLL). Here, we investigated the association of eight single nucleotide polymorphisms (SNPs) in the BAFF (TNFSF13B) and BAFF-R (TNFRSF13C) genes with risk of sporadic CLL in a group of 439 CLL patients and 477 controls. We also examined the correlation between selected SNPs and CLL clinical parameters as well as BAFF plasma levels and intracellular BAFF expression. Our results point to a possible association between the rs9514828 (CT vs. CC + TT; OR = 0.74; CI 95 % = 0.57; 0.97; p = 0.022) and rs1041569 (AT vs. AA + TT; OR = 0.72; CI 95 % = 0.54; 0.95; p = 0.021) of BAFF gene and rs61756766 (CC vs. CT; OR = 2.03; CI 95 % = 1.03; 3.99; p = 0.03) of BAFF-R gene and CLL risk. Additionally, we observed that homozygotes rs1041569 AA and TT had a slightly higher risk (HR = 1.12) for the need of treatment in comparison to AT heterozygotes. In conclusion, our results indicate that SNPs in BAFF and BAFF-R genes may be considered as potential CLL risk factors. PMID- 27468726 TI - Validation of the Danish version of the Critical Care Pain Observation Tool. AB - BACKGROUND: Assessing pain in critically ill patients is a challenge even in an intensive care unit (ICU) with a no sedation protocol. The aim of this study was to validate the Danish version of the pain assessment method; Critical Care Pain Observation Tool (CPOT) in an ICU with a no sedation protocol. METHODS: Seventy patients were included in this study. The patients were observed during a non nociceptive procedure (wash of an arm) and a nociceptive procedure (turning). Patients were observed before, during, and 15 min after the two interventions (six assessments). Two observers participated in the data collection and CPOT scores were blinded to each other. Calculations of interrater reliability, criterion validity and discriminant validity were performed to validate the Danish version of CPOT. RESULTS: The results indicated a good correlation between the two raters (all scores > 0.9 and P < 0.05). About 48 (68.6%) of the included patients were able to self-report pain. We found a significantly higher mean CPOT score at the nociceptive procedure than at rest or the non-nociceptive procedure (P < 0.05). No correlation was found between CPOT scores and physiological indicators. Patients self-reported pain and CPOT showed a significant correlation (P < 0.05). A CPOT score of >= 3 correlated with patients' self-reported pain (ROC AUC 0.83). CONCLUSION: The Danish version of CPOT can be used to assess pain in critically ill patients, also when the ICU has a no sedation protocol. CPOT scores showed a good interrater reliability and correlates well with patient's self-reported pain. PMID- 27468725 TI - Dimethylfumarate inhibits melanoma cell proliferation via p21 and p53 induction and bcl-2 and cyclin B1 downregulation. AB - Recent evidence suggests that dimethylfumarate (DMF), known as a highly potent anti-psoriatic agent, might have anti-tumorigenic properties in melanoma. It has recently been demonstrated that DMF inhibits melanoma proliferation by apoptosis and cell cycle inhibition and therefore inhibits melanoma metastasis. Nonetheless, the underlying mechanisms remain to be evaluated. To elucidate the effects of DMF on melanoma cell lines (A375, SK-Mel), we first performed cytotoxicity assays. No significant lactatedehydogenase (LDH) release could be found. In further analysis, we showed that DMF suppresses melanoma cell proliferation in a concentration-dependent manner. To examine whether these effects are conveyed by apoptotic mechanisms, we studied the amount of apoptotic nucleosomes and caspase 3/7 activity using ELISA analysis. Significant apoptosis was induced by DMF in both cell lines, and this could be paralleled with bcl-2 downregulation and PARP-1 cleavage. We also performed cell cycle analysis and found that DMF induced concentration-dependent arrests of G0/G1 as well as G2/M. To examine the underlying mechanisms of cell cycle arrest, we analyzed the expression profiles of important cell cycle regulator proteins such as p53, p21, cyclins A, B1, and D1, and CDKs 3, 4, and 6. Interestingly, DMF induced p53 and p21 yet inhibited cyclin B1 expression in a concentration-dependent manner. Other cell cycle regulators were not influenced by DMF. The knockdown of DMF induced p53 via siRNA led to significantly reduced apoptosis but had no influence on cell cycle arrest. We examined the adhesion of melanoma cells on lymphendothelial cells during DMF treatment and found a significant reduction in interaction. These data provide evidence that DMF inhibits melanoma proliferation by reinduction of important cell cycle inhibitors leading to a concentration dependent G0/G1 or G2/M cell cycle arrest and induction of apoptosis via downregulation of bcl-2 and induction of p53 and PARP-1 cleavage. Hence, DMF might be an interesting agent in the treatment of melanoma and is worth further investigation in vivo. PMID- 27468727 TI - In vivo confocal microscopy of brachycephalic dogs with and without superficial corneal pigment. AB - OBJECTIVE: To characterize canine superficial corneal pigment (SCP) in brachycephalic dogs using in vivo confocal microscopy (IVCM). ANIMALS STUDIED: Fifty-seven client-owned brachycephalic dogs from breeds predisposed to SCP (i.e., Boston Terrier, Lhasa Apso, Pekingese, Pug, and Shih Tzu). PROCEDURES: Complete ocular examination, including slit-lamp biomicroscopy, was used to determine presence or absence of SCP, and IVCM examinations were then performed. Clinical and IVCM abnormalities were recorded using a standardized scoring system and statistically compared between dogs with and without SCP. Dogs were split into two groups for analysis; Pugs and non-Pug breeds. RESULTS: Of the 57 dogs examined, 32 were Pugs and 25 were non-Pug breeds. Twenty-three Pugs (71.8%) and 10 non-Pugs (40%) displayed SCP. Six of 13 evaluated IVCM features were significantly (P < 0.05) associated with SCP in both Pugs and non-Pugs and included superficial epithelial pigment, basal epithelial pigment, Langerhans cells, anterior stromal dendritic cells, epithelial disorganization, and vascularization. Additionally, superficial epithelial leukocytes and anterior stromal dendritic cells were significantly associated with SCP in Pugs only. Many of the IVCM features associated with SCP were also observed in SCP unaffected dogs; however, they were present at a reduced frequency and confined to the perilimbal region of the cornea. CONCLUSIONS: By IVCM, SCP in dogs is characterized by microscopic features of chronic inflammation. Abnormalities were superficial and largely confined to the corneal epithelium. Superficial pigment in brachycephalic dogs appears morphologically as a centripetal corneal migration of microanatomic features normally confined to the perilimbal region of the cornea. PMID- 27468728 TI - Real-Time Cellular Imaging of Protein Poly(ADP-ribos)ylation. AB - Poly(ADP-ribos)ylation (PARylation) is an important posttranslational protein modification, and is involved in major cellular processes such as gene regulation and DNA repair. Its dysregulation has been linked to several diseases, including cancer. Despite its importance, methods to observe PARylation dynamics within cells are rare. By following a chemical biology approach, we developed a fluorescent NAD(+) analogue that proved to be a competitive building block for protein PARylation in vitro and in cells. This allowed us to directly monitor the turnover of PAR in living cells at DNA damage sites after near-infrared (NIR) microirradiation. Additionally, covalent and noncovalent interactions of selected target proteins with PAR chains were visualized in cells by using FLIM-FRET microscopy. Our results open up new opportunities for the study of protein PARylation in real time and in live cells, and will thus contribute to a better understanding of its significance in a cellular context. PMID- 27468729 TI - Social media and professionalism: does the profession need to re-think the parameters of professionalism within social media? AB - Social media is no longer a new concept, with social media platforms dominating how many communicate. It would be unrealistic to expect that dentistry would not become involved in the use of social media for professional reasons, as well as professionals using social media platforms privately. Despite it being acceptable for dental professionals to have social media presence, those dental professionals have a framework of professional, ethical and legal obligations to which they must conform when using social media. This article seeks to discuss how unintentionally professionalism may be breached by dental professionals not making a distinction between social media and other facets of professional life. There is need for a discussion about how as a profession, dentistry may perceive the effects of professional interaction with social media on the profession's wider relationship with society and whether current regulatory advice goes far enough to protecting the interests of patients. It is important for the use of social media by dental professionals to fit within the established social contract between the profession and society and failure to observe the terms of this will cause damage to the patient-professional relationship. PMID- 27468730 TI - Recurrent pleomorphic adenoma of the parotid gland: Institutional experience and review of the literature. AB - BACKGROUND: Recurrent pleomorphic adenoma (PA) of the parotid gland is a challenging surgical issue with controversy regarding management and long term outcome. METHODS: All patients who were operated for recurrent PA of the parotid gland between the years 1991 and 2013 were reviewed. Patient demographics, clinicopathologic variables, and operative details were collected retrospectively. RESULTS: A total of 22 patients were operated for recurrent PA of the parotid gland. Mean interval between recurrences was 7 and 6 years for first recurrence and second recurrence, accordingly. Second recurrence was significantly influenced by younger age at initial treatment (P = 0.009). Only two patients (9%) with a recurrence developed facial nerve paralysis following surgery. Adjuvant radiotherapy was given to nine patients with no evidence of disease progression or recurrence. There were no cases of malignant transformation. CONCLUSIONS: Recurrent PA of the parotid gland tends to occur in long intervals in a multifocal pattern. Adjuvant radiotherapy could be suggested as an alternative for surgery. J. Surg. Oncol. 2016;114:714-718. (c) 2016 Wiley Periodicals, Inc. PMID- 27468731 TI - Radiofrequency Ablation of Atrial Fibrillation: Nonrandomized Comparison of Circular versus Point-by-Point "Smart" Ablation for Achieving Circumferential Pulmonary Vein Isolation and Curing Arrhythmic Symptoms. AB - INTRODUCTION: Pulmonary vein isolation (PVI) with radiofrequency (RF) ablation is now standard care for atrial fibrillation (AF). New improvements in PVI techniques include use of catheters that measure contact-force and circular ablation catheters. These techniques have not been compared. METHODS AND RESULTS: We compared the success rate of circumferential pulmonary vein isolation (CPVI) with: (1) "point by point" RF using an irrigated tip ablation catheter with "smart touch" contact-force; (2) irrigated nMARQ circular ablation catheter in 86 patients with AF. The endpoints of the study were acute and long-term success rate of CPVI. The 2 groups had similar characteristics: Smart Touch group with 50 patients, age 62 +/- 8 years, 64% male; nMARQ group with 36 patients, 75% male, age 58.7 +/- 10 years. The type of AF was similar in the 2 groups: paroxysmal and persistent in 68% and 32% in the Navistar group versus 64% and 36% in the nMARQ group. Follow-up periods were similar (18.4 months vs. 19 months, P = 0.59). All the pulmonary veins were successfully isolated in both groups. However, PVI could not be achieved with the nMARQ in 2.7% of the pulmonary veins ablated and was completed with a Smart Touch. The long-term success rate was comparable in the 2 groups. CONCLUSION: The nMARQ and Smart Touch catheters give similar results in PVI of both paroxysmal and persistent AF. The procedural time was shorter with the nMARQ in paroxysmal AF. Need for crossover from nMARQ to Smart Touch occurred in 2.7% of PVs ablated. PMID- 27468732 TI - A cost-effectiveness modelling study of strategies to reduce risk of infection following primary hip replacement based on a systematic review. AB - BACKGROUND: A deep infection of the surgical site is reported in 0.7% of all cases of total hip arthroplasty (THA). This often leads to revision surgery that is invasive, painful and costly. A range of strategies is employed in NHS hospitals to reduce risk, yet no economic analysis has been undertaken to compare the value for money of competing prevention strategies. OBJECTIVES: To compare the costs and health benefits of strategies that reduce the risk of deep infection following THA in NHS hospitals. To make recommendations to decision makers about the cost-effectiveness of the alternatives. DESIGN: The study comprised a systematic review and cost-effectiveness decision analysis. SETTING: 77,321 patients who had a primary hip arthroplasty in NHS hospitals in 2012. INTERVENTIONS: Nine different treatment strategies including antibiotic prophylaxis, antibiotic-impregnated cement and ventilation systems used in the operating theatre. MAIN OUTCOME MEASURES: Change in the number of deep infections, change in the total costs and change in the total health benefits in quality-adjusted life-years (QALYs). DATA SOURCES: Literature searches using MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Central Register of Controlled Trials were undertaken to cover the period 1966-2012 to identify infection prevention strategies. Relevant journals, conference proceedings and bibliographies of retrieved papers were hand-searched. Orthopaedic surgeons and infection prevention experts were also consulted. REVIEW METHODS: English-language papers only. The selection of evidence was by two independent reviewers. Studies were included if they were interventions that reported THA-related deep surgical site infection (SSI) as an outcome. Mixed treatment comparisons were made to produce estimates of the relative effects of competing infection control strategies. RESULTS: Twelve studies, six randomised controlled trials and six observational studies, involving 123,788 total hip replacements (THRs) and nine infection control strategies, were identified. The quality of the evidence was judged against four categories developed by the National Institute for Health and Care Excellence Methods for Development of NICE Public Health Guidance ( http://publications.nice.org.uk/methods-for-the development-of-nice-public-health-guidance-third-edition-pmg4 ), accessed March 2012. All evidence was found to fit the two highest categories of 1 and 2. Nine competing infection control interventions [treatments (Ts) 1-9] were used in a cohort simulation model of 77,321 patients who had a primary THR in 2012. Predictions were made for cases of deep infection and total costs, and QALY outcomes. Compared with a baseline of T1 (no systemic antibiotics, plain cement and conventional ventilation) all other treatment strategies reduced risk. T6 was the most effective (systemic antibiotics, antibiotic-impregnated cement and conventional ventilation) and prevented a further 1481 cases of deep infection, and led to the largest annual cost savings and the greatest gains to QALYs. The additional uses of laminar airflow and body exhaust suits indicate higher costs and worse health outcomes. CONCLUSIONS: T6 is an optimal strategy for reducing the risk of SSI following THA. The other strategies that are commonly used among NHS hospitals lead to higher cost and worse QALY outcomes. Policy-makers, therefore, have an opportunity to save resources and improve health outcomes. The effects of laminar air flow and body exhaust suits might be further studied if policy-makers are to consider disinvesting in these technologies. LIMITATIONS: A wide range of evidence sources was synthesised and there is large uncertainty in the conclusions. FUNDING: The National Institute for Health Research Health Technology Assessment programme and the Queensland Health Quality Improvement and Enhancement Programme (grant number 2008001769). PMID- 27468733 TI - A novel mouthpiece prevents bite injuries caused by intraoperative transcranial electric motor-evoked potential monitoring. AB - PURPOSE: Intraoperative transcranial motor-evoked potential monitoring causes contraction of the masseter muscles, which may cause injuries to the oral cavity and damage to the orotracheal tube. We developed a mouthpiece made from vinyl silicone impression material to prevent these injuries. The purpose of this study was to examine its efficacy and safety. METHODS: Twenty-two patients undergoing spinal surgery under transcranial motor-evoked potential monitoring were fitted with bespoke vinyl-silicone mouthpieces by dentists before surgery. On induction of general anesthesia and orotracheal intubation, the mouthpiece was attached to the upper and lower dental arches. A lateral cervical X-ray was taken at the end of surgery to examine the condition of the orotracheal tube. The incidence of endotracheal tube deformation was compared with an historic control group of 20 patients in whom a conventional gauze bite block had been previously used before induction of the mouthpiece. The oral cavity was examined by a dentist the day before surgery and 3 days postoperatively, and intraoral injuries were recorded. RESULTS: No endotracheal tube deformation was found in 22 patients fitted with the new mouthpiece. The incidence of tube deformation (none of 22 patients, 0 %) was significantly lower than in those who had been fitted with the gauze bite block (9 of 20 patients, 45.0 %; p < 0.001). Application of the mouthpiece resulted in no tongue or tooth injuries. CONCLUSION: A novel mouthpiece reduced the incidence of damage to the endotracheal tube caused by intraoperative transcranial motor-evoked potential monitoring. PMID- 27468734 TI - Acute left ventricle failure on induction of anesthesia: a case report of reverse stress cardiomyopathy-presentation, diagnosis and treatment. AB - Reverse takotsubo cardiomyopathy (TCM) is a less common variant of classic TCM that presents within a different patient profile and with its own hemodynamic considerations. A 46-year-old woman was admitted to our hospital for laryngoscopy and possible balloon dilatation for tracheal stenosis under general anesthesia. One year prior to this admission, the patient was admitted after a motor vehicle accident with subdural hematoma, subarachnoid hemorrhage, and fracture of the eighth thoracic vertebra. She underwent uneventful anesthesia for thoracic spine surgery and tracheostomy to help her wean from the ventilator during that admission. Since her previous admission, she developed posttraumatic anxiety and depression (a neuropsychiatric disorder triggered by subdural hematoma and subarachnoid hemorrhage) and was treated with antianxiety and antidepressant medication. At this admission, the patient developed acute left ventricle failure on induction of anesthesia secondary to reverse TCM. We report a case of reverse TCM, where posttraumatic emotional stress of a neuropsychiatric disorder combined with physical stress from anesthesia and laryngoscopy triggered TCM in a patient with previous uneventful anesthesia 1 year earlier. PMID- 27468735 TI - Finer gauge of cutting but not pencil-point needles correlate with lower incidence of post-dural puncture headache: a meta-regression analysis. AB - PURPOSE: Post-dural puncture headache (PDPH) is a well-known neurological outcome caused by leakage of cerebrospinal fluid during neuraxial anesthesia. Studies aimed at assessing the efficacy of finer gauged spinal needles to reduce the incidence of PDPH have produced conflicting results. We have therefore examined the effect of the gauge of cutting needles and pencil-point needles, separately, on the incidence of PDPH. METHODS: The PubMed, EMBASE and Google Scholar databases were searched for randomized studies which compared PDPH incidence in a head-to-head analysis of individual needle gauges of similar needle designs (cutting and pencil-point). A meta-regression analysis was performed taking into account various covariates, such as needle gauge and design, mean age of patient population, surgery type, percentage of males and females in study population and year of publication. RESULTS: Of the 22 studies (n = 5631) included in the analysis, 12 (n = 3148) and ten (n = 2483) compared different gauges of cutting needles and pencil-point needles, respectively. After adjusting for covariates, meta-regression analysis was performed for all studies that randomly compared individual needle gauges of similar needle design. Whereas the incidence of PDPH inversely correlated with gauge in cutting needles (beta = -1.36 % per gauge, P = 0.037), no relationship was noted in pencil-point needles (beta = -0.32 % per gauge, P = 0.114). Female gender was the only covariate that reached a statistically significant correlation with the incidence of PDPH in both models. CONCLUSIONS: A significant relationship between needle gauge and subsequent rate of PDPH was noted in cutting needles, but not pencil-point needles. PMID- 27468736 TI - Sedation choices and mortality: a well-defined tandem? PMID- 27468737 TI - Emergency surgical airway management in Denmark: a cohort study of 452 461 patients registered in the Danish Anaesthesia Database. AB - BACKGROUND: The emergency surgical airway (ESA) is the final option in difficult airway management. We identified ESA procedures registered in the Danish Anaesthesia Database (DAD) and described the performed airway management. METHODS: We extracted a cohort of 452 461 adult patients undergoing general anaesthesia and tracheal intubation from the DAD from June 1, 2008 to March 15, 2014. Difficult airway management involving an ESA was retrieved for analysis and compared with hospitals files. Two independent reviewers evaluated airway management according to the ASAs'2003 practice guideline for difficult airway management. RESULTS: In the DAD cohort 27 out of 452 461 patients had an ESA representing an incidence of 0.06 events per thousand (95% CI; 0.04 to 0.08). A total of 12 149/452 461 patients underwent Ear-Nose and Throat (ENT) surgery, giving an ESA incidence among ENT patients of 1.6 events per thousand (95% CI; 1.0-2.4). A Supraglottic Airway Device and/or the administration of a neuromuscular blocking agent before ESA were used as a rescue in 6/27 and 13/27 of the patients, respectively. In 19/27 patients ENT surgeons performed the ESA's and anaesthetists attempted 6/27 of the ESAs of which three failed. Reviewers evaluated airway management as satisfactory in 10/27 patients. CONCLUSIONS: The incidence of ESA in the DAD cohort was 0.06 events per thousand. Among ENT patients, the ESA Incidence was 1.6 events per thousand. Airway management was evaluated as satisfactory for 10/27 of the patients. ESA performed by anaesthetists failed in half of the patients. PMID- 27468738 TI - Site-specific water-use strategies of mountain pine and larch to cope with recent climate change. AB - We aim to achieve a mechanistic understanding of the eco-physiological processes in Larix decidua and Pinus mugo var. uncinata growing on north- and south-facing aspects in the Swiss National Park in order to distinguish the short- and long term effects of a changing climate. To strengthen the interpretation of the delta(18)O signal in tree rings and its coherence with the main factors and processes driving evaporative delta(18)O needle water enrichment, we analyzed the delta(18)O in needle, xylem and soil water over the growing season in 2013 and applied the mechanistic Craig-Gordon model (1965) for the short-term responses. We found that delta(18)O needle water strongly reflected the variability of relative humidity mainly for larch, while only delta(18)O in pine xylem water showed a strong link to delta(18)O in precipitation. Larger differences in offsets between modeled and measured delta(18)O needle water for both species from the south-facing aspects were detected, which could be explained by the high transpiration rates. Different soil water and needle water responses for the two species indicate different water-use strategies, further modulated by the site conditions. To reveal the long-term physiological response of the studied trees to recent and past climate changes, we analyzed delta(13)C and delta(18)O in wood chronologies from 1900 to 2013. Summer temperatures as well as summer and annual amount of precipitations are important factors for growth of both studied species from both aspects. However, mountain pine trees reduced sensitivity to temperature changes, while precipitation changes come to play an important role for the period from 1980 to 2013. Intrinsic water-use efficiency (WUEi) calculated for larch trees since the 1990s reached a saturation point at elevated CO2 Divergent trends between pine WUEi and delta(18)O are most likely indicative of a decline of mountain pine trees and are also reflected in decoupling mechanisms in the isotope signals between needles and tree-rings. PMID- 27468739 TI - Nonalcoholic Fatty Liver Disease in Patients with Autoimmune Hepatitis: Further Reason for Teeth GNASHing? PMID- 27468740 TI - Portosystemic Shunts for "Small for Size Syndrome" Following Liver Transplantation: A Philosopher's Stone? PMID- 27468741 TI - An Online Tool for Global Benchmarking of Risk-Adjusted Surgical Outcomes. AB - BACKGROUND: Increasing evidence demonstrates significant variation in adverse outcomes following surgery between countries. In order to better quantify these variations, we hypothesize that freely available online risk calculators can be used as a tool to generate global benchmarking of risk-adjusted surgical outcomes. METHODS: This is a prospective cohort study conducted at an academic teaching hospital in South Africa (GSH). Consecutive adult patients undergoing major general or vascular surgery who met the ACS-NSQIP inclusion criteria for a 3-month period were included. Data variables required by the ACS risk calculator were prospectively collected, and patients were followed for 30 days post-surgery for the occurrence of endpoints. Calculating observed-to-expected ratios for ten outcome measures of interest generated risk-adjusted outcomes benchmarked against the ACS-NSQIP consortium. RESULTS: A total of 373 major general and vascular surgery procedures met the inclusion criteria. The GSH operative cohort varied significantly compared to the 2012 ACS-NSQIP database. The risk-adjusted O/E ratios were significant for any complication O/E 1.91 (95 % CI 1.57-2.31), surgical site infections O/E 4.76 (95 % CI 3.71-6.01), renal failure O/E 3.29 (95 % CI 1.50-6.24), death O/E 3.43 (95 % CI 2.19-5.11), and total length of stay (LOS) O/E 3.43 (95 % CI 2.19-5.11). CONCLUSION: Freely available online risk calculators can be utilized as tools for global benchmarking of risk-adjusted surgical outcomes. PMID- 27468742 TI - Population-Based Studies Should not be Used to Justify a Policy of Routine Cholangiography to Prevent Major Bile Duct Injury During Laparoscopic Cholecystectomy. AB - Iatrogenic bile duct injury at time of cholecystectomy is a rare but devastating event. A twofold higher frequency of bile duct injury during cholecystectomy without cholangiography is reported in population-based studies. Some interpret this as a cause-and-effect relationship and thus mandate routine cholangiography. A critical appraisal of population studies is required to determine whether these studies are suitable in determining the role of routine cholangiography. The literature search was performed using combinations of the forced search terms "duct injury", "population" and "cholangiography" to identify population-based studies assessing the relationship between cholangiography and iatrogenic bile duct injury. All seven population-based studies reported a numerically higher rate of bile duct injury when an intraoperative cholangiogram was not obtained during cholecystectomy. Five predate the critical view technique. Only one was limited to laparoscopic cholecystectomy. All studies identified cholangiography as a likely marker for disease severity or surgical technique. Six studies did not demonstrate a cause-and-effect relationship by not including effect modifiers. The only study to address confounders reported the same rate of injury irrespective of the use of cholangiography. Critical appraisal of population based studies does not support their use in justifying a policy of routine cholangiography to prevent major bile duct injury. PMID- 27468743 TI - Clinical Significance of the Pre-therapeutic Nodal Size in Patients Undergoing Neo-Adjuvant Treatment Followed by Esophagectomy for Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: The clinical significance of pre-therapeutic nodal size in patients with esophageal squamous cell carcinoma (ESCC) is not clear. We investigated whether nodal size was correlated with survival in patients undergoing neo adjuvant treatment followed by esophagectomy for ESCC. METHODS: In 2009-2013, 222 patients who underwent neo-adjuvant treatment followed by esophagectomy for ESCC were enrolled in this retrospective study. Nodal size was measured along the short axis of the largest node using pre-therapeutic CT images. Patients were then stratified based on this short axis, and nodal size was correlated with clinicopathological factors and survival. RESULTS: Patients with larger nodes were likely to have deeper cT, higher cN status, and poorer survival. Among the clinical factors cT, cN, cM, and nodal size, only cT and nodal size were independent prognostic factors in multivariate analysis [hazard ratio (HR) 2.0, 95 % confidence interval (CI) 1.1-3.5, p = 0.025 and HR 1.5, 95 % CI 1-2.3, p = 0.036, respectively]. In addition, nodal size was significantly associated with hematological recurrence (p = 0.007), but not lymphatic relapse (p = 0.272). CONCLUSIONS: The short axis of the largest node before neo-adjuvant treatment in patients with ESCC is a prognostic factor. PMID- 27468744 TI - Body-size spectra of biofilm-dwelling protozoa and their seasonal shift in coastal ecosystems. AB - Community-based assessment of protozoa is usually performed at a taxon-dependent resolution. As an inherent 'taxon-free' trait, however, body-size spectrum has proved to be a highly informative indicator to summarize the functional structure of a community in both community research and monitoring programs in aquatic ecosystems. To demonstrate the relationships between the taxon-free resolution of protozoan communities and water conditions, the body-size spectra of biofilm dwelling protozoa and their seasonal shift and environmental drivers were explored based on an annual dataset collected monthly from coastal waters of the Yellow Sea, northern China. Body sizes were calculated in equivalent spherical diameter (ESD). Among a total of 8 body-size ranks, S2 (19-27MUm), S3 (28-36MUm), S4 (37-50MUm) and S5 (53-71MUm) were the top four levels in frequency of occurrence, while rank S1 (13-17MUm), S2 and S4 were the dominant levels in abundance. These dominants showed a clear seasonal succession: S2/S4 (spring) >S2/S4 (summer)->S4 (autumn)->S2 (winter) in frequency of occurrence; S1 (spring) >S4 (summer)->S2 (autumn)->S1 (winter) in abundance. Bootstrapped average analysis showed a clear seasonal shift in body-size spectra of the protozoa during a 1-year cycle, and the best-matching analysis demonstrated that the temporal variations in frequency of occurrence and abundance were significantly correlated with water temperature, pH, dissolved oxygen (DO), alone or in combination with chemical oxygen demand (COD) and nutrients. Thus, the body-size spectra of biofilm-dwelling protozoa were seasonally shaped and might be used as a time and cost efficient bioindicator of water quality in marine ecosystems. PMID- 27468745 TI - Fibrophrys columna gen. nov., sp. nov: A member of the family Amphifilidae. AB - A novel Diplophrys-like organism, Fibrophrys columna, was isolated from Hiuchigaike Pond in Japan. F. columna showed a nearly orbicular or broadly elliptical cell shape and has fine filamentous, branching ectoplasmic elements emanating from both polar ends of the cell. Cells also contain orange, amber, or colorless lipid bodies. Although its whole cell morphology resembles that of the genus Diplophrys, Fibrophrys is clearly distinct from Diplophrys on the basis of 18S rDNA sequences. Molecular phylogenetic analysis showed a close relationship of F. columna with Amphifila marina, and its sequence is similar to many environmental stramenopile sequences. The cells of F. columna measured 5.0 8.3*5.6-10.3MUm and sometimes possessed hernia-like prongs instead of filamentous ectoplasmic elements. An axis-like electron-dense body was observed in the mitochondria. We also studied the ultrastructure of another Fibrophrys strain, Fibrophrys sp. E-1, which is different from the type strain of F. columna. A ladder-like pattern was recognized in the outer part of unidentified cytoplasmic membranes connected with the mitochondria. The unidentified cytoplasmic membranes were connected to the nuclear, lipid body, and mitochondrial outer membranes. We propose a new genus, Fibrophrys, and a new species, F. columna, based on these ultrastructural and molecular features. PMID- 27468746 TI - Blocking transient receptor potential vanilloid 2 channel in astrocytes enhances astrocyte-mediated neuroprotection after oxygen-glucose deprivation and reoxygenation. AB - Astrocytes play important roles in homeostatic regulation in the central nervous system and are reported to influence the outcome of ischemic injury. Regulating Ca2+ signaling of astrocytes is a promising strategy for stroke therapy. Herein, we report for the first time that transient receptor potential vanilloid 2 (TRPV2), a Ca2+ -permeable channel that is important in osmotic balance regulation, expresses in rat cortical astrocytes by immunofluorescence. Moreover, oxygen-glucose deprivation and reoxygenation (OGD/R) treatment enhanced the expression. The TRPV2 is functional because Ca2+ imaging showed that activating the TRPV2 channel in cultured astrocytes increased intracellular Ca2+ level and the increment of intracellular Ca2+ level expanded when astrocytes were treated with OGD/R. Staining with 5-ethynyl-2'-deoxyuridine (EdU) revealed that while blocking the TRPV2, it promoted the proliferation of astrocytes. Additionally, blocking the TRPV2 in astrocytes increased the synthesis of nerve growth factor (NGF) mRNA and the secretion of NGF by real-time PCR and enzyme-linked immunosorbent assay respectively. We further found that the increased secretion of NGF could be reversed by c-JunN-terminalkinase (JNK) inhibitor and blocking the TRPV2 caused the phosphorylation of JNK. These indicated that blocking the TRPV2 induced NGF secretion via the mitogen-activated protein kinase (MAPK)-JNK signaling pathway. As the promoted proliferation of astrocytes and secretion of NGF were reported to have neuroprotective effects in the early stage of stroke, we concluded that targeting the TRPV2 channel in astrocytes might be a potential new therapeutic strategy in ischemic stroke. PMID- 27468747 TI - Insulin-Like Growth Factor Axis and Gestational Diabetes Mellitus: A Longitudinal Study in a Multiracial Cohort. AB - The insulin-like growth factor (IGF) axis may be implicated in glucose homeostasis, but its longitudinal profile across gestation in relation to the development of gestational diabetes mellitus (GDM) is largely unknown. We prospectively investigated IGF axis biomarkers in early-to-midpregnancy in relation to subsequent GDM risk in a case-control study of 107 case subjects with GDM and 214 control subjects without GDM, with blood sample collection at gestational weeks 10-14, 15-26, 23-31, and 33-39. Conditional logistic regression was used, adjusting for major risk factors including prepregnancy BMI. Plasma IGF I and IGF binding protein 3 (IGFBP-3) concentrations and molar ratio of IGF-I to IGFBP-3 increased, whereas IGFBP-2 decreased throughout pregnancy. At gestational weeks 10-14, both IGF-I and IGF-I/IGFBP-3 were positively associated with GDM risk; adjusted odds ratio (OR) comparing the highest versus lowest quartile (ORQ4 Q1) was 2.93 (95% CI 1.18, 7.30) for IGF-I and 3.31 (1.10, 9.98) for IGF-I/IGFBP 3. In contrast, higher IGFBP-2 levels were related to a substantially lower risk of GDM (ORQ4-Q1 0.04 [0.01, 0.06]). Similar results were observed at gestational weeks 15-26. In sum, the IGF axis, IGFBP-2 in particular, may be implicated in the pathogenesis of GDM, with significant associations and incremental predictive value detected as early as gestational weeks 10-14, ~10-18 weeks earlier before GDM is typically screened for. PMID- 27468748 TI - Electrophysiological Study on Cognitive Function in Systemic Lupus Erythematosus Patients With Previous Neuropsychiatric Involvement. AB - This study aimed to evaluate P300 as an electrophysiological marker of cognitive function in patients with systemic lupus erythematosus (SLE) who had previous neuropsychiatric (NPSLE) involvement and were diagnosed to have cognitive impairment by standard neuropsychological tests. Event-related potentials (ERPs) were assessed by the auditory and visual oddball paradigms. Amplitude and latency of P300 at the frontal (Fz), central (Cz), and parietal (Pz) regions were determined and compared with controls. P300 detection was performed in NPSLE patients with pre-diagnosed cognitive impairment (n = 9), matched SLE patients without previous NPSLE (non-NPSLE) (n = 9), and healthy controls (n = 15). Auditory oddball task did not show any P300 abnormality between groups. Visual oddball task revealed reduced amplitude of P300 over Fz ( P = .002) and Cz ( P = .009) electrodes in NPSLE patients compared with healthy controls and among those who had predominant memory deficit ( P = .01 at Fz). Abnormal P300 was also observed in non-NPSLE patients at Fz and Cz. Using visual oddball paradigm, abnormal P300 was found in NPSLE patients over frontal and parietal regions compared with normal controls but was not discriminative from possible subclinical disease in non-NPSLE patients. In conclusion, visual oddball paradigm was a more sensitive electrophysiological marker than auditory oddball paradigm for cognitive impairment in NPSLE patients. PMID- 27468750 TI - Reactions in ultra-small droplets by tip-assisted chemistry. AB - The confinement of chemical reactions within small droplets has received much attention in the last few years. This approach has been proved successful for the in-depth study of naturally occurring chemical processes as well as for the synthesis of different sets of nanomaterials with control over their size, shape and properties. Different approaches such as the use of self-contained structures or microfluidic generated droplets have been followed over the years with success. However, novel approaches have emerged during the last years based on the deposition of femtolitre-sized droplets on surfaces using tip-assisted lithographic methods. In this feature article, we review the advances made towards the use of these ultra-small droplets patterned on surfaces as confined nano-reactors. PMID- 27468751 TI - Association between parent and child weight status among private school children in Delhi, India. AB - Over the past three decades there has been a surge in the prevalence of overweight and obesity worldwide in both adults and children. To date few studies have examined obesity in India and most have only looked at prevalence estimates. While studies in Western countries have identified parent weight status as a predictor of child weight status, there have been no studies examining this association in India. This study examined the relationship between parent weight status and child weight status using an internationally representative growth reference for children and Asian-specific action points for adults. Overall, this study found 29.6% of children and 77.7% of parents in a sample of private schools in Delhi, India were overweight/obese. Parent weight status was found to be associated with child weight status after controlling for child grade and sex. However, while maternal weight status was associated with child weight status (odds ratio=1.51, 95% confidence interval: 1.04-2.20), paternal weight status was not (odds ratio=1.10, 95% confidence interval: 0.81-1.48). The association was greatest between mothers and sons (odds ratio=2.13, 95% confidence interval: 1.39 3.27). These results provide initial evidence that parent weight status is associated with child weight status in Delhi, India. Future research should continue to explore the relationship between parent, particularly maternal, and child weight status to better understand the nature of the relationship and the differences between male and female children. Interventions to address child overweight and obesity in India should include parents as direct targets. PMID- 27468749 TI - Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus control cardiovascular reactivity and anxiety-like behavior in male mice. AB - This study tested the hypothesis that deletion of angiotensin type 1a receptors (AT1a) from the paraventricular nucleus of hypothalamus (PVN) attenuates anxiety like behavior, hypothalamic-pituitary-adrenal (HPA) axis activity, and cardiovascular reactivity. We used the Cre/LoxP system to generate male mice with AT1a specifically deleted from the PVN. Deletion of the AT1a from the PVN reduced anxiety-like behavior as indicated by increased time spent in the open arms of the elevated plus maze. In contrast, PVN AT1a deletion had no effect on HPA axis activation subsequent to an acute restraint challenge but did reduce hypothalamic mRNA expression for corticotropin-releasing hormone (CRH). To determine whether PVN AT1a deletion inhibits cardiovascular reactivity, we measured systolic blood pressure, heart rate, and heart rate variability (HRV) using telemetry and found that PVN AT1a deletion attenuated restraint-induced elevations in systolic blood pressure and elicited changes in HRV indicative of reduced sympathetic nervous activity. Consistent with the decreased HRV, PVN AT1a deletion also decreased adrenal weight, suggestive of decreased adrenal sympathetic outflow. Interestingly, the altered stress responsivity of mice with AT1a deleted from the PVN was associated with decreased hypothalamic microglia and proinflammatory cytokine expression. Collectively, these results suggest that deletion of AT1a from the PVN attenuates anxiety, CRH gene transcription, and cardiovascular reactivity and reduced brain inflammation may contribute to these effects. PMID- 27468752 TI - When hospitals switch to electronic records. PMID- 27468753 TI - Towards improved biomonitoring tools for an intensified sustainable multi-use environment. AB - The increasing use of our environment for multiple contrasting activities (e.g. fisheries, tourism) will have to be accompanied by improved monitoring of environmental quality, to avoid transboundary conflicts and ensure long-term sustainable intensified usage. Biomonitoring approaches are appropriate for this, since they can integrate biological effects of environmental exposure rather than measure individual compound concentrations. Recent advances in biomonitoring concepts and tools focus on single-cell assays and purified biological components that can be miniaturized and integrated in automated systems. Despite these advances, we are still very far from being able to deploy bioassays routinely in environmental monitoring, mostly because of lack of experience in interpreting responses and insufficient robustness of the biosensors for their environmental application. Further future challenges include broadening the spectrum of detectable compounds by biosensors, accelerate response times and combining sample pretreatment strategies with bioassays. PMID- 27468755 TI - Spasticity: the need for objective assessment. PMID- 27468754 TI - The puzzle of immune phenotypes of childhood asthma. AB - Asthma represents the most common chronic childhood disease worldwide. Whereas preschool children present with wheezing triggered by different factors (multitrigger and viral wheeze), clinical asthma manifestation in school children has previously been classified as allergic and non-allergic asthma. For both, the underlying immunological mechanisms are not yet understood in depth in children. Treatment is still prescribed regardless of underlying mechanisms, and children are not always treated successfully. This review summarizes recent key findings on the complex mechanisms of the development and manifestation of childhood asthma. Whereas traditional classification of childhood asthma is primarily based on clinical symptoms like wheezing and atopy, novel approaches to specify asthma phenotypes are under way and face challenges such as including the stability of phenotypes over time and transition into adulthood. Epidemiological studies enclose more information on the patient's disease history and environmental influences. Latest studies define endotypes based on molecular and cellular mechanisms, for example defining risk and protective single nucleotide polymorphisms (SNPs) and new immune phenotypes, showing promising results. Also, regulatory T cells and recently discovered T helper cell subtypes such as Th9 and Th17 cells were shown to be important for the development of asthma. Innate lymphoid cells (ILC) could play a critical role in asthma patients as they produce different cytokines associated with asthma. Epigenetic findings showed different acetylation and methylation patterns for children with allergic and non allergic asthma. On a posttranscriptional level, miRNAs are regulating factors identified to differ between asthma patients and healthy controls and also indicate differences within asthma phenotypes. Metabolomics is another exciting chapter important for endotyping asthmatic children. Despite the development of new biomarkers and the discovery of new immunological molecules, the complex puzzle of childhood asthma is still far from being completed. Addressing the current challenges of distinct clinical asthma and wheeze phenotypes, including their stability and underlying endotypes, involves addressing the interplay of innate and adaptive immune regulatory mechanisms in large, interdisciplinary cohorts. PMID- 27468756 TI - Stuxnet detected, Pc breaks down. PMID- 27468757 TI - Chorein interacts with alpha-tubulin and histone deacetylase 6, and overexpression preserves cell viability during nutrient deprivation in human embryonic kidney 293 cells. AB - The autophagy pathway has recently been implicated in several neurodegenerative diseases. Recently, it was reported that chorein-depleted cells showed accumulation of autophagic markers and impaired autophagic flux. Here, we demonstrate that chorein overexpression preserves cell viability from starvation induced cell death in human embryonic kidney 293 (HEK293) cells. Subsequent coimmunoprecipitation and reverse coimmunoprecipitation assays using extracts from chorein that stably overexpressed HEK293 cells revealed that chorein interacts with alpha-tubulin and histone deacetylase 6, a known alpha-tubulin deacetylater and central component of basal autophagy. Indeed, acetylated alpha tubulin immunoreactivity was significantly decreased in chorein that stably overexpressed HEK293 cells. These results suggest that chorein/histone deacetylase 6/alpha-tubulin interactions may play an important role in starvation induced cell stress, and their disruption may be one of the molecular pathogenic mechanisms of chorea-acanthocytosis.-Sasaki, N., Nakamura, M., Kodama, A., Urata, Y., Shiokawa, N., Hayashi, T., Sano, A. Chorein interacts with alpha-tubulin and histone deacetylase 6, and overexpression preserves cell viability during nutrient deprivation in human embryonic kidney 293 cells. PMID- 27468759 TI - Infiltration of myeloid cells in the pregnant uterus is affected by heme oxygenase-1. AB - Infiltrating myeloid cells in pregnant uteri play critical roles in the establishment of the placenta and maintenance of normal pregnancies. Their recruitment and proliferation are primarily mediated by the interactions of cytokines and chemokines secreted locally with their corresponding receptors. Heme oxygenase-1 (HO-1) has various physiologic properties that contribute to placental vascular development, with deficiencies in HO-1 associated with pregnancy disorders. Here, we investigated the effect of HO-1 on myeloid cell infiltration into pregnant uteri using a partial HO-1-deficient (Het, HO-1+/-) mouse model. With the use of flow cytometry, HO-1 was found predominantly expressed in circulating and uterine myeloid cells, specifically neutrophils and monocytes/macrophages. In pregnant Het uteri, the numbers of neutrophils and monocytes/macrophages were significantly reduced compared with pregnant wild-type (WT; HO-1+/+) uteri. With the use of BrdU in vivo assays, HO-1 deficiency did not affect cell proliferation or blood cell populations. With the use of PCR arrays, gene expression of cytokines (Csf1, Csf3), chemokines (Ccl1, Ccl2, Ccl6, Ccl8, Ccl11, Ccl12, Cxcl4, Cxcl9, Cxcl12), and their receptors (Ccr1, Ccr2, Ccr3, Ccr5) were also reduced significantly in Het compared with pregnant WT uteri. Moreover, with the use of flow cytometry, myeloid CSF1R and CCR2 expression in blood and uteri from both pregnant and nonpregnant mice was characterized, and a deficiency in HO-1 significantly reduced CCR2 expression in infiltrating uterine monocytes/macrophages and dendritic cells (DCs). These data reveal that HO-1 regulates not only cytokine/chemokine production in pregnant uteri but also myeloid cell receptor numbers, suggesting a role of HO-1 in the recruitment and maintenance of myeloid cells in pregnant uteri and subsequent effects on placental vascular formation. PMID- 27468758 TI - Effects of bile acids on neurological function and disease. AB - Bile acids are synthesized from cholesterol and are known to be involved with the emulsification and digestion of dietary lipids and fat-soluble vitamins. Outside of this role, bile acids can act as cell signaling effectors through binding and activating receptors on both the cell membrane and nucleus. Numerous reports have investigated these signaling pathways in conditions where the liver is damaged. More recently, effort has been made to investigate the role of bile acids in diseases outside of those associated with liver damage. This review summarizes recent findings on the influences that bile acids can exert in normal neurological function and their contribution to diseases of the nervous system, with the intent of highlighting the role of these metabolites as potential players in neurological disorders.-McMillin, M., DeMorrow, S. Effects of bile acids on neurological function and disease. PMID- 27468760 TI - Frontline Science: Coincidental null mutation of Csf2ralpha in a colony of PI3Kgamma-/- mice causes alveolar macrophage deficiency and fatal respiratory viral infection. AB - PI3Ks have been identified as key signaling proteins involved in many basic biologic processes in health and disease. Transgenic animals have been essential tools to study the underlying molecular mechanisms in this context and therefore, have been widely used to elucidate the role of these factors in many different settings. More specifically, PI3Kgamma, a subunit highly expressed in the hematopoietic system, has been implicated to play an important role in many inflammatory diseases as well as cancer. Here, we report identification of multiple, additional, previously unknown mutations in the genome of a widely used PI3Kgamma-deficient (PI3Kgamma-/-) mouse colony. These include a STOP mutation in the GM-CSFRalpha chain, leading to a complete and specific deficiency in GM-CSF signaling. PI3Kgamma-/- animals consequently lacked alveolar macrophages (AMs) and succumbed rapidly to influenza virus infection. Furthermore, PI3Kgamma-/- mice carried an additional mutation that affects mucin 2 (Muc2) transcripts. This protein is strongly involved in the regulation of colorectal cancer, and indeed, conflicting reports have indicated that PI3Kgamma-/- animals spontaneously develop colorectal tumors. Thus, we uncover previously unknown, confounding factors present in a strain of PI3Kgamma-/- mice, leading to additional deficiencies in important signaling pathways with potentially wide-ranging implications for the interpretation of previous studies. By separating the mutations, we established a unique Csf2ra-/- mouse model that allows us to study the role of cell intrinsic GM-CSFR signaling in vivo without confounding variables introduced by defective IL-5R and IL-3R signaling in mice lacking the common beta chain (Csf2rb). PMID- 27468762 TI - Use of Relational Agents to Improve Family Communication in Type 1 Diabetes: Methods. AB - BACKGROUND: Physiological and environmental risk factors interact to undermine blood glucose control during early adolescence. This has been documented to be associated with family conflict and poor adherence to diabetes management tasks. Family Teamwork is an efficacious program demonstrated to enhance family communication and reduce conflict during this vulnerable period. It was designed to be delivered to families in-person, which limited reach and potential impact. OBJECTIVE: The purpose of this paper is to present the protocol for adapting Family Teamwork for Web-based delivery. METHODS: Formative research with health care providers, parents, and adolescents will help modify Family Teamwork for Web based delivery by a relational agent (ie, a computerized character with human like features and actions). Sessions will be interactive, requiring both parent and adolescent participation, with the relational agent serving as a health coach. After programming, usability testing will be conducted to help ensure the program is easy to use. Video and instructional materials will be developed to facilitate use, and a small pilot study will be conducted to assess feasibility. Families will provide written informed consent prior to participation in any phase of the study. The Institutional Review Board at Baylor College of Medicine reviewed and approved the protocol (H-37245). RESULTS: Formative research is underway. No results are available at this time. CONCLUSIONS: This research has the potential to make an important contribution to diabetes management by using technology to enhance the reach of an efficacious program. PMID- 27468763 TI - An Efficient CuxO Photocathode for Hydrogen Production at Neutral pH: New Insights from Combined Spectroscopy and Electrochemistry. AB - Light-driven water splitting is one of the most promising approaches for using solar energy in light of more sustainable development. In this paper, a highly efficient p-type copper(II) oxide photocathode is studied. The material, prepared by thermal treatment of CuI nanoparticles, is initially partially reduced upon working conditions and soon reaches a stable form. Upon visible-light illumination, the material yields a photocurrent of 1.3 mA cm(-2) at a potential of 0.2 V vs a reversible hydrogen electrode at mild pH under illumination by AM 1.5 G and retains 30% of its photoactivity after 6 h. This represents an unprecedented result for a nonprotected Cu oxide photocathode at neutral pH. The photocurrent efficiency as a function of the applied potential was determined using scanning electrochemical microscopy. The material was characterized in terms of photoelectrochemical features; X-ray photoelectron spectroscopy, X-ray absorption near-edge structure, fixed-energy X-ray absorption voltammetry, and extended X-ray absorption fine structure analyses were carried out on pristine and used samples, which were used to explain the photoelectrochemical behavior. The optical features of the oxide are evidenced by direct reflectance spectroscopy and fluorescence spectroscopy, and Mott-Schottky analysis at different pH values explains the exceptional activity at neutral pH. PMID- 27468764 TI - Utilization of Google enterprise tools to georeference survey data among hard-to reach groups: strategic application in international settings. AB - BACKGROUND: As geospatial data have become increasingly integral to health and human rights research, their collection using formal address designations or paper maps has been complicated by numerous factors, including poor cartographic literacy, nomenclature imprecision, and human error. As part of a longitudinal study of people who inject drugs in Tijuana, Mexico, respondents were prompted to georeference specific experiences. RESULTS: At baseline, only about one third of the 737 participants were native to Tijuana, underscoring prevalence of migration/deportation experience. Areas frequented typically represented locations with no street address (e.g. informal encampments). Through web-based cartographic technology and participatory mapping, this study was able to overcome the use of vernacular names and difficulties mapping liminal spaces in generating georeferenced data points that were subsequently analyzed in other research. CONCLUSION: Integrating low-threshold virtual navigation as part of data collection can enhance investigations of mobile populations, informal settlements, and other locations in research into structural production of health at low- or no cost. However, further research into user experience is warranted. PMID- 27468765 TI - Biomechanical evaluation of polymethyl methacrylate with the addition of various doses of cefazolin, vancomycin, gentamicin, and silver microparticles. AB - OBJECTIVES: Numerous studies have examined the biomechanics of polymethyl methacrylate (PMMA) with added antibiotics, but direct comparison between studies is difficult. Our purpose was to evaluate the effects of the addition of antibiotic drugs and silver on compressive and bending strength of PMMA. Our null hypothesis was that there would be no significant difference in the compressive strength or bending strength of PMMA with the addition of silver or varying amounts of antibiotic drugs. METHODS: Polymethyl methacrylate was mixed with cefazolin, gentamicin, vancomycin, or silver; the control was PMMA alone. Antibiotic groups contained 20 g PMMA and 0.5 g, 1 g, 2 g, or 3 g of antibiotic. Silver groups had 0.25 g silver powder alone added to 20 g PMMA or silver with PMMA and 0, 0.5 g or 1 g of antibiotic. Samples underwent four-point bending and compression testing in air at room temperature and prevailing humidity. Pairwise comparisons between groups and to the ASTM and ISO standards were performed. RESULTS: Compression: All antibiotic and silver groups were weaker than the control. Samples with cefazolin tended to be stronger than other antibiotic groups with equivalent doses of antibiotic. All groups were above the ASTM standard, except 3 g vancomycin. Four-point bending: The addition of antibiotics did not significantly affect bending strength in groups with lower doses of antibiotics. The silver + PMMA group was weaker than the control. No groups were significantly below the ISO standard except the 3 g vancomycin group. CLINICAL SIGNIFICANCE: The addition of antibiotic or silver decreased the biomechanical strength in all samples, but not below the ASTM or ISO standard for most groups. The addition of cefazolin appears to affect strength the least, while high doses of vancomycin alter strength the most. PMID- 27468766 TI - Vitamin-D Receptor (VDR) Gene Polymorphisms (TaqI, FokI) in Turkish Patients with Hashimoto's Thyroiditis: Relationship to the Levels of Vit-D and Cytokines. AB - BACKGROUND: Hashimoto's thyroiditis (HT) is a common autoimmune disease. Vitamin D is an important regulator of immune system. It has been shown in several studies that vitamin D prevents the development of lots of autoimmune diseases. There are some studies that prove vitamin D receptor (VDR) gene polymorphism increases the risk of Hashimoto's thyroiditis. In this study, we aimed to investigate the association between HT and level of 25(OH)D3, IL-2, IL-4, IL-5, TNF-alpha and IFN-gamma and VDR FokI and TaqI gene polymorphism. Moreover, to find out whether low levels of vitamin D affect HT pathogenesis over inflammatory parameters. METHODS: We performed a case-control study that included 136 cases with HT (49 euthyroid, 49 subclinical hypothyroid, 38 hypothyroid patients) and 50 healthy control. Serum levels of 25(OH)D3, glucose, insulin, parathyroid hormone, calcium, phosphorus, alkaline phosphatase were measured and IL-4, IL-5, TNF-alpha, IFN-gamma analysis were performed with ELISA kits in all 186 subjects. Genetic analysis for VDR FokI and TaqI gene polymorphisms were done by RFLP in all subjects. RESULTS: Mean serum 25(OH)D levels were 14.88+/-8.23 ng/ml in patient with HT and 15.52+/-1.34 ng/ml in healthy controls. There were no statically significant differences between the groups in terms of vitamin D levels (P=0.977). Prevalence of vitamin D insufficiency in HT cases was significantly higher than controls (p=0.02). Although serum IL-2, IL-4, TNF-alpha and IFN-gamma were significantly higher in HT patients, there were no significant differences regarding IL-5 levels. Significant differences were observed between the groups regarding the genotype of TaqI but no differences regarding FokI genotype. CONCLUSION: Vitamin D insufficiency is associated with HT. There is a relationship between VDR TaqI gene polymorphism and HT. Although vitamin D levels are low in both patient and control group, detection of high level of inflammatory parameters in HT group makes us think that low level of vitamin D does not affect HT pathogenesis over these parameters. PMID- 27468767 TI - Beta-cell Management in Type 2 Diabetes: Beneficial Role of Nutraceuticals. AB - Inadequate functional beta cell mass seems to be the primary cause of type 2 diabetes. Increased oxidative stress and inflammation are the leading causes of betacell death. Preservation of functional beta-cell mass in type 2 diabetes is a critical target for type 2 diabetes management. Numerous studies have demonstrated beneficial effects of dietary components on beta cell management in type 2 diabetes, through multiple mechanisms. These dietary components modulate intercellular cascades that inhibit inflammatory molecule synthesis, the formation of free radicals, and nuclear damage, as well as induce antioxidant enzyme expression. The present review article focuses on dietary components and seeks to summarize their mechanism(s) in the prevention of diabetes initiation and progression through beta-cell management in type 2 diabetes. PMID- 27468768 TI - Ten Years. PMID- 27468769 TI - State of origin: Australian states use widely different resources for hospital management of hip fracture, but achieve similar outcomes. AB - Objective Hospital management of hip fracture varies widely with regard to length of stay, delivery of post-surgical care and costs. The present study compares the association between hospital utilisation and costs and patient outcomes in the six Australian states. Methods The present study was a retrospective cohort study of linked administrative databases for 2530 Australian veterans and war widows aged >=65 years, hospitalised for hip fracture in 2008-09. Department of Veterans' Affairs datasets for hospital episodes, residential aged care admissions and date of death were linked. Patient characteristics, hospital utilisation and process data, rates of mortality and residential care placement and delivery of community services were compared for patients from each of the states. Results There were no significant differences in fracture incidence, patient demographics or fracture type among the states. Adjusted total mean length of hospital stay ranged from 24.7 days (95% confidence interval (CI) 22.3 27.5 days) to 35.0 days (95% CI 32.6-37.6 days; P<0.001) and adjusted total hospital cost ranged between A$24792 (95% CI A$22191-A$27700) and A$35494 (95% CI A$32853-A$38343; P<0.001). Rates of referral to rehabilitation ranged from 31.7% to 50.4% (P=0.003). At 1 year, there were no significant differences between states for key outcome determinants of mortality (P=0.71) or for the proportion of patients who retained their independent living status (P=0.66). Conclusion Hospital resources for management of hip fracture differ substantially among the Australian states. Key medium-term patient outcomes do not show significant differences. A potential for substantial cost-efficiencies without increased risk to patient welfare is suggested. What is known about this topic? Hospital resources deployed in the initial management of hip fracture differ widely between countries, regions and individual hospitals. Patient outcomes also vary widely, but are inconsistently associated with resource outlays. What does this paper add? The paper describes the different resource outlays for management of hip fracture in six Australian jurisdictions and the absence of equivalent differences in medium-term patient outcomes. What are the implications for practitioners? Efficiencies in hospital management of hip fracture may be achievable without negative consequences for patients. The elements of models of care should be examined for their contribution to early and later patient outcomes. PMID- 27468771 TI - A review and exploration of sociotechnical ergonomics. AB - A holistic review of ergonomic history shows that science remains important for general occupational health and safety (OSH), the broad society, culture, politics and the design of everyday things. Science provides an unconventional and multifaceted viewpoint exploring ergonomics from a social, corporate and OSH perspective. Ergonomic solutions from this mindset may redefine the science, and it will change with companies that change within this socially hyper-connected world. Authentic corporate social responsibility will counter 'misleadership' by not approaching ergonomics with an afterthought. The review concludes that ergonomics will be stronger with social respect and ergonomic thinking based on the optimisation of anthropometric data, digital human models, computer-aided tools, self-empowerment, job enrichment, work enlargement, physiology, industrial psychology, cybernetic ergonomics, operations design, ergonomic-friendly process technologies, ergonomic empowerment, behaviour-based safety, outcome-based employee wellness and fatigue risk management solutions, to mention a few. PMID- 27468772 TI - Introduction: priority setting, equitable access and public involvement in health care. AB - Purpose - The purpose of this paper is to introduce the special issue on improving equitable access to health care through increased public and patient involvement (PPI) in prioritization decisions by discussing the conceptualization, scope and rationales of PPI in priority setting that inform the special issue. Design/methodology/approach - The paper employs a mixed methods approach in that it provides a literature review and a conceptual discussion of the common themes emerging in the field of PPI and health priority setting. Findings - The special issue focuses on public participation that is collective in character, in the sense that the participation relates to a social, not personal, decision and is relevant to whole groups of people and not single individuals. It is aimed at influencing a decision on public policy or legal rules. The rationales for public participation can be found in democratic theory, especially as they relate to the social and political values of legitimacy and representation. Originality/value - The paper builds on previous definitions of public participation by underlining its collective character. In doing so, it develops the work by Parry, Moyser and Day by arguing that, in light of the empirical evidence presented in this issue, public participatory activities such as protests and demonstrations should no longer be labelled unconventional, but should instead be labelled as "contestatory participation". This is to better reflect a situation in which these modes of participation have become more conventional in many parts of the world. PMID- 27468773 TI - Patterns of public participation. AB - Purpose - The paper summarizes data from 12 countries, chosen to exhibit wide variation, on the role and place of public participation in the setting of priorities. The purpose of this paper is to exhibit cross-national patterns in respect of public participation, linking those differences to institutional features of the countries concerned. Design/methodology/approach - The approach is an example of case-orientated qualitative assessment of participation practices. It derives its data from the presentation of country case studies by experts on each system. The country cases are located within the historical development of democracy in each country. Findings - Patterns of participation are widely variable. Participation that is effective through routinized institutional processes appears to be inversely related to contestatory participation that uses political mobilization to challenge the legitimacy of the priority setting process. No system has resolved the conceptual ambiguities that are implicit in the idea of public participation. Originality/value - The paper draws on a unique collection of country case studies in participatory practice in prioritization, supplementing existing published sources. In showing that contestatory participation plays an important role in a sub-set of these countries it makes an important contribution to the field because it broadens the debate about public participation in priority setting beyond the use of minipublics and the observation of public representatives on decision-making bodies. PMID- 27468774 TI - Between consensus and contestation. AB - Purpose - Noting that discussions of public participation and priority setting typically presuppose certain political theories of democracy, the purpose of this paper is to discuss two theories: the consensual and the agonistic. The distinction is illuminating when considering the difference between institutionalized public participation and contestatory participation. Design/methodology/approach - The approach is a theoretical reconstruction of two ways of thinking about public participation in relation to priority setting in health care, drawing on the work of Habermas, a deliberative theorist, and Mouffe, a theorist of agonism. Findings - The different theoretical approaches can be associated with different ways of understanding priority setting. In particular, agonistic democratic theory would understand priority setting as system of inclusions and exclusions rather than the determination of a consensus of social values, which is the typical deliberative way of thinking about the issues. Originality/value - The paper shows the value of drawing out explicitly the tacit assumptions of practices of political participation in order to reveal their scope and limitations. It suggests that making such theoretical presuppositions explicit has value for health services management in recognizing these implicit choices. PMID- 27468775 TI - Public involvement in health priority setting: future challenges for policy, research and society. AB - Purpose - The purpose of this paper is to reflect on the findings of this special issue and discusses the future challenges for policy, research and society. The findings suggest that challenges emerge as a result of legitimacy deficits of both consensus and contestatory modes of public involvement in health priority setting. Design/methodology/approach - The paper draws on the discussions and findings presented in this special issue. It seeks to bring the country experiences and case studies together to draw conclusions for policy, research and society. Findings - At least two recurring themes emerge. An underlying theme is the importance, but also the challenge, of establishing legitimacy in health priority setting. The country experiences suggest that we understand very little about the conditions under which representative, or authentic, participation generates legitimacy and under which it will be regarded as insufficient. A second observation is that public participation takes a variety of forms that depend on the opportunity structures in a given national context. Given this variety the conceptualization of public participation needs to be expanded to account for the many forms of public participation. Originality/value - The paper concludes that the challenges of public involvement are closely linked to the question of how legitimate processes and decisions can be generated in priority setting. This suggests that future research must focus more narrowly on conditions under which legitimacy are generated in order to expand the understanding of public involvement in health prioritization. PMID- 27468776 TI - An observational study of antiretroviral drug resistance in treatment-naive patients with HIV infection in New Zealand, from 2007 to 2011. AB - Background Genotypic testing for antiretroviral drug resistance is recommended for all patients newly diagnosed with HIV infection. This study sought to quantify the prevalence of antiretroviral drug resistance in treatment-naive patients with HIV infection in New Zealand. METHODS: All genotypic antiretroviral drug resistance testing in New Zealand is performed at LabPLUS, Auckland City Hospital. The clinicians who requested antiretroviral drug resistance testing during the period 2007-2011 were contacted and were asked to identify which patients with HIV infection were treatment-naive at the time of testing. Results of the antiretroviral drug resistance tests for treatment-naive patients with HIV infection were reviewed and the prevalence of resistance determined. RESULTS: Two hundred and 10 treatment-naive patients with HIV infection who had antiretroviral drug resistance testing performed were included; 20 (10%) were found to have a significant resistance mutation. Nine patients had virus resistant to one or more nucleoside reverse transcriptase inhibitors, 13 to non-nucleoside reverse transcriptase inhibitors and one to protease inhibitors. CONCLUSIONS: The prevalence of antiretroviral drug resistance in treatment-naive patients with HIV infection identified in this study is comparable to rates identified in studies from North America, the UK and Europe. This prevalence demonstrates the need for antiretroviral drug resistance testing for all treatment-naive patients with HIV infection in New Zealand. PMID- 27468779 TI - Sticky Patches on Lipid Nanoparticles Enable the Selective Targeting and Killing of Untargetable Cancer Cells. AB - Effective targeting by uniformly functionalized nanoparticles is limited to cancer cells expressing at least two copies of targeted receptors per nanoparticle footprint (approximately >=2 * 10(5) receptor copies per cell); such a receptor density supports the required multivalent interaction between the neighboring receptors and the ligands from a single nanoparticle. To enable selective targeting below this receptor density, ligands on the surface of lipid vesicles were displayed in clusters that were designed to form at the acidic pH of the tumor interstitium. Vesicles with clustered HER2-targeting peptides within such sticky patches (sticky vesicles) were compared to uniformly functionalized vesicles. On HER2-negative breast cancer cells MDA-MB-231 and MCF7 {expressing (8.3 +/- 0.8) * 10(4) and (5.4 +/- 0.9) * 10(4) HER2 copies per cell, respectively}, only the sticky vesicles exhibited detectable specific targeting (KD ~ 49-69 nM); dissociation (0.005-0.009 min(-1)) and endocytosis rates (0.024 0.026 min(-1)) were independent of HER2 expression for these cells. MDA-MB-231 and MCF7 were killed only by sticky vesicles encapsulating doxorubicin (32-40% viability) or alpha-particle emitter (225)Ac (39-58% viability) and were not affected by uniformly functionalized vesicles (>80% viability). Toxicities on cardiomyocytes and normal breast cells (expressing HER2 at considerably lower but not insignificant levels) were not observed, suggesting the potential of tunable clustered ligand display for the selective killing of cancer cells with low receptor densities. PMID- 27468780 TI - The long-term outcome of subthreshold depression in later life. AB - BACKGROUND: Subthreshold depression (SUBD) in later life is common and important as prodromal state and prominent risk factor in the development of major depressive disorder (MDD). Indicated prevention can reduce the incidence of MDD among people with SUBD substantially, but needs to be targeted to those that are truly at risk of developing MDD. METHOD: N = 341 eligible participants with SUBD were included from the first (1992/1993), second (1995/1996) and third (1998/1999) cycle from the Longitudinal Aging Study Amsterdam (LASA) by using a two-stage screening design. LASA is an ongoing prospective cohort study in The Netherlands among the older population (55-85 years). At baseline (1992/1993) N = 3107 participants were interviewed and follow-up cycles were conducted every 3 years until 2008/2009, resulting in maximal 17 years of observational period. The proportion of people that developed MDD, remained SUBD, or recovered from SUBD was measured and Cox proportional regression analyses were performed to investigate 29 putative predictors of MDD and recovery from SUBD. RESULTS: N = 153 (44.9%) recovered from SUBD, N = 138 (40.5%) remained chronically SUBD, and N = 50 (14.7%) developed MDD (incidence rate 15.1/1000 person-years). Women, high neuroticism, more chronic diseases, high body mass index, smoking and less social support predicted conversion to MDD. Men, low neuroticism and absence of pain predicted recovery from SUBD. CONCLUSIONS: Although older people with SUBD are clearly at risk of developing MDD, the majority did not, even after a long and thorough follow-up. Given the risk factors that were uncovered, targeting and prevention of MDD in those at very high risk is feasible. PMID- 27468781 TI - Giant Surface Conductivity Enhancement in a Carbon Nanotube Composite by Ultraviolet Light Exposure. AB - Carbon nanotube composites are lightweight, multifunctional materials with readily adjustable mechanical and electrical properties-relevant to the aerospace, automotive, and sporting goods industries as high-performance structural materials. Here, we combine well-established and newly developed characterization techniques to demonstrate that ultraviolet (UV) light exposure provides a controllable means to enhance the electrical conductivity of the surface of a commercial carbon nanotube-epoxy composite by over 5 orders of magnitude. Our observations, combined with theory and simulations, reveal that the increase in conductivity is due to the formation of a concentrated layer of nanotubes on the composite surface. Our model implies that contacts between nanotube-rich microdomains dominate the conductivity of this layer at low UV dose, while tube-tube transport dominates at high UV dose. Further, we use this model to predictably pattern conductive traces with a UV laser, providing a facile approach for direct integration of lightweight conductors on nanocomposite surfaces. PMID- 27468782 TI - Pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia of the left lower extremity in a 14-year-old female: a case report. AB - BACKGROUND: Pseudomyogenic hemangioendothelioma is a rare soft tissue tumor usually found in young adults, predominantly males. Fibrous dysplasia is a common benign bone tumor, which accounts for 5~7 % of all the primary benign bone tumors. However, pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia is extremely rare. To the best of our knowledge, this is the first case of pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia. CASE PRESENTATION: This study describes a case of a 14-year-old female who suffered from pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia of the left lower extremity. The patient underwent two operations successively due to pathological fractures in the left femur and tibia in a local hospital. She was diagnosed with fibrous dysplasia according to the postoperative pathological examinations. However, less than 1 year later, she was diagnosed with a recurrence of fibrous dysplasia in her left femur during a follow-up in our hospital. She underwent a curettage and grafting in the left femur. Postoperative pathological examinations demonstrated the diagnosis of fibrous dysplasia. Nevertheless, she presented to our clinic with a chief complaint of pain and swelling in her left tibia and calcaneus 4 months later. The patient underwent fine-needle aspiration in her left tibia. According to the histological and immunohistochemical findings, the diagnosis of pseudomyogenic hemangioendothelioma was confirmed by an expert pathology consultant. Finally, the patient had to undergo an amputation of the left thigh. Postoperative pathological examinations confirmed the diagnosis of pseudomyogenic hemangioendothelioma. Postoperative follow-up at 3 months disclosed no evidence of recurrent disease and no residual side effects from therapy. CONCLUSIONS: Pseudomyogenic hemangioendothelioma is a rare endothelial neoplasm which often mimics myoid and epithelioid tumors morphologically. For the diagnosis, the immunostaining is very important but not decisive and enough. Analysis based on any single factor or incomplete information may easily lead to arbitrary conclusion. Clinical information including age, gender, tumor location, disease course, and recurrence is important for appropriate diagnosis, and full understanding of the tumor is indispensable. PMID- 27468783 TI - Video-assisted removal of metal pellet fragments from the vertebral canal following gunshot injury and long-term outcome in a cat. AB - OBJECTIVE: To describe the surgical management and long-term outcome of a spinal gunshot injury in a cat. CLINICAL REPORT: A two-year-old, 4.2 kg castrated European Shorthair male cat was referred for evaluation of bilateral acute hindlimb paralysis with loss of deep pain perception in the right hindlimb associated with a perforating gunshot wound in the left side of the flank. Based on the clinical findings, the injury was localized to the fourth lumbar-first sacral spinal cord segment. The orthogonal spinal radiographs and computed tomography examination showed several metal pellet fragments within the vertebral canal of the sixth lumbar vertebra. A left mini-hemilaminectomy of the sixth lumbar vertebra pedicle combined with a mini dorsal laminectomy over the sixth to seventh lumbar vertebrae disc space were performed. A 2.4 mm 30 degrees arthroscope was then introduced within the spinal canal to improve visibility and help with the fragment extraction. The cat was discharged from the hospital five days after surgery and the owners were encouraged to continue passive and active physiotherapy movements. RESULTS: The cat was ambulatory with a plantigrade stance eight weeks following surgery. At the last follow-up examination (24 months postoperatively), the cat was able to jump on chairs, although intermittent urinary and faecal incontinence, proprioceptive deficits, and plantigrade stance were still present. CLINICAL SIGNIFICANCE: Decompressive surgery may promote neurological status improvement following spinal gunshot injury. PMID- 27468784 TI - Binding and Pharmacokinetics of the Sodium Channel Blocking Toxins (Saxitoxin and the Tetrodotoxins). AB - Tetrodotoxin (TTX) found in diverse variety of animals including puffer fishes, some newts, frogs and limited number of non-vertebrate species (6 different phyla). The saxitoxin (STX) and the TTX are small molecules composed of 7,8,9 guanidinium and 1,2,3 guanidinium groups, respectively in their structures. These groups provide positive charge to the molecules and are believed to interact with negatively charged Glu755 and Asp400 residues in domain II and I of the sodium channel strongly. The pharmacokinetic studies (absorption, distribution and accumulation) reported on Takifugu rubripes, Takifugu pardalis, Takifugu niphobles, Takifugu vermicularis, Takifugu snyderi, etc. revealed that higher concentration of TTX is accumulated in liver than in the skin or other tissues. Although TTX is also accumulated in the skin of various marine species (secretory glands) and the excess of TTX are emitted through skin which acts as a defence agent for those species. STX showed high toxicity on crab and other animals, due to its accumulation in the tissues and resistance to the sodium channel proteins. It concluded that TTX and STX based toxicities are developed on the species by the absorption, distribution and accumulation of toxins in tissues. Also the ingestion of these species (marine species) as food may allow transferring toxin to the human being. PMID- 27468785 TI - Pharmacotherapy & Surgical Interventions Available for Obesity Management and Importance of Pancreatic Lipase Inhibitory Phytomolecules as Safer Anti-Obesity Therapeutics. AB - The humans worldwide are facing obesity as a major clinical threat because it is linked with cardiovascular diseases which often have serious consequences. Treatments available for body weight loss do not produce permanent weight loss and they often bear some side effects. To achieve safer antiobesetic therapeutics, researchers are moving towards plant-based therapeutic formulations. Many phytomolecules have been identified as anti-lipolytic functions but none of them have reached up to the clinical level. So there is an essential need to develop effective anti-obesetic medications which not only produce sufficient weight loss but also lack side effects. Plants may prove promising option for the same. In this article, medications and surgical procedures have been reviewed and dealt for weight loss and the role of phytomolecules in anti-obesetic therapeutics has been explored. PMID- 27468786 TI - Indole based Tubulin Polymerization Inhibitors: An Update on Recent Developments. AB - The exploration of cancer microenvironment and its physiology have exposed a number of potential molecular targets for selective therapeutic intervention by anti-cancer agents. Microtubules are basic cell components formed by polymerization of alphabeta heterodimers which play a pivotal role in cellular functions as well as cell division. Drugs that can control the microtubule assembly either by hindering tubulin polymerization or by obstructing microtubule disassembly are of great importance in anti-cancer therapy. Diverse classes of naturally occurring as well as synthetic and semi-synthetic compounds with an indole nucleus induce microtubule polymerization and depolymerization and thereby change tubulin dynamics. Rapid development of several novel tubulin polymerization inhibitors has been observed over the past few years and some of them have associated vascular disrupting properties too. The present review starts with the structure, function and importance of microtubules in a eukaryotic cell. The well characterized tubulin binding domains and the corresponding inhibitors including their mechanism of action is also a part of this article. The report mainly focuses on the brief synthetic methodology with the relevant SAR studies of different indole derived molecules that have been reported in the past few years as potential inhibitors of tubulin polymerization is discussed. This review will provide the up-to-date evidence-base for synthetic chemists as well as biologists to design and synthesize new active molecules to inhibit tubulin polymerization. PMID- 27468787 TI - Corrigendum to: Approaches to management of complaints and notifications about health practitioners in Australia. AB - In 2005, the Australian Productivity Commission made a recommendation that a national health registration regimen and a consolidated national accreditation regimen be established. On 1 July 2010, the National Registration and Accreditation Scheme (NRAS) for health practitioners came into effect and the Australian Health Practitioner Regulation Agency (AHPRA) became the single national oversight agency for health professional regulation. It is governed by the Health Practitioner Regulation National Law Act (the National Law). While all states and territories joined NRAS for registration and accreditation, NSW did not join the scheme for the handling of complaints, but retained its existing co regulatory complaint-handling system. All other states and territories joined the national notification (complaints) scheme prescribed in the National Law. Because the introduction of NRAS brings with it new processes and governance around the management of complaints that apply to all regulated health professionals in all states and territories except NSW, where complaints management remains largely unchanged, there is a need for comparative analysis of these differing national and NSW approaches to the management of complaints/notifications about health professionals, not only to allow transparency for consumers, but also to assess consistency of decision making around complaints/notifications across jurisdictions. This paper describes the similarities and differences for complaints/notifications handling between the NRAS and NSW schemes and briefly discusses subsequent and potential changes in other jurisdictions. PMID- 27468789 TI - The test-retest reliability of the latent construct of executive function depends on whether tasks are represented as formative or reflective indicators. AB - This study investigates the test-retest reliability of a battery of executive function (EF) tasks with a specific interest in testing whether the method that is used to create a battery-wide score would result in differences in the apparent test-retest reliability of children's performance. A total of 188 4-year olds completed a battery of computerized EF tasks twice across a period of approximately two weeks. Two different approaches were used to create a score that indexed children's overall performance on the battery-i.e., (1) the mean score of all completed tasks and (2) a factor score estimate which used confirmatory factor analysis (CFA). Pearson and intra-class correlations were used to investigate the test-retest reliability of individual EF tasks, as well as an overall battery score. Consistent with previous studies, the test-retest reliability of individual tasks was modest (rs ~ .60). The test-retest reliability of the overall battery scores differed depending on the scoring approach (rmean = .72; rfactor_score = .99). It is concluded that the children's performance on individual EF tasks exhibit modest levels of test-retest reliability. This underscores the importance of administering multiple tasks and aggregating performance across these tasks in order to improve precision of measurement. However, the specific strategy that is used has a large impact on the apparent test-retest reliability of the overall score. These results replicate our earlier findings and provide additional cautionary evidence against the routine use of factor analytic approaches for representing individual performance across a battery of EF tasks. PMID- 27468790 TI - The Influence of Corticosteroids on Diagnostic Accuracy of Biopsy for Primary Central Nervous System Lymphoma. AB - Classical neurosurgical teaching suggests that corticosteroid administration reduces the diagnostic yield of stereotactic brain biopsy for primary central nervous system lymphoma (PCNSL). In a single-center series spanning 6 years, we reviewed 155 consecutive biopsy patients, 135 treated with prebiopsy corticosteroids. PCNSL was correctly diagnosed on initial biopsy in 15 of 16 steroid-treated patients; in the single nondiagnostic specimen, polymerase chain reaction reanalysis by an outside institution showed evidence of lymphoproliferative disease consistent with PCNSL. Our data challenge the notion that it is necessary to withhold corticosteroid therapy for cerebral edema in patients awaiting stereotactic biopsy for suspected PCNSL. PMID- 27468791 TI - The role of hyperinsulinemia as a cardiometabolic risk factor independent of obesity in polycystic ovary syndrome. AB - The aim of this study was to utilize various insulin resistance measuring methods to determine whether insulin resistance and other parameters impact the serum lipid levels of polycystic ovary syndrome (PCOS) patients and how the serum lipid levels in these patients are affected by the body mass index (BMI). Our dataset included patients between the ages of 16 and 42 (N = 228) from the outpatient endocrinology clinic of the Department of Obstetrics and Gynecology, who demonstrated increased hair growth and bleeding disorders and came for a routine oral glucose tolerance test (OGTT). Differences in the serum lipid levels were evaluated by t-test and linear regression analysis after adjusting for BMI. A stepwise regression model was constructed to evaluate the influence of each variable on the lipid levels. In PCOS patients, we found that dyslipidemia is more prevalent among hyperinsulinemic women compared with normoinsulinemic women, even after normalizing for BMI. PCOS patients with insulin resistance, determined by the insulin sensitivity index (ISI) method, showed more significant lipid abnormalities such as low high-density lipoprotein (HDL) and apo-A levels and high total cholesterol, low-density lipoprotein (LDL) and apo-B levels than if insulin resistance (IR) determination was based on insulin level or homeostatic model assessment (HOMA). PMID- 27468792 TI - Efficacy of Local Antimicrobials in the Non-Surgical Treatment of Patients With Periodontitis and Diabetes: A Systematic Review. AB - BACKGROUND: Patients with diabetes present a worse response to periodontal treatment. Local antimicrobials as an adjunct to scaling and root planing (SRP) provide additional benefits in the treatment of periodontitis in healthy patients. This review aims to evaluate the effects of local antimicrobials as an adjunct to SRP, compared with SRP alone, on periodontal clinical parameters of patients with chronic periodontitis (CP) and diabetes mellitus (DM). METHODS: Only randomized controlled trials with: 1) at least 6 months of follow-up; 2) SRP, in combination with local antimicrobials; and 3) patients with periodontitis and DM were considered eligible. MEDLINE, EMBASE, and LILACS databases were searched for articles published up to January 2016. Random-effects meta-analyses were conducted for clinical attachment level (CAL), probing depth (PD), bleeding on probing, and gingival index change after treatment. RESULTS: Of 153 papers potentially relevant to this review, six were included. The majority of trials showed a significant PD reduction and CAL gain associated with use of local antimicrobials in patients with type 1 and type 2 DM. Only studies that included well-controlled patients and applied antimicrobials at the deepest sites or sites with baseline PD >=5 mm presented significant PD reduction and CAL gain. CONCLUSION: In patients with DM and CP, use of local antimicrobials as an adjunct to SRP may result in additional benefits compared with SRP alone in PD reduction and CAL gain, especially in well-controlled individuals and deep sites. PMID- 27468793 TI - Low Social Position, Periodontal Disease, and Poor Oral Health-Related Quality of Life in Adults With Systemic Arterial Hypertension. AB - BACKGROUND: There is little evidence on the association between periodontal disease and oral health-related quality of life (OHRQoL) in individuals with chronic diseases, including hypertension. The aim of this study is to identify relationships among sociodemographic characteristics, smoking, tooth loss, dental caries, periodontal status, and OHRQoL in adults with systemic arterial hypertension. METHODS: A cross-sectional study involving 195 adults (mean age: 55.7 years) with systemic arterial hypertension used interviews and oral examinations to collect data on sociodemographic characteristics (age, sex, income); use of antihypertensive medication; smoking; tooth loss; dental caries; periodontal status (bleeding on probing, calculus, and attachment loss); and OHRQoL/oral health impact profile. The Wilson and Cleary (Wilson IB, Cleary PD. JAMA 1995;273:59-65) conceptual model was used to test direct and indirect relationships among variables using structural equation modeling. RESULTS: Lower age, male sex, smoking, and lower income directly predicted worse periodontal status. Tooth loss, dental caries, worse periodontal status, and smoking were directly linked to poor OHRQoL. Age was indirectly linked to worse periodontal status via income. Income and smoking indirectly predicted poor OHRQoL via periodontal status. CONCLUSIONS: Findings support an effect of periodontal disease on OHRQoL in people with systemic arterial hypertension. Periodontal status mediated associations of sociodemographic characteristics and smoking with OHRQoL through different pathways. PMID- 27468794 TI - Interventions for Dental Implant Placement in Atrophic Edentulous Mandibles: Vertical Bone Augmentation and Alternative Treatments. A Meta-Analysis of Randomized Clinical Trials. AB - BACKGROUND: The purpose of the current study is to assess which vertical bone augmentation techniques are most effective for restoring atrophic posterior areas of the mandible with dental implants and compare these procedures with alternative treatments. METHODS: Electronic literature searches in PubMed (MEDLINE), Ovid, and the Cochrane Library were conducted to identify all relevant articles published up to July 1, 2015. Eligibility was based on inclusion criteria, and quality assessments were conducted. The primary outcome variables were implant and prosthetic failure. After data extraction, meta-analyses were performed. RESULTS: Out of 527 potentially eligible papers, 14 randomized clinical trials were included. Out of these 14 studies, four trials assessed short implants (5 to 8 mm) as an alternative to vertical bone augmentation in sites with a residual ridge height of 5 to 8 mm. No statistically significant differences were found in implant (odds ratio [OR]: 1.02; 95% confidence interval [CI]: 0.31 to 3.31; P = 0.98; I2: 0%) or prosthetic failure (OR: 0.64; 95% CI: 0.21 to 1.96; P = 0.43; I2: 0%) after 12 months of loading. However, complications at treated sites increased with the augmentation procedures (OR: 8.33; 95% CI: 3.85 to 20.0; P <0.001; I2: 0%). There was no evidence of any vertical augmentation procedure being of greater benefit than any other for the primary outcomes (implant and prosthetic failure). CONCLUSIONS: Short implants in the posterior area of the mandible seem to be preferable to vertical augmentation procedures, which present similar implant and prosthetic failure rates but greater morbidity. All the vertical augmentation technique comparisons showed similar intergroup results. PMID- 27468795 TI - Propolis Improves Periodontal Status and Glycemic Control in Patients With Type 2 Diabetes Mellitus and Chronic Periodontitis: A Randomized Clinical Trial. AB - BACKGROUND: Propolis is a natural resin made by bees from various plant sources and exerts antimicrobial, anti-inflammatory, immunomodulatory, antioxidant, and antidiabetic properties. The purpose of this study is to assess adjunctive benefit of propolis supplementation in individuals with chronic periodontitis (CP) and type 2 diabetes mellitus (DMt2) receiving scaling and root planing (SRP). METHODS: A 6-month masked, randomized clinical trial comparing SRP with placebo (placebo + SRP group, n = 26) or SRP combined with a 6-month regimen of 400 mg oral propolis once daily (propolis + SRP group, n = 24) was performed in patients with long-standing DMt2 and CP. Treatment outcomes included changes in hemoglobin (Hb) A1c (primary outcome), fasting plasma glucose (FPG), serum N? (carboxymethyl) lysine (CML), and periodontal parameters (secondary outcomes). RESULTS: After 3 and 6 months, average HbA1c levels in the propolis group decreased significantly by 0.82% and 0.96% units, respectively (P <0.01); however, there were no significant differences in the placebo group. Likewise, FPG and CML levels were significantly reduced in the propolis group, but not in the placebo group. After therapy, periodontal parameters of CP were significantly improved in both groups. The propolis group showed significantly greater probing depth reduction and clinical attachment level gain than the control group after 3 and 6 months. CONCLUSION: A 6-month regimen of 400 mg propolis once daily is a potentially viable adjunct to SRP that significantly reduces levels of HbA1c, FPG, and CML, and improves periodontal therapy outcome in people with DMt2 and CP. PMID- 27468796 TI - Gingival Crevicular Fluid and Plasma Levels of Transglutaminase-2 and Oxidative Stress Markers in Cyclosporin A-Induced Gingival Overgrowth. AB - BACKGROUND: Transglutaminase (TGM)-2 has been shown to contribute to fibrosis by extracellular matrix accumulation in some organs and is activated by intracellular reactive oxygen species. The aim of this study is to investigate levels of gingival crevicular fluid (GCF) and plasma TGM-2 and oxidative stress markers (OSMs) in cyclosporin A (CsA)-induced gingival overgrowth (GO). METHODS: The study enrolled 20 healthy (H) individuals; 20 patients with gingivitis (G); 20 CsA-medicated patients with GO (CsA GO+); and 20 CsA-medicated patients without GO (CsA GO-). GCF and plasma levels of TGM-2 were analyzed by enzyme linked immunosorbent assay. Spectrofluorometry was used to analyze thiobarbituric acid reactive substance (TBARS); ferric-reducing antioxidant power (FRAP); total oxidant status (TOS); and total antioxidant capacity (TAC). RESULTS: GCF TGM-2 level was elevated in CsA GO+ compared with G (P = 0.048) and H (P = 0.001) groups. GCF TBARS level was elevated in CsA GO+ compared with other groups (CsA GO- group: P = 0.003; G group: P <0.001; and H group: P <0.001) and was higher in CsA GO- than in H (P = 0.048). GCF FRAP level was lower in CsA GO- than in H (P = 0.04). Both CsA GO+ and CsA GO- groups had lower GCF TOS levels than H (P <0.001 and P = 0.002) and G (P = 0.003 and P = 0.04). GCF TAC was higher in CsA GO+ than in H (P = 0.02). Plasma TGM-2 level was elevated in CsA GO+ compared with G (P = 0.048) and H (P = 0.002). Plasma FRAP level was higher in H and CsA GO- than in CsA GO+ (P = 0.008 and P = 0.02). CONCLUSIONS: CsA use significantly alters GCF and plasma levels of TGM-2 and OSMs. TGM-2 may contribute to CsA-induced GO in CsA-treated patients by changing GCF and plasma levels of OSMs. Further studies are needed to prove causality and its direction. PMID- 27468797 TI - Correlation Between Gingival Crevicular Fluid Hemoglobin Content and Periodontal Clinical Parameters. AB - BACKGROUND: Probing depth (PD) and bleeding on probing (BOP) are essential clinical parameters used for periodontal diagnosis. This study investigated whether detection of hemoglobin (Hb) in gingival crevicular fluid (GCF), along with PD and BOP, would improve diagnostic accuracy. METHODS: After plaque index (PI) was measured, GCF was collected from the gingival sulci of 401 anterior teeth in the maxilla and mandible from 184 patients who had entered periodontal maintenance therapy. Clinical parameters (gingival index [GI], PD, clinical attachment level [CAL], and BOP) were recorded. Hb values in GCF were assessed by immunochromatography. Moreover, cutoff values for PI, GI, and CAL based on the degree of PD and amount of GCF were created and analyzed. RESULTS: Hb was detected in 64.8% of GCF samples in 105 BOP-negative (-) sites in the periodontally stable group out of 107 sites that were less than all cutoff values. There were 71 BOP(-) sites in the periodontal-management-required group out of 122 sites that were more than all cutoff values, although no improvement in periodontal disease was observed. Hb was detected in 88.7% of GCF samples from these 71 BOP(-) sites. CONCLUSIONS: Hb was observed in more than 60% of GCF samples in BOP(-) gingival sulci in both periodontally stable and periodontal management-required groups. These results suggest inspection of Hb derived from microbleeding in gingival sulci may serve as an index for preclinical diagnosis. PMID- 27468799 TI - Polyglutamic Acid-Gated Mesoporous Silica Nanoparticles for Enzyme-Controlled Drug Delivery. AB - Mesoporous silica nanoparticles (MSNs) are highly attractive as supports in the design of controlled delivery systems that can act as containers for the encapsulation of therapeutic agents, overcoming common issues such as poor water solubility and poor stability of some drugs and also enhancing their bioavailability. In this context, we describe herein the development of polyglutamic acid (PGA)-capped MSNs that can selectively deliver rhodamine B and doxorubicin. PGA-capped MSNs remain closed in an aqueous environment, yet they are able to deliver the cargo in the presence of pronase because of the hydrolysis of the peptide bonds in PGA. The prepared solids released less than 20% of the cargo in 1 day in water, whereas they were able to reach 90% of the maximum release of the entrapped guest in ca. 5 h in the presence of pronase. Studies of the PGA-capped nanoparticles with SK-BR-3 breast cancer cells were also undertaken. Rhodamine-loaded nanoparticles were not toxic, whereas doxorubicin-loaded nanoparticles were able to efficiently kill more than 90% of the cancer cells at a concentration of 100 MUg/mL. PMID- 27468800 TI - In vivo monitoring of lung inflammation in CFTR-deficient mice. AB - BACKGROUND: Experimentally, lung inflammation in laboratory animals is usually detected by the presence of inflammatory markers, such as immune cells and cytokines, in the bronchoalveolar lavage fluid (BALF) of sacrificed animals. This method, although extensively used, is time, money and animal life consuming, especially when applied to genetically modified animals. Thus a new and more convenient approach, based on in vivo imaging analysis, has been set up to evaluate the inflammatory response in the lung of CFTR-deficient (CF) mice, a murine model of cystic fibrosis. METHODS: Wild type (WT) and CF mice were stimulated with P. aeruginosa LPS, TNF-alpha and culture supernatant derived from P. aeruginosa (strain VR1). Lung inflammation was detected by measuring bioluminescence in vivo in mice transiently transgenized with a luciferase reporter gene under the control of a bovine IL-8 gene promoter. RESULTS: Differences in bioluminescence (BLI) signal were revealed by comparing the two types of mice after intratracheal challenge with pro-inflammatory stimuli. BLI increased at 4 h after stimulation with TNF-alpha and at 24 h after administration of LPS and VR1 supernatant in CF mice with respect to untreated animals. The BLI signal was significantly more intense and lasted for longer times in CF animals when compared to WT mice. Analysis of BALF markers: leukocytes, cytokines and histology revealed no significant differences between CF and WT mice. CONCLUSIONS: In vivo gene delivery technology and non-invasive bioluminescent imaging has been successfully adapted to CFTR-deficient mice. Activation of bIL-8 transgene promoter can be monitored by non-invasive BLI imaging in the lung of the same animal and compared longitudinally in both CF or WT mice, after challenge with pro-inflammatory stimuli. The combination of these technologies and the use of CF mice offer the unique opportunity of evaluating the impact of therapies aimed to control inflammation in a CF background. PMID- 27468801 TI - Vortex knots in tangled quantum eigenfunctions. AB - Tangles of string typically become knotted, from macroscopic twine down to long chain macromolecules such as DNA. Here, we demonstrate that knotting also occurs in quantum wavefunctions, where the tangled filaments are vortices (nodal lines/phase singularities). The probability that a vortex loop is knotted is found to increase with its length, and a wide gamut of knots from standard tabulations occur. The results follow from computer simulations of random superpositions of degenerate eigenstates of three simple quantum systems: a cube with periodic boundaries, the isotropic three-dimensional harmonic oscillator and the 3-sphere. In the latter two cases, vortex knots occur frequently, even in random eigenfunctions at relatively low energy, and are constrained by the spatial symmetries of the modes. The results suggest that knotted vortex structures are generic in complex three-dimensional wave systems, establishing a topological commonality between wave chaos, polymers and turbulent Bose-Einstein condensates. PMID- 27468802 TI - Antiferroelectric Nature of CH3NH3PbI3-xClx Perovskite and Its Implication for Charge Separation in Perovskite Solar Cells. AB - Perovskite solar cells (PSCs) have been attracted scientific interest due to high performance. Some researchers have suggested anomalous behavior of PSCs to the polarizations due to the ion migration or ferroelectric behavior. Experimental results and theoretical calculations have suggested the possibility of ferroelectricity in organic-inorganic perovskite. However, still no studies have been concretely discarded the ferroelectric nature of perovskite absorbers in PSCs. Hysteresis of P-E (polarization-electric field) loops is an important evidence to confirm the ferroelectricity. In this study, P-E loop measurements, in-depth structural study, analyses of dielectric behavior and the phase transitions of CH3NH3PbI3-xClx perovskite were carried out and investigated. The results suggest that CH3NH3PbI3-xClx perovskite is in an antiferroelectric phase at room temperature. The antiferroelectric phase can be switched to ferroelectric phase by the poling treatment and exhibits ferroelectric-like hysteresis P-E loops and dielectric behavior around room temperature; namely, the perovskite can generate a ferroelectric polarization under PSCs operating conditions. Furthermore, we also discuss the implications of ferroelectric polarization on PSCs charge separation. PMID- 27468803 TI - CO2 Emission Increases with Damage Severity in Moso Bamboo Forests Following a Winter Storm in Southern China. AB - Despite the prevalence of disturbances in forests, the effects of disturbances on soil carbon processes are not fully understood. We examined the influences of a winter storm on soil respiration and labile soil organic carbon (SOC) of a Moso Bamboo (Phyllostachys heterocycle) plantation in the Wuyi Mountains in Southern China from May 2008 to May 2009. We sampled stands that were damaged at heavy, moderate, and light levels, which yielded aboveground biomass inputs to the soil at 22.12 +/- 0.73 (mean +/- 1 s.e.m.), 10.40 +/- 1.09, and 5.95 +/- 0.73 Mg per hectare, respectively. We found that soil respiration rate and annual cumulative CO2 emissions were significantly higher in heavily damaged sites than moderately and lightly damaged sites. Soil temperature was the most important environmental factor affecting soil respiration rate across all studied stands. However, soil respiration sensitivity to temperature (Q10) decreased in heavily damaged sites. Microbial biomass carbon and its proportion to total SOC increased with damage intensity. Soil respiration rate was positively correlated to microbial biomass carbon and soil moisture. Our results indicated that the increase of soil respiration following canopy disturbance from winter storm resulted from increased microbial biomass carbon, soil moisture, and temperature. PMID- 27468804 TI - Surgical correction of bilateral metacarpophalangeal valgus with curved osteotomies and type II external skeletal fixation in a seven-month-old alpaca. AB - OBJECTIVE: To report the successful surgical correction of severe bilateral metacarpophalangeal valgus angular limb deformities in a seven-month-old intact male alpaca cria using curved osteotomies stabilized with type II external skeletal fixation. METHODS: Using a 21 mm crescentic shaped oscillating saw blade, bilateral osteotomies were performed in the distal metaphyses of the fused third and fourth metacarpal bones to correct valgus angular limb deformity of the metacarpophalangeal joints. Axial alignment of each limb was achieved by medially rotating the distal metacarpus in the frontal plane along the curved osteotomies. The osteotomies were stabilized using type II external skeletal fixators. RESULTS: The alpaca was immediately weight-bearing following the surgical procedure and no to minimal lameness was observed during healing of the osteotomies. Evaluation at five and 10 months following the surgery demonstrated acceptable axial alignment in the left forelimb while moderate to severe varus deformity (overcorrection) was observed in the right. CLINICAL SIGNIFICANCE: Curved osteotomy of the distal metacarpus stabilized with type II external skeletal fixation can provide a favourable outcome in older alpaca crias affected with metacarpophalangeal angular limb deformities. Placement of the distal transfixation pins relative to the metacarpal physes should be carefully evaluated as overcorrection is possible, especially if growthpotential remains in only one physis of the fused third and fourth metacarpal bones. PMID- 27468805 TI - Reduced Protein Synthesis Fidelity Inhibits Flagellar Biosynthesis and Motility. AB - Accurate translation of the genetic information from DNA to protein is maintained by multiple quality control steps from bacteria to mammals. Genetic and environmental alterations have been shown to compromise translational quality control and reduce fidelity during protein synthesis. The physiological impact of increased translational errors is not fully understood. While generally considered harmful, translational errors have recently been shown to benefit cells under certain stress conditions. In this work, we describe a novel regulatory pathway in which reduced translational fidelity downregulates expression of flagellar genes and suppresses bacterial motility. Electron microscopy imaging shows that the error-prone Escherichia coli strain lacks mature flagella. Further genetic analyses reveal that translational errors upregulate expression of a small RNA DsrA through enhancing its transcription, and deleting DsrA from the error-prone strain restores motility. DsrA regulates expression of H-NS and RpoS, both of which regulate flagellar genes. We demonstrate that an increased level of DsrA in the error-prone strain suppresses motility through the H-NS pathway. Our work suggests that bacteria are capable of switching on and off the flagellar system by altering translational fidelity, which may serve as a previously unknown mechanism to improve fitness in response to environmental cues. PMID- 27468807 TI - Recovery of White Matter following Pediatric Traumatic Brain Injury Depends on Injury Severity. AB - Previous studies in pediatric traumatic brain injury (TBI) have been variable in describing the effects of injury severity on white-matter development. The present study used diffusion tensor imaging to investigate prospective sub-acute and longitudinal relationships between early clinical indicators of injury severity, diffusion metrics, and neuropsychological outcomes. Pediatric patients with TBI underwent magnetic resonance imaging (MRI) (n = 78, mean [M] = 10.56, standard deviation [SD] = 2.21 years) at the sub-acute stage after injury (M = 5.55, SD = 3.05 weeks), and typically developing children were also included and imaged (n = 30, M = 10.60, SD = 2.88 years). A sub-set of the patients with TBI (n = 15) was followed up with MRI 2 years post-injury. Diffusion MRI images were acquired at sub-acute and 2-year follow-up time points and analyzed using Tract Based Spatial Statistics. At the sub-acute stage, mean diffusivity and axial diffusivity were significantly higher in the TBI group compared with matched controls (p < 0.05). TBI severity significantly predicted diffusion profiles at the sub-acute and 2-year post-injury MRI. Patients with more severe TBI also exhibited poorer information processing speed at 6-months post-injury, which in turn correlated with their diffusion metrics. These findings highlight that the severity of the injury not only has an impact on white-matter microstructure, it also impacts its recovery over time. Moreover, findings suggest that sub-acute microstructural changes may represent a useful prognostic marker to identify children at elevated risk for longer term deficits. PMID- 27468806 TI - Genomic analysis of three Bifidobacterium species isolated from the calf gastrointestinal tract. AB - Ruminant animals contribute significantly to the global value of agriculture and rely on a complex microbial community for efficient digestion. However, little is known of how this microbial-host relationship develops and is maintained. To begin to address this, we have determined the ability of three Bifidobacterium species isolated from the faeces of newborn calves to grow on carbohydrates typical of a newborn ruminant diet. Genome sequences have been determined for these bacteria with analysis of the genomes providing insights into the host association and identification of several genes that may mediate interactions with the ruminant gastrointestinal tract. The present study provides a starting point from which we can define the role of potential beneficial microbes in the nutrition of young ruminants and begin to influence the interactions between the microbiota and the host. The differences observed in genomic content hint at niche partitioning among the bifidobacterial species analysed and the different strategies they employ to successfully adapt to this habitat. PMID- 27468809 TI - Historical occupational isocyanate exposure levels in two Canadian provinces. AB - Isocyanates such as toluene 2, 4-diisocyanate (TDI), methylene bisphenyl isocyanate (MDI), and hexamethylene diisocyanate (HDI) are known sensitizers and exposure to these chemicals can result in isocyanate-induced asthma-the leading cause of occupational asthma. A newly created exposure database was available containing occupational isocyanate measurements spanning 1981-1996 from Ontario and British Columbia (BC)-two of the largest provinces in Canada. The aim was to describe the historical measurements relative to exposure thresholds, ascertain differences in the data between provinces, and identify time trends. Descriptive statistics of the observations were summarized and stratified by isocyanate species and province. Chi-square tests and Student's t-test were performed to determine differences between provinces. To investigate time trends in the odds of a measurement exceeding the limit of detection (LOD) and time-weighted average (TWA), mixed effects logistic regression models were constructed. In total, 6,984 isocyanate measurements were analyzed, the majority of which were below the LOD (79%). Overall, 8.3% of samples were in excess of the 2014 TLV-TWA of 0.005 ppm. Comparing the two provinces, the proportion of samples exceeding the LOD and TLV TWA was greater in BC for all isocyanate species. Differences in time trends were also observed between provinces-the odds of a sample exceeding the TLV-TWA decreased over time in the case of MDI (Ontario only), TDI (both Ontario and BC), and other isocyanates (BC only). Our finding that a majority of the exposure measurements was below the LOD is similar to that reported by others. Differences between provinces may be due the fact that isocyanates are classified as a designated substance in Ontario and must adhere to specific exposure control regulations. Limitations of the database, such as finite number of variables and measurements available until 1996 only, presents challenges for more in-depth analysis and generalization of results. An argument is made that a Canadian occupational exposure database be maintained to facilitate risk assessments as well as for occupational epidemiology research. PMID- 27468810 TI - Diabetes Stimulates Osteoclastogenesis by Acidosis-Induced Activation of Transient Receptor Potential Cation Channels. AB - Patients with type 1 diabetes have lower bone mineral density and higher risk of fractures. The role of osteoblasts in diabetes-related osteoporosis is well acknowledged whereas the role of osteoclasts (OCLs) is still unclear. We hypothesize that OCLs participate in pathological bone remodeling. We conducted studies in animals (streptozotocin-induced type 1 diabetic mice) and cellular models to investigate canonical and non-canonical mechanisms underlying excessive OCL activation. Diabetic mice show an increased number of active OCLs. In vitro studies demonstrate the involvement of acidosis in OCL activation and the implication of transient receptor potential cation channel subfamily V member 1 (TRPV1). In vivo studies confirm the establishment of local acidosis in the diabetic bone marrow (BM) as well as the ineffectiveness of insulin in correcting the pH variation and osteoclast activation. Conversely, treatment with TRPV1 receptor antagonists re-establishes a physiological OCL availability. These data suggest that diabetes causes local acidosis in the BM that in turn increases osteoclast activation through the modulation of TRPV1. The use of clinically available TRPV1 antagonists may provide a new means to combat bone problems associated with diabetes. PMID- 27468811 TI - Self-assembled monolayers of alendronate on Ti6Al4V alloy surfaces enhance osteogenesis in mesenchymal stem cells. AB - Phosphonates have emerged as an alternative for functionalization of titanium surfaces by the formation of homogeneous self-assembled monolayers (SAMs) via Ti O-P linkages. This study presents results from an investigation of the modification of Ti6Al4V alloy by chemisorption of osseoinductive alendronate using a simple, effective and clean methodology. The modified surfaces showed a tailored topography and surface chemistry as determined by SEM microscopy and RAMAN spectroscopy. X-ray photoelectron spectroscopy revealed that an effective mode of bonding is created between the metal oxide surface and the phosphate residue of alendronate, leading to formation of homogenous drug distribution along the surface. In-vitro studies showed that alendronate SAMs induce differentiation of hMSC to a bone cell phenotype and promote bone formation on modified surfaces. Here we show that this novel method for the preparation of functional coatings on titanium-based medical devices provides osseoinductive bioactive molecules to promote enhanced integration at the site of implantation. PMID- 27468808 TI - Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer. AB - Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3), a tumor suppressor gene, is downregulated in various cancers. We previously reported the tumor-inhibitory effects of the REIC/Dkk-3 gene, delivered by a conventional adenoviral vector (Ad-CAG-REIC) in pancreatic cancer. Here, we developed an Ad REIC vector with a novel gene expression system, termed the super gene expression (SGE) system, and assessed its therapeutic effects relative to those of Ad-CAG REIC in pancreatic cancer cells. Human pancreatic cancer cell lines ASPC1 and MIAPaCa2 were used. REIC/Dkk-3 expression was assessed by western blot analysis. Relative cell viability and apoptotic effects were examined in vitro. The anti tumor effects of Ad-REIC treatment were assessed in the mouse xenograft model. Compared with Ad-CAG-REIC, Ad-SGE-REIC elicited a significant increase in REIC protein expression in the cells studied. Relative to Ad-CAG-REIC, Ad-SGE-REIC reduced cell viability and induced apoptosis in the ASPC1 and MIAPaCa2 cell lines in vitro, and achieved superior tumor growth inhibition in the mouse xenograft model. Compared with conventional Ad-REIC agents, Ad-SGE-REIC provided enhanced inhibitory effects against tumor growth. Our results indicate that Ad-SGE-REIC is an innovative therapeutic tool for pancreatic cancer. PMID- 27468812 TI - Estimating true incidence of O157 and non-O157 Shiga toxin-producing Escherichia coli illness in Germany based on notification data of haemolytic uraemic syndrome. AB - Shiga toxin-producing Escherichia coli (STEC) is an important cause of gastroenteritis (GE) and haemolytic uraemic syndrome (HUS). Incidence of STEC illness is largely underestimated in notification data, particularly of serogroups other than O157 ('non-O157'). Using HUS national notification data (2008-2012, excluding 2011), we modelled true annual incidence of STEC illness in Germany separately for O157 and non-O157 STEC, taking into account the groups' different probabilities of causing bloody diarrhoea and HUS, and the resulting difference in their under-ascertainment. Uncertainty of input parameters was evaluated by stochastic Monte Carlo simulations. Median annual incidence (per 100 000 population) of STEC-associated HUS and STEC-GE was estimated at 0.11 [95% credible interval (CrI) 0.08-0.20], and 35 (95% CrI 12-145), respectively. German notification data underestimated STEC-associated HUS and STEC-GE incidences by factors of 1.8 and 32.3, respectively. Non-O157 STEC accounted for 81% of all STEC-GE, 51% of all bloody STEC-GE and 32% of all STEC-associated HUS cases. Non O157 serogroups dominate incidence of STEC-GE and contribute significantly to STEC-associated HUS in Germany. This might apply to many other countries considering European surveillance data on HUS. Non-O157 STEC should be considered in parallel with STEC O157 when searching aetiology in patients with GE or HUS, and accounted for in modern surveillance systems. PMID- 27468813 TI - Development of Monoclonal Antibody Against Chlorinated 192tyrosine Containing ApoAI Peptide to Screen Quality of Human High Density Lipoprotein (HDL). AB - ApoAI, a major protein component of HDL is considered to be a key factor which contributes for HDL's cardio- protective functions. ApoAI is sensitive to myeloperoxidase mediated oxidative modifications under chronic inflammatory conditions such as atherosclerosis. The amino acid tyrosine at position 192 of ApoAI is considered to be one of the vulnerable sites for oxidation which impairs HDL functions and its quality. The presence of oxidized ApoAI in plasma may serve as a useful indicator of CVD risks in humans, but its detection in the clinical settings requires monoclonal antibodies (mAbs) with high specificity. In this study, we have developed mAbs against chloro- tyrosine at position 192 of ApoAI. We designed a small synthetic peptide of 7 amino acids length containing modified tyrosine residue (189-LAE-3-Cl-Y-HAK-195) based on antigenicity prediction. We coupled this peptide to Keyhole Limpet Hemocyanin (KLH) for generating mAbs. Hybridoma clones, KLH-ApoAI-F2 and KLH-ApoAI-H9, were found to be highly specific to chloro-192Tyr containing peptide of ApoAI and not to either nitro-192Tyr containing or to chloro-166Tyr and nitro-166Tyr containing peptides of ApoAI. The utility of these mAbs for screening the quality of HDL as an indicator of CVD risks in humans is discussed. PMID- 27468814 TI - Cardioregulatory Functions of Neuropeptides and Peptide Hormones in Insects. AB - Neuropeptides and peptide hormones from non-neuronal tissues play important roles in the regulation of insect life. In recent years, the rapid development of analytical techniques has contributed to the discovery of more than 30 families of peptide neurohormones that differ structurally and functionally. Although the discovery of the first neuropeptide occurred almost forty years ago, our knowledge about their full mode of activities, primary structures, synthesis, interactions with receptors or places of action increases gradually and there is still much to unravel. However, one thing is certain. Neuropeptides perform an extremely diverse range of activities. One neuropeptide can affect physiology in different ways. The neuropeptides can act as neurotransmitters, co-transmitters as well as neuromodulators. Most of these molecules have diverse pleiotropic activities on different tissues and organs. Their mode of action includes allatotropic, myotropic, cardiotropic or gonadotropic effects. Activity of some of them is conserved among most of insect species, indicating crucial roles in insect physiology and age of these systems. On the other hand, activity of other neuropeptides and peptide hormones is highly diverse, depending on species or even stages of development. This may indicate that some compounds have taken over the function of others. Insect heart work is regulated in a very complex manner. Myocardium activity undergoes regulation both, by nervous and hormonal way. What is important is that these same compounds can influent on heart as both nervous and hormonal factors. For that reason, the regulation of myocardium is still unclear. In this paper, we summarize the existing knowledge regarding cardioactivity and the involvement of insect neurohormones and some peptide hormones from non-neural tissues to regulation of insect myocardium. PMID- 27468815 TI - Recent Advances in Ligand and Structure Based Screening of Potent Quorum Sensing Inhibitors Against Antibiotic Resistance Induced Bacterial Virulence. AB - BACKGROUND: Antibiotic resistance is a growing threat in the treatment of bacterial diseases. Bacterial invasion and its virulence can cause damage to the host cells via quorum sensing mechanism which is responsible for the intercellular communication among bacteria that regulates expression of many genes. Quorum sensing (QS) differentially expresses specific sets of genes which may produce resistance. Researchers have been devoted to develop more potent compounds against bacterial resistant quorum sensing inhibitors. METHODS: A number of anti-quorum sensing approaches have been documented to screen potent inhibitors against quorum sensing induced bacterial virulence. Experimental screening of a large chemical compound library against a quorum sensing biological target is an established technology for lead identification but it is expensive, laborious and time consuming. Therefore, computer-aided high throughput ligand and structure based virtual screening are most effective pharmacoinformatic tools prior to experiment in this context. RESULTS: Ligand based screening includes quantitative structure-activity relationship (QSAR) and pharmacophore generation whereas techniques of structure based virtual screening include molecular docking. The study in this direction can increase the findings of hit rates and decrease cost of drug design and development by producing potent natural as well as synthetic anti-quorum sensing compounds. CONCLUSION: Most recent patent coverage on ligand and structure based design of novel bioactive quorum sensing inhibitors has been presented here. The paper has also critically reviewed the screening and design of potent quorum sensing inhibitor leads that would help in patenting novel leads active against bacterial virulence and minimizing antibiotic resistance among bacterial pathogens. PMID- 27468816 TI - Caenorhabditis elegans: A Model for Studying Human Pathogen Biology. AB - Novel clinical strategies need to be evolved, as pathogens, especially the ones that infect the human, develop resistance. To do so, host pathogen biology needs to be clearly understood and this can be done using a nematode worm, Caenorhabditis elegans, which harbours the same virulent microbes. Over several decades, the worm has been used to study host-microbe interaction with reference to immune response of the worm, antimicrobial molecules secreted, cell death in the worm body, quorum sensing network of the bacteria and fast or slow worm death. This mini review gives a bird's eye view of the directions that have been taken in these areas to date. Currently, the worm has been proposed to be an ideal model for high throughput screening of natural and synthetic drugs against a variety of bacteria. Experimental systems that allow this screening have been patented. Caenorhabditis elegans, thus, is one of the very effective models for studying pathogens that infect human. PMID- 27468817 TI - Enzymes- An Existing and Promising Tool of Food Processing Industry. AB - BACKGROUND: The enzyme catalyzed process technology has enormous potential in the food sectors as indicated by the recent patents studies. It is very well realized that the adaptation of the enzyme catalyzed process depends on the availability of enzyme in affordable prices. OBJECTIVE: Enzymes may be used in different food sectors like dairy, fruits & vegetable processing, meat tenderization, fish processing, brewery and wine making, starch processing and many other. Commercially only a small number of enzymes are used because of several factors including instability of enzymes during processing and high cost. METHOD: More and more enzymes for food technology are now derived from specially selected or genetically modified microorganisms grown in industrial scale fermenters. Enzymes with microbial source have commercial advantages of using microbial fermentation rather than animal and plant extraction to produce food enzymes. CONCLUSION: At present only a relatively small number of enzymes are used commercially in food processing. But the number is increasing day by day and field of application will be expanded more and more in near future. The purpose of this review is to describe the practical applications of enzymes in the field of food processing. PMID- 27468818 TI - Direct inference of site strength in basic solids upon CO2 adsorption: enthalpy entropy compensation effects. AB - The adsorption of CO2 coupled to calorimetry is a state-of-the-art technique for characterizing the basic properties of solids. In this paper, we show that the differential heat and entropy curves measured upon CO2 adsorption on a basic solid can be reasonably estimated from a single CO2 isotherm with no need for any independent heat (calorimetric) measurement. Our method relies on two important observations: (1) formulation of generalized F-H-TS thermodynamic isotherms, the former (F) being directly generated from the raw CO2 isotherms, and (2) the presence of unexpected enthalpy-entropy compensation effects upon CO2 adsorption linking the integral enthalpy and entropy of adsorption until saturation for different solids. Our thermodynamic method has been validated using a broad library of basic solids with variable site strength and heterogeneity. Finally, a new scale of basicity is proposed using the parameters fitted from the thermodynamic isotherm (free energy basis) as descriptors of basic strength. This method opens an avenue to the inference of site strength of basic solids without the need for expensive calorimeters. PMID- 27468819 TI - Phenotypic and functional characteristics of IL-21-expressing CD8(+) T cells in human nasal polyps. AB - Although CD4(+) T cells are recognized to play an important role in the inflammatory response of nasal polyps (NPs), the biological functions of CD8(+) T cells in polypogenesis remain unclear. In this study, we analyzed cell markers, cytokine expression and transcription factors in IL-21-expressing CD8(+) T cells in polyp tissues of NP patients. The results showed that the majority of IL-21 producing CD8(+) T cells were effector memory cells and they co-expressed IFN gamma. IL-21-expressing CD8(+) T cells in polyp tissues expressed higher CXCR5, PD-1, and ICOS levels than cells in control tissues and showed significantly higher T-bet and Bcl-6 expression levels compared with IL-21(-)CD8(+) T cells. Purified polyp CD8(+) T cells promoted IgG production from isolated polyp B cells in vitro, and recombinant IL-12 modulated the expression of IL-21, IFN-gamma and CD40L in purified polyp CD8(+) T cells. Moreover, the percentage of IL 21(+)CD8(+) T cells in polyp tissues was positively correlated with endoscopic and CT scan scores in NP patients. These findings indicated that polyp CD8(+) T cells, by co-expressing IL-21 and IFN-gamma and other markers, display a Tfh cell functionality, which is associated with the clinical severity of NP patients. PMID- 27468821 TI - Redistribution of Cav2.1 channels and calcium ions in nerve terminals following end-to-side neurorrhaphy: ionic imaging analysis by TOF-SIMS. AB - The P/Q-type voltage-dependent calcium channel (Cav2.1) in the presynaptic membranes of motor nerve terminals plays an important role in regulating Ca2+ transport, resulting in transmitter release within the nervous system. The recovery of Ca2+-dependent signal transduction on motor end plates (MEPs) and innervated muscle may directly reflect nerve regeneration following peripheral nerve injury. Although the functional significance of calcium channels and the levels of Ca2+ signalling in nerve regeneration are well documented, little is known about calcium channel expression and its relation with the dynamic Ca2+ ion distribution at regenerating MEPs. In the present study, end-to-side neurorrhaphy (ESN) was performed as an in vivo model of peripheral nerve injury. The distribution of Ca2+ at regenerating MEPs following ESN was first detected by time-of-flight secondary ion mass spectrometry, and the specific localization and expression of Cav2.1 channels were examined by confocal microscopy and western blotting. Compared with other fundamental ions, such as Na+ and K+, dramatic changes in the Ca2+ distribution were detected along with the progression of MEP regeneration. The re-establishment of Ca2+ distribution and intensity were correlated with the functional recovery of muscle in ESN rats. Furthermore, the re-clustering of Cav2.1 channels after ESN at the nerve terminals corresponded with changes in the Ca2+ distribution. These results indicated that renewal of the Cav2.1 distribution within the presynaptic nerve terminals may be necessary for initiating a proper Ca2+ influx and shortening the latency of muscle contraction during nerve regeneration. PMID- 27468822 TI - [The challenge of the spine : Pros and cons of modern therapeutic approaches]. PMID- 27468823 TI - Lornoxicam injection is inferior to betamethasone in the treatment of subacromial impingement syndrome : A prospective randomized study of functional outcomes. AB - BACKGROUND: Subacromial impingement syndrome (SIS) is one of the most frequent shoulder pathologies. Initial treatment is conservative. Subacromial injection of drugs achieves a high concentration at the pathologic site with less drug use and fewer systemic side effects. Glucocorticoids are most frequently injected. One concern with steroid use is the wide array of potential systemic and local complications. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also peripherally acting and can be used locally. Although intraarticular (IA) use of NSAIDs is common in orthopedic practice, it is mostly restricted to the knee joint. Reports of local NSAID for joint pathologies are relatively rare. This study compared the efficacy of single-dose subacromial injections of betamethasone and lornoxicam for treatment of SIS. METHODS: Subacromial injections of either 7.0 mg betamethasone or 8 mg lornoxicam were received by 70 patients with mean age 53 (46-68) years. Treatment outcome was assessed with Constant-Murley and UCLA questionnaires before injection and at 2-, 4-, and 6 week follow-ups. RESULTS: The change in outcome scores compared to pretreatment was higher in the steroid group at all follow-ups (p < 0.001). Patients in the steroid group showed a significant improvement at all follow-ups compared to pretreatment (p <0.001) and previous follow-ups (p <0.05) at all times. Patients in the lornoxicam group showed a significant functional improvement in week 2 (p <0.001), which was not evident in the following weeks (p >0.05). Although functional recovery halted after week 2, outcome scores remained significantly higher than the pretreatment values at all weeks (p <0.001). CONCLUSION: Although a single subacromial lornoxicam injection provides rapid functional recovery, which partially extends into the intermediate term, its results are inferior to betamethasone and it may be an alternative only in patients where corticosteroids are contraindicated. PMID- 27468824 TI - Increasing phosphorus concentration in the extraradical hyphae of Rhizophagus irregularis DAOM 197198 leads to a concomitant increase in metal minerals. AB - Plants associated with arbuscular mycorrhizal fungi (AMF) acquire phosphorus via roots and extraradical hyphae. How soil P level affects P accumulation within hyphae and how P in hyphae influences the accumulation of metal minerals remains little explored. A bi-compartmented in vitro cultivation system separating a root compartment (RC), containing a Ri T-DNA transformed carrot root associated to the AMF Rhizophagus irregularis DAOM 197198, from a hyphal compartment (HC), containing only the extraradical hyphae, was used. The HC contained a liquid growth medium (i.e., the modified Strullu-Romand medium containing P in the form of KH2PO4) without (0 MUM) or adjusted to 35, 100, and 700 MUM of KH2PO4. The accumulation of P and metal minerals (Ca, Mg, K, Na, Fe, Cu, Mn) within extraradical hyphae and AMF-colonized roots, and the expression of the phosphate transporter gene GintPT were assessed. The expression of GintPT in the extraradical hyphae did not differ in absence of KH2PO4 or in presence of 35 and 100 MUM KH2PO4 in the HC but was markedly reduced in presence of 700 MUM KH2PO4. Hyphal P concentration was significantly lowest in absence of KH2PO4, intermediate at 35 and 100 MUM KH2PO4 and significantly highest in presence of 700 MUM KH2PO4 in the HC. The concentrations of K, Mg, and Na were positively associated with the concentration of P in the extraradical hyphae developing in the HC. Similarly, P concentration in extraradical hyphae in the HC was related to P concentration in the growth medium and influenced the concentration of K, Mg, and Na. The accumulation of the metal mineral K, Mg, and Na in the extraradical hyphae developing in the HC was possibly related to their function in neutralizing the negative charges of PolyP accumulated in the hyphae. PMID- 27468825 TI - Subjective memory complaints in elderly: relationship with health status, multimorbidity, medications, and use of services in a population-based study. AB - BACKGROUND: This study examines the associations between subjective memory complaints (SMC) and health variables: multimorbidity, presence of certain diseases, health perceived state, difficulties seeing and hearing, pain, and use of medications and health services. Furthermore, we aim to identify risk groups based on multimorbidity and calculate the effect size for each of these relationships. METHODS: Cross-sectional epidemiological study using a face-to face interview with a structured questionnaire. SAMPLE SIZE: 1,342 people aged 65 years and older taken from a random sample of the census tracts. SMC were studied using questions regarding memory complaints. RESULTS: Multimorbidity and polypharmacy are associated with SMC, so are impaired vision and hearing. SMC are more frequently present in people who use health services more intensively and exhibit reduced functional activity as a result of diseases. With respect to specific diseases, only cerebrovascular accidents and chronic constipation were associated with SMC. In regression analysis, predictors of SMC were vision and hearing impairment, poor self-perceived health, pain, and general practitioner visits. However, the effect size of these factors is low. The variables that indicate risk groups are number of diseases, reduced functional activity, hearing impairment, and poor self-perceived health. CONCLUSIONS: Memory complaints are a heterogeneous phenomenon. Our results confirm that multimorbidity, polypharmacy, greater use of health services, pain, and poor self-perceived health are associated with SMC. We identified two risk groups with a high percentage of complaints and a healthy group with a low percentage. Detecting these factors and these risk and healthy groups is useful in achieving proper patients management. PMID- 27468826 TI - Molecular and cellular effects of a novel hydroxamate-based HDAC inhibitor - belinostat - in glioblastoma cell lines: a preliminary report. AB - Histone deacetylase (HDAC) inhibitors are now intensively investigated as potential cytostatic agents in many malignancies. Here, we provide novel information concerning the influence of belinostat (Bel), a hydroxamate-based pan HDAC inhibitor, on glioblastoma LN-229 and LN-18 cells. We found that LN-229 cells stimulated with 2 MUmol/L of Bel for 48 h resulted in 70 % apoptosis, while equivalent treatment of LN-18 cells resulted in only 28 % apoptosis. In LN-229 cells this effect was followed by up-regulation of pro-apoptotic genes including Puma, Bim, Chop and p21. In treated LN-18 cells only p21 was markedly overexpressed. Simultaneously, LN-229 cells treated with 2 MUmol/L of Bel for 48 h exhibited down-regulation of molecular chaperones GRP78 and GRP94 at the protein level. In contrast, in LN-18 cells Western blot analysis did not show any marked changes in GRP78 nor GRP94 expression. Despite noticeable overexpression of p21, there were no signs of evident G1 nor G2/M cell cycle arrest, however, the reduction in number of the S phase cells was observed in both cell lines. These results collectively suggest that Bel can be considered as potential anti glioblastoma agent. To our knowledge this is the first report presenting the effects of belinostat treatment in glioblastoma cell lines. PMID- 27468827 TI - The renal effects of ALK inhibitors. AB - Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. In clinical practice, three small molecule inhibitors of ALK-1 are used, namely crizotinib, ceritinib and alectinib. Several more agents are in active pre-clinical and clinical studies. Crizotinib is approved for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). According to the package insert and published literature, treatment with crizotinib appears to be associated with kidney failure as well as an increased risk for the development and progression of renal cysts. In addition, this agent is associated with development of peripheral edema and rare electrolyte disorders. This review focuses on the adverse renal effects of Crizotinib in clinical practice. PMID- 27468828 TI - Comparative transcriptomics of rice plants under cold, iron, and salt stresses. AB - Abiotic stresses such as salinity, iron toxicity, and low temperatures are the main limiting factors of rice (Oryza sativa L.) yield. The elucidation of the genes involved in responses to these stresses is extremely important to understand the mechanisms that confer tolerance, as well as for the development of cultivars adapted to these conditions. In this study, the RNA-seq technique was used to compare the transcriptional profile of rice leaves (cv. BRS Querencia) in stage V3, exposed to cold, iron, and salt stresses for 24 h. A range of 41 to 51 million reads was aligned, in which a total range of 88.47 to 89.21 % was mapped in the reference genome. For cold stress, 7905 differentially expressed genes (DEGs) were observed, 2092 for salt and 681 for iron stress; 370 of these were common to the three DEG stresses. Functional annotation by software MapMan demonstrated that cold stress usually promoted the greatest changes in the overall metabolism, and an enrichment analysis of overrepresented gene ontology (GO) terms showed that most of them are contained in plastids, ribosome, and chloroplasts. Saline stress induced a more complex interaction network of upregulated overrepresented GO terms with a relatively low number of genes compared with cold stress. Our study demonstrated a high number of differentially expressed genes under cold stress and a greater relationship between salt and iron stress levels. The physiological process most affected at the molecular level by the three stresses seems to be photosynthesis. PMID- 27468830 TI - De-Privatizing Self-Harm: Remembering the Social Self in How to Forget. AB - This article reads Malu De Martino's 2010 film Como Esquecer (How to Forget) as a case study in self-harm as a mode of expression and self-inquiry. Drawing on disability and queer theory, psychoanalysis, and sociology of medicine, the author argues that How to Forget charts a "crip" epistemology of self-harm and theorizes a "social self." That is to say, the film models an orientation towards self-harm that offers a coalitional and social therapeutic understanding. Based on this reading, the author suggests the application of practices of knowing with, or knowing-in-relation as "cripistemology" to a broader therapeutic, research, and lay context. PMID- 27468831 TI - Documentation of Capacity Assessment and Subsequent Consent in Patients Identified With Delirium. AB - BACKGROUND: Delirium is highly prevalent in the general hospital patient population, characterized by acute onset, fluctuating levels of consciousness, and global impairment of cognitive functioning. Mental capacity, its assessment and subsequent consent are therefore prominent within this cohort, yet under explored. AIM: This study of patients with delirium sought to determine the processes by which consent to medical treatment was attempted, how capacity was assessed, and any subsequent actions thereafter. METHOD: A retrospective documentation review of patients identified as having a delirium for the twelve months February 2013 to January 2014 was undertaken. Inclusion and exclusion criteria were used; demographic and descriptive data collected. A total of n=1153 patients were identified with n=310 meeting inclusion criteria. RESULT: A random sample of one hundred patients were subsequently reviewed. One third of patients (n=33) had documentation relating to consent, while four patients had documentation relating to capacity. Median delirium duration was three days, with treatment refusal occurring in twenty-two patients and "duty of care" being used as an apparent beneficent related treatment framework in twelve patients. CONCLUSIONS: While impaired decision-making was indicated, the review was unable to indicate what patient characteristics flag the need for capacity assessment. Documentation relating to consent processes (whether patient or substitute) appeared deficient for this cohort. PMID- 27468829 TI - Ebola virus disease and critical illness. AB - As of 20 May 2016 there have been 28,646 cases and 11,323 deaths resulting from the West African Ebola virus disease (EVD) outbreak reported to the World Health Organization. There continue to be sporadic flare-ups of EVD cases in West Africa.EVD presentation is nonspecific and characterized initially by onset of fatigue, myalgias, arthralgias, headache, and fever; this is followed several days later by anorexia, nausea, vomiting, diarrhea, and abdominal pain. Anorexia and gastrointestinal losses lead to dehydration, electrolyte abnormalities, and metabolic acidosis, and, in some patients, acute kidney injury. Hypoxia and ventilation failure occurs most often with severe illness and may be exacerbated by substantial fluid requirements for intravascular volume repletion and some degree of systemic capillary leak. Although minor bleeding manifestations are common, hypovolemic and septic shock complicated by multisystem organ dysfunction appear the most frequent causes of death.Males and females have been equally affected, with children (0-14 years of age) accounting for 19 %, young adults (15 44 years) 58 %, and older adults (>=45 years) 23 % of reported cases. While the current case fatality proportion in West Africa is approximately 40 %, it has varied substantially over time (highest near the outbreak onset) according to available resources (40-90 % mortality in West Africa compared to under 20 % in Western Europe and the USA), by age (near universal among neonates and high among older adults), and by Ebola viral load at admission.While there is no Ebola virus specific therapy proven to be effective in clinical trials, mortality has been dramatically lower among EVD patients managed with supportive intensive care in highly resourced settings, allowing for the avoidance of hypovolemia, correction of electrolyte and metabolic abnormalities, and the provision of oxygen, ventilation, vasopressors, and dialysis when indicated. This experience emphasizes that, in addition to evaluating specific medical treatments, improving the global capacity to provide supportive critical care to patients with EVD may be the greatest opportunity to improve patient outcomes. PMID- 27468832 TI - Bone morphogenetic protein 2 stimulates chondrogenesis of equine synovial membrane-derived progenitor cells. AB - OBJECTIVES: Bone morphogenetic protein 2 (BMP-2) is critical for skeletal and cartilage development, homeostasis and repair. This study was conducted to clone and characterize equine BMP-2, develop expression constructs for equine BMP-2, and to determine whether BMP-2 can stimulate chondrogenesis of equine synovial membrane-derived progenitor cells (SMPC). METHODS: Equine BMP-2 cDNA was amplified from chondrocyte RNA, and then transferred into an expression plasmid and adenoviral vector. Effective expression of equine BMP-2 was confirmed using a BMP reporter cell line. SMPC were isolated from synovium, expanded through two passages and transferred to chondrogenic cultures, with recombinant human (rh) transforming growth factor beta 1 (TGF-beta1) or rhBMP-2. Chondrogenesis was assessed by up-regulation of collagen types II and X, and aggrecan mRNA, secretion of collagen type II protein and sulfated glycosaminoglycans (sGAG), and by alkaline phosphatase induction. Chondrogenic stimulation of SMPC by the equine BMP-2 adenovirus was assessed by sGAG secretion and histology. RESULTS: The mature equine BMP-2 peptide is identical to human and murine peptides. Recombinant human BMP-2 and TGF-beta1 stimulated equivalent amounts of collagen type II protein in SMPC pellets, but sGAG secretion was doubled by BMP-2. Neither factor stimulated hypertrophic marker expression. The equine BMP-2 adenoviral vector induced chondrogenesis comparably to rhBMP-2 protein, with no indication of hypertrophy. CLINICAL SIGNIFICANCE: Bone morphogenetic protein 2 is a potent inducer of SMPC non-hypertrophic chondrogenesis, supporting the use of this combination for articular cartilage repair applications. PMID- 27468833 TI - Editorial (Thematic Issue: Toxins and Their Role as Therapeutic Agents). PMID- 27468834 TI - A self-assembled chiral-aptasensor for ATP activity detection. AB - Circular dichroism (CD) has allowed the construction of various chiral nanomaterials for different applications, including biosensing. However, the determination of a simple target-specific, economical, and biocompatible platform using CD with intracellular detection and in situ molecular probing is still required. Here, we show that a DNA zip-fastener structure self-assembled chiral aptasensor based on gold nanoparticle heterodimers provided an outstanding capability to quantify adenosine-5'-triphosphate (ATP) by addition. The conjugation of two ATP molecules to an adenosine aptamer allowed the formation of a stable ring structure, which formed an ATP-ring adhesive scaffold upon interaction with DNA complementary sequences linked with large gold nanoparticles, the latter were able to drop and result in a decrease in CD signal. We also showed that these low-cytotoxicity and polyethylene glycol (PEG) steady nanoconjugates were also a one-step incubation technique for the quantification and monitoring of ATP in living cells modified by cell penetrating peptides (TAT) or Cy5. The results showed that the linear intracellular detection range was from 1.5 to 4.2 mM with a limit of detection (LOD) of 0.2 mM. Our findings suggest that this chiroplasmonic sensor is a promising approach for investigating biogenic biomolecules inside cells and living organisms and for assessing their biological activity. PMID- 27468835 TI - Utilising a paediatric version of the indicator of sedation need for children's dental care: a pilot study. AB - AIM: To assess the treatment outcomes of using inhalation sedation for comprehensive dental care in children by utilising a modified version of the indicator of sedation need tool. METHODS: Investigating the outcomes of dental treatment of patients referred to the sedation unit at the Leeds Dental Institute when the paediatric version of the indicator of sedation need (p-IOSN) was utilised. RESULTS: Forty patients of mean age 9.99 (SD = 3.14) years were followed up to ascertain treatment outcomes when the p-IOSN was used. Of the total of 40 children included, 20 scored 6 on p-IOSN. Treatment completion rate was 72.5 %. Although major differences existed between age and treatment outcomes, they failed to achieve statistical significance. No significant association was found between gender and p-IOSN of any score with any treatment outcome. CONCLUSIONS: p-IOSN may be a useful tool that can be used to predict those child patients who would benefit from sedation for their dental treatment. However, the p-IOSN is still in a developmental stage and further research is required prior to its use on clinical grounds. PMID- 27468837 TI - Erratum to: Pharmacokinetics, Safety, and Efficacy of Chemoembolization with Doxorubicin-Loaded Tightly Calibrated Small Microspheres in Patients with Hepatocellular Carcinoma. PMID- 27468838 TI - Renal Angiomyolipoma: Mid- to Long-Term Results Following Embolization with Onyx. AB - PURPOSE: Percutaneous transcatheter embolization is currently the preferred treatment for ruptured or enlarging renal angiomyolipoma (AML), although the optimum choice of embolic material has not yet been established. We present mid- to long-term outcomes following embolization of AMLs with Onyx. MATERIALS AND METHODS: Ten AMLs in seven patients (including two with tuberous sclerosis) were embolized with Onyx. Patients were followed-up clinically, with tumour size and renal function measured pre- and post-procedure. RESULTS: Mean pre-treatment AML size was 63.4 mm (range 42-100). Mean clinical follow-up was 431.4 days (range 153-986) and imaging follow-up 284.2 days (range 30-741). There was no haemorrhage from treated lesions within the follow-up period. Of patients who had cross-sectional imaging pre- and post-procedure, mean decrease in AML size of 22 mm was seen after Onyx embolization (p = 0.0058, 95 % CI 9.13-34.87). No significant difference between serum creatinine was seen pre- and post-procedure (p = 0.54, 95 % CI 8.63-4.85). CONCLUSIONS: Onyx embolization of renal AMLs is effective in the medium to long term, with theoretical benefits in safety and durability of result. PMID- 27468836 TI - Perceived oral discomfort and pain in children and adolescents with intellectual or physical disabilities as reported by their legal guardians. AB - AIM: This was, firstly, to study the occurrence of oral pain and discomfort, using the Dental Discomfort Questionnaire (DDQ), in children and adolescents with intellectual or physical disabilities, compared with controls. Secondly, was to analyse the relationship between pain and discomfort, as measured by the DDQ, and dental health, as well as oral hygiene habits and dietary habits. METHODS: The study included 135 children and adolescents (12-18 years), registered at the Child and Adolescent Habilitation Unit in Goteborg and Sodra Bohuslan, Sweden, and 135 gender- and age-matched controls. The children's legal guardians completed a questionnaire comprising the DDQ and questions on oral hygiene and dietary habits. Data on dental health were retrieved from dental records. RESULTS: The DDQ total mean score was higher for the study group, compared with the control group, 3.2 (SD 2.9) vs. 1.6 (SD 2.0), respectively (p = 0.001). Furthermore, children and adolescents with a severe intellectual disability had higher total mean DDQ scores than children with a mild intellectual disability, 4.8 (SD 4.2) vs. 2.4 (SD 2.9), respectively (p = 0.034), and also higher than children with a physical disability, 2.2 (SD 2.1) (p = 0.012). There were no differences in DMFT between children with disabilities and age-matched controls. There was no relationship between the DDQ scores and oral hygiene/dietary habits in children with disabilities. CONCLUSIONS: Children and adolescents with intellectual or physical disabilities experienced oral discomfort and pain more often than matched controls. Dental health expressed as DMFT could not be related to the DDQ responses. PMID- 27468839 TI - Treatment of Unstable Intertrochanteric Fractureswith Proximal Femoral Nail Antirotation II: Our Experience in Indian Patients. AB - INTRODUCTION: Unstable intertrochanteric fractures are difficult to manage and the choice of implant is critical for fracture fixation. The purpose of this study was to evaluate the functional and radiological outcome of proximal femoral nail antirotationII (PFNA II) in the treatment of unstable intertrochanteric fractures. MATERIALS AND METHODS: We reviewed 45 patients of unstable intertrochanteric fractures, who were treated with the PFNA II between 2011 and 2013. Of which, 3 patients were died within 6 months of follow up. Hence, 42 patients were available for the study including 26 men and 16 women. The mean age was 61 years (range, 35 -90). Clinical evaluation was done using Harris hip score. The position of the blade in the femoral head was evaluated using Cleveland zones and tip apex distance. The fracture reduction was assessed using the Garden Alignment Index and postoperative fracture gap (mm) measurement. RESULTS: The mean follow up period was 15.3 months (range, 9-27). Excellent to good results were accounted for 78% of cases according to Harris hip score. No cases of cut out or breakage of the implant noted. Implant removal was done in 2 patients due to persistent anterior thigh pain. CONCLUSION: We recommend PFNA II for fixation of unstable intertrochanteric fractures with less operative time and low complication rate. However, proper operative technique is important for achieving fracture stability and to avoid major complications. PMID- 27468841 TI - On the Design of Smart Homes: A Framework for Activity Recognition in Home Environment. AB - A smart home is a home environment enriched with sensing, actuation, communication and computation capabilities which permits to adapt it to inhabitants preferences and requirements. Establishing a proper strategy of actuation on the home environment can require complex computational tasks on the sensed data. This is the case of activity recognition, which consists in retrieving high-level knowledge about what occurs in the home environment and about the behaviour of the inhabitants. The inherent complexity of this application domain asks for tools able to properly support the design and implementation phases. This paper proposes a framework for the design and implementation of smart home applications focused on activity recognition in home environments. The framework mainly relies on the Cloud-assisted Agent-based Smart home Environment (CASE) architecture offering basic abstraction entities which easily allow to design and implement Smart Home applications. CASE is a three layered architecture which exploits the distributed multi-agent paradigm and the cloud technology for offering analytics services. Details about how to implement activity recognition onto the CASE architecture are supplied focusing on the low level technological issues as well as the algorithms and the methodologies useful for the activity recognition. The effectiveness of the framework is shown through a case study consisting of a daily activity recognition of a person in a home environment. PMID- 27468840 TI - High oxygen extraction and slow recovery of muscle deoxygenation kinetics after neuromuscular electrical stimulation in COPD patients. AB - PURPOSE: It was hypothesized that patients with chronic obstructive pulmonary disease (COPD) would exhibit a slow muscle deoxygenation (HHb) recovery time when compared with sedentary controls. METHODS: Neuromuscular electrical stimulation (NMES 40 and 50 mA, 50 Hz, 400 us) was employed to induce isometric contraction of the quadriceps. Microvascular oxygen extraction (uO2EF) and HHb were estimated by near-infrared spectroscopy (NIRS). Recovery kinetic was characterized by measuring the time constant Tau (HHb-tau). Torque and work were measured by isokinetic dynamometry in 13 non-hypoxaemic patients with moderate-to-severe COPD [SpO2 = 94.1 +/- 1.6 %; FEV1 (% predict) 48.0 +/- 9.6; GOLD II-III] and 13 age- and sex-matched sedentary controls. RESULTS: There was no desaturation in either group during NMES. Torque and work were reduced in COPD versus control for 40 and 50 mA [torque (Nm) 50 mA = 28.9 +/- 6.9 vs 46.1 +/- 14.2; work (J) 50 mA = 437.2 +/- 130.0 vs. 608.3 +/- 136.8; P < 0.05 for all]. High uO2EF values were observed in the COPD group at both NMES intensities (corrected by muscle mass 50 mA = 6.18 +/- 1.1 vs. 4.68 +/- 1.0 %/kg; corrected by work 50 mA = 0.12 +/- 0.05 vs. 0.07 +/- 0.02 %/J; P < 0.05 for all). Absolute values of HHb-tau (50 mA = 31.11 +/- 9.27 vs. 18.08 +/- 10.70 s), corrected for muscle mass (50 mA 3.80 +/- 1.28 vs. 2.05 +/- 1.45 s/kg) and corrected for work (50 mA = 0.08 +/- 0.04 vs. 0.03 +/- 0.02 s/J) were reduced in COPD (P < 0.05 for all). The variables behaviour for 40 mA was similar to those of 50 mA. CONCLUSIONS: COPD patients exhibited a slower muscle deoxygenation recovery time after NMES. The absence of desaturation, low torque and work, high uO2EF and high values for recovery time corrected by muscle mass and work suggest that intrinsic muscle dysfunction has an impact on muscle recovery capacity. PMID- 27468842 TI - A comprehensive survey of energy-aware routing protocols in wireless body area sensor networks. AB - Wireless body area sensor network is a special purpose wireless sensor network that, employing wireless sensor nodes in, on, or around the human body, makes it possible to measure biological parameters of a person for specific applications. One of the most fundamental concerns in wireless body sensor networks is accurate routing in order to send data promptly and properly, and therefore overcome some of the challenges. Routing protocols for such networks are affected by a large number of factors including energy, topology, temperature, posture, the radio range of sensors, and appropriate quality of service in sensor nodes. Since energy is highly important in wireless body area sensor networks, and increasing the network lifetime results in benefiting greatly from sensor capabilities, improving routing performance with reduced energy consumption presents a major challenge. This paper aims to study wireless body area sensor networks and the related routing methods. It also presents a thorough, comprehensive review of routing methods in wireless body area sensor networks from the perspective of energy. Furthermore, different routing methods affecting the parameter of energy will be classified and compared according to their advantages and disadvantages. In this paper, fundamental concepts of wireless body area sensor networks are provided, and then the advantages and disadvantages of these networks are investigated. Since one of the most fundamental issues in wireless body sensor networks is to perform routing so as to transmit data precisely and promptly, we discuss the same issue. As a result, we propose a classification of the available relevant literature with respect to the key challenge of energy in the routing process. With this end in view, all important papers published between 2000 and 2015 are classified under eight categories including 'Mobility-Aware', 'Thermal Aware', 'Restriction of Location and Number of Relays', 'Link-aware', 'Cluster- and Tree-Based', 'Cross-Layer', 'Opportunistic', and 'Medium Access Control'. We, then, provide a full description of the statistical analysis of each category in relation to all papers, current hybrid protocols, and the type of simulators used in each paper. Next, we analyze the distribution of papers in each category during various years. Moreover, for each category, the advantages and disadvantages as well as the number of issued papers in different years are given. We also analyze the type of layer and deployment of mathematical models or algorithmic techniques in each category. Finally, after introducing certain important protocols for each category, the goals, advantages, and disadvantages of the protocols are discussed and compared with each other. PMID- 27468843 TI - Ventilation-associated pneumonia and probiotics: many clues do not make evidence. PMID- 27468844 TI - Ventilation-associated pneumonia and probiotics: many clues do not make evidence. Response to comments by Colombo and Codazzi. PMID- 27468845 TI - Children under ... not admitted. PMID- 27468846 TI - The influence of hydrological conditions on phytoplankton community structure and cyanopeptide concentration in dammed lowland river. AB - Study results show continuous summer-autumn dominance of toxic cyanobacteria in plankton not only in the strongly eutrophicated lowland Siemianowka reservoir, but also along 130 km of Narew river below the lake. The negative effects of eutrophication of the reservoir reach far outside its boundaries. One of the symptoms of eutrophication was a mass development of cyanobacteria, including the toxin-producing Planktothrix agardhii. In the reservoir, the biomass of the species strongly correlated with the concentration of microcystins. Redundancy analysis (RDA) identified seven environmental variables as significantly influencing phytoplankton composition in the Narew river: discharge, conductivity, temperature, dissolved oxygen, orthophosphates, silicate ions, and total phosphorous. Higher discharge in the river and higher rates of flushing induced faster dilution of limnoplankton in downstream river and had positive effects on the decrease of cyanobacterial biomass and microcystin concentration. PMID- 27468847 TI - Physical-chemical determinant properties of biological communities in continental semi-arid waters. AB - Throughout human history, water has undergone changes in quality. This problem is more serious in dry areas, where there is a natural water deficit due to climatic factors. The aims of this study, therefore, were (i) to verify correlations between physical attributes, chemical attributes and biological metrics and (ii) from the biological attributes, to verify the similarity between different points of a body of water in a tropical semi-arid region. Samples were collected every 2 months, from July 2009 to July 2011, at seven points. Four physical attributes, five chemical attributes and four biological metrics were investigated. To identify the correlations between the physicochemical properties and the biological metrics, hierarchical cluster analysis (HCA) and canonical correlation analysis (CCA) were applied. Nine classes of phytoplankton were identified, with the predominance of species of cyanobacteria, and ten families of macroinvertebrates. The use of HCA resulted in the formation of three similar groups, showing that it was possible to reduce the number of sampling points when monitoring water quality with a consequent reduction in cost. Group I was formed from the waters at the high end of the reservoir (points P1, P2 and P3), group II by the waters from the middle third (points P4 and P5), and group III by the waters from the lower part of the reservoir (points P6 and P7). Richness of the phytoplanktons Cyanophyceae, Chorophyceae and Bacillariophyceae was the attribute which determined dissimilarity in water quality. Using CCA, it was possible to identify the spatial variability of the physicochemical attributes (TSS, TKN, nitrate and total phosphorus) that most influence the metrics of the macroinvertebrates and phytoplankton present in the water. Low macroinvertebrate diversity, with a predominance of indicator families for deterioration in water quality, and the composition of phytoplankton showing a predominance of cyanobacteria, suggests greater attention to the management of water resources. PMID- 27468848 TI - Monitoring of airborne particulate matter at mountainous urban sites. AB - Concentrations of various size fractions (TSP, PM10, PM2.5, and PM1.0) of particulate matter (PM) were measured at two mountainous sites, Buk Han (BH) and Gwan AK (GA), along with one ground reference site at Gwang Jin (GJ), located in Seoul, South Korea for the 4 years from 2010 to 2013. The daily average concentrations of TSP, PM10, PM2.5, and PM1.0 at BH were 47.9 +/- 32.5, 37.0 +/- 24.6, 20.6 +/- 12.9, and 15.3 +/- 9.53 MUg m(-3), respectively. These values were slightly larger than those measured at GA while much lower than those measured at the reference site (GJ). Seasonal variations in PM concentrations were consistent across all locations with a relative increase in concentrations observed in spring and winter. Correlation analysis showed clear differences in PM concentrations between the mountainous sites and the reference site. Analysis of these PM concentrations indicated that the distribution of PM in the mountainous locations was affected by a number of manmade sources from nearby locations, including both traffic and industrial emissions. PMID- 27468849 TI - Neglected epiphyseal injuries of the distal end of the radius with ulnar impaction: analysis of distal osteotomy of both bones using a dorsal midline approach. AB - BACKGROUND: To evaluate results of a technique for treating neglected epiphyseal injuries of the distal radius with ulnar impaction. MATERIALS AND METHODS: This retrospective study involved six cases (four males; two females), all of whom sustained the primary injury during childhood (range 9-12 years of age). All presented with wrist deformity and ulnar-sided wrist pain. They were managed with osteotomy of the distal radius, osteotomy and shortening of the ulna, harvesting the bone grafts, and distal radioulnar joint (DRUJ) reduction performed simultaneously through a dorsal midline approach. Mean follow-up was 30 months (range 24-36). RESULTS: Deformity correction and pain relief was observed in all patients. Flexion arc increased from an average of 60 degrees to 102.5 degrees , supination from an average of 31.67 degrees to 67.50 degrees , and pronation from an average of 30.83 degrees to 61.67 degrees . The mean preoperative DASH score was 87.5, which improved to 18.72 postoperatively. CONCLUSION: Neglected epiphyseal injuries of the distal radius are difficult to manage and many variations are described for handing each of the associated problems. Our technique provides an option for managing this injury with an easy surgical approach, single incision, and cost effectiveness. All the four components of the surgery, which include osteotomy of the distal radius, osteotomy of the ulna, harvesting the bone grafts, and DRUJ reduction were done through a single incision and in a single sitting. Level of evidence IV. PMID- 27468850 TI - Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features. AB - BACKGROUND: The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients. RESULTS: We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non malignant lung tissues have higher microbiota alpha diversity than the paired tumors. CONCLUSIONS: Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings. PMID- 27468851 TI - Single agent blinatumumab as frontline therapy for an 85-year-old patient with B cell precursor acute lymphoblastic leukemia. PMID- 27468852 TI - Suspected encephalitis with Candida tropicalis and Fusarium detected by unbiased RNA sequencing. PMID- 27468853 TI - Correlation between JAK2 allele burden and pulmonary arterial hypertension and hematological parameters in Philadelphia negative JAK2 positive myeloproliferative neoplasms. An Egyptian experience. AB - Myeloproliferative neoplasms are characterized by a common stem cell-derived clonal proliferation, but are phenotypically diverse. JAK2 is mutated (V617F) in more than 90 % of patients with polycythemia vera (PV) and approximately 60 % of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Pulmonary arterial hypertension (PAH) is a major complication of several hematological disorders. Chronic myeloproliferative disorders associated with PAH have been included in group five for which the etiology is unclear and/or multifactorial. The aim of this study is to screen Egyptian Philadelphia negative JAK2 positive myeloproliferative neoplasm patients for the presence of PAH and its correlation with JAK2 allele burden. We also made a review for correlation of JAK2 allele with hematological parameters comparing our results to others. We enrolled 60 patients with Philadelphia negative myeloproliferative neoplasms. All patients enrolled in the study were subjected to laboratory and imaging workup in the form of CBC, liver, kidney profile, bone marrow examination, abdominal ultrasonography, and transthoracic echocardiography. Our results revealed that 7 patients out of 60 (11.67 %) had pulmonary arterial hypertension, 3 patients with PMF, 2 patients with PRV, and 2 patients with ET, and its correlation with JAK2 allele burden was not statistically significant. Correlation analysis between JAK2 V617F allele burden and other parameters revealed: statistical significant correlation with age, HB, HCT, PLT, UA, LDH, and splenic diameter but insignificant correlation with WBCs and PAH. Pulmonary arterial hypertension prevalence in our study was 11.67 % and no significant correlation with JAK 2 allele burden. Our study is the largest one up to our knowledge that studies the association between its prevalence and JAK2 burden. PMID- 27468854 TI - Detection of non-CLL-like monoclonal B cell lymphocytosis increases dramatically in the very elderly, while detection of CLL-like populations varies by race: findings in a multiethnic population-based cohort of elderly women. AB - Monoclonal B cell lymphocytosis (MBL) is both a marker of immune senescence and a potential precursor of B cell malignancy. Most MBL populations have a chronic lymphocytic leukemia-like (CLL-like) immunophenotype, but those that are CD5 negative (non-CLL-like) are also recognized and may represent a distinct diagnostic entity. To date, MBL studies have taken place in relatively homogenous populations, although risk of CLL varies across racial groups and geographic regions. We report flow cytometry data from 597 ethnically diverse 64-94-year-old women from across the USA who are participants in the Women's Health Initiative (WHI) Long-Life Study (LLS). Overall, MBL was detected in 26 % of the participants and included 20.9 % with a CLL-like immunophenotype, 5 % with a non CLL-like immunophenotype, and 1.3 % with both. White and Hispanic women were more than twice as likely to have a CLL-like MBL population detected than African American women, corrected for age (P = 0.003). By contrast, detection of non-CLL like MBL did not vary significantly by race, but did increase markedly with advancing age, being present in 12.7 % of those aged 85 and older. We provide new evidence that rates of detection of CLL-like MBL are lower in African Americans, and further suggest that non-CLL-like clonal expansions should be regarded as distinct from CLL-like MBL. PMID- 27468855 TI - Cortical thickness development of human primary visual cortex related to the age of blindness onset. AB - Blindness primarily induces structural alteration in the primary visual cortex (V1). Some studies have found that the early blind subjects had a thicker V1 compared to sighted controls, whereas late blind subjects showed no significant differences in the V1. This implies that the age of blindness onset may exert significant effects on the development of cortical thickness of the V1. However, no previous research used a trajectory of the age of blindness onset-related changes to investigate these effects. Here we explored this issue by mapping the cortical thickness trajectory of the V1 against the age of blindness onset using data from 99 blind individuals whose age of blindness onset ranged from birth to 34 years. We found that the cortical thickness of the V1 could be fitted well with a quadratic curve in both the left (F = 11.59, P = 3 * 10-5) and right hemispheres (F = 6.54, P = 2 * 10-3). Specifically, the cortical thickness of the V1 thinned rapidly during childhood and adolescence and did not change significantly thereafter. This trend was not observed in the primary auditory cortex (A1), primary motor cortex (M1), or primary somatosensory cortex (S1). These results provide evidence that an onset of blindness before adulthood significantly affects the cortical thickness of the V1 and suggest a critical period for cortical development of the human V1. PMID- 27468856 TI - Genetic effects of FASN, PPARGC1A, ABCG2 and IGF1 revealing the association with milk fatty acids in a Chinese Holstein cattle population based on a post genome wide association study. AB - BACKGROUND: A previous genome-wide association study deduced that one (ARS-BFGL NGS-39328), two (Hapmap26001-BTC-038813 and Hapmap31284-BTC-039204), two (Hapmap26001-BTC-038813 and BTB-00246150), and one (Hapmap50366-BTA-46960) genome wide significant single nucleotide polymorphisms (SNPs) associated with milk fatty acids were close to or within the fatty acid synthase (FASN), peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A), ATP binding cassette, sub-family G, member 2 (ABCG2) and insulin-like growth factor 1 (IGF1) genes. To further confirm the linkage and reveal the genetic effects of these four candidate genes on milk fatty acid composition, genetic polymorphisms were identified and genotype-phenotype associations were performed in a Chinese Holstein cattle population. RESULTS: Nine SNPs were identified in FASN, among which SNP rs41919985 was predicted to result in an amino acid substitution from threonine (ACC) to alanine (GCC), five SNPs (rs136947640, rs134340637, rs41919992, rs41919984 and rs41919986) were synonymous mutations, and the remaining three (rs41919999, rs132865003 and rs133498277) were found in FASN introns. Only one SNP each was identified for PPARGC1A, ABCG2 and IGF1. Association studies revealed that FASN, PPARGC1A, ABCG2 and IGF1 were mainly associated with medium-chain saturated fatty acids and long-chain unsaturated fatty acids, especially FASN for C10:0, C12:0 and C14:0. Strong linkage disequilibrium was observed among ARS-BFGL-NGS-39328 and rs132865003 and rs134340637 in FASN (D' > 0.9), and among Hapmap26001-BTC-038813 and Hapmap31284 BTC-039204 and rs109579682 in PPARGC1A (D' > 0.9). Subsequently, haplotype-based analysis revealed significant associations of the haplotypes encompassing eight FASN SNPs (rs41919999, rs132865003, rs134340637, rs41919992, rs133498277, rs41919984, rs41919985 and rs41919986) with C10:0, C12:0, C14:0, C18:1n9c, saturated fatty acids (SFA) and unsaturated fatty acids (UFA) (P = 0.0204 to P < 0.0001). CONCLUSION: Our study confirmed the linkage between the significant SNPs in our previous genome-wide association study and variants in FASN and PPARGC1A. SNPs within FASN, PPARGC1A, ABCG2 and IGF1 showed significant genetic effects on milk fatty acid composition in dairy cattle, indicating their potential functions in milk fatty acids synthesis and metabolism. The findings presented here provide evidence for the selection of dairy cows with healthier milk fatty acid composition by marker-assisted breeding or genomic selection schemes, as well as furthering our understanding of technological processing aspects of cows' milk. PMID- 27468857 TI - NIH Prepares to Launch Precision Medicine Study. AB - The NIH has awarded $55 million to several institutions to launch the Precision Medicine Initiative Cohort Program, which aims to enroll at least 1 million Americans between 2016 and 2020 in a long-term study. Organizers say the program will facilitate collaboration among researchers, potentially accelerating the development of personalized therapies for cancer and other diseases. PMID- 27468858 TI - EUS-guided intrahepatic portosystemic shunt with direct portal pressure measurements: a novel alternative to transjugular intrahepatic portosystemic shunting. AB - BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunting involves the creation of a low-resistance channel between the portal vein (PV) and the hepatic vein (HV), and is routinely performed under angiography. The aims were to evaluate (1) safety and technical feasibility; (2) procedural duration; and (3) subjective workload assessment of EUS-guided intrahepatic portosystemic shunt (EIPS). METHODS: Five Yorkshire pigs were used in the study. The HV or inferior vena cava (IVC) was identified using a linear-array echoendoscope and accessed with a 19-G FNA needle preloaded with a digital pressure wire. Mean pressure was recorded. The needle was advanced into the PV, where pressure measurements were again taken, and ultimately exchanged over a guidewire. A lumen-apposing metal stent was deployed under EUS and fluoroscopic guidance, with distal and proximal ends positioned inside the PV and HV (IVC), respectively. Dilation was performed, and pressure measurements repeated. The National Aeronautics and Space Administration (NASA) Task Load Index (TLI) was scored. Animals survived 2 weeks before necropsy. RESULTS: EIPS was successful in 5 out of 5 pigs. Mean time required for EUS identification, needle access, pressure measurement, and stent placement was 43 (31-55) minutes. NASA TLI scores revealed moderate workload. Mean baseline pressure measurements were PV 7.0 (5-9) and HV/IVC 5.0 (3-7) mm Hg and PV 6.3 (5-7) and HV/IVC 6.0 (4-7) mm Hg after. All animals survived 2 weeks. No bleeding was seen on necropsy. CONCLUSIONS: This study demonstrates the technical feasibility of EIPS using LAMS, with direct portal pressure measurement, in a survival model. In addition, the procedure was performed quickly with moderate technical demand. PMID- 27468860 TI - Stereoselective synthesis of strained cage compounds via gold-catalyzed allene functionalization. AB - The diastereoselective synthesis of strained adducts that show cage-like structures has been accomplished directly from allenyl-beta-lactams through gold catalysis. PMID- 27468859 TI - The Revised Inventory of the Dimensions of Emerging Adulthood (IDEA-R) and Substance Use Among College Students. AB - Transition-to-adulthood themes, or thoughts and feelings about emerging adulthood, have been measured by the Inventory of the Dimensions of Emerging Adulthood (IDEA) and found to be associated with substance use among emerging adults. It has been suggested, however, that the IDEA is lengthy and may not include the most unique and theoretically relevant constructs of emerging adulthood. The Revised Inventory of the Dimensions of Emerging Adulthood (IDEA-R) was developed as an alternative instrument, but research has yet to determine the relationship between the IDEA-R and substance use among emerging adults (ages 18 25 years). College students completed surveys indicating their identification with transition-to-adulthood themes and substance use. Logistic regression models examined the associations between transition-to-adulthood themes and marijuana use and binge drinking, respectively. Participants who felt emerging adulthood was a time of identity exploration were less likely to report marijuana use, while feelings of experimentation/possibility were positively associated with marijuana use and binge drinking. The IDEA-R may be useful for identifying correlates of substance use among emerging adults. Future research should evaluate the IDEA-R among representative samples of emerging adults to confirm the findings of this study. Health professionals working in substance use prevention may consider targeting the themes of identity exploration and experimentation/possibility in programs intended for emerging adults. PMID- 27468862 TI - Characterization of clinical and environmental isolates of Vibrio cidicii sp. nov., a close relative of Vibrio navarrensis. AB - Four Vibrio spp. isolates from the historical culture collection at the Centers for Disease Control and Prevention, obtained from human blood specimens (n=3) and river water (n=1), show characteristics distinct from those of isolates of the most closely related species, Vibrio navarrensis and Vibrio vulnificus, based on phenotypic and genotypic tests. They are specifically adapted to survival in both freshwater and seawater, being able to grow in rich media without added salts as well as salinities above that of seawater. Phenotypically, these isolates resemble V. navarrensis, their closest known relative with a validly published name, but the group of isolates is distinguished from V. navarrensis by the ability to utilize l-rhamnose. Average nucleotide identity and percent DNA-DNA hybridization values obtained from the pairwise comparisons of whole-genome sequences of these isolates to V. navarrensis range from 95.4-95.8 % and 61.9 64.3 %, respectively, suggesting that the group represents a different species. Phylogenetic analysis of the core genome, including four protein-coding housekeeping genes (pyrH, recA, rpoA and rpoB), places these four isolates into their own monophyletic clade, distinct from V. navarrensis and V. vulnificus. Based on these differences, we propose these isolates represent a novel species of the genus Vibrio, for which the name Vibrio cidicii sp. nov. is proposed; strain LMG 29267T (=CIP 111013T=2756-81T), isolated from river water, is the type strain. PMID- 27468861 TI - Risk-based approach for systematic development of gastroretentive drug delivery system. AB - The research envisioned was the development of diltiazem hydrochloride effervescent floating matrix tablet using a risk-based approach. Preliminarily, the in vitro drug release profile was derived which theoretically simulated the in vivo condition after oral administration. Considering this as a rationale, the formulation development was initiated with defining the quality target product profile (QTPP) and critical quality attributes (CQAs). The preliminary studies were conducted to screen material attributes and process parameters followed by their risk assessment studies to select the plausible factors affecting the drug product CQAs, i.e., floating lag time and drug release profile. A 3(2) full factorial design was used to estimate the effect of the amount of swelling polymer (X 1) and gas-generating agent (X 2) on percent drug release (Q t1h and Q t8h) and floating lag time. Response and interaction plots were generated to examine the variables. Selection of an optimized formulation was done using desirability function and further validated. The model diagnostic plots represent the absence of outliers. The optimized formula obtained by the software was further validated, and the result of drug release and floating lag time was close to the predicted values. In a clear and concise way, the current investigations report the successful development of an effervescent floating matrix tablet for twice daily administration of diltiazem hydrochloride. PMID- 27468863 TI - Mitochondrial replacement techniques: egg donation, genealogy and eugenics. AB - Several objections against the morality of researching or employing mitochondrial replacement techniques have been advanced recently. In this paper, I examine three of these objections and show that they are found wanting. First I examine whether mitochondrial replacement techniques, research and clinical practice, should not be carried out because of possible harms to egg donors. Next I assess whether mitochondrial replacement techniques should be banned because they could affect the study of genealogical ancestry. Finally, I examine the claim that mitochondrial replacement techniques are not transferring mitochondrial DNA but nuclear DNA, and that this should be prohibited on ethical grounds. PMID- 27468864 TI - The moral unacceptability of abandoning human embryos. AB - The focus of this paper is on the ethics of the act of wilfully "abandoning" human embryos. I offer a critique of this unique behaviour, which draws on empirical data about who wilfully abandons their surplus embryos and why. I argue that wilful embryo abandonment is in all cases avoidable. Given this, I make three observations which speak to the moral unacceptability of embryo abandonment. The first has to do with the abandoner's unfair treatment of the clinic storing their abandoned embryos, and the second the abandoner's apparent lack of sympathy for the plight of other people like them, who require assistance (e.g. donated embryos) in pursuing their family-building goals. The third observation has to do with the abandoner's failure to meet their responsibility for directing the handling of their embryos, and what their reaction to that responsibility (through abandonment) says about their moral character in certain respects. There is good reason to conclude that wilful embryo abandonment is morally unacceptable. One implication of this normative conclusion is that clinics have reasonable grounds for justifying the design of their policies and practices so as to make wilful embryo abandonment impossible. PMID- 27468865 TI - Richard Selzer. PMID- 27468866 TI - M30/M65 ratio predicts the outcome of paclitaxel chemotherapy for NSCLC. AB - PURPOSE: Paclitaxel is an effective treatment for some of the non-small-cell lung cancer (NSCLC) patients. However, prediction of the outcome of paclitaxel treatment at the early stage of the chemotherapy is difficult. M30 and M65 are circulating fragments of cytokeratin 18 released during apoptosis or necrosis, respectively, and have been used as markers to evaluate chemotherapy in some cancers. Here, we aimed to examine M30 and M65 values for predicting the therapeutic outcome of paclitaxel treatment of NSCLC. METHODS: The serum levels of M30 and M65 before and after paclitaxel treatment in advance-stage NSCLC patients were analyzed, and compared to those in healthy controls. The importance of the M30 and M65 levels to the outcome of chemotherapy was analyzed. RESULT: We found that the serum M30 and M65 levels were higher in patients with NSCLC (n = 44) than in control healthy subjects (n = 56) (p < 0.001). Two days after paclitaxel treatment, the serum levels of both M30 and M65 significantly increased in NSCLC patients (p < 0.001). Neither marker alone significantly correlated with overall patient survival, but the ratio of M30 vs M65 appeared to be an important prognostic factor for the overall survival of the patients (p < 0.01). CONCLUSION: Our results suggest that the serum M30/M65 ratio may be a prognostic factor for the outcome of paclitaxel treatment in NSCLC. PMID- 27468868 TI - Multiple myeloma, immunotherapy and minimal residual disease. AB - Multiple myeloma (MM) is an incurable heterogeneous hematological malignancy in which relapse is characterized by re-growth of residual tumor and immune suppression with a complex biology that affects many aspects of the disease and its response to treatment. The bone marrow microenvironment, including immune cells, plays a central role in MM pathogenesis, survival, and drug resistance. The advances in basic and translational research, introduction of novel agents, particularly combination therapies, improved indicators of quality of life and survival. Minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) has revolutionized monitoring of treatment response in MM. The importance of MFC methodology will be further strengthened by the ongoing international standardization efforts. Results of MRD testing provide unique and clinically important information and demonstrated the prognostic significance of MRD in patients, leading to regulate treatment intensity in many contemporary protocols. In this review, we will summarize the principal approaches in MM immunotherapy, focusing how new agents have potential in the treatment of MM and application of MRD detection by MFC as a surrogate endpoint would allow quicker evaluation of treatment outcomes and rapid identification of effective new therapies. PMID- 27468867 TI - Urinary circulating DNA detection for dynamic tracking of EGFR mutations for NSCLC patients treated with EGFR-TKIs. AB - PURPOSE: Changes in EGFR profiles of non small cell lung cancer (NSCLC) patients correlates to clinical outcome. Extracting quality tumor tissue remains a challenge for molecular profiling. Our study aims to ascertain the clinical relevance of urinary cell free DNA as an alternative tumor material source. METHODS: 150 patients with activating EGFR mutation and received EGFR-TKIs were recruited to participate in the serial monitoring study. Matched primary tumor samples were taken together with blood and urine specimens before the initiation of TKIs. The EGFR mutation testing was performed and quantified using ddPCR. For serial time point measurements, urine and blood samples were extracted at 1-month intervals for duration of 9 months. RESULTS: Urinary ctDNA yielded a close agreement of 88 % on EGFR mutation status when compared to primary tissue at baseline. Almost all samples detected via urine specimens were uncovered in plasma samples. Analysis of urinary cell free DNA at different time points showed a strong correlation to treatment efficacy. Interestingly, a secondary EGFR mutation T790M was detected for 53 % of the patients during monitoring. The results were corroborated with the plasma ctDNA analysis. The T790M+ group had a reduced median survival when compared to the wildtype group. CONCLUSION: Urinary cell free DNA may be a potential alternative to conventional primary tissue based EGFR mutation testing. Our findings showed that the assay sensitivity was comparable to results from blood plasma. Urinary samples being noninvasive and readily available have clinical utility for monitoring of EGFR TKI treatment. PMID- 27468869 TI - Incidence of preleukemic fusion genes in healthy subjects. AB - The diagnostics of leukemia relies upon multi-parametric approach involving a number of different pathology disciplines such as flow cytometry, histopathology, cytogenetics and molecular genetics [fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR)]. Childhood leukemia is often determined by the presence of specific chromosomal translocation that entails the generation of preleukemic fusion genes (PFG). In the last two decades, several studies have reported observations that PFG are present in healthy population and not necessarily result in leukemia. The first such study by Limpens and colleagues on t(14/18)/ BCL2-JH [1] and next in line [2, 3] led to many questions regarding the significance of these chromosomal translocations in leukemogenesis. However, the data on the incidence of PFG are contradictive. This review aims to highlight the molecular genetic approaches used by various studies with regard to differences in diagnostics and incidence of PFG in healthy subjects. The focus is on the incidence and prevalence of the most common PFG such as TEL-AML1, MLL-AF4, BCR ABL (p190), AML1-ETO, PML-RARA, and CBFB-MYH11 detected in umbilical cord blood, in neonatal blood spots (Guthrie cards (GC)), bone marrow, peripheral blood and tissues of amortized fetuses. We conclude that the incidence of PFG is significantly higher than incidence of leukemia and more sophisticated analysis of PFG in leukemogenic cell populations is warranted to relate the occurrence of PFG with leukemia. The emerging notion is that only those PFG may contribute to development of leukemia which arise in stem cells at specific time windows during development. Thus, screening of PFG in subpopulations of stem cells may be a challenge for assessment of predisposition to leukemia and for validation of cell transplant to minimize donor cell-derived leukemia. PMID- 27468870 TI - MiR-129-5p is down-regulated and involved in migration and invasion of gastric cancer cells by targeting interleukin-8. AB - Expression of microRNA-129-5p (miR-129-5p) has been reported to decrease in gastric cancer (GC). However, little information is available about how miR-129 5p affects cell migration and invasion of GC. Cancer samples and matched non tumor adjacent tissues were obtained from patients with GC. Besides, peripheral blood samples were collected from both the patients and healthy volunteers. Expression of miR-129-5p was analyzed by real-time PCR (RT-PCR). After transfection with miR-129-5p mimics, miR-129-5p inhibitor, or negative controls in human GC cell line SGC-7901, cell viability, colony-formation ability, migration, and invasion assay were evaluated. Luciferase reporter assay, RT-PCR, and enzyme-linked immunosorbent assay (ELISA) were performed to explore whether interleukin-8 was a target of miR-129-5p. Further, small interfering RNA (siRNA) against IL-8 was transfected into cells, and then the effects of miR-129-5p inhibitor on migration and invasion were assessed. MiR-129-5p was down-regulated in both GC samples and blood samples compared to their matched non-tumor adjacent tissues and healthy volunteers (both P < 0.05). Compared to the control group, transfection with miR-129-5p inhibitor markedly increased the cell viability, colony-forming ability, and numbers of migrated and invaded cells. Luciferase reporter assay confirmed that IL-8 was a direct target of miR-129-5p, and IL-8 was negatively regulated by miR-129-5p. Co-transfection of miR-129-5p inhibitor with si-IL-8 reversed the effect of miR-129-5p inhibitor on the migration and invasion of the cells. MiR-129-5p and regulates migration and invasion of GC cells by targeting IL-8. PMID- 27468871 TI - Frameshift mutations of OGDH, PPAT and PCCA genes in gastric and colorectal cancers. AB - Metabolic reprogramming is a hallmark of cancer. However, genetic alterations in metabolism-related genes are largely unknown. The aim of this study was to identify whether somatic mutations in OGDH, PPAT and PCCA genes known to be involved in amino acid or nucleotide metabolism are mutated in gastric cancer (GC) and colorectal cancer (CRC). By public database search, we identified that OGDH, PPAT and PCCA genes harbor mononucleotide repeats that may serve as mutation targets in cancers with microsatellite instability (MSI). We analyzed the repeats for the presence of the mutations in 90 GCs and 141 CRCs using single strand conformation polymorphism (SSCP) and samples of 10 patients with shifted bands were sequenced. We found frameshift mutations of OGDH (3 cases), PCCA (5 cases) and PPAT (2 cases) in the cancers. These mutations were exclusively detected in MSI-high (MSI-H), and not in MSI-low or MSI-stable (MSI-L/MSS) cancers. We also analyzed 16 CRCs for the presence of intratumoral heterogeneity (ITH) and found that one CRC harbored regional ITH for OGDH frameshift mutation showing very rare frequency of OGDH mutation ITH in colorectal cancer tissues. Our data indicate that amino acid/nucleotide metabolism-related genes OGDH, PPAT and PCCA acquire somatic mutations in MSH-H GCs and CRCs and that mutational ITH may occur in at least some of these tumors. Collectively, our results may extend our insight into the involvement of amino acid/nucleotide metabolism in the pathogenesis of cancer for, in particular, MSI-H GCs and CRCs. PMID- 27468872 TI - Activation of the ER stress and calcium signaling in angiomyolipoma. AB - Renal angiomyolipomas (AMLs) are uncommon benign tumors that occur sporadically or as a part of tuberous sclerosis complex (TSC). Risk of life threatening hemorrhage is the main clinical concern. Although several evidences suggest that hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is crucial for these tumors, modulation of other metabolic pathways might affect tumor growth and progression. Therefore, we aimed to further characterize angiomyolipoma by TSC1/TSC2 expression, hypoxic status, expression of endoplasmic reticulum (ER) stress markers and calcium transport from the ER through the inositol 1,4,5-trisphosphate (IP3) receptors. Despite our expectations, angiomyolipoma were not hypoxic, as determined by absent expression of the carbonic anhydrase IX, which is a reliable marker of hypoxia. This was in accord with very low expression of TSC1 (that is associated with HIF activation) and a high expression of TSC2. Angiomyolipoma specimens also showed a significant upregulation of an anti-apoptotic marker Bcl2 when compared to healthy kidney tissue supporting the induction of pro-survival signaling. Moreover, angiomyolipoma specimens showed the overexpression of the ER stress markers XBP1, CHOP and ATF4 as well as of the mediators of calcium metabolism, namely the type 1 and 2, but not the type 3 IP3 receptors. These data suggest that the ER stress response, survival and calcium metabolism-related pathways but not hypoxia is an important component of the angiomyolipoma pathogenesis. PMID- 27468873 TI - MicroRNA-433 inhibits migration and invasion of ovarian cancer cells via targeting Notch1. AB - We aimed to determine the effects of miR-433 on the malignant behaviors of ovarian cancer cells, as well as to elucidate the possible mechanisms of ovarian cancer development. A total of 9 ovarian cancer tissues and 9 matched normal ovary tissues were obtained, and the expression levels of miR-433 and Notch1 were then determined by real-time PCR. Human ovarian cancer cell lines SKOV3 and OVCAR3 were transfected with miR-433 mimics, negative miR-control and Notch1 siRNA. The expression of Notch1 protein in transfected cells was determined by western blot. In addition, the proliferation, migration and invasion of SKOV3 and OVCAR3 cells in vitro were then evaluated using Cell Counting Kit 8, wound healing assay and Transwell invasion assay, respectively. Besides, bioinformatics methods and luciferace reporter assay were performed to confirm whether Notch1 was a direct target of miR-433. The expression of miR-433 was markedly down regulated while Notch1 expression was significantly up-regulated in ovarian cancer tissues compared with matched normal ovary tissues. Overexpression of miR 433 significantly inhibited the migration and invasion of ovarian cancer cells, but had not significant effects on cell proliferation. In addition, Notch1 was a direct target of miR-433. Besides, down-regulation of Notch1 inhibited the invasion of ovarian cancer cells. Our findings indicate that miR-433 may inhibit cell migration and invasion in the development of ovarian cancer via down regulation of Notch1. Notch1 may serve as a potential target in cancer therapy. PMID- 27468874 TI - B-cell translocation gene 3 overexpression inhibits proliferation and invasion of colorectal cancer SW480 cells via Wnt/beta-catenin signaling pathway. AB - Increasing evidences have shown that B-cell translocation gene 3 (BTG3) inhibits metastasis of multiple cancer cells. However, the role of BTG3 in colorectal cancer (CRC) and its possible mechanism have not yet been reported. In our study, we evaluated BTG3 expression in several CRC cell lines. Then, pcDNA3.1-BTG3 was transfected into SW480 cells. We found that BTG3 was upregulated in SW480 cells after overexpression plasmid transfection. BTG3 overexpression significantly inhibited cell growth and decreased PCNA (proliferating cell nuclear antigen) and Ki67 levels. BTG3 overexpression markedly downregulated Cyclin D1 and Cyclin E1 levels, whereas elevated p27. Overexpression of BTG3 arrested the cell cycle at G1 phase, which was abrogated by p27 silencing. Furthermore, migration, invasion and EMT of SW480 cells were significantly suppressed by BTG3 overexpression. Further investigations showed the inhibition of Wnt/beta-catenin signaling pathway. We then used GSK3beta specific inhibitor SB-216763 to activate the Wnt/beta-catenin signaling pathway. We found that Wnt/beta-catenin signaling pathway activation reversed the effect of BTG3 overexpression on cell proliferation, cell cycle progression, invasion and EMT. In conclusion, BTG3 overexpression inhibited cell growth, induced cell cycle arrest and suppressed the metastasis of SW480 cells via the Wnt/beta-catenin signaling pathway. BTG3 may be considered as a therapeutic target in CRC treatment. PMID- 27468875 TI - MicroRNA-182 suppresses clear cell renal cell carcinoma migration and invasion by targeting IGF1R. AB - The purpose of our study was aimed to determine the functional role of microRNA (miR)-182 in clear cell renal cell carcinoma (ccRCC) and try to clarify its underlying molecular mechanism. Expression of miR-182 in both cancer and peripheral blood samples was analyzed by quantitative real-time PCR (qRT-PCR). Human RCC line Caki-1 cells were transfected with miR-182 mimic, miR-182 inhibitor, or negative controls, and then the cell viability, colony-formation ability, migration, and invasion assay were determined. Luciferase reporter assay, qRT-PCR and Western blotting were used to determine whether insulin-like growth factor 1 receptor (IGF1R) was a target of miR-182. Further, small interfering RNA (siRNA) against IGF1R was co-transfected with miR-182 inhibitor into cells, and then the effects on migration and invasion were assessed. MiR-182 was down-regulated in both cancer and blood samples compared to the matched non tumor adjacent tissues and healthy volunteers, respectively (both P<0.05). Compared to the control group, cell viability, colony-forming ability, and numbers of migrated and invaded cells were significantly decreased by transfection with miR-182 mimic but were markedly increased by miR-182 inhibitor (all P < 0.05). Luciferase reporter assay confirmed that IGF1R was a target gene of miR-182, and IGF1R was negatively regulated by miR-182. Co-transfection of miR 182 inhibitor with si-IGF1R reversed the effect of miR-182 inhibitor on the migration and invasion of the cells. MiR-182 functions as an anti-oncogene in ccRCC, and miR-182-mediated inhibition of cell migration and invasion might be through directly targeting IGF1R. PMID- 27468876 TI - Noscapine inhibits human hepatocellular carcinoma growth through inducing apoptosis in vitro and in vivo. AB - Noscapine, a phthalideisoquinoline alkaloid derived from opium, has been demonstrated as a promising anti-tumor compound against various cancers. However, the anti-cancer activity of noscapine in hepatocellular carcinoma has not been defined. In this study, we investigate the inhibitive effects of noscapine on human hepatocellular carcinoma (HCC) using both in vitro and in vivo models. In vitro proliferation assay showed that noscapine suppressed HepG2 and Huh7 cells in dose- and time-dependent manners. With a mouse xenograft model, noscapine showed notable inhibition on HCC tumor growth in vivo without suppression of body weight. Moreover, apoptotic induction and regulation of related signalings by noscapine were examined by nuclear DNA staining, TUNEL, and western blotting assays. Results showed that noscapine induced apoptosis in HCC cells both in vitro and in vivo. Further studies indicated that noscapine induced antive capsase-3, cleavage PARP, and decreased the ratio of Bcl-2/Bax. Hence, these data indicates that noscapine selectively suppresses HCC cell growth through apoptosis induction, providing evidence for application of noscapine as a novel agent against human hepatocellular carcinoma. PMID- 27468877 TI - Notch1 is associated with the multidrug resistance of hypoxic osteosarcoma by regulating MRP1 gene expression. AB - Hypoxia and Notch signaling pathway are closely related and both participate in cell proliferation and drug resistance of tumors. However, the molecular mechanisms of hypoxia and Notch signaling pathway in cell proliferation and drug resistance of osteosarcoma (OS) remain unclear. In this study, to further evaluate the role of hypoxia and Notch1 on drug resistance of OS, we investigated the influence of inhibiting Notch1 pathway by Notch1 small interference RNA (siRNA) on human MG-63 OS cells in hypoxia. Our data showed that hypoxia promoted OS cell proliferation, induced the G0/G1-S-G2/M phase transition, and increased multidrug resistance of human OS cells. Western blot analysis suggested that hypoxia increased the expression of HIF-1alpha, Notch1, and multidrug resistance protein-1 (MRP1) in human OS cells. Notch1 siRNA inhibits proliferation and increases apoptosis of hypoxic OS cells. Finally, these hypoxic OS cells can be sensitized to multidrug treatment through inhibition of the Notch protein expression by siRNA. Repression of the Notch protein expression resulted in down regulation of MRP1 protein. These data support the conclusion that Notch signaling is up-regulated in human OS cells under hypoxia and Notch1 may represent a viable target to overcome chemoresistant OS cells in a hypoxic niche by regulating MRP1 gene expression. PMID- 27468878 TI - The quality of life following allogeneic hematopoietic stem cell transplantation a multicenter retrospective study. AB - Although allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers a unique curative potential, it may be connected with high treatment-related morbidity and mortality. Besides many organ complications, allo-HSCT may significantly affect quality of life (QOL). PATIENTS AND METHODS: Between January 2011 and December 2012, five hundred and ninety patients (pts) from 6 transplant centers in the Czech Republic filled in the questionnaire for the quantitative measurement of QOL using Functional Assessment of Cancer Therapy-General (FACT-G) version 4. Study cohort characteristics were as follows: 325 males, 340 pts received myeloablative conditioning, 383 pts received PBPC, representation of diagnoses; acute leukemia (n=270), bone marrow failure (n=36), chronic myeloid leukemia (n=74), myelodysplastic/myeloproliferative syndrom (n=110), lymphoproliferative disease (n=93). The median age at allo-HSCT was 43 years (range: 1.7 - 71.0), the median time from allo-HSCT to questionnaire completing was 3.8 years (range: - 0.2 - 21.6). The earliest allo-HSCT was performed in November 1989, the last in September 2012. In this retrospective study, we investigated the impact of various factors on the QOL after allo-HSCT: age, gender, diagnosis, type of conditioning, time from diagnosis to allo-HSCT, disease stage, graft type, donor type, time from allo-HSCT to questionnaire completing, GVHD, relapse. Only data from patients who were more than 3 months after allo-HSCT were used for the multivariate analysis. The overall results of the total FACT-G score (median=85.0; range: 29-108) as well as the results of each specific dimension - PWB (median=23.0; range: 5-28), SWB (median=24.0; range: 7-28), EWB (median= 19.0; range: 4-24), FWB (mean=21.0; range: 2-28) showed a value in the highest quartile of the possible evaluation. In multivariate analysis, an inferior QOL score was reported for patients with aGVHD (p=0.002), cGVHD (p<0.001), QOL decreased with increasing age (p=0.048) and increased with time elapsed since allo-HSCT (p<0.001).Allogeneic HSCT represents an important intervention into the overall integrity of the organism. In particular, the development of GVHD can cause very serious organ, but also mental problems which can significantly reduce the QOL. The QOL is steadily increasing with increasing interval from allo-HSCT but improvement and disappearance of these complications may take many years, and sometimes these effects may probably persist permanently. PMID- 27468879 TI - The role of CRP, PCT, IL-6 and presepsin in early diagnosis of bacterial infectious complications in paediatric haemato-oncological patients. AB - Bacterial infection is the most common complication in paediatric oncological patients during cancer treatment. A suitable tool for early prediction of unfavourable course of infection is still needed. We performed a prospective longitudinal observational study to evaluate of the role of serum biomarkers (C reactive protein, procalcitonin, interleukin-6, presepsin) in the early diagnosis of bacteraemia (gram-negative versus gram-positive) in patients with haematological malignancies. We observed 69 febrile episodes in 33 patients (17 male, 16 female; 1.5-18.9 years, mean 7.31 years, median 5 years). Within this sample, there were 22 cases of positive blood cultures, 16 cases of sepsis, 38 cases of fever with no signs or symptoms of sepsis, and two deaths from infectious complications. All markers tested had good negative predictive value (73% - 93%). CRP was characterized by good specificity for registration bacteraemia (96%, 95% CI: 85% - 99%), but other results were inconclusive. We identified comparably balanced sensitivity (64% - 81%) and specificity (61% - 88%) for interleukin-6 and procalcitonin, and we proved their quality to predict positive blood culture and clinical signs of sepsis as well. Patients with gram negative bacteraemia had significantly elevated levels of PCT and IL-6 in comparison with a group of patients with gram-positive bacteraemia (p = 0.04 for PCT and p = 0.005 for IL-6). Presepsin was characterized by poor specificity (27%, 95% CI: 15% - 43%) and positive predictive value (24%, 95% CI: 12 - 39%) for predicting bacteraemia, and by better sensitivity (84%, 95% CI: 55% - 98%) and specificity (58%, 95% CI: 42% - 73%) for predicting clinical signs of sepsis. PMID- 27468880 TI - Retrospective analysis of efficacy of trastuzumab in adjuvant treatment of HER 2 positive early breast cancer - single institution experience. AB - Addition of trastuzumab to chemotherapy is the cornerstone of adjuvant treatment of early HER2 positive breast cancer. Clinical trials and metaanalyses of adjuvant trastuzumab have shown significant reduction in risk of recurrence and death. Nevertheless, the real magnitude of the effect of any drug must be reevaluated in daily clinical conditions, due to the fact that daily clinical practice often differs from conditions in clinical trials. In order to measure the benefit of adding adjuvant trastuzumab in HER 2 positive early breast cancer treatment, we have performed retrospective analysis in a single institution on consecutive patients divided in 2 cohorts: one, treated in "pre - trastuzumab" and the other in "trastuzumab era". Between 2003 and 2012, 258 consecutive HER 2 positive patients with early breast cancer have been treated with adjuvant chemotherapy, 103 patients did not received trastuzumab (patients treated from 2003 till 2007), and 155 (patients treated from 2008 till 2012) received trastuzumab. Patients who received trastuzumab experienced significantly longer median disease-free survival (107 vs. 92 months, LR: 11.6, p <0.001); breast cancer-specific survival (130 vs. 117 months, LR: 10.7, p < 0.001) and median overall survival (123 vs. 108 months LR = 11.6, p < 0.001). The benefits of adding trastuzumab were independent of chemotherapy regimen and hormonal therapy. This retrospective analysis has shown a clear, statistically significant benefit of adjuvant trastuzumab in treatment of early, HER2 positive breast cancer in daily clinical practice, and confirmed the results of the registration clinical trials. PMID- 27468881 TI - Immune checkpoints in aggressive breast cancer subtypes. AB - Immune checkpoints are molecules referred to inhibitory pathways in the immune system that play a pivotal role in prevention of autoimmunity and oncogenesis. The aim of the study was to evaluate expression levels of selected immune checkpoints- PD-1 (programmed cell death protein 1), and PD-L1 (programmed cell death 1 ligand 1) in breast cancer patients, suitable for breast conservation and sentinel node biopsy and determine their associations with clinicopathological factors.Expression of the genes coding for PD-1 and PD-L1 was analyzed in formalin-fixed paraffin-embedded specimens using real-time PCR. mRNA expression levels were determined using beta actin (ACTB) as an endogenous control. There was a trend towards significance between higher PD-1 and PD-L1 levels in triple negative breast cancers (p=0.1). Higher PD-L1 expression was also found in aggressive breast cancer subtypes e.g. triple negative and HER2 (human epidermal growth factor receptor 2) -positive as compared with subtypes with better prognosis such as luminal A and luminal BHER2-negative (p=0.05). There was a trend towards significance in higher PD-1 levels in triple negative and HER-2 positive breast cancers (p=0.1). A statistically significant difference was found between PD-L1 expression and tumor grade (p=0.01). Elevated PD-L1 levels were noted in G3 tumors. Immunogenicity appears to be gaining importance in triple negative and HER2-positive molecular subtypes of breast cancer, and the results in this study provide a basis for further investigation into the role of immune checkpoints in breast cancer. PMID- 27468882 TI - Single-agent cytarabine is insufficient for the treatment of human mantle cell lymphoma in mouse xenograft model. AB - Mantle cell lymphoma is an aggressive type of B-cell non-Hodgkin lymphoma with adverse prognosis. It was demonstrated that alternation of CHOP and DHAP chemotherapy improved outcome of mantle cell lymphoma patients. However, which components of DHAP, cisplatin, cytarabine, or both, were responsible for the improved outcome remained unclear. To answer this question, antitumor efficacies of equally toxic doses of cytarabine, cisplatin, and three different combinations were compared in vivo using mouse xenograft models of mantle cell lymphoma. We demonstrated that cisplatin, alone or with cytarabine, is significantly superior to single-agent cytarabine in both eliminating lymphoma cells and suppressing their proliferation rate. PMID- 27468883 TI - Detection of oncogenic mutations in cervical carcinoma using method High Resolution Melting (HRM). AB - Oncogenic mutations in proto-oncogenes and tumor suppressor genes represent one of key events in cancerogenesis. In this study, we analysed mutation status in PIK3CA, KRAS and EGFR proto-oncogenes and TP53 tumor suppressor gene in a cohort of twenty-four patients diagnosed with squamous cell carcinoma or adenocarcinoma using the screening method "High Resolution Melting" (HRM). Positive findings were confirmed and identified by Sanger sequencing. Totally, we detected DNA sequence changes in targeted regions in seven patients (7/24, 29.2%). In PIK3CA gene, we found six sequence changes in four patients (4/24, 16.7%) and four of them were confirmed as oncogenic mutations. In KRAS gene, we detected sequence changes in four patients (4/24, 16.7%). Conversely, we identified pathogenic or potentially pathogenic sequence changes neither in EGFR nor TP53 genes. Our results suggest that sequence changes are specific neither for a certain histological subtype, clinical stage nor lymph node involvement and they appear independently on the presence of HPV (human papillomavirus) infection since early clinical stages. We observed the correlation between the presence of DNA sequence changes and hTERC gene amplification, but we did not find a significant relationship between the identified DNA sequence changes and detected copy-number alterations using the technique of array-CGH (array-based comparative genomic hybridization). Regardless our results confirmed an important role of oncogenic mutations in PIK3CA and KRAS genes in the neoplastic transformation process in the cervical carcinoma pathogenesis. Their identification in the early clinical stages should encourage further studies to better understand these mutations and exploit them for more detailed diagnostics. PMID- 27468884 TI - Regulatory T cells are an important prognostic factor in breast cancer: a systematic review and meta-analysis. AB - The clinical relevance of regulatory T cell (Treg) infiltration in breast cancer (BC) remains controversial, and no recent meta-analysis has been published on this subject. Our aim was to identify the precise relationship between Tregs and the prognosis and clinic-pathological features of BC. Eligible articles were identified with a MEDLINE database search over a period up to March 2015. Our meta-analysis was performed using STATA software 11.0 and Review Manager 5.3. The correlations between Treg infiltration and clinico-pathological features and BC prognosis were analyzed. Subgroup and sensitivity analyses, as well as meta regression, were conducted. Eighteen published studies (including 8,562 patients) were eligible. Overall survival (OS) and disease-, recurrence-, and progression free survival (DFS/RFS/PFS) were correlated with Treg infiltration (OR=2.03 (95% CI, 1.40-2.95; P=0.000) and 1.48 (95% CI, 1.00-2.19; P=0.050), respectively), including 3-, 5-, and 10-year mortality rates. In addition, low Treg infiltration was present in estrogen receptor (ER)-positive tumors (P=0.000), progesterone receptor (PR)-positive tumors (P=0.003), Her2-negative tumors (P=0.000) and histological grade I/II tumors (P=0.001). No publication bias was observed with the exception of OS. Subgroup analysis suggested that the mortality rate of the high Treg infiltration subgroup was increased compared with the low Treg infiltration subgroup among ER-positive patients. Treg infiltration indicated a poorer prognosis for BC and is related to ER, PR, and Her2 status and histological grade. Thus, Treg infiltration could help predict outcomes and guide clinical therapy. PMID- 27468885 TI - MicroRNAs in urine supernatant as potential non-invasive markers for bladder cancer detection. AB - Urinary bladder carcinoma contributes to 4% of newly diagnosed oncological diseases in the Czech Republic. Biomarkers for its early non-invasive detection are therefore highly desirable. Urine seems to be an ideal source of such biomarkers due to the content of cell-free nucleic acids, especially microRNAs (miRNAs).To find potential biomarkers among miRNAs in urine supernatant, we examined in total 109 individuals (36 controls and 73 bladder cancer patients) in three phases. In the first - discovery - phase, microarray cards with 381 miRNAs were used for miRNA analysis of 13 controls and 46 bladder cancer patients. In the second - verification - phase, the results of this first phase were verified on the same groups of subjects by single-target qPCR assays for the selected miRNAs. For the third - validation - phase, new independent samples of urine supernatant (23 controls and 27 bladder cancer patients) were analyzed using single-target qPCR assays for 13 verified in the previous phase. The results of all phases were normalized to miR-191, miR-28-3p, and miR-200b, which were selected as suitable for our study by the qBase+(r).We found that miR-125b, miR 30b, miR-204, miR-99a, and miR-532-3p are significantly down-regulated in patients' urine supernatant. In our experiments, the analysis of miR-125 levels provided the highest AUC (0.801) with 95.65% specificity and 59.26% sensitivity, the analysis of miR-99a lead to AUC (0.738) with 82.61% specificity and 74.07% sensitivity. We demonstrate that levels of these miRNAs could potentially serve as promising diagnostic markers for the non-invasive diagnostics of bladder cancer. PMID- 27468886 TI - Clinical value of high expression level of CD71 in acute myeloid leukemia. AB - CD71 (transferrin receptor 1, TfR-1) is a type II membrane glycoprotein and associated closely with tumors. It was recognized as an indication for diagnosing acute erythroid leukemia (AEL). High expression level of CD71 has been identified as a negative prognostic marker for many solid tumors. However, whether CD71 should be identified as an adverse marker in acute myeloid leukemia (AML) remained conflicting. We studied 214 AML patients for analysis of clinical and laboratory data. Taking the CD71 expression level of 60% as a standard, we divided our patients into two groups. We discovered that AML with high expression level of CD71 was prone to linked with severe anemia (P=0.004), thrombocytopenia (P<0.001) and complex karyotype (P=0.024) and had increasing expression level of CD117 (P=0.001). No statistically significant correlations in age, gender, WBC counting, molecular markers between the two groups. And moreover, high expression level of CD71 did not alter the pattern of survival time. PMID- 27468887 TI - The impact of p16 and HER2 expression on survival in patients with ovarian carcinoma. AB - The purpose of this study was to investigate the impact of p16 and HER2 expression on survival in patients with ovarian carcinoma.This descriptive analytic, cross-sectional study, was conducted on 47 paraffin blocks of epithelial ovarian tumors. Suitable slides were prepared to evaluate HER2 and p16 by immunohistochemistry using HercepTest kit (DAKO) and p16INK4A kit (DAKO, code 5334). Clinical information and pathology data were extracted from patients' medical and pathology records. Data entry and analysis was done by SPSS (version 16) software. Chi-square test, Mann-Whitney test, t-test, Kruskal-Wallis test, log rank test and Kaplan-Meier method were used. The mean age of the patients was 51.6 years (range 19-71 years). The most common histological type of epithelial ovarian cancer was serous adenocarcinoma (68.1%). P16 expression was detected in 34% of epithelial ovarian tumors. P16 expression was significantly associated with stage of disease (P = 0.04) and overall survival (P = 0.001), but HER2 expression was not associated with overall survival, stage of disease and tumor histological type.Expression of p16 may be used as a prognostic factor of overall survival and stage of disease, while HER2 expression may not be used as a prognostic factor of overall survival. PMID- 27468888 TI - New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations. AB - BACKGROUND: The RET proto-oncogene is responsible for the pathogenesis of hereditary (98%) and sporadic (40%) medullary thyroid carcinoma (MTC). In sporadic MTC, somatic RET mutations are associated with a poor prognosis. OBJECTIVES: We looked at the genetic profile of patients with advanced and metastatic MTC. The correlation between these mutations and outcome was also investigated. METHODS: 70 patients with advanced and metastatic sporadic MTC were studied. Exons 10-11 and 13-16 of RET were analysed by direct sequencing. All cases were studied for RAS and the majority also for TERT mutations. RET/RAS negative cases were analysed for other oncogene mutations. RESULTS: 64/70 cases (91.4%) showed a somatic mutation, while 6 (8.6%) were negative. Among the mutated cases, RET mutations, mainly M918T, were the most prevalent (93.8%). K- or H-RAS mutations were present in 6.2% of cases and were mutually exclusive with RET. No other mutations were found. Four tumours showed two RET somatic mutations. We found a complex somatic RET alteration in 6/60 (10%) RET-positive sporadic MTC cases. A positive correlation between a poor prognosis and the multiple number of RET mutations was found. CONCLUSIONS: This study showed a high prevalence of somatic RET mutations in advanced and metastatic MTCs. RAS mutations were present in a small percentage of cases and mutually exclusive with RET mutations. In a small number of cases, more than one RET mutation was present in the same tissue. RET double mutations and, to a lesser extent, also complex mutations showed a worse outcome. PMID- 27468889 TI - Evaluating the consequences of rheumatoid arthritis. AB - Patients and non-patients tend to attach different utility values to the state of suffering from specific illnesses. This observation naturally leads to the question whose utility values should be used as the basis in cost-effectiveness analysis (CEA). Intuitively, one would presume that patients are better informed about the consequences of their illness, and public authorities should, therefore, use the patients' utility values in CEA. Contrary to this presumption, it has been argued that society at large should determine which values are to be used and not the patients because, in the end, it is societal resources that are to be allocated. Against this background, we use data from a discrete choice experiment (DCE) that was completed by patients of rheumatoid arthritis (RA) and non-patients to explore the discrepancies between the two groups' utility estimates for typical consequences of RA. Our results indicate that both groups attach remarkably similar part-worth utilities to the symptoms pain, fatigue, and functional limitations. However, non-patients significantly undervalue the ability to work when compared to patients. PMID- 27468890 TI - Arabidopsis JINGUBANG Is a Negative Regulator of Pollen Germination That Prevents Pollination in Moist Environments. AB - The molecular mechanism of pollen germination and pollen tube growth has been revealed in detail during the last decade, while the mechanism that suspends pollen grains in a dormant state is largely unclear. Here, we identified the JINGUBANG (JGB) gene by screening pollen-specific genes for those that are unnecessary for pollen germination. We showed that the pollen of the jgb loss-of function mutant exhibited hyperactive germination in sucrose-only medium and inside the anther, while this phenotype was rescued by the transgenic expression of JGB in jgb plants. JGB contains seven WD40 repeats and is highly conserved in flowering plants. Overexpression of JGB inhibits pollen germination. These results indicate that JGB is a novel negative regulator of pollen germination. In addition, we found that jasmonic acid (JA) abundance was significantly elevated in jgb pollen, while exogenous application of methyl jasmonate rescued the inhibition of pollen germination in plants overexpressing JGB Based on the molecular features of JGB and on the finding that it interacts with a known JA biosynthesis-related transcription factor, TCP4, we propose that JGB, together with TCP4, forms a regulatory complex that controls pollen JA synthesis, ensuring pollination in moist environments. PMID- 27468891 TI - MODD Mediates Deactivation and Degradation of OsbZIP46 to Negatively Regulate ABA Signaling and Drought Resistance in Rice. AB - Plants have evolved complicated protective mechanisms to survive adverse conditions. Previously, we reported that the transcription factor OsbZIP46 regulates abscisic acid (ABA) signaling-mediated drought tolerance in rice (Oryza sativa) by modulating stress-related genes. An intrinsic D domain represses OsbZIP46 activity, but the detailed mechanism for the repression of OsbZIP46 activation remains unknown. Here, we report an OsbZIP46-interacting protein, MODD (Mediator of OsbZIP46 deactivation and degradation), which is homologous to the Arabidopsis thaliana ABSCISIC ACID-INSENSITIVE5 binding protein AFP. MODD was induced by ABA and drought stress, but the induction was much slower than that of OsbZIP46 In contrast to OsbZIP46, MODD negatively regulates ABA signaling and drought tolerance, and inhibits the expression of OsbZIP46 target genes. We found that MODD negatively regulates OsbZIP46 activity and stability. MODD represses OsbZIP46 activity via interaction with the OsTPR3-HDA702 corepressor complex and downregulation of the histone acetylation level at OsbZIP46 target genes. MODD promotes OsbZIP46 degradation via interaction with the U-box type ubiquitin E3 ligase OsPUB70. Interestingly, the D domain is required for both deactivation and degradation of OsbZIP46 via its interaction with MODD. These findings show that plants fine-tune their drought responses by elaborate regulatory mechanisms, including the coordination of activity and stability of key transcription factors. PMID- 27468893 TI - Mechanical Ventilation During Cardiopulmonary Bypass. PMID- 27468894 TI - Contained Rupture of an Aortic Root With Multilobulated Pseudoaneurysm in a Patient With Behcet's Disease. PMID- 27468892 TI - The Central domain of RyR1 is the transducer for long-range allosteric gating of channel opening. AB - The ryanodine receptors (RyRs) are intracellular calcium channels responsible for rapid release of Ca(2+) from the sarcoplasmic/endoplasmic reticulum (SR/ER) to the cytoplasm, which is essential for the excitation-contraction (E-C) coupling of cardiac and skeletal muscles. The near-atomic resolution structure of closed RyR1 revealed the molecular details of this colossal channel, while the long range allosteric gating mechanism awaits elucidation. Here, we report the cryo-EM structures of rabbit RyR1 in three closed conformations at about 4 A resolution and an open state at 5.7 A. Comparison of the closed RyR1 structures shows a breathing motion of the cytoplasmic platform, while the channel domain and its contiguous Central domain remain nearly unchanged. Comparison of the open and closed structures shows a dilation of the S6 tetrahelical bundle at the cytoplasmic gate that leads to channel opening. During the pore opening, the cytoplasmic "O-ring" motif of the channel domain and the U-motif of the Central domain exhibit coupled motion, while the Central domain undergoes domain-wise displacement. These structural analyses provide important insight into the E-C coupling in skeletal muscles and identify the Central domain as the transducer that couples the conformational changes of the cytoplasmic platform to the gating of the central pore. PMID- 27468895 TI - Transcatheter Aortic Valve Replacement: Clinical Update on Access Approaches in the Contemporary Era. PMID- 27468896 TI - The effect of combining photoinitiator systems on the color and curing profile of resin-based composites. AB - OBJECTIVE: To evaluate the effect of combining camphorquinone (CQ) and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO) on the color and curing profile of resin-based composites. METHODS: Experimental composites were produced with different CQ and TPO molar concentrations: CQ-only, 3CQ:1TPO, 1CQ:1TPO, 1CQ:3TPO, and TPO-only. Polywave LED was characterized using a beam profiler. Block-shaped samples (5mm*5mm*3mm depth) were cured in a custom-designed mold with a polywave LED positioned to compare the regions exposed to the 420-495nm and 380-420nm LED emittances. To map the cure profile, degree of conversion (DC) of longitudinal cross-sections from each block were evaluated by FT-NIR. Color, light-transmittance and light-absorption during curing were evaluated on specimens 1-3mm thick. Data were analyzed using ANOVA/Tukey's test (alpha=0.05; beta=0.2). RESULTS: Though the polywave LED beam profile was non-uniform, up to a depth of 2mm no differences in DC were found among the composites containing CQ with TPO added up to 50%, regardless of the position under the curing tip. Composites with higher TPO concentration showed a decrease in DC beginning with a depth of 1mm, while composites with higher or similar CQ concentrations did not show decreased DC until a depth of 3mm. Higher TPO concentration reduced initial yellowness and color change after curing; and lower CQ concentration decreased light-absorption at greater depths. SIGNIFICANCE: The combination of CQ with TPO added up to 50% reduced the yellowness and color change of composites after curing without affecting cure efficiency up to a depth of 2mm. PMID- 27468898 TI - Cu isotopic signature in blood serum of liver transplant patients: a follow-up study. AB - End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient's condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about -0.500/00). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the delta(65)Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure. PMID- 27468897 TI - Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans. AB - BACKGROUND: Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions. RESULTS: The single nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity. Examples associated with ancient trans-specific balancing selection are also discovered. Allelic imbalance in chromatin accessibility and divergence in transcription factor motif sequences indicate that these balanced polymorphisms cause distinct regulatory variation. However, a majority of these variants show no association with the expression level of the target gene. Instead, single-cell experimental data for gene expression and chromatin accessibility demonstrate that heterozygous sequences can lower cell-to-cell variability in proportion to selection strengths. This negative correlation is more pronounced for highly expressed genes and consistently observed when using different data and methods. Based on mathematical modeling, we hypothesize that extrinsic noise from fluctuations in transcription factor activity may be amplified in homozygotes, whereas it is buffered in heterozygotes. While high expression levels are coupled with intrinsic noise reduction, regulatory heterozygosity can contribute to the suppression of extrinsic noise. CONCLUSIONS: This mechanism may confer a selective advantage by increasing cell population homogeneity and thereby enhancing the collective action of the cells, especially of those involved in the defense systems in humans. PMID- 27468899 TI - The levels of bone turnover markers 25(OH)D and PTH and their relationship with bone mineral density in postmenopausal women in a suburban district in China. AB - : This study evaluated the levels of bone turnover markers (BTMs) and investigated relationships between them and bone mineral density (BMD) in postmenopausal women in China suburban district. The prevalence of osteoporosis was 25.03 % at lumbar spine and 6.23 % at femoral neck, and BTMs were negatively correlated with BMDs. INTRODUCTION: The aims of this study were to evaluate the levels of bone turnover markers (BTMs), including serum N-terminal procollagen of type I collagen (P1NP), beta C-terminal cross-linked of type I collagen (beta CTX), 25-hydroxyvitamin D [25(OH)D], and parathyroid hormone (PTH), and to investigate relationships between these markers and bone mineral density (BMD) as well the prevalence of osteoporosis in postmenopausal women of suburban district. METHODS: A population of 4822 postmenopausal women aged 55-69 years old (62.22 +/ 6.75) from the suburban district was recruited voluntarily. BMD was measured at the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry; 2251 women in this group had the serum BTMs 25(OH)D and PTH tested. RESULTS: The prevalence of osteoporosis was 25.03 % at lumbar spine and 6.23 % at femoral neck. The median (interquartile range) values of serum P1NP, beta-CTX, 25(OH)D, and PTH were 59.3 ng/mL (44.7-75.52), 0.370 ng/mL (0.280 0.490), 23.0 ng/mL (17.1-30.5), and 31.4 pg/mL (24.9-39.7), respectively. Serum P1NP and beta-CTX levels presented significantly negative correlations with BMDs at the all the sites (Betastd = -0.098 to -0.208, respectively, P < 0.001), whereas PTH levels were negatively correlated with BMDs of the femoral neck and total hip (Betastd = -0.062 and -0.054, P < 0.01, respectively). Serum 25(OH)D had positive associations with BMDs at total hip (Betastd = 0.051, P < 0.01). CONCLUSIONS: The BMD of postmenopausal women in China suburban area is higher than that in downtown area, and over 60 % of the participants had their serum 25(OH)D level over 20 ng/mL. BTMs were negatively correlated with BMDs, suggesting that BTMs are reliable factors for early declines in BMD. PMID- 27468900 TI - Applying ethnic-specific bone mineral density T-scores to Chinese women in the USA. AB - : Caucasian reference data are used to classify bone mineral density in US women of all races. However, use of Chinese American reference data yields lower osteoporosis prevalence in Chinese women. The reduction in osteoporosis labeling may be relevant for younger Chinese women at low fracture risk. INTRODUCTION: Caucasian reference data are used for osteoporosis classification in US postmenopausal women regardless of race, including Asians who tend to have lower bone mineral density (BMD) than women of white race. This study examines BMD classification by ethnic T-scores for Chinese women. METHODS: Using BMD data in a Northern California healthcare population, Chinese women aged 50-79 years were compared to age-matched white women (1:5 ratio), with femoral neck (FN), total hip (TH), and lumbar spine (LS) T-scores calculated using Caucasian versus Chinese American reference data. RESULTS: Comparing 4039 Chinese and 20,195 white women (44.8 % age 50-59 years, 37.5 % age 60-69 years, 17.7 % age 70-79 years), Chinese women had lower BMD T-scores at the FN, TH, and LS (median T-score 0.29 0.72 units lower across age groups, p < 0.001) using Caucasian reference data. Using Chinese American BMD reference data resulted in an average +0.47, +0.36, and +0.48 units higher FN, TH, and LS T-scores, respectively, reducing the prevalence of osteoporosis (T-score <= -2.5) in Chinese women at the FN (16.7 to 6.6 %), TH (9.8 to 3.2 %), and LS (23.2 to 8.9 %); osteoporosis prevalence at any one of three sites fell from 29.6 to 12.6 % (22.4 to 8.1 % for age 50-64 years and 43.2 to 21.0 % for age 65-79 years). CONCLUSION: Use of Chinese American BMD reference data yields higher (ethnic) T-scores by 0.4-0.5 units, with a large proportion of Chinese women reclassified from osteoporosis to osteopenia. The reduction in osteoporosis labeling with ethnic T-scores may be relevant for younger Chinese women at low fracture risk. PMID- 27468901 TI - Sclerostin does not play a major role in the pathogenesis of skeletal complications in type 2 diabetes mellitus. AB - : In contrast to previously reported elevations in serum sclerostin levels in diabetic patients, the present study shows that the impaired bone microarchitecture and cellular turnover associated with type 2 diabetes mellitus (T2DM)-like conditions in ZDF rats are not correlated with changes in serum and bone sclerostin expression. INTRODUCTION: T2DM is associated with impaired skeletal structure and a higher prevalence of bone fractures. Sclerostin, a negative regulator of bone formation, is elevated in serum of diabetic patients. We aimed to relate changes in bone architecture and cellular activities to sclerostin production in the Zucker diabetic fatty (ZDF) rat. METHODS: Bone density and architecture were measured by micro-CT and bone remodelling by histomorphometry in tibiae and femurs of 14-week-old male ZDF rats and lean Zucker controls (n = 6/group). RESULTS: ZDF rats showed lower trabecular bone mineral density and bone mass compared to controls, due to decreases in bone volume and thickness, along with impaired bone connectivity and cortical bone geometry. Bone remodelling was impaired in diabetic rats, demonstrated by decreased bone formation rate and increased percentage of tartrate-resistant acid phosphatase-positive osteoclastic surfaces. Serum sclerostin levels (ELISA) were higher in ZDF compared to lean rats at 9 weeks (+40 %, p < 0.01), but this difference disappeared as their glucose control deteriorated and by week 14, ZDF rats had lower sclerostin levels than control rats (-44 %, p < 0.0001). Bone sclerostin mRNA (qPCR) and protein (immunohistochemistry) were similar in ZDF, and lean rats at 14 weeks and genotype did not affect the number of empty osteocytic lacunae in cortical and trabecular bone. CONCLUSION: T2DM results in impaired skeletal architecture through altered remodelling pathways, but despite altered serum levels, it does not appear that sclerostin contributes to the deleterious effect of T2DM in rat bone. PMID- 27468903 TI - The Growing Pediatric Health Gap: Environmental Injustice Threatens Our Future. PMID- 27468902 TI - Discordance between fat mass index and body mass index is associated with reduced bone mineral density in women but not in men: the Busselton Healthy Ageing Study. AB - : The obesity-BMD relationship is complex. In 3045 middle-aged adults, we found that in women (but not men) with discordant fat mass index (FMI)/BMI categories, higher body fat for BMI was associated with lower BMD, suggesting that increased fat mass without an accompanying increase in lean mass may be deleterious to bone. INTRODUCTION: The relationship between obesity and BMD is complex. FMI (fat mass (kg) / height (m)2) is a more accurate measure of fatness than BMI, and depending on body composition, some individuals have discordant BMI/FMI categories. We examined associations between FMI, BMI and BMD in participants in the Busselton Healthy Ageing Study. METHODS: Body composition and BMD of the hip, spine and total body were measured using DXA in 3045 participants (1644 females) aged 45-67 years. Using standard BMI/FMI categories, the participants were classified as underweight/fat deficit, normal, overweight/excess fat, obese I and obese II-III. RESULTS: BMI and FMI categories were concordant in 77.3 % of females and 71.2 % of males. There were 12.9 % females and 13.2 % males in a higher FMI than BMI category (high body fat for BMI), whereas 9.8 % females and 15.6 % males were in a lower category (low body fat for BMI). Females with high body fat for BMI had significantly lower covariate-adjusted BMD at the femoral neck, total hip and total body (differences of 3.8, 5.1 and 2.6 %, respectively, all P < 0.05) than females with low body fat for BMI and lower total body BMD than women with concordant FMI/BMI (by 1.4 %, P = 0.04). In males, BMD did not differ significantly between those who were concordant or discordant for FMI/BMI categories. CONCLUSION: In women (but not men) with discordant FMI/BMI categories, higher body fat for BMI was associated with lower BMD, suggesting that increased fat mass without an accompanying increase in lean mass may be deleterious to bone. PMID- 27468904 TI - Optimally controlling the human connectome: the role of network topology. AB - To meet ongoing cognitive demands, the human brain must seamlessly transition from one brain state to another, in the process drawing on different cognitive systems. How does the brain's network of anatomical connections help facilitate such transitions? Which features of this network contribute to making one transition easy and another transition difficult? Here, we address these questions using network control theory. We calculate the optimal input signals to drive the brain to and from states dominated by different cognitive systems. The input signals allow us to assess the contributions made by different brain regions. We show that such contributions, which we measure as energy, are correlated with regions' weighted degrees. We also show that the network communicability, a measure of direct and indirect connectedness between brain regions, predicts the extent to which brain regions compensate when input to another region is suppressed. Finally, we identify optimal states in which the brain should start (and finish) in order to minimize transition energy. We show that the optimal target states display high activity in hub regions, implicating the brain's rich club. Furthermore, when rich club organization is destroyed, the energy cost associated with state transitions increases significantly, demonstrating that it is the richness of brain regions that makes them ideal targets. PMID- 27468905 TI - Changes in Cognitive Function Following Bariatric Surgery: a Systematic Review. AB - Increased body mass is directly associated with reduced cognitive function. The aim of this study was to systematically review the effect of bariatric weight loss surgery on cognitive function. A comprehensive and unrestricted literature search was conducted using the following databases: MEDLINE, EMBASE, PubMed, Scopus, Web of Sciences, and the Cochrane Library. A total of 414 publications were identified, of which 18 were included in the final review. Cognitive function as measured by a number of different assessment tools was shown to improve following surgically induced weight loss in most studies. Significant and rapid weight loss resulting from bariatric surgery is associated with prompt and sustained improvements in cognitive function including memory, executive function, and cognitive control. PMID- 27468906 TI - Endobarrier(r) in Grade I Obese Patients with Long-Standing Type 2 Diabetes: Role of Gastrointestinal Hormones in Glucose Metabolism. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of Endobarrier(r) in grade 1 obese T2DM patients with poor metabolic control and the role of gastro-intestinal hormone changes on the metabolic outcomes. METHODS: Twenty-one patients aged 54.1 +/- 9.5 years, diabetes duration 14.8 +/- 8.5 years, BMI 33.4 +/- 1.9 kg/m2, and HbA1c 9.1 +/- 1.3 %, under insulin therapy, were implanted with Endobarrier(r). Fasting concentrations of PYY, ghrelin and glucagon, and AUC for GLP-1 after a standard meal test were determined prior to and at months 1 and 12 after implantation. RESULTS: Patients lost 14.9 +/- 5.7 % of their total body weight. HbA1c decreased 1.3 % in the first month, but at the end of the study, the reduction was 0.6 %. HbA1c <= 7 % was achieved in 26.3 % of patients. No differences in GLP-1 AUC values were found before and after implant. Fasting plasma ghrelin and PYY concentrations increased from month 1 to 12. Conversely, fasting plasma glucagon concentrations decreased at month 1 and increased thereafter. Weight (beta 0.152) and HbA1c decrease at month 1 (beta 0.176) were the only variables predictive of HbA1c values at 12 months (adjusted R 2 for the model 0.693, p = 0.001). Minor adverse events occurred in 14 % of patients and major events in 9.5 %. CONCLUSIONS: Endobarrier(r) in T2DM patients with grade I obesity and poor metabolic control is associated with significant weight decrease and moderate reduction in HbA1c at month 12. Our data do not support a role for GLP-1 in the metabolic improvement in this subset of patients. PMID- 27468908 TI - Phylogenetic characterisation of two novel Anaplasmataceae from Australian Ixodes holocyclus ticks: 'Candidatus Neoehrlichia australis' and 'Candidatus Neoehrlichia arcana'. AB - Recently, two novel species of Anaplasmataceae were detected in the Australian paralysis tick, Ixodes holocyclus, by 16S rRNA gene metabarcoding. Analysis of these sequences suggested that these novel organisms are closely related to the genus 'Candidatus Neoehrlichia'. In this study, phylogenetic analysis of 16S rRNA (1264 bp), groESL (1047 bp) and gltA (561 bp) gene sequences, and concatenated (2872 bp) sequences, all concur that these novel species belong in the genus 'Candidatus Neoehrlichia' and are most closely related to, but distinct from the only other recognised members of this genus, 'Candidatus Neoehrlichia mikurensis' and 'Candidatus Neoehrlichia lotoris'. Based on their unique molecular signature, we propose to designate these species 'Candidatus Neoehrlichia australis' (reference strain HT41R) and 'Candidatus Neoehrlichia arcana' (reference strain HT94R). Identical 'Candidatus Neoehrlichia australis' 16S rRNA, groESL and gltA sequences were detected in 34/391 (8.7 %) individual Ixodes holocyclus ticks, and sequences were most similar to 'Candidatus Neoehrlichia lotoris' (96.2 %, 83.1 % and 67.2 %, respectively) and 'Candidatus Neoehrlichia mikurensis' (96.2 %, 84 % and 68.4 % respectively). Likewise, identical 'Candidatus Neoehrlichia arcana' 16S rRNA, groESL and gltA sequences were detected in 12/391 (3.1 %) Ixodes holocyclus ticks, and sequences were most similar to 'Candidatus Neoehrlichia lotoris' (98.5 %, 88.7 % and 79.3 %, respectively) and 'Candidatus Neoehrlichia mikurensis' (96.3 %, 84 % and 67.4 % respectively). These new species are the first Anaplasmataceae (except Wolbachia spp.) to be found to be endemic to Australia. The pathogenic consequences of these organisms are yet to be determined. PMID- 27468909 TI - Hooking-Up, Religiosity, and Sexting Among College Students. AB - The purpose of this study was to evaluate the mediation effect of sexting, and taking sexually suggestive photos on religiosity and hooking-up with three separate sexual outcomes. A web-based survey examined the relationship between religiosity and the three hooking-up outcomes among students reporting sexting or taking a sexually suggestive photo in the last 30 days (n = 231). Sexting, as well as taking sexually suggestive photos mediated the relationship between religiosity and hooking-up among females. Sexting may be initiated by females as a way to engage in a nonphysical sexual interaction, which ultimately predisposes them to a physical sexual outcome. PMID- 27468907 TI - MILEPOST Multicenter Randomized Controlled Trial: 12-Month Weight Loss and Satiety Outcomes After pose SM vs. Medical Therapy. AB - BACKGROUND: Pose SM is an endolumenal weight-loss intervention in which suture anchors are placed endoscopically in the gastric fundus/distal gastric body. Observational studies of pose have shown safe, effective weight loss. Twelve month results of a randomized controlled trial comparing weight loss and satiety after pose vs. conventional medical therapy are reported. METHODS: Subjects with classes I-II obesity were randomized in a 3:1 ratio to pose or diet/exercise guidance only (control). Pose subjects received gastric fundus and distal body suture-anchor plications with diet/exercise counseling. Total body (%TBWL) and excess weight loss (%EWL) were assessed at 6 and 12 months. Analysis of covariance (ANCOVA) was used to analyze 12-month %TBWL. Satiety changes were assessed at 6 and 12 months. RESULTS: From November 2013 to July 2014, 44 subjects were randomized (34, 77.3 % female; mean age, 38.3 +/- 10.7 years; body mass index, 36.5 +/- 3.4 kg/m2) to pose (n = 34) or control (n = 10) groups in three centers. Mean pose procedure time was 51.8 +/- 14.5 min; pose subjects received a mean 8.8 +/- 1.3 fundal and 4.2 +/- 0.7 distal body plications. Twelve month TBWL: pose, 13.0 % (EWL, 45.0 %), n = 30 vs. control group, 5.3 % (18.1 %), n = 9; significant mean difference, 7.7 % (95 % CI 2.2, 13.2; p < 0.01). Pose subjects showed significant reductions in satiety parameters (p < 0.001); controls experienced reduced caloric intake and satiety volume (p < 0.05). No serious device- or procedure-related adverse events occurred. CONCLUSIONS: In a randomized controlled trial at 12 months, pose-treated subjects had significantly greater weight loss than those treated with diet/exercise guidance alone. At 6 and 12 months, pose subjects showed significant reduction in satiety parameters. STUDY REGISTRATION: clinicaltrials.gov identifier # NCT01843231. PMID- 27468910 TI - Role of endoscopy to predict a leak after esophagectomy. AB - PURPOSE: After esophageal surgery, many centers conduct a routine diagnostic test before reintroducing oral intake. However, the clinical value in asymptomatic patients has been questioned. Therefore, we left this decision to the discretion of the operating surgeon and documented the data prospectively. METHODS: Between 2007 and 2013, 185 consecutive patients underwent elective esophageal resection in our institution. The decision as to whether an endoscopy was to be performed as a routine-check or when a leak was clinically suspected was at the discretion of the operating surgeon. An immediate endoscopy was performed on emerging clinical signs of a leak. If a routine check was planned, it was performed between postoperative days 5-7. RESULTS: Of the 185 patients, 84 % had an endoscopy of the anastomosis during the hospital stay. Of the patients who underwent an endoscopy, 61 % were on a routine-check. In this group, one patient showed a leak at the time of endoscopy, 11 patients had pathological findings, 3 of these patients developed a leak later. Eighty-three patients had no pathological findings; nevertheless, 7 developed a leak later. In the on-demand group, 10 patients showed a leak at the time of endoscopy. CONCLUSIONS: In a minority of patients, a routine-check of the anastomosis between days 5-7 revealed pathological findings that later led to an anastomotic leak (3/11). In contrast, a routine-check without pathological findings could not rule out the development of a future leak (7/83). Therefore, we conclude that routine postoperative studies to identify leaks after esophageal resection are not justified. PMID- 27468911 TI - Psychological Interventions for Neuropsychiatric Disturbances in Mild and Moderate Alzheimer's Disease: Current Evidences and Future Directions. AB - The occurrence of the neuropsychiatric disturbances is common feature in dementia. Nonpharmacological interventions are the first approach to manage these symptoms. We reviewed the available literature data on psychological interventions for neuropsychiatric disturbances in Alzheimer's disease (AD) focusing on the significant impact on people with dementia and their caregivers. Reminiscence interventions showed evidences of an improvement in cognition and mood in people with dementia as well as a decrease in caregiver burden. Reality orientation therapy was related to an increase in cognition, a decrease in dysfunctional behaviors and a reduced risk of institutionalization among people with AD. However, the potential benefits need a continued program. Cognitive stimulation therapy showed improvement on the functional ability and decrease negative emotional symptoms, when combined with acetylcholinesterase inhibitor. Studies based on behavioral approaches found a significant reduction in disruptive behaviors following intervention, agitated speech, a reduction in entry into a restricted area and a reduction in wandering frequency across participants. There is evidence that only multicomponent interventions can decrease caregivers' psychological morbidity and reduce their burden. The challenge for future research in psychological approaches in dementia is related to the need of larger and high quality evidence-base studies with well define outcomes aiming their effectiveness through a well-design protocol to evaluate their benefits. PMID- 27468912 TI - Inpatient transfer to a care home for end-of-life care: What are the views and experiences of patients and their relatives? A systematic review and narrative synthesis of the UK literature. AB - BACKGROUND: Transfers from hospital or 'hospice palliative care units' to care homes for end-of-life care are an increasingly common part of clinical practice but are a source of anxiety and distress for patients, relatives and healthcare professionals. AIM: To understand the experiences of patients discharged to care homes for end-of-life care. DESIGN: Systematic review and narrative synthesis of the UK literature concerning inpatient transfer from a hospital or hospice palliative care unit to a care home for end-of-life care. RESULTS: The published literature is very limited: only three papers and one conference abstract were identified, all of low quality using Gough's weight of evidence assessment. No papers examined transfer from hospital: all were of transfers from hospices and were retrospective case note reviews. Many patients were reported to have been negative or ambivalent about moving and experienced feelings of anxiety or abandonment when transferred. Relatives were often either vehemently opposed or ambivalent. Although some came to accept transfer, others reported the transfer to have seriously affected their loved one's quality of life and that the process of finding a care home had been traumatic. No studies investigated patients' views prospectively, the views of staff or the processes of decision-making. CONCLUSION: The UK literature is very limited, despite such transfers being an increasingly common part of clinical practice and a source of concern to patients, relatives and staff alike. Further research is urgently needed in this area, especially studies of patients themselves, in order to understand their experiences and views. PMID- 27468913 TI - What palliative care-related problems do patients with drug-resistant or drug susceptible tuberculosis experience on admission to hospital? A cross-sectional self-report study. AB - BACKGROUND: The new World Health Organization's 'End TB' strategy specifies palliative care within its strategic pillars. Limited data on patient-reported problems are available to inform an effective care response. AIM: We aimed to (1) identify most burdensome problems, (2) compare intensity of problems for drug susceptible and drug-resistant tuberculosis and (3) identify predictors of problem identifiers. DESIGN: Cross-sectional self-report quantitative study. SETTING/PARTICIPANTS: Self-report palliative care problems (physical, psychological, social and spiritual) were collected among patients on admission to a general district hospital with tuberculosis and multidrug-resistant tuberculosis wards in South Africa. RESULTS: Totally, 114 patients were recruited. The items with worst score responses were worry (60.5%), pain (42.1%), help and advice to plan for the future (35.1%), symptoms (29.0%) and ability to share feelings (25.1%). In ordinal logistic regression, age was predictive of a higher (worse) score for total Palliative Outcome Scale total score (0.058, 95% confidence interval = 0.0018-0.099, p = 0.005) and Factor 2 (interpersonal wellbeing: 0.038, 95% confidence interval = 0.003-0.073, p = 0.031). Interestingly, multidrug-resistant tuberculosis was predictive of lower (better) score for both total Palliative Outcome Scale score and Factor 1 (physical and psychological wellbeing). Weight, human immunodeficiency virus status and prior treatment were not significantly associated with any of the three. CONCLUSION: Currently, patients with drug-susceptible tuberculosis are only admitted to hospital with complications, explaining their worse scores. The high burden of physical and psychosocial problems experienced by our sample provides strong evidence of the need for palliative care alongside potentially curative options. PMID- 27468914 TI - Analgesic requirements and pain experience after caesarean section under neuraxial anesthesia in women with preeclampsia. AB - OBJECTIVE: We determined pain experience and analgesic usage in women with preeclampsia (PE) after caesarean section (CS). METHOD: We conducted a one-year retrospective case (PE), control (healthy pregnancy HP) study in women undergoing CS. RESULTS: Sixty-two women were included. Cases received more intrathecal bupivacaine (mean difference 0.4 mg) and in the first six hours postoperatively received (mean +/- SD, % or median (interquartile range, IQR)), less oxycodone (11.5 +/- 3.9 mg versus 14.3 +/- 5.1 mg, p < 0.031), less often received parecoxib (43% versus 100%, p < 0.001), and reported less maximum pain scores (0 (0,5) versus 4 (3,6), p < 0.005). CONCLUSION: Women with PE received less analgesia and experienced less pain compared to controls. PMID- 27468915 TI - First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome. AB - Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer (CRC) linked to germline defects in Mismatch Repair (MMR) genes. We present here, the first molecular study of the correlation between CRC and mutations occurring in these genes performed in twenty-one unrelated Algerian families. The presence of germline mutations in MMR genes, MLH1, MSH2 and MSH6 genes was tested by sequencing all exons plus adjacent intronic sequences and Multiplex ligand dependent probe amplification (MLPA) for testing large genomic rearrangements. Pathogenic mutations were identified in 20 % of families with clinical suspicion on HNPCC. Two novel variants described for the first time in Algerian families were identified in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T, c.1030C>T, the most described ones, were also detected in Algerian families. Furthermore, the families HNPCC caused by MSH6 germline mutation may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. In this study, we confirmed that MSH2, MLH1, and MSH6 contribute to CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the identification of Lynch syndrome patients in Algerian families. PMID- 27468916 TI - Response of the Tail of the Ventral Tegmental Area to Aversive Stimuli. AB - The GABAergic tail of the ventral tegmental area (tVTA), also named rostromedial tegmental nucleus (RMTg), exerts an inhibitory control on dopamine neurons of the VTA and substantia nigra. The tVTA has been implicated in avoidance behaviors, response to drugs of abuse, reward prediction error, and motor functions. Stimulation of the lateral habenula (LHb) inputs to the tVTA, or of the tVTA itself, induces avoidance behaviors, which suggests a role of the tVTA in processing aversive information. Our aim was to test the impact of aversive stimuli on the molecular recruitment of the tVTA, and the behavioral consequences of tVTA lesions. In rats, we assessed Fos response to lithium chloride (LiCl), beta-carboline, naloxone, lipopolysaccharide (LPS), inflammatory pain, neuropathic pain, foot-shock, restraint stress, forced swimming, predator odor, and opiate withdrawal. We also determined the effect of tVTA bilateral ablation on physical signs of opiate withdrawal, and on LPS- and LiCl-induced conditioned taste aversion (CTA). Naloxone-precipitated opiate withdrawal induced Fos in MU opioid receptor-positive (15%) and -negative (85%) tVTA cells, suggesting the presence of both direct and indirect mechanisms in tVTA recruitment during withdrawal. However, tVTA lesion did not impact physical signs of opiate withdrawal. Fos induction was also present with repeated, but not single, foot shock delivery. However, such induction was mostly absent with other aversive stimuli. Moreover, tVTA ablation had no impact on CTA. Although stimulation of the tVTA favors avoidance behaviors, present findings suggest that this structure may be important to the response to some, but not all, aversive stimuli. PMID- 27468917 TI - Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice. AB - The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate the direct inhibitory effect of GABAB receptor (GABABR) and D2 DA receptor (D2R) activation in VTA DA neurons. Here we examined the effect of the DA neuron-specific loss of GIRK channels on D2R-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors. Selective ablation of Girk2 in DA neurons did not alter the baseline excitability of VTA DA neurons but significantly reduced the magnitude of D2R dependent inhibitory somatodendritic currents and blunted the impact of D2R activation on spontaneous activity and neuronal excitability. Mice lacking GIRK channels in DA neurons exhibited increased locomotor activation in response to acute cocaine administration and an altered locomotor sensitization profile, as well as increased responding for and intake of cocaine in an intravenous self administration test. These mice, however, showed unaltered cocaine-induced conditioned place preference. Collectively, our data suggest that feedback inhibition to VTA DA neurons, mediated by GIRK channel activation, tempers the locomotor stimulatory effect of cocaine while also modulating the reinforcing effect of cocaine in an operant-based self-administration task. PMID- 27468918 TI - Counterconditioning During Reconsolidation Prevents Relapse of Cocaine Memories. AB - Relapse to drug abuse is often caused by exposure to drug-associated cues that evoke craving. Therefore, disruption of the cue-drug memory can prevent relapse. Memories destabilize and become temporarily labile upon their retrieval, and re stabilize in a process termed reconsolidation. Pharmacological disruption of reconsolidation prevents relapse in animal models, yet may evoke side effects. Therefore, behavioral procedures capable of preventing cue-induced craving and relapse are extremely valuable. Aversion therapies, in which drug-paired cues are re-associated (counterconditioned) with aversive consequences, have limited success, because the previous cue-drug memory may recover, triggering relapse. Here, we prevented the memory recovery and relapse to cocaine seeking by applying aversive counterconditioning during memory reconsolidation. Mice were trained to seek cocaine in a conditioned place preference procedure. The cocaine-associated compartment was then counterconditioned with lithium chloride (LiCl)-induced malaise, preceded by a brief exposure to the compartment (memory retrieval). Relapse was assessed in a reinstatement test. We found that aversive counterconditioning conducted shortly after memory retrieval (during reconsolidation) induced a long-lasting prevention of relapse to cocaine seeking. However, mice relapsed when counterconditioned without, before, or long after memory retrieval, or when receiving LiCl without place counterconditioning. Our findings suggest that post-retrieval aversive counterconditioning leads to relapse prevention, possibly by replacing the cue-drug with a cue-aversion memory, thereby the cue ceases to evoke craving. Moreover, we found that a similar memory replacement procedure prevented relapse of conditioned place aversion. Hence, this novel procedure can also prevent relapse of aversive memories, providing a safe approach to alter various maladaptive behaviors. PMID- 27468919 TI - A study of prognostic factors in 45 cases of atypical meningioma. AB - BACKGROUND: Atypical meningioma differs from Grade I meningioma in terms of high recurrence rate and short life expectancy. We evaluated the clinical course of atypical meningioma and investigated prognostic factors affecting its outcomes. METHOD: We reviewed 45 patients with atypical meningioma who underwent surgical intervention between January 2000 and December 2013. The mean age of the patients and mean follow-up period was 58.7 years and 81.0 months, respectively. Analyses included factors such as patient age, gender, location and size of tumor, extent of surgical resection (Simpson Grading System), and MIB-1 labeling index (LI). Univariate analysis was used to detect prognostic factors associated with recurrence and survival. RESULTS: The 5-year recurrence-free rate for all 45 patients was 58.4 %; 5- and 10-year survival rates were 83.2 % and 79.9 %, respectively. In univariate analyses, age >60 years, and MIB-1 LI correlated with disease recurrence, whereas age >60 years, subtotal surgical resection, MIB-1 LI, and indication for radiotherapy correlated with death. MIB-1 LI levels higher than 12.8 % and 19.7 % predicted recurrence and death, respectively. In our cohort, 26 patients received postoperative radiotherapy including conventional radiation (n = 21) or gamma knife radiosurgery (n = 5). Postoperative radiotherapy did not decrease recurrence rates in our cohort (p = 0.63). Six and two patients who died during the study period underwent conventional radiation and radiosurgery, respectively. CONCLUSIONS: Age, male gender, extent of surgical resection, and higher MIB-1 LI influenced the outcome of atypical meningioma. In our cohort, postoperative radiotherapy failed to provide long-term tumor control. Following incomplete surgical resection of atypical meningioma in elderly patients, adjuvant postoperative radiotherapy may not be an ideal treatment option, particularly when MIB-1 LI is higher than 19.7 %. PMID- 27468920 TI - Multicenter phase II study of combination therapy with cetuximab and S-1 in patients with KRAS exon 2 wild-type unresectable colorectal cancer previously treated with irinotecan, oxaliplatin, and fluoropyrimidines (KSCC 0901 study). AB - PURPOSE: Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines. METHODS: The study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400 mg/m(2), followed by weekly infusion at 250 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2) orally twice daily for 28 days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status. RESULTS: Thirty-seven patients were eligible. The median PFS was 5.5 months, the median OS was 13.5 months, the ORR was 29.7 %, and the DCR was 73.0 %. The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1. Grade 3-4 adverse events that occurred in >10 % of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia. CONCLUSIONS: Combination therapy with cetuximab and S 1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer. PMID- 27468921 TI - Protein expression of ATP-binding cassette transporters ABCC10 and ABCC11 associates with survival of colorectal cancer patients. AB - PURPOSE: This study investigated the prognostic importance of protein expression of ATP-binding cassette (ABC) transporters ABCC10 and ABCC11 in colorectal cancer. METHODS: Protein content of ABCC10 and ABCC11 was assessed in tumor tissue blocks of 140 colorectal cancer patients and associated with survival of patients with regard to 5-fluorouracil-based therapy. RESULTS: Low ABCC10 protein content in tumors increased hazard ratio of patient's death more than three times in comparison with high ABCC10-expressing tumors (P = 0.004). In contrast, the low ABCC11 content increased the hazard ratio of cancer recurrence in patients almost four times (P = 0.016). Analysis of patients treated with regimens based on 5-fluorouracil revealed that patients with low ABCC11 content in their tumors had shorter disease-free interval than those with higher content (P = 0.024). CONCLUSIONS: The present study shows for the first time that the protein expression of ABCC10 significantly associates with overall survival and the expression of ABCC11 with disease-free interval of colorectal cancer patients and provides strong impulse for further validation of their prognostic value in colorectal cancer. PMID- 27468922 TI - Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline. AB - PURPOSE: To assess the link between early tumor shrinkage (ETS) and progression free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data. METHODS: Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated. RESULTS: A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79]. CONCLUSION: A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication. PMID- 27468923 TI - Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional Portuguese cohort study. AB - BACKGROUND: A contemporary US study showed an increase in the use of chemotherapy in the last decade for some patients with stage-I breast cancer; with a rise in more intensive regimens, and declining use of anthracyclines. Nevertheless, there is still uncertainty on the absolute benefit of chemotherapy for these patients and the optimal regimen. In this study we compare those findings with the patterns of care among a Portuguese cohort of stage-I breast cancers. METHODS: Retrospective cohort study of patients with stage-I breast cancer diagnosed from 2006 to 2008 at four Portuguese institutions. The use and type of chemotherapy was evaluated. RESULTS: Among patients with stage I-III breast cancer 39.4% (n = 682) had stage I disease. Of the 595 eligible patients, 22.4% were treated with chemotherapy, 33.9% aged <55 years vs. 12.7% aged >65 years (p < 0.001). Thirteen percent of patients with hormone receptor (HR)+/HER2- tumors, 52.7% of patients with HER2+ and 66.0% of patients with HR-/HER2- received chemotherapy (p < 0.001). In addition, we found inter-institutional variability, with the use of chemotherapy ranging from 0.0% to 43.4% (p < 0.001). Eighty-five percent of patients treated with chemotherapy received less-intensive regimens with anthracycline-based regimens, such as doxorubicin and cyclophosphamide, being the most frequently used, while docetaxel and cyclophosphamide was only used in 1.5% of cases. CONCLUSIONS: Overall, almost one-quarter of patients received chemotherapy with institutional variability. When treated, mostly less-intensive associations including anthracyclines were used, which contrasts with contemporary US practice. This study highlights the need for health-services research to understand local practices and tailor quality improvement interventions. PMID- 27468924 TI - Revisiting sulfur H-bonds in proteins: The example of peroxiredoxin AhpE. AB - In many established methods, identification of hydrogen bonds (H-bonds) is primarily based on pairwise comparison of distances between atoms. These methods often give rise to systematic errors when sulfur is involved. A more accurate method is the non-covalent interaction index, which determines the strength of the H-bonds based on the associated electron density and its gradient. We applied the NCI index on the active site of a single-cysteine peroxiredoxin. We found a different sulfur hydrogen-bonding network to that typically found by established methods, and we propose a more accurate equation for determining sulfur H-bonds based on geometrical criteria. This new algorithm will be implemented in the next release of the widely-used CHARMM program (version 41b), and will be particularly useful for analyzing water molecule-mediated H-bonds involving different atom types. Furthermore, based on the identification of the weakest sulfur-water H bond, the location of hydrogen peroxide for the nucleophilic attack by the cysteine sulfur can be predicted. In general, current methods to determine H bonds will need to be reevaluated, thereby leading to better understanding of the catalytic mechanisms in which sulfur chemistry is involved. PMID- 27468926 TI - Ambient Air Pollution Is Associated With the Severity of Coronary Atherosclerosis and Incident Myocardial Infarction in Patients Undergoing Elective Cardiac Evaluation. AB - BACKGROUND: The effect of air pollution exposure on atherosclerosis severity or incident clinical events in patients with coronary artery disease is not known. METHODS AND RESULTS: We conducted a prospective longitudinal cohort study of 6575 Ohio residents undergoing elective diagnostic coronary angiography. Multinomial regression and Cox proportional hazards models were used to assess the relationship between exposure to fine particulate matter <2.5 MUm in diameter (PM2.5) and nitrogen dioxide on coronary artery disease severity at baseline and risk of myocardial infarction, stroke, or all-cause mortality over 3 years of follow-up. Among participants with coronary artery disease, exposure to PM2.5 levels was associated with increased likelihood of having coronary atherosclerosis that was mild (odds ratio 1.43, 95% CI 1.11-1.83, P=0.005) and severe (odds ratio 1.63, 95% CI 1.26-2.11, P<0.0001), with the effect on severe coronary artery disease being significantly increased compared with mild disease (Ptrend=0.03). Exposure to higher PM2.5 levels was also significantly associated with increased risk of incident myocardial infarction (hazard ratio 1.33, 95% CI 1.02-1.73, P=0.03) but not stroke or all-cause mortality. The association of PM2.5 with incident myocardial infarction was not affected after adjustment for Framingham Adult Treatment Panel III (ATP III) risk score or statin therapy. In comparison, there were no significant associations between nitrogen dioxide levels and all-cause mortality or risk of stroke after adjustment for Framingham ATP III risk score. CONCLUSIONS: Exposure to PM2.5 increased the likelihood of having severe coronary artery disease and the risk of incident myocardial infarction among patients undergoing elective cardiac evaluation. These results suggest that ambient air pollution exposure may be a modifiable risk factor for risk of myocardial infarction in a highly susceptible patient population. PMID- 27468925 TI - Obesity and Subtypes of Incident Cardiovascular Disease. AB - BACKGROUND: Obesity is a risk factor for various subtypes of cardiovascular disease (CVD), including coronary heart disease (CHD), heart failure (HF), and stroke. Nevertheless, there are limited comparisons of the associations of obesity with each of these CVD subtypes, particularly regarding the extent to which they are unexplained by traditional CVD mediators. METHODS AND RESULTS: We followed 13 730 participants in the Atherosclerosis Risk in Communities (ARIC) study who had a body mass index >=18.5 and no CVD at baseline (visit 1, 1987 1989). We compared the association of higher body mass index with incident HF, CHD, and stroke before and after adjusting for traditional CVD mediators (including systolic blood pressure, diabetes mellitus, and lipid measures). Over a median follow-up of 23 years, there were 2235 HF events, 1653 CHD events, and 986 strokes. After adjustment for demographics, smoking, physical activity, and alcohol intake, higher body mass index had the strongest association with incident HF among CVD subtypes, with hazard ratios for severe obesity (body mass index >=35 versus normal weight) of 3.74 (95% CI 3.24-4.31) for HF, 2.00 (95% CI 1.67-2.40) for CHD, and 1.75 (95% CI 1.40-2.20) for stroke (P<0.0001 for comparisons of HF versus CHD or stroke). Further adjustment for traditional mediators fully explained the association of higher body mass index with CHD and stroke but not with HF (hazard ratio 2.27, 95% CI 1.94-2.64). CONCLUSIONS: The link between obesity and HF was stronger than those for other CVD subtypes and was uniquely unexplained by traditional risk factors. Weight management is likely critical for optimal HF prevention, and nontraditional pathways linking obesity to HF need to be elucidated. PMID- 27468927 TI - Is Mitral Valve Repair Superior to Mitral Valve Replacement in Elderly Patients? Comparison of Short- and Long-Term Outcomes in a Propensity-Matched Cohort. AB - BACKGROUND: Because of demographic changes, a growing number of elderly patients present with mitral valve (MV) disease. Although mitral valve repair (MV-repair) is the "gold standard" treatment for MV disease, in elderly patients, there is controversy about whether MV-repair is superior to mitral valve replacement. We reviewed results after MV surgery in elderly patients treated over the past 20 years. METHODS AND RESULTS: Our in-hospital database was explored for patients who underwent MV surgery between 1994 and 2015. Survival data, obtained from the National Health Service central register, were complete for all patients. Of 1776 patients with MV disease, 341 were aged >=75 years. Patients with repeat cardiac surgery, endocarditis, and concomitant aortic valve replacement were excluded. This yielded 221 MV-repair and 120 mitral valve replacement patients. Concomitant procedures included coronary artery bypass grafting in 135 patients (39.6%) and tricuspid valve surgery in 50 patients (14.7%). Thirty-day mortality was 5.4% (MV repair) versus 9.2% (mitral valve replacement, P=0.26). Overall 1- and 5-year survival was 90.7%, 74.2% versus 81.3%, 61.0% (P<0.01). Median survival after MV repair was 7.8 years, close to 8.5 years (95% CI: 8.2-9.4) in the age-matched UK population (ratio 0.9). Rate of re-operation for MV-dysfunction was 2.3% versus 2.5% (mitral valve replacement, P=1.0). After propensity matching, patients after MV-repair still had improved survival at 1, 2, and 5 years (93.4%, 91.6%, 76.9% versus 77.2%, 75.2%, 58.7%, P=0.03). CONCLUSIONS: Excellent outcomes can be achieved after MV surgery in elderly patients. Long-term survival is superior after MV-repair and the re-operation rate is low. MV-repair should be the preferred surgical approach in elderly patients. PMID- 27468928 TI - Geographic and Temporal Variation in Cardiac Implanted Electric Devices to Treat Heart Failure. AB - BACKGROUND: Cardiac implantable electric devices are commonly used to treat heart failure. Little is known about temporal and geographic variation in use of cardiac resynchronization therapy (CRT) devices in usual care settings. METHODS AND RESULTS: We identified new CRT with pacemaker (CRT-P) or defibrillator generators (CRT-D) implanted between 2008 and 2013 in the United States from a commercial claims database. For each implant, we characterized prior medication use, comorbidities, and geography. Among 17 780 patients with CRT devices (median age 69, 31% women), CRT-Ps were a small and increasing share of CRT devices, growing from 12% to 20% in this study period. Compared to CRT-D recipients, CRT-P recipients were older (median age 76 versus 67), and more likely to be female (40% versus 30%). Pre-implant use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers was low in both CRT-D (46%) and CRT-P (31%) patients. The fraction of CRT-P devices among all new implants varied widely across states. Compared to the increasing national trend, the share of CRT-P implants was relatively increasing in Kansas and relatively decreasing in Minnesota and Oregon. CONCLUSIONS: In this large, contemporary heart failure population, CRT-D use dwarfed CRT-P, though the latter nearly doubled over 6 years. Practice patterns vary substantially across states and over time. Medical therapy appears suboptimal in real-world practice. PMID- 27468929 TI - Association of Age at Menopause With Incident Heart Failure: A Prospective Cohort Study and Meta-Analysis. AB - BACKGROUND: Early age (<45 years) at menopause has been postulated to be associated with increased cardiovascular disease risk; however, evidence of its relation with heart failure (HF) incidence is limited. We examined whether age at menopause is associated inversely with HF incidence in the Atherosclerosis Risk In Communities (ARIC) study and summarized all existing data in a meta-analysis. METHODS AND RESULTS: In ARIC, data were obtained from 5629 postmenopausal women (mean age 56 years, 26% with bilateral oophorectomy) without HF. During a median follow-up of 21.4 years, 965 incident HF events occurred. In a Cox regression model adjusted for reproductive health and HF risk factors, the hazard ratios for incident HF across categories of age at menopause (<45, 45-49, 50-54, and >=55 years) were 1.32, 1.17, 1.00 (referent), and 1.12, respectively. Compared with women with later onset of menopause (aged >=45 years), those with early menopause had elevated HF risk (hazard ratio 1.20, 95% CI 1.01-1.43). For the meta analysis, we searched Medline and Embase for articles published through December 2015 that prospectively evaluated age at menopause and HF risk. Summarized estimates from the 3 included studies (3568 events) showed higher HF risk among women with early menopause compared with those with later menopause (hazard ratio 1.33, 95% CI 1.15-1.53). CONCLUSIONS: These results provided evidence that early age at menopause is associated with a modestly greater risk of HF. Identification of women with early menopause offers a window of opportunity to implement interventions that will improve overall cardiovascular health during the postmenopausal years. PMID- 27468930 TI - High throughput screening of starch structures using carbohydrate microarrays. AB - In this study we introduce the starch-recognising carbohydrate binding module family 20 (CBM20) from Aspergillus niger for screening biological variations in starch molecular structure using high throughput carbohydrate microarray technology. Defined linear, branched and phosphorylated maltooligosaccharides, pure starch samples including a variety of different structures with variations in the amylopectin branching pattern, amylose content and phosphate content, enzymatically modified starches and glycogen were included. Using this technique, different important structures, including amylose content and branching degrees could be differentiated in a high throughput fashion. The screening method was validated using transgenic barley grain analysed during development and subjected to germination. Typically, extreme branching or linearity were detected less than normal starch structures. The method offers the potential for rapidly analysing resistant and slowly digested dietary starches. PMID- 27468931 TI - Comparative proteomic analysis of the shoot apical meristem in maize between a ZmCCT-associated near-isogenic line and its recurrent parent. AB - The ZmCCT, one of the most important genes affecting photoperiod response, delays flowering under long-day conditions in maize (Zea mays). In this study we used the isobaric tags for relative and absolute quantification (iTRAQ) technique based proteomics approach to identify differentially expressed proteins between a near-isogenic line (NIL) and its recurrent parent, contrasting in alleles of ZmCCT. A total of 5,259 distinct proteins were identified. Among them, 386 proteins were differentially expressed between NIL-cml line (ZmCCT-positive) and H4 line (ZmCCT-negative). Functional categorization showed that the differentially proteins were mainly involved in energy production, photosynthesis, signal transduction, and cell organization and biogenesis. Our results showed that during shoot apical meristem (SAM) development cell division proteins, carbohydrate metabolism-related proteins, and flower inhibition-related proteins were more abundant in the ZmCCT-positive line than the ZmCCT-negative line. These results, taken together with morphological observations, showed that the effect of ZmCCT on flowering might be caused by its effect on one or all of these biological processes. Although the exact roles of these putative related proteins remain to be examined, our results obtained using the proteomics approach lead to a better understanding of the photoperiodicity mechanism in maize plants. PMID- 27468932 TI - Cytomolecular discrimination of the Am chromosomes of Triticum monococcum and the A chromosomes of Triticum aestivum using microsatellite DNA repeats. AB - The cytomolecular discrimination of the Am- and A-genome chromosomes facilitates the selection of wheat-Triticum monococcum introgression lines. Fluorescence in situ hybridisation (FISH) with the commonly used DNA probes Afa family, 18S rDNA and pSc119.2 showed that the more complex hybridisation pattern obtained in T. monococcum relative to bread wheat made it possible to differentiate the Am and A chromosomes within homoeologous groups 1, 4 and 5. In order to provide additional chromosomal landmarks to discriminate the Am and A chromosomes, the microsatellite repeats (GAA)n, (CAG)n, (CAC)n, (AAC)n, (AGG)n and (ACT)n were tested as FISH probes. These showed that T. monococcum chromosomes have fewer, generally weaker, simple sequence repeat (SSR) signals than the A-genome chromosomes of hexaploid wheat. A differential hybridisation pattern was observed on 6Am and 6A chromosomes with all the SSR probes tested except for the (ACT)n probe. The 2Am and 2A chromosomes were differentiated by the signals given by the (GAA)n, (CAG)n and (AAC)n repeats, while only (GAA)n discriminated the chromosomes 3Am and 3A. Chromosomes 7Am and 7A could be differentiated by the lack of (GAA)n and (AGG)n signals on 7A. As potential landmarks for identifying the Am chromosomes, SSR repeats will facilitate the introgression of T. monococcum chromatin into wheat. PMID- 27468933 TI - Palliative Care in Undergraduate Medical Education-How Far Have We Come? AB - PURPOSE: There is an increasing demand for quality palliative care teaching within undergraduate medical education. Studies suggest that many junior doctors feel underprepared to perform end-of-life care. Previous systematic reviews on palliative care teaching within medical schools have identified significant variability and lack of consistency in teaching. This review aims to update the literature on the current status of palliative care teaching to undergraduates within medical schools. METHOD: A systematic review was undertaken on articles published from December 2001 to November 2015 on palliative care teaching for undergraduate medical students. In all, 650 abstract citations were obtained, of which 126 were relevant to the research questions. Thematic analysis was performed on remaining articles according to whether they discussed content and/or methodology of palliative care education, and data collated. RESULTS: There is greater consistency in the content being delivered as part of end-of life care education within medical schools. The most frequently taught topics include attitudes to death and dying, communication skills, and pain management. Pediatric care and religious/cultural issues are less frequently addressed. Teaching institutions are also utilising a broader range of teaching modalities. CONCLUSION: There is significant progress in palliative care education within medical schools. Ongoing challenges relate to correlating our current practice in medical education to professional recommendations and the expressed needs of junior doctors to practice competent end-of-life care. PMID- 27468934 TI - Reclassification of Pseudomonas sp. PB-6250T as Lysobacter firmicutimachus sp. nov. AB - Strain PB-6250T, isolated from soil in Japan, was first identified in 1992. In contrast to its original taxonomic classification, its 16S rRNA gene sequence showed the highest similarity (99.2 %) to the sequence of Lysobacter enzymogenes DSM 2043T, with Lysobacter antibioticus DSM 2044T being the next most closely related species (98.7 %) with a validly published name. Chemotaxonomic data (fatty acid profile, quinone and polar lipid composition) and the G+C content of strain PB-6250T were compared with those of the closely related type strains L. enzymogenes LMG 8762T, L. antibioticus LMG 8760T, L. capsici DSM 19286T and L. gummosus LMG 8763T; this supported the affiliation of strain PB-6250T to the genus Lysobacter. Phylogenetic analyses, DNA-DNA-hybridization data, biochemical and physiological characteristics strongly supported the genotypic and phenotypic differentiation of strain PB-6250T from species of Lysobacter with validly published names. Strain PB-6250T, therefore represents a novel species, for which the name Lysobacter firmicutimachus sp. nov. is proposed. The type strain is PB 6250T (=LMG 28994T=DSM 102073T). PMID- 27468935 TI - ALK Immunohistochemistry in NSCLC: Discordant Staining Can Impact Patient Treatment Regimen. AB - INTRODUCTION: Diagnostic immunohistochemistry (IHC) is increasingly accepted as a screening method for anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements in NSCLC. We have sought to establish an ongoing robust external quality assessment process to gauge quality of anaplastic lymphoma kinase (ALK) IHC, which can have an impact on interpretation of patient samples. METHODS: Unstained tissue and cell line samples were distributed on a quarterly basis to participating laboratories from 30 countries. Participants stained the slide using their routine diagnostic ALK IHC method and returned the slide along with their in-house control and methodology details. Slides were assessed by a team of pathologists and scientists. RESULTS: Overall, there was a mean pass rate of 83% (range 71%-98%), with 38 variations in staining protocol. Methods included the following: the Roche D5F3 assay (65% of users, pass rate 93%); Novocastra 5A4 (15% of users, pass rate 65%); Cell Signaling Technology D5F3 (7% of users, pass rate 91%), and Dako ALK1 (5% of users, pass rate 50%). Choice of methodology directly affected final interpretation of distributed ALK-positive and ALK negative NSCLC cases, which were correctly identified by 89% and 88% of participants, respectively. Antibody detection method was a contributing factor in false-negative staining results. The choice of laboratory controls was found to be unsuitable, and as such, in-house control recommendations are also provided. CONCLUSIONS: ALK IHC is a robust screening technique, but there is concern that some diagnostic laboratories are using inadequate staining methods, which has a direct impact on final interpretation. External assessment helps provide laboratories with continued confidence in their ALK IHC testing. PMID- 27468936 TI - Circulating Tumor Cells Detected in the Tumor-Draining Pulmonary Vein Are Associated with Disease Recurrence after Surgical Resection of NSCLC. AB - Tumor recurrence after surgical resection of NSCLC obstructs long-term disease free survival in approximately 50% of cases. Our data suggest that combining circulating tumor cell enumeration (as single cells or clusters) in tumor draining pulmonary vein and peripheral blood (assessed by CellSearch) at the time of NSCLC surgery better identifies those patients at higher risk for lung cancer recurrence than does peripheral circulating tumor cell number alone. PMID- 27468937 TI - A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma. AB - INTRODUCTION: In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible. METHODS: Short footprint mutation enrichment next generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC. RESULTS: Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with rociletinib, a rapid decrease in urine T790M levels was observed by day 21. CONCLUSIONS: DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples. PMID- 27468938 TI - ctDNA Determination of EGFR Mutation Status in European and Japanese Patients with Advanced NSCLC: The ASSESS Study. AB - INTRODUCTION: To offer patients with EGFR mutation-positive advanced NSCLC appropriate EGFR tyrosine kinase inhibitor treatment, mutation testing of tumor samples is required. However, tissue/cytologic samples are not always available or evaluable. The large, noninterventional diagnostic ASSESS study (NCT01785888) evaluated the utility of circulating free tumor-derived DNA (ctDNA) from plasma for EGFR mutation testing. METHODS: ASSESS was conducted in 56 centers (in Europe and Japan). Eligible patients (with newly diagnosed locally advanced/metastatic treatment-naive advanced NSCLC) provided diagnostic tissue/cytologic and plasma samples. DNA extracted from tissue/cytologic samples was subjected to EGFR mutation testing using local practices; designated laboratories performed DNA extraction/mutation testing of blood samples. The primary end point was level of concordance of EGFR mutation status between matched tissue/cytologic and plasma samples. RESULTS: Of 1311 patients enrolled, 1288 were eligible. Concordance of mutation status in 1162 matched samples was 89% (sensitivity 46%, specificity 97%, positive predictive value 78%, and negative predictive value 90%). A group of 25 patients with apparent false-positive plasma results was overrepresented for cytologic samples, use of less sensitive tissue testing methodologies, and smoking habits associated with high EGFR mutation frequency, indicative of false negative tumor results. In cases in which plasma and tumor samples were tested with identical highly sensitive methods, positive predictive value/sensitivity were generally improved. CONCLUSIONS: These real-world data suggest that ctDNA is a feasible sample for EGFR mutation analysis. It is important to conduct mutation testing of both tumor and plasma samples in specialized laboratories, using robust/sensitive methods to ensure that patients receive appropriate treatments that target the molecular features of their disease. PMID- 27468940 TI - Satisfaction of patients with Peyronie's disease after plaque surgery and bovine pericardium graft. AB - INTRODUCTION: Plaque and bovine pericardium graft surgery is a useful tool for treating Peyronie's disease. OBJECTIVE: To determine patient satisfaction following this operation. MATERIALS AND METHODS: This was a retrospective, observational and descriptive study. We collected data from the medical records of patients who underwent surgery between 2004 and 2015 and were evaluated through a postoperative satisfaction questionnaire. RESULTS: Twenty-eight operations were performed. Curve correction was achieved in 26 patients (95.3%). One patient (3.57%) required residual curve correction using Yachia's technique, and 1 patient (3.57%) had a severe complication consisting of prosthetic infection and urethrocutaneous fistulae. Twenty-one patients (75%) expressed satisfaction with the surgery. CONCLUSIONS: Our results show an acceptable level of satisfaction among our patients, with a low number of complications. However, further prospective, controlled and randomised studies are needed. PMID- 27468941 TI - Spatial occupancy patterns and activity of arid rangeland cattle grazing small riparian pastures. AB - The spatial occupancy patterns and activity of cattle grazing three riparian pastures was investigated in northeastern Oregon using Global Positioning System (GPS) collars logging at 1-sec intervals. Cattle consistently selected plant communities as grazing areas that had forage in sufficient volume to meet their requirements and favored communities as resting areas that were dry and open. Cattle were stationary for more than 50% of the time in each pasture and consistently rested between dark and 04:00 hours. Interaction with stream channels was found to be 1-2% of total occupancy time and occurred on less than 10% of channel length. Cattle were indifferent or avoided channel areas relative to their area and, when in this zone, they spent most of their time moving not resting. Cattle did not prefer the stream bank zone and spent only 2% of their time in that zone. When occupied, the stream bank zone was used as a travel corridor to gain access to water or cross the channel to access other pasture areas. These results are in contrast with the general belief that cattle are a primary occupant of the stream bank/channel area; additional research is needed to define factors influencing cattle occupancy. PMID- 27468942 TI - EPR studies of intermolecular interactions and competitive binding of drugs in a drug-BSA binding model. AB - Understanding intermolecular interactions between drugs and proteins is very important in drug delivery studies. Here, we studied different binding interactions between salicylic acid and bovine serum albumin (BSA) using electron paramagnetic resonance (EPR) spectroscopy. Salicylic acid was labeled with a stable radical (spin label) in order to monitor its mobilized (free) or immobilized (bound to BSA) states. In addition to spin labeled salicylic acid (SL salicylic acid), its derivatives including SL-benzoic acid, SL-phenol, SL benzene, SL-cyclohexane and SL-hexane were synthesized to reveal the effects of various drug binding interactions. EPR results of these SL-molecules showed that hydrophobic interaction is the main driving force. Whereas each of the two functional groups (-COOH and -OH) on the benzene ring has a minute but detectable effect on the drug-protein complex formation. In order to investigate the effect of electrostatic interaction on drug binding, cationic BSA (cBSA) was synthesized, altering the negative net charge of BSA to positive. The salicylic acid loading capacity of cBSA is significantly higher compared to that of BSA, indicating the importance of electrostatic interaction in drug binding. Moreover, the competitive binding properties of salicylic acid, ibuprofen and aspirin to BSA were studied. The combined EPR results of SL-salicylic acid/ibuprofen and SL ibuprofen/salicylic acid showed that ibuprofen is able to replace up to ~83% of bound SL-salicylic acid, and salicylic acid can replace only ~14% of the bound SL ibuprofen. This indicates that ~97% of all salicylic acid and ibuprofen binding sites are shared. On the other hand, aspirin replaces only ~23% of bound SL salicylic acid, and salicylic acid replaces ~50% of bound SL-aspirin, indicating that ~73% of all salicylic acid and aspirin binding sites are shared. These results show that EPR spectroscopy in combination with the spin labeling technique is a very powerful method to investigate drug binding dynamics in detail. PMID- 27468943 TI - Is Anyone Paying Attention to Physician Report Cards? The Impact of Increased Availability on Consumers' Awareness and Use of Physician Quality Information. AB - OBJECTIVE: To determine if the release of health care report cards focused on physician practice quality measures leads to changes in consumers' awareness and use of this information. PRIMARY DATA SOURCES: Data from two rounds of a survey of the chronically ill adult population conducted in 14 regions across the United States, combined with longitudinal information from a public reporting tracking database. Both data were collected as part of the evaluation for Aligning Forces for Quality, a nationwide quality improvement initiative funded by the Robert Wood Johnson Foundation. STUDY DESIGN: Using a longitudinal design and an individual-level fixed effects modeling approach, we estimated the impact of community public reporting efforts, measured by the availability and applicability of physician quality reports, on consumers' awareness and use of physician quality information (PQI). PRINCIPAL FINDINGS: The baseline level of awareness was 12.6 percent in our study sample, drawn from the general population of chronically ill adults. Among those who were not aware of PQI at the baseline, when PQI became available in their communities for the first time, along with quality measures that are applicable to their specific chronic conditions, the likelihood of PQI awareness increased by 3.8 percentage points. For the same group, we also find similar increases in the uses of PQI linked to newly available physician report cards, although the magnitudes are smaller, between 2 and 3 percentage points. CONCLUSIONS: Specific contents of physician report cards can be an important factor in consumers' awareness and use of PQI. Policies to improve awareness and use of PQI may consider how to customize quality report cards and target specific groups of consumers in dissemination. PMID- 27468944 TI - Using Respondent-Driven Sampling to Recruit Illegal Drug Purchasers to Evaluate a Drug Market Intervention. AB - BACKGROUND: Violent drug markets are not as prominent as they once were in the United States, but they still exist and are associated with significant crime and lower quality of life. The drug market intervention (DMI) is an innovative strategy that uses focused deterrence, community engagement, and incapacitation to reduce crime and disorder associated with these markets. Although studies show that DMI can reduce crime and overt drug activity, one perspective is prominently missing from these evaluations: those who purchase drugs. OBJECTIVES: This study explores the use of respondent-driven sampling (RDS)-a statistical sampling method-to approximate a representative sample of drug users who purchased drugs in a targeted DMI market to gain insight into the effect of a DMI on market dynamics. METHODS: Using RDS, we recruited individuals who reported hard drug use (crack or powder cocaine, heroin, methamphetamine, or illicit use of prescriptions opioids) in the last month to participate in a survey. The main survey asked about drug use, drug purchasing, and drug market activity before and after DMI; a secondary survey asked about network characteristics and recruitment. CONCLUSIONS: Our sample of 212 respondents met key RDS assumptions, suggesting that the characteristics of our weighted sample approximate the characteristics of the drug user network. The weighted estimates for market purchasers are generally valid for inferences about the aggregate population of customers, but a larger sample size is needed to make stronger inferences about the effects of a DMI on drug market activity. PMID- 27468945 TI - Clinical and Laboratory Consequences of Platelet Transfusion in Shiga Toxin Mediated Hemolytic Uremic Syndrome. AB - Recent studies suggest that platelet transfusions are harmful in patients with thrombotic thrombocytopenic purpura, an entity of thrombotic microangiopathies. As the typical or Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome (STEC-HUS) is also classified as thrombotic microangiopathy, we complement these data with an analysis of 250 patients from the German O104:H4 STEC-HUS outbreak. The effect of platelet transfusion in 44 patients who received platelet transfusions vs 206 control patients was investigated. Criteria for both groups were severe thrombocytopenia less than 50/nL, severe hemolysis with administration of packed red blood cells, and a complicated clinical course with admission to intensive care units. Readouts were clinical complications and changes in routine clinical chemistry and whole blood count. Chemistry values at admission and demographic parameters were comparable. Platelet transfusions were administered in 44 cases a median of 7 (interquartile range, 6-9) days after diarrhea onset. After platelet transfusion, we observed a transient and slight increase in inflammation parameters. No significant difference in major complications such as seizures, or requirement for ventilation or renal replacement therapy could be observed. Thrombotic events such as thrombosis or embolism were comparably rare in both groups (2.3% in platelet transfused vs 4.4% in controls, P=not significant). The mortality was not significantly different (0% vs 2.6%, P=not significant) in our study cohort, but overall in the outbreak, 6 of 711 STEC-HUS patients in Germany died of a procedural-related bleeding complications. In conclusion, platelet transfusions seem comparably safe in adult STEC-HUS patients, considering both the possible necessity for invasive procedures and potential risk for severe bleeding. PMID- 27468946 TI - Identification of nuclear localization signal within goldfish Tgf2 transposase. AB - The structure of goldfish (Carassius auratus) Tgf2 transposase is still poorly understood, although it can mediate efficient gene transfer in teleost fish. We hypothesized the existence of a nuclear localization signal (NLS) within Tgf2 transposase to assist transport into the nucleus. To explore this, 15 consecutive amino acid residues (656-670 aa) within the C-terminus of Tgf2 transposase were predicted in silico to be a NLS domain. The pEGFP-C1-Tgf2TP(?31C) plasmid encoding the NLS-domain-deleted Tgf2 transposase fused to EGFP was constructed, and transfected into 293T cells. After transfection with pEGFP-C1-Tgf2TP(?31C), EGFP was not detected in the nucleus alone, while 67.0% of cells expressed EGFP only in the cytoplasm. In contrast, after transfection with control plasmids containing C- or N-terminal truncated Tgf2 transposases with an intact NLS domain, EGFP was not detected in the cytoplasm alone, while approximately 40% of cells expressed EGFP only in the nucleus, and the remaining 60% expressed EGFP in both the nucleus and cytoplasm. Our results demonstrated that loss of the NLS domain results in expression in the cytoplasm but not in the nucleus. These findings suggest that 15 aa residues located from 656 to 670 aa within the C terminus of Tgf2 transposase can function as a NLS to assist the transfer of the transposase into the nucleus where it mediates DNA transposition. PMID- 27468947 TI - CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development. AB - Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767m dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny. PMID- 27468948 TI - Gene expression classification using epigenetic features and DNA sequence composition in the human embryonic stem cell line H1. AB - Epigenetic factors are known to correlate with gene expression in the existing studies. However, quantitative models that accurately classify the highly and lowly expressed genes based on epigenetic factors are currently lacking. In this study, a new machine learning method combines histone modifications, DNA methylation, DNA accessibility, transcription factors, and trinucleotide composition with support vector machines (SVM) is developed in the context of human embryonic stem cell line (H1). The results indicate that the predictive accuracy will be markedly improved when the epigenetic features are considered. The predictive accuracy and Matthews correlation coefficient of the best model are as high as 95.96% and 0.92 for 10-fold cross-validation test, and 95.58% and 0.92 for independent dataset test, respectively. Our model provides a good way to judge a gene is either highly or lowly expressed gene by using genetic and epigenetic data, when the expression data of the gene is lacking. And a web server GECES for our analysis method is established at http://202.207.14.87:8032/fuwu/GECES/index.asp, so that other scientists can easily get their desired results by our web-server, without going through the mathematical details. PMID- 27468949 TI - Association of acute kidney injury with adverse post-operative outcomes after living donor liver transplantation. PMID- 27468950 TI - Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. AB - Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 MUg/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational. PMID- 27468951 TI - MERS-CoV spike protein: Targets for vaccines and therapeutics. AB - The disease outbreak caused by Middle East respiratory syndrome coronavirus (MERS CoV) is still ongoing in the Middle East. Over 1700 people have been infected since it was first reported in September 2012. Despite great efforts, licensed vaccines or therapeutics against MERS-CoV remain unavailable. The MERS-CoV spike (S) protein is an important viral antigen known to mediate host-receptor binding and virus entry, as well as induce robust humoral and cell-mediated responses in humans during infection. In this review, we highlight the importance of the S protein in the MERS-CoV life cycle, summarize recent advances in the development of vaccines and therapeutics based on the S protein, and discuss strategies that can be explored to develop new medical countermeasures against MERS-CoV. PMID- 27468952 TI - Dual-Confined Sulfur Nanoparticles Encapsulated in Hollow TiO2 Spheres Wrapped with Graphene for Lithium-Sulfur Batteries. AB - Lithium-sulfur (Li-S) batteries are attractive owing to their higher energy density and lower cost compared with the universally used lithium-ion batteries (LIBs), but there are some problems that stop their practical use, such as low utilization and rapid capacity-fading of the sulfur cathode, which is mainly caused by the shuttle effect, and the uncontrollable deposition of lithium sulfide species. Herein, we report the design and fabrication of dual-confined sulfur nanoparticles that were encapsulated inside hollow TiO2 spheres; the encapsulated nanoparticles were prepared by a facile hydrolysis process combined with acid etching, followed by "wrapping" with graphene (G-TiO2 @S). In this unique composite architecture, the hollow TiO2 spheres acted as effective sulfur carriers by confining the polysulfides and buffering volume changes during the charge-discharge processes by means of physical force from the hollow spheres and chemical binding between TiO2 and the polysulfides. Moreover, the graphene wrapped skin provided an effective 3D conductive network to improve the electronic conductivity of the sulfur cathode and, at the same time, to further suppress the dissolution of the polysulfides. As results, the G-TiO2 @S hybrids exhibited a high and stable discharge capacity of up to 853.4 mA h g-1 over 200 cycles at 0.5 C (1 C=1675 mA g-1 ) and an excellent rate capability of 675 mA h g 1 at a current rate of 2 C; thus, G-TiO2 @S holds great promise as a cathode material for Li-S batteries. PMID- 27468953 TI - Gender-related differences on short- and long-term outcomes of patients undergoing transcatheter aortic valve implantation. AB - OBJECTIVES: This study aimed to compare gender-related differences in outcomes of patients undergoing TAVI over a long-term follow-up period. BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been considered the standard therapy for patients with inoperable or high-risk symptomatic aortic stenosis. The influence of gender-related differences in outcomes of patients undergoing TAVI is currently on debate. METHODS: From January 2008 to January 2015, 819 patients (49% men) underwent TAVI and were included in a multicenter Brazilian registry. Patients were followed-up and clinical outcomes were evaluated according to the updated Valve Academic Research Consortium-2 criteria. RESULTS: Mean follow-up was 497 +/- 478 days. Compared with women, men had a lower rate of major or life-threatening bleeding (12.0% vs. 20.6%; HR = 0.57 [95CI% 0.40-0.81]; P = 0.001), and major vascular complications (6% vs. 11.7%; HR = 0.50 [95CI% 0.31 0.82]; P = 0.004). At 30 days, all-cause mortality was lower in men than in women (6.5% vs. 11.5%; P = 0.013), however, cumulative all-cause mortality was similar between groups (25.9% vs. 29.7%, men and women, respectively, HR = 0.92 [95CI% 0.71-1.19]; P = 0.52) over the entire follow-up period. By adjusted Cox regression model, renal function, diabetes, peripheral artery disease, and chronic obstructive pulmonary disease (COPD) remained independently predictors of all-cause mortality. CONCLUSIONS: In this large-scale study evaluating patients undergoing TAVI, 30-day mortality was higher among women than men driven by significant higher rates of major or life-threatening bleeding and major vascular complications. However, all-cause mortality on long-term follow-up was similar between groups. (c) 2016 Wiley Periodicals, Inc. PMID- 27468954 TI - Characterization, localization and temporal expression of crustacean hyperglycemic hormone (CHH) in the behaviorally rhythmic peracarid crustaceans, Eurydice pulchra (Leach) and Talitrus saltator (Montagu). AB - Crustacean hyperglycemic hormone (CHH) has been extensively studied in decapod crustaceans where it is known to exert pleiotropic effects, including regulation of blood glucose levels. Hyperglycemia in decapods seems to be temporally gated to coincide with periods of activity, under circadian clock control. Here, we used gene cloning, in situ hybridization and immunohistochemistry to describe the characterization and localization of CHH in two peracarid crustaceans, Eurydice pulchra and Talitrus saltator. We also exploited the robust behavioral rhythmicity of these species to test the hypothesis that CHH mRNA expression would resonate with their circatidal (12.4h) and circadian (24h) behavioral phenotypes. We show that both species express a single CHH transcript in the cerebral ganglia, encoding peptides featuring all expected, conserved characteristics of other CHHs. E. pulchra preproCHH is an amidated 73 amino acid peptide N-terminally flanked by a short, 18 amino acid precursor related peptide (CPRP) whilst the T. saltator prohormone is also amidated but 72 amino acids in length and has a 56 residue CPRP. The localization of both was mapped by immunohistochemistry to the protocerebrum with axon tracts leading to the sinus gland and into the tritocerebrum, with striking similarities to terrestrial isopod species. We substantiated the cellular position of CHH immunoreactive cells by in situ hybridization. Although both species showed robust activity rhythms, neither exhibited rhythmic transcriptional activity indicating that CHH transcription is not likely to be under clock control. These data make a contribution to the inventory of CHHs that is currently lacking for non-decapod species. PMID- 27468955 TI - Appetite regulating factors in dourado, Salminus brasiliensis: cDNA cloning and effects of fasting and feeding on gene expression. AB - The dourado, Salminus brasiliensis (Cuvier, 1816) is a freshwater piscivorous Characin native to South American rivers. Owing to the high quality of its flesh and its fast growth, it is the object of both capture fisheries and fish farming. However, very little is known about the endocrine regulation of feeding and metabolism of dourado. In this study, cDNAs for orexin, CART and CCK were isolated in dourado, and their mRNA tissue distributions examined. In order to assess the role of these peptides in the regulation of feeding of dourado, the effects of fasting and feeding on mRNA expression levels of orexin, CART and CCK in the brain as well as CCK in the intestine were assessed. Whereas orexin and CCK have widespread mRNA distributions in the brain and peripheral organs, CART seems to be mostly limited to the brain. Orexin brain expression increased with fasting and displayed periprandial changes, suggesting it is involved in both long- and short-term regulation of feeding and appetite. CART and CCK hypothalamic expressions were not affected by fasting, but displayed periprandial changes with post-feeding decreases, suggesting roles in short-term satiation. CCK expression in the anterior intestine was not affected by fasting and did not display periprandial changes. Overall, our results suggest that orexin, CART and CCK are involved in the physiology of feeding of dourado. PMID- 27468956 TI - Effects of long distance translocation on corticosterone and testosterone levels in male rattlesnakes. AB - Translocation is an increasingly common conservation tool used to augment declining populations or to remove nuisance animals from areas of human conflict. Studies show that venomous snakes translocated long distances may wander and experience increased mortality. However, potential sub-lethal physiological effects on translocated snakes remain unknown. We conducted an experimental study on free-ranging rattlesnakes to test the hypothesis that long distance translocation is stressful. The glucocorticoid response to translocation was variable among snakes. There was some evidence that translocation may be stressful, as baseline corticosterone levels in most snakes rose following translocation, whereas levels remained consistent in control snakes. Interestingly, testosterone levels rose dramatically following translocation, possibly reflecting effects of interaction with new environmental cues and/or resident snakes, or effects of navigation in a new environment. Corticosterone and testosterone were positively correlated. Our study shows that long distance translocation can affect steroid hormone concentrations in rattlesnakes, a result that should be taken into consideration when managing nuisance snakes or repatriating animals to the wild. PMID- 27468957 TI - The Prodromal Questionnaire: a case for IRT-based adaptive testing of psychotic experiences? AB - Computerized adaptive tests (CATs) for positive and negative psychotic experiences were developed and tested in N = 5705 help-seeking, non-psychotic young individuals. Instead of presenting all items, CATs choose a varying number of different items during test administration depending on respondents' previous answers, reducing the average number of items while still obtaining accurate person estimates. We assessed the appropriateness of two-parameter logistic models to positive and negative symptoms of the Prodromal Questionnaire (PQ), computed measurement precision of all items and resulting adaptive tests along psychotic dimensions by Real Data Simulations (RDS), and computed indices for criterion and predictive validities of the CATs. For all items, mean absolute differences between observed and expected response probabilities were smaller than 0.02. CAT-POS predicted transition to psychosis and duration of hospitalization in individuals at-risk for psychosis, and CAT-NEG was suggestively related to later functioning. Regarding psychosis risk classifications of help-seeking individuals, CAT-POS performed less than the PQ 16. Adaptive testing based on self-reported positive and negative symptoms in individuals at-risk for psychosis is a feasible method to select patients for further risk classification. These promising findings need to be replicated prospectively in a non-selective sample that also includes non-at-risk individuals. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27468958 TI - Porphyromonas gingivalis increases the invasiveness of oral cancer cells by upregulating IL-8 and MMPs. AB - Recent studies indicate that chronic inflammation promotes the aggressiveness of cancers. However, the direct molecular mechanisms underlying a functional link between chronic periodontitis, the most common form of oral inflammatory diseases, and the malignancy of oral cancer remain unknown. To elucidate the role of chronic periodontitis in progression of oral cancer, we examined the effect of Porphyromonas gingivalis (P. gingivalis), a major pathogen that causes chronic periodontitis, on the invasiveness of oral squamous cell carcinoma (OSCC) cells, including SCC-25, OSC-20 and SAS cells. Exposures to P. gingivalis promoted the invasive ability of OSC-20 and SAS cells via the upregulation of matrix metalloproteinases (MMPs), specifically MMP-1 and MMP-2. However, P. gingivalis infected SCC-25 cells did not exhibit changes in their invasive properties or the low expression levels of MMPs. In an effort to delineate the molecular players that control the invasiveness, we first assessed the level of interleukin-8 (IL 8), a well-known inflammatory cytokine, in P. gingivalis-infected OSCC cells. IL 8 secretion was substantially increased in the OSC-20 and SAS cells, but not in the SCC-25 cells, following P. gingivalis infection. When IL-8 was directly applied to SCC-25 cells, their invasive ability and MMP level were significantly increased. Furthermore, the downregulation of IL-8 in P. gingivalis-infected OSC 20 and SAS cells attenuated their invasive potentials and MMP levels. Taken together, our findings strongly suggest that P. gingivalis infection plays an important role in the promotion of the invasive potential of OSCC cells via the upregulation of IL-8 and MMPs. PMID- 27468959 TI - Successful treatments with polymyxin B hemoperfusion and recombinant human thrombomodulin for fulminant Clostridium difficile-associated colitis with septic shock and disseminated intravascular coagulation: a case report. AB - BACKGROUND: Clostridium difficile (CD)-associated colitis (CDAC) is endemic and a common nosocomial enteric disease encountered by surgeons in modern hospitals due to prophylactic or therapeutic antibiotic therapies. Currently, the incidence of fulminant CDAC, which readily causes septic shock followed by multiple organ dysfunction syndromes, is increasing. Fulminant CDAC requires surgeons to perform a prompt surgery, such as subtotal colectomy, to remove the septic source. It is known that fulminant CDAC is caused by the shift from an inflammatory response at a local mucosal level to a general systemic inflammatory reaction in which CD toxin-induced mediators' cascades disseminate. Recently, it has been proven that polymyxin B hemoperfusion (PMX-HP) improves septic shock and recombinant human thrombomodulin (rhTM) controls disseminated intravascular coagulation (DIC). In addition, clinically and basically, it has been shown that these treatments can control serous chemical mediators. Therefore, it is considered that these treatments are promising ones for patients with fulminant CDAC. In the current report, we present that these treatments without surgery contributed to the improvement of sepsis due to fulminant CDAC. CASE PRESENTATION: We encountered a case who developed fulminant CDAC with septic shock and DIC after laparoscopic gastrectomy for gastric cancer. At admission to the intensive care unit, his APACHE II score was 22, which indicated an estimated risk of hospital death of 42.4 %. Our therapies were not the subtotal colectomy to remove septic sources but the combination treatments with both PMX-HP and rhTM. These combination therapies resulted in excellent outcomes, namely the dramatic improvement of septic shock and DIC and the patient's survival. We speculate that these combination therapies completely inhibit the CD toxin-induced mediators' cascades and correspond to the removal of septic sources. CONCLUSIONS: We recommend both PMX-HP and rhTM for patients who develop fulminant CDAC with septic shock and DIC to increase the survival benefit and replace the need for surgical treatment. PMID- 27468960 TI - Chylous ascites associated with intestinal obstruction from volvulus due to Petersen's hernia: report of a case. AB - BACKGROUND: Chylous ascites is an uncommon finding which is usually associated with recent abdominal/oncologic or retroperitoneal surgery. It is not usually seen in cases of acute obstruction. CASE PRESENTATION: A patient who had previously undergone a laparoscopy-assisted distal gastrectomy with Roux-en-Y reconstruction for early gastric cancer presented with acute abdominal pain and epigastric fullness. Computed tomography suggested small bowel obstruction due to volvulus. We were able to reduce the volvulus and close a Petersen's hernia without resecting the bowel; a large amount of chylous ascites was an incidental finding. CONCLUSIONS: We present a case of chylous ascites occurring in a setting of small bowel obstruction due to Petersen's hernia, 3 years after successful distal gastrectomy for early gastric cancer, with no evidence of tumor recurrence. PMID- 27468961 TI - N-Butylphthalide (NBP) ameliorated cerebral ischemia reperfusion-induced brain injury via HGF-regulated TLR4/NF-kappaB signaling pathway. AB - N-Butylphthalide (NBP) has been known to have potential neuroprotective effects in Alzheimer's disease and stroke animal models. Hepatocyte-growth factor (HGF), with strong angiogenic properties, exerted protective role in brain injury. The present study was aimed to investigate the possible anti-inflammatory effects of NBP on the brain injury of rats with cerebral ischemia reperfusion (IR) and astrocytes activation induced by lipopolysaccharide (LPS) treatment. Our results showed that cerebral IR induced brain damage with down-regulation of HGF and astrocytes activation. NBP treatment significantly increased HGF expression and activated cMet/PI3K/AKT signaling pathway, stimulating mTOR activity and suppressing apoptosis in brain tissues. Also NBP inhibited pro-inflammatory cytokines expression, including IL-6, IL-1beta, and TNFalpha, via TLR4/NF-kappaB suppression. Anti-HGF treatment enhanced TLR4 expression while HGF could suppress TLR4 activation and its down-streaming signals, attenuating inflammation finally. Notably, NBP up-regulated HGF and down-regulated TLR4 expression significantly in the astrocytes combined with the treatment of TLR4 inhibitor than the cells only treated with TLR4 inhibitor, suggesting that NBP could further suppress TLR4 activation, suggesting that NBP might impede TLR4 through up-regulating HGF expression. These results suggested that NBP treatment significantly ameliorated cerebral IR-induced brain injury by inhibiting TLR4/NF-kappaB-associated inflammation regulated by HGF. PMID- 27468962 TI - (1)H, (13)C and (15)N resonance assignments for the response regulator CheY3 from Rhodobacter sphaeroides. AB - Rhodobacter sphaeroides has emerged as a model system for studies of the complex chemotaxis pathways that are a hallmark of many non-enteric bacteria. The genome of R. sphaeroides encodes two sets of flagellar genes, fla1 and fla2, that are controlled by three different operons. Each operon encodes homologues of most of the proteins required for the well-studied E. coli chemotaxis pathway. R. sphaeroides has six homologues of the response regulator CheY that are localized to and are regulated by different clusters of chemosensory proteins in the cell and have different effects on chemotaxis. CheY6 is the major CheY stopping the fla1 flagellar motor and associated with a cytoplasmically localised chemosensory pathway. CheY3 and CheY4 are associated with a membrane localised polar chemosensory cluster, and can bind to but not stop the motor. CheY6 and either CheY3 or CheY4 are required for chemotaxis. We are using NMR spectroscopy to characterise and compare the structure and dynamics of CheY3 and CheY6 in solution. We are interested in defining the conformational changes that occur upon activation of these two proteins and to identify differences in their properties that can explain the different functions they play in chemotaxis in R. sphaeroides. Here we present the (1)H, (13)C and (15)N assignments for CheY3 in its active, inactive and Mg(2+)-free apo form. These assignments provide the starting point for detailed investigations of the structure and function of CheY3. PMID- 27468965 TI - Silver-Russell syndrome in Hong Kong. AB - OBJECTIVES: To examine the molecular pathogenetic mechanisms, (epi)genotype phenotype correlation, and the performance of the three clinical scoring systems namely Netchine et al, Bartholdi et al, and Birmingham scores-for patients with Silver-Russell syndrome in Hong Kong. METHODS: This retrospective case series was conducted at two tertiary genetic clinics, the Clinical Genetic Service, Department of Health, and clinical genetic clinic in Queen Mary Hospital in Hong Kong. All records of patients with suspected Silver-Russell syndrome under the care of the two genetic clinics between January 2010 and September 2015 were retrieved from the computer database. RESULTS: Of the 28 live-birth patients with Silver-Russell syndrome, 35.7% had H19 loss of DNA methylation, 21.4% had maternal uniparental disomy of chromosome 7, 3.6% had mosaic maternal uniparental disomy of chromosome 11, and the remaining 39.3% were Silver-Russell syndrome of unexplained molecular origin. No significant correlation between (epi)genotype and phenotype could be identified between H19 loss of DNA methylation and maternal uniparental disomy of chromosome 7. Comparison of molecularly confirmed patients and patients with Silver-Russell syndrome of unexplained origin revealed that postnatal microcephaly and cafe-au-lait spots were more common in the latter group, and body and limb asymmetry was more common in the former group. Performance analysis showed the Netchine et al and Birmingham scoring systems had similar sensitivity in identifying Hong Kong Chinese subjects with Silver-Russell syndrome. CONCLUSION: This is the first territory-wide study of Silver-Russell syndrome in Hong Kong. The clinical features and the spectrum of underlying epigenetic defects were comparable to those reported in western populations. PMID- 27468964 TI - Initial results of selective renal parenchymal clamping with an adjustable kidney clamp in nephron-sparing surgery: an easy way to minimise renal ischaemia. AB - INTRODUCTION: A renal parenchymal clamp has been used at our centre since March 2012. It is used in position over the kidney to achieve optimal vascular control of a tumour while minimising parenchymal ischaemia. This study aimed to report the feasibility, surgical outcome, and oncological control of a kidney clamp in partial nephrectomy. METHODS: This study was conducted at a teaching hospital in Hong Kong. Partial nephrectomies performed from January 2009 to March 2015 were reviewed. The tumour characteristics and surgical outcomes of kidney clamp were studied and compared with traditional hilar clamping. RESULTS: A total of 92 patients were identified during the study period. Kidney clamps were used in 20 patients and hilar clamping in 72, with a mean follow-up of 27 and 37 months, respectively. For patients in whom a kidney clamp was applied, all tumours were exophytic to a different extent and the majority (90%) were located at the polar region. The PADUA (preoperative aspects and dimensions used for an anatomical) classification nephrometry score was also lower than those in whom hilar clamping was used (7.07 vs 8.34; P=0.002). The clamp was used in open, laparoscopic, and robot-assisted surgery. Operating time was shorter (207 +/- 72 mins vs 306 +/- 80 mins; P<0.001) and estimated blood loss was lower (205 +/- 191 mL vs 331 +/- 275 mL; P=0.045) with kidney clamp. No acute kidney injury occurred. Postoperative renal function was comparable between the two groups. CONCLUSIONS: Partial nephrectomy using parenchymal clamping is safe and feasible in selected cases. The postoperative renal function and oncological control were satisfactory. PMID- 27468966 TI - Agenesis of the dorsal pancreas: systematic review of a clinical challenge. AB - BACKGROUND: Agenesis of the dorsal pancreas is a rare malformation. Since 1911 and until 2008, 53 cases have been reported. Several authors have recently described the association of this anomaly with neoplasia of the ventral pancreas, thus we performed a systematic review of the literature from 2008 to 2015. METHODS: A systematic review of the MedLine and ISI Web of Science Databases from 2008 until 2015 was carried out, and 30 articles which met the inclusion criteria were identified that included a total of 53 patients: 7 children and 46 adults. CONCLUSIONS: Although dorsal pancreatic agenesis is a rare malformation, given its association with non-alcoholic pancreatitis and neoplasia of the residual pancreas, physicians should maintain an expectant attitude. PMID- 27468967 TI - Association of KRAS gene mutations with depression in older metastatic colorectal cancer patients. AB - BACKGROUND: Cancer patients with depression or anxiety have poor survival, and the interaction between mental and physical problems in older patients may exacerbate this problem. K-ras oncogene (KRAS) mutation may play a role in the development of psychosocial distress and may be associated with poor survival of metastatic colorectal cancer (mCRC) patients. This study investigated the association between KRAS gene mutations and psychosocial morbidity to explore the possible cancer/psychosis relationship in older mCRC patients. METHODS: In this study, 62 newly diagnosed mCRC patients were recruited and completed the Hospital Anxiety and Depression Scale (HADS). Demographic data were also collected, and clinicopathological data were retrieved from medical records. KRAS mutations were assessed via PCR analysis of tissue specimens from the patients. RESULTS: The results showed that 28 of the 62 participants (45.2%) had positive screens for possible depression, and 45 of the 62 participants (72.6%) had positive screens for anxiety. The KRAS mutation rate was 40.3% (25/62), and 19 of the 25 patients with KRAS mutations (76.0%) had probable depression, whereas only 24.3% of the patients with wild-type KRAS were probably depressed (p < 0.05). The KRAS mutation was associated with higher HADS depression scores, independent of gender and performance status (p < 0.05), but not with higher HADS anxiety or total scores. CONCLUSIONS: KRAS mutations were associated with depression severity and higher rates of probable depression in older mCRC patients. Depression should be assessed and treated as early as possible in older mCRC patients with the KRAS mutation. Further studies are needed to verify our current findings using a larger sample size. PMID- 27468968 TI - Fine-needle aspiration cytology yield as a basis for morphological, molecular, and cytogenetic diagnosis in alk-positive anaplastic large cell lymphoma with atypical clinical presentation. AB - ALK positive anaplastic large cell lymphoma is a T-cell lymphoma usually occurring in children and young adults. It frequently involves lymph nodes and extranodal sites and is associated with favorable prognosis. A 20-year old man was admitted for painful mass in the left axilla with overlying skin redness. Clinical presentation and US findings were highly suspicious for sarcoma. Definitive diagnosis was established cytolologically and using ancillary technologies from cytological samples. Fine needle aspiration cytology of tumor mass (lymph node conglomerate and surrounding tissue) show predominance of large, pleomorphic, atypical cells with large nuclei and vacuolised cytoplasm. Atypical cells immunocytochemically were positive for LCA, CD30, CD3, EMA, and ALK; negative for CD15 and CD56. NPM-ALK transcript was detected by reverse transcriptase-polymerase chain reaction (RT-PCT). Molecular analysis of TCRbeta and TCRgamma genes demonstrated clonal TCR genes rearrangement. Complex karyotype with multiple numerical and structural changes was found on conventional cytogenetics. These findings excluded sarcoma and corroborated the diagnosis of ALK positive ALCL. Cutaneous involvement in ALCL can clinically mimic sarcoma, especially in cases with localized disease without B symptoms. In those cases, immunostaining, PCR, and conventional cytogenetics are helpful to exclude sarcoma. Diagn. Cytopathol. 2017;45:51-54. (c) 2016 Wiley Periodicals, Inc. PMID- 27468969 TI - Apigenin Inhibits Cancer Stem Cell-Like Phenotypes in Human Glioblastoma Cells via Suppression of c-Met Signaling. AB - Glioblastoma (GBM) is a highly malignant human brain tumor with limited treatment choices. The extremely aggressive characteristics of GBM result from GBM stem cells (GSCs), a subpopulation in tumor having self-renewal potential and resistance to chemotherapy and radiotherapy. Therefore, eliminating GSCs is an effective strategy to treat this fatal disease. In this study, we investigated the therapeutic effects of dietary flavonoids, including apigenin, quercetin, and naringenin, against cancer stem cell-like phenotypes of human GBM cell lines U87MG and U373MG. Among flavonoids studied, apigenin and quercetin significantly suppressed not only the self-renewal capacity such as cell growth and clonogenicity, but also the invasiveness of GBM stem-like cells. Notably, apigenin blocked the phosphorylation of c-Met and its downstream effectors, transducer and activator of transcription 3, AKT (Protein kinase B), and mitogen activated protein kinase in the GSCs, thereby reducing the expression levels of GSC markers such as CD133, Nanog, and Sox2. These results suggest that the GSC inhibition effect of apigenin may be caused by downregulation of c-Met signaling pathway. PMID- 27468970 TI - Neuroprotective effect of propofol against excitotoxic injury to locomotor networks of the rat spinal cord in vitro. AB - Although neuroprotection to contain the initial damage of spinal cord injury (SCI) is difficult, multicentre studies show that early neurosurgery under general anaesthesia confers positive benefits. An interesting hypothesis is that the general anaesthetic itself might largely contribute to neuroprotection, although in vivo clinical settings hamper studying this possibility directly. To further test neuroprotective effects of a widely used general anaesthetic, we studied if propofol could change the outcome of a rat isolated spinal cord SCI model involving excitotoxicity evoked by 1 h application of kainate with delayed consequences on neurons and locomotor network activity. Propofol (5 MUm; 4-8 h) enhanced responses to GABA and depressed those to NMDA together with decrease in polysynaptic reflexes that partly recovered after 1 day washout. Fictive locomotion induced by dorsal root stimuli or NMDA and serotonin was weaker the day after propofol application. Kainate elicited a significant loss of spinal neurons, especially motoneurons, whose number was halved. When propofol was applied for 4-8 h after kainate washout, strong neuroprotection was observed in all spinal areas, including attenuation of motoneuron loss. Although propofol had minimal impact on recovery of electrophysiological characteristics 24 h later, it did not further depress network activity. A significant improvement in disinhibited burst periodicity suggested potential to ameliorate neuronal excitability in analogy to histological data. Functional recovery of locomotor networks perhaps required longer time due to the combined action of excitotoxicity and anaesthetic depression at 24 h. These results suggest propofol could confer good neuroprotection to spinal circuits during experimental SCI. PMID- 27468971 TI - Ethanol in herbal medicinal products for children : Data from pediatric studies and pharmacovigilance programs. AB - Herbal medicinal products are indispensable in children, e. g., in functional gastrointestinal diseases and coughs and colds, especially when available in liquid dosing forms for which dosing can be adapted ideally to different age groups. Despite being generally accepted as safe, the ethanol content of many of these products, necessary for Galenic reasons, has raised questions regarding their safety. Therefore, safety data from more than 50,000 children in noninterventional pediatric studies with these products, as well as data from routine clinical use in several million children, were assessed. No evidence of the involvement of the ethanol content in any adverse drug reactions was found. This allows us to conclude that these herbal medicinal products are safe in the age groups for which they are authorized or registered and that the present labeling is adequate to allow for their safe use in the pediatric population. PMID- 27468972 TI - Daniel Bovet, Nobelist: muscle relaxants in anaesthesia : The role played by two neglected protagonists. AB - In 1957, Professor Daniel Bovet received the Nobel Prize in Physiology or Medicine for his studies on various compounds including the muscle relaxants gallamine and succinylcholine that became very useful in anaesthesia. Textbooks credit Professor Bovet for the discovery of these drugs. However, although he indeed did discover their pharmacological character, the actual syntheses were made by Ernest Fourneau and Reid Hunt, respectively; sadly, these two scientists have largely been ignored. In this paper, a brief biography of Bovet is presented along with some of his more notable accomplishments. Particular emphasis has been placed on gallamine and succinylcholine along with their history. In an attempt to undo the "injustice" dealt to both Fourneau and Hunt, brief accounts of their history, story and character are provided. PMID- 27468973 TI - Disseminated superficial actinic porokeratosis (DSAP): significant improvement after local administration of calcipotriol/betamethasone gel? AB - Porokeratosis is defined as a disorder of keratinization characterized by one or more atrophic patches surrounded by a clinically and histologically distinctive hyperkeratotic ridgelike border called the cornoid lamella. Lesions are most commonly located on the sun-exposed sides of trunk and extremities, while exclusive facial involvement has been also reported. Despite that the exact risk of cutaneous malignancy developing in porokeratosis is unknown, it is confirmed by series of case reports, including squamous cell carcinoma, basal cell carcinoma and even melanoma. Although no definite cure exists, a number of treatment modalities, from topical medications to laser and light devices, have been reported with variable success. Although promising, reports of disseminated superficial actinic porokeratosis treated with vitamin D3 analogs are rare. No satisfactory enough effect is obtained also with calcipotriol monotherapy.We report a case of disseminated superficial actinic porokeratosis in a 80-year-old female patient, successfully treated with combination of topical calcipotriol/betamethasone gel. A significant improvement was noticed after 3 weeks; almost full resolution of the clinical symptoms without appearance of fresh lesions was achieved in the second month. To the best of our knowledge, this is the first report of successful treatment with full resolution in a short interval, by simultaneous application of vitamin D3 analog (calcipotriol) and corticosteroid (betamethasone), combined in a one commercial product as a gel for treatment of keratinocyte proliferation's disorder such as psoriasis vulgaris. This promising new entity seems to be more effective, because of the simultaneous synergetic effects of the substations, namely the normalization of the proliferation of the keratinocytes by calcipotriol on one hand, and the reducing of the inflammation by the corticosteroid on another. Sun protection stays always mandatory, as well as the regular clinical observation, regarding the risk of malignant transformation. PMID- 27468974 TI - Stress-Related Job Analysis for Medical Students on Surgical Wards in Germany. AB - OBJECTIVE: Working conditions in hospitals generate stress within all professional groups. The aim of this study was to find out how German medical students during their senior student clerkship in surgery perceive their own stress and the stress of surgical residents. This was measured using "Instrument zur stressbezogenen Arbeitsanalyse bei KlinikArztInnen (ISAK-K)," a validated questionnaire of the German statutory occupational accident insurance system (BGW). DESIGN AND SETTING: This bi-institutional paper-and-pencil survey was performed on 52 medical students in their sixth year, who had been working in a surgical department for 4 months. Data were compared with those of the BGW on the stress perceived by physicians working in German surgical departments. RESULTS: The stress levels measured with the ISAK-K were similar in students and in physicians working in surgery. Students believe that surgical residents experience a higher time pressure (p < 0.03). Those students planning a surgical career feel to be more exposed to time pressure (p < 0.01), but to be more free to decide how to work (p < 0.03) than their "nonsurgical" colleagues do. In addition, in contrast to the "nonsurgical" students, students interested in surgery believe that surgical residents have more possibilities to learn at work (p < 0.05) and that they can rely on their supervisors (p < 0.03). All students believe that surgical residents commonly need to take decisions without having enough information (p < 0.05). When compared with the BGW data students overestimate the stress of surgical residents. CONCLUSIONS: Students overestimate time pressure and uncertainty of surgical residents. A possible way to increase their interest in surgery is offering a better insight in surgeons' work and strategies to deal with these stressors. PMID- 27468976 TI - The absence of pleiotrophin modulates gene expression in the hippocampus in vivo and in cerebellar granule cells in vitro. AB - Pleiotrophin (PTN) is a secreted growth factor recently proposed to act as a neuromodulatory peptide in the Central Nervous System. PTN appears to be involved in neurodegenerative diseases and neural disorders, and it has also been implicated in learning and memory. Specifically, PTN-deficient mice exhibit a lower threshold for LTP induction in the hippocampus, which is attenuated in mice overexpressing PTN. However, there is little information about the signaling systems recruited by PTN to modulate neural activity. To address this issue, the gene expression profile in hippocampus of mice lacking PTN was analyzed using microarrays of 22,000 genes. In addition, we corroborated the effect of the absence of PTN on the expression of these genes by silencing this growth factor in primary neuronal cultures in vitro. The microarray analysis identified 102 genes that are differentially expressed (z-score>3.0) in PTN null mice, and the expression of eight of those modified in the hippocampus of KO mice was also modified in vitro after silencing PTN in cultured neurons with siRNAs. The data obtained indicate that the absence of PTN affects AKT pathway response and modulates the expression of genes related with neuroprotection (Mgst3 and Estrogen receptor 1, Ers 1) and cell differentiation (Caspase 6, Nestin, and Odz4), both in vivo and in vitro. PMID- 27468977 TI - Comparison of two ultrasound-guided injection techniques targeting the sacroiliac joint region in equine cadavers. AB - OBJECTIVES: To compare the accuracy and distribution of injectate for cranial (CR) and caudomedial (CM) ultrasound-guided injections of equine sacroiliac joints. METHODS: Both sacroiliac joints from 10 lumbosacropelvic specimens were injected using cranial parasagittal (CR; curved 18 gauge, 25 cm spinal needles) and caudomedial (CM; straight 18 gauge, 15 cm spinal needles) ultrasound-guided approaches. Injectate consisted of 4 ml iodinated contrast and 2 ml methylene blue. Computed tomographical (CT) scans were performed before and after injections. Time for needle guidance and repositioning attempts were recorded. The CT sequences were analysed for accuracy and distribution of contrast. RESULTS: Intra-articular contrast was detected in sacroiliac joints following 15/40 injections. The CR and CM approaches deposited injectate <=2 cm from sacroiliac joint margins following 17/20 and 20/20 injections, respectively. Median distance of closest contrast to the sacroiliac joint was 0.4 cm (interquartile range [IQR]: 1.5 cm) for CR approaches and 0.6 cm (IQR: 0.95 cm) for CM approaches. Cranial injections resulted in injectate contacting lumbosacral intertransverse joints 15/20 times. Caudomedial injections were perivascular 16/20 times. LIMITATIONS: Safety and efficacy could not be established. CLINICAL RELEVANCE: Cranial and CM ultrasound-guided injections targeting sacroiliac joints were very accurate for periarticular injection, but accuracy was poor for intra-articular injection. Injectate was frequently found in contact with interosseous sacroiliac ligaments, as well as neurovascular and synovial structures in close vicinity of sacroiliac joints. PMID- 27468978 TI - Renal disease related to Waldenstrom macroglobulinaemia: incidence, pathology and clinical outcomes. AB - The incidence and prognostic impact of nephropathy related to Waldenstrom macroglobulinaemia (WM) is currently unknown. We performed a retrospective study to assess biopsy-confirmed WM-related nephropathy in a cohort of 1391 WM patients seen at a single academic institution. A total of 44 cases were identified, the estimated cumulative incidence was 5.1% at 15 years. There was a wide variation in kidney pathology, some directly related to the WM: amyloidosis (n = 11, 25%), monoclonal-IgM deposition disease/cryoglobulinaemia (n = 10, 23%), lymphoplasmacytic lymphoma infiltration (n = 8, 18%), light-chain deposition disease (n = 4, 9%) and light-chain cast nephropathy (n = 4, 9%), and some probably related to the WM: thrombotic microangiopathy (TMA) (n = 3, 7%), minimal change disease (n = 2, 5%), membranous nephropathy (n = 1, 2%) and crystal storing tubulopathy (n = 1, 2%). The median overall survival in patients with biopsy-confirmed WM-related nephropathy was 11.5 years, shorter than for the rest of the cohort (16 years, P = 0.03). Survival was better in patients with stable or improved renal function after treatment (P = 0.05). Based on these findings, monitoring for renal disease in WM patients should be considered and a kidney biopsy pursued in those presenting with otherwise unexplained renal failure and/or nephrotic syndrome. PMID- 27468979 TI - Ultrasound to evaluate effectiveness of hyperbaric oxygen therapy. PMID- 27468975 TI - Acidosis and Urinary Calcium Excretion: Insights from Genetic Disorders. AB - Metabolic acidosis is associated with increased urinary calcium excretion and related sequelae, including nephrocalcinosis and nephrolithiasis. The increased urinary calcium excretion induced by metabolic acidosis predominantly results from increased mobilization of calcium out of bone and inhibition of calcium transport processes within the renal tubule. The mechanisms whereby acid alters the integrity and stability of bone have been examined extensively in the published literature. Here, after briefly reviewing this literature, we consider the effects of acid on calcium transport in the renal tubule and then discuss why not all gene defects that cause renal tubular acidosis are associated with hypercalciuria and nephrocalcinosis. PMID- 27468980 TI - Targeted imaging of EGFR overexpressed cancer cells by brightly fluorescent nanoparticles conjugated with cetuximab. AB - To improve the treatment efficiency and reduce side effects in cancer therapy, accurate diagnosis of cancer cell types at a molecular level is highly desirable. Fluorescent nanoparticles (NPs) are especially suitable for detecting molecular biomarkers of cancer with advantages of superior brightness, easy decoration and high resolution. However, the conventional organic fluorophores, conjugated polymers, and inorganic quantum dots suffer from the drawbacks of aggregation caused quenching (ACQ), low photostability, and heavy metal toxicity, respectively, which severely restrict their applications in NPs-based fluorescence imaging. To overcome these limitations, herein, we have developed fluorescent nanoparticles based on a t-BuPITBT-TPE fluorophore derived from aggregation-induced emission (AIE)-active tetraphenylethene. Through encapsulating t-BuPITBT-TPE within biocompatible DSPE-PEG and further decorating with a monoclonal antibody cetuximab (C225), the obtained t-BuPITBT-TPE-C225 NPs can be used for targeted imaging of non-small cell lung cancer cells with an overexpressed epidermal growth factor receptor (EGFR). The specific targeting ability of t-BuPITBT-TPE-C225 NPs has been well verified by confocal microscopy and flow cytometry experiments. The t-BuPITBT-TPE-C225 NPs have shown significant advantages in terms of highly efficient red emission, good bio-compatibility, and excellent photostability. This work provides a promising method for precise diagnosis of cancer cells by antibody-functionalized fluorescent NPs with high brightness. PMID- 27468981 TI - Reversible Electrochemical Modulation of a Catalytic Nanosystem. AB - A catalytic system based on monolayer-functionalized gold nanoparticles (Au NPs) that can be electrochemically modulated and reversibly activated is reported. The catalytic activity relies on the presence of metal ions (Cd(2+) and Cu(2+) ), which can be complexed by the nanoparticle-bound monolayer. This activates the system towards the catalytic cleavage of 2-hydroxypropyl-p-nitrophenyl phosphate (HPNPP), which can be monitored by UV/Vis spectroscopy. It is shown that Cu(2+) metal ions can be delivered to the system by applying an oxidative potential to an electrode on which Cu(0) was deposited. By exploiting the different affinity of Cd(2+) and Cu(2+) ions for the monolayer, it was also possible to upregulate the catalytic activity after releasing Cu(2+) from an electrode into a solution containing Cd(2+) . Finally, it is shown that the activity of this supramolecular nanosystem can be reversibly switched on or off by oxidizing/reducing Cu/Cu(2+) ions under controlled conditions. PMID- 27468982 TI - Cross-modal distractors modulate oscillatory alpha power: the neural basis of impaired task performance. AB - Unexpected novel sounds capture one's attention, even when irrelevant to the task pursued (e.g., playing video game). This often comes at a cost to the task (e.g., slower responding). The neural basis for this behavioral distraction effect is not well understood and is subject of this study. Our approach was motivated by findings from cuing paradigms suggesting a link between modulations in oscillatory activity and voluntary attention shifts. The current study tested whether oscillatory activity is also modulated by a task-irrelevant auditory distractor, reflecting a neural signature of an involuntary shift of attention and accounting for the impaired task performance. We reanalyzed magnetoencephalographic data collected via an auditory-visual distraction paradigm in which a task-relevant visual stimulus was preceded by a task irrelevant sound on each trial. In 87.5% this was a regular sound (Standard); in 12.5% this was a novel sound (Distractor). We compared nonphase locked oscillatory activity in a time window prior to the visual target as a function of the experimental manipulation (Distractor, Standard). We found low power in the pretarget time window for Distractors compared to Standards in the alpha and beta frequency bands. Importantly, individual alpha power correlated with response speed on a trial-by-trial basis for the Distractor only. Sources were localized to the occipital cortex, and also to the parietal and supratemporal cortices. These findings support our hypothesis that the distractor-related alpha power modulation indexes an involuntary shift of attention which accounts for the impaired task performance. PMID- 27468983 TI - We need a comprehensive approach to health promotion. PMID- 27468984 TI - Planning for the next generation of public health advocates: evaluation of an online advocacy mentoring program. AB - Issue addressed Despite being viewed as a core competency for public health professionals, public health advocacy lacks a prominent place in the public health literature and receives minimal coverage in university curricula. The Public Health Advocacy Institute of Western Australia (PHAIWA) sought to fill this gap by establishing an online e-mentoring program for public health professionals to gain knowledge through skill-based activities and engaging in a mentoring relationship with an experienced public health advocate. This study is a qualitative evaluation of the online e-mentoring program. Methods Semi structured interviews were conducted with program participants at the conclusion of the 12-month program to examine program benefits and determine the perceived contribution of individual program components to overall advocacy outcomes. Results Increased mentee knowledge, skills, level of confidence and experience, and expanded public health networks were reported. Outcomes were dependent on participants' level of commitment, time and location barriers, mentoring relationship quality, adaptability to the online format and the relevance of activities for application to participants' workplace context. Program facilitators had an important role through the provision of timely feedback and maintaining contact with participants. Conclusion An online program that combines public health advocacy content via skill-based activities with mentoring from an experienced public health advocate is a potential strategy to build advocacy capacity in the public health workforce. So what? Integrating advocacy as a core component of professional development programs will help counteract current issues surrounding hesitancy by public health professionals to proactively engage in advocacy, and ensure that high quality, innovative and effective advocacy leadership continues in the Australian public health workforce. PMID- 27468985 TI - Diabetes foot care education movies for Aboriginal people: Bran nue leg. PMID- 27468989 TI - GLUT1 deficiency: progress in unraveling its genetic basis. PMID- 27468987 TI - Dual leucine zipper kinase regulates expression of axon guidance genes in mouse neuronal cells. AB - BACKGROUND: Recent genetic studies in model organisms, such as Drosophila, C. elegans and mice, have highlighted a critical role for dual leucine zipper kinase (DLK) in neural development and axonal responses to injury. However, exactly how DLK fulfills these functions remains to be determined. Using RNA-seq profiling, we evaluated the global changes in gene expression that are caused by shRNA mediated knockdown of endogenous DLK in differentiated Neuro-2a neuroblastoma cells. RESULTS: Our analysis led to the identification of numerous up- and down regulated genes, among which several were found to be associated with system development and axon guidance according to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, respectively. Because of their importance in axonal growth, pruning and regeneration during development and adult life, we then examined by quantitative RT-PCR the mRNA expression levels of the identified axon guidance genes in DLK-depleted cells. Consistent with the RNA-seq data, our results confirmed that loss of DLK altered expression of the genes encoding neuropilin 1 (Nrp1), plexin A4 (Plxna4), Eph receptor A7 (Epha7), Rho family GTPase 1 (Rnd1) and semaphorin 6B (Sema6b). Interestingly, this regulation of Nrp1 and Plxna4 mRNA expression by DLK in Neuro-2a cells was also reflected at the protein level, implicating DLK in the modulation of the function of these axon guidance molecules. CONCLUSIONS: Collectively, these results provide the first evidence that axon guidance genes are downstream targets of the DLK signaling pathway, which through their regulation probably modulates neuronal cell development, structure and function. PMID- 27468988 TI - Increased vascular eNOS and cystathionine-gamma-lyase protein after 6 weeks oral administration of 3, 5, 7, 3', 4'-pentamethoxyflavone to middle-aged male rats. AB - Effects of treatment of middle-aged male rats with 3, 5, 7, 3', 4' pentamethoxyflavone (PMF) on vascular and perivascular adipose tissue (PVAT) functions and blood chemistry were investigated. Rats received PMF (22 mg/kg), orally or vehicle, twice a day for 6 weeks. The PMF-treated rats had lower serum glucose, higher HDL-C levels, but no change in other parameters. Thoracic aortic and mesenteric rings of PMF treated rats produced lower maximal contraction to phenylephrine that was normalized by NG-nitro-L-arginine (L-NA) or endothelial removal. The aortic- and mesenteric rings of the PMF treated rats showed improved relaxation to acetylcholine, but not to glyceryl trinitrate, and had higher eNOS protein. DL-propargylglycine (PAG) caused greater increase in the baseline tension of the PMF-treated aortic ring and higher contraction to low concentrations of phenylephrine. PVAT lowered the contractile response of the L NA pretreated aortic rings to phenylephrine for both groups, but PAG had no effect. The cystathionine-gamma-lyase (CSE) protein of the thoracic rings, but not of the PVAT, shows increased expression after PMF treatment. Overall, PMF treatment of middle aged rats appeared to increase production of NO and H2S from the blood vessels by upregulating the expression of eNOS and CSE. PMF also decreased fasting serum glucose and increased HDL-C levels, with no toxicity to liver and kidney functions. Thus, PMF is a novel compound for possible use as a health product to prevent and/or to reduce the development of diabetes type II and/or cardiovascular disease. PMID- 27468990 TI - Chitinibacter fontanus sp. nov., isolated from a spring. AB - A bacterial strain, designated STM-7T, was isolated from a spring in Taiwan and characterized using a polyphasic taxonomy approach. Cells of strain STM-7T were Gram-staining-negative, aerobic, poly-beta-hydroxybutyrate-accumulating, motile by a single polar flagellum, rod-shaped, surrounded by a thick capsule and formed milky-white colonies. Growth occurred at 15-37 degrees C (optimum, 25-30 degrees C), at pH 6-8 (optimum, pH 6-7) and with 0-2 % NaCl (optimum, 0-1 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain STM-7T belonged to the genus Chitinibacter and was most closely related to Chitinibacter tainanensis S1T with a sequence similarity of 97.3 %. Strain STM-7T contained summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0 as the predominant fatty acids. The major hydroxyl fatty acids were C12 : 0 3-OH and C16 : 0 3-OH. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an uncharacterized aminophospholipid, an uncharacterized glycolipid and an uncharacterized phospholipid. The major isoprenoid quinone was Q-8. The DNA G+C content of the genomic DNA was 52.4 mol%. The DNA-DNA hybridization value for strain STM-7T with Chitinibacter tainanensis BCRC 17254T was less than 47 %. On the basis of the phylogenetic inference and phenotypic data, strain STM-7T should be classified as a representative of a novel species, for which the name Chitinibacter fontanus sp. nov. is proposed. The type strain is STM-7T (=BCRC 80923T=LMG 29289T=KCTC 42982T). PMID- 27468991 TI - (Hydro)peroxide ligands on colloidal cerium oxide nanoparticles. AB - Anhydrous H2O2 reacts with organic colloidal solutions of ceria nanoparticles to form a stable surface peroxo/hydroperoxo species with the release of oleate capping ligands into solution. A new optical spectroscopic signature was identified for cerium-peroxo/hydroperoxo species in solution and correlated with solid-state IR spectroscopy and chemical reactivity. PMID- 27468992 TI - Effect of Age Group on Technical-Tactical Performance Profile of the Serve in Men's Volleyball. AB - The aim of this study was to analyze the technical-tactical performance profile of the serve for various age groups and categories of competition in men's volleyball. The sample comprised 13,262 serves performed by 986 players in 299 sets observed in various categories of competition (U-14, U-16, U-19, national senior, and international senior). An observational design was used. The variables studied were category of competition, type of execution, and serve performance. The results showed that for higher age groups (senior categories), there were significantly fewer jump serves and poorer serve performance, regardless of players' maturity and training development. The use of the jump serves increased the serve risk while attempting to hinder the organization of the opponent attack. This paper discusses the serve evolution and the implications on the training process at the different age groups in men's volleyball. PMID- 27468993 TI - Emergence of plant and rhizospheric microbiota as stable interactomes. AB - The growing human population and depletion of resources have necessitated development of sustainable agriculture. Beneficial plant-microbe associations have been known for quite some time now. To maintain sustainability, one could show better reliance upon beneficial attributes of the rhizosphere microbiome. To harness the best agronomic traits, understanding the entire process of recruitment, establishment, and maintenance of microbiota as stable interactome within the rhizosphere is important. In this article, we highlight the process of recruitment and establishment of microbiota within rhizosphere. Further, we have discussed the interlinkages and the ability of multiple (microbial and plant) partners to interact with one another forming a stable plant holobiont system. Lastly, we address the possibility of exploring the knowledge gained from the holobiont system to tailor the rhizosphere microbiome for better productivity and maintenance of agroecosystems. The article provide new insights into the broad principles of stable plant-microbe interactions which could be useful for sustaining agriculture and food security. PMID- 27468994 TI - Overexpression of pathogen-induced grapevine TIR-NB-LRR gene VaRGA1 enhances disease resistance and drought and salt tolerance in Nicotiana benthamiana. AB - The NBS-LRR proteins encoded by the majority of R genes represent important intracellular receptors that directly or indirectly recognize pathogen effector proteins, which subsequently activate plant defense responses. In this study, a novel Plasmopara viticola-induced TIR-NBS-LRR gene, named VaRGA1, was cloned from leaf tissues of a highly downy mildew-resistant Vitis amurensis "Shuanghong" grapevine. The fluorescence signal of the VaRGA1-GFP fusion protein was clearly partitioned to the cytoplasm and nucleus. The expression of the VaRGA1 gene was strongly induced during early stages of infection by P. viticola, and was also significantly upregulated after drought and salt treatments. Accordingly, grapevine leaves transiently expressing the VaRGA1 gene manifested increased resistance to P. viticola, and the overexpression of the VaRGA1 gene in Nicotiana benthamiana conferred enhanced resistance to Phytophthora parasitica through the activation of salicylic acid (SA) signaling and phenylpropanoid pathways and could also increase tolerance to drought and salt stresses at the germination and vegetable growth stages. These findings indicate that the grapevine VaRGA1 gene may function as the immune and non-immune receptors against biotic and abiotic stresses and that there may be signaling overlap between biotic and abiotic responses. PMID- 27468995 TI - Novel Insights into the Organization of Laticifer Cells: A Cell Comprising a Unified Whole System. AB - Laticifer cells are specialized plant cells that synthesize and accumulate latex. Studies on laticifers have lagged behind in recent years, and data regarding the functional role of laticifers and their fitness benefit still remain elusive. Laticifer differentiation and its impact on plant growth and development also remain to be investigated. Here, cellular, molecular, and genetic tools were developed to examine the distribution, differentiation, ontogeny, and other characteristic features, as well as the potential developmental role of laticifer cells in the latex-bearing plant Euphorbia lathyris. The organization of the laticiferous system within the E. lathyris plant body is reported, emerging as a single elongated and branched coenocytic cell, constituting the largest cell type existing in plants. We also report the ontogeny and organization of laticifer cells in the embryo and the identification of a laticifer-associated gene expression pattern. Moreover, the identification of laticifer- and latex deficient mutants (pil mutants) allowed for the identification of distinct loci regulating laticifer differentiation, growth, and metabolic activity. Additionally, pil mutants revealed that laticifer cells appear nonessential for plant growth and development, thus pointing toward their importance, instead, for specific ecophysiological adaptations of latex-bearing plants in natural environments. PMID- 27468996 TI - Core Mechanisms Regulating Developmentally Timed and Environmentally Triggered Abscission. AB - Drought-triggered abscission is a strategy used by plants to avoid the full consequences of drought; however, it is poorly understood at the molecular genetic level. Here, we show that Arabidopsis (Arabidopsis thaliana) can be used to elucidate the pathway controlling drought-triggered leaf shedding. We further show that much of the pathway regulating developmentally timed floral organ abscission is conserved in regulating drought-triggered leaf abscission. Gene expression of HAESA (HAE) and INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) is induced in cauline leaf abscission zones when the leaves become wilted in response to limited water and HAE continues to accumulate in the leaf abscission zones through the abscission process. The genes that encode HAE/HAESA-LIKE2, IDA, NEVERSHED, and MAPK KINASE4 and 5 are all necessary for drought-induced leaf abscission. Our findings offer a molecular mechanism explaining drought-triggered leaf abscission. Furthermore, the ability to study leaf abscission in Arabidopsis opens up a new avenue to tease apart mechanisms involved in abscission that have been difficult to separate from flower development as well as for understanding the mechanistic role of water and turgor pressure in abscission. PMID- 27468997 TI - Cortisol Stress Response Variability in Early Adolescence: Attachment, Affect and Sex. AB - Attachment, affect, and sex shape responsivity to psychosocial stress. Concurrent social contexts influence cortisol secretion, a stress hormone and biological marker of hypothalamic-pituitary-adrenal axis activity. Patterns of attachment, emotion status, and sex were hypothesized to relate to bifurcated, that is, accentuated and attenuated, cortisol reactivity. The theoretical framework for this study posits that multiple individual differences mediate a cortisol stress response. The effects of two psychosocial stress interventions, a modified Trier Social Stress Test for Teens and the Frustration Social Stressor for Adolescents were developed and investigated with early adolescents. Both of these protocols induced a significant stress reaction and evoked predicted bifurcation in cortisol responses; an increase or decrease from baseline to reactivity. In Study I, 120 predominantly middle-class, Euro-Canadian early adolescents with a mean age of 13.43 years were studied. The girls' attenuated cortisol reactivity to the public performance stressor related significantly to their self-reported lower maternal-attachment and higher trait-anger. In Study II, a community sample of 146 predominantly Euro-Canadian middle-class youth, with an average age of 14.5 years participated. Their self-reports of higher trait-anger and trait-anxiety, and lower parental attachment by both sexes related differentially to accentuated and attenuated cortisol reactivity to the frustration stressor. Thus, attachment, affect, sex, and the stressor contextual factors were associated with the adrenal cortical responses of these adolescents through complex interactions. Further studies of individual differences in physiological responses to stress are called for in order to clarify the identities of concurrent protective and risk factors in the psychosocial stress and physiological stress responses of early adolescents. PMID- 27468998 TI - Use of a Thrombin Fibrin Sealant in Reducing Blood Loss in Revision Hip Arthroplasty. AB - We present a retrospective evaluation assessing the use of a novel fibrin sealant, Quixil((r)) (OMRIX Biopharmaceuticals S.A.) in reducing blood transfusions following revision total hip replacement surgery. Forty four patients underwent revision total hip replacement surgery using Quixil((r)), while 45 patients underwent revision total hip replacement surgery without the use of Quixil((r)). The duration of surgery and patient demographics were similar in both groups. Average blood loss was 1,010ml in the Quixil((r)) group versus 1,021ml in the non-Quixil group. The use of cell saver and intra-operative blood transfusion were similar in both groups. The mean pre-operative Haemoglobin was 13.0 g/dl in the Quixil((r)) group versus 12.4 g/dl in the non-Quixil group. The mean post-operative haemoglobin was 10.2 g/dl and 9.1 g/dl in the Quixil((r)) and non-Quixil groups respectively. There was no difference in the blood transfused post-operatively between the two groups. Total units of blood transfused in Quixil((r)) versus non-Quixil group were 60 verus 86. Total units of intra operative blood transfused in Quixil((r)) versus non-Quixil group were 16 versus 23. The use of fibrin tissue adhesive in revision total hip arthroplasty seems to be an effective and reliable means to reduce blood-transfusion requirements and prevent post-operative decreases in hemoglobin. PMID- 27468999 TI - Species Differences in Microsomal Oxidation and Glucuronidation of 4-Ipomeanol: Relationship to Target Organ Toxicity. AB - 4-Ipomeanol (IPO) is a model pulmonary toxicant that undergoes P450-mediated metabolism to reactive electrophilic intermediates that bind to tissue macromolecules and can be trapped in vitro as the NAC/NAL adduct. Pronounced species and tissue differences in IPO toxicity are well documented, as is the enzymological component of phase I bioactivation. However, IPO also undergoes phase II glucuronidation, which may compete with bioactivation in target tissues. To better understand the organ toxicity of IPO, we synthesized IPO-glucuronide and developed a new quantitative mass spectrometry-based assay for IPO glucuronidation. Microsomal rates of glucuronidation and P450-dependent NAC/NAL adduct formation were compared in lung, kidney, and liver microsomes from seven species with different target organ toxicities to IPO. Bioactivation rates were highest in pulmonary and renal microsomes from all animal species (except dog) known to be highly susceptible to the extrahepatic toxicities induced by IPO. In a complementary fashion, pulmonary and renal IPO glucuronidation rates were uniformly low in all experimental animals and primates, but hepatic glucuronidation rates were high, as expected. Therefore, with the exception of the dog, the balance between microsomal NAC/NAL adduct and glucuronide formation correlate well with the risk for IPO-induced pulmonary, renal, and hepatic toxicities across species. PMID- 27469000 TI - Analysis of Mechanism-Based Inhibition of CYP 3A4 by a Series of Fluoroquinolone Antibacterial Agents. AB - A series of fluoroquinolone compounds (compounds 1-9), which contain a common quinolone scaffold, inactivated the metabolic activity of CYP3A. The purpose of this study was to identify mechanism-based inhibition (MBI) among these fluoroquinolone compounds by metabolite profiling to elucidate the association of the substructure and MBI potential. Reversibility of MBI after incubation with potassium ferricyanide differed among the test compounds. Representative quasi irreversible inhibitors form a metabolite-intermediate (MI) complex with the heme of CYP3A4 according to absorption analysis. Metabolite profiling identified the cyclopropane ring-opened metabolites from representative irreversible inhibitors, suggesting irreversible binding of the carbon-centered radical species with CYP3A4. On the other hand, the oxime form of representative quasi-irreversible inhibitors was identified, suggesting generation of a nitroso intermediate that could form the MI complex. Metabolites of compound 10 with a methyl group at the carbon atom at the root of the amine moiety of compound 8 include the oxime form, but compound 10 did not show quasi-irreversible inhibition. The docking study with CYP3A4 suggested that a methyl moiety introduced at the carbon atom at the root of the primary amine disrupts formation of the MI complex between the heme and the nitroso intermediate because of steric hindrance. This study identified substructures of fluoroquinolone compounds associated with the MBI mechanism; introduction of substituted groups inducing steric hindrance with the heme of P450 can prevent formation of an MI complex. Our series of experiments may be broadly applicable to prevention of MBI at the drug discovery stage. PMID- 27469001 TI - Defining the Role of the NADH-Cytochrome-b5 Reductase 3 in the Mitochondrial Amidoxime Reducing Component Enzyme System. AB - The importance of the mitochondrial amidoxime reducing component (mARC) containing enzyme system in N-reductive metabolism has been studied extensively. It catalyzes the reduction of various N-hydroxylated compounds and therefore acts as the counterpart of cytochrome P450- and flavin-containing monooxygenase catalyzed oxidations at nitrogen centers. This enzyme system was found to be responsible for the activation of amidoxime and N-hydroxyguanidine prodrugs in drug metabolism. The synergy of three components (mARC, cytochrome b5, and the appropriate reductase) is crucial to exert the N-reductive catalytic effect. Previous studies have demonstrated the involvement of the specific isoforms of the molybdoenzyme mARC and the electron transport protein cytochrome b5 in N reductive metabolism. To date, the corresponding reductase involved in N reductive metabolism has yet to be defined because previous investigations have presented ambiguous results. Using small interfering RNA-mediated knockdown in human cells and assessing the stoichiometry of the enzyme system reconstituted in vitro, we provide evidence that NADH-cytochrome-b5 reductase 3 is the principal reductase involved in the mARC enzyme system and is an essential component of N reductive metabolism in human cells. In addition, only minimal levels of cytochrome-b5 reductase 3 protein are sufficient for catalysis, which impeded previous attempts to identify the reductase. PMID- 27469002 TI - Pseudoflavitalea rhizosphaerae gen. nov., sp. nov., isolated from rhizosphere of tomato, and proposal to reclassify Flavitalea soli as Pseudoflavitalea soli comb. nov. AB - A bacterial strain, designated T16R-265T, was isolated from rhizosphere of tomato in Buyeo-gun, Chungcheongnam-do, South Korea. The strain was Gram-stain-negative, aerobic, non-flagellated and rod- or long-rod-shaped. It grew at the range of 10 40 degrees C (optimum 28-30 degrees C), pH 6.0-9.0 (optimum pH 7.0) and with 0 3 % (w/v) NaCl (optimum 0 %). 16S rRNA gene sequence analysis showed that strain T16R-265T had the highest sequence similarity (98.0 %) with Flavitalea soli KIS20 3T and low sequence similarities of below 95 % with all other taxa. The phylogenetic tree revealed that the strain formed a robust monophyletic line with Flavitalea soli KIS20-3T separable from other clades. The predominant quinone of strain T16R-265T was MK-7, the polar lipids consisted of large amounts of phosphatidylethanolamine and an unknown lipid, and the major fatty acids were iso C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. DNA-DNA hybridization values with Flavitalea soli KACC 17319T were below 70 %. The DNA G+C content of strain T16R 265T is 46.2 mol%. Based on phylogenetic evidence and the results of phenotypic, genotypic and chemotaxonomic analyses, strain T16R-265T represents a novel species of a new genus, for which the name Pseudoflavitalea rhizosphaerae gen. nov., sp. nov. is proposed. The type strain of the type species is T16R-265T (=KACC 18655T=NBRC 111880T). We also propose the reclassification of Flavitalea soli as Pseudoflavitalea soli comb. nov. (type strain KIS20-3T=KACC 17319T=JCM 19937T). PMID- 27469003 TI - Fully Automated Headspace Bubble-in-Drop Microextraction. AB - A fully automated headspace bubble-in-drop microextraction (automated HS-BID) method, coupled to gas chromatography/mass spectrometric (GC/MS) analysis, was developed for the analysis of nitro musks in environmental water samples. The entire procedure, including the extraction of the analytes by HS-BID and GC/MS analysis of the analyte-enriched solvent, was completely automated. In BID, a certain volume of air is introduced into the extraction solvent droplet, enlarging the surface area of the extraction solvent droplet in relation to the water sample without increasing its volume, significantly enhancing extraction efficiency. Compared to conventional single drop microextraction, the developed method has higher extraction efficiency due to the enlarged surface area of the extraction solvent droplet. Under the optimized conditions (1.0 mL of sample solution, using 1.0 MUL of 1-octanol containing of 0.5 MUL of air bubble, at 40 degrees C for extraction for 20 min), the automated HS-BID gave low limits of detections (between 0.012 and 0.042 MUg/L), good linearity (from 0.1 to 20 MUg/L and from 0.2 to 50 MUg/L, with r(2) between 0.9909 and 0.9958, depending on analytes), and good repeatability of the extractions (relative standard deviations, below 4.7%, n = 5). The developed procedure was applied to determine nitro musks in environmental water samples and was demonstrated to be efficient, labor-free, economical, and environmentally benign. PMID- 27469005 TI - Development and Initial Validation of a New Practice Context Assessment Tool for Ambulatory Practices Engaged in Quality Improvement. AB - Variable success with quality improvement (QI) efforts in ambulatory care is often attributed to differences in local contexts. Identifying and addressing patient-, practice-, or community-level contextual factors might improve implementation of QI projects. The authors developed and validated a framework for a Practice Context Assessment (PCA), and then created the PCA instrument to glean insights from staff on contextual factors and distributed it at 10 ambulatory practice sites. The PCA framework showed acceptable expert-assessed content validity, with content validity index scores ranging from 0.74 (community engagement) to 0.97 (leadership). The PCA instrument comprised several scales grouped into 7 domains with Cronbach alpha scores from 0.83 (leadership) to 0.95 (patient and family engagement). The PCA framework provides a valid construct to help ambulatory practices understand contextual issues that might influence QI projects. A revised version of the PCA instrument is now ready for further testing. PMID- 27469004 TI - An Open Data Format for Visualization and Analysis of Cross-Linked Mass Spectrometry Results. AB - Protein-protein interactions are an important element in the understanding of protein function, and chemical cross-linking shotgun mass spectrometry is rapidly becoming a routine approach to identify these specific interfaces and topographical interactions. Protein cross-link data analysis is aided by dozens of algorithm choices, but hindered by a lack of a common format for representing results. Consequently, interoperability between algorithms and pipelines utilizing chemical cross-linking remains a challenge. pepXML is an open, widely used format for representing spectral search algorithm results that has facilitated information exchange and pipeline development for typical shotgun mass spectrometry analyses. We describe an extension of this format to incorporate cross-linking spectral search results. We demonstrate application of the extension by representing results of multiple cross-linking search algorithms. In addition, we demonstrate adapting existing pepXML-supporting software pipelines to analyze protein cross-linking results formatted in pepXML. Graphical Abstract ?. PMID- 27469007 TI - Beyond Objectivity and Subjectivity: The Intersubjective Foundations of Psychological Science. AB - The question of whether psychology can properly be regarded as a science has long been debated (Smedslund in Integrative Psychological & Behavioral Science, 50, 185-195, 2016). Science is typically understood as a method for producing reliable knowledge by testing falsifiable claims against objective evidence. Psychological phenomena, however, are traditionally taken to be "subjective" and hidden from view. To the extent that science relies upon objective observation, is a scientific psychology possible? In this paper, I argue that scientific psychology does not much fail to meet the requirements of objectivity as much as the concept of objectivity fails as a methodological principle for psychological science. The traditional notion of objectivity relies upon the distinction between a public, observable exterior and a private, subjective interior. There are good reasons, however, to reject this dichotomy. Scholarship suggests that psychological knowledge arises neither from the "inside out" (subjectively) nor from the outside-in (objectively), but instead intersubjective processes that occur between people. If this is so, then objectivist methodology may do more to obscure than illuminate our understanding of psychological functioning. From this view, we face a dilemma: Do we, in the name of science, cling to an objective epistemology that cuts us off from the richness of psychological activity? Or do we seek to develop a rigorous intersubjective psychology that exploits the processes through which we gain psychological knowledge in the first place? If such a psychology can produce systematic, reliable and useful knowledge, then the question of whether its practices are "scientific" in the traditional sense would become irrelevant. PMID- 27469006 TI - An evaluation of the psychometric properties of the Indicator of Relative Need (IoRN) instrument. AB - BACKGROUND: The Indicator of Relative Need (IoRN) instrument is designed for both health and social care services to measure function and dependency in older people. To date, the tool has not undergone assessment of validity. We report two studies aimed to evaluate psychometric properties of the IoRN. METHODS: The first study recruited patients receiving social care at discharge from hospital, those rehabilitating in intermediate care, and those in a rehabilitation at home service. Participants were assessed using the IoRN by a single researcher and by the clinical team at baseline and 8 weeks. Comparator instruments (Barthel ADL, Nottingham Extended ADL and Townsend Disability Scale) were also administered. Overall change in ability was assessed with a 7 point Likert scale at 8 weeks. The second study analysed linked routinely collected, health and social care data (including IoRN scores) to assess the relationship between IoRN category and death, hospitalisation and care home admission as a test of external validity. RESULTS: Ninety participants were included in the first study, mean age 77.9 (SD 12.0). Cronbach's alpha for IoRN subscales was high (0.87 to 0.93); subscales showed moderate correlation with comparator tools (r = 0.43 to 0.63). Cohen's weighted kappa showed moderate agreement between researcher and clinician IoRN category (0.49 to 0.53). Two-way intraclass correlation coefficients for IoRN subscales in participants reporting no change in ability were high (0.88 to 0.98) suggesting good stability; responsiveness coefficients in participants reporting overall change were equal to or better than comparator tools. 1712 patients were included in the second study, mean age 81.0 years (SD 7.7). Adjusted hazard ratios for death, care home admission and hospitalisation in the most dependent category compared to the least dependent IoRN category were 5.9 (95 % CI 2.0 17.0); 7.2 (95 % CI 4.4-12.0); 1.1 (95 % CI 0.5-2.6) respectively. The mean number of allocated hours of care 6 months after assessment was higher in the most dependent group compared to the least dependent group (5.6 vs 1.4 h, p = 0.005). CONCLUSIONS: Findings from these analyses support the use of the IoRN across a range of clinical environments although some limitations are highlighted. PMID- 27469008 TI - Physical activity-related social control and social support in older adults: Cognitive and emotional pathways to physical activity. AB - A survey of 217 older adults assessed physical activity-related positive and negative social control and emotional and informational support, using structural equation modeling to investigate mediational effects of emotional responses and behavioral intentions on physical activity. There were significant indirect effects of social control and social support on intentions as mediated by positive, but not negative, emotional responses, and significant indirect effects of emotional responses on physical activity as mediated by intentions. These findings help to identify the cognitive and emotional pathways by which social control and social support may promote or detract from physical activity in later life. PMID- 27469009 TI - 'Haematological cancers, they're a funny bunch': A qualitative study of non Hodgkin's lymphoma patient experiences of unmet supportive care needs. AB - Despite high levels of psychological distress, there is a scarcity of research on unmet supportive care needs in haematological cancer patients. This qualitative study used an in-depth interpretative phenomenological approach to investigate the needs reported by six non-Hodgkin's lymphoma patients and explored how these needs consequently shaped the patient experience. Emergent themes included the following: concerns for family, information needs and the need for psychological support. Participants reported feeling different to other cancer patients. Lack of understanding of their diagnosis by friends and family and lack of access to relevant support services are notable unmet needs that differ from previous findings. PMID- 27469013 TI - Content of Asthmagen Natural Rubber Latex Allergens in Commercial Disposable Gloves. AB - The use of natural rubber latex (NRL) gloves in many occupations may lead to latex sensitization, allergic asthma, and skin reactions. Due to their good properties and environmental safety NRL gloves are still being used in the healthcare setting, but also in the food industry, by hairdressers, cleaners, etc. The aim of our study was to assess the protein and NRL allergen content in commercial gloves by different methods, including a new assay. Twenty commercially available NRL gloves were analyzed. Protein extraction was performed according to the international standard ASTM D-5712. Total protein content was measured with a modified Lowry method, NRL content with the CAP Inhibition Assay, the Beezhold ELISA Inhibition Assay, and an innovative ELISA with IgY-antibodies extracted from eggs of NRL-immunized hens (IgY Inhibition Assay). We found a high protein content in a range of 215.0-1304.7 MUg/g in 8 out of the 20 NRL gloves. Seven of the 20 gloves were powdered, four of them with a high protein content. In gloves with high protein content, the immunological tests detected congruently high levels of NRL allergen. We conclude that a high percentage of commercially available NRL gloves still represent a risk for NRL allergy, including asthma. The modified Lowry Method allows to infer on the latex allergen content. PMID- 27469014 TI - Friedreich's ataxia and advanced heart failure: An ethical conundrum in decision making. PMID- 27469016 TI - Lung transplantation and gender effects on survival of recipients with cystic fibrosis. AB - BACKGROUND: The overall life expectancy of women with cystic fibrosis (CF) is shorter compared with men with CF without accounting for lung transplant recipients. However, it is unclear how donor and recipient gender impact long term outcomes in patients with CF who undergo lung transplantation. The purpose of this study was to determine if the gender disadvantage seen in women with CF before transplant continues to exist after lung transplant and if this is impacted by donor gender. METHODS: Patients with CF entered in the International Society for Heart and Lung Transplantation registry who were at least 18 years old and received a lung transplant between January 2000 and December 2012 were included and divided into groups based on donor-recipient gender combinations. Kaplan-Meier curves were used to determine post-transplant rates of overall survival and bronchiolitis obliterans syndrome (BOS)-free survival. RESULTS: The analysis included 4,971 patients undergoing lung transplantation for CF. There was no significant difference in BOS-free survival or overall survival rates between genders or between gender-matched vs gender-mismatched recipients after lung transplantation. However, women with CF underwent transplantation at a younger age and died at an earlier overall age than men with CF. CONCLUSIONS: Survival after lung transplantation and time to the development of BOS did not differ based on gender or donor-recipient gender combination. However, women with CF continue to demonstrate a poorer overall life expectancy, as their pre transplant disadvantage could not be overcome after lung transplantation. PMID- 27469015 TI - Right ventricular response to pulsatile load is associated with early right heart failure and mortality after left ventricular assist device. AB - BACKGROUND: Right ventricular (RV) adaptation to afterload is crucial for patients undergoing continuous-flow left ventricular assist device (cf-LVAD) implantation. We hypothesized that stratifying patients by RV pulsatile load, using pulmonary arterial compliance (PAC), and RV response to load, using the ratio of central venous to pulmonary capillary wedge pressure (CVP:PCWP), would identify patients at high risk for early right heart failure (RHF) and 6-month mortality after cf-LVAD. METHODS: During the period from January 2008 to June 2014, we identified 151 patients at our center with complete hemodynamics prior to cf-LVAD. Pulsatile load was estimated using PAC indexed to body surface area (BSA), according to the formula: indexed PAC (PACi) = [SV / (PAsystolic - PAdiastolic)] / BSA, where SV is stroke volume and PA is pulmonary artery. Patients were divided into 4 hemodynamic groups by PACi and CVP:PCWP. RHF was defined as the need for unplanned RVAD, inotropic support >=14 days or death due to RHF within 14 days. Risk factors for RHF and 6-month mortality were examined using logistic regression and Cox proportional hazards modeling. RESULTS: Sixty one patients (40.4%) developed RHF and 34 patients (22.5%) died within 6 months. Patients with RHF had lower PACi (0.92 vs 1.17 ml/mm Hg/m2, p = 0.008) and higher CVP:PCWP (0.48 vs 0.37, p = 0.001). Higher PACi was associated with reduced risk of RHF (adjusted odds ratio [adj-OR] 0.61, 95% confidence interval [CI] 0.39 to 0.94, p = 0.025) and low PACi with increased risk of 6-month mortality (adjusted hazard ratio [adj-HR] 3.18, 95% CI 1.40 to 7.25, p = 0.006). Compared to patients with low load (high PACi) and adequate right heart response to load (low CVP:PCWP), patients with low PACi and high CVP:PCWP had an increased risk of RHF (OR 4.74, 95% CI 1.23 to 18.24, p = 0.02) and 6-month mortality (HR 8.68, 95% CI 2.79 to 26.99, p < 0.001). CONCLUSIONS: A hemodynamic profile combining RV pulsatile load and response to load identifies patients at high risk for RHF and 6-month mortality after cf-LVAD. PMID- 27469017 TI - Insurance status by region at the time of heart transplantation: Implications for survival. AB - BACKGROUND: Heart transplantation outcomes differ by health insurance status and geographic region of the United States. We hypothesized that heart transplantation survival would be affected by health insurance status within certain United Network for Organ Sharing (UNOS) regions. METHODS: We used data from the UNOS thoracic database to classify health insurance status into private or public (private/self-pay or Medicare/Medicaid) for all first-time heart transplant recipients between July 2006 and September 2013. We applied Cox proportional hazards regression to estimate hazard ratio (HR) and 95% confidence interval (CI) for the influences of health insurance status on 1-year and long term survival in heart transplant recipients by UNOS region. RESULTS: Mean survival time among 10,474 patients was 942 days +/- 704. All key demographic and clinical variables varied significantly across UNOS regions. With respect to 1 year survival, patients in Region 2 had a higher hazard of mortality (HR, 1.49; 95% CI, 1.03, 2.15) if they had public vs private insurance. When we restricted the analysis to be conditional on 1-year survival, 2 contiguous regions, Region 10, including Indiana, Ohio, Michigan (HR, 2.30; 95% CI, 1.23, 4.28), and Region 11 (HR, 1.85; 95% CI, 1.15, 2.97), including the upper South, had poor survival associated with public vs private insurance. CONCLUSIONS: The data we present invite targeted efforts by certain UNOS regions to improve the standard of care and/or eligibility thresholds for heart transplant recipients. PMID- 27469019 TI - Control of sinus tachycardia as an additional therapy in patients with decompensated heart failure (CONSTATHE-DHF): A randomized, double-blind, placebo controlled trial. PMID- 27469018 TI - Transition from parenteral to oral treprostinil in pulmonary arterial hypertension. AB - BACKGROUND: Parenteral prostanoids are effective treatment for pulmonary arterial hypertension, but long-term pump infusion systems have significant delivery related safety and convenience limitations. METHODS: Subjects with a favorable risk profile transitioned from parenteral to oral treprostinil using a protocol driven titration during 5 days of inpatient observation. Baseline and Week 24 assessments included 6-minute walk distance, echocardiogram, right heart catheterization, pharmacokinetics, treatment satisfaction and quality of life. Thirty-three subjects (76% female, mean age 50 years) enrolled; 85% were using subcutaneous treprostinil with a median dose of 57 (range 25 to 111) ng/kg/min. Participants were using background, approved non-prostanoid therapy, including 9 on 2 oral therapies; baseline right atrial pressure and cardiac output were in the normal range. All 33 subjects transitioned to oral treprostinil therapy within 4 weeks, but 2 transitioned back to parenteral drug before Week 24. At Week 24, subjects were taking a median total daily dose of 44 (15 to 75) mg, with 25 of 31 using a 3-times-daily regimen at 7- to 9-hour intervals. RESULTS: The 6 minute walk distance was preserved (median +17 m [-98 to 95 m]) at its baseline of 446 m. Hemodynamic variables, including pulmonary vascular resistance, were similar at Week 24 except for mixed venous saturation, which dropped from a median of 71% to 68% (p < 0.001). Overall quality of life and treatment satisfaction measures did not change; however, mood-related symptom and treatment convenience subscores improved. Common adverse effects included headache, nausea, flushing and diarrhea. CONCLUSIONS: Lower risk patients managed on parenteral treprostinil may be candidates for transition to a more convenient, oral form of the drug. PMID- 27469020 TI - Pathways from maternal depression to young adult offspring depression: an exploratory longitudinal mediation analysis. AB - Maternal depression in the peri-natal period is associated with increased risk for young adult depression in offspring. This study explored mediation of these links via trajectories of child conduct and emotional problems (Strengths and Difficulties Questionnaire) from ages 4-16 years old in data from the Avon Longitudinal Study of Parents and Children cohort (n = 13373). Through gender specific structural equation models, a composite measure of exposure to early maternal depression (Edinburgh Postnatal Depression Scale), predicted young adult depression at age 18 (Revised Clinical Interview Schedule - distal outcome). Mediational effects were then estimated by testing which parts of joint piecewise latent trajectory models for child/adolescent conduct and emotional problems were associated with both exposure and distal outcome. For girls, only conduct problems in early childhood were consistently indicated to mediate effects of early maternal depression on risk of young adulthood depression. Some evidence for a pathway via changing levels of childhood and adolescent emotional difficulties was also suggested. For boys, by contrast, the differing models gave less consistent findings providing some evidence for a small time-specific indirect effect via early childhood conduct problems. In addition to its practice implications the current methodological application offers considerable potential in exploratory longitudinal developmental mediation studies. (c) 2016 The Authors International Journal of Methods in Psychiatric Research Published by John Wiley & Sons Ltd. PMID- 27469021 TI - N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement. AB - RATIONALE: Chronic exposure to drugs of abuse changes glutamatergic transmission in human addicts and animal models. N-acetylcysteine (NAC) is a cysteine prodrug that indirectly activates cysteine-glutamate antiporters. In the extrasynaptic space, NAC restores basal glutamate levels during drug abstinence and normalizes increased glutamatergic tone in rats during reinstatement to drugs of abuse. In initial clinical trials, repeated NAC administration seems to be promising for reduced craving in cocaine addicts. OBJECTIVE: In this study, NAC-amide, called AD4 or NACA, was examined in intravenous cocaine self-administration and extinction/reinstatement procedures in rats. We investigated the behavioral effects of AD4 in the olfactory bulbectomized (OBX) rats, considered an animal model of depression. Finally, we tested rats injected with AD4 or NAC during 10 daily extinction training sessions to examine subsequent cocaine seeking. RESULTS: AD4 (25-75 mg kg(-1)) given acutely did not alter the rewarding effects of cocaine in OBX rats and sham-operated controls. However, at 6.25-50 mg kg(-1), AD4 decreased dose-dependently cocaine seeking and relapse triggered by cocaine priming or drug-associated conditioned cues in both phenotypes. Furthermore, repeated treatment with AD4 (25 mg kg(-1)) or NAC (100 mg kg(-1)) during daily extinction trials reduced reinstatement of drug-seeking behavior in sham-operated controls. In the OBX rats only, AD4 effectively blocked cocaine-seeking behavior. CONCLUSIONS: Our results demonstrate that AD4 is effective at blocking cocaine seeking behavior, highlighting its potential clinical use toward cocaine use disorder. PMID- 27469022 TI - Improvement of attention with amphetamine in low- and high-performing rats. AB - RATIONALE: Attentional deficits occur in a range of neuropsychiatric disorders, such as schizophrenia and attention deficit hyperactivity disorder. Psychostimulants are one of the main treatments for attentional deficits, yet there are limited reports of procognitive effects of amphetamine in preclinical studies. Therefore, task development may be needed to improve predictive validity when measuring attention in rodents. OBJECTIVES: This study aimed to use a modified signal detection task (SDT) to determine if and at what doses amphetamine could improve attention in rats. METHODS: Sprague-Dawley rats were trained on the SDT prior to amphetamine challenge (0.1, 0.25, 0.75 and 1.25 mg/kg). This dose range was predicted to enhance and disrupt cognition with the effect differing between individuals depending on baseline performance. RESULTS: Acute low dose amphetamine (0.1 and 0.25 mg/kg) improved accuracy, while the highest dose (1.25 mg/kg) significantly disrupted performance. The effects differed for low- and high-performing groups across these doses. The effect of amphetamine on accuracy was found to significantly correlate with baseline performance in rats. CONCLUSIONS: This study demonstrates that improvement in attentional performance with systemic amphetamine is dependent on baseline accuracy in rats. Indicative of the inverted U-shaped relationship between dopamine and cognition, there was a baseline-dependent shift in performance with increasing doses of amphetamine. The SDT may be a useful tool for investigating individual differences in attention and response to psychostimulants in rodents. PMID- 27469023 TI - Exposure of Free-Ranging Wild Carnivores and Domestic Dogs to Canine Distemper Virus and Parvovirus in the Cerrado of Central Brazil. AB - Human population growth around protected areas increases the contact between wild and domestic animals, promoting disease transmission between them. This study investigates the exposure of free-ranging wild carnivores and domestic dogs to canine distemper virus (CDV) and parvovirus in Emas National Park (ENP) in the Cerrado savanna of central Brazil. Serum samples were collected from 169 wild carnivores, including the maned wolf (Chrysocyon brachyurus), crab-eating fox (Cerdocyon thous), hoary fox (Pseudalopex vetulus), puma (Puma concolor), ocelot (Leopardus pardalis), pampas cat (Leopardus colocolo), jaguarundi (Herpailurus yagouaroundi), striped hog-nosed skunk (Conepatus semistriatus) and coati (Nasua nasua), and from 35 domestic dogs living on rural properties bordering ENP. Serological tests showed that 10.6% of wild carnivores (maned wolves, crab-eating foxes and ocelots) and 71.4% of domestic dogs were exposed to CDV, and 56.8% of wild carnivores, including all species sampled except coatis, and 57.1% of domestic dogs were exposed to parvovirus. This report is the first to indicate that the free-ranging pampas cat, jaguarundi and striped hog-nosed skunk are exposed to parvovirus. CDV and parvovirus deserve attention in ENP, and it is extremely important to monitor the health of carnivore populations and perform molecular diagnosis of the viruses to determine the possible involvement of the domestic dog in their transmission. PMID- 27469025 TI - Sphingomonas prati sp. nov., isolated from alpine meadow soil. AB - A Gram-staining-negative, non-motile, orange-coloured and rod-shaped aerobic bacterium, designated W18RDT, was isolated from the alpine meadow soil of the Tibetan plateau. Phylogenetic analysis based on 16S rRNA gene sequences positioned strain W18RDT as a representative of a novel species under the genus Sphingomonas which was most closely related to Sphingomonas fennica DSM 13665T with a sequence similarity level of 97.14 %. Meanwhile, it also had a high level of sequence similarity with Sphingomonas laterariae DSM 25432T (96.51 %), Sphingomonas haloaromaticamans CGMCC 1.10206T (96.43 %) and Sphingomonas formosensis DSM 24164T (96.26 %). The G+C content of the genomic DNA of the type strain W18RDT was 66.4mol%. DNA-DNA relatedness for the type strain W18RDT with respect to its closest phylogenetic relative Sphingomonas. fennica DSM 13665Twas 21.54+/-1.2 %. Major cellular fatty acids in strain W18RDT were C16 : 1omega7c and/or C16 : 1omega6c (48.12 %), C18 : 1omega7c and/or C18 : 1omega6c (21.98 %) and C14 : 0 2-OH (14.93 %), with ubiquinone-10 (Q-10) as the predominant respiratory quinone. The polar lipid profile of the strain consisted of phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, phosphatidylcholine, diphosphatidylglycerol and two unknown lipids. Based on the evidence from a combination of phenotypic, taxonomic and phylogenetic analyses, strain W18RDT represents a novel species of the genus Sphingomonas, for which the name Sphingomonas prati sp. nov. is proposed. The type strain is W18RDT (=CGMCC 1.15645T=DSM 103336T). PMID- 27469024 TI - Nitric oxide promotes epidermal stem cell migration via cGMP-Rho GTPase signalling. AB - The migration and reepithelization of epidermal stem cells (ESCs) are the most critical processes in wound healing. The gaseous messenger nitric oxide (NO) has multiple biological effects, but its actions on ESCs are poorly understood. In this study, an NO donor, S-nitroso-N-acetylpenicillamine (SNAP), was found to facilitate the in vitro migration of human ESCs (huESCs) in both live-imaging and scratch models. In addition, pull-down assays demonstrated that SNAP could activate the small GTPases RhoA and Rac1 of the Rho family, but not Cdc42. Moreover, the effects of SNAP on the migration and F-actin polymerization of ESCs could be blocked by inhibitors of cGMP, PKG, RhoA or Rac1, and by a specific siRNA of RhoA or Rac1, but not by a Cdc42 inhibitor or siRNA. Furthermore, the roles of NO in ESC migration via cGMP-Rho GTPase signalling in vivo were confirmed by tracing 5-bromo-2-deoxyuridine (BrdU)-labelled cells in a superficial, partial-thickness scald mouse model. Thus, the present study demonstrated that the NO donor SNAP could promote huESC migration in vitro. Furthermore, NO was found to induce ESC migration via cGMP-Rho GTPase RhoA and Rac1 signalling, but not Cdc42 signalling, both in vivo and in vitro. PMID- 27469026 TI - Molecular characterization of norovirus GII.17 detected in healthy adult, intussusception patient, and acute gastroenteritis children in Thailand. AB - Noroviruses (NoVs) have been recognized as a leading cause of sporadic cases and outbreaks of acute gastroenteritis in all age groups. During the surveillance of NoVs in Chiang Mai, Thailand, four cases of the novel GII.17 NoVs were sporadically detected by RT-PCR in 2014-2015. The first case of GII.17 was detected in a healthy adult who worked for a restaurant. The second case was found in a pediatric patient who admitted to the hospital with intussusception. The third and fourth cases were found in acute gastroenteritis children. Phylogenetic analysis clearly demonstrated that GII.17 NoVs detected in this study were genetically closely related with the novel GII.17 Kawasaki reference strains. These four GII.17 NoV positive specimens were also tested by two immunochromatographic test kits in order to evaluate the sensitivity for GII.17 NoV detection. The viral loads in those specimens were determined by real-time RT PCR. The sensitivity of GII.17 NoV detection varies by individual test kits and also depending on the amount of the viruses contained in the fecal specimens. In summary, our study reported the detection of novel GII.17 NoVs in a wide range of subjects with and without diarrhea. Therefore, continued comprehensive screening and genetic molecular characterization of NoV strains circulating in this area need to be further investigated. PMID- 27469027 TI - Non-human primates in HIV research: Achievements, limits and alternatives. AB - An ideal model for HIV-1 research is still unavailable. However, infection of non human primates (NHP), such as macaques, with Simian Immunodeficiency Virus (SIV) recapitulates most virological, immunological and clinical hallmarks of HIV infection in humans. It has become the most suitable model to study the mechanisms of transmission and physiopathology of HIV/AIDS. On the other hand, natural hosts of SIV, such as African green monkeys and sooty mangabeys that when infected do not progress to AIDS, represent an excellent model to elucidate the mechanisms involved in the capacity of controlling inflammation and disease progression. The use of NHP-SIV models has indeed enriched our knowledge in the fields of: i) viral transmission and viral reservoirs, ii) early immune responses, iii) host cell-virus interactions in tissues, iv) AIDS pathogenesis, v) virulence factors, vi) prevention and vii) drug development. The possibility to control many variables during experimental SIV infection, together with the resemblance between SIV and HIV infections, make the NHP model the most appropriate, so far, for HIV/AIDS research. Nonetheless, some limitations in using these models have to be considered. Alternative models for HIV/AIDS research, such as humanized mice and recombinant forms of HIV-SIV viruses (SHIV) for NHP infection, have been developed. The improvement of SHIV viruses that mimic even better the natural history of HIV infection and of humanized mice that develop a greater variety of human immune cell lineages, is ongoing. None of these models is perfect, but they allow contributing to the progress in managing or preventing HIV infection. PMID- 27469028 TI - Dynamical manipulation of electromagnetic polarization using anisotropic meta mirror. AB - Polarization control of electromagnetic wave is very important in many fields. Here, we propose an active meta-mirror to dynamically manipulate electromagnetic polarization state at a broad band. This meta-mirror is composed of a double layered metallic pattern backed by a metallic flat plate, and the active elements of PIN diodes are integrated into the meta-atom to control the reflection phase difference between two orthogonal polarization modes. Through switching the operating state of the PIN diodes, the meta-mirror is expected to achieve three polarization states which are left-handed, right-handed circular polarizations and linear polarization, respectively. We fabricated this active meta-mirror and validated its polarization conversion performance by measurement. The linearly polarized incident wave can be dynamically converted to right-handed or left handed circular polarization in the frequency range between 3.4 and 8.8 GHz with the average loss of 1 dB. Furthermore, it also can keep its initial linear polarization state. PMID- 27469029 TI - miR-30c regulates proliferation, apoptosis and differentiation via the Shh signaling pathway in P19 cells. AB - MicroRNAs (miRNAs) are small, non-coding single-stranded RNAs that suppress protein expression by binding to the 3' untranslated regions of their target genes. Many studies have shown that miRNAs have important roles in congenital heart diseases (CHDs) by regulating gene expression and signaling pathways. We previously found that miR-30c was highly expressed in the heart tissues of aborted embryos with ventricular septal defects. Therefore, this study aimed to explore the effects of miR-30c in CHDs. miR-30c was overexpressed or knocked down in P19 cells, a myocardial cell model that is widely used to study cardiogenesis. We found that miR-30c overexpression not only increased cell proliferation by promoting cell entry into S phase but also suppressed cell apoptosis. In addition, we found that miR-30c inhibited dimethyl sulfoxide-induced differentiation of P19 cells. miR-30c knockdown, in contrast, inhibited cell proliferation and increased apoptosis and differentiation. The Sonic hedgehog (Shh) signaling pathway is essential for normal embryonic development. Western blotting and luciferase assays revealed that Gli2, a transcriptional factor that has essential roles in the Shh signaling pathway, was a potential target gene of miR-30c. Ptch1, another important player in the Shh signaling pathway and a transcriptional target of Gli2, was downregulated by miR-30c overexpression and upregulated by miR-30c knockdown. Collectively, our study revealed that miR-30c suppressed P19 cell differentiation by inhibiting the Shh signaling pathway and altered the balance between cell proliferation and apoptosis, which may result in embryonic cardiac malfunctions. PMID- 27469030 TI - Sur8 mediates tumorigenesis and metastasis in colorectal cancer. AB - Sur8, a scaffold protein of the Ras pathway, interacts with Ras and Raf and modulates the Ras-extracellular signal-regulated kinase (ERK) pathway. Here we show that Sur8 is overexpressed in established human colorectal cancer (CRC) cell lines and CRC patient tissues. Moreover, Sur8 expression is increased during liver metastasis in CRC patients. Sur8 knockdown decreases ERK and Akt activities in CRC cell lines, regardless of their K-Ras, B-Raf or PI3K mutation status. Overexpression or knockdown of Sur8 increases or decreases, respectively, the proliferation or transformation of CRC cell lines. Sur8 knockdown attenuates the migration and invasion of HCT116 CRC cells. Subcutaneous or orthotopic injection of HCT116 cells harboring a doxycycline (Dox)-mediated Sur8 knockdown system in nude mice resulted in decreased tumorigenic potential and inhibited the liver metastatic potential of HCT116 cells. Taken together, our data support the role of Sur8 as a promoter of tumorigenesis and liver metastasis in CRC through its modulation of the Ras-ERK and PI3K-Akt signaling pathways. PMID- 27469031 TI - Validation of a multi-omics strategy for prioritizing personalized candidate driver genes AB - Significant heterogeneity between different tumors prevents the discovery of cancer driver genes, especially in a patient-specific manner. We previously prioritized five personalized candidate mutation-driver genes in a hyper-mutated hepatocellular carcinoma patient using a multi-omics strategy. However, the roles of the prioritized driver genes and patient-specific mutations in hepatocarcinogenesis are unclear. We investigated the impact of the tumor-mutated allele on structure-function relationship of the encoded protein and assessed both loss- and gain-of-function of these genes and mutations on hepatoma cell behaviors in vitro. The prioritized mutation-driver genes act as tumor suppressor genes and inhibit cell proliferation and migration. In addition, the loss-of function effect of the patient-specific mutations promoted cell proliferation and migration. Of note, the HNF1A S247T mutation significantly reduced the HNF1A transcriptional activity for hepatocyte nuclear factor 4 alpha (HNF4A) but did not disrupt nuclear localization of HNF1A. The results provide evidence for supporting the validity of our proposed multi-omics strategy, which supplies a new avenue for prioritizing mutation-drivers towards personalized cancer therapy. PMID- 27469032 TI - Accelerating global innovation to address antibacterial resistance: introducing CARB-X. AB - A global response to the chronic shortfall in antibiotic innovation is urgently needed to combat antimicrobial resistance. Here, we introduce CARB-X, a new global public-private partnership that will invest more than US$350 million in the next 5 years to accelerate the progression of a diverse portfolio of innovative antibacterial products into clinical trials. PMID- 27469034 TI - Exome array analysis of ischaemic stroke: results from a southern Swedish study. AB - BACKGROUND AND PURPOSE: Genome-wide association (GWA) studies have identified a few risk loci for ischaemic stroke, but these variants explain only a small part of the genetic contribution to the disease. Coding variants associated with amino acid substitutions or premature termination of protein synthesis could have a large effect on disease risk. We performed an exome array analysis for ischaemic stroke. METHODS: Patients with ischaemic stroke (n = 2385) and control subjects (n = 6077) from three Swedish studies were genotyped with the Illumina HumanOmniExpressExome BeadChip. Single-variant association analysis and gene based tests were performed of exome variants with minor allele frequency of < 5%. A separate GWA analysis was also performed, based on 700 000 genotyped common markers and subsequent imputation. RESULTS: No exome variant or gene was significantly associated with all ischaemic stroke after Bonferroni correction (all P > 1.8 * 10-6 for single-variant and >4.15 * 10-6 for gene-based analysis). The strongest association in single-variant analysis was found for a missense variant in the DNAH11 gene (rs143362381; P = 5.01 * 10-6 ). In gene-based tests, the strongest association was for the ZBTB20 gene (P = 7.9 * 10-5 ). The GWA analysis showed that the sample was homogenous (median genomic inflation factor = 1.006). No genome-wide significant association with overall ischaemic stroke risk was found. However, previously reported associations for the PITX2 and ZFHX3 gene loci with cardioembolic stroke subtype were replicated (P = 7 * 10-15 and 6 * 10 3 ). CONCLUSIONS: This exome array analysis did not identify any single variants or genes reaching the pre-defined significance level for association with ischaemic stroke. Further studies on exome variants should be performed in even larger, well-defined and subtyped samples. PMID- 27469035 TI - Follow a recipe to prescribe phosphate during hemodialysis. AB - The addition of phosphorus (P) to the dialysate (LD) in the form of enema Casen(r) is common practice in patients with hypophosphatemia. The estimation of the amount to be used and the identification of the problems that may can occur are not well defined. As a result of our work we propose a practical approach of how to proceed to increase phosphate concentration in the hemodialysate. We present a reasoned formula to calculate how much enema has to be added and the problems that may arise. PMID- 27469033 TI - Direct small-molecule inhibitors of KRAS: from structural insights to mechanism based design. AB - KRAS is the most frequently mutated oncogene in human cancer. In addition to holding this distinction, unsuccessful attempts to target this protein have led to the characterization of RAS as 'undruggable'. However, recent advances in technology and novel approaches to drug discovery have renewed hope that a direct KRAS inhibitor may be on the horizon. In this Review, we provide an in-depth analysis of the structure, dynamics, mutational activation and inactivation, and signalling mechanisms of RAS. From this perspective, we then consider potential mechanisms of action for effective RAS inhibitors. Finally, we examine each of the many recent reports of direct RAS inhibitors and discuss promising avenues for further development. PMID- 27469036 TI - Is the renal kallikrein-kinin system a factor that modulates calciuria? AB - Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK). Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H) that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%). These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics. PMID- 27469038 TI - Reply to: Xue FS, et al. Association of acute kidney injury with adverse postoperative outcomes after living donor liver transplantation. PMID- 27469039 TI - Catching a virus in a molecular net. AB - A metal-organic molecular net composed of tannic acid (TA) and iron(iii) was constructed around the brome mosaic virus (BMV) particle to determine whether the added net could act as a transport barrier for water, and if the net could stabilize the virus in physically or chemically challenging environments. This new virus engineering strategy is expected to provide benefits both in the study and technological applications of viruses. For instance, a virus wrapped in a thin molecular layer could be extracted from solution either in air or vacuum, and its structure, composition and even internal dynamics could be interrogated by methods not compatible with a liquid environment. Atomic force microscopy (AFM) studies of Fe(iii)-TA coated BMV in liquid and in air supported a marked resistance to dehydration when compared to wtBMV. Native charge detection mass spectrometry (CDMS), was employed to estimate the number of molecules in the molecular net which wrapped the virus. The CDMS data suggested that less than one molecular monolayer wrapped the virus. Additionally, it was found, that this very thin molecular coat was sufficient to render the coated viruses resistant to storage conditions that typically lead to virus disassembly over time. A temporary coat imparting increased resistance to disassembly could be useful in adding time delay control or alleviate required storage conditions of engineered viruses for therapeutic purposes. PMID- 27469037 TI - Objective support for subjective reports of successful inner speech in two people with aphasia. AB - People with aphasia frequently report being able to say a word correctly in their heads, even if they are unable to say that word aloud. It is difficult to know what is meant by these reports of "successful inner speech". We probe the experience of successful inner speech in two people with aphasia. We show that these reports are associated with correct overt speech and phonologically related nonword errors, that they relate to word characteristics associated with ease of lexical access but not ease of production, and that they predict whether or not individual words are relearned during anomia treatment. These findings suggest that reports of successful inner speech are meaningful and may be useful to study self-monitoring in aphasia, to better understand anomia, and to predict treatment outcomes. Ultimately, the study of inner speech in people with aphasia could provide critical insights that inform our understanding of normal language. PMID- 27469040 TI - Biochar prepared from castor oil cake at different temperatures: A voltammetric study applied for Pb(2+), Cd(2+) and Cu(2+) ions preconcentration. AB - Biochar is a carbonaceous material similar produced by pyrolysis of biomass under oxygen-limited conditions. Pyrolysis temperature is an important parameter that can alters biochar characteristics (e.g. surface area, pore size distribution and surface functional groups) and affects it efficacy for adsorption of several probes. In this work, biochar samples have been prepared from castor oil cake using different temperatures of pyrolysis (200-600 degrees C). For the first time, a voltammetric procedure based on carbon paste modified electrode (CPME) was used to investigate the effect of temperature of pyrolysis on the adsorptive characteristics of biochar for Pb(II), Cd(II) and Cu(II) ions. Besides the electrochemical techniques, several characterizations have been performed to evaluate the physicochemical properties of biochar in function of the increase of the pyrolysis temperature. Results suggest that biochar pyrolized at 400 degrees C (BC400) showed a better potential for ions adsorption. The CPME modified with BC400 showed better relative current signal with adsorption affinity: Pb(II)>Cd(II)>Cu(II). Kinetic studies revealed that the pseudo-second order model describes more accurately the adsorption process suggesting that the surface reactions control the adsorption rate. Values found for amount adsorbed were 15.94+/-0.09; 4.29+/-0.13 and 2.38+/-0.39MUgg(-1) for Pb(II), Cd(II) and Cu(II) ions, respectively. PMID- 27469041 TI - Remediation of hexavalent chromium contaminated soil by biochar-supported zero valent iron nanoparticles. AB - In this study, a kind of high-efficiency and low-cost biochar-supported zero valent iron nanoparticles (nZVI@BC) was synthesised and used in the remediation of Cr(VI)-contaminated soil. The remediation tests indicated that the immobilisation efficiency of Cr(VI) and Crtotal was 100% and 91.94%, respectively, by 8g nZVI@BC per kg soil for 15 d of remediation. Further investigations showed that exchangeable Cr was almost completely converted to Fe Mn oxides and organic matter. Moreover, nZVI@BC could effectively improve soil fertility and reduce the leachability of Fe caused by nZVI. At the same time, the cabbage mustard growth experiments indicated that the phytotoxicity of Cr(VI) and Fe in the seedlings was effectively decreased by nZVI@BC treatment, and that the cabbage mustard growth was enhanced. PMID- 27469042 TI - Photocatalytic decomposition of selected estrogens and their estrogenic activity by UV-LED irradiated TiO2 immobilized on porous titanium sheets via thermal chemical oxidation. AB - The removal of endocrine disrupting compounds (EDCs) remains a big challenge in water treatment. Risks associated with these compounds are not clearly defined and it is important that the water industry has additional options to increase the resiliency of water treatment systems. Titanium dioxide (TiO2) has potential applications for the removal of EDCs from water. TiO2 has been immobilized on supports using a variety of synthesis methods to increase its feasibility for water treatment. In this study, we immobilized TiO2 through the thermal-chemical oxidation of porous titania sheets. The efficiency of the material to degrade target EDCs under UV-LED irradiation was examined under a wide range of pH conditions. A yeast-estrogen screen assay was used to complement chemical analysis in assessing removal efficiency. All compounds but 17beta-estradiol were degraded and followed a pseudo first-order kinetics at all pH conditions tested, with pH 4 and pH 11 showing the most and the least efficient treatments respectively. In addition, the total estrogenic activity was substantially reduced even with the inefficient degradation of 17beta-estradiol. Additional studies will be required to optimize different treatment conditions, UV-LED configurations, and membrane fouling mitigation measures to make this technology a more viable option for water treatment. PMID- 27469043 TI - Oxygen vacancy induced fast lithium storage and efficient organics photodegradation over ultrathin TiO2 nanolayers grafted graphene sheets. AB - In this work we have developed a unique structure of ultrathin (5nm) TiO2 nanolayers grafted graphene nanosheets (TiO2/G) and integrated oxygen vacancy (VO) into TiO2 to enhance its lithium storage and photocatalytic performances. The defective TiO2/G was synthesized by a solvothermal and subsequent thermal treatment method. When treated in a H2 atmosphere, the resulting TiO2-x/G(H2) has lower crystallinity, smaller crystal size, richer surface VO, higher surface area, larger pore volume, and lower charge transfer resistance than that reduced by NaBH4 solid, i.e., TiO2-x/G(NaBH4). More importantly, the surface VO in the TiO2-x/G(H2) could remarkably inhibit the recombination of photogenerated electron-hole pairs compared with the bulk Vo in the TiO2-x/G(NaBH4). As a result, the combination of all the factors contributed to the superiority of TiO2 x/G(H2), which demonstrated not only 70% higher specific capacity, longer cycling performance (1000 cycles) and better rate capability for lithium-ion battery, but also higher photocatalytic activity and 1.5 times faster degradation rate for organic pollutants removal than TiO2-x/G(NaBH4). The findings in this work will benefit the fundamental understanding of TiO2/G surface chemistry and advance the design and preparation of functional materials for energy storage and water treatment. PMID- 27469044 TI - Continuous treatment of non-sterile hospital wastewater by Trametes versicolor: How to increase fungal viability by means of operational strategies and pretreatments. AB - Hospital wastewaters have a high load of pharmaceutical active compounds (PhACs). Fungal treatments could be appropriate for source treatment of such effluents but the transition to non-sterile conditions proved to be difficult due to competition with indigenous microorganisms, resulting in very short-duration operations. In this article, coagulation-flocculation and UV-radiation processes were studied as pretreatments to a fungal reactor treating non-sterile hospital wastewater in sequential batch operation and continuous operation modes. The influent was spiked with ibuprofen and ketoprofen, and both compounds were successfully degraded by over 80%. UV pretreatment did not extent the fungal activity after coagulation-flocculation measured as laccase production and pellet integrity. Sequential batch operation did not reduce bacteria competition during fungal treatment. The best strategy was the addition of a coagulation flocculation pretreatment to a continuous reactor, which led to an operation of 28days without biomass renovation. PMID- 27469045 TI - Potential application of aerobic denitrifying bacterium Pseudomonas aeruginosa PCN-2 in nitrogen oxides (NOx) removal from flue gas. AB - Conventional biological removal of nitrogen oxides (NOx) from flue gas has been severely restricted by the presence of oxygen. This paper presents an efficient alternative for NOx removal at varying oxygen levels using the newly isolated bacterial strain Pseudomonas aeruginosa PCN-2 which was capable of aerobic and anoxic denitrification. Interestingly, nitric oxide (NO), as the obligatory intermediate, was negligibly accumulated during nitrate and nitrite reduction. Moreover, normal nitrate reduction with decreasing NO accumulation was realized under O2 concentration ranging from 0 to 100%. Reverse transcription and real time quantitative polymerase chain reaction (RT-qPCR) analysis revealed that high efficient NO removal was attributed to the coordinate regulation of gene expressions including napA (for periplasmic nitrate reductase), nirS (for cytochrome cd1 nitrite reductase) and cnorB (for NO reductase). Further batch experiments demonstrated the immobilized strain PCN-2 possessed high capability of removing NO and nitrogen dioxide (NO2) at O2 concentration of 0-10%. A biotrickling filter established with present strain achieved high NOx removal efficiencies of 91.94-96.74% at inlet NO concentration of 100-500ppm and O2 concentration of 0-10%, which implied promising potential applications in purifying NOx contaminated flue gas. PMID- 27469046 TI - Who founded Buddhism? Notes on the psychological effectiveness of religious objects. AB - Starting with an outline of Buddhist history from a psychoanalytic perspective, this paper uses ideas from philosophy and psychoanalysis to consider the nature of the psychological effectiveness of religious objects. It suggests that the development of the devotional cult of Buddhas 'without form' such as Amitabha, at first-glance surprising when juxtaposed with the founding vision of Gautama Siddhartha, tells us a great deal about the psychological needs that impel the evolution of religious thinking. Distinguishing religious objects from mythological ones, it argues that 'religious objects' are, more specifically, allegorical objects that can be encountered in the second person; that these may not always be well described as 'illusion'; and that they may in some cases be better understood as providing opportunities for experience that, like the transference in psychoanalysis, may have far-reaching psychological impacts. PMID- 27469047 TI - Special issue on commissioning. PMID- 27469048 TI - Commissioning: perspectives from the ground. AB - Primary Health Networks (PHNs) have been tasked with two key objectives to be achieved through commissioning. Public value aims can be achieved by developing operational capability in the context of an authorising environment. Public value will need to focus on system level outcomes from multiple perspectives, including a consumer perspective. The authorising environment will require policymakers to allow time for PHNs to mature into their role. It will require an environment of effective collaboration amongst multiple stakeholders including consumers. The operational capability will need to ensure highly competent managers and clinical leadership working in a symbiotic relationship. Although some Medicare Locals demonstrated commissioning capacity and capability, this will need to be scaled up at-pace in the new healthcare landscape in order for PHNs to optimally fulfil their roles. PMID- 27469049 TI - Something old, something new, something borrowed, something blue? Reviewing the evidence on commissioning and health services. AB - The concept of commissioning is starting to gain traction in the Australian health system. Primary Care Networks began operations in July 2015 with a remit around commissioning health services. Despite the centrality of this concept, we know relatively little about commissioning in Australia. Other systems have experimented with it for some time, and this paper reviews the evidence and lessons inherent within the international literature. The study defines commissioning, and explores experiences of others who have adopted commissioning approaches and the evidence concerning the outcomes of these experiments. Commissioning is a difficult topic in many senses and its application to a complex area such as health reform can make it even more challenging. Ultimately, this evidence suggests that commissioning is more than simply a technical or operational process, but one that is value-based and relational. This is not to downplay the technical aspects, which in many jurisdictions have resulted in explicit and evidenced-based approaches to planning and priority setting. However, if new commissioning organisations, such as Primary Health Networks, are to have an impact, they need to balance the operational and relational elements of commissioning. PMID- 27469050 TI - Commissioning for healthcare: a case study of the general practitioners After Hours Program. AB - A strong primary healthcare system that is effective and efficient is a priority for health reform in Australia. Commissioning to support primary healthcare delivery has received increasing attention as part of healthcare reform in Australia and beyond. The aim of this paper is to present a case study of transitioning to an activity-based model for the provision of GP after-hours services in Australia. The GP After-Hours Program utilised a commissioning model that comprised of needs assessment, service development, provider engagement and evaluation. Evaluation of the new model showed a 17% increase in after-hours services, with service providers indicating that they were satisfied with the new process. Examination of the experience of implementation suggests that the commissioning model provided a useful framework for guiding activity-based funding for after-hours services. However, relational factors, such as engagement with the community, knowledge of the wider context and legitimacy of the commissioning body, can affect the implementation process. PMID- 27469051 TI - Commissioning in New Zealand: learning from the past and present. AB - Over the past 25 years, New Zealand has had significant experience with two very different approaches to commissioning health and disability support services. The first is the purchaser-provider split model adopted during the 1990s. The second is the approach that replaced it in 2001, the District Health Board model, which is still in place today. Although the New Zealand health system has several desirable characteristics and recent developments in commissioning arrangements are improvements on earlier approaches, the system is slow at reorienting care, particularly towards primary healthcare services. Alternative arrangements have strengths and weaknesses but the current 'alliancing' approach in New Zealand needs time to consolidate and demonstrate whether it can deliver before those alternatives are seriously considered. PMID- 27469052 TI - A rapid review of the impact of commissioning on service use, quality, outcomes and value for money: implications for Australian policy. AB - The aim of this systematic review was to assess evidence of the impact of commissioning on health service use, quality, outcomes and value for money and to consider findings in the Australian context. Systematic searches of the literature identified 444 papers and, after exclusions, 36 were subject to full review. The commissioning cycle (planning, contracting, monitoring) formed a framework for analysis and impacts were assessed at individual, subpopulation and population levels. Little evidence of the effectiveness of commissioning at any level was available and observed impacts were highly context-dependent. There was insufficient evidence to identify a preferred model. Lack of skills and capacity were cited as major barriers to the implementation of commissioning. Successful commissioning requires a clear policy framework of national and regional priorities that define agreed targets for commissioning agencies. Engagement of consumers and providers, especially physicians, was considered to be critically important but is time consuming and has proven difficult to sustain. Adequate information on the cost, volume and quality of healthcare services is critically important for setting priorities, and for contracting and monitoring performance. Lack of information resulted in serious problems. High-quality nationally standardised performance measures and data requirements need to be built into contracts and ongoing monitoring and evaluation. In Australia, there is significant work to be done in areas of policy and governance, funding systems and incentives, patient enrolment or registration, information systems, individual and organisational capacity, community engagement and experience in commissioning. PMID- 27469053 TI - Regional health workforce planning through action research: lessons for commissioning health services from a case study in Far North Queensland. AB - Creating a stable and sustainable health workforce in regional, rural and remote Australia has long been a challenge to health workforce planners, policy makers and researchers alike. Traditional health workforce planning is often reactive and assumes continuation of current patterns of healthcare utilisation. This demonstration project in Far North Queensland exemplifies how participatory regional health workforce planning processes can accurately model current and projected local workforce requirements. The recent establishment of Primary Health Networks (PHNs) with the intent to commission health services tailored to individual healthcare needs underlines the relevance of such an approach. This study used action research methodology informed by World Health Organization (WHO) systems thinking. Four cyclical stages of health workforce planning were followed: needs assessment; health service model redesign; skills-set assessment and workforce redesign; and development of a workforce and training plan. This study demonstrated that needs-based loco-regional health workforce planning can be achieved successfully through participatory processes with stakeholders. Stronger health systems and workforce training solutions were delivered by facilitating linkages and planning processes based on community need involving healthcare professionals across all disciplines and sectors. By focusing upon extending competencies and skills sets, local health professionals form a stable and sustainable local workforce. Concrete examples of initiatives generated from this process include developing a chronic disease inter-professional teaching clinic in a rural town and renal dialysis being delivered locally to an Aboriginal community. The growing trend of policy makers decentralising health funding, planning and accountability and rising health system costs increase the future utility of this approach. This type of planning can also assist the new PHNs to commission health services that meet the needs of the population and contribute to service and system improvement and innovation. PMID- 27469054 TI - Regional adaptation of collagen in skeletal muscle to repeated bouts of strenuous eccentric exercise. AB - This study investigated the injured region-specific alterations of factors related to the "repeated bout effect" (RBE), i.e., when the first bout of eccentric exercise generates resistance to injuries from the second bout of the same exercise. Wistar rats were divided into single injury (SI) and repeated injury (RI) groups. The right gastrocnemius muscle was subjected to a bout of eccentric contractions (ECs) at the age of 14 weeks in the SI group and 10 and 14 weeks in the RI group. The number of injured fibers after the last bout of ECs was lower in RI than in SI. In the SI group, injured fibers after ECs were mainly located in the superficial region of muscle and expressed myosin heavy chain (MHC) IIx and IIb. Prior to the second bout of ECs, the fiber-type composition in the RI group showed decreased MHC IIx and IIb fibers and increased MHC IIa fibers compared with those in the SI group. However, most regenerating fibers showed either MHC IIx or IIb expression. Heat shock protein 72 and total collagen contents in whole muscle were higher in the RI group than in the SI group; however, only the collagen expression in the RI group was more intense than that in the SI group in the superficial region of muscle. These findings suggest that increased collagen may play a more important role in the injured region of muscle than the other factors in RBE. PMID- 27469055 TI - Using the Behaviour Change Wheel to identify interventions to facilitate the transfer of information on medication changes on electronic discharge summaries. AB - BACKGROUND: There is evidence that the transfer of information on medication changes on patient discharge summaries is poor. By considering the completion of an electronic discharge summary as a behavior, the various components of the behavior can be targeted to improve their completion so that they consistently include information on medication changes. OBJECTIVES: Study objectives were to identify the barriers and facilitators to junior doctors completing information on medication changes on electronic discharge summaries, including why these occurred. METHODS: In this qualitative study, 12 semi-structured interviews were conducted with junior doctors. An interview topic guide based around the COM-B model (Capability, Opportunity, Motivation, Behavior) within the Behavior Change Wheel (BCW) was used. Transcripts of the interviews were analyzed using framework analysis to identify key categories emerging from the data. Barriers and facilitators to completing information on medication changes on discharge summaries were identified. These were then mapped to behavioral components within the COM-B model to help design tailored interventions to affect change. RESULTS: Nine categories were identified that encompassed the identified barriers and facilitators. The identified barriers and facilitators influenced all aspects of the COM-B model. CONCLUSIONS: Use of the BCW as a theoretical lens for this study enabled interventions to be identified that targeted specific components of behavior. It is the implementation of all these interventions that may be required to influence behavior change and ensure all electronic discharge summaries contain information on medication changes. All intervention functions were relevant but key functions were education, enablement and persuasion. Other institutions can use the BCW and the COM-B model to develop their own tailored interventions to achieve these functions. PMID- 27469057 TI - Outcomes of Repeat Keratoplasty for Failed Therapeutic Keratoplasty. PMID- 27469056 TI - Coupling among Microbial Communities, Biogeochemistry, and Mineralogy across Biogeochemical Facies. AB - Physical properties of sediments are commonly used to define subsurface lithofacies and these same physical properties influence subsurface microbial communities. This suggests an (unexploited) opportunity to use the spatial distribution of facies to predict spatial variation in biogeochemically relevant microbial attributes. Here, we characterize three biogeochemical facies-oxidized, reduced, and transition-within one lithofacies and elucidate relationships among facies features and microbial community biomass, richness, and composition. Consistent with previous observations of biogeochemical hotspots at environmental transition zones, we find elevated biomass within a biogeochemical facies that occurred at the transition between oxidized and reduced biogeochemical facies. Microbial richness-the number of microbial taxa-was lower within the reduced facies and was well-explained by a combination of pH and mineralogy. Null modeling revealed that microbial community composition was influenced by ecological selection imposed by redox state and mineralogy, possibly due to effects on nutrient availability or transport. As an illustrative case, we predict microbial biomass concentration across a three-dimensional spatial domain by coupling the spatial distribution of subsurface biogeochemical facies with biomass-facies relationships revealed here. We expect that merging such an approach with hydro-biogeochemical models will provide important constraints on simulated dynamics, thereby reducing uncertainty in model predictions. PMID- 27469058 TI - Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice. AB - Chemokines and their receptors are key regulators of immune cell trafficking and activation. Recent findings suggest that they may also play pathophysiological roles in psychiatric diseases like depression and anxiety disorders. The CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are functionally involved in neuroinflammation as well as anti-infectious and autoimmune responses. However, their influence on behavior remains unknown. Here we characterized the functional role of the CCR4-CCL17 chemokine-receptor axis in the modulation of anxiety-related behavior, locomotor activity, and object exploration and recognition. Additionally, we investigated social exploration of CCR4 and CCL17 knockout mice and wild type (WT) controls. CCR4 knockout (CCR4(-/ )) mice exhibited fewer anxiety-related behaviors in the elevated plus-maze, diminished locomotor activity, exploratory behavior, and social exploration, while their recognition memory was not affected. In contrast, CCL17 deficient mice did not show an altered behavior compared to WT mice regarding locomotor activity, anxiety-related behavior, social exploration, and object recognition memory. In the dark-light and object recognition tests, CCL17(-/-) mice even covered longer distances than WT mice. These data demonstrate a mechanistic or developmental role of CCR4 in the regulation of locomotor and exploratory behaviors, whereas the ligand CCL17 appears not to be involved in the behaviors measured here. Thus, either CCL17 and the alternative ligand CCL22 may be redundant, or CCL22 is the main activator of CCR4 in these processes. Taken together, these findings contribute to the growing evidence regarding the involvement of chemokines and their receptors in the regulation of behavior. PMID- 27469059 TI - Overexpression of AT2R in the solitary-vagal complex improves baroreflex in the spontaneously hypertensive rat. AB - The aim of this study was to investigate the physiological effects of increased angiotensin II type 2 receptor (AT2R) expression in the solitary-vagal complex (nucleus of the solitary tract/dorsal motor nucleus of the vagus; NTS/DVM) on baroreflex function in non-anaesthetised normotensive (NT) and spontaneously hypertensive rats (SHR). Ten week old NT Holtzman and SHR were microinjected with either an adeno-associated virus expressing AT2R (AAV2-CBA-AT2R) or enhanced green fluorescent protein (control; AAV2-CBA-eGFP) into the NTS/DVM. Baroreflex and telemetry recordings were performed on four experimental groups: 1) NTeGFP, 2) NTAT2R, 3) SHReGFP and 4) SHRAT2R (n=4-7/group). Following in-vivo experimental procedures, brains were harvested for gene expression analysis. Impaired bradycardia in SHReGFP was restored in SHR rats overexpressing AT2R in the NTS/DMV. mRNA levels of angiotensin converting enzyme decreased and angiotensin converting enzyme 2 increased in the NTS/DMV of SHRAT2R compared to SHReGFP. Increased levels of pro-inflammatory cytokine mRNA levels in the SHReGFP group also decreased in the SHRAT2R group. AT2R overexpression did not elicit any significant change in mean arterial pressure (MAP) in all groups from baseline to 4weeks post viral transfection. Both SHReGFP and SHRAT2R showed a significant elevation in MAP compared to the NTeGFP and NTAT2R groups. Increased AT2R expression within the NTS/DMV of SHR was effective at improving baroreflex function but not MAP. We propose possible mediators involved in improving baroreflex are in the ANG II/ACE2 axis, suggesting a potential beneficial modulatory effect of AT2R overexpression in the NTS/DMV of neurogenic hypertensive rats. PMID- 27469060 TI - Neuropeptide Y associated with asthma in young adults. AB - OBJECTIVE: Neuropeptide Y, a widely circulating neurotransmitter, plays a pivotal role in energy balance, immunomodulation and asthma, and several NPY polymorphisms are promising genetic risk factors for asthma and obesity. We explored the associations of candidate NPY gene polymorphisms with prevalent asthma and its relationship with obesity in young adult asthma patients free of other chronic medical morbidity. METHODS: Five common gene variants of NPY (rs16147 (-399T/C), rs17149106 (-602G/T), rs16140 (+1000C/G), rs5573 (+1201A/G), rs5574 (+5327C/T)) previously validated to account for most of the NPY expression in vitro and in vivo were investigated in 126 physician-diagnosed asthma patients without other chronic medical morbidity and 182 healthy controls (21-35years). Plasma levels of NPY, adiponectin, and CRP were determined using ELISA, and IL-6 was measured by Luminex in a subgroup of 70 patients and 69 age- and sex-matched healthy controls. RESULTS: In logistic regression models controlling for gender and obesity, the CT genotype of rs5574 (OR=0.54, 95%CI: 0.30-0.89) and the GT genotype of rs17149106 (OR=5.58, 95%CI: 1.09-28.54) were significantly associated with asthma. No significant interaction between NPY SNP polymorphisms and obesity were detected. Plasma NPY level was correlated with adiponectin levels (p<0.05). Compared with the healthy controls, patients with asthma had higher BMI (p<0.001), adiponectin (p<0.05), IL-6 (p=0.001) and CRP (p<0.001), and lower NPY levels (p<0.01). CONCLUSIONS: The CT genotype of rs5574 and the GT genotype of rs17149106 are significantly associated with prevalent asthma. PMID- 27469062 TI - Direct oxidative pathway from amplex red to resorufin revealed by in situ confocal imaging. AB - Amplex Red (AR) is a very useful chemical probe that is employed in biochemical assays. In these assays, the non-fluorescent AR is converted to resorufin (RS), which strongly absorbs in the visible region (lambdaabs = 572 nm) and yields strong fluorescence (lambdafluo = 583 nm). Even if AR is commonly used to report on enzymatic oxidase activities, an increasing number of possible interferences have been reported, thus lowering the accuracy of the so-called AR assay. As a redox-based reaction, we propose here to directly promote the conversion of AR to RS by means of electrochemistry. The process was first assessed by classic electrochemical and spectroelectrochemical investigations. In addition, we imaged the electrochemical conversion of AR to RS at the electrode surface by in situ confocal microscopy. The coupling of methodologies allowed to demonstrate that RS is directly formed from AR by an oxidation step, unlike what was previously reported. This gives a new insight in the deciphering of AR assays' mechanism and about their observed discrepancy. PMID- 27469061 TI - Transactional sex among young women in rural South Africa: prevalence, mediators and association with HIV infection. AB - INTRODUCTION: Young adolescent women in sub-Saharan Africa are three to four times more likely to be HIV-positive than boys or men. One of the relationship dynamics that is likely to be associated with young women's increased vulnerability to HIV is transactional sex. There are a range of HIV-related risk behaviours that may drive this vulnerability. However, to date, limited epidemiological data exist on the role of transactional sex in increasing HIV acquisition, especially among young women in sub-Saharan Africa. Our paper presents data on the prevalence of self-reported engagement in transactional sex and explores whether transactional sex is associated with increased risk of HIV infection among a cohort of young, rural, sexually active South African women. We also explore whether this relationship is mediated through certain HIV-related risk behaviours. METHODS: We analyzed baseline data from a phase III trial of conditional cash transfers for HIV prevention of 693 sexually active, school going young women aged 13-20 years in rural South Africa. We examined the association between young women's engagement in transactional sex and HIV infection. Transactional sex is defined as a non-commercial, non-marital sexual relationship whereby sex is exchanged for money and/or gifts. We explored whether this relationship is mediated by certain HIV-related risk behaviours. We used logistic and multinomial regression and report unadjusted and adjusted odds ratios with 95% CI. RESULTS: Overall, 14% (n=97) of sexually active young women reported engaging in transactional sex. Engagement in transactional sex was associated with an increased risk of being HIV-positive (aOR: 2.5, CI: 95% 1.19 5.25, p=0.01). The effect size of this association remained nearly unchanged when adjusted for certain other dimensions of HIV risk that might help explain the underlying pathways for this relationship. CONCLUSIONS: This study provides quantitative support demonstrating that transactional sex is associated with HIV infection in young women. Even though the specific variables tested do not mediate the relationship, a potential explanation for this association may be that the men with whom young women are having sex belong to networks of sexually connected individuals who are at a "high risk" for HIV infection. The results highlight the importance of structural intervention approaches that can alter the context of young women's HIV risk. PMID- 27469063 TI - Coronary artery bifurcation narrowing treated by Axxess stent implantation: The CARINAX registry. AB - OBJECTIVES: To compare the safety and efficacy of the AxxessTM biolimus-eluting stent with the second-generation drug-eluting stent (DES) in the treatment of bifurcation lesions. BACKGROUND: The AxxessTM is a dedicated bifurcation stent, designed to cover the lesion at the carina level. METHODS: Between April 2012 and August 2014, 165 patients with de novo bifurcation lesions were treated with the AxxessTM stent (Axxess group). A propensity-score matched group of 165 patients treated with DES in the same period was selected (Control group). The primary objectives were (1) the procedural complication rate, including side branch (SB) occlusion and trouble in SB access after main vessel stenting; and (2) the device, the angiographic, and the procedural success rate. RESULTS: Procedural complications occurred in 1 patient (0.6%) in the Axxess group and in 20 patients (12%) in the Control group (OR = 0.03; 95% confidence interval 0.005-0.27; P < 0.001). Device success was obtained in 164 (99.5%) patients in the Axxess group and in all in the Control group (P = 1.00). Angiographic success was obtained in all patients. Inaccurate AxxessTM stent position occurred in 21 (13%) patients, and was more often associated with moderate-to-severe calcifications and distal lesion site. Procedural success was obtained in 91.5% patients in the Axxess group and in 90% patients in the Control group (P = 0.72). CONCLUSIONS: The present registry suggests that the AxxessTM stent (1) may represent a valid alternative approach for the treatment of bifurcation lesions and (2) should be avoided in moderate-to-severe calcifications and/or in distal lesions. (c) 2016 Wiley Periodicals, Inc. PMID- 27469064 TI - Role of biobanking in urology: a review. AB - In the current era of individualized medicine, a biorepository of human samples is essential to support clinical and translational research. There have been limited efforts in this arena within the field of urology, as cost, logistical and ethical issues represent significant deterrents to biobanking. The Johns Hopkins Brady Urological Institute Biorepository was founded in 1994 as a resource to facilitate discovery. Since its inception, the biorepository has enabled numerous research endeavours including pivotal trials leading to the regulatory approval of four diagnostic tests for prostate cancer. In the present review, we discuss the current state of biobanking within urology, outline the specific ethical and financial challenges to biobanking as well as solutions, and describe the operations of a successful urological biorepository. PMID- 27469066 TI - The Association of Higher Plasma Macrophage Migration Inhibitory Factor Levels with Lower Bone Mineral Density and Higher Bone Turnover Rate in Postmenopausal Women. AB - BACKGROUND: Despite evidence from animal and clinical studies showing the detrimental effects of macrophage migration inhibitory factor (MIF) on bone metabolism, there are no clinical studies relating circulating MIF levels to osteoporosis-related phenotypes. This cross-sectional study investigated the association of plasma MIF with bone mineral density (BMD), bone turnover markers (BTMs), and prevalence of osteoporosis in postmenopausal Korean women. METHODS: A total of 246 women not taking any medications or diagnosed with any diseases that could affect bone metabolism were enrolled. BMD values at the lumbar spine, femoral neck, and total femur, and blood levels of MIF and BTMs were measured in all subjects. Osteoporosis was defined by World Health Organization criteria. RESULTS: Before and after adjustment for confounding variables, higher MIF levels were significantly associated with lower BMD values at all measured sites and higher levels of all BTMs. All BMD values and BTMs significantly changed in a dose-dependent fashion across increasing MIF quartile. When participants were divided into two groups according to osteoporosis status, postmenopausal women with osteoporosis demonstrated 24.2% higher plasma MIF levels than those without osteoporosis (P=0.041). The odds ratio per each standard deviation increment of MIF levels for prevalent osteoporosis was 1.32 (95% confidence interval, 1.01 to 1.73). CONCLUSION: This study provides the first epidemiological evidence that higher plasma MIF may be associated with higher risk of osteoporosis resulting from lower bone mass and higher bone turnover rate, and thus it could be a potential biomarker of poor bone health outcomes in postmenopausal women. PMID- 27469067 TI - Cholestyramine Use for Rapid Reversion to Euthyroid States in Patients with Thyrotoxicosis. AB - Cholestyramine (CS) is an ion exchange resin, which binds to iodothyronines and would lower serum thyroid hormone level. The use of CS added to conventional antithyroid drugs to control thyrotoxicosis has been applied since 1980's, and several studies indicate that using CS in combination with methimazole (MZ) produces a more rapid decline in serum thyroid hormones than with only MZ treatment. Our recent retrospective review of five patients taking high dose MZ and CS, compared to age-, gender-, initial free thyroxine (T4) level-, and MZ dose-matched 12 patients with MZ use only, showed more rapid decline of both free T4 and triiodothyronine levels without more adverse events. CS could be safely applicable short-term adjunctive therapy when first-line antithyroid medications are not enough to adequately control severe thyrotoxicosis or side effects of antithyroid drug would be of great concern. PMID- 27469065 TI - Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss. AB - Excess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved in energy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptide tyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while other molecules such as fibroblast growth factor 21, chemerin, irisin, secreted frizzle-related protein-4, total bile acids, and heme oxygenase-1 have been linked to energy homeostasis regulation more recently and the specific role of each one of them has not been fully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation by the macronutrient composition of the diet as well as diet-induced weight loss. PMID- 27469068 TI - A new in vitro hemagglutinin inhibitor screening system based on a single-vesicle fusion assay. AB - Hemagglutinin (HA) from the influenza virus plays a pivotal role in the infection of host mammalian cells and is, therefore, a druggable target, similar to neuraminidase. However, research involving the influenza virus must be conducted in facilities certified at or above Biosafety Level 2 because of the potential threat of the contagiousness of this virus. To develop a new HA inhibitor screening system without intact influenza virus, we conceived a single-vesicle fusion assay using full-length recombinant HA. In this study, we first showed that full-length recombinant HA can mediate membrane fusion in ensemble and single-vesicle fusion assays. The fluorescence resonance energy transfer (FRET) frequency pattern of single-vesicle complexes completely differed when the inhibitors targeted the HA1 or HA2 domain of HA. This result indicates that analysing the FRET patterns in this assay can provide information regarding the domains of HA inhibited by compounds and compounds' inhibitory activities. Therefore, our results suggest that the assay developed here is a promising tool for the discovery of anti-influenza virus drug candidates as a new in vitro inhibitor screening system against HA from the influenza virus. PMID- 27469069 TI - Field endocrinology of nonhuman primates: past, present, and future. AB - In the past few decades, research on nonhuman primate endocrinology has moved from the lab to the field, leading to a huge increase in both the breadth and depth of primate field studies. Here, I discuss the past, present, and future of primate field endocrinology. I review the history of the field, and go on to discuss methodological developments and the issues that they sometimes entail. Next, I consider ways in which we might conceptualize the role of hormones, and focus on the need to distinguish proximate from ultimate levels of explanation. Current potentially problematic issues in the field include: 1) an inability to obtain noninvasive measurements of Central Nervous System (CNS) rather than peripheral hormone concentrations; 2) research questions that become stuck (e.g., questions regarding sexual swelling expression mechanisms); 3) data dredging and post-hoc linking of hormones to any plausible variable, leading to a lack of clarity on their role in animal ecology and behavior. I finish by discussing several unanswered questions that might benefit from further research. These are how we might: 1) best obtain measurements for CNS hormone concentrations non invasively; 2) measure hormone receptor expression alongside hormone concentrations; 3) consider the human endocrinology literature more thoroughly and perhaps take more multimarker approaches; 4) better consider the social environment, including audience and dyadic familiarity effects; and 5) apply our findings to conservation issues. PMID- 27469070 TI - Fathers' decline in testosterone and synchrony with partner testosterone during pregnancy predicts greater postpartum relationship investment. AB - The transition to parenthood has been associated with declines in testosterone among partnered fathers, which may reflect males' motivation to invest in the family. Moreover, preliminary evidence has found that couples show correlations in hormone levels across pregnancy that may also be linked to fathers' preparation for parenthood. The current study used repeated-measures sampling of testosterone across pregnancy to explore whether fathers' change in T, and correlations with mothers' T, were associated with fathers' and mothers' postpartum investment. In a sample of 27 couples (54 individuals) expecting their first child, both parents' salivary testosterone was measured multiple times across pregnancy. At approximately 3.5months postpartum, participants rated their investment, commitment, and satisfaction with their partner. A multilevel model was used to measure change in testosterone over time and associations between mother and father testosterone. Fathers who showed stronger declines in T across pregnancy, and stronger correlations with mothers' testosterone, reported higher postpartum investment, commitment, and satisfaction. Mothers reported more postpartum investment and satisfaction if fathers showed greater prenatal declines in T. These results held even after controlling for paternal investment, commitment, and satisfaction measured prenatally at study entry. Our results suggest that changes in paternal testosterone across pregnancy, and hormonal linkage with the pregnant partner, may underlie fathers' dedication to the partner relationship across the transition to parenthood. PMID- 27469071 TI - Psychotropic drug prescriptions in Western European nursing homes. AB - BACKGROUND: Despite the numerous warnings of European and national drug agencies as well as clinical guidelines since the year 2004, psychotropic drugs are still frequently used in dementia. A systematic review comparing the use of psychotropic drugs in nursing homes from different European countries is lacking. OBJECTIVE: The aim of this study was to examine prescription rates of psychotropic drug use in nursing home patients between different Western European countries since the first warnings were published. METHODS: A literature review was performed and the various psychotropic prescribing rates in European nursing homes were investigated. The prescription rates of antipsychotic and antidepressants were pooled per country. Other classes of psychotropic drugs could not be pooled because of the limited number of studies found. RESULTS: Thirty-seven studies on antipsychotic drug use and 27 studies on antidepressant drug use conducted in 12 different European countries. The antipsychotic use in nursing homes ranged from 12% to 59% and antidepressant use from 19% to 68%. The highest rates of antipsychotic drug prescription were found in Austria, Ireland, and Belgium while for antidepressants in Belgium, Sweden, and France. CONCLUSIONS: Despite warnings about the side effects and recommendation to focus on non-pharmacological interventions, antipsychotics and antidepressants are commonly used drugs in nursing homes. The data suggest that Norway does best with regards having a low antipsychotic drug usage. Studies are needed to explain the differences between Norway and other European countries. PMID- 27469072 TI - Nut intake and stroke risk: A dose-response meta-analysis of prospective cohort studies. AB - We aim to quantify the effects of nut intake on risk of stroke by a dose-response meta-analysis with a random-effects model. Two databases (PubMed and Emabse) were searched for prospective cohort studies regarding nut intake and stroke risk. Studies were included if they fulfilled the predefined criteria. Eleven articles encompassing fourteen cohort studies were included in final analysis. The pooled relative risk (RR) of stroke for the highest versus (vs.) lowest category of nut intake was 0.88 (95% confidence interval [CI] 0.80-0.97). The power to detect a RR of 0.88 for the highest versus vs. lowest category of nut intake was 86.2%. In multiple subset analyses by gender, location, and stroke subtype, the inverse association was only found in women (RR = 0.84, 95% CI 0.73-0.96) and Asia (RR = 0.79, 95% CI 0.67-0.93). In the dose-response meta-analysis, evidence for a nonlinear association between nut intake and stroke risk was observed and a RR of 0.86 was conferred for 12 g/day. Based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, the quality of evidence was moderate. In conclusions, finding from current meta-analysis of fourteen cohort studies indicates that nut intake may be related to decreased risk of stroke. PMID- 27469073 TI - Dual mode of cancer cell destruction for pancreatic cancer therapy using Hsp90 inhibitor loaded polymeric nano magnetic formulation. AB - Heat Shock Protein 90 (Hsp90) has been extensively explored as a potential drug target for cancer therapies. 17- N-allylamino- 17-demethoxygeldanamycin (17AAG) was the first Hsp90 inhibitor to enter clinical trials for cancer therapy. However, native drug is being shown to have considerable anticancer efficacy against pancreatic cancer when used in combination therapy regime. Further, magnetic hyperthermia has shown to have promising effects against pancreatic cancer in combination with known cyto-toxic drugs under both target and non targeted scenarios. Hence, in order to enhance the efficacy of 17AAG against pancreatic cancer, we developed poly (lactic-co-glycolic acid) (PLGA) coated, 17AAG and Fe3O4 loaded magnetic nanoparticle formulations by varying the relative concentration of polymer. We found that polymer concentration affects the magnetic strength and physicochemical properties of formulation. We were also able to see that our aqueous dispensable formulations were able to provide anti pancreatic cancer activity for MIA PaCa-2 cell line in dose and time dependent manner in comparison to mice fibroblast cell lines (L929). Moreover, the in-vitro magnetic hyperthermia against MIA PaCa-2 provided proof principle that our 2-in-1 particles may work against cancer cell lines effectively. PMID- 27469074 TI - Achieving a robust drug release from extended release tablets using an integrated continuous mixing and direct compression line. AB - In the present work the viability of integrated continuous mixing and compression processes for manufacturing of extended release (ER) matrix tablets was investigated in terms of dissolution behavior. The purpose was also to evaluate the combined effect of processing variables and compositional variables on the release robustness. The continuous process was provoked by a challenging formulation design, including variable powder characteristics and compositions of high and low amount of poorly soluble and poorly flowing drug substance (ibuprofen). Additionally a relatively low amount of two different ER matrix former grades (standard granulation grade CR and direct compression grade DC2 of hydroxypropyl methylcellulose, HPMC) was used to challenge the system. Robust ibuprofen release was obtained faster when HPMC CR was used. However, robust release was also achieved when using HPMC DC2 at high ibuprofen content, even though it took slightly longer time to reach the steady state of the process. Due to its poor flow properties, HPMC CR would be very challenging to use in traditional direct compression. The results showed that by using continuous processing it is possible to manufacture and achieve robust performance of compositions that would not be possible with traditional batch processing due to for instance poorly flowability. PMID- 27469076 TI - Vascular Imaging Outcomes of Childhood Primary Angiitis of the Central Nervous System. AB - BACKGROUND: Inflammation affecting cerebral blood vessels is a common cause of stroke in children. Arterial abnormalities on vascular imaging are an important risk factor for stroke recurrence. We aimed to describe the vascular imaging outcomes in children with primary angiitis of the central nervous system after 12 months and identify factors associated with vascular progression and stroke recurrence. METHODS: We retrospectively analyzed clinical and neuroimaging data from the BrainWorks Registry of children with large-vessel primary angiitis of the central nervous system. Neuroimaging was collected at baseline and at least 12-month follow-up, and vascular outcome was categorized as improved, stable, or progressed based on comparison of magnetic resonance angiography. Univariate clinical and neuroimaging predictors were associated with outcome by Fisher exact test. RESULTS: Our study consisted of 27 children; 20 male; median age was 7.92 years (range, two to 15 years). Twelve patients received steroids (44%). Median follow-up time was 16 months (range, 12 to 56 months). Vascular imaging outcome was categorized as improved in 37%, stable in 22%, and progressed in 41% of patients. Discordant progression, defined as progression and improvement occurring simultaneously across multiple vessels, was observed in 26%. Stroke recurred in 15%, occurring exclusively in the group with progression on follow-up imaging (P = 0.02). CONCLUSIONS: After 12 months, 40% of children with primary angiitis of the central nervous system demonstrated progression on vascular imaging, without apparent clinical or angiographic predictors. Stroke recurrence was associated with vascular progression. Discordant progression is a newly described angiographic finding. Further studies are necessary to determine if this represents a unique characteristic of inflammatory arteriopathies. PMID- 27469075 TI - Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable. AB - Rearrangement of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable (BCLU), particularly in the setting of double hit lymphoma (DHL). However, little is known about outcomes of patients who demonstrate MYC rearrangement without evidence of BCL2 or BCL6 rearrangement (single hit) or amplification (>4 copies) of MYC. We identified 87 patients with single hit lymphoma (SHL), 22 patients with MYC-amplified lymphoma (MYC amp) as well as 127 DLBCL patients without MYC rearrangement or amplification (MYC normal) and 45 patients with DHL, all treated with either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or intensive induction therapy. For SHL and MYC amp patients, the 2 year progression-free survival rate (PFS) was 49% and 48% and 2-year overall survival rate (OS) was 59% and 71%, respectively. SHL patients receiving intensive induction experienced higher 2-year PFS (59% vs. 23%, P = 0.006) but similar 2-year OS as compared with SHL patients receiving R-CHOP. SHL DLBCL patients treated with R-CHOP, but not intensive induction, experienced significantly lower 2-year PFS and OS (P < 0.001 for both) when compared with MYC normal patients. SHL patients appear to have a poor prognosis, which may be improved with receipt of intensive induction. PMID- 27469077 TI - Patch-test results using Korean standard series: a 5-year retrospective review. AB - BACKGROUND: There have been few studies regarding the results of the Korean standard patch test. OBJECTIVES: The purpose of this study was to analyze the type and frequency of common contact allergens in Korea and to compare the results with those of previous reports. METHODS: From June 2009 to June 2014, 330 patients with suspected allergic contact dermatitis who visited our clinic were tested using the Korean standard patch test. RESULTS: The highest sensitization rate was found for nickel sulfate (47.58%). There was a significant gender difference in the prevalence of sensitization to nickel sulfate (OR = 2.41, p = .0004) and wool alcohol (OR = 2.85, p = .0358). Higher sensitization to nickel sulfate (OR = 1.18, p = .0159), 4-phenylenediamine (OR = 1.23, p= .003), tixocortol-21-pivalte (OR 1.48, p = .0212) and lower sensitization to thimerosal (OR = 0.77, p = .0023) were associated with increasing age. Patients with allergic contact dermatitis on the scalp had a significantly higher risk of sensitization to 4-phenylenediamine (OR = 3.07, p = .0013). Patients with allergic contact dermatitis on the hands had significantly higher risks of sensitization to wool alcohol (OR = 3.44, p = .0083), formaldehyde (OR = 2.52, p = .0178), and colophony (OR = 2.05, p = .0499). CONCLUSIONS: These results demonstrate trends in patch test results in Korea and the basis for the presumption of the route of allergen exposure. PMID- 27469078 TI - Dimerization of Colloidal Particles through Controlled Aggregation for Enhanced Properties and Applications. AB - Devising syntheses capable of precisely manipulating matter on the nanoscale is central to many areas of research. The underlying motivation is fueled by the fact that at the nanometer scale, the property has a strong correlation with the structure. One such nanostructure that has accrued much attention is the dimer-a structure composed of two colloidal particles separated by a small gap. This Focus Review discusses how colloidal stability can be strategically manipulated to induce dimerization, together with effective purification steps to further improve yields. We conclude the article by providing representative examples for how dimers composed of plasmonic nanoparticles leads to structures with tunable optical properties and strong electric near-fields, ideal for application in surface-enhanced Raman spectroscopy. PMID- 27469079 TI - CD2-CD58 interactions are pivotal for the activation and function of adaptive natural killer cells in human cytomegalovirus infection. AB - The existence and expansion of adaptive NK-cell subsets have been linked to HCMV infection. Phenotypically, a majority of adaptive NK cells expresses the activating receptor NKG2C and CD57. Some of the molecular factors driving the expansion of NKG2C+ CD57+ NK cells in HCMV infection have been identified. The direct interaction of adaptive NK cells with HCMV-infected cells, preceding the expansion, however, remains less studied. Recently, adaptive NK cells were reported to express higher levels of the co-activating receptor CD2. We explored whether CD2 was directly involved in the response of adaptive NK cells to HCMV. In a co-culture system of human PBMCs and productively infected fibroblasts, we observed an upregulation of CD69, CD25, and HLA-DR on all NK cells. However, only in adaptive NK cells was this increase largely blocked by antibodies against CD2 and CD58. Functionally, this blockade also resulted in diminished production of IFN-gamma and TNF-alpha by adaptive human NK cells in response to HCMV-infected cells. Our results demonstrate that binding of CD2 to upregulated CD58 on infected cells is a critical event for antibody-mediated activation and subsequent effector functions of adaptive NKG2C+ CD57+ NK cells during the antiviral response. PMID- 27469081 TI - Gradient-based solvent suppression methods on a benchtop spectrometer. AB - Benchtop NMR emerges as an appealing alternative to widely extend the scope of NMR spectroscopy in harsh environments and for on-line monitoring. Obviously, the use of low-field magnets induces a dramatic reduction of the spectral resolution leading to frequent peak overlaps. This issue is even more serious because applications such as chemical process monitoring involve the use of non deuterated solvents, leading to intense and broad peaks overlapping with the signals of interest. In this article, we highlight the need for efficient suppression methods compatible with flowing samples, which is not the case of the common pre-saturation approaches. Thanks to a gradient coil included in our benchtop spectrometer, we were able to implement modern and efficient solvent suppression blocks such as WET or excitation sculpting to deliver quantitative spectra in the conditions of the on-line monitoring. While these methods are commonly used at high field, this is the first time that they are investigated on a benchtop setting. Their analytical performance is evaluated and compared under static and on-flow conditions. The results demonstrate the superiority of gradient-based methods, thus highlighting the relevance of implementing this device on benchtop spectrometers. The comparison of major solvent suppression methods reveals an optimum performance for the WET-180-NOESY experiment, both under static and on-flow conditions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27469080 TI - Reducing falls in Parkinson's disease: interactions between donepezil and the 5 HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. AB - Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer's disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle-treated group, the combined treatment greatly reduced (Cohen's d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall-prone moments suggested that this treatment improved the efficacy and speed of re-instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait. PMID- 27469082 TI - A brief history and review of modern casting techniques in early onset scoliosis. AB - PURPOSE: Body casts have a long history in the treatment of spinal deformity. Currently the use of body casts is limited to early onset scoliosis. Here, we aim to provide a brief narrative of the evolution of cast application for the management of spinal deformity. METHODS: A history of cast application is provided with a brief review of the orthopedic literature. The current indications for cast application and the authors' preferred technique are described. RESULTS: Serial casting is an effective treatment method for early onset scoliosis. It may be definitive for most idiopathic curves or used to delay surgical intervention in more severe idiopathic, syndromic and even congenital curves. CONCLUSIONS: Surgeons who treat children with early onset scoliosis should familiarize themselves with serial cast application techniques. PMID- 27469084 TI - Sensitive SERS detection of miRNA via enzyme-free DNA machine signal amplification. AB - In this work, an enzyme-free signal amplified detection platform is described for miRNA detection with a DNA fueled molecular machine. Coupling SERS technology with multiple amplification modes, this flexible biosensing system exhibits high sensitivity and specificity. PMID- 27469083 TI - Hemodynamic changes in a rat parietal cortex after endothelin-1-induced middle cerebral artery occlusion monitored by optical coherence tomography. AB - A blockage of the middle cerebral artery (MCA) on the cortical branch will seriously affect the blood supply of the cerebral cortex. Real-time monitoring of MCA hemodynamic parameters is critical for therapy and rehabilitation. Optical coherence tomography (OCT) is a powerful imaging modality that can produce not only structural images but also functional information on the tissue. We use OCT to detect hemodynamic changes after MCA branch occlusion. We injected a selected dose of endothelin-1 (ET-1) at a depth of 1 mm near the MCA and let the blood vessels follow a process first of occlusion and then of slow reperfusion as realistically as possible to simulate local cerebral ischemia. During this period, we used optical microangiography and Doppler OCT to obtain multiple hemodynamic MCA parameters. The change trend of these parameters from before to after ET-1 injection clearly reflects the dynamic regularity of the MCA. These results show the mechanism of the cerebral ischemia-reperfusion process after a transient middle cerebral artery occlusion and confirm that OCT can be used to monitor hemodynamic parameters. PMID- 27469085 TI - Iridoid glycoside permethylation enhances chromatographic separation and chemical ionization. AB - RATIONALE: While natural products isolated from medicinal plants can serve as a rich source of biologically active metabolites, mixtures of structurally related compounds of a polar nature are often difficult to chemically resolve by traditional separation techniques. Chemical derivatization to reduce metabolite polarity combined with liquid chromatography (LC) is the strategy presented here to resolve a mixture of structurally related natural product glycosides solvent extracted from the medicinal herb Teucrium polium for mass spectrometric characterization. METHODS: The partially purified plant extract was subjected to chemical derivatization and electrospray ionization mass spectrometry (ESI-MS) fragmentation pattern analysis allowed for structural characterization of iridoid and secoiridoid glycosides. Selected ions were subjected to tandem mass spectrometric (MS/MS) analysis with a relatively higher-energy collision dissociation to assist in structural elucidation. RESULTS: Permethylation replaced all protons from free hydroxyl and amino groups with methyls and resulted in increases in both hydrophobicity, for facilitated chromatographic separation, and proton affinity, for enhanced chemical ionization. Protonated and/or sodiated adducts were observed for the six compounds detected in positive ion mode ESI-MS with a mass accuracy of less than 2 ppm. CONCLUSIONS: Permethylation combined with LC/MS analysis is shown here to be an effective chemical practice for separating and characterizing iridoid glucosinolates and is expected to be well suited for the chemical characterization of other polar natural-product mixtures of closely related compounds. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27469086 TI - A pill too hard to swallow: how the NHS is limiting access to high priced drugs. PMID- 27469087 TI - Perceptual-motor behaviour during a simulated pedestrian crossing. AB - This study used a novel research paradigm to examine gait control during real time between-person collision avoidance. Ten young adults (M=20.1+/-1.52years) were required to walk across a six metre simulated pedestrian crossing, while avoiding a collision with one or two oncoming pedestrians. The potential for social interaction was manipulated by having the oncoming pedestrians walk with (2MP) or without (2P) looking at a mobile phone. Participants took longer to complete the crossing when avoiding a collision with two oncoming pedestrians (2MP: M=5.68s; 2P: M=5.74s) in comparison with baseline (M=4.96s). Gait velocity decreased and was more variable when avoiding a collision during the 2P condition, whilst the anterior-posterior separation distance between pedestrians and the participants at the initiation of peak mediolateral deviation was significantly smaller in 2MP compared to 2P. These findings offer preliminary understanding on how gait control may be adapted to changes in the availability of other persons' gaze orientation information. Future work is needed to further understand how different adaptive behaviours emerge relative to other persons during pedestrian crossings. PMID- 27469088 TI - Correlation analysis of enzyme activities and deconstruction of ammonia pretreated switchgrass by bacterial-fungal communities. AB - The mixed microbial communities that occur naturally on lignocellulosic feedstocks can provide feedstock-specific enzyme mixtures to saccharify lignocelluloses. Bacterial-fungal communities were enriched from switchgrass bales to deconstruct ammonia-pretreated switchgrass (DSG). Correlation analysis was carried out to elucidate the relationship between microbial decomposition of DSG by these communities, enzymatic activities produced and enzymatic saccharification of DSG using these enzyme mixtures. Results of the analysis showed that beta-glucosidase and xylosidase activities limited the extent of microbial deconstruction and enzymatic saccharification of DSG. The results also underlined the importance of ligninase activity for the enzymatic saccharification of pretreated lignocellulosic feedstock. The bacterial-fungal communities developed in this research can be used to produce enzyme mixtures to deconstruct DSG, and the results from the correlation analysis can be used to optimize these enzyme mixtures for efficient saccharification of DSG to produce second-generation biofuels. PMID- 27469089 TI - Biologically pretreated sugarcane top as a potential raw material for the enhancement of gaseous energy recovery by two stage biohythane process. AB - The aim of the present study was to develop a suitable pretreatment method to enhance the microbial degradation of lignocellulosic biomass and to maximize the overall energy recovery by using biohythane process. An efficient and eco friendly biological pretreatment was used. Maximum lignin removal using biological pretreatment of sugarcane top was 60.4% w/w after 21d incubation at 28 degrees C in static condition. Confocal microscopy observation and FTIR analysis confirmed the removal of lignin from sugarcane top. The maximum hydrogen production rate (Rm), hydrogen production potential (P) and lag time (lambda) using pretreated sugarcane top were 16.76mL/g-VS/h, 87.40mL/g-VS and 3.38h respectively. The maximum methane production potential using spent medium of dark fermentation was 180.86mL/g-VS with the lag time of 2.9d. The overall gaseous energy recovery was 37.7% which is 54% higher than that of the untreated one. PMID- 27469090 TI - The optimization of l-lactic acid production from sweet sorghum juice by mixed fermentation of Bacillus coagulans and Lactobacillus rhamnosus under unsterile conditions. AB - The cost reduction of raw material and sterilization could increase the economic feasibility of l-lactic acid fermentation, and the development of an cost effective and efficient process is highly desired. To improve the efficiency of open fermentation by Lactobacillus rhamnosus based on sweet sorghum juice (SSJ) and to overcome sucrose utilization deficiency of Bacillus coagulans, a mixed fermentation was developed. Besides, the optimization of pH, sugar concentration and fermentation medium were also studied. Under the condition of mixed fermentation and controlled pH, a higher yield of 96.3% was achieved, compared to that (68.8%) in sole Lactobacillus rhamnosus fermentation. With an optimized sugar concentration and a stepwise-controlled pH, the l-lactic acid titer, yield and productivity reached 121gL(-1), 94.6% and 2.18gL(-1)h(-1), respectively. Furthermore, corn steep powder (CSP) as a cheap source of nitrogen and salts was proved to be an efficient supplement to SSJ in this process. PMID- 27469091 TI - Effects of torrefaction on hemicellulose structural characteristics and pyrolysis behaviors. AB - The effects of torrefaction on hemicellulose characteristics and its pyrolysis behaviors were studied in detail. The oxygen content decreased significantly after torrefaction, leading to the increase of high heating value. Two dimensional perturbation correlation analysis based on diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) was performed to characterize the structural evolutions. It was found the dehydration of hydroxyls and the dissociation of branches were the main reactions at low torrefaction temperature. When the temperature further increased, the depolymerization of hemicellulose and the fragmentation of monosaccharide residues occurred. The distributed activation energy model with double Gaussian functions based on reaction-order model was used to investigate the pyrolysis kinetics. The results showed that torrefaction enhanced the activation energy for degradation reactions while lowered that for condensation reactions, and increased the devolatilization contribution of condensation reactions. Besides, torrefaction decreased the yields of typical pyrolytic products, such as acids, furans, alicyclic ketones and so on. PMID- 27469092 TI - (1)H nuclear magnetic resonance-based metabolomics study of earthworm Perionyx excavatus in vermifiltration process. AB - In this study, (1)H nuclear magnetic resonance (NMR)-based metabolomics approach was used to characterize the metabolic response of the earthworm Perionyx excavatus in continuous vermifiltration for two months under hydraulic loading rates of 1m(3)m(-2)d(-1) (VF1) and 1.5m(3)m(-2)d(-1) (VF1.5). Both VF1 and VF1.5 showed higher removal of chemical oxygen demand and total nitrogen than the biofilter without earthworms. Principal component analysis of the NMR spectra of earthworm metabolites showed significant separations between those not subjected to wastewater filtration (control) and VF1 or VF1.5. Temporal variations of earthworm biomass, and the identified metabolites that are significantly different between control, VF1 and VF1.5 revealed that worms underwent increasing metabolic activity within 20days in VF1 and 14days in VF1.5, then decreasing metabolic activity. The use of NMR-based metabolomics in monitoring earthworm metabolism was demonstrated to be a novel approach in studying engineered vermifiltration systems. PMID- 27469093 TI - Removal of phosphate from aqueous solution using magnesium-alginate/chitosan modified biochar microspheres derived from Thalia dealbata. AB - The objective of this study was to determine the feasibility of using magnesium alginate/chitosan modified biochar microspheres to enhance removal of phosphate from aqueous solution. The introduction of MgCl2 substantially increased surface area of biochar (116.2m(2)g(-1)), and both granulation with alginate/chitosan and modification with magnesium improved phosphate sorption on the biochars. Phosphate sorption on the biochars could be well described by a simple Langmuir model, and the MgCl2-alginate modified biochar microspheres exhibited the highest phosphate sorption capacity (up to 46.56mgg(-1)). The pseudo second order kinetic model better fitted the kinetic data, and both the Yoon-Nelson and Thomas models were superior to other models in describing phosphate dynamic sorption. Precipitation with minerals and ligand exchange were the possible mechanisms of phosphate sorption on the modified biochars. These results imply that MgCl2 alginate modified biochar microspheres have potential as a green cost-effective sorbent for remediating P contaminated water environment. PMID- 27469094 TI - Direct conversion of cellulose and hemicellulose to fermentable sugars by a microbially-driven Fenton reaction. AB - The aim of this work was to develop a microbially-driven Fenton reaction that fragments cellulose and hemicellulose, degrades cellodextrins and xylodextrins, and produces short-chain oligosaccharides and monomeric sugars in a single bioreactor. The lignocellulose degradation system operates at neutral pH and does not require addition of conventional lignocellulose-degrading enzymes, thus avoiding problems associated with enzyme accessibility and specificity. The ability to produce useful bioproducts was demonstrated by production of the bioplastic polyhydroxybutyrate with the xylan degradation products as starting substrate. PMID- 27469095 TI - Alcohol-to-acid ratio and substrate concentration affect product structure in chain elongation reactions initiated by unacclimatized inoculum. AB - The objective of the study was to investigate whether the ratio of ethanol to acetate affects yield and product structure in chain elongation initiated by unacclimatized mixed cultures. The effect of varying the substrate concentration, while maintaining the same ratio of alcohol to acid, was also investigated. With a high substrate concentration, an alcohol to acid ratio >2:1 provided sufficient electron donor capacity for the chain elongation reaction. With an ethanol to acetate ratio of 3:1 (300mM total carbon), the highest n-caproate concentration (3033+/-98mg/L) was achieved during the stable phase of the reaction. A lower substrate concentration (150mM total carbon) gave a lower yield of products and led to reduced carbon transformation efficiency compared with other reaction conditions. The use of unacclimatized inoculum in chain elongation can produce significant amounts of odd-carbon-number carboxylates as a result of protein hydrolysis. PMID- 27469096 TI - Struvite crystallization under a marine/brackish aquaculture condition. AB - The results in this study show that struvite was formed in the digester at pH 7.7 due to the magnesium naturally present and the released ammonia and phosphate, resulting in low phosphate concentration in the digester. Apparently the digester already provided proper conditions for struvite formation. Under the brackish condition, the estimated thermodynamic solubility product and enthalpy change of struvite formation were 10(-13.06) and 25.7kJmol(-1), respectively. The average crystal size under marine/brackish condition decreased with pH, but increased with temperature. X-ray diffraction measurements indicate struvite (NH4MgPO4.6H2O) and dittmarite (NH4MgPO4.H2O) were predominant phosphorus species produced in filtrates of the digester. However, struvite and newberyite (HMgPO4.3H2O) were the predominant species precipitated from synthetic brackish waters after dosing MgCl2. It is pronounced that (waste)water characteristics played also an important role on the nature of phosphate precipitates. Under high NH4(+) condition, phosphorus precipitates containing ammonia were dominant, compared to other amorphous phosphates. PMID- 27469097 TI - Physicochemical properties and combustion behavior of duckweed during wet torrefaction. AB - Wet torrefaction of duckweed was carried out in the temperature range of 130-250 degrees C to evaluate the effects on physicochemical properties and combustion behavior. The physicochemical properties of duckweed samples were investigated by ultimate analysis, proximate analysis, FTIR, XRD and SEM techniques. It was found that wet torrefaction improved the fuel characteristics of duckweed samples resulting from the increase in fixed carbon content, HHVs and the decrease in nitrogen and sulfur content and atomic ratios of O/C and H/C. It can be seen from the results of FTIR, XRD and SEM analyses that the dehydration, decarboxylation, solid-solid conversion, and condensation polymerization reactions were underwent during wet torrefaction. In addition, the results of thermogravimetric analysis (TGA) in air indicated that wet torrefaction resulted in significant changes on combustion behavior and combustion kinetics parameters. Duckweed samples after wet torrefaction behaved more char-like and gave better combustion characteristics than raw sample. PMID- 27469098 TI - Polyoxygenated ursane and oleanane triterpenes from Siphonodon celastrineus. AB - Twenty polyoxygenated triterpenes, including nineteen ursanes and one oleanane, were characterized from the stem material of Siphonodon celastrineus (Celastraceae) through the application of spectroscopic techniques and chemical transformation. Three of the ursane-type triterpenoids possessed the rare 13,27 cyclopropane ring skeleton. PMID- 27469099 TI - Stress tolerance of transgenic barley accumulating the alfalfa aldose reductase in the cytoplasm and the chloroplast. AB - Barley represents one of the major crops grown worldwide; its genetic transformation provides an important tool for the improvement of crop quality and tolerance to environmental stress factors. Biotic and abiotic stresses produce reactive oxygen species in the plant cells that can directly oxidize the cellular components including lipid membranes; resulting in lipid peroxidation and subsequently the accumulation of reactive carbonyl compounds. In order to protect barley plants from the effects of stress-produced reactive carbonyls, an Agrobacterium-mediated transformation was carried out using the Medicago sativa aldose reductase (MsALR) gene. In certain transgenic lines the produced MsALR enzyme was targeted to the chloroplasts to evaluate its protective effect in these organelles. The dual fluorescent protein-based method was used for the evaluation of tolerance of young seedlings to diverse stresses; our results demonstrated that this technique could be reliably applied for the detection of cellular stress in a variety of conditions. The chlorophyll and carotenoid content measurements also supported the results of the fluorescent protein-based method and the stress-protective effect of the MsALR enzyme. Targeting of MsALR into the chloroplast has also resulted in increased stress tolerance, similarly to the observed effect of the cytosolic MsALR accumulation. The results of the DsRed/GFP fluorescent protein-based method indicated that both the cytosol and chloroplast accumulation of MsALR can increase the abiotic stress tolerance of transgenic barley lines. PMID- 27469100 TI - Trueness of four different milling procedures used in dental CAD/CAM systems. AB - OBJECTIVES: Milling is a crucial step in producing restorations using computer aided design and computer-aided manufacturing (CAD/CAM) systems. In this study the trueness of currently available milling devices was evaluated. MATERIALS AND METHODS: Thirty clinical cases (ten inlays, ten crowns, ten onlays) were milled from ceramic blocks using four different milling approaches: five axis with IMES CORiTEC 450i, four axis with CEREC MCXL, four axis with CEREC MCXL-EF and five axis with inLab MCX5. The milled restorations were scanned and the occlusal and inner surfaces compared to the originally calculated 3D surface using difference analysis software. The (90-10 %) / 2 percentile of the distances were calculated and analysed using one-way ANOVA with the post hoc Scheffe test (alpha = 0.05). Chipping of marginal areas were visually examined and analysed using one-way ANOVA with a post hoc Tamhane test (alpha = 0.05). RESULTS: At inner surfaces, the milling trueness of IMES (33.9 +/- 16.3 MUm), X5 (32.3 +/- 9.7 MUm) and MCXL EF (34.4 +/- 7.5 MUm) was significantly better (p < 0.001) than that of MCXL (62.1 +/- 17.1 MUm). At occlusal surfaces, MCXL-EF (25.7 +/- 9.3 MUm) showed significant higher accuracy (p < 0.001) than MCXL (48.7 +/- 23.3 MUm) and X5 (40.9 +/- 20.4 MUm). IMES produced the most chipping (p < 0.001). CONCLUSIONS: Five-axis milling devices yield high trueness. MCXL-EF is competitive and may allow chairside fabrication with good milling results. CLINICAL RELEVANCE: Accurate milling is required for well-fitting restorations and thereby requires fewer manual finishing steps, yields smaller marginal gaps, resistance to secondary caries and longevity of restorations. PMID- 27469101 TI - Effect of root canal irrigating solutions on the compressive strength of tricalcium silicate cements. AB - OBJECTIVES: The aim of this study was to evaluate the effect of root canal irrigants on the compressive strength of hydraulic tricalcium silicate cements. MATERIALS AND METHODS: Specimens (n = 60) of tricalcium silicate materials-Group 1: White ProRoot mineral trioxide aggregate (MTA), Group 2: NeoMTA Plus, Group 3: White MTA Angelus, and Group 4: Biodentine were exposed to one of the solutions (n = 20): Phosphate buffered saline (PBS; control), 3 % NaOCl, or 17 % EDTA for 5 min while being suspended in PBS. Compressive strength values were evaluated after 7 days of storage. The data were statistically analyzed by two-way ANOVA and Tukey's multiple comparison test (P = 0.05). RESULTS: Biodentine (BD) showed significantly higher compressive strength than the other materials (P < 0.05) in the control group. When exposed to NaOCl, compressive strength of WMTA and WMTA-A decreased significantly (P < 0.05), while EDTA decreased the compressive strength of all the cements compared to the control (P < 0.05). There was no significant difference in the compressive strength of BD and NMTA-P when exposed to NaOCl or EDTA. CONCLUSIONS: Biodentine and NeoMTA Plus did not show a significant reduction in compressive strength when exposed to NaOCl. EDTA reduced the compressive strength of the cements tested. CLINICAL SIGNIFICANCE: Tricalcium silicates were differentially influenced by root canal irrigants. It is essential to understand the composition of these materials prior to clinical use. Traces of irrigants from the root canal wall must be thoroughly removed. PMID- 27469102 TI - Fitting accuracy of zirconia single crowns produced via digital and conventional impressions-a clinical comparative study. AB - OBJECTIVES: This study focused on the clinical investigation of the internal and marginal fit of CAD/CAM-fabricated zirconia single crowns produced via conventional and digital impression techniques. MATERIALS AND METHODS: In a private practice, 20 molar teeth, one from each of 20 patients, were prepared with a circumferential 1.0-mm deep chamfer and an occlusal reduction of 1.5 mm. Conventional impression (CI) taking with a polyvinylsiloxane material (Aquasil Monophase + Aquasil XLV; Dentsply, Konstanz, Germany) and intraoral scanning (IS) (Cara TRIOS; Heraeus, Hanau, Germany) of each of the preparations was performed, and then two respective zirconia copings per tooth were produced (20 crowns per group). The marginal and internal fit of the restorations was evaluated employing a replica technique. For statistical analysis, a pairwise comparison (Wilcoxon rank test) was performed. RESULTS: Zirconia single crowns produced with the IS technique revealed a statistically significant better precision of internal fit only in specific areas (chamfer area/occlusal area). The evaluation of marginal fit showed no significant differences between the two groups. All restorations of both groups offered internal and marginal gaps within the postulated clinical tolerance ranges. CONCLUSIONS: CAD/CAM-fabricated zirconia single crowns produced with CI and IS techniques offer adequate marginal and internal precision. However, the IS technique provides lower internal gaps in some specific areas. CLINICAL RELEVANCE: The clinical precision of fit of restorations produced with a CI and an IS technique appeared to be equivalent. Therefore, the IS technique can be rated as a suitable alternative for the manufacturing of single crowns. PMID- 27469103 TI - Recent advances in modified atmosphere packaging and edible coatings to maintain quality of fresh-cut fruits and vegetables. AB - Processing of fruits and vegetables generates physiological stresses in the still living cut tissue, leading to quality deterioration and shorter shelf life as compared with fresh intact produces. Several strategies can be implemented with the aim to reduce the rate of deterioration of fresh-cut commodities. Such strategies include low temperature maintenance from harvest to retail and the application of physical and chemical treatments such as modified atmosphere packaging (MAP) with low O2 and high CO2 levels and antioxidant dips. Other technologies such as edible coatings with natural additives, new generation of coatings using nanotechnological solutions such as nanoparticles, nanoencapsulation, and multilayered systems, and nonconventional atmospheres such as the use of pressurized inert/noble gases and high levels of O2 have gained a lot of interest as a possibility to extend the shelf life of minimally processed fruits and vegetables. However, the high perishability of these products challenges in many cases their marketability by not achieving sufficient shelf life to survive the distribution system, requiring the combination of treatments to assure safety and quality. This review reports the recent advances in the use of MAP, edible coatings, and the combined effect of both technologies to extend the shelf life of fresh-cut fruits and vegetables. PMID- 27469105 TI - Evaluation of transradial body-powered prostheses using a robotic simulator. AB - BACKGROUND: Transradial body-powered prostheses are extensively used by upper limb amputees. This prosthesis requires large muscle forces and great concentration by the patient, often leading to discomfort, muscle fatigue, and skin breakdown, limiting the capacity of the amputee to conduct daily activities. Since body-powered prostheses are commonplace, understanding their optimal operation to mitigate these drawbacks would be clinically meaningful. OBJECTIVES: To find the optimal operation of the prosthesis where the activation force is minimized and the grip force is maximized. STUDY DESIGN: Experimental design. METHODS: A computer-controlled robotic amputee simulator capable of rapidly testing multiple elbow, shoulder, and scapular combinations of the residual human arm was constructed. It was fitted with a transradial prosthesis and used to systematically test multiple configurations. RESULTS: We found that increased shoulder flexion, scapular abduction, elbow extension, and the placement of the ring harness near the vertebra C7 correlate with higher gripper operation efficiency, defined as the ratio of grip force to cable tension. CONCLUSION: We conclude that force transmission efficiency is closely related to body posture configuration. These results could help guide practitioners in clinical practice as well as motivate future studies in optimizing the operation of a body-powered prosthesis. Clinical relevance The results from this study suggest that clinicians ought to place the ring harness inferior and to the sound side of the vertebra prominens in order to maximize grip efficiency. The results will also help clinicians better instruct patients in body posture during prosthesis operation to minimize strain. PMID- 27469104 TI - Anti-inflammatory and Anti-oxidative Effects of Dexpanthenol on Lipopolysaccharide Induced Acute Lung Injury in Mice. AB - The aim of this study is to investigate the effects of dexpanthenol in a model of acute lung injury (ALI) induced by lipopolysaccharides (LPS). Lung injury was induced by exposure to atomized LPS. Mice were randomly divided into four groups: control group; Dxp (500 mg/kg) group; LPS group; LPS + Dxp (500 mg/kg) group. The effects of dexpanthenol on LPS-induced neutrophil recruitment, cytokine levels, total protein concentration, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) contents were examined. Additionally, lung tissue was examined by histology to investigate the changes in pathology in the presence and absence of dexpanthenol. In LPS-challenged mice, dexpanthenol significantly improved lung edema. Dexpanthenol also markedly inhibited the LPS-induced neutrophiles influx, protein leakage, and release of TNF-alpha and IL-6 in bronchoalveolar lavage fluid (BALF). Furthermore, dexpanthenol attenuated MPO activity and MDA contents and increased SOD and GSH activity in the LPS-challenged lung tissue. These data suggest that dexpanthenol protects mice from LPS-induced acute lung injury by its anti-inflammatory and anti-oxidative activities. PMID- 27469106 TI - Novel Genes Encoding Hexadecanoic Acid Delta6-Desaturase Activity in a Rhodococcus sp. AB - cis-6-Hexadecenoic acid, a major component of human sebaceous lipids, is involved in the defense mechanism against Staphylococcus aureus infection in healthy skin and closely related to atopic dermatitis. Previously, Koike et al. (Biosci Biotechnol Biochem 64:1064-1066, 2000) reported that a mutant strain of Rhodococcus sp. produced cis-6-hexadecenoate derivatives from palmitate alkyl esters. From the mutant Rhodococcus strain, we identified and sequenced two open reading frames present in an amplified 5.7-kb region; these open reading frames encoded tandemly repeated Delta6-desaturase-like genes, Rdes1 and Rdes2. A phylogenetic tree indicated that Rdes1 and Rdes2 were different from previously known Delta6-desaturase genes, and that they formed a new cluster. Rdes1 and Rdes2 were each introduced into vectors and then expressed separately in Escherichia coli, and the fatty acid composition of the transformed cells was analyzed by gas chromatography and mass spectrometry. The amount of cis-6 hexadecenoic acid was significantly higher in Rdes1- or Rdes2-transformed E. coli cells (twofold and threefold, respectively) than in vector-only control cells. These results showed that cis-6-hexadecenoic acid was produced in E. coli cells by the rhodococcal Delta6-desaturase-like proteins. PMID- 27469107 TI - The Relation of Maternal Birth Weight to African-American and Non-Latina White Twin Pregnancy Outcomes: A Population-Based Study. AB - Objectives The authors investigated the association between maternal birth weight and adverse birth outcome as measured by rates of low birth weight (<2500 g, LBW), preterm birth (<37 weeks, PTB), and small for gestational age (weight <10th percentile for gestational age, SGA) among African American and White twin pregnancies. Methods Stratified and multivariable regression analyses were performed on the Illinois transgenerational dataset of non-Latina African American and non-Latina White twin pairs (born 1989-1991) and their mothers (born 1956-1976). Results Former LBW (n = 104) and non-LBW (n = 742) African American mothers had LBW rates in both twins of 76 and 56 %, respectively; RR (95 % CI) = 1.4 (1.2-1.6). Former LBW (n = 105) and non-LBW (n = 2136) White mothers had LBW rates in both twins of 41 and 34 %, respectively; RR = 1.2 (0.9-1.5). In multivariable regression models, the adjusted (controlling for maternal age, education, marital status, parity, prenatal care usage, and cigarette smoking) RR of LBW in both twins among former LBW (compared to non-LBW) African American and White mothers equaled 1.4 (1.2-1.6) and 1.2 (0.9-1.5), respectively. Maternal LBW was associated with a modestly increased risk of PTB but not SGA among African American twin pregnancies: adjusted RR = 1.3 (1.1-1.4) and 1.1 (0.8-1.5), respectively. Conclusions In African American twin pregnancies, maternal LBW is a risk factor for LBW in both twins. Further research is needed to determine whether a similar generational association occurs among non-Latina White twin pregnancies. PMID- 27469108 TI - Potential Use of Food/Activity, Parenting Style, and Caregiver Feeding Style Measurement Tools with American Indian Families: A Brief Report. AB - Objective To provide preliminary descriptive data on caregiver and child weight status, parenting styles, feeding styles, and feeding practices of a small American Indian sample. Methods Participants included a subsample of American Indian caregivers (n = 23) identified from a larger study that was conducted in five states. Using previously validated instruments, means, standard deviations, and ranges for general parenting styles, feeding styles, and feeding practices were explored. Results In general, most caregivers reported healthy feeding practices. Most caregivers scored higher on responsive compared to restrictive or permissive in general parenting. Of the sample, 12 caregivers (52.2 %) were classified in the indulgent feeding style category, 5 caregivers (21.7 %) were classified as authoritative, 5 (21.7 %) uninvolved, and 1 (4.3 %) authoritarian. Conclusions More investigations are needed to explore questions raised by this study about using common tools that measure childhood obesity with American Indian families. PMID- 27469109 TI - Health Care Changes for Children with Special Health Care Needs, 2005-2011. AB - Objective This study compared health care utilization of children with special health care needs in 2005/06 and 2009/10. Methods Using data from the National Survey of Children with Special Health Care Needs, this study compared the health care utilization of children with special health care needs in 2005/06 (n = 40,723) and 2009/10 (n = 40,242). Descriptive statistics characterize the sample during the 2005/06 and 2009/10 surveys. Logistic regression models examined the unmet needs for specific health care and support services, delayed care, coordinated care, and medical home. Results Compared to 2005/06, in 2009/10 children with special health care needs had greater unmet dental and therapy needs and less care coordination of health services as well as access to medical home services. Conclusions These findings indicate that additional measures are needed to improve the health care access of children with special health care needs. PMID- 27469110 TI - Birth Weight and Early Cognitive Skills: Can Parenting Offset the Link? AB - Objectives There is an enduring negative association between low birth weight (<2500 g) and early childhood cognitive skills. This study examines if parenting practices meaningfully contribute to or offset birth weight disparities in cognitive development prior to formal schooling. Methods This study uses the ECLS B, a nationally representative sample of live births in the United States in 2001. Unlike studies focused on one or two measures of parenting and investment, this study considers a wide array parenting measures collected at multiple time points, tracked from before birth across 5 years of development. Results Regression results show that nearly 50 % of the low-birth-weight gap in early math and reading ability is associated with family socioeconomic status. Between family OLS regressions show that parenting practices, including "parental interaction," "cognitive stimulation," and "parent quality", are negatively associated with low birth weight and positively associated with improved cognitive skill among all children. After adjustment for family socioeconomic status, parenting practices did little to offset (by mediation or moderation) remaining birth weight disparities in early cognitive development. Conclusions Effective parenting is positively associated with cognitive development, but parenting is not a panacea-the developmental disadvantages associated with poor child health are not linked to parenting practices. We argue that birth weight disparities are rooted in biology and cannot easily be offset by parenting practices. PMID- 27469112 TI - Zika virus: a new arboviral public health problem. AB - Zika virus (ZIKV) is a single-stranded RNA virus in the Flaviviridae family and transmitted to human through infected mosquitos (Aedes aegypti and Aedes albopictus). Virus is closely related with other flaviviruses; dengue virus, yellow fever virus, West Nile virus, and Japanese encephalitis virus phylogenetically. Due to the possible relationship between virus and clinical features including microcephaly, ventricule, and eye deformities, Guillain-Barre syndrome increases the interest on this virus gradually. Along with the vector borne transmission, exposure via blood transfusion and sexual contact are further concerns. Since December 2015, CDC reported 440.000-1.300.000 possible cases in Brazil and as of 19 January 2016, El Salvador, Venezuela, Colombia, Brazil, Surinam, French Guana, Honduras, Mexico, and Panama are the countries with active epidemic. CDC recommends ZIKV screening for all pregnants including asymptomatic cases those living in the active epidemic areas. Recently, virus is detected in the USA and most European countries including UK, Netherlands, Denmark, Switzerland, and Italy as a travel-associated infection. Owing to the changing world with increased capabilities for transportation globally, this vector-borne infection represents a valuable marker for the ability of spreading of any infection from its original area that it was first seen. In this review, we summarized the up-to-date data and reports in terms of the importance of the ZIKV infection in the public health. PMID- 27469111 TI - Pontibacter litorisediminis sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-flagellated, motile by gliding and ovoid or rod-shaped bacterial strain, designated YKTF-7T, was isolated from a tidal flat sediment on the Yellow Sea, South Korea. Strain YKTF-7T grew optimally at pH 7.0 8.0, at 30-37 degrees C and in the presence of 0.5-2.0 % (w/v) NaCl. A neighbour joining phylogenetic tree based on 16S rRNA gene sequences showed that strain YKTF-7T fell within the clade comprising the type strains of species of the genus Pontibacter, clustering with the type strains of Pontibacterodishensis and Pontibacterkorlensis with which it exhibited 98.0-98.7 % sequence similarity. Strain YKTF-7T exhibited 16S rRNA gene sequence similarities of 94.7-96.8 % to the type strains of the other species of the genus Pontibacter and of less than 91.7 % to those of other recognized species. Strain YKTF-7T contained MK-7 as the predominant menaquinone and summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B) and iso-C15 : 0 as the major fatty acids. The major polar lipids were phosphatidylethanolamine and two unidentified lipids. The DNA G+C content of strain YKTF-7T was 54.0 mol%, and its mean DNA-DNA relatedness values with the type strains of P. odishensis and P. korlensis were 25 and 14 %, respectively. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain YKTF-7T is separated from recognized species of the genus Pontibacter. On the basis of the data presented, strain YKTF 7T is considered to represent a novel species of the genus Pontibacter, for which the name Pontibacterlitorisediminis sp. nov. is proposed. The type strain is YKTF 7T(=KCTC 52252T=NBRC 112298T). PMID- 27469113 TI - The effect of visualization on visual search performance : Does visualization trump vision? AB - Striking results recently demonstrated that visualizing search for a target can facilitate visual search for that target on subsequent trials (Reinhart et al. 2015). This visualization benefit was even greater than the benefit of actually repeating search for the target. We registered a close replication and generalization of the original experiment. Our results show clear benefits of repeatedly searching for the same target, but we found no benefit associated with visualization. The difficulty of the search task and the ability to monitor compliance with instructions to visualize are both possible explanations for the failure to replicate, and both should be carefully considered in future research exploring this interesting phenomenon. PMID- 27469114 TI - Sleeping patterns of Swedish women experiencing a stillbirth between 2000-2014 - an observational study. AB - BACKGROUND: External (to the fetus) stressors may act together with maternal factors as well as fetal and placental factors to increase the risk of stillbirth. Data published in 2011 indicate non-left side sleeping positions, particularly the supine one, is such a stressor; we do not know, however, if this new knowledge has influenced the choice of sleeping position among pregnant women. METHODS: Using a web-based questionnaire made available at the home page of the Swedish national infant foundation we collected information on sleeping positions among women who gave birth to a stillborn baby between 2000 and 2014. RESULTS: The questionnaire was completed by 583 women. About one third of the women reporting their sleeping position stated that they lay down on their the left side when going to bed, and another third reported lying down as often on the left as on the right side. Figures for typically going to bed on the left side the 4 weeks preceding the stillbirth was as follows: 72 (30 %) of 242 between 2011 and 2014 and 86 (27 %) of 313 between 2000 and 2010. Among the 240 women who remembered their position when waking up on the day the stillbirth was diagnosed, 63 (26 %) reported a supine position. CONCLUSION: Our data indicate that one third of the women went to bed on the left side the month before the stillbirth. The data are consistent with the notion that efforts in Sweden to advise women to lie on their left side when going to bed may decrease the rate of stillbirth. PMID- 27469116 TI - Physicochemical characterization of titanium dioxide pigments using various techniques for size determination and asymmetric flow field flow fractionation hyphenated with inductively coupled plasma mass spectrometry. AB - Seven commercial titanium dioxide pigments and two other well-defined TiO2 materials (TiMs) were physicochemically characterised using asymmetric flow field flow fractionation (aF4) for separation, various techniques to determine size distribution and inductively coupled plasma mass spectrometry (ICPMS) for chemical characterization. The aF4-ICPMS conditions were optimised and validated for linearity, limit of detection, recovery, repeatability and reproducibility, all indicating good performance. Multi-element detection with aF4-ICPMS showed that some commercial pigments contained zirconium co-eluting with titanium in aF4. The other two TiMs, NM103 and NM104, contained aluminium as integral part of the titanium peak eluting in aF4. The materials were characterised using various size determination techniques: retention time in aF4, aF4 hyphenated with multi angle laser light spectrometry (MALS), single particle ICPMS (spICPMS), scanning electron microscopy (SEM) and particle tracking analysis (PTA). PTA appeared inappropriate. For the other techniques, size distribution patterns were quite similar, i.e. high polydispersity with diameters from 20 to >700 nm, a modal peak between 200 and 500 nm and a shoulder at 600 nm. Number-based size distribution techniques as spICPMS and SEM showed smaller modal diameters than aF4-UV, from which mass-based diameters are calculated. With aF4-MALS calculated, light scattering-based "diameters of gyration" (Og) are similar to hydrodynamic diameters (Oh) from aF4-UV analyses and diameters observed with SEM, but much larger than with spICPMS. A Og/Oh ratio of about 1 indicates that the TiMs are oblate spheres or fractal aggregates. SEM observations confirm the latter structure. The rationale for differences in modal peak diameter is discussed. PMID- 27469115 TI - SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2. AB - Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFalpha or TRAIL and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNFalpha induced sub-G0 DNA fragmentation in sensitive lines and birinapant alone also induced significant G2-M cell-cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFalpha, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation-induced TNFalpha, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/- BIRC2 These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations. Cancer Res; 76(18); 5442-54. (c)2016 AACR. PMID- 27469117 TI - Contralateral Prophylactic Mastectomy (CPM) Consensus Statement from the American Society of Breast Surgeons: Data on CPM Outcomes and Risks. PMID- 27469119 TI - Limiting Axillary Surgery for Patients with Initial Biopsy-Proven Axillary Metastases After Preoperative Chemotherapy: To Clip or Not to Clip? PMID- 27469118 TI - Contralateral Prophylactic Mastectomy Consensus Statement from the American Society of Breast Surgeons: Additional Considerations and a Framework for Shared Decision Making. PMID- 27469120 TI - Sex Disparity in Gastric Cancer: Female Sex is a Poor Prognostic Factor for Advanced Gastric Cancer. AB - BACKGROUND: The overall incidence of gastric cancer (GC) is higher in males than females. Specifically, signet ring cell carcinoma (SRC) is more frequently observed in younger female patients. However, limited information focused on sex specific differences in GC has been reported. The aim of our study was to analyze clinicopathological differences between sex groups to reveal sex disparities in GC. METHODS: We retrospectively analyzed 4722 patients with GC who underwent gastrectomy (females: 1586 (33.6 %); males: 3136 (66.4 %), and analyzed clinicopathological features between these sex groups. The overall survival (OS) rate was investigated between the two sex groups, with special reference to the pathologic World Health Organization GC classifications. Immunohistochemistry staining of sex hormone receptors, including the estrogen receptor (ER)-alpha, ER beta, progesterone receptor, and androgen receptor, was performed according to sex and pathological classification. RESULTS: Female patients were significantly associated with a younger age, poorly differentiated adenocarcinoma, and SRC compared with males. Female patients showed a significantly poorer OS than male patients, especially among those with advanced GC (AGC) aged <=45 years. In females with AGC, those with SRC had a significantly poorer OS than those with other histologies. Moreover, the expression of ER-beta was different between females and males with SRC. CONCLUSIONS: Females with GC were significantly younger and had a different SRC histology compared with males. Furthermore, females had significantly poorer prognostic factors among young patients with SRC. Thus, young female GC patients with SRC are a main target group in which to improve prognosis. PMID- 27469122 TI - Adjuvant Chemotherapy: What's the Rush? PMID- 27469121 TI - A Prospective, Single Arm, Multi-site, Clinical Evaluation of a Nonradioactive Surgical Guidance Technology for the Location of Nonpalpable Breast Lesions during Excision. AB - OBJECTIVES: This study was a multicenter evaluation of the SAVI SCOUT((r)) breast localization and surgical guidance system using micro-impulse radar technology for the removal of nonpalpable breast lesions. The study was designed to validate the results of a recent 50-patient pilot study in a larger multi-institution trial. The primary endpoints were the rates of successful reflector placement, localization, and removal. METHODS: This multicenter, prospective trial enrolled patients scheduled to have excisional biopsy or breast-conserving surgery of a nonpalpable breast lesion. From March to November 2015, 154 patients were consented and evaluated by 20 radiologists and 16 surgeons at 11 participating centers. Patients had SCOUT((r)) reflectors placed up to 7 days before surgery, and placement was confirmed by mammography or ultrasonography. Implanted reflectors were detected by the SCOUT((r)) handpiece and console. Presence of the reflector in the excised surgical specimen was confirmed radiographically, and specimens were sent for routine pathology. RESULTS: SCOUT((r)) reflectors were successfully placed in 153 of 154 patients. In one case, the reflector was placed at a distance from the target that required a wire to be placed. All 154 lesions and reflectors were successfully removed during surgery. For 101 patients with a preoperative diagnosis of cancer, 86 (85.1 %) had clear margins, and 17 (16.8 %) patients required margin reexcision. CONCLUSIONS: SCOUT((r)) provides a reliable and effective alternative method for the localization and surgical excision of nonpalpable breast lesions using no wires or radioactive materials, with excellent patient, radiologist, and surgeon acceptance. PMID- 27469123 TI - How Often Is Treatment Effect Identified in Axillary Nodes with a Pathologic Complete Response After Neoadjuvant Chemotherapy? AB - BACKGROUND: False-negative rates (FNR) of sentinel node biopsy (SNB) after neoadjuvant chemotherapy (NAC) in node-positive (N+) breast cancer patients are <10 % when >=3 negative SNs are obtained. Marking positive nodes has been suggested to reduce FNR. Identification of treatment effect in the nodes post-NAC is an alternative to decrease FNR. We evaluated the frequency of treatment effect in N+ patients after a pathologic complete response (pCR) with NAC. METHODS: Biopsy-proven N+ patients receiving NAC were identified. Patients with nodal pCR after axillary lymph node dissection (ALND) or SNB with dual mapping and >=3 SNs removed were evaluated for treatment effect; ALND and SNB patients were compared. RESULTS: From January 2009 to December 2015, 528 N+ patients received NAC. Of these, 204 had a nodal pCR, 135 had an ALND, and 69 had SNB. Median age was 49 years, 15 % were hormone receptor positive (HR+)/HER2-, 27 % triple negative, and 58 % HER2+. The median number of nodes removed in ALND patients was 17 versus 4 in SNB patients. Treatment effect in nodes was identified in 192 patients (94 %) and was more common in ALND versus SNB patients (97 vs 88 %; p = .02). HR+ patients and patients without a breast pCR were less likely to have treatment effect in the nodes (p = .05). Other characteristics did not differ. CONCLUSIONS: Following NAC, SNs with treatment effect were retrieved in 88 % of patients without marking nodes, suggesting that nodal clipping may not be necessary to achieve an acceptable FNR. Longer follow-up is needed to determine regional recurrence rates in the SN-only cohort. PMID- 27469124 TI - Classification of Indeterminate Melanocytic Lesions by MicroRNA Profiling. AB - PURPOSE: Identification of indeterminate melanocytic skin lesions capable of neoplastic progression is suboptimal and may potentially result in unnecessary morbidity from surgery. MicroRNAs (miRs) may be useful in classifying indeterminate Spitz tumors as having high or low risk for malignant behavior. METHODS: RNA was extracted from paraffin-embedded tissues of benign nevi, benign Spitz tumors, indeterminate Spitz tumors, and Spitzoid melanomas in adults (n = 62) and children (n = 28). The expression profile of 12 miRs in adults (6 miRs in children) was analyzed by real-time polymerase chain reaction. RESULTS: Benign Spitz lesions were characterized by decreased expression of miR-125b and miR-211, and upregulation of miR-22, compared with benign nevi (p < 0.05). A comparison of Spitzoid melanomas to benign nevi revealed overexpression of miR-21, miR-150, and miR-155 in the malignant primaries (p < 0.05). In adults, Spitzoid melanomas exhibited upregulation of miR-21, miR-150, and miR-155 compared with indeterminate Spitz lesions. Indeterminate Spitz lesions with low-risk pathologic features had lower miR-21 and miR-155 expression compared with Spitzoid melanoma tumors in adults (p < 0.05), while pathologic high-risk indeterminate Spitz lesions had increased levels of miR-200c expression compared with low-risk indeterminate lesions (p < 0.05). Pediatric Spitzoid melanomas exhibited increased miR-21 expression compared with indeterminate Spitz lesions (p < 0.05). Moreover, miR-155 expression was increased in indeterminate lesions with mitotic counts >1 and depth of invasion >1 mm, suggesting miR-155 expression is associated with histological characteristics. CONCLUSIONS: miR expression profiles can be measured in indeterminate Spitz tumors and correlate with markers of malignant potential. PMID- 27469126 TI - Fifteen-minute consultation on the healthy child: breast feeding. AB - Despite extensive evidence about the benefits of breast feeding for both infants and mothers, breastfeeding rates in the UK remain low. Most infants presenting with feeding issues are otherwise well but are often over diagnosed with clinical conditions such as maternal milk insufficiency, cow's milk intolerance or reflux. With simple advice and troubleshooting common problems, all child health professionals can support mothers to establish and continue breast feeding exclusively for longer. PMID- 27469125 TI - Comparative Analysis of Breast Cancer Phenotypes in African American, White American, and West Versus East African patients: Correlation Between African Ancestry and Triple-Negative Breast Cancer. AB - INTRODUCTION: Triple-negative breast cancer (TNBC) is more common among African American (AA) and western sub-Saharan African breast cancer (BC) patients compared with White/Caucasian Americans (WA) and Europeans. Little is known about TNBC in east Africa. METHODS: Invasive BC diagnosed 1998-2014 were evaluated: WA and AA patients from the Henry Ford Health System in Detroit, Michigan; Ghanaian/west Africans from the Komfo Anokye Teaching Hospital in Kumasi, Ghana; and Ethiopian/east Africans from the St. Paul's Hospital Millennium Medical College in Addis Ababa, Ethiopia. Histopathology and immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), and HER2/neu expression was performed in Michigan on formalin-fixed, paraffin-embedded samples from all cases. RESULTS: A total of 234 Ghanaian (mean age 49 years), 94 Ethiopian (mean age 43 years), 272 AA (mean age 60 years), and 321 WA (mean age 62 years; p = 0.001) patients were compared. ER-negative and TNBC were more common among Ghanaian and AA compared with WA and Ethiopian cases (frequency ER-negativity 71.1 and 37.1 % vs. 19.8 and 28.6 % respectively, p < 0.0001; frequency TNBC 53.2 and 29.8 % vs. 15.5 and 15.0 %, respectively, p < 0.0001). Among patients younger than 50 years, prevalence of TNBC remained highest among Ghanaians (50.8 %) and AA (34.3 %) compared with WA and Ethiopians (approximately 16 % in each; p = 0.0002). CONCLUSIONS: This study confirms an association between TNBC and West African ancestry; TNBC frequency among AA patients is intermediate between WA and Ghanaian/West Africans consistent with genetic admixture following the west Africa-based trans-Atlantic slave trade. TNBC frequency was low among Ethiopians/East Africans; this may reflect less shared ancestry between AA and Ethiopians. PMID- 27469127 TI - What is a ketogenic diet and how does it affect the use of medicines? PMID- 27469128 TI - Synthesis and preliminary in vitro kinase inhibition evaluation of new diversely substituted pyrido[3,4-g]quinazoline derivatives. AB - The synthesis of new diversely substituted pyrido[3,4-g]quinazolines is described. The inhibitory potencies of prepared compounds toward a panel of five CMGC protein kinases (CDK5, CLK1, DYRK1A, CK1, GSK3), that are known to play a potential role in Alzheimer's disease, were evaluated. The best overall kinase inhibition profile was found for nitro compound 4 bearing an ethyl group at the 5 position. PMID- 27469130 TI - 1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2). AB - Indoleamine 2,3-dioxygenase 2 (IDO2) is a potential therapeutic target for the treatment of diseases that involve immune escape such as cancer. In contrast to IDO1, only a very limited number of inhibitors have been described for IDO2 due to inherent difficulties in expressing and purifying a functionally active, soluble form of the enzyme. Starting from our previously discovered highly efficient 4-aryl-1,2,3-triazole IDO1 inhibitor scaffold, we used computational structure-based methods to design inhibitors of IDO2 which we then tested in cellular assays. Our approach yielded low molecular weight inhibitors of IDO2, the most active displaying an IC50 value of 51MUM for mIDO2, and twofold selectivity over hIDO1. These compounds could be useful as molecular probes to investigate the biological role of IDO2, and could inspire the design of new IDO2 inhibitors. PMID- 27469129 TI - Synthesis, structure and antimicrobial evaluation of a new gossypol triazole conjugates functionalized with aliphatic chains and benzyloxy groups. AB - Synthetic limitations in the copper-catalyzed azide alkyne cycloaddition (CuAAC) on gossypol's skeleton functionalized with alkyne (2) or azide (3) groups have been indicated. Modified approach to the synthesis of new gossypol-triazole conjugates yielded new compounds (24-31) being potential fungicides. Spectroscopic studies of triazole conjugates 24-31 have revealed their structures in solution, i.e., the presence of enamine-enamine tautomeric forms and pi-pi stacking intramolecular interactions between triazole arms. Biological evaluation of the new gossypol-triazole conjugates revealed the potency of 30 and 31 derivatives, having triazole-benzyloxy moieties, comparable with that of miconazole against Fusarium oxysporum. The results of HPLC evaluation of ergosterol content in different fungi strains upon treatment of gossypol and its derivatives enabled to propose a mechanism of antifungal activity of these compounds. PMID- 27469131 TI - Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype. AB - BACKGROUND: Asparagine Synthetase Deficiency (ASNSD; OMIM #615574) is a newly described rare autosomal recessive neurometabolic disorder, characterised by congenital microcephaly, severe psychomotor delay, encephalopathy and progressive cerebral atrophy. To date, seven families and seven missense mutations in the ASNSD disease causing gene, ASNS, have been published. METHODS: We report two further affected infant sisters from a consanguineous Indian family, who in addition to the previously described features had diaphragmatic eventration. Both girls died within the first 6 months of life. Whole exome sequencing (WES) was performed for both sisters to identify the pathogenic mutation. The clinical and biochemical parameters of our patient are compared to previous reports. RESULTS: WES demonstrated a homozygous novel missense ASNS mutation, c.1019G > A, resulting in substitution of the highly conserved arginine residue by histidine (R340H). CONCLUSION: This report expands the phenotypic and mutation spectrum of ASNSD, which should be considered in neonates with congenital microcephaly, seizures and profound neurodevelopmental delay. The presence of diaphragmatic eventration suggests extracranial involvement of the central nervous system in a disorder that was previously thought to exclusively affect the brain. Like all previously reported patients, these cases were diagnosed with WES, highlighting the clinical utility of next generation sequencing in the diagnosis of rare, difficult to recognise disorders. PMID- 27469132 TI - Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs. AB - Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n = 9), MPS II (n = 13), MPS III (n = 23), MPS VI (n = 7), beta-galactosidase deficiency (n = 7), mucolipidosis (ML) type II, II/III and III (n = 51), alpha-mannosidosis (n = 11), fucosidosis (n = 4), sialidosis (n = 5), Pompe disease (n = 3), aspartylglucosaminuria (n = 4), and galactosialidosis (n = 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results. PMID- 27469133 TI - The Spectrum of PAH Mutations and Increase of Milder Forms of Phenylketonuria in Sweden During 1965-2014. AB - Newborn screening (NBS) for phenylketonuria (PKU) which has a continuum of disease severities has been performed for more than 50 years. The screening method has undergone a continuous development with not only improvements of the positive predictive value but also identification of milder forms of the disease. With the introduction of genetic testing the confirmation of the diagnosis has improved. The Swedish NBS is centralized to one laboratory, which also performs confirmatory testing.Here we present the results of NBS for PKU in Sweden during 1965-2014 describing an increase in diagnosed patients and a shift in the spectrum of phenylalanine hydroxylase (PAH) mutations towards an increasing heterogeneity. Milder mutations common in southern Europe and the Middle East together with lowering of the recall level for phenylalanine (Phe) have led to a shift towards milder phenotypes among the patients identified by the screening program. The inclusion of a Phe and tyrosine (Tyr) ratio as an additional marker has improved the positive predictive value to the present 0.92. Also discussed is what impact earlier sampling has had on the prediction of disease severity, concluding that the shift of age at sampling from 72 to 48 h does not increase the risk of missing patients in need of treatment. PMID- 27469134 TI - Endovascular management of ruptured basilar artery dissection with two overlapping Low-profile Visualized Intraluminal Support stents. AB - The optimal endovascular treatment method of ruptured basilar artery dissection still remains controversial. We reported a case with ruptured basilar artery dissection involving the left anterior inferior cerebellar artery. The dissecting aneurysm was successfully treated with two overlapping Low-profile Visualized Intraluminal Support stents and the preservation of antegrade blood flow of the anterior inferior cerebellar artery was achieved. Three-month and six-month follow-ups revealed good clinical and angiographic results, although controversies regarding long-term stability remained to be addressed. PMID- 27469135 TI - Ex-vivo release of Pipeline Embolization Device polytetrafluoroethylene (PTFE) sleeves for improved distal landing zone accuracy in-vivo: A technical note. AB - BACKGROUND: Distal landing zone accuracy is critical in some intracranial aneurysms treated with the Pipeline Embolization Device (PED), and delayed opening of the distal end of the device can complicate the procedure. Here, we report a technical nuance that facilitates accurate placement of the distal end of the PED by ex-vivo, pre-implantation release of the PED Flex polytetrafluoroethylene (PTFE) sleeves. TECHNICAL NOTE: The PED Flex is partially pushed out of the introducer sheath ex-vivo, pre-implantation until the distal PED opens entirely and the PTFE sleeves are located distal to the device. Without inverting the PTFE sleeves, the PED is carefully pulled back into the introducer sheath placing the PTFE sleeves inside the device. The PED is loaded into the microcatheter and advanced toward the site of implantation. When the PED is initially deployed and pushed out of the microcatheter, it opens immediately and provides an anchor for the remainder of the deployment process. We present a video (supplementary material) that illustrates the technique along with an illustrative case. CONCLUSION: Ex-vivo, pre-implantation release of the PTFE sleeves is an option in aneurysm treatment where distal landing accuracy is critical. Even without the protection of the PTFE sleeves, our clinical observation shows that the PED can be advanced safely through the microcatheter in selected cases. PMID- 27469136 TI - Detection and Confirmation of Deafness-Causing Copy Number Variations in the STRC Gene by Massively Parallel Sequencing and Comparative Genomic Hybridization. AB - OBJECTIVE: Copy number variations (CNVs), a major cause of genetic hearing loss, most frequently involve the STRC gene, located on chr15q15.3 and causally related to autosomal recessive non-syndromic hearing loss (ARNSHL) at the DFNB16 locus. The interpretation of STRC sequence data can be challenging due to the existence of a virtually identical pseudogene, pSTRC, that promotes complex genomic rearrangements in this genomic region. Targeted genomic enrichment with massively parallel sequencing (TGE+MPS) has emerged as the preferred method by which to provide comprehensive genetic testing for hearing loss. We aimed to identify CNVs in the STRC region using established and validated bioinformatics methods. METHODS: We used TGE+MPS to identify the genetic cause of hearing loss. The CNV results were confirmed with customized array comparative genomic hybridization (array CGH). RESULTS: Three probands with progressive mild to moderate hearing loss were found among 40 subjects with ARNSHL to segregate homozygous STRC deletions and gene to pseudogene conversion. Array CGH showed that the deletions/conversions span multiple genes outside of the exons captured by TGE+MPS. CONCLUSION: These data further validate the necessity to integrate the detection of both simple variant changes and complex genomic rearrangements in the clinical diagnosis of genetic hearing loss. PMID- 27469137 TI - EYA4 gene functions as a prognostic marker and inhibits the growth of intrahepatic cholangiocarcinoma. AB - BACKGROUND: The molecular prognostic markers and carcinogenesis of intrahepatic cholangiocarcinoma (ICC) have not been well documented. The purpose of this study was to investigate the prognostic value of the eyes absent homolog 4 (EYA4) gene in ICC and its biological effects on ICC growth in vitro and in vivo. METHODS: One hundred twelve patients with ICC who underwent hepatectomy were enrolled in the study. EYA4 mRNA and EYA4 protein levels in ICC and adjacent non-tumoral tissues were evaluated using real-time quantitative polymerase chain reaction and immunohistochemical staining, respectively. EYA4 protein levels in ICC cells were determined using western blot analysis. The associations between EYA4 expression and clinicopathologic features of ICC were analyzed. To identify independent prognostic factors, univariate and multivariate analyses were performed. The biological effects of EYA4 on ICC cells were evaluated by establishing stable EYA4-overexpressing transfectants in vitro, and EYA4's effects on tumor growth were evaluated by intra-tumoral injection of EYA4-expressing plasmids in a NOD/SCID murine model of xenograft tumors. RESULTS: ICC tissues had significantly lower EYA4 mRNA and protein levels compared with adjacent non-tumoral tissues (both P < 0.001). Univariate and multivariate analyses showed that EYA4 protein level, tumor number, adjacent organ invasion, lymph node metastasis, and tumor differentiation were independent prognostic factors for disease-free survival and overall survival (all P < 0.05). In vitro, EYA4 overexpression inhibited tumor cell growth, foci formation, and cell invasiveness. In vivo, intra-tumoral injection of EYA4-expressing plasmids significantly inhibited ICC growth in the murine xenograft model compared with the control group (P < 0.05). CONCLUSION: EYA4 gene functioned as a molecular prognostic marker in ICC, and its overexpression inhibited tumor growth in vitro and in vivo. PMID- 27469138 TI - Flavobacterium terriphilum sp. nov., isolated from soil. AB - A novel aerobic, yellow-pigmented, Gram-stain-negative, rod-shaped bacterial strain, CUG00004T, was isolated from a soil sample. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CUG00004T was a member of the genus Flavobacterium and showed high sequence similarity with Flavobacterium soli DSM 19725T (96.9 %) and Flavobacterium glaciei CGMCC 0499T (95.6 %). The level of DNA-DNA relatedness between strain CUG00004T and F. soli DSM 19725T and F. glaciei CGMCC 1.5380T was 42.5 and 43.4 %, respectively. Strain CUG00004T was moderately alkaliphilic and grew optimally at pH 8.0, at 28 degrees C and in the presence of 0-1 % (w/v) NaCl. This organism contained menaquinone-6 (MK-6) as the only isoprenoid quinone and iso-C15 : 0, iso-C17 : 0 3-OH, anteiso-C15 : 0 and summed feature 9 (comprising iso-C17 : 1omega9c and/or C16 : 0 10-methyl) as the major fatty acids. The DNA G+C content of strain CUG00004T was 36.3 mol%. On the basis of phylogenetic, physiological and chemotaxonomic analyses, strain CUG00004T represents a novel species, for which the name Flavobacterium terriphilum sp. nov. is proposed. The type strain is CUG00004T (=CCTCC AB 2014151T=KCTC 42876T). PMID- 27469140 TI - Isoflurane Preconditioning Induces Neuroprotection by Up-Regulation of TREK1 in a Rat Model of Spinal Cord Ischemic Injury. AB - This study aimed to explore the neuroprotection and mechanism of isoflurane on rats with spinal cord ischemic injury. Total 40 adult male Sprague-Dawley rats were divided into the four groups (n=10). Group A was sham-operation group; group B was ischemia group; group C was isoflurane preconditioning group; group D was isoflurane preconditioning followed by ischemia treatment group. Then the expressions of TWIK-related K+ channel 1 (TREK1) in the four groups were detected by immunofluorescent assay, real time-polymerase chain reactions (RT-PCR) and western blot. The primary neurons of rats were isolated and cultured under normal and hypoxic conditions. Besides, the neurons under two conditions were transfected with green fluorescent protein (GFP)-TREK1 and lentivirual to overexpress and silence TREK1. Additionally, the neurons were treated with isoflurane or not. Then caspase-3 activity and cell cycle of neurons under normal and hypoxic conditions were detected. Furthermore, nicotinamide adenine dinucleotide hydrate (NADH) was detected using NAD+/NADH quantification colorimetric kit. Results showed that the mRNA and protein expressions of TREK1 increased significantly in group C and D. In neurons, when TREK1 silenced, isoflurane treatment improved the caspase-3 activity. In hypoxic condition, the caspase-3 activity and sub-G1 cell percentage significantly increased, however, when TREK1 overexpressed the caspase-3 activity and sub-G1 cell percentage decreased significantly. Furthermore, both isoflurane treatment and overexpression of TREK1 significantly decreased NADH. In conclusion, isoflurane induced neuroprotection in spinal cord ischemic injury may be associated with the up-regulation of TREK1. PMID- 27469141 TI - The Effect of (1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-Olide (LS-1) from Lobophyyum sp. on the Apoptosis Induction of SNU-C5 Human Colorectal Cancer Cells. AB - (1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1), a marine cembrenolide diterpene, has anticancer activity against colon cancer cells such as HT-29, SNU-C5/5-FU (fluorouracil-resistant SNU-C5) and SNU-C5. However, the action mechanism of LS-1 on SNU-C5 human colon cancer cells has not been fully elucidated. In this study, we investigated whether the anticancer effect of LS 1could result from apoptosis via the modulation of Wnt/beta-catenin and the TGF beta pathways. When treated with the LS-1, we could observe the apoptotic characteristics such as apoptotic bodies and the increase of sub-G1 hypodiploid cell population, increase of Bax level, decrease of Bcl-2 expression, cleavage of procaspase-3 and cleavage of poly (ADP-ribose) polymerase in SNU-C5 cells. Furthermore, the apoptosis induction of SNU-C5 cells upon LS-1 treatment was also accompanied by the down-regulation of Wnt/beta-catenin signaling pathway via the decrease of GSK-3beta phosphorylation followed by the decrease of beta-catenin level. In addition, the LS-1 induced the activation of TGF-beta signaling pathway with the decrease of carcinoembryonic antigen which leads to decrease of c-Myc, an oncoprotein. These data suggest that the LS-1 could induce the apoptosis via the down-regulation of Wnt/beta-catenin pathway and the activation of TGF-beta pathway in SNU-C5 human colon cancer cells. The results support that the LS-1 might have potential for the treatment of human colon cancer. PMID- 27469139 TI - A combination of two antibodies recognizing non-overlapping epitopes of HER2 induces kinase activity-dependent internalization of HER2. AB - The human epidermal growth factor receptor 2 (HER2/ErbB2) is overexpressed in a number of human cancers. HER2 is the preferred heterodimerization partner for other epidermal growth factor receptor (EGFR) family members and is considered to be resistant to endocytic down-regulation, properties which both contribute to the high oncogenic potential of HER2. Antibodies targeting members of the EGFR family are powerful tools in cancer treatment and can function by blocking ligand binding, preventing receptor dimerization, inhibiting receptor activation and/or inducing receptor internalization and degradation. With respect to antibody induced endocytosis of HER2, various results are reported, and the effect seems to depend on the HER2 expression level and whether antibodies are given as individual antibodies or as mixtures of two or more. In this study, the effect of a mixture of two monoclonal antibodies against non-overlapping epitopes of HER2 was investigated with respect to localization and stability of HER2. Individual antibodies had limited effect, but the combination of antibodies induced internalization and degradation of HER2 by multiple endocytic pathways. In addition, HER2 was phosphorylated and ubiquitinated upon incubation with the antibody combination, and the HER2 kinase activity was found to be instrumental in antibody-induced HER2 down-regulation. PMID- 27469142 TI - Pyrrole-Derivative of Chalcone, (E)-3-Phenyl-1-(2-Pyrrolyl)-2-Propenone, Inhibits Inflammatory Responses via Inhibition of Src, Syk, and TAK1 Kinase Activities. AB - (E)-3-Phenyl-1-(2-pyrrolyl)-2-propenone (PPP) is a pyrrole derivative of chalcone, in which the B-ring of chalcone linked to beta-carbon is replaced by pyrrole group. While pyrrole has been studied for possible Src inhibition activity, chalcone, especially the substituents on the B-ring, has shown pharmaceutical, anti-inflammatory, and anti-oxidant properties via inhibition of NF-kappaB activity. Our study is aimed to investigate whether this novel synthetic compound retains or enhances the pharmaceutically beneficial activities from the both structures. For this purpose, inflammatory responses of lipopolysaccharide (LPS)-treated RAW264.7 cells were analyzed. Nitric oxide (NO) production, inducible NO synthase (iNOS) and tumor necrosis factor-alpha (TNF alpha) mRNA expression, and the intracellular inflammatory signaling cascade were measured. Interestingly, PPP strongly inhibited NO release in a dose-dependent manner. To further investigate this anti-inflammatory activity, we identified molecular pathways by immunoblot analyses of nuclear fractions and whole cell lysates prepared from LPS-stimulated RAW264.7 cells with or without PPP pretreatment. The nuclear levels of p50, c-Jun, and c-Fos were significantly inhibited when cells were exposed to PPP. Moreover, according to the luciferase reporter gene assay after cotransfection with either TRIF or MyD88 in HEK293 cells, NF-kappaB-mediated luciferase activity dose-dependently diminished. Additionally, it was confirmed that PPP dampens the upstream signaling cascade of NF-kappaB and AP-1 activation. Thus, PPP inhibited Syk, Src, and TAK1 activities induced by LPS or induced by overexpression of these genes. Therefore, our results suggest that PPP displays anti-inflammatory activity via inhibition of Syk, Src, and TAK1 activity, which may be developed as a novel anti-inflammatory drug. PMID- 27469143 TI - Sensitization of 5-Fluorouracil-Resistant SNUC5 Colon Cancer Cells to Apoptosis by alpha-Mangostin. AB - 5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5 fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5 FU bears a significant importance. In the present study, we have found that alpha mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of alpha-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4 HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that alpha-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated alpha-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that alpha-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5 FU by activating apoptosis pathway. PMID- 27469145 TI - Burden of end-stage kidney disease: North Africa. AB - Geographical, ecological, and genetic factors result in many similarities among the six main countries of the African Sahara, including the epidemiology of kidney disease. With an average incidence of 182 and prevalence of 522 patients with end-stage kidney disease (ESKD) per million population, North Africa (NA) spends $650 million on dialysis and transplantation despite an estimated annual loss of 600,000 life years. The health burden of ESKD is not limited to its directly-related morbidity and mortality but affects even more significantly other body systems, particularly the cardiovascular system. In addition, dialysis units are reservoirs for infectious agents, such as hepatitis-C (HCV) and -B (HBV) viruses, and methicillin-resistant staphylococci (MRSA), which threaten the health of the community. Shortage of financial resources eventually creates inequity of health care at large since only the rich are able to find their way around the limited public services. ESKD is no exception; inequity being even further augmented by the trade of organs, particularly in Egypt. This is attributed to high demand in the absence of a deceased donor program and in the presence of a pool of young, healthy, unemployed potential donors who have no access to any social security plans. Many attempts to face the challenge of accommodating ESKD management in NA are underway, including relevant legislations, promoting deceased donor transplants, chronic kidney disease (CKD) prevention and early detection programs, and generating nontraditionally directed financial resources. PMID- 27469144 TI - Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABAA-ergic Systems. AB - It has been known that RA, one of major constituents of Perilla frutescens which has been used as a traditional folk remedy for sedation in oriental countries, shows the anxiolytic-like and sedative effects. This study was performed to know whether RA may enhance pentobarbital-induced sleep through gamma-aminobutyric acid (GABA)A-ergic systems in rodents. RA (0.5, 1.0 and 2.0 mg/ kg, p.o.) reduced the locomotor activity in mice. RA decreased sleep latency and increased the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleeping mice. RA also increased sleeping time and number of falling sleep mice after treatment with sub hypnotic pentobarbital (28 mg/kg, i.p.). In electroencephalogram (EEG) recording, RA (2.0 mg/kg) not only decreased the counts of sleep/wake cycles and REM sleep, but also increased the total and NREM sleep in rats. The power density of NREM sleep showed the increase in delta-waves and the decrease in alpha-waves. On the other hand, RA (0.1, 1.0 and 10 MUg/ml) increased intracellular Cl- influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase (GAD65/67) and GABAA receptors subunits except beta1 subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through GABAA-ergic transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia. PMID- 27469146 TI - End-stage renal disease care in South Asia: demographics, economics, and opportunities. AB - The epidemiologies of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in South Asia are not well defined. Small studies suggest that there is a predominant affliction of younger individuals and presence of risk factors beyond the traditional ones like diabetes and hypertension. The underprivileged poor who do not have access to healthcare facilities are affected disproportionately, present late, and lack means to afford treatment. Renal replacement therapy (RRT) is not widely available and is mostly delivered through expensive private-sector hospitals. There are no CKD detection or prevention programs, and reimbursement for RRT is not available to most people. As more patients present for treatment, the limited infrastructure will come under further strain. There is an urgent need to identify unique preventable risk factors related to causation and progression of CKD and to institute appropriate care. South Asian countries need local solutions by tapping into local resources as well as innovating and coordinating so that a comprehensive care plan can be put in place. New models of integrated noncommunicable disease care delivery through manpower restructuring and technological support will help reduce the disease burden. PMID- 27469147 TI - Current burden of end-stage kidney disease and its future trend in China. AB - INTRODUCTION: Understanding the status and trends of patients with ESKD is important to evaluate and predict its impact on the health care system in China. METHODS: Available publications and/or presentations from national and regional dialysis and transplantation registries were collected. RESULTS AND DISCUSSION: A national report in 1999 revealed that the prevalence and incidence of dialysis in China were 33.2 per million population (pmp) and 15.3 pmp, respectively. The numbers were updated to 237.3 pmp and 15.4 pmp in 2012. In big cities like Beijing and Shanghai, the numbers are much higher, with prevalence and incidence of 524.6 pmp and 107.3 pmp in Beijing in 2011, and 544.7 pmp and 82.9 pmp in Shanghai in 2011, respectively. The majority of patients received hemodialysis, accounting for 89.5% in 1999 and 89.1% in 2012. The increased prevalence of dialysis is partly due to increased affordability of dialysis; while affordability and accessibility still limit renal replacement therapy in China. Regarding causes of end-stage kidney disease in China, about half of the patients are diagnosed glomerulonephritis. The surge of hypertension and diabetes during the 1990s will probably have profound effects on prevalence and etiology of kidney disease in China. PMID- 27469148 TI - The role of the Kidney Foundation of Bangladesh in promoting kidney care in a resource-limited environment. AB - BACKGROUND: Prior to 2003 in Bangladesh, ~ 80% of kidney-failure patients could not afford treatment. The Kidney Foundation Bangladesh (KFB) was formed in 2003 with an aim to create awareness, to promote prevention of kidney disease to families and population, at risk as well as offer treatment to those afflicted with kidney failure. METHODS: KFB runs a 150-bed hospital for treatment of kidney disease, dialysis, and transplantation at an affordable price. New patients visiting the OPD pay only US$ 5.00 to consult a specialist, and dialysis and transplant patients pay US$1 for each consultation. All laboratory tests are discounted by 30% for all patients except patients with dialysis and transplantation who enjoy a 50% discount. Patients on HD pay only US$ 20.00 per session, and a renal transplant surgery costs US$ 3,000.00. RESULTS: From October 2004 to December 2014, there were 102,578 patients who received treatment in OPD in KFB at an affordable price. Similarly, more than 40,000 people per year benefited from various laboratory tests. A total of 11,099 patients were admitted in KFB hospital from January 2010 to December 2014. Of them, 2,409 (22%) were diagnosed as ESRD, and all of them were initially managed with dialysis either through a noncuffed catheter (82%) or by an AV fistula (8%); of the 388 continued on HD, 300 underwent transplantation, 289 agreed to shift to CAPD treatment, and rest of the patients were shifted to other HD centers. Simultaneously, a total of 3,600 patients were screened in rural, urban, and disadvantaged populations from 2004 to 2007 for detection of CKD. CONCLUSION: KFB is offering treatment for patients with kidney disease and kidney failure, not only at an affordable price, but also without compromising quality. PMID- 27469149 TI - The impact of kidney foundations in alleviating the burden of CKD in India - an example, Tamilnad Kidney Research Foundation. AB - Chronic kidney disease (CKD) is a major public health problem in India. The CKD registry of India has been formed to understand the epidemiology of CKD in India. Due to health economics in India, the majority of CKD-affected patients cannot afford renal replacement therapy (RRT) services. There is an unmet need to improve the awareness of kidney disease in India, and the focus should be on prevention and early detection of CKD by screening high risk populations. The Tamilnad Kidney Research (TANKER) Foundation is a charitable trust established in 1993 with the aim to improve awareness and provide quality affordable treatment to underprivileged patients. TANKER is supported by contributions from well wishers. It has three arms: i) treatment arm, ii) research arm, and iii) awareness and screening arm. TANKER Foundation offers free and subsidized dialysis twice weekly to 227 underprivileged patients. TANKER dialysis has been supported by state government funding schemes. TANKER actively supports and conducts research in nephrology. More than 100,000 people have benefitted from TANKER's kidney awareness programs. The screening programs have provided for early detection of CKD in both urban and rural areas. TANKER award functions are held annually to recognize research and exemplary service to society. The TANKER Foundation can be used as a model for developing countries to address the unmet needs in CKD management. PMID- 27469150 TI - Kidney transplantation in the Middle East. AB - AIMS: To delineate the kidney transplantation programs in the Middle East and to provide a comparative summary with other international datasets where deemed appropriate. PATIENTS AND METHODS: Data regarding kidney transplantation as the treatment of choice amongst renal replacement therapies in different countries in the Middle East was analyzed from 2004 to 2013. The number of kidney transplants and the source of kidneys were important topics of comparison. All data was collected from published reports and international registries. RESULTS: Eight of 23 countries in the Middle East had active kidney transplantation programs from both living and deceased donors in 2013. The kidney transplantation rate in 2013 was 11.5 per million population in the Middle East compared with 31.68 in America, 27.38 in Europe, 5.68 in the Western Pacific, 3.38 in South Asia, and 0.5 in Africa. The proportion of kidney transplants from deceased donors was 69.5%, 63.1%, 60.9%, 30.2%, 19.4%, and 6.2% in Europe, America, the Western Pacific, the Middle East, South Asia, and Africa, respectively. CONCLUSIONS: Public education on the subject of brain death and cadaveric organs as a reliable source of saving lives and provision of better infrastructure could increase the rate of kidney transplantation from brain-dead donors. Lack of funds and a negative attitudes towards organ donation are the main barriers in the Middle East. PMID- 27469151 TI - Clinical nephrology research in low-resource settings: opportunities, priorities, and challenges for young investigators. AB - The increased recognition of the growing, worldwide burden of kidney disease has led to calls for prioritizing nephrology research in a global context. However, many challenges exist for young investigators interested in studying kidney disease in low-resource global settings. A lack of clear research priorities, limited funding options, poor infrastructure, difficulty forming partnerships, and unestablished paths for career advancement are a few examples. To discuss these issues, we held a moderated panel discussion in March 2015 as part of the 10th Conference on Kidney Disease in Disadvantaged Populations in Cape Town, South Africa. A group of senior investigators discussed research priorities for studying kidney disease in a global context, collaborations for clinical research, and strategies for dealing with the unique challenges faced by young investigators working in this field. PMID- 27469152 TI - Promotion of kidney care in countries with limited resources: How does the National Kidney Foundation of South Africa fare? AB - INTRODUCTION: An often-quoted remark is to present problems as challenges, which invariably end up in the "in-box", eventually to be swept under the carpet. The chronic kidney disease burden in the South African black population poses a challenging crisis requiring immediate intervention even in a country with limited resources. Aims, materials, and methods: The National Kidney Foundation of South Africa (NKFSA) reports on 3 major projects. The schools project is aimed at prevention, early diagnosis, and appropriate management of chronic kidney disease (CKD) on a national basis. The second "urgency" is to educate primary healthcare workers (including doctors) about relevant kidney diseases and their treatment. The third illustrates the suboptimal number of dialysis facilities and the dismal number of kidney transplants performed in the public sector compared to treatment in the private sector. This accentuates the unacceptable two-tiered system in South Africa (SA). RESULTS: The NKFSA school survey showed that in black adolescent learners, hypertension was found in 12% of females and 16% of males (often associated with familial hypertension). An increase in body mass index (BMI) showed better correlation in hypertensive females than in males (p < 0.004). Of 4 obese females, 3 had newly diagnosed type II diabetes. Urine dipsticks showed 1 student with hematuria, 1 with overt proteinuria, and many with active urinary tract infections. The educational book will appear as continuing medical education (CME) articles in two issues of the South African Medical Journal. The prevalence of patients obtaining treatment for end-stage renal disease (ESRD) (2012) was 73 pmp in the public and 620 pmp in the private sector. Depending on the region, the mean number of live-related transplants pmp/year varied between 0.6 and 5.3 (average 2.2) in the public and 10 to 33 (average 20.4) in the private sector. Deceased donor (DD) transplants varied between 0.75 and 7.0 (average 3.5) pmp/year in the public and 5.2 to 24.0 (average 17.1) in the private sector. CONCLUSIONS: The schools project has demonstrated that early prevalence of hypertension in the black population validates the need for an extensive, nationwide study, which should result in prevention and early diagnosis of hypertension thus reducing progression to renal failure. We hope to enhance the education, of both public and medical personnel, on the major problems of CKD in SA through the CME articles. The huge disparity in the treatment of ESRD between the public and private sectors as well as a marked variation in regional treatment needs urgent attention. Because living donor transplants in the black population remains very limited, novel methods of obtaining more DD organs must be formulated. PMID- 27469153 TI - Nephrology in Africa - challenges of practice in resource-limited environment. AB - Chronic kidney disease (CKD), a major public health problem, is especially challenging for patients and healthcare personnel in Africa, a region with poor economic resources and a massive shortage of health-care workers. The burden of kidney disease is increased in poorly-resourced regions due to increased exposure to infections, poverty, poor access to healthcare, and genetic predisposition to kidney disease, contributing further to the problems when managing CKD and acute kidney injury. The vast majority of patients do not have access to renal replacement therapy. Urgent attention to cost of dialysis is required for wider expansion of services so that renal replacement therapy is affordable for the governments and populations of Africa. Priority needs to be given to prevention and treatment of acute kidney injury. Lack of resources has hampered the widespread utilization of prevention strategies; these are optimally delivered in a primary healthcare setting by doctors, nurses, and other healthcare workers with access to protocols for screening, disease management, achievement of treatment goals (with availability of therapy to retard progression), and criteria for referral to specialist and nephrology expertise. A regional or national renal registry is an important initiative to obtain accurate data on the burden of disease and outcomes of therapeutic interventions. PMID- 27469154 TI - Prevalence and incidence of renal disease in disadvantaged communities in Europe. AB - Despite well-established, publicly-funded national health systems, kidney disease inequalities exist in Europe. There are differences between countries in rates of treated end-stage renal disease, at least some of which appears explained by organizational and economic factors. Pooling of chronic kidney disease (CKD) prevalence data is allowing new like-for-like comparisons between countries, which suggest that there are also differences in underlying rates of kidney disease. The few studies that exist suggest a paradoxically lower rate of earlier stages of kidney disease in ethnic minority groups, which have long been known to have higher rates of end-stage disease. Once on renal replacement therapy, children of South Asian and Black origin are now being reported to have lower rates of survival and lower chances of receiving a kidney transplant. New challenges are reportedly being faced by renal services with immigrants arriving in Europe requiring immediate dialysis with limited ability to communicate with clinical staff and increased infection risk. And data are at last emerging on the risk of chronic kidney disease in Europe's biggest minority, disadvantaged population, the Roma. A public health approach to address these issues requires, as a first step, the extent of the problem to be measured. PMID- 27469155 TI - Chronic kidney disease and end-stage renal disease in disadvantaged communities of North America: an investigational challenge to limit disease progression and cardiovascular risk. AB - Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are growing public health issues associated with significant morbidity and mortality around the world. In the United States, Black and Hispanic minorities suffer higher rates of CKD and ESRD, mostly attributed to Diabetic Kidney Disease (DKD). DKD is the leading cause of both CKD and ESRD in the developed world and disproportionately affects minority populations such as African Americans, Hispanic Americans, and Aboriginal Americans in comparison with Whites. This review will discuss the incidence, prevalence, and etiology of renal disease in disadvantaged minorities in the U.S. and will take a closer look at diabetic kidney disease as it is the primary cause of kidney disease in these populations. PMID- 27469156 TI - Chronic kidney disease of uncertain etiology in Sri Lanka is a possible sequel of interstitial nephritis! AB - INTRODUCTION: The majority of published data on chronic kidney disease of uncertain etiology (CKDu) is on asymptomatic patients who were detected in screening programs. The clinicopathological profile of a group of patients presenting with acute symptoms and renal dysfunction from CKDu endemic regions in Sri Lanka was studied. METHODS: 59 patients > 10 years of age with backache, feverish fatigue feeling, dysuria, joint pain, or dyspepsia, singly or in combination with elevated serum creatinine (> 116 and > 98 umol/L for male and females, respectively) were included in the study. Those patients who had normal sized kidneys were biopsied after excluding clinically detectable causes for renal dysfunction. Histology was scored with activity and chronicity indices. These patients' urinary sediment and inflammatory markers were checked. Patients were stratified into three groups based on duration of symptom onset to the time of biopsy. The natural course of the disease was described using serial mean serum creatinine and histological activity as well as chronicity indices in these 3 groups. RESULTS: These patients' mean age, occupation, and sex ratio were 44 (9) years, 57 farmers, and male : female 55 : 4, respectively. Mean serum creatinine at biopsy was 143.8 (47.9) umol/L. Elevated inflammatory markers and active urine sediment were reported. Histology was compatible with an interstitial nephritis with a mixture of acute and chronic tubulointerstitial lesions and glomerular scarring. In the natural course of an acute episode of CKDu, serum creatinine and histological activity were reduced while histological chronicity increased. CONCLUSION: CKDu may be preceded by an acute episode of tubulointerstitial nephritis (TIN). PMID- 27469157 TI - HIV-associated renal disease - an overview. AB - The cause of the human immunodeficiency virus (HIV) epidemic in South Africa (SA) was worsened by the denial by key political players that HIV causes acquired immunodeficiency syndrome (AIDS). South Africa continues to have the highest rate of HIV world-wide, which has had a huge impact on the development of both chronic kidney disease and acute kidney injury. Fortunately, there is now an effective antiretroviral therapy (ART) roll-out program. SA is also dealing with a collision of epidemics of HIV, tuberculosis, and non-communicable disease, particularly hypertension and diabetes. This has been evidenced by recent data seen in the reinstated SA renal registry. There is also an unacceptably high rate of tuberculosis in regions of SA, this has led to high rates of granulomatous interstitial nephritis (GIN) and case reports of TB-GIN immune reconstitution inflammatory syndrome (IRIS). HIV-associated nephropathy (HIVAN) remains common in SA and responds well to ART. The definitive diagnosis requires a renal biopsy, which is often not possible in many regions of sub-Saharan Africa. Unfortunately, there is still a high rate of HIVAN in SA due to late presentation and lack of effective screening for renal disease in HIV-positive patients. Transplantation for HIV-positive donors to positive recipients offers a unique and encouraging way forward for these patients. PMID- 27469158 TI - Overview of dialysis in indigenous compared to nonindigenous Australians. AB - INTRODUCTION: Indigenous Australians (Aboriginal and Torres Strait Islanders, ATSI) make up 3% of the total Australian population [1] and comprised ~ 10% of new patients beginning renal replacement for end-stage kidney disease (ESKD) in Australia during 2013 [2]. In this study, we examined the differences in characteristics, incidence, and prevalence of different modalities of dialysis and survival between indigenous and nonindigenous Australians. METHODS: We examined outcomes of all adults (aged >= 18 years at the start of renal replacement therapy (RRT)) in the ANZDATA registry who started RRT from 1st Jan 2003 to 31st Dec 2013 in Australia. Adjusted patient survival on dialysis was calculated using standard techniques. RESULTS: A total of 25,528 participants were included, of whom 2,447 (9.5%) were indigenous Australians. Use of facility hemodialysis was more common among indigenous people, odds ratio (OR) 1.79 (95% confidence interval (CI), 1.37, 2.35). Of several interactions between indigenous status and other comorbidities, the most clinically significant was one with diabetes. In fully adjusted models, compared to nonindigenous with diabetes; death risk was higher for indigenous people with diabetes, HR 1.15 (95% CI, 1.06, 1.25). There was no difference between the two groups without diabetes, HR 0.86 (95% CI, 0.73, 1.05). There was no variation in the risks associated with ethnicity over year of dialysis start. CONCLUSION: There are differences in adjusted outcomes of indigenous Australians compared to nonindigenous with ESKD. Interactions suggest that the influence of reported comorbidities may differ in this group. Further investigations will be valuable in closing the gap and improving health outcome of indigenous Australians on RRT. PMID- 27469159 TI - Community-acquired acute kidney injury in adults in Africa. AB - AIMS: We review recent published data on demographics, causes, diagnoses, treatment, and outcome of acute kidney injury (AKI) in Africa. METHODS: A review of the incidence, etiology, diagnoses, and treatment of AKI in adults in Africa from studies published between the years 2000 and 2015. RESULTS: The incidence of AKI in hospitalized patients in Africa ranges from 0.3 to 1.9% in adults. Between 70 and 90% of cases of AKI are community acquired. Most patients with AKI are young with a weighted mean age of 41.3 standard deviation (SD) 9.3 years, and a male to female ratio of 1.2 : 1.0. Medical causes account for between 65 and 80% of causes of AKI. This is followed by obstetric causes in 5 - 27% of cases and surgical causes in 2 - 24% of cases. In the reported studies, between 17 and 94% of patients who needed dialysis received this. The mortality of AKI in adults in Africa ranged from 11.5 to 43.5%. CONCLUSIONS: Most reported cases of AKI in Africa originate in the community. The low incidence of hospital-acquired AKI is likely to be due to under ascertainment. Most patients with AKI in Africa are young and have a single precipitating cause. Prominent among these are infection, pregnancy complications and nephrotoxins. Early treatment can improve clinical outcomes. PMID- 27469160 TI - Nephrology training curriculum and implications for optimal kidney care in the developing world. AB - An effective workforce is essential for delivery of high-quality chronic disease care. Low-income nations are challenged by a dearth and/or maldistribution of an essential workforce required for all chronic disease care including chronic kidney disease (CKD). Nephrology education and training in developed countries have grown at pace with the technological advancement in the practice of medicine in order to meet the standards required of kidney health professionals towards high-quality, patient-centered medical care. The standards designed by institutions and/or professional societies, such as Royal Colleges and Medical Councils in high-income nations with well-developed health systems and infrastructures, are often not easily translatable to issues critical to nephrology practice in low-income nations. Little or no guidance is provided on common nephrological issues of regional nature or pertaining to ethnic minorities and disadvantaged groups living in those countries. There is an emergent need for a training curriculum that meets the needs and peculiarities of the developing nations, and this needs to leverage on the existing and well-validated systems of training across the globe. We evaluated nephrology training programs across 25 upper-middle and high-income nations to identify best practices and opportunities for adoption in low-income nations. We reviewed training guidelines from major professional societies on content and process of training. There are similarities and differences in structure, content, and process of training programs across countries, and there are clearly adoptable concepts/frameworks for application in low-income nations. We provide recommendations and a strategic plan for the future focus of nephrology training in the developing world to align with current trends in technological advancement and development as well as the need for emphasis on prevention of CKD. The essential competencies (patient- and population--based) required of a nephrologist in a developing world setting are outlined with practical measures and an action plan for adoption. PMID- 27469161 TI - Success stories showing the diversity of kidney foundations: Turkish Kidney Foundation. AB - Founded in 1985, the Turkish Kidney Foundation serves the society with 3 dialysis centers and a 113-bed general hospital. Interacting with public authorities and advocating end-stage renal disease (ESRD) patients' rights are essential services of this non-governmental organization (NGO). Over the last 30 years, keeping with the trend of chronic kidney disease (CKD) in the country, the foundation raised awareness in the population for this condition and prepared an activity road map by using statistical facts and data. Goals were set keeping in mind the local culture and traditions, debating on them with colleagues, PR agencies, and other experts in this field. The best strategy embrace the society, and all activities are made as cost-effective as possible in keeping with a tight budget. Various communication channels, especially social media, are used to communicate the message to the public, always keeping in mind that such messages are to be succinct and precise. Every effort is taken to make our foundation reliable and trustworthy in the eyes of the public at large. Reliability, credibility, and trust are the key success corner stones of our NGO. Every opportunity is taken to capitalize on participation of celebrities and real stories of people. Testimonies of real ESRD patients are always interesting and can touch the hearts of the rest of the population. PMID- 27469162 TI - Bipolar Electrochemistry for Concurrently Evaluating the Stability of Anode and Cathode Electrocatalysts and the Overall Cell Performance during Long-Term Water Electrolysis. AB - Electrochemical efficiency and stability are among the most important characteristics of electrocatalysts. These parameters are usually evaluated separately for the anodic and cathodic half-cell reactions in a three-electrode system or by measuring the overall cell voltage between the anode and cathode as a function of current or time. Here, we demonstrate how bipolar electrochemistry can be exploited to evaluate the efficiency of electrocatalysts for full electrochemical water splitting while simultaneously and independently monitoring the individual performance and stability of the half-cell electrocatalysts. Using a closed bipolar electrochemistry setup, all important parameters such as overvoltage, half-cell potential, and catalyst stability can be derived from a single galvanostatic experiment. In the proposed experiment, none of the half reactions is limiting on the other, making it possible to precisely monitor the contribution of the individual half-cell reactions on the durability of the cell performance. The proposed approach was successfully employed to investigate the long-term performance of a bifunctional water splitting catalyst, specifically amorphous cobalt boride (Co2B), and the durability of the electrocatalyst at the anode and cathode during water electrolysis. Additionally, by periodically alternating the polarization applied to the bipolar electrode (BE) modified with a bifunctional oxygen electrocatalyst, it was possible to explicitly follow the contributions of the oxygen reduction (ORR) and the oxygen evolution (OER) half reactions on the overall long-term durability of the bifunctional OER/ORR electrocatalyst. PMID- 27469163 TI - Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice. AB - Human neocortical 15-29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting <150 ms with a stereotypical waveform. Computational modeling uniquely designed to infer the electrical currents underlying these signals showed that beta events could emerge from the integration of nearly synchronous bursts of excitatory synaptic drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (~50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function. PMID- 27469164 TI - Structure and genome release of Twort-like Myoviridae phage with a double-layered baseplate. AB - Bacteriophages from the family Myoviridae use double-layered contractile tails to infect bacteria. Contraction of the tail sheath enables the tail tube to penetrate through the bacterial cell wall and serve as a channel for the transport of the phage genome into the cytoplasm. However, the mechanisms controlling the tail contraction and genome release of phages with "double layered" baseplates were unknown. We used cryo-electron microscopy to show that the binding of the Twort-like phage phi812 to the Staphylococcus aureus cell wall requires a 210 degrees rotation of the heterohexameric receptor-binding and tripod protein complexes within its baseplate about an axis perpendicular to the sixfold axis of the tail. This rotation reorients the receptor-binding proteins to point away from the phage head, and also results in disruption of the interaction of the tripod proteins with the tail sheath, hence triggering its contraction. However, the tail sheath contraction of Myoviridae phages is not sufficient to induce genome ejection. We show that the end of the phi812 double stranded DNA genome is bound to one protein subunit from a connector complex that also forms an interface between the phage head and tail. The tail sheath contraction induces conformational changes of the neck and connector that result in disruption of the DNA binding. The genome penetrates into the neck, but is stopped at a bottleneck before the tail tube. A subsequent structural change of the tail tube induced by its interaction with the S. aureus cell is required for the genome's release. PMID- 27469165 TI - Atomic-resolution structure of a disease-relevant Abeta(1-42) amyloid fibril. AB - Amyloid-beta (Abeta) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Abeta(1-40) and Abeta(1-42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Abeta(1-42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer's disease (AD) patients. Although small Abeta oligomers are believed to be the neurotoxic species, Abeta amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Abeta(1-42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15-42 forming a double-horseshoe-like cross-beta-sheet entity with maximally buried hydrophobic side chains. Residues 1-14 are partially ordered and in a beta-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure. PMID- 27469167 TI - The role of laparoscopic sleeve gastrectomy as a treatment for morbid obesity; review of outcomes. AB - BACKGROUND: Global prevalence of obesity has soared. Where lifestyle and medical treatments have failed, laparoscopic sleeve gastrectomy (LSG) is increasingly regarded as a good surgical procedure for morbid obesity. Following the introduction of LSG, we assessed our surgical outcomes. METHODS: We reviewed a consecutive series of LSGs from January 2009 to January 2015. Our primary focus was to assess the success of this procedure on the percentage excess body weight loss (%EWL), Body Mass Index (BMI), hypertension and diabetes. Additionally, we evaluated the rate of procedure-related complications. RESULTS: There were 183 consecutive patients evaluated. Median age was 45 years (24-73). The majority were female (73.2 %, n = 134). At 1 year post-op, median %EWL was 57.6 %. There was an associated median reduction in BMI of 16 kg/m2 (0-33). At 2 years, median %EWL was sustained at 58.4 %. The median reduction in BMI was 16 kg/m2 (4-32). At 2-year post-op, 78.9 % of diabetic patients had their diabetic medications completely discontinued, while a further 15.8 % having their medication reduced. 34.6 % of hypertensive patients had their antihypertensives discontinued, with 50 % having medications reduced. There was no procedure related mortality. 3.3 % (n = 6) of patients had a confirmed staple-line leak. CONCLUSION: This study shows LSG is a safe and successful management strategy for morbid obesity. In addition to the direct effects of sustained weight loss, it highlights indirect effects that LSG has on obesity-related health issues, with substantial reduction in diabetic and anti-hypertensive medications. Our results reaffirm international studies of the beneficial effects of LSG on Type II diabetes and hypertension. PMID- 27469166 TI - FAR-RED ELONGATED HYPOCOTYL3 activates SEPALLATA2 but inhibits CLAVATA3 to regulate meristem determinacy and maintenance in Arabidopsis. AB - Plant meristems are responsible for the generation of all plant tissues and organs. Here we show that the transcription factor (TF) FAR-RED ELONGATED HYPOCOTYL3 (FHY3) plays an important role in both floral meristem (FM) determinacy and shoot apical meristem maintenance in Arabidopsis, in addition to its well-known multifaceted roles in plant growth and development during the vegetative stage. Through genetic analyses, we show that WUSCHEL (WUS) and CLAVATA3 (CLV3), two central players in the establishment and maintenance of meristems, are epistatic to FHY3 Using genome-wide ChIP-seq and RNA-seq data, we identify hundreds of FHY3 target genes in flowers and find that FHY3 mainly acts as a transcriptional repressor in flower development, in contrast to its transcriptional activator role in seedlings. Binding motif-enrichment analyses indicate that FHY3 may coregulate flower development with three flower-specific MADS-domain TFs and four basic helix-loop-helix TFs that are involved in photomorphogenesis. We further demonstrate that CLV3, SEPALLATA1 (SEP1), and SEP2 are FHY3 target genes. In shoot apical meristem, FHY3 directly represses CLV3, which consequently regulates WUS to maintain the stem cell pool. Intriguingly, CLV3 expression did not change significantly in fhy3 and phytochrome B mutants before and after light treatment, indicating that FHY3 and phytochrome B are involved in light-regulated meristem activity. In FM, FHY3 directly represses CLV3, but activates SEP2, to ultimately promote FM determinacy. Taken together, our results reveal insights into the mechanisms of meristem maintenance and determinacy, and illustrate how the roles of a single TF may vary in different organs and developmental stages. PMID- 27469168 TI - Mismatch between cuticle deposition and area expansion in fruit skins allows potentially catastrophic buildup of elastic strain. AB - MAIN CONCLUSION: The continuous deposition of cutin and wax during leaf and fruit growth is crucial to alleviate elastic strain of the cuticle, minimize the risk of failure and maintain its barrier functions. The cuticular membrane (CM) is a lipoidal biopolymer that covers primary surfaces of terrestrial plants. CMs have barrier functions in water and solute transfer and pathogen invasion. These require intact CMs throughout growth. This is a challenge particularly for fruit, because they increase in area from initiation through to maturity. Our paper investigates the effects of cutin and wax deposition on strain buildup in the CM. We use developing fruits and leaves of apple (Malus * domestica) and sweet cherry (Prunus avium) as models. The hypothesis was that the continuous deposition of the CM prevents the buildup of excessive elastic strain in fruit and leaves. Strains were quantified from decreases in surface area of CMs after isolation from epidermal discs, after wax extraction and from increases in surface area during development. Cuticle mass per unit area increased throughout development in apple fruit, and leaves of apple and sweet cherry. In sweet cherry fruit, however, CM mass increased only initially, but thereafter decreased as the surface expanded rapidly. The release of strain on CM isolation was low in apple fruit and leaves and sweet cherry leaves, but high in sweet cherry fruit. Conversely, strains fixed by the deposition of wax and cutin were high in apple fruit and leaves and sweet cherry leaves, but low in sweet cherry fruit. Our results indicate that in expanding organs, deposition of cutin and wax in the CM allows conversion of elastic to plastic strain. Hence, any lack of such deposition allows buildup of high, potentially catastrophic, elastic strain. PMID- 27469170 TI - Maternal-Foetal Diabetes Modifies Neonatal Fc Receptor Expression on Human Leucocytes. AB - This study investigated the expression of the neonatal Fc receptor (FcRn) in maternal blood, cord blood and placental cells and determined IgG levels in maternal blood and cord blood from diabetic mothers. Peripheral blood, cord blood and placenta samples were collected from 26 mothers with normoglycaemia (non diabetic, ND group) and 52 with hyperglycaemia (26 with mild gestational hyperglycaemia, MGH group, and 26 with type 2 diabetes mellitus, DM-2 group). Cells expressing CD19(+) and FcRn were identified by flow cytometry. Total IgG and its subclasses were quantified by ELISA. Maternal blood from DM-2 and cord blood from MGH exhibited a higher proportion of CD19(+) expression by B cells. DM 2 showed a lower proportion of CD19(+) cells in placenta. FcRn expression increased in cells from cord blood and placenta from MGH. Maternal blood, cord blood and placenta cells from DM-2 showed lower FcRn expression. Blood IgG levels were lower in DM-2, and cord blood IgG levels were higher in MGH. The highest levels of IgG4 were detected in the blood of hyperglycaemic mothers. The highest IgG3 and IgG4 levels in cord blood were detected in MGH, and the lowest IgG2 and IgG3 levels in DM-2. Maternal hyperglycaemia compromised placental transfer of IgG1, IgG3 and IgG4. The results suggest that regardless of hyperglycaemia degree, it decreases FcRn expression in placenta and blood cells and compromises the production and transfer of antibodies from maternal blood to newborns. PMID- 27469171 TI - Impact of implant-abutment connection on osteoimmunological and microbiological parameters in short implants: a randomized controlled clinical trial. AB - OBJECTIVES: The study aimed to determine the levels of soluble receptor activator of nuclear factor-kB ligand (sRANKL) and osteoprotegerin (OPG) as well as their relative calculated ratio in peri-implant crevicular fluid (PICF) obtained around two different types of implant-abutment connection on short implants following a 12-month monitoring period. Moreover, the levels of a number of oral bacterial species were investigated in the corresponding submucosal biofilm samples. MATERIALS AND METHODS: Thirty short implants were randomly placed in posterior maxillary edentulous sites using a split-mouth design in 15 periodontally healthy subjects. Tapered interference fit (TIF) and taper-integrated screwed-in (TIS) types of implant-abutment connections were selected for investigation. PICF and submucosal biofilm samples were collected 1 month after surgery and repeated 12 months after prosthetic loading. Clinical parameters, including probing depth, dichotomous presence of bleeding on probing, and plaque index, were recorded and digital periapical radiographs were taken at each time point. sRANKL and OPG levels in PICF were analyzed using an enzyme-linked immunosorbent assay. Total bacterial levels, as well as levels of Fusobacterium nucleatum, Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Prevotella intermedia, and Streptococcus oralis, were analyzed in the corresponding submucosal biofilm samples using quantitative real-time polymerase chain reaction. RESULTS: The total amount of sRANKL in TIF implants was 2.64-fold lower than that in TIS implants at baseline (P < 0.001), whereas similar levels were found after 12 months (P > 0.05). Accordingly, OPG and RANKL/OPG ratio were similar between the groups at each time point (P > 0.05). Microbiological results were similar in both groups at each time point (P > 0.05). CONCLUSION: The results of this longitudinal study suggested that sRANKL and OPG in PICF, as well as microbiological parameters in submucosal biofilms, were similar between TIF and TIS implants, after a 12-month monitoring period, despite early differences in the former. Therefore, the type of implant-abutment connection does not appear to influence longitudinally the levels of osteoimmunological and microbiological markers in the peri-implant tissues of short implants. PMID- 27469172 TI - Topotactic synthesis of the overlooked multilayer silicene intercalation compound SrSi2. AB - Silicene, a 2D honeycomb lattice of Si atoms similar to graphene, is expected to be a platform for nanoelectronics and home to novel quantum phenomena. Unlike graphene, free-standing silicene is notoriously difficult to stabilize, while strong hybridization of silicene with substrates destroys its desirable properties. On the other hand, Dirac cones of silicene are effectively realized in a bulk - stoichiometric ionic multilayer silicene intercalation compound CaSi2. Besides, a number of new 2D silicene-based materials are synthesized employing CaSi2 as a precursor. However, the rather complex atomic structure of CaSi2 and fresh opportunities of physical and chemical breakthroughs drive the search for alternative compounds with silicene networks. Here, a new polymorph of SrSi2 is synthesized, enjoying both the structure of intercalated multilayer silicene and the simplest possible stacking of silicene sheets. The MBE-quality synthesis accomplished on Si(001) and Si(111) surfaces leads to epitaxial films of SrSi2 with orientation controlled by the substrate, as revealed by XRD, RHEED and electron microscopy studies. The structural SrSi2/Si relation is mirrored in the transport properties of the films. PMID- 27469173 TI - Effect of waist circumference on the association between serum 25-hydroxyvitamin D and serum lipids: results from the National Health and Nutrition Examination Survey 2001-2006. AB - OBJECTIVE: To examine the interaction between waist circumference (WC) and serum 25-hydroxyvitamin D (25(OH)D) level in their associations with serum lipids. DESIGN: Cross-sectional study. The associations of serum 25(OH)D with total cholesterol, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), LDL-C:HDL-C and TAG were examined using multiple linear regression. Effect modification by WC was assessed through cross-product interaction terms between 25(OH)D and WC categories (abdominal overweight, 80-<88 cm in females/94-<102 cm in males; abdominal obesity, >=88 cm in females/>=102 cm in males). SETTING: The US National Health and Nutrition Examination Survey waves 2001-2006. SUBJECTS: Non pregnant fasting participants (n 4342) aged >=20 years. RESULTS: Lower 25(OH)D levels were significantly associated with lower HDL-C levels as well as with higher LDL-C:HDL-C and TAG levels in abdominally obese participants, but not in abdominally overweight or normal-waist participants. In contrast, lower 25(OH)D levels were associated with lower levels of total cholesterol and LDL-C in abdominally overweight and normal-waist participants only, but this association was only partly significant. However, a significant difference in the association between 25(OH)D and the lipids according to WC category was found only for LDL C:HDL-C (P for interaction=0.02). CONCLUSIONS: Our results from this large, cross sectional sample suggest that the association between lower 25(OH)D levels and an unfavourable lipid profile is stronger in individuals with abdominal obesity than in those with abdominal overweight or a normal WC. PMID- 27469174 TI - Yeasts from sub-Antarctic region: biodiversity, enzymatic activities and their potential as oleaginous microorganisms. AB - Various microbial groups are well known to produce a range of extracellular enzymes and other secondary metabolites. However, the occurrence and importance of investment in such activities have received relatively limited attention in studies of Antarctic soil microbiota. Sixty-one yeasts strains were isolated from King George Island, Antarctica which were characterized physiologically and identified at the molecular level using the D1/D2 region of rDNA. Fifty-eight yeasts (belonging to the genera Cryptococcus, Leucosporidiella, Rhodotorula, Guehomyces, Candida, Metschnikowia and Debaryomyces) were screened for extracellular amylolytic, proteolytic, esterasic, pectinolytic, inulolytic xylanolytic and cellulolytic activities at low and moderate temperatures. Esterase activity was the most common enzymatic activity expressed by the yeast isolates regardless the assay temperature and inulinase was the second most common enzymatic activity. No cellulolytic activity was detected. One yeast identified as Guehomyces pullulans (8E) showed significant activity across six of seven enzymes types tested. Twenty-eight yeast isolates were classified as oleaginous, being the isolate 8E the strain that accumulated the highest levels of saponifiable lipids (42 %). PMID- 27469175 TI - CT enterography: Mannitol versus VoLumen. AB - INTRODUCTION: Several different neutral oral contrast agents have been trialled in magnetic resonance and CT enterography (CTE). In the Auckland region, Mannitol 2.5% and VoLumen are both used in CTE. This study compares the performance of these two neutral oral contrast agents in CTE. METHODS: Computed tomography enterography data were collected from 25 consecutive studies that used either Mannitol or VoLumen in 2014. All images were reviewed by three radiologists blinded to the type of oral contrast. Each quadrant was assessed for maximum distension, proportion of bowel loops distended, presence of inhomogeneous content and bowel wall visibility. Assessment also included whether the contrast agent reached the caecum and an overall subjective quality assessment. Patients were invited to answer a questionnaire regarding tolerability of the preparations. RESULTS: Mannitol achieves better wall visibility in the right upper quadrant, left upper quadrant and left lower quadrant (P < 0.01). Overall differences in study quality favours Mannitol (P < 0.01) with 48% of the Mannitol studies being considered excellent compared with 4% of the VoLumen studies. There was no difference in maximal distension or proportion of loops distended. CONCLUSION: Mannitol in CTE achieves studies of a better quality than and is a viable alternative to VoLumen. PMID- 27469177 TI - Molecular Genetics of Cystic Fibrosis Transmembrane Conductance Regulator: Genotype and Phenotype. AB - The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene encodes an epithelial ion channel. Although one mutation remains the most common cause of CF (F508del), there have been more than 2000 reported variations in CFTR. For the most part, individuals who carry only one mutation (heterozygotes) have no symptoms; individuals who inherit deleterious mutations from both parents have CF. However, growing awareness of CFTR mutations that do not ever or do not always cause CF, and individuals with mild or single-organ system manifestations of CFTR-related disease have made this Mendelian relationship more complex. PMID- 27469176 TI - Background and Epidemiology. AB - Cystic fibrosis (CF) is the most common autosomal-recessive disease in white persons. Significant advances in therapies and outcomes have occurred for people with CF over the past 30 years. Many of these improvements have come about through the concerted efforts of the CF Foundation and international CF societies; networks of CF care centers; and the worldwide community of care providers, researchers, and patients and families. There are still hurdles to overcome to continue to improve the quality of life, reduce CF complications, prolong survival, and ultimately cure CF. This article reviews the epidemiology of CF, including trends in incidence and prevalence, clinical characteristics, common complications, and survival. PMID- 27469178 TI - Cystic Fibrosis Diagnosis and Newborn Screening. AB - The diagnosis of cystic fibrosis (CF) has evolved over the past decade as newborn screening has become universal in the United States and elsewhere. The heterogeneity of phenotypes associated with CF transmembrane conductance regulator (CFTR) dysfunction and mutations in the CFTR gene has become clearer, ranging from classic pancreatic-insufficient CF to manifestations in only 1 organ system to indeterminate diagnoses identified by newborn screening. The tools available for diagnosis have also expanded. This article reviews the newest diagnostic criteria for CF, newborn screening, prenatal screening and diagnosis, and indeterminate diagnoses in newborn-screened infants and symptomatic adults. PMID- 27469180 TI - Respiratory System Disease. AB - Respiratory system involvement in cystic fibrosis is the leading cause of morbidity and mortality. Defects in the cystic fibrosis transmembrane regulator (CFTR) gene throughout the sinopulmonary tract result in recurrent infections with a variety of organisms including Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, and nontuberculous mycobacteria. Lung disease occurs earlier in life than once thought and ideal methods of monitoring lung function, decline, or improvement with therapy are debated. Treatment of sinopulmonary disease may include physiotherapy, mucus-modifying and antiinflammatory agents, antimicrobials, and surgery. In the new era of personalized medicine, CFTR correctors and potentiators may change the course of disease. PMID- 27469179 TI - Cystic Fibrosis: Microbiology and Host Response. AB - The earliest descriptions of lung disease in people with cystic fibrosis (CF) showed the involvement of 3 interacting pathophysiologic elements in CF airways: mucus obstruction, inflammation, and infection. Over the past 7 decades, our understanding of CF respiratory microbiology and inflammation has evolved with the introduction of new treatments, increased longevity, and increasingly sophisticated laboratory techniques. This article reviews the current understanding of infection and inflammation and their roles in CF lung disease. It also discusses how this constantly evolving information is used to inform current therapeutic strategies, measures and predictors of disease severity, and research priorities. PMID- 27469181 TI - Nutrition and Growth in Cystic Fibrosis. AB - Close attention to nutrition and growth is essential in caring for children with cystic fibrosis (CF). Growth and nutritional status should be monitored as part of routine CF care. Children with CF should achieve growth and nutritional status comparable with that of well-nourished children without CF. Children with CF are at risk for nutritional deficiencies. Optimal nutritional and growth status may be difficult to attain in this population given risk of insufficient caloric intake and likelihood of increased caloric expenditure. Various methods to attain optimal nutritional status may be used, including oral supplementation, behavioral treatment, pharmacotherapy, and enteral nutrition. PMID- 27469182 TI - Gastrointestinal, Pancreatic, and Hepatobiliary Manifestations of Cystic Fibrosis. AB - Pulmonary disease is the primary cause of morbidity and mortality in people with cystic fibrosis (CF), but significant involvement within gastrointestinal, pancreatic, and hepatobiliary systems occurs as well. As in the airways, defects in CFTR alter epithelial surface fluid, mucus viscosity, and pH, increasing risk of stasis through the various hollow epithelial-lined structures of the gastrointestinal tract. This exerts secondary influences that are responsible for most gastrointestinal, pancreatic, and hepatobiliary manifestations of CF. Understanding these gastrointestinal morbidities of CF is essential in understanding and treating CF as a multisystem disease process and improving overall patient care. PMID- 27469184 TI - Transplantation. AB - Despite improvement in median life expectancy and overall health, some children with cystic fibrosis (CF) progress to end-stage lung or liver disease and become candidates for transplant. Transplants for children with CF hold the promise to extend and improve the quality of life, but barriers to successful long-term outcomes include shortage of suitable donor organs; potential complications from the surgical procedure and immunosuppressants; risk of rejection and infection; and the need for lifelong, strict adherence to a complex medical regimen. This article reviews the indications and complications of lung and liver transplantation in children with CF. PMID- 27469183 TI - Endocrine Disorders in Cystic Fibrosis. AB - Cystic fibrosis is frequently complicated by endocrine disorders. Diabetes can be expected to affect most with CF and pancreatic insufficiency and varies widely in age of onset, but early identification and treatment improve morbidity and mortality. Short stature can be exacerbated by relative delay of puberty and by use of inhaled corticosteroids. Bone disease in CF causes fragility fractures and should be assessed by monitoring bone mineral density and optimizing vitamin D status. Detecting and managing endocrine complications in CF can reduce morbidity and mortality in CF. These complications can be expected to become more common as the CF population ages. PMID- 27469185 TI - Psychosocial Challenges/Transition to Adulthood. AB - Advances in the health care of individuals with cystic fibrosis have resulted in more than half of the population older than the age of 18 living longer, fuller lives. This success brings about the need for new areas of improvement and development including the mastery of transitioning from pediatric to adult health care and attention to psychosocial needs. This article reviews key components of the process of transitioning to adult care and some important psychosocial considerations. PMID- 27469187 TI - Cystic Fibrosis. PMID- 27469186 TI - New Therapeutic Approaches to Modulate and Correct Cystic Fibrosis Transmembrane Conductance Regulator. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are clinically available personalized medicines approved for some individuals with cystic fibrosis (CF) to target the underlying defect of disease. This review summarizes strategies used to develop CFTR modulators as therapies that improve function and availability of CFTR protein. Lessons learned from dissemination of ivacaftor across the CF population responsive to this therapy and future approaches to predict and monitor treatment response of CFTR modulators are discussed. The goal remains to expand patient-centered and personalized therapy to all patients with CF, ultimately improving life expectancy and quality of life for this disease. PMID- 27469189 TI - Permanent culture and parasitic impact of the microalga Coccomyxa parasitica, isolated from horse mussel Modiolus kurilensis. AB - Animals with deformed shells and microalgal invasion have been identified in the natural population of the horse mussel species Modiolus kurilensis of Peter the Great Bay in the Sea of Japan. The haemolymph is initially infested with algae, followed by the rectum, siphons, mantles and gonads located in the posterior body areas. Mantles, which are primarily exposed to light, are major depots for algae. The microscopic analysis of algal cells has revealed the absence of flagella and pyrenoids, the presence of single chloroplast, and reproduction by autosporulation, with dispores prevailing over tetraspores. These results, together with the nearly complete sequence analysis of small subunit (SSU) 18S rDNA (1728bp), have confirmed that these cells are Coccomyxa parasitica. A newly developed method of isolating microalgae from mollusk tissues has facilitated the continuous pure - probably axenic - culture of C. parasitica, thereby providing a description of the time course of each life stage. Histological analyses have revealed significant haemocyte infiltration into the mantles, gonads, kidneys and digestive gland tissues infested with microalgae and the gill tissues, in which the intruder was not identified. Algal encapsulation with major focal areas of fibrosis and amorphic necrosis has been revealed in these infested organs. The spaces between the gonad follicles and digestive gland tubules were significantly widened as these areas were filled with a mass of algae and phagocytic haemocytes, showing acini with a thickened basement membrane. The mantles and kidneys of Modiolus displayed significant morphological deviations of different cells in epithelial, connective and muscle tissues, resulting in the dysfunction of the infested organs. Therefore, C. parasitica, which reproduces in the culture, regardless of the host, is a facultative parasite, causing major pathological alterations, such as anomalous histomorphological patterns and infested organ dysfunctions. PMID- 27469190 TI - Comment on "A Biochemical Evaluation on Inflammatory Markers after Ureteroscopic Lithotripsy". PMID- 27469191 TI - The Association Between Adolescent Obesity and Disability Incidence in Young Adulthood. AB - PURPOSE: To evaluate the longitudinal relationship between obesity during adolescence and development of disability during young adulthood. METHODS: A cohort of 8,032 individuals aged 11-21 years enrolled in 1994-1995 (Wave I) of the National Longitudinal Study of Adolescent to Adult Health, followed up in 1996 (Wave II) and in 2001-2002 (Wave III). Individuals were divided into four categories based on weight and height of Wave II and Wave III: (1) developing obesity; (2) persistent obesity; (3) no obesity; and (4) obesity reversal. Disability was measured in Wave III using a measure of functional limitations and the Short Form 36 physical functioning scale. Logistic regression was used to predict the probability of disability as a function of weight category. RESULTS: Compared with their nonobese peers, adolescents developing obesity (adjusted odds ratio: 1.83 [95% confidence interval: 1.51-2.22]) and with persistent obesity (adjusted odds ratio: 2.09 [95% confidence interval: 1.64-2.67]) had a higher odds of having a functional limitation in Wave III. CONCLUSIONS: Developing obesity and persistent obesity during adolescence were significantly associated with increased disability in young adulthood. PMID- 27469192 TI - Parent Perspectives About Sexual Minority Adolescent Participation in Research and Requirements of Parental Permission. AB - PURPOSE: Lesbian, gay, bisexual, transgender, and other sexual and gender minority (LGBTQ) adolescents and young adults experience health inequities relative to heterosexuals but may be reluctant to participate in research that requires guardian permission. Institutional review boards are often reluctant to approve studies without parental permission because of concerns about parent reactions. There is little to no data from the parent's perspective on these issues. We aimed to understand parent perspectives on parental permission requirements for minimal risk studies of LGBTQ health inequities. METHODS: We conducted semistructured interviews with 31 parents of LGBTQ individuals. We presented a vignette describing an HIV behavioral surveillance protocol and assessed beliefs about whether parental permission should be required under various conditions (i.e., varying adolescent demographics, study procedures). RESULTS: Most parents (74.2%) believed that parental permission should not be required, and this percent increased when considering adolescent participants for whom permission would be less feasible or potentially more dangerous (e.g., homeless adolescents). Qualitative analyses revealed that many parents were concerned about research quality and negative consequences for adolescents if permission was required. Others wanted to help support their child in making decisions about research and health care. CONCLUSIONS: Most parents believed that parental permission should not be required for a minimal risk study, and the reasons for their beliefs fell squarely in line with federal regulations regarding adolescent self-consent to research. Studies of LGBTQ adolescent health inequities should receive waivers of parental permission to obtain representative samples and minimize risk of harm to the adolescent. PMID- 27469193 TI - Far-infrared radiation protects viability in a cell model of Spinocerebellar Ataxia by preventing polyQ protein accumulation and improving mitochondrial function. AB - Far infrared radiation (FIR) is currently investigated as a potential therapeutic strategy in various diseases though the mechanism is unknown. Presently, we tested if FIR mediates beneficial effects in a cell model of the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3). SCA3 is caused by a mutation leading to an abnormal polyglutamine expansion (PolyQ) in ataxin-3 protein. The consequent aggregation of mutant ataxin-3 results in disruption of vital cell functions. In this study, neuroblastoma cells (SK-N-SH) was transduced to express either non-pathogenic ataxin-3-26Q or pathogenic ataxin-3-78Q proteins. The cells expressing ataxin-3-78Q demonstrated decreased viability, and increased sensitivity to metabolic stress in the presence rotenone, an inhibitor of mitochondrial respiration. FIR exposure was found to protect against these effects. Moreover, FIR improved mitochondrial respiratory function, which was significantly compromised in ataxin-3-78Q and ataxin-3-26Q expressing cells. This was accompanied by decreased levels of mitochondrial fragmentation in FIR treated cells, as observed by fluorescence microscopy and protein expression analysis. Finally, the expression profile LC3-II, Beclin-1 and p62 suggested that FIR prevent the autophagy inhibiting effects observed in ataxin-3-78Q expressing cells. In summary, our results suggest that FIR have rescuing effects in cells expressing mutated pathogenic ataxin-3, through recovery of mitochondrial function and autophagy. PMID- 27469194 TI - Comparison between corneal elevation maps using different reference surfaces with Scheimpflug-Placido topographer. AB - The purpose of this study was to compare the anterior and posterior elevation measurements using different reference surfaces (spheric, aspheric, and aspherotoric) with Scheimpflug-Placido topography in simple myopic and keratoconus patients. 600 eyes of 600 patients undergoing screening for keratorefractive surgery (500 simple myopic, 100 keratoconus stage 1 and 2) in Sohag refractive center, Egypt, were examined by Scheimpflug-Placido topography (Sirius, CSO, Italy) for both the anterior and posterior corneal elevation maps using the spheric, aspheric, and aspherotoric reference surfaces. 100 keratoconic eyes showed higher discriminating power using the aspherotoric reference surface in both the anterior and posterior elevation maps. The use of aspherotoric reference surface gives more data for eyes with keratoconus and its use is more informative in screening. PMID- 27469195 TI - Vascular rarefaction at the choriocapillaris in acute posterior multifocal placoid pigment epitheliopathy viewed on OCT angiography. AB - Few cases have been reported describing choroidal vasculature in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) using optical coherence tomography (OCT) angiography. We report choroidal vasculature changes in an APMPPE patient with the clinical course characterized by OCT angiography. A 39 year-old female was referred to us for bilateral multiple white spots in bilateral fundus. The best-corrected visual acuity was 20/20 in the right eye and 20/50 in the left eye. Multiple yellowish-white placoid lesions were observed in bilateral fundus, and fluorescein angiography showed a "block early, stain late" pattern at the placoid lesions characteristic of APMPPE. The placoid lesion represented vascular rarefaction at the choriocapillaris in the OCT angiography en face view. While the clinical course of symptoms and most of the low vascular rarefaction lesions regressed in 6 months, some new lesions were subclinically noted. Blurred vision recurred at 9 months from the first visit, and the vascular rarefaction lesions developed in different areas than those observed in the initial visit. Multiple yellowish-white placoid lesions in an APMPPE patient represented vascular rarefaction at the choriocapillaris in OCT angiography. The vascular rarefaction recovered and then recurred during the clinical course. OCT angiography can visualize changes of the choroidal vessels during APMPPE. PMID- 27469196 TI - Medicinal plant diversity and traditional healing practices in eastern Nepal. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The rich floral and ethnic composition of eastern Nepal and the widespread utilization of locally available medicinal plants offer remarkable opportunity for ethnomedicinal research. The present paper aims to explore medicinal plant diversity and use in the remote villages of eastern Nepal. It also aims to evaluate ethnopharmacological significance of the documented use reports and identify species of high indigenous priority. MATERIALS AND METHODS: The study was undertaken in four villages located in the Sankhuwasabha district in eastern Nepal. Ethnomedicinal information was collected through structured interviews. The homogeneity of informant's knowledge and the relative importance of documented medicinal plants were validated by informant consensus factor and use value, respectively. Species preference for treatment of particular diseases was evaluated through fidelity level. RESULTS: We reported medicinal properties of 48 species belonging to 33 families and 40 genera, for the treatment of 37 human ailments. The uses of 10 medicinal plants were previously undocumented. The informant consensus factor (FIC) ranged between 0.38 and 1 with about 50% of values greater than 0.80 and over 75% of values greater than 0.70, indicating moderate to high consensus among the informants on the use of medicinal plants in the region. Swertia chirayita was the most preferred species with significantly high use values, followed by Paris polyphylla and Neopicrorhiza scrophulariiflora. CONCLUSIONS: The remote villages in eastern Nepal possess rich floral and cultural diversity with strong consensus among informants on utilization of plants for local healthcare. The direct pharmacological evidence for medicinal properties of most species indicates high reliability of documented information. Careful and systematic screening of compounds isolated from these plants could possibly provide good opportunity for the discovery of novel medicines to treat life-threatening human diseases. We recommend prioritization of medicinal plants and reinforcement of existing cultivation practices for sustainable management of high-priority species. PMID- 27469197 TI - Screening of six Ayurvedic medicinal plants for anti-obesity potential: An investigation on bioactive constituents from Oroxylum indicum (L.) Kurz bark. AB - ETHNOPHARMACOLOGICAL RELEVANCE: As an effort to identify newer anti-obesity lead(s) we have selected 13 plant materials from the six plant species which have been reported in Indian Ayurvedic medicine as remedy against complications affecting glucose and lipid homeostasis. AIM OF THE STUDY: In vitro screening of six Indian Ayurvedic medicinal plants on anti-adipogenic and pancreatic lipase (PL) inhibition potential followed by bioactivity guided isolation from most active plant material. MATERIALS AND METHODS: In vitro anti-adipogenic assay using 3T3-L1 preadipocytes and pancreatic lipase (PL) inhibition assay were performed for hexanes, dichloromethane, ethyl acetate and methanolic extracts of all the plant materials. Bioactivity guided isolation approach was used to identify active constituent for anti-adipogenesis and PL inhibition assay. Inhibition of lipid accumulation and adipogenic transcription factor was measured by oil Red 'O' staining and quantitative real-time PCR method respectively. RESULTS: Ethyl acetate extract of Oroxylum indicum bark was found to be most active in screening of anti-adipogenesis (59.12+/-1.66% lipid accumulation as compared to control at 50MUg/mL dose) and PL inhibition (89.12+/-6.87% PL inhibition at 250MUg/mL dose) assays. Further, three bioactive flavonoids were isolated and identified as oroxylin A, chrysin and baicalein from O. indicum bark. Oroxylin A, chrysin, and baicalein were inhibited lipid accumulation in 3T3 L1 preadipocytes (75.00+/-5.76%, 70.21+/-4.23% and 77.21+/-5.49% lipid accumulation respectively in comparison to control at 50MUM dose) and PL enzyme (69.86+/-2.96%, 52.08+/-2.14% and 45.06+/-2.42% PL inhibition respectively at 250MUg/mL dose). In addition, oroxylin A and chrysin also inhibited PPARgamma and C/EBPalpha, major adipogenic transcription factors, in 3T3L-1 preadipocytes during adipogenesis process at 50MUM dose. CONCLUSION: The present study augurs the anti-obesity potential of well practiced Ayurvedic herb O. indicum and its flavonoids. PMID- 27469198 TI - Age dependent neuroprotective effects of medhya rasayana prepared from Clitoria ternatea Linn. in stress induced rat brain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Indian traditional medicinal system in Ayurveda suggests several preparations, known as medhya rasayanas, of diverse plant origin to enhance the health in general, reduce stress and improve brain function in particular during ageing. These effects in the context of contemporary knowledge and the underlying mechanisms are not clearly understood. Autophagy and DNA damage induced repair are inter-related quintessential pathways and are significantly altered during stress and ageing. Hence, medhya rasayana prepared from Clitoria ternatea (locally known as shankhpushpi) was used to test these effects in Wistar rat model of various age groups upon stereotaxic mediated kainic acid induced brain injury. MATERIALS AND METHODS: The rodent experiments were carried out in one, twelve and eighteen months old male Wistar rats. The rats were orally fed with medhya rasayana prepared from Clitoria ternatea (3g per kg body weight/day) for 60 days. Stereotaxic mediated kainate stress to the hippocampus was performed on day 61. The rats were sacrificed on 66th day and the brain tissues were analyzed histologically and measured for autophagy, base excision repair and antioxidant enzyme activities. In addition, cognitive functions were analyzed by employing novel object recognition task and Morris water maze tests. The gene expression profile of hippocampus was assessed by microarray hybridization and two genes are validated. RESULTS: Our study showed significant decrease of autophagy by medhya rasayana in both 12 and 18 months old rats. The hippocampal CA3 cellularity were increased in stereotaxic mediated stressed rats by medhya rasayana. There were no significant differences in constitutive base excision repair and antioxidant enzyme activities. Medhya rasayana treatment also significantly increased episodic memory in rats. Microarray experiments for pathway specific gene expression analysis showed altered expression of genes of long-term potentiation, axon guidance, neuroactive ligand-receptor interaction, regulation of autophagy, lysosome, homologous recombination and nucleotide excision repair pathways in adult rats by medhya rasayana. CONCLUSIONS: In the present study, we show that reduction in autophagy is crucial for medhya rasayana induced protection of rat hippocampal cells and that artificially enhanced autophagy protects the brain cell damage by maintaining the selective DNA damage repair pathway and removal of reactive oxygen species to inhibit apoptosis. These findings suggest autophagy directed pathways by medhya rasayana prepared from C. ternatea protects the brain cells from stress induced injury. PMID- 27469199 TI - Utilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest. METHODS: Fifteen plants were selected from the book 'Diagnosis and treatment of diseases in Ayurveda' by Vaidya Bhagwan Dash and Lalitesh Kashyap, based on their frequency of use in the formulations used for the treatment of six diseases with neuromuscular symptoms similar to botulism. Phytochemicals from these plants were screened using in silico, and in vitro methods. Structures of 570 reported phytochemicals from 14 plants were docked inside six reported BoNT/A light chain crystal structures using ensemble docking module in Maestro (Schrodinger, LLE). RESULTS: From the docking scores and structural diversity, nine compounds including acoric acid 1, three flavonoids, three coumarins derivatives, one kava lactone were selected and screened using an in vitro HPLC-based protease assay. The bioassay results showed that several compounds possess BoNT/A LC inhibition of 50-60% when compared to positive controls NSC 84094 and CB7967495 (80-95%). CONCLUSION: Further testing of the active compounds identified from Ayurvedic literature and structure-activity studies of acoric acid 1 using more sensitive bioassays is under way. The identification of acoric acid 1, a novel scaffold against BoNT/A, exemplifies the utility of Ayurvedic literature for the discovery of novel drug leads. PMID- 27469200 TI - Pharmacokinetics and comparative metabolic profiling of iridoid enriched fraction of Picrorhiza kurroa - An Ayurvedic Herb. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Picrosides I, II and apocynin are the main active principles present in the roots and rhizomes of Picrorhiza kurroa Royle ex. Benth (Kutki). Ethno-medicinally, the plant is used for the treatment of liver, upper respiratory tract disorders and dyspepsia, since long in Ayurveda. AIM OF THE STUDY: This study attempts to determine the pharmacokinetic profile of picrosides I, II and apocynin in rats after oral administration of iridoid enriched fraction (IRF) and to recognize the pattern of its metabolites as such in IRF and in plasma. MATERIALS AND METHODS: A simple, precise, specific and sensitive RP-HPLC method was developed for simultaneous quantification of picrosides I, II and apocynin in rat plasma and in plant extract. Acetonitrile (ACN) and water was used as a solvent system with a gradient elution for pharmacokinetic studies using HPLC-PDA (Flow rate: 1.0mL/min) and metabolic profiling through UPLC-MS (Flow rate: 0.5mL/min) in selected reaction monitoring. A comparative study was performed in order to recognize the pattern and fate of metabolites in rat plasma up to 24h after single oral administration of IRF. RESULTS: Developed method produced more than 85% recovery of the targeted metabolites in rat plasma. The content of picrosides I, II and apocynin in IRF were found 5.7%, 18.3% and 27.3% w/w, respectively. The mean plasma concentration versus time profiles of picroside I, II and apocynin resulted in peak plasma concentration (Cmax) 244.9, 104.6 and 504.2ng/mL with half-life (t1/2) 14, 8 and 6h, respectively. Other pharmacokinetic parameters such as time to reach Cmax (tmax), area under curve (AUC), absorption (ka) and elimination (ke) constant, volume of distribution (Vd) were also determined. Pattern recognition analysis showed fate of 18 metabolites in rat plasma up to 24h out of 26 present in IRF. CONCLUSION: The information gained from this study postulates the basic pharmacokinetic profiling of picroside I, II and apocynin as well as fate of other metabolites after oral administration of IRF, demonstrating scientific basis of its traditional use in Ayurveda. PMID- 27469201 TI - ALA-induced photodynamic effect on viability, apoptosis and secretion of S100 protein, secreted by colon cancer cells in vitro. AB - BACKGROUND: S100 protein is a proven prognostic factor in cancers. In colorectal cancers, its secretion correlates with clinical stage of the disease. Photodynamic therapy (PDT) is used as a supporting therapy in treatment of this particular cancer. The main aim of our study was to estimate the effect of photodynamic therapy with 5-aminolevulinic acid (ALA) in sublethal doses (ALA PDT) on the secretion of S100 protein by colon cancer cells. METHODS: Investigations were performed on two colon cancer cell lines. The SW480 cell line is a culture containing locally malignant cancer. The SW620 line is characterized by high metastatic activity. Each line was exposed to different concentrations of photosensitizer's precursor-ALA, and various level of light radiation. Afterwards, cell viability, using MTT and LDH assays and apoptosis of both lines was assessed. Then measurement of S100 protein concentration was performed using a 2-step enzyme immunoassay. RESULTS: After application of ALA PDT the S100 protein concentration was reduced by 27% in SW480 cell line and by 30% in SW620 cell line. At the same time there has been no increase in the concentration of S100 protein in cells exposed to the light alone. It was demonstrated that the more aggressive line SW620 releases higher levels of S100 proteins in comparison with the line SW480. CONCLUSION: The outcome of this study presented beneficial effect of ALA-PDT on persistent colon cancer cells. This therapy leads to decrease of S100 protein concentration in both colon cancer cell lines: SW480 and SW620. PMID- 27469202 TI - New Types of Planar Chiral [2.2]Paracyclophanes and Construction of One-Handed Double Helices. AB - New types of planar chiral (Rp )- and (Sp )-4,7,12,15-tetrasubstituted [2.2]paracyclophanes were synthesized from racemic 4,12 dihydroxy[2.2]paracyclophane as the starting compound. Regioselective dibromination and transformation afforded a series of planar chiral (Rp )- and (Sp )-4,7,12,15-tetrasubstituted [2.2]paracyclophanes, which can be used as chiral building blocks. In this study, left- and right-handed double helical structures were constructed via chemoselective Sonogashira-Hagihara coupling. The double helical compounds were excellent circularly polarized luminescence (CPL) emitters with large molar extinction coefficients, good photoluminescence quantum efficiencies, and large CPL dissymmetry factors. PMID- 27469203 TI - Opening to the otherwise: The discipline of listening and the necessity of free association for psychoanalytic praxis. AB - It is argued that only free-association methodically opens the discourse of self consciousness (the representations available to reflective awareness) to the voicing of the repressed. The method is key to Freud's originality and the sine qua non of any genuinely psychoanalytic process. Clinical procedures which do not prioritize a steadfast and ongoing commitment to this method (instead emphasizing either interpretative formulations, as decisive acts that appear to fix and finalize the meaning of a particular lived experience, or the vicissitudes of transference-countertransference in the immediate treatment situation) all too readily entrap the treatment, limiting its capacity to divulge the power of unconscious processes. Influenced by Laplanche, Freud's 1920 principles of lifefulness and deathfulness (the binding and unbinding of psychic energy in representations) facilitate an understanding of the unique significance of free associative discourse in opening the representational textuality of self consciousness to the voicing of that which is otherwise than representationality and reason. The 'otherwise' is intimated as the returning force of the repressed, as the 'unfathomable navel' of 'thing-presentations,' experienced and expressed within the text of awareness, yet not translatable into the law and order of its logical and rhetorical reflections. Free-associative discourse thus affects self consciousness in a way that is radically different from other creative procedures ('psychosynthetic' or integratively interpretive). In this respect, the status of free-associative praxis as necessary for a genuinely psychoanalytic process is justified. PMID- 27469205 TI - Art therapy for patients with depression: expert opinions on its main aspects for clinical practice. AB - BACKGROUND: Art therapy is based mainly on clinical experience and is rarely described and evaluated scientifically. There is a need for further exploration of its use in patients with depression. AIM: The aim of this study was to explore what experts consider to be the main aspects of art therapy in clinical practice for patients with depression. METHOD: Eighteen occupational therapists experienced and educated in art therapy participated. The experts answered three rounds of Delphi questionnaires and ranked their agreement with 74 assertions. Consensus was defined as 70% or higher. RESULTS: The experts agreed more on assertions about theoretical frames of reference than about clinical practice. The main aspects of art therapy were agreed to be the patients' opportunity to express themselves verbally and through making art. It was equally important that art tasks provided an opportunity to address depressive thoughts, feelings, life experiences, and physical symptoms. CONCLUSIONS: Experts in the field of art therapy considered that the main aspect of clinical practice in art therapy for patients with depression is that art themes should promote expression related to both to depression and personal history. PMID- 27469206 TI - Regarding "Endovascular Treatment of Very Small Intracranial Aneurysms: Meta Analysis". PMID- 27469207 TI - Reply. PMID- 27469204 TI - Protein phosphatase 1 abrogates IRF7-mediated type I IFN response in antiviral immunity. AB - Interferon (IFN) regulatory factor 7 (IRF7) plays a key role in the production of IFN-alpha in response to viral infection, and phosphorylation at IRF7 C-terminal serine sites is prelude to its function. However, phosphatases that negatively regulate IRF7 phosphorylation and activity have not been reported. In this study, we have identified a conserved protein phosphatase 1 (PP1)-binding motif in human and mouse IRF7 proteins, and shown that PP1 physically interacts with IRF7. Exogenous expression of PP1 subunits (PP1alpha, beta, or gamma) ablates IKKepsilon-stimulated IRF7 phosphorylation and dramatically attenuates IRF7 transcriptional activity. Inhibition of PP1 activity significantly increases IRF7 phosphorylation and IRF7-mediated IFN-alpha production in response to Newcastle disease virus (NDV) infection or Toll-like receptor 7 (TLR7) challenge, leading to impaired viral replication. In addition, IFN treatment, TLR challenges and viral infection induce PP1 expression. Our findings disclose for the first time a pivotal role for PP1 in impeding IRF7-mediated IFN-alpha production in host immune responses. PMID- 27469208 TI - Comparing Preliminary and Final Neuroradiology Reports: What Factors Determine the Differences? AB - BACKGROUND AND PURPOSE: Trainees' interpretations of neuroradiologic studies are finalized by faculty neuroradiologists. We aimed to identify the factors that determine the degree to which the preliminary reports are modified. MATERIALS AND METHODS: The character length of the preliminary and final reports and the percentage character change between the 2 reports were determined for neuroradiology reports composed during November 2012 to October 2013. Examination time, critical finding flag, missed critical finding flag, trainee level, faculty experience, imaging technique, and native-versus-non-native speaker status of the reader were collected. Multivariable linear regression models were used to evaluate the association between mean percentage character change and the various factors. RESULTS: Of 34,661 reports, 2322 (6.7%) were read by radiology residents year 1; 4429 (12.8%), by radiology residents year 2; 3663 (10.6%), by radiology residents year 3; 2249 (6.5%), by radiology residents year 4; and 21,998 (63.5%), by fellows. The overall mean percentage character change was 14.8% (range, 0% 701.8%; median, 6.6%). Mean percentage character change increased for a missed critical finding (+41.6%, P < .0001), critical finding flag (+1.8%, P < .001), MR imaging studies (+3.6%, P < .001), and non-native trainees (+4.2%, P = .018). Compared with radiology residents year 1, radiology residents year 2 (-5.4%, P = .002), radiology residents year 3 (-5.9%, P = .002), radiology residents year 4 ( 8.2%, P < .001), and fellows (-8.7%; P < .001) had a decreased mean percentage character change. Senior faculty had a lower mean percentage character change ( 6.88%, P < .001). Examination time and non-native faculty did not affect mean percentage character change. CONCLUSIONS: A missed critical finding, critical finding flag, MR imaging technique, trainee level, faculty experience level, and non-native-trainee status are associated with a higher degree of modification of a preliminary report. Understanding the factors that influence the extent of report revisions could improve the quality of report generation and trainee education. PMID- 27469209 TI - Relative ADC and Location Differ between Posterior Fossa Pilocytic Astrocytomas with and without Gangliocytic Differentiation. AB - BACKGROUND AND PURPOSE: Pilocytic astrocytomas, the most common posterior fossa tumors in children, are characterized by KIAA1549-BRAF fusions and shows excellent 5-year survival rates. Pilocytic astrocytoma with gangliocytic differentiation, a recently defined pilocytic astrocytoma variant that includes glial and neuronal elements similar to a ganglioglioma, may be distinguished from a classic ganglioglioma by molecular, radiologic, and histopathologic features. This study investigated whether imaging could distinguish posterior fossa pilocytic astrocytoma with and without gangliocytic differentiation. MATERIALS AND METHODS: Preoperative MRIs (+/- CTs) of 41 children (age range, 7 months to 15 years; mean age, 7.3 +/- 3.7 years; 58.5% male) with pilocytic astrocytoma with gangliocytic differentiation (n = 7) or pilocytic astrocytoma (n = 34) were evaluated; differences in tumor location, morphology, and minimum relative ADC between tumor types were compared (Wilcoxon rank sum test, Fisher exact test). Histopathology and BRAF fusion/mutation status were reviewed. Associations of progression-free survival with diagnosis, imaging features, and BRAF status were examined by Cox proportional hazards models. RESULTS: Pilocytic astrocytoma with gangliocytic differentiation appeared similar to pilocytic astrocytoma but had lower minimum relative ADC (mean, 1.01 +/- 0.17 compared with 2.01 +/- 0.38 for pilocytic astrocytoma; P = .0005) and was more commonly located within midline structures (P = .0034). BRAF status was similar for both groups. Non-total resection (hazard ratio, 52.64; P = .0002), pilocytic astrocytoma with gangliocytic differentiation diagnosis (hazard ratio, 4.66; P = .0104), and midline involvement (hazard ratio, 3.32; P = .0433) were associated with shorter progression-free survival. CONCLUSIONS: Minimum relative ADC and tumor location may be useful adjuncts to histopathology in differentiating pilocytic astrocytoma with gangliocytic differentiation from pilocytic astrocytoma. Shorter progression free survival in pilocytic astrocytoma with gangliocytic differentiation is likely due to a propensity for involvement of midline structures and poor resectability. PMID- 27469210 TI - Contralateral Hypoplastic Venous Draining Sinuses Are Associated with Elevated Intracranial Pressure in Unilateral Cerebral Sinovenous Thrombosis. AB - Variations in cerebral venous development can influence the ability to regulate drainage. In cerebral sinovenous thrombosis, these variations can be associated with elevated intracranial pressure. We present a series of pediatric patients with unilateral cerebral sinovenous thrombosis and investigate whether the contralateral venous sinus size increases the risk of developing elevated intracranial pressure. Patients diagnosed with a unilateral cerebral sinovenous thrombosis were identified by querying our institutional radiology data base. The difference in the occurrence of elevated intracranial pressure in patients with cerebral sinovenous thrombosis with and without hypoplastic venous sinuses was studied. Twelve cases of unilateral cerebral sinovenous thrombosis met the inclusion criteria and had sufficient images. Six patients had hypoplastic contralateral venous sinuses. The presence of hypoplastic contralateral venous sinus in the setting of thrombosis of a dominant sinus was associated with elevation of intracranial pressure (83% versus 0%, P = .015). Patients with cerebral sinovenous thrombosis and contralateral hypoplastic venous sinuses are at higher risk of developing elevated ICP and may benefit from screening with an ophthalmologic examination. PMID- 27469211 TI - Pediatric Patients Demonstrate Progressive T1-Weighted Hyperintensity in the Dentate Nucleus following Multiple Doses of Gadolinium-Based Contrast Agent. AB - BACKGROUND AND PURPOSE: While there have been recent reports of brain retention of gadolinium following gadolinium-based contrast agent administration in adults, a retrospective series of pediatric patients has not previously been reported, to our knowledge. We investigated the relationship between the number of prior gadolinium-based contrast agent doses and increasing T1 signal in the dentate nucleus on unenhanced T1-weighted MR imaging. We hypothesized that despite differences in pediatric physiology and the smaller gadolinium-based contrast agent doses that pediatric patients are typically administered based on weighted adjusted dosing, the pediatric brain would also demonstrate dose-dependent increasing T1 signal in the dentate nucleus. MATERIALS AND METHODS: We included children with multiple gadolinium-based contrast agent administrations at our institution. A blinded reader placed ROIs within the dentate nucleus and adjacent cerebellar white matter. To eliminate reader bias, we also performed automated ROI delineation of the dentate nucleus, cerebellar white matter, and pons. Dentate-to-cerebellar white matter and dentate-to pons ratios were compared with the number of gadolinium-based contrast agent administrations. RESULTS: During 20 years at our institution, 280 patients received at least 5 gadolinium-based contrast agent doses, with 1 patient receiving 38 doses. Sixteen patients met the inclusion/exclusion criteria for ROI analysis. Blinded reader dentate-to cerebellar white matter ratios were significantly associated with gadolinium based contrast agent doses (rs = 0.77, P = .001). The dentate-to-pons ratio and dentate-to-cerebellar white matter ratios based on automated ROI placement were also significantly correlated with gadolinium-based contrast agent doses (t = 4.98, P < .0001 and t = 2.73, P < .02, respectively). CONCLUSIONS: In pediatric patients, the number of prior gadolinium-based contrast agent doses is significantly correlated with progressive T1-weighted dentate hyperintensity. Definitive confirmation of gadolinium deposition requires tissue analysis. Any potential clinical sequelae of gadolinium retention in the developing brain are unknown. Given this uncertainty, we suggest taking a cautious stance, including the use, in pediatric patients, of higher stability, macrocyclic agents, which in both human and animal studies have been shown to be associated with lower levels of gadolinium deposition, and detailed documentation of dosing. Most important, a patient should not be deprived of a well-indicated contrasted MR examination. PMID- 27469213 TI - Variability of Cerebral Deep Venous System in Preterm and Term Neonates Evaluated on MR SWI Venography. AB - BACKGROUND AND PURPOSE: The anatomy of the deep venous system is characterized by a great variability that might play an important role in the pathogenesis of brain lesions in the preterm brain. The aim of this study was to compare the anatomy of cerebral subependymal veins evaluated on SWI venography in 3 groups of neonates with normal brain MR imaging (very preterm [gestational age <32 weeks], moderate-to-late preterm [gestational age >=32 to <=37 weeks], and term neonates [gestational age >37 weeks]) and to evaluate the influence of preterm birth on development of subependymal veins. MATERIALS AND METHODS: SWI venographies of 84 very preterm, 31 moderate-to-late preterm, and 50 term neonates were retrospectively evaluated. Subependymal vein anatomy was classified into 6 different patterns: type 1 represented the classic pattern and types 2-6 were considered anatomic variants. A chi2 test was used to evaluate differences between the distributions of subependymal vein patterns. RESULTS: A significant difference (P = .011) was noticed between the 6 patterns based on gestational age. Type 1 was more frequent in term neonates (68%) than in both very preterm (41.7%) and moderate-to-late preterm neonates (56.5%). Anatomic variants were more common in very preterm neonates (66%) than in both moderate-to-late preterm (41%) and term neonates (36%). Interhemispheric asymmetry was more frequent in very preterm (59.5%) and moderate-to-late preterm neonates (51.6%) than in term neonates (34%; P = .017). Sex and monozygotic twin birth did not significantly affect the frequency of subependymal vein patterns (P = .0962). CONCLUSIONS: The deep venous system of the neonatal brain shows a large spectrum of anatomic variants with higher variability of subependymal vein anatomy in preterm than term neonates, likely related to the influence of the preterm birth and epigenetic factors on subependymal vein development. PMID- 27469212 TI - Intracranial Vessel Wall MRI: Principles and Expert Consensus Recommendations of the American Society of Neuroradiology. AB - Intracranial vessel wall MR imaging is an adjunct to conventional angiographic imaging with CTA, MRA, or DSA. The technique has multiple potential uses in the context of ischemic stroke and intracranial hemorrhage. There remain gaps in our understanding of intracranial vessel wall MR imaging findings and research is ongoing, but the technique is already used on a clinical basis at many centers. This article, on behalf of the Vessel Wall Imaging Study Group of the American Society of Neuroradiology, provides expert consensus recommendations for current clinical practice. PMID- 27469214 TI - Reply. PMID- 27469215 TI - Embryologic Anatomic Variations: Challenges in Intra-Arterial Chemotherapy for Intraocular Retinoblastoma. PMID- 27469216 TI - Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome. AB - High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs (52%) at the initial time point analyzed, including 12 (25%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time point analyzed were associated with shorter time-to treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution has prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL. PMID- 27469217 TI - ATRX loss in glioneuronal tumors with neuropil-like islands indicates similarity to diffuse astrocytic tumors. AB - Glioneuronal tumor with neuropil-like islands (GTNI) is a rare, recently described neoplasm, whose pathogenesis has not been studied extensively. The role of ATRX mutations, a class-defining alteration in diffuse astrocytic neoplasms, has not been assessed in GTNIs previously. We therefore aimed to assess the status of ATRX, along with IDH1, 1p/19q and p53, in cases of GTNI in order to evaluate the molecular profile of these tumors. All cases of GTNI diagnosed at our Institute were retrieved and clinicopathological features were reviewed. Immunohistochemistry for ATRX, IDH1 and p53 was performed. We identified four cases of GTNI, majority of which occurred in young adults. Loss of ATRX immunoexpression, a surrogate marker for ATRX mutation, was seen in all four cases. All cases were immunopositive for p53, while IDH1 positivity was seen in all three cases assessed. 1p/19q codeletion was absent in the three cases analyzed. These results indicate that the molecular pathogenesis of GTNIs similar to that of diffuse astrocytic tumors. Further, the loss of ATRX expression is seen in both the glial as well as neuronal components, indicating that both arise from the same tumor stem/progenitor cell and that the latter may be a metaplastic change. Thus, loss of ATRX immunoexpression, shown for the first time in these tumors, along with immunopositivity for p53 and IDH1, indicates that these tumors are molecular astrocytomas, and their clinical behaviour is likely to recapitulate that of ATRX-mutant and IDH-mutant diffuse astrocytomas of the same grade. PMID- 27469218 TI - Octadecabacterponticola sp. nov., isolated from seawater. AB - A Gram-stain-negative, non-spore-forming, non-flagellated and coccoid, ovoid or rod-shaped bacterial strain, HDSW-34T, was isolated from seawater of Hwang-do on the Yellow Sea, South Korea, and subjected to a taxonomic study using a polyphasic approach. Strain HDSW-34T grew optimally at 30 degrees C, at pH 7.0 8.0 and in the presence of 1.0-2.0 % (w/v) NaCl. Neighbour-joining, maximum likelihood and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain HDSW-34Tclustered with the type strains of four species of the genus Octadecabacter, showing 96.7-97.6 % sequence similarity. Strain HDSW-34T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids detected in strain HDSW-34T were phosphatidylcholine, phosphatidylglycerol, one unidentified aminolipid and one unidentified lipid. The DNA G+C content of strain HDSW-34T was 62.0 mol% and its DNA-DNA relatedness values with Octadecabacterantarcticus CIP 106731T and Octadecabacterarcticus DSM 13978T were 11-18 %. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain HDSW-34T is separated from other recognized species of the genus Octadecabacter. On the basis of the data presented, strain HDSW-34T is considered to represent a novel species of the genus Octadecabacter, for which the name Octadecabacterponticola sp. nov. is proposed. The type strain is HDSW-34T (= KCTC 52250T=NBRC 112296T). PMID- 27469219 TI - Delivery of Nanoparticles for Treatment of Brain Tumor. AB - BACKGROUND: Malignant brain tumor is a highly challenging disease for diagnosis, treatment, and management. Cytotoxicity, distribution and the ability to cross blood brain barrier are some of the most significant issues for the chemotherapy of brain tumors. Nanotechnology has been widely exploited in drug delivery with great potential in improving the drug efficiency and efficacy. The advent of nanotechnology would greatly facilitate the early detection and treatment of brain tumors. This review will be primarily focused on current nano drug delivery system for brain cancer therapy. Meanwhile, the existing impediments for therapeutic nanomedicines and critical analysis of the different delivery nanoparticles are also discussed. METHODS: We systematically evaluated the major factors that impact the current nanomedicines for brain tumor therapy. Meanwhile, various nanoparticle-based formulations for brain cancer detection and therapy are evaluated. RESULTS: 124 papers were included in this review. From the analysis of the nanomaterials, seven major nanomaterials have been discussed regarding the functionality and current therapeutic significance. The review also explains in detail about the different types of nanomaterials and their functionalities. This shows that each of these nanomaterials has specialized functions for the treatment of various kinds of brain cancer. CONCLUSION: Nanomaterials provide a viable potential diagnosis mechanis. In the future, more research needs to be focused on developing a better diagnosis tool for detection of cancer on an urgent basis. Blood-brain barrier and cytotoxicity are some of the primary root causes for the impediment of treatment of cancer using nanoparticles. Therefore, different delivery systems should be exploited for the nanoparticles to surmount these issues. PMID- 27469221 TI - Association between clinical variables and mortality after parathyroidectomy in maintenance hemodialysis patients. AB - BACKGROUND: We investigated factors associated with all-cause mortality and cardiovascular disease (CVD)-associated mortality after parathyroidectomy (PTX) in patients on maintenance hemodialysis (HD). METHODS: Our study population consisted of 161 consecutive HD patients who underwent PTX before 2009 and 354 consecutive HD patients without PTX as controls from those visiting the Kaohsiung Chang Gung Memorial Hospital, Taiwan between 2009 and 2013. All-cause and CVD mortality with clinical variables were compared in PTX and non-PTX HD patients. RESULTS: PTX patients had significantly lower all-cause and CVD mortality than controls. Multivariate logistic regression analyses showed PTX patients had a lower odds ratio for all-cause mortality than those without (odds ratio = .35, 95% confidence interval = .16 to .74). Association analysis based on clinical variables revealed patients with higher hemoglobin, albumin, creatinine, and HD adequacy index-Kt/V levels had significantly decreased risk of all-cause mortality. CONCLUSIONS: PTX in HD patients reduces the risk of death. PMID- 27469222 TI - Remyelination researchers regroup after proof-of-concept setback in multiple sclerosis. PMID- 27469220 TI - Potential Use of Cyclodextrin Complexes for Enhanced Stability, Anti-inflammatory Efficacy, and Ocular Bioavailability of Loteprednol Etabonate. AB - Loteprednol etabonate (LE) is a soft corticosteroid that maintains therapeutic activity with much reduced adverse effects. Yet, its ocular bioavailability is hindered by its poor aqueous solubility. Early attempts of LE complexation with cyclodextrins (CDs) did not involve the study of the effects of various complexation methods on the characteristics of the complexes formed. Formulation of complexes into different delivery systems as well in vitro and in vivo assessments has not been accomplished in the earlier studies. In this study, complexation of LE with each of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and beta-cyclodextrin (beta-CD) by kneading, freeze drying, and co-precipitation was attempted. These complexes were incorporated into gels, drops, and ocuserts using hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), and sodium alginate (ALG). These formulae were examined with respect to drug content, pH, viscosity, in vitro release, and stability for 6 months. Kinetic analysis of release data was done. Selected formulations were assessed for their efficacy in the treatment of ocular allergic conjunctivitis and their ocular bioavailability in rabbits' eyes. All formulations exhibited accepted drug content, pH, and viscosity. The drug release was increased by complexation particularly with HP-beta-CD in the order of ocuserts >= drops > gels, being the highest for HPMC preparations that also exhibited the greatest stability and anti-inflammatory activity especially in case of LE-HP-beta-CD complexes. Ocuserts of co-precipitated LE-HP-beta-CD using HPMC (5% w/w) and Carbopol 934P (0.1% w/w) provided a significantly enhanced stability (p < 0.05), ocular anti-inflammatory efficacy (p < 0.05), and ocular bioavailability (p < 0.0001), to be represented as a potential ocular delivery system of LE. PMID- 27469223 TI - DNA vaccines against Zika virus speed into clinical trials. PMID- 27469224 TI - FDA approvals for the first 6 months of 2016. PMID- 27469225 TI - PARPs pick-up. PMID- 27469226 TI - Cancer model consortium debuts. PMID- 27469227 TI - Patent watch: Supreme Court decision impacts the strength of US patents. PMID- 27469228 TI - Jim O'Neill. PMID- 27469229 TI - Acute myeloid leukaemia drugs market. PMID- 27469230 TI - Cancer: Allosteric phosphatase inhibitor puts brake on cancer cells. PMID- 27469231 TI - Rare diseases: Bacterial peptide reverses Wilson disease. PMID- 27469232 TI - Cancer: Combination therapy for lung cancer. PMID- 27469233 TI - Breast cancer: FASN inhibitor increases survival. PMID- 27469234 TI - Autoimmune disease: Re-establishing immune tolerance. PMID- 27469235 TI - The role of retrieval mode and retrieval orientation in retrieval practice: insights from comparing recognition memory testing formats and restudying. AB - The effectiveness of retrieval practice for aiding long-term memory, referred to as the testing effect, has been widely demonstrated. However, the specific neurocognitive mechanisms underlying this phenomenon remain unclear. In the present study, we sought to explore the role of pre-retrieval processes at initial testing on later recognition performance by using event-related potentials (ERPs). Subjects studied two lists of words (Chinese characters) and then performed a recognition task or a source memory task, or restudied the word lists. At the end of the experiment, subjects received a final recognition test based on the remember-know paradigm. Behaviorally, initial testing (active retrieval) enhanced memory retention relative to restudying (passive retrieval). The retrieval mode at initial testing was indexed by more positive-going ERPs for unstudied items in the active-retrieval tasks than in passive retrieval from 300 to 900 ms. Follow-up analyses showed that the magnitude of the early ERP retrieval mode effect (300-500 ms) was predictive of the behavioral testing effect later on. In addition, the ERPs for correctly rejected new items during initial testing differed between the two active-retrieval tasks from 500 to 900 ms, and this ERP retrieval orientation effect predicted differential behavioral testing gains between the two active-retrieval conditions. Our findings confirm that initial testing promotes later retrieval relative to restudying, and they further suggest that adopting pre-retrieval processing in the forms of retrieval mode and retrieval orientation might contribute to these memory enhancements. PMID- 27469236 TI - The LD loop as an important structural element required for transmission of the allosteric signal in the HtrA (DegP) protease from Escherichia coli. AB - High-temperature requirement A (HtrA; DegP) from Escherichia coli, an important element of the extracytoplasmic protein quality-control system, is a member of the evolutionarily conserved family of serine proteases. The characteristic feature of this protein is its allosteric mode of activation. The regulatory loops, L3, L2, L1 and LD, play a crucial role in the transmission of the allosteric signal. Yet, the role of LD has not been fully elucidated. Therefore, we undertook a study to explain the role of the individual LD residues in inducing and maintaining the proteolytic activity of HtrA. We investigated the influence of amino acid substitutions located within the LD loop on the kinetics of a model substrate cleavage as well as on the dynamics of the oligomeric structure of HtrA. We found that the mutations that were expected to disturb the loop's structure and/or interactions with the remaining regulatory loops severely diminished the proteolytic activity of HtrA. The opposite effect, that is, increased activity, was observed for G174S substitution, which was predicted to strengthen the interactions mediated by LD. HtrAG174S protein had an equilibrium shifted toward the active enzyme and formed preferentially high-order oligomeric forms. PMID- 27469237 TI - Maternal anti-HBVs suppress the immune response of infants to hepatitis B vaccine. AB - It is still controversial whether maternal anti-HBV antibodies (anti-HBVs) affect the infants' immune response to hepatitis B virus (HBV) vaccination. This multicentre study aims to address this question. First, we determined whether the transplacental transfer of maternal anti-HBVs occurs by measuring the titres of 90 anti-HBVs-positive pregnant women and their newborns. The anti-HBVs-positive rates of newborns ranged from 89.7% to 100.0%, depending on the maternal anti HBVs titres. Secondly, we investigated the effects of maternal anti-HBVs on the immune response of infants to HBV vaccination. A total of 1063 mother-and-infant pairs were enrolled and divided into three groups with maternal anti-HBVs titres of <10 IU/L (negative - 37.9%), 10-499 and >=500 IU/L. The infants' anti-HBVs positive rate and titres were negatively correlated with maternal anti-HBVs titres: the anti-HBVs-positive rate of infants were 88.9% (360/405), 84.5% (381/451) and 77.3% (160/207) in mothers with low, intermediate and high antibody titres, respectively, P<.0001. Median titres of anti-HBVs (IU/L) among infants were 169.1, 141.0 and 79.4, respectively, P=.020. One hundred and sixty-two infants were negative for anti-HBVs after the standard vaccination, and 120 of 131 of these infants (91.6%) reached anti-HBVs positivity after the first "booster" dose. The maternal anti-HBVs titres did not significantly affect infant response to this booster. In summary, transplacental transfer of anti-HBVs occurs and high titres of maternal anti-HBVs may suppress the immune response of infants to the standard HBV vaccination. The current schedule of the 0, 1 and 6 month may not be the optimal choice of infants with anti-HBVs-positive mothers. PMID- 27469238 TI - Pharmacogenetics of tardive dyskinesia: an updated review of the literature. AB - Tardive dyskinesia (TD) is a serious and potentially irreversible side effect of long-term exposure to antipsychotic medication characterized by involuntary trunk, limb and orofacial muscle movements. Various mechanisms have been proposed for the etiopathophysiology of antipsychotic-induced TD in schizophrenia patients with genetic factors playing a prominent role. Earlier association studies have focused on polymorphisms in CYP2D6, dopamine-, serotonin-, GABA- and glutamate genes. This review highlights recent advances in the genetic investigation of TD. Recent promising findings were obtained with the HSPG2, DPP6, MTNR1A, SLC18A2, PIP5K2A and CNR1 genes. More research, including collection of well-characterized samples, enhancement of genome-wide strategies, gene-gene interaction and epigenetic analyses, is needed before genetic tests with clinical utility can be made available for TD. PMID- 27469240 TI - Increased Risk of Peptic Ulcers Following a Cholecystectomy for Gallstones. AB - This retrospective cohort study examined the relationship between a cholecystectomy and the subsequent risk of peptic ulcers using a population-based database. Data for this study were retrieved from the Taiwan Longitudinal Health Insurance Database 2005. This study included 5209 patients who had undergone a cholecystectomy for gallstones and 15,627 sex- and age-matched comparison patients. We individually tracked each patient for a 5-year period to identify those who subsequently received a diagnosis of peptic ulcers. We found that of the 20,836 sampled patients, 2033 patients (9.76%) received a diagnosis of peptic ulcers during the 5-year follow-up period: 674 from the study group (12.94% of the patients who underwent a cholecystectomy) and 1359 from the comparison group (8.70% of the comparison patients). The stratified Cox proportional hazard regressions showed that the adjusted hazard ratio (HR) for peptic ulcers during the 5-year follow-up period was 1.48 (95% CI = 1.34~1.64) for patients who underwent a cholecystectomy than comparison patients. Furthermore, the adjusted HRs of gastric ulcers and duodenal ulcers during the 5-year follow-up period were 1.70 and 1.71, respectively, for patients who underwent a cholecystectomy compared to comparison patients. This study demonstrated a relationship between a cholecystectomy and a subsequent diagnosis of peptic ulcers. PMID- 27469239 TI - The effects of lymph node status on predicting outcome in ER+ /HER2- tamoxifen treated breast cancer patients using gene signatures. AB - BACKGROUND: Lymph node (LN) status is the most important prognostic variable used to guide ER positive (+) breast cancer treatment. While a positive nodal status is traditionally associated with a poor prognosis, a subset of these patients respond well to treatment and achieve long-term survival. Several gene signatures have been established as a means of predicting outcome of breast cancer patients, but the development and indication for use of these assays varies. Here we compare the capacity of two approved gene signatures and a third novel signature to predict outcome in distinct LN negative (-) and LN+ populations. We also examine biological differences between tumours associated with LN- and LN+ disease. METHODS: Gene expression data from publically available data sets was used to compare the ability of Oncotype DX and Prosigna to predict Distant Metastasis Free Survival (DMFS) using an in silico platform. A novel gene signature (Ellen) was developed by including patients with both LN- and LN+ disease and using Prediction Analysis of Microarrays (PAM) software. Gene Set Enrichment Analysis (GSEA) was used to determine biological pathways associated with patient outcome in both LN- and LN+ tumors. RESULTS: The Oncotype DX gene signature, which only used LN- patients during development, significantly predicted outcome in LN- patients, but not LN+ patients. The Prosigna gene signature, which included both LN- and LN+ patients during development, predicted outcome in both LN- and LN+ patient groups. Ellen was also able to predict outcome in both LN- and LN+ patient groups. GSEA suggested that epigenetic modification may be related to poor outcome in LN- disease, whereas immune response may be related to good outcome in LN+ disease. CONCLUSIONS: We demonstrate the importance of incorporating lymph node status during the development of prognostic gene signatures. Ellen may be a useful tool to predict outcome of patients regardless of lymph node status, or for those with unknown lymph node status. Finally we present candidate biological processes, unique to LN- and LN+ disease, that may indicate risk of relapse. PMID- 27469241 TI - HIF-1 regulates insect lifespan extension by inhibiting c-Myc-TFAM signaling and mitochondrial biogenesis. AB - Diapause (developmental arrest) is characterized by dramatic depression of metabolic activity and profoundly extends insect lifespan, similar to the Caenorhabditis elegans dauer stage and Drosophila longevity; however, the molecular mechanism of low metabolism in insect diapause is unclear. Here, we show that HIF-1alpha expression is significantly increased in diapause-destined pupal brains compared to nondiapause-destined pupal brains and that HIF-1alpha negatively regulates mitochondrial biogenesis. HIF-1alpha mediates this effect by inhibiting c-Myc activity via proteasome-dependent degradation of c-Myc. The mitochondrial transcription factor A (TFAM), which encodes a key factor involved in mitochondrial transcription and mitochondrial DNA replication, is activated by the binding of c-Myc to the TFAM promoter, thereby inducing transcription. Loss of TFAM expression is a major factor contributing to reducing the mitochondrial activity. Thus, the HIF-1alpha-c-Myc-TFAM signaling pathway participates in the regulation of mitochondrial activity for insect diapause or lifespan extension. PMID- 27469242 TI - Placebo-controlled study of rTMS combined with Lokomat(r) gait training for treatment in subjects with motor incomplete spinal cord injury. AB - High-frequency rTMS combined with gait training improves lower extremity motor score (LEMS) and gait velocity in SCI subjects who are able to walk over ground. The aim of this study was to optimize the functional outcome in early phases of gait rehabilitation in SCI using rTMS as an additional treatment to physical therapy. The present study included 31 motor incomplete SCI subjects randomized to receive real or sham rTMS, just before Lokomat gait training (15 subjects for real, 16 for sham rTMS). rTMS consisted of one daily session for 20 days over vertex (at 20 Hz). The subjects were evaluated using modified Ashworth scale (MAS) for spasticity, upper and lower extremity motor score (UEMS and LEMS, respectively), ten meters walking test (10MWT) and Walking Index for SCI (WISCI II) for gait at baseline, after last rTMS session, and during follow-up. UEMS and LEMS improved significantly after last session in both groups and during follow up period. The improvement was greater in real than in sham rTMS group. At follow up, 71.4 % of the subjects after real rTMS and 40 % of the subjects after sham rTMS could perform 10MWT without significant differences in gait velocity, cadence, step length and WISCI-II between both groups. We conclude that 20 sessions of daily high-frequency rTMS combined with Lokomat gait training can lead to clinical improvement of gait in motor incomplete SCI. Such combined treatment improved motor strength in lower extremity in incomplete SCI subjects and in upper extremity in those with cervical SCI. PMID- 27469244 TI - Instructional practices for evidence-based practice with pre-registration allied health students: a review of recent research and developments. AB - The aim of this study is to update a previous review published in this journal on the effectiveness of teaching and assessment interventions for evidence based practice in health professions, and to determine the extent to which the five recommendations made from that review have been implemented. The Integrating Theory, Evidence and Action method was used to synthesise all published evidence from 2011 to 2015, which addressed instructional practices used for evidence based practice with pre-registration allied health students. Seventeen articles were found to meet the inclusion criteria, and were analysed for both their individual rigour and relationship to the five recommendations. The evidence reviewed in this study was diverse in both its geographical setting and the allied health disciplines represented. Most of the evidence used less rigorous methods, and the evidence base is generally exploratory in nature. To date, the five recommendations regarding instructional practices in this area have been implemented to varying degrees. Many current practices promote social negotiation, collaborative decision-making and collaborative learning, so the social constructivist approach is being adopted. However, the prior knowledge of students is not being assessed as a basis for scaffolding, communication of evidence based practice to varying audiences is rarely addressed and the role of clinicians in the learning of evidence based practice knowledge, skills, beliefs and attitudes remains limited. PMID- 27469243 TI - What physicians reason about during admission case review. AB - Research suggests that physicians perform multiple reasoning tasks beyond diagnosis during patient review. However, these remain largely theoretical. The purpose of this study was to explore reasoning tasks in clinical practice during patient admission review. The authors used a constant comparative approach-an iterative and inductive process of coding and recoding-to analyze transcripts from 38 audio-recorded case reviews between junior trainees and their senior residents or attendings. Using a previous list of reasoning tasks, analysis focused on what tasks were performed, when they occurred, and how they related to the other tasks. All 24 tasks were observed in at least one review with a mean of 17.9 (Min = 15, Max = 22) distinct tasks per review. Two new tasks-assess illness severity and patient decision-making capacity-were identified, thus 26 tasks were examined. Three overarching tasks were identified-assess priorities, determine and refine the most likely diagnosis and establish and refine management plans that occurred throughout all stages of the case review starting from patient identification and continuing through to assessment and plan. A fourth possible overarching task-reflection-was also identified but only observed in four instances across three cases. The other 22 tasks appeared to be context dependent serving to support, expand, and refine one or more overarching tasks. Tasks were non-sequential and the same supporting task could serve more than one overarching task. The authors conclude that these findings provide insight into the 'what' and 'when' of physician reasoning during case review that can be used to support professional development, clinical training and patient care. In particular, they draw attention to the iterative way in which each task is addressed during a case review and how this finding may challenge conventional ways of teaching and assessing clinical communication and reasoning. They also suggest that further research is needed to explore how physicians decide why a supporting task is required in a particular context. PMID- 27469245 TI - The Frequency and Energy of Snoring Sounds Are Associated with Common Carotid Artery Intima-Media Thickness in Obstructive Sleep Apnea Patients. AB - Obstructive sleep apnea (OSA) is a known risk factor for atherosclerosis. We investigated the association of common carotid artery intima-media thickness (CCA IMT) with snoring sounds in OSA patients. A total of 30 newly diagnosed OSA patients with no history of cardiovascular diseases were prospectively enrolled for measuring mean CCA-IMT with B-mode ultrasonography, body mass index, metabolic syndrome, 10-year cardiovascular disease risk score, high-sensitivity C reactive protein, and homocysteine. Good-quality signals of full-night snoring sounds in an ordinary sleep condition obtained from 15 participants were further acoustically analyzed (Included group). All variables of interest were not significantly different (all p > 0.05) between the included and non-included groups except for diastolic blood pressure (p = 0.037). In the included group, CCA-IMT was significantly correlated with snoring sound energies of 0-20 Hz (r = 0.608, p = 0.036) and 652-1500 Hz (r = 0.632, p = 0.027) and was not significantly associated with that of 20-652 Hz (r = 0.366, p = 0.242) after adjustment for age and sex. Our findings suggest that underlying snoring sounds may cause carotid wall thickening and support the large-scale evaluation of snoring sound characters as markers of surveillance and for risk stratification at diagnosis. PMID- 27469246 TI - Del Nido cardioplegia in the setting of minimally invasive aortic valve surgery. AB - The purpose of this study is to report our experience with del Nido cardioplegia (DNC) in the setting of minimally invasive aortic valve surgery. Forty-six consecutive patients underwent minimally invasive aortic valve replacement (AVR) through a "J" ministernotomy: twenty-five patients received the DNC (Group 1) and 21 patients received standard blood cardioplegia (SBC) (Group 2). The rate of ventricular fibrillation at unclamping was significantly lower in the DNC group (12% vs 52%, p=0.004), as well as postoperative creatinine kinase-MB (CK-MB) values (11.4+/-5.2 vs 17.7+/-6.9 ug/L, p=0.004). There were no deaths, myocardial infarctions or major complications in either group. Less postoperative use of intravenous insulin (28% vs 81%, p<0.001) was registered in the DNC group. In conclusion, the DNC is easy to use and safe during minimally invasive AVR, providing a myocardial protection at least equivalent to our SBC, improved surgical efficiency, minimal cost and less blood glucose perturbations. PMID- 27469247 TI - Are adjunct subvalvular techniques more effective than isolated restrictive annuloplasty for treating ischemic mitral regurgitation? AB - This review focused on whether subvalvular techniques are more effective than isolated restrictive annuloplasty in addressing ischemic mitral regurgitation (MR). Searching identified 445 papers and, following a selection process, we ended up with 10 articles. Two were propensity-matched studies, four retrospective and four prospective, non-randomized studies. The end points of interest were late recurrence of MR, other early echocardiographic outcomes of mitral function and early mortality. All studies focusing on echocardiographic measurements showed improved results in the groups where subvalvular repair techniques were used. In almost all studies, the recurrence of MR postoperatively was less when subvalvular techniques were used. No difference in early or in hospital mortality was demonstrated in all four studies that included comparisons. We conclude that subvalvular techniques in combination with annuloplasty are safe and may better address ischemic MR than the use of annuloplasty ring alone. PMID- 27469248 TI - [Functional status, self-rated health and level of physical activity of patients with osteoarthritis]. AB - OBJECTIVE: To describe the functional status and self-rated health of patients with osteoarthritis (OA) in Primary Care, and checking their relationship with the level of physical activity and sociodemographic characteristics. DESIGN: Study of prevalence and cross association. SETTING: Primary Care Clinics. PARTICIPANTS: Adult patients with a diagnosis of OA in any joint in their clinical records. Out of a total of 487 selected, 346 (71.0%) took part in the study. MAIN MEASUREMENTS: Functional capacity (WOMAC scale), self-rated quality of life (EuroQol- 5D questionnaire), physical activity (IPAQ questionnaire), number of affected joints, pain level, and sociodemographic characteristics. RESULTS: A mean score of 30.2 (SD: 20.8; CI 95% CI: 28.0 to 32.4) was obtained on the WOMAC scale, with pain, stiffness, and functional capacity scores of 6.5 (SD: 4.8), 1.9 (SD: 2.0), and 21.7 (SD: 15.7), respectively. The score showed a linear trend (P<.001) compared to the level of physical activity, being 41.1 (SD: 19.9) in inactive subjects, 24.3 (SD: 18.7) in subjects with moderate activity, and 22.3 (SD: 19.8) in subjects with intense activity. In the multiple linear regression, the score on the WOMAC scale, as well as that obtained in self-rated health status, maintained their association with physical activity level after adjusting for sociodemographic variables and the number of affected joints. CONCLUSIONS: In patients with OA, pain and functional capacity are the most affected dimensions. Functional status and self-rated health status are higher in active patients, regardless of the number of joints affected and their demographic characteristics. PMID- 27469249 TI - Yunnan snub-nosed monkey research of the Kunming Institute of Zoology, Chinese Academy of Sciences. PMID- 27469250 TI - The big bang of genome editing technology: development and application of the CRISPR/Cas9 system in disease animal models. AB - Targeted genome editing technology has been widely used in biomedical studies. The CRISPR-associated RNA-guided endonuclease Cas9 has become a versatile genome editing tool. The CRISPR/Cas9 system is useful for studying gene function through efficient knock-out, knock-in or chromatin modification of the targeted gene loci in various cell types and organisms. It can be applied in a number of fields, such as genetic breeding, disease treatment and gene functional investigation. In this review, we introduce the most recent developments and applications, the challenges, and future directions of Cas9 in generating disease animal model. Derived from the CRISPR adaptive immune system of bacteria, the development trend of Cas9 will inevitably fuel the vital applications from basic research to biotechnology and bio-medicine. PMID- 27469251 TI - Generation of genetically modified mice using CRISPR/Cas9 and haploid embryonic stem cell systems. AB - With the development of high-throughput sequencing technology in the post-genomic era, researchers have concentrated their efforts on elucidating the relationships between genes and their corresponding functions. Recently, important progress has been achieved in the generation of genetically modified mice based on CRISPR/Cas9 and haploid embryonic stem cell (haESC) approaches, which provide new platforms for gene function analysis, human disease modeling, and gene therapy. Here, we review the CRISPR/Cas9 and haESC technology for the generation of genetically modified mice and discuss the key challenges in the application of these approaches. PMID- 27469252 TI - Application of the genome editing tool CRISPR/Cas9 in non-human primates. AB - In the past three years, RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system has been used to facilitate efficient genome editing in many model and non-model animals. However, its application in nonhuman primates is still at the early stage, though in view of the similarities in anatomy, physiology, behavior and genetics, closely related nonhuman primates serve as optimal models for human biology and disease studies. In this review, we summarize the current proceedings of gene editing using CRISPR/Cas9 in nonhuman primates. PMID- 27469253 TI - Advances and perspectives in the application of CRISPR/Cas9 in insects. AB - Insects compose more than half of all living organisms on earth, playing essential roles in global ecosystems and forming complex relationships with humans. Insect research has significant biological and practical importance. However, the application of genetic manipulation technology has long been restricted to several model insects only, such as gene knockout in Drosophila, which has severely restrained the development of insect biology research. Recently, with the increase in the release of insect genome data and the introduction of the CRISPR/Cas9 system for efficient genetic modification, it has been possible to conduct meaningful functional studies in a broad array of insect species. Here, we summarize the advances in CRISPR/Cas9 in different insect species, discuss methods for its promotion, and consider its application in future insect studies. This review provides detailed information about the application of the CRISPR/Cas9 system in insect research and presents possible ways to improve its use in functional studies and insect pest control. PMID- 27469254 TI - Modeling postpartum depression in rats: theoretic and methodological issues. AB - The postpartum period is when a host of changes occur at molecular, cellular, physiological and behavioral levels to prepare female humans for the challenge of maternity. Alteration or prevention of these normal adaptions is thought to contribute to disruptions of emotion regulation, motivation and cognitive abilities that underlie postpartum mental disorders, such as postpartum depression. Despite the high incidence of this disorder, and the detrimental consequences for both mother and child, its etiology and related neurobiological mechanisms remain poorly understood, partially due to the lack of appropriate animal models. In recent decades, there have been a number of attempts to model postpartum depression disorder in rats. In the present review, we first describe clinical symptoms of postpartum depression and discuss known risk factors, including both genetic and environmental factors. Thereafter, we discuss various rat models that have been developed to capture various aspects of this disorder and knowledge gained from such attempts. In doing so, we focus on the theories behind each attempt and the methods used to achieve their goals. Finally, we point out several understudied areas in this field and make suggestions for future directions. PMID- 27469255 TI - Research proceedings on amphibian model organisms. AB - Model organisms have long been important in biology and medicine due to their specific characteristics. Amphibians, especially Xenopus, play key roles in answering fundamental questions on developmental biology, regeneration, genetics, and toxicology due to their large and abundant eggs, as well as their versatile embryos, which can be readily manipulated and developed in vivo. Furthermore, amphibians have also proven to be of considerable benefit in human disease research due to their conserved cellular developmental and genomic organization. This review gives a brief introduction on the progress and limitations of these animal models in biology and human disease research, and discusses the potential and challenge of Microhyla fissipes as a new model organism. PMID- 27469256 TI - Molecular cloning and anti-HIV-1 activities of APOBEC3s from northern pig-tailed macaques (Macaca leonina). AB - Northern pig-tailed macaques (NPMs, Macaca leonina) are susceptible to HIV-1 infection largely due to the loss of HIV-1-restricting factor TRIM5alpha. However, great impediments still exist in the persistent replication of HIV-1 in vivo, suggesting some viral restriction factors are reserved in this host. The APOBEC3 proteins have demonstrated a capacity to restrict HIV-1 replication, but their inhibitory effects in NPMs remain elusive. In this study, we cloned the NPM A3A-A3H genes, and determined by BLAST searching that their coding sequences (CDSs) showed 99% identity to the corresponding counterparts from rhesus and southern pig-tailed macaques. We further analyzed the anti-HIV-1 activities of the A3A-A3H genes, and found that A3G and A3F had the greatest anti-HIV-1 activity compared with that of other members. The results of this study indicate that A3G and A3F might play critical roles in limiting HIV-1 replication in NPMs in vivo. Furthermore, this research provides valuable information for the optimization of monkey models of HIV-1 infection. PMID- 27469257 TI - Early embryonic development and transplantation in tree shrews. AB - As a novel experimental animal model, tree shrews have received increasing attention in recent years. Despite this, little is known in regards to the time phases of their embryonic development. In this study, surveillance systems were used to record the behavior and timing of copulations; embryos at different post copulation stages were collected and cultured in vitro; and the developmental characteristics of both early-stage and in vitro cultured embryos were determined. A total of 163 females were collected following effective copulation, and 150 were used in either unilateral or bilateral oviduct embryo collections, with 307 embryos from 111 females obtained (conception rate=74%). Among them, 237 embryos were collected from 78 females, bilaterally, i.e., the average embryo number per female was 3.04; 172 fertilized eggs collected from 55 females, bilaterally, were cultured for 24-108 h in vitro for developmental observations; finally, 65 embryos from 23 bilateral cases and 70 embryos from 33 unilateral cases were used in embryo transplantation. PMID- 27469258 TI - Immunomodulatory properties of medicinal mushrooms: differential effects of water and ethanol extracts on NK cell-mediated cytotoxicity. AB - Medicinal mushrooms have been used for centuries in Asian countries owing to their beneficial effects on health and longevity. Previous studies have reported that a single medicinal mushroom may produce both stimulatory and inhibitory effects on immune cells, depending on conditions, but the factors responsible for this apparent dichotomy remain obscure. We show here that water and ethanol extracts of cultured mycelium from various species (Agaricus blazei Murrill, Antrodia cinnamomea, Ganoderma lucidum and Hirsutella sinensis) produce opposite effects on NK cells. Water extracts enhance NK cell cytotoxic activity against cancer cells, whereas ethanol extracts inhibit cytotoxicity. Water extracts stimulate the expression and production of cytolytic proteins (perforin and granulysin) and NKG2D/NCR cell surface receptors, and activate intracellular signaling kinases (ERK, JNK and p38). In contrast, ethanol extracts inhibit expression of cytolytic and cell surface receptors. Our results suggest that the mode of extraction of medicinal mushrooms may determine the nature of the immunomodulatory effects produced on immune cells, presumably owing to the differential solubility of stimulatory and inhibitory mediators. These findings have important implications for the preparation of medicinal mushrooms to prevent and treat human diseases. PMID- 27469260 TI - Correction: Electronic structure of the boron fullerene B14 and its silicon derivatives B13Si+, B13Si- and B12Si2: a rationalization using a cylinder model. AB - Correction for 'Electronic structure of the boron fullerene B14 and its silicon derivatives B13Si+, B13Si- and B12Si2: a rationalization using a cylinder model' by Long Van Duong et al., Phys. Chem. Chem. Phys., 2016, 18, 17619-17626. PMID- 27469261 TI - Defining the role of pneumococcal neuraminidases and O-glycosidase in pneumococcal haemolytic uraemic syndrome. AB - The host and bacterial factors that lead to development of pneumococcal haemolytic uraemic syndrome (pHUS) remain poorly defined; however, it is widely believed that pneumococcal exposure of the Thomsen-Friedenreich antigen (T antigen) on host surfaces is a key step in pathogenesis. Two enzymatic activities encoded by pneumococci determine the level of T-antigen exposed. Neuraminidases cleave terminal sialic acid to expose the T-antigen which is subsequently cleaved by O-glycosidase Eng. While a handful of studies have examined the role of neuraminidases in T-antigen exposure, no studies have addressed the potential role of O-glycosidase. This study used 29 pHUS isolates from the USA and 31 serotype-matched controls. All isolates contained eng, and no significant correlation between enzymatic activity and disease state (pHUS and blood non-pHUS isolates) was observed. A prior study from Taiwan suggested that neuraminidase NanC contributes to the development of pHUS. However, we observed no difference in nanC distribution. Similar to previously published data, we found no significant correlation between neuraminidase activity and disease state. Accurate quantification of these enzymatic activities from bacteria grown in whole blood is currently impossible, but we confirmed that there were no significant correlations between disease state and neuraminidase and O glycosidase transcript levels after incubation in blood. Genomic sequencing of six pHUS isolates did not identify any genetic elements possibly contributing to haemolytic uraemic syndrome. These findings support the hypothesis that while exposure of T-antigen may be an important step in disease pathogenesis, host factors likely play a substantial role in determining which individuals develop haemolytic uraemic syndrome after pneumococcal invasive disease. PMID- 27469259 TI - Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive? AB - Diabetes strongly predisposes to cardiovascular disease (CVD), the leading cause of mortality in these patients, as well as in the entire population. Hyperglycemia is an important cardiovascular risk factor as shown by the observation that even transient periods of hyperglycemia, despite return to normoglycemia during follow-up, increase the risk for CVD, a phenomenon termed 'hyperglycemic memory'. The molecular mechanisms underlying this phenomenon remain largely unknown. As inflammation plays an important role in the pathogenesis of atherosclerosis, we propose that long-term functional reprogramming of monocytes and macrophages, induced by hyperglycemia, plays an important role in the phenomenon of hyperglycemic memory leading to cardiovascular complications in patients with diabetes. In this review, we discuss recent insights showing that innate immune cells possess the capacity to reprogram their function through epigenetically mediated rewiring of gene transcription, a process termed 'trained immunity'. The long-term reprogramming of monocytes can be induced by microbial as well as metabolic products, and involves a shift in cellular metabolism from oxidative phosphorylation to aerobic glycolysis. We hypothesize that hyperglycemia in diabetes patients induces long term activation of monocytes and macrophages through similar mechanisms, thereby contributing to plaque development and subsequent macrovascular complications. PMID- 27469262 TI - The Role of Transoral Robotic Surgery in the Management of HPV Negative Oropharyngeal Squamous Cell Carcinoma. AB - The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is on the rise. This is largely due to the rapid increase in HPV positive OPSCC, which has been shown to confer a survival advantage. HPV negative OPSCC, however, has a more aggressive tumor biology and is a challenge to treat with standard current therapies. Chemoradiation has demonstrated poor locoregional control in HPV negative OPSCC, and open surgeries are associated with high morbidity. Transoral robotic surgery (TORS) has been proposed as an option to both intensify treatment and decrease surgical morbidity for patients with HPV negative OPSCC. TORS can be utilized as a primary treatment or in persistent, recurrent, or second primary OPSCC. There is emerging data showing improved functional outcomes with TORS versus open surgery or chemoradiation. Unfortunately, there have been no randomized trials comparing TORS to chemoradiation in HPV negative OPSCC. This article will review utility of TORS for HPV negative OPSCC. PMID- 27469263 TI - Determining Adequate Margins in Head and Neck Cancers: Practice and Continued Challenges. AB - Margin assessment remains a critical component of oncologic care for head and neck cancer patients. As an integrated team, both surgeons and pathologists work together to assess margins in these complex patients. Differences in method of margin sampling can impact obtainable information and effect outcomes. Additionally, what distance is an "adequate or clear" margin for patient care continues to be debated. Ultimately, future studies and potentially secondary modalities to augment pathologic assessment of margin assessment (i.e., in situ imaging or molecular assessment) may enhance local control in head and neck cancer patients. PMID- 27469264 TI - A phospholipid transfer function of ER-mitochondria encounter structure revealed in vitro. AB - As phospholipids are synthesized mainly in the endoplasmic reticulum (ER) and mitochondrial inner membranes, how cells properly distribute specific phospholipids to diverse cellular membranes is a crucial problem for maintenance of organelle-specific phospholipid compositions. Although the ER-mitochondria encounter structure (ERMES) was proposed to facilitate phospholipid transfer between the ER and mitochondria, such a role of ERMES is still controversial and awaits experimental demonstration. Here we developed a novel in vitro assay system with isolated yeast membrane fractions to monitor phospholipid exchange between the ER and mitochondria. With this system, we found that phospholipid transport between the ER and mitochondria relies on membrane intactness, but not energy sources such as ATP, GTP or the membrane potential across the mitochondrial inner membrane. We further found that lack of the ERMES component impairs the phosphatidylserine transport from the ER to mitochondria, but not the phosphatidylethanolamine transport from mitochondria to the ER. This in vitro assay system thus offers a powerful tool to analyze the non-vesicular phospholipid transport between the ER and mitochondria. PMID- 27469265 TI - Dose-rate-dependent damage of cerium dioxide in the scanning transmission electron microscope. AB - Beam damage caused by energetic electrons in the transmission electron microscope is a fundamental constraint limiting the collection of artifact-free information. Through understanding the influence of the electron beam, experimental routines may be adjusted to improve the data collection process. Investigations of CeO2 indicate that there is not a critical dose required for the accumulation of electron beam damage. Instead, measurements using annular dark field scanning transmission electron microscopy and electron energy loss spectroscopy demonstrate that the onset of measurable damage occurs when a critical dose rate is exceeded. The mechanism behind this phenomenon is that oxygen vacancies created by exposure to a 300keV electron beam are actively annihilated as the sample re-oxidizes in the microscope environment. As a result, only when the rate of vacancy creation exceeds the recovery rate will beam damage begin to accumulate. This observation suggests that dose-intensive experiments can be accomplished without disrupting the native structure of the sample when executed using dose rates below the appropriate threshold. Furthermore, the presence of an encapsulating carbonaceous layer inhibits processes that cause beam damage, markedly increasing the dose rate threshold for the accumulation of damage. PMID- 27469266 TI - Linkage disequilibrium amongst ITGA2B and ITGB3 gene variants in patients with Glanzmann thrombasthenia confirms that most disease-causing mutations are recent. AB - We recently reported mutation analysis of the largest cohort of Glanzmann thrombasthenia (GT) patients so far examined. Sanger sequencing of coding regions, splice sites, upstream and downstream regions of the ITGA2B and ITGB3 genes identified 78 causal genetic variants (55 novel); 4 large deletions or duplications were also detected. We have now analysed the expression of non causal gene polymorphisms in the sequenced regions of both genes in selected members of this cohort. We identified 10 mostly silent variants in ITGA2B and 37 in ITGB3; all were present in control donor databases. Three non-synonymous single nucleotide polymorphisms present were human platelet alloantigen (HPA) variants. A series of haplogroups, often including HPA-3b in ITGA2B, repeated with little variation across unrelated families of wide geographical origins and with different GT-causing mutations whether in ITGA2B or ITGB3. In contrast, a deleterious heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B shared a common ITGA2B haplogroup composed of at least five gene polymorphisms and re occurred in seven European families with no known family relationships. Our results highlight the value of gene polymorphism analysis in GT and are consistent with the bulk of disease-causing mutations in GT being of recent origin. PMID- 27469267 TI - Laing distal myopathy with a novel mutation in exon 34 of the MYH7 gene. AB - We investigated a four-generation family of German ancestry with distal myopathy. Four individuals in two generations were affected. Foot and toe extensor paresis progressing very slowly over decades was the core neurological sign, reflected by fatty infiltration of the lower leg extensor muscles on muscle MRI. Additionally, finger extensor paresis was present in two patients and quadriceps muscle paresis in one. Distal sensory signs had initially given rise to the diagnosis of axonal Charcot-Marie-Tooth (CMT) disease. Two patients had extended verrucae of their foot sole, which may or may not be part of the disease spectrum. All four patients had a novel c.4645G > C mutation in exon 34 of the MYH7 gene that was not present in three clinically unaffected family members. Muscle biopsy of one patient revealed a myopathic pattern associated with type 1 muscle fibre atrophy and core-like lesions in many muscle fibres consistent with a myosin-related myopathy. We conclude that some of the typical clinical signs such as extensor weakness of the big toe and the little finger may only develop in the further course of the disease. PMID- 27469268 TI - Angiopoietin-like protein 8 (ANGPTL8) in pregnancy: a brown adipose tissue derived endocrine factor with a potential role in fetal growth. AB - Angiopoietin-like protein 8 (ANGPTL8), a protein implicated in lipid and glucose homeostasis, is present only in mammals, suggesting that it is involved in processes unique to these vertebrates such as pregnancy and homeothermy. We explored the role of ANGPTL8 in maternal-fetal crosstalk and its relationship with newborn adiposity. In a longitudinal analysis of healthy pregnant women, ANGPTL8 levels decreased progressively during pregnancy although remained higher than levels in the postpartum period. In a cross-sectional observational study of women with or without gestational diabetes mellitus (GDM), and their offspring, ANGPTL8 levels were higher in venous cord blood than those in maternal blood and were significantly lower in GDM patients than those in healthy women. Infants small for gestational age and with low-fat mass had the highest ANGPTL8 cord blood levels. Studies in vitro revealed that ANGPTL8 was secreted by brown adipocytes and its expression was increased in experimental models of white-to brown fat conversion. In addition, ANGPTL8 induced the expression of markers of brown adipocytes. The high levels of ANGPTL8 found in fetal life together with its relationship with newborn adiposity and brown adipose tissue point to ANGPTL8 as a potential new player in the modulation of the thermogenic machinery during the fetal-neonatal transition. PMID- 27469269 TI - Stanniocalcin-1 attenuates ischemic cardiac injury and response of differentiating monocytes/macrophages to inflammatory stimuli. AB - Stanniocalcin-1 (STC-1) is a multifunctional glycoprotein with antioxidant and anti-inflammatory properties. Ischemic myocardial necrosis generates "danger" signals that perpetuate detrimental inflammatory reactions often involving monocyte recruitment and their subsequent differentiation into proinflammatory macrophages. Therefore, we evaluated the effects of recombinant STC-1 (rSTC-1) on monocyte phenotype and in a mouse model of myocardial infarction. Using an established protocol to differentiate human monocytes into macrophages, we demonstrated that rSTC-1 did not alter morphology of the differentiated cells, toll-like receptor (TLR) 4 expression, or expression of the myeloid cell marker CD11b. However, rSTC-1 treatment before differentiation attenuated the rise in the expression of CD14, a TLR4 coreceptor and pathogen sensor that propagates innate immune responses, and suppressed levels of inflammatory cytokines produced by the differentiated cells in response to the CD14-TLR4 ligand lipopolysaccharide. Moreover, rSTC-1 treatment reduced CD14 expression in monocytes stimulated with endogenous danger signals. Interestingly, the effects of rSTC-1 on CD14 expression were not reproduced by a superoxide dismutase mimetic. In mice with induced myocardial infarcts, intravenous administration of rSTC-1 decreased CD14 expression in the heart as well as levels of tumor necrosis factor alpha, C-X-C motif ligand 2, interleukin 1 beta, and myeloperoxidase. It also suppressed the formation of scar tissue while enhancing cardiac function. The data suggests that one of the beneficial effects of STC-1 might be attributed to suppression of CD14 on recruited monocytes and macrophages that limits their inflammatory response. STC-1 may be a promising therapy to protect the heart and other tissues from ischemic injury. PMID- 27469271 TI - Utilizing on- and off-line monitoring tools to follow a kinetic resolution step during flow synthesis. AB - In situ reaction monitoring tools offer the ability to track the progress of a synthetic reaction in real time to facilitate reaction optimization and provide kinetic/mechanistic insight. Herein, we report the utilization of flow NMR, flow IR, and other off-line spectroscopy tools to monitor the progress of a flow chemistry reaction. The on-line and off-line tools were selected to facilitate the stereoselective kinetic resolution of a key racemic monomer, which lacked a chromophore, making conventional reaction monitoring difficult. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27469270 TI - The infant gut bacterial microbiota and risk of pediatric asthma and allergic diseases. AB - Among the many areas being revolutionized by the recent introduction of culture independent microbial identification techniques is investigation of the relationship between close contact with large animals, antibiotics, breast feeding, mode of birth, and other exposures during infancy as related to a reduced risk of asthma and allergic disease. These exposures were originally clustered under the "Hygiene Hypothesis" which has evolved into the "Microbiota Hypothesis". This review begins by summarizing epidemiologic studies suggesting that the common feature of these allergy risk-related exposures is their influence on the founding and early development of a child's gut microbiota. Next, studies using culture-independent techniques are presented showing that children who have experienced the exposures of interest have altered gut microbiota. Finally, selected mouse and human studies are presented which begin to corroborate the protective exposures identified in epidemiologic studies by elucidating mechanisms through which microbes can alter immune development and function. These microbially driven immune alterations demonstrate that microbial exposures in many cases could alter the risk of subsequent allergic disease and asthma. Hopefully, a better understanding of how microbes influence allergic disease will lead to safe and effective methods for reducing the prevalence of all forms of allergic disease. PMID- 27469272 TI - Transcallosal connectivity of the human cortical motor network. AB - The organisational and architectural configuration of white matter pathways connecting brain regions has ramifications for all facets of the human condition, including manifestations of incipient neurodegeneration. Although diffusion tensor imaging (DTI) has been used extensively to visualise white matter connectivity, due to the widespread presence of crossing fibres, the lateral projections of the corpus callosum are not normally detected using this methodology. Detailed knowledge of the transcallosal connectivity of the human cortical motor network has, therefore, remained elusive. We employed constrained spherical deconvolution (CSD) tractography-an approach that is much less susceptible to the influence of crossing fibres, in order to derive complete in vivo characterizations of white matter pathways connecting specific motor cortical regions to their counterparts and other loci in the opposite hemisphere. The revealed patterns of connectivity closely resemble those derived from anatomical tracing in primates. It was established that dorsal premotor cortex (PMd) and supplementary motor area (SMA) have extensive interhemispheric connectivity-exhibiting both dense homologous projections, and widespread structural relations with every other region in the contralateral motor network. Through this in vivo portrayal, the importance of non-primary motor regions for interhemispheric communication is emphasised. Additionally, distinct connectivity profiles were detected for the anterior and posterior subdivisions of primary motor cortex. The present findings provide a comprehensive representation of transcallosal white matter projections in humans, and have the potential to inform the development of models and hypotheses relating structural and functional brain connectivity. PMID- 27469273 TI - Connectivity-based parcellation of the macaque frontal cortex, and its relation with the cytoarchitectonic distribution described in current atlases. AB - Through its connectivity with the rest of the brain, a cortical region constrains its function. The advent of MRI methods such as diffusion-weighted imaging tractography allows us to estimate whole-brain anatomical connectivity at multiple seed regions in the same subject. This makes it possible to use data driven techniques to define the spatial boundaries between adjacent brain regions characterized by sharply different connectivity. This approach has recently been employed to identify connectivity-based subdivisions of the human frontal lobe bearing an apparent similarity with cytoarchitectural subdivisions. However, the spatial relationships between the boundaries of cytoarchitectonic areas and tractography-based subdivisions remain largely hypothetical. In this work we present the first tractography-based parcellation of the frontal lobes in macaques. Diffusion-weighted data for tractography were acquired on ex vivo macaque brain specimens, ruling out the presence of various sources of noise present in acquisitions on living subjects. An unsupervised multivariate technique consistently showed the presence of 11 tractography-driven subdivisions in the frontal lobe across specimens. Comparison with several microstructural atlases suggested a heterogeneous relationship of these subdivisions with cytoarchitectonic areas: caudal frontal, medial and orbitofronal subdivisions featured the most consistent relationship between modalities, while lateral prefrontal subdivisions mostly differed from atlas-based cytoarchitectonic subdivisions. Other subdivisions were reminiscent of the organization of anatomical projections of the caudal motor cortex, as well as of the intrinsic orbitofrontal networks. Hence, although some cytoarchitectural and connectivity based subdivisions share a similar spatial distribution, they should not necessarily be considered as equivalent. Instead, connectivity-based subdivisions appear to provide complementary information on the spatial organization of anatomical connectivity. PMID- 27469274 TI - CO2 capture enhancement in InOF-1 via the bottleneck effect of confined ethanol. AB - CO2 capture of InOF-1 was enhanced 3.6-fold, at 1 bar and 30 degrees C, by confining EtOH within its pores. Direct visualisation by single crystal X-ray diffraction revealed that EtOH divides InOF-1 channels in wide sections separated by "bottlenecks" caused by EtOH molecules bonded to the MU2-OH functional groups of InOF-1. PMID- 27469275 TI - Usability of patient experience surveys in Australian primary health care: a scoping review. AB - Monitoring patient experience is essential for stimulating innovation in health care and improving quality and accountability. Internationally, standardised approaches are used to collect patient experience information, but in Australian primary health care (PHC), little is known about which patient experience surveys are used and which aspects of experience they measure. This prevents routine inclusion of patient experience data in quality improvement or system performance measurement. A scoping review was undertaken to identify relevant surveys. Data on survey availability, psychometric properties, target population, method and frequency of administration were extracted. Survey items were mapped against six dimensions of patient experience described internationally. Ninety-five surveys were identified; 34 were developed for use in Australia. Surveys vary in content, size, aspects of experience measured and methods of administration. The quality of data collected and the extent to which it is used in quality improvement is unclear. Collection of patient experience data in Australian PHC is not well developed or standardised and there are few publicly available instruments. There is a need to clearly identify the purposes for which data are to be used and to develop an integrated approach that articulates these collections with other quality and performance data. Some options are discussed. PMID- 27469278 TI - Associated Demographic Factors of Instrumental and Emotional Feeding in Parents of Hong Kong Children. AB - BACKGROUND: Instrumental and emotional feeding have been associated with obesogenic dietary behaviors and obesity in children. Therefore, identifying parents who are more likely to use detrimental feeding styles may be helpful for tailoring interventions. OBJECTIVE: This study examines the demographic variation of instrumental and emotional feeding by using a sample of the Hong Kong population. DESIGN: A cross-sectional research is presented. Instrumental and emotional feeding styles were assessed. PARTICIPANTS: A total of 3,742 Hong Kong parents from 27 kindergartens, with children aged 2 to 7 years old, were enrolled in this study. MAIN OUTCOME MEASURES: Instrumental and emotional feeding styles were assessed by a validated Parental Feeding Style Questionnaire. STATISTICAL ANALYSIS: Differences among the demographic characteristics in parental feeding styles were compared by independent t test or analysis of variance. Multiple linear regressions were performed to determine the associated demographic factors. RESULTS: A greater tendency to adopt instrumental feeding was associated with younger children (beta=-.07), feeding a daughter (beta=.05), and a mother having a full-time job (beta=.10). By contrast, a greater tendency to adopt emotional feeding was associated with younger children (beta=-.07), feeding a daughter (beta=.06), a mother having a full-time job (beta=.16), or a lower parental education level (beta=-.11). CONCLUSIONS: Parents with full-time jobs, lower education levels, or who were nurturing a younger child may be more likely to use unhealthy feeding styles. Researchers should consider developing intervention strategies that focus on decreasing emotional and instrumental feeding styles for full-time employed or less-educated parents of younger children, particularly daughters. PMID- 27469279 TI - Neuromuscular response of the trunk to sudden gait disturbances: Forward vs. backward perturbation. AB - The study aimed to analyse neuromuscular activity of the trunk comparing four different perturbations during gait. Thirteen subjects (28+/-3yrs) walked (1m/s) on a split-belt treadmill, while 4 (belt) perturbations (F1, F2, B1, B2) were randomly applied. Perturbations differed, related to treadmill belt translation, in direction (forward (F)/backward (B)) and amplitude (20m/s(2) (1)/40m/s(2) (2)). Trunk muscle activity was assessed with a 12-lead-EMG. EMG-RMS [%] (0-200ms after perturbation; normalized to RMS of normal gait) was analyzed for muscles and four trunk areas (ventral left/right; dorsal left/right). Ratio of ventral:dorsal muscles were calculated. Muscle onset [ms] was determined. Data analysis was conducted descriptively, followed by ANOVA (post hoc Tukey-Kramer (alpha=0.05)). All perturbations lead to an increase in EMG-RMS (428+/-289%). F1 showed the lowest and F2 the highest increase for the flexors. B2 showed the highest increase for the extensors. Significant differences between perturbations could be observed for 6 muscles, as well as the 4 trunk areas. Ratio analysis revealed no significant differences (range 1.25 (B1) to 1.71 (F2) between stimuli. Muscle response time (ventral: 87.0+/-21.7ms; dorsal: 88.4+/-17.0ms) between stimuli was only significant (p=0.005) for the dorsal muscles. Magnitude significantly influences neuromuscular trunk response patterns in healthy adults. Regardless of direction ventral muscles always revealed higher relative increase of activity while compensating the walking perturbations. PMID- 27469280 TI - Similarities between obesity in pets and children: the addiction model. AB - Obesity in pets is a frustrating, major health problem. Obesity in human children is similar. Prevailing theories accounting for the rising obesity rates - for example, poor nutrition and sedentary activity - are being challenged. Obesity interventions in both pets and children have produced modest short-term but poor long-term results. New strategies are needed. A novel theory posits that obesity in pets and children is due to 'treats' and excessive meal amounts given by the 'pet-parent' and child-parent to obtain affection from the pet/child, which enables 'eating addiction' in the pet/child and results in parental 'co dependence'. Pet-parents and child-parents may even become hostage to the treats/food to avoid the ire of the pet/child. Eating addiction in the pet/child also may be brought about by emotional factors such as stress, independent of parental co-dependence. An applicable treatment for child obesity has been trialled using classic addiction withdrawal/abstinence techniques, as well as behavioural addiction methods, with significant results. Both the child and the parent progress through withdrawal from specific 'problem foods', next from snacking (non-specific foods) and finally from excessive portions at meals (gradual reductions). This approach should adapt well for pets and pet-parents. Pet obesity is more 'pure' than child obesity, in that contributing factors and treatment points are essentially under the control of the pet-parent. Pet obesity might thus serve as an ideal test bed for the treatment and prevention of child obesity, with focus primarily on parental behaviours. Sharing information between the fields of pet and child obesity would be mutually beneficial. PMID- 27469282 TI - Robust observer-based absolute stabilization for Lur'e singularly perturbed systems with state delay. AB - This paper is concerned with the problem of robust observer-based absolute stabilization for Lur'e singularly perturbed time-delay systems. The aim is to design a suitable observer-based feedback control law such that the resulting closed-loop system is absolutely stable. First, a full-order state observer is constructed. Based on the linear matrix inequality (LMI) technique, a delay dependent sufficient condition is presented such that the observer error system is absolutely stable. Then, for observer-based feedback control, by introducing some slack matrices, a sufficient condition for input-to-state stability (ISS) of the closed-loop system with regard to the observer error is presented. Thus, the absolute stabilization of the closed-loop system can be guaranteed based on the ISS property. In addition, the criteria presented are both independent of the small parameter and the upper bound for the absolute stability can be obtained in a workable algorithm. Finally, two numerical examples are provided to illustrate the effectiveness of the developed methods. PMID- 27469283 TI - Routine high-precision analysis of triple water-isotope ratios using cavity ring down spectroscopy. AB - RATIONALE: Water isotope analysis for delta(2) H and delta(18) O values via laser spectroscopy is routine for many laboratories. While recent work has added the delta(17) O value to the high-precision suite, it does not follow that researchers will routinely obtain high precision (17) O excess (Delta(17) O). We demonstrate the routine acquisition of high-precision delta(2) H, delta(17) O, delta(18) O, d, and Delta(17) O values using a commercially available laser spectroscopy instrument. METHODS: We use a Picarro L2140-i cavity ring-down spectroscopy analyzer with discrete liquid injections into an A0211 vaporization module by a Leap Technologies LC PAL autosampler. The instrument is run in two modes: (1) as recommended by the manufacturer (default mode) and (2) after modifying select default settings and using alternative data types (advanced mode). Reference waters analyzed over the course of 15 months while running unknown samples are used to assess system performance. RESULTS: The default mode provides precision for delta(2) H, delta(17) O, delta(18) O, d, and Delta(17) O values that may be sufficient for many applications. When using the advanced mode, we reach a higher level of precision for delta(2) H, delta(17) O, delta(18) O, d, and Delta(17) O values (0.4 mUr, 0.04 mUr, 0.07 mUr, 0.5 mUr, and 8 MUUr, respectively, where mUr = 0.001 = 0/00, and MUUr = 10(-6) ) in a shorter amount of time and with fewer syringe actuations than in the default mode. The improved performance results from an increase in the total integration time for each injected water pulse. CONCLUSIONS: Our recommended approach for routine delta(2) H, delta(17) O, delta(18) O, d and Delta(17) O measurements with the Picarro L2140-i is to make use of conditioning vials, use fewer injections (5 per vial) with greater pulse duration (520 seconds (s) per injection) and use only the first 120 s for delta(2) H measurements and all 520 s for delta(17) O and delta(18) O measurements. Although the sample throughput is 10 unknowns per day, our optimal approach reduces the number of syringe actuations, the effect of memory, and the total analysis time, while improving precision relative to the default approach. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27469281 TI - Combining Varenicline (Chantix) with Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in a Rodent Model of Alcoholism. AB - BACKGROUND: This study examined whether varenicline (VAR), or naltrexone (NTX), alone or in combination, reduces alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake. METHODS: Alcohol-experienced P rats that had been drinking alcohol (15% v/v) for 2 h/d for 4 weeks were fed either vehicle (VEH), VAR alone (0.5, 1.0, or 2.0 mg/kg body weight [BW]), NTX alone (10.0, 15.0, or 20.0 mg/kg BW), or VAR + NTX in 1 of 4 dose combinations (0.5 VAR + 10.0 NTX, 0.5 VAR + 15.0 NTX, 1.0 VAR + 10.0 NTX, or 1.0 VAR + 15.0 NTX) at 1 hour prior to alcohol access for 10 consecutive days, and the effects on alcohol intake were assessed. RESULTS: When administered alone, VAR in doses of 0.5 or 1.0 mg/kg BW did not alter alcohol intake but a dose of 2.0 mg/kg BW decreased alcohol intake. This effect disappeared when drug treatment was terminated. NTX in doses of 10.0 and 15.0 mg/kg BW did not alter alcohol intake but a dose of 20.0 mg/kg BW decreased alcohol intake. Combining low doses of VAR and NTX into a single medication reduced alcohol intake as well as did high doses of each drug alone. Reduced alcohol intake occurred immediately after onset of treatment with the combined medication and continued throughout prolonged treatment. CONCLUSIONS: Low doses of VAR and NTX, when combined in a single medication, reduce alcohol intake in a rodent model of alcoholism. This approach has the advantage of reducing potential side effects associated with each drug. Lowering the dose of NTX and VAR in a combined treatment approach that maintains efficacy while reducing the incidence of negative side effects may increase patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake. PMID- 27469284 TI - A closer look at strategies for preserving salivary gland function after radiotherapy in the head and neck region. AB - Radiation-induced damage to the salivary glands remains a major complication of using radiation therapy to treat head and neck cancer, and it has led a wide range of research attempting to resolve the problem. From this perspective, we sought to briefly discuss relevant and timely approaches aimed at protecting or regenerating irradiated salivary glands, thereby preventing the development of salivary hypofunction or rescuing the functional properties of damaged glands. Such findings include molecular, cell, tissue, organ, and drug-based therapies. PMID- 27469285 TI - Stemness of spermatogonial stem cells encapsulated in alginate hydrogel during cryopreservation. AB - This study investigated the effect of spermatogonial stem cell encapsulated in alginate hydrogel during cryopreservation, as cells were protected against damage during cryopreservation within the hydrogel. Spermatogonial stem cells were isolated from the testes of Balb/c mice pups (6 days old), purified in laminin coated dishes and CD90.1 microbeads, encapsulated in alginate hydrogel and then cryopreserved. After thawing, cell viability and Spermatogonial stem cell (SSC) colony diameter were evaluated. After RNA was isolated and cDNA was synthesised, the expression of stemness genes was considered using RT real-time PCR. Finally, spermatogonial stem cells labelled with BrdU were transplanted to busulfan azoospermic mouse models. Lin28a and Sall4 genes were significantly upregulated after cryopreservation in alginate hydrogel. However, cell viability was significantly decreased. The diameter of colonies consisting of spermatogonial stem cells freeze-thawed in alginate microbeads showed no significant difference with fresh spermatogonial stem cells and the control group. The injection of freeze-thawed spermatogonial stem cells encapsulated in alginate hydrogel resulted in spermatogenesis recovery. Alginate mimics the extracellular matrices (ECM) for spermatogonial stem cells; therefore, it can support stemness potential during the cell cryopreservation process and restart spermatogenesis after transplantation. PMID- 27469286 TI - Pulse Size Distributions in Tunable Resistive Pulse Sensing. AB - The use of resistive pulse sensors for submicron particle size measurements relies on a clear understanding of pulse size distributions. Here, broadening of such distributions has been studied and explained using conical pores and nominally monodisperse polystyrene particles 200-800 nm in diameter. The use of tunable resistive pulse sensing (TRPS) enabled continuous in situ control of the pore size during experiments. Pulse size distributions became broader when the pore size was increased and featured two distinct peaks. Similar distributions were generated using finite element simulations, which suggested that relatively large pulses are produced by particles with trajectories passing near to the edge of the pore. Other experiments determined that pulse size distributions are independent of applied voltage but broaden with increasing pressure applied across the membrane. The applied pressure could also be reversed in response to a pulse, which enabled repeated measurement of individual particles moving back and forth through the pore. Hydrodynamic and electrophoretic focusing each appear to affect particle trajectories under certain conditions. PMID- 27469287 TI - Difficile indeed. PMID- 27469288 TI - The nutrition transition and adolescents' diets in low- and middle-income countries: a cross-cohort comparison. AB - OBJECTIVE: To investigate changes in dietary diversity and dietary composition among adolescents in four developing countries. DESIGN: We analysed dietary diversity and consumption of seven food groups and foods with added sugars as reported by adolescents from two cohorts growing up 8 years apart, when they were aged about 12 years. SETTING: Ethiopia, India (Andhra Pradesh), Peru and Vietnam in 2006 and 2013. SUBJECTS: Adolescents (n 3659) from the older cohort (OC) born in 1995/96 and adolescents (n 7422) from the younger cohort (YC) born in 2001/02 (N 11 081). RESULTS: Controlling for other factors, dietary diversity increased in Peru (OC=4.89, YC=5.34, P<0.001) and Ethiopia (OC=3.52, YC=3.94, P=0.001). Dietary diversity was stable in India (OC=4.28, YC=4.29, P=0.982) and Vietnam (OC=4.71, YC=4.73, P=0.814); however, changes in dietary composition were observed. YC adolescents were more likely to consume eggs (India: +32 %, P=0.038; Vietnam: +50 %, P<0.001) and milk and dairy (India: +12 %, P=0.029; Vietnam: +46 %, P<0.001). Other notable shifts included meat consumption in Peru (+72 %, P<0.001) and consumption of fruit and vegetables in Ethiopia (+36 %, P<0.001). Compared with OC, the prevalence of added sugar consumption was greater among the YC in Ethiopia (+35 %, P=0.001) and Vietnam (+44 % P<0.001). Between 2006 and 2013, disparities in dietary diversity associated with household wealth and place of residence declined, although this varied by country. No marked gender disparities in dietary diversity were evident. CONCLUSIONS: We found significant changes over time in dietary diversity among adolescents in four countries consistent with the hypothesis of the nutrition transition. PMID- 27469289 TI - Management of Radiation Therapy Oncology Group grade 4 urinary adverse events after radiotherapy for prostate cancer. AB - OBJECTIVE: To describe the management of Radiation Therapy Oncology Group (RTOG) grade 4 urinary adverse events (UAEs) after radiotherapy (RT) for prostate cancer (PCa). METHODS: We conducted a single-centre retrospective review, over a 6-year period (2010-2015), to identify men with RTOG grade 4 UAEs after RT for PCa. RT was classified as combined therapy (radical prostatectomy [RP] followed by external beam radiotherapy [EBRT], EBRT + low-dose-rate [LDR] brachytherapy, EBRT + high-dose-rate [HDR] brachytherapy or other combinations of RT) or monotherapy RT. UAEs were classified as outlet (urethral stricture, bladder neck contracture, prostate necrosis, or recto-urethral fistula) or bladder (contraction, necrosis, fistula, ureteric stricture or haemorrhage) UAEs. RESULTS: We identified 73 men with a mean age of 73 years. Of these, 44 (60%) received combined therapy, consisting of RP + EBRT (n = 19), HDR brachytherapy + EBRT (n = 19), LDR brachytherapy + EBRT (n = 5), and other combined RT (n = 1). Twenty-nine (40%) patients had monotherapy consisting of EBRT (n = 4), HDR brachytherapy (n = 11), LDR brachytherapy (n = 12), or proton beam therapy (n = 2). UAEs were isolated to the bladder in six men (8%), the outlet in 52 men (71%), and to both in 15 men (21%). UAE management included: conservative in 21 (29%), indwelling catheters in 12 (16%), reconstructive in 19 (26%), and urinary diversion (UD) in 23 men (32%). Reconstruction included: ureteric (n = 4), recto-urethral fistula repair (n = 2), and posterior urethroplasty (n =13), of which 14/16 surgeries (88%) with follow up >90 days were successful. CONCLUSIONS: Although the incidence of RTOG grade 4 UAEs after PCa radiation treatment is not well defined, their associated morbidity is significant, and approximately one third of patients with these high grade complications require UD. Conversely, only about a quarter of patients can be managed with conservative strategies or local surgeries. Reconstruction is successful in selected patients. PMID- 27469290 TI - Fibrin-targeting delivery: a novel platform for cardiac regenerative medicine. PMID- 27469292 TI - A neural network-based method for spectral distortion correction in photon counting x-ray CT. AB - Spectral CT using a photon counting x-ray detector (PCXD) shows great potential for measuring material composition based on energy dependent x-ray attenuation. Spectral CT is especially suited for imaging with K-edge contrast agents to address the otherwise limited contrast in soft tissues. We have developed a micro CT system based on a PCXD. This system enables both 4 energy bins acquisition, as well as full-spectrum mode in which the energy thresholds of the PCXD are swept to sample the full energy spectrum for each detector element and projection angle. Measurements provided by the PCXD, however, are distorted due to undesirable physical effects in the detector and can be very noisy due to photon starvation in narrow energy bins. To address spectral distortions, we propose and demonstrate a novel artificial neural network (ANN)-based spectral distortion correction mechanism, which learns to undo the distortion in spectral CT, resulting in improved material decomposition accuracy. To address noise, post reconstruction denoising based on bilateral filtration, which jointly enforces intensity gradient sparsity between spectral samples, is used to further improve the robustness of ANN training and material decomposition accuracy. Our ANN-based distortion correction method is calibrated using 3D-printed phantoms and a model of our spectral CT system. To enable realistic simulations and validation of our method, we first modeled the spectral distortions using experimental data acquired from (109)Cd and (133)Ba radioactive sources measured with our PCXD. Next, we trained an ANN to learn the relationship between the distorted spectral CT projections and the ideal, distortion-free projections in a calibration step. This required knowledge of the ground truth, distortion-free spectral CT projections, which were obtained by simulating a spectral CT scan of the digital version of a 3D-printed phantom. Once the training was completed, the trained ANN was used to perform distortion correction on any subsequent scans of the same system with the same parameters. We used joint bilateral filtration to perform noise reduction by jointly enforcing intensity gradient sparsity between the reconstructed images for each energy bin. Following reconstruction and denoising, the CT data was spectrally decomposed using the photoelectric effect, Compton scattering, and a K-edge material (i.e. iodine). The ANN-based distortion correction approach was tested using both simulations and experimental data acquired in phantoms and a mouse with our PCXD-based micro-CT system for 4 bins and full-spectrum acquisition modes. The iodine detectability and decomposition accuracy were assessed using the contrast-to-noise ratio and relative error in iodine concentration estimation metrics in images with and without distortion correction. In simulation, the material decomposition accuracy in the reconstructed data was vastly improved following distortion correction and denoising, with 50% and 20% reductions in material concentration measurement error in full-spectrum and 4 energy bins cases, respectively. Overall, experimental data confirms that full-spectrum mode provides superior results to 4 energy mode when the distortion corrections are applied. The material decomposition accuracy in the reconstructed data was vastly improved following distortion correction and denoising, with as much as a 41% reduction in material concentration measurement error for full-spectrum mode, while also bringing the iodine detectability to 4-6 mg ml(-1). Distortion correction also improved the 4 bins mode data, but to a lesser extent. The results demonstrate the experimental feasibility and potential advantages of ANN-based distortion correction and joint bilateral filtration-based denoising for accurate K-edge imaging with a PCXD. Given the computational efficiency with which the ANN can be applied to projection data, the proposed scheme can be readily integrated into existing CT reconstruction pipelines. PMID- 27469293 TI - Erratum to "A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood" [Psychoneuroendocrinology 63 (2016) 109 118]. PMID- 27469291 TI - Delivery of Hydrogen Sulfide by Ultrasound Targeted Microbubble Destruction Attenuates Myocardial Ischemia-reperfusion Injury. AB - Hydrogen sulfide (H2S) is an attractive agent for myocardial ischemia-reperfusion injury, however, systemic delivery of H2S may cause unwanted side effects. Ultrasound targeted microbubble destruction has become a promising tool for organ specific delivery of bioactive substance. We hypothesized that delivery of H2S by ultrasound targeted microbubble destruction attenuates myocardial ischemia reperfusion injury and could avoid unwanted side effects. We prepared microbubbles carrying hydrogen sulfide (hs-MB) with different H2S/C3F8 ratios (4/0, 3/1, 2/2, 1/3, 0/4) and determined the optimal ratio. Release of H2S triggered by ultrasound was investigated. The cardioprotective effect of ultrasound targeted hs-MB destruction was investigated in a rodent model of myocardial ischemia-reperfusion injury. The H2S/C3F8 ratio of 2/2 was found to be an optimal ratio to prepare stable hs-MB with higher H2S loading capability. Ultrasound targeted hs-MB destruction triggered H2S release and increased the concentration of H2S in the myocardium and lung. Ultrasound targeted hs-MB destruction limited myocardial infarct size, preserved left ventricular function and had no influence on haemodynamics and respiratory. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. Delivery of H2S to the myocardium by ultrasound targeted hs-MB destruction attenuates myocardial ischemia-reperfusion injury and may avoid unwanted side effects. PMID- 27469294 TI - Comparison of clinical and radiographic parameters around short (6 to 8 mm in length) and long (11 mm in length) dental implants placed in patients with and without type 2 diabetes mellitus: 3-year follow-up results. AB - OBJECTIVE: To compare the clinical and radiographic parameters around short (6 to 8 mm in length) and long (11 mm in length) dental implants placed in patients with and without type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: Forty five male patients with T2DM (Group-1) and 42 male non-diabetic controls (Group 2) who had undergone implant therapy in the posterior mandible were included. Depending upon the length of the implant, patients were divided into two subgroups: (a) patients with short implants (6-8 mm long) and (b) patients with long implants (11 mm long). Peri-implant plaque index (PI), bleeding on probing (BOP), probing depth (PD) and crestal bone loss (CBL) were measured at 18 and 36 months of follow-up in both groups. Hemoglobin A1c (HbA1c) levels were measured at baseline and after 18 and 36 months of follow-up in both groups. P-values less than 0.05 were considered statistically significant. RESULTS: The mean age of patients in groups 1 and 2 was 42.5 and 40.6 years, respectively. The mean HbA1c levels at baseline among patients in groups 1 and 2 were 7.7% and 4.5%, respectively. At 18 and 36 months of follow-up, the mean HbA1c levels among patients in groups 1 and 2 were 6.6% and 4.5% and 6.5% and 4.4%, respectively. The mean duration of T2DM among patients that received short and long implants was 4.3 years and 4.1 years, respectively. There was no significant difference in PI, BOP, PD and CBL around implants placed in both groups at 18 and 36 months of follow-up. Success rate of short and long dental implants was 100% in both groups. CONCLUSION: Short implants can demonstrate clinical and radiographic stability in a manner similar to conventional long implants in patients with and without T2DM. The role of oral hygiene and glycemic maintenance in this scenario cannot be disregarded. PMID- 27469295 TI - High osteoprotegerin is associated with development of foot ulcer in type 1 diabetes. AB - BACKGROUND AND AIM: The bone-related peptide osteoprotegerin has been linked to vascular calcification and peripheral vascular disease. We investigated the association between osteoprotegerin and development of foot complications in persons with type 1 diabetes. MATERIALS AND METHODS: Prospective observational study of 573 persons with type 1 diabetes, 225 women; age [mean+/-SD] 42.3+/ 10.3years. Plasma osteoprotegerin was measured by ELISA. RESULTS: Median (IQR) osteoprotegerin was 2.80(2.35-3.63)MUg/L and follow-up time (median (range)) was 12.7(0.1-15.6)years. Endpoints included: new foot ulceration (n=153), Charcot foot (n=14), vascular surgery/amputation (n=53), loss of foot pulse (n=57), and peripheral neuropathy (n=99). In unadjusted analyses, higher osteoprotegerin was associated with development of all endpoints (p<=0.026). Higher osteoprotegerin remained associated with development of foot ulcer, and the combination of vascular surgery/amputation, loss of foot pulse and neuropathy (p<=0.001) in a sex and age adjusted model. After further adjustment (nephropathy status, smoking, HbA1c, systolic blood pressure, serum cholesterol, high sensitivity C reactive protein, eGFR, and presence of neuropathy and/or claudication and/or foot ulcer at baseline), higher osteoprotegerin remained associated with development of foot ulcer (HR (95% CI) per doubling: 1.75 (1.04-2.97); p=0.037). CONCLUSION: Higher osteoprotegerin levels were associated with development of foot ulcer, even after comprehensive adjustment. PMID- 27469296 TI - Physical activity and its correlation to diabetic retinopathy. AB - PURPOSE: The lack of physical activity, along with obesity, smoking, hypertension and hyperglycaemia are considered as risk factors for the occurrence of diseases such as diabetes. Primary objective of the study was to investigate potential correlation between physical activity and diabetic retinopathy. PATIENTS AND METHODS: Three hundred and twenty patients were included in the study: 240 patients with diabetes type 2 (80 patients with mild to moderate non proliferative diabetic retinopathy, 80 patients with severe to very severe non proliferative diabetic retinopathy and 80 ones with proliferative diabetic retinopathy) were compared with 80 non-diabetic patients (control group). Physical activity of patients was assessed by the international physical activity questionnaire (IPAQ, 2002). HbA1c and BMI were also measured in diabetic patients. Group comparisons were attempted for levels of physical activity and sedentary behavior. RESULTS: Total physical activity was decreased in patients with severe to very severe non-proliferative diabetic retinopathy and proliferative diabetic retinopathy as compared to patients with mild to moderate non-proliferative diabetic retinopathy and to the control group (p<0.05). Significant negative correlation was detected between HbA1c levels, BMI and physical activity (both p<0.05). Moreover, significant negative correlation between the severity of diabetic retinopathy and physical activity has been demonstrated (p<0.05). CONCLUSIONS: Increased physical activity is associated with less severe levels of diabetic retinopathy, independent of the effects of HbA1c and BMI. PMID- 27469297 TI - Temporally stable adaptation is robust, incomplete and specific. AB - Sensorimotor adaptation, the process that reduces movement errors by learning from sensory feedback, is often studied within a session of about half an hour. Within such a single session, adaptation generally reaches plateau before errors are completely removed. However, adaptation may complete on longer timescales: the slow components of error-based adaptation are associated with good retention. In this study, we tested how adaptation evolves over time by asking participants to perform six adaptation sessions on different days. In these sessions, participants performed a three-dimensional reaching task while visual feedback about endpoint errors was rotated around the cyclopean eye. In addition, context specificity of the adaptation was addressed by measuring inter-limb transfer and transfer to visual and proprioceptive perceptual tasks. We show that from the second session on, the adaptation was retained almost completely across sessions. However, after six learning sessions, adaptation still reached plateau before errors were completely removed. The adaptation was specific: the adaptation did neither transfer to the other hand, nor to the visual, and only marginally to the proprioceptive perceptual estimates. We conclude that motor adaptation is robust, specific and incomplete. PMID- 27469298 TI - A review of the predictive role of functional imaging in patients with mucosal primary head and neck cancer treated with radiation therapy. AB - Advanced radiotherapy techniques, such as intensity-modulated radiotherapy, have been reported to reduce toxicities by improving the dose conformity in mucosal primary head and neck cancer (MPHNC). However, to further optimize the therapeutic ratio, details on individual patient and disease characteristics may be necessary to tailor treatments. This is likely to include identifying poor responders for treatment intensification and good responders for de-escalation strategies. Non-invasive, repeatable imaging biomarkers are attractive modalities in both pre-treatment and intra-treatment response prediction with a view to individualized treatment options. This review has assessed the current literature on the prognostic/predictive role of widely available functional imaging (FI) studies such as fMRI(functional magnetic resonance imaging), functional computed tomography (fCT) and positron-emission-tomography(PET). A literature search was carried out using Medline, Embase and PubMed. Studies were included if imaging was undertaken pre and/or during radiotherapy (with or without the addition of chemotherapy and/or surgery). A total of 99 relevant studies were identified: 14 fMRI, 10 fCT, 59 FDG-PET and 16 non-FDG-PET studies. These articles were reviewed to identify imaging parameters demonstrating a correlation with patient outcome or a factor considered to impact on patient outcome and thus likely to be of potential predictive value in MPHNC and associated future radiotherapy treatment directions. Several studies have demonstrated that both pre-treatment and mid treatment FDG-PET is predictive of outcomes. However, further studies are required to confirm the role of other imaging studies including fMRI and PET using other tracers. There is large heterogeneity within and between published studies, including tumour sites, treatment options, outcome endpoints and parameters assessed. We propose a minimum set of factors that should be reported and make recommendations for studies evaluating the predictive utility in MPHNC. PMID- 27469299 TI - Plasmon resonances in semiconductor materials for detecting photocatalysis at the single-particle level. AB - Hot carriers, generated via the non-radiative decay of localized surface plasmon, can be utilized in photovoltaic and photocatalytic devices. In recent years, most studies have focused on conventional plasmon materials like Au and Ag. However, they suffer from several drawbacks like low energy of the generated hot carriers and a high charge-carrier recombination rate. To resolve these problems, here, we propose the plasmon resonances in heavily self-doped titanium oxide (TiO1.67) to realize effective hot carrier generation. Since the plasmon resonant energy of TiO1.67 nanoparticles (2.56 eV) is larger than the bandgap (2.15 eV), plasmon resonances through interband transition can realize both the generation and separation of hot carriers and bring a new strategy for visible-light photodegradation. The photodegradation rate for methyl orange was about 0.034 min(-1). More importantly, the combination of plasmonic and catalytic properties makes it feasible to investigate the degradation process of different materials and different structures at the single particle level in situ. By detecting the scattering shift, we demonstrated that the TiO1.67 dimer (Deltalambda/DeltalambdaRIU = 0.16) possesses a higher photodegradation rate than an individual nanoparticle (Deltalambda/DeltalambdaRIU = 0.09). We hope this finding may be a beginning, paving the way toward the development of semiconductor plasmonic materials for new applications beyond noble metals. PMID- 27469300 TI - Endogenous signal peptides in recombinant protein production by Pichia pastoris: From in-silico analysis to fermentation. AB - For extracellular recombinant protein production, the efficiency of five endogenous secretion signal peptides (SPs) of Pichia pastoris, SP13 (MLSTILNIFILLLFIQASLQ), SP23 (MKILSALLLLFTLAFA), SP24 (MKVSTTKFLAVFLLVRLVCA), SP26 (MWSLFISGLLIFYPLVLG), SP34 (MRPVLSLLLLLASSVLA), selected based on their D score which quantifies the signal peptide-ness of a given sequence segment, was investigated using recombinant human growth hormone (rhGH) as the model protein. The expression was conducted under glyceraldehyde-3-phosphate dehydrogenase promoter (PGAP). The highest secretion efficiency among endogenous SPs was obtained by SP23 followed by SP24, SP34, SP13 and SP26, respectively. The fermentation characteristics of rhGH production by the use of SP23, the most favorable endogenous SP of P.pastoris, and Saccharomyces cerevisiae alpha-mating factor prepro sequence (alpha-MF) were compared. With respect to the SP23 which is 73 amino acids shorter in length compared to alpha-MF, in high cell density cultures, where carbon and energy source are limited, the substitution of SP23 for alpha-MF seems promising. alpha-MF higher secretion efficiency was verified by major physicochemical properties including hydropathy index, isoelectric point, and aliphatic index. Regarding the examined endogenous SPs, there was no clear correlation between secretion efficiency and major physicochemical properties when each of these properties was considered independently. To find a correlation, factors such as protein N-terminus effect, length of the SP, secondary structure of the SP, and interactions of the selected properties should also be investigated. PMID- 27469301 TI - Recent advances in cured raw ham manufacture. AB - Cured raw hams are a valuable and popular group of meat products. The consumption and international trade have increased during the last years, therefore new technologies to accelerate the production process and to increase product quality and safety are needed. In the current review, an overview of European protected cured raw hams is presented. Furthermore, traditional methods for cured raw ham production together with recent advantages in the techniques for pretreatment (trimming, blade tenderization, and freeze-thawing), curing/salting (tumbling, vacuum impregnation, pulsed pressure, ultrasound, pulsed electric fields, simultaneous thawing/salting), drying/ripening (Quick-Dry-Slice-process, oil drop application, high temperature short time process) and postprocessing (vacuum and modified atmosphere packaging, high hydrostatic pressure, high pressure carbon dioxide, high pressure carbon dioxide with ultrasound) are described. Moreover, application techniques and effects of protective cultures and starter cultures, such as molds, yeasts, coagulase-negative staphylococci and lactic acid bacteria, on cured raw ham quality and safety are reviewed. PMID- 27469303 TI - Olympus chose not to alert US doctors of infections linked to its duodenoscopes. PMID- 27469302 TI - Thymic DCs derived IL-27 regulates the final maturation of CD4(+) SP thymocytes. AB - IL-27, as a pleiotropic cytokine, promotes the differentiation of naive T cells to Th1, while suppressing Th2 and Th17 differentiation in the periphery. However, the role of IL-27 in the thymocyte development remains unknown. Here we showed that IL-27 was highly expressed in thymic plasmacytoid dendritic cells (pDCs) while its receptor expression was mainly detected in CD4(+) single-positive (SP) thymocytes. Deletion of the p28 subunit in DCs resulted in a reduction of the most mature Qa-2(+) subsets of CD4(+) SP T cells. This defect was rescued by intrathymic administration of exogenous IL-27. In vitro differentiation assay further demonstrated that IL-27 alone was able to drive the maturation of the newly generated 6C10(+)CD69(+)CD4(+) SP cells into Qa-2(+) cells. Collectively, this study has revealed an important role of thymic DCs-derived IL-27 in the regulation of the phenotypic maturation of CD4(+) SP thymocytes. PMID- 27469304 TI - Multivalent Inhibitors of Channel-Forming Bacterial Toxins. AB - Rational design of multivalent molecules represents a remarkable modern tool to transform weak non-covalent interactions into strong binding by creating multiple finely-tuned points of contact between multivalent ligands and their supposed multivalent targets. Here, we describe several prominent examples where the multivalent blockers were investigated for their ability to directly obstruct oligomeric channel-forming bacterial exotoxins, such as the pore-forming bacterial toxins and B component of the binary bacterial toxins. We address problems related to the blocker/target symmetry match and nature of the functional groups, as well as chemistry and length of the linkers connecting the functional groups to their multivalent scaffolds. Using the anthrax toxin and AB5 toxin case studies, we briefly review how the oligomeric toxin components can be successfully disabled by the multivalent non-channel-blocking inhibitors, which are based on a variety of multivalent scaffolds. PMID- 27469305 TI - The Regulation of Secondary Metabolism in Photorhabdus. AB - A general definition of secondary metabolism is that it consists of the metabolic pathways and the products of metabolism that are not absolutely required for the survival of the organism. Using this definition, it is now well established that Photorhabdus elaborate an extensive secondary metabolism during the post exponential phase of bacterial growth. This secondary metabolism includes, but is not limited to, the production of light, a stilbene antibiotic and an anthraquinone pigment. In this chapter, the role of secondary metabolism during the life cycle of Photorhabdus will be discussed. Recent work has shown that secondary metabolism in Photorhabdus is required for the mutualistic association between the bacteria and its nematode partner, in particular bacterial secondary metabolism is required to support normal nematode growth and development. An isogenic population of Photorhabdus is phenotypically heterogenous and this facilitates functional partitioning within the population. The relationship between secondary metabolism and the various phenotypic and phase variants that exist in populations of Photorhabdus will also be discussed. Finally, this chapter will also describe the various regulatory nodes that have been identified as being part of the complex regulatory network that is used to control the temporal expression of secondary metabolism in Photorhabdus. PMID- 27469306 TI - Response: Commentary: Heart rate variability and self-control-A meta-analysis. PMID- 27469307 TI - Diffusion-weighted MRI abnormalities in an outbreak of Streptococcus agalactiae Serotype III, multilocus sequence type 283 meningitis. AB - PURPOSE: In 2015, an outbreak of group B streptococcal (GBS) infection caused by Streptococcus agalactiae Serotype III, multilocus sequence type 283, related to consuming infected raw freshwater fish, affected more than 200 patients in Singapore. We describe the clinical, laboratory, and neuroimaging features of a subgroup of adults with central nervous system (CNS) infections caused by GBS. MATERIALS AND METHODS: The database of the Singapore Neurologic Infections Program (SNIP), a national multicenter study for surveillance of infectious neurologic disease, was reviewed to select patients with GBS CNS infection during the outbreak. Cases were diagnosed on the basis of clinical features, cerebrospinal fluid (CSF) findings and identification or isolation of Streptococcus agalactiae in the blood or CSF. Demographic, clinical and neuroradiological information was obtained prospectively and retrospectively abstracted. RESULTS: Fourteen patients (6 male, 8 female; median age, 58 years) presented with fever, meningism, headache, encephalopathy, focal neurological deficits, and/or seizures. All except two were previously healthy. Diffusion weighted imaging (DWI) on admission was abnormal in 13 patients, showing tiny hyperintensities in the subarachnoid space (7 patients), ventricles (6 patients) and brain parenchyma (8 patients); 5 patients had cerebellar abnormalities. CONCLUSION: Among healthy non-pregnant adults infected with Serotype III, multilocus sequence type 283 GBS meningitis linked to eating infected raw freshwater fish, DWI detected small pus collections and unusual cerebellar involvement. A collaborative national surveillance system that includes MRI can be helpful during unusual food-borne zoonotic infectious disease outbreaks. LEVEL OF EVIDENCE: 4 J. Magn. Reson. Imaging 2017;45:507-514. PMID- 27469309 TI - Pattern of Physical Activity Among Sri Lankan Adults in the District of Colombo: A Cross-sectional Study. AB - Physical inactivity is a modifiable risk factor of many non-communicable diseases. The aim of this study was to assess the pattern of physical activity among Sri Lankan adults in the district of Colombo, Sri Lanka. The study was carried out among a sample of 1320 adults aged 20 to 59 years, selected using stratified, cluster sampling method. Physical activity was assessed using the long form of the International Physical Activity Questionnaire validated for Sri Lanka. The prevalence of sufficient physical activity was 82.0% (CI = 78.5-85.0) for males and 79.7% (CI = 76.5-82.6) for females. The odds of having sufficient activity were lower with increase in the level of urbanisation. Activity was achieved mainly through domestic and transport related activity. Only 21.7% carried out at least some activity for leisure. As Sri Lanka continues to urbanize, it is important to find strategies to increase the level of activity especially at leisure. PMID- 27469308 TI - Engineered mesenchymal cell-based patches as controlled VEGF delivery systems to induce extrinsic angiogenesis. AB - Therapeutic over-expression of Vascular Endothelial Growth Factor (VEGF) by transduced progenitors is a promising strategy to efficiently induce angiogenesis in ischemic tissues (e.g. limb muscle and myocardium), but tight control over the micro-environmental distribution of the dose is required to avoid induction of angioma-like tumors. Therapeutic VEGF release was achieved by purified transduced adipose mesenchymal stromal cells (ASC) that homogeneously produce specific VEGF levels, inducing only normal angiogenesis after injection in non-ischemic tissues. However, the therapeutic potential of this approach mostly in the cardiac field is limited by the poor cell survival and the restricted area of effect confined to the cell-injection site. The implantation of cells previously organized in vitro in 3D engineered tissues could overcome these issues. Here we hypothesized that collagen sponge-based construct (patch), generated by ASC expressing controlled VEGF levels, can function as delivery device to induce angiogenesis in surrounding areas (extrinsic vascularization). A 7-mm-thick acellular collagen scaffold (empty), sutured beneath the patch, provided a controlled and reproducible model to clearly investigate the ongoing angiogenesis in subcutaneous mice pockets. VEGF-expressing ASC significantly increased the capillary in-growth inside both the patch itself and the empty scaffold compared to naive cells, leading to significantly improved survival of implanted cells. These data suggest that this strategy confers control (i) on angiogenesis efficacy and safety by means of ASC expressing therapeutic VEGF levels and (ii) over the treated area through the specific localization in an engineered collagen sponge-based patch. STATEMENT OF SIGNIFICANCE: Development of efficient pro angiogenic therapies to restore the micro-vascularization in ischemic tissues is still an open issue. Although extensively investigated, the promising approach based on injections of progenitors transduced to over-express Vascular Endothelial Growth Factor (VEGF) has still several limitations: (i) need of a tight control over the microenvironmental VEGF dose to avoid angioma-like tumor growth; (ii) poor implanted cell survival; (iii) effect area restricted mainly to the injection sites. Here, we aimed to overcome these drawbacks by generating a novel cell-based controlled VEGF delivery device. In particular, transduced mesenchymal cells, purified to release a sustained, safe and efficient VEGF dose, were organized in three-dimensional engineered tissues to improve cell survival and provide a uniform vascularization throughout both the mm-thick implanted constructs themselves and the surrounding area. PMID- 27469310 TI - Anemia Status in Relation to Body Mass Index Among Women of Childbearing Age in Bangladesh. AB - Undernutrition and micronutrient deficiency disorders together constitute a major public health concern in Bangladesh. Among many vitamin and mineral deficiency diseases, iron-deficiency anemia remains the most persistent and has been shown to contribute to high maternal and child morbidity and mortality in the country. In parallel with micronutrient malnutrition, the country is also experiencing a rising epidemic of overweight and obesity due to changing pattern in dietary behavior and body mass index status. Previous empirical studies have demonstrated a strong correlation between body weight and anemia status. However, results remain inconclusive and for Bangladesh such evidence is nonexistent. To this end, we conducted this study using Bangladesh Demographic and Health Survey 2011 data with an aim to explore the association between body mass index and anemia status among adult women in Bangladesh. According to the findings, age between 15 and 29 years ( P < .001, OR = 1.30, 95% CI = 1.12-1.49), experiencing first birth before reaching the age of 18 years ( P < .001, OR = 1.31, 95% CI = 1.15-1.50), lack of access to potable water ( P = .013, OR = 1.467, 95%CI = 1.085- 1.982), being underweight ( P < .001, 95% CI = 1.208-1.570) and normal weight ( P < .001, 95% CI = 1.819-2.516) were significantly associated with anemia status. PMID- 27469311 TI - Comments on "Prediction of low-risk breast cancer using perfusion parameters and apparent diffusion coefficient". PMID- 27469312 TI - Flow and pressure measurements in aneurysms and arteriovenous malformations with phase contrast MR imaging. AB - PURPOSE: To explore phase contrast (PC) magnetic resonance imaging of aneurysms and arteriovenous malformations (AVM). PC imaging obtains a vector field of the velocity and can yield additional hemodynamic information, including: volume flow rate (VFR) and intravascular pressure. We expect to find lower VFR distal to aneurysms and higher VFR in vessels of the AVM. MATERIALS AND METHODS: Five cerebral aneurysm and three AVM patients were imaged with PC techniques and compared to VFR of a healthy cohort. VFR was calculated in vessel segments in each patient and compared statistically to the healthy cohort by computing the z score. Intravascular pressure was calculated in the aneurysms and in the nidus of each AVM. RESULTS: We found that patients with aneurysm had z<-0.48 in vessels distal to the aneurysm (reduced flow), while AVM patients had z>6 in some vessels supplying and draining the nidus (increased flow). Pressures in aneurysms were highly variable between subjects and location, while in the nidus of the AVM patients; pressure trended higher in larger AVMs. CONCLUSION: The study findings confirm the expectation of lower distal flow in aneurysm and higher arterial and venous flow in AVM patients. PMID- 27469313 TI - Rapid and reliable tract-based spatial statistics pipeline for diffusion tensor imaging in the neonatal brain: Applications to the white matter development and lesions. AB - PURPOSE: The relatively poor image contrast and variation in the neonatal brain size are technical challenges associated with the typical tract-based spatial statistics (TBSS) for the target identification and normalization. This study aimed to develop a rapid and reliable pipeline for the neonatal TBSS. MATERIALS AND METHODS: A rapid TBSS strategy was proposed based on the group-wise target choice for fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). The most representative subject of the entire group was identified via (a) initial group-averaged template creation (b) followed by identification of the target with the minimum warp displacement score between the individual and the group-averaged template. The computation time, registration quality, measurement of regional values, and statistical analyses were evaluated in two applications: brain white matter development in normal term neonates, and alterations in preterm neonates with white matter lesions compared to the matched controls. These performances in the proposed pipeline were compared with those in the typical and previous neonatal TBSS workflows. RESULTS: Target choice using the proposed strategy is faster, compared with the previous TBSS pipelines, especially with the increase of the sample size. Registration errors between individuals and the target are assessed through warp displacement scores. Smaller warp displacement scores are observed for the proposed method than the typical pipeline. Due to the relatively accurate registration, the proposed method results in lower standard deviations and higher averaged values of FA across subjects. Additionally, more areas with significant changes related to the development and white matter lesions are detected using the proposed method than previous TBSS pipelines. The proposed pipeline provides stronger correlation between FA and gestational age, and larger difference between preterm neonates with white matter lesions and controls. CONCLUSION: The proposed TBSS pipeline improves the efficiency and reliability of the DTI analysis in the neonatal brain. PMID- 27469314 TI - Optimizing the ICE decoupling element distance to improve monopole antenna arrays for 7 Tesla MRI. AB - The induced current elimination (ICE) method has been previously applied to decouple monopole coil arrays in ultrahigh field MRI. However, the method creates low B1+ spots near the decoupling elements. In this study, we aim to improve the performance of ICE-decoupled monopole array in human head imaging at 7 Tesla. Eight-channel ICE-decoupled monopole arrays were optimized by varying the position of the decoupling elements. A series of numerical studies were performed using the co-simulation method. In simulation, decoupling performance, quality (Q ) values and transmit field (B1+) were comparatively investigated. In addition, we constructed an optimized ICE-decoupled monopole array and compared its performance with the unoptimized array. The simulation results showed that a good trade-off between decoupling and B1+ loss can be obtained when decoupling elements were moved 2.5-cm away from coil elements. This was validated by in-vivo MR imaging using the constructed array. Compared with the unoptimized ICE decoupled monopole array, the optimized array had a more homogeneous transmit field and no dark spots or signal cancellations in the MR images. PMID- 27469315 TI - Temporal-spatial mean-shift clustering analysis to improve functional MRI activation detection. AB - Cluster analysis (CA) is often used in functional magnetic resonance imaging (fMRI) analysis to improve detection of functional activations. Commonly used clustering techniques typically only consider spatial information of a statistical parametric image (SPI) in their calculations. This study examines incorporating the temporal characteristics of acquired fMRI data with mean-shift clustering (MSC) for fMRI analysis to enhance activation detections. Simulated data and real fMRI data was used to compare the commonly used cluster analysis with MSC using a feature space containing temporal characteristics. Receiver Operating Characteristic curves show that improvements in low contrast to noise scenarios using MSC over CA and our previous MSC technique at all tested simulated activation sizes. The proposed MSC technique with a feature space using both temporal and spatial data characteristics shows improved activation detection for both simulated and real Blood oxygen level dependent (BOLD) fMRI data (approximately 60% increase). The proposed techniques are useful in techniques that inherently have low contrast to noise ratios, such as non-proton imaging or high resolution BOLD fMRI. PMID- 27469316 TI - Connecting chromosome replication with cell growth in bacteria. AB - For bacteria to proliferate they must duplicate their genetic material so that it can be passed to their progeny. This requires that DNA replication is coordinated with cell growth and division. In the natural environment bacterial growth is dynamic and strongly influenced by changes in nutrient availability. Recent studies have found that bacteria utilize a range of regulatory systems, many of them species-specific, to coordinate DNA replication with cell growth. This variability likely reflects the diverse lifestyles of different bacterial types. PMID- 27469318 TI - Cultural Differences in the Reciprocal Relations between Emotion Suppression Coping, Depressive Symptoms and Interpersonal Functioning among Adolescents. AB - The current study examined the prospective relations between emotion suppression and maladjustment (i.e., depressive symptoms, family stress events, peer stress events, and family and peer support) among Vietnamese American (n = 372) and European American adolescents (n = 304). We found that at baseline Vietnamese Americans adolescents reported greater use of emotion suppression coping than European American adolescents. Multi-group structural equation modeling indicated that for European American teens emotion suppression was significantly related to increased depression symptoms and decreased quality of peer relationships. In contrast, for the Vietnamese Americans teens emotion suppression relations to later maladjustment was either nonsignificant or attenuated relative to the European American. These findings suggest ethnic group differences in both the utilization, and consequences and function of emotion suppression among Vietnamese American and European American adolescents. PMID- 27469317 TI - DSM-5 Posttraumatic Stress Disorder Symptom Structure in Disaster-Exposed Adolescents: Stability across Gender and Relation to Behavioral Problems. AB - Given the significant modifications to posttraumatic stress disorder (PTSD) symptom criteria from DSM-IV to DSM-5, a better understanding of the dimensionality underlying DSM-5 PTSD symptoms among adolescents is needed. However, to date, whether gender moderates the latent structure of DSM-5 PTSD symptoms in youth remains unclear. Meanwhile, little is known about how distinct PTSD dimensions relate to adolescent behavioral problems. The aim of this study was to fill these gaps. A sample of 1184 disaster-exposed Chinese adolescents (53.8 % girls) with age ranging from 13 to 17 years (M = 14.3, SD = 0.8) completed the PTSD Checklist for DSM-5, and the Withdrawn, Aggressive Behavior, and Delinquent Behavior subscales of the Youth Self-Report. Confirmatory factor analyses revealed that the seven-factor hybrid PTSD model provided the best fit to the data for both girls and boys. Measurement equivalence of this model held across gender, although girls had higher mean scores than boys on some factors. Differential patterns of associations emerged between PTSD dimensions and behavioral problems, with anhedonia symptoms most strongly relating to social withdrawal, and externalizing behavior symptoms most strongly relating to aggression and delinquency. These findings further support the gender invariance and external criterion validity of the newly refined hybrid model that best represents DSM-5 PTSD symptom structure in youth, and carry implications for accurate assessment, diagnosis, and gender comparison of DSM-5 PTSD symptomatology, and potential symptom targets for PTSD intervention among adolescent disaster survivors. PMID- 27469319 TI - The Longitudinal Effects of Oppositional Defiant Disorder Symptoms on Academic and Occupational Functioning in the Transition to Young Adulthood. AB - The young adult years are particularly important for accruing the education and work experience needed for long-term economic stability. We examine the effects of symptoms of ODD at baseline (i.e., T1 ages 12 to 18 years; N = 662; 48 % male) and of increases in these symptoms on academic and occupational functioning in young adulthood (i.e., T6 ages 22 to 29 years; N = 478; 45 % male) using multiple measures; including achievement levels (i.e., educational attainment, occupational prestige, and income) and financial and work stress (i.e., debt, financial strain, and perceived workplace stress). Our findings show that both adolescent levels of and increases in symptoms of ODD influence academic and occupational functioning in young adulthood. We discuss the implications of ODD symptoms for accruing economic capital in young adulthood, as well as approaches to detecting and intervening that are needed to halt the potentially cascading effects of ODD symptoms. PMID- 27469320 TI - Risk factors associated with bleeding after multi antithrombotic therapy during implantation of cardiac implantable electronic devices. AB - Previous studies showed that continuous anticoagulation or single antiplatelet therapy during implantations of cardiac implantable electronic devices (CIED) was relatively safe. However, the safety of continuous multi antithrombotic therapy (AT) in patients undergoing CIED interventions has not been clearly defined. We sought to evaluate the safety of this therapy during CIED implantations. A total of 300 consecutive patients (mean 69 years old, 171 males) with CIED implantations were enrolled in this study. The patients were divided into 6 groups [No-AT, oral anticoagulant therapy (OAT), single antiplatelet therapy (SAPT), OAT and SAPT, dual antiplatelet therapy (DAPT), triple AT (TAT)], and the perioperative complications were evaluated. Clinically significant pocket hematomas (PH) were defined as PH needing surgical intervention, prolonged hospitalizations, interruption of AT, or blood product transfusions. There were 129, 89, 49, 20, 10, and 3 patients in No-AT, OAT, SAPT, OAT + SAPT, DAPT, and TAT groups, respectively. The occurrence of clinically significant PH and thromboembolism did not differ among 6 groups (p = 0.145 and p = 0.795, respectively). However, high HAS-BLED score and valvular heart disease (VHD) were associated with clinically significant PH (p = 0.014 and p = 0.015, respectively). Continuous multi AT may be tolerated, but patients with high HAS BLED score or VHD would require a careful attention during CIED implantations. PMID- 27469322 TI - Corrigendum. PMID- 27469321 TI - Comparison of salt with low-dose furosemide and carperitide for treating acute decompensated heart failure: a single-center retrospective cohort study. AB - Hypertonic saline with furosemide has been proposed for a long time as an effective therapeutic option for the treatment of acute decompensated heart failure (ADHF). We previously reported the efficacy of continuous infusion of 1.7 % hypertonic saline plus low-dose furosemide in treatment for ADHF. Although this therapeutic strategy can be a useful option for effective decongestion in treatment for ADHF, there is no study that assesses the effect and safety of saline supplementation compared with standard therapy in Japan. The aim of this study was to investigate the efficacy, safety, and cost-effectiveness of 1.7 % hypertonic saline plus low-dose furosemide infusion compared with carperitide. We compared clinical outcomes, adverse events, and cost for patients receiving carperitide (carperitide group) with those for patients receiving 1.7 % hypertonic saline plus low-dose furosemide (salt group) during the initial hospitalization for ADHF. The cost analysis was performed on the basis of the previous report about cost-effectiveness of acute heart failure. A total of 175 ADHF patients received either carperitide (n = 111) or 1.7 % hypertonic saline plus low-dose furosemide infusion (n = 64) as initial treatment. There were no differences in length of hospital stay (27 +/- 19 vs. 25 +/- 16 day, p = 0.170) and infusion period (7.2 +/- 6.1 vs. 8.4 +/- 7.5 day, p = 0.474) between the two groups. The incidence of rehospitalization did not differ at 1 month (7.6 vs. 6.6 %, p = 1.000) and 1 year (36.8 vs. 37.7 %, p = 0.907) between the two groups. The Kaplan-Meier curves revealed no significant difference for 1 year all-cause mortality between the two groups (log-rank, p = 0.724). The single hospitalization cost was 95,314 yen lower and the yearly hospitalization cost 125,628 yen lower in the salt group compared with the carperitide group. Thus, intravenous 1.7 % hypertonic saline plus low-dose furosemide infusion is as effective as carperitide in terms of clinical outcome and is a cost-effective therapeutic strategy for the treatment of ADHF. PMID- 27469323 TI - Computational Screening of Drug Solvates. AB - PURPOSE: Solvates are mainly undesired by-products during the pharmaceutical development of new drugs. In addition, solvate formation may also distort solubility measurements. The presented study introduces a simple computational approach that allows for the identification of drug solvent pairs which most likely form crystalline solid phases. METHODS: The mixing enthalpy as a measure for drug-solvent complementarity is obtained by computational liquid phase thermodynamics (COSMO-RS theory). In addition a few other simple descriptors were taking into account describing the shape and topology of the drug and the solvent. Using an extensive dataset of drug solvent pairs a simple and statistically robust model is developed which allows for a rough assessment of a solvent's ability to form a solvate. RESULTS: Similar to the related issue of cocrystal screening, the mixing (or excess) enthalpy of the subcooled liquid mixture of the drug-solvent pair proves to be an important quantity controlling solvate formation. Due to the fact that many solvates form inclusion compounds, the solvent shape is another important factor influencing solvate formation. Solvates forming channel-like voids in the solid state are predicted less well. CONCLUSION: The approach ranks any drug-solvent pair that forms a solvate before any non-solvate by a probability of about 81% (AUC = 0.81), giving a significant advantage over any trial and error approach. Hence it can help to identify suitable solvent candidates early in the drug development process. PMID- 27469324 TI - Characterization of Pharmacokinetics in the Gottingen Minipig with Reference Human Drugs: An In Vitro and In Vivo Approach. AB - PURPOSE: This study aims to expand our understanding of the mechanisms of drug absorption, distribution, metabolism and excretion in the Gottingen minipig to aid a knowledge-driven selection of the optimal species for preclinical pharmaceutical research. METHODS: The pharmacokinetics of seven reference compounds (antipyrine, atenolol, cimetidine, diazepam, hydrochlorothiazide, midazolam and theophylline) was investigated after intravenous and oral dosing in minipigs. Supportive in vitro data were generated on hepatocellularity, metabolic clearance in hepatocytes, blood cell and plasma protein binding and metabolism routes. RESULTS: Systemic plasma clearance for the seven drugs ranged from low (1.1 ml/min/kg, theophylline) to close to liver blood flow (37.4 ml/min/kg, cimetidine). Volume of distribution in minipigs ranged from 0.7 L/kg for antipyrine to 3.2 L/kg for hydrochlorothiazide. A gender-related difference of in vivo metabolic clearance was observed for antipyrine. The hepatocellularity for minipig was determined as 124 Mcells/g liver, similar to the values reported for human. Based on these data a preliminary in vitro to in vivo correlation (IVIVC) for metabolic clearance measured in hepatocytes was investigated. Metabolite profiles of diazepam and midazolam compared well between minipig and human. CONCLUSIONS: The results of the present study support the use of in vitro metabolism data for the evaluation of minipig in preclinical research and safety testing. PMID- 27469325 TI - Scarcity of autoreactive human blood IgA+ memory B cells. AB - Class-switched memory B cells are key components of the "reactive" humoral immunity, which ensures a fast and massive secretion of high-affinity antigen specific antibodies upon antigenic challenge. In humans, IgA class-switched (IgA+ ) memory B cells and IgA antibodies are abundant in the blood. Although circulating IgA+ memory B cells and their corresponding secreted immunoglobulins likely possess major protective and/or regulatory immune roles, little is known about their specificity and function. Here, we show that IgA+ and IgG+ memory B cell antibodies cloned from the same healthy humans share common immunoglobulin gene features. IgA and IgG memory antibodies have comparable lack of reactivity to vaccines, common mucosa-tropic viruses and commensal bacteria. However, the IgA+ memory B-cell compartment contains fewer polyreactive clones and importantly, only rare self-reactive clones compared to IgG+ memory B cells. Self reactivity of IgAs is acquired following B-cell affinity maturation but not antibody class switching. Together, our data suggest the existence of different regulatory mechanisms for removing autoreactive clones from the IgG+ and IgA+ memory B-cell repertoires, and/or different maturation pathways potentially reflecting the distinct nature and localization of the cognate antigens recognized by individual B-cell populations. PMID- 27469326 TI - Cyclin D1 expression in peripheral T-cell lymphomas. AB - Cyclin D1 is an important regulator of the cell cycle and overexpression of this protein by immunohistochemistry is characteristically seen in mantle cell lymphoma and other B-cell neoplasms. However, little is known about the expression of this protein in T-cell lymphomas. Cyclin-dependent kinase pathway inhibitors are in development, therefore identifying cyclin D1-positive T-cell lymphomas may provide a therapeutic target in a disease where novel treatments are urgently needed. We collected 200 peripheral T-cell lymphomas from three institutions including the following types of cases: 34 anaplastic large cell lymphoma, ALK+, 44 anaplastic large cell lymphoma, ALK negative, 68 peripheral T cell lymphomas, not otherwise specified, 24 angioimmunoblastic T-cell lymphomas, 7 extranodal NK/T-cell lymphomas, 4 enteropathy associated T-cell lymphomas, 3 hepatosplenic T-cell lymphomas, 12 cutaneous T-cell lymphomas, and 4 large granular lymphocytic leukemias. Immunohistochemical stains for cyclin D1 protein (SP4 clone) were performed on paraffin-embedded tissue. In a subset of cases, IGH/CCND1 fluorescence in situ hybridization analysis was also performed. Cyclin D1 staining was predominantly seen in anaplastic large cell lymphoma, including 8 of 34 cases with ALK+ anaplastic large cell lymphoma (24%), and 3 of 44 cases of ALK-negative (7%) anaplastic large cell lymphoma. Three cases of peripheral T cell lymphoma, not otherwise specified, were also positive (3/68, 4%). All other T-cell lymphomas were negative for cyclin D1. In four of the cyclin D1-positive T cell lymphomas by immunohistochemistry, fluorescence in situ hybridization analysis was negative for IGH/CCND1 translocation or extra copies of the CCND1 gene. Cyclin D1 overexpression by immunohistochemistry is not limited to B-cell lymphomas and is also observed in some peripheral T-cell lymphomas, particularly in anaplastic large cell lymphoma, ALK+. Cyclin D1 expression was not associated with extra copies or translocation of the CCND1 gene. Cyclin D1 overexpression may be the result of a post-translational phenomenon and may represent a potential therapeutic target using agents that target the cyclin-dependent kinase pathway. PMID- 27469327 TI - Recurrent fusion of the genes FN1 and ALK in gastrointestinal leiomyomas. AB - Leiomyomas of the gastrointestinal tract are mostly found in the esophagus, stomach, and colon. Genetic information about them is very limited and no fusion genes have been described. We present herein cytogenetic and molecular genetic analyses of two gastrointestinal leiomyomas found in the esophagus and small intestine. The esophageal leiomyoma had the karyotype 45,Y,der(X)t(X;6)(p22;p21),inv(2)(p23q35),add(6)(p21),-11[cp6]/46,XY[7]. The intestinal leiomyoma karyotype was 46,X,add(X)(q2?),der(2)add(2)(p23)add(2)(q33),add(4)(p14),add(14)(q22)[10]/47,XX, 12[2]/46,XX[1]. RNA-sequencing detected FN1-ALK fusion transcripts in both tumors. RT-PCR together with Sanger sequencing verified the presence of the FN1 ALK fusion transcripts. Fluorescence in situ hybridization using an ALK breakapart probe further confirmed the rearrangement of the ALK gene. Immunohistochemical investigation of ALK in the leiomyoma of the small intestine revealed positivity with strong granular cytoplasmatic staining in the tumor cells. This is the first ever ALK fusion reported in gastrointestinal leiomyomas. Our results are of potential clinical importance because crizotinib, a selective ALK inhibitor, has demonstrated effect in patients whose tumors harbor ALK rearrangements. Thus, ALK emerges as a possible therapeutic target in patients whose tumors, including gastrointestinal leiomyomas, carry ALK fusions. PMID- 27469328 TI - A novel morphological approach to gonads in disorders of sex development. AB - Disorders of sex development are defined as congenital conditions with discordance between the phenotype, the genotype, the karyotype, and the hormonal profile. The disorders of sex development consensus classification established in 2005 are mainly based on chromosomal and biological data. However, histological anomalies are not considered. The aims of this study were to define the specific pathological features of gonads in various groups of disorders of sex development in order to clarify the nosology of histological findings and to evaluate the tumor risk in case of a conservative approach. One hundred and seventy-five samples from 86 patients with disorders of sex development were analyzed following a strict histological reading protocol. The term 'gonadal dysgenesis' for the histological analysis was found confusing and therefore excluded. The concept of 'dysplasia' was subsequently introduced in order to describe the architectural disorganization of the gonad (various degrees of irregular seminiferous tubules, thin albuginea, fibrous interstitium). Five histological types were identified: normal gonad, hypoplastic testis, dysplastic testis, streak gonad, and ovotestis. The analysis showed an association between undifferentiated gonadal tissue, a potential precursor of gonadoblastoma, and dysplasia. Dysplasia and undifferentiated gonadal tissue were only encountered in cases of genetic or chromosomal abnormality ('dysgenesis' groups in the disorders of sex development consensus classification). 'Dysgenetic testes', related to an embryonic malformation of the gonad, have variable histological presentations, from normal to streak. Conversely, gonads associated with hormonal deficiencies always display a normal architecture. A loss of expression of AMH and alpha inhibin was identified in dysplastic areas. Foci of abnormal expression of the CD117 and OCT4 immature germ cells markers in dysplasia and undifferentiated gonadal tissue were associated with an increased risk of neoplasia. This morphological analysis aims at clarifying the histological classification and gives an indication of tumor risk of gonads in disorders of sex development. PMID- 27469329 TI - Intrapancreatic distal common bile duct carcinoma: Analysis, staging considerations, and comparison with pancreatic ductal and ampullary adenocarcinomas. AB - Distal common bile duct carcinoma is a poorly characterized entity for reasons such as variable terminology and difficulty in determining site of origin of intrapancreatic lesions. We compared clinicopathologic features of pancreatobiliary-type adenocarcinomas within the pancreas, but arising from the distal common bile duct, with those of pancreatic and ampullary origin. Upon careful review of 1017 pancreatoduodenectomy specimens with primary adenocarcinoma, 52 (5%) qualified as intrapancreatic distal common bile duct carcinoma. Five associated with an intraductal papillary neoplasm were excluded; the remaining 47 were compared to 109 pancreatic ductal adenocarcinomas and 133 ampullary carcinomas. Distal common bile duct carcinoma patients had a younger median age (58 years) than pancreatic ductal adenocarcinoma patients (65 years) and ampullary carcinoma patients (68 years). Distal common bile duct carcinoma was intermediate between pancreatic ductal adenocarcinoma and ampullary carcinoma with regard to tumor size and rates of node metastases and margin positivity. Median survival was better than for pancreatic ductal adenocarcinoma (P=0.0010) but worse than for ampullary carcinoma (P=0.0006). Distal common bile duct carcinoma often formed an even band around the common bile duct and commonly showed intraglandular neutrophil-rich debris and a small tubular pattern. Poor prognostic indicators included node metastasis (P=0.0010), lymphovascular invasion (P=0.0299), and margin positivity (P=0.0069). Categorizing the tumors based on size also had prognostic relevance (P=0.0096), unlike categorization based on anatomic structures invaded. Primary distal common bile duct carcinoma is seen in younger patients than pancreatic ductal adenocarcinoma or ampullary carcinoma. Its prognosis is significantly better than pancreatic ductal adenocarcinoma and worse than ampullary carcinoma, at least partly because of differences in clinical presentation. Use of size-based criteria for staging appears to improve its prognostic relevance. Invasive pancreatobiliary-type distal common bile duct carcinomas are uncommon in the West and have substantial clinicopathologic differences from carcinomas arising from the pancreas and ampulla. PMID- 27469330 TI - Correlation of exon 3 beta-catenin mutations with glutamine synthetase staining patterns in hepatocellular adenoma and hepatocellular carcinoma. AB - The current clinical practice is based on the assumption of strong correlation between diffuse glutamine synthetase expression and beta-catenin activation in hepatocellular adenoma and hepatocellular carcinoma. This high correlation is based on limited data and may represent an oversimplification as glutamine synthetase staining patterns show wide variability in clinical practice. Standardized criteria for interpreting diverse glutamine synthetase patterns, and the association between each pattern and beta-catenin mutations is not clearly established. This study examines the correlation between glutamine synthetase staining patterns and beta-catenin mutations in 15 typical hepatocellular adenomas, 5 atypical hepatocellular neoplasms and 60 hepatocellular carcinomas. Glutamine synthetase staining was classified into one of the three patterns: (a) diffuse homogeneous: moderate-to-strong cytoplasmic staining in >90% of lesional cells, without a map-like pattern, (b) diffuse heterogeneous: moderate-to-strong staining in 50-90% of lesional cells, without a map-like pattern, and (c) patchy: moderate-to-strong staining in <50% of lesional cells (often perivascular), or weak staining irrespective of the extent, and all other staining patterns (including negative cases). Sanger sequencing of CTNNB1 exon 3 was performed in all cases. Of hepatocellular tumors with diffuse glutamine synthetase staining (homogeneous or heterogeneous), an exon 3 beta-catenin mutation was detected in 33% (2/6) of typical hepatocellular adenoma, 75% (3/4) of atypical hepatocellular neoplasm and 17% (8/47) of hepatocellular carcinomas. An exon 3 mutation was also observed in 15% (2/13) of hepatocellular carcinomas with patchy glutamine synthetase staining. The results show a modest correlation between diffuse glutamine synthetase immunostaining and exon 3 beta-catenin mutations in hepatocellular adenoma and hepatocellular carcinoma with discrepancy rates >50% in both hepatocellular adenoma and hepatocellular carcinoma. The interpretation of beta-catenin activation based on glutamine synthetase staining should be performed with caution, and the undetermined significance of various glutamine synthetase patterns should be highlighted in pathology reports. PMID- 27469331 TI - High fidelity of driver chromosomal alterations among primary and metastatic renal cell carcinomas: implications for tumor clonal evolution and treatment. AB - Recent studies have demonstrated considerable genomic heterogeneity in both primary and metastatic renal cell carcinoma (RCC). This mutational diversity has serious implications for the development and implementation of targeted molecular therapies. We evaluated 39 cases of primary RCC tumors with their matched metastatic tumors to determine if the hallmark chromosomal anomalies of these tumors are preserved over the course of disease progression. Thirty-nine matched pairs of primary and metastatic RCCs (20 clear cell RCC, 16 papillary RCC, and 3 chromophobe RCC) were analyzed. All clear cell RCC and papillary RCC tumors were evaluated for chromosome 3p deletion, trisomy 7 and 17 using fluorescence in situ hybridization. Chromophobe RCC tumors were evaluated for genetic alterations in chromosomes 1, 2, 6, 10, and 17. Of the 20 clear cell RCC tumors, 18 primary tumors (90%) showed a deletion of chromosome 3p and were disomic for chromosomes 7 and 17. All molecular aberrations were conserved within the matched metastatic tumor. Of the 16 papillary RCC tumors, 10 primary tumors (62%) showed trisomy for both chromosomes 7 and 17 without 3p deletion. These molecular aberrations and others were conserved in the paired metastatic tumors. Of the three chromophobe RCC tumors, multiple genetic anomalies were identified in chromosomes 1, 2, 6, 10, and 17. These chromosomal aberrations were conserved in the matched metastatic tumors. Our results demonstrated genomic fidelity among the primary and metastatic lesions in RCCs. These findings may have important clinical and diagnostic implications. PMID- 27469333 TI - PELI1 expression is correlated with MYC and BCL6 expression and associated with poor prognosis in diffuse large B-cell lymphoma. AB - PELI is a family of E3 ubiquitin ligases that regulate protein activity through a post-translational modification, ubiquitination. While PELI1 has been found to play a pivotal role in inflammatory processes through the activation of Toll-like receptor signaling and the NF-kB pathway, the role of PELI1 in oncogenesis has not been the subject of much investigation. We aimed to explore PELI1 expression in various malignant lymphomas and identify clinicopathologic significance. Immunohistochemistry for PELI1 was performed on a total of 502 cases, including 406 B-cell, 76 T or NK-cell, and 20 Hodgkin lymphomas. High expression of PELI1 was found in high-grade B-cell lymphoma cases such as diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma, whereas low-grade B-cell lymphoma, T/NK-cell lymphoma, and Hodgkin lymphoma cases showed very low levels of expression. In vitro cell line studies, the results of western blot, and RT PCR were concordant with those of the immunohistochemical results; RL7, Pfeiffer, SUDHL-2, DOHH2, and Ramos cell lines showed high levels of PELI1 protein and mRNA expression. In 182 diffuse large B-cell lymphoma, PELI1 expression was positively correlated with the expression of MYC, BCL6, BCL2, and MUM1 (Spearman's rho=0.427, 0.507, 0.246, and 0.137, respectively; P<0.001, <0.001, 0.001, and 0.066, respectively). In diffuse large B-cell lymphoma, high expression of PELI1 was associated with frequent bone marrow involvement (P=0.013) and shorter relapse-free survival (P=0.002). Our results suggest that PELI1 might participate in B-cell maturation or oncogenic activation of aggressive B-cell lymphomas, both during and after germinal center stages. PMID- 27469332 TI - Clinicopathological effects of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors. AB - Recently, several studies have reported that dysfunctions in protein phosphatase 2A (PP2A) caused by alterations in protein phosphatase 2 regulatory subunit A, alpha (PPP2R1A) are responsible for tumorigenesis and tumor progression in several types of cancers. The impact of PPP2R1A mutations remains unknown in gastrointestinal stromal tumors (GISTs), although mutations in KIT and PDGFRA, which result in constitutive activation of the receptor tyrosine kinase pathway, are important in GIST tumorigenesis. In this study, we performed mutation analysis of PPP2R1A to examine the frequency of PPP2R1A mutations and their clinicopathological correlation in 94 GIST cases. In addition, we performed an in vitro analysis to investigate the effects of PPP2R1A mutations on cell proliferation and kinase phosphorylation in GIST cells. Seventeen GIST cases (18%) harbored mutations in PPP2R1A. All but one of these 17 cases harbored a KIT, PDGFRA, HRAS, NRAS, or KRAS mutation as the oncogenic driver mutation, and the remaining case was immunohistochemically negative for succinate dehydrogenase B (SDHB). Multivariate analysis showed that larger tumor size, higher mitotic rate, and PPP2R1A mutation are independent prognostic factors for overall survival; however, PPP2R1A mutation was not an independent prognostic factor for disease-free survival. The transduction of GIST cells with mutant PPP2R1A induced an accelerated growth rate via increased phosphorylation of Akt1/2, ERK1/2, and WNK1, a kinase associated with angiogenesis. In addition, the transduction of GIST cells with mutant PPP2R1A caused increased c-kit phosphorylation, suggesting that c-kit is also a target of PP2A, reinforcing the tumorigenic capabilities of c-kit. Furthermore, the transducing GIST cells with wild-type PP2A dephosphorylated mutant c-kit. This study provides a new insight into the biology of GISTs and their phosphatase activity, and activated PP2A could be a therapeutic target in GISTs. PMID- 27469334 TI - Paraburkholderia caffeinilytica sp. nov., isolated from the soil of a tea plantation. AB - A novel bacterium, designated strain CF1T, was isolated from a soil sample of a tea plantation and its taxonomic position was determined using a polyphasic approach. Strain CF1T was a Gram-stain-negative, facultatively anaerobic, non sporulating, non-motile and rod-shaped bacterium. Optimum growth occurred at 25 degrees C and pH 6.0. Comparative analysis of the 16S rRNA gene sequence showed that the isolate belongs to the genus Paraburkholderia, showing highest levels of similarity with respect to Paraburkholderia sediminicola LMG 24238T (98.44 %). Additionally, strain CF1T, P. sediminicola LMG 24238T and Paraburkholderia aspalathi LMG 27731 formed a distinct group in the phylogenetic tree based on 16S rRNA gene sequences. The predominant ubiquinone was Q-8, and the polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminophospholipid, two unidentified aminolipids and two unidentified polar lipids. The DNA G+C content was 60.2 mol%, and the major fatty acids were C16 : 0, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c). The DNA-DNA relatedness values between strain CF1T and its close relatives including P. sediminicola LMG 24238T and P. aspalathi LMG 27731 49.3+/-0.4 % and 38.3+/-0.5 %, respectively. On the basis of phylogenetic analysis, phenotypic and genotypic data, it is concluded that the isolate represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia caffeinilytica sp. nov. is proposed. The type strain is CF1T (=LMG 28690T=CGMCC 1.15103T). PMID- 27469335 TI - Neuroprotective effect of bee venom is mediated by reduced astrocyte activation in a subchronic MPTP-induced model of Parkinson's disease. AB - Bee venom (BV), also known as apitoxin, is widely used in traditional oriental medicine to treat immune-related diseases. Recent studies suggest that BV could be beneficial for the treatment of neurodegenerative diseases. Parkinson's disease (PD) is the second most common neurodegenerative disease next to Alzheimer's disease, and PD pathologies are closely associated with neuroinflammation. Previous studies have suggested the neuroprotective effects of BV in animal models of PD are due to the modulation of inflammation. However, the molecular mechanisms responsible for the anti-neuroinflammatory effect of BV have not been elucidated in astrocytes. Here, the authors investigated the neuroprotective effects of BV and pramipexole (PPX; a positive control) in a subchronic MPTP-induced murine PD model. Both BV and PPX prevented MPTP-induced impairments in motor performance and reduced dopaminergic neuron loss, and furthermore, these neuroprotective effects of BV and PPX were found to be associated with reduced astroglial activation in vivo PD model. However, in MPP(+) treated primary cultured astrocytes, BV modulated astrocyte activation, whereas PPX did not, indicating that the neuroprotective effects of PPX were not mediated by neuroinflammation. These findings suggest that BV should be considered a potential therapeutic or preventive agent for PD and other neuroinflammatory associated disorders. PMID- 27469336 TI - Novel hybrids of drug with bioactive heterocycles for enhancing biological activity. AB - A novel series of aceclofenac hybridised with 1,2,4-triazolo-[3,4-b]-1,3,4 thiadiazoles were designed using molecular hybridization approach and synthesised 6a-j. The structural integrity was confirmed by analytical methods. The hybrid molecules were subjected to in vitro cytotoxic studies against four human cancer cell lines PA-1, OAW-42, T47-D and MCF-7 by MTT assay method. The results indicate that the hybrid molecules bearing halogen on phenyl ring in 6th position of triazolo-thiadiazole exhibited significant cytotoxic activity. The test compounds were also screened for antifungal activity against two strains. PMID- 27469337 TI - The use of matrix training to promote generative language with children with autism. AB - Matrix training consists of planning instruction by arranging components of desired skills across 2 axes. After training with diagonal targets that each combine 2 unique skill components, responses to nondiagonal targets, consisting of novel combinations of the components, may emerge. A multiple-probe design across participants was used to evaluate matrix training with known nouns (e.g., cat) and verbs (e.g., jumping) with 5 children with autism spectrum disorders (ASD). Following baseline of Matrix 1 and a generalization matrix, diagonal targets within Matrix 1 were trained as noun-verb combinations (e.g., cat jumping). Posttests showed recombinative generalization within Matrix 1 and the generalization matrix for 4 participants. For 1 participant, diagonal training across multiple matrices was provided until correct responding was observed in the generalization matrix. Results support the use of matrix training to promote untrained responses for learners with ASD and offer a systematic way to evaluate the extent of generalization within and across matrices. PMID- 27469338 TI - Impact of Preoperative Atrial Fibrillation on Postoperative Thromboembolic Events After Left Ventricular Assist Device Implantation. AB - BACKGROUND: The incidence of atrial fibrillation (AF) among patients undergoing left ventricular assist device (LVAD) implantation is high. However, the impact of AF on clinical outcomes has not been clarified. We reviewed our 9-year experience of continuous flow (CF) LVADs to determine the impact of preoperative AF on stroke, device thrombosis, and survival. METHODS: Between March 2006 and May 2015, 231 patients underwent implantation of 240 CF LVADs, 127 (52.9%) as bridge to transplantation and 113 (47.1%) as destination therapy. Effect of AF on postoperative outcomes was assessed by using Kaplan-Meier survival and Cox proportional hazard regression. RESULTS: There were 78 patients (32.5%) with preoperative AF with a mean age of 55.7 +/- 11.4 years. A similar incidence of stroke was found in patients with and without AF, 12.8% versus 16.0%, respectively (p = 0.803). Survival was similar, with 1-, 6-, 12-, and 24-month survivals of 96.2%, 91.7%, 84.5%, and 69.2%, respectively, for AF patients, versus 93.1%, 85.0%, 79.4%, and 74.1%, respectively, for non-AF patients (p = 0.424). Preoperative AF was not a significant independent predictor of survival with the use of Cox proportional hazard regression (hazard ratio 1.08, 95% confidence interval: 0.66 to 1.76). CONCLUSIONS: Preoperative AF was associated with a similar incidence of postoperative stroke, device thrombosis, and survival. On the basis of these data, it seems unnecessary to perform a left atrial appendage ligation or to alter postoperative anticoagulation in patients with AF undergoing LVAD implantation. PMID- 27469340 TI - Left Ventricular Assist Device Inflow Angle and Pump Positional Change Over Time Adverse Impact on Left Ventricular Assist Device Function. AB - BACKGROUND: This study investigates the impact of left ventricular assist device (LVAD) inflow cannula angulation, pump positional change over time, and the incidence of thrombotic pump dysfunction in a large cohort of HeartMate II (HM2) patients. METHODS: Patients (n = 326) who received primary HM2 LVAD between January 2008 and December 2013 at a single institution were retrospectively reviewed. Patients who underwent pump exchange (PE) for pump dysfunction, patients who had pump dysfunction (PD) but did not require pump exchange, and patients with normal LVAD pump dysfunction (NL) were compared. Pump positional change and angle of the inflow cannula with respect to the angle between inflow cannula and the LVAD body (IL angle) were measured from routine chest radiograph at postoperation, before discharge, and follow-up. Pump positional change was assessed based on pump positional differences between discharge and follow-up. Patients were also grouped by IL acute angulation (less than 65 degrees) and pump positional change. RESULTS: There were 21, 15, and 290 patients in the PE group, PD group, and NL group, respectively. There were significant differences in IL angle between PE and NL at all timepoints: postoperation (PD 63.6 +/- 12.5, NL 70.6 +/- 12.3; p = 0.018), before discharge (PD 64.4 +/- 12.8, NL 69.5 +/- 10.5; p = 0.039), and follow-up (PD 62.6 +/- 14.2, NL 67.9 +/- 11.2; p = 0.002). However, the IL angle was insignificant between PE and PD groups and between PD and NL groups. Sixty-seven percent of the PE group had pump positional change as opposed to 36% of the NL group (p = 0.019). Eighty-four of 101 patients with pump positional change and 75 of 91 patients with acute angulation at postoperation did not have pump dysfunction. CONCLUSIONS: Pump positional change may contribute to LVAD dysfunction or failure, but it does not entirely account for observed pump dysfunction or failure. PMID- 27469339 TI - Does Lymph Node Count Influence Survival in Surgically Resected Non-Small Cell Lung Cancer? AB - BACKGROUND: The prognostic significance of the number of lymph nodes sampled (NLNS) during resection for non-small cell lung cancer (NSCLC) is unclear. The NLNS is influenced by many factors, and some have argued that it should be a surrogate for quality. We sought to determine the influence of the NLNS on overall survival and cancer-specific survival for surgically resected NSCLC. METHODS: The California Cancer Registry was queried from 2004 to 2011 for cases of stage I to III NSCLC treated with surgical resection, identifying 16,393 patients. Kaplan-Meier and Cox proportional hazards modeling were used to determine the influence of NLNS on overall survival and cancer-specific survival. RESULTS: In all, 15,195 patients had information regarding nodal sampling. Eighty percent (13,167 of 15,195) were treated with lobectomy. Patients who were younger, male, non-Hispanic white, highest socioeconomic status, higher stage, or larger size tumor had more nodes removed. Sampling fewer than 10 nodes was associated with poorer overall survival when compared with sampling 10 or more nodes after adjustment for demographic and clinical factors for stage I: overall survival hazard ratio 1.78 (95% confidence interval: 1.54 to 2.05, p < 0.0001), hazard ratio 1.43 (95% confidence interval: 1.27 to 1.59, p < 0.0001), and hazard ratio 1.16 (95% confidence interval: 1.05 to 1.28, p = 0.004), for 0, 1 to 3, and 4 to 10 nodes, respectively. Of patients who underwent sublobar resection, 43.8% had no nodes sampled. CONCLUSIONS: For NSCLC, the NLNS influenced both overall survival and cancer-specific survival, but the influence is dependent on stage. Surgeons should perform mediastinal lymphadenectomy to maximize patient survival, but the optimal NLNS remains unclear. PMID- 27469341 TI - Targeting ADAM17 Sheddase Activity in Cancer. AB - A disintegrin and metalloprotease (ADAM)17 is a sheddase, capable of releasing the ectodomains of membrane proteins such as growth factors (e.g. Epidermal Growth Factor Receptor ligands), cytokines and their receptors, adhesion and signaling molecules. These activities regulate several physiological and pathological processes including inflammation, tumor growth and metastatic progression. In this review, we will summarize ADAM17 biology and focus on its role in cancer and the possible usage of ADAM17 inhibitors in cancer therapy. Recent achievements in this area include the development of small molecule metalloprotease inhibitors with enhanced specificity for ADAM17, monoclonal antibodies, and synthetic short RNA molecules for gene silencing. These approaches successfully inhibited cancer cell growth and invasiveness or sensitized them to cytotoxic drugs, ionizing radiations or targeted therapies, in preclinical studies. These findings suggest the repositioning of ADAM17 inhibitors, which have yet proven unsuccessful as anti-inflammatory agents, for the development of new anti-cancer therapies, particularly in EGFR ligand dependent cancers. Future studies should address ADAM17 inhibitors as short-term treatments in combination with different anti-cancer therapies. PMID- 27469342 TI - The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research. AB - BACKGROUND: The renin angiotensin system (RAS) plays an important role in inflammation and fibrosis. The classical axis of the RAS, formed by angiotensin converting en-zyme (ACE), angiotensin II (Ang II) and angiotensin receptor type 1 (AT1), activates several cell functions and molecular signaling pathways related to tissue injury, inflammation and fibrosis. In sharp contrast, the RAS axis composed by angiotensin converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor exerts opposite effects in relation to inflammatory response and tissue fibrosis. OBJECTIVE: In this review, we have the aim to summarize recent findings on the anti-inflammatory and anti-fibrogenic role of ACE2/Ang-(1-7)/Mas axis in the context of basic research, experimental human dis-eases and clinical studies. RESULTS: Several studies showed that ACE2/Angiotensin-(1-7)/Mas axis reduces cytokine release and inhibits signaling pathways of tissue fibrosis in experimental models of human diseases including atherosclerosis, cerebral ischemia, obesity, chronic kidney disease, liver diseases and asthma. On the other hand, very few data was provided by clinical studies. CONCLUSION: Experimental studies clearly support the anti-inflammatory and anti-fibrotic effects of ACE2/ Ang-(1-7)/Mas axis. Clinical studies, especially phase III and IV trials, will be necessary to establish the therapeutic role of ACE2/Ang-(1 7)/Mas axis in controlling inflammation in different human diseases. PMID- 27469343 TI - Bullous Pemphigoid with Lymphocytic Colitis: A Case Report and Short Literature Review. AB - The association of autoimmune bullous diseases (i.e., bullous pemphigoid, linear IgA disease, mucous membrane pemphigoid and IgA pemphigus) and inflammatory bowel disease, namely ulcerative colitis and Crohn's disease has formerly been reported. However, to our knowledge, we report herein the first case of lymphocytic colitis with concomitant bullous pemphigoid. PMID- 27469344 TI - Obesity: The obesity epidemic in the USA - no end in sight? PMID- 27469345 TI - Lipidomics for studying metabolism. AB - Many thousands of lipid species exist and their metabolism is interwoven via numerous pathways and networks. These networks can also change in response to cellular environment alterations, such as exercise or development of a disease. Measuring such alterations and understanding the pathways involved is crucial to fully understand cellular metabolism. Such demands have catalysed the emergence of lipidomics, which enables the large-scale study of lipids using the principles of analytical chemistry. Mass spectrometry, largely due to its analytical power and rapid development of new instruments and techniques, has been widely used in lipidomics and greatly accelerated advances in the field. This Review provides an introduction to lipidomics and describes some common, but important, cellular metabolic networks that can aid our understanding of metabolic pathways. Some representative applications of lipidomics for studying lipid metabolism and metabolic diseases are highlighted, as well as future applications for the use of lipidomics in studying metabolic pathways. PMID- 27469346 TI - Gut microbiota: Antibiotics do not affect metabolism in obesity. PMID- 27469347 TI - Erratum: Osteocytic signalling pathways as therapeutic targets for bone fragility. PMID- 27469348 TI - Review article: Diagnostic accuracy of risk stratification tools for patients with chest pain in the rural emergency department: A systematic review. AB - Risk stratification tools for patients presenting to rural EDs with undifferentiated chest pain enable early definitive treatment in high-risk patients. This systematic review compares the most commonly used risk stratification tools used to predict the risk of major adverse cardiac event (MACE) for patients presenting to rural EDs with chest pain. A comprehensive search of MEDLINE and Embase for studies published between January 2011 and January 2015 was undertaken. Study quality was assessed using QUADAS-2 criteria and the PRISMA guidelines.Eleven studies using eight risk stratification tools met the inclusion criteria. The percentage of MACE in the patients stratified as suitable for discharge, and the percentage of patients whose scores would have recommended admission that did not experience a MACE event were used as comparisons. Using the findings of a survey of emergency physicians that found a 1% MACE rate acceptable in discharged patients, the EDACS-ADP was considered the best performer. EDACS-ADP had one of the lowest rates of MACE in those discharged (3/1148, 0.3%) and discharged one of the highest percentage of patients (44.5%). Only the GRACE tool discharged more patients (69% - all patients with scores <100) but had a MACE rate of 0.3% in discharged patients. The HFA/CSANZ guidelines achieved zero cases of MACE but discharged only 1.3% of patients.EDACS ADP can potentially increase diagnostic efficiency of patients presenting at ED with chest pain. Further assessment of tool in a rural context is recommended. PMID- 27469349 TI - Pre-treatment MRI minimum apparent diffusion coefficient value is a potential prognostic imaging biomarker in cervical cancer patients treated with definitive chemoradiation. AB - BACKGROUND: Diffusion Weighted (DW) Magnetic Resonance Imaging (MRI) has been studed in several cancers including cervical cancer. This study was designed to investigate the association of DW-MRI parameters with baseline clinical features and clinical outcomes (local regional control (LRC), disease free survival (DFS) and disease specific survival (DSS)) in cervical cancer patients treated with definitive chemoradiation. METHODS: This was a retrospective study approved by an institutional review board that included 66 women with cervical cancer treated with definitive chemoradiation who underwent pre-treatment MRI at our institution between 2012 and 2013. A region of interest (ROI) was manually drawn by one of three radiologists with experience in pelvic imaging on a single axial CT slice encompassing the widest diameter of the cervical tumor while excluding areas of necrosis. The following apparent diffusion coefficient (ADC) values (*10(-3) mm(2)/s) were extracted for each ROI: Minimum - ADCmin, Maximum - ADCmax, Mean - ADCmean, and Standard Deviation of the ADC - ADCdev. Receiver operating characteristic (ROC) curves were built to choose the most accurate cut off value for each ADC value. Correlation between imaging metrics and baseline clinical features were evaluated using the Mann Whitney test. Confirmatory multi-variate Cox modeling was used to test associations with LRC (adjusted by gross tumor volume - GTV), DFS and DSS (both adjusted by FIGO stage). Kaplan Meyer curves were built for DFS and DSS. A p-value < 0.05 was considered significant. Women median age was 52 years (range 23-90). 67 % had FIGO stage I-II disease while 33 % had FIGO stage III-IV disease. Eighty-two percent had squamous cell cancer. Eighty-eight percent received concurrent cisplatin chemotherapy with radiation. Median EQD2 of external beam and brachytherapy was 82.2 Gy (range 74-84). RESULTS: Women with disease staged III-IV (FIGO) had significantly higher mean ADCmax values compared with those with stage I-II (1.806 (0.4) vs 1.485 (0.4), p = 0.01). Patients with imaging defined positive nodes also had significantly higher mean (+/-SD) ADCmax values compared with lymph node negative patients (1.995 (0.3) vs 1.551 (0.5), p = 0.03). With a median follow-up of 32 months (range 5-43) 11 patients (17 %) have developed recurrent disease and 8 (12 %) have died because of cervical cancer. ROC curves based on DSS showed optimal cutoffs for ADCmin (0.488 * 10(-3)), ADCmean (0.827 * 10(-3)), ADCmax (1.838 * 10(-3)) and ADCdev (0.148 * 10(-3)). ADCmin higher than the cutoff was significantly associated with worse DFS (HR = 3.632-95 % CI: 1.094-12.054; p = 0.035) and DSS (HR = 4.401-95 % CI: 1.048-18.483; p = 0.043). CONCLUSION: Pre treatment ADCmax measured in the primary tumor may be associated with FIGO stage and lymph node status. Pre-treatment ADCmin may be a prognostic factor associated with disease-free survival and disease-specific survival in cervical cancer patients treated with definitive chemoradiation. Prospective validation of these findings is currently ongoing. PMID- 27469350 TI - Effects of Chain Length and Saturability of Fatty Acids on Phospholipids and Proteins in Plasma Membranes of Bovine Mammary Gland. AB - Free fatty acids (FFAs) in plasma are essential substrates for de novo synthesis of milk fat, or directly import into mammary cells. The physico-chemical properties of mammary cells membrane composition affected by FFAs with different chain lengths and saturability are unclear yet. Employing GC, FTIR and fluorescence spectroscopy, the adsorption capacity, phospholipids content, membrane proteins conformation, lipid peroxidation product, and free sulfhydryl of plasma membranes (PMs) interacted with different FFAs were determined. The mammary cells PMs at 38 and 39.5 degrees C showed different adsorption capacities: acetic acid (Ac) > stearic acid (SA) > beta-hydroxybutyric acid (BHBA) > trans10, cis12 CLA. In the FTIR spectrum, the major adsorption peaks appeared at 2920 and 2850 cm-1 for phospholipids, and at 1628 and 1560 cm-1 for membrane proteins. The intensities of PMs-FFAs complexes were varied with the FFAs species and their initial concentrations. The beta-sheet and turn structures of membrane proteins were transferred into random coil and alpha-helix after BHBA, SA and trans10, cis12 CLA treatments compared with Ac treatment. The quenching effects on the fluorescence of endogenous membrane protein, 1, 8-ANS, NBD-PE, and DHPE entrapped in PMs by LCFA were different from those of short chain FFAs. These results indicate that the adsorption of FFAs could change membrane protein conformation and polarity of head group in phospholipids. This variation of the mammary cells PMs was regulated by carbon chain length and saturability of FFAs. PMID- 27469351 TI - A microbiological method for determining serum levels of broad spectrum beta lactam antibiotics in critically ill patients. AB - BACKGROUND: Recent studies show that suboptimal blood levels of beta-lactam antibiotics are present in intensive care unit (ICU) patients. A common reference method for assessing drug concentrations is liquid chromatography coupled with mass-spectrometry (LC-MS) which is highly accurate but rarely available outside reference centres. Thus, our aim was to develop a microbiological method for monitoring beta-lactam antibiotic serum levels which could be used at any hospital with a microbiological laboratory. METHODS: The method was developed as a 96-well broth microdilution format to assess the concentrations of cefotaxime (CTX), meropenem (MER), and piperacillin (PIP). Patient serum containing antibiotics were diluted in suspensions of bacteria with known minimal inhibitory concentrations (MICs). Serum antibiotic concentrations were calculated by dividing the MIC with the dilution factor at which the serum inhibited growth of the bacterial suspension. Serum (n=88) from ICU patients at four hospitals in south-east Sweden were analysed and compared to LC-MS analysis. RESULTS: The overall accuracy and precision for spiked samples and patient samples was within the pre-set target of +/-20.0% for all drugs. There was a significant correlation between the microbiological assay and LC-MS for the patient samples (CTX: r=0.86, n=31; MER: r=0.96, n=11; PIP: r=0.88, n=39) and the agreement around the clinical cut-off for CTX (4.0mg/l), MER (2.0mg/l) and PIP (16.0mg/l) was 90%, 100% and 87%, respectively. CONCLUSION: The microbiological method has a performance for determination of serum levels of meropenem, piperacillin and cefotaxime suitable for clinical use. It is an inexpensive method applicable in any microbiology laboratory. PMID- 27469353 TI - Investigating mortality heterogeneity among neighbourhoods of a highly industrialised Italian city: a meta-regression approach. AB - OBJECTIVES: The purpose of this study was to investigate the role of various predictors to explain spatial mortality heterogeneity in Taranto. METHODS: Direct age-adjusted death rates (ADR) at a neighbourhood level for the period 1998-2010 were examined. SO2, PM10, distance from pollution sources, and socioeconomic status (SES) were tested as predictors within a meta-regression framework. We used tau (2) to quantify heterogeneity in ADR and I (2) statistic with 95 % confidence intervals to estimate the proportion of total variation across neighbourhoods attributable to the between-neighbourhood heterogeneity. RESULTS: High heterogeneity resulted for all and natural causes of death for both genders. One neighbourhood (Paolo VI) was detected as an outlier for all predictors except SO2, among males. After accounting for SES, moderate heterogeneity among residuals was observed for all-causes of death and was correlated with SO2. Higher concentrations of PM10 were observed in neighbourhoods close to the industrial site and higher concentrations of SO2 in neighbourhoods more distant from the industrial site. CONCLUSIONS: SES and air pollutants were predictors of spatial heterogeneity in ADR. Different distributions of SO2 and PM10 in the city suggested two exposure patterns. PMID- 27469352 TI - "I Won't Out Myself Just to Do a Survey": Sexual and Gender Minority Adolescents' Perspectives on the Risks and Benefits of Sex Research. AB - Sexual and gender minority (SGM) adolescents under age 18 are underrepresented in sexual health research. Exclusion of SGM minors from these studies has resulted in a lack of knowledge about the risks and benefits youth experience from sexual health research participation. Institutional Review Boards' (IRB) overprotective stances toward research risks and requirements for guardian consent for SGM research are significant barriers to participation, though few have investigated SGM youth's perspectives on these topics. This study aimed to empirically inform decisions about guardian consent for sexuality survey studies involving SGM youth. A total of 74 SGM youth aged 14-17 completed an online survey of sexual behavior and SGM identity, and a new measure that compared the discomfort of sexual health survey completion to everyday events and exemplars of minimal risk research (e.g., behavioral observation). Youth described survey benefits and drawbacks and perspectives on guardian permission during an online focus group. Participants felt about the same as or more comfortable completing the survey compared to other research procedures, and indicated that direct and indirect participation benefits outweighed concerns about privacy and emotional discomfort. Most would not have participated if guardian permission was required, citing negative parental attitudes about adolescent sexuality and SGM issues and not being "out" about their SGM identity. Findings suggest that sexual health survey studies meet minimal risk criteria, are appropriate for SGM youth, and that recruitment would not be possible without waivers of guardian consent. Decreasing barriers to research participation would dramatically improve our understanding of sexual health among SGM youth. PMID- 27469354 TI - Evaluation of the biosafety of recombinant lactic acid bacteria designed to prevent and treat colitis. AB - Inflammatory bowel diseases (IBDs) affect the gastrointestinal tract and are characterized by recurrent inflammation that requires lifelong therapies. Probiotics such as lactic acid bacteria (LAB) have been proposed to complement current treatment protocols for these patients; however, their characteristics are strain dependent. In this regard, certain novel characteristics are only possible through the genetic modification of these beneficial micro-organisms. Different delivery systems, such as protein delivery of anti-oxidant enzymes and anti-inflammatory cytokines, have been shown to be effective in preventing and treating IBD in animal models. In this study, the safety of the recombinant LAB (recLAB) Streptococcus thermophilus CRL807 : CAT, S. thermophilus CRL807 : SOD, Lactococcus lactis NCDO2118 pXILCYT : IL-10, L. lactis MG1363 pValac : IL-10 and L. lactis MG1363 pGroESL : IL-10 with proven beneficial effects was compared to their progenitor strains S. thermophilus CRL807, L. lactis NCDO2118 or L. lactis MG1363. The prolonged administration of these genetically modified strains showed that they were just as safe as the native strains from which they derive, as demonstrated by normal animal growth and relative organ weights, absence of microbial translocation from the gastrointestinal tract, normal blood parameters and intestinal histology. The results show the potential use of these recLAB in future therapeutic formulations; however, the use of modern bio-containment systems is required for the future acceptance of these recLAB by the medical community and patients with IBD. PMID- 27469355 TI - Prognostic Value of 18F-FLT PET in Patients with Neuroendocrine Neoplasms: A Prospective Head-to-Head Comparison with 18F-FDG PET and Ki-67 in 100 Patients. AB - : Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors arising in various organs and with a large span of aggressiveness and survival rates. The Ki-67 proliferation index is presently used as the key marker of prognosis, and treatment guidelines are largely based on this index. 3'-deoxy-3' 18F-fluorothymidine (18F-FLT) is a proliferation tracer for PET imaging valuable in the monitoring of disease progression and treatment response in various types of cancer. However, until now only data from 10 patients with NEN were available in the literature. The aim of the present study was to investigate 18F-FLT PET as a prognostic marker for NENs in comparison with 18F-FDG PET and Ki-67 index. METHODS: One hundred patients were PET-scanned with both 18F-FLT and 18F-FDG within the same week, and the prognostic value of a positive scan was examined in terms of progression-free survival (PFS) and overall survival (OS). The correlation between the Ki-67 index and 18F-FLT uptake was also investigated. RESULTS: Thirty-seven percent of patients had a positive 18F-FLT PET scan, and 49% had 18F-FDG PET-positive foci. Patients with a high 18F-FLT uptake had a significantly shorter OS and PFS than patients with low or no 18F-FLT uptake. No correlation was found between Ki-67 index and 18F-FLT uptake. In a multivariate analysis 18F-FLT, 18F-FDG, and Ki-67 all were significant prognostic markers of PFS. For OS, only 18F-FDG and Ki-67 remained significant. CONCLUSION: 18F-FLT PET has prognostic value in NEN patients but when 18F-FDG PET and Ki-67 index are also available, a multivariate model revealed that 18F-FLT PET only adds information regarding PFS but not OS, whereas 18F-FDG PET remains predictive of both PFS and OS. However, a clinically robust algorithm including 18F-FLT in addition to 18F-FDG and Ki-67 could not be found. Accordingly, the exact role, if any, of 18F-FLT PET in NENs remains to be established. PMID- 27469357 TI - Counting Rate Characteristics and Image Distortion in Preclinical PET Imaging During Radiopharmaceutical Therapy. AB - : PET may provide important information on the response during radiopharmaceutical therapy (RPT). Emission of radiation from the RPT radionuclide may disturb coincidence detection and impair image resolution. In this study, we tested the feasibility of performing intratherapeutic PET on 3 preclinical PET systems. METHODS: Using 22Na point sources and phantoms filled with 18F, as well as a phantom filled with either 99mTc or 177Lu, we evaluated the coincidence counting rate and spatial resolution when both a PET and a therapeutic radionuclide were in the PET system. Because 99mTc has a suitable half-life and is easy obtainable, we used it as a substitute for a generic therapeutic radionuclide. RESULTS: High activities of 99mTc deteriorated the coincidence counting rate from the 18F-filled phantom and the 22Na point source on all 3 systems. The counting rate could be corrected to a high degree on one of the systems by its dead-time correction. Spatial resolution was degraded at high 99mTc activities for all systems. On one of the systems, 177Lu increased the coincidence counting rate and slightly affected the spatial resolution. The results for high 177Lu activities were similar to those for 99mTc. CONCLUSION: Intratherapeutic imaging might be a feasible method of studying the response to RPT. However, some sensitive preclinical PET systems, unable to handle high counting rates, will have count losses and may also introduce image artifacts. PMID- 27469356 TI - Epileptic Activity Increases Cerebral Amino Acid Transport Assessed by 18F Fluoroethyl-l-Tyrosine Amino Acid PET: A Potential Brain Tumor Mimic. AB - : O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET is a well-established method increasingly used for diagnosis, treatment planning, and monitoring in gliomas. Epileptic activity, frequently occurring in glioma patients, can influence MRI findings. Whether seizures also affect 18F-FET PET imaging is currently unknown. The aim of this retrospective analysis was to investigate the brain amino acid metabolism during epileptic seizures by 18F-FET PET and to elucidate the pathophysiologic background. METHODS: Ten patients with 11 episodes of serial seizures or status epilepticus, who underwent MRI and 18F-FET PET, were studied. The main diagnosis was glioma World Health Organization grade II-IV (n = 8); 2 patients suffered from nonneoplastic diseases. Immunohistochemical assessment of LAT1/LAT2/CD98 amino acid transporters was performed in seizure-affected cortex (n = 2) and compared with glioma tissues (n = 3). RESULTS: All patients exhibited increased seizure-associated strict gyral 18F-FET uptake, which was reversible in follow-up studies or negative shortly before and without any histologic or clinical signs of tumor recurrence. 18F-FET uptake corresponded to structural MRI changes, compatible with cortical vasogenic and cytotoxic edema, partial contrast enhancement, and hyperperfusion. Patients with prolonged postictal symptoms lasting up to 8 wk displayed intensive and widespread (>= 1 lobe) cortical 18F FET uptake. LAT1/LAT2/CD98 was strongly expressed in neurons and endothelium of seizure-affected brains and less in reactive astrocytosis. CONCLUSION: Seizure activity, in particular status epilepticus, increases cerebral amino acid transport with a strict gyral 18F-FET uptake pattern. Such periictal pseudoprogression represents a potential pitfall of 18F-FET PET and may mimic brain tumor. Our data also indicate a seizure-induced upregulation of neuronal, endothelial, and less astroglial LAT1/LAT2/CD98 amino acid transporter expression. PMID- 27469358 TI - What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2. AB - : Positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) are a potential therapy for anxiety, schizophrenia, and addiction. Aside from pathophysiologic imaging studies, an mGluR2 PET tracer would enable confirmation of sufficient central target engagement and assist dose selection for proof-of-concept studies of PAM compounds. 11C-JNJ-42491293, a novel high affinity radioligand (human 50% inhibitory concentration = 9.6 nM) for the PAM site of mGluR2, was evaluated as a selective mGluR2 PAM PET tracer. METHODS: In vitro and ex vivo autoradiography binding experiments in Wistar and in mGluR2 knockout and wildtype rats as well as in vivo biodistribution and brain PET imaging studies in wildtype and mGluR2 knockout rats in a primate and in humans were performed. RESULTS: In vitro binding studies and in vivo imaging studies in Wistar rats showed moderate brain uptake, with a distribution pattern fully consistent with the reported intracerebral distribution of mGluR2. Given these promising findings, biodistribution, dosimetry, and brain kinetic modeling of 11C JNJ-42491293 were determined in humans. Because of an unexpected high myocardial retention, additional 11C-JNJ-42491293 imaging studies were performed in recently available mGluR2 knockout and wildtype rats and in a monkey using a structurally distinct mGluR2 PAM ligand with affinity for the same site, demonstrating off target binding in vivo that could not have been anticipated from previous in vitro experiments. To date, the target of this non-mGluR2 tracer binding remains unknown. CONCLUSION: On the basis of in vivo selectivity issues suggested by human distribution and demonstrated in knockout rat models, 11C-JNJ-42491293 was considered unsuitable as a specific PET ligand for in vivo imaging of mGluR2. These results emphasize the importance of elaborated in vitro/in vivo comparative studies and, when available, validation with knockout animal models or structurally distinct ligands with affinity for the same site, in radiotracer development. PMID- 27469359 TI - In Vivo Imaging of Human 11C-Metformin in Peripheral Organs: Dosimetry, Biodistribution, and Kinetic Analyses. AB - : Metformin is the most widely prescribed oral antiglycemic drug, with few adverse effects. However, surprisingly little is known about its human biodistribution and target tissue metabolism. In animal experiments, we have shown that metformin can be labeled by 11C and that 11C-metformin PET can be used to measure renal function. Here, we extend these preclinical findings by a first in-human 11C-metformin PET dosimetry, biodistribution, and tissue kinetics study. METHODS: Nine subjects (3 women and 6 men) participated in 2 studies: in the first study, human radiation dosimetry and biodistribution of 11C-metformin were estimated in 4 subjects (2 women and 2 men) by whole-body PET. In the second study, 11C-metformin tissue kinetics were measured in response to both intravenous and oral radiotracer administration. A dynamic PET scan with a field of view covering target tissues of metformin (liver, kidneys, intestines, and skeletal muscle) was obtained for 90 (intravenous) and 120 (oral) min. RESULTS: Radiation dosimetry was acceptable, with effective doses of 9.5 MUSv/MBq (intravenous administration) and 18.1 MUSv/MBq (oral administration). Whole-body PET revealed that 11C-metformin was primarily taken up by the kidneys, urinary bladder, and liver but also to a lesser extent in salivary glands, skeletal muscle, and intestines. Reversible 2-tissue-compartment kinetics was observed in the liver, and volume of distribution was calculated to be 2.45 mL/mL (arterial input) or 2.66 mL/mL (portal and arterial input). In the kidneys, compartmental models did not adequately fit the experimental data, and volume of distribution was therefore estimated by a linear approach to be 6.83 mL/mL. Skeletal muscle and intestinal tissue kinetics were best described by 2-tissue-compartment kinetics and showed only discrete tracer uptake. Liver 11C-metformin uptake was pronounced after oral administration of the tracer, with tissue-to-blood ratio double what was observed after intravenous administration. Only slow accumulation of 11C-metformin was observed in muscle. There was no elimination of 11C metformin through the bile both during the intravenous and during the oral part of the study. CONCLUSION: 11C-metformin is suitable for imaging metformin uptake in target tissues and may prove a valuable tool to assess the impact of metformin treatment in patients with varying metformin transport capacity. PMID- 27469360 TI - 123I-Iodobenzovesamicol SPECT Imaging of Cholinergic Systems in Dementia with Lewy Bodies. AB - : Cholinergic alterations in dementia with Lewy bodies (DLB) have been widely documented in postmortem studies, whereas in vivo studies are sparse, particularly at the subcortical level. We used 123I-iodobenzovesamicol, a SPECT radiotracer of the vesicular acetylcholine transporter, to evaluate in vivo in DLB the integrity of the 3 main cholinergic pathways-the Ch1 (septohippocampal), the Ch4 (innominatocortical), and the Ch5 (pontothalamic) cholinergic pathways-as well as the striatal cholinergic interneurons. In addition, we assessed the involvement of the cholinergic system in cognitive and neuropsychiatric disorders in DLB patients. METHODS: Twelve healthy volunteers (median age, 72 y; interquartile range, 6.25 y) and 11 DLB patients (median age, 76 y; interquartile range, 10.50 y) underwent a dynamic 123I-iodobenzovesamicol SPECT scan and an MRI scan. MR images were automatically segmented, providing the volumes of several regions of interest, including the striatum and cholinergic terminals in Ch1 (hippocampus), Ch4 (cortical lobes), and Ch5 (thalamus). For each region of interest and each subject, pharmacokinetic modeling allowed calculation of the nondisplaceable binding potential (BPND) values for the binding of 123I iodobenzovesamicol to the vesicular acetylcholine transporter. A neuropsychological evaluation of participants was performed with the Mini-Mental State Examination and the Grober-Buschke, Set, visual discrimination, Benton, and Wechsler tests, and cognitive fluctuations and apathy were also assessed. RESULTS: Compared with BPND values for healthy subjects, BPND values for DLB patients were significantly lower in the Ch4 terminal regions of the anterior cingulate cortex and the superior and inferior parietal cortices (P = 0.0006, 0.0015, and 0.0023, respectively), in the Ch5 terminal region of the thalamus (P = 0.0003), and in the striatum (P = 0.0042). All of the neuropsychological test scores were significantly lower in DLB patients than in healthy subjects. Four DLB patients with apathy and 4 DLB patients without apathy were identified. For the anterior cingulate cortex, compared with BPND values in healthy subjects, BPND values were significantly lower in patients with apathy (P = 0.004) and were unchanged in patients without apathy. CONCLUSION: Our results confirm the existence in DLB of cholinergic alterations, reaching both cortical and subcortical levels, including the Ch5 pathway and the striatum. Alterations in cholinergic transmission in the anterior cingulate cortex could be closely associated with the development of apathy. PMID- 27469361 TI - Matrix Metalloproteinase-Targeted Imaging of Lung Inflammation and Remodeling. AB - : Imaging techniques for detection of molecular and cellular processes that precede or accompany lung diseases are needed. Matrix metalloproteinases (MMPs) play key roles in the development of pulmonary pathology. The objective of this study was to investigate the feasibility of in vivo MMP-targeted molecular imaging for detection of lung inflammation and remodeling. METHODS: Lung-specific IL-13 transgenic (Club cell 10-kDa protein [CC10]-IL-13 Tg) mice and wild-type littermates were used in this study. Lung structure, gene expression, and MMP activity were assessed by histology, real-time reverse transcription polymerase chain reaction, Western blotting, and zymography. MMP activation was imaged by in vivo small-animal SPECT/CT followed by ex vivo planar imaging. Signal specificity was addressed using a control tracer. The correlation between in vivo MMP signal and gene expression was addressed. RESULTS: CC10-IL-13 Tg mice developed considerable pulmonary tissue remodeling and inflammation. CD68, MMP-12, and MMP 13 were significantly higher in CC10-IL-13 Tg lungs. On in vivo small-animal SPECT/CT and ex vivo planar images, the MMP signal was significantly higher in the lungs of CC10-IL-13 Tg mice than wild-type animals. Furthermore, a nonbinding analog tracer showed significantly lower accumulation in CC10-IL-13 Tg lungs relative to the specific tracer. There was a significant correlation between small-animal SPECT/CT-derived MMP signal and CD68 expression in the lungs (r = 0.70, P < 0.01). CONCLUSION: Small-animal SPECT/CT-based MMP-targeted imaging of the lungs is feasible and reflects pulmonary inflammation. If validated in humans, molecular imaging of inflammation and remodeling can potentially help early diagnosis and monitoring of the effects of therapeutic interventions in pulmonary diseases. PMID- 27469362 TI - 18F-FDG PET for Measurement of Response and Prediction of Outcome to Relapsed or Refractory Mantle Cell Lymphoma Therapy with Bendamustine-Rituximab. AB - : In a single-arm, phase 2 clinical trial, bendamustine-rituximab (BR) demonstrated an overall response rate of 82% among 45 patients with relapsed or refractory mantle cell lymphoma (MCL), with manageable tolerability. A prespecified 18F-FDG PET analysis was conducted to assess the predictive value of the metabolic response to BR compared with the response by International Working Group (IWG) criteria. METHODS: Adult patients with relapsed or refractory MCL underwent 18F-FDG PET at screening and after 6 cycles of BR therapy. Scans were reviewed by a central facility and scored using the 5-point Deauville scale, comparing uptake to the liver and mediastinum in up to 6 lesions, to determine metabolic response rates, indicated by negative posttreatment scans. Metabolic responses were compared with study outcomes assessed by IWG criteria. RESULTS: Complete 18F-FDG PET data were available for 32 of 45 patients. All patients had positive baseline scans, with baseline scores ranging from 4 to 5. Complete metabolic responses (CMR) were observed in 24 (75%) patients after 6 cycles of BR. Patients attaining a CMR had a 96% overall response rate by IWG criteria, with 62.5% achieving a complete response. Of the 8 patients not attaining a CMR, 6 responded to BR but none achieved a complete response. CMR was associated with a greater 1-y progression-free survival of 91.5%, compared with 12.5% without CMR; a longer median duration of response of 20.6 mo, compared with 7.8 mo; and improved overall survival at 1 y. 18F-FDG PET data from patients with refractory or advanced disease demonstrated CMR in more than half. CONCLUSION: Compared with positive end-of-treatment 18F-FDG PET, negative scans, indicating a CMR, were predictive of improved 1-y survival, duration of response, and overall survival for patients with relapsed or refractory MCL receiving BR. PMID- 27469363 TI - Molecular Imaging of Immunotherapy Targets in Cancer. AB - Immunotherapy has emerged as a promising alternative in the arsenal against cancer by harnessing the power of the immune system to specifically target malignant tissues. As the field of immunotherapy continues to expand, researchers will require newer methods for studying the interactions between the immune system, tumor cells, and immunotherapy agents. Recently, several noninvasive imaging strategies have been used to map the biodistribution of immune checkpoint molecules, monitor the efficacy and potential toxicities of the treatments, and identify patients who are likely to benefit from immunotherapies. In this review, we outline the current applications of noninvasive techniques for the preclinical imaging of immunotherapy targets and suggest future pathways for molecular imaging to contribute to this developing field. PMID- 27469364 TI - Mediating Role of Mindfulness on the Associations of Friendship Quality and Subjective Vitality. AB - This research investigated the mediator role of mindfulness on the relationship between friendship quality and subjective vitality. Participants were 273 university students (M age = 21 years, SD = 1.1) who completed a questionnaire package that included the Friendship Quality Scale, the Cognitive and Affective Mindfulness Scale, and the Subjective Vitality Scale. Both mindfulness and subjective vitality were correlated positively with friendship quality and subjective vitality was correlated positively with mindfulness. Mindfulness mediated the relationship between friendship quality and subjective vitality. Together, the findings illuminate the importance of friendship quality in psychological and cognitive adjustment. PMID- 27469365 TI - Intentional or Negligent Homicide? Evidence for Juror Decision Making. AB - The present study examined the influence of specific evidence and testimonies on a juror's decision to make a verdict of intentional or negligent homicide in a Civil law country. Italian students (N = 280; M age = 25.0 years, SD = 2.9) read different affidavits characterized by the presence or absence of three elements against the defendant: motive, skill in use of weapons, and previous violence toward the victim. Participants then decided a verdict and provided a confidence judgment on their decision. Results showed that the presence of motive, skill, and previous violence influenced the jurors' decision, significantly changing the verdict from negligent to intentional homicide. The findings were discussed in terms of the folk-concept approach of intentionality. PMID- 27469366 TI - Autophagy confers resistance to lipopolysaccharide-induced mouse hepatocyte injury. AB - During sepsis, bacterial products, particularly LPS, trigger injury in organs such as the liver. This common condition remains largely untreatable, in part due to a lack of understanding of how high concentrations of LPS cause cellular injury. In the liver, the lysosomal degradative pathway of autophagy performs essential hepatoprotective functions and is induced by LPS. We, therefore, examined whether hepatocyte autophagy protects against liver injury from septic levels of LPS. Mice with an inducible hepatocyte-specific knockout of the critical autophagy gene Atg7 were examined for their sensitivity to high-dose LPS. Increased liver injury occurred in knockout mice, as determined by significantly increased serum alanine aminotransferase levels, histological evidence of liver injury, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, and effector caspase-3 and -7 activation. Hepatic inflammation and proinflammatory cytokine induction were unaffected by the decrease in hepatocyte autophagy. Although knockout mice had normal NF-kappaB signaling, hepatic levels of Akt1 and Akt2 phosphorylation in response to LPS were decreased. Cultured hepatocytes from knockout mice displayed a generalized defect in Akt signaling in response to multiple stimuli, including LPS, TNF, and IL-1beta. Akt activation mediates hepatocyte resistance to TNF cytotoxicity, and anti-TNF antibodies significantly decreased LPS-induced liver injury in knockout mice, indicating that the loss of autophagy sensitized to TNF dependent liver damage. Hepatocyte autophagy, therefore, protects against LPS induced liver injury. Conditions such as aging and steatosis that impair hepatic autophagy may predispose to poor outcomes from sepsis through this mechanism. PMID- 27469367 TI - How host regulation of Helicobacter pylori-induced gastritis protects against peptic ulcer disease and gastric cancer. AB - The bacterial pathogen Helicobacter pylori is the etiological agent of a range of gastrointestinal pathologies including peptic ulcer disease and the major killer, gastric adenocarcinoma. Infection with this bacterium induces a chronic inflammatory response in the gastric mucosa (gastritis). It is this gastritis that, over decades, eventually drives the development of H. pylori-associated disease in some individuals. The majority of studies investigating H. pylori pathogenesis have focused on factors that promote disease development in infected individuals. However, an estimated 85% of those infected with H. pylori remain completely asymptomatic, despite the presence of pathogenic bacteria that drive a chronic gastritis that lasts many decades. This indicates the presence of highly effective regulatory processes in the host that, in most cases, keeps a check on inflammation and protect against disease. In this minireview we discuss such known host factors and how they prevent the development of H. pylori-associated pathologies. PMID- 27469369 TI - Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications. AB - Opioids are one of the most prescribed drug classes for treating acute pain. However, chronic use is often associated with tolerance as well as debilitating side effects, including nausea and dependence, which are mediated by the central nervous system, as well as constipation emerging from effects on the enteric nervous system. These gastrointestinal (GI) side effects limit the usefulness of opioids in treating pain in many patients. Understanding the mechanism(s) of action of opioids on the nervous system that shows clinical benefit as well as those that have unwanted effects is critical for the improvement of opioid drugs. The opioidergic system comprises three classical receptors (MU, delta, kappa) and a nonclassical receptor (nociceptin), and each of these receptors is expressed to varying extents by the enteric and intestinal extrinsic sensory afferent nerves. The purpose of this review is to discuss the role that the opioidergic system has on enteric and extrinsic afferent nerves in the lower GI tract in health and diseases of the lower GI tract, particularly inflammatory bowel disease and irritable bowel syndrome, and the implications of opioid treatment on clinical outcomes. Consideration is also given to emerging developments in our understanding of the immune system as a novel source of endogenous opioids and the mechanisms underlying opioid tolerance, including the potential influence of opioid receptor splice variants and heteromeric complexes. PMID- 27469368 TI - Identification of food-grade subtilisins as gluten-degrading enzymes to treat celiac disease. AB - Gluten are proline- and glutamine-rich proteins present in wheat, barley, and rye and contain the immunogenic sequences that drive celiac disease (CD). Rothia mucilaginosa, an oral microbial colonizer, can cleave these gluten epitopes. The aim was to isolate and identify the enzymes and evaluate their potential as novel enzyme therapeutics for CD. The membrane-associated R. mucilaginosa proteins were extracted and separated by DEAE chromatography. Enzyme activities were monitored with paranitroanilide-derivatized and fluorescence resonance energy transfer (FRET) peptide substrates, and by gliadin zymography. Epitope elimination was determined in R5 and G12 ELISAs. The gliadin-degrading Rothia enzymes were identified by LC-ESI-MS/MS as hypothetical proteins ROTMU0001_0241 (C6R5V9_9MICC), ROTMU0001_0243 (C6R5W1_9MICC), and ROTMU0001_240 (C6R5V8_9MICC). A search with the Basic Local Alignment Search Tool revealed that these are subtilisin-like serine proteases belonging to the peptidase S8 family. Alignment of the major Rothia subtilisins indicated that all contain the catalytic triad with Asp (D), His (H), and Ser (S) in the D-H-S order. They cleaved succinyl-Ala Ala-Pro-Phe-paranitroanilide, a substrate for subtilisin with Pro in the P2 position, as in Tyr-Pro-Gln and Leu-Pro-Tyr in gluten, which are also cleaved. Consistently, FRET substrates of gliadin immunogenic epitopes comprising Xaa-Pro Xaa motives were rapidly hydrolyzed. The Rothia subtilisins and two subtilisins from Bacillus licheniformis, subtilisin A and the food-grade Nattokinase, efficiently degraded the immunogenic gliadin-derived 33-mer peptide and the immunodominant epitopes recognized by the R5 and G12 antibodies. This study identified Rothia and food-grade Bacillus subtilisins as promising new candidates for enzyme therapeutics in CD. PMID- 27469370 TI - Globalization of heart failure trials: no turning back on this paradigm. PMID- 27469371 TI - Simultaneous dual-isotope solid-state detector SPECT for improved tracking of white blood cells in suspected endocarditis. AB - Aims: High-energy resolution and sensitivity of novel cadmium-zinc-telluride (CZT) detector equipped SPECT systems facilitate simultaneous imaging of multiple isotopes and may enhance the detection of molecular/cellular signals. This may refine the detection of endocarditis. This study was designed to determine the feasibility and diagnostic accuracy of simultaneous imaging of inflammation with 111In-labeled white blood cells (WBCs) and myocardial perfusion with 99mTc sestamibi, for localization of WBCs relative to the valve plane in suspected endocarditis. Methods and results: A dedicated cardiac CZT camera (Discovery 530c, GE Healthcare) was employed. Anthropomorphic thorax phantom studies were followed by clinical studies in 34 patients with suspected infection of native valves (n = 12) or implants (n = 22). Simultaneous 111In-WBC/99mTc perfusion imaging was performed, and compared with standard 111In-WBC planar scintigraphy and SPECT-CT. Phantom studies ruled out significant radioisotope crosstalk. Downscatter on 99mTc images was not observed for 111In activity as high as 2.5*99mTc activity. In patients, image quality was superior for CZT imaging vs. conventional SPECT-CT and planar scintigraphy (P < 0.01). Cadmium-zinc-telluride dual isotope imaging improved reader confidence for detection of inflammatory foci. Diagnostic accuracy based on surgery or Duke Criteria during follow-up was highest for CZT imaging (P < 0.001). Conclusion: Novel CZT SPECT technology improves the accuracy of molecular/cellular cardiac imaging. Simultaneous multi isotope imaging with 111In and 99mTc is feasible and aids in the workup of suspected endocarditis. PMID- 27469373 TI - Persistent stem cell-driven inflammation in patients with prior MI and stroke. PMID- 27469374 TI - A dolus of i.v. amiodarone. PMID- 27469375 TI - Cardiac manifestations of sarcoidosis: diagnosis and management. AB - Approximately 5% of patients with sarcoidosis will have clinically manifest cardiac involvement presenting with one or more of ventricular arrhythmias, conduction abnormalities, and heart failure. Cardiac presentations can be the first (and/or an unrecognized) manifestation of sarcoidosis in a variety of circumstances. Cardiac symptoms are usually dominant over extra-cardiac as most patients with clinically manifest disease have minimal extra-cardiac disease and up to two-thirds have isolated cardiac sarcoidosis (CS). It is estimated that another 20-25% of pulmonary/systemic sarcoidosis patients have asymptomatic cardiac involvement (clinically silent disease). The extent of left ventricular dysfunction seems to be the most important predictor of prognosis among patients with clinically manifest CS. In addition, the extent of myocardial late gadolinium enhancement is emerging as an important prognostic factor. The literature shows some controversy regarding outcomes for patients with clinically silent CS and larger studies are needed. Immunosuppression therapy (usually with corticosteroids) has been suggested for the treatment of clinically manifest CS despite minimal data supporting it. Fluorodeoxyglucose Positron Emission Tomography imaging is often used to detect active disease and guide immunosuppression. Patients with clinically manifest disease often need device therapy, typically with implantable cardioverter defibrillators. PMID- 27469376 TI - Classification of Proteus penneri lipopolysaccharides into core region serotypes. AB - The frequency of P. penneri isolation from hospital patients, mostly from urine and wounds, keeps on growing, and numerous isolates are multi-drug resistant. P. penneri rods produce lipopolysaccharide (LPS), which may lead to the septic shock. Until now, O-specific polysaccharide has been the best structurally and serologically characterized region of P. penneri LPS. It is worth having an insight into the serological specificity of both poly- and oligosaccharide parts of P. penneri LPS. The P. penneri core region is less structurally diverse than OPS, but still, among other enterobacterial LPS core regions, it is characterized by structural variability. In the present study, the serological reactivity of 25 P. penneri LPS core regions was analyzed by ELISA, passive immunohemolysis and Western blot technique using five polyclonal P. penneri antisera after or without their adsorption with the respective LPSs. The results allowed the assignment of the tested strains to five new core serotypes, which together with published serological studies led to the creation of the first serotyping scheme based on LPS core reactivities of 35 P. penneri and three P. mirabilis strains. Together with the O types scheme, it will facilitate assigning Proteus LPSs of clinical isolates into appropriate O and R serotypes. PMID- 27469377 TI - HIV-1 replication in central nervous system increases over time on only protease inhibitor therapy. AB - There are concerns about central nervous system (CNS)-replication of HIV-1 in patients on boosted protease inhibitors. Purpose of this study was to compare HIV 1 viral loads (VLs) from patients treated with only boosted dual protease inhibitor (bdPI), versus combination antiretroviral therapy (cART group), containing two nucleoside analogue reverse transcriptase inhibitors (NRTI) and a third partner. All patients from a large German HIV-treatment cohort with available medication, clinical and demographic data, including results from simultaneous HIV-1 viral load (VL) assessments in cerebrospinal fluid (CSF) and blood plasma, were retrospectively evaluated as controlled cross-sectional study. CSF had been obtained from patients with variable neurological symptoms during 2005-2014. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Overall, 155 patients were evaluable (bdPI: 24; cART: 131). At time of CSF-collection, both groups were comparable in age, gender, CD4-cell counts, or primary HIV-transmission risks, though bdPI patients were clinically more advanced. The proportion of patients with undetectable HIV-1 (<50 copies/ml) in CSF was lower for bdPI group (25 vs 49.6 %; p = 0.026), but similar in plasma (46 vs 41 %). Median CSF-VL was higher in bdPI group (600 vs 50 copies/ml; p = 0.027) and similar in plasma. Mean VL CSF/plasma ratio was 342.91 for bdPI- and 54.48 for cART patients (p < 0.001). Pearson's regression analysis revealed a trend for an elevated VL-ratio over time within bdPI group. HIV-1 replication was higher and more frequently detectable in CSF from bdPI patients, indicating a worse CNS penetration effectiveness of used boosted PI. Within bdPI group, measured CNS-viral replication was increasing over time, suggesting an over time impaired HIV-1 suppression in CSF. PMID- 27469379 TI - Targeting the mitogen-activated protein kinase pathway in low-grade serous carcinoma of the ovary. AB - Until recently, there has been little change in the management of epithelial ovarian cancer with the majority of women receiving identical systemic therapy, regardless of histological subtype. The heterogeneity of epithelial ovarian cancer is now well established, with distinct subtypes characterized by specific molecular alterations and patterns of clinical behavior. Low-grade serous carcinoma is a rare subtype associated with an indolent biological behavior and inherent resistance to chemotherapy. The mitogen-activated protein kinase pathway plays a prominent role in the pathogenesis of low-grade serous carcinoma, and provides an attractive target for novel therapeutic agents. Selumetinib, a MEK1/2 inhibitor, demonstrates promising efficacy in women with relapsed low-grade serous carcinoma, and further trials of MEK-inhibition are underway. Translational research will be essential to identify predictive biomarkers for this treatment approach. PMID- 27469380 TI - Molecular systematics and biodiversity of oniscidean isopods in the groundwater calcretes of central Western Australia. AB - Groundwater calcrete aquifers of central Western Australia have been shown to contain a high diversity of stygobiont (subterranean aquatic) invertebrates, with each species confined to an individual calcrete and the entire system resembling a 'subterranean archipelago' containing hundreds of isolated calcretes. Here, we utilised alternative sampling techniques above the water table and uncovered a significant fauna of subterranean terrestrial oniscidean isopods from the calcretes. We explored the diversity and evolution of this fauna using molecular analyses based on one mitochondrial gene, Cytochrome C Oxidase Subunit I (COI), two Ribosomal RNA genes (28S and 18S), and one protein coding nuclear gene, Lysyl tRNA Synthetase (LysRS). The results from 12 calcretes showed the existence of 36 divergent DNA lineages belonging to four oniscidean families (Paraplatyarthridae, Armadillidae, Stenoniscidae and Philosciidae). Using a combination of phylogenetic and species delimitation methods, we hypothesized the occurrence of at least 27 putative new species of subterranean oniscideans, of which 24 taxa appeared to be restricted to an individual calcrete, lending further support to the "subterranean island hypothesis". Three paraplatyarthrid species were present on adjacent calcretes and these exceptions possessed more ommatidia and body pigments compared with the calcrete-restricted taxa, and are likely to represent troglophiles. The occurrence of stenoniscid isopods in the calcretes of central Western Australia, a group previously only known from the marine littoral zone, suggests a link to the marine inundation of the Eucla basin during the Late Eocene. The current oniscidean subterranean fauna consists of groups known to be subtropical, littoral and benthic, reflecting different historical events that have shaped the evolution of the fauna in the calcretes. PMID- 27469381 TI - The analgesic efficacy of sciatic nerve block in addition to femoral nerve block in patients undergoing total knee arthroplasty: a systematic review and meta analysis. AB - The aim of this meta-analysis was to assess the postoperative analgesic efficacy of sciatic nerve block when combined with femoral nerve block after total knee arthroplasty. Outcomes included resting pain scores (analogue scale, 0-100), intravenous morphine consumption at 12 h, 24 h and 48 h postoperatively, and functional outcomes comprising knee flexion, distance walked, and length of stay. Twelve randomised controlled trials were included, with a total of 600 patients. When combined with femoral nerve block, sciatic nerve block significantly reduced resting pain scores at 12 h postoperatively with a mean difference of 10 (95% CI: -15 to -5; p < 0.00001). Resting pain scores at 24 h, and intravenous morphine consumption at 12 h, 24 h and 48 h postoperatively were also significantly reduced, but without clinical significance beyond 12 h and without affecting functional outcomes. In conclusion, sciatic nerve block confers additional postoperative analgesia within the first 12 postoperative hours compared with femoral nerve block alone for patients undergoing total knee arthroplasty. PMID- 27469382 TI - Gastrointestinal stromal tumour masquerading as a cyst in the lesser sac. AB - Gastrointestinal stromal tumours (GISTs) are solid tumours of the gastrointestinal tract, mostly found in the stomach and intestine. They rarely present as cystic lesions. A 74-year-old woman referred to the hepatopancreaticobiliary unit, with 3 months history of upper abdominal discomfort. Abdominal ultrasound scan showed a large cystic lesion in the epigastric region suggestive of a pancreatic pseudocyst. The CT-scan showed a 6.6*6*6.3 cm size cyst related to the pancreas and extending to the hepatogastric omentum. Endoscopic ultrasound (EUS) scan was suggestive of a pancreatic pseudocyst. Aspirated Cyst fluid via EUS showed benign cytology with normal amylase, lipase and tumour markers (CEA, CA-19.9 and CA-125). She was referred as a case of pancreatic pseudocyst. After surgical excision, the histopathology confirmed the presence GIST in the wall of the cystic lesion. The possibility of GIST should be kept in mind in the presence of unusual features of a cyst on abdominal imaging. PMID- 27469383 TI - Expanding the range of immunopathology in neuromyelitis optica spectrum disorder. AB - Neuromyelitis optica (NMO) spectrum disorder typically associates with a pathognomonic antibody response directed against aquaporin 4 and a unique immunopathological signature characterised by loss of aquaporin 4 expression. We describe a tumefactive presentation of NMO in which a biopsy specimen demonstrated active demyelination and reactive astrocytes with preserved surface aquaporin 4 immunoreactivity and dystrophic processes. While the astrocytic pathology is more typical of classical multiple sclerosis, a positive NMO-IgG (1:80) and subsequent clinical presentation with an area postrema syndrome is consistent with a diagnosis of NMO spectrum disorder. This report expands the immunopathological features that have been reported in NMO spectrum disorder. PMID- 27469378 TI - C-type lectin receptors in tuberculosis: what we know. AB - Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), is recognized by a number of pathogen recognition receptors (PRRs), either soluble or predominantly expressed on the surface of various cells of innate and adaptive immunity. C-type lectin receptors (CTLRs) are a class of PRRs which can recognize a variety of endogenous and exogenous ligands, thereby playing a crucial role in immunity, as well as in maintaining homeostasis. Mtb surface ligands, including mannose-capped lipoarabinomannan and cord factor, are important immune modulators which recently have been found to be directly recognized by several CTLRs. Receptor ligation is followed by cellular activation, mainly via nuclear factor kappaB mediated by a series of adaptors with subsequent expression of pro inflammatory cytokines. Mtb recognition by CTLRs and their cross talk with other PRRs on immune cells is of key importance for the better understanding of the Mtb induced complexity of the host immune responses. Epidemiological studies have shown that single nucleotide polymorphisms (SNPs) in several PRRs, as well as the adaptors in their signaling cascades, are directly involved in the susceptibility for developing disease and the disease outcome. In addition, an increasing number of CTLRs have been studied for their functional effects in the pathogenesis of TB. This review summarizes current knowledge regarding the various roles played by different CTLRs in TB, as well as the role of their SNPs associated with disease susceptibility and outcome in different human populations. PMID- 27469384 TI - Ciprofloxacin and statin interaction: a cautionary tale of rhabdomyolysis. AB - A 62-year-old woman presented to hospital, on general practitioner (GP) advice, with a 15-day history of slowly progressing muscle weakness. Results showed newly deranged liver function and creatine kinase (CK) of >24 000. Prior medical history includes previous myocardial infarction and recurrent urinary tract infection. 4 days prior to symptom onset, the patient developed typical urinary tract infection symptoms, treated with ciprofloxacin. The patient had been taking simvastatin (40 mg nocte) for 13 years and had never previously taken ciprofloxacin. Initial management included intravenous crystalloid fluids and discontinuation of simvastatin. CK level fell, liver function slowly improved and renal function remained stable. Muscle weakness improved and the patient became independently able to perform activities of daily living. While the interactions between statins and other antibiotics are well documented, the interaction between statins and ciprofloxacin is less so. The consequences of this interaction can have potentially serious outcomes. PMID- 27469385 TI - Thoracic intramedullary chordoma without bone involvement: a rare clinical entity. AB - An 8-year-old boy presented with a 1-year history of low backache, followed by paraparesis and urinary incontinence. MRI of the thoracic spine revealed an intramedullary, intensely contrast-enhancing lesion extending from T11 to L1 vertebral level, consistent with astrocytoma, ependymoma or haemangioblastoma. A diagnosis of intramedullary chordoma was made on tissue biopsy and immunohistochemical study. This is the second report of an intramedullary chordoma without bone involvement in English literature. After 6 months of follow up, patient showed good clinical outcome in terms of improvement in power in lower limbs and backache. PMID- 27469386 TI - Refractory tension pneumothorax as a result of an internally displaced thoracoamniotic shunt in an infant with a congenital pulmonary airway malformation. AB - Antenatally, congenital pulmonary airway malformation (CPAM) causing fetal hydrops can be palliated with thoracoamniotic shunts, which may become displaced in utero. We report a case of an infant born at 34 weeks gestational age with an antenatally diagnosed macrocystic lung lesion, fetal hydrops and an internally displaced thoracoamniotic shunt. The infant suffered refractory pneumothoraces despite multiple chest drains, and stabilised only after surgical resection of the lesion. Intraoperatively, the shunt was noted to form a connection between a type I CPAM and the pleural space. As the shunt was displaced internally, this complication was not immediately obvious during the initial resuscitation. In infants with large cystic lung lesions, clinicians should be aware that internally displaced thoracoamniotic shunts could contribute to refractory tension pneumothoraces and anticipate the need for advanced neonatal resuscitation, including early thoracocentesis or chest drain insertion. Furthermore, displaced shunts may require early surgical intervention. PMID- 27469387 TI - Retinopathy of prematurity screening leading to cardiopulmonary arrest: fatal complication of a benign procedure. AB - A 6-week-old female infant born at 31 weeks of gestation was brought to the ophthalmology office for retinopathy of prematurity (ROP) screening. One drop of phenylephrine (2.5%) and tropicamide (1%) ophthalmic solution was instilled in each eye for ROP evaluation. She was breast fed about 5 min after receiving the medication. She was covered in a blanket and soon her mother could not feel her suckling. Cardiopulmonary resuscitation was initiated with return of spontaneous circulation in 1-2 min. She was admitted to the paediatric intensive care unit and monitored overnight. After an uncomplicated hospital course, she was discharged the following day. It was determined that the eye drops had induced cardiopulmonary arrest (CPA) as apnoea and bradycardia of prematurity resolve by 36 weeks and CPA occurred within minutes of the medication administration. Identification of CPA, prompt intervention and awareness of the offending agent is of prime importance in management of such complications. PMID- 27469389 TI - Mixed Matrix Carbon Molecular Sieve and Alumina (CMS-Al2O3) Membranes. AB - This work shows mixed matrix inorganic membranes prepared by the vacuum-assisted impregnation method, where phenolic resin precursors filled the pore of alpha alumina substrates. Upon carbonisation, the phenolic resin decomposed into several fragments derived from the backbone of the resin matrix. The final stages of decomposition (>650 degrees C) led to a formation of carbon molecular sieve (CMS) structures, reaching the lowest average pore sizes of ~5 A at carbonisation temperatures of 700 degrees C. The combination of vacuum-assisted impregnation and carbonisation led to the formation of mixed matrix of CMS and alpha-alumina particles (CMS-Al2O3) in a single membrane. These membranes were tested for pervaporative desalination and gave very high water fluxes of up to 25 kg m(-2) h(-1) for seawater (NaCl 3.5 wt%) at 75 degrees C. Salt rejection was also very high varying between 93-99% depending on temperature and feed salt concentration. Interestingly, the water fluxes remained almost constant and were not affected as feed salt concentration increased from 0.3, 1 and 3.5 wt%. PMID- 27469388 TI - Serial testing for latent tuberculosis using QuantiFERON-TB Gold In-Tube: A Markov model. AB - Healthcare workers (HCWs) in low-incidence settings are often serially tested for latent TB infection (LTBI) with the QuantiFERON-TB Gold In-Tube (QFT) assay, which exhibits frequent conversions and reversions. The clinical impact of such variability on serial testing remains unknown. We used a microsimulation Markov model that accounts for major sources of variability to project diagnostic outcomes in a simulated North American HCW cohort. Serial testing using a single QFT with the recommended conversion cutoff (IFN-g > 0.35 IU/mL) resulted in 24.6% (95% uncertainty range, UR: 23.8-25.5) of the entire population testing false positive over ten years. Raising the cutoff to >1.0 IU/mL or confirming initial positive results with a (presumed independent) second test reduced this false positive percentage to 2.3% (95%UR: 2.0-2.6%) or 4.1% (95%UR: 3.7-4.5%), but also reduced the proportion of true incident infections detected within the first year of infection from 76.5% (95%UR: 66.3-84.6%) to 54.8% (95%UR: 44.6-64.5%) or 61.5% (95%UR: 51.6-70.9%), respectively. Serial QFT testing of HCWs in North America may result in tremendous over-diagnosis and over-treatment of LTBI, with nearly thirty false-positives for every true infection diagnosed. Using higher cutoffs for conversion or confirmatory tests (for initial positives) can mitigate these effects, but will also diagnose fewer true infections. PMID- 27469390 TI - Reexamination of structures, stabilities, and electronic properties of holmium doped silicon clusters HoSi n (n = 12-20). AB - The total energies, growth patterns, equilibrium geometries, relative stabilities, hardnesses, intramolecular charge transfer, and magnetic moments of HoSi n (n = 12-20) clusters have been reexamined theoretically using two different density functional schemes in combination with relativistic small-core Stuttgart effective core potentials (ECP28MWB) for the Ho atoms. The results show that when n = 12-15, the most stable structures are predicted to be exohedral frameworks with a quartet ground state, but when n = 16-20, they are predicted to be endohedral frameworks with a sextuplet ground state. These trend in stability across the clusters (gauged from their dissociation energies) was found to be approximately the same regardless of the DFT scheme used in the calculations, with HoSi13, HoSi16, HoSi18, and HoSi20 calculated to be more stable than the other clusters. The results obtained for cluster hardness indicated that doping the Ho atom into Si13 and Si16 leads to the most stable HoSi n clusters, while doping Ho into the other Si n clusters increases the photochemical sensitivity of the cluster. Analyses of intracluster charge transfer and magnetic moments revealed that charge always shifts from the Ho atom to the Si n cluster during the creation of exohedral HoSi n (n = 12-15) structures. However, the direction of charge transfer is reversed during the creation of endohedral HoSi n (n = 16 20) structures, which implies that Ho acts as an electron acceptor when it is encapsulated in the Si n cage. Furthermore, when the most stable exohedral HoSi n (n = 12-15) structures are generated, the 4f electrons of Ho are virtually unchanged and barely participate in intracluster bonding. However, in the most stable endohedral HoSi n (n = 16-20) frameworks, a 4f electron does participate in bonding. It does this by transferring to the 5d orbital, which hybridizes with the 6s and 6p orbitals and then interacts with Si valence sp orbitals. Meanwhile, the total magnetic moments of the HoSi n (n = 16-20) clusters are considerably higher than those of HoSi n (n = 12-15). Interestingly, the endohedral HoSi16 and HoSi20 clusters can be viewed as the most suitable building blocks for novel high density magnetic storage nanomaterials and for novel optical and optoelectronic photosensitive nanomaterials, respectively. PMID- 27469391 TI - A relativistic DFT probe of polypyrrolic macrocyclic diuranium(III) complexes with terminal solvents and iodines. AB - Relativistic density functional theory finds that two isomers of a diuranium(III) complex of a polypyrrolic macrocycle (H4L) feature active sites on uranium moieties, allowing for their potential application in activating industrially and economically important small molecules. To address this, a series of adducts [(X)nU2(L)]((2-m)+) (X = THF, I(-) and HI; n = 1 and 2; m = 0, 1 and 2) have been examined. The coordination from X to the exposed uranium(s) changes the general geometry and electronic structure slightly. Thermodynamic calculations reveal that iodine termination is energetically favored over THF/HI coordination. Graphical abstract Scalar and spin-orbit coupling relativistic DFT calculation reveals that the active sites on the uranium moieties of [U2(L)](2+) lead to formation of adducts [(THF)nU2(L)](2+), [InU2(L)]((2-n)+) and [(HI)nU2(L)](2+) (n = 1 and 2). Coordination to the exposed uranium(s) changes geometrical and electronic properties slightly, but iodine termination is the most energetically favored. PMID- 27469393 TI - Former Johnson and Johnson executives are convicted over off label marketing. PMID- 27469392 TI - New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding. AB - Bradykinin (BK) is a nonapeptide involved in several pathophysiological conditions including among others, septic and haemorrhagic shock, anaphylaxis, arthritis, rhinitis, asthma, inflammatory bowel disease. Accordingly, BK antagonists have long been sought after for therapeutic intervention. Action of BK is mediated through two different G-protein coupled receptors known as B1 and B2. Although there are several B1 antagonists reported in literature, their pharmacological profile is not yet optimal so that new molecules need to be discovered. In the present work we have constructed an atomistic model of the B1 receptor and docked diverse available non-peptide antagonists in order to get a deeper insight into the structure-activity relationships involving binding to this receptor. The model was constructed by homology modeling using the chemokine CXC4 and bovine rhodopsin receptors as template. The model was further refined using molecular dynamics for 600ns with the protein embedded in a POPC bilayer. From the refinement process we obtained an average structure that was used for docking studies using the Glide software. Antagonists selected for the docking studies include Compound 11, Compound 12, Chroman28, SSR240612, NPV-SAA164 and PS020990. The results of the docking study underline the role of specific receptor residues in ligand binding. The results of this study permitted to define a pharmacophore that describes the stereochemical requirements of antagonist binding, and can be used for the discovery of new compounds. PMID- 27469395 TI - Childhood ADHD and Delayed Reinforcement: A Direct Comparison of Performance on Hypothetical and Real-Time Delay Tasks. AB - OBJECTIVE: Individuals with ADHD have been shown to prefer smaller sooner over larger later rewards. This has been explained in terms of abnormally steeper discounting of the value of delayed reinforcers. Evidence for this comes from different experimental paradigms. In some, participants experience delay in the laboratory (real-time delay tasks; R-TD), in others they imagine the delay to reinforcers (hypothetical delay tasks; HD). METHOD: We directly contrasted the performance of 7- to 12-year-old children with ADHD (n = 23) and matched controls (n = 23) on R-TD and HD tasks with monetary rewards. RESULTS: Children with ADHD displayed steeper temporal discounting on the R-TD, but not the HD tasks. CONCLUSION: These findings suggest that the experience of waiting prior to the delivery of rewards is an important determinant of heightened temporal discounting in ADHD-a finding consistent with models that emphasize the aversive nature of delay for children. PMID- 27469394 TI - Superharmonic microbubble Doppler effect in ultrasound therapy. AB - The introduction of microbubbles in focused ultrasound therapies has enabled a diverse range of non-invasive technologies: sonoporation to deliver drugs into cells, sonothrombolysis to dissolve blood clots, and blood-brain barrier opening to deliver drugs into the brain. Current methods for passively monitoring the microbubble dynamics responsible for these therapeutic effects can identify the cavitation position by passive acoustic mapping and cavitation mode by spectral analysis. Here, we introduce a new feature that can be monitored: microbubble effective velocity. Previous studies have shown that echoes from short imaging pulses had a Doppler shift that was produced by the movement of microbubbles. Therapeutic pulses are longer (>1 000 cycles) and thus produce a larger alteration of microbubble distribution due to primary and secondary acoustic radiation force effects which cannot be monitored using pulse-echo techniques. In our experiments, we captured and analyzed the Doppler shift during long therapeutic pulses using a passive cavitation detector. A population of microbubbles (5 * 10(4)-5 * 10(7) microbubbles ml(-1)) was embedded in a vessel (inner diameter: 4 mm) and sonicated using a 0.5 MHz focused ultrasound transducer (peak-rarefactional pressure: 75-366 kPa, pulse length: 50 000 cycles or 100 ms) within a water tank. Microbubble acoustic emissions were captured with a coaxially aligned 7.5 MHz passive cavitation detector and spectrally analyzed to measure the Doppler shift for multiple harmonics above the 10th harmonic (i.e. superharmonics). A Doppler shift was observed on the order of tens of kHz with respect to the primary superharmonic peak and is due to the axial movement of the microbubbles. The position, amplitude and width of the Doppler peaks depended on the acoustic pressure and the microbubble concentration. Higher pressures increased the effective velocity of the microbubbles up to 3 m s(-1), prior to the onset of broadband emissions, which is an indicator for high magnitude inertial cavitation. Although the microbubble redistribution was shown to persist for the entire sonication period in dense populations, it was constrained to the first few milliseconds in lower concentrations. In conclusion, superharmonic microbubble Doppler effects can provide a quantitative measure of effective velocities of a sonicated microbubble population and could be used for monitoring ultrasound therapy in real-time. PMID- 27469396 TI - Functional Impairment in Children With Externalizing Behavior Disorders: Psychometric Properties of the Weiss Functional Impairment Rating Scale-Parent Report in a German Clinical Sample. AB - OBJECTIVE: To examine the psychometric properties of a German adaptation of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) in a clinical sample of children (4-12 years) with externalizing behavior disorders. METHOD: Data were collected within two clinical trials (N = 264). Factorial validity, reliability, and divergent validity from symptoms of ADHD and oppositional defiant disorder (ODD) were assessed. RESULTS: Confirmatory factor analyses revealed that a bifactor model consistent with the theoretical assumption of a general construct of impairment (total scale) and additional specific factors (subscales) provided satisfactory data fit. Model-based reliability estimates showed that both the general construct and specific factors accounted for item variance. Internal consistencies were >.70, part-whole corrected item-scale correlations mostly >.30. Correlations between the WFIRS-P Scales and ADHD and ODD symptoms were low to moderate. CONCLUSION: The results support the factorial validity, reliability, and divergent validity of the WFIRS-P. PMID- 27469397 TI - Gray Matter Increase in Motor Cortex in Pediatric ADHD: A Voxel-Based Morphometry Study. AB - OBJECTIVE: Several studies report that ADHD is associated with reduced gray matter (GM), whereas others report no differences in GM volume between ADHD patients and controls, and some even report more GM volume in individuals with ADHD. These conflicting findings suggest that reduced GM is not a universal finding in ADHD, and that more research is needed to delineate with greater accuracy the range of GM alterations. METHOD: The present study aimed to identify GM alterations in ADHD using pediatric templates. 19 drug-naive ADHD patients and 18 controls, all aged 7 to 14 years, were scanned using magnetic resonance imaging. RESULTS: Relative to the controls, the ADHD patients had more GM, predominantly in the precentral and supplementary motor areas. Moreover, there were positive correlations between GM volume in these areas and ADHD scale scores. CONCLUSION: The clinical and pathophysiological significance of increased GM in the motor areas remains to be elucidated by additional research. PMID- 27469398 TI - Design of a novel plasmonic nanoconjugated analytical tool for ultrasensitive antigen quantification. AB - To date, while various diagnostic approaches for antigen detection have been proposed, most are too expensive, lengthy and limited in sensitivity for clinical use. Nanoparticle systems with unique material properties, however, circumvent these problems and offer improved accuracy and sensitivity over current methods like the enzyme-linked immunosorbent assay (ELISA). Herein, we present a novel functionalization strategy of plasmonic nanoparticle probes capable of specific quantification of antigens directly in clinical samples. A nanoconjugation strategy that allows one to perform an intensity depletion immuno-linked assay (IDILA), involving specific antibodies that target the antigen of interest was designed to obtain a calibration curve and achieve the quantification of the antigen in clinical samples in the same experiment using a microplate reader (i.e., an UV-vis spectrophotometer). Finally, the IDILA methodology allowed specific detection of various clinically relevant antigens, with significantly improved sensitivity over the ELISA. Furthermore, the assay was shown to be robust, reliable, cheap and rapid, diagnosing antigens in clinical serum samples within 2 hours. PMID- 27469399 TI - Intra-abdominal packing with laparotomy pads and QuikClotTM during damage control laparotomy: A safety analysis. AB - BACKGROUND: Intra-abdominal packing with laparotomy pads (LP) is a common and rapid method for hemorrhage control in critically injured patients. Combat GauzeTM and Trauma PadsTM ([QC] Z-Medica QuikClot(r)) are kaolin impregnated hemostatic agents, that in addition to LP, may improve hemorrhage control. While QC packing has been effective in a swine liver injury model, QC remains unstudied for human intra-abdominal use. We hypothesized QC packing during damage control laparotomy (DCL) better controls hemorrhage than standard packing and is safe for intracorporeal use. METHODS: A retrospective review (2011-2014) at a Level-I Trauma Center reviewed all patients who underwent DCL with intentionally retained packing. Clinical characteristics, intraoperative and postoperative parameters, and outcomes were compared with respect to packing (LP vs. LP+QC). All complications occurring within the patients' hospital stays were reviewed. A p<=0.05 was considered significant. RESULTS: 68 patients underwent DCL with packing; (LP n=40; LP+QC n=28). No difference in age, BMI, injury mechanism, ISS, or GCS was detected (Table 1, all p>0.05). LP+QC patients had a lower systolic blood pressure upon ED presentation and greater blood loss during index laparotomy than LP patients. LP+QC patients received more packed red blood cell and fresh frozen plasma resuscitation during index laparotomy (both p<0.05). Despite greater physiologic derangement in the LP+QC group, there was no difference in total blood products required after index laparotomy until abdominal closure (LP vs LP+QC; p>0.05). After a median of 2days until abdominal closure in both groups, no difference in complications rates attributable to intra-abdominal packing (LP vs LP+QC) was detected. CONCLUSION: While the addition of QC to LP packing did not confer additional benefit to standard packing, there was no additional morbidity identified with its use. The surgeons at our institution now select augmented packing with QC for sicker patients, as we believe this may have additional advantage over standard LP packing. A randomized controlled trial is warranted to further evaluate the intra-abdominal use of advanced hemostatic agents, like QC, for both hemostasis and associated morbidity. PMID- 27469400 TI - A report of a novel technique: The comprehensive fibular autograft with double metal locking plate fixation (cFALP) for refractory post-operative diaphyseal femur fracture non-union treatment. AB - INTRODUCTION: The refractory post-operative diaphyseal femur fracture (DFF) non union is extremely difficult to treat and remains severe challenges for orthopedists. Although several traditional internal fixations and novel biomedical techniques have been used in managing this complication, its treatment is still fraught with severe challenges. PATIENTS AND METHODS: Starting from 1999, 5 patients after three previous internal fixation operations showing refractory DFF non-union underwent the comprehensive fibular autograft with double metal locking plates fixation (cFALP) surgery. The autogenous fibular was first harvested and non-evenly split into two halves in a longitudinal manner. After retracting all previous internal fixation(s), the larger half strut fibula was hammered into the femur canal while the smaller half was fragmented into small pieces and filled surrounding the DFF site. Two locking compression plate were fixed on the lateral and anterior (or antero-lateral) side of the femur, respectively. RESULTS: The follow-up ranged from 60 to 96 weeks. All cases (100%) achieved bony union without severe complications. The mean time to union was 36+/ 14.7 weeks (range 24-60 weeks). CONCLUSION: The cFALP is a promising surgical modality for DFF non-union treatment. However, because fibular harvest may cause severe complications, the cFLAP should only be considered in refractory DFF non union cases. PMID- 27469401 TI - Enhanced cephalomedullary nail lag screw placement and intraoperative tip-apex distance measurement with a novel computer assisted surgery system. AB - OBJECTIVE: The goal of this study was to evaluate the ability of a novel computer assisted surgery system to guide ideal placement of a lag screw during cephalomedullary nailing and then accurately measure the tip-apex distance (TAD) measurement intraoperatively. DESIGN: Retrospective case review. SETTING: Level II trauma hospital. PATIENTS: The initial 98 consecutive clinical cases treated with a cephalomedullary nail in conjunction with a novel computer assisted surgery system were retrospectively reviewed. INTERVENTION: A novel computer assisted surgery system was utilized to enhance lag screw placement during cephalomedullary nailing procedures. The computer assisted surgery system calculates the TAD intraoperatively after final lag screw placement. MAIN OUTCOME MEASURES: The ideal TAD was considered to be within a range of 5mm-20mm. The ability of the computer assisted surgery system (CASS) to assist in placement of a lag screw within the ideal TAD was evaluated. Intraoperative TAD measurements provided by the computer assisted surgery system were then compared to standard postoperative TAD measurements on PACS (picture archiving and communication system) images to determine whether these measurements are equivalent. RESULTS: 79 cases (80.6%) were available with complete information for a retrospective review. All cases had CASS TAD and PACS TAD measurements >5mm and<20mm. In addition, no significant difference could be detected between the intraoperative CASS TAD and the postoperative PACS TAD (p=0.374, Wilcoxon Test; p=0.174, paired T-Test). A cut-out rate of 0% was observed in all patients who were treated with CASS in this case series (95% CI: 0 - 3.01%). CONCLUSIONS: The novel computer assisted surgery system tested here is an effective and reliable adjunct that can be utilized for optimal lag screw placement in cephalomedullary nailing procedures. The computer assisted surgery system provides an accurate intraoperative TAD measurement that is equivalent to the standard postoperative measurement utilizing PACS images. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 27469402 TI - Changes in the syndesmotic reduction after syndesmotic screw fixation for ankle malleolar fractures: One-year longitudinal evaluations using computer tomography. AB - INTRODUCTION: To evaluate time-dependent changes in the syndesmotic reduction after syndesmotic screw fixation and one year after screw removal for ankle malleolar fractures, and to assess whether the incidence of syndesmotic malreduction changes depending on the measurement method. METHODS: We assessed twenty patients who underwent syndesmotic screw fixation for ankle fractures. The syndesmotic screws were removed after six weeks of the fracture surgery. Syndesmotic reduction was assessed within two weeks of the fracture surgery and one year after the screw removal using the axial computer tomographic images. Side-to-side differences in the anterior and posterior tibiofibular distances, anteroposterior fibular translation, and fibular rotation were measured. RESULTS: The mean anterior tibiofibular distance was 0.7mm after syndesmotic fixation. It increased to 1.9mm at one year after screw removal (p=0.002). After syndesmotic fixation, four ankles had malreduction of the anterior tibiofibular distance, including three ankles with widening and one with overtightening. At one year, eight ankles had malreduction, all of whom had widening. The other measurement values did not change over time (0.1mm vs. 0.6mm for the posterior tibiofibular distance, 0.2mm vs. 0.3mm for the anteroposterior fibular translation, and 0.7 degrees vs. 0 degrees for the fibular rotation). The incidences of malreduction were significantly different depending on the definition of malreduction, ranging from 10% to 50% after syndesmotic fixation (p=0.01) and from 20% to 60% at one year after screw removal (p=0.02). CONCLUSIONS: The anterior tibiofibular distance widened after one year of syndesmotic screw removal. The incidence of malreduction varied depending on the measurement method. PMID- 27469403 TI - Prediction of early mortality following hip fracture surgery in frail elderly: The Almelo Hip Fracture Score (AHFS). AB - BACKGROUND: Hip fractures are common in the elderly and have a high risk of early mortality. Identification of patients at high risk of early mortality could contribute to enhanced quality of care. A simple scoring system is essential for preoperative identification of patients at high risk of early mortality in clinical practice. Of risk models published, The Nottingham Hip Fracture Score (NHFS) shows the most promising results so far. However, there is still room for improvement. METHODS: A cohort study including 850 patients was conducted over a period of 5,5 yr. The NHFS was adjusted for cognitive impairment (NHFS-a) and tested. Patients who died within 30days following hip fracture surgery (early mortality group) were compared to survivors. Independent risk factors for early mortality were assessed. A new hip fracture score for frail elderly was developed: the Almelo Hip Fracture Score (AHFS). The NHFS-a and the AHFS were compared for accuracy and predictive validity. RESULTS: Sixty-four (7.5%) patients died within 30days following hip fracture surgery. The AHFS predicts the risk of early mortality better than the NHFS-a (p<0.05). Using cut-off points of AHFS <= 9 and AHFS >= 13, patients could be divided into a low, medium or high risk group. The area under the curve improved with the AHFS compared to the NHFS a (0.82 versus 0.72). The likelihood ratio test reveals a significantly better fit of the AHFS in comparison with the NHFS-a (p<0.001). CONCLUSIONS: The AHFS can identify frail elderly at high risk of early mortality following hip fracture surgery accurately. With the AHFS, the patient can be classified into the low, medium or high risk group, which contributes to enhanced quality of care in clinical practice. PMID- 27469404 TI - Investigation of non-covalent complexations of Ca(II) and Mg(II) ions with insulin by using electrospray ionization mass spectrometry. AB - RATIONALE: Insulin is a peptide hormone secreted by pancreatic beta-cells. Ca(II) and Mg(II) ions play an important role in the secretion of insulin. There is no study about a direct complexation of Ca(II) or Mg(II) with insulin and their equilibrium constants. Electrospray ionization mass spectrometry (ESI-MS) is a practical method for the monitoring of non-covalent complexes such as Ca(II) insulin and Mg(II)-insulin. Here, the equilibrium constants of Ca(II)-insulin and Mg(II)-insulin non-covalent complexes have been calculated after ESI-MS measurements in aqueous solutions. METHODS: The effects of pH, competitive binding, ion exchange, and Na(I) and K(I) ions on Ca(II)-insulin and Mg(II) insulin complexation have been examined by measuring by ESI-MS. The dissociation equilibrium constants (K1 and K2 ) of Ca(II)-insulin and Mg(II)-insulin complexes were calculated from the binomial graph derived from the ESI-MS normalized peak intensities. The MS/MS spectra of the complexes have been examined. RESULTS: The dissociation equilibrium constants were found to K1 : 1.29 * 10(-4) M and K2 : 9.69 * 10(-4) M for the Ca(II)-insulin complexes, and K1 : 1.37 * 10(-4) M and K2 : 9.12 * 10(-4) M for Mg(II)-insulin complexes. Ca(II) ions have higher complexation capability with insulin than Mg(II) ions. CONCLUSIONS: The binding equilibrium constants of Ca(II)- and Mg(II)-insulin non-covalent complexes have been determined successfully by ESI-MS. Ca(II) and Mg(II) ions are involved in the insulin secretion by forming non-covalent complexes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27469405 TI - Pro-survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia. AB - Dinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including chronic lymphocytic leukaemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-kappaB, p38, PI3K/AKT and RAF/MEK/ERK. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL2 family such as MCL1 and BCL-xL (also termed BCL2L1). Finally, we showed that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and the BCL2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of cyclin-dependent kinase inhibitors in CLL in combination with other relevant targeted therapies. PMID- 27469406 TI - Novel Phosphate Modified Cathepsin B Linkers: Improving Aqueous Solubility and Enhancing Payload Scope of ADCs. AB - In an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel phosphate bridged Cathepsin B sensitive linker was developed to enable the targeted delivery of glucocorticoids. Phosphate bridging of the Cathepsin B sensitive linkers allows for payload attachment at an aliphatic alcohol. As small molecule drug-linkers, these aqueous soluble phosphate containing drug-linkers were found to have robust plasma stability coupled with rapid release of payload in a lysosomal environment. Site-specific ADCs were successfully made between these drug-linkers and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. These ADCs demonstrated in vitro targeted delivery of glucocorticoids to a representative cell line as measured by changes in glucocorticoid receptor (GR) mediated gene mRNA levels. This novel linker expands the scope of potential ADC payloads by allowing an aliphatic alcohol to be a stable, yet cleavable attachment site. This phosphate linker may have broad utility for internalizing ADCs as well as other targeted delivery platforms. PMID- 27469407 TI - Esophageal cancer: anatomic particularities, staging, and imaging techniques. AB - Cancer of the esophagus is a tumor with aggressive behavior that is usually diagnosed in advanced stages. The absence of serosa allows it to spread quickly to neighboring mediastinal structures, and an extensive lymphatic drainage network facilitates tumor spread even in early stages. The current TNM classification, harmonized with the classification for gastric cancer, provides new definitions for the anatomic classification, adds non-anatomic characteristics of the tumor, and includes tumors of the gastroesophageal junction. Combining endoscopic ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging provides greater accuracy in determining the initial clinical stage, and these imaging techniques play an essential role in the selection, planning, and evaluation of treatment. In this article, we review some particularities that explain the behavior of this tumor and we describe the current TNM staging system; furthermore, we discuss the different imaging tests available for its evaluation and include a diagnostic algorithm. PMID- 27469408 TI - Intravascular lymphoma mimicking vasculitis. AB - Intravascular lymphoma is a rare malignancy which is characterized by a proliferation of atypical appearing B cells, generally confined to vascular lumina. A tissue biopsy demonstrating the pathology is required to make a diagnosis. The tumor is often disseminated at the time of diagnosis and prognosis is poor, even with aggressive chemotherapy. Neurologic presentations of this neoplasm can be quite varied. This report documents the presence of intravascular lymphoma diagnosed on a brain biopsy in a 60-year-old man. He initially presented 6months before brain biopsy with chest pain and hypotension, warranting coronary artery bypass graft surgery. Four months later, he presented with signs attributed to a stroke (diaphoresis, slumped over in a chair and left hand weakness). He subsequently developed a sudden onset wide-based gait, left leg numbness, word finding difficulties and worsening confusion. A MRI study showed multiple infarcts in the brain, including cerebellum. Invasive angiogram suggested vasculitis. He was started on a course of treatment for presumed central nervous system vasculitis. He continued to develop signs suggestive of ongoing infarct development and a biopsy from the right parietal was taken. The biopsy showed atypical intravascular CD20 positive staining B cells, consistent with intravascular lymphoma. PMID- 27469409 TI - When should we test for voltage-gated potassium channel complex antibodies? A retrospective case control study. AB - Patients with voltage-gated potassium channel (VGKC)-complex antibodies are increasingly recognized as having central, peripheral or combined phenotypes. With increasing awareness, more patients are tested and the clinical spectrum is expanding. Consequently, clinicians may be uncertain as to which patients should or should not be tested. Previous studies have identified common clinical features, but none has looked at the usefulness of these in predicting seropositive disease. We conducted a case-control study of patients tested for VGKC-complex antibodies over 10years at a regional tertiary neurology centre determining which clinical/biochemical features were associated with antibody positive disease. We found a marked increase in the numbers tested, although the percentage positive remained low. Antibody titre was highest in central disease (p<0.001). Time from presentation to testing was shorter in those with VGKC disease (p=0.01). Seizures were present in 11 (69%) of those with VGKC-disease versus three (18%) without (odds ratio [OR] 10.3, 95% confidence interval [CI]: 2.0-52.7, p=0.005). There was an inverse correlation between the antibody titre and serum sodium. A multivariate model selected seizures and hyponatraemia as predictive of VGKC disease (sensitivity 75% and specificity 82%); faciobrachial dystonic movements were specific but insensitive. Interestingly serum alkaline phosphatase was higher in those with VGKC-disease (p=0.016) and highest in those with peripheral disease (p=0.015). An ALP>70u/L was strongly associated with antibody positivity (OR 4.11 95% CI: 1.43-11.8, p=0.007) with a sensitivity of 74.2%. The presence of seizures, faciobrachial movements, and hyponatraemia should raise suspicion of VGKC-disease; alkaline phosphatase may represent a novel biomarker, particularly in those with peripheral disease. PMID- 27469410 TI - Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. AB - We evaluated the differences in sonographic parameters in carpal tunnel syndrome (CTS) patients with normal and mildly abnormal nerve conduction studies (NCS). This was a prospective cross-sectional study. We assessed 169 wrists (101 patients) with a clinical diagnosis of carpal tunnel syndrome (CTS), as well as 20 healthy controls (40 wrists). 49 wrists were classified as mild NCS-positive and 38 as NCS-negative based on our laboratory NCS normal values. The cross sectional area (CSA) of the median nerve at the carpal tunnel inlet and mid forearm were measured and the wrist-to-forearm ratio (WFR) was calculated. 26% of the NCS-negative group had abnormal CSA. The CSA and WFR also differed significantly between the two groups. There was significant correlation between the sonographic and electrophysiologic variables. Ultrasound was diagnostic for CTS in a third of the NCS-negative wrists. Ultrasound may be useful in clinical CTS patients with normal or borderline NCS. PMID- 27469411 TI - Caspase-related apoptosis genes in gliomas by RNA-seq and bioinformatics analysis. AB - Gliomas are the most common malignant tumors of the brain. The aim of this study is to identify caspase-dependent apoptotic genes and uncover their potential regulatory mechanism in glioma progression. Human glioma cell line U251 was used. Three experiment groups were set as control group, H2O2 group (treated with H2O2) and caspase inhibitor group (treated with caspase inhibitor). For samples in each group, RNA-sequencing was performed on Illumina platform and differentially expressed genes (DEGs) between any two of the three groups were selected using NOISeq package. By overlapping analysis, the caspase inhibitor-related DEGs were further screened out, followed by enrichment analyses. Drugs associating with these genes were selected by WebGestalt. Protein-protein interaction (PPI) network analysis was conducted based on SRINIG database. A set of 105 caspase inhibitor-related DEGs were identified, which were significantly enriched in cellular components related functions (for example, TUBB2A, RPSA and RPL5); and metabolism related pathways (for example, PSMC3, KHSRP, RPL5 and RPSA). In addition, KHSRP and TUBB2A were significantly associated with several drugs such as cefotaxime, cefacetrile and netilmicin. Besides, PSMC3 and RPL5 were identified as crucial nodes in the PPI network. Several crucial genes in gliomas cells such as TUBB2A, RPSA, RPL5, PSMC3 and KHSRP were identified, which might play significant roles in apoptosis in a caspase-dependent manner. These genes might also involve in the regulation of metabolism related functions and pathways. KHSRP and TUBB2A might be novel targets of three drugs, cefotaxime, cefacetrile and netilmicin. PMID- 27469412 TI - Optimization of tumor resection with intra-operative magnetic resonance imaging. AB - Intra-operative MRI (ioMRI) may be used to optimize tumor resection. Utilization of this technology allows for the removal of residual tumor mass following initial tumor removal, maximizing the extent of resection. This, in turn, has been shown to lead to improved outcomes. Individual studies have examined the impact of ioMRI on the rate of extended resection, but a comprehensive review of this topic is needed. A literature review of the MEDLINE, EMBASE, CENTRAL, and Google Scholar databases revealed 12 eligible studies. This included 804 primary operations and 238 extended resections based on ioMRI findings. Use of ioMRI led to extended tumor resection in 13.3-54.8% of patients (mean 37.3%). Stratification by tumor type showed additional resection occurred, on average, in 39.1% of glioma resections (range 13.3-70.0%), 23.5% of pituitary tumor resections (range 13.3-33.7%), and 35.0% of nonspecific tumor resections (range 17.5-40%). Tumor type (glioma vs. pituitary) did not significantly influence the rate of further excision following ioMRI (p=0.309). There was no difference in secondary resection rate between studies limited to pediatric patients and those including adults (p=0.646). Thus, the use of intra-operative MRI frequently results in further resection of tumors. It is primarily used for the resection of gliomas and pituitary tumors. Tumor type does not appear to be a significant contributing factor to the rate of secondary tumor removal. Limited evidence suggests that extended resection may translate into improved clinical outcomes and mortality rates. However, results have not been unanimous, while clinical effect sizes have often been modest. PMID- 27469413 TI - Combination Ti/PEEK ALIF cage for anterior lumbar interbody fusion: Early clinical and radiological results. AB - Anterior lumbar interbody fusion (ALIF) is a common procedure for patients with degenerative pathologies of the lumbar spine. In this study, the clinical and radiological outcomes of a combination titanium/polyetheretherketone (Ti/PEEK) ALIF cages in one, two and three-level surgery were evaluated. Over an 18-month time period, a prospective single surgeon series of 20 implants (15 patients) were included in the study, with minimum 10-months follow-up. From these 15 patients, two were supplemented with posterior percutaneous pedicle screw fixation for additional stability. Radiological follow-up with fine cut CT scan at 9-12months was performed to evaluate early fusion rates, and integration of the Titanium/PEEK cage at the endplate junction. 20 implants were followed for a minimum of 10months, and a mean of 15months. A 95% (19/20 implants) fusion rate with no implant related complications was achieved at the mean 15-month postoperative mark. Patients experienced statistically significant improvement in pain and functional outcomes (SF12 and ODI) compared to their pre-operative status. A single patient with a non-union at L5/S1 (smoker) did not experience any improvement in symptoms. A Ti-PEEK cage, with allograft and BMP-2 to achieve interbody fusion is an effective implant for use in anterior lumbar surgery with high fusion rates, no lucency around the titanium endplates at follow-up, and with promising early results. PMID- 27469414 TI - Sex and the treatment effect in the Chinese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) trial. AB - In the randomized controlled trial of NeuroAiD versus placebo following ischemic stroke, there was a trend for sex influencing the treatment effect of NeuroAiD in improving functional outcome following ischemic stroke (p=0.075). PMID- 27469415 TI - Optical coherence tomography imaging of optic disc cavernous haemangioma. AB - Optic disc cavernous haemangiomas are either found incidentally or after presentation with vitreous haemorrhage. They are characterised by a cluster of grapes appearance to the multiple vascular saccules that make up the tumour. They are more often found in the retinal periphery but rarely occur at the optic disc. Optical coherence tomography (OCT) imaging may be a useful non-invasive imaging modality to follow-up these lesions. We present the case of an asymptomatic 60 year-old lady referred from her optometrist with a lesion overlying the optic disc and the ensuing diagnosis of cavernous haemangioma using fundus fluorescein angiography and OCT. PMID- 27469416 TI - Rapid increase in resistance to third generation cephalosporins, imipenem and co resistance in Klebsiella pneumoniae from isolated from 7,140 blood-cultures (2010 2014) using EARS-Net data in Spain. AB - INTRODUCTION: An analysis was made about the evolution of resistance to 3rd generation cephalosporins, imipenem, and other antibiotics in invasive isolates of Klebsiella pneumoniae (K. pneumoniae) according to the Spanish EARS-Net database (2010-2014). METHODS: Forty-two hospitals from 16 Autonomous Communities with an approximate population coverage of 33% participated. RESULTS: A total 7,140 pneumoniae corresponding to the same number of patients were studied. Overall resistance percentages (I+R) were: cefotaxime 15.8%, ceftazidime 13.7%, imipenem 1.7%, ciprofloxacin 20.1%, tobramycin 14.1%, gentamicin 10.4%, and amikacin 1.9%. Resistance to 3rd generation cephalosporins increased from 9.8% (2010) to 19% (2014); to ciprofloxacin from 15.4% (2010) to 19.6% (2014); to gentamicin from 6.2% (2010) to 10.3% (2014) and to tobramycin from 7.1% (2010) to 14.2% (2014) (p<.001 in all cases). Combined resistance to 3rd generation cephalosporins, ciprofloxacin, and aminoglycosides increased from 3.3% (2010) to 9.7% (2014) (p<.001). Resistance to imipenem also increased from 0.27% (2010) to 3.46% (2014) (p<.001). A total of 121 isolates were resistant to imipenem, of which 104 (86%) produced carbapenemases: 74 OXA-48, 14 VIM, 9 KPC (6 KPC-2 and 3 KPC-3), 6 IMP, and 1 GES. CONCLUSIONS: Over the 5 year period (2010-2014), resistance to 3rd generation cephalosporins in invasive K. pneumoniae in Spain has doubled. The combined resistance to 3rd generation cephalosporins, ciprofloxacin, and aminoglycosides has tripled, and imipenem resistance has increased almost 13 times, mostly due to the spread of carbapenemase-producing isolates. PMID- 27469417 TI - Mycotic abdominal aortic aneurysm due to Listeria monocytogenes. PMID- 27469418 TI - Single session family therapy in youth mental health: can it help? AB - OBJECTIVE: The objective of this study was to assess the effectiveness of single session therapy in meeting the needs of young people and their families on first presentation to a mental health service. METHOD: We conducted a quantitative analysis of routinely collected data using self- and family member-reported session and outcome rating scales. RESULTS: Both young people and their family members rate single session therapy sessions highly. In addition, both young people and their families rate the young person's mental health and well-being to have improved after the single session therapy intervention, with mothers rating the young person's improvement most highly. CONCLUSIONS: Single session therapy is an effective tool in improving both self- and parent-rated individual, interpersonal, social and overall well-being for young people presenting to a mental health service. PMID- 27469419 TI - Risk prediction tool for grade re-classification in men with favourable-risk prostate cancer on active surveillance. AB - OBJECTIVE: To create a nomogram for men on active surveillance (AS) for prediction of grade re-classification (GR) above Gleason score 6 (Grade group >2) at surveillance biopsy. PATIENTS AND METHODS: From a cohort of men enrolled in an AS programme, a multivariable model was used to identify clinical and pathological parameters predictive of GR. Nomogram performance was assessed using receiver operating characteristic curves, calibration, and decision curve analysis. RESULTS: Of 1 374 men, 254 (18.50%) were re-classified to Gleason >=7 on surveillance prostate biopsy. Variables predictive of GR were earlier year of diagnosis [<=2004 vs >=2005; odds ratio (OR) 2.16, P < 0.001], older age (OR 1.05, P < 0.001), higher prostate-specific antigen density [OR 1.19 (per 0.1 unit increase), P = 0.04], bilateral disease (OR 2.86, P < 0.001), risk strata (low risk vs very-low-risk, OR 1.79, P < 0.001), and total number of biopsies without GR (OR 0.68, P < 0.001). On internal validation, a nomogram created using the multivariable model had an area under the curve of 0.757 (95% confidence interval 0.730-0.797) for predicting GR at the time of next surveillance biopsy. CONCLUSION: The nomogram described is currently being used at each return visit to assess the need for a surveillance biopsy, and could increase retention in AS. PMID- 27469420 TI - Survey of Clostridium difficile infection surveillance systems in Europe, 2011. AB - To develop a European surveillance protocol for Clostridium difficile infection (CDI), existing national CDI surveillance systems were assessed in 2011. A web based electronic form was provided for all national coordinators of the European CDI Surveillance Network (ECDIS-Net). Of 35 national coordinators approached, 33 from 31 European countries replied. Surveillance of CDI was in place in 14 of the 31 countries, comprising 18 different nationwide systems. Three of 14 countries with CDI surveillance used public health notification of cases as the route of reporting, and in another three, reporting was limited to public health notification of cases of severe CDI. The CDI definitions published by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the European Centre for Disease Prevention and Control (ECDC) were widely used, but there were differing definitions to distinguish between community- and healthcare-associated cases. All CDI surveillance systems except one reported annual national CDI rates (calculated as number of cases per patient-days). Only four surveillance systems regularly integrated microbiological data (typing and susceptibility testing results). Surveillance methods varied considerably between countries, which emphasises the need for a harmonised European protocol to allow consistent monitoring of the CDI epidemiology at European level. The results of this survey were used to develop a harmonised EU-wide hospital-based CDI surveillance protocol. PMID- 27469422 TI - Correlation between pre-operative buccal bone thickness and soft tissue changes around immediately placed and restored implants in the maxillary anterior region: A 2-year prospective study. AB - OBJECTIVES: This study evaluated the correlation between pre-operative buccal cortical bone thickness and peri-implant tissue response following immediate placement and restoration of implants in the maxillary aesthetic zone. MATERIAL AND METHODS: Eighteen patients (3 males, 15 females) with an age range of 19-57 years requiring the replacement of a single maxillary anterior tooth were included in this prospective study. Patients were selected on the basis of defined criteria: intact socket walls, absence of any acute infection in the sockets, absence of any gingival marginal pathology and attainment of a high primary stability (>=30 Ncm) at implant placement. Regardless of buccal bone thickness, all participating patients underwent the same treatment strategy that involved removal of the failed tooth, flapless surgery, immediate implant placement, grafting of the implant-socket gap and connection of a screw-retained provisional restoration. Buccal bone thickness was evaluated using pre-operative CBCT scans. Intra-oral photographs were taken before implant placement (baseline) and at 1- and 2-year follow-up to assess soft tissue changes around the implants. Aesthetic evaluation was carried out using the pink esthetic score (PES). RESULTS: All implants remained osseointegrated during the follow-up period of 2 years with mesial papilla, distal papilla, and mid-facial gingiva showing a mean recession of 0.06 +/- 0.71 mm, 0.25 +/- 0.78 mm, and 0.22 +/- 0.83 mm, respectively. Pink esthetic score values improved from a median value of 9 (IQR 8.75-10.25) pre-operatively to 11 (IQR 9.75-12) at the end of 2 years. No significant correlation was found between buccal bone thickness (range 0.45-1.24 mm) and soft tissue or aesthetic changes. CONCLUSIONS: Within the limits of this study, no significant correlation could be found between pre-operative buccal bone width and the soft tissue and aesthetic outcome following immediate implant placement and restoration in the anterior maxilla. Therefore, favourable clinical and aesthetic outcomes could be achieved by applying a strict selection criteria and treatment protocol regardless of the initial thickness of the buccal bone. PMID- 27469421 TI - Effects of a lifestyle modification programme to reduce the number of risk factors for metabolic syndrome: a randomised controlled trial. AB - OBJECTIVE: To determine the effectiveness of a personal support lifestyle education programme (PSMetS) for reducing risk factors in individuals with metabolic syndrome (MetS). DESIGN: A two-arm randomised controlled trial. SETTING: Companies in metropolitan Tokyo, Japan. SUBJECTS: Male workers with diagnosed MetS or a high risk for MetS according to the Counselling Guidance Program, Japan (n 193). RESULTS: The reduction in the number of risk factors for MetS (as defined according to the criteria published by the Japanese Ministry of Health, Labor and Welfare in April 2007 (MHLW-MetS)) in the PSMetS group was not significantly different from that in the usual care group by van Elteren's test (baseline-adjusted P=0.075) for intention-to-treat (ITT), while it was significant (baseline-adjusted P=0.038) for per-protocol set (PPS). The proportion of MHLW-MetS was significantly different between groups by van Elteren's test (baseline-adjusted P=0.031). Two components of MHLW-MetS showed significant reductions in the PSMetS group: waist circumference (baseline adjusted P=0.001) and BMI (baseline-adjusted P=0.002). PPS and ITT analyses showed similar results. CONCLUSIONS: For male workers with MHLW-MetS or a high risk of MHLW-MetS, PSMetS reduced the number of risk factors for MHLW-MetS. PMID- 27469423 TI - Leishmaniasis Gone Viral: Social Media and an Outbreak of Cutaneous Leishmaniasis. AB - This report details how social media communication was used in a group of teens to diagnose cutaneous leishmaniasis that they acquired during a trip to Israel. Their posts quickly brought the cluster to the attention of the teens and their parents, leading to prompt recognition of the true etiology of their lesions and appropriate treatment. PMID- 27469424 TI - Neural assemblies revealed by inferred connectivity-based models of prefrontal cortex recordings. AB - We present two graphical model-based approaches to analyse the distribution of neural activities in the prefrontal cortex of behaving rats. The first method aims at identifying cell assemblies, groups of synchronously activating neurons possibly representing the units of neural coding and memory. A graphical (Ising) model distribution of snapshots of the neural activities, with an effective connectivity matrix reproducing the correlation statistics, is inferred from multi-electrode recordings, and then simulated in the presence of a virtual external drive, favoring high activity (multi-neuron) configurations. As the drive increases groups of neurons may activate together, and reveal the existence of cell assemblies. The identified groups are then showed to strongly coactivate in the neural spiking data and to be highly specific of the inferred connectivity network, which offers a sparse representation of the correlation pattern across neural cells. The second method relies on the inference of a Generalized Linear Model, in which spiking events are integrated over time by neurons through an effective connectivity matrix. The functional connectivity matrices inferred with the two approaches are compared. Sampling of the inferred GLM distribution allows us to study the spatio-temporal patterns of activation of neurons within the identified cell assemblies, particularly their activation order: the prevalence of one order with respect to the others is weak and reflects the neuron average firing rates and the strength of the largest effective connections. Other properties of the identified cell assemblies (spatial distribution of coactivation events and firing rates of coactivating neurons) are discussed. PMID- 27469425 TI - The continuous and discrete molecular orbital x-ray bands from Xe(q+) (12<=q<=29) +Zn collisions. AB - In this paper, the x-ray emissions are measured by the interaction of 1500-3500 keV Xe(q+) (q = 12, 15, 17, 19, 21, 23, 26 and 29) ions with Zn target. When q < 29, we observe Ll, Lalpha, Lbeta1, Lbeta2 and Lgamma characteristic x-rays from Xe(q+) ions and a broad M-shell molecular orbital (MO) x-ray band from the transient quasi-molecular levels. It is found that their yields quickly increase with different rates as the incident energy increases. Besides, the widths of the broad MO x-ray bands are about 0.9-1.32 keV over the energy range studied and are proportional to v(1/2) (v = projectile velocity). Most remarkably, when the projectile charge state is 29, the broad x-ray band separates into several narrow discrete spectra, which was never observed before in this field. PMID- 27469426 TI - Laser in situ keratomileusis for high hyperopia with corneal vertex centration and asymmetric offset. AB - PURPOSE: To investigate refractive outcomes and induction of corneal higher order aberrations (HOA) in eyes that underwent laser-assisted in situ keratomileusis (LASIK) for high hyperopia correction using an aberration neutral profile with corneal vertex centration and asymmetric offset. METHODS: A total of 24 consecutive patients (38 eyes) who underwent LASIK by one surgeon using AMARIS 750S excimer laser and a Carriazo-Pendular microkeratome for flap creation were retrospectively analyzed. Eyes targeted for plano and with correction in the maximum hyperopic meridian strictly higher than +4D were included in the retrospective analysis. Patients were reviewed at 1, 3, and 6 months postoperatively. Postoperative monocular corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA), manifest refraction, and corneal wavefront aberrations were compared with respective preoperative metrics. RESULTS: Mean preoperative spherical equivalent and refractive astigmatism was +4.07 +/- 0.90 D and 1.37 +/- 1.26 D, respectively, reducing to +0.28 +/- 0.58D (p<0.0001) and 0.49 +/- 0.47 D (p = 0.0001) at the last postoperative visit. Six months postoperatively, 78% of eyes achieved a UDVA of 20/25 or better. No eye lost more than 2 Snellen lines of CDVA at any follow-up. There was a statistically significant induction of vertical trefoil (+0.104 +/- 0.299 um, p<0.05), vertical coma (-0.181 +/- 0.463 um, p<0.01), horizontal coma (+0.198 +/- 0.663 um, p<0.05), spherical aberration (-0.324 +/- 0.281 um, p<0.0001), secondary vertical trefoil (+0.018 +/- 0.044 um, p<0.01), and secondary horizontal coma (+0.026 +/- 0.083 um, p<0.05). CONCLUSIONS: Laser-assisted in situ keratomileusis for high hyperopia using corneal vertex centration with asymmetric offset results in significant improvement in refraction and visual acuity although affected by significant induction of some higher order aberrations. PMID- 27469427 TI - CO2, the greenhouse effect and global warming: from the pioneering work of Arrhenius and Callendar to today's Earth System Models. AB - Climate warming during the course of the twenty-first century is projected to be between 1.0 and 3.7 degrees C depending on future greenhouse gas emissions, based on the ensemble-mean results of state-of-the-art Earth System Models (ESMs). Just how reliable are these projections, given the complexity of the climate system? The early history of climate research provides insight into the understanding and science needed to answer this question. We examine the mathematical quantifications of planetary energy budget developed by Svante Arrhenius (1859 1927) and Guy Stewart Callendar (1898-1964) and construct an empirical approximation of the latter, which we show to be successful at retrospectively predicting global warming over the course of the twentieth century. This approximation is then used to calculate warming in response to increasing atmospheric greenhouse gases during the twenty-first century, projecting a temperature increase at the lower bound of results generated by an ensemble of ESMs (as presented in the latest assessment by the Intergovernmental Panel on Climate Change). This result can be interpreted as follows. The climate system is conceptually complex but has at its heart the physical laws of radiative transfer. This basic, or "core" physics is relatively straightforward to compute mathematically, as exemplified by Callendar's calculations, leading to quantitatively robust projections of baseline warming. The ESMs include not only the physical core but also climate feedbacks that introduce uncertainty into the projections in terms of magnitude, but not sign: positive (amplification of warming). As such, the projections of end-of-century global warming by ESMs are fundamentally trustworthy: quantitatively robust baseline warming based on the well-understood physics of radiative transfer, with extra warming due to climate feedbacks. These projections thus provide a compelling case that global climate will continue to undergo significant warming in response to ongoing emissions of CO2 and other greenhouse gases to the atmosphere. PMID- 27469428 TI - Ursolic acid, a potential anticancer compound for breast cancer therapy. AB - There are growing interests in the health benefits associated with consumption of fruits and vegetables, especially for the prevention of cancer, cardiovascular, or other chronic diseases. Epidemiological studies and clinical trials suggest that these health benefits are strongly associated with phytochemicals found in fruits and vegetables. Ursolic acid is a naturally synthesized pentacyclic triterpenoid, widely distributed in different fruits and vegetables. Current research suggested that ursolic acid and its derivatives exhibited anticancer activity, anti-inflammatory effects, and induction of apoptosis in several human cancer cells. In particular, ursolic acid inhibited breast cancer proliferation by inducing cell G1/G2 arrest and regulating the expression of key proteins in signal transduction pathways. In addition, ursolic acid induced apoptosis in human breast cancer cells through intrinsic and extrinsic apoptotic pathways. Ursolic acid was also determined to scavenge free radicals and have potent anti inflammation activity. The purpose of this paper is to review recent literature on anticancer activity of ursolic acid and focus on its mechanisms of action. PMID- 27469429 TI - The evolution of the cancer formulary review in Canada: Can centralization improve the use of economic evaluation? AB - Public reimbursement of drugs is a costly proposition for health care systems. Decisions to add drugs to the public formulary are often guided by review processes and committees. The evolution of the formulary review process in Canada's publicly funded health system is characterized by increased centralization and systematization. In the past, the review of evidence and recommendation was conducted at the regional level, but was replaced with the pan Canadian Oncology Drug Review in 2011. We assess the extent to which centralization and systematization of the review process have responded to past challenges, focusing on the use of economic evaluation in the process. Past challenges with economic evaluation experienced by regionalized review committees were identified from literature and qualitative data collected in the province of Nova Scotia. We categorize these using a typology with a macro-, meso, and micro level hierarchy, which provides a useful framework for understanding at which level change is required, and who has the authority to influence change. Using grounded theory methods, we identify approaches used by Nova Scotia past committee members to compensate for perceived shortcomings of the process. These include an undue reliance on other committee members, on the multidisciplinarity of the committee, and on past decisions. Using a policy analysis approach, we argue that centralization and systematization of the review process only partially address the shortcomings of the previous regionalized process. Lessons from Canada can inform policy discussions across all health systems, where similar challenges with the formulary review process have been identified. (c) 2016 The Authors. The International Journal of Health Planning and Management published by John Wiley & Sons Ltd. PMID- 27469430 TI - Effects of neuregulin-1 administration on neurogenesis in the adult mouse hippocampus, and characterization of immature neurons along the septotemporal axis. AB - Adult hippocampal neurogenesis is associated with learning and affective behavioural regulation. Its diverse functionality is segregated along the septotemporal axis from the dorsal to ventral hippocampus. However, features distinguishing immature neurons in these regions have yet to be characterized. Additionally, although we have shown that administration of the neurotrophic factor neuregulin-1 (NRG1) selectively increases proliferation and overall neurogenesis in the mouse ventral dentate gyrus (DG), likely through ErbB3, NRG1's effects on intermediate neurogenic stages in immature neurons are unknown. We examined whether NRG1 administration increases DG ErbB3 phosphorylation. We labeled adultborn cells using BrdU, then administered NRG1 to examine in vivo neurogenic effects on immature neurons with respect to cell survival, morphology, and synaptogenesis. We also characterized features of immature neurons along the septotemporal axis. We found that neurogenic effects of NRG1 are temporally and subregionally specific to proliferation in the ventral DG. Particular morphological features differentiate immature neurons in the dorsal and ventral DG, and cytogenesis differed between these regions. Finally, we identified synaptic heterogeneity surrounding the granule cell layer. These results indicate neurogenic involvement of NRG1-induced antidepressant-like behaviour is particularly associated with increased ventral DG cell proliferation, and identify novel distinctions between dorsal and ventral hippocampal neurogenic development. PMID- 27469431 TI - Mitofusin 2 regulates the oocytes development and quality by modulating meiosis and mitochondrial function. AB - Mitofusin-2 (Mfn2), one of the mitochondrial dynamic proteins plays a key role in maintaining the integrity of mitochondrial morphology and function. However, it is unknown if Mfn2 influences the quality of oocytes in the process of development by modulating mitochondrial function in vitro. In this study, immature oocytes were transfected with Mfn2-siRNA for 16 h. We found that the expression level of the Mfn2 gene was significantly lower than those of the control group. The rates of maturation and fertility were also found to have declined. Moreover, mitochondrial structure and function, especially the morphogenesis of spindles, were observed as abnormal during meiosis. Thus, the above findings indicate that down-regulation of Mfn2 may have an impact on the maturation and fertilization of immature oocytes in vitro by modulating meiosis and mitochondrial function. PMID- 27469432 TI - Early life overnutrition induced by litter size manipulation decreases social play behavior in adolescent male rats. AB - Several studies have investigated the effects of artificial litter size adjustment on offspring development. Social play behavior is important for neurobehavioral development and is impaired in several developmental psychiatric disorders. This study therefore investigated the effect of litter size on play behavior in adolescent rats. On postnatal day (PND) 2, litters were adjusted to a small litter (SL) size of 3 pups per dam or normal litter (NL) size of 12 pups per dam. Maternal behaviors scored daily during the first week of lactation (PND2 8) revealed that arched nursing and pup licking behaviors were increased in dams with SLs versus those with NLs. SL offspring exhibited accelerated weight gain and advanced development of physical landmarks and reflexes, possibly due to overnutrition. Social isolation lasting 3.5h prior to social play behavioral testing produced a higher frequency and duration of pouncing, pinning, sniffing, and grooming in both male and female offspring. However, male SL offspring exhibited a lower frequency of pouncing and pinning when compared with male NL offspring, while no litter size-dependent differences were observed in social behaviors unrelated to play (sniffing and grooming). These findings identify a possible sexually dimorphic influence of litter size in the development of social behavior. Given that social behaviors such as play behavior are vital for normal cognitive and social development, these findings have important implications for developmental and neuropsychiatric research. PMID- 27469433 TI - Characterization of p75 neurotrophin receptor expression in human dental pulp stem cells. AB - Human adult dental pulp stem cells (DPSC) are a heterogeneous stem cell population, which are able to differentiate down neural, chondrocyte, osteocyte and adipocyte lineages. We studied the expression pattern of p75 neurotrophin receptors (p75NTR), a marker of neural stem cells, within human DPSC populations from eight donors. p75NTR are expressed at low levels (<10%) in DPSC. Importantly, p75(+) DPSC represent higher expression levels of SOX1 (neural precursor cell marker), SOX2 (cell pluripotency marker) and nestin (neural stem cell marker) in comparison to p75(-) DPSC. Our results suggest that p75(+) hDPSC may denote a subpopulation with greater neurogenic potential. PMID- 27469434 TI - Effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on spontaneously hypertensive rats, an animal model of attention deficit/hyperactivity disorder. AB - The current treatment of choice for attention deficit hyperactivity disorder (ADHD) is pharmacotherapy. A search for new treatment options is underway, however, as the wide application of drugs to the general population of patients with ADHD is limited by side effects and the variance of pharmacokinetic effects of the drugs in each patient. In the present study, we applied repetitive transcranial magnetic stimulation (rTMS), a non-invasive treatment used in a number of other psychiatric disorders, to spontaneously hypertensive rats (SHRs), an animal model of ADHD, in order to assess the efficacy of the treatment in modifying behavioural symptoms as well as levels of dopamine, noradrenaline, serotonin, and brain-derived neurotrophic factor (BDNF). A total of fifteen sessions of high-frequency rTMS treatment were administered. Behavioural symptoms were observed using open field, Y-maze, and elevated plus-maze tests. Upon completion of the experiments, rats were sacrificed, and the neurochemical changes in brain tissue were analysed using high performance liquid chromatography and Western blotting. The SHRs treated with rTMS tended to exhibit less locomotor activity in the open field test over the course of treatment, but there was no improvement in inattention as measured by the Y-maze test. Furthermore, BDNF concentration increased and noradrenaline concentration decreased in the prefrontal cortex of SHRs treated with rTMS. The results of the present preclinical study indicate that rTMS may constitute a new modality of treatment for patients with ADHD, through further evaluation of specific treatment parameters as well as safety and efficacy in humans are required. PMID- 27469436 TI - Penicillium subrubescens is a promising alternative for Aspergillus niger in enzymatic plant biomass saccharification. AB - In industrial applications, efficient mixtures of polysaccharide-degrading enzymes are needed to convert plant biomass into fermentable sugars. Most of the commercially produced lignocellulolytic enzymes are from a limited number of filamentous fungi, such as Trichoderma and Aspergillus species. In contrast, the plant biomass-degrading capacity of Penicillia has been less explored. We performed growth profiling of several Penicillia on diverse plant biomass-related substrates demonstrating the capacity particularly of Penicillium subrubescens to degrade crude lignocellulose feedstock, as well as polysaccharides, and metabolise their monomeric components. We focussed on the lignocellulolytic potential of P. subrubescens FBCC1632, which produced a variable set of (hemi )cellulolytic activities on plant biomass substrates with activity levels comparable to those of Aspergillus niger. The good ability of the extracellular enzyme mixtures produced by P. subrubescens to saccharify complex plant biomasses, wheat bran and sugar beet pulp, indicated a high potential for this strain as a producer of industrial enzyme cocktails. PMID- 27469437 TI - Artificial Versus Natural Teeth for Preclinical Endodontic Training: A Randomized Controlled Trial. AB - INTRODUCTION: The aim of this study was to compare preclinical endodontic training solely on artificial teeth (AT) versus training on natural teeth (NT) with regard to students' performance on NT in an objective structured practical examination (OSPE) in a randomized trial. METHODS: Forty-three students were randomly allocated to training on AT (test, n = 20) or NT (control, n = 23). Practical training included intraoral root canal treatment of all tooth types on mannequin heads. Students' performance was assessed via an OSPE first on AT (TrueTooth Mandibular Molar; DELendo, Santa Barbara, CA) and then on a lower mandibular NT. Assessment was performed during the OSPE (13 items) and afterward on teeth and radiographs (22 items). The Mann-Whitney U and Wilcoxon tests compared performance between or within groups. Regression analysis and Bland Altman plots were used to assess agreement between AT and NT performance. RESULTS: The performance between training groups did not significantly differ on NT (P = .761/Mann-Whitney) or AT (P = .278). The performance on NT was significantly lower than that on AT in the test group (P < .05, Wilcoxon) but not the control group (P > .05). Performance on AT did not significantly predict performance in NT, with relative and proportional bias being present. CONCLUSIONS: Within the limitations of this study, training on AT seems suitable to prepare students for endodontic treatment on NT. Because performance on AT does not predict performance on NT, assessment using AT should be regarded with caution, and control of training success using NT might be more reliable. PMID- 27469435 TI - Nitric oxide and pH modulation in gynaecological cancer. AB - Nitric oxide plays several roles in cellular physiology, including control of the vascular tone and defence against pathogen infection. Neuronal, inducible and endothelial nitric oxide synthase (NOS) isoforms synthesize nitric oxide. Cells generate acid and base equivalents, whose physiological intracellular concentrations are kept due to membrane transport systems, including Na+ /H+ exchangers and Na+ /HCO3- transporters, thus maintaining a physiological pH at the intracellular (~7.0) and extracellular (~7.4) medium. In several pathologies, including cancer, cells are exposed to an extracellular acidic microenvironment, and the role for these membrane transport mechanisms in this phenomenon is likely. As altered NOS expression and activity is seen in cancer cells and because this gas promotes a glycolytic phenotype leading to extracellular acidosis in gynaecological cancer cells, a pro-inflammatory microenvironment increasing inducible NOS expression in this cell type is feasible. However, whether abnormal control of intracellular and extracellular pH by cancer cells regards with their ability to synthesize or respond to nitric oxide is unknown. We, here, discuss a potential link between pH alterations, pH controlling membrane transport systems and NOS function. We propose a potential association between inducible NOS induction and Na+ /H+ exchanger expression and activity in human ovary cancer. A potentiation between nitric oxide generation and the maintenance of a low extracellular pH (i.e. acidic) is proposed to establish a sequence of events in ovarian cancer cells, thus preserving a pro-proliferative acidic tumour extracellular microenvironment. We suggest that pharmacological therapeutic targeting of Na+ /H+ exchangers and inducible NOS may have benefits in human epithelial ovarian cancer. PMID- 27469438 TI - Pregnancy after intracytoplasmic sperm injection following extended sperm preparation and hormone therapy in an azoospermic man with maturation arrest and microlithiasis: a case report and literature review. AB - In the management of azoospermia, a combination of testicular sperm extraction and intracytoplasmic sperm injection (ICSI) is usually the most successful option for fatherhood. However, an outstanding question remains: How can at least a few spermatozoa be obtained from the ejaculate, thus avoiding the need for a surgical procedure? A 36-year-old man presented to Assisted Reproduction Unit with his 26 year-old wife. The ultrasound assessment revealed bilateral microlithiasis. Two spermograms revealed absolute azoospermia. Levels of follicle-stimulating hormone (FSH) and luteinising hormone were normal-low. The patient underwent 10 months of treatment with clomiphene citrate. A bilateral testicular sperm extraction failed to retrieve spermatozoa and revealed a maturation arrest at spermatocyte/spermatid stages depending on the tubules. Clomiphene citrate was replaced with recombinant FSH (rFSH). After 9-month treatment with rFSH, motile spermatozoa from droplets of ejaculate pellet were cryopreserved as a single straw. Ovarian stimulation was provided using classic antagonist protocol, and five mature oocytes were collected. Two consecutive fresh semen samples on the day of ICSI yielded seven motile spermatozoa, and fertilisation was achieved in all five oocytes. On day 3, two embryos were transferred, yielding positive beta human chorionic gonadotropin and a healthy delivery of a boy and a girl. PMID- 27469439 TI - T-cell development is regulated by the coordinated function of proximal and distal Lck promoters active at different developmental stages. AB - Expression of Lck, a T-cell lineage-specific tyrosine kinase critical for T-cell development and activation, can be mediated by either proximal or distal lck promoter. We generated BAC transgenic mice in which BAC lck promoter was deleted and bred these transgenes to an Lck knockout background. Lck-PROX mice, in which only the proximal promoter is functional, have maximal Lck protein and normal thymic development through CD4- CD8- double negative (DN) and CD4+ CD8+ double positive (DP) stages, but undetectable Lck later in development and reduced mature single positive thymocytes. In contrast, Lck-DIST mice, in which only distal promoter was functional, are deficient in Lck protein in DN and DP thymocytes and severely defective in early T-cell development, with a block at the DN3-DN4 beta checkpoint equivalent to complete Lck knockouts. The ability of the proximal lck promoter to support thymic development is independent of Fyn; while, in contrast, the distal lck promoter alone is completely unable to support development in the absence of Fyn. Notably, normal thymocyte development is restored by presence of both proximal and distal promoters, even when independently expressed on different lck genes. These results define distinct and complementary requirements for proximal and distal lck promoters during T-cell development. PMID- 27469440 TI - Value co-creation in healthcare through positive deviance. AB - PURPOSE: To explore how converging fields of co-creation and positive deviance may increase value in healthcare. METHODS: Informed by research in positive deviance, patient engagement, value co-creation, and quality improvement, we propose a positive deviance approach to co-creation of health. RESULTS: Co creation has shown to improve health outcomes with regard to multiple health conditions. Positive deviance has also shown to improve outcomes in multiple healthcare and patient community environments. CONCLUSION: A positive deviance co creation framework may aid in achieving improved outcomes for patients, care teams and their respective healthcare organizations. PMID- 27469441 TI - Adoption and impact of an eConsult system in a fee-for-service setting. PMID- 27469442 TI - New rules for Medicaid managed care - Do they undermine payment reform? PMID- 27469443 TI - Impact of dual energy characterization of urinary calculus on management. AB - INTRODUCTION: Dual energy CT (DECT) is a recent technique that is increasingly being used to differentiate between calcium and uric acid urinary tract calculi. The aim of this study is to determine if urinary calculi composition analysis determined by DECT scanning results in a change of patient management. METHOD: All patients presenting with symptoms of renal colic, who had not previously undergone DECT scanning underwent DECT KUB. DECT data of all patients between September 2013 and July 2015 were reviewed. Urinary calculi composition based on dual energy characterization was cross-matched with patient management and outcome. RESULTS: A total of 585 DECT KUB were performed. 393/585 (67%) DECT scans revealed urinary tract calculi. After excluding those with isolated bladder or small asymptomatic renal stones, 303 patients were found to have symptomatic stone(s) as an explanation for their presentation. Of these 303 patients, there were 273 (90.1%) calcium calculi, 19 (6.3%) uric acid calculi and 11 (3.4%) mixed calculi. Of those with uric acid calculi, 15 were commenced on dissolution therapy. Twelve of those commenced on dissolution therapy had a successful outcome, avoiding need for surgical intervention (lithotripsy or stone retrieval). Three patients failed dissolution therapy and required operative intervention for definitive management of the stone. CONCLUSION: Predicting urinary tract calculi composition by DECT plays an important role in identifying patients who may be managed with dissolution therapy. Identification of uric acid stone composition altered management in 15 of 303 (5.0%) patients, and was successful in 12, thereby avoiding surgery and its attendant risks. PMID- 27469448 TI - Evaluation of Singing Vocal Health in Yakshagana Singers. AB - INTRODUCTION: Yakshagana, a popular traditional folk art from Karnataka, India, includes singing and dancing. Yakshagana singer or Bhagavata plays an important role in singing and conducting the performance. The present study aims to assess the singing vocal health using Singing Voice Handicap Index-10 (SVHI-10) in these singers and to compare between those who report voice problem and those who do not. METHOD: A cross-sectional study was carried out on 26 Bhagavata using demographic questionnaire and SVHI-10 in the Kannada language. Descriptive statistics was used to summarize the data. Independent sample t test was used to compare the responses for demographic variables between the two groups of singers with and without voice problems. The difference in scores of SVHI-10 between the two groups was analyzed using Pearson's chi-square test. RESULTS: Of the Bhagavata, 38% reported to have experienced voice problems, which affected their singing, with higher total SVHI-10 score (31.2 +/- 5.7) compared with those who did not report any problems (16.81 +/- 9.56). A statistically significant difference between the groups was noted in the emotional domain and total scores. CONCLUSION: The present study provides preliminary information on the voice handicap reported by Bhagavata. The singers reporting voice problems scored higher on SVHI-10. A healthy singing voice is essential for Yakshagana singers, and voice problems can have a significant impact on their performance and livelihood. Hence, results of the present study indicate the need to understand these singers' voice problems and their impact more comprehensively, and educate them about voice care. PMID- 27469444 TI - Long-term effects of perinatal exposure to low doses of cadmium on the prostate of adult male rats. AB - Developmental toxicity caused by environmental exposure to heavy metals during the perinatal period has raised questions about offspring health. Cadmium (Cd) is an endocrine-disrupting chemical with the potential to interfere with morphogenesis and susceptibility to diseases in reproductive organs. Taking into account that in the rat prostate morphogenesis occurs during the perinatal period, and that pregnant females absorb and retain more dietary Cd than their non-pregnant counterparts, it is important to understand the effects of perinatal Cd exposure on the adult rat prostate. Therefore this study investigated the effects of gestational and lactational Cd exposure on adult offspring rat prostate histopathology. Pregnant rats (n = 20) were divided into two groups: Control (treated with aqueous solution of sodium acetate 10 mg/l) and treated (treated with aqueous solution of cadmium acetate 10 mg/l) administered in the drinking water. After weaning, male offspring from different litters (n = 10) received food and water 'ad libitum'. The animals were euthanized at postnatal day 90 (PND90), the ventral prostates (VPs) were removed, weighed and examined histopathologically. Blood was collected for the measurement of testosterone (T) levels. Immunohistochemistry for androgen receptor (AR) and Ki67, and a TUNEL assay were performed. There were no differences in T levels, cell proliferation and apoptosis indexes, or AR immunostaining between the experimental groups. Stromal inflammatory foci and multifocal inflammation increased significantly in the treated group. These changes were associated with inflammatory reactive epithelial atypia and stromal fibrillar rearrangement. In conclusion, VP was permanently affected by perinatal Cd exposition, with increased incidence of inflammatory disorders with ageing. PMID- 27469449 TI - Phonatory Strategies of Male Vocalists in Singing Diatonic Scales With Various Dynamic Shapings. AB - This work aimed to investigate glottal adduction in the case of the singing of diatonic D major ascending scales with different dynamic shapings on vowel [a:] by 10 classically trained male singers. The parameters obtained by inverse filtering-closed quotient (CQ), normalized amplitude quotient (NAQ), and the level difference between the first two partials of the glottal flow waveform spectrum (H1-H2)-all indicated statistically significant systematic changes when singers sang (1) with habitual dynamics without intentional dynamic changes; (2) with sempre crescendo from piano to forte; and (3) with sempre diminuendo from forte to piano. Adduction on average was lower if the tone with the same pitch was sung piano compared with when it was sung forte. The piano tones with the limit of one and the same dynamic task were sung with lower adduction on average compared with one octave higher or lower tones sung forte, although here the agreement between different parameters was poorer and the individual variability was greater. There was only a moderate negative correlation between CQ and NAQ (r = -0.41) but a strong negative correlation between CQ and H1-H2 (r = -0.8). CQ showed a moderate positive correlation with sound level but no significant correlation with pitch. NAQ showed a strong and significant positive correlation with pitch but not with sound level (except when it was calculated only at constant pitch). Some of the most experienced singers used quite high glottal adduction levels, questioning the concept of whether flow phonation is always the favorite classical style. PMID- 27469450 TI - Efficacy of Six Tasks to Clear Laryngeal Mucus Aggregation. AB - PURPOSE: Clinicians commonly teach patients alternative clearing behaviors to reduce coughing and hard throat clearing with the assumption that these behaviors clear mucus from the vocal folds. Yet there is limited evidence of the effectiveness of these alternative behaviors at clearing mucus. This study's purpose was to evaluate the efficacy of reducing laryngeal mucus aggregation using alternative approaches in comparison with hard coughing and hard throat clearing in people with and without voice disorders. METHOD: Mucus aggregation of 46 participants, 22 with and 24 without voice disorders, was evaluated from stroboscopy recordings taken before and after each of six clearing behaviors: hard coughing, hard throat clearing, silent coughing, soft throat clearing, dry swallowing, and swallowing with a fluid bolus. Each participant performed each clearing behavior twice. Two trained raters evaluated mucus aggregation for type, thickness, and pooling. RESULTS: Of the six clearing behaviors studied, only hard throat clearing changed vocal fold mucus aggregation. The features of mucus aggregation that were changed by hard throat clearing were the severity of mucus thickness and the presence of type 3 mucus. CONCLUSIONS: Despite the widespread clinical use of alternative clearing behaviors, the results of this study indicate that hard throat clearing is the only clearing behavior to have a significant impact on removing mucus aggregation from the vocal folds. This finding should be further investigated in a larger scale study. If the results of this study are replicated, clinicians should consider changing their use and description of alternative clearing behaviors in clinical practice. PMID- 27469452 TI - Clinical significance of newly emerged isolated del(20q) in patients following cytotoxic therapies. PMID- 27469453 TI - Commentary: Comparison of historical medical spending patterns among the BRICS and G7. PMID- 27469454 TI - In vitro fermentability and prebiotic potential of soyabean Okara by human faecal microbiota. AB - At present, there is a huge interest in finding new prebiotics from agrofood industrial waste, such as the soyabean by-product Okara, rich in insoluble dietary fibre. A previous treatment of Okara with high hydrostatic pressure assisted by the food-grade enzyme Ultraflo (r) L achieved a 58.2 % increment in its soluble dietary fibre (SDF) contents. Therefore, potential prebiotic effect of both treated and native Okara was assayed using 48 h, pH-controlled, anaerobic batch cultures inoculated with human faecal slurries, which simulate the human gut. Changes in faecal microbiota were evaluated using 16S rRNA-based fluorescence in situ hybridisation, whereas release of SCFA and lactic acid was assessed by HPLC. Both Okara samples exhibited potential prebiotic effects but Okara treated to maximise its SDF content showed higher SCFA plus lactic acid, better growth promotion of beneficial bacteria, including bifidobacteria after 4 and 48 h and lactobacilli after 4 h of fermentation, and a greater inhibition of potentially harmful bacterial groups such as clostridia and Bacteroides. Differences found between fructo-oligosaccharides and Okara substrates could be attributed to the great complexity of Okara's cell wall, which would need longer times to be fermented than other easily digested molecules, thus allowing an extended potential prebiotic effect. These results support an in vitro potential prebiotic effect of Okara. PMID- 27469455 TI - Do college students improve their grades by using prescription stimulants nonmedically? AB - INTRODUCTION: Many college students engage in nonmedical use of prescription stimulants (NPS) because they believe it provides academic benefits, but studies are lacking to support or refute this belief. METHODS: Using a longitudinal design, 898 undergraduates who did not have an ADHD diagnosis were studied. Year 3 GPA (from college records) of four groups was compared: Abstainers (did not engage in NPS either year; 68.8%); Initiators (NPS in Year 3 but not Year 2; 8.7%); Desisters (NPS in Year 2 but not Year 3; 5.8%); and Persisters (NPS in both years; 16.7%). Generalized estimating equations regression was used to estimate the association between NPS and change in GPA, controlling for sex and Year 2 GPA. RESULTS: GPA increased significantly within Abstainers (p<0.05), but did not change significantly within the other groups. Overall, the relationship between NPS pattern group and change in GPA was not statistically significant (p=0.081). NPS was generally infrequent, but Persisters used more frequently than Desisters (11.7 versus 3.4days in Year 2) and Initiators (13.6 versus 4.0days in Year 3, both ps<0.001), controlling for sex and Year 2 GPA. CONCLUSIONS: We cannot rule out the possibility that NPS prevented declines in GPA, but we can conclude that students who engaged in NPS showed no increases in their GPAs and gained no detectable advantages over their peers. The results suggest that prevention and intervention strategies should emphasize that the promise of academic benefits from NPS is likely illusory. PMID- 27469456 TI - The Italian Giuseppe Muscatello (1866-1951) and his contributions to our understanding of childhood spina bifida aperta and occulta. PMID- 27469457 TI - Bladder perforation by ventriculoperitoneal shunt. AB - BACKGROUND: Bladder perforation by ventriculoperitoneal shunt is a rare complication that has been describe in 19 cases in prior literature. CASE DESCRIPTION: This work describes the case of a 4-month-old baby who presented with extrusion of the distal catheter through the urethra. The patient underwent a laparotomy; the catheter was cut close to the bladder wall and repositioned into the peritoneal cavity. The bladder wall was sutured, and the remaining distal portion of the catheter was removed through the urethra. DISCUSSION AND CONCLUSION: Based on this single experience and a literature review, the authors classified the clinical signs and symptoms of bladder perforation by the ventriculoperitoneal shunt catheter. Finally, the authors propose a more conservative approach for this rare complication. PMID- 27469458 TI - Treatment Effects of a Primary Care Intervention on Parenting Behaviors: Sometimes It's Relative. AB - The goal of this brief report is to demonstrate the utility of quantifying parental discipline practices as relative frequencies in measuring changes in parenting behavior and relations to child behavior following intervention. We explored comparisons across methodological approaches of assessing parenting behavior via absolute and relative frequencies in measuring improvements in parent-reported disciplinary practices (increases in positive parenting practices in response to child behavior; decreases in inconsistent discipline and use of corporal punishment) and child behavior problems. The current study was conducted as part of a larger clinical trial to evaluate the efficacy of a collaborative care intervention for behavior problems, ADHD, and anxiety in pediatric primary care practices (Doctor Office Collaborative Care; DOCC). Participants were 321 parent-child dyads (M child age = 8.00, 65 % male children) from eight pediatric practices that were cluster randomized to DOCC or enhanced usual care (EUC). Parents reported on their own discipline behaviors and child behavior problems. While treatment-related decreases in negative parenting were found using both the absolute and relative frequencies of parenting behaviors, results were different for positive parenting behaviors, which showed decreases when measured as absolute frequencies but increases when measured as relative frequencies. In addition, positive parenting was negatively correlated with child behavior problems when using relative frequencies, but not absolute frequencies, and relative frequencies of positive parenting mediated relations between treatment condition and outcomes. Our findings indicate that the methods used to measure treatment-related change warrant careful consideration. PMID- 27469459 TI - Monomeric adiponectin modulates nitric oxide release and calcium movements in porcine aortic endothelial cells in normal/high glucose conditions. AB - AIMS: Perivascular adipose tissue can be involved in the process of cardiovascular pathology through the release of adipokines, namely adiponectins. Monomeric adiponectin has been shown to increase coronary blood flow in anesthetized pigs through increased nitric oxide (NO) release and the involvement of adiponectin receptor 1 (AdipoR1). The present study was therefore planned to examine the effects of monomeric adiponectin on NO release and Ca(2+) transients in porcine aortic endothelial cells (PAEs) in normal/high glucose conditions and the related mechanisms. MAIN METHODS: PAEs were treated with monomeric adiponectin alone or in the presence of intracellular kinases blocker, AdipoR1 and Ca(2+)-ATPase pump inhibitors. The role of Na(+)/Ca(2+) exchanger was examined in experiments performed in zero Na(+) medium. NO release and intracellular Ca(2+) were measured through specific probes. KEY FINDINGS: In PAE cultured in normal glucose conditions, monomeric adiponectin elevated NO production and [Ca(2+)]c. Similar effects were observed in high glucose conditions, although the response was lower and not transient. The Ca(2+) mobilized by monomeric adiponectin originated from an intracellular pool thapsigargin- and ATP-sensitive and from the extracellular space. Moreover, the effects of monomeric adiponectin were prevented by kinase blockers and AdipoR1 inhibitor. Finally, in normal glucose condition, a role for Na(+)/Ca(2+) exchanger and Ca(2+)-ATPase pump in restoring Ca(2+) was found. SIGNIFICANCE: Our results add new information about the control of endothelial function elicited by monomeric adiponectin, which would be achieved by modulation of NO release and Ca(2+) transients. A signalling related to Akt, ERK1/2 and p38MAPK downstream AdipoR1 would be involved. PMID- 27469460 TI - Characterizing Lyme Disease Surveillance in an Endemic State. AB - Lyme disease (LD) is the most common vector-borne disease in Maryland and the United States. Surveillance for LD is valuable for understanding the burden of the disease, particularly to assess whether the disease is spreading and to appreciate who is affected. However, not all cases of LD in Maryland are reported, and surveillance practices vary across each of Maryland's 24 local health departments (LHDs). To better understand this variability and to systematically characterize the surveillance process, we surveyed Maryland's LHDs regarding LD surveillance. The Maryland Local Health Department Lyme Disease Surveillance Survey has been administered annually since 2011. Questions asked each year included whether all LD reports are investigated or only a subset, and how many reports are not entered into the surveillance database. Since 2011, Maryland has lost surveillance personnel for LD. Each year from 2009 to 2012, a median 3598 (range 2462 to 5722) reports were not entered into the surveillance database and hence not investigated. These reports represent 43-55% of all reports received for the year. Over time, more LHDs chose to streamline their LD investigation approach by investigating only those reports that met the criteria for laboratory evidence of infection: in 2008, 5 (21%) LHDs investigated only a subset of LD reports; by 2013, this increased to 15 (63%). There is wide variability across LHDs in how LD investigations are conducted. Maryland LHDs have experienced a loss of LD surveillance personnel with a concomitant increase in the number of LHDs adopting a streamlined approach to investigating cases. These findings underscore the tremendous burden of LD on the public health agencies and highlight the need for alternative approaches that can both reduce burden and preserve surveillance data quality. PMID- 27469461 TI - Social desirability may explain why some caregivers of overweight children report less frequent high calorie food intake. PMID- 27469462 TI - Use of a latency-based demand assessment to identify potential demands for functional analyses. AB - Unlike potential tangible positive reinforcers, which are typically identified for inclusion in functional analyses empirically using preference assessments, demands are most often selected arbitrarily or based on caregiver report. The present study evaluated the use of a demand assessment with 12 participants who exhibited escape-maintained problem behavior. Participants were exposed to 10 demands, with aversiveness measured by average latency to the first instance of problem behavior. In subsequent functional analyses, results of a demand condition that included the demand with the shortest latency to problem behavior resulted in identification of an escape function for 11 of the participants. In contrast, a demand condition that included the demand with the longest latency resulted in identification of an escape function for only 5 participants. The implication of these findings is that for the remaining 7 participants, selection of the demand for the functional analysis without using the results of the demand assessment could have produced a false-negative finding. PMID- 27469463 TI - Yimella radicis sp. nov., an endophytic actinobacterium isolated from the root of Paris polyphylla Smith var. yunnanensis. AB - An endophytic actinobacterial strain, designated py1292T, was isolated from the root of Paris polyphylla Smith var. yunnanensis collected from Yunnan province, China, and subjected to a polyphasic taxonomic characterization. Phylogenetic analysis based on 16S rRNA gene sequences placed the isolate in the family Dermacoccaceae and clustered with Yimella lutea (showing the highest similarity of 99.1 %). DNA-DNA relatedness between strain py1292T and Y. lutea YIM 45900T was 45.6+/-3.2 % (reciprocal 47.8+/-3.6 %). The novel isolate was found to be a Gram-staining-positive rod, catalase- and oxidase-positive. It grew at pH 6.0 8.0, with 0-9 % NaCl and at 20-45 oC, optimally at pH 7.0, with 0-3 % NaCl and at 28 oC. The predominant menaquinone was MK-8(H4), while the polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, two unknown phospholipids and two unknown polar lipids. The major cellular fatty acids were iso-C15 : 0, iso-C16 : 0, iso-C17 : 0 and anteiso-C17 : 0. The whole-cell hydrolysates contained mannose, ribose, rhamnose, glucose and galactose. The peptidoglycan contained alanine, glycine, serine, aspartic acid, glutamic acid and lysine. The genomic DNA G+C content was determined to be 65.6 mol%. Phylogenetic, phenotypic and chemotaxonomic data (especially the same peptidoglycan type) showed that strain py1292T should be classified as a representative of a novel species of the genus Yimella, for which the name Yimella radicis sp. nov. is proposed. The type strain is py1292T (=KCTC 39612T=LMG 29070T). PMID- 27469464 TI - Neurodegenerative disease: Lithium promotes accumulation of brain iron via tau suppression. PMID- 27469465 TI - Genetics: Alzheimer risk variants affect children's brains. PMID- 27469466 TI - Reliability and Responsiveness of NutriQoL(r) Questionnaire. AB - INTRODUCTION: NutriQoL(r) (Nestle Health Science, Vevay, Switzerland) is a questionnaire developed to assess the health-related quality-of-life (HRQoL) of patients with home enteral nutrition (HEN) irrespective of their underlying condition and route of administration. The aim of this work is assessing the questionnaire's reliability and responsiveness to change. METHODS: Two cohorts of patients with HEN and their primary caregivers were enrolled to assess reliability and responsiveness, respectively. All participants had to be 18 years of age or older, without mental deterioration (<=3 or 4 errors in the Pfeiffer's test) and with sufficient functional status (>40 points on Karnovsky's performance status scale). When the patients' ability to respond to the questionnaire was impaired due to underlying disease, their caregivers answered on their behalf. NutriQoL was administered in two and three visits to reliability and responsiveness cohorts, respectively. Test-retest reliability and internal consistency were assessed by the intra-class correlation coefficient (ICC) and the Cronbach's alpha, respectively. Responsiveness was evaluated by standardized effect size and standardized response mean between basal visit and third visit. Finally, the minimal clinically important difference (MCID) was estimated. RESULTS: A total of 54 and 86 participants were recruited to the reliability and responsiveness cohort, respectively. Thirty-five caregivers were selected to assess the inter-observer reliability. ICC values confirmed the good reproducibility level (ICC >0.75) of the questionnaire in both "physical functioning and activities of daily living" and "social life" domains and total score. The assessment of internal consistency in both domains of the questionnaire showed good internal consistency in visit 2. ICC showed the excellent agreement level between caregiver and patient in the global NutriQoL score. Finally, patients classified as having a minimal change in their health reported a mean (standard deviation) MCID in NutriQoL score of 0.63 (11.51). CONCLUSION: NutriQoL is a reliable and unique instrument to measure the HRQoL in HEN patients. NutriQoL detects changes in the health status of the patient. Nevertheless, further research is needed to determine the full extent of the questionnaire responsiveness. PMID- 27469467 TI - Impact of population ageing on growing demand for emergency transportation to emergency departments in Western Australia, 2005-2020. AB - OBJECTIVE: The aim of the present paper is to quantify the impact of population ageing on demand for emergency transportation (ET) to EDs in Western Australia (WA). METHODS: A population-based longitudinal study using the statewide ED presentation data from 2005-2014 was used to predict ET demand in 2020, stratified by age group and sex. RESULTS: From 2005 to 2014, 14.9% of all ED presentations arrived by ET. The number rose from 94 369 (13.9%) in 2005 to 153 374 (15.5%) in 2014, a compound annual growth of 5.5%. Of those presentations, 55.2% resulted in hospital admission. The proportion was higher in older age groups (64.5% in 65-74 years, 67.1% in 75-84 years and 68.4% in >=85 years). Of ED presentations arriving by ET in age group >=65 years, 70.9% were Australasian Triage Scale category 1, 2 or 3. The rate of ET per 1000 population increased in all age groups and sex. The highest growth was in the older age groups: from 86.6, 187.0 and 512.1 in ages 65-74 years, 75-84 years and >=85 years, respectively, in 2005 to 102.5, 226.7 and 613.6 in 2014, and are expected to increase to 115.1, 264.3 and 707.7 by 2020. The ET demands in these age groups were projected to increase annually by 5.0%, 3.6% and 4.9%, respectively, in the next 6 years, comparing to less than 4.5% in the younger age groups. CONCLUSION: There has been a continuous rise in ET demand in WA, particularly in older people who have a higher urgency and requirement for admission. PMID- 27469468 TI - Editorial: Personalized Medicine in Inflammatory Bowel Diseases: Myth or Reality? PMID- 27469469 TI - Efficiently Evaluating Heavy Metal Urban Soil Pollution Using an Improved Entropy Method-Based Topsis Model. AB - Urban soil pollution is evaluated utilizing an efficient and simple algorithmic model referred to as the entropy method-based Topsis (EMBT) model. The model focuses on pollution source position to enhance the ability to analyze sources of pollution accurately. Initial application of EMBT to urban soil pollution analysis is actually implied. The pollution degree of sampling point can be efficiently calculated by the model with the pollution degree coefficient, which is efficiently attained by first utilizing the Topsis method to determine evaluation value and then by dividing the evaluation value of the sample point by background value. The Kriging interpolation method combines coordinates of sampling points with the corresponding coefficients and facilitates the formation of heavy metal distribution profile. A case study is completed with modeling results in accordance with actual heavy metal pollution, proving accuracy and practicality of the EMBT model. PMID- 27469470 TI - Intradermal drug delivery by nanogel-peptide conjugates; specific and efficient transport of temoporfin. AB - Nanogels offer many unique features rendering them as very attractive candidates for drug delivery. However, for their applications the loading capacity and specific encapsulation, in particular for hydrophobic drugs, in a complex media are two critical factors. In this work, we report for the first time on the preparation of nanogel-peptide conjugates with the ability of specific encapsulation of temoporfin (m-THPC). The peptide was selected based on combinatorial means and it was conjugated to polyglycerol as the nanogel precursor. We observed that the loading capacity of nanogels improved 16 times upon peptide conjugation. Skin penetrations tests in barrier deficient skin showed that nanogel-peptide conjugates enhance the penetration of m-THPC in the viable skin layers efficiently. This study indicates that nanogel-peptide conjugates could be used as unique carriers with high loading capacity for hydrophobic compounds, which provides the basis for the design of advanced topical drug delivery systems. PMID- 27469471 TI - Viability of endothelial cells after ultrasound-mediated sonoporation: Influence of targeting, oscillation, and displacement of microbubbles. AB - Microbubbles (MBs) have been shown to create transient or lethal pores in cell membranes under the influence of ultrasound, known as ultrasound-mediated sonoporation. Several studies have reported enhanced drug delivery or local cell death induced by MBs that are either targeted to a specific biomarker (targeted microbubbles, tMBs) or that are not targeted (non-targeted microbubbles, ntMBs). However, both the exact mechanism and the optimal acoustic settings for sonoporation are still unknown. In this study we used real-time uptake patterns of propidium iodide, a fluorescent cell impermeable model drug, as a measure for sonoporation. Combined with high-speed optical recordings of MB displacement and ultra-high-speed recordings of MB oscillation, we aimed to identify differences in MB behavior responsible for either viable sonoporation or cell death. We compared ntMBs and tMBs with identical shell compositions exposed to long acoustic pulses (500-50,000cycles) at various pressures (150-500kPa). Propidium iodide uptake highly correlated with cell viability; when the fluorescence intensity still increased 120s after opening of the pore, this resulted in cell death. Higher acoustic pressures and longer cycles resulted in more displacing MBs and enhanced sonoporation. Non-displacing MBs were found to be the main contributor to cell death, while displacement of tMBs enhanced reversible sonoporation and preserved cell viability. Consequently, each therapeutic application requires different settings: non-displacing ntMBs or tMBs are advantageous for therapies requiring cell death, especially at 500kPa and 50,000cycles, whereas short acoustic pulses causing limited displacement should be used for drug delivery. PMID- 27469472 TI - Multi-layered nanofibrous mucoadhesive films for buccal and sublingual administration of drug-delivery and vaccination nanoparticles - important step towards effective mucosal vaccines. AB - Nanofibre-based mucoadhesive films were invented for oromucosal administration of nanocarriers used for delivery of drugs and vaccines. The mucoadhesive film consists of an electrospun nanofibrous reservoir layer, a mucoadhesive film layer and a protective backing layer. The mucoadhesive layer is responsible for tight adhesion of the whole system to the oral mucosa after application. The electrospun nanofibrous reservoir layer is intended to act as a reservoir for polymeric and lipid-based nanoparticles, liposomes, virosomes, virus-like particles, dendrimers and the like, plus macromolecular drugs, antigens and/or allergens. The extremely large surface area of nanofibrous reservoir layers allows high levels of nanoparticle loading. Nanoparticles can either be reversibly adsorbed to the surface of nanofibres or they can be deposited in the pores between the nanofibres. After mucosal application, nanofibrous reservoir layers are intended to promote prolonged release of nanoparticles into the submucosal tissue. Reversible adsorption of model nanoparticles as well as sufficient mucoadhesive properties were demonstrated. This novel system appears appropriate for the use in oral mucosa, especially for sublingual and buccal tissues. To prove this concept, trans-/intramucosal and lymph-node delivery of PLGA-PEG nanoparticles was demonstrated in a porcine model. This system can mainly be used for sublingual immunization and the development of "printed vaccine technology". PMID- 27469474 TI - A TP-FRET-based two-photon fluorescent probe for ratiometric visualization of endogenous sulfur dioxide derivatives in mitochondria of living cells and tissues. AB - A ratiometric two-photon fluorescent probe for SO2 derivatives was first proposed based on acedan-merocyanine dyads via a TP-FRET strategy. It was successfully applied to visualization of the fluctuations of enzymatically generated SO2 derivatives in the mitochondria of HepG2 cells and rat liver tissues using two photon fluorescence microscopy imaging. PMID- 27469473 TI - Changes in microbial composition and the prevalence of foodborne pathogens in crab marinated in soy sauce produced by six manufacturing plants. AB - BACKGROUND: The present study examined the changes in microbiological composition during the production process of crab marinated in soy sauce, potential microbial hazards, potential contamination routes and effective critical control points. Crab and soy sauce samples were obtained from six different manufacturing plants at different stages, and their microbiological content was comprehensively assessed by quantitative and qualitative analyses. RESULTS: The results revealed the following: (1) the final products contained 4.0 log colony-forming units (CFU) g-1 aerobic plate counts (APCs) and 1.1 log CFU g-1 coliforms, which may have been introduced from the raw materials (the level of APCs in raw crab and soy sauce mixed with other ingredients was 3.8 log CFU g-1 and 4.0 log CFU mL-1 respectively); (2) marination of crab in soy sauce may allow cross-contamination by coliforms; (3) only Bacillus cereus and Staphylococcus aureus were qualitatively detected in samples at different stages of manufacture (detection rate of 28 and 5.6% respectively), and these bacteria may impact the microbiological quality and safety of crab marinated in soy sauce; and (4) bacterial counts were either maintained or increased during the manufacturing process (suggesting that no particular step can be targeted to reduce bacterial counts). CONCLUSION: Proper management of raw materials and the marination process are effective critical control points, and alternative interventions may be needed to control bacterial quantity. The results provide important basic information about the production of crab marinated in soy sauce and may facilitate effective implementation of sanitary management practices in related industries and research fields. (c) 2016 Society of Chemical Industry. PMID- 27469475 TI - Vacuum pressure generation via microfabricated converging-diverging nozzles for operation of automated pneumatic logic. AB - Microfluidic devices with integrated pneumatic logic enable automated fluid handling without requiring external control instruments. These chips offer the additional advantage that they may be powered by vacuum and do not require an electricity source. This work describes a microfluidic converging-diverging (CD) nozzle optimized to generate vacuum at low input pressures, making it suitable for microfluidic applications including powering integrated pneumatic logic. It was found that efficient vacuum pressure was generated for high aspect ratios of the CD nozzle constriction (or throat) width to height and diverging angle of 3.6(o). In specific, for an inlet pressure of 42.2 psia (290.8 kPa) and a volumetric flow rate of approximately 1700 sccm, a vacuum pressure of 8.03 psia (55.3 kPa) was generated. To demonstrate the capabilities of our converging - diverging nozzle device, we connected it to a vacuum powered peristaltic pump driven by integrated pneumatic logic and obtained tunable flow rates from 0 to 130 MUL/min. Finally, we demonstrate a proof of concept system for use where electricity and vacuum pressure are not readily available by powering a CD nozzle with a bicycle tire pump and pressure regulator. This system is able to produce a stable vacuum sufficient to drive pneumatic logic, and could be applied to power automated microfluidics in limited resource settings. PMID- 27469476 TI - [Surgical treatment of posterosuperior impingement (PSI)]. AB - OBJECTIVE: To restore the physiologic anterior and posterior capsular volume to achieve an anatomic central contact point of the glenohumeral articulation and treatment of concomitant glenohumeral injuries due to posterosuperior impingement (PSI). INDICATIONS: Plateauing of clinical improvement despite adequate nonsurgical treatment (for at least 6-12 months). CONTRAINDICATIONS: General contraindications for elective arthroscopic surgery. SURGICAL TECHNIQUE: Diagnostic arthroscopy of the glenohumeral joint through the posterior portal to assess stability of the biceps-labral complex even in the Abduction and External Rotation (ABER) position to confirm the diagnosis of PSI and to detect concomitant glenohumeral injuries. In most cases posterosuperior SLAP (superior labrum anterior posterior) repair or tenodesis of the long head of the biceps. POSTOPERATIVE MANAGEMENT: Arm sling for 6 weeks with limited range of motion. Free active range of motion of elbow and wrist. Limited shoulder external rotation for 6 weeks. Free shoulder range of motion from week 7, full daily life activities after 12 weeks. Modification of the postoperative management according to intraoperative findings. RESULTS: At our hospital 18 overhead athletes (6 women, 12 men, mean age 31 years) with PSI without SLAP lesion or rotator cuff tear underwent isolated plication of the anteroinferior capsule after primary nonsurgical treatment. At a mean period of 9 months, 16 patients returned to their pre-injury sports activity level, 2 patients had to give up their sports due to persisting shoulder problems. At a mean follow-up of 27 months (range 12 55 months) the Walch Duplay score was on average 82.9 +/- 8.3 for men and 73.8 +/ 5.9 for women. PMID- 27469477 TI - DprA is required for natural transformation and affects pilin variation in Neisseria gonorrhoeae. AB - Natural transformation is the main means of horizontal genetic exchange in the obligate human pathogen Neisseria gonorrhoeae and drives the spread of antibiotic resistance and virulence determinants. Transformation can be divided into four steps: (1) DNA binding, (2) DNA uptake, (3) DNA processing and (4) DNA recombination into the chromosome. The DNA processing enzyme DprA has been shown to shuttle incoming ssDNA to the recombination enzyme RecA during transformation in Bacillus subtilis and Streptococcus pneumoniae. Here, we investigate the role of DprA during transformation in N. gonorrhoeae. Inactivation of dprA completely abrogated transformation of gyrB1-encoding DNA, which confers nalidixic acid resistance. The presence of the DNA uptake sequence enhances DNA uptake and transformation by binding to the minor pilus protein ComP. Loss of transformation in the dprA null mutants was independent of the DNA uptake sequence. DprA mutants exhibited increased RecA-dependent pilin variation suggesting that DprA affects pilin variation. Unlike the exquisite UV sensitivity of a recA mutant, inactivation of dprA did not affect survival following UV irradiation. These results demonstrate that DprA has a conserved function during transformation, and reveal additional effects of DprA in N. gonorrhoeae during pilin variation. PMID- 27469478 TI - Role of Abnormal Sperm Morphology in Predicting Pregnancy Outcomes. AB - The evaluation of strict morphology for predicting successful pregnancy has been controversial, nevertheless remains an essential component of semen analysis. Patients with teratozoospermia (abnormal strict morphology) have traditionally been counseled to undergo assisted reproduction. However, recent studies suggest that patients with abnormal sperm morphology alone should not be precluded from attempting natural conception before undergoing assisted reproduction. The goal of this review is to provide an update on the evaluation of sperm morphology for prognosis in assisted reproductive techniques such as intrauterine insemination and in vitro fertilization with or without intracytoplasmic sperm injection. Additionally, we propose a logical approach to the evaluation of a patient with teratozoospermia seeking fertility treatment. PMID- 27469479 TI - Pharmacogenetics to prevent maniac affective switching with treatment for bipolar disorder: CYP2D6. PMID- 27469480 TI - Bioimpedance: Has Its Time Finally Come? PMID- 27469481 TI - Heart Failure With "Mid-Range" Ejection Fraction-New Opportunities. PMID- 27469483 TI - Acneiform Eruption at the Site of Healed Herpes Zoster: A Case of Wolf's Isotopic Response. PMID- 27469482 TI - Worsening Renal Function during Management for Chronic Heart Failure with Reduced Ejection Fraction: Results From the Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study. AB - OBJECTIVES: To assess prognostic meaning of worsening renal failure (WRF) occurring during management of chronic heart failure (HF) with reduced ejection fraction. BACKGROUND: When WRF develops during titration of HF medical therapy, it commonly leads to less aggressive care. METHODS: A total of 151 patients enrolled in a prospective, randomized study of standard of care (SOC) HF therapy versus SOC plus a goal N-terminal pro-B type natriuretic peptide (NT-proBNP) < 1000 pg/mL were examined. Cardiovascular (CV) event (defined as worsening HF, hospitalization for HF, significant ventricular arrhythmia, acute coronary or cerebral ischemia, or CV death) at 1 year relative to WRF (defined as any reduction in estimated glomerular filtration rate) 90 days postenrollment were tabulated. RESULTS: Those developing WRF by 3 months had an average 14% reduction in estimated glomerular filtration rate. There was no difference in incidence of WRF between study arms (43% in SOC, 57% in NT-proBNP, P = .29). During the first 3 months of therapy titration, incident WRF was associated with numerically fewer CV events at 1 year compared with those without WRF (mean 0.81 vs 1.16 events, P = .21). WRF was associated trend toward fewer CV events in the SOC arm (hazard ratio 0.45, 95% confidence interval 0.16-1.24, P = .12); the NT-proBNP-guided arm had numerically lower CV event rates regardless of WRF. Subjects with NT-proBNP <1000 pg/mL and WRF received higher doses of guideline directed medical therapies, lower doses of loop diuretics, and had significantly lower CV event rates (P < .001). CONCLUSIONS: Modest degrees of WRF are common during aggressive HF with reduced ejection fraction management, but we found no significant association with CV outcomes. HF care guided by NT-proBNP was not associated with more WRF compared with SOC, and led to benefit regardless of final renal function. PMID- 27469484 TI - Diagnosis of a Minute Melanoma Assisted by Automated Multi-Camera-Array Total Body Photography. PMID- 27469485 TI - Cyclical Inguinal Keratoderma: A New Clinical Entity or a Variant of Pityriasis Rubra Pilaris? PMID- 27469486 TI - Sporotrichoid Mycobacterium chelonae. PMID- 27469487 TI - Oral isotretinoin: A new treatment alternative for generalized lichen amyloidosis. PMID- 27469488 TI - Efferocytosis and extrusion of leukocytes determine the progression of early mycobacterial pathogenesis. AB - Macrophages and neutrophils are the first responders to invading pathogens and contribute strongly to the host defense against intracellular pathogens. The collective interplay and dynamic interactions between these leukocytes are to a large extent not understood. In the present study, we have investigated their role using a combination of confocal laser-scanning and electron microscopy in a zebrafish model for tuberculosis, a local Mycobacterium marinum infection in the tissue of the larval tail fin. Our results show that neutrophils are efficient in phagocytosis of mycobacteria and that they contribute largely to their dissemination. Macrophages appear to play a major role in efferocytosis, phagocytosis of dead cells that contain bacterial content. Phagocytic cells with large bacterial aggregates are formed that can be extruded out of the tissue after cell death. Alternatively, these excessively infected cells can undergo necrosis leading to immediate recruitment of surrounding leukocytes and subsequent phagocytosis of released bacteria. Our data show that these necrotic burst events result in progression of the infection, whereas extrusion abates the infection. PMID- 27469489 TI - Changes in the influence of affect and cognition over time on consumer attitude formation toward nanotechnology: A longitudinal survey study. AB - Insights into how consumer attitudes toward nanotechnology are formed and develop are crucial for understanding and anticipating possible barriers in consumer acceptance of nanotechnology applications. In this study, the influence of affect and cognition on overall opinion is investigated longitudinally for emerging nanotechnologies, and compared with conventional technologies. Overall, in attitude formation toward nanotechnology applications, people rely relatively more on affect than cognition. Over time, reliance on affect decreases whereas reliance on cognition increases for nanotechnology. This suggests that over time nanotechnology applications have become somewhat more integrated within people's already existing knowledge structure. However, for conventional technologies the influence of affect and cognition on overall attitude remains stable over time. The current study shows that it is essential to address both affective and cognitive aspects of public opinion of nanotechnology. PMID- 27469490 TI - Folate-Chitosan Nanoparticles Loaded with Ursolic Acid Confer Anti-Breast Cancer Activities in vitro and in vivo. AB - Ursolic acid (UA) has proved to have broad-spectrum anti-tumor effects, but its poor water solubility and incompetent targeting property largely limit its clinical application and efficiency. Here, we synthesized a nanoparticle-based drug carrier composed of chitosan, UA and folate (FA-CS-UA-NPs) and demonstrated that FA-CS-UA-NPs could effectively diminish off-target effects and increase local drug concentrations of UA. Using MCF-7 cells as in vitro model for anti cancer mechanistic studies, we found that FA-CS-UA-NPs could be easily internalized by cancer cells through a folate receptor-mediated endocytic pathway. FA-CS-UA-NPs entered into lysosome, destructed the permeability of lysosomal membrane, and then got released from lysosomes. Subsequently, FA-CS-UA NPs localized into mitochondria but not nuclei. The prolonged retention of FA-CS UA-NPs in mitochondria induced overproduction of ROS and destruction of mitochondrial membrane potential, and resulted in the irreversible apoptosis in cancer cells. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model. These results suggested that FA-CS-UA-NPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti cancer drug delivery system. PMID- 27469491 TI - Readiness to Change Predicts Drinking: Findings from 12-Month Follow-Up of Alcohol Use Disorder Outpatients. AB - AIM: To test whether measures of readiness to change (RTC) re-assessed every 3 months had predictive value for change in alcohol use over 12 months in a sample of adult outpatients with alcohol use disorder (AUD). METHODS: Of the case, 78 outpatients were followed monthly over one year and averaged 9.0 interviews each (total observations = 704). Alcohol abstinence days and heavy drinking days were assessed monthly using a 30-day timeline follow-back procedure. RTC was assessed using 3 'readiness rulers' (importance, readiness, and confidence to change, measured on a 0-10 visual analog scale). The effect of RTC on alcohol use over time was tested every 3 months using negative binomial generalized estimating equations (GEE), controlling for gender, age, baseline alcohol dependence severity and AUD treatment status (ongoing vs. ceased). RESULTS: GEE models showed highly significant effects of readiness and confidence to change on respective alcohol outcomes. Effects of importance to change were weaker. CONCLUSION: As hypothesized, higher RTC scores were associated with improved alcohol use outcomes in this longitudinal study. The strongest effects were for confidence to change. Finding significant predictive validity prospectively is consistent with a theoretical view of RTC as a dynamic construct. Further research might clarify how AUD treatment could actually elicit or increase RTC. PMID- 27469492 TI - CD271 regulates the proliferation and motility of hypopharyngeal cancer cells. AB - CD271 (p75 neurotrophin receptor) plays both positive and negative roles in cancer development, depending on the cell type. We previously reported that CD271 is a marker for tumor initiation and is correlated with a poor prognosis in human hypopharyngeal cancer (HPC). To clarify the role of CD271 in HPC, we established HPC cell lines and knocked down the CD271 expression using siRNA. We found that CD271-knockdown completely suppressed the cells' tumor-forming capability both in vivo and in vitro. CD271-knockdown also induced cell-cycle arrest in G0 and suppressed ERK phosphorylation. While treatment with an ERK inhibitor only partially inhibited cell growth, CDKN1C, which is required for maintenance of quiescence, was strongly upregulated in CD271-depleted HPC cells, and the double knockdown of CD271 and CDKN1C partially rescued the cells from G0 arrest. In addition, either CD271 depletion or the inhibition of CD271-RhoA signaling by TAT Pep5 diminished the in vitro migration capability of the HPC cells. Collectively, CD271 initiates tumor formation by increasing the cell proliferation capacity through CDKN1C suppression and ERK-signaling activation, and by accelerating the migration signaling pathway in HPC. PMID- 27469493 TI - Telangiectatic osteosarcoma: a review of 87 cases. AB - PURPOSES: Telangiectatic osteosarcoma (TOS) is a rare subtype of osteosarcoma. We analyzed (1) oncologic outcome in a large homogeneous series and (2) the role of prognostic factors on prognosis, local recurrence and metastasis. METHODS: Eighty seven patients (47 males, 54 %) were retrospectively analyzed. All except 4 had extracompartmental disease, and ten patients had lung metastasis at diagnosis. Pathologic fracture was present in 27 cases (31 %). Seventy-eight patients were treated with neoadjuvant chemotherapy; nine had surgery as first treatment. Limb salvage surgery was performed in 71 cases, amputation in 14, and rotationplasty in one. One patient died before surgery. Possible prognostic factors were statistically evaluated. RESULTS: Overall survival was 60.7 % at 10 years of follow-up. Fifty-one patients were disease-free (58.6 %), 2 were alive with disease (2.3 %), 31 died with disease (35.6 %), and 3 died of other causes (3.4 %). Ten local recurrences were observed (11 %). Twenty-five patients (29 %) developed lung (22) or bone (3) metastases. No statistical difference was found considering age, metastases at diagnosis, gender, pathologic fracture, tumor volume, compartmental status, number of neoadjuvant chemotherapy agents and treatment. Induced necrosis was significant at both univariate and multivariate analysis (p < 0.0001). CONCLUSIONS: TOS does not have a poor prognosis as previously reported in literature, with a survival of about 60 % at 10 years. Most of patients can be cured with neoadjuvant chemotherapy plus surgery (limb sparing surgery is possible and safe). Tumor response to chemotherapy as induced necrosis was the only significant prognostic factors on survival, even if small tumor volume at diagnosis correlates with better prognosis at univariate analysis. LEVEL OF EVIDENCE: IV. PMID- 27469497 TI - Resident Aggression and Abuse in Assisted Living. AB - This article estimates the prevalence and identifies risk factors of resident aggression and abuse in assisted living facilities. We conducted multivariate analyses of resident-level data from an analytic sample of 6,848 older Americans in the 2010 National Survey of Residential Care Facilities. Nationwide, 7.6% of assisted living residents engaged in physical aggression or abuse toward other residents or staff in the past month, 9.5% of residents had exhibited verbal aggression or abuse, and 2.0% of resident engaged in sexual aggression or abuse toward other residents or staff. Dementia and severe mental illness were significant risk factors for all three types of resident aggression and abuse. Resident aggression and abuse in assisted living facilities is prevalent and warrants greater attention from policy makers, researchers, and long-term care providers. Future research is needed to support training and prevention efforts to mitigate this risk. PMID- 27469496 TI - Actin Filament Structures in Migrating Cells. AB - Cell migration is necessary for several developmental processes in multicellular organisms. Furthermore, many physiological processes such as wound healing and immunological events in adult animals are dependent on cell migration. Consequently, defects in cell migration are linked to various diseases including immunological disorders as well as cancer progression and metastasis formation. Cell migration is driven by specific protrusive and contractile actin filament structures, but the types and relative contributions of these actin filament arrays vary depending on the cell type and the environment of the cell. In this chapter, we introduce the most important actin filament structures that contribute to mesenchymal and amoeboid cell migration modes and discuss the mechanisms by which the assembly and turnover of these structures are controlled by various actin-binding proteins. PMID- 27469495 TI - A multiple-image-based method to evaluate the performance of deformable image registration in the pelvis. AB - Deformable image registration (DIR) is essential for adaptive radiotherapy (RT) for tumor sites subject to motion, changes in tumor volume, as well as changes in patient normal anatomy due to weight loss. Several methods have been published to evaluate DIR-related uncertainties but they are not widely adopted. The aim of this study was, therefore, to evaluate intra-patient DIR for two highly deformable organs-the bladder and the rectum-in prostate cancer RT using a quantitative metric based on multiple image registration, the distance discordance metric (DDM). Voxel-by-voxel DIR uncertainties of the bladder and rectum were evaluated using DDM on weekly CT scans of 38 subjects previously treated with RT for prostate cancer (six scans/subject). The DDM was obtained from group-wise B-spline registration of each patient's collection of repeat CT scans. For each structure, registration uncertainties were derived from DDM related metrics. In addition, five other quantitative measures, including inverse consistency error (ICE), transitivity error (TE), Dice similarity (DSC) and volume ratios between corresponding structures from pre- and post- registered images were computed and compared with the DDM. The DDM varied across subjects and structures; DDMmean of the bladder ranged from 2 to 13 mm and from 1 to 11 mm for the rectum. There was a high correlation between DDMmean of the bladder and the rectum (Pearson's correlation coefficient, R p = 0.62). The correlation between DDMmean and the volume ratios post-DIR was stronger (R p = 0.51; 0.68) than the correlation with the TE (bladder: R p = 0.46; rectum: R p = 0.47), or the ICE (bladder: R p = 0.34; rectum: R p = 0.37). There was a negative correlation between DSC and DDMmean of both the bladder (R p = -0.23) and the rectum (R p = -0.63). The DDM uncertainty metric indicated considerable DIR variability across subjects and structures. Our results show a stronger correlation with volume ratios and with the DSC using DDM compared to using ICE and TE. The DDM has the potential to quantitatively identify regions of large DIR uncertainties and consequently identify anatomical/scan outliers. The DDM can, thus, be applied to improve the adaptive RT process for tumor sites subject to motion. PMID- 27469498 TI - US proposes to expand fixed payments to cardiac care. PMID- 27469499 TI - Varying levels of small microcalcifications and macrophages in ATTR and AL cardiac amyloidosis: implications for utilizing nuclear medicine studies to subtype amyloidosis. AB - BACKGROUND: Recently, there has been much interest in using nuclear medicine studies to noninvasively identify and subtype cardiac amyloidosis. In particular, modified bone scans using (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) and (99m)Tc-pyrophosphate ((99m)Tc-PYP) are being used to selectively identify patients with ATTR amyloidosis rather than AL amyloidosis. The morphologic basis underlying the selectivity of these imaging modalities for ATTR amyloidosis has been unclear. METHODS: To determine if variations in microcalcifications and/or macrophages within ATTR and AL amyloidosis might be responsible for the selectivity for these imaging modalities, 8 endomyocardial biopsies of ATTR amyloidosis and 7 endomyocardial biopsies of AL amyloidosis were stained with von Kossa calcium stains and with immunohistochemistry for the macrophage marker CD68. RESULTS: Compared with AL amyloidosis, there was a greater density of small microcalcifications in cases of ATTR amyloidosis (mean=16.8 vs. 6.5 per 200* field, P=.008). In contrast, there were fewer macrophages in ATTR amyloidosis compared with AL amyloidosis (mean=2.5 vs. 11.7 per 200* field, P=.0004). The density of microcalcifications within each group was not related to patient age, echocardiographic features of cardiac function, or serum levels of calcium and creatinine. CONCLUSIONS: These data suggest that microcalcifications but not macrophages likely underlie the selectivity of modified bone scans for ATTR amyloidosis and suggest that other pathologic entities containing microcalcifications might also result in positive scans with these imaging modalities. PMID- 27469500 TI - Factor Structure and Administration Measurement Invariance of the Beliefs Toward Mental Illness Scale in Latino College Samples: Paper-Pencil Versus Internet Administrations. AB - The psychometric properties of the paper-pencil and online versions of the Beliefs Toward Mental Illness Scale (BTMI) were examined in two studies with Latina/o individuals. In Study 1, 316 Latina/o participants completed the BTMI in a paper-pencil mode. The original three-factor model was found to be a poor fit model for the sample. Subsequent exploratory and confirmatory factor analyses identified a four-factor model as the best fitting model for the sample. The identified factors were Dangerousness, Social Dysfunction, Incurability, and Embarrassment. In Study 2, the identified best fit model was tested with 280 Latina/o participants who completed the BTMI online. The four-factor model had adequate fit. A series of measurement invariance tests on the fit model supported equal factor loadings, but rejected equivalent intercepts across paper-pencil and online administration methods, though partially equivalent intercepts and residuals were found. Consequently, modality-specific norms are recommended, depending on whether paper-pencil or online venues are utilized for administration. PMID- 27469501 TI - Steroid pulse therapy prevents restenosis following balloon dilatation for esophageal stricture. AB - PURPOSE: This study aimed to evaluate the effectiveness of intravenous steroid pulse therapy following balloon dilatation for esophageal stenosis and stricture in children. METHODS: The study enrolled six children, including three with congenital esophageal stenosis and three with anastomotic strictures after surgery for esophageal atresia, all of whom were treated by balloon dilatation combined with high-dose intravenous methylprednisolone pulse therapy. Methylprednisolone was injected intravenously at a dose of 20 mg/kg/day for 2 days, starting from the day of dilatation, followed by 10 mg/kg/day for 2 days, for a total of 4 days. RESULTS: Esophageal stricture recurred in all three patients with congenital esophageal stenosis despite repeated balloon dilatation without methylprednisolone. However, the symptoms of dysphagia improved and did not recur after systemic steroid pulse therapy following balloon dilatation. Symptoms also resolved in all three patients with anastomotic strictures following balloon dilatation with systemic steroid pulse therapy. All six patients remained asymptomatic after 6-21 months follow-up, with no complications. CONCLUSION: Intravenous methylprednisolone pulse therapy following balloon dilatation is safe and effective for the treatment of esophageal stenosis and strictures in children. PMID- 27469502 TI - Laparoscopic repair of sliding inguinal hernia in female children. AB - PURPOSE: To evaluate the safety and feasibility of laparoscopic repair of sliding inguinal hernia in female children. METHODS: Laparoscopic percutaneous extraperitoneal closure (LPEC) was performed in 482 female inguinal hernia children between 2006 and 2015. Fourteen of these patients were associated with sliding inguinal hernia, and these 14 patients were enrolled and reviewed retrospectively. RESULTS: The mean age and the body weight at the operation was 9.6 months and 7.8 kg. Seven patients required the reduction of the ovary under general anesthesia. Laparoscopy, however, revealed that five patients had severe sliding of fallopian tube into the inguinal canal. One of these five patients received a simple LPEC, but developed the recurrence due to the low ligation of the hernia sac, and needed the second hernia repair under inguinal approach. Other four patients with fallopian tube sliding required the dissection of the fallopian tube and peritoneal repair, or the conversion to inguinal approach; therefore they had longer surgical time compared to those without fallopian tube sliding. CONCLUSION: LPEC is safe and feasible for the sliding inguinal hernia repair except the cases with fallopian tube sliding. Patients with fallopian tube sliding required additional procedure or conversion to inguinal approach. PMID- 27469503 TI - Effects of SEMA3 polymorphisms in Hirschsprung disease patients. AB - PURPOSE: Recently, genetic markers within a locus on 7q21.11 containing the SEMA3A, SEMA3C, and SEMA3D genes were reported to be associated with Hirschsprung disease (HSCR). Here, we investigated three polymorphisms, rs1583147, rs12707682, and rs11766001, at this locus to determine their potential contributions to the susceptibility of Indonesian HSCR patients. METHODS: Three variants were analyzed in 60 non-syndromic HSCR patients and 118 ethnicity-matched controls for association studies by genotyping. RESULTS: The risk allele frequencies of SEMA3 rs12707682 (allele C) and rs1583147 (allele T) is higher in cases, 53 and 23 %, than in controls, at 42 and 13 %, respectively. However, these frequency differences were not statistically significant with p value of 0.06 and 0.023, respectively. These findings were consistent with transmission disequilibrium test results with p values of 0.041 and 0.11 for rs12707682 and rs1583147, respectively. Furthermore, the frequencies of SEMA3 rs11766001 risk allele in HSCR cases and controls were 1.7 and 0.8 %, respectively. CONCLUSIONS: SEMA3 rs12707682 and rs1583147 variants are not common risk factors for HSCR in Indonesia. The rarity of the SEMA3 rs11766001 polymorphism in Indonesian population might be due to a founder effect. PMID- 27469504 TI - Relationship between physician-judged functioning level and self-reported disabilities in elderly people with locomotive disorders. AB - PURPOSE: Locomotive disorders due to musculoskeletal involvement are one of the main causes requiring long-term care services in aging Japan. "Locomotive syndrome (LoS)" is a concept referring to the condition under which people require assistance from others or at risk in future. The object of this study is to examine the relationship between self-reported measure and physician-judged degrees on ADL disability in elder people with locomotive disorders. METHODS: In a cross-sectional study, 711 patients who were aged 65 years old or more were recruited from 49 outpatient clinics and hospitals. We investigated ADL disabilities by self-reported questionnaire (Geriatric Locomotive Function Scale 25: GLFS-25) and physician-judged grading (Locomotive Dysfunction Grade: LDG) and examined the relationship between these two. RESULTS: We classified the severity of locomotive disability by clinical phenotype into six grades: LDG Grade 1 (N = 77), Grade 2 (213), Grade 3 (139), Grade 4 (162), Grade 5 (78), and Grade 6 (42). The mean of GLFS-25 was 25.9. The mean of GLFS-25 was 5.68 for Grade 1, 14.33 for Grade 2, 22.34 for Grade 3, 35.40 for Grade 4, 43.25 for Grade 5, and 60.24 for Grade 6. Significant differences of GLFS-25 scores were found between adjacent LDGs. CONCLUSIONS: Physician-judged grade of locomotive dysfunction was significantly related to self-reported assessment scale on ADL disability. Physician-judged dysfunction grade is readily administered scale and useful to assess the severity of locomotive dysfunction. Self-reported scale provides precise information on ADL disabilities due to locomotive organ dysfunction and is useful to develop intervention programs. PMID- 27469505 TI - Longitudinal patterns of pain in patients with diffuse and limited systemic sclerosis: integrating medical, psychological, and social characteristics. AB - PURPOSE: Pain is a common but understudied quality of life concern in systemic sclerosis (SSc). This investigation sought to describe patient-reported pain during the early phase of the disease and to examine potential predictors of this over time. METHODS: A prospective cohort (N = 316) of patients with early-disease SSc from the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS) were followed for 3 years. Multilevel modeling was used to describe longitudinal changes in pain and the extent to which pain variance was explained by disease type, emotional health, perceived physical health, health worry, and social support. RESULTS: Patient-reported pain remained relatively stable, with slight improvement over time. More severe disease type was associated with worse initial pain, but the association was reduced to nonsignificance after accounting for the psychosocial variables. Better emotional health and perceived physical health were associated with lower initial pain. There were marginal interactive effects for perceived physical health and social support such that initial perceptions of poorer physical health, and higher social support, were predictive of greater improvements in pain over time. CONCLUSIONS: These data suggest that emotional health, perceived physical health, and social support are more relevant to longitudinal SSc pain than disease severity and that perceived physical health and social support may impact pain trajectories. Researchers and rheumatology health professionals should consider these factors in comprehensive pain models and pain management protocols. PMID- 27469506 TI - The challenge of measuring intra-individual change in fatigue during cancer treatment. AB - PURPOSE: To evaluate how well three different patient-reported outcomes (PROs) measure individual change. METHODS: Two hundred and fourteen patients (from two sites) initiating first or new chemotherapy for any stage of breast or gastrointestinal cancer participated. The 13-item FACIT Fatigue scale, a 7-item PROMIS(r) Fatigue Short Form (PROMIS 7a), and the PROMIS(r) Fatigue computer adaptive test (CAT) were administered monthly online for 6 months. Reliability of measured change was defined, under a population mixed effects model, as the ratio of estimated systematic variance in rate of change to the estimated total variance of measured individual differences in rate of change. Precision of individual measured change, the standard error of measurement of change, was given by the square root of the rate-of-change sampling variance. Linear and quadratic models were examined up to 3 and up to 6 months. RESULTS: A linear model for measured change showed the following by 6 and 3 months, respectively: PROMIS CAT (0.363 and 0.342); PROMIS SF (0.408 and 0.533); FACIT (0.459 and 0.473). Quadratic models offered no noteworthy improvement over linear models. Both reliability and precision results demonstrate the need to improve the measurement of intra-individual change. CONCLUSIONS: These results illustrate the challenge of reliably measuring individual change in fatigue with a level of confidence required for intervention. Optimizing clinically useful measurement of intra-individual differences over time continues to pose a challenge for PROs. PMID- 27469507 TI - Demequina litorisediminis sp. nov., isolated from a tidal flat, and emended description of the genus Demequina. AB - A Gram-stain-positive, facultatively anaerobic, non-spore-forming, non flagellated and rod-shaped or ovoid bacterial strain, GHD-1T, was isolated from a tidal flat sediment on the Yellow Sea, South Korea. It grew optimally at 30 degrees C, at pH 6.5-8.0 and in the presence of 1.0-2.0 % (w/v) NaCl. A neighbour joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain GHD-1T fell within the cluster comprising the type strains of species of the genus Demequina. Strain GHD-1T exhibited 16S rRNA gene sequence similarity values of 97.0-98.8 % to the type strains of Demequinaglobuliformis, D. salsinemoris, D. flava, D. sediminicola and D. activiva, and of 95.5-96.9 % to the type strains of the other species of the genus Demequina. The peptidoglycan type of strain GHD-1T is A4beta based on l-Orn-l-Ser-l-Asp. It contained DMK-9(H4) and DMK-8(H4) as the major menaquinones and anteiso-C15 : 0, C16 : 0, iso-C16 : 0 and anteiso-C17 : 0 as the major fatty acids. The major polar lipids were phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and one unidentified glycolipid. The DNA G+C content of strain GHD-1T was 68.7 mol%, and its DNA-DNA relatedness values with the type strains of five phylogenetically related species of the genus Demequina were 13-29 %. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain GHD-1T is separated from other recognized species of the genus Demequina. On the basis of the data presented, strain GHD-1T is considered to represent a novel species of the genus Demequina, for which the name Demequina litorisediminis sp. nov. is proposed. The type strain is GHD-1T (=KCTC 52260T=NBRC 112299T). PMID- 27469508 TI - Stable Isotope Resolved Metabolomics Reveals the Role of Anabolic and Catabolic Processes in Glyphosate-Induced Amino Acid Accumulation in Amaranthus palmeri Biotypes. AB - Biotic and abiotic stressors often result in the buildup of amino acid pools in plants, which serve as potential stress mitigators. However, the role of anabolic (de novo amino acid synthesis) versus catabolic (proteolytic) processes in contributing to free amino acid pools is less understood. Using stable isotope resolved metabolomics (SIRM), we measured the de novo amino acid synthesis in glyphosate susceptible (S-) and resistant (R-) Amaranthus palmeri biotypes. In the S-biotype, glyphosate treatment at 0.4 kg ae/ha resulted in an increase in total amino acids, a proportional increase in both (14)N and (15)N amino acids, and a decrease in soluble proteins. This indicates a potential increase in de novo amino acid synthesis, coupled with a lower protein synthesis and a higher protein catabolism following glyphosate treatment in the S-biotype. Furthermore, the ratio of glutamine/glutamic acid (Gln/Glu) in the glyphosate-treated S- and R biotypes indicated that the initial assimilation of inorganic nitrogen to organic forms is less affected by glyphosate. However, amino acid biosynthesis downstream of glutamine is disproportionately disrupted in the glyphosate treated S-biotype. It is thus concluded that the herbicide-induced amino acid abundance in the S biotype is contributed by both protein catabolism and de novo synthesis of amino acids such as glutamine and asparagine. PMID- 27469511 TI - Cholic acid therapy in Zellweger spectrum disorders. AB - INTRODUCTION: Zellweger spectrum disorders (ZSDs) are characterized by a failure in peroxisome formation, caused by autosomal recessive mutations in different PEX genes. At least some of the progressive and irreversible clinical abnormalities in patients with a ZSD, particularly liver dysfunction, are likely caused by the accumulation of toxic bile acid intermediates. We investigated whether cholic acid supplementation can suppress bile acid synthesis, reduce accumulation of toxic bile acid intermediates and improve liver function in these patients. METHODS: An open label, pretest-posttest design study was conducted including 19 patients with a ZSD. Participants were followed longitudinally during a period of 2.5 years prior to the start of the intervention. Subsequently, all patients received oral cholic acid and were followed during 9 months of treatment. Bile acids, peroxisomal metabolites, liver function and liver stiffness were measured at baseline and 4, 12 and 36 weeks after start of cholic acid treatment. RESULTS: During cholic acid treatment, bile acid synthesis decreased in the majority of patients. Reduced levels of bile acid intermediates were found in plasma and excretion of bile acid intermediates in urine was diminished. In patients with advanced liver disease (n = 4), cholic acid treatment resulted in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor reduction in bile acid intermediates. CONCLUSIONS: Oral cholic acid therapy can be used in the majority of patients with a ZSD, leading to at least partial suppression of bile acid synthesis. However, caution is needed in patients with advanced liver disease due to possible hepatotoxic effects. PMID- 27469512 TI - Management of Serotonin Syndrome and Neuroleptic Malignant Syndrome. AB - OPINION STATEMENT: Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) can present similarly and range in severity from mild to life-threatening. Although they are easily misdiagnosed, each is distinct clinically and pathophysiologically. It is important to distinguish between the two, as therapeutic options differ. An accurate and thorough medication history plus knowledge of the various clinical presentations of both syndromes are the first steps in management. After this, removing the offending agents and aggressive supportive care are crucial. This includes controlling muscle rigidity and hyperthermia, providing cardiovascular support, and alleviating agitation. In severe cases, paralysis, sedation, and intubation are required. Agents to reverse either surplus serotonergic activity or dopamine blockage can be useful. However, the diagnosis must be clear, as use of these agents in the incorrect syndrome can worsen symptoms. In pharmacologically refractory cases of NMS, electroconvulsive therapy should be pursued. PMID- 27469509 TI - A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2 hydroxyglutaric aciduria type II mouse model. AB - D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II. PMID- 27469513 TI - Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters. AB - Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment refractory depressed patients. Previous studies suggest that ketamine's antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine's side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1-D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine's enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 MUM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID- 27469515 TI - On-scene factors that predict severe injury of patients involved in frontal crashes of passenger cars. AB - PURPOSE: We sought to determine on-scene factors that predict severe injury to the occupants of passenger cars involved in frontal crashes. METHODS: From January 2011 to December 2014, we collected data from patients who were taken to two emergency centres following a frontal motor vehicle crash. Binomial logistic regression was used to model the effects of occupant characteristics (sex, age, body mass index), vehicle damage (according to the collision deformation classification code), and safety devices on severe injuries (injury severity score >15). RESULTS: Of 344 subjects, 75 (21.8 %) had severe injuries. Sex, seat belt status, extent of vertical crash, intrusion, and deformation extent (DE) were significantly different between severe and non-severe injuries. After adjusting for confounders, non-use of seat belt tripled the odds of severe injury [odds ratio (OR) 2.7, 95 % confidence interval (CI) 1.461-5.105]. DE >=4 and intrusion increased the risk of severe injury (OR 2.4, 95 % CI 1.120-5.204 and OR 5.2, 95 % CI 2.525-10.780, respectively). A combination model to predict severe injury using intrusion, seat belt use, and DE >=4 demonstrated 56.0 % sensitivity, 88.9 % specificity, and 58.4 % positive predictive value (AUC = 0.781, 95 % CI 0.734-0.824). CONCLUSIONS: For passenger cars involved in a frontal crash, intrusion, unbelted status, and DE >=4 are good predictors of severe injury. Sequential criteria using vehicle DE, seat belt use, and intrusion can be used by first responders to triage patients involved in a frontal collision. PMID- 27469514 TI - An Illustration of Inverse Probability Weighting to Estimate Policy-Relevant Causal Effects. AB - Traditional epidemiologic approaches allow us to compare counterfactual outcomes under 2 exposure distributions, usually 100% exposed and 100% unexposed. However, to estimate the population health effect of a proposed intervention, one may wish to compare factual outcomes under the observed exposure distribution to counterfactual outcomes under the exposure distribution produced by an intervention. Here, we used inverse probability weights to compare the 5-year mortality risk under observed antiretroviral therapy treatment plans to the 5 year mortality risk that would had been observed under an intervention in which all patients initiated therapy immediately upon entry into care among patients positive for human immunodeficiency virus in the US Centers for AIDS Research Network of Integrated Clinical Systems multisite cohort study between 1998 and 2013. Therapy-naive patients (n = 14,700) were followed from entry into care until death, loss to follow-up, or censoring at 5 years or on December 31, 2013. The 5-year cumulative incidence of mortality was 11.65% under observed treatment plans and 10.10% under the intervention, yielding a risk difference of -1.57% (95% confidence interval: -3.08, -0.06). Comparing outcomes under the intervention with outcomes under observed treatment plans provides meaningful information about the potential consequences of new US guidelines to treat all patients with human immunodeficiency virus regardless of CD4 cell count under actual clinical conditions. PMID- 27469517 TI - Age-related heterogeneity of Burkitt lymphoma. PMID- 27469516 TI - Anxiety and depression strongly associated with sexual risk behaviors among networks of young men in Dar es Salaam, Tanzania. AB - This study tested the association between mental health scores and sexual risk behaviors among male members of social groups known as "camps" in Dar es Salaam, Tanzania. Anxiety and depression were measured using the HSCL-25 and condom use and sexual partner concurrency were assessed through self-report. A total of 1113 sexually active men with an average age of 27 years were included in the analyses. Higher anxiety and depression scores were significantly associated with both condom use (Anxiety AOR = 0.58, 95% CI: 0.44, 0.77; Depression AOR = 0.60, 95% CI: 0.47, 0.77) and concurrency (Anxiety AOR = 2.32, 95% CI: 1.73, 3.12; Depression AOR = 2.08, 95% CI: 1.60, 2.70). The results of this study provide information salient to the development of effective HIV prevention interventions targeting populations with high burdens of anxiety and depression. The feasibility and effect of integrating mental health promotion activities into HIV prevention interventions should be explored. PMID- 27469518 TI - Low-grade inflammation may moderate the effect of behavioral treatment for chronic pain in adults. AB - The purpose of the present pilot study was to explore the moderating role of basal inflammation on the effects of behavioral pain treatment in 41 patients with long-standing pain. Baseline pro-inflammatory status moderated behavioral treatment outcomes: higher pre-treatment levels of Tumor Necrosis Factor (TNF) alpha and Interleukin (IL)-6 were related to less improvement in pain intensity, psychological inflexibility and in mental health-related quality of life. The treatment outcomes improved in the subgroup that had low levels of pro inflammatory cytokines at baseline, while the subjects with higher pro inflammatory status did not. Altogether, results indicate that low-grade inflammation may influence the behavioral treatment outcomes and provide a possible explanation of the heterogeneity in treatment response. PMID- 27469521 TI - Educated Risks Offer Big Rewards. PMID- 27469520 TI - Multiple Cafe au Lait Spots in a Group of Fair-Skinned Children without Signs or Symptoms of Neurofibromatosis Type 1. AB - BACKGROUND: The presence of six or more cafe au lait (CAL) spots is a criterion for the diagnosis of neurofibromatosis type 1 (NF-1). Children with multiple CAL spots are often referred to dermatologists for NF-1 screening. The objective of this case series is to characterize a subset of fair-complected children with red or blond hair and multiple feathery CAL spots who did not meet the criteria for NF-1 at the time of their last evaluation. METHODS: We conducted a chart review of eight patients seen in our pediatric dermatology clinic who were previously identified as having multiple CAL spots and no other signs or symptoms of NF-1. RESULTS: We describe eight patients ages 2 to 9 years old with multiple, irregular CAL spots with feathery borders and no other signs or symptoms of NF-1. Most of these patients had red or blond hair and were fair complected. All patients were evaluated in our pediatric dermatology clinic, some with a geneticist. The number of CAL spots per patient ranged from 5 to 15 (mean 9.4, median 9). CONCLUSION: A subset of children, many with fair complexions and red or blond hair, has an increased number of feathery CAL spots and appears unlikely to develop NF-1, although genetic testing was not conducted. It is important to recognize the benign nature of CAL spots in these patients so that appropriate screening and follow-up recommendations may be made. PMID- 27469522 TI - MyPlate, MyState-Personalizing Your Plate with Your Local Flavors, Foods, and Recipes. PMID- 27469523 TI - Is There a Special Diet for Thalassemia? PMID- 27469524 TI - Mitotic Spindle Assembly: Building the Bridge between Sister K-Fibers. AB - The mitotic spindle performs the task of physically dividing the genetic material between the newly formed daughter cells. To achieve this, bundles of microtubules and associated proteins orchestrate forces that spatially organize and then separate the chromosomes. In the classic view of the spindle, the kinetochore microtubules (k-fibers) are tensed and, thus, straight, whereas interpolar bundles are curved and do not interact with k-fibers close to the spindle equator. The updated view of the spindle depicts k-fibers as curved and interacting with newly identified interpolar bundles, called bridging fibers, along their length. In this Opinion, we propose and discuss scenarios for the origin of this structure in the context of known spindle assembly mechanisms. PMID- 27469525 TI - Surgery along the embryological planes for colon cancer: a systematic review of complete mesocolic excision. AB - BACKGROUND: Complete mesocolic excision (CME) for colonic cancer offers a surgical specimen of higher quality, with higher number of lymph nodes compared to conventional colectomy. However, evidence on oncological outcomes is limited. The aim of the present study is to review recent literature and provide more information regarding the effect of CME colectomy on short- and long-term outcomes. METHOD: PubMed and MEDLINE databases were searched, and articles in English reporting data on CME were reviewed. Intraoperative events; postoperative morbidity and mortality; histopathological characteristics, including macroscopic assessment, number, and status of retrieved lymph nodes; and oncological outcomes were the end-points. RESULTS: Thirty-two studies were analyzed. As regards the macroscopic assessment, a larger specimen (p = 0.02) that contains a higher number of lymph nodes (p < 0.00001) is acquired after CME. Two studies report a higher disease-free survival, in stage I and II and particularly in stage III disease after CME. CME by laparoscopy offers comparable outcomes, as regards intraoperative blood loss and immediate postoperative morbidity and mortality rates. Specimen quality is similar after either approach, for cancers located at the right and left colon, but not at the transverse colon. CONCLUSION: There is strong evidence that CME offers a longer central pedicle that contains more lymph nodes than conventional surgery for colon cancer. CME represents the surgical background for the maximum lymph node harvest, an important quality marker for the surgical outcome. However, and according to present data, there is limited evidence that colectomy in terms of CME leads to improved long-term oncological outcomes. PMID- 27469526 TI - The role of sub-hippocampal versus hippocampal regions in bitemporal lobe epilepsies. AB - OBJECTIVE: We aimed at better delineating the functional anatomical organization of bitemporal lobe epilepsy. METHODS: We studied the epileptogenic zone (EZ) by quantifying the epileptogenicity of brain structures explored by depth electrodes in patients investigated by stereoelectroencephalography (SEEG). We compared 15 patients with bilateral mesial temporal lobe epilepsy (BTLE) and 15 patients with unilateral mesial temporal lobe epilepsy (UTLE). This quantification was performed using the 'Epileptogenicity Index' (EI). RESULTS: Age at epilepsy onset, and epilepsy duration, were not statistically different in both groups. UTLE patients more frequently displayed maximal epileptogenicity in hippocampal structures, whereas BTLE patients had maximal values in subhippocampal areas (entorhinal cortex, temporal pole, parahippocampal cortex). CONCLUSIONS: Our results suggest different organization of the EZ in the two groups. SIGNIFICANCE: BTLE was associated with more involvement of subhippocampal regions, a result in agreement with known anatomical connections between the two temporal lobes. PMID- 27469527 TI - Using facial electromyography to detect preserved emotional processing in disorders of consciousness: A proof-of-principle study. AB - OBJECTIVE: To examine whether emotional functioning can be observed in patients who are behaviourally non-responsive using peripheral markers of emotional functioning. METHOD: We tested two patients, both diagnosed as being in a vegetative state (VS) following hypoxia secondary to cardiac arrest. Thirty-seven healthy participants with no history of neurological illness served as a control group. The activity of two facial muscles (zygomaticus major, corrugator supercilii) was measured using facial electromyography (EMG) to probe for patterned responses that differentiate between auditorily presented joke and non joke stimuli in VS patients. RESULTS: One of the two VS patients we tested demonstrated greater zygomatic and reduced corrugator activity in response to jokes compared with non-jokes. Critically, these responses followed the pattern and temporal profile of muscle activity observed in our healthy control sample. CONCLUSIONS: Despite their behaviorally non-responsive profile, some patients diagnosed as VS appear to retain some aspects of emotional experience. SIGNIFICANCE: Our findings represent, to our knowledge, the first demonstration that a patient diagnosed as VS can exhibit intact emotional responses to humor as assessed by facial EMG. Therefore, our approach may constitute a feasible bedside tool capable of providing novel insight into the mental and emotional lives of patients who are behaviourally non-responsive. PMID- 27469528 TI - Electrophysiological correlates of word recognition memory process in patients with ischemic left ventricular dysfunction. AB - OBJECTIVE: The relationship between left ventricular ejection fraction (LVEF) and cognitive performance in patients with coronary artery disease without overt heart failure is still under debate. In this study we combine behavioral measures and event-related potentials (ERPs) to verify whether electrophysiological correlates of recognition memory (old/new effect) are modulated differently as a function of LVEF. METHODS: Twenty-three male patients (12 without [LVEF>55%] and 11 with [LVEF<40%] left ventricular dysfunction), and a Mini Mental State Examination score >25 were enrolled. ERPs were recorded while participants performed an old/new visual word recognition task. RESULTS: A late positive ERP component between 350 and 550ms was differentially modulated in the two groups: a clear old/new effect (enhanced mean amplitude for old respect to new items) was observed in patients without LVEF dysfunction; whereas patients with overt LVEF dysfunction did not show such effect. In contrast, no significant differences emerged for behavioral performance and neuropsychological evaluations. CONCLUSIONS: These data suggest that ERPs may reveal functional brain abnormalities that are not observed at behavioral level. SIGNIFICANCE: Detecting sub-clinical measures of cognitive decline may contribute to set appropriate treatments and to monitor asymptomatic or mildly symptomatic patients with LVEF dysfunction. PMID- 27469529 TI - Expression of the inhibitory Ly49E receptor is not critically involved in the immune response against cutaneous, pulmonary or liver tumours. AB - Natural killer (NK) lymphocytes are part of the innate immune system and are important in immune protection against tumourigenesis. NK cells display a broad repertoire of activating and inhibitory cell surface receptors that regulate NK cell activity. The Ly49 family of NK receptors is composed of several members that recognize major histocompatibility complex class I (MHC-I) or MHC-I-related molecules. Ly49E is a unique inhibitory member, being triggered by the non-MHC-I related protein urokinase plasminogen activator (uPA) in contrast to the known MHC-I-triggering of the other inhibitory Ly49 receptors. Ly49E also has an uncommon expression pattern on NK cells, including high expression on liver DX5( ) NK cells. Furthermore, Ly49E is the only Ly49 member expressed by epidermal gammadelta T cells. As gammadelta T cells and/or NK cells have been shown to be involved in the regulation of cutaneous, pulmonary and liver malignancies, and as uPA is involved in tumourigenesis, we investigated the role of the inhibitory Ly49E receptor in the anti-tumour immune response. We demonstrate that, although Ly49E is highly expressed on epidermal gammadelta T cells and liver NK cells, this receptor does not play a major role in the control of skin tumour formation or in lung and liver tumour development. PMID- 27469530 TI - Increase of polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls in human milk from China in 2007-2011. AB - A national survey was conducted to determine polychlorinated dibenzo-p-dioxins and dibenofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in human milk samples collected from 16 provinces in China to assess current exposure and temporal trends in China. The arithmetic mean concentration of total TEQ (PCDD/Fs and dl-PCBs) in 2011 is 6.7pgTEQg-1 lipid with a range of 2.9 15.4pgTEQg-1 lipid in 2011. Levels have been compared to data obtained during a previous national study conducted in 2007. The mean of PCDD/Fs has increased about 32.6% and 99.9% for total TEQ concentration (3.7pgTEQg-1 lipid in 2007 vs 4.9pgTEQg-1 lipid in 2011) and mass concentration (66.7pgg-1 lipid in 2007 vs 133.3pgg-1 lipid in 2011) during the period of 2007-2011, respectively. Continuous surveillance on PCDD/Fs and dl-PCBs in human milk is critical to evaluate the human health effect and environment impact in China. PMID- 27469531 TI - Infrared Response of Sub-Micron-Scale Structures of Polyoxymethylene: Surface Polaritons in Polymers. AB - An investigation of the infrared (IR) spectra of polyoxymethylene (POM) mold plates was undertaken to determine the sub-micron-scale morphology and molecular orientation. The nest-structured cells concerned with the orientation were observed from scanning electron microscope (SEM) measurements with the aid of Raman spectroscopy. The intensity of the anomalous IR reflectance peak of the C-O stretching A2 mode depends on the widths of the POM layers in the SEM image along the orientation direction. The results suggest that the spectral features originate from the Berreman effect of the bulk polaritons and the radiative surface polaritons. Moreover, the IR spectra of certain treated samples suggest that enhancement of the electromagnetic fields from the gap modes and transition dipole-dipole coupling influence the spectral shapes. PMID- 27469532 TI - Different effect of testosterone and oestrogen on urinary excretion of metformin via regulating OCTs and MATEs expression in the kidney of mice. AB - The aim of this study was to investigate the effect of testosterone and oestrogen on regulating organic cation transporters (Octs) and multidrug and toxin extrusions (Mates) expression in the kidney of mice and urinary excretion of metformin. 8 week-old male db/db mice were treated with estradiol (5 mg/kg), testosterone (50 mg/kg) or olive oil with same volume. Metformin (150 mg/kg) was injected in daily for successive 7 days. Plasma, urine and tissue concentrations of metformin were determined by liquid chromatography-tandem mass spectrometry (LCMS) assay. Western blotting and Real-time PCR analysis were successively used to evaluate the renal protein and mRNA expression of Octs and MATEs. After treatment, the protein expression of Mate1 and Oct2 in testosterone group was significantly increased than those in control group (both P < 0.05). The protein expression of Mate1 and Oct2 in estradiol group was significantly reduced by 29.4% and 43.3%, respectively, compared to those in control group (all P < 0.05). These data showed a good agreement with the change in mRNA level (all P < 0.05). The plasma metformin concentration (ng/ml) in mice treated with estradiol was significantly higher than control and testosterone group (677.56 +/- 72.49 versus 293.92 +/- 83.27 and 261.46 +/- 79.45; P < 0.01). Moreover, testosterone increased the metformin urine excretion of mice while estradiol decreasing (both P < 0.01). Spearman correlation analysis showed that gonadal hormone was closely associated with Mate1 and Oct2 expression and metformin urine excretion in db/db mice (all P < 0.05). Testosterone and oestrogen exerted reverse effect on metformin urinary excretion via regulating Octs and Mates expression in the kidney of mice. PMID- 27469533 TI - Updating Taenia asiatica in humans and pigs. AB - An epidemiological study on taeniasis and cysticercosis in northern India has recently updated the epidemiology of Taenia asiatica. Practically, all the detected cases of taeniasis were caused by T. asiatica, cited for the first time in humans in that country. The finding widens the geographical distribution of T. asiatica, a species wrongly considered an exclusive South-Eastern Asian parasite. Due to the introduction of molecular techniques in Taenia diagnosis, the species is slowly showing its true distribution. A human Taenia species with cosmopolitan hosts (the same as the other two Taenia species) but limited to a specific geographical area and not affected by globalisation would certainly be hard to believe. Regarding cysticercosis, there is a remarkable finding concerning T. asiatica pig cysticercosis, specifically the presence of the cysticercus of T. asiatica not only in the liver (its preferential infection site) but also in muscle. This is the first time that the cysticercus of T. asiatica has been found in muscle in a naturally infected pig. This fact is actually relevant since people are at a greater risk of becoming infected by T. asiatica than previously expected since the liver is no longer the only site of pig infection. The Taenia species causing Taenia saginata-like taeniasis around the world, as well as pig and human cysticercosis, should always be molecularly confirmed since T. asiatica could be involved. PMID- 27469534 TI - Morphological and enzymatical observations in Oncomelania hupensis after molluscicide treatment: implication for future molluscicide development. AB - A preparation of niclosamide named 50 % wettable powder of niclosamide ethanolamine salt (WPN), the only chemical molluscicide available in China, has been widely used for Oncomelania hupensis control over the past 20 years, but its molluscicidal mechanism has not been elucidated yet. Recently, a derivative of niclosamide, the salt of quinoid-2',5-dichloro-4'-nitro-salicylanilide (Liu Dai Shui Yang An, LDS), has been proven to have equivalent molluscicidal effects as WPN but with lower cost and significantly lower toxicity to fish than WPN. In our previous study, gene expression profiling of O. hupensis showed significantly effects after these two molluscicides had been applied. This study was designed to use morphological and enzymological analyses to further elucidate the mechanism by which these molluscicides cause snail death. After WPN or LDS treatment, the number of mitochondria of O. hupensis was reduced and their cristae appeared unclear, heterochromatin gathered to be polarized, ribosome numbers of the rough endoplasmic reticulums (rERs) decreased, myofilaments in muscle cells became disordered and loose, and cytoplasm in some liver cells was concentrated. Damage of cell structures and organelles suggested inhibited movement ability and effects on liver and energy metabolism following treatment. In parallel, activities of enzymes related with carbohydrate metabolism were inhibited except lactate dehydrogenase (LDH) increased in muscle tissue, and activities of enzymes related with stress response increased followed by decreasing to lower levels than those of the H2O-treated group. This shift of carbohydrate metabolism patterns led to insufficient energy supply and lactic acid accumulation, and variations of nitric oxide synthase (NOS), alanine aminotransferase (ALT), and superoxide dismutase (SOD) during process of molluscicide treatment suggested a stress response of snail to the molluscicides at early stages and later fatal damage in liver and nervous system. In general, effects of WPN and LDS were similar although LDS-treated snails showed more serious damage in the liver and a stronger inhibition of enzymes related with aerobic respiration and stress response. This was consistent with the transcriptome profile obtained previously. However, considering enzyme activities at post-transcriptional and protein levels, comprehensive identification and annotation of potential enzyme-related genes and regulation pattern would be necessary to provide great benefit for understanding of potential mechanism of these molluscicides and even for future molluscicide development. PMID- 27469535 TI - New detection method in experimental mice for schistosomiasis: ClinProTool and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Oncomelania hupensis snails along the Yangtze River and the low positive rate and infectiosity of human and livestock schistosomiasis still pose a threat to public health in China. Adult blood flukes were recognized as Schistosoma japonicum, which are found in the portal system of the sentinel mice bred in the laboratory for 35 days after contact with the water. However, 35 days was too long from the field test to dissection, and the dissection in the laboratory was also time consuming and labor-intensive. Serum peptides in mice at different times after infection were measured by matrix-assisted laser desorption/ionization time-of flight mass spectrometry. ClinProTool was used to establish the proteomic detection pattern (PDP), based on the differentially expressed peptide between the infection and healthy control groups. Under experimental conditions, characteristic PDP were detected in 5 % (3/60), 35 % (21/60), 75 % (45/60), 87.93 % (51/58), and 98.15 % (53/54) of infected mice from weeks 1 to 5 post-infection, whereas ELISA and dissection examination for adult blood flukes missed the first 2 weeks. At 35 days post-infection, the infectiosity assay showed 40 % (4/10), 50 % (5/10), and 80 % (8/10) positivity with the PDP test in mice infected with 4, 6, and 10 cercariae, respectively, as well as 100 % (10/10) positivity in mice infected with 14, 18, and 22 cercariae. Five stored sera of positive sentinel mice with parasite detection were verified correctly in the PDP test. The results confirm that PDP can be used as a rapid and early detection method for S. japonicum infection in experimental mice, which are expected to apply in early surveillance for schistosomiasis. PMID- 27469537 TI - Patient-reported outcomes after open carpal tunnel release using a standard protocol with 1 hand therapy visit. AB - STUDY DESIGN: Retrospective case series. INTRODUCTION: Open carpal tunnel release (OCTR) is a common treatment for carpal tunnel syndrome, but there is no consensus on the number of hand therapy visits needed to achieve optimal patient outcomes. PURPOSE OF THE STUDY: The purpose is to examine changes in patient reported symptoms and function over a 12-week period after OCTR with 1 postoperative hand therapy visit. METHODS: Eligible subjects were consecutive patients treated with a standard OCTR protocol by a fellowship trained hand surgeon that included 1 hand therapy visit at 10-14 days postoperatively. Patients were excluded from participation if they had additional surgery at the time of OCTR, had another upper extremity diagnosis that required therapeutic intervention, or received more or less than 1 visit of hand therapy. Responses on the Boston Carpal Tunnel Questionnaire (BCTQ) were collected at preoperative and 3 postoperative time points: at the hand therapy visit, 6 weeks, and 12 weeks. Change over time in the BCTQ Symptom Severity Scale and Functional Status Scale was assessed. RESULTS: A total of 134 patients who were treated with the standard protocol had a complete BCTQ data set. Both BCTQ scales showed significant improvement over time. The Symptom Severity Scale showed significant improvement by the hand therapy visit at 10-14 days postoperatively, whereas significant improvement on the Functional Status Scale did not occur until 6 weeks postoperatively. The magnitude of change from preoperative to 12 weeks postoperative was 1.51 points on the Symptom Severity Scale and 0.91 points on the Functional Status Scale. Complication rates were low with an incidence of 13% for pillar pain and palm pain combined. CONCLUSIONS: Patient-reported symptoms and function improved significantly up to 12 weeks after OCTR. Moreover, there was a low incidence of pillar and palm pain. In a retrospective review of patients with a favorable prognosis based on having no need for extra surgical procedures or additional therapy visits, one therapy visit associated with improvements in symptoms and function, a low incidence of pillar/palm pain and favorable 12-weeks outcomes. There appears to be a subset of less complicated patients for whom one visit can allow for favorable outcomes. LEVEL OF EVIDENCE: 2B. PMID- 27469536 TI - Morphological, molecular and MALDI-TOF mass spectrometry identification of ixodid tick species collected in Oromia, Ethiopia. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) technology has recently been reported as a promising method for arthropods identification. More recently, our laboratory reported the correct identification of tick species via the MALDI-TOF MS protein spectra profiling of legs from fresh specimens. The aim of the present study was to assess the use of MALDI-TOF MS for correct identification of ixodid tick species preserved in 70 % ethanol during field collection in Ethiopia. Following morphological identification of 12 tick species, the legs from 85 tick specimens were subjected to MALDI-TOF MS. Spectral analysis revealed an intra-species reproducibility and inter-species specificity that were consistent with the morphological classification. To support the results of the MALDI-TOF MS tick species identification, 41 tick specimens comprising 3 to 5 specimens per tick species were used to create a reference spectra database, which was evaluated using the spectra of the 44 remaining tick specimens. The blind tests revealed that 100 % of the tick specimens studied by MALDI-TOF MS were correctly identified. A relevant Log score value (LSV) of >1.8 was recorded for all of the tick species studied by MALDI-TOF MS, except for Rhipicephalus praetextatus. The morphological and MALDI-TOF MS identifications were confirmed by sequencing the 12S ribosomal RNA (rRNA) gene of 40 tick specimens belonging to 11 ixodid species. Taken together, the results of the present study indicate that MALDI-TOF MS is a reliable tool for tick species identification, even after preservation in ethanol, provided that a reference spectra database is built from specimens that represent the respective species stored under the same conditions. PMID- 27469538 TI - A user's survey of the clinical application and content validity of the DASH (Disabilities of the Arm, Shoulder and Hand) outcome measure. AB - STUDY DESIGN: Survey. PURPOSE OF THE STUDY: To elicit feedback on the clinical use and content validity of the Disabilities of the Arm, Shoulder and Hand (DASH) outcome measure from frontline users of the instrument. METHODS: A cross sectional survey was administered to registered DASH users and inquired about how the DASH was being used and to identify the informational value of items of the DASH (content validity). RESULTS: About 172 completed the survey. One or both of the DASH and/or QuickDASH were consistently (89.5%) being used. About 90% were using it in adults (21-65 years), and at least 70% were using it across the entire extremity, and to a lesser extent, 10% reported using it in isolated neck injuries. Most respondents (66.9%-75.8%) were using the DASH in musculoskeletal (MSK) disorders, with some applying it for other more unique or non-MSK conditions (2.5%-16.6%). All but 1 of the 30 DASH items had at least 10% endorsement as being informative, and 4 items were identified as being problematic by greater than 20%. CONCLUSIONS: The DASH is being used as intended (whole extremity and MSK conditions), and in addition, it is being used in different body regions and diverse conditions. LEVEL OF EVIDENCE: Not applicable (descriptive survey). PMID- 27469539 TI - Stroke etiologic subtype may influence the rate of hyperdense middle cerebral artery sign disappearance after intravenous thrombolysis. AB - Disappearance of hyperdense middle cerebral artery sign (HMCAS) on non-contrast brain computed tomography (CT) scan is a reliable sign of arterial recanalization after intravenous (IV) thrombolysis for ischemic stroke. We aimed to assess whether stroke etiologic subtype may influence the rate of HMCAS disappearance and the clinical outcome after IV thrombolysis. We conducted a retrospective analysis of data prospectively collected from 1031 consecutive stroke patients treated with IV thrombolysis. Outcome measures were HMCAS disappearance on follow up CT scan within 22-36 h of IV thrombolysis, neurologic improvement (NIH Stroke Scale [NIHSS] <=4 points from baseline or NIHSS score of 0) at 7 days, and modified rankin scale (mRS) <=1 at 3 months. Of 256 patients with HMCAS on admission CT scan, 125 had a cardioembolic stroke, 67 a stroke due to large artery atherosclerosis (LAA), 58 a stroke of undetermined etiology, and six a stroke secondary to carotid artery dissection. HMCAS disappearance occurred in 145 (56.6 %) patients, neurologic improvement in 122 (55.0 %) patients, and mRS <=1 in 64 (32.8 %) patients. Compared with cardioembolic stroke patients, patients with stroke due to LAA had lower odds ratios (OR) for HMCAS disappearance (OR 0.29, 95 % CI 0.15-0.58, p < 0.001), neurologic improvement (OR 0.42, 95 % CI 0.22-0.82, p = 0.011), and mRS <=1 (OR 0.18, 95 % CI 0.06-0.52, p = 0.002). No significant differences in outcome measures were found between cardioembolic strokes and strokes of undetermined etiology. This study suggests that stroke due to LAA is associated with lower rates of HMCAS disappearance, neurologic improvement, and mRS <=1 after IV thrombolysis, compared with cardioembolic stroke. PMID- 27469540 TI - A small-angle X-ray scattering study of alpha-synuclein from human red blood cells. AB - alpha-synuclein (alpha-syn) is the main component of Lewy bodies, which are neuropathological hallmarks of patients with Parkinson's disease. As it has been controversial whether human alpha-syn from erythrocytes exists as a tetramer under physiological conditions, we tried solving this issue by the small-angle X ray solution scattering method. Under two different conditions (high ionic strength with a Tris buffer and low ionic strength with an ammonium acetate buffer), no evidence was found for the presence of tetramer. When comparing erythrocyte and recombinant alpha-syn molecules, we found no significant difference of the molecular weight and the secondary structure although the buffer conditions strongly affect the radius of gyration of the protein. The results indicate that, even though a stable tetramer may not be formed, conformation of alpha-syn depends much on its environment, which may be the reason for its tendency to aggregate in cells. PMID- 27469541 TI - A prospective evaluation of outcomes of two tapered implant systems. AB - The purpose of this prospective clinical study was to evaluate survival rate (SVR - i.e. fixtures still in place at the end of the observation period) and success rate (SCR - i.e. bone resorption around the implant neck) of two tapered implant systems. Both systems were equipped with a tapered connection, one requiring bone level (BL) placement, while the other required soft-tissue-level (STL) placement. In the period between January 1996 and October 2011, 133 fixtures were inserted, 90 in females and 43 in males, with a mean age of 60+/-11 years. The mean post surgical follow-up was 64+/-38 months. Several clinical parameters were evaluated as potential outcome conditioners. An SPSS program was used for statistical analysis and a Cox analysis was performed. The SVR was 100% since no fixtures were lost. SCR, expressed through the mean marginal bone loss, was 88%. No significant differences were found, for most of the variables investigated with the exception of bone grafting and implant type: STL implants showed a better clinical outcome than BL implants when bone grafting was performed simultaneously with implant placement. Tapered implants are reliable devices for oral rehabilitation of jaws. PMID- 27469542 TI - Clinical outcome of a two-piece implant system with an internal hexagonal connection: a prospective study. AB - The purpose of this prospective clinical study was to evaluate the survival rate (SVR - i.e. fixtures still in place at the end of the observation period) and success rate (SCR - i.e. bone resorption around implant neck) of an implant system characterized by cylindrical and tapered implants, both provided with an internal hexagonal connection. In the period between January 1996 and October 2011, 52 implants with internal hexagonal connection were inserted in 21 females and 31 males, mean age 54+/-11 years. The mean post-surgical follow-up was 44.6+/ 34.4 months. Several parameters were evaluated as potential outcome conditioners: age, gender, smoking, replaced tooth, periodontal disease, fixture shape (i.e. cylindrical or tapered), jaw location (i.e. maxilla or mandible), bone graft, immediate loading, post-extractive placement, type of prosthesis (i.e. single crown or bridge), edentulism, implant diameter and length. An SPSS statistical program was used and Cox regression analysis performed. SVR was 100% since no fixtures were lost. SCR, expressed through the mean marginal bone loss, was 77%. No significant differences were found, for most of the parameters analyzed, with the exception of prosthetic bridges, where implants supporting this type of rehabilitation showed a worse clinical outcome in comparison to single crown rehabilitations. Internal hexagonal connection is a reliable tool for oral rehabilitation. PMID- 27469543 TI - Maxillary sinus by-pass with tilted implants via tapered-screw bone expanders in low density bone: one year follow -up of a case series. AB - In the present paper the use of tapered-screw bone expanders (TSBEs) is proposed, in combination with the placement of tilted implants in close proximity to the anterior sinus wall, solving the problem of the reduced height of the alveolar bone in the sub-antral area. The Authors named the procedure: Tilted Implant Expansion Osteotomy (TIEO). Fifteen patients (10 females and 5 males, mean age 47.8+/-8.15 years) with distal edentulous maxillae were enrolled in this study. For each edentulous site 2 implants were placed, the anterior implant in the area of the most anterior missing tooth while, the posterior implant, immediately in front of the maxillary sinus, with an inclined position. Adopting the aforesaid procedure, 34 cylindrical two-piece implants were placed, 17 of which were placed in tilted position, in order to by-pass the maxillary sinus. After a healing period of 4-6 months, the second stage surgery was performed. The cases were finalized by metal-ceramic cementable restorations with a variable number of elements, from 2 to 4, without any cantilever element. The post finalization follow-up was at 12 months. Survival rate was 100% since no fixtures were lost. At the one-year follow-up the clinical and radiological appearance of the soft and hard tissues was optimal and no pathological signs were recorded. TIEO is a promising surgical procedure for oral rehabilitation of maxillary edentulous sites and represents a therapeutic alternative to sinus lift techniques. PMID- 27469544 TI - Endoscopically controlled hydraulic sinus lift in combination with rotary instruments: one-year follow-up of a case series. AB - The aim of this study was to evaluate a sinus lift via crestal approach (SLVCA) case series, performed with rotary instruments and hydraulic pressure, analyzed under endoscopic control. Sixteen patients (11 female, 5 male, mean age 47.13+/ 8.07 years) candidates for SLVCA were enrolled in this study. Twenty-two cylindrical two-piece implants were placed. After a suitable period of time needed for the consolidation of the graft (mean value 5.78+/-1.49 months), the bone augmentation was assessed by means of intraoral X-ray exams before the surgical procedure of re-entry. After a functional load with temporary acrylic fixed prosthesis, on Peek abutments, for a span of 4 months, the cases were finalized with cemented metal-ceramic prosthesis (10 single crowns, 6 bridges). The post finalization follow-up was at 12 months. During the perforation of the sinus floor via rotary instruments no perforations of the sinus membrane were observed either during the hydraulic detachment or simultaneous filling of the subantral space with the graft material. Survival rate was 94.5% since one fixture was lost, but immediately replaced with a new one. At the one-year follow up the clinical and radiological appearance of the soft and hard tissues was optimal and no pathological signs were recorded. The SLVCA performed with rotary instruments and hydraulic pressure is a reliable grafting procedure for oral rehabilitation of maxillary edentulous sites. PMID- 27469545 TI - Modified connective tissue punch technique to increase the vestibular/buccal keratinized tissue on flapless implant surgery: a case series. AB - The aim of this article is to show a simple and predictable technique to enhance both the vestibular/buccal (V/B) gingival thickness (GT) and keratinized tissue width (KTW) improving the soft-tissue profile after flapless implant placement. The technique proposed was named Modified Connective Tissue Punch (MCTP). Fourteen patients (6 men and 8 women) aged between 35 and 69 years (mean value 48.07+/-13.023 years) were enrolled in this case series. Seventeen implant sites were submitted to flapless procedure. The connective punch (CP) was harvested with a motor-driven circular tissue punch and then a full-split dissection was executed, in order to create a deep pouch, beyond the mucogingival junction, on the V/B side. In this recipient site the CP was placed. The normal flapless surgical protocol was used; implants were inserted and covered with transgingival healing cap screws. GT and KTW were measured: both immediately before and after surgery; at the time of the prosthetic finalization (3-4months, respectively, for mandible and maxilla); 1 year post surgery follow-up. GT was measured at 1 mm, 2 mm and 5 mm on the V/B side, from the outline of the punch. Both KTW and GT at 1 and 2 mm can be effectively increased, while no significant effects for GT at 5 mm can be expected from this technique. Furthermore, the mean values of KTW and GT at 1 mm and 2 mm show significant increases at 3-4 months post-operative, while no further significant increments are shown at 1 year post-operative follow up. The Authors recommend the use of the MCTP technique to reduce the number of aesthetic complications and soft tissue defects in flapless implant surgery. Longer follow-ups are needed to evaluate the stability of peri-implant tissues over time. PMID- 27469546 TI - Guided bone regeneration by means of a preformed titanium foil: A case of severe atrophy of edentulous posterior mandible. AB - The aim of this case report was to evaluate the potential of preformed titanium foil (PTF) as membrane, used together with a mouldable allograft paste, for guided bone regeneration in a case of severe mandibular posterior atrophy involving the alveolar nerve. In order to create a rigid barrier to the competitive growth of soft tissues and a stable volume for the colonization of the osteoprogenitor cells, a foil of pure titanium was pre-shaped by means of a stereolithographic model, obtained from a CT-scan of the patient. This procedure showed promising results, allowing to maximize the outcome and simplifying the surgical phase. PMID- 27469547 TI - Retrospective study on bone-level and soft-tissue-level cylindrical implants. AB - The purpose of this prospective clinical study was to evaluate the survival rate (SVR - i.e. fixtures still in place at the end of the observation period) and success rate (SCR - i.e. bone resorption around implant neck) of two cylindrical implant systems. Both systems were equipped with a tapered connection, one requiring a bone-level (BL) placement, while the other a soft-tissue-level (STL) placement. In the period between January 1996 and October 2011, a total of 150 implants (76 in females and 74 in males, mean age 60+/-11 years) were inserted. The mean post-surgical follow-up was 84+/-47 months. Several parameters were evaluated as potential outcome conditioners: age, gender, diabetes, smoking, periodontitis, type of edentulism, replaced tooth, jaw location (i.e. maxilla or mandible), bone graft, immediate loading, post-extractive, type of prosthesis, implant diameter and length. An SPSS program was used for statistical analysis. Only two fixtures were lost, therefore SVR was 98.7%. SCR, expressed through the mean marginal bone loss, was 92%. The mean peri-implant bone loss was 0.121.47 mm for BL implants and 0.041.3 mm for STL implants. None of the studied variables had a statistical significant impact on SVR or SCR. Cylindrical implants are reliable for oral rehabilitation. PMID- 27469548 TI - The influence of ?conical plus octagonal? internal connection on implant survival and success rate: a retrospective study of 66 fixtures. AB - Implant oral rehabilitation has become one of the most successful dentistry techniques over the last 30 years. However, peri-implantitis is the most important complication in implant dentistry. Peri-implantits can be caused by inadequate implant-abutment connections (IAC). The aim of our study is to evaluate the influence of ?conical plus octagonal? (i.e. I-Fix connection) on implant survival and success rate. All the implants included in this study were of a completely new type (I-Fix implants and abutments by FMD Falappa Medical Devices S.p.A. Rome, Italy). Sixty-six implants were inserted in males and females. The implants were of different diameters and lengths, inserted both in the mandible and in the maxilla with immediate or delayed loading, with guided bone regeneration (GBR), and post-extractive surgery. All implants were provided with I-Fix connection, 64 abutments using passing screws and 2 using full screws. None of the 66 implants were lost (i.e. survival rate - SVR = 100%). Cox regression analysis demonstrated that diabetes (p=0.0074), GBR (p=0.0115), maxilla (p=0.0117) and smoking (p=0.0194) have a statistical significant impact on clinical outcome (i.e. greater bone resorption around implant neck). Our data show that I-Fix connection did not influence SVR. This finding demonstrates that I-Fix design seemed to significantly affect the survival rate of the implants in a recent meta-analysis. In spite of the limits of our study, I-Fix connection has been demonstrated to be efficient in closing the gap between implant and abutment and maintaining a good connection over time. PMID- 27469549 TI - Clinical outcome of 215 transmucosal implants with a conical connection: a retrospective study after 5-year follow-up. AB - The purpose of this retrospective clinical study was to evaluate the survival rate (i.e. SVR ? fixtures still in place at the end of the observation period) and success rate (i.e. SCR - bone resorption around implant neck) of an implant system characterized by cylindrical and tapered implants, both types of implant being equipped with a conical connection with an internal octagon (COC), both implant types having a 1.8 mm smooth neck, positioned above the bone crest level. A total of 65 subjects received 215 COCs between January 1996 and October 2011. All COCs were placed and restored by three experienced dental surgeons. The mean follow-up was 84+/-44 months. The patients involved in the study were both male (30) and female (35), of whom 30 were smokers (less than 20 cigarettes/day) and none was diabetic. The implants differed in terms of diameter and length, and were inserted both in the mandible (97) and in the maxilla (118). Sixty-seven implants were single tooth rehabilitations, and 148 prosthetic bridges. Fourteen had guided bone regeneration (GBR), and 10 were placed in post-extractive sites. Forty of the implants were provided with passing-screw abutments and 175 with full-screw abutments. The data were analyzed using descriptive statistics. None of the implants failed before prosthetic restoration, resulting in an SVR=100% after loading. The radiographic and clinical data revealed well-maintained, hard and soft tissue around the COCs, with an SCR=92.6%. Cox regression analyses did not detect any variables with statistical impact on the clinical outcome. In conclusion, Shiner XT implants are reliable tools for oral rehabilitation. PMID- 27469550 TI - Guided bone regeneration in distal mandibular atrophy by means of a preformed titanium foil: a case series. AB - The aim of this case series was to evaluate the clinical outcome of preformed titanium foil (PTF) to perform guided bone regeneration (GBR) in posterior mandibular atrophies. Thirteen patients (4 male; 9 female; mean age 58.85+/-10.16 years), with class II division C atrophy, according to Misch, were selected to perform GBR by means of PTF, using a moldable allograft paste as graft material. The devices, made of a 0.2mm thick pure titanium foil, were pre-shaped using stereolithographic models obtained from CT-scan of the patients? recipient sites. In the second stage, performed at 6.35+/-2.15 months, 23 cylindrical two-piece implants were placed and the devices removed. At four months, the implants were exposed and submitted to progressive prosthetic load for a span of 4 months. The cases were finalized by means of metal-ceramic cementable restorations. The post finalization follow-up was at 12 months. Survival rate (i.e. SVR) was 100% since no fixtures were lost. At the one-year follow up, the clinical appearance of the soft tissues was optimal and no pathological signs on probing were recorded. The success rate (i.e. SCR) was 82.6% and the average peri-implant bone reabsorption was 0.99+/-0.59 mm. The results suggest good potentialities of this method for bone volume augmentation in distal mandibular atrophies, allowing to maximize the outcome and simplifying the surgical phase. PMID- 27469551 TI - Prevention of bacterial leakage at implant-abutment connection level: an in vitro study of the efficacy of three different implant systems. AB - Peri-implantitis is the main cause of implant failures. Peri-implantitis is provoked by the presence of bacterial infiltration around Implant-Abutment Connection (IAC). Reduction of bacterial leakage may be achieved by improving the accuracy and precision of the two pieces of IAC. The aim of the present in vitro study was to evaluate bacterial microleakage from the inside to the outside of the IAC, testing the efficacy of three new designs of internal conical connection (FN - nano-fix -, NQ - uNiQo - and Elisir implant systems by FMD, Rome, Italy). To identify the efficacy of three new IAC, the passage of genetically modified Escherichia coli across IAC was evaluated. A total of 17 implants were used (5 FN, 6 NQ and 6 Elisir). All implants were immerged in a bacterial culture for 48 h and bacteria amount was then measured inside and outside IAC with Real-time PCR. Bacterial quantification was performed by Real-Time Polymerase Chain Reaction using the absolute quantification with the standard curve method. In all the tested implants, bacteria were found in the inner side, with a median percentage of 1.9% FN, 1.4% NQ and 2.6% Elisir. The analysis revealed that in both cases (internally and externally), bacteria grew in the first 48 hours but subsequently started to die, probably due to nutrient consumption. Of the three, the most efficacious connection was NQ. Within the limitations of this study, it was concluded that the best implant connection reducing bacterial leakage al IAC level was NQ (NQ implant system by FMD, Rome, Italy). PMID- 27469552 TI - The use of resorbable heterologous cortical lamina as a new sinus lift floor: a technical note. AB - Some graft materials such as a heterologous porcine cortical lamina have an excellent capacity in creating recipient sites that can be filled with cortico spongious collagenated bone paste that reabsorbs, allowing for the reformation of good-quality bone. In this work a technique is proposed which makes use of resorbable cortical lamina in order to create a new sinus floor that can be filled with cortico-spongious bone paste. The adequate vascularisation of the graft combined with the integration of the lamina, which does not need to be removed, makes it possible to propose this technique as a potential alternative to those used so far. PMID- 27469553 TI - The use of resorbable cortical lamina and micronized collagenated bone in the regeneration of atrophic crestal ridges: a surgical technique. Case series. AB - Some graft materials, such as micronized and collagenated bone, have an excellent capacity to be reabsorbed, allowing for the reformation of good-quality bone, but do not have the mechanical characteristics that would allow for stability in terms of shape and size. In this study, a technique is proposed which makes use of resorbable cortical lamina in order to create recipient sites that can be filled with micronized collagenated bone paste. The adequate vascularization of the graft combined with the integration of the lamina, which does not need to be removed, makes it possible to propose this technique as a potential alternative to those used to date. PMID- 27469554 TI - Oxygen high level laser therapy is efficient in treatment of chronic periodontitis: a clinical and microbiological study using PCR analysis. AB - In periodontology, lasers have been suggested for the photodynamic therapy (PDT). Such therapy can be defined as the inactivation of cells, microorganisms or molecules induced by light and not by heat. The aim of our study is to assess the effect of Oxygen high-level laser therapy (OHLLT) in removing all bacterial deposits on root or implant surface by means of mechanical instrumentation and laser irradiation. OHLLT has two effects on targeted bacteria and tissues, decontamination and biostimulation. A total of 33 patients were randomly selected with a diagnosis of chronic periodontitis. The patients enrolled were 16 females and 17 males, six smokers and 4 diabetic patients. For each patient a periodontal charting was performed, assessing probing depth, plaque index and bleeding on probing at baseline and after 6 months. Microbiological analysis were performed with PCR Real Time, using paper tips to withdraw gingival fluid in periodontal pockets before and after treatment, at baseline and after 6 months. All patients were treated with OHLLT at baseline, after 1 week, after 2 weeks and every month for 6 months. After 6 months, all periodontal pockets were treated successfully, without complications and no significant differences in results. All clinical parameters showed an improvement, with a decrease both of plaque index (average decrease of 75%), bleeding on probing (average decrease of 62%) and probing depth (average decrease of 1.8 mm). After the treatment, a remarkable decrease in bacteria amount, both for each species and for total bacteria was observed except for Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis demonstrating that this laser protocol is effective on periodontitis treatment. OHLLT is efficient in treatment of chronic periodontitis as demonstrated by clinical and microbiological parameters, going beyond the traditional periodontal therapy. PMID- 27469555 TI - Effects of laser biostimulation on the epithelial tissue for keratinized layer differentiation: an in vitro study. AB - Gingival augmentation techniques proposed in the international literature do not exclude a surgical component, which determines consequent post-surgical discomfort and results are not always predictable. In recent years, the introduction of laser biostimulation has led to a less invasive approach, particularly in the treatment of periodontally compromised patients, limiting the surgical phase to seriously compromised cases, with regeneration techniques for the restoration of a correct periodontal tissue anatomy. The aim of this in vitro study is to establish the validity of laser biostimulation in order to develop the epithelial keratinized layer of the tissue by stimulating fibroblasts keratinocytes organotypic cultures and fibroblasts and keratinocytes mono cultures. We created two groups (test and control), each one composed of 3 fibroblast cultures, 3 keratinocyte cultures and 3 organotypic cultures. We performed laser irradiation of test group with Wiser Doctor Smile Lambda, Flat Top Handpiece, at 50 J/cm2 of fluency with one application every 40 h for a total of 5 applications. Forty-eight h after the last laser application, we investigated the presence and amount of keratins 5 and 8 with citofluorymetric and western blotting analyses. Analyses showed an increase in keratin synthesis in test group cultures, showing a remarkable increase in production of keratin 8 in co-cultures test. Laser biostimulation can considerably enhance keratin synthesis when applied with high energy doses and repeated applications to keratinocytes-fibroblasts co-cultures. PMID- 27469556 TI - Low-level laser therapy and invisible removal aligners. AB - It seems that Low Level Laser Therapy (LLLT) stimulates orthodontic tooth movements, increasing the alveolar bone turnover. The aim of this study is to evaluate how LLLT can influence the orthodontic treatment with invisible removal aligner. A sample of 21 subjects was divided into two groups, a laser group (10 patients) and a control group (11 patients). All subjects were instructed to wear each aligner 12 hours a day for 2 weeks. Laser external bio-stimulation was given in the laser group every second week. The laser group successfully finished the treatment, while at 3rd ? 5th aligner the control group did not finish the treatment. Laser treatment seemed to be better than treatment without laser. LLLT combined with aligners is able to favour, in 12 hours, the same tooth movement obtained by wearing the aligner 22 hours a day, according to the traditional protocol. This aspect could be useful for those patients who prefer not to use the aligners during the day. LLLT makes invisible removal aligner treatment more comfortable also because during the day the patients have to wear the aligners less hours than the treatment without laser. PMID- 27469557 TI - Correlation between dysfunctional occlusion and periodontal bacterial profile. AB - The aim of this study is to compare the evolution in bacterial profile at evident periodontitis sites following two types of treatment - oral hygiene procedures alone (Group 1) and oral hygiene plus occlusal adjustment through selective grinding (Group 2). The presence of periodontal disease was ascertained by clinical examination (redness, oedema, probe depth, bleeding-on-probing). Bacterial profiling was carried out via phase contrast microscopy on plaque samples taken from periodontitis sites in both patient groups. Bacterial populations were characterized in terms of coccus content before (T0) and at monthly intervals after treatment (T1-6) over a period of six months. Static and dynamic occlusion was evaluated only in Group 2 patients. Whereas the poor pre treatment bacterial profile was re-established progressively over the evaluation period in Group 1 patients, coccus populations flourished in Group 2 patients, reaching healthy levels (>70%) two months after occlusal adjustment, and clinical examination confirmed an absence of periodontal inflammation in these patients. Occlusal adjustment can lead to a marked, stable improvement in periodontal health in terms of bacterial profile and clinical appearance, presumably by obviating tissue distress caused by occlusal dysfunction, thereby providing unfavourable conditions for bacterial growth. Bacterial profiling is an effective indicator of periodontal health. PMID- 27469558 TI - Evaluation of the efficacy of a new oral gel as an adjunct to home oral hygiene in the management of chronic periodontitis. A microbiological study using PCR analysis. AB - The use of chemical devices for non-surgical periodontal therapy has led to new treatment strategies aiming primarily at infection control and oral bacterial load. Over the last few decades adjunctive chemical devices has been subjected to many scientific and medical studies. The purpose of the present study was to assess the effect of a new oral gel named Parodongel on the red complex organisms using Polymerase Chain Reaction (PCR) for microbiological analysis. A total of 10 patients with a diagnosis of chronic periodontitis in the age group >25 years, were selected. None of these patients had received any surgical or non-surgical periodontal therapy and demonstrated radiographic evidence of moderate bone loss. Four non-adjacent sites in separate quadrants were selected in each patient for monitoring based on criteria that the sites will localize chronic periodontitis. Microbial analysis (MA) was performed at baseline and at day 15. Paired T-Test was used to detect statistical significant reduction of specific bacteria. The results showed statistically significant reduction of the overall bacterial loading and Treponema Denticola from baseline to day 15. Parodongel can be used as an effective local drug delivery together with oral home care in treatment of chronic periodontitis. PMID- 27469559 TI - Evaluation of the efficacy of a new oral gel containing carvacrol and thymol for home oral care in the management of chronic periodontitis using PCR analysis: a microbiological pilot study. AB - The use of chemical devices for domestic oral hygiene in periodontal patients has led to new treatment strategies aiming primarily at a control of infection. Over the last few years, carvacrol and thymol (CT) have been subjected to many scientific and medical studies. The purpose of the present study was to assess the effect of CT on the red complex bacteria using Polymerase Chain Reaction (PCR) for microbiological analysis. Five patients with a diagnosis of chronic periodontitis in the age group >25 years, were selected. None of these patients had received any surgical or non-surgical periodontal therapy and demonstrated radiographic evidence of moderate bone loss. After scaling and root planning, patients received a CT gel to be used at home. Four non-adjacent sites in separate quadrants were selected in each patient for monitoring, based on criteria that the sites localize chronic periodontitis. Microbial analysis (MA) was analyzed at baseline and at day 15. SPSS program was used for statistical purposes and a paired samples correlation was performed at the end of the observation period. Although an absolute reduction was observed among the studied bacteria (i.e. Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum, Campylobacter rectus and Total bacteria loading) none reach a statistical significant value. The present study demonstrated that CT gel has a small impact on oral biofilm. Additional studies are needed to detect the efficacy of CT gel. PMID- 27469560 TI - Why should patients with systemic disease and tobacco smokers go to the dentist? AB - Periodontal diseases (PD) affect about half of the adult population all over the world. PD is caused by bacterial infection which induces an inflammatory response with progressive destruction of the periodontal tissues and finally the loss of teeth. Tobacco smoking (TS), alcohol consumption, and systemic diseases (SDs), such as cardiovascular diseases, diabetes mellitus, respiratory diseases, osteoporosis, malnutrition and stress, are considered additional risk factors. This short review examines the potential causal association between PD, TS and SDs. There is strong evidence that PD is associated with an increased risk of SDs. In addition, many patients with SDs are also affected by PD, which can be mild or severe, and tobacco smokers manifest a greater risk of developing PD. The aim of this manuscript is to investigate the effects of periodontal therapy on the management of SDs and influence of TS on PD. This manuscript includes many randomized controlled trials and reviews to test the effects of different periodontal therapies for patients with SDs. A definite conclusion on the relationship between PD and SDs is lacking, however, there is sufficient evidence to justify periodontal treatment to prevent SDs; in fact, PD is prevalent in the middle-aged population and can have a significant impact on systemic health. PMID- 27469561 TI - The ecological catastrophe of oral diseases: a possible link between periodontitis and protozoa. AB - Periodontal disease (PD) is one of the prevalent diseases in the adult population. The ethiology of PD has never been completely understood, however, loss of balance between the host immune system and the microbial virulence of PD pathogens may be considered the trigger of PD. In fact, the immune system, activated by microbiological agents, attacks the host and not the biofilm bacteria, causing the destruction of periodontal tissue, alveolar bone and loss of teeth. Parasites may play an important role in the pathology of PD. The first studied and the most common parasite in the oral cavity is Entamoeba gingivalis. A possible link between E. gingivalis and PD has never been demonstrated completely, however E. gingivalis is infrequently found in people without PD. In addition, there is evidence that E. gingivalis could favour the onset and progression of PD. In conclusion, we can assert that E. gingivalis and PD may be correlated. This relationship can open new therapeutical approaches for treating PD, particularly in cases refractory to therapy. PMID- 27469562 TI - Bacterial load of periodontal pathogens among italian patients with chronic periodontitis: a comparative study of three different areas. AB - The aim of the present study was to evaluate the mean bacterial load of some periodontal pathogenic bacteria in Italian patients affected by chronic periodontitis. The sample consisted of 1,762 patients with a clinical diagnosis of chronic periodontitis based on the criteria of the American Academy of Periodontology sampled in the period 2013-2015; 1,323 patients were from Northern Italy, 317 from Central Italy and 122 from Southern Italy. Samples for microbiological analysis were collected from the four sites of the greatest probing depth in each patient and then processed by quantitative polymerase chain reaction. Periodontal pathogens have the following percentage respect to total bacteria load: Aggregatibacter actinomycetemcomitans 0.1%, Campylobacter rectus 2%, Fusobacterium nucleatum 8%, Porphyromonas gingivalis 6%, Treponema denticola 2% and Tannerella forsythia 1.5%. There are significant differences in bacterial load among the different geographical areas both for the total bacterial and for the single species. The results of our study in this Italian population showed that a different geographic distribution exists among periodontal pathogens. We hypothesize that these differences in bacterial load could be related to genetic and environmental factors. Additional studies are necessary to confirm these data and to get more insight on additional factors, which may play a role in periodontal pathogens in different geographic areas. PMID- 27469563 TI - Infectogenomics: lack of association between VDR, IL6, IL10 polymorphisms and ?red complex? bacterial load in a group of Italian adults with chronic periodontal disease. AB - Periodontitis is a multifactorial disease that, if untreated, may cause teeth loss. Clinicians and researchers have reported that genetic factors influence the clinical manifestations of periodontal disease (PD), modulating both inflammation of the mucous membranes and loss of alveolar bone. The acquisition of new nowledge about genetic susceptibility of PD, would directly impact on prognosis and treatment of the disease. In addition, a better understanding of PD pathogenesis could improve the diagnostic tools for the prevention and therapies for modulation of immune responses and treatment of PD. In this study, we evaluated genetic polymorphisms of VRD, IL6 and IL10 and amounts of periodontal pathogens in Italian adults affected by PD. We included 326 cases classified according the criteria of the American Academy of Periodontology. No significant differences in bacterial load were found in patients carrying PD susceptibility alleles of IL6, IL10 and VDR genes. In conclusion, no interaction between genetic factors and amount of periodontal pathogens in periodontal pockets were found in PD patients. PMID- 27469564 TI - Evaluation of light-emitting diode (LED-835 NM) application over human gingival fibroblast: an in vitro study. AB - Since the laser and photomodulation were discovered over 50 years, they have been used for many applications in medicine and in dentistry also. In particular, light-emitting diodes therapy (LT) achieved a great success in medical treatment and photo-therapy. In the decades, LT has been used for several therapeutic purposes. Many beneficial effects have been demonstrated in vitro and in vivo, including antibacterial, antiviral, antitumor, cell differentiation, immune potentiating and tissue repair activities. Beneficial effects of LT have also been observed in clinical settings. Although there are lots of cell culture studies in low-level laser therapy, there are only a few cell culture studies in LT that have similar characteristics. The aim of this study was to investigate the effects of LT on primary human gingival fibroblast cells (HGF) on elastin (ELN) gene activation using Real Time PCR. ELN gene activation is directly connected with elastin protein production and HGF functionality. Human gingival tissue biopsies were obtained from three healthy patients during tooth extraction. The gingival specimens were fragmented with a scalpel and transferred in culture dishes containing Dulbecco?s modified Eagle medium supplemented with 20% fetal calf serum (FBS) and antibiotics, i.e. penicillin 100U/ml and streptomycin 100MUg/ml. Cells were incubated in a humidified atmosphere of 5% CO2 at 37C. The medium was changed the next day and twice a week. After 15 days, the samples of gingival tissue were removed from the culture dishes. Cells were harvested after an additional 24 h incubation. Human gingival fibroblasts at the second passage were seeded on multiple 6-well plates. The cells stimulation was performed with a light-emitting diodes (LEDs) medical device type E-Light. The LED irradiation seems to be directly correlated with the elastin (ELN) gene activation. Interestingly, ELN gene expression in the cultured human gingival fibroblasts seems to be inversely related to the patients? age; in fact, its expression tends to decrease with aging. In summary, the result of the present study shows that LED irradiation promoted ELN gene expression more in elderly than in younger adults. PMID- 27469565 TI - Oral squamous cell carcinoma: diagnostic markers and prognostic indicators. AB - OSCC is the most frequent malignant tumour of the oral cavity, accounting for more than 90% of malignant tumours of this anatomic region and it often arises from precursor lesions. Aside from tobacco and alcohol consumption, further determinants have been considered to increase the risk of OSCC development, such as micronutrient deficiencies, chronic traumatism, poor oral hygiene and viruses. Recurrence, survival and conversely, mortality depends on numerous and different biological, histological, macroscopic and microscopic factors that have been investigated in order to define causes, to help diagnosis and to refine appropriate treatments that perfectly fit with the different features of OSCCs. For this purpose, during the last decades, the improvement of scientific technologies and molecular analyses have allowed to investigate markers and genetic and epigenetic factors, in order to clarify their responsibilities related to early diagnosis and OSCC progression and prognosis in order to address them as targets in future selective and individually-shaped therapies. This review will focus on the etiology, advances in diagnostic markers and prognostic indicators for oral cancers. PMID- 27469566 TI - Lights and shadows of bone augmentation in severe resorbed mandible in combination with implant dentistry. AB - Edentulous mandible frequently undergoes severe bone atrophy with problems of prosthetic instability. Instability of the lower denture may cause difficulties with eating and speech, ulcerations of the oral mucosa for lower denture trauma, loss of facial vertical dimension. These problems may be solved by bone augmentation of severe resorption of edentulous mandible. The aim of this short review is to describe surgical techniques for bone augmentation of the severe resorption of edentulous mandible. In this paper, we define a severe resorption of edentulous mandible as a mandibular height in the symphyseal area of 12 mm or less as measured on a standardized lateral cephalogram. Bone grafts and distraction osteogenesis have allowed improving implantology from an experimental to a consolidate dental procedure. It is currently a valuable treatment modality in the prosthetic treatment of severe resorption of edentulous mandible. Numerous techniques have been developed for the rehabilitation of edentulous mandible with fixed or removable mandibular dentures. Today, the options for the restoration of the severe resorption of edentulous mandible with implants can be categorized as follows: insertion of short and narrow implants and a fixed or removable prosthesis; augmentation of the bone with the use of distraction osteogenesis or grafting procedures in combination with the insertion of dental implants loaded with fixed or removable prosthesis; placement of a transosteal dental implants supporting a denture. PMID- 27469567 TI - Success of immediate versus standard loaded implants: a short literature review. AB - Oral rehabilitation with implant-supported restorations has become a successful therapy resulting in high survival rate (SR). Recently, some reports have stated that submerged implants have no differences in SR compared to transmucosal implants. It was also reported that a reduction in timing of implant loading (from 12-24 weeks to 6-8 weeks) does not affect the predictability and SR of the implants. In particular, the reduction of the loading period is well accepted by the full edentulous patient, due to the functional and aesthetic problems related to denture wearing. The purpose of this report is to evaluate the SR of immediate loading implants (ILIs) compared to placing implants in native bone, with bone graft, in post-extraction sites, with the help of computer guided implant dentistry. The aim of this short review is therefore, to assess whether ILIs achieve similar clinical outcomes when compared to conventional loading protocols. As stated in preview reviews, we can affirm that there is no difference in SR at ILIs against delayed implants and with respect to placing implants in native bone, with bone graft, in post-extraction sites, with the use of computer guided implant dentistry. Keeping in mind the limitations of the present review, we can affirm that ILIs have a similar SR when compared to conventional loading protocols. PMID- 27469568 TI - A histologic assessment of a HYBENX(r) oral tissue decontaminant in vital pulp therapy in dogs. AB - The aim of this study was to assess HYBENX(r) Oral Tissue Decontaminant (HOTD) in treating vital pulp exposure in a canine model. The use of HOTD solution was compared to an accepted and standard regimen for vital pulp exposure, an application of a commercial calcium hydroxide product (Ca(OH)2). Both control and experimental treatments were followed by restoration with a commercial zinc oxide and eugenol obtundant intermediate restorative material and thermal insulator (ZOE). At 7 days there was 100% pulp vitality with HOTD and 50% with Ca(OH)2. New dentin formation was seen in 62.5% of the HOTD treated pulps and none of the Ca(OH)2 treatment group. The vital pulp exposures at day 21 post treatment with HOTD also showed significant improvement over Ca(OH)2 in the presence of odontoblasts, new dentin formation and pulp survivability. The presence of odontoblasts and new dentin was noted in 71% of the HOTD cases versus 50% of the survivable Ca(OH)2 cases. Furthermore, 100% of HOTD cases had vital pulps versus 62.5% of Ca(OH)2 cases. The 60-day specimens of both experimental and control techniques exhibited histologically similar appearances and were similar in outcomes. HOTD treatment at day 7 showed a significant positive difference, both in the formation of new dentin and tooth vitality. HOTD proved better for the post 21-day specimens and equivalent for the 60-day pulp specimens with no evidence of untoward tissue reactions or results. PMID- 27469569 TI - Bacteria prevalence in a large Italian population sample: a clinical and microbiological study. AB - The present study detects those bacterial species which are more strongly related to bleeding on probing, suppuration and smoking in periodontal-affected patients. Nine hundred and fifty-one patients with periodontal diseases were admitted to the Department of Periodontology and Implantology, Dental School of Bologna University where they underwent microbiological tests for six periodontal pathogens (Actinomyces actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, Fusobacterium nucleatum and Tannerella forsythia). Cluster analysis explored the variables that mostly influence both the presence and absolute?relative bacterial load. Logistic regression and multivariate linear regression quantifies these relations. The probability of recovering bacteria belonging to the Red Complex is greater by 25 48% in presence of bleeding on probing. When probing depth is less than 3 mm the probability of presence of each bacterial species is inferior in comparison with depth >6 mm both for Red Complex (of 20-37%), the Orange complex (of 41-61%) and Actinomyces actinomycetemcomitans (46%). Total bacterial cell count increases with pocket depth above all for the Red Complex. As Treponema Denticola and Tannerella Forsytia presence is associated with bleeding on probing and Prevotella intermedia presence with suppuration and smoking. The examination of these three as indicators of periodontitis evolution is suggested. PMID- 27469570 TI - An overview on bone reconstruction of atrophic maxilla: success parameters and critical issues. AB - Long-term success rate of implants inserted in atrophic maxilla is ensured through sufficient bone volume in edentulous sites. Reconstructive surgery is necessary before implant placement to regenerate bone defects caused by atrophy, dental trauma, extractions or periodontal disease. Success rate of implants is related to the correct position and angulation of implants in residual crest, so that height and thickness of bone augmentation can allow predictable results. The most popular surgical procedures to obtain bone augmentation are: bone grafts, guided bone regeneration, maxillary sinus floor elevation, and bone osteogenesis distraction. Bone graft is the gold standard technique to achieve bone augmentation of edentulous crests and to obtain appropriate bone volume and morphology. Guided bone regeneration is a surgical technique that uses barrier membranes to promote osteoblast cells proliferation and exclude other cells such as epithelium and connective tissue cells. Guided bone regeneration is often combined with bone grafting procedures. Sinus floor elevation procedures are elective treatments when there is insufficient bone height for implant insertion in maxilla. Sinus floor elevation for implant insertion in maxilla in conjunction with autologous bone was described with long-term follow-up. Bone osteogenesis distraction is the process of bone generation between two bone segments in response to tensile stress. The aim of this short review is to analyze the different methods of increasing bone in atrophic maxilla: bone grafts, guided bone regeneration, maxillary sinus floor elevation, and bone osteogenesis distraction. PMID- 27469571 TI - Radiofrequency treatments: what can we expect? AB - Among non-ablative procedures in aesthetic medicine, the radiofrequency (RF) is one of the most popular for the treatment of face and body skin laxity. It can be classified as a physical bio-stimulation that produces a temperature increase on biological structures, using electromagnetic waves. The term encompasses devices having substantial differences in energy, wavelengths, handpieces dimension and structure. Moreover, for some of these, the protocols are only partially defined. The aim of this short review is to clarify some aspecst of the RF therapy starting from the physics, passing through the mechanism of action and finally, with the most suitable protocols. Contrary to mechanic waves, electromagnetic waves, physics are always transversal to the impulse and this leads to the different energy distribution in capacitive (monopolar) or resistive (bi- or multi-polar) applications. The thermal damage as therapeutic effect is a postulate that needs to be discussed and the same is true for the terms ?non surgical? and ?non-ablative?, often recurrent in the scientific literature. Protocols must be optimized according to the machine and the patient, keeping in mind the possibilities of biostimulation in terms of immediate improvement and of long lasting investment in skin rejuvenation. It is mandatory to understand the possibilities and limitations of each device to perform useful, safe and correct medical treatments. PMID- 27469572 TI - Non-ablative radio-frequency rejuvenation: a histological and bio-molecular report. AB - Radiofrequency machines for medical use are known to produce moderate clinical improvement of skin laxity without invasive procedures. Numerous equipment with different characteristics have been proposed after the introduction in 2002 of the first FDA approved device. This report is aimed to test if RF treatment is effective when performed at low frequency and low energy level. Two RF treatments were performed unilaterally 7 and 2 days before a planned eyebrow lifting surgery, with a radiofrequency device with 0.52 to 0.7 MHz frequencies, maximum energy of 200 W, used at 40% of its power. A bipolar handpiece with a diameter of 30 mm and a maximum power of 9-9.5 W was massaged along the temporal area for 10 min. Skin samples of treated and untreated sides were collected during surgery and processed for histologic examination and RT-PCR analysis, to test differences in gene activation in a panel of proteins that are relevant in extracellular matrix of dermal connective tissue. The histological examination of the samples showed that the treatment induced a loss of the typical oriented structure in the reticular dermis. The study through RT-PCR evidenced that ELN, the gene codifying for Elastine was strongly enhanced. Some collagen-tested genes (COL1A1, COL3A1 and COL9A1) were inhibited by the treatment, whereas COL2A1 and COL11 were activated. The genes responsible for Metallo-proteases (MMP) 2, 3 and 13 were depressed, while the MMP9 was stimulated. Gene codifying for Hyaluronic synthase 1 (HAS1), Hyluronidase 1 (HYAL1), Neutrophyl elastase (Elane), Desmoplakin (DSP) and GDF6 were inhibited. Insulin like growth factor (IGF1) gene activity was enhanced. RF treatment, with the tested non-ablative equipment, produced histological effects and change in DNA expression of some extracellular matrix related genes, confirming the biostimulatory role of this procedure. PMID- 27469573 TI - Design of an anti-adhesive surface by a pilicide strategy. AB - Biofilm formation on surfaces is one of major problems in medical, cosmetic and food industries. Nowadays any efficient treatment is known, as consequence, research of new strategies to inhibit biofilm formation is urgent. Recently, virstatin, which interferes with bacterial type IV pili formation, has demonstrated a capacity to inhibit biofilm formation developed by Acinetobacter baumannii after 24h. In this study, we aim to elaborate anti-adhesive surfaces preventing biofilm development by the covalent immobilization of virstatin on silicon surface. Surfaces were functionalized by self-assembled monolayers of two aminosilanes (11-aminoundecyltrimethoxysilane (AUTMS) and 3 aminopropyltrimethoxysilane (APTMS)). Then, virstatin (2mM) was immobilized on those modified surfaces. We observed an increase in surface hydrophobicity of AUTMS modified substratum leading to an increase of A. baumannii ATCC 17978 adhesion (after 4h). Immobilization of virstatin molecule on APTMS modified surface was efficient to decrease cell attachment by 32.1+/-5.7% compared to unmodified surface. As virstatin is known to inhibit type IV pili formation in solution, the observed decrease of bacterial adhesion might be due to this pilicide action. We also demonstrated that hydrophobicity of strains plays a role in adhesion according to surface properties. In conclusion, immobilized virstatin succeeded to inhibit bacterial attachment of various Acinetobacter baumannii strains comparing to APTMS modified support. PMID- 27469574 TI - Interfacial molecular interactions based on the conformation recognition between the insoluble antitumor drug AD-1 and DSPC. AB - In this study, molecular interactions between the anti-cancer agent 20(R)-25 methoxyl-dammarane-3beta, 12beta, 20-triol (AD-1) and phospholipid 1,2-Distearoyl sn-glycero-3-phosphocholine (DSPC) were investigated using the Langmuir film balance technique. The characteristics of binary Langmuir monolayers consisting of DSPC and AD-1 were conducted on the basis of the surface pressure-area per molecule (pi-A) isotherms. It was found that the drug was able to become efficiently inserted into preformed DSPC monolayers, indicating a preferential interaction between AD-1 and DSPC. For the examined lateral pressure at 20mN/m, the largest negative values of DeltaGex were found for the AD-1/DSPC monolayer, which should be the most stable. Based on the calculated values of DeltaGex, we found that the AD-1/DSPC systems exhibited the best mixed characteristics when the molar fraction of the AD-1 was 0.8; at that relative concentration, the AD-1 molecules can mix better and interact with the phospholipid molecules. In addition, the drug-DSPC binary supramolecular structure was also deposited on the mica plates as shown by atomic force microscopy (AFM). Finally, molecular docking calculations explained satisfactorily that, based on the conformations interactions (conformation recognition), even at an AD-1/DSPC molar ratio as high as 8:2, the interfacial stabilization of the AD-1/DSPC system was fairly strong due to hydrophobic interactions. A higher loading capacity of DSPC might be possible, as it is associated with a more flexible geometrical environment, which allows these supramolecular structures to accept larger increases in drug loading upon steric binding. PMID- 27469575 TI - Participation of purines in the modulation of inflammatory response in rats experimentally infected by Cryptococcus neoformans. AB - The present study was carried out to assess the participation of purines in the activation and modulation of inflammatory response of rats experimentally infected by Cryptococcus neoformans. Twenty four Wistar rats were divided into two groups of 12 animals each: Group A - uninfected control group and Group B - infected by C. neoformans. Blood was collected 20 and 50 days post-infection (PI) from six animals of each group in order to verify purine levels (adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine (ADO), inosine (INO), hypoxanthine (HYPO), xanthine (XAN) and uric acid (URIC)). ATP levels were significantly increased (P < 0.05) in serum from infected animals on days 20 and 50 PI, as well as adenosine levels after 20 days PI on rats. On day 50 PI, levels of adenosine and uric acid were also reduced, but the levels of inosine and xanthine increased in animals infected by the fungus (P < 0.05). Therefore, it was possible to conclude that the purine levels in serum were altered and that these changes may be able to influence the pathogenesis of the disease caused by C. neoformans due the participation of purines (ATP and adenosine main) in the activation and modulation of inflammatory response. PMID- 27469576 TI - CYP2D6 *6/*6 genotype and drug interactions as cause of haloperidol-induced extrapyramidal symptoms. AB - A 66-year-old male Caucasian, received 1 mg of haloperidol orally and rapidly developed severe iatrogenic extrapyramidal symptoms. Treatment was immediately discontinued, and the side effects resolved. Haloperidol is mainly metabolized by Phase I CYP2D6 and to the lesser extent by CYP3A4 and by Phase II UGT2B7 enzymes. Genotyping was performed revealing CYP2D6*6/*6, CYP3A4*1/*1, and UGT2B7 -161 C/T genotypes, implicating poor, extensive and intermediate metabolism, respectively. Of the CYPs, haloperidol is metabolized by CYP2D6 and CYP3A4 primarily. It was the introduction of ciprofloxacin which was a trigger for the development of adverse drug reaction due to inhibition of CYP3A4, which was in presented patient main metabolic pathway for haloperidol since he was CYP2D6 poor metabolizer. Presented case report highlights the importance of genotyping. Pharmacogenetics testing should be considered when drug toxicity is suspected, polymorphic metabolic pathways used and drugs concomitantly applied. PMID- 27469577 TI - The Complexity of the His Bundle: Understanding Its Anatomy and Physiology through the Lens of the Past and the Present. AB - In this paper, we describe the anatomy and physiology of the His bundle and describe the mechanisms by which permanent His-bundle pacing can be accomplished. PMID- 27469578 TI - Usefulness of blood and cerebrospinal fluid laboratory testing to predict bacterial meningitis in the emergency department. AB - INTRODUCTION: The classic clinical presentation of bacterial meningitis (BM) is observed in less than half of the cases in adults, and symptoms are less specific in children, the elderly or immunocompromised, and other chronic patients. The usual signs and symptoms do not provide optimal sensitivity and specificity for distinguishing possible BM from viral meningitis (VM), which may lead to a delay in the appropriate antimicrobial therapy. Society therefore stands to benefit from the development of effective, objective, and rapid tools able to predict and identify patients with BM. These tools include laboratory tests for blood and cerebrospinal fluid (CSF). The aim of this review is to summarise recently published scientific evidence in order to clarify existing controversies and compare the usefulness and diagnostic ability of the different parameters used to predict BM. DEVELOPMENT: Systematic search of the main bibliographic databases and platforms to identify articles published between January 2000 and January 2016. We selected 59 articles that meet the objectives of this review. CONCLUSIONS: CSF lactate, proportion of polymorphonuclear leukocytes, and CSF glucose, as well as serum procalcitonin (PCT), are the independent factors most predictive of bacterial aetiology. The model that combines serum PCT and CSF lactate achieves the highest predictive power for BM, with a sensitivity and specificity exceeding 99%. We should consider BM when CSF lactate >33 md/dL and/or PCT>0.25ng/mL. PMID- 27469579 TI - Analysis of the new code stroke protocol in Asturias after one year. Experience at one hospital. AB - INTRODUCTION: Prehospital code stroke (CS) systems have been proved effective for improving access to specialised medical care in acute stroke cases. They also improve the prognosis of this disease, which is one of the leading causes of death and disability in our setting. The aim of this study is to analyse results one year after implementation of the new code stroke protocol at one hospital in Asturias. PATIENTS AND METHODS: We prospectively included patients who were admitted to our tertiary care centre as per the code stroke protocol for the period of one year. RESULTS: We analysed 363 patients. Mean age was 69 years and 54% of the cases were men. During the same period in the previous year, there were 236 non-hospital CS activations. One hundred forty-seven recanalisation treatments were performed (66 fibrinolysis and 81 mechanical thrombectomies or combined treatments), representing a 25% increase with regard to the previous year. CONCLUSIONS: Recent advances in the management of acute stroke call for coordinated code stroke protocols that are adapted to the needs of each specific region. This may result in an increased number of patients receiving early care, as well as revascularisation treatments. PMID- 27469580 TI - Streptomyces pini sp. nov., an actinomycete isolated from phylloplane of pine (Pinus sylvestris L.) needle-like leaves. AB - A novel siderophore-producing actinomycete, designated PL19T, was isolated from the Scots-pine needle-like leaves collected from TNAU campus, Coimbatore, India. The isolate was chemoorganotrophic in nutrition and able to grow at 30 degrees C, and the optimum pH and NaCl facilitated the growth pH 6-11 and 0-8 % (w/v), respectively. The cells are filamentous and the mycelia formed are basically of wide and intricately branched substrate mycelium from which aerial mycelia arises, later gets differentiated into spores that are warty and arranged spirally. The 16S rRNA gene of strain PL19T was sequenced and was highly similar to the type strains of species of the genus Streptomyces, including Streptomyces barkulensis RC1831T (98.8 % pairwise similarity), Streptomyces fenghuangensis GIMN4.003T (98.2 %), Streptomyces nanhaiensis SCSIO 01248T (98.0 %), Streptomyces radiopugnans R97T (97.9 %), Streptomyces atacamensis C60T (97.8 %) and Streptomyces macrosporus NBRC 14749T (97.2 %), all of which were subjected to taxonomical characterization using a polyphasic approach. The strains showed unique carbon utilization patterns, and it possesses iso-C16 : 0 anteiso-C15 : 0 and anteiso-C17 : 0 as a major cellular fatty acids. The cell-wall was dominated with ll-type diaminopimelic acid, and the menaquinone type was MK-9(H6, H8). These chemotaxonomic evidences placed strain PL19T within the genus Streptomyces. The determination of G+C ratio (69.5 mol%) and DNA-DNA hybridization values (13.4 31.8 % with the phylogenetically related species) helped in further hierarchical classification of strain PL19T. Based on morphological, physiological and chemotaxonomic data as well as DNA-DNA hybridization values, strain PL19T could be distinguished from the evolutionarily closest species currently available. All these collective data show that strain PL19T represents a novel species of the genus Streptomyces, for which the name Streptomyces pini sp. nov. is proposed. The type strain is PL19T (=NRRL B-24728T=ICMP 17783T). PMID- 27469581 TI - What can the Canadians and Americans learn from each other's health care systems? AB - Numerous papers have been written comparing the Canadian and US healthcare systems, and a number of health policy experts have recommended that the Americans implement their single-payer system to save 12-20% of its healthcare expenditures. This paper is different in that it assumes that neither country will undertake a significant philosophic or structural change in their healthcare system, but there are lessons to be learned that are inherent in one that could be a major breakthrough for the other. Following the model in Canada and in Western Europe, the USA could implement universal health insurance so that the 32.0 million (2015) Americans still uninsured would have at least minimal coverage when incurring medical expenditures. Also, the USA could use smart cards to evaluate eligibility and to process health insurance claims; these changes resulting in an estimated 15% reduction in US health expenditures without adversely effecting access or quality of care. Such a strategy would result in the eventual loss of 2.5 million white-collar jobs at hospitals, physician offices and insurance companies, a long-term economic gain. Only a few would agree with the statement that Canada already functions with a multi-payer reimbursement system as evidenced by (1) a federal-provincial, tax-supported plan, administered by each of the provinces, providing universal coverage for hospital and physician services and (2) roughly 60% of its residents receiving employer-paid health insurance benefits, underwritten primarily by investor-owned plans, that are less than effective to reimburse for pharmaceuticals, dental and other healthcare services. What could be learned from the USA and particularly from Western European countries is possibly implementing an approach, whereby at least upper-income Canadians could opt out of their federal-provincial plan and purchase private insurance coverage - being eligible for far more comprehensive "private" benefits for hospital, physician, pharmaceutical, dental and other healthcare services. Aside from generating billions of additional needed revenues from the private sector, it could (1) help eliminate long waits for non-emergent physicians' care by appointing newly minted specialists to their medical staffs; (2) offer prompt admissions for elective cases to "private" wings of hospitals; (3) increase available funding for what is currently an undercapitalized system; (4) enhance the system's sluggish operations; and (5) encourage more competition among various providers. Although such a two-tier approach, such as available in the USA and elsewhere, is politically dead on arrival in Canada today, private insurance being already legal and commonly available there. Interestingly, this recommended solution is utilized in most western European countries where there is a higher percentage than in Canada of public (versus private) funding of their total health expenditures. Because of various vested interests, attempts to implement any of the aforementioned proposals will undoubtedly result in considerable political rancor. There is greater likelihood, however, that the Canadians because their need to be more effective and efficient in their delivery of care, and their overall long-term fiscal outlook will agree to the further privatization of their healthcare system before the Americans will mandate universal access, use the smart card to process insurance eligibility and claims or will impose price controls on high-tech services and on pharmaceuticals. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27469582 TI - Scleroderma Lung Study II-clarity or obfuscation? PMID- 27469584 TI - Reliability of parent report measures of sleep in children with Down syndrome. AB - BACKGROUND: Behavioural sleep disturbances are common among children with Down syndrome (DS). However, tools used to detect and evaluate behavioural sleep disturbances were developed for typically developing children and have not been evaluated for use among children with DS. The current study evaluates the psychometric properties of three measures of behavioural sleep disturbances that are currently being used with children with intellectual and developmental disabilities, including children with DS. METHOD: Caregivers of 30 children with DS rated their child's sleep with the Behavioral Evaluation of Disorders of Sleep (BEDS), Children's Sleep Habits Questionnaire (CSHQ) and Sleep Disturbances Scale for Children (SDSC). Caregivers also provided information on sleep diagnoses and completed a 7-night sleep and behaviour diary. RESULTS: The study investigated the rate of detecting sleep problems, internal consistency, and convergent and concurrent validity of the BEDS, CSHQ and SDSC. Children with DS were reported to exhibit behavioural sleep disturbances at different rates depending on the measure used; 0% BEDS, 79.3% CSHQ and 17.2% SDSC. Internal consistency was comparable for all three measures for their total scores. However, when evaluating the internal consistency of subscale scores, those on the CSHQ and SDSC performed more strongly. The subscales of the CSHQ performed best when evaluating convergent and concurrent validity, with the SDSC subscales performing moderately well. CONCLUSION: The study findings suggest that, among children with DS, the CSHQ and its subscales performed in a psychometrically sound and theoretically appropriate manner in relation to other measures of sleep, medical history of sleep problems, and daily reports of sleep and associated behaviours. The SDSC performed moderately well. When evaluating behavioural sleep disturbances among children with DS, the CSHQ is recommended based on its stronger psychometric properties. PMID- 27469583 TI - Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. AB - BACKGROUND: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide. METHODS: This randomised, double blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2.0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129. FINDINGS: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2.19 in the mycophenolate mofetil group (95% CI 0.53 3.84) and 2.88 in the cyclophosphamide group (1.19-4.58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0.24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0.019). INTERPRETATION: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech. PMID- 27469585 TI - Subacromial anaesthetics increase asymmetry of scapular kinematics in patients with subacromial pain syndrome. AB - BACKGROUND: Subacromial pain syndrome (SAPS) and scapular dyskinesis are closely associated, but the role of pain is unknown. We hypothesized that pain results in asymmetrical scapular kinematics, and we expected more symmetrical kinematics after infiltration of subacromial anaesthetics. OBJECTIVE: To investigate the effect of subacromial anaesthetics on scapular kinematics in patients with SAPS. DESIGN: Observational cohort study. METHODS: We evaluated shoulder kinematics in 34 patients clinically and radiologically (magnetic resonance arthrography) identified with unilateral SAPS using three-dimensional electromagnetic motion analysis (Flock of Birds). Scapular internal rotation, upward rotation and posterior tilt of the affected shoulder were compared with the kinematics of the unaffected shoulder and following subacromial anaesthetics. Additionally, the association of pain (Visual Analogue Scale, VAS) and scapular rotation was analysed. RESULTS: Compared with the contralateral healthy shoulder, 5 degrees more (95% CI 0.4-9.7, p = 0.034) scapular internal rotation was observed in the affected shoulder at 110-120 degrees of abduction. Following subacromial anaesthetics in the affected shoulder, internal rotation increased (2 degrees , 95% CI 0.5-3.9, p = 0.045) and posterior tilt decreased (3 degrees , 95% CI 1.5 5.0, p = 0.001) at 110-120 degrees of abduction. Less scapular upward rotation was significantly associated with higher pain scores before infiltration (R = 0.45, p = 0.013). CONCLUSIONS: More scapular internal rotation was observed in affected shoulders of patients with SAPS compared with unaffected shoulders. Subacromial infiltration did not restore kinematics toward symmetrical scapular motion. These findings suggest that subacromial anaesthesia is not an effective means to instantly restore symmetry of shoulder motion. PMID- 27469586 TI - Major milestones in translational oncology. AB - Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. Today, translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies regarding the molecular pathways involved in tumorigenesis. In this Forum article, we highlight the state of the art of translational oncology in five major cancer types. We illustrate the use of molecular profiling to subtype colorectal cancer for both diagnosis and treatment, and summarize the results of a nationwide screening program for ovarian cancer based on detection of a tumor biomarker in serum. Additionally, we discuss how circulating tumor DNA can be assayed to safely monitor breast cancer over the course of treatment, and report on how therapy with immune checkpoint inhibitors is proving effective in advanced lung cancer. Finally, we summarize efforts to use molecular profiling of prostate cancer biopsy specimens to support treatment decisions. Despite encouraging early successes, we cannot disregard the complex genetics of individual susceptibility to cancer nor the enormous complexity of the somatic changes observed in tumors, which urge particular attention to the development of personalized therapies. PMID- 27469587 TI - Optimization of coronary optical coherence tomography imaging using the attenuation-compensated technique: a validation study. AB - Aim: To optimize conventional coronary optical coherence tomography (OCT) images using the attenuation-compensated technique to improve identification of plaques and the external elastic lamina (EEL) contour. Methods and Results: The attenuation-compensated technique was optimized via manipulating contrast exponent C, and compression exponent N, to achieve an optimal contrast and signal to-noise ratio (SNR). This was applied to 60 human coronary lesions (38 native and 22 stented) ex vivo conventional coronary OCT images acquired from heart autopsies of 10 patients and matching histology was available as reference. Three independent reviewers assessed the conventional and attenuation-compensated OCT images blindly for plaque characteristics and EEL detection. Conventional OCT and compensated OCT assessment were compared against histology. Using an optimized algorithm, the attenuation-compensated OCT images had a 2-fold improvement in contrast between different tissues in both stented and non-stented epicardial coronaries (P < 0.05). Overall sensitivity and specificity for plaque classification increased from 84 to 89% and from 92 to 94%, respectively, with substantial agreement among the three reviewers (Fleiss' Kappa k, 0.72 and 0.71, respectively). Furthermore, operators were 2.5 times more likely to identify the EEL contour in the attenuation-compensated OCT images (k = 0.72) than in the conventional OCT images (k = 0.36). Conclusion: The attenuation-compensated technique can be retrospectively applied to conventional OCT images and improves the detection of plaque characteristics and the EEL contour. This approach could complement conventional OCT imaging in the evaluation of plaque characteristics and quantify plaque burden in the clinical setting. PMID- 27469588 TI - Fractional flow reserve by computerized tomography and subsequent coronary revascularization. AB - AIMS: Fractional flow reserve by computerized tomography (FFR-CT) provides non invasive functional assessment of the hemodynamic significance of coronary artery stenosis. We determined the FFR-CT values, receiver operator characteristic (ROC) curves, and predictive ability of FFR-CT for actual standard of care guided coronary revascularization. METHODS AND RESULTS: Consecutive outpatients who underwent coronary CT angiography (coronary CTA) followed by invasive angiography over a 24-month period from 2012 to 2014 were identified. Studies that fit inclusion criteria (n = 75 patients, mean age 66, 75% males) were sent for FFR-CT analysis, and results stratified by coronary artery calcium (CAC) scores. Coronary CTA studies were re-interpreted in a blinded manner, and baseline FFR-CT values were obtained retrospectively. Therefore, results did not interfere with clinical decision-making. Median FFR-CT values were 0.70 in revascularized (n = 69) and 0.86 in not revascularized (n = 138) coronary arteries (P < 0.001). Using clinically established significance cut-offs of FFR-CT <=0.80 and coronary CTA >=70% stenosis for the prediction of clinical decision-making and subsequent coronary revascularization, the positive predictive values were 74 and 88% and negative predictive values were 96 and 84%, respectively. The area under the curve (AUC) for all studied territories was 0.904 for coronary CTA, 0.920 for FFR CT, and 0.941 for coronary CTA combined with FFR-CT (P = 0.001). With increasing CAC scores, the AUC decreased for coronary CTA but remained higher for FFR-CT (P < 0.05). CONCLUSION: The addition of FFR-CT provides a complementary role to coronary CTA and increases the ability of a CT-based approach to identify subsequent standard of care guided coronary revascularization. PMID- 27469589 TI - CORR Insights((r)): Hindfoot Arthrodesis with the Blade Plate: Increased Risk of Complications and Nonunion in a Complex Patient Population. PMID- 27469591 TI - Commentary: Greater Emotional Gain from Giving in Older Adults: Age-Related Positivity Bias in Charitable Giving. PMID- 27469590 TI - Corticosteroid Injections Give Small and Transient Pain Relief in Rotator Cuff Tendinosis: A Meta-analysis. AB - BACKGROUND: The ability of injection of corticosteroids into the subacromial space to relieve pain ascribed to rotator cuff tendinosis is debated. The number of patients who have an injection before one gets relief beyond what a placebo provides is uncertain. QUESTIONS/PURPOSES: We asked: (1) Do corticosteroid injections reduce pain in patients with rotator cuff tendinosis 3 months after injection, and if so, what is the number needed to treat (NNT)? (2) Are multiple injections better than one single injection with respect to pain reduction at 3 months? METHODS: We systematically searched seven electronic databases for randomized controlled trials of corticosteroid injection for rotator cuff tendinosis compared with a placebo injection. Eligible studies had at least 10 adults and used pain intensity as an outcome measure. The Hedges's g as adjusted pooled standardized mean difference (SMD) (which expresses the size of the intervention effect in each study relative to the total variability observed among pooled studies) and NNT were calculated at assessment points less than 1 month, 1-2 months, and 2-3 months. The protocol of this study was registered at the international prospective register of systematic reviews. Eleven studies of 726 patients satisfied our criteria for data pooling. Three studies containing 292 patients used repeat injections. A random effects model was used owing to substantial heterogeneity among studies. The funnel plot indicated the possibility of some missing studies, but Orwin's fail-safe N and Duval and Tweedie's trim and fill suggested that missing studies would not significantly affect the results. RESULTS: Corticosteroid injection did not reduce pain intensity in adult patients with rotator cuff tendinosis more than a placebo injection at the 3-month assessment. A small transient pain relief occurred at the assessment between 4 and 8 weeks with a SMD of 0.52 (range, 0.27-0.78) (p < 0.001). At least five patients must be treated for one patient's pain to be transiently reduced to no more than mild. Multiple injections were not found to be more effective than a single injection at any time. CONCLUSIONS: Corticosteroid injections provide-at best-minimal transient pain relief in a small number of patients with rotator cuff tendinosis and cannot modify the natural course of the disease. Given the discomfort, cost, and potential to accelerate tendon degeneration associated with corticosteroids, they have limited appeal. Their wide use may be attributable to habit, underappreciation of the placebo effect, incentive to satisfy rather than discuss a patient's drive toward physical intervention, or for remuneration, rather than their utility. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 27469592 TI - Incisional hernias after laparoscopic and robotic right colectomy. AB - PURPOSE: Incisional hernia (IH) is a common complication after colectomy, with impacts on both health care utilization and quality of life. The true incidence of IH after minimally invasive colectomy is not well described. The purpose of this study was to examine IH incidence after minimally invasive right colectomies (RC) and to compare the IH rates after laparoscopic (L-RC) and robotic (R-RC) colectomies. METHODS: This is a retrospective review of patients undergoing minimally invasive RC at a single institution from 2009 to 2014. Only patients undergoing RC for colonic neoplasia were included. Patients with previous colectomy or intraperitoneal chemotherapy were excluded. Three L-RC patients were included for each R-RC patient. The primary outcome was IH rate based on clinical examination or computed tomography (CT). Univariate and multivariate time-to event analyses were used to assess predictors of IH. RESULTS: 276 patients where included, of which 69 had undergone R-RC and 207 L-RC. Patient and tumor characteristics were similar between the groups, except for higher tumor stage in L-RC patients. Both the median time to diagnosis (9.2 months) and the overall IH rate were similar between the groups (17.4 % for R-RC and 22.2 % for L-RC), as were all other postoperative complications. In multivariable analyses, the only significant predictor of IH was former or current tobacco use (hazard raio 3.0, p = 0.03). CONCLUSIONS: This study suggests that the incidence of IH is high after minimally invasive colectomy and that this rate is equivalent after R-RC and L RC. Reducing the IH rate represents an important opportunity for improving quality of life and reducing health care utilization after minimally invasive colectomy. PMID- 27469593 TI - Author's response to "letter to the editor: lower vitamin D status may explain racial disparities in all-cause mortality among younger commercially insured women with incident metastatic breast cancer". PMID- 27469594 TI - A Survey of BRCA1, BRCA2, and PALB2 mutations in women with breast cancer in Trinidad and Tobago. AB - The mortality rate from breast cancer in the nation of Trinidad and Tobago is among the highest of any country in the Caribbean region. The contribution of inherited gene mutations to the burden of breast cancer in Trinidad and Tobago has not been studied. We examined the prevalence of mutations in three susceptibility genes (BRCA1, BRCA2, and PALB2) in breast cancer patients in Trinidad and Tobago. We studied 268 unselected breast cancer patients from Trinidad and Tobago and looked for mutations across the entire coding sequences of BRCA1, BRCA2, and PALB2. Overall, 28 of 268 patients (10.4 %) had a mutation in one of the three genes, including 15 in BRCA1, ten in BRCA2, two in PALB2, and one in both BRCA2 and PALB2. There were 25 different mutations identified; of these, four mutations were seen in two patients each. Given the high prevalence of mutations, it is reasonable to offer genetic testing for these three genes to all breast cancer patients in Trinidad and Tobago. PMID- 27469595 TI - Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma. AB - Cancer-associated fibroblasts (CAFs) are classified into various functional subtypes such as fibroblast activation protein-alpha (FAP-alpha), fibroblast specific protein-1 (FSP-1), platelet-derived growth factor receptor-alpha (PDGFR alpha), and PDGFR-beta. In this study, we compared the expression of CAF-related proteins in invasive lobular carcinoma (ILC) with those in invasive carcinoma of no special type (NST) and assessed the implications of the differences observed. Using tissue microarrays of 104 ILC and 524 invasive carcinoma (NST) cases, immunohistochemistry for CAF-related proteins [podoplanin, prolyl 4-hydroxylase, FAP-alpha, FSP-1/S100A4, PDGFR-alpha, PDGFR-beta, and chondroitin sulfate proteoglycan (NG2)] was conducted. In invasive carcinoma (NST), tumor cells expressed a high level of PDGFR-alpha, whereas ILC tumor cells expressed high levels of podoplanin, prolyl 4-hydroxylase, FAP-alpha, and FSP-1/S100A4. In stromal cells of invasive carcinoma (NST), high expression levels of prolyl 4 hydroxylase, PDGFR-alpha, and NG2 were observed, whereas ILC stromal cells expressed high levels of FAP-alpha, FSP-1/S100A4, and PDGFR-beta. In ILC, tumoral FSP-1/S100A4 positivity was associated with higher Ki-67 labeling index (p = 0.010) and non-luminal A type cancer (p = 0.014). Stromal PDGFR-alpha positivity was associated with lymph node metastasis (p = 0.011). On survival analysis of entire cases, tumoral FSP-1/S100A4 positivity (p = 0.002), stromal podoplanin positivity (p = 0.041), and stromal FSP-1/S100A4 negativity (p = 0.041) were associated with shorter disease-free survival; only tumoral FSP-1/S100A4 positivity (p = 0.044) was associated with shorter overall survival. In ILC, the expression of FAP-alpha and FSP-1/S100A4 was higher in both tumor and stromal cells than that observed in invasive carcinoma (NST). These results indicate that CAFs are a potential target in ILC treatment. PMID- 27469596 TI - Brain Activity and Functional Connectivity Associated with Hypnosis. AB - Hypnosis has proven clinical utility, yet changes in brain activity underlying the hypnotic state have not yet been fully identified. Previous research suggests that hypnosis is associated with decreased default mode network (DMN) activity and that high hypnotizability is associated with greater functional connectivity between the executive control network (ECN) and the salience network (SN). We used functional magnetic resonance imaging to investigate activity and functional connectivity among these three networks in hypnosis. We selected 57 of 545 healthy subjects with very high or low hypnotizability using two hypnotizability scales. All subjects underwent four conditions in the scanner: rest, memory retrieval, and two different hypnosis experiences guided by standard pre-recorded instructions in counterbalanced order. Seeds for the ECN, SN, and DMN were left and right dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and posterior cingulate cortex (PCC), respectively. During hypnosis there was reduced activity in the dACC, increased functional connectivity between the dorsolateral prefrontal cortex (DLPFC;ECN) and the insula in the SN, and reduced connectivity between the ECN (DLPFC) and the DMN (PCC). These changes in neural activity underlie the focused attention, enhanced somatic and emotional control, and lack of self-consciousness that characterizes hypnosis. PMID- 27469597 TI - Eating and arterial endothelial function: a meta-analysis of the acute effects of meal consumption on flow-mediated dilation. AB - Given that endothelial dysfunction precedes atherosclerotic cardiovascular disease, exploring the parameters that modify postprandial flow-mediated dilation (FMD) is important for public health. The objectives of the study are to estimate the population effect of meal ingestion on FMD and to determine how the effect varied based on patient characteristics and modifiable methodological features. Articles published before June 2015 were located using MEDLINE, PubMed and Web of Science. One hundred fifty-four effects were derived from 78 articles involving 2,548 subjects were selected. Included articles required measurement of FMD in adults before and after meal ingestion. Effects were analysed using an unstandardized mean gain random effects model, and significant moderators were analysed using meta-regression. Meal consumption significantly reduced FMD by a heterogeneous mean effect size delta (Delta) of -2.03 (95% CI: [-2.28, -1.77]), an ~2% reduction in FMD. FMD reductions were larger among normal weight individuals, males, those with a cardio-metabolic disorder, those with elevated baseline FMD, and individuals with impaired glucose tolerance at baseline. Macronutrient meal ingestion significantly reduced FMD, an effect that was moderated by body mass index, sex and two-way interactions between disease status and both baseline FMD and baseline blood glucose levels. PMID- 27469598 TI - Olig2 regulates Purkinje cell generation in the early developing mouse cerebellum. AB - The oligodendrocyte transcription factor Olig2 plays a crucial role in the neurogenesis of both spinal cord and brain. In the cerebellum, deletion of both Olig2 and Olig1 results in impaired genesis of Purkinje cells (PCs) and Pax2(+) interneurons. Here, we perform an independent study to show that Olig2 protein is transiently expressed in the cerebellar ventricular zone (VZ) during a period when PCs are specified. Further analyses demonstrate that Olig2 is expressed in both cerebellar VZ progenitors and early-born neurons. In addition, unlike in the ganglionic eminence of the embryonic forebrain where Olig2 is mostly expressed in proliferating progenitors, Olig2(+) cells in the cerebellar VZ are in the process of leaving the cell cycle and differentiating into postmitotic neurons. Functionally, deletion of Olig2 alone results in a preferential reduction of PCs in the cerebellum, which is likely mediated by decreased neuronal generation from their cerebellar VZ progenitors. Furthermore, our long-term lineage tracing experiments show that cerebellar Olig gene-expressing progenitors produce PCs but rarely Pax2(+) interneurons in the developing cerebellum, which opposes the "temporal identity transition" model of the cerebellar VZ progenitors stating that majority of Pax2(+) interneuron progenitors are transitioned from Olig2(+) PC progenitors. PMID- 27469599 TI - Telomere Length Among Older U.S. Adults: Differences by Race/Ethnicity, Gender, and Age. AB - OBJECTIVE: We examine race/ethnic, gender, and age differences in telomere length (TL) within a diverse, nationally representative sample of older adults. METHOD: Data come from 5,228 White, Black, and Hispanic respondents aged 54+ in the 2008 Health and Retirement Study. TL was assayed from saliva using quantitative polymerase chain reaction (qPCR) by comparing telomere sequence copy number with a single gene copy number (T/S ratio). Linear regression was used to examine TL by race/ethnicity, gender, and age adjusting for social, economic, and health characteristics. RESULTS: Women had longer TL than men (p < .05). Blacks ( p < .05) and Hispanics ( p < .10) had longer TL than Whites. Black women and men had the longest TL relative to other groups ( p < .05), while White men had the shortest TL ( p < .05). Black women and Hispanic men showed greater differences in TL with age. DISCUSSION: Findings indicate social patterns in TL by race/ethnicity, gender, and age among older adults do not reflect differences observed in most population health outcomes. PMID- 27469601 TI - Intertunnel Relationships in the Tibia During Reconstruction of Multiple Knee Ligaments: How to Avoid Tunnel Convergence. AB - BACKGROUND: Knee dislocations are rare but potentially devastating injuries, often involving tears of multiple knee ligaments. Several studies have reported improved clinical and functional outcomes with surgical management of torn knee ligaments compared with nonsurgical management. Most multiple ligament reconstruction techniques involve creating several tunnels for various reconstruction grafts, posing a risk of tunnel convergence in the proximal tibia. PURPOSE: To assess the risk of tunnel convergence and determine the optimal tunnel placement for the reconstruction of multiple ligaments in the tibia. STUDY DESIGN: Descriptive laboratory study. METHODS: Three-dimensional knee models were developed using customized software from computed tomography images of 21 patients. Mimics software was used to create tunnels for each of the 4 primary ligamentous structures, replicating a surgical approach that would be used in actual multiple ligament reconstruction surgery. The tunnel orientation was varied in anatomically relevant directions to find orientations that did not result in tunnel convergence. RESULTS: There was a high risk of tunnel convergence (66.7%) between the posterior cruciate ligament (PCL) and posterior oblique ligament (POL) tunnels when the POL tunnel was aimed toward the Gerdy tubercle as suggested in the literature. No tunnel convergence was observed when the POL tunnel was aimed 15 mm medial to the Gerdy tubercle. No tunnel convergence was observed between the anterior cruciate ligament (ACL) and POL. Tunnel convergence was observed between the PCL and superficial medial collateral ligament (sMCL) in 19.0% of cases when the sMCL tunnel was aimed transversely across the tibia. Aiming the sMCL tunnel transversely and directing 30 degrees distally significantly increased the mean distance between the sMCL and PCL to 6.9 mm (P < .001), and no tunnel convergence was observed. No tunnel convergence was observed between the PCL and posterolateral corner tunnels or between the ACL and PCL tunnels. CONCLUSION: There is a high risk of tunnel convergence in the proximal tibia during the reconstruction of multiple knee ligaments. Aiming the POL tunnel 15 mm medial to the Gerdy tubercle and the sMCL tunnel transversely across the tibia (anterior to the fibula) and 30 degrees distal to the horizontal plane reduces the risk of tunnel convergence. CLINICAL RELEVANCE: The tunnel orientation of the POL and sMCL on the tibia should be adjusted to avoid convergence with the PCL tunnel during multiple ligament knee reconstruction. PMID- 27469600 TI - Obesity and Falls in a Prospective Study of Older Men: The Osteoporotic Fractures in Men Study. AB - OBJECTIVE: The aim of this study is to evaluate fall rates across body mass index (BMI) categories by age group, considering physical performance and comorbidities. METHOD: In the Osteoporotic Fractures in Men (MrOS) study, 5,834 men aged >=65 reported falls every 4 months over 4.8 (+/-0.8) years. Adjusted associations between BMI and an incident fall were tested using mixed-effects models. RESULTS: The fall rate (0.66/man-year overall, 95% confidence interval [CI] = [0.65, 0.67]) was lowest in the youngest, normal weight men (0.44/man year, 95% CI = [0.41, 0.47]) and greatest in the oldest, highest BMI men (1.47 falls/man-year, 95% CI = [1.22, 1.76]). Obesity was associated with a 24% to 92% increased fall risk in men below 80 ( ptrend <= .0001, p for interaction by age = .03). Only adjustment for dynamic balance test altered the BMI-falls association substantially. DISCUSSION: Obesity was independently associated with higher fall rates in men 65 to 80 years old. Narrow walk time, a measure of gait stability, may mediate the association. PMID- 27469602 TI - Mechanical behavior and microstructure of compressed Ti foams synthesized via freeze casting. AB - Pure Ti and Ti-5%W foams were prepared via freeze casting. The porosity and grain size of both the materials were 32-33% and 15-17um, respectively. The mechanical behavior of the foams was investigated by uniaxial compression up to a plastic strain of ~0.26. The Young's moduli of both foams were ~23GPa, which was in good agreement with the value expected from their porosity. The Young's moduli of the foams were similar to the elastic modulus of cortical bones, thereby eliminating the osteoporosis-causing stress-shielding effect. The addition of W increased the yield strength from ~196MPa to ~235MPa. The microstructure evolution in the grains during compression was studied using electron backscatter diffraction (EBSD) and X-ray line profile analysis (XLPA). After compression up to a plastic strain of ~0.26, the average dislocation densities increased to ~3.4*10(14)m(-2) and ~5.9*10(14)m(-2) in the Ti and Ti-W foams, respectively. The higher dislocation density in the Ti-W foam can be attributed to the pinning effect of the solute tungsten atoms on dislocations. The experimentally measured yield strength was in good agreement with the strength calculated from the dislocation density and porosity. This study demonstrated that the addition of W to Ti foam is beneficial for biomedical applications, because the compressive yield strength increased while its Young's modulus remained similar to that of cortical bones. PMID- 27469603 TI - The effect of grinding on the mechanical behavior of Y-TZP ceramics: A systematic review and meta-analyses. AB - The aim of this study was to systematically review the literature to assess the effect of grinding on the mechanical properties, structural stability and superficial characteristics of Y-TZP ceramics. The MEDLINE via PubMed and Web of Science (ISI - Web of Knowledge) electronic databases were searched with included peer-reviewed publications in English language and with no publication year limit. From 342 potentially eligible studies, 73 were selected for full-text analysis, 30 were included in the systematic review with 20 considered in the meta-analysis. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias. Statistical analyses were performed using RevMan 5.1, with random effects model, at a significance level of 0.05. A descriptive analysis considering phase transformation, Y-TZP grain size, Vickers hardness, residual stress and aging of all included studies were executed. Four outcomes were considered in the meta-analyses (factor: grinding x as-sintered) in global and subgroups analyses (grinding tool, grit-size and cooling) for flexural strength and roughness (Ra) data. A significant difference (p<0.05) was observed in the global analysis for strength, favoring as-sintered; subgroup analyses revealed that different parameters lead to different effects on strength. In the global analysis for roughness, a significant difference (p<0.05) was observed between conditions, favoring grinding; subgroup analyses revealed that different parameters also lead to different effects on roughness. High heterogeneity was found in some comparisons. Generally grinding promotes decrease in strength and increase in roughness of Y-TZP ceramics. However, the use of a grinding tool that allows greater accuracy of the movement (i.e. contra angle hand-pieces coupled to slowspeed turbines), small grit size (<50MUm) and the use of plenty coolant seem to be the main factors to decrease the defect introduction and allow the occurrence of the toughening transformation mechanism, decreasing the risk of deleterious impact on Y-TZP mechanical properties. PMID- 27469604 TI - Limitations to providing adult cystic fibrosis care in Europe: Results of a care centre survey. AB - BACKGROUND: There are a growing number of adults in Europe with a projected increase of 75% over the next decade. There is concern that provision of care will not be sufficient to meet needs. We aimed to establish the level of CF service throughout Europe. METHODS: An online survey designed by clinicians and patient representatives to explore level of service. RESULTS: Training opportunities for clinicians and resources (physical and manpower) to provide care to adults with CF are limited in Europe. Although specific adult CF care has been identified, teams continue to be supported by paediatric colleagues and many adults are still being admitted to paediatric wards. In some centres, service delivery, particularly infection control and access to some CF medication is insufficient and in many places poor personnel resources limits access to comprehensive multidisciplinary teams. CONCLUSIONS: This survey shows an urgent need for the development of resources for adult CF care, in both physical space and appropriately trained clinicians. PMID- 27469605 TI - [Post-spinal hyperacute subdural hematoma]. PMID- 27469606 TI - Uncovering the density of nanowire surface trap states hidden in the transient photoconductance. AB - The gain of nanoscale photoconductors is closely correlated with surface trap states. Mapping out the density of surface trap states in the semiconductor bandgap is crucial for engineering the performance of nanoscale photoconductors. Traditional capacitive techniques for the measurement of surface trap states are not readily applicable to nanoscale devices. Here, we demonstrate a simple technique to extract the information on the density of surface trap states hidden in the transient photoconductance that is widely observed. With this method, we found that the density of surface trap states of a single silicon nanowire is ~10(12) cm(-2) eV(-1) around the middle of the upper half bandgap. PMID- 27469607 TI - Negative ion mode atmospheric pressure ionization methods in lignin mass spectrometry: A comparative study. AB - RATIONALE: Mass spectrometry with atmospheric pressure ionization is the most promising method for studying the structure of natural lignin, which is the second most abundant biopolymer in nature. The goal of this study is to compare the efficiency and characteristics of different types of ionization techniques (ESI, APCI, and APPI) in the negative ion mode by the example of softwood lignin. METHODS: As the subjects of the study, we selected a preparation of spruce dioxane lignin and several phenols, simulating the basic structural fragments of the lignin macromolecule. High-resolution mass spectra were recorded using an Orbitrap mass spectrometer. Acetone was used as a solvent for samples and a dopant in photoionization mode. The ionization conditions were optimized to achieve the maximum intensity of the mass spectra. RESULTS: The formation of deprotonated lignin molecules is characteristic of all the studied types of ionization; partial fragmentation of the biopolymer occurs in all ionization modes. ESI in the presence of ammonia yields low-intensity signals, leads to a significant decrease in ionization efficiency with increasing molecular weight of lignin oligomers, gives high-intensity impurity peaks in the mass spectra, and demonstrates selectivity for more polar structures. The ionization efficiency increases sharply in the order of ESI < APCI < APPI. The two latter methods are characterized by similar mechanisms of ionization; they ensure detection of approximately 1900 spruce lignin oligomers in the range of molecular weights up to 1.8 kDa. The determination of the elemental composition of oligolignols enabled the four main groups of compounds to be distinguished. CONCLUSIONS: Photoionization using acetone as a dopant is distinguished by a significantly higher intensity of signals and the lowest sensitivity to contaminants present in the lignin preparation. This ionization method can be considered as preferred for studying the dioxane lignin preparations of woody plants. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27469609 TI - Global cost of physical inactivity is estimated at $67.5bn a year. PMID- 27469608 TI - Central venous catheter tip migration due to tracheal extubation: a prospective randomized study. AB - Considerable numbers of patients undergo central venous catheterization (CVC) under mechanical ventilation. We hypothesized that the return of spontaneous breathing and tracheal extubation could be associated with distal CVC tip migration towards intracardiac positions due to decreasing intrathoracic pressures and subsequent readjustment of mediastinal organs. Patients scheduled for cardiac surgery were randomized for right or left internal jugular vein (IJV) CVC placement under general anesthesia and mechanical ventilation. CVC tips were positioned at the cavoatrial junction and measured at the time of placement, postoperatively under mechanical ventilation, and after tracheal extubation until 48 h after surgery. Measurement methods included intravascular electrocardiography (ECG) P-wave amplitude, transesophageal echocardiography, and chest radiography (CXR). Out of 70 patients, 60 were eligible for final statistical analysis (31 right and 29 left IJV CVC). According to ECG interpretation, CVC tip positions remained below the pericardiac reflection point in the distal superior vena cava over the course of the three measurement intervals. The ECG revealed significant proximal migration of CVC tips from the time of placement to the time of tracheal extubation (1.19 +/- 0.55 vs. 0.62 +/- 0.31 mV; P < 0.001). A CXR using CVC tip to carina distances revealed no significant tip migrations in the time between postoperative assessment and following tracheal extubation (5.1 +/- 1.7 vs. 5.3 +/- 1.5 cm; P = 0.196). In patients with CVCs positioned at the cavoatrial junction, tracheal extubation was not associated with significant postoperative CVC tip malposition, but tended to undergo proximal migration. This trend should be considered particularly in left sided thoracocervical puncture approaches to avoid unfavorable CVC tip positions. PMID- 27469610 TI - Incidental detection of abnormal 99mTc-sestamibi uptake in the sternum and ribcage from multiple myeloma by SPECT myocardial perfusion imaging. PMID- 27469613 TI - Two new Cu(ii) and La(iii) 2D coordination polymers, synthesis and in situ structural analysis by X-ray diffraction. AB - Two new coordination polymers were synthesized solvothermally using 4,4' dimethoxy-3,3'-biphenyldicarboxylic acid (H2dmbpdc), and di- and trivalent metal salts (Cu(NO3)2.2.5H2O and La(NO3)3.6H2O). Their structures were determined by single-crystal X-ray diffraction analysis, and their thermal stability was evaluated by thermogravimetric analysis. The copper compound Cu(dmbpdc)(DMF; N,N dimethylformamide), CPO-71-Cu, is based on the well known copper acetate paddlewheel secondary building unit. The asymmetric unit comprises one copper cation with one DMF molecule and one linker molecule coordinated. The lanthanum compound La2(dmbpdc)3(DMF)(H2O)3, CPO-72-La, is formed from a dimer of nine coordinate, edge sharing lanthanum cations. To this dimer, three water molecules and one DMF molecule are coordinated in an ordered fashion. In addition, the asymmetric unit contains three crystallographically unique linker molecules. Both CPO-71-Cu and CPO-72-La form two-dimensional layered structures, and topological analyses reveal sql topologies with point symbol 4(4).6(2) and vertex symbol 4.4.4.4.6(2).6(2). The thermal behavior of CPO-71-Cu was investigated in an in situ structural analysis by variable temperature powder- and single-crystal X-ray diffraction. PMID- 27469611 TI - The role of nuclear cardiac imaging in risk stratification of sudden cardiac death. AB - Sudden cardiac death (SCD) represents a significant portion of all cardiac deaths. Current guidelines focus mainly on left ventricular ejection fraction (LVEF) as the main criterion for SCD risk stratification and management. However, LVEF alone lacks both sensitivity and specificity in stratifying patients. Recent research has provided interesting data which supports a greater role for advanced cardiac imaging in risk stratification and patient management. In this article, we will focus on nuclear cardiac imaging, including left ventricular function assessment, myocardial perfusion imaging, myocardial blood flow quantification, metabolic imaging, and neurohormonal imaging. We will discuss how these can be used to better understand SCD and better stratify patient with both ischemic and non-ischemic cardiomyopathy. PMID- 27469614 TI - Coping strategies used by children and adolescents born with esophageal atresia - a focus group study obtaining the child and parent perspective. AB - BACKGROUND: Esophageal atresia (EA) is a rare malformation, which requires surgical treatment. Survival rates today reach 95%, but EA remains a significant cause of chronic morbidity with increased risk of psychosocial problems and impaired health-related quality of life (HRQOL). No study of coping strategies of children with EA has been reported in the literature to date, but increased knowledge could lead to improved outcomes and better HRQOL. METHODS: Standardized focus groups with children with EA and their parents were conducted to identify issues related to health care needs and HRQOL, with group members relating their coping experiences. Identified coping statements were content analysed using a card sorting procedure and descriptive statistics. RESULTS: Thirty families (18 children 8-17 years; 32 parents of children with EA 2-17 years) participated in 10 focus groups. A total of 590 coping statements were recorded. Nine coping strategies were identified: problem solving (n = 116), avoidance (n = 95), recognizing responsibility (n = 71), confronting (n = 70), seeking social support (n = 63), positive reappraisal (n = 58), emotional expression (n = 46), acceptance (n = 40) and distancing (n = 31). Nine situational contexts were identified: nutritional intake (n = 227), communication of one's health condition (n = 78), self-perception when experiencing troublesome symptoms (n = 59), appearance of body or scar(s) (n = 57), physical activities like sport and play (n = 43), sleep (n = 34), hospital care (n = 33), stigmatization and social exclusion (n = 30) and medication intake (n = 29). CONCLUSIONS: Focus group methodology contributed to an increased understanding of disease-specific coping processes among children and adolescence with EA. Findings illustrate that they use several coping strategies, some of which they seem to adopt at early age and use in disease-related contexts of physical, social and emotional character. Such coping may influence health and HRQOL in children with EA. In view of the importance of establishing good coping strategies early in life, health care professionals should integrate coping aspects into care management. Future studies are warranted. PMID- 27469615 TI - A Study on Topographical Properties and Surface Wettability of Monolithic Zirconia after Use of Diverse Polishing Instruments with Different Surface Coatings. AB - PURPOSE: To investigate the surface topography parameters and wettability of monolithic zirconia (MZ) using polishing instruments with different coatings. MATERIALS AND METHODS: MZ specimens (N = 50, n = 10 per group) (12 * 12 * 1.8 mm3 ) were highly polished. Five polishing systems were studied: BG: silicon carbide polishers; CG: diamond-impregnated ceramic polisher kit; EV: synthetically bonded grinder interspersed with diamond; SL: urethane-coated paper with aluminum oxide grits; and DB: diamond bur (8 MUm). Specimens were initially roughened with 220 MUm grit diamond burs (10 seconds, 160,000 rpm). After baseline measurements, they were further polished for 10 seconds using a slow-speed handpiece under water coolant, except for SL using a custom-made device (7.5 N), with speed ranging between 5000 and 30,000 rpm. Topographical changes were evaluated considering (a) weight (digital scale), (b) volume loss (digital microscope), (c) vertical height loss (digital microscope), (d) surface roughness (Ra) (profilometer), and (e) surface wettability (goniometer, water). RESULTS: Compared to baseline, material loss from the surface after polishing (DeltaW) ranged between 0.00 +/- 0.0001*10-1 and -0.03 +/- 0.008*10-1 g (SLa < CGa < BGa < DBb < EVc ) and the volume loss (DeltaV) between 900 +/- 3*10-5 and 2459 +/- 7*10 5 MUm3 (SLa < BGa < CGa,b < DBb < EVc ). The vertical height loss (?VH) was highest for SL (-18.911 +/- 3.5) and lowest for EV 55.19 +/- 6.3 MUm (SLa < BGa < CGa,b < DBb < EVc ). The surface roughness (MUm) difference (?Ra) was lowest for DB (-0.14 +/- 0.02) and the highest for EV (0.86 +/- 0.42) (DBa < BGa < SLa < CGa < EVb ). BG showed the lowest contact angle difference (?SW) -2.79 +/- 0.8 degrees and EV the highest (3.93 +/- 3.1 degrees ) (BGa < DBa < SLa < CGa < EVa ). CONCLUSIONS: All polishing instruments performed similarly when ?Ra values were considered. SL, BG, and CG produced the least material loss. Synthetically bonded rubber bur interspersed with diamond (EV) could not be suggested for polishing MZ. PMID- 27469612 TI - Metabolites of milk intake: a metabolomic approach in UK twins with findings replicated in two European cohorts. AB - PURPOSE: Milk provides a significant source of calcium, protein, vitamins and other minerals to Western populations throughout life. Due to its widespread use, the metabolic and health impact of milk consumption warrants further investigation and biomarkers would aid epidemiological studies. METHODS: Milk intake assessed by a validated food frequency questionnaire was analyzed against fasting blood metabolomic profiles from two metabolomic platforms in females from the TwinsUK cohort (n = 3559). The top metabolites were then replicated in two independent populations (EGCUT, n = 1109 and KORA, n = 1593), and the results from all cohorts were meta-analyzed. RESULTS: Four metabolites were significantly associated with milk intake in the TwinsUK cohort after adjustment for multiple testing (P < 8.08 * 10-5) and covariates (BMI, age, batch effects, family relatedness and dietary covariates) and replicated in the independent cohorts. Among the metabolites identified, the carnitine metabolite trimethyl-N aminovalerate (beta = 0.012, SE = 0.002, P = 2.98 * 10-12) and the nucleotide uridine (beta = 0.004, SE = 0.001, P = 9.86 * 10-6) were the strongest novel predictive biomarkers from the non-targeted platform. Notably, the association between trimethyl-N-aminovalerate and milk intake was significant in a group of MZ twins discordant for milk intake (beta = 0.050, SE = 0.015, P = 7.53 * 10-4) and validated in the urine of 236 UK twins (beta = 0.091, SE = 0.032, P = 0.004). Two metabolites from the targeted platform, hydroxysphingomyelin C14:1 (beta = 0.034, SE = 0.005, P = 9.75 * 10-14) and diacylphosphatidylcholine C28:1 (beta = 0.034, SE = 0.004, P = 4.53 * 10-16), were also replicated. CONCLUSIONS: We identified and replicated in independent populations four novel biomarkers of milk intake: trimethyl-N-aminovalerate, uridine, hydroxysphingomyelin C14:1 and diacylphosphatidylcholine C28:1. Together, these metabolites have potential to objectively examine and refine milk-disease associations. PMID- 27469616 TI - Monobenzoporphyrins as Sensitizers for Dye-Sensitized Solar Cells: Observation of Significant Spacer-Group Effect. AB - A series of monobenzoporphyrins (WH1-WH4) bearing different conjugated spacer groups were designed and synthesized as sensitizers for dye-sensitized solar cells. Although a phenyl spacer only has a minimal impact on the absorption bands of the monobenzoporphyrin, an ethynylphenyl (WH3) or a vinyl (WH4) spacer redshifts and broadens the absorption bands of the dyes to result in much enhanced light-harvesting ability. Dye-sensitized solar cells based on these monobenzoporphyrin dyes displayed remarkable differences in power conversion efficiencies (PCEs). The monobenzoporphyrin bearing no spacer (WH1) resulted in a PCE of only 0.5 %; in contrast, the monobenzoporphyrin bearing vinyl spacers (WH4) achieved a PCE of 5.2 %. The high efficiency of the WH4 cell is attributed to the higher light-harvesting ability, the lesser extent of aggregation on the TiO2 surface, and the more favorable electron-density distributions of the HOMO and LUMO for electron injection and collection. This work demonstrates the exceptional tunability of benzoporphyrins as sensitizers for dye-sensitized solar cells. PMID- 27469617 TI - Congenital anomalies of lumbosacral spine: A pictorial review. AB - Congenital malformations of the lumbosacral spine include spinal dysraphism and caudal anomalies. Most often, these malformations are discovered prenatally or in early infancy, but some are not diagnosed until late childhood or adulthood. The purpose of this pictorial review is to illustrate the multi-modality imaging characteristics in these complex anomalies and to provide a systematic radiological approach aiming at improving diagnostic accuracy. PMID- 27469618 TI - Serological monitoring of backyard chickens in Central Macedonia-Greece can detect low transmission of West Nile virus in the absence of human neuroinvasive disease cases. AB - During 2010-13, West Nile virus (WNV) epidemics occurred in Greece with high numbers of human cases. In parallel, WNV serological surveillance utilizing domestic birds was applied mainly in Central Macedonia, as well as in other areas of the country, and allowed efficient detection of WNV activity during this period. The objective of the study was to evaluate the sensitivity of chicken based WNV surveillance in periods of low-level virus transmission (2014-15) in a well-studied area, i.e. the epicenter of the 2010 WNV epidemic (Central Macedonia), which is considered endemic since then. WNV activity was monitored via determination of antiviral immune responses in juvenile backyard chickens. The birds were sampled twice per transmission period. WNV-specific antibodies were detected by ELISA in 2.8% out of 255 chickens sampled early in the 2014 transmission period (95% CI: 1-6%). Continued virus transmission was detected at the end of the period, as 4.2% out of 240 sampled chickens seroconverted to WNV (95% CI: 2-8%). Although 14 human neuroinvasive cases occurred in Greece during 2014, no such cases were reported in the study area. During the 2015 early warning period, antibodies against WNV were not detected in sampled chickens (n=250, 95% CI: 0-2%). However, humoral immune responses were detected in 6 out of 240 chicken sampled at the end of the transmission period (2.5%; 95% CI: 1 6%), indicating continued WNV activity. No human cases were reported in Greece during 2015. All samples were negative with real-time RT-PCR. Serological surveillance of chickens resulted in identification of areas with low WNV activity levels during 2014-15, and provided indications of its overwintering in Central Macedonia. The findings suggest that surveillance based on serological testing of domestic birds is sensitive and able to detect low-level of WNV enzootic transmission, in the absence of human cases. PMID- 27469619 TI - Spatial and temporal epidemiology of Mycobacterium leprae infection among leprosy patients and household contacts of an endemic region in Southeast Brazil. AB - BACKGROUND: Leprosy is a chronic infectious disease that remains a public health problem in low- and middle-income countries. Household contacts of leprosy patients (HHCs) have increased risk of developing disease and are important links in the chain of transmission of Mycobacterium leprae. Based on epidemiological and operational factors, the global elimination strategy depends on the geographic stratification of endemic areas to intensify control activities. The purpose of the study was to integrate epidemiological indicators and serology into the spatial and temporal analysis of M. leprae infection, in order to understanding of the dynamics of transmission, essential information for the control of leprosy. METHODOLOGY: Using location-based technologies and epidemiological data obtained from leprosy cases (N=371) and HHCs (N=53), during a 11year period (2004-2014), we explored the spatial and temporal distribution of diagnosed cases: stratified according their disease manifestation; and of subclinical infection among HHCs: determined by serology (anti-PGL-I ELISA and anti-NDO-LID rapid lateral-flow test); in order to assess the distribution pattern of the disease and the areas of greatest risk of illness, in a highly endemic municipality (Ituiutaba, MG) in the southeast region of Brazil. RESULTS: Seropositivity among HHCs was: 17% (9/53) for anti-PGL-I ELISA; and 42% for the NDO-LID rapid lateral-flow test. Forty-nine percent of the contacts were seropositive to at least one of the immunological tests. DISCUSSION: We observed substantial spatial heterogeneity of cases throughout the urban perimeter. Even so, four main clusters of patients and three main clusters of subclinical infection were identified. CONCLUSIONS: Spatio-temporal epidemiology associated to serological assessment can identify high-risk areas imbedded within the overall epidemic municipality, to prioritize active search of new cases as well support prevention strategies in these locations of greater disease burden and transmission. Such techniques should become increasingly useful and important in future action planning of health interventions, as decisions must be made to effectively allocate limited resources. PMID- 27469620 TI - Association between dietary patterns and blood lipid profiles among Chinese women. AB - OBJECTIVE: The present study aimed to identify dietary patterns and explore their associations with blood lipid profiles among Chinese women. DESIGN: In a cross sectional study, we identified dietary patterns using principal component analysis of data from three consecutive 24 h dietary recalls. The China Health and Nutrition Survey (CHNS) collected blood samples in the morning after an overnight fast and measured total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C) and TAG. SETTING: Data were from the 2009 wave of the CHNS. SUBJECTS: We studied 2468 women aged 18-80 years from the CHNS. RESULTS: We identified three dietary patterns: traditional southern (high intakes of rice, pork and vegetables), snack (high intakes of fruits, eggs and cakes) and Western (high intakes of poultry, fast foods and milk). The traditional southern pattern was inversely associated with HDL-C (beta=-0.68; 95 % CI -1.22, -0.14; P<0.05). The snack pattern was significantly associated with higher TAG (beta=4.14; 95 % CI 0.44, 7.84; P<0.05). The Western pattern was positively associated with TC (beta=2.52; 95 % CI 1.03, 4.02; P<0.01) and LDL-C (beta=2.26; 95 % CI 0.86, 3.66; P<0.01). CONCLUSIONS: We identified three dietary patterns that are significantly associated with blood lipid profiles. This information is important for developing interventions and policies addressing dyslipidaemia prevention among Chinese women. PMID- 27469621 TI - Beta thalassaemia intermedia due to co-inheritance of three unique alpha globin cluster duplications characterised by next generation sequencing analysis. PMID- 27469622 TI - Findings on the interaction of the antimicrobial peptide cecropin-melittin with a gold surface from molecular dynamics studies. AB - The immobilization of gold nanoparticles (AuNPs) with antimicrobial peptides (AMPs) is a new and promising way to enhance both the activity and targeting capabilities of AMPs. However, a full understanding of the adsorption process underlying these materials is still lacking. Cecropin-melittin is a peptide with a broad antimicrobial activity while displaying low hemolytic properties, whose conjugation with AuNPs has not been studied before. In this context, we report the investigation of the adsorption process of the cecropin-melittin peptide, with (CM-SH) and without (CM) cysteine at its C-terminus, onto a gold surface based on all-atom MD simulations. Our results show that the way the peptides approach the surface dictates the final conformation and the time required to achieve it in both CM-SH and CM cases. Most important, it is demonstrated that the presence of cysteine promotes a faster conformational stabilization during the lockdown regime of the CM-SH peptide, noticeably affecting this by acting as a preferential anchoring point. This investigation represents a first step in rationalizing, with atomistic detail, some experimentally observed features of CM SH and CM immobilized gold nanoparticles. PMID- 27469623 TI - Coaching and health. PMID- 27469624 TI - Survey of diagnostic and typing capacity for Clostridium difficile infection in Europe, 2011 and 2014. AB - Suboptimal laboratory diagnostics for Clostridium difficile infection (CDI) impedes its surveillance and control across Europe. We evaluated changes in local laboratory CDI diagnostics and changes in national diagnostic and typing capacity for CDI during the European C. difficile Infection Surveillance Network (ECDIS Net) project, through cross-sectional surveys in 33 European countries in 2011 and 2014. In 2011, 126 (61%) of a convenience sample of 206 laboratories in 31 countries completed a survey on local diagnostics. In 2014, 84 (67%) of these 126 laboratories in 26 countries completed a follow-up survey. Among laboratories that participated in both surveys, use of CDI diagnostics deemed 'optimal' or 'acceptable' increased from 19% to 46% and from 10% to 15%, respectively (p < 0.001). The survey of national capacity was completed by national coordinators of 31 and 32 countries in 2011 and 2014, respectively. Capacity for any C. difficile typing method increased from 22/31 countries in 2011 to 26/32 countries in 2014; for PCR ribotyping from 20/31 countries to 23/32 countries, and specifically for capillary PCR ribotyping from 7/31 countries to 16/32 countries. While our study indicates improved diagnostic capability and national capacity for capillary PCR ribotyping across European laboratories between 2011 and 2014, increased use of 'optimal' diagnostics should be promoted. PMID- 27469626 TI - Refined clinical scoring in comparative EAE studies does not enhance the chance to observe statistically significant differences. AB - Considering the 3R rules of animal experimentation, we asked if refined scoring of experimental autoimmune encephalomyelitis (EAE) in mice improves documentation of clinical EAE allowing to perform a more powerful statistical analysis. Surprisingly, refined EAE scoring failed to improve statistical outcome comparing the overall disease courses between two groups of mice. PMID- 27469625 TI - The TMSB4 Pseudogene LncRNA Functions as a Competing Endogenous RNA to Promote Cartilage Degradation in Human Osteoarthritis. AB - Mechanical stress plays a key role in the development of cartilage degradation in osteoarthritis (OA). Nevertheless, the role of long noncoding RNAs in mechanical stress-induced regulation of chondrocytes remains unclear. The aim of this study was to explore the function of mechanical stress-related long noncoding RNAs in cartilage. Tissue samples were collected from 50 patients and chondrocytes were exposed to cyclic tensile strain (CTS). A total of 107 lncRNAs were differentially expressed in damaged cartilage versus intact cartilage. Of these lncRNAs, 51 were upregulated and 56 were downregulated in the damaged tissue. The TMSB4 pseudogene, lncRNA-MSR, was upregulated in the damaged cartilage and was activated in chondrocytes in response to mechanical stress. Furthermore, lncRNA MSR regulated the expression of TMSB4 by competing with miRNA-152 in chondrocytes. Our results demonstrated that upregulation of lncRNA-MSR initiates pathological changes that lead to cartilage degradation, and the inhibition of lncRNA-MSR could represent a potential therapeutic target for OA. PMID- 27469627 TI - Relationship Between Operating Room Teamwork, Contextual Factors, and Safety Checklist Performance. AB - BACKGROUND: Studies show that using surgical safety checklists (SSCs) reduces complications. Many believe SSCs accomplish this by enhancing teamwork, but evidence is limited. Our study sought to relate teamwork to checklist performance, understand how they relate, and determine conditions that affect this relationship. STUDY DESIGN: Using 2 validated tools for observing and coaching operating room teams, we evaluated the association between checklist performance with surgeon buy-in and 4 domains of surgical teamwork: clinical leadership, communication, coordination, and respect. Hospital staff in 10 South Carolina hospitals observed 207 procedures between April 2011 and January 2013. We calculated levels of checklist performance, buy-in, and measures of teamwork, and evaluated their relationship, controlling for patient and case characteristics. RESULTS: Few teams completed most or all SSC items. Teams more often completed items considered procedural "checks" than conversation "prompts." Surgeon buy-in, clinical leadership, communication, a summary measure of teamwork overall, and observers' teamwork ratings positively related to overall checklist completion (multivariable model estimates from 0.04, p < 0.05 for communication to 0.17, p < 0.01 for surgeon buy-in). All measures of teamwork and surgeon buy in related positively to completing more conversation prompts; none related significantly to procedural checks (estimates from 0.10, p < 0.01 for communication to 0.27, p < 0.001 for surgeon buy-in). Patient age was significantly associated with completing the checklist and prompts (p < 0.05); only case duration was positively associated with performing more checks (p < 0.10). CONCLUSIONS: Surgeon buy-in and surgical teamwork characterized by shared clinical leadership, open communication, active coordination, and mutual respect were critical in prompting case-related conversations, but not in completing procedural checks. Findings highlight the importance of surgeon engagement and high-quality, consistent teamwork for promoting checklist use and ensuring a safe surgical environment. PMID- 27469629 TI - Exploring the Mechanisms of Exercise Intolerance in Patients With HFpEF: Are We too "Cardiocentric?". PMID- 27469628 TI - Molecular characterization of Tps1 and Treh genes in Drosophila and their role in body water homeostasis. AB - In insects, trehalose serves as the main sugar component of haemolymph. Trehalose is also recognized as a mediator of desiccation survival due to its proposed ability to stabilize membranes and proteins. Although the physiological role of trehalose in insects has been documented for decades, genetic evidence to support the importance of trehalose metabolism remains incomplete. We here show on the basis of genetic and biochemical evidence that the trehalose synthesis enzyme Tps1 is solely responsible for the de novo synthesis of trehalose in Drosophila. Conversely, a lack of the gene for the trehalose hydrolyzing enzyme Treh causes an accumulation of trehalose that is lethal during the pupal period, as is observed with Tps1 mutants. Lack of either Tps1 or Treh results in a significant reduction in circulating glucose, suggesting that the maintenance of glucose levels requires a continuous turnover of trehalose. Furthermore, changes in trehalose levels are positively correlated with the haemolymph water volume. In addition, both Tps1 and Treh mutant larvae exhibit a high lethality after desiccation stress. These results demonstrate that the regulation of trehalose metabolism is essential for normal development, body water homeostasis, and desiccation tolerance in Drosophila. PMID- 27469630 TI - Can Academic Cardiology Divisions Survive? PMID- 27469890 TI - Aspergillus fumigatus spore proteomics and genetics reveal that VeA represses DefA-mediated DNA damage response. AB - Aspergillus fumigatus reproduces and infects host by forming a high number of small asexual spores (conidia). The velvet proteins are global transcriptional regulators governing the complex process of conidiogenesis in this fungus. Here, to further understand the velvet-mediated regulation, we carried out comparative proteomic analyses of conidia of wild type (WT) and three velvet mutants (DeltaveA, DeltavelB and DeltavosA). Cluster analysis of 184 protein spots showing at least 1.5-fold differential accumulation between WT and mutants reveal the clustering of WT- DeltaveA and DeltavelB-DeltavosA. Among 43 proteins identified by Nano-LC-ESI-MS/MS, 23 including several heat shock proteins showed more than two-fold reduction in both the ?velB and ?vosA conidia. On the contrary, three proteins exhibited more than five-fold increase in ?veA only, including the putative RNA polymerase II degradation factor DefA. The deletion of defA resulted in a reduced number of conidia and restricted colony growth. In addition, the defA deletion mutant conidia showed hypersensitivity against the DNA damaging agents NQO and MMS, while the DeltaveA mutant conidia were more resistant against to NQO. Taken together, we propose that VeA controls protein level of DefA in conidia, which are dormant and equipped with multiple layers of protection against environmental cues. PMID- 27469891 TI - Proteomic analysis of soybean root exposed to varying sizes of silver nanoparticles under flooding stress. AB - Silver nanoparticles (Ag-NPs) are excessively used as antibacterial agents; however, environmental interaction specifically with the plants remain uncertain. To study the size-dependent effects of Ag-NPs on soybean under flooding, a proteomic technique was used. Morphological analysis revealed that treatment with Ag-NPs of 15nm promoted soybean growth under flooding compared to 2 and 50-80nm. A total of 228 common proteins that significantly changed in abundance under flooding without and with Ag-NPs of 2, 15, and 50-80nm. Under varying sizes of Ag NPs, number of protein synthesis related proteins decreased compared to flooding while number of amino acid synthesis related proteins were increased under Ag-NPs of 15nm. Hierarchical clustering identified the ribosomal proteins that increased under Ag-NPs of 15nm while decreased under other sizes. In silico protein-protein interaction indicated the beta ketoacyl reducatse 1 as the most interacted protein under Ag-NPs of 15nm while least interacted under other sizes. The beta ketoacyl reductase 1 was up-regulated under Ag-NPs of 15nm while its enzyme activity was decreased. These results suggest that the different sizes of Ag-NPs might affect the soybean growth under flooding by regulating the proteins related to amino acid synthesis and wax formation. BIOLOGICAL SIGNIFICANCE: This study highlighted the response of soybean proteins towards varying sizes of Ag NPs under flooding stress using gel-free proteomic technique. The Ag NPs of 15nm improved the length of root including hypocotyl of soybean. The proteins related to protein metabolism, cell division/organization, and amino acid metabolism were differentially changed under the varying sizes of Ag NPs. The protein synthesis related proteins were decreased while amino acid metabolism-related proteins were increased under varying sizes of Ag NPs. The ribosomal proteins were increased under Ag NPs of 15nm. The beta ketoacyl reductase 1 was identified as the most interacted protein under varying sizes of Ag NPs. The mRNA expression level of beta ketoacyl reductase was up-regulated under Ag NPs of 15nm while its activity was decreased. These results suggest that the Ag NPs of 15nm improved the soybean growth under flooding stress by increasing the proteins related to amino acid synthesis and waxes formation. PMID- 27469892 TI - Identification of plum and peach seed proteins by nLC-MS/MS via combinatorial peptide ligand libraries. AB - Plum (Prunus domestica L.) and peach (Prunus persica (L.) Batsch) seed proteins are a source of bioactive peptides. These seeds, though, are usual residues produced during canning and beverage preparation that, in most cases, are irreversibly lost. The recovery and identification of these proteins might be of importance in human nutrition. This work employs the combinatorial peptide ligand libraries (CPLLs) technology as a tool to reduce the proteins dynamic concentration range. The most suitable extraction and CPLL capture conditions have been obtained and applied for the comprehensive identification of seed proteins. The analysis of recovered species by nLC-MS/MS has allowed the identification of 141 and 97 unique gene products from plum and peach seeds, respectively. It was possible to identify 16 proteins belonging to the Prunus genus. Moreover, a high number of histones and seed storage proteins were identified. Additionally, 21 and 14 bioactive peptides previously identified were found within protein sequences in plum and peach seeds, respectively. SIGNIFICANCE: Plums and peaches seeds are cheap sources of proteins that are irretrievably lost after canning and beverage production. Although this kind of residues has been used in animal feed or production of biofuel, they are usually incinerated or sent to landfills, wasting their huge potential. In order to exploit this, it is important to comprehensively study proteins present in plum and peach seeds. Nevertheless, since proteomics analysis is in most cases handicapped by the presence of high-abundance proteins masking the detection of the low-abundance ones, it is important to overcome this challenge. In this sense, combinatorial peptide ligand libraries (CPLLs) have been used in this work to reduce the dynamic protein concentration range to enable the identification of a higher amount of proteins than employing conventional methods. In this work, the better extracting conditions have been optimized and up to 141 and 97 unique gene products from plum and peach seeds have been found, respectively. Moreover, 21 and 14 peptides previously identified as bioactive peptides were ascertained within protein sequences in plum and peach seeds, respectively. For that reason, this research takes the first step in the recovery of these valuable proteins and in the extraction of bioactive peptides, which could be successfully adopted in human nutrition. PMID- 27469893 TI - [The bio-psycho-social model and the International Classification of Functioning, Disability and Health : Examples of using the model, its parts and the items]. AB - BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) can be used in practice in a variety of ways. OBJECTIVES: The aim of this work is to illustrate some of the most important ways of using the ICF and some aspects of their theoretical concepts. MATERIALS AND METHODS: Database searches (PubMed, Rehadat, and Google Scholar) were conducted for studies concerning the use of the ICF in practice. RESULTS: For all aspects of the ICF, and many of the intended ways of using it, there are concrete developments and examples or indications for their implementation into practice in different contexts. In particular, the common language and the bio-psycho-social model is widely accepted and applied in practice. At the level of chapters, there are a few developments and examples of practical applications of the ICF. When using the ICF based on Items, however, diverse developments of different theoretical and methodological quality are available. CONCLUSION: The multitude of different adaptations of the ICF for practice illustrates the great effort to the implementation in practice. However, this also shows that no comprehensive solution to the satisfaction of concerned protagonists was found. Research is needed on the theoretical foundations of the ICF, capturing the current practice of using the ICF and in the creation of specific instructions for ways to use the ICF in practice. PMID- 27469894 TI - Purse-String-Assisted Full-Thickness Skin Graft: An Underutilized Technique to Reduce Graft Size and Improve Outcomes. PMID- 27469895 TI - Genetic association between SNPs in the DGAT1 gene and milk production traits in Murrah buffaloes. AB - This study identified polymorphisms in the DGAT1 gene in Murrah buffaloes and investigated the associations to milk production and quality traits (milk, fat and protein yields and percentages, somatic cell count). Genomic DNA was extracted from hair follicles collected from the tail of 196 females. Three SNPs were identified in DGAT1 gene by sequencing. Statistical analyses were performed to verify the linkage and the association between polymorphisms and traits. The estimated value of r (2) between two SNPs in exon 17 (g.11,783G > A and g.11,785 T > C) was 0.029. SNP g.11,785 T > C was significantly associated (P < 0.05) to fat and protein percentage. Dominance effect was significant for milk and fat yields and protein percentage (P < 0.05). The additive effect of the SNP g.11,785 T > C was significant for protein production and somatic cell count (P < 0.05). It indicates that assisted marker selection might be done with considerations to balance production and udder health. PMID- 27469897 TI - Using the 'Think Aloud' Technique to Explore Quality of Life Issues During Standard Quality-of-Life Questionnaires in Patients With Atrial Fibrillation. AB - AIMS AND OBJECTIVES: To investigate whether using the 'think aloud' technique during standard quality of life surveys provides useful additional information about patients' experiences of living with atrial fibrillation (AF) and health related quality of life (HRQoL). BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia and has serious health consequences, particularly ischaemic stroke, high rates of morbidity and mortality and poor HRQoL. Standard quality-of-life questionnaires are often used but may not provide sufficient detail of patients' experiences living with AF. DESIGN: A qualitative interpretative study based on semi-structured interviews. METHODS: Patients with AF (n=12) were recruited from the Choice of Health Options in Prevention of Cardiovascular Events-in Atrial Fibrillation (CHOICE-AF), a risk factor management program. Participants were interviewed using a 'think aloud' technique with questions guided by the AF Effects on Quality Of Life Questionnaire (AFEQT) and the Short Form-12 (SF-12). Interviews were audio-recorded, transcribed and analysed thematically. RESULTS: Participants had a median age of 71 years (interquartile range 52 to 77 years), and included four women and eight men. Four themes were identified related to experiences of living with AF and HRQoL including: (1) the adverse impact of atrial fibrillation symptoms, treatments, and related knowledge; (2) loss of function or independence; (3) the influence of age; and (4) approach to life. CONCLUSIONS: Atrial fibrillation, especially in older adults, creates an additional layer of requirements for self-management onto existing self-care needs. Even for patients with relatively high HRQoL, the 'think aloud' technique together with standard HRQoL questionnaires can help identify additional issues that can be addressed by health professionals to improve the HRQoL of these patients. PMID- 27469896 TI - Partial sequencing reveals the transposable element composition of Coffea genomes and provides evidence for distinct evolutionary stories. AB - The Coffea genus, 124 described species, has a natural distribution spreading from inter-tropical Africa, to Western Indian Ocean Islands, India, Asia and up to Australasia. Two cultivated species, C. arabica and C. canephora, are intensively studied while, the breeding potential and the genome composition of all the wild species remained poorly uncharacterized. Here, we report the characterization and comparison of the highly repeated transposable elements content of 11 Coffea species representatives of the natural biogeographic distribution. A total of 994 Mb from 454 reads were produced with a genome coverage ranging between 3.2 and 15.7 %. The analyses showed that highly repeated transposable elements, mainly LTR retrotransposons (LTR-RT), represent between 32 and 53 % of Coffea genomes depending on their biogeographic location and genome size. Species from West and Central Africa (Eucoffea) contained the highest LTR RT content but with no strong variation relative to their genome size. At the opposite, for the insular species (Mascarocoffea), a strong variation of LTR-RT was observed suggesting differential dynamics of these elements in this group. Two LTR-RT lineages, SIRE and Del were clearly differentially accumulated between African and insular species, suggesting these lineages were associated to the genome divergence of Coffea species in Africa. Altogether, the information obtained in this study improves our knowledge and brings new data on the composition, the evolution and the divergence of wild Coffea genomes. PMID- 27469898 TI - A biomechanical comparison between expert and novice manual materials handlers using a multi-joint EMG-assisted optimization musculoskeletal model of the lumbar spine. AB - Expertise is a key factor modulating the risk of low back disorders (LBD). Through years of practice in the workplace, the typical expert acquires high level specific skills and maintains a clean record of work-related injuries. Ergonomic observations of manual materials handling (MMH) tasks show that expert techniques differ from those of novices, leading to the idea that expert techniques are safer. Biomechanical studies of MMH tasks performed by experts/novices report mixed results for kinematic/kinetic variables, evoking potential internal effect of expertise. In the context of series of box transfers simulated by actual workers, detailed internal loads predicted by a multiple joint EMG-assisted optimization lumbar spine model are compared between experts and novices. The results confirmed that the distribution of internal moments are modulated by worker expertise. Experts flexed less their lumbar spine and exerted more active muscle forces while novices relied more on passive resistance of the muscles and ligamentous spine. More specifically for novices, the passive contributions came from global extensor muscles, selected local extensor muscles, and passive structures of the lumbar spine (ligaments and discs). The distinctive distribution of internal forces was not concomitant with a similar effect on joint forces, these forces being dependent on external loading which was equivalent between experts and novices. From a safety standpoint, the present results suggest that experts were more efficient than novices in partitioning internal moment contributions to balance net (external) loading. Thus, safer handling practices might be seen as a result of experts' experience. PMID- 27469899 TI - Therapeutic drug monitoring for sofosbuvir and daclatasvir in transplant recipients with chronic hepatitis C and advanced renal disease. PMID- 27469900 TI - Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis. AB - BACKGROUND & AIMS: Neonatal sclerosing cholangitis (NSC) is a severe neonatal onset cholangiopathy commonly leading to liver transplantation (LT) for end-stage liver disease in childhood. Liver biopsy findings histopathologically resemble those in biliary atresia (BA); however, in NSC extrahepatic bile ducts are patent, whilst in BA their lumina are obliterated. NSC is commonly seen in consanguineous kindreds, suggesting autosomal recessive inheritance. METHODS: From 29 NSC patients (24 families) identified, DNA was available in 24 (21 families). Thirteen (7 male) patients (12 families) of consanguineous parentage were selected for whole exome sequencing. Sequence variants were filtered for homozygosity, pathogenicity, minor allele frequency, quality score, and encoded protein expression pattern. RESULTS: Four of 13 patients were homozygous and two were compound heterozygous for mutations in the doublecortin domain containing 2 gene (DCDC2), which encodes DCDC2 protein and is expressed in cholangiocyte cilia. Another 11 patients were sequenced: one (with one sibling pair) was compound heterozygous for DCDC2 mutations. All mutations were protein-truncating. In available liver tissue from patients with DCDC2 mutations, immunostaining for human DCDC2 and the ciliary protein acetylated alpha-tubulin (ACALT) showed no expression (n=6) and transmission electron microscopy found that cholangiocytes lacked primary cilia (n=5). DCDC2 and ACALT were expressed in NSC patients without DCDC2 mutations (n=22). Of the patients carrying DCDC2 mutations, one died awaiting LT; five came to LT, of whom one died 2years later. The other 4 are well. CONCLUSION: Among 24 NSC patients with available DNA, 7 had mutations in DCDC2 (6 of 19 families). NSC patients in substantial proportion harbour mutations in DCDC2. Their disease represents a novel liver-based ciliopathy. LAY SUMMARY: Neonatal sclerosing cholangitis (NSC) is a rare genetic form of liver disease presenting in infancy. Through next generation sequencing we identified mutations in the gene encoding for doublecortin domain containing 2 (DCDC2) protein in a group of NSC children. DCDC2 is a signalling and structural protein found in primary cilia of cholangiocytes. Cholangiocytes are the cells forming the biliary system which is the draining system of the liver. PMID- 27469901 TI - Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. AB - BACKGROUND & AIMS: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. METHODS: Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. RESULTS: In the overall safety population (n=3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n=3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 [4.6-6.3]). CONCLUSIONS: In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. LAY SUMMARY: The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment. PMID- 27469902 TI - Epidemiology of onychomycosis in Serbia: a laboratory-based survey and risk factor identification. AB - Onychomycosis is a fungal infection of the fingernails and/or toenails caused by dermatophytes, yeasts and non-dermatophyte moulds. The epidemiology of onychomycosis in Serbia is yet to be fully established. This epidemiological study was aimed at evaluating the epidemiology of onychomycosis in a sample of the Serbian patients at risk of onychomycosis, to determine the fungal aetiological agents and to identify the possible risk factors. The study population included 374 patients from six centres in Serbia with suspected onychomycosis. Demographic data, data about comorbidities, lifestyle, clinical aspects of onychomycosis, trauma, excessive perspiration and personal and family history of previous onychomycosis were studied. Laboratory confirmation of diagnosis was done by direct microscopy, fungal culture and PCR. Diagnosis of onychomycosis was confirmed in 50.8% of patients, who tested positive to at least one laboratory test (direct microscopy, fungal culture or PCR). Trichophyton rubrum was predominant both on toenails (85.98%) and on fingernails (38.46%). Independent risk factors for onychomycosis were: old age (OR = 2.285; P < 0.001), family history of previous onychomycosis and/or tinea pedis (OR = 2.452; P = 0.005), excessive perspiration (OR = 2.165; P = 0.002) and higher degree of hyperkeratosis (OR = 1.755; P = 0.020). This is a first epidemiological study of onychomycosis from Serbia. PMID- 27469904 TI - Petasis-Ugi ligands: New affinity tools for the enrichment of phosphorylated peptides. AB - Affinity chromatography is a widespread technique for the enrichment and isolation of biologics, which relies on the selective and reversible interaction between affinity ligands and target molecules. Small synthetic affinity ligands are valuable alternatives due to their robustness, low cost and fast ligand development. This work reports, for the first time, the use of a sequential Petasis-Ugi multicomponent reaction to generate rationally designed solid-phase combinatorial libraries of small synthetic ligands, which can be screened for the selection of new affinity adsorbents towards biological targets. As a proof of concept, the Petasis-Ugi reaction was here employed in the discovery of affinity ligands suitable for phosphopeptide enrichment. A combinatorial library of 84 ligands was designed, synthesized on a chromatographic solid support and screened in situ for the specific binding of phosphopeptides binding human BRCA1C-terminal domains. The success of the reaction on the chromatographic matrix was confirmed by both inductively coupled plasma atomic emission spectroscopy and fluorescence microscopy. Three lead ligands were identified due to their superior performance in terms of binding capacity and selectivity towards the phosphorylated moiety on peptides, which showed the feasibility of the Petasis-Ugi reaction for affinity ligand development. PMID- 27469903 TI - Liquid chromatography-tandem mass spectrometric assay for the T790M mutant EGFR inhibitor osimertinib (AZD9291) in human plasma. AB - A method for the quantitative analysis by ultra-performance liquid chromatography tandem mass spectrometry of the highly selective irreversible covalent inhibitor of EGFR-TK, osimertinib in human plasma was developed and validated, using pazopanib as an internal standard. The validation was performed in a range from 1 to 1000ng/ml, with the lowest level corresponding to the lower limit of quantitation. Gradient elution was performed on a 1.8MUm particle trifunctional bonded C18 column by 1% (v/v) formic acid in water, and acetonitrile as mobile phase. The analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer after positive ionization with the heated electrospray interface. Within-day precisions ranged from 3.4 to 10.3%, and between-day precisions from 3.8 to 10.4%, accuracies were 95.5-102.8%. Plasma (either lithium heparin or sodium EDTA) pretreatment was performed by salting-out assisted liquid-liquid extraction using acetonitrile and magnesium sulfate. This method was used to analyze the osimertinib blood plasma levels of five adult patients with metastatic T790M mutated non-small cellular lung carcinoma for therapeutic drug monitoring purposes. PMID- 27469905 TI - Quantification of cefazolin in serum and adipose tissue by ultra high performance liquid chromatography-Tandem mass spectrometry (UHPLC-MS/MS): application to a pilot study of obese women undergoing cesarean delivery. AB - Higher doses of cefazolin are required in obese patients for preoperative antibiotic prophylaxis, owing to its low lipophilicity. An ultra high performance liquid chromatography-tandem mass spectrometry method was developed to quantify cefazolin in serum and adipose tissue from 6 obese patients undergoing cesarean delivery, and using stable-isotope labeled cefazolin as an internal standard. The method has a 2MUg/g lower limit of quantitation. The concentration in adipose tissue was 3.4+/-1.6MUg/mL, which is less than half of the reported minimum inhibitory concentration of 8MUg/mL for cefazolin. Serum cefazolin concentrations were more than 30-fold higher than in adipose tissue. PMID- 27469907 TI - Effect of Endometrial Stem Cell-derived Cytokine Cocktail on a Mouse Model of Myocardial Reperfusion Injury. AB - Objective To study the effect of endometrial stem cells (EnSCs) derived cytokine cocktail (EdCC) on myocardial ischemic reperfusion injury (I/R) in a mouse model. Methods EdCC was concentrated from the culture medium of EnSCs with Millipore ultra-filtration technology and was administrated to a myocardial I/R mouse models through tail vein injection. The infarct area was determined by TTC/Evans Blue staining. The apoptotic cells were counted by TUNEL assay and the protein level of cleaved caspase 3 was evaluated by Western blotting. Results The EdCC extraction efficiency was (222.4+/-29.3) MUg/10(6) cells in every 24 h,but the protein gradually degraded under-80 C storage. As compared with I/R group,100 MUg fresh EdCC decreased infarct area (P=0.001),reduced apoptotic nuclei in the infarct border (P=0.019),and inhibited cleaved caspase 3 expression (P=0.002). Increasing EdCC dosage did not further reduce the infarct area. The myocardial protective effect of EdCC diminished after 90 days' storage under-80 C. Conclusion EdCC reduces myocardial I/R injury through protecting cardiomyocytes from apoptosis within 30 days storage under-80 C. PMID- 27469908 TI - Effect of Qi-regulating,Phlegm-resolving,and Blood-promoting Prescription on Rat Coronary Microvascular Thrombosis and Coronary Microvascular Occlusion. AB - Objective To explore the effect of qi-regulating,phlegm-resolving,and blood promoting prescription on coronary microvascular thrombosis and coronary microvascular occlusion in rat models. Methods Totally 125 healthy clean-grade male SD rats weighing (300+/-25) g were sequentially numbered and then randomly divided into treatment group (n=60),control group (n=60) and blank group (n=5).Rats in the treatment group and control group received apical left ventricular injection of sodium laurate to establish rat models of coronary microvascular thrombosis. Then,rats in the control group were given distilled water by gavage one day before operation and after surgery. In contrast,rats in the treatment group were given qi-regulating,phlegm-resolving,and blood-promoting prescription by gavage one day before operation and after surgery. Five rats from both treatment group and control group were killed at each of six time points (1 hour,24th hour,7th day,14th day,21th day,and 28th day),and the myocardium specimens were harvested. The 5 rats in the blank group did not receive any special treatment and were given normal feeding;in the 28th day,they were sacrificed to obtain the myocardial specimens. Pathological sections of rat myocardial tissues were made to observe and compare the degrees of coronary microvascular thrombosis and coronary microvascular obstruction.Results In the treatment group and the control group,coronary microvascular thrombosis occurred 1 hour after apical sodium laurate injection and reached the peak at the 24th hour. Compared with the blank group,the treatment group and the control group showed different degree of coronary microvascular obstruction. Comparison between the treatment group and the control group at each time point showed that the coronary microvascular thrombosis in the treatment group was significantly lower than that in the control group (P<0.05 or P<0.01).The severity of coronary microvascular occlusion was significantly milder in the treatment group than in the control group (P<0.05 or P<0.01).Conclusions Apical left ventricular injection of sodium laurate successfully established rat models of coronary microvascular thrombosis. Qi-regulating,phlegm-resolving,and blood-promoting prescription can reduce coronary microvascular thrombosis and improve coronary microvascular obstruction. PMID- 27469909 TI - Expressions of CCAAT/enhancer-binding Protein Homologous Protein and Calnexin in the Hippocampus of a Mouse Model of Mesial Temporal Lobe Epilepsy. AB - Objective To explore the temporal and spatial distribution of CCAAT/enhancer binding protein homologous protein (CHOP) and calnexin (CNX) in the dentate gyrus of mesial temporal lobe epilepsy (mTLE) mouse model. Methods We used kainic acid (KA) to induce acute phase (12 h and 24 h) mTLE mouse models and performed Western blotting and immunofluorescence to detect the different expressions and distribution pattern of CHOP and CNX in CA3 of the hippocampus. Results Compared with the controls,the expressions of CHOP(F=1.136,P=0.4069) and CNX (F=2.378,P=0.2087) did not increase in CA3 of hippocampus 12 h following KA injection in the acute phase of mTLE mouse models,whereas the expressions in CA1 and CA3 of hippocampus 24 h after injection were significantly higher (F=8.510,P=0.0362;F=6.968,P=0.0497,respectively). As shown by immunofluorescence analysis,CHOP was expressed mainly in CA3 of hippocampus 12 h after KA injection,and increased in CA1 and CA3 24 h after KA administration. Compared with the controls,the expressions of CHOP(F=24.480,P=0.0057) and CNX (F=7.149,P=0.0478) were significantly higher 24 h after KA injection.Conclusions The expression of CHOP increases along with the progression of seizures,indicating the increased level of endoplasmic reticulum stress. An increasing number of CNX,which serves as molecular chaperone,may be needed to facilitate the unfolded protein to complete the folding process. PMID- 27469910 TI - Impact of the Action Time of Inducers on Differentiation of 3T3-L1 Cells. AB - Objective To explore the effect of the action time of inducers on the differentiation of 3T3-L1 cells to adipocytes. Methods According to the "Cocktail" method,3T3-L1 cells were divided into three groups according to the action time of inducers,with the action time being 2,3 or 4 days,respectively. Cell morphology was observed using inverted microscope and adipose content were detected by Oil red "O" staining and detection of triglyceride. The cell viability was identified by trypan blue staining method. Results The proportion of samples (n=12) with differentiation rate above 80% in group A was 66% (12/18),while the differentiation rate of all the samples (n=18)in group B and group C were above 80%. For the Oil red "O",the OD value at 510 nm in group C was 2.59+/-0.17,which was significantly higher than that in group A (2.12+/ 0.47;F=6.62,P=0.0001)and group B (2.20+/-0.17;F=5.15,P=0.0001),while no significant difference was found between group A and group B (F=1.14,P=0.74). As for the triglyceride,the value in group C was (1351.04+/-119.01)ng/ml,which was significantly higher than that in group A[ (1077.88+/ 272.75)ng/ml;F=6.73,P=0.001] and group B [(1089.38+/ 115.39)ng/ml;F=5.78,P=0.001],while no difference was found between group A and group B (F=0.27,P=0.64). The cell viability in group A,B,and C was (98.3+/ 1.2)%,(98.5+/-1.8)%,and (98.9+/-2.1)%,respectively,showing no significant difference (F=0.18,P=0.83). Conclusions The modified procedure for the differentiation of 3T3-L1 cells to adipocytes can increase the differentiation rate and thus may be applied for establishing adipocyte models. The recommended action time is three days. PMID- 27469912 TI - Associations of White Blood Cell Count,Alanine Aminotransferase,and Aspartate Aminotransferase in the First Trimester withGestational Diabetes Mellitus. AB - Objective To explore the associations of white blood cell (WBC) count,alanine aminotransferase (ALT),and aspartate aminotransferase(AST) in the first trimester of pregnancy with gestational diabetes mellitus (GDM). Methods Totally 725 GDM women and 935 women who remained euglycemic throughout pregnancy were enrolled in this study. Pre-pregnancy weight/height were recorded. WBC,ALT,and AST levels were detected between 8 and 12 weeks of pregnancy.At 24 to 28 weeks of pregnancy,the glucose and insulin levels were measured. The WBC,ALT,and AST levels were compared between two groups,and the associations of WBC,ALT,and AST levels with the blood glucose and insulin levels were retrospectively analyzed. Meanwhile,the potential associations of those factors with the occurrence of GDM were analzyed. Results WBC count [9.41(8.15,10.84)?10(9)/L vs. 9.04 (7.64,10.37)?10(9)/L,P=1.0?10(-5)] and ALT levels [18.00(12.00,30.00)U/L vs. 16.00 (11.00,26.00)U/L,P=0.004] in the first trimester of pregnancy were significantly increased in GDM subjects than in normal glucose tolerance(NGT)subjects;however,the AST level showed no significant difference between these two groups [41.00 (26.00,43.00)U/L vs. 41.00 (23.00,43.00)U/L,P=0.588]. Logistic regression analysis illustrated that elevated WBC count was an independent risk factor for GDM after adjustment for age,pre pregnancy body mass index,blood pressure,and family history of diabetes(OR=1.119,P=0.001). The ROC curve revealed that threshold of WBC count was 7.965?10(9)/L(AUC=0.566,P=1?10(-5)),which had a sensitivity of 79.4% and a specificity of 31.3%. Multivariate linear regression analysis showed that homeostasis model assessment of insulin resistance was positively correlated with WBC count(B=0.051,P=0.022,R(2)=0.083);1-hour blood glucose after oral 50 grams of sugar (B=0.044,P=0.001,R(2)=0.044) and fasting plasma true insulin(B=0.214,P=0.032,R(2)=0.066) were positively correlated with WBC count;1 hour true insulin after 100 grams oral glucose to lerance test(OGTT) was positively correlated with AST (B=0.616,P=1.85?10(-5),R(2)=0.052);2-hour true insulin after 100 grams OGTT was positively correlated with ALT (B=0.148,P=0.027)and AST(B=0.936,P=3.71?10(-8),R(2)=0.077);and 3-hour true insulin after 100 grams oral glucose tolerance test(OGTT) was positively correlated with ALT (B=0.189,P=0.002) and AST (B=0.688,P=7.25?10( 6),R(2)=0.067).Conclusions The WBC count in the first trimester of pregnancy can increase the risk of GDM. Thus,WBC count may be a useful predictors of GDM. PMID- 27469911 TI - Value of Chloride Clearance Test in Differential Diagnosis of Gitelman Syndrome. AB - Objective To investigate the value of chloride clearance test in differential diagnosis of Gitelman syndrome (GS). Methods For patients with hypokalemic metabolic alkalosis and highly suspected GS,clinical data were documented and SLC12A3 gene screening was performed as gold standard to diagnose GS. Hydrochlorothiazide (HCT) test and furosemide (FUR) test were performed according to the standard process. Baseline and maximal increasement of chloride excretion fraction (FECl,the net and relative increase measured as epsilonFECl) were compared between patients and controls to evaluated the reaction to the corresponding diuretics. Receiver operating characteristic (ROC) curve was used to evaluate the sensitivity and specificity of HCT test in GS diagnosis. Results Totally 27 patients and 20 health controls received HCT test. Among those patients,23 were diagnosed with GS genetically. When using the net and relative epsilonFECl to diagnose GS,the areas under the ROC curve were 0.987 (95% CI:0.963~1.000,P<0.001) and 0.984 (95%CI:0.950~1.000,P<0.001),respectively. When a reasonable cutoff value for epsilonFECl was selected,the sensitivity and specificity were both higher than 95%. Eight patients received both HCT test and FUR test. Five of them showed decreased reaction to HCT(net epsilonFECl<=2.86% or relative epsilonFECl<=223%),while normal reaction to FUR.SLC12A3 mutations confirmed their GS. Three patients with blunt reaction to FUR showed normal reaction to HCT,finally they were diagnosed as BS clinically because no SLC12A3 gene mutation was detected. Conclusion Comprehensive application of HCT test and FUR test to evaluate the diuretic reaction can effectively differentiate GS and BS. PMID- 27469913 TI - Clinical Characteristics of Ulcerative Colitis Complicated with Opportunistic Infections in Elderly Patients. AB - Objective To summarize the clinical features,management,and outcome of ulcerative colitis (UC) complicated with opportunistic infections in the elderly patients. Methods The clinical data of 43 elderly UC patients in Peking Union Medical College Hospital from 2006 to 2016 were retrospectively analyzed. These patients were divided into two groups for comparisons:the infection group (complicated with opportunistic infection,n=14) and control group (without opportunistic infection,n=29). Results In the infection group,there were 10 men(71.4%),with an average age of (65.0+/-4.3) years (60-75 years) and a median disease course of 11.0 (3.5,52.5) months. Compared with the control group,the infection group had significantly higher proportion of extensive colitis (78.6% vs. 44.8%,P=0.04). The proportion of severe colitis was also higher in the infection group,but the difference was not statistically significant(50.0% vs. 20.7%;Chi(2)=2.58,P=0.11). Compared with the control group,the infection group had significantly longer hospital stay[(35.7+/-13.8)d vs.(22.0+/-15.8)d,P=0.01].The proportions of organ failure and mortality were significantly higher in the infection group[(21.4% vs. 0),(7.1% vs. 0)]. The proportions of emergent operation (50.0% vs. 17.2%;Chi(2)=3.54,P=0.06) and steroid dependence or resistance (64.3% vs. 43.8%;Chi(2)=1.27,P=0.26) were higher in the infection group,but the difference was not statistically significant. Conclusions In the elderly UC patients,opportunistic infection is associated with higher disease activity,higher medical cost,and worse prognosis. Early detection and correct treatment is mandatory to improve patient outcome. PMID- 27469914 TI - Prognostic Superiority of Log Odds of Positive Lymph Nodes in Stage 3 Colorectal Cancer. AB - Objective To evaluate the prognostic value of the log odds of positive lymph nodes (LODDS) in stage 3 colorectal cancer (CRC) patients who have undergone curative resection. Methods We performed a retrospective review of 175 stage 3 CRC patients who underwent curative resection in Peking Union Medical College Hospital from 2005 to 2012. Patients were categorized respectively according to the AJCC/UICC N grade,the metastatic lymph node ratio (LNR),and the ratio of their LODDS. The relationship between the N grade,LNR,LODDS,and overall survival (OS) rates were assessed.Results The five-year disease-free survival (DFS) was significantly different among stage 3 CRC patients in different N grade (Chi(2)=33.1,P=0.000),LNR (Chi(2)=14.3,P=0.001),and LODDS (Chi(2)=14.9,P=0.001). Univariate analysis showed that TNM stage (Chi(2)=27.0,P=0.000),cancerous node(Chi(2)=3.6,P=0.040),N grade (Chi(2)=33.1,P=0.000),LNR (Chi(2)=14.3,P=0.001),and LODDS (Chi(2)=30.4,P=0.000) were related to OS. Multivariate analysis indicated that TNM stage (HR:1.84,95%CI:1.59~6.29,P=0.001) and LODDS classification (HR:1.34,95%CI:1.01~1.80,P=0.047) were independent prognostic factors for OS in stage 3 CRC patients. Conclusion LODDS is a good prognostic indicator in stage 3 CRC patients who have undergone curative resection. PMID- 27469915 TI - Efficiency of Sunitinib in Chinese Patients with Advanced Progressive Pancreatic Neuroendocrine Tumor. AB - Objective To explore the efficiency of sunitinib in Chinese pancreatic neuroendocrine tumors (pNET) patients. Methods Advanced pNET patients who had accepted sunitinib treatment in the oncology department of PUMC Hospital from January 2009 to June 2015 after disease progression were enrolled in this study. Data collection included clinicopathological characteristics,medical therapies and outcomes. Results Eighteen pNET patients were collected. The overall response rate (ORR) was 27.7% and the disease control rate (DCR) was 83.3%. Nine patients received sunitinib as the first-line therapy and 9 as the second/post-second line. The median progression-free survival (mPFs)(12 month vs. 12 month;HR:0.92,95%CI:0.31-2.75,P=0.88),ORR (22.2% vs.33.3%;Chi(2)=0.055,P=0.98),and DCR (88.9% vs.77.8%;Chi(2)=0.4,P=0.98)showed no significant difference between first-line therapy and post-second line therapy. The mPFS of Ki-67>=10% and Ki-67<10% group patients was not significantly different (8 months vs. 13 months;HR:1.13,95% CI:0.34-3.77,P=0.845). The commonly reported adverse events included bone marrow suppression,diarrhea,roteinuria,hypertension,and rash. Conclusions First-line or second/post-second line sunitinib treatment has certain antitumor activity in Chinese patients with advanced pNET. The efficiency and commonly reported adverse events of Sunitinib are consistent with the known Western data. PMID- 27469916 TI - Anesthesia Strategies and Perioperative Optimization for Patients with Ankylosing Spondylitis Undergoing Total Hip Replacement Surgery. AB - Objective To identify the characteristics of anesthesia and perioperative management for ankylosing spondylitis (AS) patients undergoing total hip arthroplasty (THA). Methods Totally 63 patients scheduled for single THA in PUMC Hospital from January 1st 2013 to June 1st 2015 were included in this retrospective analysis,among whom 21 patients were diagnosed of AS. The perioperative clinical data included:demographic data,American Society of Anesthesiologists (ASA) classification,medical history,airway assessment,preoperative laboratory examinations,electrocardiogram,pulmonary function tests,intubation information,operation time,intraoperative intake and output volume,postoperative hospital stay,and postoperative complications. Results Significantly fewer AS patients undergoing THA were evaluated as ASA classification I than non-AS patients (9.5% vs. 33.3%,P=0.041). AS patients had significantly higher level of preoperative high-sensitivity C-reactive protein [(17.0+/-14.8)mg/L vs.(4.3+/-7.1)mg/L,P<0.001],platelets [(275.0+/-71.3)*10(9)/L vs. (237.7+/-68.0)*10(9)/L,P=0.048] and neutrophils [(4.7+/-1.7)*10(9)/L vs. (3.9+/-1.4)*10(9)/L,P=0.044] and higher incidence of pulmonary function abnormality (42.9% vs.16.7%,P=0.024).More AS patients were induced with scoline (14.3% vs.0,P=0.012). More AS patients underwent THA with Mallampati classification 3 (28.6% vs.7.1%,P=0.022),reduced neck extension(47.6% vs.2.4%,P<0.001),Cormack-Lehane classification2(56.3% vs.15.4%,P=0.002)and 3 (18.8% vs.0,P=0.005),while much fewer AS patients had Cormack-Lehane classification1 (25.0% vs.84.6%,P<0.001).A variety of difficult airway tools were used in intubation (AS group:Macintosh laryngoscope:14%,Macintosh laryngoscope with stylet:38%,visualization laryngoscope:24%,visualization stylet:10% and fiber bronchoscope:14%;non-AS group:57%,24%,12%,5% and 2%,respectively). The use of intraoperative autologous blood transfusion (33.3% vs.11.9%,P=0.041) and postoperative 24 h drainage (61.9% vs.31.0%,P=0.019) were more common in AS group. However,no statistical difference existed in the success rate of first intubation,postoperative hemoglobin,postoperative hematocrit,and postoperative hospitalization(all P>0.05). Conclusions AS patients undergoing THA have elevated preoperative inflammatory markers,with high incidence of pulmonary function abnormality and difficult airway. In consideration of high risk of surgery and anesthesia,adequate airway evaluation and optimization of perioperative management are needed to ensure the patients' safety. PMID- 27469917 TI - Comparison of Multislice Spiral CT Dual Phase and Somatosatatin Receptor Scintigraphy in the Diagnosis of Pancreas Neuroendocrine Tumors. AB - Objective To compare the sensitivity of multislice spiral CT dual phase and somatosatatin receptor scintigraphy (SRS) in the diagnosis of pancreas nuroendocrine tumors (pNET). Methods Totally 28 patients with pathologically confirmed pNET recieved both CT dual phase contrast and SRS and the results were compared. Results Of these 28 pNET patients,26 (92.8%) were accurately diagnosed by CT dual-phase scan and 20 (71.4%) by SRS (P=0.031).In the functioning pNET cases,the diagnosis sensitivity of CT dual phase scan and SRS was 94.1% (16/17)and 58.8% (10/17)(P=0.218). In the non-functioning pNET cases,the sensitivity was 90.9% (10/11) and 90.9% (10/11) (P=0.740).Diagnostic sensitivity of CT dual phase scan and SRS for pNET without metastasis was 90.4% (19/21) and 57.1% (12/21) (P=0.125).The sensitivity for pNET with metastasis was 100%(7/7)and 100% (7/7). Corresponding to the pathological grading,the diagnostic sensitivity of CT dual phase scanning and SRS was 84.6% (11/13) and 53.8% (7/13) for G1,100% (12/12) and 83.3% (10/12) for G2,and 100% (3/3) and 100% (3/3) for G3. The diagnostic sensitivity of CT dual phase scan and SRS for pNET with diameter less than or equal to 2.0 cm was 94.7% (18/19) and 52.6% (10/19) (P=0.008). For pNET with diameter more than 2.0 cm,the sensitivity was 92.8% (13/14) and 100% (14/14). Conclusions Compared with SRS,dual phase CT scan is more sensitive in diagnosing pNET,especially for those in lower pathological stages. For lesions sized less than or equal to 2.0 cm,SRS should be combined with other imaging examinations to minimize false negative results. PMID- 27469918 TI - Value of CT Density Measurements in Distinguishing Parathyroid Adenoma,Thyroid,and Lymph Node. AB - Objective To explore the value of multi-phase contrast-enhanced computed tomography in the differential diagnosis of parathyroid adenoma,lymph node,and thyroid. Methods The enhanced multi-slice CT (MSCT) results of 21 parathyroid adenoma patients were analyzed,and their postoperative pathological specimens were examined. During the MSCT,the plain CT scan was recorded,along with the density of thyroid adenoma,lymph nodes,and thyroid at 35 s and 65 s (D0,D35,D65) following the injection of contrast medium. Results During the D0 phase,there was significant difference in CT values between the parathyroid adenoma and thyroid parenchyma[(45?12) HU vs.(90?15)HU,P=0.007]. According to ROC curve,75 HU,with 95.2% sensitivity and specificity,was the critical value for distinguishing the density of parathyroid adenoma and that of thyroid parenchyma. At 35 s following the injection of contrast medium,there was significant difference in the enhancement degree between parathyroid adenoma and lymph node[(182?39) HU vs.(80?20)HU,P=0.004]. According to ROC curve,111 HU,with 95.2 % sensitivity and specificity,was the critical value for distinguishing the density of parathyroid adenoma and that of lymph node 35 s following the injection of contrast medium. At 35 s to 65 s following the injection of contrast medium,the parathyroid adenoma experienced a decline in density,which was dramatically different from parathyroid adenoma,however,lymph node experienced a rise in density. Conclusion Enhanced CT measurements at different time points enable the differentiation among parathyroid adenomas,lymph nodes,and thyroid. PMID- 27469919 TI - Computed Tomography Signs for Active Severe Gastrointestinal Bleeding. AB - Objective To summarize the positive signs on multi-detector CT angiography (CTA) for active severe gastrointestinal bleeding (GIB).Methods We retrospectively evaluated the clinical records and CT images of 93 patients with active severe GIB confirmed by digital subtraction angiography (DSA),endoscopy or surgery. The positive CT signs indicating the locations and causes of the bleeding were recorded. Results Intraluminal extravasation of contrast material was identified in 44 cases (47.3%),vascular malformation was found in 22 cases (23.7%),gastrointestinal tumor was detected in 18 cases (19.4%),focal or segmental abnormal bowel mucosal enhancement was present in 7 cases (7.5%),and diverticulum with abnormal enhancement was found in 2 cases (2.2%). Conclusion Positive signs for active severe GIB on CT are diverse and thus should be carefully interpreted in clinical setting. PMID- 27469920 TI - Value of High-frequency Ultrasound in the Diagnosis of Peripheral Nerve Compression in Rheumatoid Arthritis Patients. AB - Objective To evaluate the value of high-frequency ultrasound (HFUS) in diagnosing peripheral nerve compression in patients with rheumatoid arthritis (RA). Methods The upper limb nerves were evaluated by HFUS in 80 RA patients (RA group) and 60 non-RA patients (control group),then the incidence of peripheral nerve compression was recorded respectively. RA patients with/without neurological symptoms were compared in terms of age,disease course,Health Assessment Questionnaire Disability Index (HAQ-DI) score,and clinical disease activity index (CDAI). Results The incidence of upper limb nerve compression in RA group was significantly higher than that in control group(15.0% vs. 3.3%,P=0.046).The patients with nerve compression was older [(60.2+/-11.4)y vs.(49.2+/ 7.9)y;t=2.343,P=0.039] and had longer disease course [(9.50+/-5.99) y vs. (5.88+/ 3.87)y;t=2.639,P=0.023] and higher HAQ-DI score (1.58+/-0.75 vs.0.85+/ 0.67;t=2.490,P=0.030). These two groups had no statistical differences in CDAI (14.50+/-11.68 vs.16.62+/-9.24;t=1.141,P=0.278).Conclusions Peripheral neuropathies are common extra-articular manifestations in RA patients. HFUS can be valuable in patients suspected of RA. PMID- 27469922 TI - Value of Contrast-enhanced Ultrasound for Small Focal Liver Lesions. AB - Objective To explore the diagnostic value of contrast-enhanced ultrasound (CEUS)for small focal liver lesions (FLLs). Methods The clinical data,CEUS findings,and pathology of 69 patients with small FLLs were retrospectively analyzed. Patients were grouped according to size of FLLs and the performance of CEUS was compared. Results The accuracy,sensitivity,specificity,positive predictive value,and negative predictive value of CEUS for the 69 FLLs were 94.2%,95.2%,93.8%,87.0%,and 97.8%,respectively. Rate of fast wash-out in portal vein phase was lower in group of diameters <=2 cm than that in group of diameters>2 cm (P<0.05). Conclusions CEUS has a high diagnostic value for small FLLs.However,the CEUS findings of malignant lesions smaller than 2 cm are not typical in the portal phase and therefore the diagnosis should also be based on clinical features. PMID- 27469921 TI - Value of High-frequency Ultrasound in the Diagnosis of Supinator Syndrome. AB - Objective To evaluate the diagnostic value of high-frequency ultrasound in the diagnosis of supinator syndrome (SD). Methods Ten patients with supinator syndrome (SD group) and 20 healthy volunteers (control group) underwent ultrasonographic examination. Axial and long-axis views of the radial nerve were taken where the nerves enters the supinator muscle entrance. The maximum transverse diameter and anteroposterior diameter were also measured. Results High-frequency ultrasound clearly revealed the images and course of radial nerve deep branch in two groups. The SD group had swollen nerves and the maximum transverse diameter and anteroposterior diameter were (3.50?0.39)mm and (4.30?0.47)mm,respectively,which were significantly larger than in the control group [(1.10?0.17)mm,t=-29.67,P=0.00;(1.00?0.16)mm,t=-36.72,P=0.00). The causes (including synovial cyst nearby and radial artery recurrent branch) of nerve entrapment were revealed directly in 4 patients in SD group. Conclusions High frequency ultrasound can clearly display the radial nerve deep branch around the elbow joint. SD patients have swollen nerves at the entrance of the supinator muscle,where the diameters of these nerves are abnormally enlarged. PMID- 27469923 TI - Correlation between Ultrasound-guided Diffuse Optical Tomography and Hypoxia inducible Factor-1Alpha of Breast Cancer. AB - Objective To investigate the correlation between ultrasound-guided diffuse optical tomography (US-DOT) and hypoxia-inducible factor-1Alpha (HIF-1Alpha) of breast cancer. Methods Totally 69 patients with pathologically confirmed breast cancer underwent preoperative conventional breast ultrasonography examinations and US-DOT at Peking Union Medical College Hospital From October 2007 to February 2010 were enrolled in this study.After surgery,immunohistochemical staining of HIF-1Alpha and CD34 were performed,and the differences of total hemoglobin concentration (THC) and microvessel density (MVD) between HIF-1Alpha positive and negative groups were analyzed. Results HIF-1Alpha was positive in 12 cases (17.4%) and negative in 57 cases (82.6%). The average THC and MVD of HIF-1Alpha positive cases were (274.763+/-77.661) MUmol/L and (33.8+/-10.8)/0.2 mm(2) respectively. The average THC and MVD of HIF-1Alpha-negative cases were (228.059+/-65.760)MUmol/L and (28.4+/-7.4)/0.2 mm(2). MVD(t=2.049,P=0.04) and THC(t=2.167,P=0.034) of HIF-1Alpha-positive group were significantly higher than those of HIF-1Alpha-negative group. Conclusions HIF-1Alpha can promote tumor angiogenesis and thus increase the blood supply and THC. As an indicator of tumor blood supply,THC can indirectly reflect the angiogenic activity of breast cancer. PMID- 27469925 TI - Serial Thyroglobulin Variation Trend Shortly after Radioiodine Therapy in Poorly to Moderately Differentiated Recurrent Thyroid Cancer. AB - Objective To dynamically observe the early change of thyroglobulin(Tg) levels after (131)I therapy in differentiated thyroid cancer(DTC) patients. Methods The study enrolled 22 post-total-thyroidectomy DTC patients and they were stratified as low to intermediate recurrence according to the 2009 American Thyroid Association Guidelines. The clinical data including pre-ablation stimulated Tg (ps-Tg),corresponding thyroid stimulating hormone(TSH),anti-thyroglobulin (TgAb) values,and the afterwards parameters were dynamically measured each week in the first month after (131)I therapy. Values collected at the first time were defined as Tg 0 and TSH0,while Tg1 and TSH1 were collected at the first week after (131)I therapy respectively. Then the variation trend curves of Tg were drawn,and factors influencing the variation of Tg were analyzed. Two groups were divided according to Tg levels:G1 (Tg<=0.1 ng/ml,n=9) and G2(Tg>0.1 ng/ml,n=13). Results The rates of negative Tg were 4.5%,18.0%,27.0%,36.0%,and 41.0%,respectively,exactly before (131)I therapy and the 1(st),2(nd),3(rd),and 4(th) week after the therapy. One-way analysis of variance showed that the two groups statistically differed in age (F=3.182,P=0.04) and remnant thyroid (U=4.849,P=0.026). Multivariate logistic regression analysis showed that early negative Tg was related to remnant thyroid tissue (OR:2.132;95%Cl:1.418- 6.532,P=0.009). Conclusions Negative Tg can be achieved in nearly half of DTC patients by the end of first month after (131)I therapy. The negative conversion is closely related with the volume of remnant thyroid tissue. PMID- 27469926 TI - Clinical Application and Research Advances of CT Myocardial Perfusion Imaging. AB - Computed tomography (CT)-based myocardial perfusion imaging (CTP)has been widely recognized as a one-station solution for the imaging of myocardial ischemia related diseases. This article reviews the clinical scanning protocols,analytical methods,and research advances of CTP in recent years and briefly discusses its limitations and future development. PMID- 27469927 TI - Research Advances in CKLFSF-like MARVEL Transmembrane Domain Containing Member 3. AB - CKLF-like MARVEL transmembrane domain containing member/chemokine-like factor super family member (CKLFSF/CMTM) is a novel tumor suppressor gene. CMTM3 is broadly expressed in normal human tissues and evolutionary conserved,especially in testis,spleen,and some cells of peripheral blood mononuclear cells. However,its expression is undetectable or down-regulated in most carcinoma cell lines and tissues. Restoration of CMTM3 may inhibit the proliferation,migration,and invasion of carcinoma cells. Although the exact mechanism of its anti-tumor activity remains unclear,CKLFSF3/CMTM3 is closely connected with immune system and associated with sex during tumorigenesis. The study advances of CKLFSF3/CMTM3 are elaborated in this review as CMTM3 may be a new target in the gene therapies for tumors,especially genitourinary tumors,while further studies on CMTM3 and its anti-tumor mechanisms are warranted. PMID- 27469928 TI - Transient Receptor Potential Melastatin 2:an Ion Channel for Oxidative Stress Sensing. AB - Transient receptor potential (TRP) channel is a superfamily of cation channels located on the cell membrane. TRP channels are classified into seven subfamilies based on the amino acid sequence homology,and transient receptor potential melastatin 2(TRPM2) is the second member of the TRPM subfamily. More evidences have revealed the important roles of TRPM2 in physiological and pathological events such as release of insulin from pancreatic Beta-cells,inflammatory cytokines production from cells,and oxidative stress-induced cell death. As a cellular sensor for oxidative stress channel,TRPM2 is activated by a variety of factors. TRPM2 is a potential therapeutic target for oxidative stress-related diseases. PMID- 27469930 TI - Dietary whey reduces energy intake and alters hypothalamic gene expression in obese phyto-oestrogen-deprived male rats. AB - Removing dietary phyto-oestrogens in adult male rats causes obesity and diabetes. As whey proteins have been reported to reduce food intake and improve glucose homoeostasis, we investigated whether they could attenuate susceptibility to obesity and diabetes due to phyto-oestrogen deprivation. To this end, thirty male Wistar rats were fed a high-phyto-oestrogen (HP) or a phyto-oestrogen-free (PF) diet for 10 weeks; six rats from each group were killed. The remaining HP animals (six animals) continued receiving the HP diet for 6 weeks. The remaining PF rats (twelve rats) were divided in two groups: one was given the PF diet and the other a variation of the PF diet plus whey protein (PF-W). Body weight, food intake and adipose tissue weights were recorded. Hypothalamic mRNA expressions of orexigenic (neuropeptide Y, agouti-related protein (AgRP)) and anorexigenic (pro opiomelanocortin (POMC), cocaine-amphetamine-related transcript (CART)) neuropeptides were quantified by real-time PCR. Serum glucose, insulin and total thyroxine (T4), thyroid-stimulating hormone, testosterone and oestradiol were assessed. After 10 weeks of PF diet, increased body weight, adiposity and energy intake, with up-regulation of AgRP and down-regulation of POMC', were observed. Longer treatment exacerbated these results, increased total T4 levels, reduced oestradiol levels and impaired glucose homoeostasis. PF-W reduced energy intake and increased POMC expression; however, body weight and adiposity remained unchanged. PF-W could not prevent the hormonal changes or the high circulating glucose levels induced by phyto-oestrogen deprivation, but reduced fasting insulin. These data demonstrate that, although 6 weeks of whey administration could not prevent obesity in phyto-oestrogen-deprived rats, the reduction in energy intake and circulating insulin could be beneficial with longer treatments. PMID- 27469931 TI - Low-Energy Amorphization of Ti1Sb2Te5 Phase Change Alloy Induced by TiTe2 Nano Lamellae. AB - Increasing SET operation speed and reducing RESET operation energy have always been the innovation direction of phase change memory (PCM) technology. Here, we demonstrate that ~87% and ~42% reductions of RESET operation energy can be achieved on PCM cell based on stoichiometric Ti1Sb2Te5 alloy, compared with Ge2Sb2Te5 and non-stoichiometric Ti0.4Sb2Te3 based PCM cells at the same size, respectively. The Ti1Sb2Te5 based PCM cell also shows one order of magnitude faster SET operation speed compared to that of the Ge2Sb2Te5 based one. The enhancements may be caused by substantially increased concentration of TiTe2 nano lamellae in crystalline Ti1Sb2Te5 phase. The highly electrical conduction and lowly thermal dissipation of the TiTe2 nano-lamellae play a major role in enhancing the thermal efficiency of the amorphization, prompting the low-energy RESET operation. Our work may inspire the interests to more thorough understanding and tailoring of the nature of the (TiTe2)n(Sb2Te3)m pseudobinary system which will be advantageous to realize high-speed and low-energy PCM applications. PMID- 27469933 TI - Streptococcus halotolerans sp. nov. isolated from the respiratory tract of Marmota himalayana in Qinghai-Tibet Plateau of China. AB - Two Gramstaining-positive, catalase-negative, alpha-hemolytic, coccus-shaped organisms were isolated separately from the respiratory tracts of two Marmota himalayana animals from the Qinghai-Tibet Plateau, PR China. Morphological, biological, biochemical, and molecular genetic studies were performed on these two isolates (HTS9T and HTS12). Their biochemical characteristics, such as acid production from different sugars and enzymatic activities, indicated that they represented a member of the genus Streptococcus. They are most closely related to Streptococcus thoraltensis CIP 105518T based on sequence analysis of their 16S rRNA, groEL, sodA and rpoB genes, with similarities of 97.6, 89.9, 92.6 and 91.1 % the four genes respectively. The whole genome phylogenetic tree reconstructed using 372 core genes from 65 genomes of members of the genus Streptococcus validates that HTS9T forms a distinct subline and exhibits specific phylogenetic affinity with S. thoraltensis. In silico DNA-DNA hybridization of HTS9T showed a DNA reassociation value of 32.1 %, closest to that of S. thoraltensis CIP 105518T. Based on their phenotypic characteristics and in particular the phylogenetic findings (DNA-DNA hybridization, three phylogenetic trees built from the partial 16S rRNA/housekeeping genes, and from 372 core genes of 65 genomes of members of the genus Streptococcus), we propose with confidence that strains HTS9T and HTS12 should be classified as representing a novel species of the genus Streptococcus, Streptococcus halotolerans sp. nov. The type strain is HTS9T (=DSM 101996T=CGMCC1.15532T). Genome analysis of Streptococcus halotolerans sp. nov. shows that its genome is 1 823 556 bp long with a DNA G+C content of 39.9 mol% and contains 2068 genes. PMID- 27469932 TI - Acro-Dermato-Ungual-Lacrimal-Tooth Syndrome: An Uncommon Member of the Ectodermal Dysplasias. AB - Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare form of autosomal dominant ectodermal dysplasia due to mutations in the TP63 gene, a locus that has also been implicated in other syndromic forms of ectodermal dysplasia. It shares many phenotypic characteristics with other TP63 gene mutation syndromes, often making an accurate diagnosis difficult. Long-term management and follow-up of the various sequelae of ectodermal dysplasia require an accurate diagnosis. We report a familial case of ADULT syndrome in a daughter, mother, and son and provide a brief review of the clinical characteristics of this syndrome. PMID- 27469934 TI - Symptomatic Nonsyndromic Pancarpal Coalition: Report of a Rare Case and Review of the Literature. AB - Carpal coalition, the union of 2 or more carpal bones, can be congenital or acquired. Congenital, nonsyndromic carpal coalition usually presents in otherwise healthy individuals. The most common coalition is between the lunate and the triquetrum, followed by the capitate and the hamate. Pancarpal coalition, or coalition of all or most of the bones of the carpus, is an extremely rare finding and usually occurs as part of a syndrome. We present a nonsyndromic case of this rare entity, in a 28-year-old woman of West African descent, with symptoms of left hand and wrist pain. Our literature review revealed only 1 other reported case of isolated, nonsyndromic symptomatic pancarpal coalition. PMID- 27469935 TI - Morphology and Mobility of the Reconstructed Basilar Joint of the Pollicized Index Finger. AB - PURPOSE: To evaluate outcome and function of the reconstructed basilar thumb joint after index finger pollicization in patients presenting congenital thumb deficiency. METHODS: Plain radiographs and 4-dimensional dynamic volume computed tomography scan were used to evaluate the outcome of 23 pollicizations performed on 14 children between 1996 and 2009. The mean follow-up was 8 years. Patients performed continuous movements of thumb opposition during the imaging studies. Four-dimensional scan images made it possible to visualize mobility within the reconstructed joint. RESULTS: In 14 cases, union occurred in the metacarpal head/metacarpal base interface. In the 9 other cases, there was a nonunion at this interface. The reconstructed joint was mobile in 20 cases, including 3 in which there was also mobility at the site of the nonunion. In 3 cases in our series, mobility was present only at the site of the nonunion, between the base and the head of the second metacarpal. Remodeling and flattening out of the metacarpal head occurred in 16 of 23 cases. The transposed metacarpal head remained spherical in 7 cases. CONCLUSIONS: The reconstructed joint adapts, both morphologically and functionally, allowing movement on all 3 spatial planes. Existing mechanical constraints on the reconstructed joint may explain its remodeled appearance. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 27469936 TI - Measurement Properties of the Brief Michigan Hand Outcomes Questionnaire in Patients With Dupuytren Contracture. AB - PURPOSE: The brief Michigan Hand Outcomes Questionnaire (briefMHQ) was developed as a shorter version of the Michigan Hand Outcomes Questionnaire (MHQ), but its measurement properties have not been investigated in patients with Dupuytren contracture. The objective of the study was to investigate the reliability, validity, responsiveness, and interpretability of the briefMHQ. METHODS: Fifty seven patients diagnosed with Dupuytren contracture completed the briefMHQ as well as the full-length MHQ and Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire at baseline. Two to 14 days after baseline and 1 year after collagenase injection or surgery, patients again filled out the briefMHQ. Reliability was determined using the intraclass correlation coefficient and by calculating internal consistency (Cronbach alpha). Validity was tested by quantifying correlations with the full-length MHQ and QuickDASH. Responsiveness, based on the standardized response mean and the minimally clinically important change, was also determined. RESULTS: The briefMHQ had an intraclass correlation coefficient of 0.87, Cronbach alpha of 0.88, and correlations of r = 0.88 and 0.82 with the original MHQ and QuickDASH, respectively. The standardized response mean was 0.9 and the minimally clinically important change was 7 points. CONCLUSIONS: Overall, the briefMHQ demonstrates excellent reliability, good validity, and high responsiveness in patients with Dupuytren contracture. CLINICAL RELEVANCE: The briefMHQ is an accurate and time-saving tool to evaluate patients with Dupuytren contracture and the effect of a corresponding treatment. PMID- 27469937 TI - Intraneural Nodular Fasciitis in a Child: A Case Report and Review of the Literature. AB - We present the case of an 11-year-old boy with intraneural nodular fasciitis of the median nerve at the distal part of the carpal tunnel. Complete excision of the involved median nerve and cable grafting using 4 fascicular segments of the sural nerve was performed for persistent pain and numbness after initial resection of the tumor in piecemeal fashion. Pain and numbness were completely resolved and there was no evidence of recurrence 24 months after the final surgery. PMID- 27469938 TI - Isoxazole mediated synthesis of 4-(1H)pyridones: improved preparation of antimalarial candidate GSK932121. AB - A new synthesis of the antimalarial clinical candidate GSK932121 is described. This approach has two key reactions, the selective acylation of an unprotected 3 hydroxymethyl-5-methyl isoxazole and the reductive N-O bond cleavage of the previously functionalized isoxazole derivative, to give the 4-(1H)pyridone ring present in the final structure. The complete synthesis consists of 5 steps (versus 10 steps in previously published reports) and has enabled the preparation of the material in kilogram scale to support clinical studies. PMID- 27469939 TI - Associations of objectively measured moderate-to-vigorous physical activity and sedentary behavior with quality of life and psychological well-being in prostate cancer survivors. AB - PURPOSE: Although evidence is building on the positive effects of physical activity for prostate cancer survivors, less is known about the possible independent effects of sedentary behavior on quality of life and psychological well-being in this population. We determined the extent to which objectively measured moderate-to-vigorous physical activity (MVPA) and sedentary behavior were independently associated with quality of life, anxiety, and depressive symptoms in prostate cancer survivors. METHODS: An exploratory cross-sectional analysis was undertaken on baseline data from a multicenter, cluster randomized controlled trial on the efficacy of a clinician referral and 12-week exercise program for men who had completed active treatment for prostate cancer. Multiple regression analyses were performed using data from 98 prostate cancer survivors who wore hip-mounted accelerometers (time spent sedentary defined as <100 counts per minute [CPM]; MVPA defined as >1,951 CPM) and completed self-report instruments on their quality of life, anxiety, and depressive symptoms. Results were compared with minimal clinically important differences for the quality of life scales. RESULTS: Independent of sedentary behavior, increases in MVPA of between 15 and 33 min/day were associated with clinically important (but not statistically significant) improvements in three quality of life scales (insomnia, diarrhea, and financial difficulties). Independent of MVPA, decreases in sedentary behavior of 119 and 107 min/day were associated with clinically important (but not statistically significant) improvements in physical functioning and role functioning, respectively. CONCLUSION: Within our exploratory study, modest increases in MVPA and more substantive decreases in sedentary behavior were independently associated with clinically important improvements in several quality of life scales. Further research, including prospective studies, is required to understand sedentary behavior across larger and more representative samples (in terms of their physical, psychological, and social functioning and their engagement in physical activity) of prostate cancer survivors. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000609055. PMID- 27469940 TI - Early induction of direct hemoperfusion with a polymyxin-B immobilized column is associated with amelioration of hemodynamic derangement and mortality in patients with septic shock. AB - This study was conducted to clarify the effectiveness of induction timing of direct hemoperfusion with a polymyxin-B immobilized column (PMX-DHP) for amelioration of hemodynamic derangement and outcome in patients with septic shock. Suspected Gram-negative septic shock patients who received PMX-DHP therapy from January 2010 to December 2014 in our ICU were enrolled in this study. The patients were divided into two groups that received PMX-DHP therapy within 8 h (early group) and more than 8 h (late group) from catecholamine administration. Changes in catecholamine dose [catecholamine index (CAI)], catecholamine dose/mean arterial pressure [catecholamine index pressure (CAIP)], PaO2/FiO2 and PEEP level were determined at the start of and 24 h after the start of PMX-DHP therapy. Ventilator-free days (VFD), ICU-free days (IFD), 28-day and hospital mortality were also determined. There were no significant differences in patients' characteristics between the two groups. CAI and CAIP were significantly decreased in the early group. PaO2/FiO2 was not changed whereas PEEP level in the early group was significantly decreased during PMX-DHP therapy. IFD and VFD were not different in the two groups. Mortality at 28 days was significantly improved in the early group. Endotoxin acts as an early mediator in sepsis patients with suspected Gram-negative infection. Earlier induction of PMX-DHP therapy as in our study is closely associated with earlier weaning from hemodynamic derangement and with improvement of mortality. Therefore, early induction of PMX-DHP therapy is recommended for the treatment of septic shock in patients with presumed Gram negative infection. PMID- 27469941 TI - Human Rhinovirus B and C Genomes from Rural Coastal Kenya. AB - Primer-independent agnostic deep sequencing was used to generate three human rhinovirus (HRV) B genomes and one HRV C genome from samples collected in a household respiratory survey in rural coastal Kenya. The study provides the first rhinovirus genomes from Kenya and will help improve the sensitivity of local molecular diagnostics. PMID- 27469942 TI - Whole-Genome Draft Sequences of Six Commensal Fecal and Six Mastitis-Associated Escherichia coli Strains of Bovine Origin. AB - The bovine gastrointestinal tract is a natural reservoir for commensal and pathogenic Escherichia coli strains with the ability to cause mastitis. Here, we report the whole-genome sequences of six E. coli isolates from acute mastitis cases and six E. coli isolates from the feces of udder-healthy cows. PMID- 27469943 TI - Draft Genome Sequence of Lewinella sp. Strain 4G2 Isolated from the Coastal Sea Surface Microlayer. AB - We report here the draft genome of Lewinella sp. strain 4G2, isolated from the sea surface microlayer (SML) of a coastal marine inlet. The genome sequence of strain 4G2 should contribute to understanding the lifestyles of bacteria living in the SML. PMID- 27469944 TI - Draft Genome Sequence of Raffaelea quercivora JCM 11526, a Japanese Oak Wilt Pathogen Associated with the Platypodid Beetle, Platypus quercivorus. AB - The Japanese oak wilt pathogen Raffaelea quercivora and the platypodid beetle, Platypus quercivorus, cause serious mass mortality of Quercus spp. in Japan. Here, we present the first draft genome sequence of R. quercivora JCM 11526 to increase our understanding of the mechanism of pathogenicity and symbiosis with the ambrosia beetle. PMID- 27469945 TI - Whole-Genome Sequence of Enteractinococcus helveticum sp. nov. Strain UASWS1574 Isolated from Industrial Used Waters. AB - We report here the whole-genome shotgun sequences of the strain UASWS1574 of the undescribed Enteractinococcus helveticum sp. nov., isolated from used water. This is the first genome registered for the whole genus. PMID- 27469947 TI - Draft Genome Sequence of the Mycobacterium tuberculosis Complex Pathogen M. mungi, Identified in a Banded Mongoose (Mungos mungo) in Northern Botswana. AB - Mycobacterium mungi, a Mycobacterium tuberculosis complex pathogen, has emerged in banded mongoose in northern Botswana and Northwest Zimbabwe. The pathogen is transmitted through infected secretions used in olfactory communication behavior (K. A. Alexander, C. E. Sanderson, M. H. Larsen, S. Robbe-Austerman, M. C. Williams, and M. V. Palmer, mBio 7(3):e00281-16, 2016, http://dx.doi.org/10.1128/mBio.00281-16). We announce here the draft genome sequence of this emerging pathogen. PMID- 27469946 TI - Complete Genome Sequence of Bacillus subtilis subsp. subtilis Strain ?6. AB - Bacillus subtilis ?6 is a genome-reduced strain that was cured from six prophages and AT-rich islands. This strain is of great interest for biotechnological applications. Here, we announce the full-genome sequence of this strain. Interestingly, the conjugative element ICEBs1 has most likely undergone self excision in B. subtilis ?6. PMID- 27469948 TI - Complete Genome Sequence of a Putative Densovirus of the Asian Citrus Psyllid, Diaphorina citri. AB - Here, we report the complete genome sequence of a putative densovirus of the Asian citrus psyllid, Diaphorina citri Diaphorina citri densovirus (DcDNV) was originally identified through metagenomics, and here, we obtained the complete nucleotide sequence using PCR-based approaches. Phylogenetic analysis places DcDNV between viruses of the Ambidensovirus and Iteradensovirus genera. PMID- 27469949 TI - Draft Genome Sequence of the Emerging Bivalve Pathogen Vibrio tubiashii subsp. europaeus. AB - Vibrio tubiashii subsp. europaeus is a bivalve pathogen isolated during episodes of mortality affecting larval cultures in different shellfish hatcheries. Here, we announce the draft genome sequence of the type strain PP-638 and describe potential virulence factors, which may provide insight into the mechanism of pathogenicity. PMID- 27469950 TI - Genome Sequence of a Proteus mirabilis Strain Isolated from the Salivary Glands of Larval Lucilia sericata. AB - We announce a draft genome sequence of a Proteus mirabilis strain derived from Lucilia sericata salivary glands. This strain is demonstrated to attract and induce oviposition by L. sericata, a common blow fly important to medicine, agriculture, and forensics. The genome sequence will help dissect interkingdom communication between the species. PMID- 27469951 TI - Draft Genome Sequence of the Plant Growth-Promoting Cupriavidus gilardii Strain JZ4 Isolated from the Desert Plant Tribulus terrestris. AB - We isolated the plant endophytic bacterium Cupriavidus gilardii strain JZ4 from the roots of the desert plant Tribulus terrestris, collected from the Jizan region, Saudi Arabia. We report here the draft genome sequence of JZ4, together with several enzymes related to plant growth-promoting activity, environmental adaption, and antifungal activity. PMID- 27469952 TI - Draft Genome Sequence of an Oceanobacillus sp. Strain Isolated from Soil in a Burial Crypt. AB - We present the draft genome of an Oceanobacillus sp. strain isolated from spores found in soil samples from a burial crypt of the Cathedral of Sant'Antonio Abate in Castelsardo, Italy. The data obtained indicated the closest relation of the strain with Oceanobacillus caeni. PMID- 27469953 TI - A Narnavirus in the Trypanosomatid Protist Plant Pathogen Phytomonas serpens. AB - We describe here a new RNA virus (PserNV1) from the plant protist parasite Phytomonas serpens (family Trypanosomatidae, Kinetoplastida, supergroup Excavata). The properties of PserNV1 permit assignment to the genus Narnavirus (Narnaviridae), the first reported from a host other than fungi or oomycetes. PMID- 27469954 TI - Complete Genome Sequences of Two Methicillin-Sensitive Staphylococcus aureus Isolates Representing a Population Subset Highly Prevalent in Human Colonization. AB - Here, we report the high-quality draft genome sequences of two methicillin susceptible Staphylococcus aureus isolates, 08-02119 and 08-02300. Belonging to sequence type 582 (ST582) and ST7, both isolates are representatives of clonal lineages often associated with asymptomatic colonization of humans. PMID- 27469955 TI - First Complete Genome Sequence of Suakwa aphid-borne yellows virus from East Timor. AB - We present here the first complete genomic RNA sequence of the polerovirus Suakwa aphid-borne yellows virus (SABYV), from East Timor. The isolate sequenced came from a virus-infected pumpkin plant. The East Timorese genome had a nucleotide identity of 86.5% with the only other SABYV genome available, which is from Taiwan. PMID- 27469956 TI - Draft Genome Sequence of Toxigenic Corynebacterium ulcerans Strain 03-8664 Isolated from a Human Throat. AB - Corynebacterium ulcerans is an emergent pathogen infecting wild and domesticated animals worldwide that may serve as reservoirs for zoonotic infections. In this study, we present the draft genome of C. ulcerans strain 03-8664. The draft genome has 2,428,683 bp, 2,262 coding sequences, and 12 rRNA genes. PMID- 27469957 TI - Draft Genome Sequences of the Antimicrobial Producers Pseudomonas sp. TAA207 and Pseudomonas sp. TAD18 Isolated from Antarctic Sediments. AB - We report here the draft genome sequence of the Pseudomonas sp. TAA207 and Pseudomonas sp. TAD18 strains, isolated from Antarctic sediments during a summer campaign near coastal areas of Terra Nova Bay (Antarctica). Genome sequence knowledge allowed the identification of genes associated with the production of bioactive compounds and antibiotic resistance. Furthermore, it will be instrumental for comparative genomics and the fulfillment of both basic and application-oriented investigations. PMID- 27469958 TI - Complete Genome Sequence of an Avian Paramyxovirus Representative of Putative New Serotype 13. AB - Here, we report the complete genome sequence of a virus of a putative new serotype of avian paramyxovirus (APMV). The virus was isolated from a white fronted goose in Ukraine in 2011 and designated white-fronted goose/Ukraine/Askania-Nova/48-15-02/2011. The genomic characterization of the isolate suggests that it represents the novel avian paramyxovirus group APMV 13. PMID- 27469959 TI - Complete Genome Sequence of a Virulent Newcastle Disease Virus Strain Isolated from a Clinically Healthy Duck (Anas platyrhynchos domesticus) in Pakistan. AB - Here, we report the complete genome sequence of a virulent Newcastle disease virus (vNDV) strain, duck/Pakistan/Lahore/AW-123/2015, isolated from apparently healthy laying ducks (Anas platyrhynchos domesticus) from the province of Punjab, Pakistan. The virus has a genome length of 15,192 nucleotides and is classified as member of subgenotype VIIi, class II. PMID- 27469960 TI - Draft Genome Sequence of Fonsecaea monophora Strain CBS 269.37, an Agent of Human Chromoblastomycosis. AB - The black yeast Fonsecaea monophora is one of the main etiologic agents of chromoblastomycosis in humans. Its pathogenicity profile is more invasive than that of related Fonsecaea species, causing brain infection in addition to (sub)cutaneous infections. PMID- 27469961 TI - Complete Genome Sequence of Cyanobium sp. NIES-981, a Marine Strain Potentially Useful for Ecotoxicological Bioassays. AB - Cyanobium sp. NIES-981 is a marine cyanobacterium isolated from tidal flat sands in Okinawa, Japan. Here, we report the complete 3.0-Mbp genome sequence of NIES 981, which is composed of a single chromosome, and its annotation. This sequence information may provide a basis for developing an ecotoxicological bioassay using this strain. PMID- 27469962 TI - Complete Genome Sequence of Photobacterium sp. Strain J15, Isolated from Seawater of Southwestern Johor, Malaysia. AB - Here, we report the genome sequences of Photobacterium sp. strain J15, isolated from seawater in Johor, Malaysia, with the ability to produce lipase and asparaginase. The PacBio genome sequence analysis of Photobacterium sp. strain J15 generated revealed its potential in producing enzymes with different catalytic functions. PMID- 27469963 TI - Full-Genome Sequence of a Neuroinvasive West Nile Virus Lineage 2 Strain from a Fatal Horse Infection in South Africa. AB - We report here the complete genome sequence of a lineage 2 West Nile virus (WNV) strain that resulted in fatal neurological disease in a horse in South Africa. Several recent reports exist of neurological disease associated with lineage 2 WNV in humans and horses in South Africa and Europe; however, there are a lack of sequencing data from recent fatal cases in Southern Africa, where these strains likely originate. A better understanding of the genetic composition of highly neuroinvasive lineage 2 strains may facilitate the identification of putative genetic factors associated with increased virulence. PMID- 27469964 TI - Complete Genome Sequences of Escherichia coli O157:H7 Strains SRCC 1675 and 28RC, Which Vary in Acid Resistance. AB - The level of acid resistance among Escherichia coli O157:H7 strains varies, and strains with higher resistance to acid may have a lower infectious dose. The complete genome sequences belonging to two strains of Escherichia coli O157:H7 with different levels of acid resistance are presented here. PMID- 27469965 TI - Draft Genome Sequence of Photorhabdus luminescens Strain DSPV002N Isolated from Santa Fe, Argentina. AB - Here, we report the draft genome sequence of Photorhabdus luminescens strain DSPV002N, which consists of 177 contig sequences accounting for 5,518,143 bp, with a G+C content of 42.3% and 4,701 predicted protein-coding genes (CDSs). From these, 27 CDSs exhibited significant similarity with insecticidal toxin proteins from Photorhabdus luminescens subsp. laumondii TT01. PMID- 27469966 TI - Draft Genome Sequence of Agrobacterium rhizogenes Strain NCPPB2659. AB - This work reports the draft genome sequence of Agrobacterium rhizogenes strain NCPPB2659 (also known as strain K599). The assembled genome contains 5,277,347 bp, composed of one circular chromosome, the pRi2659 virulence plasmid, and 17 scaffolds pertaining to the linear chromosome. The wild-type strain causes hairy root disease in dicots and has been used to make transgenic hairy root cultures and composite plants (nontransgenic shoots with transgenic roots). Disarmed variants of the strain have been used to produce stable transgenic monocot and dicot plants. PMID- 27469967 TI - Draft Genome Sequence of Lactobacillus delbrueckii Strain #22 Isolated from a Patient with Short Bowel Syndrome and Previous d-Lactic Acidosis and Encephalopathy. AB - d-Lactic acidosis with associated encephalopathy caused by overgrowth of intestinal lactic acid bacteria is a rarely diagnosed neurological complication of patients with short bowel syndrome. Here, we report the draft genome sequence of Lactobacillus delbrueckii strain #22 isolated from a patient with short bowel syndrome and previous d-lactic acidosis/encephalopathy. PMID- 27469968 TI - Genome Sequence of Bacillus anthracis Strain Tangail-1 from Bangladesh. AB - Soil was collected in July 2013 at a site where a cow infected with anthrax had been the month before. Selective culturing yielded Bacillus anthracis strain Tangail-1. Here, we report the draft genome sequence of this Bacillus anthracis isolate that belongs to the canonical A.Br.001/002 clade. PMID- 27469969 TI - Draft Genome Sequence of Ustilago trichophora RK089, a Promising Malic Acid Producer. AB - The basidiomycetous smut fungus Ustilago trichophora RK089 produces malate from glycerol. De novo genome sequencing revealed a 20.7-Mbp genome (301 gap-closed contigs, 246 scaffolds). A comparison to the genome of Ustilago maydis 521 revealed all essential genes for malate production from glycerol contributing to metabolic engineering for improving malate production. PMID- 27469970 TI - Rewiring a secondary metabolite pathway towards itaconic acid production in Aspergillus niger. AB - BACKGROUND: The industrially relevant filamentous fungus Aspergillus niger is widely used in industry for its secretion capabilities of enzymes and organic acids. Biotechnologically produced organic acids promise to be an attractive alternative for the chemical industry to replace petrochemicals. Itaconic acid (IA) has been identified as one of the top twelve building block chemicals which have high potential to be produced by biotechnological means. The IA biosynthesis cluster (cadA, mttA and mfsA) has been elucidated in its natural producer Aspergillus terreus and transferred to A. niger to enable IA production. Here we report the rewiring of a secondary metabolite pathway towards further improved IA production through the overexpression of a putative cytosolic citrate synthase citB in a A. niger strain carrying the IA biosynthesis cluster. RESULTS: We have previously shown that expression of cadA from A. terreus results in itaconic acid production in A. niger AB1.13, albeit at low levels. This low-level production is boosted fivefold by the overexpression of mttA and mfsA in itaconic acid producing AB1.13 CAD background strains. Controlled batch cultivations with AB1.13 CAD + MFS + MTT strains showed increased production of itaconic acid compared with AB1.13 CAD strain. Moreover, preliminary RNA-Seq analysis of an itaconic acid producing AB1.13 CAD strain has led to the identification of the putative cytosolic citrate synthase citB which was induced in an IA producing strain. We have overexpressed citB in a AB1.13 CAD + MFS + MTT strain and by doing so hypothesize to have targeted itaconic acid production to the cytosolic compartment. By overexpressing citB in AB1.13 CAD + MFS + MTT strains in controlled batch cultivations we have achieved highly increased titers of up to 26.2 g/L IA with a productivity of 0.35 g/L/h while no CA was produced. CONCLUSIONS: Expression of the IA biosynthesis cluster in Aspergillus niger AB1.13 strain enables IA production. Moreover, in the AB1.13 CAD strain IA production resulted in overexpression of a putative cytosolic citrate synthase citB. Upon overexpression of citB we have achieved titers of up to 26.2 g/L IA with a productivity of 0.35 g/L/h in controlled batch cultivations. By overexpressing citB we have also diminished side product formation and optimized the production pathway towards IA. PMID- 27469971 TI - Corrigendum to "Interferon-alpha repressed telomerase along with G1-accumulation of Daudi cells" [Cancer Letters 142 (1) (1999) 23-30]. PMID- 27469972 TI - Foreign-born status as a predictor of engagement in HIV care in a large US metropolitan health system. AB - We sought to determine the linkage to and retention in HIV care after HIV diagnosis in foreign-born compared with US-born individuals. From a clinical data registry, we identified 619 patients aged >=18 years with a new HIV diagnosis between 2000 and 2012. Timely linkage to care was the proportion of patients with an ICD-9 code for HIV infection (V08 or 042) associated with a primary care or infectious disease physician within 90 days of the index positive HIV test. Retention in HIV care was the presence of an HIV primary care visit in each 6 month period of the 24-month measurement period from the index HIV test. We used Cox regression analysis with adjustment for hypothesized confounders (age, gender, race/ethnicity, substance abuse, year, and location of HIV diagnosis). Foreign-born individuals comprised 36% (225/619) of the cohort. Index CD4 count was 225/ul (IQR 67-439/ul) in foreign-born compared with 328/ul (IQR 121-527/ul) in US-born individuals (p < .001). The proportion linked to care was 87% (196/225) in foreign-born compared with 77% (302/394) in US-born individuals (p = .002). The adjusted hazard ratio of linkage to HIV care in foreign-born compared with US-born individuals was 1.28 (95% confidence interval [CI], 1.05-1.56). Once linked, there was no difference in retention in care or virologic suppression at 24 months. These results show that despite late presentation to HIV care, foreign born persons can subsequently engage in HIV care as well as US-born persons. Interventions that promote HIV screening in foreign-born persons are a promising way to improve outcomes in these populations. PMID- 27469973 TI - Olfactory Impairment in Chronic Rhinosinusitis Using Threshold, Discrimination, and Identification Scores. AB - Differences in testing modalities and cut-points used to define olfactory dysfunction contribute to the wide variability in estimating the prevalence of olfactory dysfunction in chronic rhinosinusitis (CRS). The aim of this study is to report the prevalence of olfactory impairment using each component of the Sniffin' Sticks test (threshold, discrimination, identification, and total score) with age-adjusted and ideal cut-points from normative populations. Patients meeting diagnostic criteria for CRS were enrolled from rhinology clinics at a tertiary academic center. Olfaction was assessed using the Sniffin' Sticks test. The study population consisted of 110 patients. The prevalence of normosmia, hyposmia, and anosmia using total Sniffin' Sticks score was 41.8%, 20.0%, and 38.2% using age-appropriate cut-points and 20.9%, 40.9%, and 38.2% using ideal cut-points. Olfactory impairment estimates for each dimension mirrored these findings, with threshold yielding the highest values. Threshold, discrimination, and identification were also found to be significantly correlated to each other (P < 0.001). In addition, computed tomography scores, asthma, allergy, and diabetes were found to be associated with olfactory dysfunction. In conclusion, the prevalence of olfactory dysfunction is dependent upon olfactory dimension and if age-adjusted cut-points are used. The method of olfactory testing should be chosen based upon specific clinical and research goals. PMID- 27469974 TI - Experiences and Perceptions of Physical Activity Among South Asian and Anglo Australians With Type 2 Diabetes or Cardiovascular Disease: Implications for Clinical Practice. AB - Research indicates that there are worryingly low levels of physical activity among South Asians compared with Anglo-Australians with type 2 diabetes and/or cardiovascular disease (CVD). We compared perceptions, barriers, and enablers of physical activity in these groups. We used a qualitative design, conducting in depth, semistructured iterative interviews in Victoria with 57 South Asian and Anglo-Australian participants with either type 2 diabetes or CVD. While both groups exhibited knowledge of the value of physical activity in health maintenance and disease management, they wished for more specific and culturally tailored advice from clinicians about the type, duration, and intensity of physical activity required. Physical activity identities were tied to ethnic identities, with members of each group aspiring to meet the norms of their culture regarding engagement with physical activity as specific exercise or as incidental exercise. Individual personal exercise was deemed important by Anglo Australians whereas South Asians preferred family-based physical activity. PMID- 27469975 TI - User Experience and Care Integration in Transitional Care for Older People From Hospital to Home: A Meta-Synthesis. AB - This meta-synthesis aimed to improve understanding of user experience of older people, carers, and health providers; and care integration in the care of older people transitioning from hospital to home. Following our systematic search, we identified and synthesized 20 studies, and constructed a comprehensive framework. We derived four themes: (1) 'Who is taking care of what? Trying to work together"; (2) 'Falling short of the mark'; (3) 'A proper discharge'; and (4) 'You adjust somehow.' The themes that emerged from the studies reflected users' experience of discharge and transitional care as a social process of 'negotiation and navigation of independence (older people/carers), or dependence (health providers).' Users engaged in negotiation and navigation through the interrogative strategies of questioning, discussion, information provision, information seeking, assessment, and translation. The derived themes reflected care integration that facilitated, or a lack of care integration that constrained, users' experiences of negotiation and navigation of independence/dependence. PMID- 27469976 TI - In vitro synthesis of linear alpha-1,3-glucan and chemical modification to ester derivatives exhibiting outstanding thermal properties. AB - Bio-based polymer is considered as one of potentially renewable materials to reduce the consumption of petroleum resources. We report herein on the one-pot synthesis and development of unnatural-type bio-based polysaccharide, alpha-1,3 glucan. The synthesis can be achieved by in vitro enzymatic polymerization with GtfJ enzyme, one type of glucosyltransferase, cloned from Streptococcus salivarius ATCC 25975 utilizing sucrose, a renewable feedstock, as a glucose monomer source, via environmentally friendly one-pot water-based reaction. The structure of alpha-1,3-glucan is completely linear without branches with weight average molecular weight (Mw) of 700 kDa. Furthermore, acetate and propionate esters of alpha-1,3-glucan were synthesized and characterized. Interestingly, alpha-1,3-glucan acetate showed a comparatively high melting temperature at 339 degrees C, higher than that of commercially available thermoplastics such as PET (265 degrees C) and Nylon 6 (220 degrees C). Thus, the discovery of crystalline alpha-1,3-glucan esters without branches with high thermal stability and melting temperature opens the gate for further researches in the application of thermoplastic materials. PMID- 27469978 TI - Response to: 'Infliximab and CT-P13 immunogenicity assessment in PLANETAS and PLANETRA main and extension studies: utility of laboratory methods description' by Francesca Meacci et al. PMID- 27469977 TI - A novel heterozygous COL4A4 missense mutation in a Chinese family with focal segmental glomerulosclerosis. AB - Focal segmental glomerulosclerosis (FSGS) is the most common glomerular histological lesion associated with high-grade proteinuria and end-stage renal disease. Histologically, FSGS is characterized by focal segmental sclerosis with foot process effacement. The aim of this study was to identify the disease causing mutation in a four-generation Chinese family with FSGS. A novel missense mutation, c.1856G>A (p.Gly619Asp), in the collagen type IV alpha-4 gene (COL4A4) was identified in six patients and it co-segregated with the disease in this family. The variant is predicted to be disease-causing and results in collagen IV abnormalities. Our finding broadens mutation spectrum of the COL4A4 gene and extends the phenotypic spectrum of collagen IV nephropathies. Our study suggests that exome sequencing is a cost-effective and efficient approach for identification of disease-causing mutations in phenotypically complex or equivocal disorders. Timely screening for COL4A3/COL4A4 mutations in patients with familial FSGS may help both accurately diagnose and treat these patients. PMID- 27469979 TI - Nitrite formation from vegetable sources and its use as a preservative in cooked sausage. AB - BACKGROUND: Due to the potential health risk associated with nitrites, nitrite alternatives from natural sources in meat products have been investigated. We compared the nitrate contents of young radish, lettuce and commercial vegetable powder (cabbage and Chinese cabbage). We also investigated the effect of incubation time and salt addition on vegetable nitrite formation from vegetable sources. The antioxidant and antimicrobial effects of vegetable nitrite in cooked sausage were also compared with sodium nitrite. RESULTS: Young radish produced the greatest amount of nitrite after 24 h of incubation at 38 degrees C. On average, an approximately 32% reduction of nitrite was observed in sausage during 4 weeks of storage. Lipid oxidation in sausage was significantly prevented by vegetable nitrite produced from vegetable powder or young radish. The colour of the sausage prepared with young radish was most similar to that of the sausage with sodium nitrite. The addition of young radish to sausage significantly prevented the growth of Listeria monocytogenes at 4 degrees C and Staphylococcus aureus at 8 degrees C. CONCLUSION: Young radish was more effective as a natural antioxidant and antimicrobial agent as compared to commercial vegetable powder, which is currently used to make natural meat products, indicating that young radish has a high potential as a natural preservative. (c) 2016 Society of Chemical Industry. PMID- 27469980 TI - Design and comparative anticonvulsant activity assessment of CNS-active alkyl carbamoyl imidazole derivatives. AB - A novel series of carbamoyl derivatives of alkylimidazole has been designed and their anticonvulsant activity was comparatively evaluated in the mice- and rats maximal-electroshock (MES), subcutaneous-metrazol (scMet) seizure tests and the mice-6Hz psychomotor (6Hz) models. The ten new designed molecules contain in their chemical structure imidazole, alkyl side-chain and carbamate as three potential active moieties. In spite of the close structural features of the carbamoyl imidazole derivatives only compounds 7, 8, 13 and 16 were active at the MES test with ED50 values ranging from 12 to 20mg/kg coupled with high protective index (PI=TD50/ED50) values of 4.1-7.3 after ip administration to rats. A similar phenomenon was observed in mice where compounds 7, 8, 9, 12 had MES-ED50 values of 14-26mg/kg. Compounds 7 and 13 also demonstrated anticonvulsant activity in the 6Hz model with ED50 values of 32 and 44mg/kg, respectively. As the most active entities, compounds 7, 8 followed by 13 and 16, thus offer an optimal efficacy-safety profile and consequently, might be promising candidates for development as new antiepileptics. PMID- 27469981 TI - Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic. AB - Omadacycline is novel, aminomethyl tetracycline antibiotic being developed for oral and intravenous (IV) administration for the treatment of community-acquired bacterial infections. Omadacycline is characterized by an aminomethyl substituent at the C9 position of the core 6-member ring. Modifications at this position result in an improved spectrum of antimicrobial activity by overcoming resistance known to affect older generation tetracyclines via ribosomal protection proteins and efflux pump mechanisms. In vitro, omadacycline has activity against Gram positive and Gram-negative aerobes, anaerobes, and atypical pathogens including Legionella and Chlamydia spp. Omadacycline offers once daily oral and IV dosing and a clinical tolerability and safety profile that compares favorably with contemporary antibiotics used across serious community-acquired infections where resistance has rendered many less effective. In studies in patients with complicated skin and skin structure infections, including those with MRSA infections, omadacycline exhibited an efficacy and tolerability profile that was comparable to linezolid. Ongoing and planned clinical studies are evaluating omadacycline as monotherapy for treating serious community-acquired bacterial infections including Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community-Acquired Bacterial Pneumonia (CABP). This review provides an overview of the discovery, microbiology, nonclinical data, and available clinical safety and efficacy data for omadacycline, with reference to other contemporary tetracycline-derived antibiotics. PMID- 27469982 TI - Bortezomib inhibits bacterial and fungal beta-carbonic anhydrases. AB - Inhibition of the beta-carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic fungi (Cryptococcus neoformans, Candida albicans, Candida glabrata, Malassezia globosa) and bacteria (three isoforms from Mycobacterium tuberculosis, Rv3273, Rv1284 and Rv3588), as well from the insect Drosophila melanogaster (DmeCA) and the plant Flaveria bidentis (FbiCA1) with the boronic acid peptidomimetic proteosome inhibitor bortezomib was investigated. Bortezomib was a micromolar inhibitor of all these enzymes, with KIs ranging between 1.12 and 11.30MUM. Based on recent crystallographic data it is hypothesized that the B(OH)2 moiety of the inhibitor is directly coordinated to the zinc ion from the enzyme active site. The class of boronic acids, an under-investigated type of CA inhibitors, may lead to the development of anti-infectives with a novel mechanism of action, based on the pathogenic organisms CA inhibition. PMID- 27469983 TI - Potential for adaptation to climate change in a coral reef fish. AB - Predicting the impacts of climate change requires knowledge of the potential to adapt to rising temperatures, which is unknown for most species. Adaptive potential may be especially important in tropical species that have narrow thermal ranges and live close to their thermal optimum. We used the animal model to estimate heritability, genotype by environment interactions and nongenetic maternal components of phenotypic variation in fitness-related traits in the coral reef damselfish, Acanthochromis polyacanthus. Offspring of wild-caught breeding pairs were reared for two generations at current-day and two elevated temperature treatments (+1.5 and +3.0 degrees C) consistent with climate change projections. Length, weight, body condition and metabolic traits (resting and maximum metabolic rate and net aerobic scope) were measured at four stages of juvenile development. Additive genetic variation was low for length and weight at 0 and 15 days posthatching (dph), but increased significantly at 30 dph. By contrast, nongenetic maternal effects on length, weight and body condition were high at 0 and 15 dph and became weaker at 30 dph. Metabolic traits, including net aerobic scope, exhibited high heritability at 90 dph. Furthermore, significant genotype x environment interactions indicated potential for adaptation of maximum metabolic rate and net aerobic scope at higher temperatures. Net aerobic scope was negatively correlated with weight, indicating that any adaptation of metabolic traits at higher temperatures could be accompanied by a reduction in body size. Finally, estimated breeding values for metabolic traits in F2 offspring were significantly affected by the parental rearing environment. Breeding values at higher temperatures were highest for transgenerationally acclimated fish, suggesting a possible role for epigenetic mechanisms in adaptive responses of metabolic traits. These results indicate a high potential for adaptation of aerobic scope to higher temperatures, which could enable reef fish populations to maintain their performance as ocean temperatures rise. PMID- 27469984 TI - Dihydromyricetin enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro partially via the activation of Wnt/beta-catenin signaling pathway. AB - Substantial evidence has demonstrated that the decreased osteogenic differentiation of bone mesenchymal stem cells (BMSCs) is closely related to bone metabolic diseases. Thus, it is very important to develop several potentially useful therapeutic agents to enhance BMSC osteogenesis. Flavonoids show promise in enhancing bone mass. Dihydromyricetin (DMY), a type of flavonoid, has not yet been investigated regarding its effects on BMSC osteogenesis. To investigate the effects of DMY on osteogenesis, human BMSCs were induced with or without DMY. We found that DMY (0.1-50 MUm) exhibited no cytotoxic effect on proliferation, but increased alkaline phosphatase activity, osteoblast-specific gene expression, and mineral deposition. It also enhanced active beta-catenin expression and reduced dickkopf-1(DKK1) and sclerostin expression. The Wnt/beta-catenin signaling pathway inhibitor (DKK1 and beta-catenin-specific siRNA) decreased the enhanced bone mineral formation caused by DMY. Taken together, these findings reveal that DMY enhances osteogenic differentiation of human BMSCs partly through Wnt/beta catenin in vitro. PMID- 27469985 TI - Retroperitoneal Hemangiopericytoma in a young woman. Case report and literature review. AB - Hemangiopericytoma (HPC) is a primary tumor with mesenchymal vascular origin that represents 1% of all vascular neoplasm. HPC develops from the Zimmerman's pericytes around capillaries venules and it is possible to observe it frequently in the extremities, pelvis, retroperitoneum, head, neck and meninges. The only definitive parameter of malignancy is the development of recurrence or distant metastases. This report describes a case of symptomatic retroperitoneal HPC in a young female patient treated by surgical complete removal of the mass, and literature review. Despite the relatively simple surgical management of retroperitoneal Hemangiopericytoma, its diagnosis still remains difficult and often is incidentally. Patients should undergo a close long-term follow up, by periodic CT scan, due to the high probability of local recurrence or distant metastases that can occur also many years after surgery. KEY WORDS: Hemangiopericytoma (HPC), Retroperitoneum, Surgery. PMID- 27469986 TI - Informed consent in emergency care research: An oxymoron? AB - Emergency care needs to be underpinned by the highest quality evidence. However, research involving critically ill patients in the emergency setting has unique ethical, logistical and regulatory issues. Informed consent is a well-established principle in conventional research. In this article, we discuss informed consent as it pertains to the difficulties of research in the emergency setting. Alternatives to informed consent are discussed. Human research ethics committees require a greater understanding of consent issues in emergency care research for Australia to remain competitive internationally. PMID- 27469987 TI - Gestational length assignment based on last menstrual period, first trimester crown-rump length, ovulation, and implantation timing. AB - PURPOSE: Understanding the natural length of human pregnancy is central to clinical care. However, variability in the reference methods to assign gestational age (GA) confound our understanding of pregnancy length. Assignation from ultrasound measurement of fetal crown-rump length (CRL) has superseded that based on last menstrual period (LMP). Our aim was to estimate gestational length based on LMP, ultrasound CRL, and implantation that were known, compared to pregnancy duration assigned by day of ovulation. METHODS: Prospective study in 143 women trying to conceive. In 71 ongoing pregnancies, gestational length was estimated from LMP, CRL at 10-14 weeks, ovulation, and implantation day. For each method of GA assignment, the distribution in observed gestational length was derived and both agreement and correlation between the methods determined. RESULTS: Median ovulation and implantation days were 16 and 27, respectively. The gestational length based on LMP, CRL, implantation, and ovulation was similar: 279, 278, 276.5 and 276.5 days, respectively. The distributions for observed gestational length were widest where GA was assigned from CRL and LMP and narrowest when assigned from implantation and ovulation day. The strongest correlation for gestational length assessment was between ovulation and implantation (r = 0.98) and weakest between CRL and LMP (r = 0.88). CONCLUSIONS: The most accurate method of predicting gestational length is ovulation day, and this agrees closely with implantation day. Prediction of gestational length from CRL and known LMP are both inferior to ovulation and implantation day. This information could have important implications on the routine assignment of gestational age. PMID- 27469989 TI - [A new approach to normative studies of motor development]. PMID- 27469988 TI - Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta analysis. AB - OBJECTIVE: To assess the effect of treatment for cervical intraepithelial neoplasia (CIN) on obstetric outcomes and to correlate this with cone depth and comparison group used. DESIGN: Systematic review and meta-analysis. DATA SOURCES: CENTRAL, Medline, Embase from 1948 to April 2016 were searched for studies assessing obstetric outcomes in women with or without previous local cervical treatment. DATA EXTRACTION AND SYNTHESIS: Independent reviewers extracted the data and performed quality assessment using the Newcastle-Ottawa criteria. Studies were classified according to method and obstetric endpoint. Pooled risk ratios were calculated with a random effect model and inverse variance. Heterogeneity between studies was assessed with I(2) statistics. MAIN OUTCOME MEASURES: Obstetric outcomes comprised preterm birth (including spontaneous and threatened), premature rupture of the membranes, chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage, and cervical stenosis. Neonatal outcomes comprised low birth weight, admission to neonatal intensive care, stillbirth, APGAR scores, and perinatal mortality. RESULTS: 71 studies were included (6 338 982 participants: 65 082 treated/6 292 563 untreated). Treatment significantly increased the risk of overall (<37 weeks; 10.7% v 5.4%; relative risk 1.78, 95% confidence interval 1.60 to 1.98), severe (<32-34 weeks; 3.5% v 1.4%; 2.40, 1.92 to 2.99), and extreme (<28-30 weeks; 1.0% v 0.3%; 2.54, 1.77 to 3.63) preterm birth. Techniques removing or ablating more tissue were associated with worse outcomes. Relative risks for delivery at <37 weeks were 2.70 (2.14 to 3.40) for cold knife conisation, 2.11 (1.26 to 3.54) for laser conisation, 2.02 (1.60 to 2.55) for excision not otherwise specified, 1.56 (1.36 to 1.79) for large loop excision of the transformation zone, and 1.46 (1.27 to 1.66) for ablation not otherwise specified. Compared with no treatment, the risk of preterm birth was higher in women who had undergone more than one treatment (13.2% v 4.1%; 3.78, 2.65 to 5.39) and with increasing cone depth (<=10-12 mm; 7.1% v 3.4%; 1.54, 1.09 to 2.18; >=10-12 mm: 9.8% v 3.4%, 1.93, 1.62 to 2.31; >=15-17 mm: 10.1% v 3.4%; 2.77, 1.95 to 3.93; >=20 mm: 10.2% v 3.4%; 4.91, 2.06 to 11.68). The choice of comparison group affected the magnitude of effect. This was higher for external comparators, followed by internal comparators, and ultimately women with disease who did not undergo treatment. In women with untreated CIN and in pregnancies before treatment, the risk of preterm birth was higher than the risk in the general population (5.9% v 5.6%; 1.24, 1.14 to 1.35). Spontaneous preterm birth, premature rupture of the membranes, chorioamnionitis, low birth weight, admission to neonatal intensive care, and perinatal mortality were also significantly increased after treatment. : CONCLUSIONS: Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment further increases that risk. The frequency and severity of adverse sequelae increases with increasing cone depth and is higher for excision than for ablation. PMID- 27469990 TI - Factors driving the use of dermoscopy in Europe: a pan-European survey. AB - BACKGROUND: When used correctly, dermoscopy is an essential tool for helping clinicians in the diagnosis of skin diseases and the early detection of skin cancers. Despite its proven benefits, there is a lack of data about how European dermatologists use dermoscopy in everyday practice. OBJECTIVES: To identify the motivations, obstacles and modifiable factors influencing the use of dermoscopy in daily dermatology practice across Europe. METHODS: All registered dermatologists in 32 European countries were invited to complete an online survey of 20 questions regarding demographic and practice characteristics, dermoscopy training and self-confidence in dermoscopic skills, patterns of dermoscopy use, reasons for not using dermoscopy and attitudes relating to dermoscopy utility. RESULTS: We collected 7480 valid answers, of which 89% reported use of dermoscopy. The main reasons for not using dermoscopy were lack of equipment (58% of nonusers) and lack of training (42%). Dermoscopy training during residency was reported by 41% of dermoscopy users and by 12% of nonusers (P < 0.001). Dermatologists working in public hospitals were the least likely to use dermoscopy. High use of dermoscopy across the spectrum of skin diseases was reported by 62% of dermoscopy users and was associated with dermoscopy training during residency, the use of polarized light and digital dermoscopy devices, longer dermoscopy practice, younger age and female gender. CONCLUSIONS: Expanding access to dermoscopy equipment, especially in public healthcare facilities and establishing dermoscopy training during dermatology residency would further enhance the substantially high dermoscopy use across European countries. PMID- 27469991 TI - Posttraumatic Stress Related to Hyperglycemia: Prevalence in Adults with Type I Diabetes. AB - Prevalence of hyperglycemia-related posttraumatic stress (PTS) was assessed in 239 adults with type 1 diabetes using the posttraumatic stress diagnostic scale (PDS; Foa, Posttraumatic stress diagnostic scale manual, National Computer Systems, Inc., Minneapolis, 1995) by an anonymous online survey. Additionally, this study aimed to identify variables related to hyperglycemia-related PTS. Over 30 % of participants reported symptoms consistent with PTSD related to hyperglycemia with standard PDS scoring, and 10 % with more conservative scoring. Hierarchical multiple regression analyses indicated that diabetes self-management behavior and perceived helplessness about hyperglycemia predicted PTSD with standard scoring. Perceived death threat, self-management behavior, helplessness about hyperglycemia, and severity of hypoglycemia in past month predicted PTSD using more conservative scoring. Perceived helplessness, hypoglycemia severity, perceived death-threat, HbA1c, and self-management behavior predicted PTS severity. When fear, helplessness, and perceived death-threat were combined to represent an overall cognitive appraisal factor, this variable was the strongest predictor of PTSD and PTS severity. Scores for PTSD symptom clusters appeared similar to data on hypoglycemia-related PTS. PMID- 27469992 TI - RuvB-Like Protein 2 (Ruvbl2) Has a Role in Directing the Neuroectodermal Differentiation of Mouse Embryonic Stem Cells. AB - Although many factors have been identified to be involved in the development of the neuroectoderm during embryogenesis, it is still important to identify novel factors that convert undifferentiated embryonic cells into neuroectoderm. RuvB like protein 2 (Ruvbl2) is known to regulate gene expression via chromatin remodeling by participating in multi-protein complexes, but its role during embryonic development is not well known. In this study, we established Ruvbl2 overexpressing mouse embryonic stem cells and examined their capacity to specifically differentiate into neuroectoderm and confirmed the specific expression of RUVBL2 in early embryonic neuroectoderm. Our results suggest that Ruvbl2 has a role in the differentiation of neuroectoderm during early embryogenesis. PMID- 27469993 TI - Multiple response optimization of processing and formulation parameters of Eudragit RL/RS-based matrix tablets for sustained delivery of diclofenac. AB - CONTEXT: Multiple response optimization is an efficient technique to develop sustained release formulation while decreasing the number of experiments based on trial and error approach. OBJECTIVE: Diclofenac matrix tablets were optimized to achieve a release profile conforming to USP monograph, matching Voltaren(r)SR and withstand formulation variables. The percent of drug released at predetermined multiple time points were the response variables in the design. Statistical models were obtained with relative contour diagrams being overlaid to predict process and formulation parameters expected to produce the target release profile. MATERIALS AND METHODS: Tablets were prepared by wet granulation using mixture of equivalent quantities of Eudragit RL/RS at overall polymer concentration of 10-30%w/w and compressed at 5-15KN. RESULTS AND DISCUSSION: Drug release from the optimized formulation E4 (15%w/w, 15KN) was similar to Voltaren, conformed to USP monograph and found to be stable. Substituting lactose with mannitol, reversing the ratio between lactose and microcrystalline cellulose or increasing drug load showed no significant difference in drug release. Using dextromethorphan hydrobromide as a model soluble drug showed burst release due to higher solubility and formation of micro cavities. CONCLUSION: A numerical optimization technique was employed to develop a stable consistent promising formulation for sustained delivery of diclofenac. PMID- 27469994 TI - Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism. AB - We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-gamma expressions and higher TNF-alpha, IL-6, IL-1beta and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-gamma and TNF-alpha expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-alpha, IL-6 and IL-1beta expressions in VAT and lower TNF-alpha in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny. PMID- 27469996 TI - Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid. AB - Docosahexaenoic acid (22:6n-3; DHA) is known to play a critical role in postnatal brain development. However, there have been no studies investigating the preventive effect of DHA on prenatal valproic acid (VPA)-induced behavioral and molecular alterations in offspring. The present study was to evaluate the neuroprotective effects in offspring using maternal feeding of DHA to rats exposed to VPA in pregnancy. In the present study, rats were exposed to VPA on day 12.5 of pregnancy; DHA was administered at the dosages of 100, 300 and 500 mg/kg/day for 3 weeks from day 1 to 21 of pregnancy. The results showed that maternal feeding of DHA to the prenatal exposed to VPA (1) prevented VPA-induced learning and memory impairment but did not change social-related behavior, (2) increased total DHA content in offspring plasma and hippocampus, (3) rescued VPA induced neuronal loss and apoptosis of pyramidal cells in hippocampal CA1, (4) influenced the content of malondialdehyde and glutathione and the activities of superoxide dismutase and glutathione in the hippocampus, (5) altered levels of apoptosis-related proteins (Bcl-2, Bax and caspase-3) and inhibited the activity of caspase-3 in offspring hippocampus and (6) enhanced relative levels of p CaMKII and p-CREB proteins in the hippocampus. These findings suggest that maternal feeding with DHA may prevent prenatal VPA-induced impairment of learning and memory, normalize several different molecules associated with oxidative stress and apoptosis in the hippocampus of offspring, and exert preventive effects on prenatal VPA-induced brain dysfunction. PMID- 27469995 TI - Restriction of dietary methyl donors limits methionine availability and affects the partitioning of dietary methionine for creatine and phosphatidylcholine synthesis in the neonatal piglet. AB - Methionine is required for protein synthesis and provides a methyl group for >50 critical transmethylation reactions including creatine and phosphatidylcholine synthesis as well as DNA and protein methylation. However, the availability of methionine depends on dietary sources as well as remethylation of demethylated methionine (i.e., homocysteine) by the dietary methyl donors folate and choline (via betaine). By restricting dietary methyl supply, we aimed to determine the extent that dietary methyl donors contribute to methionine availability for protein synthesis and transmethylation reactions in neonatal piglets. Piglets 4-8 days of age were fed a diet deficient (MD-) (n=8) or sufficient (MS+) (n=7) in folate, choline and betaine. After 5 days, dietary methionine was reduced to 80% of requirement in both groups to elicit a response. On day 8, animals were fed [(3)H-methyl]methionine for 6h to measure methionine partitioning into hepatic protein, phosphatidylcholine, creatine and DNA. MD- feeding reduced plasma choline, betaine and folate (P<.05) and increased homocysteine ~3-fold (P<.05). With MD- feeding, hepatic phosphatidylcholine synthesis was 60% higher (P<.05) at the expense of creatine synthesis, which was 30% lower during MD- feeding (P<.05); protein synthesis as well as DNA and protein methylation were unchanged. In the liver, ~30% of dietary label was traced to phosphatidylcholine and creatine together, with ~50% traced to methylation of proteins and ~20% incorporated in synthesized protein. Dietary methyl donors are integral to neonatal methionine requirements and can affect methionine availability for transmethylation pathways. PMID- 27469997 TI - Reach of Individuals at Risk for Cardiovascular Disease by Proactive Recruitment Strategies in General Practices, Job Centers, and Health Insurance. AB - PURPOSE: Reach of individuals at risk for cardiovascular disease (CVD) constitutes a major determinant of the population impact of preventive effort. This study compares three proactive recruitment strategies regarding their reach of individuals with CVD risk factors. METHOD: Individuals aged 40-65 years were invited to a two-stage cardio-preventive program including an on-site health screening and a cardiovascular examination program (CEP) using face-to-face recruitment in general practices (n = 671), job centers (n = 1049), and mail invitations from health insurance (n = 894). The recruitment strategies were compared regarding the following: (1) participation rate; (2) participants' characteristics, i.e., socio-demographics, self-reported health, and CVD risk factors (smoking, physical activity, fruit/vegetable consumption, body mass index, blood pressure, high-density lipoprotein, triglycerides, and glycated hemoglobin); and (3) participation factors, i.e., differences between participants and non-participants. RESULTS: Screening participation rates were 56.0, 32.8, and 23.5 % for the general practices, the job centers, and the health insurance, respectively. Among eligible individuals for the CEP, respectively, 80.3, 65.5, and 96.1 % participated in the CEP. Job center clients showed the lowest socio-economic status and the most adverse CVD risk pattern. Being female predicted screening participation across all strategies (OR = 1.45, 95 % CI 1.07 1.98; OR = 1.34, 95 % CI 1.04-1.74; OR = 1.62, 95 % CI 1.16-2.27). Age predicted screening participation only within health insurance (OR = 1.04, 95 % CI 1.01 1.06). Within the general practices and the job centers, CEP participants were less likely to be smokers than non-participants (OR = 0.49, 95 % CI 0.26-0.94; OR = 0.42, 95 % CI 0.20-0.89). CONCLUSION: The recruitment in general practices yielded the highest reach. However, job centers may be useful to reduce health inequalities induced by social gradient. PMID- 27469998 TI - A Systematic Review and Meta-Analysis on Self-Management for Improving Risk Factor Control in Stroke Patients. AB - PURPOSE: The aims of this review were to describe the self-management interventions used to improve risk factor control in stroke patients and quantitatively assess their effects on the following: 1) overall risk factor control from lifestyle behaviour (i.e. physical activity, diet and nutrition, stress management, smoking, alcohol, and medication adherence), and medical risk factors (i.e. blood pressure, cholesterol, blood glucose) and (2) individual risk factors. METHOD: We systematically searched the PubMed, PsycINFO, CINAHL and Cochrane Database of Systematic Reviews databases to September 2015 to identify relevant randomized controlled trials investigating self-management to improve stroke risk factors. The self-management interventions were qualitatively described, and the data included in meta-analyses. RESULTS: Fourteen studies were included for review. The model estimating an effect averaged across all stroke risk factors was not significant, but became significant when four low-quality studies were removed (SMD = 0.10 [95 % CI = 0.02 to 0.17], I 2 = 0 %, p = 0.01). Subgroup analyses revealed a significant effect of self-management interventions on lifestyle behaviour risk factors (SMD = 0.15 [95 % CI = 0.04 to 0.25], I 2 = 0 %, p = 0.007) but not medical risk factors. Medication adherence was the only individual risk factor that self-management interventions significantly improved (SMD = 0.31 [95 % CI = 0.07 to 0.56], I 2 = 0 %, p = 0.01). CONCLUSION: Self management interventions appear to be effective at improving overall risk factor control; however, more high-quality research is needed to corroborate this observation. Self-management has a greater effect on lifestyle behaviour risk factors than medical risk factors, with the largest effect at improving medication adherence. PMID- 27469999 TI - Mitochondrial DNA mutations in iPS cells: mtDNA integrity as standard iPSC selection criteria? PMID- 27470000 TI - SPATA2 - Keeping the TNF signal short and sweet. PMID- 27470001 TI - Retraction: 'A pair of transposon-derived proteins regulate active DNA demethylation in Arabidopsis'. PMID- 27470003 TI - No Differences in Symptom Burden Between Colorectal Cancer Patients Receiving Curative Versus Palliative Chemotherapy. AB - CONTEXT: Colorectal cancer (CRC) is one of the most common cancers worldwide. Patients with CRC may have multiple cooccurring symptoms as a result of their disease or its treatment. Little is known about potential differences in symptom burden in CRC patients scheduled to receive curative versus palliative chemotherapy (CTX). OBJECTIVES: The purposes of this study were to investigate the overall symptom burden of patients with CRC before their first CTX treatment or before the initiation of a new CTX regimen and to evaluate for differences in symptom occurrence, severity, and distress between patients with CRC who were scheduled to receive curative versus palliative CTX. METHODS: Consecutive patients with CRC were recruited (n = 120), and symptoms were assessed using the Memorial Symptom Assessment Scale before the initiation of the CTX. The most common symptoms that occurred in >=30% of the patients were evaluated. Differences in occurrence rates and severity and distress scores between the curative (n = 68) and palliative (n = 52) patient groups were evaluated using binary logistic regression and ordinal logistic regression analyses, respectively. RESULTS: In both groups, patients reported an average of 10 cooccurring symptoms. Worrying (65%), lack of energy (59%), feeling drowsy (54%), feeling bloated (53%), pain (51%), and difficulty sleeping (50%) were the most prevalent symptoms. Problems with sexual interest had the highest severity and distress scores in both groups. For the 13 most common symptoms, no significant differences were found between the two patient groups on any of the Memorial Symptom Assessment Scale dimensions (i.e., occurrence, severity, distress). CONCLUSION: Regardless of the reason for CTX, CRC patients experience a large number of cooccurring symptoms. PMID- 27470002 TI - The role of midkine in the inflammatory process and its correlation with other inflammatory markers in renal transplant recipients. AB - BACKGROUND: Midkine (MK), which is expressed in the proximal tubular epithelial cells of the kidney, is thought to have a role in the pathophysiology of inflammation-related renal diseases. Both immunological and nonimmunological mechanisms may affect renal functions negatively during the early and late post transplantation periods. We aimed in our study to evaluate the relationship of MK with clinical findings and inflammatory markers, including high sensitivity C reactive protein (hs-CRP), interleukin (IL-6) and tumor necrosis factor (TNF alpha) in the pretransplant and post-transplant period. METHODS: Forty-one consecutive patients transplanted from living related donors were included in this prospective observational study. All patients received the same immunosuppressive treatment protocol. MK, hsCRP, IL-6 and TNF-alpha levels were measured before and 2 months after renal transplantation. RESULTS: Pretransplant MK levels correlated positively with hsCRP (r = 0.41, p = 0.004) and IL-6 (r = 0.58, p<0.001). The mean post-transplant MK level was found to be higher than the pretransplant level (143 +/- 350 pg/mL, 2792 +/- 4235 pg/mL respectively, p = <0.001), while the mean hsCRP, IL-6 and TNF-alpha levels did not change significantly. Post-transplant IL-6 correlated significantly with MK (r = 0.388, p = 0.012), hsCRP (r = 0.41, p = 0.007) and TNF-alpha (r = 0.348, p = 0.026). There was no significant correlation between clinical findings and inflammatory markers. CONCLUSIONS: MK may be a good inflammatory marker in renal transplant recipients as in other inflammatory diseases. Moreover, it seems that it is not affected by factors other than inflammation during the post-transplantation period. PMID- 27470004 TI - Mammalian CD1 and MR1 genes. AB - All higher vertebrates share the fundamental components of the adaptive immune system: the B cell receptor, the T cell receptor, and classical MHC proteins. At a more detailed level, their immune systems vary considerably, especially with respect to the non-polymorphic MHC class I-like proteins. In mammals, the CD1 family of lipid-presenting proteins is encoded by clusters of genes of widely divergent sizes and compositions. Another MHC class I-like protein, MR1, is typically encoded by a single gene that is highly conserved among species. Based on mammalian genomes and the available data on cellular expression profiles and protein structure, we review MR1 genes and families of CD1 genes in modern mammals from a genetic and functional perspective. Understanding the CD1 and MR1 systems across animal species provides insights into the specialized functions of the five types of CD1 proteins and facilitates careful consideration of animal models for human diseases in which immune responses to lipids and bacterial metabolites play a role. PMID- 27470006 TI - Type 1 diabetes: the need for culture-appropriate nutritional information for carbohydrate counting. PMID- 27470005 TI - IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity. AB - Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood. Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3-dioxygenase (IDO) in steady-state lymph nodes (LNs). IDO expression by LN pDCs was closely dependent on MHCII-mediated, antigen-dependent, interactions with Treg. We further established that IDO production by pDCs was necessary to confer suppressive function to Tregs. During EAE development, IDO expression by pDCs was required for the generation of Tregs capable of dampening the priming of encephalitogenic T cell and disease severity. Thus, we describe a novel crosstalk between pDCs and Tregs: Tregs shape tolerogenic functions of pDCs prior to inflammation, such that pDCs in turn, promote Treg suppressive functions during autoimmunity. PMID- 27470007 TI - Fertility depression among cheese-making Penicillium roqueforti strains suggests degeneration during domestication. AB - Genetic differentiation occurs when gene flow is prevented, due to reproductive barriers or asexuality. Investigating the early barriers to gene flow is important for understanding the process of speciation. Here, we therefore investigated reproductive isolation between different genetic clusters of the fungus Penicillium roqueforti, used for maturing blue cheeses, and also occurring as food spoiler or in silage. We investigated premating and postmating fertility between and within three genetic clusters (two from cheese and one from other substrates), and we observed sexual structures under scanning electron microscopy. All intercluster types of crosses showed some fertility, suggesting that no intersterility has evolved between domesticated and wild populations despite adaptation to different environments and lack of gene flow. However, much lower fertility was found in crosses within the cheese clusters than within the noncheese cluster, suggesting reduced fertility of cheese strains, which may constitute a barrier to gene flow. Such degeneration may be due to bottlenecks during domestication and/or to the exclusive clonal replication of the strains in industry. This study shows that degeneration has occurred rapidly and independently in two lineages of a domesticated species. Altogether, these results inform on the processes and tempo of degeneration and speciation. PMID- 27470008 TI - Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9): Impact of PCSK9 on Major Adverse Cardiac and Cerebrovascular Events. AB - Statins are the most widely prescribed drugs to reduce serum low density lipoprotein cholesterol (LDL-C) by inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. LDL-C reduction is associated with a decreased risk of atherosclerotic cardiovascular disease (ASCVD), including cardiovascular disease (CVD) and stroke. Statins reduce LDL-C by 30 to 40%, and the combination with other lipid-lowering agents such as ezetimibe leads to a further reduction by 20 to 25%. However, even the combination of these two agents might not be sufficient in high risk patients to require aggressive LDL-C reduction. Therefore, starting from observations on individuals with loss-of-function in proprotein convertase subtilisin/kexin type 9 (PCSK9), which was associated with lower LDL-C levels and CVD rates, monoclonal antibodies (mAbs) against PCSK9 were developed. To date, two mAbs, alirocumab and evolocumab, have received approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In the present review we give an overview about pathophysiological and clinical aspects as well as evidence for these drugs with respect to cerebrovascular events. PMID- 27470009 TI - Does somatosensation change with age in children and adolescents? A systematic review. AB - BACKGROUND: Somatosensory modalities, such as touch, proprioception and haptic ability, greatly influence the achievement of developmental milestones for children. Describing somatosensory impairment, natural variability and typical or expected developmental changes across age groups will help establish frameworks for intervention in clinical populations. This systematic review aimed to determine how different somatosensory modalities develop across childhood into adolescence to use as a point of reference for children at risk of somatosensory impairment. METHODS: Searches of five electronic databases were undertaken through EBSCO-host (MEDLINE, CINAHL, PsycINFO, SPORTDiscus and ERIC) for studies measuring at least one somatosensory modality in typically developing individuals between birth and 18 years and analysed by age. Characteristics of studies were collected including country of origin, sample size, demographics and outcome measure used. Quality assessment and data extraction were performed by two independent reviewers. RESULTS: Twenty three cross-sectional studies were included from a total of 188 articles retrieved: 8 examined aspects of touch, 5 proprioception and 10 haptic ability. Variability of study designs and variation in assessment tools precluded any formal meta-analysis. CONCLUSIONS: Somatosensation matures through childhood into adolescence; however, the present review found the pattern of somatosensory development varied depending on the assessment tool used and the aspect of somatosensation being measured, making it difficult to describe typical performance. There is a need for comprehensive assessment batteries to measure the somatosensation, including touch, proprioception and haptic ability, of children at risk of somatosensory impairment to aid in the development of effective interventions. PMID- 27470010 TI - Estimation of dietary arginine requirements for Longyan laying ducks. AB - This study aimed to establish the arginine requirements of Longyan ducks from 17 to 31 wk of age based on egg production, egg quality, plasma, and ovarian indices, as well as the expression of vitellogenesis-related genes. In total, 660 Longyan ducks with similar body weight at 15 wk of age were assigned randomly to 5 treatments, each with 6 replicates of 22 birds, and fed a corn-corn gluten meal basal diet (0.66% arginine) supplemented with either 0, 0.20%, 0.40%, 0.60%, or 0.80% arginine. Dietary arginine did not affect egg production by laying ducks, but it increased (linear, P < 0.01) the egg weight at 22 to 31 and 17 to 31 wk of age. Dietary arginine increased the yolk color score (linearly, P < 0.05) and the yolk percentage (quadratic, P < 0.05), where the maximum values were obtained with 1.26% arginine. Dietary arginine affected the total shell percentage and shell thickness, with the highest values using 1.46% arginine (P < 0.01). The weight and number of small yellow follicles (SYFs) increased (quadratic, P < 0.05) with the dietary arginine level and there was a quadratic response (P < 0.05) in terms of the SYFs weight/ovarian weight; the highest values were obtained in ducks fed 1.26% arginine. The plasma arginine concentration exhibited a quadratic (P < 0.05) response to dietary arginine. The plasma progesterone concentration decreased (linear, P < 0.05) as dietary arginine increased. The mRNA abundance of the very low density lipoprotein receptor-b increased in the second large yellow follicle membranes (quadratic, P < 0.05) with the dietary arginine level, where the highest value occurred with 1.26% arginine. According to the regression model, the dietary arginine requirements for Longyan laying ducks aged 17 to 31 wk are 1.06%, 1.13%, 1.22%, and 1.11% to obtain the maximum yolk percentage, SYFs number, SYFs weight, and SYFs weight/ovarian weight, respectively. PMID- 27470011 TI - Ruthenium(II) polypyridyl complexes with 1,8-naphthalimide group as DNA binder, photonuclease, and dual inhibitors of topoisomerases I and IIalpha. AB - Two ruthenium(II) polypyridyl complexes containing 1,8-naphthalimide group as DNA binders, photonucleases, and inhibitors of topoisomerases I and IIalpha are evaluated. The binding properties of [Ru(phen)2(pnip)]2+ {1; phen=1,10 phenanthroline; pnip=12-[N-(p-phenyl)-1,8-napthalimide]- imidazo[4',5'-f] [1,10]phenanthroline} and [Ru(bpy)2(pnip)]2+ (2; bpy=2,2'-bipyridine) with calf thymus DNA increases with increasing the bulkiness and hydrophobic character of ancillary ligands, although the two complexes possess high affinities for DNA via intercalation. Moreover, photoirradiation (lambda=365nm) of the two complexes are found to induce strand cleavage of closed circular pBR322 plasmid DNA via singlet oxygen mechanism, while complex 1 displays more effective photocleavage activity than complex 2 under the same conditions. Topoisomerase inhibition and DNA strand passage assay reflect that complexes 1 and 2 are efficient dual poisons of topoisomerases I and IIalpha. PMID- 27470013 TI - Use of the trochanteric flip osteotomy to facilitate internal fixation of a femoral head fracture. AB - We report the case of a 42-year-old male who suffered a fracture-dislocation of the femoral head. After a closed reduction of the hip, this proceeded to an open reduction with internal fixation of the fractured femoral head, in addition to labral repair and micro-fracture of an articular cartilage defect. After considering the risks to the femoral head blood supply, the trochanteric flip osteotomy was used. This provided ample and safe exposure. At 14 months follow up, the patient-reported outcome measures are favourable: modified Harris Hip Score (81/100), the non-arthritic hip score (92.5/100) and SF-12 (41/48). PMID- 27470012 TI - Anticancer activity of Ru- and Os(arene) compounds of a maleimide-functionalized bioactive pyridinecarbothioamide ligand. AB - With the aim of increasing the accumulation of Ru anticancer agents in the tumor, a targeted delivery strategy based on a maleimide anchor for the biological vector human serum albumin (HSA) was developed. A group of piano stool Ru- and Os(eta6-arene) complexes carrying a maleimide-functionalized N-phenyl-2 pyridinecarbothioamide (PCA) ligand was designed allowing for covalent conjugation to biological thiols. The complexes were characterized by NMR spectroscopy, ESI-MS, elemental analysis and single-crystal X-ray diffraction analysis. The compounds were shown to undergo halido/aqua ligand exchange reactions in aqueous solution, depending mainly on the metal center and the nature of the halide. In vitro cytotoxicity studies revealed low potency which is explained by the observed high reactivity of the maleimide to the thiol of l cysteine (Cys), while the metal center itself shows little affinity to amino acids of the model protein lysozyme. PMID- 27470014 TI - Idiopathic pseudoaneurysm in a patient with breast implants. AB - Aneurysms and pseudoaneurysms of the internal mammary artery (IMA) are rare and the etiology uncertain although iatrogenic causes have been described. A 64-year old woman suffered hematoma and bleeding from a pseudoaneurysm probably originating from a branch of the right IMA 16 years after breast implant surgery. After clinical assessment, the patient underwent surgery with resection of the aneurysm and ligation of the arterial branch. No early postoperative complications were reported. Pseudoaneurysms in small vessels such as the IMA or its branches are not well described in the literature. Proper diagnosis with imaging is of importance in order to determine treatment as each case is unique. Some cases can be managed conservatively. PMID- 27470015 TI - Iatrogenic oesophageal perforation during placement of an endoscopic vacuum therapy device. AB - Endoscopic vacuum-assisted closure (VAC) is increasingly being used as a means of managing perforations or anastomotic leaks of the upper gastrointestinal (GI) tract. Published outcomes are favourable, with few mentions of complications or morbidity. We present a case in which the management of a gastric perforation with endoscopic vacuum therapy was complicated by cervical oesophageal perforation. The case highlights the risks of such endoscopic therapeutic procedures and is the first report in the literature to describe significant visceral injury during placement of a VAC device for upper GI perforation. Iatrogenic oesophageal perforation is an inherent risk to upper GI endoscopy and the risk increases in therapeutic endoscopic procedures. Complications may be reduced by management under a multidisciplinary team in a centre with specialist upper GI services. There is no doubt that the endoscopic VAC approach is becoming established practice, and training in its use must reflect its increasingly widespread adoption. PMID- 27470016 TI - Hydrological conditions regulate dissolved organic matter quality in an intermittent headwater stream. From drought to storm analysis. AB - Storms and droughts are an essential driver for the dissolved organic matter (DOM) concentration in headwater streams. However, the relationship between DOM quality and discharge (Q) has not been addressed in depth and the impact of other hydro-climatic or biogeochemical drivers has not been explored. In this study DOM quality variability was explored at seasonal and storm event scales during an intensive 2.5-year-long sampling in a Mediterranean stream characterized by a severe summer drought. DOM quality was described in terms of absorbance and fluorescence properties. Most of the DOM properties were strongly related to discharge revealing the input of allochthonous, degraded, aromatic, humic and increased-molecular-size DOM under high flow conditions. However, these relationships disappeared or reversed during drying and rewetting periods. Each DOM response at the storm event scale (DOM-Q hysteresis) was outlined with two descriptors that summarised its trend (dilution/flushing/chemostasis) and shape (linear/nonlinear response). Multiple linear regression and commonality analysis showed that, in addition to the magnitude of storm episodes, antecedent hydrological conditions, namely pre-event basal flow and the magnitude of the previous storm event, played a significant role in regulating the trends and shapes of DOM-Q hysteresis. PMID- 27470017 TI - Faecal contamination of household drinking water in Rwanda: A national cross sectional study. AB - Unsafe drinking water is a leading cause of morbidity and mortality, especially among young children in low-income settings. We conducted a national survey in Rwanda to determine the level of faecal contamination of household drinking water and risk factors associated therewith. Drinking water samples were collected from a nationally representative sample of 870 households and assessed for thermotolerant coliforms (TTC), a World Health Organization (WHO)-approved indicator of faecal contamination. Potential household and community-level determinants of household drinking water quality derived from household surveys, the 2012 Rwanda Population and Housing Census, and a precipitation dataset were assessed using multivariate logistic regression. Widespread faecal contamination was present, and only 24.9% (95% CI 20.9-29.4%, n=217) of household samples met WHO Guidelines of having no detectable TTC contamination, while 42.5% (95% CI 38.0-47.1%, n=361) of samples had >100TTC/100mL and considered high risk. Sub national differences were observed, with poorer water quality in rural areas and Eastern province. In multivariate analyses, there was evidence for an association between detectable contamination and increased open waste disposal in a sector, lower elevation, and water sources other than piped to household or rainwater/bottled. Risk factors for intermediate/high risk contamination (>10TTC/100mL) included low population density, increased open waste disposal, lower elevation, water sources other than piped to household or rainwater/bottled, and occurrence of an extreme rain event the previous day. Modelling suggests non-household-based risk factors are determinants of water quality in this setting, and these results suggest a substantial proportion of Rwanda's population are exposed to faecal contamination through drinking water. PMID- 27470019 TI - HIV from the global to the local scale. PMID- 27470018 TI - Intake of Phthalate-tainted Foods and Serum Thyroid Hormones in Taiwanese Children and Adolescents. AB - On April-May, 2011, phthalates, mainly Di-(2-ethylhexyl) phthalate (DEHP), were deliberately added to a variety of foodstuff as a substitute emulsifier in Taiwan. This study investigated the relationship between DEHP-tainted foodstuffs exposure and thyroid function in possibly affected children and adolescents. Two hundred fifty participants <18 years possibly exposed to DEHP were enrolled in this study between August 2012 and January 2013. Questionnaires were used to collect details on their past exposure to DEHP-tainted food items. Blood and urine samples were collected for biochemical workups to measure current exposure derived from three urinary DEHP metabolites using a creatinine excretion-based model. More than half of 250 participants were estimated to be exposed to DEHP tainted foods found to exceed the recommend tolerable daily intake of DEHP established by the European Food Safety Authority (<50 MUg/kg/day). The median daily DEHP intake (DDI) among those 250 participants was 46.52 MUg/kg/day after multiple imputation. This value was ~10-fold higher than the current median DEHP intake (4.46 MUg/kg/day, n = 240). Neither past nor current DEHP exposure intensity was significantly associated with serum thyroid profiles. Future studies may want to follow the long-term health effects of this food scandal in affected children and adolescents. PMID- 27470020 TI - Atazanavir dose reduction: one size does not fit all. PMID- 27470021 TI - Dual antiretroviral therapy: finding a place in the battle. PMID- 27470022 TI - Time for a revolution in tracking the HIV epidemic. PMID- 27470023 TI - Geographical mobility and heterogeneity of the HIV epidemic. PMID- 27470024 TI - HIV, cardiovascular disease, and stroke in sub-Saharan Africa. PMID- 27470025 TI - Corrections. PMID- 27470026 TI - Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial. AB - BACKGROUND: Thai patients with HIV have higher exposure to HIV protease inhibitors than do white people and dose reduction might be possible. We compared the efficacy of low-dose with standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai patients with HIV. METHODS: In this randomised, open-label, non-inferiority trial, we recruited patients aged 18 years or older who were receiving ritonavir-boosted protease-inhibitor-based antiretroviral therapy (ART) with HIV plasma viral loads of less than 50 copies per mL, an alanine aminotransferase concentration of less than 200 IU/L, and a creatinine clearance of at least 60 mL/min from 14 hospitals in Thailand. We excluded patients who had active AIDS-defining disease or opportunistic infections, had a history of an HIV viral load of 1000 copies per mL or more after 24 weeks of any ritonavir-boosted protease-inhibitor-based ART, used concomitant medications that could interact with the study drugs, were pregnant or lactating, had illnesses that might change the effect of the study drugs, or had a history of sensitivity to the study drugs. A biostatistician at the study coordinating centre randomly allocated patients (1:1) to switch the protease inhibitor for oral atazanavir 200 mg and ritonavir 100 mg or for atazanavir 300 mg and ritonavir 100 mg once daily, both with two nucleoside or nucleotide reverse transcriptase inhibitors at recommended doses. Randomisation was done with a minimisation schedule, stratified by recruiting centre, use of tenofovir, and use of indinavir as a component of the preswitch regimen. The primary endpoint was the proportion of patients with viral loads of less than 200 copies per mL at week 48, and we followed up patients every 12 weeks. Treatments were open label, the non inferiority margin was -10%, and all patients who received at least one dose of study medication were analysed. This trial is registered with ClinicalTrials.gov, number NCT01159223. FINDINGS: Between July 6, 2011, and Dec 23, 2013, we randomly assigned 559 patients: 279 to receive atazanavir 200 mg and ritonavir 100 mg (low dose) and 280 to atazanavir 300 mg and ritonavir 100 mg (standard dose). At week 48, 265 (97.1%) of 273 in the low-dose group and 267 (96.4%) of 277 in the standard-dose group had viral loads of less than 200 copies per mL (difference 0.68; 95% CI -2.29 to 3.65). Seven (3%) of 273 in the low-dose group and 21 (8%) of 277 in the standard-dose group discontinued their assigned treatment (p=0.01). 46 (17%) of 273 participants in the low-dose group and 97 (35%) of 277 in the standard-dose group had total bilirubin grade 3 or higher toxicity (>=3.12 mg/dL; p<0.0001). INTERPRETATION: A switch to low-dose atazanavir should be recommended for Thai patients with well controlled HIV viraemia while on regimens based on boosted protease inhibitors. FUNDING: The National Health Security Office and Kirby Institute for Infection and Immunity in Society. PMID- 27470027 TI - Efficacy and safety of contemporary dual-drug antiretroviral regimens as first line treatment or as a simplification strategy: a systematic review and meta analysis. AB - BACKGROUND: Some guidelines recommended two-drug antiretroviral therapies as alternative regimens to triple therapy in selected patients with the aim of reducing drug burden and toxicity and preserving future treatment options. We aimed to assess the efficacy and safety of dual-therapy versus triple therapy as first-line treatment or in treatment simplification. METHODS: For this systematic review and meta-analysis, we searched Medline, Embase (via OVID), the Cochrane Trial Registry, and major conference proceedings for randomised trials published between Jan 1, 2008, and Dec 31, 2015. We included studies comparing dual-therapy (from two independent classes) antiretroviral regimens as a first-line or a switch strategy (in virologically suppressed individuals) with standard triple drug regimens. Our primary outcome was the risk of virological failure (non completion=failure) at the 48 week timepoint. We did a random-effect meta analysis to pool the relative risk (RR) or odds ratio (OR) for each of the outcomes. FINDINGS: For the primary outcome, we included 21 studies (11 first line and ten switch studies), providing data for 4821 individuals (2478 in dual therapy groups and 2343 in control groups). Overall, the RR of failure with dual therapy compared with triple-therapy (control) groups was 1.14 (95% CI 0.91 1.43). In first-line studies, the RR of failure for dual-therapy versus control groups was 1.17 (0.94-1.47; I(2)=51%), which reduced to 1.05 (0.86-1.28; I(2)=26%) on exclusion of maraviroc-containing studies. In switch studies, the RR of failure for dual-therapy versus control groups was 1.21 (0.72-2.02; I(2)=67%), which reduced to 1.13 (0.64-1.99; I(2)=61%) after exclusion of maraviroc containing studies. In patients with a baseline viral load of more than 100 000 copies per mL, RR of failure for dual-therapy versus control groups was 1.24 (1.03-1.49), which reduced to 1.18 (0.94-1.47) on excluding maraviroc-containing studies. We recorded the ORs for dual-therapy versus control groups for serious adverse events (1.16 [0.92-1.48]), adverse events (0.82 [0.52-1.28]), and mutations (2.11 [1.32-3.36]). INTERPRETATION: Dual therapy, especially with regimens excluding maraviroc, could be safe and efficacious, particularly in patients with baseline viral loads of less than 100 000 copies per mL. However, dual therapy seems to have a greater risk of selecting resistance mutations compared with standard triple therapy. FUNDING: None. PMID- 27470030 TI - Transurethral ventral buccal mucosa graft inlay urethroplasty for reconstruction of fossa navicularis and distal urethral strictures: surgical technique and preliminary results. AB - OBJECTIVES: To introduce a novel surgical technique for the reconstruction of distal urethral strictures using buccal mucosal graft (BMG) through a transurethral approach. METHODS: A retrospective institution chart review was conducted of all the patients who underwent a transurethral ventral BMG inlay urethroplasty from March 2014 to March 2016. Patients with greater than one-year follow-up were included. Steps of the procedure: transurethral ventral wedge resection of the stenosed segment and transurethral delivery and spread fixation of appropriate BMG inlay into the resultant urethrotomy. The patients were followed for post-operative complications and stricture recurrence with uroflow, PVR, cystoscopy and outcome questionnaires. RESULTS: Three patients with a minimum of 12-month follow-up are included in this case series. The mean age of the patients was 42 years (35-53); mean stricture length was 2.1 cm (1-4). All patients had at least 2 previous failed procedures. Mean follow-up was 18 months (12-24). There were no stricture recurrences or fistula. Mean pre- and post operative uroflow values were 4.3 (0-8) and 19 (16-26), respectively. Neither penile chordee nor changes in sexual function were noted in patients on follow up. CONCLUSION: Transurethral ventral BMG inlay urethroplasty is a feasible option for treatment of fossa navicularis strictures. This single-stage technique allows for avoiding skin incision or urethral mobilization. It helps to prevent glans dehiscence, fistula formation and avoids the use of genital skin flaps in all patients, especially those affected with LS. This novel surgical technique is an effective treatment alternative for men with distal urethral strictures. PMID- 27470053 TI - Attitudes of nurses towards family involvement in the care for patients with cardiovascular diseases. AB - INTRODUCTION: There is increasing evidence supporting the relationship between family support and patient outcomes. Therefore, involving families in the care of cardiovascular patients is expected to be beneficial for patients. The quality of the encounter with families highly depends on the attitudes of nurses towards the importance of families in patient care. AIM: The aim of this study was to describe the attitudes of nurses towards family involvement in patient care and to investigate the individual contributions of demographic, professional and regional background characteristics. METHOD: A survey was distributed among cardiovascular nurses attending an international conference in Norway and a national conference in Belgium. Nurses were asked to complete a questionnaire, including the Families' Importance in Nursing Care - Nurses' Attitudes scale. The study population consisted of respondents from Belgium ( n = 348) and from Scandinavian countries (Norway, Sweden and Denmark; n = 77). RESULTS: In general, nurses viewed the family as important in care. However, attitudes towards actively inviting families to take part in patient care were less positive. Higher educational level and a main practice role in research, education or management were significantly associated with more positive attitudes. Furthermore, the attitudes of respondents living in Scandinavia were more positive as compared to the attitudes of respondents living in Belgium. CONCLUSION: Education on the importance of families and active family involvement in patient care seems to be necessary in basic, undergraduate education, but also in clinical practice. More research is necessary in order to explore the cultural and regional differences in the attitudes of nurses towards the involvement of families in patient care. PMID- 27470029 TI - Heterogeneity of the HIV epidemic in agrarian, trading, and fishing communities in Rakai, Uganda: an observational epidemiological study. AB - BACKGROUND: Understanding the extent to which HIV burden differs across communities and the drivers of local disparities is crucial for an effective and targeted HIV response. We assessed community-level variations in HIV prevalence, risk factors, and treatment and prevention service uptake in Rakai, Uganda. METHODS: The Rakai Community Cohort Study (RCCS) is an open, population-based cohort of people aged 15-49 years in 40 communities. Participants are HIV tested and interviewed to obtain sociodemographic, behavioural, and health information. RCCS data from Aug 10, 2011, to May 30, 2013, were used to classify communities as agrarian (n=27), trading (n=9), or lakeside fishing sites (n=4). We mapped HIV prevalence with Bayesian methods, and characterised variability across and within community classifications. We also assessed differences in HIV risk factors and uptake of antiretroviral therapy and male circumcision between community types. FINDINGS: 17 119 individuals were included, 9215 (54%) of whom were female. 9931 participants resided in agrarian, 3318 in trading, and 3870 in fishing communities. Median HIV prevalence was higher in fishing communities (42%, range 38-43) than in trading (17%, 11-21) and agrarian communities (14%, 9-26). Antiretroviral therapy use was significantly lower in both men and women in fishing communities than in trading (age-adjusted prevalence risk ratio in men 0.64, 95% CI 0.44-0.97; women 0.53, 0.42-0.66) and agrarian communities (men 0.55, 0.42-0.72; women 0.65, 0.54-0.79), as was circumcision coverage among men (vs trading 0.48, 0.42-0.55; vs agrarian 0.64, 0.56-0.72). Self-reported risk behaviours were significantly higher in men than in women and in fishing communities than in other community types. INTERPRETATION: Substantial heterogeneity in HIV prevalence, risk factors, and service uptake in Rakai, Uganda, emphasises the need for local surveillance and the design of targeted HIV responses. High HIV burden, risk behaviours, and low use of combination HIV prevention in fishing communities make these populations a priority for intervention. FUNDING: National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, and the National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; the Bill & Melinda Gates Foundation; and the Johns Hopkins University Center for AIDS Research. PMID- 27470054 TI - Indeterminate CT pulmonary angiogram: Why and does it matter? AB - INTRODUCTION: This study assessed the rate of indeterminate CT pulmonary angiogram (CTPA) in a general hospital and evaluated potential contributing factors to an indeterminate CTPA and patients' eventual clinical outcome. METHODS: Four hundred and three consecutive CTPA and their finalised report from 01/08/2012 to 05/12/2012 at Waitemata DHB were reviewed retrospectively. Patient demographics, scan parameters and average Hounsfield unit (HU) of the main pulmonary trunk (PT) and likely cause of indeterminate study were documented. Studies were categorised into diagnostic, suboptimal or non-diagnostic studies. Univariate and multiple regression analyses were employed. RESULTS: Six per cent (n = 24) of the studies were deemed indeterminate which included suboptimal and non-diagnostic studies. Seven pregnant patients were scanned during the study period and four of the seven studies were deemed indeterminate. In univariate analysis, predictors of indeterminate studies included 'weight' (P = 0.022), 'average HU of PT' (P < 0.0001) and 'effective dose' (P = 0.0003). In the multivariate logistic regression model, only 'average HU of PT' was associated with indeterminate studies (OR = 0.99, 95%CI: 0.99, 1.00). Twelve of 24 indeterminate studies had suboptimal pulmonary enhancement with causes including suboptimal timing of contrast bolus, hyperdynamic state due to pregnancy and transient interruption of contrast. Three patients had excessive noise due to body habitus. Eight studies had motion artefacts and one patient had left lower lobe pneumonia which decreased the accuracy. A third of the indeterminate studies were clinically considered as negative by referring clinicians. CONCLUSIONS: Pulmonary trunk average Hounsfield unit is a predictor of indeterminate CT pulmonary angiogram. PMID- 27470055 TI - Coagulation parameters in patients with cirrhosis and portal vein thrombosis treated sequentially with low molecular weight heparin and vitamin K antagonists. AB - BACKGROUND/AIMS: Information on coagulation for cirrhotics on anticoagulants is scanty. We investigated plasma from 23 cirrhotics treated with low-molecular weight-heparin (LMWH) followed by vitamin K antagonists (VKA). METHODS: On days 1 4 patients received full-dose LMWH. On day-5 VKA was started and LMWH was terminated when INR therapeutic-interval was reached. Blood was collected at peak and trough during LMWH, LMWH+VKA and VKA. Non-cirrhotics on VKA were included as controls. RESULTS: Anti-factor Xa increased from baseline-to-peak during LMWH. During LMWH+VKA was high and reverted to zero during VKA. INR was slightly high at baseline, trough or peak during LMWH and increased to 2.2 during LMWH+VKA or VKA. Mean VKA weekly-doses for cirrhotics and controls were 28.5mg and 28.6mg. Protein C decreased upon VKA, but not to the expected extent. Endogenous-thrombin potential (ETP) decreased from baseline (1436nMmin) to trough (1258nMmin) and peak (700nMmin) during LMWH and was further reduced during LMWH+VKA (395nMmin). CONCLUSIONS: Target-INR for cirrhotics can be reached by VKA dosages similar to those for non-cirrhotics. ETP reduction parallels the effect of LMWH and/or VKA. Whether these parameters represent the antithrombotic action elicited by these drugs remains to be determined by clinical-trials and laboratory-measurements. ETP, being a global-test reflecting both pro- and anti-coagulants targeted by antithrombotic drugs, seems the candidate for these trials. PMID- 27470056 TI - Robot-assisted minimally invasive esophagectomy. AB - Esophagolymphadenectomy is the cornerstone of multimodality treatment for resectable esophageal cancer. The preferred surgical approach is transthoracic, with a two-field lymph node dissection and gastric conduit reconstruction. A minimally invasive approach has been shown to reduce postoperative complications and increase quality of life. Robot-assisted minimally invasive esophagectomy (RAMIE) was developed to facilitate this complex thoracoscopic procedure. RAMIE has been shown to be safe with good oncologic results and reduced morbidity. The use of RAMIE opens new indications for curative surgery in patients with T4b tumors, high mediastinal tumors, and lymph node metastases after neoadjuvant treatment. PMID- 27470059 TI - Releasing intracellular product to prepare whole cell biocatalyst for biosynthesis of Monascus pigments in water-edible oil two-phase system. AB - Selective releasing intracellular product in Triton X-100 micelle aqueous solution to prepare whole cell biocatalyst is a novel strategy for biosynthesis of Monascus pigments, in which cell suspension culture exhibits some advantages comparing with the corresponding growing cell submerged culture. In the present work, the nonionic surfactant Triton X-100 was successfully replaced by edible plant oils for releasing intracellular Monascus pigments. High concentration of Monascus pigments (with absorbance nearly 710 AU at 470 nm in the oil phase, normalized to the aqueous phase volume approximately 142 AU) was achieved by cell suspension culture in peanut oil-water two-phase system. Furthermore, the utilization of edible oil as extractant also fulfills the demand for application of Monascus pigments as natural food colorant. PMID- 27470057 TI - [Robotic approach to hepatobiliary surgery. German version]. AB - Robot-assisted hepatobiliary surgery has been steadily growing in recent years. It represents an alternative to the open and laparoscopic approaches in selected patients. Endowristed instruments and enhanced visualization provide important advantages in terms of selective bleeding control, microsuturing, and dissection. Cholecystectomies and minor hepatectomies are being performed with comparable results to open and laparoscopic surgery. Even complex procedures, such as major and extended hepatectomies, can have excellent outcomes, in expert hands. The addition of indocyanine green fluorescence provides an additional advantage for recognition of the vascular and biliary anatomy. Future innovations will allow for expanding its use and indications. Robotic surgery has become a very important component of modern minimally invasive surgery and the development of new robotic technology will facilitate a broader adoption of this technique. PMID- 27470058 TI - Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition. AB - Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age-related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers' nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age-matched young controls and aged (20-month-old) animals. HELP-tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9 weeks old with more significant changes at 6 months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease. PMID- 27470060 TI - Cardiac Device Implant Skin Closure with a Novel Adjustable, Coaptive Tape-Based Device. AB - BACKGROUND: The purpose of this study was to compare a unique zip-type adjustable coaptive tape-based skin closure device to traditional subcuticular sutures in three domains: time, cosmesis, and wound closure-related outcomes in cardiac implantable electronic device (CIED) procedures. METHODS: A total of 40 patients were enrolled in a prospective randomized controlled trial to assess time to wound closure, as well as cosmesis and wound closure-related outcomes. RESULTS: The adjustable coaptive tape-based skin closure device had shorter overall closure time (78 +/- 6.6 seconds vs 216 +/- 21.5 seconds; P < 0.001) and mean closure time per centimeter (18.0 +/- 2.0 s/cm vs 50.1 +/- 6.7 s/cm; P < 0.001) versus sutures, with less intersurgeon and interpatient variability with the use of adjustable coaptive device versus sutures (P < 0.001). There was no difference between groups in postoperative pain or scar cosmesis during the follow-up period. Neither group had any closure-related adverse events. CONCLUSIONS: The adjustable coaptive tape-based skin closure device demonstrated shorter closure times with less variability when compared to sutures. It is a safe and acceptable alternative to sutures for skin closure following CIED implantation. PMID- 27470061 TI - Quantitative Optical Coherence Tomography Angiography of Radial Peripapillary Capillaries in Glaucoma, Glaucoma Suspect, and Normal Eyes. AB - PURPOSE: To evaluate the quantitative characteristics of the radial peripapillary capillary (RPC) network in glaucoma, glaucoma suspect, and normal eyes using speckle variance optical coherence tomography angiography (OCT-A). To determine correlations between RPC density, nerve fiber layer (NFL) thickness, and visual field indices. DESIGN: Cross-sectional study. METHODS: OCT-A images of RPCs were acquired at a single institution using a custom-built 1060 nm system from 3 groups: unilateral glaucoma (10 eyes from 5 subjects), glaucoma suspects (6 eyes from 3 subjects), and normal control eyes (16 eyes from 9 normal subjects). Peripapillary NFL thickness measurements were determined using spectral-domain optical coherence tomography. Glaucoma and glaucoma suspects also underwent automated 30-2 Humphrey visual field analysis. Manual tracing techniques were used to quantify RPC density in the OCT-A images. Data were analyzed using a linear mixed model with 1 fixed-effect covariate. Correlations between main outcome measures (RPC density, NFL thickness, and visual field index) were determined. RESULTS: Mean age was not significantly different between the 3 groups (P = .25). The density of RPCs was significantly lower in glaucomatous eyes compared with matched-peripapillary regions in the fellow eye, glaucoma suspect group, and normal group (all P < .001). RPC density was strongly correlated with NFL thickness (P < .001) and visual field index (P < .001). CONCLUSIONS: Significant reductions in RPC density were correlated with sites of NFL decrease and visual field loss in glaucoma. Speckle variance OCT-A allows visualization and quantification of RPCs and may therefore be a useful tool for indirectly quantifying and monitoring retinal ganglion cell axonal injury in glaucoma. PMID- 27470062 TI - Anti-TNFalpha Treatment for HLA-B27-Positive Ankylosing Spondylitis-Related Uveitis. AB - PURPOSE: To assess the long-term efficacy of the most widely used anti-tumor necrosis factor alpha (TNFalpha) agents for treatment of HLA-B27-positive ankylosing spondylitis (AS)-related uveitis. DESIGN: Retrospective cohort study. METHODS: The medical records of 143 patients with HLA-B27-positive AS who visited Seoul St. Mary's Hospital and were taking an anti-TNFalpha agent for at least 1 year were studied. Subjects were divided into 3 groups according to anti-TNFalpha treatment: Group 1 (infliximab, 66), Group 2 (adalimumab, 45), and Group 3 (etanercept, 32). RESULTS: Mean age was 41.0 +/- 13.0 years, and 97 patients (67.8%) were male. Mean follow-up period was 70.6 +/- 37.9 months. In cases of active ocular inflammation at the onset of anti-TNFalpha treatment, patients showed improved activity of uveitis after 24.0 +/- 15.0 days (Group 1), 17.9 +/- 6.0 days (Group 2), and 25.9 +/- 18.0 days (Group 3). After the anti-TNFalpha treatment, 71 of 94 patients (32 [76.2%] in Group 1, 26 [78.8%] in Group 2, and 13 [68.4%] in Group 3) remained without uveitis relapse. A reduction in the number of systemic medications was achieved in 129 patients (90.2%). Twenty-eight cases of minor side effects were observed, and 4 cases were tuberculosis leading to discontinuation of anti-TNFalpha treatment. CONCLUSIONS: Infliximab, adalimumab, and etanercept were effective for treating and reducing the number of uveitis relapses in HLA-B27-positive AS. However, the risk of serious infections was noted, so ophthalmologists should consider the possibility that prolonged use of biologic agents may result in systemic side effects. PMID- 27470064 TI - Spiribacter roseus sp. nov., a moderately halophilic species of the genus Spiribacter from salterns. AB - Four pink-pigmented, non-motile, Gram-staining-negative and moderately halophilic curved rods, designated strains SSL50T, SSL25, SSL97 and SSL4, were isolated from a saltern located in Isla Cristina, Huelva, south-west Spain. Phylogenetic analyses based on 16S rRNA gene sequences showed that they were members of the genus Spiribacter, most closely related to Spiribacter curvatus UAH-SP71T (99.3 99.5 % sequence similarity) and Spiribacter salinus M19-40T (96.5-96.7 %). Other related strains were Alkalilimnicola ehrlichii MLHE-1T (95.1-95.3 %), Arhodomonas recens RS91T (95.1-95.2 %) and Arhodomonas aquaeolei ATCC 49307T (95.0-95.1 %), all members of the family Ectothiorhodospiraceae. The major fatty acids were C18 : 1omega6c and/or C18 : 1omega7c, C16 : 0 and C12 : 0. The DNA G+C range was 64.0 66.3 mol%. The DNA-DNA hybridization values between strains SSL50T, SSL25, SSL97, SSL4 and S. piribacter. curvatus UAH-SP71T were 37-49 %. The average nucleotide identity (ANIb) values between the genome of strain SSL50T and those of the two other representatives of the genus Spiribacter, S. curvatus UAH-SP71T and S. salinus M19-40T, were 82.4 % and 79.1 %, respectively, supporting the proposal of a novel species of the genus Spiribacter. On the basis of the polyphasic analysis, the four new isolates are considered to represent a novel species of the genus Spiribacter, for which the name Spiribacter roseus sp. nov. is proposed. The type strain is SSL50T (=CECT 9117T=IBRC-M 11076T). PMID- 27470063 TI - Oleanolic acid ameliorates cognitive dysfunction caused by cholinergic blockade via TrkB-dependent BDNF signaling. AB - Oleanolic acid is a naturally occurring triterpenoid and is widely present in food and medicinal plants. To examine the effect of oleanolic acid on memory deficits, we employed a cholinergic blockade-induced cognitive deficit mouse model. A single administration of oleanolic acid significantly increased the latency on the passive avoidance task and affected the alternation behavior on the Y-maze task and the exploration time on the novel object recognition task, indicating that oleanolic acid reverses the cognitive impairment induced by scopolamine. In accordance with previous reports, oleanolic acid enhanced extracellular-signal-regulated kinase 1/2 (ERK1/2) and cAMP response element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Interestingly, ameliorating effect of oleanolic acid on scopolamine-induced memory impairment was abolished by N2-(2 {[(2-oxoazepan-3-yl)amino]carbonyl}phenyl)benzo[b]thiophene-2-carboxamide (ANA 12), a potent and specific inhibitor of tropomyosin receptor kinase B (TrkB), in the passive avoidance task. Similarly, oleanolic acid significantly evoked long term potentiation in a dose-dependent manner, which was diminished by ANA-12 treatment as shown in the electrophysiology study. Together, these results imply that oleanolic acid ameliorates scopolamine-induced memory impairment by modulating the BDNF-ERK1/2-CREB pathway through TrkB activation in mice, suggesting that oleanolic acid would be a potential therapeutic agent for the treatment of cognitive deficits. PMID- 27470065 TI - Structure or entropy in reporting cardiac CT findings. PMID- 27470067 TI - Prediction of Periodontal Inflammation via Metabolic Profiling of Saliva. AB - Periodontal disease is characterized by chronic inflammation in subgingival areas, where a vast array of inflammation-associated metabolites are likely produced from tissue breakdown, increased vascular permeability, and microbial metabolism and then eventually show a steady flow into saliva. Thus, prolonged periodontal inflammation is a key feature of disease activity. Although salivary metabolomics has drawn attention for its potential use in diagnosis of periodontal disease, few authors have used that to investigate periodontal inflammation detection. In this pilot study, the authors explored the use of salivary metabolites to reflect periodontal inflammation severity with a recently proposed parameter-periodontal inflamed surface area (PISA)-used to quantify the periodontal inflammatory burden of individual patients with high accuracy. Following PISA determination, whole saliva samples were collected from 19 subjects before and after removal of supragingival plaque and calculus (debridement) with an ultrasonic scaler to assess the influence of the procedure on salivary metabolic profiles. Metabolic profiling of saliva was performed with gas chromatography coupled to time-of-flight mass spectrometry, followed by multivariate regression analysis with orthogonal projections to latent structures (OPLS) to investigate the relationship between PISA and salivary metabolic profiles. Sixty-three metabolites were identified. OPLS analysis showed that postdebridement saliva provided a more refined model for prediction of PISA than did predebridement samples, which indicated that debridement may improve detection of metabolites eluted from subgingival areas in saliva, thus more accurately reflecting the pathophysiology of periodontitis. Based on the variable importance in the projection values obtained via OPLS, 8 metabolites were identified as potential indicators of periodontal inflammation, of which the combination of cadaverine, 5-oxoproline, and histidine yielded satisfactory accuracy (area under the curve = 0.881) for diagnosis of periodontitis. The authors' findings identified potential biomarkers that may be useful for reflecting the severity of periodontal inflammation as part of monitoring disease activity in periodontitis patients. PMID- 27470066 TI - The Importance of Serine Phosphorylation of Ameloblastin on Enamel Formation. AB - FAM20C is a newly identified kinase on the secretory pathway responsible for the phosphorylation of serine residues in the Ser-x-Glu/pSer motifs in several enamel matrix proteins. Fam20C-knockout mice showed severe enamel defects very similar to those in the ameloblastin ( Ambn)-knockout mice, implying that phosphoserines may have a critical role in AMBN function. To test this hypothesis, we generated amelogenin ( Amel) promoter-driven Ambn-transgenic mice, in which Ser48, Ser226, and Ser227 were replaced by aspartic acid (designated as D-Tg) or alanines (designated as A-Tg). The negative charge of aspartic acid is believed to be able to mimic the phosphorylation state of serine, while alanine is a commonly used residue to substitute serine due to their similar structure. Using Western immunoblotting and quantitative polymerase chain reaction, the authors identified transgenic lines expressing transgenes somewhat higher (Tg+) or much higher (Tg++) than endogenous Ambn. The lower incisors collected from 7-d-old and 7-wk old mice were analyzed by histology, scanning electron microscopy, immunohistochemistry, and Western immunoblotting to examine the morphology and microstructure changes in enamel, as well as the expression pattern of enamel matrix proteins. The A-Tg+ and A-Tg++ mice displayed severe enamel defects in spite of the expression level of transgenes, while the D-Tg+ and D-Tg++ mice showed minor to mild enamel defects, indicating that the D-Tg transgenes disturbed enamel formation less than the A-Tg transgenes did. Our results suggest that the phosphorylation state of serines is likely an essential component for the integrity of AMBN function. PMID- 27470068 TI - Effect of Sleep and Salivary Glucose on Gingivitis in Children. AB - It has been shown that inadequate sleep has deleterious effects on health by suppressing immunity and promoting inflammation. The aim of this study was to investigate the effect of sleep and salivary glucose levels on the development of gingivitis in a prospective longitudinal study of Kuwaiti children. Data were collected from 10-y-old children ( N = 6,316) in 2012 and again in 2014. Children were approximately equally distributed from 138 elementary schools representing the 6 governorates of Kuwait. Calibrated examiners conducted oral examination, self-reported sleep evaluation interviews, anthropomorphic measurements, and unstimulated whole saliva sample collection. Salivary glucose levels were measured by a florescent glucose oxidase method; values of salivary glucose >=1.13 mg/dL were defined as high glucose levels. A multilevel random intercept and slope analysis was conducted to determine the relationship between sleep duration and gingivitis on 3 levels: within schools, among children, and over time. The outcome was the progression of the extent of gingival inflammation in children over time. The main independent variables were the number of daily sleep hours and salivary glucose levels. Other explanatory variables and confounders assessed were governorate, dental caries and restorations, and obesity by waist circumference (adjusted for snacking and sex). Gingivitis increased over time in children who had shorter sleep duration ( P < 0.05). Salivary glucose levels >1.13 mg/dL predicted gingivitis ( P < 0.05). Children who had more decayed or filled teeth had more gingivitis ( P < 0.05). No significant association was found between gingivitis and obesity. The level of gingivitis was different among the 6 governorates of Kuwait. Additionally, there was a strong clustering effect of the observations within schools and among children across time. Longitudinal analysis of 6,316 Kuwaiti children revealed that shorter sleep duration and higher salivary glucose levels were both associated with increased gingival inflammation. PMID- 27470028 TI - Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015. AB - BACKGROUND: Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015. METHODS: For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification. FINDINGS: Global HIV incidence reached its peak in 1997, at 3.3 million new infections (95% uncertainty interval [UI] 3.1-3.4 million). Annual incidence has stayed relatively constant at about 2.6 million per year (range 2.5-2.8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38.8 million (95% UI 37.6-40.4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1.8 million deaths (95% UI 1.7-1.9 million) in 2005, to 1.2 million deaths (1.1-1.3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections. INTERPRETATION: Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030. FUNDING: Bill & Melinda Gates Foundation, and National Institute of Mental Health and National Institute on Aging, National Institutes of Health. PMID- 27470069 TI - Silica Coating of Nonsilicate Nanoparticles for Resin-Based Composite Materials. AB - This study was designed to develop and characterize a silica-coating method for crystalline nonsilicate ceramic nanoparticles (Al2O3, TiO2, and ZrO2). The hypothesis was that the coated nonsilicate nanoparticles would stably reinforce a polymeric matrix due to effective silanation. Silica coating was applied via a sol-gel method, with tetraethyl orthosilicate as a silica precursor, followed by heat treatment. The chemical and microstructural characteristics of the nanopowders were evaluated before and after silica coating through x-ray diffraction, BET (Brunauer-Emmett-Teller), energy-dispersive x-ray spectroscopy, field emission scanning electron microscopy, and transmission electron microscopy analyses. Coated and noncoated nanoparticles were silanated before preparation of hybrid composites, which contained glass microparticles in addition to the nanoparticles. The composites were mechanically tested in 4-point bending mode after aging (10,000 thermal cycles). Results of all chemical and microstructural analyses confirmed the successful obtaining of silica-coated nanoparticles. Two distinct aspects were observed depending on the type of nanoparticle tested: 1) formation of a silica shell on the surface of the particles and 2) nanoparticle clusters embedded into a silica matrix. The aged hybrid composites formulated with the coated nanoparticles showed improved flexural strength (10% to 30% higher) and work of fracture (35% to 40% higher) as compared with composites formulated with noncoated nanoparticles. The tested hypothesis was confirmed: silanated silica-coated nonsilicate nanoparticles yielded stable reinforcement of dimethacrylate polymeric matrix due to effective silanation. The silica-coating method presented here is a versatile and promising novel strategy for the use of crystalline nonsilicate ceramics as a reinforcing phase of polymeric composite biomaterials. PMID- 27470071 TI - Cutaneous Malignancies in Pediatric Solid Organ Transplant Recipients. AB - Pediatric organ transplant recipients (POTRs) are at risk of developing malignancies due to a combination of immunosuppression, impaired DNA damage repair, and infection with oncogenic viruses. The most commonly developed malignancies in this population are skin cancers, which include nonmelanoma skin cancer, melanoma, Kaposi's sarcoma, and anogenital carcinoma. The literature shows that skin cancers account for 13% to 55% of all cancers that occur after transplantation. Given the increasing number and life expectancy of POTRs, prevention and management of skin cancer in these patients is essential, but there is a substantial knowledge gap in our understanding of the differences in skin cancer development, prevention, and management between POTRs and adult organ transplant recipients (AOTRs), for whom more data are available. Substantial differences have been observed in the patterns of malignancy development between POTRs and AOTRs, and data specific to pediatric populations are needed. The objective of this review is to provide updated information on posttransplantation skin cancer development in POTRs, including epidemiologic research on transplant patients and disease development, medication management, surveillance, and education efforts. PMID- 27470070 TI - Genetic engineering of Pseudomonas chlororaphis GP72 for the enhanced production of 2-Hydroxyphenazine. AB - BACKGROUND: The biocontrol strain Pseudomonas chlororaphis GP72 isolated from the green pepper rhizosphere synthesizes three antifungal phenazine compounds, 2 Hydroxyphenazine (2-OH-PHZ), 2-hydroxy-phenazine-1-carboxylic acid (2-OH-PCA) and phenazine-1-carboxylic acid (PCA). PCA has been a commercialized antifungal pesticide registered as "Shenqinmycin" in China since 2011. It is found that 2-OH PHZ shows stronger fungistatic and bacteriostatic activity to some pathogens than PCA. 2-OH-PHZ could be developed as a potential antifungal pesticide. But the yield of 2-OH-PHZ generally is quite low, such as P. chlororaphis GP72, the production of 2-OH-PHZ by the wide-type strain is only 4.5 mg/L, it is necessary to enhance the yield of 2-OH-PHZ for its application in agriculture. RESULTS: Different strategies were used to improve the yield of 2-OH-PHZ: knocking out the negative regulatory genes, enhancing the shikimate pathway, deleting the competing pathways of 2-OH-PHZ synthesis based on chorismate, and improving the activity of PhzO which catalyzes the conversion of PCA to 2-OH-PHZ, although the last two strategies did not give us satisfactory results. In this study, four negative regulatory genes (pykF, rpeA, rsmE and lon) were firstly knocked out of the strain GP72 genome stepwise. The yield of 2-OH-PHZ improved more than 60 folds and increased from 4.5 to about 300 mg/L. Then six key genes (ppsA, tktA, phzC, aroB, aroD and aroE) selected from the gluconeogenesis, pentose phosphate and shikimate pathways which used to enhance the shikimate pathway were overexpressed to improve the production of 2-OH-PHZ. At last a genetically engineered strain that increased the 2-OH-PHZ production by 99-fold to 450.4 mg/L was obtained. CONCLUSIONS: The 2-OH-PHZ production of P. chlororaphis GP72 was greatly improved through disruption of four negative regulatory genes and overexpression of six key genes, and it is shown that P. chlororaphis GP72 could be modified as a potential cell factory to produce 2-OH-PHZ and other phenazine biopesticides by genetic and metabolic engineering. PMID- 27470072 TI - 3D printed simulation models based on real patient situations for hands-on practice. AB - During the last few years, the curriculum of many dentistry schools in Germany has been reorganised. Two key aspects of the applied changes are the integration of up-to-date teaching methods and the promotion of interdisciplinarity. To support these efforts, an approach to fabricating individualised simulation models for hands-on courses employing 3D printing is presented. The models are based on real patients, thus providing students a more realistic preparation for real clinical situations. As a wide variety of dental procedures can be implemented, the simulation models can also contribute to a more interdisciplinary dental education. The data used for the construction of the models were acquired by 3D surface scanning. The data were further processed with 3D modelling software. Afterwards, the models were fabricated by 3D printing with the PolyJet technique. Three models serve as examples: a prosthodontic model for training veneer preparation, a conservative model for practicing dental bonding and an interdisciplinary model featuring carious teeth and an insufficient crown. The third model was evaluated in a hands-on course with 22 fourth-year dental students. The students answered a questionnaire and gave their personal opinion. Whilst the concept of the model received very positive feedback, some aspects of the implementation were criticised. We discuss these observations and suggest ways for further improvement. PMID- 27470073 TI - A combined microwave pretreatment/solvent extraction process for the production of oil from palm fruit: optimisation, oil quality and effect of prolonged exposure. AB - BACKGROUND: Conventional palm oil milling involves multiple stages after fruit collection; in particular, oil clarification introduces water into the pressed oil, which results in a large quantity of wastewater. RESULTS: A combined process of microwave pretreatment and solvent extraction to mill crude palm oil, without introducing water or steam, is described. An excellent yield (up to 30%) of oil was obtained with pretreatment in a 42 L, 1000 W and 2450 MHz microwave oven followed by hexane extraction. The optimum conditions (10 min microwave pretreatment and 12 h solvent extraction) yielded an oil with a low free fatty acid content (<1.0%) and an acceptable anisidine value (<3.0 meq kg-1 ). The oil had a fatty acid composition not resembling those of conventional crude palm oil and crude palm kernel oil. In the pretreatment, the leached oil had 6.3% lauric acid whereas the solvent extracted oil had only 1.5% lauric acid. Among the factors affecting the oil quality, microwave pretreatment affected the oil quality significantly; however, an optimised duration that would ensure high efficiency in solvent extraction also resulted in ruptured fruitlets, although not to the extent of causing excessive oxidation. In fact, microwave pretreatment should exceed 12 min; after only 15 min, the oil had 1-methylcyclopentanol (12.96%), 1-tetradecanol (9.44%), 1-nonadecene (7.22%), nonanal (7.13%) and 1 tridecene (5.09%), which probably arose from the degradation of fibres. CONCLUSION: Microwave pretreatment represents an alternative milling process for crude palm oil compared with conventional processes in the omission of wet treatment with steam. (c) 2016 Society of Chemical Industry. PMID- 27470074 TI - Evidence of iteroparity in the widely distributed diadromous fish inanga Galaxias maculatus and potential implications for reproductive output. AB - Gaps in understanding variability among populations of inanga Galaxias maculatus in the timing of reproduction were addressed in southern New Zealand (NZ), where G. maculatus constitutes a declining fishery. Reproductive activity was delayed by 1 month on the west coast compared with the east coast and the west coast spawning season was prolonged into winter. The evidence for post-spawning survival of some fish was unequivocal from histological studies. These older and larger fish contributed disproportionately to egg production. Estimates of fecundity were considerably lower than those previously calculated for NZ populations. The importance of quality habitats being available during critical life history periods are highlighted. It was apparent that some streams supported fish that were larger and in better condition and that this translated into greatly increased fecundity. Future research should focus on whether this is a legacy of these fish experiencing better pre-settlement marine habitat as larvae, or higher quality instream habitat enhancing the growth and development of adults. PMID- 27470075 TI - Cathelicidin-encoding Lactococcus lactis promotes mucosal repair in murine experimental colitis. AB - BACKGROUND AND AIM: The preventive effect of intrarectal administration of mouse cathelicidin (mCRAMP) and oral administration of mCRAMP-encoding Lactococcus lactis (N4I) has been shown in murine experimental colitis. It is pivotal to understand the ability of N4I whether it can promote mucosal repair in existing colitis. METHODS: Mice with dextran sulfate sodium-induced ulcerative colitis (UC) were treated orally with L. lactis or its transformed strain with or without nisin induction. The body weight, clinical symptoms, and histological changes of colonic tissues were determined. Sulfasalazine was used as a reference drug. Young adult mouse colon cells were used to further elucidate the direct action and possible mechanisms of mCRAMP to promote colonic wound repair. RESULTS: Results showed that N4I could improve the clinical symptoms, maintain crypt integrity and preserve mucus-secreting layer in colitis animals. The preparation also could prevent cell death and promote cell proliferation. In contrast, effective dose of sulfasalazine only alleviated clinical symptoms but not the mucosal damage and repair in the colon. In vitro study further showed that mCRAMP could directly promote wound repair by accelerating cell migration but not cell proliferation through the GPCR/MAPK pathway. CONCLUSIONS: mCRAMP-encoding L. lactis could be a potential therapeutic preparation better than the traditional anti-inflammatory agent in the treatment of UC. PMID- 27470076 TI - The making of 'Boomergeddon': the construction of the Baby Boomer generation as a social problem in Britain. AB - High-profile claims about the problem of the 'Baby Boomer' generation, made in media and policy circles in recent years, have contributed to an awakened interest in the sociology of generations. While many claims focus on resource issues arising from the existence of a relatively large cohort (for example, pensions and healthcare), they contain an implicit moral critique of the generation associated with the postwar 'boom' of the Sixties. This article examines the development of the cultural script of the Baby Boomer problem in British newspapers over a 26-year period, to examine how shifts in the discourse about the Boomer generation relate to wider social, economic, cultural and political trends. PMID- 27470077 TI - Fabrication and Manipulation of Ciliary Microrobots with Non-reciprocal Magnetic Actuation. AB - Magnetically actuated ciliary microrobots were designed, fabricated, and manipulated to mimic cilia-based microorganisms such as paramecia. Full three dimensional (3D) microrobot structures were fabricated using 3D laser lithography to form a polymer base structure. A nickel/titanium bilayer was sputtered onto the cilia part of the microrobot to ensure magnetic actuation and biocompatibility. The microrobots were manipulated by an electromagnetic coil system, which generated a stepping magnetic field to actuate the cilia with non reciprocal motion. The cilia beating motion produced a net propulsive force, resulting in movement of the microrobot. The magnetic forces on individual cilia were calculated with various input parameters including magnetic field strength, cilium length, applied field angle, actual cilium angle, etc., and the translational velocity was measured experimentally. The position and orientation of the ciliary microrobots were precisely controlled, and targeted particle transportation was demonstrated experimentally. PMID- 27470078 TI - Noninvasive low-frequency electromagnetic stimulation of the left stellate ganglion reduces myocardial infarction-induced ventricular arrhythmia. AB - Noninvasive magnetic stimulation has been widely used in autonomic disorders in the past few decades, but few studies has been done in cardiac diseases. Recently, studies showed that low-frequency electromagnetic field (LF-EMF) might suppress atrial fibrillation by mediating the cardiac autonomic nervous system. In the present study, the effect of LF-EMF stimulation of left stellate ganglion (LSG) on LSG neural activity and ventricular arrhythmia has been studied in an acute myocardium infarction canine model. It is shown that LF-EMF stimulation leads to a reduction both in the neural activity of LSG and in the incidence of ventricular arrhythmia. The obtained results suggested that inhibition of the LSG neural activity might be the causal of the reduction of ventricular arrhythmia since previous studies have shown that LSG hyperactivity may facilitate the incidence of ventricular arrhythmia. LF-EMF stimulation might be a novel noninvasive substitute for the existing implant device-based electrical stimulation or sympathectomy in the treatment of cardiac disorders. PMID- 27470080 TI - Beyond Epstein-Barr virus: genetic predisposition of natural killer T-cell lymphoma. PMID- 27470079 TI - Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study. AB - BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS: We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS: Associations exceeding the genome-wide significance threshold (p<5 * 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4.21 * 10(-19), odds ratio [OR] 1.84 [95% CI 1.61-2.11] in meta analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2.38, p value for haplotype 2.32 * 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION: To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING: Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1). PMID- 27470082 TI - Cumulative burden of disease: a relevant measure of the late side-effects of cancer treatment. PMID- 27470081 TI - Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study. AB - BACKGROUND: The magnitude of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is not known. Using medically ascertained data, we applied the cumulative burden metric to compare chronic cardiovascular health conditions in survivors of Hodgkin's lymphoma and general population controls. METHODS: For this study, participant data were obtained from two ongoing cohort studies at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE) and the St Jude Long-term Follow-up Study (SJLTFU). SJLIFE is a cohort study initiated on April 27, 2007, to enable longitudinal clinical evaluation of health outcomes of survivors of childhood cancer treated or followed at St Jude Children's Research Hospital, and SJLTFU is an administrative system-based study initiated in 2000 to collect outcome and late toxicity data for all patients treated at the hospital for childhood cancer. The patient cohort for our study was defined as patients treated at St Jude Children's Research Hospital who reached 18 years of age and were at least 10 years post-diagnosis of pathologically confirmed primary Hodgkin's lymphoma. Outcomes in the Hodgkin's lymphoma survivors were compared with a sample of SJLIFE community control participants, aged 18 years or older at the time of assessment, frequency-matched based on strata defined by 5-year age blocks within each sex, who were selected irrespective of previous medical history. All SJLIFE participants underwent assessment for 22 chronic cardiovascular health conditions. Direct assessments, combined with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) version 4.03 grading schema. Occurrences and CTCAE grades of the conditions for eligible non-SJLIFE participants were accounted for by multiple imputation. The mean cumulative count (treating death as a competing risk) was used to estimate cumulative burden. FINDINGS: Of 670 survivors treated at St Jude Children's Research Hospital, who survived 10 years or longer and reached age 18 years, 348 were clinically assessed in the St Jude Lifetime Cohort Study (SJLIFE); 322 eligible participants did not participate in SJLIFE. Age and sex frequency-matched SJLIFE community controls (n=272) were used for comparison. At age 50 years, the cumulative incidence of survivors experiencing at least one grade 3-5 cardiovascular condition was 45.5% (95% CI 36.6-54.3), compared with 15.7% (7.0-24.4) in community controls. The survivor cohort at age 50 experienced a cumulative burden of 430.6 (95% CI 380.7-480.6) grade 1-5 and 100.8 (77.3-124.3) grade 3-5 cardiovascular conditions per 100 survivors; these numbers were appreciably higher than those in the control cohort (227.4 [192.7-267.5] grade 1-5 conditions and 17.0 [8.4-27.5] grade 3-5 conditions per 100 individuals). Myocardial infarction and structural heart defects were the major contributors to the excess grade 3-5 cumulative burden in survivors. High cardiac radiation dose (>=35 Gy) was associated with an increased proportion of grade 3-5 cardiovascular burden, whereas increased anthracyline dose was not. INTERPRETATION: The true effect of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is reflected in the cumulative burden. Survivors aged 50 years will experience more than two times the number of chronic cardiovascular health conditions and nearly five times the number of more severe (grade 3-5) cardiovascular conditions compared with community controls and, on average, have one severe, life threatening, or fatal cardiovascular condition. The cumulative burden metric provides a more comprehensive approach for assessing overall morbidity compared with currently used cumulative incidence based analytic methodologies, and will assist clinical researchers when designing future trials and refining general practice screening guidelines. FUNDING: US National Cancer Institute, St Baldrick's Foundation, and American Lebanese Syrian Associated Charities. PMID- 27470083 TI - Dual NRF2 paralogs in Coho salmon and their antioxidant response element targets. AB - The transcription factor NFE2L2 (Nuclear Factor, Erythroid 2-Like 2, or NRF2) plays a key role in maintaining the redox state within cells. Characterization of this pathway has extended to fish, most notably zebrafish (Danio rerio), in which two paralogs of the transcription factor exist: Nrf2a, an activator, and Nrf2b, a negative regulator during embryogenesis. Only one ARE target has been thoroughly delineated in zebrafish, and this deviated from the canonical sequence derived from studies in mammals. In general, the mechanistic pathway has not been characterized in non-model aquatic organisms that are commonly exposed to environmental pollutants. The current study compares the zebrafish paralogs to those found in a non-model teleost, the ecologically important salmonid, Oncorhnychus kisutch (coho salmon). Two salmon paralogs, Nrf2A and -2B, described here were found to possess only slightly greater identity between one another (84% of amino acids) than to the singleton ortholog of the esocid Esox lucius (80 82%), the nearest non-salmonid outgroup. Unlike one of the zebrafish forms, each is a strong activating factor based on sequence homology and in vitro testing. To uncover functional target AREs in coho, promoter flanking sequences were isolated for five genes that protect cells against oxidative stress: heme oxygenase 1, peroxiredoxin 1, glutamate-cysteine ligase, and the glutathione S-transferases pi and rho (hmox1, prdx1, gclc, gstp, and gstr). All except gstr had functional elements and all fit the standard mammalian-derived canonical sequence, unlike the motif found in zebrafish gstp. Expression studies demonstrate the presence of both Nrf2 paralogs in multiple organs, although in differing ratios. Collectively, our findings extend the conservation of Nrf2 and the ARE to salmonids, and should help inform future work in teleosts on mechanisms of redox control, as well as responsiveness of this pathway and its downstream antioxidant gene targets to chemical exposures in the environment. PMID- 27470084 TI - Nitrogen stable isotope variability in tissues of juvenile tilapia Oreochromis aureus: empirical and modelling results. AB - RATIONALE: Studies on diet or trophic interactions of organisms based on stable isotopes require accurate estimates of how quickly stable isotope ratios change in the investigated tissues. However, rates of isotope turnover in fish tissues, especially in omnivorous species, are poorly understood. METHODS: We conducted a diet-shift study using juvenile tilapia to (i) empirically estimate the isotopic turnover rates of nitrogen in the dorsal muscle, liver, fin and backbone; (ii) model the relative contributions of metabolism and growth to the total isotopic turnover in each tissue; and (iii) develop a non-lethal approach for estimating body nitrogen stable isotope ratios for threatened or endangered species. Isotopic analyses were performed using a Flash EA CN elemental analyser coupled to a ThermoFinnigan Delta Plus mass spectrometer. RESULTS: Nitrogen isotopic turnover rates were consistently ranked in the order backbone > liver > muscle > fin due to the relatively lower metabolic rates of muscle and fin tissue. Backbone tissue turned over significantly faster than other tissues, suggesting the potential for a multiple-tissue stable isotope approach to the study of movement and trophic position over different time scales for omnivorous fish. However, fin tissue had the longest half-life, at 57.81 days, indicating that this tissue is more useful than muscle as a long-term dietary indicator. CONCLUSIONS: The change in nitrogen isotope ratios in dorsal muscle was mainly regulated by somatic growth, but metabolic activity markedly stimulated the turnover rate of backbone. This study is one of a few to demonstrate significant variation in the delta(15) N turnover rates among multiple tissues of a single organism, especially for omnivorous fish. Our results, to some extent, also indirectly contribute to the conservation of threatened or endangered species. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470085 TI - Immunoprotective effects of oral intake of heat-killed Lactobacillus pentosus strain b240 in elderly adults: a randomised, double-blind, placebo-controlled trial - CORRIGENDUM. PMID- 27470086 TI - Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib. AB - Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2*/1.5*/2.0* greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (>=1.2*), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each >=1.5*), as well as opportunistic infections and gastrointestinal perforations (>=2*), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations. PMID- 27470087 TI - A phase II investigator-initiated pilot study with low-dose cyclosporine A for the treatment of articular involvement in primary Sjogren's syndrome. AB - This study aims to investigate the efficacy and safety of low-dose cyclosporine A (CyA) in patients with primary Sjogren's syndrome (pSS) and articular involvement. This phase II open-label clinical study included 30 patients meeting the American-European Consensus group criteria for pSS with active joint involvement under stable symptomatic therapy. Treatment consisted of approximately 2 mg kg(-1) body weight of CyA day(-1) over a period of 16 weeks. The primary endpoint was defined as a reduction in the number of painful and/or swollen joints at end of treatment (EOT). Secondary endpoints included the changes in general health, sicca symptoms, European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI), arthrosonography, and safety profile. At baseline (BL), the mean number of tender joints (68 count) was 16.2 (+/-13.2) and at EOT 10.4 (+/-11.9; p = 0.002). The mean number of swollen joints (66 counts) was reduced from 3.2 (+/-3.3) at BL to 1.3 (+/-3.2) at EOT (p < 0.001). Overall, 21 (70 %) and 13 (43.3 %) patients had a reduction of two or more tender and swollen joints, respectively, in the 68/66 joint counts. The disease activity score (DAS28) showed a statistically and clinically meaningful decrease over the 16-week period of treatment. Treatment was well tolerated, and adverse events were consistent with the known safety profile of CyA (e.g., hypertension, headache). In this pilot study, promising effects of low-dose CyA treatment on articular involvement were observed in patients with pSS justifying further controlled studies in this indication. No new or unexpected safety observations were made. TRIAL REGISTRATION: Low-Dose Cyclosporin A in Primary Sjogren Syndrome (CYPRESS), ClinicalTrials.gov Identifier: NCT01693393 . PMID- 27470088 TI - Improved WOMAC score following 16-week treatment with bromelain for knee osteoarthritis. AB - Treatment with bromelain-containing enzyme preparation for 3-4 weeks is effective for treatment of knee osteoarthritis (OA). Here, we aimed to assess 16-week treatment with bromelain in mild-to-moderate knee OA patients. We performed a randomized, single-blind, active-controlled pilot study. Forty knee OA patients were randomized to receive oral bromelain (500 mg/day) or diclofenac (100 mg/day). Primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) analyzed by Wilcoxon signed rank test. Secondary outcome was the short-form 36 (SF-36). Plasma malondialdehyde (MDA) and nitrite were measured as oxidative stress markers. There was no difference in WOMAC and SF-36 scores compared between bromelain and diclofenac groups after 4 weeks. At week 4, the improvement of total WOMAC and pain subscales from baseline was observed in both groups; however, two patients given diclofenac had adverse effects leading to discontinuation of diclofenac. However, observed treatment difference was inconclusive. At week 16 of bromelain treatment, the patients had improved total WOMAC scores (12.2 versus 25.5), pain subscales (2.4 versus 5.6), stiffness subscales (0.8 versus 2.0), and function subscales (9.1 versus 17.9), and physical component of SF-36 (73.3 versus 65.4) as compared with baseline values. OA patients had higher plasma MDA, nitrite, and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated whole blood but lower plasma alpha tocopherol than control subjects. Plasma MDA and LPS-stimulated PGE2 production were decreased at week 16 of bromelain treatment. Bromelain has no difference in reducing symptoms of mild-to-moderate knee OA after 4 weeks when compared with diclofenac. PMID- 27470090 TI - Lanthanide-based metal-organic frameworks as luminescent probes. AB - Lanthanide-based metal-organic frameworks (Ln-MOFs), as notable materials, are constructed by Ln3+ ions and organic ligands, or Ln3+ ions functionalizing non-Ln MOFs, and exhibit promising applications in various fields. Over the past decades, quite a lot of investigations of Ln-MOFs have been carried out, and many good results have been obtained. Among these results, Ln-MOFs as luminescent probes for unique detection are gradually becoming a hot topic due to their fast and effective luminescent response for the targeted substance. In this perspective article, we discuss the construction of luminescent Ln-MOFs, their applications in possible detection mechanisms, and summarize some examples of Ln MOFs as luminescent probes for sensing cations, anions and small molecules. PMID- 27470089 TI - Synthetic biology and microbioreactor platforms for programmable production of biologics at the point-of-care. AB - Current biopharmaceutical manufacturing systems are not compatible with portable or distributed production of biologics, as they typically require the development of single biologic-producing cell lines followed by their cultivation at very large scales. Therefore, it remains challenging to treat patients in short time frames, especially in remote locations with limited infrastructure. To overcome these barriers, we developed a platform using genetically engineered Pichia pastoris strains designed to secrete multiple proteins on programmable cues in an integrated, benchtop, millilitre-scale microfluidic device. We use this platform for rapid and switchable production of two biologics from a single yeast strain as specified by the operator. Our results demonstrate selectable and near-single dose production of these biologics in <24 h with limited infrastructure requirements. We envision that combining this system with analytical, purification and polishing technologies could lead to a small-scale, portable and fully integrated personal biomanufacturing platform that could advance disease treatment at point-of-care. PMID- 27470091 TI - Understanding the role of synaptopodin and the spine apparatus in Hebbian synaptic plasticity - New perspectives and the need for computational modeling. AB - Synaptopodin (SP) is a proline-rich actin-associated protein essential for the formation of a spine apparatus (SA) in dendritic spines. The SA consists of stacks of smooth endoplasmic reticulum (sER) contiguous with the meshwork of somatodendritic ER. Spines of SP-deficient mice contain sER but no SA, demonstrating that SP is necessary for the assembly of ER cisterns into the more complex SA organelle. Although the SA was described decades ago, its function was difficult to investigate and remained elusive, in part because reliable markers for the SA were missing. After SP was identified as an essential component and a reliable marker of the SA, a role of SP/SA in hippocampal synaptic plasticity could be firmly established using loss-of-function approaches. Further studies revealed that SP/SA participate in the regulation of Ca2+-dependent spine specific Hebbian plasticity and in activity-dependent changes in the spine actin cytoskeleton. In this review we are summarizing recent progress made on SP/SA in Hebbian plasticity and discuss open questions such as causality, spatiotemporal dynamics and complementarity of SP/SA-dependent mechanisms. We are proposing that computational modeling of spine Ca2+-signaling and actin remodeling pathways could address some of these issues and could indicate future research directions. Moreover, reaction-diffusion simulations could help to identify key feedforward and feedback regulatory motifs regulating the switch between an LTP and an LTD signaling module in SP/SA-containing spines, thus helping to find a unified view of SP/SA action in Hebbian plasticity. PMID- 27470093 TI - Differential involvement of Ca2+/calmodulin-dependent protein kinases and mitogen activated protein kinases in the dopamine D1/D5 receptor-mediated potentiation in hippocampal CA1 pyramidal neurons. AB - Dopaminergic neurotransmission modulates and influences hippocampal CA1 synaptic plasticity, learning and long-term memory mechanisms. Investigating the mechanisms involved in the slow-onset potentiation induced by the dopamine D1/D5 receptor agonists in hippocampal CA1 region, we have reported recently that it could play a role in regulating synaptic cooperation and competition. We have also shown that a sustained activation of MEK/MAP kinase pathway was involved in the maintenance of this long-lasting potentiation (Shivarama Shetty, Gopinadhan, & Sajikumar, 2016). However, the molecular aspects of the induction of dopaminergic slow-onset potentiation are not known. Here, we investigated the involvement of MEK/MAPK pathway and Ca2+-calmodulin-dependent protein kinases (CaMKII and CaMKIV) in the induction and maintenance phases of the D1/D5 receptor mediated slow-onset potentiation. We report differential involvement of these kinases in a dose-dependent manner wherein at weaker levels of dopaminergic activation, both CaMKII and MEK1/2 activation is necessary for the establishment of potentiation and with sufficiently stronger dopaminergic activation, the role of CaMKII becomes dispensable whereas MEK activation remains crucial for the long lasting potentiation. The results are interesting in view of the involvement of the hippocampal dopaminergic system in a variety of cognitive abilities including memory formation and also in neurological diseases such as Alzheimer's disease and Parkinson's disease. PMID- 27470094 TI - Modulating the selectivity of affinity absorbents to multi-phosphopeptides by a competitive substitution strategy. AB - Although many affinity adsorbents have been developed for phosphopeptides enrichment, high-specifically capturing the multi-phosphopeptides is still a big challenge. Here, we investigated the mechanism of phosphate ion coordination and substitution on affinity adsorbents surfaces and modulated the selectivity of affinity adsorbents to multi-phosphopeptides based on the different capability of mono- and multi-phosphopeptides in competitively substituting the pre-coordinated phosphate ions at strong acidic condition. We demonstrated both the species of pre-coordinated phosphate ions and the substituting conditions played crucial roles in modulating the enrichment selectivity to multi-phosphopeptides, and the pre-coordinated affinity materials with relative more surfaces positive charges exhibited better enrichment efficiency due to the cooperative effect of electrostatic interaction and competitive substitution. Finally, an enrichment selectivity of 85% to multi-phosphopeptides was feasibly achieved with 66% improvement in identification numbers for complex protein sample extracted from HepG2 cells. Data are available via ProteomeXchange with identifier PXD004252. PMID- 27470092 TI - Bridging the Gap: Towards a cell-type specific understanding of neural circuits underlying fear behaviors. AB - Fear and anxiety-related disorders are remarkably common and debilitating, and are often characterized by dysregulated fear responses. Rodent models of fear learning and memory have taken great strides towards elucidating the specific neuronal circuitries underlying the learning of fear responses. The present review addresses recent research utilizing optogenetic approaches to parse circuitries underlying fear behaviors. It also highlights the powerful advances made when optogenetic techniques are utilized in a genetically defined, cell-type specific, manner. The application of next-generation genetic and sequencing approaches in a cell-type specific context will be essential for a mechanistic understanding of the neural circuitry underlying fear behavior and for the rational design of targeted, circuit specific, pharmacologic interventions for the treatment and prevention of fear-related disorders. PMID- 27470095 TI - Evaluation of poly(90% biscyanopropyl/10% cyanopropylphenyl siloxane) capillary columns for the gas chromatographic quantification of trans fatty acids in non hydrogenated vegetable oils. AB - Current gas chromatographic (GC) methods for the analysis of fatty acids (FA) were optimized primarily for the quantification of the trans 18:1 FAs (18:1 tFAs) produced during the partial hydrogenation of fats and oils. Recent regulatory action regarding the application of partial hydrogenation in the processing of edible fats and oils may reshape the FA composition of these products. The higher content in 18:3 tFAs compared to 18:1 tFAs of most refined non-hydrogenated vegetable oils (RNHVO), and the challenge in their quantification applying current methods, suggest the need for new methodologies. This manuscript describes a simple GC method for the analysis of FAs in RNHVOs utilizing a 100m (0.25mm I.D.) capillary column coated with poly(90% biscyanopropyl/10% cyanopropylphenyl siloxane) (90% BCS). The optimization of the chromatographic conditions and the detection of co-eluting compounds were carried out by applying comprehensive two dimensional gas chromatography with online reduction (GC OR*GC). Results showed that 90% BCS capillary columns operated at the elution temperature of 162 degrees C provide the separation of the 18:1, 18:2 and 18:3 tFAs, contained in RNHVOs, from other components. A minor constituent of Canola oil, 16:3n-3, partially co-eluted with trans-18:1 FAMEs. This simple GC method showed the ability to measure trans-fat in RNHVOs at the level of 0.5g/100g, providing comparable quantitative results to the more complex GC*GC methodology. PMID- 27470097 TI - "I feel good and I am not overweight" - A qualitative study of considerations underlying lay people's self-assessments of unhealthy diets. AB - It has been suggested that optimistic self-assessments of unhealthy diets constitute a barrier to the promotion of healthier eating practices. In order to discuss possible reasons for such optimistic assessments, knowledge about the considerations underlying self-assessments of unhealthy diets is needed. The aim of this qualitative study is to explore this issue by comparing considerations underlying the assessments of people who overestimate the healthiness of their unhealthy diets with those of people who express more realistic assessments. Interviewees were recruited among those respondents to the Danish National Survey of Diet and Physical Activity 2011-2013, who had been accorded a low diet index score. A thematic analysis of qualitative interviews is undertaken (N = 16). When interviewees are asked to assess the healthiness of their diets, they draw upon their nutritional knowledge and their perceptions of healthy eating practices. However, these considerations tend to be overruled by more decisive criteria. Thus, diets are assessed as being not exactly healthy, but nevertheless healthy enough - so long as interviewees feel good. Moreover, a personal history of weight status and weight concerns emerge as decisive criteria in self assessments. Those who experience problems in these areas tend to be realistic about the unhealthy character of their diets, while optimistic assessments appear to be linked to tendencies to perceive oneself as not being overweight, not having experienced weight gain or loss, or not being concerned about weight. This study concludes that decisive criteria in lay people's self-assessments of unhealthy diets - with regard to feeling and looking good - differ markedly from the criteria employed in food-based dietary guidelines. These broader criteria of assessment should be recognized by professionals engaged in planning health promotion strategies with reference to dietary health. PMID- 27470096 TI - Immunogenicity of a novel tetravalent vaccine formulation with four recombinant lipidated dengue envelope protein domain IIIs in mice. AB - We developed a novel platform to express high levels of recombinant lipoproteins with intrinsic adjuvant properties. Based on this technology, our group developed recombinant lipidated dengue envelope protein domain IIIs as vaccine candidates against dengue virus. This work aims to evaluate the immune responses in mice to the tetravalent formulation. We demonstrate that 4 serotypes of recombinant lipidated dengue envelope protein domain III induced both humoral and cellular immunity against all 4 serotypes of dengue virus on the mixture that formed the tetravalent formulation. Importantly, the immune responses induced by the tetravalent formulation in the absence of the exogenous adjuvant were functional in clearing the 4 serotypes of dengue virus in vivo. We affirm that the tetravalent formulation of recombinant lipidated dengue envelope protein domain III is a potential vaccine candidate against dengue virus and suggest further detailed studies of this formulation in nonhuman primates. PMID- 27470098 TI - Snacking now or later? Individual differences in following intentions or habits explained by time perspective. AB - Even when individuals are aware of long-term health effects of their diet, and form healthy intentions, they often engage in relatively unhealthy snacking habits. Some individuals fall back on unhealthy habits more easily than others. We aim to explore whether time perspective can explain why some individuals are more prone to rely on habits and others on intentions. Study 1 (N = 1503) provides a first exploration of the role of time perspective by exploring individual differences in perception of long-term and short-term consequences. In accordance with our hypotheses, Study 1 shows that habits are associated with short-term consequences and intentions with long-term consequences. Study 2 (N = 1497) shows that the effects of habits on snacking behaviour are strengthened by a present time perspective, whereas the effects of intentions on snacking behaviour are strengthened by a future time perspective. These findings imply that there is a fundamental difference in the guiding function of intentions and habits which might explain individual differences in following intentions versus habits. Individuals with a long-term perspective are more inclined to follow intentions and individuals with a short-term perspective are more inclined to follow habits. PMID- 27470099 TI - Relationship between Iodine Content in Household Iodized Salt and Thyroid Volume Distribution in Children. AB - OBJECTIVE: To assess the effect of different levels of salt iodine content on thyroid volume (ThV) distribution using data from the 1999, 2011, and 2014 Chinese national iodine deficiency disorder (IDD) surveys. METHODS: Probability proportion to size (PPS) sampling method was used to obtain a representative national sample of 34,547, 38,932, and 47,188 Chinese children aged 8-10 years in 1999, 2011, and 2014 Chinese national IDD surveys, respectively. The iodine content in household iodized salt and urinary iodine concentration were measured and thyroid ultrasound examination was performed. The data were analyzed by SAS software using histograms and box plots. The skewness and kurtosis were calculated for testing the normality of ThV. RESULTS: The median iodine content in household iodized salt dropped from 42.30 mg/kg in 1999 to 25.00 mg/kg in 2014. The median urinary iodine concentration of children aged 8-10 years decreased from 306.0 MUg/L in 1999 to 197.9 MUg/L in 2014. The median and interquartile range (IQR) of ThV in 1999, 2011, and 2014 surveys were 3.44 mL and 1.50 mL, 2.60 mL and 1.37 mL, 2.63 mL and 1.25 mL, respectively. The skewness and kurtosis of ThV distribution in 1999, 2011, and 2014 surveys were 1.34 and 5.84, 0.98 and 3.54, 1.27 and 5.49, respectively. CONCLUSION: With reduced salt iodization levels, the median urinary iodine concentration and median ThV of children decreased significantly, and the symmetry of the ThV distribution improved. PMID- 27470100 TI - Prevalence of Thyroid Nodules and Its Relationship with Iodine Status in Shanghai: a Population-based Study. AB - OBJECTIVE: This study was designed to evaluate the prevalence of thyroid nodules (TNs) and its relationship with urine iodine concentrations (UICs) after the regional rapid economic growth and lifestyle changes. METHODS: A cross-sectional survey was conducted in the general population aged 15-69 years. A questionnaire regarding general and personal characteristics and relevant information was administered. Ultrasonography of the thyroid was performed, and serum triiodothyronine (T3), tetraiodothyronine (T4), serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free tetraiodothyronine (FT4), thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), and TSH receptor antibody (TRAb) levels were measured for each individual subject. RESULTS: The prevalence rates of TNs in the whole population, females and males were 27.76%, 34.04%, and 21.60%, respectively. The prevalence of multiple nodules increased with age, whereas the prevalence peaks differed between males and females. The median UICs in the whole population and females with non-TNs were higher than those of subjects with TNs (P=0.0035, P=0.0068). The median UICs in subjects with a single TN were higher than those in subjects with multiple TNs (P=0.0164, P=0.0127). The result showed a U-shaped curve relationship between UIC and prevalence of TNs. The prevalence of TNs was the lowest when the UIC was 140-400 MUg/L. CONCLUSION: The prevalence of TNs was nearly 30% and increased with age. The relationship between UIC and prevalence of TNs is U-shaped, with an increase in risk when the UIC was <140 MUg/L and >400 MUg/L. Very low or high UIC levels need attention and correction. PMID- 27470101 TI - Epidemiology of Diabetes in Adults Aged 35 and Older from Shanghai, China. AB - OBJECTIVE: This study aimed to investigate the epidemiology of diabetes in adults from Shanghai, aged 35 and older, in 2013. METHODS: We estimated the diabetes prevalence in a representative sample of 18,736 adults who were selected through a multistage stratified cluster sampling process. A standard questionnaire containing questions about demographic characteristics and lifestyle factors was distributed. After an overnight fast of at least 10 hours, a venous blood sample was collected from each participant. For each patient without a history of diabetes, another blood sample was drawn 120 min after an oral glucose tolerance test to identify undiagnosed diabetes and prediabetic condition. RESULTS: Among Shanghai residents aged 35 and above, the overall weighted prevalence of diabetes was 17.6% [95% confidence interval (CI): 16.4%-18.8%]. The prevalences were 19.3% in men and 15.8% in women as well as 19.1%, 15.4%, and 16.1% in urban, suburban, and rural residents, respectively. In addition, the weighted prevalence of prediabetes was 16.5% (95% CI: 15.3%-17.8%), with the prevalences of 16.5% in men, 16.6% in women, 15.2% in urban residents, 18.0% in suburban residents, and 18.5% in rural residents. Among all patients with diabetes, 68.1% (95% CI: 64.3% 71.6%) were aware of their status, 63.5% (95% CI: 60.0%-66.9%) received diabetes treatment, but only 35.1% (95% CI: 32.4%-37.8%) had adequate glycemic control. CONCLUSION: In Shanghai, diabetes and prediabetes are highly prevalent. However, 1/3rd of diabetes cases are undiagnosed, and the rate of glycemic control is low. PMID- 27470102 TI - Expression and Purification of Recombinant Hepatitis Delta Virus (HDV) Antigen for Use in a Diagnostic ELISA for HDV Infection Using the High-Density Fermentation Strategy in Escherichia coli. AB - OBJECTIVE: Hepatitis Delt a Virus (HDV) antigen is widely used as a capture antigen in ELISAs for the identification of HDV infection; large amounts of recombinant HDV antigen with active antigenicity are required for this purpose. METHODS: Reconstruct the gene of HDV antigen based on the bias code of Escherichia coli, the recombinant protein expresses by high-density fermentation with fed-batch feeding strategy, and purify by immobilized metal chromatography. The sensitivity and specificity of this antigen detect by ELISA method. RESULTS: The expression of HDV antigen can reach 20% of the total cell mass in the soluble form. The recombinant HDV antigen can be conveniently purified (98%) by immobilized metal ion affinity chromatography (IMAC) using the interaction between a His-tag and nickel ions. Production of recombinant HDV antigen can reach 0.5 g/L under conditions of high-density cell fermentation. Applied to the diagnostic ELISA method, the recombinant HDV antigen shows excellent sensitivity (97% for IgM and 100% for IgG) and specificity (100% for IgG and IgM) for the detection of anti-HDV antibodies. CONCLUSION: Expression and purification the recombinant HDV antigen as a candidate protein for application in a diagnostic ELISA for HDV infection. Large-scale production of the protein can be achieved using the high-density fermentation strategy. PMID- 27470103 TI - Legionella dumoffii Tex-KL Mutated in an Operon Homologous to traC-traD is Defective in Epithelial Cell Invasion. AB - OBJECTIVE: To understand the mechanism of invasion by Legionella dumoffii. METHODS: The L. dumoffii strain Tex-KL was mutated using the Tn903 derivative, Tn903dIIlacZ. After screening 799 transposon insertion mutants, we isolated one defective mutant. We then constructed the gene-disrupted mutant, KL16, and studied its invasion of and intracellular growth in HeLa and A549 cells, and in A/J mice survival experiments. The structure of traC-traD operon was analyzed by RT-PCR. RESULTS: The transposon insertion was in a gene homologous to Salmonella typhi traC, which is required for the assembly of F pilin into the mature F pilus structure and for conjugal DNA transmission. Results from RT-PCR suggested that the traC-traD region formed an operon. We found that when the traC gene was disrupted, invasion and intracellular growth of L. dumoffii Tex-KL were impaired in human epithelial cells. When mice were infected by intranasal inoculation with a traC deficient mutant, their survival significantly increased when compared to mice infected with the wild-type strain.. CONCLUSION: Our results indicated that the traC-traD operon is required for the invasion and intracellular growth abilities of L. dumoffii Tex-KL in epithelial cells. PMID- 27470104 TI - Damage to Hippocampus of Rats after Being Exposed to Infrasound. AB - OBJECTIVE: The objective was to observe damage of hippocampus in rats after exposure to infrasound, and to assess HSP70 expression in hippocampus. METHODS: SD rats in the experimental group were exposed to 140 dB (8 Hz) infrasound for 2 h per day for 3 days. The morphology of the hippocampus was examined by transmission electronic microscopic (TEM). Cell apoptosis was observed by TUNEL staining at 0 h, 24 h, 48 h, and 2 w after exposure. HSP70 expression was detected by immunohistochemistry (IHC) and Western blotting (WB). RESULTS: TEM showed that hippocampus was significantly damaged by exposure, and exhibited recovery 1 week after exposure. The TUNEL data showed that neuronal apoptosis after exposure was significantly higher than in the control rats at 24 h and 48 h, and the apoptotic cells decreased one week after exposure. IHC and WB showed HSP70 expression was significantly higher in the exposed rats, peaked at 24 h. CONCLUSION: Exposure to 140 dB (8 Hz) infrasound for 2 h per day for 3 days appeared to induce damage to the hippocampus of rats, based on changes in ultrastructure and increased cell apoptosis. However, recovery from the damage occurred overtime. HSP70 expression also increased after the exposure and decreased by 48. PMID- 27470105 TI - Detection and Analysis of Ebola Virus in Sierra Leone-China Friendship Biosafety Laboratory from March 11 to April 20, 2015. AB - Ebola virus disease reemerged in Western Africa in 2014. Chinese Center for Disease Control and Prevention dispatched the first Ebola virus (EBOV) detection team to run newly established Sierra Leone-China Friendship Biological Safety Laboratory. The aims of study were to understand epidemiology, clinical manifestations and survival time of EBOV in patient's blood. A total of 913 specimens were tested between March 11 and April 20, 2015. EBOV positivity occurred in 7.37% of the blood and 0.53% in throat swabs. Most commonly reported symptoms of laboratory confirmed patients were intense fatigue, anorexia, and fever. EBOV RNAs persisted in blood for almost 4 weeks and the real-time RT-PCR Ct values showed close correlation with the sampling time after onset. PMID- 27470106 TI - Antimicrobial Resistance, Virulence Profile, and Molecular Characterization of Listeria monocytogenes Isolated from Ready-to-eat Food in China, 2013-2014. AB - We aimed to investigate the potential pathogenic profile and antibiotic resistance of Listeria monocytogenes isolated from ready-to-eat food in China. Antimicrobial resistance was determined by broth microdilution following the Clinical and Laboratory Standards Institute protocol. Molecular serotyping, virulence, and resistance genes were identified using PCR. Multi-locus sequence typing was performed on resistant strains. A total of 11.53% (113/980) isolates were resistant, from which 82.3% (93/113) harbored all the virulence genes tested. The resistant strains were subtyped into 18 sequence types (STs), from which ST2, ST5, ST8, and ST9 were involved in listeriosis. This study indicated that several L. monocytogenes isolates from ready-to-eat foods in China have pathogenic potential and are resistant to antibiotics, including antibiotics used as medicines by humans for listeriosis treatment. PMID- 27470107 TI - Effects of Exogenous Carbon Monoxide Releasing Molecules on the Development of Zebrafish Embryos and Larvae. AB - The use of exogenous carbon monoxide releasing molecules (CORMs) provides promise for clinical application; however, the hazard potential of CORMs in vivo remains poorly understood. The developmental toxicity of CORM-3 was investigated by exposure to concentrations ranging from 6.25 to 400 MUmol/L during 4-144 h post fertilization. Toxicity endpoints of mortality, spontaneous movement, heart rate, hatching rate, malformation, body length, and larval behavior were measured. CORM 3 disrupted the progression of zebrafish larval development at concentrations exceeding 50 MUmol/L, resulting in embryonic developmental toxicity. PMID- 27470108 TI - A Computerized Evaluation of Sensory Memory and Short-term Memory Impairment After Rapid Ascent to 4280 m. AB - To evaluate the effect of acute high-altitude exposure on sensory and short-term memory using interactive software, we transported 30 volunteers in a sport utility vehicle to a 4280 m plateau within 3 h. We measured their memory performance on the plain (initial arrival) and 3 h after arrival on the plateau using six measures. Memory performance was significantly poorer on the plateau by four of the six measures. Furthermore, memory performance was significantly poorer in the acute mountain sickness (AMS) group than in the non-AMS group by five of the six measures. These findings indicate that rapid ascent to 4280 m and remaining at this altitude for 3 h resulted in decreased sensory and short-term memory, particularly among participants who developed AMS. PMID- 27470109 TI - The Revision of Aluminum-containing Food Additive Provisions in China. AB - The aim of this study was to revise the provisions for aluminum-containing food additives in GB 2760-2011 (The National Food Safety Standard for Use of Food Additives), in order to reduce aluminum exposure among the Chinese population. According to the latest risk assessment results of JECFA and China on aluminum and the actual use of aluminum-containing food additives in certain products, the aluminum-containing food additive-related provisions in GB 2760-2011 were revised. Those revisions included narrowing down the applicable food categories and adjusting the maximum use level of aluminum potassium sulfate and aluminum ammonium sulfate, repealing nine aluminum-containing food additives in puffed food and repealing the use of sodium aluminum phosphate, sodium aluminosilicate and starch aluminum octenylsuccinate in all food. After revision of the use of aluminum food additive provisions, the weekly dietary intake of aluminum in the Chinese population can be reduced to a safe level. PMID- 27470110 TI - End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data. AB - RNA-seq protocols that focus on transcript termini are well suited for applications in which template quantity is limiting. Here we show that, when applied to end-sequencing data, analytical methods designed for global RNA-seq produce computational artifacts. To remedy this, we created the End Sequence Analysis Toolkit (ESAT). As a test, we first compared end-sequencing and bulk RNA seq using RNA from dendritic cells stimulated with lipopolysaccharide (LPS). As predicted by the telescripting model for transcriptional bursts, ESAT detected an LPS-stimulated shift to shorter 3'-isoforms that was not evident by conventional computational methods. Then, droplet-based microfluidics was used to generate 1000 cDNA libraries, each from an individual pancreatic islet cell. ESAT identified nine distinct cell types, three distinct beta-cell types, and a complex interplay between hormone secretion and vascularization. ESAT, then, offers a much-needed and generally applicable computational pipeline for either bulk or single-cell RNA end-sequencing. PMID- 27470111 TI - Global genome nucleotide excision repair is organized into domains that promote efficient DNA repair in chromatin. AB - The rates at which lesions are removed by DNA repair can vary widely throughout the genome, with important implications for genomic stability. To study this, we measured the distribution of nucleotide excision repair (NER) rates for UV induced lesions throughout the budding yeast genome. By plotting these repair rates in relation to genes and their associated flanking sequences, we reveal that, in normal cells, genomic repair rates display a distinctive pattern, suggesting that DNA repair is highly organized within the genome. Furthermore, by comparing genome-wide DNA repair rates in wild-type cells and cells defective in the global genome-NER (GG-NER) subpathway, we establish how this alters the distribution of NER rates throughout the genome. We also examined the genomic locations of GG-NER factor binding to chromatin before and after UV irradiation, revealing that GG-NER is organized and initiated from specific genomic locations. At these sites, chromatin occupancy of the histone acetyl-transferase Gcn5 is controlled by the GG-NER complex, which regulates histone H3 acetylation and chromatin structure, thereby promoting efficient DNA repair of UV-induced lesions. Chromatin remodeling during the GG-NER process is therefore organized into these genomic domains. Importantly, loss of Gcn5 significantly alters the genomic distribution of NER rates; this has implications for the effects of chromatin modifiers on the distribution of mutations that arise throughout the genome. PMID- 27470112 TI - Solvent Free Lipase Catalysed Synthesis of Ethyl Laurate: Optimization and Kinetic Studies. AB - The current research work represents solvent free enzymatic synthesis of fatty acid ethyl ester; ethyl laurate. Immobilized lipase Fermase CALBTM10,000 was used for the synthesis of ethyl laurate from ethanol and lauric acid. The influence of process parameters such as catalyst loading, speed of agitation, mole ratio, molecular sieves and temperature were studied. Fermase CALBTM10,000 offered a conversion of 92.46 % at 60 degrees C in 4 h at optimized condition. The experimental data was best fitted by the Random Bi-Bi model with inhibition of both the substrates i.e. lauric acid and ethanol. The following kinetic parameters were retrieved from the model: Vmax = 1.243 * 103 mmol/min/g enzyme; KA = 0.1283 mmol; KB = 8.51 mmol; KiA = 5.098 mmol; and SSE = 0.0142. The activation energy for the enzymatic esterification was also determined and calculated to be 28.49 kJ/mol. A maximum conversion of 71 % was obtained after 5 successive reuse of Fermase CALBTM10,000 lipase. PMID- 27470113 TI - ESPEN guideline on ethical aspects of artificial nutrition and hydration. PMID- 27470114 TI - The importance of obstructive sleep apnoea and hypopnea pathophysiology for customized therapy. AB - The objective of this study is to highlight the importance of anatomical and not anatomical factors' identification for customized therapy in OSAHS patients. The data sources are: MEDLINE, The Cochrane Library and EMBASE. A systematic review was performed to identify studies that analyze the role of multiple interacting factors involved in the OSAHS pathophysiology. 85 out of 1242 abstracts were selected for full-text review. A variable combinations pathophysiological factors contribute to realize differentiated OSAHS phenotypes: a small pharyngeal airway with a low resistance to collapse (increased critical closing pressure), an inadequate responses of pharyngeal dilator muscles (wakefulness drive to breathe), an unstable ventilator responsiveness to hypercapnia (high loop gain), and an increased propensity to wake related to upper airway obstruction (low arousal threshold). Identifying if the anatomical or not-anatomical factors are predominant in each OSAHS patient represents the current challenge in clinical practice, moreover for the treatment decision-making. In the future, if a reliable and accurate pathophysiological pattern for each OSAHS patient can be identified, a customized therapy will be feasible, with a significant improvement of surgical success in sleep surgery and a better understanding of surgical failure. PMID- 27470115 TI - Surgical conditions during FESS; comparison of dexmedetomidine and remifentanil. AB - To compare dexmedetomidine with remifentanil in functional endoscopic sinus surgery (FESS) in regards to intra-operative bleeding, anesthetic consumption and post-operative recovery. Randomized, double blind study. Tertiary care medical center. Fifty patients with nasal polyposis who had been scheduled for FESS were randomly divided into two groups. In group D (n = 25), dexmedetomidine 1 ug/kg infused intravenous (IV) over 10 min before anesthesia induction, followed by a continuous of 0.7 ug/kg/h infusion during operation. In group R (n = 25), 1 ug/kg remifentanil IV bolus, was administered with induction of anesthesia and continued 0.25-0.50 ug/kg/min during operation. Heart rates, mean arterial pressure, end tidal CO2, end tidal sevoflurane were recorded. The amount of bleeding, surgical field condition for bleeding and the time to reach Aldrete recovery score 9-10 were recorded. Postoperative nausea, vomiting, pain, shivering, sedation were followed up over 24 h. There was no significant difference between groups according to the amount of bleeding during surgery, assessment of surgical field condition, consumption of sevoflurane, scores of postoperative VAS, rates of nausea and vomiting, shivering, demands of additional analgesic medication (P > 0.05). The time to reach Aldrete recovery score 9-10, sedation scores at the postoperative first hour were significantly higher in group D (P = 0.001). We concluded that in comparison to remifentanil, dexmedetomidine during FESS for controlled hypotension is of limited value as it has no additional benefits in terms of control of hypotension and amount of bleeding in the surgical field and it is associated with higher recovery time and first-hour postoperative sedation scores. PMID- 27470116 TI - Comparison of drain versus no-drain thyroidectomy: a meta-analysis. AB - Despite minimal evidence, thyroid drains are routinely used as a precaution against hematoma in thyroidectomy. We undertook the present meta-analysis to evaluate the patient outcomes associated with post-surgical drainage, and whether it offers any advantage over no drainage in patients undergoing thyroidectomy. Randomized and two-arm studies comparing the efficacy of total or partial thyroidectomy with or without post-surgery drainage, in patients undergoing thyroid surgery were included. Medline, Cochrane, EMBASE, and Google Scholar databases were searched until January 22, 2015, using the terms, "thyroidectomy, subtotal thyroidectomy, total thyroidectomy, drainage, thyroid cancer, and goiter." The primary outcome of interest includes postoperative complications such as infection, hematoma, hemorrhage, hypoparathyroidism, recurrent laryngeal nerve palsy, seroma, and duration of hospital stay. 14 studies comprising of 1927 patients were included in the present analysis. The overall analysis revealed that patients in the drain group were more likely to have a higher postoperative infection rate than no-drain group (pooled OR = 2.94, 95 % CI 1.27-6.85, P = 0.012). Similarly, patients in the drain group had a longer hospital stay in comparison to those in the no-drain group (pooled difference in mean = 1.16, 95 % CI 0.72-1.59, P < 0.001). No statistically significant differences between the groups were found for hematoma, hemorrhage, hypoparathyroidism, recurrent laryngeal nerve palsy, and seroma. In conclusion, the current practice of post surgical drainage in thyroidectomy did not offer any significant advantage. On the contrary, post-surgical infection rate and duration of hospital stay was higher in patients in the drain group. PMID- 27470119 TI - NHS "haemorrhaging money" on clinical negligence claims, defence bodies warn. PMID- 27470118 TI - Relationship between soluble Semaphorin4D and cognitive impairment in patients with obstructive sleep apnea-hypopnea syndrome. AB - To investigate the relationship between plasma soluble semaphorin4D (sSema4D) and obstructive sleep apnea-hypopnea syndrome (OSAHS), and to ascertain the effect of sSema4D on cognitive dysfunction in patients with OSAHS. We prospectively recruited 30 men with moderate-severe OSAHS diagnosed by polysomnography, and 30 healthy controls with matched gender, age and education level. Montreal Cognitive Assessment (MoCA) was administered to determine cognitive impairment. Plasma sSema4D levels were measured. Among the total of 60 study patients, the overall plasma sSema4D level was 7.81 +/- 1.91 ng/ml. Plasma sSema4D level in OSAHS group was significantly higher than that in controls (8.92 +/- 1.79 vs 6.70 +/- 1.28 ng/ml, p < 0.001). In OSAHS subgroup, patients with cognition impairment (CI) had higher plasma sSema4D level (10.50 +/- 1.16 vs 8.00 +/- 1.41 ng/ml, p < 0.001) and apnea-hypopnea index (AHI) (48.1 +/- 14.0 vs 30.3 +/- 9.2, p < 0.001) than those in non-CI group. Multiple logistic regression revealed that plasma sSema4D level (AOR 2.824, 95 % CI 1.562-5.103; p = 0.001) and BMI (AOR 2.237, 95 % CI 1.345-3.722; p = 0.002) were significantly associated with OSAHS, and plasma sSema4D was a significant predictor of CI after adjustment for other confounders (AOR 4.956, 95 % CI 1.581-15.538; p = 0.006). OSAHS patients, especially those with cognition impairment, are featured by elevated plasma sSema4D level, and sSema4D is significantly associated with cognition impairment induced by OSAHS. PMID- 27470117 TI - Overexpression of DCLK1 is predictive for recurrent disease in major salivary gland malignancies. AB - Salivary gland carcinomas are a rare malignancy. Therefore, little is known about biomarkers and cancer stem cells in salivary gland malignancies. Double cortin like kinase 1 (DCLK1) is a promising therapeutic target and cancer stem cell marker, predominantly investigated in pancreatic and colorectal cancer. The purpose of this study was to investigate the expression of DCLK1 in major and minor salivary gland carcinomas and its influence on survival. We examined a total of 80 patients with major or minor salivary gland cancer in this retrospective study. Immunohistochemistry with anti-DCLK1 antibody was applied to assess the expression of DCLK1. Moreover, we evaluated the impact of DCLK1 on overall and disease-free survival. DCLK1 expression could be detected in 66.3 % of all examined cases. Overexpression of DCLK1 was associated with reduced overall and disease-free survival in patients with major salivary gland cancer. Disease-free survival reached statistical significance (p = 0.0107). However, expression of DCLK1 had no influence on survival in patients with minor salivary gland cancer. Since treatment of recurrent disease in oncologic patients is utterly challenging, DCLK1 may be a promising prognostic biomarker that helps to identify patients with a high risk for recurrence of major salivary gland carcinoma. PMID- 27470120 TI - Silicon nanoparticles more effectively alleviated UV-B stress than silicon in wheat (Triticum aestivum) seedlings. AB - The role of silicon (Si) in alleviating biotic as well as abiotic stresses is well known. However, the potential of silicon nanoparticle (SiNP) in regulating abiotic stress and associated mechanisms have not yet been explored. Therefore, in the present study hydroponic experiments were conducted to investigate whether Si or SiNp are more effective in the regulation of UV-B stress. UV-B (ambient and enhanced) radiation caused adverse effect on growth of wheat (Triticum aestivum) seedlings, which was accompanied by declined photosynthetic performance and altered vital leaf structures. Levels of superoxide radical and H2O2 were enhanced by UV-B as also evident from their histochemical stainings, which was accompanied by increased lipid peroxidation (LPO) and electrolyte leakage. Activities of superoxide dismutase and ascorbate peroxidase were inhibited by UV B while catalase and guaiacol peroxidase, and all non-enzymatic antioxidants were stimulated by UV-B. Although, nitric oxide (NO) content was increased at all tested combinations, but its maximum content was observed under SiNps together with UV-B enhanced treatment. Pre-additions of SiNp as well as Si protected wheat seedlings against UV-B by regulating oxidative stress through enhanced antioxidants. Data indicate that SiNp might have protected wheat seedlings through NO-mediated triggering of antioxidant defense system, which subsequently counterbalance reactive oxygen species-induced damage to photosynthesis. Further, SiNp appear to be more effective in reducing UV-B stress than Si, which is related to its greater availability to wheat seedlings. PMID- 27470121 TI - Surveillance of Tobacco Use Among South Asians in the US: Are We Underestimating Prevalence? AB - This study employed a randomized split sample survey to assess the accuracy of standard tobacco surveillance measures among South Asians living in the US. 219 South Asian adults completed a web-based survey of "standard" tobacco use questions, as they appear in national surveillance surveys, and half were randomly assigned to also receive questions about South Asian tobacco products. Prevalence of tobacco use was compared by experimental condition, assessed by only the standard questions for the control group (N = 116) and by both standard and South Asian questions for the experimental group (N = 103). Among the experimental group, sensitivity and negative predictive value (NPV) of the standard use definitions were calculated, considering the inclusive definitions as the "gold standard." Prevalence of any tobacco product use was higher among the experimental group, as was prevalence of smokeless tobacco (SLT) use, relative to the control group (34.7 vs. 17.2 % and 21.2 vs. 4.3 %, respectively). 70.6 and 33.3 % of true tobacco users (any product) and SLT users were correctly classified by the respective standard product questions. A majority of gutka, paan with tobacco, and supari with tobacco users (69, 86, and 75 %, respectively) did not otherwise endorse the standard SLT questions. Current tobacco surveillance measures may underestimate the use of tobacco in the South Asian population residing in the US. These results indicate that careful consideration must be given to how tobacco-related questions are presented to minority populations. PMID- 27470123 TI - BASCULE syndrome: old wine in new bottles? PMID- 27470122 TI - Health Messaging and African-American Infant Sleep Location: A Randomized Controlled Trial. AB - : Infant-parent bedsharing increases the risk of SIDS and other sleep-related deaths. Despite AAP recommendations to avoid bedsharing, public health efforts have been unsuccessful in changing behaviors. African-American infants are more than twice as likely to die from SIDS and other sleep-related deaths, and are also twice as likely to bedshare with their parents. Further, African-American parents have a high degree of self-efficacy with regards to preventing infant suffocation, but low self-efficacy with regards to SIDS risk reduction. It is unclear whether messages emphasizing suffocation prevention will decrease bedsharing. To evaluate the impact of specific health messages on African American parental decisions regarding infant sleep location. We conducted a randomized, controlled trial of African-American mothers of infants. The control group received standard messaging emphasizing AAP-recommended safe sleep practices, including avoidance of bedsharing, for the purposes of SIDS risk reduction. The intervention group received enhanced messaging emphasizing safe sleep practices, including avoidance of bedsharing, for both SIDS risk reduction and suffocation prevention. Participants completed interviews at 2-3 weeks, 2-3 months, and 5-6 months after the infant's birth. 1194 mothers were enrolled in the study, and 637 completed all interviews. Bedsharing, both usually (aOR 1.005 [95 % CI 1.003, 1.006]) and last night (aOR 1.004 [95 % CI 1.002, 1.007]) increased slightly but statistically significantly with infant age (p < 0.001). Receipt of the enhanced message did not impact on sleep location. Maternal belief that bedsharing increased the risk of SIDS or suffocation declined over 6 months (p < 0.001) and did not differ by group assignment. African-American mothers who received an enhanced message about SIDS risk reduction and suffocation prevention were no less likely to bedshare with their infants. CLINICAL TRIALS REGISTRATION: Clinical Trials.gov identifier NCT01361880. PMID- 27470125 TI - Development of metoprolol tartrate-loaded sustained-release pellets: effect of talc on the mechanism of drug release. AB - Talc is one of the most commonly used antiadherents in the coating film. However, the mechanism of influence of talc on drug release has yet to be fully understood. In this study, metoprolol tartrate (MT)-loaded Eudragit NE 30 D coated sustained-release (SR) pellets were prepared using talc as an antiadherent in the layering and coating processes. Talc significantly reduced the stickiness of the layered or coated substrates, thus enhancing the process smoothness. Moreover, the incorporation of talc into the coating film significantly affected drug release. The water vapor permeability and drug permeability of free films increased as the concentration of talc increased. Importantly, talc had a dynamic effect on the drug release. The drug release rate of the pellets in the initial stage (within 2 h) increased with increasing talc concentrations, which exceeded the critical pigment volume concentration resulted in leaks formation in the coated film. However, subsequent swelling of the membrane and expansion of the copolymer network eliminated the influence of talc and the drug release was then controlled by the polymeric membrane. These results suggest that talc contributed to the reduction of the sticking of layered or coated substrates, and facilitated the manufacturing process and drug release properties. PMID- 27470124 TI - Associations of polymorphisms in TXNIP and gene-environment interactions with the risk of coronary artery disease in a Chinese Han population. AB - Single nucleotide polymorphisms (SNPs) in thioredoxin-interacting protein (TXNIP) gene may modulate TXNIP expression, then increase the risk of coronary artery disease (CAD). In a two-stage case-control study with a total of 1818 CAD patients and 1963 controls, we genotyped three SNPs in TXNIP and found that the variant genotypes of SNPs rs7212 [odds ratio (OR) = 1.26, P = 0.001] and rs7211 (OR = 1.23, P = 0.005) were significantly associated with increased CAD risk under a dominant model. In haplotype analyses, compared with the reference haplotype, haplotype 'G-T' had a 1.22-fold increased risk of CAD (P = 0.003). We also observed the cumulative effects of SNPs rs7212 and rs7211 on CAD risk and the severity of coronary atherosclerosis. Moreover, the gene-environment interactions among the variant genotypes of SNP rs7212, smoking habit, alcohol drinking habit and history of type 2 diabetes were associated with a 3.70-fold increased risk of CAD (P < 0.001). Subsequent genotype-phenotype correlation analyses further observed the significant effects of SNP rs7212 on TXNIP mRNA expression, plasma TXNIP and malondialdehyde levels. Taken together, our data suggest that TXNIP SNPs may individually and cumulatively affect CAD risk through a possible mechanism for regulating TXNIP expression and gene-environment interactions. PMID- 27470126 TI - Risk buffering and resource access shape valuation of out-group strangers. AB - Unlike other primates, humans exhibit extensive inter-group tolerance and frequently build relationships with out-group members. Despite its common occurrence, little is known about the conditions leading to out-group relationship building in humans. What are the social and ecological factors promoting valuation of out-group members as potential social partners? Do they differ from those promoting valuation of in-group members? We propose that opportunities for non-local resource access and resource buffering, crucial in the human foraging niche, will increase valuation of out-group strangers. Using survey and experimental data collected among three Bolivian horticultural populations, we find that individuals with fewer non-locally available resources and more information about out-groups demonstrate more generosity toward out group strangers, but not in-group strangers. The effects are specific to subjective resource access, not objective measures of access, and out-group exposure, not stereotypes. Further, depending on the measure, existing network connections affect both out-group and in-group giving, suggesting that new partnerships from both in-groups and out-groups may bolster one's networks. Our results illustrate how evolved human psychology is sensitive to the costs and benefits of both out-group and in-group relationships, but underscore that the social and ecological factors favoring new relationships with in-group versus out group strangers may differ. PMID- 27470128 TI - The growing structural and functional complexity of the LSD1/KDM1A histone demethylase. AB - LSD1 was the first discovered histone demethylase. Using a flavin-dependent oxidative mechanism, LSD1 demethylates the N-terminal tail of histone H3 in the context of a variety of developmental processes. This functional complexity involves the association with nuclear factors and non-coding RNAs. A number of exciting studies are uncovering the bases of these specific and diverse molecular interactions, which occur both at catalytic and non-catalytic regions of the enzyme. Alternative splicing and post-translation modifications represent further layers for modulating this complex molecular network. By combining structural methods with the usage of chemically modified histones, it is becoming possible to visualize how LSD1 and associated co-repressors recognize the nucleosome. The enzyme clamps the nucleosomal particle through multivalent interactions mediated by the non-catalytic domains, which represent prospective sites for drug design. PMID- 27470127 TI - Searching for clarity in muddy water: future considerations for classifying compulsive sexual behavior as an addiction. PMID- 27470130 TI - Short-term treadmill exercise in a cold environment does not induce adrenal Hsp72 and Hsp25 expression. AB - Heat shock proteins (Hsps) have a critical role in maintaining cellular homeostasis and in protecting cells from a range of acute and chronic stressful conditions. Treadmill running exercise results in increased Hsp72 and Hsp25 levels in various tissues and heat production during exercise has been shown to be the main factor for the increased levels of Hsp72 in myocardium. Since the adrenal gland plays a vital role in general response to stress, regulation of Hsps in adrenal glands following stressful events seems to be critical for controlling the whole-body stress response appropriately. This study tested the hypothesis of whether elevation of temperature is solely responsible for exercise induced adrenal Hsp72 and Hsp25 expression. Female Sprague-Dawley rats (3 months old) were randomly assigned to either a sedentary control group or one of two treadmill-running groups: a cold exercise group run in a cold room at 4 degrees C (CE), and a warm exercise group run at 25 degrees C temperature (WE). Animals were run 60 min a day at 30 m min-1 speed for 4 consecutive days following adaptation to treadmill exercise. Exercise resulted in a significant elevation of body temperature only in the WE group (p < 0.05). Adrenal Hsp72 and Hsp25 levels were significantly higher in the WE group compare to the other groups (p < 0.05). These data demonstrated that exercise-related elevations of body temperature could be the only factor for the inductions of adrenal Hsp72 and Hsp25 expression. PMID- 27470131 TI - Theoretical and mathematical foundation of the Virtual Cell Based Assay - A review. AB - There is a need to interpret in vitro concentration-viability data in terms of the actual concentration that the cells are exposed to, rather than the nominal concentration applied to the test system. We have developed a process-based model to simulate the kinetics and dynamics of a chemical compound in cell-based in vitro assays. In the present paper we describe the mathematical equations governing this model as well as the parameters that are needed to run the model. The Virtual Cell Based Assay (VCBA) is an integrated model composed of: [1] a fate and transport model; [2] a cell partitioning model; [3] a cell growth and division model; [4] a toxicity and effects model; [5] the experimental set up. The purpose of the VCBA is to simulate the medium and intracellular concentrations, which can be used on its own to design and interpret in vitro experiments, and in combination with physiologically based kinetic (PBK) models to perform in vitro to in vivo extrapolation. The results can be used in chemical risk assessment to link an external dose to an internal effect or vice versa, using solely in vitro and in silico tools and thereby avoiding animal testing. PMID- 27470129 TI - The effects of two-stage carotid occlusion on spatial memory and pro-inflammatory markers in the hippocampus of rats. AB - The purpose of this study was to evaluate the effects of cerebral hypoperfusion on cognitive ability, TNFalpha, IL1beta and PGE2 levels in both hippocampi in a modified two-vessel occlusion model. Both common carotid arteries of adult male Wistar rats were permanently occluded with an interval of 1 week between occlusions. Learning and memory were significantly decreased after 1 month. This reduction was not significant after 2 months, which may be attributed to blood flow compensation. The TNFalpha level was significantly increased after 3 h and 1 day. IL1beta was significantly increased after 1 day. After a week there was no significant difference in pro-inflammatory levels. Furthermore, there was no difference between right and left hippocampi. It is possible that TNFalpha and IL1beta elevation initiates pathologic processes that contribute to memory impairment. PMID- 27470132 TI - Rifampicin-induced injury in L02 cells is alleviated by 4-PBA via inhibition of the PERK-ATF4-CHOP pathway. AB - Endoplasmic reticulum (ER) stress-induced cell injury plays an important role in the development of drug-induced liver injury (DILI). However, little is known about the contribution of ER stress to RFP-induced cell injury. In our study, L02 cells were treated with different concentrations of RFP for different time intervals, and cell apoptosis, the survival rate, and the gene and protein expression of GRP78, PERK, ATF4, and CHOP were measured. Additionally, L02 cells were transfected with CHOP-siRNA or a CHOP-over expression plasmid or administered 4-PBA before treatment with RFP. We found that RFP increased the cell apoptosis rate, decreased cell survival, and increased the protein and gene levels of GRP78, PERK, ATF4 and CHOP in both a dose-dependent and a time dependent manner. Following the transient knockdown of CHOP and treatment with RFP, cell apoptosis decreased and the survival rate increased. Overexpression of CHOP produced the opposite effects. Treatment with 4-PBA decreased the protein and gene expression of GRP78, PERK, ATF4 and CHOP. Additionally, 4-PBA reduced cell apoptosis, increased cell survival and decreased the level of ALT, AST, AKP, LDH and ATP in the cell culture supernatant. These results indicate that 4-PBA alleviates RFP-induced injury in L02 cells via inhibition of the PERK-ATF4-CHOP pathway. PMID- 27470133 TI - In vitro toxicity testing of cigarette smoke based on the air-liquid interface exposure: A review. AB - Cigarette smoke is a complex aerosol comprising particulate phase and gaseous vapour phase. The air-liquid interface exposure provides a possible technical means to implement whole smoke exposure for the assessment of tobacco products. In this review, the research progress in the in vitro toxicity testing of cigarette smoke based on the air-liquid interface exposure is summarized. The contents presented involve mainly cytotoxicity, genotoxicity, oxidative stress, inflammation, systems toxicology, 3D culture and cigarette smoke dosimetry related to cigarette smoke, as well as the assessment of electronic cigarette aerosol. Prospect of the application of the air-liquid interface exposure method in assessing the biological effects of tobacco smoke is discussed. PMID- 27470134 TI - Prognostic role of PD-L1 in malignant solid tumors: a meta-analysis. AB - PURPOSE: The aim of this study was to elucidate the rates and prognostic roles of programmed cell death ligand 1 (PD-L1) immunohistochemical (IHC) expression in various malignant tumors through a systematic review and meta-analysis. METHOD: The current study included 16,176 patients from 97 eligible studies. We investigated PD-L1 expression and its correlation with survival rate in various malignant tumors. RESULTS: The estimated rate of PD-L1 IHC expression was 0.449 (95% confidence interval [CI] 0.404-0.495). The highest and lowest PD-L1 expression levels were found in thyroid cancer (0.829, 95% CI 0.781-0.868) and small-cell neuroendocrine carcinoma (0.005, 95% CI 0.000-0.080), respectively. PD L1 expression was significantly correlated with poorer overall survival and disease-free survival rates (hazard ratios 1.276, 95% CI 1.097-1.486 and 1.304, 95% CI 1.034-1.644, respectively). However, PD-L1 IHC expression was significantly correlated with worse overall survival rates in patients with esophageal cancer and renal cell carcinoma and with worse disease-free survival rates in patients with colorectal cancer, hepatocellular carcinoma, and renal cell carcinoma. CONCLUSIONS: Our results show that PD-L1 expression rates and the correlations with survival varied between tumor types. Detailed evaluation criteria for PD-L1 will have to be standardized before application to specific tumor types. PMID- 27470135 TI - Prognostic significance of CD24 and CD44 in breast cancer: a meta-analysis. AB - OBJECTIVE: Numerous studies have focused on the prognostic roles of CD24 and CD44 in breast cancer, but the results have been equivocal. The aim of this study was to gain better insight into the relationship between expression of CD24 and of CD44, either alone or in combination, and prognostic parameters in breast cancer. METHODS: Publications addressing the associations of CD24 or CD44 expression with survival outcome in breast cancer were selected for the meta-analysis according to defined criteria. Studies were pooled and odds ratios (ORs) or hazard ratios (HRs) were calculated. Publication bias and sensitivity analyses were also conducted. RESULTS: Sixteen studies comprising 5,697 breast cancer cases were included in our meta-analysis. Overall, CD24 overexpression was significantly associated with histological grade (OR = 1.52; 95% CI 1.12-2.06, p = 0.007), stage (OR = 1.74; 95% CI 1.27-2.40, p<0.001), shortened overall survival (HR = 1.48; 95% CI 1.21-1.80, p<0.001) and disease-free survival (HR 1.45, 95% CI 1.19 1.76, p<0.001), while no such association was observed when we limited our analysis to CD44 and CD44+/CD24- phenotypes. Subgroup analyses for CD24 according to the studies categorized by ethnicity, staining patterns and follow-up period were also conducted, and supported the stability of the prognostic role of CD24. CONCLUSIONS: Our study demonstrated that the putative stem cell marker CD24 was significantly associated with worse survival based on the obtained data. In particular, CD24 may play a role in tumorigenesis and cancer progression. However, further large-scale studies are needed to confirm these findings. PMID- 27470136 TI - 3D structure determination of a protein in living cells using paramagnetic NMR spectroscopy. AB - Determining the three-dimensional structure of a protein in living cells remains particularly challenging. We demonstrated that the integration of site-specific tagging proteins and GPS-Rosetta calculations provides a fast and effective way of determining the structures of proteins in living cells, and in principle the interactions and dynamics of protein-ligand complexes. PMID- 27470137 TI - Diurnal glycemic fluctuation is associated with severity of coronary artery disease in prediabetic patients: Possible role of nitrotyrosine and glyceraldehyde-derived advanced glycation end products. AB - BACKGROUND: Glucose fluctuation (GF) is a risk factor for coronary artery disease (CAD). However, it remains unknown whether specific indices of GF are risk factors for CAD. Therefore, we evaluated the relationship between GF, as determined by a continuous glucose monitoring system (CGMS) or the glucose level at 2h after a 75-g oral glucose tolerance test (75g OGTT 120), and the severity of CAD in prediabetic patients. We also evaluated whether nitrotyrosine (NT) and glyceraldehyde-derived advanced glycation end-products (Glycer-AGE) were induced by GF. METHODS: Twenty-eight prediabetic patients underwent coronary angiography (CAG), and the Gensini score and the SYNTAX score were evaluated as the severity of CAD, while the mean amplitude of glycemic excursions (MAGE) by CGMS and 75g OGTT 120 were evaluated. Serum NT and Glycer-AGE were measured. RESULTS: The MAGE was closely associated with the Gensini score (r=0.742, p<0.001) and the SYNTAX score (r=0.776, p<0.001), respectively. The 75g OGTT 120 was not associated with the Gensini score (r=0.36, p=0.06), but it was significantly associated with the SYNTAX score (r=0.413, p=0.036). Multiple linear regression analysis showed that the MAGE was the only independent determinant for the severity of CAD. The levels of NT and Glycer-AGE were significantly higher in the high MAGE group than in the low MAGE group. CONCLUSIONS: Diurnal GF is associated with the severity of CAD, even in prediabetic patients. GF, NT, and Glycer-AGE may play a pathological role in the progression of CAD. PMID- 27470138 TI - Radiologic findings of Fusarium pneumonia in neutropenic patients. AB - In neutropenic patients, lungs are involved in 50%-80% of cases of fusariosis, but imaging of pulmonary fusariosis has been previously described as indistinguishable from other invasive mould diseases. Our attempt was to identify a radiological pattern that may distinguish pulmonary fusariosis from other mould diseases. We examined the CT findings of nine neutropenic haematology patients with invasive fusariosis. As control group for comparison, we examined 14 invasive mould diseases (11 aspergillosis, 3 mucormycosis) in haematology patients with similar underlying disease and timing of CT imaging. Chest-CT in invasive fusariosis showed small airways (7/9) or peribronchial (5/9) infiltrates, less frequently macronodular consolidations (4/9) with hypodense sign, but without halo sign or occluded-vessel sign. The control group presented macronodular consolidations with occluded-vessel sign in all of the cases; the halo and the hypodense signs were observed, respectively, in 100% and 82% of aspergillosis, and in 67% and 100% of mucormycosis. Sinusitis was documented by CT in 7/7 fusariosis, 2/2 mucormycosis and 5/7 aspergillosis; maxillary and ethmoid sinuses were involved in 7/7 fusariosis, in most of the cases with hyperdense opacification (rarely observed in the controls). We concluded that no radiological findings can discriminate between different mould infections, but invasive fusariosis should be suspected if chest-CT demonstrates pulmonary infiltrates with the hypodense sign, but without the halo or the occluded-vessel signs. Suspicion is greater in the presence of hyperdense maxillary and ethmoid sinusitis. PMID- 27470140 TI - Characterization of T-DNA insertion mutants with decreased virulence in the entomopathogenic fungus Beauveria bassiana JEF-007. AB - The bean bug, Riptortus pedestris, is a major agricultural pest that reduces crop quality and value. Chemical pesticides have contributed to pest management, but resistance to these chemicals has significantly limited their use. Alternative strategies with different modes of action, such as entomopathogenic fungi, are therefore of great interest. Herein, we explored how entomopathogenic fungi can potentially be used to control the bean bug and focused on identifying virulence related genes. Beauveria bassiana (JEF isolates) were assayed against bean bugs under laboratory conditions. One isolate, JEF-007, showed >80 % virulence by both spray and contact exposure methods. Agrobacterium tumefaciens-mediated transformation (AtMT) of JEF-007 generated 249 random transformants, two of which (B1-06 and C1-49) showed significantly reduced virulence against Tenebrio molitor and R. pedestris immatures. Both species were used for rapid screening of virulence-reduced mutants. The two transformants had different morphologies, conidial production, and thermotolerance than the wild type. To determine the localization of the randomly inserted T-DNA, thermal asymmetric interlaced (TAIL) PCR was conducted and analysis of the two clones found multiple T-DNA insertions (two in B1-06 and three in C1-49). Genes encoding complex I intermediate associated protein 30 (CIA30) and the autophagy protein (Atg22) were possibly disrupted by the T-DNA insertion and might be involved in the virulence. This work provides a strong platform for future functional genetic studies of bean bug pathogenic B. bassiana. The genes putatively involved in fungal virulence should be experimentally validated by knockdown in future studies. PMID- 27470139 TI - Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice. AB - Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARalpha challenge demonstrated the dysregulation of PPARalpha signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21's crucial co receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver. PMID- 27470141 TI - Heterologous expression of cellulase genes in natural Saccharomyces cerevisiae strains. AB - Enzyme cost is a major impediment to second-generation (2G) cellulosic ethanol production. One strategy to reduce enzyme cost is to engineer enzyme production capacity in a fermentative microorganism to enable consolidated bio-processing (CBP). Ideally, a strain with a high secretory phenotype, high fermentative capacity as well as an innate robustness to bioethanol-specific stressors, including tolerance to products formed during pre-treatment and fermentation of lignocellulosic substrates should be used. Saccharomyces cerevisiae is a robust fermentative yeast but has limitations as a potential CBP host, such as low heterologous protein secretion titers. In this study, we evaluated natural S. cerevisiae isolate strains for superior secretion activity and other industrially relevant characteristics needed during the process of lignocellulosic ethanol production. Individual cellulases namely Saccharomycopsis fibuligera Cel3A (beta glucosidase), Talaromyces emersonii Cel7A (cellobiohydrolase), and Trichoderma reesei Cel5A (endoglucanase) were utilized as reporter proteins. Natural strain YI13 was identified to have a high secretory phenotype, demonstrating a 3.7- and 3.5-fold higher Cel7A and Cel5A activity, respectively, compared to the reference strain S288c. YI13 also demonstrated other industrially relevant characteristics such as growth vigor, high ethanol titer, multi-tolerance to high temperatures (37 and 40 degrees C), ethanol (10 % w/v), and towards various concentrations of a cocktail of inhibitory compounds commonly found in lignocellulose hydrolysates. This study accentuates the value of natural S. cerevisiae isolate strains to serve as potential robust and highly productive chassis organisms for CBP strain development. PMID- 27470142 TI - Inhibition of poly(adenosine diphosphate-ribose) polymerase using quinazolinone nucleus. AB - Poly(adenosine diphosphate-ribose) polymerase (PARP) is a group of enzymes with several subtypes and it manages various ailment such as cancer, inflammatory disorders, diabetes mellitus, neuronal injury, HIV infection, Parkinsonism, aging, and ischemia-reperfusion injury. Various PARP inhibitors share a common property of bicyclic lactam in its main structural frame. The core moiety containing bicyclic lactam rings are isoquinolinones, dihydroisoquinolinones, quinazolinediones, phthalazinones, quinazolinones, and phenanthridones. The quinazolinone with diverse substituents displayed low nanomolar inhibition. Quinazolinone is an important and vital molecule in the field of medicinal chemistry possessing multitude pharmacological actions. Though the chemistry of quinazolinones has been discussed through centuries, its concise role on PARP inhibition needed a special consideration. The aim of this review is to discover the effect of quinazolinone substitutents and its role in PARP inhibition. This precise review will discuss the effect of quinazolinones on PARP subtypes such as PARP-1, PARP-2, PARP-5a, and PARP-5b. In addition to its pharmacological actions, PARP inhibitors can also act as a chemosensitizing agent, and it is used in combination with the other anticancer agents. This summarization will definitely be a supportive report for the scientist working toward the novelty in the quinazolinone nucleus and its role in PARP inhibition. PMID- 27470143 TI - Bacterial production and structure-functional validation of a recombinant antigen binding fragment (Fab) of an anti-cancer therapeutic antibody targeting epidermal growth factor receptor. AB - Fragment engineering of monoclonal antibodies (mAbs) has emerged as an excellent paradigm to develop highly efficient therapeutic and/or diagnostic agents. Engineered mAb fragments can be economically produced in bacterial systems using recombinant DNA technologies. In this work, we established recombinant production in Escherichia coli for monovalent antigen-binding fragment (Fab) adopted from a clinically used anticancer mAB drug cetuximab targeting epidermal growth factor receptor (EGFR). Recombinant DNA constructs were designed to express both polypeptide chains comprising Fab in a single vector and to secrete them to bacterial periplasmic space for efficient folding. Particularly, a C-terminal engineering to confer an interchain disulfide bond appeared to be able to enhance its heterodimeric integrity and EGFR-binding activity. Conformational relevance of the purified final product was validated by mass spectrometry and crystal structure at 1.9 A resolution. Finally, our recombinant cetuximab-Fab was found to have strong binding affinity to EGFR overexpressed in human squamous carcinoma model (A431) cells. Its binding ability was comparable to that of cetuximab. Its EGFR-binding affinity was estimated at approximately 0.7 nM of Kd in vitro, which was quite stronger than the binding affinity of natural ligand EGF. Hence, the results validate that our construction could serve as an efficient platform to produce a recombinant cetuximab-Fab with a retained antigen-binding functionality. PMID- 27470145 TI - ASTRO APEx(r) and RO-ILSTM are applicable to medical malpractice in radiation oncology. AB - AIM: To analyze malpractice trials in radiation oncology and assess how ASTRO APEx(r) and RO-ILSTM apply to such cases. METHODS: The Westlaw database was reviewed using PICOS/PRISMA methods. Fisher's exact and Mann-Whitney U tests were used to find factors associated with outcomes. RESULTS: Of 34 cases identified, external beam was used in 26 (77%). The most common factors behind malpractice were excessive toxicity (80%) and lack of informed consent (66%). ASTRO APEx pillars and ROI-LS had applicability to all but one case. Factors favoring the defendant included statute of limitations (odds ratio: 8.1; 95% CI: 1.3-50); those favoring the plaintiff included patient death (odds ratio: 0.7; 95% CI: 0.54-0.94). CONCLUSION: APEx and RO-ILS are applicable to malpractice trials in radiation oncology. PMID- 27470144 TI - A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. AB - Long-QT syndrome (LQTS) is an arrhythmogenic disorder characterised by prolongation of the QT interval in the electrocardiogram, which can lead to sudden cardiac death. Pharmacological treatments are far from optimal for congenital forms of LQTS, while the acquired form, often triggered by drugs that (sometimes inadvertently) target the cardiac hERG channel, is still a challenge in drug development because of cardiotoxicity. Current experimental models in vitro fall short in predicting proarrhythmic properties of new drugs in humans. Here, we leveraged a series of isogenically matched, diseased and genetically engineered, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC CMs) from patients to test a novel hERG allosteric modulator for treating congenital LQTS, drug-induced LQTS or a combination of the two. By slowing IK r deactivation and positively shifting IK r inactivation, the small molecule LUF7346 effectively rescued all of these conditions, demonstrating in a human system that allosteric modulation of hERG may be useful as an approach to treat inherited and drug-induced LQTS Furthermore, our study provides experimental support of the value of isogenic pairs of patient hiPSC-CMs as platforms for testing drug sensitivities and performing safety pharmacology. PMID- 27470146 TI - Engineering tyrosine electron transfer pathways decreases oxidative toxicity in hemoglobin: implications for blood substitute design. AB - Hemoglobin (Hb)-based oxygen carriers (HBOC) have been engineered to replace or augment the oxygen-carrying capacity of erythrocytes. However, clinical results have generally been disappointing due to adverse side effects linked to intrinsic heme-mediated oxidative toxicity and nitric oxide (NO) scavenging. Redox-active tyrosine residues can facilitate electron transfer between endogenous antioxidants and oxidative ferryl heme species. A suitable residue is present in the alpha-subunit (Y42) of Hb, but absent from the homologous position in the beta-subunit (F41). We therefore replaced this residue with a tyrosine (betaF41Y, Hb Mequon). The betaF41Y mutation had no effect on the intrinsic rate of lipid peroxidation as measured by conjugated diene and singlet oxygen formation following the addition of ferric(met) Hb to liposomes. However, betaF41Y significantly decreased these rates in the presence of physiological levels of ascorbate. Additionally, heme damage in the beta-subunit following the addition of the lipid peroxide hydroperoxyoctadecadieoic acid was five-fold slower in betaF41Y. NO bioavailability was enhanced in betaF41Y by a combination of a 20% decrease in NO dioxygenase activity and a doubling of the rate of nitrite reductase activity. The intrinsic rate of heme loss from methemoglobin was doubled in the beta-subunit, but unchanged in the alpha-subunit. We conclude that the addition of a redox-active tyrosine mutation in Hb able to transfer electrons from plasma antioxidants decreases heme-mediated oxidative reactivity and enhances NO bioavailability. This class of mutations has the potential to decrease adverse side effects as one component of a HBOC product. PMID- 27470147 TI - Triggering the Chemical Instability of an Ionic Liquid under High Pressure. AB - Ionic liquids are an interesting class of materials due to their distinguished properties, allowing their use in an impressive range of applications, from catalysis to hypergolic fuels. However, the reactivity triggered by the application of high pressure can give rise to a new class of materials, which is not achieved under normal conditions. Here, we report on the high-pressure chemical instability of the ionic liquid 1-allyl-3-methylimidazolium dicyanamide, [allylC1im][N(CN)2], probed by both Raman and IR techniques and supported by quantum chemical calculations. Our results show a reaction occurring above 8 GPa, involving the terminal double bond of the allyl group, giving rise to an oligomeric product. The results presented herein contribute to our understanding of the stability of ionic liquids, which is of paramount interest for engineering applications. Moreover, gaining insight into this peculiar kind of reactivity could lead to the development of new or alternative synthetic routes to achieve, for example, poly(ionic liquids). PMID- 27470148 TI - Attention Deficit Hyperactive Disorder and Occurrence of Tic Disorders in Children and Adolescents-What is the Verdict. AB - The United States Food and Drug Administration currently states that the use of stimulants in patients with tic disorders and/or family history of tic disorders including Tourette's syndrome is contraindicated. Patients with attention deficit hyperactivity disorder (ADHD), however, are at increased risk of tics regardless of stimulants use. After evaluating the most recent literature on the incidence of tic disorders in pediatric patients treated with stimulants for ADHD, it is reasonable to say that the incidence of tics and the severity of tics are not increased by the use of these medications. For patients with pre-existing tic disorders, the usual recommended dosing of stimulants should be used because supratherapeutic doses of this class of medications, specifically dextroamphetamine, have shown to exacerbate tic disorders. PMID- 27470149 TI - Comments on "rhTNFR:Fc Suppresses the Development of Endometriosis in a Mouse Model by Downregulating Cell Proliferation and Invasiveness". PMID- 27470151 TI - Genes Linked to Endometriosis by GWAS Are Integral to Cytoskeleton Regulation and Suggests That Mesothelial Barrier Homeostasis Is a Factor in the Pathogenesis of Endometriosis. AB - Endometriosis, defined by the presence of ectopic endometrial lesions, is a common disease in reproductive-age women that profoundly affects patients' quality of life. Various pathogenic models have been proposed, but the origin of endometriosis remains elusive. In this article, we propose that the mesothelial barrier, which protects the underlying stroma from endometrial transplants present in retrograde menstrual fluid, can be compromised by activation of the epithelial to mesenchymal transition (EMT) repair mechanism that lead to temporary loss of barrier integrity. Absent of the mesothelial barrier, endometrial cells can more readily adhere to the underlying peritoneal stroma and establish endometrial lesions. The hypothesis is based on the clinical and experimental observations that correlate the location of endometrial lesions with areas of mesothelial damage, together with genetic evidence that 4 genes associated with endometriosis are direct regulators of the actin-cytoskeleton, which coordinates mesothelial barrier integrity. It supports past observations that implicate the peritoneum in the pathogenesis of endometriosis and unifies previously disparate theories that endometriosis may be triggered by infection, mechanical damage, and inflammation since each of these mechanisms can induce EMT in the mesothelium. If the hypothesis is correct, inhibition of EMT in the mesothelial barrier provides a novel paradigm for the prevention and treatment of endometriosis. PMID- 27470150 TI - Maternal Weight Gain Regulates Omega-3 Fatty Acids in Male, Not Female, Neonates. AB - The fetus largely depends on maternal supply and placental transport for its source of long-chain polyunsaturated fatty acids (LCPUFAs), which are essential for proper neurological and cardiovascular development. Pregnancy complications such as diabetes reduces neonatal LCPUFA supply, but little is known of how fatty acid delivery is affected by maternal body type or weight gain in uncomplicated pregnancies. In a cross-sectional study of maternal-neonatal pairs at term, we sought to determine the effect of gestational weight gain on neonatal LCPUFA supply. Forty maternal-neonatal pairs of uncomplicated (no gestational hypertension or diabetes) term pregnancies were recruited upon admission to Oregon Health & Science University Labor & Delivery for scheduled cesarean section. Maternal and umbilical cord plasma fatty acid profiles were measured using gas chromatography-mass spectrophotometry. First trimester weight gain was negatively correlated with maternal n-3 LCPUFA ( r = -0.80, P = .0002), and this was not affected by fetal sex. High maternal weight gain in the first trimester was negatively associated with cord n-3 polyunsaturated fatty acid levels ( r = 0.70, P = .03) and placental thickness ( r = -0.69, P = .03) in male, but not female, offspring. High maternal weight gain in the first trimester is associated with a thinner placenta and low levels of n-3 LCPUFA in male offspring. Further study is required to confirm that male offspring are at a higher risk of poor outcomes associated with high maternal weight gain early in pregnancy. PMID- 27470152 TI - Antibiotics Prophylaxis for Operative Hysteroscopy. AB - OBJECTIVE: To evaluate the incidence of infectious complications and effect of prophylactic antibiotic administration during operative hysteroscopic procedures. METHODS: A multicentric randomized controlled trial was conducted between January 2012 and December 2013. Women (n = 180) affected by endometrial hyperplasia, myomas, or endometrial polyps undergoing operative hysteroscopy were randomized to receive cefazolin 2 g intravenously 30 minutes prior to the procedure (n = 91) and no treatment (n = 89). RESULTS: No statistical difference in terms of postoperative fever (2.4% vs 2.3%, P = .99), endometritis (0% vs 0%), pain (6.0% vs 10.4%, P = .40), cervicitis-vaginitis (0% vs 0%), pelvic abscess (0% vs 0%), pelvic inflammatory disease (0% vs 0%), and bleeding (0% vs 0%) was noticed. No statistical difference in terms of side effects attributable to antibiotic prophylaxis such as allergy (0% vs 4.8%, P = .12), nausea (10.7% vs 17.4%, P = .27), vomiting (3.6% vs 4.6%, P = .99), diarrhea (4.8% vs 5.4%, P = .99), cephalea (9.5% vs 3.5%, P = .13), dizziness (4.8% vs 2.3%, P = .44), and meteorism (5.4% vs 3.4%, P = .99) was noticed. CONCLUSION: The results of the current study support the recommendation not to prescribe routine antibiotic prophylaxis prior to operative hysteroscopy. PMID- 27470153 TI - Does caregiver participation in decision making within child welfare agencies influence children's primary and mental health care service use? AB - BACKGROUND: Many children in contact with child welfare agencies do not receive needed health services. These agencies have used participatory decision making (PDM) practices as a way to increase families' use of recommended services. However, we lack evidence of whether caregiver participation in PDM increases children's use of health services. This study uses a national sample of children involved with child welfare to compare their health service use between those children serve through a PDM practice and those who did not experience it. METHODS: Cross-sectional analyses using the 2009-2010 National Survey of Child and Adolescent Well-Being. Propensity score analysis accounted for observed selection bias. PDM practice was measured as whether the caregiver was included in decision-making during service planning meetings. Health service use was measured as child's receipt of any primary or mental health care services in the past year. Primary health care need was measured using standardized measures and caseworker report. The sample was comprised of children ages 2-17 with primary or mental health needs in contact with a child welfare agency. RESULTS: In the unmatched sample of 1,358 children, 14% were served through a PDM service practice, and 12% had a primary health care and 37% a mental health need. Families served through PDM were also reported by caseworkers as more cooperative during the child welfare investigation, and with fewer reports of domestic violence and agency re-referrals (P < 0.05). Analyses using matched samples showed that for primary health care, 59% of PDM children received services compared with 40% for non-PDM children (P = 0.004). Group differences were not significant for mental health services. CONCLUSIONS: Lower-risk families were more likely to be served through PDM which was positively associated with child use of primary health services. Inclusion of caregivers in decision making may not be sufficient to overcome barriers to children's mental health service use. PMID- 27470154 TI - Gambling and Problem Gambling among Canadian Urban Aboriginals. AB - OBJECTIVE: To assess the prevalence of gambling and problem gambling in urban Aboriginals in the Canadian Prairie provinces and to determine the predictors of problem gambling. METHOD: In total, 1114 Aboriginals living in 15 cities in Alberta, Saskatchewan, and Manitoba were recruited via posters and direct solicitation at Native Friendship Centres, shopping malls, and other locations where Aboriginals congregated. They each completed a self-administered 5- to 10 minute survey. RESULTS: Urban Aboriginals in the present sample were found to have a much higher level of gambling participation than the general Canadian public, especially for electronic gambling machines, instant lotteries, and bingo. Their intensity of participation in terms of number of formats, frequency of play, and gambling expenditure was also very high. This, in turn, is an important contributing factor to their very high rate of problem gambling, which was found to be 27.2%. Problem gambling was higher in males, unemployed people, and cities having the highest proportion of their population consisting of urban Aboriginals. CONCLUSIONS: Urban Aboriginal people appear to have some of the highest known rates of problem gambling of any group in Canada. This is attributable to having many more risk factors for problem gambling, such as a greater level of participation in gambling, greater participation in continuous forms of gambling (e.g., electronic gambling machines), younger average age, higher rates of substance abuse and mental health problems, and a range of disadvantageous social conditions (e.g., poverty, unemployment, poor education, cultural stress) that are conducive to the development of addictive behaviour. PMID- 27470156 TI - Early onset scoliosis. A comprehensive guide from the Oxford meetings. PMID- 27470157 TI - [Not Available]. PMID- 27470155 TI - Short communication: antiviral activity of porcine IFN-lambda3 against porcine epidemic diarrhea virus in vitro. AB - A new family of IFNs called type III IFN or IFN-lambda has been described, and shown to induce antiviral activity against several viruses in the cell culture. In this study, the molecular cloning, expression, and antiporcine epidemic diarrhea virus (PEDV) activity of porcine IFN-lambda3 (poIFN-lambda3) were reported. The full-length poIFN-lambda3 cDNA sequence encoded 196 amino acids with a 23 amino acid signal peptide. Sequence alignments showed that poIFN lambda3 had an amino acid sequence similarity to Ovis aries (78.1 %), Bos taurus (76.0 %), Tupaia belangeri (71.3 %), Equus caballus (69.9 %), and Homo sapiens (69.9 %). The phylogenetic analysis based on the genomic sequences indicated that poIFN-lambda3 is located in the same branch as B. taurus and O. aries IFN lambda3. The poIFN-lambda3 without a signal anchor sequence was efficiently expressed in Escherichia coli, and the purified recombinant poIFN-lambda3 exhibited significant antiviral effects against PEDV in a dose- and time dependent manner. This inhibitory effect of poIFN-lambda3 on PEDV was observed under three different treatment conditions. The highest inhibition of PEDV was observed in Vero E6 cell cultures pretreated with poIFN-lambda3 (prior to PEDV infection). In addition, poIFN-lambda3 was able to induce the expression of IFN stimulated genes, including ISG15, OAS1, and Mx1 in Vero E6 cells. These data demonstrate that poIFN-lambda3 has antiviral activity against PEDV and may serve as a useful biotherapeutic candidate to inhibit PEDV or other viruses in swine. PMID- 27470158 TI - ? PMID- 27470159 TI - Towards a Medicine of the Invisible: bioethics and relationship in "The Little Prince". AB - The Little Prince is one of the most famous fables. In this paper, we attempt to look at three bioethical issues through the Little Prince's eyes: the end-of-life context, the patient-physician relationship and prevention/precaution. The fable gives us the basis for a perspective we have called 'Medicine of the Invisible', which is value-focused. The Little Prince suggests that we seek the invisible-the "thing that is important", the "matters of consequence", even on a gnoseological and epistemological level-as a new type of 'clinical data' which may help to make healthcare more ethical and effective. However, this invisible is attainable only within a relationship, in which the physician needs to be tamed by the patient and the patient needs to be tamed by the physician-each one becoming responsible for the other, each one becoming himself through the dialogue with the other. Responsibility is also projected towards the future, against those threats to life that are still unseen and unknown: owning a part of the world entails the ethical imperative to act, in order to safeguard life. But, without a relationship-saturated with lived time, shared experiences, and individual's uniqueness-no meaning and no value can be given. For this reason, the Medicine of the Invisible reminds bioethics that "the thing that is important is the thing that is not seen". PMID- 27470160 TI - Genetics of childhood steroid-sensitive nephrotic syndrome. AB - The pathogenesis of childhood-onset nephrotic syndrome (NS), disparity in incidence of NS among races, and variable responses to therapies in children with NS have defied explanation to date. In the last 20 years over 50 genetic causes of steroid-resistant nephrotic syndrome (SRNS) have been identified, and at least two disease loci for two pathologic variants of SRNS (focal segmental glomerulosclerosis and membranous nephropathy) have been defined. However, the genetic causes and risk loci for steroid-sensitive nephrotic syndrome (SSNS) remain elusive, partly because SSNS is relatively rare and also because cases of SSNS vary widely in phenotypic expression over time. A recent study of a well defined modest cohort of children with SSNS identified variants in HLA-DQA1 as a risk factor for SSNS. Here we review what is currently known about the genetics of SSNS and also discuss how recent careful phenotypic and genomic studies reinforce the role of adaptive immunity in the molecular mechanisms of SSNS. PMID- 27470161 TI - Are we measuring blood pressure correctly in children, particularly in obesity? PMID- 27470162 TI - Outpatient management of selected young febrile infants without antibiotics. AB - OBJECTIVE: To analyse the outpatient management of selected febrile infants younger than 90 days without systematic lumbar puncture and antibiotics. METHODS: A prospective registry-based cohort study including all the infants <=90 days with fever without a source (FWS) who were evaluated in a paediatric emergency department (ED) over a 7-year period (September 2007-August 2014). We analysed the outcome of those infants with low-risk criteria for serious bacterial infection (SBI) managed as outpatients without antibiotics and without undergoing a lumbar puncture. Low-risk criteria: Well appearing, older than 21 days of age, no leucocyturia, absolute neutrophil count <=10 000, serum C reactive protein <=20 mg/L, procalcitonin <0.5 ng/mL and no clinical deterioration during the stay in the ED (always <24 hours). RESULTS: 1472 infants with FWS attended the ED. Of these, 676 were classified to be at low risk for SBI without performing a lumbar puncture. After staying <24 hours in the short-stay unit of the ED, 586 (86.6%) were managed as outpatients without antibiotics. Two patients were diagnosed with SBI: one occult bacteraemia and one bacterial gastroenteritis. Both were afebrile when evaluated again and did well. No patient returned to the ED due to clinical deterioration. Fifty-one infants (8.7%) returned to the ED mainly due to persistence of fever or irritability. None was diagnosed with definite SBI or non bacterial meningitis. CONCLUSIONS: Outpatient management without antibiotics and systematic lumbar puncture is appropriate for selected febrile infants younger than 3 months of age with close follow-up. PMID- 27470163 TI - Medical and social issues of child refugees in Europe. AB - In mid-2015, there were an estimated 20.2 million refugees in the world; over half of them are children. Globally, this is the highest number of refugees moving across borders in 20 years. The rights of refugee children to access healthcare and be free from arbitrary detention are enshrined in law. Unaccompanied asylum-seeking children have a statutory medical assessment, but refugee children arriving with their families do not. Paediatricians assessing both unaccompanied and accompanied refugee children must be alert to the possibilities of nutritional deficiencies, infectious diseases, dental caries and mental health disorders and be aware of the national and international health guidance available for support. PMID- 27470164 TI - Risks of inadequate nutrition in disabled children: four cases of scurvy. PMID- 27470165 TI - Oceanobacillus longus sp. nov., a moderately halophilic bacterium isolated from a salt lake. AB - A Gram-stain-positive, endospore-forming, long rod-shaped, strictly aerobic, moderately halophilic bacterium, designated strain T9BT, was isolated from a brine sample of the hypersaline lake Aran-Bidgol in Iran. Cells of strain T9BT were motile and produced colonies with a brown pigment. Growth occurred between 1.0 and 20 % (w/v) NaCl and the isolate grew optimally at 5.0 % (v/w) NaCl. The optimum pH and temperature for growth of the strain were pH 7.0 and 35 degrees C, while it was able to grow over pH and temperature ranges of pH 6.0-9.0 and 25 45 degrees C. Phylogenetic analysis based on the comparison of 16S rRNA gene sequences revealed that strain T9BT is a member of the genus Oceanobacillus. The closest relative to this strain was Oceanobacillus rekensis PT-11T with a similarity of 97.4 %, followed by Oceanobacillus profundus CL-MP28T and Oceanobacillus polygoni SA9T with 97.3 and 97.1 % similarity, respectively. The major cellular fatty acids of the isolate were anteiso-C15 : 0, iso-C14 : 0 and iso-C16 : 0. The polar lipids of strain T9BT consisted of phosphatidylglycerol, diphosphatidylglycerol, three phospholipids and one aminoglycolipid. It contained MK-7 as the predominant menaquinone and meso-diaminopimelic acid in the cell-wall peptidoglycan. The G+C content of the genomic DNA of this strain was 42.9 mol%. Phylogenetic analysis, DNA-DNA hybridization data and phenotypic characteristics allowed strain T9BT to be differentiated from other members of the genus Oceanobacillus. A novel species, Oceanobacillus longus sp. nov., is therefore proposed to accommodate this strain. The type strain is T9BT (=IBRC-M 10703T=LMG 29250T). PMID- 27470166 TI - Fitness costs of herbicide resistance across natural populations of the common morning glory, Ipomoea purpurea. AB - Although fitness costs associated with plant defensive traits are widely expected, they are not universally detected, calling into question their generality. Here, we examine the potential for life-history trade-offs associated with herbicide resistance by examining seed germination, root growth, and above ground growth across 43 naturally occurring populations of Ipomoea purpurea that vary in their resistance to RoundUp(r), the most commonly used herbicide worldwide. We find evidence for life-history trade-offs associated with all three traits; highly resistant populations had lower germination, shorter roots, and smaller above-ground size. A visual exploration of the data indicated that the type of trade-off may differ among populations. Our results demonstrate that costs of adaptation may be present at stages other than simply the production of progeny in this agricultural weed. Additionally, the cumulative effect of costs at multiple life cycle stages can result in severe consequences to fitness when adapting to novel environments. PMID- 27470167 TI - eSNPO: An eQTL-based SNP Ontology and SNP functional enrichment analysis platform. AB - Genome-wide association studies (GWASs) have mined many common genetic variants associated with human complex traits like diseases. After that, the functional annotation and enrichment analysis of significant SNPs are important tasks. Classic methods are always based on physical positions of SNPs and genes. Expression quantitative trait loci (eQTLs) are genomic loci that contribute to variation in gene expression levels and have been proven efficient to connect SNPs and genes. In this work, we integrated the eQTL data and Gene Ontology (GO), constructed associations between SNPs and GO terms, then performed functional enrichment analysis. Finally, we constructed an eQTL-based SNP Ontology and SNP functional enrichment analysis platform. Taking Parkinson Disease (PD) as an example, the proposed platform and method are efficient. We believe eSNPO will be a useful resource for SNP functional annotation and enrichment analysis after we have got significant disease related SNPs. PMID- 27470169 TI - Oral delivery of dsRNA lipoplexes to German cockroach protects dsRNA from degradation and induces RNAi response. AB - BACKGROUND: In the past years, the concept of RNAi application for insect pest control has been proposed, considering the disruption of vital genes. However, the efficiency of RNAi is variable between different insect groups, especially by oral delivery of dsRNA. The purpose of this study is to assess the possibilities of RNAi as a tool for pest control using oral delivery of the dsRNAs encapsulated by liposome in the German cockroach Blattella germanica, which is highly sensitive to RNAi by injection of dsRNAs. RESULTS: Injecting dsRNA into the abdomen of B. germanica caused dramatic depletion of essential alpha-tubulin gene and mortality. In contrast, oral delivery of the naked dsRNA resulted in lower RNAi efficiency, accounting for rapid degradation of the dsRNA in the midgut of B. germanica. Notably, we have further demonstrated that continuous ingestion of dsRNA lipoplexes in which dsRNA was encapsulated with a cationic liposome carrier was sufficient to slow down the degradation of dsRNA in the midgut and to increase the mortality of the German cockroach by significantly inhibiting alpha tubulin expression in the midgut. CONCLUSION: We provide empirical evidence that the formulation of dsRNA lipoplexes could be a plausible approach for insect pest control based on RNAi. (c) 2016 Society of Chemical Industry. PMID- 27470168 TI - Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption. AB - BACKGROUND: Repeated exposure to addictive drugs or alcohol triggers glutamatergic and gamma-aminobutyric acidergic (GABAergic) plasticity in many neuronal populations. The dorsomedial striatum (DMS), a brain region critically involved in addiction, contains medium spiny neurons (MSNs) expressing dopamine D1 or D2 receptors, which form direct and indirect pathways, respectively. It is unclear how alcohol-evoked plasticity in the DMS contributes to alcohol consumption in a cell type-specific manner. METHODS: Mice were trained to consume alcohol using an intermittent-access two-bottle-choice drinking procedure. Slice electrophysiology was used to measure glutamatergic and GABAergic strength in DMS D1- and D2-MSNs of alcohol-drinking mice and control mice. In vivo chemogenetic and pharmacologic approaches were employed to manipulate MSN activity, and their consequences on alcohol consumption were measured. RESULTS: Repeated cycles of alcohol consumption and withdrawal in mice strengthened glutamatergic transmission in D1-MSNs and GABAergic transmission in D2-MSNs. In vivo chemogenetic excitation of D1-MSNs, mimicking glutamatergic strengthening, promoted alcohol consumption; the same effect was induced by D2-MSN inhibition, mimicking GABAergic strengthening. Importantly, suppression of GABAergic transmission via D2 receptor-glycogen synthase kinase-3beta signaling dramatically reduced excessive alcohol consumption, as did selective inhibition of D1-MSNs or excitation of D2-MSNs. CONCLUSIONS: Our results suggest that repeated cycles of excessive alcohol intake and withdrawal potentiate glutamatergic strength exclusively in D1-MSNs and GABAergic strength specifically in D2-MSNs of the DMS, which concurrently contribute to alcohol consumption. These results provide insight into the synaptic and cell type-specific mechanisms underlying alcohol addiction and identify targets for the development of new therapeutic approaches to alcohol abuse. PMID- 27470170 TI - Stress reactivity in childhood functional abdominal pain or irritable bowel syndrome. AB - BACKGROUND: Frequent abdominal pain (AP) in childhood has been shown to be associated with elevated experience of stress and with deficits in stress coping, but psychophysiological stress reactivity has been studied rarely. METHODS: We examined whether children with frequent AP show altered reactions of the parasympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis during and following an afternoon laboratory social stress task in comparison to healthy children and children with anxiety disorders. Twenty-four children with frequent AP (18 with functional AP and six with irritable bowel syndrome; M = 9.9 years), and 24 healthy controls underwent stressful free speech and arithmetic tasks. Twelve children with anxiety disorders served as second comparison sample. Groups were compared regarding parasympathetic reaction and saliva cortisol concentration. RESULTS: We found no differences in parasympathetic withdrawal between the groups. Concerning the HPA axis, we detected an attenuated cortisol reactivity in children with AP compared to both other groups. CONCLUSIONS: This study provides preliminary evidence that childhood AP is not associated with altered parasympathetic withdrawal during stress. It seems to be related to a down-regulated reactivity of the HPA axis. This pattern was ascertained in comparison to healthy children and also in comparison to children with anxiety disorders. SIGNIFICANCE: Childhood abdominal pain could be related to down regulated HPA axis reactivity to stress but not to altered parasympathetic reaction. Children with abdominal pain and children with anxiety disorders exhibit a divergent stress-related HPA axis reaction. PMID- 27470172 TI - Cochrane Physical and Rehabilitation Medicine: A New Field to Bridge Between Best Evidence and the Specific Needs of Our Field. PMID- 27470171 TI - Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein-specific antibodies. AB - Alzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Abeta deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Abeta pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Abeta deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age-related and brain region-specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Abeta in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP-transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP-transgenic mouse and one APP-transgenic rat model. We observed remarkable differences in expression levels and brain region-specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP-transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals. PMID- 27470173 TI - Brain Gaming: A User's Product Guide for the Clinician. PMID- 27470174 TI - Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study. AB - BACKGROUND: Tackling severe acute malnutrition (SAM) is a global health priority. Heightened risk of non-communicable diseases (NCD) in children exposed to SAM at around 2 years of age is plausible in view of previously described consequences of other early nutritional insults. By applying developmental origins of health and disease (DOHaD) theory to this group, we aimed to explore the long-term effects of SAM. METHODS: We followed up 352 Malawian children (median age 9.3 years) who were still alive following SAM inpatient treatment between July 12, 2006, and March 7, 2007, (median age 24 months) and compared them with 217 sibling controls and 184 age-and-sex matched community controls. Our outcomes of interest were anthropometry, body composition, lung function, physical capacity (hand grip, step test, and physical activity), and blood markers of NCD risk. For comparisons of all outcomes, we used multivariable linear regression, adjusted for age, sex, HIV status, and socioeconomic status. We also adjusted for puberty in the body composition regression model. FINDINGS: Compared with controls, children who had survived SAM had lower height-for-age Z scores (adjusted difference vs community controls 0.4, 95% CI 0.6 to 0.2, p=0.001; adjusted difference vs sibling controls 0.2, 0.0 to 0.4, p=0.04), although they showed evidence of catch-up growth. These children also had shorter leg length (adjusted difference vs community controls 2.0 cm, 1.0 to 3.0, p<0.0001; adjusted difference vs sibling controls 1.4 cm, 0.5 to 2.3, p=0.002), smaller mid-upper arm circumference (adjusted difference vs community controls 5.6 mm, 1.9 to 9.4, p=0.001; adjusted difference vs sibling controls 5.7 mm, 2.3 to 9.1, p=0.02), calf circumference (adjusted difference vs community controls 0.49 cm, 0.1 to 0.9, p=0.01; adjusted difference vs sibling controls 0.62 cm, 0.2 to 1.0, p=0.001), and hip circumference (adjusted difference vs community controls 1.56 cm, 0.5 to 2.7, p=0.01; adjusted difference vs sibling controls 1.83 cm, 0.8 to 2.8, p<0.0001), and less lean mass (adjusted difference vs community controls 24.5, -43 to -5.5, p=0.01; adjusted difference vs sibling controls -11.5, -29 to 6, p=0.19) than did either sibling or community controls. Survivors of SAM had functional deficits consisting of weaker hand grip (adjusted difference vs community controls -1.7 kg, 95% CI -2.4 to -0.9, p<0.0001; adjusted difference vs sibling controls 1.01 kg, 0.3 to 1.7, p=0.005,)) and fewer minutes completed of an exercise test (sibling odds ratio [OR] 1.59, 95% CI 1.0 to 2.5, p=0.04; community OR 1.59, 95% CI 1.0 to 2.5, p=0.05). We did not detect significant differences between cases and controls in terms of lung function, lipid profile, glucose tolerance, glycated haemoglobin A1c, salivary cortisol, sitting height, and head circumference. INTERPRETATION: Our results suggest that SAM has long term adverse effects. Survivors show patterns of so-called thrifty growth, which is associated with future cardiovascular and metabolic disease. The evidence of catch-up growth and largely preserved cardiometabolic and pulmonary functions suggest the potential for near-full rehabilitation. Future follow-up should try to establish the effects of puberty and later dietary or social transitions on these parameters, as well as explore how best to optimise recovery and quality of life for survivors. FUNDING: The Wellcome Trust. PMID- 27470175 TI - Infection-related cancers: prioritising an important and eliminable contributor to the global cancer burden. PMID- 27470176 TI - Long term health status of children recovering from severe acute malnutrition. PMID- 27470177 TI - Global burden of cancers attributable to infections in 2012: a synthetic analysis. AB - BACKGROUND: Infections with certain viruses, bacteria, and parasites are strong risk factors for specific cancers. As new cancer statistics and epidemiological findings have accumulated in the past 5 years, we aimed to assess the causal involvement of the main carcinogenic agents in different cancer types for the year 2012. METHODS: We considered ten infectious agents classified as carcinogenic to human beings by the International Agency for Research on Cancer. We calculated the number of new cancer cases in 2012 attributable to infections by country, by combining cancer incidence estimates (from GLOBOCAN 2012) with estimates of attributable fraction (AF) for the infectious agents. AF estimates were calculated from the prevalence of infection in cancer cases and the relative risk for the infection (for some sites). Estimates of infection prevalence, relative risk, and corresponding 95% CIs for AF were obtained from systematic reviews and pooled analyses. FINDINGS: Of 14 million new cancer cases in 2012, 2.2 million (15.4%) were attributable to carcinogenic infections. The most important infectious agents worldwide were Helicobacter pylori (770 000 cases), human papillomavirus (640 000), hepatitis B virus (420 000), hepatitis C virus (170 000), and Epstein-Barr virus (120 000). Kaposi's sarcoma was the second largest contributor to the cancer burden in sub-Saharan Africa. The AFs for infection varied by country and development status-from less than 5% in the USA, Canada, Australia, New Zealand, and some countries in western and northern Europe to more than 50% in some countries in sub-Saharan Africa. INTERPRETATION: A large potential exists for reducing the burden of cancer caused by infections. Socioeconomic development is associated with a decrease in infection-associated cancers; however, to reduce the incidence of these cancers without delay, population-based vaccination and screen-and-treat programmes should be made accessible and available. FUNDING: Fondation de France. PMID- 27470178 TI - Integrative Review of Instruments to Measure Team Performance During Neonatal Resuscitation Simulations in the Birthing Room. AB - OBJECTIVE: To identify instruments appropriate to measure interprofessional team performance in neonatal resuscitation (NR), describe the validity and reliability of extant NR instruments, and determine instruments for use in interprofessional birthing room NR simulations. DATA SOURCES: The Cumulative Index to Nursing and Allied Health Literature, Ovid MEDLINE, Proquest, ScienceDirect, PubMed, and Scopus databases were searched. STUDY SELECTION: We used inclusion and exclusion criteria and screened 641 abstracts from January 2000 through December 2014 for relevance to the research question. We reviewed 78 full-text primary research publications in English and excluded 37 publications not specific to pediatrics or neonatology. After in-depth review of the 41 studies that remained, we excluded additional studies if they did not have an interprofessional focus, include psychometric information, or include a measurement instrument. Ten publications met the inclusion criteria. DATA EXTRACTION AND SYNTHESIS: Studies were reviewed, categorized, and scored to identify instruments to measure interprofessional team performance in simulations of birthing room NR. A social ecological model was used as a guide framework to identify multiple influencing factors at various levels that affect team performance. Ten instruments with documentation of validity and reliability for technical competence and team processes in interprofessional birthing room NR teams were identified. CONCLUSION: Extant instruments rarely address the multiple factors that may impede interprofessional team performance in birthing room NR. It is necessary for researchers to engage in rigorous psychometric testing of measurement instruments to ensure their validity and reliability for interprofessional NR teams and consider tests or updates (if necessary) of extant instruments rather than the development of new instruments. PMID- 27470179 TI - Missed Opportunities for Postpartum Behavioral and Psychosocial Health Care and Acceptability of Screening Options. AB - OBJECTIVE: To examine occurrence of health care provider discussion of postpartum women's behavioral and psychosocial health, acceptability of screening, and access to a provider with whom to comfortably discuss sensitive topics. DESIGN: Mail survey during the first postpartum year. SETTING: Community dwelling. PARTICIPANTS: Postpartum women (N = 168) from diverse backgrounds. METHODS: Using vital records, we drew a random sample that was stratified on race/ethnicity and income from a Southwestern U.S. community. Potential participants were mailed a questionnaire about health care and screening in the areas of depression, diet, physical activity, smoking, and alcohol use during the postpartum period. RESULTS: Women reported that discussion of depression most often occurred (51%) during health care encounters, and discussion of weight least often occurred (14%). More than 94% of women indicated they would "welcome" or "not mind" screenings for depression, diet, physical activity, alcohol use, or smoking at health care visits. More than 90% welcomed screening during their infants' pediatric health care visits. Most (86%) reported that screening on an electronic device at their health care visits was acceptable. Most (84%) were interested in completing a screening at home on a Web site. Also, 58% of women without health insurance compared with 24% of those with insurance indicated that they lacked a health professional with whom they could comfortably discuss sensitive topics such as depression. CONCLUSION: Wide gaps exist in postpartum behavioral and psychosocial health care. Most women find a variety of screening settings and methods acceptable. PMID- 27470180 TI - Standardized Discharge Information After Short-Stay Hysterectomy and Relationships With Self-Care Confidence, Perceived Recovery, and Satisfaction. AB - We report on the development and investigation of standardized, nurse-delivered discharge information to women after same-day hysterectomy, including the relationships among discharge information, self-care confidence, perceived recovery, and satisfaction. Fifty-one women reported high levels of self-care confidence and various levels of perceived recovery 48 to 72 hours after surgery. They were satisfied to highly satisfied with their experiences and with the discharge information provided. The important role of standardized patient discharge information is highlighted. PMID- 27470182 TI - Readily functionalizable phosphonium-tagged fluorescent coumarins for enhanced detection of conjugates by mass spectrometry. AB - Fluorescent coumarins are an important class of small-molecule organic fluorophores ubiquitous in different well-established and emerging fields of research including, among others, biochemistry and chemical biology. The present work aims at covering the poor detectability of coumarin-based conjugates by mass spectrometry while keeping important photophysical properties of the coumarin core. In this context, the synthesis of readily functionalizable phosphonium tagged coumarin derivatives enabling a dual mass-tag and fluorescence labelling of analytes or (bio)molecules of interest through a single-step protocol, is reported. The utility of these coumarins is illustrated through the preparation of fluorogenic substrates that facilitated identification of the peptide fragment released by specific proteolytic cleavages. PMID- 27470181 TI - Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke. AB - Microglia become activated during cerebral ischemia and exert pro-inflammatory or anti-inflammatory role dependent of microglial polarization. NADPH oxidase (NOX) dependent reactive oxygen species (ROS) production in microglia plays an important role in neuronal damage after ischemic stroke. Recently, NOX and ROS are consistently reported to participate in the microglial activation and polarization; NOX2 inhibition or suppression of ROS production are shown to shift the microglial polarization from M1 toward M2 state after stroke. The voltage gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. However, the effect of Hv1 proton channel on microglial M1/M2 polarization state after cerebral ischemia remains unknown. In this study, we investigated the role of microglial Hv1 proton channel in modulating microglial M1/M2 polarization during the pathogenesis of ischemic cerebral injury using a mouse model of photothrombosis. Following photothrombotic ischemic stroke, wild-type mice presented obvious brain infarct, neuronal damage, and impaired motor coordination. However, mice lacking Hv1 (Hv1(-/-)) were partially protected from brain damage and motor deficits compared to wild-type mice. These rescued phenotypes in Hv1(-/-) mice in ischemic stroke is accompanied by reduced ROS production, shifted the microglial polarization from M1 to M2 state. Hv1 deficiency was also found to shift the M1/M2 polarization in primary cultured microglia. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent generation of reactive oxygen species (ROS) in the brain. ROS participate in microglial activation and polarization. However, the effect of Hv1 on microglial M1/M2 polarization state after cerebral ischemia remains unknown. Hv1 deficiency was found to shift the microglial polarization from M1 to M2 state in ischemic stroke accompanied by reduced ROS production. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke. PMID- 27470183 TI - Randomized clinical trial of the use of glyceryl trinitrate patches to aid arteriovenous fistula maturation. AB - BACKGROUND: Arteriovenous fistulas are critical for haemodialysis, but maturation rates remain poor. Experimental and anecdotal evidence has supported the use of transdermal glyceryl trinitrate (GTN) patches. The aim of this RCT was to determine whether use of a GTN patch aids arteriovenous fistula maturation. METHODS: Patients referred for arteriovenous fistula formation were eligible. The GTN or placebo patch was applied immediately after surgery and left in situ for 24 h. The primary outcome measure was the change in venous diameter at 6 weeks after fistula formation. The secondary outcome measure was clinical fistula patency at 6 weeks. RESULTS: Of 200 patients recruited (533 screened), 101 were randomized to the placebo group and 99 to the GTN group. Of these, 81 and 86 respectively completed surgery, and had follow-up data available at 6 weeks. Improvements in venous diameter were similar in the two groups: mean(s.d.) increase 2.3(1.9) mm in the placebo group compared with 2.2(1.8) mm in the GTN group (P = 0.704). The fistula failure rate did not differ significantly between the two groups: 23 per cent for placebo and 28 per cent for GTN (P = 0.596). CONCLUSION: GTN transdermal patches used for 24 h after surgery did not improve arteriovenous fistula maturation. REGISTRATION NUMBER: NCT01685710 (http://www.clinicaltrials.gov). PMID- 27470184 TI - Performance of two different digital evaluation systems used for assessing pre clinical dental students' prosthodontic technical skills. AB - INTRODUCTION: Proper integration of newly emerging digital assessment tools is a central issue in dental education in an effort to provide more accurate and objective feedback to students. The study examined how the outcomes of students' tooth preparation were correlated when evaluated using traditional faculty assessment and two types of digital assessment approaches. Specifically, incorporation of the Romexis Compare 2.0 (Compare) and Sirona prepCheck 1.1 (prepCheck) systems was evaluated. Additionally, satisfaction of students based on the type of software was evaluated through a survey. MATERIAL AND METHODS: Students in a second-year pre-clinical prosthodontics course were allocated to either Compare (n = 42) or prepCheck (n = 37) systems. All students received conventional instruction and used their assigned digital system as an additional evaluation tool to aid in assessing their work. Examinations assessed crown preparations of the maxillary right central incisor (#8) and the mandibular left first molar (#19). All submissions were graded by faculty, Compare and prepCheck. RESULTS: Technical scores did not differ between student groups for any of the assessment approaches. Compare and prepCheck had modest, statistically significant correlations with faculty scores with a minimum correlation of 0.3944 (P = 0.0011) and strong, statistically significant correlations with each other with a minimum correlation of 0.8203 (P < 0.0001). A post-course student survey found that 55.26% of the students felt unfavourably about learning the digital evaluation protocols. A total of 62.31% felt favourably about the integration of these digital tools into the curriculum. CONCLUSIONS: Comparison of Compare and prepCheck showed no evidence of significant difference in students' prosthodontics technical performance and perception. PMID- 27470185 TI - Telomere length covaries with personality in wild brown trout. AB - The prevalence of consistent among-individual differences in behaviour, or personality, makes adaptive sense if individuals differ in stable state variables that shift the balance between the costs and benefits of their behavioural decisions. These differences may give rise to both individual differences in, and covariance among, behaviours that influence an individual's exposure to risks. We here study the link between behaviour and a candidate state variable previously overlooked in the study of state-dependent personality variation: telomere length. Telomeres are the protective endcaps of chromosomes and their erosion with age is thought to play a crucial role in regulating organismal senescence and intrinsic lifespan. Following evidence that shorter telomeres may reduce the lifespan of animals in a wide range of taxa, we predict individuals with shorter telomeres to behave more boldly and aggressively. In order to test this, we measured telomere length and behaviour in wild juvenile brown trout (Salmo trutta). We found individuals with shorter fin telomeres to behave consistently more boldly and aggressively under controlled conditions in the laboratory. No such relationship was found with muscle telomere length 3-4months after the behavioural assays. We suggest that telomere dynamics are an important factor integrating personality traits with other state variables thought to be important in the regulation of behaviour, such as metabolism, disease resistance and growth. PMID- 27470186 TI - Application of gas chromatography/tandem mass spectrometry to determine a wide range of petrogenic alkylated polycyclic aromatic hydrocarbons in biotic samples. AB - RATIONALE: Due to the inherent toxicity of these compounds, analysis of petrogenic alkylated polycyclic aromatic hydrocarbons (PAHs) and heteroaromatic compounds in environmental samples is crucial. However, most existing methods are not sensitive enough when the analyte concentrations are low. Gas chromatography/tandem mass spectrometry (GC/MS/MS) is well suited to tackle this challenge, but methods are yet to be fully developed. METHODS: A gas chromatograph coupled with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode was applied for the analysis. MRM transitions and analytical conditions were optimized for the cluster analysis of 24 different compound classes of alkylated PAHs and heteroaromatics present in crude oils. Further, the method was verified and applied to analyze the body burden of these compounds in crude oil-exposed haddock eggs. RESULTS: A comprehensive and sensitive method for the determination of C1-C4 alkylated naphthalenes, benzothiophenes, fluorenes, phenanthrenes, dibenzothiophenes, chrysenes, pyrenes and fluoranthenes was developed. The method showed good precision (RSD <15%), and the obtained concentrations were similar to those obtained by traditional GC/MS analysis. CONCLUSIONS: We demonstrate the successful application of this method towards crude oil-exposed fish eggs, where we are able to precisely measure total PAH body burden below 0.5 MUg/g. The demonstrated method facilitates further miniaturization in sample preparation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470187 TI - Raman spectral characteristics of magmatic-contact metamorphic coals from Huainan Coalfield, China. AB - Normal burial metamorphism of coal superimposed by magmatic-contact metamorphism makes the characteristics of the Raman spectrum of coal changed. Nine coal samples were chosen at a coal transect perpendicular to the intrusive dike, at the No. 3 coal seam, Zhuji Coal Mine, Huainan Coalfield, China, with different distances from dike-coal boundary (DCB). Geochemical (proximate and ultimate) analysis and mean random vitrinite reflectance (R0, %) indicate that there is a significant relationship between the values of volatile matter and R0 in metamorphosed coals. Raman spectra show that the graphite band (G band) becomes the major band but the disordered band (D band) disappears progressively, with the increase of metamorphic temperature in coals, showing that the structural organization in high-rank contact-metamorphosed coals is close to that of well crystallized graphite. Evident relationships are observed between the calculated Raman spectral parameters and the peak metamorphic temperature, suggesting some spectral parameters have the potentials to be used as geothermometers for contact metamorphic coals. PMID- 27470188 TI - Australia and New Zealand Faculty of Radiation Oncology Lung Interest Cooperative: 2015 consensus guidelines for the use of advanced technologies in the radiation therapy treatment of locally advanced non-small cell lung cancer. PMID- 27470189 TI - Histone deacetylase inhibitors stimulate the susceptibility of A549 cells to a plasma-activated medium treatment. AB - The number of potential applications of non-thermal atmospheric pressure plasma (NTAPP) discharges in medicine, particularly in cancer therapy, has increased in recent years. NTAPP has been shown to affect cells not only by direct irradiation, but also by an indirect treatment with previously prepared plasma activated medium (PAM). Histone deacetylase (HDAC) inhibitors have the potential to enhance susceptibility to anticancer drugs and radiation. The aim of the present study was to demonstrate the advantage of the combined application of PAM and HDAC inhibitors on A549 cancer cell survival and elucidate the underlying mechanisms. Cell death with DNA breaks in the nucleus was greater using combined regimens of PAM and HDAC inhibitors such as trichostatin A (TSA) and valproic acid (VPA) than a single PAM treatment and was accompanied by the activation of poly (ADP-ribose) polymerase-1 (PARP-1), depletion of ATP, and elevations in intracellular calcium levels. Moreover, the expression of Rad 51, a DNA repair factor in homologous recombination pathways, was significantly suppressed by the treatment with HDAC inhibitors. These results demonstrate that HDAC inhibitors may synergistically induce the sensitivity of cancer cells to PAM components. PMID- 27470190 TI - Impact of training on concordance among rheumatologists and dermatologists in the assessment of patients with psoriasis and psoriatic arthritis. AB - OBJECTIVE: To evaluate the impact of training on the reliability among dermatologists and rheumatologists in the assessment of psoriatic arthritis (PsA) patients. METHODS: Overall, 9 hospital-based rheumatologists and 8 hospital-based dermatologists met in Reggio Emilia, Italy on October 2015 to assess 17 PsA patients. After 1 month, physicians underwent a 3-h training session by 4 recognized experts and then assessed 19 different PsA patients according to a modified Latin square design. Measures included tender (TJC) and swollen joint count (SJC), dactylitis, enthesitis, Schober test, psoriasis body surface area (BSA), Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), and static physician's global assessment of PsA disease activity (sPGA). Variance components analyses were performed to estimate the intraclass correlation coefficient (ICC). RESULTS: TJC and enthesitis-measured pre-training by dermatologists or rheumatologists revealed moderate-substantial agreement (ICC: 0.4-0.8). In contrast, SJC and Schober test showed fair (ICC: 0.2-0.4) and moderate agreement, respectively (ICC: 0.4-0.6), while poor agreement (ICC: 0 0.2) was represented by dactylitis. Moderate-substantial (ICC: 0.4-0.8) agreement was observed for most skin measures by dermatologists and rheumatologists, apart from BSA, where fair agreement (ICC: 0.2-0.4) was observed. Agreement levels were similar before and after training for arthritis measures. In contrast, levels of agreement after training for 3 of the 4 skin measures were increased for dermatologists and all 4 skin measures were increased for rheumatologists. CONCLUSIONS: Substantial to excellent agreement was observed for TJC, enthesitis, PASI, and sPGA. Rheumatologists benefited from training to a greater extent. PMID- 27470191 TI - Harlequin Ichthyosis: A Surgical Perspective. AB - Limb constriction or encasement in patients with harlequin ichthyosis can cause tissue injury resulting in necrosis and auto-amputation. Surgical release of constrictive plaques has been previously demonstrated, but the perioperative and intraoperative considerations surrounding this infrequent intervention have not been discussed in detail. This report documents a case of harlequin ichthyosis requiring surgical treatment, focusing on the importance of early surgical consultation, risks of surgery, indications for and timing of surgical intervention, and the details of the operation. PMID- 27470192 TI - Colour blindness and driving. PMID- 27470193 TI - The simplicity principle in perception and cognition. AB - The simplicity principle, traditionally referred to as Occam's razor, is the idea that simpler explanations of observations should be preferred to more complex ones. In recent decades the principle has been clarified via the incorporation of modern notions of computation and probability, allowing a more precise understanding of how exactly complexity minimization facilitates inference. The simplicity principle has found many applications in modern cognitive science, in contexts as diverse as perception, categorization, reasoning, and neuroscience. In all these areas, the common idea is that the mind seeks the simplest available interpretation of observations- or, more precisely, that it balances a bias toward simplicity with a somewhat opposed constraint to choose models consistent with perceptual or cognitive observations. This brief tutorial surveys some of the uses of the simplicity principle across cognitive science, emphasizing how complexity minimization in a number of forms has been incorporated into probabilistic models of inference. WIREs Cogn Sci 2016, 7:330-340. doi: 10.1002/wcs.1406 For further resources related to this article, please visit the WIREs website. PMID- 27470194 TI - Diversity of Clostridium difficile PCR ribotypes in Europe: results from the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), 2012 and 2013. AB - Clostridium difficile infection (CDI) is the major cause of infective diarrhoea in healthcare environments. As part of the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), the largest C. difficile epidemiological study of its type, PCR ribotype distribution of C. difficile isolates in Europe was investigated. PCR ribotyping was performed on 1,196 C. difficile isolates from diarrhoeal samples sent to the European coordinating laboratory in 2012-13 and 2013 (from two sampling days) by 482 participating hospitals from 19 European countries. A total of 125 ribotypes were identified, of which ribotypes 027 (19%, n =222), 001/072 (11%, n = 134) and 014/020 (10%, n = 119) were the most prevalent. Distinct regional patterns of ribotype distribution were noted. Of 596 isolates from patients with toxin-positive stools (CDI cases), ribotype 027 accounted for 22% (32/144) of infections in cases aged from 18 to less than 65 years, but the prevalence decreased in those aged >= 65 years (14% (59/412)) and further decreased in those aged >= 81 years (9% (18/195)). The prevalence of ribotype 027 and 176, but not other epidemic strains, was inversely proportional to overall ribotype diversity (R(2) = 0.717). This study highlights an increased diversity of C. difficile ribotypes across Europe compared with previous studies, with considerable intercountry variation in ribotype distribution. Continuous surveillance programmes are necessary to monitor the changing epidemiology of C. difficile. PMID- 27470195 TI - Identification of metabolic biomarkers in patients with type 2 diabetic coronary heart diseases based on metabolomic approach. AB - Type 2 diabetic coronary heart disease (T2DM-CHD) is a kind of serious and complex disease. Great attention has been paid to exploring its mechanism; however, the detailed understanding of T2DM-CHD is still limited. Plasma samples from 15 healthy controls, 13 coronary heart disease (CHD) patients, 15 type 2 diabetes mellitus (T2DM) patients and 28 T2DM-CHD patients were analyzed in this research. The potential biomarkers of CHD and T2DM were detected and screened out by (1)H NMR-based plasma metabolic profiling and multivariate data analysis. About 11 and 12 representative metabolites of CHD and T2DM were identified respectively, mainly including alanine, arginine, proline, glutamine, creatinine and acetate. Then the diagnostic model was further constructed based on the previous metabolites of CHD and T2DM to detect T2DM-CHD with satisfying sensitivity of 92.9%, specificity of 93.3% and accuracy of 93.2%, validating the robustness of (1)H NMR-based plasma metabolic profiling to diagnostic strategy. The results demonstrated that the NMR-based metabolomics approach processed good performance to identify diagnostic plasma biomarkers and most identified metabolites related to T2DM and CHD could be considered as predictors of T2DM-CHD as well as the therapeutic targets for prevention, which provided new insight into diagnosing and forecasting of complex diseases. PMID- 27470196 TI - The origin of chromosomal inversions as a source of segmental duplications in the Sophophora subgenus of Drosophila. AB - Chromosomal inversions can contribute to the adaptation of organisms to their environment by capturing particular advantageous allelic combinations of a set of genes included in the inverted fragment and also by advantageous functional changes due to the inversion process itself that might affect not only the expression of flanking genes but also their dose and structure. Of the two mechanisms originating inversions -ectopic recombination, and staggered double strand breaks and subsequent repair- only the latter confers the inversion the potential to have dosage effects and/or to generate advantageous chimeric genes. In Drosophila subobscura, there is ample evidence for the adaptive character of its chromosomal polymorphism, with an important contribution of some warm-climate arrangements such as E1+2+9+12. Here, we have characterized the breakpoints of inversion E12 and established that it originated through the staggered-break mechanism like four of the five inversions of D. subobscura previously studied. This mechanism that also predominates in the D. melanogaster lineage might be prevalent in the Sophophora subgenus and contribute to the adaptive character of the polymorphic and fixed inversions of its species. Finally, we have shown that the D. subobscura inversion breakpoint regions have generally been disrupted by additional structural changes occurred at different time scales. PMID- 27470197 TI - Xanthomonas Whole Genome Sequencing: Phylogenetics, Host Specificity and Beyond. PMID- 27470198 TI - DILEMMAS OF COMMUNITY-DIRECTED MASS DRUG ADMINISTRATION FOR LYMPHATIC FILARIASIS CONTROL: A QUALITATIVE STUDY FROM URBAN AND RURAL TANZANIA. AB - There has in recent years been a growing interest in the social significance of global health policy and associated interventions. This paper is concerned with neglected tropical disease control, which prescribes annual mass drug administration to interrupt transmission of, among others, lymphatic filariasis. In Tanzania, this intervention is conducted through community-directed distribution, which aims to improve drug uptake by promoting community participation and local ownership in the intervention. However, the average uptake of drugs often remains too low to achieve the intended interruption of transmission. The qualitative research presented here followed the implementation of mass drug administration in Lindi and Morogoro Regions, Tanzania, in 2011 to understand the different forms of involvement in the campaign and the experiences of stakeholders of their part in community-directed distribution. Some health care workers, community leaders and drug distributors were generally positive about the intervention, emphasizing that the drugs were welcome. Other stakeholders, including the drug-receiving population, reported facing a number of dilemmas of uncertainty, authority and exclusion pertaining to their roles in the intervention. These dilemmas should be of interest to donors, policymakers and implementers. Community-directed distribution relies on social relations between the many different stakeholders. Successful and justifiable interventions for lymphatic filariasis require implementers to recognize the central role of sociality and that the voices and priorities of people count. PMID- 27470199 TI - Spin slush in an extended spin ice model. AB - We present a new classical spin liquid on the pyrochlore lattice by extending spin ice with further neighbour interactions. We find that this disorder-free spin model exhibits a form of dynamical heterogeneity with extremely slow relaxation for some spins, while others fluctuate quickly down to zero temperature. We thus call this state spin slush, in analogy to the heterogeneous mixture of solid and liquid water. This behaviour is driven by the structure of the ground-state manifold which extends the celebrated two-in/two-out ice states to include branching structures built from three-in/one-out, three-out/one-in and all-in/all-out tetrahedra defects. Distinctive liquid-like patterns in the magnetic correlations serve as a signature of this intermediate range order. Possible applications to materials as well the effects of quantum tunnelling are discussed. PMID- 27470200 TI - Comparison of semen variables, sperm DNA damage and sperm membrane proteins in two male layer breeder lines. AB - Semen variables are affected by the breed and strain of chicken. The present study was undertaken to compare the semen quality in two lines of adult chickens with particular reference to sperm chromatin condensation, sperm DNA damage and sperm membrane proteins. Semen from a PD3 and White Leghorn control line was collected at 46 and 47 weeks and 55 weeks of age. The semen was evaluated for gross variables and sperm chromatin condensation by aniline blue staining. Sperm DNA damage was assessed by using the comet assay at 47 weeks of age and sperm membrane proteins were assessed at 55 weeks of age. The duration of fertility was studied by inseminating 100 million sperm once into the hens of the same line as well as another line. The eggs were collected after insemination for 15days and incubated. The eggs were candled on 18th day of incubation for observing embryonic development. The White Leghorn control line had a greater sperm concentration and lesser percentage of morphologically abnormal sperm at the different ages where assessments occurred. There was no difference in sperm chromatin condensation, DNA damage and membrane proteins between the lines. Only low molecular weight protein bands of less than 95kDa were observed in samples of both lines. The line from which semen was used had no effect on the duration over which fertility was sustained after insemination either when used in the same line or another line. Thus, from the results of the present study it may be concluded that there was a difference in gross semen variables between the lines that were studied, however, the sperm chromatin condensation, DNA damage, membrane proteins and duration over which fertility was sustained after insemination did not differ between the lines. PMID- 27470201 TI - New technique for fertilizing eggs of burbot, asp and ide under hatchery conditions. AB - The development of a new protocol for egg fertilization may increase embryo survival and benefit the aquaculture process. In the present study, a new technique of partially adding sperm to activated eggs in the artificial fertilization of burbot (Lota lota), ide (Leuciscus idus) and asp (Aspius aspius) eggs was evaluated. If the same volume of sperm was divided into two or three parts and added to eggs in 30-60s intervals, it significantly improved embryo survival at the eyed-egg-stage of development. In the present study, the periodic addition of spermatozoa to eggs affected fertilization (ide and asp) and embryo survival rates (ide, asp and burbot) and might be successfully applied under hatchery conditions. PMID- 27470202 TI - Kinetic studies of CO2 methanation over a Ni/gamma-Al2O3 catalyst. AB - The production of methane by reacting CO2 with H2 (CO2 methanation) has the potential for producing synthetic natural gas, which could be exported using the existing infrastructure for the distribution of natural gas. The methanation of CO2 was investigated over a wide range of partial pressures of products and reactants using (i) a gradientless, spinning-basket reactor operated in batch mode and (ii) a laboratory-scale packed bed reactor operated continuously. The rate and selectivity of CO2 methanation, using a 12 wt% Ni/gamma-Al2O3 catalyst, were explored at temperatures 445-497 K and pressures up to 20 bar. Research with the batch reactor showed that the rate increased with increasing partial pressures of H2 and CO2 when the partial pressures of these reactants were low; however, the rate of reaction was found to be insensitive to changes in the partial pressures of H2 and CO2 when their partial pressures were high. A convenient method of determining the effect of H2O on the rate of reaction was also developed using the batch reactor and the inhibitory effect of H2O on CO2 methanation was quantified. The kinetic measurements were compared with a mathematical model of the reactor, in which different kinetic expressions were explored. The kinetics of the reaction were found to be consistent with a mechanism in which adsorbed CO2 dissociated to adsorbed CO and O on the surface of the catalyst with the rate-limiting step being the subsequent dissociation of adsorbed CO. The ability of the kinetic expressions to predict the results from the continuous, packed-bed reactor was explored, with some discrepancies discussed. PMID- 27470203 TI - Risk Factors for Domestic Child Sex Trafficking in the United States. AB - Despite increased effort to respond to human trafficking at national and state levels, very little empirical research has been conducted on domestic child sex trafficking. This study retrospectively examines associations between multiple risk factors and domestic child sex trafficking (i.e., entry into the commercial sex industry under the age of 18) in a sample of individuals aged 16 and older currently involved in the commercial sex industry ( N = 273). Two primary research questions are addressed: (1) What set of risk factors, prior to entering the commercial sex industry, are associated with domestic child sex trafficking and (2) what group differences, if any, exist in risk factors between current or former domestic child sex-trafficking victims and non-trafficked adults engaged in the commercial sex industry? A cross-sectional survey was administered using Respondent-Driven Sampling (RDS) in five cities in one Midwestern state. Overall, 115 participants (48.3%) were identified as current or former domestic child sex trafficking victims. Bivariate results suggest that childhood emotional and sexual abuse, rape, ever running away from home, having family members in sex work, and having friends who purchased sex were significantly associated with domestic child sex trafficking. Multivariate results indicate that domestic child sex trafficking victims were significantly more likely to have ever run away and to be a racial/ethnic minority than non-trafficked adults engaged in the commercial sex industry. Findings can inform state-level policies on human trafficking and assist child protection and juvenile justice agencies in developing prevention and intervention responses to commercial sexual exploitation. PMID- 27470204 TI - Western scrub-jays (Aphelocoma californica) solve multiple-string problems by the spatial relation of string and reward. AB - String-pulling is a widely used paradigm in animal cognition research to assess what animals understand about the functionality of strings as a means to obtain an out-of-reach reward. This study aimed to systematically investigate what rules Western scrub-jays (Aphelocoma californica) use to solve different patterned string tasks, i.e. tasks in which subjects have to choose between two or more strings of which only one is connected to the reward, or where one is more efficient. Arranging strings in a parallel configuration showed that the jays were generally capable of solving multiple-string tasks and acted in a goal directed manner. The slanted and crossed configurations revealed a reliance on a "proximity rule", that is, a tendency to choose the string-end closest to the reward. When confronted with strings of different lengths attached to rewards at different distances the birds chose according to the reward distance, preferring the reward closest to them, and were sensitive to the movement of the reward, but did not consistently prefer the shorter and therefore more efficient string. Generally, the scrub-jays were successful in tasks where the reward was closest to the string-ends they needed to pull or when string length and reward distance correlated, but the birds had problems when the wrong string-end was closest to the reward or when the food items were in close proximity to each other. These results show that scrub-jays had a partial understanding of the physical principles underlying string-pulling but relied on simpler strategies such as the proximity rule to solve the tasks. PMID- 27470205 TI - Layer contributions to the nonlinear acoustic radiation from stratified media. AB - This study presents the thorough investigation of the second harmonic generation scenario in a three fluid layer system. An emphasis is on the evaluation of the nonlinear parameter B/A in each layer from remote measurements. A theoretical approach of the propagation of a finite amplitude acoustic wave in a multilayered medium is developed. In the frame of the KZK equation, the weak nonlinearity of the media, attenuation and diffraction effects are computed for the fundamental and second harmonic waves propagating back and forth in each of the layers of the system. The model uses a gaussian expansion to describe the beam propagation in order to quantitatively evaluate the contribution of each part of the system (layers and interfaces) to its nonlinearity. The model is validated through measurements on a water/aluminum/water system. Transmission as well as reflection configurations are studied. Good agreement is found between the theoretical results and the experimental data. The analysis of the second harmonic field sources measured by the transducers from outside the stratified medium highlights the factors that favor the cumulative effects. PMID- 27470206 TI - Incidental finding of lymphoma after septoplasty. AB - INTRODUCTION: Septoplasty, or surgical correction of the deviated septum, is an elective, routinely performed rhinologic procedure to address nasal airway obstruction. In many cases, resected septal cartilage and bone fragments are sent for pathologic review, although there is no consensus on this practice. We reported two cases of incidentally diagnosed lymphoma after elective septoplasty and discussed clinical presentation, diagnosis, and management. METHODS: Retrospective chart review of two patients who underwent septoplasty at a tertiary academic medical center and found to have incidental lymphoma based on histopathology. RESULTS: Two patients who underwent septoplasty had an incidental diagnosis of lymphoma on pathologic analysis. One patient was noted to have an S shaped septal deviation that produced bilateral nasal obstruction. She underwent a difficult septoplasty, in which the mucoperichondrial flap was firmly adherent to the underlying septum and bone. Final pathology demonstrated diffuse large B cell lymphoma. She was treated with chemoradiation and remained free of disease at 59 months. The other patient had a history of nasal trauma, which produced left septal deviation. He underwent an uncomplicated septoplasty, with pathology that demonstrated low-grade B-cell lymphoma. Because there was no evidence of active disease, the decision was made to not treat and to observe the patient clinically. CONCLUSIONS: This is the first reported series of septal lymphoma incidentally diagnosed on routine septoplasty. Although histopathologic review of specimens from routine nasal and sinus surgery is not routinely performed, this report highlighted the importance of this process, on a case-by-case basis, in detecting unexpected malignancies that otherwise were clinically silent. PMID- 27470207 TI - Gap-plasmon based broadband absorbers for enhanced hot-electron and photocurrent generation. AB - Plasmonic hot-electron generation has recently come into focus as a new scheme for solar energy conversion. So far, however, due to the relatively narrow bandwidth of the surface plasmon resonances and the insufficient resonant light absorption, most of plasmonic photocatalysts show narrow-band spectral responsivities and small solar energy conversion efficiencies. Here we experimentally demonstrate that a three-layered nanostructure, consisting of a monolayer gold-nanoparticles and a gold film separated by a TiO2 gap layer (Au NPs/TiO2/Au-film), is capable of near-completely absorbing light within the whole visible region. We show that the Au-NPs/TiO2/Au-film device can take advantage of such strong and broadband light absorption to enhance the generation of hot electrons and thus the photocurrent under visible irradiation. As compared to conventional plasmonic photocatalysts such as Au-NPs/TiO2 nanostructures, a 5 fold-enhanced incident photon-to-current conversion efficiency is achieved within the entire wavelength range 450-850 nm in the Au-NPs/TiO2/Au-film device. Simulations show good agreements with the experimental results, demonstrating that only the plasmon-induced losses contribute to the enhanced photocurrent generation of the Au-NPs/TiO2/Au-film device. PMID- 27470208 TI - No direct effect of an elective caesarean section on the phenotypic and functional characteristics of maternal peripheral blood T lymphocytes. AB - PROBLEM: The short term effect of the caesarean delivery on the phenotypic and functional characteristics of the peripheral blood leukocytes of the mother is unknown. METHOD OF STUDY: We determined the composition and activation status of the maternal peripheral blood leukocytes isolated within 4h before and within 24h after elective caesarean delivery with neuraxial anaesthesia. Furthermore, we determined the proliferative and cytotoxic response of these leukocytes to several stimulators. RESULTS: No significant differences in the percentage of CD4+CD25bright and CD8+CD28- T cells or the expression of activation markers FoxP3, CD69 and HLA-DR were observed in peripheral blood drawn before caesarean delivery compared to after caesarean delivery. Also the alloreactive immune responses in samples taken before and after the caesarean delivery were similar. CONCLUSION: Our results show that the phenotype and immune response of maternal peripheral blood T cells obtained before elective caesarean delivery are not different from those obtained after caesarean delivery. This knowledge will facilitate sample collection for future studies on the immune response in term pregnancies. PMID- 27470209 TI - Incompatibility of lyophilized inactivated polio vaccine with liquid pentavalent whole-cell-pertussis-containing vaccine. AB - A hexavalent vaccine containing diphtheria toxoid, tetanus toxoid, whole cell pertussis, Haemophilius influenza type B, hepatitis B and inactivated polio vaccine (IPV) may: (i) increase the efficiency of vaccination campaigns, (ii) reduce the number of injections thereby reducing needlestick injuries, and (iii) ensure better protection against pertussis as compared to vaccines containing acellular pertussis antigens. An approach to obtain a hexavalent vaccine might be reconstituting lyophilized polio vaccine (IPV-LYO) with liquid pentavalent vaccine just before intramuscular delivery. The potential limitations of this approach were investigated including thermostability of IPV as measured by D antigen ELISA and rat potency, the compatibility of fluid and lyophilized IPV in combination with thimerosal and thimerosal containing hexavalent vaccine. The rat potency of polio type 3 in IPV-LYO was 2 to 3-fold lower than standardized on the D-antigen content, suggesting an alteration of the polio type 3 D-antigen particle by lyophilization. Type 1 and 2 had unaffected antigenicity/immunogenicity ratios. Alteration of type 3 D-antigen could be detected by showing reduced thermostability at 45 degrees C compared to type 3 in non-lyophilized liquid controls. Reconstituting IPV-LYO in the presence of thimerosal (TM) resulted in a fast temperature dependent loss of polio type 1-3 D antigen. The presence of 0.005% TM reduced the D-antigen content by ~20% (polio type 2/3) and ~60% (polio type 1) in 6h at 25 degrees C, which are WHO open vial policy conditions. At 37 degrees C, D-antigen was diminished even faster, suggesting that very fast, i.e., immediately after preparation, intramuscular delivery of the conceived hexavalent vaccine would not be a feasible option. Use of the TM-scavenger, l-cysteine, to bind TM (or mercury containing TM degradation products), resulted in a hexavalent vaccine mixture in which polio D-antigen was more stable. PMID- 27470210 TI - Sexting among singles in the USA: prevalence of sending, receiving, and sharing sexual messages and images. AB - Background: The transmission of sexual images and messages via mobile phone or other electronic media (sexting) has been associated with a variety of mostly negative social and behavioural consequences. Research on sexting has focussed on youth, with limited data across demographics and with little known about the sharing of private sexual images and messages with third parties. Methods: The present study examines sexting attitudes and behaviours, including sending, receiving, and sharing of sexual messages and images, across gender, age, and sexual orientation. A total of 5805 single adults were included in the study (2830 women; 2975 men), ranging in age from 21 to 75+ years. Results: Overall, 21% of participants reported sending and 28% reported receiving sexually explicit text messages; both sending and receiving 'sexts' was most common among younger respondents. Although 73.2% of participants reported discomfort with unauthorised sharing of sexts beyond the intended recipient, of those who had received sext images, 22.9% reported sharing them with others (on average with 3.17 friends). Participants also reported concern about the potential consequences of sexting on their social lives, careers, and psychosocial wellbeing. Conclusion: Views on the impact of sexting on reputation suggest a contemporary struggle to reconcile digital eroticism with real-world consequences. These findings suggest a need for future research into negotiations of sexting motivations, risks, and rewards. PMID- 27470211 TI - Analysis of extended haplotype in Korean cattle (Hanwoo) population. AB - Korean cattle (Hanwoo) are categorized into three breeds based on color: brown, brindle, and black. Among these breeds, brown Hanwoo has been subjected to intensive selection to improve meat traits. To identify genetic traces driven by recent selection in brown Hanwoo, we scanned the genomes of brown and brindle Hanwoo using a bovine SNP chip. We identified 17 candidate selection signatures in brown Hanwoo and sequenced four candidate regions from 10 individuals each of brown and brindle Hanwoo. In particular, non-synonymous SNPs in the ADSL gene (K88M, L189H, and R302Q) might have had mutational effects on protein structure as a result of altering the purine pathway during nucleotide breakdown. The ADSL gene was previously reported to affect meat quality and yield in livestock. Meat quality and yield are main breeding goals for brown Hanwoo, and our results support a potential causal influence of non-synonymous SNPs in the ADSL gene. [BMB Reports 2016; 49(9): 514-519]. PMID- 27470212 TI - Enhancement of UV-induced nucleotide excision repair activity upon forskolin treatment is cell growth-dependent. AB - Forskolin (FSK), an adenylyl cyclase activator, has recently been shown to enhance nucleotide excision repair (NER) upon UV exposure. However, our study revealed that this effect was detected in human skin epithelial ARPE19 cells only in growing cells, but not in non-cycling cells. When the cells were grown at low density (70% confluence), FSK was capable of stimulating cAMP responsive element binding (CREB) phosphorylation, a marker for FSK-stimulated PKA activation, and resulted in a significant increase of NER activity compared to control treatment. However, cells grown under 100% confluent conditions showed neither FSK-induced CREB phosphorylation nor the resulting NER enhancement. These findings indicate that cellular growth is critical for FSK-induced NER enhancement and suggest that cellular growth conditions should be considered as a variable while evaluating a reagent's pharmacotherapeutic efficacy. [BMB Reports 2016; 49(10): 566-571]. PMID- 27470214 TI - Simultaneous destabilization of beta-catenin and Ras via targeting of the axin RGS domain as a potential therapeutic strategy for colorectal cancer. AB - Mutations of APC and KRAS are frequently observed in human colorectal cancers (CRCs) and the Wnt/beta-catenin and Ras pathways are consequently activated in a significant proportion of CRC patients. Mutations in these two genes are also known to synergistically induce progression of CRCs. Through a series of studies, we have demonstrated that inhibition of the Wnt/beta-catenin signaling pathway negatively regulates Ras stability, therefore, Ras abundance is increased together with beta-catenin in both mice and human CRCs harboring adenomatous polyposis coli (APC) mutations. In a recent study, we identified KY1220, a small molecule that simultaneously degrades beta-catenin and Ras by inhibition of the Wnt/beta-catenin pathway, and obtained its derivative KYA1797K, which has improved activity and solubility. We found that KYA1797K binds the RGS domain of axin and enhances the binding affinity of beta-catenin or Ras with the beta catenin destruction complex components, leading to simultaneous destabilization of beta-catenin and Ras via GSK3beta activation. By using both in vitro and in vivo studies, we showed that KYA1797K suppressed the growth of CRCs harboring APC and KRAS mutations through destabilization of beta-catenin and Ras. Therefore, our findings indicate that the simultaneous destabilization of beta-catenin and Ras via targeting axin may serve as an effective strategy for inhibition of CRCs. [BMB Reports 2016; 49(9): 455-456]. PMID- 27470213 TI - Dynamics of ARF regulation that control senescence and cancer. AB - ARF is an alternative reading frame product of the INK4a/ARF locus, inactivated in numerous human cancers. ARF is a key regulator of cellular senescence, an irreversible cell growth arrest that suppresses tumor cell growth. It functions by sequestering MDM2 (a p53 E3 ligase) in the nucleolus, thus activating p53. Besides MDM2, ARF has numerous other interacting partners that induce either cellular senescence or apoptosis in a p53-independent manner. This further complicates the dynamics of the ARF network. Expression of ARF is frequently disrupted in human cancers, mainly due to epigenetic and transcriptional regulation. Vigorous studies on various transcription factors that either positively or negatively regulate ARF transcription have been carried out. However, recent focus on posttranslational modifications, particularly ubiquitination, indicates wider dynamic controls of ARF than previously known. In this review, we discuss the role and dynamic regulation of ARF in senescence and cancer. [BMB Reports 2016; 49(11): 598-606]. PMID- 27470215 TI - Long-term follow-up of one-piece fronto-orbital advancement with distraction but without a bandeau for coronal craniosynostosis: Review of 26 consecutive cases. AB - To adopt the traditional fronto-orbital advancement technique designed by Tessier in the application of a distraction technique, the frontal bone flap should be detached before the distraction. In order to maximize the merit and potency of the distraction, we have applied the "one-piece cranioplasty" technique without bandeau for coronal craniosynostosis. Our new surgical technique was used to treat 10 unilateral and 16 bilateral craniosynosis patients between February 2005 and August 2014. Satisfactory results were achieved in all patients. An average distraction of 25.2 mm was possible without detachment from the dura mater. The average cephalic index (width/length * 100) decreased from 98.3 to 89.9 after 3 months postoperatively and was maintained at 88.6 until 6.4 years on average after the operation. In 10 unilateral coronal synostotic patients, the endocranial angulation of the anteroposterior axis was improved from 165.3 degrees to 174.8 degrees after 3 months postoperatively and was maintained at 174.5 degrees until 5.8 years on average after the operation. Our present findings indicate that the novel one-piece fronto-orbital advancement with distraction approach appears to be less invasive and is suitable for correcting single-suture coronal craniosynostoses, except for the complex form of this condition, even at longer follow-up intervals. PMID- 27470216 TI - The effect of low hemoglobin levels on outcomes of radiotherapy following microscopically complete resection of locally advanced SCCHN: Implications for the future. AB - This study investigated the prognostic implications of pre-radiotherapy hemoglobin levels after microscopically complete (R0) resection of locally advanced squamous cell carcinoma of the head-and-neck (SCCHN) and reviewed the question "should anemia be corrected?". A total of 225 patients receiving R0 resection and postoperative irradiation were retrospectively evaluated. Pre radiotherapy hemoglobin levels (<12 vs. >=12 g/dl) plus eight factors (T-/N category, AJCC-stage, performance score, gender, age, tumor site, and histologic grading) were analyzed for locoregional control and survival. Hemoglobin levels of <12 and >=12 g/dl were associated with 3-year locoregional control rates of 67% and 84%, respectively, and 5-year locoregional control rates of 63% and 74%, respectively (p = 0.029). On multivariate analysis of locoregional control, hemoglobin levels achieved significance (hazard ratio [HR] 1.97; 95%-confidence interval [95%-CI] 1.02-3.81; p = 0.043). Hemoglobin levels of <12 and >=12 g/dl were associated with 3-year survival rates of 55% and 87%, respectively, and 5 year survival rates of 25% and 71%, respectively (p < 0.001). On multivariate analysis of survival, hemoglobin levels were significant (HR 2.91; 95%-CI 1.67 5.22; p < 0.001). Thus, pre-radiotherapy hemoglobin is an independent predictor for outcomes after R0-resection of SCCHN. Levels <12 g/dl were associated with worse outcomes than >=12 g/dl. Tumor cell oxygenation and correction of anemia appear important also after R0-resection. PMID- 27470218 TI - Four decades of stem cell transplantation for Fanconi anaemia in the Netherlands. AB - This article presents the haematopoietic stem cell transplantation (SCT) results of the complete Dutch Fanconi anaemia (FA) patient cohort. Sixty-eight Dutch FA patients have been transplanted since 1972. In total, 63 (93%) patients engrafted, 54 after first SCT and 9 after second SCT. Fludarabine (FLU)-based conditioning was associated with decreased graft failure (odds ratio 0.21, P = 0.01), decreased early mortality (hazard ratio 0.25, P = 0.01) and improved 5 year overall survival (FLU 87.8% [standard error (SE) 5.1%] versus non-FLU 59.3% [SE 9.5%], P = 0.01). Late mortality was mainly caused by squamous cell carcinoma. Twenty-two patients were treated with the current Dutch FA conditioning regimen (FLU 150 mg/m(2) and cyclophosphamide 30 mg/kg +/- anti thymocyte globulin - no irradiation). Stem cell donors were matched related (n = 8) or alternative donors (n = 14). Stable engraftment after first SCT was achieved in 19 (86%) patients. At a median follow-up of 3.9 years 20 (91%) patients are alive. Our study provides a unique overview of a nation-wide SCT cohort illustrating the major improvements in treatment regimen and patient outcome in recent years. It shows that a non-irradiation and busulfan-free conditioning regimen can be used successfully, also in alternative donor SCT. Furthermore, it underlines the importance of late cancer screening and comprehensive care for this complex disorder. PMID- 27470217 TI - TGR5 suppresses high glucose-induced upregulation of fibronectin and transforming growth factor-beta1 in rat glomerular mesangial cells by inhibiting RhoA/ROCK signaling. AB - RhoA/ROCK can cause renal inflammation and fibrosis in the context of diabetes by activating nuclear factor-kappaB (NF-kappaB). TGR5 is known for its role in maintaining metabolic homeostasis and anti-inflammation, which is closely related to NF-kappaB inhibition. Given that TGR5 is highly enriched in kidney, we aim to investigate the regulatory role of TGR5 on fibronectin (FN) and transforming growth factor-beta1 (TGF-beta1) in high glucose (HG)-treated rat glomerular mesangial cells (GMCs). Both the factors are closely related to renal inflammations and mediated by NF-kappaB. Moreover, our study determines whether such regulation is achieved by the inhibition of RhoA/ROCK and the subsequent NF kappaB suppression. Polymerase chain reaction was taken to test the mRNA level of TGR5. Western blot was used to measure the protein expressions of TGR5, FN, TGF beta1, p65, IkappaBalpha, phospho-MYPT1 (Thr853), and MYPT1. Glutathione S transferase-pull down and immunofluorescence were conducted to test the activation of RhoA, the distribution of TGR5, and p65, respectively. Electrophoretic mobility shift assay was adopted to measure the DNA binding activity of NF-kappaB. In GMCs, TGR5 activation or overexpression significantly suppressed FN and TGF-beta1 protein expressions, NF-kappaB, and RhoA/ROCK activation induced by HG or transfection of constitutively active RhoA. By contrast, TGR5 RNA interference caused enhancement of FN, TGF-beta1 protein expressions, increase of RhoA/ROCK activation. However, TGR5 cannot suppress RhoA/ROCK activation when a selective Protein kinase A (PKA) inhibitor was used. This study suggests that in HG-treated GMCs, TGR5 significantly suppresses the NF kappaB-mediated upregulation of FN and TGF-beta1, which are hallmarks of diabetic nephropathy. These functions are closely related to the suppression of RhoA/ROCK via PKA. PMID- 27470219 TI - Variations in pollen counts between Indianapolis, IN, and Dayton, OH, in spring 2013 and 2014. PMID- 27470220 TI - TGF-beta1 rs1982073 polymorphism contributes to radiation pneumonitis in lung cancer patients: a meta-analysis. AB - Transforming growth factor beta 1(TGF-beta1) polymorphism was associated with radiation pneumonitis (RP) susceptibility, but their results have been inconsistent. The PubMed and CNKI were searched for case-control studies published up to Januray 01, 2016 was Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In this meta-analysis, we assessed eight publications involving 368 radiation pneumonitis cases and 855 controls of the association between TGF-beta1 T869C (rs1982073) and G915C (rs1800471) polymorphism and RP susceptibility. Our analysis suggested that TGF beta1 T869C rs1982073 polymorphism was associated with lower RP risk for CT combined CC versus TT model (OR = 0.58, 95% CI = 0.43-0.77). However, for the G915C rs1800471 polymorphism, no association was found between the polymorphism and the susceptibility to RP in GC combined CC versus GG model (OR = 0.82, 95% CI = 0.50-1.35). These results from the meta-analysis suggest that T869C rs1982073 polymorphism of TGF-beta1 may be associated with RP risk, and there may be no association between G915C polymorphism and RP risk. PMID- 27470221 TI - In memoriam of Professor Irving Gottesman (1930-2016). PMID- 27470222 TI - A review of semi-synthetic biopolymer complexes: modified polysaccharide nano carriers for enhancement of oral drug bioavailability. AB - Semi-synthetic biopolymer complexes (SSBCs) have potential as nano-carriers for oral drug delivery due to their exceptional properties obtained by merging the properties of synthetic (e.g. good thermal and mechanical properties) with natural polymers (e.g. biocompatibility); thus, forming a new class of biopolymer materials incorporating the best of both worlds. Despite development in drug delivery systems, oral administration of therapeutic agent is still preferred. Several nano-polymeric systems has been prepared and characterized based on both synthetic polymers and natural polymers, each with its limitations and advantages. Among natural polymers, alginate, chitosan, and hyaluronic acid (HA) have been studied broadly for the fabrication of nanoparticles systems. This review discusses a newly investigated class of polymer called SSBCs as oral drug nano-carriers. It also discusses certain significant structural and functional attributes or effects which are essential to be taken into consideration when an oral drug delivery system is developed. The review is aimed at describing complexation of few natural polymers (e.g. polysaccharides) with selected synthetic polymers or synthetic chemicals to indicate some of the factors that influence preparation, solubility, formation, and stability of these SSBCs. PMID- 27470223 TI - Forming heterojunction: an effective strategy to enhance the photocatalytic efficiency of a new metal-free organic photocatalyst for water splitting. AB - Photocatalytic water splitting is a new technology for the conversion and utilization of solar energy and has a potential prospect. One important aspect of enhancing the photocatalytic efficiency is how to improve the electron-hole separation. Up to now, there is still no ideal strategy to improve the electron hole separation. In this article, for metal-free organic photocatalysts, we propose a good strategy- forming heterojunction, which can effectively improve the electron-hole separation. We provide a metal-free organic photocatalyst g C12N7H3 for water splitting. The stability of g-C12N7H3 has been investigated, the X-ray diffraction spectra has been simulated. Using first-principles calculations, we have systematically studied the electronic structure, band edge alignment, and optical properties for the g-C12N7H3. The results demonstrated that g-C12N7H3 is a new organocatalyst material for water splitting. In order to enhance the photocatalytic efficiency, we provided four strategies, i.e., multilayer stacking, raising N atoms, forming g-C9N10/g-C12N7H3 heterojunction, and forming graphene/g-C12N7H3 heterojunction. Our research is expected to stimulate experimentalists to further study novel 2D metal-free organic materials as visible light photocatalysts. Our strategies, especially forming heterojunction, will substantially help to enhance the photocatalytic efficiency of metal-free organic photocatalyst. PMID- 27470225 TI - Pregnancy outcomes after treatment for preinvasive cervical lesions. PMID- 27470224 TI - Prescription opioid poisoning across urban and rural areas: identifying vulnerable groups and geographic areas. AB - AIMS: To determine (1) whether prescription opioid poisoning (PO) hospital discharges spread across space over time, (2) the locations of 'hot-spots' of PO related hospital discharges, (3) how features of the local environment contribute to the growth in PO-related hospital discharges and (4) where each environmental feature makes the strongest contribution. DESIGN: Hierarchical Bayesian Poisson space-time analysis to relate annual discharges from community hospitals to postal code characteristics over 10 years. SETTING: California, USA. PARTICIPANTS: Residents of 18 517 postal codes in California, 2001-11. MEASUREMENTS: Annual postal code-level counts of hospital discharges due to PO poisoning were related to postal code pharmacy density, measures of medical need for POs (i.e. rates of cancer and arthritis-related hospital discharges), economic stressors (i.e. median household income, percentage of families in poverty and the unemployment rate) and concentration of manual labor industries. FINDINGS: PO-related hospital discharges spread from rural and suburban/exurban 'hot-spots' to urban areas. They increased more in postal codes with greater pharmacy density [rate ratio (RR) = 1.03; 95% credible interval (CI) = 1.01, 1.05], more arthritis-related hospital discharges (RR = 1.08; 95% CI = 1.06, 1.11), lower income (RR = 0.85; 95% CI = 0.83, 0.87) and more manual labor industries (RR = 1.15; 95% CI = 1.10, 1.19 for construction; RR = 1.12; 95% CI = 1.04, 1.20 for manufacturing industries). Changes in pharmacy density primarily affected PO-related discharges in urban areas, while changes in income and manual labor industries especially affected PO-related discharges in suburban/exurban and rural areas. CONCLUSIONS: Hospital discharge rates for prescription opioid (PO) poisoning spread from rural and suburban/exurban hot-spots to urban areas, suggesting spatial contagion. The distribution of age-related and work-place related sources of medical need for POs in rural areas and, to a lesser extent, the availability of POs through pharmacies in urban areas, partly explain the growth of PO poisoning across California, USA. PMID- 27470226 TI - Self-efficacy for HIV Prevention Among Refugee Hispanic Women in South Florida. AB - The number of refugees increased in recent years due to factors worldwide, including violence, wars, political strife, and natural disasters. Refugees who are Hispanic women (RHW) in South Florida are a vulnerable population at risk of acquiring HIV infection. Although studies have shown a relationship between self efficacy for HIV prevention and behavior changes, none have studied RHW. The purpose of this study was to assess whether predictors suggested by the literature were related to self-efficacy for HIV prevention in a sample of RHW. The study is a secondary analysis that uses baseline data from a randomized controlled experimental study, SEPA. A total of 99 refugee Hispanic women from South Florida, 18-50 years of age, participated in the study. There were two predictors of self-efficacy. HIV knowledge was positively related to self efficacy, and living with a partner was inversely related to self-efficacy for HIV prevention. Culturally competent sexual health education interventions in this population may impact self-efficacy for HIV prevention. PMID- 27470227 TI - Kinematic and electromyographic analysis in patients with patellofemoral pain syndrome during single leg triple hop test. AB - Possible delays in pre-activation or deficiencies in the activity of the dynamic muscle stabilizers of the knee and hip joints are the most common causes of the patellofemoral pain syndrome (PFPS). The aim of the study was to compare kinematic variables and electromyographic activity of the vastus lateralis, biceps femoris, gluteus maximus and gluteus medius muscles between patients with PFPS and health subjects during the single leg triple hop test (SLTHT). This study included 14 female with PFPS (PFPS group) and 14 female healthy with no history of knee pain (Healthy group). Kinematic and EMG data ware collected through participants performed a single session of the SLTHT. The PFPS group exhibited a significant increase (p<0.05) in the EMG activity of the biceps femoris and vastus lateralis muscles, when compared with the healthy group in pre activity and during the stance phase. This same result was also found for the vastus lateralis muscle (p<0.05) when analyzing the EMG activity during the eccentric phase of the stance phase. In kinematic analysis, no significant differences were found between the groups. These results indicate that biceps femoris and vastus lateralis muscles mainly during the pre-activation phase and stance phases of the SLTHT are more active in PFPS group among healthy group. PMID- 27470228 TI - Stressful life events and leucocyte telomere length: Do lifestyle factors, somatic and mental health, or low grade inflammation mediate this relationship? Results from a cohort of Danish men born in 1953. AB - Exposure to psychosocial stress is associated with increased risk of a number of somatic and mental disorders with relation to immune system functioning. We aimed to explore whether stressful events in early and recent life was associated with leucocyte telomere length (TL), which is assumed to reflect the accumulated burden of inflammation and oxidative stress occurring during the life course. We specifically aimed to address whether childhood constitutes a sensitive period and how much of the relation between stressful life events and TL is mediated through somatic and mental health, lifestyle, and markers of low-grade inflammation. A cohort of Danish men born in 1953 has been followed since birth in the Metropolit Cohort. These men underwent a health examination including blood sampling in 2010 and a subset of 324 also had a quantitative PCR-based measurement of TL. The relation between stressful life events and TL was analysed using structural equation modelling, which also provided an estimate of the proportion of the total effect mediated by somatic and mental health (cardiovascular disease, body mass and depressive mood), lifestyle factors, and low grade inflammation (C-reactive protein (CRP), interleukin (IL)-6 and IL-10). Total number of stressful events experienced during the life course was not associated with TL. In terms of sensitive periods, we found that number of stressful events in childhood was associated with shorter TL (betaper number stressful events in childhood=-0.02(SE=-0.02); P=0.05). This relation was particularly strong for being placed away from home (beta=-0.16; P<0.000). Thirty percent of the total effect of stressful events in childhood on TL was mediated by the included variables, with the largest proportion being mediated through depressive mood (16%) and CRP (9%). This study suggests that stressful events in childhood are associated with shorter TL in middle-aged men and that part of this relation is explained by depressive mood and low grade inflammation. PMID- 27470229 TI - High avidity HSV-1 antibodies correlate with absence of amnestic Mild Cognitive Impairment conversion to Alzheimer's disease. AB - Amnestic Mild Cognitive Impairment (aMCI) is an alteration in cognitive abilities that can progress to Alzheimer's disease (AD), a condition in which herpes simplex type 1 (HSV-1) infection might play a pathogenetic role. Prognostic indexes capable of predicting aMCI conversion to AD are only partially understood. The objective of the present work is to verify whether HSV-1 immune responses is involved in conversion of aMCI to AD and correlate with grey matter brain morphometry. Two homogeneous groups of individuals who did or did not convert to AD over a 24-months period were selected after retrospective analysis of a cohort of patients with a diagnosis of aMCI. The selection of subjects was based on: a) clinical follow-up; b) neurocognitive evaluation at baseline and after 24months; c) availability of serum and DNA samples at baseline. 36 aMCI individuals, 21 of whom did (aMCI-converters) and 15 of whom did not (aMCI-non converters) convert to AD, were included in the study. HSV-1 antibody (Ab) titers, avidity index and APOE genotyping were performed in all the enrolled individuals at baseline. Brain magnetic resonance imaging (MRI) by 1.5T scanner results at baseline were available as well in most (29/36) of these individuals. HSV-1-specific Ab titers were increased at baseline in aMCI-non-converters, and the avidity of these Ab was significantly higher in aMCI-non-converter compared to aMCI-converter (p=0.0018). Receiver operating characteristics analysis showed that HSV-1 avidity had a predictive value in distinguishing between aMCI-non converters and aMCI-converters (p<0.0001). Notably, a positive correlation was detected as well between HSV-1 antibody titers and MRI-evaluated cortical volumes in the left hippocampus and amigdala (pcorr<0.05). In conclusion, stronger HSV-1 specific humoral responses associate with protection against AD conversion and better-preserved cortical volumes. These results reinforce the hypothesis for a role for HSV-1 in the pathogenesis of AD. PMID- 27470230 TI - Non-opioid anesthetic drug abuse among anesthesia care providers: a narrative review. AB - PURPOSE: The objective of this narrative review is to provide an overview of the problem of non-opioid anesthetic drug abuse among anesthesia care providers (ACPs) and to describe current approaches to screening, therapy, and rehabilitation of ACPs suffering from non-opioid anesthetic drug abuse. SOURCE: We first performed a search of all literature available on PubMed prior to April 11, 2016. The search was limited to articles published in Spanish and English, and the following key words were used: anesthesiology, anesthesia personnel, AND substance-related disorders. We also searched Ovid MEDLINE(r) databases from 1946 April 11, 2016 using the following search terms: anesthesiology OR anesthesia, OR nurse anesthetist OR anesthesia care provider OR perioperative nursing AND substance-related disorders. PRINCIPAL FINDINGS: Despite an increased awareness of drug abuse among ACPs and improvements in preventive measures, the problem of non-opioid anesthetic drug abuse remains significant. While opioids are the most commonly abused anesthesia medications among ACPs, the abuse of non-opioid anesthetics is a significant cause of morbidity, mortality, and professional demise. CONCLUSION: Early detection, effective therapy, and long-term follow-up help ACPs cope more effectively with the problem and, when possible, resume their professional activities. There is insufficient evidence to determine the ability of ACPs to return safely to anesthesia practice after rehabilitation, though awareness of the issue and ongoing treatment are necessary to minimize patient risk from potentially related clinical errors. PMID- 27470231 TI - Failure of the air-Q((r)) laryngeal airway to facilitate exchange with the Arndt Airway Exchange Catheter. PMID- 27470233 TI - Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial. AB - PURPOSE: Postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. The pathophysiology of POCD remains elusive, but previous work showed that intravenous lidocaine may be protective against POCD, possibly by modulating cerebral inflammation. We hypothesized that intravenous lidocaine would attenuate the cerebral inflammatory response to cardiopulmonary bypass (CPB) by reducing the transcerebral activation gradients of platelets, leukocytes, and/or platelet-leukocyte conjugates. METHODS: We studied 202 patients undergoing cardiac surgery with CPB in this prospective randomized double-blinded placebo-controlled trial. Subjects were randomized to receive either intravenous lidocaine (bolus + 48-hr infusion) or placebo (identical infusion volume and duration). Paired jugular venous and radial arterial blood samples were drawn at several time points and analyzed by fluorescence-activated cell sorting to identify activated platelets and platelet-leukocyte conjugates. Transcerebral activation gradients were calculated by subtracting arterial values from venous values and were compared between groups using repeated measures regression models with covariate adjustment for age, sex, surgery type, and CPB duration. RESULTS: Beginning after aortic cross-clamp release and peaking ten minutes after the termination of CPB, the mean (SD) transcerebral activation gradient of platelet-monocyte conjugates decreased in lidocaine-treated vs placebo-treated patients [-1.84 (11.47) mean linear fluorescence intensity (MLFI) vs 1.46 (13.88) MLFI, respectively; mean difference, -4.08 MLFI; 95% confidence interval, -7.86 to -0.29; P = 0.03). No difference was seen at any time point for activated platelets or for platelet-neutrophil conjugates. CONCLUSION: While lidocaine did not affect the systemic or transcerebral activation of platelets or leukocytes, we did observe a reduction in the transcerebral activation of platelet-monocyte conjugates after aortic cross-clamp release. This may be a manifestation of reduced cerebral inflammation during cardiopulmonary bypass in response to treatment with lidocaine. This trial was registered at ClinicalTrials.gov (NCT00938964). PMID- 27470232 TI - A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients. AB - PURPOSE: Inhaled milrinone (iMil) has been used for the treatment of pulmonary hypertension (PH) but its efficacy, safety, and prophylactic effects in facilitating separation from cardiopulmonary bypass (CPB) and preventing right ventricular (RV) dysfunction have not yet been evaluated in a clinical trial. The purpose of this study was to investigate if iMil administered before CPB would be superior to placebo in facilitating separation from CPB. METHODS: High-risk cardiac surgical patients with PH were randomized to receive iMil or placebo after the induction of anesthesia and before CPB. Hemodynamic parameters and RV function were evaluated by means of pulmonary artery catheterization and transesophageal echocardiography. The groups were compared for the primary outcome of the level of difficulty in weaning from CPB. Among the secondary outcomes examined were the reduction in the severity of PH, the incidence of RV failure, and mortality. RESULTS: Of the 124 patients randomized, the mean (standard deviation [SD]) EuroSCORE II was 8.0 (2.6), and the baseline mean (SD) systolic pulmonary artery pressure (SPAP) was 53 (9) mmHg. The use of iMil was associated with increases in cardiac output (P = 0.03) and a reduction in SPAP (P = 0.04) with no systemic hypotension. Nevertheless, there was no difference in the combined incidence of difficult or complex separation from CPB between the iMil and control groups (30% vs 28%, respectively; absolute difference, 2%; 95% confidence interval [CI], -14 to 18; P = 0.78). There was also no difference in RV failure between the iMil and control groups (15% vs 14%, respectively; difference, 1%; 95% CI, -13 to 12; P = 0.94). Mortality was increased in patients with RV failure vs those without (22% vs 2%, respectively; P < 0.001). CONCLUSION: In high-risk cardiac surgery patients with PH, the prophylactic use of iMil was associated with favourable hemodynamic effects that did not translate into improvement of clinically relevant endpoints. This trial was registered at ClinicalTrials.gov; identifier: NCT00819377. PMID- 27470235 TI - Newer isn't always better: comparative effectiveness of sevoflurane and isoflurane in cardiac surgery. PMID- 27470236 TI - Focal brachial enhancement deficit: a normal anatomic variant? AB - OBJECTIVE: To identify the incidence of brachialis enhancement deficits (BEDs) on contrast-enhanced elbow MRIs and determine if there is an association between the presence of BEDs and presenting symptoms, other imaging findings, or patient positioning. MATERIALS AND METHODS: Elbow MRIs from 138 patients (64 males, mean age 45.3 years) were reviewed. The presence, size, and degree of enhancement of BEDs as well as degree of elbow flexion, relative degree of forearm rotation, and additional finding of pathology on the MRI were recorded. RESULTS: BEDs were found in 54 % (75/138) of contrast-enhanced elbow MRIs. No statistically significant difference was seen between age, gender, presenting symptoms and the presence of BEDs. The BEDs varied considerably in size and degree of diminished enhancement compared to adjacent muscle. There was a very significant correlation between degree of elbow flexion and presence of BEDs (p < 0.0001) and a significant inverse correlation between cross-sectional size of BEDs and degree of flexion (p < 0.01). There was no significant correlation between BED enhancement difference and degree of flexion and no significant correlation between degree of forearm rotation and cross-sectional area or enhancement difference of the BEDs. No correlation was found between the presence of BEDs and other pathology present on the MRI. CONCLUSION: BEDs are a common, likely asymptomatic phenomenon seen on post contrast elbow MRIs. The etiology of BEDs is uncertain, but they may represent a vascular phenomenon related to elbow flexion causing diminished enhancement related to brachialis compression. PMID- 27470237 TI - The stigma of mental disorders: A millennia-long history of social exclusion and prejudices. PMID- 27470238 TI - 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. AB - It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure. PMID- 27470241 TI - Reduced Efficacy of Praziquantel Against Schistosoma mansoni Is Associated With Multiple Rounds of Mass Drug Administration. AB - BACKGROUND: Mass drug administration (MDA) with praziquantel is the cornerstone of schistosomiasis control in sub-Saharan Africa. The effectiveness of this strategy is dependent on the continued high efficacy of praziquantel; however, drug efficacy is rarely monitored using appropriate statistical approaches that can detect early signs of wane. METHODS: We conducted a repeated cross-sectional study, examining children infected with Schistosoma mansoni from 6 schools in Uganda that had previously received between 1 and 9 rounds of MDA with praziquantel. We collected up to 12 S. mansoni egg counts from 414 children aged 6-12 years before and 25-27 days after treatment with praziquantel. We estimated individual patient egg reduction rates (ERRs) using a statistical model to explore the influence of covariates, including the number of prior MDA rounds. RESULTS: The average ERR among children within schools that had received 8 or 9 previous rounds of MDA (95% Bayesian credible interval [BCI], 88.23%-93.64%) was statistically significantly lower than the average in schools that had received 5 rounds (95% BCI, 96.13%-99.08%) or 1 round (95% BCI, 95.51%-98.96%) of MDA. We estimate that 5.11%, 4.55%, and 16.42% of children from schools that had received 1, 5, and 8-9 rounds of MDA, respectively, had ERRs below the 90% threshold of optimal praziquantel efficacy set by the World Health Organization. CONCLUSIONS: The reduced efficacy of praziquantel in schools with a higher exposure to MDA may pose a threat to the effectiveness of schistosomiasis control programs. We call for the efficacy of anthelmintic drugs used in MDA to be closely monitored. PMID- 27470242 TI - More Furious Than Ever: Escherichia coli-Acquired Co-resistance Toward Colistin and Carbapenems. PMID- 27470239 TI - Early Height and Weight Changes in Children Using Cotrimoxazole Prophylaxis With Antiretroviral Therapy. AB - BACKGROUND: The growth benefits of cotrimoxazole during early antiretroviral therapy (ART) are not well characterized. METHODS: Individuals enrolled in the Therapeutics Research, Education, and AIDS Training in Asia Pediatric HIV Observational Database were included if they started ART at ages 1 month-14 years and had both height and weight measurements available at ART initiation (baseline). Generalized estimating equations were used to identify factors associated with change in height-for-age z-score (HAZ), follow-up HAZ >= -2, change in weight-for-age z-score (WAZ), and follow-up WAZ >= -2. RESULTS: A total of 3217 children were eligible for analysis. The adjusted mean change in HAZ among cotrimoxazole and non-cotrimoxazole users did not differ significantly over the first 24 months of ART. In children who were stunted (HAZ < -2) at baseline, cotrimoxazole use was not associated with a follow-up HAZ >= -2. The adjusted mean change in WAZ among children with a baseline CD4 percentage (CD4%) >25% became significantly different between cotrimoxazole and non-cotrimoxazole users after 6 months of ART and remained significant after 24 months (overall P < .01). Similar changes in WAZ were observed in those with a baseline CD4% between 10% and 24% (overall P < .01). Cotrimoxazole use was not associated with a significant difference in follow-up WAZ in children with a baseline CD4% <10%. In those underweight (WAZ < -2) at baseline, cotrimoxazole use was associated with a follow-up WAZ >= -2 (adjusted odds ratio, 1.70 vs not using cotrimoxazole [95% confidence interval, 1.28-2.25], P < .01). This association was driven by children with a baseline CD4% >=10%. CONCLUSIONS: Cotrimoxazole use is associated with benefits to WAZ but not HAZ during early ART in Asian children. PMID- 27470244 TI - Long-Lasting Persistence of Zika Virus in Semen. PMID- 27470243 TI - Human Leukocyte Antigen-G: A Promising Prognostic Marker of Disease Progression to Improve the Control of Human African Trypanosomiasis. AB - BACKGROUND: Human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense can be diagnosed in the early hemolymphatic stage (stage 1 [S1]) or meningoencephalitic stage (stage 2 [S2]). Importantly, individuals harbouring high and specific antibody responses to Tbg antigens but negative parasitology are also diagnosed in the field (seropositive [SERO]). Whereas some develop the disease in the months following their initial diagnosis (SERO/HAT), others remain parasitologically negative for long periods (SERO) and are apparently able to control infection. Human leucocyte antigen (HLA)-G, an immunosuppressive molecule, could play a critical role in this variability of progression between infection and disease. METHODS: Soluble HLA-G (sHLA-G) was measured in plasma for patients in the SERO (n = 65), SERO/HAT (n = 14), or HAT (n = 268) group and in cerebrospinal fluid for patients in S1 (n = 55), early S2 (n = 93), or late S2 (n = 110). Associations between these different statuses and the soluble level or genetic polymorphisms of HLA-G were explored. RESULTS: Plasma sHLA-G levels were significantly higher in HAT (P = 6 * 10-7) and SERO/HAT (P = .007) than SERO patients. No difference was observed between the SERO/HAT and HAT groups. Within the HAT group, specific haplotypes (HG010102 and HG0103) displayed increased frequencies in S1 (P = .013) and late S2 (P = .036), respectively. CONCLUSIONS: These results strongly suggest the involvement of HLA-G in HAT disease progression. Importantly, high plasma sHLA-G levels in SERO patients could be predictive of subsequent disease development and could represent a serological marker to help guide therapeutic decision making. Further studies are necessary to assess the predictive nature of HLA-G and to estimate both sensitivity and specificity. PMID- 27470245 TI - Genotoxicity of quinolone antibiotics in chlorination disinfection treatment: formation and QSAR simulation. AB - Lots of unexpected disinfection by-products were formed during the chlorination disinfection of contaminated water bodies, leading to a potential threat to human health and ecological safety. In this study, SOS/umu assay was used to trace the genotoxicity variation of 20 quinolone compounds during the chlorination disinfection. Furthermore, two- and three-dimensional quantitative structure activity relationship models were developed based on the electronic and hydrophobic properties of the quinolones, which were used to quantify the impact of the different structural features of the compounds on their genotoxicity variation. The results revealed that quinolones bearing hydrophilic substituents with less H-bond donors and negative charge at the 1-position of the quinolone ring exhibited a positive correlation with genotoxicity elevation. More notably, the chlorination of quinolones in both ultrapure water and secondary effluent matrices provided comparable levels of genotoxicity, indicating that our research could potentially be used to evaluate the environmental risk of quinolone antibiotics in chlorination disinfection treatment. PMID- 27470246 TI - Effect of metal ions and petrochemicals on bioremediation of chlorpyrifos in aerobic sequencing batch bioreactor (ASBR). AB - Application of chlorpyrifos (CP) has increased its environmental concentration. Increasing CP concentration has increased chances of adverse health effects. Its removal from environment has attained researcher's attention. CP degrading bacterial strains were isolated from wastewater and agricultural soil. Finally, selected five bacterial strains were identified using 16S rRNA nucleotide sequence analysis as Pseudomonas kilonensis SRK1, Serratia marcescens SRK2, Bacillus pumilus SRK4, Achromobacter xylosoxidans SRK5, and Klebsiella sp. T13. Interaction studies among bacterial strains demonstrated possibility for development of five membered bacterial consortium. Biodegradation potential of bacterial consortium was investigated in the presence of petrochemicals and trace metals. About 98 % CP removal was observed in sequencing batch reactors at inoculum level, 10 %; pH, 7; CP concentration, 400 mgL-1, and HRT, 48 h. Experimental data has shown an excellent fit to first order growth model. Among all petrochemicals only toluene (in low concentration) has stimulatory effect on biodegradation of CP. Addition of petrochemicals (benzene, toluene, and xylene) in high concentration (100 mg L-1) inhibited bacterial activity and decreased CP removal. At low concentration i.e., 1 mg L-1 of inorganic contaminants (Cu, Hg, and Zn) >96 % degradation was observed. Addition of Cu(II) in low concentration has stimulated CP removal efficiency. Hg(II) in all concentrations has strongly inhibited biodegradation rate except at 1 mgL-1. In simulated pesticide, wastewater CP removal efficiency decreased to 77.5 %. Outcomes of study showed that both type and concentration of petrochemicals and trace metals influenced biodegradation of CP. PMID- 27470248 TI - "LOVE TO HATE" pesticides: felicity or curse for the soil microbial community? An FP7 IAPP Marie Curie project aiming to establish tools for the assessment of the mechanisms controlling the interactions of pesticides with soil microorganisms. AB - Pesticides end up in soil where they interact with soil microorganisms in various ways. On the Yin Side of the interaction, pesticides could exert toxicity on soil microorganisms, while on the Yang side of interaction, pesticides could be used as energy source by a fraction of the soil microbial community. The LOVE TO HATE project is an IAPP Marie Curie project which aims to study these complex interactions of pesticides with soil microorganisms and provide novel tools which will be useful both for pesticide regulatory purposes and agricultural use. On the Yin side of the interactions, a new regulatory scheme for assessing the soil microbial toxicity of pesticides will be proposed based on the use of advanced standardized tools and a well-defined experimental tiered scheme. On the Yang side of the interactions, advanced molecular tools like amplicon sequencing and functional metagenomics will be applied to define microbes that are involved in the rapid transformation of pesticides in soils and isolate novel pesticide biocatalysts. In addition, a functional microarray has been designed to estimate the biodegradation genetic potential of the microbial community of agricultural soils for a range of pesticide groups. PMID- 27470250 TI - Echo color Doppler ultrasound: a valuable diagnostic tool in the assessment of arteriovenous fistula in hemodialysis patients. AB - A functioning vascular access is a critical requirement to improve the quality of life in hemodialysis patients, so monitoring and surveillance of vascular access play key roles in identifying all dysfunctions and reducing the huge economic cost as well as adequacy of dialysis.In our five-year experience, a study protocol has been used and improved with the help of ultrasonography.Doppler ultrasound is an excellent and sensitive modality for hemodialysis access evaluation, one of techniques employed for arteriovenous fistulae (AVF) study, not only as a preoperative tool, but also in post-operative monitoring of AVF maturation. In addition, the current guidelines recommend AVF surveillance by access blood flow measurement and the correction of hemodynamic stenosis in order to prolong access survival. Doppler ultrasound is readily available, directly used by nephrologists, non-invasive, safe, inexpensive, reproducible, although it requires more clinical skill and time to perform and proper equipment. Ultrasonography imaging can substantially reduce the number of subsequent invasive angiographic procedures. In our opinion, Doppler ultrasound should have a crucial place in the interdisciplinary cooperation in AVF monitoring and it should be included as part of an integrated vascular access management program. PMID- 27470247 TI - Vitellogenin and vitellogenin receptor gene expression and 20-hydroxyecdysone concentration in Macrobrachium rosenbergii exposed to chlordecone. AB - Chlordecone is a persistent organochlorine pesticide widely used in Guadeloupe (French West Indies) to control the banana weevil Cosmopolites sordidus. Although it was previously highlighted that chlordecone may affect the reproduction and growth of vertebrate species, little information is available on the chlordecone effects in invertebrates. The present study investigated the effects of chlordecone on a hormone and a protein having key roles in reproduction and growth of the decapod crustacean Macrobrachium rosenbergii, by measuring the 20 hydroxyecdysone concentration, vitellogenin, and vitellogenin receptor gene expression, as well as the bioconcentration of chlordecone in exposed prawns. First, the results revealed that chlordecone was accumulated in M. rosenbergii. Then, it was found that Vg and VgR gene expression were increased in male and female M. rosenbergii exposed to chlordecone for 90 and 240 days, while the 20 hydroxyecdysone concentrations were decreased. This work suggests that chlordecone accumulates in prawn tissues and could affect key molecules involved in the reproduction and the growth of the invertebrate M. rosenbergii. However, many questions remain unresolved regarding the impacts of chlordecone on growth and reproduction and the signaling pathways responsible for these effects, as well as the potential role of confounding factors present in in situ studies. PMID- 27470249 TI - Combined remediation of pyrene-contaminated soil with a coupled system of persulfate oxidation and phytoremediation with ryegrass. AB - The in situ chemical oxidation technology (ISCO) and phytoremediation for PAHs have been studied respectively, but few focus on the feasibility of combining persulfate with ryegrass. This literature revealed the effect of persulfate oxidation on the growth of ryegrass and the removal ratios of pyrene in the couple system of persulfate oxidation and phytoremediation. The results demonstrated that half of pyrene in test soil was oxidized by persulfate in 7 days and then the residual pyrene concentration was decreased to a lower level by ryegrass in the following 2 months in oxidation treatment and drip washing and plants (OWP) and oxidation treatment and drip washing and plants and fertilization (OWFP) treatment. Ryegrass could grow well after persulfate oxidation with the oxidized soil washed by water. Ryegrass in OWP and OWFP treatments had higher ratios of overground and underground biomass. However, the seeds of ryegrass cannot germinate when drip washing was omitted. Pyrene together with residual persulfate changed soil enzyme activities. Drip washing and the growth of ryegrass made soil enzyme activities tend to returned to normal levels. Persulfate oxidation and phytoremediation were compatible to make contributions to the dissipation of pyrene. Persulfate oxidation activated by heat had higher removal efficiency of PAHs and phytoremediation could further decrease the pyrene concentration in spiked soil. PMID- 27470252 TI - The risk of bleeding with tunneled dialysis catheter placement. AB - PURPOSE: The purpose of this study was to evaluate the risk of bleeding associated with tunneled dialysis catheter (TDC) placement in a large population of hemodialysis patients who were either anticoagulated or were taking antithrombotic medications. METHODS: Medical records obtained over a two-year period were queried in order to select two groups of study cases. The first was a Med group (n = 458), cases which had a TDC placed while taking the antithrombotic medications (warfarin, clopidogrel or acetylsalicylic acid [ASA]) which were not discontinued or held. The second was a Declot Failure (DF) group (n = 941) and consisted of cases in which a TDC had been placed immediately following a failed arteriovenous access thrombectomy procedure in which they had been anticoagulated using unfractionated heparin. The results obtained in these two groups were compared to the incidence of bleeding observed in a cohort of 6555 TDC placements that had been performed previously referred to as the Control group. RESULTS: The incidence of bleeding in the Control group was 0.46%. The incidence of bleeding in the DF group was 0.44% and in the Med group was 0.36%. No patient had bleeding that required transfusion, hospitalization, or catheter removal. CONCLUSIONS: Based upon these data, it seems reasonable to classify the TDC placement procedure as having a very low risk of bleeding and to not require preprocedure laboratory testing. The value of suspending antithrombotic medications prior to TDC placement cannot be supported. PMID- 27470251 TI - The association of mineral metabolism with vascular access patency. AB - BACKGROUND: Declining kidney function leads to progressively dysregulated mineral homeostasis and contributes to vascular calcification and a pro-inflammatory milieu, both of which play a critical role in loss of dialysis vascular access patency. We designed this study to examine the relationship between markers of bone and mineral metabolism, vitamin D replacement medications, and vascular access outcomes. We hypothesized that higher levels of calcium, phosphorous, parathyroid hormone (PTH), and albumin are independently associated with vascular access patency and that vitamin D supplementation is associated with lower risk of access failure. METHODOLOGY: We abstracted data on 204 consecutive patients referred for angiographic evaluation of their permanent arteriovenous access over a 25-month period. We followed patients from the time of access salvage until subsequent referral for access failure. RESULTS: The incidence of vascular access failure did not differ by serum phosphorus, PTH, calcium, calcium-phosphorus product or albumin level. Patients receiving any vitamin D replacement therapy, however, had a lower incidence of access failure compared to those receiving no therapy. Those receiving vitamin D3 therapy with or without paricalcitol (Zemplar, Abbot Laboratories, Abbot Park, IL) or calcitriol had an adjusted HR = 0.18 compared to those receiving no vitamin D therapy. CONCLUSIONS: This study suggests a relationship between vitamin D3 usage and better vascular access patency, independent of the effect of vitamin D on PTH. Though this relationship needs more rigorous investigation prior to clinical application, the known differences in the pro- and anti-inflammatory effects of various vitamin D metabolites provide a potential mechanism for these clinical observations. PMID- 27470253 TI - [Distal radius fractures - Evidence is Shlevidence]. PMID- 27470254 TI - [Therapy of a gunshot fracture to the midfoot]. AB - We report on a soldier with a gunshot wound to the midfoot. The diaphysis of MT 5 was pounded to pieces and there was a fracture in the diaphysis of MT 4. After debridement and fixation of MT 4 and MT 5 to MT 2 and 3 via two Kirschner wires we conducted a second look procedure with reconstruction of MT 5 via a piece of iliac crest. After eight weeks of unloading and removal of the last wire we started to put successively heavier weight on the foot. PMID- 27470255 TI - [Determination of training costs associated with surgical procedures during specialization as an orthopaedic and trauma surgeon]. AB - BACKGROUND: Trauma surgery is a discipline in which the training phase for specialization requires a technical and time-intensive learning curve, including the repetitive training of manual skills. This results in prolonged operation times and thus elevated costs. OBJECTIVES: The present study retrospectively examines operations in trauma surgery and orthopaedics at a Munich university hospital according to the required curriculum for further specialist training. The duration of procedures at the various training levels and the resulting costs were compared. MATERIAL AND METHODS: Based on digital surgical records, more than 2,000 surgical interventions were analysed and checked that they fulfilled the practical requirements. Patients with multiple injuries and polytrauma, in addition to irregularly complex cases, were removed from the calculation to ensure high comparability of the individual cases. This yielded more than 1,000+ cases for evaluation. The per-minute cost was calculated to allow for the translation of operating time into costs. RESULTS: The study shows a prolonged duration of operating time of 19.75 % when the procedure was conducted by residents. This prolongation can be split into 37 subgroups according to body region and type of procedure. The prolongation of operation time could be quantified as a specific prolongation per cluster, in addition to cumulative prolongation. By including the operating costs, the operation-dependent training costs are shown as an exact sum of Euros. CONCLUSION: Surgical training of residents costs hospitals the appropriate amounts of time and money and reduces the overall number of procedures performed, justifying special consideration of the financing of training hospitals. PMID- 27470256 TI - Using Simulation in Clinical Education: Psoriasis Area and Severity Index (PASI) Score Assessment. AB - BACKGROUND: The use of simulation-based learning in the medical field has many benefits, including patient safety, health care professional confidence, accelerating diagnostic and therapeutic procedures, meeting the unfulfilled demand for medical personnel, and lowering of medical errors. Developing of interactive learning tools for teaching a simulated clinical case studies program, is highly needed to improve specialist nurses and middle grade health care professionals skills and competency. AIM: Assess the outcomes of a simulated problem-based learning educational activity for scoring the Psoriasis Area and Severity Index (PASI). METHODS: 33 training health care professionals took part in the simulation activity. Before commencing the teaching program, every participant answered a pre-simulation activity confidence and competence levels questionnaire. The simulation activity was carried out in 3 phases: Phase 1: interactive instructor-learner format; Phase 2: Peer-led tutorial; Phase 3: completely independent student led learning adopting a "Problem solving" approach. At the end, every participant completed a questionnaire for post simulation activity confidence and competence levels. RESULTS: The percentage of agreement with the reference PASI score was progressively improving which reflects improvement of the learners' skills after adopting the repetitive learner engagement approach. All participants expressed positive attitudes toward the simulation-based course. The overall mean for the student satisfaction subscale was 4.33/5, whereas the overall mean for the selfconfidence subscale was 4.15/5. CONCLUSION: Simulation-based teaching is an effective way to teach health care professionals. This approach led to improving attitudes, behaviors, interaction, confidence and overall performance leading to potential increased patient safety and better clinical outcomes. The next step is to implement simulation-based training effectively and efficiently in standard teaching. PMID- 27470258 TI - Evaluating the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on perceived ability to work in breast cancer survivors during the first year post-treatment. AB - PURPOSE: To describe the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on breast cancer survivors' (BCS) perceived ability to work post-treatment. METHODS: The sample included 22 chemotherapy-treated (Ctx+) and 22 chemotherapy-naive (Ctx-) female BCS. Data was collected at the following three time points: baseline (post-surgery, pre-chemotherapy), 1 month (1 M) post chemotherapy, and approximately 1 year (1 Y) later. The presence, frequency, number, and severity of CIPN-sx were self-reported using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire (FACT/GOG-Ntx) version 4, a validated 11-item CIPN measure. Perceived ability to work was measured using an item from the Functional Well Being subscale of the FACT/GOG-Ntx. RESULTS: At 1 Y, more than 50 % of Ctx+ reported discomfort, numbness, or tingling in their hands or feet; weakness; or difficulty feeling small objects. The presence, number, and severity of these symptoms were correlated with being less able to work for Ctx+ at 1 M but not 1 Y. Results of a regression analysis using CIPN-sx to predict work ability found that models combining (1) hand numbness and trouble feeling small objects, (2) trouble buttoning buttons and trouble feeling small objects, (3) foot numbness and foot pain, (4) foot numbness and trouble walking, and (5) trouble hearing and hand pain each predicted survivors who were "not at all" able to work at 1 M. CONCLUSIONS: Unresolved CIPN-sx may play a role in challenges working for BCS post-treatment. These findings highlight the need for research to explore the impact that CIPN-sx have on BCS' ability to work, as well as the development of interventions to improve work function in BCS with CIPN-sx. PMID- 27470257 TI - A Comparison of Current Guidelines of Five International Societies on Clostridium difficile Infection Management. AB - Clostridium difficile infection (CDI) is increasingly recognized as an emerging healthcare problem of elevated importance. Prevention and treatment strategies are constantly evolving along with the apperance of new scientific evidence and novel treatment methods, which is well-reflected in the differences among consecutive international guidelines. In this article, we summarize and compare current guidelines of five international medical societies on CDI management, and discuss some of the controversial and currently unresolved aspects which should be addressed by future research. PMID- 27470260 TI - No man's land: information needs and resources of men with metastatic castrate resistant prostate cancer. AB - The majority of men treated for prostate cancer will eventually develop castrate resistant disease (CRPC) with metastases (mCRPC). There are several options for further treatment: chemotherapy, third-line hormone therapy, radium, immunotherapy, and palliation. Current ASCO guidelines for survivors of prostate cancer recommend that an individual's information needs at all stages of disease are assessed and that patients are provided with or referred to the appropriate sources for information and support. Earlier reviews have highlighted the dearth of such services and we wished to see if the situation had improved more recently. Unfortunately, we conclude that there is still a lack of good-quality congruent information easily accessible specifically for men with mCRPC and insufficient data regarding the risks, harms, and benefits of different management plans. More research providing a clear evidence base about treatment consequences using patient reported outcome measures is required. PMID- 27470259 TI - Randomized controlled trial of supportive-expressive group therapy and body-mind spirit intervention for Chinese non-metastatic breast cancer patients. AB - PURPOSE: This study aimed to evaluate the efficacy of supportive-expressive group (SEG) therapy and body-mind-spirit (BMS) intervention on emotional suppression and psychological distress in Chinese breast cancer patients. METHODS: This three arm randomized controlled trial assigned 157 non-metastatic breast cancer patients to BMS, SEG, or social support control group. SEG focused on emotional expression and group support, whereas BMS emphasized relaxation and self-care. All groups received 2-h weekly sessions for 8 weeks. The participants completed measurements on emotional suppression, perceived stress, anxiety, and depression at baseline and three follow-up assessments in 1 year. RESULTS: Using latent growth modeling, overall group difference was found for emotional suppression (chi 2(2) = 8.88, p = 0.012), marginally for perceived stress (chi 2(2) = 5.70, p = 0.058), but not for anxiety and depression (chi 2(2) = 0.19-0.94, p > 0.05). Post-hoc analyses revealed a significant and moderate reduction (Cohen d = 0.55, p = 0.007) in emotional suppression in SEG compared to control group, whereas BMS resulted in a marginally significant and moderate fall (d = 0.46, p = 0.024) in perceived stress. Neither SEG nor BMS significantly improved anxiety and depression (d < 0.20, p > 0.05). CONCLUSIONS: The present results did not demonstrate overall effectiveness for either BMS or SEG therapy in the present sample of Chinese non-metastatic breast cancer patients. The participants appear to derive only modest benefits in terms of their psychological well-being from either intervention. PMID- 27470262 TI - Racial/Ethnic Differences in Emotional Health: A Longitudinal Study of Immigrants' Adolescent Children. AB - First, discrimination was conceptualized as a major source of stress for immigrants' adolescent children. Next, such children's emotional health (indicated by measures of self-esteem and depression) was examined for possible associations with discrimination, psychosocial supports, and social structure; additionally, race/ethnicity's possible moderating role in such associations was evaluated. Data from the first 2 waves of the Children of Immigrants Longitudinal Study (1991-2006) were employed, focusing on 3 groups: Asians, Hispanics, and Whites. Linear regression analyses were used to weigh how discrimination, psychosocial supports, and social structure measured at Wave 1 and Wave 2 related to self-esteem and depression measured at Wave 2. Asians exhibited the highest level of depression and were most likely to perceive discrimination; Asians' self esteem was also low, compared to other groups'. Discrimination and psychosocial supports appeared to operate differentially in explaining the 3 groups' emotional health. PMID- 27470263 TI - Receipt of Recommended Adolescent Vaccines Among Youth With Special Health Care Needs. AB - We examined vaccination coverage among youth with special health care needs (YSHCN) using data from parents of adolescents (11-17 years) who responded to a statewide survey in 2010-2012 (n = 2156). Using a validated screening tool, we identified 29% of adolescents as YSHCN. Weighted multivariable logistic regression assessed associations between special health care needs and receipt of tetanus booster, meningococcal, and human papillomavirus (HPV) vaccines. Only 12% of youth had received all 3 vaccines, with greater coverage for individual vaccines (tetanus booster, 91%; meningococcal, 32%; HPV, 26%). YSHCN had greater odds of HPV vaccination than other youth (33% vs 23%, OR = 1.70, 95% CI = 1.16 2.50) but vaccination coverage was similar ( P >= .05) for other outcomes. In subgroup analyses, HPV vaccination also differed depending on the number and type of special health care needs identified. Findings highlight low levels of vaccination overall and missed opportunities to administer recommended vaccines among all youth, including YSHCN. PMID- 27470264 TI - Transformation of masked benzyl alcohols to o-aminobenzaldehydes through C-H activation: a facile approach to quinazolines. AB - Direct transformation of a directing group to important synthetic units would provide a high atom efficiency synthetic approach in synthetic chemistry. Herein, a convenient protocol for the synthesis of o-aminobenzaldehyde and benzoxazole derivatives from benzyl alcohols has been developed by employing (N,N dimethyl)oxamoyl amide as a directing group in a palladium-catalyzed intramolecular amination. Furthermore, the attached directing center may not only be transformed into the product, but may also be further applied to generate synthetically important quinazoline and quinoline units. Finally, a high atom efficiency one-pot, two-step approach to form quinazolines from benzyl alcohol derivatives has been achieved in good yields, thus demonstrating its high utility. PMID- 27470261 TI - An Evidence-Based Review of Early Intervention and Prevention of Posttraumatic Stress Disorder. AB - We present an evidence-based review of post-trauma interventions used to prevent posttraumatic stress disorder (PTSD). Literature search of PubMed from 1988 to March 2016 using keywords "Early Intervention AND Prevention of PTSD" yielded 142 articles, of which 52 intervention studies and 6 meta-analyses were included in our review. Trauma-focused cognitive behavioral therapy and modified prolonged exposure delivered within weeks of a potentially traumatic event for people showing signs of distress have the most evidence in the treatment of acute stress and early PTSD symptoms, and the prevention of PTSD. Even though several pharmacological agents have been tried, only hydrocortisone prior to high-risk surgery, severe traumatic injury, or during acute sepsis has adequate evidence for effectiveness in the reduction of acute stress symptoms and prevention of PTSD. There is an urgent need to determine the best targets for interventions after trauma to accelerate recovery and prevent PTSD. PMID- 27470266 TI - Factors Influencing Pap Screening Use Among African Immigrant Women. AB - PURPOSE: Papanicolau (Pap) screenings disparities exist for immigrant women in the United States. This study sought to have an understanding of factors influencing Pap screening among sub-Saharan African immigrant women. METHOD: This is a qualitative descriptive study. Women were recruited from the community and by word of mouth following institutional review board approval. Data were gathered through in-depth focus group and demographic questionnaires. Interview sessions were digitally recorded and transcribed verbatim. Transcripts were analyzed for themes. FINDINGS: Twenty-two women aged 24 to 65 years were interviewed. Barriers to screening included low knowledge of screening, cost, cultural beliefs, fear and communication issues. Motivators to improve Pap use include provider's recommendations, enlightenment, and family support. DISCUSSION: Interventions addressing the barriers peculiar to this population may alleviate these barriers and improve Pap screening use in this population. Providers have the opportunity to influence screening attitudes of African-born women by providing awareness and patient-targeted interventions. PMID- 27470265 TI - Nocardioides baekrokdamisoli sp. nov., isolated from soil of a crater lake. AB - A novel actinobacterial strain, B2-12T, was isolated from soil of a crater lake, Baekrokdam, Hallasan, Jeju, Republic of Korea. Cells of strain B2-12T were Gram stain-positive, non-motile, non-spore-forming and coccoid to short-rod-shaped. Phylogenetic analysis, based on 16S rRNA gene sequencing, showed that strain B2 12T belonged to the genus Nocardioides and shared highest sequence similarity with 'Nocardioidespaucivorans' KIS31-44 (98.4 %). The predominant isoprenoid quinone was MK-8(H4). The major fatty acids of strain B2-12T were C16 : 1 (omega7c and/or omega6c), summed feature 9 (iso-C17 : 1omega9c and/or C16 : 0 10 methyl), C17 : 0 10-methyl, iso-C16 : 0, C16 : 0 and C17 : 1omega6c. The diagnostic diamino acid in the cell-wall peptidoglycan was ll-diaminopimelic acid. It contained diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol as the polar lipids. The DNA G+C content was 67.0 mol%. Based on phylogenetic, chemotaxonomic and phenotypic data, 16S rRNA gene sequence comparisons and DNA-DNA hybridization data, strain B2-12T represents a novel species in the genus Nocardioides, for which the name Nocardioidesbaekrokdamisolisp. nov. is proposed. The type strain is B2-12T (=KCTC 39748T=NRRL B-65313T=DSM 100725T). PMID- 27470267 TI - The Impact of Traditional Health Beliefs on the Health Practices of Women From Southern Taiwan. AB - PURPOSE: This study investigated the health beliefs of Taiwanese women in Anping, an urban district in Taiwan that was introduced to Western medicine in the 1860s. DESIGN: A qualitative design with content analysis was used. Fourteen Anping women aged 44 to 84 years were interviewed. RESULTS: The women integrated both traditional and Western biomedicine without any dissonance. Three themes were found: cultural beliefs about medicine-diet homology or the lack of a distinction between medicine and food, reliance on both doctor and deity, and a pattern of health practice based on situational decision making about which health practice to employ. IMPLICATIONS: Understanding health-related viewpoints in Chinese culture and its rationale will help health workers provide culturally competent care. PMID- 27470269 TI - Circularly Polarized Luminescence of Chiral Perylene Diimide Based Enantiomers Triggered by Supramolecular Self-Assembly. AB - Two perylene diimide (PDI) enantiomers (d/l-PDI) incorporating the d/l-alanine moiety have been designed and synthesized. d/l-PDI in chloroform displays bright yellow fluorescence that is redshifted to orange-red when the solvent contains a methanol fraction of 99 vol %. No circular dichroism (CD) or circularly polarized luminescence (CPL) signals were observed for d/l-PDI enantiomers in CHCl3 . Interestingly, the d/l-PDI enantiomers exhibit clear mirror-image Cotton effects and CPL emission in the aggregate state. The optical anisotropy factor (glum ) is as high as 0.02 at fm =99 %, which can be attributed to self-assembly through intermolecular pi-pi interactions in the aggregate state. PMID- 27470268 TI - Ubiquitin Ligase, Fbw7, Targets CDX2 for Degradation via Two Phosphodegron Motifs in a GSK3beta-Dependent Manner. AB - : Drosophila caudal-related homeobox transcription factor 2 (CDX2) drives differentiation of the intestinal epithelium. Loss of CDX2 expression has been reported in several colorectal cancers and cancer cell lines with a potential inverse correlation between CDX2 levels and tumor stage. Ubiquitination of CDX2 leading to its downregulation has been implicated in several studies; however, the E3 ubiquitin ligases involved in CDX2 ubiquitination have largely remained unknown. Here, it is mechanistically determined that the E3 ubiquitin ligase Fbw7 promotes CDX2 ubiquitination and degradation through two phosphodegron motifs present within CDX2 in a GSK3beta-dependent manner leading to its reduced expression and function in colon cancer cells. Fbw7, through its WD domain, interacted with CDX2 both in a heterologous HEK293T cell system and in colon cancer cells. GSK3beta was also present in the same complex as determined by coimmunoprecipitation. Furthermore, overexpression of both Fbw7 or GSK3beta down regulated endogenous CDX2 expression and function; however, both failed to inhibit endogenous CDX2 when either of them were depleted in colon cancer cells. Fbw7-mediated inhibition of CDX2 expression also led to reduced CDX2 transactivation and growth arrest of colon cancer cells. Both GSK3beta and Fbw7 degraded mutant-CDX2 having either of the Cdc4-phosphodegron (CPD) motifs disrupted (CDX2-S60A or CDX-S281A), but were unable to degrade mutant-CDX2 having both CPDs disrupted (CDX2-S60,64,281A). IMPLICATIONS: Taken together, these findings demonstrate that Fbw7 negatively regulates CDX2 expression in a GSK3beta dependent manner through two CPDs present in CDX2. Mol Cancer Res; 14(11); 1097 109. (c)2016 AACR. PMID- 27470270 TI - Real-time Kinematic Positioning of INS Tightly Aided Multi-GNSS Ionospheric Constrained PPP. AB - Real-time Precise Point Positioning (PPP) technique is being widely applied for providing precise positioning services with the significant improvement on satellite precise products accuracy. With the rapid development of the multi constellation Global Navigation Satellite Systems (multi-GNSS), currently, about 80 navigation satellites are operational in orbit. Obviously, PPP performance is dramatically improved with all satellites compared to that of GPS-only PPP. However, the performance of PPP could be evidently affected by unexpected and unavoidable severe observing environments, especially in the dynamic applications. Consequently, we apply Inertial Navigation System (INS) to the Ionospheric-Constrained (IC) PPP to overcome such drawbacks. The INS tightly aided multi-GNSS IC-PPP model can make full use of GNSS and INS observations to improve the PPP performance in terms of accuracy, availability, continuity, and convergence speed. Then, a set of airborne data is analyzed to evaluate and validate the improvement of multi-GNSS and INS on the performance of IC-PPP. PMID- 27470272 TI - Aspergillosis in Domesticated Birds. PMID- 27470271 TI - Correlated evolution of body and fin morphology in the cichlid fishes. AB - Body and fin shapes are chief determinants of swimming performance in fishes. Different configurations of body and fin shapes can suit different locomotor specializations. The success of any configuration is dependent upon the hydrodynamic interactions between body and fins. Despite the importance of body fin interactions for swimming, there are few data indicating whether body and fin configurations evolve in concert, or whether these structures vary independently. The cichlid fishes are a diverse family whose well-studied phylogenetic relationships make them ideal for the study of macroevolution of ecomorphology. This study measured body, and caudal and median fin morphology from radiographs of 131 cichlid genera, using morphometrics and phylogenetic comparative methods to determine whether these traits exhibit correlated evolution. Partial least squares canonical analysis revealed that body, caudal fin, dorsal fin, and anal fin shapes all exhibited strong correlated evolution consistent with locomotor ecomorphology. Major patterns included the evolution of deep body profiles with long fins, suggestive of maneuvering specialization; and the evolution of narrow, elongate caudal peduncles with concave tails, a combination that characterizes economical cruisers. These results demonstrate that body shape evolution does not occur independently of other traits, but among a suite of other morphological changes that augment locomotor specialization. PMID- 27470273 TI - On the Pathology of Some Specific Granulomata in Horses and Cattle. PMID- 27470274 TI - Lipid based delivery and immuno-stimulatory systems: Master tools to combat leishmaniasis. AB - Disease management of leishmaniasis is appalling due to lack of a human vaccine and the toxicity and resistance concerns with limited therapeutic drugs. The challenges in development of a safe vaccine for generation and maintenance of robust antileishmanial protective immunity through a human administrable route of immunization can be addressed through immunomodulation and targeted delivery. The versatility of lipid based particulate system for deliberate delivery of diverse range of molecules including immunomodulators, antigens and drugs have essentially found pivotal role in design of proficient vaccination and therapeutic strategies against leishmaniasis. The prospects of lipid based preventive and curative formulations for leishmaniasis have been highlighted in this review. PMID- 27470275 TI - Structural and Kinetic Characteristics of 1,4-Dioxane-Degrading Bacterial Consortia Containing the Phylum TM7. AB - 1,4-Dioxane-degrading bacterial consortia were enriched from forest soil (FS) and activated sludge (AS) using a defined medium containing 1,4-dioxane as the sole carbon source. These two enrichments cultures appeared to have inducible tetrahydrofuran/dioxane and propane degradation enzymes. According to qPCR results on the 16S rRNA and soluble di-iron monooxygenase genes, the relative abundances of 1,4-dioxane-degrading bacteria to total bacteria in FS and AS were 29.4% and 57.8%, respectively. For FS, the cell growth yields (Y), maximum specific degradation rate (Vmax), and half-saturation concentration (Km) were 0.58 mg-protein/mg-dioxane, 0.037 mg-dioxane/mg-protein?h, and 93.9 mg/l, respectively. For AS, Y, Vmax, and Km were 0.34 mg-protein/mg-dioxane, 0.078 mg dioxane/mg-protein?h, and 181.3 mg/l, respectively. These kinetics data of FS and AS were similar to previously reported values. Based on bacterial community analysis on 16S rRNA gene sequences of the two enrichment cultures, the FS consortium was identified to contain 38.3% of Mycobacterium and 10.6% of Afipia, similar to previously reported literature. Meanwhile, 49.5% of the AS consortium belonged to the candidate division TM7, which has never been reported to be involved in 1,4-dioxane biodegradation. However, recent studies suggested that TM7 bacteria were associated with degradation of non-biodegradable and hazardous materials. Therefore, our results showed that previously unknown 1,4-dioxane degrading bacteria might play an important role in enriched AS. Although the metabolic capability and ecophysiological significance of the predominant TM7 bacteria in AS enrichment culture remain unclear, our data reveal hidden characteristics of the TM7 phylum and provide a perspective for studying this previously uncultured phylotype. PMID- 27470276 TI - Immunochromatographic Strip Assay for Detection of Cronobacter sakazakii in Pure Culture. AB - Cronobacter sakazakii (C. sakazakii) is a foodborne pathogen, posing a high risk of disease to infants and immunocompromised individuals. In order to develop a quick, easy, and sensitive assay for detecting C. sakazakii, a rabbit anti-C. sakazakii immunoglobulin G (IgG) was developed using sonicated cell protein from C. sakazakii. The developed anti-C. sakazakii (IgG) was of good quality and purity, as well as species-specific. The developed rabbit anti-C. sakazakii IgG was attached to the surface of a sulforhodamine B-encapsulated liposome to form an immunoliposome. A test strip was then prepared by coating goat anti-rabbit IgG onto the control line and rabbit anti-C. sakazakii IgG onto the test line, respectively, of a plastic-backed nitrocellulose membrane. A purple color signal both on the test line and the control line indicated the presence of C. sakazakii in the sample, whereas purple color only on the control line indicated the absence of C. sakazakii in the sample. This immunochromatographic strip assay could produce results in 15 min with a limit of detection of 107 CFU/ml in C. sakazakii culture. The immunochromatographic strip assay also showed very good specificity without cross-reactivity with other tested Cronobacter species. Based on these results, the developed immunochromatographic strip assay is efficient for the detection of C. sakazakii and has high potential for on-site detection. PMID- 27470278 TI - The Anti-Adipogenic Activity of a New Cultivar, Pleurotus eryngii var. ferulae 'Beesan No. 2', through Down-Regulation of PPAR gamma and C/EBP alpha in 3T3-L1 Cells. AB - Adipogenesis is one of the cellular processes and a highly controlled program. Nowadays, inhibition of adipogenesis has received attention as an effective way to regulate obesity. In the current study, we investigated the inhibition effect of a chloroform extract of Pleurotus eryngii var. ferulae 'Beesan No. 2' (CEBT) on adipogenesis in 3T3-L1 murine preadipocytes. Pleurotus eryngii var. ferulae is one of many varieties of King oyster mushroom and has been reported to have various biological activities, including antitumor and anti-inflammation effects. Biological activities of 'Beesan No. 2', a new cultivar of Pleurotus eryngii var. ferulae, have not yet been reported. In this study, we found that CEBT suppressed adipogenesis in 3T3-L1 cells through inhibition of key adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha. Additionally, CEBT reduced the expression of the IRS/PI3K/Akt signaling pathway and its downstream factors, including mammalian target of rapamycin and p70S6 kinase, which stimulate adipogenesis. Furthermore, beta-catenin, a suppressor of adipogenesis, was increased in CEBT treated cells. These results indicate that Pleurotus eryngii var. ferulae 'Beesan No. 2' effectively inhibited adipogenesis, so this mushroom has potential as an anti-obesity food and drug. PMID- 27470277 TI - Acceptor Specificity of Amylosucrase from Deinococcus radiopugnans and Its Application for Synthesis of Rutin Derivatives. AB - The transglycosylation activity of amylosucrase (ASase) has received significant attention owing to its use of an inexpensive donor, sucrose, and broad acceptor specificity, including glycone and aglycone compounds. The transglycosylation reaction of recombinant ASase from Deinococcus radiopugnans (DRpAS) was investigated using various phenolic compounds, and quercetin-3-O-rutinoside (rutin) was found to be the most suitable acceptor molecule used by DRpAS. Two amino acid residues in DRpAS variants (DRpAS Q299K and DRpAS Q299R), assumed to be involved in acceptor binding, were constructed by site-directed mutagenesis. Intriguingly, DRpAS Q299K and DRpAS Q299R produced 10-fold and 4-fold higher levels of rutin transglycosylation product than did the wild-type (WT) DRpAS, respectively. According to in silico molecular docking analysis, the lysine residue at position 299 in the mutants enables rutin to more easily position inside the active pocket of the mutant enzyme than in that of the WT, due to conformational changes in loop 4. PMID- 27470279 TI - The Anti-Rotaviral and Anti-Inflammatory Effects of Hyrtios and Haliclona Species. AB - The marine sponges Hyrtios and Haliclona species, both of which are known to produce secondary bioactive metabolites, were used to extract 1304KO-327 and 1304KO-328. Such secondary metabolites are potentially antibacterial, antiviral, anti-inflammatory, antitumoral, antifungal, and antiplasmodial. In the present study, the effects of 1304KO-327 and 1304KO-328 were studied for their clinical and pathological importance. The cytotoxicity of 1304KO-327 and 1304KO-328 was assessed via MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on HT-29, Caco-2, and Raw 264.7 cells. Rotavirus-infected Caco-2 cells were used to prove the antiviral effects of the marine sponge extracts. The test results cogently proved that the virus-inhibiting effects of the sponge extracts improved with extract concentration. Anti-inflammatory effects of the marine sponge extracts were tested on Lipopolysaccharide-treated Raw 264.7 cells. Nitric oxide and cytokine were produced by treatment of the cells with LPS and the inhibiting effects of the sponge extracts on IL-1beta formation were investigated. This study found that the NO production was decreased dose dependently, and IL-1beta formation was significantly reduced by the marine sponge extracts. PMID- 27470280 TI - Extracellular Proteome Profiling of Bacillus pumilus SCU11 Producing Alkaline Protease for Dehairing. AB - Bacillus pumilus is one of the most characterized microorganisms that are used for high-level production of select industrial enzymes. A novel B. pumilus SCU11 strain possessing high alkaline protease activity was obtained in our previous work. The culture supernatant of this strain showed efficient dehairing capability with minimal collagen damage, indicating promising potential applications in the leather industry. In this study, the strain's extracellular proteome was identified by LC-MS/MS-based shotgun proteomic analysis, and their related secretory pathways were characterized by BLAST searches. A total of 513 proteins, including 100 actual secreted and 413 intracellular proteins, were detected in the extracellular proteome. The functions of these secreted proteins were elucidated and four complete secretory systems (Sec, Tat, Com, and ABC transporter) were proposed for B. pumilus. These data provide B. pumilus a comprehensive extracellular proteome profile, which is a valuable theoretical and applicative basis for future genetic modifications and development of industrial enzymes. PMID- 27470281 TI - Proteomic Analysis of Polycyclic Aromatic Hydrocarbons (PAHs) Degradation and Detoxification in Sphingobium chungbukense DJ77. AB - Polycyclic aromatic hydrocarbons (PAHs) are commonly present xenobiotics in natural and contaminated soils. We studied three (phenanthrene, naphthalene, and biphenyl) xenobiotics, catabolism, and associated proteins in Sphingobium chungbukense DJ77 by two-dimensional gel electrophoresis (2-DE) analysis. Comparative analysis of the growth-dependent 2-DE results revealed that the intensity of 10 protein spots changed identically upon exposure to the three xenobiotics. Among the upregulated proteins, five protein spots, which were putative dehydrogenase, dioxygenase, and hydrolase and involved in the catabolic pathway of xenobiotic degradation, were induced. Identification of these major multifunctional proteins allowed us to map the multiple catabolic pathway for phenanthrene, naphthalene, and biphenyl degradation. A part of the initial diverse catabolism was converged into the catechol degradation branch. Detection of intermediates from 2,3-dihydroxy-biphenyl degradation to pyruvate and acetyl CoA production by LC/MS analysis showed that ring-cleavage products of PAHs entered the tricarboxylic acid cycle, and were mineralized in S. chungbukense DJ77. These results suggest that S. chungbukense DJ77 completely degrades a broad range of PAHs via a multiple catabolic pathway. PMID- 27470282 TI - Identification and Characterization of Putative Integron-Like Elements of the Heavy-Metal-Hypertolerant Strains of Pseudomonas spp. AB - Pseudomonas strains isolated from the heavily contaminated Lubin copper mine and Zelazny Most post-flotation waste reservoir in Poland were screened for the presence of integrons. This analysis revealed that two strains carried homologous DNA regions composed of a gene encoding a DNA_BRE_C domain-containing tyrosine recombinase (with no significant sequence similarity to other integrases of integrons) plus a three-component array of putative integron gene cassettes. The predicted gene cassettes encode three putative polypeptides with homology to (i) transmembrane proteins, (ii) GCN5 family acetyltransferases, and (iii) hypothetical proteins of unknown function (homologous proteins are encoded by the gene cassettes of several class 1 integrons). Comparative sequence analyses identified three structural variants of these novel integron-like elements within the sequenced bacterial genomes. Analysis of their distribution revealed that they are found exclusively in strains of the genus Pseudomonas. PMID- 27470283 TI - Insights into the Usage of Nucleobase Triplets and Codon Context Pattern in Five Influenza A Virus Subtypes. AB - Influenza A virus is a single-stranded RNA virus with a genome of negative polarity. Owing to the antigenic diversity and cross concrete shift, an immense number of novel strains have developed astronomically over the years. The present work deals with the codon utilization partialness among five different influenza A viruses isolated from human hosts. All the subtypes showed the homogeneous pattern of nucleotide utilization with a little variation in their utilization frequencies. A lower bias in codon utilization was observed in all the subtypes as reflected by higher magnitudes of an efficacious number of codons. Dinucleotide analysis showed very low CpG utilization and a high predilection of A/T-ending codons. The H5N1 subtype showed noticeable deviation from the rest. Codon pair context analysis showed remarkable depletion of NNC-GNN and NNT-ANN contexts. The findings alluded towards GC-compositional partialness playing a vital role, which is reflected in the consequential positive correlation between the GC contents at different codon positions. Untangling the codon utilization profile would significantly contribute to identifying novel drug targets that will pacify the search for antivirals against this virus. PMID- 27470284 TI - The changes of gene expression profiling between segmental vitiligo, generalized vitiligo and healthy individual. AB - BACKGROUND: Vitiligo is a common acquired depigmentation skin disease characterized by loss or dysfunction of melanocytes within the skin lesion, but its pathologenesis is far from lucid. The gene expression profiling of segmental vitiligo (SV) and generalized vitiligo (GV) need further investigation. OBJECTIVE: To better understanding the common and distinct factors, especially in the view of gene expression profile, which were involved in the diseases development and maintenance of segmental vitiligo (SV) and generalized vitiligo (GV). METHODS: Peripheral bloods were collected from SV, GV and healthy individual (HI), followed by leukocytes separation and total RNA extraction. The high-throughput whole genome expression microarrays were used to assay the gene expression profiles between HI, SV and GV. Bioinformatics tools were employed to annotated the biological function of differently expressed genes. Quantitative PCR assay was used to validate the gene expression of array. RESULTS: Compared to HI, 239 over-expressed genes and 175 down-expressed genes detected in SV, 688 over-expressed genes and 560 down-expressed genes were found in GV, following the criteria of log2 (fold change)>=0.585 and P value<0.05. In these differently expressed genes, 60 over-expressed genes and 60 down-expressed genes had similar tendency in SV and GV. Compared to SV, 223 genes were up regulated and 129 genes were down regulated in GV. In the SV with HI as control, the differently expressed genes were mainly involved in the adaptive immune response, cytokine cytokine receptor interaction, chemokine signaling, focal adhesion and sphingolipid metabolism. The differently expressed genes between GV and HI were mainly involved in the innate immune, autophagy, apoptosis, melanocyte biology, ubiquitin mediated proteolysis and tyrosine metabolism, which was different from SV. While the differently expressed genes between SV and GV were mainly involved in the metabolism pathway of purine, pyrimidine, glycolysis and sphingolipid. CONCLUSIONS: Above results suggested that they not only shared part bio-process and signal pathway, but more important, they utilized different biological mechanism in their pathogenesis and maintenance. Our results provide a comprehensive view on the gene expression profiling change between SV and GV especially in the side of leukocytes, and may facilitate the future study on their molecular mechanism and theraputic targets. PMID- 27470285 TI - Optimizing Transgene Configuration and Protein Fusions to Maximize Dopamine Production for the Gene Therapy of Parkinson's Disease. AB - Pharmacological dopamine replacement therapies provide the most well-established treatments for Parkinson's disease (PD). However, these long-term treatments can lead to motor complications and off-target effects. ProSavin((r)), a lentiviral vector (LV)-based gene therapy approach aimed at restoring local and continuous dopamine production, through delivery of three enzymes in the dopamine biosynthesis pathway, was demonstrated to be safe and well-tolerated in a phase I/II clinical study of patients with advanced PD. Although improvements in motor behaviour were observed, the data indicated that higher levels of dopamine replacement might be required to maximize benefit. We attempted to increase production of dopamine, and its precursor L-Dopa in LV-transduced cells, by optimizing the gene order in the ProSavin expression cassette, and by creating fusions of two or three of the transgenes, using linker sequences. In vitro analysis showed that several gene arrangements provided significantly increased dopamine and/or L-Dopa production compared with ProSavin, and that LV titers and transgene expression were not affected by introducing gene fusions. One vector, equine infectious anemia virus (EIAV)-TCiA, was selected for further characterization and showed significant improvements in dopamine and L-Dopa production compared with ProSavin, in human neuronal cells. Further characterization of EIAV-TCiA demonstrated expression of all three dopamine enzymes in vivo and faithful delivery and integration of the expected gene expression cassette within the genome of target cells, as assessed by Northern and Southern blotting. In conclusion, we have developed a novel LV vector with an increased capacity for L-Dopa and dopamine production compared with the current ProSavin vector. Clinical evaluation of this vector will be performed to assess the benefits in patients with PD. PMID- 27470287 TI - Cytomegalovirus Status and the Outcome of T Cell-Replete Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation. AB - Cytomegalovirus (CMV) serostatus of donor and recipient are frequently used in algorithms of donor selection, whereas the impact of CMV reactivation on transplantation-related mortality, leukemia control, and overall survival (OS) remains controversial. Therefore, we retrospectively studied the impact of latent or active CMV infections on the outcome and occurrence of graft-versus-host disease (GVHD) after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (SCT) in 294 patients during the period from 2004 to 2010. CMV viral load was routinely monitored in plasma using a quantitative PCR. Preemptive antiviral therapy was initiated when the viral load in plasma exceeded a predefined threshold. In a proportional hazards model, a seropositive recipient was significantly associated with increased occurrence of acute GVHD. However the CMV serostatus of both recipient and donor and the presence of active CMV infection was not associated with the occurrence of relapses, chronic GVHD, or OS. We conclude that in the presence of viral load monitoring and preemptive treatment, latent or active CMV infection does not substantially affect the OS after T cell-replete RIC allogeneic SCT. PMID- 27470286 TI - Outcomes after Unrelated Umbilical Cord Blood Transplantation for Children with Osteopetrosis. AB - Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34+ cells infused was 14 * 107/kg and 3.4 * 105/kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor. PMID- 27470288 TI - Clinical Application of the Dried Blood Spot Method in the Measurement of Blood Busulfan Concentration. AB - The dried blood spot (DBS) method, which is a simple technique for blood sample processing involving the placement of a drop of whole blood onto filter paper, has been used recently in clinical pharmacology to determine blood concentrations of various drugs. This study examined the feasibility of the clinical application of the DBS method for individual busulfan dose adjustments. Pharmacokinetic (PK) parameters of blood samples for busulfan measurements determined using the DBS method were compared with those using plasma separation (the conventional method). Blood samples were collected from patients receiving i.v. busulfan as a conditioning regimen before allogeneic hematopoietic stem cell transplantation at Toranomon Hospital, Japan. Samples collected 2, 4, and 6 hours after the start of the first drip infusion were processed by DBS or the conventional method. The area under the blood concentration-time curve (AUC) and other PK parameters were calculated to compare the 2 methods. Divergence of <20% in each parameter was considered acceptable. The divergence range for each parameter was as follows: blood concentration at 2 hours after the start of drip infusion, .6 to 8.2%; at 4 hours, .3 to 10.0%; at 6 hours, .3 to 14.2%; and AUC0-infinity, .0 to 10.3%. None of the PK parameters showed a divergence between the DBS method and the conventional method exceeding 20%, suggesting that both methods are well correlated. The clinical application of blood sample processing with the DBS method in the measurement of blood busulfan concentration may therefore be feasible, but further studies are needed to confirm these findings. PMID- 27470289 TI - Improved Outcome of Refractory/Relapsed Acute Myeloid Leukemia after Post Transplantation Cyclophosphamide-Based Haploidentical Transplantation with Myeloablative Conditioning and Early Prophylactic Granulocyte Colony-Stimulating Factor-Mobilized Donor Lymphocyte Infusions. AB - We carried out post-transplantation cyclophosphamide (PTCy)-based haploidentical peripheral blood stem cell transplantation in 51 patients with refractory/relapsed acute myeloid leukemia not in remission. The first 10 patients received nonmyeloablative conditioning followed by planned granulocyte colony-stimulating factor (G-CSF)-mobilized donor lymphocyte infusions (DLIs) on days 35, 60, and 90. No patient developed graft-versus-host disease (GVHD), but 90% had disease progression between 3 and 6 months. A subsequent 41 patients received myeloablative conditioning (MAC); the first 20 patients did not receive DLIs (MAC group) and the next 21 patients received G-CSF-mobilized DLIs (G-DLI) on days 21, 35, and 60 (MAC-DLI group). The incidence of disease progression and progression-free survival at 18 months were 66% and 25% in the MAC group compared with 21.4% and 61.9% in the MAC-DLI group (P = .01). Chronic GVHD but not acute GVHD was increased in the MAC-DLI group (41.2% versus 11%, P = .05). Natural killer cell alloreactive donor was associated with lower incidence of disease progression in the MAC but not in MAC-DLI group. The only factor favorably influencing disease progression and progression-free survival was administration of G-DLI after myeloablative conditioning. Our study shows that early administration of G-DLI is feasible after PTCy-based haploidentical hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia and might be associated with improved survival after MAC. PMID- 27470291 TI - A content review of cognitive process measures used in pain research within adult populations. AB - BACKGROUND AND OBJECTIVE: Previous research suggests that measures of cognitive process may be confounded by the inclusion of items that also assess cognitive content. The primary aims of this content review were to: (1) identify the domains of cognitive processes assessed by measures used in pain research; and (2) determine if pain-specific cognitive process measures with adequate psychometric properties exist. DATABASES AND DATA TREATMENT: PsychInfo, CINAHL, PsycArticles, MEDLINE, and Academic Search Complete databases were searched to identify the measures of cognitive process used in pain research. Identified measures were double coded and the measure's items were rated as: (1) cognitive content; (2) cognitive process; (3) behavioural/social; and/or (4) emotional coping/responses to pain. RESULTS: A total of 319 scales were identified; of these, 29 were coded as providing an un-confounded assessment of cognitive process, and 12 were pain-specific. The cognitive process domains assessed in these measures are Absorption, Dissociation, Reappraisal, Distraction/Suppression, Acceptance, Rumination, Non-Judgment, and Enhancement. Pain-specific, un-confounded measures were identified for: Dissociation, Reappraisal, Distraction/Suppression, and Acceptance. Psychometric properties of all 319 scales are reported in supplementary material. CONCLUSIONS: To understand the importance of cognitive processes in influencing pain outcomes as well as explaining the efficacy of pain treatments, valid and pain-specific cognitive process measures that are not confounded with non-process domains (e.g., cognitive content) are needed. The findings of this content review suggest that future research focused on developing cognitive process measures is critical in order to advance our understanding of the mechanisms that underlie effective pain treatment. SIGNIFICANCE: Many cognitive process measures used in pain research contain a 'mix' of items that assess cognitive process, cognitive content, and behavioural/emotional responses. Databases searched: PsychInfo, CINAHL, PsycArticles, MEDLINE and Academic Search Complete. This review describes the domains assessed by measures assessing cognitive processes in pain research, as well as the strengths and limitations of these measures. PMID- 27470290 TI - Fludarabine/Busulfan versus Fludarabine/Melphalan Conditioning in Patients Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation for Lymphoma. AB - There is at present little data to guide the choice of conditioning for patients with lymphoma undergoing reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). In this study, we compared the outcomes of patients undergoing RIC SCT who received fludarabine and melphalan (FluMel), the standard RIC regimen used by the Spanish Group of Transplantation, and fludarabine and busulfan (FluBu), the standard RIC regimen used by the Dana-Farber Cancer Institute/Brigham and Women's Hospital. We analyzed 136 patients undergoing RIC SCT for lymphoma with either FluBu (n = 61) or FluMel (n = 75) conditioning between 2007 and 2014. Median follow-up was 36 months. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 13% with FluBu and 36% with FluMel (P = .002). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 3.3% with FluBu and 31% with FluMel (P < .0001). The cumulative incidence of relapse at 1 year was 29% with FluBu and 10% with FluMel (P = .08). The 3-year disease-free survival rate was 47% with FluBu and 36% with FluMel (P = .24), and the 3-year overall survival rate was 62% with FluBu and 48% with FluMel (P = .01). In multivariable analysis, FluMel was associated with a higher risk of acute grades II to IV GVHD (HR, 7.45; 95% CI, 2.30 to 24.17; P = .001) and higher risk of NRM (HR, 4.87; 95% CI, 1.36 to 17.44; P = .015). The type of conditioning was not significantly associated with relapse or disease free survival in multivariable models. However, conditioning regimen was the only factor significantly associated with overall survival: FluMel conditioning was associated with a hazard ratio for death of 2.78 (95% CI, 1.23 to 6.27; P = .014) compared with FluBu. In conclusion, the use of FluBu as conditioning for patients undergoing SCT for lymphoma was associated with a lower risk of acute GVHD and NRM and improved overall survival when compared with FluMel in our retrospective study. These results confirm the differences between these RIC regimens in terms of toxicity and efficacy and support the need for comparative prospective studies. PMID- 27470292 TI - Human norovirus in untreated sewage and effluents from primary, secondary and tertiary treatment processes. AB - Wastewater treatments are considered important means to control the environmental transmission of human norovirus (NoV). Information about NoV concentrations in untreated and treated effluents, their seasonality and typical removal rates achieved by different treatment processes is required to assess the effectiveness of sewage treatment processes in reducing human exposure to NoV. This paper reports on a characterisation of concentrations of NoV (genogroups I and II) in untreated sewage (screened influent) and treated effluents from five full scale wastewater treatment works (WwTW) in England. Results are shown for effluent samples characteristic of primary- (primary settlement, storm tank overflows), secondary- (activated sludge, trickling filters, humus tanks) and tertiary (UV disinfection) treatments. NoV occurrence in untreated sewage varied between years. This variation was consistent with the annual variation of the virus in the community as indicated by outbreak laboratory reports. Significant differences were found between mean NoV concentrations in effluents subject to different levels of treatment. Primary settlement achieved approximately 1 log10 removal for both genogroups. Concentrations of NoV and Escherichia coli in untreated sewage were of the same order of magnitude of those in storm tank overflows. Of the secondary treatments studied, activated sludge was the most effective in removing NoV with mean log10 removals of 3.11 and 2.34 for GI and GII, respectively. The results of this study provide evidence that monitoring of NoV in raw sewage or treated effluents could provide early warning of an elevated risk for NoV and potentially help prevent outbreaks through environmental exposure. They also provide evidence that elimination of stormwater discharges and improvement of the efficiency of activated sludge for NoV removal would be effective for reducing the risk of environmental transmission. PMID- 27470293 TI - Chemical modeling for precipitation from hypersaline hydrofracturing brines. AB - Hypersaline hydrofracturing brines host very high salt concentrations, as high as 120,000-330,000 mg/L total dissolved solids (TDS), corresponding to ionic strengths of 2.1-5.7 mol/kg. This is 4-10 times higher than for ocean water. At such high ionic strengths, the conventional equations for computing activity coefficients no longer apply; and the complex ion-interactive Pitzer model must be invoked. The authors herein have used the Pitzer-based PHREEQC computer program to compute the appropriate activity coefficients when forming such precipitates as BaSO4, CaSO4, MgSO4, SrSO4, CaCO3, SrCO3, and BaCO3 in hydrofracturing waters. The divalent cation activity coefficients (gammaM) were computed in the 0.1 to 0.2 range at 2.1 mol/kg ionic strength, then by 5.7 mol/kg ionic strength, they rose to 0.2 for Ba(2+), 0.6 for Sr(2+), 0.8 for Ca(2+), and 2.1 for Mg(2+). Concurrently, the [Formula: see text] was 0.02-0.03; and [Formula: see text] was 0.01-0.02. While employing these Pitzer-derived activity coefficients, the authors then used the PHREEQC model to characterize precipitation of several of these sulfates and carbonates from actual hydrofracturing waters. Modeled precipitation matched quite well with actual laboratory experiments and full-scale operations. Also, the authors found that SrSO4 effectively co-precipitated radium from hydrofracturing brines, as discerned when monitoring (228)Ra and other beta-emitting species via liquid scintillation; and also when monitoring gamma emissions from (226)Ra. PMID- 27470294 TI - Characterization of circular RNAs landscape in multiple system atrophy brain. AB - Circular RNAs (circRNAs) have been recently identified as a naturally occurring family of widespread and diverse endogenous non-coding RNAs that may regulate gene expression in mammals. They are unusually stable RNA molecules with cell type- or developmental stage-specific expression patterns. However, the role of circRNAs in pathology of complex disease is entirely unknown. Here, we report the specific circular transcriptome in the multiple system atrophy (MSA) brain as determined by RNA sequencing. Five circRNAs, namely IQCK, MAP4K3, EFCAB11, DTNA, and MCTP1, were identified and validated as specifically over-expressed in MSA frontal cortex. The expression levels of linear transcripts were not significantly altered and thus did not follow the pattern of their circular counterparts. Further analysis of expression of five MSA-specific circRNAs revealed their over-expression in the white matter of the MSA cortical tissue. Together, this is the first report describing perturbation of circular transcriptome in alpha-synucleinopathies. PMID- 27470295 TI - Fat grafting for alleviating persistent pain after breast cancer treatment: A randomized controlled trial. AB - BACKGROUND: Persistent pain is a common side effect of breast cancer treatment, affecting 24-52% of women after mastectomy. Recent studies have described analgesic effects of fat grafting in various settings. We aimed to investigate whether fat grafting had an analgesic effect on persistent pain after mastectomy and whether fat grafting had a remodeling effect on the mastectomy scar. METHODS: This study was conducted as a randomized controlled trial. Patients were randomized to either receive fat grafting to the pain-afflicted area around the missing breast or a control group without any intervention. A total of 18 unilaterally mastectomized women with persistent pain >=3 on the numerical rating scale were enrolled. Patients were examined at the baseline and at 3 and 6 months by using the DoloTest((r)), visual analog scale (VAS) pain score, neuropathic pain symptom inventory, and patient and observer scar assessment scale. RESULTS: A total of 15 patients were analyzed (fat grafted n = 8, control n = 7). The average amount of grafted fat was 71 +/- 24.6 mL. Fat grafting showed a significant improvement in the pain as measured on the VAS pain scale (p = 0.001) with an average reduction of 54.9% and as measured on the neuropathic pain symptom inventory (p = 0.002). Furthermore, a significant improvement was observed in health-related quality of life (p = 0.007) and the quality of the scar (p < 0.001). CONCLUSION: This is the first randomized controlled trial evaluating the analgesic effect of fat grafting. Fat grafting is a safe and effective technique for alleviating persistent pain after mastectomy. PMID- 27470297 TI - Determining the geographical origin of Asian longhorn beetle (Anoplophora glabripennis) specimens using stable isotope and trace element analyses. AB - BACKGROUND: An outbreak of EU-quarantine-listed pest Anoplophora glabripennis (Motschulsky) (Coleoptera: Cerambicidae), the Asian longhorn beetle, in Kent (UK) resulted in environmentally and financially costly eradication action being taken. In this study the potential of using multi-element stable isotope or trace element analyses to determine the geographical origin of individual specimens has been investigated. RESULTS: The isotope ratios of A. glabripennis individuals for hydrogen varied within and across five locations. Carbon isotope ratios fell within the expected values for C3 plants (trees using the photosynthetic pathway common for moderate climates). Nitrogen isotope ratios indicated separation of UK laboratory from US (New York, Ohio, Massachusetts) beetles, while sulphur isotope ratios distinguished beetles from New York against the other four locations. Three trace elements (TEs) separated UK laboratory-reared beetles from US beetles (Ohio and New York) with ~ 68% confidence. CONCLUSIONS: Stable isotope and TE analyses show potential to differentiate between newly arrived A. glabripennis individuals and those from previously undetected in-country populations, which would be of immediate practical benefit in making appropriate strategic decisions on surveillance and eradication. Analyses of additional samples from (i) the same populations, (ii) different locations and (iii) a variety of host trees will enhance the overall picture. (c) 2016 Crown copyright. Pest Management Science (c) 2016 Society of Chemical Industry. PMID- 27470296 TI - SIRT1-mediated ERbeta suppression in the endothelium contributes to vascular aging. AB - SIRT1 has many important molecular functions in aging, and the estrogen receptors (ERs) have a vasculoprotective effect, although the detailed mechanism for the roles of SIRT1 and ERs in vascular aging remains unclear. We found that ERbeta expression in the endothelium was reduced in aging mice, and the expression of ERalpha and SIRT1 did not change, while SIRT1 activity declined. Further investigation showed that the ERbeta expression was regulated by SIRT1 through complexes of SIRT1-PPARgamma/RXR-p300 that bind to a PPRE (PPAR response element) site on the ERbeta promoter, and the declined SIRT1 function in aging mice was due to compromised phosphorylation at S154. A single-mutant SIRT1-C152(D) restored the reduced ERbeta expression in the endothelium with minimized reactive oxygen species generation and DNA damage and increased mitochondrial function and fatty acid metabolism. In high-fat diet aging mice, the endothelium-specific delivery of ERbeta or SIRT1-C152(D) on the vascular wall reduced the circulating lipids with ameliorated vascular damage, including the restored vessel tension and blood pressure. We conclude that SIRT1-mediated ERbeta suppression in the endothelium contributes to vascular aging, and the modulation of SIRT1 phosphorylation through a single-mutant SIRT1-C152(D) restores this effect. PMID- 27470298 TI - Precipitous Dehydroepiandrosterone Declines Reflect Decreased Physical Vitality and Function. AB - Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, peak in young adulthood and then decrease dramatically with age. However, there is extensive variation in this age-related hormone decline, suggesting an early decrement may be associated with lower vitality and be prognostic of poor health in old age. To determine whether DHEA-S and DHEA are correlated with physical indices of vitality, hormone levels were analyzed with respect to clinical health histories, physical functioning including grip strength, gait speed and repetitive standing, and self-reported chronic pain. The participants (N = 1,214) were 35-86 years of age from a nationally representative survey, Midlife Development in the United States. DHEA-S and DHEA below age-expected levels were associated with more chronic illness conditions and self-reported persistent pain and pain sensitivity upon manual palpation. Additionally, lower DHEA-S and DHEA correlated with poorer performance on tests of physical functioning by middle age suggesting a more precipitous decline is already indicative of reduced vigor and physical strength. When considered with respect to age- and gender-typical norms, larger decrements in DHEA-S and DHEA may be causally related to the loss of physical vitality. Conversely, when hormone secretion is sustained in older adults, it conveys reduced risk for the physical weakness and ailments that precede frailty. PMID- 27470299 TI - A Comparison of Objective Physical Performance Tests and Future Mortality in the Elderly People. AB - Background: Physical performance is an important predictor of mortality, but little is known on the comparative prognostic utility of different objective physical performance tests in community-dwelling older adults. We compared the prognostic usefulness of several objective physical performance tests on mortality, adjusting our analyses for potential confounders. Methods: Among 3,099 older community-dwelling participants included in the Progetto Veneto Anziani study, 2,096 were followed for a mean of 4.4 years. Physical performance tests measured were Short Physical Performance Battery (SPPB), 4-meter gait speed, chair stands time, leg extension and flexion, handgrip strength, and 6-Minute Walking Test (6MWT), treated as continuous variables and categorized in gender specific quartiles. The main outcome was mortality assessed with death certificates. Results: Participants who died during the follow-up (n = 327) scored significantly worse in all physical performance tests measured at baseline than those who survived (n = 1,769). Using a Harrell's C-index, the highest C index was observed for 6MWT in men (C-index = 0.735; 95% confidence interval [CI]: 0.701-0.770, p < .0001) and SPPB in women (C-index = 0.781; 95% CI: 0.740 0.822, p = .0009). However, in both genders, only SPPB, 4-meter walking speed, and 6MWT are significant predictors of mortality. Analyses using sex-specific quartiles substantially confirmed these findings. Conclusions: Slow gait speed, 6MWT, and SPPB are significant predictors for mortality in community-dwelling older men and women. Physicians should consider using these tests to identify elderly individuals who are at higher risk of death to improve clinical decision making. PMID- 27470300 TI - The Testicular Hormones AMH, InhB, INSL3, and Testosterone Can Be Independently Deficient in Older Men. AB - Background: Late-onset hypogonadism is symptomatically diverse and not fully explained by circulating testosterone level. The adult testes secrete four distinct hormones (testosterone, AMH, INSL3, and InhB) into the circulation. Testosterone and InhB have proven dynamic regulation, with limited information available for AMH and INSL3. During aging, there is cellular senescence, which may underlie the diversity of hypogonadism. This leads to the postulate that the relative levels (profile) of the four testicular hormones in older men are variable and cannot be evaluated by the measurement of one hormone. Methods: 111 men aged 19-50 years and 98 men aged 70-90 years were examined. The circulating levels of the testicular hormones were measured using ELISAs, and the variation in the levels of hormones was analyzed by various correlative analyses. Results: All four hormones were largely or totally independent. Some men were deficient in multiple hormones, but no man had multiple elevated hormones. The average hormonal levels were lower in older men, with diverse profiles of the four testicular hormones. Hence, some men had one or more hormones below the reference range, with testosterone the most conserved. Consequently, testosterone levels were not indicative of the complete state of the endocrine testes. Conclusions: The four hormones vary independently of each other, in younger and older men. This indicates that they are regulated dynamically rather than influenced by endocrine cell number. Older men exhibited diverse profiles of low levels of testicular hormones, suggesting that the testes age differently between men. Testosterone alone inadequately describes gonadal states. PMID- 27470301 TI - Operationalizing Frailty in the Atherosclerosis Risk in Communities Study Cohort. AB - Background: Factors that may contribute to the development of frailty in late life have not been widely investigated. The Atherosclerosis Risk in Communities (ARIC) Study cohort presents an opportunity to examine relationships of midlife risk factors with frailty in late life. However, we first present findings on the validation of an established frailty phenotype in this predominantly biracial population of older adults. Methods: Among 6,080 participants, we defined frailty based upon the Cardiovascular Health Study (CHS) criteria incorporating measures of weight loss, exhaustion, slow walking speed, low physical activity, and low grip strength. Criterion and predictive validity of the frailty phenotype were estimated from associations between frailty status and participants' physical and mental health status, physiologic markers, and incident clinical outcomes. Results: A total of 393 (6.5%) participants were classified as frail and 50.4% pre-frail, similar to CHS (6.9% frail, 46.6% pre-frail). In age-adjusted analyses, frailty was concurrently associated with depressive symptoms, low self rated health, low medication adherence, and clinical biomarker levels (ie, cholesterol, hemoglobin A1c, white blood cell count, C-reactive protein, and hemoglobin). During 1-year follow-up, frailty was associated with falls, low physical ability, fatigue, and mortality. Conclusions: These findings support the validity of the CHS frailty phenotype in the ARIC Study cohort. Future studies in ARIC may elucidate early-life exposures that contribute to late-life frailty. PMID- 27470302 TI - Association Between Lifestyle Factors and the Incidence of Multimorbidity in an Older English Population. AB - Background: Evidence on the role of lifestyle factors in relation to multimorbidity, especially in elderly populations, is scarce. We assessed the association between five lifestyle factors and incident multimorbidity (presence of >=2 chronic conditions) in an English cohort aged >=50 years. Methods: We used data from waves 4, 5, and 6 of the English Longitudinal Study of Ageing. Data on smoking, alcohol consumption, physical activity, fruit and vegetable consumption, and body mass index were extracted and combined to generate a sum of unhealthy lifestyle factors for each individual. We examined whether these lifestyle factors individually or in combination predicted multimorbidity during the subsequent wave. We used marginal structural Cox proportional hazard models, adjusted for both time-constant and time-varying factors. Results: A total of 5,476 participants contributed 232,749 person-months of follow-up during which 1,156 cases of incident multimorbidity were recorded. Physical inactivity increased the risk of multimorbidity by 33% (adjusted hazard ratio [aHR]: 1.33, 95% confidence interval [CI]: 1.03-1.73). The risk was about two to three times higher when inactivity was combined with obesity (aHR: 2.87, 95% CI: 1.55-5.31) or smoking (aHR: 2.35, 95% CI: 1.36-4.08) and about four times when combined with both (aHR: 3.98, 95% CI: 1.02-17.00). Any combination of 2, 3, and 4 or more unhealthy lifestyle factors significantly increased the multimorbidity hazard, compared with none, from 42% to 116%. Conclusion: This study provides evidence of a temporal association between combinations of different unhealthy lifestyle factors with multimorbidity. Population level interventions should include reinforcing positive lifestyle changes in the population to reduce the risk of developing multimorbidity. PMID- 27470303 TI - A novel bedside test for ACPA: the CCPoint test is moving the laboratory to the rheumatologist's office. AB - Rheumatoid Arthritis (RA) is an autoimmune destructive joint disease affecting 1 % of the general population. In recent years, the benefits of identifying RA at an early stage and initiating therapy before joint damage occurs have been acknowledged. An elevated anti-citrullinated peptide antibody (ACPA) level serves as a marker for the early diagnosis of RA. Often the diagnosis is delayed because conventional methods of antibody detection require referral to a specific laboratory. In the current study, we determined the diagnostic accuracy of a new lateral flow point-of-care kit available for ACPA detection in the rheumatologist office. The presence of ACPA was determined by the visually read, qualitative rapid CCPoint(r) test (Euro-Diagnostica, Malmo, Sweden) compared to routinely used ELISA assays (Immunoscan CCPlus(r)-Euro-Diagnostica, Sweden, and QuantLite(r) CCP3-INOVA Diagnostics Inc., USA), in the sera of 184 patients: early RA(n = 38), established RA (n = 84), inflammatory arthritis(n = 34) and systemic lupus erythematosus (SLE) (n = 28). ACPA was detected in 18/38(47 %), 53/84(63 %), 2/34(6 %) and 2/28(7 %) of patients with early RA, established RA, inflammatory arthritis and SLE, respectively. The sensitivity and specificity, negative and positive predictive values of the CCPoint(r) test were equivalent to the Immunoscan CCPlus(r) and Quanta Lite(r) CCP3 ELISA assays. Correlation between ACPA positive results detected in the different assays was 97 %, while negative agreement reached 98 %. Excellent correlation (100 %) was observed between CCPoint(r) results obtained using capillary blood versus serum. CCPoint(r) is a novel technology that allows for a rapid accurate analysis of ACPA and diagnosis during the patient's visit in the rheumatologist office. PMID- 27470304 TI - Facial tremors in patients with and without parkinsonism. AB - Facial (lip and jaw) tremors can be an early sign of Parkinson's disease (PD), essential tremor and other parkinsonisms. Its response to acute dopaminergic therapy and further predictive clinical diagnosis has not been previously addressed. The aim of this study was to evaluate facial tremors response to acute dopaminergic therapy and further predictive value for clinical diagnosis. A retrospective review of medical records from patients with recent onset of facial tremor, with or without parkinsonism, submitted to acute levodopa challenge for clinical prediction of sustained long-term dopaminergic response was conducted. Twenty-eight out of 559 patients (5 %) had facial tremors, which responded to levodopa in 46 % of patients. Facial tremors response to acute levodopa challenge showed 92 % sensitivity and 93 % specificity to predict a final PD diagnosis. In PD patients, facial tremor magnitude of response to levodopa was not different from that of hand rest tremor (p = 0.8). Facial tremors, although infrequent, can be an early sign of PD. Positive response to acute levodopa challenge predicts long-term PD diagnosis. PMID- 27470305 TI - The economic burden of the care and treatment for people with Alzheimer's disease: the outlook for the Czech Republic. AB - The aim of this paper is to specify the cost of treatment and care for people with Alzheimer's disease (AD) in the Czech Republic and also with a view to the future. Data availability is evaluated as well as the quality of cost comparison with other developed countries. Data for the Czech Republic will include data from the health insurance company regarding medicines and treatment, as well as a selected home caring for people with dementia and, ultimately, the Social Security Administration. The basic methods include an analysis of data from publicly available sources, direct interviews with the representatives of nursing homes caring for people with dementia and the representative of the Social Security Administration of the Czech Republic. Items will be specified within the category of direct costs. For the study, the indirect costs related to the loss of patient as well as caring person productivity are not considered. Costs for treatment and care are based from the data on 4162 patients, the costs of a bed from data on 391 beds in homes for the elderly. The average annual cost per patient with AD in the Czech Republic was calculated and came to the amount of 12,783 EUR. These items include outpatient care, inpatient care in a medical facility, inpatient care in homes and medications. In terms of share of these items on the direct costs, the largest item are services provided by special homes which contributes to the direct costs by 94 %, medications create 1 % and treatment (both outpatient and inpatient) 5 %. In the case of home care the total costs are lower at 4698 EUR. The Czech Republic as well as other developed countries are faced with the problem of unified accounting cost of people suffering from Alzheimer's disease. This then causes the calculation of the economic burden to be very difficult and indicative values. PMID- 27470307 TI - Realistic Silver Optical Constants for Plasmonics. AB - Silver remains the preferred conductor for optical and near-infrared plasmonics. Many high-profile studies focus exclusively on performance simulation in such applications. Almost invariably, these use silver optical data either from Palik's 1985 handbook or, more frequently, an earlier Johnson and Christy (J&C) tabulation. These data are inconsistent, making it difficult to ascertain the reliability of the simulations. The inconsistency stems from challenges in measuring representative properties of pristine silver, due to tarnishing on air exposure. We demonstrate techniques, including use of silicon-nitride membranes, to access the full capabilities of multiple-angle, spectrometric-ellipsometry to generate an improved data set, representative of overlayer-protected, freshly deposited silver films on silicon-nitride and glass. PMID- 27470306 TI - Organocatalytic vinylogous Mannich reaction of trimethylsiloxyfuran with isatin derived benzhydryl-ketimines. AB - A family of chiral quaternary 3-aminooxindole butenolides has been synthesized by BINOL-derived phosphoric acid-catalyzed addition of trimethylsiloxyfuran to isatin-derived ketimines. Such a vinylogous Mannich-type reaction was found to produce diastereoisomeric butenolides in good yields and in most cases high enantiomeric excesses. The configurational assignment of the obtained products was safely performed by chemical correlation. A computational study of the transition state allowed rationalizing the obtained stereochemical outcome, highlighting the possible binding modes of the catalyst-imine-nucleophile transition complex. PMID- 27470308 TI - Quality of treatment plans and accuracy of in vivo portal dosimetry in hybrid intensity-modulated radiation therapy and volumetric modulated arc therapy for prostate cancer. AB - BACKGROUND AND PURPOSE: Delivering selected parts of volumetric modulated arc therapy (VMAT) plans using step-and-shoot intensity modulated radiotherapy (IMRT) beams has the potential to increase plan quality by allowing specific aperture positioning. This study investigates the quality of treatment plans and the accuracy of in vivo portal dosimetry in such a hybrid approach for the case of prostate radiotherapy. MATERIAL AND METHODS: Conformal and limited-modulation VMAT plans were produced, together with five hybrid IMRT/VMAT plans, in which 0%, 25%, 50%, 75% or 100% of the segments were sequenced for IMRT, while the remainder were sequenced for VMAT. Integrated portal images were predicted for the plans. The plans were then delivered as a single hybrid beam using an Elekta Synergy accelerator with Agility head to a water-equivalent phantom and treatment time, isocentric dose and portal images were measured. RESULTS: Increasing the IMRT percentage improves dose uniformity to the planning target volume (p<0.01 for 50% IMRT or more), substantially reduces the volume of rectum irradiated to 65Gy (p=0.02 for 25% IMRT) and increases the monitor units (p<0.001). Delivery time also increases substantially. All plans show accurate delivery of dose and reliable prediction of portal images. CONCLUSIONS: Hybrid IMRT/VMAT can be efficiently planned and delivered as a single beam sequence. Beyond 25% IMRT, the delivery time becomes unacceptably long, with increased risk of intrafraction motion, but 25% IMRT is an attractive compromise. Integrated portal images can be used to perform in vivo dosimetry for this technique. PMID- 27470310 TI - Effect of Changes in Sleep Quantity and Quality on Depressive Symptoms Among Korean Children. AB - This study aims to determine whether changes in sleep quantity and quality in childhood are associated with incidence of depressive symptoms. We used the three waves of the Korean Children & Youth Panel Survey (2011-2013). Statistical analysis using a generalized estimating equation model was performed. The 2,605 subjects analyzed included 1,453 students in 2012 and 1,152 students in 2013 without depressive symptoms in the prior year. We found that deteriorated or consistently poor sleep quality were important risk factors for depressive symptoms in children. We suggest that early detection and intervention of poor sleep quality in elementary school is required to reduce early onset depressive symptoms. PMID- 27470309 TI - HPV Vaccination Status and Mandate Support for School-Aged Adolescents Among College Females. AB - The purpose of this study was to describe college-aged females' human papillomavirus (HPV) knowledge and beliefs, perceptions and perceived benefits of the HPV vaccine, and identify characteristics associated with vaccination status and support for HPV vaccine mandates. Data were collected from 1,105 females by an Internet-delivered questionnaire during February to March 2011. This descriptive study utilizes chi2 tests and t-tests to compare participant responses. HPV-related knowledge scores were 8.08 out of 11 points. Those who initiated HPV vaccination were significantly younger, single, engaged in sex, were sexually active, and had a Pap test. Participants who had more friends receiving the vaccine were significantly more likely to support mandates for 9-11 and 12-17 years and were more likely to complete the HPV vaccination cycle. Findings suggest the importance of educational programs adopted and delivered by school nurses, which aim to improve student knowledge and reduce misconceptions related to the HPV vaccine and vaccination mandates. PMID- 27470311 TI - My Sister's Keeper: Sibling Social Support and Chronic Illness. AB - Through her stories and mine, my sister and I allow the outside world to see the ways in which we grapple with a critical health incident along her journey of living with lupus. Lupus is a chronic, autoimmune disease that is difficult to recognize and to diagnose. The ambiguous nature of the disease creates considerable confusion for the ill person as well as her support system. Using an illness narrative, I analyze a real life event linked to chronic illness, invisibility, living loss, liminality and family-and more specifically, to social support within the sibling relationship. PMID- 27470312 TI - An improved (15) N tracer approach to study denitrification and nitrogen turnover in soil incubations. AB - RATIONALE: Denitrification (the reduction of oxidized forms of inorganic nitrogen (N) to N2 O and N2 ) from upland soils is considered to be the least well understood process in the global N cycle. The main reason for this lack of understanding is that the terminal product (N2 ) of denitrification is extremely difficult to measure against the large atmospheric background. METHODS: We describe a system that combines the (15) N-tracer technique with a 40-fold reduced N2 (2% v/v) atmosphere in a fully automated incubation setup for direct quantification of N2 and N2 O emissions. The delta(15) N values of the emitted N2 and N2 O were determined using a custom-built gas preparation unit that was connected to a DELTA V Plus isotope ratio mass spectrometer. The system was tested on a pasture soil from sub-tropical Australia under different soil moisture conditions and combined with (15) N tracing in extractable soil N pools to establish a full N balance. RESULTS: The method proved to be highly sensitive for detecting N2 (1.12 MUg N h(-1) kg(-1) dry soil (ds)) and N2 O (0.36 MUg N h( 1) kg(-1) ds) emissions. The main end product of denitrification in the investigated soil was N2 O for both water contents, with N2 accounting for only 3% to 13% of the total denitrification losses. Between 90 and 95% of the added (15) N fertiliser could be recovered in N gases and extractable soil N pools. CONCLUSIONS: The high and N2 O-dominated denitrification rates found in this study are pointing at both the high ecological and the agronomic importance of denitrification in subtropical pasture soils. The new system allows for a direct and highly sensitive detection of N2 and N2 O fluxes from soils and may help to significantly improve our mechanistic understanding of N cycling and denitrification in terrestrial agro-ecosystems. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470313 TI - The Value of Systematic Reviews in Estimating the Cost and Barriers to Translation in Tissue Engineering. AB - Little quantitative data exist concerning barriers that impede translation from bench to bedside. We systematically reviewed synthetic or biosynthetic polymer nerve scaffolds for peripheral nerve repair to study a defined research area that is beyond the discovery phase and has potential for clinical application. Using electronic and manual search methods, we identified published English language articles, where scaffolds were tested in preclinical animal models. A systematic review of these 416 reports estimated all costs related to the use of animals, surgery, and evaluation methods. The research studied 17 different nerves in eight animal species, with use of 65 evaluation methods at an estimated cost of $61,264,910 for the preclinical studies. A total of 127 surveys were sent to authors, of whom 12 could not be accessed electronically and 45 (39%) responded. Major causes for failure to translate included lack of a commercial partner, insufficient financial resources, a research program not involved in translation, and lack of expertise in regulatory affairs. This review emphasizes the urgent need for standardization of preclinical models and the need to establish better collaboration between laboratory investigators, clinicians, and the companies involved in commercialization. It identifies important areas for education of future investigators in the process of translation from discovery to improved health such as those funded by the National Institutes of Health Clinical and Translational Science Awards. PMID- 27470314 TI - Congenital heart disease in adults. PMID- 27470315 TI - Severe West Nile virus meningoencephalitis in a pediatric renal transplant recipient: successful recovery and long-term neuropsychological outcome. AB - West Nile Virus is an arbovirus that has rapidly spread throughout the United States since the first case was described in Queens, New York in 1999. There has been increasing reports of both community-acquired and organ-derived infections in renal transplant recipients. In immunocompromised individuals, WNV infection is a life-threatening disease with significant neurological morbidity. We report the only pediatric case of community-acquired WNV disease in a renal transplant recipient to undergo detailed long-term neuropsychological assessment. Increased surveillance and prompt treatment of WNV meningoencephalitis is critical, and our report highlights the effectiveness of immunosuppression reduction without compromising allograft outcomes. PMID- 27470316 TI - Mutation analysis of 19 autosomal short tandem repeats in Chinese Han population from Shanghai. AB - The mutation of short tandem repeat (STR) loci is affected by several factors, such as sex, age, and DNA architectures. Previous studies have shown a different profile of mutation rates at autosomal STR loci among populations. It is important to provide population data and reveal underlying factors influencing the evaluation of STR mutation rates. In this study, we performed a comprehensive analysis on the mutation of 19 autosomal STR loci through 124,773 parent-child allelic transfers from 5846 paternity testing cases. A total of 197 mutations were observed including 187 single-step mutations. The observed mutation rates ranged from 0.15 * 10-3 (TH01) to 4.57 * 10-3 (FGA), and the average mutation rate across all the 19 loci was 1.58 * 10-3. Furthermore, the average mutation rate of STR loci increases with the paternal conception ages and remains relatively stable in different maternal age groups, which suggest the profile of paternal conception ages as a potential factor influencing the evaluation of STR mutation rates and the ratio of paternal versus maternal mutation rate in populations. Multidimensional scaling analysis (MDS) shows a difference in the profile of mutation rates at 13 CODIS STR loci among ethnical groups. Based on our data, our results support that short alleles are biased towards expansion mutation and longer alleles favor contraction mutation. In conclusion, our results provide useful information for further investigation on STR mutation in forensic genetics and population genetics. PMID- 27470317 TI - Visualization of the powder pocket and its influence on staining in firearm barrels in experimental contact shots. AB - The powder pocket or soot cavity is a morphologic characteristic of a close contact shot. In a research project concerning staining inside the barrel, the influence of the powder pocket on these traces was investigated.According to the 'triple contrast method', thin pads containing a mixture of acrylic paint, radiocontrast agent and blood were glued on plastic boxes which were coated with a 3-4-mm-thick silicone layer. The containers filled with 10 % ballistic gelatine, were stored for at least 60 h at 4 degrees C. Thirty-three contact shots were realized using different pistols and 22 lr, .32 auto, .38 special and 9-mm Luger with different barrel length using subsonic, non-deforming ammunition.The documentation comprised endoscopy, high speed video and computer tomography (CT) of the target models. Using image analysis, the ballooning of the silicone coat was studied (lateral view projection).High-speed video confirmed the actual comprehension of the behaviour of muzzle gases in contact shots. The powder cavity rises in about 1.5 to 2 ms, preceding the maximum of the temporary cavity, and the powder pocket's collapse takes 2.5 to 3 ms.The size of the silicone dome increased with decreasing barrel length. Comparing semi-automatic pistols of 4 in. barrel length in the calibres, .32 auto and 9-mm Luger, there were no significant differences of the powder pocket size. Material transport was observed, against and perpendicularly to the shooting direction. CT showed undermining and gas inclusions inside the powder pocket. A correlation between amount and pattern of the staining inside the barrel and the volume of the powder pocket was not observed. PMID- 27470318 TI - Genetic variation of 17 STR loci in a Mexican Mestizo population from Mexico City. AB - Genetic data from 17 autosomal short tandem repeat (STR) loci found in the Powerplex(r) ESX 17 System (Promega, Madison, WI, USA) was evaluated in 162 unrelated Mexican Mestizo individuals from Mexico City. Allele frequencies and forensic parameters were estimated for the 17 STRs. All loci analyzed were in Hardy-Weinberg equilibrium in the studied population and showed not any signs of linkage between loci. The combined power of discrimination and the power of exclusion for the 16 aSTRs studied were 1-2.56409.10-19 and 99.999938 %, respectively. Genetic distances reveal a close relationship within different populations of Mexican Mestizos. The obtained data might be useful for population genetics research and for individual identification and paternity testing in forensic science. PMID- 27470319 TI - Case report: on the use of the HID-Ion AmpliSeqTM Ancestry Panel in a real forensic case. AB - In the absence of any other conclusive forensic evidence, DNA profiling is the method of choice for body identification. This study focuses on the case of a carbonized corpse whose complete autosomal short tandem repeat (STR) profile could not lead to direct identification by the investigators. To assist in the progress of investigation, we endeavoured to determine the biogeographical origin and eye colour of the deceased individual. Along with Y chromosome and mitochondrial DNA analyses, we applied a next-generation sequencing (NGS) approach to the study of ancestry informative markers (AIMs) using the HID-Ion AmpliSeqTM Ancestry Panel launched by Thermo Fisher Scientific. This work gave us the opportunity to test this new technology in a real forensic case. Although this study highlights the benefits of such a combined approach, as it markedly improves the specificity of the biogeographical profile, it also underlines the need for the accurate characterization of a larger collection of reference populations and the necessity of caution in data interpretation. PMID- 27470320 TI - Concentrations of cyanide in blood samples of corpses after smoke inhalation of varying origin. AB - Cyanide (CN) blood concentration is hardly considered during routine when evaluating smoke gas intoxications and fire victims, although some inflammable materials release a considerable amount of hydrogen cyanide. CN can be significant for the capacity to act and can in the end even be the cause of death. Systematic data concerning the influence of different fire conditions, especially those of various inflammable materials, on the CN-blood concentration of deceased persons do not exist. This study measured the CN level in 92 blood samples of corpses. All persons concerned were found dead in connection with fires and/or smoke gases. At the same time, the carboxyhemoglobin (COHb) level was determined, and the corpses were examined to detect pharmaceutical substances, alcohol and drugs. Furthermore, we analysed autopsy findings and the investigation files to determine the inflammable materials and other circumstances of the fires. Due to the inflammable materials, the highest concentration of CN in the victims was found after enclosed-space fires (n = 45) and after motor-vehicle fires (n = 8). The CN levels in these two groups (n = 53) were in 47 % of the cases toxic and in 13 % of the cases lethal. In victims of charcoal grills (n = 17) and exhaust gases (n = 6), no or only traces of CN were found. Only one case of the self-immolations (n = 12) displayed a toxic CN level. The results show that CN can have considerable significance when evaluating action ability and cause of death with enclosed-space fires and with motor vehicle fires. PMID- 27470321 TI - Exercise Is Medicine Initiative: Physical Activity as a Vital Sign and Prescription in Adult Rehabilitation Practice. AB - To support rehabilitation health care professionals' efforts to increase physical activity levels among their outpatient rehabilitation and postdischarge patients, we review the Exercise is Medicine (EIM) initiative. The EIM initiative was launched in 2007 jointly by the American College of Sports Medicine and American Medical Association. Three principles underlie the EIM initiative. First, physical activity should be monitored as a vital sign; second, physical activity is an effective medical modality and should be prescribed; and third, success of their vision requires top down and bottom up efforts by 3 key stakeholder groups: health care providers, exercise professionals, and the community. The target weekly physical activity level is 150 minutes of moderate-to-vigorous physical activity, as established by the Centers for Disease Control and Prevention and World Health Organization. Persons falling below the weekly target physical activity level should be prescribed physical activity and/or referred to an exercise professional for implementation support. Selection of an exercise professional for referral is based on the patient's risk stratification and need to participate in clinically supervised physical activity. PMID- 27470322 TI - Novel combination of sorafenib and biochanin-A synergistically enhances the anti proliferative and pro-apoptotic effects on hepatocellular carcinoma cells. AB - Sorafenib (SOR) is the first-line treatment for hepatocellular carcinoma (HCC). However, its use is hindered by the recently expressed safety concerns. One approach for reducing SOR toxicity is to use lower doses in combination with other less toxic agents. Biochanin-A (Bio-A), a promising isoflavone, showed selective toxicity to liver cancer cells. We postulated that combining SOR and Bio-A could be synergistically toxic towards HCC cells. We further evaluated the underlying mechanism. Cytotoxicity assay was performed to determine the IC50 of Bio-A and SOR in HepG2, SNU-449 and Huh-7 cells. Then, combination index in HepG2 was evaluated using Calcusyn showing that the concurrent treatment with lower concentrations of SOR and Bio-A synergistically inhibited cell growth. Our combination induced significant arrest in pre-G and G0/G1 cell cycle phases and decrease in cyclin D1 protein level. Concomitantly, SOR/Bio-A reduced Bcl-2/Bax ratio. Furthermore, this co-treatment significantly increased caspase-3 &-9 apoptotic markers, while decreased anti-apoptotic and proliferative markers; survivin and Ki-67, respectively. Active caspase-3 in HepG2, SNU-449 and Huh-7 confirmed our synergism hypothesis. This study introduces a novel combination, where Bio-A synergistically enhanced the anti-proliferative and apoptotic effects of SOR in HCC cells, which could serve as a potential effective regimen for treatment. PMID- 27470323 TI - Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. AB - : Major bleeding with low molecular weight heparin (LMWH) therapy occurs in up to 5% of patients and its anticoagulation is only partially reversed by protamine sulfate. We studied the ability of ciraparantag (PER977), a novel agent that reverses LMWH in preclinical studies, to reverse LMWH in healthy volunteers. METHODS: In this phase 1/2 trial, 4 cohorts of 10 healthy volunteers received escalating doses of ciraparantag (100 to 300mg) or placebo (8:2 ratio) approximately 4h after a single subcutaneous dose of enoxaparin, 1.5mg/kg. Safety, pharmacokinetic and pharmacodynamic effects were assessed. RESULTS: Complete reversal of enoxaparin anticoagulation, measured by a reduction of whole blood clotting time, was observed in all subjects who received a single ciraparantag dose ranging from 100mg to 300mg. The anticoagulation reversal occurred rapidly after bolus injection and persisted for the duration of the study. At 12h and 24h, the differences in whole blood clotting time in the treated group compared to placebo were no longer significant, consistent with the decline in enoxaparin concentrations and anticoagulation effects. No procoagulant signals were detected as measured by D-dimer, F1.2, and tissue factor pathway inhibitor levels. Ciraparantag was well tolerated with only transient, minor side effects. CONCLUSION: Ciraparantag reverses the whole blood clotting time induced by enoxaparin in a dose related manner and produces no procoagulant signal or deleterious adverse events in doses up to 300mg. PMID- 27470324 TI - SePARating thrombosis and hemostasis? PMID- 27470325 TI - Oncology Education in Medical Schools: Towards an Approach that Reflects Australia's Health Care Needs. AB - Cancer has recently overtaken heart disease to become the number 1 cause of mortality both globally and in Australia. As such, adequate oncology education must be an integral component of medical school if students are to achieve learning outcomes that meet the needs of the population. The aim of this review is to evaluate the current state of undergraduate oncology education and identify how Australian medical schools can improve oncology learning outcomes for students and, by derivative, improve healthcare outcomes for Australians with cancer. The review shows that oncology is generally not well represented in medical school curricula, that few medical schools offer mandatory oncology or palliative care rotations, and that junior doctors are exhibiting declining oncology knowledge and skills. To address these issues, Australian medical schools should implement the Oncology Education Committee's Ideal Oncology Curriculum, enact mandatory oncology and palliative care clinical rotations for students, and in doing so, appreciate the importance of students' differing approaches to learning. PMID- 27470327 TI - The asphericity of the metabolic tumour volume in NSCLC: correlation with histopathology and molecular markers. AB - PURPOSE: Asphericity (ASP) is a tumour shape descriptor based on the PET image. It quantitates the deviation from spherical of the shape of the metabolic tumour volume (MTV). In order to identify its biological correlates, we investigated the relationship between ASP and clinically relevant histopathological and molecular signatures in non-small-cell lung cancer (NSCLC). METHODS: The study included 83 consecutive patients (18 women, aged 66.4 +/- 8.9 years) with newly diagnosed NSCLC in whom PET/CT with 18F-FDG had been performed prior to therapy. Primary tumour resection specimens and core biopsies were used for basic histopathology and determination of the Ki-67 proliferation index. EGFR status, VEGF, p53 and ALK expression were obtained in a subgroup of 44 patients. The FDG PET images of the primary tumours were delineated using an automatic algorithm based on adaptive thresholding taking into account local background. In addition to ASP, SUVmax, MTV and some further descriptors of shape and intratumour heterogeneity were assessed as semiquantitative PET measures. RESULTS: SUVmax, MTV and ASP were associated with pathological T stage (Kruskal-Wallis, p = 0.001, p < 0.0005 and p < 0.0005, respectively) and N stage (p = 0.017, p = 0.003 and p = 0.002, respectively). Only ASP was associated with M stage (p = 0.026). SUVmax, MTV and ASP were correlated with Ki-67 index (Spearman's rho = 0.326/p = 0.003, rho = 0.302/p = 0.006 and rho = 0.271/p = 0.015, respectively). The latter correlations were considerably stronger in adenocarcinomas than in squamous cell carcinomas. ASP, but not SUVmax or MTV, showed a tendency for a significant association with the extent of VEGF expression (p = 0.058). In multivariate Cox regression analysis, ASP (p < 0.0005) and the presence of distant metastases (p = 0.023) were significantly associated with progression-free survival. ASP (p = 0.006), the presence of distant metastases (p = 0.010), and Ki-67 index (p = 0.062) were significantly associated with overall survival. CONCLUSION: The ASP of primary NSCLCs on FDG PET images is associated with tumour dimensions and molecular markers of proliferation and angiogenesis. PMID- 27470328 TI - 18F-FDG PET/CT imaging factors that predict ischaemic stroke in cancer patients. AB - PURPOSE: 18F-FDG PET/CT can acquire both anatomical and functional images in a single session. We investigated which factors of 18F-FDG PET/CT imaging have potential as biomarkers for an increased risk of ischaemic stroke in cancer patients. METHODS: From among cancer patients presenting with various neurological symptoms and hemiparesis, 134 were selected as eligible for this retrospective analysis. A new infarct lesion on brain MRI within 1 year of FDG PET/CT defined future ischaemic stroke. The target-to-background ratio (TBR) of each arterial segment was used to define arterial inflammation on PET imaging. Abdominal obesity was defined in terms of the area and proportion of visceral adipose tissue (VAT), subcutaneous adipose tissue and total adipose tissue (TAT) on a single CT slice at the umbilical level. RESULTS: Ischaemic stroke confirmed by MRI occurred in 30 patients. Patients with stroke had higher TBRs in the carotid arteries and abdominal aorta (P < 0.001) and a higher VAT proportion (P = 0.021) and TAT proportion (P = 0.041) than patients without stroke. Multiple logistic regression analysis showed that TBRs of the carotid arteries and abdominal aorta, VAT and TAT proportions, and the presence of a metabolically active tumour were significantly associated with future ischaemic stroke. Combining PET and CT variables improved the power for predicting future ischaemic stroke. CONCLUSION: Our findings suggest that arterial FDG uptake and hypermetabolic malignancy on PET and the VAT proportion on CT could be independent predictors of future ischaemic stroke in patients with cancer and could identify those patients who would benefit from medical treatment. PMID- 27470326 TI - A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism. AB - PURPOSE: To systematically review the previous studies and current status of positron emission tomography (PET) molecular imaging research in atypical parkinsonism. METHODS: MEDLINE, ISI Web of Science, Cochrane Library, and Scopus electronic databases were searched for articles published until 29th March 2016 and included brain PET studies in progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS). Only articles published in English and in peer-reviewed journals were included in this review. Case-reports, reviews, and non-human studies were excluded. RESULTS: Seventy-seven PET studies investigating the dopaminergic system, glucose metabolism, microglial activation, hyperphosphorilated tau, opioid receptors, the cholinergic system, and GABAA receptors in PSP, MSA, and CBS patients were included in this review. Disease specific patterns of reduced glucose metabolism have shown higher accuracy than dopaminergic imaging techniques to distinguish between parkinsonian syndromes. Microglial activation has been found in all forms of atypical parkinsonism and reflects the known distribution of neuropathologic changes in these disorders. Opioid receptors are decreased in the striatum of PSP and MSA patients. Subcortical cholinergic dysfunction was more severe in MSA and PSP than Parkinson's disease patients although no significant changes in cortical cholinergic receptors were seen in PSP with cognitive impairment. GABAA receptors were decreased in metabolically affected cortical and subcortical regions in PSP patients. CONCLUSIONS: PET molecular imaging has provided valuable insight for understanding the mechanisms underlying atypical parkinsonism. Changes at a molecular level occur early in the course of these neurodegenerative diseases and PET imaging provides the means to aid differential diagnosis, monitor disease progression, identify of novel targets for pharmacotherapy, and monitor response to new treatments. PMID- 27470329 TI - Birt-Hogg-Dube Syndrome Presenting as a Nevus Comedonicus-Like Lesion in an 8 Year-Old Boy. AB - Birt-Hogg-Dube syndrome is an uncommon genodermatosis characterized by hair follicle hamartomas and an increased risk of pneumothorax and renal cell carcinoma. Recognition of cutaneous manifestations is essential because it allows for early screening and management of systemic complications. We present the case of an 8-year-old boy with a recently described cystic and comedonal variant of the classic fibrofolliculoma, which had been present since birth. PMID- 27470331 TI - Ligustrazine alleviates acute pancreatitis by accelerating acinar cell apoptosis at early phase via the suppression of p38 and Erk MAPK pathways. AB - OBJECTIVE: This study aimed to investigate the role of ligustrazine on apoptosis and inflammatory reaction in acute pancreatitis. METHODS: Rats and acinar cells were treated with caerulein to induce acute pancreatitis models. Cell models were treated with saline, p38 inhibitor, Erk inhibitor and ligustrazine. Then, the levels of TNF-alpha, IL-1beta and IL-6 were determined by ELISA assay, the protein levels of p38, Erk1/2, p53 and cleaved caspase3 were determined by western blotting, and apoptosis were measured by flow cytometry. Rat models were treated with saline and ligustrazine. Plasma amylase and pancreatic myeloperoxidase activity and the levels of TNF-alpha, IL-1beta and IL-6 in rats were determined. The protein levels of p38, Erk1/2, p53 and cleaved caspase3 in pancreas tissues were determined by western blotting, and pancreas tissues were also performed TUNEL staining to observe apoptosis status. RESULTS: Ligustrazine downregulated the levels of TNF-alpha, IL-1beta, IL-6. The protein levels of p38 and Erk were reduced by p38 inhibitor, Erk inhibitor and ligustrazine, while the levels of p53 and cleaved caspase 3 were upregulated. Apoptosis of AP acinar cells and cells in AP rat models was promoted after treated with ligustrazine. Plasma amylase and pancreatic myeloperoxidase activity in AP rat models were reduced by ligustrazine. CONCLUSION: Ligustrazine alleviates acute pancreatitis by accelerating acinar cell apoptosis at early phase via the suppression on p38 and Erk MAPK pathways. It is capable of attenuating the severity of acute pancreatitis and may have a therapeutic effect on patients with acute pancreatitis. PMID- 27470332 TI - Ursolic acid regulates aging process through enhancing of metabolic sensor proteins level. AB - We previously reported that Ursolic Acid (UA) ameliorates skeletal muscle performance through satellite cells proliferation and cellular energy status. In studying the potential role of the hypothalamus in aging, we developed a strategy to pursue UA effects on the hypothalamus anti-aging proteins such as; SIRT1, SIRT6, PGC-1beta and alpha-Klotho. In this study, we used a model of aging animals (C57BL/6). UA dissolved in Corn oil (20mg/ml) and then administrated (200mg/Kg i.p injection) to mice, twice daily for 7days. After treatment times, the mice perfused and the hypothalamus isolated for preparing of tissue to Immunofluorescence microscopy. The data illustrated that UA significantly increased SIRT1 (~3.5+/-0.3 folds) and SIRT-6 (~1.5+/-0.2 folds) proteins overexpression (P<0.001). In addition, our results showed that UA enhanced alpha Klotho (~3.3+/-0.3) and PGC-1beta (~2.6+/-0.2 folds) proteins levels (P<0. 01). In this study, data were analyzed using SPSS 16 (ANOVA test). To the best of our knowledge, it seems that UA through enhancing of anti-aging biomarkers (SIRT1 and SIRT6) and PGC-1beta in hypothalamus regulates aging-process and attenuates mitochondrial-related diseases. In regard to the key role of alpha-Klotho in aging, our data indicate that UA may be on the horizon to forestall diseases of aging. PMID- 27470330 TI - Shining evolutionary light on human sleep and sleep disorders. AB - Sleep is essential to cognitive function and health in humans, yet the ultimate reasons for sleep-i.e. 'why' sleep evolved-remain mysterious. We integrate findings from human sleep studies, the ethnographic record, and the ecology and evolution of mammalian sleep to better understand sleep along the human lineage and in the modern world. Compared to other primates, sleep in great apes has undergone substantial evolutionary change, with all great apes building a sleeping platform or 'nest'. Further evolutionary change characterizes human sleep, with humans having the shortest sleep duration, yet the highest proportion of rapid eye movement sleep among primates. These changes likely reflect that our ancestors experienced fitness benefits from being active for a greater portion of the 24-h cycle than other primates, potentially related to advantages arising from learning, socializing and defending against predators and hostile conspecifics. Perspectives from evolutionary medicine have implications for understanding sleep disorders; we consider these perspectives in the context of insomnia, narcolepsy, seasonal affective disorder, circadian rhythm disorders and sleep apnea. We also identify how human sleep today differs from sleep through most of human evolution, and the implications of these changes for global health and health disparities. More generally, our review highlights the importance of phylogenetic comparisons in understanding human health, including well-known links between sleep, cognitive performance and health in humans. PMID- 27470333 TI - Geranylgeranylacetone induces apoptosis via the intrinsic pathway in human melanoma cells. AB - The aim of this study was to test the anti-cancer effects of geranylgeranylacetone (GGA), an isoprenoid compound, on human melanoma cells. Human melanoma cell lines G361, SK-MEL-2, and SK-MEL-5 were treated with GGA at various doses (1-100MUM). Cell viability was measured by crystal violet assay. Western blot analysis was adopted to detect marker proteins of apoptosis. GGA significantly reduced the viability of G361, SK-MEL-2, and SK-MEL-5 human melanoma cells at concentrations above 10MUM. Western blot analysis showed the phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK) after GGA treatment, as well as activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage. GGA also induced p53 and Bax expression, but did not affect expression of Bcl-2 and MITF. These findings suggest that GGA induces apoptosis through the intrinsic pathway. Accordingly, GGA should be considered for further development as a potential agent for melanoma. PMID- 27470334 TI - Lipopolysaccharide potentiates endothelin-1-induced proliferation of pulmonary arterial smooth muscle cells by upregulating TRPC channels. AB - Lipopolysaccharide (LPS) and endothelin-1 (ET-1) are critical pathogenic factors in sepsis-induced pulmonary hypertension; however it is unknown whether they have a coordinated action in the pathogenesis of this disease. Here we found that although LPS did not change the contractility of rat pulmonary arterial smooth muscle cells (PASMCs) in response to ET-1, it significantly promoted ET-1-induced PASMC proliferation. Measurement of ET-1-evoked Ca(2+) transients in PASMCs showed that LPS dramatically enhanced Ca(2+) influx mediated by transient receptor potential canonical (TRPC) channels. LPS did not directly activate TRPC channels, instead it selectively upregulated the expression of TRPC3 and TRPC4 in pulmonary arteries. Small interfering RNA (siRNA) and chemical blockers against TRPC channels abolished LPS-induced PASMC proliferation. LPS-induced cell proliferation and TRPC expression was mediated by the Ca(2+)-dependent calcineurin/NFAT signaling pathway. We suggest that blocking TRPC channels could be an effective strategy in controlling pulmonary arterial remodeling after endotoxin exposure. PMID- 27470335 TI - Anti-tumor activity of arjunolic acid against Ehrlich Ascites Carcinoma cells in vivo and in vitro through blocking TGF-beta type 1 receptor. AB - We aimed to evaluate therapeutic potential of arjunolic acid (AA), in Terminalia Arjuna bark, on Ehrlich Ascites carcinoma (EAC) in-vivo and in-vitro. EAC was induced in fifty female Swiss albino mice. Two doses of AA was used 100 and 250mg/kg. Arjunulic acid reduced tumor volume and cells count. AA decreased EAC cells viability and increased cell toxicity. Moreover, AA reduced TNF-alpha, IL 1beta, TGF-beta, TGF-beta type I receptor and latency-associated peptide levels associated with elevated IL-10 in-vivo and in-vitro. In conclusion, AA produced antitumor activity against EAC by increasing cytotoxicity and apoptosis and partially blocking the TGF-betaR1 and affecting inflammatory cytokine levels. PMID- 27470336 TI - Anti-obesity effect of Crinum asiaticum var. japonicum Baker extract in high-fat diet-induced and monogenic obese mice. AB - This study determined the anti-obesity effect of Crinum asiaticum var. japonicum Baker extract (CAE) on adipocytes and obese mice. The inhibitory effects of CAE on adipocyte differentiation and adipogenesis were determined using differentiation induction medium in 3T3-L1 cells. To get an insight into underlying molecular actions of CAE, we investigated the changes in the expression levels of genes involved in lipogenesis by CAE treatment using qRT PCR. CAE strongly suppressed adipocyte differentiation through downregulation of PPARgamma, C/EBPalpha, C/EBP beta, and aP2. CAE treatment could also suppress the expression levels of ACC, FAS, LPL and HMGCR gene in 3T3-L1 cells. Male C57BL/6 strain and C57BL/6J-ob/ob strain mice were fed with HFD containing 60% fat and normal diet in the presence or absence of 25, 50, and 100mg/kg CAE for 7 weeks. CAE supplementation could highly suppress the body weight gain and epididymal fat accumulation without changes in food uptake in both obese models. Increases in total cholesterol, LDL-cholesterol and triglyceride were highly suppressed in the presence of CAE. In summary, CAE has an anti-obesity effect and this anti-obesity potential might be associated with downregulation of genes involved in adipocyte differentiation and lipogenesis. PMID- 27470337 TI - Assessment of erythropoietin for treatment of anemia in chronic kidney failure- ESRD patients. AB - BACKGROUND AND OBJECTIVE: Currently there is an inadequate data regarding effective management of anemia in chronic kidney disease (CKD) patients who are on dialysis. In CKD patients' anemia mainly develops from decreased renal synthesis of erythropoietin (EPO) and iron deficiency. Our current study focused to effective management of anemia in CKD patients'. STUDY DESIGN: Prospective observational case series study. METHODS: Eligible patients were assigned to three study groups according to initial hemoglobin level i.e. Group I having Hb level below 11g/dL, Group II with Hb level of 11-13g/dL, and Group III with Hb level more than 13g/dL. Intravenous dosing of ESA's calculated according to the range of 150-300IU or equivalent microgram quantity per kilogram body weight was administered to patients in divided doses per week; alone or in combination with iron supplements. RESULTS: Study population (n=163; 100%), of which 124 subjects (76%) patients were treated with erythropoietin and iron supplements; rest of 39 (24%) patients were treated with only erythropoietin. The estimation of hemoglobin content revealed Group I (98 patients) Hb were increased significantly from 9.0+/-1.2g/dl at baseline to 10.9+/-1.7g/dl. No significant changes in Group II and Group III were observed. CONCLUSIONS: Study suggests use of erythropoietin along with iron for treatment of renal failure associated anemia is more beneficial for CKD patients having low Hb. Also study conclude the use of lower than normal dose (150-300IU) of ESA is appropriate when hemoglobin reaches 11g/dl in hemodialysis patients. PMID- 27470338 TI - Polydatin induces bone marrow stromal cells migration by activation of ERK1/2. AB - Bone marrow stromal cells (BMSCs) have proven to be useful for the treatment of numerous human diseases. However, the reparative ability of BMSCs is limited by their poor migration. Polydatin, widely used in traditional Chinese remedies, has proven to exert protective effects to BMSCs. However, little is known about its role in BMSCs migration. In this study, we studied the effects of polydatin on rat BMSCs migration using the scratch wound healing and transwell migration assays. Our results showed polydatin could promote BMSCs migration. Further experiments showed activation of ERK 1/2, but not JNK, was required for polydatin induced BMSCs migration, suggesting that polydatin may promote BMSCs migration via the ERK 1/2 signaling pathways. Taken together, our results indicate that polydatin might be beneficial for stem cell replacement therapy by improving BMSCs migration. PMID- 27470339 TI - Expression pattern of NMDA receptors reveals antiepileptic potential of apigenin 8-C-glucoside and chlorogenic acid in pilocarpine induced epileptic mice. AB - The present study was aimed to evaluate the effect of apigenin 8-C-glucoside (Vitexin) and chlorogenic acid on epileptic mice induced by pilocarpine and explored its possible mechanisms. Intraperitonial administration of pilocarpine (85mg/kg) induced seizure in mice was assessed by behavior observations, which is significantly (p>0.05) reduced by apigenin 8-C-glucoside (AP8CG) (10mg/kg) and chlorogenic acid (CA) (5mg/kg), similar to diazepam. Seizure was accompanied by an imbalance in the levels of Gamma-aminobutyric acid (GABA) and glutamate in the pilocarpine administered group. Moreover, convulsion along with reduced acetylcholinesterase, increased monoamine oxidase and oxidative stress was observed in epileptic mice brain. AP8CG and CA significantly restored back to normal levels even at lower doses. Further, increased lipid peroxidation and nitrite content was also significantly attenuated by AP8CG and CA. However, CA was found to be more effective when compared to AP8CG. In addition, the mRNA expression of N-methyl-d-aspartate receptor (NMDAR), mGluR1 and mGlu5 was significantly (P<=0.05) inhibited by AP8CG and CA in a lower dose. The mRNA expression of GRIK1 did not differ significantly in any of the group and showed a similar pattern of expression. Our result shows that AP8CG and CA selectively inhibit NMDAR, mGluR1 and mGlu5 expression. Modification in the provoked NMDAR calcium response coupled with neuronal death. Hence, these findings underline that the polyphenolics, AP8CG and CA have exerted antiepileptic and neuroprotective activity by suppressing glutamate receptors. PMID- 27470340 TI - Crocin, the main active saffron constituent, mitigates dichlorvos-induced oxidative stress and apoptosis in HCT-116 cells. AB - The protective effects of Crocin (CRO), a carotenoid with wide spectrum of pharmacological effects, against the cytotoxicity and the apoptosis produced by exposure to Dichlorvos (DDVP) in HCT116 cells were investigated in this work. The cytotoxicity was monitored by cell viability, ROS generation, antioxidant enzymes activities, malondialdehyde (MDA) production and DNA fragmentation. The apoptosis was assessed through the measurement of the mitochondrial transmembrane potential (DeltaPsim) and caspases activation. The results indicated that pretreatment of HCT116 cells with CRO, 2h prior to DDVP exposure, significantly increased the survival of cells, inhibited the ROS generation, modulated the activities of catalase (CAT) and superoxide dismutase (SOD) and reduced the MDA level. The reduction in mitochondrial membrane potential, DNA fragmentation and caspases activation were also inhibited by CRO. These findings suggest that CRO can protect HCT116 cells from DDVP-induced oxidative stress and apoptosis. PMID- 27470341 TI - Artesunate obliterates experimental hepatocellular carcinoma in rats through suppression of IL-6-JAK-STAT signalling. AB - Activation of the IL-6 mediated JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) oncogenic signalling plays a major role in hepatocellular carcinoma pathogenesis. The aim of this study is to assess the anti-tumour, anti-proliferative and apoptotic potential of artesunate and its capacity to modulate JAK-STAT pathway in a nitrosodiethylamine mediated experimental hepatocellular carcinoma model. Administration of nitrosodiethylamine (200mg/kg body weight by i.p. Injections) to rats resulted in alterations of liver pathophysiological parameters such as increased relative liver weight, and increased tumour nodule occurrence. It also increased the levels of serum marker enzymes (AST, ALT, ALP, LDH, and gammaGT) and tumour biomarker (AFP) levels suggestive of its capacity to cause liver tumourigenesis. Additionally, the immunohistochemistry of liver sections pertaining to nitrosodiethylamine administered animals showed increased detection of AgNOR, PCNA, and GST-Pi positive cells suggestive of its capacity to promote liver proliferation associated tumourigenesis. On the contrary, artesunate (25mg/kg bodyweight) supplementation to nitrosodiethylamine administered animals decreased all the above mentioned pathophysiological, biochemical, and immunohistochemistry parameters suggesting its anti-tumour and anti-proliferative potential. Furthermore, immunoblot analysis showed significant up-regulation of IL-6, GP130, JAK-2, STAT-3 (pY705), Bcl-xL, Bcl-2 and simultaneous down-regulation of Caspase 3, PARP and SOCS-3 in nitrosodiethylamine administered animals. Nevertheless, the immunoblot analysis revealed vice-versa on artesunate supplementation to nitrosodiethylamine administered animals, indicating promotion of the feedback loop inhibition mechanism through SOCS3 up-regulation thereby leading to suppression of JAK-STAT signalling. Overall all these findings substantiate that artesunate promotes anti-tumour, anti-proliferation and apoptosis against nitrosodiethylamine mediated hepatocellular carcinoma. PMID- 27470342 TI - Cooperative antiproliferative and differentiation-enhancing activity of medicinal plant extracts in acute myeloid leukemia cells. AB - Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with poor prognosis and limited treatment options. Sea buckthorn (Hippophae rhamnoides) berries, dog rose (Rosa canina) rosehips, and garden sage (Salvia officinalis) and oregano (Origanum vulgare) aerial parts are widely used in traditional medicine and exhibit antitumor effects in preclinical models. However, these plants remain scarcely tested for antileukemic activity. Here, we show that their water-ethanol leaf extracts reduced the growth and viability of AML cells and, at non-cytotoxic doses, potentiated cell differentiation induced by a low concentration of 1alpha,25-dihydroxyvitamin D3, the hormonal form of vitamin D, in a cell type-dependent manner. The latter effect was accompanied by upregulation of the vitamin D receptor protein components and its transcriptional activity. Furthermore, at minimally effective doses the extracts cooperated with one another to produce marked cytostatic effects associated with a partial S phase arrest and a modest induction of apoptosis. In contrast, these combinations only slightly affected the growth and viability of proliferating normal human peripheral blood mononuclear cells. In addition, the extracts strongly inhibited microsomal lipid peroxidation and protected normal erythrocytes against hypoosmotic shock. Our results suggest that further exploration of the enhanced antileukemic effects of the combinations tested here may lead to the development of alternative therapeutic and preventive approaches against AML. PMID- 27470343 TI - Fish oil prevents colon cancer by modulation of structure and function of mitochondria. AB - Cancer cells are more susceptible to metabolic perturbations due to impaired electron transport chain (ETC) that promote uncontrolled proliferation. Mitochondria play a pivotal role in bioenergetics and apoptosis, hence are considered as a promising target in tumor cell eradication. Therefore, the present study is designed to elucidate chemopreventive action of fish oil (FO) in combination with corn oil (CO) on mitochondria in colorectal cancer (CRC). Male Wistar rats were divided into groups depending on dietary regimen-Control group, FO+CO(1:1) and FO+CO(2.5:1). These groups were further subdivided depending on whether these received a weekly intraperitoneal injection of ethylenediamine tetra-acetic acid (EDTA) or N,N-dimethylhydrazine dihydrochloride (DMH) for a period of 4 weeks. The animals sacrificed 48h and 16 weeks after EDTA/DMH treatment constituted initiation and post-initiation phase respectively. The structural and functional alterations in mitochondria were evaluated using transmission electron microscopy (TEM) and by assaying electron transport chain (ETC) enzymes. Mitochondrial lipid composition and cholesterol levels were also assessed. DMH treatment led to mitochondrial degeneration, disrupted cristae and a significant decrease in ETC complexes suggestive of metabolic reprogramming. Moreover, an increase in cholesterol and cardiolipin (CL) levels in post initiation phase led to evasion of apoptosis. FO in both the ratios resulted in stabilization and increase in number of mitochondria, however, FO+CO(2.5:1)+DMH group also exhibited mitophagy and crystolysis alongwith altered dynamics in ETC which facilitated apoptosis. It also decreased cholesterol and CL levels to increase apoptosis. Fish oil targets mitochondria in a dose dependent manner that augments apoptosis and hence attenuates carcinogenesis. PMID- 27470344 TI - Inhibition of autophagy sensitizes MDR-phenotype ovarian cancer SKVCR cells to chemotherapy. AB - AUTOPHAGY: is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. CHEMORESISTANCE: is a major challenge in the clinical treatment of ovarian cancer, of which the underlying mechanisms remain unknown. OBJECTIVE: The aim of the present study was to explore the role of autophagy in vincristine (VCR) resistant ovarian cancer cells. METHODS: The SKOV3 parental cell line and SKVCR, the VCR-resistant ovarian carcinoma cells were used. 3-MA (3-Methyladenine) and CQ (Chloroquine) were also used as autophagy inhibitors. CCK8 (Cell Counting Kit 8) was used to detect cell viability, quantitative real-time PCR and Western blot were used to detect the expressions of mRNA and protein, MDC staining and flow cytometry were used to detect autophagy and apoptosis, respectively. RESULTS: Compared with parental SKOV3 cells, SKVCR cells showed Multidrug Resistance (MDR). SKVCR cells demonstrated higher autophagy levels than SKOV3 cells, which could be inhibited by 3-MA and CQ. In SKVCR cells, VCR increased apoptosis levels further, 3-MA and CQ inhibited autophagy and potentiated the cytotoxicity by VCR. Moreover, 3-MA and CQ overcame the acquired VCR resistance in SKVCR cells by enhancing VCR-induced cytotoxicity, and promote apoptosis. CONCLUSIONS: Our data indicate that autophagy has a protective role in the multi-drug resistant SKVCR cells. The inhibition of autophagy increases the killing effects of VCR by increasing apoptosis and inhibiting autophagy, suggesting a better strategy for the treatment of drug-resistant SKVCR cells. PMID- 27470345 TI - Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation. AB - Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20MUg/kg) group: mice received exenatide (10 or 20MUg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20MUg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms. PMID- 27470346 TI - MiR-769 promoted cell proliferation in human melanoma by suppressing GSK3B expression. AB - MicroRNAs (miRNAs) are short, non-coding RNAs with post-transcriptional regulatory function, playing crucial roles in cancer development and progression of human melanoma. Previous studies have indicated that miR-769 was implicated in diverse biological processes. However, the underlying mechanism of miR-769 in human melanoma has not been intensively investigated. In this present study, we aimed to investigate the role of miR-769 and its target genes in human melanoma. We found that miR-769 expression was strongly increased in human melanoma cells and clinical tissues compared with their corresponding controls. Overexpression of miR-769 promoted cell proliferation in human melanoma cell line A375, whereas miR-769-in reverses the function. Glycogen synthase kinase-3 Beta (GSK3B), a potential target gene of miR-769, and was validated by luciferase assay. Further studies revealed that miR-769 regulated cell proliferation of human melanoma by directly suppressing GSK3B expression and the knockdown of GSK3B expression reversed the effect of miR-769-in on human melanoma cell proliferation. In summary, our data demonstrated that miR-769 might act as a tumor promoter by targeting GSK3B during development of human melanoma. PMID- 27470347 TI - Interferon beta improves the efficacy of low dose cisplatin by inhibiting NF kappaB/p-Akt signaling on HeLa cells. AB - The purpose of this study was to evaluate the anticancer efficacy of interferon beta in combination with low dose of cisplatin on human cervical cancer progression, as well as its principal action mechanism. The combination treatment synergistically potentiated the effect of interferon beta on cell growth inhibition and DNA damage on HeLa cells by repressing NF-kappaB/p-Akt signaling. Synergistic targeting of these pathways has a therapeutic potential. Further, the combination treatment ameliorated the expression of pro-apoptotic Bax, and decreased the expression of anti-apoptotic protein Bcl-2. Additionally, the expression of active PARP was significantly increased and MMP-9 level was decreased in combination group as compared to the expression seen for the treatment with interferon beta or cisplatin alone. Results demonstrate that the synergistic inhibitory effects of interferon beta and low dose of cisplatin on human cervical cancer cells and also suggest that the inhibition of NF-kappaB/p Akt signaling pathway plays a critical role in the anticancer effects of combination treatment along with the induction of PARP. Therefore, the combination of interferon beta and cisplatin may be a useful treatment for human cervical cancer, with a greater effectiveness than other treatments. PMID- 27470348 TI - Epidermal growth factor (EGF) triggers the malignancy of hemangioma cells via activation of NF-kappaB signals. AB - Hemangioma (HA) is tumor formed by hyper-proliferation of vascular endothelial cells. However, the role and mechanisms of epidermal growth factor (EGF) on the progression of HA are not well illustrated. Our present study revealed that EGF can significantly promote the in vitro proliferation and motility of HA cells, which was confirmed by the up regulation of Bcl-2, proliferating cell nuclear antigen (PCNA), and metalloproteinase-2 (MMP-2) and MMP-9. The pharmacological inhibition of NF-kappaB, while not ERK1/2 or PI3K/Akt, attenuated EGF induced cell proliferation and expression of MMP-2 and MMP-9. EGF treatment also increased the phosphorylation, nuclear translocation and transcriptional activities of NF-kappaB in HA cells. These data suggested that NF-kappaB plays an essential role in EGF induced malignancy of HA cells. Furthermore, EGF treatment also increased the phosphorylation of IkappaB and IKKalpha, while not IKKbeta or IKKgamma. The knockdown of IKKalpha reversed EGF induced activation of NF-kappaB. EGF treatment also decreased the phosphorylation of GSK-3beta and increased its activities in both HDEC and CRL-2586 EOMA cells. LiCl, a potent GSK-3beta inhibitor, can obviously reverse EGF induced up regulation of p65 phosphorylation. Collectively, our study revealed that EGF can trigger the malignancy of HA cells via induction of proliferation and invasion. The activation of NF-kappaB through IKKalpha/IkappaBalpha and GSK-3beta signal is essential for this process. It suggested that EGF/NF-kappaB signal may represent a novel therapeutic target for the treatment of human HA. PMID- 27470349 TI - 3B, a novel photosensitizer, inhibits glycolysis and inflammation via miR-155-5p and breaks the JAK/STAT3/SOCS1 feedback loop in human breast cancer cells. AB - Compared to normal cells, most cancer cells produce ATP by glycolysis under aerobic conditions rather than via the tricarboxylic acid cycle (TCA). This study is intended to determine whether 3B, a novel photosensitizer, can inhibit glycolysis and inflammation in breast cancer cells. We showed that 3B had the ability to repress glucose consumption as well as the generation of ATP, lactate and lactate dehydrogenase. 3B-PDT not only inhibited the expression of IL-1beta and IL-6 but also affected the JAK-STAT3 inflammatory pathway in vitro. The present study showed that 3B featured a significant inhibitory effect on the expression of microRNA-155-5p and SOCS1 might serve as a target gene. In vivo studies revealed that 3B inhibited tumor growth and exhibited almost no side effects. Therefore, through the anti-glycolytic effect and breakage of the JAK/STAT3/SOCS1 feedback loop via miR-155-5p, 3B may potentially serve as a potential therapeutic agent against breast cancer. PMID- 27470350 TI - Extracts from plastrum testudinis reverse glucocorticoid-induced spinal osteoporosis of rats via targeting osteoblastic and osteoclastic markers. AB - Extracts from plastrum testudinis (PTE), an important traditional Chinese medicine, have been demonstrated promotion of osteoblastic function in vitro. This study aims to investigate the protective effect of PTE on glucocorticoid induced osteoporosis(GIOP) in vivo and analyze therapeutic targets of PTE on GIOP. SD rats were randomly assigned to two experiments: preventive and therapeutic experiments, in which rats respectively received oral PTE at the same time of glucocorticoid injection or after glucocorticoid injection inducing osteoporosis. BMD, microarchitecture, biomechanics, bone metabolism markers and histomorphology were evaluated. mRNA and protein expression of OPG, Runx2, CTSK and MMP9 were examined.Results showed bone quality and bone quantity were significantly elevated by PTE. Histomorphometry showed thicker and denser bone trabecularsand more osteoblasts and less osteoclasts in group of PTE intervention. The mRNA expression of OPG was significantly upregulated whereas expression of CTSK was significantly downregulatedin different groups of PTE intervention. Stronger immunostaining for Runx2 and weaker immunostaining for CTSK were observed in groups of PTE intervention. This demonstrated that PTE may reverse GIOP in prevention and management via targeting OPG, Runx2 and CTSK in mRNA and protein levels. PMID- 27470351 TI - Histone deacetylase inhibitor, Romidepsin (FK228) inhibits endometrial cancer cell growth through augmentation of p53-p21 pathway. AB - OBJECTIVE: Romidepsin (FK228), a Histone Deacetylase (HDAC) inhibitor, has been used for anti-cancer therapies. However, the anti-cancer effect of FK228 and its underlying mechanism in endometrial carcinoma (EC) have not been studied. The aime of this study was to investigate the anti-cancer effects of FK228 and the associated mechanism(s) in EC. METHODS: Ishikawa and HEC-1-A endometrial cancer cells were treated with 8nM concentration of FK228 and cell growth was measured by XTT assay. The cell cycle distribution and cell death were measured by flow cytometry, immunofluorescence, respectively. The mNRA and protein expressions were analyzed by quantitative RT-PCR and western blot, respectively. RESULTS: Based on assays carried out in EC cell lines, it was observed that FK228 inhibited EC cell proliferation in a dose and time-dependent manner. Furthermore, following treatment with FK228 for 48h, there were significant induction of apoptosis and cell cycle arrest at G0/G1 phase in EC cells. Moreover, FK228 treatment significantly increased the mRNA and protein expressions of p53, p21, cleaved caspases such as 3, 7 and 8 and PARP. Further, FK228 treatment increased the levels of acetylated histone H3 and H4 that confirms the HDAC inhibition. CONCLUSION: In conclusion, FK228 inhibits EC tumor cell proliferation and induces apoptosis by activation caspase/PARP via the induction of p53/p21 signaling cascades, suggesting that FK228 is a potential therapeutic agent for EC. PMID- 27470352 TI - Atorvastatin suppresses NLRP3 inflammasome activation via TLR4/MyD88/NF-kappaB signaling in PMA-stimulated THP-1 monocytes. AB - AIMS: Increasing evidence shows that NLRP3 inflammasome is closely associated with the progression of atherosclerosis. The purpose of the present study was to evaluate the effects of atorvastatin on NLRP3 inflammasome in PMA-stimulated THP 1 cells and explore its underlying mechanism. METHODS: Human monocytic THP-1 cells were pretreated with atorvastatin for 1h and then induced by PMA for 48h. Total protein was collected for real-time PCR and Western blot analysis. Cytokine IL-1beta release was detected by ELISA assay. And the NF-kappaB p65 translocation was detected by cellular NF-kappaB translocation kit. RESULTS: It was shown that atorvastatin significantly reduced the expression of NLRP3, the cleavage of caspase-1 and IL-1beta in PMA-induced THP-1 cells. Moreover, Bay (a NF-kappaB inhibitor) treatment greatly suppressed the expression of NLRP3, the cleavage of caspase-1 and IL-1beta in PMA-induced THP-1 cells, suggesting that the activation of NF-kappaB pathway takes part in regulating the expression of NLRP3 inflammasome. In addition, atorvastatin markedly inhibited the up-regulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and the activation of nuclear factor kappa b (NF-kappaB) in PMA-stimulated THP-1 cells. CONCLUSIONS: Atorvastatin exerts an anti-inflammatory effect by inhibiting NLRP3 inflammasome through suppressing TLR4/MyD88/NF-kappaB pathway in PMA-induced THP 1 monocytes. PMID- 27470353 TI - Xiaoxianggou attenuates atherosclerotic plaque formation in endogenous high Ang II ApoE(-/-) mice via the inhibition of miR-203 on the expression of Ets-2 in endothelial cells. AB - BACKGROUND: Atherosclerosis is a chronic immune-inflammatory disorder and one of the leading causes responsible for cardiovascular morbidity and mortality. Traditional Chinese medicine treatment with multi-targets has shown prospects for the therapeutic effect on atherosclerosis. Thus, this study aims to investigate whether xiaoxianggou has benefit for reducing the atherosclerotic plaque area in endogenous high Ang II ApoE(-/-) mice and investigated the underlying mechanisms. METHODS: Endogenous high Ang II ApoE(-/-) mice model was generated by using two kidney one clip (2K1C). All mice were treated by intragastric administration with xiaoxianggou two times a week for 16 weeks. En face plaque area was analyzed by oil-red O staining. Serum anti-OxLDL antibodies were measured by ELISA assay. Expression of miR-203 and Ets-2 were evaluated using qRT-RCR and western blotting analysis, respectively. RESULTS: This study revealed that xiaoxianggou treatment dose-dependently reduced the atherosclerotic plaque area and serum autoantibodies against oxLDL, elevated miR-203 expression and reduced Ets-2 expression in endogenous high Ang II ApoE(-/-) mice. In primary arterial ECs, Xiaoxianggou reverses the reduced miR-203 expression and the elevated Ets-2 expression induced by AngII, which was further recovered by miR-203 inhibitor. Additionally, miR-203 regulated the expression of Ets-2 by targeting Ets-2-3' UTR. Moreover, miR-203 inhibitor reversed the reduction of atherosclerotic lesion area induced by Xiaoxianggou. CONCLUSIONS: These findings present that xiaoxianggou plays an anti atherosclerotic role in endogenous high Ang II ApoE(-/-) mice model, which is partly due to its antioxidant actions against atherosclerosis and the inhibition of miR-203 on the expression of Ets-2 in endothelial cells. PMID- 27470354 TI - The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway. AB - Cervical cancer has been the fourth most common cancer killing many women across the world. Carnosic acid (CA), as a phenolic diterpene, has been suggested to against cancer, exerting protective effects associated with inflammatory cytokines. It is aimed to demonstrate the therapeutic role of carnosic acid against cervical cancer and indicate its underlying molecular mechanisms. 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was performed to assess the possible anti-proliferative effects of carnosic acid. And also, colony formation was used to further estimate carnosic acid's ability in suppressing cervical cancer cells proliferation. Flow cytometry assays were performed here to indicate the alterations of cervical cancer cells cycle and the development of apoptosis. Western blot assays and RT-PCR were also applied to clarify the apoptosis-associated signaling pathways affected by reactive oxygen species (ROS) generation. And immunofluorescence was used to detect ROS-positive cells. In vivo experiments, CaSki xenograft model samples of nude mice were involved to further elucidate the effects of carnosic acid. In our results, we found that carnosic acid exerted anti-tumor ability in vitro supported by up-regulation of apoptosis and ROS production in cervical cancer cells. Also, acceleration of ROS led to the phospharylation of (c-Jun N-terminal kinase (JNK) and its-related signals, as well as activation of Endoplasmic Reticulum (ER) stress, promoting the progression of apoptosis via stimulating Caspase3 expression. The development and growth of xenograft tumors in nude mice were found to be inhibited by the administration of carnosic acid for five weeks. And the suppressed role of carnosic acid in proliferation of cervical cancer cells and apoptosis of nude mice with tumor tissues were observed in our study. Taken together, our data indicated that carnosic acid resulted in apoptosis both in vitro and vivo experiments via promoting ROS and activating JNK signaling pathways in human cervical cancer cells, which supplied a potential therapy for the application of carnosic acid in clinical treatment. PMID- 27470355 TI - In silico screening of novel inhibitors of M17 Leucine Amino Peptidase (LAP) of Plasmodium vivax as therapeutic candidate. AB - M17 LAP (Leucine Amino Peptidase) plays an important role in the hydrolysis of amino acids essential for growth and development of Plasmodium vivax (Pv), the pathogen causing malaria. In this paper a homology model of PvLAP was generated using MODELLER v9.15. From different in-silico methods such as structure based, ligand based and de novo drug designing a total of 90 compounds were selected for docking studies. A final list of 10 compounds was prepared. The study reported the identification of 2-[(3-azaniumyl-2-hydroxy-4-phenylbutanoyl) amino]-4 methylpentanoate as the best inhibitor in terms of docking score and pharmacophoric features. The reliability of the binding mode of the inhibitor is confirmed by molecular dynamics (MD) simulation study with GROMACS software for a simulation time of 20ns in water environment. Finally, in silico ADMET analysis of the inhibitors using MedChem Designer v3 evaluated the drug likeness of the best hits to be considered for industrial pharmaceutical research. PMID- 27470356 TI - miR-204-5p regulates cell proliferation and metastasis through inhibiting CXCR4 expression in OSCC. AB - MicroRNAs (miRNAs) are important small molecules in cancer including oral squamous cell carcinoma (OSCC) which regulate gene expression at post transcriptional levels. MiR-204-5p acts as a tumor suppressor in some of cancers, but the role of it in OSCC is not known. The aim of this study is to investigate the expression and functional roles of miR-204-5p in OSCC. The results showed that the expression of miR-204-5p was lower in cancer tissues or cells. Next, cell proliferation, cell cycle, migration and invasion were detected. It was found that miR-204-5p could enhance OSCC cell proliferation and metastasis. MiR 204-5p was predicted as a regulatory miRNA of CXCR4 in OSCC, and the data analysis indicated that there was a negatively relationship between miR-204-5p and CXCR4 expression in OSCC tissues from the patients. In a conclusion, our findings suggested that miR-204-5p may function as an inhibitory RNA molecule in OSCC by targeting CXCR4. PMID- 27470357 TI - Antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract. AB - Currently, there is no effective vaccine available, and chemotherapy is the main approach for treatment of cutaneous leishmaniasis (CL). During recent decades, studies have demonstrated that a number of plant-derived compounds may act as new therapeutic tools against leishmaniasis. This study was evaluated the antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier (oak) extract. The total amount of phenolic and flavonoid compounds was measured in oak extract. High performance liquid chromatography (HPLC) analysis was also performed to determine the amount of quercetin and gallic acid in this plant. This extract (0-80g/mL) was evaluated in vitro against promastigote and intracellular amastigote forms of Leishmania major (MRHO/IR/75/ER) using MTT assay and in a macro-phage model, respectively. Then oak extract was tested on CL in infected male BALB/c mice with L. major in order to evaluate the antileishmanial activity topically. Moreover, cytotoxicity effects of oak in murine macrophage cells were tested by MTT assay. Antioxidative activity of oak was also determined by the 2,2-diphenyl-1,1-picrylhydrazyl (DPPH) scavenging test. The amount of phenolic and flavonoid compounds in the oak extract was 57.50 and 1.86%, respectively. The amount of quercetin and gallic acid in the oak extract was 0.0064 and 0.22%, respectively. The findings revealed that oak significantly (P<0.05) inhibited the growth rate of promastigote of (IC50 12.65MUg/mL) and amastigotes (IC50 10.31MUg/mL) as a dose-dependent response. In the in vivo assay, after 4 weeks of treatment, 91.6, 66.66, and 50% recovery was observed in the infected mice treated with 20, 10, and 5mg/kg of oak extract, respectively. After treatment of the infected mice with the concentration of 10 and 20mg/kg of oak, the mean diameter of lesions, parasite load and mean number of parasites was significantly (P<0.05) reduced. Selectivity index of greater than 10 for oak revealed that oak extract had no cytotoxic effects on macrophage cells. Moreover, DPPH test demonstrated that radical inhibition occurred at greater power with increasing the concentration of oak. To conclude, the present study showed potent antileishmanial and antioxidant activity of oak extract; whereas this plant had no toxic effect on mammalian cells. PMID- 27470358 TI - Inhibitory effects of hyperoside on lung cancer by inducing apoptosis and suppressing inflammatory response via caspase-3 and NF-kappaB signaling pathway. AB - Lung cancer is one of the most common malignancies in the world and the most threatening cancer to human health. Effective therapies based on non-cytotoxic induction in cell inflammation- and apoptosis-responsive pathways are thought to represent a novel advance in treating lung cancer. However, many studies are still required for effective pharmaceutical to induce cancer cell death. Hyperoside (Hyp) is the chief component of some Chinese herbs with anticancer effect. Here, we investigated the role of hyperoside on the lung cancer cell migration, invasion, inflammation and apoptosis in A549 cells in vitro and xenografts of nude mice in vivo. A549 cells were injected in nude mice for establishing tumors. Our results showed that hyperoside suppressed the proliferation, migration and invasion. Additionally, apoptosis was induced by hyperoside via Bcl-2/Bax-regulated Caspase3 activation, suggesting that hyperoside might inhibit lung cancer progression through apoptotic induction. And also, hyperoside could prevent progression and development of lung cancer through inactivating NF-kappaB signaling pathway. Subsequently, inflammatory cytokines, including TNF-alpha, IL-6, IL-1beta and IL-18, were down-regulated significantly. And animal experiments also illustrated that the tumor volume and weight were reduced after hyperoside administration, which was also through apoptosis induction and prevention of inflammation response by Caspase3 activation and NF kappaB inactivation. To our knowledge, it was the first time to evaluate the effects of hyperoside on preventing progression and development of lung cancer in vivo and in vitro to assess the possible therapies of hyperoside as a future approach for preventing lung cancer progression and development. PMID- 27470359 TI - [6]-Shogaol, a dietary phenolic compound, induces oxidative stress mediated mitochondrial dependant apoptosis through activation of proapoptotic factors in Hep-2 cells. AB - Ginger (Zingiber officinale) is a well-known herb used in ethnomedicine. [6] shogaol, a phenolic nature is a major constituent of ginger. In this study, we investigated the anticancer activity of [6]-shogaol in Laryngeal cancer (Hep-2) cells. We demonstrated the effects of [6]-shogaol on the cell growth and apoptosis in Hep-2 cells were analyzed by the generation of reactive oxygen species (ROS), the level of mitochondrial membrane potential (DeltaYm), DNA damage and apoptotic morphological changes were analyzed by AO/EtBr, AO and Hoechst staining. Further, apoptotic protein expressions were analyzed by western blot analysis. Our results indicated that [6]-shogaol induces apoptosis as evidenced by loss of cell viability, enhanced ROS, lipid peroxidation results in altered mitochondrial membrane potential, increased DNA damage in Hep-2 cells. Further, the prooxidant role of [6]-shogaol inhibit Bcl-2 expression with the simultaneous up-regulation of Bax, Cytochrome c, Caspase-9 and -3 protein expressions were observed in Hep-2 cells. Thus, [6]-shogaol induces apoptosis in Hep-2 cells through inducing oxidative damage and modulate apoptotic marker expressions. Therefore, [6]-shogaol might be used as a therapeutic agent for the treatment of laryngeal cancer. PMID- 27470361 TI - MiR-433 inhibits retinoblastoma malignancy by suppressing Notch1 and PAX6 expression. AB - Retinoblastoma (RB) is the most frequent primary intraocular cancer. It has been demonstrated by previous studies that retinoblastoma is initiated primarily by the inactivation of the retinoblastoma Rb1 gene in retinal cells. However, additional genetic alterations than Rb1 mutation could play important roles in the process of transforming benign retinal cells into retinoblastoma tumor cells. In this study, we identified that microRNA miR-433 is one of such genetic factors. We found that the expression levels of miR-433 were downregulated in RB tissues. We also determined that miR-433 negatively regulated RB cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis of RB cells. We used bioinformatics method to predict and confirmed that Notch1 and PAX6 were miR-433 target genes in RB cells. Importantly, we demonstrated that restoration of Notch1 and PAX6 expression partially rescued the inhibition of cell proliferation and metastasis induced by miR-433 overexpression, suggesting that miR-433 regulates RB cell proliferation and metastasis through suppressing the expression of Notch1 and PAX6. PMID- 27470360 TI - Carnosic acid nanoparticles suppress liver ischemia/reperfusion injury by inhibition of ROS, Caspases and NF-kappaB signaling pathway in mice. AB - Living donor liver transplantation (LDLT) requires ischemia/reperfusion (I/R), which can lead to early graft injury. However, the detailed molecular mechanism of I/R injury remains unclear. Carnosic acid, as a phenolic diterpene with function of anti-inflammation, anti-cancer, anti-bacterial, anti-diabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Nanoparticulate drug delivery systems have been known to better the bioavailability of drugs on intranasal administration compared with only drug solutions. Administration of carnosic acid nanoparticles was thought to be sufficient to lead to considerable inhibition of liver injury progression induced by ischemia/reperfusion. In our study, liver ischemia/reperfusion injury was established successfully with C57BL/6 animal model. 10 and 20mg/kg carnosic acid nanoparticles were injected to mice for five days prior to ischemia. After liver ischemia/reperfusion, the levels of serum AST, ALT and APL were increased, which was attenuated by pre-treatment with carnosic acid nanoparticles. In addition, carnosic acid nanoparticles inhibited ROS production via its related signals regulation. And carnosic acid nanoparticles also suppressed the ischemia/reperfusion-induced up-regulation in the pro-apoptotic protein and mRNA levels of Bax, Cyto-c, Apaf-1 and Caspase-9/3 while increased ischemia/reperfusion-induced decrease of anti-apoptotic factor of Bcl-2. Further, ischemia/reperfusion-induced inflammation was also inhibited for carnosic acid nanoparticles administration via inactivating NF-kappaB signaling pathway, leading to down-regulation of pro-inflammatory cytokines releasing. In conclusion, our study suggested that carnosic acid nanoparticles protected against liver ischemia/reperfusion injury via its role of anti-oxidative, anti apoptotic and anti-inflammatory bioactivity. PMID- 27470362 TI - Plumbagin triggers DNA damage response, telomere dysfunction and genome instability of human breast cancer cells. AB - AIM: Natural plant products are increasingly being used in cancer therapeutic studies due to their reduced normal cell toxicity. In this study, the anti-cancer properties of plumbagin, a naphthoquinone derivative extracted from the roots of Plumbago, were evaluated in breast cancer cells. METHODS: To evaluate the effects of plumbagin on breast cancer cell types, we employed a variety of techniques comprising cell viability, cell cycle assay, comet assay, western blotting, immunocytochemistry, measurement of telomerase activity, telomere restriction fragment length, quantitative fluorescence in situ hybridisation, along with gene expression analysis of untreated cells. RESULTS: Plumbagin treatment induced cytotoxicity in human breast cancer cells along with cell cycle arrest, DNA damage and cell death leading to apoptosis. Plumbagin was also found to suppress the telomerase activity in cancer cells accompanied by telomere attrition. Telomere shortening was corroborated by reduced telomere fluorescence on chromosome ends and genome instability. CONCLUSION: Together, these findings may suggest the application of plumbagin as adjuvant modality in breast cancer therapeutics. PMID- 27470363 TI - Molecular and histological changes in cerebral cortex and lung tissues under the effect of tramadol treatment. AB - Tramadol abuse is one of the most frequent health problems in Egypt and worldwide. In most cases, tramadol abused by men face a problem with premature ejaculation. Tramadol like other opioids induces a decrease in plasma antioxidant levels, which may reflect a failure of the antioxidant defense mechanism against oxidative damage. The present work aimed to study the possible deleterious effects of oral administration of tramadol on brain and lung tissues in rats. Twenty adult male albino rats were divided into two groups; a control administered with normal saline and tramadol-treated (40mg/kg b.w.) group for 20 successive days. At the end of experimental period, blood was collected and specimens from brains and lungs were taken for histopathological and molecular studies. Malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities were measured in serum of control and tramadol-treated groups. Brain and lung specimens were histopathological evaluated using light microscopy. The expression levels of apoptotic related genes; Bcl-2, Bax and Caspase-3 were study in brain and lung tissues using RT-PCR analysis. We recorded a significant increase MDA level, while antioxidant enzymes; GSH, SOD and CAT were significantly decreased after tramadol-treatment. The obtained results revealed that tramadol induced a remarkable histomorphological changes in rats' brains (cerebral cortex and hippocampus) and severe histopathological changes in rats' lung when compared to that of control. On molecular level, the expression of the pro-apoptotic Bax and Caspase-3 showed a significant increase whereas the anti-apoptotic Bcl-2 decreased markedly indicating that tramadol is harmful at cellular level and can induce apoptotic changes in brain tissues. Our data confirmed the risk of increased oxidative stress, neuronal and pulmonary damage due to tramadol abuse. Although tramadol is reported to be effective in pain management, its toxicity should be kept in mind. PMID- 27470364 TI - IRE1alpha-TRAF2-ASK1 pathway is involved in CSTMP-induced apoptosis and ER stress in human non-small cell lung cancer A549 cells. AB - BACKGROUND: CSTMP, a Tetramethylpyrazine (TMP) analogue, is designed and synthesized based on the pharmacophores of TMP and resveratrol. Recent studies showed that CSTMP had strong protective effects in endothelial cells apoptosis by its anti-oxidant activity. However, the pharmacological function of CSTMP in cancer have not been elucidated to date. The objective of this study was to investigate the anti-cancer effect of CSTMP against human non-small cell lung cancer (NSCLC) A549 cells and the underlying mechanisms. METHODS: The cell proliferation and apoptosis were detected by MTT assay and flow cytometry. Caspases activity was determined spectrophotometricaly at 405nm using a microtiter plate reader. Western blot and real-time PCR was used to assess the protein and mRNA expression. Immunoprecipitation was used to examine the protein protein interactions. RESULTS: CSTMP inhibited the proliferation and induced cell cycle arrest and apoptosis of A549 cells. Caspase3, 8, 9 and PARP-1 activation, and Bax/Bcl-2 ratio analyses demonstrated that the anti-cancer effect of CSTMP in A549 cells was mediated by promoting caspase- and mitochondria-dependent apoptosis. Furthermore, CSTMP induced ER stress in A549 cells as evidenced by elevated levels of GRP78, GRP94, CHOP, IRE1alpha, TRAF2, p-ASK1 and p-JNK, activation of caspase12 and 4, and enhanced formation of an IRE1alpha-TRAF2-ASK1 complex. Knockdown of IRE1alpha by siRNA suppressed activation of IRE1alpha, TRAF2, p-ASK1 and p-JNK in CSTMP treated A549 cells. In addition, the effects of CSTMP on the formation of an IRE1alpha-TRAF2-ASK1 complex, caspase- and mitochondria-dependent apoptosis were also reversed by IRE1alpha siRNA in A549 cells. CONCLUSIONS: Collectively, we showed that CSTMP induced apoptosis of A549 cells were through IRE1alpha-TRAF2-ASK1 complex-mediated ER stress, JNK activation, and mitochondrial dysfunction. These insights on this novel compound CSTMP may provide a novel anti-cancer candidate for the treatment of NSCLC. PMID- 27470365 TI - LATS2 as a poor prognostic marker regulates non-small cell lung cancer invasion by modulating MMPs expression. AB - Large tumor suppressor 2 (LATS2) plays significant roles in tumorigenesis and cancer progression. This study was aimed to analyze the correlation between LATS2 expression and clinicopathologic features and its prognostic significance in non small cell lung cancer (NSCLC). LATS2 expression was examined in 73 NSCLC clinical specimens and 22 normal lung tissues using immunohistochemistry. Low levels of LATS2 protein were inversely associated with the T classification (P=0.001), N classification (P=0.005) and clinical stage (P=0.001) in NSCLC patients. Patients with lower LATS2 expression had a significantly shorter overall survival than patients with high LATS2 expression. Multivariate analysis suggested that low expression of LATS2 was an independent prognostic indicator (P=0.002) for the survival of patients with NSCLC. Furthermore, overexpression of LATS2 resulted in mobility inhibition in NSCLC cell lines A549 and H1299, and reduced protein level of matrix metalloproteinase-2 (MMP-2) and MMP-9. On the contrary, LATS2 siRNA treatment enhanced cell mobility and increased MMP-2 and MMP-9 protein expression level. In conclusion, low expression of LATS2 is a potential unfavorable prognostic factor and promoted cell invasion and migration in NSCLC. PMID- 27470366 TI - Inhibition of long non-coding RNA IGF2AS has profound effect on inducing neuronal growth and protecting local-anesthetic induced neurotoxicity in dorsal root ganglion neurons. AB - BACKGROUND: Long non-coding RNA IGF2AS was initially identified as a cancer regulator in wilm's tumors. In this study, IGF2AS was investigated of its functions in inducing neural development and protecting local-anesthetic induced neurotoxicity in dorsal root ganglion (DRG) in spinal cord. METHODS: Explant of mouse spinal cord DRG was transfected with IGF2AS specific siRNA. The effect of IGF2AS inhibition on neural development was assessed by neurite growth assay, qRT PCR and western blot assay, respectively. IGF2AS-downregulated DRG explant was then exposed to local anesthetic agent, lidocaine in vitro. The possible protective effects of IGF2AS inhibition on lidocaine-induced DRG neuron apoptosis and neurite loss were further assessed by TUNEL assay, neurite growth assay, qRT PCR and western blot assays. RESULTS: SiRNA-mediated IGF2AS inhibition promoted neuronal growth, and induced IGF2, BDNF and NT3 upregulations at both gene and protein expressions. In lidocaine-exposed DRG neurons, endogenous IGF2AS inhibition was effective to protect local-anesthetic induced neuronal apoptosis and neurite loss. Further molecular characterization demonstrated that the neuronal protection of IGF2AS inhibition was also associated with upregulations of IGF2, BDNF and NT3 in DRG neurons. CONCLUSIONS: Inhibiting endogenous IGF2AS may promote neuronal growth and protect local-anesthetic induced neurotoxicity in DRG neurons, possibly through complimentary IGF2 upregulation and autocrine activation neurotrophin genes. PMID- 27470367 TI - The protective effect of the earthworm active ingredients on hepatocellular injury induced by endoplasmic reticulum stress. AB - The earthworm is a widely used Chinese herbal medicine. There are more than 40 prescriptions including earthworms in the "Compendium of Materia Medica". TCM theory holds that earthworms exert antispasmodic and antipyretic effects through the liver meridian to calm the liver. However, the clinical effect of earthworms on liver injury has not been clearly demonstrated. We have previously established a method to extract the active ingredients from earthworms (hereinafter referred to as EWAs) [1]. In the present study, we observed protective effect of the EWAs on tunicamycin-induced ERS (endoplasmic reticulum stress) model in human hepatic L02 cells. The results showed that the EWAs promote proliferation and reduced apoptosis of ERS model in L02 cells (P<0.01). The up-regulation of ERS-related proteins, including PERK (protein kinase RNA-like endoplasmic reticulum kinase), eIF2a (eukaryotic translation initiation factor 2a), ATF4 (activating transcription factor 4) and CHOP (CCAAT/enhancer binding protein homologous protein), in L02 cell under ERS was inhibited by treatment of the EWAs (P<0.01). In summary, our data suggest the EWAs can significant attenuate ERS-induced hepatocyte injury via PERK-eIF2a-ATF4 pathway. PMID- 27470368 TI - HMGA1 facilitates tumor progression through regulating Wnt/beta-catenin pathway in endometrial cancer. AB - Recent studies have identified a unique role for high mobility group protein A1 (HMGA1) as a major regulator of tumor progression and in diverse tumor models. Emerging evidences indicate that overexpressed HMGA1 facilitates multiple malignant phenotypes of cancer cells, however, the oncogenic activities of HMGA1 in endometrial cancer (EC) remains elusive. Here we showed that HMGA1 was more frequently expressed in human EC tissues compared to non-tumor tissues. Elevated HMGA1 was significantly associated with advanced clinical stage. Wound-healing assay and transwell assay showed that HMGA1 can positively regulate cell migration and invasion. Mechanistically, luciferase reporter assay and Western blotting assay demonstrated that activation of Wnt/beta-catenin pathway contributed to the oncogenic activity of HMGA1. Taken together, our data reveal that HMGA1 may function as an oncogene and modulate EC cell migration and invasion by activating Wnt/beta-catenin pathway, implying that suppression of HMGA1 might be a potential therapeutic strategy for EC. PMID- 27470369 TI - Cryptotanshinone induces melanoma cancer cells apoptosis via ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion. AB - Melanoma is the most serious type of skin cancer because it is highly frequency of drug resistance and can spread earlier and more quickly than other skin cancers. The objective of this research was to investigate the anticancer effects of cryptotanshinone on human melanoma cells in vitro, and explored its mechanisms of action. Our results have shown that cryptotanshinone could inhibit cell proliferation in human melanoma cell lines A2058, A375, and A875 in a dose- and time-dependent manner. In addition, flow cytometry assay showed that cryptotanshinone inhibited the proliferation of human melanoma cell line A375 by blocking cell cycle progression in G2/M phase and inducing apoptosis in a concentration-dependent manner. Moreover, western blot analysis indicated that the occurrence of its apoptosis was associated with upregulation of cleaved caspases-3 and pro-apoptotic protein Bax while downregulation of anti-apoptotic protein Bcl-2. Meanwhile, cryptotanshinone could decrease the levels of reactive oxygen species (ROS). Furthermore, cryptotanshinone also blocked A375 cell migration and invasion in vitro which was associated with the downregulation with MMP-9. Taken together, these results suggested that cryptotanshinone might be a potential drug in human melanoma treatment by inhibiting proliferation, inducing apoptosis via ROS-mitochondrial apoptotic pathway and blocking cell migration and invasion. PMID- 27470370 TI - Synthesis and photodynamic activity of unsymmetrical A3B tetraarylporphyrins functionalized with l-glutamate and their Zn(II) and Cu(II) metal complex derivatives. AB - Four novel unsymmetrical A3B porphyrins 1, 2, 3 and 4 were synthesized following Lindsey procedure. Porphyrins 3 and 4 include one and three l-glutamate groups, respectively, and all porphyrins were metallated with Zn(II) (1a-4a) or Cu(II) (1b-4b). Porphyrins and metalloporphyrins presented values of singlet oxygen quantum yields (PhiD) ranging from 0.21 to 0.67. The tetraaryl derivatives in this study showed phototoxicity in SiHa cells with IC50 values ranging from <0.01 to 6.56+/-0.11MUM, the metalloporphyrin 4a showed the lowest IC50 value. Comparing the phototoxic activity between all porphyrins, functionalization of porphyrins with glutamate increased 100 times phototoxic activity (1 (IC50 4.81+/ 0.34MUM) vs. 3 (IC50 0.04+/-0.02MUM) and 2 (IC50 5.19+/-0.42MUM) vs. 4 (IC50 0.05+/-0.01MUM)). This increased activity could be attributed to reduced hydrophobicity and increased PhiDelta, given by functionalization with l glutamate. Metalloporphyrins 3a (IC50 0.04+/-0.01MUM) and 4a (IC50<0.01MUM) presented the best values of phototoxic activity. Therefore, functionalization and zinc metalation increased the phototoxic activity. SiHa cells treated with porphyrins 3, 4, 3a and 4a at a final concentration of 10MUM, showed increased activity of caspase-3 enzyme compared to the negative control; indicating the induction of apoptosis. Differential gene expression pattern in SiHa cells was determined; treatments with metalloporphyrins 4a and 4b were performed, respectively, comparing the expression with untreated control. Treatments in both cases showed similar gene expression pattern in upregulated genes, since they share about 25 biological pathways and a large number of genes. According to the new photophysical properties related to the structural improvement and phototoxic activity, these molecules may have the potential application as photosensitizers in the photodynamic therapy. PMID- 27470371 TI - Evaluation of antidiabetic effect of total calystegines extracted from Hyoscyamus albus. AB - BACKGROUND: Hyoscyamus albus L. (Solanaceae) an old medicinal plant is a rich source of tropane and nortropane alkaloids which confers to this plant a number of very interesting and beneficial therapeutic effects. PURPOSE: Calystegines that are polyhydroxylated alkaloids and imino-sugars poccess significant glycosidases inhibitory activities and are therefore good candidats for the treatment of diabetes mellitus. STUDY DESIGN: Calystegines extracted from Hyoscyamys albus seeds were tested for teir acute oral toxicity and investigated for their in-vivo antidiabetic effect on Streptozotocine induced diabetes in mice. METHODES: Calystegines were extracted from the seeds plant using an Ion exchange column; the remaining extract was then administrated orally to mice at several single doses for acute toxicity assay. A dose of 130mg/kg streptozotocine was injected to mice to induce diabetes mellitus, and diabetic mice were treated orally during 20days with 10mg/kg and 20mg/kg calystegines and 20mg/kg glibenclamide as the reference drug. RESULTS: Acute oral toxicity showed that calystegines are not toxic up to a dose of 2000mg/kg with absence of any signs of intoxication and damages in Liver and kidney tissues. The nortropane alkaloids markedly reduced blood glucose levels and lipid parameters of diabetic mice to normal concentrations after 20days of treatment at 10mg/kg and 20mg/kg (p<0.05). Histopathological study of diabetic mice pancreas indicated that calystegines of Hyoscyamus albus have minimized streptozotocine damages on beta-cells of islets of langerhans, stimulated beta-cells regeneration and improved with this insulin secretion. CONCLUSION: The findings of this study suggest that calystegines are potent antidiabetic agents with antihyperglicemic and hypolipidemic effects, and a protective fonction on pancreas in streptozotocin induced diabetes in mice. PMID- 27470372 TI - Chrysin, a flavonoid attenuates histological changes of hyperammonemic rats: A dose dependent study. AB - Chrysin (5,7-dihydroxyflavone) is a major component of some traditional medicinal herbs present in honey, propolis and many plant extracts. The study was aimed to illuminate the effect of chrysin in the pathogenesis of ammonium chloride (NH4Cl) induced hyperammonemic rat model in a dose dependent manner. Rats were injected with NH4Cl (100mg/kg b.w.) by intraperitonially (i.p) thrice a week for 8 consecutive weeks for the induction of experimental hyperammonemia. Hyperammonemic rats were treated with chrysin by orally at a dose of 25, 50 & 100mg/kg b.w. respectively. Protective effect of chrysin against hyperammonemia was evaluated by performing biochemical estimations and morphopathological investigations of hematoxylin and eosin stained sections of liver, brain and kidney tissues. Supplementation of chrysin reinstated the levels of blood ammonia, plasma urea, uric acid, total bilirubin, creatinine, brain glutamate, glutamine, nitric oxide (NO) and the activities of Na(+)/K(+)-ATPase, and liver marker enzymes. On the other hand increased level of plasma urea was observed in chrysin treated rats as compared with hyperammonemic rats. Chrysin administration caused distortion of hepatic, brain and kidney architecture as shown by histological examination. Chrysin at a dose (100mg/kg b.w.) showed an utmost decline in the level of all biochemical estimations. Both biochemical and morphological studies clearly revealed that chrysin protects against cell injury induced by ammonia intoxication in a dose-response manner with respect to endogenous antioxidants and hypoammonemic effects. PMID- 27470373 TI - "Effects of recombinant human erythropoietin high mimicking abuse doses on oxidative stress processes in rats". AB - Although many studies highlight how long-term moderate dose of Recombinant Human Erythropoietin (rHuEPO) treatments result in beneficial and antioxidants effects, few studies take into account the effects that short-term high doses of rHuEPO (mimicking abuse conditions) might have on the oxidative stress processes. Thus, the aim of this study was to investigate the in vivo antioxidant activity of rHuEPO, administered for a short time and at high doses to mimic its sports abuse as doping. Male Wistar healthy rats (n=36) were recruited for the study and were treated with three different concentrations of rHuEPO: 7.5, 15, 30MUg/kg. Plasma concentrations of erythropoietin, 8-epi Prostaglandin F2alpha, plasma and urinary concentrations of NOx were evaluated with specific assay kit, while hematocrit levels were analyzed with an automated cell counter. Antioxidant activity of rHuEPO was assessed analyzing the possible variation of the plasma scavenger capacity against hydroxylic and peroxylic radicals by TOSC (Total Oxyradical Scavenging Capacity) assay. Statistical analyses showed higher hematocrit values, confirmed by a statistically significant increase of plasmatic EPO concentration. An increase in plasma scavenging capacity against peroxyl and hydroxyl radicals, in 8-isoprostane plasmatic concentrations and in plasmatic and urinary levels of NOX were also found in all the treated animals, though not always statistically significant. Our results confirm the literature data regarding the antioxidant action of erythropoietin administered at low doses and for short times, whereas they showed an opposite incremental oxidative stress action when erythropoietin is administered at high doses. PMID- 27470374 TI - Protective effect of procyanidins extracted from the lotus seedpod on immune function injury induced by extremely low frequency electromagnetic field. AB - This study aimed to evaluate the protective effect of Lotus seedpod procyanidins (LSPCs) from extremely low frequency electromagnetic field (ELF-EMF) exposure (50Hz, 8mT, 28 days) and their protective mechanism against radiation damage. The results showed that LSPCs increased the organ index of mice and made the damaged blood-producing function and cytokine(INF-gamma, TNF-alpha, IL-2, IL-6 and IL-10 in spleen) levels by ELF-EMF-irradiation recovered to normal appearance. And experimental results proved that dosing LSPCs inhibit more stagnation of splenocytes in G0/G1 phase caused by ELF-EMF, thus the spleen cells from G0/G1 phase to S phase shift, restore normal cell metabolism, promote the splenocytes proliferation, reduced the apoptosis of spleen cells, effective protect the damage induced by the ELF-EMF radiation. In addition, LSPCs prevented the decline of DNA content caused by ELF-EMF. Western blot determinated the levels of apoptosis genes including Bcl-2, Bax, Bcl-cl, Caspase-3 and Caspase-9. The results revealed that a significant suppression in Bcl-2 expression and increase in Bax, Caspase-3 and Caspase-9 expression in splenic cells in ELF-EMF group. However, LSPCs restored these changes. Taking these results together, it may be summarized that LSPCs could protect hematopoietic tissues and the immune system from ELF-EMF. And it may be hypothesized that ELF-EMF-induced apoptosis in splenocytes might occur via triggers the trans-activation of Bax and activates caspases-3 and -9, which then cleaves the death substrates, leading to apoptosis in splenocytes of mice treated with ELF-EMF. PMID- 27470375 TI - Eupatilin inhibits the apoptosis in H9c2 cardiomyocytes via the Akt/GSK-3beta pathway following hypoxia/reoxygenation injury. AB - Eupatilin, a pharmacologically active flavone derived from the Artemisia plant species, has been reported to have anti-oxidant, anti-inflammatory, anti allergic, and neuroprotective activities against cerebral ischemia/reperfusion (I/R). However, the role of eupatilin in myocardial I/R injury remains unclear. In the present study, we aimed to investigate the potential molecular mechanisms against hypoxia/reoxygenation (H/R) induced cardiomyocytes apoptosis in vitro. Our results showed that eupatilin markedly improved the cell viability and decreased lactate dehydrogenase (LDH) release. Eupatilin also suppressed oxidative stress and apoptosis in H9c2 cells after myocardial I/R injury. Furthermore, eupatilin obviously increased the phosphorylation of Akt and GSK 3beta in H9c2 cells. Our results suggested that eupatilin could provide significant cardioprotection against myocardial I/R injury, and the potential mechanisms might involve inhibition of cardiomyocyte apoptosis through activating the Akt/GSK-3beta signaling pathway. PMID- 27470376 TI - Genistein as antioxidant and antibrowning agents in in vivo and in vitro: A review. AB - Genistein is a phytoestrogen with diverse biological activities. It is a potent antioxidant and antibrowning agent in in vivo and in vitro. Genistein acts as a preventative and therapeutic effects for cancers, postmenopausal syndrome, osteoporosis and cardiovascular diseases in animals and humans. Gensitein possesses cancer related enzyme-inhibitory effect and substantially inhibits skin carcinogenesis and cutaneous aging induced by ultraviolet (UV) light in mice and photodamage in humans. Two-stage skin carcinogenesis showed genistein exhibited a moderate inhibition of ornithine decarboxylase activity through blockage of DNA adducts formation. The anticancer, anti-inflammatory, cardio-protective and enzyme-inhibitory effects of genistein might be related to their antioxidant activities. Genistein also altered the Maillard reaction pathway by trapping the advanced glycation end products (AGEs) both in biological and protein-lactose suspensions. As a result, soy isoflavone can be used to enrich or fortify different types of food products. PMID- 27470377 TI - Chemical composition, efficacy and safety of Pistacia vera (var. Fandoghi) to inactivate protoscoleces during hydatid cyst surgery. AB - At present, various scolicidal agents have been used for inactivation of protoscoleces during hydatid cyst surgery, however, they are associated with serious adverse side effects including sclerosing colangititis (biliary tract fibrosis), liver necrosis and methaemoglobinaemia. This investigation was designed to evaluate the chemical composition and in vitro scolicidal effects of Pistacia vera (var. Fandoghi) essential oil against protoscoleces of hydatid cysts and also its toxicity in mice model. The components of the P. vera essential oil were identified by gas chromatography/mass spectroscopy (GC/MS) analysis. Protoscoleces were aseptically aspirated from sheep livers having hydatid cysts. Various concentrations of the essential oil (25-200MUl/mL) were used for 5-30min. Viability of protoscoleces was confirmed using eosin exclusion test (0.1% eosin staining). In addition, forty male NIH mice were used to determine the acute and sub-acute toxicity of P. vera essential oil for 2 and 14 days, respectively. The main components of P. vera essential oil were limonene (26.21%), alpha-pinene (18.07%), alpha-thujene (9.31%) and alpha-terpinolene (9.28%). Findings of the present study demonstrated that the P. vera essential oil at the concentrations of 100 and 200MUl/mL killed 100% protoscoleces after 10 and 5min of exposure, respectively. The LD50 values of intraperitoneal injection of the P. vera essential oil was 2.69ml/kg body weight, and the maximum nonfatal doses were 1.94ml/kg body weight. No significant difference (P>0.05) was observed in the clinical chemistry and hematological parameters following oral administrations of P. vera essential oil at the doses 0.1, 0.2, and 0.4ml/kg for 14 days. The obtained findings demonstrated new chemical composition and promising scolicidal activity of the P. vera with no significant toxicity which might be used as a natural scolicidal agent in hydatid cyst surgery. PMID- 27470378 TI - Protocatechuic acid inhibits osteoclast differentiation and stimulates apoptosis in mature osteoclasts. AB - BACKGROUND: Imbalance in bone remodeling causes osteoporosis. PURPOSE: In the present study, we identified that protocatechuic acid inhibits osteoclast differentiation and induces apoptosis in RAW264.7 murine macrophage cells. METHODS: Tartrate-resistance acid phosphatase (TRAP) activity was used to determine osteoclast formation. Oxidative stress was analyzed through ROS, lipid peroxide and antioxidant enzyme activities. Osteoclast and inflammatory marker expressions were determined through western blot. Apoptosis induction was determined through membrane potential analysis, Cyt c release and caspase activation. RESULTS: Protocatechuic acid dose dependently reduced RANKL-induced tartrate-resistance acid phosphatase (TRAP) activity and multinucleated osteoclasts formation. Protocatechuic acid inhibited oxidative stress by reducing ROS and lipid peroxide levels with concomitant increase in antioxidant status. Osteoclast specific marker expression (MMP, c-Src, TRAP, TRAF-6, Cathepsin) and transcription factor AP-1 and NFATc1 expression were significantly down regulated by protocatechuic acid. Further, MAPK activation and inflammatory proteins such as NF-kB and COX-2 expressions were significantly down regulated by protocatechuic acid treatment. Further, protocatechuic acid enhanced Nrf-2 translocation into the nucleus. In mature osteoclasts, protocatechuic acid induced apoptosis by inducing mitochondrial membrane potential, cytochrome c release and caspase activation. INTERPRETATION: The present findings shows evidence that, protocatechuic acid prevents osteoclast differentiation through regulating oxidative stress, inflammation and inducing apoptosis in RAW264.7 murine macrophage cells. PMID- 27470379 TI - Upregulation of the long non-coding RNA BANCR correlates with tumor progression and poor prognosis in esophageal squamous cell carcinoma. AB - Esophageal squamous cell cancer was one of the most lethal tumors. The lack of effective early diagnosis and treatment ways brings its mortality quite high. Esophageal squamous dysplasia (ESD), is the only histopathology that predicts the development of ESCC. Recent evidence indicates that long noncoding RNAs (lncRNAs) play a critical role in the tumor progression and poor prognosis. BRAF activated non-coding RNA (BANCR) is a 693-bp transcript with a potential functional role in melanoma cell migration. The clinical significance of BANCR, and its' relationship with precancerous lesion of ESCC are unclear. Expression of BANCR was analyzed in 142 ESCC tissues and eight ESCC cell lines using quantitative polymerase chain reaction (qPCR) assays. We further analyzed the BANCR expression level in plasma and precancerous lesion of ESCC. In our results, BANCR levels in plasma were significantly higher in ESCC patients than in normal controls and correlated well with the presence of tumor status. Besides, BANCR expression increased significantly from low to high-grade intraepithelial neoplasia. Additionally, increased BANCR expression was associated with worse histologic grade, advanced TNM stage, more lymph node metastasis, and shorter survival of ESCC patients. The expression level of BANCR reverts to normal after the tumor has been resected, and the expression level of BANCR increased with the disease progression. Increased BANCR expression was found to be an independent prognostic factor for ESCC. In summary, BANCR may be a novel tumor biomarker for early detection, a prospective prognostic indicator and a potential therapeutic target for ESCC and ESD patients. PMID- 27470380 TI - Targeting the interaction of Aurora kinases and SIRT1 mediated by Wnt signaling pathway in colorectal cancer: A critical review. AB - The Aurora kinases belong to the family of serine/threonine kinase, a central regulator of mitosis and their expression increased during G2/M phase. It is classified into Aurora A, B and C, each has distinct roles in cellular processes, which includes regulation of spindle assembly, function of centrosomes, cytoskeleton and cytokinesis. During cancer growth, their rapid increase makes most attractive marker for cancer treatment at present. However Aurora A kinase is known to be a marker for cancer therapy, the most important serine/threonine kinase of Aurora B kinase involvement in cancer is still inadequate. Subsequently, the recent findings revealed that the class III histone deacetylase of SIRT1 is a key regulator to activate Aurora kinases from S phase damaged DNA through Wnt signaling pathway. Even if both Aurora A kinase and SIRT1 serve as a marker for cancer therapy, the present review reveals it is interaction in Wnt signaling pathway that solely for colorectal cancer. PMID- 27470381 TI - Celecoxib and omega-3 fatty acids alone and in combination with risperidone affect the behavior and brain biochemistry in amphetamine-induced model of schizophrenia. AB - The implications of oxidative stress and neuro-inflammation in the pathogenesis of schizophrenia have been elucidated. Despite their effectiveness against positive symptoms of schizophrenia, antipsychotics have limited effectiveness against negative and cognitive symptoms and are associated with remarkable adverse effects. The use of celecoxib or omega-3 in schizophrenia may have beneficial effects. This study aimed to evaluate the possible efficacies of celecoxib, omega-3 or the combination of celecoxib+risperidone and omega-3+ risperidone compared to risperidone on the behavior and brain biochemistry in rats. In the present study, an amphetamine-induced model of schizophrenia in adult male rats was used to evaluate the effects of celecoxib, omega-3, celecoxib+risperidone and omega-3+ risperidone on the behavior of animals and on brain lipid peroxidation or tumor necrosis factor-alpha. In the water maze task, celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone significantly decreased the latency time compared to amphetamine-treated group. Celecoxib, omega-3, celecoxib+risperidone, omega-3+risperidone also significantly reversed the decreased spontaneous alternation induced by amphetamine in the Y-maze task. In the social interaction task, groups treated with celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone spent less time to recognize foreign animals than animals in the amphetamine-treated group. Increased brain MDA and TNF-alpha levels due to amphetamine were significantly reduced in groups treated with celecoxib+risperidone or omega-3+ risperidone. The present findings showed that celecoxib or omega-3 can attenuate amphetamine- induced behavioral impairment and these effects may be associated with their ability to decrease lipid peroxidation and cytokine release. Celecoxib or omega-3 may be promising candidates as adjuvant therapy for schizophrenia. PMID- 27470382 TI - Purmorphamine increased adhesion, proliferation and expression of osteoblast phenotype markers of human dental pulp stem cells cultured on beta-tricalcium phosphate. AB - OBJECTIVES: Growth factors play a significant role in cell proliferation and differentiation during different stages of the bone repair. However, several limitations have been brought researchers attention to an osteoinductive small molecule including Purmorphamine. In this study, we aimed to evaluate the effect of Purmorphamine on adhesion, proliferation and differentiation of human dental pulp stem cells (hDPSCs) seaded on beta-tricalcium phosphate (beta-TCP) granules. METHODS: hDPSCs were established from extracted wisdom teeth of healthy volenteers. Cells at passage 3 were seeded on beta-TCP in the presence or absence of Purmorphamine. Cell adhesion and proliferation were assessed using scanning electeron microscopy (SEM) and DNA counting assay, respectively, after 1, 3 and 5days. Then, hDPSCs seeded on beta-TCP were subjected to osteogenic medium with or without Purmorphamine. After 7 and 14days osteogenic diffrentiation capability of hDPSCs were determined using real-time RT-PCR and alkaline phosphatase (ALP) activity assay. RESULTS: The significant increase in amount of DNA was observed at day 3 and 5 in the presence of Purmorphamine. SEM imaging also was confirmed the DNA counting assay; in all given time points, hDPSC attachment and growth was significantly higher in the presence of Purmorphamine. ALP activity was increased by Purmorphamine at both 7 and 14days of induction. Purmorphamine showed to effect on osteopontin expression at earlier stage of osteogenic differentiation, whereas for osteocalcin expression, this effect was more evident at later stage of differentiation. CONCLUSION: Purmorphamine had a promotive effect on adhesion, proliferation and osteogenic differentiation of hDPSCs cultured on beta-TCP. The outcome of the current study would help in development of in vitro culture conditions for better osteogenic differentiation of hDPSCs prior to transplantation. PMID- 27470384 TI - Genetics and metabolic deregulation following cancer initiation: A world to explore. AB - Cancer is a group of highly complex and heterogeneous diseases with several causes. According to the stochastic model, cancer initiates from mutation in somatic cells, leading to genomic instability and cell transformation. This canonical pathway of carcinogenesis is related to the discovery of important mechanisms that regulate cancer initiation. However, there are few studies describing genetic and metabolic alterations that deregulate transformed cells, resulting in epithelial-mesenchymal transition (EMT) and its most dramatic consequence, the metastasis. This review summarizes the main genetics and metabolic changes induced by reactive oxygen species (ROS) that lead to EMT. PMID- 27470383 TI - Daphnetin ameliorates 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis through Nrf-2-Keap1 and NF-kappaB pathways. AB - Cancer is a faction of disorders that conjugated primarily with oxidative imbalance. In mammary carcinoma, oxidative stress secondarily changes various gene expressions and signalling pathways that bring genomic instability and mutagenic alterations that fascinating carcinogenesis. Several coumarin compounds are active against various malignancies. Among them, daphnetin (DAP) exhibits valuable safety and bioactivity profile that contributes towards its efficacy against cancer. In this study, the antioxidative and chemotherapeutic potential of DAP against 7,12-dimethylbenz(a)anthracene (DMBA)- induced mammary carcinogenesis was evaluated in female Sprague-Dawley rats. Besides this, we have determined the effect of DAP on Keap1-Nrf-2, associated HO-1 and NF-kappaB expressions behind the antioxidative and anti-proliferating activity. In our findings, a protective effect of DAP was established against lipid peroxidation, enzymic (Total SOD, MnSOD, CuZnSOD, CAT, GPx) and non-enzymic (GSH) antioxidative markers in serum, liver, kidney and breast tissue of both control and experimental groups. An up-regulation of protective Nrf-2 & HO-1 with a synchronized suppression in Keap1 & NF-kappaB mRNA and protein expressions were observed. DAP revealed the inhibition of p-AKT which accountable for decrease in NF-kappaB expressions but shown to be ineffective on p-ERK1/2. This study revealed that DAP inhibits mammary carcinogenesis through multiple mechanisms. Dual efficacy of DAP on Nrf-2-Keap1 pathway and NF-kappaB expressions propose it as a potential chemotherapeutic agent in mammary cancer management. PMID- 27470385 TI - Expression profile of plasma microRNAs in nonsyndromic cleft lip and their clinical significance as biomarkers. AB - OBJECTIVE: The aim of this study was to determine the expression profile of plasma microRNAs in nonsyndromic cleft lip (NSCL) and their clinical significance as biomarkers. METHODS: Agilent human miRNA microarray chips were used to analyze three NSCL plasma samples (mixed as CL group) and three normal plasma samples (mixed as Control group). Six selected plasma miRNAs were validated using qRT-PCR between another 13 CL and 11 healthy children. The receiver operating characteristic (ROC) curve analysis was applied for three elevated miRNAs, miR-16 2-3p, miR-365a-3p and miR-877-5p. Their target genes were further assessed using gene ontology and pathway analysis. RESULTS: The plasma miRNA differentially expressed (fold change >=2) amounted to 305. In particular, it had been validated that miR-16-2-3p, miR-365a-3p and miR-877-5p were elevated in NSCL plasma samples. ROC curve analysis revealed that each microRNA was able to significantly discriminate NSCL subjects from normal controls. Gene ontology and pathway analysis revealed that many processes over-represented in CL are related to system development process, regulation of nitrogen compound metabolic process, FoxO signaling pathway and the ErbB signaling pathway. CONCLUSION: Our study demonstrated that plasma miR-16-2-3p, miR-365a-3p and miR-877-5p might become biomarkers to diagnose NSCL and dysregulation of these miRNAs might be involved in the progression of NSCL. PMID- 27470386 TI - Endothelium- and smooth muscle-dependent vasodilator effects of Citrus aurantium L. var. amara: Focus on Ca(2+) modulation. AB - Neroli, the essential oil of Citrus aurantium L. var. amara, is a well characterized alleviative agent used to treat cardiovascular symptoms. However, because it has been found to have multiple effects, its mechanism of action requires further exploration. We sought to clarify the mechanism underlying the actions of neroli in mouse aorta. In aortic rings from mice precontracted with prostaglandin F2 alpha, neroli induced vasodilation. However, relaxation effect of neroli was decreased in endothelium-denuded ring or pre-incubation with the nitric oxide synthase inhibitor NG-Nitro-l-arginine-methyl ester (L-NAME). And also, neroli-induced relaxation was also partially reversed by 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), a soluble guanylyl cyclase (sGC) inhibitor. In addition, neroli inhibited extracellular Ca(2+)-dependent, depolarization-induced contraction, an effect that was concentration dependent. Pretreatment with the non-selective cation channel blocker, Ni(2+), attenuated neroli-induced relaxation, whereas the K(+) channel blocker, tetraethylammonium chloride, had no effect. In the presence of verapamil, added to prevent Ca(2+) influx via smooth muscle voltage-gated Ca(2+) channels, neroli-induced relaxation was reduced by the ryanodine receptor (RyR) inhibitor ruthenium red. Our findings further indicate that the endothelial component of neroli-induced vasodilation is partly mediated by the NO-sGC pathway, whereas the smooth muscle component involves modulation of intracellular Ca(2+) concentration through inhibition of cation channel-mediated extracellular Ca(2+) influx and store-operated Ca(2+) release mediated by the RyR signaling pathway. PMID- 27470387 TI - Activity of myricetin and other plant-derived polyhydroxyl compounds in human LDL and human vascular endothelial cells against oxidative stress. AB - Studies indicate that oxidative modifications of endothelium and LDL play a preeminent role in atherogenesis; therefore, the preservation of the endothelial antioxidant capacity and the inhibition of LDL oxidation by use of plant-derived compounds are an appealing strategy against several vascular disorders. On this basis, baicalein, eupatorin, galangin, magnolol, myricetin, oleuropein, silibinin and bilobalide were studied against various oxidative conditions. The radical scavenging capacity was analysed using DPPH and ORAC assays. Furthermore, the LDL oxidation was detected by measuring the formation of thiobarbituric acid reactive substances (TBARS) and by monitoring the oxidation kinetics. Further, we used cultured HUVEC to investigate the activities of the polyhydroxyl compounds towards the oxidative stress induced by H2O2. The lowest levels of TBARS were observed in the presence of oleuropein and baicalein, while myricetin, magnolol and eupatorin inhibited these ones to a lesser extent. In addition, oleuropein and myricetin exhibited higher protection in copper-induced LDL oxidation kinetics. However, only myricetin and galangin showed significant protective effects against H2O2 oxidative injury in HUVEC cells. Taken all together the results indicate myricetin as the most active agent among the selected plant derived polyhydroxyl compounds, with prominent capacities against ox-LDL and ROS production in HUVEC. PMID- 27470388 TI - CXCL10/CXCR3 axis promotes the invasion of gastric cancer via PI3K/AKT pathway dependent MMPs production. AB - CXCR3, a G-protein coupled chemokine receptor, has been found to be overexpressed in many tumors and act as an independent prognostic marker. However, it is still unclear whether CXCR3 is involved in gastric cancer progression. In this study, we found that CXCR3 was markedly expressed in gastric cancer cells and tissues. High CXCR3 expression correlated with advanced tumor stage, vascular invasion, lymph node metastasis and poor survival of gastric cancer patients. Activation of CXCR3 by one of its ligands CXCL10 promoted the invasion and migration of gastric cancer BGC-823 and MGC-803 cells, and increased the secretion and activities of MMP-2 and MMP-9. However, the effects of CXCL10 on gastric cancer cells were attenuated by CXCR3 siRNA transfection. Furthermore, overexpression of CXCR3 enhanced CXCL10-mediated cell invasion and migration of gastric cancer MKN28 cells. In addition, CXCR3 time-dependently induced activation of AKT. PI3K/AKT pathway was required for CXCR3-mediated gastric cancer cell invasion, migration and MMP-2/9 production. Together, our findings suggest that CXCL10/CXCR3 axis promotes gastric cancer cell invasion and migration by upregulating MMP-2 and MMP 9 production via PI3K/AKT pathway. Thus, CXCR3 could be a potential target for the gastric cancer treatment. PMID- 27470389 TI - Tetrahydroberberrubine attenuates lipopolysaccharide-induced acute lung injury by down-regulating MAPK, AKT, and NF-kappaB signaling pathways. AB - Acute lung injury (ALI) is a life-threatening syndrome that is characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality worldwide. Here, we studied the protective effect of tetrahydroberberrubine (THBru), a berberine derivative, on a mouse model of lipopolysaccharide (LPS)-induced acute lung injury that was established in our previous studies. The results showed that a single oral administration of THBru significantly decreased the lung wet to dry weight (W/D) ratio at doses of 2, 10 and 50mg/kg administered 1h prior to LPS challenge (30mg/kg, intravenous injection). Histopathological changes, such as pulmonary edema, infiltration of inflammatory cells and coagulation, were also attenuated by THBru. In addition, THBru markedly decreased the total cell counts, total protein and nitrate/nitrite content in bronchoalveolar lavage fluid (BALF), significantly decreased tumor necrosis factor-alpha (TNF-alpha) and nitrate/nitrite content in the plasma, and reduced the myeloperoxidase (MPO) activity in the lung tissues. Additionally, THBru (10MUM) significantly decreased the content of TNF-alpha and nitric oxide (NO) in LPS-induced THP-1 cells in vitro. Moreover, THBru significantly suppressed the activation of the MAPKs JNK and p38, AKT, and the NF-kappaB subunit p65 in LPS-induced THP-1 cells. These findings confirm that THBru attenuates LPS-induced acute lung injury by inhibiting the release of inflammatory cytokines and suppressing the activation of MAPKs, AKT, and NF kappaB signaling pathways, which implicates it as a potential therapeutic agent for ALI or sepsis. PMID- 27470390 TI - Interference of lysine-specific demethylase 1 inhibits cellular invasion and proliferation in vivo in gastric cancer MKN-28 cells. AB - BACKGROUND: Lysine-specific demethylase 1(LSD1), the first identified histone demethylase, plays an important role in the epigenetic regulation of gene activation and repression. Up-regulated LSD1expression has been reported in several malignant tumors.Our aim, therefore, was to better understand the mechanisms underlying the upregulation of LSD1 in gastric cancer. METHODS: We used lentiviral shRNA to knockdown LSD1 in the gastric cancer MKN-28 cell line. Cell proliferation was measured by MTT assay while cell apoptosis was assessed by Annexin V-FITC/PI double staining flow cytometry. The invasive potential of gastric cancer cells was determined by matrigel invasion assay. Protein expression was detected by Western blot. In vivo, the effect of knocking down LSD1 on tumor growth and protein expression in gastric cancer cells in nude mice was investigated. RESULTS: LSD1 knockdown in MKN-28 cell lines resulted in increasing the activity of cisplatin in vitro and the inhibition of cancer cell proliferation and invasion, and induced cell apoptosis. The expression of TGF beta1, VEGF, Bcl-2, beta-catenin, p-ERK and p-Smad 2/3 proteins was inhibited in LSD1 knockdown cells. Moreover, in an in vivo model of gastric cancer, LSD1 knockdown suppressed tumor growth and protein expression. CONCLUSION: LSD1 knockdown affected the fuction of gastric cancer MKN-28 cell line. LSD1 may be a latent target in the diagnosis and therapy of gastric cancer. PMID- 27470391 TI - Differential role of microRNAs in the pathogenesis and treatment of Esophageal cancer. AB - Esophageal cancer (EC) is the most invasive disease associated with inclusive poor prognosis. EC usually is found as either adenocarcinoma (EAC) or squamous cell carcinomas (ESCC). ESCC forms in squamous cells and highly occurs in the upper third of the esophagus. EAC appears in glandular cells and ordinarily develops in the lower one third of the esophagus near the stomach. Barrett's esophagus (BE) is a metaplastic precursor of EAC. There is a persistent need for improving our understanding of the molecular basis of this disease. MicroRNAs (miRNAs) demonstrate an uncovered class of small, non-coding RNAs that can negatively regulate the protein coding gene, and are associated with approximately all known physiological and pathological processes, especially cancer. MiRNAs can affect cancer pathogenesis, playing a crucial role as either oncogenes or tumor suppressors. The recent emergence of observations on the role of miRNAs in cancer and their functions has induced many investigations to examine their relevance to esophageal cancer. In esophageal cancer, miRNA dysregulation plays a crucial role in cancer prognosis and in patients' responsiveness to neo-adjuvant and adjuvant therapies. In this review, the oncogenic, tumor suppressive, and drug resistance related roles of miRNAs, and their involvement in the pathogenesis and treatment of esophageal cancer were summarized. PMID- 27470392 TI - Nephroprotective and antioxidant properties of Artemisia arborescens hydroalcoholic extract against oestroprogestative-induced kidney damages in rats. AB - OBJECTIVE: Currently, medicinal plants are found to have biological and pharmacological activities and are used in various domains. This study, carried out on Wistar rats, evaluates the beneficial effects of Artemisia arborscens extract on oestroprogestative-induced damages in kidney. MATERIALS AND METHODS: Thirty-six 3-month-old Wistar rats were divided into 4 batches of nine each: a control group, a group of rats receiving oestroprogestative treatment, a group undergoing oestroprogestative treatment after receiving Artemisia arborescens extract in drinking water, and a group that received only Artemisia arborescens. RESULTS: Artemisia arborescens extract was found to optimize many parameters which were shifted to pathological values as a consequence of oestroprogestative toxicity: plasma creatinine and urea levels were decreased, uric acid and proteins were restored to normal values. The alteration of renal architecture was also suppressed. In addition, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities that had been reduced in kidney of the treated group were restored by Aretmisia arborscens-based treatments and, therefore, the lipid peroxidation level was reduced in the renal tissue compared to the control group. CONCLUSION: The obtained results confirmed that the Artemisia-based treatment allowed efficient protection against oestroprogestative induced nephrotoxicity by restoring the activities of kidney. The protective effect of Artemisia arborescens was mainly attributed to antioxidant properties as well as the presence of phenolic acids and flavonoids detected by means of HPLC. PMID- 27470393 TI - IGF1R and c-met as therapeutic targets for colorectal cancer. AB - The type 1 IGF receptor (IGF1R) and mesenchymal-epithelial transition (MET) are hetrodimeric and transmembrane receptor tyrosine kinases, which are frequently overexpressed by several tumor types, including colorectal cancer (CRC). These receptors bind to their specific ligands, insulin growth factors (IGFs) and hepatocyte growth factor (HGF), respectively, and promote signaling cascades which mediates many functions such as proliferation and protection against apoptosis, cell scattering, tumor cell motility, invasion and metastasis. In patients with metastatic colorectal cancer (mCRC), IGF1R and c-met expression confer resistance to cetuximab (monoclonal antibodies against EGFR). Therefore, the c-met and IGF1R are now an attractive novel target for anticancer therapy. In this review, we will describe correlation between two receptors and their activation effects in tumor cells, and finally introduce useful and available strategies for their targeting. PMID- 27470394 TI - Hemolin triggers cell survival on fibroblasts in response to serum deprivation by inhibition of apoptosis. AB - Fibroblasts are the main cellular component of connective tissues and play important roles in health and disease through the production of collagen, fibronectin and growth factors. Under certain conditions, such as wound healing, fibroblasts intensify their metabolic demand, while the restriction of nutrients affect matrix composition, cell metabolism and behavior. In lepidopterans, wound healing is regulated by ecdysteroid hormones, which upregulate multifunctional proteins such as hemolin. However, the role of hemolin in cell proliferation and wound healing is not clear. rLosac is a recombinant hemolin from the caterpillar Lonomia obliqua whose proliferative and cytoprotective effects on endothelial cells have been described. Here, we show that rLosac induces a marked cell survival effect on fibroblast submitted to serum deprivation, which is observable as early as 24h, as demonstrated through the MTT assay, as well as an increase in migration of human dermal fibroblasts (HDF). No effects on cell proliferation or cell cycle distribution of fibroblasts in normal conditions were observed, suggesting that rLosac induces an effect in stressful conditions such serum deprivation but not when nutrient are sufficient. By flow cytometry, rLosac caused an apparent dose-dependent increase in cells in the S phase of the cell cycle and a significant reduction of cells with fragmented DNA. Furthermore, treatment with rLosac results in a significant decrease in the production of reactive oxygen species and in the loss of mitochondrial membrane potential, indicating that a reduction in oxidative stress is involved in rLosac-mediated cytoprotection. Our results also show an up-regulation of Bcl-2 and a down regulation of Bax protein levels, inhibition of cytochrome c release and a reduction in caspase-3 levels, all considered critical factors for apoptosis. Moreover, rLosac treatment reduces the morphological changes induced by prolonged serum deprivation including the emergence of apoptotic bodies, nucleus fragmentation, cytoplasmic vacuolization and loss of extracellular matrix organization. The wound scratch test assay revealed that rLosac could enhance wound healing in vitro. Altogether, these findings suggest that rLosac strongly induces cellular protection in conditions of stress by serum deprivation preventing damage and loss of mitochondrial function by inhibiting apoptosis. This finding opens a new perspective to further understand the role of hemolin proteins during cellular processes such as wound healing and development. PMID- 27470395 TI - Antidiabetic activity of Syzygium calophyllifolium in Streptozotocin-Nicotinamide induced Type-2 diabetic rats. AB - The study was initiated to determine the antidaibetic activity of Syzygium calophyllifolium in Streptozotocin-Nicotinamide (STZ-NA) induced diabetic rats. The rats were treated with 100 and 200mg/kg of the Syzygium calophyllifolium bark methanol extract (SCBM) and compared with the diabetic, normal and standard glibenclamide groups. The blood glucose level and body weight of the rats in different groups were monitored at regular intervals. The serum, blood biochemical and histopathological parameters of liver, kidney and pancreas were also analyzed. In vivo antioxidants like SOD, CAT, GST, GSH and GR levels were estimated in liver and kidney. SCBM (100mg/kg) extract could reduce the blood glucose level from the 15th day itself (213.67mg/dL) and the best reduction was observed till the end of the study with 259.25mg/dL (200mg/kg). Initial decrease in body weight was recovered after drug treatment and an increase in body weight was observed on the 4th week. The haematological parameters like total haemoglobin, packed cell volume percentage, total WBC and RBC content were found normal compared to that of normal untreated rats. Glibenclamide was also equally effective. The higher dose of SCBM extract could normalize the triglycerides, HDL, cholesterol and VLDL constituents in blood serum to the levels almost similar to that of normal rats. The results of the in vivo antioxidant levels showed that there are no significant difference in SOD, GSH and GR levels in all the groups compared to the normal control. SCBM and SMBM at 200mg/kg dose were much effective over the lower dose. The histology revealed that SCBM 200mg/kg could protect the cellular architecture of liver kidney and pancreas. The results from the study confirm ethnopharmacological significance of the plant and could be taken further for the development of an effective pharmaceutical drug against diabetes. PMID- 27470396 TI - Antitumor and immunomodulatory activities of thiosemicarbazones and 1,3-Thiazoles in Jurkat and HT-29 cells. AB - Cancer remains a high incidence and mortality disease, causing around 8.2 million of deaths in the last year. Current chemotherapy needs to be expanded, making research for new drugs a necessary task. Immune system modulation is an emerging concept in cancer cell proliferation control. In fact, there are a number of mechanisms underlying the role immune system plays in tumor cells. In this work, we describe the structural design, synthesis, antitumor and immunomodulatory potential of 31 new 1,3-thiazole and thiosemicarbazone compounds. Cisplatin was used as anticancer drug control. Cytotoxicity against J774A.1 macrophages and antitumor activity against HT-29 and Jurkat cells was determined. These 1,3 thiazole and thiosemicarbazone compounds not only exhibited cytotoxicity in cancer cells, but were able to cause irreversible cancer cell damage by inducing necrosis and apoptosis. In addition, these compounds, especially pyridyl thiazoles compounds, regulated immune factors such as interleukin 10 and tumor necrosis factor, possible by directing immune system in favor of modulating cancer cell proliferation. By examining their pharmacological activity, we were able to identify new potent and selective anticancer compounds. PMID- 27470397 TI - Calcitonin gene-related peptide in aerobic exercise induces collateral circulation development in rat ischemia myocardium. AB - PURPOSE: Aerobic exercise may offer favorable effects for coronary perfusion in the myocardial ischemia area, although the underlying molecular mechanisms remain unclear. This study was designed to investigate the effect of aerobic exercise on the collateral circulation in the ischemia myocardium and to evaluate calcitonin gene-related peptide (CGRP) changes during this process. METHODS AND RESULTS: Wistar rats were randomly divided into 3 groups of 7 rats each: a sham operated group (Sham), a myocardial ischemia-only group (MI) and a MI plus aerobic exercise group (MI+AE). The rat myocardial ischemia model was established by injecting isoprenaline (2mg/kg, i.p.). The aerobic exercise training consisted of swimming (40min/d, 5d/wk) for 4 weeks. At the end-points, after echocardiographic analysis was performed, blood and ischemia myocardium samples were collected and analyzed by ELISA to quantify the CGRP protein. The dorsal root ganglia were isolated and analyzed by reverse transcription polymerase chain reaction (RT-PCR) to examine the CGRP mRNA expression, and ischemia myocardium capillary density was evaluated by immunohistochemistry. Our data showed that the capillary density in the left ventricle and heart function were significantly decreased with decreased CGRP production in the MI rats, which were reversed by aerobic exercise in the MI+AE rats. CONCLUSION: These results indicate that aerobic exercise may alleviate myocardial ischemia through collateral circulation development with increased CGRP production. CGRP may play an important role in developing the collateral circulation. PMID- 27470398 TI - Antioxidant and antitumor efficacy of Luteolin, a dietary flavone on benzo(a)pyrene-induced experimental lung carcinogenesis. AB - The present study is designed to assess the antioxidant and antitumor potential of luteolin against benzo(a)pyrene [B(a)P]-induced lung carcinogenesis in Swiss albino mice. Here, we reported that oral administration of B(a)P (50mg/kg body weight) to mice resulted in raised lipid peroxides (LPO), lung specific tumor markers such as carcinoembryonic antigen (CEA) and neuron specific enolase (NSE) with concomitant decrease in the levels of both enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione-s-transferase (GST), and non enzymatic antioxidants such as reduced glutathione (GSH), vitamin E and vitamin C. Luteolin treatment (15mg/kg body weight, p.o) significantly counteracted all these alterations and maintained cellular normalcy. Moreover, assessment of protein expression levels by western blot analysis revealed that luteolin treatment effectively negates B(a)P-induced upregulated expression of proliferating cell nuclear antigen (PCNA), cytochrome P450 1A1 (CYP1A1) and nuclear factor-kappa B (NF-kappaB). Furthermore, histopathology of lung tissue and immunohistochemistry of CYP1A1 were carried out to substantiate the anti- lung cancer effect of luteolin. Overall, these findings confirm the chemopreventive potential of luteolin against B(a)P induced lung carcinogenesis. PMID- 27470399 TI - Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial. AB - BACKGROUND: Cytokines are involved in the development of metabolic abnormalities that may result in metabolic syndrome (MetS). Since curcumin has shown anti inflammatory properties, the aim of this study was to evaluate the effect of curcumin supplementation on serum cytokines concentrations in subjects with MetS. METHODS: This study was a post-hoc analysis of a randomized controlled trial in which males and females with diagnosis of MetS, according to the criteria defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines, were studied. Subjects who met the inclusion criteria were randomly assigned to either curcumin (daily dose of 1g/day) or a matched placebo for a period of 8 weeks. RESULTS: One hundred and seventeen subjects were assigned to either curcumin (n=59) or placebo (n=58) groups. Within-group analysis revealed significant reductions in serum concentrations of TNF-alpha, IL-6, TGF-beta and MCP-1 following curcumin supplementation (p<0.001). In the placebo group, serum levels of TGF-beta were decreased (p=0.003) but those of IL-6 (p=0.735), TNF alpha (p=0.138) and MCP-1 (p=0.832) remained unaltered by the end of study. Between-group comparison suggested significantly greater reductions in serum concentrations of TNF-alpha, IL-6, TGF-beta and MCP-1 in the curcumin versus placebo group (p<0.001). Apart from IL-6, changes in other parameters remained statistically significant after adjustment for potential confounders including changes in serum lipids and glucose levels, and baseline serum concentration of the cytokines. CONCLUSION: Results of the present study suggest that curcumin supplementation significantly decreases serum concentrations of pro-inflammatory cytokines in subjects with MetS. PMID- 27470400 TI - LncRNA CCAT2 predicts poor prognosis and regulates growth and metastasis in small cell lung cancer. AB - LncRNA colon cancer-associated transcript 2 (CCAT2) was firstly discovered and found overexpressed in colorectal cancer, and identified as is oncogenic lncRNA. However, the significance of CCAT2 in small cell lung cancer (SCLC) remains unclear. The expression of CCAT2 in SCLC tissues and cell lines was detected, and the association between CCAT2 expression and clinicopathological factors was analyzed. Cell proliferation and invasion assays were conducted by using SCLC cell lines transfected with CCAT2-siRNA or NC-siRNA. In our results, CCAT2 expression was elevated in SCLC tissues and cell lines, and correlated with malignant status and poor prognosis of SCLC patients. Furthermore, knockdown of CCAT2 expression effectively suppressed SCLC cell growth and metastasis in vitro. In conclusion, CCAT2 serves as an oncogenic lncRNA, and an independent unfavorable prognostic factor in SCLC patients. PMID- 27470401 TI - LncRNA-MEG3 inhibits cell proliferation of endometrial carcinoma by repressing Notch signaling. AB - BACKGROUND: The long non-coding RNA MEG3 has shown functional role as a tumor suppressor in many cancer types, excluding endometrial carcinoma (EC). Thus, this study tried to reveal the MEG3 dysregulation in EC samples and potential functional mechanism due to its regulation on Notch signaling pathway. METHODS: The expression profiles of MEG3 and two Notch signaling molecules, Notch1 and Hes1, were detected in both EC tissues and cell lines through real time PCR and western blot analysis. Lentiviral vector carrying whole MEG3 transcript or shRNA targeting MEG3 (shMEG3) was transfected for MEG3 dysfunction studies, and cell proliferation was analyzed through MTT and colony-formation assays. Xenograft models were also established by subcutaneous implantation and tumor growth was compared under MEG3 dysregulation. RESULTS: Significant downregulation of MEG3 was observed in EC samples compared to control, while the protein levels of Notch1 and Hes1 were both upregulated. Cell proliferation was obviously inhibited by MEG3 overexpression, while opposite improved result was obtained in MEG3 knockout cells. Interestingly, MEG3-induced changes could be reversed by Notch1 regulators. Moreover, MEG3 overexpressing tumors showed strongly repressed growth in vivo, along with Notch signaling inhibition. CONCLUSION: Downregulated MEG3 exhibited an anti-proliferative role in EC by repressing Notch signaling pathway. PMID- 27470402 TI - The effect of quercetin nanoparticle on cervical cancer progression by inducing apoptosis, autophagy and anti-proliferation via JAK2 suppression. AB - Cervical cancer is a cause of cancer death, making it as the one of the most common cause for death among women globally. Though many studies before have explored a lot for cervical cancer prevention and treatment, there are still a lot far from to know based on the molecular mechanisms. Janus kinase 2 (JAK2) has been reported to play an essential role in the progression of apoptosis, autophagy and proliferation for cells. We loaded gold-quercetin into poly (dl lactide-co-glycolide) nanoparticles to cervical cancer cells due to the propertities of quercetin in ameliorating cellular processes and the easier absorbance of nanoparticles. Here, in our study, quercetin nanoparticles (NQ) were administrated to cells to investigate the underlying mechanism by which the cervical cancer was regulated. First, JAK2-inhibited carvical cancer cell lines were involved for our experiments in vitro and in vivo. Western blotting, quantitative RT-PCR (qRT-PCR), ELISA, Immunohistochemistry, and flow-cytometric analysis were used to determine the key signaling pathway regulated by JAK2 for cervical cancer progression. And the role of quercetin nanoparticles was determined during the process. Data here indicated that JAK2, indeed, expressed highly in cancer cell lines compared to the normal cervical cells. And apoptosis and autophagy were found in JAK2-inhibited cancer cells through activating Caspase-3, and suppressing Cyclin-D1 and mTOR regulated by Signal Transducer and Activator of Transcription (STAT) 3/5 and phosphatidylinositide 3-kinase/protein kinases (PI3K/AKT) signaling pathway. The cervical cancer cells proliferation was inhibited. Further, tumor size and weight were reduced by inhibition of JAK2 in vivo experiments. Notably, administration with quercetin nanoparticles displayed similar role with JAK2 suppression, which could inhibit cervical cancer cells proliferation, invasion and migration. In addition, autophogy and apoptosis were induced, promoting cervical cancer cell death. To our knowledge, it was the first time to evaluate the role of quercetin nanoparticles in improving cervical cancer from apoptosis, autophagy and proliferation, which could be a potential target for future therapeutic approach clinically. PMID- 27470403 TI - Erythropoietin attenuates renal and pulmonary injury in polymicrobial induced sepsis through EPO-R, VEGF and VEGF-R2 modulation. AB - Sepsis remains the most important cause of acute kidney injury (AKI) and acute lung injury (ALI) in critically ill patients. The cecal ligation and puncture (CLP) model in experimental mice reproduces most of the clinical features of sepsis. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and pro angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO protection through the expression of the EPO/EPO receptor (EPO-R) and VEGF/VEF-R2 systems in kidneys and lungs of mice undergoing CLP-induced sepsis. Male inbred Balb/c mice were divided in three experimental groups: Sham, CLP, and CLP+EPO (3000IU/kg sc). Assessment of renal functional parameters, survival, histological examination, immunohistochemistry and/or Western blottings of EPO-R, VEGF and VEGF-R2 were performed at 18h post-surgery. Mice demonstrated AKI by elevation of serum creatinine and renal histologic damage. EPO treatment attenuates renal dysfunction and ameliorates kidney histopathologic changes. Additionally, EPO administration attenuates deleterious septic damage in renal cortex through the overexpression of EPO-R in tubular interstitial cells and the overexpression of the pair VEGF/VEGF-R2. Similarly CLP induced ALI, as evidenced by parenchymal lung histopathologic alterations, was ameliorated through pulmonary EPO-R, VEGF and VEGF-R2 over expression suggesting and improvement in endothelial survival and functionality. This study demonstrates that EPO exerts protective effects in kidneys and lungs in mice with CLP-induced sepsis through the expression of EPO-R and the regulation of the VEGF/VEGF-R2 pair. PMID- 27470404 TI - Pharmacokinetics, tissue distribution and anti-tumor effect of low density lipoprotein peptide conjugated submicron emulsions. AB - Docetaxel (Doc) is a potent chemotherapy for cancer but its application is limited by poor water solubility and high risk of side effects. To improve these issues, low density lipoprotein receptor (LDLR) targeted peptide-RLT (CEKLKEAFRLTRKRGLKLA) modified Docetaxel-loaded submicron emulsions (RLT-DocSEs) had been developed. Docetaxel-loaded SEs (DocSEs) and cationic DocSEs (DocCSEs) were also prepared for comparison. To evaluate the tumor-targeting ability and anti-tumor efficacy, DocSEs, DocCSEs, and RLT-DocSEs were administrated intravenously to rats respectively. The pharmacokinetic parameters of three formulations were significantly different. In vivo distribution study was conducted in mice and the results indicated that RLT-DocSEs possessed increased tumor targeting ability than DocSEs and DocCSEs. RLT-DocSEs also resulted in a higher tumor inhibition rate and a better anti-tumor efficacy in mice. All the results suggested that RLT-DocSEs could be a potential formulation for the injection of Doc with enhanced tumor targeting and anti-tumor efficacy. PMID- 27470405 TI - The defensin from avocado (Persea americana var. drymifolia) PaDef induces apoptosis in the human breast cancer cell line MCF-7. AB - Antimicrobial peptides (AMPs) are cytotoxic to cancer cells; however, mainly the effects of AMPs from animals have been evaluated. In this work, we assessed the cytotoxicity of PaDef defensin from avocado (Persea americana var. drymifolia) on the MCF-7 cancer cell line (a breast cancer cell line) and evaluated its mechanism of action. PaDef inhibited the viability of MCF-7 cells in a concentration-dependent manner, with an IC50=141.62MUg/ml. The viability of normal peripheral blood mononuclear cells was unaffected by this AMP. Additionally, PaDef induced apoptosis in MCF-7 cells in a time-dependent manner, but did not affect the membrane potential or calcium flow. In addition, PaDef IC50 induced the expression of cytochrome c, Apaf-1, and the caspase 7 and 9 genes. Likewise, this defensin induced the loss of mitochondrial Deltapsim and increased the phosphorylation of MAPK p38, which may lead to MCF-7 apoptosis by the intrinsic pathway. This is the first report of an avocado defensin inducing intrinsic apoptosis in cancer cells, which suggests that it could be a potential therapeutic molecule in the treatment of cancer. PMID- 27470406 TI - Neuroprotective effects of lotus seedpod procyanidins on extremely low frequency electromagnetic field-induced neurotoxicity in primary cultured hippocampal neurons. AB - The present study investigated the protective effects of lotus seedpod procyanidins (LSPCs) on extremely low frequency electromagnetic field (ELF-EMF) induced neurotoxicity in primary cultured rat hippocampal neurons and the underlying molecular mechanism. The results of MTT, morphological observation, superoxide dismutase (SOD) and malondialdehyde (MDA) assays showed that compared with control, incubating neurons under ELF-EMF exposure significantly decreased cell viability and increased the number of apoptotic cells, whereas LSPCs evidently protected the hippocampal neurons against ELF-EMF-induced cell damage. Moreover, a certain concentration of LSPCs inhibited the elevation of intracellular reactive oxygen species (ROS) and Ca(2+) level, as well as prevented the disruption of mitochondrial membrane potential induced by ELF-EMF exposure. In addition, supplementation with LSPCs could alleviate DNA damage, block cell cycle arrest at S phase, and inhibit apoptosis and necrosis of hippocampal neurons under ELF-EMF exposure. Further study demonstrated that LSPCs up-regulated the activations of Bcl-2, Bcl-xl proteins and suppressed the expressions of Bad, Bax proteins caused by ELF-EMF exposure. In conclusion, these findings revealed that LSPCs protected against ELF-EMF-induced neurotoxicity through inhibiting oxidative stress and mitochondrial apoptotic pathway. PMID- 27470407 TI - Chemoprotective action of lotus seedpod procyanidins on oxidative stress in mice induced by extremely low-frequency electromagnetic field exposure. AB - With the increasing use of electromagnetic technology, the effects of extremely low-frequency electromagnetic fields (ELF-EMF) on biological systems, central neurotransmitter systems, and human health have attracted extensive attention worldwide. In this study, lotus seedpod procyanidins (LSPCs) were evaluated for their protective effects on ELF-EMF induced oxidative stress injury in mice. Sixty male ICR mice were used for the experiment. The mice were randomly divided into five equal groups. The control group did not receive LSPCs or ELF-EMF but orally received normal saline. The ELF-EMF group received ELF-EMF exposure plus normal saline orally. The other three groups received ELF-EMF exposure plus LSPCs orally (60, 90, or 120mg kg(-1).bw, respectively). Each group exposed to ELF-EMF at 8 mT, 4h day(-1) for 28 consecutive days after administration daily of LSPCs or normal saline to mice for 15 consecutive days with the exception of the control group. Thereafter, blood and cerebral cortex of the mice were analyzed for antioxidant indices, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), glutathione-S transferase (GST) and malondialdehyde (MDA). LSPCs administration at different doses significantly inhibited oxidative stress damage of mice induced by ELF-EMF. LSPCs treatment augmented SOD, CAT, GSH-Px, GR and GST activity. Furthermore, administration significantly lowered MDA level in LSPCs treatment groups LSPCs. All results indicated LSPCs can effectively prevent oxidative stress injury induced by ELF-EMF exposure, which may be related to its ability of scavenging free radicals and stimulating antioxidant enzyme activity. PMID- 27470408 TI - TCH1036, a indeno[1,2-c]quinoline derivative, potentially inhibited the growth of human brain malignant glioma (GBM) 8401 cells via suppression of the expression of Suv39h1 and PARP. AB - A newly synthesized Indeno[1,2-c]quinoline derivative, which has previously been found to potentially trap DNA-topoisomerase cleavage complexes more effectively than camptothecin, could effectively inhibit the proliferation of a variety of cancers, such as breast cancer treated with TCH1030. In this study, we further explore the activity of the TCH1036, TCH1259 and TCH1030 compounds in suppressing the growth of human brain malignant glioma (GBM) 8401 cells, in addition to elucidating the related mechanisms. According to tests of cytotoxicity, the GBM cells were more sensitive to the inhibitory effects of the TCH1036 compound than to those of the other two compounds. Moreover, the accumulation of GBM cells in the sub-G1 and G2/M phases was clearly induced by the TCH1036 compound in a dose dependent manner. A screening of the majority of histone-modifier enzymes indicated that the expression of Suv39h1 in the GBM cells was attenuated by treatment with each of the TCH compounds, an observation which was further confirmed by Western blotting. The increase in active-form caspase 3 in the GBM cells treated with TCH compounds caused a high degree of poly (ADP-ribose) polymerase (PARP) cleavage and also enhanced the high ratio of hypodiploid GBM cells in the sub-G1 phase. In molecular docking simulations, it was observed that the stable forms of the TCH compounds could successfully insert into the catalytic pocket of PARP, with the highest affinity being between PARP and the TCH1036 compound. These findings suggested that the TCH1036 compound would be a promising compound in the treatment of brain malignant glioma. PMID- 27470409 TI - Hypolipidemic effect of dihydroisoquinoline oxaziridine in high-fat diet-fed rats. AB - Obesity is a serious health problem that increases the risk of many complications, including diabetes and cardiovascular disease. This study aims to evaluate, for the first time, the effects of oxaziridine 3 on lipoprotein lipase activity in the serum of rats fed with a high-fat diet (HFD) on body weight, lipid profile and liver-kidney functions. The administration of oxaziridine 3 to HFD-rats lowered body weight and inhibited the lipase activity of obese rats leading to notable decrease of T-Ch, TGs and LDL-Ch levels accompanied with an increase in HDL-Ch concentration in serum. Moreover, the findings of this study revealed that oxaziridine 3 helped to protect liver tissue from the appearance of fatty cysts. Additionally, oxaziridine 3 administration to HFD-rats induces antioxidant activity proven by the increase of superoxide dismutase (SOD) and catalase (CAT) activities and the decrease in Thiobarbituric acid reactive substances (TBARS) levels. It also induces the protection of liver-kidney functions confirmed by a decrease in the levels of toxicity parameters in blood. PMID- 27470410 TI - Loss of Raf kinase inhibitor protein is associated with malignant progression in hepatic fibrosis. AB - Raf kinase inhibitory protein (RKIP), besides regulating important intracellular signaling cascades, was described to be associated with progression, metastasis and prognosis in several human neoplasms. But its role in hepatic fibrogenesis remains unclear. In the present study, we found that the absence of RKIP expression significantly enhanced the proliferation of HSC-T6 cells. Reduced RKIP expression promoted the activation of HSCs and the accumulation of collagen, as evidenced by the increases in the levels of collagen I and alpha-smooth muscle actin. Moreover, down-regulating RKIP expression led to severe histopathological changes and collagen accumulation in hepatic tissues of rats with liver fibrosis. Furthermore, the absence of RKIP promoted the activation of ERK/MAPK pathway in vitro and in vivo. Our findings clearly demonstrate an inverse correlation between RKIP level and the degree of the liver injury and fibrosis. Loss of RKIP may be associated with malignant progression in hepatic fibrosis. PMID- 27470411 TI - Human toxoplasmosis-Searching for novel chemotherapeutics. AB - The protozoan Toxoplasma gondii, an obligate intracellular parasite, is an etiological agent of human and animal toxoplasmosis. Treatment regimens for T. gondii-infected patients have not essentially changed for years. The most common chemotherapeutics used in the therapy of symptomatic toxoplasmosis are a combination of pyrimethamine and sulfadiazine plus folinic acid or a combination of pyrimethamine with lincosamide or macrolide antibiotics. To protect a fetus from parasite transplacental transmission, therapy of pregnant women is usually based on spiramycin, which is quite safe for the organism, but not efficient in the treatment of infected children. Application of recommended drugs limits replication of T. gondii, however, it may be associated with numerous an severe adverse effects. Moreover, medicines have no impact on the tissue cysts of the parasite located predominantly in a brain and muscles. Thus, there is urgent need to develop new drugs and establish "gold standard" treatment. In this review classical treatment of toxoplasmosis as well as potential compounds active against T. gondii have been discussed. For two last decades studies on the development of new anti-T. gondii medications have been focused on both natural and novel synthetic compounds based on existing chemical scaffolds. They have revealed several promising drug candidates characterized by a high selectivity, the low IC50 (the half maximal inhibitory concentration) and low cytotoxicity towards host cells. These drugs are expected to replace or supplement current anti-T. gondii drug arsenal soon. PMID- 27470412 TI - Effect of resveratrol and rosuvastatin on experimental diabetic nephropathy in rats. AB - The development of diabetic nephropathy (DN) relays mainly on control of blood glucose and restrains hyperglycemic-induced oxidative stress. Hence, the effect administration of resveratrol (RSV) (5mg/kg) alone or in combination with rosuvastatin (RSU) (10mg/kg) on development and progression of diabetic nephropathy (DN) was evaluated. Oral treatment of diabetic rats with RSV alone or co-administered with RSU improved renal dysfunction indicated by a significant decrease in serum creatinine, urinary protein and urinary TGF-beta1 when compared with diabetic control rats. Also, a significant increase in body weight, relative kidney weight with a significant decrease in serum glucose and glycated hemoglobin in diabetic treated groups when compared with diabetic control group. Hyperglycemic-induced oxidative stress in diabetic control rats indicated by a significant decrease in renal activities of catalase, superoxide dismutase, glutathione peroxidase and reduced glutathione level with a significant increase in malondialdehyde levels. However, oral treatment of diabetic rats with RSV alone or co-administered with RSU improved the antioxidant status back to control values. Similarly, mRNA analysis of quantitative real time-PCR substantiated that RSV with RSU notably normalizes the renal expression of TGF-beta1, fibronectin, NF-kappaB/p65, Nrf2, Sirt1 and FoxO1 in the diabetic group of rats. The histopathological observations of the combined treated diabetic rats effectively protect the kidneys from hyperglycemic-induced oxidative damage. These findings confirmed the renoprotective effects of RSV with RSU treatment through improving glycemic control and attenuating oxidative stress damage in renal tissues of diabetic rats. PMID- 27470414 TI - Turkish propolis supresses MCF-7 cell death induced by homocysteine. AB - Elevated plasma homocysteine (Hcy) level is a most important risk factor for various vascular diseases including coronary, cerebral and peripheral arterial and venous thrombosis. Propolis is produced by honeybee from various oils, pollens and wax materials. Therefore, it has various biological properties including antioxidant, antitumor and antimicrobial activities. This study investigated the effects of propolis and Hcy on apoptosis in cancer cells. According to our findings, Hcy induced apoptosis in human breast adenocarcinoma (MCF-7) cells by regulating numerous genes and proteins involved in the apoptotic signal transduction pathway. In contrast, treatment with propolis inhibited caspase- 3 and -9 induced by Hcy in MCF-7 cells. It can be concluded that Hcy may augment the activity of anticancer agents that induce excessive reactive oxygen species (ROS) generation and apoptosis in their target cells. In contrast to the previous studies herein we found that propolis in low doses protected cancer cells inhibiting cellular apoptosis mediated by intracellular ROS-dependent mitochondrial pathway. PMID- 27470413 TI - Directional modification of chrysin for exerting apoptosis and enhancing significantly anti-cancer effects of 10-hydroxy camptothecin. AB - Chrysin, one of natural flavonoid compounds, has recently been found to possess anti-inflammatory, antiallergic and anticancer properties. To increase its anticancer effects, 5 chrysin derivates were synthesized on the base of DNA intercalator structure. The inhibiting effects of chrysin and its derivatives on cancer cells Hela, BGC823, MCF-7, HepG2, and normal cells HEK-293, were evaluated by MTT assays. 5-(2'-amino) phenyl-7-cyclohexanemethylchrysin (Ch-1), a unique chrysin derivate, killed all the cancer cells but kept above 60% survival rate in normal cells HEK-293 at 62.5MUM. Treated with chrysin from 250MUM to 500MUM, those cells were still maintained above 60% survival rate. The result of circular dichroism spectra showed that Ch-1 could intercalate DNA while chrysin had no effects on DNA. Interestingly, Hela cells survival rates were 95% and 10%, after treated with 20MUM and 30MUM of Ch-1, respectively. Both intrinsic and extrinsic apoptotic pathway were identified in regulating the cell death caused by Ch-1 in Hela cells. p53, the upstream regulator of apoptotic pathway were extremely significantly up-regulated in Hela cells treated with 25MUM Ch-1. Moreover, the inhibiting effects and apoptotic related proteins responses to Ch-1 on Hela cells were abolished after pre-treated with Pifithrin-alpha (Pft-alpha), a p53 inhibitor. So, p53-depedent apoptosis is the crucial factor governing the inhibiting effects of Ch-1 in Hela cells. Amazingly, Ch-1 at non-toxic concentration (2.5-10MUM) enhanced significantly anti-cancer effect of 10-hydroxy camptothecin (HCPT) on Hela, BGC823, and MCF-7 cells. PMID- 27470415 TI - Pharmacological evidence for the involvement of the NMDA receptor and nitric oxide pathway in the antidepressant-like effect of lamotrigine in the mouse forced swimming test. AB - Lamotrigine is an anticonvulsant agent that shows clinical antidepressant properties. The aim of the present study was to investigate the involvement of N methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) synthesis in possible antidepressant-like effect of lamotrigine in forced swimming test (FST) in mice. Intraperitoneal administration of lamotrigine (10mg/kg) decreased the immobility time in the FST (P<0.01) without any effect on locomotor activity in the open-field test (OFT), while higher dose of lamotrigine (30mg/kg) reduced the immobility time in the FST (P<0.001) as well as the number of crossings in the OFT. Pretreatment of animals with NMDA (75mg/kg), l-arginine (750mg/kg, a substrate for nitric oxide synthase [NOS]) or sildenafil (5mg/kg, a phosphodiesterase [PDE] 5 inhibitor) reversed the antidepressant-like effect of lamotrigine (10mg/kg) in the FST. Injection of l nitroarginine methyl ester (l-NAME, 10mg/kg, a non-specific NOS inhibitor), 7 nitroindazole (30mg/kg, a neuronal NOS inhibitor), methylene blue (20mg/kg, an inhibitor of both NOS and soluble guanylate cyclase [sGC]), or MK-801 (0.05mg/kg), ketamine (1mg/kg), and magnesium sulfate (10mg/kg) as NMDA receptor antagonists in combination with a sub-effective dose of lamotrigine (5mg/kg) diminished the immobility time of animals in the FST compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the OFT. Based on our findings, it is suggested that the antidepressant-like effect of lamotrigine might mediated through inhibition of either NMDA receptors or NO-cGMP synthesis. PMID- 27470416 TI - Long noncoding RNA BDNF-AS regulates ketamine-induced neurotoxicity in neural stem cell derived neurons. AB - BACKGROUND: Ketamine is an anesthetic commonly used in both humans and animals. Emerging evidence has demonstrated that ketamine may induce neurotoxicity in neural stem cell-derived neurons. In this work, we investigated whether long noncoding RNA (lncRNA) Brain derived neurotrophic factor antisense (BDNF-AS) was involved in ketamine-induced neurotoxicity in differentiation of mouse embryonic neural stem cells. METHODS: Mouse embryonic neural stem cells were differentiated in vitro, and treated with ketamine. The corresponding change in gene expression levels of BDNF and BDNF-AS were assessed by qRT-PCR. BDNF-AS was subsequently downregulated by siRNA. And its effect on protecting neuronal apoptosis, promoting neurite regrowth, and activating TrkB signaling pathways were assessed by TUNEL assay, neurite outgrowth assay, and western blot assay, respectively. RESULTS: In ketamine-injured mouse embryonic neural stem cell-derived neurons, BDNF was downregulated, whereas BDNF-AS was upregulated in dose-dependent manner. SiRNA-mediated BDNF-AS downregulation ameliorated neuronal apoptosis, induced neurite outgrowth, and phosphorylated TrkB signaling pathway after ketamine induce neurotoxicity in mouse embryonic neural stem cell-derived neurons. CONCLUSIONS: Inhibition of BDNF-AS is a novel method to protect ketamine-induced neurotoxicity in mouse embryonic neural stem cell-derived neurons, very likely through the activation of TrkB signaling pathway. PMID- 27470417 TI - Endocytosis regulates membrane localization and function of the fusogen EFF-1. AB - Cell fusion is essential for sexual reproduction and formation of muscles, bones, and placenta. Two families of cell fusion proteins (Syncytins and FFs) have been identified in eukaryotes. Syncytins have been shown to form the giant syncytial trophoblasts in the placenta. The FFs are essential to fuse cells in the skin, reproductive, excretory, digestive and nervous systems in nematodes. EFF-1 (Epithelial Fusion Failure 1), a member of the FF family, is a type I membrane glycoprotein that is essential for most cell fusions in C. elegans. The crystal structure of EFF-1 ectodomain reveals striking structural similarity to class II fusion glycoproteins from enveloped viruses (e.g. dengue and rubella) that mediate virus to cell fusion. We found EFF-1 to be present on the plasma membrane and in RAB-5-positive early endosomes, with EFF-1 recycling between these 2 cell compartments. Only when EFF-1 proteins transiently arrive to the surfaces of 2 adjacent cells do they dynamically interact in trans and mediate membrane fusion. EFF-1 is continuously internalized by receptor-mediated endocytosis via the activity of 2 small GTPases: RAB-5 and Dynamin. Here we propose a model that explains how EFF-1 endocytosis together with interactions in trans can control cell-cell fusion. Kontani et al. showed that vacuolar ATPase (vATPase) mutations result in EFF-1-dependent hyperfusion. 1 We propose that vATPase is required for normal degradation of EFF-1. Failure to degrade EFF-1 results in delayed hyperfusion and mislocalization to organelles that appear to be recycling endosomes. EFF-1 is also required to fuse neurons as part of the repair mechanism following injury and to prune dendrites. We speculate that EFF-1 may regulate neuronal tree like structures via endocytosis. Thus, endocytosis of cell-cell fusion proteins functions to prevent merging of cells and to sculpt organs and neurons. PMID- 27470422 TI - Different roles of ROS and Nrf2 in Cr(VI)-induced inflammatory responses in normal and Cr(VI)-transformed cells. AB - Hexavalent chromium (Cr(VI)) is classified as a human carcinogen. Cr(VI) has been associated with adenocarcinomas and squamous cell carcinoma of the lung. The present study shows that acute Cr(VI) treatment in human bronchial epithelial cells (BEAS-2B) increased inflammatory responses (TNF-alpha, COX-2, and NF kB/p65) and expression of Nrf2. Cr(VI)-induced generation of reactive oxygen species (ROS) are responsible for increased inflammation. Despite the fact that Nrf2 is a master regulator of response to oxidative stress, silencing of Nrf2 in the acute Cr(VI) treatment had no effect on Cr(VI)-induced inflammation. In contrast, in Cr(VI)-transformed (CrT) cells, Nrf2 is constitutively activated. Knock-down of this protein resulted in decreased inflammation, while silencing of SOD2 and CAT had no effect in the expression of these inflammatory proteins. Results obtained from the knock-down of Nrf2 in CrT cells are very different from the results obtained in the acute Cr(VI) treatment. In BEAS-2B cells, knock-down of Nrf2 had no effect in the inflammation levels, while in CrT cells a decrease in the expression of inflammation markers was observed. These results indicate that before transformation, ROS plays a critical role while Nrf2 not in Cr(VI) induced inflammation, whereas after transformation (CrT cells), Nrf2 is constitutively activated and this protein maintains inflammation while ROS not. Constitutively high levels of Nrf2 in CrT binds to the promoter regions of COX-2 and TNF-alpha, leading to increased inflammation. Collectively, our results demonstrate that before cell transformation ROS are important in Cr(VI)-induced inflammation and after transformation a constitutively high level of Nrf2 is important. PMID- 27470423 TI - Comparison of ultrasound-guided endometrial polypectomy carried out on the oocyte retrieval day and the first day of ovarian stimulation in IVF-ICSI cycles. AB - In this retrospective cohort study, the effect of endometrial polypectomy carried out on the day of oocyte retrieval and on the first day of ovarian stimulation in patients with a large (>=10 mm) endometrial polyp undergoing IVF and intractyoplasmic sperm injection (ICSI) was investigated and compared. A total of 74 eligible IVF-ICSI cycles in 74 women who underwent endometrial polypectomy on either the day of oocyte pick-up (late polypectomy group, 39 cycles) or the first day of ovarian stimulation (early polypectomy group, 35 cycles) between January 2007 and July 2012 were included in this study. Patient characteristics between early and late polypectomy groups were similar. Total dose and days of recombinant human FSH administered, numbers of retrieved oocytes, mature oocytes, fertilized oocytes, grade 1 or 2 embryos and embryos transferred between the two groups were also similar, as was clinical pregnancy rate per cycle, embryo implantation rate and spontaneous abortion rate between the two groups. Therefore, endometrial polypectomy on the day of oocyte retrieval could be a more patient-friendly option for patients with a large endometrial polyp undergoing IVF-ICSI. PMID- 27470424 TI - Role of Chronic Inflammation in Myopia Progression: Clinical Evidence and Experimental Validation. AB - Prevention and treatment of myopia is an important public problem worldwide. We found a higher incidence of myopia among patients with inflammatory diseases such as type 1 diabetes mellitus (7.9%), uveitis (3.7%), or systemic lupus erythematosus (3.5%) compared to those without inflammatory diseases (p<0.001) using data from children (<18years old) in the National Health Insurance Research database. We then examined the inhibition of myopia by atropine in Syrian hamsters with monocular form deprivation (MFD), an experimental myopia model. We found atropine downregulated inflammation in MFD eyes. The expression levels of c Fos, nuclear factor kappaB (NFkappaB), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha were upregulated in myopic eyes and downregulated upon treatment with atropine. The relationship between the inflammatory response and myopia was investigated by treating MFD hamsters with the immunosuppressive agent cyclosporine A (CSA) or the inflammatory stimulators lipopolysaccharide (LPS) or peptidoglycan (PGN). Myopia progression was slowed by CSA application but was enhanced by LPS and PGN administration. The levels of c-Fos, NF-kappaB, IL-6, and TNF-alpha were upregulated in LPS- and PGN-treated eyes and downregulated by CSA treatment. These findings provide clinical and experimental evidence that inflammation plays a crucial role in the development of myopia. PMID- 27470425 TI - Fine mapping of Restorer-of-fertility in pepper (Capsicum annuum L.) identified a candidate gene encoding a pentatricopeptide repeat (PPR)-containing protein. AB - KEY MESSAGE: Using fine mapping techniques, the genomic region co-segregating with Restorer - of - fertility ( Rf ) in pepper was delimited to a region of 821 kb in length. A PPR gene in this region, CaPPR6 , was identified as a strong candidate for Rf based on expression pattern and characteristics of encoding sequence. Cytoplasmic-genic male sterility (CGMS) has been used for the efficient production of hybrid seeds in peppers (Capsicum annuum L.). Although the mitochondrial candidate genes that might be responsible for cytoplasmic male sterility (CMS) have been identified, the nuclear Restorer-of-fertility (Rf) gene has not been isolated. To identify the genomic region co-segregating with Rf in pepper, we performed fine mapping using an Rf-segregating population consisting of 1068 F2 individuals, based on BSA-AFLP and a comparative mapping approach. Through six cycles of chromosome walking, the co-segregating region harboring the Rf locus was delimited to be within 821 kb of sequence. Prediction of expressed genes in this region based on transcription analysis revealed four candidate genes. Among these, CaPPR6 encodes a pentatricopeptide repeat (PPR) protein with PPR motifs that are repeated 14 times. Characterization of the CaPPR6 protein sequence, based on alignment with other homologs, showed that CaPPR6 is a typical Rf-like (RFL) gene reported to have undergone diversifying selection during evolution. A marker developed from a sequence near CaPPR6 showed a higher prediction rate of the Rf phenotype than those of previously developed markers when applied to a panel of breeding lines of diverse origin. These results suggest that CaPPR6 is a strong candidate for the Rf gene in pepper. PMID- 27470426 TI - Next-century ocean acidification and warming both reduce calcification rate, but only acidification alters skeletal morphology of reef-building coral Siderastrea siderea. AB - Atmospheric pCO2 is predicted to rise from 400 to 900 ppm by year 2100, causing seawater temperature to increase by 1-4 degrees C and pH to decrease by 0.1-0.3. Sixty-day experiments were conducted to investigate the independent and combined impacts of acidification (pCO2 = 424-426, 888-940 ppm-v) and warming (T = 28, 32 degrees C) on calcification rate and skeletal morphology of the abundant and widespread Caribbean reef-building scleractinian coral Siderastrea siderea. Hierarchical linear mixed-effects modelling reveals that coral calcification rate was negatively impacted by both warming and acidification, with their combined effects yielding the most deleterious impact. Negative effects of warming (32 degrees C/424 ppm-v) and high-temperature acidification (32 degrees C/940 ppm-v) on calcification rate were apparent across both 30-day intervals of the experiment, while effects of low-temperature acidification (28 degrees C/888 ppm v) were not apparent until the second 30-day interval-indicating delayed onset of acidification effects at lower temperatures. Notably, two measures of coral skeletal morphology-corallite height and corallite infilling-were negatively impacted by next-century acidification, but not by next-century warming. Therefore, while next-century ocean acidification and warming will reduce the rate at which corals build their skeletons, next-century acidification will also modify the morphology and, potentially, function of coral skeletons. PMID- 27470427 TI - Measuring the subjective: revisiting the psychometric properties of three rating scales that assess the acute effects of hallucinogens. AB - OBJECTIVE: In the present study we explored the psychometric properties of three widely used questionnaires to assess the subjective effects of hallucinogens: the Hallucinogen Rating Scale (HRS), the Mystical Experience Questionnaire (MEQ), and the Addiction Research Center Inventory (ARCI). METHODS: These three questionnaires were administered to a sample of 158 subjects (100 men) after taking ayahuasca, a hallucinogen whose main active component is N,N dimethyltryptamine (DMT). A confirmatory factorial study was conducted to check the adjustment of previous data obtained via theoretical proposals. When this was not possible, we used an exploratory factor analysis without restrictions, based on tetrachoric and polychoric matrices and correlations. RESULTS: Our results sparsely match the theoretical proposals of the authors, perhaps because previous studies have not always employed psychometric methods appropriate to the data obtained. However, these data should be considered preliminary, pending larger samples to confirm or reject the proposed structures obtained. CONCLUSIONS: It is crucial that instruments of sufficiently precise measurement are utilized to make sense of the information obtained in the study of the subjective effects of psychedelic drugs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470428 TI - Training model for control of an internal carotid artery injury during transsphenoidal surgery. AB - OBJECTIVES: As the adoption of endoscopic endonasal approaches (EEA) continues to proliferate, increasing numbers of internal carotid artery (ICA) injuries are reported. The objective of this study was to develop a synthetic ICA injury training model that could mimic this clinical scenario and be portable, repeatable, reproducible, and without risk of biological contamination. METHODS: Based on computed tomography of a human head, we constructed a synthetic model using selective laser sintering with polyamide nylon and glass beads. Subsequently, the model was connected to a pulsatile pump using 6-mm silicon tubing. The pump maintains a pulsatile flow of an artificial blood-like fluid at a variable pressure to simulate heart beats. Volunteer surgeons with different levels of training and experience were provided simulation training sessions with the models. Pre- and posttraining questionnaires were completed by each of the participants. RESULTS: Pre- and posttraining questionnaires suggest that repeated simulation sessions improve the surgical skills and self-confidence of trainees. CONCLUSION: This ICA injury model is portable; reproducible; and avoids ethical, biohazard, religious, and legal problems associated with cadaveric models. A synthetic ICA injury model for EEA allows recurring training that may improve the surgeon's ability to maintain endoscopic visualization, control catastrophic bleeding, decrease psychomotor stress, and develop effective team strategies to achieve hemostasis. LEVEL OF EVIDENCE: NA Laryngoscope, 127:38-43, 2017. PMID- 27470429 TI - A Comparison of Markov and Discrete-Time Microsimulation Approaches: Simulating the Avoidance of Alcohol-Attributable Harmful Events from Reduction of Alcohol Consumption Through Treatment of Alcohol Dependence. AB - BACKGROUND AND OBJECTIVE: When modelling the pathophysiology of a disease, it is important to select a modelling approach that can adequately replicate its course. The objective of this paper was to compare the outcomes obtained by the Markov and discrete-time microsimulation modelling approaches using nalmefene clinical trial data. METHODS: Markov and microsimulation modelling approaches assessing alcohol dependence treatment with psychosocial support with or without nalmefene were compared in terms of the modelled evolution of patients' alcohol consumption and the resulting occurrence of alcohol-attributable harmful events over 1 year. RESULTS: Comparison of the proportion of the modelled population at different levels of alcohol consumption over time revealed systematic differences arising from the different modelling techniques: a lower number of patients reaching abstinence, a higher number of patients at higher drinking levels, and, overall, a smoother evolution of alcohol consumption in the microsimulation. Reasons are discussed in the paper. While the models produced similar occurrences of alcohol-attributable harmful events as a whole, distinct results for the individual events were observed, explained by the specific pathophysiology of occurrence of these events and how their implementation was adapted to fit the limitations of the compared modelling approaches; however, these differences were only statistically significant for one of the eight events. CONCLUSIONS: For a general public health or health economic assessment of alcohol use disorders, it is possible to achieve similar results with the compared approaches. To assess a patients' disease course, taking into consideration alcohol-attributable harmful events, the microsimulation approach may provide more precise results. However, further external validation of the models is needed and this additional precision may be outweighed by the greater computational burden of a microsimulation approach. PMID- 27470430 TI - Pharmacokinetic Bioequivalence of Two Inhaled Tiotropium Bromide Formulations in Healthy Volunteers. AB - BACKGROUND AND OBJECTIVE: A novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 ug/capsule) while maintaining the same delivered dose (10 ug/actuation). This study describes the pharmacokinetic bioequivalence to the reference product. METHODS: This randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 MUg delivered dose) of the study medication, separated by a 14 day washout period: tiotropium 10 MUg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler((r)) (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid-liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (C max), area under the concentration-time curve (AUC) from time zero hours to the last observed concentration at time t (AUC t ), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80-125 %. Safety assessment was a secondary endpoint. RESULTS: A total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: C max (CI 87.26-106.60 %), AUC t (CI 101.33-111.64 %), and AUC0.5 (CI 97.95-113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration). CONCLUSIONS: Both products containing tiotropium 10 ug delivered dose DPI were bioequivalent and showed good tolerability and a similar safety profile. PMID- 27470431 TI - Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms. AB - Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) globally, and novel treatments are urgently needed. Current therapeutic approaches for diabetic nephropathy (DN) are focussing on blood pressure control with inhibitors of the renin-angiotensin-aldosterone system, on glycaemic and lipid control, and life-style changes. In this review, we highlight new molecular insights aiding our understanding of the initiation and progression of DN, including glomerular insulin resistance, dysregulation of cellular substrate utilisation, podocyte-endothelial communication, and inhibition of tubular sodium coupled glucose reabsorption. We believe that these mechanisms offer new therapeutic targets that can be exploited to develop important renoprotective treatments for DN over the next decade. PMID- 27470433 TI - Impact of inflammatory bowel disease on Japanese patients' quality of life: results of a patient questionnaire survey. AB - BACKGROUND: Inflammatory bowel disease (IBD) has a significant negative impact on quality of life (QOL); however, the direct impact of IBD on several aspects of patients' lives is unknown. The IMPACT survey was conducted in Europe in 2010 2011 to determine this impact. We conducted the IMPACT survey in Japan and compared the results between subgroups of patients with ulcerative colitis (UC) and Crohn's disease (CD). METHODS: The 52-item IMPACT survey questionnaire assessing treatment and the impact of IBD on patients' lives was translated into Japanese and administered to IBD patients recruited through patient advocacy groups. RESULTS: Between June 2013 and January 2014, 172 Japanese IBD patients completed the questionnaire (including 84 UC and 83 CD patients). Half of all patients (84/172, 48.8 %) were satisfied with their treatment plan, and half of those who had undergone surgery were satisfied with the outcome (46/87, 52.9 %). Although 34.9 % (60/172) of patients had not been hospitalized in 5 years, 50.0 % (86/172) had been hospitalized for more than 10 days. During the most recent flare, 49.4 % (85/172) of patients had to reschedule appointments because of IBD. Moreover, 32.0 % (55/172) of patients had to make adjustments such as working part-time or at home to avoid taking sick days; 35.5 % (61/172) of patients felt that they had lost a job because of IBD. CONCLUSIONS: Our survey results indicate that IBD patients' lives and social activities are affected by the deterioration of QOL due to IBD and its symptoms. PMID- 27470432 TI - The effect of lengthening contractions on neuromuscular junction structure in adult and old mice. AB - Skeletal muscles of old mice demonstrate a profound inability to regenerate fully following damage. Such a failure could be catastrophic to older individuals where muscle loss is already evident. Degeneration and regeneration of muscle fibres following contraction-induced injury in adult and old mice are well characterised, but little is known about the accompanying changes in motor neurons and neuromuscular junctions (NMJs) following this form of injury although defective re-innervation of muscle following contraction-induced damage has been proposed to play a role in sarcopenia. This study visualised and quantified structural changes to motor neurons and NMJs in Extensor digitorum longus (EDL) muscles of adult and old Thy1-YFP transgenic mice during regeneration following contraction-induced muscle damage. Data demonstrated that the damaging contraction protocol resulted in substantial initial disruption to NMJs in muscles of adult mice, which was reversed entirely within 28 days following damage. In contrast, in quiescent muscles of old mice, ~15 % of muscle fibres were denervated and ~80 % of NMJs showed disruption. This proportion of denervated and partially denervated fibres remained unchanged following recovery from contraction-induced damage in muscles of old mice although ~25 % of muscle fibres were completely lost by 28 days post-contractions. Thus, in old mice, the failure to restore full muscle force generation that occurs following damage does not appear to be due to any further deficit in the percentage of disrupted NMJs, but appears to be due, at least in part, to the complete loss of muscle fibres following damage. PMID- 27470435 TI - De novo transcriptome assembly and polymorphism detection in two highly divergent evolutionary units of Bosca's newt (Lissotriton boscai) endemic to the Iberian Peninsula. AB - This article reports the de novo transcriptome assemblies of two highly divergent evolutionary units of the Iberian endemic Bosca's newt, Lissotriton boscai. These two units are distributed mostly allopatrically but overlap in the central southwestern coastal region of Portugal. The resources we provide include the raw sequence reads, the assembled transcripts, the annotation and SNPs called for both lineages. PMID- 27470434 TI - Development of a scoring system for differentiating IgG4-related sclerosing cholangitis from primary sclerosing cholangitis. AB - BACKGROUND: Recent research has shown that a substantial number of patients with primary sclerosing cholangitis (PSC) can also have elevated serum/tissue IgG4. The aim of our study was to develop a simple scoring system for the discrimination of IgG4-related sclerosing cholangits (IgG4-SC) from PSC. METHODS: Patients with IgG4-SC (n = 39) and PSC (n = 76) who had intrahepatic/hilar strictures were included. Candidate-differentiating variables included patient age, other organ involvement (OOI), inflammatory bowel disease, serum IgG4, and cholangiographic features. A scoring system was developed on the basis of these variables, and its performance was internally validated using a bootstrapping based method. RESULTS: The scoring system in the final model included age (<30 years, 0 points; 30-39 years, 1 point; 40-49 years, 2 points; 50-59 years, 3 points; >=60 years, 4 points), OOI (no, 0 points; yes, 3 points), and beaded appearance (yes, 0 points; no, 2 points). The patients were classified according to their total score into three categories: 0-4 points, probable PSC; 5-6 points, indicating diagnostic steroid trial; 7-9 points, probable IgG4-SC. The discrimination between IgG4-SC and PSC using the scoring system was excellent (area under the receiver operating characteristic curve, 0.986). CONCLUSIONS: A reliable differentiation of IgG4-SC from PSC can be made using the scoring system presented here. We suggest the diagnosis of IgG4-SC at a cutoff of 7 points or higher and the indication of diagnostic steroid trial at 5 or 6 points. External validation of our scoring system is warranted. PMID- 27470436 TI - The random dot tachistogram: a novel task that elucidates the functional architecture of decision. AB - Reaction times are long and variable, almost certainly because they result from a process that accumulates noisy decision signals over time, rising to a threshold. But the origin of the variability is still disputed: is it because the incoming sensory signals are themselves noisy? Or does it arise within the brain? Here we use a stimulus - the random dot tachistogram - which demands spatial integration of information presented essentially instantaneously; with it, we demonstrate three things. First, that the latency distributions still show the variability characteristic of LATER, implying that there must be two integrators in series. Secondly, that since this variability persists despite removal of all temporal noise from the stimulus, or even trial-to-trial spatial variation, it must come from within the nervous system. Finally, that the average rate of rise of the decision signal depends linearly on how many dots move in a given direction. Taken together, this suggests a rather simple, two-stage model of the overall process. The first, detection, stage performs local temporal integration of stimuli; the local, binary, outcomes are linearly summed and integrated by LATER units in the second stage, that perform the final global decision by a process of racing competition. PMID- 27470437 TI - Abstracts from the International Anal Neoplasia Society Scientific Meeting, March 13-15, 2015, Atlanta, GA, USA - The Second Interdisciplinary Forum on Anal Neoplasia. PMID- 27470439 TI - Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 2. The biological variability of the murine Local Lymph Node Assay (LLNA) for skin sensitisation. AB - The Local Lymph Node Assay (LLNA) is the most common in vivo regulatory toxicology test for skin sensitisation, quantifying potency as the EC3, the concentration of chemical giving a threefold increase in thymidine uptake in the local lymph node. Existing LLNA data can, along with clinical data, provide useful comparator information on the potency of sensitisers. Understanding of the biological variability of data from LLNA studies is important for those developing non-animal based risk assessment approaches for skin allergy. Here an existing set of 94 EC3 values for 12 chemicals, all tested at least three times in the same vehicle have been analysed by calculating standard deviations (SD) for logEC3 values. The SDs range from 0.08 to 0.22. The overall SD for the 94 logEC3 values is 0.147. Thus the 95% confidence limits (2xSD) for LLNA EC3 values are within a factor of 2, comparable to those for physico-chemical measurements such as partition coefficients and solubility. The residual SDs of Quantitative Mechanistic Models (QMMs) based on physical organic chemistry parameters are similar to the overall SD of the LLNA, indicating that QMMs of this type are unlikely to be bettered for predictive accuracy. PMID- 27470440 TI - Migration limits for children's toys are nothing to play with. AB - The European Commission and its independent Scientific Committee on Health and Environmental Risks (SCHER) published their final Opinion on estimates of the amount of toy materials ingested by children. The SCHER was asked to review available data on the ingestion of the following three types of toy material by children, and evaluate whether the ingestion amounts which formed the basis for the migration limits of 19 elements in the Toy Safety Directive are still appropriate or whether they should be changed. In the final Opinion the SCHER considers the ingestion amounts mentioned above to be appropriate, and that these ingestion amounts should remain classified as daily amounts rather than weekly. PMID- 27470441 TI - Reproductive toxicity of ZishenYutai pill in rats: Perinatal and postnatal development study. AB - ZishenYutai pill (ZYP) is one of the most commonly used Chinese patent medicines for threatened miscarriage. Although ZYP is widely used, its toxic effects are rarely assessed. We aimed to investigate whether ZYP had reproductive toxicity during perinatal and postnatal period. Pregnant rats (F0) were continuously exposed to 6, 12 and 24 g/kg body weight/d of ZYP by intragastric administration from gestation day15 to post-natal day21. Vehicle and propylthiouracil (PTU, 15 mg/kg) were used as the negative control and positive control, respectively. The mating was done between the treatment (ZYP or PTU) group and negative control group when the F1 pups were born 63-70 days. Body weight, reproductive ability, physical development and neurodevelopment of F0, F1 and F2 pups were observed. The reproductive capacity of F0 and F1 generation decreased significantly after PTU exposure; however, the body weight and reproductive ability of F0, the physical development, weight, feed consumption and reproductive ability of F1, as well as the physical development and body weight of F2 rats were not significantly changed in the ZYP-treated group compared with the negative control group. ZYP exposure had no perinatal toxicity in 3 generations of rats and may be widely used for miscarriage. PMID- 27470443 TI - Surface modification of hollow magnetic Fe3O4@NH2-MIL-101(Fe) derived from metal organic frameworks for enhanced selective removal of phosphates from aqueous solution. AB - Hollow magnetic Fe3O4@NH2-MIL-101(Fe) derived from metal-organic frameworks are fabricated through a general facile strategy. The synthetic parameters are regulated to control the shape of the as-prepared samples. The concentration of phosphates decreased sharply from the initial 0.60 to 0.045 mg.L(-1) with the exposure time in 50 minutes. The correlation between the most significant parameters such as contact time, adsorbent dose, pH, as well as adsorption capacities was optimized, and the effects of these parameters on the removal efficiency of phosphates were investigated. Surface functionalization of magnetic hollow materials is a well-designed way to bridge the gap between high adsorption activity, excellent separation and recovery of phosphates from the water treatment system. Therefore, it exhibits a remarkable selective removal of phosphates from aqueous solution. PMID- 27470442 TI - Dynamic transcription factor activity networks in response to independently altered mechanical and adhesive microenvironmental cues. AB - Multiple aspects of the local extracellular environment profoundly affect cell phenotype and function. Physical and chemical cues in the environment trigger intracellular signaling cascades that ultimately activate transcription factors (TFs) - powerful regulators of the cell phenotype. TRACER (TRanscriptional Activity CEll aRrays) was employed for large-scale, dynamic quantification of TF activity in human fibroblasts cultured on hydrogels with a controlled elastic modulus and integrin ligand density. We identified three groups of TFs: responders to alterations in ligand density alone, substrate stiffness or both. Dynamic networks of regulatory TFs were constructed computationally and revealed distinct TF activity levels, directionality (i.e., activation or inhibition), and dynamics for adhesive and mechanical cues. Moreover, TRACER networks predicted conserved hubs of TF activity across multiple cell types, which are significantly altered in clinical fibrotic tissues. Our approach captures the distinct and overlapping effects of adhesive and mechanical stimuli, identifying conserved signaling mechanisms in normal and disease states. PMID- 27470444 TI - HP1BP3 expression determines maternal behavior and offspring survival. AB - Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3(-/-) deficient mouse dams, which could be rescued by co-fostering with wild-type dams. Hp1bp3(-/-) females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety-like behavior in the open-field and elevated-plus-maze tests. In contrast, Hp1bp3(-/-) females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety-associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety-related behavior in mice and call for exploring ways to manipulate this epigenetic process. PMID- 27470445 TI - Single cell analysis revealed a coexistence of NOTCH1 and TP53 mutations within the same cancer cells in chronic lymphocytic leukaemia patients. PMID- 27470446 TI - Corrigendum to "Tangeretin, a citrus pentamethoxyflavone, antagonizes ABCB1 mediated multidrug resistance by inhibiting its transport function" [Pharm. Res. 110 (2016) 193-204]. PMID- 27470447 TI - Retinoids and PPAR agonists: Promising partners in neurodegenerative diseases? PMID- 27470448 TI - Delivery of therapeutics with nanoparticles: what's new in cancer immunotherapy? AB - The application of nanotechnology to the treatment of cancer or other diseases has been boosted during the last decades due to the possibility to precise deliver drugs where needed, enabling a decrease in the drug's side effects. Nanocarriers are particularly valuable for potentiating the simultaneous co delivery of multiple drugs in the same particle for the treatment of heavily burdening diseases like cancer. Immunotherapy represents a new concept in the treatment of cancer and has shown outstanding results in patients treated with check-point inhibitors. Thereby, researchers are applying nanotechnology to cancer immunotherapy toward the development of nanocarriers for delivery of cancer vaccines and chemo-immunotherapies. Cancer nanovaccines can be envisioned as nanocarriers co-delivering antigens and adjuvants, molecules often presenting different physicochemical properties, in cancer therapy. A wide range of nanocarriers (e.g., polymeric, lipid-based and inorganic) allow the co formulation of these molecules, or the delivery of chemo- and immune-therapeutics in the same system. Finally, there is a trend toward the use of biologically inspired and derived nanocarriers. In this review, we present the recent developments in the field of immunotherapy, describing the different systems proposed by categories: polymeric nanoparticles, lipid-based nanosystems, metallic and inorganic nanosystems and, finally, biologically inspired and derived nanovaccines. WIREs Nanomed Nanobiotechnol 2017, 9:e1421. doi: 10.1002/wnan.1421 For further resources related to this article, please visit the WIREs website. PMID- 27470449 TI - 1-Year Outcomes of FFRCT-Guided Care in Patients With Suspected Coronary Disease: The PLATFORM Study. AB - BACKGROUND: Coronary computed tomographic angiography (CTA) plus estimation of fractional flow reserve using CTA (FFRCT) safely and effectively guides initial care over 90 days in patients with stable chest pain. Longer-term outcomes are unknown. OBJECTIVES: The study sought to determine the 1-year clinical, economic, and quality-of-life (QOL) outcomes of using FFRCT instead of usual care. METHODS: Consecutive patients with stable, new onset chest pain were managed by either usual testing (n = 287) or CTA (n = 297) with selective FFRCT (submitted in 201, analyzed in 177); 581 of 584 (99.5%) completed 1-year follow-up. Endpoints were adjudicated major adverse cardiac events (MACE) (death, myocardial infarction, unplanned revascularization), total medical costs, and QOL. RESULTS: Patients averaged 61 years of age with a mean 49% pre-test probability of coronary artery disease. At 1 year, MACE events were infrequent, with 2 in each arm of the planned invasive group and 1 in the planned noninvasive cohort (usual care strategy). In the planned invasive stratum, mean costs were 33% lower with CTA and selective FFRCT ($8,127 vs. $12,145 usual care; p < 0.0001); in the planned noninvasive stratum, mean costs did not differ when using an FFRCT cost weight of zero ($3,049 FFRCT vs. $2,579; p = 0.82), but were higher when using an FFRCT cost weight equal to CTA. QOL scores improved overall at 1 year (p < 0.001), with similar improvements in both groups, apart from the 5-item EuroQOL scale scores in the noninvasive stratum (mean change of 0.12 for FFRCT vs. 0.07 for usual care; p = 0.02). CONCLUSIONS: In patients with stable chest pain and planned invasive coronary angiography, care guided by CTA and selective FFRCT was associated with equivalent clinical outcomes and QOL, and lower costs, compared with usual care over 1-year follow-up. (The PLATFORM Study: Prospective LongitudinAl Trial of FFRct: Outcome and Resource IMpacts [PLATFORM]; NCT01943903). PMID- 27470450 TI - Integrating FFRCT Into Routine Clinical Practice: A Solid PLATFORM or Slippery Slope? PMID- 27470452 TI - Ischemic Heart Disease in New-Onset Heart Failure, or Finding Waldo: Where's Waldo? PMID- 27470451 TI - Underutilization of Coronary Artery Disease Testing Among Patients Hospitalized With New-Onset Heart Failure. AB - BACKGROUND: Although ischemic coronary artery disease (CAD) is the most common etiology of heart failure (HF), the extent to which patients with new-onset HF actually undergo an ischemic work-up and/or revascularization is not well defined. OBJECTIVES: This study sought to analyze the patterns of testing for ischemic CAD and revascularization in patients with new-onset HF. METHODS: This was a retrospective cohort study using Truven Health MarketScan Commercial and Medicare databases from 2010 to 2013. The occurrence of noninvasive and invasive ischemic CAD testing and revascularization procedures were examined among patients with new inpatient HF diagnoses during the index hospitalization and within 90 days of admission. RESULTS: Among 67,161 patients identified with new onset HF during an inpatient hospitalization, only 17.5% underwent testing for ischemic CAD during the index hospitalization, increasing to 27.4% at 90 days. Among patients with new-onset HF, only 2.1% underwent revascularization during the index hospitalization for HF; by 90 days, the revascularization rate had increased to 4.3%. Of the tests performed for ischemic CAD, stress testing (nuclear stress testing or stress echocardiography) was performed in 7.9% of new onset HF patients during the index hospitalization (14.6% within 90 days), whereas coronary angiography was performed in 11.1% of patients during the index hospitalization (16.5% within 90 days). In adjusted analyses, HF patients carrying a baseline diagnosis of CAD had greater odds of noninvasive ischemic testing (odds ratio: 1.25; 95% confidence interval: 1.17 to 1.33; p < 0.0001), as well as invasive ischemic testing (odds ratio: 1.93; 95% confidence interval: 1.83 to 2.05; p < 0.0001), at the index hospitalization than those without baseline CAD. CONCLUSIONS: The majority of patients hospitalized for new-onset HF did not receive testing for ischemic CAD either during hospitalization or within 90 days, which suggests significant underutilization of ischemic CAD assessment in new-onset HF patients. PMID- 27470453 TI - Refining Stroke Prediction in Atrial Fibrillation Patients by Addition of African American Ethnicity to CHA2DS2-VASc Score. AB - BACKGROUND: Prior studies show that African-American patients have a higher risk of stroke compared with Caucasians. OBJECTIVES: This study hypothesized addition of African-American ethnicity to CHA2DS2-VASc (congestive heart failure, hypertension, age >=75 years, diabetes, previous stroke, vascular disease, age 65 to 74, and female sex) score might improve stroke prediction in patients with atrial fibrillation (AF). METHODS: Medicare claims from January 2010 to December 2012 identified patients with newly diagnosed AF. The CHA2DS2-VASc was calculated on the basis of diagnoses in claims incurred during 12 months before first AF diagnosis. Ethnicity was identified from the Beneficiary Summary File. CHA2DS2 VASc-R score was calculated by giving 1 additional point for African-American ethnicity. The primary outcome was stroke, defined by primary diagnosis on acute inpatient admissions after the initial AF diagnosis. We used proportional hazards regression to determine the relationship between stroke and the CHA2DS2-VASc or a revised CHA2DS2-VASc-R score. RESULTS: Of 460,417 patients with AF, 390,590 (85%) were non-Hispanic whites, 31,702 (7%) were non-Hispanic African Americans, and the remainder were other non-white ethnicities. Mean age was 79.2 +/- 8.0 years, with 60% females. Overall, 16,703 stroke events occurred, and 151,441 (32.7%) patients died during a mean follow-up period of 18.0 months. Compared with CHA2DS2-VASc, CHA2DS2-VASc-R score improved the fit of the model significantly as measured by the log likelihood ratio statistic (p < 0.001). Among individual risk factors in CHA2DS2-VASc-R score, only prior stroke, age >=75 years, and female sex had a stronger association with incident stroke than African-American ethnicity. CONCLUSIONS: In patients >65 years of age with newly diagnosed AF, the addition of ethnicity to CHA2DS2-VASc score significantly improved stroke prediction. PMID- 27470454 TI - Stroke Prediction in Atrial Fibrillation: Is it Black and White? PMID- 27470455 TI - High-Output Heart Failure: A 15-Year Experience. AB - BACKGROUND: High-output heart failure (HF) is an unusual cause of cardiac failure that has not been well-characterized. OBJECTIVES: This study sought to characterize the etiologies, pathophysiology, clinical and hemodynamic characteristics, and outcomes of high-output HF in the modern era. METHODS: We performed a retrospective analysis of all consecutive patients referred to the Mayo Clinic catheterization laboratory for hemodynamic assessment between 2000 and 2014. Subjects with definite HF, as defined by the Framingham criteria, were compared to controls of similar age and sex. RESULTS: The most common etiologies of high-output HF (n = 120) were obesity (31%), liver disease (23%), arteriovenous shunts (23%), lung disease (16%), and myeloproliferative disorders (8%). Compared with controls (n = 24), subjects with high-output HF displayed eccentric left ventricular remodeling, greater natriuretic peptide activation, higher filling pressures, pulmonary hypertension, and increased cardiac output, despite similar ejection fraction. Elevated cardiac output in high-output HF patients was related to both lower arterial afterload (decreased systemic vascular resistance) and higher metabolic rate. Mortality was increased in high output HF as compared with controls (hazard ratio: 3.4; 95% confidence interval: 1.6 to 7.6). Hemodynamics and outcomes were poorest amongst patients with the lowest systemic vascular resistance. CONCLUSIONS: High-output HF is an important cause of clinical HF in the modern era that is related to excessive vasodilation, and most frequently caused by obesity, arteriovenous shunts, and liver disease. Given the high mortality and increasing prevalence of these comorbidities in Western countries, high-output HF must be considered in the differential diagnosis of patients presenting with dyspnea, congestion, and a normal ejection fraction. PMID- 27470456 TI - High-Output Heart Failure Revisited. PMID- 27470458 TI - Late Causes of Death After Congenital Heart Defects: A Population-Based Study From Finland. PMID- 27470457 TI - Late Causes of Death After Pediatric Cardiac Surgery: A 60-Year Population-Based Study. AB - BACKGROUND: Comprehensive information regarding causes of late post-operative death following pediatric congenital cardiac surgery is lacking. OBJECTIVES: The study sought to analyze late causes of death after congenital cardiac surgery by era and defect severity. METHODS: We obtained data from a nationwide pediatric cardiac surgery database and Finnish population registry regarding patients who underwent cardiac surgery at <15 years of age at 1 of 5 universities or 1 district hospital in Finland from 1953 to 2009. Noncyanotic and cyanotic defects were classified as simple and severe, respectively. Causes of death were determined using International Classification of Diseases diagnostic codes. Deaths among the study population were compared to a matched control population. RESULTS: Overall, 10,964 patients underwent 14,079 operations, with 98% follow up. Early mortality (<30 days) was 5.6% (n = 613). Late mortality was 10.4% (n = 1,129). Congenital heart defect (CHD)-related death rates correlated with defect severity. Heart failure was the most common mode of CHD-related death, but decreased after surgeries performed between 1990 and 2009. Sudden death after surgery for atrial septal defect, ventricular septal defect, tetralogy of Fallot, and transposition of the great arteries decreased to zero following operations from 1990 to 2009. Deaths from neoplasms, respiratory, neurological, and infectious disease were significantly more common among study patients than controls. Pneumonia caused the majority of non-CHD-related deaths among the study population. CONCLUSIONS: CHD-related deaths have decreased markedly but remain a challenge after surgery for severe cardiac defects. Premature deaths are generally more common among patients than the control population, warranting long term follow-up after congenital cardiac surgery. PMID- 27470460 TI - Does the Baseline Coronary Lesion Length Impact Outcomes With IVUS-Guided Percutaneous Coronary Intervention? PMID- 27470459 TI - Reducing Health Inequities in the U.S.: Recommendations From the NHLBI's Health Inequities Think Tank Meeting. AB - The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes; 2) develop research platforms that optimize the ability to conduct informative and innovative research, and promote systems science approaches; 3) develop networks of collaborators and stakeholders, and launch transformative studies that can serve as benchmarks; 4) optimize the use of new data sources, platforms, and natural experiments; and 5) develop unique transdisciplinary training programs to build research capacity. Confronting health inequities will require engaging multiple disciplines and sectors (including communities), using systems science, and intervening through combinations of individual, family, provider, health system, and community targeted approaches. Details of the panel's remarks and recommendations are provided in this report. PMID- 27470461 TI - Colonoscopy and Risk of Infective Endocarditis in the Elderly. PMID- 27470462 TI - Bioresorbable Scaffold Thrombosis: Why BRS Size Matters. PMID- 27470463 TI - Reply: Bioresorbable Scaffold Thrombosis: Why BRS Size Matters. PMID- 27470464 TI - Testosterone and Cardiac Diastolic Function. PMID- 27470465 TI - Reply: Testosterone and Cardiac Diastolic Function. PMID- 27470467 TI - Quantification of viable helminth eggs in samples of sewage sludge. AB - For the application of sewage sludge as fertilizer, it is of fundamental importance the absence of pathogenic organisms, such as viable helminth eggs. Thus, the quantification of these organisms has to be carried out by means of the application of reliable and accurate methodologies. Nevertheless, until the present date, there is no consensus with regard to the adoption of a universal methodology for the detection and quantification of viable helminth eggs. It is therefore necessary to instigate a debate on the different protocols currently in use, as well as to assemble relevant information in order to assist in the development of a more comprehensive and accurate method to quantify viable helminth eggs in samples of sewage sludge and its derivatives. PMID- 27470468 TI - Reverse osmosis membrane composition, structure and performance modification by bisulphite, iron(III), bromide and chlorite exposure. AB - Reverse osmosis (RO) membrane exposure to bisulphite, chlorite, bromide and iron(III) was assessed in terms of membrane composition, structure and performance. Membrane composition was determined by Rutherford backscattering spectrometry (RBS) and membrane performance was assessed by water and chloride permeation, using a modified version of the solution-diffusion model. Iron(III) dosage in presence of bisulphite led to an autooxidation of the latter, probably generating free radicals which damaged the membrane. It comprised a significant raise in chloride passage (chloride permeation coefficient increased 5.3-5.1 fold compared to the virgin membrane under the conditions studied) rapidly. No major differences in terms of water permeability and membrane composition were observed. Nevertheless, an increase in the size of the network pores, and a raise in the fraction of aggregate pores of the polyamide (PA) layer were identified, but no amide bond cleavage was observed. These structural changes were therefore, in accordance with the transport properties observed. PMID- 27470466 TI - Rapid construction of metabolite biosensors using domain-insertion profiling. AB - Single-fluorescent protein biosensors (SFPBs) are an important class of probes that enable the single-cell quantification of analytes in vivo. Despite advantages over other detection technologies, their use has been limited by the inherent challenges of their construction. Specifically, the rational design of green fluorescent protein (GFP) insertion into a ligand-binding domain, generating the requisite allosteric coupling, remains a rate-limiting step. Here, we describe an unbiased approach, termed domain-insertion profiling with DNA sequencing (DIP-seq), that combines the rapid creation of diverse libraries of potential SFPBs and high-throughput activity assays to identify functional biosensors. As a proof of concept, we construct an SFPB for the important regulatory sugar trehalose. DIP-seq analysis of a trehalose-binding-protein reveals allosteric hotspots for GFP insertion and results in high-dynamic range biosensors that function robustly in vivo. Taken together, DIP-seq simultaneously accelerates metabolite biosensor construction and provides a novel tool for interrogating protein allostery. PMID- 27470469 TI - Investigations of inorganic and organic fouling behaviors, antifouling and cleaning strategies for pressure retarded osmosis (PRO) membrane using seawater desalination brine and wastewater. AB - By employing seawater desalination brine (SWBr) and wastewater brine (WWBr) as the feed pair, membrane fouling behaviors as well as antifouling and cleaning strategies for the state-of-the-art thin-film composite polyethersulfone (TFC PES) hollow fiber membrane have been systematically investigated under pressure retarded osmosis (PRO) operations. Fouling on the polyamide selective layer induced by the SWBr draw solution is relatively mild because of the outstanding membrane rejection and the hydration antifouling layer formed by the permeating water. However, using WWBr as the feed causes fast and severe internal concentration polarization (ICP) and fouling within the porous PES substrate, which result in dramatic flux and power density declines. In addition, the PRO fouling upon and within the porous substrate is highly irreversible. Experimental data show that both anti-scalant pretreatment and pH adjustment of WWBr could effectively mitigate inorganic fouling, while increasing feed flow velocity along the substrate surface is ineffective for fouling control. To clean the fouled membranes, hydraulic-pressure induced backwash and flushing with alkaline and NaOCl solutions on the fouled surface are effective strategies to remove foulants and regenerate membranes with a flux recovery of 83-90%. However, osmotic backwash shows low cleaning efficiency in PRO. In summary, a proper combination of feed pretreatment and membrane cleaning strategies has been demonstrated in this study to sustain PRO operations with a high water flux and power density. PMID- 27470470 TI - Home-based Reach-to-Grasp training for people after stroke is feasible: a pilot randomised controlled trial. AB - OBJECTIVE: To determine feasibility of a randomised controlled trial (RCT) of home-based Reach-to-Grasp training after stroke. DESIGN: single-blind parallel group RCT. PARTICIPANTS: Residual arm deficit less than 12 months post-stroke. INTERVENTIONS: Reach-to-Grasp training in 14 one-hour therapist's visits over 6 weeks, plus one hour self-practice per day (total 56 hours). CONTROL: Usual care. MAIN MEASURES: Action Research Arm Test (ARAT), Wolf Motor Function Test (WMFT), pre-randomisation, 7, 12, 24 weeks post-randomisation. RESULTS: Forty-seven participants (Reach-to-Grasp=24, usual care=23) were randomised over 17 months. Reach-to-Grasp participants received a median (IQR) 14 (13,14) visits, and performed 157 (96,211) repetitions per visit; plus 30 minutes (22,45) self practice per day. Usual care participants received 10.5 (5,14) therapist visits, comprising 38.6 (30,45) minutes of arm therapy with 16 (6,24) repetitions of functional tasks per visit. Median ARAT scores in the reach-to-grasp group were 8.5 (3.0,24.0) at baseline and 14.5 (3.5,26.0) at 24 weeks compared to median of 4 at both time points (IQR: baseline (3.0,14.0), 24 weeks (3.0,30.0)) in the usual-care group. Median WMFT tasks completed at baseline and 24 weeks were 6 (3.0,11.5) and 8.5 (4.5,13.5) respectively in the reach-to-grasp group and 4 (3.0,10.0), 6 (3.0,14.0) in the usual care group. Incidence of arm pain was similar between groups. The study was stopped before 11 patients reached the 24 weeks assessment. CONCLUSIONS: An RCT of home-based Reach-to-Grasp training after stroke is feasible and safe. With ARAT being our preferred measure it is estimated that 240 participants will be needed for a future two armed trial. PMID- 27470472 TI - [Standardized feeding practice for preterm infants and optimized the nutritional management]. PMID- 27470471 TI - Maribacter litorisediminis sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-spore-forming, non-flagellated, non-gliding and rod-shaped bacterial strain, HPTF-2T, was isolated from a tidal flat in the Yellow Sea in South Korea, and subjected to a taxonomic study using a polyphasic approach. Strain HPTF-2T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain HPTF-2T fell within the clade comprising the type strains of species of the genus Maribacter. Strain HPTF-2T exhibited 16S rRNA gene sequence similarity values of 97.1-98.0 % to the type strains of Maribacter stanieri, M. orientalis, M. arcticus, M. dokdonensis, M. confluentis, M. aquivivus, M. sedimenticola and M. caenipelagi, and of 95.1-96.7 % to the type strains of the other species of the genus Maribacter. Strain HPTF-2T contained MK 6 as the predominant menaquinone and iso-C17 : 0 3-OH, iso-C15 : 0 and iso-C15 : 1 G as the major fatty acids. The major polar lipids of strain HPTF-2T were phosphatidylethanolamine and two unidentified lipids. Mean DNA-DNA relatedness values of strain HPTF-2T with the type strains of the nine phylogenetically related species of the genus Maribacter were 10-26 %. The DNA G+C content of strain HPTF-2T was 38.4 mol%. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain HPTF-2T is separated from other species of the genus Maribacter. On the basis of the data presented, strain HPTF-2T represents a novel species of the genus Maribacter, for which the name Maribacter litorisediminis sp. nov. is proposed. The type strain is HPTF-2T (=KCTC 52251T=NBRC 112297T). PMID- 27470473 TI - [Confusion and thinking in the management of patent ductus arteriosus in preterm infants]. PMID- 27470474 TI - [Recommendations for feeding preterm or low birth weight infants after hospital discharge]. PMID- 27470475 TI - [Recommendation for promoting the practice of human milk using and breast feeding for the preterm infant in neonatal intensive care unit]. PMID- 27470476 TI - [The recommendation of classifying construction and management of pediatric intensive care unit in China]. PMID- 27470477 TI - [NO. 141: intermittent fever, cough, wheezing for 30 days, rashes for 19 days]. PMID- 27470478 TI - [A case of neonatal anisodamine poisoning]. PMID- 27470479 TI - [Report of a case with multicentric Castleman's disease associated with EB virus infection]. PMID- 27470480 TI - [Application of research advance in airway pressure release ventilation in children]. PMID- 27470481 TI - [The clinical application of biologicals in juvenile idiopathic arthritis]. PMID- 27470482 TI - Chitosan/lecithin liposomal nanovesicles as an oral insulin delivery system. AB - In the present work, insulin-chitosan polyelectrolyte complexes associated to lecithin liposomes were investigated as a new carrier for oral delivery of insulin. The preparation was characterized in terms of particle size, zeta potential and encapsulation efficiency. Surface tension measurements revealed that insulin-chitosan polyelectrolyte complexes have some degree of hydrophobicity and should be added to lecithin liposomal dispersion and not the vice versa to prevent their adsorption on the surface. Stability of insulin was enhanced when it was associated to liposomes. Significant reduction of blood glucose levels was noticed after oral administration of liposomal preparation to streptozotocin diabetic rats compared to control. The hypoglycemic activity was more prolonged compared to subcutaneously administered insulin. PMID- 27470483 TI - Political and economic transformations in Ukraine: The view from psychiatry. AB - This article examines contemporary Ukrainian psychiatry through the voices of patients, practitioners, and advocates, focusing on shifting objects of knowledge, interventions, and institutional transitions. Currently, we are witnessing the reconfiguration of psychiatry on a global scale through neoliberal rhetoric combined with the call for global mental health. The goal of the movement for global mental health is to scale up psychiatric treatments through greater access to psychiatric drugs, justified through the framing of distress as an illness. Neoliberal rhetoric suggests that cutting social service expenditure through the privatization and decentralization of the health care system will stimulate economic growth and, in the long term, combat poverty. This paper traces how these dynamics are playing out in Ukraine, drawing on ethnographic fieldwork conducted at a psychiatric hospital in south-central Ukraine from 2008 2010, while working with a non-governmental organization. PMID- 27470485 TI - Synthesis and application of hexagonal perovskite BaNiO3 with quadrivalent nickel under atmospheric and low-temperature conditions. AB - A hexagonal perovskite BaNiO3 with unusually high-valence nickel(iv) was synthesized under atmospheric and low-temperature conditions by an ethylenediamine-derived wet-chemical route. Secondary phases disappeared with increase in the pH value, and the single-phase BaNiO3 was successfully synthesized at pH 10. The specific surface area was ~32 m(2) g(-1), which is significantly enhanced compared to the BaNiO3 (0.3 m(2) g(-1)) synthesized by flux-mediated crystal growth. The BaNiO3 was used as an oxygen-evolution reaction (OER) catalyst, and the specific mass activity was ~5 times higher than that of the BaNiO3 synthesized by flux-mediated crystal growth. As a result, the ethylenediamine-derived sol-gel synthesis could be a simple technique to prepare crystalline compounds such as perovskites and spinels, with unusually high valence transition metals. PMID- 27470484 TI - Insights into the abundance and diversity of abyssal megafauna in a polymetallic nodule region in the eastern Clarion-Clipperton Zone. AB - There is growing interest in mining polymetallic nodules in the abyssal Clarion Clipperton Zone (CCZ) in the Pacific. Nonetheless, benthic communities in this region remain poorly known. The ABYSSLINE Project is conducting benthic biological baseline surveys for the UK Seabed Resources Ltd. exploration contract area (UK-1) in the CCZ. Using a Remotely Operated Vehicle, we surveyed megafauna at four sites within a 900 km(2) stratum in the UK-1 contract area, and at a site ~250 km east of the UK-1 area, allowing us to make the first estimates of abundance and diversity. We distinguished 170 morphotypes within the UK-1 contract area but species-richness estimators suggest this could be as high as 229. Megafaunal abundance averaged 1.48 ind. m(-2). Seven of 12 collected metazoan species were new to science, and four belonged to new genera. Approximately half of the morphotypes occurred only on polymetallic nodules. There were weak, but statistically significant, positive correlations between megafaunal and nodule abundance. Eastern-CCZ megafaunal diversity is high relative to two abyssal datasets from other regions, however comparisons with CCZ and DISCOL datasets are problematic given the lack of standardised methods and taxonomy. We postulate that CCZ megafaunal diversity is driven in part by habitat heterogeneity. PMID- 27470486 TI - Incidence rate of amyloidosis in patients from a medical care program in Buenos Aires, Argentina: a prospective cohort. AB - BACKGROUND: There are limited data concerning the incidence density (ID) of ATTRwt, AL and AA amyloidosis in the Argentinean population. Our aim was to estimate the ID of ATTRwt, AL and AA amyloidosis at the Hospital Italiano Medical Care Program in Buenos Aires, Argentina. METHODS: Population was all members of a hospital-based health maintenance organization who were affiliated since January 2006 to December 2014. Each person was followed contributing time at risk since January 2006 or enrollment date to the final date. Incident cases of amyloidosis were captured from the institutional registry of amyloidosis. Incidence rate was calculated with 95% confidence intervals. RESULTS: During the nine-year study period, there were 15 patients with ATTRwt, 12 with AL and 2 with AA amyloidosis for 1 105 152 person-years of follow-up. The crude ID of ATTRwt amyloidosis was 13.5 (95%CI 8.1-22.4), that of AL amyloidosis 11 (95%CI: 6-19) and that of AA amyloidosis 1.8 (95%CI: 0.5-7.2) per 1 000 000 person-years. The highest ID was found in men (31.7 for ATTRwt, 15.9 for AL and 2.27 for AA amyloidosis per 1 000 000 person-years). The ID adjusted to the population of the city of Buenos Aires was 6.46 (95%CI: 3.17-9.74) for ATTRwt, 6.13 (95%CI: 2.57-9.7) for AL and 1.21 (95%CI: 0.56 to 2.99) for AA amyloidosis. CONCLUSIONS: This is the first paper to report the incidence density of ATTRwt, AL and AA amyloidosis in Latin America. Our results are consistent with other studies from other regions. Although systemic amyloidosis is a rare disease, it is a major health problem because of its morbi-mortality. PMID- 27470487 TI - Stereoselectivity in Autoionization Reactions of Hydrogenated Molecules by Metastable Noble Gas Atoms: The Role of Electronic Couplings. AB - Focus in the present paper is on the analysis of total and partial ionization cross sections, measured in absolute value as a function of the collision energy, representative of the probability of ionic product formation in selected electronic states in Ne*-H2 O, H2 S, and NH3 collisions. In order to characterize the imaginary part of the optical potential, related to electronic couplings, we generalize a methodology to obtain direct information on the opacity function of these reactions. Such a methodology has been recently exploited to test the real part of the optical potential (S. Falcinelli et al., Chem. Eur. J., 2016, 22, 764 771). Depending on the balance of noncovalent contributions, the real part controls the approach of neutral reactants, the removal of ionic products, and the structure of the transition state. Strength, range, and stereoselectivity of electronic couplings, triggering these and many other reactions, are directly obtained from the present investigation. PMID- 27470488 TI - Sources of (co)variation in alternative siring routes available to male great tits (Parus major). AB - Males of socially monogamous species can increase their siring success via within pair and extra-pair fertilizations. In this study, we focused on the different sources of (co)variation between these siring routes, and asked how each contributes to total siring success. We quantified the fertilization routes to siring success, as well as behaviors that have been hypothesized to affect siring success, over a five-year period for a wild population of great tits Parus major. We considered siring success and its fertilization routes as "interactive phenotypes" arising from phenotypic contributions of both members of the social pair. We show that siring success is strongly affected by the fecundity of the social (female) partner. We also demonstrate that a strong positive correlation between extra-pair fertilization success and paternity loss likely constrains the evolution of these two routes. Moreover, we show that more explorative and aggressive males had less extra-pair fertilizations, whereas more explorative females laid larger clutches. This study thus demonstrates that (co)variation in siring routes is caused by multiple factors not necessarily related to characteristics of males. We thereby highlight the importance of acknowledging the multilevel structure of male fertilization routes when studying the evolution of male mating strategies. PMID- 27470490 TI - Sequences of a co-existing SXT element, a chromosomal integron (CI) and an IncA/C plasmid and their roles in multidrug resistance in a Vibrio cholerae O1 El Tor strain. AB - The ongoing seventh cholera pandemic is attributed to Vibrio cholerae O1 El Tor biotype strains. Although antibiotic therapy ameliorates symptoms in patients and reduces pathogen transfer to the environment, multidrug resistance remains a major clinical threat. An O1 El Tor strain isolated from a patient in 1998 was intermediate or resistant to 13 antibiotics and could potentially produce extended-spectrum beta-lactamase (ESBL), which is very rare in O1 strains. Using genome sequencing, three relevant genetic elements were identified in this strain: a hybrid SXT element (ICEVchCHN1307); a new IncA/C plasmid (pVC1307); and a chromosomal integron. Twenty antibiotic resistance genes were located on them, including blaTEM-1, blaCTX-M-14 and phenotypically silenced tetRA genes. These data elucidate the role of individual genetic components in antibiotic resistance and the accumulation of drug resistance genes in V. cholerae. PMID- 27470489 TI - Evolution of hepatitis E virus-associated meningo-polyradiculoneuropathy on ribavirin. PMID- 27470491 TI - SOXF transcription factors in cardiovascular development. AB - Cardiovascular development during embryogenesis involves complex changes in gene regulatory networks regulated by a variety of transcription factors. In this review we discuss the various reported roles of the SOXF factors: SOX7, SOX17 and SOX18 in cardiac, vascular and lymphatic development. SOXF factors have pleiotropic roles during these processes, and there is significant redundancy and functional compensation between SOXF family members. Despite this, evidence suggests that there is some specificity in the transcriptional programs they regulate which is necessary to control the differentiation and behaviour of endothelial subpopulations. Furthermore, SOXF factors appear to have an indirect role in regulating cardiac mesoderm specification and differentiation. Understanding how SOXF factors are regulated, as well as their downstream transcriptional target genes, will be important for unravelling their roles in cardiovascular development and related diseases. PMID- 27470492 TI - Two-Step Oxidation of Refractory Gold Concentrates with Different Microbial Communities. AB - Bio-oxidation is an effective technology for treatment of refractory gold concentrates. However, the unsatisfactory oxidation rate and long residence time, which cause a lower cyanide leaching rate and gold recovery, are key factors that restrict the application of traditional bio-oxidation technology. In this study, the oxidation rate of refractory gold concentrates and the adaption of microorganisms were analyzed to evaluate a newly developed two-step pretreatment process, which includes a high temperature chemical oxidation step and a subsequent bio-oxidation step. The oxidation rate and recovery rate of gold were improved significantly after the two-step process. The results showed that the highest oxidation rate of sulfide sulfur could reach to 99.01 % with an extreme thermophile microbial community when the pulp density was 5%. Accordingly, the recovery rate of gold was elevated to 92.51%. Meanwhile, the results revealed that moderate thermophiles performed better than acidophilic mesophiles and extreme thermophiles, whose oxidation rates declined drastically when the pulp density was increased to 10% and 15%. The oxidation rates of sulfide sulfur with moderate thermophiles were 93.94% and 65.73% when the pulp density was increased to 10% and 15%, respectively. All these results indicated that the two-step pretreatment increased the oxidation rate of refractory gold concentrates and is a potential technology to pretreat the refractory sample. Meanwhile, owing to the sensitivity of the microbial community under different pulp density levels, the optimization of microbial community in bio-oxidation is necessary in industry. PMID- 27470493 TI - Biological Synthesis of Baicalein Derivatives Using Escherichia coli. AB - Two baicalein derivatives, baicalin and oroxylin A, were synthesized in this study. These derivatives exhibit diverse biological activities, such as anxiolytic and anticancer activities as well as memory enhancement. In order to synthesize baicalin from aglycon baicalein using Escherichia coli, we utilized a glycosyltransferase that regioselectively transfers glucuronic acid from UDP glucuronic acid to the 7-hydroxy group of baicalein. To increase baicalin productivity, an araA deletion E. coli mutant, which accumulates UDP-glucuronic acid, was used, and ugd, which converts UDP-glucose to UDP-glucuronic acid, was overexpressed. Using these strategies, approximately 720.3 uM baicalin was synthesized from 1,000 uM baicalein. Oroxylin A was then synthesized from baicalein. Two O-methyltransferases (OMTs), ROMT-15 and POMT-9, were tested to examine the production of oroxylin A from baicalein. E. coli harboring ROMT-15 and E. coli harboring POMT-9 produced reaction products that had different retention times, indicating that they are methylated at different positions; the structure of the reaction product from POMT-9 was consistent with oroxylin A, whereas that from ROMT-15 was 7-O-methyl baicalein. Using E. coli harboring POMT 9, approximately 50.3 mg/l of oroxylin A (177 uM) was synthesized from 54 mg/l baicalein (200 uM). PMID- 27470494 TI - Prediction of postoperative opioid analgesia using clinical-experimental parameters and electroencephalography. AB - BACKGROUND: Opioids are often used for pain treatment, but the response is often insufficient and dependent on e.g. the pain condition, genetic factors and drug class. Thus, there is an urgent need to identify biomarkers to enable selection of the appropriate drug for the individual patient, a concept known as personalized medicine. Quantitative sensory testing (QST) and clinical parameters can provide some guidance for response, but better and more objective biomarkers are urgently warranted. Electroencephalography (EEG) may be suitable since it assesses the central nervous system where opioids mediate their effects. METHODS: Clinical parameters, QST and EEG (during rest and tonic pain) was recorded from patients the day prior to total hip replacement surgery. Postoperative pain treatment was performed using oxycodone and piritramide as patient-controlled analgesia. Patients were stratified into responders and non-responders based on pain ratings 24 h post-surgery. Parameters were analysed using conventional group wise statistical methods. Furthermore, EEG was analysed by machine learning to predict individual response. RESULTS: Eighty-one patients were included, of which 51 responded to postoperative opioid treatment (30 non-responders). Conventional statistics showed that more severe pre-existing chronic pain was prevalent among non-responders to opioid treatment (p = 0.04). Preoperative EEG analysis was able to predict responders with an accuracy of 65% (p = 0.009), but only during tonic pain. CONCLUSIONS: Chronic pain grade before surgery is associated with the outcome of postoperative pain treatment. Furthermore, EEG shows potential as an objective biomarker and might be used to predict postoperative opioid analgesia. SIGNIFICANCE: The current clinical study demonstrates the viability of EEG as a biomarker and with results consistent with previous experimental results. The combined method of machine learning and electroencephalography offers promising results for future developments of personalized pain treatment. PMID- 27470495 TI - Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells. AB - Microvessel endothelial cells form part of the blood-brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. Cardiolipin is a mitochondrial phospholipid required for function of the electron transport chain and ATP generation. We examined the role of cardiolipin in maintaining mitochondrial function necessary to support barrier properties of brain microvessel endothelial cells. Knockdown of the terminal enzyme of cardiolipin synthesis, cardiolipin synthase, in hCMEC/D3 cells resulted in decreased cellular cardiolipin levels compared to controls. The reduction in cardiolipin resulted in decreased mitochondrial spare respiratory capacity, increased pyruvate kinase activity, and increased 2-deoxy-[(3) H]glucose uptake and glucose transporter-1 expression and localization to membranes in hCMEC/D3 cells compared to controls. The mechanism for the increase in glucose uptake was an increase in adenosine-5'-monophosphate kinase and protein kinase B activity and decreased glycogen synthase kinase 3 beta activity. Knockdown of cardiolipin synthase did not affect permeability of fluorescent dextran across confluent hCMEC/D3 monolayers grown on Transwell((r)) inserts. In contrast, knockdown of cardiolipin synthase resulted in an increase in 2-deoxy [(3) H]glucose transport across these monolayers compared to controls. The data indicate that in hCMEC/D3 cells, spare respiratory capacity is dependent on cardiolipin. In addition, reduction in cardiolipin in these cells alters their cellular energy status and this results in increased glucose transport into and across hCMEC/D3 monolayers. Microvessel endothelial cells form part of the blood brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. In human adult brain endothelial cell hCMEC/D3 monolayers cultured on Transwell((r)) plates, knockdown of cardiolipin synthase results in decrease in mitochondrial cardiolipin and decreased mitochondrial spare respiratory capacity. The reduced cardiolipin results in an increased activity of adenosine monophosphate kinase (pAMPK) and protein kinase B (pAKT) and decreased activity of glycogen synthase kinase 3 beta (pGSK3beta) which results in elevated glucose transporter-1 (GLUT-1) expression and association with membranes. This in turn increases 2-dexoyglucose uptake from the apical medium into the cells with a resultant 2-deoxyglucose movement into the basolateral medium. PMID- 27470496 TI - Relation between chronic rhinosinusitis and gastroesophageal reflux in adults: systematic review. AB - INTRODUCTION: The relationship between gastroesophageal reflux disease (GERD) and chronic rhinosinusitis (CRS) is still a controversial issue in literature. OBJECTIVE: A systematic review of the association between these two diseases in adult patients. METHODS: Systematic review in PubMed and Cochrane Database with articles published between 1951 and 2015. We included all articles that specifically studied the relationship between CRS and GERD. RESULTS: Of the 436 articles found, only 12 met the inclusion criteria. Eight cross-sectional articles suggest a relation between CRS and GERD, especially on CRS that is refractory to clinical or surgical treatment. However, the groups are small and methodologies are different. Four other longitudinal studies have assessed the effect of treatment with proton pump inhibitors (PPIs) on the improvement of symptoms of CRS, but the results were conflicting. CONCLUSIONS: There seems to be relative prevalence of reflux with intractable CRS. There is still a lack of controlled studies with a significant number of patients to confirm this hypothesis. Few studies specifically assess the impact of treatment of reflux on symptom improvement in patients with CRS. PMID- 27470497 TI - Evaluation of aesthetic and functional outcomes in rhinoplasty surgery: a prospective study. AB - INTRODUCTION: Evaluation of surgery outcome measured by patient satisfaction or quality of life is very important, especially in plastic surgery. There is increasing interest in self-reporting outcomes evaluation in plastic surgery. OBJECTIVE: The aim of our study was to determine patient satisfaction in regard to nose appearance and function with the use of a validated questionnaire, before and after rhinoplasty surgery. METHODS: A prospective study was realized at a tertiary centre. All rhinoplasty surgeries performed in adults between February 2013 and August 2014 were included. Many patients underwent additional nasal surgery such as septoplasty or turbinoplasty. The surgical procedures and patients' characteristics were also recorded. RESULTS: Among 113 patients, 107 completed the questionnaires and the follow-up period. Analysis of pre-operative and post-operative Rhinoplasty Evaluation Outcome showed a significant improvement after 3 and 6 months in functional and aesthetic questions (p<0.01). In the pre-operative, patients anxious and insecure had a worse score (p<0.05). Difference in improvement of scores was not significant when groups were divided on basis of other nasal procedures, primary or revision surgery and open versus closed approach. CONCLUSION: We found that patients with lower literacy degree were more satisfied with the procedure. Rhinoplasty surgery significantly improved patient quality of life regarding nose function and appearance. PMID- 27470498 TI - Variations on a Precision Medicine Theme: One Size Fits Some. PMID- 27470499 TI - Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure. PMID- 27470500 TI - Effectiveness of school-based humanistic counselling for psychological distress in young people: Pilot randomized controlled trial with follow-up in an ethnically diverse sample. AB - OBJECTIVES: The aim of this study was to pilot a test of the effectiveness of school-based humanistic counselling (SBHC) in an ethnically diverse group of young people (aged 11-18 years old), with follow-up assessments at 6 and 9 months. DESIGN: Pilot randomized controlled trial, using linear-mixed effect modelling and intention-to-treat analysis to compare changes in levels of psychological distress for participants in SBHC against usual care (UC). TRIAL REGISTRATION: ISRCTN44253140. METHODS: In total, 64 young people were randomized to either SBHC or UC. Participants were aged between 11 and 18 (M = 14.2, SD = 1.8), with 78.1% of a non-white ethnicity. The primary outcome was psychological distress at 6 weeks (mid-therapy), 12 weeks (end of therapy), 6-month follow-up and 9-month follow-up. Secondary measures included emotional symptoms, self esteem and attainment of personal goals. RESULTS: Recruitment and retention rates for the study were acceptable. Participants in the SBHC condition, as compared with participants in the UC condition, showed greater reductions in psychological distress and emotional symptoms, and greater improvements in self-esteem, over time. However, at follow-up, only emotional symptoms showed significant differences across groups. CONCLUSIONS: The study adds to the pool of evidence suggesting that SBHC can be tested and that it brings about short-term reductions in psychological and emotional distress in young people, across ethnicities. However, there is no evidence of longer-term effects. PRACTITIONER POINTS: School based humanistic counselling can be an effective means of reducing the psychological distress experienced by young people with emotional symptoms in the short term. The short-term effectiveness of school-based humanistic counselling is not limited to young people of a White ethnicity. There is no evidence that school-based humanistic counselling has effects beyond the end of therapy. PMID- 27470501 TI - A role for the endocannabinoid system in premature luteal regression and progesterone withdrawal in lipopolysaccharide-induced early pregnancy loss model. AB - STUDY QUESTION: What is the role of the endocannabinoid system (eCS) in the alterations of the endocrine system in a murine model of lipopolysaccharide (LPS) induced miscarriage? SUMMARY ANSWER: In 7-days pregnant wild type, but not cannabinoid receptor type 1 knockout (CB1-KO) mice, LPS increased COX-2 expression and prostaglandin F2alpha (PGF2alpha) production in the uterus leading to lower expression of prolactin receptor in the ovary and a marked regression of corpora lutea (CL), suggesting that the eCS mediates the deleterious effects of LPS on reproductive events. WHAT IS KNOWN ALREADY: Appropriate systemic progesterone levels are critical for a successful pregnancy outcome. Precocious loss of luteal progesterone (P4) secretion leads to miscarriage in rodents. We have previously shown that LPS administration to pregnant mice induces embryonic resorption accompanied by a dramatic decrease in systemic progesterone levels in a murine model of inflammatory miscarriage, with the eCS mediating these LPS induced deleterious effects. STUDY DESIGN SAMPLES/MATERIALS, METHODS: CD1 wild type (WT) and CB1-KO mice were randomly allocated to Vehicle (saline; i.p.) or LPS (0.5 MUg/g body weight; i.p.) treated groups: (WT-Vehicle; WT-LPS; CB1-KO Vehicle and CB1-KO-LPS). A single injection was given on day 7 of pregnancy and tissues (blood, ovary, uterus) were collected 6, 12, 24 and 48 h later. P4 and PGF2alpha plasma levels were determined by radioimmunoassay. Cyclooxygenase-2 (COX-2) mRNA (RT-PCR) and protein (Western blot) content in uterus was assayed. COX-2 and prolactin receptor (PrlR) mRNA levels in the ovary were assayed by RT PCR. Tissue morphology of the CL was assessed by haematoxylin-eosin staining. MAIN RESULTS AND THE ROLE OF CHANCE: Treatment of 7-day pregnant WT mice with LPS induced a P4 withdrawal (p < 0.05), increased in uterine COX-2 mRNA and protein expression (p < 0.05) as well as an increase in uterine PGF2alpha production (p < 0.05). These changes were absent in LPS-treated 7-day pregnant CB1-KO mice. In ovarian tissues, LPS treatment to 7-day pregnant WT mice induced a downregulation of PrlR mRNA expression (p < 0.05) together with an increase in COX-2 mRNA expression (p < 0.05) and PGF2alpha content (p < 0.05). These effects were absent in the CB1-KO mice. Collectively, our results suggest a role for the eCS mediating LPS-induced deleterious effects on reproductive tissues. LIMITATIONS, REASONS FOR CAUTION: An important caveat of this study is the endocrine differences between mice and humans during pregnancy (e.g. P4 is produced by the CL throughout pregnancy in mice, whereas this is not the case in humans), which limits the extrapolation of the results presented here. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide new insights in the role of the endocannabinoid system in the physiopathology of reproduction as well as the role of this endogenous system as a mediator of LPS deleterious effects on reproductive tissues. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: Dr Ana Maria Franchi was funded by Agencia Nacional para la Promocion Cientifica y Tecnologica (PICT 2010/0813 and PICT 2013/0097) and by Consejo Nacional de Investigaciones Cientificas y Tecnicas (PIP 2012/0061). The authors have no competing interests. PMID- 27470502 TI - Irinotecan metabolite SN38 results in germ cell loss in the testis but not in the ovary of prepubertal mice. AB - STUDY QUESTION: Does the Irinotecan metabolite 7-ethyl-10-hydroxycamptothecan (SN38) damage the gonads of male and female prepubertal mice? SUMMARY ANSWER: The Irinotecan metabolite SN38 reduces germ cell numbers within the seminiferous tubules of mouse testes at concentrations that are relevant to cancer patients, while in contrast it has little if any effect on the female germ cell population. WHAT IS KNOWN ALREADY: Little is known about the role of the chemotherapeutic agent Irinotecan on female fertility, with only one article to date reporting menopausal symptoms in perimenopausal women treated with Irinotecan, while no data are available either on adult male fertility or on the impact of Irinotecan on the subsequent fertility of prepubertal cancer patients, female or male. STUDY DESIGN SIZE, DURATION: Male and female gonads were obtained from postnatal day 5 C57BL/6 mice and exposed in vitro to a range of concentrations of the Irinotecan metabolite SN38: 0.002, 0.01, 0.05, 0.1 or 1 ug ml-1 for the testis and 0.1, 1, 2.5 or 5 ug ml-1 for the ovary, with treated gonads compared to control gonads not exposed to SN38. SN38 was dissolved in 0.5% dimethyl sulfoxide, with controls exposed to the same concentration of diluent. The number of testis fragments used for each analysis ranged between 3 and 9 per treatment group, while the number of ovaries used for each analysis ranged between 4 and 12 per treatment group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Neonatal mouse gonads were developed in vitro, with tissue analysed at the end of the 4-6 day culture period, following immunofluorescence or hematoxylin and eosin staining. Statistical analyses were performed using one-way ANOVA followed by Bonferroni post-hoc test for normally distributed data and Kruskal-Wallis test followed by Dunns post-test for non parametric data. MAIN RESULTS AND THE ROLE OF CHANCE: Abnormal testis morphology was observed when tissues were exposed to SN38, with a smaller seminiferous tubule diameter at the highest concentration of SN38 (1 ug ml-1, p < 0.001 versus control) and increased number of Sertoli cell-only tubules at the two highest concentrations of SN38 (0.1 ug ml-1, p < 0.001; 1 ug ml-1, p < 0.0001, both versus control). Within seminiferous tubules, a dose response decrease was observed in both germ cell number (mouse vasa homologue (MVH)-positive cells) and in proliferating cell number (bromodeoxyuridine (BrdU)-positive cells), with significance reached at the two highest concentrations of SN38 (0.1 ug ml-1, p < 0.01 for both; 1 ug ml-1, p < 0.001-MVH, p < 0.01-BrdU; all versus control). No change was seen in protein expression of the apoptotic marker cleaved caspase 3. Double immunofluorescence showed that occasional proliferating germ cells were present in treated testes, even after exposure to the highest drug concentration. When prepubertal ovaries were treated with SN38, no effect was seen on germ cell number, apoptosis or cell proliferation, even after exposure to the highest drug concentrations. LIMITATIONS REASONS FOR CAUTION: As with any study using in vitro experiments with an experimental animal model, caution is required when extrapolating the present findings to humans. Differences between human and mouse spermatogonial development also need to be considered when assessing the effect of chemotherapeutic exposure. However, the prepubertal testes and ovaries used in the present studies contain germ cell populations that are representative of those found in prepubertal patients, and experimental tissues were exposed to drug concentrations within the range found in patient plasma. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the prepubertal mouse ovary is relatively insensitive to exposure to the Irinotecan metabolite SN38, while it induces a marked dose-dependent sensitivity in the testicular germ cell population. The study identifies the importance of further investigation to identify the risk of infertility in young male cancer patients treated with Irinotecan. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: Work supported by Medical Research Grant (MRC) grant G1002118 and Children with Cancer UK grant 15-198. The authors declare that there is no conflict of interest that could prejudice the impartiality of the present research. PMID- 27470503 TI - Estimating the effect of plant-provided food supplements on pest consumption by omnivorous predators: lessons from two coccinellid beetles. AB - BACKGROUND: Plant-provided food supplements can influence biological pest control by omnivorous predators in two counteracting ways: they can (i) enhance predator populations, but (ii) reduce pest consumption by individual predators. Yet the majority of studies address only one of these aspects. Here, we first tested the influence of canola (Brassica napus L.) pollen supplements on the life history of two ladybeetle species: Hoppodamia variegata (Goeze) and Coccinella septempunctata (L.). We then developed a theoretical model to simulate total pest consumption in the presence and absence of pollen supplements. RESULTS: Supplementing a prey diet with canola pollen increased H. variegata larval survival from 50 to 82%, and C. septempunctata female oviposition by 1.6-fold. Model simulations revealed a greater benefit of pollen supplements when relying on C. septempunctata for pest suppression than on H. variegata. CONCLUSION: For these two predators, the tested pollen serves as an essential supplement to a diet of prey. However, the benefit of a mixed prey-pollen diet was not always sufficient to overcome individual decrease in pest consumption. Taken together, our study highlights the importance of addressing both positive and negative roles of plant-provided food supplements in considering the outcome for biological control efforts that rely on omnivorous predators. (c) 2016 Society of Chemical Industry. PMID- 27470505 TI - The impact of the TelEmergency program on rural emergency care: An implementation study. AB - Introduction Timely, appropriate intervention is key to improving outcomes in many emergent conditions. In rural areas, it is particularly challenging to assure quality, timely emergency care. The TelEmergency (TE) program, which utilizes a dual nurse practitioner and emergency medicine-trained, board certified physician model, has the potential to improve access to quality emergency care in rural areas. The objective of this study was to examine how the implementation of the TE program impacts rural hospital Emergency Department (ED) operations. Methods Methods included a before and after study of the effect of the TE program on participating rural hospitals between January 2007 and December 2008. Data on ED and hospital operations were collected one year prior to and one year following the implementation of TE. Data from participating hospitals were combined and compared for the two time periods. Results Nine hospitals met criteria for inclusion and participated in the study. Total ED volumes did not significantly change with TE implementation, but ED admissions to the same rural hospital significantly increased following TE implementation (6.7% to 8.1%, p value = 0.02). Likewise, discharge rates from the ED declined post-initiation (87.1% to 80.0%, p-value = 0.003). ED deaths and transfer rates showed no significant change, while the rate of patient discharge against medical advice significantly increased with TE use. Discussion In this analysis, we found a significant increase in the rate of ED admissions to rural hospitals with TE use. These findings may have important implications for the quality of emergency care in rural areas and the sustainability of rural hospitals' EDs. PMID- 27470504 TI - A review on host-pathogen interactions: classification and prediction. AB - The research on host-pathogen interactions is an ever-emerging and evolving field. Every other day a new pathogen gets discovered, along with comes the challenge of its prevention and cure. As the intelligent human always vies for prevention, which is better than cure, understanding the mechanisms of host pathogen interactions gets prior importance. There are many mechanisms involved from the pathogen as well as the host sides while an interaction happens. It is a vis-a-vis fight of the counter genes and proteins from both sides. Who wins depends on whether a host gets an infection or not. Moreover, a higher level of complexity arises when the pathogens evolve and become resistant to a host's defense mechanisms. Such pathogens pose serious challenges for treatment. The entire human population is in danger of such long-lasting persistent infections. Some of these infections even increase the rate of mortality. Hence there is an immediate emergency to understand how the pathogens interact with their host for successful invasion. It may lead to discovery of appropriate preventive measures, and the development of rational therapeutic measures and medication against such infections and diseases. This review, a state-of-the-art updated scenario of host pathogen interaction research, has been done by keeping in mind this urgency. It covers the biological and computational aspects of host-pathogen interactions, classification of the methods by which the pathogens interact with their hosts, different machine learning techniques for prediction of host-pathogen interactions, and future scopes of this research field. PMID- 27470506 TI - Reporting quality of randomised controlled trial abstracts among high-impact general medical journals: a review and analysis. AB - OBJECTIVE: The aim of this study was to assess adherence to the Consolidated Standards of Reporting Trials (CONSORT) for Abstracts by five high-impact general medical journals and to assess whether the quality of reporting was homogeneous across these journals. DESIGN: This is a descriptive, cross-sectional study. SETTING: Randomised controlled trial (RCT) abstracts in five high-impact general medical journals. PARTICIPANTS: We used up to 100 RCT abstracts published between 2011 and 2014 from each of the following journals: The New England Journal of Medicine (NEJM), the Annals of Internal Medicine (Annals IM), The Lancet, the British Medical Journal (The BMJ) and the Journal of the American Medical Association (JAMA). MAIN OUTCOME: The primary outcome was per cent overall adherence to the 19-item CONSORT for Abstracts checklist. Secondary outcomes included per cent adherence in checklist subcategories and assessing homogeneity of reporting quality across the individual journals. RESULTS: Search results yielded 466 abstracts, 3 of which were later excluded as they were not RCTs. Analysis was performed on 463 abstracts (97 from NEJM, 66 from Annals IM, 100 from The Lancet, 100 from The BMJ, 100 from JAMA). Analysis of all scored items showed an overall adherence of 67% (95% CI 66% to 68%) to the CONSORT for Abstracts checklist. The Lancet had the highest overall adherence rate (78%; 95% CI 76% to 80%), whereas NEJM had the lowest (55%; 95% CI 53% to 57%). Adherence rates to 8 of the checklist items differed by >25% between journals. CONCLUSIONS: Among the five highest impact general medical journals, there is variable and incomplete adherence to the CONSORT for Abstracts reporting checklist of randomised trials, with substantial differences between individual journals. Lack of adherence to the CONSORT for Abstracts reporting checklist by high-impact medical journals impedes critical appraisal of important studies. We recommend diligent assessment of adherence to reporting guidelines by authors, reviewers and editors to promote transparency and unbiased reporting of abstracts. PMID- 27470507 TI - Comparison of virtual unenhanced CT images of the abdomen under different iodine flow rates. AB - OBJECTIVE: To assess the effect of varying iodine flow rate (IFR) and iodine concentration on the quality of virtual unenhanced (VUE) images of the abdomen obtained with dual-energy CT. METHODS: 94 subjects underwent unenhanced and triphasic contrast-enhanced CT scan of the abdomen, including arterial phase, portal venous phase, and delayed phase using dual-energy CT. Patients were randomized into 4 groups with different IFRs or iodine concentrations. VUE images were generated at 70 keV. The CT values, image noise, SNR and CNR of aorta, portal vein, liver, liver lesion, pancreatic parenchyma, spleen, erector spinae, and retroperitoneal fat were recorded. Dose-length product and effective dose for an examination with and without plain phase scan were calculated to assess the potential dose savings. Two radiologists independently assessed subjective image quality using a five-point scale. The Kolmogorov-Smirnov test was used first to test for normal distribution. Where data conformed to a normal distribution, analysis of variance was used to compare mean HU values, image noise, SNRs and CNRs for the 4 image sets. Where data distribution was not normal, a nonparametric test (Kruskal-Wallis test followed by stepwise step-down comparisons) was used. The significance level for all tests was 0.01 (two-sided) to allow for type 2 errors due to multiple testing. RESULTS: The CT numbers (HU) of VUE images showed no significant differences between the 4 groups (p > 0.05) or between different phases within the same group (p > 0.05). VUE images had equal or higher SNR and CNR than true unenhanced images. VUE images received equal or lower subjective image quality scores than unenhanced images but were of acceptable quality for diagnostic use. Calculated dose-length product and estimated dose showed that the use of VUE images in place of unenhanced images would be associated with a dose saving of 25%. CONCLUSIONS: VUE images can replace conventional unenhanced images. VUE images are not affected by varying iodine flow rates and iodine concentrations, and diagnostic examinations could be acquired with a potential dose saving of 25%. PMID- 27470508 TI - The embedded organ sign. PMID- 27470509 TI - Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II-Induced Abdominal Aortic Aneurysms in C57BL/6 Mice-Brief Report. AB - OBJECTIVE: Gain-of-function mutations of PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-associated viral (AAV) vector expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)-induced abdominal aortic aneurysms. APPROACH AND RESULTS: In an initial study, male C57BL/6 mice were injected intraperitoneally with either an empty vector or PCSK9 gain-of-function mutation (D377Y). AAV at 3 doses and fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII for 4 weeks. Plasma PCSK9 concentrations were increased dose dependently in mice injected with AAV containing PCSK9D377Y mutation and positively associated with elevations of plasma cholesterol concentrations. Infection with intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas in C57BL/6 mice infused with AngII. Therefore, the intermediate dose was used in subsequent experiments. We then determined effects of PCSK9D377Y.AAV infection on 5 normolipidemic mouse strains, demonstrating that C57BL/6 mice were the most susceptible to this AAV infection. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male low-density lipoprotein receptor(-/-) mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent abdominal aortic aneurysmal formation, compared to low-density lipoprotein receptor(-/-) mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male low-density lipoprotein receptor(-/-) mice did not influence AngII-induced abdominal aortic aneurysms. CONCLUSION: AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting abdominal aortic aneurysms in C57BL/6 mice infused with AngII. PMID- 27470511 TI - Neutrophil Extracellular Traps Promote Angiogenesis: Evidence From Vascular Pathology in Pulmonary Hypertension. AB - OBJECTIVE: Inflammation and dysregulated angiogenesis are features of endothelial dysfunction in pulmonary hypertension. Neutrophil extracellular traps (NETs), produced by dying neutrophils, contribute to pathogenesis of numerous vascular disorders but their role in pulmonary hypertension has not been studied. We sought evidence of (NETs) formation in pulmonary hypertension and investigated the effect of NETs on endothelial function. APPROACH AND RESULTS: Plasma and lung tissues of patients with pulmonary hypertension were analyzed for NET markers. The effects of NETs on endothelial function were studied in vitro and in vivo. Patients with chronic thromboembolic pulmonary hypertension and idiopathic pulmonary hypertension showed elevated plasma levels of DNA, neutrophil elastase, and myeloperoxidase. NET-forming neutrophils and extensive areas of NETosis were found in the occlusive plexiform lesions and vascularized intrapulmonary thrombi. NETs induced nuclear factor kappaB-dependent endothelial angiogenesis in vitro and increased vascularization of matrigel plugs in vivo. Angiogenic responses were associated with increased release of matrix metalloproteinase-9, heparin binding epidermal growth factor-like growth factor, latency-associated peptide of the transforming growth factor beta1, and urokinase-type plasminogen activator, accompanied by increased endothelial permeability and cell motility. NETs-induced responses depended on myeloperoxidase/H2O2-dependent activation of Toll-like receptor 4/nuclear factor kappaB signaling. NETs stimulated the release of endothelin-1 in HPAECs (human pulmonary artery endothelial cells) and stimulated pulmonary smooth muscle cell proliferation in vitro. CONCLUSIONS: We are the first to implicate NETs in angiogenesis and provide a functional link between NETs and inflammatory angiogenesis in vitro and in vivo. We demonstrate the potential pathological relevance of this in 2 diseases of disordered vascular homeostasis, pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. PMID- 27470510 TI - 12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-gamma-Linolenic Acid, Inhibits Thrombosis via Galphas Signaling in Platelets. AB - OBJECTIVE: Dietary supplementation with polyunsaturated fatty acids has been widely used for primary and secondary prevention of cardiovascular disease in individuals at risk; however, the cardioprotective benefits of polyunsaturated fatty acids remain controversial because of lack of mechanistic and in vivo evidence. We present direct evidence that an omega-6 polyunsaturated fatty acid, dihomo-gamma-linolenic acid (DGLA), exhibits in vivo cardioprotection through 12 lipoxygenase (12-LOX) oxidation of DGLA to its reduced oxidized lipid form, 12(S) hydroxy-8Z,10E,14Z-eicosatrienoic acid (12(S)-HETrE), inhibiting platelet activation and thrombosis. APPROACH AND RESULTS: DGLA inhibited ex vivo platelet aggregation and Rap1 activation in wild-type mice, but not in mice lacking 12-LOX expression (12-LOX(-/-)). Similarly, wild-type mice treated with DGLA were able to reduce thrombus growth (platelet and fibrin accumulation) after laser-induced injury of the arteriole of the cremaster muscle, but not 12-LOX(-/-) mice, supporting a 12-LOX requirement for mediating the inhibitory effects of DGLA on platelet-mediated thrombus formation. Platelet activation and thrombus formation were also suppressed when directly treated with 12(S)-HETrE. Importantly, 2 hemostatic models, tail bleeding and arteriole rupture of the cremaster muscle, showed no alteration in hemostasis after 12(S)-HETrE treatment. Finally, the mechanism for 12(S)-HETrE protection was shown to be mediated via a Galphas linked G-protein-coupled receptor pathway in human platelets. CONCLUSIONS: This study provides the direct evidence that an omega-6 polyunsaturated fatty acid, DGLA, inhibits injury-induced thrombosis through its 12-LOX oxylipin, 12(S) HETrE, which strongly supports the potential cardioprotective benefits of DGLA supplementation through its regulation of platelet function. Furthermore, this is the first evidence of a 12-LOX oxylipin regulating platelet function in a Gs alpha subunit-linked G-protein-coupled receptor-dependent manner. PMID- 27470512 TI - Fibroblast Growth Factor 12 Is a Novel Regulator of Vascular Smooth Muscle Cell Plasticity and Fate. AB - OBJECTIVE: Vascular smooth muscle cells (VSMCs) modulate their phenotype between synthetic and contractile states in response to environmental changes; this modulation plays a crucial role in the pathogenesis of restenosis and atherosclerosis. Here, we identified fibroblast growth factor 12 (FGF12) as a novel key regulator of the VSMC phenotype switch. APPROACH AND RESULTS: Using murine models and human specimens, we found that FGF12 was highly expressed in contractile VSMCs of normal vessel walls but was downregulated in synthetic VSMCs from injured and atherosclerotic vessels. In human VSMCs, FGF12 expression was inhibited at the transcriptional level by platelet-derived growth factor-BB. Gain and loss-of-function experiments showed that FGF12 was both necessary and sufficient for inducing and maintaining the quiescent and contractile phenotypes of VSMCs. FGF12 inhibited cell proliferation through the p53 pathway and upregulated the key factors involved in VSMC lineage differentiation, such as myocardin and serum response factor. Such FGF12-induced phenotypic change was mediated by the p38 MAPK (mitogen-activated protein kinase) pathway. Moreover, FGF12 promoted the differentiation of mouse embryonic stem cells and the transdifferentiation of human dermal fibroblasts into SMC-like cells. Furthermore, adenoviral infection of FGF12 substantially decreased neointima hyperplasia in a rat carotid artery injury model. CONCLUSIONS: In general, FGF family members induce a synthetic VSMC phenotype. Interestingly, the present study showed the unanticipated finding that FGF12 belonging to FGF family, strongly induced the quiescent and contractile VSMC phenotypes and directly promoted VSMC lineage differentiation. These novel findings suggested that FGF12 could be a new therapeutic target for treating restenosis and atherosclerosis. PMID- 27470513 TI - E-Selectin Inhibition Mitigates Splenic HSC Activation and Myelopoiesis in Hypercholesterolemic Mice With Myocardial Infarction. AB - OBJECTIVE: Atherosclerosis is a chronic disease characterized by lipid accumulation in the arterial wall. After myocardial infarction (MI), atherosclerotic plaques are infiltrated by inflammatory myeloid cells that aggravate the disease and increase the risk of secondary myocardial ischemia. Splenic myelopoiesis provides a steady flow of myeloid cells to inflamed atherosclerotic lesions after MI. Therefore, targeting myeloid cell production in the spleen could ameliorate increased atherosclerotic plaque inflammation after MI. APPROACH AND RESULTS: Here we show that MI increases splenic myelopoiesis by driving hematopoietic stem and progenitor cells into the cell cycle. In an atherosclerotic mouse model, E-selectin inhibition decreased hematopoietic stem and progenitor cell proliferation in the spleen after MI. This led to reduced extramedullary myelopoiesis and decreased myeloid cell accumulation in atherosclerotic lesions. Finally, we observed stable atherosclerotic plaque features, including smaller plaque size, reduced necrotic core area, and thicker fibrous cap after E-selectin inhibition. CONCLUSIONS: Inhibiting E-selectin attenuated inflammation in atherosclerotic plaques, likely by reducing leukocyte recruitment into plaques and by mitigating hematopoietic stem and progenitor cell activation in the spleen of mice with MI. PMID- 27470515 TI - Interaction Between HIV-1 Nef and Calnexin: From Modeling to Small Molecule Inhibitors Reversing HIV-Induced Lipid Accumulation. AB - OBJECTIVE: HIV-infected patients are at an increased risk of developing atherosclerosis, in part because of downmodulation and functional impairment of ATP-binding cassette A1 (ABCA1) cholesterol transporter by the HIV-1 protein Nef. The mechanism of this effect involves Nef interacting with an ER chaperone calnexin and disrupting calnexin binding to ABCA1, leading to ABCA1 retention in ER, its degradation and resulting suppression of cholesterol efflux. However, molecular details of Nef-calnexin interaction remained unknown, limiting the translational impact of this finding. APPROACH AND RESULTS: Here, we used molecular modeling and mutagenesis to characterize Nef-calnexin interaction and to identify small molecule compounds that could block it. We demonstrated that the interaction between Nef and calnexin is direct and can be reconstituted using recombinant proteins in vitro with a binding affinity of 89.1 nmol/L measured by surface plasmon resonance. The cytoplasmic tail of calnexin is essential and sufficient for interaction with Nef, and binds Nef with an affinity of 9.4 nmol/L. Replacing lysine residues in positions 4 and 7 of Nef with alanines abrogates Nef-calnexin interaction, prevents ABCA1 downregulation by Nef, and preserves cholesterol efflux from HIV-infected cells. Through virtual screening of the National Cancer Institute library of compounds, we identified a compound, 1[(7-oxo-7H-benz[de]anthracene-3-yl)amino]anthraquinone, which blocked Nef calnexin interaction, partially restored ABCA1 activity in HIV-infected cells, and reduced foam cell formation in a culture of HIV-infected macrophages. CONCLUSION: This study identifies potential targets that can be exploited to block the pathogenic effect of HIV infection on cholesterol metabolism and prevent atherosclerosis in HIV-infected subjects. PMID- 27470514 TI - Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction. AB - OBJECTIVES: Chronic hypertension is the most critical risk factor for cardiovascular disease, heart failure, and stroke. APPROACH AND RESULTS: Here we show that wild-type mice infused with angiotensin II develop hypertension, cardiac hypertrophy, perivascular fibrosis, and endothelial dysfunction with enhanced stromal interaction molecule 1 (STIM1) expression in heart and vessels. All these pathologies were significantly blunted in mice lacking STIM1 specifically in smooth muscle (Stim1(SMC-/-)). Mechanistically, STIM1 upregulation during angiotensin II-induced hypertension was associated with enhanced endoplasmic reticulum stress, and smooth muscle STIM1 was required for endoplasmic reticulum stress-induced vascular dysfunction through transforming growth factor-beta and nicotinamide adenine dinucleotide phosphate oxidase dependent pathways. Accordingly, knockout mice for the endoplasmic reticulum stress proapoptotic transcriptional factor, CCAAT-enhancer-binding protein homologous protein (CHOP(-/-)), were resistant to hypertension-induced cardiovascular pathologies. Wild-type mice infused with angiotensin II, but not Stim1(SMC-/-) or CHOP(-/-) mice showed elevated vascular nicotinamide adenine dinucleotide phosphate oxidase activity and reduced phosphorylated endothelial nitric oxide synthase, cGMP, and nitrite levels. CONCLUSIONS: Thus, smooth muscle STIM1 plays a crucial role in the development of hypertension and associated cardiovascular pathologies and represents a promising target for cardiovascular therapy. PMID- 27470519 TI - Biocatalytic approaches to a key building block for the anti-thrombotic agent ticagrelor. AB - three complementary biocatalytic routes were examined for the synthesis of the cyclopropyl amine (1R,2S)-2, which is a key building block for the anti thrombotic agent ticagrelor 1. By employing either a ketoreductase, amidase or lipase biocatalyst, the key building blocks for synthesis of the amine 2 were obtained in 99.9, 92.5 and 46.3 ee, respectively. PMID- 27470517 TI - Computational discovery of Epstein-Barr virus targeted human genes and signalling pathways. AB - Epstein-Barr virus (EBV) plays important roles in the origin and the progression of human carcinomas, e.g. diffuse large B cell tumors, T cell lymphomas, etc. Discovering EBV targeted human genes and signaling pathways is vital to understand EBV tumorigenesis. In this study we propose a noise-tolerant homolog knowledge transfer method to reconstruct functional protein-protein interactions (PPI) networks between Epstein-Barr virus and Homo sapiens. The training set is augmented via homolog instances and the homolog noise is counteracted by support vector machine (SVM). Additionally we propose two methods to define subcellular co-localization (i.e. stringent and relaxed), based on which to further derive physical PPI networks. Computational results show that the proposed method achieves sound performance of cross validation and independent test. In the space of 648,672 EBV-human protein pairs, we obtain 51,485 functional interactions (7.94%), 869 stringent physical PPIs and 46,050 relaxed physical PPIs. Fifty eight evidences are found from the latest database and recent literature to validate the model. This study reveals that Epstein-Barr virus interferes with normal human cell life, such as cholesterol homeostasis, blood coagulation, EGFR binding, p53 binding, Notch signaling, Hedgehog signaling, etc. The proteome-wide predictions are provided in the supplementary file for further biomedical research. PMID- 27470516 TI - Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM. AB - OBJECTIVE: Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. APPROACH AND RESULTS: Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. CONCLUSIONS: We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation. PMID- 27470520 TI - Data science at the National Institute of Dental and Craniofacial Research: Changing dental practice. PMID- 27470518 TI - Clinical Pharmacokinetics and Pharmacodynamics of Afatinib. AB - Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential. PMID- 27470521 TI - "Predatory" publishing and open access in dentistry. PMID- 27470522 TI - Antibiotic use. PMID- 27470523 TI - Authors' response. PMID- 27470525 TI - Evidence-based clinical practice guideline for the use of pit-and-fissure sealants: A report of the American Dental Association and the American Academy of Pediatric Dentistry. AB - BACKGROUND: This article presents evidence-based clinical recommendations for the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars in children and adolescents. A guideline panel convened by the American Dental Association (ADA) Council on Scientific Affairs and the American Academy of Pediatric Dentistry conducted a systematic review and formulated recommendations to address clinical questions in relation to the efficacy, retention, and potential side effects of sealants to prevent dental caries; their efficacy compared with fluoride varnishes; and a head-to-head comparison of the different types of sealant material used to prevent caries on pits and fissures of occlusal surfaces. TYPES OF STUDIES REVIEWED: This is an update of the ADA 2008 recommendations on the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars. The authors conducted a systematic search in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other sources to identify randomized controlled trials reporting on the effect of sealants (available on the US market) when applied to the occlusal surfaces of primary and permanent molars. The authors used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the quality of the evidence and to move from the evidence to the decisions. RESULTS: The guideline panel formulated 3 main recommendations. They concluded that sealants are effective in preventing and arresting pit-and-fissure occlusal carious lesions of primary and permanent molars in children and adolescents compared with the nonuse of sealants or use of fluoride varnishes. They also concluded that sealants could minimize the progression of noncavitated occlusal carious lesions (also referred to as initial lesions) that receive a sealant. Finally, based on the available limited evidence, the panel was unable to provide specific recommendations on the relative merits of 1 type of sealant material over the others. CONCLUSIONS AND PRACTICAL IMPLICATIONS: These recommendations are designed to inform practitioners during the clinical decision-making process in relation to the prevention of occlusal carious lesions in children and adolescents. Clinicians are encouraged to discuss the information in this guideline with patients or the parents of patients. The authors recommend that clinicians reorient their efforts toward increasing the use of sealants on the occlusal surfaces of primary and permanent molars in children and adolescents. PMID- 27470524 TI - Sealants for preventing and arresting pit-and-fissure occlusal caries in primary and permanent molars: A systematic review of randomized controlled trials-a report of the American Dental Association and the American Academy of Pediatric Dentistry. AB - BACKGROUND: National Health and Nutrition Examination Survey 2011-2012 data indicated that, in the United States, nearly one-fourth of children and over one half of adolescents experienced dental caries in their permanent teeth. The purpose of this review was to summarize the available clinical evidence regarding the effect of dental sealants for the prevention and management of pit-and fissure occlusal carious lesions in primary and permanent molars, compared with a control without sealants, with fluoride varnishes, or with other head-to head comparisons. TYPE OF STUDIES REVIEWED: The authors included parallel and split mouth randomized controlled trials that included at least 2 years of follow-up, which they identified using MEDLINE (via PubMed), Embase, LILACS, the Cochrane Central Register of Controlled Trials, and registers of ongoing trials. Pairs of reviewers independently conducted the selection of studies, data extraction, risk of bias assessments, and quality of the evidence assessments by using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Of 2,869 records screened, the authors determined that 24 articles (representing 23 studies) proved eligible. Moderate-quality evidence suggested that participants who received sealants had a reduced risk of developing carious lesions in occlusal surfaces of permanent molars compared with those who did not receive sealants (odds ratio [OR], 0.15; 95% confidence interval [CI], 0.08-0.27) after 7 or more years of follow-up. When the authors compared studies whose investigators had compared sealants with fluoride varnishes, they found that sealants reduced the incidence of carious lesions after 7 or more years of follow-up (OR, 0.19; 95% CI, 0.07-0.51); however, this finding was supported by low-quality evidence. On the basis of the evidence, the authors could not provide a hierarchy of effectiveness among the studies whose investigators had conducted head-to-head comparisons. The investigators of 2 trials provided information about adverse events, but they did not report any adverse events. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Available evidence suggests that sealants are effective and safe to prevent or arrest the progression of noncavitated carious lesions compared with a control without sealants or fluoride varnishes. Further research is needed to provide information about the relative merits of the different types of sealant materials. PMID- 27470526 TI - Making the office manager decision. PMID- 27470527 TI - The ethics of dental treatment during pregnancy. PMID- 27470528 TI - Dental sealants. PMID- 27470529 TI - Performance evaluation of a slow-release packing material-embedded functional microorganisms for biofiltration. AB - A composite packing material (CM-5) was prepared in this study, mainly consisting of compost with functional microorganisms, calcium carbonate (CaCO3), perlite, cement and plant fiber. To get stronger compressive strength, mass ratios of these components were optimized based on single factor experiments, and finally adding amounts of perlite, cement, plant fiber, CaCO3, compost and binder at 18%, 18%, 7%, 13%, 17% and 27%, respectively. According to the optimum proportion, CM 5 was extruded in cylindrical shape (12 mm in diameter and 20 mm in length) with a bulk density of 470 kg m-3, a moisture retention capacity of 49% and the microbial counts of * 105 CFU g-1 of packing material. The cumulative release rates of total organic carbon (TOC) and total nitrogen (TN) from CM-5 were 3.1% and 6.5%, respectively, after 19 times extraction in distilled water. To evaluate the H2S removal capacity, CM-5 was compared with an organic (corncob) and an inorganic (ceramsite) packing material in three biofilters. The results showed that CM-5 had higher H2S removal capacity compared with corncob and ceramsite. CM 5 could avoid the large fluctuation of pH value and pressure drop during the operation. The maximum H2S removal capacity of CM-5 was 12.9 g m-3 h-1 and the removal efficiency could maintain over 95.4% when the inlet H2S loading rate was lower than 11.3 g m-3 h-1 without any addition of nutrients and pH buffer substances. Besides, only 2-3 days were needed for the recovery of biofiltration performance after about two weeks of idle period. PMID- 27470530 TI - In vitro studies with renal proximal tubule cells show direct cytotoxicity of Androctonus australis hector scorpion venom triggered by oxidative stress, caspase activation and apoptosis. AB - Scorpion envenomation injures a number of organs, including the kidney. Mechanisms proposed to explain the renal tubule injury include direct effects of venom on tubule epithelial cells, as well as indirect effects of the autonomic nervous system, and inflammation. Here, we report direct effects of Androctonus australis hector (Aah) scorpion venom on the viability of Renal Proximal Tubule (RPT) cells in vitro, unlike distal tubule and collecting duct cells. Extensive NucGreen nuclear staining was observed in immortalized rabbit RPT cells following treatment with Aah venom, consistent with cytotoxicity. The involvement of oxidative stress is supported by the observations that 1) anti-oxidants mitigated the Aah venom-induced decrease in the number of viable RPT cells, and 2) Aah venom-treated RPT cells were intensively stained with the CellROX((r)) Deep Red reagent, an indicator of Reactive Oxygen Species (ROS). Relevance to normal RPT cells is supported by the red fluorescence observed in Aah venom treated primary rabbit RPT cell cultures following their incubation with the Flica reagent (indicative of caspase activation and apoptosis), and the green fluorescence of Sytox Green (indicative of dead cells). PMID- 27470531 TI - Desired and side effects of the supplementation with l-glutamine and l glutathione in enteric glia of diabetic rats. AB - BACKGROUND/AIMS: Enteric neuropathy associated with Diabetes Mellitus causes dysfunction in the digestive system, such as: nausea, diarrhea, constipation, vomiting, among others. The aim of this study was to compare the effects of supplementation with 2% l-glutamine and 1% l-glutathione on neurons and enteric glial cells of ileum of diabetic rats. METHODS: Thirty male Wistar rats have been used according to these group distributions: Normoglycemic (N), Normoglycemic supplemented with l-glutamine (NG), Normoglycemic supplemented with l-glutathione (NGO), Diabetic (D), Diabetic supplemented with l-glutamine (DG) and Diabetic supplemented with l-glutathione (DGO). After 120days, the ileum was processed for immunohistochemistry of HuC/D and S100beta. Quantitative and morphometric analysis have been performed. RESULTS: Diabetic rats presented a decrease in the number of neurons when compared to normoglycemic animals. However, diabetes was not associated with a change in glial density. l-Glutathione prevented the neuronal death in diabetic rats. l-Glutathione increased a glial proliferation in diabetic rats. The neuronal area in diabetic rats increased in relation to the normoglycemics. The diabetic rats supplemented with l-glutamine and l-glutathione showed a smaller neuronal area in comparison to diabetic group. The glial cell area was a decreased in the diabetics. The diabetic rats supplemented with l glutamine and l-glutathione did not have significant difference in the glial cell body area when compared to diabetic rats. CONCLUSION: It is concluded that the usage of l-glutamine and l-glutathione as supplements presents both desired and side effects that are different for the same substance in considering normoglycemic or diabetic animals. PMID- 27470532 TI - Tuberous Sclerosis Complex Associated with Vascular Anomalies or Overgrowth. AB - BACKGROUND: Dysregulation of the mammalian target of rapamycin pathway is the underlying pathogenic mechanism in tuberous sclerosis complex (TSC). Other syndromes caused by genetic alterations in this pathway frequently manifest as vascular anomalies or asymmetric overgrowth. Rarely, these features have been documented in TSC. OBJECTIVE: To collate cases of TSC with vascular anomaly or overgrowth that have been published and to assemble additional recent cases, as this finding has been underreported. METHODS: TSC cases from three pediatric dermatology referral centers on two continents were reviewed to identify individuals noted to have hemihypertrophy or vascular anomalies. RESULTS: We report five additional cases of TSC associated with vascular anomalies or overgrowth that contribute to our understanding of some of the pathways and treatments involved in vascular anomalies. CONCLUSION: Hemihypertrophy and vascular anomalies may be more frequent in the setting of TSC than previously appreciated. A common pathogenetic mechanism may tie these manifestations together. PMID- 27470533 TI - Yeast diversity of sourdoughs and associated metabolic properties and functionalities. AB - Together with acidifying lactic acid bacteria, yeasts play a key role in the production process of sourdough, where they are either naturally present or added as a starter culture. Worldwide, a diversity of yeast species is encountered, with Saccharomyces cerevisiae, Candida humilis, Kazachstania exigua, Pichia kudriavzevii, Wickerhamomyces anomalus, and Torulaspora delbrueckii among the most common ones. Sourdough-adapted yeasts are able to withstand the stress conditions encountered during their growth, including nutrient starvation as well as the effects of acidic, oxidative, thermal, and osmotic stresses. From a technological point of view, their metabolism primarily contributes to the leavening and flavour of sourdough products. Besides ethanol and carbon dioxide, yeasts can produce metabolites that specifically affect flavour, such as organic acids, diacetyl, higher alcohols from branched-chain amino acids, and esters derived thereof. Additionally, several yeast strains possess functional properties that can potentially lead to nutritional and safety advantages. These properties encompass the production of vitamins, an improvement of the bioavailability of phenolic compounds, the dephosphorylation of phytic acid, the presence of probiotic potential, and the inhibition of fungi and their mycotoxin production. Strains of diverse species are new candidate functional starter cultures, offering opportunities beyond the conventional use of baker's yeast. PMID- 27470534 TI - Methods and issues in studies of CRE. AB - Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging and troublesome group of pathogens. Risk factor studies, outcome studies, and randomized trials are three types of studies conducted to answer different types of questions regarding CRE. These studies pose different types of challenges. We discuss issues in the design and analyses of case-control studies, cohort studies, and randomized trials aimed to address various research questions regarding CRE. PMID- 27470535 TI - Plasma Leptin in Patients at Intermediate to High Cardiovascular Risk With and Without Type 2 Diabetes Mellitus. AB - BACKGROUND: A number of clinical studies have demonstrated that leptin concentrations are related to the metabolic disturbances that constitute the metabolic syndrome (MetS) and to diabetes mellitus (DM). AIM: To investigate possible determinants of leptin concentrations in a sample of patients at high cardiovascular (CV) risk carrying two or more features of the MetS and to investigate if any difference exist between at risk patients with or without DM. METHODS: Serum leptin concentrations were measured in 60 consecutive male patients affected by at least two CV risk factors which belong to the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) definition of MetS: 30 patients affected by type 2 DM (T2DM) and 30 nondiabetic patients (non-T2DM). Nineteen healthy subjects were included in the study as a control group (HC). RESULTS: Leptin was significantly higher in patients carrying two or more features of the MetS compared with HC (P = 0.02). Stratifying MetS patients for DM, we found that leptin level was higher in non-T2DM patients (7.8 ng/ml), intermediate in T2DM (6.2 ng/ml), and lower in HC (4.6 ng/ml). In MetS patients, a positive correlation was found between leptin and waist, triglycerides, and number of MetS criteria. After stratification for T2DM, the correlations were still significant in the non-T2DM but not in the T2DM group. CONCLUSIONS: In our sample of moderate-to-high-risk patients, leptin level is positively associated with waist circumference and triglycerides but only in non-T2DM patients. Our data suggest that diabetic subjects could modulate leptin production in a different way compared with patients carrying other MetS-related anomalies. PMID- 27470536 TI - Controlling nanowire growth through electric field-induced deformation of the catalyst droplet. AB - Semiconductor nanowires with precisely controlled structure, and hence well defined electronic and optical properties, can be grown by self-assembly using the vapour-liquid-solid process. The structure and chemical composition of the growing nanowire is typically determined by global parameters such as source gas pressure, gas composition and growth temperature. Here we describe a more local approach to the control of nanowire structure. We apply an electric field during growth to control nanowire diameter and growth direction. Growth experiments carried out while imaging within an in situ transmission electron microscope show that the electric field modifies growth by changing the shape, position and contact angle of the catalytic droplet. This droplet engineering can be used to modify nanowires into three dimensional structures, relevant to a range of applications, and also to measure the droplet surface tension, important for quantitative development of strategies to control nanowire growth. PMID- 27470537 TI - Ultrafast capillary electrophoresis/mass spectrometry of controlled substances with optical isomer separation in about a minute. AB - RATIONALE: Analysis of forensic evidence by information-rich technologies such as mass spectrometry (MS) is one of the fastest growing areas in forensic analysis. To provide more accurate identification of forensic evidence, in the past few years there has been a growing interest in moving this technology to the field for on-site, real-time analysis. To this end, several portable mass spectrometers have been introduced; however, the analysis of controlled substances could be complicated by the existence of various isomers including optical isomers in which sentencing may depend on the identification of the isomer. To date very few portable separation devices are capable of separating and identifying the optical isomers. METHODS: In this study, the application of the portable ultrafast capillary electrophoresis (UFCE) to the separation of controlled substances is presented and the results are compared with the results obtained from a bench-top CE system. Both a nominal mass ion trap mass spectrometer and an accurate mass orbitrap mass spectrometer were interfaced with CE using a porous tip capillary. RESULTS: A mixture of several controlled substances can be separated and detected using UFCE/MS in about a minute using field strengths of >=1000 V/cm. Furthermore, separation and detection of underivatized optical isomers of amphetamine, cathinone, nor-mephedrone, and pregabalin using UFCE/MS can be achieved with an analysis time of less than two minutes. Resolutions of 1.3, 3.7 and 3.8 were achieved for pregabalin, cathinone and nor-mephedrone, respectively, under UFCE/MS conditions. CONCLUSIONS: Amphetamine, cathinone, nor-mephedrone and pregabalin were separated and detected in about a minute, demonstrating the utility of the portable CE instrument for the analysis of controlled substances and their optical isomers. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470538 TI - TB vaccines in clinical development. AB - The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on TB Vaccines in Clinical Development, and Clinical Research: Data and Findings. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1-S30]. PMID- 27470539 TI - Disruption of trophic interactions involving the heather beetle by atmospheric nitrogen deposition. AB - Elevated nitrogen (N) deposition impacts the structure and functioning of heathland ecosystems across Europe. Calluna plants under high N-inputs are very sensitive to secondary stress factors, including defoliation attacks by the heather beetle. These attacks result in serious damage or death of Calluna, its rapid replacement by grasses, and the subsequent loss of heathland. We know very little about the mechanisms that control the populations and trigger outbreaks of the heather beetle, impeding proper management measures to mitigate the damage. We investigated the effects of N deposition on the relationships between the heather beetle, its host plant, and two arthropod predators at building (rejuvenated through fire) and mature heathlands. The study combines field manipulation experiments simulating a range of N deposition rates (0, 1, 2, 5 g N m-2 year-1 for 2 years, and 5.6 g N m-2 year-1 for 10 years), and food-choice laboratory experiments testing the preferences of adults and larvae of the heather beetle for N-treated Calluna plants, and the preferences of predators for larvae grown on plants with different N-content. The larvae of the heather beetle achieved the highest abundances after the long-term (10-year) addition of N at mature Calluna plots in the field. Contrary to the adults, the larvae foraged preferentially on the most N-rich Calluna shoots under laboratory conditions. Predators showed no aggregative numerical responses to the accumulation of heather beetle larvae at high N-input experimental plots. During the feeding trials, predators consumed a small number of larvae, both in total and per individual, and systematically avoided eating the larvae reared on high-N Calluna shoots. Our study showed that the most severe defoliation damage by the heather beetle is inflicted at the larval stage under prolonged availability of high-N inputs, and that arthropod predators might not act as effective regulators of the beetle's populations. PMID- 27470540 TI - A simple, rapid, low-cost technique for naked-eye detection of urine-isolated TMPRSS2:ERG gene fusion RNA. AB - The TMPRSS2:ERG gene fusion is one of a series of highly promising prostate cancer (PCa) biomarker alternatives to the controversial serum PSA. Current methods for detecting TMPRSS2:ERG are limited in terms of long processing time, high cost and the need for specialized equipment. Thus, there is an unmet need for less complex, faster, and cheaper methods to enable gene fusion detection in the clinic. We describe herein a simple, rapid and inexpensive assay which combines robust isothermal amplification technique with a novel visualization method for evaluating urinary TMPRSS2:ERG status at less than USD 5 and with minimal equipment. The assay is sensitive, and rapidly detects as low as 10(5) copies of TMPRSS2:ERG transcripts while maintaining high levels of specificity. PMID- 27470542 TI - October 2013 (vol. 209, no. 4, page 323.e4 online, 324 in print). PMID- 27470541 TI - Oxidation and interaction of DJ-1 with 20S proteasome in the erythrocytes of early stage Parkinson's disease patients. AB - Parkinson's disease (PD) is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ 1, the product of the causative gene of a familial form of PD, plays a significant role in anti-oxidative defence to protect cells from oxidative stress. DJ-1 undergoes preferential oxidation at the cysteine residue at position 106 (Cys-106) under oxidative stress. Here, using specific antibodies against Cys 106-oxidized DJ-1 (oxDJ-1), it was found that the levels of oxDJ-1 in the erythrocytes of unmedicated PD patients (n = 88) were higher than in those of medicated PD patients (n = 62) and healthy control subjects (n = 33). Elevated oxDJ-1 levels were also observed in a non-human primate PD model. Biochemical analysis of oxDJ-1 in erythrocyte lysates showed that oxDJ-1 formed dimer and polymer forms, and that the latter interacts with 20S proteasome. These results clearly indicate a biochemical alteration in the blood of PD patients, which could be utilized as an early diagnosis marker for PD. PMID- 27470543 TI - MALAT1 promotes the proliferation and invasion of thyroid cancer cells via regulating the expression of IQGAP1. AB - BACKGROUND: Increasing evidence indicated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a key regulator in the proliferation and invasion of several cancers. However, the function of MALAT1 in the development of thyroid cancer has not been experimentally established. METHODS: The expression of MALAT1 and IQGAP1 in thyroid cancer tissues and cells were detected by quantitative real-time PCR and western blot. The effects of MALAT1 and IQGAP1 on the cell proliferation and invasion of thyroid cancer cells were detected with a 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium 4 (MTT) assay and a Transwell assay, respectively. FTC-133 or SW1736 transfected with si MALAT1 or pcDNA-MALAT1 were injected subcutaneously into 4-week-olds BALB/c mice to examine the impact of MALAT1 on the tumor development of thyroid cancer in vivo. RESULTS: In this study, we discovered the higher level of MALAT-1 and expression of IQGAP1 in thyroid cancer tissues and in thyroid cancer cells compared to that in the control. MTT and Transwell assay showed that the proliferation and invasion of FTC-133 cells with MALAT-1 knockdown were inhibited. Moreover, MALAT-1 could upregulate the expression of IQGAP1 in thyroid cancer cells. In addition, IQGAP1 knockdown reversed the decreasing cell proliferation and invasion of thyroid cancer induced by MALAT-1 overexpression. Finally, the study in vivo verified that MALAT-1 promoted the tumor growth of thyroid cancer. CONCLUSION: Our study indicated that MALAT1 promoted the proliferation and invasion of thyroid cancer cells via regulating the expression of IQGAP1. PMID- 27470544 TI - Increased MALAT1 expression predicts poor prognosis in esophageal cancer patients. AB - AIM: This study was designed to determine the expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in patients with esophageal cancer (EC). In addition, we attempted to seek the prognostic value of MALAT1 in EC based on its expression. METHODS: The expression of MALAT1 in EC tissues and cell lines were measured by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). The association between MALAT1 expression and the clinical characteristics was analyzed using Chi-square test. Kaplan-Meier survival curves were plotted to describe the overall survival of EC patients with different expression of MALAT1. Cox regression analysis was per formed to evaluate the prognostic value of MALAT1 for EC patients. RESULTS: Expression levels of MALAT1 were significantly higher in EC tissues and cells than the controls (P<0.05). MALAT1 expression was tightly related to lymphatic invasion (P=0.018), distant metastasis (P=0.033) and tumor differentiation (P=0.025), but shared no association with age, gender and tumor location (P>0.05). In addition, patients with high MALAT1 expression had a shorter overall survival than those with low MALAT1 (P<0.001). The results of Cox analysis shown that MALAT1 was significantly linked with the prognosis of EC patients (HR=6.638; P=0.000; 95% CI=2.948-14.947). CONCLUSION: Taken together, the expression of MALAT1 could be a predictor for prognosis of EC patients. PMID- 27470545 TI - Review on mechanisms and interactions in concomitant use of herbs and warfarin therapy. AB - The effectiveness of warfarin, an oral anticoagulant originally derived from a plant, is strongly affected by patient's characteristics such as the age, presence of comorbidities, and concomitant use of another drug. Warfarin has the potential to interact with many drugs, medicinal plants, and food, which increases the risk of adverse events. A critical analysis of scientific literature was conducted to assess the interferences of medicinal plants with blood haemostasis and then with warfarin anticoagulation. We found 58 different plants that may alter the blood haemostasis and anticoagulation with warfarin. The herbs that showed the greatest potential to interact with warfarin include garlic, ginger, ginkgo, St. John's wort, and ginseng, i.e. plants normally consumed as food and also used for therapeutic purposes. The interactions between drugs and herbs are varied because of the complex chemical matrix of plants. Mainly coumarins, quinones, xanthones, terpenes, lignans, and vitamin K showed significant influence on warfarin treatment. In general, these plants can potentiate the effect of warfarin by stimulating anticoagulation in multiple ways, and the clinical outcome associated with this interaction is the increase of bleeding risk. Moreover, potential interactions between herbal products and drugs are a safety concern, especially for drugs with a narrow therapeutic index or for patients receiving drug treatment for chronic diseases, and both of these apply to warfarin pharmacotherapy. Therefore, this review article summarises the data on the influence of medicinal plants on warfarin treatment and analyses this information in view of the interaction targets. The relevant plants were categorised according to their target, and their effects are discussed in order to organise the isolated information and to highlight the need of further discussion and new studies on the safety of herbal medicines and warfarin. PMID- 27470546 TI - Synergistic cytotoxicity of BIIB021 with triptolide through suppression of PI3K/Akt/mTOR and NF-kappaB signal pathways in thyroid carcinoma cells. AB - The effec.t of BIIB021, a novel heat shock protein 90 (hsp90) inhibitor, on survival of thyroid carcinoma cells has not been evaluated. In this study, the impact of BIIB021 alone or in combination with the histone acetyltransferase inhibitor triptolide on survival of thyroid carcinoma cells was identified. In 8505C and TPC-1 thyroid carcinoma cells, BIIB021 caused cell death in conjunction with alterations in expression of hsp90 client proteins. Cotreatment of both BIIB021 and triptolide, compared with treatment of BIIB021 alone, decreased cell viability, and increased the percentage of dead cells and cytotoxic activity. All of the combination index values were lower than 1.0, suggesting synergistic activity of BIIB021 with triptolide in induction of cytotoxicity. In treatment of both BIIB021 and triptolide, compared with treatment of BIIB021 alone, the protein levels of total and phospho-p53, and cleaved caspase-3 were elevated, while those of total Akt, phospho-mTOR, phospho-4EBP1, phospho-S6K, phospho-NF kappaB, survivin, X-linked inhibitor of apoptosis protein (xIAP), cellular inhibitor of apoptosis protein (cIAP) and acetyl. histone H4 were reduced. These results suggest that BIIB021 has a cytotoxic activity accompanied by regulation of hsp90 client proteins in thyroid carcinoma cells. Moreover, the synergism between BIIB021 and triptolide in induction of cytotoxicity is associated with the inhibition of PI3K/Akt/mTOR and NF-kappaB signal pathways, the underexpression of survivin and the activation of DNA damage response in thyroid carcinoma cells. PMID- 27470547 TI - Preparation of asiaticoside-loaded coaxially electrospinning nanofibers and their effect on deep partial-thickness burn injury. AB - Sodium alginate and chitosan were in favor of wound healing. However, the two polymers were not compatible in one formulation due to the electrostatic interaction. Coaxially electrospinning technology could make two or more noneletrospun polymers to be electrospun in independent core and shell layer. Asiaticoside-loaded coaxially electrospinning nanofibers of alginate, polyvinyl alcohol (PVA) and chitosan (alginate/PVA/chitosan) were prepared and evaluated. Morphologies and microstructure of nanofibers were observed with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Drug release in vitro of coaxial nanofibers was also evaluated. Deep partial-thickness burn injury were established and used to evaluate the improved healing effect of asiaticoside-loaded coaxial nanofibers. Drug-loaded coaxial nanofibers prepared with the optimized formulations and technologies had the obvious core-shell structure. Coaxial nanofibers showed faster drug release profiles in vitro and this facilitated wound healing. Its healing effect on rats with deep partial thickness burn injury was also significant based on morphology, wound healing ratio, and pathological sections. Positive expression of vascular endothelial growth factor (VEGF), cluster of differentiation 31 (CD31), and proliferating cell nuclear antigen (PCNA), and down regulation of tumor necrosis factor (TNF) and interleukin-6 (IL-6) also validated the improved effect of wound healing. In general, the asiaticoside-loaded coaxial nanofibers had obvious core-shell structure with smooth surface and uniform diameter. Its healing effect on deep partial-thickness burn injury of rats was obvious. Asiaticoside-loaded coaxial nanofibers provide a novel promising option for treatment of deep partial thickness burn injury. PMID- 27470548 TI - SIRT1 activator ameliorates the renal tubular injury induced by hyperglycemia in vivo and in vitro via inhibiting apoptosis. AB - We aimed to explore the role of SIRT1 in apoptosis in human kidney proximal tubule epithelial (HK-2) cells, and to determine whether resveratrol (RSV, a SIRT1 activator) could ameliorate apoptosis in rats with streptozotocin-induced diabetes mellitus (DM) and/or in high glucose (HG, 30mM) - stimulated HK-2 cells. Rats were distributed randomly into three groups: 1) control group, 2) DM group, and 3) DM with RSV group (DM+RSV; rats treated with 30mg/kg/d of RSV for 16 weeks). The physical, biochemical, and morphological parameters were then examined. Additionally, the deacetylase activity of SIRT1, and the expression levels of SIRT1 and of representative apoptosis markers, such as p53, acetylated p53, cleaved caspase-3, caspase-9, and cleaved PARP, were measured. HK-2 cells were stimulated by HG for different lengths of time to study the effect of HG on apoptosis. HK-2 cells were treated with or without RSV (25MUM) to investigate if RSV has a protective effect on HG-induced apoptosis. A gene-specific small interfering RNA against SIRT1 was used to study the role of SIRT1 in apoptosis. More apoptosis was found in the DM rats than in the control rats. Similarly, the expression levels of cleaved caspase-3, cleaved PARP, and acetylated p53 were significantly higher, and the level of SIRT1 was significantly lower, in the HK-2 cells that were cultured under HG conditions than those in the HK-2 cells that were cultured under low glucose (5.5mM) conditions. Notably, treatment with RSV lessened the HG-induced changes in the levels of apoptosis indicators, and this inhibition of HG-induced apoptosis in HK-2 cells by RSV treatment was abolished by SIRT1 silencing. Our study showed that hyperglycemia contributes to apoptosis in rat kidney and HK-2 cells. SIRT1 activation by RSV can reduce urinary albumin excretion and proximal tubule epithelial apoptosis both in vitro and in vivo. Based on our study, SIRT1/p53 axis played an important role in the hyperglycemia induced apoptosis. These findings indicated that the increased expression of SIRT1, mediated by RSV, is a possible mechanism by which RSV prevents renal tubular injury in diabetic nephropathy (DN). So RSV has great clinical significance and could provide the basis for the new way to effective treatment to contain the morbidity and mortality associated with DN. PMID- 27470550 TI - Decreased expression of microRNA-148a predicts poor prognosis in ovarian cancer and associates with tumor growth and metastasis. AB - OBJECTIVE: MicroRNA-148a (MiR-148a) had been reported to take part in some cancer progresses, but its clinical significance in ovarian cancer had been rarely reported. The purpose of this study was to evaluate the prognostic value of miR 148a as well as its roles in ovarian cancer progression. METHODS: Relative expression of miR-148a in the plasma specimens of ovarian cancer patients was detected by qRT-PCR. Chi-square test was used to analyze the relationship between miR-148a expression and clinical characteristics. The overall survival was analyzed by Kaplan-Meier method and Cox regression analysis was used to evaluate the prognostic value of miR-148a. In addition, the ovarian cancer cell line SKOV 3 was separately transfected with pcDNA3-microRNA-148a over-expression vector and pcDNA3 empty vector to detect the functional roles of miR-148a in ovarian cancer progression. RESULTS: Decreased level of plasma miR-148a was observed in ovarian cancer patients compared with healthy controls. The expression level was associated with histopathologic grade, TNM stage and lymph node metastasis (P<0.05 for all). Besides, patients with high level of miR-148a had a longer survival time than those with low level (40.3 months vs 31.6 months, log rank test, P=0.002). Cox regression analysis indicated that miR-148a might be a potential biomarker for ovarian cancer prognosis (HR=1.699, 95%CI=1.175-2.456, P=0.005). Moreover, cell experiments confirmed that miR-148a could inhibit proliferation, migration and invasion of ovarian cancer cells. CONCLUSION: MiR 148a may be a potential prognostic factor for ovarian cancer and it can suppress tumor progression. PMID- 27470549 TI - Transferrin-conjugated polymeric nanomedicine to enhance the anticancer efficacy of edelfosine in acute myeloid leukemia. AB - In this study, transferrin (Tf)-conjugated polyethylene glycol (PEG)-poly-l lysine (PLL)-poly(lactic-co-glycolic acid) (PLGA) (PEG-PLL-PLGA)-based micellar formulations were successfully prepared for the delivery of edelfosine (EDS) in leukemia treatment. The micelles were nanosized and presented spherical shaped particles. Our in vitro data suggest that the nanoformulations maintain the biological activity of drugs for longer periods and lead to a continuous release of active drug. The enhanced cellular uptake of EDS-TM resulted in significantly higher cytotoxic effect in K562 leukemia cells. Cell cycle analysis further demonstrated the significantly higher G2/M phase arrest of cancer cells. Immunoblot analysis clearly revealed the potential of EDS-TM in inducing apoptosis of cancer cells which could improve the anticancer efficacy in leukemia. Importantly, EDS-M and EDS-TM significantly prolonged the circulation profile of EDS throughout until 24h, indicating the potential of targeted nanoparticulate delivery system. The prolonged blood circulation potential of micellar formulations might improve the therapeutic potential of drug by increasing its bioavailability in the serum. It would be worthwhile evaluating the effects of the EDS-loaded micelles on cancer cells in vivo for clinical application. PMID- 27470551 TI - Up-regulated microRNA-155 expression is associated with poor prognosis in cervical cancer patients. AB - BACKGROUND: MicroRNAs (miRNAs) play important roles in tumor development and progression. The purposes of the study was to investigate the role of miR-155 in cervical cancer. METHODS: Quantitative real-time RT-PCR (qRT-PCR) was performed to examine miR-155 expression in cervical cancer tissues and adjacent non cancerous tissues. The association with overall survival of patients was analyzed by Kaplan-Meier survival analysis. Small interfering RNA (siRNA) was used to suppress miR-155 expression in cervical cancer cells. In vitro assays were performed to further explore the biological functions of miR-155 in cervical cancer. RESULTS: We found that miR-155 expression was markedly up-regulated in cervical cancer tissues and correlated with FIGO stage, lymph nodes metastasis, vascular invasion and HPV. Patients with high miR-155 expression level had poorer overall survival than those with low miR-155 expression. Furthermore, multivariate Cox regression analysis suggested that increased miR-155 was an independent prognostic indicator for cervical cancer (P=0.007; HR=2.320; 95%CI: 1.259-4.276). Moreover, knockdown of miR-155 was demonstrated to inhibit cell proliferation, migration, and invasion in vitro. CONCLUSION: Our study presents that miR-155 is a novel molecule involved in cervical cancer progression, which provide a potential prognostic biomarker and therapeutic target. PMID- 27470552 TI - Hepatoprotective and antioxidant potential of Asphodeline lutea (L.) Rchb. roots extract in experimental models in vitro/in vivo. AB - The aim of this study was to investigate the effect of Asphodeline lutea (L.) Rchb. dry root extract (ALE) administered alone and against carbon tetrachloride (CCl4)-induced liver injury in vitro/in vivo. The dried roots of A. lutea were extracted with 70% ethanol and was characterized with HPLC-UV. Hepatoprotective potential was investigated by in vivo/in vitro assays in Wistar rats as well as antioxidant properties. At concentrations ranging from 10 to 200MUg/mL of ALE significant cytotoxic effects on isolated hepatocytes were found. ALE showed some toxicity in Wistar rats discerned by increased ALT (Alanine transaminase), ALP (Alkaline phosphatase) activities and MDA (malondialdehyde) quantity, decreased GSH (reduced glutathione) levels without affecting the activity of the antioxidant enzymes (GPx (Gluthatione peroxidase), GR (Glutathione reductase) and GST (Glutathione-S-transferase activity)). The antioxidant and hepatoprotective potential of ALE was also observed in vitro/in vivo against CCl4-induced liver injury, where ALE normalizes all the examined parameters perturbated by CCl4 administration. In addition, ALE preserved the decreased cytochrome P450 level and EMND (Ethylmorphine-N-Demethylase) activity without affecting AH (Aniline 4 Hydroxylase) activity. ALE is rich in anthraquinones, naphthalenes and caffeic acid. The pro-oxidant effects of ALE could be due to naphthalene and anthraquinone bioactivation pathways involving toxic metabolites. PMID- 27470553 TI - Nanomedicine-based combination of gambogic acid and retinoic acid chlorochalcone for enhanced anticancer efficacy in osteosarcoma. AB - In this study, gambogic acid (GA) and retinoic acid chlorochalcone (RACC) co loaded glycol chitosan nanoparticle was successfully developed and studied for its therapeutic efficacy against osteosarcoma cancer cells. The GA/RACC loaded glycol chitosan nanoparticles (RGNP) was nanosized and exhibited a controlled release of drug in either pH 7.4 and pH 5.0. Owing to the strong positive charge on the RGNP surface, efficiency cellular uptake was observed in cancer cells. Moreover, a synergistic combination of GA and RACC were effectively suppressed the tumor growth progression. The half maximal inhibitory concentration (IC50) values in MG63 cells were 0.89MUg/ml and 0.35MUg/ml for GA and RGNP after 24h. The results clearly suggest the synergist effect of GA and RACC in effectively inhibiting the cancer cell proliferation. The RGNP as expected induced a remarkably higher apoptosis of cancer cells with ~28%. Overall, combination of GA and RACC encapsulated in a nanocarrier could be an effective strategy to treat osteosarcoma. Future studies will focus on the in vivo evaluation of GA/RACC loaded polymeric nanoparticles. PMID- 27470554 TI - Pelargonidin improves memory deficit in amyloid beta25-35 rat model of Alzheimer's disease by inhibition of glial activation, cholinesterase, and oxidative stress. AB - Alzheimer's disease (AD) is a multifactorial disorder with devastating outcomes and few mostly palliative available therapeutic strategies. Pelargonidin (Pel), an anthocyanin compound, is an estrogen receptor agonist with lower side effects versus estrogen. This study examined neuroprotective effect of Pel on intrahippocampal amyloid beta25-35 (Abeta) rat model of AD. Rats were divided into groups of sham, Abeta, and Pel-pretreated Abeta (10mg/kg; p.o.). Animals underwent Morris water maze (MWM) test in addition to measurement of hippocampal oxidative stress, acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS). Pel pretreatment of Abeta group significantly improved escape latency and distance swum in MWM versus Abeta group and attenuated hippocampal malondialdehyde (MDA) and increased catalase activity with no significant change of nitrite. Meanwhile, Pel improved hippocampal AChE activity and lowered GFAP level with no significant change of iNOS. Our results suggest that Pel could improve Abeta25-35-induced memory deficit through mitigation of oxidative stress, cholinergic dysfunction, and astrocyte reaction. PMID- 27470555 TI - Clinical verification of a novel urinary microRNA panal: 133b, -342 and -30 as biomarkers for diabetic nephropathy identified by bioinformatics analysis. AB - BACKGROUND: Because microvascular disease is one of the major drivers of diabetic complications, early detection of diabetic nephropathy (DN) by assessing the expression of exosomal microRNAs (miRNAs) in DN patients and healthy controls, may be of clinical value. The aim of this study wasto identify a novel miRNA panel of DN by combining bioinformatics analysis of miRNA databases and clinical verification to evaluate the significance of this panel as urine biomarkers for type 2 diabetic nephropathy (T2DN). PATIENTS AND METHODS: Public miRNA databases e.g miro-Ontology and miRWalk were analyzed and a novel panel of 3 microRNAs was retrieved. Meanwhile, combinatorial target prediction algorithms were applied. Multiple case-matched normal were examined by quantative RT-PCR for differential expression in urine exosomes from 210 participants, and the three identified miRNAs were validated as DN biomarkers. RESULTS: We found urinary exosomalmiR 133b, miR-342, and miR-30a were expressed at significantly elevated levels in T2DN patients (P<0.001) compared to normal. Furthermore, high-level expression of the 3 miRNAs was associated withHbA1c,systolic-diastolic blood pressure, LDL, serum creatinine, urinary albumin creatinine ratio and estimated glomerular filtration rate(eGFR). Moreover, 39.3%, 19.6% and 17.9% of patients with normo albuminuria had positive (miR-133b, miR-342 and miR-30a, respectively); indicating the possibility of molecular changes in these patients before onset of albuminuria. CONCLUSION: We have identified novel urinary exosomal miRNA biomarkers of DN which were altered not only in micro and macroalbuminuric groups but also in some normoalbuminuria cases prior to albuminuria. PMID- 27470556 TI - Gene expression profiling of common signal transduction pathways affected by rBMSCs/F92A-Cav1 in the lungs of rat with pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, inflammation and suppressed apoptosis of smooth muscle cells. Our previous studies have found that rat bone marrow-derived mesenchymal stem cells (rBMSCs) transduced with a mutant caveolin-1(F92A-Cav1) could enhance endothelial nitric oxide synthase (eNOS) activity and improve pulmonary vascular remodeling, but the potential mechanism is not yet fully explored. The present study was to investigate the gene expression profile upon rBMSCs/F92A Cav1delivered to PAH rat to evaluate the role of F92A-Cav1 in its regulation. METHODS: PAH was induced with monocrotaline (MCT, 60mg/kg) prior to delivery of lentiviral vector transduced rBMSCs expressing Cav1 or F92A-Cav1. Gene expression profiling was performed using Rat Signal Transduction PathwayFinder array. The expression changes of 84 key genes representing 10 signal transduction pathways in rat following rBMSCs/F92A-Cav1 treatment was examined. RESULTS: Screening with the Rat Signal Transduction PathwayFinder R2 PCR Array system and subsequent western blot, immunohistochemistry or real time PCR analysis revealed that F92A Cav1 modified rBMSCs can inhibit the inflammation factors (TNF-alpha, Icam1 and C/EBPdelta), pro-proliferation genes (c-Myc, Bcl2a1d, Notch1and Hey2), oxidative stress gene (Hmox1) and activate cell cycle arrested gene Cdkn1a, ameliorating inflammation and inhibiting cell proliferation in PAH rat. CONCLUSION: rBMSCs/F92A-Cav1 inhibits inflammation and cell proliferation by regulating signaling pathways that related to inflammation, proliferation, cell cycle and oxidative stress. PMID- 27470558 TI - The association of Phosphatase and tensin homolog (PTEN) deletion and prostate cancer risk: A meta-analysis. AB - OBJECTIVE: Phosphatase and tensin homolog (PTEN) deleted on chromosome 10, a tumor suppressor that negatively regulates the phosphoinositide-3-kinase(PI3K) which has been implicated in a number of human malignancies including prostate cancer. However the prognostic value of PTEN deletion in prostate cancer patient's diagnosis and the mechanism of PTEN deletion in prostate cancer development still remain unclear. METHOD: A meta-analysis of 26 published studies including 8097 prostate cancer patients was performed. RESULTS: Compared to PTEN normal patients, PTEN deletion patients showed a higher aggressive Gleason score(OR: 1.284, 95%CI=1.145-1.439) and pathological stage(OR: 1.628, 95%CI=1.270 2.087) which generally had a higher risk in prostate replace(HR: 1.738, 95%CI=1.264-2.390). Significant association between PTEN deletion and ERG rearrangements in prostate cancer development was also proved that compared to PTEN normal patients, patients with PTEN deletion showed a higher risk in ERG rearrangements(OR: 1.345, 95%CI=1.102-1.788). CONCLUSION: This study indicated that patients with PTEN deletion were associated with higher pathological stage or Gleason score and a higher risk in prostate cancer replace potentially represent a novel clinically relevant event to identify individuals at increased risk for the occurrence, progression and prognosis of prostate cancer. Prostate cancer patients with PTEN deletion usually had a higher risk in ERG rearrangements than other patients may be a potential new area for identifying poor prognosis patients and selecting patients for targeted therapies which required confirmation through adequately designed prospective studies. PMID- 27470557 TI - Preparation, pharmacokinetics and pharmacodynamics of ophthalmic thermosensitive in situ hydrogel of betaxolol hydrochloride. AB - Conventional ophthalmic formulations often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of the drug in the precorneal area. To solve those problems, a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system was prepared and evaluated, the system was composed of poloxamer analogs and polycarbophil (PCP) and betaxolol hydrochloride (BH) was selected as model drug. The concentrations of poloxamer 407 (P407) (22% (w/v)) and poloxamer 188 (P188) (3.5% (w/v)) were identified through central composite design-response surface methodology (CCD-RSM). The BH in situ hydrogel (BH-HG) was liquid solution at low temperature and turned to semisolid at eye temperature. BH-HG showed good stability and biocompatibility, which fulfilled the requirements of ocular application. In vitro studies indicated that addition of PCP enhanced the viscosity of BH-HG and the release results of BH from BH-HG demonstrated a sustained release behavior of BH because of the gel dissolution. In vivo pharmacokinetics and pharmacodynamics studies indicated that the BH-HG formulation resulted in an improved bioavailability and a significantly lower intraocular pressure (IOP). The results suggested BH-HG could be potentially used as an in situ gelling system for ophthalmic delivery to enhance the bioavailability and efficacy. PMID- 27470559 TI - Bauhinia variegata (Caesalpiniaceae) leaf extract: An effective treatment option in type I and type II diabetes. AB - Among various metabolic disorders, diabetes mellitus is one of the most common disorder. Present study was designed to evaluate the effectiveness of aqueous extract of Bauhinia variegata leaves (AE) in animal models of type I and type II diabetes. Type I diabetes was induced by streptozotocin at the dose of 55mg/kg (i.p.) in male Sprague Dawley rats while type II diabetes was induced by high fat diet and streptozotocin at the dose of 35mg/kg (i.p.). Diabetic animals were treated with AE at the dose of 250, 500 and 1000mg/kg. Glipizide (5mg/kg) was used as standard treatment drug. Treatment was given for 28days. Parameters evaluated were body weight, plasma glucose, cholesterol, triglyceride, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, total proteins, albumin, creatinine and bun urea nitrogen. In type II diabetes, high density lipoprotein levels in plasma and plasma insulin level were also evaluated. Histopathological study of pancreases were carried out in type I study. AE showed significant decrease in plasma glucose significantly. AE was also found to decrease cholesterol, triglyceride, creatinine and blood urea nitrogen level in both types of diabetes. AE did not show any significant effect on plasma levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase. AE was found to increase the albumin and total protein levels. Histopathological study showed that AE decreases the necrotic changes in the pancreatic tissue. Aqueous extract of B. variegata leaves was found effective in treatment of both type I and type II diabetes. PMID- 27470560 TI - Procyanidin-rich extract of natural cocoa powder causes ROS-mediated caspase-3 dependent apoptosis and reduction of pro-MMP-2 in epithelial ovarian carcinoma cell lines. AB - Over the last four centuries, cocoa and chocolate have been described as having potential medicinal value. As of today, Theobroma cacao L. (Sterculiaceae) and its products are consumed worldwide. They are of great research interest because of the concentration dependent antioxidant as well as pro-oxidant properties of some of their polyphenolic constituents, specially procyanidins and flavan-3-ols such as catechin. This study was aimed at investigating the cellular and molecular changes associated with cytotoxicity, caused due pro-oxidant activity of cocoa catechins and procyanidins, in ovarian cancer cell lines. Extract of non alkalized cocoa powder enriched with catechins and procyanidins was used to treat human epithelial ovarian cancer cell lines OAW42 and OVCAR3 at various concentrations <=1000MUg/mL. The effect of treatment on intracellular reactive oxygen species (ROS) levels was determined. Apoptotic cell death, post treatment, was evaluated microscopically and using flow cytometry by means of annexin propidium iodide (PI) dual staining. Levels of active caspase-3 as a pro apoptotic marker and matrix metalloproteinase 2 (MMP2) as an invasive potential marker were detected using Western blotting and gelatin zymography. Treatment with extract caused an increase in intracellular ROS levels in OAW42 and OVCAR3 cell lines. Bright field and fluorescence microscopy of treated cells revealed apoptotic morphology and DNA damage. Increase in annexin positive cell population and dose dependent upregulation of caspase-3 confirmed apoptotic cell death. pro MMP2 was found to be downregulated in a dose dependent manner in cells treated with the extract. Treated cells also showed a reduction in MMP2 activity. Our data suggests that cocoa catechins and procyanidins are cytotoxic to epithelial ovarian cancer, inducing apoptotic morphological changes, DNA damage and caspase 3 mediated cell death. Downregulation of pro-MMP2 and reduction in active MMP2 levels imply a decrease in invasive potential of the cells. Apoptosis and MMP2 downregulation appear to be linked to the increase in intracellular ROS levels, caused due to the prooxidant effect of cocoa procyanidin extract. PMID- 27470561 TI - High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania. AB - Visceral leishmaniasis (VL) has been considered as one of the most fatal form of leishmaniasis which affects 70 countries worldwide. Increased drug resistance in Indian subcontinent urged the need of new antileishmanial compounds with high efficacy and negligible toxicity. Imipramine compounds have shown impressive antileishmanial activity. To find out most potent analogue from imipramine series and explore the inhibitory activity of imipramine, we docked imipramine analogues (n=93,328) against trypanothione reductase in three sequential modes. Furthermore, 98 ligands having better docking score than reference ligand were subjected to ADME and toxicity, binding energy calculation and docking validation. Finally, Molecular dynamic and single point energy was estimated for best two ligands. This study uncovers the inhibitory activity of imipramine against Leishmania parasites. PMID- 27470562 TI - Beta-asarone protects against MPTP-induced Parkinson's disease via regulating long non-coding RNA MALAT1 and inhibiting alpha-synuclein protein expression. AB - OBJECTIVE: Numerous long non-coding RNAs (lncRNA) have been identified in neurodegenerative disorders including Parkinson's disease (PD). Emerging evidence demonstrates that beta-asarone functions as neuroprotective effects in both in vitro and in vivo models. However, the role of beta-asarone and its potential mechanism in PD remain not completely clear. METHODS: MPTP-induced PD mouse model and SH-SY5Y cells subjected to MPP+ as its in vitro model were used to evaluate the effects of beta-asarone on PD. LncRNA MALAT1 and alpha-synuclein expression were determined by real-time PCR and western blot methods. RESULTS: beta-Asarone significantly increased the TH+ cells number and decreased the expression levels of MALAT1 and alpha-synuclein in midbrain tissue of PD mice. RNA pull-down and immunoprecipitation assays confirmed that MALAT1 associated with alpha-synuclein, leading to the increased stability of alpha-synuclein and its expression in SH SY5Y cells. beta-asarone elevated the viability of cells exposed to MPP+. Either overexpressed MALAT1 or alpha-synuclein could canceled the protective effect of beta-asarone on cell viability. In PD mice, pcDNA-MALAT1 also decreased the TH+ cells number and increased the alpha-synuclein expression in PD mice with treatment of beta-asarone. CONCLUSION: beta-Asarone functions as a neuroprotective effect in both in vivo and in vitro models of PD via regulating MALAT1 and alpha-synuclein expression. PMID- 27470563 TI - Investigation of the effect of safranal and crocin pre-treatment on hepatic injury induced by infrarenal aortic occlusion. AB - Ischemia-reperfusion (IR) injury of the liver is an unresolved problem that occurs during certain surgical approaches, including hepatic, cardiac and aortic operations. In this study we aimed to investigate whether crocin and safranal had protective effects on liver IR injury induced in an infrarenal aortic clamping (IRAC) model. Male Wistar-Albino rats (n=32) were divided into four groups with 8 animals each as follows: Sham, IR, IR+crocin, and IR+safranal. The infrarenal aorta (IRA) was clamped for 60min for the ischemic period and allowed to reperfuse for 120min. Blood and tissue samples were collected for biochemical, histological and immunohistological analysis. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were found to be significantly higher in the IR group than the sham group (respectively; p=0.015, p<0.001). There were significant differences between the IR group and the IR+crocin group or the IR+safranal group in AST levels (respectively; p=0.02, p<0.001). ALT showed a significant decrease in the IR+crocin group compared to the IR group (p<0.05). We also observed histopathological changes among the groups. Bax and Caspase-3 expression in the IR group was remarkably higher than in the other groups. Caspase-3 and Bax expression in the IR+crocin and the IR+safranal groups were significantly lower than in the IR group. Nevertheless, there were no significant differences in BCL2 expression among the groups. IRAC is a cause of IR injury in the liver. This study showed that crocin and safranal have protective effects on IR induced liver injury. PMID- 27470564 TI - Effect of 3-keto-1,5-bisphosphonates on obese-liver's rats. AB - Obesity is associated with an oxidative stress status, which is defined by an excess of reactive oxygen species (ROS) vs. the antioxidant defense system. We report in this present work, the link between fat deposition and oxidative stress markers using a High Fat Diet-(HFD) induced rat obesity and liver-oxidative stress. We further determined the impact of chronic administration of 3-keto-1, 5 BPs 1 (a & b) (40MUg/kg/8 weeks/i.p.) on liver's level. In fact, exposure of rats to HFD during 16 weeks induced body and liver weight gain and metabolic disruption with an increase on liver Alanine amino transferase (ALAT) and Aspartate aminotransferase (ASAT) concentration. HFD increased liver calcium level as well as free iron, whereas, it provoked a decrease on liver lipase activity. HFD also induced liver-oxidative stress status vocalized by an increase in reactive oxygen species (ROS) as superoxide radical (O2), hydroxyl radical (OH) and Hydrogen peroxide (H2O2). Consequently, different deleterious damages as an increase on Malon Dialdehyde MDA, Carbonyl protein PC levels with a decrease in non-protein sulfhydryls NPSH concentrations, have been detected. Interestingly, our results demonstrate a decrease in antioxidant enzymes activities such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx) and peroxidases (POD). Importantly, 3-keto-1,5-bisphosphonates treatment corrected the majority of the deleterious effects caused by HFD, but it failed to correct some liver's disruptions as mineral profile, oxidative damages (PC and NPSH levels) as well as SOD and lipase activities. Our investigation point that 3-keto-1,5-bisphosphonates could be considered as safe antioxidant agents on the hepatic level that should also find other potential biological applications. PMID- 27470565 TI - Simvastatin inhibits glucose uptake activity and GLUT4 translocation through suppression of the IR/IRS-1/Akt signaling in C2C12 myotubes. AB - Simvastatin,a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, is clinically used in the prevention and treatment of cardiovascular diseases. Numerous studies demonstrate that statins increase the risk of new-onset diabetes in long-term therapy, but mechanisms underpinning this effect are still unclear. Here, we investigated whether simvastatin inhibited the glucose uptake activity and the underlying mechanisms in C2C12 myotubes. Our studies showed that simvastatin significantly inhibited glucose uptake activity and GLUT4 translocation, whereas the effect was reversible with mevalonolactone (ML), which acts as an intermediate of cholesterol synthesis pathway. Mechanistically, the inhibition of glucose uptake and GLUT4 translocation elicited by simvastatin were associated with the suppression of the insulin receptor (IR)/IR substrate (IRS)/Akt signaling cascade. Simvastatin suppressed the phosphorylation of IR, IRS-1 and Akt, and total expression of IR or IRS-1, but did not affect Akt. Furthermore, simvastatin decreased Rac1 GTP binding. In conclusion, our findings indicate that simvastatin suppresses glucose uptake activity and GLUT4 translocation via IR-dependent IRS-1/PI3K/Akt pathway. These results provide an important new insight into the mechanism of statins on insulin sensitivity which may be associated with new-onset diabetes. PMID- 27470566 TI - Poly-carboxylic acids functionalized chitosan nanocarriers for controlled and targeted anti-cancer drug delivery. AB - The present study evaluates the in-vitro cisplatin (CDDP) release from four different poly oxalates cross-linked chitosan (CS) nanocomposites. The poly oxalates were synthesized from the reaction of four different dicarboxylic acids with ethylene glycol (EG). The encapsulation of CDDP on CS cross-linked with Oxalic acid-EG, Succinic acid-EG, Citric acid-EG and tartaric acid-EG carriers were carried out by the ionic gelation technique. The poly-oxalate nanocarriers were characterized by scanning electron microscopy, atomic force microscopy, X ray diffraction studies and zeta potential analysis. The stability of poly oxalates was calculated by the density functional theory (DFT) using Gaussview 05. Excellent drug release kinetics and good biocompatibility of nanocomposites were observed for the in-vitro analysis. The unloaded poly oxalate nanocomposites perform to have a low inherent cytotoxicity, whereas the loaded nanocomposites were as active as free CDDP in the MCF-7 cancer cell line. The tumor growth inhibitions of CDDP-loaded nanocomposites are more or equal to that of free CDDP. Taken together, these two poly oxalate nanocomposites are established as promising drug carriers for the delivery of CDDP. PMID- 27470567 TI - Antidiabetic, antihyperlipidemic and anti-inflammatory effects of tilianin in streptozotocin-nicotinamide diabetic rats. AB - Flavonoids from medicinal plants have been used in traditional medicine to treat a variety of prevalent diseases. Flavones activate the signaling pathways promoting fuel metabolism and insulin sensitizing in hepatocytes and adipocytes, which suggests that flavones may have the potential to exert in vivo antidiabetic and antihyperlipidemic effects. Thus, the aim of the current study was to determine the antidiabetic, antihyperlipidemic and anti-inflammatory effects of tilianin in diabetic rats. Also, to understand the mechanism involved using in vitro 3T3-L1 cells and tissues from experimental animals treated with test samples through molecular profile studies. Non insulin-dependent diabetic mellitus (NIDDM) rats were treated over a short period (for 10 days) with 60mg/Kg/day of tilianin. After treatment, a biochemical blood profile was determined. Also, adipose and thoracic aortic tissues were used to determine pro inflammatory profile, adiponectin and adhesion molecules by real-time PCR. In 3T3 L1 cells pretreated with tilianin (10MUM), PPARalpha, PPARgamma, GLUT4, FATP-1 and ACSL-1 mRNA expression were measured. In order to explain the potential PPARalpha interaction with tilianin, a docking study with PPARalpha was carried out. Thus, intragastric administration of tilianin and metformin induced a decrease in plasma glucose (GLU) in diabetic rats on day 6, and remained significantly lower until the end of the treatment; also blood triacylglycerides (TAG) and cholesterol (CHOL) (p<0.05) were diminished. Moreover, IL-1beta and IL 18 expression was significantly decreased in adipose tissue (p<0.05); meanwhile adiponectin was significantly overexpressed (p<0.05). Besides, ICAM-1 expression was significantly reduced in aortic tissue (p<0.05). In 3T3-L1 cells it was found that tilianin increased PPARalpha and ACSL1 mRNA levels (p<0.05). Finally, tilianin docking studies with PPARalpha showed polar interactions with Glu269, Tyr314, His 440 and Tyr464 residues. In conclusion, short-term tilianin treatment might exert its antidiabetic and antihyperlipidemic effect by modulating a pro inflammatory profile, and increasing adiponectin expression. In addition, our results suggest the possible interaction of tilianin with PPARalpha. PMID- 27470568 TI - Urtica dioica leaves modulates hippocampal smoothened-glioma associated oncogene 1 pathway and cognitive dysfunction in chronically stressed mice. AB - The present study was aimed to evaluate the effect of Urtica dioica (UD) extract against chronic unpredictable stress (CUS)-induced associative memory dysfunction and attempted to explore the possible mechanism. Male Swiss albino mice (25-30g) were divided into six groups, viz. group-I received 0.3% carboxymethyl cellulose and served as control (CTRL), group II was exposed to CUS (21days) and received vehicle (CUS), group III was subjected to CUS and received Hypericum perforatum extract (350mg/kg, p.o.) (CUS+HYP), group IV received Hypericum perforatum extract (350mg/kg, p.o.) (CTRL+HYP); group V was subjected to CUS and received UD extract (50mg/kg, p.o.) (CUS+UD), group VI received UD extract (50mg/kg, p.o.) (CTRL+UD). CUS significantly induced body weight loss (p<0.05) and associative memory impairment in step down task (p<0.05) as compared to control mice. CUS significantly downregulated Smo (p<0.05), Gli1 (p<0.01), cyclin D1 (p<0.05), BDNF (p<0.01), TrKB (p<0.01) and MAPK1 (p<0.01) mRNA expression in hippocampus as compared to control mice. CUS significantly increased the levels of TBARS (p<0.01) and nitric oxide (p<0.001), and decreased catalase (p<0.001) and total thiol (p<0.01) in plasma resulting in oxidative stress and inflammation. Chronic UD administration significantly reverted CUS mediated body weight loss (p<0.05) and cognitive impairment (p<0.05). UD administration significantly decreased the levels of TBARS (p<0.01) and nitric oxide (p<0.05), and increased the levels of catalase (p<0.01) and total thiol (p<0.05) in plasma. Chronic UD administration significantly upregulated hippocampal Smo (p<0.05), Gli1 (p<0.001), cyclin D1 (p<0.05), BDNF (p<0.05), TrKB (p<0.05) and MAPK1 (p<0.05) in stressed mice. Further, UD extract did not reverse cyclopamine induced downregulation of Gli1 and Ptch1 mRNA in hippocampal slices. UD modulated Smo-Gli1 pathway in the hippocampus as well as exerted anti-inflammatory and antioxidant effects. UD extract might prove to be effective for stress mediated neurological disorders. PMID- 27470569 TI - Fluvastatin combined with benazepril may contribute to the favorable prognosis of patients with atrial fibrillation. AB - The aim of this study was to observe the clinical efficacy of fluvastatin combined with benazepril in the treatment of patients with atrial fibrillation (AF). A total of 92 patients with AF were randomly assigned to the case group (n=46), in which the patients were treated with fluvastatin (80mg) plus benazepril (10mg), or to the control group (n=46), in which the patients were treated with fluvastatin (80mg). The conversion rate of sinus rhythm was higher in the case group than in the control group (P<0.05). The case group had more treatment-effective patients than the control group, with fewer treatment ineffective patients (P<0.05). The LVEDd, LVESd, LAD, and LVEF indexes in the case group were lower than in the control group after 6 months of treatment (all P<0.05). Levels of hs-CRP were also lower in patients in the case group than in patients in the control group after 1 month of treatment (P<0.05). After 12 months, renin and Ang II concentrations were lower in patients in the case group than in the control group (both P<0.05). Significant differences in IL-6 and TNF alpha expression were found between the two groups after 1 month, 6 months, and 12 months of treatment (all P<0.05). Compared to patients in the control group, the levels of total cholesterol (TC), triglycerides, and LDL-C in the case group were lower after 6 and 12 months of treatment (all P<0.05), while the HDL level was higher (P<0.05). Treatment with fluvastatin combined with benazepril further increased the conversion rate of sinus rhythm and significantly improved the quality of life and prognosis of AF patients. PMID- 27470570 TI - In-silico screening for DNA-dependent protein kinase (DNA-PK) inhibitors: Combined homology modeling, docking, molecular dynamic study followed by biological investigation. AB - DNA-dependent protein kinase (DNA-PK) is a key enzyme in non-homologous DNA end joining (NHEJ) repair pathway. The targeted inhibition of such enzyme would furnish a valuable option for cancer treatment. In this study we report the development of validation of enzyme homology model, and the subsequent use of this model to perform docking-based virtual screening against a database of FDA approved drugs. The nominated highest ranking hits (Praziquantel and Dutasteride) were subjected to biological investigation. Additionally, molecular dynamic study was carried-out for binding mode exploration. Results of the biological evaluation revealed that both compounds inhibit the DNA-PK enzymatic activity at relatively high concentration levels with an IC50 of 17.3MUM for praziquantel and >20MUM for dutasteride. Furthermore, both agents enhanced the anti-proliferative effects of doxorubicin and cisplatin on breast cancer (MCF7) and lung cancer (A549) cell lines. This result indicates that these two hits are good candidate as DNA-PK inhibitors and worth further structural modifications to enhance their enzyme inhibitory effects. PMID- 27470571 TI - Candesartan attenuates angiogenesis in hepatocellular carcinoma via downregulating AT1R/VEGF pathway. AB - Angiotensin II type 1 receptor (AT1R) was reported to express in many types of tumors, promoting tumor growth and angiogenesis. We herein examined AT1R expression in liver cancer and the potential antitumor effects of AT1R antagonist Candesartan in liver cancer. We found that AT1R expression was positively correlated with VEGF-A expression and microvascular density (MVD) in 40 HCC patients. Angiotensin II and Candesartan neither had effects on the proliferation of liver cancer cells in vitro. However, Angiotensin II upregulated AT1R protein expression and promoted production of VEGF-A in liver cancer cells in a dose dependent manner. Candesartan was able to reverse this process in a dose dependent manner. Moreover, Candesartan downregulated the expression of VEGF-A in SMMC-7721 bearing xenografts in mice and inhibited tumor growth and angiogenesis in vivo. Our data suggested that AT1R antagonist Candesartan might be useful to suppress liver cancer by inhibiting angiogenesis. PMID- 27470572 TI - Long noncoding RNA CCDC26 as a potential predictor biomarker contributes to tumorigenesis in pancreatic cancer. AB - Pancreatic cancer (PC) is the fourth most common cancer worldwide and has the least patient survival rate of any cancer. Emerging studies have demonstrated that long noncoding RNAs (lncRNAs) were present in cancer patients and have shown great potential as powerful markers and therapeutic targets. However, little is known about the role of lncRNAs in PC. The present study aimed to investigate the expression pattern, clinical significance and biological function of lncRNA CCDC26 (CCDC26) in PC. With quantitative real-time PCR, we analyzed CCDC26 expression levels in 40 PC patients. We found that the CCDC26 expression was significantly higher in PC tissues than in normal tissues. CCDC26 levels were correlated with tumor size, tumor number, and reduced overall survival (OS). Univariate and multivariate analysis showed that CCDC26 expression is an independent prognostic factor of OS in patients with PC. Additionally, ROCAUC of CCDC26 was up to 0.663, implicating that CCDC26 could be a diagnostic marker for distinguishing PC from normal. Knockdown of CCDC26 expression by small interfering RNA significantly promoted growth arrest and apoptosis. Moreover, we found that the expression of CCDC26 was positively correlated with PCNA and Bcl2. Our data suggest that CCDC26 may be identified as a novel oncogene in PC, and responsible for growth and apoptosis of cancer cell, partly by regulating the PCNA and Bcl2 expression. This work provides a novel biomarker and therapeutic target of PC for cancer clinic in future. PMID- 27470573 TI - Hesperidin and tiger nut reduced carcinogenicity of DMBA in female rats. AB - Nutritional studies recommend the regular consumption of fruits and vegetables to favor a healthy quality of life. This study was carried out to evaluate the efficacy of hesperidin and tiger nut against the carcinogenic activity of DMBA in female rats. 72 adult Sprague Dawley female rats were divided equally into six groups: control group (I); Hesperidin treated group (II); Tiger Nut treated group (III); DMBA treated group (IV); HES-DMBA treated group (V); and TN-DMBA treated group (VI). There was a significant increase in serum levels of carcinoembryonic antigen, total sialic acid, progesterone, estradiol, ALT, AST, LDH, urea and creatinine, and significant decrease in reduced glutathione level, superoxide dismutase, catalase and glutathione peroxidase activities of DMBA treated group compared to control. In conclusion, our results suggested that supplementation of diets with hesperidin provided antioxidant and chemoprotective activities more significant than tiger nut against the toxicity of DMBA in breast, liver and kidney tissues. PMID- 27470574 TI - Rosemary extract reduces Akt/mTOR/p70S6K activation and inhibits proliferation and survival of A549 human lung cancer cells. AB - Compounds of plant origin and food components have attracted scientific attention for use as agents for cancer prevention and treatment. Rosemary extract contains polyphenols that were shown to have anti-cancer and other health benefits. The survival pathways of Akt, mammalian target of rapamycin (mTOR) and p70S6K, and the apoptotic protein poly ADP ribose polymerase (PARP) are key modulators of cancer cell growth and survival. In this study, we examined the effects of rosemary extract on proliferation, survival and apoptosis of human non-small cell lung cancer (NSCLC) cells and its influence on signaling events. Human NSCLC adenocarcinoma A549 cells were used. Cell proliferation and clonogenic survival were assessed using specific assays. Immunoblotting was used to examine total and phosphorylated levels of Akt, mTOR and p70S6K, and cleavage of PARP. Rosemary extract dose-dependently inhibited cell proliferation and reduced clonogenic survival of A549 cells, while PARP cleavage, an indicator of apoptosis, was enhanced. Rosemary extract significantly reduced total and phosphorylated/activated Akt, mTOR and p70S6K levels. In conclusion, rosemary extract inhibited proliferation, blocked clonogenic survival, and enhanced apoptosis of A549 lung cancer cells. These effects were associated with inhibition of Akt and downstream mTOR and p70S6K activity. Our data suggest that rosemary extract may have considerable anti-tumor and chemoprevention properties in lung cancer and deserves further systematic investigation in animal models of lung cancer. PMID- 27470575 TI - Secoisolariciresinol diglucoside rich extract of L. usitatissimum prevents diabetic colon cancer through inhibition of CDK4. AB - BACKGROUND: There is increased risk of colon cancer in both men and women having diabetes. The objective of the study was to evaluate the role of Secoisolariciresinol diglucoside rich extract(SRE) of L.usissatisimum(flaxseed) in colon cancer associated with type 2 diabetes mellitus. MATERIAL AND METHODS: Diabetes was induced by administering high fat diet with low dose streptozotocin model. After 6 weeks, diabetes was confirmed and 1,2 dimethylhydrazine(25mg/kg, sc) weekly administration was from 6th to 18th weeks. Rats were treated with the SRE(500mg/kg) orally from 6th to 24th week. After 24 weeks, various biochemical and enzymatic parameters were estimated. Animals were sacrificed and colon tissue was separated and subjected to analysis of histopathological, PCNA studies and mRNA expression of CDK4. RESULTS: Disease control rats depicted hyperglycaemia, hyperinsulinaemia, elevated pro-inflammatory cytokines and cancer biomarker levels, and marked presence of proliferating cells. Treatment with SRE controlled hyperglycaemia, hyperinsulinaemia, reduced pro-inflammatory cytokines and cancer biomarker levels, and decreased no. of proliferating cells. We found that disease control rats depicted over expression of CDK4 mRNA levels which were reduced by SRE treatment. CONCLUSIONS: SRE of L. usitatissimum exhibited chemopreventive effect in colon cancer associated with type 2 diabetes mellitus which might be mediated through inhibition of CDK4. PMID- 27470576 TI - Corrigendum to "An amino acid depleted cell-free protein synthesis system for the incorporation of non-canonical amino acid analogs into proteins" [J. Biotechnol. 178 (2014) 12-22]. PMID- 27470578 TI - A Study Space Analysis and Narrative Review of Trauma-Informed Mediators of Dating Violence. AB - Research linking child maltreatment and dating violence in adolescence and emerging adulthood has proliferated in the past two decades; however, the precise mechanisms by which these experiences are related remain elusive. A trauma informed perspective suggests four particularly promising mediators: maladaptive attachment, emotion regulation difficulties, emotional distress, and hostility. The current article characterizes the status of the empirical literature examining these four mediators using a study space analysis and a narrative review of existing research. An extensive literature search identified 42 papers (44 studies) that met the following criteria: (1) at least one measure of child maltreatment (emotional, physical, sexual, neglect, or exposure to intimate partner violence); (2) a measure of one of the four mediator variables; (3) a measure of dating violence perpetration or victimization; and (4) a sample of adolescents or young adults. The study space analysis suggested several important observations about the research on this topic, including a dearth of studies examining hostility as a mediator and little research using prospective designs or clinical samples. There are also limitations with the conceptualization and measurement of dating violence, child maltreatment, and some of the mediator variables. In addition, few studies examined more than one mediator variable in the same study. The narrative review suggested that maladaptive attachment (specifically insecure attachment styles), emotion regulation difficulties (specifically regulation of the emotion of anger), and emotional distress construed broadly represent promising mediators of the association between child maltreatment and dating violence, but conclusions about mediation must remain tentative given the state of the literature. The discussion offers recommendations for improved theoretical and empirical rigor to advance future research on mechanisms linking child maltreatment and dating violence. PMID- 27470577 TI - Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. AB - The transcription factor Keap1-Nrf2 system plays a key role in inflammation which is involved in depression. We found lower expression of Keap1 and Nrf2 proteins in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of hippocampus in mice with depression-like phenotype compared to control mice. Serum levels of pro inflammatory cytokines in Nrf2 knock-out (KO) mice were higher than those of wild type mice, suggestive of enhanced inflammation in KO mice. Decreased brain derived neurotrophic factor (BDNF) and its receptor tropomyosin-receptor-kinase B (TrkB) signaling in the PFC, CA3 and DG plays a role in the depression-like phenotype of Nrf2 KO mice. TrkB agonist 7,8-dihydroxyflavone, but not antagonist ANA-12, produced antidepressant effects in Nrf2 KO mice, by stimulating TrkB in the PFC, CA3 and DG. Pretreatment with Nrf2 activator sulforaphane (SFN) prevented the depression-like phenotype induced after repeated social defeat stress. Interestingly, dietary intake of 0.1% glucoraphanin (a precursor of SFN) containing food during juvenile and adolescent stages also prevented the depression-like phenotype evoked in adulthood, after repeated social defeat stress. These findings suggest that Keap1-Nrf2 system plays a key role in depression and that dietary intake of SFN-rich food during juvenile stages and adolescence can confer stress resilience in adulthood. PMID- 27470579 TI - Upper aerodigestive injuries from detergent ingestion in children. AB - OBJECTIVES: To describe the clinical presentations and management of detergent pod ingestion at a tertiary children's hospital. STUDY DESIGN: Case series. METHODS: A retrospective chart review of children diagnosed with detergent pod ingestion from June 2010 and March 2015. RESULTS: Nine cases of detergent pod ingestion were included over a 5-year period. The average age was 26.3 months (range, 11-43 months). Eight (89%) of the cases were female. The patients had ingested laundry detergent pods (n = 7) and dishwasher detergent pods (n = 2). The majority of patients (67%) had more than one clinical manifestation from ingestion. Presenting symptoms included emesis (78%), respiratory symptoms (56%), throat pain (22%), drooling (33%), and foaming at the mouth (33%). The management of patients depended on the severity of their symptoms and included admission to an overnight observation unit (n = 5), discharge to home directly from the emergency department (n = 2), and admission to the hospital (n = 2). Two (22%) children underwent esophagogastroduodenoscopy. One child (11%) required intubation from bilateral vocal fold immobility. CONCLUSION: Injuries to the upper aerodigestive tract after detergent ingestion range from mild gastrointestinal symptoms to respiratory compromise. The majority of children improve with observation alone; however, clinicians should maintain a low threshold for endoscopic evaluation in cases of severe symptoms and airway involvement. LEVEL OF EVIDENCE: 4. Laryngoscope, 2016 127:509-512, 2017. PMID- 27470580 TI - Identification and validation of single nucleotide polymorphisms as tools to detect hybridization and population structure in freshwater stingrays. AB - Single nucleotide polymorphism (SNP) markers were identified and validated for two stingrays species, Potamotrygon motoro and Potamotrygon falkneri, using double digest restriction-site associated DNA (ddRAD) reads using 454-Roche technology. A total of 226 774 reads (65.5 Mb) were obtained (mean read length 289 +/- 183 bp) detecting a total of 5399 contigs (mean contig length: 396 +/- 91 bp). Mining this data set, a panel of 143 in silico SNPs was selected. Eighty-two of these SNPs were successfully validated and 61 were polymorphic: 14 in P. falkneri, 21 in P. motoro, 3 in both species and 26 fixed for alternative variants in both species, thus being useful for population analyses and hybrid detection. PMID- 27470581 TI - Crystal structure and genetic modifications of FI-CMCase from Aspergillus aculeatus F-50. AB - Cellulose is the major component of the plant cell wall and the most abundant renewable biomass on earth, and its decomposition has proven to be very useful in many commercial applications. Endo-1,4-beta-d-glucanase (EC 3.2.1.4; endoglucanase), which catalyzes the random hydrolysis of 1,4-beta-glycosidic bonds of the cellulose main chain to cleave cellulose into smaller fragments, is the key cellulolytic enzyme. An endoglucanase isolated from Aspergillus aculeatus F-50 (FI-CMCase), which is classified into the glycoside hydrolase (GH) family 12, was demonstrated to be effectively expressed in the industrial strain Pichia pastoris. Here, the crystal structure and complex structures of P. pastoris expressed FI-CMCase were solved to high resolution. The overall structure is analyzed and compared to other GH12 members. In addition, the substrate surrounding residues were engineered to search for variants with improved enzymatic activity. Among 14 mutants constructed, one with two-fold increase in protein expression was identified, which possesses a potential to be further developed as a commercial enzyme product. PMID- 27470582 TI - Intracellular co-localization of the Escherichia coli enterobactin biosynthetic enzymes EntA, EntB, and EntE. AB - Bacteria utilize small-molecule iron chelators called siderophores to support growth in low-iron environments. The Escherichia coli catecholate siderophore enterobactin is synthesized in the cytoplasm upon iron starvation. Seven enzymes are required for enterobactin biosynthesis: EntA-F, H. Given that EntB-EntE and EntA-EntE interactions have been reported, we investigated a possible EntA-EntB EntE interaction in E. coli cells. We subcloned the E. coli entA and entB genes into bacterial adenylate cylase two-hybrid (BACTH) vectors allowing for co expression of EntA and EntB with N-terminal fusions to the adenylate cyclase fragments T18 or T25. BACTH constructs were functionally validated using the CAS assay and growth studies. Co-transformants expressing T18/T25-EntA and T25/T18 EntB exhibited positive two-hybrid signals indicative of an intracellular EntA EntB interaction. To gain further insights into the interaction interface, we performed computational docking in which an experimentally validated EntA-EntE model was docked to the EntB crystal structure. The resulting model of the EntA EntB-EntE ternary complex predicted that the IC domain of EntB forms direct contacts with both EntA and EntE. BACTH constructs that expressed the isolated EntB IC domain fused to T18/T25 were prepared in order to investigate interactions with T25/T18-EntA and T25/T18-EntE. CAS assays and growth studies demonstrated that T25-IC co-expressed with the EntB ArCP domain could complement the E. coli entB(-) phenotype. In agreement with the ternary complex model, BACTH assays demonstrated that the EntB IC domain interacts with both EntA and EntE. PMID- 27470584 TI - Alpha-synuclein and beta-amyloid - different targets, same players: calcium, free radicals and mitochondria in the mechanism of neurodegeneration. AB - Two of the most devastating neurodegenerative diseases are consequences out of misfolding and aggregation of key proteins-alpha synuclein and beta-amyloid. Although the primary targets for the two proteins are different, they both share a common mechanism that involves formation of pore-like structure on the plasma membrane, consequent dysregulation of calcium homeostasis, mitochondrial dysfunction and oxidative damage. The combined effect of all this factors ultimately leads to neuronal cell death. Whereas beta amyloid acts on the astrocytic plasma membrane, exhibiting a tight dependence to the membrane cholesterol content, alpha-synuclein does not distinguish between type of membrane or cell. Additionally, oligomeric forms of both proteins produce reactive oxygen species through different mechanisms: beta-amyloid through activation of the NADPH oxidase and alpha-synuclein through non-enzymatic way. Finally, both peptides in oligomeric form induce mitochondrial depolarisation through calcium overload and free radical production that ultimately lead to opening of the mitochondrial permeability transition pore and trigger cell death. PMID- 27470583 TI - ACER3 supports development of acute myeloid leukemia. AB - No new therapy for acute myeloid leukemia (AML) has been approved for more than 30 years. To effectively treat AML, new molecular targets and therapeutic approaches must be identified. In silico analysis of several databases of AML patients demonstrated that the expression of alkaline ceramidase 3 (ACER3) significantly inversely correlates with the overall survival of AML patients. To determine whether ACER3 supports AML development, we employed an shRNA-encoding lentivirus system to inhibit acer3 expression in human AML cells including NB4, U937, and THP-1 cells. The ACER3 deficiency resulted in decreased cell growth and colony formation, elevated apoptosis, and lower AKT signaling of leukemia cells. Our study indicates that ACER3 contributes to AML pathogenesis, and suggests that alkaline ceramidase inhibition is an option to treat AML. PMID- 27470585 TI - RKIP phosphorylation-dependent ERK1 activation stimulates adipogenic lipid accumulation in 3T3-L1 preadipocytes overexpressing LC3. AB - 3T3-L1 preadipocytes undergo adipogenesis in response to treatment with dexamethaxone, 1-methyl-3-isobutylxanthine, and insulin (DMI) through activation of several adipogenic transcription factors. Many autophagy-related proteins are also highly activated in the earlier stages of adipogenesis, and the LC3 conjugation system is required for formation of lipid droplets. Here, we investigated the effect of overexpression of green fluorescent protein (GFP)-LC3 fusion protein on adipogenesis. Overexpression of GFP-LC3 in 3T3-L1 preadipocytes using poly-l-lysine-assisted adenoviral GFP-LC3 transduction was sufficient to produce intracellular lipid droplets. Indeed, GFP-LC3 overexpression stimulated expression of some adipogenic transcription factors (e.g., C/EBPalpha or beta, PPARgamma, SREBP2). In particular, SREBP2 was highly activated in preadipocytes transfected with adenoviral GFP-LC3. Also, phosphorylation of Raf kinase inhibitory protein (RKIP) at serine 153, consequently stimulating extracellular signal regulated kinase (ERK)1 activity, was significantly increased during adipogenesis induced by either poly-l-lysine-assisted adenoviral GFP-LC3 transduction or culture in the presence of dexamethasone, 1-methyl-3 isobutylxanthine, and insulin. Furthermore, RKIP knockdown promoted ERK1 and PPARgamma activation, and significantly increased the intracellular accumulation of triacylglycerides in DMI-induced adipogenesis. In conclusion, GFP-LC3 overexpression in 3T3-L1 preadipocytes stimulates adipocyte differentiation via direct modulation of RKIP-dependent ERK1 activity. PMID- 27470586 TI - Inactivation of the FoxO3a transcription factor is associated with the production of reactive oxygen species during protein kinase CK2 downregulation-mediated senescence in human colon cancer and breast cancer cells. AB - We previously showed that protein kinase CK2 downregulation mediates senescence through the reactive oxygen species (ROS)-p53-p21(Cip1/WAF1) pathway in various human cells. In the present study, we investigated whether the FoxO3a transcription factor is associated with ROS production during CK2 downregulation induced senescence in human colon cancer HCT116 and breast cancer MCF-7 cells. FoxO3a overexpression suppressed ROS production and p53 stabilization induced by a CK2alpha knockdown. CK2alpha downregulation induced nuclear export of FoxO3a through stimulation of AKT-mediated phosphorylation of FoxO3a and decreased transcription of its target genes (Cu/ZnSOD, MnSOD, and catalase). In contrast, CK2alpha overexpression inhibited AKT-mediated FoxO3a phosphorylation. This resulted in nuclear accumulation of FoxO3a, and elevated expression of its target genes. Therefore, these data indicate for the first time that CK2 downregulation stimulates ROS generation by inhibiting FoxO3a during premature senescence in human colon and breast cancer cells. PMID- 27470587 TI - High Podocalyxin levels promote cell viability partially through up-regulation of Annexin A2. AB - Podocalyxin (PODXL) is a highly glycosylated and sialylated transmembrane protein that is up-regulated in various types of tumors and whose expression levels positively correlate with tumor grade. We previously found Podxl to be highly expressed in murine tumorigenic neural stem/progenitor cells (NSPs). Here we investigated the effects of elevated Podxl levels in these cells. NSPs overexpressing Podxl did not form brain tumors upon intracranial transplantations, indicating that high levels of this gene alone are not sufficient for tumor initiation. However, Podxl overexpression had a positive effect on cell number, sphere formation and cell viability, indicating that it might in this way contribute to the development and/or maintenance of tumors. Proteome analyses of Podxl-overexpressing and control NSPs revealed increased levels of Annexin A2 (ANXA2). We also found increased transcript levels, indicating that PODXL stimulates expression of the Anxa2 gene. Lack of Anxa2 in Podxl-overexpressing NSPs resulted in reduced viability of these cells, suggesting that PODXL-mediated pro-survival effects can at least in part be explained by increased ANXA2 levels. Finally, our data indicate that Podxl overexpression activates the MAP kinase (MAPK) pathway which in turn up-regulates Anxa2 expression. Our data indicate a novel molecular connection between PODXL and ANXA2: both exert pro-survival effects in NSPs, and PODXL positively regulates ANXA2 expression through the MAPK pathway. PMID- 27470588 TI - Springtime precipitation effects on the abundance of fluorescent biological aerosol particles and HULIS in Beijing. AB - Bioaerosols and humic-like substances (HULIS) are important components of atmospheric aerosols, which can affect regional climate by acting as cloud condensation nuclei and some of which can damage human health. Up to date, release of bioaerosols and HULIS initiated by precipitation is still poorly understood. Here we present different release processes for bioaerosols, non bioaerosols and HULIS during a precipitation event in Beijing, China. Large fungal-spore-like aerosols were emitted at the onset and later weak stage of precipitation, the number concentration of which increased by more than two folds, while the number concentration of bacteria-like particles doubled when the precipitation strengthened. Besides, a good correlation between protein-like substances that were measured simultaneously by on-line and off-line fluorescence techniques consolidated their applications to measure bioaerosols. Furthermore, our EEM results suggest that the relative contribution of water-soluble HULIS to microbial materials was enhanced gradually by the rain event. PMID- 27470589 TI - Description of Ancylomarina subtilis gen. nov., sp. nov., isolated from coastal sediment, proposal of Marinilabiliales ord. nov. and transfer of Marinilabiliaceae, Prolixibacteraceae and Marinifilaceae to the order Marinilabiliales. AB - A Gram-stain-negative, facultatively anaerobic, moderately halophilic, filamentous, non-motile bacterium, designated FA102T, was isolated from marine sediment from the coast of Weihai, PR China. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain FA102T formed a distinct evolutionary lineage within the family Marinifilaceae and its closest relative was Marinifilum fragile JCM 15579T (93.2 % sequence similarity). The DNA G+C content of the novel strain was 36.5 mol%. The predominant cellular fatty acids and respiratory quinone were iso-C15 : 0 and iso-C15 : 0 3-OH, and MK-7, respectively. On the basis of the phylogenetic, phenotypic and physiological data, strain FA102T represents a novel genus and species, for which the name Ancylomarina subtilis gen. nov., sp. nov. is proposed. The type strain of Ancylomarina subtilis is FA102T (=KCTC 42257T=DSM 28825T=CICC 10902T). Furthermore, a new order named Marinilabiliales is proposed to accommodate three families previously classified in the order Bacteroidales. Marinilabiliales ord. nov. encompasses the families Marinilabiliaceae, Prolixibacteraceae and Marinifilaceae. PMID- 27470590 TI - Microfluidic production of multiple emulsions and functional microcapsules. AB - Recent advances in microfluidics have enabled the controlled production of multiple-emulsion drops with onion-like topology. The multiple-emulsion drops possess an intrinsic core-shell geometry, which makes them useful as templates to create microcapsules with a solid membrane. High flexibility in the selection of materials and hierarchical order, achieved by microfluidic technologies, has provided versatility in the membrane properties and microcapsule functions. The microcapsules are now designed not just for storage and release of encapsulants but for sensing microenvironments, developing structural colours, and many other uses. This article reviews the current state of the art in the microfluidic-based production of multiple-emulsion drops and functional microcapsules. The three main sections of this paper discuss distinct microfluidic techniques developed for the generation of multiple emulsions, four representative methods used for solid membrane formation, and various applications of functional microcapsules. Finally, we outline the current limitations and future perspectives of microfluidics and microcapsules. PMID- 27470591 TI - The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. AB - The Class III phosphoinositide 3-kinase Vps34 (vacuolar protein sorting 34) plays important roles in endocytic trafficking, macroautophagy, phagocytosis, cytokinesis and nutrient sensing. Recent studies have provided exciting new insights into the structure and regulation of this lipid kinase, and new cellular functions for Vps34 have emerged. This review critically examines the wealth of new data on this important enzyme, and attempts to integrate these findings with current models of Vps34 signalling. PMID- 27470593 TI - Unravelling the mechanisms regulating muscle mitochondrial biogenesis. AB - Skeletal muscle is a tissue with a low mitochondrial content under basal conditions, but it is responsive to acute increases in contractile activity patterns (i.e. exercise) which initiate the signalling of a compensatory response, leading to the biogenesis of mitochondria and improved organelle function. Exercise also promotes the degradation of poorly functioning mitochondria (i.e. mitophagy), thereby accelerating mitochondrial turnover, and preserving a pool of healthy organelles. In contrast, muscle disuse, as well as the aging process, are associated with reduced mitochondrial quality and quantity in muscle. This has strong negative implications for whole-body metabolic health and the preservation of muscle mass. A number of traditional, as well as novel regulatory pathways exist in muscle that control both biogenesis and mitophagy. Interestingly, although the ablation of single regulatory transcription factors within these pathways often leads to a reduction in the basal mitochondrial content of muscle, this can invariably be overcome with exercise, signifying that exercise activates a multitude of pathways which can respond to restore mitochondrial health. This knowledge, along with growing realization that pharmacological agents can also promote mitochondrial health independently of exercise, leads to an optimistic outlook in which the maintenance of mitochondrial and whole-body metabolic health can be achieved by taking advantage of the broad benefits of exercise, along with the potential specificity of drug action. PMID- 27470594 TI - Biosynthesis of polyamines and polyamine-containing molecules. AB - Polyamines are evolutionarily ancient polycations derived from amino acids and are pervasive in all domains of life. They are essential for cell growth and proliferation in eukaryotes and are essential, important or dispensable for growth in bacteria. Polyamines present a useful scaffold to attach other moieties to, and are often incorporated into specialized metabolism. Life has evolved multiple pathways to synthesize polyamines, and structural variants of polyamines have evolved in bacteria, archaea and eukaryotes. Among the complex biosynthetic diversity, patterns of evolutionary reiteration can be distinguished, revealing evolutionary recycling of particular protein folds and enzyme chassis. The same enzyme activities have evolved from multiple protein folds, suggesting an inevitability of evolution of polyamine biosynthesis. This review discusses the different biosynthetic strategies used in life to produce diamines, triamines, tetra-amines and branched and long-chain polyamines. It also discusses the enzymes that incorporate polyamines into specialized metabolites and attempts to place polyamine biosynthesis in an evolutionary context. PMID- 27470592 TI - Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance. AB - Serpins are a widely distributed family of high molecular mass protein proteinase inhibitors that can inhibit both serine and cysteine proteinases by a remarkable mechanism-based kinetic trapping of an acyl or thioacyl enzyme intermediate that involves massive conformational transformation. The trapping is based on distortion of the proteinase in the complex, with energy derived from the unique metastability of the active serpin. Serpins are the favoured inhibitors for regulation of proteinases in complex proteolytic cascades, such as are involved in blood coagulation, fibrinolysis and complement activation, by virtue of the ability to modulate their specificity and reactivity. Given their prominence as inhibitors, much work has been carried out to understand not only the mechanism of inhibition, but how it is fine-tuned, both spatially and temporally. The metastability of the active state raises the question of how serpins fold, whereas the misfolding of some serpin variants that leads to polymerization and pathologies of liver disease, emphysema and dementia makes it clinically important to understand how such polymerization might occur. Finally, since binding of serpins and their proteinase complexes, particularly plasminogen activator inhibitor-1 (PAI-1), to the clearance and signalling receptor LRP1 (low density lipoprotein receptor-related protein 1), may affect pathways linked to cell migration, angiogenesis, and tumour progression, it is important to understand the nature and specificity of binding. The current state of understanding of these areas is addressed here. PMID- 27470595 TI - Prestin and the good vibrations. AB - In a recent paper published in the Biochemical Journal, Lolli et al. presented evidence that the C-terminal STAS (sulfate transporter and anti-sigma factor antagonist) domain of the motor protein prestin possesses an anion-binding site. This discovery might shed light on an aspect of the function of this mysterious and fascinating protein that is crucial for the human hearing system. PMID- 27470596 TI - Cardiometabolic risk and gut microbial phytoestrogen metabolite phenotypes. AB - Recent evidence supports that the gut microbial community, independently and/or interactively with dietary intake, is a target for reducing cardiovascular disease risk through its effects on cardiometabolic risk factors. Dietary phytoestrogens may be a source for interactive effects. Phytoestrogens, such as isoflavones, lignans, and flavonoids, are compounds found in plants that have estrogenic or antiestrogenic activities, as well as antioxidant, antiproliferative, or apoptotic actions. Given these physiological activities, phytoestrogens may have a role in cardiometabolic health. Some phytoestrogens consumed in the diet undergo biotransformation through gut bacterial metabolism to other compounds that may exhibit similar or different physiological activity than the parent compound. There is interindividual variability in the capability to metabolize phytoestrogens to their metabolites, and there is a resulting phenotype that can be evaluated based on urinary metabolite excretion. Evidence suggests that phytoestrogen metabolites and/or phenotypes are associated with cardiometabolic risk factors, such as blood pressure, abdominal obesity, and serum lipids, triglycerides, glucose, and inflammatory markers. The objective of this review was to provide an overview of the observed associations between gut microbial phytoestrogen metabolites and metabolite phenotypes with cardiometabolic risk factors, with focus on the more extensively studied isoflavone metabolites. PMID- 27470597 TI - Fokker-Planck formalism in magnetic resonance simulations. AB - This paper presents an overview of the Fokker-Planck formalism for non-biological magnetic resonance simulations, describes its existing applications and proposes some novel ones. The most attractive feature of Fokker-Planck theory compared to the commonly used Liouville - von Neumann equation is that, for all relevant types of spatial dynamics (spinning, diffusion, stationary flow, etc.), the corresponding Fokker-Planck Hamiltonian is time-independent. Many difficult NMR, EPR and MRI simulation problems (multiple rotation NMR, ultrafast NMR, gradient based zero-quantum filters, diffusion and flow NMR, off-resonance soft microwave pulses in EPR, spin-spin coupling effects in MRI, etc.) are simplified significantly in Fokker-Planck space. The paper also summarises the author's experiences with writing and using the corresponding modules of the Spinach library - the methods described below have enabled a large variety of simulations previously considered too complicated for routine practical use. PMID- 27470598 TI - Screening vs. non-screening detected colorectal cancer: Differences in pre therapeutic work up and treatment. AB - Objectives To compare preoperative staging, multidisciplinary team-assessment, and treatment in patients with screening detected and non-screening detected colorectal cancer. Methods Data on patient and tumour characteristics, staging, multidisciplinary team-assessment and treatment in patients with screening and non-screening detected colorectal cancer from 2008 to 2012 were collected from the Stockholm-Gotland screening register and the Swedish Colorectal Cancer Registry. Results The screening group had a higher proportion of stage I disease (41 vs. 15%; p < 0.001), a more complete staging of primary tumour and metastases and were more frequently multidisciplinary team-assessed than the non-screening group ( p < 0.001). In both groups, patients with endoscopically resected cancers were less completely staged and multidisciplinary team-assessed than patients with surgically resected cancers ( p < 0.001). No statistically significant differences were observed between the screening and non-screening groups in the use of neoadjuvant treatment in rectal cancer (68 vs.76%), surgical treatment with local excision techniques in stage I rectal cancer (6 vs. 9%) or adjuvant chemotherapy in stages II and III disease (46 vs. 52%). Emergency interventions for colorectal cancer occurred in 4% of screening participants vs. 11% of non compliers. Conclusions Screening detected cancer patients were staged and multidisciplinary team assessed more extensively than patients with non-screening detected cancers. Staging and multidisciplinary team assessment prior to endoscopic resection was less complete compared with surgical resection. Extensive surgical and (neo)adjuvant treatment was given in stage I disease. Participation in screening reduced the risk of emergency surgery for colorectal cancer. PMID- 27470599 TI - Optimal interleukin-7 receptor-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on casein kinase 2 activity. AB - Interleukin-7 and interleukin-7 receptor are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/interleukin-7 receptor-mediated signaling promotes leukemogenesis. The protein kinase, casein kinase 2, is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Herein, we show that while interleukin-7 had a minor but significant positive effect on casein kinase 2 activity in leukemia T-cells, casein kinase 2 activity was mandatory for optimal interleukin-7/interleukin-7 receptor-mediated signaling. Casein kinase 2 pharmacological inhibition impaired signal transducer and activator of transcription 5 and phosphoinositide 3 kinase/v-Akt murine thymoma viral oncogene homolog 1 pathway activation triggered by interleukin-7 or by mutational activation of interleukin-7 receptor. By contrast, forced expression of casein kinase 2 augmented interleukin-7 signaling in human embryonic kidney 293T cells reconstituted with the interleukin-7 receptor machinery. Casein kinase 2 inactivation prevented interleukin-7-induced B-cell lymphoma 2 upregulation, maintenance of mitochondrial homeostasis and viability of T-cell acute lymphoblastic leukemia cell lines and primary leukemia cells collected from patients at diagnosis. Casein kinase 2 inhibition further abrogated interleukin-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and cell cycle progression. Notably, casein kinase 2 was also required for the viability of mutant interleukin-7 receptor expressing leukemia T-cells. Overall, our study identifies casein kinase 2 as a major player in the effects of interleukin-7 and interleukin 7 receptor in T-cell acute lymphoblastic leukemia. This further highlights the potential relevance of targeting casein kinase 2 in this malignancy. PMID- 27470600 TI - Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients. AB - The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR4.0) and 17% (MR4.5) of patients at 2 years; 58% of the enrolled patients achieved a MR4.0 at least once, with a sustained MR4.0 in 52% of them. With a median observation of 29 months (range 24-37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391). PMID- 27470601 TI - Ciprofloxacin versus colistin prophylaxis during neutropenia in acute myeloid leukemia: two parallel patient cohorts treated in a single center. AB - Patients undergoing intensive chemotherapy for acute myeloid leukemia are at high risk for bacterial infections during therapy-related neutropenia. However, the use of specific antibiotic regimens for prophylaxis in afebrile neutropenic acute myeloid leukemia patients is controversial. We report a retrospective evaluation of 172 acute myeloid leukemia patients who received 322 courses of myelosuppressive chemotherapy and had an expected duration of neutropenia of more than seven days. The patients were allocated to antibiotic prophylaxis groups and treated with colistin or ciprofloxacin through 2 different hematologic services at our hospital, as available. The infection rate was reduced from 88.6% to 74.2% through antibiotic prophylaxis (vs without prophylaxis; P=0.04). A comparison of both antibiotic drugs revealed a trend towards fewer infections associated with ciprofloxacin prophylaxis (69.2% vs 79.5% in the colistin group; P=0.07), as determined by univariate analysis. This result was confirmed through multivariate analysis (OR: 0.475, 95%CI: 0.236-0.958; P=0.041). The prophylactic agents did not differ with regard to the microbiological findings (P=0.6, not significant). Of note, the use of ciprofloxacin was significantly associated with an increased rate of infections with pathogens that are resistant to the antibiotic used for prophylaxis (79.5% vs 9.5% in the colistin group; P<0.0001). The risk factors for higher infection rates were the presence of a central venous catheter (P<0.0001), mucositis grade III/IV (P=0.0039), and induction/relapse courses (vs consolidation; P<0.0001). In conclusion, ciprofloxacin prophylaxis appears to be of particular benefit during induction and relapse chemotherapy for acute myeloid leukemia. To prevent and control drug resistance, it may be safely replaced by colistin during consolidation cycles of acute myeloid leukemia therapy. PMID- 27470602 TI - Chromosome abnormalities at onset of complete remission are associated with worse outcome in patients with acute myeloid leukemia and an abnormal karyotype at diagnosis: CALGB 8461 (Alliance). AB - Achievement of complete remission is essential for long-term survival of acute myeloid leukemia patients. We evaluated the prognostic significance of cytogenetics at complete remission in 258 adults with de novo acute myeloid leukemia and abnormal pre-treatment karyotypes, treated on Cancer and Leukemia Group B front-line studies, with cytogenetic data at onset of morphological complete remission. Thirty-two patients had abnormal karyotypes at time of initial complete remission. Of these, 28 had at least 1 abnormality identified pre-treatment, and 4 acute myeloid leukemia-related abnormalities not detected pre-treatment. Two hundred and twenty-six patients had normal remission karyotypes. Patients with abnormal remission karyotypes were older (P<0.001), had lower pre-treatment white blood counts (P=0.002) and blood blast percentages (P=0.004), were less often classified as Favorable and more often as Adverse among European LeukemiaNet Genetic Groups (P<0.001), and had shorter disease-free survival (median 0.6 vs. 0.9 years; P<0.001) and overall survival (median 1.2 vs. 2.2 years; P<0.001) than patients with normal remission karyotypes. Sixteen patients with normal remission karyotypes also harbored non-clonal abnormalities unrelated to pre-treatment karyotypes. They had shorter overall survival than 210 patients with only normal metaphases (P=0.04). Forty-eight patients with any clonal or non-clonal chromosome abnormality at complete remission had worse disease-free survival (median 0.6 vs. 1.0 years; P<0.001) and overall survival (median 1.2 vs. 2.5 years; P<0.001) than 210 patients with exclusively normal metaphases. In multivariable analyses, after adjustment for age, the presence of any remission abnormality was associated with shorter disease-free survival (P=0.03) and overall survival (P=0.01). We conclude that detection of any abnormality at complete remission is an adverse prognostic factor. (clinicaltrials.gov identifier: 00048958). PMID- 27470603 TI - Unexpected macrophage-independent dyserythropoiesis in Gaucher disease. AB - Gaucher disease is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34+ cells of patients and controls. CD34- cells were differentiated into macrophages and co cultivated with erythroblasts. We showed an accelerated differentiation of erythroid progenitors without maturation arrest from patients compared to controls. This abnormal differentiation persisted in the patients when the same experiments were performed without macrophages, which strongly suggested that dyserythropoiesis in Gaucher disease is secondary to an inherent defect in the erythroid progenitors. The accelerated differentiation was associated with reduced cell proliferation. As a result, less mature erythroid cells were generated in vitro in the Gaucher disease cultures compared to the control. We then compared the biological characteristics of untreated patients according to their anemic status. Compared to the non-anemic group, the anemic patients exhibit higher plasma levels of growth differentiation factor-15, a marker of ineffective erythropoiesis, but they had no indicators of hemolysis and similar reticulocyte counts. Taken together, these results demonstrated an unsuspected dyserythropoiesis that was independent of the macrophages and could participate, at least in part, to the basis of anemia in Gaucher disease. PMID- 27470604 TI - MicroRNA expression-based outcome prediction in acute myeloid leukemia: novel insights through cross-platform integrative analyses. PMID- 27470606 TI - Paraneoplastic neuropsychiatric syndrome presenting as delirium. AB - Delirium in patients with cancer is associated with poor outcomes, but reversible causes need to be ruled out. We report the case of a 59-year-old woman who was presented with behavioural and cognitive changes over 2 weeks. She was non-verbal and combative, requiring involuntary admission and declaration of incompetence to make healthcare treatment decisions. Infectious and metabolic investigations and initial brain imaging were unremarkable. She was diagnosed with limited-stage small cell lung cancer and a paraneoplastic neuropsychiatric syndrome. Owing to the patient's delirium, chemotherapy delivery required pharmacological and physical restraints. After 2 cycles of chemotherapy, she could participate in the decision process and was discharged home. She completed radical chemo radiotherapy and has remained free of disease progression for 18 months. Paraneoplastic neuropsychiatric syndromes, although rare, are potentially treatable and need to be excluded as a cause of delirium. PMID- 27470605 TI - Effect of age and body weight on toxicity and survival in pediatric acute myeloid leukemia: results from NOPHO-AML 2004. AB - Treatment for pediatric acute myeloid leukemia is very toxic and the association between outcome and age and Body Mass Index is unclear. We investigated effect of age and Body Mass Index on toxicity and survival in pediatric acute myeloid leukemia. We studied all patients who completed first induction course of NOPHO AML 2004 (n=318). Toxicity following induction and consolidation courses (n=6) was analyzed. The probabilities of toxicity and death were determined using time to-event analyses with Cox multivariate proportional hazard regression for comparative analyses. Age 10-17 years was associated with sepsis with hypotension [hazard ratio 2.3 (95% confidence interval 1.1-4.6)]. Being overweight (>1 standard deviation) was associated with requiring supplemental oxygen [1.9 (1.0 3.5)]. The 5-year event-free and overall survival were 47% and 71%. Children aged 10-17 years showed a trend for inferior 5-year overall survival compared to children aged 2-9 (64% vs. 76%; P=0.07). Infants showed a trend for superior 5 year event-free survival (66% vs. 43%; P=0.06). Overweight children aged 10-17 years showed a trend for superior survival [5-year event-free survival 59% vs. 40% (P=0.09) and 5-year overall survival 78% vs. 56% (P=0.06)] compared to healthy weight children aged 10-17 years. In conclusion, children aged 10-17 years and overweight children had a higher risk of grade 3-4 toxicity. Children aged 10-17 years showed inferior survival, but, unexpectedly, in this age group overweight children tended to have increased survival. This suggests different pharmacokinetics of chemotherapeutic drugs in adolescents and warrants further studies. PMID- 27470607 TI - Prognostic value of endocan in prostate cancer: clinicopathologic association between serum endocan levels and biochemical recurrence after radical prostatectomy. AB - PURPOSE: To assess the diagnostic capability of serum endocan level in association with clinicopathologic features and its impact on biochemical progression-free survival in patients with prostate cancer (PCa). METHODS: A total of 86 patients with localized prostate cancer were treated with open radical prostatectomy (RP). The control group included 80 patients who were referred to the urology outpatient clinic with normal rectal examination and prostate-specific antigen (PSA) levels. The patients' characteristics, baseline PSA value, and serum endocan levels were recorded. The patients were followed up with the measurement of PSA concentration every 3 months during the first year, thereafter every 6 months until 5 years, then yearly after surgery. The primary endpoint of follow-up was the time of biochemical recurrence. RESULTS: The median serum endocan levels were 3.14 ng/mL in the RP group and 2.98 ng/mL in the control group (p = 0.122). A total of 86 patients who underwent RP for PCa were divided into 2 groups based on a cutoff serum endocan level of 1.8 ng/mL. The distribution of Gleason score and biochemical failure rate were significantly higher in patients with serum endocan >=1.8 ng/mL (p = 0.031 and p = 0.047). The biochemical recurrence-free time for endocan >=1.8 ng/mL and <1.8 ng/mL were 38 and 56 months, respectively (p = 0.041). Spearman correlation analysis showed a linear relationship between endocan expression and Gleason score (p = 0.025, p = 0.511). Multivariate analysis revealed that elevated serum endocan level (>=1.8 ng/mL) was a significant predictor of biochemical progression-free survival (hazard ratio 2.44; 95% confidence interval 1.78-3.23; p = 0.001). CONCLUSIONS: The current study indicates that endocan has a close relationship with tumor recurrence in PCa. PMID- 27470608 TI - Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience. AB - PURPOSE: Combination therapy with dabrafenib and trametinib is safer and more effective than BRAF inhibitor-based monotherapy for metastatic melanoma. METHODS: We retrospectively analyzed BRAF-mutated metastatic melanoma patients treated at our institution with daily oral dabrafenib 300 mg and trametinib 2 mg from November 2013 to April 2016. This clinical record included both untreated and previously treated stage IV melanomas. Physical examination and laboratory examinations were performed monthly and disease re-evaluations were performed every 3 months. RESULTS: A total of 48 patients (24 male, 24 female) with BRAF mutated metastatic melanoma received dabrafenib and trametinib; median age was 48 years (range 23-75). Median follow-up was 362.5 days (range 72-879). Best overall response rate consisted of 6.2% (3 patients) complete response, 64.6% (31) partial response, and 25% (12) stable disease; median time to best response was 11 weeks (range 5.7-125.5). Progression of disease was seen in 19 patients (39.6%), with median time to progression (TTP) of 26 weeks (range 8-54). A total of 15 patients (31.2%) died due to progression of disease. Median progression free survival and median overall survival were not reached. To date, 30 patients (62.5%) are still under treatment. A total of 27 (56.2%) patients had at least one adverse event (AE); grade 3-4 AEs were seen in 4 cases (8.3%). The main toxicities were fever (25%), skin rash (14.6%), arthralgias (10.4%), and aspartate aminotransferase/alanine aminotransferase increase (8.3%). Treatment dose was reduced in 7 subjects (14.6%), with only one case of discontinuation due to AE. CONCLUSIONS: Our data, using combined targeted therapy, are in line with the scientific literature in terms of both safety and effectiveness in a real life setting. PMID- 27470609 TI - Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case Control Analysis. AB - INTRODUCTION: It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF alpha, the relationship between AD and RA remains unknown. OBJECTIVE: To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. METHODS: We performed a nested case-control study of more than 8.5 million commercially insured adults (aged >=18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. RESULTS: AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08 0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. CONCLUSION: There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD. PMID- 27470611 TI - Copper-catalyzed intramolecular aryl-bicyclization of diynes with diaryliodonium salts via vinyl cations. AB - A novel protocol for the synthesis of polycyclic compounds from linear diynes and diaryliodonium salts has been realized. The reaction proceeded through Cu catalyzed arylation of alkynes to generate two vinyl carbocation intermediates that subsequently reacted with arene groups to form fused rings containing diene moieties. PMID- 27470610 TI - A primary care Web-based Intervention Modeling Experiment replicated behavior changes seen in earlier paper-based experiment. AB - OBJECTIVES: Intervention Modeling Experiments (IMEs) are a way of developing and testing behavior change interventions before a trial. We aimed to test this methodology in a Web-based IME that replicated the trial component of an earlier, paper-based IME. STUDY DESIGN AND SETTING: Three-arm, Web-based randomized evaluation of two interventions (persuasive communication and action plan) and a "no intervention" comparator. The interventions were designed to reduce the number of antibiotic prescriptions in the management of uncomplicated upper respiratory tract infection. General practitioners (GPs) were invited to complete an online questionnaire and eight clinical scenarios where an antibiotic might be considered. RESULTS: One hundred twenty-nine GPs completed the questionnaire. GPs receiving the persuasive communication did not prescribe an antibiotic in 0.70 more scenarios (95% confidence interval [CI] = 0.17-1.24) than those in the control arm. For the action plan, GPs did not prescribe an antibiotic in 0.63 (95% CI = 0.11-1.15) more scenarios than those in the control arm. Unlike the earlier IME, behavioral intention was unaffected by the interventions; this may be due to a smaller sample size than intended. CONCLUSIONS: A Web-based IME largely replicated the findings of an earlier paper-based study, providing some grounds for confidence in the IME methodology. PMID- 27470612 TI - Vanillin attenuates negative effects of ultraviolet A on the stemness of human adipose tissue-derived mesenchymal stem cells. AB - Ultraviolet A (UVA) irradiation induces various changes in cell biology. The objective of this study was to determine the effect of vanillin on UVA irradiation-induced damages in the stemness properties of human adipose tissue derived mesenchymal stem cells (hAMSCs). UVA-antagonizing mechanisms of vanillin were also examined. The results revealed that vanillin attenuated UVA-induced reduction of the proliferative potential and stemness of hAMSCs evidenced by increased proliferative activity in BrdU incorporation assay and upregulation of stemness-related genes (OCT4, NANOG and SOX2) in response to vanillin treatment. UVA-induced reduction in mRNA level of hypoxia-inducible factor (HIF)-1alpha was significantly recovered by vanillin. In addition, the antagonizing effect of vanillin on UVA was found to be mediated by reduced production of PGE2 through inhibiting JNK and p38 MAPK. Taken together, these findings showed that vanillin could improve the reduced stemness of hAMSCs induced by UVA. The effect of vanillin is mediated by upregulating HIF-1alpha via inhibiting PGE2-cAMP signaling. Therefore, vanillin might be used as an antagonizing agent to mitigate the effects of UVA. PMID- 27470613 TI - Aflatoxin M1 cytotoxicity against human intestinal Caco-2 cells is enhanced in the presence of other mycotoxins. AB - Aflatoxin M1 (AFM1), a class 2B human carcinogen, is the only mycotoxin with established maximum residue limits (MRLs) in milk. Toxicological data for other mycotoxins in baby food, containing cereals and milk, either in isolation or in combination with AFM1, are sparse. The aim of this study was to investigate the cytotoxicity of AFM1, ochratoxin A (OTA), zearalenone (ZEA), and alpha-zearalenol (alpha-ZOL), individually and in combinations, in human Caco-2 cells. The tetrazolium salt (MTT) assay demonstrated that (i) OTA and AFM1 had similar cytotoxicity, which was higher than that of ZEA and alpha-ZOL, after a 72 h exposure; and (ii) the quaternary combination had the highest cytotoxicity, followed by tertiary and binary combinations and individual mycotoxins. Isobologram analysis indicated that the presence of OTA, ZEA, and/or alpha-ZOL with AFM1 led to additive and synergistic cytotoxicity in most combinations. The cytotoxicity of OTA was similar to that of AFM1, suggesting that OTA in food poses a health risk to consumers. Furthermore, AFM1 cytotoxicity increased dramatically in the presence of OTA, ZEA, and/or alpha-ZOL (p < 0.01), indicating that the established MRLs for AFM1 should be re-evaluated considering its frequent co-occurrence with other mycotoxins in baby food which contains milk and cereals. PMID- 27470614 TI - Strategies in genotoxicity testing. PMID- 27470615 TI - Toxicological evaluation of arachidonic acid (ARA)-rich oil and docosahexaenoic acid (DHA)-rich oil. AB - The safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina was separately evaluated by testing for gene mutations, clastogenicity, and aneugenicity, and by conducting 28-day and 90-day dietary studies in Wistar rats. The results of all genotoxicity tests were negative. The 28-day and 90-day studies involved dietary exposure to 1000, 2500, and 5000 mg per kg bw of the DHA-rich and ARA-rich oils and two control diets: water and corn oil (vehicle control). There were no treatment-related effects of either the DHA rich or ARA-rich oils on clinical observations, body weight, food consumption, behavior, hematology, clinical chemistry, coagulation, urinalysis parameters, or necropsy findings. Increases in cholesterol and triglyceride levels were considered related to a high oil diet and non-adverse. The no observable adverse effect level (NOAEL) for both the DHA-rich and ARA-rich oils was 5000 mg per kg bw, the highest dose tested. The results confirm that these oils possess toxicity profiles similar to those of other currently marketed oils and support the safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina for their proposed uses in food. PMID- 27470616 TI - Ethics pitfalls in publishing: complex problem. PMID- 27470617 TI - Syphilis: a fresh look at an old foe. AB - Syphilis remains a pressing public health problem globally across different populations including men who have sex with men and pregnant women. It is timely to review what international surveillance data tell us and the evidence behind public health interventions aimed at controlling syphilis. A reinvigorated response to the re-emergence of syphilis is required. PMID- 27470619 TI - Fault-tolerant error correction with the gauge color code. AB - The constituent parts of a quantum computer are inherently vulnerable to errors. To this end, we have developed quantum error-correcting codes to protect quantum information from noise. However, discovering codes that are capable of a universal set of computational operations with the minimal cost in quantum resources remains an important and ongoing challenge. One proposal of significant recent interest is the gauge color code. Notably, this code may offer a reduced resource cost over other well-studied fault-tolerant architectures by using a new method, known as gauge fixing, for performing the non-Clifford operations that are essential for universal quantum computation. Here we examine the gauge color code when it is subject to noise. Specifically, we make use of single-shot error correction to develop a simple decoding algorithm for the gauge color code, and we numerically analyse its performance. Remarkably, we find threshold error rates comparable to those of other leading proposals. Our results thus provide the first steps of a comparative study between the gauge color code and other promising computational architectures. PMID- 27470620 TI - [Efficacy of 104-week sequential therapy with telbivudine or entecavir in HBeAg positive chronic hepatitis B patients with suboptimal responses to 24-week therapy with pegylated interferon-alpha-2a]. AB - OBJECTIVE: To investigate the efficacy and safety of 104-week sequential therapy with telbivudine or entecavir in HBeAg-positive chronic hepatitis B (CHB) patients with suboptimal responses to 24-week pegylated interferon-alpha-2a (PEG IFN-alpha-2a) therapy. METHODS: A total of 130 HBeAg-positive CHB patients with HBV DNA>=5.0 lg IU/ml and a reduction in HBsAg quantitation < 1 lg IU/ml compared with baseline who received PEG-IFN-alpha-2a therapy for 24 weeks were enrolled and randomly divided into telbivudine group and entecavir group, and 5 of them were lost. HBeAg clearance rate and seroconversion rate, HBV DNA clearance rate, safety, and drug resistance rate at week 104 were observed. The t-test, chi square test, or multivariate Cox regression analysis were used for statistical analysis of different types of data. RESULTS: At week 104 of treatment, HBV DNA clearance rate showed no significant difference between the telbivudine group and entecavir group (P = 0.363), and the telbivudine group had significantly higher HBeAg clearance rate and HBeAg seroconversion rate than the entecavir group (HBeAg clearance rate: 61.29% vs 23.81%, P < 0.01; HBeAg seroconversion rate: 51.61% vs 19.05%, P < 0.01). Male sex and telbivudine therapy were baseline predictors of HBeAg seroconversion. The multivariate Cox regression analysis (Forward LR, a = 0.05) showed that the presence or absence of HBeAg seroconversion at week 104 was significantly associated with male sex (HR = 4.917), a reduction in HBsAg > 0.5 lg IU/ml at week 12 of treatment compared baseline (HR = 3.514), and a reduction in HBeAg > 1 lg COI at week 12 of treatment compared baseline (HR = 8.651). CONCLUSION: In HBeAg-positive CHB patients with suboptimal responses to 24-week PEG-IFNalpha-2a therapy, the sequential therapy with telbivudine helps achieve better HBeAg clearance rate and seroconversion rate compared with the sequential therapy with entecavir and can be used as a therapeutic regimen for such patients. A reduction in HBeAg > 1 lg COI at week 12 of treatment compared baseline can be used as a predictive factor for HBeAg seroconversion at week 104. PMID- 27470621 TI - [Characteristics of HBV transmission in families with HBsAg-positive fathers and familial clustering of HBV infection]. AB - OBJECTIVE: To investigate the characteristics of hepatitis B virus (HBV) transmission among family members in families with familial clustering of HBV infection and poor outcomes, as well as the prevalence and distribution characteristics of HBsAg in offspring with different parental HBsAg status. METHODS: The general information of each member in families with poor outcomes were collected from 2007 to 2010, and serological test was performed to analyze the prevalence and distribution of HBsAg in family members. The chi-square test or Fisher's exact test was used to analyze and compare the sex of offspring and the prevalence of HBsAg in them in 266 nuclear families with different paternal and maternal HBsAg status. RESULTS: The positive rates of HBsAg in parents, siblings, children, and spouses of the probands were 20%, 88.2%, 76.8%, and 9.5%, respectively. The nuclear families with HBsAg-positive fathers and HBsAg-negative mothers had a significantly increased proportion of male offspring (male/female ratio = 2.02) compared with those with HBsAg-positive mothers and HBsAg-negative fathers (1.22) or those with HBsAg-negative fathers and mothers (0.96). In addition, in the nuclear families with HBsAg-positive fathers and HBsAg-negative mothers, the male offspring had a significantly higher HBsAg positive rate than female offspring (37.4% vs 13.8%), while in those with HBsAg-positive mothers and HBsAg-negative fathers or those with HBsAg-negative fathers and mothers, HBsAg positive rate showed no significant difference between male and female offspring. CONCLUSION: In families with familial clustering of HBV infection and poor outcomes, mother-to-child transmission is still the major route of HBV transmission, but father-to-child transmission also plays a role in HBV transmission in this special population. Positive HBsAg in fathers is associated with the increased proportion of male offspring, and father-to-son transmission of HBV is higher than father-to-daughter transmission. PMID- 27470622 TI - [Prognostic analysis of acute-on-chronic liver failure after withdrawal of nucleos(t)ide analogues for antiviral treatment of chronic hepatitis B]. AB - OBJECTIVE: To investigate the prognostic factors for acute-on-chronic liver failure (ACLF) after the withdrawal of nucleos(t)ide analogues (NAs) for the antiviral treatment of chronic hepatitis B (CHB). METHODS: The clinical data of 67 hospitalized patients with ACLF after withdrawal of NAs for the antiviral treatment of CHB were analyzed retrospectively. RESULTS: The HBeAg status before initial treatment and after recurrence, course of the antiviral treatment, duration from the withdrawal of NAs to recurrence, and type of NAs before and after withdrawal were not associated with the prognosis of ACLF. The Cox univariate regression analysis showed that serum bilirubin, international normalization ratio, serum creatinine, model of end-stage of liver disease (MELD) score, hepatic encephalopathy, and concurrent infection were associated with the 12-week death. The Cox multivariate regression analysis showed that MELD score and hepatic encephalopathy were independent predictors for 12-week death. The area under the receiver operating characteristic curve for the MELD score to predict 12-week death was 0.906, with an optimal cutoff value of 32, a sensitivity of 82.9%, a specificity of 88.5%, a positive predictive value of 91.9%, and a negative predictive value of 76.7%. CONCLUSION: MELD score and hepatic encephalopathy are closely associated with the prognosis of patients with ACLF after withdrawal of NAs for the antiviral treatment of CHB. PMID- 27470623 TI - [Telbivudine for prevention of perinatal transmission in pregnant women infected with hepatitis B virus in immune-tolerant phase: a study of efficacy and safety of drug withdrawal]. AB - OBJECTIVE: To observe the success rate of telbivudine (LdT) for the prevention of perinatal transmission of hepatitis B virus (HBV) and the incidence of alanine aminotransferase (ALT) elevation during LdT treatment and after LdT withdrawal in HBV-infected pregnant woman with high viremia in immune-tolerant phase and receiving LdT treatment at the end of pregnancy, and to evaluate the efficacy of LdT in the prevention of perinatal transmission and the safety for pregnant women. METHODS: Pregnant women infected with HBV in immune-tolerant phase who had normal ALT levels (<=40 U/L) and high viremia (HBV DNA >=6 log10 IU/ml) with positive HBeAg were enrolled as subjects. All pregnant women received antiviral treatment with LdT at the end of pregnancy to prevent perinatal transmission of HBV. All infants received standard combined immunoprophylaxis. Failure for prevention of perinatal transmission of HBV was defined as positive HBsAg or HBV DNA in infants 7 months of age (or at one month after the third injection of hepatitis B vaccine). Liver function, HBV DNA, and HBV serological markers were evaluated at baseline, after 1 month of treatment, before childbirth, and 1, 3, and 6 months after drug withdrawal. SPSS 16.0 software was used to analyze the data. Between-group comparison of continuous data was made by t test, and comparison of categorical data was made by chi-square test. RESULTS: One hundred and four pregnant women (treatment group) received oral administration of 600 mg LdT once a day, and 25 pregnant women (observation group) did not receive any antiviral therapy. The success rate for the prevention of perinatal transmission was significantly higher in the treatment group than in the observation group (100% vs 89.47%, chi (2) = 9.862, P = 0.028). There was no significant difference in the incidence of ALT elevation during treatment and within 6 months after drug withdrawal between the treatment group and the observation group (4.81% (5/104) vs 4.00% (1/25), chi (2) = 0.030, P = 1.000). In the treatment group, the mean HBV DNA at baseline was significantly higher than that before childbirth (8.20+/ 0.78 vs 3.98+/-0.90 log10IU/ml, t = 6.979, P < 0.001). One hundred patients with drug withdrawal had HBV DNA increased to 8.11+/-0.80 log10 IU/ml at one month after childbirth. CONCLUSION: LdT treatment at the end of pregnancy can effectively reduce the incidence of perinatal transmission of HBV in pregnant women with high viremia in immune-tolerant phase. The immediate drug withdrawal after childbirth is safe for the mother. The incidence of hepatitis is low after drug withdrawal. PMID- 27470624 TI - [Role of glycogen synthase kinase-3beta in development of severe hepatitis liver failure caused by hepatitis B virus]. AB - OBJECTIVE: To investigate the role of glycogen synthase kinase-3beta (GSK3beta) in the development of severe hepatitis liver failure (SHLF) caused by the hepatitis B virus. METHODS: Twelve patients with chronic hepatitis B (CHB) (CHB group), 12 patients with SHLF caused by hepatitis B virus (SHLF group), and 8 normal subjects (control group), who were admitted to Beijing You'an Hospital from January 2009 to December 2011, were included in this study. Their liver tissues were collected to do some clinical examinations. The GSK3beta activity in the liver tissue was detected with a GSK3beta activity assay kit. Western blot was used to determine the expression of p-GSK3, total GSK3, and -actin. The paraffin sections of liver tissue were prepared for immunofluorescence assay. All data were expressed as mean+/-standard deviation, and comparison between groups was made by least significant difference t test. P < 0.05 was considered statistically significant. RESULTS: Western blot results showed that compared with the control group, the CHB group had a higher level of p-GSK3beta and the SHLF group had a significantly lower level of p-GSK3beta (P = 0.0342). The immunofluorescence assay results showed that the SHLF group had a significantly lower level of p-GSK3beta than the control group. GSK3beta activity assay results showed that compared with the control group, the CHB group had a significantly lower GSK3beta activity and the SHLF group had a significantly higher GSK3beta activity (P = 0.0289), which were consistent with the results of Western blot and immunofluorescence assay. CONCLUSION: GSK3 is activated in the development of SHLF, so it is an important signaling molecule in the pathogenesis of SHLF. Inhibiting its activity may play a role in the prevention and treatment of SHLF. PMID- 27470625 TI - [Clinical value of contrast-enhanced ultrasound in evaluating portal hypertension in patients with decompensated liver cirrhosis]. AB - OBJECTIVE: To investigate the correlation between contrast-enhanced ultrasound parameters and hepatic venous pressure gradient (HVPG), and to develop a new noninvasive method for the evaluation of portal hypertension in patients with decompensated liver cirrhosis. METHODS: One-hundred patients with decompensated liver cirrhosis were examined by contrast-enhanced ultrasound, and the dynamic images were collected for offline analysis. The contrast arrival time was obtained in the hepatic artery (HA), portal vein (PV), and hepatic vein (HV), and HA-HV transit time (HA-HVTT) and PV-HV transit time (PV-HVTT) were calculated. At the same time, HVPG was measured within 24 hours after contrast-enhanced ultrasound, Pearson correlation analysis was performed between each parameter and HVPG, and the receiver operating characteristic (ROC) curve was also used for analysis. RESULTS: HV arrival time (HVAT), HA-HVTT, and PV-HVTT were negatively correlated with HVPG (r = -0.385, -0.409, and -0.572, respectively). The area under the ROC curve (AUROC) was 0.903 for PV-HVTT < 2.5 s in judging HVPG>= l0 mmHg in patients with decompensated liver cirrhosis, and the sensitivity and specificity were 74.4% and 89.5%, respectively. The AUROC was 0.861 for PV-HVTT < 1.5 s in judging HVPG>=l6 mmHg in these patients, and the sensitivity and specificity were 80.4% and 81.5%, respectively. CONCLUSIONS: HVAT and intrahepatic transit time demonstrate negative linear correlations with HVPG in patients with decompensated liver cirrhosis, and among all parameters, PV-HVTT shows the strongest correlation with HVPG and can be used to determine and predict the severity of portal hypertension. PMID- 27470626 TI - [Sole percutaneous microwave coagulation versus its combination with transcatheter arterial chemoembolization for treatment of primary hepatoma: a comparison study]. AB - OBJECTIVE: To evaluate the efficacy and adverse effects of sole percutaneous microwave coagulation therapy (PMCT) compared to that of PMCT combining with transcatheter arterial chemoembolization (TACE) for the treatment of primary hepatoma. METHODS: A total of 50 patients diagnosed with primary hepatocellular carcinoma were recruited and divided into two groups. Group A included 15 patients only treated with PMCT. The other 35 ones falling into group B were treated with PMCT in combination with TACE. Analysis of therapeutic efficacy and adverse effects were conducted. RESULTS: The objective effect rates in group A and group B were 40.0% and 62.8%, respectively. There was no significant difference between the two groups(P = 0.136). The one-year survival rates of the two groups were 46.6% and 71.4%,respectively(P = 0.095);and the two-year survival rates were 26.7% and 42.8%,respectively (P = 0.048). No grade III adverse effects or beyond were observed. CONCLUSION: PCMT combining with TACE is safe and more effective in one-year survival than PCMT alone for the treatment of primary hepatocellular carcinoma. PMID- 27470627 TI - [Establishment and evaluation of a mouse model of nonalcoholic steatohepatitis related hepatocellular carcinoma]. AB - OBJECTIVE: To establish an apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) double-knockout (ApoE(-/-)/LDLR(-/-)) mouse model of nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) induced by high-fat and high-cholesterol (HFHC) diet. METHODS: ApoE(-/-) knockout mice were crossed with LDLR(-/-) knockout mice to obtain ApoE(-/-)/LDLR(-/-) mice. The ApoE(-/ )/LDLR(-/-) mice mated with each other, and the offspring were injected with low dose streptozotocin (STZ) at 2-3 days after birth. Some mice were fed with HFHC diet after weaning as the model group (n = 15), and some mice were fed with normal diet as the control group (n = 15). Mice were sacrificed at the end of weeks 10, 16, and 20 (5 mice at each time point). The body weight was measured. Liver tissue and blood were collected to measure biochemical parameters, evaluate the pathological changes in the liver tissue by HE staining, oil red O staining, and Masson staining, and detect the expression of glypican-3 (a marker of HCC) by immunohistochemical staining. RESULTS: The model group had significantly higher levels of fasting blood glucose and total cholesterol than the control group (P < 0.01). Serum levels of alanine aminotransferase, aspartate aminotransferase, and total triglyceride gradually increased with time in the model group; at week 20, there were significant differences in above three indices between the two groups (P < 0.05). HE staining showed that compared with the control group at the corresponding time point, the model group developed sequential histological changes: NASH at week 10, dysplastic nodules at week 16, and early HCC at week 20. Oil red O staining showed that in the model group, the degree of liver steatosis increased within 10 weeks and gradually decreased later. Masson staining demonstrated that the model group developed pathological changes: mild perisinusoidal fibrosis at week 16 and bridging fibrosis around tumors at week 20. HE staining, oil red O staining, and Masson staining showed that no histological or pathological changes were found in the control group. Glypican-3 was detected in the nodules at week 16 and in the cytoplasm of HCC cells at week 20 in the model group. CONCLUSION: The mouse model of NASH-related HCC can be developed by giving STZ injection to neonatal ApoE(-/-)/LDLR(-/-) mice and feeding them with HFHC diet after weaning for 20 weeks. Early HCC may develop directly from NASH. PMID- 27470628 TI - [Role of PI3K/AKT signaling pathway in clonogenicity and tumorigenicity of CD90+ stem-like cells of the hepatocellular carcinoma cell line MHCC-97H]. AB - OBJECTIVE: To investigate the influence of the PI3K/AKT signaling pathway on the proportion and characteristics of the stem-like CD90(+) subpopulation of the human hepatocellular carcinoma (HCC) cell line MHCC-97. METHODS: MHCC-97H cultures were treated with the PI3K/AKT pathway inhibitor LY294002. The proportion of the CD90(+) subpopulation was determined by flow cytometry, and the expression of related proteins was measured by Western blot. The clonogenicity of CD90(+) and CD90(-) cells was measured by plate colony formation assay. The tumorigenicity was compared between CD90(+) and CD90(-) subpopulations (with different concentrations) in xenograft experiments in nude mice, and the changes in tumorigenicity after the addition of LY294002 were evaluated. The changes in the expression of CD90, SHP2, P-AKT, and AKT in CD90(+) and CD90(-) cell xenografts after the addition of LY294002 were examined. Data were analyzed using t test. RESULTS: LY294002 was capable of reducing the proportion of CD90(+) HCC stem cells from 2.98%+/-0.08% to 0.78%+/-0.08% (t = 32.400, P < 0.01) and reducing the clonogenicity of CD90(+) subpopulation from 95.13%+/-3.78% to 61.82%+/-7.23% (t = 7.617, P < 0.01). However, it showed no significant effect on the clonogenicity of CD90(-) subpopulation. LY294002 also reduced the tumorigenicity of CD90(+) subpopulation and the expression of CD90, SHP2, and P AKT in related HCC stem cells, but it did not significantly affect the expression of AKT. LY294002 had no significant inhibitory effect on the tumorigenicity of CD90(-) cells. CONCLUSION: The CD90(+) subpopulation of MHCC-97H cells has the characteristics of stem cells and is dependent on the PI3K/AKT signaling pathway. PMID- 27470630 TI - [Strategies in clinical diagnosis and treatment of steroid-resistant acute rejection after orthotopic liver transplantation]. AB - OBJECTIVE: To explore the diagnostic evidence and treatment strategies for steroid-resistant acute rejection (SRAR) after orthotopic liver transplantation. METHODS: A retrospective analysis was performed among 1038 patients undergoing orthotopic liver transplantation in our hospital from January 2004 to December 2013. A total of 169 acute rejection (AR) episodes occurred in 153 patients. Sixteen of the patients were diagnosed with SRAR because of no response to large dose steroid pulse therapy. The diagnosis and treatment of the 16 patients were analyzed retrospectively. Comparison of data was made by chi2 test or t test, and a P value of <0.05 was considered to be significant. RESULTS: The incidence of AR after liver transplantation was 14.74% (153/1038) in all the patients. The incidence of SRAR was 9.47% (16/169) in patients with AR. In the 16 patients with SRAR, 3 were treated with anti-CD3 monoclonal antibody (OKT3), 9 were treated with monoclonal antibody against IL-2 receptor, and 4 received antithymocyte globulin (ATG) therapy. After treatment, SRAR was reversed in 12 of the 16 patients and caused death of the other 4 patients, yielding a reversal rate of 75% and a mortality rate of 25%. CONCLUSION: SRAR after liver transplantation has a low incidence rate but poor prognosis. The diagnosis of SRAR is mainly based on the clinical manifestation, laboratory test, liver biopsy, and poor response or rejection to methyl prednisolone pulse therapy. ATG and OKT3 achieve substantial outcomes in most of the patients in the treatment of SRAR. Particularly, compared with OKT3, ATG achieves a higher reversal rate and fewer adverse reactions, which is expected to become the first-line treatment of SRAR. PMID- 27470629 TI - [Effect of polyene phosphatidyl choline on hepatocyte steatosis via PPARalpha/CPT 1A pathway]. AB - OBJECTIVE: To investigate the effect of polyene phosphatidyl choline (PPC) on hepatocyte steatosis and the possible role of the peroxisome proliferators activated receptor alpha (PPARalpha)/carnitine palmityl transferase 1A (CPT-1A) pathway in the treatment. METHODS: L02 hepatocyte steatosis was induced with PPC treatment, and Oil Red O staining and triglyceride measurement were used to evaluate the influence of PPC on the degree of steatosis. Quantitative PCR and Western blot were used to measure the changes in mRNA and protein of CPT-1A, followed by using GW6471 to specifically inhibit the PPARalpha pathway. The changes in the above indices were observed, and one-way analysis of variance and LSD method for pairwise comparison were used to analyze the data. RESULTS: Compared with the blank control and DMSO group, the PPC treatment group had a significantly lower triglyceride content after steatosis (214.97+/-25.53 and 219.62+/-19.40 MUg/mg vs 163.82+/-14.94 MUg/mg, F = 6.90, P < 0.05), but had significantly higher levels of mRNA (0.36+/-0.04 and 0.37+/-0.04 vs 0.75+/-0.09, F = 38.37, P < 0.05) and protein of CPT-1A. After inhibition by GW6471, a specific PPARalpha inhibitor, the content of triglyceride showed no significant difference between the blank control group, DMSO group, and PPC treatment group (244.04+/-22.38 MUg/mg vs 242.27+/-18.71 MUg/mg vs 225.41+/-27.63 MUg/mg, F = 0.59, P > 0.05), and the levels of mRNA (0.16+/-0.06 vs 0.17+/-0.02 vs 0.18+/ 0.04, F = 0.18, P > 0.05) and protein of CPT-1A also showed no significant difference between the three groups. CONCLUSION: PPC may relieve hepatocyte steatosis through activation of the PPARalpha/CPT-1A pathway. PMID- 27470631 TI - [Clinical features of drug-induced autoimmune hepatitis and drug-induced liver injury: a comparative analysis]. AB - OBJECTIVE: To investigate the clinical features of drug-induced autoimmune hepatitis (DIAIH) and its therapeutic strategies, and to provide a reference for early diagnosis and treatment of this disease and prevention of chronicity. METHODS: The clinical data of 116 patients with drug-induced liver injury (DILI) or DIAIH confirmed by medical history, liver biochemistry, and liver biopsy were analyzed retrospectively. Among these patients, 13 had DIAIH and 103 had simple DILI (30 patients in the hepatocyte-type group and 73 in the cholestasis/mixed type group). The population characteristics, major drugs inducing the diseases, clinical manifestations, liver biochemical parameters, liver pathological features, and clinical outcome were compared between groups. The Kruskal-wallis H test was used for comparison and the Mann-Whitney U test was used for comparison between any two groups. The chi-square test was used for comparison of categorical data, and the R*C chi-square test was used for comparison of rates between the three groups; in the case of significant differences, the R*C contingency table was used for comparison between any two groups. RESULTS: The patients with DIAIH had a mean age of 53.54+/-8.28 years, and the mean age was 35.13+/-13.46 and 46.99+/-14.82 years for the hepatocyte-type group and cholestasis/mixed-type group, respectively. The disease was mainly induced by a combination of various drugs. The patients with DIAIH had significantly higher serum levels of alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, and alkaline phosphatase and a significantly higher positive rate of anti-nuclear antibody than those with DILI (all P < 0.05). In patients with DIAIH, the liver pathological features and the features of response to treatment were as follows: obvious interface hepatitis, proliferation of small bile ducts, and mixed inflammatory cell infiltration in the portal area, including eosinophils and plasma cells, and the short-term corticosteroid therapy had a good therapeutic effect. CONCLUSION: DIAIH has a low incidence and is more common in the female population, with the features of tissue injury in both DILI and autoimmune hepatitis. The short-term corticosteroid therapy can prevent disease progression and reduce chronicity. PMID- 27470632 TI - [Efficacy of tenofovir monotherapy or lamivudineadefovir dipivoxil combination therapy in treatment of lamivudine-resistant chronic hepatitis B]. PMID- 27470633 TI - [Wilson's disease misdiagnosed as "nephritis" : a report of one case]. PMID- 27470634 TI - [Alcoholic liver cirrhosis combined leukemoid reaction: a case report]. PMID- 27470635 TI - [Research advances in the role of CX3CL1 and its receptor in liver diseases]. AB - In recent years, an increasing number of studies have found that the interaction between CX3CL1 and its receptor plays an important role in a series of inflammatory, infectious, and neurological processes and in various cancers. Therefore, its therapeutic targeting represents a promising treatment strategy for diseases. This review summarizes the structure, biological function, and mechanism of signal transduction of CX3CL1 and its receptor, and introduces the research progress in CX3CL1 and its receptor in hepatitis, hepatic fibrosis, cirrhosis, and hepatoma. PMID- 27470636 TI - [Significance of HBsAg quantification in guiding clinical treatment of chronic hepatitis B]. AB - Serum hepatitis B surface antigen (HBsAg) quantification can reflect the level of HBV replication and can be used as a surrogate maker for the evaluation of infected cells. Recent studies have shown that HBsAg quantification can help to distinguish the nature history of chronic hepatitis B and predict spontaneous clearance of HBsAg and the risk of progressive liver diseases. The dynamic change in HBsAg helps to predict the therapeutic effects of interferon and nucleoside analogues and sustained virologic response, guide withdrawal, and improve and optimize the therapeutic strategy for chronic hepatitis B in clinical practice. These issues have become the hot topics in recent years. However, the cut-off values of HBsAg level in patient management and various therapeutic strategies have not been determined. This article reviews the research advances in the significance of HBsAg quantification in the natural history and optimized treatment of chronic hepatitis B. PMID- 27470637 TI - Structurally-driven Enhancement of Thermoelectric Properties within Poly(3,4 ethylenedioxythiophene) thin Films. AB - Due to the rising need for clean energy, thermoelectricity has raised as a potential alternative to reduce dependence on fossil fuels. Specifically, thermoelectric devices based on polymers could offer an efficient path for near room temperature energy harvesters. Thus, control over thermoelectric properties of conducting polymers is crucial and, herein, the structural, electrical and thermoelectric properties of poly(3,4-ethylenedioxythiophene) (PEDOT) thin films doped with p-toluenesulfonate (Tos) molecules were investigated with regards to thin film processing. PEDOT: Tos thin films were prepared by in-situ polymerization of (3,4-ethylenedioxythiophene) monomers in presence of iron(III) p-toluenesulfonate with different co-solvents in order to tune the film structure. While the Seebeck coefficient remained constant, a large improvement in the electrical conductivity was observed for thin films processed with high boiling point additives. The increase of electrical conductivity was found to be solely in-plane mobility-driven. Probing the thin film structure by Grazing Incidence Wide Angle X-ray Scattering has shown that this behavior is dictated by the structural properties of the PEDOT: Tos films; specifically by the thin film crystallinity combined to the preferential edge-on orientation of the PEDOT crystallites. Consequentially enhancement of the power factor from 25 to 78.5 MUW/mK(2) has been readily obtained for PEDOT: Tos thin films following this methodology. PMID- 27470638 TI - Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro. AB - RATIONALE: PKP2, encoding plakophilin 2 (PKP2), is the most common causal gene for arrhythmogenic cardiomyopathy. OBJECTIVE: To characterize miRNA expression profile in PKP2-deficient cells. METHODS AND RESULTS: Control and PKP2-knockdown HL-1 (HL-1(Pkp2-shRNA)) cells were screened for 750 miRNAs using low-density microfluidic panels. Fifty-nine miRNAs were differentially expressed. MiR-184 was the most downregulated miRNA. Expression of miR-184 in the heart and cardiac myocyte was developmentally downregulated and was low in mature myocytes. MicroRNA-184 was predominantly expressed in cardiac mesenchymal progenitor cells. Knockdown of Pkp2 in cardiac mesenchymal progenitor cells also reduced miR-184 levels. Expression of miR-184 was transcriptionally regulated by the E2F1 pathway, which was suppressed in PKP2-deficient cells. Activation of E2F1, on overexpression of its activator CCND1 (cyclin D1) or knockdown of its inhibitor retinoblastoma 1, partially rescued miR-184 levels. In addition, DNA methyltransferase-1 was recruited to the promoter region of miR-184, and the CpG sites at the upstream region of miR-184 were hypermethylated. Treatment with 5 aza-2'-deoxycytidine, a demethylation agent, and knockdown of DNA methyltransferase-1 partially rescued miR-184 level. Pathway analysis of paired miR-184:mRNA targets identified cell proliferation, differentiation, and death as the main affected biological processes. Knockdown of miR-184 in HL-1 cells and mesenchymal progenitor cells induced and, conversely, its overexpression attenuated adipogenesis. CONCLUSIONS: PKP2 deficiency leads to suppression of the E2F1 pathway and hypermethylation of the CpG sites at miR-184 promoter, resulting in downregulation of miR-184 levels. Suppression of miR-184 enhances and its activation attenuates adipogenesis in vitro. Thus, miR-184 contributes to the pathogenesis of adipogenesis in PKP2-deficient cells. PMID- 27470640 TI - Renal functional reserve and renal hemodynamics in hypertensive patients. AB - The renal functional reserve (RFR) is the ability of the kidneys to increase renal plasma flow and glomerular filtration rate (GFR) in response to protein intake. It is a measure of functional and anatomic integrity of nephrons. It is not known what relation between RFR and kidney Doppler parameters. We aimed to study the relation between the RFR and renal hemodynamic parameters in hypertensive patients with and without nephropathy who had normal kidney function. Twenty-four hypertensive subjects with nephropathy (HTN-n, n = 10) and hypertension without nephropathy (HTN, n = 14) were included in the study. Control group included 11 healthy subjects. Baseline GFR (GFR1) and GFR after intake of egg protein 1 mg/kg of body weight were determined (GFR2). RFR was calculated by the following formula: (GFR2-GFR1)/GFR1 * 100%. Doppler ultrasonography was performed. Arterial blood pressure (BP), body mass index (BMI), and estimated GFR were also recorded. HTN and HTN-n groups had impaired levels of RFR compared with controls (p < 0.05), significantly decreased value of flow velocity parameters (Vmax, Vmin), and increased RRI compared with controls. There was significant negative correlation of RFR with blood pressure levels (sBP, r = -0.435, p = 0.009; dBP, r = -0.504, p = 0.002), RRI (r = -0.456, p = 0.008), micro albuminuria (MAU, r = -0.366, p = 0.031) and positive correlation with Vmax and Vmin (r = 0.556, p = 0.001 and r = 0.643, respectively, p < 0.001). Linear regression showed that RRI and MAU were independent predictors of decreased RFR. RFR is lower in hypertensive patients despite near-normal level of kidney function and is related to particular level of BP. RRI and MAU were independent predictors of decreased RFR. PMID- 27470639 TI - Alternative Splicing of Titin Restores Diastolic Function in an HFpEF-Like Genetic Murine Model (TtnDeltaIAjxn). AB - RATIONALE: Patients with heart failure with preserved ejection fraction (HFpEF) experience elevated filling pressures and reduced ventricular compliance. The splicing factor RNA-binding motif 20 (RBM20) regulates the contour length of titin's spring region and thereby determines the passive stiffness of cardiomyocytes. Inhibition of RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce passive stiffness. OBJECTIVE: To determine the therapeutic potential of upregulating compliant titin isoforms in an HFpEF-like state in the mouse. METHODS AND RESULTS: Constitutive and inducible cardiomyocyte-specific RBM20-inhibited mice were produced on a Ttn(DeltaIAjxn) background to assess the effect of upregulating compliant titin at the cellular and organ levels. Genetic deletion of the I-band-A-band junction (IAjxn) in titin increases strain on the spring region and causes a HFpEF-like syndrome in the mouse without pharmacological or surgical intervention. The increased strain represents a mechanical analog of deranged post-translational modification of titin that results in increased passive myocardial stiffness in patients with HFpEF. On inhibition of RBM20 in Ttn(DeltaIAjxn) mice, compliant titin isoforms were expressed, diastolic function was normalized, exercise performance was improved, and pathological hypertrophy was attenuated. CONCLUSIONS: We report for the first time a benefit from upregulating compliant titin isoforms in a murine model with HFpEF-like symptoms. Constitutive and inducible RBM20 inhibition improves diastolic function resulting in greater tolerance to exercise. No effective therapies exists for treating this pervasive syndrome; therefore, our data on RBM20 inhibition are clinically significant. PMID- 27470641 TI - Phosphoproteome Characterization of Human Colorectal Cancer SW620 Cell-Derived Exosomes and New Phosphosite Discovery for C-HPP. AB - Identification of all phosphorylation forms of known proteins is a major goal of the Chromosome-Centric Human Proteome Project (C-HPP). Recent studies have found that certain phosphoproteins can be encapsulated in exosomes and function as key regulators in tumor microenvironment, but no deep coverage phosphoproteome of human exosomes has been reported to date, which makes the exosome a potential source for the new phosphosite discovery. In this study, we performed highly optimized MS analyses on the exosomal and cellular proteins isolated from human colorectal cancer SW620 cells. With stringent data quality control, 313 phosphoproteins with 1091 phosphosites were confidently identified from the SW620 exosome, from which 202 new phosphosites were detected. Exosomal phosphoproteins were significantly enriched in the 11q12.1-13.5 region of chromosome 11 and had a remarkably high level of tyrosine-phosphorylated proteins (6.4%), which were functionally relevant to ephrin signaling pathway-directed cytoskeleton remodeling. In conclusion, we here report the first high-coverage phosphoproteome of human cell-secreted exosomes, which leads to the identification of new phosphosites for C-HPP. Our findings provide insights into the exosomal phosphoprotein systems that help to understand the signaling language being delivered by exosomes in cell-cell communications. The mass spectrometry proteomics data have been deposited to the ProteomeXchange consortium with the data set identifier PXD004079, and iProX database (accession number: IPX00076800). PMID- 27470642 TI - Novelties in the Diagnosis and Treatment of Angioedema. AB - Angioedema is defined as local, noninflammatory, self-limiting edema that is circumscribed owing to increased leakage of plasma from the capillaries located in the deep layers of the skin and the mucosae. Two mediators, histamine and bradykinin, account for most cases of angioedema. Angioedema can occur with wheals as a manifestation of urticaria, and this form is frequently allergic. In the present review, we discuss nonallergic angioedema without wheals, which can be divided into 3 acquired and 4 hereditary forms. Histamine is the mediator in acquired angioedema of unknown etiology (idiopathic histaminergic acquired angioedema), whereas in other forms the main mediator is bradykinin. Angioedema can be caused by C1-inhibitor deficiency (C1-INH-hereditary angioedema and C1-INH acquired angioedema), mutations in coagulation factor XII (FXII-hereditary angioedema), and treatment with angiotensin-converting enzyme inhibitors (ACEI acquired angioedema). Etiology remains unclear in acquired angioedema (idiopathic nonhistaminergic acquired angioedema) and in 1 type of hereditary angioedema (hereditary angioedema of unknown origin). Several treatments are licensed for hereditary C1-INH deficiency. Plasma-derived and recombinant C1-INHs, the bradykinin receptor blocker icatibant, and the plasma kallikrein inhibitor ecallantide have been approved for on-demand treatment to reverse angioedema symptoms. Attenuated androgen and plasma-derived C1-INH are approved for prophylaxis. PMID- 27470643 TI - Profiles of Birch Sensitization (Bet v 1, Bet v 2, and Bet v 4) and Oral Allergy Syndrome Across Italy. AB - BACKGROUND: Birch allergy (BA) is a common pollinosis caused by the allergens Bet v 1, Bet v 2, and Bet v 4. Oral allergy syndrome (OAS) is frequently associated with BA. A gradient of sensitization to birch allergen across Europe has been reported. Therefore, this study aimed to investigate the birch sensitization profile, including OAS, across Italy. METHODS: We performed a retrospective study of 854 patients (391 males, mean age 35.9 years, range 18-93 years): 196 patients were recruited in Genoa, 188 in northern Italy, 359 in central Italy, and 111 in southern Italy. Serum IgE to Bet v 1, Bet v 2, and Bet v 4 was assessed, and OAS was analyzed. RESULTS: With respect to the geographical path Genoa-North-Center South, the frequency of sensitization to Bet v 1 decreased significantly (P<.0001) from Genoa (95.41%) to southern Italy (58.56%). The frequency of sensitization to Bet v 2 increased significantly (P<.0001) from Genoa (6.12%) to southern Italy (52.25%). The frequency of Bet v 4 also increased significantly (P=.0002) from Genoa (6.12%) to southern Italy (14.41%). The distribution of patients with OAS differed significantly across the areas (P<.0001), the most marked difference ranging between 33.5% in Genoa and 76.9% in northern Italy. The frequency of birch allergens correlated with OAS in central Italy only. CONCLUSIONS: The present study demonstrated a significant difference between sensitization to birch and its clinical expression across Italy. PMID- 27470644 TI - Identification of Putative Kunitz-Type Proteinase Inhibitor as an Allergenic Protein in Potato. PMID- 27470645 TI - Exudative Erythema Multiforme Due to Cyclobenzaprine. PMID- 27470646 TI - Anaphylaxis to 2 NSAIDs in a Patient Who Tolerated ASA. PMID- 27470648 TI - Experience With Rapid Desensitization to Chemotherapy in a Type B Hospital. PMID- 27470647 TI - Disseminated BCG Infectious Disease and Hyperferritinemia in a Patient With a Novel NEMO Mutation. PMID- 27470649 TI - Delayed Allergic Reaction to Acenocoumarol With a Positive Lymphocyte Transformation Test. PMID- 27470650 TI - Kinetics of in Vitro Response to beta-Lactoglobulin in Children Allergic to and Tolerant of Cow's Milk Protein. PMID- 27470651 TI - Hevea brasiliensis Rather Than Latex. PMID- 27470652 TI - Reply to "Hevea brasiliensis Rather Than Latex". PMID- 27470653 TI - Clinical and molecular characterization of a boy with intellectual disability, facial dysmorphism, minor digital anomalies and a complex IL1RAPL1 intragenic rearrangement. AB - X-linked intellectual disability accounts for 10-12% of cases of cognitive impairment in males. Mutations in IL1RAPL1 are an emerging form of apparently non syndromic X-linked intellectual disability. We report a 8-year-old intellectually disabled boy with speech delay, and unusual facial and digital anomalies who showed a novel and complex IL1RAPL1 rearrangement. It was defined by two intragenic non-contiguous duplications inherited from the unaffected mother. Chromosome X inactivation study on the mother's blood leukocytes, urinary sediment and buccal swab did not show a significant skewed inactivation. Comparison with previously described patients with IL1RAPL1 disruption was carried. Although data on craniofacial features were scanty in many papers, subtle facial dysmorphism with a thin upper lip seemed a quietly represented picture without any other genotype-phenotype correlations. Our study expands the molecular repertoire of IL1RAPL1 mutations in intellectual disability and points out the need of more accurate clinical descriptions to better define the related phenotype. PMID- 27470654 TI - Advancing non-invasive neuromodulation clinical trials in children: Lessons from perinatal stroke. AB - Applications of non-invasive brain stimulation including therapeutic neuromodulation are expanding at an alarming rate. Increasingly established scientific principles, including directional modulation of well-informed cortical targets, are advancing clinical trial development. However, high levels of disease burden coupled with zealous enthusiasm may be getting ahead of rational research and evidence. Experience is limited in the developing brain where additional issues must be considered. Properly designed and meticulously executed clinical trials are essential and required to advance and optimize the potential of non-invasive neuromodulation without risking the well-being of children and families. Perinatal stroke causes most hemiplegic cerebral palsy and, as a focal injury of defined timing in an otherwise healthy brain, is an ideal human model of developmental plasticity. Advanced models of how the motor systems of young brains develop following early stroke are affording novel windows of opportunity for neuromodulation clinical trials, possibly directing neuroplasticity toward better outcomes. Reviewing the principles of clinical trial design relevant to neuromodulation and using perinatal stroke as a model, this article reviews the current and future issues of advancing such trials in children. PMID- 27470655 TI - Ketogenic diet guidelines for infants with refractory epilepsy. AB - BACKGROUND: The ketogenic diet (KD) is an established, effective non pharmacologic treatment for drug resistant childhood epilepsy. For a long time, the KD was not recommended for use in infancy (under the age of 2 years) because this is such a crucial period in development and the perceived high risk of nutritional inadequacies. Indeed, infants are a vulnerable population with specific nutritional requirements. But current research shows that the KD is highly effective and well tolerated in infants with epilepsy. Seizure freedom is often achieved and maintained in this specific patient group. There is a need for standardised protocols and management recommendations for clinical use. METHOD: In April 2015, a project group of 5 experts was established in order to create a consensus statement regarding the clinical management of the KD in infants. The manuscript was reviewed and amended by a larger group of 10 international experts in the KD field. Consensus was reached with regard to guidance on how the diet should be administered and in whom. RESULTS: The resulting recommendations include patient selection, pre-KD counseling and evaluation, specific nutritional requirements, preferred initiation, monitoring of adverse effects at initiation and follow-up, evaluation and KD discontinuation. CONCLUSION: This paper highlights recommendations based on best evidence, combined with expert opinions and gives directions for future research. PMID- 27470656 TI - Highly Facet-Dependent Photocatalytic Properties of Cu2 O Crystals Established through the Formation of Au-Decorated Cu2 O Heterostructures. AB - This work confirms the presence of a large facet-dependent photocatalytic activity of Cu2 O crystals through sparse deposition of gold particles on Cu2 O cubes, octahedra, and rhombic dodecahedra. Au-decorated Cu2 O rhombic dodecahedra and octahedra showed greatly enhanced photodegradation rates of methyl orange resulting from a better separation of the photogenerated electrons and holes, with the rhombic dodecahedra giving the best efficiency. Au-Cu2 O core-shell rhombic dodecahedra also displayed a better photocatalytic activity than pristine rhombic dodecahedra. However, Au-deposited Cu2 O cubes, pristine cubes, and Au deposited small nanocubes bound by entirely {100} facets are all photocatalytically inactive. X-ray photoelectron spectra (XPS) showed identical copper peak positions for these Au-decorated crystals. Remarkably, electron paramagnetic resonance (EPR) measurements indicated a higher production of hydroxyl radicals for the photoirradiated Cu2 O rhombic dodecahedra than for the octahedra, but no radicals were produced from photoirradiated Cu2 O cubes. The Cu2 O {100} face may present a high energy barrier through its large band edge bending and/or electrostatic repulsion, preventing charge carriers from reaching to this surface. The conventional photocatalysis model fails in this case. The facet-dependent photocatalytic differences should be observable in other semiconductor systems whenever a photoinduced charge-transfer process occurs across an interface. PMID- 27470657 TI - High-dose therapy and autologous stem cell transplantation may only be applicable to selected patients with secondary CNS diffuse large B-cell lymphoma. PMID- 27470658 TI - Structure and dynamics of H. pylori 98-10 C5-cytosine specific DNA methyltransferase in complex with S-adenosyl-l-methionine and DNA. AB - Helicobacter pylori is a Gram-negative bacterium that inhabits the human gastrointestinal tract, and some strains of this bacterium cause gastric ulcers and cancer. DNA methyltransferases (MTases) are promising drug targets for the treatment of cancer and other diseases that are also caused by epigenetic alternations of the genome. The C5-cytosine specific DNA methyltransferase from H. pylori (M. Hpy C5mC) catalyzes the transfer of the methyl group from the cofactor S-adenosyl-l-methionine (AdoMet) to the flipped cytosine of the substrate DNA. Herein we report the sequence analyses, 3-D structure modeling and molecular dynamics simulations of M. Hpy C5mC, when complexed with AdoMet as well as DNA. We analyzed the protein-DNA interactions prominently established by the flipped cytosine and the interactions between the protein and cofactor in the active site. We propose that the contacts made by cytosine O2 with Arg155 and Arg157, and the water-mediated interactions with cytosine N3 may be essential for the activity of methyl transfer as well as the deprotonation at the C5 position in our C5mC model. Specific recognition of DNA was mediated mainly by residues from Ser221-Arg229 and Ser243-Gln246 of the target recognition domain (TRD) and some residues of the loop Ser75-Lys83 from the large domain. These findings are further supported by alanine scanning mutagenesis studies. The results reported here explain the sequence, structure and binding features necessary for the recognition between the cofactor and the substrate by the key epigenetic enzyme, M. Hpy C5mC. PMID- 27470659 TI - The mitochondrial genome of booklouse, Liposcelis sculptilis (Psocoptera: Liposcelididae) and the evolutionary timescale of Liposcelis. AB - Bilateral animals are featured by an extremely compact mitochondrial (mt) genome with 37 genes on a single circular chromosome. To date, the complete mt genome has only been determined for four species of Liposcelis, a genus with economic importance, including L. entomophila, L. decolor, L. bostrychophila, and L. paeta. They belong to A, B, or D group of Liposcelis, respectively. Unlike most bilateral animals, L. bostrychophila, L. entomophila and L. paeta have a bitipartite mt genome with genes on two chromosomes. However, the mt genome of L. decolor has the typical mt chromosome of bilateral animals. Here, we sequenced the mt genome of L. sculptilis, and identified 35 genes, which were on a single chromosome. The mt genome fragmentation is not shared by the D group of Liposcelis and the single chromosome of L. sculptilis differed from those of booklice known in gene content and gene arrangement. We inferred that different evolutionary patterns and rate existed in Liposcelis. Further, we reconstructed the evolutionary history of 21 psocodean taxa with phylogenetic analyses, which suggested that Liposcelididae and Phthiraptera have evolved 134 Ma and the sucking lice diversified in the Late Cretaceous. PMID- 27470660 TI - High throughput genomic sequencing of bioaerosols in broiler chicken production facilities. AB - Chronic inhalation exposure to agricultural dust promotes the development of chronic respiratory diseases among poultry workers. Poultry dust is composed of dander, chicken feed, litter bedding and microbes. However, the microbial composition and abundance has not been fully elucidated. Genomic DNA was extracted from settled dust and personal inhalable dust collected while performing litter sampling or mortality collection tasks. DNA libraries were sequenced using a paired-end sequencing-by-synthesis approach on an Illumina HiSeq 2500. Sequencing data showed that poultry dust is predominantly composed of bacteria (64-67%) with a small quantity of avian, human and feed DNA (< 2% of total reads). Staphylococcus sp. AL1, Salinicoccus carnicancri and Lactobacillus crispatus were the most abundant bacterial species in personal exposure samples of inhalable dust. Settled dust had a moderate relative abundance of these species as well as Staphylococcus lentus and Lactobacillus salivarius. There was a statistical difference between the microbial composition of aerosolized and settled dust. Unlike settled dust composition, aerosolized dust composition had little variance between samples. These data provide an extensive analysis of the microbial composition and relative abundance in personal inhalable poultry dust and settled poultry dust. PMID- 27470661 TI - Cortical network dysfunction caused by a subtle defect of myelination. AB - Subtle white matter abnormalities have emerged as a hallmark of brain alterations in magnetic resonance imaging or upon autopsy of mentally ill subjects. However, it is unknown whether such reduction of white matter and myelin contributes to any disease-relevant phenotype or simply constitutes an epiphenomenon, possibly even treatment-related. Here, we have re-analyzed Mbp heterozygous mice, the unaffected parental strain of shiverer, a classical neurological mutant. Between 2 and 20 months of age, Mbp(+/-) versus Mbp(+/+) littermates were deeply phenotyped by combining extensive behavioral/cognitive testing with MRI, 1H-MR spectroscopy, electron microscopy, and molecular techniques. Surprisingly, Mbp dependent myelination was significantly reduced in the prefrontal cortex. We also noticed a mild but progressive hypomyelination of the prefrontal corpus callosum and low-grade inflammation. While most behavioral functions were preserved, Mbp(+/-) mice exhibited defects of sensorimotor gating, as evidenced by reduced prepulse-inhibition, and a late-onset catatonia phenotype. Thus, subtle but primary abnormalities of CNS myelin can be the cause of a persistent cortical network dysfunction including catatonia, features typical of neuropsychiatric conditions. GLIA 2016;64:2025-2040. PMID- 27470663 TI - Investigation into the interaction of losartan with human serum albumin and glycated human serum albumin by spectroscopic and molecular dynamics simulation techniques: A comparison study. AB - The interaction between losartan and human serum albumin (HSA), as well as its glycated form (gHSA) was studied by multiple spectroscopic techniques and molecular dynamics simulation under physiological conditions. The binding information, including the binding constants, effective quenching constant and number of binding sites showed that the binding partiality of losartan to HSA was higher than to gHSA. The findings of three-dimensional fluorescence spectra demonstrated that the binding of losartan to HSA and gHSA would alter the protein conformation. The distances between Trp residue and the binding sites of the drug were evaluated on the basis of the Forster theory, and it was indicated that non radiative energy transfer from HSA and gHSA to the losartan happened with a high possibility. According to molecular dynamics simulation, the protein secondary and tertiary structure changes were compared in HSA and gHSA for clarifying the obtained results. PMID- 27470662 TI - Carbapenem-resistant Enterobacteriaceae in special populations: Solid organ transplant recipients, stem cell transplant recipients, and patients with hematologic malignancies. AB - Carbapenem-resistant Enterobacteriaceae (CRE) are a major global public health concern and pose a serious threat to immunocompromised hosts, particularly patients with hematologic malignancies and solid organ (SOT) and stem cell transplant recipients. In endemic areas, carbapenem-resistant Klebsiella pneumoniae infections occur in 1-18% of SOT recipients, and patients with hematologic malignancies represent 16-24% of all patients with CRE bacteremia. Mortality rates approaching 60% have been reported in these patient populations. Early diagnosis and rapid initiation of targeted therapy is critical in the management of immunocompromised hosts with CRE infections, as recommended empiric regimens are not active against CRE. Therapeutic options are limited by antibiotic-associated toxicities, interactions with immunosuppressive agents, and paucity of antibiotic options currently available. Prevention of CRE infection in these patients requires a multidisciplinary approach involving hospital epidemiology and antimicrobial stewardship. Large, multicenter studies are needed to develop risk-stratification tools to assist in guiding the management of these individuals. PMID- 27470664 TI - Hyperuricemia, the kidneys, and the spectrum of associated diseases: a narrative review. AB - Hyperuricemia (elevated serum uric acid) is prevalent, and an important mediator of gout, an increasingly common condition. In addition, hyperuricemia is associated with metabolic syndrome, diabetes, hypertension, and kidney and cardiovascular diseases. Although it remains controversial whether hyperuricemia is a causal factor for kidney disease, the kidneys play a major role in the regulation of serum uric acid levels. Approximately two-thirds of the uric acid produced in humans is excreted by the kidneys. The handling of urate in the renal proximal tubule is extensive, as uric acid undergoes filtration, reabsorption, and secretion. Variations in renal urate handling have been shown to influence the risk of gout. In observational studies, hyperuricemia has been shown to predict kidney disease onset and progression, with a variety of mechanisms implicated. Because of this close association between hyperuricemia and kidney disease, and due to limited studies on the topic, it is important to conduct future studies on the treatment of hyperuricemia to slow kidney disease progression and improve cardiovascular survival in patients with chronic kidney disease. Furthermore, it is important to monitor for gout in patients with kidney disease and to follow the guidelines for treatment of hyperuricemia in this group of patients. This narrative review provides an in-depth discussion of the link between serum uric acid levels, renal handling of uric acid, and diseases associated with dysfunction in uric acid homeostasis. PMID- 27470665 TI - Treatment Outcomes and Tolerability Following Initiation of GLP-1 Receptor Agonists Among Type 2 Diabetes Patients in Primary Care Practices in Germany. AB - BACKGROUND: The aim was to investigate real-world treatment outcomes and tolerability of GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes in Germany. METHODS: Patients from 323 primary care practices who started any GLP-1RA therapy (89 Byetta, 108 Bydureon, 347 Victoza patients) between January 1, 2011, and December 31, 2013 (index date) were analyzed retrospectively (Disease Analyzer database, Germany). Changes from baseline in HbA1c, weight, and hypoglycemia were evaluated in 3 follow-up periods of 0-6, 7 12, and 13-18 months. RESULTS: A total of 544 diabetes patients (mean age: 57.9 years; men: 54%) were eligible for the study. Mean (SD) HbA1c (%) decreased from 8.3 (1.4) at baseline to 7.4 (1.2) in 6 months, 7.6 (1.3) in 7-12 months and 7.6 (1.4) in 13-18 months, respectively ( P < .001 for all), while the proportion of patients with HbA1c <7% increased from 15% at baseline to 38%, 36% and 35% in the corresponding periods ( P < .0001 for all). Multivariate-adjusted beta coefficients corresponding to changes in HbA1c (%) from baseline were -.52, -.44, and -.44, respectively, in the follow-up periods for baseline HbA1c (%) ( P < .0001 for all). The prevalence of hypoglycemia at baseline was 0.7%; this did not change significantly after treatment. CONCLUSIONS: In clinical practice, GLP-1RA treatment was associated with improved glycemic control without increased hypoglycemia for up to 18 months. The higher the baseline HbA1c, the greater the HbA1c reduction recorded. PMID- 27470666 TI - Bolus Calculator Settings in Well-Controlled Prepubertal Children Using Insulin Pumps Are Characterized by Low Insulin to Carbohydrate Ratios and Short Duration of Insulin Action Time. AB - BACKGROUND: The "500 rule" has been used extensively to find the insulin to carbohydrate ratio (ICR) for carbohydrate counting (CC). Duration of insulin action (DIA) is often recommended to be set to 4 hours. Data are lacking on validating these routines in young children. METHODS: ICR was calculated by dividing carbohydrate grams by insulin units. Insulin sensitivity factor (ISF) was defined by the 100 rule (100 divided by total daily insulin dose [TDD]). DIA was set to 3 hours. ICR, ISF, and DIA were adjusted continuously. Data for this retrospective analysis were taken from pump downloads at a routine visit. ICR and ISF were recalculated to rules (ICR/ISF multiplied by TDD). RESULTS: A total of 21 prepubertal children aged 7.0 +/- 2.3 (mean +/- SD), range 2-10 years, with diabetes duration 3.0 +/- 1.9, range 0.5-7.7 years, used the pump bolus calculator for CC. HbA1c IFCC (NGSP) was 53 +/- 6 mmol/mol (7.0 +/- 0.5%). None had experienced severe hypoglycemia (unconsciousness/seizures) since diabetes diagnosis. TDD was 0.7 +/- 0.1 U/kg/24 h (range 0.5-1.0), and the percentage basal insulin 38 +/- 11%. Median breakfast rule was 211 (Q, quartiles 162;310), and for other meals 434 (Q 301;496). Median ISF rule was 113 (Q 100;128) in the morning, and 120 (Q 104;134) during the rest of the day. DIA was 2.6 +/- 0.5 h (range 2-3) and target BG 5.3 +/- 0.4 mmol/l (range 5.0-6.0). CONCLUSIONS: Prepubertal children seem to need more bolus insulin for meals than calculated from the 500 rule, especially at breakfast, but less insulin for corrections than calculated from the 100 rule. Two to 3 hours seems to be the appropriate range for DIA in this age group. PMID- 27470668 TI - Gene transcription profiling in wild and laboratory-exposed eels: Effect of captivity and in situ chronic exposure to pollution. AB - Aquatic ecosystems are subjected to a variety of man-induced stressors but also vary spatially and temporally due to variation in natural factors. In such complex environments, it remains difficult to detect, dissociate and evaluate the effects of contaminants in wild organisms. In this context, the aim of this study was to test whether the hepatic transcriptome profile of fish may be used to detect in situ exposure to a particular contaminant. Transcriptomic profiles from laboratory-exposed and wild eels sampled along a contamination gradient were compared. During laboratory experiments, fish were exposed during 45days to different pollutants (Hg, PCBs, OCPs or Cd) or natural factors (temperature, salinity or low food supply) at levels close to those found in the sampling sites. A strong difference was observed between the transcriptomic profiles obtained from wild and laboratory-exposed animals (whatever the sites or experimental conditions), suggesting a general stress induced by captivity in the laboratory. Among the biological functions that were up-regulated in laboratory eels in comparison to wild eels, histone modification was the most represented. This finding suggests that laboratory conditions could affect the epigenome of fish and thus modulate the transcriptional responses developed by fish in response to pollutant exposure. Among experimental conditions, only the transcription profiles of laboratory animals exposed to cold temperature were correlated with those obtained from wild fish, and more significantly with fish from contaminated sites. Common regulated genes were mainly involved in cell differentiation and liver development, suggesting that stem/progenitor liver cells could be involved in the adaptive response developed by fish chronically exposed to pollutant mixtures. PMID- 27470667 TI - Toxicity of natural mixtures of organic pollutants in temperate and polar marine phytoplankton. AB - Semivolatile and persistent organic pollutants (POPs) undergo atmospheric transport before being deposited to the oceans, where they partition to phytoplankton organic matter. The goal of this study was to determine the toxicity of naturally occurring complex mixtures of organic pollutants to temperate and polar phytoplankton communities from the Mediterranean Sea, the North East (NE) Atlantic, and Southern Oceans. The cell abundance of the different phytoplankton groups, chlorophyll a concentrations, viability of the cells, and growth and decay constants were monitored in response to addition of a range of concentrations of mixtures of organic pollutants obtained from seawater extracts. Almost all of the phytoplankton groups were significantly affected by the complex mixtures of non-polar and polar organic pollutants, with toxicity being greater for these mixtures than for single POPs or simple POP mixtures. Cocktails' toxicity arose at concentrations as low as tenfold the field oceanic levels, probably due to a higher chemical activity of the mixture than of simple POPs mixtures. Overall, smaller cells were the most affected, although Mediterranean picophytoplankton was significantly more tolerant to non-polar POPs than picophytoplankton from the Atlantic Ocean or the Bellingshausen Sea microphytoplankton. PMID- 27470670 TI - Evaluating SoilGen2 as a tool for projecting soil evolution induced by global change. AB - To protect soils against threats, it is necessary to predict the consequences of human activities and global change on their evolution on a ten to hundred year time scale. Mechanistic modelling of soil evolution is then a useful tool. We analysed the ability of the SoilGen model to be used for projections of soil characteristics associated to various soil threats: vertical distributions of <2MUm fraction, organic carbon content (OC), bulk density and pH. This analysis took the form of a functional sensitivity analysis in which we varied the initial conditions (parent material properties) and boundary conditions (co-evolution of precipitation and temperature; type and amount of fertilization and tillage as well as duration of agriculture). The simulated scenario variants comprised anthroposequences in Luvisols at two sites with one default scenario, six variants for initial conditions and 12 variants for boundary conditions. The variants reflect the uncertainties to our knowledge of parent material properties or reconstructed boundary conditions. We demonstrated a sensitivity of the model to climate and agricultural practices for all properties. We also conclude that final model results are not significantly affected by the uncertainties of boundary conditions for long simulations runs, although influenced by uncertainties on initial conditions. The best results were for organic carbon, although improvements can be reached through calibration or by incorporating a dynamic vegetation growth module in SoilGen. Results were poor for bulk density due to a fixed-volume assumption in the model, which is not easily modified. The <2MUm fraction depth patterns are reasonable but the process of clay new formation needs to be added to obtain the belly shape of the Bt horizon. After calibration for organic carbon under agriculture, the model is suitable for producing soil projections due to global change. PMID- 27470669 TI - Variations of fine particle physiochemical properties during a heavy haze episode in the winter of Beijing. AB - Chemical composition, morphology, size and mixture of fine particles were measured in a heavy haze and the post-haze air in Beijing in January 2012. With the occurrence of haze, the concentrations of gaseous and particulate pollutants including organics, sulfate, nitrate, and ammonium grew gradually. The hourly averaged PM2.5 concentration increased from 118MUgm(-3) to 402MUgm(-3) within 12h. In contrast, it was less than 10MUgm(-3) in the post-haze air. Occupying approximately 46% in mass, organics were the major component of PM1 in both the haze and post-haze air. Analysis of individual particles in the size range of 0.2 1.1MUm revealed that secondary-like particles and soot particles were always the majority, and most soot particles had a core-shell structure. The number ratio of secondary-like particles to soot particles in accumulation mode in the haze air was about 2:1, and that in the post-haze air was 8:1. These results indicate both secondary particle formation and primary emission contributed substantially to the haze. The mode size of the haze particles was about 0.7MUm, and the mode size of the post-haze particles was 0.4MUm, indicating the remarkable growth of particles in haze. However, the ratios of the core size to shell size of core shell structure soot particles in the haze were similar to those in the post-haze air, suggesting a quick aging of soot particles in either the haze air or the post-haze air. PMID- 27470671 TI - Evaluation of leaf removal as a means to reduce nutrient concentrations and loads in urban stormwater. AB - While the sources of nutrients to urban stormwater are many, the primary contributor is often organic detritus, especially in areas with dense overhead tree canopy. One way to remove organic detritus before it becomes entrained in runoff is to implement a city-wide leaf collection and street cleaning program. Improving our knowledge of the potential reduction of nutrients to stormwater through removal of leaves and other organic detritus on streets could help tailor more targeted municipal leaf collection programs. This study characterized an upper ideal limit in reductions of total and dissolved forms of phosphorus and nitrogen in stormwater through implementation of a municipal leaf collection and street cleaning program in Madison, WI, USA. Additional measures were taken to remove leaf litter from street surfaces prior to precipitation events. Loads of total and dissolved phosphorus were reduced by 84 and 83% (p<0.05), and total and dissolved nitrogen by 74 and 71% (p<0.05) with an active leaf removal program. Without leaf removal, 56% of the annual total phosphorus yield (winter excluded) was due to leaf litter in the fall compared to 16% with leaf removal. Despite significant reductions in load, total nitrogen showed only minor changes in fall yields without and with leaf removal at 19 and 16%, respectively. The majority of nutrient concentrations were in the dissolved fraction making source control through leaf removal one of the few treatment options available to environmental managers when reducing the amount of dissolved nutrients in stormwater runoff. Subsequently, the efficiency, frequency, and timing of leaf removal and street cleaning are the primary factors to consider when developing a leaf management program. PMID- 27470672 TI - Linking environment-productivity trade-offs and correlated uncertainties: Greenhouse gas emissions and crop productivity in paddy rice production systems. AB - In comparative life cycle assessments of agricultural production systems, analyses of both the trade-offs between environmental impacts and crop productivity and of the uncertainties specific to agriculture such as fluctuations in greenhouse gas (GHG) emissions and crop yields are crucial. However, these two issues are usually analyzed separately. In this paper, we present a framework to link trade-off and uncertainty analyses; correlated uncertainties are integrated into environment-productivity trade-off analyses. We compared three rice production systems in Japan: a system using a pelletized, nitrogen-concentrated organic fertilizer made from poultry manure using closed air composting techniques (high-N system), a system using a conventional organic fertilizer made from poultry manure using open-air composting techniques (low-N system), and a system using a chemical compound fertilizer (conventional system). We focused on two important sources of uncertainties in paddy rice cultivation methane emissions from paddy fields and crop yields. We found trade-offs between the conventional and high-N systems and the low-N system and the existence of positively correlated uncertainties in the conventional and high-N systems. We concluded that our framework is effective in recommending the high-N system compared with the low-N system, although the performance of the former is almost the same as the conventional system. PMID- 27470673 TI - Comparing molecular composition of dissolved organic matter in soil and stream water: Influence of land use and chemical characteristics. AB - Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS) was used to examine the molecular composition of dissolved organic matter (DOM) from soils under different land use regimes and how the DOM composition in the catchment is reflected in adjacent streams. The study was carried out in a small area of the Schwingbach catchment, an anthropogenic-influenced landscape in central Germany. We investigated 30 different soil water samples from 4 sites and different depths (managed meadow (0 5cm, 40-50cm), deciduous forest (0-5cm), mixed-coniferous forest (0-5cm) and agricultural land (0-5cm, 40-50cm)) and 8 stream samples. 6194 molecular formulae and their magnitude-weighted parameters ((O/C)w, (H/C)w, (N/C)w, (AI-mod)w, (DBE/C)w, (DBE/O)w, (DBE-O)w, (C#)w, (MW)w) were used to describe the molecular composition of the samples. The samples can be roughly divided in three groups. Group 1 contains samples from managed meadow 40-50cm and stream water, which are characterized by high saturation compared to samples from group 2 including agricultural samples and samples from the surface meadow (0-5cm), which held more nitrogen containing and aromatic compounds. Samples from both forested sites (group 3) are characterized by higher molecular weight and O/C ratio. Environmental parameters vary between sites and among these parameters pH and nitrate significantly affect chemical composition of DOM. Results indicate that most DOM in streams is of terrestrial origin. However, 120 molecular formulae were detected only in streams and not in any of the soil samples. These compounds share molecular formulae with peptides, unsaturated aliphatics and saturated FA CHO/FA-CHOX. Compounds only found in soil samples are much more aromatic, have more double bonds and a much lower H/C ratio but higher oxygen content, which indicates the availability of fresh plant material and less microbial processed material compared to stream samples. PMID- 27470674 TI - Diet, bite force and skull morphology in the generalist rodent morphotype. AB - For many vertebrate species, bite force plays an important functional role. Ecological characteristics of a species' niche, such as diet, are often associated with bite force. Previous evidence suggests a biomechanical trade-off between rodents specialized for gnawing, which feed mainly on seeds, and those specialized for chewing, which feed mainly on green vegetation. We tested the hypothesis that gnawers are stronger biters than chewers. We estimated bite force and measured skull and mandible shape and size in 63 genera of a major rodent radiation (the myomorph sigmodontines). Analysis of the influence of diet on bite force and morphology was made in a comparative framework. We then used phylogenetic path analysis to uncover the most probable causal relationships linking diet and bite force. Both granivores (gnawers) and herbivores (chewers) have a similar high bite force, leading us to reject the initial hypothesis. Path analysis reveals that bite force is more likely influenced by diet than the reverse causality. The absence of a trade-off between herbivores and granivores may be associated with the generalist nature of the myomorph condition seen in sigmodontine rodents. Both gnawing and chewing sigmodontines exhibit similar, intermediate phenotypes, at least compared to extreme gnawers (squirrels) and chewers (chinchillas). Only insectivorous rodents appear to be moving towards a different direction in the shape space, through some notable changes in morphology. In terms of diet, natural selection alters bite force through changes in size and shape, indicating that organisms adjust their bite force in tandem with changes in food items. PMID- 27470675 TI - Identification of excitatory premotor interneurons which regulate local muscle contraction during Drosophila larval locomotion. AB - We use Drosophila larval locomotion as a model to elucidate the working principles of motor circuits. Larval locomotion is generated by rhythmic and sequential contractions of body-wall muscles from the posterior to anterior segments, which in turn are regulated by motor neurons present in the corresponding neuromeres. Motor neurons are known to receive both excitatory and inhibitory inputs, combined action of which likely regulates patterned motor activity during locomotion. Although recent studies identified candidate inhibitory premotor interneurons, the identity of premotor interneurons that provide excitatory drive to motor neurons during locomotion remains unknown. In this study, we searched for and identified two putative excitatory premotor interneurons in this system, termed CLI1 and CLI2 (cholinergic lateral interneuron 1 and 2). These neurons were segmentally arrayed and activated sequentially from the posterior to anterior segments during peristalsis. Consistent with their being excitatory premotor interneurons, the CLIs formed GRASP- and ChAT-positive putative synapses with motoneurons and were active just prior to motoneuronal firing in each segment. Moreover, local activation of CLI1s induced contraction of muscles in the corresponding body segments. Taken together, our results suggest that the CLIs directly activate motoneurons sequentially along the segments during larval locomotion. PMID- 27470676 TI - African American Race Is Associated With Poorer Outcomes in Heart Failure Patients. AB - Health care disparities associated with African American race may influence event free survival in patients with heart failure (HF). A secondary data analysis included 863 outpatients enrolled in a multicenter HF registry. Cox regression was used to determine whether African American race was associated with shorter HF event-free survival after controlling for covariates. The multivariable adjusted hazard ratios (95% confidence intervals [CI]) of older age (1.03, 95% CI = [1.01, 1.04]), New York Heart Association (NYHA) functional class (1.73, 95% CI = [1.29, 2.31]), depressive symptoms (1.05, 95% CI = [1.02, 1.07]), and African American race (1.64, 95% CI = [1.01, 2.68]) were predictors of shorter event-free survival (all ps < .05). Comparisons showed that NYHA functional class was predictive of shorter event-free survival in Caucasians (1.81, 95% CI = [1.33, 2.46]) but not in African Americans (1.24, 95% CI = [.40, 3.81]). African Americans with HF experienced a disparate risk of shorter event-free survival not explained by a variety of risk factors. PMID- 27470677 TI - Using Embedded Sensors in Independent Living to Predict Gait Changes and Falls. AB - This study explored using Big Data, totaling 66 terabytes over 10 years, captured from sensor systems installed in independent living apartments to predict falls from pre-fall changes in residents' Kinect-recorded gait parameters. Over a period of 3 to 48 months, we analyzed gait parameters continuously collected for residents who actually fell ( n = 13) and those who did not fall ( n = 10). We analyzed associations between participants' fall events ( n = 69) and pre-fall changes in in-home gait speed and stride length ( n = 2,070). Preliminary results indicate that a cumulative change in speed over time is associated with the probability of a fall ( p < .0001). The odds of a resident falling within 3 weeks after a cumulative change of 2.54 cm/s is 4.22 times the odds of a resident falling within 3 weeks after no change in in-home gait speed. Results demonstrate using sensors to measure in-home gait parameters associated with the occurrence of future falls. PMID- 27470678 TI - Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification. AB - Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivo and in vitro rodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification. Cell mineralization studies showed that elevated inorganic phosphate rapidly induced VSMC calcification. Hypoxia strongly enhanced elevated inorganic phosphate-induced VSMC calcification and osteogenic transdifferentiation, as seen by osteogenic marker expression. Hypoxia-inducible factor-1 (HIF-1), the key hypoxic transcription factor, was essential for enhanced VSMC calcification. Targeting HIF-1 expression in murine VSMC blocked calcification in hypoxia with elevated inorganic phosphate while HIF-1 activators, including clinically used FG 4592/Roxadustat, recreated a procalcifying environment. Elevated inorganic phosphate rapidly activated HIF-1, even in normal oxygenation; an effect mediated by HIF-1alpha subunit stabilization. Thus, hypoxia synergizes with elevated inorganic phosphate to enhance VSMC osteogenic transdifferentiation. Our work identifies HIF-1 as an early CKD-related pathological event, prospective marker, and potential target against vascular calcification in CKD-relevant conditions. PMID- 27470679 TI - C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E. AB - Acute kidney injury (AKI) is exacerbated in C-reactive protein transgenic mice but alleviated in Smad3 knockout mice. Here we used C-reactive protein transgenic/Smad3 wild-type and C-reactive protein transgenic/Smad3 knockout mice to investigate the signaling mechanisms by which C-reactive protein promotes AKI. Serum creatinine was elevated, and the extent of tubular epithelial cell necrosis following ischemia/reperfusion-induced AKI was greater in C-reactive protein transgenics but was blunted when Smad3 was deleted. Exacerbation of AKI in C reactive protein transgenics was associated with increased TGF-beta/Smad3 signaling and expression of the cyclin kinase inhibitor p27, but decreased phosphorylated CDK2 and expression of cyclin E. Concomitantly, tubular epithelial cell proliferation was arrested at the G1 phase in C-reactive protein transgenics with fewer cells entering the S-phase cell cycle as evidenced by fewer bromodeoxyuridine-positive cells. In contrast, the protection from AKI in C reactive protein transgenic/Smad3 knockout mice was associated with decreased expression of p27 and promotion of CDK2/cyclin E-dependent G1/S transition of tubular epithelial cells. In vitro studies using tubular epithelial cells showed that C-reactive protein activates Smad3 via both TGF-beta-dependent and ERK/MAPK cross talk mechanisms, Smad3 bound directly to p27, and blockade of Smad3 or the Fc receptor CD32 prevented C-reactive protein-induced p27-dependent G1 cell cycle arrest. In vivo, treatment of C-reactive protein transgenics with a Smad3 inhibitor largely improved AKI outcomes. Thus, C-reactive protein may promote AKI by impairing tubular epithelial cell regeneration via the CD32-Smad3-p27-driven inhibition of the CDK2/cyclin E complex. Targeting Smad3 may offer a new treatment approach for AKI. PMID- 27470680 TI - Transitioning from parenteral to inhaled prostacyclin therapy in pulmonary arterial hypertension. AB - BACKGROUND: Parenteral prostacyclin therapy for PAH has allowed for improvements in functional status, quality of life and mortality. Parenteral therapies however carry an increased risk of line-associated complications. Inhaled prostacyclins are an attractive alternative therapy; however, limited data exists supporting the safety and outcomes after transition. METHODS: We describe a retrospective observational analysis of adults with PAH who were transitioned from a parenteral prostacyclin to inhaled treprostinil at our institution. Endpoints include duration of transition, hospital length of stay, adverse effects during transition, and cardiopulmonary function post transition. RESULTS: Eight patients were included, all of which were on triple therapy. Seven patients receiving intravenous prostacyclin therapy were transitioned in an ICU setting, while one patient was transitioned from subcutaneous treprostinil as an outpatient. The average ICU and hospital length of stay was 4.1 +/- 0.7 days. Patient preference was the most common reason for transition (n = 5), followed by line complication (n = 2), and intolerance to parenteral therapy (n = 1). One adverse event was observed while initiating inhaled treprostinil that only required slowing of the transition process. On follow-up (19.6 +/- 11.1 months) functional class did not change, and non-parametric test showed no change in 6MWD after transition (p = 0.62). One patient failed inhaled therapy necessitating transition back to intravenous therapy. CONCLUSION: Transitioning patients from parenteral to inhaled prostacyclin therapy can be safely accomplished in specialized centers over a 48-72 h period. Patient preference was overwhelming the most prevalent reason for transition. PMID- 27470681 TI - Efficacy of tranexamic acid in haemoptysis: A randomized, controlled pilot study. AB - BACK GROUND: Haemoptysis is a life threatening condition irrespective of aetiology. Tranexamic acid (TA), a potent anti-fibrinolytic agent, has been shown to control bleeding, decrease transfusion requirement in knee & hip arthroplasty, coronary artery bypass grafting and heavy menstrual bleeding. TA also has mortality benefit in bleeding from surgical and trauma patients. But the studies, regarding efficacy and safety of TA in controlling haemoptysis are conflicting. METHOD: In this single blinded, prospective study, total 66 patients with sub massive haemoptysis were randomized into treatment (T) and placebo control (C) groups. Group-T received intravenous (IV) TA in a loading dose of 1 g, followed by 1 g TA over 8 h infusion and group-C received IV 0.9% normal saline. The severity of haemoptysis was assessed by quantity, frequency and visual analogue scale (VAS) score. RESULTS: On day 2, frequency, quantity and VAS score of haemoptysis were 2.23 +/- 2.11/day, 34.19 +/- 67.0 ml and 14.72 +/- 15.7 respectively in Group-T and 2.29 +/- 2.0/day, 90.4 +/- 79.0 ml and 31.33 +/- 22.12 respectively in group-C. In group-T 16.27% patients needed intervention as compared to 38.1% in group-C (p 0.053). The mean blood transfusion (1.58 +/- 0.88 & 1.67 +/- 0.669 units) and hospital stay (4.14 +/- 3.18 & 5.48 +/- 3.26 days) was also lower in group-T as compared to group-C. Group-T had better outcomes as compared to group-C, but statistically significant only for VAS score (p 0.001). During study no adverse event of the drug was noted. CONCLUSION: TA decreases severity of haemoptysis and can be used as a bridging therapy in acute haemoptysis before definitive intervention can be under taken. PMID- 27470682 TI - Evaluation of adiponectin profile in Italian patients affected by obstructive sleep apnea syndrome. AB - Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder; obesity represents a major risk factor for the development and progression of OSAS although obese patients do not necessarily suffer from OSAS. Adipose tissue communicates with lung in both physiologic and pathologic conditions through the production of adipokines, hormones active in metabolic and inflammatory processes. To explore the extent to which Acrp30 impacts on pathophysiology of OSAS and whether these proteins could be considered as targets for both diagnosis and therapy through enzyme-linked immunosorbent assay, western blotting analysis and fast protein liquid chromatography we have analyzed total levels as well as oligomer distribution in OSAS patients. Our data demonstrated that total Acrp30 serum levels were statistically reduced in OSAS patients compared to controls (p value = 0.02). Within a selected subgroup of OSAS patients with a BMI<30, Acrp30 levels were still statistically lower in OSAS than in control group (p value < 0.05). In addition, more severe patients (AHI>15) exhibited a more pronounced reduction of Acrp30 levels. Interestingly, this reduction is mainly due to a specific decrease of the HMW oligomers, those exhibiting major biological significance. In conclusion, our results strongly suggest a role for Acrp30 oligomerization in OSAS; in fact, the down-regulation of Acpr30 and its HMW oligomers seems to be correlated to illness status independently of concomitant presence of obesity. In addition, this reduction is mainly due to the high-weight oligomers of Acrp30 suggesting a functional role of this adipokine in OSAS. PMID- 27470683 TI - School Nurses on the Front Lines of Medicine: An Adolescent Female Student with Severe Abdominal Pain. AB - Abdominal pain is a common chief complaint encountered by school nurses. This article explains the etiology of abdominal pain in children and adolescents, describes the office assessment, and delineates life-threatening conditions associated with severe abdominal pain that may prompt the school nurse to transfer the student to a local emergency department. PMID- 27470684 TI - Evaluation of QuantiFERON-TB Gold Plus for Detection of Mycobacterium tuberculosis infection in Japan. AB - Performance of interferon-gamma (IFN-gamma) release assays still needs to be improved. The data on the performance of QuantiFERON-TB Gold Plus (QFT-Plus), a new-generation of QFT assay are limited. This study evaluated the diagnostic performance of QFT-Plus, and compared to that of QuantiFERON-TB Gold In-Tube (QFT GIT). Blood samples were collected from 162 bacteriologically confirmed tuberculosis (TB) patients and 212 Mycobacterium tuberculosis-uninfected volunteers; these samples were then tested with QFT-GIT and QFT-Plus. The IFN gamma concentration of QFT-Plus was lower than that of QFT-GIT in TB patients (p < 0.001). Receiver operating characteristic curves were compared between QFT-GIT and QFT-Plus. Both assays showed area under the curve values over 0.99 without significant difference. Using the conventional cut-off (0.35 IU/mL) for QFT-GIT, QFT-Plus had a lower sensitivity of 91.1% compared to 96.2% (p = 0.008) at its optimum cut-off (0.168 IU/mL) with the same specificity. Moreover, IFN-gamma values were significantly reduced with age in QFT-GIT (p = 0.035) but not in QFT Plus. The diagnostic performance of QFT-Plus was as accurate as that of QFT-GIT despite a lack of TB7.7 antigen and despite the decrease in quantitative values. However, the cut-off value for QFT-Plus should be considered independently from that of QFT-GIT to obtain the best sensitivity without compromising specificity. PMID- 27470685 TI - Histopathological and genetic analysis of extraocular muscle in chronic progressive external ophthalmoplegia. PMID- 27470686 TI - Continuing Delay in the Diagnosis of Slipped Capital Femoral Epiphysis. AB - OBJECTIVE: To evaluate whether the time from symptom onset to diagnosis of slipped capital femoral epiphysis (SCFE) has improved over a recent decade compared with reports of previous decades. STUDY DESIGN: Retrospective review of 481 patients admitted with a diagnosis of SCFE at three large pediatric hospitals between January 2003 and December 2012. RESULTS: The average time from symptom onset to diagnosis of SCFE was 17 weeks (range, 0-to 169). There were no significant differences in time from symptom onset to diagnosis across 2-year intervals of the 10-year study period (P = .94). The time from evaluation by first provider to diagnosis was significantly shorter for patients evaluated at an orthopedic clinic (mean, 0 weeks; range, 0-0 weeks) compared with patients evaluated by a primary care provider (mean, 4 weeks; range, 0-52 weeks; r = 0.24; P = .003) or at an emergency department (mean, 6 weeks, range, 0-104 weeks; r = 0.36; P = .008). Fifty-two patients (10.8%) developed a second SCFE after treatment of the first affected side. The time from the onset of symptoms to diagnosis for the second episode of SCFE was significantly shorter (r = 0.19; P < .001), with mean interval of 11 weeks (range, 0-104 weeks) from symptom onset to diagnosis. There were significantly more cases of mildly severe SCFE, as defined by the Wilson classification scheme, in second episodes of SCFE compared with first episodes of SCFE (OR, 4.44; P = .001). CONCLUSION: Despite reports documenting a lag in time to the diagnosis of SCFE more than a decade ago, there has been no improvement in the speed of diagnosis. Decreases in both the time to diagnosis and the severity of findings for the second episode of SCFE suggest that the education of at-risk children and their families (or providers) may be of benefit in decreasing this delay. PMID- 27470687 TI - Body Mass Index at 3 Years of Age: Cascading Effects of Prenatal Maternal Depression and Mother-Infant Dynamics. AB - OBJECTIVE: To investigate the effects of mothers' prenatal depression on parenting during infancy, ensuing childhood regulation, and body mass index (BMI) at age 3 years. STUDY DESIGN: The sample (N = 284) included teen mothers (n = 157), adult mothers with low education (n = 69), and adult mothers with high education (n = 58), and their first-born children. Maternal depressive symptoms were assessed prenatally through self-report; observational methods and self report were used to assess mothers' parenting at 4, 6, and 8 months and children's regulation at 18, 24, and 30 months of age. Child BMI was measured at 36 months of age in the laboratory. RESULTS: Structural equation modeling supported mediating processes such that mothers who reported more depressive symptoms prenatally exhibited less positive parenting during infancy. In turn, less positive parenting predicted lower levels of child regulation during toddlerhood, which predicted higher child BMIs at 36 months of age, even after controlling for infant birth weight and concurrent maternal BMI. Models comparing groups (teen mothers, adult low-educated mothers, and adult-high educated mothers) indicated mean differences in maternal depression, parenting, and child regulation, but similar patterns of prediction across groups. CONCLUSIONS: The present study provides evidence of cascading psychosocial processes beginning prenatally and continuing through infancy, toddlerhood, and into early childhood. Results have implications for family-wide intervention strategies to help lower the risk for early onset obesity in children. PMID- 27470688 TI - Intubation Attempts Increase the Risk for Severe Intraventricular Hemorrhage in Preterm Infants-A Retrospective Cohort Study. AB - OBJECTIVE: To evaluate whether neonates exposed to multiple intubation attempts within the first 4 days after birth have an increased incidence of intraventricular hemorrhage (IVH). STUDY DESIGN: This is a retrospective cohort study of infants intubated during the first 4 days after birth. Infants had birth weights (BWs) less than 1500 g and were admitted to the neonatal intensive care unit (NICU) at the University of California, San Diego, between January 1, 2005, and July 30, 2009. A subgroup analysis was done for infants with BW less than 750 g. RESULTS: A total of 308 infants with BW <1500 g, including 102 with a BW <750 g, were intubated within the first 4 days of life. The number of intubation attempts was significantly greater in infants with a BW <750 g who had severe IVH compared with those with mild or no IVH (OR 1.395, 95% CI 1.090-1.786, P = .008). For infants with BW <1500 g, the number of intubation attempts in the delivery room was significantly greater for infants with severe IVH (OR 1.317, 95% CI 1.052-1.649, P = .016). CONCLUSION: Increased intubation attempts were associated with increased incidence of severe IVH in infants with BW less than 750 g and in infants less than 1500 g who were intubated only in the delivery room. Prospective studies are needed to further evaluate the relationship between intubation attempts and severe IVH. PMID- 27470689 TI - In-Toeing Is Often a Primary Care Orthopedic Condition. AB - OBJECTIVE: To evaluate in-toeing consults to a pediatric orthopedic clinic to determine the proportion that could be managed by a primary care physician. STUDY DESIGN: A prospective registry was created for 143 consecutive children referred to a pediatric orthopedic clinic for "in-toeing." Each patient underwent a careful history and physical examination, which included a rotational profile. We recorded the final diagnosis, treatment offered, follow-up visit results, and the source of the referral. RESULTS: After pediatric orthopedic evaluation, 85% of patients had a confirmed diagnosis of in-toeing, and 15% had a different final diagnosis. Seventy-four percent of patients had 1 consultation visit, 18% had 2, and 8% had >2 visits. None of the referred patients was a candidate for treatment by casting or surgery. CONCLUSION: In most cases, in-toeing is a normal variation of development that can be managed by counseling and observation by the primary care physician alone. Rare cases of severe in-toeing >2 standard deviations from the mean should likely still prompt referral to a pediatric orthopedic surgeon for potential intervention. PMID- 27470690 TI - Papilledema and Spinal Ependymoma: When Eyes are Windows to the Spinal Cord. PMID- 27470691 TI - Sex hormone binding globulin and anti-tumor necrosis factor-alpha therapy. PMID- 27470692 TI - Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns. AB - OBJECTIVE: To assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent association of CSO with BPD or death. STUDY DESIGN: We performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at <=28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure. RESULTS: In the study infants, mean gestational age at birth was 25.2 +/- 1.2 weeks and mean birth weight was 700 +/- 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P < .0001), which corresponds to a 7% higher daily supplemental oxygen value. CONCLUSION: In high risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD. PMID- 27470693 TI - 18-Month Follow-Up of Infants Cared for in a Single-Family Room Neonatal Intensive Care Unit. AB - OBJECTIVES: To determine whether the single-family room (SFR)-neonatal intensive care unit (NICU) is associated with improved 18-month neurodevelopmental outcome, especially in infants of mothers with high maternal involvement. STUDY DESIGN: An 18-month follow-up was undertaken that compared infants born <30 weeks gestational age; 123 from a SFR-NICU vs 93 from an open-bay NICU. Infants were divided into high vs low maternal involvement based on days/week of kangaroo care, breast/bottle feeding, and maternal care. Infants with high vs low maternal involvement in the SFR and open-bay NICUs were compared on the Bayley Cognitive, Language, and Motor scores and Pervasive Developmental Disorders autism screen. RESULTS: There were more mothers in the high maternal involvement SFR than in the high maternal involvement open-bay group (P = .002). Infants with high maternal involvement in both NICUs had greater Cognitive (P = .029) and Language (P < .000) scores than infants with low maternal involvement. Effect sizes within NICU were moderate to large in the SFR-NICU for Language scores and moderate for the Language composite in the open-bay NICU. The number of days of maternal involvement was greater in the SFR than open-bay NICU (P < .000), and length of stay was shorter in the high maternal involvement SFR than high maternal involvement open-bay NICU (P = .024). Kangaroo and maternal care predicted Cognitive (kangaroo, P = .003) and Language scores (P = .015, P = .032, respectively). Infants with >=1 symptom of autism were more likely to be in the open-bay low maternal involvement group vs the SFR high maternal involvement group (OR = 4.91, 95% CI = 2.2-11.1). CONCLUSIONS: High maternal involvement is associated with improved 18-month neurodevelopmental outcome, especially in infants cared for in a SFR-NICU. PMID- 27470695 TI - Development of simple high-precision two-dimensional dose-distribution measurement method for proton beam therapy using imaging plate and EBT3. AB - Although there are several two-dimensional (2D) dose-distribution measurement methods using proton beam therapy, they all have drawbacks; hence, there is no standard method established worldwide. The purpose of this study was to develop a simple, high-precision 2D distribution measurement method for proton beam therapy that uses an imaging plate and EBT3. First, we expanded the maximum readable dose (saturation dose) in the imaging plate. The method involves (i) the control of the fading phenomenon by an annealing process and (ii) the control of the photostimulated luminescence (PSL) phenomenon using a longpass filter (LPF). In method (i), upon heating at 80 degrees C, the PSL became 0.485 times the room temperature, and in method (ii), we attenuated the PSL by a factor of 0.245 using an LPF. Thus, by combining methods (i) and (ii), we expanded the saturation dose to 2 Gy. Thus, it was possible to measure the imaging plate and EBT3 in the same dose range. We simultaneously measured the percent depth dose using imaging plate and EBT3. We defined a correction factor to match the measured values-which had a reduced sensitivity because of the linear energy transfer (LET) dependence of the imaging plate and EBT3-with reference data and developed a correction factor function. Subsequently, by defining the relative LET dependence of imaging plate and EBT3 as the relative sensitivity and converting the relationship imaging plate between the relative sensitivity and correction factor into a function, we obtained a sensitivity-correction function. By employing this function, measurements with the same accuracy as the reference data were performed using the imaging plate and EBT3. PMID- 27470694 TI - Gestational Age and Kindergarten School Readiness in a National Sample of Preterm Infants. AB - OBJECTIVE: To examine the association of gestational age with school readiness in kindergarten reading and math skills. We hypothesized that compared with infants born at 39-41 weeks, infants born at lower gestational ages would have poorer school readiness. STUDY DESIGN: The study sample comprised 5250 children from the Early Childhood Longitudinal Study, Birth Cohort, assessed with specialized reading and math assessments at kindergarten. Poor school readiness was characterized by reading and math theta scores >=1.5 SD below the sample mean. The aOR and 95% CI of poor school readiness were estimated using multivariate logistic regression, examining gestational age continuously and categorically (very preterm [VPT], moderate/late preterm [M/LPT], early term [ET], and term). Pairwise comparisons were performed to test for differences by gestational age category. RESULTS: There was an association between gestational age and poor school readiness for reading and math, with the suggestion of a threshold effect in children born at >=32 weeks gestation. In adjusted models, in VPT infants, the aORs of poor school readiness in reading and math were 2.58 (95% CI, 1.29-5.15) and 3.38 (95% CI, 1.66-6.91), respectively. For infants born M/LPT and ET, the odds of poor school readiness in reading did not differ from those of children born full-term, however. CONCLUSIONS: Compared with term infants, the highest odds of poor school readiness in reading and math were seen in VPT infants, with lower odds of poor school readiness in children born at >=32 weeks gestation. Ongoing developmental surveillance before kindergarten is indicated for VPT infants. PMID- 27470696 TI - Solar degradation of diclofenac using Eosin-Y-activated TiO2: cost estimation, process optimization and parameter interaction study. AB - Diclofenac (DCF), a widely used non-steroidal anti-inflammatory drug, is a commonly detected substance that readily accumulates in tissues of aquatic fish and poses a threat to wildlife and freshwater quality. Advanced Oxidation Processes have been employed as an alternative due to the inadequacy of conventional treatment methods of trace contaminants. This study utilized an innovative method of solar-activation of TiO2 using Eosin-Y dye for the degradation of DCF. Furthermore, the study incorporated a central composite design (CCD) to optimize the dye concentration and estimated the cost for the present process. Optimized parameters for light intensity (750 mW/cm2), Eosin-Y dye concentration (2 mg/L), TiO2 loading (37.5 mg/cm2) and DCF concentration (25 mg/L) were determined through a CCD. The optimized parameters convey a DCF degradation rate of 40% and 49% for 2 ppm (low range) and 4 ppm (high range) dye concentrations, respectively, for a 5-minute reaction time. Cost estimation for the materials used was for the current process was also performed. It was determined that the additional cost of using 4 ppm instead of 2 ppm to achieve only 10% more DCF degradation is not warranted and would require additional treatment to remove subsequently formed halogenated compounds. PMID- 27470697 TI - Endoscopic posterior cricoid split with costal cartilage graft: A fifteen-year experience. AB - OBJECTIVE: To evaluate outcomes of the endoscopic posterior cricoid split with rib graft (EPCS/RG) procedure in the treatment of subglottic stenosis (SGS), posterior glottic stenosis (PGS), and bilateral vocal fold immobility (BVFI). STUDY DESIGN: Retrospective chart review. METHODS: Chart review of all patients who underwent EPCS/RG at a single tertiary-care facility between 1999 and 2014. Patients were grouped based on the primary indication for the procedure. Decannulation was the primary endpoint. Secondary endpoints were the number of subsequent airway procedures and length of hospitalization. RESULTS: Thirty-three patients were identified; 32 had tracheotomy. Overall decannulation rate was 65.6%. Subgroup analysis demonstrated the following decannulation rates: 53.8% for SGS, 100% for PGS, and 28.6% for BVFI. Fisher exact test found a significant difference in overall decannulation rates between groups (P = 0.002). Operation specific decannulation rates for patients who never required an open procedure were 23% for SGS, 91.6% for PGS, and 28.6% for BVFI. This difference was also statistically significant (P = 0.001). Multivariate logistic regression analysis found prematurity had a positive correlation with decannulation that approached statistical significance (P < 0.051; odds ratio 6.1; 95% confidence interval 0.99, 37.6). The percentage of patients who underwent repeat airway procedures for the groups was 61.5% for SGS, 16.6 % for PGS, and 14.3% for BVFI. The median length of hospitalization after EPCS/RG was 3 days. CONCLUSION: This represents the largest series of patients who have undergone EPCS/RG and demonstrates that the majority of patients can be decannulated after this procedure. Patients with PGS had the highest operation-specific decannulation rates. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:252-257, 2017. PMID- 27470698 TI - Role of the antioxidant defence system and telomerase in arsenic-induced genomic instability. AB - Arsenic (AS) is a reactive oxygen species (ROS)-inducer carcinogen, whose mode of action is still unclear. To defend against ROS, cells use enzymatic and non enzymatic antioxidants, such as superoxide dismutase (SOD) and catalase. Failure of antioxidant systems (AXS) can result in dicentric chromosomes formation as well as telomere associations for the reduced activity of telomerase. In order to clarify the long-term effects of a past AS exposure, we evaluated the efficiency of the AXS and the telomerase activity in the progeny of arsenite-treated cells named ASO (arsenic shake-off) cells, previously obtained from arsenite-treated V79 cells and selected by shake-off. Despite SOD1 expression level correlated to the level of ROS observed over time, no changes of the relative amount of antioxidant activities were observed in ASO cells. Moreover, we found that clones characterised by low levels of SOD1 and high levels of ROS acquired a transformed phenotype. Treatment with 5-azacytidine determined an increase of SOD1 expression in a clone and decrease in one other, suggesting that aberrant DNA methylation may be responsible for the abnormal expression of SOD 1 or SOD1 inhibitor genes in different clones. TRAP assay results showed that the progeny of arsenite treated cells were characterised by a time-dependent decrease of telomerase activity. Integrated results suggest that the increases of ROS levels are accompanied by defective telomerase activity. Finally, we propose that cells escaping the arsenite-induced death perpetuated the memory of past exposure via ROS likely because antioxidant and telomerase activity impairment and ultimately acquire a transformed phenotype. PMID- 27470699 TI - Genotoxic and inflammatory effects of nanofibrillated cellulose in murine lungs. AB - Nanofibrillated cellulose (NFC) is a sustainable and renewable nanomaterial, with diverse potential applications in the paper and medical industries. As NFC consists of long fibres of high aspect ratio, we examined here whether TEMPO (2,2,6,6-tetramethyl-piperidin-1-oxyl) oxidised NFC (length 300-1000nm, thickness 10-25nm), administrated by a single pharyngeal aspiration, could be genotoxic to mice, locally in the lungs or systemically in the bone marrow. Female C57Bl/6 mice were treated with four different doses of NFC (10, 40, 80 and 200 ug/mouse), and samples were collected 24h later. DNA damage was assessed by the comet assay in bronchoalveolar lavage (BAL) and lung cells, and chromosome damage by the bone marrow erythrocyte micronucleus assay. Inflammation was evaluated by BAL cell counts and analysis of cytokines and histopathological alterations in the lungs. A significant induction of DNA damage was observed at the two lower doses of NFC in lung cells, whereas no increase was seen in BAL cells. No effect was detected in the bone marrow micronucleus assay, either. NFC increased the recruitment of inflammatory cells to the lungs, together with a dose-dependent increase in mRNA expression of tumour necrosis factor alpha, interleukins 1beta and 6, and chemokine (C-X-C motif) ligand 5, although there was no effect on the levels of the respective proteins. The histological analysis showed a dose-related accumulation of NFC in the bronchi, the alveoli and some in the cytoplasm of macrophages. In addition, neutrophilic accumulation in the alveolar lung space was observed with increasing dose. Our findings showed that NFC administered by pharyngeal aspiration caused an acute inflammatory response and DNA damage in the lungs, but no systemic genotoxic effect in the bone marrow. The present experimental design did not, however, allow us to determine whether the responses were transient or could persist for a longer time. PMID- 27470700 TI - ROS-dependent genotoxicity, cell cycle perturbations and apoptosis in mouse bone marrow cells exposed to formulated mixture of cypermethrin and chlorpyrifos. AB - Swiss albino mice were exposed to formulated cypermethrin (CMR) and/or or chlorpyrifos (CPF) through oral gavages for 60 days. Test doses of CMR (0.69, 1.38 or 2.76mg/kg/day) or CPF (0.5, 1.0 or 2.0mg/kg/day) or CMR + CPF (0.69 + 0.5, 1.38 + 1.0 or 2.76 + 2.0mg/kg/day) were based on the acute oral median lethal doses of CMR or CPF. Chromosome aberrations (CA), micronucleus (MN) induction, cell cycle perturbations, apoptosis and reactive oxygen species (ROS) generation were analysed in bone marrow cells. To explore the involvement of ROS induction, HaCat cells were exposed in vitro to arbitrary concentrations of CMR and/or CPF. Exposure of CMR (2.76mg/kg/day) induced significant inhibition of mitotic index. Significant (P < 0.01) frequencies of CA and MN were observed with the CMR at 1.38mg/kg/day, whereas CPF or its mixture CMR + CPF showed at highest doses. Chromosome/chromatid breaks and fragments were found to be major aberrations in all the treatment groups. Highest doses of CMR or CMR + CPF revealed significant (P < 0.01 or 0.001) elevation of G0/G1 peak, while CPF exposed cells revealed significant (P < 0.01) declined in G1 phase. Decline in S phase was observed with highest dose of CMR only. Apoptosis induction measured by gating cell population beside G1 peak showed 3- to 4-fold increase in apoptotic cells in CPF-exposed mice as compared to control or CMR or CMR + CPF-treated mice. Further, all the treatment groups in vivo as well as in vitro revealed significant generation of ROS in comparison with the control group. Present results, together with the earlier reports, which substantiate ROS generation may be major cause of genotoxicity, cell cycle perturbations and apoptosis, nonetheless co-exposure of low doses of CMR and CPF mixture does not potentiate genotoxicity. PMID- 27470702 TI - Influence of stimulus size on revealing non-cardinal color mechanisms. AB - Multiple studies have shown that performance of subjects on a number of visual tasks is worse for non-cardinal than cardinal colors, especially in the red green/luminance (RG/LUM) and tritan/luminance (TRIT/LUM) color planes. Inspired by neurophysiological evidence that suppressive surround input to receptive fields is particularly sensitive to luminance, we hypothesized that non-cardinal mechanisms in the RG/LUM and TRIT/LUM planes would be more sensitive to stimulus size than are isoluminant non-cardinal mechanisms. In Experiment 1 we tested 9-10 color-normal subjects in each of the three color planes (RG/TRIT, RG/LUM, and TRIT/LUM) on visual search at four bull's-eye dot sizes (0.5 degrees /1 degrees , 1 degrees /2 degrees , 2 degrees /4 degrees , and 3 degrees /6 degrees center/annulus dot diameter). This study yielded a significant main effect of dot size in each of the three color planes. In Experiment 2 we tested the same hypothesis using noise masking, at three stimulus sizes (3 degrees , 6 degrees and 9 degrees diameter Gabors), again in all three color planes (5 subjects per color plane). This experiment yielded, in the RG/TRIT plane, a significant main effect of stimulus size; in the RG/LUM plane, significant evidence for non cardinal mechanisms only for the 9 degrees stimulus; but in the TRIT/LUM plane no evidence for non-cardinal mechanisms at any stimulus size. These results suggest that non-cardinal mechanisms, particularly in the RG/LUM color plane, are more sensitive to stimulus size than are non-cardinals in the RG/TRIT plane, supporting our hypothesis. PMID- 27470703 TI - When Inert Becomes Active: A Fascinating Route for Catalyst Design. AB - In this Personal Account, we review the work of our group in the area of environmental and energy-related nanocatalysis over the past seven years. We focus on understanding the fundamental mechanisms that control the properties of atomic clusters and nanoparticles - a form of matter that is intermediate between atoms and their bulk counterpart. The emphasis is on the theoretical design of effective catalysts based on cheap and abundant elements. The main idea that stands behind our work is that even catalytically inactive or completely inert materials can be functionalized at the nanoscale via the size, structure, morphology, and support effects. Such an approach opens up new ways to design catalytically active systems based on materials never before considered as catalysts. In particular, we demonstrate that hexagonal boron nitride (h-BN), which has been traditionally considered an inert material, can be functionalized and become active for a number of catalytic reactions involving oxygen activation, oxidation by molecular oxygen, and the oxygen reduction reaction. PMID- 27470701 TI - Coccomyxa actinabiotis sp. nov. (Trebouxiophyceae, Chlorophyta), a new green microalga living in the spent fuel cooling pool of a nuclear reactor. AB - Life can thrive in extreme environments where inhospitable conditions prevail. Organisms which resist, for example, acidity, pressure, low or high temperature, have been found in harsh environments. Most of them are bacteria and archaea. The bacterium Deinococcus radiodurans is considered to be a champion among all living organisms, surviving extreme ionizing radiation levels. We have discovered a new extremophile eukaryotic organism that possesses a resistance to ionizing radiations similar to that of D. radiodurans. This microorganism, an autotrophic freshwater green microalga, lives in a peculiar environment, namely the cooling pool of a nuclear reactor containing spent nuclear fuels, where it is continuously submitted to nutritive, metallic, and radiative stress. We investigated its morphology and its ultrastructure by light, fluorescence and electron microscopy as well as its biochemical properties. Its resistance to UV and gamma radiation was assessed. When submitted to different dose rates of the order of some tens of mGy . h-1 to several thousands of Gy . h-1 , the microalga revealed to be able to survive intense gamma-rays irradiation, up to 2,000 times the dose lethal to human. The nuclear genome region spanning the genes for small subunit ribosomal RNA-Internal Transcribed Spacer (ITS) 1-5.8S rRNA-ITS2-28S rRNA (beginning) was sequenced (4,065 bp). The phylogenetic position of the microalga was inferred from the 18S rRNA gene. All the revealed characteristics make the alga a new species of the genus Coccomyxa in the class Trebouxiophyceae, which we name Coccomyxa actinabiotis sp. nov. PMID- 27470704 TI - Non-recruitment to and selection bias in studies using echocardiography in haemodialysis patients. AB - BACKGROUND: It is unknown whether patients recruited to renal cardiac imaging studies are fully representative of the investigated population and whether there are differences in characteristics and survival between participants and non participants (excluded or declined consent). Subjects and Methods Four hundred thirty-five maintenance haemodialysis patients were screened in an observational, prospective study. Baseline demographics, laboratory results, social deprivation scores and survival data were collected from patient records. All patients were followed-up until death, renal transplantation or 16 November 2015. RESULTS: Forty-four patients were excluded (16 language barrier, 10 mental incapacity, 9 severe co-morbid illness and 9 because of immobility), 172 patients declined consent (84% due to reluctance to attend for an extra visit) and 219 patients were recruited. Excluded patients had a lower mean haemoglobin (10.2 g/dL vs 10.7 g/dL), phosphate (4.15 mg/dL vs 4.74 mg/dL), albumin (3.6 g/dL vs 3.8 g/dL) and higher C-reactive protein (3.2 mg/dL vs 1.6 mg/dL) compared with recruited patients. No difference was identified between groups for Charleston comorbidity index (P = 0.115) or social deprivation scores. After a median follow-up of 29.7 (25th-75th percentile, 21.1-34.3) months, there were 141 deaths. In a multivariable Cox regression model adjusting for BMI, age, Charleston comorbidity index, haemoglobin, albumin, smoking status and diabetes mellitus, patients who declined consent had an adjusted HR of 1.70, 95% CI 1.10-2.52, and excluded patients had an adjusted HR of 1.30, 95% CI 0.75-2.25, for all-cause mortality compared with recruited patients. CONCLUSIONS: Patients recruited to the study had longer survival compared with non-participants. Research studies should document phenotypes of non-participants to aid interpretation and generalizability of results. PMID- 27470705 TI - An integrated process for the extraction of fuel and chemicals from marine macroalgal biomass. AB - We describe an integrated process that can be applied to biomass of the green seaweed, Ulva fasciata, to allow the sequential recovery of four economically important fractions; mineral rich liquid extract (MRLE), lipid, ulvan, and cellulose. The main benefits of our process are: a) its simplicity and b) the consistent yields obtained from the residual biomass after each successive extraction step. For example, dry Ulva biomass yields ~26% of its starting mass as MRLE, ~3% as lipid, ~25% as ulvan, and ~11% as cellulose, with the enzymatic hydrolysis and fermentation of the final cellulose fraction under optimized conditions producing ethanol at a competitive 0.45 g/g reducing sugar. These yields are comparable to those obtained by direct processing of the individual components from primary biomass. We propose that this integration of ethanol production and chemical feedstock recovery from macroalgal biomass could substantially enhance the sustainability of marine biomass use. PMID- 27470706 TI - Health-Related Quality of Life in Patients With alpha1 Antitrypsin Deficency: A Cross Sectional Study. AB - BACKGROUND: Measures of health related quality of life (HRQoL) in patients with alpha1-antitrypsin deficiency (AATD) can help to determine the impact of the disease and provide an important insight into the intervention outcomes. There is few data regarding this issue in the literature. The aim of this study is to assess the relationship between HRQoL and gender, functional parameters and history of hospitalizations in patients with AATD. METHODS: This is a cross sectional study of 26 patients with severe AATD recruited in the pulmonology outpatient clinic at a tertiary care medical center. Social-demographic, clinical and functional parameters were recorded and HRQoL was assessed with the Portuguese version of the medical outcome study short form-36 (SF-36) self administered questionnaire. RESULTS: Older patients, females and patients with at least one hospitalization in the previous year due to respiratory disease had statistical lower scores in some dimensions of the SF-36 questionnaire. Superior FEV1 and higher distance mark in the 6-min walking test distance influenced positively several dimensions of the questionnaire. Higher scores in the mMRC scale influenced negatively the HRQoL. CONCLUSIONS: These data suggests that older and female patients with AATD have worse HRQoL. Hospitalizations and functional markers of respiratory disease progression influenced negatively the HRQoL, suggesting that the SF-36 questionnaire could be useful as an outcome for AATD patients with lung involvement. PMID- 27470707 TI - Short-term outcome of percutaneous treatment of pulmonary sequestration in a pediatric hospital in the Andes: A case series. PMID- 27470708 TI - Microparticle content of platelet concentrates is predicted by donor microparticles and is altered by production methods and stress. AB - In circulation, shedding of microparticles from a variety of viable cells can be triggered by pathological activation of inflammatory processes, by activation of coagulation or complement systems, or by physical stress. Elevated microparticle content (MPC) in donor blood might therefore indicate a clinical condition of the donor which, upon transfusion, might affect the recipient. In blood products, elevated MPC might also represent product stress. Surprisingly, the MPC in blood collected from normal blood donors is highly variable, which raises the question whether donor microparticles are present in-vivo and transfer into the final blood component, and how production methods and post-production processing might affect the MPC. We measured MPC using ThromboLUX in (a) platelet-rich plasma (PRP) of 54 apheresis donors and the corresponding apheresis products, (b) 651 apheresis and 646 pooled platelet concentrates (PCs) with plasma and 414 apheresis PCs in platelet additive solution (PAS), and (c) apheresis PCs before and after transportation, gamma irradiation, and pathogen inactivation (N = 8, 7, and 12 respectively). ThromboLUX-measured MPC in donor PRP and their corresponding apheresis PC samples were highly correlated (r = 0.82, P = .001). The average MPC in pooled PC was slightly lower than that in apheresis PC and substantially lower in apheresis PC stored with PAS rather than plasma. Mirasol Pathogen Reduction treatment significantly increased MPC with age. Thus, MPC measured in donor samples might be a useful predictor of product stability, especially if post-production processes are necessary. PMID- 27470709 TI - Leukapheresis in patients newly diagnosed with acute myeloid leukemia. AB - Hyperleukocytosis is present in 5 to 20 percent of patients with newly diagnosed acute myeloid leukemia (AML). The management of hyperleukocytosis, when symptoms of leukostasis occur, includes intensive supportive care and interventions for rapid cytoreduction. Leukapheresis is a rapid and effective means of cytoreduction and has been used in AML patients. In the current study, we evaluated the outcomes of 68 newly diagnosed AML patients that underwent leukapheresis and the effects of leukapheresis on various laboratory parameters. A total of 127 leukapheresis cycles were performed. The median number of leukapheresis cycles was 2 (range, 1-8). The overall survival for all patients was 4.2 months (95% CI 1.2-9.7 months). The median overall survival for patients who achieved complete remission after induction chemotherapy was significantly higher (19.1 months [95% CI 12.1-41.8 months]) than patients that did not achieve complete remission (0.46 months [95% CI 0.33-0.99 months]). Stepwise logistic regression demonstrated that elevated number of peripheral blasts, low platelet count and elevated bilirubin at AML diagnosis were predictive of death within a week. Leukapheresis was effective in reducing the peripheral blood leukocytes and leukemia blasts and was a safe procedure with regard to organ function, coagulation parameters, red blood cells and platelet count. The high initial response rates in newly diagnosed AML patients fit to receive intensive chemotherapy suggest that leukapheresis could be beneficial in reducing the complications associated with hyperleukocytosis until systemic intensive chemotherapy commences. PMID- 27470710 TI - Does smoking, age or gender affect the protein phenotype of extracellular vesicles in plasma? AB - Extracellular vesicles (EVs) are involved in several diseases, which have formed the basis for the potential use of EV analyses in a clinical setting. The protein phenotype of EVs can provide information on the functionality of the vesicles and may be used for identification of disease-related biomarkers. With this extensive study of 161 healthy individuals it was elucidated that certain markers of plasma EVs are influenced by demographic variations such as gender, age and smoking status. When the purpose is to use EVs as a diagnostic tool, it should be emphasized how important it is to choose the correct demographic group when comparing marker levels of plasma EVs. PMID- 27470711 TI - Circulating extracellular vesicles: Their role in tissue repair and regeneration. AB - Extracellular vesicles (EVs) have been a growing interest of the scientific community in recent years due to the wide possibilities of their evaluation as biomarkers of disease, and their potential to be used as therapeutic agents or vehicles. EVs that circulate in plasma carry proteins and nucleic acids, potentially to distant locations in the body where they can interfere with several cellular processes. To aid understanding of this rapidly evolving field, circulating EVs, including immune cell-derived ones, are reviewed here. Their cellular origins and described functions are discussed in a perspective of their contribution to regenerative processes. Different techniques for EV engineering and examples of their application are reviewed as a strong future direction of EV research. A summary of important aspects yet to be addressed ties up this review. PMID- 27470714 TI - Tabanidae (Diptera) of the American Museum of Natural History Collection. AB - A checklist of Tabanidae in the American Museum of Natural History was compiled. Over 9,000 specimens were studied. The currently accepted taxa names have been listed based on general catalogs and recent publications. Where possible, modern locality names are given and determiners of each species are provided. A total of 882 species are listed in alphabetical order; including 52 primary and 219 secondary types. The collection includes a substantial global representation of species records for this family. PMID- 27470715 TI - Land flatworms of the genus Pasipha (Platyhelminthes, Geoplanidae) in Argentina, with description of three new species. AB - The genus Pasipha Ogren & Kawakatsu, 1990 currently includes 22 species, most of them recorded in the Brazilian Atlantic Forest. Recently, Pasipha hauseri was documented in north-eastern Argentina, thus extending its distribution range. This paper reports new records of the genus Pasipha in the Interior Atlantic Forest ecoregion in Argentina, with the description of three new species: Pasipha atla sp. nov., Pasipha johnsoni sp. nov., and Pasipha mbya sp. nov. These new species exhibit similarities in internal anatomy, such as pharynx cylindrical, extrabulbar prostatic vesicle with folded walls and proximally forked, male atrium highly folded, being at least two times longer than the female atrium and with small folds in their proximal portion. However, they can be distinguished from each other mainly by the secretion types discharged into the prostatic vesicle as well as into the male and female atria. In addition, they have different colour patterns on the dorsal surface. PMID- 27470712 TI - Collaborative Interferon-gamma and Interleukin-17 Signaling Protects the Oral Mucosa from Staphylococcus aureus. AB - Infections with Staphylococcus aureus are a continuing and growing problem in community and hospital settings. Preclinical animal modeling of S. aureus relies on experimental infection, which carries some limitations. We describe here a novel, spontaneous model of oral staphylococcal infection in double knockout mice, deficient in the receptors for IL-17 (IL-17RA) and interferon (IFN)-gamma (IFNgammaRI), beginning at 6 to 8 weeks of age. IFNgammaRI(-/-)IL17RA(-/-) (GRAKO) mice developed progressive oral abscesses. Cytometric methods revealed extensive neutrophilic infiltration of oral tissues in GRAKO mice; further investigation evidenced that IL-17 predominated neutrophil defects in these mice. To investigate the contribution of IFN-gamma signaling to this native host defense to S. aureus, we observed perturbations of monocyte recruitment and macrophage differentiation in the oral tissues of GRAKO mice, and CXCL9/chemokine ligand receptor (CXCR)3-driven recruitment of T-cell oral tissues and draining lymph nodes. To address the former finding, we depleted macrophages and monocytes in vivo from IL17RA(-/-) mice using liposomes loaded with clodronate. This treatment elicited oral abscesses, recapitulating the phenotype of GRAKO mice. From these findings, we propose novel collaborative functions of IL-17 and IFN gamma, acting through neutrophils and macrophages, respectively, in native mucocutaneous host defenses to S. aureus. PMID- 27470713 TI - Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit. AB - The conserved RNA-binding protein Musashi1 (MSI1) has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation and as a key oncogenic factor in numerous solid tumors, including glioblastoma. To explore the potential use of MSI1 targeting in therapy, we studied MSI1 in the context of radiation sensitivity. Knockdown of MSI1 led to a decrease in cell survival and an increase in DNA damage compared to control in cells treated with ionizing radiation. We subsequently examined mechanisms of double-strand break repair and found that loss of MSI1 reduces the frequency of nonhomologous end-joining. This phenomenon could be attributed to the decreased expression of DNA-protein kinase catalytic subunit, which we have previously identified as a target of MSI1. Collectively, our results suggest a role for MSI1 in double-strand break repair and that its inhibition may enhance the effect of radiotherapy. PMID- 27470717 TI - A new species of Hypostomus Lacepede, 1803 (Siluriformes: Loricariidae) from rio Itapicuru basin, Bahia State, Brazil. AB - A small-bodied new species of Hypostomus is described from the rio Itapicuru basin, Bahia, Brazil. The new species is distinguished from most congeners mainly by having the lower caudal-fin lobe distinctly longer than the upper lobe and absence of conspicuous dark spots on posterior half of body. It differs particularly from congeners occurring in northeastern coastal Brazilian drainages and the rio Sao Francisco basin by having the anterior portion of the abdomen completely plated and the posterior portion plated only on a narrow median line, leaving large lateral areas naked, dark spots on anterior portion of trunk similar in size or slightly larger than those on head, absence of conspicuous spots on posterior half of trunk and caudal fin, and absence of keels on head and trunk. PMID- 27470716 TI - Chromosomal relationships of Simulium armoricanum and its undescribed sister species in the Simulium vernum species group (Diptera: Simuliidae). AB - The banding sequence of the polytene chromosomes of Simulium armoricanum Doby & David from England, Portugal, and Spain was resolved relative to the standard map for the S. vernum group. The species is characterized by 11 fixed inversions, one nearly fixed inversion, and three common polymorphisms. The sister species of S. armoricanum is proposed as a formally undescribed species discovered in samples from Portugal. It shares one unique inversion with S. armoricanum, but otherwise differs by eight fixed or nearly fixed rearrangements. Simulium armoricanum and its newly discovered sister species, informally referred to as Simulium 'IL-8', are members of a larger clade of Palearctic species defined by a small pericentric inversion in chromosome III. Among the simuliid species occupying the same streams with S. armoricanum was the first record, chromosomally confirmed, of S. aureum Fries sensu stricto in Portugal. Successful chromosomal analysis of samples of S. armoricanum 17 years after initial fixation demonstrates the importance of storing cytologically fixed larvae at subzero temperatures. PMID- 27470718 TI - A remarkable fossil leptosaldine bug from Mid-Cretaceous Burmese amber (Hemiptera: Heteroptera: Leptopodomorpha: Leptopodidae). AB - A new genus and species of leptosaldine bugs, Leptosaldinea cobbeni gen. et sp. nov. (Hemiptera: Heteroptera: Leptopodidae) is described and illustrated from Burmese Middle Cretaceous (Albian-Cenomanian) amber found in Kachin State, northern Myanmar. This is the third record of a leptosaldine bug from Burmese amber. A brief analysis of the characters and systematic relationships of Leptosaldinae is provided. PMID- 27470719 TI - An annotated checklist of click-beetles (Coleoptera, Elateridae) from Iran. AB - The fauna of Iranian Elateridae (Coleoptera: Elateroidea) is summarized in this paper. In total 245 species from 58 genera and 7 subfamilies Agrypninae Candeze (13 genera, 36 species), Cardiophorinae Candeze (4 genera, 55 species), Cebrioninae Latreille (2 genera, 6 species), Dendrometrinae Gistel (13 genera, 28 species), Elaterinae Leach (23 genera, 104 species), Lissominae Laporte (1 genus, 1 species) and Negastriinae Nakane & Kishii (2 genera, 15 species) are listed in literature as the fauna of Iran. Totally 74 species are endemic to Iran. PMID- 27470720 TI - New replacement name Kuznetsoviella (Ostracoda): a correction. AB - Recently it was found (Doweld 2016) that the generic name Aenigma Kuznetsova (1957: 68; type species A. jucunda Kuznetsova, by original designation) of fossil Ostracoda from the Lower Cretaceous (Barremian) of Tegchaj, North-Eastern Azerbaijan, former USSR (Transcaucasia), is already preoccupied by a marine gastropod molluscan generic name Aenigma Newman (1836: 499), which is in active current use in zoology (Coleoptera: Carabidae), along with a few other known homonyms, Aenigma Amsel (1956: 288) [Lepidoptera], Aenigma Koch (in Martini & Chemnitz 1846: 1, unpaginated) [Mollusca], Aenigma Karsch (1878: 825) [Arachnida], Aenigma Strecker (1876: 122) [Lepidoptera]. Therefore, a new replacement name was proposed, Kuznetsovia Doweld (2016: 68). However, it was overlooked that this generic name is already preoccupied by Kuznetsovia Kammerer (2006: 269) [Arthropoda], escaped from Nomenclator Zoologicus and Zoobank. In this connection, to resolve unexpected homonymy with an arthropod generic name, in accordance with article 60 of the International Code of Zoological Nomenclature (1999), a new replacement name is proposed for the fossil Ostracoda genus:. PMID- 27470721 TI - A new species of Heleobia (Caenogastropoda: Cochliopidae) from the Chilean Altiplano. AB - Cochliopidae Tryon, 1866 is a diverse family of caenogastropods that lives in a wide variety of aquatic habitats primarily in the New World (Hershler &Thompson 1992). In Chile, the species of the group have been traditionally assigned to the genus Littoridina Souleyet, 1852 using conchological characters (Biese 1944, 1947; Stuardo, 1961; Valdovinos 2006) but according to anatomical studies and phylogenetic analysis the majority of them have been reassigned to the genus Heleobia Stimpson, 1865 (Hershler & Thompson 1992; Collado et al. 2011a; Kroll et al. 2012; Collado et al. 2013; Collado et al. 2016). Here we formally describe a new species of the genus Heleobia from Spring 1 in the Carcote saltpan, Chilean Altiplano, based on molecular and morphological characters. Snails from this locality were previously shown to be distinct based on DNA sequences (Collado et al. 2013; Collado et al. 2016). PMID- 27470722 TI - First record of Bombylisoma Rondani (Diptera: Bombyliidae) from China and an identification key to the Chinese genera of Bombyliinae. AB - Bombylisoma Rondani is a genus of bee flies belonging to the subfamily Bombyliinae (Hull, 1973). It is easily identified by the following characters: Head usually as broad as thorax; hind-margin of eyes indented; wings often small, narrowed at base with at least alula reduced; hind femora often without macrochaetae; body usually more elongate even narrow conical or cylindrical, macrochaetae usually weak often hair-like especially those posterior to the wings; cell r5 open, pulvilli well-developed; male terminalia with gonocoxite without prominent crest; parameral sheath, bearing paired horn-like outgrowths (Greathead & Evenhuis, 2001). Bombylisoma includes two known species from the Oriental Region: B. ghorpadei Kapoor & Agarwal, 1979 and B. resplendens Brunetti, 1909 (Evenhuis & Greathead, 2015). No species has previously been reported from China. Recently, one specimen of Bombylisoma collected from Yunnan was found in the Bernice Pauahi Bishop Museum. In the present paper this species, B. resplendens Brunetti, is redescribed and this represents the first record of the genus from China. A key to the genera of the Bombyliinae from China is presented. PMID- 27470723 TI - Pseudocromata, a new genus of Ochlerini based on a new species from Ecuador (Pentatomidae: Discocephalinae). AB - The tribe Ochlerini was defined by Rolston (1981) based on the position of abdominal trichobothria (lateral to the spiracles), insertion of the labium well behind the apex of the head (usually in line with the eyes), and the superior surface of the distal metatarsomere in females excavate or flattened. Rolston's (1992) revision of the tribe included 28 genera. With subsequent additions there are now either 33 or 35 genera depending on the inclusion or exclusion of Melambyrsus Breddin (listed as nomen dubium by Rolston 1992) and Candeocoris Roell & Campos (2015) which has character-states intermediate between Ochlerini and Discocephalini. With few exceptions the members of the tribe are inornately colored, typically shades of black, brown or tan Campos & Grazia (2006). Exceptions are species in the genera Cromata Rolston and the aforementioned Candeocoris which have colorful blotches on the scutellum and corium. PMID- 27470725 TI - On the resolution of a long standing issue surrounding the holotype of Cnemaspis podihuna Deraniyagala, 1944 (Reptilia: Gekkonidae). AB - The number of species in the genus Cnemaspis Strauch, 1887 has grown rapidly, and it currently comprises more than 100 species (Grismer et al. 2014; Amarasinghe et al. 2015). The Sri Lankan endemic and vulnerable day-gecko Cnemaspis podihuna Deraniyagala, 1944 (Ministry of the Environment 2012) was first described by Deraniyagala from the Lahugala-Maha Oya, Eastern Province on the basis of one holotype and four paratypes [incorrectly reported as three paratypes by Karunarathna et al. 2010]. There had been no further collections or sightings made of this species until Wickramasinghe (2000) rediscovered the species from Koslanda in the Badulla District (National Museums of Sri Lanka, Colombo, NMSL RG 21a-e). Wickramasinghe and Munindradasa (2007) collected a further four specimens (NMSL 20061001-4) around the type locality. Recently, Sri Lankan members of the day-gecko genus Cnemaspis were reviewed and redescribed morphologically by two groups of researchers: Wickramasinghe and Munindradasa (2007) and Manamendra Arachchi et al. (2007). The former group considered the holotype lost. Therefore, they designated a neotype plus syntypes for C. podihuna. This action was invalidated by Pethiyagoda (2007) following the International Code of Zoological Nomenclature (ICZN 1999). PMID- 27470724 TI - On the type locality of Sorubim trigonocephalus Miranda-Ribeiro, 1920 (Siluriformes: Pimelodidae). AB - Sorubim trigonocephalus was described in 1920 by Alipio de Miranda Ribeiro, based on a single specimen collected in a locality identified as "Porto Velho", during the "Comissao das Linhas Telegraficas Estrategicas de Mato Grosso ao Amazonas" (more commonly known as Rondon Commission). Given that the type locality is Porto Velho, the species has been referred to the Madeira River basin (Lundberg & Littmann, 2003; Littmann, 2007; Eschmeyer et al., 2016). Nevertheless, after its description, no additional specimens were collected in the Madeira basin despite several ichthyological expeditions undertaken to the area (Santos, 1996; Camargo & Giarrizzo, 2007; Rapp Py-Daniel et al., 2007; Perin et al., 2007; Pedroza et al., 2012; Casatti et al., 2013; Queiroz et al., 2013a), some of them including region of Porto Velho (Fowler, 1913; Araujo et al., 2009; Torrente-Vilara et al., 2011; Queiroz et al., 2013b). PMID- 27470726 TI - Description of new members of the family Cylindroleberididae (Ostracoda: Cylindroleberidoidea) from the Southern Ocean. AB - We report new ostracod data (Family Cylindroleberididae) based on material collected during the German Expeditions onboard the research vessel "Polarstern" from bathyal and abyssal zones (sampling depth range from 1030 to 3963 m) in the Weddell and Scotia Seas and Drake Passage in 2002 and 2005. Four species belonging to four genera were identified in these collections. A new species, Synasterope pseudomystax, is illustrated and described. A first occurrence of an adult female is registered for Archasterope weddellensis (Kornicker, 1975). Additional description for Parasterope cf. styx Kornicker, 1975 is given. Description of Bathyleberis grossmani Kornicker, 1975 is supplemented with new data on the distribution. Additionally, keys for all species known for Antarctic waters are included. PMID- 27470727 TI - Description of a new species of the genus Hulecoeteomyia (Diptera: Culicidae) from Meghalaya, India. AB - Female and male adults, female and male genitalia, pupa and larva of Hulecoeteomyia cherrapunjiensis, a new mosquito species, are described from Meghalaya, India. Keys to separate larvae and adults are provided. PMID- 27470728 TI - Two new species and new records of Cerambycidae (Insecta, Coleoptera) from Itatiaia National Park, Rio de Janeiro, Brazil. AB - The descriptions of two species of Lamiinae, Lepturges (Lepturges) batesi sp. nov. (Acanthocinini) and Onocephala chicomendes sp. nov. (Onocephalini) and an addendum of Cerambycinae and Lamiinae to the list of species of Cerambycidae in the Itatiaia National Park are presented. The data are based on fieldwork conducted over the last six years. Eighteen species of Cerambycinae and 21 of Lamiinae are recorded, with a total of 39 new distribution records. PMID- 27470729 TI - Two new species of the feather mite genus Trouessartia (Acari: Trouessartiidae) from Asia. AB - Two new feather mite species of the genus Trouessartia Canestrini are described from birds captured in Meghalaya (India): Trouessartia longidenticulata Constantinescu sp. n. from Pycnonotus cafer (Linnaeus) (Passeriformes, Pycnonotidae) and Trouessartia dicruri Constantinescu sp. n. from Dicrurus aeneus (Vieillot) (Passeriformes, Dicruridae). In the genus Trouessartia, males of T. longidenticulata show a unique character state in having the lamellae of the opisthosomal lobes with long and sharp denticles. Both sexes of T. dicruri differ from closely related T. delicatula Gaud, 1952 by smaller body size (T. dicruri males are 420-452 long, females 500-532 long, vs. c. 575 and 595, respectively in T. delicatula); males have the adanal apodemes without apophyses and the terminal lamellae in a shape of a parallelogram (vs. the adanal apodemes have a pair of apophyses and the terminal lamellae are semi-ovate); the opisthosomal lobes do not touch each other at the inner margins (vs. the opisthosomal lobes touch each other at the inner margins, at the level of setae h3); in females, setae h1 are lanceolate (vs. spiculiform). PMID- 27470730 TI - New species and a record of myrmecophilous mites of the families Neopygmephoridae and Microdispidae (Acari: Heterostigmatina:
Pygmephoroidea) associated with Lasius umbratus (Hymenoptera: Formicidae) from Western Siberia, Russia. AB - Two new myrmecophilous species of the family Neopygmephoridae (Acari: Pygmephoroidea), Petalomium brevicaudus sp. nov. and P. kurganiensis sp. nov. are described from the ant Lasius umbratus Nylander (Hymenoptera: Formicidae: Formicinae) in Western Siberia, Russia. Another myrmecophilous species of the family Microdispidae (Acari: Pygmephoroidea), Caesarodispus brevipes Mahunka, 1981, was also collected from the ant L. umbratus in Western Siberia, Russia. It is recorded from Russia for the first time and is redescribed in the present paper. PMID- 27470731 TI - New genus and new species of Neoibidionini from the Neotropical region (Coleoptera, Cerambycidae, Cerambycinae). AB - One new genus and six new species are described from the Neotropical region: Heterachthes hildebranti, H. skillmani, and H. noguerai, from Mexico; Compsibidion morrisi, from Bolivia; Tropidion wappesi, from Bolivia; and Biraidion, new genus, type species B. martinsi sp. nov., from Bolivia. Biraidion, Compsibidion morrisi, and Tropidion wappesi are included in previous keys. PMID- 27470732 TI - Some species of Munidopsis from the Gulf of Mexico, Florida Straits and Caribbean Sea (Decapoda: Munidopsidae), with the description of two new species. AB - During two cruises to the Gulf of Mexico and Caribbean Sea, some specimens of squat lobsters belonging to the genus Munidopsis Whiteaves, 1874 (family Munidopsidae Ortmann, 1898) were collected. The present collection comprises five species, where two are considered as new species: M. karukera, closely related to M. ariadne Macpherson, 2011, from the Mediterranean Sea; and M. tuerkayi, which resembles M. kareenae Ahyong, 2013, from New Zealand. The specimens were caught at six stations between 522 and 1162 m; some were associated with live cold-water corals, such as Lophelia pertusa (Linnaeus, 1758), Enallopsammia profunda (Pourtales, 1867) and Candidella imbricata (Johnson, 1862). PMID- 27470733 TI - The sexuales of Cinara palaestinensis Hille Ris Lambers, the Aleppo pine aphid (Hemiptera: Aphididae Lachninae). AB - The male and the oviparous female of Cinara palaestinensis Hille Ris Lambers, the Aleppo pine aphid, are recorded for the first time, in populations on Pinus halepensis in Italy. Description and illustrations are provided together with additional notes on taxonomy, ecology and distribution of the species. PMID- 27470734 TI - New species of Evaniodini (Braconidae: Doryctinae) from Brazil. AB - A new species, Evaniodes costatus Valerio sp. nov., belonging to the tribe Evanoidini is described and illustrated. The new species is compared with the five species currently known to occur in the genus Evaniodes Szepligeti. PMID- 27470735 TI - A new species of Xiphovelia Lundblad, 1933 and notes on Pseudovelia Hoberlandt, 1950 (Heteroptera: Veliidae) from Vietnam. AB - The genus Xiphovelia Lundblad is recorded for the first time from Vietnam and X. vietnamica sp. nov. is described as new. Photographs of the male and female dorsal habitus, male legs, and male genitalic structures are provided. Pseudovelia vittiformis Ye, Polhemus & Bu, 2013 and P. tibialis tibialis Esaki & Miyamoto, 1955 are newly recorded from Vietnam. Together with two other species of Pseudovelia Hoberlandt from southern Vietnam, four species of Pseudovelia are now known from the country. A distribution map for the species of Xiphovelia and Pseudovelia occurring in Vietnam also is provided. PMID- 27470736 TI - Limnocentropus kritsaneepaibooni new species (Limnocentropodidae: Trichoptera) from Shan State, Myanmar, with faunistic data for the family. AB - A new species of Limnocentropus, Limnocentropus kritsaneepaibooni n. sp. from Keng Tung Province, Shan State, Myanmar, is described and figured. Three other, previously described species of Limnocentropus are newly recorded for Myanmar, including L. apollon Malicky 1999, L. sammuanensis Malicky & Chantaramongkol 1989, and L. siribhumensis Malicky & Chantaramongkol 1989, resulting in 7 species of the family found in Myanmar. PMID- 27470737 TI - Two new species of Onciderini Thomson, 1860 (Coleoptera, Cerambycidae, Lamiinae) from South America. AB - Two new species of Onciderini are described and illustrated: Oncideres tavakiliani, from Brazil (Para), and Clavidesmus egeri, from Peru. Oncideres defectiofasciata Gilmour, 1950 is a junior synonym of O. chevrolatii Thomson, 1868. The following four new country records are reported: O. crassicornis Bates, 1865 (Paraguay); O. glebulenta Martins, 1981 (Paraguay); O. gutturator (Fabricius, 1775) (Venezuela); and O. repandator (Fabricius, 1793) (Peru). PMID- 27470738 TI - Sponges of the family Axinellidae (Porifera: Demospongiae) in Indonesia. AB - Nine species in five genera of the family Axinellidae, including three new species, Axinella badungensis sp. nov., A. balinensis sp. nov. and Phycopsis pesgalli sp. nov. are recorded from Indonesian waters within the limits of the Western Coral Triangle province. Descriptions and discussion of those species are presented here. Four new combinations, Phakettia arbora (Sim, Kim & Byeon, 1990) comb.nov., P. trachys (De Laubenfels, 1954) comb.nov., Echinoclathria retepora (Lendenfeld, 1887) comb.nov. and Amphimedon hispidula (Ridley, 1884) comb.nov. are also established here. The distributions of species previously described are here extended to the study area with the exception of Phakellia atypica which seems so far restricted to Indonesia. PMID- 27470739 TI - Sinobatis brevicauda n. sp., a new deep-water legskate (Rajiformes, Anacanthobatidae) and first generic record from the western Indian Ocean. AB - A new deep-water legskate, Sinobatis brevicauda, is described based on two specimens caught on the remote Saya de Malha Bank in the central western Indian Ocean. The new species is easily distinguished from all other described anacanthobatids by the short tail. It is the only Sinobatis species described from the western Indian Ocean and differs from the other anacanthobatid legskates in this area by its large size and light coloration. All other species of Sinobatis are described from the eastern Indian and, particularly, western Pacific oceans. In addition to the short tail, the new species clearly differs from its morphologically closest congener, the Australian S. bulbicauda, in a bicolored white and grayish ventral coloration with gray and white blotches (vs. uniformly pale or white and skin somewhat translucent) and a filamentous tail without flattened, bulbous tip. Furthermore, it is distinguished by several morphometric and meristic differences, e.g. a longer body (length 65% TL vs. 39 61% TL), longer head (dorsal length 34% TL vs. 21-31% TL, ventral length 41% TL vs. 23-36% TL), longer snout (preorbital length 28-29% TL vs. 14-26% TL, preoral length 30% TL vs. 16-28% TL, prenasal length 28% TL vs. 14-25% TL), and fewer diplospondylous (102-112 vs. 121-142) and total (131-141 vs. 148-168) vertebrae. S. brevicauda clearly differs from the other anacanthobatids in the western Indian Ocean, Anacanthobatis marmorata and Indobatis ori, by having a much shorter tail, strongly different coloration, much larger size, and in many morphometric and meristic differences. PMID- 27470740 TI - Generic redescription, two new species, and a key to the species of the cicada genus Ariasa Distant, 1905 with the description of a new genus (Hemiptera: Cicadidae: Cicadinae: Fidicinini). AB - The cicada genus Ariasa Distant, 1905 is redescribed. Ariasa albimaculosa n. sp. is described from Colombia and A. bartletti n. sp. is described from Peru. The current 14 species of Ariasa are listed along with their synonymies, known distribution of each species, and a key to the species is provided. The first records of Ariasa bilaqueata (Uhler, 1903) for Peru and French Guiana are provided. Cracenpsaltria brasiliorum (Kirkaldy, 1909) rev. stat., n. comb. is determined to be the correct name for the taxon Cicada marginata Olivier, 1790 and the new genus Cracenpsaltria n. gen. is erected for the taxon. The distribution of C. brasiliorum rev. stat., n. comb. is expanded to include Bolivia and Peru. PMID- 27470741 TI - On the genus Cosmopelma Simon, 1889 (Araneae, Barychelidae). AB - Among neotropical mygalomorph spider families, Barychelidae is one of the most neglected in taxonomic studies. Most genera have never been revised and only the original descriptions are available. Herein, one of these more obscure genera, Cosmopelma Simon, 1892, with two described species in Brazil and Venezuela, is revised. The type species C. decoratum Simon, 1889 is redescribed, and the male is described for first time. A new species, C. ceplac sp. nov., is described, and new occurrences are presented. Additionally, C. dentatum Fischel, 1927, whose holotype is lost, is considered a nomen dubium. Cosmopelma is an endemic genus, known only from the state of Bahia in northeastern Brazil. PMID- 27470742 TI - Morphology and DNA barcoding reveal a new species of Eudicella from East Africa (Coleoptera: Scarabaeidae: Cetoniinae). AB - A new species of Eudicella White, 1839 (Coleoptera: Scarabaeidae: Cetoniinae), is described from Uganda and Kenya: E. nana new species. Morphological and genetic analyses of the new taxon and phenotypically allied species are given. Eudicella nana is compared with its hypothesized sister species, E. darwiniana Kraatz, 1880, and diagnostic characters that distinguish it from other species occurring in the same region are provided. PMID- 27470743 TI - Stapecolis, new genus of Ochlerini (Hemiptera: Pentatomidae: Discocephalinae). AB - A cladistic analysis of the Herrichela clade (Ochlerini) was conducted to solve problems concerning the systematics of the genus Alitocoris Sailer; this recovered monophyletic groups which are considered to be new genera. Stapecolis gen. nov. is here proposed for two species (S. latus sp. nov. and S. bimaculatus sp. nov.) representing one of those monophyletic groups. The new genus is supported by ten synapomorphies, five of them pertaining to the morphology of the pygophore have not been found together in any other genera of Ochlerini. The female genitalia also has characteristics different from closely related genera. PMID- 27470745 TI - The European species of Foersterella Dalla Torre (Hymenoptera: Tetracampidae), including the description of two new species. AB - The European species of Foersterella Dalla Torre 1897 (Hymenoptera: Tetracampidae) are treated, including two previously described species, F. erdoesi Boucek and F. reptans (Nees), and two new species, F. angusticornis sp. nov. and F. fuscicornis sp. nov. Morphological concepts of the species are based mainly on characters in the male antenna, which females lack, and with the exception of F. erdoesi females are currently not possible to identify to species. A key for the identification of species is included, as well as illustrations to facilitate the identification. PMID- 27470744 TI - Two new species of Microcosmodes Strand (Coleoptera: Carabidae: Panagaenini) from Oman and Iran. AB - Two new species of the genus Microcosmodes Strand, M. arabicus from Oman and M. persicus from Iran, are described, compared with related taxa, and their affinities are discussed. The species are very similar and belong to the same species group. PMID- 27470746 TI - Review of the genus Tricheops Newman (Coleoptera: Cerambycidae: Cerambycinae) with description of two new species from Western Australia. AB - Two new species of Tricheops Newman, T. remus sp. nov. and T. guillemeti sp. nov. from Western Australia are described and illustrated. The genus Tricheops is redescribed and a key to species is provided. The structures associated with the unusual three-lobed eyes of Tricheops and Bardistus Newman are discussed. PMID- 27470748 TI - Two new water beetles from the South African Cape (Coleoptera, Hydraenidae). AB - Pterosthetops nitidus sp. nov. and Oomtelecopon namaqum sp. nov. are described from the Western and Northern Cape Provinces of South Africa respectively. Diagnostic notes are provided for each species, together with details of occupied microhabitats. PMID- 27470747 TI - Two new species of quill mites (Acari: Syringophilidae) associated with the Chestnut-fronted Helmetshrike Prionops scopifrons (Peters) (Passeriformes: Vangidae) in Kenya. AB - Two new species of syringophilid mites collected from Prionops scopifrons (Peters) (Passeriformes: Vangidae) in Kenya are described: Neoaulonastus prionops sp. nov. and Picobia meru sp. nov. They are the first syringophilid records from birds of the family Vangidae. PMID- 27470749 TI - Two new species of the genus Apolygus China (Hemiptera: Heteroptera: Miridae: Mirinae) from the Korean Peninsula, with a key to Korean Apolygus species. AB - Two new species of the genus Apolygus are described from the Korean Peninsula: A. rubrifasciatus sp. nov. and A. atriclavus sp. nov. Descriptions and diagnoses, and some biological information are presented with photographs and illustrations. A key to the Korean Apolygus species is also provided. PMID- 27470751 TI - Alpheid shrimps (Decapoda: Caridea) of the Trindade & Martin Vaz Archipelago, off Brazil, with new records, description of a new species of Synalpheus and remarks on zoogeographical patterns in the oceanic islands of the tropical southern Atlantic. AB - The present study deals with shrimps of the family Alpheidae collected in the shallow waters around the remote Trindade & Martin Vaz Archipelago, situated 1200 km off the coast of Espirito Santo, Brazil. A few additional samples came from dredges on top of the seamounts of the Vitoria-Trindade Seamount Chain. A total of 23 species in eight genera are reported, the vast majority representing new records for the area. One species is described as new, Synalpheus trinitatis sp. nov., based on the type material from Trindade Island. The new species clearly belongs to the Synalpheus brooksi Coutiere, 1909 species complex, differing from all its other members by at least two morphological features. Four species represent new records for Brazil and the southwestern Atlantic: Alpheopsis aequalis Coutiere, 1897 sensu lato, Alpheopsis chalciope de Man, 1910 sensu lato, Alpheus crockeri (Armstrong, 1941) and Prionalpheus gomezi Martinez-Iglesias & Carvacho, 1991; the two species of Alpheopsis are recorded from the Atlantic Ocean for the first time. The colour pattern of the recently described Alpheus rudolphi Almeida & Anker, 2011, a species endemic to Brazil, is shown for the first time and compared to the colour patterns of the four closely related species of the A. armatus Rathbun, 1901 complex from the Caribbean-Florida region. A brief zoogeographical analysis of the alpheid fauna of the oceanic islands of the tropical southern Atlantic (Trindade & Martin Vaz, Fernando de Noronha, Atol das Rocas, Sao Pedro & Sao Paulo, Ascension, Saint Helena, Cape Verde, Sao Tome & Principe) is also provided. PMID- 27470750 TI - Erratum: CHATMONGKON SUWANNAPOOM, ZHI-YONG YUAN, JIN-MIN CHEN, MIAN HOU, HAI-PENG ZHAO, LI-JUN WANG, TRUONG SON NGUYEN, TRUONG Q. NGUYEN, ROBERT W. MURPHY, JAQUELINE SULLIVAN, DAVID S. MCLEOD & JING CHE (2016) Taxonomic revision of the Chinese Limnonectes (Anura, Dicroglossidae) with the description of a new species from China and Myanmar. Zootaxa, 4093: 181-200. PMID- 27470752 TI - Phylogeny and revision of a colorful Neotropical genus of rove beetles: Xenopygus Bernhauer (Coleoptera: Staphylinidae). AB - Xenopygus Bernhauer is one of the most colorful staphylinid beetles and widespread in the Neotropical region. The aim of this study was to test the monophyly of Xenopygus based on adult morphology and to review the current species. Cladistic analysis was performed with six ingroup species, including two new species. Xenopygus is a monophyletic group supported by: antennomere V as wide as long to slightly wider, antennomere VII two times wider than long and superior line of pronotal hypomere developed, continuous on the anterior angle of pronotum. Xenopygus is composed of six species, four previously described and two new species, with the following topology: ((X. analis+(X. bicolor+X. confusus))+(X. cordovensis+(X. sancticamillus, sp. nov.+ X. petilicolis, sp. nov.))). Xenopygus is the sister group to a clade formed by species of Dysanellus and Xanthopygus, corroborating previous phylogenetic studies. The genus, and all its species were redescribed, an identification key was produced and illustration diagnostic plates and distribution maps were also provided. PMID- 27470753 TI - Eleven new species of Athacryvac Braet & van Achterberg from the Neotropical Region (Hymenoptera, Braconidae, Rogadinae). AB - The neotropical genus Athacryvac Braet & van Achterberg was recently described based on two species from French Guiana. Despite the resemblance of these species with the diverse and widespread genus Aleiodes, the authors opted to erect the new genus based on several synapomorphies. With the analysis of more comprehensive morphological and geographical variation we propose reclassifying Athacryvac as a subgenus within Aleiodes. In this paper we describe 11 new neotropical species of the subgenus Athacryvac: Aleiodes (Athacryvac) achterbergi Shimbori & Penteado-Dias sp. nov., Aleiodes (Athacryvac) amazoniensis Shimbori & Almeida sp. nov., Aleiodes (Athacryvac) braeti Shimbori & Shaw sp. nov., Aleiodes (Athacryvac) choco Shimbori sp. nov., Aleiodes (Athacryvac) donaldquickei Shimbori & Penteado-Dias sp. nov., Aleiodes (Athacryvac) gonzalezi Shimbori & Shaw sp. nov., Aleiodes (Athacryvac) paradoxus Shimbori & Penteado-Dias sp. nov., Aleiodes (Athacryvac) soaresi Shimbori & Penteado-Dias sp. nov., Aleiodes (Athacryvac) tico Shimbori & Shaw sp. nov., Aleiodes (Athacryvac) torresi Shimbori & Shaw sp. nov., Aleiodes (Athacryvac) zaldivari Shimbori & Almeida sp. nov. We also provide new morphological and distributional data for the previously described A. alternatus and A. fuscatus, as well as the description of the male of the later species. The 13 known species of Aleiodes (Athacryvac) stat. nov. are restricted to the Neotropical Region, ranging from southern Mexico to southern Brazil. With our current results, there are 104 described neotropical Aleiodes species. PMID- 27470754 TI - Caddisflies (Trichoptera) and diatoms of some springs in the vicinity of Lodz (Central Poland). AB - The distribution, species richness and ecology of Trichoptera, the diversity of benthic diatoms, and hydrochemical data in 7 springs in the vicinity of Lodz were investigated in 2011. In total, 17 Trichoptera taxa and more than 300 diatom taxa were collected from the studied springs. Trichoptera and especially diatom taxa are very sensitive indicators of ecological conditions; both showed a strong response to degradation in lowland springs. On the basis of faunal, diatom microfloral, and hydrochemical data, the typology of springs of the vicinity of Lodz is proposed. Two groups of factors (differentiating and non-differentiating) which contribute to distinguishing the studied springs are described. Additional experiments and observations were done on Trichoptera, including their life cycles, biology, and larval diet. In particular, the abundance of common diatom taxa in the guts of Silo sp. larvae was investigated. PMID- 27470755 TI - Larvae of Hydropsyche angustipennis (Trichoptera, Hydropsychidae) as indicators of stream contamination by heavy metals in Lodz agglomeration. AB - A biomonitoring technique was employed to assess metal contamination of several degraded urban streams in the Lodz agglomeration. Presence of heavy metals (Zn, Cu, Fe, Cd, Pb, Cr, was determined in whole bodies of Hydropsyche angustipennis larvae. Larvae of H. angustipennis were the only caddisflies living in most of investigated streams. These metals as well as other environmental variables were investigated in sediments or free waters of urban streams and in a stretch of a similar size of the Grabia River (reference site), outside the city but still in the vicinity of the Lodz agglomeration. The results of our research demonstrated different levels of contamination of urban streams as well as a correlation between environmental and larval tissue concentrations of heavy metals. Significant differences among sites were observed for metal concentrations in H. angustipennis larval bodies and larval responses to metals were time specific. The highest concentration of heavy metals was observed during the spring months. Differences were evident among various heavy metal levels in the bodies of larvae collected from different streams and at different sampling stations in the same stream. PMID- 27470756 TI - A new species of Neoephemera McDunnough, 1925 (Ephemeroptera: Neoephemeridae) from North Carolina and Virginia. AB - Neoephemera eatoni sp. nov. is described based on nymphs, imagos, and eggs from North Carolina and Virginia, USA. Nymphs of the new species are associated only with hornleaf riverweed (Podostemum ceratophyllum) growing on the surfaces of cobbles and boulders in moderate to swift flows, at a depth of up to one meter. Life stages were associated by laboratory rearing. Nymphs of the new species are distinguished from other Nearctic Neoephemera by the following combination of characters: all legs are short and stout, with overall lengths subequal to each other; tibial and tarsal lengths are subequal on all legs; tarsal claws are sharply curved; anterolateral projections on the pronotum and mesonotum are reduced; and anterosubmedian tubercles are absent from the pronotum. Male and female imagos exhibit unique abdominal maculations; the anterior protuberance of the mesonotum is obovate; and distinct leg banding patterns are absent. Male imagos have the fore tibia at least 2* the length of mid and hind tibiae, and female imagos have all legs subequal in length. Our new species may be most closely related to N. youngi based on imagos of the two species each having a small spine posteromedially on abdominal tergum II and having annulated terminal filaments. An updated key to North American species is provided. PMID- 27470757 TI - Balitora chipkali, a new species of stone loach (Teleostei: Balitoridae) from the northern Western Ghats of India, with a note on the distribution of B. laticauda. AB - Balitora chipkali, a new species of stone loach, is described from the westward flowing Astoli tributary of the Kali River system in the northern part of the Western Ghats, India. The species differs from its congeners in a combination of characters that includes: a single pair of maxillary barbels; a large eye, of diameter greater than 15% head length (HL); snout length less than 4 times eye diameter; gape of mouth less than 30% HL; upper lip with 9-12 papillae in first series and 3-8 papillae in second series; flattened body, of depth less than 15% standard length; caudal-peduncle length less than three times its depth, 66-68 lateral line scales, 11 caudal vertebrae excluding compound centrum, third infraorbital sensory canal tube straight; and a distinct color pattern with almost round 7 dorsal saddles not reaching lateral irregular crossbar markings. Balitora chipkali forms a monophyletic group with B. laticauda as its sister taxon in a phylogeny based on a concatenated cytochrome b (Cytb) and cytochrome oxidase subunit 1 (COI) gene fragments. Raw genetic distance between B. chipkali and B. laticauda was 1.9-2.2% based on COI and 3.4-4.3% based on Cytb partial gene sequences, which was far more than the intra-species variation in widely separated populations of B. laticauda. Based on molecular and morphological analysis, we also provide new locality records for B. laticauda and delimit its distribution to eastward-flowing tributaries of the Krishna River system in the northern Western Ghats. PMID- 27470758 TI - Description of four new South American species of Desmiphorini (Coleoptera, Cerambycidae). AB - Four new Desmiphorini are described: Inermestoloides ecuadorensis from Ecuador; I. birai and I. drumonti from Brazil (Amazonas); and Estola orellana from Ecuador. Estola orellana sp. nov. is included in a previous key. A key to species of Inermestoloides Breuning, 1966 is provided. PMID- 27470759 TI - Lysmata leptodactylus, a new species of lysmatid shrimp (Crustacea: Decapoda: Caridea) from China. AB - A new species of lysmatid shrimp, Lysmata leptodactylus n. sp., is described and illustrated based on specimens collected from the subtidal zone in Guangdong province, South China Sea. The new species bears distinctly unequal second pereiopods and uniquely elongated gracile dactyli of the ambulatory pereiopods. These characters, combined with the rostral formula, and stylocerite proportion, immediately distinguish Lysmata leptodactylus n. sp. from all known species of lysmatid shrimp. PMID- 27470760 TI - Two newly introduced tropical bark and ambrosia beetles (Coleoptera: Curculionidae, Scolytinae) damaging figs (Ficus carica) in southern Italy. AB - In summer 2014, the bark beetle Hypocryphalus scabricollis (Eichhoff) and the ambrosia beetle Xyleborus bispinatus Eichhoff, species new to Italy and Europe, respectively, were found for the first time in south-eastern Sicily (Italy). Large infestations of the two species were recorded in many plantations of common fig (Ficus carica L.) both in 2014 and 2015. Data concerning insect characteristics, taxonomy, and distribution are briefly reported. PMID- 27470761 TI - A remarkable new species of Sicophion Gauld, 1979 (Hymenoptera: Ichneumonidae) from Peru, with a key to the species. AB - The small Neotropical genus Sicophion currently comprises two described species. The genus is recorded for the first time in Peru and S. yana sp. n. is described. A key to species is also presented. PMID- 27470762 TI - Taxonomic revision of Collaria Provancher, 1872 (Hemiptera: Miridae) with the description of a new species from the Afrotropical region. AB - Collaria Provancher (Mirinae: Stenodemini) is a genus of grass-feeding plant bugs with 14 recognized species. The present work presents a taxonomic revision of the genus, including redescriptions of all species and the description of C. schwartzi sp. nov. from Central and Eastern Africa. The female genitalia of C. boliviana and C. villiersi, and the male and female genitalia of C. improvisa and C. obscuricornis are described for the first time. New distributional records for the Neotropical region are provided. A key to separate all the species and illustrations of the male and female genitalia of almost all the species are included. We highlight the need to produce better series of specimens with accurate host-plant data. PMID- 27470763 TI - Redescription of Bythotrephes arcticus Lilljeborg, 1901 (Crustacea:Cladocera: Onychopoda) and confirmation of an independent species status of the distant Transcaucasian populations of the genus Bythotrephes Leydig. AB - Two species of the genus Bythotrephes Leydig, B. arcticus Lilljeborg and B. transcaucasicus Behning, forming a group of close species, are redescribed on the basis of type material and other materials from Northern Eurasia. They were investigated with the application of detailed morphological analysis, including intra- and interpopulation variability and the original scheme of morphometric measurements. The lectotypes and paralectotypes of the species were selected. B. arcticus compared with other species of the genus, seem more evolutionary primitive and less specialized, judging from its large body size, comparatively short tl I, short and straight caudal process, well developed distal setae on two proximal endopodital segments of tl I, and large number of claws. B. arcticus tends to occur in small and shallow water bodies, while B. transcaucasicus was predominantly found in pelagic zone of large and deep Transcaucasian lakes. B. arcticus is probably mainly distributed along the tundra and northern forest area of the Eurasian continent and the nearest islands from Scandinavia to Eastern Siberia. Its documented easternmost locality is situated near the northern part of the Yenisei River, whereas B. transcaucasicus was recorded in the second half of 19th-first half of 20th century in three closely situated mountain lakes in Turkey, Georgia, and Armenia. The presence of B. arcticus in Northern Kazakhstan and B. transcaucasicus in the distant Transcaucasia is linked with their (or their ancestor) hypothetical displacement to the south in the period of ice ages. More recent surveys of Transcaucasian lakes have not revealed the presence of B. transcaucasicus. The rare findings of this species in the past can imply that it could also be missed in the process of collecting but, on the other hand, it cannot be excluded that B. transcaucasicus become extinct as a result of an anthropogenic or other impact on Transcaucasian lakes. PMID- 27470764 TI - A cryptic palm-pitviper species (Squamata: Viperidae: Bothriechis) from the Costa Rican highlands, with notes on the variation within B. nigroviridis. AB - Middle America is one of the most biodiverse regions in the world, harboring an exceptional number of rare and endemic species. This is especially true of Middle American cloud forests, where montane specialists occupy restricted, high elevation ranges making them attractive candidates for investigating historical biogeography and speciation. One such highland-restricted species, the black speckled palm-pitviper (Bothriechis nigroviridis), occupies the Central, Tilaran, and Talamanca Cordilleras in Costa Rica and Panama. In this study, we investigate the genetic and morphological variation among populations of B. nigroviridis by inferring a multilocus phylogeny (21 individuals) and analyzing meristic scale characters with a principal component analysis (64 individuals). We find B. nigroviridis sensu stricto to be composed of two deeply divergent lineages, one with a restricted range in the northern and central Cordillera Talamanca and the other ranging throughout the Central, Tilaran, and Talamanca Cordilleras. Furthermore, these two lineages are morphologically distinct, with previously unrecognized differences in several characters allowing us to name and diagnose a new species B. nubestris sp. nov. We also examine the genetic and morphological variation within B. nigroviridis and discuss biogeographic hypotheses that may have led to the diversification of Bothriechis lineages. PMID- 27470765 TI - Rhynchorhina mauritaniensis, a new genus and species of wedgefish from the eastern central Atlantic (Elasmobranchii: Batoidea: Rhinidae). AB - A new wedgefish, Rhynchorhina mauritaniensis gen. et sp. nov., is described from three specimens collected in the shallow waters of the shoal "Banc d'Arguin", off Mauritania (Eastern Central Atlantic). The new genus is mainly distinguished from its close relatives, members of the genus Rhynchobatus, by its snout shape, more broadly rounded like that of the shark-ray Rhina ancylostoma, instead of being typically wedge-shaped as in Rhynchobatus species. The new species resembles the common West African wedgefish, Rhynchobatus lubberti, in having a similar colour pattern, but differs in snout shape. The new genus is supported as genetically distinct by comparative analysis of the mitochondrial NADH2 gene. PMID- 27470766 TI - A re-appraisal of the widely-distributed freshwater crab genus Sinopotamon Bott, 1967, from China, with establishment of a new genus (Crustacea: Decapoda: Potamidae). AB - Freshwater crabs of the genus Sinopotamon Bott, 1967 (family Potamidae) are widely distributed along the Yangtze River (= Chang Jiang) drainage and are endemic to China. Two distinct clades can be distinguished within Sinopotamon s. lato. on the basis of morphological and molecular data. One clade corresponds to Sinopotamon s. str., with the type species Potamon (Potamon) davidi Rathbun, 1904, and 11 other species, all which occur in the Sichuan Basin (including Sichuan Province and Chongqing City) and reach the border areas of adjacent Shaanxi, Hubei, and Guizhou provinces. A new genus, Longpotamon gen. nov., is proposed for the second clade, with Sinopotamon exiguum Dai, 1997, designated as the type species. Sinopotamon s. str. can be distinguished from Longpotamon gen. nov. by the shape of the male telson and by characters of the male first gonopod and the female vulvae. These differences are supported by the mitochondrial 16S rDNA and cytochrome oxidase subunit I (COI) genetic data. Longpotamon gen. nov. is the largest clade, with 73 known species and a wide distribution along the Yangtze River drainage extending north to the Yellow River drainage and south to the eastern side of Wuyishan Range. The two genera overlap in the Sichuan Basin and the adjacent provinces. PMID- 27470767 TI - Contribution to our knowledge of the whitefly genus Aleuroclava Singh (Hemiptera: Aleyrodidae) in China, including Taiwan and Hong Kong, with descriptions of two new species. AB - Two new whitefly species, Aleuroclava sterculiae sp. nov., collected from Sterculia nobilis (Malvales: Sterculiaceae) of Qingxiu hill park (Guangxi, China), and Aleuroclava rosae sp. nov., collected from Stranvaesia sp. (Rosales: Rosaceae) of Maoer Mountain (Guangxi, China), are described with morphology, line illustrations, photographs and scanning electron microscope (SEM) images. In addition, two other whitefly species, Aleuroclava lefroyi (Sundararaj & David) and Aleuroclava manii (David), are reported as new to the fauna of China, and are discussed. An identification key to Aleuroclava species known from Mainland China, Taiwan and Hong Kong is provided. The specimens are deposited in the Insect Collection of Yangzhou University (YZU). PMID- 27470768 TI - Contribution to the knowledge of the oribatid mite genus Aeroppia (Acari, Oribatida, Oppiidae). AB - Two new species of the genus Aeroppia (Oribatida, Oppiidae) are described from upper soil and leaf litter in the primary evergreen lowland rainforest in Peru. Aeroppia friedrichi sp. nov. differs from A. nasalis Mahunka, 1984 by the absence of striate ornamentation on the notogaster and notogastral setae h1, and the presence of setiform adanal setae ad1. Aeroppia longisensilla sp. nov. differs from A. adjacens Mahunka, 1985 by the smaller body size and long bothridial setae. The supplementary descriptions of Aeroppia consimilis (Banks, 1910) and A. magnipilosa (Ewing, 1909) are presented, based on material from U.S.A. A new generic diagnosis for Aeroppia is given. The taxonomic status of the subgenus Aeroppia (Paraeroppia) Sanyal, 2009 is discussed, resulting in the following taxonomic proposal: Aeroppia Hammer, 1961 (=Aeroppia (Paraeroppia) Sanyal, 2009 syn. nov.). PMID- 27470769 TI - New species of Dinychus Kramer, 1886 from fragments of the former Gondwanaland (Acari: Uropodina: Dinychidae). AB - We describe two new species of Dinychus Kramer, 1886 from fragments of the former Gondwanaland supercontinent. Dinychus indica sp. nov. from India belongs to the Dinychus woelkei-group It differs from the previously known Dinychus species on the basis of the sculptural pattern of the sternal and genital shields of female. The female of Dinychus chilensis sp. nov. from Chile has a quadrangular genital shield, which is a unique character state in the genus Dinychus. New keys to the Central and South American Dinychus and to Dinychus woelkei-group are presented. PMID- 27470770 TI - Two new species and new records of Stilicoderus Sharp from China (Coleoptera, Staphylinidae, Paederinae). AB - Two new species of the genus Stilicoderus Sharp, 1889 from China are described and illustrated: S. maolini sp. nov. (Jiangxi, Hunan) of the S. variolosus group and S. chengrani sp. nov. (Xizang) of the S. signatus group. Additional records of eleven described species of Stilicoderus are given. PMID- 27470771 TI - Rediscovery of the 220-year-old holotype of the Banded Iguana, Brachylophus fasciatus (Brongniart, 1800) in the Paris Natural History Museum. AB - The Paris Natural History Museum herpetological collection (MNHN-RA) has seven historical specimens of Brachylophus spp. collected late in the 18th and early in the 19th centuries. Brachylophus fasciatus was described in 1800 by Brongniart but its type was subsequently considered as lost and never present in MNHN-RA collections. We found that 220 year old holotype among existing collections, registered without any data, and we show that it was donated to MNHN RA from Brongniart's private collection after his death in 1847. It was registered in the catalogue of 1851 but without any data or reference to its type status. According to the coloration (uncommon midbody saddle-like dorsal banding pattern) and morphometric data given in its original description and in the subsequent examination of the type in 1802 by Daudin and in 1805 by Brongniart we found that lost holotype in the collections. Another MNHN-RA specimen has Horn Islands (Wallis and Futuna) as the collection location but we show that most of the collections given to MNHN-RA by its collector, Louis Arnoux, have mixed localities in the MNHN-RA catalogues. We thus conclude that the locality is wrong and that the species never inhabited those islands located west of Western Samoa and north-east of Fiji. PMID- 27470772 TI - Revision of the genus Eueupithecia Prout, 1910 from Argentina (Lepidoptera, Geometridae, Sterrhinae). AB - A new species is described from Argentina: Eueupithecia vollonoides sp. n. and a differential diagnosis from E. cisplatensis Prout, 1910 is given. The genus Eueupithecia Prout, 1910 (Sterrhinae), so far having been retained to be monotypic, includes two species now. PMID- 27470773 TI - Inventory of the freshwater fishes from a densely collected area in South America a case study of the current knowledge of Neotropical fish diversity. AB - We herein analyse the history of the description of the freshwater fish fauna from three drainages in one of the most densely collected areas of Brazil, and possibly of South America, the Rio Grande do Sul State, southern Brazil. An updated inventory of the freshwater fish species from rio Uruguay (partial) in Brazil, Laguna dos Patos (complete) and rio Tramandai basins (complete) is presented. We found the number of new species described in these drainages increased nearly 56% since 1981, reaching a total of 422 species, but even now 10% of this number still corresponds to undescribed species. This rate of species description suggests that previous estimates of the Neotropical fish fauna are low, and we predict a final number of Neotropical fishes larger than the largest prediction estimate (8,000 species), after other regions of South and Central Americas become densely sampled. We discuss and attempt to demonstrate that species diversity knowledge is historically and strictly related to collecting efforts. We also demonstrate that the ecoregions in eastern South America with the highest density of species per area correspond to the areas more densely sampled in collections, and this may represent a bias in such kinds of analyses. This uneven sampling in Brazilian regions is apparently associated with the uneven distribution of Zoological research centers in different regions of the country. Small-sized species represents an important source of new species, along with little explored regions or little explored habitats, sometimes associated with restricted range species, and species complexes that need revisionary work. In contrast to other Neotropical regions, Atheriniformes are relatively diverse, sharing the fifth place in species richness with Gymnotiformes, and there is a remarkably high number of species of Rivulidae. Eight species are endemic to the rio Tramandai drainage, 68 to the Laguna dos Patos system, and 78 to the rio Uruguay drainage. Almost 10% of the freshwater fish species are "Critically Endangered", "Endangered" or "Vulnerable" according to the IUCN criteria, with Rivulidae as the family with the largest number of threatened species. PMID- 27470774 TI - Phylogeny of the Gondwanan beetle family Ulodidae (Tenebrionoidea). AB - Ulodidae is a small family of saproxylic and fungus feeding beetles restricted to New Zealand, Australia, Chile and New Caledonia. The phylogeny of this family is presented for the first time, based on a cladistic analysis of 53 adult characters from 16 ulodid genera, rooted with Parahelops Waterhouse (Promecheilidae). The topology shows Arthopus Sharp at the base of the tree and confirms the placement of Meryx Latreille as a member of Ulodidae and closely related to the Chilean genus Trachyderas Philippi & Philippi. The extinct New Zealand genus Waitomophylax Leschen & Rhode was placed among a clade consisting of Brouniphylax Strand, Exohadrus Broun, and Pteroderes Germain. Two new genera and two new species are described: Ulobostrichus gen. n. (type species: Ulobostrichus monteithi sp. n.) and Ulocyphaleus gen. n. (type species: Cyphaleus valdivianus Philippi & Philippi, 1864, now U. valdivianus (Philippi & Philippi) n. comb.; U. laetus sp. n.). Dipsaconia pyritosa Pascoe is designated as the type species of Dipsaconia Pascoe and a lectotype was designated for C. valdivianus. A fully illustrated key to the genera and a checklist of the 16 genera and 42 species is included. Based on the phylogeny, the following characters are derived in the family: tuberculate body surface and the presence of scales and /or encrustations. The presence of pore-fields in the abdominal cuticle has evolved at least three times in Meryx Latreille (Australia), Syrphetodes Pascoe (New Zealand) and Trachyderastes Kaszab (New Caledonia). PMID- 27470775 TI - The 'scorpion shrimp', a new species of the genus Metapontonia (Crustacea: Decapoda: Palaemonidae) from Taiwan, with new generic record from Papua New Guinea. AB - A new species of shrimp Metapontonia scorpio symbiotic with scleractinian coral Diploastrea heliopora is described from Taiwan. The species belongs to the smallest symbiotic shrimps of the family Palaemonidae. It is remarkable by a unique ability to turn its last two pleonites with tail fan dorsally over the 4th and preceding pleonal segments, thus resembling scorpions. For such movement, the respective opposing dorsal margins of the 4th 6th segments are deeply concave. The new species is characterized by a short dorsally directed rostrum, incomplete orbit, semicircular scaphocerite, and medially concave basal antennular segment. The only species of the genus, M. fungiacola, is compared with the new species based on morphology and DNA. Metapontonia fungiacola is for the first time reported from Taiwan and Papua New Guinea. The morphological and colour variability of the species is discussed. The scleractinian corals Platygyra lamellina (Merulinidae), Lobophyllia hemprichii, cf. Micromusa sp., Symphyllia cf. radians (Lobophylliidae), and Galaxea sp. (Oculinidae), are new host records for the species. PMID- 27470776 TI - Linderiella jebalae sp. nov. (Crustacea: Branchiopoda: Anostraca), a new species from the Rif mountains (northern Morocco). AB - A new species of fairy shrimp, Linderiella jebalae sp. nov., was found in temporary ponds located in the Rif region of northern Morocco. Morphological characters of females, such as the basal long warty outgrowth of the antennae, the highly developed cuticular papillae in the second genital segment, and the presence of a keel-shaped process directed posteriorly in dorsal side of the brood pouch, clearly distinguish this species from the others of the genus. In the case of males, the basiomedial antennal outgrowth and the distal segment of the antenna are diagnostic features for the species. Cyst ornamentation, characterized by thick, blunt and sometimes truncated spines, also separate this species. This is the fourth known Palaearctic Linderiella species, all of them described recently (from 1980s onwards) and located in a restricted area, from south-eastern France to Iberian Peninsula and Morocco. PMID- 27470777 TI - Review of Rhinotora (Diptera, Heleomyzidae) with description of a new species and key to all known heleomyzid species from Brazil. AB - Rhinotora Schiner, 1868, are a rare group of flies, previously including seven species distributed in the Americas, six of them occurring in Brazil. This work aims to provide a taxonomic review for Rhinotora Schiner, with addition of two species in the genus: Rhinotora fonsecai, which is transferred back to its original genus, and R. paschoali sp. nov. New distributional records are presented for R. lopesi and R. travassosi. A key to the all known heleomyzid species recorded from Brazil is provided. PMID- 27470778 TI - Three new species of Xenotarsonemus (Acari: Tarsonemidae) from the northwestern region of Sao Paulo State, Brazil. AB - Three new species of Xenotarsonemus Beer (Acari, Tarsonemidae), X. demitei n. sp., X. kaingang n. sp. and X. luziae n. sp., are described based on specimens collected from plants in native vegetation in the northwestern region of the Sao Paulo State, Brazil. PMID- 27470780 TI - A revision of the subgenus Xizicus (Paraxizicus) Liu, 2004 (Orthoptera: Tettigoniidae: Meconematinae). AB - The paper reviews the subgenus Xizicus (Paraxizicus) Liu, 2004, and describes one new species, i.e. Xizicus (Paraxizicus) furcistylus sp. nov. A key to the species and the distribution data are provided, as well as illustrations of important morphological characters of Xizicus (Paraxizicus) biprocerus (Shi & Zhang,1996) and Xizicus (Paraxizicus) anisocercus Liu, 2004 are given. PMID- 27470779 TI - A cryptic new species of Indigo Snake (genus Drymarchon) from the Florida Platform of the United States. AB - Indigo Snakes (genus Drymarchon) occur from northern Argentina northward into to the United States, where they inhabit southern Texas and disjunct populations in Mississippi, Florida and Georgia. Based on allopatry and morphological differences Collins (1991) hypothesized that the two United States taxa-the Western Indigo Snake, D. melanurus erebennus (Cope, 1860), and the Eastern Indigo Snake, D. couperi (Holbrook, 1842)-deserved full species recognition. Building upon this hypothesis with molecular and morphological analyses we illustrate that D. couperi is split into two distinct lineages. Based on the General Lineage Concept of Species, we describe the lineage that occurs along the Gulf coast of Florida and Mississippi as a new species, Drymarchon kolpobasileus. The new species is distinguished from D. couperi by a suite of morphological features, including a shorter and shallower head, deeper and shorter 7th infralabial scales, and shorter temporal scales. Overall, the presence of a deep 7th infralabial scale provides the best univariate identifier of D. kolpobasileus sp. nov. This study illustrates the usefulness of using both morphological and genetic data in refining accurate descriptions of geographical distributions. PMID- 27470781 TI - Revision of the Neotropical genus Carvalhoiella De Carlo (Heteroptera: Nepomorpha: Naucoridae). AB - The genus Carvalhoiella De Carlo, 1963 includes saucer bugs (Heteroptera: Naucoridae) that live predominantly on the vertical rocks next to falls and cascades of waterfalls. Thus far, it has been recorded only in South America and includes three described species. In the present paper, based on type specimens and additional material, we present detailed distributions and diagnostic information of the three described species of Carvalhoiella and the descriptions of two new species from central-western Brazil: C. acuminata sp. nov. and C. helenae sp. nov. An illustrated taxonomic key also is presented. PMID- 27470782 TI - Contribution to the Dermestidae (Coleoptera) of Thailand with description of two new species. AB - The following new species from Thailand are described, illustrated and compared with related species: Anthrenus (Nathrenus) herrmanni sp. nov., and Adelaidia thailandica sp. nov. A differential diagnosis as well as additional faunistic records are provided. A new faunistic record for Trinodes tonkineus Pic, 1922 is given. PMID- 27470783 TI - A new ant genus from southern Argentina and southern Chile, Patagonomyrmex (Hymenoptera: Formicidae). AB - The ant genus Pogonomyrmex (Hymenoptera: Formicidae: Myrmicinae) comprises 71 described species that occur in North America, South America, and Hispaniola, and it is the nominal genus in the recently established tribe Pogonomyrmecini. A molecular phylogeny using 3,647 base pairs from fragments of one mitochondrial gene (cytochrome oxidase I) and five nuclear genes (long-wavelength rhodopsin, elongation factor 1alpha F1, elongation factor 1alpha F2, wingless, rudimentary) inferred that Pogonomymrex was not monophyletic. The vast majority of species belonged to a monophyletic clade (Pogonomyrmex sensu stricto), whereas species in the Po. angustus-group formed a second lineage outside of Pogonomyrmex and Hylomyrma, the latter being the only other genus in the tribe. To maintain monophyly of Pogonomyrmex, we create the genus Patagonomyrmex gen. n., which consists of the three angustus-group species (Patagonomyrmex angustus comb. n., Patagonomyrmex laevigatus comb. n., and Patagonomyrmex odoratus comb. n.) that are sister to all other pogonomyrmecines. The genus is restricted to southern Argentina and southern and southcentral Chile. Workers are characterized by: (1) poorly-developed psammophore that consists of short to medium-length hairs scattered over the ventral surface of the head, (2) anterior clypeal margin strongly convex in full-face view, (3) clypeus strongly convex in profile, (4) superior and inferior propodeal spines long, (5) dorsal surface of promesonotum smooth and shiny, lacking rugae or if rugae present, then interrugae strongly granulate-punctate, (6) anteroventral margin of peduncle of the petiole with a small, acuminate spine, and (7) palp formula 5,4. We also provide information on biology, distribution maps, and a key to workers, queens, and males in English and Spanish. PMID- 27470784 TI - Morphology of Immatures of Acanthoderini (Cerambycidae, Lamiinae). AB - Morphological descriptions and comparisons of immatures of five species of Acanthoderini are presented. Larvae and pupae of Psapharochrus cylindricus (Bates, 1861) and P. vetustus (Bates, 1880), larva of P. jaspideus (Germar, 1824), and pupae of Oreodera glauca (Linnaeus, 1758) and Steirastoma stellio Pascoe, 1866, from Brazil, are described; larvae of the two latter species are redescribed. Until now, immatures of 20 species of this tribe were known. Remarks on characters in Acanthoderini and genera with known immatures are also included. PMID- 27470785 TI - Taxonomy of Atopsyche Banks (Trichoptera: Hydrobiosidae) from Brazil: New species, distributional notes and identification key. AB - Three new species of Atopsyche Banks 1905 are described and illustrated from Brazil: Atopsyche diamantina n. sp., A. kamakan n. sp., and A. muelleri n. sp. New records of A. apurimac Schmid 1989, A. sanctipauli Flint 1974, A. serica Ross 1953, and A. zernyi Flint 1974 are included, as well as the first records to states of Bahia, Goias, and Rio Grande do Sul. Atopsche rinconi Holzenthal & Cressa 2002 is recorded from Brazil for the first time. An identification key is also provided for species of the genus from Brazil. Moreover additional characters and illustrations of A. sanctipauli and A. zernyi are presented. PMID- 27470786 TI - New brachypterous species of Dichotomius (Selenocopris) Burmeister (Coleoptera: Scarabaeidae: Scarabaeinae) with the definition of species groups and taxonomic notes in the subgenus. AB - Five species groups of Dichotomius (Selenocopris) are defined and separated in an illustrated key in the first effective attempt of systematization of the subgenus. Four new brachypterous species of Selenocopris are described and the also brachypterous Dichotomius ingens (Luederwaldt) is redescribed. These species are diagnosed, illustrated and assigned to the quadraticeps species group. Taxonomic issues on the subgenus are discussed. PMID- 27470787 TI - Two new species of Eneopterinae crickets (Orthoptera: Gryllidae) from Luzon, Philippines. AB - Luzon Island is considered as the largest island in the Philippines and is characterized by a considerable biodiversity encompassing many endemic plant and animal species. In this paper, two new species of Eneopterinae crickets: (1) Lebinthus polillensis n. sp., and (2) Paranisitra septentria n. sp. are described and an updated key to the Philippines species of the subfamily Eneopterinae is provided. PMID- 27470788 TI - Revision of the Afrotropical genus Fernandea Melichar, 1912 (Hemiptera: Fulgoromorpha: Dictyopharidae), with description of a new species from Equatorial Guinea. AB - The Afrotropical planthopper genus Fernandea Melichar, 1912 (Hemiptera: Fulgoromorpha: Dictyopharidae: Dictyopharinae: Orthopagini) is revised to include two species: F. conradti Melichar, 1912 (the type species), with material studied from Cameroon, Equatorial Guinea (Bioko island) and Togo, and F. latifemorata sp. nov., described as new from mainland Equatorial Guinea. A lectotype is designated and a redescription is provided for F. conradti together with habitus photographs and detailed illustrations of the male and female terminalia which are published for the first time. PMID- 27470789 TI - Description of Cryptaphelenchus iranicus n. sp. (Nematoda: Ektaphelenchinae) recovered from bark samples of Pinus nigra from Iran. AB - Cryptaphelenchus iranicus n. sp., recovered from bark and wood samples of a weakened Pinus nigra in Kermanshah Province, western Iran, is described. The new species has females with body length of 250-330 um and males 230-275 um long, lip region set-off from body contour, 7-8 MUm long stylet with small basal swellings, excretory pore located at 1.5-2.0 body diam. posterior to median bulb, post vulval uterine sac short, 7-10 um long and conical female posterior body end (tail) ending to a pointed tip. Males of the new species have seven (1+2+2+2) caudal papillae and a short mucro at tail tip. Based on morphological characters, the new species is close to C. cirrus, C. latus and C. leptocaudus. Phylogenetic analyses using the D2/D3 fragment of 28S rDNA show the new species forming a clade with other Cryptaphelenchus species with maximal (1.00) Bayesian posterior probability (BPP) in Bayesian inference and 100% bootstrap value (BS) in the maximum likelihood method. The Cryptaphelenchus clade forms a monophyletic group with members of subfamily Ektaphelenchinae. PMID- 27470790 TI - Warning: potential problems for taxonomy on the horizon? AB - Whether or not a species might reasonably be described without the preservation of a type specimen is a matter of ongoing discussion among taxonomists (Dubois & Nemesio 2007; Minteer et al. 2014; Krell & Wheeler 2014; Lobl et al. 2016; Marshall & Evenhuis 2016; Santos et al. 2016). Here, we attempt to make our own contribution to the topic. PMID- 27470791 TI - New species of the genus Elachisina (Gastropoda: Elachisinidae) from northeastern Brazil. AB - The family Elachisinidae Ponder, 1985 includes minute marine gastropods that live predominantly in the sublittoral zone (Ponder & Keyzer 1998; Rolan & Rubio 2001; Rolan & Gofas 2003). Most elachisinids have been included in the genus Elachisina Dall, 1918 based on their shell morphology (Waren 1996; Rolan & Rubio 2001; Rolan & Gofas 2003), consequently, very little is known about the habitat and ecological niche of the species (Ponder & Keyzer 1998; Rolan & Gofas 2003). Elachisina floridana (Rehder, 1943) is the only Atlantic congener collected alive, and is known to live beneath rocks and in rocky crevices in the intertidal zone to about 1 m depth in the Bahamas and Caribbean Sea (Ponder 1985; Ponder & Keyzer 1998; Rolan & Gofas 2003; Redfern 2013). Eastern Atlantic E. canarica (Nordsieck & Garcia-Talavera, 1979) was also collected alive from the Canary Islands, but with no information on the habitat (Rolan & Gofas 2003). The islands of the northeastern Atlantic and West Africa are the regions with the greatest Elachisina richness known, totaling nine species (Rolan & Rubio 2001; Rolan & Gofas 2003). Only E. floridana has been recognized so far to be widely distributed throughout the Western Atlantic (Rolan & Gofas 2003; Rios 2009; Redfern 2013). PMID- 27470792 TI - Redescription of Thalassodes antithetica Herbulot, 1962, an endemic moth from Inner Seychelles (Lepidoptera: Geometridae: Geometrinae). AB - The Seychelles archipelago is characterized by an exceptionally high level of endemism in certain taxa, including at least 275 endemic species of Lepidoptera (Legrand 1966; Gerlach & Matyot 2006; De Prins & De Prins 2015). Despite the fact that endemics are the main objects of conservation efforts, information regarding endemic Seychelles Lepidoptera is very poor, because the majority of them are known from a single or a few specimens (Legrand 1966; Gerlach and Matyot 2006; Bolotov et al. 2014, 2015). The emerald moth specimens are lacking in extensive samples obtained by earlier collectors (Fletcher 1910; Scott 1910; Fryer 1912). Further, two emerald moth species in the genus Thalassodes Guenee, 1858 have been reported from Seychelles, i.e., the widespread T. quadraria Guenee, 1858 (Legrand 1966; Gerlach & Matyot 2006; De Prins & De Prins 2015) and the endemic T. antithetica Herbulot, 1962. The latter species is known from eight specimens, collected between 1959 and 1963 (Legrand 1966; Gerlach & Matyot 2006). Herbulot (1962) provided a very short description of this species without any illustration. The protologue consists of a description of some external characters, i.e., antennae, palpi and legs, as well as the pattern of markings, but the male and female genitalia are not described. As the main diagnostic features, Herbulot (1962) noted two specific characters in the male morphology, namely the hind tibia with a single pair of spurs and an exceptional development of the lateral processes (octavals) on the posterior margin of the eighth sternite. PMID- 27470793 TI - A new deep-water Astyris species (Buccinoidea: Columbellidae) from the southeastern Pacific. AB - Marine mollusks from northern Chile and from the Region de Atacama in particular have been sparsely documented, and only a few works have reviewed the area (see Araya & Araya, 2015; Labrin et al. 2015; Araya & Valdes 2016). Mollusks from deep water and offshore areas are one of the least known groups and, apart from some classic works from the 19th century, only McLean (1970), Bernard (1983), Veliz and Vasquez (2000), Fraussen & Haddorn (2000), Houart (2003), Vilvens & Sellanes (2010), and Araya (2013) have included deep-water molluscan species from northern Chile. Among the Neogastropoda, the Columbellidae constitute a quite diverse and well-distributed family of small snails, with about seven hundred extant species distributed in 70 genera (deMaintenon, 2014). Most columbellids are active epibenthic carnivores or scavengers; their shells are small, normally between 3 and 20 mm in height and they can have determinate growth, with many adult shells presenting a thickened outer lip with denticles on the interior surface (Squires, 2015). In the southeastern Pacific off Chile this family is represented by only 14 species, all from shallow water, mostly found in the northern and central parts of the country (Valdovinos, 1999). PMID- 27470794 TI - Cis regius, a new species of Cis Latreille (Coleoptera: Ciidae) from Southern Africa. AB - Cis Latreille is the most diverse genus of Ciidae with 350 species and a worldwide distribution (Oliveira et al. 2013). It houses more than a half of the described ciid species, but the available phylogenetic analyses based on molecular data suggest that Cis is polyphyletic (Buder et al. 2008; Lopes-Andrade & Grebennikov 2015). Currently, there is no thoroughly accepted subgeneric classification for Cis and parts of the species are organized into artificial species-groups (Lawrence 1971; Lopes-Andrade et al. 2003; Lopes-Andrade 2008; Oliveira et al. 2013). PMID- 27470795 TI - The millipede genus Enghoffosoma Golovatch, 1993 recorded in Vietnam
for the first time, with descriptions of three new species (Diplopoda, Polydesmida, Paradoxosomatidae). AB - The genus Enghoffosoma is recorded from Vietnam for the first time, altogether with six species involved. Two species, E. lanceolatum Likhitrakarn et al., 2014 and E. anchoriforme Likhitrakarn et al., 2014, were previously known only from the western part of Laos, thus being new to the fauna of Vietnam. One more species, Sundanina fedorenkoi Golovatch, 2016, very recently described from Dak Lak Province, southern Vietnam, is formally transferred to Enghoffosoma, comb. nov., based both on a strict topotype and a sample from Lam Dong Province, southern Vietnam. Three other species are described as new: E. triangulare sp. nov., E. retrorsum sp. nov. and E. digitatum sp. nov. A key to all six species of Enghoffosoma currently known to occur in Vietnam is provided. PMID- 27470796 TI - Description of a new species of Sitana Cuvier, 1829 from southern India. AB - A new species of Sitana to the ponticeriana group is described herein from southern Tamil Nadu, India. Sitana marudhamneydhal sp.nov. is most similar to Sitana visiri, from which it differs in body scalation and dewlap size. Much like Sitana visiri, the breeding of this species coincides with the North-East monsoon rains (October to December), an adaptation related to its geographic location which receives higher rainfall during the North-East monsoon than the South-West monsoon. PMID- 27470797 TI - New Neanurinae (Collembola: Neanuridae) from Central China. AB - Three new species, two of Vitronura and one of Lobellina of subfamily Neanurinae (Neanuridae, Collembola) from Central China are described. In addition a key for valid Lobellina species is included. PMID- 27470798 TI - Ampharetidae (Annelida: Polychaeta) from cold seeps off Pakistan and hydrothermal vents off Taiwan, with the description of three new species. AB - The new ampharetid species Eclysippe yonaguniensis sp. nov. and Glyphanostomum bilabiatum sp. nov. from the Yonaguni Knoll IV hydrothermal field off the coast of Taiwan and Pavelius makranensis sp. nov. from the cold seeps in the Makran accretionary prism off the coast of Pakistan are described. Amage cf. ehlersi Reuscher, Fiege & Imajima, 2015 and Anobothrus dayi Imajima, Reuscher & Fiege, 2013 are newly recorded from the Yonaguni Knoll IV hydrothermal field. PMID- 27470799 TI - A new species of the genus Peltogaster Rathke, 1842 (Cirripedia: Rhizocephala: Peltogastridae) parasitizing the hermit crab Pagurixus boninensis (Melin, 1939) from the Bonin Islands, Japan. AB - A new rhizocephalan species, Peltogaster unigibba n. sp., is described from the host hermit crab, Pagurixus boninensis (Melin, 1939), from the Bonin Islands, Japan. Of the16 known species of Peltogaster now currently recognised, P. unigibba n. sp., and P. contorta Boschma, 1958 share a left lobe that projects beyond the mantle aperture. The two species can be distinguished from one another by the position of the opening of the mantle aperture. The new species most closely resembles P. naushonensis Reinhard, 1946 in its internal structure, but clearly differs in the relative length of the colleteric glands. Peltogaster unigibba n. sp. represents the first record of a rhizocephalan from the oceanic Bonin Islands, and the second record of a rhizocephalan from an oceanic island in the northern hemisphere. PMID- 27470800 TI - Not "Alona" monacantha Sars, 1901, but Coronatella hardingi (Brehm, 1957) Crustacea: Branchiopoda: Cladocera) in the Afrotropics. AB - Many taxa formerly housed in the lump genus Alona Baird, 1843 remain data deficient. These species are often overlooked or wrongly identified during faunistic and ecological studies. "Alona" hardingi (Brehm, 1957) is a lesser known taxon, hidden for decades under records of "Alona" monacantha Sars, 1901. Both taxa have recently been allocated to the genus Coronatella Dybowski & Grochowski, 1894, yet without revision of the former. The morphology of Coronatella hardingi (Brehm, 1957), a widespread and abundant species in Afrotropical freshwater habitats, is examined here for the first time, including the first description of the male. The species is redescribed, based on populations from Southern Africa and confirmed as a good species and a valid sibling of the Neotropical C. monacantha (Sars, 1901) and the SE Asian C. acuticostata (Sars, 1903). The study of the Afrotropical C. hardingi allows a better understanding of this small tropical species complex, for which a diagnosis is included. PMID- 27470801 TI - A new species of wedgefish Rhynchobatus cooki (Rhinopristiformes, Rhinidae) from the Indo-West Pacific. AB - A new dwarf wedgefish, Rhynchobatus cooki sp. nov. is described from a single female from a Jakarta fish market (Indonesia) and 11 specimens collected at Jurong fish market (Singapore). First collected in 1934, the broader ichthyological community have been aware of this distinctive but little known ray since the late 1990's. Rhynchobatus cooki is the smallest of the wedgefishes (to 81 cm TL) and has the lowest vertebral count (fewer than 107 centra). It is also distinguishable from its congeners based on its long, hastate snout, very strongly undulate anterior pectoral-fin margin, coloration and aspects of its squamation. The dorsal coloration is mainly dark and distinctively marked with white blotches, spots and streaks, and has a dark cruciate marking on the interorbit and a prominent white border around the body margin. Unlike most other wedgefish species, the snout tip lacks dark blotches and there is no black pectoral-fin marking. It shares well-developed rostral spines with a much larger Atlantic species (Rhynchobatus luebberti), but these spines are confined to the snout tip (rather than being more numerous and extending in paired rows along the rostral ridges nearly to the eyes). No additional specimens have been observed since 1996, despite an increased recent effort to survey the chondrichthyan fauna of South-East Asia and collect biological data for species, raising concerns over its conservation status. PMID- 27470802 TI - A new species of Pseudogekko (Squamata: Gekkonidae) from the Romblon Island Group, Central Philippines. AB - We describe a new species of lizard in the genus Pseudogekko from Sibuyan and Tablas islands in the Romblon Island Group of the central Philippines. The new species is diagnosed from other Philippine Pseudogekko by body size and shape, color pattern, and multiple differences in scale characteristics. Pseudogekko isapa sp. nov. has been collected only twice from leaves of shrubs in forested habitat on Sibuyan and Tablas islands. The distinctive new species of false gecko is undoubtedly endemic to this single, isolated island group. The fact that populations of such a distinctive new species of Pseudogekko has escaped notice of herpetologists on the reasonably well-studied and largely protected Sibuyan Island further emphasizes the secretive and forest-dependent habits of Philippine false geckos. These characteristics of their behavior and natural history render them difficult to study and challenge biologists' efforts to accurately assess their conservation status. PMID- 27470803 TI - A new species of kukri snake (Squamata: Colubridae: Oligodon Fitzinger, 1826) from Con Dao Islands, southern Vietnam. AB - We describe a new kukri snake, Oligodon condaoensis sp. nov., from Con Dao Islands, southern Vietnam based on the morphological characters of four specimens. It differs from other congeners by a combination of the following characters: medium size in adults (total length up to 552 mm); 17-17-15 dorsal scale rows; deeply forked hemipenes without spines and papillae, extending to subcaudal 13 or 14; 11-13 maxillary teeth, the posterior three being enlarged; cloacal plate undivided; head scalation complete; nasal divided; presubocular absent; 168-176 ventrals; 33-37 subcaudals; overall dorsal coloration dark gray, faint body stripes present or absent; and ventral coloration cream to dark gray without rectangular blotches. We also provide a list of 43 species of amphibians and terrestrial reptiles recorded from Con Dao Islands. PMID- 27470804 TI - Immature biology and morphology of an obligate myrmecophilous butterfly Catapaecilma major moltrechti (Wileman) (Lepidoptera: Lycaenidae) from Taiwa. AB - The immature biology and morphology of Catapaecilma major moltrechti (Wileman) from Taiwan are reported. The larva of this taxon is proven to be largely predacious on a few scale insect species attended by ant Crematogester rogenhoferi in satellite nests constructed by the ants, but it also consumes plant material within or near ants' satellite nests in elder instars. The discovery of the food habit of this taxon is interesting as the larva of C. major is known to be phytophagous in India and Sri Lanka. PMID- 27470805 TI - The first records of Mesocapnia (Plecoptera: Capniidae) from China with description of a new species. AB - Three species of the capniid genus Mesocapnia are reported from the Inner Mongolia Autonomous Region of China, M. variabilis and M. gorodkovi, and M. daxingana sp. nov. These are the first records for the genus from China, extending the distribution of Mesocapnia into the Inner Mongolia Autonomous Region. PMID- 27470806 TI - New species, redescription and taxonomic notes in the Dichotomius (Luederwaldtinia) batesi (Harold) species-group (Coleoptera: Scarabaeidae: Scarabaeinae). AB - This paper deals with taxonomic issues of the Dichotomius (Luederwaldtinia) batesi (Harold) species-group. We describe Dichotomius benesi n. sp. from Panama, and redescribe and designate a lectotype for Dichotomius ocellatopunctatus (Felsche) from Venezuela, both hemi-brachypterous species. We also do brief comments on the taxonomy of this species-group. Dichotomius joelus, previously assigned to this group, is here considered to be a new synonym of D. opacipennis and then to belong to Dichotomius geminatus species-group. PMID- 27470807 TI - Going beyond the tip of the Drosophilidae iceberg: New Cladochaeta Coquillett, 1900 (Diptera: Drosophilidae) from Brazil. AB - Drosophilidae comprises more than 4,000 described species worldwide. Despite the huge number of papers published on the genus Drosophila Fallen, 1823, large parts of the family are still poorly known. The drosophiline genus Cladochaeta Coquillet, 1900 has more than 100 Neotropical and several southern Nearctic described species, but there is quite a large number of undescribed species. The Brazilian fauna of the genus was studied and 12 new species are herein described Cladochaeta armatopsis nov. sp., C. balbiae nov. sp., C. paraitinga nov. sp., C. asapha nov. sp., C.chauliodactyla nov. sp., C. conicophallus nov. sp., C. dicrophallus nov. sp., C.grimaldii nov. sp., C. atlantica nov. sp., C. periotoi nov. sp., C. phallotrixa nov. sp. and C. stigmata nov. sp. We set the first record of C. arthrostyla Grimaldi & Nguyen, 1999 for northeastern Brazil a species otherwise known from Costa Rica, and the first record of C. bomplandi (Malloch, 1934) for the state of Minas Gerais, a species known for northeastern Argentina and southern Brazil. The descriptions include photographs for each species and detailed illustrations of the male terminalia in different views. A synopsis on the taxonomy and natural history of the genus is provided, as well as comments about the relationships of species in the genus, a discussion on problems of male terminalia sclerite homology and the problem of association between males and females. PMID- 27470808 TI - A revised classification of the family Dasyatidae (Chondrichthyes: Myliobatiformes) based on new morphological and molecular insights. AB - The higher-level taxonomy of the stingrays (Dasyatidae) has never been comprehensively reviewed. Recent phylogenetic studies, supported by morphological data, have provided evidence that the group is monophyletic and consists of four major subgroups, the subfamilies Dasyatinae, Neotrygoninae, Urogymninae and Hypolophinae. A morphologically based review of 89 currently recognised species, undertaken for a guide to the world's rays, indicated that most of the currently recognised dasyatid genera are not monophyletic groups. These findings were supported by molecular analyses using the NADH2 gene for about 77 of these species, and this topology is supported by preliminary analyses base on whole mitochondrial genome comparisons. These molecular analyses, based on data generated from the Chondrichthyan Tree of Life project, are the most taxon-rich data available for this family. Material from all of the presently recognised genera (Dasyatis, Pteroplatytrygon and Taeniurops [Dasyatinae]; Neotrygon and Taeniura [Neotrygoninae]; Himantura and Urogymnus [Urogymninae]; and Makararaja and Pastinachus [Hypolophinae]), are included and their validity largely supported. Urogymnus and the two most species rich genera, Dasyatis and Himantura, are not considered to be monophyletic and were redefined based on external morphology. Seven new genus-level taxa are erected (Megatrygon and Telatrygon [Dasyatinae]; Brevitrygon, Fluvitrygon, Fontitrygon, Maculabatis and Pateobatis [Urogymninae], and an additional three (Bathytoshia, Hemitrygon and Hypanus [Dasyatinae]) are resurrected from the synonymy of Dasyatis. The monotypic genus Megatrygon clustered with 'amphi-American Himantura' outside the Dasyatidae, and instead as the sister group of the Potamotrygonidae and Urotrygonidae. Megatrygon is provisionally retained in the Dasyatinae pending further investigation of its internal anatomy. The morphologically divergent groups, Bathytoshia and Pteroplatytrygon, possibly form a single monophyletic group so further investigation is needed to confirm the validity of Pteroplatytrygon. A reclassification of the family Dasyatidae is provided and the above taxa are defined based on new morphological data. PMID- 27470809 TI - A review of species of the genera Protapalochrus Erichson and Paratinoides L. Medvedev (Coleoptera, Malachiidae). AB - The species of the genera Protapalochrus Evers, 1987 and Paratinoides L. Medvedev, 1964 are reviewed. A new subgenus, Protapalochrus (Latapalochrus) Tshernyshev, subgen. n. with type species P. puncticollis (Wittmer, 1970) is proposed. P. arcticus (L. Medvedev, 1958) comb. n. is transferred from Paratinoides L. Medvedev. Two species, Apalochrus chamaeleon Evers, 1971 syn. n. and Troglocollops eversi Iablokoff-Khnzorian, 1988 syn. n. are synonymized under P. puncticollis. The status and position of Apalochrus chamaeleon var. chamaeleonoides Evers, 1971 is discussed. Figures of male external appearance, special structures, genitalia, and distribution map for species are given, and a key to all species of the genus Protapalochrus is provided. PMID- 27470810 TI - Biogeography of Abyssocythere and Dutoitella (Ostracoda), with descriptions of three new species. AB - Ostracods have an extensive fossil record and are widely applied in palaeoenvironmental reconstructions. Here, we investigate the biogeography of two common and widespread genera, Abyssocythere and Dutoitella. Both appeared in the Cretaceous and are widely distributed in modern deep seas, but all species are restricted in distribution. The earliest record of Dutoitella is from shallow water, while the earliest Abyssocythere is from the deep sea. The Southern Ocean/Southern Atlantic seem to have been the area where both genera originated, and from which they eventually colonised other oceans. Dutoitella diversified into at least eleven species during Campanian-Eocene times, and by the end of the Eocene, the genus had spread to the Indian Ocean. This pattern continued after the establishment of the psychrosphere into the Neogene, with the development of numerous Miocene species. Abyssocythere, with 15 species, while also diversifying in the late Cretaceous South Atlantic, appears to have developed fewer species than Dutoitella. Finally, we describe three new species from the Southern Ocean (Abyssocythere bensoni sp. nov., Dutoitella karanovicae sp. nov. and Dutoitella richarddinglei sp. nov.), re-illustrate the types of Abyssocythere squalidentata (Brady, 1880) and Dutoitella suhmi (Brady, 1880), and study the soft parts of the genus Dutoitella, which were previously undocumented. PMID- 27470811 TI - Vulykhia, a new generic replacement name for Concavites Bondarenko & Minzhin 1981 (Anthozoa: Heliolitoidea) non Jeannet 1951 (Cephalopoda: Ammonitida). AB - The genus Concavites was established by Bondarenko & Minzhin (1981: 110) for fossil Upper Ordovician heliolitoids (Anthozoa) from Mongolian Altaj (Western and Eastern Mongolia, Central Eurasia), Kazakhstan (Northern Tien Shan) and Australia (Gondwana). However, the name is preoccupied by Concavites Jeannet (1951: 34), a fossil ammonite (Cephalopoda: Ammonitida: Oppeliidae), in current use (Arkell & al. 1957). PMID- 27470812 TI - Protaeropsis, a new replacement generic name for fossil Sphenaster Jeffery, 1999 (Echinoidea: Spatangida) nec Wilcoxon, 1970 (Protista: Haptomonada). AB - The genus Sphenaster was erected by Jeffery (in Smith et al. 1999: 131) for a distinctive fossil echinoid of the Thanetian (Palaeocene) age from Spain and considered to be the most ancient element of the echinoid family Aeropsidae Clark, 1917 (Spatangida, Echinoidea). Unfortunately, up to now (Kroh 2010), it was not realized that the generic name Sphenaster is invalid, being a junior homonym of Sphenaster Wilcoxon, 1970: 80, a genus of fossil protist (Haptomonada). PMID- 27470813 TI - Description of the female of Catocala toropovi Saldaitis et al. 2014 (Lepidoptera, Erebidae). AB - Catocala toropovi Saldaitis, Kons & Borth, 2014 was recently described from the valleys of the Ili and Charyn rivers in southeast Kazakhstan. This species is similar to C. repudiata Staudinger, 1888 and C. optima Staudinger, 1888, but differs on morphological as well as genetic characters (Saldaitis et al. 2014). Catocala toropovi was described based on male specimens, as females were unknown at the time. During studies of Lepidoptera in Xinjiang Province, China, two females of C. toropovi were collected, and this paper provides a brief description and analysis of the female of this species. PMID- 27470814 TI - Argentinian phlebotomine fauna, new records of Phlebotominae (Diptera: Psychodidae) for the country and the province of Chaco. AB - Sand flies are insects of medical and veterinary importance, because some species are able to transmit several pathogens such as Bartonella spp., Phlebovirus spp., and protozoan parasites of the genus Leishmania (Ross). They are widely distributed in the Americas, with recordings ranging from Canada to Argentina. Approximately 500 Phlebotominae species are known in the Americas, of which it is considered that at least 56 are involved in the transmission of leishmaniasis (Maroli et al. 2012). Previous studies have shown that the phlebotomine fauna in Argentina consists of 32 species distributed in 14 provinces (Quintana et al. 2012; Sabio et al. 2015; Salomon et al. 2010). Of these species, Lutzomyia longipalpis (Lutz & Neiva), Nyssomyia neivai (Pinto), Ny. whitmani (Antunes & Countinho), Cortelezzii complex [Evandromyia cortelezzii (Brethes) - Ev. sallesi (Galvao & Coutinho)], Micropygomyia quinquefer (Dyar) and Migonemyia migonei (Franca) have been found with DNA of Leishmania spp. (Moya et al. 2015). Five new records of species in the province of Chaco, obtained from different projects carried out between 2001 and 2015, four of which are also new records for Argentina, are described in this article. Their importance as potential vectors and the correct determination of the sympatric species is also discussed. PMID- 27470815 TI - A new species of Vargapupa Pall-Gergely, 2015 and a new synonym of Pseudopomatias Mollendorff, 1885 (Gastropoda: Caenogastropoda: Pupinidae). AB - Revision of the genus Pseudopomatias Mollendorff, 1885 and its relatives (Pall Gergely et al. 2015) resulted in the recognition of four genera, which agree in the (usually slender) turriform, spindle-shaped or almost cylindrical shell and the regularly ribbed teleoconch, except sometimes for the last half whorl. The genus Vargapupa Pall-Gergely, 2015, which differs from Pseudopomatias by possessing a basal keel, includes two species, one from Vietnam, and another from Laos. PMID- 27470816 TI - Resurrection of the family Aetobatidae (Myliobatiformes) for the pelagic eagle rays, genus Aetobatus. AB - Molecular and morphological data show that the pelagic eagle rays of the genus Aetobatus form a distinct family-level grouping separate from the true eagle rays, Aetomylaeus and Myliobatis (family Myliobatidae). The family Aetobatidae is herein resurrected to include the pelagic eagle rays and definitions are provided for this family and for the Myliobatidae. The key characters separating Aetobatidae from Myliobatidae are: pectoral fins joining head at level of eyes (vs. below level of eyes), internasal flap deeply notched (vs. nearly straight), free rear tip of pectoral fins broadly rounded (vs. angular), spiracles dorsolateral on head and visible in dorsal view (spiracles lateral on head and not visible in dorsal view), dorsal fin with obvious free rear tip (vs. no free rear tip evident, posterior margin joining dorsal surface of tail). PMID- 27470817 TI - A new addition to the genus Anthalona Van Damme, Sinev & Dumont, 2011 (Branchiopoda: Anomopoda: Chydoridae). AB - Continued fine-tuning of taxonomy in the Chydoridae Dybowksi & Grochowski, 1894 (Crustacea: Branchiopoda: Anomopoda) is important for the assessment of the diversity in this speciose family and our progress in chydorid biogeography and evolution. The continuation of the taxonomical study of single taxa, however tedious and seemingly unimportant, provides a fundamental basis for applied fields. Within this context, morphological studies on lesser known taxa and the establishment of their validity should continue, as so many uncertainties remain, e.g., in the lump genus Alona Baird, 1843 (Van Damme et al. 2010). Recent studies suggest that we are still far from a realistic image on cladoceran diversity, in particular for the Chydoridae (Forro et al. 2008, Van Damme et al. 2010). The current correspondence discusses the validity and the position of a single species, Alona milleri Kiser, 1948, originally described from the Pearl River, China (Kiser 1948). PMID- 27470818 TI - Zora alpina Kulczynski, 1915 (Araneae: Miturgidae): description of the male, redescription of the female. AB - Zora Koch, 1847 is a small genus distributed in the Holarctic region. The genus comprises 16 species, 14 of them distributed in the Palaearctic region and two from the Neartic (World Spider Catalog 2016). The European fauna includes 11 species (Nentwig et al. 2016), 8 of which are present in Italy (Pantini & Isaia 2016). Zora has historically been placed in several different families, but is now in the Miturgidae Simon, 1886 following the phylogenetic analyses of Ramirez (2014). PMID- 27470819 TI - Larval morphology of benthic and interstitial water mites (Acari: Hydrachnidia) from a Luxembourgian stream. AB - During a project of the Luxembourg National Museum of Natural History the parasitism of water mites dwelling a small stream (Lurenzgriecht) in the southern part of the country (Gutland) was investigated. The first step of the project was to clarify the taxonomy of the larvae of all stream-dwelling species. For that reason emergence traps were installed in the stream during 2002 and emptied every 14 days to obtain parasitized hosts. Additionally, rearing experiments were implemented in the laboratory to produce larvae of well-defined species/mothers but only with partly success. The stream has a well-known water mite inventory of 22 species, almost equally composed of true benthic species and species strongly adapted to hyporheic interstitial. The larvae of five species (Torrenticola elliptica, Atractides pumilus, Feltria motasi, Ljania macilenta, Neoacarus hibernicus) were described here as new to science. Due to the poor quality and availability of former descriptions a re-description was made for another species living in the stream (Sperchon denticulatus-gr.) and, additionally, for Hygrobates fluviatilis, a common stream-dwelling species of the area. The larvae of nine species of the Lurenzgriecht had already been sufficiently described for identification purposes (Protzia eximia, Sperchonopsis verrucosa, Sperchon clupeifer, S. thienemanni, Lebertia glabra, Atractides fonticolus, Feltria rouxi, Ljania bipapillata, Aturus fontinalis). The larvae of some other species (Aturus crinitus, Kongsbergia spp., Stygohydracarus subterraneus, Arrenurus haplurus) could neither be reared in the lab nor attributed to species for taxonomic reasons. With the exception of Kongsbergia spp. (no known larva of the genus worldwide) and Aturus crinitus (a rare species in the Lurenzgriecht) an identification key was compiled for the larvae of all known species of the stream using the new descriptions and all available information on the other ones. PMID- 27470820 TI - DNA barcoding the phyllosoma of Scyllarides squammosus (H. Milne Edwards, 1837) (Decapoda: Achelata: Scyllaridae). AB - Scyllarides has the largest number of species with commercial importance within the Scyllaridae family. As for other achelate lobsters, however, little is known of the unique long-lived planktonic phyllosoma stages of any of these tropical and temperate species. Recently, a large and diverse collection of Scyllaridae phyllosoma, compiled from cruises along the Coral Sea and spanning several years, has been analysed. Molecular evidence from DNA-barcoding and phylogenetic analyses is provided here on the identity of S. squammosus phyllosoma larvae, including stages that were previously undescribed or poorly known. As a consequence, the growth and morphological changes that occur during the mid- to late-stages of S. squammosus larval development is now well-documented. Furthermore, an additional collection of S. squammosus larvae, described by Alain Michel and thought to be no longer extant, were discovered in the crustacean collection of the Museum national d'Histoire naturelle, Paris. This new molecular and morphological information is complemented by a review of the literature. As a result, descriptions of key larval characters by a number of authors were evaluated and appear to suggest the existence of distinct groups of larvae within Scyllarides. From a combination of adult and larval morphology, and molecular data, the results presented here revealed inconsistencies with regard to the affinities of species assigned to Scyllarides. This new evidence will contribute to future studies addressing the phylogenetic relationships within the genus. PMID- 27470821 TI - Geophilus pygmaeus (Chilopoda: Geophilidae): clarifying morphology, variation and geographic distribution. AB - The European centipede Geophilus pygmaeus (Chilopoda: Geophilidae) has been known since 1880. It has been repeatedly reported since then and its validity has never been questioned. Nevertheless, a complete description of the species and an unambiguous diagnosis are still lacking. Based on the examination of one of the syntypes and > 110 specimens from 28 other localities, we provide here a full description and illustration of the morphology of G. pygmaeus and a revised and updated overview of the geographic range of the species. G. pygmaeus is less than 2 cm long, has 41-47 pairs of legs and differs from all other European species of Geophilus in a combination of characters including the shape of the forcipular apparatus and a unique arrangement of the coxal pores. G. pygmaeus is distributed through the Southern Limestone Alps, between the Bergamasque Prealps in the West and the Slovene Prealps in the East, and in the northernmost Dinarides. Published records from other European areas are actually erroneous or uncertain. PMID- 27470822 TI - An integrative taxonomy on the locally endangered species of the Korean Scarabaeus (Coleoptera, Scarabaeidae). AB - The ball-rolling dung beetles of the genus Scarabaeus are very ecologically important for the recycling of feces of large herbivores and the related nature management. There has been a significant decline, however, in the numbers of many species at the population and individual levels. S. typhon is currently thought to be the sole member of Scarabaeus distributed in Korea; however, that species underwent serious local extinctions in the 1970s. Before planning a full-scale species recovery, it is important to have an understanding of the exact species diversity and genetic structures of the focal species. We therefore attempted an integrative taxonomy focused on the Korean population of S. typhon and also on S. pius and S. sacer, which were once thought to be distributed in Korea, using both morphological and molecular approaches. The results of both approaches reveal the Korean species of Scarabaeus to be S. typhon and S. pius. In particular, our molecular results inferred from cytochrome c oxidase subunit I genetic analysis show that S. typhon should be considered a single species despite having various haplotypes throughout its wide geographical range from Europe to Korea. We identified two distinct lineages of S. pius (groups A and B) across a wide distributional range. We conclude that the Korean specimens of S. pius belong to group A and that S. pius is new to Korea under the current taxonomic treatment. PMID- 27470823 TI - Two new species of Philopteroides (Phthiraptera: Ischnocera: Philopteridae) of the beckeri species-group, from New Guinean painted berrypeckers (Aves: Passeriformes: Paramythiidae). AB - Two new species of the louse genus Philopteroides Mey, 2004 are described and illustrated from two host species of painted berrypeckers, endemic to New Guinea: Philopteroides sinancorellus n. sp. ex Oreocharis arfaki (Meyer, 1875) (tit berrypecker), and Philopteroides gigas n. sp. ex Paramythia montium De Vis, 1892 (crested berrypecker). Both louse species belong to the beckeri species-group based on their short, broad preantennal areas, and shallow median indentations of the hyaline margin. The description of these two new species brings the total number of Philopteroides species to 15. An amended key to the beckeri species group is included. PMID- 27470824 TI - Clarification of the katydid genus Uchuca Giglio-tos, 1898 (Orthoptera: Tettigoniidae): A new species in the Brazilian Amazon Rainforest. AB - This paper accomplishes three tasks: Firstly, description of a new species, Uchuca almeirina sp. nov., from the Brazilian Amazon Rainforest, specifically from Monte Dourado, Almeirim, Para. Secondly, it is proposed that Uchuca macroptera Montealegre-Z & Morris, 2003 be made a synonym of Uchuca ferreirai (Piza, 1976). Thirdly, a compilation of the generic distribution is presented, which includes new records of Uchuca amacayaca Montealegre-Z & Morris (2003) in Brazil and Uchuca similis Montealegre-Z & Morris (2003) in Colombia and Brazil, and the amplification of the occurrences of U. ferreirai. PMID- 27470825 TI - The genus Dromanthomorphus Pic, 1921 (Coleoptera, Cleroidea: Malachiidae) in South-East Asia. AB - South-East Asian species of the genus Dromanthomorphus Pic, 1921 and several species provisionally attributed to Hadrocnemus Kraatz, 1895 are studied, and their taxonomic position is specified. Three new species are described from the Philippines: D. subflabellatus Tshernyshev, sp. n., D. restrictus Tshernyshev, sp. n. and D. subtilis Tshernyshev, sp. n. Seven species are transferred from Hadrocnemus to Dromanthomorphus, D. apoensis (Wittmer, 1999) comb. n., D. blaisei (Pic, 1926) comb. n., D. chiangensis (Wittmer, 1999) comb. n., D. depressicornis (Pic, 1919) comb. n., D. gravieri (Pic, 1923) comb. n., D. javanus (Wittmer, 1989) comb. n. and D. tonkineus (Pic, 1919) comb. n. Three species are transferred from Dromanthomorphus to Oculapalochrus Tshernyshev, 2015, O. ranuensis Wittmer 1990 comb. n., O. saigonensis (Pic, 1951) comb. n. and O. suttoni Wittmer, 1995 comb. n., and two species from Dromanthomorphus to Mimapalochrus Tshernyshev, 2015, M. cingalensis (Champion, 1921) comb. n. and M. dolokensis Wittmer, 1999 comb. n. Illustrations of male external appearance, metathoracic appendage, urites and genitalia, and distribution maps are provided. A determination key to all species of Dromanthomorphus from South-East Asia is also proposed. PMID- 27470826 TI - A new species of Platyseius Berlese (Acari: Mesostigmata: Blattisociidae) from Iran, and a key to the world species of the genus. AB - We describe a new species of Platyseius Berlese, 1916 belonging to the subglaber species group, P. persicus sp. nov., on the basis of adult females collected in moist soil and litter in Kashmar, northeastern Iran and Nowshahr, northern Iran. A key to females of Platyseius is presented. PMID- 27470827 TI - On the Cryptops subgenus Trichocryptops Verhoeff, 1937, with a discussion of the problems of differentiating Cryptops species (Chilopoda: Scolopendromorpha: Cryptopidae). AB - Three putative species comprising Verhoeff's Cryptops subgenus Trichocryptops are here reviewed. There is little justification for the retention of the subgenus and the three species previously assigned to it are here placed in synonymy with the subgenus Cryptops. Cryptops (T.) malaccanus Verhoeff, 1937, closely resembles Nepalese C. doriae Pocock, 1891, and it is proposed that it be regarded as its junior subjective synonym. Cryptops doriae, as presently understood, is widely distributed and quite variable. Cryptops (T.) brachyraphe Attems, 1934, and C. (T.) iucundus Wurmli, 1972, are very similar but bearing in mind the present paucity of material, they are here retained as separate species. The possible characters distinguishing populations of C. doriae, C. nepalensis Lewis, 1999 and the three "Trichocryptops" species and C. niuensis Chamberlin, 1920, are reviewed. The current situation is far from satisfactory. Individual variation, possible ontogenetic changes, a relative paucity of morphological characters and small numbers of individuals render decisions as to the status of some Cryptops specimens problematical and subjective. PMID- 27470828 TI - A new species of Anthiadinae (Teleostei: Serranidae) from Sao Pedro and Sao Paulo Archipelago, Brazil, Equatorial Atlantic. AB - A new species of Anthiadinae, Odontanthias cauoh, is described from Sao Pedro and Sao Paulo Archipelago (SPSPA), Brazil, Equatorial Atlantic. The new species differs from its only Atlantic congener by a combination of several characters: pectoral-fin rays 20; total gill rakers on first arch 39; vomerine tooth patch with a posterior prolongation; pelvic fin not reaching base of last anal-fin ray; dorsal, anal and pelvic fins scaleless; and coloration (dorsal, anal, and pelvic fins mostly dark red). The record of the new species contributes to increase the fish endemism in SPSPA. PMID- 27470830 TI - JULIANA CHAMORRO-RENGIFO & HOLGER BRAUN (2016) Phlugis ocraceovittata and its ultrasonic calling song (Orthoptera, Tettigoniidae, Phlugidini). Zootaxa, 4107: 439-443. PMID- 27470829 TI - A new species of Anacaena Thomson, 1859 from South Africa (Coleoptera: Hydrophilidae). AB - Anacaena namaqua sp. nov. is described from the Northern Cape and Western Cape provinces of South Africa, in an area transitional between the fynbos and succulent karoo biomes. The habitus, aedeagus, femoral pubescence and habitats of the new species are illustrated, together with details of its ecology. A key to all Anacaena confirmed from South Africa to date is also provided. PMID- 27470831 TI - A comprehensive checklist of earthworm species and subspecies from Vietnam (Annelida: Clitellata: Oligochaeta: Almidae, Eudrilidae, Glossoscolecidae, Lumbricidae, Megascolecidae, Moniligastridae, Ocnerodrilidae, Octochaetidae). AB - The comprehensive checklist of earthworms in Vietnam is presented here listing 24 genera and 212 species arranged in eight families. For each species, bibliographic citations are given, including the original descriptions as well as notable citations affecting taxonomic status or distributional reports of a species. Distributions of each species are also provided. The bibliography contains all relevant papers for Vietnamese earthworms. Of 212 species, 114 have been recorded only in Vietnam, and 25 are cosmopolitan. New combinations are made for Amynthas acalifornicus (Do & Huynh, 1991) comb. nov., A. binhgiaensis (Le, 1994) comb. nov., Metaphire catbaensis (Thai & Le, 1993) comb. nov., M. khoii (Do & Tran, 1994) comb. nov., M. phaluongana (Do & Huynh, 1992) comb. nov., and M. mangophila (Nguyen, 2011) comb. nov., M. tripidoporophoratus (Thai & Nguyen, 1993) comb. nov. Additionally, Pheretima paraalexandri Nguyen, 2011 is treated as a junior synonym of Amynthas polychaetiferus (Thai, 1984). PMID- 27470832 TI - Benthic myodocopid Ostracoda (Philomedidae) from the Southern Ocean. AB - This study is based on the material of myodocopid ostracodes of the family Philomedidae collected by the Russian Antarctic Polar Expeditions (1963-2007) and the Germany Expeditions on R/V "Polarstern" (1990-2002) from the continental shelf and upper slope near the Mawson and Davis stations, the Weddell Seas, the region of the South Shetland Islands near the Russian Polar station "Molodezhnaya" and adjacent waters. Eight philomedid species belonging to two genera were identified in these collections. Scleroconcha tuberculata sp. nov. is described and figured as a new species. Additional descriptions and figures for the species S. gallardoi Kornicker, 1971, Philomedes assimilis Brady, 1907, P. charcoti Daday, 1908, P. heptatrix Kornicker, 1975, P. rotunda Skogsberg, 1920, P. orbicularis Brady, 1907 and P. tetrathrix Kornicker, 1975 are given. Keys for all species of the mentioned genera known from the Southern Ocean are presented. A list of sampling stations and species collected is provided in the Appendix 1. PMID- 27470833 TI - The Mysidae (Crustacea: Peracarida: Mysida) in fresh and oligohaline waters of the Mediterranean. Taxonomy, biogeography, and bioinvasion. AB - A census of Mysidae yielded a total of twelve species plus two non-nominotypical subspecies found so far in fresh and oligohaline waters of the Mediterranean, all belonging to the subfamily Mysinae. Among the nine species in fresh-waters, three are stenoendemics, namely of a single lake (Diamysis lacustris), of two neighbouring river systems (Paramysis kosswigi) or of karstic cave waters (Troglomysis vjetrenicensis). Four species-T. vjetrenicensis, D. lacustris, D. fluviatilis, and Paramysis adriatica sp. nov. described in this paper-are confined to freshwater tributaries of the Adriatic Sea (NE-Mediterranean). This strengthens previous findings about the outstanding role of the Adriatic basin for the endemic diversity of freshwater Mysidae within the Mediterranean. This is possibly related to alternating marine and freshwater-terrestrial phases during the Pliocene-Pleistocene in this semi-enclosed basin. Based on current knowledge, freshwater populations of D. mesohalobia heterandra are also confined to the Adriatic basin; this taxon, however, shows many more populations in brackish waters of the E-Mediterranean and Marmora basins. Two freshwater species (Limnomysis benedeni, Hemimysis anomala) are wide-range invaders of Ponto-Caspian origin, with recent expansion into fresh and brackish waters of the NW Mediterranean. A further immigrant to this part of the Mediterranean, Neomysis integer, is of NE-Atlantic origin and occurs only marginally in fresh-water. Five among the nine species found at least once in fresh-water were also reported in oligohaline conditions, mostly also at even higher salinities. A total of eight species plus two subspecies were recorded in oligohaline waters (S = 0.5-5). Among these, only one oligohalobious stenoendemic, Diamysis hebraica, inhabits streams at the Levantine coast. In the historical biogeographical context, the current distribution of only one out of nine indigenous species in an- to oligohaline waters of the Mediterranean, namely the mainly meso- to polyhalobious Mesopodopsis slabberi, may date back to the early Pliocene flooding of the Mediterranean by Atlantic waters and to later events. For most species, the biogeographical pattern points to a primary origin in the brackish (Miocene) Paratethys; solely the cave-dwelling T. vjetrenicensis has more ancient roots in the Tethyan (Mesogeic) Sea. Both these hypotheses are supported by chorological data and mainly the mineral composition of statoliths. The statoliths are composed of CaCO3 as the metastable crystal phase vaterite in nine species plus two subspecies considered versus the otherwise more common CaF2 (fluorite) in only three species (or in 7 + 2 versus two Mediterranean indigenes). All 12 + 2 Mediterranean taxa are figured and described in detail, particularly regarding P. adriatica sp. nov. and the substantially redescribed T. vjetrenicensis Stammer, 1933. Supplementary descriptions are given for P. kosswigi Bacescu, 1948, D. hebraica Almeida Prado-Por, 1981, and N. integer (Leach, 1814). A key to the 14 taxa is given including additional three species of potential future invaders. The tribe Mysini Haworth, 1825, is revised by detachment of the newly defined tribe Paramysini and of the revalidated Hemimysini Czerniavsky, 1882. A key to the resulting six tribes of the subfamily Mysinae is given. PMID- 27470834 TI - Review of Dissomphalus Ashmead, 1893 (Hymenoptera, Bethylidae) from Espirito Santo, Brazil, with description of twenty-one new species. AB - Forty-two species of Dissomphalus Ashmead, 1893 are reviewed, 21 of them are described and illustrated: Dissomphalus botocudus sp. nov., D. fredi sp. nov., D. tupinikim sp. nov., D. guarani sp. nov., D. congo sp. nov., D. rosangelae sp. nov., D. w-aedeagus sp. nov., D. amana sp. nov., D. potyra sp. nov., D. pyata sp. nov., D. clovisi sp. nov., D. kuara sp. nov., D. miriamae sp. nov., D. cacirus sp. nov., D. mirim sp. nov., D. secretus sp. nov., D. caparao sp. nov., D. capixaba sp. nov., D. ibirapitanga sp. nov., D. purius sp. nov. and D. taiabocu sp. nov. Six species are registered for the first time from Espirito Santo: D. brasiliensis Kieffer, D. bahiensis Redighieri & Azevedo, D. dumosus Evans, D. incomptus Evans, D. refertus Alencar & Azevedo and D. umbilicus Azevedo. Three species were reidentified: D. napo Evans, D. truncatus Azevedo and D. vallensis Azevedo. Among fifteen species-groups which recognized in the genus, amana species-group; amplus species-group and secretus species-group are newly proposed. PMID- 27470835 TI - Trimma tevegae and T. caudomaculatum revisited and redescribed (Acanthopterygii, Gobiidae), with descriptions of three new similar species from the western Pacific. AB - A redescription and diagnosis of Trimma tevegae, based on 50 additional specimens from the type locality at Rabaul, New Britain is provided, and contrasted with the redescription and diagnosis of T. caudomaculatum, based on the type material and an additional 22 specimens from various western Pacific localities. Trimma tevegae may most easily be recognized by the lack of a blue stripe (dark in preservative) in the dorsal midline of the snout, and a short second spine in the first dorsal fin, reaching posteriorly to the origin or first few ray bases of the second dorsal fin. Trimma caudomaculatum can be identified by the blue stripe from the snout along the dorsal midline, the blue spots and stripes in front of the eye, on the opercle and beneath the eye (dark in preserved material), and the very elongate second dorsal spine, usually extending to beyond the end of the second dorsal fin. Three similar-looking new species are described. Trimma burridgeae and T. hollemani are morphologically very close to each other, differing mainly in the length of the second dorsal spine (to the posterior base of the second dorsal fin or beyond in T. burridgeae; to the anterior base of that fin in T. hollemani). These two species differ by over 9% of the bases of the COI gene. Trimma corerefum is the most distinctive of the species, differing in lacking a blue stripe on the dorsal surface of the snout, in the pigment pattern around the eye, in having fewer cephalic sensory papillae (free neuromasts) in rows d', ea, ep, f, r and ot, and in a shorter fifth pelvic fin ray (34-45% length of fourth pelvic ray). The morphological differences between the species are reinforced by the results of a barcode analysis of the COI gene, based on 105 specimens. PMID- 27470836 TI - New taxa of Carpomyini, with special emphasis on Goniglossum (Diptera: Tephritidae: Trypetinae). AB - Goniglossum Rondani, hitherto a monobasic genus, is reinstated from synonymy under Carpomya Costa. A second species, Goniglossum liat n. sp., is described nearly two centuries after the description of the first species and 160 years after the description of Goniglossum. G. liat is described from Israel (also known from Turkey) and compared with G. wiedemanni (Meigen), an essentially European species, which is the type-species of Goniglossum and the only other known congener. The two species differ in details of the mesonotal and pleural color pattern (e.g., tip of scutellum with three small black spots in G. wiedemanni, whereas with one large spot in G. liat), structure of the male and female terminalia (e.g., the aculeus of G. wiedemanni is distinctly narrower apically than that of G. liat, and its tip has significantly fewer teeth), and host plant associations (Bryonia alba L. and B. dioica Jacq. are hosts of G. wiedemanni, whereas Bryonia cretica L. and B. syriaca Boiss. are hosts of G. liat). Myiopardalis Bezzi is also reinstated from synonymy under Carpomya. C. tica Norrbom, originally described in Carpomya, is transferred to Norrbomella, new genus, as its type and only included species. PMID- 27470838 TI - Two new species of Chromadoridae (Chromadorida: Nematoda) from the East China Sea. AB - Two new species of Chromadoridae, a family of free-living marine nematodes, are described from intertidal sediments of the East China Sea. Ptycholaimellus pirus sp. nov. is characterized by having a cuticle with six longitudinal rows of double dots and long somatic setae, relatively long cephalic setae, a pear-shaped terminal pharyngeal bulb occupying less than 30% of pharyngeal length, and an elongate conical tail. The new species is distinguished from all related species by the unique character of the cuticle, with six longitudinal rows of horizontal double dots, and the pear-shaped terminal pharyngeal bulb. Hypodontolaimus ventrapophyses sp. nov. is characterized by having a cylindrical body with a slightly expanded anterior end and a conical tail, a homogeneous cuticle with lateral differentiation of two longitudinal rows of larger dots, a well developed pharynx with oval-shaped buccal bulb and terminal bulb, and a large ventral gland. Males have slender, strongly curved spicules and a gubernaculum with a ventral apophysis, and precloacal supplements are absent. The new species differs from all related species in this genus by the structure of the gubernaculum, which has a ventral apophysis. PMID- 27470837 TI - Revision of the Taiwanese species of the genus Leptophion Cameron, 1901 (Hymenoptera: Ichneumonidae: Ophioninae), with a discussion of their phenology and distribution. AB - We revise the Taiwanese species of the ophionine genus Leptophion Cameron, 1901. As a result, three species, including a new species, are recognized. Two of them were identified as L. maculipennis (Cameron, 1905) and L. radiatus (Uchida, 1956), both of which had been previously recorded in Taiwan; we redescribe them based on Taiwanese specimens. We describe a single new species as L. giganteus Shimizu & Watanabe, sp. nov. The phenology and distribution of the species are briefly discussed. A key to the Taiwanese species of Leptophion and additional couplets to the key proposed by Gauld & Mitchell (1981) are also provided. PMID- 27470839 TI - New fossil genus of Silvanidae (Insecta: Coleoptera) from Baltic amber (Tertiary, Eocene). AB - The fossil silvanid beetle Mistran ot gen. et sp. nov. is described from Baltic amber. The new taxon is illustrated and compared with morphologically close extant and fossil taxa. A checklist of fossil Silvanidae is provided. PMID- 27470840 TI - New and interesting species of the genus Bryaxis Kugelann, 1794 (Coleoptera, Staphylinidae, Pselaphinae) from Croatia. AB - New data on the genus Bryaxis Kugelann, 1974 from Croatia are presented. Two new species, Bryaxis bedeki sp. nov. and Bryaxis biokovensis sp. nov. are described and illustrated. Bryaxis issensis (J. Muller, 1909) is redescribed based on six males collected at the type locality, in the cave Spilja kod Vlore on the island of Vis, and the aedeagus of this species is figured for the first time. New distributional data of Bryaxis scapularis (Reitter, 1881), Bryaxis crepsensis crepsensis (J. Muller, 1947), Bryaxis stolzi (Machulka, 1932), and Bryaxis erichsonii erichsonii (Kiesenwetter, 1849) are also provided. PMID- 27470841 TI - Passandra septentrionaria sp. nov.: the first described species of Passandridae (Coleoptera: Cucujoidea) from Eocene Baltic amber. AB - Based on two relatively well-preserved specimens from Eocene Baltic amber, Passandra septentrionaria sp. nov. is described and illustrated. It is the first formally described species of Passandridae from Baltic amber, and the first known European representative of the family. The global distribution of extant Passandra Dalman is mapped, and the historical distribution of the group is briefly discussed. PMID- 27470842 TI - Wallaceochromis gen. nov, a new chromidotilapiine cichlid genus (Pisces: Perciformes) from West Africa. AB - A new genus, Wallaceochromis, is described for the chromidotilapiine cichlids of the Pelvicachromis humilis group. It differs from Pelvicachromis sensu stricto in the number and arrangement of tubular infraorbitals, a straighter and sloping dorsal head profile with a low supraoccipital crest, higher abdominal vertebral counts (14-15 vs. 13-14), and in displaying a pattern of vertical bars on the body in several behavioral situations. PMID- 27470843 TI - Redescription of Dardjilingia Yang (Hemiptera: Heteroptera: Pentatomidae) from India. AB - The genus Dardjilingia Yang, 1936 (Hemiptera: Pentatomidae: Pentatominae: Lestonocorini), comprising a single species, Dardjilingia nigriventris Yang, 1936, is redescribed and illustrated, including the descriptions of male and female genitalia for the first time. The genus Dardjilingia is removed from the present tribe Lestonocorini. PMID- 27470844 TI - A review of the genus Eotmethis (Orthoptera, Acridoidea, Pamphagidae) with two new species and key to known species of the genus from China. AB - Two new species of the genus Eotmethis Bey-Bienko, 1948, namely Eotmethis inditibialis sp. nov. and Eotmethis shizuishanensis sp. nov. from the Ningxia Hui Autonomous Region are described in this paper. The new species Eotmethis inditibialis sp. nov. differs from all known species of the genus by inner side of hind tibia purple in the middle. The new species Eotmethis shizuishanensis sp. nov. is similar to Eotmethis xiai Ye, Shi & Zhi, 2015, differs from latter by tegmina of male shorter, reaching to 4th abdominal tergite, R vein without branch, M vein with one branch, Cu vein without branch and lower knee-lobe of hind femur yellow on inner side. The type specimens are deposited in College of Life Sciences, Hebei University, Baoding, China. Key to known species of the genus Eotmethis Bey-Bienko, 1948 is given. PMID- 27470845 TI - Discovery of a new species of the brachyelytrous net-winged beetle genus Alyculus (Coleoptera: Lycidae) from Peninsular Malaysia. AB - The net-winged beetle genus Alyculus Kasantsev is reported from Peninsular Malaysia for the first time and a new species, A. malaypeninsularis sp. nov., is described and illustrated. An expanded identification key to Alyculus males is provided and the biology and distribution of the species are discussed. PMID- 27470846 TI - New talitrids from South Africa (Amphipoda, Senticaudata, Talitroidea, Talitridae) with notes on their ecology. AB - Based on new talitrid amphipod collections from South Africa one new genus, Capeorchestia gen. nov., and one new species, Africorchestia meridionalis sp. nov., are described and Africorchestia quadrispinosa (K.H. Barnard, 1916) is redescribed. Eorchestia Bousfield, 1984 is redescribed. Based on this redescription Orchestia dassenensis (K.H. Barnard, 1916) is moved to Eorchestia and the Tasmanian species Eorchestia palustris Richardson, 1993 and E. rupestris Richardson, 1993 are moved to Microrchestia Bousfield, 1984. The current knowledge about the ecology of Capeorchestia capensis (Dana, 1853), Africorchestia quadrispinosa and A. meridionalis is summarized. PMID- 27470847 TI - Revision of southern African species of the anglerfish genus Chaunax
(Lophiiformes: Chaunacidae), with descriptions of three new species. AB - Species of the anglerfish genus Chaunax occurring off southern Africa are reviewed and nine species are recognized: C. africanus, C. apus, C. flammeus, C. penicillatus, C. russatus, C. suttkusi, and three newly described species. Chaunax atimovatae sp. nov. is distinguished by having numerous tiny melanophores on the skin and a mixture of bifurcate and simple spinules on its dorsal surface, scattered rounded green spots circled by yellow on its dorsal surface, 9 or 10 rakers on the second gill arch, and 2 neuromasts in the upper preopercular, 11-14 in the pectoral, 31-37 in the lateral-line proper. Chaunax heemstraorum sp. nov. is distinguished by a combination of all dermal spinules simple, large green spots on the dorsal surface, 10-12 rakers on the second gill arch; and 3 neuromasts in the upper preopercular, 13-18 in the pectoral, 37-42 in the lateral line proper, and usually 5 on the caudal-fin base. Chaunax hollemani sp. nov. is distinguished by cirri on top of the head, head width 16.0-18.5% SL, pre preopercle length 26.8-28.5% SL, 9 rakers on the second gill arch, and 2 neuromasts in the upper preopercular, 11-14 in the pectoral, and 33-38 in the lateral-line proper. A key to species found in the study region is provided. PMID- 27470848 TI - The genus Anisoscelis Latreille (Hemiptera: Heteroptera: Coreidae: Coreinae: Anisoscelini): new species, taxonomical arrangements, distributional records and key. AB - Anisoscelis currently comprises nine species and has been recorded from Texas (here recorded for the first time) on the south of the United States of North America across Mexico, Central and South America, but absent in Chile and the Great and Lesser Antilles; Anisoscelis (Bitta) flavolineatus Blanchard, 1849 is placed in synonym under Anisoscelis (Bitta) alipes Guerin-Meneville, 1831, and Anisoscelis (Bitta) flavolineatus osunai Brailovsky and Mayorga, 1995 is placed in synonymy under Anisoscelis (Bitta) hymenipherus Westwood, 1840; Anisoscelis (Anisoscelis) marginellus (Dallas) previously considered a subspecies under Anisoscelis (Anisoscelis) foliaceus (Fabricius) is removed to specific rank; a new species A. (Bitta) luridus from Mexico is described. Photographs of dorsal habitus and parameres and key to the known species are included. New distributional records for most of the species are given; food plants records are included with an apparent trophic preferences for member of the genus Passiflora. A complete checklist, with subgeneric position of each species is given. PMID- 27470849 TI - Description of a new early-derivative mite, Pentasetacus plicatus n. sp. (Acariformes, Eriophyoidea), and remarks on the systematic position of pentasetacines. AB - A new vagrant early-derivative eriophyoid mite species Pentasetacus plicatus n. sp. (GeneBank accession number KT070291) is described from Araucaria araucana (Molina) K.Koch from Chile and Peru with the aid of conventional and confocal laser scanning microscopy. Observations on the gnathosoma of the new species indicate that the oral stylet is bent in the middle and twice shorter than the infracapitular and cheliceral stylets. A trough-like subcapitulum originated from the palpcoxae, and swollen basal parts of chelicerae bearing putative cheliceral seta, were observed under CLSM in specimens with disjointed mouth parts. Males with an exposed gonopore under an uncovered genital coverflap and remnants of soft genital organs were registered. Contrary to other eriophyoids, the plates of the longitudinal bridge in P. plicatus n. sp. and other pentasetacines are not fused so that the genital slit continues posterior to the spermathecal apparatus. The previously established taxon Pentasetacidae Shevchenko, Bagnyuk, Sukhareva, 1991 is proposed for the eriophyoids bearing five prodorsal shield setae (Loboquintus and Pentasetacus); a refined diagnosis of Pentasetacidae is given. PMID- 27470850 TI - A new genus and species of cardinalfish (Percomorpha, Apogonidae, Sphaeramiini) from the coastal waters of Vietnam: luminescent or not? AB - Xeniamia atrithorax is a diminutive new genus and new species. The following combination of melanophore patterns is unique among known apogonids: a large cluster of melanophores in the skin anterior to the insertion of the pelvic-fin base, then extending forward along the sides of the isthmus; posterior portion of the oral chamber is black with melanophores extending below the gill apparatus forward along the base of the oral chamber thence along the basibranchials ending posterior to and below the level of the tongue; a line of large melanophores extends along the inner side of the ceratohyals; black to blackish stomach; and the anterior portion of the intestine is mostly pale with few black spots becoming more densely spotted with melanophores past the first bend and black from the second intestinal turn to the anus. The peritoneum is silvery with scattered melanophores that are more densely distributed along the lower portion of the abdominal cavity. There are two pale, large pyloric caeca at the connection between the stomach and intestine. The combination of eight first dorsal spines, two supernumerary dorsal spines, one supraneural, lacking an ossified basisphenoid, two epurals and fused hypurals 1+2, preopercle with a smooth ridge and edges, fourth dorsal spine longer than third distinguish this cardinalfish from all other genera. This new genus may be related to Jaydia in the Sphaeramiini rather than with the Ostorhinchini or Siphamiini. Possible luminescent activity is inferred from anatomy and unique melanization patterns versus suppression of light from luminescent prey in the alimentary canal. A table lists suspected and known luminescent apogonids. PMID- 27470851 TI - Contribution to the knowledge of Neoperla (Plecoptera: Perlidae) from Hainan Province of China. AB - The species of the perlid genus Neoperla are reviewed from Hainan Province, China. Three species of Neoperla, N. minuta sp. nov., N. wuzhishana sp. nov., and N. sexlobata sp. nov. are described from this island province and compared with other taxa. A provisional key is presented to the known Neoperla males from Hainan Province. PMID- 27470852 TI - A review of the Oriental leafhopper genera Thampoa Mahmood and Guheswaria Thapa (Hemiptera: Cicadellidae: Typhlocybinae). AB - The genus Guheswaria Thapa is recorded for the first time from China; two new species, Thampoa quinquemaculata sp. nov. and Guheswaria brevicula sp. nov. are described; one species, Guheswaria linguplata rec. nov. is newly recorded from China; and one new combination, Thampoa alata (Dworakowska, 1994) comb. nov. (from Guheswaria) is proposed. A checklist and updated keys to species of Thampoa and Guheswaria are provided. PMID- 27470853 TI - Paracercion ambiguum sp. nov. from Lang Son, Vietnam (Zygoptera: Coenagrionidae). AB - One new species of Paracercion Weekers and Dumont, 2004 (Paracercion ambiguum Kompier & Yu, 2016, holotype male, Vietnam, Lang Son province, Huu Lien Nature Reserve, 1-XII-2013, deposited in Institute of Entomology, College of Life Sciences of Nankai University, Tianjin, China) is proposed on the basis of molecular and morphological evidence. A COI gene tree is presented for Paracercion species and several morphologically related genera. The species is described and illustrated for both sexes. Diagnostic figures of the genital ligula and caudal appendages are provided. PMID- 27470854 TI - Acroteriobatus omanensis (Batoidea: Rhinobatidae), a new guitarfish from the Gulf of Oman. AB - The recently resurrected genus Acroteriobatus is represented in the western Indian Ocean by eight species, including a new guitarfish Acroteriobatus omanensis sp. nov. This small species (reaching ~60 cm TL) was discovered off Oman in an investigation of the chondrichthyan fauna of the Arabian in 2002 and 2003. Its distinctiveness from other members of the genus Acroteriobatus is strongly supported by molecular data. Acroteriobatus omanensis sp. nov. differs from all other members of the genus by its very narrowly pointed snout and having a dense pattern of small, symmetrically arranged ocelli each consisting of a white spot surrounded by a darker rim. Acroteriobatus annulatus and A. ocellatus have a more-or-less ocellated dorsal colour pattern but the markings are larger and differ in form (ocelli consisting of a small dark central spot surrounded by a dark-edged pale ring in A. annulatus; larger, irregularly shaped ocelli with pale centres surrounded by a dark brown rim in A. ocellatus). PMID- 27470855 TI - The first data on species diversity of leeches (Hirudinea) in the Irtysh River Basin, East Kazakhstan. AB - The Irtysh River is one of the major waterways of the Republic of Kazakhstan. The river originates in the territory of Mongolia and China, flows through the East Kazakhstan and falls into the Ob River in the Western Siberia of Russia. The Kazakhstan section of the river, with length of 1698 km and water resources about 43.8 km3 (Dyusebaeva 2012), is situated on the border of the West Siberian Plain, the Altai Mountains and the Kazakh Uplands. As the river crosses various natural zones, characteristics of its hydrological regime is very diverse. In the south, in the area of Ust-Kamenogorsk, the valley of the Irtysh extends. In the upper reaches up to the city of Semey (formerly Semipalatinsk), the river is surrounded by plain and mountain landscapes. Downstream from Semey, the Irtysh enters the West Siberian Plain and flows to north-west through dry steppes. The riverbed is unstable: sometimes it is very tortuous, sometimes it is broken into branches, and, there are a lot of sand spits. The hydrological level of the Kazakhstan part of the Irtysh River is regulated with the cascade of storage reservoirs near the towns Bukhtarma, Ust-Kamenogorsk and Shulbinsk. PMID- 27470856 TI - On a new species of the rare syllid genus Exogonoides (Annelida, Phyllodocida, Syllidae). AB - The genus Exogonoides Day, 1963, was described probably based on a single specimen, broken into two pieces (Aguado & San Martin 2008) and no other specimens of the type species, E. antennata Day, 1963, were ever found, which characterizes this species and, until now, the very genus Exogonoides, as 'singletons' (Lim et al. 2012). Although described as a member of the Syllidae Grube, 1850, the positioning of the genus in the family was recently questioned (Aguado & San Martin 2008), since the pharynx of the holotype was dissected for the original description and not preserved with the specimen, resulting that the presence of the proventricle, considered the main synapomorphy of the family, could not be confirmed. PMID- 27470857 TI - Redescription and lectotype designation of Chasmogenus abnormalis (Sharp), with notes on its distribution. AB - Chasmogenus Sharp, 1882 is a relatively small genus of 43 described species of aquatic beetles assigned to the subfamily Acidocerinae of Hydrophilidae (Hansen 1999; Short & Hebauer 2006; Short & Fikacek 2011, 2013; Clarkson & Ferreira-Jr. 2014). It is distributed in all zoogeographic regions except the Nearctic, with the highest species richness known from the Afrotropical (18 spp.) and Neotropical (15 spp.) Regions. Only four species have been described from the Oriental Region: C. abnormalis (Sharp, 1890), C. rubricollis (Regimbart, 1903), C. larsi Hebauer, 1995, and C. cattienus Hebauer, 2002. Of these, only C. abnormalis was recorded multiple times after its description. PMID- 27470858 TI - Two new, brachypterous Limnellia species from the Venezuelan Andes (Diptera: Ephydridae). AB - Two new, brachypterous species of Limnellia are described from specimens collected in the Venezuelan Andes: L. vounitis (Trujillo: Bocon, La Cristalina (Andes; 09 degrees 14.7'N, 70 degrees 19.1'W; 2500 m)) and L. flavifrontis (Merida: Merida, Sierra Nevada National Park (Laguna Negra; 8 degrees 47.1'N; 70 degrees 48.4'W; 3300 m)). To facilitate identification of these unusual species, we have included a diagnosis of the tribe Scatellini and of the genus Limnellia and have also provided an annotated key to the South American genera of this tribe. The descriptions are supplemented with illustrations, photographs, and scanning electron micrographs of external structures and structures of the male terminalia. PMID- 27470859 TI - Fourteen new species of Heterospilus Haliday (Hymenoptera, Braconidae: Doryctinae) from Brazil. AB - Fourteen new species of the genus Heterospilus Haliday found in semideciduous mesophilic forest areas at Sao Paulo State, Brazil are described. They are: Heterospilus ayewai sp. n., H. caetetus sp. n., H. fernandesi sp. n., H. fiorelinii sp. n., H. granulosus sp. n., H. homalos sp. n., H. intervalesi sp. n., H. japi sp.n., H. meloi sp. n., H. mesopleuron sp. n., H. periotoi sp. n., H. riveroni sp. n., H. sormusi sp. n., and H. virginensis sp. n. Heterospilus species are characterized by the sculpturation of the vertex: granulate, striate, rugose, or smooth, without sculpturation. All specimens of Heterospilus in this study are in the species group with a smooth, unsculptured vertex. PMID- 27470860 TI - Two new whiprays, Maculabatis arabica sp. nov. and M. bineeshi sp. nov. (Myliobatiformes: Dasyatidae), from the northern Indian Ocean. AB - Two new medium-sized whiprays, Maculabatis arabica sp. nov. and M. bineeshi sp. nov., are described from specimens collected in coastal habitats of the northern Indian Ocean, off India and Pakistan. Both species superficially resemble M. randalli (Last, Manjaji-Matsumoto & Moore), and appear to have been confused with a more widely distributed whipray M. gerrardi Gray, and another undescribed species from the Indian Ocean. Maculabatis arabica sp. nov. (attains at least 63 cm DW) is diagnosed by a combination of external characters, i.e. morphometrics (e.g. relatively short disc, narrow interspaces between paired structures on the head), squamation (relatively slow denticle development and a characteristic denticle band shape), plain dorsal disc coloration (rather than spotted), and tail light brown and banded beyond the caudal sting in juveniles but almost plain in adults. Maculabatis bineeshi sp. nov. (attains at least 66 cm DW) is diagnosed by a combination of characters, i.e. morphometrics (e.g. suboval to weakly rhombic disc in young), squamation (rapid denticle development and broad denticle band with margins truncate near pectoral-fin insertions), plain dorsal disc coloration (no white spots), and a dark blackish tail (especially in young) with weakly mottled banding on its dorsal surface beyond the caudal sting. Maculabatis arabica sp. nov. appears to be confined to the Arabian Sea (from Pakistan to western India), whereas M. bineeshi sp. nov. occurs in the Arabian Sea (off Pakistan and northwestern India) and in the Bay of Bengal (confirmed off Odisha, eastern India). PMID- 27470861 TI - Annotated checklist of Dryopidae and Heteroceridae (Coleoptera: Byrrhoidea) of Iran. AB - The distribution of Dryopidae and Heteroceridae (Coleoptera: Byrrhoidea) of Iran is summarized. A total of ten species of Dryopidae in three genera (Dryops Olivier, Parahelichus Lobl & Smetana, and Praehelichus Lobl & Smetana), and 18 species of Heteroceridae in two genera (Augyles Schiodte and Heterocerus Fabricius) are listed. Augyles hispidulus (Kiesenwetter, 1843) (Heteroceridae) is recorded from Iran for the first time. PMID- 27470862 TI - A comprehensive inventory of the Gulf of Alaska sponge fauna with the description of two new species and geographic range extensions. AB - Two new species, Hamacantha (Vomerula) cassanoi n. sp. and Prosuberites salgadoi n. sp., are described from the eastern Gulf of Alaska in the North Pacific Ocean. These are the first records of the genera Hamacantha and Prosuberites from Alaska. We also report two geographic range extensions for the region. Geodia japonica Sollas, 1888 was previously known only from Japan and is now recorded from the Gulf of Alaska. We also document the first record of Rhizaxinella cervicornis Thiele, 1898 from the Gulf of Alaska. Our comprehensive inventory of the sponge fauna of the Gulf of Alaska confirms the presence of 52 taxa with an additional 38 taxa suspected of occurring in the region. This is a much lower number of species than that recorded from neighbouring regions like the Aleutian Islands and British Columbia. PMID- 27470863 TI - A review of the Nearctic linyphiid spider Arcuphantes fragilis (Araneae, Linyphiidae) and closely related species. AB - The Western Nearctic species Arcuphantes fragilis Chamberlin & Ivie, 1943 and several closely related species are reviewed. Seven species are recognized, including two new species: A. cavaticus Chamberlin & Ivie, 1943, A. decoratus Chamberlin & Ivie, 1943, A. fragilis Chamberlin & Ivie, 1943, A. dentatus n. sp., A. curvomarginatus n. sp., A. potteri Chamberlin & Ivie, 1943, and A. sylvaticus Chamberlin & Ivie, 1943. The female of A. decoratus is described for the first time. These seven species share a same genital type, distinguishing them from other congeners, with small differences among them. Illustrations for A. dentatus n. sp., SEM images and digital photographs for all seven species are presented. Descriptions of new species, redescriptions of known species and a key for the seven species are provided. PMID- 27470864 TI - Protorhabditis hortulana sp. n. (Rhabditida, Protorhabditidae) from southern Iberian Peninsula, one of the smallest free-living soil nematodes known, with a compendium of the genus. AB - A new species of the genus Protorhabditis is described from agricultural areas in the South East of the Iberian Peninsula. Protorhabditis hortulana sp. n. is distinguished by its very small body length (189-222 MUm in females), lateral field with two longitudinal wings, lip region rounded with fused lips, stoma 10 13 MUm long lacking glottoid apparatus, pharynx with distinctly swollen metacorpus, excretory pore and deirids at basal bulb level, female reproductive system outstretched and spermatheca with self-sperm, vulva slightly postequatorial (V=54-62), female tail conoid (14-19 MUm, c= 11.7-17.6, c'= 1.6 2.4) with finely rounded tip, and males unknown. Description, measurements and illustrations, including SEM photographs are provided. A compendium of species of Protorhabditis is also given and illustrated. PMID- 27470865 TI - Leeches of the genus Helobdella (Clitellata: Hirudinida) from Sao Paulo, Brazil with descriptions of two new species using micro-computed tomography and a new record of Barbronia weberi (Blanchard 1897). AB - Leeches are an important group of macroinvertebrates found in the benthic zone of rivers, streams, lakes and ponds. Despite their ecological importance and potential as bioindicators, little is known about the diversity of leeches in Brazil, where only a few sporadic studies have been performed. Six locations in the region of Sorocaba, in the state of Sao Paulo, were sampled in order to study the diversity of predatory leeches. Besides traditional dissections, micro computed tomography was used to access the internal morphology of the new species Helobdella chaviensis n. sp. and Helobdella schlenzae n. sp. Four additional native species were found and redescribed using traditional techniques. The invasive species Barbronia weberi (Blanchard 1897) was reported in the Tiete River for the first time. PMID- 27470866 TI - A new long-snouted species of Corydoras Lacepede, 1803 (Siluriformes: Callichthyidae) from the rio Madeira basin. AB - A new species of Corydoras is described from the rio Aripuana, rio Madeira basin, Mato Grosso State, Brazil. The new species can be distinguished from its congeners by the presence of the following features: long mesethmoid, with anterior tip well developed, conspicuously larger than 50% of bone length; posterior margin of dorsal-fin spine with serrations directed towards tip of spine; one to two longitudinal black stripes on flanks; absence of a black blotch across the eyes (mask); absence of a large black blotch on dorsal fin; and transversal black bars on caudal fin. Comments on endemism in interfluvial region between Madeira and Tapajos rivers are briefly discussed. PMID- 27470867 TI - Pareiorhaphis vetula, a new armored catfish from the headwaters of the Rio Doce basin, Brazil (Siluriformes: Loricariidae). AB - A new species of Pareiorhaphis is described from the upper Rio Doce basin. The description is based on a series of specimens recently collected in small headwater tributaries to the Rio Guanhaes, a tributary of the Rio Santo Antonio, left bank of the Rio Doce in Minas Gerais State, eastern Brazil. Pareiorhaphis vetula, new species, is a small loricariid catfish with dark brown spots irregularly scattered over a brown background on the dorsal surface of body and along flanks. The new species differs from all other Pareiorhaphis species by having the maxillary barbel completely adnate to the lower lip and by adult males possessing a particularly elongate, sharply pointed, conical urogenital papilla. In addition, Pareiorhaphis vetula is further distinguished from most congeners by having a shorter pelvic-fin spine, or by possessing more numerous premaxillary teeth, and by lacking a dorsal-fin spinelet. A comparison with congeners P. nasuta, P. scutula and P. proskynita, which also occur in headwater streams of the Rio Doce basin is also presented. PMID- 27470868 TI - A review of Sri Lankan Brignolia including the description of four new species (Araneae: Oonopidae). AB - Sri Lankan species of the genus Brignolia Dumitrescu & Georgescu, 1983 are reviewed and four new species are described: B. carlmulleri sp. nov., B. meemure sp. nov., B. ondaatjei sp. nov. and B. shyami sp. nov. All new species are described based on both sexes. New data on B. ambigua (Simon, 1893), B. parumpunctata (Simon, 1893), B. ratnapura Platnick et al., 2011 and B. trichinalis (Benoit, 1979) are given. A total of 10 species are now known from Sri Lanka. B. ambigua, B. carlmulleri sp. nov., B. meemure sp. nov., B. ondaatjei sp. nov., B. ratnapura, B. shyami sp. nov. and B. sinharaja are endemic to the island. A key and a distribution map for Sri Lankan Brignolia are provided. PMID- 27470869 TI - Systematic studies of the genus Aegialomys Weksler, Percequillo and Voss, 2006 (Rodentia: Cricetidae: Sigmodontinae): Annotated catalogue of the types of the species-group taxa. AB - The genus Aegialomys was described to encompass the former Oryzomys xanthaeolus group, and includes nowadays two species: A. xanthaeolus and A. galapagoensis. Although not very confusing, the taxonomic history of the genus is long, comprising the description of five nominal taxa along the last 180 years: Mus galapagoensis Waterhouse, 1839; Oryzomys bauri Allen, 1892; Oryzomys xanthaeolus Thomas, 1894; Oryzomys baroni Allen, 1897; and Oryzomys xanthaeolus ica Osgood, 1944. Here we gathered and documented all available information about the type material of Aegialomys on which the species names were based, re-described their morphometric and morphological characters, commented their synonyms and taxonomic history, and compiled information about type localities. Additionally, we established a neotype for O. bauri in order to define the nominal taxon objectively. PMID- 27470870 TI - Description of a new species of Namalycastis (Annelida: Nereididae: Namanereidinae) from the Brazilian coast with a phylogeny of the genus. AB - The subfamily Namanereidinae represents one of the few groups of Polychaeta strongly adapted to low salinity and freshwater. Recently, some new species of the subfamily have been described, but no new phylogenetic analyses for the group have been undertaken since 1999. Here, we describe a new species of Namanereidinae, Namalycastis caetensis sp. nov., and provide a morphology-based phylogenetic analysis of the genus Namalycastis with the aim of assessing the evolutionary relationships for this new species. The designation of this new species is supported by the presence of elongated falcigers (also known as pseudospinigers, an unusual character in the genus), lack of an anterior cleft in the prostomium, slightly indistinct cirrophores, four pairs of tentacular cirri, and subconical acicular ligulae. Our results suggest that Namalycastis caetensis is closely related to N. geayi and N. fauveli. The existence of poorly characterized species, from a morphological and molecular point of view, still limits our understanding of Namanereidinae relationships. PMID- 27470871 TI - Descriptions of two new species of Afrotropical Psychodidae (Diptera). AB - Two new species of moth flies (Diptera: Psychodidae: Psychodinae) are described and illustrated on the basis of male morphological characters. Neoarisemus nyahururuensis sp. nov. was collected in the vicinity of Thomson's Falls (Nyahururu) in Kenya and Tonnoiriella veronikae sp. nov. in Toamasina province, Madagascar, Analamazaotra 1.4 km SSW Andasibe vill. (Perinet). PMID- 27470872 TI - Species of Coenosia Meigen (Diptera, Muscidae) described by Fritz van Emden from the British Museum Ruwenzori Expedition of 1934-1935. AB - All the species of Coenosia Meigen (Diptera, Muscidae) described by Fritz van Emden from the British Museum (Natural History) Ruwenzori Expedition of 1934-1935 (Emden 1940), supplemented by species from the Entomological Expedition to Abyssinia of 1926-1927 (Emden 1941), were studied, a total of 51 species. All types are deposited in the Natural History Museum, London, UK. For each species, a diagnosis is given and photographs of the 10 holotypes and of their labels are presented. Dissections and illustrations of the male terminalia were made when paratypes or identified specimens were available; all terminalia are described for the first time. One new synonym is proposed: C. kilembana (Emden, 1940) as a junior synonym of C. rebmanni Speiser, 1924; and three subspecies had their status revised and were elevated to species rank: C. brunneigena Emden, 1940, previously a subspecies of C. heterocnemis Emden, 1940; and C. albisquama (Emden, 1940) and C. argentescens (Emden, 1940), both previously subspecies of C. niveifrons (Stein, 1913). PMID- 27470873 TI - An annotated checklist of the psyllids of New Zealand (Hemiptera: Psylloidea). AB - A checklist of extant species of Psylloidea in New Zealand is presented. The list is structured according to the latest taxonomic classification of families, subfamilies and genera. It includes 99 species, 71 of which are formally described and named, along with information on the host plants and the natural enemies as aspects that are either species-specific or assist in their recognition. An updated distribution of each species is given based on literature records and material held in the major New Zealand entomological collections and databases, including from very recent field surveys. A new record for New Zealand is Phellopsylla formicosa. PMID- 27470875 TI - A new species of Oiovelia (Heteroptera: Gerromorpha: Veliidae) from Mesoamerica, with an identification key to the genus. AB - Oiovelia johnpolhemi sp. nov. is described and illustrated based on macropterous specimens collected in Mexico and Belize. This species is the tenth of the genus, and represents its first record outside South America. An updated identification key and distribution maps of all species of Oiovelia are presented. Finally, photographs of the macropterous form of O. spumicola Spangler are presented for the first time. PMID- 27470874 TI - A new burrowing crayfish of the genus Fallicambarus Hobbs, 1969 (Decapoda: Cambaridae) from the Red River Drainage of the southcentral United States. AB - A new primary burrowing crayfish, Fallicambarus schusteri, is described from the Red River drainage of extreme southeastern Oklahoma and southwestern Arkansas and is placed in the subgenus Fallicambarus. The species occurs in roadside ditches that seasonally flood and have silt and silt-loam dominated soils. Falllicambarus schusteri differs from all other members of the genus Fallicambarus in possessing a thin gradually tapering central projection and a wide triangular cephalic process on the first pleopod of form I males, a sufflamen on the cheliped, and an antennal scale that is widest at its midpoint. PMID- 27470876 TI - Two new species of the genus Stenichnus Thomson (Coleoptera, Staphylinidae, Scydmaeninae) from Zhejiang, East China. AB - Two new species of the glandulariine genus Stenichnus are described: St. zhejiangensis sp. n. and St. donggonganus sp. n., both of which are discovered from Zhejiang Province, East China. PMID- 27470877 TI - BARRY J. RICHARDSON (2016) New genera, new species and redescriptions of Australian jumping spiders (Araneae: Salticidae). Zootaxa, 4114: 501-560. PMID- 27470878 TI - Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. AB - Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ~5 mL.min(-1).1.73 m(-2) and ~30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL.min(-1).1.73 m(-2)). In contrast, blood pressure lowering, estimated glomerular filtration rate, and albuminuric effects are preserved, and perhaps exaggerated in chronic kidney disease. With regard to long-term clinical outcomes, the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) in patients with type 2 diabetes mellitus and established cardiovascular disease randomly assigned to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus. PMID- 27470879 TI - Imidazolium-embedded iodoacetamide-functionalized silica-based stationary phase for hydrophilic interaction/reversed-phase mixed-mode chromatography. AB - A novel imidazolium-embedded iodoacetamide-functionalized silica-based stationary phase has been prepared by surface radical chain-transfer polymerization. The stationary phase was characterized by Fourier transform infrared spectrometry, thermogravimetric analysis, and element analysis. Fast and efficient separations of polar analytes, such as nucleosides and nucleic acid bases, water-soluble vitamins and saponins, were well achieved in hydrophilic interaction chromatography mode. Additionally, a mixed mode of hydrophilic interaction and reversed-phase could be also obtained in the analysis of polar and nonpolar compounds, including weak acidic phenols, basic anilines and positional isomers, with high resolution and molecular-planarity selectivity, outperforming the commercially available amino column. Moreover, simultaneous separation of polar and nonpolar compounds was also achieved. In conclusion, the multimodal retention capabilities of the imidazolium-embedded iodoacetamide-functionalized silica based column could offer a wide range of retention behavior and flexible selectivity toward hydrophilic and hydrophobic compounds. PMID- 27470881 TI - [New thoughts are needed for the study of liver cancer recurrence and metastasis]. AB - In the recent years, our knowledge on cancer and metastasis has been renewed, and therefore new thoughts are needed for the study of cancer metastasis. Based on the fact that cancer is a systemic and dynamic disease which is caused by multiple factors, involves various genes, and has multiple stages, more studies should be conducted in the following aspects: (1) intervention of cancer metastasis; (2) systemic intervention focusing on the nervous system, immune status, endocrine, and metabolism; (3) studies on improving residual cancer and microenvironment; (4) studies on multimodality therapy, especially the combination of eradication and modification; (5) dynamic studies on cancer metastasis, especially the intervention leading to increased metastatic potential after tumor eradication. PMID- 27470880 TI - In-column ATR-FTIR spectroscopy to monitor affinity chromatography purification of monoclonal antibodies. AB - In recent years many monoclonal antibodies (mAb) have entered the biotherapeutics market, offering new treatments for chronic and life-threatening diseases. Protein A resin captures monoclonal antibody (mAb) effectively, but the binding capacity decays over repeated purification cycles. On an industrial scale, replacing fouled Protein A affinity chromatography resin accounts for a large proportion of the raw material cost. Cleaning-in-place (CIP) procedures were developed to extend Protein A resin lifespan, but chromatograms cannot reliably quantify any remaining contaminants over repeated cycles. To study resin fouling in situ, we coupled affinity chromatography and Fourier transform infrared (FTIR) spectroscopy for the first time, by embedding an attenuated total reflection (ATR) sensor inside a micro-scale column while measuring the UV 280 nm and conductivity. Our approach quantified the in-column protein concentration in the resin bed and determined protein conformation. Our results show that Protein A ligand leached during CIP. We also found that host cell proteins bound to the Protein A resin even more strongly than mAbs and that typical CIP conditions do not remove all fouling contaminants. The insights derived from in-column ATR-FTIR spectroscopic monitoring could contribute to mAb purification quality assurance as well as guide the development of more effective CIP conditions to optimise resin lifespan. PMID- 27470882 TI - [Molecular mechanism and pathological evaluation strategies for recurrence and metastasis of liver cancer]. AB - The strong invasiveness and metastasis of hepatocellular carcinoma (HCC) are not only the important pathological mechanisms of high recurrence rate and poor long term outcome, but also the important pathological basis for developing individualized regimens to control metastasis and recurrence in clinical practice. This article introduces the important molecular events in invasion metastasis cascade discovered in recent years, including the formation mechanism of metastatic niches, methods for molecular pathological evaluation, and standardized pathological diagnosis. PMID- 27470883 TI - [Multidisciplinary therapeutic strategies for recurrence and metastasis of liver cancer]. AB - With the development of early diagnostic and surgical techniques, the postoperative outcome of patients with liver cancer is gradually improved, but long-term outcome remains unsatisfactory. The therapeutic methods for recurrent tumors include multidisciplinary therapeutic methods such as reoperation, local treatment, and systematic treatment. Multidisciplinary therapies can improve the overall response of recurrent liver cancer, and it can combine various therapies from different disciplines according to the patient's condition and take advantages of each therapy in order to achieve the best therapeutic effect. PMID- 27470884 TI - [Prediction and preventive strategies for recurrence after surgery for hepatocellular carcinoma]. AB - Many advances have been achieved in the clinical and basic studies on metastasis and recurrence of hepatocellular carcinoma (HCC) over the past 20 years. The achievements mainly include the following aspects: (1) a group of molecules related to metastasis and recurrence including osteopontin have been identified, and multi-molecular predictive models for metastasis have been established and optimized; (2) it has been found that the imbalance of immune response in tumor microenvironment is important in promoting metastasis and can be used to predict metastasis and recurrence; (3) it has been found and confirmed that interferon can prevent postoperative recurrence, and patients with a lower miR-26a expression level can achieve greater benefits; (4) the breakthroughs in liquid biopsy and immunotherapy bring a promising future for the prediction, prevention, and treatment of HCC metastasis and recurrence. However, these predictive models still need to be validated by multi-center studies, and the effects of adjuvant transarterial chemoembolization and targeted therapy with sorafenib still need further evaluation. PMID- 27470885 TI - [HBsAg clearance rate in patients with HBeAg-positive chronic hepatitis B: a comparative effect analysis based on the real world]. AB - OBJECTIVE: To investigate HBsAg clearance rate in previously untreated patients with HBeAg-positive chronic hepatitis B (CHB) treated with nucleos(t)ides and interferons and its influencing factors based on the clinical diagnosis and treatment dat. METHODS: A retrospective cohort study was conducted in 1 767 previously untreated HBeAg-positive CHB patients who visited Beijing You'an Hospital from February 14, 2008 to December 31, 2012. HBsAg clearance rates were calculated for patients with different characteristics, and the Cox regression model was used to investigate the influencing factors for HBsAg clearance. RESULTS: The overall annual HBsAg clearance rate was 0.46% in 1767 patients, and in the patients treated with adefovir, entecavir, telbivudine, and common interferon, the annual HBsAg clearance rate was 0.52%, 0.47%, 0.45%, and 1.18%, respectively. No patients in the lamivudine and pegylated interferon-alpha groups experienced HBsAg clearance, which might be due to the small sample size. The univariate analysis showed that HBsAg clearance rate was associated with the patient's age when he/she visited the hospital and baseline HBsAg titer level. After adjustment for other factors, the patients treated with common interferon had a significantly higher possibility of HBsAg clearance than those treated with entecavir (HR = 8.33, 95% CI: 1.19-58.50, P = 0.0329), but the possibility of HBsAg clearance showed no significant difference between patients treated with other nucleos(t)ides and entecavir. The patients aged>=50 years had a probability of HBsAg clearance 4.92 times that of those aged < 50 years (HR = 4.92, 95% CI: 1.38-17.50, P = 0.0139) and the patients with baseline HBsAg titer level < 3 log10 IU/ml had a probability of HBsAg clearance 22.77 times higher than that of those with baseline HBsAg titer level>=3 log10 IU/ml (HR = 23.77, 95% CI: 6.17 91.51, P < 0.0001). CONCLUSION: The previously untreated CHB patients achieve a low annual HBsAg clearance rate under current antiviral therapeutic regimens, especially nucleos(t)ides. Baseline HBsAg titer level is closely associated with HBsAg clearance. PMID- 27470886 TI - [Role and clinical significance of Th17/Treg balance in patients with severe exacerbation of hepatitis B]. AB - OBJECTIVE: To investigate the role of Th17/Treg balance in immune mechanism in severe exacerbation of hepatitis B. METHODS: The clinical data of 41 patients with chronic hepatitis B were collected, and according to the conditions during hospitalization, these patients were divided into exacerbation group (19 patients) and improvement group (22 patients). On admission, at weeks 1 and 2 of treatment, and at the end of treatment, flow cytometry was used to measure the frequencies of Th17 and Treg cells in peripheral blood, and enzyme-linked immunosorbent assay was used to determine the serum levels of interleukin-17 (IL 17), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta). The dynamic changes in the frequencies of Th17 and Treg cells were compared between the two groups, and the correlation between clinical indices for hepatitis and cytokines was analyzed. The t-test was used for comparison between groups, a one way analysis of variance was used for comparison within one group across different time points, and Pearson correlation analysis was performed. RESULTS: With disease progression, the exacerbation group showed an increase in the frequency of Th17 cells and a relatively low frequency of Treg cells; compared with the improvement group, the exacerbation group had a higher frequency of Th17 cells and a lower frequency of Treg cells. Th17/Treg ratio gradually increased with exacerbation and decreased with improvement in conditions; in the exacerbation group and the improvement group, Th17/Treg ratio was positively correlated with total bilirubin and negatively correlated with prothrombin activity. In the exacerbation group and the improvement group, Th17 cells were positively correlated with IL-17, and Treg cells were positively correlated with IL-10 and TGF-beta. CONCLUSION: Th17 and Treg cells play important roles in severe exacerbation of hepatitis B, and Th17/Treg ratio may be used as an immunobiological marker for the judgment of severity during severe exacerbation of hepatitis B. PMID- 27470887 TI - [Role of glucose-6-phosphate dehydrogenase in hepatitis B virus replication and its possible mechanism of action]. AB - OBJECTIVE: To investigate the role of glucose-6-phosphate dehydrogenase (G6PD) in hepatitis B virus (HBV) replication and its possible mechanism of action. METHODS: Tissue microarray, quantitative real-time PCR, and Western blot were performed to analyze the differences in G6PD expression levels in the HBV positive and HBV-negative liver tissues, HepG2.2.15 cells, and HepG2 cells. The siRNA transfection technique was used to knock down G6PD gene in HepG2.2.15 cells for 48 hours. Chemiluminescence was used for HBsAg and HBeAg quantification in supernatant, and quantitative real-time PCR was used to measure HBV DNA, type I interferon (IFN), and downstream IFN-stimulated genes. The t-test was used for comparison between groups. RESULTS: G6PD expression was significantly upregulated in the HBV-positive liver tissues and cells compared with HBV-negative liver tissues and cells, and the stain intensity and immunohistochemical scores were 89.69+/-54.92 and 31.90+/-18.62, respectively (P < 0.05). After G6PD expression in HepG2.2.15 cells was interfered by siRNA, the quantitative levels of HBV DNA, HBsAg, and HBeAg in supernatant were reduced significantly, and the mRNA expression levels of IFNalpha1, IFNbeta1, and five downstream IFN-stimulated genes (OAS1, ISG15, OAS3, EIF2alpha, and PKR) increased significantly (all P < 0.05). CONCLUSION: G6PD plays a vital role in HBV replication, and its mechanism of action in regulating HBV replication may be related to type I IFN signaling pathway. PMID- 27470888 TI - [Association between interleukin-18 gene polymorphisms and hepatocellular carcinoma caused by hepatitis B virus]. AB - OBJECTIVE: To investigate the association between the single nucleotide polymorphisms (SNPs) IL-18-137G/C (rs187238) and IL-18-607A/C (rs1946518) in interleukin-18 (IL-18) gene and hepatocellular carcinoma (HCC) caused by the hepatitis B virus (HBV). METHODS: The subjects were divided into HBV-related HCC group (109 patients), chronic HBV infection group (113 patients), and healthy control group (127 patients). The polymerase chain reaction-ligase detection reaction (PCR-LDR) was used to determine the alleles and genotypes of the two SNPs IL-18-137G/C and IL-18-607A/C. The t-test and chi-square test were used for baseline data. The chi-square test was used to investigate the differences in genotype and allele frequencies across the three groups. Non-conditional logistic regression analysis was used to compare the odds ratios (ORs) and 95% confidence intervals (CIs) for different genotypes/alleles in predicting the risk of HBV related HCC. RESULTS: The HBV-related HCC group showed significantly higher AA genotype and A allele frequencies of the SNP IL-18-607A/C than the healthy control group (AA genotype frequency: 29.4% vs 18.1%, chi (2) = 4.152, P < 0.05; A allele frequency: 54.6% vs 44.1%, 5.169, P < 0.05), which were positively correlated with the risk of HBV-related HCC (AA genotype frequency: OR = 1.879, 95% CI: 1.020-3.464; A allele frequency: OR = 1.524, 95% CI: 1.059-2.193). The chronic HBV infection group had a significantly higher A allele frequency of the SNP IL-18-607A/C than the healthy control group (54.0% vs 44.1%, chi (2) = 4.680, P < 0.05), which was positively correlated with the risk of chronic HBV infection (OR = 1.487, 95% CI: 1.037-2.132). The genotype and allele frequencies of the SNP IL-18-607A/C showed no significant differences between the HBV-related HCC group and the chronic HBV infection group (P > 0.05). The genotype and allele frequencies of the SNP IL-18-137G/C showed no significant differences between any two groups of the three groups (P > 0.05). CONCLUSION: The AA genotype and A allele frequencies of the SNP IL-18-607A/C are positively correlated with the morbidity of HBV-related HCC, and the A allele frequency of the SNP IL-18-607A/C is positively correlated with the morbidity of chronic HBV infection. PMID- 27470889 TI - [Influence of leptin receptor gene K109R polymorphism on the risk of nonalcoholic fatty liver disease and its interaction with PNPLA3 I148M polymorphism]. AB - OBJECTIVE: To investigate the influence of leptin receptor (LEPR) gene K109R polymorphism on the risk of nonalcoholic fatty liver disease (NAFLD) and its interaction with PNPLA3 I148M polymorphism in the Han Chinese population in Qingdao, China. METHODS: Blood samples were collected from 296 NAFLD patients and 321 healthy controls, and the genotypes of these patients were determined by PCR and genotyping. Related statistical analyses were performed to compare genotypes, alleles, and clinical data between the two groups. Generalized multifactor dimensionality reduction (GMDR) was used to investigate the interaction between LEPR K109R and PNPLA3 I148M genes. RESULTS: The distribution of LEPR K109R genotypes and alleles showed no significant differences between the NAFLD group and the control group (P > 0.05). PNPLA3 I148M gene polymorphisms were closely associated with the risk of NAFLD, and the risk of NAFLD in G mutant gene carriers was 2.07 times that in patients who did not carry this gene (OR = 2.07, 95% CI 1.423-3.013, P < 0.001). The joint action of LEPR K109R and PNPLA3 I148M significantly increased the risk of NAFL (OR = 3.393, 95% CI 1.856-6.201, P < 0.001). CONCLUSION: In the Han Chinese population in Qingdao, LEPR K109R gene polymorphism is not associated with the risk of NAFLD, but its interaction with PNPLA3 I148M polymorphism can significantly increase the risk of NAFLD. PMID- 27470890 TI - [Diagnostic criteria for HBV-related acute-on-chronic pre-liver failure]. AB - OBJECTIVE: To investigate the diagnostic criteria for HBV-related acute-on chronic pre-liver failure (pre-ACLF) which can effectively predict the risk of liver failure. METHODS: A total of 1279 patients with severe icteric chronic hepatitis B (CHB) and/or severe acute exacerbation of CHB were enrolled. The influence of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil), international normalized ratio (INR) of prothrombin time, sex, and age on the incidence rate of acute-on chronic liver failure (ACLF) was analyzed, the diagnostic criteria for pre-ACLF and predictive model for ACLF were developed. The chi-square test was used for comparison of categorical variables, and the independent samples t-test was used for continuous data; multivariate logistic regression analysis was performed to evaluate the risk of liver failure. RESULTS: The baseline serum levels of ALT, AST, and TBil, and INR were independent risk factors for liver failure (P < 0.05). The diagnostic criteria for pre-ACLF were as follows: (1) INR>=1.30; (2) AST>=10*upper limit of normal (ULN) and obvious jaundice (TBil>=51.3 MUmol/L), or TBil>=342.0 MUmol/L. These criteria had a positive predictive value of 45.9%, a negative predictive value of 89.8%, a sensitivity of 69.1%, and a specificity of 76.9%. The predictive model for the risk of ACLF was PY = 1=e(X)/(1+e(X)) (PY represented positive results of logistic regression analysis), X = 10.245+0.026*AST(ULN)-0.025*AST(ULN)+0.046*TBil(mg/dl) + 4.642*INR+0.049*age(years). The patients with higher PY values tended to have a higher incidence rate of ACLF. The incidence rate of ACLF was 75.3% in patients with PY>=0.60, more than 50% in patients with a PY value of 0.40-0.59, and 1.8% in patients with PY < 0.10 (P < 0.01). CONCLUSION: The diagnostic criteria for pre-ACLF and predictive model can effectively evaluate the risk of HBV-related ACLF. PMID- 27470891 TI - [Preventive and therapeutic effects of rapamycin against autoimmune hepatitis and liver fibrosis and possible mechanisms]. AB - OBJECTIVE: To investigate the preventive and therapeutic effects of rapamycin (RAPA) on autoimmune hepatitis and liver fibrosis induced by concanavalin A (ConA) and possible mechanisms. METHODS: Female C57BL/6 mice aged 8 weeks were randomly divided into normal control group, ConA model group, and ConA+RAPA treatment group. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured; hematoxylin-eosin and Masson staining and Knodell HAI and Ishak scoring systems were used to evaluate the degrees of liver inflammation and fibrosis. Gradient centrifugation was used to separate mononuclear cells, flow cytometry was used to measure CD4(+)/CD8(+) ratio, and intracellular cytokine staining was performed to measure the levels of interferon gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor beta (TGF-beta) in immune cells. The t-test was used for data comparison between groups. RESULTS: The RAPA treatment group showed a significant reduction in serum ALT level compared with the ConA model group (P < 0.05). Liver inflammatory injury was reduced significantly, and there was no obvious fibrous tissue proliferation. The level of TGF-beta in mononuclear cells was reduced significantly, and the treatment group had a significantly lower level of TGF beta than the model group (8.91%+/-1.25% vs 16.65%+/-2.05%, P < 0.05). The proportions of CD4(+) and CD8(+)T cells in the liver were reduced, and the treatment group had significantly lower proportions of CD4(+) and CD8(+)T cells than the model group (proportion of CD4(+)T cells: 4.09%+/-1.20% vs 8.91%+/ 0.69%, P < 0.05; proportion of CD8(+)T cells: 3.28%+/-0.66% vs 9.68%+/-1.46%, P < 0.05). The proportion of Th1 cells was reduced, and the treatment group had a significantly lower proportion of Th1 cells than the model group (1.02%+/-0.06% vs 2.83%+/-0.21%, P < 0.05); the proportions of Th3 and Tr1 regulatory T cells were increased, and the treatment group had significantly higher proportions of Th3 and Tr1 regulatory T cells than the model group (proportion of Th3 regulatory T cells: 59.53%+/-9.82% vs 47.13%+/-4.79%, P < 0.05; proportion of Tr1 regulatory T cells: 10.63%+/-2.27% vs 7.09%+/-1.66%, P < 0.05), but the proportion of Th2 cells showed no significant difference between the two groups (P > 0.05). CONCLUSION: RAPA can promote the differentiation of Th3/Tr1 cells, reduce the expression of TGF-beta in mononuclear cells, slow down the progression of chronic hepatitis induced by ConA into liver fibrosis, and thus prevent liver fibrosis. PMID- 27470892 TI - [Influence of gut microecology on the pathogenesis and treatment of nonalcoholic fatty liver disease]. AB - OBJECTIVE: To establish a rat model of nonalcoholic fatty liver disease (NAFLD) using high-fat diet, and to dynamically observe the influence of the changes in gut microbiota on the development and progression of NAFLD in rats during and after modeling. METHODS: Sprague-Dawley rats were given high-fat diet to establish the model of NAFLD, and these rats were randomly divided into high-fat group, antibiotic pretreatment group, antibiotic treatment group, restricted diet group, and control group. The rats were sacrificed in different feeding periods, and 16sRNA fluorescent quantitative PCR was used to analyze the changes in ileocecal microbiota in rats. The liver pathological scores were determined, and enzymatic colorimetry was used to measure blood lipid level in serum and liver homogenate. The sample mean t-test was used for comparison between groups. RESULTS: Compared with the high-fat group, the restricted diet group showed the most significant improvements in quality of life and biochemical parameters. In the restricted diet group, the number of probiotics (Bifidobacterium and Lactobacillus) at the end of the ileum gradually increased and tended to increase over the time of intervention, and the most significant difference between this group and the high-fat group occurred at the 10th week (Bifidobacterium: 0.91+/ 0.23 vs 0.28+/-0.12, P < 0.05; Lactobacillus: 0.78+/-0.04 vs 0.21+/-0.03, P < 0.05), while the number of enterococci decreased. There were no significant differences in enteric bacilli between groups (all P > 0.05). At the 10th week, the liver pathological scores in the control group, antibiotic treatment group, and restricted diet group were 1.13+/-1.74, 4.86+/-0.86, and 2.94+/-1.91, respectively, significantly lower than 7.09+/-2.03 in the high fat group (all P < 0.05). CONCLUSION: Diet structure change and antibiotic intervention can adjust gut microecology, alleviate the lesions of NAFLD, and thus provide new strategies for the prevention and treatment of NAFLD from the perspective of microecology. PMID- 27470893 TI - [Malnutrition status and body composition in patients with liver cirrhosis]. PMID- 27470894 TI - [T cell receptor repertoire in patients with HBV-related hepatocellular carcinoma]. PMID- 27470895 TI - [Efficacy of transjugular intrahepatic portosystemic shunt with covered stents in treatment of portal hypertension in patients with primary liver cancer]. PMID- 27470896 TI - [Role of transforming growth factor-beta signaling pathway in liver fibrosis during the development of liver cirrhosis]. PMID- 27470897 TI - [Short-term efficacy of Harvoni in treatment of hepatitis C after liver transplantation]. PMID- 27470898 TI - [One case of Alagille syndrome misdiagnosed as Wilson's disease]. PMID- 27470899 TI - [Advances in diagnosis and treatment of hepatopulmonary syndrome]. AB - Hepatopulmonary syndrome is a disease with abnormal gas exchange caused by liver diseases, with the feature of abnormal oxygenation caused by intrapulmonary vasodilation. This article introduces the pathogenesis, natural course, clinical manifestations, diagnostic methods, and therapeutic measures of this disease and discusses potential therapeutic measures besides liver transplantation. PMID- 27470900 TI - Rapid Brownian Motion Primes Ultrafast Reconstruction of Intrinsically Disordered Phe-Gly Repeats Inside the Nuclear Pore Complex. AB - Conformational behavior of intrinsically disordered proteins, such as Phe-Gly repeat domains, alters drastically when they are confined in, and tethered to, nan channels. This has challenged our understanding of how they serve to selectively facilitate translocation of nuclear transport receptor (NTR)-bearing macromolecules. Heterogeneous FG-repeats, tethered to the NPC interior, nonuniformly fill the channel in a diameter-dependent manner and adopt a rapid Brownian motion, thereby forming a porous and highly dynamic polymeric meshwork that percolates in radial and axial directions and features two distinguishable zones: a dense hydrophobic rod-like zone located in the center, and a peripheral low-density shell-like zone. The FG-meshwork is locally disrupted upon interacting with NTR-bearing macromolecules, but immediately reconstructs itself between 0.44 MUs and 7.0 MUs, depending on cargo size and shape. This confers a perpetually-sealed state to the NPC, and is solely due to rapid Brownian motion of FG-repeats, not FG-repeat hydrophobic bonds. Elongated-shaped macromolecules, both in the presence and absence of NTRs, penetrate more readily into the FG meshwork compared to their globular counterparts of identical volume and surface chemistry, highlighting the importance of the shape effects in nucleocytoplasmic transport. These results can help our understanding of geometrical effects in, and the design of, intelligent and responsive biopolymer-based materials in nanofiltration and artificial nanopores. PMID- 27470901 TI - Transient hypogammaglobulinemia and severe atopic dermatitis: Open-label treatment with immunoglobulin in a case series. AB - BACKGROUND: We reported on six infants between 5 and 11 months old, with transient hypogammaglobulinemia of infancy and severe refractory atopic dermatitis, who were treated with open-label immunoglobulin (Ig) after conventional therapy failed. All six infants had an IgG level of <225 mg/dL, elevated eosinophil and IgE levels, and no urine or stool protein losses, but they did exhibit hypoalbuminemia. OBJECTIVE: To evaluate the utility of open label immunoglobulin in infants with severe atopic dermatitis for whom conventional therapy failed. We reviewed the clinical utility of intravenous immunoglobulin in the treatment of severe atopic dermatitis, the most recent research in the field, and suggested mechanisms for its benefit. METHODS: The six infants were identified from a retrospective chart review at the University of California Los Angeles Allergy and Immunology outpatient pediatric clinic. RESULTS: All six patients were treated with 400 mg/kg/month of intravenous immunoglobulin and had normalization of their IgG and albumin levels, and all but one had clinically improved atopic dermatitis. CONCLUSION: Infants with severe atopic dermatitis who did not respond to conventional therapy avoidance may benefit from intravenous immunoglobulin therapy. PMID- 27470903 TI - Back to Earth Sites: From "nasty and unsightly" landfilling to final sink and geological repository. PMID- 27470902 TI - Preventive effect of Desferal on sperm motility and morphology. AB - Transition metal ions, mainly iron, are involved in the generation of highly reactive hydroxyl radicals, which are the most powerful inducers of oxidative damage to all biomolecules. The lipids in sperm membranes are highly susceptible to oxidation. Sperm lipid peroxidation (LPO) leads to decrease of motility and reduction of likelihood for sperm-oocyte fusion. The excess radical production may affect also the spermatozoa morphology. The aim of the present study was to investigate the effect of Desferal on the LPO, motility, and morphology of boar sperm subjected to oxidative stress. After collection, the ejaculates were equally separated and diluted in a commercial semen extender (experiment 1) or in physiological saline (experiment 2). The ejaculates of the 2 experiments were divided into aliquots, which were incubated with one of the following agents: FeSO4 (0.1mM), H2 O2 (0.5mM), or FeSO4 + H2 O2 (Fenton system), in the presence or absence of Desferal. The application of Desferal in the incubation medium had a protective effect against FeSO4 + H2 O2 -induced sperm damage, namely, decrease of LPO; decrease the quantity of immotile spermatozoa and decrease the number of morphological abnormalities, regardless of the used medium. In experiment 2, the presence of FeSO4 in the incubation medium induced LPO in the same range as the combination FeSO4 + H2 O2 , in which the effect was reduced by Desferal. Thus, the supplement of Desferal to media used for sperm storage and processing could be a useful tool for diminishing oxidative injury and improving the quality of the semen. PMID- 27470905 TI - Community midwifery initiatives in fragile and conflict-affected countries: a scoping review of approaches from recruitment to retention. AB - BACKGROUND: Birth assisted by skilled health workers is one of the most effective interventions for reducing maternal and neonatal mortality. Fragile and conflict affected states and situations (FCAS), with one-third of global maternal deaths, face significant challenges in achieving skilled care at birth, particularly in health workforce development. The importance of community-level midwifery services to improve skilled care is internationally recognized, but the literature on FCAS is limited. This review aimed to examine community midwifery (CMW) approaches, from recruitment to retention, in FCAS. METHODS: This scoping review design adapted Arksey and O'Malley's six-stage framework. Data collection included systematic searching of seven databases, purposive hand-searching of reference lists and web sites, and stakeholder engagement for additional information. Potential sources were screened against inclusion and exclusion criteria. Included sources were appraised for methodological quality using the McGill University Mixed Methods Appraisal Tool. Data were analysed thematically, using deductive (i.e. cadre definition, recruitment, education, deployment and retention) and inductive coding (i.e. capacity, gender and insecurity). RESULTS: Twenty-three sources were included, of 2729 identified, discussing community midwifery programmes in six FCAS (i.e. eight for Sudan, six for Afghanistan, three each for Mali and Yemen, two for South Sudan and one for Somalia). Source quality was relatively poor, and cadre definitions were context dependent. Major enablers for effective CMW programmes were community linkages and acceptance, while barriers included inappropriate recruitment, non-standardized education, weak supportive environment, political insecurity and violence. CONCLUSIONS: While community engagement and acceptance were crucial, CMW programmes were weakened by inappropriate recruitment and training, lack of support and general insecurity. Further research and implementation evidence is needed to aid policy makers, donors and implementing agencies in developing and implementing effective CMW programmes in FCAS. PMID- 27470908 TI - Influence of carboxylation on osteocalcin detection by mass spectrometry. AB - RATIONALE: Osteocalcin is a small, abundant bone protein that is difficult to detect using high-throughput tandem mass spectrometry (MS/MS) proteomic approaches from bone protein extracts, and is predominantly detected by non-MS immunological methods. Here, we analyze bovine osteocalcin and its post translational modifications to determine why a protein of this size goes undetected. METHODS: Osteocalcin was purified from cow bone using well established methods. Intact osteocalcin or trypsin-digested osteocalcin were separated using an Agilent 1200 series high-performance liquid chromatography (HPLC) system and analyzed using a ThermoScientific LTQ-Orbitrap XL after fragmentation with higher-energy collision dissociation. Data were analyzed using Mascot or Prosight Lite. RESULTS: Our results support previous findings that the cow osteocalcin has up to three carboxylations using both intact osteocalcin and digested forms. Using Mascot, we were able to detect osteocalcin peptides, but no fragments that localized the carboxylations. Full annotation using Prosight Lite of the intact (three carboxylations), N-terminal peptide (one carboxylation), and middle peptide (two carboxylations) showed complete fragmentation was present, but complete neutral loss was observed. CONCLUSIONS: Osteocalcin carboxylation, and its associated neutral losses, makes high-throughput detection of this protein challenging; however, alternative fragmentation or limited purification can overcome these challenges. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470909 TI - Paucisymptomatic Dermoid Cyst with Fatal Outcome. AB - Dermoid cysts of the central nervous system can cause devastating complications because of the mass effect of meningitis due to sinus tract. We report the case of a 5-month-old girl who presented with a crusted lesion of the occipital region of the scalp. Clinical examination noted skin abnormalities suggestive of occult dysraphism. Magnetic resonance imaging (MRI) was recommended, however, 40 days after this evaluation, and before the MRI could be performed, the girl presented with neurologic complications. Unfortunately, the diagnosis of dermoid cyst was made after the onset of severe complications that led to her death. The findings in this case emphasize the importance of more prompt MRI evaluation, particularly in cases where cranial or spinal dysraphism is suspected to have any connection to the skin as a pit or tract. Should we perform an urgent MRI for any cutaneous sign of dysraphism to avoid a dramatic evolution? PMID- 27470907 TI - Distribution and factors associated with salivary secretory leukocyte protease inhibitor concentrations. AB - OBJECTIVES: This cross-sectional study examined the distribution and correlates of salivary secretory leukocyte protease inhibitor (SLPI) concentrations within a multinational cohort of men. METHODS: Extracellular SLPI was measured in oral gargle cell supernatants of 378 men from three countries using an ELISA-based assay. Risk factor data were collected by a questionnaire. Factors associated with SLPI were assessed using linear and logistic regression for continuous and categorical SLPI, respectively. RESULTS: Among men aged 18-73 years, the median SLPI concentration was 492.0 ng ml-1 (range: 2.3-1919.9). In multivariable modeling, men in Brazil and younger men (18-30 years) were more likely to have higher levels of SLPI [adjusted odds ratio (aOR) 3.84; 95% confidence interval (CI): 1.94-7.59, and aOR 3.84; 95% CI: 1.98-7.43, respectively]. Men with a self reported sexually transmitted diseases diagnosis in the past 6 months were more likely to have higher SLPI levels (aOR 2.98; 95% CI: 1.1-7.83) and men reporting bleeding/swollen gums were less likely to have higher SLPI (aOR 0.34; 95% CI: 0.15-0.79). Similar results were observed for linear regression models. CONCLUSIONS: Secretory leukocyte protease inhibitor concentrations varied significantly by country and decreased with increasing age. The interaction between SLPI, modifiable factors, and oral infections that influence cancer risk warrants further investigation. PMID- 27470910 TI - Ginsenoside Rb1 alleviates aluminum chloride-induced rat osteoblasts dysfunction. AB - Osteoblasts dysfunction, induced by aluminum (Al), plays a critical role in the osteoporosis etiology. Ginsenoside Rb1 (Rb1) has the therapeutic properties for osteoporosis. This study aimed to assess the efficiency of Rb1 in ameliorating Al induced osteoblasts dysfunction. The osteoblasts were divided into four groups: Rb1-treated group (RG, 0.0145mg/mL Rb1), control group (CG, 0), AlCl3-treated group (AG, 0.126mg/mL AlCl3.6H2O), AlCl3+Rb1-treated group (ARG, 0.0145mg/mL Rb1 and 0.126mg/mL AlCl3.6H2O). After 24h of culture, the osteoblasts viability, the transforming growth factor-beta1 (TGF-beta1), bone morphogenetic protein-2 (BMP 2), the insulin-like growth factor I (IGF-I), core-binding factor alpha1 (Cbfalpha1) mRNA expressions, glutathione perioxidase (GSH-Px) and superoxide dismutase (SOD) activities, and reactive oxygen species (ROS) concentration were determined. The osteoblasts ultrastructural features were also observed. In the ARG, the osteoblasts viability, TGF-beta1, BMP-2, IGF-I and Cbfalpha1 mRNA expressions and the GSH-Px and SOD activities were significantly increased, the ROS concentration was significantly decreased, and osteoblasts histology lesion was attenuated compared with the AG. These results demonstrated that Rb1 could significantly reverse osteoblasts viability and osteoblasts growth regulation factor, inhibit oxidative stress, and attenuate histology lesion in the osteoblasts with AlCl3. These results indicate that Rb1 can effectively alleviate the AlCl3-induced osteoblasts dysfunction. PMID- 27470912 TI - {Tc(NO)(Cp)(PPh3)}(+) - a novel technetium(i) core. AB - Reactions between [Tc(I)(NO)X2(PPh3)2(CH3CN)] complexes (X = Cl, Br) and KCp form the pseudotetrahedral organotechnetium compounds [Tc(I)(NO)(Cp)(PPh3)X]. The halide ligands can readily be replaced by other halides or organometallic ligands giving access to a novel family of technetium(i) compounds with the robust {Tc(NO)(Cp)(PPh3)}(+) core. PMID- 27470913 TI - Changes in the prevalence of lipodystrophy, metabolic syndrome and cardiovascular disease risk in HIV-infected men. AB - Background Although it significantly improves HIV-related outcomes, some components of combination antiretroviral therapy (ART) cause lipodystrophy syndrome. The composition of combination ART has changed over time but the impact on lipodystrophy prevalence is unknown. METHODS: One hundred HIV-infected males underwent dual-energy X-ray absorptiometry scanning, serum lipid testing and completed a questionnaire in a cross-sectional study in 2010. Thirty-four participants of a 1998 study cohort were re-evaluated in 2010. The same parameters were used to define and compare lipodystrophy, metabolic syndrome and cardiovascular disease (CVD) risk in the two time periods. RESULTS: In 2010, the prevalence of lipodystrophy was lower when compared with 1998 (53% v. 69%, P=0.012), despite higher mean age (51.8 v. 42.1 years, P<0.0001), duration of HIV (165 v. 86 months, P<0.0001), ART exposure (129 v. 38 months, P<0.0001), CD4+ cell count (601 v. 374 cells uL(-1), P<0.0001) and waist circumference (95.5 v. 89.9cm P<0.0001). Cholesterol (5.0 v. 5.6mmolL(-1), P=0.0001) and triglycerides (1.9 v. 3.7mmolL(-1), P<0.0001) were significantly lower in 2010. Factors associated with an increased risk of lipodystrophy in 2010 were duration of HIV infection and low-density lipoprotein cholesterol, whereas current tenofovir or abacavir use was associated with a decreased risk of lipodystrophy. On multivariate analysis low-density lipoprotein cholesterol (OR, 2.65; CI, 1.4-4.9) remained significant for an increased risk and current tenofovir or abacavir use with reduced risk of lipodystrophy (OR, 0.096; CI, 0.011-0.83). In 2010 there was a higher prevalence of metabolic syndrome (33 v. 28%) and higher median Framingham CVD risk (9.9% (5.7-14.6) v. 8.2% (4.5-12.9). CONCLUSION: Despite ageing and longer duration of HIV infection and ART exposure, the prevalence of lipodystrophy in HIV-infected men significantly declined over a 12-year period. However, a trend exists toward a higher prevalence of metabolic syndrome and increased CVD risk. PMID- 27470911 TI - Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants. AB - Sepsis caused by Gram-positive bacterial pathogens is a major fatal disease but its molecular basis remains elusive. Toll-like receptor 2 (TLR2) has been implicated in the orchestration of inflammation and sepsis but its role appears to vary for different pathogen species and clones. Accordingly, Staphylococcus aureus clinical isolates differ substantially in their capacity to activate TLR2. Here we show that strong TLR2 stimulation depends on high-level production of phenol-soluble modulin (PSM) peptides in response to the global virulence activator Agr. PSMs are required for mobilizing lipoproteins, the TLR2 agonists, from the staphylococcal cytoplasmic membrane. Notably, the course of sepsis caused by PSM-deficient S. aureus is similar in wild-type and TLR2-deficient mice, but TLR2 is required for protection of mice against PSM-producing S. aureus. Thus, a crucial role of TLR2 depends on agonist release by bacterial surfactants. Modulation of this process may lead to new therapeutic strategies against Gram-positive infections. PMID- 27470916 TI - Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. AB - Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8.3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8.3%), BCOR/BCORL1 in 7 patients (3.4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence. PMID- 27470918 TI - Sarcopenia Is Recognized as an Independent Condition by an International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) Code. PMID- 27470917 TI - Changes in perception of treatment efficacy are associated to the magnitude of the nocebo effect and to personality traits. AB - The nocebo effect in motor performance consists in a reduction of force and increase of fatigue following the application of an inert treatment that the recipient believes to be effective. This effect is variable across individuals and it is usually stronger if conditioning -exposure to the active effect of the treatment- precedes a test session, in which the treatment is inert. In the current explorative study we used a conditioning procedure to investigate whether subjective perception of treatment effectiveness changes between the conditioning and the test session and whether this change is related to dispositional traits and to the nocebo-induced reduction of force. Results showed that 56.1% of participants perceived the treatment as more effective in the test than in the conditioning session, had a more pronounced reduction of force, felt more effort and sense of weakness and were characterized by lower levels of optimism and higher anxiety traits compared to the other 43.9% of participants, who conversely perceived the treatment as less effective in the test session than in the conditioning. These findings highlight for the first time a link between changes in perception of treatment effectiveness, personality traits and the magnitude of the nocebo response in motor performance. PMID- 27470919 TI - Erratum. PMID- 27470920 TI - Applications of visible light photoredox catalysis to the synthesis of natural products and related compounds. AB - Covering: 2008 to 2016The total synthesis of natural products and their derivatives continues to inspire organic chemists to identify and test new synthetic strategies and develop and explore novel methodology. In recent years, visible light photoredox catalysis has risen to prominence as a powerful technology that enables the selective formation of chemical bonds under mild reaction conditions. Herein we review applications of photoredox catalysis to the synthesis of natural products and related complex molecules, showcasing a range of powerful transformations that include: reductive couplings, photocycloadditions, intermolecular C-H functionalisation processes, fragmentations, and cyclisations. PMID- 27470922 TI - Development of "all natural" layer-by-layer redispersible solid lipid nanoparticles by nano spray drying technology. AB - Solid lipid nanoparticles (SLNs) have gained tremendous attraction as carriers for controlled drug delivery. Despite numerous advances in the field, one long standing historical challenge for their practical applications remains unmet: redispersibility after drying. In this work, a novel design of SLNs using a layer by-layer (LbL) technique was developed and the formulations were optimized by surface response methodology (Box-Behnken design). To the best of our knowledge, this is the first study reporting the fabrication of SLNs from all natural ingredients in the absence of any synthetic surfactants or coatings. The SLNs were prepared by a combined solvent-diffusion and hot homogenization method, with soy lecithin as natural emulsifier (first layer), followed by the subsequent coating with sodium caseinate (second layer) and pectin (third layer), both of which are natural food biopolymers. The adsorption of pectin coating onto caseinate was reinforced by hydrophobic and electrostatic interactions induced by a pH-driven process along with thermal treatment. The innovative nano spray drying technology was further explored to obtain ultra-fine powders of SLNs. Compared to uncoated or single-layer coated SLNs powders, which showed severe aggregation after spray drying, the well-separated particles with spherical shape and smooth surface were obtained for layer-by-layer (LbL) SLNs, which were redispersible into water without variation of dimension, shape and morphology. The SLNs were characterized by Fourier transform infrared and high-performance differential scanning calorimetry for their physical properties. The LbL-coated SLNs based on all natural ingredients have promising features for future applications as drug delivery systems, overcoming the major obstacles in conventional spray drying and redispersing SLNs-based formulations. PMID- 27470921 TI - Biofuels 2020: Biorefineries based on lignocellulosic materials. AB - The production of liquid biofuels to blend with gasoline is of worldwide importance to secure the energy supply while reducing the use of fossil fuels, supporting the development of rural technology with knowledge-based jobs and mitigating greenhouse gas emissions. Today, engineering for plant construction is accessible and new processes using agricultural residues and municipal solid wastes have reached a good degree of maturity and high conversion yields (almost 90% of polysaccharides are converted into monosaccharides ready for fermentation). For the complete success of the 2G technology, it is still necessary to overcome a number of limitations that prevent a first-of-a-kind plant from operating at nominal capacity. We also claim that the triumph of 2G technology requires the development of favourable logistics to guarantee biomass supply and make all actors (farmers, investors, industrial entrepreneurs, government, others) aware that success relies on agreement advances. The growth of ethanol production for 2020 seems to be secured with a number of 2G plants, but public/private investments are still necessary to enable 2G technology to move on ahead from its very early stages to a more mature consolidated technology. PMID- 27470923 TI - Differential relations between youth internalizing/externalizing problems and cortisol responses to performance vs. interpersonal stress. AB - Efforts to define hypothalamic-pituitary-adrenal (HPA) axis profiles conferring risk for psychopathology have yielded inconclusive results, perhaps in part due to limited assessment of the stress response. In particular, research has typically focused on HPA responses to performance tasks, while neglecting the interpersonal stressors that become salient during adolescence. In this study we investigated links between psychosocial adjustment - youth internalizing and externalizing problems, as well as competence - and HPA responses to both performance and interpersonal stressors in a normative sample of children and adolescents. Participants (n = 59) completed a set of performance (public speaking, mental arithmetic, mirror tracing) and/or interpersonal (peer rejection) tasks and gave nine saliva samples, which were assayed for cortisol. Hierarchical linear models of cortisol response trajectories in relation to child behavior checklist (CBCL) scores revealed stressor- and sex-specific associations. Whereas internalizing problems related to earlier peaking, less dynamic cortisol responses to interpersonal stress (across males and females), externalizing problems related to lower, earlier peaking and less dynamic cortisol responses to performance stress for males only, and competence-related to later peaking cortisol responses to interpersonal stress for females only. Implications for understanding contextual stress profiles underlying different forms of psychopathology are discussed. PMID- 27470924 TI - Quantification of the functional expression of the Ca2+ -activated K+ channel KCa 3.1 on microglia from adult human neocortical tissue. AB - The KCa 3.1 channel (KCNN4) is an important modulator of microglia responses in rodents, but no information exists on functional expression on microglia from human adults. We isolated and cultured microglia (max 1% astrocytes, no neurons or oligodendrocytes) from neocortex surgically removed from epilepsy patients and employed electrophysiological whole-cell measurements and selective pharmacological tools to elucidate functional expression of KCa 3.1. The channel expression was demonstrated as a significant increase in the voltage-independent current by NS309, a KCa 3.1/KCa 2 activator, followed by full inhibition upon co application with NS6180, a highly selective KCa 3.1 inhibitor. A major fraction (79%) of unstimulated human microglia expressed KCa 3.1, and the difference in current between full activation and inhibition (DeltaKCa 3.1) was estimated at 292 +/- 48 pA at -40 mV (n = 75), which equals at least 585 channels per cell. Serial KCa 3.1 activation/inhibition significantly hyperpolarized/depolarized the membrane potential. The isolated human microglia were potently activated by lipopolysaccharide (LPS) shown as a prominent increase in TNF-alpha production. However, incubation with LPS neither changed the KCa 3.1 current nor the fraction of KCa 3.1 expressing cells. In contrast, the anti-inflammatory cytokine IL-4 slightly increased the KCa 3.1 current per cell, but as the membrane area also increased, there was no significant change in channel density. A large fraction of the microglia also expressed a voltage-dependent current sensitive to the KCa 1.1 modulators NS1619 and Paxilline and an inward-rectifying current with the characteristics of a Kir channel. The high functional expression of KCa 3.1 in microglia from epilepsy patients accentuates the need for further investigations of its role in neuropathological processes. GLIA 2016;64:2065-2078. PMID- 27470925 TI - Communication between Discrete Nanostructures Triggered by Fine Tuning of an External Stimulus. AB - The design of molecular architectures able to transfer mass to each other is a field of extreme importance. In the present study it is shown that two especially designed covalently assembled nanostructures can interchange Cu(2+) ions upon an external OH(-) trigger. The obtained solid interfaces are of interest for signaling, communication, memory storage and optical devices. PMID- 27470926 TI - Characteristics of antigravity spontaneous movements in preterm infants up to 3 months of corrected age. AB - AIMS: We investigated whether spontaneous antigravity limbs movements in very low birth weight preterm infants were insufficient compared to those in term infants. The relationship between the quality of general movements (GMs) and antigravity limbs movements was also examined. METHODS: Preterm infants with very low birth weight without central nervous system disorders nor severe respiration disorders, and healthy term infants were recruited. The infants were set in a supine position. The distance between both hands and between both feet, and the height of both hands and feet from the floor were recorded at 1-3 corrected months for preterm infants, and at 1-3 months for term infants by a 3D motion capture system. The measurements were adjusted for body proportions. GMs in preterm and term infants were assessed similarly. RESULTS: Thirteen preterm and 15 term infants completed the study. In preterm infants, the distance between both hands and between both feet were longer, and the height of both hands and feet were lower than those in term infants in all measurements. In term infants, the height of both hands and feet increased as they developed, but no change was observed in preterm infants. In preterm infants with abnormal GMs, the distance between both hands was longer, and the height of both hands and feet was lower than that in those with normal GMs. There were no such differences between preterm infants with normal GMs and term infants with normal GMs. CONCLUSION: Antigravity limbs movements in preterm infants within the first 3 month of corrected age were insufficient compared with those in term infants. Furthermore, no improvement with development was observed in preterm infants. In addition, preterm infants with abnormal GMs showed worse antigravity limbs movements than preterm and term infants with normal GMs. The preterm infants with normal GMs could behave similar to the full term infants. PMID- 27470927 TI - A Video Game Promoting Cancer Risk Perception and Information Seeking Behavior Among Young-Adult College Students: A Randomized Controlled Trial. AB - BACKGROUND: Risky behaviors tend to increase drastically during the transition into young adulthood. This increase may ultimately facilitate the initiation of carcinogenic processes at a young age, highlighting a serious public health problem. By promoting information seeking behavior (ISB), young adults may become aware of cancer risks and potentially take preventive measures. OBJECTIVE: Based on the protection motivation theory, the current study seeks to evaluate the impact of challenge in a fully automated video game called Re-Mission on young adult college students' tendency to perceive the severity of cancer, feel susceptible to cancer, and engage in ISB. METHODS: A total of 216 young adults were recruited from a university campus, consented, screened, and randomized in a single-blinded format to 1 of 3 conditions: an intervention group playing Re Mission at high challenge (HC; n=85), an intervention group playing Re-Mission at low challenge (LC; n=81), and a control group with no challenge (NC; presented with illustrated pictures of Re-Mission; n=50). Measurement was conducted at baseline, immediate posttest, 10-day follow-up, and 20-day follow-up. Repeated measures mixed-effect models were conducted for data analysis of the main outcomes. RESULTS: A total of 101 young adults continued until 20-day follow-up. Mixed-effect models showed that participants in the HC and LC groups were more likely to increase in perceived susceptibility to cancer (P=.03), perceived severity of cancer (P=.02), and ISB (P=.01) than participants in the NC group. The LC group took until 10-day follow-up to show increase in perceived susceptibility (B=0.47, standard error (SE) 0.16, P=.005). The HC group showed an immediate increase in perceived susceptibility at posttest (B=0.43, SE 0.14, P=.002). The LC group exhibited no changes in perceived severity (B=0.40, SE 0.33, P=.24). On the other hand, the HC group showed a significant increase from baseline to posttest (B=0.39, SE 0.14, P=.005), maintaining this increase until 20-day follow-up (B=-0.007, SE 0.26, P=.98). Further analyses indicated that perceived threat from virtual cancer cells in the game is related to the increase in perceived severity (B=0.1, SE 0.03, P=.001), and perceived susceptibility is related to changes in ISB at 10-day follow-up (B=0.21, SE 0.08, P=.008). CONCLUSIONS: The feature of challenge with cancer cells in a virtual environment has the potential to increase cancer risk perception and ISB. The results are promising considering that the Re-Mission intervention was neither designed for cancer risk communication, nor applied among healthy individuals. Further research is needed to understand the theoretical framework underlying the effects of Re-Mission on ISB. The findings call for the development of a Web-based, game based intervention for cancer risk communication and information seeking among young adults. CLINICALTRIAL: International Standard Randomized Controlled Trial Number (ISRCTN): 15789289; http://www.controlled-trials.com/ISRCTN15789289 (Archived by WebCite at http://www.webcitation.org/6jGYZC3lZ). PMID- 27470928 TI - Growth and subsequent disappearance of a ruptured small saccular intracranial aneurysm: A morphometric and flow-dynamic analysis. AB - The growth of a ruptured small saccular aneurysm has rarely been documented. Also rare are reports of spontaneous thrombosis of ruptured small intracranial saccular aneurysms. However, there are no reported instances of ruptured small saccular aneurysms that have demonstrated an increase in size after rupture, subsequently thrombosed and disappeared from circulation. We report one such aneurysm in a patient who presented with subarachnoid hemorrhage from a ruptured small saccular aneurysm of the anterior communicating artery. The possible reasons for the initial growth and subsequent thrombosis of the aneurysm from morphometric and flow dynamic points of view are discussed. PMID- 27470929 TI - Ontogeny of sexual size dimorphism in the hornless rose chafer Pachnoda marginata (Coleoptera: Scarabaeidae: Cetoniinae). AB - Beetles of the subfamily Cetoniinae are distinct and well-known, yet their larval ontogeny, sexual size dimorphism and development remain unknown in most species. This group contains many species with large males with prominent secondary sexual structures, such as cephalic or pronotal horns and elongated forelimbs. The species studied here, Pachnoda marginata, belongs to those species without any obvious dimorphism, the males being almost indistinguishable from the females. In this paper we examine sexual dimorphism in body shape and size in this apparently 'non-dimorphic' species. We further investigate the larval development and proximate causes of sexual size dimorphism, in particular when and how the sexes diverge in their growth trajectories during ontogeny. We found that males are larger than females and that the sexes also differ in body shape - for example, males possess significantly longer forelimbs relative to body size than females. The male-biased sexual size dimorphism along with prolonged forelimbs suggests that sexual selection for larger males may not be limited merely to horned species of rose chafers. The dimorphism in size in P. marginata arises during the second larval instar and basically remains unchanged till maturity. In both sexes the maximum body mass as well as developmental time of particular larval instars were strongly correlated, but time spent in the pupal chamber was not related to previous growth and final body size. The correlation between developmental time and adult size was negative, which may be a reflection of differences in resource allocation or utilisation for growth and development among individuals. PMID- 27470930 TI - Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease. AB - An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid beta peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Abeta peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease. PMID- 27470931 TI - Original Research: Effect of sprint and strength training on glucoregulatory hormones: Effect of advanced age. AB - The aim of this study was to examine the effect of high-intensity sprint and strength training (HISST) on glucoregulatory hormones in young (20 years) and middle-aged (40 years) men. Thirty-six moderately trained men participated as volunteers in this study. After medical examination, eligible subjects were randomly assigned to one of four groups according to their age: a young training group (21.3 +/- 1.3 yrs, YT, n = 9), a young control group (21.4 +/- 1.7 yrs, YC, n = 9), a middle-aged training group (40.7 +/- 1.8 yrs, AT, n = 9), and a middle aged control group (40.5 +/- 1.8 yrs, AC, n = 9). YT and AT participated in HISST for 13 weeks. Before and after HISST, all participants performed the Wingate Anaerobic Test (WAnT). Blood samples were collected at rest, after warm-up (50% VO2max), immediately post-WAnT, and 10 min post-WAnT. Before HISST, we observed significantly higher (P < 0.05) glucose concentrations in AT (5.86 +/- 0.32 mmol.L-1) compared to YT (4.24 +/- 0.79 mmol.L-1) at rest, and in response to WAnT (6.56 +/- 0.63 mmol.L-1 vs. 5.33 +/- 0.81 mmol.L-1). Cortisol levels were significantly higher (P < 0.05) in AT than in YT in response to WAnT (468 +/- 99.50 ng.mL-1 vs. 382 +/- 64.34 ng.mL-1). Catecholamine levels measured at rest and in response to WAnT rose in a similar fashion. After HISST, this "age effect" disappeared at rest and in response to exercise in the trained groups (YT and AT). Changes in hormone concentrations with intense training are due to adaptive changes in various tissues, especially in the skeletal muscle and liver in trained subjects. HISST may, at least in part, counteract the negative "age effect" on glucose metabolism. PMID- 27470933 TI - A test of Darwin's 'lop-eared' rabbit hypothesis. AB - Integration of evolutionary and developmental biology has stimulated novel insights on the origins and maintenance of phenotypic variation. For instance, phenotypic accommodation predicts that trait covariance originates via a novel developmental input caused by genetic change in one trait, but not the other. Darwin provided a striking example of this process in the 'lop-eared' rabbit by demonstrating that artificial selection for long external ears induced variation in the external auditory meatus. Although this intriguing pattern has been interpreted as evidence of phenotypic accommodation, it is unclear whether it exists and, if it does, whether it is selectively maintained in nature. To address this concern, we examined trait covariance in natural woodrat populations that have likely undergone selection for long ears. We demonstrated a remarkably similar covariance pattern as in the 'lop-eared' rabbit, which was associated with climatic variables along a steep arid-to-moist longitudinal gradient. Thus, our results suggest that trait covariance is likely a correlated response to selection. We relate these findings to potential origins of trait covariance owing to altered developmental interactions, such as in phenotypic accommodation. Additional evidence is needed to clarify how phenotypic accommodation and correlated selection promote and maintain trait covariance in natural populations. Nonetheless, our study is the first to support a classic Darwinian example concerning domestication and natural selection. PMID- 27470932 TI - Protective Effect of Quercetin on Posttraumatic Cardiac Injury. AB - Quercetin is an important dietary flavonoid present in fruits and vegetables and has attracted attention because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play important roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This study investigates the protective effect of quercetin on trauma induced secondary cardiac injury and the mechanisms involved. Widely accepted nonlethal mechanical trauma models were established. In vivo, cardiomyocyte apoptosis and cardiac dysfunction in rats were assessed using TUNEL staining and a biological mechanic experiment system. In vitro, cell viability, tumour necrosis factor-alpha (TNF-alpha), reactive oxygen species (ROS) and [Ca(2+)]i of H9c2 cells were detected using an MTT assay, ELISA, and 2',7'-dichlorofluorescin diacetate and fluo-4 acetoxymethyl ester assays respectively. Quercetin pretreatment (20 mg/kg i.p.; 0.5 h before trauma) significantly improved posttraumatic cardiomyocyte apoptosis and cardiac dysfunction. Pretreatment with quercetin (20 MUM; 24 h before trauma plasma addition) significantly attenuated trauma-induced viability decreases, TNF-alpha increases, ROS overproduction and [Ca(2+)]i overload in H9c2 cells. In conclusion, quercetin may reverse posttraumatic cardiac dysfunction by reducing cardiomyocyte apoptosis through the suppression of TNF-alpha increases, ROS overproduction and Ca(2+) overload in cardiomyocytes, representing a potential preventive approach for the treatment of secondary cardiac injury after mechanical trauma. PMID- 27470934 TI - Survey of undeclared soy allergen levels in the most frequently recalled food categories with or without precautionary labelling. AB - A comprehensive study was designed to determine the frequency and levels of soy allergen in packaged bakery and snack food products. A representative sample of products with no soy allergen disclosed on the label was analysed using two widely used enzyme-linked immunosorbent assay (ELISA) methods. Samples were chosen that either had no soy identified on the product label or which had a soy precautionary statement. Among 558 bakery and snack products, soy protein was detected in 17% of the products using the Neogen (NE) kit and 11% of the products using the Elisa Systems (ES) kit. The disagreement rates between kits were 8.8% for bakery products and 3.3% for snack products. Overall soy protein was detected at higher frequency in bakery products than in snack foods. Among 284 bakery samples, soy protein was detected in 25% of the samples with no precautionary statement and 19% of the samples which had a precautionary statement. Among 274 snack samples, soy protein was detected in 11% of the samples with no precautionary statement and 9% of the samples which had a precautionary statement. The sample repeatability was at an acceptable level (< 9%) for each method and food commodity. The reproducibility between kits was 23% for bakery foods and 36% for snack foods. None of the bakery (21) and snack (6) products without precautionary labelling (measured level > 5 ppm) had a higher level of soy protein per serving compared with the eliciting dose10 (ED10) of 10.6 mg for soy allergic patients. But the level of soy protein per serving may be clinically relevant to a subpopulation of soy allergic patients if a more stringent eliciting dose is applied. These findings emphasise that suitable detection methodologies and references doses are crucial for labelling accuracy and the safety of soy allergic consumers. PMID- 27470935 TI - An improved synthesis of the radiolabeled prostate-specific membrane antigen inhibitor, [(18) F]DCFPyL. AB - The radiosynthesis of [(18) F]DCFPyL on 2 distinct automated platforms with full regulatory compliant quality control specifications is described. The radiotracer synthesis was performed on a custom-made radiofluorination module and the Sofie Biosciences ELIXYS. The radiofluorination module synthesis was accomplished in an average of 66 minutes from end of bombardment with an average specific activity at end of synthesis (EOS) of 4.4 TBq/MUmol (120 Ci/MUmol) and an average radiochemical yield of 30.9% at EOS. The ELIXYS synthesis was completed in an average of 87 minutes with an average specific activity of 2.2 TBq/MUmol (59.3 Ci/MUmol) and an average radiochemical yield of 19% at EOS. Both synthesis modules produced large millicurie quantities of [(18) F]DCFPyL while conforming to all standard US Pharmacopeia Chapter <823> acceptance testing criteria. PMID- 27470936 TI - Serological diagnosis of toxoplasmosis and standardization. AB - Humans can be infected by the intracellular parasite Toxoplasma gondii, which causes toxoplasmosis, a common parasitic disease. Although the infection is generally asymptomatic for most adults, severe complications may occur in some individuals, especially women in early pregnancy. Serologic diagnosis is used as a routine practice to determine the immune status for infection by T. gondii. In this review, we attempt to provide an overview of the serological diagnosis of toxoplasmosis, including diagnostic strategy, current problems in detection with specific antibodies, and the standardization of T. gondii serological detection. PMID- 27470937 TI - Trends in advanced breast cancer incidence rates after implementation of a mammography screening program in a German population. AB - BACKGROUND: Mammography screening programs (MSPs) aim to detect early-stage breast cancers in order to decrease the incidence of advanced-stage breast cancers and to reduce breast cancer mortality. We analyzed the time trends of advanced-stage breast cancer incidence rates in the target population before and after implementation of the MSP in a region of northwestern Germany. METHODS: The MSP in the Munster district started in October 2005. A total of 13,874 women with an incident invasive breast cancer (BC) was identified by the population-based epidemiological cancer registry between 2000 and 2013 in the target group 50-69 years. Multiple imputation methods were used to replace missing data on tumor stages (10.4%). The incidence rates for early-stage (UICC I) and advanced-stage (UICC II+) BC were determined, and Poisson regression analyses were performed to assess trends over time. RESULTS: The incidence rates for UICC I breast cancers increased during the step-up introduction of the MSP and remained elevated thereafter. By contrast, after increasing from 2006 to 2008, the incidence rates of UICC II+ breast cancers decreased to levels below the pre-screening period. Significantly decreasing UICC II+ incidence rates were limited to the age group 55-69 years and reached levels that were significantly lower than incidence rates in the pre-screening period. DISCUSSION: The incidence rates of advanced-stage breast cancers decreased in the age groups from 55 years to the upper age limit for screening eligibility, but not in the adjacent age groups. The findings are consistent with MSP lead time effects and seem to indicate that the MSP lowers advanced-stage breast cancer rates in the target population. PMID- 27470938 TI - Gold Nanoparticle-Mediated Targeted Delivery of Recombinant Human Endostatin Normalizes Tumour Vasculature and Improves Cancer Therapy. AB - Tumour vasculature is generally disordered because of the production of excessive angiogenic factors by tumour cells, which results in tumour progression and reduces the effectiveness of radiotherapy or chemotherapy. Transient anti angiogenic therapies that regulate tumour vascular morphology and function and improve the efficiency of antitumour therapy are under investigation. Recombinant human endostatin (Endostar/rhES) is a vascular angiogenesis-disrupting agent that has been used to treat non-small cell lung cancer (NSCLC) in the clinical setting. In this study, we used gold nanoparticles (AuNPs) as a drug-delivery system (DDS) for targeted tumour delivery of rhES for short therapy, which resulted in transient tumour vascular normalization, reduced permeability and hypoxia, strengthened blood vessel integrity, and increased blood-flow perfusion. Moreover, combination therapy with 5-FU over this timeframe was substantially more effective than 5-FU monotherapy. In conclusion, our research demonstrates the potential use of AuNPs as a drug-delivery platform for transporting rhES into a tumour to induce transient tumour vascular normalization and enhance the antitumour efficacy of cytotoxic drugs. PMID- 27470940 TI - Herbihabitans rhizosphaerae gen. nov., sp. nov., a member of the family Pseudonocardiaceae isolated from rhizosphere soil of the herb Limonium sinense (Girard). AB - The taxonomic position of an actinobacterium, designated CPCC 204279T, which was isolated from a rhizosphere soil sample of the herb Limonium sinense collected from Xinjiang Province, China, was established using a polyphasic approach. Whole cell hydrolysates of strain CPCC 204279T contained galactose and arabinose as diagnostic sugars and meso-diaminopimelic acid as the diamino acid. The muramic acid residues in the peptidoglycan were N-acetylated. The predominant menaquinone was MK-9(H4). The phospholipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannosides. The major fatty acids were iso-C16 : 0, iso-C16 : 0 2-OH, C16 : 1omega9c, iso-C16 : 1 and C16 : 0. The genomic DNA G+C content was 73.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CPCC 204279T should be placed in the family Pseudonocardiaceae, in which the strain formed a distinct lineage next to the genus Actinophytocola. Signature nucleotides in the 16S rRNA gene sequence showed that the strain contained the Pseudonocardiaceae family-specific 16S rRNA signature nucleotides and a genus specific diagnostic nucleotide signature pattern. The combination of phylogenetic analysis and phenotypic characteristics supported the conclusion that strain CPCC 204279T represents a novel species of a new genus in the family Pseudonocardiaceae, for which the name Herbihabitans rhizosphaerae gen. nov., sp. nov. is proposed. Strain CPCC 204279T (=NBRC 111774T=DSM 101727T) is the type strain of the type species. PMID- 27470941 TI - Validity of the epworth sleepiness scale as a screening tool for obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: To determine whether the Epworth Sleepiness Scale (ESS) can be improved by having a bed partner or roommate ("partner") also fill out the questionnaire; and to assess the applicability of the eight items in the questionnaire, particularly in an urban population. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was conducted to identify charts of subjects with an ESS score collected from both the subject and a partner. Consensus scores were also identified. Self-reported ESS scores were compared to partner and consensus ESS scores. The number of subjects who did not drive was determined. RESULTS: One hundred consecutive charts were included in this study. Mean ESS score was significantly higher when scored by the partner (10.4 +/- 5.8) compared to the subject (7.2 +/- 4.7). In 73% of cases, the subject underestimated their score compared to the score given by the partner. The mean difference in score was 3.2 +/- 3.5. Mean consensus ESS score was 12.3 +/- 5.4. Using an ESS score of >=10 as abnormal, subject scores did not correlate with the presence of obstructive sleep apnea (OSA; P = .095). Partner and consensus scores, however, did correlate with the presence of OSA (P = .003 and P =.039, respectively). Thirty-five percent of our subjects did not drive. CONCLUSIONS: The difference in mean ESS score obtained from the subject compared to partner implies that this diagnostic form should be completed as a consensus between the patient and partner to provide a more accurate score. LEVEL OF EVIDENCE: 4 Laryngoscope, 2016 127:525-531, 2017. PMID- 27470939 TI - Neurological disorders associated with DNA strand-break processing enzymes. AB - The termini of DNA strand breaks induced by reactive oxygen species or by abortive DNA metabolic intermediates require processing to enable subsequent gap filling and ligation to proceed. The three proteins, tyrosyl DNA phosphodiesterase 1 (TDP1), aprataxin (APTX) and polynucleotide kinase/phosphatase (PNKP) each act on a discrete set of modified strand-break termini. Recently, a series of neurodegenerative and neurodevelopmental disorders have been associated with mutations in the genes coding for these proteins. Mutations in TDP1 and APTX have been linked to Spinocerebellar ataxia with axonal neuropathy (SCAN1) and Ataxia-ocular motor apraxia 1 (AOA1), respectively, while mutations in PNKP are considered to be responsible for Microcephaly with seizures (MCSZ) and Ataxia-ocular motor apraxia 4 (AOA4). Here we present an overview of the mechanisms of these proteins and how their impairment may give rise to their respective disorders. PMID- 27470942 TI - Fast removal of copper ions from aqueous solution using an eco-friendly fibrous adsorbent. AB - Functional PET fiber (PET-AA-CS) was prepared by oxygen-plasma pretreatment and grafting of acrylic acid (AA) and low-molecular-weight chitosan (LMCS) on the polyethylene glycol terephthalate (PET) substrate. This adsorbent was targeted for quick removal of metal ion in river pollutions with an easy recycling of the fiber after emergency processing. The fabricated PET-AA-CS was characterized by the scanning electron microscope (SEM), contact angle, fourier transform infrared (FTIR) spectra and X-ray photoelectron spectroscopy (XPS) to look into its morphology, surface functional groups, and adsorption mechanism of copper ions from the aqueous solution. The overall adsorption process of copper ions on the PET-AA-CS was pH-dependent with an optimal pH value of 5.0, at which a maximum capacity of 68.97 mg g(-1) was obtained. The result of fitting also shows that adsorption process follows the Langmuir isotherm and pseudo-second-order model. Moreover, the material shows good stability during 5 cycles of adsorption and desorption, and also shows no significant effect of co-existing ions including Ca(2+), Mg(2+), K(+), Cl(-), and et al. In general, PET-AA-CS developed in this study shows significant benefit of eco-friend and cost-efficiency for fast removal of copper ions in potential river metal pollutions comparing with traditional adsorbents. PMID- 27470943 TI - Formation of microscopic particles during the degradation of different polymers. AB - This study investigated the formation and size distribution of microscopic plastic particles during the degradation of different plastic materials. Particle number concentrations in the size range 30 nm-60 MUm were measured by nanoparticle tracking analysis (NTA) and Coulter Counter techniques. Each of the plastics used exhibited a measureable increase in the release of particles into the surrounding solution, with polystyrene (PS) and polylactic acid (PLA) generating the highest particle concentrations. After 112 d, particle concentrations ranged from 2147 particles ml(-1) in the control (C) to 92,465 particles ml(-1) for PS in the 2-60 MUm size class; 1.2 * 10(5) particles ml(-1) (C) to 11.6 * 10(6) for PLA in the 0.6-18 MUm size class; and 0.2 * 10(8) particles ml(-1) (C) to 6.4 * 10(8) particles ml(-1) for PS in the 30-2000 nm size class (84 d). A classification of samples based on principal component analysis showed a separation between the different plastic types, with PLA clustering individually in each of the three size classes. In addition, particle size distribution models were used to examine more closely the size distribution data generated by NTA. Overall, the results indicate that at the beginning of plastic weathering processes chain scission at the polymer surface causes many very small particles to be released into the surrounding solution and those concentrations may vary between plastic types. PMID- 27470944 TI - DPOAEs in infants developmentally exposed to PCBs show two differently time spaced exposure sensitive windows. AB - The study aim was to identify the timing of sensitive windows for ototoxicity related to perinatal exposure to PCBs. A total of 351 and 214 children from a birth cohort in eastern Slovakia underwent otoacoustic testing at 45 and 72 months, respectively, and distortion product otoacoustic emissions (DPOAEs) at 11 frequencies were recorded. Cord and child 6-, 16-, 45-, and 72- month blood samples were analyzed for PCB 153 concentration. The PCB 153 concentration-time profiles were approximated with a system model to calculate area under the PCB*time curves (AUCs) for specific time intervals (3 and 6 months for 45 and 72 months data, respectively). DPOAE amplitudes were correlated (Spearman) with cord serum PCB and AUCs, markers of prenatal and postnatal exposure, respectively. Two exposure critical windows were identified in infants, the first related to prenatal and early postnatal and the second to postnatal exposure to PCBs. Our data have shown tonotopicity, sexual dimorphism, and asymmetry in ototoxicity of PCBs. PMID- 27470945 TI - The increase in fat content in the warm-acclimated striped hamsters is associated with the down-regulated metabolic thermogenesis. AB - It has been well known that metabolic thermogenesis plays an important role in the thermoregulation of small mammals under different temperatures, while its role in fat accumulation is far from clear. In the present study, several physiological, hormonal, and biochemical measures indicative of metabolic thermogenesis were measured in the weaning striped hamsters after acclimated to a warm condition (30 degrees C) for 1, 3 and 4months. The warm-acclimated groups significantly decreased energy intake, and simultaneously decreased nonshivering thermogenesis compared to those housed at 21 degrees C. Body fat content increased by 29.9%, 22.1% and 19.6% in the hamsters acclimated to 1, 3 or 4months, respectively relative to their counterparts maintain at 21 degrees C (P<0.05). The cytochrome c oxidase (COX) activity of brain, liver, heart and skeletal muscle, and the ratio of serum tri-iodothyronine to thyroxine significantly decreased in warm-acclimated groups compared with 21 degrees C group. COX activity and uncoupling protein 1 (UCP1) mRNA expression of brown adipose tissue (BAT) were significantly down-regulated under the warm conditions. COX activity of BAT, liver, heart and muscle were significantly negatively correlated with body fat content, and the correlation between UCP1 expression and body fat content tended to be negative. These findings suggest that the decrease in the energy spent on metabolic thermogenesis plays an important role in the fat accumulation. The attenuation of COX and UCP1-based BAT activity may be involved in body fat accumulation in animals under warm conditions. PMID- 27470946 TI - Inhibition linearizes firing rate responses in human motor units: implications for the role of persistent inward currents. AB - KEY POINTS: Motor neurons are the output neurons of the central nervous system and are responsible for controlling muscle contraction. When initially activated during voluntary contraction, firing rates of motor neurons increase steeply but then level out at modest rates. Activation of an intrinsic source of excitatory current at recruitment onset may underlie the initial steep increase in firing rate in motor neurons. We attempted to disable this intrinsic excitatory current by artificially activating an inhibitory reflex. When motor neuron activity was recorded while the inhibitory reflex was engaged, firing rates no longer increased steeply, suggesting that the intrinsic excitatory current was probably responsible for the initial sharp rise in motor neuron firing rate. ABSTRACT: During graded isometric contractions, motor unit (MU) firing rates increase steeply upon recruitment but then level off at modest rates even though muscle force continues to increase. The mechanisms underlying such firing behaviour are not known although activation of persistent inward currents (PICs) might be involved. PICs are intrinsic, voltage-dependent currents that activate strongly when motor neurons (MNs) are first recruited. Such activation might cause a sharp escalation in depolarizing current and underlie the steep initial rise in MU firing rate. Because PICs can be disabled with synaptic inhibition, we hypothesized that artificial activation of an inhibitory pathway might curb this initial steep rise in firing rate. To test this, human subjects performed slow triangular ramp contractions of the ankle dorsiflexors in the absence and presence of tonic synaptic inhibition delivered to tibialis anterior (TA) MNs by sural nerve stimulation. Firing rate profiles (expressed as a function of contraction force) of TA MUs recorded during these tasks were compared for control and stimulation conditions. Under control conditions, during the ascending phase of the triangular contractions, 93% of the firing rate profiles were best fitted by rising exponential functions. With stimulation, however, firing rate profiles were best fitted with linear functions or with less steeply rising exponentials. Firing rate profiles for the descending phases of the contractions were best fitted with linear functions for both control and stimulation conditions. These results seem consistent with the idea that PICs contribute to non-linear firing rate profiles during ascending but not descending phases of contractions. PMID- 27470948 TI - Verification of watershed vegetation restoration policies, arid China. AB - Verification of restoration policies that have been implemented is of significance to simultaneously reduce global environmental risks while also meeting economic development goals. This paper proposed a novel method according to the idea of multiple time scales to verify ecological restoration policies in the Shiyang River drainage basin, arid China. We integrated modern pollen transport characteristics of the entire basin and pollen records from 8 Holocene sedimentary sections, and quantitatively reconstructed the millennial-scale changes of watershed vegetation zones by defining a new pollen-precipitation index. Meanwhile, Empirical Orthogonal Function method was used to quantitatively analyze spatial and temporal variations of Normalized Difference Vegetation Index in summer (June to August) of 2000-2014. By contrasting the vegetation changes that mainly controlled by millennial-scale natural ecological evolution with that under conditions of modern ecological restoration measures, we found that vegetation changes of the entire Shiyang River drainage basin are synchronous in both two time scales, and the current ecological restoration policies met the requirements of long-term restoration objectives and showed promising early results on ecological environmental restoration. Our findings present an innovative method to verify river ecological restoration policies, and also provide the scientific basis to propose future emphasizes of ecological restoration strategies. PMID- 27470947 TI - Endotoxin recovery using limulus amebocyte lysate (LAL) assay. AB - A phenomenon initially reported by Chen and Vinther in 2013 [1], and now commonly referred to as low endotoxin recovery (LER), has prompted the Food and Drug Administration (FDA) to request specific data demonstrating the capability of the LAL BET method (i.e., USP <85>) to recover endotoxin from spiked samples over time. The results of these spike/hold recovery studies are expected to be included in the Biologics License Applications (BLA) for review by the Center for Drug Evaluation and Research (CDER) Hughes (2014) and Hughes et al. (2015) [2,3]. Such studies involve spiking a known amount of a surrogate endotoxin, such as purified lipopolysaccharide (LPS), into undiluted biological products and then testing at different time points to determine the recovery over time. We report here the experience and learning gained from conducting spike/hold recovery studies for a monoclonal antibody (Mab) product. Results from initial hold studies spiked with purified LPS showed rapid loss of endotoxin activity in the drug substance (DS) and significant batch-to-batch variation in the drug product (DP). After careful review and examination of the experimental details, it was determined that the study design and execution differed from the routine batch release USP <85> BET method with regard to mixing time and sampling scheme. The hold study design was subsequently revised so that the mixing time and sampling were the same as the verified USP <85> BET method used for routine batch release testing. The spike/hold recovery studies were repeated and the results demonstrated that LPS could be consistently recovered over time. These findings highlight the importance of carefully controlling sample preparation procedures in a spike/hold recovery study in order to demonstrate the suitability of using the LAL BET method for endotoxin detection. PMID- 27470949 TI - Biohistorical materials and contemporary privacy concerns-the forensic case of King Albert I. AB - The rapid advancement of technology in genomic analysis increasingly allows researchers to study human biohistorical materials. Nevertheless, little attention has been paid to the privacy of the donor's living relatives and the negative impact they might experience from the (public) availability of genetic results, even in cases of scientific, forensic or historical relevance. This issue has become clear during a cold case investigation of a relic attributed to Belgian King and World War I-hero Albert I who died, according to the official version, in a solo climbing accident in 1934. Authentication of the relic with blood stains assigned to the King and collected on the place where his body was discovered is recognised as one of the final opportunities to test the plausibility of various conspiracy theories on the King's demise. While the historical value and current technological developments allow the genomic analysis of this relic, publication of genetic data would immediately lead to privacy concerns for living descendants and relatives of the King, including the Belgian and British royal families, even after more than 80 years. Therefore, the authentication study of the relic of King Albert I has been a difficult exercise towards balancing public research interests and privacy interests. The identification of the relic was realised by using a strict genetic genealogical approach including Y-chromosome and mitochondrial genome comparison with living relatives, thereby limiting the analysis to genomic regions relevant for identification. The genetic results combined with all available historical elements concerning the relic, provide strong evidence that King Albert I was indeed the donor of the blood stains, which is in line with the official climbing accident hypothesis and contradicts widespread 'mise-en-scene' scenarios. Since publication of the haploid data of the blood stains has the potential to violate the privacy of living relatives, we opted for external and independent reviewing of (the quality of) our data and statistical interpretation by external forensic experts in haploid markers to guarantee the objectivity and scientific accuracy of the identification data analysis as well as the privacy of living descendants and relatives. Although the cold case investigation provided relevant insights into the circumstances surrounding the death of King Albert I, it also revealed the insufficient ethical guidance for current genomic studies of biohistorical material. PMID- 27470950 TI - [Pay attention to the diagnosis and treatment of sports injuries in children and adolescents]. PMID- 27470951 TI - [Focal periphyseal edema zone on MRI and clinical significance of the adolescent knee]. AB - OBJECTIVE: To investigate the MR image characteristics and clinical significance of focal periphyseal edema (FOPE) zone of the adolescent knee which was with or without trauma history, and provide the basis for the correct diagnosis and treatment. METHOD: A total of 12 patients (9 boys, age range 12-16 years, average age 14 years old, 3 girls, age range 12-15 years, average age 13 years )who had pain of the knee without the traumatic history and 16 patients (12 boys, age range 10-15 years, average age 14 years; 4 girls, age range 11-13 years, average age 12 years) who were painful in the knee after trauma were included in this study. The knee MR examinations were performed in all the patients. The characteristics of MRI between painful knee without trauma and painful knee after trauma were compared and analyzed, and the average vertical distances from the farthest of the edema area to the epiphyseal plate were measured. The vertical distances were measured respectively in sagittal view and coronal view in PD-FS and in sagittal view in T1WI, and the average for the three were calculated. At last, the images with the results of operation or follow-up examinations were compared and confirmed by double blind method. RESULTS: The MRI characteristics of FOPE zone in the 12 adolescent who complained painful knee but had no trauma showed low signal intensity in T1WI and high signal intensity in PD-FS. The edema centered at the physis and extended into both the adjacent epiphysis and metaphysic.In addition, it shaped like patches and thread, and edema range(14.5+/ 6.6)mm.The MRI findings of the 16 adolescent had pain of the knee after injury characterized by a wide range of low T1WI signal intensity and increased PD-FS signal intensity involving the articular surface of the epiphysis.The range of edema was (26.2+/-8.8)mm.There was statistically significant difference between non-traumatic edema and the edema caused by trauma (t=4.346, P<0.05). CONCLUSION: A FOPE zone of the adolescent knee is likely to be related to pain in the adolescent growth period and physiologic physeal fusion, and should not be mistaken for an abnormality, while the larger range of edema surrounding the epiphyseal plate may be associated with the trauma of the knee. PMID- 27470952 TI - [Comparative analysis of the ankle joints in juvenile male soccer players with imaging]. AB - OBJECTIVE: To investigate the characteristics of children male soccer players' ankle imaging features. METHODS: From October 2015 to February 2016, a total of 32 male children players of two soccer clubs in Guangzhou were enrolled in this study.The ages of all cases were from 10 to 14 years, average age was (11.3+/ 0.9) years.A total of 15 male children in region ordinary primary and secondary school students were set as control group, ages were from 10 to 14 years, average age was (12.1+/-1.2) years. All objects' ankle were examined by X-ray for positive and lateral positions; routine CT scanning and then on the workstation restructuring for axial, coronal and sagittal slices; and examined by MR. MR scan was with special surface coil for ankle joint for horizontal axis T2WI; coronal T1WI; coronary proton density weighted imaging (PWI); sagittal T2WI with fat suppression; sagittal PWI with isotropic and fat suppression sequence of fast field echo. The ankle bone morphological structures were observed on X-ray; the ankle bone mineral density, cortical bone thickness and sesamoid bone quantity was being observed and measured on CT; and the tenosynovitis, Achilles tendinitis, synovitis, and cancellous bone edema signal were observed on MR. RESULTS: For study group, a total of 32 cases and 64 ankles joints were completed by X-ray, CT and MR examination.A total of 15 cases and 30 ankles joints were completed by X-ray in control group, 26 ankle joints were completed by CT scan and 22 ankle joints were completed by MR examination.X-ray examination showed there was no statistically significant difference between the two groups in ankle bone structure.CT showed that navicular bone CT value was (296+/-82) HU in research group and navicular bone CT value was (266+/-107) HU in control group, the difference was statistically significant (P=0.03). MR showed the incidence of diseases in research group that the tendon sheath peripheral inflammation was 92.2% (59/64), Achilles tendon lesions was 18.8%(12/64), edema of cancellous bone was 73.4% (47/64) , lateral malleous ligaments injuried was 43.8%(28/64), synovitis or effusion in posterior ankle was 87.5% (56/64). The incidence of diseases in control group was that tendon sheath peripheral inflammation was 31.8%(7/22), Achilles tendon lesions was 0/22, edema of cancellous bone was 0/22, lateral malleous ligaments injuried was 0/22, synovitis or effusion in posterior ankle was 54.5% (12/22). There was statistically significant difference between these two groups (all P<0.05). CONCLUSION: Compared with the control group, children's male soccer players ankle bone structure, bone cortex thickness and bone mineral density there were no obvious difference. In the tenosynovitis, Achilles tendinitis, synovitis, bone marrow edema, lateral malleous ligaments injuried were significantly higher than the control group. PMID- 27470953 TI - [Classification and imaging diagnosis of Lisfranc joint injuries]. AB - OBJECTIVE: To accelerate the detection rate and accuracy of diagnosis in damage imaging of Lisfranc joint through research on the information of X-ray, CT, and MR imaging of tarsometatarsus joint (also called Lisfranc joint) damage. METHODS: A total of 153 cases of tarsometratisus damage or Lisfranc ligamentous injury patients were chosen during November 2012 to November 2015. Lisfranc injuries were classified according to the Myerson fracture displacements classification and Nunley-Vertullo low-grade injury classification. All the treatment data was performed using SPSS 17.0 software. RESULTS: For Myerson fracture displacements, there were 16 cases in Myerson I type (homolateral complete), 100 cases in Myerson II type (homolateral incomplete), and 5 cases in Myerson III type (divergent). For the low-grade injury, there were 7 cases, 24 cases, and 1 case in Nunley-Vertullo I, II, III type respectively. The probability was 14.9% (18/121) for patients that the initial survey found negative by X-ray imaging diagnosis and was confirmed by subsequent CT or MRI. It was found that the distance between the base of first (M1) and second (M2) metatarsus which was larger than 2 mm was 69.4%(84/121)from the X-ray imaging; there were small chip fractures between the base of M1 and M2 was 47.1% (57/121), and 71.2% (37/52)of small chip fractures in the inside of base of M2 from CT. On MRI, ligament disruption showed the discontinue or normal signal disappearing, and there were 15 cases in the complete disruption condition. CONCLUSION: It should be suggested to take a CT or MRI check for the patients who have highly suspicious Lisfranc injure and the X-ray imaging diagnosis was negative, since there is a certain rate of missed diagnosis for the Lisfranc injure using X-ray imaging. For children and teenagers, the sports injuries and joint strain are common style, such as the injuries caused by jump from higher platform, football/skateboarding injures, etc. If the distance between the base of M1 and M2 is larger than 2 mm or there are small chip fractures between the M1 and M2, the patients would be suspected bone fracture or Lisfranc ligament injure. Myerson II type is the most common Lisfranc joint injury , and MRI is best for Lisfranc ligament injury. PMID- 27470954 TI - [Detection the mutated protein aggregation and mitochondrial function in fibroblasts from amyotrophic lateral sclerosis patients with SOD1 gene mutations]. AB - OBJECTIVES: To explore mutant superoxide dismutase (SOD)1 protein expression and mitochondrial function in amyotrophic lateral sclerosis (ALS) patients' fibroblasts carrying different SOD1 mutations. METHODS: SOD1 gene mutation was detected using PCR and direct sequencing. Skin fibroblasts of three familial ALS patients with mutations and age/gender matched controls obtained by a punch skin biopsy were cultured. We performed immunofluorescence staining and quantitative detection of SOD1 proteins and mitochondrial membrane potential. Also, we detected the intracellular ROS by flow cytometry. RESULTS: We found that fibroblasts from familial ALS patients carried SOD1-V14M, SOD1-G16A, SOD1-C111Y mutation, respectively. The cytoplasm abnormal SOD1 protein aggregates appeared in ALS patients carrying SOD1 mutations. And the cytoplasmic/nuclear ratio of SOD1 aggregates increased 2.54, 2.80, 3.25-fold for each mutations, respectively, compared to the control group. Three SOD1 mutant groups showed loss of mitochondrial membrane potential and the ratio of red / green fluorescence intensity decreased by 36%, 124%, 142%, respectively, compared to the control group. The intracellular ROS levels also increased 3.33, 3.65, and 6.87-fold respectively. CONCLUSIONS: This work highlights that ALS alters SOD1 protein expression, mitochondrial function, and increases the ROS level even in peripheral tissues outside the central nervous system. Fibroblasts might therefore represent a powerful and minimally invasive tool to investigate ALS pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease. PMID- 27470955 TI - [Electrophysiological subtypes and long term prognosis of Guillain-Barre syndrome]. AB - OBJECTIVE: To assess the electrophysiological subtypes of Guillain-Barre syndrome (GBS) acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN), and long-term prognosis in northeastern China. METHODS: One hundred and eighteen patients with GBS were recruited between 2010 and 2012 and retrospectively reviewed. RESULTS: According to electrodiagnostic criteria, patients were classified as AMAN (49, 46.7%) or AIDP (39, 37.1%), or were unclassified (17, 16.2%). Between the AMAN and AIDP groups, age, sex, and clinical disability did not differ significantly, but the AMAN patients more frequently had preceding gastroenteritis. By 4 weeks after onset, 24.5% of the AMAN patients (12) and 33.3% of the AIDP patients (13) had regained the ability to walk; by 1 year, 77.6% of the AMAN patients (38) and 79.5% of the AIDP patients (31) could walk. Recovery was generally favorable in both subtypes. Immunotherapy was effective in patients with either AIDP or AMAN, and glucocorticoids and immunoglobulin treatment could achieve similar effect. CONCLUSIONS: AMAN and AIDP are the main subtypes of GBS in northeastern China. The prognosis of patients with AMAN is similar to that of patients with AIDP. Different immunotherapies have similar effect on long term prognosis. PMID- 27470956 TI - [Clinical outcome of mid-term follow-up of anterior cervical non-fusion surgery versus anterior cervical discectomy and fusion for cervical spondylosis]. AB - OBJECTIVE: To evaluate the clinical and radiological outcomes of artificial cervical disc replacement (Prodisc-C), dynamic cervical implant and anterior cervical discectomy and fusion (ACDF) in the treatment of cervical spondylosis. METHOD: From May 2011 to May 2013, a total of 44 cervical spondylosis patients that received cervical disc arthroplasty (Prodisc-C), dynamic cervical implant (DCI) or ACDF were retrospectively reviewed in Orthopedics Department, Beijing Chaoyang Hospital, Capital Medical University.The patients were divided into three groups by surgical methods.Parameters as gender, age, the operation time, blood loss and average hospital stay of three groups were compared.The patients were followed 3 months, 6 months, 12 months and 24 months postoperatively.Neck disability index (NDI), Japanese Orthopaedic Association (JOA) Score and Visual Analogue Scale (VAS) were used to evaluate the clinical outcomes of the three groups.We also measured the cervical lordosis, range of motion of surgical segment and adjacent segment and height of disc at pre-op and post-op. RESULT: All the patients were got at least 24 months follow-up.The differences between postoperative JOA, NDI and VAS scores and preoperative scores were of statistical significance (P<0.05). There was no statistical difference in average hospital stay, JOA, NDI and VAS recovery rate (P>0.05) among three groups.But the operative time and intraoperative blood loss were statistically different (P<0.05). Compared the pre-and postoperative ROM of C2-7, operative, upper and lower levels of each group respectively, the difference between pre-and postoperative ROM of ACDF group were of statistically significant [(16.6+/-3.6) degrees , (22.3+/-4.6) degrees , (18.1+/-3.1) degrees , P<0.05], while was no statistically significant of non-fusion group(P>0.05). There was no statistically significant difference between pre-and postoperative ROM of upper and lower levels among three groups (P>0.05), but had statistically difference in operative levels [(7.0+/-1.0) mm, (9.2+/-1.5) mm, (6.8+/-1.4) mm, P<0.05]. And there are no serious postoperative complications. CONCLUSION: Two cervical non-fusion surgery and ACDF have received good clinical effects in the treatment of spondylotic myelopathy or radicular spondylosis.The artificial cervical disc replacement and dynamic cervical implant can not only recover cervical lordosis and keep the range of motion and stability of the surgical segment, but also reduce the incidence of compensatory motion at adjacent segments and will prevent from adjacent segment degeneration. PMID- 27470957 TI - [Different posterior decompression for patients with spinal canal stenosis in the upper thoracic and cervical spine]. AB - OBJECTIVE: To retrospectively investigate the clinical manifestation of patients with spinal stenosis in the upper thoracic and cervical spine by posterior decompression in different ways. METHODS: From January 2010 to December 2015, 18 patients of that complicated phenomenon were studied in Department of Orthopaedic Surgery, China-Japan Union Hospital, Jilin University.Ten patients received one stage combined decompression (group A); while the other 8 received multi-stage posterior decompression(group B). The Visual analogue scale (JOA), thoracic Cobb and range of motion(ROM) were compared. RESULT: No statistically significant inter-group difference existed in preoperative JOA score[(9.1+/-2.6)vs (9.1+/ 2.2)]and postoperative JOA score[(15.4+/-1.2)vs(13.8+/-4.5)], but the mean recovery rate of nerve function of group A(79%+/-15%)is better than that of group B(69%+/-34%). CONCLUSION: All the approaches are effective for the treatment of patients with spinal stenosis in the upper thoracic and cervical spine, while one staged combined decompression was better than double-staged operation. PMID- 27470958 TI - [Expression and regulation of CD36 mRNA in granulosa cells and its relation with clinical characteristics of polycystic ovary syndrome]. AB - OBJECTIVE: To study the expression of CD36 mRNA in granulosa cells (GCs) of patients with polycystic ovary syndrome (PCOS) and the impact of testosterone, insulin and PPARgamma agonist rosiglitazone on GCs. METHODS: The expression of CD36 mRNA inGCs of patients with PCOS and normal controls were assayed byreal time PCR.The level of CD36 mRNA after treatment with testosterone, insulin, and rosiglitazone in GCs ofnormal controls were also tested by real-time PCR. RESULTS: (1) The expression of CD36mRNA in the GCs of PCOS was significantly higher than that of the controls (P<0.05). (2) When testosterone concentration was 1 nmol/L, CD36 mRNA increased in the GCs, but there was no significantdifference compared to the blank control, (P>0.05). When testosterone concentration was 10 nmol/L, the expression of CD36 mRNA in the GCs was higher than that in the blank control with significant difference (P<0.05). When insulin concentration was 10 nmol/L, the expression of CD36 mRNA increased but the difference was not statistically significant (P>0.05). When insulin concentration was 100 nmol/L, the expression of CD36mRNA in the GCswas higher than that in the blank control (P=0.05). When rosiglitazone concentration was 1nmol/L, the expression of PPARgamma mRNA in GCs were significantly increased compared with the blank control (P<0.05). The expression of CD36 mRNA atrosiglitazone concentrationof 10 nmol/Lwere significantly increased compared to the concentration of 1 nmol/L (P<0.05). CONCLUSION: High testosterone and insulin induced the expression of CD36 mRNA.Rosiglitazone increased CD36 mRNA in a dose related manner in GCs.Increased CD36 mRNA in the GCs of PCOS may be related to the clinical characteristics of PCOS. PMID- 27470959 TI - [The change of vaginal lactobacillus in patients with high-risk human papillomavirus infection]. AB - OBJECTIVE: To study the distribution characteristics of lactobacillus in the vaginal mucosa of patients with HPV infection. METHODS: The planting density of lactobacillus in vaginal secretions of 95 cases with HPV16/18 infection and 90 cases of normal women of childbearing age were observed by oil microscope. And the strains of vaginal lactobacilli in two groups were analyzed using species specific polymerase chain reaction (Species-specific PCR) and the distribution of vaginal lactobacilli in patients with HPV16/18 infection were investigated. RESULTS: In HPV16/18 infective groups, the planting density of lactobacillus in the vaginal mucosa was 104 (68-186)/HP. It was significantly lower than that of the normal group (234 (161-326)/HP, P<0.05). Compared with the normal group, the positive rates of lactobacillus iners, lactobacillus crispatus, and lactobacillus gasseri were significantly lower in HPV16/18 infection group (P<0.05). CONCLUSION: The HPV16/18 infection is associated with the decreased number of lactobacillus and the imbalance of vaginal flora; Lactobacillus iners, lactobacillus crispatus, and lactobacillus gasseri may play a key role in maintaining the vaginal micro ecological environment. PMID- 27470960 TI - [The causes and strategies for intraoperative rupture during clipping the anterior circulation aneurysms]. AB - OBJECTIVE: To investigate the causes and strategies for intraoperative rupture during clipping the anterior circulation aneurysms. METHODS: Nineteen patients with anterior circulation aneurysms ruptured during clipping, who admitted to the Department of Neurosurgery, Henan Provincial People's Hospital from November 2012 to February 2014, were enrolled. Their clinical data were analyzed retrospectively to summarize the causes and strategies for intraoperative rupture. RESULTS: The aneurysms ruptured during predissection in 2 cases (10.5%), during dissection in 11 cases (57.9%) and during clip application in 6 cases (31.6%). There was no residual aneurysm confirmed by postoperative CTA in 17 patients. One case with posterior communicating artery aneurysm cannot be clipped because of the serious avulsion of the aneurysm neck during clipping. The aneurysm was trapped and the patient paralysed on one side after operation. One case died postoperative 8 days because of severe cerebral edema, whose aneurysm ruptured during predissection. The Glasgow Outcome Scale (GOS) of three months after operation showed good recovery in 11, moderate recovery in 5, severe disability in 2, and death in 1 cases, respectively. CONCLUSION: Adequate preoperative evaluation for the risk factors of intraoperative rupture and excellent microsurgical techniques can prevent intraoperative rupture of intracranial aneurysms. Controlling the bleeding quickly and dissecting and clipping the aneurysm after definitely know the anatomy of the aneurysm and surrounding vasculature could be the keys to deal with intraoperative aneurysm rupture. PMID- 27470961 TI - [Effects of chrysin on sphere formation and CK2alpha expression of ovarian cancer stem-like cells derived from SKOV3 cell line]. AB - OBJECTIVE: To investigate whether inhibitory effect of chrysin on sphere formation of ovarian cancer stem-like cells(spheroids derived from human ovarian cancer SKOV3 cell line ) is involved in the down-regulating of the protein expression of casein kinase CK2alpha. METHODS: SKOV3-derived ovarian cancer stem like cells obtained by suspension culture in stem cell-condition medium using ultra-low adhesion plate were treated with various concentrations (5.0, 10.0 and 20.0 MUmol/L) of chrysin. Sphere formation assay was used to determine the sphere forming rate of SKOV3-derived ovarian cancer stem-like cells. Western blot was used to analyze the protein expressions of CK2alpha and cancer stem cell markers CD133 and CD44. Silence of CK2alpha by siRNA and ectopic expression of CK2alpha by transfection with pcDNA3.1-CK2alpha plasmid were used to explore the mechanism underlying the effect of chrysin on sphere formation of SKOV3-derived ovarian cancer stem-like cells. RESULTS: Chrysin (5.0, 10.0 and 20.0 MUmol/L) significantly reduced the sphere forming rate of SKOV3-derived ovarian cancer stem-like cells, in a concentration-dependent manner (22.3%+/-2.5% vs 14.7%+/ 2.1%, 8.6%+/- 1.7% and 3.8% +/- 1.1% respectively; P<0.05). In addition, chrysin (5.0, 10.0 and 20.0 MUmol/L) obviously down-regulated the protein expressions of CK2alpha, CD133 and CD44 in SKOV3-derived ovarian cancer stem-like cells. In combination with CK2alpha siRNA transfection and chrysin synergistically decreased sphere formation (P<0.05) and the protein expressions of CK2alpha, CD133 and CD44 in SKOV3-derived ovarian cancer stem-like cells. However, transfection with pcDNA3.1-CK2alpha plasmid attenuated inhibitory effects of chrysin on sphere formation capability and the expressions of CK2alpha, CD133 and CD44 of SKOV3-derived ovarian cancer stem-like cells. CONCLUSION: Down-regulation of CK2alpha protein expression is involved in the inhibition effect of chrysin on the sphere formation capability of SKOV3-derived ovarian cancer stem-like cells. PMID- 27470962 TI - [Follistatin-like 1-engineered mesenchymal stem cells prevent myocardial ischemic reperfusion injury]. AB - OBJECTIVE: To investigate the role of follistatin-like protein 1 (FSTL1) on bone marrow mesenchymal stem cells (BM-MSCs)-mediated cardioprotection during myocardial ischemia/reperfusion injury. METHODS: Rat bone marrow mesenchymal stem cells were isolated by whole bone marrow adherence method in vitro. A total of 60 Wistar rats were randomly divided into 4 groups: control group, ischemic /reperfusion injury (IRI) group, ischemia/reperfusion injury group treated with natural BM-MSCs (IRI+ MSC group), ischemia/reperfusion injury group treated with BM-MSCs which did not contain FSTL1 (IRI+ MSC FSTL1 siRNA group). Survival analysis was used to analyze survival time of rats, besides, expression of FSTL1 was detected by Western blotting. Myocardial pathological changes were detected by Hematoxylin and Eosin (HE) staining. Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) and enzyme-linked immunosorbent assay (ELISA) were used to determine the associated biomarkers and apoptosis 7 days after operation. RESULTS: Compared with IRI group, rats in IRI+ MSC group had a higher survival rate and lived longer. Meanwhile, IRI+ MSC group had higher FSTL1 expression in blood and myocardial tissues than IRI group. Control group showed significantly lower apoptosis rate of myocardial cells[(1.4+/-0.1)% vs (29.8+/ 4.5)%, P<0.05], less histological changes and infarction areas (0 vs 24.48+/ 4.27, P<0.05) than IRI group. Compared with IRI group, IRI+ MSC group had an improvement of apoptosis rate[(4.2+/-0.3)% vs (29.8+/-4.5)%, P<0.05], less histological injury and infarction areas (15.12+/-3.82 vs 24.48+/-4.27, P<0.01). IRI+ MSC group had lower expression of LDH, MDA, CK and higher expression of SOD than IRI group (P<0.05). However, IRI+ MSC FSTL1 siRNA group showed weaker protection of myocardial cells than IRI+ MSC group after knockdown of FSTL1 (P<0.05). CONCLUSION: FSTL1, which was secreted by BM-MSCs, plays a protective role in myocardial IRI. PMID- 27470963 TI - [Preparation of folate-targeted magnetic nanocomposites loaded with TFPI-2 plasmid and cisplatin and evaluation of its targeting and inhibitory effect on nasopharyngeal carcinoma HNE-1 cells in vitro]. AB - OBJECTIVE: To prepare a novel folate-targeted magnetic nanocomposites loaded with tissue facor pathway inhibitor 2 (TFPI-2) and cisplatin (CDDP) and to investigate its targeting ability and anti-tumor effect on nasopharyngeal carcinoma HNE-1 cells in vitro. METHODS: The copolymer folic acid-polyethylene glycol polyethyleneimine (FA-PEG-PEI) was synthesized through amidation reaction, and then FA-PEG-PEI/ magnetic nanoparticles-CDDP/TFPI-2 (MNP-CDDP/TFPI-2) nanocomposites was obtained by electrostatic adsorption between TFPI-2 plasmid and magnetic nanoparticles loaded with CDDP (MNP-CDDP) with vortex FA-PEG-PEI. (1)H Nuclear Magnetic Resonance ((1)H NMR ) was used to determine if FA-PEG-PEI was synthesized. The particle size, zeta potential and morphology were detected by dynamic light scattering (DLS) and transmission electron microscope (TEM). The content of Fe and CDDP was measured by phenanthroline and o-phenylenediamine (OPDA) colourimetry. Agarose gel electrophoresis was used to analyze the binding ability of FA-PEG-PEI/MNP-CDDP to TFPI-2 plasmid. Molecular targeted uptake of FA PEG-PEI/ MNP-CDDP/TFPI-2 coupling with green fluorescent protein (GFP) in NPC cells were observed by Prussian-blue iron staining and fluorescence microscope. The levels of TFPI-2 protein expression after transfection were evaluated by Western blot. The effects of nanocomposites on HNE-1 cells proliferation and apoptosis were measured with Cell Counting Kit-8(CCK-8) and flow cytometry. RESULTS: Special peak value of FA, PEG and PEI were showed on (1)H NMR spectrogram. The mean size and zeta potential of FA-PEG-PEI/MNP-CDDP/TFPI-2 were 141.1 nm and 21.5 mV. The nanocomposites showed a good monodispersity and an insufficient size uniformity under TEM. The content of Fe and CDDP were 116.2 MUg/ml and 92.88 MUg/ml, respectively. Agarose gel electrophoresis showed TFPI-2 could be encapsulated completely and protected from digestion of DNA enzyme as the mass ratio of FA-PEG-PEI/ MNP-CDDP and TFPI-2 plasmid was equal or higher than 1?1. More blue-stained magnetic granulars and green fluorescence were seen in folate receptor (FR)-positive HNE-1 cells than in FR-negative CNE-2 (P<0.05) under microscope and fluorescence microscope. The level of TFPI-2 protein expression in HNE-1cells increased significantly after transfection by FA-PEG PEI/ MNP-CDDP/TFPI-2, compared with other control groups (FA-PEG-PEI/MNP-CDDP group and TFPI-2 group), all P<0.05. The nanocomposites inhibitory effect on HNE 1 including cell growth inhibition rate (64.00%) and apoptosis rate (49.61%) were significantly higher than that in FA-PEG-PEI/MNP group (8.19%, 9.26%), FA-PEG PEI/TFPI-2 group (40.35%, 19.85%) and FA-PEG-PEI/MNP-CDDP group(56.15%, 36.46%)(P<0.05). CONCLUSION: FA-PEG-PEI/MNP-CDDP/TFPI-2 nanocomposites was successfully synthesized using amidation and electrostatic adsorption technology and has a good molecular targeting and inhibitory effect on FR-positive HNE 1cells in vitro. PMID- 27470964 TI - [Effect of astaxanthin on vascular smooth muscle cells proliferation induced by platelet derived growth factor-BB]. AB - OBJECTIVE: To investigate the effect of astaxanthin (AST) on vascular smooth muscle cells (VSMCs) proliferation in vitro induced by platelet derived growth factor-BB (PDGF-BB), and to explore its possible mechanism. METHODS: There were 4 groups in this experiment: blank control group, PDGF-BB group, PDGF-BB+ AST group, AST group. After the cells received different intervention for the indicated time, the cell growth was determined by Trypan blue staining; cell proliferation was demonstrated using CCK-8 kit; the cell cycle progression was analyzed by flow cytometry, and the mRNA expression of cyclin D1, cyclin E, CDK6, CDK4, cyclin kinase inhibitor protein P21 was determined by real-time PCR; reactive oxygen species (ROS) generation was detected using a Microplate reader; the total and phosphorylated forms of ERK1/2, p38 MAPK, JNK was observed in AST pretreated VSMCs in 5, 10 and 15 min after PDGF-BB treatment by Western blot analysis. RESULTS: (1) Cell viability: AST and/or PDGF-BB did not induce VSMCs necrosis with the different concentration compared with untreated cells (P>0.05). (2) Cell proliferation: PDGF-BB induced VSMCs proliferation (2.5+/-0.3 vs 1, P<0.01), while AST reversed the effect in a concentration-dependent manner when co-treated with PDGF-BB (all P<0.01); Cell cycle: Flow cytometry analysis showed that AST at a dose of 25 MUmol/L reduced the percentages of cells in S phase and increased the G0/G1 populations in PDGF-BB-stimulated VSMCs; mRNA expression of the check-point proteins: Real Time PCR results demonstrated that, compared with the control group, the mRNA expression of CDK6, CDK4, cyclin D1, cyclin E in the PDGF-BB group was higher (4.20+/-0.30, 2.90+/-0.18, 3.50+/-0.30, 2.70+/-0.11 vs 1, all P<0.01), while p21 mRNA expression was lower (0.52+/-0.03 vs 1, P<0.01), while AST reversed these effects when co-treated with PDGF-BB. (3) ROS expression: compared with the control group, ROS level was significantly higher in the PDGF-BB group (2.10+/-0.09 vs 1, P<0.01), while AST reversed the effect in a concentration-dependent manner when co-treated with PDGF-BB (all P<0.01). (4) Signaling pathway: AST blocking the proliferation of VSMCs induced by PDGF-BB was related to suppress ERK1/2, p-p38 MAPK signaling pathway, but little effect to JNK. Conclutions: These results demonstrate that AST can block the proliferation and migration of VSMCs through G0/G1 to S phase of the cell cycle arrest. Further study indicates that AST suppress PDGF-BB-induced VSMCs proliferation is associated with an inhibition of ROS generation and ERK1/2, p-p38 MAPK signal pathways. PMID- 27470965 TI - Magnetic porous carbon derived from a metal-organic framework as a magnetic solid phase extraction adsorbent for the extraction of sex hormones from water and human urine. AB - An iron-embedded porous carbon material (MIL-53-C) was fabricated by the direct carbonization of MIL-53. The MIL-53-C possesses a high surface area and good magnetic behavior. The structure, morphology, magnetic property, and porosity of the MIL-53-C were studied by scanning electron microscopy, transmission electron microscopy, vibrating sample magnetometry, and N2 adsorption. With the use of MIL 53-C as the magnetic solid-phase extraction adsorbent, a simple and efficient method was developed for the magnetic solid-phase extraction of three hormones from water and human urine samples before high-performance liquid chromatography with UV detection. The developed method exhibits a good linear response in the range of 0.02-100 ng/mL for water and 0.5-100 ng/mL for human urine samples, respectively. The limit of detection (S/N = 3) for the analytes was 0.005-0.01 ng/mL for water sample and 0.1-0.3 ng/mL for human urine sample. The limit of quantification (S/N = 10) of the analytes were in the range of 0.015-0.030 and 0.3-0.9 ng/mL, respectively. PMID- 27470966 TI - The Key to Understanding Twins. PMID- 27470967 TI - Individualized Pazopanib Dosing: A Prospective Feasibility Study in Cancer Patients. AB - PURPOSE: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically guided individualized dosing. EXPERIMENTAL DESIGN: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was =20.0 mg/L. Of these, 9 patients with a high Cmin of 51.3 mg/L (45.1%) experienced >=grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, Cmin remained above the threshold at 28.2 mg/L (25.3%). CONCLUSIONS: A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738-46. (c)2016 AACRSee related commentary by Ornstein and Rini, p. 5626. PMID- 27470969 TI - PD-1 Axis Inhibitors in EGFR- and ALK-Driven Lung Cancer: Lost Cause? AB - Programmed death axis 1 (PD-1) inhibitors have ushered in a new error of cancer immunotherapeutics for advanced smoking-associated non-small cell lung cancer. Their role in treating EGFR-mutant and ALK-rearranged lung cancer has yet to be determined. Clin Cancer Res; 22(18); 4539-41. (c)2016 AACRSee related article by Gainor et al., p. 4585. PMID- 27470968 TI - PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors. AB - PURPOSE: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs. EXPERIMENTAL DESIGN: We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Delta/+ mice that develop GISTs. RESULTS: The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFNgamma-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Delta/+ mice, imatinib downregulated IFNgamma-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition. CONCLUSIONS: PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454-65. (c)2016 AACR. PMID- 27470970 TI - Digital-Analog Quantum Simulation of Spin Models in Trapped Ions. AB - We propose a method to simulate spin models in trapped ions using a digital analog approach, consisting in a suitable gate decomposition in terms of analog blocks and digital steps. In this way, we show that the quantum dynamics of an enhanced variety of spin models could be implemented with substantially less number of gates than a fully digital approach. Typically, analog blocks are built of multipartite dynamics providing the complexity of the simulated model, while the digital steps are local operations bringing versatility to it. Finally, we describe a possible experimental implementation in trapped-ion technologies. PMID- 27470971 TI - Rheology and structure of surface crosslinked surfactant-activated microgels. AB - Nonionic surfactant-activated microgels (SAMs), composed of hydrophobic alkyl acrylates and hydrophilic hydroxyalkyl esters that utilize the effects of surfactant mediated swelling and interaction to provide pH-independent rheological properties, were previously reported as a new pathway to the rheology modification of surfactant solutions. Crosslinking was shown to play an important role in the properties of these soft microgel systems. To understand the impact of crosslinking chemistry on SAM polymers, we have compared two types of SAM polymers: a conventionally crosslinked SAM polymer via allyl pentaerythritol and a novel SAM polymer, where the surface is self-crosslinked via a reactive surfactant. We have systematically characterized the polymer's swelling, rheology and microstructure in a model system containing the polymer, sodium dodecyl sulfate (SDS) and water. Surface self-crosslinking is demonstrated to be a more effective crosslinking approach to create surfactant-mediated interactions between the microgel particles, resulting in more effective rheology modification. Internal crosslinking hinders both the full swelling of the SAM polymer as well as inter-particle bridging interactions, and is therefore less effective. To our best knowledge, this is the first report on creating a novel surface self-crosslinked microgel via a dual-functional reactive surfactant that interacts with a non-reactive surfactant to create a yield stress fluid. PMID- 27470972 TI - Abnormal photoreceptor outer segment development and early retinal degeneration in kif3a mutant zebrafish. AB - Photoreceptors are highly specialized sensory neurons that possess a modified primary cilium called the outer segment. Photoreceptor outer segment formation and maintenance require highly active protein transport via a process known as intraflagellar transport. Anterograde transport in outer segments is powered by the heterotrimeric kinesin II and coordinated by intraflagellar transport proteins. Here, we describe a new zebrafish model carrying a nonsense mutation in the kinesin II family member 3A (kif3a) gene. Kif3a mutant zebrafish exhibited curved body axes and kidney cysts. Outer segments were not formed in most parts of the mutant retina, and rhodopsin was mislocalized, suggesting KIF3A has a role in rhodopsin trafficking. Both rod and cone photoreceptors degenerated rapidly between 4 and 9 days post fertilization, and electroretinography response was not detected in 7 days post fertilization mutant larvae. Loss of KIF3A in zebrafish also resulted in an intracellular transport defect affecting anterograde but not retrograde transport of organelles. Our results indicate KIF3A plays a conserved role in photoreceptor outer segment formation and intracellular transport. PMID- 27470973 TI - Effect of antihypertensive therapy with angiotensin-converting enzyme inhibitors on chronic periodontitis: a case-control study. AB - BACKGROUND: Angiotensin-converting enzyme (ACE) downregulates the activity of bradykinin, a potent proinflammatory and immunostimulatory peptide liberated from an internal portion of kininogens. Here, we asked whether periodontitis is worsened in patients under antihypertensive treatment with ACE inhibitors. METHODS: Periodontal parameters were recorded from 30 individuals taking ACE inhibitors (case) and 35 taking a non-ACE inhibitor medication (control). Data were analyzed by nonparametric and parametric statistical tests. RESULTS: Most sociodemographic figures were similar in both groups. However, family income was statistically higher in the control group, and the percentage of sites with visible plaque (PL) was statistically higher in the case group (P = 0.043 and P = 0.005, respectively). The prevalence of individuals with chronic periodontitis varied from 31.5% in the control group to 63.4% in the case group (P = 0.001). Patients in the case group presented a 3.2-fold higher risk of having sites with pocket depth >=5 mm and a 2.9-fold higher risk of having sites with clinical attachment loss >=5 mm in comparison with those in the control group (P = 0.009 and P = 0.001, respectively; adjusted for family income and visible PL). CONCLUSION: Angiotensin-converting enzyme inhibitors may increase the prevalence and extent of chronic periodontitis in Brazilian patients. PMID- 27470976 TI - Target and non-target identification of chemical components in Lamiophlomis rotata by liquid chromatography/quadrupole time-of-flight mass spectrometry using a three-step protocol. AB - RATIONALE: As a herbal plant used in traditional Chinese medicine, Lamiophlomis rotata (Benth.) Kudo mainly displays its pharmacological effect by promoting blood circulation and hemostasis, dispelling wind, and acting as an analgesic. To identify the components contained in L. rotata, global detection and structural elucidation of both target and non-target components in the medicinal material was performed. METHODS: L. rotata was ultrasonically extracted with methanol. Separation and analysis were achieved using liquid chromatography/quadrupole time of-flight mass spectrometry (LC/QTOF-MS). A three-step protocol which included (1) potential components screening, (2) collection of qualitative information, and (3) database searching and structural elucidation was used for target and non target identification. RESULTS: A total of 42 components were tentatively identified, which included 12 iridoids (2 aglycones and 10 glucosides), 11 flavonoids (4 aglycones and 7 glucosides), and 13 phenylethanoid glycosides. Moreover, components of L. rotata extract belonging to the three main structural categories could be well separated in a 3D point plot according to their retention times, mass defects and degrees of unsaturation, facilitating the structural classification and identification in the subsequent studies. CONCLUSIONS: The results provide a reasonable picture of the components contained in L. rotata extract and promote the further pharmacodynamic and/or pharmacokinetic characterization of this medical material, meanwhile demonstrating the utility of a universal methodology for the systematical study of herbal medicines. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470975 TI - Pondering neutrophil extracellular traps with healthy skepticism. AB - The authors engage in a dialogue that evaluates critically the state of the study of neutrophil extracellular traps (NETs), a phenomenon currently the object of considerable interest, with the goal of identifying those aspects that merit clarification in order to assign the process its proper place in our current understanding of cell biology. Since the seminal observations in the Zychlinsky laboratory that described the extrusion of filaments of nuclear DNA associated with histones and granule proteins from neutrophils stimulated in vitro, many investigators have examined the phenomenon of NET formation in numerous and diverse settings. However, an overview of work in this rapidly growing field prompts several fundamental questions about NETs, including their precise composition, the mechanisms by which they arise, their clinical relevance, and the interrelationship of those observed in vitro and in vivo. In this discussion, the authors challenge interpretation of data from some experimental settings and provide recommendations for specific studies that would address the concerns raised, improve understanding of the biological relevance of NETs, and strengthen the field. PMID- 27470977 TI - Measuring Pain for Patients Seeking Physical Therapy: Can Functional Magnetic Resonance Imaging (fMRI) Help? AB - In the multidisciplinary fields of pain medicine and rehabilitation, advancing techniques such as functional magnetic resonance imaging (fMRI) are used to enhance our understanding of the pain experience. Given that such measures, in some circles, are expected to help us understand the brain in pain, future research in pain measurement is undeniably rich with possibility. However, pain remains intensely personal and represents a multifaceted experience, unique to each individual; no single measure in isolation, fMRI included, can prove or quantify its magnitude beyond the patient self-report. Physical therapists should be aware of cutting-edge advances in measuring the patient's pain experience, and they should work closely with professionals in other disciplines (eg, magnetic resonance physicists, biomedical engineers, radiologists, psychologists) to guide the exploration and development of multimodal pain measurement and management on a patient-by-patient basis. The primary purpose of this perspective article is to provide a brief overview of fMRI and inform physical therapist clinicians of the pros and cons when utilized as a measure of the patient's perception of pain. A secondary purpose is to describe current known factors that influence the quality of fMRI data and its analyses, as well as the potential for future clinical applications relevant to physical therapist practice. Lastly, the interested reader is introduced and referred to existing guidelines and recommendations for reporting fMRI research. PMID- 27470974 TI - EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. AB - Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1alpha induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies. PMID- 27470978 TI - Systematic Clinical Reasoning in Physical Therapy (SCRIPT): Tool for the Purposeful Practice of Clinical Reasoning in Orthopedic Manual Physical Therapy. AB - Background and Purpose: Clinical reasoning is essential to physical therapist practice. Solid clinical reasoning processes may lead to greater understanding of the patient condition, early diagnostic hypothesis development, and well tolerated examination and intervention strategies, as well as mitigate the risk of diagnostic error. However, the complex and often subconscious nature of clinical reasoning can impede the development of this skill. Protracted tools have been published to help guide self-reflection on clinical reasoning but might not be feasible in typical clinical settings. Case Description: This case illustrates how the Systematic Clinical Reasoning in Physical Therapy (SCRIPT) tool can be used to guide the clinical reasoning process and prompt a physical therapist to search the literature to answer a clinical question and facilitate formal mentorship sessions in postprofessional physical therapist training programs. Outcomes: The SCRIPT tool enabled the mentee to generate appropriate hypotheses, plan the examination, query the literature to answer a clinical question, establish a physical therapist diagnosis, and design an effective treatment plan. The SCRIPT tool also facilitated the mentee's clinical reasoning and provided the mentor insight into the mentee's clinical reasoning. The reliability and validity of the SCRIPT tool have not been formally studied. Discussion: Clinical mentorship is a cornerstone of postprofessional training programs and intended to develop advanced clinical reasoning skills. However, clinical reasoning is often subconscious and, therefore, a challenging skill to develop. The use of a tool such as the SCRIPT may facilitate developing clinical reasoning skills by providing a systematic approach to data gathering and making clinical judgments to bring clinical reasoning to the conscious level, facilitate self-reflection, and make a mentored physical therapist's thought processes explicit to his or her clinical mentor. PMID- 27470979 TI - Multiple Renal Arteries in Kidney Transplantation: A Systematic Review and Meta Analysis. AB - BACKGROUND: The use of grafts with multiple renal arteries (MRA) in renal transplantation has not been clearly established. MATERIAL/METHODS: A systematic literature review used predefined terms to search PubMed, EMBASE, and the Cochrane Library for all studies since 1985 that included more than 50 MRA grafts. A total of 23 studies, comprising a total of 18,289 patients, were eligible to be included in the meta-analysis. RESULTS: Patients who received an MRA graft compared to single renal artery (SRA) grafts showed significantly higher complication rates (13.8% vs. 11.0%, OR 1.393, p<0.0001), more delayed graft function (10.3% vs. 8.2%, OR 1.333, p=0.022), and had an associated significantly lower 1-year graft survival (93.2% vs. 94.5%, OR 0.819, p=0.034). Both the creatinine level and the warm ischemia time (WIT) were significantly higher in patients with MRA grafts but showed high heterogeneity (I2 98% for WIT and I2 70% for creatinine level). Although MRA grafts were associated with more complications compared to SRA grafts, long-term outcomes were similar for 5-year graft survival (81.4% vs. 81.6%) and 1- and 5-year patient survival (95.4% and 89.6% in MRA group vs. 95.4% and 87.0% in SRA group, respectively). CONCLUSIONS: MRA grafts were associated with a higher risk of complication and delayed graft function but had comparable long-term outcomes for graft and patient survival. PMID- 27470981 TI - Mental-health-related stigma among Japanese children and their parents and impact of renaming of schizophrenia. AB - AIM: Mental-health-related stigma affects help-seeking behavior and service utilization among young people. Whether mental-health-related stigma is different or correlated between parents and their children is unknown. It is also unknown whether the name change of schizophrenia in 2002 has had long-term effects on reducing stigma for adults in the general population. METHODS: We recruited 143 parent-child pairs (mean ages [SD]: 51.5 [3.6] and 21.2 [1.2] years, respectively) to complete self-report questionnaires regarding mental-health related stigma and experience. We also assessed negative stereotypes for three psychiatric disease names (old and new names of schizophrenia, and depression), and for diabetes mellitus as a physical illness comparison. The questionnaires also asked respondents to identify the old and new names of schizophrenia and dementia, respectively, among 10 names for mental and physical illnesses and conditions. RESULTS: Parents showed lower stigma levels toward mental illness and diabetes mellitus, but similar or greater stigma levels toward schizophrenia, compared with their children. Stigma levels toward mental illness in parents and their children were significantly correlated. The rate of correct identification of the old and new names for schizophrenia was higher in parents than in their children (64.7% vs 41.4%, P < 0.001). Parents who responded correctly endorsed more negative stereotypes toward the new name of schizophrenia compared with those who responded incorrectly (P = 0.049). CONCLUSION: The present findings suggest that stigma toward mental illness is shared between family members, and the name change of schizophrenia has effectively reduced stigma levels toward this disorder in adults of various ages. PMID- 27470980 TI - If Only my Leader Would just Do Something! Passive Leadership Undermines Employee Well-being Through Role Stressors and Psychological Resource Depletion. AB - The goal of this study was to develop and test a sequential mediational model explaining the negative relationship of passive leadership to employee well being. Based on role stress theory, we posit that passive leadership will predict higher levels of role ambiguity, role conflict and role overload. Invoking Conservation of Resources theory, we further hypothesize that these role stressors will indirectly and negatively influence two aspects of employee well being, namely overall mental health and overall work attitude, through psychological work fatigue. Using a probability sample of 2467 US workers, structural equation modelling supported the model by showing that role stressors and psychological work fatigue partially mediated the negative relationship between passive leadership and both aspects of employee well-being. The hypothesized, sequential indirect relationships explained 47.9% of the overall relationship between passive leadership and mental health and 26.6% of the overall relationship between passive leadership and overall work attitude. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27470982 TI - Improved diabetes management in Swedish schools: results from two national surveys. AB - BACKGROUND: Support in diabetes self-care in school is essential to achieve optimal school performance and metabolic control. Swedish legislation regulating support to children with chronic diseases was strengthened 2009. OBJECTIVE: To compare the results of a national survey conducted 2008 and 2015 measuring parents' and diabetes specialist teams' perceptions of support in school. METHOD: All pediatric diabetes centers in Sweden were invited to participate in the 2015 study. In each center, families with a child being treated for T1DM and attending preschool class or compulsory school were eligible. The parents' and the diabetes teams' opinions were collected in two separate questionnaires. RESULTS: Forty-one out of 42 eligible diabetes centers participated and 568 parents answered the parental questionnaire in 2015. Metabolic control had improved since the 2008 survey (55.2 +/- 10.6 mmol/mol, 7.2% +/- 1.0%, in 2015 compared with 61.8 +/- 12.4 mmol/mol, 7.8% +/- 1.1% in 2008). The proportion of children with a designated staff member responsible for supporting the child's self-care increased from 43% to 59%, (P < .01). An action plan to treat hypoglycemia was present for 65% of the children in 2015 compared with 55% in 2008 (P < .01). More parents were satisfied with the support in 2015 (65% compared with 55%, P < .01). CONCLUSIONS: This study shows that staff support has increased and that more parents were satisfied with the support for self-care in school in 2015 compared with 2008. More efforts are needed to implement the national legislation to achieve equal support in all Swedish schools. PMID- 27470983 TI - Evaluating the quality of implantation of percutaneous ventricular restoration device (Parachute(r)) by cardiac computed tomography. AB - BACKGROUND: The Parachute is a novel percutaneously implanted ventricular partitioning device (VPD) that has emerged as a safe and feasible treatment option for patients with heart failure following anterior wall myocardial infarction. VPD efficacy is likely dependent on optimal device placement, but to date there are no published data examining the effect of device positioning on patient outcomes. METHODS AND RESULTS: We retrospectively identified 32 patients successfully implanted with the Parachute device, all of whom underwent cardiac computed tomography (CCT) at baseline and after 6 months of follow-up. Patients were divided into two groups based on self-reported improvement in New York Heart Association (NYHA) functional class: "not improved NYHA" (n = 12) and "improved NYHA" (n = 20). There were significant differences between both groups with regard to device positioning on follow-up CCT. Compared to patients with "improved NYHA," patients with "not improved NYHA" had longer distances from device foot to left ventricular apex (8.0 +/- 4.9 vs. 2.9 +/- 4.6 mm; P = 0.01), and higher lateral angles (18.0 +/- 14 vs. 9.1 +/- 6.8 degrees; P = 0.02), respectively. There was no significant difference between the two groups in landing zone (45.4 +/- 7. vs. 45.1 +/- 6.9 mm; P = 0.92) and inferior angle (14.0 +/- 11.9 vs. 14.3 +/- 10.1 degrees; P = 0.95). There was a numerically larger malapposition area in the "not improved NYHA" group (5.1 +/- 4.5 vs. 3.2 +/- 2.2 cm2; P = 0.12). CONCLUSION: Quality of Parachute implant impacted clinical outcome, these findings should be applied prospectively in helping operators to achieve optimal implant. (c) 2016 Wiley Periodicals, Inc. PMID- 27470984 TI - Antibiotic drug discovery. AB - Due to the threat posed by the increase of highly resistant pathogenic bacteria, there is an urgent need for new antibiotics; all the more so since in the last 20 years, the approval for new antibacterial agents had decreased. The field of natural product discovery has undergone a tremendous development over the past few years. This has been the consequence of several new and revolutionizing drug discovery and development techniques, which is initiating a 'New Age of Antibiotic Discovery'. In this review, we concentrate on the most significant discovery approaches during the last and present years and comment on the challenges facing the community in the coming years. PMID- 27470987 TI - Obesity decreases the oxidant stress induced by tobacco smoke in a rat model. AB - Obesity and emphysema are associated with low-grade systemic inflammation and oxidant stress. Assuming that the oxidant stress induced by emphysema would be decreased by obesity, we analyzed the oxidant/antioxidant state in a rat model combining both diseases simultaneously. Obesity was induced using sucrose, while emphysema by exposure to tobacco smoke. End-points evaluated were: body weight, abdominal fat, plasma dyslipidemia and malondialdehyde (MDA), insulin and glucose AUC, activities of Mn-superoxide dismutase (Mn-SOD), glutathione reductase (GR), glutathione transferase (GST) and glutathione peroxidase (GPx); lung MnSOD and 3 nitrotyrosine (3-NT) immunostaining, and expression of alphaV and beta6 integrin subunits. In rats with obesity, the body weight, abdominal fat, plasma triglyceride levels, glucose AUC, insulin levels, GST activity, and alphaV and beta6 integrin expressions were amplified. The rats with emphysema had lower values of body weight, abdominal fat, plasma insulin, triglycerides and glucose AUC but higher values of plasma MDA, GPx activity, and the lung expression of the alphaV and beta6 integrins. The combination of obesity and emphysema compared to either condition alone led to diminished body weight, abdominal fat, plasma insulin MDA levels, GPx and GST activities, and alphaV and beta6 integrin expressions; these parameters were all previously increased by obesity. Immunostaining for MnSOD augmented in all experimental groups, but the staining for 3-NT only increased in rats treated with tobacco alone or combined with sucrose. Results showed that obesity reduces oxidant stress and integrin expression, increasing antioxidant enzyme activities; these changes seem to partly contribute to a protective mechanism of obesity against emphysema development. PMID- 27470986 TI - IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury. AB - Macrophages and microglia play a key role in the maintenance of nervous system homeostasis. However, upon different challenges, they can adopt several phenotypes, which may lead to divergent effects on tissue repair. After spinal cord injury (SCI), microglia and macrophages show predominantly pro-inflammatory activation and contribute to tissue damage. However, the factors that hamper their conversion to an anti-inflammatory state after SCI, or to other protective phenotypes, are poorly understood. Here, we show that IL-4 protein levels are undetectable in the spinal cord after contusion injury, which likely favors microglia and macrophages to remain in a pro-inflammatory state. We also demonstrate that a single delayed intraspinal injection of IL-4, 48 hours after SCI, induces increased expression of M2 marker in microglia and macrophages. We also show that delayed injection of IL-4 leads to the appearance of resolution phase macrophages, and that IL-4 enhances resolution of inflammation after SCI. Interestingly, we provide clear evidence that delayed administration of IL-4 markedly improves functional outcomes and reduces tissue damage after contusion injury. It is possible that these improvements are mediated by the presence of macrophages with M2 markers and resolution-phase macrophages. These data suggest that therapies aimed at increasing IL-4 levels could be valuable for the treatment of acute SCI, for which there are currently no effective treatments. GLIA 2016;64:2079-2092. PMID- 27470985 TI - Unique proteome signature of post-chemotherapy ovarian cancer ascites-derived tumor cells. AB - Eighty % of ovarian cancer patients diagnosed at an advanced-stage have complete remission after initial surgery and chemotherapy. However, most patients die within <5 years due to episodes of recurrences resulting from the growth of residual chemoresistant cells. In an effort to identify mechanisms associated with chemoresistance and recurrence, we compared the expression of proteins in ascites-derived tumor cells isolated from advanced-stage ovarian cancer patients obtained at diagnosis (chemonaive, CN) and after chemotherapy treatments (chemoresistant/at recurrence, CR) by using in-depth, high-resolution label-free quantitative proteomic profiling. A total of 2,999 proteins were identified. Using a stringent selection criterion to define only significantly differentially expressed proteins, we report identification of 353 proteins. There were significant differences in proteins encoding for immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of metabolic pathways, DNA repair mechanisms and energy metabolism pathways in CR tumor cells. In conclusion, this is the first proteomics study to comprehensively analyze ascites-derived tumor cells from CN and CR ovarian cancer patients. PMID- 27470988 TI - Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice. AB - BACKGROUND AND PURPOSE: Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of ischemic stroke. METHODS: TAFI and PAI-1 were inhibited by monoclonal antibodies in a mouse model of transient middle cerebral artery occlusion. Twenty-four hours after stroke, mice were neurologically scored, cerebral thrombotic burden was assessed, and brain infarct sizes were calculated. RESULTS: Inhibition of TAFI or PAI-1 significantly decreased cerebral infarct sizes by 50% 24 hours after stroke. This reduction in cerebral damage was associated with a significant decrease in fibrin(ogen) deposition in the ischemic brain. Concurrently, functional recovery of the animals was improved. Interestingly, combined targeting of TAFI and PAI-1 using low, and by themselves inactive, doses of antibodies improved cerebral blood flow and reduced cerebral fibrin(ogen) deposition and infarct sizes by 50%. When dual treatment was delayed to 1 hour after the start of reperfusion, it still reduced brain injury; however, this was not statistically significant. CONCLUSIONS: Targeting of PAI-1 and TAFI is protective in an ischemic stroke model by attenuating fibrin(ogen) deposition, thereby improving reperfusion. Combined inhibition has a co-operative effect that could become useful in ischemic stroke therapy. PMID- 27470989 TI - Potential Cost-Effectiveness of Ambulatory Cardiac Rhythm Monitoring After Cryptogenic Stroke. AB - BACKGROUND AND PURPOSE: Prolonged ambulatory ECG monitoring after cryptogenic stroke improves detection of covert atrial fibrillation, but its long-term cost effectiveness is uncertain. METHODS: We estimated the cost-effectiveness of noninvasive ECG monitoring in patients aged >=55 years after a recent cryptogenic stroke and negative 24-hour ECG. A Markov model used observed rates of atrial fibrillation detection and anticoagulation from a randomized controlled trial (EMBRACE) and the published literature to predict lifetime costs and effectiveness (ischemic strokes, hemorrhages, life-years, and quality-adjusted life-years [QALYs]) for 30-day ECG (primary analysis) and 7-day or 14-day ECG (secondary analysis), when compared with a repeat 24-hour ECG. RESULTS: Prolonged ECG monitoring (7, 14, or 30 days) was predicted to prevent more ischemic strokes, decrease mortality, and improve QALYs. If anticoagulation reduced stroke risk by 50%, 30-day ECG (at a cost of USD $447) would be highly cost-effective ($2000 per QALY gained) for patients with a 4.5% annual ischemic stroke recurrence risk. Cost-effectiveness was sensitive to stroke recurrence risk and anticoagulant effectiveness, which remain uncertain, especially at higher costs of monitoring. Shorter duration (7 or 14 days) monitoring was cost saving and more effective than an additional 24-hour ECG; its cost-effectiveness was less sensitive to changes in ischemic stroke risk and treatment effect. CONCLUSIONS: After a cryptogenic stroke, 30-day ECG monitoring is likely cost-effective for preventing recurrent strokes; 14-day monitoring is an attractive value alternative, especially for lower risk patients. These results strengthen emerging recommendations for prolonged ECG monitoring in secondary stroke prevention. Cost-effectiveness in practice will depend on careful patient selection. PMID- 27470990 TI - Tumor-Like Presentation of Primary Angiitis of the Central Nervous System. AB - BACKGROUND AND PURPOSE: We aimed to describe the clinical and imaging features of patients with tumor-like presentation of primary angiitis of the central nervous system. METHODS: We retrospectively analyzed 10 patients enrolled in the French primary angiitis of the central nervous system cohort, who initially presented tumor-like brain lesions and compared them with other patients within the cohort. RESULTS: The 10 patients with tumor-like presentation in the cohort were younger and had more seizures at diagnosis than the other 75 patients (median of 37 [30 48] years versus 46 [18-79] years; P=0.008; 9 [90%] with seizures versus 22 [29%], P<0.001; respectively). All 10 patients had a biopsy (stereotactic procedure in 7 and open-wedge surgery in 3). Histological findings suggestive of vasculitis were observed in 9 patients in whom conventional cerebral angiography and magnetic resonance angiography were negative. In the remaining patient, vascular imaging demonstrated diffuse bilateral large- and medium-sized vessel involvement (biopsy did not reveal vasculitis). All patients with tumor-like presentation received glucocorticoids, combined with cyclophosphamide in 9 cases. With a median follow-up of 27 (12-130) months, 5 (50%) patients relapsed, but achieved remission again after treatment intensification. CONCLUSIONS: Patients with tumor-like presentation of primary angiitis of the central nervous system represent a subgroup characterized with mainly small-sized vessel disease that requires histological confirmation because vascular imaging is often normal. Although relapses are not uncommon, global outcomes are good under treatment with glucocorticoids and cyclophosphamide. PMID- 27470991 TI - Incidence of Transient Ischemic Attack in Auckland, New Zealand, in 2011 to 2012. AB - BACKGROUND AND PURPOSE: There have been few recent population-based studies reporting the incidence (first ever) and attack rates (incident and recurrent) of transient ischemic attack (TIA). METHODS: The fourth Auckland Regional Community Stroke study (ARCOS IV) used multiple overlapping case ascertainment methods to identify all hospitalized and nonhospitalized cases of TIA that occurred in people >=16 years of age usually resident in Auckland (population >=16 years of age is 1.12 million), during the 12 months from March 1, 2011. All first-ever and recurrent new TIAs (any new TIA 28 days after the index event) during the study period were recorded. RESULTS: There were 785 people with TIA (402 [51.2%] women, mean [SD] age 71.5 [13.8] years); 614 (78%) of European origin, 84 (11%) Maori/Pacific, and 75 (10%) Asian/Other. The annual incidence of TIA was 40 (95% confidence interval, 36-43), and attack rate was 63 (95% confidence interval, 59 68), per 100 000 people, age standardized to the World Health Organization world population. Approximately two thirds of people were known to be hypertensive or were being treated with blood pressure-lowering agents, half were taking antiplatelet agents and just under half were taking lipid-lowering therapy before the index TIA. Two hundred ten (27%) people were known to have atrial fibrillation at the time of the TIA, of whom only 61 (29%) were taking anticoagulant therapy, suggesting a failure to identify or treat atrial fibrillation. CONCLUSIONS: This study describes the burden of TIA in an era of aggressive primary and secondary vascular risk factor management. Education programs for medical practitioners and patients around the identification and management of atrial fibrillation are required. PMID- 27470993 TI - Myocardial imaging using advanced applications of computed tomography and magnetic resonance imaging. PMID- 27470992 TI - Association of Major Depressive Episodes With Stroke Risk in a Prospective Study of 0.5 Million Chinese Adults. AB - BACKGROUND AND PURPOSE: Although the relationship between depression and stroke risk has been investigated, findings in previous reports were conflicting. The aim of this study was to prospectively examine the effect of major depressive episodes (MDE) on stroke incidence and further assess the potential dose-response relationship between number of depression symptoms and subsequent stroke risk in Chinese population. METHODS: A total of 199 294 men and 288 083 women aged 30 to 79 years without a history of stroke, heart disease, and cancer in the China Kadoorie Biobank cohort were followed from 2004 to 2013. A World Health Organization Composite International Diagnostic Interview-Short Form was used to access MDE according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Stroke events were ascertained through death certificates, medical records, and health insurance data. RESULTS: Past year MDE was marginally associated with a 15% increased risk of stroke (adjusted hazard ratio, 1.15; 95% confidence interval, 0.99-1.33) in the fully adjusted model, and the association was steeper and statistically significant in individuals aged <50 years, smokers, drinkers, those with higher education degree, body mass index <24.0 kg/m(2), and no history of diabetes mellitus. Moreover, there was a positive dose-response relationship between the number of depression symptoms and increased stroke risk (Ptrend=0.011). In addition, smoking status significantly interacted with MDE on stroke onset (P for multiplicative interaction=0.025). CONCLUSIONS: Findings from this large prospective study suggest that the presence of MDE is a risk factor for stroke, especially in smokers. PMID- 27470994 TI - Imaging of the myocardium using (18)F-FDG-PET/MRI. AB - The introduction of the integrated hybrid PET/MRI equipment creates the possibility to perform PET and MRI simultaneously. Depending on the clinical question, the metabolic conversion to glycolytic activity or beta-oxidation is performed before the application of FDG. Since FDG aids to evaluate the energetic metabolism of the myocytes and myocardial MRI reaches the imaging capabilities of perfusion and tissue characterization in the daily routine, FDG-PET/MRI looks to be a promising method of PET/MRI exploitation in cardiac imaging. When myocardial FDG uptake should be evaluated in association with the perfusion distribution, the cross-evaluation of FDG accumulation distribution and perfusion distribution pattern is necessary. The different scenarios may be used in the assessment of myocardium, the conversion to glycolytic activity is used in the imaging of the viable myocardium, but the glycolytic activity suppression might be used in the indications of the identification of injured myocardium by ischemia or inflammation. FDG-PET/MRI might aid to answer the clinical tasks according to the structure, current function and possibilities to improve the function in ischemic heart disease or to display the extent or activity of myocardial inflammation in sarcoidosis. The tight coupling between metabolism, perfusion and contractile function offers an opportunity for the simultaneous assessment of cardiac performance using one imaging modality. PMID- 27470996 TI - Bacterial and viral contamination of breathing circuits after extended use - an aspect of patient safety? AB - BACKGROUND: In the past, anaesthetic breathing circuits were identified as a source of pathogen transmission. It is still debated, whether breathing circuits combined with breathing system filters can be safely used for more than 1 day. The aim of this study was to evaluate the transmission risk of bacteria and also viruses via breathing circuits after extended use. METHODS: The inner and outer surface of 102 breathing circuits used for 1 day and of 101 circuits used for 7 days were examined for bacteria and viruses. Additionally, 10 and 20 breathing circuits each were examined after use on patients with pulmonary virus infection and with multidrug-resistant organism (MDRO) colonisation/infection respectively. Bacteria were detected by standard microbiological procedures; PCR techniques were applied for herpes simplex virus, cytomegalovirus, influenza, parainfluenza and respiratory syncytial virus. RESULTS: Endoluminal bacterial contamination of breathing circuits remained unchanged after 7-day vs. 1-day use (5.9% vs. 7.8%) [CI95%: -0.0886-0.0506, pnon-inferiority 0.0260]. Only outside surface contamination with bacteria belonging to environmental species or human flora increased (16.8 vs. 6.9%) [CI 95%: 0.0118 - 0.1876, pnon-inferiority 0.8660]. Viruses occurred on the patient side, but not in breathing circuits. No MDRO occurred in the 20 circuits after use on patients harbouring such germs. CONCLUSION: Endoluminal contamination of breathing circuits with bacteria did not increase after extended use. No viruses were detected in the breathing circuits using filters. Based on our results, the extended use of ABC without exceptions appears safe, if a high level of anaesthesia workplace cleaning is secured. PMID- 27470995 TI - Discovering Pair-wise Synergies in Microarray Data. AB - Informative gene selection can have important implications for the improvement of cancer diagnosis and the identification of new drug targets. Individual-gene ranking methods ignore interactions between genes. Furthermore, popular pair-wise gene evaluation methods, e.g. TSP and TSG, are helpless for discovering pair-wise interactions. Several efforts to discover pair-wise synergy have been made based on the information approach, such as EMBP and FeatKNN. However, the methods which are employed to estimate mutual information, e.g. binarization, histogram-based and KNN estimators, depend on known data or domain characteristics. Recently, Reshef et al. proposed a novel maximal information coefficient (MIC) measure to capture a wide range of associations between two variables that has the property of generality. An extension from MIC(X; Y) to MIC(X1; X2; Y) is therefore desired. We developed an approximation algorithm for estimating MIC(X1; X2; Y) where Y is a discrete variable. MIC(X1; X2; Y) is employed to detect pair-wise synergy in simulation and cancer microarray data. The results indicate that MIC(X1; X2; Y) also has the property of generality. It can discover synergic genes that are undetectable by reference feature selection methods such as MIC(X; Y) and TSG. Synergic genes can distinguish different phenotypes. Finally, the biological relevance of these synergic genes is validated with GO annotation and OUgene database. PMID- 27470997 TI - Systematic evaluation of multiple immune markers reveals prognostic factors in ovarian cancer. AB - OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Several factors prognostic for survival have been identified including the presence of certain lymphocyte markers. Tumor-infiltrating lymphocytes (TILs), particularly cytotoxic CD8+ TILs, have been shown to be most favorable for prognosis in ovarian cancer, although other immune cells including CD3+ T-cells, CD4+ T-cells, and B-cells have also demonstrated survival benefits. Although data for these markers exists, results are not uniform in the literature. Furthermore, other immunomodulatory protein markers that have been targeted in effective immunotherapies for other malignancies may prove to be favorable in ovarian cancer. METHODS: Here, extensive immunohistochemical analysis was performed on a tissue microarray, containing 135 ovarian cancer cases obtained during tumor debulking detecting 15 key lymphocyte markers such as CD3, CD4, and CD20, as well as activation and immunomodulatory molecules such as TIA-1 and PD-L1. Samples were analyzed for expression of markers in tumor islets or stroma and expression was correlated with overall survival, histotype, stage, age, debulking grade, and response to chemotherapy. RESULTS: Our results confirm the presence of CD8+ and CD20+ TILs is positively correlated with overall survival, with further multivariate modeling replicating that prognostic benefit. Additional markers of significant prognostic importance, including TIA-1, CD103 and HLA Class-II were also revealed. CONCLUSIONS: Our results further support the vital role of cytotoxic T-cells in defense against ovarian cancer and reveals new questions as to the role of B-cells in tumor control as well as the potential benefits of immunotherapy involving other immune modulating molecules. PMID- 27470998 TI - Disparities in treatment and survival for women with endometrial cancer: A contemporary national cancer database registry analysis. AB - PURPOSE: The study aim was to identify contemporary socioeconomic, racial, ethnic, and facility-related factors associated with stage at diagnosis, receipt of cancer treatment, and survival in women with endometrial cancer (EC). PATIENTS AND METHODS: Women diagnosed with EC between 1998 and 2010 were identified from the National Cancer Database. Variables associated with the outcomes of interest were assessed using multivariable Cox proportional hazards and logistic regression. RESULTS: Among 228,511 women identified, the percentage of blacks with stage IIIC/IV disease at diagnosis was nearly twice that of non-Hispanic whites (17.8% vs 9.8%; P<0.001). Patients with advanced disease who were insured with Medicare were less likely to receive standard-of-care postoperative radiotherapy and/or chemotherapy than those with private insurance (odds ratio: OR 0.80, P<0.001), as were those residing in the South (reference) in comparison to the Northeast, Atlantic, Great Lakes, and Midwest regions (OR 1.3-1.7, all P<0.001). Those residing in the Mountain region were even less likely to receive appropriate treatment (OR 0.7, P<0.001). Five-year stage IIIC/IV survival was 42.8% for non-Hispanic whites vs 24.6% for blacks (hazard ratio 1.3, P<0.001). Other factors associated with inferior 5-year survival included payer status (not insured, Medicaid, Medicare, vs private, ORs 1.2-1.3, all P<0.01), and treatment at low-volume centers (<5 vs >=30cases/year, HR 1.3, P<0.001). CONCLUSIONS AND RELEVANCE: Socioeconomic, geographic and facility-related factors predict advanced endometrial cancer stage, failure to receive cancer care, and shorter survival. Black women had especially poor survival. Nationwide standardization and concentration of treatment at high-volume centers may improve outcomes. PMID- 27470999 TI - Multiple gastric gastrointestinal stromal tumors treated by laparoscopic endoscopic cooperative surgery: A case report. AB - The typical treatment of choice for gastrointestinal stromal tumors (GIST) is surgical resection. Here we report a case of three GIST lesions resected safely by laparoscopic-endoscopic cooperative surgery (LECS). A 78-year-old woman was referred to our hospital for further treatment of an enlarging gastric submucosal tumor. Esophagogastroduodenoscopy and endoscopic ultrasonography revealed two gastric submucosal tumors. Endoscopic ultrasonography-guided fine needle aspiration was subsequently performed. The patient underwent LECS in accordance with therapeutic guidelines for GIST. Assisted by a laparoscope and using three trocars, a full-thickness resection was performed endoscopically for the 3-cm lesion and its nearby submucosal tumor, which was newly detected intraoperatively. The other lesion was also resected with an autosuture device under laparoscopy. No intraoperative or postoperative complications were observed. In LECS, endoscopic observation and resection can minimize gastric deformation and preserve gastric function. To the best of our knowledge, this is the first case of LECS performed on multiple GIST. PMID- 27471000 TI - High resolution iridocorneal angle imaging system by axicon lens assisted gonioscopy. AB - Direct visualization and assessment of the iridocorneal angle (ICA) region with high resolution is important for the clinical evaluation of glaucoma. However, the current clinical imaging systems for ICA do not provide sufficient structural details due to their poor resolution. The key challenges in achieving high quality ICA imaging are its location in the anterior region of the eye and the occurrence of total internal reflection due to refractive index difference between cornea and air. Here, we report an indirect axicon assisted gonioscopy imaging probe with white light illumination. The illustrated results with this probe shows significantly improved visualization of structures in the ICA including TM region, compared to the current available tools. It could reveal critical details of ICA and expected to aid management by providing information that is complementary to angle photography and gonioscopy. PMID- 27471001 TI - Metagenomic insight of nitrogen metabolism in a tannery wastewater treatment plant bioaugmented with the microbial consortium BM-S-1. AB - Nitrogen (N) removal in a tannery wastewater treatment plant was significantly enhanced by the bioaugmentation of the novel consortium BM-S-1. In order to identify dominant taxa responsible for N metabolisms in the different stages of the treatment process, Illumina MiSeq Sequencer was used to conduct metagenome sequencing of the microbial communities in the different stages of treatment system, including influent (I), buffering (B), primary aeration (PA), secondary aeration (SA) and sludge digestion (SD). Based on MG-RAST analysis, the dominant phyla were Proteobacteria, Bacteroidetes and Firmicutes in B, PA, SA and SD, whereas Firmicutes was the most dominant in I before augmentation. The augmentation increased the abundance of the denitrification genes found in the genera such as Ralstonia (nirS, norB and nosZ), Pseudomonas (narG, nirS and norB) and Escherichia (narG) in B and PA. In addition, Bacteroides, Geobacter, Porphyromonasand Wolinella carrying nrfA gene encoding dissimilatory nitrate reduction to ammonium were abundantly present in B and PA. This was corroborated with the higher total N removal in these two stages. Thus, metagenomic analysis was able to identify the dominant taxa responsible for dissimilatory N metabolisms in the tannery wastewater treatment system undergoing bioaugmentation. This metagenomic insight into the nitrogen metabolism will contribute to a successful monitoring and operation of the eco-friendly tannery wastewater treatment system. PMID- 27471002 TI - BH3 profiling as a tool to identify acquired resistance to venetoclax in multiple myeloma. PMID- 27471003 TI - Activation of farnesoid X receptor promotes triglycerides lowering by suppressing phospholipase A2 G12B expression. AB - As a novel mediator of hepatic very low-density lipoproteins (VLDL) secretion, phospholipase A2 G12B (PLA2G12B) is transcriptionally regulated by hepatocyte nuclear factor-4 alpha (HNF-4alpha). Farnesoid X receptor (FXR) plays a critical role in maintaining bile acids and triglycerides (TG) homeostasis. Here we report that FXR regulates serum TG level in part through PLA2G12B. Activation of FXR by chenodeoxycholic acid (CDCA) or GW4064 significantly decreased PLA2G12B expression in HepG2 cells. PLA2G12B expression was transcriptionally repressed due to an FXR-mediated up-regulation of small heterodimer partner (SHP) which functionally suppresses HNF-4alpha activity. We found that hepatic PLA2G12B expression was suppressed and serum TG level reduced in high fat diet mice treated with CDCA. Concurrently, CDCA treatment lowered hepatic VLDL-TG secretion. Our data demonstrate that activation of FXR promotes TG lowering, not only by decreasing de novo lipogenesis but also reducing hepatic secretion of TG rich VLDL particles in part through suppressing PLA2G12B expression. PMID- 27471004 TI - Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome. AB - Recently, dihydrotestosterone biosynthesis through the backdoor pathway has been implicated for the human testis in addition to the classic pathway for testosterone (T) synthesis. In the human ovary, androgen precursors are crucial for estrogen synthesis and hyperandrogenism in pathologies such as the polycystic ovary syndrome is partially due to ovarian overproduction. However, a role for the backdoor pathway is only established for the testis and the adrenal, but not for the human ovary. To investigate whether the backdoor pathway exists in normal and PCOS ovaries, we performed specific gene and protein expression studies on ovarian tissues. We found aldo-keto reductases (AKR1C1-1C4), 5alpha-reductases (SRD5A1/2) and retinol dehydrogenase (RoDH) expressed in the human ovary, indicating that the ovary might produce dihydrotestosterone via the backdoor pathway. Immunohistochemical studies showed specific localization of these proteins to the theca cells. PCOS ovaries show enhanced expression, what may account for the hyperandrogenism. PMID- 27471005 TI - The influence of residual root number and bone density on combined implant residual tooth supported prosthesis after tooth hemisection: A finite element study. AB - The aim of the present study has been to analyze the influence of residual root number and bone density on the loading distribution of restorations combining implant and residual tooth after tooth hemisection using finite element analysis. Based on the image data of two patients, one has one distal root and the other has two distal roots in the mandibular right first molar, eight models were created (four models for each patient): a single crown was placed on the implant and residual tooth in two different bone densities; two separate crowns for the implant and residual tooth in two different bone densities. Vertical force of 100 N was applied on the crowns. The results show that the increase in number of residual roots decreased the magnitude of all biomechanical parameters. Higher values were observed in models with low bone density, especially in one distal root models. The maximum values of strains in spongious bone with the model (one distal root, low spongious bone density, a single crown was placed on the implant and residual tooth) even reached 9000MUstrain. From a biomechanical point of view, when two residual roots exist, a single crown placed on the implant and distal half of the molar or two separate crowns for them seem to be an acceptable treatment option, regardless of the bone density. If there is one residual root and the bone density is low, the prosthesis which combines implant with the root might not be used. PMID- 27471006 TI - An Evaluation of Understandability of Patient Journey Models in Mental Health. AB - BACKGROUND: There is a significant trend toward implementing health information technology to reduce administrative costs and improve patient care. Unfortunately, little awareness exists of the challenges of integrating information systems with existing clinical practice. The systematic integration of clinical processes with information system and health information technology can benefit the patients, staff, and the delivery of care. OBJECTIVES: This paper presents a comparison of the degree of understandability of patient journey models. In particular, the authors demonstrate the value of a relatively new patient journey modeling technique called the Patient Journey Modeling Architecture (PaJMa) when compared with traditional manufacturing based process modeling tools. The paper also presents results from a small pilot case study that compared the usability of 5 modeling approaches in a mental health care environment. METHOD: Five business process modeling techniques were used to represent a selected patient journey. A mix of both qualitative and quantitative methods was used to evaluate these models. Techniques included a focus group and survey to measure usability of the various models. RESULTS: The preliminary evaluation of the usability of the 5 modeling techniques has shown increased staff understanding of the representation of their processes and activities when presented with the models. Improved individual role identification throughout the models was also observed. The extended version of the PaJMa methodology provided the most clarity of information flows for clinicians. CONCLUSIONS: The extended version of PaJMa provided a significant improvement in the ease of interpretation for clinicians and increased the engagement with the modeling process. The use of color and its effectiveness in distinguishing the representation of roles was a key feature of the framework not present in other modeling approaches. Future research should focus on extending the pilot case study to a more diversified group of clinicians and health care support workers. PMID- 27471007 TI - Influence of lipid bilayer properties on nanodisc formation mediated by styrene/maleic acid copolymers. AB - Copolymers of styrene and maleic acid (SMA) have gained great attention as alternatives to conventional detergents, as they offer decisive advantages for studying membrane proteins and lipids in vitro. These polymers self-insert into artificial and biological membranes and, at sufficiently high concentrations, solubilise them into disc-shaped nanostructures containing a lipid bilayer core surrounded by a polymer belt. We have used (31)P nuclear magnetic resonance spectroscopy and dynamic light scattering to systematically study the solubilisation of vesicles composed of saturated or unsaturated phospholipids by an SMA copolymer with a 3 : 1 styrene/maleic acid molar ratio at different temperatures. Solubilisation was thermodynamically rationalised in terms of a three-stage model that treats various lipid/polymer aggregates as pseudophases. The solubilising capacity of SMA(3 : 1) towards a saturated lipid is higher in the gel than in the liquid-crystalline state of the membrane even though solubilisation is slower. Although the solubilisation of mixed fluid membranes is non-selective, the presence of a non-bilayer phospholipid lowers the threshold at which the membrane becomes saturated with SMA(3 : 1) but raises the polymer concentration required for complete solubilisation. Both of these trends can be explained by considering the vesicle-to-nanodisc transfer free energies of the lipid and the polymer. On the basis of the phase diagrams thus obtained, re association of polymer-solubilised lipids with vesicles is possible under mild conditions, which has implications for the reconstitution of proteins and lipids from nanodiscs into vesicular membranes. Finally, the phase diagrams provide evidence for the absence of free SMA(3 : 1) in vesicular lipid suspensions. PMID- 27471008 TI - Fibula osteofascial flap with proximal skin paddle for intraoral reconstruction. AB - BACKGROUND: the fibula free flap has become a workhorse in intraoral reconstruction. However, its skin paddle has multiple drawbacks. The aim of this report is to establish the applicability of the fibula osteofascial flap in intraoral reconstruction. METHODS: prospectively maintained database was performed in 15 patients who underwent fibula osteofascial flap for intraoral reconstruction. Mandibular reconstruction was the main location (13 patients). Ten flaps were done following tumor resection, three due to osteoradionecrosis and two following mandible fracture/bone loss. A standard fibula flap dissection performing an anterior approach was done, adding a distal fascial flap isolated on the distal perforators (for intraoral reconstruction) and a proximal skin paddle (for external soft tissue reconstruction). RESULTS: One flap was lost due to hypercoagulable state. Fourteen flaps survived with complete oral mucosalization, resembling physiological intraoral bone coverage by 7 weeks (range: 6-8 weeks). One patient presented with delayed donor-site wound healing. The mean follow-up was 14.4 months (range: 2-33 months). Thirteen patients (87%) were without tracheotomy at last follow-up, and 14 patients (93%) were taking at least some nutrition by mouth. CONCLUSION: Fibula osteofascial flap can be safely used for intraoral reconstruction. This flap provides a stable, thin, and vascularized fascia over the fibula with minimal donor-site complications. (c) 2016 Wiley Periodicals, Inc. Microsurgery, 2016. (c) 2016 Wiley Periodicals, Inc. Microsurgery 37:276-281, 2017. PMID- 27471009 TI - Spectroscopic and Theoretical Identification of Two Thermal Isomerization Pathways for Bistable Chiral Overcrowded Alkenes. AB - Chiroptical molecular switches play an important role in responsive materials and dynamic molecular systems. Here we present the synthesis of four chiral overcrowded alkenes and the experimental and computational study of their photochemical and thermal behavior. By irradiation with UV light, metastable diastereoisomers with opposite helicity were generated through high yielding E-Z isomerizations. Kinetic studies on metastable 1-4 using CD spectroscopy and HPLC analysis revealed two pathways at higher temperatures for the thermal isomerization, namely a thermal E-Z isomerization (TEZI) and a thermal helix inversion (THI). These processes were also studied computationally whereby a new strategy was developed for calculating the TEZI barrier for second-generation overcrowded alkenes. To demonstrate that these overcrowded alkenes can be employed as bistable switches, photochromic cycling was performed, which showed that the alkenes display good selectivity and fatigue resistance over multiple irradiation cycles. In particular, switch 3 displayed the best performance in forward and backward photoswitching, while 1 excelled in thermal stability of the photogenerated metastable form. Overall, the alkenes studied showed a remarkable and unprecedented combination of switching properties including dynamic helicity, reversibility, selectivity, fatigue resistance, and thermal stability. PMID- 27471011 TI - Female preference functions drive interpopulation divergence in male signalling: call diversity in the bushcricket Ephippiger diurnus. AB - Female preferences play a major role in the elaboration and diversification of male traits: as a selective pressure on males, variation in female preferences can generate population divergence and ultimately, speciation. We studied how interpopulation differences in the shape of female mate preference functions may have shaped male advertisement signals in the bushcricket Ephippiger diurnus. This species is distributed as geographically isolated populations with striking interpopulation variation in male acoustic signals, most notably in the number of syllables per call. Here, we asked whether differences in the shape of preference functions exist among populations and whether those differences may have driven male signal evolution resulting in the observed differences in syllable numbers. Our results reveal fundamental differences in female preferences among populations, with differences in the overall preference function shape corresponding to differences in male signals. These differences in female preferences best explain the major differences in male signals among populations. The interpopulation variation in signals and preferences potentially reflects the evolutionary history of the species and may contribute to further divergence among populations and subsequent speciation. PMID- 27471010 TI - Translational profiling of retinal ganglion cell optic nerve regeneration in Xenopus laevis. AB - Unlike adult mammals, adult frogs regrow their optic nerve following a crush injury, making Xenopus laevis a compelling model for studying the molecular mechanisms that underlie neuronal regeneration. Using Translational Ribosome Affinity Purification (TRAP), a method to isolate ribosome-associated mRNAs from a target cell population, we have generated a transcriptional profile by RNA-Seq for retinal ganglion cells (RGC) during the period of recovery following an optic nerve injury. Based on bioinformatic analysis using the Xenopus laevis 9.1 genome assembly, our results reveal a profound shift in the composition of ribosome associated mRNAs during the early stages of RGC regeneration. As factors involved in cell signaling are rapidly down-regulated, those involved in protein biosynthesis are up-regulated alongside key initiators of axon development. Using the new genome assembly, we were also able to analyze gene expression profiles of homeologous gene pairs arising from a whole-genome duplication in the Xenopus lineage. Here we see evidence of divergence in regulatory control among a significant proportion of pairs. Our data should provide a valuable resource for identifying genes involved in the regeneration process to target for future functional studies, in both naturally regenerative and non-regenerative vertebrates. PMID- 27471013 TI - Points to notice during the diagnosis of soft tissue tumors according to the "Clinical Practice Guideline on the Diagnosis and Treatment of Soft Tissue Tumors". AB - To adequately treat soft tissue tumors, an accurate initial diagnosis is essential. In this article, we describe the notable points during initial diagnoses as outlined by the "Clinical Practice Guideline on the Diagnosis and Treatment of Soft Tissue Tumors". Clinical findings including pain and tumor size, growth speed, and depth, may be important in the diagnosis. In general, malignant soft tissue tumors tend to be larger than 5 cm in size, to occur in deep layers, and grow quickly. However, there are many exceptions. Magnetic resonance images can show characteristics of soft tissue tumors, but most of these are non-specific. The most reliable diagnostic procedure is histological examination. Therefore, a biopsy is mandatory. A core needle biopsy can be performed under local anesthesia at an outpatient clinic without the need for imaging guidance. In cases with deep-seated tumors, an image-guided biopsy is recommended. Incisional biopsies are also widely used procedures. In an incisional biopsy, the skin incision should be parallel to the long axis of the extremities. A meticulous hemostasis must be carried out to prevent post-biopsy hemorrhaging. If adequate hemostasis cannot be achieved, a drain is placed within the incision or at the closest possible site along the incision. Indications for an excisional biopsy are limited to superficial soft tissue tumors, less than 3 cm in size, located at a suitable distance from the nearest vital structure. Furthermore, an excisional biopsy should only be carried out after imaging studies are complete. PMID- 27471012 TI - Development of a model system for neuronal dysfunction in Fabry disease. AB - Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). It is a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. One of the hallmarks of this disorder is neuropathic pain and sympathetic and parasympathetic nervous dysfunction. The exact mechanism by which changes in AGA activity result in change in neuronal function is not clear, partly due to of a lack of relevant model systems. In this study, we report the development of an in vitro model system to study neuronal dysfunction in Fabry disease by using short-hairpin RNA to create a stable knock-down of AGA in the human cholinergic neuronal cell line, LA-N-2. We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to study specific neuronal functions such as neurotransmitter release in Fabry disease. PMID- 27471014 TI - [Hepatotoxicity associated with herbal and dietary supplements]. PMID- 27471015 TI - [Acute subdural hematoma in a patient in treatment with apixaban and acetylsalicylic acid]. PMID- 27471016 TI - Dealing with Big Numbers: Representation and Understanding of Magnitudes Outside of Human Experience. AB - Being able to estimate quantity is important in everyday life and for success in the STEM disciplines. However, people have difficulty reasoning about magnitudes outside of human perception (e.g., nanoseconds, geologic time). This study examines patterns of estimation errors across temporal and spatial magnitudes at large scales. We evaluated the effectiveness of hierarchical alignment in improving estimations, and transfer across dimensions. The activity was successful in increasing accuracy for temporal and spatial magnitudes, and learning transferred to the estimation of numeric magnitudes associated with events and objects. However, there were also a number of informative differences in performance on temporal, spatial, and numeric magnitude measures, suggesting that participants possess different categorical information for these scales. Educational implications are discussed. PMID- 27471017 TI - New potential biomarkers of acetaminophen-induced hepatotoxicity. AB - Acetaminophen (APAP) is one of the most common antipyretic and analgesic drugs. Despite various precautions patients use APAP in amounts exceeding acceptable daily doses. APAP overdosing contributes to APAP intoxication, which leads to acute liver injury or necessity of exigent liver transplantation. Biomarkers that can be helpful in early diagnosis of liver injury during APAP overdosing are studied worldwide. This review presents recent reports on new potential biomarkers and their prospective application in clinical practice. PMID- 27471019 TI - Associations between physical activity and self-rated wellbeing in European adults: A population-based, cross-sectional study. AB - Although self-rated wellbeing is an indicator of health status, it has been receiving little attention; its relationship with physical activity among adults remains inconclusive. The purpose of this study was to analyse the relationship between physical activity and several dimensions of self-rated wellbeing in European adults. This cross-sectional study was based on data from the European Social Survey round 6, 2012, comprising 40,600 European adults (18,418 men, 22,186 women) from 27 countries, with mean age 42.1+/-13.3. Meeting physical activity guidelines was assessed using World Health Organization criteria. Six dimensions of the self-rated wellbeing were assessed (evaluative wellbeing, emotional wellbeing, functioning, vitality, community wellbeing, supportive wellbeing). Men and women who attained physical activity recommended levels had better evaluative wellbeing (men, p=0.009; women, p<0.001), emotional wellbeing (men, p<0.001; women, p<0.001), functioning (men, p<0.001; women, p<0.001), vitality (men, p<0.001; women, p<0.001), supportive relationships (men, p<0.001; women, p<0.001), and wellbeing total score (men, p<0.001; women, p<0.001). Physical activity frequency was linearly associated with self-rated wellbeing in the 6 dimensions as well as the wellbeing total score (p<0.001). Attaining recommended physical activity levels is related to better self-rated wellbeing, and more frequent physical activity is linearly associated with better self-rated wellbeing in its 6 dimensions. PMID- 27471018 TI - Intervention to reduce recreational screen-time in adolescents: Outcomes and mediators from the 'Switch-Off 4 Healthy Minds' (S4HM) cluster randomized controlled trial. AB - INTRODUCTION: The primary objective was to evaluate the impact of the 'Switch-off 4 Healthy Minds' (S4HM) intervention on recreational screen-time in adolescents. METHODS: Cluster randomized controlled trial with study measures at baseline and 6-months (post-intervention). Eligible participants reported exceeding recreational screen-time recommendations (i.e., >2h/day). In total, 322 adolescents (mean age=14.4+/-0.6years) from eight secondary schools in New South Wales, Australia were recruited. The S4HM intervention was guided by Self Determination Theory and included: an interactive seminar, eHealth messaging, a behavioral contract and parental newsletters. The primary outcome was recreational screen-time. Secondary outcomes included mental health (i.e., well being, psychological distress, self-perceptions), objectively measured physical activity, and body mass index (BMI). Outcome analyses were conducted using linear mixed models and mediation was examined using a product-of-coefficients test. RESULTS: At post-intervention, significant reductions in screen-time were observed in both groups, with a greater reduction observed in the intervention group (-50min/day versus -29min, p<0.05 for both). However, the adjusted difference in change between groups was not statistically significant (mean= 21.3min/day, p=0.255). There were no significant intervention effects for mental health outcomes, physical activity or BMI. Significant mediation effects for autonomous motivation were found. CONCLUSIONS: Participants in both the S4HM intervention and control groups significantly reduced their screen-time, with no group-by-time effects. Enhancing autonomous motivation might be a useful intervention target for trials aimed at reducing adolescents' recreational screen time. TRIAL REGISTRATION: ACTRN12614000163606. PMID- 27471020 TI - The availability of medical marijuana dispensary and adolescent marijuana use. AB - PURPOSE: To examine the association between medical marijuana dispensary (MMD) availability and adolescent marijuana use. METHODS: The study sample was comprised of 8th, 10th, and 12th graders (N=14,953) from 141 schools in the 2014 Monitoring the Future study, who resided in the 18 states that had legalized medical marijuana as of January 1, 2014. Multilevel logistic regressions with random effects were conducted to quantify the cross-sectional associations of the availability of MMD within 5- and 25-mile buffers from the centroid of school zip codes with self-reported recent use (past-year) and current use (past-month) of marijuana, controlling for individual characteristics and school, zip code, and state contextual factors. RESULTS: In the combined sample, the availability of MMD was not associated with recent or current use of marijuana. Subsample analyses suggested that the availability within a 5-mile buffer was associated with a higher likelihood of recent use in 8th graders (OR=1.93, 95% CI=1.11-3.33) and the availability within a 5- to 25-mile buffer was associated with a higher likelihood of recent use in 10th graders (OR=1.33, 95% CI=1.00-1.77). The availability of MMD was not associated with recent use in 12th graders or current use in any grades. CONCLUSIONS: The availability of MMD was not associated with current use of marijuana among adolescents. There was some evidence suggesting that the availability of MMD within short to medium traveling distance may be associated with a higher level of recent use in middle schoolers who are also at a high risk of experimenting with marijuana. PMID- 27471021 TI - Sex/gender differences in smoking cessation: A review. AB - Data from treatment studies tends to show women are less likely to quit smoking than men, but these findings have been disputed, typically based on contradictory evidence from epidemiological investigations. The purpose of this review was to shed light on this conflict. We conducted a qualitative review in January 2016 to examine sources of variation in sex/gender differences for smoking cessation. We identified 214 sex/gender difference tests from 190 studies through Medline and studies were categorized into efficacy trials (k=37), effectiveness trials (k=77), prospective observational studies of cessation (k=40; current smokers transitioning to former smokers), prospective observational studies of relapse (k=6; former smokers transitioning to current smokers), cross-sectional investigations of former smoker prevalence (k=32), and community-based interventions (k=4). We also summarized evidence across time periods, countries, outcome assessments, study sample, and treatment. Evidence from efficacy and effectiveness trials, as well as prospective observational studies of relapse, demonstrated that women have more difficulty maintaining long-term abstinence than men. Findings from prospective observational studies and cross-sectional investigations were mixed and demonstrated that bio-psycho-social variation in samples across place and time may determine whether or not women or men are less likely to quit smoking. Based on these findings, we consider whether sex/gender differences in quitting meet criteria for a disparity and outline directions for further research. PMID- 27471022 TI - Evaluating a school-based fruit and vegetable co-op in low-income children: A quasi-experimental study. AB - The purpose of this study was to evaluate the effectiveness of a new school-based food co-op program, Brighter Bites (BB), to increase fruit and vegetable intake, and home nutrition environment among low-income 1st graders and their parents. This was a non-randomized controlled comparative effectiveness trial (2013-2015). Six schools received BB (n=407 parent-child dyads); six comparison schools implemented a coordinated school health program (n=310 parent-child dyads) in Houston, Texas, 2013-2015. Brighter Bites (BB) is a 16-week school-based food co op comprising weekly distribution of fresh produce (50 servings); nutrition education in schools and for parents; and weekly recipe tastings. Measurements included parent-reported home nutrition environment surveys, and food frequency questionnaires for parent and child. Intervention effects were examined using multivariate analyses. At baseline, the sample was 71% Hispanic, 24% African American; 43% of 1st graders were overweight/obese. Children receiving BB had significant increases in intake of fruit servings (P=0.046), vegetable servings (P=0.049), and decreased intake of added sugars (P=0.014). Among parents, there were significant increases in fruit consumed (P=0.032); vegetable intake increased baseline to midpoint but not post-intervention. Among BB families, there were significant improvements in the home environment including understanding and usage of nutrition facts labels to make food purchases (P<0.05), frequency of cooking (P=0.007), rules and practices regarding eating family meals (P=0.022), serving fruits (P=0.005) and vegetables (P=0.028) at meals, and limiting portion sizes (P=0.016). In conclusion, a school-based food co-op model shows promising results in improving dietary habits and home nutrition environment among low-income families. PMID- 27471023 TI - Extending and validating a human papillomavirus (HPV) knowledge measure in a national sample of Canadian parents of boys. AB - As the human papillomavirus (HPV) vaccine is now recommended for males, a reliable, comprehensive HPV knowledge measurement tool which addresses issues relevant to males is needed. We aimed to replicate, validate and test the comprehensiveness of an existing general HPV and an HPV vaccination knowledge scale in English and French. We also measured parental HPV knowledge and changes over time. An online questionnaire was administered in February (Time 1; T1) and November 2014 (Time 2; T2) to a nationally representative sample of Canadian parents of boys. Dimensionality, internal consistency and model fit were evaluated at both time points and separately in English and French sub-samples. Differences in knowledge scores were measured. Analyses were performed on 3117 participants at T1 and 1427 at T2. The 25-item HPV general knowledge and an 11 item HPV vaccination scale were unidimensional, showed high internal consistency (alpha>0.87, alpha>0.73) and had good model fit. Both general HPV and vaccine specific knowledge significantly increased over time in both languages, but remained low at T2, with only about half of the items being answered correctly. Correct responses at T2 are best explained by correct responses at T1, with some small changes from 'Don't know' at T1 to correct at T2. The extended general and vaccine-specific knowledge scales are valid, reliable and comprehensive, and could be used among parents of boys, in both English and French. Educational interventions could target specific knowledge gaps and focus on providing information rather than correcting misconceptions. PMID- 27471024 TI - Relationships between physical activity across lifetime and health outcomes in older adults: Results from the NuAge cohort. AB - This study aims to (1) describe participation in four physical activity (PA) domains across life and (2) examine the influence of PA during adolescence, early, middle, and later adulthood on health variables at older age. This observational study was conducted in 1378 generally healthy older adults (age 67 84 at baseline in 2003-2005; 52% women) in Quebec, Canada. Using a modified version of the interviewer-administered Lifetime Total Physical Activity Questionnaire (LTPAQ) and life events calendar to facilitate the recall, participants reported the frequency, duration, and intensity of occupational (OPA), commuting (CPA), household (HPA), and leisure time (LTPA) they participated in at age 15, 25, 45, and 65, and at the first follow-up (age 68-85 in 2005-2006). Fat mass, lean body mass, body mass index, waist-to-hip ratio, fasting glucose, systolic and diastolic blood pressures, self-reported chronic diseases, and socio-demographic data were assessed at baseline. Changes in PA over time differed by sex in each domain. However, there was a general decline in all PA domains in both sexes after age 65. In multiple regression analyses, LTPA at first-follow-up was associated with more favourable waist-to-hip ratio in both sexes, fat mass in women and fat mass percentage in men, whereas CPA, OPA, and HPA across life were not consistently associated with health variables. Older adults' LTPA at first follow-up was related to health variables, but PA recalled during adolescence, early adulthood, and mid-life was not. Results support the idea that current PA is positively related to better health outcomes. PMID- 27471025 TI - How reported usefulness modifies the association between neighborhood supports and walking behavior. AB - Neighborhood supports have been associated with walking, but this association may be modified by reports about the usefulness of these supports for promoting walking. This study examined the association between reported presence of neighborhood supports and walking and whether usefulness modified this association in a nationwide sample of U.S. adults. Measures of reported presence and use or potential use (i.e., usefulness) of neighborhood supports (shops within walking distance, transit stops, sidewalks, parks, interesting things to look at, well-lit at night, low crime rate, and cars following speed limit) were examined in 3973 adults who completed the 2014 SummerStyles survey. Multinomial regression models were used to examine the association between presence of supports with walking frequency (frequently, sometimes, rarely (referent)) and the role usefulness had on this association. The interaction term between reported presence and usefulness was significant for all supports (p<0.05). For adults who reported a support as useful, a positive association between presence of the support and walking frequency was observed for all supports. For adults who did not report a support as useful, the association between presence of the support and walking frequency was null for most supports and negative for sidewalks, well-lit at night, and low crime rate. The association between presence of neighborhood supports and walking is modified by reported usefulness of the support. Tailoring initiatives to meet a community's supply of and affinity for neighborhood supports may help initiatives designed to promote walking and walkable communities succeed. PMID- 27471026 TI - Does the built environment moderate the relationship between having a disability and lower levels of physical activity? A systematic review. AB - The relationship between the built environment and physical activity has been well documented. However, little is known about how the built environment affects physical activity among people with disabilities, who have disproportionately higher rates of physical inactivity and obesity. This study is the first systematic review to examine the role of the built environment as a moderator of the relationship between having a disability (physical, sensory or cognitive) and lower levels of physical activity. After conducting an extensive search of the literature published between 1990 and 2015, 2039 articles were screened, 126 were evaluated by abstract and 66 by full text for eligibility in the review. Data were abstracted using a predefined coding guide and synthesized from both qualitative and quantitative studies to examine evidence of moderation. Nine quantitative and six qualitative articles met the inclusion criteria. Results showed that most research to date has been on older adults with physical disabilities. People with disabilities described how aspects of the built environment affect neighborhood walking, suggesting a positive moderating role of features related to safety and aesthetic qualities, such as benches, lighting and stop light timing. There were mixed results among studies that examined the relationship quantitatively. Most of the studies were not designed to appropriately examine moderation. Future research should utilize valid and reliable built environment measures that are more specific to disability and should include people with and without disabilities to allow for testing of moderation of the built environment. PMID- 27471027 TI - The relationship between wealth and loneliness among older people across Europe: Is social participation protective? AB - OBJECTIVE: 1. Examine the relationship between household wealth, social participation and loneliness among older people across Europe. 2. Investigate whether relationships vary by type of social participation (charity/volunteer work, sports/social clubs, educational/training course, and political/community organisations) and gender. 3. Examine whether social participation moderates the association between wealth and loneliness. METHODS: Data (N=29,795) were taken from the fifth wave of the Survey of Health, Ageing and Retirement in Europe (SHARE), which was collected during 2013 from 14 European countries. Loneliness was measured using the short version of the Revised-University of California, Los Angeles (R-UCLA) Loneliness Scale. We used multilevel logistic models stratified by gender to examine the relationships between variables, with individuals nested within countries. RESULTS: The risk of loneliness was highest in the least wealthy groups and lowest in the wealthiest groups. Frequent social participation was associated with a lower risk of loneliness and moderated the association between household wealth and loneliness, particularly among men. Compared to the wealthiest men who often took part in formal social activities, the least wealthy men who did not participate had greater risk of loneliness (OR=1.91, 95% CI: 1.44 to 2.51). This increased risk was not observed among the least wealthy men who reported frequent participation in formal social activities (OR=1.12, 95% CI: 0.76 to 1.67). CONCLUSION: Participation in external social activities may help to reduce loneliness among older adults and potentially acts as a buffer against the adverse effects of socioeconomic disadvantage. PMID- 27471028 TI - Research gaps from evidence-based contraception guidance: the US Medical Eligibility Criteria for Contraceptive Use, 2016, and the US Selected Practice Recommendations for Contraceptive Use, 2016. PMID- 27471029 TI - Medical abortion in women with large uterine fibroids: a case series. AB - Women with fibroid uteri seeking surgical abortion often represent a unique challenge. When the uterine cavity is significantly enlarged or distorted making surgical evacuation difficult or impossible, we offer medical abortion using mifepristone followed by misoprostol beyond the standard 63- to 70-day gestational age cutoff that is typically recommended. This case series describes our regimen and outcomes for 6 patients from 10 to 13 weeks gestation underdoing outpatient medical abortion and 6 patients from 14 to 20 weeks gestation undergoing inpatient medical abortion. Three patients required evacuation for retained products and all others had successful medical abortions without complications. PMID- 27471030 TI - The C/ebp-Atf response element (CARE) location reveals two distinct Atf4 dependent, elongation-mediated mechanisms for transcriptional induction of aminoacyl-tRNA synthetase genes in response to amino acid limitation. AB - The response to amino acid (AA) limitation of the entire aminoacyl-tRNA synthetase (ARS) gene family revealed that 16/20 of the genes encoding cytoplasmic-localized enzymes are transcriptionally induced by activating transcription factor 4 (Atf4) via C/ebp-Atf-Response-Element (CARE) enhancers. In contrast, only 4/19 of the genes encoding mitochondrial-localized ARSs were weakly induced. Most of the activated genes have a functional CARE near the transcription start site (TSS), but for others the CARE is downstream. Regardless of the location of CARE enhancer, for all ARS genes there was constitutive association of RNA polymerase II (Pol II) and the general transcription machinery near the TSS. However, for those genes with a downstream CARE, Atf4, C/ebp homology protein (Chop), Pol II and TATA-binding protein exhibited enhanced recruitment to the CARE during AA limitation. Increased Atf4 binding regulated the association of elongation factors at both the promoter and the enhancer regions, and inhibition of cyclin-dependent kinase 9 (CDK9), that regulates these elongation factors, blocked induction of the AA-responsive ARS genes. Protein pull-down assays indicated that Atf4 directly interacts with CDK9 and its associated protein cyclin T1. The results demonstrate that AA availability modulates the ARS gene family through modulation of transcription elongation. PMID- 27471031 TI - NanoStringDiff: a novel statistical method for differential expression analysis based on NanoString nCounter data. AB - The advanced medium-throughput NanoString nCounter technology has been increasingly used for mRNA or miRNA differential expression (DE) studies due to its advantages including direct measurement of molecule expression levels without amplification, digital readout and superior applicability to formalin fixed paraffin embedded samples. However, the analysis of nCounter data is hampered because most methods developed are based on t-tests, which do not fit the count data generated by the NanoString nCounter system. Furthermore, data normalization procedures of current methods are either not suitable for counts or not specific for NanoString nCounter data. We develop a novel DE detection method based on NanoString nCounter data. The method, named NanoStringDiff, considers a generalized linear model of the negative binomial family to characterize count data and allows for multifactor design. Data normalization is incorporated in the model framework through data normalization parameters, which are estimated from positive controls, negative controls and housekeeping genes embedded in the nCounter system. We propose an empirical Bayes shrinkage approach to estimate the dispersion parameter in the model and a likelihood ratio test to identify differentially expressed genes. Simulations and real data analysis demonstrate that the proposed method performs better than existing methods. PMID- 27471032 TI - G-quadruplex and G-rich sequence stimulate Pif1p-catalyzed downstream duplex DNA unwinding through reducing waiting time at ss/dsDNA junction. AB - Alternative DNA structures that deviate from B-form double-stranded DNA such as G quadruplex (G4) DNA can be formed by G-rich sequences that are widely distributed throughout the human genome. We have previously shown that Pif1p not only unfolds G4, but also unwinds the downstream duplex DNA in a G4-stimulated manner. In the present study, we further characterized the G4-stimulated duplex DNA unwinding phenomenon by means of single-molecule fluorescence resonance energy transfer. It was found that Pif1p did not unwind the partial duplex DNA immediately after unfolding the upstream G4 structure, but rather, it would dwell at the ss/dsDNA junction with a 'waiting time'. Further studies revealed that the waiting time was in fact related to a protein dimerization process that was sensitive to ssDNA sequence and would become rapid if the sequence is G-rich. Furthermore, we identified that the G-rich sequence, as the G4 structure, equally stimulates duplex DNA unwinding. The present work sheds new light on the molecular mechanism by which G4-unwinding helicase Pif1p resolves physiological G4/duplex DNA structures in cells. PMID- 27471033 TI - DNA binding proteins explore multiple local configurations during docking via rapid rebinding. AB - Finding the target site and associating in a specific orientation are essential tasks for DNA-binding proteins. In order to make the target search process as efficient as possible, proteins should not only rapidly diffuse to the target site but also dynamically explore multiple local configurations before diffusing away. Protein flipping is an example of this second process that has been observed previously, but the underlying mechanism of flipping remains unclear. Here, we probed the mechanism of protein flipping at the single molecule level, using HIV-1 reverse transcriptase (RT) as a model system. In order to test the effects of long-range attractive forces on flipping efficiency, we varied the salt concentration and macromolecular crowding conditions. As expected, increased salt concentrations weaken the binding of RT to DNA while increased crowding strengthens the binding. Moreover, when we analyzed the flipping kinetics, i.e. the rate and probability of flipping, at each condition we found that flipping was more efficient when RT bound more strongly. Our data are consistent with a view that DNA bound proteins undergo multiple rapid re-binding events, or short hops, that allow the protein to explore other configurations without completely dissociating from the DNA. PMID- 27471036 TI - Beni Solow award 2015. PMID- 27471034 TI - Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragments in vitro. AB - Poly(ADP-ribose) polymerases (PARPs/ARTDs) use nicotinamide adenine dinucleotide (NAD+) to catalyse the synthesis of a long branched poly(ADP-ribose) polymer (PAR) attached to the acceptor amino acid residues of nuclear proteins. PARPs act on single- and double-stranded DNA breaks by recruiting DNA repair factors. Here, in in vitro biochemical experiments, we found that the mammalian PARP1 and PARP2 proteins can directly ADP-ribosylate the termini of DNA oligonucleotides. PARP1 preferentially catalysed covalent attachment of ADP-ribose units to the ends of recessed DNA duplexes containing 3'-cordycepin, 5'- and 3'-phosphate and also to 5'-phosphate of a single-stranded oligonucleotide. PARP2 preferentially ADP ribosylated the nicked/gapped DNA duplexes containing 5'-phosphate at the double stranded termini. PAR glycohydrolase (PARG) restored native DNA structure by hydrolysing PAR-DNA adducts generated by PARP1 and PARP2. Biochemical and mass spectrometry analyses of the adducts suggested that PARPs utilise DNA termini as an alternative to 2'-hydroxyl of ADP-ribose and protein acceptor residues to catalyse PAR chain initiation either via the 2',1"-O-glycosidic ribose-ribose bond or via phosphodiester bond formation between C1' of ADP-ribose and the phosphate of a terminal deoxyribonucleotide. This new type of post-replicative modification of DNA provides novel insights into the molecular mechanisms underlying biological phenomena of ADP-ribosylation mediated by PARPs. PMID- 27471035 TI - Cytoplasmic Drosha activity generated by alternative splicing. AB - RNase III enzyme Drosha interacts with DGCR8 to form the Microprocessor, initiating canonical microRNA (miRNA) maturation in the nucleus. Here, we re evaluated where Drosha functions in cells using Drosha and/or DGCR8 knock out (KO) cells and cleavage reporters. Interestingly, a truncated Drosha mutant located exclusively in the cytoplasm cleaved pri-miRNA effectively in a DGCR8 dependent manner. In addition, we demonstrated that in vitro generated pri-miRNAs when transfected into cells could be processed to mature miRNAs in the cytoplasm. These results indicate the existence of cytoplasmic Drosha (c-Drosha) activity. Although a subset of endogenous pri-miRNAs become enriched in the cytoplasm of Drosha KO cells, it remains unclear whether pri-miRNA processing is the main function of c-Drosha. We identified two novel in-frame Drosha isoforms generated by alternative splicing in both HEK293T and HeLa cells. One isoform loses the putative nuclear localization signal, generating c-Drosha. Further analysis indicated that the c-Drosha isoform is abundant in multiple cell lines, dramatically variable among different human tissues and upregulated in multiple tumors, suggesting that c-Drosha plays a unique role in gene regulation. Our results reveal a new layer of regulation on the miRNA pathway and provide novel insights into the ever-evolving functions of Drosha. PMID- 27471037 TI - Modification and Validation of the Triglyceride-to-HDL Cholesterol Ratio as a Surrogate of Insulin Sensitivity in White Juveniles and Adults without Diabetes Mellitus: The Single Point Insulin Sensitivity Estimator (SPISE). AB - BACKGROUND: The triglyceride-to-HDL cholesterol (TG/HDL-C) ratio was introduced as a tool to estimate insulin resistance, because circulating lipid measurements are available in routine settings. Insulin, C-peptide, and free fatty acids are components of other insulin-sensitivity indices but their measurement is expensive. Easier and more affordable tools are of interest for both pediatric and adult patients. METHODS: Study participants from the Relationship Between Insulin Sensitivity and Cardiovascular Disease [43.9 (8.3) years, n = 1260] as well as the Beta-Cell Function in Juvenile Diabetes and Obesity study cohorts [15 (1.9) years, n = 29] underwent oral-glucose-tolerance tests and euglycemic clamp tests for estimation of whole-body insulin sensitivity and calculation of insulin sensitivity indices. To refine the TG/HDL ratio, mathematical modeling was applied including body mass index (BMI), fasting TG, and HDL cholesterol and compared to the clamp-derived M-value as an estimate of insulin sensitivity. Each modeling result was scored by identifying insulin resistance and correlation coefficient. The Single Point Insulin Sensitivity Estimator (SPISE) was compared to traditional insulin sensitivity indices using area under the ROC curve (aROC) analysis and chi(2) test. RESULTS: The novel formula for SPISE was computed as follows: SPISE = 600 * HDL-C(0.185)/(TG(0.2) * BMI(1.338)), with fasting HDL-C (mg/dL), fasting TG concentrations (mg/dL), and BMI (kg/m(2)). A cutoff value of 6.61 corresponds to an M-value smaller than 4.7 mg . kg(-1) . min(-1) (aROC, M:0.797). SPISE showed a significantly better aROC than the TG/HDL-C ratio. SPISE aROC was comparable to the Matsuda ISI (insulin sensitivity index) and equal to the QUICKI (quantitative insulin sensitivity check index) and HOMA-IR (homeostasis model assessment-insulin resistance) when calculated with M-values. CONCLUSIONS: The SPISE seems well suited to surrogate whole-body insulin sensitivity from inexpensive fasting single-point blood draw and BMI in white adolescents and adults. PMID- 27471038 TI - Snoring Sounds Predict Obstruction Sites and Surgical Response in Patients with Obstructive Sleep Apnea Hypopnea Syndrome. AB - Snoring sounds generated by different vibrators of the upper airway may be useful indicators of obstruction sites in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). This study aimed to investigate associations between snoring sounds, obstruction sites, and surgical responses (>=50% reduction in the apnea hypopnea index [AHI] and <10 events/hour) in patients with OSAHS. This prospective cohort study recruited 36 OSAHS patients for 6-hour snoring sound recordings during in-lab full-night polysomnography, drug-induced sleep endoscopy (DISE), and relocation pharyngoplasty. All patients received follow-up polysomnography after 6 months. Fifteen (42%) patients with at least two complete obstruction sites defined by DISE were significantly, positively associated with maximal snoring sound intensity (40-300 Hz; odds ratio [OR], 1.25, 95% confidence interval [CI] 1.05-1.49) and body mass index (OR, 1.48, 95% CI 1.02-2.15) after logistic regression analysis. Tonsil obstruction was significantly, inversely correlated with mean snoring sound intensity (301-850 Hz; OR, 0.84, 95% CI 0.74 0.96). Moreover, baseline tonsil obstruction detected by either DISE or mean snoring sound intensity (301-850 Hz), and AHI could significantly predict the surgical response. Our findings suggest that snoring sound detection may be helpful in determining obstruction sites and predict surgical responses. PMID- 27471039 TI - Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. AB - BACKGROUND/AIMS: The Age-Related Eye Disease Study (AREDS) reported the beneficial impact of antioxidant and zinc supplements on the risk of progression to advanced stages of age-related macular degeneration (AMD). We evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD. METHODS: Among 4124 eyes (2317 subjects with a genetic specimen), 882 progressed from no AMD, early or intermediate AMD to overall advanced disease, including geographic atrophy (GA) and neovascular disease (NV) over the course of the clinical trial. Survival analysis using individual eyes as the unit of analysis was used to assess the effect of supplementation on AMD outcomes, with adjustment for demographic, environmental, ocular and genetic covariates. Interaction effects between supplement groups and individual complement factor H (CFH) Y402H and age-related maculopathy susceptibility 2 (ARMS2) genotypes, and composite genetic risk groups combining the number of risk alleles for both loci, were evaluated for their association with progression. RESULTS: Among antioxidant and zinc supplement users compared with the placebo group, subjects with a non-risk genotype for CFH (TT) had a lower risk of progression to advanced AMD (HR: 0.55, 95% CI 0.32 to 0.95, p=0.033). No significant treatment effect was apparent among subjects who were homozygous for the CFH risk allele (CC). A protective effect was observed among high-risk ARMS2 (TT) carriers (HR: 0.52, 95% CI 0.33 to 0.82, p=0.005). Similar results were seen for the NV subtype but not GA. CONCLUSIONS: The effectiveness of antioxidant and zinc supplementation appears to differ by genotype. Further study is needed to determine the biological basis for this interaction. TRIAL REGISTRATION NUMBER: NCT00594672, pre-results. PMID- 27471040 TI - Validation of an instrument to assess visual ability in children with visual impairment in China. AB - OBJECTIVE: To validate a visual ability instrument for school-aged children with visual impairment in China by translating, culturally adopting and Rasch scaling the Cardiff Visual Ability Questionnaire for Children (CVAQC). METHODS: The 25 item CVAQC was translated into Mandarin using a standard protocol. The translated version (CVAQC-CN) was subjected to cognitive testing to ensure a proper cultural adaptation of its content. Then, the CVAQC-CN was interviewer-administered to 114 school-aged children and young people with visual impairment. Rasch analysis was carried out to assess its psychometric properties. The correlation between the CVAQC-CN visual ability scores and clinical measure of vision (visual acuity; VA and contrast sensitivity, CS) were assessed using Spearman's r. RESULTS: Based on cultural adaptation exercise, cognitive testing, missing data and Rasch metrics based iterative item removal, three items were removed from the original 25. The 22-item CVAQC-CN demonstrated excellent measurement precision (person separation index, 3.08), content validity (item separation, 10.09) and item reliability (0.99). Moreover, the CVAQC-CN was unidimensional and had no item bias. The person-item map indicated good targeting of item difficulty to person ability. The CVAQC-CN had moderate correlations between CS (-0.53, p<0.00001) and VA (0.726, p<0.00001), respectively, indicating its validity. CONCLUSIONS: The 22 item CVAQC-CN is a psychometrically robust and valid instrument to measure visual ability in children with visual impairment in China. The instrument can be used as a clinical and research outcome measure to assess the change in visual ability after low vision rehabilitation intervention. PMID- 27471041 TI - Solid pseudopapillary tumors of the pancreas: Specific pathological features predict the likelihood of postoperative recurrence. AB - BACKGROUND: Since their introduction in the WHO classification, the incidence of solid pseudopapillary tumors (SPTs) of the pancreas has progressively increased, mainly because of the widespread use of cross-sectional imaging. Few recent studies have analyzed the biological behavior of SPTs, but reliable data on long term follow-up are needed. METHODS: Retrospective analysis of two Institutions with high caseload, The Department of General Surgery-Pancreas Institute, University of Verona Hospital Trust and the Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, was carried out. Data from 131 consecutive resections for SPT performed during the last three decades were collected and analyzed. RESULTS: The majority of patients were female (86.3%) with a median age of 33 (7-68) years. The prevalent location was the pancreatic tail (33.5%). Applying the WHO criteria, 16 (12.2%) SPTs were considered malignant due to the presence of at least pancreatic parenchyma (9.9%), perineural (4.6%), and/or angiovascular invasion (2.3%). After a median of 62 months after surgery, only two patients had a recurrence (1.5%). Both of them fulfilled the WHO criteria for malignant SPT (vs. 10.7% of those who did not recur, P = 0.01), had an infiltrative growth pattern (vs. 10.8%, P = 0.01), pancreatic parenchyma invasion (vs. 9.7%, P = 0.01) and capsular invasion (vs. 4.9%, P = 0.004). CONCLUSION: Overall, SPTs are associated with excellent survival results after surgical resection. Disease recurrence is extremely rare, and might occur if the primary tumor presents with either pancreatic parenchyma or capsule invasion. J. Surg. Oncol. 2016;114:597-601. (c) 2016 Wiley Periodicals, Inc. PMID- 27471042 TI - Socioeconomic status influences the toll paediatric hospitalisations take on families: a qualitative study. AB - BACKGROUND: Stress caused by hospitalisations and transition periods can place patients at a heightened risk for adverse health outcomes. Additionally, hospitalisations and transitions to home may be experienced in different ways by families with different resources and support systems. Such differences may perpetuate postdischarge disparities. OBJECTIVE: We sought to determine, qualitatively, how the hospitalisation and transition experiences differed among families of varying socioeconomic status (SES). METHODS: Focus groups and individual interviews were held with caregivers of children recently discharged from a children's hospital. Sessions were stratified based on SES, determined by the percentage of individuals living below the federal poverty level in the census tract or neighbourhood in which the family lived. An open-ended, semistructured question guide was developed to assess the family's experience. Responses were systematically compared across two SES strata (tract poverty rate of <15% or >=15%). RESULTS: A total of 61 caregivers who were 87% female and 46% non-white participated; 56% resided in census tracts with >=15% of residents living in poverty (ie, low SES). Interrelated logistical (eg, disruption in-home life, ability to adhere to discharge instructions), emotional (eg, overwhelming and exhausting nature of the experience) and financial (eg, cost of transportation and meals, missed work) themes were identified. These themes, which were seen as key to the hospitalisation and transition experiences, were emphasised and described in qualitatively different ways across SES strata. CONCLUSIONS: Families of lower SES may experience challenges and stress from hospitalisations and transitions in different ways than those of higher SES. Care delivery models and discharge planning that account for such challenges could facilitate smoother transitions that prevent adverse events and reduce disparities in the postdischarge period. TRIAL REGISTRATION NUMBER: NCT02081846; Pre-results. PMID- 27471044 TI - Can't take the heat: Temperature-enhanced toxicity in the mayfly Isonychia bicolor exposed to the neonicotinoid insecticide imidacloprid. AB - Neonicotinoid insecticide usage has increased globally in recent decades. Neonicotinoids, such as imidacloprid, are potent insect neurotoxicants that may pose a threat to non-target aquatic organisms, such as aquatic insects. In nature, insects typically live in thermally fluctuating conditions, which may significantly alter both contaminant exposures and affects. Here we investigate the relationship between temperature and time-to-effect for imidacloprid toxicity with the aquatic insect Isonychia bicolor, a lotic mayfly. Additionally, we examined the mechanisms driving temperature-enhanced toxicity including metabolic rate, imidacloprid uptake rate, and tissue bioconcentration. Experiments included acute toxicity tests utilizing sublethal endpoints and mortality, as well as respirometry and radiotracer assays with [(14)C] imidacloprid. Further, we conducted additional uptake experiments with a suite of aquatic invertebrates (including I. bicolor, Neocloeon triangulifer, Macaffertium modestum, Pteronarcys proteus, Acroneuria carolinensis, and Pleuroceridae sp) to confirm and contextualize our findings from initial experiments. The 96h EC50 (immobility) for I. bicolor at 15 degrees C was 5.81MUg/L which was approximately 3.2 fold lower than concentrations associated with 50% mortality. Assays examining the impact of temperature were conducted at 15, 18, 21, and 24 degrees C and demonstrated that time-to-effect for sublethal impairment and immobility was significantly decreased with increasing temperature. Uptake experiments with [(14)C] imidacloprid revealed that initial uptake rates were significantly increased with increasing temperature for I. bicolor, as were oxygen consumption rates. Further, in the separate experiment with multiple species across temperatures 15, 20, and 25 degrees C, we found that all the aquatic insects tested had significantly increased imidacloprid uptake with increasing temperatures, with N. triangulifer accumulating the most imidacloprid on a mass specific basis. Our acute toxicity results highlight the importance of evaluating sublethal endpoints, as profound impairments of motor function were evident far before mortality. Further, we demonstrate that temperature is a powerful modulator of sublethal toxicity within a range of environmentally relevant temperatures, impacting both uptake rates and metabolic rates of I. bicolor. Finally, we show that temperature alters imidacloprid uptake across a range of species, highlighting the physiological variation present within aquatic invertebrate communities and the challenge associated with relying solely on surrogate species. Taken together, this research points to the need to consider the role of temperature in toxicity assessments. PMID- 27471043 TI - cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness. AB - Immunologically-matched, induced pluripotent stem cell (iPSC)-derived photoreceptor precursor cells have the potential to restore vision to patients with retinal degenerative diseases like retinitis pigmentosa. The purpose of this study was to develop clinically-compatible methods for manufacturing photoreceptor precursor cells from adult skin in a non-profit cGMP environment. Biopsies were obtained from 35 adult patients with inherited retinal degeneration and fibroblast lines were established under ISO class 5 cGMP conditions. Patient specific iPSCs were then generated, clonally expanded and validated. Post-mitotic photoreceptor precursor cells were generated using a stepwise cGMP-compliant 3D differentiation protocol. The recapitulation of the enhanced S-cone phenotype in retinal organoids generated from a patient with NR2E3 mutations demonstrated the fidelity of these protocols. Transplantation into immune compromised animals revealed no evidence of abnormal proliferation or tumor formation. These studies will enable clinical trials to test the safety and efficiency of patient-specific photoreceptor cell replacement in humans. PMID- 27471046 TI - Formation kinetics of particulate films in directional drying of a colloidal suspension. AB - We observed the kinetics of formation of colloidal films through directional drying with a pinned drying interface. The volume fraction of particles accumulated at the pinned drying interface increased in two stages: it rapidly increased in the initial stage of drying and then slowly increased. The final filling factor of the dried films decreased with increasing drying flux. We found a threshold drying flux for the formation of colloidal films below which uneven films are formed at the drying interface. This threshold flux is well explained by the competition between transport of particles by flow and transport by diffusion. We also found a minimum thickness for the formation of a packed layer of particles. The formation kinetics of a packed layer of particles due to drying was discussed. PMID- 27471045 TI - TiO2 nanoparticles for the remediation of eutrophic shallow freshwater systems: Efficiency and impacts on aquatic biota under a microcosm experiment. AB - The application of nanomaterials (NMs) in the remediation of eutrophic waters, particularly in the control of internal loading of nutrients, has been started, but limited investigations evaluated the effectiveness of these new treatment approaches and of their potential impacts on species from shallow freshwater lakes. The present work investigated, under a microcosm experiment, the application of a TiO2 nanomaterial both for reducing nutrient (mainly phosphorus and nitrogen forms) desorption and release from sediments (preventive treatment PT) and for eliminating algal blooms (remediation treatment-RT). Furthermore, we also intended to assess the potential impacts of nano-TiO2 application on key freshwater species. The results showed the effectiveness of nano-TiO2 in controlling the release of phosphates from surface sediment and the subsequent reduction of total phosphorus in the water column. A reduction in total nitrogen was also observed. Such changes in nutrient dynamics contributed to a progressive inhibition of development of algae after the application of the NM in PT microcosms. Concerning the ability of nano-TiO2 to interact with algal cells, this interaction has likely occurred, mainly in RT, enhancing the formation of aggregates and their rapid settlement, thus reducing the algal bloom. Both treatments caused deleterious effects on freshwater species. In PT, Daphnia magna and Lemna minor showed a significant inhibition of several endpoints. Conversely, no inhibitory effect on the growth of Chironomus riparius was recorded. In opposite, C. riparius was the most affected species in RT microcosms. Such difference was probably caused by the formation of larger TiO2-algae aggregates in RT, under a high algal density, that rapidly settled in the sediment, becoming less available for pelagic species. In summary, despite the effectiveness of both treatments in controlling internal nutrient loading and in the mitigating algal bloom episodes, their negative effects on biota have to be seriously taken into account. PMID- 27471047 TI - Left atrial changes in early stages of heart failure with preserved ejection fraction. AB - BACKGROUND AND AIM: Increased left atrial (LA) mass was introduced as a compensatory mechanism in heart failure (HF) patients. Furthermore, atrial conduction time and LA emptying fraction is are deteriorated in HF with preserved ejection fraction (HFpEF). The aim of this study was to assess the early LA changes in HFpEF patients. METHODS: In 79 consecutive patients with HFpEF (age 61+/-8 years, NYHA class I-III, LV EF >=45%), a complete 2-dimensional, M-mode, and Doppler echocardiographic study was performed. According to the diastolic dysfunction (DD), patients were divided into three groups: Group I-29 healthy subjects (control group); Group II-HFpEF patients with mild DD; and Group III HFpEF patients with moderate DD. RESULTS: The LV mass was increased (P<.05), septal s', lateral s', septal and lateral MAPSE were decreased (P<.05, for all), E/e' ratio was increased (P<.001), LA mass and minimal volume were increased (P<.001, P<.05), LA emptying fraction was decreased (P<.05), and LA dyssynchrony was deteriorated (P<.05) in patients with mild DD compared to controls. These changes were of the same nature in patients with moderate LV DD. CONCLUSIONS: In early stage of DD, in patients with HFpEF, in addition to LV hypertrophy and compromised LV longitudinal systolic function, the LA emptying fraction is reduced, LA mass and LAV min are increased and LA dyssynchrony is significant, despite normal LA dimensions. These findings suggest early LA function deterioration irrespective of normal cavity measurements, hence a need for optimum therapy. PMID- 27471049 TI - Recovery from pneumonia requires efferocytosis which is impaired in smokers and those with low body mass index and enhanced by statins. AB - BACKGROUND: Efferocytosis (the phagocytosis of apoptotic self cells) is a key mechanism in the resolution of inflammatory processes such as community-acquired pneumonia (CAP). Efferocytosis therefore represents a modifiable target for therapy aimed at enhancing intrinsic recovery mechanisms. It is currently not known which patients recovering from CAP would mostly benefit from a strategy aimed at enhancing efferocytosis. METHODS: We recruited a cohort of patients with CAP admitted to a hospital in Liverpool. One month into recovery, subjects were invited for research bronchoscopy and bronchoalveolar lavage. An ex vivo efferocytosis assay was performed by challenging alveolar macrophages with autologous, apoptotic neutrophils. The percentage of alveolar macrophages that had undergone efferocytosis was determined by flow cytometry. We conducted a multivariable regression using a linear mixed effects model to determine which clinical parameters were most closely associated with efferocytosis. RESULTS: We observed high rates of comorbidity among this CAP cohort. Efferocytosis was measured in 22 subjects. We assessed multiple combinations of clinical parameters for association with efferocytosis and found the best-fitting model included an interaction between smoking status and prior statin use-smoking being associated with decreased efferocytosis and statin use with increased efferocytosis. These effects were modified by an association between efferocytosis and body mass index (BMI), such that as BMI increased so did efferocytosis. CONCLUSIONS: This is the first study to measure efferocytosis in patients recovering from CAP. The results suggest that smokers with low BMI have impaired efferocytosis and may benefit from a statin to boost recovery. PMID- 27471048 TI - Long-term psychosocial outcomes of low-dose CT screening: results of the UK Lung Cancer Screening randomised controlled trial. AB - BACKGROUND: The UK Lung Cancer Screening (UKLS) trial is a randomised pilot trial of low-dose CT (LDCT) screening for individuals at high risk of lung cancer. We assessed the long-term psychosocial impact on individuals participating in the UKLS trial. METHODS: A random sample of individuals aged 50-75 years was contacted via primary care. High-risk individuals who completed T0 questionnaires (baseline) were randomised to LDCT screening (intervention) or usual care (no screening control). T1 questionnaires were sent 2 weeks after baseline scan results or control assignment. T2 questionnaires were sent up to 2 years after recruitment. Measures included cancer distress, anxiety, depression and decision satisfaction. RESULTS: A total of 4037 high-risk individuals were randomised and they completed T0 questionnaires (n=2018 intervention, n=2019 control). Cancer distress was higher at T1 in intervention arm participants who received positive screening results (p<=0.001), but not at T2 (p=0.04). T2 anxiety (p<=0.001) and depression (p<=0.01) were higher in the control arm, but the absolute differences were small and not clinically relevant. At both time points, fewer control than screened participants were satisfied with their decision to participate in UKLS (p<=0.001). Regardless of trial allocation, cancer distress was higher in women (p<=0.01), participants aged <=65 years (p<=0.001), current smokers (p<=0.001), those with lung cancer experience (p<=0.001) and those recruited from the Liverpool area (p<=0.001). CONCLUSION: Lung cancer screening using LDCT appears to have no clinically significant long-term psychosocial impact on high-risk participants. Strategies for engaging and supporting underserved groups are the key to implement routine lung cancer screening in the UK. TRIAL REGISTRATION NUMBER: ISRCTN 78513845; results. PMID- 27471050 TI - Comprehensive care programme for patients with chronic obstructive pulmonary disease: a randomised controlled trial. AB - BACKGROUND: There have been no randomised controlled trials that specifically evaluate the effect of a comprehensive programme with multidisciplinary input on patients who have just been discharged from hospital after treatment of acute exacerbation of COPD (AECOPD). The aim of this study was to assess whether a comprehensive care programme would decrease hospital readmissions and length of hospital stay (LOS) for patients with COPD. METHODS: Patients discharged from hospital after an episode of AECOPD were randomised to an intervention group (IG) or usual care group (UG). The IG received a comprehensive, individualised care plan which included education from a respiratory nurse, physiotherapist support for pulmonary rehabilitation, 3-monthly telephone calls by a respiratory nurse over 1 year, and follow-up at a respiratory clinic with a respiratory specialist once every 3 months for 1 year. The UG were managed according to standard practice. The primary outcome was hospital readmission rate at 12 months. RESULTS: 180 patients were recruited (IG, N=90; UG, N=90; mean+/-SD age 74.7+/ 8.2 years, 172 (95.6%) men; mean+/-SD FEV1 45.4+/-16.6% predicted). At 12 months, the adjusted relative risk of readmission was 0.668 (95% CI 0.449 to 0.995, p=0.047) for the IG compared with the UG. At 12 months, the IG had a shorter LOS (4.59+/-7.16 vs 8.86+/-10.24 days, p<=0.001), greater improvement in mean Modified Medical Research Council Dyspnoea Scale (-0.1+/-0.6 vs 0.2+/-0.6, p=0.003) and St George's Respiratory Questionnaire score (-6.9+/-15.3 vs -0.1+/ 13.8, p=0.003) compared with the UG. CONCLUSIONS: A comprehensive COPD programme can reduce hospital readmissions for COPD and LOS, in addition to improving symptoms and quality of life of the patients. TRIAL REGISTRATION NUMBER: NCT 01108835, Results. PMID- 27471052 TI - Rotaxane-Like Structures Threaded through the Pores of Hollow Porous Nanocapusles. AB - Nanocapsules with molecules threaded through the porous shells may lead to advanced cell-mimicking functional devices. Herein, we show the feasibility of synthesizing such hybrid nanostructures by using vesicle-templated polymer nanocapsules with controlled nanopores. Ship-in-a-bottle assembly inside a nanocapsule created an internal unit. An external unit was then connected to an entrapped internal unit through pre-attached linker threaded through a nanopore in the shell of the nanocapsule. Both internal and external units are larger than the pore size and cannot cross the shell, producing a rotaxane-like structure. Successful synthesis was achieved with fairly short linkers (six and ten carbon atoms in a chain), creating an opportunity for facile synthesis of functional devices capable of cross-shell communication. PMID- 27471051 TI - Geochemistry and mercury contamination in receiving environments of artisanal mining wastes and identified concerns for food safety. AB - Artisanal small-scale gold mining (ASGM) using mercury (Hg) amalgamation has been occurring on Buru Island, Indonesia since early 2012, and has caused rapid accumulation of high Hg concentrations in river, estuary and marine sediments. In this study, sediment samples were collected from several sites downstream of the Mount Botak ASGM site, as well as in the vicinity of the more recently established site at Gogrea where no sampling had previously been completed. All sediment samples had total Hg (THg) concentrations exceeding Indonesian sediment quality guidelines and were up to 82 times this limit at one estuary site. The geochemistry of sediments in receiving environments indicates the potential for Hg-methylation to form highly bioavailable Hg species. To assess the current contamination threat from consumption of local seafood, samples of fish, molluscs and crustaceans were collected from the Namlea fish market and analysed for THg concentrations. The majority of edible tissue samples had elevated THg concentrations, which raises concerns for food safety. This study shows that river, estuary and marine ecosystems downstream of ASGM operations on Buru Island are exposed to dangerously high Hg concentrations, which are impacting aquatic food chains, and fisheries resources. Considering the high dietary dependence on marine protein in the associated community and across the Mollucas Province, and the short time period since ASGM operations commenced in this region, the results warrant urgent further investigation, risk mitigation, and community education. PMID- 27471053 TI - Antimicrobial peptides trigger a division block in Escherichia coli through stimulation of a signalling system. AB - Antimicrobial peptides are an important component of the molecular arsenal employed by hosts against bacteria. Many bacteria in turn possess pathways that provide protection against these compounds. In Escherichia coli and related bacteria, the PhoQ/PhoP signalling system is a key regulator of this antimicrobial peptide defence. Here we show that treating E. coli with sublethal concentrations of antimicrobial peptides causes cells to filament, and that this division block is controlled by the PhoQ/PhoP system. The filamentation results from increased expression of QueE, an enzyme that is part of a tRNA modification pathway but that, as we show here, also affects cell division. We also find that a functional YFP-QueE fusion localizes to the division septum in filamentous cells, suggesting QueE blocks septation through interaction with the divisome. Regulation of septation by PhoQ/PhoP may protect cells from antimicrobial peptide induced stress or other conditions associated with high-level stimulation of this signalling system. PMID- 27471055 TI - Results of Transradial Subclavian Artery Percutaneous Interventions After Bilateral or Single Access. AB - Percutaneous treatment of subclavian artery stenosis or occlusion has become more popular compared with surgical correction. We compared the early and late results of subclavian artery stenting with bilateral or single transradial access. From 2010 to 2015, we recruited 54 consecutive patients. In 35 cases, we used bilateral access, and in 19 cases, ipsilateral single access was used. Left subclavian artery was the culprit vessel in 72% of cases. There were more chronic total occlusions in the bilateral group (77% vs 21%, p = 0.0001). Transradial only approach was used in all cases, except in 2 cases in the bilateral group where crossover to femoral access was required. Stents were implanted in 94% in bilateral group and 84% in single group (p = 0.47). Procedure duration (40 [35 to 60] vs 20 [15 to 30] minutes), contrast volume (200 [200 to 350] vs 150 [100 to 200] ml and fluoroscopy time (20 [12 to 30] vs 8 [4 to 11] minutes) were higher in bilateral group (all p values <0.0001). Procedural success was 96%. Overall, we observed three <5-cm hematomas and 3 asymptomatic radial artery occlusions at hospital discharge. After successful procedure, blood pressure equalized in 94% in bilateral group and 100% in single group (p = 0.54). Major cardiovascular and cerebrovascular event-free survival up to 5 years was 97% in bilateral group compared with 84% in single group (p = 0.12). Subclavian artery patency at late follow-up was 91% in bilateral group and 95% in single group (p = 1.00). Using single or bilateral transradial approach, subclavian artery lesions or occlusions can be effectively and safely treated without the risks of femoral or brachial access. PMID- 27471056 TI - Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, Triglycerides, and Apolipoprotein B and Cardiovascular Risk in Patients With Manifest Arterial Disease. AB - Low-density lipoprotein cholesterol (LDL-C) only partly represents the atherogenic lipid burden, and a growing body of evidence suggests that non-high density lipoprotein cholesterol (non-HDL-C), triglycerides, and apolipoprotein B (apoB) are more accurate in estimating lipid-related cardiovascular disease risk. Our objective was to compare the relation among LDL-C, non-HDL-C, triglycerides, and apoB and the occurrence of future vascular events and mortality in patients with manifest arterial disease. This is a prospective cohort study of 7,216 patients with clinically manifest arterial disease in the Secondary Manifestations of Arterial Disease Study. Cox proportional hazard models were used to quantify the risk of major cardiovascular events (MACE; i.e., stroke, myocardial infarction, and vascular mortality) and all-cause mortality. Interaction was tested for type of vascular disease at inclusion. MACE occurred in 1,185 subjects during a median follow-up of 6.5 years (interquartile range 3.4 to 9.9 years). Adjusted hazard ratios (HRs) of MACE per 1 SD higher were for LDL C (HR 1.15, 95% confidence interval [CI] 1.09 to 1.22), for non-HDL-C (HR 1.17, 95% CI 1.11 to 1.23), for log(triglycerides) (HR 1.12, 95% CI 1.06 to 1.19), and for apoB HR (1.12, 95% CI 0.99 to 1.28). The relation among LDL-C, non-HDL-C, and cardiovascular events was comparable in patients with cerebrovascular disease, coronary artery disease, or polyvascular disease and absent in those with aneurysm of abdominal aorta or peripheral artery disease. In conclusion, in patients with a history of cerebrovascular, coronary artery, or polyvascular disease, but not aneurysm of abdominal aorta or peripheral artery disease, higher levels of LDL-C and non-HDL-C are related to increased risk of future MACE and of comparable magnitude. PMID- 27471054 TI - Pyruvate dehydrogenase kinase regulates hepatitis C virus replication. AB - During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1alpha (HIF-1alpha), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7.5 cells infected with or without HCV. Protein and mRNA expression of c-Myc, HIF 1alpha, and glycolytic enzymes were significantly higher in HCV-infected human liver and hepatocytes than in uninfected controls. This increase was accompanied by upregulation of serine biosynthetic enzymes, suggesting cellular metabolism was altered toward facilitated nucleotide synthesis essential for HCV replication. JQ1, a c-Myc inhibitor, and dichloroacetate (DCA), a PDK inhibitor, decreased the expression of glycolytic and serine synthetic enzymes in HCV infected hepatocytes, resulting in suppressed viral replication. Furthermore, when co-administered with IFN-alpha or ribavirin, DCA further inhibited viral replication. In summary, HCV reprograms host cell metabolism to favor glycolysis and serine biosynthesis; this is mediated, at least in part, by increased PDK activity, which provides a surplus of nucleotide precursors. Therefore, blocking PDK activity might have therapeutic benefits against HCV replication. PMID- 27471057 TI - Thermal conductivity of the cryoprotective cocktail DP6 in cryogenic temperatures, in the presence and absence of synthetic ice modulators. AB - The thermal conductivity of the cryoprotective agent (CPA) cocktail DP6 in combination with synthetic ice modulators (SIMs) is measured in this study, using a transient hot-wire method. DP6 is a mixture of 3 M dimethyl sulfoxide (DMSO) and 3 M propylene glycol, which received significant attention in the cryobiology community in recent years. Tested SIMs include 6% 1,3Cyclohexanediol, 6% 2,3Butanediol, and 12% PEG400 (percentage by volume). This study integrates the scanning cryomacroscope for visual verification of crystallization and vitrification events. It is demonstrated that the thermal conductivity of the vitrifying CPA cocktail decreases monotonically with the decreasing temperature down to -180 degrees C. By contrast, the thermal conductivity of the crystalline material increases with decreasing temperature in the same temperature range. Results of this study demonstrate that the thermal conductivity may vary by three fold between the amorphous and crystalline phases of DP6 below the glass transition temperature of DP6 (Tg = -119 degrees C). The selected SIMs demonstrate the ability to inhibit crystallization in DP6, even at subcritical cooling rates. An additional ice suppression capability is observed by the Euro Collins as a vehicle solution, disproportionate to its volume ratio in the cocktail. The implication of the observed thermal conductivity differences between the amorphous and crystalline phases of the same cocktail on cryopreservation simulations is significant in some cases and must be taken into account in thermal analyses of cryopreservation protocols. PMID- 27471058 TI - Family-Focused Therapy for Bipolar Disorder: Reflections on 30 Years of Research. AB - Family-focused therapy (FFT) is an evidence-based intervention for adults and children with bipolar disorder (BD) and their caregivers, usually given in conjunction with pharmacotherapy after an illness episode. The treatment consists of conjoint sessions of psychoeducation regarding bipolar illness, communication enhancement training, and problem-solving skills training. This paper summarizes over 30 years of research on FFT and family processes in BD. Across eight randomized controlled trials with adults and adolescents with BD, FFT and mood stabilizing medications have been found to hasten recovery from mood episodes, reduce recurrences, and reduce levels of symptom severity compared to briefer forms of psychoeducation and medications over 1-2 years. Several studies indicate that the effects of FFT on symptom improvement are greater among patients with high-expressed emotion relatives. New research focuses on FFT as an early intervention for youth at risk for BD, neuroimaging as a means of evaluating treatment mechanisms, and progress in implementing FFT in community mental health settings. PMID- 27471059 TI - Degradation of spent craft brewer's yeast by caprine rumen hyper ammonia producing bacteria. AB - Spent yeast from craft beers often includes more hops (Humulus lupulus L.) secondary metabolites than traditional recipes. These compounds include alpha- and beta- acids, which are antimicrobial to the rumen hyper ammonia-producing bacteria (HAB) that are major contributors to amino acid degradation. The objective was to determine if the hops acids in spent craft brewer's yeast (CY; ~ 3.5 mg g(-1) hops acids) would protect it from degradation by caprine rumen bacteria and HAB when compared to a baker's yeast (BY; no hops acids). Cell suspensions were prepared by harvesting rumen fluid from fistulated goats, straining and differential centrifugation. The cells were re-suspended in media with BY or CY. After 24 h (39 degrees C), HAB were enumerated and ammonia was measured. Fewer HAB and less ammonia was produced from CY than from BY. Pure culture experiments were conducted with Peptostreptococcus anaerobiusBG1 (caprine HAB). Ammonia production by BG1 from BY was greater than from CY. Ammonia production was greater when exogenous amino acids were included, but similar inhibition was observed in CY treatments. These results indicate that rumen micro organisms deaminated the amino acids in CY to a lesser degree than BY. SIGNIFICANCE AND IMPACT OF THE STUDY: Spent brewer's yeast has long been included in ruminant diets as a protein supplement. However, modern craft beers often include more hops (Humulus lupulus L.) than traditional recipes. These compounds include alpha- and beta- acids, which are antimicrobial to the rumen hyper ammonia-producing bacteria (HAB) that are major contributors to amino acid degradation. This study demonstrated that hops acids in spent craft brewer's yeast protected protein from destruction by HABin vitro. These results suggest that the spent yeast from craft breweries, a source of beneficial hops secondary metabolites, could have value as rumen-protected protein. PMID- 27471060 TI - A novel HLA-B allele, HLA-B*13:69. AB - HLA-B*13:69 allele differs from B*13:02:01 by one nucleotide substitution at position 628 from A to C. PMID- 27471061 TI - Rapid magnetic solid-phase extraction of Congo Red and Basic Red 2 from aqueous solution by ZIF-8@CoFe2 O4 hybrid composites. AB - Core-shell metal-organic framework materials have attracted considerable attention mainly due to their enhanced or new physicochemical properties compared with their single-component counterparts. In this work, a core-shell heterostructure of CoFe2 O4 -Zeolitic Imidazolate Framework-8 (ZIF-8@CoFe2 O4 ) is successfully fabricated and used as an solid-phase extraction adsorbent to efficiently extract Congo Red and Basic Red 2 dyes from contaminated aqueous solution. Vibrating sample magnetometry indicates that the saturated magnetization of ZIF-8@CoFe2 O4 is 3.3 emu/g, which is large enough for magnetic separation. The obtained hybrid magnetic metal-organic framework based material ZIF-8@CoFe2 O4 can remove the investigated dyes very fast within 1 min of the contact time. The adsorbent ZIF-8@CoFe2 O4 also shows a good reusability. After regeneration, the adsorbent can still exhibit high removal efficiency (~97%) toward Congo Red for five cycles of desorption-adsorption. This work reveals the great potential of core-shell ZIF-8@CoFe2 O4 sorbents for the fast separation and preconcentration of organic pollutants in aqueous solution before high performance liquid chromatography analysis. PMID- 27471062 TI - Plasmacytic Aortitis with Occlusion of the Right Coronary Artery. AB - BACKGROUND Inflammation of the aortic wall, known as aortitis, is a rare clinical entity which is frequently asymptomatic, or identified when the patient presents with an aortic aneurysm or dissection. It is most often caused by infection or autoimmune vasculitides such as giant cell or Takayasu's arteritis. CASE REPORT The case presented is that of a 55-year-old man with symptomatic occlusion of the right coronary artery caused by a plasmacytic aortitis suggestive of IgG4 disease, which was successfully treated with coronary artery bypass grafting and an ascending aortic graft. CONCLUSIONS A review of the current literature emphasizes how poorly the etiology and natural history of plasmacytic aortitis is understood. PMID- 27471063 TI - ED opioid prescribing is not associated with higher patient satisfaction scores. PMID- 27471064 TI - On the role of Taenia asiatica in human cases of cysticercosis. PMID- 27471065 TI - Microbial bioinformatics 2020. AB - Microbial bioinformatics in 2020 will remain a vibrant, creative discipline, adding value to the ever-growing flood of new sequence data, while embracing novel technologies and fresh approaches. Databases and search strategies will struggle to cope and manual curation will not be sustainable during the scale-up to the million-microbial-genome era. Microbial taxonomy will have to adapt to a situation in which most microorganisms are discovered and characterised through the analysis of sequences. Genome sequencing will become a routine approach in clinical and research laboratories, with fresh demands for interpretable user friendly outputs. The "internet of things" will penetrate healthcare systems, so that even a piece of hospital plumbing might have its own IP address that can be integrated with pathogen genome sequences. Microbiome mania will continue, but the tide will turn from molecular barcoding towards metagenomics. Crowd-sourced analyses will collide with cloud computing, but eternal vigilance will be the price of preventing the misinterpretation and overselling of microbial sequence data. Output from hand-held sequencers will be analysed on mobile devices. Open source training materials will address the need for the development of a skilled labour force. As we boldly go into the third decade of the twenty-first century, microbial sequence space will remain the final frontier! PMID- 27471067 TI - Mitochondrial acetyl-CoA utilization pathway for terpenoid productions. AB - Acetyl-CoA is a central molecule in the metabolism of the cell, which is also a precursor molecule to a variety of value-added products such as terpenoids and fatty acid derived molecules. Considering subcellular compartmentalization of metabolic pathways allows higher concentrations of enzymes, substrates and intermediates, and bypasses competing pathways, mitochondrion-compartmentalized acetyl-CoA utilization pathways might offer better pathway activities with improved product yields. As a proof-of-concept, we sought to explore a mitochondrial farnesyl pyrophosphate (FPP) biosynthetic pathway for the biosynthesis of amorpha-4,11-diene in budding yeast. In the present study, the eight-gene FPP biosynthetic pathway was successfully expressed inside yeast mitochondria to enable high-level amorpha-4,11-diene production. In addition, we also found the mitochondrial compartment serves as a partial barrier for the translocation of FPP from mitochondria into the cytosol, which would potentially allow minimized loss of FPP to cytosolic competing pathways. To our best knowledge, this is the first report to harness yeast mitochondria for terpenoid productions from the mitochondrial acetyl-CoA pool. We envision subcellular metabolic engineering might also be employed for an efficient production of other bio-products from the mitochondrial acetyl-CoA in other eukaryotic organisms. PMID- 27471068 TI - Production of 1-decanol by metabolically engineered Yarrowia lipolytica. AB - Medium-chain alcohols are used to produce solvents, surfactants, lubricants, waxes, creams, and cosmetics. In this study, we engineered the oleaginous yeast Yarrowia lipolytica to produce 1-decanol from glucose. Expression of a fatty acyl CoA reductase from Arabidopsis thaliana in strains of Y. lipolytica previously engineered to produce medium-chain fatty acids resulted in the production of 1 decanol. However, the resulting titers were very low (<10mg/mL), most likely due to product catabolism. In addition, these strains produced small quantities of 1 hexadecanol and 1-octadecanol. Deleting the major peroxisome assembly factor Pex10 was found to significantly increase 1-decanol production, resulting in titers exceeding 500mg/L. It also increased 1-hexadecanoland and 1-octadecanol titers, though the resulting increases were less than those for 1-decanol. These results demonstrate that Y. lipolytica can potentially be used for the industrial production of 1-decanol and other fatty alcohols from simple sugars. PMID- 27471066 TI - Clinicopathological features and prognosis of omental gastrointestinal stromal tumor: evaluation of a pooled case series. AB - Clinicopathological features and prognosis of omental GISTs are limited due to the extremely rare incidence. Therefore, the aim of the present study was to investigate the clinicopathological features and prognosis of omental GISTs. Omental GISTs cases were obtained from our center and from case reports and clinical studies extracted from MEDLINE. Clinicopathological features and survivals were analyzed. A total of 99 cases of omental GISTs were enrolled in the present study. Omental GISTs occurred predominantly in greater omentum (78/99, 78.8%). The majority of tumors exceeded 10 cm in diameter (67/98, 68.3%) and were high risk (88/96, 91.7%). Histological type was correlated with tumor location and mutational status. The five year DFS and DSS was 86.3% and 80.6%, respectively. Mitotic index was risk factor for prognosis of omental GISTs. Prognosis of omental GISTs was worse than that of gastric GISTs by Kaplan-Meier analysis. However, multivariate analysis showed that the prognosis was comparable between the two groups. The majority of omental GISTs were large and high risk. Mitotic index was risk factor for prognosis of omental GISTs. The prognosis was comparable between omental and gastric GISTs. PMID- 27471069 TI - Production of para-aminobenzoate by genetically engineered Corynebacterium glutamicum and non-biological formation of an N-glucosyl byproduct. AB - para-Aminobenzoate (PABA), a valuable chemical raw material, can be synthesized by most microorganisms. This aromatic compound is currently manufactured from petroleum-derived materials by chemical synthesis. To produce PABA from renewable resources, its production by fermentation was investigated. The evaluation of the sensitivity to PABA toxicity revealed that Corynebacterium glutamicum had better tolerance to PABA than several other microorganisms. To produce PABA from glucose, genetically engineered C. glutamicum was constructed by introducing both pabAB and pabC. The generated strain produced 20mM of PABA in a test-tube scale culture; however, during the investigation, an unidentified major byproduct was detected in the culture supernatant. Unexpectedly, the byproduct was also detected after the incubation of PABA with glucose in a buffer solution without bacterial cells. To elucidate the mechanism underlying the formation of this byproduct, PABA analogues and several kinds of sugars were mixed and analyzed. New chemical compounds were detected when incubating aniline with glucose as well as PABA with reducing sugars (mannose, xylose, or arabinose), indicating that an amino group of PABA reacted non-enzymatically with an aldehyde group of glucose. The molecular mass of the byproduct determined by LC-MS suggested that the molecule was generated from PABA and glucose with releasing a water molecule, generally known as a glycation product. Because the glycation reaction was reversible, the byproduct was easily converted to PABA by acid treatment (around pH 2-3) with HCl. Then, pab genes were screened to improve PABA production. The highest PABA concentration was achieved by a strain expressing the pabAB of Corynebacterium callunae and a strain expressing the pabC of Xenorhabdus bovienii, respectively. A plasmid harboring both the pabAB of C. callunae and the pabC of X. bovienii, the best gene combination, was introduced into a strain overexpressing the genes of the shikimate pathway. The resultant strain produced 45mM of PABA in a test-tube scale culture. Under a fermenter-controlled condition, the strain produced up to 314mM (43g/L) of PABA at 48h, with a 20% yield. To our knowledge, this is the highest concentration of PABA produced by a genetically modified microorganism ever reported. PMID- 27471071 TI - In response: Can we rely on the adequate mesorectum excision and the complete pathological response in case of rectal signet-ring cell carcinoma. PMID- 27471072 TI - Disruptive selection as a driver of evolutionary branching and caste evolution in social insects. AB - Theory suggests that evolutionary branching via disruptive selection may be a relatively common and powerful force driving phenotypic divergence. Here, we extend this theory to social insects, which have novel social axes of phenotypic diversification. Our model, built around turtle ant (Cephalotes) biology, is used to explore whether disruptive selection can drive the evolutionary branching of divergent colony phenotypes that include a novel soldier caste. Soldier evolution is a recurrent theme in social insect diversification that is exemplified in the turtle ants. We show that phenotypic mutants can gain competitive advantages that induce disruptive selection and subsequent branching. A soldier caste does not generally appear before branching, but can evolve from subsequent competition. The soldier caste then evolves in association with specialized resource preferences that maximize defensive performance. Overall, our model indicates that resource specialization may occur in the absence of morphological specialization, but that when morphological specialization evolves, it is always in association with resource specialization. This evolutionary coupling of ecological and morphological specialization is consistent with recent empirical evidence, but contrary to predictions of classical caste theory. Our model provides a new theoretical understanding of the ecology of caste evolution that explicitly considers the process of adaptive phenotypic divergence and diversification. PMID- 27471070 TI - Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes. AB - Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan-, and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group, and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle treated group (P = 0.026), and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P < 0.001). Furthermore, the results suggested that the BIC/PLGA nanofibers reduced the malignancy of C6 glioma. The experimental findings indicate that the multianticancer drug (i.e., BIC)-eluting PLGA nanofibers are favorable candidates for treating malignant glioma. PMID- 27471074 TI - Electrostatically driven drumhead resonators based on freestanding membranes of cross-linked gold nanoparticles. AB - Freestanding, nanometer-thin membranes of alkanedithiol cross-linked gold nanoparticles represent elastic, mechanically robust and electrically conductive materials, which are interesting for the fabrication of novel nano- and microelectromechanical devices. In this work we present the first electrostatically driven drumhead resonators based on such nanoparticle membranes. These circular membranes have a thickness of 33 to 52 nm, a diameter of either 50 MUm or 100 MUm, and are equally spaced from their back electrode by ~10 MUm. Using an interferometric nanovibration analyzer various vibrational modes with resonance amplitudes of up to several 100 nm could be detected when the membranes are excited by applying AC voltages (<30 V) with drive frequencies of up to 2 MHz. Further, spatial amplitude distributions of different vibrational modes could be imaged. The devices showed fundamental resonance frequencies in the high kHz range and quality factors Q up to ~2000. Finally, vibrational spectra and observed mode patterns could be well interpreted using the theory for a clamped circular membrane with negligible bending stiffness. Our findings mark an important step towards the integration of freestanding gold nanoparticle composite membranes into electromechanical devices with various applications, such as novel types of pressure or mass sensors. PMID- 27471073 TI - Liquid-solid joining of bulk metallic glasses. AB - Here, we successfully welded two bulk metallic glass (BMG) materials, Zr51Ti5Ni10Cu25Al9 and Zr50.7Cu28Ni9Al12.3 (at. %), using a liquid-solid joining process. An atomic-scale metallurgical bonding between two BMGs can be achieved. The interface has a transition layer of ~50 MUm thick. The liquid-solid joining of BMGs can shed more insights on overcoming their size limitation resulting from their limited glass-forming ability and then promoting their applications in structural components. PMID- 27471075 TI - Risk factors and clinical characteristics of the depressive state induced by pegylated interferon therapy in patients with hepatitis C virus infection: A prospective study. AB - AIM: Pegylated interferon (PegIFN) therapies for hepatitis C virus (HCV) infection often induce a depressive state. This study aimed to identify the risk factors for and clinical characteristics of PegIFN-induced depressive state. METHODS: Sixty-nine subjects with HCV who received PegIFN therapy were enrolled. Before beginning therapy, all subjects were evaluated using the Neuroticism Extraversion-Openness Five-Factor Inventory and the List of Threatening Events Questionnaire. Beck Depression Inventory (BDI) scores were also evaluated at baseline, 2-4 weeks after initiating therapy, and every 4 weeks thereafter. RESULTS: During the study, 18 subjects (24.3%) developed a depressive state (BDI >= 10). A bimodal peak of onset was observed during the early (2-8 weeks) and late (after 20 weeks) therapy phases. Moreover, we observed that baseline BDI scores (odds ratio [OR] = 1.40, P = 0.0104) and neuroticism (OR = 1.14, P = 0.0275) were significant risk factors for developing a depressive state. To determine the specific characteristics of this condition, we compared the BDI subscales between the 'PegIFN-induced' and 'general' depressive state reported previously. We found that the score at 'somatic symptoms' was higher in the 'PegIFN-induced' group. CONCLUSION: Our results indicate the following: (i) PegIFN-induced depressive state most frequently develops during the first 8 weeks of therapy; (ii) baseline BDI and neuroticism scores are risk factors for PegIFN induced depressive state; and (iii) the core symptoms of PegIFN-induced depressive state are different from those of 'general' depression. PMID- 27471076 TI - Host Integration of an Acellular Dermal Matrix: Braxon Mesh in Breast Reconstruction. PMID- 27471077 TI - The Labile Limits of Forbidden Interactions. AB - Forbidden links are defined as pairwise interactions that are prevented by the biological traits of the species. We focus here on the neglected importance of intraspecific trait variation in the forbidden link concept. We show how intraspecific trait variability at different spatiotemporal scales, and through ontogeny, reduces the expected prevalence of forbidden interactions. We also highlight how behavior can foster interactions that, from traits, would be predicted to be forbidden. We therefore discuss the drawbacks of frameworks recently developed to infer biotic interactions using available trait data (mean values). Mispredictions can have disproportionate effects on inferences about community dynamics. Thus, we suggest including intraspecific variability in trait based models and using them to guide the sampling of real interactions in the field for validation. PMID- 27471078 TI - Limitations to the Dutch cannabis toleration policy: Assumptions underlying the reclassification of cannabis above 15% THC. AB - The Netherlands has seen an increase in Delta9-tetrahydrocannabinol (THC) concentrations from approximately 8% in the 1990s up to 20% in 2004. Increased cannabis potency may lead to higher THC-exposure and cannabis related harm. The Dutch government officially condones the sale of cannabis from so called 'coffee shops', and the Opium Act distinguishes cannabis as a Schedule II drug with 'acceptable risk' from other drugs with 'unacceptable risk' (Schedule I). Even in 1976, however, cannabis potency was taken into account by distinguishing hemp oil as a Schedule I drug. In 2011, an advisory committee recommended tightening up legislation, leading to a 2013 bill proposing the reclassification of high potency cannabis products with a THC content of 15% or more as a Schedule I drug. The purpose of this measure was twofold: to reduce public health risks and to reduce illegal cultivation and export of cannabis by increasing punishment. This paper focuses on the public health aspects and describes the (explicit and implicit) assumptions underlying this '15% THC measure', as well as to what extent these are supported by scientific research. Based on scientific literature and other sources of information, we conclude that the 15% measure can provide in theory a slight health benefit for specific groups of cannabis users (i.e., frequent users preferring strong cannabis, purchasing from coffee shops, using 'steady quantities' and not changing their smoking behaviour), but certainly not for all cannabis users. These gains should be weighed against the investment in enforcement and the risk of unintended (adverse) effects. Given the many assumptions and uncertainty about the nature and extent of the expected buying and smoking behaviour changes, the measure is a political choice and based on thin evidence. PMID- 27471080 TI - Meeting report for 2015 Metabolic Engineering Summit Beijing. PMID- 27471081 TI - Early morphological diagnosis of Farber disease. PMID- 27471083 TI - Amyloid-like aggregates formation by bovine apo-carbonic anhydrase in various alcohols: A comparative study. AB - Peptides and proteins convert from their native states to amyloid fibrillar aggregates in a number of pathological conditions. Characterizing these species could provide useful information on their pathogenicity and the key factors involved in their generation. In this study, we have observed the ability of the model protein apo-bovine carbonic anhydrase (apo-BCA) to form amyloid-like aggregates in the presence of halogenated and non-halogenated alcohols. Far-UV circular dichroism, ThT fluorescence, atomic force microscopy and dynamic light scattering were used to characterize these structures. The concentration required for effective protein aggregation varied between the solvents, with non halogenated alcohols acting in a wider range. These aggregates show amyloid-like structures as determined by specific techniques used for characterizing amyloid structures. Oligomers were obtained with various size distributions, but fibrillar structures were not observed. Use of halogenated alcohols resulted into smaller hydrodynamic radii, and most stable oligomers were formed in hexafluoropropan-2-ol (HFIP). At optimal concentrations used to generate these structures, the non-halogenated alcohols showed higher hydrophobicity, which may be related to the lower stability of the generated oligomers. These oligomers have the potential to be used as models in the search for effective treatments in proteinopathies. PMID- 27471084 TI - Changes in aggregation behavior of collagen molecules in solution with varying concentrations of acetic acid. AB - A critical aggregation concentration of 0.30-0.50mg/mL was previously obtained for type I collagen at 0.1M acetic acid (AA). In the present study, the aggregation behavior of collagen in solution (0.5mg/mL) in the presence of 0.1 2.0M AA was investigated. Circular dichroism showed that the three helix structure was maintained across the whole AA concentration range. However, the ratio of positive peak intensity over negative peak intensity varied depending on the conformational state of collagen aggregates. Ultra-sensitive differential scanning calorimetry revealed that transition temperatures Tm1 and Tm2 decreased by 8.35 degrees C and 7.80 degrees C, respectively, between 0.1M and 2.0M, indicating a possible relationship between the aggregation state and the thermal effect. The surrounding polarity of collagen molecules in solution containing pyrene was investigated by fluorescence spectroscopy, which demonstrated that disaggregation of collagen aggregates was enhanced with increasing AA concentration. This observation was correlated with changes in collagen fiber size observed by atomic force microscopy. Furthermore, collagen tyrosine residues were blue-shifted in an intrinsic fluorescence spectra, further indicating changes in aggregation behavior with increasing AA concentration. Finally, the dynamic response of collagen molecules to AA was analyzed by two-dimensional correlation fluorescence spectra. PMID- 27471082 TI - Learning During Processing: Word Learning Doesn't Wait for Word Recognition to Finish. AB - Previous research on associative learning has uncovered detailed aspects of the process, including what types of things are learned, how they are learned, and where in the brain such learning occurs. However, perceptual processes, such as stimulus recognition and identification, take time to unfold. Previous studies of learning have not addressed when, during the course of these dynamic recognition processes, learned representations are formed and updated. If learned representations are formed and updated while recognition is ongoing, the result of learning may incorporate spurious, partial information. For example, during word recognition, words take time to be identified, and competing words are often active in parallel. If learning proceeds before this competition resolves, representations may be influenced by the preliminary activations present at the time of learning. In three experiments using word learning as a model domain, we provide evidence that learning reflects the ongoing dynamics of auditory and visual processing during a learning event. These results show that learning can occur before stimulus recognition processes are complete; learning does not wait for ongoing perceptual processing to complete. PMID- 27471085 TI - Improved antioxidant and anti-tyrosinase activity of polysaccharide from Sargassum fusiforme by degradation. AB - An efficient method for the degradation of polysaccharides isolated from Sargassum fusiforme (PSF) was developed by using ascorbic acid in combination with H2O2. The degradation conditions were optimized using a Box-Behnken response surface design (BBRS). The optimum conditions were established as: concentration of ascorbic acid (VC) and H2O2 17.26mM, degradation temperature 51 degrees C and degradation time 1.6h. The DPPH radical scavenging rate of the degraded polysaccharides from S. fusiforme (DPSF) obtained under the optimal conditions was determined to be 75.22+/-0.02%, which was well matched with the value (75.21%) predicted by the BBRS model. In vitro antioxidant activity of the polysaccharides was evaluated by determining their radical (hydroxyl radical, superoxide anion radical and DPPH radical) scavenging abilities, and ferric iron reducing power. The inhibitory activity on tyrosinase of DPSF was also evaluated. The results indicate that the degraded polysaccharide has superior antioxidant activity and anti-tyrosinase effect to those of the original polysaccharide. PMID- 27471086 TI - Simultaneous removal of Cr(VI) and Amido black 10B (AB10B) from aqueous solutions using quaternized chitosan coated bentonite. AB - In this study, simultaneous removal of Cr(VI) and Amido Black 10B (AB10B) using quaternized chitosan coated bentonite was investigated by a batch method. The factors affecting adsorption process such as pH, adsorbent dosage, contact time and initial concentration and the interaction of two components in binary solutions have been studied. The results showed that the antagonism effect existed between Cr(VI) and AB10B in binary systems. The equilibrium time for Cr(VI) adsorption was less than the one for AB10B adsorption. The maximum adsorption capacities of the modified bentonite, according to the Langmuir isotherm model were 847.5mg/g for AB10B and 66.6mg/g for Cr(VI) at 298K. The experimental results demonstrated that both Cr(VI) and AB10B were well described by the pseudo-second-order model. Thermodynamic study depicted that the adsorption of Cr(VI) and AB10B onto the modified bentonite was both spontaneous. The adsorption for Cr(VI) was exothermic while the one for AB10B was endoth- ermic in nature. PMID- 27471087 TI - Synthesis, characterization and evaluation of dewatering properties of chitosan grafting DMDAAC flocculants. AB - Flocculation is one of the most widely applied techniques for water treatment and sludge dewatering. A fresh environmentally friendly and powerful flocculant is highly eager in the sludge dewatering area. In this work, a highly efficient cationic flocculant, chitosan-g-PDMDAAC was synthesized through grafting a monomer, dimethy ldiallyl ammonium chloride(DMDAAC), onto chitosan initiated by ceric sulfate under ultrasonic-assisted and conventional heating condition. The graft copolymer was characterized using FT-IR, XRD and SEM. Further, the dewatering performance of municipal activated sludge was evaluated by the filter cake moisture content and specific resistance in filtration. Its application as a flocculant for wastewater treatment was investigated. The prepared chitosan-g PDMDAAC showed a highly effective flocculation capability for activated sludge compared with chitosan, polyacrylamide(PAM), cationic polyacrylamide(CPAM). PMID- 27471088 TI - Synthesis and evaluation of isometamidium-alginate nanoparticles on equine mononuclear and red blood cells. AB - Isometamidium hydrochloride (ISMM) is an effective drug for the treatment of trypanosomosis, but it causes local and systemic toxicity. Isometamidium hydrochloride has limited therapeutic index and exhibit considerable variation in their prophylactic activities. We developed a trypanocidal nanoformulation using ISMM and polymers sodium alginate/gum acacia to enhance the efficacy of the drug at lower doses, while minimizing undesirable side effects. It was characterized by transmission electron microscopy and infrared spectroscopy for evaluation of size, morphology, functional groups, etc. In vitro cytotoxicity studies were performed by metabolic resazurin assay at different concentrations of isometamidium-loaded alginate/gum acacia nanoparticles using equine peripheral blood mononuclear cells. Hemolytic assay revealed significantly less toxicity compared to the conventional drug. The results demonstrate that the developed drug delivery module can be evaluated in suitable animal models to evaluate its potency. PMID- 27471089 TI - Purification, characterization and in vitro antioxidant activities of polysaccharide from Chaenomeles speciosa. AB - A water-soluble polysaccharide named as CSP-2 was isolated and purified from Chaenomeles speciosa by DEAE-Sepharose and Sephadex G-100 column chromatography. CSP-2 was composed of galactose (Gal), rhamnose (Rha), glucose (Glc) and xylose (Xyl) with a relative molar ratio of 3.8:1.6:1.2:0.4. The average molecular weight of CSP-2 was estimated to be about 4.6*104Da. The in vitro antioxidant assay showed that CSP-2 exhibited remarkable antioxidant activities to scavenge the DPPH radical, superoxide radical, hydroxyl radical and ABTS radical and significant cytoprotective effects on H2O2-induced PC12 cells injury in a concentration-dependent manner. Overall, CSP-2 may be useful as a naturally potential antioxidant agent for application in food and medicinal fields. PMID- 27471090 TI - Regenerated cellulose/wool blend enhanced biomimetic hydroxyapatite mineralization. AB - The current article investigates the effect of bioactive cellulose/wool blend on calcium phosphate biomimetic mineralization. Regenerated cellulose/wool blend was prepared by dissolution-regeneration of neat cellulose and natural wool in 1 butyl-3-methyl imidazolium chloride [Bmim][Cl], as a solvent for the two polymers. Crystalline hydroxyapatite nanofibers with a uniform size, shape and dimension were formed after immersing the bioactive blend in simulated body fluid. The cytotoxicity of cellulose/wool/hydroxyapatite was studied using animal fibroblast baby hamster kidney cells (BHK-21) and the result displayed good cytocompatability. This research work presents a green processing method for the development of novel cellulose/wool/hydroxyapatite hybrid materials for tissue engineering applications. PMID- 27471091 TI - Radiation Synthesis of Poly(Starch/Acrylic acid) pH Sensitive Hydrogel for Rutin Controlled Release. AB - The copolymerization of starch with acrylic acid AAc using direct gamma radiation technique was performed. The effect of AAc concentrations on the gel (%) and swelling behavior were investigated. It is found that as AAc concentrations increase both gel(%) and swelling behavior increase. The Poly(starch/acrylic acid) (1:10wt%) hydrogel were selected due to its high swelling properties. From the in-vitro release study of the rutin-loaded hydrogel it is observed that it is strong pH-dependent release behavior, thus offering a maximum release as pH increased. The dextran sulphate sodium (DSS)-induced rat colitis model was treated with rutin-loaded Poly(starch/acrylic acid) (1:10wt%) hydrogel and free rutin solution by oral administration. Colitic control group showed a significant elevation in colon/body weight ratio, myeloperoxgidase activity, tumor necrosis factor, nitric oxide and malondialdehyde levels. However, glutathione level was reduced. It was found that the rutin-loaded hydrogel was more efficient than free rutin as evidenced by improvement of all measured parameters. These effects were confirmed histopathologically and may be attributed to its ability to control delivery of rutin to colon with minor early release of rutin before colon. The Poly(starch/acrylic acid) (1:10wt%) can represent a pivotal anti-inflammatory approach for patients with inflammatory bowel disease in order to increase efficacy and reduce toxicity. PMID- 27471092 TI - Bench and initial preclinical results of a novel 8 mm diameter double opposed helical biodegradable stent. AB - BACKGROUND: Metallic endovascular stents are utilized off-label in congenital heart disease. Biodegradable stents (BDS) offer potential advantages in a growing child. We have previously reported double opposed helical (DH) BDS up to 6 mm diameter (DH-6). The objectives are to investigate the bench characteristics of larger 8 mm diameter BDS (DH-8) manufactured with increasing strut thicknesses and the inflammatory profile in a porcine model. METHODS: DH-8 were manufactured with strut thicknesses 0.10, 0.12, and 0.18 mm and mechanical testing performed. Stents were deployed into the infrarenal descending aorta (DAO) of nine minipigs. At insertion (nonsurvival = 2), 1 week (n = 2), 1 month (n = 2), and 9 months (n = 3) follow-up angiography, intravascular ultrasound and histopathology were performed. RESULTS: There was superior recoil and collapse pressure with increasing strut thickness, with 0.18 mm having 1.0% elastic recoil and collapse pressure 0.75 Atmospheres. There was good wall apposition at insertion with 5 BDS (4 DH-8 and 1 DH-6) but suboptimal in 4 as the minipigs infrarenal DAO were >8 mm (deployed at iliac bifurcation). Structural integrity was maintained in 8 BDS with 1 DH-8 collapsed at 9 months, secondary to strut damage at insertion. No thrombosis was seen. There was mild inflammation and neointimal proliferation at 1 week and 1 month, but a moderate inflammatory response at 9 months. CONCLUSIONS: DH-8 with increased strut thickness had acceptable mechanical properties at the cost of an increased inflammatory response. Miniaturization to improve delivery and further investigation on the long-term inflammatory profile of thicker struts, including through degradation, is needed. (c) 2016 Wiley Periodicals, Inc. PMID- 27471093 TI - The prevalence of dental anomalies in an Australian population. AB - BACKGROUND: The aim of this study was to determine the prevalence of dental anomalies within an Australian paediatric population using panoramic radiographs. METHODS: This was a prospective review of 1050 panoramic radiographs obtained as part of a school dental screening program in suburban and rural New South Wales, Australia. RESULTS: Fifty-four (5.14%) patients had a dental anomaly present. Agenesis was noted to have occurred 69 times across 45 patients (4.28%), along with seven cases of impaction (0.6%) and three cases of supernumerary teeth (0.28%). CONCLUSIONS: Dental anomalies rarely occur in the Australian population, which possesses a wide-ranging multiethnic cohort. Despite their rarity, they can be incidentally discovered so identification and management by dental practitioners are important. PMID- 27471095 TI - Single incision laparoscopic primary and incisional ventral hernia repair as the standard of care in the ambulatory setting; Does less equal better outcomes; Case series and literature review. AB - INTRODUCTION: The consensus about whether the single port approach is advantageous remains controversial. As the ambulatory service becomes the standard of care, techniques are in evolution to augment the patient experience in this setting. This forms the basis for evaluating SILS (Single Incision Laparoscopic Surgery) prosthetic ventral hernia repair in the ambulatory setting. We report a SILS technique of ventral hernia repair using the Stryker Ideal-eyes articulating laparoscope and standard laparoscopic instruments in the day-case setting. PRESENTATION OF CASES: We report three cases of ventral hernias (one primary and two incisional). All were completed using single port techniques. They were done in the ambulatory setting and require no admission. Single incision laparoscopic repair of primary and incisional ventral hernias was completed successfully in all cases without conversion to standard laparoscopy. Median (range) operative time was 66min (39-95min). No intra- or postoperative complications were recorded. No episodes of prolonged postoperative pain were reported. We examine the literature and subsequently discuss the feasibility of ambulatory single port ventral hernia repair. CONCLUSION: SILS prosthetic repair of primary and incisional ventral hernia is easily feasible. In our series, SILS ventral hernia repair appears to be safe and effective. It may decrease parietal trauma augmenting its use in the ambulatory setting. Technology will continue to improve the wide applicability of this technique. Larger randomized trial studies are required to determine the rates of port-site incisional hernia compared with multiport laparoscopy. PMID- 27471094 TI - Degradomic and yeast 2-hybrid inactive catalytic domain substrate trapping identifies new membrane-type 1 matrix metalloproteinase (MMP14) substrates: CCN3 (Nov) and CCN5 (WISP2). AB - : Members of the CCN family of matricellular proteins are cytokines linking cells to the extracellular matrix. We report that CCN3 (Nov) and CCN5 (WISP2) are novel substrates of MMP14 (membrane-type 1-matrix metalloproteinase, MT1-MMP) that we identified using MMP14 "inactive catalytic domain capture" (ICDC) as a yeast two hybrid protease substrate trapping platform in parallel with degradomics mass spectrometry screens for MMP14 substrates. CCN3 and CCN5, previously unknown substrates of MMPs, were biochemically validated as substrates of MMP14 and other MMPs in vitro-CCN5 was processed in the variable region by MMP14 and MMP2, as well as by MMP1, 3, 7, 8, 9 and 15. CCN1, 2 and 3 are proangiogenic factors yet we found novel opposing activity of CCN5 that was potently antiangiogenic in an aortic ring vessel outgrowth model. MMP14, a known regulator of angiogenesis, cleaved CCN5 and abrogated the angiostatic activity. CCN3 was also processed in the variable region by MMP14 and MMP2, and by MMP1, 8 and 9. In addition to the previously reported cleavages of CCN1 and CCN2 by several MMPs we found that MMPs 8, 9, and 1 process CCN1, and MMP8 and MMP9 also process CCN2. Thus, our study reveals additional and pervasive family-wide processing of CCN matricellular proteins/cytokines by MMPs. Furthermore, CCN5 cleavage by proangiogenic MMPs results in removal of an angiogenic brake held by CCN5. This highlights the importance of thorough dissection of MMP substrates that is needed to reveal higher-level control mechanisms beyond type IV collagen and other extracellular matrix protein remodelling in angiogenesis. SUMMARY: We find CCN family member cleavage by MMPs is more pervasive than previously reported and includes CCN3 (Nov) and CCN5 (WISP2). CCN5 is a novel antiangiogenic factor, whose function is abrogated by proangiogenic MMP cleavage. By processing CCN proteins, MMPs regulate cell responses angiogenesis in connective tissues. PMID- 27471097 TI - Lung diaphragm tracking in CBCT images using spatio-temporal MRF. AB - In EBRT in order to monitor the intra fraction motion of thoracic and abdominal tumors, one of the standard approaches is to use the lung diaphragm apex as an internal marker. However, tracking the position of the apex from image based observations is a challenging problem, as it undergoes both position and shape variation. The purpose of this paper is to propose an alternative method for tracking the ipsi-lateral hemidiaphragm apex (IHDA) position on Cone Beam Computed Tomography (CBCT) projection images. A hierarchical method is proposed to track the IHDA position across the frames. The diaphragm state is modeled as a spatio-temporal Markov Random Field (MRF). The likelihood function is derived from the votes based on 4D-Hough space. The optimal state of the diaphragm is obtained by solving the associated energy minimization problem using graph-cuts. A heterogeneous GPU implementation is provided for the method using CUDA framework and the performance is compared with that of CPU implementation. The method was tested using 15 clinical CBCT images. The results demonstrate that the MRF formulation outperforms the full search method in terms of accuracy. The GPU based heterogeneous implementation of the proposed algorithm takes about 25s, which is 16% improvement over the existing benchmark. The proposed MRF formulation considers all the possible combinations from the 4D-Hough space and therefore results in better tracking accuracy. The GPU based implementation exploits the inherent parallelism in our algorithm to accelerate the performance thereby increasing the viability of the approach for clinical use. PMID- 27471096 TI - Simultaneous acute shoulder arthritis and multiple mononeuropathy in a newly diagnosed type 2 diabetes patient - First case report. AB - Diabetes is a common disorder that leads to the musculoskeletal symptoms such as the shoulder arthritis. The involvement of peripheral nervous system is one of the troublesome for the patients as it provokes chronic sensory symptoms, lower motor neuron involvement and autonomic symptoms. In the course of the disease there has been several types of neuropathies described. A 41-year-old male patient was admitted to the internal medicine department because of the general weakness, malaise, polydypsia and polyuria since several days. The initial blood glucose level was 780mg/dl. During the first day the continuous insulin infusion was administered. On the next day when he woke up, the severe pain in the right shoulder with limited movement, right upper extremity weakness and burning pain in the radial aspect of this extremity appeared. On examination right shoulder joint movement limitation was found with the muscle weakness and sensory symptoms in the upper limbs. The clinical picture indicated on the right shoulder arthritis and the peripheral nervous system symptoms such as the right musculocutaneous, supraspinatus, right radial nerve and left radial nerve damage. We present a first case report of simultaneous, acute involvement of the shoulder joint and multiple neuropathy in a patient with newly diagnosed type 2 diabetes, presumably in the state of ketoacidosis. PMID- 27471098 TI - Mutation in JPH2 cause dilated cardiomyopathy. PMID- 27471099 TI - Analysis of risk factors for elbow dysplasia in giant breed dogs. AB - OBJECTIVE: Identify radiographic risk factors for development of elbow dysplasia in giant breed dogs less than one year of age. METHODS: Twenty-five giant breed puppies (Bernese Mountain dogs, English Mastiff, and Newfoundland) were studied. Both elbows of each dog were radiographed monthly from two to six months of age, then every other month until radial and ulnar physeal closure, followed two months later by bilateral elbow computed tomography. Radiographic parameters measured included the presence or absence of a separate centre of ossification of the anconeal process (SCOAP), medial coronoid disease (MCD), ununited anconeal process, humeral osteochondrosis, elbow incongruity, as well as the length of the radius and ulna, radius-to-ulna ratio, and date of closure of the radial and ulnar physes. RESULTS: Fifteen dogs completed the study. Two Bernese Mountain dogs were diagnosed with MCD. Risk factors significantly associated with medial coronoid disease included dyssynchronous physeal closure and a decreased radius to-ulna ratio, both detected between eight to 11 months of age. A separate centre of ossification of the anconeal process was present in 60% of the dogs, and was not a risk factor for development of elbow dysplasia. CLINICAL SIGNIFICANCE: Transient, dyssynchronous growth of the radius and ulna may be a risk factor for development of MCD in Bernese Mountain dogs. Dyssynchronous physeal closure or decreased radius-to-ulna ratio prior to radiographic closure of the distal ulnar and radial physes warrants further study in Bernese Mountain dogs and other breeds subject to MCD development. PMID- 27471100 TI - Interactive training system for interventional electrocardiology procedures. AB - Recent progress in cardiac catheterization and devices has allowed the development of new therapies for severe cardiac diseases like arrhythmias and heart failure. The skills required for such interventions are very challenging to learn, and are typically acquired over several years. Virtual reality simulators may reduce this burden by allowing trainees to practice such procedures without risk to patients. In this paper, we propose the first training system dedicated to cardiac electrophysiology, including pacing and ablation procedures. Our framework involves the simulation of a catheter navigation that reproduces issues intrinsic to intra-cardiac catheterization, and a graphics processing unit (GPU) based electrophysiological model. A multithreading approach is proposed to compute both physical simulations (navigation and electrophysiology) asynchronously. With this method, we reach computational performances that account for user interactions in real-time. Based on a scenario of cardiac arrhythmia, we demonstrate the ability of the user-guided simulator to navigate inside vessels and cardiac cavities with a catheter and to reproduce an ablation procedure involving: extra-cellular potential measurements, endocardial surface reconstruction, electrophysiology mapping, radio-frequency (RF) ablation, as well as electrical stimulation. A clinical evaluation assessing the different aspects of the simulation is presented. This works is a step towards computerized medical learning curriculum. PMID- 27471101 TI - Mechanism of artemisinin resistance for malaria PfATP6 L263 mutations and discovering potential antimalarials: An integrated computational approach. AB - Artemisinin resistance in Plasmodium falciparum threatens global efforts in the elimination or eradication of malaria. Several studies have associated mutations in the PfATP6 gene in conjunction with artemisinin resistance, but the underlying molecular mechanism of the resistance remains unexplored. Associated mutations act as a biomarker to measure the artemisinin efficacy. In the proposed work, we have analyzed the binding affinity and efficacy between PfATP6 and artemisinin in the presence of L263D, L263E and L263K mutations. Furthermore, we performed virtual screening to identify potential compounds to inhibit the PfATP6 mutant proteins. In this study, we observed that artemisinin binding affinity with PfATP6 gets affected by L263D, L263E and L263K mutations. This in silico elucidation of artemisinin resistance enhanced the identification of novel compounds (CID: 10595058 and 10625452) which showed good binding affinity and efficacy with L263D, L263E and L263K mutant proteins in molecular docking and molecular dynamics simulations studies. Owing to the high propensity of the parasite to drug resistance the need for new antimalarial drugs will persist until the malarial parasites are eventually eradicated. The two compounds identified in this study can be tested in in vitro and in vivo experiments as possible candidates for the designing of new potential antimalarial drugs. PMID- 27471102 TI - Hearing, feeling or seeing a beat recruits a supramodal network in the auditory dorsal stream. AB - Hearing a beat recruits a wide neural network that involves the auditory cortex and motor planning regions. Perceiving a beat can potentially be achieved via vision or even touch, but it is currently not clear whether a common neural network underlies beat processing. Here, we used functional magnetic resonance imaging (fMRI) to test to what extent the neural network involved in beat processing is supramodal, that is, is the same in the different sensory modalities. Brain activity changes in 27 healthy volunteers were monitored while they were attending to the same rhythmic sequences (with and without a beat) in audition, vision and the vibrotactile modality. We found a common neural network for beat detection in the three modalities that involved parts of the auditory dorsal pathway. Within this network, only the putamen and the supplementary motor area (SMA) showed specificity to the beat, while the brain activity in the putamen covariated with the beat detection speed. These results highlighted the implication of the auditory dorsal stream in beat detection, confirmed the important role played by the putamen in beat detection and indicated that the neural network for beat detection is mostly supramodal. This constitutes a new example of convergence of the same functional attributes into one centralized representation in the brain. PMID- 27471103 TI - Readily Accessible and Predictable Naphthalene-Based Two-Photon Fluorophore with Full Visible-Color Coverage. AB - Herein we report 22 acedan-derived, two-photon fluorophores with synthetic feasibility and full coverage of visible wavelength emission. The emission wavelengths were predicted by computational analysis, which enabled us to visualize multicolor images by two-photon excitation with single wavelength, and to design a turn-on, two-photon fluorescence sensor for endogenous H2 O2 in Raw 264.7 macrophage and rat brain hippocampus ex vivo. PMID- 27471104 TI - First-Stage Development and Validation of a Web-Based Automated Dietary Modeling Tool: Using Constraint Optimization Techniques to Streamline Food Group and Macronutrient Focused Dietary Prescriptions for Clinical Trials. AB - BACKGROUND: Standardizing the background diet of participants during a dietary randomized controlled trial is vital to trial outcomes. For this process, dietary modeling based on food groups and their target servings is employed via a dietary prescription before an intervention, often using a manual process. Partial automation has employed the use of linear programming. Validity of the modeling approach is critical to allow trial outcomes to be translated to practice. OBJECTIVE: This paper describes the first-stage development of a tool to automatically perform dietary modeling using food group and macronutrient requirements as a test case. The Dietary Modeling Tool (DMT) was then compared with existing approaches to dietary modeling (manual and partially automated), which were previously available to dietitians working within a dietary intervention trial. METHODS: Constraint optimization techniques were implemented to determine whether nonlinear constraints are best suited to the development of the automated dietary modeling tool using food composition and food consumption data. Dietary models were produced and compared with a manual Microsoft Excel calculator, a partially automated Excel Solver approach, and the automated DMT that was developed. RESULTS: The web-based DMT was produced using nonlinear constraint optimization, incorporating estimated energy requirement calculations, nutrition guidance systems, and the flexibility to amend food group targets for individuals. Percentage differences between modeling tools revealed similar results for the macronutrients. Polyunsaturated fatty acids and monounsaturated fatty acids showed greater variation between tools (practically equating to a 2 teaspoon difference), although it was not considered clinically significant when the whole diet, as opposed to targeted nutrients or energy requirements, were being addressed. CONCLUSIONS: Automated modeling tools can streamline the modeling process for dietary intervention trials ensuring consistency of the background diets, although appropriate constraints must be used in their development to achieve desired results. The DMT was found to be a valid automated tool producing similar results to tools with less automation. The results of this study suggest interchangeability of the modeling approaches used, although implementation should reflect the requirements of the dietary intervention trial in which it is used. PMID- 27471106 TI - Electronic absorption spectra of imidazolium-based ionic liquids studied by far ultraviolet spectroscopy and quantum chemical calculations. AB - Electronic absorption spectra of imidazolium-based ionic liquids were studied by far- and deep-ultraviolet spectroscopy and quantum chemical calculations. The absorption spectra in the 145-300 nm region of imidazolium-based ionic liquids, [Cnmim](+)[BF4](-) (n = 2, 4, 8) and [C4mim](+)[PF6](-), were recorded using our original attenuated total reflectance (ATR) system spectrometer. The obtained spectra had two definitive peaks at ~160 and ~210 nm. Depending on the number of carbon atoms in the alkyl side chain, the peak wavelength around 160 nm changed, while that around 210 nm remained at almost the same wavelength. Quantum chemical calculation results based on the time-dependent density functional theory (TD DFT) also showed the corresponding peak shifts. In contrast, there was almost no significant difference between [C4mim](+)[BF4](-) and [C4mim](+)[PF6](-), which corresponded with our calculations. Therefore, it can be concluded that the absorption spectra in the 145-300 nm region are mainly determined by the cations when fluorine-containing anions are adopted. In addition, upon addition of organic solvent (acetonitrile) to [C4mim](+)[BF4](-), small peak shifts to the longer wavelength were revealed for both peaks at ~160 and ~210 nm. The peak shift in the deep-ultraviolet region (<=200 nm) in the presence of the solvent, which indicates the change of electronic states of the ionic liquid, was experimentally observed for the first time by using the ATR spectrometer. PMID- 27471105 TI - Circulating microRNAs in cancer: Hope or hype? AB - Circulating miRNAs are a novel class of stable, minimally invasive disease biomarkers that are considered to be valuable in diagnosis, prognosis and treatment response monitoring. Unlike intracellular miRNAs, circulating miRNAs are released from their producer cells and, based on their targeted functions, they may shuttle in and out of circulation. Their discovery has opened up new avenues for clinical realms and led to a quest for targeted biomarkers. Subsequently, as more cell-free miRNAs are being discovered, their expression is expected to provide precise information regarding disease progression and treatment outcomes, thereby fostering personalized therapeutic strategies. The significance of circulating miRNAs capitalizes on the fact that they are highly stable in body fluids and their expression levels can be detected by common techniques such as qPCR and microarray. However, discrepancies have started to emerge in terms of their reliability and their response under physiological and pathological conditions. Functional studies are still pending, which may determine whether circulating miRNAs play a role as a central component or just as an auxiliary tuner. Also, the distinct clinical signatures that they display have never been subjected to an extensive critical review and experimental validation. As a consequence, the applicability of circulating miRNAs remains a matter of deliberation, despite many intriguing perspectives about their competency. In this review, we highlight some ambiguous issues with the application of circulating miRNAs, which may warrant an immediate consideration. We propose that the circulating miRNA domain needs to be reevaluated to authenticate their specific role and to probe whether they actually carry any clinical weightage. PMID- 27471107 TI - Dynamic O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography differentiates brain metastasis recurrence from radiation injury after radiotherapy. AB - Background: The aim of this study was to investigate the potential of dynamic O (2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation injury after radiotherapy since contrast-enhanced MRI often remains inconclusive. Methods: Sixty-two patients (mean age, 55 +/- 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of 18F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test. Results: TBRs were significantly higher in recurrent metastases (n = 36) than in radiation injuries (n = 40) (TBRmax 3.3 +/- 1.0 vs 2.2 +/- 0.4, P < .001; TBRmean 2.2 +/- 0.4 vs 1.7 +/- 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001). Conclusions: The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of 18F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from radiation-induced changes with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases. PMID- 27471109 TI - Self-assessment, reflection on practice and critical thinking in nursing students. AB - In accordance with the principles of the European Higher Education Area, the aim of this study was to contribute to the implementation of self-assessment through the application of reflection on learning and critical thinking. The theoretical framework employed was Habermas's critical theory and emancipatory interest as a preliminary step to generate educational transformations. The methodological contribution is the design a student self-assessment document that promotes reflection on action and critical thinking. RESULTS AND DISCUSSION: The development of assessment through peer evaluation and other intermediate solutions until achieving self-assessment entails a shift in the educational and scientific paradigm, but also involves the implementation in practice of democratic and ethical principles, values and premises in society. Self assessment is a novel concept for students, and obliges them to reinterpret their role. Due to the diversity of students' principles, values, motivations, interests and aspirations, this reinterpretation of their role can have a positive outcome, stimulating an active and critical attitude towards group work and self-assessment; or, on the contrary, can generate a stance characterised by disinterest, passivity and lack of critical thinking. CONCLUSIONS: The forms of assessment adopted in a given educational system reflect ways of thinking related to ideologies, values, ethical principles and educational paradigms: in order to render implementation of effective self-assessment feasible, it is necessary to undertake structural and regulatory reforms. Students have little experience of reflection on practice or critical thinking. Massification and cultural and structural factors determine the form of assessment. In this context, it would seem advisable to move towards self-assessment gradually and cautiously. PMID- 27471108 TI - miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas. AB - BACKGROUND: Gliomas are based on a genetic abnormality and present with a dismal prognosis. MicroRNAs (miRNAs) are considered to be important mediators of gene expression in glioma tissues. METHODS: Real-time PCR was used to analyze the expression of microRNA-423-5p (miR-423-5p) in human glioma samples and normal brain tissue. Apoptosis, cell cycle, proliferation, immunostaining, transwell, in vitro 2D and 3D migration, and chemosensitivity assays were performed to assess the phenotypic changes in glioma cells overexpressing miRNA-423-5p. Western blotting was used to determine the expression of inhibitor of growth 4 (ING-4)in glioma tissues, and a luciferase reporter assay was conducted to confirm whether ING-4 is a direct target of miR-423-5p. Western blotting was used to identify the potential signaling pathways that are affected in glioma cell growth by miR-423 5p. Xenograft tumors were examined in vivo for the carcinogenic effects of miR 423-5p in glioma tissues. RESULTS: We first reported that miR-423-5p expression was increased in gliomas and was a potential tumor promoter via targeting ING-4. The overexpression of miR-423-5p resulted in upregulation of important signaling molecules such as p-AKT and p-ERK1/2. In clinical samples, miR-423-5p was dysregulated, and a corresponding alteration in ING-4 expression was observed (P = .0207). Furthermore, the overexpression of miR-423-5p strengthened glioma cell proliferation, angiogenesis, and invasion. Finally, miR-423-5p overexpression also strengthened GBM neurosphere formation and rendered glioma cells resistant to temozolomide (TMZ). CONCLUSION: This study establishes that miR-423-5p functions as an oncogene in glioma tissues by suppressing ING-4 and suggests that it has therapeutic potential for glioma. PMID- 27471110 TI - Chronic Repression of mTOR Complex 2 Induces Changes in the Gut Microbiota of Diet-induced Obese Mice. AB - Alterations in the gut microbiota play a crucial role in host physiology and metabolism; however, the molecular pathways underlying these changes in diet induced obesity are unclear. Mechanistic target of rapamycin (mTOR) signaling pathway is associated with metabolic disorders such as obesity and type 2 diabetes (T2D). Therefore, we examined whether changes in the regulation of mTOR signaling induced by diet (a high-fat diet [HFD] or normal-chow diet) and/or therapeutics (resveratrol [a specific inhibitor of mTOR complex 1] or rapamycin [an inhibitor of both mTOR complex 1 and 2]) altered the composition of the gut microbiota in mice. Oral administration of resveratrol prevented glucose intolerance and fat accumulation in HFD-fed mice, whereas rapamycin significantly impaired glucose tolerance and exacerbated intestinal inflammation. The abundance of Lactococcus, Clostridium XI, Oscillibacter, and Hydrogenoanaerobacterium increased under the HFD condition; however, the abundance of these species declined after resveratrol treatment. Conversely, the abundance of unclassified Marinilabiliaceae and Turicibacter decreased in response to a HFD or rapamycin. Taken together, these results demonstrated that changes in the composition of intestinal microbiota induced by changes in mTOR activity correlate with obese and diabetic phenotypes. PMID- 27471111 TI - FCTC followed by accelerated implementation of tobacco advertising bans. AB - OBJECTIVES: We sought to evaluate changes in countries' enacting advertising bans after the effect of ratifying the WHO Framework Convention on Tobacco Control (FCTC). METHODS: We compared adoption of advertising bans on five areas (TV and radio, print media, billboards, point-of-sale, sponsorship) in countries that did versus did not ratify the FCTC, accounting for years since the ratification of the Convention. RESULTS: On average, passage of complete advertising bans accelerated after FCTC ratification. The development was strongest among lower middle-income countries. Lack of state capacity was associated with lower likelihood of countries implementing complete advertising bans. Implementation of complete advertising bans slowed after 2007. CONCLUSIONS: Implementation of FCTC Article 13 was followed by increased progress towards complete advertising bans, but progress is incomplete, especially among low-income countries. Low-income countries need comprehensive support to implement FCTC as part of a broad effort to reinvigorate progress on global implementation of the FCTC. Enforcing complete bans requires constant monitoring and attacking of tobacco industry efforts to circumvent them. PMID- 27471113 TI - Surgical Lung Biopsy for Interstitial Lung Diseases. AB - This review addresses common questions regarding the role of surgical lung biopsy (SLB) in the diagnosis and treatment of interstitial lung disease (ILD). We specifically address when a SLB can be diagnostic as well as when it may be avoided; for example, when the combination of the clinical context and the imaging pattern seen on high-resolution CT (HRCT) chest scans can provide a confident diagnosis. Existing studies on the diagnostic utility as well as the complications associated with SLB are reviewed; also reviewed are the performance characteristics and reliability of HRCT scans of the chest in predicting the underlying histopathologic findings of the lung. The review is formatted in the form of answers to questions that clinicians regularly ask when considering an SLB in a patient with ILD. PMID- 27471112 TI - Acute stroke therapy: A review. AB - This review summarizes the modern early diagnosis and acute phase treatment of acute stroke. The guidelines for treatment of acute ischemic stroke underwent major changes in 2015 and endovascular therapy (catheter-based mechanical thrombectomy with a stent retriever) became the class IA indication for patients presenting within less than 6h from symptom onset who have proven occlusion of large intracerebral artery in anterior circulation. Acute stroke care organization should enable to perform effective revascularization therapy as soon as possible after the initial brain imaging whenever this examination provides indication for the procedure. PMID- 27471114 TI - Trends in Medicare Service Volume for Cataract Surgery and the Impact of the Medicare Physician Fee Schedule. AB - OBJECTIVE: To calculate the associations between Medicare payment and service volume for complex and noncomplex cataract surgeries. DATA SOURCES: The 2005-2009 CMS Part B National Summary Data Files, CMS Part B Carrier Summary Data Files, and the Medicare Physician Fee Schedule. STUDY DESIGN: Conducting a retrospective, longitudinal analysis using a fixed-effects model of Medicare Part B carriers representing all 50 states and the District of Columbia from 2005 to 2009, we calculated the Medicare payment-service volume elasticities for noncomplex (CPT 66984) and complex (CPT 66982) cataract surgeries. DATA EXTRACTION: Service volume data were extracted from the CMS Part B National Summary and Carrier Summary Data Files. Payment data were extracted from the Medicare Physician Fee Schedule. PRINCIPAL FINDINGS: From 2005 to 2009, the proportion of total cataract services billed as complex increased from 3.2 to 6.7 percent. Every 1 percent decrease in Medicare payment was associated with a nonsignificant change in noncomplex cataract service volume (elasticity = 0.15, 95 percent CI [-0.09, 0.38]) but a statistically significant increase in complex cataract service volume (elasticity = -1.12, 95 percent CI [-1.60, -0.63]). CONCLUSIONS: Reduced Medicare payment was associated with a significant increase in complex cataract service volume but not in noncomplex cataract service volume, resulting in a shift toward performing a greater proportion of complex cataract surgeries from 2005 to 2009. PMID- 27471115 TI - AdipoScan: A Novel Transient Elastography-Based Tool Used to Non-Invasively Assess Subcutaneous Adipose Tissue Shear Wave Speed in Obesity. AB - We describe a novel device called the AdipoScan that was adapted from the FibroScan to specifically assess shear wave speed (SWS) in human abdominal subcutaneous adipose tissue (scAT). Measurement reproducibility was assessed on tissue-mimicking phantoms with and without repositioning, with resultant coefficients of variation of 1% and 0%, respectively, as well as in vivo (14% and 7%, respectively). The applicability of the AdipoScan was tested on 19 non-obese volunteers, and a scAT thickness >2 cm was found to be mandatory to perform a valid measurement. Abdominal scAT SWS was assessed in 73 severely obese subjects, all candidates for bariatric surgery. Subcutaneous AT SWS was positively associated with scAT fibrosis and obesity-related co-morbidities such as hypertension, glycemic status, dyslipidemia and liver dysfunction. These results suggest that the AdipoScan could be a useful non-invasive tool to evaluate scAT fibrosis and metabolic complications in obesity. Further investigation is required to evaluate the relevance of using the AdipoScan to predict patient weight trajectories and metabolic outcomes after bariatric surgery. PMID- 27471116 TI - Intra-Operative Vector Flow Imaging Using Ultrasound of the Ascending Aorta among 40 Patients with Normal, Stenotic and Replaced Aortic Valves. AB - Stenosis of the aortic valve gives rise to more complex blood flows with increased velocities. The angle-independent vector flow ultrasound technique transverse oscillation was employed intra-operatively on the ascending aorta of (I) 20 patients with a healthy aortic valve and 20 patients with aortic stenosis before (IIa) and after (IIb) valve replacement. The results indicate that aortic stenosis increased flow complexity (p < 0.0001), induced systolic backflow (p < 0.003) and reduced systolic jet width (p < 0.0001). After valve replacement, the systolic backflow and jet width were normalized (p < 0.52 and p < 0.22), but flow complexity was not (p < 0.0001). Flow complexity (p < 0.0001), systolic jet width (p < 0.0001) and systolic backflow (p < 0.001) were associated with peak systolic velocity. The study found that aortic stenosis changes blood flow in the ascending aorta and valve replacement corrects some of these changes. Transverse oscillation may be useful for assessment of aortic stenosis and optimization of valve surgery. PMID- 27471117 TI - Ultrasound-Guided Percutaneous Tenotomy of Biceps Tendon: Technical Feasibility on Cadavers. AB - We tested the technical feasibility of ultrasound-guided percutaneous tenotomy of the long head of the biceps tendon (LHBT) in cadavers. Both shoulders of two fresh cadavers were scanned anteriorly to evaluate the extra-articular portion of the LHBT. Under ultrasound monitoring, a scalpel was advanced obliquely up to touch the superficial medial side of the LHBT, cutting it until the tendon was not visible anymore. Ultrasound evaluation was repeated after the procedure, and anatomic dissection was performed. The procedure was 100% feasible: four cuts were made to completely sever the tendon; the duration was less than 1 min. Skin incision measured 5 mm in two cases and 6 mm in two cases. Anatomic dissection confirmed complete tendon cut in all cases with proximal and distal tendon stumps very close to each other. Ultrasound-guided percutaneous LHBT tenotomy was 100% technically feasible in cadavers with a quick procedure and minimal cutaneous incision. PMID- 27471118 TI - Anisotropic Properties of Breast Tissue Measured by Acoustic Radiation Force Impulse Quantification. AB - The goal of our study was to investigate the anisotropy of normal breast glandular and fatty tissue with acoustic radiation force impulse (ARFI) quantification. A total of 137 breasts in 137 women were enrolled. These breasts were divided into the duct-apparent group and the duct-inapparent group, divided into the ligament-apparent group and the ligament-inapparent group. Shear wave velocity (SWV) in the radial (SWV(r)) and anti-radial (SWV(a-r)) directions was measured. The elastic anisotropy of glandular tissue and fatty tissue was evaluated as the ratio between SWV(r) and SWV(a-r). The SWV ratio was 1.30 +/- 0.45 for glandular tissue and 1.27 +/- 0.53 for fatty tissue in the total group. In glandular tissue, the SWV ratio of the duct-apparent group was higher than that of the duct-inapparent group (p = 0.011). In both glandular and fatty tissue, the SWV ratio was higher in the ligament-apparent group than in the ligament-inapparent group (p < 0.05 for both). SWV(r) was higher than SWV(a-r) in both glandular tissue and fatty tissue in all groups (p < 0.05 for all) except in breast fatty tissue in the ligament-inapparent group (p = 0.913). It is concluded that both breast glandular tissue and fatty tissue exhibited anisotropy of elastic behavior. To improve the diagnostic power of elastography in breast lesions, the elastic anisotropy of glandular tissue and fatty tissue should be taken into account in calculating strain ratio or elasticity ratio. PMID- 27471119 TI - Feasibility Study of Ultrasonographic Criteria for Microscopic and Macroscopic Extra-Thyroidal Extension Based on Thyroid Capsular Continuity and Tumor Contour in Patients with Papillary Thyroid Carcinomas. AB - Our purpose was to evaluate the feasibility of using ultrasonographic criteria of thyroid capsular continuity and tumor contour to differentiate macroscopic extra thyroidal extension (ETE) from microscopic ETE, as well as non-ETE from ETE. On ultrasonography, we evaluated thyroid capsular continuity (C0 = continuous, C1 = discontinuous, C2 = invisible), and thyroid tumor contour (P0 = in normal parenchyma, P1 = abutting, P2 = bulging), which were grouped into type 1-9 classifications. Either C1-2 or P1-2 was more prevalent in ETE than non-ETE. C1 and P2 tended to be associated with macroscopic ETE, whereas C0 and P1 were significantly associated with microscopic ETE. Types 6, 8 and 9 were more likely to have ETE than non-ETE; type 6 (C1 P2) and type 9 (C2 P2) were significantly associated with macroscopic ETE, whereas type 8 (C2 P1) was associated more with microscopic ETE. Macroscopic and microscopic ETE, as well as non-ETE and ETE, can be differentiated using these pre-operative ultrasonographic criteria. PMID- 27471120 TI - Influence of Skin and Subcutaneous Tissue on High-Intensity Focused Ultrasound Beam: Experimental Quantification and Numerical Modeling. AB - High-intensity focused ultrasound (HIFU) enables the non-invasive thermal ablation of tumors. However, numerical simulations of the treatment remain complex and difficult to validate in clinically relevant situations. In this context, needle hydrophone measurements of the acoustic field downstream of seven rabbit tissue layers comprising skin, subcutaneous fat and muscle were performed in different geometrical configurations. Increasing curvature and thickness of the sample were found to decrease the focusing of the beam: typically, a curvature of 0.05 mm(-1) decreased the maximum pressure by 45% and doubled the focal area. A numerical model based on k-Wave Toolbox was found to be in very good agreement with the reported measurements. It was used to extrapolate the effect of the superficial tissues on peak positive and peak negative pressure at focus, which affects both cavitation and target heating. The shape of the interface was found to have a strong influence on the values, and it is therefore an important parameter to monitor or to control in the clinical practice. This also highlights the importance of modeling realistic configurations when designing treatment procedures. PMID- 27471121 TI - Method to evaluate the quality of herbal medicines based on the dynamic changes of chemical compounds and pharmacological activity. AB - Quality control has been one of the key scientific issues in the modernization of traditional Chinese medicine. This study explored a novel method for quality evaluation of herbal medicines. High-performance liquid chromatography fingerprints and the osteoblast proliferation activity of 18 batches of Achyranthes bidentata, which were prepared with salt, were determined to establish a chromatographic database and an activity database. Correlation analyses of these databases were performed using partial least squares to obtain regression coefficients (positive and negative correlation coefficients). Then, the sums of the products of the positive and negative correlation peak areas and the corresponding coefficients, respectively, were calculated for each sample. The absolute value of the ratios of the sums of the positive and negative products were calculated, our studies showed that this ratio was significantly correlated with the proliferation activity, particularly when the activity was in the best and worst ranges. Therefore, we developed a parameter that was used to evaluate the quality of samples osteoblast proliferation activity. The quality of another ten batches of samples was assessed to verify this method. The results indicated that this method can be used for quality evaluation of herbal medicines according to the dynamic changes in the chemical compounds and activity. PMID- 27471122 TI - Upregulation of Transient Receptor Potential Canonical Channels Contributes to Endotoxin-Induced Pulmonary Arterial Stenosis. AB - BACKGROUND Septic shock is a pathologic condition caused by endotoxin-producing bacteria, and often associated with severe pulmonary hypertension. Inflammation is a major systemic response to endotoxin; however, it is unknown whether endotoxin has a direct impact on pulmonary arteries that contributes to pathogenesis of pulmonary hypertension. MATERIAL AND METHODS Rat pulmonary arteries and primary pulmonary arterial smooth muscle cells (PASMCs) were cultured in vitro and treated with lipopolysaccharide (LPS) and blockers of transient receptor potential canonical (TRPC) channels. Neointimal growth and arterial stenosis were observed on cryosections of cultured pulmonary arteries. Proliferation of PASMCs was examined by a WST-1 (water-soluble tetrazolium salt) assay. Expression of TRPC genes in pulmonary arteries and PASMCs were detected and quantified by real-time polymerase chain reaction and Western blotting. RESULTS LPS significantly induced neointimal growth and stenosis of pulmonary arteries and promoted proliferation of PASMCs. TRPC channel blockers 2 aminoethoxydiphenyl borate and SKF-96365 inhibited LPS-induced remodeling of pulmonary arteries and PASMC proliferation. Expression of TRPC1/3/4/6 was detected in pulmonary arteries and PASMCs. LPS treatment dramatically increased the expression of TRPC3 and TRPC4 at both messenger RNA and protein levels. CONCLUSIONS LPS stimulates stenosis of pulmonary arteries through enhancement of TRPC-mediated Ca2+ entry into PASMCs, which is caused by upregulation of TRPC3 and TRPC4 channels. PMID- 27471123 TI - Next-generation studies of microbial biofilm communities. AB - As we look into the future of microbial biofilm research, there is clearly an emerging focus on communities rather than populations. This represents an essential change in direction to more accurately understand how and why microorganisms assemble into communities, as well as the functional implications for such a life style. For example, current research studies shows that communities display emergent properties or functions that are not predicted from the individual single species populations, including elevated stress tolerance and resistance to antibiotics. Models for mixed species biofilms can be very simple, comprised only a handful of species or can be extremely species rich, with hundreds or thousands of species present. The future holds much promise for this area of research, where investigators will increasingly be able to resolve, at the molecular and biochemical levels, interspecies relationships and mechanisms of interaction. The outcome of these studies will greatly enhance our understanding of the ecological and evolutionary factors that drive community function in natural and engineered systems. PMID- 27471124 TI - Second malignancies in hydroxyurea and interferon-treated Philadelphia-negative myeloproliferative neoplasms. AB - OBJECTIVE: In an era of controversy in regard to 'hydroxyurea-leukaemogenicity' and when interferon-alfa2 (IFN) is being revived in the treatment of Philadelphia negative myeloproliferative neoplasms (MPNs), we aim in this single-centre observational study to describe the frequencies of second malignancies in a cohort of MPN patients treated with hydroxyurea (HU) or IFN monotherapy or the combination of these agents. PATIENTS AND METHODS: Records of a MPN cohort of 196 patients were reviewed, and a retrospective analysis was performed on 90 patients treated with HU, 38 patients treated with IFN and 68 patients treated with both IFN and HU. Logistic regression was used to compare frequencies in second malignancies. RESULTS: Patients treated with HU had a significantly higher risk of developing all second malignancies compared with patients treated with IFN [HU vs. IFN: OR of 4.01 (95%CI: 1.12-14.27, P-value: 0.023) and HU-IFN vs. IFN: OR 5.58 (95%CI: 1.55-20.15, P-value: 0.004)]. CONCLUSION: We have found an increased risk of second malignancies in MPN patients treated with HU compared with patients treated with IFN. PMID- 27471125 TI - Effects of hydrogen peroxide mouthwash on preventing ventilator-associated pneumonia in patients admitted to the intensive care unit. AB - AIMS: The aim of the study was to determine the effect of hydrogen peroxide (HP) mouthwash on the incidence of ventilator associated pneumonia (VAP) in patients admitted to the intensive care unit (ICU). METHODS: This was a randomized clinical trial conducted on 68 patients. The intervention group used 3% HP as mouthwash and the control group used mouthwashes with 0.9% normal saline (NS) twice a day. Data were collected using a questionnaire and the Modified Clinical Pulmonary Infection Score (MCPIS). MCPIS includes five items, body temperature: white blood cell count, pulmonary secretions, the ratio of pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2), and the chest X-ray. Each of these items scored 0-2. Scores >=6 were considered as VAP signs. The SPSS-20 software was employed to analyze the data. RESULTS: In total, 14.7% patients of the HP group and 38.2% patients of the NS group contracted VAP. The risk of VAP in the NS group was 2.60 times greater than that in the HP group (RR=2.60, 95% CI: 1.04-6.49, p=0.0279). The mean+/-SD MCPIS was calculated as 3.91+/-1.35 in the HP group and 4.65+/-1.55 in the NS group, a difference statistically significant (p=0.042). There were no significant differences in the risk factors for VAP between the two groups. CONCLUSION: HP mouthwash was found more effective than NS in reducing VAP. HP mouthwash can therefore be used in routine nursing care for reducing VAP. PMID- 27471126 TI - Adherence to antiretroviral therapy of Brazilian HIV-infected children and their caregivers. AB - BACKGROUND: Successful treatment of HIV-positive children requires a high level of adherence (at least 95%) to highly active antiretroviral therapy. Adherence is influenced by factors related to the child and caregivers. OBJECTIVES: To evaluate children and caregivers characteristics associated to children's adherence. METHODS: Cross-sectional study, from September 2013 to June 2015, comprising a sample of caregivers of perinatally HIV-infected children, in the age group of 1-12 years, under antiretroviral therapy for at least 6 months and on follow-up in two AIDS reference centers in Salvador, Bahia. Caregiver self reports were the sole source of 4 days adherence and sociodemographic information. Study participants who reported an intake >95% of prescribed medication were considered adherents. A variable, ("Composed Adherence"), was created to better evaluate adherence. RESULTS: We included 77 children and their caregivers. 88.3% of the caregivers were female, the median age was 38.0 years (IQR 33.5-47.5), 48.1% were white or mixed, 72.7% lived in Salvador and 53.2% had no fixed income. The 4 days child's adherence was associated only to caregivers that received less than a minimum salary (p<0.05), 70.1% of the caregivers had less than four years of formal education, 81.8% were children's relative and 53.2% of the caregivers were HIV positive. The caregiver's pharmacy refill, long term adherence and 4 days adherence, were significantly associated with composed adherence (p<0.05). Child's long-term adherence was strongly associated to the 4 days child's adherence referred by caregiver (p<0.001). CONCLUSIONS: Our results suggest the need of improvement in HIV-infected children adherence, through reinforcement of the caregivers own adherence. PMID- 27471127 TI - Validation of clinical risk scores for laparoscopic liver resections of colorectal liver metastases: A 10-year observed follow-up study. AB - OBJECTIVE: The aim of this study was to validate clinical risk scores in patients underwent laparoscopic resection of colorectal liver metastases (CLM) with 5 years follow-up or more, and assess 5- and 10-year actual survival in this group. METHODS: A total of 516 laparoscopic liver resections were performed in 406 patients with CLM between February 1998 and September 2015. A follow-up of 5 and 10 years could be assessed in 144 and 29 patients, respectively. The Fong score, pre- and postoperative Basingstoke Predictive Index (BPI), Nordlinger score, and Iwatsuki score were validated. RESULTS: Five- and ten-year cancer-related actual survival was 54% and 32%, respectively. The Fong score, pre- and postoperative BPI and the Nordlinger score divided patients into risk groups with significant difference in survival between the groups. However, predicted 5-year survival rates were lower than the actual 5-year survival (mean difference in 17%,13%, 20%, and 30%, respectively). CONCLUSION: The Fong score, pre- and postoperative BPI and the Nordlinger score systems can be used to predict survival for laparoscopically operated patients in the era of multimodal-treatment after adjusting of survival rates. The actual five- and 10-year survival after laparoscopic resection of CLM is similar to results previously published for open liver resection. J. Surg. Oncol. 2016;114:757-763. (c) 2016 Wiley Periodicals, Inc. PMID- 27471128 TI - The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNA(Ile) A4263G mutation. AB - Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNA(Ile) A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca(2+) cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNA(Ile) A4263G mutation. The mitochondrial calcium ([Ca(2+)]m) in cells from hypertensive subjects with the tRNA(Ile) A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P<0.05). Meanwhile, cytosolic calcium ([Ca(2+)]c) in hypertensive with mutation cells was higher than another three groups. After exposure to caffeine, which could increase the [Ca(2+)]c by activating ryanodine receptor on endoplasmic reticulum, [Ca(2+)]c/[Ca(2+)]m increased higher than in hypertensive with mutation cells from another three groups. Moreover, MCU expression was decreased in hypertensive with mutation cells compared with in another three groups (P<0.05). [Ca(2+)]c increased and [Ca(2+)]m decreased after treatment with Ru360 (an inhibitor of MCU) or an siRNA against MCU. In this study we found decreased MCU expression in hypertensive with mutation cells contributed to dysregulated Ca(2+) uptake into the mitochondria, and cytoplasmic Ca(2+) overload. This abnormality might be involved in the underlying mechanisms of maternally inherited hypertension in subjects carrying the mitochondrial tRNA(Ile) A4263G mutation. PMID- 27471129 TI - A chapter a day: Association of book reading with longevity. AB - Although books can expose people to new people and places, whether books also have health benefits beyond other types of reading materials is not known. This study examined whether those who read books have a survival advantage over those who do not read books and over those who read other types of materials, and if so, whether cognition mediates this book reading effect. The cohort consisted of 3635 participants in the nationally representative Health and Retirement Study who provided information about their reading patterns at baseline. Cox proportional hazards models were based on survival information up to 12 years after baseline. A dose-response survival advantage was found for book reading by tertile (HRT2 = 0.83, p < 0.001, HRT3 = 0.77, p < 0.001), after adjusting for relevant covariates including age, sex, race, education, comorbidities, self rated health, wealth, marital status, and depression. Book reading contributed to a survival advantage that was significantly greater than that observed for reading newspapers or magazines (tT2 = 90.6, p < 0.001; tT3 = 67.9, p < 0.001). Compared to non-book readers, book readers had a 23-month survival advantage at the point of 80% survival in the unadjusted model. A survival advantage persisted after adjustment for all covariates (HR = .80, p < .01), indicating book readers experienced a 20% reduction in risk of mortality over the 12 years of follow up compared to non-book readers. Cognition mediated the book reading-survival advantage (p = 0.04). These findings suggest that the benefits of reading books include a longer life in which to read them. PMID- 27471130 TI - Do racial inequities in infant mortality correspond to variations in societal conditions? A study of state-level income inequality in the U.S., 1992-2007. AB - BACKGROUND: Prior studies have examined the association between income inequality and overall infant mortality rates (IMR). We examine effects of income inequality on racial inequities in IMR over the period 1992-2007 in the U.S. METHODS: Race specific state IMR data were obtained from 1992 to 2007, from which absolute and relative IMR inequities were calculated. Fixed and random effects models, adjusted for state-level median income, percent poverty, percent high school graduates, and unemployment rate, were used to determine contemporaneous and lagged state-level associations between income inequality and racial IMR inequities. RESULTS: Racial IMR inequities varied significantly across the U.S. Contemporaneous income inequality was negatively associated with white IMR only. Two-year lagged income inequality was negatively associated with black IMR and had the most pronounced effect on racial inequities in IMR. DISCUSSION: Future studies should consider lagged effects of income inequality on IMR and other health outcomes, and should examine other potential societal conditions that may account for state-level variations in racial IMR inequities. PMID- 27471131 TI - Healthy or unhealthy migrants? Identifying internal migration effects on mortality in Africa using health and demographic surveillance systems of the INDEPTH network. AB - Migration has been hypothesised to be selective on health but this healthy migrant hypothesis has generally been tested at destinations, and for only one type of flow, from deprived to better-off areas. The circulatory nature of migration is rarely accounted for. This study examines the relationship between different types of internal migration and adult mortality in Health and Demographic Surveillance System (HDSS) populations in West, East, and Southern Africa, and asks how the processes of selection, adaptation and propagation explain the migration-mortality relationship experienced in these contexts. The paper uses longitudinal data representing approximately 900 000 adults living in nine sub-Saharan African HDSS sites of the INDEPTH Network. Event History Analysis techniques are employed to examine the relationship between all-cause mortality and migration status, over periods ranging from 3 to 14 years for a total of nearly 4.5 million person-years. The study confirms the importance of migration in explaining variation in mortality, and the diversity of the migration-mortality relationship over a range of rural and urban local areas in the three African regions. The results confirm that the pattern of migration mortality relationship is not exclusively explained by selection but also by propagation and adaptation. Consequences for public health policy are drawn. PMID- 27471132 TI - The Utility of the C-MAC as a Direct Laryngoscope for Intubation in the Emergency Department. AB - BACKGROUND: Although the C-MAC (Karl Storz, Tuttlingen, Germany) is a video laryngoscope (VL), it can also be used as a direct laryngoscope (DL). OBJECTIVE: The goal of this study was to evaluate the utility of the C-MAC as a DL for intubations in the emergency department (ED). METHODS: This was an analysis of prospectively collected continuous quality-improvement data during the 6-year period from February 1, 2009 to January 31, 2015, when both the C-MAC and Macintosh DL (Mac DL) were clinically available in our ED. This analysis included adult patients who underwent rapid sequence intubation by an emergency medicine resident in the ED with a C-MAC initially used as a DL or a Mac DL. The primary outcome measure was the first pass success (FPS). RESULTS: When the C-MAC was used as a DL, the initial DL attempt was successful in 199 of 346 (57.6%) cases. When the attempt could not be completed using the C-MAC as a DL, the operator utilized the video monitor and successfully completed the intubation using VL in 104 of 134 (77.6%) cases, thus achieving an overall FPS of 303 of 346 (87.6%). When the Mac DL was used, the FPS was 505 of 671 (75.3%). CONCLUSIONS: The C-MAC is a useful device for DL because in the event of a failed DL attempt, operators have the option of switching to the video monitor to successfully complete the intubation using VL without having to make a second attempt. PMID- 27471133 TI - Metronidazole-Induced Encephalopathy in Alcoholic Liver Disease: A Diagnostic and Therapeutic Challenge. AB - BACKGROUND: Acute encephalopathy in a patient with alcoholic liver disease (ALD) is a commonly encountered emergency situation occurring most frequently due to liver failure precipitated by varying etiologies. Acute reversible cerebellar ataxia with confusion secondary to prolonged metronidazole use has been reported rarely as a cause of encephalopathy in patients with ALD. CASE REPORT: We describe a decompensated ALD patient with recurrent pyogenic cholangitis associated with hepatolithiasis who presented to the emergency department with sudden-onset cerebellar ataxia with dysarthria and mental confusion after prolonged use of metronidazole. Magnetic resonance imaging (MRI) of the brain was suggestive of bilateral dentate nuclei hyper intensities on T2 and fluid attenuated inversion recovery sections seen classically in metronidazole-induced encephalopathy (MIE). Decompensated liver cirrhosis resulted in decreased hepatic clearance and increased cerebrospinal fluid concentration of metronidazole leading to toxicity at a relatively low total cumulative dose of 22 g. Both the clinical symptoms and MRI brain changes were reversed at 7 days and 6 weeks, respectively, after discontinuation of metronidazole. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A patient with ALD presenting with encephalopathy creates a diagnostic dilemma for the emergency physician regarding whether to continue metronidazole and treat for hepatic encephalopathy or to suspect for MIE and withhold the drug. Failure to timely discontinue metronidazole may worsen the associated hepatic encephalopathy in these patients. Liver cirrhosis patients have higher mean concentration of metronidazole and its metabolite in the blood, making it necessary to keep the cumulative dose of metronidazole to < 20 g in them. PMID- 27471134 TI - The Balloon-Microcatheter technique for treatment of coronary artery perforations. AB - Coronary perforation (CP) is a rare but potentially lethal complication of percutaneous coronary intervention (PCI). Management of CP is mainly conditioned by the extension of coronary rupture and location of the perforation. Successful treatment is highly affected by the operator's familiarity with tools and dedicated techniques to achieve prompt sealing of the disruption. We describe a "Balloon-Microcatheter" technique that may allow fast, safe, and effective management of CP with a single >= 6 Fr guiding catheter. (c) 2016 Wiley Periodicals, Inc. PMID- 27471135 TI - Two dimensional layered Co0.85Se nanosheets as a high-capacity anode for lithium ion batteries. AB - In recent years, two-dimensional (2D) layered transitional metal chalcogenides (TMCs) have received much attention as promising electrode materials in energy storage. Although recent reports on 2D TMC nanostructures have demonstrated promising electrochemical performances, the major scientific challenge is to develop a viable synthesis process to produce layered structures of chalcogenides (Co, Ni or Fe based TMCs) as anode materials. In this work, we propose the synthesis of layered Co0.85Se nanosheets in a solution based method by using a 2D oriented attachment strategy. The as-prepared Co0.85Se nanosheets exhibit specific capacities as high as 675 mA h g(-1) at 100 mA g(-1). When the current densities were further increased to 200, 500 and 1000 mA g(-1), the reversible capacities can still reach up to 645, 574 and 493 mA h g(-1) with excellent cycling life of 95, 85 and 73%, respectively. Li-ion storage performance of layered Co0.85Se nanosheets is higher than that of Co0.85Se microspheres as well as cobalt sulfide. The superior electrochemical performance of Co0.85Se nanosheets is attributed to their 2D layered structure which enhances electrical conductivity and improves diffusion pathways of the Li-ion within the host material. The synthesis method described in this work serves as a general route for the design and preparation of other 2D layered TMCs. PMID- 27471136 TI - Of Papers and Pens: Polysemes and Homophones in Lexical (mis)Selection. AB - Every word signifies multiple senses. Many studies using comprehension-based measures suggest that polysemes' senses (e.g., paper as in printer paper or term paper) share lexical representations, whereas homophones' meanings (e.g., pen as in ballpoint pen or pig pen) correspond to distinct lexical representations. Less is known about the lexical representations of polysemes compared to homophones in language production. In this study, speakers named pictures after reading sentence fragments that primed polysemes and homophones either as direct competitors to pictures (i.e., semantic-competitors), or as indirect-competitors to pictures (e.g., polysemous senses of semantic competitors, or homophonous meanings of semantic competitors). Polysemes (e.g., paper) elicited equal numbers of intrusions to picture names (e.g., cardboard) compared to in control conditions whether primed as direct competitors (printer paper) or as indirect competitors (term paper). This contrasted with the finding that homophones (e.g., pen) elicited more intrusions to picture names (e.g., crayon) compared to in control conditions when primed as direct competitors (ballpoint pen) than when primed as indirect-competitors (pig pen). These results suggest that polysemes, unlike homophones, are stored and retrieved as unified lexical representations. PMID- 27471137 TI - Acupuncture for musculoskeletal pain: A meta-analysis and meta-regression of sham controlled randomized clinical trials. AB - The aims of this systematic review were to study the analgesic effect of real acupuncture and to explore whether sham acupuncture (SA) type is related to the estimated effect of real acupuncture for musculoskeletal pain. Five databases were searched. The outcome was pain or disability immediately (<=1 week) following an intervention. Standardized mean differences (SMDs) with 95% confidence intervals were calculated. Meta-regression was used to explore possible sources of heterogeneity. Sixty-three studies (6382 individuals) were included. Eight condition types were included. The pooled effect size was moderate for pain relief (59 trials, 4980 individuals, SMD -0.61, 95% CI -0.76 to -0.47; P < 0.001) and large for disability improvement (31 trials, 4876 individuals, -0.77, -1.05 to -0.49; P < 0.001). In a univariate meta-regression model, sham needle location and/or depth could explain most or all heterogeneities for some conditions (e.g., shoulder pain, low back pain, osteoarthritis, myofascial pain, and fibromyalgia); however, the interactions between subgroups via these covariates were not significant (P < 0.05). Our review provided low-quality evidence that real acupuncture has a moderate effect (approximate 12-point reduction on the 100-mm visual analogue scale) on musculoskeletal pain. SA type did not appear to be related to the estimated effect of real acupuncture. PMID- 27471138 TI - Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action. AB - More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1 yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo 3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. PMID- 27471140 TI - Diagnostic Accuracy of High-Sensitivity Cardiac Troponin T at Presentation Combined With History and ECG for Ruling Out Major Adverse Cardiac Events. AB - STUDY OBJECTIVE: We evaluate the diagnostic accuracy of a high-sensitivity cardiac troponin T (hs-cTnT) level less than 5 ng/L or less than or equal to 14 ng/L at emergency department (ED) presentation, combined with the emergency physician's assessment of history and ECG, for ruling out major adverse cardiac events within 30 days. METHODS: This prospective observational study enrolled consecutive ED chest pain patients. Emergency physicians' assessments of patient history and ECG were collected. The primary outcome was 30-day major adverse cardiac events, defined as acute myocardial infarction, unstable angina, cardiogenic shock, ventricular arrhythmia, atrioventricular block, cardiac arrest, or death of cardiac or unknown cause. RESULTS: A total of 1,138 patients were included in the final analysis. The combination of hs-cTnT less than 5 ng/L, a nonischemic ECG result, and a nonhigh risk history was present for 29.2% of all patients and had a sensitivity of 99.2% (95% confidence interval [CI] 95.6% to 100%), negative predictive value (NPV) of 99.7% (95% CI 98.3% to 100%), and a negative likelihood ratio of 0.02 (95% CI 0 to 0.17) for 30-day major adverse cardiac events. The same combination with hs-cTnT less than or equal to 14 ng/L was present in 66.7% of the patients and had a sensitivity of 92% (95% CI 85.8% to 96.1%), NPV of 98.7% (95% CI 97.6% to 99.4%), and negative likelihood ratio of 0.11 (95% CI 0.06 to 0.20). CONCLUSION: A single hs-cTnT result of less than 5 ng/L at ED presentation when combined with a nonischemic ECG result and a nonhigh risk history identified 29% of chest pain patients at a very low risk of 30-day major adverse cardiac events. A similar strategy with hs-cTnT less than or equal to 14 ng/L was associated with a higher miss rate. PMID- 27471139 TI - Clinical Presentations and Outcomes of Children With Basilar Skull Fractures After Blunt Head Trauma. AB - STUDY OBJECTIVE: We describe presentations and outcomes of children with basilar skull fractures in the emergency department (ED) after blunt head trauma. METHODS: This was a secondary analysis of an observational cohort of children with blunt head trauma. Basilar skull fracture was defined as physical examination signs of basilar skull fracture without basilar skull fracture on computed tomography (CT), or basilar skull fracture on CT regardless of physical examination signs of basilar skull fracture. Other definitions included isolated basilar skull fracture (physical examination signs of basilar skull fracture or basilar skull fracture on CT with no other intracranial injuries on CT) and acute adverse outcomes (death, neurosurgery, intubation for >24 hours, and hospitalization for >=2 nights with intracranial injury on CT). RESULTS: Of 42,958 patients, 558 (1.3%) had physical examination signs of basilar skull fracture, basilar skull fractures on CT, or both. Of the 525 (94.1%) CT-imaged patients, 162 (30.9%) had basilar skull fracture on CT alone, and 104 (19.8%) had both physical examination signs of basilar skull fracture and basilar skull fracture on CT; 269 patients (51.2%) had intracranial injuries other than basilar skull fracture on CT. Of the 363 (91.7%) CT-imaged patients with physical examination signs of basilar skull fracture, 104 (28.7%) had basilar skull fracture on CT. Of 266 patients with basilar skull fracture on CT, 104 (39.1%) also had physical examination signs of basilar skull fracture. Of the 256 CT imaged patients who had isolated basilar skull fracture, none had acute adverse outcomes (0%; 95% confidence interval 0% to 1.4%), including none (0%; 95% confidence interval 0% to 6.1%) of 59 with isolated basilar skull fractures on CT. CONCLUSION: Approximately 1% of children with blunt head trauma have physical examination signs of basilar skull fracture or basilar skull fracture on CT. The latter increases the risk of acute adverse outcomes more than physical examination signs of basilar skull fracture. A CT scan is needed to adequately stratify the risk of acute adverse outcomes for these children. Children with isolated basilar skull fractures are at low risk for acute adverse outcomes and, if neurologically normal after CT and observation, are candidates for ED discharge. PMID- 27471141 TI - Analysis of a cohort of 101 CDAII patients: description of 24 new molecular variants and genotype-phenotype correlations. AB - Congenital dyserythropoietic anaemia type II (CDAII) is a rare autosomal recessive disease characterized by ineffective erythropoiesis, haemolysis, erythroblast morphological abnormalities, hypoglycosylation of some red blood cell membrane proteins, particularly band 3, and mutations in the SEC23B gene. We report the analysis of 101 patients from 91 families with a median follow-up of 23 years (range 0-65); 68 patients are newly reported. Clinical and haematological parameters were separately analysed in early infancy and thereafter, when feasible. Molecular analysis of the SEC23B gene confirmed the high heterogeneity of the defect, leading to the identification of 54 different mutations, 24 of which are newly described. To evaluate the genotype-phenotype correlation, patients were grouped according to their genotype (two missense mutations vs. one missense/one drastic mutation) and assigned to two different severity gradings based on laboratory data and on therapeutic needs; by this approach only a weak genotype-phenotype correlation was observed in the analysed groups. PMID- 27471142 TI - Exercise hypoxaemia as a predictor of pulmonary hypertension in COPD patients without severe resting hypoxaemia. AB - BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) in COPD is associated with morbidity and mortality. Previous studies showed a relationship between resting hypoxaemia and PH, but little is known about the relationship between exercise hypoxaemia and PH in COPD without resting hypoxaemia. METHODS: A retrospective observational study of COPD patients without resting hypoxaemia was conducted to evaluate the relationships between exercise hypoxaemia and pulmonary haemodynamics. Clinical characteristics, pulmonary function, blood gas analysis, 6-min walk distance (6MWD) and oxygen saturation of peripheral artery (SpO2 ) at the end of the 6-min walk test (6MWT) were reviewed. Correlation analysis and stepwise regression analysis were performed to identify the predictor of mean pulmonary artery pressure (mPAP). RESULTS: Eighty-four consecutive patients with a mean predicted forced expiratory volume in 1 s (FEV1 ) of 47 +/- 21% were evaluated. In univariate analysis, mPAP had negative correlations with age (r = 0.27, P < 0.05), arterial partial pressure of oxygen (PaO2 , r = -0.24, P < 0.05), % predicted forced vital capacity (FVC, r = -0.28, P < 0.05), % predicted FEV1 (r = -0.40, P < 0.001), FEV1 /FVC ratio (r = -0.33, P < 0.005), % predicted diffusion capacity for carbon monoxide (DLCO , r = -0.40, P < 0.001), 6MWD (r = 0.40, P < 0.001) and SpO2 at the end of the 6MWT (r = -0.74, P < 0.001). In stepwise regression analysis, SpO2 at the end of the 6MWT and 6MWD remained as independent predictors of mPAP (R2 = 0.60). In receiver operating characteristic (ROC) analysis, SpO2 at the end of the 6MWT presented an area under the curve of 0.896 for the prediction of PH, with a sensitivity of 0.86 and specificity of 0.84 for the cut-off point of 81%. CONCLUSION: In addition to 6MWD, exercise hypoxaemia indicates PH in patients with COPD without resting hypoxaemia. PMID- 27471143 TI - Polymerization amplified SPR-DNA assay on noncovalently functionalized graphene. AB - A highly efficient surface plasmon resonance (SPR)-based DNA assay was developed, by employing noncovalently functionalized graphene nanosheets as a substrate, and enzymatic catalysis-induced polymerization as mass relay. The objective of this strategy was manifold: first of all, to sensitize the overall SPR output by in situ optimized electrogeneration of graphene thin-film, which was characterized by atomic force microscopic topography; secondly, to regulate the self-assembly and orientation of biotinylated capture probes on nickel-chelated nitrilotriacetic acid (NTA) scaffolds, that anchored onto graphene-supported pyrenyl derivatives; and lastly, to synergize the signal amplification via real time conversion of the additive aniline into polyaniline precipitation by horseradish peroxidase-tagged reporters. With this setup, a precise and replicable DNA sensing platform for specific targets was achieved with a detection limit down to femtomolar, thus demonstrating a beneficial exploration and exploitation of two-dimensional nanomaterials as unique SPR infrastructure. The possibility of such "bottom-up" architecture mounted with "top-down" weight reactor would be most likely extensible and adaptable to protein determinations. PMID- 27471144 TI - Detecting explosive molecules from nanoliter solution: A new paradigm of SERS sensing on hydrophilic photonic crystal biosilica. AB - We demonstrate a photonic crystal biosilica surface-enhanced Raman scattering (SERS) substrate based on a diatom frustule with in-situ synthesized silver nanoparticles (Ag NPs) to detect explosive molecules from nanoliter (nL) solution. By integrating high density Ag NPs inside the nanopores of diatom biosilica, which is not achievable by traditional self-assembly techniques, we obtained ultra-high SERS sensitivity due to dual enhancement mechanisms. First, the hybrid plasmonic-photonic crystal biosilica with three dimensional morphologies was obtained by electroless-deposited Ag seeds at nanometer sized diatom frustule surface, which provides high density hot spots as well as strongly coupled optical resonances with the photonic crystal structure of diatom frustules. Second, we discovered that the evaporation-driven microscopic flow combined with the strong hydrophilic surface of diatom frustules is capable of concentrating the analyte molecules, which offers a simple yet effective mechanism to accelerate the mass transport into the SERS substrate. Using the inkjet printing technology, we are able to deliver multiple 100pico-liter (pL) volume droplets with pinpoint accuracy into a single diatom frustule with dimension around 30um*7um*5um, which allows for label-free detection of explosive molecules such as trinitrotoluene (TNT) down to 10-10M in concentration and 2.7*10-15g in mass from 120nL solution. Our research illustrates a new paradigm of SERS sensing to detect trace level of chemical compounds from minimum volume of analyte using nature created photonic crystal biosilica materials. PMID- 27471145 TI - Pre-eruptive intracoronal resorption in a third upper molar: clinical, tomographic and histological analysis. AB - Radiolucent or hypodense lesions in the crown of unerupted teeth may be due to pre-eruptive intracoronal resorption. Clinicians must be aware of this risk so that they can diagnose and appropriately treat this condition. The purpose of this study is to present a well-documented clinical case of pre-eruptive intracoronal resorption in an impacted third upper left molar of a 63 year old female patient. This was an unexpected finding, which occurred after cone-beam computed tomography was used to investigate the first upper left molar, which had an acute periradicular abscess. A multidisciplinary team followed up the case to describe clinical, radiographic and histological findings. The available treatment options were discussed, and the tooth extraction was the option chosen. Previous case studies describing such resorption in third upper molars have not been reported. This case shows that all permanent teeth in a pre-eruptive stage must be analysed radiographically to detect early pre-eruptive intracoronal resorption. PMID- 27471146 TI - Exposed to events that never happen: Generalized unsafety, the default stress response, and prolonged autonomic activity. AB - Based on neurobiological and evolutionary arguments, the generalized unsafety theory of stress (GUTS) hypothesizes that the stress response is a default response, and that chronic stress responses are caused by generalized unsafety (GU), independent of stressors or their cognitive representation. Three highly prevalent conditions are particularly vulnerable to becoming 'compromised' in terms of GU, and carry considerable health risks: Thus, GUTS critically revises and expands stress theory, by focusing on safety instead of threat, and by including risk factors that have hitherto not been attributed to stress. PMID- 27471147 TI - Redox Non-Innocence of Nitrosobenzene at Nickel. AB - Nitrosobenzene (PhNO) serves as a stable analogue of nitroxyl (HNO), a biologically relevant, redox-active nitric oxide derivative. Capture of nitrosobenzene at the electron-deficient beta-diketiminato nickel(I) complex [(i) Pr2 NNF6 ]Ni results in reduction of the PhNO ligand to a (PhNO)(./-) species coordinated to a square planar Ni(II) center in [(i) Pr2 NNF6 ]Ni(eta(2) -ONPh). Ligand centered reduction leads to the (PhNO)(2-) moiety bound to Ni(II) supported by XAS studies. Systematic investigation of structure-reactivity patterns of (PhNO)(./-) and (PhNO)(2-) ligands reveals parallels with superoxo (O2 )(./-) and peroxo (O2 )(2-) ligands, respectively, and forecasts reactivity patterns of the more transient HNO ligand. PMID- 27471148 TI - Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: Insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from the urinary steroid metabolome. AB - The steroid profile changes dramatically from prenatal to postnatal life. Recently, a novel backdoor pathway for androgen biosynthesis has been discovered. However, its role remains elusive. Therefore, we investigated androgen production from birth to one year of life with a focus on minipuberty and on production of androgens through the backdoor pathway. Additionally, we assessed the development of the specific steroid enzyme activities in early life. To do so, we collected urine specimens from diapers in 43 healthy newborns (22 females) at 13 time points from birth to one year of age in an ambulatory setting, and performed in house GC-MS steroid profiling for 67 steroid metabolites. Data were analyzed for androgen production through the classic and backdoor pathway and calculations of diagnostic ratios for steroid enzyme activities were performed. Analysis revealed that during minipuberty androgen production is much higher in boys than in girls (e.g. androsterone (An)), originates largely from the testis (Anboys-Angirls), and uses predominantly the alternative backdoor pathway (An/Et; Delta5Leu347 mutant showed a different mode of action than AOS-hydroxyperoxide complex with Trp413 in direct bonding with the OOH group of 9-hydroxyperoxide. The loss of Lys88-OOH interaction in 13 hydroxyperoxide and loss-of-interaction of Leu347 indicated the importance of Phe347 residue in hydroxyperoxide catalysis. The second mutant Phe92->Leu92 also shows a very different interaction pattern with 13-hydroxyperoxide but not with 9 hydroxyperoxide.Therefore, it can be concluded that Phe347 is more crucial for AOS functionality than Phe92. The aromatic ring of a Phenylalanine residue is important for catalysis and its mutation affects the binding of the two ligands. Another important residue is Asn278 which is an important part of the AOS catalytic site for maintaining stability and can be compared with the Arabidopsis AOS residue Asn321. Lastly, the interaction of HPL with these two derivatives involves Leu363 residue instead of Phe347 and thus, validating the importance of Phe->Leu substitution to be the reason of different modes of action that result in completely different products from same substrates. PMID- 27471162 TI - The effect of taurine and enriched environment on behaviour, memory and hippocampus of diabetic rats. AB - Diabetes mellitus (DM) has been studied recently as a major cause of cognitive deficits, memory and neurodegenerative damage. Taurine and enriched environment have stood out for presenting neuroprotective and stimulating effects that deserve further study. In this paper, we examined the effects of taurine and enriched environment in the context of diabetes, evaluating effects on behaviour, memory, death and cellular activity. Eighty-eight Wistar rats were divided into 2 groups (E=enriched environment; C=standard housing). Some animals (24/group) underwent induction of diabetes, and within each group, some animals (half of diabetics (D) and half of non-diabetics (ND)/group) were treated for 30days with taurine (T). Untreated animals received saline (S). In total, there were eight subgroups: DTC, DSC, NDTC, NDSC, DTE, DSE, NDTE and NDSE. During the experiment, short-term memory was evaluated. After 30th day of experiment, the animals were euthanized and was made removal of brains used to immunohistochemistry procedures for GFAP and cleaved caspase-3. As a result, we observed that animals treated with taurine showed better performance in behavioural and memory tasks, and the enriched environment had positive effects, especially in non-diabetic animals. Furthermore, taurine and enriched environment seemed to be able to interfere with neuronal apoptosis and loss of glial cells, and in some instances, these two factors seemed to have synergistic effects. From these data, taurine and enriched environment may have important neurostimulant and neuroprotective effects. PMID- 27471163 TI - Association of tripartite motif family-like 2 (TRIML2) polymorphisms with late onset Alzheimer's disease risk in a Korean population. AB - Apoptosis is a prominent feature in the progression of Alzheimer's disease (AD), regulated in part by the activity of p53. As tripartite motif family-like 2 (TRIML2), a member of the TRIM family of proteins, has been implicated in the regulation of p53-mediated apoptosis, we hypothesized that TRIML2 polymorphisms may result in an increased AD susceptibility. Here, we investigated the association between coding region single nucleotide polymorphisms (cSNPs) in TRIML2 and AD in a Korean population. Two cSNPs (rs79698746 and rs2279551) were genotyped using the Sequenom iPLEX((r)) Gold assay and direct sequencing in 162 AD patients and 191 controls. Multiple logistic regression models were used to determine the odds ratios, 95% confidence intervals, and p-values. Significant associations were observed between AD and the allelic frequencies of two SNPs (rs79698746, p=0.007; rs2279551, p=0.01); genotype frequencies were also significantly different between the two groups [rs79698746: p=0.003 in the codominant 2 model (CC vs. TT), p=0.01 in the dominant model (TC/CC vs. TT), p=0.016 in the recessive model (CC vs. TT/TC), and p=0.0025 in the log-additive model (TC vs. CC vs. TT); rs2279551: p=0.003 in the codominant 2 model (CC vs. TT), p=0.011 in the dominant model (TC/CC vs. TT), p=0.019 in the recessive model (CC vs. TT/TC), and p=0.0028 in the log-additive model (TC vs. CC vs. TT)]. In the haplotype analyses, CC haplotypes containing two cSNPs were significantly associated with AD (p=0.013). Taken together, these findings indicate that the C allele of both SNPs was associated with an increased risk of AD. These results suggest that TRIML2 may contribute to AD susceptibility. PMID- 27471164 TI - Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer. AB - : The androgen receptor splice variant AR-V7 has recently been discussed as a predictive biomarker for nonresponse to next-generation androgen deprivation therapy (ADT) in patients with castration-resistant prostate cancer. However, we recently identified one patient showing a response from abiraterone despite expression of AR-V7 in his circulating tumour cells (CTC). Therefore, we precisely assessed the response in a cohort of 21 AR-V7 positive castration resistant prostate cancer patients who had received therapy with abiraterone or enzalutamide. We detected a subgroup of six AR-V7 positive patients showing benefit from either abiraterone or enzalutamide. Their progression free survival was 26 d (censored) to 188 d. Four patients displayed a prostate-specific antigen decrease of >50%. When analysing prior therapies, we noticed that only one of the six patients had received next-generation ADT prior to CTC collection. As a result, we conclude that AR-V7 status in CTC cannot entirely predict nonresponse to next generation ADT and AR-V7-positive patients should not be systematically denied abiraterone or enzalutamide treatment, especially as effective alternative treatment options are still limited. PATIENT SUMMARY: A subgroup of patients can benefit from abiraterone and/or enzalutamide despite detection of AR-V7 splice variants in their circulating tumour cells. PMID- 27471165 TI - Measuring maternal mental health using the Dutch Four-Dimensional Symptom Questionnaire (4DSQ): Pregnancy-related item bias across the perinatal period. AB - OBJECTIVE: the Four-Dimensional Symptom Questionnaire (4DSQ) measures four dimensions of common psychopathology: distress, depression, anxiety and somatization. The instrument is developed and validated for general practice. A previous validation study of the 4DSQ for midwifery practice indicated that pregnant women respond differently to the items of the 4DSQ. This phenomenon is called item bias. The present study is a followup validation study in which pregnant women were followed up until one year post partum, to assess pregnancy related item bias. DESIGN: cohort study with repeated measurements. SETTING AND PARTICIPANTS: the research group consisted of participants of the Mom@Work study, a study concerning mental health in a group of 574 working pregnant women and young mothers, recruited between 2004 and 2006. Measurements in the research group took place at 33 weeks of pregnancy and post partum at 7, 13, 25 and 52 weeks. The comparison group consisted of female general practice patients, matched for age (N=835). MEASUREMENTS AND FINDINGS: pregnancy-related item bias was assessed by two methods of differential item functioning (DIF) analysis: ordinal logistic regression (OLR) and the Mantel-Haenszel (MH) method. The impact of item bias on total scale scores was estimated by linear regression. Impact of item bias was found in the somatization-, distress- and anxiety scales of the 4DSQ across the perinatal period up until 13 weeks post partum. The depression scale remained free of item bias. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: pregnant and postpartum women responded differently to the 4DSQ than the women in the comparison group up until 13 weeks post partum. Pregnancy-related item bias lead to overestimation of distress and underestimation of somatization and anxiety. The depression scale was free of bias. The 4DSQ is a valid tool for case finding and assessment of psychological conditions in the perinatal period, provided cut-off points are adapted up until 13 weeks post partum. Validation of generic questionnaires is recommended before using them in the perinatal period. PMID- 27471166 TI - Scotopic electroretinography in fishing cat (Prionailurus viverrinus) and leopard cat (Prionailurus bengalensis). AB - OBJECTIVE: To establish baseline normal scotopic electroretinograpic (ERG) parameters for two wild cat species: fishing cats (FC) and leopard cats (LC). ANIMAL STUDIED: Twelve normal, FC and eight LC kept in the Chiang Mai Night Safari Zoo, Thailand. The mean ages of FC and LC were 7.08 and 5.00 years, respectively. PROCEDURE: All animals were studied using a standard scotopic protocol of a portable, handheld, multi-species electroretinography (HMsERG). RESULTS: There were significant differences in the means of ERG b-wave amplitude of the rod response (Rod, 0.01 cd.s/m2 ), a- and b-wave amplitudes of standard light intensity of rod and cone response (Std R&C, 3 cd.s/m2 ) and b-wave amplitude of high light intensity of rod and cone response (Hi-int R&C, 10 cd.s/m2 ) with LC having higher amplitudes than FC. There was no significant difference in a- and b- wave implicit time except for the b-wave of Hi-int (P=0.03). No significant differences were observed in b/a amplitude ratios. CONCLUSIONS: Data from this report provides reference values for scotopic ERG measurements in these two wild cat species. It showed that the normal scotopic ERG responses have some differences between the two species which might be due to the skull conformation, eye size or physiology of the retina. PMID- 27471167 TI - Biome engineering-2020. AB - The gut microbiome research is going from a descriptive into an intervention phase. To optimize beneficial microbe-host interaction, we need to understand how to steer the system by modulating the nutrient input with which the system is literally fed (e.g. diets, fibres, prebiotics, human milk oligosaccharides), and we must learn how to modulate the composition of the gut microbiota by adding beneficial microbes (e.g. probiotics, faecal transplants) and by eliminating disturbing microbial members using, for example, bacteriophages in this highly complex ecosystem. The current status of the field is reviewed together with an outlook what might be expected until 2020, highlighting obstacles to progress and possible solutions to these problems. PMID- 27471169 TI - Do wholes become more than the sum of their parts in the rodent (Rattus Norvegicus) visual system? A test case with the configural superiority effect. AB - The rodent has been used to model various aspects of the human visual system, but it is unclear to what extent human visual perception can be modelled in the rodent. Research suggests rodents can perform invariant object recognition tasks in a manner comparable to humans. There is further evidence that rodents also make use of certain grouping cues, but when performing a shape discrimination they have a tendency to rely much more on local image cues than human participants. In the current work, we exploit the fact that humans sometimes discriminate better between whole shapes, rather than the parts from which they are constructed, to ask whether rodents show a classic Configural Superiority Effect. Using touchscreen-equipped operant boxes, rats were trained to discriminate 'part' or 'whole' images based off of those used by J. R. Pomerantz et al. () J Exp Psychol Hum Percept Perform, 3, 422-435. Here, we show that rats show no advantage for wholes and that they perform better when presented with simpler image parts, a pattern of effect opposite to what was seen in humans when highly comparable stimuli were used. These results add to our understanding of the similarities and differences between the human and rodent visual system, and suggest that the rodent visual system may not compute part whole relationships in a way comparable to humans. These results are significant from both a comparative anatomy perspective, and of particular relevance for those wishing to use rodents to model visuo-perceptual deficits associated with human psychiatric disorders. PMID- 27471170 TI - Low temperature excitonic spectroscopy and dynamics as a probe of quality in hybrid perovskite thin films. AB - We have developed a framework for using temperature dependent static and dynamic photoluminescence (PL) of hybrid organic-inorganic perovskites (PVSKs) to characterize lattice defects in thin films, based on the presence of nanodomains at low temperature. Our high-stability PVSK films are fabricated using a novel continuous liquid interface propagation technique, and in the tetragonal phase (T > 120 K), they exhibit bi-exponential recombination from free charge carriers with an average PL lifetime of ~200 ns. Below 120 K, the emergence of the orthorhombic phase is accompanied by a reduction in lifetimes by an order of magnitude, which we establish to be the result of a crossover from free carrier to exciton-dominated radiative recombination. Analysis of the PL as a function of excitation power at different temperatures provides direct evidence that the exciton binding energy is different in the two phases, and using these results, we present a theoretical approach to estimate this variable binding energy. Our findings explain this anomalous low temperature behavior for the first time, attributing it to an inherent fundamental property of the hybrid PVSKs that can be used as an effective probe of thin film quality. PMID- 27471168 TI - Restoration of intestinal function in an MPTP model of Parkinson's Disease. AB - Patients with Parkinson's disease often experience non-motor symptoms including constipation, which manifest prior to the onset of debilitating motor signs. Understanding the causes of these non-motor deficits and developing disease modifying therapeutic strategies has the potential to prevent disease progression. Specific neuronal subpopulations were reduced within the myenteric plexus of mice 21 days after intoxication by the intraperitoneal administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and was associated with a reduction in stool frequency, indicative of intestinal dysfunction. Oral administration of the divalent copper complex, Cu(II)(atsm), which has been shown to be neuroprotective and restore motor performance to MPTP lesioned mice, improved stool frequency and was correlated with restoration of neuronal subpopulations in the myenteric plexus of MPTP lesioned mice. Restoration of intestinal function was associated with reduced enteric glial cell reactivity and reduction of markers of inflammation. Therapeutics that have been shown to be neuroprotective in the central nervous system, such as Cu(II)(atsm), therefore also provide symptom relief and are disease modifying in the intestinal tract, suggesting that there is a common cause of Parkinson's disease pathogenesis in the enteric nervous system and central nervous system. PMID- 27471171 TI - Hurdles in the Management of Protein-Energy Wasting in Renal Patients. PMID- 27471172 TI - Modified Nutritional Recommendations to Improve Dietary Patterns and Outcomes in Hemodialysis Patients. AB - The renal diet has traditionally been regarded as one of the most complex medical nutrition therapies to teach, understand, and implement. Specifically, patients are instructed to limit fruits, vegetables, nuts, legumes, dairy, and whole grains because of both phosphorus and potassium concerns. Furthermore, hemodialysis patients are often encouraged to decrease fluid intake to control interdialytic weight gain. These restrictions can result in frustration, lack of autonomy, and the perception that there is nothing left to eat. It is possible that the traditional renal diet may be liberalized, with a focus on whole foods low in sodium and phosphorus additives, to afford patients greater choices and ultimately improved outcomes. Therefore, the objective of this review is to concisely assess the evidence in support of a renal diet focused primarily on reducing the intake of sodium and inorganic phosphorus. Finally, the limited evidence for restrictions on dietary potassium intake is summarized. PMID- 27471173 TI - Preverbal Infants Infer Third-Party Social Relationships Based on Language. AB - Language provides rich social information about its speakers. For instance, adults and children make inferences about a speaker's social identity, geographic origins, and group membership based on her language and accent. Although infants prefer speakers of familiar languages (Kinzler, Dupoux, & Spelke, 2007), little is known about the developmental origins of humans' sensitivity to language as marker of social identity. We investigated whether 9-month-olds use the language a person speaks as an indicator of that person's likely social relationships. Infants were familiarized with videos of two people who spoke the same or different languages, and then viewed test videos of those two individuals affiliating or disengaging. Results suggest that infants expected two people who spoke the same language to be more likely to affiliate than two people who spoke different languages. Thus, infants view language as a meaningful social marker and use language to make inferences about third-party social relationships. PMID- 27471174 TI - A conversation about chemoprophylaxis. PMID- 27471176 TI - Discussion. PMID- 27471177 TI - Long-term durability of aortic arch in situ stent graft fenestration requiring lifelong surveillance. AB - We report successful endovascular repair of a 61-year-old man treated for a 7.1 cm excentric aortic arch aneurysm by in situ stent graft fenestration for the brachiocephalic trunk and the left common carotid artery. Cerebral perfusion during the intervention was maintained by pump-driven extracorporal bypass to the right common carotid artery and to the left axillary artery provided with a left carotid-subclavian bypass. After 5 years of follow-up, the aortic arch in situ revascularization is still patent, the aneurysm excluded, and no endoleak detectable, although endovascular reintervention with distal aortic stent graft extension due to dilatation of the descending aorta was required. PMID- 27471175 TI - New image-processing and noise-reduction software reduces radiation dose during complex endovascular procedures. AB - BACKGROUND: A new proprietary image-processing system known as AlluraClarity, developed by Philips Healthcare (Best, The Netherlands) for radiation-based interventional procedures, claims to lower radiation dose while preserving image quality using noise-reduction algorithms. This study determined whether the surgeon and patient radiation dose during complex endovascular procedures (CEPs) is decreased after the implementation of this new operating system. METHODS: Radiation dose to operators, procedure type, reference air kerma, kerma area product, and patient body mass index were recorded during CEPs on two Philips Allura FD 20 fluoroscopy systems with and without Clarity. Operator dose during CEPs was measured using optically stimulable, luminescent nanoDot (Landauer Inc, Glenwood, Ill) detectors placed outside the lead apron at the left upper chest position. nanoDots were read using a microStar ii (Landauer Inc) medical dosimetry system. For the CEPs in the Clarity group, the radiation dose to surgeons was also measured by the DoseAware (Philips Healthcare) personal dosimetry system. Side-by-side measurements of DoseAware and nanoDots allowed for cross-calibration between systems. Operator effective dose was determined using a modified Niklason algorithm. To control for patient size and case complexity, the average fluoroscopy dose rate and the dose per radiographic frame were adjusted for body mass index differences and then compared between the groups with and without Clarity by procedure. Additional factors, for example, physician practice patterns, that may have affected operator dose were inferred by comparing the ratio of the operator dose to procedural kerma area product with and without Clarity. A one-sided Wilcoxon rank sum test was used to compare groups for radiation doses, reference air kermas, and operating practices for each procedure type. RESULTS: The analysis included 234 CEPs; 95 performed without Clarity and 139 with Clarity. Practice patterns of operators during procedures with and without Clarity were not significantly different. For all cases, procedure radiation dose to the patient and the primary and assistant operators were significantly decreased in the Clarity group by 60% compared with the non-Clarity group. By procedure type, fluorography dose rates decreased from 44% for fenestrated endovascular repair and up to 70% with lower extremity interventions. Fluoroscopy dose rates also significantly decreased, from about 37% to 47%, depending on procedure type. CONCLUSIONS: The AlluraClarity system reduces the patient and primary operator's radiation dose by more than half during CEPs. This feature appears to be an effective tool in lowering the radiation dose while maintaining image quality. PMID- 27471178 TI - Journal Club: Commentary on "A Systematic Approach for Developing a Ventilator Associated Pneumonia Prevention Bundle". PMID- 27471179 TI - Vaccine safety and social media in China. PMID- 27471181 TI - Comparison of critical methods developed for fatty acid analysis: A review. AB - Fatty acids are important nutritional substances and metabolites in living organisms. These acids are abundant in Chinese herbs, such as Brucea javanica, Notopterygium forbesii, Isatis tinctoria, Astragalus membranaceus, and Aconitum szechenyianum. This review illustrates the types of fatty acids and their significant roles in the human body. Many analytical methods are used for the qualitative and quantitative evaluation of fatty acids. Some of the methods used to analyze fatty acids in more than 30 kinds of plants, drugs, and other samples are presented in this paper. These analytical methods include gas chromatography, liquid chromatography, near-infrared spectroscopy, and NMR spectroscopy. The advantages and disadvantages of these techniques are described and compared. This review provides a valuable reference for establishing methods for fatty acid determination. PMID- 27471180 TI - Long-term outcomes following mini-crush versus culotte stenting for the treatment of unprotected left main disease: Insights from the milan and New-Tokyo (MITO) registry. AB - OBJECTIVES: This study aimed to investigate the long-term outcomes following mini crush versus culotte stenting with drug-eluting stents (DES) for the treatment of unprotected left main coronary artery (LMCA) disease. BACKGROUND: Both mini-crush and culotte stenting are considered efficacious treatment options when a planned 2-stent strategy is deemed necessary for unprotected LMCA disease. However, there are limited data available with regard to the long-term clinical outcomes of each strategy in this setting. METHODS: Between July 2002 and November 2013, 225 patients were identified. 135 patients were treated with the mini-crush technique, and 90 patients with culotte stenting. The median follow-up period was 1,263 (IQR 820-1,847) days. RESULTS: The mini-crush group had worse lesion and procedural characteristics when compared to the culotte group. There were no significant differences in major adverse cardiac events (MACE) at 5 years (mini crush 36.0% vs. culotte 41.4%, P = 0.57). Myocardial infarction (MI) and definite stent thrombosis (ST) occurred significantly higher (MI; 0 vs. 11.3%, log-rank P = 0.003, and definite ST; 0 vs. 6.3%, log-rank P = 0.02, respectively) in the culotte group. Cox regression analysis indicated that full stent coverage of the LMCA and SYNTAX score were independent predictors for MACE. CONCLUSIONS: The incidence of MACE and overall TLR were comparable between groups. However, the rates of MI and definite ST were significantly higher in the culotte group. Full stent coverage of the LMCA may reduce the incidence of MACE when a two-stent strategy is used for the treatment of unprotected LMCA disease. (c) 2016 Wiley Periodicals, Inc. PMID- 27471183 TI - Effects of melatonin during IVM in defined medium on oocyte meiosis, oxidative stress, and subsequent embryo development. AB - Melatonin may have beneficial effects when used in oocyte maturation and embryo development culture. The effect of melatonin during IVM on meiosis resumption and progression in bovine oocytes and on expression of antioxidant enzymes, nuclear fragmentation and free radicals, as well as on embryo development were assessed. Cumulus-oocyte complexes were matured in vitro with melatonin (10(-9) and 10(-6) M), FSH (positive control), or without hormones (negative control) in defined medium. Maturation rates were evaluated at 6, 12, 18, and 24 hours. Transcripts for antioxidant enzymes (CuZnSOD, MnSOD, and glutathione peroxidase 4 (GPX4)) in oocytes and cumulus cells, nuclear fragmentation in cumulus cells (TUNEL) and reactive oxygen species levels in oocytes (carboxy-H2 difluorofluorescein diacetate) were determined at 24 hours IVM. Effect of treatments on embryo development was determined after in vitro fertilization and culture. At 12 hours, meiosis resumption rates in FSH and melatonin-treated groups were similar (69.6% 81.8%, P > 0.05). At 24 hours, most oocytes were in metaphase II, with FSH showing highest rates (90.0%, P < 0.05) compared with the other groups (51.6% 69.1%, P > 0.05). In cumulus cells, MnSOD expression was higher in FSH group (P < 0.05) whereas Cu,ZnSOD transcripts were more abundant in melatonin group (10( 6)M; P < 0.05). Nuclear fragmentation in cumulus cells was highest in controls (37.4%/10,000 cells; P < 0.05) and lower in FSH and 10(-6)M melatonin (29.4% and 25.6%/10,000 cells, respectively). Reactive oxygen species levels were lower in oocytes matured with 10(-6)M melatonin than in control and FSH groups (P < 0.05). Embryo development from oocytes matured only with melatonin was similar to those matured in complete medium (P > 0.05). In conclusion, although melatonin during IVM in a defined medium does not stimulate nuclear maturation progression it does stimulate meiosis resumption and such treated oocytes support subsequent embryo development. Melatonin also shows cytoprotective effects on cumulus-oocyte complexes. PMID- 27471184 TI - Post-transplant lymphoproliferative disorder: a heterogeneous conundrum - response to Weisenburger DD & Gross TG. PMID- 27471182 TI - Health Care Infrastructure for Financially Sustainable Clinical Genomics. AB - Next-generation sequencing has evolved technically and economically into the method of choice for interrogating the genome in cancer and inherited disorders. The introduction of procedural code sets for whole-exome and genome sequencing is a milestone toward financially sustainable clinical implementation; however, achieving reimbursement is currently a major challenge. As part of a prospective quality-improvement initiative to implement the new code sets, we adopted Agile, a development methodology originally devised in software development. We implemented eight functionally distinct modules (request review, cost estimation, preauthorization, accessioning, prebilling, testing, reporting, and reimbursement consultation) and obtained feedback via an anonymous survey. We managed 50 clinical requests (January to June 2015). The fraction of pursued-to-requested cases (n = 15/50; utilization management fraction, 0.3) aimed for a high rate of preauthorizations. In 13 of 15 patients the insurance plan required preauthorization, which we obtained in 70% and ultimately achieved reimbursement in 50%. Interoperability enabled assessment of 12 different combinations of modules that underline the importance of an adaptive workflow and policy tailoring to achieve higher yields of reimbursement. The survey confirmed a positive attitude toward self-organizing teams. We acknowledge the individuals and their interactions and termed the infrastructure: human pipeline. Nontechnical barriers currently are limiting the scope and availability of clinical genomic sequencing. The presented human pipeline is one approach toward long-term financial sustainability of clinical genomics. PMID- 27471185 TI - Armband activity monitor data do not correlate with reported pain scores in patients receiving vertebroplasty. AB - BACKGROUND: Prior research on the efficacy of vertebroplasty has focused primarily on subjective, patient-reported outcomes. OBJECTIVE: To apply an armband activity monitor (SenseWear by BodyMedia Inc, USA) to patients presenting for consideration for vertebroplasty and to determine the correlation between patient-reported outcomes and quantitative activity metrics at baseline and 30 days after presentation. MATERIALS AND METHODS: Nineteen patients were enrolled (15 receiving vertebroplasty, 4 not receiving vertebroplasty). Patients reported their average pain over the past 24 hours and completed the Roland-Morris disability questionnaire at baseline and 30 days. Patients wore the SenseWear Armband activity monitor for a median of 4 days at baseline and at the 30-day time period to assess steps, metabolic equivalents expended, sedentary activity time, moderate activity time, sleep efficiency, and total sleep time. Pain and disability scores were correlated with activity monitor metrics using linear regression analysis. RESULTS: Changes in reported average pain in the past 24 hours and disability scores were not significantly different between vertebroplasty and non-vertebroplasty groups (p>0.05). Changes in activity monitor data were not significantly different between the vertebroplasty and non vertebroplasty groups (p>0.05). None of the correlations between the reported pain or disability scores and the activity monitor data were significant. CONCLUSIONS: Activity monitors can be used to objectively record changes in activity following vertebroplasty procedures. Patient-reported pain or disability scores do not correlate with activity monitor-measured activity or sleep metrics. PMID- 27471186 TI - Rapid delayed growth of ruptured supraclinoid blister aneurysm after successful flow diverting stent treatment. AB - A 62-year-old woman presented with a subarachnoid hemorrhage secondary to a ruptured right supraclinoid internal carotid artery blister aneurysm. She was treated in an emergent fashion with two flow diverting pipeline embolization devices (PED) deployed in a telescoping fashion. CT angiography performed for unrelated reasons at 7 months showed successful treatment of the aneurysm without evidence of residual aneurysm. However, a follow-up digital subtraction angiogram performed at 9 months showed a large aneurysm in a modified position compared with the original aneurysm. This is the first case of rapid regrowth of a supraclinoid blister aneurysm after successful treatment with a PED, and demonstrates the need for close follow-up for similar aneurysms treated with this novel device. PMID- 27471187 TI - Denominator fallacy revisited. PMID- 27471188 TI - Long QT Manifested as Giant and Inverted T Waves With a SCN5A Mutation. PMID- 27471189 TI - Heartbeat: Rule-out of acute myocardial infarction - risky business. PMID- 27471190 TI - Complete versus culprit-only revascularisation for ST-segment elevation myocardial infarction. PMID- 27471191 TI - Complete versus culprit-only revascularisation for ST-segment elevation myocardial infarction. PMID- 27471192 TI - Mapping corticospinal tract projection patterns in unilateral cerebral palsy. PMID- 27471193 TI - Bimetallic Metal-Organic Frameworks for Controlled Catalytic Graphitization of Nanoporous Carbons. AB - Single metal-organic frameworks (MOFs), constructed from the coordination between one-fold metal ions and organic linkers, show limited functionalities when used as precursors for nanoporous carbon materials. Herein, we propose to merge the advantages of zinc and cobalt metals ions into one single MOF crystal (i.e., bimetallic MOFs). The organic linkers that coordinate with cobalt ions tend to yield graphitic carbons after carbonization, unlike those bridging with zinc ions, due to the controlled catalytic graphitization by the cobalt nanoparticles. In this work, we demonstrate a feasible method to achieve nanoporous carbon materials with tailored properties, including specific surface area, pore size distribution, degree of graphitization, and content of heteroatoms. The bimetallic-MOF-derived nanoporous carbon are systematically characterized, highlighting the importance of precisely controlling the properties of the carbon materials. This can be done by finely tuning the components in the bimetallic MOF precursors, and thus designing optimal carbon materials for specific applications. PMID- 27471194 TI - Sex-dependent activity of the spinal excitatory amino acid transporter: Role of estrous cycle. AB - Females are more likely to experience visceral pain than males, yet mechanisms underlying this sex bias are not fully elucidated. Moreover, pain sensitivity can change throughout the menstrual cycle. Alterations in the glutamatergic system have been implicated in several pain-disorders; however, whether these are sex dependent is unclear. Thus, we aimed to investigate sex differences in the spinal cord glutamate uptake and how it varies across the estrous cycle. The activity of the glutamate transporters, excitatory amino acid transporters (EAATs) was assessed using an ex vivo aspartate radioactive uptake assay in the lumbosacral spinal cord in Sprague-Dawley male and female rats. The gene expression of EAATs, glutamate receptor subunits NR1 and NR2B and the estrogen receptors ERalpha & ERbeta in the spinal cord were also analyzed. EAAT activity was lower in females, particularly during the estrus phase, and this was the only cycle stage that was responsive to the pharmacological effects of the EAATs activator riluzole. Interestingly, EAAT1 mRNA expression was lower in high-estrogen and high-ERalpha states compared to diestrus in females. We conclude that the Spinal EAAT activity in females is different to that in males, and varies across the estrous cycle. Furthermore, the expression levels of estrogen receptors also showed a cycle dependent pattern that may affect EAATs function and expression. PMID- 27471195 TI - Diazoxide enhances excitotoxicity-induced neurogenesis and attenuates neurodegeneration in the rat non-neurogenic hippocampus. AB - Diazoxide, a well-known mitochondrial KATP channel opener with neuroprotective effects, has been proposed for the effective and safe treatment of neuroinflammation. To test whether diazoxide affects the neurogenesis associated with excitotoxicity in brain injury, we induced lesions by injecting excitotoxic N-methyl-d-aspartate (NMDA) into the rat hippocampus and analyzed the effects of a daily oral administration of diazoxide on the induced lesion. Specific glial and neuronal staining showed that NMDA elicited a strong glial reaction associated with progressive neuronal loss in the whole hippocampal formation. Doublecortin immunohistochemistry and bromo-deoxyuridine (BrdU)-NeuN double immunohistochemistry revealed that NMDA also induced cell proliferation and neurogenesis in the lesioned non-neurogenic hippocampus. Furthermore, glial fibrillary acidic protein (GFAP)-positive cells in the injured hippocampus expressed transcription factor Sp8 indicating that the excitotoxic lesion elicited the migration of progenitors from the subventricular zone and/or the reprograming of reactive astrocytes. Diazoxide treatment attenuated the NMDA induced hippocampal injury in rats, as demonstrated by decreases in the size of the lesion, neuronal loss and microglial reaction. Diazoxide also increased the number of BrdU/NeuN double-stained cells and elevated the number of Sp8-positive cells in the lesioned hippocampus. These results indicate a role for KATP channel activation in regulating excitotoxicity-induced neurogenesis in brain injury. PMID- 27471196 TI - Development of a novel ex vivo equine corneal model. AB - OBJECTIVE: To develop an ex vivo equine corneal organ culture model. Specifically, to assess the equine cornea's extracellular matrix and cellularity after 7 days using two different culture techniques: either (i) immersion system or (ii) air/liquid interface system, to determine the best ex vivo equine corneal model. ANIMALS STUDIED: Fourteen healthy equine corneas of various breeds. PROCEDURES: Equine corneas with 2 mm of perilimbal sclera were freshly harvested from 7 horses undergoing humane euthanasia. One corneal-scleral ring (CSR) from each horse was randomly placed in the (i) immersion condition organ culture system (IC), with the contralateral CSR being placed in the (ii) air/liquid interface organ culture system (ALC) for 7 days. All corneas were evaluated using serial daily gross photography, histology, qPCR, and TUNEL assay. RESULTS: corneal-scleral rings placed in the IC (i) had complete loss of corneal transparency on gross photography by 7 days, showed a significant level of corneal stromal disorganization, significantly increased alpha-SMA levels on qPCR, and apoptosis on TUNEL assay compared to controls. The ALC (ii) had weak stromal disorganization on histopathologic examination and was not significantly different from normal equine corneal controls on all other evaluated parameters. CONCLUSIONS: The air-liquid interface organ culture system maintains the equine cornea's extracellular matrix and preserves corneal transparency, while the immersion condition results in near complete degradation of normal equine corneal architecture after 7 days in culture. The air-liquid organ culture is a viable option to maintain a healthy equine cornea in an ex vivo setting for wound healing studies. PMID- 27471197 TI - Minority stress, psychological distress, and alcohol misuse among sexual minority young adults: A resiliency-based conditional process analysis. AB - BACKGROUND: Sexual minority young adults experience elevated rates of distal stress (discrimination, victimization), and related psychological distress and alcohol misuse. However, few studies have examined the degree to which personality trait differences confer risk/resilience among sexual minority young adults. We hypothesized that psychological distress would mediate the relationship between distal stress and alcohol misuse, but that these relationships would be moderated by personality trait differences. METHOD: Sexual minority young adults (N=412) were recruited nationally. Survey measures included demographic questions, minority stressors, Five Factor personality traits, and current psychological distress and alcohol misuse symptoms. We used a data-driven two-stage cluster analytic technique to empirically derive personality trait profiles, and conducted mediation and moderated mediation analyses using a regression-based approach. RESULTS: Our results supported a two-group personality profile solution. Relative to at-risk individuals, those classified as adaptive scored lower on neuroticism, and higher on agreeableness, extraversion, conscientiousness, and openness to experience. As predicted, psychological distress mediated the relationship between distal stress and alcohol misuse. However, personality moderated these relationships to the degree that they did not exist among individuals classified as adaptive. DISCUSSION: In the current study, we found that personality moderated the established relationships between distal stress, psychological distress, and alcohol misuse among sexual minority young adults. Future research is needed to further explicate these relationships, and in order to develop tailored interventions for sexual minority young adults at risk. PMID- 27471198 TI - Reasons for and consequences of vitamin K antagonist discontinuation in very elderly patients with non-valvular atrial fibrillation. AB - : Essentials Anticoagulation in the elderly is still a challenge and suspension of warfarin is common. This is an observational study reporting reasons and consequences of warfarin suspension. Vascular disease, age, time in therapeutic range, and bleedings are associated with suspension. After suspension for bleeding or frailty, patients remain at high-risk of death or complications. SUMMARY: Background Anticoagulation in elderly patients with non-valvular atrial fibrillation (NVAF) is still a challenge, and discontinuation of warfarin is common. The aim of this study was to analyze the aspects related to warfarin discontinuation in a real-world population. Methods This was an observational cohort study on very elderly NVAF patients naive to warfarin therapy (VENPAF). The included subjects were aged at least 80 years, and started using warfarin after a diagnosis of NVAF. Warfarin discontinuation was assessed, and the reason reported for discontinuation, the person who decided to stop treatment, subsequent antithrombotic therapy and mortality, ischemic and bleeding events were collected. Results Over a period of 5 years, warfarin was discontinued in 148 of 798 patients. Despite similar CHA2 DS2 -VASc scores, the frequencies of thromboembolic and major bleeding events were significantly higher (P = 0.01 and P = 0.001, respectively) and the time in therapeutic range (TTR) was significantly lower (P < 0.001) in patients who discontinued warfarin. Independent risk factors for warfarin discontinuation were vascular disease (hazard ratio [HR] 2.5, P < 0.001), age >= 85 years (HR 1.4, P = 0.04), TTR < 60% (HR 1.8, P = 0.001), and bleeding events (HR 2.3, P < 0.001). The main reasons for warfarin discontinuation were physician-perceived frailty or low life expectancy (45.9%), bleeding complications (19.6%), and sinus rhythm restoration (16.9%). Event and death rates were very high, especially in frail patients and in those with bleeding complications. Conclusions Warfarin discontinuation is frequent in very elderly patients, and is associated with increased risks of death and adverse events. Identification of elderly patients who are at high risk of bleeding and the poor quality of anticoagulation during warfarin are still unsolved clinical problems. PMID- 27471199 TI - Age-dependent increase in Kalirin-9 and Kalirin-12 transcripts in human orbitofrontal cortex. AB - KALRN (KAL) is a Rho GEF that is highly involved in regulation of the actin cytoskeleton within dendrites. There are several isoforms of the protein that arise from differential splicing of KALRN's 66 exons. KAL isoforms have different functions in development. For example, overexpression of the KAL9 and KAL12 isoforms induce dendritic elongation in early development. However, in mature neurons KAL9 overexpression reduces dendritic length, a phenotype also observed in normal human ageing. We therefore hypothesized that KAL9 would have increased expression with age, and undertook to evaluate the expression of individual KALRN exons throughout the adult lifespan. Postmortem human brain grey matter from Brodmann's area (BA) 11 and BA47 derived from a cohort of 209 individuals without psychiatric or neurodegenerative disease, ranging in age from 16 to 91 years, were analysed for KALRN expression by Affymetrix exon array. Analysis of the exon array data in an isoform-specific manner, as well as confirmatory isoform specific qPCR studies, indicated that the longer KAL9 and KAL12 isoforms demonstrated a statistically significant, but modest, increase with age. The small magnitude of the age effect suggests that inter-individual factors other than age likely contribute to a higher degree to KAL9 and KAL12 expression. In contrast to KAL9 and KAL12, global KALRN expression did not increase with age. Our work suggests that global measures of KALRN gene expression may be misleading and future studies should focus on isoform-specific quantification. PMID- 27471200 TI - Principles of practice parameters for the treatment of sleep disordered breathing in the elderly and frail elderly: the consensus of the International Geriatric Sleep Medicine Task Force. AB - Sleep disordered breathing (SDB) is a leading cause of morbidity worldwide. Its prevalence increases with age. Due to the demographic changes in industrial societies, pulmonologists and sleep physicians are confronted with a rapidly growing number of elderly SDB patients. For many physicians, it remains unclear how current guidelines for SDB management apply to elderly and frail elderly patients. The goal of this consensus statement is to provide guidance based on published evidence for SDB treatment in this specific patient group.Clinicians and researchers with expertise in geriatric sleep medicine representing several countries were invited to participate in a task force. A literature search of PubMed from the past 12 years and a systematic review of evidence of studies deemed relevant was performed.Recommendations for treatment management of elderly and frail elderly SDB patients based on published evidence were formulated via discussion and consensus.In the last 12 years, there have been surprisingly few studies examining treatment of SDB in older adults and even fewer in frail older adults. Studies that have been conducted on the management of SDB in the older patient population were rarely stratified for age. Studies in SDB treatment that did include age stratification mainly focused on middle-aged and younger patient groups. Based on the evidence that is available, this consensus statement highlights the treatment forms that can be recommended for elderly SDB patients and encourages treatment of SDB in this large patient group. PMID- 27471201 TI - Pathogen- and antibiotic-specific effects of prednisone in community-acquired pneumonia. AB - In a double-blind, randomised, placebo-controlled trial of hospitalised patients with community-acquired pneumonia (CAP), we demonstrated shorter time to clinical stability (TTCS) with adjunct corticosteroid therapy compared with placebo.We did a pre-planned, exploratory analysis of any association between microbiological diagnosis, antibiotic treatment and procalcitonin level and effect of prednisone on TTCS, mortality, and CAP complications (n=726 participants, enrolled between December 2009 and May 2014). Multiplex viral real time PCR was systematically performed in nasopharyngeal swabs beginning November 2011 (n=489). Other investigations and treatments were at the discretion of the physician. Effect modification was tested with inclusion of interaction terms in the statistical models.Reduced TTCS with prednisone was seen in all microbiological, antibiotic, procalcitonin and afebrile patient subgroups. We found evidence for a different prednisone response in patients with pneumococcal pneumonia in whom intravenous antibiotic duration was not shorter (interaction p=0.01) with prednisone, as was observed in the remaining study population. In patients without macrolide treatment, rehospitalisations were not lower with prednisone (interaction p=0.04). After adjustment for multiple testing, these subgroup effects were no longer significant.Prednisone was associated with shorter TTCS independent of CAP aetiology. In pneumococcal pneumonia, prednisone effects on secondary endpoints may be less favourable. PMID- 27471202 TI - The relationship between body fat and respiratory function in young adults. AB - The relationship between adiposity and respiratory function is poorly understood. Most studies investigating this have used indirect measures of body fat and few have assessed how changes in adiposity influence lung function.Body fat measured by bio-electrical impedance analysis, body mass index, waist circumference, spirometry, body plethysmography and transfer factor were measured at ages 32 and 38 years in 361 non-smoking, non-asthmatic participants from a population-based birth cohort.Higher percentage body fat was associated with lower spirometric and plethysmographic lung volumes, but not with airflow obstruction, or transfer factor at 32 years. Changes in adiposity between ages 32 and 38 years were inversely associated with changes in lung volumes. These associations were generally stronger in men than women, but an association between increasing adiposity and lower airway function (forced expiratory volume in 1 s/forced vital capacity) was only found in women. Similar associations were found for body mass index and waist circumference.Higher percentage body fat is associated with lower lung volumes. Direct and indirect measures of adiposity had similar associations with lung function. Adiposity had a greater effect on lung volumes in men than women but was associated with airway function only in women. There was little evidence that adiposity influenced transfer factor. PMID- 27471203 TI - beta2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis. AB - We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified beta2-adrenergic receptor agonists as the most potent inducers of CFTR function.beta2-Agonist induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled beta2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids.This proof-of concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration. PMID- 27471204 TI - Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterised by excessive pulmonary vascular remodelling involving deregulated proliferation of cells in intima, media as well as adventitia. Pulmonary arterial endothelial cell (PAEC) hyperproliferation and survival underlies the endothelial pathobiology of the disease.The indispensable involvement of Notch1 in the arterial endothelial phenotype and angiogenesis provides intriguing prospects for its involvement in the pathogenesis of PAH.We observed an increased expression of Notch1 in lungs of idiopathic PAH (IPAH) patients and hypoxia/SU5416 (SUHx) rats compared with healthy subjects. In vitro loss- and gain-of-function studies demonstrated that Notch1 increased proliferation of human PAECs (hPAECs) via downregulation of p21 and inhibited apoptosis via Bcl-2 and Survivin. Inhibition of Notch signalling using the gamma-secretase inhibitor dibenzazepine dose-dependently decreased proliferation and migration of hPAECs. Notably, Notch1 expression and transcriptional activity were increased under hypoxia in hPAECs and knockdown of Notch1 inhibited hypoxia-induced proliferation of the cells. Furthermore, in vivo treatment with a gamma-secretase inhibitor (AMG2008827) significantly reduced the right ventricular systolic pressure and right heart hypertrophy in SUHx rats.Here, we conclude that Notch1 plays a critical role in PAH and Notch inhibitors may be a promising therapeutic option for PAH. PMID- 27471205 TI - Variation in policy and practice of adolescent tuberculosis management in the WHO European Region. PMID- 27471207 TI - Sarcoidosis incidence and prevalence: a nationwide register-based assessment in Sweden. AB - Our objective was to estimate the contemporary incidence and prevalence of sarcoidosis using Swedish population-based register data.Adults with any sarcoidosis-coded visit were identified from the National Patient Register (hospitalisations 1964-2013 and outpatient care 2001-2013). Demographic and medication dispensing data were retrieved from national registers. We estimated the prevalence of sarcoidosis in 2013 overall and by county of residence. The incidence of sarcoidosis during 2003-2012 was estimated by sex, age, education level and year of diagnosis. Case definitions were varied to test their robustness.More than 16 000 individuals had a history of sarcoidosis in 2013. When defined as two or more sarcoidosis-coded visits, the prevalence was 160 per 100 000. Using different definitions, the prevalence ranged from 152 (requiring a specialist visit) to 215 per 100 000 (only one visit required). The highest prevalence was observed in northern less densely populated counties. The incidence was 11.5 per 100 000 per year and varied by -10% to +30% depending on case definition. The incidence peaked in males aged 30-50 years and in females aged 50-60 years, but did not differ by education level and was stable over time.This study represents the largest epidemiological investigation of sarcoidosis using population-based individual-level data. Age at diagnosis in men was 10 years younger than in women and geographical variation was observed. PMID- 27471208 TI - Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function. AB - This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage.Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg.day(-1) or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC >=80% versus <80% or GAP stage I versus II-III. Treatment-by subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term.Patients with both more preserved (FVC >=80% or GAP stage I) and less preserved (FVC <80% or GAP stage II-III) lung function at baseline demonstrated clinically significant disease progression at 12 months in terms of categorical decline in FVC, 6MWD and UCSD SOBQ. The magnitude of pirfenidone treatment effect was comparable between subgroups, regardless of whether lung function was classified using FVC or GAP index stage.These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population. PMID- 27471206 TI - High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study. AB - Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking.We measured high attenuation areas (HAA; percentage of lung voxels between -600 and -250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis.HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3-11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8-13.0), lower forced vital capacity (FVC) (mean adjusted difference -82 mL, 95% CI -119--44), lower 6-min walk distance (mean adjusted difference -40 m, 95% CI -1--80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43-2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39-1.79).High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. PMID- 27471210 TI - Preoperative Evaluation for Pelvic Discontinuity Using a New Reformatted Computed Tomography Scan Protocol. AB - BACKGROUND: The identification of suspected pelvic discontinuity is important for preoperative planning in revision hip arthroplasty. Computed tomography (CT) of the pelvis with reconstructions in the axial, sagittal, and coronal planes has been previously described for the identification of pelvic discontinuity but fails to show some discontinuities. The purpose of this study was to determine whether reformatted 45 degrees oblique CT scans of the pelvis, similar in projection to Judet views on plain films, provide advantages in detecting pelvic discontinuity preoperatively over standard reconstruction CT scans. We describe a new technique of reformatting conventional CT scans to present 45 degrees oblique views of the pelvis. METHODS: Using an institutional joint registry, we retrospectively identified 22 patients who had intraoperative findings of pelvic discontinuity and also had a preoperative CT scan of the pelvis. The criterion for diagnosis of pelvic discontinuity was a continuous visible fracture line involving the entire width of the anterior and posterior columns. RESULTS: In this study, standard reconstruction CT scans were 73% sensitive in identifying discontinuity based on these parameters and the addition of reformatted 45 degrees oblique CT scans increased sensitivity to 91%. CONCLUSION: Unique reconstructive techniques in revision hip arthroplasty can be used, and the operative plan may be modified if pelvic discontinuity is identified preoperatively. CT scans of the pelvis with reconstructions at 45 degrees iliac oblique and obturator oblique views in patients with suspected pelvic discontinuity provide a high level of sensitivity when the diagnosis cannot be firmly established from plain films. PMID- 27471209 TI - Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. AB - Attempts at identifying patients with an elevated risk of bleeding while on anticoagulation following acute venous thromboembolism (VTE) have largely been unsuccessful thus far. We sought to develop a clinical prediction score for bleeding during stable anticoagulation treatment after acute VTE.We performed a post hoc analysis of the pooled RE-COVER studies, two double-blind randomised "sister" trials evaluating dabigatran versus standard treatment in 5107 VTE patients.A score was derived from patients randomised to dabigatran using logistic regression analysis covering the complete follow-up period. The final model, named VTE-BLEED, included six variables and yielded a c-statistic of 0.72 (95% CI 0.67-0.76). Patients from the derivation cohort in the low-risk group (<2 points; 74% of the derivation population) had a bleeding incidence of 2.8% compared to 12.6% in the elevated-risk group (OR 5.0; 95% CI 3.5-7.1). The score proved accurate for our primary end-point, i.e. prediction of major bleeding after day 30 ("stable" anticoagulation), both in patients on dabigatran (c statistic 0.75, 95% CI 0.61-0.89) and those on warfarin (0.78, 95% CI 0.68-0.86; p=0.77 for difference).The new VTE-BLEED score accurately predicted major bleeding events in VTE patients on stable anticoagulation with both dabigatran and warfarin. PMID- 27471211 TI - Day of Surgery Affects Length of Stay and Charges in Primary Total Hip and Knee Arthroplasty. AB - BACKGROUND: Length of hospital stay (LOS) is a large driver of cost after primary total joint arthroplasty (TJA). Strategies to decrease LOS may help reduce the economic burden of TJA. This study's aim was to investigate the effect of day of the week of surgery on mean LOS and total charges following primary total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: An administrative clinical database at a large US health care system was reviewed for all primary THA and TKA admissions performed between 2010 and 2012 (n = 15,237). Of these, 14,800 cases met our inclusion criteria and were analyzed. Furthermore, the cohort was divided into early (Monday/Tuesday) and late week (Thursday/Friday) surgeries, excluding Wednesday surgeries (n = 2835). Univariate and multiple regression analyses examined the effect of each variable on LOS. RESULTS: Mean LOS for THA and TKA on Monday was 3.54 and 3.35 days and increased to 4.12 and 3.66 days on Friday (P < .0001), respectively. Late vs early week admissions had 0.358 (95% confidence interval: 0.29-0.425, P < .001) additional hospital days. Increased age (0.003 days per unit increase in age, P = .02) and severity of illness score (0.781 days per level increase, P < .001) were associated with increased LOS. Late week surgery had a greater effect on LOS for TKA than for THA. TKAs were associated with higher charges for late week surgery vs early week surgery (P < .001). CONCLUSION: Late week TJA cases, older age, and increasing severity of illness score were associated with increased LOS. Furthermore, late week TKA was associated with increased total charges. PMID- 27471212 TI - Factors Associated With Trunnionosis in the Metal-on-Metal Pinnacle Hip. AB - BACKGROUND: Trunnionosis of the tapered head-stem junction of total hip arthroplasties, either through corrosion or mechanical wear, has been implicated in early implant failure. Retrieval analysis of large numbers of failed implants can help us better understand the factors that influence damage at this interface. METHODS: In this study, we examined 120 retrieved total hip arthroplasties of one bearing design, the 36-mm diameter metal-on-metal, DePuy Pinnacle, that had been paired with 3 different stems. We measured material loss of the bearing and head-trunnion taper surfaces and collected clinical and component data for each case. We then used multiple linear regression analysis to determine which factors influenced the rate of taper material loss. RESULTS: We found 4 significant variables: (1) longer time to revision (P = .004), (2) the use of a 12/14 taper for the head-trunnion junction (P < .001), (3) decreased bearing surface wear (P = .003), and (4) vertical femoral offset (P = .05). These together explained 29% of the variability in taper material loss. CONCLUSION: Our most important finding is the effect of trunnion design. Of the 3 types studied, we found that S-ROM design was the most successful at minimizing trunnionosis. PMID- 27471214 TI - Improvement in Patient Transfer Process From the Operating Room to the PICU Using a Lean and Six Sigma-Based Quality Improvement Project. AB - BACKGROUND AND OBJECTIVES: Ineffective and inefficient patient transfer processes can increase the chance of medical errors. Improvements in such processes are high-priority local institutional and national patient safety goals. At our institution, nonintubated postoperative pediatric patients are first admitted to the postanesthesia care unit before transfer to the PICU. This quality improvement project was designed to improve the patient transfer process from the operating room (OR) to the PICU. METHODS: After direct observation of the baseline process, we introduced a structured, direct OR-PICU transfer process for orthopedic spinal fusion patients. We performed value stream mapping of the process to determine error-prone and inefficient areas. We evaluated primary outcome measures of handoff error reduction and the overall efficiency of patient transfer process time. Staff satisfaction was evaluated as a counterbalance measure. RESULTS: With the introduction of the new direct OR-PICU patient transfer process, the handoff communication error rate improved from 1.9 to 0.3 errors per patient handoff (P = .002). Inefficiency (patient wait time and non value-creating activity) was reduced from 90 to 32 minutes. Handoff content was improved with fewer information omissions (P < .001). Staff satisfaction significantly improved among nearly all PICU providers. CONCLUSIONS: By using quality improvement methodology to design and implement a new direct OR-PICU transfer process with a structured multidisciplinary verbal handoff, we achieved sustained improvements in patient safety and efficiency. Handoff communication was enhanced, with fewer errors and content omissions. The new process improved efficiency, with high staff satisfaction. PMID- 27471213 TI - Direct versus sequential immunoglobulin switch in allergy and antiviral responses. AB - Allergy is characterized by IgE production to innocuous antigens. The question whether the switch to IgE synthesis occurs via direct or sequential pathways is still unresolved. The aim of this work was to analyze the distribution of immunoglobulins (Ig) to house dust mite D. farinae and A. alternata fungus in allergic children with primarily established diagnosis and compare it to Epstein Barr antiviral (EBV) response in the same patients. In allergy patients the only significant difference was found in allergen specific IgE, likely mediated by a direct isotype switch, while antiviral response was dominated by EBV specific IgG and low level of concordant IgA and IgG4 production consistent with a minor sequential Ig switches. Taken collectively, we concluded that sequential isotype switch is likely to be a much rarer event than a direct one. PMID- 27471215 TI - How trained volunteers can improve the quality of hospital care for older patients. A qualitative evaluation within the Hospital Elder Life Program (HELP). AB - The aim of this study was to investigate, using a mixed-methods design, the added value of a trained Hospital Elder Life Program (HELP) volunteer to the quality of hospital care in the Netherlands. The trained volunteers daily stimulate older patients, at risk of a delirium, to eat, to drink, and to exercise, and they provide walking assistance and cognitive stimulation. This study showed that each group appreciated the extra attention and service from the volunteers. The positive effect on feelings of loneliness during the hospital stay was an unexpected outcome. The volunteers themselves appreciated their work. In conclusion, a HELP volunteer should be provided to every older hospital patient. PMID- 27471217 TI - Design and marketing features influencing choice of e-cigarettes and tobacco in the EU. AB - Data were analysed from the 2014 Special Eurobarometer for Tobacco survey. We estimated self-rated importance of various factors in the choice of both tobacco and electronic cigarettes (e-cigarettes) among tobacco smokers who had ever used an e-cigarette. Among ever users of tobacco and e-cigarettes (N = 2430), taste (39.4%), price (39.2%) and amount of nicotine (27.3%) were the most commonly cited reasons for choosing their brand of e-cigarettes. Those aged 15-24 were more likely to cite external packaging [adjusted prevalence ratio (aPR = 2.06, 95% CI 1.00-4.23)] and design features (aPR = 1.99, 1.20-3.29) as important. As further legislation is debated and enacted enhanced regulation of price, design and marketing features of e-cigarettes may help to reduce the appeal of e cigarettes. PMID- 27471219 TI - Measuring Handoffs: Can We Improve the Transition of Hospitalized Children? PMID- 27471218 TI - Quality Measures to Assess Care Transitions for Hospitalized Children. AB - BACKGROUND: Transitions between sites of care are inherent to all hospitalizations, yet we lack pediatric-specific transitions-of-care quality measures. We describe the development and validation of new transitions-of-care quality measures obtained from medical record data. METHODS: After an evidence review, a multistakeholder panel prioritized quality measures by using the RAND/University of California, Los Angeles modified Delphi method. Three measures were endorsed, operationalized, and field-tested at 3 children's hospitals and 2 community hospitals: quality of hospital-to-home transition record content, timeliness of discharge communication between inpatient and outpatient providers, and ICU-to-floor transition note quality. Summary scores were calculated on a scale from 0 to 100; higher scores indicated better quality. We examined between hospital variation in scores, associations of hospital-to-home transition quality scores with readmission and emergency department return visit rates, and associations of ICU-to-floor transition quality scores with ICU readmission and length of stay. RESULTS: A total of 927 charts from 5 hospitals were reviewed. Mean quality scores were 65.5 (SD 18.1) for the hospital-to-home transition record measure, 33.3 (SD 47.1) for the discharge communication measure, and 64.9 (SD 47.1) for the ICU-to-floor transition measure. The mean adjusted hospital-to home transition summary score was 61.2 (SD 17.1), with significant variation in scores between hospitals (P < .001). Hospital-to-home transition quality scores were not associated with readmissions or emergency department return visits. ICU to-floor transition note quality scores were not associated with ICU readmissions or hospital length of stay. CONCLUSIONS: These quality measures were feasible to implement in diverse settings and varied across hospitals. The development of these measures is an important step toward standardized evaluation of the quality of pediatric transitional care. PMID- 27471221 TI - Eradicating Female Genital Mutilation: A UK Perspective. PMID- 27471220 TI - Developmental Assessments in Preterm Children: A Meta-analysis. AB - CONTEXT: Developmental outcomes of very preterm (gestational age <=32 weeks) or very low birth weight (<1500 g) children are commonly reported before age 3 years although the predictive validity for later outcomes are uncertain. OBJECTIVE: To determine the validity of early developmental assessments in predicting school age cognitive deficits. DATA SOURCES: PubMed. STUDY SELECTION: English-language studies reporting at least 2 serial developmental/cognitive assessments on the same population, 1 between ages 1 and 3 years and 1 at >=5 years. DATA EXTRACTION: For each study, we calculated the sensitivity, specificity, and positive and negative predictive values of early assessment for cognitive deficit (defined as test scores 1 SD below the population mean). Pooled meta-analytic sensitivity and specificity were estimated by using a hierarchical summary receiver operator characteristic curve. RESULTS: We included 24 studies (n = 3133 children). Early assessments were conducted at 18 to 40 months and generally involved the Bayley Scales of Infant Development or the Griffiths Mental Development Scales; 11 different cognitive tests were used at school-age assessments at 5 to 18 years. Positive predictive values ranged from 20.0% to 88.9%, and negative predictive vales ranged from 47.8% to 95.5%. The pooled sensitivity (95% confidence interval) of early assessment for identifying school age cognitive deficit was 55.0% (45.7%-63.9%) and specificity was 84.1% (77.5% 89.1%). Gestational age, birth weight, age at assessment, and time between assessments did not explain between-study heterogeneity. LIMITATIONS: The accuracy of aggregated data could not be verified. Many assessment tools have been superseded by newer editions. CONCLUSIONS: Early developmental assessment has poor sensitivity but good specificity and negative predictive value for school-age cognitive deficit. PMID- 27471222 TI - Unsupervised detection and analysis of changes in everyday physical activity data. AB - Sensor-based time series data can be utilized to monitor changes in human behavior as a person makes a significant lifestyle change, such as progress toward a fitness goal. Recently, wearable sensors have increased in popularity as people aspire to be more conscientious of their physical health. Automatically detecting and tracking behavior changes from wearable sensor-collected physical activity data can provide a valuable monitoring and motivating tool. In this paper, we formalize the problem of unsupervised physical activity change detection and address the problem with our Physical Activity Change Detection (PACD) approach. PACD is a framework that detects changes between time periods, determines significance of the detected changes, and analyzes the nature of the changes. We compare the abilities of three change detection algorithms from the literature and one proposed algorithm to capture different types of changes as part of PACD. We illustrate and evaluate PACD on synthetic data and using Fitbit data collected from older adults who participated in a health intervention study. Results indicate PACD detects several changes in both datasets. The proposed change algorithms and analysis methods are useful data mining techniques for unsupervised, window-based change detection with potential to track users' physical activity and motivate progress toward their health goals. PMID- 27471223 TI - Multi-faceted implementation strategy to increase use of a clinical guideline for the diagnosis of deep venous thrombosis in primary care. AB - Background: A clinical decision rule (CDR), combined with a negative D-dimer test, can safely rule out deep venous thrombosis (DVT) in primary care. This strategy is recommended by guidelines, yet uptake by GPs is low. Objective: To evaluate a multi-faceted implementation strategy aimed at increased use of the guideline recommended CDR plus D-dimer test in primary care patients with suspected DVT. Methods: This multi-faceted implementation strategy consisted of educational outreach visits, financial reimbursements and periodical newsletters. 217 Dutch GPs (implementation group) received this strategy and included patients. Effectiveness was measured through the following patient-level outcomes: (i) proportion of non-referred patients, (ii) proportion of missed DVT cases within this group and (iii) the proportion of patients in whom the guideline was applied incorrectly. Implementation outcomes ('acceptability', 'feasibility', 'fidelity' and 'sustainability') were assessed with an online questionnaire. Patient-level outcomes were compared with those of patients included by 450 GPs, uninformed about the study's purposes providing information about usual care. Results: 336 (54%) of 619 analyzable implementation group patients were not referred, missing 6 [1.8% (95% confidence interval 0.7% to 3.9%)] DVT cases. Incorrect guideline use was observed in 199 patients (32%). Self-reported acceptability, feasibility and expected sustainability were high. Guideline use increased from 42% to an expected continuation of use of 91%. Only 32 usual care GPs included 62 patients, making formal comparison unreliable. Conclusions: This multi-faceted implementation strategy safely reduced patient referral to secondary care, despite frequently incorrect application of the guideline and resulted in high acceptability, feasibility and expected sustainability. PMID- 27471225 TI - Life on the Edge-the Biology of Organisms Inhabiting Extreme Environments: An Introduction to the Symposium. AB - Life persists, even under extremely harsh conditions. While the existence of extremophiles is well known, the mechanisms by which these organisms evolve, perform basic metabolic functions, reproduce, and survive under extreme physical stress are often entirely unknown. Recent technological advances in terms of both sampling and studying extremophiles have yielded new insight into their evolution, physiology and behavior, from microbes and viruses to plants to eukaryotes. The goal of the "Life on the Edge-the Biology of Organisms Inhabiting Extreme Environments" symposium was to unite researchers from taxonomically and methodologically diverse backgrounds to highlight new advances in extremophile biology. Common themes and new insight that emerged from the symposium included the important role of symbiotic associations, the continued challenges associated with sampling and studying extremophiles and the important role these organisms play in terms of studying climate change. As we continue to explore our planet, especially in difficult to reach areas from the poles to the deep sea, we expect to continue to discover new and extreme circumstances under which life can persist. PMID- 27471224 TI - The validation of electronic health records in accurately identifying patients eligible for colorectal cancer screening in safety net clinics. AB - BACKGROUND: While electronic health records (EHRs) play a key role in increasing colorectal cancer (CRC) screening by identifying individuals who are overdue, important shortfalls remain. OBJECTIVES: As part of the Strategies and Opportunities to STOP Colon Cancer (STOP CRC) study, we assessed the accuracy of EHR codes in identifying patients eligible for CRC screening. METHODS: We selected a stratified random sample of 800 study participants from 26 participating clinics, in the Pacific Northwest region of the USA. We compared data obtained through codes in the EHR to conduct a manual chart audit. A trained chart abstractor completed the abstraction of eligible and ineligible patients. RESULTS: Of 520 individuals in need of CRC screening, identified via the EHR, 459 were confirmed through chart review (positive predictive value = 88%). Of 280 individuals flagged as up-to-date in their screening per EHR data, 269 were confirmed through chart review (negative predictive value = 96%). Among the 61 patients incorrectly classified as eligible, 83.6% of disagreements were due to evidence of a prior colonoscopy or referral that was not captured in recognizable fields in the EHR. CONCLUSIONS: Our findings highlight importance of better capture of past screening events in the EHR. While the need for better population based data is not unique to CRC screening, it provides an important example of the use of population-based data not only for tracking care, but also for delivering interventions. PMID- 27471226 TI - The Olfactory Neuroecology of Herbivory, Hostplant Selection and Plant-Pollinator Interactions. AB - Plants experience often opposing energetic demands and selective pressures-for instance, where plants need to attract an insect that is both the pollinator and herbivore, or alternately, where plants attract prey (due to limited resources) and pollinators. Together, these selective pressures can modify the volatile signals available to the plant's mutualistic and antagonistic partners. Nevertheless, it remains an open question how changes in the information content of volatile signals modify behavioral responses in mutualists and antagonists, and what the underlying neural bases of these behaviors are. This review focuses on two systems to explore the impact of herbivory and resource availability on plant-pollinator interactions: hawkmoth-pollinated hostplants (where herbivory is common), and carnivorous bee-pollinated pitcher plants (where the plants differentially attract bee pollinators and other insect prey). We focus on (1) the volatile signals emitted from these plants because these volatiles operate as long-distance signals to attract, or deter, insect partners, (2) how this information is processed in the hawkmoth olfactory system, and (3) how volatile information changes spatiotemporally. In both the plants and their respective insect partner(s), volatile signaling, reception and behavior are dynamic and plastic, providing flexibility an ever-changing environment. PMID- 27471227 TI - Sex Differences in Defensive Behavior and Venom of The Striped Bark Scorpion Centruroides vittatus (Scorpiones: Buthidae). AB - Studies of venom variability have advanced from describing the mechanisms of action and relative potency of medically important toxins to understanding the ecological and evolutionary causes of the variability itself. While most studies have focused on differences in venoms among taxa, populations, or age-classes, there may be intersexual effects as well. Striped bark scorpions (Centruroides vittatus) provide a good model for examining sex differences in venom composition and efficacy, as this species exhibits dramatic sexual dimorphism in both size and defensive behavior; when threatened by an enemy, larger, slower females stand and fight while smaller, fleeter males prefer to run. We here add evidence suggesting that male and female C. vittatus indeed have different defensive propensities; when threatened via an electrical stimulus, females were more likely to sting than were males. We reasoned that intersexual differences in defensive phenotypes would select for venoms with different functions in the two sexes; female venoms should be effective at predator deterrence, whereas male venoms, less utilized defensively, might be better suited to capturing prey or courting females. This rationale led to our predictions that females would inject more venom and/or possess more painful venom than males. We were wrong. While females do inject more venom than males in a defensive sting, females are also larger; when adjusted for body size, male and female C. vittatus commit equal masses of venom in a sting to a potential enemy. Additionally, house mice (Mus musculus) find an injection of male venom more irritating than an equal amount of female venom, likely because male venom contains more of the toxins that induce pain. Taken together, our results suggest that identifying the ultimate causes of venom variability will, as we move beyond adaptive storytelling, be hard-won. PMID- 27471228 TI - The Morphological Diversity of Intromittent Organs: An Introduction to the Symposium. AB - Intromittent organs are structures that enter the female genital tract and deposit sperm; these organs are found in many animal taxa that use internal fertilization. Despite their shared function, they are fantastically diverse morphologically. Many of their species-specific shape differences are likely the result of sexual selection and coevolution between male and female reproductive tracts, but a growing number of studies have identified other factors that can also affect their functional anatomy. In this symposium, we united scientists who combine morphological methods with contemporary molecular, phylogenetic, and imaging techniques to study the reproductive performance of intromittent organs in invertebrate and vertebrate model systems. The result was a collection of studies discussing competing selective pressures that act on these structures, including the effects of life history, genes and development, sexual conflict, ecological interactions, the biomechanics of copulation, and phenotypic plasticity. There was also an overwhelming consensus that a full understanding of intromittent organ evolution will not be possible without complimentary studies of morphology and function in female reproductive tracts. PMID- 27471229 TI - Dameshek W. Chronic lymphocytic leukemia-an accumulative disease of immunologically incompetent lymphocytes. Blood. 1967;29(4):566-584. PMID- 27471230 TI - Dampening neutrophil integrins. PMID- 27471231 TI - IL-4 regulates B-cell receptor signaling in CLL. PMID- 27471232 TI - Two strikes against CLL. PMID- 27471233 TI - Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice. AB - Interactions between collagenous extracellular matrices and von Willebrand factor (VWF) are critical for hemostasis and thrombosis. In the present study, we investigated the contribution of an extracellular matrix (ECM) abnormality to the bleeding diathesis in thrombospondin-2 (TSP2) knockout (KO) mice. First, we performed adoptive bone marrow transplantation and observed that introduction of wild-type (WT) marrow into lethally irradiated TSP2 KO mice did not rescue the bleeding diathesis. However, platelets in transplanted mice displayed an inherent aggregation defect, which complicated interpretation. Second, we performed interposition of arterial segments denuded of endothelium. Denuded TSP2 KO arteries grafted into WT mice remained patent in vivo. In contrast, WT grafts underwent thrombosis and were completely occluded within 24 to 48 hours. The nonthrombogenic property of the TSP2 KO ECM was confirmed in vitro by exposing platelets to TSP2 KO dermal fibroblast (DF)-derived ECM. To further probe the effect of TSP2 deficiency, ECM production and deposition by WT and TSP2 KO DFs was analyzed via polymerase chain reaction, immunofluorescence, and scanning electron microscopy and showed similar patterns. In addition, atomic force microscopy (AFM) analysis of WT and TSP2 KO ECM did not reveal differences in stiffness. In contrast, reduced VWF accumulation on TSP2 KO ECM was observed when matrices were subjected to plasma under physiological flow. AFM utilizing VWF coated 2-MUm beads confirmed the weak binding to TSP2 KO ECM, providing a mechanistic explanation for the lack of thrombus formation. Therefore, our studies show that ECM assembly is critical for interaction of collagen with VWF and subsequent thrombogenic responses. PMID- 27471234 TI - T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire. AB - Factor VIII (FVIII)-neutralizing antibodies ("inhibitors") are a serious problem in hemophilia A (HA). The aim of this study was to characterize HLA-restricted T cell responses from a severe HA subject with a persistent inhibitor and from 2 previously studied mild HA inhibitor subjects. Major histocompatibility complex II tetramers corresponding to both of the severe HA subject's HLA-DRA-DRB1 alleles were loaded with peptides spanning FVIII-A2, C1, and C2 domains. Interestingly, only 1 epitope was identified, in peptide FVIII2194-2213, and it was identical to the HLA-DRA*01-DRB1*01:01-restricted epitope recognized by the mild HA subjects. Multiple T-cell clones and polyclonal lines having different avidities for the peptide-loaded tetramer were isolated from all subjects. Only high- and medium-avidity T cells proliferated and secreted cytokines when stimulated with FVIII2194-2213 T-cell receptor beta (TCRB) gene sequencing of 15 T-cell clones from the severe HA subject revealed that all high-avidity clones expressed the same TCRB gene. High-throughput immunosequencing of high-, medium-, and low-avidity cells sorted from a severe HA polyclonal line revealed that 94% of the high-avidity cells expressed the same TCRB gene as the high-avidity clones. TCRB sequencing of clones and lines from the mild HA subjects also identified a limited TCRB gene repertoire. These results suggest a limited number of epitopes in FVIII drive inhibitor responses and that the T-cell repertoires of FVIII-responsive T cells can be quite narrow. The limited diversity of both epitopes and TCRB gene usage suggests that targeting of specific epitopes and/or T-cell clones may be a promising approach to achieve tolerance to FVIII. PMID- 27471235 TI - How I diagnose and manage individuals at risk for inherited myeloid malignancies. AB - Although inherited hematopoietic malignancies have been reported clinically since the early twentieth century, the molecular basis for these diseases has only recently begun to be elucidated. Growing utilization of next-generation sequencing technologies has facilitated the rapid discovery of an increasing number of recognizable heritable hematopoietic malignancy syndromes while also deepening the field's understanding of the molecular mechanisms that underlie these syndromes. Because individuals with inherited hematopoietic malignancies continue to be underdiagnosed and are increasingly likely to be encountered in clinical practice, clinicians need to have a high index of suspicion and be aware of the described syndromes. Here, we present the methods we use to identify, test, and manage individuals and families suspected of having a hereditary myeloid malignancy syndrome. Finally, we address the areas of ongoing research in the field and encourage clinicians and researchers to contribute and collaborate. PMID- 27471236 TI - The role of Nrf2 in skeletal muscle contractile and mitochondrial function. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that confers cellular protection by upregulating antioxidant enzymes in response to oxidative stress. However, Nrf2 function within skeletal muscle remains to be further elucidated. We examined the role of Nrf2 in determining muscle phenotype using young (3 mo) and older (12 mo) Nrf2 wild-type (WT) and knockout (KO) mice. Basally, the absence of Nrf2 did not impact mitochondrial content. In intermyofibrillar mitochondria, lack of Nrf2 resulted in a 40% reduction in state 4 respiration, which coincided with a 68% increase in reactive oxygen species (ROS) emission. Nrf2 abrogation impaired in situ muscle performance, characterized by a 48% greater rate of fatigue and a 35% decrease in force within the first 5 min of stimulation. Acute treadmill exercise resulted in a 1.5-fold increase in Nrf2 activation via enhanced DNA binding in WT animals. In response to training, cytochrome-c oxidase activity increased by 20% in the WT animals; however, this response was attenuated in KO mice. Nrf2 protein was reduced 30% by training. Despite this, exercise training normalized respiration, ROS production, and muscle performance in KO mice. Our results suggest that Nrf2 transcriptional activity is increased by exercise and that Nrf2 is required for the maintenance of basal mitochondrial function as well as for the normal increase in specific mitochondrial proteins in response to training. Nonetheless, the decrements in mitochondrial function in Nrf2 KO muscle can be rescued by exercise training, suggesting that this restorative function operates via a pathway independent of Nrf2. PMID- 27471238 TI - Membrane progesterone receptor-beta, but not -alpha, in dorsal brain stem establishes sex-specific chemoreflex responses and reduces apnea frequency in adult mice. AB - We tested the hypothesis that membrane progesterone receptors (mPR) contribute to respiratory control in adult male and female mice. Mice were implanted with osmotic minipumps for continuous infusion of small interfering RNA (siRNA) directed against mPRalpha, mPRbeta, or a control solution in the fourth ventricle (to target brain stem respiratory areas) for 14 days. We then performed respiratory and metabolic recordings by whole body plethysmography at rest and in response to hypoxia (12% O2) or hypercapnia (5% CO2, 5 min each). For each treatment, we have verified with immunohistochemistry that the staining intensity of mPRalpha or mPRbeta in the brain stem is decreased. At rest, the siRNA against mPRalpha and mPRbeta increased respiratory frequency in males only. The siRNA against mPRbeta almost tripled the frequency of apneas in male and in female mice, while the siRNA against mPRalpha had no effect. Regarding respiratory chemoreflex, the siRNA against mPRbeta suppressed the response to hypoxia in male and female mice and reduced by ~50% the response to hypercapnia, while the siRNA against mPRalpha had more limited effects. Interestingly, control females had higher ventilatory response to hypoxia and hypercapnia than males, and these sex specific effects were suppressed by the siRNA against mPRbeta, whereas they were still present after treatment with the siRNA against mPRalpha. We conclude that mPRbeta reduces apnea frequency in male and female mice and establishes sex specific ventilatory chemoreflex. PMID- 27471239 TI - Effects of pacing modality on noninvasive assessment of heart rate dependency of indices of large artery function. AB - Studies investigating the relationship between heart rate (HR) and arterial stiffness or wave reflections have commonly induced HR changes through in situ cardiac pacing. Although pacing produces consistent HR changes, hemodynamics can be different with different pacing modalities. Whether the differences affect the HR relationship with arterial stiffness or wave reflections is unknown. In the present study, 48 subjects [mean age, 78 +/- 10 (SD), 9 women] with in situ cardiac pacemakers were paced at 60, 70, 80, 90, and 100 beats per min under atrial, atrioventricular, or ventricular pacing. At each paced HR, brachial cuff based pulse wave analysis was used to determine central hemodynamic parameters, including ejection duration (ED) and augmentation index (AIx). Wave separation analysis was used to determine wave reflection magnitude (RM) and reflection index (RI). Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV). Pacing modality was found to have significant effects on the HR relationship with ED (P = 0.01), central aortic pulse pressure (P = 0.01), augmentation pressure (P < 0.0001), and magnitudes of both forward and reflected waves (P = 0.05 and P = 0.003, respectively), but not cfPWV (P = 0.57) or AIx (P = 0.38). However, at a fixed HR, significant differences in pulse pressure amplification (P < 0.001), AIx (P < 0.0001), RM (P = 0.03), and RI (P = 0.03) were observed with different pacing modalities. These results demonstrate that although the HR relationships with arterial stiffness and systolic loading as measured by cfPWV and AIx were unaffected by pacing modality, it should still be taken into account for studies in which mixed pacing modalities are present, in particular, for wave reflection studies. PMID- 27471237 TI - Intermittent hypoxia induces murine macrophage foam cell formation by IKK-beta dependent NF-kappaB pathway activation. AB - Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH). Clinical studies have previously shown that OSA is an independent risk factor for atherosclerosis. Atherogenicity in OSA patients has been assumed to be associated with the NF-kappaB pathways. Although foam cells are considered to be a hallmark of atherosclerosis, how IH as in OSA affects their development has not been fully understood. Therefore, we hypothesized that IH induces macrophage foam cell formation through NF-kappaB pathway activation. To test this hypothesis, peritoneal macrophages collected from myeloid-restricted IKK-beta-deleted mice were incubated with native LDL and exposed to either IH or normoxia. After exposure, NF-kappaB pathway activity and intracellular cholesterol were measured. In control macrophages, IH significantly increased NF kappaB pathway activity by 93% compared with normoxia (P < 0.05). However, such response to IH was diminished by IKK-beta deletion (increased by +31% compared with normoxia; P = 0.64), suggesting that IKK-beta is critical for IH-induced NF kappaB pathway activation. Likewise, in control macrophages, total cholesterol was increased in IH compared with normoxia (65.7 +/- 3.8 MUg/mg cellular protein and 53.2 +/- 1.2, respectively; P < 0.05). However, this IH-induced foam cell formation was disappeared when IKK-beta was deleted (52.2 +/- 1.2 MUg/mg cellular protein for IH and 46.3 +/- 1.7 for normoxia; P = 0.55). This IH-mediated effect still existed in macrophages without LDL receptor. Taken together, our findings show that IH activates the IKK-beta-dependent NF-kappaB pathway and that this, in turn, induces foam cell formation in murine macrophages. PMID- 27471240 TI - Using devices to upregulate nonnutritive swallowing in typically developing infants. AB - The role of various sensory stimuli for stimulating swallowing in infants may be of importance for assisting infants to develop oral feeding. We evaluated the swallowing mechanism response to two devices for increasing the rate of nonnutritive swallowing in two typically developing infant age groups, ages 2-4 mo and 7-9 mo. One device was a pacifier familiar to the infant; the other was a small vibrator placed on the skin overlying the thyroid cartilage. The rate of nonnutritive swallowing while infants were awake was compared in three 10-min conditions: at rest without stimulation (spontaneous); during nonnutritive sucking with a pacifier; and over 10 min containing 18 epochs of vibratory stimulation for 10 s each. To assess whether vibration on the throat over the laryngeal area altered respiration, the mean cycle length was compared between 10 min intervals either containing vibratory stimulation or without stimulation at rest. Both the pacifier and laryngeal vibration stimulation doubled the rate of swallowing in the infants with a mean age of 3 mo 16 days and infants with a mean age of 8 mo 8 days. No differences occurred in the mean respiratory cycle length between intervals with and without vibration in either age group. Results suggest that nonnutritive sucking, vibration, or both might be beneficial in enhancing swallowing in young infants. Because vibration on the neck would not interfere with oral transfer of liquid, it might provide additional stimulation for swallowing during oral feeding. Both stimulation types should be evaluated for enhancing swallowing in infants with immature swallowing skills. PMID- 27471242 TI - Adverse inpatient outcomes during the transition to a new electronic health record system: observational study. AB - OBJECTIVE: To assess the short term association of inpatient implementation of electronic health records (EHRs) with patient outcomes of mortality, readmissions, and adverse safety events. DESIGN: Observational study with difference-in-differences analysis. SETTING: Medicare, 2011-12. PARTICIPANTS: Patients admitted to 17 study hospitals with a verifiable "go live" date for implementation of inpatient EHRs during 2011-12, and 399 control hospitals in the same hospital referral region. MAIN OUTCOME MEASURES: All cause readmission within 30 days of discharge, all cause mortality within 30 days of admission, and adverse safety events as defined by the patient safety for selected indicators (PSI)-90 composite measure among Medicare beneficiaries admitted to one of these hospitals 90 days before and 90 days after implementation of the EHRs (n=28 235 and 26 453 admissions), compared with the control group of all contemporaneous admissions to hospitals in the same hospital referral region (n=284 632 and 276 513 admissions). Analyses were adjusted for beneficiaries' sociodemographic and clinical characteristics. RESULTS: Before and after implementation, characteristics of admissions were similar in both study and control hospitals. Among study hospitals, unadjusted 30 day mortality (6.74% to 7.15%, P=0.06) and adverse safety event rates (10.5 to 11.4 events per 1000 admissions, P=0.34) did not significantly change after implementation of EHRs. There was an unadjusted decrease in 30 day readmission rates, from 19.9% to 19.0% post-implementation (P=0.02). In difference-in-differences analysis, however, there was no significant change in any outcome between pre-implementation and post implementation periods (all P>=0.13). CONCLUSIONS: Despite concerns that implementation of EHRs might adversely impact patient care during the acute transition period, we found no overall negative association of such implementation on short term inpatient mortality, adverse safety events, or readmissions in the Medicare population across 17 US hospitals. PMID- 27471243 TI - A Newborn with Distended Abdomen. PMID- 27471244 TI - Commentary. PMID- 27471245 TI - Commentary. PMID- 27471246 TI - Seizures, Dystonia, and Spasms in a 14-Year-Old Child. PMID- 27471247 TI - Undetectable Urine Calcium in a Gastric Bypass Patient. PMID- 27471248 TI - Unexpected Case of Bright Pink-Colored Plasma. PMID- 27471249 TI - Is This Patient Pregnant? PMID- 27471250 TI - What Can a Clinical Chemist Learn from Aviation? PMID- 27471251 TI - The "Madness" of William Blake. PMID- 27471252 TI - Div-Seq: Single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons. AB - Single-cell RNA sequencing (RNA-Seq) provides rich information about cell types and states. However, it is difficult to capture rare dynamic processes, such as adult neurogenesis, because isolation of rare neurons from adult tissue is challenging and markers for each phase are limited. Here, we develop Div-Seq, which combines scalable single-nucleus RNA-Seq (sNuc-Seq) with pulse labeling of proliferating cells by 5-ethynyl-2'-deoxyuridine (EdU) to profile individual dividing cells. sNuc-Seq and Div-Seq can sensitively identify closely related hippocampal cell types and track transcriptional dynamics of newborn neurons within the adult hippocampal neurogenic niche, respectively. We also apply Div Seq to identify and profile rare newborn neurons in the adult spinal cord, a noncanonical neurogenic region. sNuc-Seq and Div-Seq open the way for unbiased analysis of diverse complex tissues. PMID- 27471253 TI - Acute Kidney Injury Urine Biomarkers in Very Low-Birth-Weight Infants. AB - BACKGROUND AND OBJECTIVES: Serum creatinine (SCr)-based AKI definitions have important limitations, particularly in very low-birth-weight (VLBW) neonates. Urine biomarkers may improve our ability to detect kidney damage. We assessed the association between 14 different urine biomarkers and AKI in VLBW infants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a prospective cohort study on 113 VLBW infants (weight <=1200 g or <31 weeks' gestation) admitted to a regional neonatal intensive care unit at the University of Alabama at Birmingham between February 2012 and June 2013. SCr was measured on postnatal days 1, 2, 3, and 4 and was combined with clinically measured SCr to determine AKI according to Kidney Disease Improving Global Outcomes AKI definition (increase in SCr >=0.3 mg/dl or >=50% increase from previous lowest value). Urine was collected on the first 4 days (average number of urine collections, 3; range, 1-4). The maximum urine biomarkers and urine biomarker/creatinine levels were calculated for 12 urine biomarkers, and the minimum urine biomarker and biomarker/creatinine levels were assessed for two urine biomarkers. We compared these values between infants with and those without AKI. Ideal cutoffs, area under the receiver-operating characteristic curve , and area under the curve adjusted for gestational age were calculated. RESULTS: Cumulative incidence of AKI during the first 2 postnatal weeks was 28 of 113 (25%). Infants with AKI had higher maximum levels of urine cystatin C, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin, and alpha glutathione S-transferase (2.0, 1.8, 1.7, 1.7, and 3.7 times higher, respectively) than infants without AKI. In addition, infants with AKI had lower minimum levels of epithelial growth factor and uromodulin than those without AKI (1.4 and 1.6 times lower, respectively). Most but not all participants had their maximum (or minimum) biomarker values preceding AKI. These associations remained after adjustment for gestational age. CONCLUSIONS: Urine biomarkers measured in the first 4 days of life are associated with AKI during the first postnatal weeks. Further evaluations are necessary to determine whether these biomarkers can predict important clinical outcomes. In addition, intervention studies that use biomarkers to stratify enrollment groups are needed before bedside evaluations can be incorporated into care. PMID- 27471254 TI - SARA regulates neuronal migration during neocortical development through L1 trafficking. AB - Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the early endosomal protein Smad anchor for receptor activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppression-induced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression. PMID- 27471256 TI - Protein synthesis and degradation are essential to regulate germline stem cell homeostasis in Drosophila testes. AB - The homeostasis of self-renewal and differentiation in stem cells is controlled by intrinsic signals and their niche. We conducted a large-scale RNA interference (RNAi) screen in Drosophila testes and identified 221 genes required for germline stem cell (GSC) maintenance or differentiation. Knockdown of these genes in transit-amplifying spermatogonia and cyst cells further revealed various phenotypes. Complex analysis uncovered that many of the identified genes are involved in key steps of protein synthesis and degradation. A group of genes that are required for mRNA splicing and protein translation contributes to both GSC self-renewal and early germ cell differentiation. Loss of genes in the protein degradation pathway in cyst cells leads to testis tumors consisting of overproliferated germ cells. Importantly, in the Cullin 4-RING E3 ubiquitin ligase (CRL4) complex, we identified multiple proteins that are crucial to GSC self-renewal: pic/DDB1, a CRL4 linker protein, is not only required for GSC self renewal in flies but also for maintenance of spermatogonial stem cells (SSCs) in mice. PMID- 27471255 TI - AP-1 family members act with Sox9 to promote chondrocyte hypertrophy. AB - An analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif. Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun- and Sox9-bound regions throughout the chondrocyte genome, reflecting direct binding of each factor to the same enhancers and a potential for protein-protein interactions within AP-1- and Sox9-containing complexes. In vitro reporter analysis indicated that direct co-binding of Sox9 and AP-1 at target motifs promoted gene activity. By contrast, where only one factor can engage its DNA target, the presence of the other factor suppresses target activation consistent with protein-protein interactions attenuating transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 confirmed the requirement of Sox9 for hypertrophic chondrocyte development, and in vitro and ex vivo analyses showed that AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model in which AP-1 family members contribute to Sox9 action in the transition of chondrocytes to the hypertrophic program. PMID- 27471258 TI - Escargot and Scratch regulate neural commitment by antagonizing Notch activity in Drosophila sensory organs. AB - During Notch (N)-mediated binary cell fate decisions, cells adopt two different fates according to the levels of N pathway activation: an Noff-dependent or an Non-dependent fate. How cells maintain these N activity levels over time remains largely unknown. We address this question in the cell lineage that gives rise to the Drosophila mechanosensory organs. In this lineage a primary precursor cell undergoes a stereotyped sequence of oriented asymmetric cell divisions and transits through two neural precursor states before acquiring a neuron identity. Using a combination of genetic and cell biology strategies, we show that Escargot and Scratch, two transcription factors belonging to the Snail superfamily, maintain Noff neural commitment by directly blocking the transcription of N target genes. We propose that Snail factors act by displacing proneural transcription activators from DNA binding sites. As such, Snail factors maintain the Noff state in neural precursor cells by buffering any ectopic variation in the level of N activity. Since Escargot and Scratch orthologs are present in other precursor cells, our findings are fundamental for understanding precursor cell fate acquisition in other systems. PMID- 27471257 TI - Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex. AB - Sall4 is an essential transcription factor for early mammalian development and is frequently overexpressed in cancer. Although it is reported to play an important role in embryonic stem cell (ESC) self-renewal, whether it is an essential pluripotency factor has been disputed. Here, we show that Sall4 is dispensable for mouse ESC pluripotency. Sall4 is an enhancer-binding protein that prevents precocious activation of the neural gene expression programme in ESCs but is not required for maintenance of the pluripotency gene regulatory network. Although a proportion of Sall4 protein physically associates with the Nucleosome Remodelling and Deacetylase (NuRD) complex, Sall4 neither recruits NuRD to chromatin nor influences transcription via NuRD; rather, free Sall4 protein regulates transcription independently of NuRD. We propose a model whereby enhancer binding by Sall4 and other pluripotency-associated transcription factors is responsible for maintaining the balance between transcriptional programmes in pluripotent cells. PMID- 27471260 TI - Apoptosis regulates endothelial cell number and capillary vessel diameter but not vessel regression during retinal angiogenesis. AB - The growth of hierarchical blood vessel networks occurs by angiogenesis. During this process, new vessel growth is accompanied by the removal of redundant vessel segments by selective vessel regression ('pruning') and a reduction in endothelial cell (EC) density in order to establish an efficient, hierarchical network. EC apoptosis has long been recognised for its association with angiogenesis, but its contribution to this process has remained unclear. We generated mice in which EC apoptosis was blocked by tissue-specific deletion of the apoptosis effector proteins BAK and BAX. Using the retina as a model, we found that apoptosis made a minor contribution to the efficiency of capillary regression around arteries where apoptosis was most concentrated, but was otherwise dispensable for vessel pruning. Instead, apoptosis was necessary for the removal of non-perfused vessel segments and the reduction in EC density that occurs during vessel maturation. In the absence of apoptosis, increased EC density resulted in an increase in the diameter of capillaries, but not arteries or veins. Our findings show that apoptosis does not influence the number of vessels generated during angiogenesis. Rather it removes non-perfused vessel segments and regulates EC number during vessel maturation, which has vessel specific consequences for vessel diameter. PMID- 27471259 TI - Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment. AB - Skeletal muscle morphogenesis depends upon interactions between developing muscle fibers and the extracellular matrix (ECM) that anchors fibers to the myotendinous junction (MTJ). The pathways that organize the ECM and regulate its engagement by cell-matrix adhesion complexes (CMACs) are therefore essential for muscle integrity. Here, we demonstrate the impact of transmembrane protein 2 (tmem2) on cell-matrix interactions during muscle morphogenesis in zebrafish. Maternal zygotic tmem2 mutants (MZtmem2) exhibit muscle fiber detachment, in association with impaired laminin organization and ineffective fibronectin degradation at the MTJ. Similarly, disorganized laminin and fibronectin surround MZtmem2 cardiomyocytes, which could account for their hindered movement during cardiac morphogenesis. In addition to ECM defects, MZtmem2 mutants display hypoglycosylation of alpha-dystroglycan within the CMAC, which could contribute to the observed fiber detachment. Expression of the Tmem2 ectodomain can rescue aspects of the MZtmem2 phenotype, consistent with a possible extracellular function of Tmem2. Together, our results suggest that Tmem2 regulates cell-matrix interactions by affecting both ECM organization and CMAC activity. These findings evoke possible connections between the functions of Tmem2 and the etiologies of congenital muscular dystrophies, particularly dystroglycanopathies. PMID- 27471261 TI - Live imaging of X chromosome reactivation dynamics in early mouse development can discriminate naive from primed pluripotent stem cells. AB - Pluripotent stem cells can be classified into two distinct states, naive and primed, which show different degrees of potency. One difficulty in stem cell research is the inability to distinguish these states in live cells. Studies on female mice have shown that reactivation of inactive X chromosomes occurs in the naive state, while one of the X chromosomes is inactivated in the primed state. Therefore, we aimed to distinguish the two states by monitoring X chromosome reactivation. Thus far, X chromosome reactivation has been analysed using fixed cells; here, we inserted different fluorescent reporter gene cassettes (mCherry and eGFP) into each X chromosome. Using these knock-in 'Momiji' mice, we detected X chromosome reactivation accurately in live embryos, and confirmed that the pluripotent states of embryos were stable ex vivo, as represented by embryonic and epiblast stem cells in terms of X chromosome reactivation. Thus, Momiji mice provide a simple and accurate method for identifying stem cell status based on X chromosome reactivation. PMID- 27471262 TI - Classic Spotlight: Green Fluorescent Protein in Bacillus subtilis and the Birth of Bacterial Cell Biology. PMID- 27471263 TI - Classic Spotlight: Boxing in the FtsZ Ring, Round One. PMID- 27471265 TI - Erratum for Osorio-Valeriano et al., Biochemical Characterization of the Flagellar Rod Components of Rhodobacter sphaeroides: Properties and Interactions. PMID- 27471266 TI - Erratum for Herlihey et al., Modulation of the Lytic Activity of the Dedicated Autolysin for Flagellum Formation SltF by Flagellar Rod Proteins FlgB and FlgF. PMID- 27471267 TI - Correction for de la Mora et al., Structural Characterization of the Fla2 Flagellum of Rhodobacter sphaeroides. PMID- 27471269 TI - Functional Study and Mapping Sites for Interaction with the Target Enzyme in Retinal Degeneration 3 (RD3) Protein. AB - Retinal degeneration 3 (RD3) protein, essential for normal expression of retinal membrane guanylyl cyclase (RetGC) in photoreceptor cells, blocks RetGC catalytic activity and stimulation by guanylyl cyclase-activating proteins (GCAPs). In a mouse retina, RD3 inhibited both RetGC1 and RetGC2 isozymes. Photoreceptors in the rd3/rd3 mouse retinas lacking functional RD3 degenerated more severely than in the retinas lacking both RetGC isozymes, consistent with a hypothesis that the inhibitory activity of RD3 has a functional role in photoreceptors. To map the potential target-binding site(s) on RD3, short evolutionary conserved regions of its primary structure were scrambled and the mutations were tested for the RD3 ability to inhibit RetGC1 and co-localize with the cyclase in co-transfected cells. Substitutions in 4 out of 22 tested regions, (87)KIHP(90), (93)CGPAI(97), (99)RFRQ(102), and (119)RSVL(122), reduced the RD3 apparent affinity for the cyclase 180-700-fold. Changes of amino acid sequences outside the Lys(87) Leu(122) central portion of the molecule either failed to prevent RD3 binding to the cyclase or had a much smaller effect. Mutations in the (93)CGPAI(97) portion of a predicted central alpha-helix most drastically suppressed the inhibitory activity of RD3 and disrupted RD3 co-localization with RetGC1 in HEK293 cells. Different side chains replacing Cys(93) profoundly reduced RD3 affinity for the cyclase, irrespective of their relative helix propensities. We conclude that the main RetGC-binding interface on RD3 required for the negative regulation of the cyclase localizes to the Lys(87)-Leu(122) region. PMID- 27471270 TI - MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains. AB - MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by promoting degradation and/or repressing translation of specific target mRNAs. Several miRNAs have been identified that regulate the amplitude of the innate immune response by directly targeting Toll-like receptor (TLR) pathway members and/or cytokines. miR-33a and miR-33b (the latter present in primates but absent in rodents and lower species) are located in introns of the sterol regulatory element-binding protein (SREBP)-encoding genes and control cholesterol/lipid homeostasis in concert with their host gene products. These miRNAs regulate macrophage cholesterol by targeting the lipid efflux transporters ATP binding cassette (ABC)A1 and ABCG1. We and others have previously reported that Abca1(-/ ) and Abcg1(-/-) macrophages have increased TLR proinflammatory responses due to augmented lipid raft cholesterol. Given this, we hypothesized that miR-33 would augment TLR signaling in macrophages via a raft cholesterol-dependent mechanism. Herein, we report that multiple TLR ligands down-regulate miR-33 in murine macrophages. In the case of lipopolysaccharide, this is a delayed, Toll/interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon beta-dependent response that also down-regulates Srebf-2, the host gene for miR 33. miR-33 augments macrophage lipid rafts and enhances proinflammatory cytokine induction and NF-kappaB activation by LPS. This occurs through an ABCA1- and ABCG1-dependent mechanism and is reversible by interventions upon raft cholesterol and by ABC transporter-inducing liver X receptor agonists. Taken together, these findings extend the purview of miR-33, identifying it as an indirect regulator of innate immunity that mediates bidirectional cross-talk between lipid homeostasis and inflammation. PMID- 27471271 TI - Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1). AB - Human carcinoembryonic antigen-related cell adhesion molecule 1 (C?/Au: EACAM1) is a cell-surface signaling molecule involved in cell adhesion, proliferation, and immune response. It is also implicated in cancer angiogenesis, progression, and metastasis. This diverse set of effects likely arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other molecules. Its N-terminal Ig variable (IgV) domain has been suggested to be a principal player in these interactions. Previous crystal structures of the beta-sandwich-like IgV domain have been produced using Escherichia coli-expressed material, which lacks native glycosylation. These have led to distinctly different proposals for dimer interfaces, one involving interactions of ABED beta-strands and the other involving GFCC'C" beta-strands, with the former burying one prominent glycosylation site. These structures raise questions as to which form may exist in solution and what the effect of glycosylation may have on this form. Here, we use NMR cross-correlation measurements to examine the effect of glycosylation on CEACAM1-IgV dimerization and use residual dipolar coupling (RDC) measurements to characterize the solution structure of the non-glycosylated form. Our findings demonstrate that even addition of a single N-linked GlcNAc at potential glycosylation sites inhibits dimer formation. Surprisingly, RDC data collected on E. coli expressed material in solution indicate that a dimer using the non-glycosylated GFCC'C" interface is preferred even in the absence of glycosylation. The results open new questions about what other factors may facilitate dimerization of CEACAM1 in vivo, and what roles glycosylation may play in heterophylic interactions. PMID- 27471272 TI - Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction. AB - Although the elaborate combination of histone and non-histone protein complexes defines chromatin organization and hence regulates numerous nuclear processes, the role of chromatin organizing proteins remains unexplored at the organismal level. The highly abundant, multifunctional, chromatin-associated protein and transcriptional coactivator positive coactivator 4 (PC4/Sub1) is absolutely critical for life, because its absence leads to embryonic lethality. Here, we report results obtained with conditional PC4 knock-out (PC4(f/f) Nestin-Cre) mice where PC4 is knocked out specifically in the brain. Compared with the control (PC4(+/+) Nestin-Cre) mice, PC4(f/f) Nestin-Cre mice are smaller with decreased nocturnal activity but are fertile and show no motor dysfunction. Neurons in different areas of the brains of these mice show sensitivity to hypoxia/anoxia, and decreased adult neurogenesis was observed in the dentate gyrus. Interestingly, PC4(f/f) Nestin-Cre mice exhibit a severe deficit in spatial memory extinction, whereas acquisition and long term retention were unaffected. Gene expression analysis of the dorsal hippocampus of PC4(f/f) Nestin-Cre mice revealed dysregulated expression of several neural function-associated genes, and PC4 was consistently found to localize on the promoters of these genes, indicating that PC4 regulates their expression. These observations indicate that non-histone chromatin-associated proteins like PC4 play a significant role in neuronal plasticity. PMID- 27471274 TI - Lymphocytic oesophagitis, eosinophilic oesophagitis and compound lymphocytic eosinophilic oesophagitis I: histological and immunohistochemical findings. AB - AIMS: To report four histological-immunohistochemical oesophagitis phenotypes. METHODS: Oesophageal biopsies from 311 patients were stained with H&E and with CD3, a T cell marker. Additional immunohistochemical stains (n=413) were performed in 77 cases. RESULTS: Four histological-immunohistochemical oesophagitis phenotypes were recorded: lymphocytic oesophagitis (LyE, >=40 CD3+ lymphocytes/HPF in CD3 immunostain), eosinophilic oesophagitis (EoE, >=15 eosinophils/HPF in H&E stain), lymphocytic infiltration (<=39 CD3+/HPF) and compound lymphocytic oesophagitis-eosinophilic oesophagitis (Co LyE-EoE). At index biopsy, 28.3% (n=88) had LyE, 21.2% (n=66) EoE, 10.6% (n=33) Co LyE-EoE and 39.9% (n=124) lymphocytic infiltration. A persistent oesophagitis phenotype was found in 42.5% (37/87) in the first follow-up biopsy, in 34.4% (21/61) in the second follow-up biopsy and in 48.1% (26/54) in the third follow-up biopsy. Using betaF1 immunostain, two different surface T cell receptors were detected in LyE and Co Lye-EoE: one having >=40 betaF1+/HPF (betaF1+ high) and the other having <39 betaF1+/HPF (betaF1+ low). CONCLUSIONS: Based on the literature regarding the significance of intraepithelial lymphocytes (IELs) in the initiation of EoE, we submit that the IEL phenotypes in LyE might differ from those found in EoE as they were unable to elicit the same eosinophilic response. Recent studies disclosed that group 2 innate lymphocytes (ILC2s), enriched in EoE, remain undetected in CD3 immunostain as they lack surface markers for T, B, natural killer (NK) or NK T cells. If ILC2s also participate in the lymphocytic infiltration of EoE, then the frequency of cases with Co LyE-EoE here reported might have been much higher. The four oesophagitis phenotypes described are easy to recognise, provided that the dual staining procedure (H&E-CD3) is implemented. PMID- 27471273 TI - Molecular Basis of Chemokine CXCL5-Glycosaminoglycan Interactions. AB - Chemokines, a large family of highly versatile small soluble proteins, play crucial roles in defining innate and adaptive immune responses by regulating the trafficking of leukocytes, and also play a key role in various aspects of human physiology. Chemokines share the characteristic feature of reversibly existing as monomers and dimers, and their functional response is intimately coupled to interaction with glycosaminoglycans (GAGs). Currently, nothing is known regarding the structural basis or molecular mechanisms underlying CXCL5-GAG interactions. To address this missing knowledge, we characterized the interaction of a panel of heparin oligosaccharides to CXCL5 using solution NMR, isothermal titration calorimetry, and molecular dynamics simulations. NMR studies indicated that the dimer is the high-affinity GAG binding ligand and that lysine residues from the N loop, 40s turn, beta3 strand, and C-terminal helix mediate binding. Isothermal titration calorimetry indicated a stoichiometry of two oligosaccharides per CXCL5 dimer. NMR-based structural models reveal that these residues form a contiguous surface within a monomer and, interestingly, that the GAG-binding domain overlaps with the receptor-binding domain, indicating that a GAG-bound chemokine cannot activate the receptor. Molecular dynamics simulations indicate that the roles of the individual lysines are not equivalent and that helical lysines play a more prominent role in determining binding geometry and affinity. Further, binding interactions and GAG geometry in CXCL5 are novel and distinctly different compared with the related chemokines CXCL1 and CXCL8. We conclude that a finely tuned balance between the GAG-bound dimer and free soluble monomer regulates CXCL5-mediated receptor signaling and function. PMID- 27471275 TI - Acclimation potential of Arctic cod (Boreogadus saida) from the rapidly warming Arctic Ocean. AB - As a consequence of the growing concern about warming of the Arctic Ocean, this study quantified the thermal acclimation responses of Boreogadus saida, a key Arctic food web fish. Physiological rates for cardio-respiratory functions as well as critical maximum temperature (Tc,max) for loss of equilibrium (LOE) were measured. The transition temperatures for these events (LOE, the rate of oxygen uptake and maximum heart rate) during acute warming were used to gauge phenotypic plasticity after thermal acclimation from 0.5 degrees C up to 6.5 degrees C for 1 month (respiratory and Tc,max measurements) and 6 months (cardiac measurements). Tc,max increased significantly by 2.3 degrees C from 14.9 degrees C to 17.1 degrees C with thermal acclimation, while the optimum temperature for absolute aerobic scope increased by 4.5 degrees C over the same range of thermal acclimation. Warm acclimation reset the maximum heart rate to a statistically lower rate, but the first Arrhenius breakpoint temperature during acute warming was unchanged. The hierarchy of transition temperatures was quantified at three acclimation temperatures and was fitted inside a Fry temperature tolerance polygon to better define ecologically relevant thermal limits to performance of B. saida We conclude that B. saida can acclimate to 6.5 degrees C water temperatures in the laboratory. However, at this acclimation temperature 50% of the fish were unable to recover from maximum swimming at the 8.5 degrees C test temperature and their cardio-respiratory performance started to decline at water temperatures greater than 5.4 degrees C. Such costs in performance may limit the ecological significance of B. saida acclimation potential. PMID- 27471276 TI - Experimental tests of planar strain theory for predicting bone cross-sectional longitudinal and shear strains. AB - Understanding of the diversity of skeletal loading regimes in vertebrate long bones during locomotion has been significantly enhanced by the application of planar strain theory (PST) to in vivo bone strain data. PST is used to model the distribution of longitudinal strains normal to the bone's transverse cross section and the location of the neutral axis of bending. To our knowledge, the application of this theory to skeletal biomechanics has not been experimentally validated. We evaluated the accuracy of PST using strain measurements from emu tibiotarsi instrumented with four strain gauges and loaded in ex vivo four-point bending. Using measured strains from three-gauge combinations, PST was applied to predict strain values at a fourth gauge's location. Experimentally measured and predicted strain values correlated linearly with a slope near 1.0, suggesting that PST accurately predicts longitudinal strains. Additionally, we assessed the use of PST to extrapolate shear strains to locations on a bone not instrumented with rosette strain gauges. Guineafowl tibiotarsi were instrumented with rosette strain gauges and in vivo longitudinal and shear strains were measured during treadmill running. Individual-specific and sample-mean ratios between measured longitudinal strains from the medial and posterior bone surfaces were used to extrapolate posterior-site shear strain from shear strains measured on the medial surface. Measured and predicted shear strains at the posterior gauge site using either ratio showed trends for a positive correlation between measured and predicted strains, but the correlation did not equal 1.0 and had a non-zero intercept, suggesting that the use of PST should be carefully considered in the context of the goals of the study and the desired precision for the predicted shear strains. PMID- 27471277 TI - Evaluating the role of NRF-1 in the regulation of the goldfish COX4-1 gene in response to temperature. AB - Cold acclimation in fish typically increases muscle mitochondrial enzymes. In mammals, stressors that increase mitochondrial content are mediated though transcriptional regulators, including nuclear respiratory factor-1 (NRF-1). Focusing on the goldfish gene for cytochrome c oxidase (COX) subunit 4-1, we analysed the regulatory regions in various contexts to identify a mechanistic link between NRF-1 and cold-induced mitochondrial proliferation. Promoter analysis implicated two putative NRF-1 sites: one in the proximal promoter and a second in exon 1, which encodes the 5' untranslated region (5'-UTR). Transfection into mouse myoblasts showed that deletion of a region that included the proximal NRF-1 site reduced promoter activity by 30%; however, mutagenesis of the specific sequence had no effect. Thermal sensitivity analyses performed in rainbow trout gonadal fibroblasts (RTG-2) showed no effect of temperature (4 vs 19 degrees C) on reporter gene expression. Likewise, reporters injected into muscle of thermally acclimated goldfish (4 vs 26 degrees C) showed no elevation in expression. There was no difference in thermal responses of COX4-1 promoter reporters constructed from homologous regions of eurythermal goldfish and stenothermal zebrafish genes. NRF-1 chromatin immunoprecipitation of thermally acclimated goldfish muscle showed no temperature effect on NRF-1 binding to either the proximal promoter or 5'-UTR. It remains possible that the cold-induced upregulation of COX4-1 expression is a result of NRF-1 binding to distal regulatory regions or through indirect effects on other transcription factors. However, the proximal promoter does not appear to play a role in mediating the thermal response of the COX4-1 gene in fish. PMID- 27471278 TI - Flowing water affects fish fast-starts: escape performance of the Hawaiian stream goby, Sicyopterus stimpsoni. AB - Experimental measurements of escape performance in fishes have typically been conducted in still water; however, many fishes inhabit environments with flow that could impact escape behavior. We examined the influences of flow and predator attack direction on the escape behavior of fish, using juveniles of the amphidromous Hawaiian goby Sicyopterus stimpsoni In nature, these fish must escape ambush predation while moving through streams with high-velocity flow. We measured the escape performance of juvenile gobies while exposing them to a range of water velocities encountered in natural streams and stimulating fish from three different directions. Frequency of response across treatments indicated strong effects of flow conditions and attack direction. Juvenile S. stimpsoni had uniformly high response rates for attacks from a caudal direction (opposite flow); however, response rates for attacks from a cranial direction (matching flow) decreased dramatically as flow speed increased. Mechanical stimuli produced by predators attacking in the same direction as flow might be masked by the flow environment, impairing the ability of prey to detect attacks. Thus, the likelihood of successful escape performance in fishes can depend critically on environmental context. PMID- 27471279 TI - Insulin effects on honeybee appetitive behaviour. AB - Worker honeybees (Apis mellifera) carry out multiple tasks throughout their adult lifespan. It has been suggested that the insulin/insulin-like signalling pathway participates in regulating behavioural maturation in eusocial insects. Insulin signalling increases as the honeybee worker transitions from nurse to food processor to forager. As behavioural shifts require differential usage of sensory modalities, our aim was to assess insulin effects on olfactory and gustatory responsiveness as well as on olfactory learning in preforaging honeybee workers of different ages. Adults were reared in the laboratory or in the hive. Immediately after being injected with insulin or vehicle (control), and focusing on the proboscis extension response, bees were tested for their spontaneous response to odours, sucrose responsiveness and ability to discriminate odours through olfactory conditioning. Bees injected with insulin have higher spontaneous odour responses. Sucrose responsiveness and odour discrimination are differentially affected by treatment according to age: whereas insulin increases gustatory responsiveness and diminishes learning abilities of younger workers, it has the opposite effect on older bees. In summary, insulin can improve chemosensory responsiveness in young workers, but also worsens their learning abilities to discriminate odours. The insulin signalling pathway is responsive in young workers, although they are not yet initiating outdoor activities. Our results show strong age-dependent effects of insulin on appetitive behaviour, which uncover differences in insulin signalling regulation throughout the honeybee worker's adulthood. PMID- 27471280 TI - Effects of elevated pCO2 and feeding on net calcification and energy budget of the Mediterranean cold-water coral Madrepora oculata. AB - Ocean acidification is a major threat to calcifying marine organisms such as deep sea cold-water corals (CWCs), but related knowledge is scarce. The aragonite saturation threshold (Omegaa) for calcification, respiration and organic matter fluxes were investigated experimentally in the Mediterranean Madrepora oculata Over 10 weeks, colonies were maintained under two feeding regimes (uptake of 36.75 and 7.46 umol C polyp-1 week-1) and exposed in 2 week intervals to a consecutively changing air-CO2 mix (pCO2) of 400, 1600, 800, 2000 and 400 ppm. There was a significant effect of feeding on calcification at initial ambient pCO2, while with consecutive pCO2 treatments, feeding had no effect on calcification. Respiration was not significantly affected by feeding or pCO2 levels. Coral skeletons started to dissolve at an average Omegaa threshold of 0.92, but recovered and started to calcify again at Omegaa>=1. The surplus energy required to counteract dissolution at elevated pCO2 (>=1600 uatm) was twice that at ambient pCO2 Yet, feeding had no mitigating effect at increasing pCO2 levels. This could be due to the fact that the energy required for calcification is a small fraction (1-3%) of the total metabolic energy demand and corals even under low food conditions might therefore still be able to allocate this small portion of energy to calcification. The response and resistance to ocean acidification are consequently not controlled by feeding in this species, but more likely by chemical reactions at the site of calcification and exchange processes between the calicoblastic layer and ambient seawater. PMID- 27471281 TI - The ocelli of Archaeognatha (Hexapoda): functional morphology, pigment migration and chemical nature of the reflective tapetum. AB - The ocelli of Archaeognatha, or jumping bristletails, differ from typical insect ocelli in shape and field of view. Although the shape of the lateral ocelli is highly variable among species, most Machiloidea have sole-shaped lateral ocelli beneath the compound eyes and a median ocellus that is oriented downward. This study investigated morphological and physiological aspects of the ocelli of Machilis hrabei and Lepismachilis spp. The light-reflecting ocellar tapetum in M. hrabei is made up of xanthine nanocrystals, as demonstrated by confocal Raman spectroscopy. Pigment granules in the photoreceptor cells move behind the tapetum in the dark-adapted state. Such a vertical pigment migration in combination with a tapetum has not been described for any insect ocellus so far. The pigment migration has a dynamic range of approximately 4 log units and is maximally sensitive to green light. Adaptation from darkness to bright light lasts over an hour, which is slow compared with the radial pupil mechanism in some dragonflies and locusts. PMID- 27471283 TI - Intentional equity. PMID- 27471282 TI - Cold acclimation is accompanied by complex responses of glycosylphosphatidylinositol (GPI)-anchored proteins in Arabidopsis. AB - Cold acclimation results in changes of the plasma membrane (PM) composition. The PM is considered to contain specific lipid/protein-enriched microdomains which can be extracted as detergent-resistant plasma membrane (DRM). Previous studies in animal cells have demonstrated that glycosylphosphatidylinositol-anchored proteins (GPI-APs) can be targeted to microdomains and/or the apoplast. However, the functional significance of GPI-APs during cold acclimation in plants is not yet fully understood. In this study, we aimed to investigate the responsiveness of GPI-APs to cold acclimation treatment in Arabidopsis We isolated the PM, DRM, and apoplast fractions separately and, in addition, GPI-AP-enriched fractions were prepared from the PM preparation. Label-free quantitative shotgun proteomics identified a number of GPI-APs (163 proteins). Among them, some GPI-APs such as fasciclin-like arabinogalactan proteins and glycerophosphoryldiester phosphodiesterase-like proteins predominantly increased in PM- and GPI-AP enriched fractions while the changes of GPI-APs in the DRM and apoplast fractions during cold acclimation were considerably different from those of other fractions. These proteins are thought to be associated with cell wall structure and properties. Therefore, this study demonstrated that each GPI-AP responded to cold acclimation in a different manner, suggesting that these changes during cold acclimation are involved in rearrangement of the extracellular matrix including the cell wall towards acquisition of freezing tolerance. PMID- 27471285 TI - INFECTIOUS DISEASE. Obstacles loom along path to the end of AIDS. PMID- 27471286 TI - ANIMAL RESEARCH. Chimpanzee sanctuaries open door to more research. PMID- 27471288 TI - TURKISH SCIENCE. After failed coup, Turkey's academics feel regime's wrath. PMID- 27471287 TI - CONSERVATION BIOLOGY. Rethinking the North American wolf. PMID- 27471290 TI - Forbidden planets. PMID- 27471289 TI - EUROPE. Uncertainty reigns in Brexit Britain. PMID- 27471291 TI - PLANT BIOLOGY. Parasitic plants--A CuRe for what ails thee. PMID- 27471292 TI - SYNTHETIC BIOLOGY. On the record with E. coli DNA. PMID- 27471293 TI - CLIMATE CHANGE. The smoking gun for Atlantic circulation changes. PMID- 27471294 TI - ECOLOGY. Plant extinctions take time. PMID- 27471295 TI - BIOMEDICAL RESEARCH. Countering imprecision in precision medicine. PMID- 27471296 TI - Clarifying samples in Zika analyses. PMID- 27471297 TI - Animal-based antibodies: Obsolete. PMID- 27471298 TI - The line between science and politics. PMID- 27471299 TI - Orbital angular momentum microlaser. AB - Structured light provides an additional degree of freedom for modern optics and practical applications. The effective generation of orbital angular momentum (OAM) lasing, especially at a micro- and nanoscale, could address the growing demand for information capacity. By exploiting the emerging non-Hermitian photonics design at an exceptional point, we demonstrate a microring laser producing a single-mode OAM vortex lasing with the ability to precisely define the topological charge of the OAM mode. The polarization associated with OAM lasing can be further manipulated on demand, creating a radially polarized vortex emission. Our OAM microlaser could find applications in the next generation of integrated optoelectronic devices for optical communications in both quantum and classical regimes. PMID- 27471300 TI - Nanostructured transition metal dichalcogenide electrocatalysts for CO2 reduction in ionic liquid. AB - Conversion of carbon dioxide (CO2) into fuels is an attractive solution to many energy and environmental challenges. However, the chemical inertness of CO2 renders many electrochemical and photochemical conversion processes inefficient. We report a transition metal dichalcogenide nanoarchitecture for catalytic electrochemical CO2 conversion to carbon monoxide (CO) in an ionic liquid. We found that tungsten diselenide nanoflakes show a current density of 18.95 milliamperes per square centimeter, CO faradaic efficiency of 24%, and CO formation turnover frequency of 0.28 per second at a low overpotential of 54 millivolts. We also applied this catalyst in a light-harvesting artificial leaf platform that concurrently oxidized water in the absence of any external potential. PMID- 27471301 TI - Teaching accreditation exams reveal grading biases favor women in male-dominated disciplines in France. AB - Discrimination against women is seen as one of the possible causes behind their underrepresentation in certain STEM (science, technology, engineering, and mathematics) subjects. We show that this is not the case for the competitive exams used to recruit almost all French secondary and postsecondary teachers and professors. Comparisons of oral non-gender-blind tests with written gender-blind tests for about 100,000 individuals observed in 11 different fields over the period 2006-2013 reveal a bias in favor of women that is strongly increasing with the extent of a field's male-domination. This bias turns from 3 to 5 percentile ranks for men in literature and foreign languages to about 10 percentile ranks for women in math, physics, or philosophy. These findings have implications for the debate over what interventions are appropriate to increase the representation of women in fields in which they are currently underrepresented. PMID- 27471302 TI - Detection of the plant parasite Cuscuta reflexa by a tomato cell surface receptor. AB - Parasitic plants are a constraint on agriculture worldwide. Cuscuta reflexa is a stem holoparasite that infests most dicotyledonous plants. One exception is tomato, which is resistant to C. reflexa We discovered that tomato responds to a small peptide factor occurring in Cuscuta spp. with immune responses typically activated after perception of microbe-associated molecular patterns. We identified the cell surface receptor-like protein CUSCUTA RECEPTOR 1 (CuRe1) as essential for the perception of this parasite-associated molecular pattern. CuRe1 is sufficient to confer responsiveness to the Cuscuta factor and increased resistance to parasitic C. reflexa when heterologously expressed in otherwise susceptible host plants. Our findings reveal that plants recognize parasitic plants in a manner similar to perception of microbial pathogens. PMID- 27471303 TI - Rapid evolution accelerates plant population spread in fragmented experimental landscapes. AB - Predicting the speed of biological invasions and native species migrations requires an understanding of the ecological and evolutionary dynamics of spreading populations. Theory predicts that evolution can accelerate species' spread velocity, but how landscape patchiness--an important control over traits under selection--influences this process is unknown. We manipulated the response to selection in populations of a model plant species spreading through replicated experimental landscapes of varying patchiness. After six generations of change, evolving populations spread 11% farther than nonevolving populations in continuously favorable landscapes and 200% farther in the most fragmented landscapes. The greater effect of evolution on spread in patchier landscapes was consistent with the evolution of dispersal and competitive ability. Accounting for evolutionary change may be critical when predicting the velocity of range expansions. PMID- 27471304 TI - Arabidopsis transcriptional repressor VAL1 triggers Polycomb silencing at FLC during vernalization. AB - The determinants that specify the genomic targets of Polycomb silencing complexes are still unclear. Polycomb silencing of Arabidopsis FLOWERING LOCUS C (FLC) accelerates flowering and involves a cold-dependent epigenetic switch. Here we identify a single point mutation at an intragenic nucleation site within FLC that prevents this epigenetic switch from taking place. The mutation blocks nucleation of plant homeodomain-Polycomb repressive complex 2 (PHD-PRC2) and indicates a role for the transcriptional repressor VAL1 in the silencing mechanism. VAL1 localizes to the nucleation region in vivo, promoting histone deacetylation and FLC transcriptional silencing, and interacts with components of the conserved apoptosis- and splicing-associated protein (ASAP) complex. Sequence-specific targeting of transcriptional repressors thus recruits the machinery for PHD-PRC2 nucleation and epigenetic silencing. PMID- 27471305 TI - Growth from failure. PMID- 27471306 TI - 2D materials and van der Waals heterostructures. AB - The physics of two-dimensional (2D) materials and heterostructures based on such crystals has been developing extremely fast. With these new materials, truly 2D physics has begun to appear (for instance, the absence of long-range order, 2D excitons, commensurate-incommensurate transition, etc.). Novel heterostructure devices--such as tunneling transistors, resonant tunneling diodes, and light emitting diodes--are also starting to emerge. Composed from individual 2D crystals, such devices use the properties of those materials to create functionalities that are not accessible in other heterostructures. Here we review the properties of novel 2D crystals and examine how their properties are used in new heterostructure devices. PMID- 27471312 TI - Surgical aspects of pulmonary tuberculosis: an update. AB - Tuberculosis remains a major global medical challenge and concern. In the world's population of over 7.4 billion people, 8.6 million are estimated to be infected with Mycobacterium tuberculosis; another 2.2 billion have latent tuberculosis. There is an annual incidence of 16,000 new cases in the USA and 7-8 million new cases worldwide, of which 440,000 are multidrug-resistant or extensively multidrug-resistant, mainly in developing countries or emerging economies. According to the World Health Organization, the incidence of tuberculosis is 133 cases per 100,000 of the population; 3.3% new cases are drug resistant and 20% are already treated cases. Of the drug-resistant cases, 9.7% are extensively drug resistant. The annual global mortality attributable to tuberculosis is over 1.3 million people. The association with HIV/AIDS in 430,000 people has compounded the global concern and challenge. This review presents the historical indications for surgical treatment of tuberculosis, reviews the current literature and clinical experience, and collates this into increased awareness and contemporary understanding of the indications and need for surgery in primary active tuberculosis, adjuvant surgical therapy for multidrug-resistant tuberculosis, and the complications of chronic tuberculosis sequelae or previous tuberculosis surgery. PMID- 27471307 TI - Platelet-Derived Growth Factor-BB Protects Mesenchymal Stem Cells (MSCs) Derived From Immune Thrombocytopenia Patients Against Apoptosis and Senescence and Maintains MSC-Mediated Immunosuppression. AB - : : Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Mesenchymal stem cells (MSCs) from ITP patients (MSC ITP) do not exhibit conventional proliferative abilities and thus exhibit defects in immunoregulation, suggesting that MSC impairment might be a mechanism involved in ITP. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types. Moreover, PDGF promotes MSC proliferation. The aim of the present study was to analyze the effects of PDGF-BB on MSC-ITP. We showed that MSC-ITP expanded more slowly and appeared flattened and larger. MSC-ITP exhibited increased apoptosis and senescence compared with controls. Both the intrinsic and extrinsic pathways account for the enhanced apoptosis. P53 and p21 expression were upregulated in MSC-ITP, but inhibition of p53 with pifithrin-alpha markedly inhibited apoptosis and senescence. Furthermore, MSCs from ITP patients showed a lower capacity for inhibiting the proliferation of activated T cells inducing regulatory T cells (Tregs) and suppressing the synthesis of anti-glycoprotein (GP)IIb-IIIa antibodies. PDGF-BB treatment significantly decreased the expression of p53 and p21 and increased survivin expression in MSC-ITP. In addition, the apoptotic rate and number of senescent cells in ITP MSCs were reduced. Their impaired ability for inhibiting activated T cells, inducing Tregs, and suppressing the synthesis of anti-GPIIb-IIIa antibodies was restored after PDGF BB treatment. In conclusion, we have demonstrated that PDGF-BB protects MSCs derived from ITP patients against apoptosis, senescence, and immunomodulatory defects. This protective effect of PDGF-BB is likely mediated via the p53/p21 pathway, thus potentially providing a new therapeutic approach for ITP. SIGNIFICANCE: Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types and promotes mesenchymal stem cell (MSC) proliferation. PDGF-BB protects MSCs derived from ITP patients against apoptosis, senescence, and immunomodulatory defects. This protective effect of PDGF-BB is likely mediated via the p53/p21 pathway, thus potentially providing a new therapeutic approach for ITP. PMID- 27471313 TI - A case of pulmonary placental transmogrification. AB - Pulmonary placental transmogrification is a rare lung lesion that microscopically resembles placenta with cystic spaces filled with papillary structures. Considered a histological variant of bullous emphysema, only 30 reported cases have been published in the world's literature. We report a rare case of pulmonary placental transmogrification in a 72-year-old man, in whom the clinical presentation of the disease mimicked lung carcinoma. Histopathology of the surgically resected segment showed a complex bulla with squamous metaplasia and placental transmogrification. Whilst rare, pulmonary placental transmogrification must be ruled out in all patients presenting with unilateral bullous emphysema, without known risk factors. PMID- 27471314 TI - Clonidine and ketamine for stable hemodynamics in off-pump coronary artery bypass. AB - BACKGROUND: The current era of fast-track extubation and faster recovery after cardiac surgery requires agents that provide perioperative sedation, suppress sympathetic response, reduce opioid requirement, and maintain hemodynamic stability. METHODS: In a prospective randomized double-blind study, 75 off-pump coronary artery bypass patients were divided into 3 groups of 25 each: group A had clonidine 1 ug.kg(-1), group B had clonidine 1 ug.kg(-1) and ketamine 1 mg.kg(-1), and group C had a saline placebo. Perioperative changes in heart rate, systolic and diastolic blood pressure, sedation score, pain score, and requirement of analgesics, beta blockers, fentanyl, propofol, and inotropes were recorded, as well time to extubation, intensive care unit stay, and 30-day mortality. RESULTS: The combination of clonidine and ketamine led to stable hemodynamics and reduced beta-blocker dosage. The sedation score was highest in groups A and B up to 24 h postoperatively. The pain score was lowest in group B in the first 24 h, and the total dose of analgesics was highest in group C. Clonidine and ketamine or clonidine alone reduced extubation time, but intensive care unit stay was unchanged CONCLUSIONS: Combined low-dose clonidine and ketamine produced perioperative sedation and effective suppression of sympathetic response with stable hemodynamics. Intraoperative beta-blocker use was reduced without increasing inotrope requirement. This combination prolonged the analgesic effect of opioids, reducing postoperative pain score and analgesic requirement. Low-dose clonidine alone produced sedation but did not completely block sympathetic response. Intensive care unit stay and patient outcome were not affected by clonidine or ketamine. PMID- 27471315 TI - Subcostal closure technique for prevention of postthoracotomy pain syndrome. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of our subcostal closure technique in prevention of postthoracotomy pain syndrome. METHODS: From July 2012 to March 2015, 29 patients in whom a lobectomy was indicated underwent a thoracotomy. The thoracotomy wounds were closed using a subcostal closure technique (subcostal closure group) and outcomes were compared with 31 patients who underwent video-assisted thoracoscopic surgery (thoracoscopy group). The duration of oral opioid consumption was evaluated from medical records, and postoperative pain was evaluated by telephone interview conducted by a trained nurse practitioner who was unaware of the patient's group. RESULTS: Pain scores were higher in the thoracoscopy group compared to the subcostal closure group, reaching statistical significance (Numeric Rating Scale 0.55 +/- 0.948 in the subcostal closure group vs. 1.84 +/- 1.614 in the thoracoscopy group; p < 0.001, Clinical Pain Scale 0.24 +/- 0.435 in the subcostal closure group vs. 0.81 +/- 0.703 in the thoracoscopy group; p < 0.001). The number of patients who consumed oral opioids for longer than 2 months after the operation was significantly greater in the thoracoscopy group than the subcostal closure group (6.9% in the subcostal closure group vs. 32.3% in the thoracoscopy group; p = 0.022). CONCLUSIONS: The subcostal closure technique is useful to prevent postthoracotomy pain syndrome. PMID- 27471316 TI - Does the Cervicovaginal Microbiome Facilitate Transmission of Neisseria gonorrhoeae From Women to Men? Implications for Understanding Transmission of Gonorrhea and Advancing Vaccine Development. PMID- 27471317 TI - Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria. AB - BACKGROUND: The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. METHODS: Capillary whole blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. RESULTS: Population pharmacokinetics for lumefantrine used a 2-compartment open model with first order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3 fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. CONCLUSIONS: We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted. PMID- 27471318 TI - Effect of Statin Use on Influenza Vaccine Effectiveness. AB - BACKGROUND: Recent studies suggest that statin use may reduce influenza vaccine effectiveness (VE), but laboratory-confirmed influenza was not assessed. METHODS: Patients >=45 years old presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2014-2015 influenza seasons. Vaccination and statin use were extracted from electronic records. Respiratory samples were tested for influenza virus. RESULTS: The analysis included 3285 adults: 1217 statin nonusers (37%), 903 unvaccinated statin nonusers (27%), 847 vaccinated statin users (26%), and 318 unvaccinated statin users (10%). Statin use modified VE and the risk of influenza A(H3N2) virus infection (P = .002) but not 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) or influenza B virus infection (P = .2 and .4, respectively). VE against influenza A(H3N2) was 45% (95% confidence interval [CI], 27%-59%) among statin nonusers and -21% (95% CI, 84% to 20%) among statin users. Vaccinated statin users had significant protection against influenza A(H1N1)pdm09 (VE, 68%; 95% CI, 19%-87%) and influenza B (VE, 48%; 95% CI, 1%-73%). Statin use did not significantly modify VE when stratified by prior season vaccination. In validation analyses, the use of other cardiovascular medications did not modify influenza VE. CONCLUSIONS: Statin use was associated with reduced VE against influenza A(H3N2) but not influenza A(H1N1)pdm09 or influenza B. Further research is needed to assess biologic plausibility and confirm these results. PMID- 27471319 TI - Clinical Chemistry of Patients With Ebola in Monrovia, Liberia. AB - The development of point-of-care clinical chemistry analyzers has enabled the implementation of these ancillary tests in field laboratories in resource-limited outbreak areas. The Eternal Love Winning Africa (ELWA) outbreak diagnostic laboratory, established in Monrovia, Liberia, to provide Ebola virus and Plasmodium spp. diagnostics during the Ebola epidemic, implemented clinical chemistry analyzers in December 2014. Clinical chemistry testing was performed for 68 patients in triage, including 12 patients infected with Ebola virus and 18 infected with Plasmodium spp. The main distinguishing feature in clinical chemistry of Ebola virus-infected patients was the elevation in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma glutamyltransferase levels and the decrease in calcium. The implementation of clinical chemistry is probably most helpful when the medical supportive care implemented at the Ebola treatment unit allows for correction of biochemistry derangements and on-site clinical chemistry analyzers can be used to monitor electrolyte balance. PMID- 27471320 TI - Human P[6] Rotaviruses From Sub-Saharan Africa and Southeast Asia Are Closely Related to Those of Human P[4] and P[8] Rotaviruses Circulating Worldwide. AB - BACKGROUND: P[6] rotaviruses have been circulating with a high prevalence in African and, to a more limited extent, Asian countries, but they have not been highly prevalent in other parts of the world. METHODS: To investigate the genomic relationship between African and Asian human P[6] rotaviruses and P[4] and P[8] rotaviruses circulating worldwide, we sequenced 39 P[6] strains, collected in Ghana, Mali, Kenya and Bangladesh, providing the largest data set of P[6] rotavirus genomes isolated in low-income countries or anywhere else in the world that has been published thus far. RESULTS: Overall, the data indicate that the genetic backbone of human P[6] strains from the low-income countries are similar to those of P[4] or P[8] strains circulating worldwide. CONCLUSIONS: The observation that gene segment 4 is the main differentiator between human P[6] and non-P[6] strains suggests that the VP4 spike protein is most likely one of the main reasons preventing the rapid spread of P[6] strains to the rest of the world despite multiple introductions. These observations reinforce previous findings about the receptor specificity of P[6] rotavirus strains. PMID- 27471321 TI - Ebola Virus Makona Shows Reduced Lethality in an Immune-deficient Mouse Model. AB - Ebola virus Makona (EBOV-Makona; from the 2013-2016 West Africa outbreak) shows decreased virulence in an immune-deficient mouse model, compared with a strain from 1976. Unlike other filoviruses tested, EBOV-Makona may be slightly more virulent by the aerosol route than by the injected route, as 2 mice died following aerosol exposure, compared with no mortality among mice that received intraperitoneal injection of equivalent or higher doses. Although most mice did not succumb to infection, the detection of an immunoglobulin G antibody response along with observed clinical signs suggest that the mice were infected but able to clear the infection and recover. We hypothesize that this may be due to the growth rates and kinetics of the virus, which appear slower than that for other filoviruses and consequently give more time for an immune response that results in clearance of the virus. In this instance, the immune-deficient mouse model is unlikely to be appropriate for testing medical countermeasures against this EBOV Makona stock but may provide insight into pathogenesis and the immune response to virus. PMID- 27471322 TI - Desialylation of Neisseria gonorrhoeae Lipooligosaccharide by Cervicovaginal Microbiome Sialidases: The Potential for Enhancing Infectivity in Men. AB - Previous studies have demonstrated that Neisseria gonorrhoeae sialylates the terminal N-acetyllactosamine present on its lipooligosaccharide (LOS) by acquiring CMP-N-acetyl-5-neuraminic acid upon entering human cells during infection. This renders the organism resistant to killing by complement in normal human serum. N-acetyllactosamine residues on LOS must be free of N-acetyl-5 neuraminc acid (Neu5Ac; also known as "sialic acid") in order for organisms to bind to and enter urethral epithelial cells during infection in men. This raises the question of how the gonococcus infects men if N-acetyllactosamine residues are substituted by Neu5Ac during infection in women. Here, we demonstrate that women with gonococcal infections have levels of sialidases present in cervicovaginal secretions that can result in desialylation of (sialylated) gonococcal LOS. The principle sialidases responsible for this desialylation appear to be bacterial in origin. These studies suggest that members of the cervicovaginal microbiome can modify N. gonorrhoeae, which will enhance successful transmission to men. PMID- 27471323 TI - Drinking Alone? The Effect of an Alcohol Treatment Program on Relationship Stability for Convicted Drunk Drivers in Denmark. AB - This article tests whether an alcohol treatment program for drunk drivers in Denmark increased the stability of their relationships with spouses or cohabiting partners. The treatment program, implemented in 1990, allowed a group of offenders to avoid prison and participate in a rehabilitation program. I use it here as a natural experiment, exploiting a rich administrative dataset to show that the program marginally increases offenders' relationship stability. I also test whether increased relationship stability observed among the treated offenders results from their pardon from prison or from their participation in the rehabilitation program. Results suggest that the rehabilitation program drives the effect. These findings contribute to the literature on what alternative sanctions could be offered to offenders to improve their long-term social outcomes. PMID- 27471324 TI - How Children's Educational Outcomes and Criminality Vary by Duration and Frequency of Paternal Incarceration. AB - Existing studies of the consequences of paternal incarceration for children treat paternal incarceration as a dichotomous event (a child either experiences paternal incarceration or does not), although effects could accumulate with both the frequency and duration of paternal incarcerations. In this article I use register data on Danish children from birth cohort 1991, some of whom experienced paternal incarceration before age 15, to show how educational outcomes and criminality up to age 20 vary by frequency and total duration of paternal incarceration. The high quality of Danish register data also allows me to distinguish between paternal arrest and paternal incarceration and to show results for the total duration of paternal incarcerations conditioned on frequency of paternal incarceration. Results show that educational outcomes and criminality indeed correlate with duration and frequency of paternal incarceration, indicating that treating paternal incarceration as a dichotomous event blurs important heterogeneity in the consequences of paternal incarceration. PMID- 27471325 TI - Effects of halolactones with strong feeding-deterrent activity on the growth and development of larvae of the lesser mealworm, Alphitobius diaperinus (Coleoptera: Tenebrionidae). AB - The effects of dietary applied of beta-damascone and its synthetic derivatives gamma- and delta-halolactones, which show strong antifeedant activity, on the growth and development of larvae of the lesser mealworm, Alphitobius diaperinus Panzer (Coleoptera: Tenebrionidae), were studied. Bioassays were performed in a dose-dependent manner. In the bioassays, oat flakes treated with 1.0, 0.5, and 0.1 % (w/v) acetone solutions of the tested compound or acetone alone as control were served as food. The experiments were conducted using 2-week-old larvae with an average body weight of 4.35-4.88 mg. High correlations between antifeedant activity and larvicidal and growth-inhibitory effects were observed. Larvae reared on diets containing the compounds (at a concentration of 1 %) with high deterrent activity were characterized by a prolonged period of development, lower body weight gain, and strong tendency for cannibalism as a result of starvation. The control larvae ended their development after 24 days with a mean body weight of 22.9 mg. At the same developmental time, the mean body weights of larvae treated with the delta-halolactones gamma-chloro- and gamma-bromo-delta-lactone were only 60.3 % and 43.2 % of that of the control larvae. The larval periods for larvae on the diets containing gamma-chloro- and gamma-bromo-delta-lactone were 33 and 41 days, respectively. The larval developmental time and body weight gain were not significantly influenced by lower doses of the compounds, with the exception of gamma-bromo-delta-lactone. This compound, when applied at a concentration of 0.5 %, significantly prolonged larval development as compared to the control larvae, and caused high mortality of larvae and pupae. The adult emergence percentage was 37.51 % when this treatment was applied, as compared to 90.0 % in the control. Thus, beta-damascone derivatives with a lactone ring exhibit both dose-dependent behavioral effects and post-ingestion toxicity against A. diaperinus larvae, and may have the potential to control this pest. PMID- 27471326 TI - Why Leading Consumer Product Companies Develop Proactive Chemical Management Strategies. AB - Scholars have studied the various pressures that companies face related to socially responsible behavior when stakeholders know the particular social issues under consideration. Many have examined social responsibility in the context of environmental responsibility and the general approaches companies take regarding environmental management. The issue of currently unregulated, but potentially hazardous, chemicals in consumer products is not well understood by the general public, but a number of proactive consumer product companies have voluntarily adopted strategies to minimize use of such chemicals. These companies are exceeding regulatory requirements by restricting from their products chemicals that could harm human or environmental health, despite the fact that these actions are costly. They do not usually advertise the details of their strategies to end consumers. This article uses interviews with senior environmental directors of 20 multinational consumer product companies to investigate why these companies engage in voluntary chemicals management. The authors conclude that the most significant reasons are to achieve a competitive advantage and stay ahead of regulations, manage relationships and maintain legitimacy with stakeholders, and put managerial values into practice. Many of the characteristics related to the case of chemicals management are extendable to other areas of stakeholder management in which risks to stakeholders are either unknown or poorly understood. PMID- 27471327 TI - Stevia, Nature's Zero-Calorie Sustainable Sweetener: A New Player in the Fight Against Obesity. AB - Stevia is a plant native to South America that has been used as a sweetener for hundreds of years. Today, zero-calorie stevia, as high-purity stevia leaf extract, is being used globally to reduce energy and added sugar content in foods and beverages. This article introduces stevia, explaining its sustainable production, metabolism in the body, safety assessment, and use in foods and drinks to assist with energy reduction. The article also summarizes current thinking of the evidence for the role of nonnutritive sweeteners in energy reduction. Overall, stevia shows promise as a new tool to help achieve weight management goals. PMID- 27471328 TI - Policy learning in the Eurozone crisis: modes, power and functionality. AB - In response to the attacks on the sovereign debt of some Eurozone countries, European Union (EU) leaders have created a set of preventive and corrective policy instruments to coordinate macro-economic policies and reforms. In this article, we deal with the European Semester, a cycle of information exchange, monitoring and surveillance. Countries that deviate from the targets are subjected to increasing monitoring and more severe 'corrective' interventions, in a pyramid of responsive exchanges between governments and EU institutions. This is supposed to generate coordination and convergence towards balanced economies via mechanisms of learning. But who is learning what? Can the EU learn in the 'wrong' mode? We contribute to the literature on theories of the policy process by showing how modes of learning can be operationalized and used in empirical analysis. We use policy learning as theoretical framework to establish empirically the prevalent mode of learning and its implications for both the power of the Commission and the normative question of whether the EU is learning in the 'correct' mode. PMID- 27471329 TI - Can self-representationalism explain away the apparent irreducibility of consciousness? AB - Kriegel's self-representationalist (SR) theory of phenomenal consciousness pursues two projects. The first is to offer a positive account of how conscious experience arises from physical brain processes. The second is to explain why consciousness misleadingly appears to be irreducible to the physical i.e. to 'demystify' consciousness. This paper seeks to determine whether SR succeeds on the second project. Kriegel trades on a distinction between the subjective character and qualitative character of conscious states. Subjective character is the property of being a conscious state at all, while qualitative character determines what it is like to be in that state. Kriegel claims that SR explains why subjective character misleadingly appears irreducible, thereby neutralising the apparent irreducibility of consciousness. I argue that although SR credibly demystifies subjective character, it cannot explain why qualitative character also appears irreducible. I conclude that we should pursue the possibility of a hybrid position that combines SR with an account that does explain the apparent irreducibility of qualitative character. PMID- 27471330 TI - The Effects of Heavy Metals and Total Petroleum Hydrocarbons on Soil Bacterial Activity and Functional Diversity in the Upper Silesia Industrial Region (Poland). AB - Various inorganic and organic pollutants in industrial soils may adversely affect soil microorganisms and terrestrial ecosystem functioning. The aim of the study was to explore the relationship between the microbial activity, microbial biomass, and functional diversity of soil bacteria and the metals and total petroleum hydrocarbons (TPHs) in the Upper Silesian Industrial Region (Poland). We collected soil samples in pine-dominated forest stands and analyzed them according to a range of soil physicochemical properties, including metal content (cadmium, lead, and zinc) and TPH content. Metal concentrations were normalized to their toxicity to soil microorganisms and integrated in a toxicity index (TI). Soil microbial activity measured as soil respiration rate, microbial biomass measured as substrate-induced respiration rate, and the bacterial catabolic activity (area under the curve, AUC) assessed using Biolog(r) ECO plates were negatively related to TPH pollution as shown in multiple regressions. The canonical correspondence analysis (CCA) showed that both TPH and TI affected the community-level physiological profiles (CLPPs) of soil bacteria and the pollutants' effects were much stronger than the effects of other soil properties, including nutrient content. PMID- 27471332 TI - Drinking water vulnerability to climate change and alternatives for adaptation in coastal South and South East Asia. AB - Drinking water in much of Asia, particularly in coastal and rural settings, is provided by a variety of sources, which are widely distributed and frequently managed at an individual or local community level. Coastal and near-inland drinking water sources in South and South East (SSE) Asia are vulnerable to contamination by seawater, most dramatically from tropical cyclone induced storm surges. This paper assesses spatial vulnerabilities to salinisation of drinking water sources due to meteorological variability and climate change along the (ca. 6000 km) coastline of SSE Asia. The risks of increasing climatic stresses are first considered, and then maps of relative vulnerability along the entire coastline are developed, using data from global scale land surface models, along with an overall vulnerability index. The results show that surface and near surface drinking water in the coastal areas of the mega-deltas in Vietnam and Bangladesh-India are most vulnerable, putting more than 25 million people at risk of drinking 'saline' water. Climate change is likely to exacerbate this problem, with adverse consequences for health, such as prevalence of hypertension and cardiovascular diseases. There is a need for identifying locations that are most at risk of salinisation in order for policy makers and local officials to implement strategies for reducing these health impacts. To counter the risks associated with these vulnerabilities, possible adaptation measures are also outlined. We conclude that detailed and fine scale vulnerability assessments may become crucial for planning targeted adaptation programmes along these coasts. PMID- 27471331 TI - Addressing Self-Control Cognitions in the Treatment of Trichotillomania: A Randomized Controlled Trial Comparing Cognitive Therapy to Behaviour Therapy. AB - People with trichotillomania often have persistent negative beliefs about giving into one's habit. Central in the present study was the hypothesis that the follow up effects of cognitive therapy (CT), in which these negative beliefs are directly addressed, are better compared to the follow-up effects of behaviour therapy (BT). Fifty-six trichotillomania patients were randomly assigned to either six sessions CT or BT. Forty-eight completed their treatment. Follow-up measurements took place after a 3 months treatment-free period, and at 12 and 24 months. CT and BT both resulted in clear reductions of trichotillomania symptoms (severity, urge, inability to resist, and negative beliefs) immediately after treatment. There were no differences between the groups. Following the treatment free period, there was a reoccurrence of symptoms. In contrast to our expectation, we failed to show that CT compared to BT resulted in lower relapse rates after the treatment-free period. PMID- 27471333 TI - Assessing Global Water Storage Variability from GRACE: Trends, Seasonal Cycle, Subseasonal Anomalies and Extremes. AB - Throughout the past decade, the Gravity Recovery and Climate Experiment (GRACE) has given an unprecedented view on global variations in terrestrial water storage. While an increasing number of case studies have provided a rich overview on regional analyses, a global assessment on the dominant features of GRACE variability is still lacking. To address this, we survey key features of temporal variability in the GRACE record by decomposing gridded time series of monthly equivalent water height into linear trends, inter-annual, seasonal, and subseasonal (intra-annual) components. We provide an overview of the relative importance and spatial distribution of these components globally. A correlation analysis with precipitation and temperature reveals that both the inter-annual and subseasonal anomalies are tightly related to fluctuations in the atmospheric forcing. As a novelty, we show that for large regions of the world high-frequency anomalies in the monthly GRACE signal, which have been partly interpreted as noise, can be statistically reconstructed from daily precipitation once an adequate averaging filter is applied. This filter integrates the temporally decaying contribution of precipitation to the storage changes in any given month, including earlier precipitation. Finally, we also survey extreme dry anomalies in the GRACE record and relate them to documented drought events. This global assessment sets regional studies in a broader context and reveals phenomena that had not been documented so far. PMID- 27471334 TI - The Global S[Formula: see text] Tide in Earth's Nutation. AB - Diurnal S[Formula: see text] tidal oscillations in the coupled atmosphere-ocean system induce small perturbations of Earth's prograde annual nutation, but matching geophysical model estimates of this Sun-synchronous rotation signal with the observed effect in geodetic Very Long Baseline Interferometry (VLBI) data has thus far been elusive. The present study assesses the problem from a geophysical model perspective, using four modern-day atmospheric assimilation systems and a consistently forced barotropic ocean model that dissipates its energy excess in the global abyssal ocean through a parameterized tidal conversion scheme. The use of contemporary meteorological data does, however, not guarantee accurate nutation estimates per se; two of the probed datasets produce atmosphere-ocean driven S[Formula: see text] terms that deviate by more than 30 [Formula: see text]as (microarcseconds) from the VLBI-observed harmonic of [Formula: see text] [Formula: see text]as. Partial deficiencies of these models in the diurnal band are also borne out by a validation of the air pressure tide against barometric in situ estimates as well as comparisons of simulated sea surface elevations with a global network of S[Formula: see text] tide gauge determinations. Credence is lent to the global S[Formula: see text] tide derived from the Modern-Era Retrospective Analysis for Research and Applications (MERRA) and the operational model of the European Centre for Medium-Range Weather Forecasts (ECMWF). When averaged over a temporal range of 2004 to 2013, their nutation contributions are estimated to be [Formula: see text] [Formula: see text]as (MERRA) and [Formula: see text] [Formula: see text]as (ECMWF operational), thus being virtually equivalent with the VLBI estimate. This remarkably close agreement will likely aid forthcoming nutation theories in their unambiguous a priori account of Earth's prograde annual celestial motion. PMID- 27471335 TI - The Effects of Swelling and Porosity Change on Capillarity: DEM Coupled with a Pore-Unit Assembly Method. AB - In this study, a grain-scale modelling technique has been developed to generate the capillary pressure-saturation curves for swelling granular materials. This model employs only basic granular properties such as particles size distribution, porosity, and the amount of absorbed water for swelling materials. Using this model, both drainage and imbibition curves are directly obtained by pore-scale simulations of fluid invasion. This allows us to produce capillary pressure saturation curves for a large number of different packings of granular materials with varying porosity and/or amount of absorbed water. The algorithm is based on combining the Discrete Element Method for generating different particle packings with a pore-unit assembly approach. The pore space is extracted using a regular triangulation, with the centres of four neighbouring particles forming a tetrahedron. The pore space within each tetrahedron is referred to as a pore unit. Thus, the pore space of a particle packing is represented by an assembly of pore units for which we construct drainage and imbibition capillary pressure saturation curves. A case study on Hostun sand is conducted to test the model against experimental data from literature and to investigate the required minimum number of particles to have a Representative Elementary Volume. Then, the capillary pressure-saturation curves are constructed for Absorbent Gelling Material particles, for different combinations of porosity values and amounts of absorbed water. Each combination yields a different configuration of pore units, and thus distinctly different capillary pressure-saturation curves. All these curves are shown to collapse into one curve for drainage and one curve for imbibition when we normalize capillary pressure and saturation values. We have developed a formula for the Van Genuchten parameter [Formula: see text] (which is related to the inverse of the entry pressure) as a function of porosity and the amount of absorbed water. PMID- 27471336 TI - A geometrical multi-scale numerical method for coupled hygro-thermo-mechanical problems in photovoltaic laminates. AB - A comprehensive computational framework based on the finite element method for the simulation of coupled hygro-thermo-mechanical problems in photovoltaic laminates is herein proposed. While the thermo-mechanical problem takes place in the three-dimensional space of the laminate, moisture diffusion occurs in a two dimensional domain represented by the polymeric layers and by the vertical channel cracks in the solar cells. Therefore, a geometrical multi-scale solution strategy is pursued by solving the partial differential equations governing heat transfer and thermo-elasticity in the three-dimensional space, and the partial differential equation for moisture diffusion in the two dimensional domains. By exploiting a staggered scheme, the thermo-mechanical problem is solved first via a fully implicit solution scheme in space and time, with a specific treatment of the polymeric layers as zero-thickness interfaces whose constitutive response is governed by a novel thermo-visco-elastic cohesive zone model based on fractional calculus. Temperature and relative displacements along the domains where moisture diffusion takes place are then projected to the finite element model of diffusion, coupled with the thermo-mechanical problem by the temperature and crack opening dependent diffusion coefficient. The application of the proposed method to photovoltaic modules pinpoints two important physical aspects: (i) moisture diffusion in humidity freeze tests with a temperature dependent diffusivity is a much slower process than in the case of a constant diffusion coefficient; (ii) channel cracks through Silicon solar cells significantly enhance moisture diffusion and electric degradation, as confirmed by experimental tests. PMID- 27471337 TI - The Current Status of the Kenya Capsian. AB - East Africa is home to a rich array of stone-tool traditions that span human prehistory. It is unsurprising, therefore, that the region attracted pioneer prehistorians in the early twentieth century, including L. S. B. Leakey, E. J. Wayland and T. P. O'Brien, who created the first cultural framework for East African prehistory during the 1930s. Although aspects of this framework remain relevant today, others have become misunderstood relics of an old classification system that hinders current research. This is particularly evident in the classification of a Later Stone Age (LSA) culture - the Kenya (East African) Aurignacian, later known as Kenya (East African) Capsian. Although this cultural entity was redressed during the 1970s and 1980s and redefined as the Eburran industry, there is still mystique surrounding the current status of the Kenya Capsian, its original scope and definition, the relationship with the Eburran and its position within a modern understanding of the East African LSA. This is largely due to paradigmatic shifts in researcher attitudes, leading to the use of the Eburran as a false proxy. It is necessary now to completely remove the term Kenya Capsian as an indication of similarity among the different LSA technologies. However, there also needs to be less emphasis on the importance of the Eburran and recognition that it is just one example of a multitude of diverse localised LSA industries. This will open the way for future research into the LSA and facilitate our greater understanding of recent prehistory in East Africa. PMID- 27471338 TI - Exploitation in International Paid Surrogacy Arrangements. AB - Many critics have suggested that international paid surrogacy is exploitative. Taking such concerns as its starting point, this article asks: (1) how defensible is the claim that international paid surrogacy is exploitative and what could be done to make it less exploitative? (2) In the light of the answer to (1), how strong is the case for prohibiting it? Exploitation could in principle be dealt with by improving surrogates' pay and conditions. However, doing so may exacerbate problems with consent. Foremost amongst these is the argument that surrogates from economically disadvantaged countries cannot validly consent because their background circumstances are coercive. Several versions of this argument are examined and I conclude that at least one has some merit. The article's overall conclusion is that while ethically there is something to be concerned about, paid surrogacy is in no worse a position than many other exploitative commercial transactions which take place against a backdrop of global inequality and constrained options, such as poorly-paid and dangerous construction work. Hence, there is little reason to single surrogacy out for special condemnation. On a policy level, the case for prohibiting international commercial surrogacy is weak, despite legitimate concerns about consent and background poverty. PMID- 27471339 TI - Simultaneous Cortical Surface Labeling and Sulcal Curve Extraction. AB - Automatic labeling of the gyri and sulci on the cortical surface is important for studying cortical morphology and brain functions within populations. A method to simultaneously label gyral regions and extract sulcal curves is proposed. Assuming that the gyral regions parcellate the whole cortical surface into contiguous regions with certain fixed topology, the proposed method labels the subject cortical surface by deformably registering a network of curves that form the boundary of gyral regions to the subject cortical surface. In the registration process, the curves are encouraged to follow the fine details of the sulcal geometry and to observe the shape statistics learned from training data. Using the framework of probabilistic point set registration methods, the proposed algorithm finds the sulcal curve network that maximizes the posterior probability by Expectation-Maximization (EM). The automatic labeling method was evaluated on 15 cortical surfaces using a leave-one-out strategy. Quantitative error analysis is carried out on both labeled regions and major sulcal curves. PMID- 27471340 TI - Deep Filter Banks for Texture Recognition, Description, and Segmentation. AB - Visual textures have played a key role in image understanding because they convey important semantics of images, and because texture representations that pool local image descriptors in an orderless manner have had a tremendous impact in diverse applications. In this paper we make several contributions to texture understanding. First, instead of focusing on texture instance and material category recognition, we propose a human-interpretable vocabulary of texture attributes to describe common texture patterns, complemented by a new describable texture dataset for benchmarking. Second, we look at the problem of recognizing materials and texture attributes in realistic imaging conditions, including when textures appear in clutter, developing corresponding benchmarks on top of the recently proposed OpenSurfaces dataset. Third, we revisit classic texture represenations, including bag-of-visual-words and the Fisher vectors, in the context of deep learning and show that these have excellent efficiency and generalization properties if the convolutional layers of a deep model are used as filter banks. We obtain in this manner state-of-the-art performance in numerous datasets well beyond textures, an efficient method to apply deep features to image regions, as well as benefit in transferring features from one domain to another. PMID- 27471341 TI - Design and construction of a photobioreactor for hydrogen production, including status in the field. AB - Several species of microalgae and phototrophic bacteria are able to produce hydrogen under certain conditions. A range of different photobioreactor systems have been used by different research groups for lab-scale hydrogen production experiments, and some few attempts have been made to upscale the hydrogen production process. Even though a photobioreactor system for hydrogen production does require special construction properties (e.g., hydrogen tight, mixing by other means than bubbling with air), only very few attempts have been made to design photobioreactors specifically for the purpose of hydrogen production. We have constructed a flat panel photobioreactor system that can be used in two modes: either for the cultivation of phototrophic microorganisms (upright and bubbling) or for the production of hydrogen or other anaerobic products (mixing by "rocking motion"). Special emphasis has been taken to avoid any hydrogen leakages, both by means of constructional and material choices. The flat plate photobioreactor system is controlled by a custom-built control system that can log and control temperature, pH, and optical density and additionally log the amount of produced gas and dissolved oxygen concentration. This paper summarizes the status in the field of photobioreactors for hydrogen production and describes in detail the design and construction of a purpose-built flat panel photobioreactor system, optimized for hydrogen production in terms of structural functionality, durability, performance, and selection of materials. The motivations for the choices made during the design process and advantages/disadvantages of previous designs are discussed. PMID- 27471343 TI - Estimation of Chlamydomonas reinhardtii biomass concentration from chord length distribution data. AB - A novel method to estimate the concentration of Chlamydomonas reinhardtii biomass was developed. The method employs the chord length distribution information gathered by means of a focused beam reflectance probe immersed in the culture sample and processes the data through a feedforward multilayer perceptron. The multilayer perceptron architecture was systematically optimised through the application of a simulated annealing algorithm. The method developed can predict the concentration of microalgae with acceptable accuracy and, with further development, it could be implemented online to monitor the aggregation status and biomass concentration of microalgal cultures. PMID- 27471342 TI - Bio-optical characterization of selected cyanobacteria strains present in marine and freshwater ecosystems. AB - The optical properties, i.e., absorption and scattering spectra of ten strains of cyanobacteria from the Baltic Sea and Pomeranian lakes (Aphanizomenon flos-aquae KAC 15, Microcystis aeruginosa CCNP 1101, Anabaena sp. CCNP 1406, Synechocystis salina CCNP 1104, Phormidium sp. CCNP 1317, Nodularia spumigena CCNP 1401, Synechococcus sp. CCNP 1108, Nostoc sp. CCNP 1411, Cyanobacterium sp. CCNP 1105, Pseudanabaena cf. galeata CCNP 1312) grown under low light conditions were investigated. Moreover, the chlorophylls, carotenoids, and phycobilin composition as well as the size structure of chosen cyanobacteria were measured. Studied species revealed high diversity both in optical properties with the absorption spectra similarity index ranging from 0.67 to 0.94 and the pigment composition. The chlorophyll-specific absorption coefficient at 440 nm aph *(440) varied between 0.017 and 0.065 m2 mg-1. The influence of the package effect was only observed in the case of large filamentous cyanobacteria like N. spumigena or Nostoc sp. Interestingly, the package effect factor Qa *(675) for large-celled Anabaena sp. was 0.92. Besides chlorophyll a, only echinenone, beta-carotene, and phycocyanin were present in all analyzed cyanobacteria strains. Zeaxanthin, which is widely used as a marker pigment for cyanobacteria, was absent in the toxic N. spumigena and Anabaena sp., which are the species that occur in the Baltic Sea most frequently causing summer cyanobacterial blooms. The investigation also showed that the sample preservation technique can introduce some major errors within the absorption band affected by the phycocyanin absorption. PMID- 27471344 TI - Multicomponent fractionation of Saccharina latissima brown algae using chelating salt solutions. AB - A fractionation strategy for Saccharina latissima algal biomass was developed utilizing chelating extraction salt solutions to mediate the liberation of algal components. Alginate, cellulose, laminarin, mannitol, protein, and inorganic salts were quantified in the fractions to reveal their individual dissolution patterns. Chelation power was identified as a key parameter for liberating alginate and increasing the yield of extracted components. The most efficient fractionation was achieved using aqueous sodium citrate as the extraction solution, producing an alginate-rich soluble fraction and a salt-poor insoluble fraction rich in cellulose and protein. Extractions at decreased pH were shown to be beneficial because they decreased the M/G ratio of the extracted alginate and concentrated the protein in the insoluble fraction from which it can easily be recovered; these effects could be achieved by switching the traditional sodium carbonate extraction solution with salts that have chelation capacity at lower pH. A cyclic extraction demonstrated that the sodium citrate solution can be reused for multiple alginate extractions with the buildup of the concentrations of other valuable components in the solution. PMID- 27471345 TI - Infimal Convolution Regularisation Functionals of BV and [Formula: see text] Spaces: Part I: The Finite [Formula: see text] Case. AB - We study a general class of infimal convolution type regularisation functionals suitable for applications in image processing. These functionals incorporate a combination of the total variation seminorm and [Formula: see text] norms. A unified well-posedness analysis is presented and a detailed study of the one dimensional model is performed, by computing exact solutions for the corresponding denoising problem and the case [Formula: see text]. Furthermore, the dependency of the regularisation properties of this infimal convolution approach to the choice of p is studied. It turns out that in the case [Formula: see text] this regulariser is equivalent to the Huber-type variant of total variation regularisation. We provide numerical examples for image decomposition as well as for image denoising. We show that our model is capable of eliminating the staircasing effect, a well-known disadvantage of total variation regularisation. Moreover as p increases we obtain almost piecewise affine reconstructions, leading also to a better preservation of hat-like structures. PMID- 27471346 TI - Robust [Formula: see text] Approaches to Computing the Geometric Median and Principal and Independent Components. AB - Robust measures are introduced for methods to determine statistically uncorrelated or also statistically independent components spanning data measured in a way that does not permit direct separation of these underlying components. Because of the nonlinear nature of the proposed methods, iterative methods are presented for the optimization of merit functions, and local convergence of these methods is proved. Illustrative examples are presented to demonstrate the benefits of the robust approaches, including an application to the processing of dynamic medical imaging. PMID- 27471347 TI - Specific leaf area of European Larch (Larix decidua Mill.). AB - KEY MESSAGE: The specific leaf area of European larch depends on branch height and canopy depth, indicating that both, the effect of hydraulic limitations and low water potentials in greater branch heights, and light availability affect specific leaf area. ABSTRACT: Specific leaf area (SLA) is defined as the ratio between projected leaf area and needle dry mass. It often serves as parameter in ecosystem modelling as well as indicator for potential growth rate. We explore the SLA of European larch (Larix decidua) and the most important factors which have an influence on it. Data were collected from eight stands in Styria, Austria. The stands varied in age, elevation and species mixture. Four stands were pure larch stands with only minor proportions of Norway spruce (Picea abies), whereas the other four were mixed stands of larch and spruce. In each stand 15 representative sample trees were felled. The crown of each sample tree was divided into three sections of equal length and in each section a random sample of needles was taken for determining projected leaf area and dry mass of 50 needles. The mean SLA of larch was established to be 117 cm2 g-1 with a standard deviation of +/-27.9 cm2 g-1. SLA varies within the crown, but neither between different mixtures nor years of observation nor social position of the trees. A mixed-effects model, with the plots as random effect, revealed that SLA of larch decreased with increasing branch height (p = 0.0012) and increased with increasing canopy depth (p = 0.029). We conclude that both the hydraulic limitations due to low water potentials in greater branch heights and light availability affect specific leaf area. PMID- 27471348 TI - Public Perceptions, Beliefs and Experiences of Fostering and Adoption: A National Qualitative Study in South Africa. AB - In South Africa, rates of adoption remain low while the number of fostered children continually rises. Little is known about the public perceptions, beliefs and experiences that inform decisions to either foster or adopt in South Africa. This qualitative research explored these issues among a national sample of childless adults, biological parents, kin and non-kin fostering parents and prospective and successful adopters. Fostering is driven predominantly by access to subsidies but is also informed by socio-cultural beliefs. Low adoption rates are influenced by an absence of subsidies, poor access to quality adoptive services and a lack of information about adoption. PMID- 27471350 TI - Concise Review of Optical Coherence Tomography in Clinical Practice. AB - Optical coherence tomography (OCT) is a novel image modality with higher resolution in the catheterization laboratory. It can differentiate tissue characteristics and provide detailed information, including dissection, tissue prolapse, thrombi, and stent apposition. In this study, we comprehensively reviewed the current pros and cons of OCT clinical applications and presented our clinical experiences associated with the advantages and limitations of this new imaging modality. PMID- 27471351 TI - Critical Questions about PARADIGM-HF and the Future. AB - Cardiovascular (CV) diseases in general and heart failure (HF) in particular are major contributors to death and morbidity and are also recognized as important drivers of health care expenditure. The PARADIGM-HF trial was a pivotal trial designed to compare the long-term effects of LCZ696 with enalapril in patients with symptomatic HF with reduced ejection fraction (HFrEF). This review article presents an in-depth view of the PARADIGM-HF trial and the implications of the results in the management of patients with HF and is based on peer reviewed manuscripts, editorials, perspectives and opinions written about the PARADIGM-HF trial. The article presents the key safety and efficacy results of the trial with specific emphasis on the clinical implications of these findings. The review highlights the highly statistically significant, 20% reduction in the primary composite endpoint of cardiovascular death or HF hospitalization, and a 16% reduction in the risk of death from any cause. It also provides an overview of the design, clinical findings, limitations and special areas of clinical interest. The review discusses the future of LCZ696 and additional trials that seek to answer questions in other sub-populations of patients with HF. The article reiterates what has been concluded by many experts in the field of HF- the introduction of LCZ696 into routine clinical care, while dependent on the regulatory approvals in various countries as well as acceptance by physicians, payers and patients, will change the treatment landscape for patients with HFrEF. PMID- 27471352 TI - ARNI: A New Paradigm for the Treatment of Heart Failure in Taiwan? PMID- 27471349 TI - Neuroimmunomodulation in the Gut: Focus on Inflammatory Bowel Disease. AB - Intestinal immunity is finely regulated by several concomitant and overlapping mechanisms, in order to efficiently sense external stimuli and mount an adequate response of either tolerance or defense. In this context, a complex interplay between immune and nonimmune cells is responsible for the maintenance of normal homeostasis. However, in certain conditions, the disruption of such an intricate network may result in intestinal inflammation, including inflammatory bowel disease (IBD). IBD is believed to result from a combination of genetic and environmental factors acting in concert with an inappropriate immune response, which in turn interacts with nonimmune cells, including nervous system components. Currently, evidence shows that the interaction between the immune and the nervous system is bidirectional and plays a critical role in the regulation of intestinal inflammation. Recently, the maintenance of intestinal homeostasis has been shown to be under the reciprocal control of the microbiota by immune mechanisms, whereas intestinal microorganisms can modulate mucosal immunity. Therefore, in addition to presenting the mechanisms underlying the interaction between immune and nervous systems in the gut, here we discuss the role of the microbiota also in the regulation of neuroimmune crosstalk involved in intestinal homeostasis and inflammation, with potential implications to IBD pathogenesis. PMID- 27471353 TI - TSOC-HFrEF Registry: A Registry of Hospitalized Patients with Decompensated Systolic Heart Failure: Description of Population and Management. AB - INTRODUCTION: Heart failure (HF) is a medical condition with a rapidly increasing incidence both in Taiwan and worldwide. The objective of the TSOC-HFrEF registry was to assess epidemiology, etiology, clinical management, and outcomes in a large sample of hospitalized patients presenting with acute decompensated systolic HF. METHODS: The TSOC-HFrEF registry was a prospective, multicenter, observational survey of patients presenting to 21 medical centers or teaching hospitals in Taiwan. Hospitalized patients with either acute new-onset HF or acute decompensation of chronic HFrEF were enrolled. Data including demographic characteristics, medical history, primary etiology of HF, precipitating factors for HF hospitalization, presenting symptoms and signs, diagnostic and treatment procedures, in-hospital mortality, length of stay, and discharge medications, were collected and analyzed. RESULTS: A total of 1509 patients were enrolled into the registry by the end of October 2014, with a mean age of 64 years (72% were male). Ischemic cardiomyopathy and dilated cardiomyopathy were diagnosed in 44% and 33% of patients, respectively. Coronary artery disease, hypertension, diabetes, and chronic renal insufficiency were the common comorbid conditions. Acute coronary syndrome, non-compliant to treatment, and concurrent infection were the major precipitating factors for acute decompensation. The median length of hospital stay was 8 days, and the in-hospital mortality rate was 2.4%. At discharge, 62% of patients were prescribed either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 60% were prescribed beta-blockers, and 49% were prescribed mineralocorticoid receptor antagonists. CONCLUSIONS: The TSOC-HFrEF registry provided important insights into the current clinical characteristics and management of hospitalized decompensated systolic HF patients in Taiwan. One important observation was that adherence to guideline-directed medical therapy was suboptimal. PMID- 27471354 TI - Association of Serum Bilirubin with SYNTAX Score and Future Cardiovascular Events in Patients Undergoing Coronary Intervention. AB - BACKGROUND: Bilirubin has emerged as an important endogenous antioxidant molecule, and increasing evidence shows that bilirubin may protect against atherosclerosis. The SYNTAX score has been developed to assess the severity and complexity of coronary artery disease. The aim of this study was to evaluate whether serum bilirubin levels are associated with SYNTAX scores and whether they could be used to predict future cardiovascular events in patients undergoing coronary intervention. METHODS: Serum bilirubin levels and other blood parameters in patients with at least 12-h fasting states were determined. The primary endpoint was any composite cardiovascular event within 1 year, including death, nonfatal myocardial infarction, and target-vessel revascularization. RESULTS: In total, 250 consecutive patients with stable coronary artery disease (mean age 70 +/- 13) who had received coronary intervention were enrolled. All study subjects were divided into two groups: group 1 was defined as high SYNTAX score (> 22), and group 2 was defined as low SYNTAX score (<= 22). Total bilirubin levels were significantly lower in the high SYNTAX score group than in the low SYNTAX score group (0.51 +/- 0.22 vs. 0.72 +/- 0.29 mg/dl, p < 0.001). By multivariate analysis, serum total bilirubin levels were identified as an independent predictor for high SYNTAX score (adjusted odds ratio: 0.28, 95% confidence interval 0.04-0.42; p = 0.004). Use of the Kaplan-Meier analysis demonstrated a significant difference in 1-year cardiovascular events between high (> 0.8 mg/dl), medium (> 0.5, <= 0.8 mg/dl), and low (<= 0.5 mg/dl) bilirubin levels (log-rank test p = 0.011). CONCLUSIONS: Serum bilirubin level is associated with SYNTAX score and predicts future cardiovascular events in patients undergoing coronary intervention. PMID- 27471355 TI - Activin A Predicts Left Ventricular Remodeling and Mortality in Patients with ST Elevation Myocardial Infarction. AB - BACKGROUND: Activin A levels increase in a variety of heart diseases including ST elevation myocardial infarction (STEMI). The aim of this study is to investigate whether the level of activin A can be beneficial in predicting left ventricular remodeling, heart failure, and death in patients with ST-elevation myocardial infarction (STEMI). METHODS: We enrolled 278 patients with STEMI who had their activin A levels measured on day 2 of hospitalization. Echocardiographic studies were performed at baseline and were repeated 6 months later. Thereafter, the clinical events of these patients were followed for a maximum of 3 years, including all-cause death and readmission for heart failure. RESULTS: During hospitalization, higher activin A level was associated with higher triglyceride level, lower left ventricular ejection fraction (LVEF), and lower left ventricular end diastolic ventricular volume index (LVEDVI) in multivariable linear regression model. During follow-up, patients with activin A levels > 129 pg/ml had significantly lower LVEF, and higher LVEDVI at 6 months. Kaplan-Meier survival curves showed that activin A level > 129 pg/ml was a predictor of all cause death (p = 0.022), but not a predictor of heart failure (p = 0.767). CONCLUSIONS: Activin A level > 129 pg/ml predicts worse left ventricular remodeling and all-cause death in STEMI. PMID- 27471357 TI - A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of STA-2 (Green Tea Polyphenols) in Patients with Chronic Stable Angina. AB - BACKGROUND: Green tea intake has been shown to improve endurance capacity in animal studies, but whether it has a similar effect on humans remains unclear. A randomized, double-blinded, parallel-controlled study was conducted to evaluate the short-term effect of STA-2, a pharmaceutical preparation of green tea polyphenols, in patients with effort-induced angina and documented positive exercise tolerance test. METHODS: A total of 79 patients recruited from three medical centers were randomly assigned to receive 2 STA-2 250 mg capsules, each containing 100 mg green tea polyphenols, three times daily, or placebo for six weeks after two consecutive symptom-limited treadmill exercise tests to ascertain the reproducibility of exercise tolerance. RESULTS: There was no difference in total exercise tolerance time from baseline to Week 6 between two groups (p = 0.639). There were also no observed improvements in subgroup analyses stratified by age, gender, and BMI categories. However, a significant reduction in low density lipoprotein levels was shown in patients in the STA-2 group (-8.99 +/- 19.18 mg/dL) versus the placebo group (0.57 +/- 19.77 mg/dL), p = 0.037, with greater benefits in patients not taking antihyperlipidemic drugs (STA-2: -9.10 +/ 19.96 mg/dL vs. placebo: 4.42 +/- 15.08 mg/dL, p = 0.037). CONCLUSIONS: STA-2 treatment for 6 weeks did not increase exercise time as measured on a treadmill. However, this study also indicated that STA-2 treatment could have potential beneficial effects on LDL-cholesterol concentrations. PMID- 27471356 TI - In-Hospital Tele-ECG Triage and Interventional Cardiologist Activation of the Infarct Team for STEMI Patients is Associated with Improved Late Clinical Outcomes. AB - BACKGROUND: Due to recent advances, door-to-balloon time (D2BT) has been reduced significantly for patients with ST-segment elevation myocardial infarction (STEMI). However, whether this reduction can be translated into a concrete mortality or morbidity benefit is still the subject of controversy. We conducted a before-and-after study to determine the impact of in-hospital tele electrocardiography (ECG) triage and interventional cardiologist activation of the infarct team on D2BT and long-term clinical outcomes in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). METHODS: A total of 272 consecutive patients with acute STEMI undergoing PPCI were enrolled in our study, comprising 102 tele-ECG patients and 170 conventional triage patients. Major adverse cardiovascular and cerebral vascular events (MACCE), including death, recurrent nonfatal MI, nonfatal stroke, and angina-driven target vessel revascularization were recorded during a 3-year follow-up. RESULTS: The median D2BT of the tele-ECG group was significantly shorter than control group (79 minutes vs. 109 minutes, p < 0.001). The tele-ECG triage group had a higher percentage of patients reaching the D2BT goal (< 90 minutes) (78% vs. 55%; p < 0.001). The MACCE rate was significantly lower in the Tele-ECG versus the control group (23.5% vs. 38.2%, p = 0.012). Tele-ECG group had a lower mortality rate which did not reached statistical significance (2% vs. 5.9%, p = 0.102). In multivariable Cox proportional hazards analyses, the implementation of tele-ECG triage (HR = 0.43, p = 0.003) and the presence of moderate or severe mitral regurgitation at presentation (HR = 1.87, p = 0.029) were discovered as independently associated with MACCE. CONCLUSIONS: In-hospital tele-ECG triage and interventional cardiologist activation can shorten D2BT and is associated with improved late clinical outcomes during a 3-year follow-up in STEMI patients undergoing PPCI. PMID- 27471358 TI - A Pilot Study on Culottes versus Crossover Single Stenting for True Coronary Bifurcation Lesions. AB - BACKGROUND: The purpose of our study was to compare clinical and angiographic outcomes of planned culottes technique with that of provisional crossover single stenting in the treatment of true coronary bifurcation lesions (CBL) with drug eluting stent (DES). METHODS: True CBL patients (n = 104) were randomly assigned to either the provisional stenting of the side branch (crossover group) or the culottes group. Additional side branch (SB) stenting in the crossover group was required if there was thrombolysis in myocardial infarction flow <= 1 flow). The primary end point was the occurrence of major adverse cardiac events (MACE) at nine months, including cardiac death, myocardial infarction, target lesion/vessel revascularization and in-stent thrombosis. The secondary end point was angiographic in-segment restenosis at nine months. RESULTS: The rate of MACE at nine months was similar between the crossover and culottes groups (7.7% vs. 7.7%, p = 1.000). Additional SB stenting in the crossover group was required in 3.8% of patients. There was one procedural occlusion of SB in the crossover group. At nine months, the rate of in-segment restenosis was similar in the parent main vessel (0% vs. 1.9%, p = 1.000), main branch (1.9% vs. 7.7%, p = 0.363) and SB (17.3% vs. 9.6%, p = 0.250) between the crossover and culottes groups, respectively. CONCLUSIONS: This study demonstrated that there is no significant difference in cumulative MACE or in-segment restenosis between crossover and culottes groups. Larger randomized clinical trials are warranted to re-evaluate the outcomes of the provisional crossover stenting versus the culottes stenting techniques utilizing DES for true CBL. PMID- 27471359 TI - Gentiana scabra Reduces SR-A Expression and Oxidized-LDL Uptake in Human Macrophages. AB - BACKGROUND: Macrophages can imbibe low-density lipoprotein (LDL) through scavenger receptors to become foam cells, which is critical in the initiation and progression of atherosclerosis. Mounting evidence suggests that the anti inflammatory nature of Chinese herbs have the capacity to halt the complex mechanisms underlying atherosclerosis. This study examined the effects of Chinese herbs on foam cell formation. METHODS: Chinese herbs were obtained from the Sun Ten pharmaceutic company. Using oxidized LDL (OxLDL) uptake and a cell toxicity assay, we screened more than 30 types of Chinese herbs. Western blotting was used to determine expressions of scavenger receptors (SRs) and extracellular-signal regulated kinase (ERK) activities. RESULTS: We found that Gentiana scabra reduced oxidized LDL uptake effectively in THP-1 macrophages (p < 0.05 vs. OxLDL treated control). Moreover, treatment with Gentiana scabra in THP-1 macrophages resulted in decreased expression of scavenger receptor- A (SR-A) (p < 0.05 vs. control). Molecular investigation revealed that Gentiana scabra inhibited SR-A protein expression, possibly by regulating ERK signaling pathways (p < 0.05 vs. control). CONCLUSIONS: By regulating SR-A expression, Gentiana scabra reduced oxidized LDL uptake in human macrophages. These results support the potential use of Gentiana scabra in treating atherosclerosis. PMID- 27471360 TI - Posture and Gender Differentially Affect Heart Rate Variability of Symptomatic Mitral Valve Prolapse and Normal Adults. AB - BACKGROUND: Heart rate variability (HRV) has been shown to be a useful measure of autonomic activity in healthy and mitral valve prolapsed (MVP) subjects. However, the effects of posture and gender on HRV in symptomatic MVP and normal adults had not been elucidated in Taiwan. METHODS: A total of 118 MVP patients (7 males, 39 +/- 7 years old; and 111 females, 42 +/- 13 years old) and 148 healthy control (54 males, 28 +/- 4 years old; and 94 females, 26 +/- 6 years old) were investigated. The diagnosis of MVP was confirmed by cross-sectional echocardiography. A locally developed Taiwanese machine was used to record the HRV parameters for MVP and control groups in three stationary positions. Thereafter, the HRV time-domain parameters, and the frequency-domain parameters derived from fast Fourier transform or autoregressive methods were analyzed. RESULTS: The MVP group showed a decrease in time domain parameters and obtunded postural effects on frequency domain parameters moreso than the control group. Though the parasympathetic tone was dominant in female (higher RMSSD, nHF and lower nLF vs. male), the sympathetic outflow was higher in MVP female (lower SDNN, NN50 and higher nLF vs. normal female). While the parasympathetic activity was lower in male, sympathetic outflow was dominant in MVP male (lower nHF and higher nLF vs. normal male). CONCLUSIONS: Both MVP female and male subjects had elevated levels of sympathetic outflow. The obtunded postural effects on frequency domain measures testified to the autonomic dysregulation of MVP subjects. PMID- 27471361 TI - Dynamics of Concomitant Functional Mitral Regurgitation in Patients with Aortic Stenosis Undergoing TAVI. AB - BACKGROUND: The aim of this study was to investigate the echocardiographic features of functional mitral regurgitation (MR) in patients with aortic stenosis (AS) pre- and post-trans catheter aortic valve implantation (TAVI). METHODS: The study subjects consisted of 79 patients with severe AS, who underwent TAVI. The echocardiographic parameters related to MR severity prior to TAVI and the change in these parameters and MR severity within one month after implantation were retrospectively evaluated. RESULTS: The mean left ventricular ejection fraction (LVEF) was 53 +/- 12%, and the mean MR severity was 1.2 +/- 0.7. Among the baseline parameters, age (p = 0.019, r = 0.264), LV mass (p = 0.017, r = 0.269), deceleration time (DT) (p = 0.019, r = -0.266), left atrial diameter (p = 0.003, r = 0.325), were related to pre-procedure MR severity. After TAVI, the grade of MR (1.2 +/- 0.7 vs. 0.8 +/- 0.6, p < 0.001) and MR duration (43 +/- 19% vs. 31 +/ 23%, p < 0.001) were significantly decreased. The grade of pre-procedural MR (p < 0.001) was a predictor of residual MR after TAVI. However, there was not a significant change in the left ventricular echocardiographic parameters after TAVI [LVEF (53 +/- 12 vs. 52 +/- 11, p = 0.285), and LV mass (302 +/- 84 vs. 306 +/- 76 g, p = 0.495)]. CONCLUSIONS: In patients with severe AS, functional MR is related to age, LV mass, DT and left atrial diameter. TAVI improves MR in these patients, even before LV remodelling occurs. PMID- 27471362 TI - Effects of Acetaminophen on Left Atrial Contractility. AB - BACKGROUND: It has been observed that acetaminophen shows cardioprotective efficacy in mammals. In this study, we investigated the electromechanical effects of acetaminophen on the left atrium (LA). METHODS: Conventional microelectrodes were used to record the action potentials (AP) in rabbit LA preparations. The action potential duration (APD) at repolarization levels of 90%, 50% and 20% of the AP amplitude (APD90, APD50, and APD20, respectively), resting membrane potential, and contractile force were measured during 2 Hz electrical stimulation before and after sequential acetaminophen administration to the LA. RESULTS: Acetaminophen (0.1, 0.3, 1, and 3 mM) reduced APD20 from 9.4 +/- 1.2 to 8.0 +/- 1.1 (p < 0.05), 7.1 +/- 0.8 (p < 0.05), 7.8 +/- 1.1, and 6.8 +/- 1.2 ms (p < 0.05), respectively, and APD50 from 20.2 +/- 1.9 to 17.4 +/- 2.0, 15.6 +/- 1.8 (p < 0.05), 15.8 +/- 2.2 (p < 0.05), and 14.1 +/- 2.4 ms (p < 0.05), respectively, in a concentration-dependent manner. APD90 was reduced from 72.0 +/- 3.6 to 64.7 +/- 4.2, 61.9 +/- 4.3, 60.5 +/- 3.7, and 53.4 +/- 4.4 ms (p < 0.05), respectively. Acetaminophen increased LA contractility from 45 +/- 9 to 52 +/- 10 (p < 0.05), 55 +/- 9 (p < 0.01), 58 +/- 9 (p < 0.01), and 60 +/- 9 mg (p < 0.01), respectively, in a concentration-dependent manner. In the presence of the NOS inhibitor L-NAME or PKG-I inhibitor DT-2, additional acetaminophen treatment did not significantly increase LA contractility. CONCLUSIONS: Acetaminophen modulated the electromechanical characteristics of LA by inhibiting the NOS and PKG I pathway, and then contributed to the positive inotropic effect. PMID- 27471363 TI - Optimal Duration of Coronary Ligation and Reperfusion for Reperfusion Injury Study in a Rat Model. AB - BACKGROUND: Reperfusion injury (RI) has an important impact on the clinical prognosis for patients with acute myocardial injury who had their coronary blood flow reestablished. However, no studies to date have investigated the timeframe of coronary occlusion and reperfusion effects on RI. METHODS: A total of 100 rats were divided into 4 groups based on the coronary ligation period: 30, 60, 120, and 180 min, and each group was further divided into 5 subgroups with different reperfusion periods: 0, 30, 60, 120, and 180 min. R0 was the baseline of each subgroup. All animals received the same protocols for designed ligation and reperfusion periods. Evans blue and 2,3,5-triphenyltetrazolium chloride were used to distinguish different myocardial injury areas: area at risk (AAR) and myocardial necrosis. The differences of the ratios of the necrotic area to AAR between each subgroup and baseline were further averaged to calculate an overall value of each heart. RESULTS: The relative RI percentages showed significant differences (0.8 +/- 2.3%, 4.9 +/- 3.3%, 10.8 +/- 3.1%, and 20.3 +/- 3.6% respectively, p < 0.001) at different time points of reperfusion but not at different time points of ligation (p = 0.593). The effects of different time courses in RI showed that the L120R180 group (43.4 +/- 2.3%) had the highest RI difference with the baseline group. CONCLUSIONS: Maximal RI occurred at the timeframe of L120R180 in our animal model. This result may be utilized to assess the substantial benefits of RI therapies in an experimental rat model setting. PMID- 27471364 TI - Severe Coronary Spasm in Systemic Lupus Erythematosus Resulting in Recurrent Occlusions and Guide Wire Fracture. AB - Middle-aged female patients with systemic lupus erythematosus (SLE) have an increased risk of coronary artery disease and myocardial infarction (MI). We report a case of left anterior descending coronary artery (LAD) MI associated with severe coronary spasm in both the LAD and left circumflex artery, complicated with fracture of the distal wire within the microcatheter which was successfully removed by manual aspiration using an inflation device. From this series of rare complications of SLE with MI, severe coronary spasm and guide wire fracture, we underscore that clinicians performing coronary intervention should be aware of an elevated chance of possible severe coronary spasms in SLE patients. PMID- 27471365 TI - A Case of Metanephric Adenoma and Acute Myocardial Infarction. AB - Metanephric adenoma (MA) is a rare neoplasm that acounts for 0.2% of adult renal neoplasms. MAs are typically discover incidentally during detailed examinations for nonspecific symptoms such as abdominal or flank pain, hematuria, fever and palpable abdominal mass. Additionally, polycythemia has occasionally been reported as well. Herein we describe a case of metanephric adenoma which was an incidental finding in the course of a clinical autopsy in a patient with complete AV block and polycythemia. Histologically, the tumor was composed of small and uniform tubular structures reminiscent of renal tubuli, without signs of cellular atypia and pleomorphism. Such tumor histomorphology was consistent with the diagnosis of metanephric adenoma. Thrombosis is a common complication of polycythemia that often causes death. Polycythemia with an increasing number of blood cells causes hyperviscosity and, in 20-40% of cases, lethal thrombosis or hemorrhage. Hyperviscosity and coronary artery disease in our patient caused acute myocardial infarction with the subsequent rupture of posterior left ventricle wall and hemopericardium. PMID- 27471366 TI - Silent and Malignant Early Repolarization Syndrome Mimicking Hyper-Acute ST Elevation Myocardial Infarction. AB - A 55-year-old male with underlying type 2 diabetes mellitus and hypertension presented at our emergency department with ventricular fibrillation-related cardiac arrest. Hyper-acute ST elevation myocardial infarction was the preliminary diagnosis by 12-lead electrocardiography, which simultaneously showed J point ST elevation and tall T waves. However, the echocardiography showed concentric left ventricle hypertrophy and preserved left ventricular systolic function with no regional wall motion abnormalities, and coronary angiography did not show any critical coronary artery lesion. Malignant early repolarization syndrome was diagnosed, and an implantable cardioverter defibrillator was implanted. Early repolarization syndrome is associated with J point elevation, and more involved leads and an increased J point elevation amplitude can increase the risk of arrhythmogenicity. In summary, we report a case with asymptomatic type 3 early repolarization syndrome-induced idiopathic ventricular fibrillation mimicking hyper-acute ST elevation myocardial infarction. PMID- 27471367 TI - Latent Left Ventricular Outflow Tract Obstruction Due to Accessory Mitral Valve in a 12-Year-Old Boy. AB - Accessory mitral valve (AMV) is a rare congenital anomaly which can cause left ventricular outflow tract (LVOT) obstruction. Patients with isolated AMV usually present with exertional dyspnea, chest pain, or syncope during the first ten years of life. In patients with AMV, detection of latent LVOT obstruction can be clinically challenging. We here present a case of AMV causing latent LVOT obstruction in an adolescent, which was diagnosed by echocardiography with dobutamine provocation and finally treated by successful surgical resection. PMID- 27471368 TI - Is Shorter Door-to-Balloon Time Associated with a Double Risk of Major Adverse Cardiac Events? Use of Drug-Eluting Stents Should Be Considered. PMID- 27471369 TI - Reply to the Letter to the Editor for the Article Entitled "Effects of Door-to Balloon Times on Outcomes in Taiwanese Patients Receiving Primary Percutaneous Coronary Intervention: A Report of Taiwan Acute Coronary Syndrome Full Spectrum Registry" Published in the Journal of Acta Cardiologica Sinica in 2015 (2015;31:215-225). PMID- 27471370 TI - Integrating cognitive behavioral therapy into primary care settings. PMID- 27471371 TI - Implementing cognitive behavioral therapy in specialty medical settings. AB - This article is an introduction to the second issue of a two-part Special Series on integrating cognitive behavioral therapy (CBT) into medical settings. The first issue focused on integrating CBT into primary care, and this issue focuses on implementing CBT in other specialty medical settings, including cancer treatment, HIV care, and specialized pediatric medical clinics. Models for treatment delivery to improve ease of implementation are also discussed, including telehealth and home-delivered treatment. The six articles in this series provide examples of how to transport CBT techniques that are largely designed for implementation in outpatient mental health settings to specialized medical settings, and discuss unique considerations and recommendations for implementation. PMID- 27471372 TI - Pachychoroid neovasculopathy in extramacular choroidal neovascularization. AB - PURPOSE: To review a series of extramacular choroidal neovascular membranes (CNVMs) in the context of their choroidal features, as determined by optical coherence tomography (OCT). METHODS: Patients with extramacular CNVMs were identified from a tertiary care center through a review of records. The charts and cases were reviewed using multimodal imaging including fundus photography, OCT, fluorescein angiography (FA), and indocyanine angio-graphy (ICG). RESULTS: Of six patients with extramacular CNVMs evaluated in this series, four patients (66.7%) exhibited pachychoroidopathy on OCT imaging under or adjacent to the extramacular CNVM. All four of these patients also exhibited pachychoroidopathy in the macular OCT distant from the CNVM. CONCLUSION: Pachychoroidopathy is implicated in some cases of extramacular CNVMs. This represents the first report, to our knowledge, of pachychoroidopathy in extramacular CNVM. PMID- 27471373 TI - The intraocular pressure-lowering properties of intravenous paracetamol. AB - AIM: The aim of this paper was to investigate the intraocular pressure (IOP) changing properties of a single standard dose of intravenous (IV) paracetamol and compare it to that of topical timolol, oral acetazolamide, and no treatment. METHODS: A prospective, randomized, investigator-blind, parallel-group study was conducted in 73 eyes of 52 subjects. Subjects received a single dose of IV paracetamol (1 g), oral acetazolamide (250 mg), topical timolol (0.5%, one drop), or no treatment. Baseline IOP was measured, and the measurement was repeated at 1, 2, 4, and 6 hours after treatment. RESULTS: Paracetamol reduced IOP from baseline by -10.8% (95% confidence interval [CI]: -4.9% to -16.8%, P=0.146) at 1 hour, -13.3% (95% CI: -8.3% to -18.4%, P=0.045) at 2 hours, -11.8% (95% CI: -5.5% to -18.4%, P=1.000) at 4 hours, and -23.9% (95% CI: -17.8% to -30.1%, P=0.006) at 6 hours after treatment. In the no-treatment group, the change was -2.9% (95% CI: +1.0% to -6.7%, P= referent) at 1 hour, -2.1% (95% CI: +2.9% to -7.2%, P= referent) at 2 hours, -7.6% (95% CI: -3.9% to -11.2%, P= referent) at 4 hours, and -6.9% (95% CI: -3.6% to -10.2%, P= referent) at 6 hours. Acetazolamide reduced IOP by -18.8% (95% CI: -12.7% to -24.8%, P=0.000) at 1 hour, -26.2% (95% CI: -18.2% to -34.2%, P=0.001) at 2 hours, -24.6% (95% CI: -16.9% to -32.3%, P=0.000) after 4 hours, and -26.9% (95% CI: -19.6% to -34.3%, P=0.000) 6 hours after treatment. Timolol reduced IOP by -31.2% (95% CI: -26.7% to -35.7%, P=0.000) at 1 hour, -27.7% (95% CI: -20.7% to -34.8%, P=0.000) at 2 hours, -28.7% (95% CI: -21.1% to -36.2%, P=0.000) at 4 hours, and -21.3% (95% CI: -13.4% to 30.0%, P=0.030) at 6 hours after treatment. The average change in IOP for the no treatment group was -4.8% (95% CI: -2.6% to -6.9%, P= referent). It was -15.7% (95% CI: -9.3% to -22.1%, P=0.021) for paracetamol, -23.1% (95% CI: -16.4% to 29.8%, P=0.000) for acetazolamide, and -25.3% for the timolol group (95% CI: 19.4% to -31.2%, P=0.000). The maximal change in IOP for the no-treatment group was -9.2% (95% CI: -3.2% to -15.3%, P= referent). It was -25.9% (95% CI: -16.6% to -35.2%, P=0.009) for paracetamol, -33.8% (95% CI: -25.5% to -42.1%, P=0.000) for acetazolamide, and -36.8% (95% CI: -31.0% to -42.5%, P=0.000) for the timolol group. CONCLUSION: Intravenously administered paracetamol shows IOP-lowering properties over the first 6 hours after administration. Clinicians performing IOP measurements in patients who have received IV paracetamol in the preceding 6 hours should interpret these measurements with caution. Further studies are needed to investigate the IOP-changing properties of paracetamol. PMID- 27471374 TI - Wide-field optical coherence tomography angiography using extended field imaging technique to evaluate the nonperfusion area in retinal vein occlusion. AB - PURPOSE: Optical coherence tomography angiography (OCTA) is a newly developed technology which allows us to reconstruct the three-dimensional chorioretinal vasculature without dye injection. OCTA is a noninvasive, rapid, and reproducible method to assess retinal ischemia. However, one of its limitations is the size of scanning area. A novel yet simple technique to expand the scan length on optical coherence tomography has been reported as an extended field imaging (EFI) technique. It involves imaging the posterior pole through trial frames fitted with a +20 diopter lens. We applied this technique to OCTA to evaluate retinal vein occlusion. MATERIALS AND METHODS: Ten eyes of nine patients with retinal vein occlusion were studied. The average age was 69.0 years (range: 49-93 years). We obtained OCTA images by using RTVue XR Avanti OCT with AngioVue((r)). The images of OCTA with scan size of 8*8 mm were obtained with and without EFI, and then they were compared. RESULTS: OCTA with EFI technique was performed successfully in all eyes. The nonperfusion area was well defined in superficial capillary plexus layer. The images with EFI were able to capture the larger area of the fundus by an average of 188.5% than those without EFI. The posterior pole inside the vascular arcade was well covered with this technique. The area of the fundus imaged by OCTA with EFI technique was even larger than that of fluorescein angiography using Heidelberg Retina Angiograph 2, which captured a 30 degrees field. CONCLUSION: Our results suggested that OCTA with EFI technique is very useful to evaluate the retinal ischemia in retinal vein occlusion. PMID- 27471375 TI - Simvastatin attenuates radiation-induced salivary gland dysfunction in mice. AB - OBJECTIVE: Statins are widely used lipid-lowering drugs, which have pleiotropic effects, such as anti-inflammation, and vascular protection. In our study, we investigated the radioprotective potential of simvastatin (SIM) in a murine model of radiation-induced salivary gland dysfunction. DESIGN: Ninety-six Institute of Cancer Research mice were randomly divided into four groups: solvent + sham irradiation (IR) (Group I), SIM + sham IR (Group II), IR + solvent (Group III), and IR + SIM (Group IV). SIM (10 mg/kg body weight, three times per week) was administered intraperitoneally 1 week prior to IR through to the end of the experiment. Saliva and submandibular gland tissues were obtained for biochemical, morphological (hematoxylin and eosin staining and Masson's trichrome), and Western blot analysis at 8 hours, 24 hours, and 4 weeks after head and neck IR. RESULTS: IR caused a significant reduction of salivary secretion and amylase activity but elevation of malondialdehyde. SIM remitted the reduction of saliva secretion and restored salivary amylase activity. The protective benefits of SIM may be attributed to scavenging malondialdehyde, remitting collagen deposition, and reducing and delaying the elevation of transforming growth factor beta1 expression induced by radiation. CONCLUSION: SIM may be clinically useful to alleviate side effects of radiotherapy on salivary gland. PMID- 27471376 TI - The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats. AB - BACKGROUND: In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system - the thymus and the spleen. METHODS: The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. RESULTS: There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. CONCLUSION: Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen-dependent manner. PMID- 27471377 TI - Treatment satisfaction among men with concurrent benign prostatic hyperplasia and erectile dysfunction treated with tadalafil or other phosphodiesterase type-5 inhibitor combinations. AB - OBJECTIVE: Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) frequently co-occur in men aged >=40, along with lower urinary tract symptoms (LUTS) secondary to BPH. Given little real-world evidence on treatment use or satisfaction with treatment for concurrent BPH/LUTS and/or ED, this study examined medication regimens and differences in satisfaction and health-related quality of life (HRQoL) across regimens among men with concurrent BPH and ED. METHODS: A cross-sectional study was conducted using an Internet survey of participants recruited through an online panel. Respondents (N=736) included men (aged >=40) who self-reported a diagnosis of both ED and BPH with prescription treatment in the past 3 months for both conditions. Treatment satisfaction (eg, convenience and ease of planning) and HRQoL (eg, International Prostate Symptom Score, sleep quality) were self-reported. Generalized linear models examined the association of regimen with treatment satisfaction and HRQoL, adjusting for covariates (eg, age and comorbidities). RESULTS: Final analyses included participants (N=507) using: tadalafil once-daily monotherapy (22%), tadalafil for ED with an alternate BPH therapy (36%), or another phosphodiesterase type-5 inhibitor (PDE5-I) combination (41%). These groups represented the major categories of treatment regimens found in the sample, excluded participants with ambiguous regimens, and were aligned with current standard of care for BPH and ED. Overall, patients reported moderate levels of BPH and a moderate-to-severe degree of ED. Tadalafil monotherapy patients had higher treatment satisfaction scores and greater reported ease of treatment planning and convenience than PDE5 I combination patients. No significant intergroup differences were found on HRQoL. CONCLUSION: A majority of patients (59%) took tadalafil alone or in combination for BPH/ED treatment. Tadalafil monotherapy patients reported greater treatment satisfaction than patients taking PDE5-I combination therapy. Higher satisfaction for both effectiveness and convenience of once-daily tadalafil may inform both patient and clinician decisions regarding pharmacotherapy regimens. PMID- 27471378 TI - Clinical importance of achieving biochemical control with medical therapy in adult patients with acromegaly. AB - In acromegaly, achieving biochemical control (growth hormone [GH] level <1.0 ng/mL and age- and sex-normalized levels of insulin-like growth factor 1 [IGF-1]) through timely diagnosis and appropriate treatment provides an opportunity to improve patient outcomes. Diagnosis of acromegaly is challenging because it is rooted in observing subtle clinical manifestations, and it is typical for acromegaly to evolve for up to 10 years before it is recognized. This results in chronic exposure to elevated levels of GH and IGF-1 and delay in patients receiving appropriate treatment, which consequently increases mortality risk. In this review, the clinical impact of elevated GH and IGF-1 levels, the effectiveness of current therapies, and the potential role of novel treatments for acromegaly will be discussed. Clinical burden of acromegaly and benefits associated with management of GH and IGF-1 levels will be reviewed. Major treatment paradigms in acromegaly include surgery, medical therapy, and radiotherapy. With medical therapies, such as somatostatin analogs, dopamine agonists, and GH receptor antagonists, a substantial proportion of patients achieve reduced GH and normalized IGF-1 levels. In addition, signs and symptoms, quality of life, and comorbidities have also been reported to improve to varying degrees in patients who achieve biochemical control. Currently, there are several innovative therapies in development to improve patient outcomes, patient use, and access. Timely biochemical control of acromegaly ensures that the patient can ultimately improve morbidity and mortality from this disease and its extensive consequences. PMID- 27471379 TI - Parental preference for fluoride varnish: a new concept in a rapidly developing nation. AB - OBJECTIVE: The objective of this study was to investigate parental preference for fluoride varnish in a country where the average percentage of dental caries in young children is up to ~73%. Consequently, the aim of this study, despite being a pilot, was to create a nationwide project in the State of Qatar to promote oral health in children. METHODS: A cross-sectional perspective study was conducted at Hamad Medical Corporation in Qatar. Parents of children aged <=5 years were offered an interview survey. A total of 200 questionnaires were completed (response rate =100%). The study was conducted between December 1, 2014 and March 30, 2015, and included all children aged >1 year and <5 years who came to the outpatient clinics for well-child and sick visits. We also included children who were admitted to the inpatient wards. RESULTS: The mean age of participant children was 2.8+/-1.1 years. When inquiring regarding parents' knowledge and awareness of dental health, we found that >90% of families were aware that dental health affects the health of the whole body. The study showed that ~70% of parents were not aware of the existence of fluoride varnish, but would allow a health provider to apply fluoride varnish. Furthermore, ~80% of parents would not stop brushing their child's teeth and would not skip dentist appointments if varnish was to be applied. Approximately 40% of parents conveyed some concerns regarding the safety of fluoride varnish, despite being considered as a new concept. The main concern was that the child might swallow some of the fluoride. Another important concern expressed by parents was the availability of the fluoride varnish in all clinics. CONCLUSION: The robust positive attitude of parents in this sample suggests that introducing fluoride varnish is feasible and acceptable in our community. Actions to augment fluoride varnish acceptability in the developing world, such as focusing on safety, could be important in the disseminated implementation of fluoride varnish. PMID- 27471380 TI - Acute exacerbation of COPD: is it the "stroke of the lungs"? AB - Chronic obstructive pulmonary disease (COPD) is one of the top five major causes of morbidity and mortality worldwide. Despite worldwide health care efforts, costs, and medical research, COPD figures demonstrate a continuously increasing tendency in mortality. This is contrary to other top causes of death, such as neoplasm, accidents, and cardiovascular disease. A major factor affecting COPD related mortality is the acute exacerbation of COPD (AECOPD). Exacerbations and comorbidities contribute to the overall severity in individual patients. Despite the underestimation by the physicians and the patients themselves, AECOPD is a really devastating event during the course of the disease, similar to acute myocardial infarction in patients suffering from coronary heart disease. In this review, we focus on the evidence that supports the claim that AECOPD is the "stroke of the lungs". AECOPD can be viewed as: a Semicolon or disease's full stop period, Triggering a catastrophic cascade, usually a Relapsing and Overwhelming event, acting as a Killer, needing Emergent treatment. PMID- 27471381 TI - Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo. AB - The aim of the present study was to develop a novel dosage form of multivesicular liposomes for oleanolic acid (OA) to overcome its poor solubility, prolong therapeutic drug levels in the blood, and enhance the antitumor effect on hepatocellular carcinoma. OA-encapsulated multivesicular liposomes (OA-MVLs) were prepared by a double-emulsion method, and the formulation was optimized by the central composite design. The morphology, particle size, and drug-loading efficiency of OA-MVLs were investigated. Furthermore, OA-MVLs were also characterized both in vitro and in vivo. The results showed that OA-MVLs were spherical particles with an average particle size of 11.57 MUm and an encapsulation efficiency of 82.3%+/-0.61%. OA-MVLs exhibited a sustained-release pattern in vitro, which was fitted to Ritger-Peppas equation. OA-MVLs inhibited the growth of human HepG2 cells which was confirmed by the MTT assay and fluorescence microscopy detection. The in vivo release of OA from OA-MVLs exhibited a sustained manner, indicating a longer circulation time compared to OA solution. The in vivo toxicity study indicated that medium-dose OA-MVLs exerted no toxic effect on the hosts. Importantly, OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice. In conclusion, the poorly soluble OA could be encapsulated into MVLs to form a novel controlled-release drug delivery system. The present study may hold promise for OA-MVLs as a new dosage form for sustained-release drug delivery in cancer therapy. PMID- 27471383 TI - "Smart" nickel oxide based core-shell nanoparticles for combined chemo and photodynamic cancer therapy. AB - We report "smart" nickel oxide nanoparticles (NOPs) as multimodal cancer therapy agent. Water-dispersible and light-sensitive NiO core was synthesized with folic acid (FA) connected bovine serum albumin (BSA) shell on entrapped doxorubicin (DOX). The entrapped drug from NOP-DOX@BSA-FA was released in a sustained way (64 hours, pH=5.5, dark conditions) while a robust release was found under red light exposure (in 1/2 hour under lambdamax=655 nm, 50 mW/cm(2), at pH=5.5). The cell viability, thiobarbituric acid reactive substances and diphenylisobenzofuran assays conducted under light and dark conditions revealed a high photodynamic therapy potential of our construct. Furthermore, we found that the combined effect of DOX and NOPs from NOP-DOX@BSA-FA resulted in cell death approximately eightfold high compared to free DOX. We propose that NOP-DOX@BSA-FA is a potential photodynamic therapy agent and a collective drug delivery system for the systemic administration of cancer chemotherapeutics resulting in combination therapy. PMID- 27471382 TI - Controlled release of recombinant human cementum protein 1 from electrospun multiphasic scaffold for cementum regeneration. AB - Periodontitis is a major cause for tooth loss, which affects about 15% of the adult population. Cementum regeneration has been the crux of constructing the periodontal complex. Cementum protein 1 (CEMP1) is a cementum-specific protein that can induce cementogenic differentiation. In this study, poly(ethylene glycol) (PEG)-stabilized amorphous calcium phosphate (ACP) nanoparticles were prepared by wet-chemical method and then loaded with recombinant human CEMP1 (rhCEMP1) for controlled release. An electrospun multiphasic scaffold constituted of poly(epsilon-caprolactone) (PCL), type I collagen (COL), and rhCEMP1/ACP was fabricated. The effects of rhCEMP1/ACP/PCL/COL scaffold on the attachment proliferation, osteogenic, and cementogenic differentiations of human periodontal ligament cells, (PDLCs) were systematically investigated. A critical size defect rat model was introduced to evaluate the effect of tissue regeneration of the scaffolds in vivo. The results showed that PEG-stabilized ACP nanoparticles formed a core-shell structure with sustained release of rhCEMP1 for up to 4 weeks. rhCEMP1/ACP/PCL/COL scaffold could suppress PDLCs proliferation behavior and upregulate the expression of cementoblastic markers including CEMP1 and cementum attachment protein while downregulating osteoblastic markers including osteocalcin and osteopontin when it was cocultured with PDLCs in vitro for 7 days. Histology analysis of cementum after being implanted with the scaffold in rats for 8 weeks showed that there was cementum-like tissue formation but little bone formation. These results indicated the potential of using electrospun multiphasic scaffolds for controlled release of rhCEMP1 for promoting cementum regeneration in reconstruction of the periodontal complex. PMID- 27471384 TI - Vitamin E succinate-conjugated F68 micelles for mitoxantrone delivery in enhancing anticancer activity. AB - Mitoxantrone (MIT) is a chemotherapeutic agent with promising anticancer efficacy. In this study, Pluronic F68-vitamine E succinate (F68-VES) amphiphilic polymer micelles were developed for delivering MIT and enhancing its anticancer activity. MIT-loaded F68-VES (F68-VES/MIT) micelles were prepared via the solvent evaporation method with self-assembly under aqueous conditions. F68-VES/MIT micelles were found to be of optimal particle size with the narrow size distribution. Transmission electron microscopy images of F68-VES/MIT micelles showed homogeneous spherical shapes and smooth surfaces. F68-VES micelles had a low critical micelle concentration value of 3.311 mg/L, as well as high encapsulation efficiency and drug loading. Moreover, F68-VES/MIT micelles were stable in the presence of fetal bovine serum for 24 hours and maintained sustained drug release in vitro. Remarkably, the half maximal inhibitory concentration (IC50) value of F68-VES/MIT micelles was lower than that of free MIT in both MDA-MB-231 and MCF-7 cells (two human breast cancer cell lines). In addition, compared with free MIT, there was an increased trend of apoptosis and cellular uptake of F68-VES/MIT micelles in MDA-MB-231 cells. Taken together, these results indicated that F68-VES polymer micelles were able to effectively deliver MIT and largely improve its potency in cancer therapy. PMID- 27471385 TI - In vitro and in vivo biocompatibility and osteogenesis of graphene-reinforced nanohydroxyapatite polyamide66 ternary biocomposite as orthopedic implant material. AB - Graphene and its derivatives have been receiving increasing attention regarding their application in bone tissue engineering because of their excellent characteristics, such as a vast specific surface area and excellent mechanical properties. In this study, graphene-reinforced nanohydroxyapatite/polyamide66 (nHA/PA66) bone screws were prepared. The results of scanning electron microscopy observation and X-ray diffraction data showed that both graphene and nHA had good dispersion in the PA66 matrix. In addition, the tensile strength and elastic modulus of the composites were significantly improved by 49.14% and 21.2%, respectively. The murine bone marrow mesenchymal stem cell line C3H10T1/2 exhibited better adhesion and proliferation in graphene reinforced nHA/PA66 composite material compared to the nHA/PA66 composites. The cells developed more pseudopods, with greater cell density and a more distinguishable cytoskeletal structure. These results were confirmed by fluorescent staining and cell viability assays. After C3H10T1/2 cells were cultured in osteogenic differentiation medium for 7 and 14 days, the bone differentiation-related gene expression, alkaline phosphatase, and osteocalcin were significantly increased in the cells cocultured with graphene reinforced nHA/PA66. This result demonstrated the bone-inducing characteristics of this composite material, a finding that was further supported by alizarin red staining results. In addition, graphene reinforced nHA/PA66 bone screws were implanted in canine femoral condyles, and postoperative histology revealed no obvious damage to the liver, spleen, kidneys, brain, or other major organs. The bone tissue around the implant grew well and was directly connected to the implant. The soft tissues showed no obvious inflammatory reaction, which demonstrated the good biocompatibility of the screws. These observations indicate that graphene-reinforced nHA/PA66 composites have great potential for application in bone tissue engineering. PMID- 27471386 TI - Evaluation of oxidant, antioxidant, and S100B levels in patients with conversion disorder. AB - INTRODUCTION: Various psychodynamic, neurobiological, genetic, and sociocultural factors are believed to be involved in the etiology of conversion disorder (CD). Oxidative metabolism has been shown to deteriorate in association with many health problems and psychiatric disorders. We evaluated oxidative metabolism and S100B levels in the context of this multifactorial disease. METHODS: Thirty-seven patients with CD (25 females and 12 males) and 42 healthy volunteers (21 females and 21 males), all matched for age and sex, were included in this study. The total oxidant status, total antioxidant status, oxidative stress index, and S100B levels were compared between the two groups. RESULTS: The total oxidant status, oxidative stress index, and S100B levels were significantly higher in patients with CD than in the control group, whereas the total antioxidant status was significantly lower. CONCLUSION: CD is associated with deterioration of oxidative metabolism and increased neuronal damage. PMID- 27471387 TI - Involvement of upregulation of miR-210 in a rat epilepsy model. AB - Epilepsy is a common type of neurological disorder with complex etiology. The mechanisms are still not clear. MicroRNAs are endogenous noncoding RNAs with many physiological activities. Multiple microRNAs were abnormally expressed in status epilepticus, including miR-210. In this study, we applied lithium chloride and pilocarpine to induce epileptic activity and aimed to disclose the potential mechanisms. Our data showed that miR-210 was significantly upregulated in hippocampus one day after modeling (P<0.05 vs control) and the high expression of miR-210 lasted for at least 30 days. By contrast, gamma-aminobutyric acid (GABA) level significantly decreased concurrently after modeling (P<0.05 vs control). To question whether miR-210 could be a potential therapeutic target for epilepsy, miR-210 inhibitor was administrated through intrahippocampal injection after epilepsy modeling. Our data showed that morphological changes of hippocampal neurons and apoptosis triggered by epilepsy were mitigated by miR-210 inhibition. More importantly, the expressions of GABA-related proteins, including GABAA receptor alpha1, glutamate decarboxylase, and GABA transporter 1, were significantly elevated after epilepsy modeling in both mRNA and protein levels 3 days postmodeling (P<0.05 vs control), which were mitigated by miR-210 inhibitor treatment (P<0.05 vs model). In addition, epilepsy-induced upregulation of GABA transaminase was alleviated by miR-210 inhibitor. Taken together, these data implicated potential roles of miR-210 in lithium chloride-pilocarpine-induced epilepsy model and miR-210 could serve as a potential therapeutic target in status epilepticus. PMID- 27471388 TI - Is there a relationship between fracture healing and mean platelet volume? AB - OBJECTIVES: Platelet volume has been defined to be a marker that shows thrombocyte activation and function and it is measured as mean platelet volume (MPV). MPV shows the mean volume of circulating thrombocytes and it is one of the routine parameters in complete blood count. Increased thrombocyte volume is associated with thrombocyte activation. PATIENTS AND METHODS: This study included 76 patients who were operated on due to fractures of long tubular bones. Patients who had union without any additional interventions were defined as group I, and patients who needed additional interventions due to nonunion or inadequate union were defined as group II. The control group included healthy volunteers who did not have a fracture. Hematologic test values of the patients that were obtained at admission to emergency ward were recorded. RESULTS: The groups were not statistically different in terms of age, sex, and the affected extremity. There were significant differences between group I and group II in terms of mean erythrocyte sedimentation rate, C-reactive protein, and MPV values (P<0.001), but there were no significant differences between group I and the control group. There was also no statistically significant difference among groups in terms of hematologic and biochemical variables. CONCLUSION: In our study, fractures in patients who had lower MPV values than controls during the inflammation process healed without any problem, but fractures in patients with high MPV values more frequently needed additional surgical interventions. PMID- 27471389 TI - Efficacy and safety outcomes of ticagrelor compared with clopidogrel in elderly Chinese patients with acute coronary syndrome. AB - OBJECTIVE: This study was designed to investigate the efficacy and safety outcomes of ticagrelor in comparison with clopidogrel on a background of aspirin in elderly Chinese patients with acute coronary syndrome (ACS). PATIENTS AND METHODS: A double-blinded, randomized controlled study was conducted, and 200 patients older than 65 years with the diagnosis of ACS were assigned 1:1 to take ticagrelor or clopidogrel. The course of treatment was required to continue for 12 months. RESULTS: The median age of the whole cohort was 79 years (range: 65-93 years), and females accounted for 32.5% (65 patients). Baseline characteristics and clinical diagnosis had no significant difference between patients taking ticagrelor and clopidogrel; they were also balanced with respect to other treatments (P>0.05 for all). The risk of cardiovascular death was significantly lower in patients taking ticagrelor compared with clopidogrel, as was the risk of myocardial infarction (P<0.05 for all); there was no difference in the risk of stroke (P>0.05). Ticagrelor was more effective than clopidogrel in decreasing the primary efficacy end point (cardiovascular death, myocardial infarction, and stroke, P<0.05). The all-cause mortality was not significantly different between patients taking ticagrelor and clopidogrel (P>0.05). The difference in the risk of bleeding, platelet inhibition and patient outcomes major bleeding (life threatening bleeding and others), and platelet inhibition and patient outcomes minor bleeding was not evident between patients taking ticagrelor and clopidogrel (P>0.05 for all). CONCLUSION: The current study in elderly Chinese patients with ACS demonstrated that ticagrelor reduced the primary efficacy end point at no expense of increased bleeding risk compared with clopidogrel, suggesting that ticagrelor is a suitable alternative for use in elderly Chinese patients with ACS. PMID- 27471390 TI - Comparison of continuous epidural infusion and programmed intermittent epidural bolus in labor analgesia. AB - BACKGROUND: This study aims to investigate differences between continuous epidural infusion (CEI) and programmed intermittent epidural bolus (IEB) analgesia for the Chinese parturients undergoing spontaneous delivery and to approach their safety to parturients and neonates. METHODS: Two hundred healthy American Society of Anesthesiologists class I or II, term (>=37 weeks' gestation), nulliparous women who requested analgesia for labor were recruited. Epidural analgesia was initiated with a solution of 0.15% ropivacaine 10 mL and maintained with 0.1% ropivacaine mixed with sufentanil 0.3 MUg/mL by CEI at a rate of 5 mL/h combined with a patient-controlled epidural analgesia (PCEA) bolus of 5 mL of ropivacaine sufentanil mixture or IEB of 5 mL of ropivacaine sufentanil mixture combined with a PCEA bolus of 5 mL of ropivacaine sufentanil mixture. The lockout interval was 20 minutes in each arm between the CEI and the IEB group. After 20 minutes of first dosage, visual analog scale (VAS) score was obtained every 60 minutes. The maternal and fetal outcome and total consumption of analgesic solution were compared. RESULTS: There was no difference in demographic characteristics, duration of first and second stages, delivery methods, sensory block, fetal Apgar scores, and the maternal outcomes between the CEI and IEB groups. There was a significant difference in VAS scores and epidural ropivacaine total consumption between the two groups (IEB vs CEI: 51.27+/-9.61 vs 70.44+/-12.78 mg, P<0.01). CONCLUSION: The use of programmed IEB mixed with PCEA improved labor analgesia compared to CEI mixed with PCEA, which could act as maintenance mode for epidural labor analgesia. PMID- 27471392 TI - Feeling "overloaded" and "shortcomings": milieu therapists' experiences of vulnerability in caring for severely mentally ill patients. AB - BACKGROUND: Milieu therapists' relationships with patients with severe mental illnesses are viewed as challenging. Elucidating vulnerability from their perspective in daily face-to-face encounters with patients might contribute to extending our knowledge about milieu therapists' vulnerability and the dynamics of the interaction between patients in mental health services and expertise in building caring and therapeutic relationships. The aim of this project was to study educated milieu therapists' experiences of their own vulnerability in their interactions with patients in mental health services. MATERIALS AND METHODS: The data collection method was focus-group interviews. Thirteen part-time master's in mental health students (eight nurses, three social workers, two social educators) participated. All participants had experience with community or specialized mental health services (2-8 years). RESULTS: The milieu therapists mainly related their experiences of vulnerability to negative feelings elicited by challenging work conditions, disclosed as two main themes: 1) "overloaded", by the possibility of being physically and mentally hurt and the burdens of long-lasting close relationships; milieu therapists were extremely vulnerable because of their difficulty in protecting themselves; and 2) "shortcomings", connected to feelings of despair associated with not acting in concordance with their professional standards and insecurity about their skills to handle challenging situations, which was a threat to their professional integrity. There seemed to be coherence between vulnerability and professional inauthenticity. A misunderstanding that professionalism refers to altruism seems to increase milieu therapist vulnerability. CONCLUSION: Vulnerability in health care is of interest to multiple disciplines, and is of relevance for knowledge development in higher education. Extended knowledge and understanding about milieu therapists' vulnerability might strengthen their personal and professional integrity in professional practice in mental health services. Health care managers' focus on the supervision of individual professionals in practice and practical training is important. Further research on the coherence between vulnerability and professionalism is recommended. PMID- 27471391 TI - Matrix metalloproteinases in exercise and obesity. AB - Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent endoproteinases that have the ability to break down extracellular matrix. The large range of MMPs' functions widens their spectrum of potential role as activators or inhibitors in tissue remodeling, cardiovascular diseases, and obesity. In particular, MMP-1, -2, and -9 may be associated with exercise and obesity. Thus, the current study reviewed the effects of different types of exercise (resistance and aerobic) on MMP-1, -2, and -9. Previous studies report that the response of MMP-2 and -9 to resistance exercise is dependent upon the length of exercise training, since long-term resistance exercise training increased both MMP-2 and 9, whereas acute bout of resistance exercise decreased these MMPs. Aerobic exercise produces an inconsistent result on MMPs, although some studies showed a decrease in MMP-1. Obesity is related to a relatively lower level of MMP-9, indicating that an exercise-induced increase in MMP-9 may positively influence obesity. A comprehensive understanding of the relationship between exercise, obesity, and MMPs does not exist yet. Future studies examining the acute and chronic responses of these MMPs using different subject models may provide a better understanding of the molecular mechanisms that are associated with exercise, obesity, and cardiovascular disease. PMID- 27471393 TI - Postoperative radiation in esophageal squamous cell carcinoma and target volume delineation. AB - Esophageal cancer is the sixth leading cause of cancer death worldwide, and patients who are treated with surgery alone, without neoadjuvant therapies, experience frequent relapses. Whether postoperative therapies could reduce the recurrence or improve overall survival is still controversial for these patients. The purpose of our review is to figure out the value of postoperative adjuvant therapy and address the disputes about target volume delineation according to published data. Based on the evidence of increased morbidity and disadvantages on patient survival caused by postoperative chemotherapy or radiotherapy (RT) alone provided by studies in the early 1990s, the use of postoperative adjuvant therapies in cases of esophageal squamous cell carcinoma has diminished substantially and has been replaced gradually by neoadjuvant chemoradiation. With advances in surgery and RT, accumulating evidence has recently rekindled interest in the delivery of postoperative RT or chemoradiotherapy in patients with stage T3/T4 or N1 (lymph node positive) carcinomas after radical surgery. However, due to complications with the standard radiation field, a nonconforming modified field has been adopted in most studies. Therefore, we analyze different field applications and provide suggestions on the optimization of the radiation field based on the major sites of relapse and the surgical non-clearance area. For upper and middle thoracic esophageal carcinomas, the bilateral supraclavicular and superior mediastinal areas remain common sites of recurrence and should be encompassed within the clinical target volume. In contrast, a consensus has yet to be reached regarding lower thoracic esophageal carcinomas; the "standard" clinical target volume is still recommended. Further studies of larger sample sizes should focus on different recurrence patterns, categorized by tumor locations, refined classifications, and differing molecular biology, to provide more information on the delineation of target volumes. PMID- 27471394 TI - Decreased expression of SLC 39A14 is associated with tumor aggressiveness and biochemical recurrence of human prostate cancer. AB - OBJECTIVE: Solute carrier family 39, member 14 (SLC39A14), has been identified as a potential biomarker for various cancers. However, its roles in prostate cancer (PCa) are still unclear. The aim of this study was to investigate the clinical significance of SLC39A14 in patients with PCa and its functions in malignant phenotypes of PCa cells. PATIENTS AND METHODS: Subcellular localization and expression pattern of SLC39A14 protein were examined by immunohistochemistry. Then, the associations of SLC39A14 expression with various clinicopathological features and clinical outcome of patients with PCa were statistically evaluated. Subsequently, the effects of SLC39A14 overexpression and knockdown on PCa cell proliferation and motility were, respectively, examined by Cell Counting Kit-8, transwell, and wound-healing assays. RESULTS: The immunoreactive scores of SLC39A14 protein in human PCa tissues were significantly lower than those in normal prostate tissues. Based on the Taylor dataset, SLC39A14 downregulation occurred more frequently in patients with PCa with a higher Gleason score (P<0.001), advanced clinical stage (P=0.008), presence of metastasis (P=0.009), and prostate-specific antigen failure (P=0.006). More interestingly, the survival analysis identified SLC39A14 as an independent factor for predicting the biochemical recurrence-free survival of patients with PCa (P=0.017). Functionally, the enforced expression of SLC39A14 could suppress cell proliferation, invasion, and migration of PCa cell lines in vitro, which could be reversed by the knockdown of SLC39A14. CONCLUSION: Decreased expression of SLC39A14 may lead to malignant phenotypes of PCa cells and aggressive tumor progression in patients with PCa. Importantly, SLC39A14 may function as a tumor suppressor and a biomarker for screening patients with biochemical recurrence following radical prostatectomy. PMID- 27471395 TI - Survival prognostic factors for patients with synchronous brain oligometastatic non-small-cell lung carcinoma receiving local therapy. AB - INTRODUCTION: Clinical evidence for patients with synchronous brain oligometastatic non-small-cell lung carcinoma is limited. We aimed to summarize the clinical data of these patients to explore the survival prognostic factors for this population. METHODS: From September 1995 to July 2011, patients with 1-3 synchronous brain oligometastases, who were treated with stereotactic radiosurgery (SRS) or surgical resection as the primary treatment, were identified at Shanghai Chest Hospital. RESULTS: A total of 76 patients (22 patients underwent brain surgery as primary treatment and 54 patients received SRS) were available for survival analysis. The overall survival (OS) for patients treated with SRS and brain surgery as the primary treatment were 12.6 months (95% confidence interval [CI] 10.3-14.9) and 16.4 months (95% CI 8.8-24.1), respectively (adjusted hazard ratio =0.59, 95% CI 0.33-1.07, P=0.08). Among 76 patients treated with SRS or brain surgery, 21 patients who underwent primary tumor resection did not experience a significantly improved OS (16.4 months, 95% CI 9.6-23.2), compared with those who did not undergo resection (11.9 months, 95% CI 9.7-14.0; adjusted hazard ratio =0.81, 95% CI 0.46-1.44, P=0.46). Factors associated with survival benefits included stage I-II of primary lung tumor and solitary brain metastasis. CONCLUSION: There was no significant difference in OS for patients with synchronous brain oligometastasis receiving SRS or surgical resection. Among this population, the number of brain metastases and stage of primary lung disease were the factors associated with a survival benefit. PMID- 27471396 TI - Lobaplatin for the treatment of SK-MES-1 lung squamous cell line in vitro and in vivo. AB - Lung squamous cell carcinoma is the second-largest histological subtype of lung cancer, which is the leading cause of cancer-related death worldwide. Lobaplatin, one of the third-generation platinum compounds, has shown encouraging anticancer activity in a variety of tumors. The aim of this study was to determine the therapeutic efficacy of lobaplatin on p53-mutant lung squamous cancer cells SK MES-1. In order to evaluate the antitumor effect of lobaplatin, several in vitro and in vivo analyses were carried out, including Cell Counting Kit-8 (CCK-8), fluorescence-activated cell sorter, Western blot, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Findings showed that lobaplatin could inhibit cell proliferation and induce apoptosis of SK-MES-1 cells in vitro through both intrinsic and extrinsic apoptotic pathways in a time- and dose-dependent manner. In addition, lobaplatin could arrest cell cycle at S phase in SK-MES-1. Lobaplatin has obvious antitumor efficacy in human SK-MES-1 xenograft models; therefore, it seems to be a promising candidate in lung squamous cancer therapy. PMID- 27471397 TI - Interleukin-32alpha inactivates JAK2/STAT3 signaling and reverses interleukin-6 induced epithelial-mesenchymal transition, invasion, and metastasis in pancreatic cancer cells. AB - Interleukin (IL)-32 is a newly discovered cytokine that has multifaceted roles in inflammatory bowel disease, cancer, and autoimmune diseases and participates in cell apoptosis, cancer cell growth inhibition, accentuation of inflammation, and angiogenesis. Here, we investigated the potential effects of IL-32alpha on epithelial-mesenchymal transition, metastasis, and invasion, and the JAK2/STAT3 signaling pathway in pancreatic cancer cells. The human pancreatic cancer cell lines PANC-1 and SW1990 were used. Epithelial-mesenchymal transition-related markers, including E-cadherin, N-cadherin, Vimentin, Snail, and Zeb1, as well as extracellular matrix metalloproteinases (MMPs), including MMP2, MMP7, and MMP9, were detected by immunofluorescence, Western blotting, and real-time polymerase chain reaction. The activation of JAK2/STAT3 signaling proteins was detected by Western blotting. Wound healing assays, real-time polymerase chain reaction, and Western blotting were performed to assess cell migration and invasion. The effects of IL-32alpha on the IL-6-induced activation of JAK2/STAT3 were also evaluated. In vitro, we found that IL-32alpha inhibits the expressions of the related markers N-cadherin, Vimentin, Snail, and Zeb1, as well as JAK2/STAT3 proteins, in a dose-dependent manner in pancreatic cancer cell lines. Furthermore, E-cadherin expression was increased significantly after IL-32alpha treatment. IL-32alpha downregulated the expression of MMPs, including MMP2, MMP7, and MMP9, and decreased wound healing in pancreatic cancer cells. These consistent changes were also found in IL-6-induced pancreatic cancer cells following IL-32alpha treatment. This study showed that reversion of epithelial mesenchymal transition, inhibition of invasiveness and metastasis, and activation of the JAK2/STAT3 signaling pathway could be achieved through the application of exogenous IL-32alpha. PMID- 27471398 TI - Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus. AB - OBJECTIVE: To compare the treatment outcomes of sorafenib plus transarterial chemoembolization (TACE) vs TACE alone in patients with hepatocellular carcinoma (HCC) and hepatic vein tumor thrombus (HVTT). METHODS: Twenty patients who were initially diagnosed with HCC and HVTT and received TACE combined with sorafenib during February 2009 to October 2013 were included in the study. To minimize selection bias, these patients were compared with 60 case-matched controls selected from a pool of 81 patients (in a 1:3 ratio) who received TACE alone during the same period. The primary end point was overall survival (OS). The secondary end points were time to progression, disease control rate, and adverse events. RESULTS: After a median follow-up period of 12.5 months (range, 1.03 44.23 months), the OS of the combined group was found to be significantly higher compared with the monotherapy group (14.9 vs 6.1 months, P=0.010). The time to progression was found to be significantly longer in the combined group (4.9 vs 2.4 months, P=0.016). Univariate and multivariate analyses revealed that the treatment allocation was an independent predictor of OS. CONCLUSION: Sorafenib plus TACE was well tolerated and was more effective in treating patients with advanced HCC and HVTT. Future trials with prospective larger samples are required to validate these results. PMID- 27471399 TI - Long noncoding RNA AFAP1-AS1, a potential novel biomarker to predict the clinical outcome of cancer patients: a meta-analysis. AB - A number of studies have demonstrated that the expression level of actin filament associated protein 1 antisense RNA 1 (AFAP1-AS1) was upregulated in various cancers. High expression of AFAP1-AS1 is associated with an increased risk of metastasis and a poor prognosis in cancer patients. The electronic search was conducted in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang database. We collected relevant articles to explore the association between the expression levels of AFAP1-AS1 and lymph node metastasis, distant metastasis, overall survival, relapse-free survival, and progression-free survival. A total of 1,017 patients from eight studies were finally included. The results showed that cancer patients with high AFAP1-AS1 expression suffered an increased risk of developing lymph node metastasis (odds ratio =3.19, 95% confidence interval [CI]: 2.11-4.83, P<0.00001) and distant metastasis (odds ratio =3.05, 95% CI: 1.84-5.04, P<0.0001). Moreover, we found that patients with high AFAP1-AS1 expression also had a poorer overall survival (hazard ratio [HR]: 1.98, 95% CI: 1.57-2.38, P=0.000), a worse progression-free survival (HR: 1.73, 95% CI: 1.11-2.35, P=0.000), and a shorter recurrence-free survival (HR: 1.96, 95% CI: 1.02-2.90, P=0.000) than those with low AFAP1-AS1 expression. High expression of AFAP1-AS1 was associated with poor clinical outcome. AFAP1-AS1 might serve as a potential novel biomarker for indicating the clinical outcomes in human cancers. PMID- 27471400 TI - Combined heavy smoking and drinking predicts overall but not disease-free survival after curative resection of locoregional esophageal squamous cell carcinoma. AB - INTRODUCTION: The prognostic impact of smoking and drinking on esophageal squamous cell carcinoma (ESCC) was scarcely discussed. We investigated the prognostic value of smoking and drinking and their relationships with clinicopathological characteristics in a large cohort of patients with locoregional ESCC. PATIENTS AND METHODS: We retrospectively analyzed 488 patients who underwent curative treatment at a single institution between January 2007 and December 2008. A chi-square test was used to evaluate the relationships between smoking and drinking and clinicopathological variables, the Kaplan-Meier method was used for 5-year overall survival (OS) and disease-free survival, and Cox proportional hazards models were applied for univariate and multivariate analyses of variables with respect to OS and disease-free survival. RESULTS: Heavy smokers were more likely to have advanced Tumor-Node-Metastases (TNM) stage and higher neutrophil/lymphocyte ratio at diagnosis (P<0.05). Drinkers were more likely to have advanced TNM stage, to present with a larger tumor, and to undergo multidisciplinary treatment (P<0.05). For patients who used neither heavy tobacco nor alcohol, used either tobacco or alcohol, and used both, the 5-year OS rates and OS times were 57.4%, 46.4%, and 39.1% (P<0.05) and not reached, 55.2 months, and 41.2 months (P<0.05), respectively. On multivariate analysis, patients who both heavily smoked and drank had 1.392 times the risk of dying during follow-up compared with neither-users (95% CI =1.020-1.901, P=0.037). CONCLUSION: We identified that combined heavy smoking and drinking might predict poor prognosis in ESCC patients. PMID- 27471401 TI - Erratum: Prolonged length of stay associated with air leak following pulmonary resection has a negative impact on hospital margin [Erratum]. AB - [This corrects the article on p. 187 in vol. 8, PMID: 27274293.]. PMID- 27471402 TI - Proton pump inhibitors for the treatment of patients with erosive esophagitis and gastroesophageal reflux disease: current evidence and safety of dexlansoprazole. AB - Gastroesophageal reflux disease is the most common upper gastroenterology disorder in the US. It is associated with a variety of complications and significantly impacts quality of life. Proton pump inhibitors are the most effective treatment. Dexlansoprazole modified release (MR) is a proton pump inhibitor that employs a novel release formulation that prolongs its absorption and allows for more flexibility in dosing. Dexlansoprazole MR can be dosed without regard to food intake or time of day, and once-daily dosing may replace twice-daily dosing of other agents. Dexlansoprazole MR is effective for healing and maintenance of erosive esophagitis, and for the treatment of nonerosive disease, including nocturnal gastroesophageal reflux disease. Dexlansoprazole MR is safe and well tolerated, and can improve quality of life. PMID- 27471403 TI - Genetic basis of Cowden syndrome and its implications for clinical practice and risk management. AB - Cowden syndrome (CS) is an often difficult to recognize hereditary cancer predisposition syndrome caused by mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In addition to conferring increased cancer risks, CS also predisposes individuals to developing hamartomatous growths in many areas of the body. Due to the rarity of CS, estimates vary on the penetrance of certain phenotypic features, such as macrocephaly and skin findings (trichilemmomas, mucocutaneous papules), as well as the conferred lifetime cancer risks. To address this variability, separate clinical diagnostic criteria and PTEN testing guidelines have been created to assist clinicians in the diagnosis of CS. As knowledge of CS increases, making larger studies of affected patients possible, these criteria continue to be refined. Similarly, the management guidelines for cancer screening and risk reduction in patients with CS continue to be updated. This review will summarize the current literature on CS to assist clinicians in staying abreast of recent advances in CS knowledge, diagnostic approaches, and management. PMID- 27471404 TI - Diagnostic accuracy of urinary neutrophil gelatinase-associated lipocalin in patients with septic acute kidney injury. AB - BACKGROUND: Sepsis is the most common cause of acute kidney injury (AKI). Very few studies have investigated the predictive properties of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a marker of AKI in septic patients. The aim of this study is to examine uNGAL in septic patients with and without AKI and to evaluate its predictive value. METHODS: We prospectively studied 155 patients with sepsis over a period of 1 year. Urine was analyzed for neutrophil gelatinase-associated lipocalin at 12, 24, and 48 hours after admission. Patients with <24-hour stay and those with chronic kidney disease were excluded. AKI was classified according to the Acute Kidney Injury Network guidelines. RESULTS: The differences in mean change of uNGAL at 12, 24, and 48 hours were 80.00+/-7.00 ng/mL and 128.13+/-22.46 ng/mL, respectively in septic AKI, and 02.07+/-0.80 ng/mL and 26.13+/-15.12 ng/mL, respectively in septic non-AKI. At baseline or 12 hours, the cutoff value of 34.32 ng/mL had a sensitivity and specificity of 86.36 and 80.60, respectively and an area under curve of 0.81 (95% CI: 0.73-0.89) for predicting AKI. At the cutoff value 199.99 ng/mL sensitivity and specificity of 90.0 and 64.66, respectively and an area under curve of 0.82 (95% CI, 0.75-0.88) for predicting AKI. CONCLUSION: The baseline or 12-hour uNGAL is highly sensitive but a less specific predictor of AKI in septic patients. PMID- 27471405 TI - Effects of socioeconomic status on physical and mental health of hemodialysis patients in Japan: differences by age, period, and cohort. AB - STUDY PURPOSE: Whether or not socioeconomic status (SES)-related differences in the health of hemodialysis patients differ by age, period, and birth cohort remains unclear. We examined whether SES-related gaps in physical and mental health change with age, period, and birth cohort for hemodialysis patients. METHODS: Data were obtained from repeated cross-sectional surveys conducted in 1996, 2001, 2006, and 2011, with members of a national patients' association as participants. We used raking adjustment to create a database which had similar characteristics to the total sample of dialysis patients in Japan. SES was assessed using family size-adjusted income levels. We divided patients into three groups based on their income levels: below the first quartile, over the second quartile and under the third quartile, and over the fourth quartile. We used the number of dialysis complications as a physical health indicator and depressive symptoms as a mental health indicator. We used a cross-classified random-effects model that estimated fixed effects of age categories and period as level-1 factors, and random effects of birth cohort as level-2 factors. RESULTS: Relative risk of dialysis complications in respondents below the first quartile compared with ones over the fourth quartile was reduced in age categories >60 years. Mean differences in depressive symptoms between respondents below the first quartile and ones over the fourth quartile peaked in the 50- to 59-year-old age group, and were reduced in age groups >60 years. In addition, mean differences varied across periods, widening from 1996 to 2006. There were no significant birth cohort effects on income differences for dialysis complications or depressive symptoms. CONCLUSION: The number of dialysis complications and depressive symptoms in dialysis patients were affected by income differences, and the degree of these differences changed with age category and period. PMID- 27471406 TI - Cancer pharmacogenomics, challenges in implementation, and patient-focused perspectives. AB - Cancer pharmacogenomics is an evolving landscape and has the potential to significantly impact cancer care and precision medicine. Harnessing and understanding the genetic code of both the patient (germline) and the tumor (somatic) provides the opportunity for personalized dose and therapy selection for cancer patients. While germline DNA is useful in understanding the pharmacokinetic and pharmacodynamic disposition of a drug, somatic DNA is particularly useful in identifying drug targets and predicting drug response. Molecular profiling of somatic DNA has resulted in the current breadth of targeted therapies available, expanding the armamentarium to battle cancer. This review provides an update on cancer pharmacogenomics and genomics-based medicine, challenges in applying pharmacogenomics to the clinical setting, and patient perspectives on the use of pharmacogenomics to personalize cancer therapy. PMID- 27471407 TI - A glimmer of hope in American pain medicine? PMID- 27471409 TI - Extent of dispensing prescription-only medications without a prescription in community drug retail outlets in Addis Ababa, Ethiopia: a simulated-patient study. AB - PURPOSE: This study was aimed at assessing the extent of dispensing prescription only medications without a prescription in community drug retail outlets (CDROs) of Addis Ababa, Ethiopia. METHODS: A descriptive cross-sectional observational study design was used to sample 31 pharmacies, 25 drug stores, and two rural drug vendors from August 11, 2015, to October 21, 2015, through a simple random sampling method. A simulated-patient method of visit was implemented to collect data. Requests of six tracer prescription-only medicines (amoxicillin + clavulanic acid capsule, amitriptyline, captopril, glibenclamide [also known as glyburide], omeprazole capsule, and sildenafil citrate) and upper respiratory tract infection were selected as the simulated clinical scenario. RESULTS: Amoxicillin-clavulanic acid capsule was dispensed when requested in 87.93% of the dispensaries. All of the CDROs dispensed omeprazole upon request. Sildenafil citrate (Viagra) was in stock in 96.55% of the CDROs, all of which issued the requested number of tablets without asking why or for whom the drug was needed. Amitriptyline, captopril, and glibenclamide (glyburide) were dispensed in 84.48%, 89.65%, and 87.93% of CDROs upon the provision of an empty container. Antibiotics were obtained from 75.86% of CDROs for presentation of upper respiratory tract infection symptoms. Among the dispensed antibiotics, the most common was amoxicillin (93.18%), followed by amoxicillin-clavulanic acid capsule (72.72%), and azithromycin (50%). Only 4.5% of the dispensaries asked about drug allergies, and 15.9% of the CDROs informed the simulated patient about the possible side effects of the drugs. CONCLUSION: This study revealed a very high rate of dispensing of prescription-only medicines without a prescription. Antimicrobials and drugs for chronic diseases were obtained with ease from almost all of the randomly sampled CDROs. Putting good dispensing practice into effect and adhering to the existing national laws and regulations regarding the same are necessary. It is also necessary to adopt a strong and explicit line of action, especially toward the irrational use of antibiotics. PMID- 27471408 TI - Alveolar bone loss in osteoporosis: a loaded and cellular affair? AB - Maxillary and mandibular bone mirror skeletal bone conditions. Bone remodeling happens at endosteal surfaces where the osteoclasts and osteoblasts are situated. More surfaces means more cells and remodeling. The bone turnover rate in the mandibular alveolar process is probably the fastest in the body; thus, the first signs of osteoporosis may be revealed here. Hormones, osteoporosis, and aging influence the alveolar process and the skeletal bones similarly, but differences in loading between loaded, half-loaded, and unloaded bones are important to consider. Bone mass is redistributed from one location to another where strength is needed. A sparse trabeculation in the mandibular premolar region (large intertrabecular spaces and thin trabeculae) is a reliable sign of osteopenia and a high skeletal fracture risk. Having dense trabeculation (small intertrabecular spaces and well-mineralized trabeculae) is generally advantageous to the individual because of the low fracture risk, but may imply some problems for the clinician. PMID- 27471411 TI - Population pharmacokinetic modeling of glibenclamide in poorly controlled South African type 2 diabetic subjects. AB - AIM: The aim of this study was to describe the pharmacokinetics (PK) of glibenclamide in poorly controlled South African type 2 diabetic subjects using noncompartmental and model-based methods. METHODS: A total of 24 subjects with type 2 diabetes were administered increasing doses (0 mg/d, 2.5 mg/d, 5 mg/d, 10 mg/d, and 20 mg/d) of glibenclamide daily at 2-week intervals. Plasma glibenclamide, glucose, and insulin determinations were performed. Blood sampling times were 0 minute, 30 minutes, 60 minutes, 90 minutes, and 120 minutes (post breakfast sampling) and 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, and 420 minutes (post lunch sampling) on days 14, 28, 42, 56, and 70 for doses of 0 mg, 2.5 mg, 5.0 mg, 10 mg, and 20 mg, respectively. Blood sampling was performed after the steady state was reached. A total of 24 individuals in the data set contributed to a total of 841 observation records. The PK was analyzed using noncompartmental analysis methods, which were implemented in WinNonLin((r)), and population PK analysis using NONMEM((r)). Glibenclamide concentration data were log transformed prior to fitting. RESULTS: A two compartmental disposition model was selected after evaluating one-, two-, and three-compartmental models to describe the time course of glibenclamide plasma concentration data. The one-compartment model adequately described the data; however, the two-compartment model provided a better fit. The three-compartment model failed to achieve successful convergence. A more complex model, to account for enterohepatic recirculation that was observed in the data, was unsuccessful. CONCLUSION: In South African diabetic subjects, glibenclamide demonstrates linear PK and was best described by a two-compartmental model. Except for the absorption rate constant, the other PK parameters reported in this study are comparable to those reported in the scientific literature. The study is limited by the small study sample size and inclusion of poorly controlled type 2 diabetic subjects. PMID- 27471410 TI - Managing pregnancy in chronic kidney disease: improving outcomes for mother and baby. AB - Parenthood is a central focus for women with chronic kidney disease, but raises important fears and uncertainties about risks to their own and their baby's health. Pregnancy in women with background kidney disease, women receiving dialysis, or those with a functioning kidney transplant poses a challenging clinical scenario, associated with high maternal-fetal morbidity and potential impact on maternal renal health. Improvements in care over recent decades have led to a paradigm shift with cautious optimism and growing interest regarding pregnancies in women with chronic kidney disease. In this review, we discuss obstetric and renal outcomes, and practical aspects of management of pregnancy in this complex cohort. PMID- 27471412 TI - A method for establishing class III medical device equivalence: sodium hyaluronate (GenVisc 850) for the treatment of knee osteoarthritis. AB - Although the concept of equivalence for drugs (generics) and biologics (biosimilars) has been readily adopted, the concept of equivalence or indistinguishable characteristics for class III medical devices has yet to be specifically addressed regarding a defined regulatory approval process in the US. In September 2015, GenVisc 850(r) (sodium hyaluronate), a hyaluronic acid approved for the treatment of knee osteoarthritis, was approved by the US Food and Drug Administration (FDA) based upon indistinguishable characteristics in comparison to an approved branded hyaluronic acid (Supartz(r)/Supartz FXTM). The purpose of this paper is to review the methodology and report the main outcomes used to demonstrate clinical comparability of GenVisc 850 with Supartz/Supartz FX. The FDA approval was collectively attained using prospectively defined methods for preclinical, physical, and chemical testing, as well as noninferiority in clinical performance comparisons. Evidence from five randomized controlled studies of Supartz/Supartz FX vs saline control injections (used for Supartz approval), two randomized controlled trials of GenVisc 850 vs saline control injections, and one randomized controlled study of GenVisc 850 vs Supartz/Supartz FX provided evidence of safety for GenVisc 850. Efficacy was further assessed based on assessment of the same Supartz studies and three prospectively identified GenVisc 850 studies. A Bayesian network meta-analysis was used to demonstrate that the clinical efficacy of GenVisc 850 was noninferior to Supartz/Supartz FX and superior to saline control. Overall, safety of GenVisc 850 was similar to that of Supartz/Supartz FX and saline control injections, while efficacy of GenVisc 850 was noninferior to that of Supartz/Supartz FX and superior to saline control injections. PMID- 27471413 TI - Durable intermediate-to long-term outcomes after minimally invasive transiliac sacroiliac joint fusion using triangular titanium implants. AB - BACKGROUND: Sacroiliac joint (SIJ) fusion (SIJF), first performed 95 years ago, has become an increasingly accepted surgical option for chronic SIJ dysfunction. Few studies have reported intermediate- or long-term outcomes after SIJF. OBJECTIVE: The objective of this study is to determine patient-based outcomes after SIJF for chronic SIJ dysfunction due to degenerative sacroiliitis or SIJ disruption at >=3 years of follow-up. METHODS: Consecutive patients who underwent SIJF prior to December 2012 were contacted over phone or through email. Participants completed questionnaires in clinic, over phone or by email, regarding SIJ pain, activities related to SIJ dysfunction, and the Oswestry Disability Index. Charts were reviewed to extract baseline parameters and the clinical course of follow-up. RESULTS: One hundred seven patients were eligible and participated in this study. Mean (standard deviation) preoperative SIJ pain score was 7.5 (1.7). At mean follow-up of 3.7 years, the mean SIJ pain score was 2.6 (representing a 4.8-point improvement from baseline, P<0.0001) and the mean Oswestry Disability Index was 28.2. The ability to perform activities commonly impaired by SIJ dysfunction showed positive improvements in most patients. SIJ revision surgery was uncommon (five patients, 4.7%). Fourteen patients (13.1%) underwent contralateral SIJF during follow-up, 25.2% of patients had additional non-SIJ-related lumbar spine or hip surgeries during follow-up. CONCLUSION: In intermediate- to long-term follow-up, minimally invasive transiliac SIJF was associated with improved pain, low disability scores, and improved ability to perform activities of daily living. PMID- 27471414 TI - Bilateral posterior cervical cages provide biomechanical stability: assessment of stand-alone and supplemental fixation for anterior cervical discectomy and fusion. AB - INTRODUCTION: Supplemental posterior instrumentation has been widely used to enhance stability and improve fusion rates in higher risk patients undergoing anterior cervical discectomy and fusion (ACDF). These typically involve posterior lateral mass or pedicle screw fixation with significant inherent risks and morbidities. More recently, cervical cages placed bilaterally between the facet joints (posterior cervical cages) have been used as a less disruptive alternative for posterior fixation. The purpose of this study was to compare the stability achieved by both posterior cages and ACDF at a single motion segment and determine the stability achieved with posterior cervical cages used as an adjunct to single- and multilevel ACDF. METHODS: Seven cadaveric cervical spine (C2-T1) specimens were tested in the following sequence: intact, C5-C6 bilateral posterior cages, C6-C7 plated ACDF with and without posterior cages, and C3-C5 plated ACDF with and without posterior cages. Range of motion in flexion extension, lateral bending, and axial rotation was measured for each condition under moment loading up to +/-1.5 Nm. RESULTS: All fusion constructs significantly reduced the range of motion compared to intact in flexion extension, lateral bending, and axial rotation (P<0.05). Similar stability was achieved with bilateral posterior cages and plated ACDF at a single level. Posterior cages, when placed as an adjunct to ACDF, further reduced range of motion in both single- and multilevel constructs (P<0.05). CONCLUSION: The biomechanical effectiveness of bilateral posterior cages in limiting cervical segmental motion is comparable to single-level plated ACDF. Furthermore, supplementation of single- and multilevel ACDF with posterior cervical cages provided a significant increase in stability and therefore may be a potential, minimally disruptive option for supplemental fixation for improving ACDF fusion rates. PMID- 27471416 TI - Occupational hazards among the abattoir workers associated with noncompliance to the meat processing and waste disposal laws in Malaysia. AB - PURPOSE: This study aims to investigate the occupational hazards among the abattoir workers associated with noncompliance to the meat processing and waste disposal laws in Terengganu State, Malaysia. Occupational hazards are the major source of morbidity and mortality among the animal workers due to exposure to many hazardous situations in their daily practices. Occupational infections mostly contracted by abattoir workers could be caused by iatrogenic or transmissible agents, including viruses, bacteria, fungi, and parasites and the toxins produced by these organisms. MATERIALS AND METHODS: The methodology was based on a cross-sectional survey using cluster sampling technique in the four districts of Terengganu State, Malaysia. One hundred and twenty-one abattoir workers from five abattoirs were assessed using a validated structured questionnaire and an observation checklist. RESULTS: The mean and standard deviation of occupational hazards scores of the workers were 2.32 (2.721). Physical, chemical, biological, psychosocial, musculoskeletal, and ergonomics hazards were the major findings of this study. However, the highest prevalence of occupational hazards identified among the workers was injury by sharp equipment such as a knife (20.0%), noise exposure (17.0%), and due to offensive odor within the abattoir premises (12.0%). CONCLUSION: The major occupational hazards encountered by the workers in the study area were physical, chemical, biological, psychosocial, musculoskeletal, and ergonomics hazards. To ensure proper control of occupational health hazards among the abattoir workers, standard design and good environmental hygiene must be taken into consideration all the time. Exposure control plan, which includes risk identification, risk characterization, assessment of workers at risk, risk control, workers' education/training, and implementation of safe work procedures, should be implemented by the government and all the existing laws governing the abattoir operation in the country should be enforced. PMID- 27471417 TI - The Lebanese-Syrian crisis: impact of influx of Syrian refugees to an already weak state. AB - BACKGROUND: Lebanon, a small Middle Eastern country facing constant political and national unity challenges with a population of approximately 300,000 Palestinian and Iraqi refugees, has welcomed more than 1.2 million Office of the United Nations Commissioner for Refugees (UNHCR)-registered Syrian refugees since 2012. The Government of Lebanon considers individuals who crossed Lebanese-Syrian borders since 2011 as "displaced", emphasizing its long-standing position that Lebanon is not a state for refugees, refusing to establish camps, and adopting a policy paper to reduce their numbers in October 2014. Humanitarian response to the Syrian influx to Lebanon has been constantly assembling with the UNHCR as the main acting body and the Lebanon Crisis Response Plan as the latest plan for 2016. METHODS: Review of secondary data from gray literature and reports focusing on the influx of Syrian refugees to Lebanon by visiting databases covering humanitarian response in complex emergencies. Limitations include obtaining majority of the data from gray literature and changing statistics due to the instability of the situation. RESULTS: The influx of Syrian refugees to Lebanon, an already weak and vulnerable state, has negatively impacted life in Lebanon on different levels including increasing demographics, regressing economy, exhausting social services, complicating politics, and decreasing security as well as worsened the life of displaced Syrians themselves. CONCLUSION: Displaced Syrians and Lebanese people share aggravating hardships of a mutual and precarious crisis resulting from the Syrian influx to Lebanon. Although a lot of response has been initiated, both populations still lack much of their basic needs due to lack of funding and nonsustainable program initiatives. The two major recommendations for future interventions are to ensure continuous and effective monitoring and sustainability in order to alleviate current and future suffering in Lebanon. PMID- 27471415 TI - Asthma-related emergency department use: current perspectives. AB - Asthma is one of the most common chronic pediatric diseases. Patients with asthma often present to the emergency department for treatment for acute exacerbations. These patients may not have a primary care physician or primary care home, and thus are seeking care in the emergency department. Asthma care in the emergency department is multifaceted to treat asthma patients appropriately and provide quality care. National and international guidelines exist to help drive clinical care. Electronic and paper-based tools exist for both physicians and patients to help improve emergency, home, and preventive care. Treatment of patients with asthma should include the acute exacerbation, long-term management of controller medications, and controlling triggers in the home environment. We will address the current state of asthma research in emergency medicine in the US, and discuss some of the resources being used to help provide a medical home and improve care for patients who suffer from acute asthma exacerbations. PMID- 27471419 TI - Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant. AB - Insomnia, a highly prevalent disorder, can be detrimental to patients' overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia. PMID- 27471418 TI - Unihemispheric sleep and asymmetrical sleep: behavioral, neurophysiological, and functional perspectives. AB - Sleep is a behavior characterized by a typical body posture, both eyes' closure, raised sensory threshold, distinctive electrographic signs, and a marked decrease of motor activity. In addition, sleep is a periodically necessary behavior and therefore, in the majority of animals, it involves the whole brain and body. However, certain marine mammals and species of birds show a different sleep behavior, in which one cerebral hemisphere sleeps while the other is awake. In dolphins, eared seals, and manatees, unihemispheric sleep allows them to have the benefits of sleep, breathing, thermoregulation, and vigilance. In birds, antipredation vigilance is the main function of unihemispheric sleep, but in domestic chicks, it is also associated with brain lateralization or dominance in the control of behavior. Compared to bihemispheric sleep, unihemispheric sleep would mean a reduction of the time spent sleeping and of the associated recovery processes. However, the behavior and health of aquatic mammals and birds does not seem at all impaired by the reduction of sleep. The neural mechanisms of unihemispheric sleep are unknown, but assuming that the neural structures involved in sleep in cetaceans, seals, and birds are similar to those of terrestrial mammals, it is suggested that they involve the interaction of structures of the hypothalamus, basal forebrain, and brain stem. The neural mechanisms promoting wakefulness dominate one side of the brain, while those promoting sleep predominates the other side. For cetaceans, unihemispheric sleep is the only way to sleep, while in seals and birds, unihemispheric sleep events are intermingled with bihemispheric and rapid eye movement sleep events. Electroencephalogram hemispheric asymmetries are also reported during bihemispheric sleep, at awakening, and at sleep onset, as well as being associated with a use-dependent process (local sleep). PMID- 27471421 TI - A role for respiratory therapists in shaping Canada's changing health policy landscape. PMID- 27471420 TI - Ultrasound and stethoscope as tools in medical education and practice: considerations for the archives. AB - OBJECTIVES: In recent years, the use and portability of ultrasound has threatened the utility of the stethoscope, with many debating and even advocating its replacement. The authors set out to assess opinions in this regard among faculty within a medical school and specifically within an anatomy department where ultrasound is incorporated into the curriculum from the first term. METHODS: A debate was elicited during a biweekly Anatomy Journal Club session and was centered on three published papers presented. Several questions were raised regarding the possible replacement of stethoscope - the value of early exposure to students as well as how ultrasound and stethoscope should be considered by physicians, students, and teachers. RESULTS: The general consensus was that the stethoscope should not be replaced but should be used in conjunction with emerging portable ultrasound. Caution was given that technology could "overcomplicate" diagnosis and lead to increased tests resulting in increased cost of care. In terms of exposing students to ultrasound, just as the stethoscope requires practice to use effectively, so does the ultrasound and should be introduced as early on as possible. As is the case with the stethoscope, students may not initially appreciate all the finer details on ultrasound; however, continual use would improve skill. CONCLUSION: The stethoscope should always remain part of the physical examination and ultrasound should be used in addition to, not replacement of. As technology advances the need for apprenticeship, training increases and students of the medical profession should be exposed to these technologies as early as possible. Hence, it is not yet time to archive the stethoscope. Perhaps never. PMID- 27471423 TI - Patient and family centred care in respiratory therapy: A fundamental right? PMID- 27471422 TI - Comparison of cardiac rehabilitation outcomes in individuals with respiratory, cardiac or no comorbidities: A retrospective review. AB - OBJECTIVE: To describe the prevalence and impact of respiratory comorbidities on patients undergoing cardiac rehabilitation (CR). METHODS: A retrospective review of a CR database (1999 to 2004) of patients with ischemic heart disease with >=10 pack per year (ppy) smoking history and respiratory comorbidities (RC), non respiratory comorbidities (NRC) and no comorbidities (NC) was performed. Primary outcomes at zero, six and 12 months included peak oxygen uptake (VO2peak), maximum workload, resting heart rate, ventilatory anaerobic threshold and anthropometrics. Analyses were performed on individuals who completed the program, adjusting for age, sex and baseline VO2peak. RESULTS: Of 5922 patients, 1247 had >=10 ppy smoking history: 77 (6.2%) had RC; 957 (76.7%) had NRC; and 213 (17.1%) had NC. The program completion rate for each group was similar for the RC (46.8%), NRC (55.8%) and NC groups (57.3%) (P=0.26). The RC group had the lowest baseline fitness levels (P<0.002). For VO2peak, there were significant differences among groups (P=0.02) and improvements over program duration (P<0.0001). There were no significant differences in other outcomes. CONCLUSIONS: There was a low prevalence of patients with comorbid chronic obstructive pulmonary disease in CR when based on physician referral documentation. This is likely underestimated and/or reflects a referral bias. Diagnostic testing at CR entry would provide a more accurate measure of the prevalence and severity of disease. CR participation resulted in significant and similar improvements in most key CR outcomes in all groups including similar completion rate. A CR model was effective for patients with coexisting RCs. Strategies to improve access and diagnosis should be explored. PMID- 27471424 TI - Home care in respiratory therapy. PMID- 27471425 TI - A positive methacholine challenge based on specific airway conductance: A case report. AB - A 30-year-old Caucasian man presented to the pulmonary function laboratory for a methacholine challenge test. Following inhalation of the final dose of methacholine, the forced expiratory volume in 1 s (FEV1) was 8% below baseline. However, the patient complained of chest tightness and dyspnea, similar to the symptoms he experienced after running. Repeat specific airway conductance was found to be 73% below baseline, indicating marked airway hyper-responsiveness. Because the reduction in specific airway conductance was accompanied by familiar symptoms, the post-test probability of asthma increases, even in the absence of a 20% reduction in FEV1. PMID- 27471426 TI - Can Control Banding be Useful for the Safe Handling of Nanomaterials? A Systematic Review. AB - OBJECTIVES: Control banding (CB) is a risk management strategy that has been used to identify and recommend exposure control measures to potentially hazardous substances for which toxicological information is limited. The application of CB and level of expertise required for implementation and management can differ depending on knowledge of the hazard potential, the likelihood of exposure, and the ability to verify the effectiveness of exposure control measures. A number of different strategies have been proposed for using CB in workplaces where exposure to engineered nanomaterials (ENMs) can occur. However, it is unclear if the use of CB can effectively reduce worker exposure to nanomaterials. A systematic review of studies was conducted to answer the question "can control banding be useful to ensure adequate controls for the safe handling of nanomaterials." METHODS: A variety of databases were searched to identify relevant studies pertaining to CB. Database search terms included 'control', 'hazard', 'exposure' and 'risk' banding as well as the use of these terms in the context of nanotechnology or nanomaterials. Other potentially relevant studies were identified during the review of articles obtained in the systematic review process. Identification of studies and the extraction of data were independently conducted by the reviewers. Quality of the studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS). The quality of the evidence was evaluated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: A total of 235 records were identified in the database search in which 70 records were determined to be eligible for full-text review. Only two studies were identified that met the inclusion criteria. These studies evaluated the application of the CB Nanotool in workplaces where ENMs were being handled. A total of 32 different nanomaterial handling activities were evaluated in these studies by comparing the recommended exposure controls using CB to existing exposure controls previously recommended by an industrial hygienist. It was determined that the selection of exposure controls using CB were consistent with those recommended by an industrial hygienist for 19 out of 32 (59.4%) job activities. A higher level of exposure control was recommended for nine out of 32 (28.1%) job activities using CB while four out of 32 (12.5%) job activities had in place exposure controls that were more stringent than those recommended using CB. After evaluation using GRADE, evidence indicated that the use of CB Nanotool can recommend exposure controls for many ENM job activities that would be consistent with those recommended by an experienced industrial hygienist. CONCLUSION: The use of CB for reducing exposures to ENMs has the potential to be an effective risk management strategy when information is limited on the health risk to the nanomaterial and/or there is an absence of an occupational exposure limit (OEL). However, there remains a lack of evidence to conclude that the use of CB can provide adequate exposure control in all work environments. Additional validation work is needed to provide more data to support the use of CB for the safe handling of ENMs. PMID- 27471427 TI - Present-day oxidative subsidence of organic soils and mitigation in the Sacramento-San Joaquin Delta, California, USA. AB - Subsidence of organic soils in the Sacramento-San Joaquin Delta threatens sustainability of the California (USA) water supply system and agriculture. Land surface elevation data were collected to assess present-day subsidence rates and evaluate rice as a land use for subsidence mitigation. To depict Delta-wide present-day rates of subsidence, the previously developed SUBCALC model was refined and calibrated using recent data for CO2 emissions and land-surface elevation changes measured at extensometers. Land-surface elevation change data were evaluated relative to indirect estimates of subsidence and accretion using carbon and nitrogen flux data for rice cultivation. Extensometer and leveling data demonstrate seasonal variations in land-surface elevations associated with groundwater-level fluctuations and inelastic subsidence rates of 0.5-0.8 cm yr-1. Calibration of the SUBCALC model indicated accuracy of +/-0.10 cm yr-1 where depth to groundwater, soil organic matter content and temperature are known. Regional estimates of subsidence range from <0.3 to >1.8 cm yr-1. The primary uncertainty is the distribution of soil organic matter content which results in spatial averaging in the mapping of subsidence rates. Analysis of leveling and extensometer data in rice fields resulted in an estimated accretion rate of 0.02 0.8 cm yr-1. These values generally agreed with indirect estimates based on carbon fluxes and nitrogen mineralization, thus preliminarily demonstrating that rice will stop or greatly reduce subsidence. Areas below elevations of -2 m are candidate areas for implementation of mitigation measures such as rice because there is active subsidence occurring at rates greater than 0.4 cm yr-1. PMID- 27471428 TI - Vector-like top/bottom-quark partners and Higgs physics at the LHC. AB - Vector-like quarks (VLQ) that are partners of the heavy top and bottom quarks are predicted in many extensions of the standard model (SM). We explore the possibility that these states could explain not only the long-standing anomaly in the forward-backward asymmetry in b-quark production at LEP, [Formula: see text], but also the more recent [Formula: see text]2[Formula: see text] deviation of the cross section for the associated Higgs production with top-quark pairs at the LHC, [Formula: see text]. Introducing three illustrative models for VLQs with different representations under the SM gauge group, we show that the two anomalies can be resolved while satisfying all other theoretical and experimental constraints. In this case, the three different models predict VLQ states in the 1 2 TeV mass range that can be soon probed at the LHC. In a second step, we discuss the sensitivity on the VLQ masses and couplings that could be obtained by means of a percent level accuracy in the measurement of ratios of partial Higgs decay widths, in particular [Formula: see text] and [Formula: see text]. We show that top and bottom VL partners with masses up to [Formula: see text]5 TeV and exotic VLQs with masses in the 10 TeV range can be probed at the high-luminosity LHC. PMID- 27471430 TI - A test of general relativity using the LARES and LAGEOS satellites and a GRACE Earth gravity model: Measurement of Earth's dragging of inertial frames. AB - We present a test of general relativity, the measurement of the Earth's dragging of inertial frames. Our result is obtained using about 3.5 years of laser-ranged observations of the LARES, LAGEOS, and LAGEOS 2 laser-ranged satellites together with the Earth gravity field model GGM05S produced by the space geodesy mission GRACE. We measure [Formula: see text], where [Formula: see text] is the Earth's dragging of inertial frames normalized to its general relativity value, 0.002 is the 1-sigma formal error and 0.05 is our preliminary estimate of systematic error mainly due to the uncertainties in the Earth gravity model GGM05S. Our result is in agreement with the prediction of general relativity. PMID- 27471429 TI - Heavy-flavour and quarkonium production in the LHC era: from proton-proton to heavy-ion collisions. AB - This report reviews the study of open heavy-flavour and quarkonium production in high-energy hadronic collisions, as tools to investigate fundamental aspects of Quantum Chromodynamics, from the proton and nucleus structure at high energy to deconfinement and the properties of the Quark-Gluon Plasma. Emphasis is given to the lessons learnt from LHC Run 1 results, which are reviewed in a global picture with the results from SPS and RHIC at lower energies, as well as to the questions to be addressed in the future. The report covers heavy flavour and quarkonium production in proton-proton, proton-nucleus and nucleus-nucleus collisions. This includes discussion of the effects of hot and cold strongly interacting matter, quarkonium photoproduction in nucleus-nucleus collisions and perspectives on the study of heavy flavour and quarkonium with upgrades of existing experiments and new experiments. The report results from the activity of the SaporeGravis network of the I3 Hadron Physics programme of the European Union 7[Formula: see text] Framework Programme. PMID- 27471435 TI - Endogenous electromagnetic forces emissions during cell respiration as additional factor in cancer origin. AB - BACKGROUND: Seven decades ago, a seminal paper by Dr. Denham Harman in (J Gerontol 11(3):298-300, 1956), introduced a theory stating that there are good reasons for assuming that endogenous irradiation in the living cells could lead to cancer via an obscure mechanism. The main purpose of this manuscript is to shed some light in said mechanism by proposing a five-step eukaryotic cell cancer triggering cycle. In other words, a new factor is introduced, namely the recently found emissions of electromagnetic forces (EMFs) as a possible causing agent in diseases, including cancer. METHODS: Introduced is an eukaryotic cell cancer inducing cycle. It includes five sequential steps of endogenous biological process that are backed by published scientific reports. RESULTS AND DISCUSSION: It is a known fact that in order to achieve homeostasis, toxic reactive oxygen species (ROS) i.e. H2O2 molecules are broken down by the protein enzyme catalase. During this reaction EMFs are generated (Embi in AIS Physics 2(3):226-230, 2016). The EMFs recording breakthrough was possible due to the introduction of a novel table top microscopy technique to detect EMFs by using Prussian Blue Stain and nano-sized iron particles. There are different roots in molecular and clinical biology through which DNA damage could be programmed, EMFs emitted (during cell respiration) are herein proposed as an additional cause. PMID- 27471434 TI - High EZH2 expression is correlated to metastatic disease in pediatric soft tissue sarcomas. AB - BACKGROUND: Enhancer of Zeste Drosophila Homologue 2 (EZH2) is a key regulator of transcription as a member of polycomb repressive complex 2 (PRC2) which exerts repression of downstream genes and is correlated to invasiveness and progression of different tumours. Therefore, we evaluated the expression of PRC2 proteins in pediatric soft tissue sarcoma (rhabdomyosarcoma, RMS and extraosseous Ewing sarcoma, EES) correlating them to the clinical outcome of the patients. METHODS: We analyzed PRC2 protein expression by quantitative real time PCR, western blotting and immunohistochemistry in 17 soft tissue sarcomas (11 RMS and 6 EES) enrolled at Paediatric Oncology Units of the Second University of Naples. Expression analysis was performed for EZH2, SUZ12 and EED. RESULTS: Enhancer of Zeste Drosophila Homologue 2 was expressed with a different degree in 60 % of samples. Interestingly, the magnitude of EZH2 up regulation was significantly higher in patients presenting lymph node and/or distant metastases at the diagnosis. Moreover, patients overexpressing EZH2 had a lower probability of survival compared to patients negative or with low EZH2 expression. CONCLUSIONS: Our study suggests that high EZH2 expression is associated to increased aggressiveness of the disease. Therefore, drugs that control its activity could be potentially used in the epigenetic target treatment of tumors with these alterations. PMID- 27471436 TI - Treatment of lean and diet-induced obesity (DIO) mice with a novel stable obestatin analogue alters plasma metabolite levels as detected by untargeted LC MS metabolomics. AB - INTRODUCTION: Obestatin is a controversial gastrointestinal peptide purported to have metabolic actions. OBJECTIVES: This study investigated whether treatment with a stable obestatin analogue (PEG-OB(Cys10, Cys13)) changed plasma metabolite levels firstly in lean and subsequently in diet-induced obesity (DIO) C57BL6/J mice. METHODS: Untargeted LC-HRMS metabolomics experiments were carried out in ESI + mode with plasma extracts from both groups of animals. Data were normalised, multivariate and univariate statistical analysis performed and metabolites of interest putatively identified. RESULTS: In lean mice, 39 metabolites were significantly changed by obestatin treatment and the majority of these were increased, including various C16 and C18 moieties of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and monoacylglycerol, along with vitamin A, vitamin D3, tyrosine, acetylcarnitine and 2alpha-(hydroxymethyl)-5alpha-androstane-3beta,17beta-diol. Decreased concentrations of glycolithocholic acid, 3-dehydroteasterone and various phospholipids were observed. In DIO mice, 25 metabolites were significantly affected and strikingly, the magnitudes of changes here were generally much greater in DIO mice than in lean mice, and in contrast, the majority of metabolite changes were decreases. Four metabolites affected in both groups included glycolithocholic acid, and three different long-chain (C18) phospholipid molecules (phosphatidylethanolamine, platelet activating factor (PAF), and monoacylglycerol). Metabolites exclusively affected in DIO mice included various phosphatidylcholines, lysophosphatidylcholines and fatty acyls, as well as creatine and oxidised glutathione. CONCLUSION: This investigation demonstrates that obestatin treatment affects phospholipid turnover and influences lipid homeostasis, whilst providing convincing evidence that obestatin may be acting to ameliorate diet-induced impairments in lipid metabolism, and it may influence steroid, bile acid, PAF and glutathione metabolism. PMID- 27471437 TI - Urinary antihypertensive drug metabolite screening using molecular networking coupled to high-resolution mass spectrometry fragmentation. AB - INTRODUCTION: Mass spectrometry is the current technique of choice in studying drug metabolism. High-resolution mass spectrometry in combination with MS/MS gas phase experiments has the potential to contribute to rapid advances in this field. However, the data emerging from such fragmentation spectral files pose challenges to downstream analysis, given their complexity and size. OBJECTIVES: This study aims to detect and visualize antihypertensive drug metabolites in untargeted metabolomics experiments based on the spectral similarity of their fragmentation spectra. Furthermore, spectral clusters of endogenous metabolites were also examined. METHODS: Here we apply a molecular networking approach to seek drugs and their metabolites, in fragmentation spectra from urine derived from a cohort of 26 patients on antihypertensive therapy. The mass spectrometry data was collected on a Thermo Q-Exactive coupled to pHILIC chromatography using data dependent analysis (DDA) MS/MS gas-phase experiments. RESULTS: In total, 165 separate drug metabolites were found and structurally annotated (17 by spectral matching and 122 by classification based on a clustered fragmentation pattern). The clusters could be traced to 13 drugs including the known antihypertensives verapamil, losartan and amlodipine. The molecular networking approach also generated clusters of endogenous metabolites, including carnitine derivatives, and conjugates containing glutamine, glutamate and trigonelline. CONCLUSIONS: The approach offers unprecedented capability in the untargeted identification of drugs and their metabolites at the population level and has great potential to contribute to understanding stratified responses to drugs where differences in drug metabolism may determine treatment outcome. PMID- 27471439 TI - Large-scale Globally Propagating Coronal Waves. AB - Large-scale, globally propagating wave-like disturbances have been observed in the solar chromosphere and by inference in the corona since the 1960s. However, detailed analysis of these phenomena has only been conducted since the late 1990s. This was prompted by the availability of high-cadence coronal imaging data from numerous spaced-based instruments, which routinely show spectacular globally propagating bright fronts. Coronal waves, as these perturbations are usually referred to, have now been observed in a wide range of spectral channels, yielding a wealth of information. Many findings have supported the "classical" interpretation of the disturbances: fast-mode MHD waves or shocks that are propagating in the solar corona. However, observations that seemed inconsistent with this picture have stimulated the development of alternative models in which "pseudo waves" are generated by magnetic reconfiguration in the framework of an expanding coronal mass ejection. This has resulted in a vigorous debate on the physical nature of these disturbances. This review focuses on demonstrating how the numerous observational findings of the last one and a half decades can be used to constrain our models of large-scale coronal waves, and how a coherent physical understanding of these disturbances is finally emerging. PMID- 27471438 TI - Drosophila suzukii population response to environment and management strategies. AB - Drosophila suzukii causes economic damage to berry and stone fruit worldwide. Laboratory-generated datasets were standardized and combined on the basis of degree days (DD), using Gompertz and Cauchy curves for survival and reproduction. Eggs transitioned to larvae at 20.3 DD; larvae to pupae at 118.1 DD; and pupae to adults at 200 DD. All adults are expected to have died at 610 DD. Oviposition initiates at 210 DD and gradually increases to a maximum of 15 eggs per DD at 410 DD and subsequently decreases to zero at 610 DD. These data were used as the basis for a DD cohort-level population model. Laboratory survival under extreme temperatures when DD did not accumulate was described by a Gompertz curve based on calendar days. We determined that the initiation of the reproductive period of late dormant field-collected female D. suzukii ranged from 50 to 800 DD from January 1. This suggests that D. suzukii females can reproduce early in the season and are probably limited by availability of early host plants. Finally, we used the DD population model to examine hypothetical stage-specific mortality effects of IPM practices from insecticides and parasitoids at the field level. We found that adulticides applied during the early season will result in the largest comparative population decrease. It is clear from model outputs that parasitism levels comparable to those found in field studies may have a limited effect on population growth. Novel parasitoid guilds could therefore be improved and would be valuable for IPM of D. suzukii. PMID- 27471440 TI - The influence of graphic warning labels on efficacy beliefs and risk perceptions: a qualitative study with low-income, urban smokers. AB - BACKGROUND: Health communication theories indicate that messages depicting efficacy and threat might promote behavior change by enhancing individuals' efficacy beliefs and risk perceptions, but this has received little attention in graphic warning label research. We explored low socioeconomic status (SES) smokers' perceptions of theory-based graphic warning labels to inform the development of labels to promote smoking cessation. METHODS: Twelve graphic warning labels were developed with self-efficacy and response efficacy messages paired with messages portraying high, low, or no threat from smoking. Self efficacy messages were designed to promote confidence in ability to quit, while response efficacy messages were designed to promote confidence in the ability of the Quitline to aid cessation. From January - February 2014, we conducted in depth interviews with 25 low SES adult men and women smokers in Baltimore, Maryland, U.S. Participants discussed the labels' role in their self-efficacy beliefs, response efficacy beliefs about the Quitline, and risk perceptions (including perceived severity of and susceptibility to disease). Data were analyzed through framework analysis, a type of thematic analysis. RESULTS: Efficacy messages in which participants vicariously experienced the characters' quit successes were reported as most influential to self-efficacy beliefs. Labels portraying a high threat were reported as most influential to participants' perceived severity of and susceptibility to smoking risks. Self-efficacy messages alone and paired with high threat were seen as most influential on self-efficacy beliefs. Labels portraying the threat from smoking were most motivational for calling the Quitline, followed by labels showing healthy role models who had successfully quit using the Quitline. CONCLUSIONS: Role model-based efficacy messages might enhance the effectiveness of labels by making smokers' self efficacy beliefs about quitting most salient and enhancing the perceived efficacy of the Quitline. Threatening messages play an important role in enhancing risk perceptions, but findings suggest that efficacy messages are also important in the impact of labels on beliefs and motivation. Our findings could aid in the development of labels to address smoking disparities among low SES populations in the U.S. PMID- 27471441 TI - Pros and Cons of Using the Informed Basis Set to Account for Hemodynamic Response Variability with Developmental Data. AB - Conventional analysis of functional magnetic resonance imaging (fMRI) data using the general linear model (GLM) employs a neural model convolved with a canonical hemodynamic response function (HRF) peaking 5 s after stimulation. Incorporation of a further basis function, namely the canonical HRF temporal derivative, accounts for delays in the hemodynamic response to neural activity. A population that may benefit from this flexible approach is children whose hemodynamic response is not yet mature. Here, we examined the effects of using the set based on the canonical HRF plus its temporal derivative on both first- and second-level GLM analyses, through simulations and using developmental data (an fMRI dataset on proprioceptive mapping in children and adults). Simulations of delayed fMRI first-level data emphasized the benefit of carrying forward to the second-level a derivative boost that combines derivative and nonderivative beta estimates. In the experimental data, second-level analysis using a paired t-test showed increased mean amplitude estimate (i.e., increased group contrast mean) in several brain regions related to proprioceptive processing when using the derivative boost compared to using only the nonderivative term. This was true especially in children. However, carrying forward to the second-level the individual derivative boosts had adverse consequences on random-effects analysis that implemented one-sample t-test, yielding increased between-subject variance, thus affecting group-level statistic. Boosted data also presented a lower level of smoothness that had implication for the detection of group average activation. Imposing soft constraints on the derivative boost by limiting the time-to-peak range of the modeled response within a specified range (i.e., 4-6 s) mitigated these issues. These findings support the notion that there are pros and cons to using the informed basis set with developmental data. PMID- 27471443 TI - Mapping Multiplex Hubs in Human Functional Brain Networks. AB - Typical brain networks consist of many peripheral regions and a few highly central ones, i.e., hubs, playing key functional roles in cerebral inter-regional interactions. Studies have shown that networks, obtained from the analysis of specific frequency components of brain activity, present peculiar architectures with unique profiles of region centrality. However, the identification of hubs in networks built from different frequency bands simultaneously is still a challenging problem, remaining largely unexplored. Here we identify each frequency component with one layer of a multiplex network and face this challenge by exploiting the recent advances in the analysis of multiplex topologies. First, we show that each frequency band carries unique topological information, fundamental to accurately model brain functional networks. We then demonstrate that hubs in the multiplex network, in general different from those ones obtained after discarding or aggregating the measured signals as usual, provide a more accurate map of brain's most important functional regions, allowing to distinguish between healthy and schizophrenic populations better than conventional network approaches. PMID- 27471442 TI - Neural Biomarkers for Dyslexia, ADHD, and ADD in the Auditory Cortex of Children. AB - Dyslexia, attention deficit hyperactivity disorder (ADHD), and attention deficit disorder (ADD) show distinct clinical profiles that may include auditory and language-related impairments. Currently, an objective brain-based diagnosis of these developmental disorders is still unavailable. We investigated the neuro auditory systems of dyslexic, ADHD, ADD, and age-matched control children (N = 147) using neuroimaging, magnetencephalography and psychoacoustics. All disorder subgroups exhibited an oversized left planum temporale and an abnormal interhemispheric asynchrony (10-40 ms) of the primary auditory evoked P1 response. Considering right auditory cortex morphology, bilateral P1 source waveform shapes, and auditory performance, the three disorder subgroups could be reliably differentiated with outstanding accuracies of 89-98%. We therefore for the first time provide differential biomarkers for a brain-based diagnosis of dyslexia, ADHD, and ADD. The method allowed not only allowed for clear discrimination between two subtypes of attentional disorders (ADHD and ADD), a topic controversially discussed for decades in the scientific community, but also revealed the potential for objectively identifying comorbid cases. Noteworthy, in children playing a musical instrument, after three and a half years of training the observed interhemispheric asynchronies were reduced by about 2/3, thus suggesting a strong beneficial influence of music experience on brain development. These findings might have far-reaching implications for both research and practice and enable a profound understanding of the brain-related etiology, diagnosis, and musically based therapy of common auditory-related developmental disorders and learning disabilities. PMID- 27471445 TI - A Citation-Based Analysis and Review of Significant Papers on Timing and Time Perception. AB - Time is an important dimension of brain function, but little is yet known about the underlying cognitive principles and neurobiological mechanisms. The field of timing and time perception has witnessed tremendous growth and multidisciplinary interest in the recent years with the advent of modern neuroimaging and neurophysiological approaches. In this article, I used a data mining approach to analyze the timing literature published by a select group of researchers (n = 202) during the period 2000-2015 and highlight important reviews as well as empirical articles that meet the criterion of a minimum of 100 citations. The qualifying articles (n = 150) are listed in a table along with key details such as number of citations, names of authors, year and journal of publication as well as a short summary of the findings of each study. The results of such a data driven approach to literature review not only serve as a useful resource to any researcher interested in timing, but also provides a means to evaluate key papers that have significantly influenced the field and summarize recent progress and popular research trends in the field. Additionally, such analyses provides food for thought about future scientific directions and raises important questions about improving organizational structures to boost open science and progress in the field. I discuss exciting avenues for future research that have the potential to significantly advance our understanding of the neurobiology of timing, and propose the establishment of a new society, the Timing Research Forum, to promote open science and collaborative work within the highly diverse and multidisciplinary community of researchers in the field of timing and time perception. PMID- 27471444 TI - The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes. AB - HIGHLIGHTS Computational techniques provide accurate descriptions of the structure and dynamics of biological systems, contributing to their understanding at an atomic level.Classical MD simulations are a precious computational tool for the processes where no chemical reactions take place.QM calculations provide valuable information about the enzyme activity, being able to distinguish among several mechanistic pathways, provided a carefully selected cluster model of the enzyme is considered.Multiscale QM/MM simulation is the method of choice for the computational treatment of enzyme reactions offering quantitative agreement with experimentally determined reaction parameters.Molecular simulation provide insight into the mechanism of both the catalytic activity and inhibition of monoamine oxidases, thus aiding in the rational design of their inhibitors that are all employed and antidepressants and antiparkinsonian drugs. Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological, and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors, and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM, and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed. PMID- 27471446 TI - Taurine and Epidermal Growth Factor Belong to the Signature of First-Episode Psychosis. AB - This study evaluated the levels of two amino acid derivatives taurine and spermine in first-episode psychosis (FEP) patients and their response to antipsychotic treatment. The levels of taurine and spermine were significantly up regulated in antipsychotic-naive FEP patients compared to control subjects (CS). Treatment of FEP patients with antipsychotic drugs significantly reduced the positive symptoms of schizophrenia. This positive effect was accompanied by a significant reduction of taurine and spermine to the levels measured in CS. General linear model was used to establish associations of taurine and spermine with the levels of cytokines and growth factors, measured in our previous experiments using the same study sample. There was a strong association between taurine and epidermal growth factor (EGF). Both biomarkers significantly correlated with the disease symptoms as well as with the effectiveness of antipsychotic treatment. Accordingly one can conclude that taurine and EGF belong to the signature of FEP. Most probably they reflect altered oxidative stress and corrupted function of N-methyl-D-aspartate (NMDA) receptors in FEP. PMID- 27471447 TI - Body Image Distortion and Exposure to Extreme Body Types: Contingent Adaptation and Cross Adaptation for Self and Other. AB - Body size misperception is common amongst the general public and is a core component of eating disorders and related conditions. While perennial media exposure to the "thin ideal" has been blamed for this misperception, relatively little research has examined visual adaptation as a potential mechanism. We examined the extent to which the bodies of "self" and "other" are processed by common or separate mechanisms in young women. Using a contingent adaptation paradigm, experiment 1 gave participants prolonged exposure to images both of the self and of another female that had been distorted in opposite directions (e.g., expanded other/contracted self), and assessed the aftereffects using test images both of the self and other. The directions of the resulting perceptual biases were contingent on the test stimulus, establishing at least some separation between the mechanisms encoding these body types. Experiment 2 used a cross adaptation paradigm to further investigate the extent to which these mechanisms are independent. Participants were adapted either to expanded or to contracted images of their own body or that of another female. While adaptation effects were largest when adapting and testing with the same body type, confirming the separation of mechanisms reported in experiment 1, substantial misperceptions were also demonstrated for cross adaptation conditions, demonstrating a degree of overlap in the encoding of self and other. In addition, the evidence of misperception of one's own body following exposure to "thin" and to "fat" others demonstrates the viability of visual adaptation as a model of body image disturbance both for those who underestimate and those who overestimate their own size. PMID- 27471448 TI - Evoked Electromyographically Controlled Electrical Stimulation. AB - Time-variant muscle responses under electrical stimulation (ES) are often problematic for all the applications of neuroprosthetic muscle control. This situation limits the range of ES usage in relevant areas, mainly due to muscle fatigue and also to changes in stimulation electrode contact conditions, especially in transcutaneous ES. Surface electrodes are still the most widely used in noninvasive applications. Electrical field variations caused by changes in the stimulation contact condition markedly affect the resulting total muscle activation levels. Fatigue phenomena under functional electrical stimulation (FES) are also well known source of time-varying characteristics coming from muscle response under ES. Therefore, it is essential to monitor the actual muscle state and assess the expected muscle response by ES so as to improve the current ES system in favor of adaptive muscle-response-aware FES control. To deal with this issue, we have been studying a novel control technique using evoked electromyography (eEMG) signals to compensate for these muscle time-variances under ES for stable neuroprosthetic muscle control. In this perspective article, I overview the background of this topic and highlight important points to be aware of when using ES to induce the desired muscle activation regardless of the time-variance. I also demonstrate how to deal with the common critical problem of ES to move toward robust neuroprosthetic muscle control with the Evoked Electromyographically Controlled Electrical Stimulation paradigm. PMID- 27471449 TI - Corrigendum: Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity. AB - [This corrects the article on p. 351 in vol. 9, PMID: 26483626.]. PMID- 27471450 TI - Olfactory Sensory Activity Modulates Microglial-Neuronal Interactions during Dopaminergic Cell Loss in the Olfactory Bulb. AB - The mammalian olfactory bulb (OB) displays robust activity-dependent plasticity throughout life. Dopaminergic (DA) neurons in the glomerular layer (GL) of the OB are particularly plastic, with loss of sensory input rapidly reducing tyrosine hydroxylase (TH) expression and dopamine production, followed by a substantial reduction in DA neuron number. Here, we asked whether microglia participate in activity-dependent elimination of DA neurons in the mouse OB. Interestingly, we found a significant reduction in the number of both DA neurons and their synapses in the OB ipsilateral to the occluded naris (occluded OB) within just 7 days of sensory deprivation. Concomitantly, the volume of the occluded OB decreased, resulting in an increase in microglial density. Microglia in the occluded OB also adopted morphologies consistent with activation. Using in vivo 2-photon imaging and histological analysis we then showed that loss of olfactory input markedly altered microglial-neuronal interactions during the time that DA neurons are being eliminated: both microglial process motility and the frequency of wrapping of DA neuron somata by activated microglia increased significantly in the occluded OB. Furthermore, we found microglia in the occluded OB that had completely engulfed components of DA neurons. Together, our data provide evidence that loss of olfactory input modulates microglial-DA neuron interactions in the OB, thereby suggesting an important role for microglia in the activity-dependent elimination of DA neurons and their synapses. PMID- 27471451 TI - Discrepancies between Multi-Electrode LFP and CSD Phase-Patterns: A Forward Modeling Study. AB - Multi-electrode recordings of local field potentials (LFPs) provide the opportunity to investigate the spatiotemporal organization of neural activity on the scale of several millimeters. In particular, the phases of oscillatory LFPs allow studying the coordination of neural oscillations in time and space and to tie it to cognitive processing. Given the computational roles of LFP phases, it is important to know how they relate to the phases of the underlying current source densities (CSDs) that generate them. Although CSDs and LFPs are distinct physical quantities, they are often (implicitly) identified when interpreting experimental observations. That this identification is problematic is clear from the fact that LFP phases change when switching to different electrode montages, while the underlying CSD phases remain unchanged. In this study we use a volume conductor model to characterize discrepancies between LFP and CSD phase-patterns, to identify the contributing factors, and to assess the effect of different electrode montages. Although we focus on cortical LFPs recorded with two dimensional (Utah) arrays, our findings are also relevant for other electrode configurations. We found that the main factors that determine the discrepancy between CSD and LFP phase-patterns are the frequency of the neural oscillations and the extent to which the laminar CSD profile is balanced. Furthermore, the presence of laminar phase-differences in cortical oscillations, as commonly observed in experiments, precludes identifying LFP phases with those of the CSD oscillations at a given cortical depth. This observation potentially complicates the interpretation of spike-LFP coherence and spike-triggered LFP averages. With respect to reference strategies, we found that the average-reference montage leads to larger discrepancies between LFP and CSD phases as compared with the referential montage, while the Laplacian montage reduces these discrepancies. We therefore advice to conduct analysis of two-dimensional LFP recordings using the Laplacian montage. PMID- 27471452 TI - Improving a Bimanual Motor Skill Through Unimanual Training. AB - When we learn a bimanual motor skill (e.g., rowing a boat), we often break it down into unimanual practices (e.g., a rowing drill with the left or right arm). Such unimanual practice is thought to be useful for learning bimanual motor skills efficiently because the learner can concentrate on learning to perform a simpler component. However, it is not so straightforward to assume that unimanual training (UT) improves bimanual performance. We have previously demonstrated that motor memories for reaching movements consist of three different parts: unimanual specific, bimanual-specific, and overlapping parts. According to this scheme, UT appears to be less effective, as its training effect is only partially transferred to the same limb for bimanual movement. In the present study, counter intuitively, we demonstrate that, even after the bimanual skill is almost fully learned by means of bimanual training (BT), additional UT could further improve bimanual skill. We hypothesized that this effect occurs because UT increases the memory content in the overlapping part, which might contribute to an increase in the memory for bimanual movement. To test this hypothesis, we examined whether the UT performed after sufficient BT could improve the bimanual performance. Participants practiced performing bimanual reaching movements (BM) in the presence of a novel force-field imposed only on their left arm. As an index for the motor performance, we used the error-clamp method (i.e., after-effect of the left arm) to evaluate the force output to compensate for the force-field during the reaching movement. After sufficient BT, the training effect reached a plateau. However, UT performed subsequently improved the bimanual performance significantly. In contrast, when the same amount of BT was continued, the bimanual performance remained unchanged, highlighting the beneficial effect of UT on bimanual performance. Considering memory structure, we also expected that BT could improve unimanual performance, which was confirmed by another experiment. These results provide a new interpretation of why UT was useful for improving a bimanual skill, and propose a practical strategy for enhancing performance by performing training in various contexts. PMID- 27471453 TI - Activation of Dopamine Receptors in the Nucleus Accumbens Promotes Sucrose Reinforced Cued Approach Behavior. AB - Dopamine receptor activation in the nucleus accumbens (NAc) promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety. PMID- 27471454 TI - Association between Exposure to the Chinese Famine in Different Stages of Early Life and Decline in Cognitive Functioning in Adulthood. AB - OBJECTIVE: To investigate whether exposure to the Chinese Famine in different life stages of early life is associated with cognitive functioning decline in adulthood. METHODS: We recruited 1366 adults born between 1950 and 1964 and divided them into fetal-exposed, early childhood-exposed (1-3 years old during the famine), mid childhood-exposed (4-6 years old during the famine), late childhood-exposed (7-9 years old during the famine), and non-exposed groups. A selection of cognitive tests was administered to assess their cognitive performance. Association between malnutrition in different famine exposure periods and adult cognitive performance was estimated by multivariate logistic and multiple linear regression analyses. RESULTS: There were significant differences in cognitive performance between subjects exposed to famine during different life stages. For the general cognitive tests, fetal-exposed period was associated with decreased scores of the Mini-Mental State Examination (MMSE), and late childhood-exposed with decreased scores of the Montreal Cognitive Assessment (MoCA). We also found exposure to famine during mid and late childhood was associated with worse performance on the Stroop color and word test. CONCLUSION: Famine exposure in utero and during childhood is associated with overall and specific cognitive decline, affecting selective attention and response inhibition particularly. PMID- 27471455 TI - Imaging Imageability: Behavioral Effects and Neural Correlates of Its Interaction with Affect and Context. AB - The construct of imageability refers to the extent to which a word evokes a tangible sensation. Previous research (Westbury et al., 2013) suggests that the behavioral effects attributed to a word's imageability can be largely or wholly explained by two objective constructs, contextual density and estimated affect. Here, we extend these previous findings in two ways. First, we show that closely matched stimuli on the three measures of contextual density, estimated affect, and human-judged imageability show a three-way interaction in explaining variance in LD RTs, but that imagebility accounts for no additional variance after contextual density and estimated affect are entered first. Secondly, we demonstrate that the loci and functional connectivity (via graphical models) of the brain regions implicated in processing the three variables during that task are largely over-lapping and similar. These two lines of evidence support the conclusion that the effect usually attributed to human-judged imageability is largely or entirely due to the effects of other correlated measures that are directly computable. PMID- 27471456 TI - Shutting Down Sensorimotor Interferences after Stroke: A Proof-of-Principle SMR Neurofeedback Study. AB - INTRODUCTION: Neurofeedback training aims at learning self-regulation of brain activity underlying cognitive, emotional or physiological functions. Despite of promising investigations on neurofeedback as a tool for cognitive rehabilitation in neurological diseases, such as after stroke, there is still a lack of research on feasibility and efficiency of neurofeedback in this field. METHODS: The present study aimed at investigating behavioral and electrophysiological effects of 10 sessions of sensorimotor rhythm (SMR) neurofeedback in a 74-years-old stroke patient (UG20). Based on previous results in healthy young participants, we hypothesized that SMR neurofeedback leads to a decrease in sensorimotor interferences and improved stimulus processing, reflected by changes in event related potentials (ERPs) and electrophysiological coherence. To assess whether UG20 benefited from the training as much as healthy persons of a similar age, a healthy control group of N = 10 elderly persons was trained as well. Before and after neurofeedback training, participants took part in a multichannel electroencephalography measurement conducted during a non-verbal and a verbal learning task. RESULTS: Both UG20 and the healthy controls were able to regulate their SMR activity during neurofeedback training. Moreover, in a non-verbal learning task, changes in ERPs and coherence were observed after training: UG20 showed a better performance in the non-verbal learning task and a higher P3 amplitude after training than before, and coherence between central and parietal electrodes decreased after training. The control group also showed a behavioral improvement in the non-verbal learning task and tendencies for higher P3 amplitudes and decreased central-parietal coherence after training. Single-case analyses indicated that the changes observed in UG20 were not smaller than the changes in healthy controls. CONCLUSION: Neurofeedback can be successfully applied in a stroke patient and in healthy elderly persons. We suggest that SMR neurofeedback leads to a shutting-down of sensorimotor interferences which benefits semantic encoding and retrieval. PMID- 27471457 TI - Restricted Arm Swing Affects Gait Stability and Increased Walking Speed Alters Trunk Movements in Children with Cerebral Palsy. AB - Observational research suggests that in children with cerebral palsy, the altered arm swing is linked to instability during walking. Therefore, the current study investigates whether children with cerebral palsy use their arms more than typically developing children, to enhance gait stability. Evidence also suggests an influence of walking speed on gait stability. Moreover, previous research highlighted a link between walking speed and arm swing. Hence, the experiment aimed to explore differences between typically developing children and children with cerebral palsy taking into account the combined influence of restricting arm swing and increasing walking speed on gait stability. Spatiotemporal gait characteristics, trunk movement parameters and margins of stability were obtained using three dimensional gait analysis to assess gait stability of 26 children with cerebral palsy and 24 typically developing children. Four walking conditions were evaluated: (i) free arm swing and preferred walking speed; (ii) restricted arm swing and preferred walking speed; (iii) free arm swing and high walking speed; and (iv) restricted arm swing and high walking speed. Double support time and trunk acceleration variability increased more when arm swing was restricted in children with bilateral cerebral palsy compared to typically developing children and children with unilateral cerebral palsy. Trunk sway velocity increased more when walking speed was increased in children with unilateral cerebral palsy compared to children with bilateral cerebral palsy and typically developing children and in children with bilateral cerebral palsy compared to typically developing children. Trunk sway velocity increased more when both arm swing was restricted and walking speed was increased in children with bilateral cerebral palsy compared to typically developing children. It is proposed that facilitating arm swing during gait rehabilitation can improve gait stability and decrease trunk movements in children with cerebral palsy. The current results thereby partly support the suggestion that facilitating arm swing in specific situations possibly enhances safety and reduces the risk of falling in children with cerebral palsy. PMID- 27471458 TI - Motor Cortex Excitability and BDNF Levels in Chronic Musculoskeletal Pain According to Structural Pathology. AB - The central sensitization syndrome (CSS) encompasses disorders with overlapping symptoms in a structural pathology spectrum ranging from persistent nociception [e.g., osteoarthritis (OA)] to an absence of tissue injuries such as the one presented in fibromyalgia (FM) and myofascial pain syndrome (MPS). First, we hypothesized that these syndromes present differences in their cortical excitability parameters assessed by transcranial magnetic stimulation (TMS), namely motor evoked potential (MEP), cortical silent period (CSP), short intracortical inhibition (SICI) and short intracortical facilitation (SICF). Second, considering that the presence of tissue injury could be detected by serum neurotrophins, we hypothesized that the spectrum of structural pathology (i.e., from persistent nociception like in OA, to the absence of tissue injury like in FM and MPS), could be detected by differential efficiency of their descending pain inhibitory system, as assessed by the conditioned pain modulation (CPM) paradigm. Third, we explored whether brain-derived neurotrophic factor (BDNF) had an influence on the relationship between motor cortex excitability and structural pathology. This cross-sectional study pooled baseline data from three randomized clinical trials. We included females (n = 114), aged 19-65 years old with disability by chronic pain syndromes (CPS): FM (n = 19), MPS (n = 54), OA (n = 27) and healthy subjects (n = 14). We assessed the serum BDNF, the motor cortex excitability by parameters the TMS measures and the change on numerical pain scale [NPS (0-10)] during CPM-task. The adjusted mean (SD) on the SICI observed in the absence of tissue injury was 56.36% lower than with persistent nociceptive input [0.31(0.18) vs. 0.55 (0.32)], respectively. The BDNF was inversely correlated with the SICI and with the change on NPS (0-10)during CPM-task. These findings suggest greater disinhibition in the motor cortex and the descending pain inhibitory system in FM and MPS than in OA and healthy subjects. Likewise, the inter-hemispheric disinhibition as well as the dysfunction in the descending pain modulatory system is higher in chronic pain without tissue injury compared to a structural lesion. In addition, they suggest that a greater level of serum BDNF may be involved in the processes that mediate the disinhibition of motor cortex excitability, as well as the function of descending inhibitory pain modulation system, independently of the physiopathology mechanism of musculoskeletal pain syndromes. PMID- 27471460 TI - Visual Cortex Inspired CNN Model for Feature Construction in Text Analysis. AB - Recently, biologically inspired models are gradually proposed to solve the problem in text analysis. Convolutional neural networks (CNN) are hierarchical artificial neural networks, which include a various of multilayer perceptrons. According to biological research, CNN can be improved by bringing in the attention modulation and memory processing of primate visual cortex. In this paper, we employ the above properties of primate visual cortex to improve CNN and propose a biological-mechanism-driven-feature-construction based answer recommendation method (BMFC-ARM), which is used to recommend the best answer for the corresponding given questions in community question answering. BMFC-ARM is an improved CNN with four channels respectively representing questions, answers, asker information and answerer information, and mainly contains two stages: biological mechanism driven feature construction (BMFC) and answer ranking. BMFC imitates the attention modulation property by introducing the asker information and answerer information of given questions and the similarity between them, and imitates the memory processing property through bringing in the user reputation information for answerers. Then the feature vector for answer ranking is constructed by fusing the asker-answerer similarities, answerer's reputation and the corresponding vectors of question, answer, asker, and answerer. Finally, the Softmax is used at the stage of answer ranking to get best answers by the feature vector. The experimental results of answer recommendation on the Stackexchange dataset show that BMFC-ARM exhibits better performance. PMID- 27471459 TI - Mismatch Negativity to Threatening Voices Associated with Positive Symptoms in Schizophrenia. AB - Although the general consensus holds that emotional perception is impaired in patients with schizophrenia, the extent to which neural processing of emotional voices is altered in schizophrenia remains to be determined. This study enrolled 30 patients with chronic schizophrenia and 30 controls and measured their mismatch negativity (MMN), a component of auditory event-related potentials (ERP). In a passive oddball paradigm, happily or angrily spoken deviant syllables dada were randomly presented within a train of emotionally neutral standard syllables. Results showed that MMN in response to angry syllables and angry derived non-vocal sounds was significantly decreased in individuals with schizophrenia. P3a to angry syllables showed stronger amplitudes but longer latencies. Weaker MMN amplitudes were associated with more positive symptoms of schizophrenia. Receiver operator characteristic analysis revealed that angry MMN, angry-derived MMN, and angry P3a could help predict whether someone had received a clinical diagnosis of schizophrenia. The findings suggested general impairments of voice perception and acoustic discrimination in patients with chronic schizophrenia. The emotional salience processing of voices showed an atypical fashion at the preattentive level, being associated with positive symptoms in schizophrenia. PMID- 27471461 TI - Glomerular and Mitral-Granule Cell Microcircuits Coordinate Temporal and Spatial Information Processing in the Olfactory Bulb. AB - The olfactory bulb processes inputs from olfactory receptor neurons (ORNs) through two levels: the glomerular layer at the site of input, and the granule cell level at the site of output to the olfactory cortex. The sequence of action of these two levels has not yet been examined. We analyze this issue using a novel computational framework that is scaled up, in three-dimensions (3D), with realistic representations of the interactions between layers, activated by simulated natural odors, and constrained by experimental and theoretical analyses. We suggest that the postulated functions of glomerular circuits have as their primary role transforming a complex and disorganized input into a contrast enhanced and normalized representation, but cannot provide for synchronization of the distributed glomerular outputs. By contrast, at the granule cell layer, the dendrodendritic interactions mediate temporal decorrelation, which we show is dependent on the preceding contrast enhancement by the glomerular layer. The results provide the first insights into the successive operations in the olfactory bulb, and demonstrate the significance of the modular organization around glomeruli. This layered organization is especially important for natural odor inputs, because they activate many overlapping glomeruli. PMID- 27471462 TI - A Comparison of Physiological Signal Analysis Techniques and Classifiers for Automatic Emotional Evaluation of Audiovisual Contents. AB - This work focuses on finding the most discriminatory or representative features that allow to classify commercials according to negative, neutral and positive effectiveness based on the Ace Score index. For this purpose, an experiment involving forty-seven participants was carried out. In this experiment electroencephalography (EEG), electrocardiography (ECG), Galvanic Skin Response (GSR) and respiration data were acquired while subjects were watching a 30-min audiovisual content. This content was composed by a submarine documentary and nine commercials (one of them the ad under evaluation). After the signal pre processing, four sets of features were extracted from the physiological signals using different state-of-the-art metrics. These features computed in time and frequency domains are the inputs to several basic and advanced classifiers. An average of 89.76% of the instances was correctly classified according to the Ace Score index. The best results were obtained by a classifier consisting of a combination between AdaBoost and Random Forest with automatic selection of features. The selected features were those extracted from GSR and HRV signals. These results are promising in the audiovisual content evaluation field by means of physiological signal processing. PMID- 27471463 TI - Dynamical Integration of Language and Behavior in a Recurrent Neural Network for Human-Robot Interaction. AB - To work cooperatively with humans by using language, robots must not only acquire a mapping between language and their behavior but also autonomously utilize the mapping in appropriate contexts of interactive tasks online. To this end, we propose a novel learning method linking language to robot behavior by means of a recurrent neural network. In this method, the network learns from correct examples of the imposed task that are given not as explicitly separated sets of language and behavior but as sequential data constructed from the actual temporal flow of the task. By doing this, the internal dynamics of the network models both language-behavior relationships and the temporal patterns of interaction. Here, "internal dynamics" refers to the time development of the system defined on the fixed-dimensional space of the internal states of the context layer. Thus, in the execution phase, by constantly representing where in the interaction context it is as its current state, the network autonomously switches between recognition and generation phases without any explicit signs and utilizes the acquired mapping in appropriate contexts. To evaluate our method, we conducted an experiment in which a robot generates appropriate behavior responding to a human's linguistic instruction. After learning, the network actually formed the attractor structure representing both language-behavior relationships and the task's temporal pattern in its internal dynamics. In the dynamics, language behavior mapping was achieved by the branching structure. Repetition of human's instruction and robot's behavioral response was represented as the cyclic structure, and besides, waiting to a subsequent instruction was represented as the fixed-point attractor. Thanks to this structure, the robot was able to interact online with a human concerning the given task by autonomously switching phases. PMID- 27471465 TI - Antioxidant and Hepatoprotective Potentiality of Randia dumetorum Lam. Leaf and Bark via Inhibition of Oxidative Stress and Inflammatory Cytokines. AB - Randia dumetorum Lam. (RD) (Rubiaceae) is traditionally used by some tribes of Assam and Manipur of North East India for the treatment of liver ailments. In this context, to scientifically validate this indigenous traditional knowledge, we have evaluated the antioxidant and hepatoprotective activity of RD leaf and bark. The methanol extracts of RD leaf and bark were evaluated for in vitro antioxidant activity which exhibited good antioxidant activity in terms of reducing power assay, total antioxidant assay and DPPH (1,1-diphenyl-2 picrylhydrazyl) radical scavenging assay. Total phenolic and flavonoid content were found to be 112 +/- 3.24 mg and 138 +/- 2.46 mg gallic acid equivalents/g extract and 2.6 +/- 0.26 mg and 3.34 +/- 0.31 mg rutin equivalents/g extract respectively for RD leaf and bark methanol extracts. The in vivo hepato protective activity of the RD leaf and bark extract was evaluated against carbon tetrachloride (CCl4) induced hepatic damage in male wistar rats. CCl4 administration induced hepatic damage in rats resulted in increased levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, thiobarbituric acid reacting substances, albumin, bilirubin, TNF alpha, IL-1beta and decreased levels of total protein and antioxidant enzymes like superoxide dismutase, catalase, and glutathione reductase. RD leaf and bark methanol extracts pre-treatment exhibited protection against CCl4 induced hepatotoxicity by reversing all the abnormal parameters to significant levels. Histopathological results revealed that RD leaf and bark extracts at 400 mg/kg protects the liver from damage induced by CCl4. The results of this study scientifically validate the traditional use of RD leaf and bark for the treatment of liver ailments. PMID- 27471464 TI - Anti-inflammatory and Antioxidant Effects of Flavonoid-Rich Fraction of Bergamot Juice (BJe) in a Mouse Model of Intestinal Ischemia/Reperfusion Injury. AB - The flavonoid-rich fraction of bergamot juice (BJe) has demonstrated anti inflammatory and antioxidant activities. The aim of work was to test the beneficial effects of BJe on the modulation of the ileum inflammation caused by intestinal ischemia/reperfusion (I/R) injury in mice. To understand the cellular mechanisms by which BJe may decrease the development of intestinal I/R injury, we have evaluated the activation of signaling transduction pathways that can be induced by reactive oxygen species production. Superior mesenteric artery and celiac trunk were occluded for 30 min and reperfused for 1 h. The animals were sacrificed after 1 h of reperfusion, for both histological and molecular examinations of the ileum tissue. The experimental results demonstrated that BJe was able to reduce histological damage, cytokines production, adhesion molecules expression, neutrophil infiltration and oxidative stress by a mechanism involved both NF-kappaB and MAP kinases pathways. This study indicates that BJe could represent a new treatment against inflammatory events of intestinal I/R injury. PMID- 27471466 TI - In vitro Antibacterial Activity of Combretum edwardsii, Combretum krausii, and Maytenus nemorosa and Their Synergistic Effects in Combination with Antibiotics. AB - The study investigated the antibacterial activity of crude extracts of C. edwardsii, Combretum krausii, and Maytenus nemorosa as well as their interactions with selected antibiotics against drug resistant bacterial strains. Using the rapid p-iodonitrotetrazolium chloride colorimetric assay, minimum inhibitory concentration values of plant extracts and antibiotics were determined. The interactions of plant extracts and antibiotics were studied using a checkerboard method. The MICs of the plant extracts and antibiotics were in the range of 0.037 6.25 and 0.001-2.5 mg/ml, respectively. The plant fractions tested in the present study displayed varying levels of antibacterial activity depending on the bacterial strains. Generally, Staphylococcus aureus was the most susceptible of the three strains of bacteria while the other two beta-lactamase producing Gram negative bacteria were the most resistant. The hexane leaf extract of M. nemorosa was the most active (MIC = 37 MUg/ml) against S. aureus. Ethyl acetate leaf extract of C. krausii was the most active against Klebsiella pneumoniae and ethyl acetate leaf extract of C. edwardsii was the most active against Escherichia coli. Synergistic interactions were detected in 13% of the combinations against E. coli, 27% of the combinations against K. pneumoniae and 80% of the combinations against S. aureus. The few synergistic interactions observed in the present study suggest that the crude extracts of the leaves of M. nemorosa, C. edwardsii, and C. krausii could be potential sources of broad spectrum antibiotic resistance modifying compounds. PMID- 27471467 TI - A Missense Mutation of the Gene Encoding Synaptic Vesicle Glycoprotein 2A (SV2A) Confers Seizure Susceptibility by Disrupting Amygdalar Synaptic GABA Release. AB - Synaptic vesicle glycoprotein 2A (SV2A) is specifically expressed in the membranes of synaptic vesicles and modulates action potential-dependent neurotransmitter release. To explore the role of SV2A in the pathogenesis of epileptic disorders, we recently generated a novel rat model (Sv2a(L174Q) rat) carrying a missense mutation of the Sv2a gene and showed that the Sv2a(L174Q) rats were hypersensitive to kindling development (Tokudome et al., 2016). Here, we further conducted behavioral and neurochemical studies to clarify the pathophysiological mechanisms underlying the seizure vulnerability in Sv2a(L174Q) rats. Sv2a(L174Q) rats were highly susceptible to pentylenetetrazole (PTZ) induced seizures, yielding a significantly higher seizure scores and seizure incidence than the control animals. Brain mapping analysis of Fos expression, a biological marker of neural excitation, revealed that the seizure threshold level of PTZ region-specifically elevated Fos expression in the amygdala in Sv2a(L174Q) rats. In vivo microdialysis study showed that the Sv2a(L174Q) mutation preferentially reduced high K(+) (depolarization)-evoked GABA release, but not glutamate release, in the amygdala. In addition, specific control of GABA release by SV2A was supported by its predominant expression in GABAergic neurons, which were co-stained with antibodies against SV2A and glutamate decarboxylase 1. The present results suggest that dysfunction of SV2A by the missense mutation elevates seizure susceptibility in rats by preferentially disrupting synaptic GABA release in the amygdala, illustrating the crucial role of amygdalar SV2A GABAergic system in epileptogenesis. PMID- 27471468 TI - A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience. AB - The state of consciousness induced by N,N-dimethyltryptamine (DMT) is one of the most extraordinary of any naturally-occurring psychedelic substance. Users consistently report the complete replacement of normal subjective experience with a novel "alternate universe," often densely populated with a variety of strange objects and other highly complex visual content, including what appear to be sentient "beings." The phenomenology of the DMT state is of great interest to psychology and calls for rigorous academic enquiry. The extremely short duration of DMT effects-less than 20 min-militates against single dose administration as the ideal model for such enquiry. Using pharmacokinetic modeling and DMT blood sampling data, we demonstrate that the unique pharmacological characteristics of DMT, which also include a rapid onset and lack of acute tolerance to its subjective effects, make it amenable to administration by target-controlled intravenous infusion. This is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery. Simulations of our model demonstrate that this approach will allow research subjects to be induced into a stable and prolonged DMT experience, making it possible to carefully observe its psychological contents, and provide more extensive accounts for subsequent analyses. This model would also be valuable in performing functional neuroimaging, where subjects are required to remain under the influence of the drug for extended periods. Finally, target-controlled intravenous infusion of DMT may aid the development of unique psychotherapeutic applications of this psychedelic agent. PMID- 27471469 TI - Mechanism and Physiologic Significance of the Suppression of Cholesterol Esterification in Human Interstitial Fluid. AB - Cholesterol esterification in high density lipoproteins (HDLs) by lecithin:cholesterol acyltransferase (LCAT) promotes unesterified cholesterol (UC) transfer from red cell membranes to plasma in vitro. However, it does not explain the transfer of UC from most peripheral cells to interstitial fluid in vivo, as HDLs in afferent peripheral lymph are enriched in UC. Having already reported that the endogenous cholesterol esterification rate (ECER) in lymph is only 5% of that in plasma, we have now explored the underlying mechanism. In peripheral lymph from 20 healthy men, LCAT concentration, LCAT activity (assayed using an optimized substrate), and LCAT specific activity averaged, respectively, 11.8, 10.3, and 84.9% of plasma values. When recombinant human LCAT was added to lymph, the increments in enzyme activity were similar to those when LCAT was added to plasma. Addition of apolipoprotein AI (apo AI), fatty acid-free albumin, Intralipid, or the d < 1.006 g/ml plasma fraction had no effect on ECER. During incubation of lymph plus plasma, the ECER was similar to that observed with buffer plus plasma. When lymph was added to heat-inactivated plasma, the ECER was 11-fold greater than with lymph plus buffer. Addition of discoidal proteoliposomes of apo AI and phosphatidycholine (PC) to lymph increased ECER 10 fold, while addition of apo AI/PC/UC disks did so by only six-fold. We conclude that the low ECER in lymph is due to a property of the HDLs, seemingly substrate inhibition of LCAT by excess cell-derived UC. This is reversed when lymph enters plasma, consequent upon redistribution of UC from lymph HDLs to plasma lipoproteins. PMID- 27471470 TI - MicroRNA Profiling during Craniofacial Development: Potential Roles for Mir23b and Mir133b. AB - Defects in mid-facial development, including cleft lip/palate, account for a large number of human birth defects annually. In many cases, aberrant gene expression results in either a reduction in the number of neural crest cells (NCCs) that reach the frontonasal region and form much of the facial skeleton or subsequent failure of NCC patterning and differentiation into bone and cartilage. While loss of gene expression is often associated with developmental defects, aberrant upregulation of expression can also be detrimental. microRNAs (miRNAs) are a class of non-coding RNAs that normally repress gene expression by binding to recognition sequences located in the 3' UTR of target mRNAs. miRNAs play important roles in many developmental systems, including midfacial development. Here, we take advantage of high throughput RNA sequencing (RNA-seq) from different tissues of the developing mouse midface to interrogate the miRs that are expressed in the midface and select a subset for further expression analysis. Among those examined, we focused on four that showed the highest expression level in in situ hybridization analysis. Mir23b and Mir24.1 are specifically expressed in the developing mouse frontonasal region, in addition to areas in the perichondrium, tongue musculature and cranial ganglia. Mir23b is also expressed in the palatal shelves and in anterior epithelium of the palate. In contrast, Mir133b and Mir128.2 are mainly expressed in head and trunk musculature. Expression analysis of mir23b and mir133b in zebrafish suggests that mir23b is expressed in the pharyngeal arch, otic vesicle, and trunk muscle while mir133b is similarly expressed in head and trunk muscle. Functional analysis by overexpression of mir23b in zebrafish leads to broadening of the ethmoid plate and aberrant cartilage structures in the viscerocranium, while overexpression of mir133b causes a reduction in ethmoid plate size and a significant midfacial cleft. These data illustrate that miRs are expressed in the developing midface and that Mir23b and Mir133b may have roles in this developmental process. PMID- 27471471 TI - NOX2 Inhibition Impairs Early Muscle Gene Expression Induced by a Single Exercise Bout. AB - Reactive oxygen species (ROS) participate as signaling molecules in response to exercise in skeletal muscle. However, the source of ROS and the molecular mechanisms involved in these phenomena are still not completely understood. The aim of this work was to study the role of skeletal muscle NADPH oxidase isoform 2 (NOX2) in the molecular response to physical exercise in skeletal muscle. BALB/c mice, pre-treated with a NOX2 inhibitor, apocynin, (3 mg/kg) or vehicle for 3 days, were swim-exercised for 60 min. Phospho-p47(phox) levels were significantly upregulated by exercise in flexor digitorum brevis (FDB). Moreover, exercise significantly increased NOX2 complex assembly (p47(phox)-gp91(phox) interaction) demonstrated by both proximity ligation assay and co-immunoprecipitation. Exercise-induced NOX2 activation was completely inhibited by apocynin treatment. As expected, exercise increased the mRNA levels of manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx), citrate synthase (CS), mitochondrial transcription factor A (tfam) and interleukin-6 (IL-I6) in FDB muscles. Moreover, the apocynin treatment was associated to a reduced activation of p38 MAP kinase, ERK 1/2, and NF-kappaB signaling pathways after a single bout of exercise. Additionally, the increase in plasma IL-6 elicited by exercise was decreased in apocynin-treated mice compared with the exercised vehicle-group (p < 0.001). These results were corroborated using gp91-dstat in an in vitro exercise model. In conclusion, NOX2 inhibition by both apocynin and gp91dstat, alters the intracellular signaling to exercise and electrical stimuli in skeletal muscle, suggesting that NOX2 plays a critical role in molecular response to an acute exercise. PMID- 27471472 TI - Red Cell Properties after Different Modes of Blood Transportation. AB - Transportation of blood samples is unavoidable for assessment of specific parameters in blood of patients with rare anemias, blood doping testing, or for research purposes. Despite the awareness that shipment may substantially alter multiple parameters, no study of that extent has been performed to assess these changes and optimize shipment conditions to reduce transportation-related artifacts. Here we investigate the changes in multiple parameters in blood of healthy donors over 72 h of simulated shipment conditions. Three different anticoagulants (K3EDTA, Sodium Heparin, and citrate-based CPDA) for two temperatures (4 degrees C and room temperature) were tested to define the optimal transportation conditions. Parameters measured cover common cytology and biochemistry parameters (complete blood count, hematocrit, morphological examination), red blood cell (RBC) volume, ion content and density, membrane properties and stability (hemolysis, osmotic fragility, membrane heat stability, patch-clamp investigations, and formation of micro vesicles), Ca(2+) handling, RBC metabolism, activity of numerous enzymes, and O2 transport capacity. Our findings indicate that individual sets of parameters may require different shipment settings (anticoagulants, temperature). Most of the parameters except for ion (Na(+), K(+), Ca(2+)) handling and, possibly, reticulocytes counts, tend to favor transportation at 4 degrees C. Whereas plasma and intraerythrocytic Ca(2+) cannot be accurately measured in the presence of chelators such as citrate and EDTA, the majority of Ca(2+)-dependent parameters are stabilized in CPDA samples. Even in blood samples from healthy donors transported using an optimized shipment protocol, the majority of parameters were stable within 24 h, a condition that may not hold for the samples of patients with rare anemias. This implies for as short as possible shipping using fast courier services to the closest expert laboratory at reach. Mobile laboratories or the travel of the patients to the specialized laboratories may be the only option for some groups of patients with highly unstable RBCs. PMID- 27471473 TI - Addition of Selenium Nanoparticles to Electrospun Silk Scaffold Improves the Mammalian Cell Activity While Reducing Bacterial Growth. AB - Silk possesses many beneficial wound healing properties, and electrospun scaffolds are especially applicable for skin applications, due to their smaller interstices and higher surface areas. However, purified silk promotes microbial growth. Selenium nanoparticles have shown excellent antibacterial properties and are a novel antimicrobial chemistry. Here, electrospun silk scaffolds were doped with selenium nanoparticles to impart antibacterial properties to the silk scaffolds. Results showed significantly improved bacterial inhibition and mild improvement in human dermal fibroblast metabolic activity. These results suggest that the addition of selenium nanoparticles to electrospun silk is a promising approach to improve wound healing with reduced infection, without relying on antibiotics. PMID- 27471475 TI - The Regenerative Potential of Female Skeletal Muscle upon Hypobaric Hypoxic Exposure. AB - AIM: The aim of this study was to determine whether a 14-day trekking expeditions, in high altitude hypoxic environment, triggers redox disturbance at the level of satellite cells (adult stem cells) in young women. METHODS: We collected muscle biopsies from Vastus Lateralis muscle for both single fiber analysis and satellite cells isolation. The samples collected before (PRE Hypoxia) and after (POST-Hypoxia) the trekking in the Himalayas were compared. Satellite cells were investigated for oxidative stress (oxidant production, antioxidant enzyme activity, and lipid damage), mitochondrial potential variation, gene profile of HIF, and myogenic transcription factors (Pax7, MyoD, myogenin), and miRNA expression (miR-1, miR-133, miR-206). RESULTS: The nuclear domain analysis showed a significant fusion and consequent reduction of the Pax7(+) satellite cells in the single mature fibers. The POST-Hypoxia myoblasts obtained by two out of six volunteers showed high superoxide anion production and lipid peroxidation along with impaired dismutase and catalase and mitochondrial potential. The transcription profile and miRNA expression were different for oxidized and non-oxidized cells. CONCLUSIONS: The present study supports the phenomenon of hypobaric-hypoxia-induced oxidative stress and its role in the impairment of the regenerative capacity of satellite cells derived from the V. Lateralis muscle of young adult female subjects. PMID- 27471474 TI - Serotoninergic and Circadian Systems: Driving Mammary Gland Development and Function. AB - Since lactation is one of the most metabolically demanding states in adult female mammals, beautifully complex regulatory mechanisms are in place to time lactation to begin after birth and cease when the neonate is weaned. Lactation is regulated by numerous different homeorhetic factors, all of them tightly coordinated with the demands of milk production. Emerging evidence support that among these factors are the serotonergic and circadian clock systems. Here we review the serotoninergic and circadian clock systems and their roles in the regulation of mammary gland development and lactation physiology. We conclude by presenting our hypothesis that these two systems interact to accommodate the metabolic demands of lactation and thus adaptive changes in these systems occur to maintain mammary and systemic homeostasis through the reproductive cycles of female mammals. PMID- 27471476 TI - Corrigendum: Detection of a Novel DSPP Mutation by NGS in a Population Isolate in Madagascar. AB - [This corrects the article on p. 70 in vol. 7, PMID: 26973538.]. PMID- 27471477 TI - Suicide Prevention Public Service Announcements Impact Help-Seeking Attitudes: The Message Makes a Difference. AB - Suicide continues to be one of the most serious public health challenges. Public service announcements (PSAs) are frequently used to address this challenge, but are rarely sufficiently evaluated to determine if they meet the intended goals, or are associated with potential iatrogenic effects. Although it is challenging to assess the relative impact of different PSA modalities, our group previously noted that one billboard message failed to show the same benefits as one TV ad [e.g., Klimes-Dougan and Lee (1)]. The purpose of this study was to extend these findings to test critical aspects of suicide prevention billboard messaging. Although both simulated billboard messages presented had identical supporting messages, we predicted that the more personal billboard message, focused on saving one's life, would cause more favorable help-seeking attitudes than the message focused on suicide. Young adult university students (N = 785) were randomly assigned to one of three conditions; one of two billboard simulations or a TV ad simulation. Help-seeking attitudes, maladaptive coping, and reports of concern and distress were evaluated. The results of this study suggest some relative benefits in endorsement of favorable help-seeking attitudes for one of the billboard conditions - stop depression from taking another life. Although further research is needed to determine what methods will alter the risk for suicide in the population, the results of this study provide a useful first step showing that some billboard messaging may favorably influence help-seeking attitudes. PMID- 27471478 TI - Free Energy and Virtual Reality in Neuroscience and Psychoanalysis: A Complexity Theory of Dreaming and Mental Disorder. AB - The main concepts of the free energy (FE) neuroscience developed by Karl Friston and colleagues parallel those of Freud's Project for a Scientific Psychology. In Hobson et al. (2014) these include an innate virtual reality generator that produces the fictive prior beliefs that Freud described as the primary process. This enables Friston's account to encompass a unified treatment-a complexity theory-of the role of virtual reality in both dreaming and mental disorder. In both accounts the brain operates to minimize FE aroused by sensory impingements including interoceptive impingements that report compliance with biological imperatives-and constructs a representation/model of the causes of impingement that enables this minimization. In Friston's account (variational) FE equals complexity minus accuracy, and is minimized by increasing accuracy and decreasing complexity. Roughly the brain (or model) increases accuracy together with complexity in waking. This is mediated by consciousness-creating active inference by which it explains sensory impingements in terms of perceptual experiences of their causes. In sleep it reduces complexity by processes that include both synaptic pruning and consciousness/virtual reality/dreaming in REM. The consciousness-creating active inference that effects complexity-reduction in REM dreaming must operate on FE-arousing data distinct from sensory impingement. The most relevant source is remembered arousals of emotion, both recent and remote, as processed in SWS and REM on "active systems" accounts of memory consolidation/reconsolidation. Freud describes these remembered arousals as condensed in the dreamwork for use in the conscious contents of dreams, and similar condensation can be seen in symptoms. Complexity partly reflects emotional conflict and trauma. This indicates that dreams and symptoms are both produced to reduce complexity in the form of potentially adverse (traumatic or conflicting) arousals of amygdala-related emotions. Mental disorder is thus caused by computational complexity together with mechanisms like synaptic pruning that have evolved for complexity-reduction; and important features of disorder can be understood in these terms. Details of the consilience among Freudian, systems consolidation, and complexity-reduction accounts appear clearly in the analysis of a single fragment of a dream, indicating also how complexity reduction proceeds by a process resembling Bayesian model selection. PMID- 27471479 TI - Can 28-Month-Old Children Learn Spatial Prepositions Robustly from Pictures? Yes, When Narrative Input Is Provided. AB - The learning of spatial prepositions is assumed to be based on experience in space. In a slow mapping study, we investigated whether 31 German 28-month-old children could robustly learn the German spatial prepositions hinter [behind] and neben [next to] from pictures, and whether a narrative input can compensate for a lack of immediate experience in space. One group of children received pictures with a narrative input as a training to understand spatial prepositions. In two further groups, we controlled (a) for the narrative input by providing unconnected speech during the training and (b) for the learning material by training the children on toys rather than pictures. We assessed children's understanding of spatial prepositions at three different time points: pretest, immediate test, and delayed posttest. Results showed improved word retention in children from the narrative but not the control group receiving unconnected speech. Neither of the trained groups succeeded in generalization to novel referents. Finally, all groups were instructed to deal with untrained material in the test to investigate the robustness of learning across tasks. None of the groups succeeded in this task transfer. PMID- 27471480 TI - Commentary: "An Evaluation of Universal Grammar and the Phonological Mind"-UG Is Still a Viable Hypothesis. AB - Everett (2016b) criticizes The Phonological Mind thesis (Berent, 2013a,b) on logical, methodological and empirical grounds. Most of Everett's concerns are directed toward the hypothesis that the phonological grammar is constrained by universal grammatical (UG) principles. Contrary to Everett's logical challenges, here I show that the UG hypothesis is readily falsifiable, that universality is not inconsistent with innateness (Everett's arguments to the contrary are rooted in a basic confusion of the UG phenotype and the genotype), and that its empirical evaluation does not require a full evolutionary account of language. A detailed analysis of one case study, the syllable hierarchy, presents a specific demonstration that people have knowledge of putatively universal principles that are unattested in their language and these principles are most likely linguistic in nature. Whether Universal Grammar exists remains unknown, but Everett's arguments hardly undermine the viability of this hypothesis. PMID- 27471481 TI - Toward a Better Understanding of the Relationship between Belief in the Paranormal and Statistical Bias: The Potential Role of Schizotypy. AB - The present paper examined relationships between schizotypy (measured by the Oxford-Liverpool Inventory of Feelings and Experience; O-LIFE scale brief), belief in the paranormal (assessed via the Revised Paranormal Belief Scale; RPBS) and proneness to statistical bias (i.e., perception of randomness and susceptibility to conjunction fallacy). Participants were 254 volunteers recruited via convenience sampling. Probabilistic reasoning problems appeared framed within both standard and paranormal contexts. Analysis revealed positive correlations between the Unusual Experience (UnExp) subscale of O-LIFE and paranormal belief measures [RPBS full scale, traditional paranormal beliefs (TPB) and new age philosophy]. Performance on standard problems correlated negatively with UnExp and belief in the paranormal (particularly the TPB dimension of the RPBS). Consideration of specific problem types revealed that perception of randomness associated more strongly with belief in the paranormal than conjunction; both problem types related similarly to UnExp. Structural equation modeling specified that belief in the paranormal mediated the indirect relationship between UnExp and statistical bias. For problems presented in a paranormal context a framing effect occurred. Whilst UnExp correlated positively with conjunction proneness (controlling for perception of randomness), there was no association between UnExp and perception of randomness (controlling for conjunction). PMID- 27471482 TI - Interdependent Mechanisms for Processing Gender and Emotion: The Special Status of Angry Male Faces. AB - While some models of how various attributes of a face are processed have posited that face features, invariant physical cues such as gender or ethnicity as well as variant social cues such as emotion, may be processed independently (e.g., Bruce and Young, 1986), other models suggest a more distributed representation and interdependent processing (e.g., Haxby et al., 2000). Here, we use a contingent adaptation paradigm to investigate if mechanisms for processing the gender and emotion of a face are interdependent and symmetric across the happy angry emotional continuum and regardless of the gender of the face. We simultaneously adapted participants to angry female faces and happy male faces (Experiment 1) or to happy female faces and angry male faces (Experiment 2). In Experiment 1, we found evidence for contingent adaptation, with simultaneous aftereffects in opposite directions: male faces were biased toward angry while female faces were biased toward happy. Interestingly, in the complementary Experiment 2, we did not find evidence for contingent adaptation, with both male and female faces biased toward angry. Our results highlight that evidence for contingent adaptation and the underlying interdependent face processing mechanisms that would allow for contingent adaptation may only be evident for certain combinations of face features. Such limits may be especially important in the case of social cues given how maladaptive it may be to stop responding to threatening information, with male angry faces considered to be the most threatening. The underlying neuronal mechanisms that could account for such asymmetric effects in contingent adaptation remain to be elucidated. PMID- 27471483 TI - From Grouping to Coupling: A New Perceptual Organization in Vision, Psychology, and Biology. AB - In this work, perceptual organization has been studied with the same spirit and phenomenological methods used by Gestalt psychologists. This was accomplished through new conditions that cannot be explained in terms of the classical principles of grouping. Perceptual grouping represents the way through which our visual system builds integrated elements on the basis of the maximal homogeneity among the components of the stimulus pattern. Our results demonstrated the inconsistency of organization by grouping, and more importantly, the inconsistency of the principle of similarity. On the contrary, they suggested the unique role played by the principle of dissimilarity among elements that behaves like an accent or a visual emphasis within a whole. The principle of accentuation was here considered as imparting a directional structure to the elements and to the whole object thus creating new phenomena. The salience of the resulting phenomena reveals the supremacy of dissimilarity in relation to similarity and the fact that it belongs to a further organization dynamics that we called "coupling." In biology, coupling and its principle of accentuation are very strongly related to disruptive camouflage. Moreover, they are source of sexual attraction. They advertise the presence and elicit species identification/communication. In human beings accentuation is needed to show ourselves to others, to understand the way we dress, choose, and create clothes or invent fashion, the way we change our body accentuating several parts and hiding some others, the way we use maquillage. The existence of maquillage itself is derived from the need to accentuate something with the purpose to increase sexual attraction, to exhibit physical strength and beauty, to show or hide social status (e.g., being the king, a warrior, a priest, etc.). Last but not least, accentuation plays a basic role also in making it easier or difficult to read and understand written words. PMID- 27471484 TI - The Relationship between Ethnic Classroom Composition and Turkish-Origin and German Students' Reading Performance and Sense of Belonging. AB - Past research on ethnic composition effects on migrant and ethnic majority students' performance has reported inconclusive results: Some studies have found no relationship between the proportion of migrant students in school and students' performance, some revealed positive effects, whereas others showed negative effects of the proportion of migrant students. Most of the studies did not consider whether an increase in the proportion of migrant students in the classroom has different effects on migrant and ethnic majority students' performance. For this reason, the present study (N = 9215) extends previous research by investigating the cross-level interaction effect of the proportion of Turkish-origin students in classrooms on Turkish-origin and German students' reading performance with data based on the German National Assessment Study 2008/2009 in the school subject German. In addition, we examined the cross-level interaction effect of Turkish-origin students' proportion on sense of belonging to school for Turkish-origin and German students, as sense of belonging has been shown to be an important predictor of well-being and integration. No cross-level interaction effect on performance emerged. Only a small negative main effect of the Turkish-origin students' proportion on all students' performance was found. As predicted, we showed a cross-level interaction on sense of belonging. Only Turkish-origin students' sense of belonging was positively related to the proportion of Turkish-origin students: The more Turkish-origin students there were in a classroom, the higher Turkish-origin students' sense of belonging. German students' sense of belonging was not related to the ethnic classroom composition. Implications of the results in the educational context are discussed. PMID- 27471485 TI - Eye Movements during Art Appreciation by Students Taking a Photo Creation Course. AB - Previous studies have focused on the differences in the art appreciation process between individuals, and indicated that novice viewers of artworks, in comparison to experts, rarely consider the creation process of the artwork or how this may relate to style. However, behavioral changes in individuals after educational interventions have not been examined. Art education researchers claim that technical knowledge and creation experiences help novice viewers to pay attention to technical features of artwork. Therefore, an artistic photo creation course was designed and conducted to help students acquire techniques and procedural knowledge of photo creation. The present study verified whether students' viewing strategies during appreciation of photographs changed after the course. Twenty one students participated in two sessions, viewing the same 12 photographs before and after the course. Based on the analysis of recorded eye movements, the results indicated that the students' perceptual exploration became more active with photographs containing recognizable subjects (i.e., humans and objects), and their global saccades increased when they viewed classic photography, one of the categories of photography covered in the course. Interview data after the course indicated that students became aware of the technical effects in photographs. These results suggest that students' viewing strategies may change following a course, as assessed by behavioral measures of eye movements. Further examination is needed to validate this approach to educational effect measurement. PMID- 27471486 TI - Thou Shalt Be Reproducible! A Technology Perspective. AB - This article elaborates on reproducibility in psychology from a technological viewpoint. Modern open source computational environments are shown and explained that foster reproducibility throughout the whole research life cycle, and to which emerging psychology researchers should be sensitized, are shown and explained. First, data archiving platforms that make datasets publicly available are presented. Second, R is advocated as the data-analytic lingua franca in psychology for achieving reproducible statistical analysis. Third, dynamic report generation environments for writing reproducible manuscripts that integrate text, data analysis, and statistical outputs such as figures and tables in a single document are described. Supplementary materials are provided in order to get the reader started with these technologies. PMID- 27471487 TI - Videogames and Therapy: A Narrative Review of Recent Publication and Application to Treatment. AB - Individuals who play videogames can interact with virtual worlds, resulting in emotional and intellectual connections that have therapeutic implications in the hands of a skilled and informed therapist. There is research available in the literature that suggests that videogames are a viable option in psychotherapy. The present article provides a review of the literature available in the use of videogames in treatment, discusses the importance of disseminating the findings in the literature, and discusses the integration of videogames in treatment. PMID- 27471488 TI - Corrigendum: Impact of Player Injuries on Teams' Mental States, and Subsequent Performances, at the Rugby World Cup 2015. AB - [This corrects the article on p. 807 in vol. 7, PMID: 27375511.]. PMID- 27471490 TI - Ventricular Tract Hemorrhage Following Intracranial Nail Removal: Utility of Real time Endovascular Assistance. AB - Penetrating brain trauma commonly results in occult neurovascular injury. Detailed cerebrovascular imaging can evaluate the relationship of intracranial foreign bodies to major vascular structures, assess for traumatic pseudoaneurysms, and ensure hemostasis during surgical removal. We report a case of a self-inflicted intracranial nail gun injury causing a communicating ventricular tract hemorrhage upon removal, as well as a delayed pseudoaneurysm. Pre- and post-operative vascular imaging, as well as intra-operative endovascular assistance, was critical to successful foreign body removal in this patient. This report demonstrates the utility of endovascular techniques for the assessment and treatment of occult cerebrovascular injuries from intracranial foreign bodies. PMID- 27471489 TI - Comparisons of Portable Sleep Monitors of Different Modalities: Potential as Naturalistic Sleep Recorders. AB - BACKGROUND: Humans spend more than one-fourth of their life sleeping, and sleep quality has been significantly linked to health. However, the objective examination of ambulatory sleep quality remains a challenge, since sleep is a state of unconsciousness, which limits the reliability of self-reports. Therefore, a non-invasive, continuous, and objective method for the recording and analysis of naturalistic sleep is required. OBJECTIVE: Portable sleep recording devices provide a suitable solution for the ambulatory analysis of sleep quality. In this study, the performance of two activity-based sleep monitors (Actiwatch and MTN-210) and a single-channel electroencephalography (EEG)-based sleep monitor (SleepScope) were compared in order to examine their reliability for the assessment of sleep quality. METHODS: Twenty healthy adults were recruited for this study. First, data from daily activity recorded by Actiwatch and MTN-210 were compared to determine whether MTN-210, a more affordable device, could yield data similar to Actiwatch, the de facto standard. In addition, sleep detection ability was examined using data obtained by polysomnography as reference. One simple analysis included comparing the sleep/wake detection ability of Actiwatch, MTN-210, and SleepScope. Furthermore, the fidelity of sleep stage determination was examined using SleepScope in finer time resolution. RESULTS: The results indicate that MTN-210 demonstrates an activity pattern comparable to that of Actiwatch, although their sensitivity preferences were not identical. Moreover, MTN-210 provides assessment of sleep duration comparable to that of the wrist worn Actiwatch when MTN-210 was attached to the body. SleepScope featured superior overall sleep detection performance among the three methods tested. Furthermore, SleepScope was able to provide information regarding sleep architecture, although systemic bias was found. CONCLUSION: The present results suggest that single-channel EEG-based sleep monitors are the superior option for the examination of naturalistic sleep. The current results pave a possible future use for reliable portable sleep assessment methods in an ambulatory rather than a laboratory setting. PMID- 27471491 TI - Bone Marrow Adipose Tissue: A New Player in Cancer Metastasis to Bone. AB - The bone marrow is a favored site for a number of cancers, including the hematological malignancy multiple myeloma, and metastasis of breast and prostate cancer. This specialized microenvironment is highly supportive, not only for tumor growth and survival but also for the development of an associated destructive cancer-induced bone disease. The interactions between tumor cells, osteoclasts and osteoblasts are well documented. By contrast, despite occupying a significant proportion of the bone marrow, the importance of bone marrow adipose tissue is only just emerging. The ability of bone marrow adipocytes to regulate skeletal biology and hematopoiesis, combined with their metabolic activity, endocrine functions, and proximity to tumor cells means that they are ideally placed to impact both tumor growth and bone disease. This review discusses the recent advances in our understanding of how marrow adipose tissue contributes to bone metastasis and cancer-induced bone disease. PMID- 27471492 TI - Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking? AB - Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely "functional," i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/beta-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/beta-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID- 27471495 TI - Growth of Streptococcus mutans in Biofilms Alters Peptide Signaling at the Sub population Level. AB - Streptococcus mutans activates multiple cellular processes in response to the formation of a complex between comX-inducing peptide (XIP) and the ComR transcriptional regulator. Bulk phase and microfluidic experiments previously revealed that ComR-dependent activation of comX is altered by pH and by carbohydrate source. Biofilm formation is a major factor in bacterial survival and virulence in the oral cavity. Here, we sought to determine the response of S. mutans biofilm cells to XIP during different stages of biofilm maturation. Using flow cytometry and confocal microscopy, we showed that exogenous addition of XIP to early biofilms resulted in robust comX activation. However, as the biofilms matured, increasing amounts of XIP were required to activate comX expression. Single-cell analysis demonstrated that the entire population was responding to XIP with activation of comX in early biofilms, but only a sub-population was responding in mature biofilms. The sub-population response of mature biofilms was retained when the cells were dispersed and then treated with XIP. The proportion and intensity of the bi-modal response of mature biofilm cells was altered in mutants lacking the Type II toxins MazF and RelE, or in a strain lacking the (p)ppGpp synthase/hydrolase RelA. Thus, competence signaling is markedly altered in cells growing in mature biofilms, and pathways that control cell death and growth/survival decisions modulate activation of comX expression in these sessile populations. PMID- 27471493 TI - Exercise Regulation of Marrow Adipose Tissue. AB - Despite association with low bone density and skeletal fractures, marrow adipose tissue (MAT) remains poorly understood. The marrow adipocyte originates from the mesenchymal stem cell (MSC) pool that also gives rise to osteoblasts, chondrocytes, and myocytes, among other cell types. To date, the presence of MAT has been attributed to preferential biasing of MSC into the adipocyte rather than osteoblast lineage, thus negatively impacting bone formation. Here, we focus on understanding the physiology of MAT in the setting of exercise, dietary interventions, and pharmacologic agents that alter fat metabolism. The beneficial effect of exercise on musculoskeletal strength is known: exercise induces bone formation, encourages growth of skeletally supportive tissues, inhibits bone resorption, and alters skeletal architecture through direct and indirect effects on a multiplicity of cells involved in skeletal adaptation. MAT is less well studied due to the lack of reproducible quantification techniques. In recent work, osmium-based 3D quantification shows a robust response of MAT to both dietary and exercise intervention in that MAT is elevated in response to high-fat diet and can be suppressed following daily exercise. Exercise-induced bone formation correlates with suppression of MAT, such that exercise effects might be due to either calorie expenditure from this depot or from mechanical biasing of MSC lineage away from fat and toward bone, or a combination thereof. Following treatment with the anti-diabetes drug rosiglitazone - a PPARgamma-agonist known to increase MAT and fracture risk - mice demonstrate a fivefold higher femur MAT volume compared to the controls. In addition to preventing MAT accumulation in control mice, exercise intervention significantly lowers MAT accumulation in rosiglitazone-treated mice. Importantly, exercise induction of trabecular bone volume is unhindered by rosiglitazone. Thus, despite rosiglitazone augmentation of MAT, exercise significantly suppresses MAT volume and induces bone formation. That exercise can both suppress MAT volume and increase bone quantity, notwithstanding the skeletal harm induced by rosiglitazone, underscores exercise as a powerful regulator of bone remodeling, encouraging marrow stem cells toward the osteogenic lineage to fulfill an adaptive need for bone formation. Thus, exercise represents an effective strategy to mitigate the deleterious effects of overeating and iatrogenic etiologies on bone and fat. PMID- 27471494 TI - Microbial Changes during Pregnancy, Birth, and Infancy. AB - Several healthy developmental processes such as pregnancy, fetal development, and infant development include a multitude of physiological changes: weight gain, hormonal, and metabolic changes, as well as immune changes. In this review, we present an additional important factor which both influences and is affected by these physiological processes-the microbiome. We summarize the known changes in microbiota composition at a variety of body sites including gut, vagina, oral cavity, and placenta, throughout pregnancy, fetal development, and early childhood. There is still a lot to be discovered; yet several pieces of research point to the healthy desired microbial changes. Future research is likely to unravel precise roles and mechanisms of the microbiota in gestation; perhaps linking the metabolic, hormonal, and immune changes together. Although some research has started to link microbial dysbiosis and specific microbial populations with unhealthy pregnancy complications, it is important to first understand the context of the natural healthy microbial changes occurring. Until recently the placenta and developing fetus were considered to be germ free, containing no apparent microbiome. We present multiple study results showing distinct microbiota compositions in the placenta and meconium, alluding to early microbial colonization. These results may change dogmas and our overall understanding of the importance and roles of microbiota from the beginning of life. We further review the main factors shaping the infant microbiome-modes of delivery, feeding, weaning, and exposure to antibiotics. Taken together, we are starting to build a broader understanding of healthy vs. abnormal microbial alterations throughout major developmental time-points. PMID- 27471497 TI - Single-Genotype Syntrophy by Rhodopseudomonas palustris Is Not a Strategy to Aid Redox Balance during Anaerobic Degradation of Lignin Monomers. AB - Rhodopseudomonas palustris has emerged as a model microbe for the anaerobic metabolism of p-coumarate, which is an aromatic compound and a primary component of lignin. However, under anaerobic conditions, R. palustris must actively eliminate excess reducing equivalents through a number of known strategies (e.g., CO2 fixation, H2 evolution) to avoid lethal redox imbalance. Others had hypothesized that to ease the burden of this redox imbalance, a clonal population of R. palustris could functionally differentiate into a pseudo-consortium. Within this pseudo-consortium, one sub-population would perform the aromatic moiety degradation into acetate, while the other sub-population would oxidize acetate, resulting in a single-genotype syntrophy through acetate sharing. Here, the objective was to test this hypothesis by utilizing microbial electrochemistry as a research tool with the extracellular-electron-transferring bacterium Geobacter sulfurreducens as a reporter strain replacing the hypothesized acetate-oxidizing sub-population. We used a 2 * 4 experimental design with pure cultures of R. palustris in serum bottles and co-cultures of R. palustris and G. sulfurreducens in bioelectrochemical systems. This experimental design included growth medium with and without bicarbonate to induce non-lethal and lethal redox imbalance conditions, respectively, in R. palustris. Finally, the design also included a mutant strain (NifA(*)) of R. palustris, which constitutively produces H2, to serve both as a positive control for metabolite secretion (H2) to G. sulfurreducens, and as a non-lethal redox control for without bicarbonate conditions. Our results demonstrate that acetate sharing between different sub populations of R. palustris does not occur while degrading p-coumarate under either non-lethal or lethal redox imbalance conditions. This work highlights the strength of microbial electrochemistry as a tool for studying microbial syntrophy. PMID- 27471496 TI - Dendritic Cells: A Double-Edged Sword in Immune Responses during Chagas Disease. AB - Dendritic cells (DCs) are the most important member of the antigen presenting cells group due to their ability to recognize antigen at the infection site and their high specialized antigen internalization capacity. These cells have central role in connecting the innate and adaptive immune responses against Trypanosoma cruzi, the causative agent of Chagas disease. These first line defense cells modulate host immune response depending on type, maturation level, cytokine milieu and DC receptor involved in the interactions with T. cruzi, influencing the development of the disease clinic forms. Here, we present a review of DCs-T. cruzi interactions both in human and murine models, pointing out the parasite ability to manipulate DCs activity for the purpose of evading innate immune response and assuring its own survival and persistence. PMID- 27471498 TI - Protective Vaccination against Blood-Stage Malaria of Plasmodium chabaudi: Differential Gene Expression in the Liver of Balb/c Mice toward the End of Crisis Phase. AB - Protective vaccination induces self-healing of otherwise fatal blood-stage malaria of Plasmodium chabaudi in female Balb/c mice. To trace processes critically involved in self-healing, the liver, an effector against blood-stage malaria, is analyzed for possible changes of its transcriptome in vaccination protected in comparison to non-protected mice toward the end of the crisis phase. Gene expression microarray analyses reveal that vaccination does not affect constitutive expression of mRNA and lincRNA. However, malaria induces significant (p < 0.01) differences in hepatic gene and lincRNA expression in vaccination protected vs. non-vaccinated mice toward the end of crisis phase. In vaccination protected mice, infections induce up-regulations of 276 genes and 40 lincRNAs and down-regulations of 200 genes and 43 lincRNAs, respectively, by >3-fold as compared to the corresponding constitutive expressions. Massive up-regulations, partly by >100-fold, are found for genes as RhD, Add2, Ank1, Ermap, and Slc4a, which encode proteins of erythrocytic surface membranes, and as Gata1 and Gfi1b, which encode transcription factors involved in erythrocytic development. Also, Cldn13 previously predicted to be expressed on erythroblast surfaces is up regulated by >200-fold, though claudins are known as main constituents of tight junctions acting as paracellular barriers between epithelial cells. Other genes are up-regulated by <100- and >10-fold, which can be subgrouped in genes encoding proteins known to be involved in mitosis, in cell cycle regulation, and in DNA repair. Our data suggest that protective vaccination enables the liver to respond to P. chabaudi infections with accelerated regeneration and extramedullary erythropoiesis during crisis, which contributes to survival of otherwise lethal blood-stage malaria. PMID- 27471499 TI - Development of an Efficient Bacterial Consortium for the Potential Remediation of Hydrocarbons from Contaminated Sites. AB - The intrinsic biodegradability of hydrocarbons and the distribution of proficient degrading microorganisms in the environment are very crucial for the implementation of bioremediation practices. Among others, one of the most favorable methods that can enhance the effectiveness of bioremediation of hydrocarbon-contaminated environment is the application of biosurfactant producing microbes. In the present study, the biodegradation capacities of native bacterial consortia toward total petroleum hydrocarbons (TPH) with special emphasis to poly aromatic hydrocarbons were determined. The purpose of the study was to isolate TPH degrading bacterial strains from various petroleum contaminated soil of Assam, India and develop a robust bacterial consortium for bioremediation of crude oil of this native land. From a total of 23 bacterial isolates obtained from three different hydrocarbons contaminated samples five isolates, namely KS2, PG1, PG5, R1, and R2 were selected as efficient crude oil degraders with respect to their growth on crude oil enriched samples. Isolates KS2, PG1, and R2 are biosurfactant producers and PG5, R1 are non-producers. Fourteen different consortia were designed involving both biosurfactant producing and non-producing isolates. Consortium 10, which comprises two Bacillus strains namely, Bacillus pumilus KS2 and B. cereus R2 (identified by 16s rRNA sequencing) has shown the best result in the desired degradation of crude oil. The consortium showed degradation up to 84.15% of TPH after 5 weeks of incubation, as revealed from gravimetric analysis. FTIR (Fourier transform infrared) and GCMS (Gas chromatography-mass spectrometer) analyses were correlated with gravimetric data which reveals that the consortium has removed a wide range of petroleum hydrocarbons in comparison with abiotic control including different aliphatic and aromatic hydrocarbons. PMID- 27471500 TI - cj0371: A Novel Virulence-Associated Gene of Campylobacter jejuni. AB - Campylobacter jejuni is the major cause of human bacterial diarrhea worldwide. Its pathogenic mechanism remains poorly understood. cj0371 is a novel gene that was uncovered using immunoscreening. There have been no previous reports regarding its function. In this study, we constructed an insertion mutant and complement of this gene in C. jejuni and examined changes in virulence. We observed that the cj0371 mutant showed significantly increased invasion and colonization ability. We also investigated the role of cj0371 in motility, chemotaxis, and growth kinetics to further study its function. We found that the cj0371 mutant displays hypermotility, enhanced chemotaxis, and enhanced growth kinetics. In addition, we localized the Cj0371 protein at the poles of C. jejuni by fluorescence microscopy. We present data that collectively significantly proves our hypothesis that cj0371 is a new virulence-associated gene and through the influence of chemotaxis plays a negative role in C. jejuni pathogenicity. PMID- 27471501 TI - Structural Analysis and Biological Toxicity of Aflatoxins B1 and B2 Degradation Products Following Detoxification by Ocimum basilicum and Cassia fistula Aqueous Extracts. AB - This study showed the comparison between Ocimum basilicum and Cassia fistula (leaves and branch) aqueous extracts for their ability to detoxify of aflatoxins B1 and B2 (AFB1; 100 MUg L(-1) and AFB2; 50 MUg L(-1)) by In Vitro assays and decontamination studies. Results indicated that O. basilicum leaves extract was found to be highly significant (P < 0.05) in degrading AFB1 and AFB2, i.e., 90.4 and 88.6%, respectively. However, O. basilicum branch, C. fistula leaves and branch extracts proved to be less efficient in degrading these aflatoxins, under optimized conditions, i.e., pH 8, temperature 30 degrees C and incubation period of 72 h. Moreover the antifungal activity of these plants extracts were also tested. The findings depicted that O. basilicum leaves extract showed maximum growth inhibition of aflatoxigenic isolates, i.e., 82-87% as compared to other tested plants extracts. The structural elucidation of degraded toxin products by LCMS/MS analysis showed that nine degraded products of AFB1 and AFB2 were formed. MS/MS spectra showed that most of the products were formed by the removal of double bond in the terminal furan ring and modification of lactone group indicating less toxicity as compared to parent compounds. Brine shrimps bioassay further confirmed the low toxicity of degraded products, showing that O. basilicum leaves extract can be used as an effective tool for the detoxification of aflatoxins. PMID- 27471502 TI - Genome Analysis of a New Rhodothermaceae Strain Isolated from a Hot Spring. AB - A bacterial strain, designated RA, was isolated from water sample of a hot spring on Langkawi Island of Malaysia using marine agar. Strain RA is an aerophilic and thermophilic microorganism that grows optimally at 50-60 degrees C and is capable of growing in marine broth containing 1-10% (w/v) NaCl. 16S rRNA gene sequence analysis demonstrated that this strain is most closely related (<90% sequence identity) to Rhodothermaceae, which currently comprises of six genera: Rhodothermus (two species), Salinibacter (three species), Salisaeta (one species), Rubricoccus (one species), Rubrivirga (one species), and Longimonas (one species). Notably, analysis of average nucleotide identity (ANI) values indicated that strain RA may represent the first member of a novel genus of Rhodothermaceae. The draft genome of strain RA is 4,616,094 bp with 3630 protein coding gene sequences. Its GC content is 68.3%, which is higher than that of most other genomes of Rhodothermaceae. Strain RA has genes for sulfate permease and arylsulfatase to withstand the high sulfur and sulfate contents of the hot spring. Putative genes encoding proteins involved in adaptation to osmotic stress were identified which encode proteins namely Na(+)/H(+) antiporters, a sodium/solute symporter, a sodium/glutamate symporter, trehalose synthase, malto oligosyltrehalose synthase, choline-sulfatase, potassium uptake proteins (TrkA and TrkH), osmotically inducible protein C, and the K(+) channel histidine kinase KdpD. Furthermore, genome description of strain RA and comparative genome studies in relation to other related genera provide an overview of the uniqueness of this bacterium. PMID- 27471503 TI - T4 Phage Tail Adhesin Gp12 Counteracts LPS-Induced Inflammation In Vivo. AB - Bacteriophages that infect Gram-negative bacteria often bind to the bacterial surface by interaction of specific proteins with lipopolysaccharide (LPS). Short tail fiber proteins (tail adhesin, gp12) mediate adsorption of T4-like bacteriophages to Escherichia coli, binding surface proteins or LPS. Produced as a recombinant protein, gp12 retains its ability to bind LPS. Since LPS is able to exert a major impact on the immune response in animals and in humans, we have tested LPS-binding phage protein gp12 as a potential modulator of the LPS-induced immune response. We have produced tail adhesin gp12 in a bacterial expression system and confirmed its ability to form trimers and to bind LPS in vitro by dynamic light scattering. This product had no negative effect on mammalian cell proliferation in vitro. Further, no harmful effects of this protein were observed in mice. Thus, gp12 was used in combination with LPS in a murine model, and it decreased the inflammatory response to LPS in vivo, as assessed by serum levels of cytokines IL-1 alpha and IL-6 and by histopathological analysis of spleen, liver, kidney and lungs. Thus, in future studies gp12 may be considered as a potential tool for modulating and specifically for counteracting LPS-related physiological effects in vivo. PMID- 27471504 TI - Porcine CD3(+)NKp46(+) Lymphocytes Have NK-Cell Characteristics and Are Present in Increased Frequencies in the Lungs of Influenza-Infected Animals. AB - The CD3(-)NKp46(+) phenotype is frequently used for the identification of natural killer (NK) cells in various mammalian species. Recently, NKp46 expression was analyzed in more detail in swine. It could be shown that besides CD3(-)NKp46(+) lymphocytes, a small but distinct population of CD3(+)NKp46(+) cells exists. In this study, we report low frequencies of CD3(+)NKp46(+) lymphocytes in blood, lymph nodes, and spleen, but increased frequencies in non-lymphatic organs, like liver and lung. Phenotypic analyses showed that the majority of CD3(+)NKp46(+) cells coexpressed the CD8alphabeta heterodimer, while a minor subset expressed the TCR-gammadelta, which was associated with a CD8alphaalpha(+) phenotype. Despite these T-cell associated receptors, the majority of CD3(+)NKp46(+) lymphocytes displayed a NK-related phenotype (CD2(+)CD5(-)CD6( )CD16(+)perforin(+)) and expressed mRNA of NKp30, NKp44, and NKG2D at similar levels as NK cells. Functional tests showed that CD3(+)NKp46(+) lymphocytes produced IFN-gamma and proliferated upon cytokine stimulation to a similar extent as NK cells, but did not respond to the T-cell mitogen, ConA. Likewise, CD3(+)NKp46(+) cells killed K562 cells with an efficiency comparable to NK cells. Cross-linking of NKp46 and CD3 led to degranulation of CD3(+)NKp46(+) cells, indicating functional signaling pathways for both receptors. Additionally, influenza A(H1N1)pdm09-infected pigs had reduced frequencies of CD3(+)NKp46(+) lymphocytes in blood, but increased frequencies in the lung in the early phase of infection. Thus, CD3(+)NKp46(+) cells appear to be involved in the early phase of influenza infections. In summary, we describe a lymphocyte population in swine with a mixed phenotype of NK and T cells, with results so far indicating that this cell population functionally resembles NK cells. PMID- 27471507 TI - Editorial: Plant Silicon Interactions between Organisms and the Implications for Ecosystems. PMID- 27471506 TI - Differential Molecular Responses of Rapeseed Cotyledons to Light and Dark Reveal Metabolic Adaptations toward Autotrophy Establishment. AB - Photosynthesis competent autotrophy is established during the postgerminative stage of plant growth. Among the multiple factors, light plays a decisive role in the switch from heterotrophic to autotrophic growth. Under dark conditions, the rapeseed hypocotyl extends quickly with an apical hook, and the cotyledon is yellow and folded, and maintains high levels of the isocitrate lyase (ICL). By contrast, in the light, the hypocotyl extends slowly, the cotyledon unfolds and turns green, the ICL content changes in parallel with cotyledon greening. To reveal metabolic adaptations during the establishment of postgerminative autotrophy in rapeseed, we conducted comparative proteomic and metabolomic analyses of the cotyledons of seedlings grown under light versus dark conditions. Under both conditions, the increase in proteases, fatty acid beta-oxidation and glyoxylate-cycle related proteins was accompanied by rapid degradation of the stored proteins and lipids with an accumulation of the amino acids. While light condition partially retarded these conversions. Light significantly induced the expression of chlorophyll-binding and photorespiration related proteins, resulting in an increase in reducing-sugars. However, the levels of some chlorophyllide conversion, Calvin-cycle and photorespiration related proteins also accumulated in dark grown cotyledons, implying that the transition from heterotrophy to autotrophy is programmed in the seed rather than induced by light. Various anti-stress systems, e.g., redox related proteins, salicylic acid, proline and chaperones, were employed to decrease oxidative stress, which was mainly derived from lipid oxidation or photorespiration, under both conditions. This study provides a comprehensive understanding of the differential molecular responses of rapeseed cotyledons to light and dark conditions, which will facilitate further study on the complex mechanism underlying the transition from heterotrophy to autotrophy. PMID- 27471508 TI - Conservation Agriculture Practices in Rainfed Uplands of India Improve Maize Based System Productivity and Profitability. AB - Traditional agriculture in rainfed uplands of India has been experiencing low agricultural productivity as the lands suffer from poor soil fertility, susceptibility to water erosion and other external pressures of development and climate change. A shift toward more sustainable cropping systems such as conservation agriculture production systems (CAPSs) may help in maintaining soil quality as well as improving crop production and farmer's net economic benefit. This research assessed the effects over 3 years (2011-2014) of reduced tillage, intercropping, and cover cropping practices customized for maize-based production systems in upland areas of Odisha, India. The study focused on crop yield, system productivity and profitability through maize equivalent yield and dominance analysis. Results showed that maize grain yield did not differ significantly over time or among CAPS treatments while cowpea yield was considered as an additional yield in intercropping systems. Mustard and horsegram grown in plots after maize cowpea intercropping recorded higher grain yields of 25 and 37%, respectively, as compared to those without intercropping. Overall, the full CAPS implementation, i.e., minimum tillage, maize-cowpea intercropping and mustard residue retention had significantly higher system productivity and net benefits than traditional farmer practices, i.e., conventional tillage, sole maize cropping, and no mustard residue retention. The dominance analysis demonstrated increasing benefits of combining conservation practices that exceeded thresholds for farmer adoption. Given the use of familiar crops and technologies and the magnitude of yield and income improvements, these types of CAPS should be acceptable and attractive for smallholder farmers in the area. This in turn should support a move toward sustainable intensification of crop production to meet future household income and nutritional needs. PMID- 27471505 TI - Nutritional and Nanotechnological Modulators of Microglia. AB - Microglia are the essential responders to alimentary, pharmacological, and nanotechnological immunomodulators. These neural cells play multiple roles as surveyors, sculptors, and guardians of essential parts of complex neural circuitries. Microglia can play dual roles in the central nervous system; they can be deleterious and/or protective. The immunomodulatory effects of alimentary components, gut microbiota, and nanotechnological products have been investigated in microglia at the single-cell level and in vivo using intravital imaging approaches, and different biochemical assays. This review highlights some of the emerging questions and topics from studies involving alimentation, microbiota, nanotechnological products, and associated problems in this area of research. Some of the advantages and limitations of in vitro and in vivo models used to study the neuromodulatory effects of these factors, as well as the merits and pitfalls of intravital imaging modalities employed are presented. PMID- 27471509 TI - Group 3 LEA Protein, ZmLEA3, Is Involved in Protection from Low Temperature Stress. AB - Late embryogenesis abundant (LEA) proteins are a family of small highly hydrophilic proteins that accumulate at the onset of seed desiccation and in response to adverse conditions such as drought, salinity, low temperature, or water deficit. In previous studies, we demonstrated that ZmLEA3 could enhance the transgenic tobacco tolerance to osmotic and oxidative stresses. Here, we demonstrated that the transcription of ZmLEA3 in the maize stems could be significantly induced by low temperature and osmotic stresses and by treatment with abscisic acid (ABA) and H2O2. Further study indicated that ZmLEA3 is a single copy gene in the maize genome. The ZmLEA3 protein could protect lactate dehydrogenase (LDH) activity at low temperatures. The overexpression of ZmLEA3 conferred tolerance to low-temperature stress to transgenic tobacco, yeast (GS115) and E. coli (BL21). PMID- 27471510 TI - Modification of Leaf Glucosinolate Contents in Brassica oleracea by Divergent Selection and Effect on Expression of Genes Controlling Glucosinolate Pathway. AB - Modification of the content of secondary metabolites opens the possibility of obtaining vegetables enriched in these compounds related to plant defense and human health. We report the first results of a divergent selection for glucosinolate (GSL) content of the three major GSL in leaves: sinigrin (SIN), glucoiberin (GIB), and glucobrassicin (GBS) in order to develop six kale genotypes (Brassica oleracea var. acephala) with high (HSIN, HIGIB, HGBS) and low (LSIN, LGIB, LGBS) content. The aims were to determine if the three divergent selections were successful in leaves, how each divergent selection affected the content of the same GSLs in flower buds and seeds and to determine which genes would be involved in the modification of the content of the three GSL studied. The content of SIN and GIB after three cycles of divergent selection increased 52.5% and 77.68%, and decreased 51.9% and 45.33%, respectively. The divergent selection for GBS content was only successful and significant for decreasing the concentration, with a reduction of 39.04%. Mass selection is an efficient way of modifying the concentration of individual GSLs. Divergent selections realized in leaves had a side effect in the GSL contents of flower buds and seeds due to the novo synthesis in these organs and/or translocation from leaves. The results obtained suggest that modification in the SIN and GIB concentration by selection is related to the GSL-ALK locus. We suggest that this locus could be related with the indirect response found in the GBS concentration. Meantime, variations in the CYP81F2 gene expression could be the responsible of the variations in GBS content. The genotypes obtained in this study can be used as valuable materials for undertaking basic studies about the biological effects of the major GSLs present in kales. PMID- 27471511 TI - Physiological Mechanisms Underlying the High-Grain Yield and High-Nitrogen Use Efficiency of Elite Rice Varieties under a Low Rate of Nitrogen Application in China. AB - Selecting rice varieties with a high nitrogen (N) use efficiency (NUE) is the best approach to reduce N fertilizer application in rice production and is one of the objectives of the Green Super Rice (GSR) Project in China. However, the performance of elite candidate GSR varieties under low N supply remains unclear. In the present study, differences in the grain yield and NUE of 13 and 14 candidate varieties with two controls were determined at a N rate of 100 kg ha( 1) in field experiments in 2014 and 2015, respectively. The grain yield for all of the rice varieties ranged from 8.67 to 11.09 t ha(-1), except for a japonica rice variety YG29, which had a grain yield of 6.42 t ha(-1). HY549 and YY4949 produced the highest grain yield, reflecting a higher biomass production and harvest index in 2014 and 2015, respectively. Total N uptake at maturity (TNPM) ranged from 144 to 210 kg ha(-1), while the nitrogen use efficiency for grain production (NUEg) ranged from 35.2 to 62.0 kg kg(-1). Both TNPM and NUEg showed a significant quadratic correlation with grain yield, indicating that it is possible to obtain high grain yield and NUEg with the reduction of TNPM. The correlation between N-related parameters and yield-related traits suggests that promoting pre-heading growth could increase TNPM, while high biomass accumulation during the grain filling period and large panicles are important for a higher NUEg. In addition, there were significant and negative correlations between the NUEg and N concentrations in leaf, stem, and grain tissues at maturity. Further improvements in NUEg require a reduction in the stem N concentration but not the leaf N concentration. The daily grain yield was the only parameter that significantly and positively correlated with both TNPMand NUEg. This study determined variations in the grain yield and NUE of elite candidate GSR rice varieties and provided plant traits that could be used as selection criteria in breeding N-efficient rice varieties. PMID- 27471512 TI - Assessment of Potential Risks of Dietary RNAi to a Soil Micro-arthropod, Sinella curviseta Brook (Collembola: Entomobryidae). AB - RNAi-based genetically engineered (GE) crops for the management of insect pests are likely to be commercialized by the end of this decade. Without a workable framework for conducting the ecological risk assessment (ERA) and a standardized ERA protocol, however, the utility of RNAi transgenic crops in pest management remains uncertain. The overall goal of this study is to assess the risks of RNAi based GE crops on a non-target soil micro-arthropod, Sinella curviseta, which could be exposed to plant-protected dsRNAs deposited in crop residues. Based on the preliminary research, we hypothesized that insecticidal dsRNAs targeting at the western corn rootworm, Diabrotica virgifera virgifera, a billion-dollar insect pest, has no adverse impacts on S. curviseta, a soil decomposer. Following a tiered approach, we tested this risk hypothesis using a well-designed dietary RNAi toxicity assay. To create the worst-case scenario, the full-length cDNA of v ATPase subunit A from S. curviseta were cloned and a 400 bp fragment representing the highest sequence similarity between target pest and non-target arthropods was selected as the template to synthesize insecticidal dsRNAs. Specifically, 10-days old S. curviseta larvae were subjected to artificial diets containing v-ATPase A dsRNAs from both D. v. virgifera (dsDVV) and S. curviseta (dsSC), respectively, a dsRNA control, beta-glucuronidase, from plant (dsGUS), and a vehicle control, H2O. The endpoint measurements included gene expression profiles, survival, and life history traits, such as developmental time, fecundity, hatching rate, and body length. Although, S. curviseta larvae developed significantly faster under the treatments of dsDVV and dsSC than the vehicle control, the combined results from both temporal RNAi effect study and dietary RNAi toxicity assay support the risk hypothesis, suggesting that the impacts of ingested arthropod-active dsRNAs on this representative soil decomposer are negligible. PMID- 27471514 TI - Proteomic and Physiological Analyses Reveal Putrescine Responses in Roots of Cucumber Stressed by NaCl. AB - Soil salinity is a major environmental constraint that threatens agricultural productivity. Different strategies have been developed to improve crop salt tolerance, among which the effects of polyamines have been well-reported. To gain a better understanding of the cucumber (Cucumis sativus L.) responses to NaCl and unravel the underlying mechanism of exogenous putrescine (Put) alleviating salt induced damage, comparative proteomic analysis was conducted on cucumber roots treated with NaCl, and/or Put for 7 days. The results showed that exogenous Put restored the root growth inhibited by NaCl. Sixty-two differentially expressed proteins implicated in various biological processes were successfully identified by MALDI-TOF/TOF MS. The four largest categories included proteins involved in defense response (24.2%), protein metabolism (24.2%), carbohydrate metabolism (19.4%), and amino acid metabolism (14.5%). Exogenous Put up-regulated most identified proteins involved in carbohydrate metabolism, implying an enhancement in energy generation. Proteins involved in defense response and protein metabolism were differently regulated by Put, which indicated the roles of Put in stress resistance and proteome rearrangement. Put also increased the abundance of proteins involved in amino acid metabolism. Meanwhile, physiological analysis showed that Put could further up-regulated the levels of free amino acids in salt stressed-roots. In addition, Put also improved endogenous polyamines contents by regulating the transcription levels of key enzymes in polyamine metabolism. Taken together, these results suggest that Put may alleviate NaCl-induced growth inhibition through degradation of misfolded/damaged proteins, activation of stress defense, and the promotion of carbohydrate metabolism to generate more energy. PMID- 27471513 TI - Transcription Factors and Plants Response to Drought Stress: Current Understanding and Future Directions. AB - Increasing vulnerability of plants to a variety of stresses such as drought, salt and extreme temperatures poses a global threat to sustained growth and productivity of major crops. Of these stresses, drought represents a considerable threat to plant growth and development. In view of this, developing staple food cultivars with improved drought tolerance emerges as the most sustainable solution toward improving crop productivity in a scenario of climate change. In parallel, unraveling the genetic architecture and the targeted identification of molecular networks using modern "OMICS" analyses, that can underpin drought tolerance mechanisms, is urgently required. Importantly, integrated studies intending to elucidate complex mechanisms can bridge the gap existing in our current knowledge about drought stress tolerance in plants. It is now well established that drought tolerance is regulated by several genes, including transcription factors (TFs) that enable plants to withstand unfavorable conditions, and these remain potential genomic candidates for their wide application in crop breeding. These TFs represent the key molecular switches orchestrating the regulation of plant developmental processes in response to a variety of stresses. The current review aims to offer a deeper understanding of TFs engaged in regulating plant's response under drought stress and to devise potential strategies to improve plant tolerance against drought. PMID- 27471515 TI - Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction. AB - Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria * ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen. PMID- 27471517 TI - Simplified Assay for Epigenetic Age Estimation in Whole Blood of Adults. AB - Biological age is not always concordant with chronological age and the departures are of interest for understanding how diseases and environmental insults affect tissue function, organismal health, and life expectancy. The best-known biological age biomarker is telomere length, but there are more accurate biomarkers as the recently developed based in epigenetic, transcriptomic, or biochemical changes. The most accurate are the epigenetic biomarkers based on specific changes in DNA methylation referred as DNA methylation age measures (DmAM). Here, we have developed and validated a new DmAM that addresses some limitations of the previously available. The new DmAM includes the study in whole blood (WB) of 8 CpG sites selected as the most informative on a training set of 390 healthy subjects. The 8 CpG DmAM showed better accuracy than other DmAM based in few CpG in an independent validation set of 335 subjects. Results were not significantly influenced by sex, smoking, or variation in blood cell subpopulations. In addition, the new 8 CpG DmAM was amenable to study in a single multiplex reaction done with methylation-sensitive single-nucleotide primer extension (MS-SNuPE), a methodology based on commercially available reagents and run in capillary electrophoresis sequencers. In this way, the high cost of DNA methylation microarrays or of a pyrosequencer, which are needed for alternative DmAM, was avoided. Performance of the DmAM with MS-SNuPE was assessed in a set of 557 donors, showing high call rate (>97%), low CV (<3.3%) and high accuracy (Mean Absolute Deviation = 6.07 years). Therefore, the 8 CpG DmAM is a feasible and accurate tool for assessing the epigenetic component of biological age in blood of adults. PMID- 27471518 TI - Functional characterization of the water-soluble organic carbon of size fractionated aerosol in the southern Mississippi Valley. AB - The chemical content of water-soluble organic carbon (WSOC) as a function of particle size was characterized in Little Rock, Arkansas in winter and spring 2013. The objectives of this study were to (i) compare the functional characteristics of coarse, fine and ultrafine WSOC and (ii) reconcile the sources of WSOC for periods when carbonaceous aerosol was the most abundant particulate component. The WSOC accounted for 5 % of particle mass for particles with deltap > 0.96 MUm and 10 % of particle mass for particles with deltap < 0.96 MUm. Non exchangeable aliphatic (H-C), unsaturated aliphatic (H-C-C=), oxygenated saturated aliphatic (H-C-O), acetalic (O-CH-O) and aromatic (Ar-H) protons were determined by proton nuclear magnetic resonance (1H-NMR). The total non exchangeable organic hydrogen concentrations varied from 4.1 +/- 0.1 nmol m-3 for particles with 1.5 < deltap < 3.0 MUm to 73.9 +/- 12.3 nmol m-3 for particles with deltap < 0.49 MUm. The molar H/C ratios varied from 0.48 +/- 0.05 to 0.92 +/ 0.09, which were comparable to those observed for combustion-related organic aerosol. The R-H was the most abundant group, representing about 45 % of measured total non-exchangeable organic hydrogen concentrations, followed by H-C-O (27 %) and H-C-C= (26 %). Levoglucosan, amines, ammonium and methanesulfonate were identified in NMR fingerprints of fine particles. Sucrose, fructose, glucose, formate and acetate were associated with coarse particles. These qualitative differences of 1H-NMR profiles for different particle sizes indicated the possible contribution of biological aerosols and a mixture of aliphatic and oxygenated compounds from biomass burning and traffic exhausts. The concurrent presence of ammonium and amines also suggested the presence of ammonium/aminium nitrate and sulfate secondary aerosol. The size-dependent origin of WSOC was further corroborated by the increasing delta13C abundance from -26.81 +/- 0.18 0/00 for the smallest particles to -25.93 +/- 0.31 0/00 for the largest particles and the relative distribution of the functional groups as compared to those previously observed for marine, biomass burning and secondary organic aerosol. The latter also allowed for the differentiation of urban combustion-related aerosol and biological particles. The five types of organic hydrogen accounted for the majority of WSOC for particles with deltap > 3.0 MUm and deltap < 0.96 MUm. PMID- 27471516 TI - Organic Acids: The Pools of Fixed Carbon Involved in Redox Regulation and Energy Balance in Higher Plants. AB - Organic acids are synthesized in plants as a result of the incomplete oxidation of photosynthetic products and represent the stored pools of fixed carbon accumulated due to different transient times of conversion of carbon compounds in metabolic pathways. When redox level in the cell increases, e.g., in conditions of active photosynthesis, the tricarboxylic acid (TCA) cycle in mitochondria is transformed to a partial cycle supplying citrate for the synthesis of 2 oxoglutarate and glutamate (citrate valve), while malate is accumulated and participates in the redox balance in different cell compartments (via malate valve). This results in malate and citrate frequently being the most accumulated acids in plants. However, the intensity of reactions linked to the conversion of these compounds can cause preferential accumulation of other organic acids, e.g., fumarate or isocitrate, in higher concentrations than malate and citrate. The secondary reactions, associated with the central metabolic pathways, in particularly with the TCA cycle, result in accumulation of other organic acids that are derived from the intermediates of the cycle. They form the additional pools of fixed carbon and stabilize the TCA cycle. Trans-aconitate is formed from citrate or cis-aconitate, accumulation of hydroxycitrate can be linked to metabolism of 2-oxoglutarate, while 4-hydroxy-2-oxoglutarate can be formed from pyruvate and glyoxylate. Glyoxylate, a product of either glycolate oxidase or isocitrate lyase, can be converted to oxalate. Malonate is accumulated at high concentrations in legume plants. Organic acids play a role in plants in providing redox equilibrium, supporting ionic gradients on membranes, and acidification of the extracellular medium. PMID- 27471519 TI - Cross-Sectional Study of Polybrominated Flame Retardants and Self-Reported Attention Deficit Hyperactivity Disorder in US Youth Aged 12-15 (NHANES 2003 2004). AB - Background. Animal toxicity tests and epidemiological studies suggest that exposure to PBDEs can alter attention behavior, yet few studies have examined their association with diagnosis of attention deficit hyperactivity disorder (ADHD) in adolescents. Methods. Logistic regression was used to examine the cross sectional association between ADHD and lipid and non-lipid adjusted blood serum concentrations of 2',4-tribromodiphenyl ether (BDE-28), 2,2',4,4' tetrabromodiphenylether (BDE-47), 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), 2,2',4,4',5,5'-pentabromodiphenyl ether (BDE-100), 2,2',4,4',5,5' hexabromodiphenyl ether (BDE-153), serum PBDEs, above/below the 75th percentile of serum PBDEs, and tertiles of serum PBDE in 12-15-year-olds (N = 292) using the National Health and Nutrition Examination Survey (NHANES) 2003-2004. Results. The ADHD weighted prevalence was 13.57%. The weighted adjusted odds ratios (AOR) and 95% confidence interval (CI) between ADHD diagnosis and lipid adjusted BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, serum total PBDE, serum PBDE concentrations above the 75th percentile, and serum PBDE concentrations in the second or third tertile were 1.16 (95% CI: 0.51, 2.67), 1.36 (95% CI: 0.72, 2.56), 1.51 (95% CI: 0.70, 3.25), 1.53 (95% CI: 0.73, 3.23), 1.43 (95% CI: 0.57, 3.56), 1.41 (0.71, 2.83), 0.59 (0.10, 3.56), 6.16 (1.19, 31.90), and 0.99 (0.23, 4.29). Conclusions. We observed no association between serum PBDE concentrations and ADHD in US youths. PMID- 27471520 TI - Clinical and immuno-proteomic approach on Lantana camara pollen allergy-a major health hazard. AB - BACKGROUND: The incidence of allergic diseases is increasing gradually and is a global burden affecting the socio-economic quality of life. Identification of allergens is the first step towards paving the way for therapeutic interventions against atopic diseases. Our previous investigation figured out that total pollen load correlated significantly with the rise of respiratory allergy in a subtropical city in India. The most dominant pollen responsible for IgE sensitivity in most patients emerged to be from Lantana camara (LC) an obnoxious weed growing in and around suburban areas of West Bengal. In this study, we identified allergenic components from this shrub using an immunoproteomic approach. METHODS: Determination of dominant pollen species was done using aerobiological sampling during two consecutive years and correlated with hospitalization and skin prick test. Serum was collected from LC positive patients and checked for in vitro allergenicity using ELISA and Histamine assay. Total proteome was profiled in SDS-PAGE, 2D PAGE and immunoblotted to detect IgE binding proteins which were further identified using mass spectrometry. RESULTS: Lantana camara pollen emerged as a significant contributor from the correlation study with hospital admission of the respiratory allergy sufferers and its extract demonstrated an elevated IgE response in ELISA and histamine release assay tests. Five IgE reactive bands/zones were observed in 1D blot which resolved to 12 allergo-reactive spots in the 2D blot. Mass spectrometric analysis identified nine spots that grouped into four diverse proteins. Pathogenesis related Thaumatin-like protein was found to be one of the major allergens in Lantana camara. CONCLUSIONS: This is to our knowledge the first attempt to identify allergens from Lantana camara using a proteomic approach. The allergens identified thereof can be used to prepare hypoallergenic vaccine candidates and design immunotherapy trials against LC pollen and other aeroallergen carriers which are cross-reactive and harbor similar proteins. PMID- 27471522 TI - Root Canal Morphology of Permanent Mandibular Premolars in Iranian Population: A Systematic Review. AB - INTRODUCTION: It is essential for clinicians to have knowledge about root canal configuration, although its morphology varies largely in different ethnicities and even in different individuals within the same ethnic group. The current study reviewed the root canal configuration of root canals in mandibular first and second premolars among Iranian population based on independent epidemiological studies. METHODS AND MATERIALS: A comprehensive search was conducted on retrieved articles related to root canal configuration and prevalence of each types of root canal in mandibular premolars based on Vertucci's classification. An electronic search was conducted in Medline, Scopus and Google Scholar from January 1984 to September 2015. RESULTS: In eleven studies conducted in eight provinces, 1644 mandibular first premolars and 1268 second premolars were investigated. Within mandibular first premolars, 70.9% were Vertucci's type I, followed by 10.4% type III, 7.18% type IV, 5.23% type II and 5.16% type V. In addition, among mandibular second premolars, 82.86% were type I, 6.25 type III, 5.32% type II, 4.27% type IV, and 0.69% type V. CONCLUSION: These results highlight the necessity of searching for additional possible root canals by clinicians. Moreover, these results indicated the ethnical characteristics of Iranian population regarding the morphology of mandibular premolars compared to other populations. PMID- 27471524 TI - Working Length Determination Using Cone-Beam Computed Tomography, Periapical Radiography and Electronic Apex Locator in Teeth with Apical Periodontitis: A Clinical Study. AB - INTRODUCTION: The purpose of this clinical study was to compare the accuracy of working length (WL) determination using cone-beam computed tomography (CBCT), conventional periapical radiographies and electronic apex locator. METHODS AND MATERIALS: This study was conducted during root canal treatment of 19 patients with a total of 30 single-rooted teeth diagnosed with apical periodontitis. After taking the initial parallel periapical radiographies, the initial file was advanced into the canal until the WL was detected by the apex locator. Subsequently, the WL was measured and WL radiographies were taken with the file set in the canal. Afterwards, CBCT images were acquired. These three measurements were tabulated and compared and the data were analyzed using the Friedman test. The level of significance was set at 0.05. RESULTS: The mean values for WL determination by electronic apex locator, periapical radiograph and CBCT images were 22.25, 22.43 and 22.65, respectively which was not statistically significant (P>0.05). CONCLUSION: Working length determination using CBCT images was precise when compared to radiographic method and electronic apex locator. PMID- 27471523 TI - Indexing of Iranian Publications in Well-known Endodontic Textbooks: A Scientometric Analysis. AB - INTRODUCTION: Quoting an article in well-known textbooks is held as a credit for that paper. The numbers of Iranian publications mentioned in endodontic textbooks have increased during recent years. The aim of this investigation was to evaluate the number of Iranian articles quoted in eminent endodontic textbooks. METHODS AND MATERIALS: Three known textbooks (Ingle's Endodontics, Seltzer and Bender's Dental Pulp and Cohen's Pathways of the Pulp) were chosen and all the editions of the textbooks since 2000 were investigated for quoted Iranian publications. Only Iranian authors with affiliations from a domestic university were chosen. All references at the end of each chapter were read by hand searching, and results were noted. The trend and percentage of Iranian publications in different editions of the textbooks were also calculated. The number of citations of these publications in Google Scholar and Scopus databases were also obtained. RESULTS: The number of Iranian publications in all well-known textbooks have notably increased since 2000. The number and percentage of Iranian publications in the latest edition of Cohen's Pathways of the Pulp was higher compared to other textbooks as well as the previous edition of the same text. CONCLUSION: Number and percentage of Iranian publications in the field of endodontics in all three textbooks have remarkably increased since 2000. PMID- 27471525 TI - Antimicrobial Efficacy and Cytocompatibility of Calcium Hypochlorite Solution as a Root Canal Irrigant: An in Vitro Investigation. AB - INTRODUCTION: The purpose of this study was to compare the antimicrobial efficacy of sodium hypochlorite (SH) and calcium hypochlorite (CH) against Enterococcus faecalis (E. faecalis) using quantitative real-time polymerase chain reaction (qPCR) analysis and also to compare their cytocompatibility on L929 murine fibroblasts using Mossman's tetrazolium toxicity (MTT) assay. METHODS AND MATERIALS: A broth micro-dilution susceptibility test was used to determine the minimum inhibitory concentration (MIC) of each irrigant against E. faecalis. Then, the root canals of 50 mature extracted human mandibular premolars were contaminated with E. faecalis and were randomly divided into three groups according to the irrigant used (n=20). Canals were irrigated with SH in group I (n=20) and CH in group II (n=20) at their obtained MIC. In group III (n=10), sterile saline was used. Microbial sampling was performed before and after biomechanical preparation. Quantitative PCR was used to quantify E. faecalis in the root canal samples. For cytocompatibility assessment, L929 murine fibroblasts were exposed to various concentrations of the irrigants. RESULTS: Irrigation with test materials resulted in significant reduction in colony forming units (CFU) in post-instrumentation samples (with the MIC values of SH and CH against E. faecalis being 0.5% and 5%, respectively). However, the reduction in the normal saline group was not significant (P=0.203). In addition, 5% CH was more effective than 0.5% SH (P=0.006) in eliminating E. faecalis. Among the different concentrations of tested irrigants, 0.5% CH and 5% SH showed the least and the most cytotoxicity, respectively (P<0.001). The cytotoxicity of 5% CH and 0.5% SH was similar (P=0.99), and lower than 2.5% SH (P<0.001). CONCLUSION: CH at an MIC of 5% was effective in eliminating E. faecalis in planktonic state and also its biofilm and exhibited comparable cytocompatibility to that of 0.5% SH. PMID- 27471521 TI - CIHR Canadian HIV Trials Network Coinfection and Concurrent Diseases Core Research Group: 2016 Updated Canadian HIV/Hepatitis C Adult Guidelines for Management and Treatment. AB - Background. Hepatitis C virus (HCV) coinfection occurs in 20-30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Purpose. To update national standards for management of HCV-HIV coinfected adults in the Canadian context with evolving evidence for and accessibility of effective and tolerable DAA therapies. The document addresses patient workup and treatment preparation, antiviral recommendations overall and in specific populations, and drug-drug interactions. Methods. A standing working group with HIV-HCV expertise was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published HCV antiviral data and update Canadian HIV-HCV Coinfection Guidelines. Results. The gap in sustained virologic response between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All coinfected individuals should be assessed for interferon free, Direct Acting Antiviral HCV therapy. Regimens vary in content, duration, and success based largely on genotype. Reimbursement restrictions forcing the use of pegylated interferon is not acceptable if optimal patient care is to be provided. Discussion. Recommendations may not supersede individual clinical judgement. Treatment advances published since December 2015 are not considered in this document. PMID- 27471526 TI - Comparison of Tooth Discoloration Induced by Calcium-Enriched Mixture and Mineral Trioxide Aggregate. AB - INTRODUCTION: The aim of this in vitro study was to evaluate the tooth discoloration induced by calcium-enriched mixture (CEM) cement and mineral trioxide aggregate (MTA). METHODS AND MATERIALS: Forty five endodontically treated human maxillary central incisors were selected and divided into three groups (n=15) after removing the coronal 3 mm of the obturating materials. In the MTA group, white MTA plug was placed in pulp chamber and coronal zone of the root canal. In CEM cement group, CEM plug was placed in the tooth in the same manner. In both groups, a wet cotton pellet was placed in the access cavity and the teeth were temporarily sealed. After 24 h the teeth were restored with resin composite. In the negative control group the teeth were also restored with resin composite. The color change in the cervical third of teeth was measured with a colorimeter and was repeated 3 times for each specimen. The teeth were kept in artificial saliva for 6 months. After this period, the color change was measured again. Data were collected by Commission International de I'Eclairage's L*a*b color values, and corresponding Delta E values were calculated. The results were analyzed using the one-way ANOVA and post-hoc Tukey's test with the significance level defined as 0.05. RESULTS: There was no significant differences between CEM group and control group in mean discoloration. The mean tooth discoloration in MTA group was significantly greater than CEM and control groups (P<0.05). CONCLUSION: According to the result of the present study CEM cement did not induce tooth discoloration after six months. Therefore it can be used in vital pulp therapy of esthetically sensitive teeth. PMID- 27471528 TI - Efficacy of ProTaper and Mtwo Retreatment Files in Removal of Gutta-percha and GuttaFlow from Root Canals. AB - INTRODUCTION: The aim of this in vitro study was to compare the efficacy of ProTaper retreatment (ProTaper R) and Mtwo retreatment (Mtwo R) files in removing gutta-percha and GuttaFlow from endodontically treated straight root canals. METHODS AND MATERIALS: The root canals of 60 human mandibular single-rooted premolars were prepared and randomly divided into two groups (n=30). In groups A and B the root canals were obturated using lateral condensation of gutta-percha plus AH 26 and GuttaFlow, respectively. The canal orifices were temporarily sealed and the roots were incubated for 3 months at 37(o)C and 100% humidity. Primary cone-beam computed tomography (CBCT) images were taken after incubation period. The specimens in each group were randomly divided into two subgroups (n=15). ProTaper R files (D1, D2, and D3) were used in groups A1 and B1 while Mtwo R files (25/0.05 and 15/0.05) were used in groups A2 and B2. The time required to extirpate the root filling was also recorded. After retreatment, another CBCT scan was taken at the same position. The volume of remaining filling materials inside the canals was calculated before and after retreatment. The data was analyzed using the two-way ANOVA and independent t-test. RESULTS: The remaining filling materials in the canals treated with ProTaper were less than Mtwo. The remaining volume of GuttaFlow was less than gutta-percha regardless of the system applied. Mtwo R files removed root fillings faster than ProTaper R. CONCLUSION: ProTaper R removed filling material more efficiently compared to Mtwo R which required less time to remove root filling material. PMID- 27471527 TI - The Antibacterial Efficacy of Photo-Activated Disinfection, Chlorhexidine and Sodium Hypochlorite in Infected Root Canals: An in Vitro Study. AB - INTRODUCTION: This study compared the efficacy of light-activated low-power laser, 2% chlorhexidine (CHX) and 2.5% NaOCl in eliminating Enterococcus faecalis (E. faecalis) from the root canal system. METHODS AND MATERIALS: The root canals of 60 maxillary central incisors were contaminated with E. faecalis and then the bacteria were incubated for 24 h. All the root canals were instrumented in a crown-down manner with #4 and 3 Gates-Glidden drills, followed by RaCe rotary files (40/0.10, 35/0.08, and 30/0.06). The samples were randomly assigned to three experimental groups and one control group (n=15). In the control group no intervention was made. In the photo-activated disinfection (PAD) group, laser therapy was undertaken with diode laser beams (with an output power of 100 mW/cm(2)) for 120 sec. For the other two experimental groups, root canals were irrigated either with 5 mL of 2% CHX or 2.5% NaOCl solutions, respectively. The Kruskal-Wallis test was used to compare the CFU values of the bacteria and post hoc Bonferroni test was used for pairwise comparisons. The level of significance was set at 0.05. RESULTS: The inhibition of bacterial growth in all the experimental groups was significantly superior to the control group (P<0.05). There was no significant difference between the effect of PAD and 2% CHX (P=0.05). The effect of 2.5% NaOCl was significantly better than that of the PAD technique (P<0.001). In addition, 2.5% NaOCl was significantly better than 2% CHX (P=0.007). CONCLUSION: Photodynamic therapy was effective in reducing the E. faecalis counts in comparison with the control group, but 2.5% NaOCl solution was the most effective protocol. PMID- 27471529 TI - Effect of Citric Acid and Ethylenediaminetetraacetic Acid on the Surface Morphology of Young and Old Root Dentin. AB - INTRODUCTION: The aim of this in vitro study was to evaluate the effect of 10% citric acid and 17% ethylenediaminetetraacetic acid (EDTA) irrigating solutions on the surface morphology of young and old root dentin by determining the number and diameter of dentinal tubules using scanning electron microscopy (SEM). METHODS AND MATERIALS: Fifty healthy human teeth collected from young (<=30 years) and old (>=60 years) individuals (n=25) were first prepared with a Largo bur #2 to produce smear layer on the root canal surface. Subsequently, the crowns and the root middle and apical thirds were sectioned and removed, and the cervical thirds were sectioned vertically in the buccal-lingual direction into two equal halves. The obtained samples were then immersed in 2.5% sodium hypochlorite for 30 min and randomly separated into two treatment groups for each age group. In each age group, ten samples were selected as controls and did not receive any type of treatment. The rest of the specimens were then rinsed, dried and treated for 4 min with 10% citric acid or 17% EDTA. The samples were then assessed with SEM regarding the number and diameter of dentinal tubules. All data were assessed using Student's t-test. The level of significance was set at 0.05. RESULTS: Regardless of the type of treatment, no significant differences were observed in the number of open tubules between the young and old root dentin (P>0.05). Nonetheless, the diameter of the tubules in the old root dentin was larger when 17% EDTA was used (P<0.05). Both, young and old root dentin did not differ with the 10% citric acid treatment (P>0.05). CONCLUSION: The results showed that 17% EDTA treatment induced a significant demineralization in old root dentin. PMID- 27471530 TI - Antibacterial Activity of MTA Fillapex and AH 26 Root Canal Sealers at Different Time Intervals. AB - INTRODUCTION: The main goal of endodontic treatment is elimination of bacteria and their by-products from infected root canals. This study compared the antibacterial effect of two different sealers, AH 26 and MTA Fillapex, on 4 microorganisms 24, 48 and 72 h and 7 days after mixing. METHODS AND MATERIALS: The microorganisms used in this study consisted of Lactobacillus acidophilus (ATCC 4356), Lactobacillus casei (ATCC 39392), Staphylococcus aureus (ATCC 25923) and Enterococcus faecalis (ATCC 29212). This test is based on the growth of bacteria and turbidity measurement technique using a spectrophotometer, and direct contact was conducted. Multiple comparisons were carried out using repeated-measures ANOVA followed by Tukey's test and student's t-test. The level of significance was set at 0.05. RESULTS: The antibacterial activity in the indirect technique was more than the technique with both sealers. In the direct technique the antibacterial activity on all microorganisms were lower for MTA Fillapex sealer. In the indirect technique, both sealers exhibited similar antibacterial properties. CONCLUSION: The antibacterial effect of MTA Fillapex sealer was significantly less than that of AH 26 sealer in the direct technique. The antibacterial effects of both sealers were similar in the indirect technique. PMID- 27471531 TI - Comparison of Microleakage of MTA and CEM Cement Apical Plugs in Three Different Media. AB - INTRODUCTION: Microleakage is of the causes of endodontic treatment failure. The aim of this in vitro study, was to compare the microleakage of mineral trioxide aggregate (MTA) and calcium-enriched mixture (CEM) cement apical plugs in three environments. METHODS AND MATERIALS: A total of 130 human extracted single rooted teeth were collected. After decoronation, preparation of the root canal space and simulation of open apices, 5 teeth were selected as positive and negative control groups and the rest of the samples were randomly divided into two groups (MTA plug and CEM cement plug) and each group was divided into 3 subgroups (dry, contaminated with saliva and contaminated with blood). In each group apical plug was placed into the canal. After full setting of the apical plug, microleakage of the samples were evaluated using fluid filtration method and the data were analyzed using two-way analysis of variance. RESULTS: In dry and saliva contaminated environments, the leakage of MTA samples were 40.906+/-2.081 and 39.608+/-2.081, respectively which was significantly more than that of CEM cement samples (26.977+/-2.081 and 27.000+/-2.081, respectively). However, in blood contaminated environments, the amount of leakage in MTA group (21.640+/-2.081) was significantly lower than CEM cement group (44.358+/-2.081). CONCLUSION: According to the results of this study, in dry and saliva-contaminated conditions CEM cement provides significantly better seal in comparison to MTA. PMID- 27471532 TI - Effect of Amperage and Field of View on Detection of Vertical Root Fracture in Teeth with Intracanal Posts. AB - INTRODUCTION: This study sought to assess the effects of amperage (mA) and field of view (FOV) on intracanal metal post artifacts and the diagnostic parameters for detection of vertical root fracture (VRF) in teeth with intracanal posts. METHODS AND MATERIALS: In this diagnostic study, 80 human single-canal teeth were evaluated by cone-beam computed tomography (CBCT). Nickel chrome cast posts were placed into root canals after root canal therapy and canal preparation. In the test group, fracture was induced by an instron machine while no fracture was induced in the control group. Deterministic and probabilistic sensitivity and specificity values at different exposure settings were statistically analyzed using the one-way ANOVA and pairwise comparisons were performed by Tukey's test. RESULTS: Significant differences were found between the two groups in terms of deterministic (P<0.0001) and probabilistic (P<0.013) sensitivity and deterministic (P<0.037) and probabilistic (P<0.0001) specificity at different FOV and mA combinations. CONCLUSION: A smaller FOV and lower mA should be preferably used for detection of VRFs in teeth with intracanal posts. PMID- 27471533 TI - A Clinical Update on the Different Methods to Decrease the Occurrence of Missed Root Canals. AB - One of the main causes of endodontic treatment failure is the clinician's inability to localize all the root canals. Due to the complex anatomy of the root canal system, missed canals are not uncommon. There are several strategies to decrease the possibility of missed root canals starting with good pre-operative radiographies. In order to overcome the limitations of conventional radiographies, cone-beam computed tomography (CBCT) can be considered. A correct access cavity preparation is of pivotal importance in localizing the orifices of the root canals. Furthermore, ultrasonics are very important devices to find missed canals. Increasing magnification and illumination enhance the possibility of finding all root canals during root canal treatment. The purpose of the present paper was to review all of the above techniques and devices. PMID- 27471535 TI - Efficacy of a Novel Rotary System in Reduction of Intracanal Bacteria: An in Vitro Study. AB - INTRODUCTION: This in vitro study aimed to assess the effectiveness of a single file rotary system (OneShape) in reduction of intracanal bacteria. METHODS AND MATERIALS: Eighty one single-rooted mandibular first premolars with single canals were used. Six samples were selected as aseptic control group. Seventy five remaining specimens were infected by Enterococcus faecalis and incubated for 72 h at 37( degrees )C. Then they were randomly divided into three groups (n=25). In each group, cleaning and shaping procedures were done using either two conventional rotary systems (ProTaper and iRace), or the single-file system (OneShape). Microbial samples from the intracanal environment were taken by paper points in two steps, before and after instrumentation. Then, they were diluted and plated in blood agar. In order to compare bacterial reduction and turbidity, the Kruskal-Wallis test was used followed by the Chi-Square and Mann-Whitney tests for pairwise comparison. The level of significance was set at 0.05. RESULTS: The control group didn't show any bacterial growth. The pre- and post instrumentation samples were significantly different between three groups (P=0.02). Hence, there was no significant differences between turbidity of samples (P>0.05). CONCLUSION: OneShape system is efficient in bacterial reduction. In this regard ProTaper is the most effective system in intracanal bacterial reduction followed by iRaCe and OneShape, respectively. PMID- 27471534 TI - Bacterial Leakage of Mineral Trioxide Aggregate, Calcium-Enriched Mixture and Biodentine as Furcation Perforation Repair Materials in Primary Molars. AB - INTRODUCTION: Adequate seal of iatrogenically perforated area within the root canal system can improve the long term treatment prognosis. This in vitro study evaluated the sealing ability of mineral trioxide aggregate (MTA), calcium enriched mixture (CEM) cement and Biodentine in repair of furcation perforation in primary molars. METHODS AND MATERIALS: A total of 61 freshly extracted primary mandibular second molars were randomly divided into three groups (n=17) and 10 teeth were put in negative (without perforation, n=5) and positive (perforated without repair, n=5) control groups. Turbidity was used as the criteria of bacterial leakage, when detected in the model of dual-chamber leakage. Data were analyzed using the Chi-Square and Kaplan-Meier survival analysis in SPSS software. The level of significance was set at 0.05. RESULTS: All positive samples showed turbidity, whereas none of the negative samples allowed bacterial leakage. There was no significant difference between the number of turbidity samples in repaired teeth with all test materials (P=0.13). No significant difference was also detected in the mean survival time (P>0.05). CONCLUSION: CEM cement and Biodentine showed promising results as perforation repair materials and can be recommended as suitable alternatives of MTA for repair of furcation perforation of primary molars. PMID- 27471536 TI - In Vitro Evaluation of Different Solvents for Retrieval of Mineral Trioxide Aggregate and Calcium-Enriched Mixture. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of different solvents; carbonic acid (H2CO3), hydrochloric acid (HCl), chlorhexidine (CHX) and sodium hypochlorite (NaOCl) on the surface hardness of mineral trioxide aggregate (MTA) and calcium-enriched mixture (CEM) cement. METHODS AND MATERIALS: Plexiglass molds were prepared and filled with Angelus MTA or CEM cement and then exposed to 2% carbonic acid, 37% hydrochloric acid, 2% chlorhexidine, 5.25% sodium hypochlorite and normal saline at intervals of 1 and 21 days, respectively (n=4). Surface microhardness of all specimens was analyzed by a universal testing machine and an electron microscope for some selected samples. Data were analyzed using the three-way ANOVA. Subgroup analysis was performed by Student's t-test, One-way ANOVA and Tukey's tests. The level of significance was set at 0.05. RESULTS: On the first day, all solvents and on 21(st) day HCl, and H2CO3 were more effective in reducing the microhardness of MTA compared to CEM cement (P<0.05). CONCLUSION: The two experimental cements were differently affected by the solvents at specific time intervals. The solvents were more effective on MTA. PMID- 27471537 TI - Shaping Ability of Single-file Systems with Different Movements: A Micro-computed Tomographic Study. AB - INTRODUCTION: This study aimed to perform a rigorous sample standardization and also evaluate the preparation of mesiobuccal (MB) root canals of maxillary molars with severe curvatures using two single-file engine-driven systems (WaveOne with reciprocating motion and OneShape with rotary movement), using micro-computed tomography (micro-CT). METHODS AND MATERIALS: Ten MB roots with single canals were included, uniformly distributed into two groups (n=5). The samples were prepared with a WaveOne or OneShape files. The shaping ability and amount of canal transportation were assessed by a comparison of the pre- and post instrumentation micro-CT scans. The Kolmogorov-Smirnov and t-tests were used for statistical analysis. The level of significance was set at 0.05. RESULTS: Instrumentation of canals increased their surface area and volume. Canal transportation occurred in coronal, middle and apical thirds and no statistical difference was observed between the two systems (P>0.05). In apical third, significant differences were found between groups in canal roundness (in 3 mm level) and perimeter (in 3 and 4 mm levels) (P<0.05). CONCLUSION: The WaveOne and One Shape single-file systems were able to shape curved root canals, producing minor changes in the canal curvature. PMID- 27471538 TI - Root Canal Treatment of a Maxillary Second Premolar with Two Palatal Root Canals: A Case Report. AB - Accurate diagnosis of the root canal morphology and anatomy is essential for thorough shaping and cleaning of the entire root canal system and consequent successful treatment. This report describes a case of maxillary second premolar with two roots and three root canals (two mesial and distal palatal canals). The case report underlines the importance of complete knowledge about root canal morphology and possible variations, coupled with clinical and radiographic examination in order to increase the ability of clinicians to treat difficult cases. PMID- 27471539 TI - Removal of a Broken Instrument from a Tooth with Apical Periodontitis Using a Novel Approach. AB - Instrument breakage during treatment can lead to serious complications and carries the risk of treatment failure. When a file breaks in the canal, bypassing or removal can be difficult and the long-term prognosis of the tooth may be compromised. Sometimes surgery may be indicated for removal of the broken segment. Often some part of the root cannot be cleaned because of blockage by the broken file. This report presents a specific approach in non- surgical removal of a broken file from a maxillary lateral incisor with a buccal sinus tract and a broken instrument in the apical third which was partially over extended into the periapical lesion. The broken file was accessed through the sinus tract and pushed into the canal. The canal was cleaned and shaped, filled with mineral trioxide aggregate (MTA). CONCLUSION: A sinus tract can be a specific path to reach the root tip and get access to remove the foreign materials pushed beyond the root canal space. PMID- 27471431 TI - Measurement of the [Formula: see text] production cross section in the all-jets final state in pp collisions at [Formula: see text][Formula: see text]. AB - The cross section for [Formula: see text] production in the all-jets final state is measured in pp collisions at a centre-of-mass energy of 8 [Formula: see text] at the LHC with the CMS detector, in data corresponding to an integrated luminosity of 18.4 [Formula: see text]. The inclusive cross section is found to be [Formula: see text] [Formula: see text]. The normalized differential cross sections are measured as a function of the top quark transverse momenta, [Formula: see text], and compared to predictions from quantum chromodynamics. The results are reported at detector, parton, and particle levels. In all cases, the measured top quark [Formula: see text] spectra are significantly softer than theoretical predictions. PMID- 27471540 TI - Conservative Management of Unset Mineral Trioxide Aggregate Root-End Filling: A Case Report. AB - This case report presents conservative management of unset mineral trioxide aggregate (MTA) after being placed as a root-end filling material following periapical surgery. Periapical surgery was indicated for a maxillary lateral incisor of a 15-year-old male due to persistent exudate and a large periapical lesion. During surgery Angelus MTA was placed as root-end filling. The next session it was noticed that MTA had failed to completely set. In an orthograde approach, calcium-enriched mixture (CEM) cement was used to obturate the root canal space. The patient was followed up for 27 months and did not exhibit any clinical signs and symptoms. Radiographic images showed complete healing of the lesion. PMID- 27471541 TI - Single-Visit Pulp Revascularization of a Nonvital Immature Permanent Tooth Using Biodentine. AB - An 11-year-old female patient was referred with a chief complaint of pain in the right mandibular second premolar. Clinical and radiographic examinations showed secondary caries under an old composite restoration, a negative response to a pulp test and an immature root with an open apex. After root canal cleaning and shaping, bleeding was invoked in the canal up to 2 mm short of the cemento-enamel junction (CEJ). After 10 min to allow clotting at this level, a plug of Biodentine was placed over the blood clot and the tooth was temporized with glass ionomer cement. At the next visit, the tooth was free of symptoms and a permanent filling was placed. Clinical and radiographic examinations during a two-year follow-up showed complete root maturation and intact supporting soft tissues without sinus tract, pain or swelling. CONCLUSION: The use of Biodentine in a single-visit apexification protocol to treat an immature permanent tooth with necrotic pulp can create a suitable environment for revascularization, resulting in the completion of root maturation. PMID- 27471543 TI - Development and validation of a stock addiction inventory (SAI). AB - BACKGROUND: Investing in financial markets is promoted and protected by the government as an essential economic activity, but can turn into a gambling addiction problem. Until now, few scales have widely been used to identify gambling addicts in financial markets. This study aimed to develop a self-rating scale to distinguish them. In addition, the reliability and validity of the stock addiction inventory (SAI) were demonstrated. METHODS: A set of questionnaires, including the SAI, south oaks gambling screen (SOGS), and DSM-5 diagnostic criteria, for gambling disorder was completed by 1005 participants. Factor analysis, internal consistency testing, t tests, analysis of variance, and partial correlation analysis were conducted to verify the reliability and validity of SAI. RESULTS: The factor analysis results showed the final SAI consisting of two factors and nine items. The internal consistency and concurrent validity of SAI were verified. The Cronbach's alpha for the total scale was 0.892, and the SAI and its factors were significantly correlated with SOGS. CONCLUSIONS: This study developed a specific scale for financial market investments or trading; this scale proved to be reliable and valid. Our scale expands the understanding of gambling addiction in financial markets and provides a diagnostic reference. PMID- 27471544 TI - In situ hybridization for the detection of rust fungi in paraffin embedded plant tissue sections. AB - BACKGROUND: Rust fungi are obligate pathogens with multiple life stages often including different spore types and multiple plant hosts. While individual rust pathogens are often associated with specific plants, a wide range of plant species are infected with rust fungi. To study the interactions between these important pathogenic fungi and their host plants, one must be able to differentiate fungal tissue from plant tissue. This can be accomplished using the In situ hybridization (ISH) protocol described here. RESULTS: To validate reproducibility using the ISH protocol, samples of Chrysanthemum * morifolium infected with Puccinia horiana, Gladiolus * hortulanus infected with Uromyces transversalis and Glycine max infected with Phakopsora pachyrhizi were tested alongside uninfected leaf tissue samples. The results of these tests show that this technique clearly distinguishes between rust pathogens and their respective host plant tissues. CONCLUSIONS: This ISH protocol is applicable to rust fungi and potentially other plant pathogenic fungi as well. It has been shown here that this protocol can be applied to pathogens from different genera of rust fungi with no background staining of plant tissue. We encourage the use of this protocol for the study of plant pathogenic fungi in paraffin embedded sections of host plant tissue. PMID- 27471542 TI - Sex-Dependent Effects of Dietary Genistein on Echocardiographic Profile and Cardiac GLUT4 Signaling in Mice. AB - This study aimed to determine whether genistein diet resulted in changes in cardiac function, using echocardiography, and expression of key proteins involved in glucose uptake by the myocardium. Intact male and female C57BL/6J mice (aged 4 6 weeks) were fed either 600 mg genistein/kg diet (600 G) or 0 mg genistein/kg diet (0 G) for 4 weeks. Echocardiography data revealed sex-dependent differences in the absence of genistein: compared to females, hearts from males exhibited increased systolic left ventricle internal dimension (LVIDs), producing a decrease in function, expressed as fractional shortening (FS). Genistein diet also induced echocardiographic changes in function: in female hearts, 600G induced a 1.5-fold (P < 0.05) increase in LVIDs, resulting in a significant decrease in FS and whole heart surface area when compared to controls (fed 0 G). Genistein diet increased cardiac GLUT4 protein expression in both males (1.51 fold, P < 0.05) and females (1.76-fold, P < 0.05). However, no effects on the expression of notable intracellular signaling glucose uptake-regulated proteins were observed. Our data indicate that consumption of genistein diet for 4 weeks induces echocardiographic changes in indices of systolic function in females and has beneficial effects on cardiac GLUT4 protein expression in both males and females. PMID- 27471546 TI - Erratum to: Circular sequence comparison: algorithms and applications. AB - [This corrects the article DOI: 10.1186/s13015-016-0076-6.]. PMID- 27471547 TI - Evaluation of the accuracy of diagnostic scales for a syndrome in Chinese medicine in the absence of a gold standard. AB - BACKGROUND: The concept of syndromes (zhengs) is unique to Chinese medicine (CM) and difficult to measure. Expert consensus is used as a gold standard to identify zhengs and evaluate the accuracy of existing diagnostic scales for zhengs. But, the use of expert consensus as a gold standard is problematic because the diagnosis of zhengs by expert consensus is not 100 % accurate. This study aimed to evaluate the accuracy of standardized diagnostic scales for a syndrome zhengs in the absence of a gold standard, with application to internal wind (nei feng) syndrome in ischemic stroke patients. METHODS: A total of 204 participants (age 41-84 years) with ischemic stroke were assessed by the stroke syndrome differentiation diagnostic criterion (SSDC), ischemic stroke TCM syndrome diagnostic scale (ISDS), and expert syndrome differentiation (ESD). The diagnostic tests and data collection process were conducted over a 10-month period (February 2008 to November 2008) in 10 hospitals across nine cities in China. The Bayesian method was used to estimate the accuracy of the SSDC, ISDS, and ESD. RESULTS: For internal wind syndrome, the estimated sensitivities and specificities of the SSDC, ISDS, and ESD without use of a gold standard were respectively: [Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]; and [Formula: see text], [Formula: see text]. CONCLUSION: After adjusting for imperfect gold standard bias, we found that both the sensitivity and specificity of the ISDS were higher than those of the SSDC for diagnosis of internal wind syndrome in ischemic stroke patients. PMID- 27471548 TI - Comments on the article: "Syrian refugees in Lebanon: the search for universal health coverage". AB - This letter intends to clarify information and misconceptions found in the article "Syrian refugees in Lebanon: the search for universal health coverage" which was published June 1st, 2016, and to challenge the core notion of fragmentation as presented by the authors. It also highlights the fact that the article does not recognize the severe shortage in refugees health financing and unmet promises by the international community, and calls for immediate action and far greater support from that community to address the needs of refugees in Lebanon. PMID- 27471545 TI - Biological Computation Indexes of Brain Oscillations in Unattended Facial Expression Processing Based on Event-Related Synchronization/Desynchronization. AB - Estimation of human emotions from Electroencephalogram (EEG) signals plays a vital role in affective Brain Computer Interface (BCI). The present study investigated the different event-related synchronization (ERS) and event-related desynchronization (ERD) of typical brain oscillations in processing Facial Expressions under nonattentional condition. The results show that the lower frequency bands are mainly used to update Facial Expressions and distinguish the deviant stimuli from the standard ones, whereas the higher-frequency bands are relevant to automatically processing different Facial Expressions. Accordingly, we set up the relations between each brain oscillation and processing unattended Facial Expressions by the measures of ERD and ERS. This research first reveals the contributions of each frequency band for comprehension of Facial Expressions in preattentive stage. It also evidences that participants have emotional experience under nonattentional condition. Therefore, the user's emotional state under nonattentional condition can be recognized in real time by the ERD/ERS computation indexes of different frequency bands of brain oscillations, which can be used in affective BCI to provide the user with more natural and friendly ways. PMID- 27471549 TI - Genome sequence of OXA-23 producing Acinetobacter baumannii IHIT7853, a carbapenem-resistant strain from a cat belonging to international clone IC1. AB - BACKGROUND: Multidrug resistance in Acinetobacter baumannii has dramatically increased in recent years worldwide. Thus, last-line antibiotics like carbapenems are increasingly being used which in turn further augments selection pressure for resistant strains. Resistance to carbapenems in A. baumannii is frequently mediated by carbapenemases, particularly OXA-23 and OXA-58. Carbapenemase producing bacteria are mainly described in human patients and the intestinal tract represents a common source for such pathogens. In this study, we sequenced and analyzed the genome of A. baumannii IHIT7853, a carbapenem-resistant, OXA-23 producing strain isolated from cystitis in a cat in 2000 in Germany. RESULTS: Phylogenetic analysis revealed that IHIT7853 belonged to the globally distributed international clone IC1 and MLST type ST1/ST231 (Pasteur/Oxford MLST scheme). A phylogenetic tree based on the maximum common genome of 18 A. baumannii isolates placed IHIT7853 close to human clinical isolates, such as the multidrug-resistant (MDR) outbreak strain AYE that was isolated from a patient with pneumonia and cystitis in 2001 in France. The OXA-23 plasmid sequence could be determined as 53,995 bp in size, possessing resistance genes strA and strB in addition to bla OXA-23. CONCLUSIONS: The analysis of the genome of IHIT7853 reveals that companion animals carry MDR A. baumannii that resemble relevant clonal lineages involved in severe infections in humans. As urinary tract infections are often caused by bacteria that reside in the intestinal tract, future studies should unveil, if the animal gut serves as a source for MDR A. baumannii. PMID- 27471551 TI - Virus-like attachment sites as structural landmarks of plants retrotransposons. AB - BACKGROUND: The genomic data available nowadays has enabled the study of repetitive sequences and their relationship to viruses. Among them, long terminal repeat retrotransposons (LTR-RTs) are the largest component of most plant genomes, the Gypsy and Copia superfamilies being the most common. Recently it has been found that Del lineage, an LTR-RT of Gypsy superfamily, has putative virus like attachment (vl-att) sites. This signature, originally described for retroviruses, is recognized by retroviral integrase conferring specificity to the integration process. RESULTS: Here we retrieved 26,092 putative complete LTR-RTs from 10 lineages found in 10 fully sequenced angiosperm genomes and found putative vl-att sites that are a conserved structural landmark across these genomes. Furthermore, we reveal that each plant genome has a distinguishable LTR RT lineage amplification pattern that could be related to the vl-att sites diversity. We used these patterns to generate a specific quick-response (QR) code for each genome that could be used as a barcode of identification of plants in the future. CONCLUSIONS: The universal distribution of vl-att sites represents a new structural feature common to plant LTR-RTs and retroviruses. This is an important finding that expands the information about the structural similarity between LTR-RT and retroviruses. We speculate that the sequence diversity of vl att sites could be important for the life cycle of retrotransposons, as it was shown for retroviruses. All the structural vl-att site signatures are strong candidates for further functional studies. Moreover, this is the first identification of specific LTR-RT content and their amplification patterns in a large dataset of LTR-RT lineages and angiosperm genomes. These distribution patterns could be used in the future with biotechnological identification purposes. PMID- 27471550 TI - Interactions between kidney disease and diabetes: dangerous liaisons. AB - BACKGROUND: Type 2 diabetes mellitus (DM) globally affects 18-20 % of adults over the age of 65 years. Diabetic kidney disease (DKD) is one of the most frequent and dangerous complications of DM2, affecting about one-third of the patients with DM2. In addition to the pancreas, adipocytes, liver, and intestines, the kidneys also play an important role in glycemic control, particularly due to renal contribution to gluconeogenesis and tubular reabsorption of glucose. METHODS: In this review article, based on a report of discussions from an interdisciplinary group of experts in the areas of endocrinology, diabetology and nephrology, we detail the relationship between diabetes and kidney disease, addressing the care in the diagnosis, the difficulties in achieving glycemic control and possible treatments that can be applied according to the different degrees of impairment. DISCUSSION: Glucose homeostasis is extremely altered in patients with DKD, who are exposed to a high risk of both hyperglycemia and hypoglycemia. Both high and low glycemic levels are associated with increased morbidity and shortened survival in this group of patients. Factors that are associated with an increased risk of hypoglycemia in DKD patients include decreased renal gluconeogenesis, deranged metabolic pathways (including altered metabolism of medications) and decreased insulin clearance. On the other hand, decrease glucose filtration and excretion, and inflammation-induce insulin resistance are predisposing factors to hyperglycemic episodes. CONCLUSION: Appropriate glycaemic monitoring and control tailored for diabetic patients is required to avoid hypoglycaemia and other glycaemic disarrays in patients with DM2 and kidney disease. Understanding the renal physiology and pathophysiology of DKD has become essential to all specialties treating diabetic patients. Disseminating this knowledge and detailing the evidence will be important to initiate breakthrough research and to encourage proper treatment of this group of patients. PMID- 27471552 TI - The Expression Levels of XLF and Mutant P53 Are Inversely Correlated in Head and Neck Cancer Cells. AB - XRCC4-like factor (XLF), also known as Cernunnos, is a protein encoded by the human NHEJ1 gene and an important repair factor for DNA double-strand breaks. In this study, we have found that XLF is over-expressed in HPV(+) versus HPV(-) head and neck squamous cell carcinoma (HNSCC) and significantly down-regulated in the HNSCC cell lines expressing high level of mutant p53 protein versus those cell lines harboring wild-type TP53 gene with low p53 protein expression. We have also demonstrated that Werner syndrome protein (WRN), a member of the NHEJ repair pathway, binds to both mutant p53 protein and NHEJ1 gene promoter, and siRNA knockdown of WRN leads to the inhibition of XLF expression in the HNSCC cells. Collectively, these findings suggest that WRN and p53 are involved in the regulation of XLF expression and the activity of WRN might be affected by mutant p53 protein in the HNSCC cells with aberrant TP53 gene mutations, due to the interaction of mutant p53 with WRN. As a result, the expression of XLF in these cancer cells is significantly suppressed. Our study also suggests that XLF is over-expressed in HPV(+) HNSCC with low expression of wild type p53, and might serve as a potential biomarker for HPV(+) HNSCC. Further studies are warranted to investigate the mechanisms underlying the interactive role of WRN and XLF in NHEJ repair pathway. PMID- 27471553 TI - Anti-ALK Antibodies in Patients with ALK-Positive Malignancies Not Expressing NPM ALK. AB - Patients with Nucleophosmin (NPM)- Anaplastic Lymphoma Kinase (ALK) fusion positive Anaplastic Large Cell Lymphoma produce autoantibodies against ALK indicative of an immune response against epitopes of the chimeric fusion protein. We asked whether ALK-expression in other malignancies induces specific antibodies. Antibodies against ALK were detected in sera of one of 50 analysed ALK-expressing neuroblastoma patients, 13 of 21 ALK positive non-small cell lung carcinoma (NSCLC) patients, 13 of 22 ALK translocation-positive, but NPM-ALK negative lymphoma patients and one of one ALK-positive rhabdomyosarcoma patient, but not in 20 healthy adults. These data suggest that boosting a pre-existent anti-ALK immune response may be more feasible for patients with ALK-positive NSCLC, lymphomas and rhabdomyosarcomas than for tumours expressing wild-type ALK. PMID- 27471554 TI - Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2. AB - Cervical cancer is a second leading cancer death in women world-wide, with most cases in less developed countries. Notch signaling is highly conserved with its involvement in many cancers. In the present study, we established stable cervical cell lines with Notch activation and inactivation and found that Notch activation played a suppressive role in cervical cancer cells. Meanwhile, the transient overexpression of the active intracellular domain of all four Notch receptors (ICN1, 2, 3, and 4) also induced the suppression of cervical cancer Hela cell growth. ICN1 also induced cell cycle arrest at phase G1. Notch1 signaling activation affected the expression of serial genes, especially the genes associated with cAMP signaling, with an increase of genes like THBS1, VCL, p63, c Myc and SCG2, a decrease of genes like NR4A2, PCK2 and BCL-2. Particularly, The nuclear receptor NR4A2 was observed to induce cell proliferation via MTT assay and reduce cell apoptosis via FACS assay. Furthermore, NR4A2's activation could reverse ICN1-induced suppression of cell growth while erasing ICN1-induced increase of tumor suppressor p63. These findings support that Notch signaling mediates cervical cancer cell growth suppression with the involvement of nuclear receptor NR4A2. Notably, Notch/NR4A2/p63 signaling cascade possibly is a new signling pathway undisclosed. PMID- 27471555 TI - Complement Component 1, s Subcomponent Overexpression is an Independent Poor Prognostic Indicator in Patients with Urothelial Carcinomas of the Upper Urinary Tract and Urinary Bladder. AB - PURPOSE: Urothelial carcinoma of the urinary bladder and upper tract is prevalent. By subjecting a documented transcriptome data set of urothelial carcinoma of bladder (GSE31684) to data mining and focusing on genes linked to peptidase activity (GO:0008233), we recognized C1S as the most significantly upregulated gene related to an advanced tumor status and metastasis. We subsequently analyzed the association of both C1S mRNA and its encoded protein expression with the clinical and pathological significance. MATERIALS AND METHODS: We used real-time reverse transcription polymerase chain reaction to detect C1S transcription levels in 20 cases each of urothelial carcinoma of bladder and upper tract. An immunohistochemical stain was conducted to determine C1s protein expression levels in patients with urothelial carcinoma of upper tract (n = 340) and urinary bladder (n = 295). Furthermore, we examined the correlation of C1s expression with clinicopathological characteristics, disease specific survival, and metastasis-free survival. RESULTS: C1S transcription levels were significantly high in patients with advanced-stage tumors of both groups (all P < .05). Immunohistochemical analysis revealed that C1s expression levels were significantly associated with adverse clinicopathological parameters in both groups of urothelial carcinoma (all P < .05). C1s overexpression predicted poor disease-specific and metastasis-free survival rates for both urothelial carcinoma groups in the univariate analysis, and it was also an independent prognostic factor in the multivariate analysis (all P < .05). CONCLUSIONS: C1s may play a pivotal role in urothelial carcinoma progress and can represent a vital prognostic marker and a promising new therapeutic target in urothelial carcinoma. PMID- 27471556 TI - Exploration and Validation of C-Reactive Protein/Albumin Ratio as a Novel Inflammation-Based Prognostic Marker in Nasopharyngeal Carcinoma. AB - BACKGROUND: The prognostic value of C-reactive protein/albumin ratio (CRP/Alb), a novel inflammation-based marker, remains unknown in nasopharyngeal carcinoma (NPC). METHODS: We conducted a retrospective review of 1572 consecutive patients with non-metastatic NPC. Patients were randomly divided into a training set (n = 514) and validation set (n = 1058). The prognostic value of the CRP/Alb ratio and the modified Glasgow prognostic score (mGPS; a well-recognized inflammation-based score) was assessed. RESULTS: Receiver-operating characteristic analysis identified 0.05 as the optimal CRP/Alb cut-off value for disease failure in the training set. Patients with a CRP/Alb > 0.05 had poorer overall survival (OS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) in the training set (all P < 0.05). These results were confirmed in the validation set (all P < 0.05) and the whole cohort (all P < 0.001). In multivariate analysis of the entire cohort, the pretreatment CRP/Alb ratio was an independent prognostic factor for OS (HR, 1.394; 95% CI, 1.004-1.937; P = 0.048) and DMFS (HR, 1.545; 95% CI, 1.124-2.122; P = 0.007), but not for DFS (P = 0.083). The mGPS had no significant independent prognostic value for any end-point. CONCLUSION: CRP/Alb ratio is an useful prognostic indicator in patients with NPC, independent of disease stage. PMID- 27471557 TI - The Degree of Lipiodol Accumulation Can Be an Indicator of Successful Treatment for Unresectable Hepatocellular Carcinoma (HCC) Patients - in the Case of Transcatheter Arterial Chemoembolization (TACE) and External Beam Radiotherapy (EBRT). AB - PURPOSE: Transcatheter arterial chemoembolization (TACE) in combination with external beam radiotherapy (EBRT) results in improved survival due to better local control in patients with unresectable hepatocellular carcinoma (HCC). The purpose of this study was to investigate lipiodol accumulation, as it reflects tumor burden and is a potential prognostic factor, in HCC patients treated with TACE/EBRT. METHODS AND MATERIALS: We retrospectively studied 147 patients with unresectable HCC treated with TACE and EBRT. Clinical features, adverse reactions, and prognostic factors were analyzed. All patients were treated with TACE 1-6 times in combination with EBRT (44-66 Gy) in dose of 2 Gy/fraction given once a day five times a week. Tumor status and laboratory findings were followed. The degree of lipiodol accumulation was assessed by computed tomography before EBRT, and was categorized as either complete/intense or low/moderate. RESULTS: The response rate of tumor size after EBRT was 68.2%, median survival was 23.1 months, and overall survival rates were 86.6%, 49.2%, and 28.2% at 1, 2, and 3 years, respectively. Univariate analysis showed that lower hemoglobin levels, higher alkaline phosphatase levels, Child-Pugh B, negative alpha-fetoprotein (AFP) response after EBRT, poor treatment response after EBRT, tumor diameter >10 cm, and poor lipiodol accumulation were unfavorable prognostic factors. On multivariate analysis, higher hemoglobin levels, Child-Pugh A, decreased AFP levels after treatment, Helical Tomotherapy (HT) and intense lipiodol accumulation after TACE were significant favorable predictors. CONCLUSIONS: The degree of lipiodol accumulation before EBRT is a prognostic factor in patients with unresectable HCC. Increased AFP levels after EBRT are always associated with poor survival. HT is recommended as a potentially better EBRT modality than three dimensional conformal radiation therapy (3D-CRT). PMID- 27471559 TI - Centrosomal Protein of 55 Regulates Glucose Metabolism, Proliferation and Apoptosis of Glioma Cells via the Akt/mTOR Signaling Pathway. AB - INTRODUCTION: Glioma is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and the progression of glioma are elusive and controversial. Centrosomal protein of 55 (CEP55) was initially described as a highly coiled-coil protein that plays critical roles in cell division, but was recently identified as being overexpressed in many human cancers. The function of CEP55 has not previously been characterized in glioma. We aim to discover the effect and mechanism of CEP55 in glioma development. METHOD: qRT-PCR and immunohistochemistry were used to analyze CEP55 expression. Glucose uptake, western blot, MTS, CCK-8, Caspase-3 activity and TUNEL staining assays were performed to investigate the role and mechanism of CEP55 on glioma cell process. RESULTS: We found that the levels of CEP55 expression were upregulated in glioma. In addition, CEP55 appeared to regulate glucose metabolism of glioma cells. Furthermore, knockdown of CEP55 inhibited cell proliferation and induced cell apoptosis in glioma. Finally, we provided preliminary evidence that knockdown of CEP55 inhibited glioma development via suppressing the activity of Akt/mTOR signaling. CONCLUSIONS: Our results demonstrated that CEP55 regulates glucose metabolism, proliferation and apoptosis of glioma cells via the Akt/mTOR signaling pathway, and its promotive effect on glioma tumorigenesis can be a potential target for glioma therapy in the future. PMID- 27471558 TI - Gut Microbiota Imbalance and Base Excision Repair Dynamics in Colon Cancer. AB - Gut microbiota are required for host nutrition, energy balance, and regulating immune homeostasis, however, in some cases, this mutually beneficial relationship becomes twisted (dysbiosis), and the gut flora can incite pathological disorders including colon cancer. Microbial dysbiosis promotes the release of bacterial genotoxins, metabolites, and causes chronic inflammation, which promote oxidative DNA damage. Oxidized DNA base lesions are removed by base excision repair (BER), however, the role of this altered function of BER, as well as microbiota-mediated genomic instability and colon cancer development, is still poorly understood. In this review article, we will discuss how dysbiotic microbiota induce DNA damage, its impact on base excision repair capacity, the potential link of host BER gene polymorphism, and the risk of dysbiotic microbiota mediated genomic instability and colon cancer. PMID- 27471560 TI - Genomic/Epigenomic Alterations in Ovarian Carcinoma: Translational Insight into Clinical Practice. AB - Ovarian carcinoma is the most lethal gynecological malignancy worldwide. Recent advance in genomic/epigenomic researches will impact on our prevention, detection and intervention on ovarian carcinoma. Detection of germline mutations in BRCA1/BRCA2, mismatch repair genes, and other genes in the homologous recombination/DNA repair pathway propelled the genetic surveillance of most hereditary ovarian carcinomas. Germline or somatic mutations in SMARCA4 in familial and sporadic small cell carcinoma of the ovary, hypercalcemia type, lead to our recognition on this rare aggressive tumor as a new entity of the atypical teratoma/rhaboid tumor family. Genome-wide association studies have identified many genetic variants that will contribute to the evaluation of ovarian carcinoma risk and prognostic prediction. Whole exome sequencing and whole genome sequencing discovered rare mutations in other drive mutations except p53, but demonstrated the presence of high genomic heterogeneity and adaptability in the genetic evolution of high grade ovarian serous carcinomas that occurs in cancer progression and chemotherapy. Gene mutations, copy number aberrations and DNA methylations provided promising biomarkers for the detection, diagnosis, prognosis, therapy response and targets of ovarian cancer. These findings underscore the necessity to translate these potential biomarkers into clinical practice. PMID- 27471562 TI - Prognostic Value of Neoadjuvant Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma with Low Pre-treatment Epstein-Barr Virus DNA: a Propensity-matched Analysis. AB - BACKGROUND: The aim of this study is to investigate the prognostic value of neoadjuvant chemotherapy (NCT) in locoregionally advanced nasopharyngeal carcinoma (NPC) with low pre-treatment Epstein-Barr virus (EBV) DNA in the era of intensity-modulated radiotherapy (IMRT). METHODS: Data on 1099 locoregionally advanced NPC patients treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance influence of covariates. Patient survival between NCT and non-NCT groups were compared. RESULTS: The cut off value of pre-treatment Epstein-Barr virus DNA (pre-DNA) was 1550 copies/ml for DMFS (area under curve [AUC], 0.655; sensitivity, 0.819; specificity, 0.445). For the 145 pairs selected by PSM, the 3-year distant metastasis-free survival (DMFS), overall survival (OS), disease-free survival (DFS) and locoregional relapse-free survival (LRRFS) rates were 98.6% vs. 93.7% (P = 0.101), 95.8% vs. 94.4% (P = 0.881), 91.7% vs. 87.5% (P = 0.309) and 94.4% vs. 95.0% (P = 0.667), respectively. Multivariate analysis did not identify NCT as an independent prognostic factor (P > 0.05 for all rates), and stratified analysis based on overall stage (III and IV) and N category (N0-1 and N2-3) also got the same results. CONCLUSION: NCT was not established as an independent prognostic factor, and it should not be used in locoregionally advanced NPC with low pre-DNA. PMID- 27471563 TI - A Point Mutation in DNA Polymerase beta (POLB) Gene Is Associated with Increased Progesterone Receptor (PR) Expression and Intraperitoneal Metastasis in Gastric Cancer. AB - Increased expression of progesterone receptor (PR) has been reported in gastric cancer (GC). We have previously identified a functional T889C point mutation in DNA polymerase beta (POLB), a DNA repair gene in GC. To provide a detailed analysis of molecular changes associated with the mutation, human cDNA microarrays focusing on 18 signal transduction pathways were used to analyze differential gene expression profiles between GC tissues with T889C mutant in POLB gene and those with wild type. Among the differentially expressed genes, notably, PR was one of the significantly up-regulated genes in T889C mutant POLB tissues, which were subsequently confirmed in POLB gene transfected AGS cell line. Interestingly, patients with T889C mutation and PR positivity were associated with higher incidence of intraperitoneal metastasis (IM). In vitro studies indicate that PR expression was upregulated in AGS cell line when transfected with T889C mutant expression vector. Cotransfection of T889C mutant allele and PR gene induced cell migration in the cell line. These data demonstrated that T889C mutation-associated PR overexpression results in increased IM. Therefore, T889C mutation-associated PR overexpression may serve as a biomarker for an adverse prognosis for human GC. PMID- 27471561 TI - Proteomic Upregulation of Fatty Acid Synthase and Fatty Acid Binding Protein 5 and Identification of Cancer- and Race-Specific Pathway Associations in Human Prostate Cancer Tissues. AB - Protein profiling studies of prostate cancer have been widely used to characterize molecular differences between diseased and non-diseased tissues. When combined with pathway analysis, profiling approaches are able to identify molecular mechanisms of prostate cancer, group patients by cancer subtype, and predict prognosis. This strategy can also be implemented to study prostate cancer in very specific populations, such as African Americans who have higher rates of prostate cancer incidence and mortality than other racial groups in the United States. In this study, age-, stage-, and Gleason score-matched prostate tumor specimen from African American and Caucasian American men, along with non malignant adjacent prostate tissue from these same patients, were compared. Protein expression changes and altered pathway associations were identified in prostate cancer generally and in African American prostate cancer specifically. In comparing tumor to non-malignant samples, 45 proteins were significantly cancer-associated and 3 proteins were significantly downregulated in tumor samples. Notably, fatty acid synthase (FASN) and epidermal fatty acid-binding protein (FABP5) were upregulated in human prostate cancer tissues, consistent with their known functions in prostate cancer progression. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3) was also upregulated in tumor samples. The Metastasis Associated Protein 3 (MTA3) pathway was significantly enriched in tumor samples compared to non-malignant samples. While the current experiment was unable to detect statistically significant differences in protein expression between African American and Caucasian American samples, differences in overrepresentation and pathway enrichment were found. Structural components (Cytoskeletal Proteins and Extracellular Matrix Protein protein classes, and Biological Adhesion Gene Ontology (GO) annotation) were overrepresented in African American but not Caucasian American tumors. Additionally, 5 pathways were enriched in African American prostate tumors: the Small Cell Lung Cancer, Platelet-Amyloid Precursor Protein, Agrin, Neuroactive Ligand-Receptor Interaction, and Intrinsic pathways. The protein components of these pathways were either basement membrane proteins or coagulation proteins. PMID- 27471564 TI - Narrowing Resection of Parametrial Tissues Is Feasible in Low-Risk Cases of Stage IA2-IB1 Cervical Cancer. AB - BACKGROUND: Radical hysterectomy with pelvic lymphadenectomy is the standard surgical treatment for patients with stage IA2-IB1 cervical cancer, but the wide excision increases the complications. OBJECTIVE: To analyze the feasibility of narrowing resection of parametrial tissues in stage IA2-IB1 cervical cancer. STUDY DESIGN: Retrospectively analyzed the pathological and clinical data of patients with stage IA2-IB1 cervical cancer who received radical hysterectomy with pelvic lymphadenectomy in OB/GYN Hospital, Fudan University, China from Jan 2008 to Dec 2011. The affected factors of parametrial metastases and outcomes were discussed. The single factor analysis was made with chi2 test, and the relationship of the resection width of parametrial tissues and the patients' outcomes was analyzed with chi2 test and log-rank. P-values <0.05 were considered statistically significant. RESULTS: There were 31 cases recurred, 26 cases died of cervical cancer in 513 patients during the follow-up period (from 2 months to 66 months, averaged 39 months). The low-risk factors included diameter of tumor <=2cm, depth of cervical myometrial invasion<1/2 and without lymph vascular involvement. There were no parametrial metastases in cases with all three low risk factors. Whether the resection width of parametrial tissues >=3cm or not had no statistically significant effect on progression free survival (PFS) or overall survival (OS) of low-risk patients. D2-40 and CD31 were related with parametrial metastases, but not with recurrence or outcomes. CONCLUSIONS: The resection width of parametrial tissues has no effect on PFS and OS of low-risk patients, and narrowing resection of parametrial tissues (<3cm) is feasible. PMID- 27471433 TI - Event generator tunes obtained from underlying event and multiparton scattering measurements. AB - New sets of parameters ("tunes") for the underlying-event (UE) modelling of the pythia8, pythia6 and herwig++ Monte Carlo event generators are constructed using different parton distribution functions. Combined fits to CMS UE proton-proton ([Formula: see text]) data at [Formula: see text] and to UE proton-antiproton ([Formula: see text]) data from the CDF experiment at lower [Formula: see text], are used to study the UE models and constrain their parameters, providing thereby improved predictions for proton-proton collisions at 13[Formula: see text]. In addition, it is investigated whether the values of the parameters obtained from fits to UE observables are consistent with the values determined from fitting observables sensitive to double-parton scattering processes. Finally, comparisons are presented of the UE tunes to "minimum bias" (MB) events, multijet, and Drell Yan ([Formula: see text] lepton-antilepton+jets) observables at 7 and 8[Formula: see text], as well as predictions for MB and UE observables at 13[Formula: see text]. PMID- 27471565 TI - Magnetofection Based on Superparamagnetic Iron Oxide Nanoparticles Weakens Glioma Stem Cell Proliferation and Invasion by Mediating High Expression of MicroRNA 374a. AB - Glioma stem cells belong to a special subpopulation of glioma cells that are characterized by strong proliferation, invasion and drug resistance capabilities. Magnetic nanoparticles are nanoscale biological materials with magnetic properties. In this study, CD133(+) primary glioma stem cells were isolated from patients and cultured. Then, magnetic nanoparticles were used to mediate the transfection and expression of a microRNA-374a overexpression plasmid in the glioma stem cells. Transmission electron microscopy detected the presence of significant magnetic nanoparticle substances within the CD133(+) glioma stem cells after transfection. The qRT-PCR and Northern blot results showed that the magnetic nanoparticles could be used to achieve the transfection of the microRNA 374a overexpression plasmid into glioma stem cells and the efficient expression of mature microRNA-374a. The MTT and flow cytometry results showed that the proliferation inhibition rate was significantly higher in cells from the microRNA 374a transfection group than in cells from the microRNA-mut transfection group; additionally, the former cells presented significant cell cycle arrest. The Transwell experiments confirmed that the overexpression of microRNA-374a could significantly reduce the invasiveness of CD133(+) glioma stem cells. Moreover, the high expression of microRNA-374a mediated by the magnetic nanoparticles effectively reduced the tumourigenicity of CD133(+) glioma stem cells in nude mice. The luciferase assays revealed that mature microRNA-374a fragments could bind to the 3'UTR of Neuritin (NRN1), thereby interfering with Neuritin mRNA expression. The qRT-PCR and Western blotting results showed that the overexpression of microRNA-374a significantly reduced the expression of genes such as NRN1, CCND1, CDK4 and Ki67 in glioma stem cells. Thus, magnetic nanoparticles can efficiently mediate the transfection and expression of microRNA expression plasmids in mammalian cells. The overexpression of microRNA-374a can effectively silence NRN1 expression, thereby inhibiting the proliferation, invasion and in vivo tumourigenicity of human glioma stem cells. PMID- 27471569 TI - SOX4 Promotes Progression in OLP-Associated Squamous Cell Carcinoma. AB - BACKGROUND: The development of oral squamous cell carcinoma (OSCC) is a multistep process that involves in both genetic alterations and epigenetic modifications. Previous studies suggest SOX4 might function as an oncogene or a tumor suppressor in different types of cancers. However, whether SOX4 involves in promoting the progression of oral precancer to cancer is unknown. METHODS: Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to identify the proteins that may be differentially expressed between oral lichen planus (OLP) and OLP-associated OSCC (OLP-OSCC) formalin-fixed paraffin-embedded (FFPE) tissues. Immunohistochemistry (IHC) and Western blotting were performed to evaluate SOX4 expression between OLP and OLP-OSCC tissues and among oral cancer cell lines and normal human oral keratinocytes (NHOKs). SOX4 siRNA was used to knock down the expression of SOX4 in UM1 oral cancer cells. MTT, cell counting, migration and Matrigel invasion assays were utilized to examine the effect of SOX4 down-regulation on proliferation, migration and invasion capacity of UM1 cells. RESULTS: LC-MS/MS analysis showed that 88 proteins including SOX4 were only identified in OLP-OSCC FFPE tissues when compared to OLP FFPE tissues. IHC confirmed that SOX4 expression was significantly higher in OLP-OSCC than OLP and Western blot analysis indicated that SOX4 was over-expressed in UM1/UM2 cells when compared to NHOKs. Knockdown of SOX4 significantly inhibited the proliferation, migration and invasion of UM1 cells (P<0.01). CONCLUSIONS: Our study indicated that SOX4 is significantly upregulated in OLP-OSCC versus OLP tissues. In addition, down-regulation of SOX4 led to significantly reduced proliferation, migration and invasion capability of oral cancer cells. These findings suggest that SOX4 might be actively involved in the progression of OLP to OSCC. PMID- 27471571 TI - Rho GTPase RhoJ is Associated with Gastric Cancer Progression and Metastasis. AB - Rho GTPases play a pivotal role in tumor progression by regulating tumor cell migration and invasion. However, the role of Rho GTPases in gastric cancer (GC) remains unexplored. This study aimed to investigate the clinical implications of RhoJ, which is an uncharted member of Rho family. RhoJ expression in human GC cell lines and surgical specimens from GC patients were analyzed. Moreover, in vitro gain-of-function analysis was performed to evaluate the malignant phenotypes of RhoJ-overexpressing GC cells. The extent of RhoJ expression varied among GC cell lines and GC patients. YCC-9 cell line displayed the strongest expression, while YCC-10, -11, and -16 showed scant expressions. Of the 70 GC patients, 34 (48.6%) had RhoJ expression in their GC tissue, and patients with high RhoJ expression had more diffuse type GC (73.5% vs. 41.7%), were at more advanced stages (stage III, IV: 85.3% vs. 58.4%), and had more frequent metastasis (47.1% vs. 11.1%), denoting that RhoJ has a potential role in GC progression and metastasis. High RhoJ expression significantly correlated with poor overall survival and recurrence-free survival after surgical resection of gastric cancer. Finally, In vitro gain-of-function experiments showed 41.3% enhanced motility and 60.4% enhanced invasiveness in RhoJ-overexpressing GC cells compared to control, with negligible difference in cell proliferation. Collectively, high RhoJ expression is an independent negative prognostic factor for the survival outcome of GC and correlated with the increased cell motility and invasiveness. PMID- 27471567 TI - Cytotoxic Chemotherapy as First-Line Therapy for Advanced Non-Small-Cell Lung Cancer in Taiwan: Daily Practice. AB - AIM: Cytotoxic chemotherapy is the standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) without specific gene alterations. This study examined the prescription pattern and the survival outcome of cytotoxic chemotherapy regimens in daily practice in Taiwan. METHODS: We established a population-based cohort of patients diagnosed with advanced NSCLC between 2005 and 2009 using the databases of Taiwan Cancer Registry and National Health Insurance in Taiwan. We then analyzed chemotherapy prescriptions and the survival outcomes of patients. RESULTS: A total of 25,008 patients with advanced NSCLC were identified, 17,443 (70.0%) of which received first-line chemotherapy and were therefore included in this study. Among them, 11,551 (66.2%) patients had adenocarcinoma and 3,292 (18.9%) patients had squamous cell carcinoma (SCC). Approximately 70% of the patients were diagnosed with NSCLC in medical centers. Platinum-based doublet chemotherapy was administered to 66.9% of the patients. Among all chemotherapy regimens, platinum with gemcitabine (33.8%) was the most common, irrespective of geographic region. The second and third most common regimens were vinorelbine alone (13.0%) and platinum with docetaxel (11.6%). The prevalence of platinum-based doublet chemotherapy regimens decreased from 71.4% in 2005 to 64.1% in 2009. Among patients with adenocarcinoma histology, those who received platinum with pemetrexed had longer OS than did patients who received other platinum-based regimens (p < 0.001). CONCLUSION: Our findings reaffirm that in real-world practice, treatment plans of advanced NSCLC should be drawn up according to histology type. PMID- 27471568 TI - Inhibition of Regulatory Volume Decrease Enhances the Cytocidal Effect of Hypotonic Shock in Hepatocellular Carcinoma. AB - Background : Hypotonic shock induces cytocidal effects through cell rupture, and cancer therapy based on this mechanism has been clinically administered to hepatocellular carcinoma patients. We herein investigated the effectiveness of hypotonic shock combined with the inhibition of regulatory volume decrease as cancer therapy for hepatocellular carcinoma. Methods : Morphological changes in human hepatocellular carcinoma cell lines were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes under hypotonic shock with or without chloride, potassium, or water channel blockers were observed using a high-resolution flow cytometer. In order to investigate cytocidal effects, the number of surviving cells was compared after exposure to hypotonic solution with and without each channel blocker (re-incubation experiment). Results : Video recordings showed that cells exposed to distilled water rapidly swelled and then ruptured. Cell volume measurements revealed regulatory volume decrease under mild hypotonic shock, whereas severe hypotonic shock increased the number of broken fragments as a result of cell rupture. Moreover, regulatory volume decrease was inhibited in cells treated with each channel blocker. Re-incubation experiments showed the cytocidal effects of hypotonic shock in cells exposed to hypotonic solution, and additional treatments with each channel blocker enhanced these effects. Conclusion : The inhibition of regulatory volume decrease with chloride, potassium, or water channel blockers may enhance the cytocidal effects of hypotonic shock in hepatocellular carcinoma. Hypotonic shock combined with the inhibition of regulatory volume decrease was a more effective therapy than hypotonic shock alone. PMID- 27471570 TI - Prognostic Impact of Thrombospodin-2 (THBS2) Overexpression on Patients with Urothelial Carcinomas of Upper Urinary Tracts and Bladders. AB - PURPOSE: Urothelial carcinoma (UC) is a type of tumor, especially of the urinary bladder, that affects people worldwide. Clarification of its detailed tumor biology and discovery of potential targets for developing treatment strategies are imperative because of frequent recurrences and poor prognosis of advanced UCs. By data mining a published dataset of UC of bladder (UCB) transcriptome (GSE31684) from Gene Expression Omnibus, National Center of Biotechnology Information (GEO, NCBI), we identified that THBS2 was the most significantly upregulated gene among those related to structural molecule activity (GO:0005198). Therefore, we evaluated the clinical significance and prognostic impact of thrombospondin-2 (THBS2) protein, A.K.A. TSP2, which encoded by THBS2 gene. MATERIALS AND METHODS: THBS2 immunostaining was performed in 340 UCs of upper urinary tract (UC-UUTs) and 295 UCBs; subsequently, both groups were dichotomized into high- and low-expression subgroups. Moreover, statistical analyses were performed to correlate the association between THBS2 expression and clinicopathological parameters with two survival indexes: disease-specific survival (DSS) and metastasis-free survival (MeFS). RESULTS: High THBS2 immunoexpression was significantly associated with advanced primary tumor status, nodal metastasis, and vascular invasion in both UC-UUT and UCB groups (all P <= .001). In addition, THBS2 overexpression was linked to adverse DSS and MeFS in univariate analyses and served as an independent prognosticator indicating poor outcomes in both groups in multivariate analyses. CONCLUSION: THBS2 may play a crucial role in UC progression and may be a novel prognostic marker. Additional investigations to elucidate the molecular pathway are necessary for developing potential THBS2-targeted therapies for UCs. PMID- 27471572 TI - Bleomycin (BLM) Induces Epithelial-to-Mesenchymal Transition in Cultured A549 Cells via the TGF-beta/Smad Signaling Pathway. AB - The epithelial-to-mesenchymal transition (EMT) is a crucial cellular event in wound healing, tissue repair, and cancer progression in adult tissues, with the interactions with numerous signals. In this study, we aimed to determine whether bleomycin (BLM), an agent that causes pulmonary fibrosis, induces the EMT of the alveolar epithelial cell line A549 and investigated the possible mechanisms. We examined the EMT involved changes in cell morphology, isoform switching of the fibroblast growth factor receptor 2 (FGFR2) by alternative splicing, and expression of the phenotypic markers including E-cadherin, vimentin, and alpha SMA using RT-PCR, Western blotting, and immunofluorescence assays. A TGF beta/Smad inhibitor was used to determine whether coculture with BLM would inhibit the EMT of A549 cells. The results showed that BLM induced the EMT of A549 cells possibly via the TGF-beta/Smad signaling pathway, evident from the decrease in the expression of E-cadherin and increase in the expression on vimentin. PMID- 27471566 TI - Cancer of the Pancreas: Molecular Pathways and Current Advancement in Treatment. AB - Pancreatic cancer is one of the most lethal cancers among all malignances, with a median overall survival of <1 year and a 5-year survival of ~5%. The dismal survival rate and prognosis are likely due to lack of early diagnosis, fulminant disease course, high metastasis rate, and disappointing treatment outcome. Pancreatic cancers harbor a variety of genetic alternations that render it difficult to treat even with targeted therapy. Recent studies revealed that pancreatic cancers are highly enriched with a cancer stem cell (CSC) population, which is resistant to chemotherapeutic drugs, and therefore escapes chemotherapy and promotes tumor recurrence. Cancer cell epithelial to mesenchymal transition (EMT) is highly associated with metastasis, generation of CSCs, and treatment resistance in pancreatic cancer. Reviewed here are the molecular biology of pancreatic cancer, the major signaling pathways regulating pancreatic cancer EMT and CSCs, and the advancement in current clinical and experimental treatments for pancreatic cancer. PMID- 27471573 TI - Hepatocellular Carcinoma and Diffusion-Weighted MRI: Detection and Evaluation of Treatment Response. AB - Differentiating between cancerous tissue and healthy liver parenchyma could represent a challenge with the only conventional Magnetic Resonance (MR) imaging. Diffusion weighted imaging (DWI) exploits different tissue characteristics to conventional Magnetic Resonance Imaging (MRI) sequences that enhance hepatocellular carcinoma (HCC) detection, characterization, and post-treatment evaluation. Detection of HCC is improved by DWI, infact this technology increases conspicuity of lesions that might otherwise not be identified due to obscuration by adjacent vessels or due to low contrast between the lesion and background liver. It is important to remember that DWI combined with contrast-enhanced MRI has higher sensitivity than DWI alone, and that some patients are not eligible for use of contrast on CT and MRI; in these patients DWI has a prominent role. MRI has advanced beyond structural anatomic imaging to now showing pathophysiologic processes. DWI is a promising way to characterize lesions utilizing the inherent contrast within the liver and has the benefit of not requiring contrast injection. DWI improves detection and characterization of HCC. Proposed clinical uses for DWI include: assessing prognosis, predicting response, monitoring response to therapy, and distinguishing tumor recurrence from treatment effect. Ideally, DWI will help risk stratify patients and will participate in prognostic modeling. PMID- 27471575 TI - A Technical Perspective for Understanding Quantitative Arterial Spin-Labeling MR Imaging Using Continuous ASL. AB - The current paper describes visually the system of CBF measurement by continuous ASL using schematic illustration. I also discussed the effects of the parameters used in continuous ASL to CBF values as measured with ASL-MRI. PMID- 27471576 TI - Intra-Hepatic Spillage of Gallstones as a Late Complication of Laparoscopic Cholecystectomy: MR Imaging Findings. AB - BACKGROUND: Spillage of gallstones in the abdominal cavity may rarely occur during the course of laparoscopic cholecystectomy. Dropped gallstones in the peritoneal and extra-peritoneal cavity are usually asymptomatic. However, they may lead to abscess formation with an estimated incidence of about 0.3%. Common locations of the abscess are in the abdominal wall followed by the intra abdominal cavity, usually in the sub-hepatic or retro-peritoneum inferior to the sub-hepatic space. CASE REPORT: We hereby describe an unusual case of infected spilled gallstones in the right sub-phrenic space, prospectively detected on abdominal MRI performed two years after laparoscopic cholecystectomy, in a patient with only a mild right-sided abdominal complaint. CONCLUSIONS: This case highlights the role of MRI in suggesting the right diagnosis in cases with vague or even absent symptomatology. In our case the patient's history together with high quality abdomen MRI allowed the correct diagnosis. Radiologists should be aware of this rare and late onset complication, even after many years from surgery as an incidental finding in almost asymptomatic patients. PMID- 27471574 TI - Effects of Animal Venoms and Toxins on Hallmarks of Cancer. AB - Animal venoms are a cocktail of proteins and peptides, targeting vital physiological processes. Venoms have evolved to assist in the capture and digestion of prey. Key venom components often include neurotoxins, myotoxins, cardiotoxins, hematoxins and catalytic enzymes. The pharmacological activities of venom components have been investigated as a source of potential therapeutic agents. Interestingly, a number of animal toxins display profound anticancer effects. These include toxins purified from snake, bee and scorpion venoms effecting cancer cell proliferation, migration, invasion, apoptotic activity and neovascularization. Indeed, the mechanism behind the anticancer effect of certain toxins is similar to that of agents currently used in chemotherapy. For example, Lebein is a snake venom disintegrin which generates anti-angiogenic effects by inhibiting vascular endothelial growth factors (VEGF). In this review article, we highlight the biological activities of animal toxins on the multiple steps of tumour formation or hallmarks of cancer. We also discuss recent progress in the discovery of lead compounds for anticancer drug development from venom components. PMID- 27471577 TI - Clinically Unjustified Diagnostic Imaging - a Worrisome Tendency in Today's Medical Practice. AB - BACKGROUND: The purpose of the study was to evaluate the percentage of unjustified examinations among all the CT and MRI studies performed by two radiology departments and to determine the types of examinations which are most commonly carried out unnecessarily. MATERIAL/METHODS: Three radiologists assessed the justification of CT and MRI examinations performed during a period of 14 days based on the referrals. The radiologists assessed 799 referrals for CT scans (847 examinations of a particular part of the body) and 269 MRI referrals (269 examinations). The criteria for justification were: medical expertise and the guidelines. During the first stage radiologists divided the examinations into 3 groups: justified, unjustified and the examinations of questionable justification. The second step was to determine the reasons why the studies were considered as unjustified or of questionable justification. RESULTS: 73 of 1116 examinations (6.54%) were considered to be unjustified or of a questionable justification. There were 59 CT scans (59/847=6.97%) and 14 MRI studies (14/269=5.20%). The most common reasons to consider them as unjustified or of questionable justification were: inadequate method of diagnostic imaging chosen as a first-line tool and lacking or insufficient clinical details. CONCLUSIONS: In our investigation 6.54% of both CT and MRI examinations were considered as unjustified or of questionable justification, which is lower than described in other studies (from 7% to 26%). The assessment was based only on referrals, therefore a total share of these examinations is likely to be higher. PMID- 27471578 TI - Complete genome of Nitrosospira briensis C-128, an ammonia-oxidizing bacterium from agricultural soil. AB - Nitrosospira briensis C-128 is an ammonia-oxidizing bacterium isolated from an acid agricultural soil. N. briensis C-128 was sequenced with PacBio RS technologies at the DOE-Joint Genome Institute through their Community Science Program (2010). The high-quality finished genome contains one chromosome of 3.21 Mb and no plasmids. We identified 3073 gene models, 3018 of which are protein coding. The two-way average nucleotide identity between the chromosomes of Nitrosospira multiformis ATCC 25196 and Nitrosospira briensis C-128 was found to be 77.2 %. Multiple copies of modules encoding chemolithotrophic metabolism were identified in their genomic context. The gene inventory supports chemolithotrophic metabolism with implications for function in soil environments. PMID- 27471579 TI - Impact of Non-Pulmonary Visceral Metastases in the Prognosis and Practice of Metastatic Testicular Germ Cell Tumors. AB - Non-pulmonary visceral metastases, in bones, brain and liver, represent nearly the 10% of metastatic sites of advanced germ cell tumors and are associated with poor prognosis. This review article summarizes major evidences on the impact of different visceral sites on the prognosis, treatment and clinical outcome of patients with germ cell tumors. The clinic-biological mechanisms by which these metastatic sites are associated with poor clinical outcome remain unclear. The multimodality treatment showed a potential better survival, in particular in patients with relapsed disease. Patients with advanced germ cell tumors with visceral metastases should be referred to centers with high expertise in the clinical management of such disease. PMID- 27471580 TI - Immune Checkpoint Inhibitors and Prostate Cancer: A New Frontier? AB - Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), agents that provide durable disease control and long term survival are still needed. It is a fact that a tumor-induced immunosuppressive status (mediated by aberrant activation of inhibitory immune checkpoint pathways as a mechanism to evade host immune surveillance) plays a crucial role in the pathogenesis of cancer, including prostate cancer (PC), making CRPC patients suitable candidates for immunotherapy. Therefore, growing interest of anticancer research aims at blocking immune checkpoints (mainly targeting CTLA-4 and PD1/PD-L1 pathways) to restore and enhance cellular-mediated antitumor immunity and achieve durable tumor regression. In this review, we describe the current knowledge regarding the role of immune checkpoints in mediating PC progression, focusing on CTLA-4 and PD1 pathways. We also provide current clinical data available, an update on ongoing trials of immune checkpoint inhibitors in PC. Finally, we discuss the necessity to identify prognostic and predictive biomarkers of immune activity, and we analyze new immune checkpoints with a role as promising targets for PC therapy. PMID- 27471581 TI - How Grim is Pancreatic Cancer? AB - Pancreatic ductal carcinoma continues to be the most lethal malignancy with rising incidence. It is the fourth most common cause of cancer death in the western world due to its low treatment success rate. In addition, because of its rapid growth and silent course, diagnosis is often only established in the advanced stages. As one of the most aggressive malignancies, the treatment of this disease is a great challenge to clinicians. This paper reviewed the natural history of pancreatic cancer, the current clinical practice and the future in pancreatic cancer management. PMID- 27471582 TI - Contemporary Treatment of Metastatic Renal Cell Carcinoma. AB - The introduction of targeted therapy has revolutionized the treatment of patients with metastatic renal cell carcinoma (mRCC). The current standard of care focuses on the inhibition of angiogenesis through the targeting of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR). Over the past few years, research exploring novel targeted agents has blossomed, leading to the approval of various targeted therapies. Furthermore, results from the CheckMate025 and the METEOR trials have brought about two additional novel options: the programmed cell death 1 (PD-1) checkpoint inhibitor nivolumab and the MET/VEGFR/AXL inhibitor cabozantinib, respectively. With the variety of therapeutic agents available for treatment of mRCC, research examining appropriate sequencing and combinations of the drugs is ongoing. This review discusses the role of prognostic criteria, such as those from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. It also covers the current standard of treatment for mRCC with targeted therapy in first , second-, and third-line setting. Additionally, the novel mechanism of action of nivolumab and cabozantinib, therapeutic sequencing and ongoing clinical trials are discussed. PMID- 27471583 TI - Splice Variants of Androgen Receptor and Prostate Cancer. AB - Over the last ten years, two new-generation hormonal drugs and two chemotherapeutic agents have been approved for the treatment of metastatic castration-resistant prostate cancer. Unfortunately, some patients have primary resistance to them and the others eventually develop secondary resistance. It has recently been suggested that the presence of androgen receptor splice variants plays a leading role in the primary and secondary resistance to the new hormonal drugs, whereas their presence seem to have only a partial effect on the activity of the chemotherapeutic agents. The aim of this paper is to review the published data concerning the role of androgen receptor splice variants in prostate cancer biology, and their potential use as biomarkers when making therapeutic decisions. PMID- 27471432 TI - Identification of boosted, hadronically decaying W bosons and comparisons with ATLAS data taken at [Formula: see text] TeV. AB - This paper reports a detailed study of techniques for identifying boosted, hadronically decaying W bosons using 20.3 fb[Formula: see text] of proton-proton collision data collected by the ATLAS detector at the LHC at a centre-of-mass energy [Formula: see text]. A range of techniques for optimising the signal jet mass resolution are combined with various jet substructure variables. The results of these studies in Monte Carlo simulations show that a simple pairwise combination of groomed jet mass and one substructure variable can provide a 50 % efficiency for identifying W bosons with transverse momenta larger than 200 GeV while maintaining multijet background efficiencies of 2-4 % for jets with the same transverse momentum. These signal and background efficiencies are confirmed in data for a selection of tagging techniques. PMID- 27471584 TI - Progress in Treatment of Viral Infections in Children with Acute Lymphoblastic Leukemia. AB - In children, the most commonly encountered type of leukemia is acute lymphoblastic leukemia (ALL). An important source of morbidity and mortality in ALL are viral infections. Even though allogeneic transplantations, which are often applied also in ALL, carry a recognized risk for viral infections, there are multiple factors that make ALL patients susceptible to viral infections. The presence of those factors has an influence in the type and severity of infections. Currently available treatment options do not guarantee a positive outcome for every case of viral infection in ALL, without significant side effects. Side effects can have very serious consequences for the ALL patients, which include nephrotoxicity. For this reason a number of strategies for personalized intervention have been already clinically tested, and experimental approaches are being developed. Adoptive immunotherapy, which entails administration of ex vivo grown immune cells to a patient, is a promising approach in general, and for transplant recipients in particular. The ex vivo grown cells are aimed to strengthen the immune response to the virus that has been identified in the patients' blood and tissue samples. Even though many patients with weakened immune system can benefit from progress in novel approaches, a viral infection still poses a very significant risk for many patients. Therefore, preventive measures and supportive care are very important for ALL patients. PMID- 27471585 TI - Sequence comparison, molecular modeling, and network analysis predict structural diversity in cysteine proteases from the Cape sundew, Drosera capensis. AB - Carnivorous plants represent a so far underexploited reservoir of novel proteases with potentially useful activities. Here we investigate 44 cysteine proteases from the Cape sundew, Drosera capensis, predicted from genomic DNA sequences. D. capensis has a large number of cysteine protease genes; analysis of their sequences reveals homologs of known plant proteases, some of which are predicted to have novel properties. Many functionally significant sequence and structural features are observed, including targeting signals and occluding loops. Several of the proteases contain a new type of granulin domain. Although active site residues are conserved, the sequence identity of these proteases to known proteins is moderate to low; therefore, comparative modeling with all-atom refinement and subsequent atomistic MD-simulation is used to predict their 3D structures. The structure prediction data, as well as analysis of protein structure networks, suggest multifarious variations on the papain-like cysteine protease structural theme. This in silico methodology provides a general framework for investigating a large pool of sequences that are potentially useful for biotechnology applications, enabling informed choices about which proteins to investigate in the laboratory. PMID- 27471587 TI - Examination of crime and similar concepts in the medical law. AB - Crime is a human behavior that has captivated the thoughts of scholars of various disciplines throughout history. Philosophers, sociologists, psychologists and others have investigated and analyzed the concept of crime from different aspects. Crime is the main topic of criminal law, and in its legal meaning is a well-known term with a certain conceptual load that should not be confused with similar concepts such as guilt, civil crime (quasi tort), and particularly, the disciplinary transgression. Although crime has common points with all the above, it is an independent concept with unique effects, features, and descriptions that distinguish it from similar acts. This article aims to determine the difference between the concepts of crime, guilt, civil crime and disciplinary transgression through enumeration of the related issues as well as examples of medical disciplinary crimes and transgressions. Identifying and distinguishing these concepts can improve the procedure of prosecuting crimes and disciplinary transgression, bring punishment to criminals and transgressors, and facilitate compensation of pecuniary and non-pecuniary losses due to committers' fault or failure. Thus we may avoid taking a wrong route that can lead to infringement of individuals' rights. PMID- 27471590 TI - Readability of informed consent forms in clinical trials conducted in a skin research center. AB - Obtaining informed consents is one of the most fundamental principles in conducting a clinical trial. In order for the consent to be informed, the patient must receive and comprehend the information appropriately. Complexity of the consent form is a common problem that has been shown to be a major barrier to comprehension for many patients. The objective of this study was to assess the readability of different templates of informed consent forms (ICFs) used in clinical trials in the Center for Research and Training in Skin Diseases and Leprosy (CRTSDL), Tehran, Iran. This study was conducted on ICFs of 45 clinical trials of the CRTSDL affiliated with Tehran University of Medical Sciences. ICFs were tested for reading difficulty, using the readability assessments formula adjusted for the Persian language including the Flesch-Kincaid reading ease score, Flesch-Kincaid grade level, and Gunning fog index. Mean readability score of the whole text of ICFs as well as their 7 main information parts were calculated. The mean +/- SD Flesch Reading Ease score for all ICFs was 31.96 +/- 5.62 that is in the difficult range. The mean +/- SD grade level was calculated as 10.71 +/- 1.8 (8.23-14.09) using the Flesch-Kincaid formula and 14.64 +/- 1.22 (12.67-18.27) using the Gunning fog index. These results indicate that the text is expected to be understandable for an average student in the 11(th) grade, while the ethics committee recommend grade level 8 as the standard readability level for ICFs. The results showed that the readability scores of ICFs assessed in our study were not in the acceptable range. This means they were too complex to be understood by the general population. Ethics committees must examine the simplicity and readability of ICFs used in clinical trials. PMID- 27471586 TI - Students' medical ethics rounds: a combinatorial program for medical ethics education. AB - It has long been a common goal for both medical educators and ethicists to develop effective methods or programs for medical ethics education. The current lecture-based courses of medical ethics programs in medical schools are demonstrated as insufficient models for training "good doctors''. In this study, we introduce an innovative program for medical ethics education in an extra curricular student-based design named Students' Medical Ethics Rounds (SMER). In SMER, a combination of educational methods, including theater-based case presentation, large group discussion, expert opinions, role playing and role modeling were employed. The pretest-posttest experimental design was used to assess the impact of interventions on the participants' knowledge and attitude regarding selected ethical topics. A total of 335 students participated in this study and 86.57% of them filled the pretest and posttest forms. We observed significant improvements in the knowledge (P < 0.0500) and attitude (P < 0.0001) of participants. Interestingly, 89.8% of participants declared that their confidence regarding how to deal with the ethical problems outlined in the sessions was increased. All of the applied educational methods were reported as helpful. We found that SMER might be an effective method of teaching medical ethics. We highly recommend the investigation of the advantages of SMER in larger studies and interdisciplinary settings. PMID- 27471589 TI - Patients' satisfaction with inpatient services provided in hospitals affiliated to Tehran University of Medical Sciences, Iran, during 2011-2013. AB - Implementation of patient feedback is considered as a critical part of effective and efficient management in developed countries. The main objectives of this study were to assess patient satisfaction with the services provided in hospitals affiliated to Tehran University of Medical Sciences, Iran, identify areas of patient dissatisfaction, and find ways to improve patient satisfaction with hospital services. This cross-sectional study was conducted in 3 phases. After 2 initial preparation phases, the valid instrument was applied through telephone interviews with 21476 participants from 26 hospitals during August, 2011 to February, 2013.Using the Satisfaction Survey tool, information of patient's demographic characteristics were collected and patient satisfaction with 15 areas of hospital services and the intent to return the same hospitals were assessed. The mean score of overall satisfaction with hospital services was 16.86 +/- 2.72 out of 20. It was found that 58% of participants were highly satisfied with the services provided. Comparison of mean scores showed physician and medical services (17.75 +/- 4.02), laboratory and radiology services (17.67 +/- 3.66), and privacy and religious issues (17.55 +/- 4.32) had the highest satisfaction. The patients were the most dissatisfied with the food services (15.50 +/- 5.54). It was also found that 83.7% of the participants intended to return to the same hospital in case of need, which supported the measured satisfaction level. Patient satisfaction in hospitals affiliated to Tehran University of Medical Sciences was high. It seems that the present study, with its large sample size, has sufficient reliability to express the patient satisfaction status. Moreover, appropriate measures should be taken in some areas (food, cost, and etc.) to increase patient satisfaction. PMID- 27471591 TI - Organ transplantation and gender differences: a paradigmatic example of intertwining between biological and sociocultural determinants. AB - Organ transplantation, e.g., of the heart, liver, or kidney, is nowadays a routine strategy to counteract several lethal human pathologies. From literature data and from data obtained in Italy, a striking scenario appears well evident: women are more often donors than recipients. On the other hand, recipients of organs are mainly males, probably reflecting a gender bias in the incidence of transplant-related pathologies. The impact of sex mismatch on transplant outcome remains debated, even though donor-recipient sex mismatch, due to biological matters, appears undesirable in female recipients. In our opinion, the analysis of how sex and gender can interact and affect grafting success could represent a mandatory task for the management of organ transplantation. PMID- 27471588 TI - Patient advocacy from the clinical nurses' viewpoint: a qualitative study. AB - One of the advanced nursing care procedures emphasized by nursing organizations around the world is patient or nursing advocacy. In addition to illustrating the professional power of nursing, it helps to provide effective nursing care. The aim of the present study was to explain the concept of patient advocacy from the perspective of Iranian clinical nurses. This was a qualitative study that examined the viewpoint and experiences of 15 clinical nurses regarding patient advocacy in nursing. The nurses worked in intensive care units (ICUs), coronary care units (CCUs), and emergency units. The study participants were selected via purposeful sampling. The data was collected through semi-structured interviews and analyzed using content analysis. Data analysis showed that patient advocacy consisted of the two themes of empathy with the patient (including understanding, being sympathetic with, and feeling close to the patient) and protecting the patients (including patient care, prioritization of patients' health, commitment to the completion of the care process, and protection of patients' rights). The results of this study suggest that nurses must be empathetic toward and protective of their patients. The results of the present study can be used in health care delivery, nursing education, and nursing management and planning systems to help nurses accomplish their important role as patient advocates. It is necessary to further study the connections between patient advocacy and empathy. PMID- 27471592 TI - 1,25-Dihydroxyvitamin D3 modulates calcium transport in goat mammary epithelial cells in a dose- and energy-dependent manner. AB - BACKGROUND: Calcium is a vital mineral and an indispensable component of milk for ruminants. The regulation of transcellular calcium transport by 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3, the active form of vitamin D) has been confirmed in humans and rodents, and regulators, including vitamin D receptor (VDR), calcium binding protein D9k (calbindin-D9k), plasma membrane Ca(2+)-ATPase 1b (PMCA1b), PMAC2b and Orai1, are involved in this process. However, it is still unclear whether 1,25-(OH)2D3 could stimulate calcium transport in the ruminant mammary gland. The present trials were conducted to study the effect of 1,25 (OH)2D3 supplementation and energy availability on the expression of genes and proteins related to calcium secretion in goat mammary epithelial cells. METHODS: An in vitro culture method for goat secreting mammary epithelial cells was successfully established. The cells were treated with different doses of 1,25 (OH)2D3 (0, 0.1, 1.0, 10.0 and 100.0 nmol/L) for calcium transport research, followed by a 3-bromopyruvate (3-BrPA, an inhibitor of glucose metabolism) treatment to determine its dependence on glucose availability. Cell proliferation ratios, glucose consumption and enzyme activities were measured with commercial kits, and real-time quantitative polymerase chain reaction (RT-qPCR), and western blots were used to determine the expression of genes and proteins associated with mammary calcium transport in dairy goats, respectively. RESULTS: 1,25-(OH)2D3 promoted cell proliferation and the expression of genes involved in calcium transport in a dose-dependent manner when the concentration did not exceed 10.0 nmol/L. In addition, 100.0 nmol/L 1,25-(OH)2D3 inhibited cell proliferation and the expression of associated genes compared with the 10.0 nmol/L treatment. The inhibition of hexokinase 2 (HK2), a rate-limiting enzyme in glucose metabolism, decreased the expression of PMCA1b and PMCA2b at the mRNA and protein levels as well as the transcription of Orai1, indicating that glucose availability was required for goat mammary calcium transport. The optimal concentration of 1,25 (OH)2D3 that facilitated calcium transport in this study was 10.0 nmol/L. CONCLUSIONS: Supplementation with 1,25-(OH)2D3 influenced cell proliferation and regulated the expression of calcium transport modulators in a dose- and energy dependent manner, thereby highlighting the role of 1,25-(OH)2D3 as an efficacious regulatory agent that produces calcium-enriched milk in ruminants when a suitable energy status was guaranteed. PMID- 27471593 TI - Volume kinetic evaluation of fluid turnover after oral intake of tap water, lemonade and saline in volunteers. AB - BACKGROUND: Volume kinetic fluid turnover of three beverages was investigated for the purpose of estimating their rates of absorption and elimination as well as their maximum effect on the blood volume. The results were then used to simulate the effects of ingesting different combinations of these fluids. METHOD: Ten healthy volunteers ingested 0.5 L of tap water, lemonade (90 g/L carbohydrates) and isotonic saline (9 g/L) on different occasions. Venous blood samples for measurement of the blood haemoglobin (Hb), haematocrit and glucose concentrations were collected on 10 occasions over 2 h. A kinetic model based on haemoglobin dilution and urinary excretion was used to estimate the rate of absorption, the blood volume expansion over time, and the rate of elimination. Obtained kinetic data was used to simulate combinations of the three beverages in order to reach a predetermined goal of a 1:1 hydration of the blood volume and peripheral tissues over 6 h. RESULTS: Tap water had the fastest absorption but primarily hydrated peripheral tissues. Maximum hydration was reached after 17 min. Lemonade effectively expanded the blood volume and was absorbed and excreted at a high rate. The maximum hydration from isotonic saline occurred 60 min after ingestion. Slow excretion could make it possible to use saline to prolong the effects of the other two beverages. CONCLUSIONS: It is possible to use the kinetic model to evaluate fluid turnover and compartmental distribution. Composition and timing of fluid intake can be calculated mathematically to meet predetermined goals of hydration and distribution. TRIAL REGISTRATION: NCT01360333 Date of registration: 05/23/2011. PMID- 27471594 TI - 'Black bronchoscopy': a case of active mycobacterial tuberculosis. AB - A 63-year-old male presents with chronic cough and hemoptysis. Computed tomography of the chest revealed a left lower lobe (LLL) area of consolidation with prominent ipsilateral hilar lymphadenopathy. Bronchoscopic airway examination revealed black mucosal discoloration and airway narrowing at the superior segment of the LLL. Bronchoalveolar lavage from the corresponding site grew mycobacterial tuberculosis. The patient's symptoms subsided with anti tuberculous therapy with a significant decrease in the size of the LLL mass. PMID- 27471595 TI - Neurocysticercosis in pregnancy: maternal and fetal outcomes. AB - Neurocysticercosis (NCC) is a parasitic infection with the larvae of Taenia solium from contaminated pork. It is a leading cause of seizures in the developing world. Symptoms may be secondary to live or degenerating cysts, or previous infection causing calcification or gliosis. Diagnosis is based on clinical presentation, radiological confirmation of intracranial lesions and immunological testing. Management involves symptom control with antiepileptics and antiparasitic agents. Few cases have been described of maternal NCC during pregnancy. We describe a 25-year-old female presenting to a London hospital with secondary generalized seizures. MRI of the brain confirmed a calcified lesion in the right parietal lobe, and she gave a corroborative history of NCC during her childhood in India. She was stabilized initially on antiepileptics, but during her pregnancy presented with breakthrough seizures and radiological evidence of NCC reactivation. She was managed symptomatically with antiepileptics and completed the pregnancy to term with no fetal complications. PMID- 27471596 TI - Bilateral genu valgum: an unusual presentation of juvenile primary hyperparathyroidism. AB - Primary hyperparathyroidism is a generalized disorder of bone and mineral metabolism caused by autonomous secretion of parathyroid hormone. It is primarily seen in adults with typical age of presentation between third and fifth decades of life. Juvenile hyperparathyroidism is a rare disorder. The common presentations in order of incidence are fatigue and lethargy, headache, nephrolithiasis, nausea, abdominal pain, vomiting and polydipsia. Though skeletal symptoms include bone pains and fractures, but the presence of limb deformity is atypical. We report a case of young girl who presented with isolated progressive genu valgum of both lower limbs and pigeon-shaped chest deformity. She was found to have hypercalcemia and hypophosphatemia with raised parathyroid hormone levels. The neck imaging showed a single adenoma in the left inferior parathyroid gland. The surgical removal of parathyroid adenoma was performed. PMID- 27471597 TI - The DKA that wasn't: a case of euglycemic diabetic ketoacidosis due to empagliflozin. AB - Sodium glucose co-transporter (SGLT-2) inhibitor is a relatively new medication used to treat diabetes. At present, the Food and Drug Administration (FDA) has only approved three medications (canagliflozin, dapagliflozin and empagliflozin) in this drug class for the management of Type 2 diabetes. In May 2015, the FDA issued a warning of ketoacidosis with use of this drug class. Risk factors for the development of ketoacidosis among patients who take SGLT-2 inhibitors include decrease carbohydrate intake/starvation, acute illness and decrease in insulin dose. When identified, immediate cessation of the medication and administration of glucose must be done, and in some instances, starting an insulin drip might be necessary. We present a case of a patient with diabetes mellitus being on empagliflozin (SGLT-2 antagonist) who was admitted for acute cholecystitis. The hospital course was complicated by euglycemic diabetic ketoacidosis after being kept nothing per orem before a contemplated cholecystectomy. PMID- 27471598 TI - Hypomagnesemia as a potentially life-threatening adverse effect of omeprazole. AB - Hypomagnesemia can be caused by a wide range of diseases (e.g. gastrointestinal disorders, kidney diseases or endocrine disorders), but it can also be a side effect of several drugs. It can be asymptomatic or cause many different clinical symptoms, and the clinical manifestations mainly depend on the rate of development rather than the actual serum magnesium concentration. We here present a 40-year-old female patient with Torsade de pointes ventricular tachycardia and cardiac arrest caused by severe hypomagnesemia as an adverse effect of the proton pump inhibitor omeprazole. PMID- 27471599 TI - An unusual presentation of xanthogranulomatous pyelonephritis: psoas abscess with reno-colic fistula. AB - Xanthogranulomatous pyelonephritis (XGP) is a rare histological subset of pyelonephritis characterized by being a chronic destructive granulomatous inflammation of the renal parenchyma. XGP is classified according to the extent of disease into two entities: within the renal cortex (focal or segmental XGP) or diffuse spread with pelvic communication (diffuse XGP). Although rare, XGP can have fatal complications including perinephric, psoas abscess, nephro-cutaneous fistula and reno-colic fistula. Only few studies have reported XGP complicated with psaos abcess and reno-colic fistula. Our aim is to add to the literature and share our experience with a case of extensive XGP eroding into the psoas muscle and ascending colon leading to severe sepsis that was successfully managed. We report a 56-year-old woman who was found to have XGP complicated by psoas abscess and reno-colic fistula managed by antibiotics, nephrostomy, and subsequent nephrectomy and partial colectomy. PMID- 27471600 TI - The Application of OCTA in Assessment of Anti-VEGF Therapy for Idiopathic Choroidal Neovascularization. AB - Purpose. To assess the morphology of idiopathic choroidal neovascularization (ICNV) by optical coherence tomography angiography (OCTA) and determine the therapeutic effects of intravitreal antivascular endothelial growth factor (anti VEGF). Method. Patients with naive ICNV were assessed by spectral domain optical coherence tomography (SD-OCT) and OCTA in this observational study. The timing of observation was before treatment, 1 day after treatment with intravitreal anti VEGF injection, and 1 month after the treatment. The central retina thickness (CRT) on SD-OCT, selected CNV area, and flow area on OCTA were measured. Results. A total of 17 eyes from 17 patients with ICNV were included in this study. OCTA showed visible irregular choroidal neovascularization with "tree-in-bud" form on outer retinal layer. After treatment, as well as in the 1-day follow-up, CNV decreased in size from the periphery, and the vessel density was reduced. As shown on OCTA, the selected CNV area and flow area were significantly reduced compared to pretreatment. The rate of CNV vessel area changes was higher on OCTA than the changes in CRT on SD-OCT at 1-day and 1-month follow-up. Conclusion. Intravitreal injection of anti-VEGF is effective for idiopathic choroidal neovascularization, and the treatment outcomes are observable after 1 day. OCTA provides a useful approach for monitoring and evaluating the treatment of intravitreal anti-VEGF for CNV. PMID- 27471601 TI - Novel Pattern of Iron Deposition in the Fascicula Nigrale in Patients with Parkinson's Disease: A Pilot Study. AB - Background and Purpose. To determine whether the pattern of iron deposition in the fascicula nigrale in patients with Parkinson's disease would be different from age-matched controls by utilizing quantitative susceptibility mapping to measure susceptibility change. Methods. MRIs of the brain were obtained from 34 subjects, 18 with Parkinson's disease and 16 age- and gender-matched controls. Regions of interest were drawn around the fascicula nigrale and substantia nigra using SWI mapping software by blinded investigators. Statistical analyses were performed to determine susceptibility patterns of both of these regions. Results. Measurements showed significantly increased susceptibility in the substantia nigra in Parkinson's patients and an increased rostral-caudal deposition of iron in the fascicula nigrale in all subjects. This trend was exaggerated with significant correlation noted with increasing age in the Parkinson group. Conclusion. The pattern of an exaggerated iron deposition gradient of the fascicula nigrale in the Parkinson group could represent underlying tract dysfunction. Significant correlation of increasing iron deposition with increasing age may be a cumulative effect, possibly related to disease duration. PMID- 27471602 TI - Synthesis, Molecular Modeling, and Biological Evaluation of Novel Tetrahydro-beta Carboline Hydantoin and Tetrahydro-beta-Carboline Thiohydantoin Derivatives as Phosphodiesterase 5 Inhibitors. AB - Two series of fused tetrahydro-beta-carboline hydantoin and tetrahydro-beta carboline thiohydantoin derivatives with a pendant 2,4-dimethoxyphenyl at position 5 were synthesized, and chiral carbons at positions 5 and 11a swing from R,R to R,S, S,R, and S,S. The prepared analogues were evaluated for their capacity to inhibit phosphodiesterase 5 (PDE5) isozyme. The R absolute configuration of C-5 in the beta-carboline hydantoin derivatives was found to be essential for the PDE5 inhibition. Chiral carbon derived from amino acid even if of the S configuration (L-tryptophan) may lead to equiactive or more active isomers than those derived from amino acid with the R configuration (D tryptophan). This expands the horizon from which efficient PDE5 inhibitors can be derived and may offer an economic advantage. The thiohydantoin derivatives were less active than their hydantoin congeners. PMID- 27471603 TI - Prevalence of Tinea Capitis among School Children in Nok Community of Kaduna State, Nigeria. AB - In recent years, the prevalence of tinea capitis, an infection of the scalp by dermatophytes, has increased in children worldwide. This cross-sectional study was carried out to determine the prevalence and risk factor of tinea capitis among school children in Nok community of Kaduna State, Nigeria. A total of 100 children were screened and 45% were diagnosed to have tinea capitis after fungal culture and microscopy. The prevalence of tinea capitis among girls was higher (51.4%) than that among boys (41.5%) but not significantly different (p = 0.402). The prevalence with respect to age was lower for the age group 5-10 years (42.6%) than that of 11-15 years (50%) but was not significantly different (p = 0.524). Trichophyton rubrum (28.8%) and Microsporum canis (22.7%) were the most prevalent dermatophytes isolated and the least were Trichophyton verrucosum (4.5%) and Trichophyton tonsurans (4.5%). There were 73.3% single infection while 26.7% had 2-4 dermatophytes of the genera Microsporum and Trichophyton. The predisposing factors with statistically significant association with tinea capitis were number of children in the family (p = 0.02) and sharing of the same bed (p = 0.002). This indicates the high tendencies of spread of tinea capitis through human-to human mode of transmission and possible animal contact. Community health education on the cause, mode of transmission, prevention, and prompt treatment of tinea capitis is recommended. PMID- 27471604 TI - Developmental Variation of Indian Thermophilic Variety of Scuttle Fly Megaselia (Megaselia) scalaris (Loew, 1866) (Diptera: Phoridae) on Different Substrates. AB - The scuttle flies (Diptera: Phoridae) are important in forensic dipterology, because of their necrophagous habit. They are amongst the first wave of insects visiting human corpses in mechanically barricaded environments; hence their immature stages are generally used for estimation of PMI. The effect of different substrates commonly used for developmental studies was studied to analyze the variation of growth of the thermophilic variety of Megaselia (M.) scalaris prevalent in India on GDM, EDM, and SMS (n = 3). One approach of PMI estimation depends on larvae collected from the crime scene and comparing them with reference data derived from larval rearing to establish PMI. Results showed that there was a significant variation in avg. length (F(2,111) = 15.79873, p = 0.000000917), width (F(2,111) = 14.60528, p = 0.00000234), and biomass (F(2,111) = 37.01727, p = 0.000000000000482) of the immature stages in the three media and the larvae grow maximally in the SMS medium. The results of the present study thus provide baseline data on the growth and developmental pattern of the Megaselia (M.) scalaris, which can be utilized in conjunction with specific geoclimatic reference data, for forensic entomological studies and also for using the phorid as a biocontrol agent of pestiferous insects. PMID- 27471605 TI - DC vaccine generated by ALA-PDT-induced immunogenic apoptotic cells for skin squamous cell carcinoma. AB - Dendritic cell (DC) vaccines were generated by apoptotic squamous cell carcinoma (SCC) cells induced by 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT). ALA-PDT-DC vaccine inhibited the growth of SCC in mice, indicating that immunogenic apoptotic cells can activate an effective antitumor adaptive immunity and lead to a DC vaccine-based cancer immunotherapy. PMID- 27471606 TI - The dual role of NK cells in antitumor reactions triggered by ionizing radiation in combination with hyperthermia. AB - Classical tumor therapy consists of surgery, radio(RT)- and/or chemotherapy. Additive immunotherapy has gained in impact and antitumor in situ immunization strategies are promising to strengthen innate and adaptive immune responses. Immunological effects of RT and especially in combination with immune stimulation are mostly described for melanoma. Since hyperthermia (HT) in multimodal settings is capable of rendering tumor cells immunogenic, we analyzed the in vivo immunogenic potential of RT plus HT-treated B16 melanoma cells with an immunization and therapeutic assay. We focused on the role of natural killer (NK) cells in the triggered antitumor reactions. In vitro experiments showed that RT plus HT-treated B16 melanoma cells died via apoptosis and necrosis and released especially the danger signal HMGB1. The in vivo analyses revealed that melanoma cells are rendered immunogenic by RT plus HT. Especially, the repetitive immunization with treated melanoma cells led to an increase in NK cell number in draining lymph nodes, particularly of the immune regulatory CD27(+)CD11b(-) NK cell subpopulation. While permanent NK cell depletion after immunization led to a significant acceleration of tumor outgrowth, a single NK cell depletion two days before immunization resulted in significant tumor growth retardation. The therapeutic model, a local in situ immunization closely resembling the clinical situation when solid tumors are exposed locally to RT plus HT, confirmed these effects. We conclude that a dual and time-dependent impact of NK cells on the efficacy of antitumor immune reactions induced by immunogenic tumor cells generated with RT plus HT exists. PMID- 27471607 TI - An oncofetal antigen, IMP-3-derived long peptides induce immune responses of both helper T cells and CTLs. AB - Insulin-like growth factor II mRNA-binding protein 3 (IMP-3), an oncofetal antigen identified using genome-wide cDNA microarray analyses, is overexpressed in several malignancies. IMP-3-derived cytotoxic T lymphocyte (CTL) epitopes have been used for peptide-based immunotherapies against various cancers. In addition to CTLs, induction of tumor-associated antigen (TAA)-specific helper T (Th) cells is crucial for establishment of effective antitumor immunity. In this study, we aimed to identify IMP-3-derived long peptides (IMP-3-LPs) carrying CTL and promiscuous Th-cell epitopes for use in cancer immunotherapy. IMP-3-derived Th cell epitopes that bind to multiple HLA-class II molecules were predicted by in silico analysis, and their immunogenicity was determined by utilizing human T cells. We identified two highly immunogenic IMP-3-LPs presented by multiple HLA class II molecules. One of the IMP-3-LPs encompassed two CTL epitopes that have been used for peptide-vaccine immunotherapy in ongoing clinical trials. IMP-3-LPs specific Th cells responded to autologous dendritic cells (DCs) loaded with the recombinant IMP-3 proteins, suggesting that these s (LPs) can be naturally processed and presented. The IMP-3-LPs and specific Th cells augmented the expansion of IMP-3-specific CTLs, which was further enhanced by programmed cell death-1 (PD-1) blockade. In addition, IMP-3-LP encapsulated in liposomes was efficiently cross-presented in vitro, and this LP successfully cross-primed CTLs in HLA-A2 transgenic mice (Tgm) in vivo. Furthermore, one of the IMP-3-LPs induced IMP-3-specific Th cells from peripheral blood mononuclear cells (PBMCs) of head-and-neck malignant tumor (HNMT) patients. These findings suggest the potential usefulness of IMP-3-LPs in propagating both Th cells and CTLs and may have implications for IMP-3-LPs-based cancer immunotherapy. PMID- 27471608 TI - Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis. AB - Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics. PMID- 27471609 TI - Tumor relapse prevented by combining adoptive T cell therapy with Salmonella typhimurium. AB - We recently reported that therapeutic vaccination with live tumor antigen producing Salmonella typhimurium rescues dysfunctional endogenous T cell responses and eradicates long-established tumors refractory to alphaCTLA-4 and alphaPD-L1 checkpoint inhibitor blockade. Here, we show that live intravenously injected or heat-killed (HK) intratumorally injected Salmonella typhimurium, even when not producing tumor antigen, synergize with adoptive T cell therapy to eradicate tumors. These data demonstrate that the combination of adoptive T cell transfer with the injection of live or dead Salmonella typhimurium is a promising approach for cancer treatment. PMID- 27471610 TI - Inhibition of formyl peptide receptor 1 reduces the efficacy of anticancer chemotherapy against carcinogen-induced breast cancer. AB - The loss-of-function mutation of formyl peptide receptor 1 (FPR1) has a negative impact on the progression-free and overall survival of breast cancer patients treated with anthracycline-based adjuvant chemotherapy. This effect may be attributed to the fact that chemotherapy-induced antitumor immunity requires FPR1 and that such anticancer immune responses are responsible for the long-term effects of chemotherapy. Here, we investigated the possible contribution of FPR1 to the efficacy of a combination of mitoxantrone (MTX) and cyclophosphamide (CTX) for the treatment of hormone-induced breast cancer. Breast cancer induced by a combination of medroxyprogesterone acetate (MPA) and 7,12 Dimethylbenz[a]anthracene (DMBA) could be successfully treated with MTX plus CTX in thus far that tumor growth was retarded and overall survival was extended (as compared to vehicle-only treated controls). However, the therapeutic efficacy of the combination therapy was completely abolished when FPR1 receptors were blocked by means of cyclosporin H (CsH). Future genetic studies on neoadjuvant chemotherapy-treated breast cancers are warranted to validate these findings at the clinical level. PMID- 27471612 TI - Tasquinimod modulates tumor-infiltrating myeloid cells and improves the antitumor immune response to PD-L1 blockade in bladder cancer. AB - The infiltration of myeloid cells helps tumors to overcome immune surveillance and imparts resistance to cancer immunotherapy. Thus, strategies to modulate the effects of these immune cells may offer a potential therapeutic benefit. We report here that tasquinimod, a novel immunotherapy which targets S100A9 signaling, reduces the immunosuppressive properties of myeloid cells in preclinical models of bladder cancer (BCa). As single anticancer agent, tasquinimod treatment was effective in preventing early stage tumor growth, but did not achieve a clear antitumor effect in advanced tumors. Investigations of this response revealed that tasquinimod induces an increase in the expression of a negative regulator of T cell activation, Programmed-death-ligand 1 (PD-L1). This markedly weakens its antitumor immunity, yet provokes an "inflamed" milieu rendering tumors more prone to T cell-mediated immune attack by PD-L1 blockade. Interestingly, the combination of tasquinimod with an Anti-PD-L1 antibody enhanced the antitumor immune response in bladder tumors. This combination synergistically modulated tumor-infiltrating myeloid cells, thereby strongly affecting proliferation and activation of effector T cells. Together, our data provide insight into the rational combination of therapies that activate both innate and adaptive immune system, such as the association of S100A9-targeting agents with immune checkpoints inhibitors, to improve the response to cancer immunotherapeutic agents in BCa. PMID- 27471613 TI - Intratumoral delivery of mTORC2-deficient dendritic cells inhibits B16 melanoma growth by promoting CD8(+) effector T cell responses. AB - Dendritic cells (DC) play a pivotal role in the induction and regulation of immune responses. In cancer, DC-based vaccines have proven to be safe and to elicit protective and therapeutic immunological responses. Recently, we showed that specific mTORC2 (mechanistic target of rapamycin complex 2) deficiency in DC enhances their ability to promote Th1 and Th17 responses after LPS stimulation. In the present study, bone marrow-derived mTORC2-deficient (Rictor(-/-)) DC were evaluated as a therapeutic modality in the murine B16 melanoma model. Consistent with their pro-inflammatory profile (enhanced IL-12p70 production and low PD-L1 expression versus control DC), intratumoral (i.t.) injection of LPS-activated Rictor(-/-) DC slowed B16 melanoma growth markedly in WT C57BL/6 recipient mice. This antitumor effect was abrogated when Rictor(-/-) DC were injected i.t. into B16-bearing Rag(-/-) mice, and also after selective CD8(+) T cell depletion in wild-type hosts in vivo, indicating that CD8(+) T cells were the principal regulators of tumor growth after Rictor(-/-) DC injection. I.t. administration of Rictor(-/-) DC also reduced the frequency of myeloid-derived suppressor cells within tumors, and enhanced numbers of IFNgamma(+) and granzyme-B(+) cytotoxic CD8(+) T cells both in the spleens and tumors of treated animals. These data suggest that selective inhibition of mTORC2 activity in activated DC augments their pro-inflammatory and T cell stimulatory profile, in association with their enhanced capacity to promote protective CD8(+) T cell responses in vivo, leading to slowed B16 melanoma progression. These novel findings may contribute to the design of more effective DC-based vaccines for cancer immunotherapy. PMID- 27471614 TI - CD8(+) Tregs promote GVHD prevention and overcome the impaired GVL effect mediated by CD4(+) Tregs in mice. AB - Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (Allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemia (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4(+) or CD8(+) T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4(+) iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8(+) iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4(+) and CD8(+) iTregs could achieve the optimal goal of Allo-HCT. Indeed, the combinational therapy was superior to CD4(+) or CD8(+) iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4(+) and CD8(+) effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8(+) iTregs possess elevated expression of multiple cytolytic molecules compared to CD4(+) iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4(+) and CD8(+) iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses. PMID- 27471615 TI - A novel dendritic cell targeting HPV16 E7 synthetic vaccine in combination with PD-L1 blockade elicits therapeutic antitumor immunity in mice. AB - Human papilliomavirus (HPV) oncogene E7, essential for the transformation and maintenance of the malignancy of cervical cancer cells, represents an ideal tumor specific antigen for vaccine development. However, due to the poor immunogenicity of E7 protein, an effective therapeutic E7 vaccine is still lacking. Dendritic cells (DCs) are probably the most potent antigen presenting cells for the induction of cytotoxic T lymphocyte (CTL) response, which is crucial for tumor control. In this study, we tested whether targeting the E7 antigen to DCs in vivo would elicit therapeutic antitumor CTL response. We generated the DEC205-specific single-chain variable fragment (scFv) and E7 long peptide fusion protein [scFv(DEC205)-E7] based on the novel method of protein assembly we recently developed. This fusion protein vaccine demonstrated highly efficient DC-targeting in vivo and elicited much stronger protective CTL response than non-DC-targeting control vaccine in naive mice. Furthermore, the scFv(DEC205)-E7 vaccine showed significant therapeutic antitumor response in TC-1 tumor bearing mice. Importantly, PD-L1 blockade further improved the therapeutic effect of the scFv(DEC205)-E7 vaccine. Thus, the current study suggests an efficient strategy for cervical cancer immunotherapy by combining the DC(DEC205)-targeting E7 vaccine and PD-L1 blockade. PMID- 27471611 TI - Prioritization schema for immunotherapy clinical trials in glioblastoma. AB - BACKGROUND: Emerging immunotherapeutic strategies for the treatment of glioblastoma (GBM) such as dendritic cell (DC) vaccines, heat shock proteins, peptide vaccines, and adoptive T-cell therapeutics, to name a few, have transitioned from the bench to clinical trials. With upcoming strategies and developing therapeutics, it is challenging to critically evaluate the practical, clinical potential of individual approaches and to advise patients on the most promising clinical trials. METHODS: The authors propose a system to prioritize such therapies in an organized and data-driven fashion. This schema is based on four categories of factors: antigenic target robustness, immune-activation and effector responses, preclinical vetting, and early evidence of clinical response. Each of these categories is subdivided to focus on the most salient elements for developing a successful immunotherapeutic approach for GBM, and a numerical score is generated. RESULTS: The Score Card reveals therapeutics that have the most robust data to support their use, provides a reference prioritization score, and can be applied in a reiterative fashion with emerging data. CONCLUSIONS: The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population. PMID- 27471616 TI - Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy. AB - Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 (-/-) and Mlkl (-/-) tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 (-/-) and Mlkl (-/-) cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity. PMID- 27471618 TI - Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs. AB - Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C-C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C-C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80(+) macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5(+) Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth. PMID- 27471619 TI - Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota. AB - Reduced anticancer efficacy of cyclophosphamide and platinum salts has been reported in animals treated with anti-Gram-positive antibiotics. These effects were related to translocation of Gram-positive bacteria during mucositis with subsequent induction of cytotoxic oxygen reactive species and tumor invasion by pathogenic Th17 cells. To assess these hypotheses in a clinical setting, we identified patients receiving cyclophosphamide for chronic lymphocytic leukemia (CLL) and cisplatin for relapsed lymphoma. Data originated from the CLL8 trial (NCT00281918) and the Cologne Cohort of Neutropenic Patients (NCT01821456). Relevant antibiotics were defined as compounds with primary activity against Gram positive bacteria. We evaluated their impact on response, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier methodology and Cox proportional hazards regression analysis. Among 800 available CLL patients, those receiving anti-Gram-positive antibiotics (n = 45/800) achieved a significantly lower overall response rate (OR 74.3% vs. 90.2%, p = 0.007). Patients with anti Gram-positive antibiotics progressed significantly earlier, had a reduced OS (median PFS 14.1 vs. 44.1 mo, p < 0.001; median OS 56.1 vs. 91.7 mo, p < 0.001) and multivariate analysis showed that administration of anti-Gram-positive antibiotic treatment was independently associated with reduced PFS (Hazard ratio (HR) 2.090, p = 0.001) and OS (HR 2.966, p < 0.001). Of 122 patients with relapsed lymphoma, those treated with anti-Gram-positive antibiotics (n = 21/122) achieved a significantly lower OR rate (70.3% vs. 42.9%, p = 0.016). Patients with anti-Gram-positive antibiotics progressed significantly earlier than others (median PFS 2.3 vs. 11.5 mo, p = 0.001). As for multivariate analysis, the use of anti-Gram-positive antibiotics was independently associated with reduced PFS (HR 2.237, p = 0.012) and OS (HR 7.831, p < 0.001). Our data supports a potential negative impact of anti-Gram-positive antibiotics on the anticancer activity of cyclophosphamide and cisplatin in a clinical setting. PMID- 27471620 TI - A Tec kinase BTK inhibitor ibrutinib promotes maturation and activation of dendritic cells. AB - Ibrutinib, a BTK inhibitor, is currently used to treat various hematological malignancies. We evaluated whether ibrutinib treatment during development of murine bone marrow-derived dendritic cells (DCs) modulates their maturation and activation. Ibrutinib treatment increased the proportion of CD11c(+) DCs, upregulated the expression of MHC-II and CD80 and downregulated Ly6C expression by DCs. Additionally, ibrutinib treatment led to an increase in MHC-II(+), CD80(+) and CCR7(+) DCs but a decrease in CD86(+) DCs upon LPS stimulation. LPS/ibrutinib-treated DCs displayed increased IFNbeta and IL-10 synthesis and decreased IL-6, IL-12 and NO production compared to DCs stimulated with LPS alone. Finally, LPS/ibrutinib-treated DCs promoted higher rates of CD4(+) T cell proliferation and cytokine production compared to LPS only stimulated DCs. Taken together, our results indicate that ibrutinib enhances the maturation and activation of DCs to promote CD4(+) T cell activation which could be exploited for the development of DC-based cancer therapies. PMID- 27471621 TI - NLRC5 elicits antitumor immunity by enhancing processing and presentation of tumor antigens to CD8(+) T lymphocytes. AB - Cancers can escape immunesurveillance by diminishing the expression of MHC class I molecules (MHC-I) and components of the antigen-processing machinery (APM). Developing new approaches to reverse these defects could boost the efforts to restore antitumor immunity. Recent studies have shown that the expression of MHC I and antigen-processing molecules is transcriptionally regulated by NOD-like receptor CARD domain containing 5 (NLRC5). To investigate whether NLRC5 could be used to improve tumor immunogenicity, we established stable lines of B16-F10 melanoma cells expressing NLRC5 (B16-5), the T cell co-stimulatory molecule CD80 (B16-CD80) or both (B16-5/80). Cells harboring NLRC5 constitutively expressed MHC I and LMP2, LMP7 and TAP1 genes of the APM. The B16-5 cells efficiently presented the melanoma antigenic peptide gp10025-33 to Pmel-1 TCR transgenic CD8(+) T cells and induced their proliferation. In the presence of CD80, B16-5 cells stimulated Pmel-1 cells even without the addition of gp100 peptide, indicating that NLRC5 facilitated the processing and presentation of endogenous tumor antigen. Upon subcutaneous implantation, B16-5 cells showed markedly reduced tumor growth in C57BL/6 hosts but not in immunodeficient hosts, indicating that the NLRC5 expressing tumor cells elicited antitumor immunity. Following intravenous injection, B16-5 and B16-5/80 cells formed fewer lung tumor foci compared to control cells. In mice depleted of CD8(+) T cells, B16-5 cells formed large subcutaneous and lung tumors. Finally, immunization with irradiated B16-5 cells conferred protection against challenge by parental B16 cells. Collectively, our findings indicate that NLRC5 could be exploited to restore tumor immunogenicity and to stimulate protective antitumor immunity. PMID- 27471622 TI - CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma. AB - Immature myeloid cells such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages play a vital role in the tumor immune escape and tumor progression. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4), as a negative immune checkpoint, is highly expressed in numerous solid tumors. However, precise functions of CTLA4 in head and neck squamous cell carcinoma (HNSCC) have not yet been elucidated. In this study, we demonstrated that the ratio of CD8(+)/CTLA4 can be used as a potential index with a clinical prognostic value for HNSCC. Using immunocompetent transgenic mouse model with spontaneous HNSCC, we directly observed that targeting CTLA4 decreases MDSCs and M2 macrophages and promotes T cell activation in both tumor microenvironment and macro-environment. In all, our study provides direct evidence in vivo and proposes a rationale for CTLA4 inhibition as a future therapeutic strategy in patients with HNSCC. PMID- 27471617 TI - Trial Watch-Small molecules targeting the immunological tumor microenvironment for cancer therapy. AB - Progressing malignancies establish robust immunosuppressive networks that operate both systemically and locally. In particular, as tumors escape immunosurveillance, they recruit increasing amounts of myeloid and lymphoid cells that exert pronounced immunosuppressive effects. These cells not only prevent the natural recognition of growing neoplasms by the immune system, but also inhibit anticancer immune responses elicited by chemo-, radio- and immuno therapeutic interventions. Throughout the past decade, multiple strategies have been devised to counteract the accumulation or activation of tumor-infiltrating immunosuppressive cells for therapeutic purposes. Here, we review recent preclinical and clinical advances on the use of small molecules that target the immunological tumor microenvironment for cancer therapy. These agents include inhibitors of indoleamine 2,3-dioxigenase 1 (IDO1), prostaglandin E2, and specific cytokine receptors, as well as modulators of intratumoral purinergic signaling and arginine metabolism. PMID- 27471623 TI - Macrophages and c-Myc cross paths. AB - The c-Myc transcription factor has recently been proposed as a bona fide M2 macrophage marker. Although this finding represents a major step forward in the identification of different macrophage subsets, it also opens up the potential for speculation concerning the possible functions of c-Myc in macrophages and the implications for health and disease. PMID- 27471624 TI - Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases. AB - Tumor infiltrating lymphocytes in primary breast cancer (TIL) are acknowledged measures of disease free survival (DFS) in adjuvant and neoadjuvant settings. Little is known about the biology of metastasis infiltrating lymphocytes (mTIL) although the local immunity of the metastatic site may critically influence the infiltrate composite. To address this question, we compared mTIL with their matched TIL in 87 breast cancer patients and their corresponding distant metastasis at four different anatomical locations. Sections of surgical specimen were immunohistochemically analyzed for CD4(+), CD8(+) and CD20(+) lymphocytes in three different tumor compartments: intratumoral lymphocytes (iTIL) defined as lymphocytes in direct contact with breast cancer cells, stromal lymphocytes (sTIL) located within the intratumoral stromal tissue and invasive-margin lymphocytes (imTIL). Overall, we found fewer (p < 0.001) mTIL than TIL. Within the tumor compartments, imTIL were more frequent than sTIL and iTIL both within metastases and the matched primary tumors (PT) (p < 0.001). CD4(+) T cells were more numerous than CD8(+) T cells and CD20(+) B cells (p < 0.001). There was a similar pattern in PT and their corresponding metastasis. Only patients with brain metastases differed from the others displaying less CD20(+) B cells at the infiltrative margin of the PT (p < 0.05). In summary, mTIL were significantly reduced within metastases but still mirrored the infiltrate pattern of the PT, interestingly regardless of the metastatic anatomical locations investigated. Our results suggest that the PT assigns the infiltrating lymphocyte pattern resumed at the metastatic site. PMID- 27471626 TI - Predictive immune markers in advanced melanoma patients treated with ipilimumab. AB - Myeloid-derived suppressor cells (MDSCs) and chronic inflammatory factors induce immunosuppression and disease progression in advanced melanoma patients. They could serve as important markers allowing the identification of patients with high risk of melanoma progression as well as the detection of those patients who may benefit from the therapy with ipilimumab. PMID- 27471625 TI - Investigating the association between allergen-specific immunoglobulin E, cancer risk and survival. AB - Prior findings linking allergy and cancer have been inconsistent, which may be driven by diverse assessment methods. We used serum specific immunoglobulin E (IgE) against common inhalant allergens that was assessed prior to cancer diagnosis in studying this association. We selected 8,727 Swedish men and women who had measurements of serum allergen-specific IgE and total IgE between 1992 and 1996. Multivariable Cox regression using age as a timescale was performed to assess the associations of IgE sensitization, defined by any levels of serum specific IgE >=35 kU/L, with risk of overall and specific cancers. A test for trend was performed by assigning scores derived from allergen-specific IgE levels at baseline as an ordinal scale. Kaplan-Meier curves and log-rank test were used to assess cancer survival by IgE sensitization status. During a mean follow-up of 16 year, 689 persons were diagnosed with cancer. We found an inverse association between IgE sensitization and cancer risk, with a hazard ratio (HR) of 0.83 and 95% confidence intervals (CI) of 0.70-0.99. A similar trend was seen with specific IgE scores overall (Ptrend = 0.007) and in women (Ptrend = 0.01). Although IgE sensitization was not associated with risk of common site-specific cancers, serum specific IgE scores were inversely associated with melanoma risk in men and women combined, and with risk of female breast and gynecological cancers combined. No association with survival was observed. The association between circulating IgE levels and incident cancer may point toward a role of T helper 2 (TH2)-biased response in development of some cancers. PMID- 27471627 TI - miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer. AB - Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu. PMID- 27471628 TI - AIM2 inflammasome mediates Arsenic-induced secretion of IL-1 beta and IL-18. AB - Chronic sterile inflammation has been implicated in the pathogenesis of many cancers, including skin cancer. Chronic arsenic exposure is closely associated with the development of skin cancer. However, there is a lack of understanding how arsenic induces chronic inflammation in the skin. Interleukin-1 family cytokines play a central role in regulating immune and inflammatory response. IL 1alpha, IL-1beta and IL-18 are three pro-inflammatory cytokines in IL-1 family. Their secretion, especially the secretion of IL-1beta and IL-18, is regulated by inflammasomes which are multi-protein complexes containing sensor proteins, adaptor protein and caspase-1. The data from current study show sub-chronic arsenic exposure activates AIM2 inflammasome which in turn activates caspase-1 and enhances the secretion of IL-1beta and IL-18 in HaCaT cells and the skin of BALB/c mice. In addition, arsenic-promoted activation of AIM2 inflammasome and increase of IL-1beta/IL-18 production are inhibited by PKR inhibitor in HaCaT cells or in the skin of PKR mutant mice, indicating a potential role of PKR in arsenic-induced sterile inflammation. PMID- 27471629 TI - mRNA-based dendritic cell immunization improves survival in ret transgenic mouse melanoma model. AB - Malignant melanoma is characterized by a rapid progression, metastasis to distant organs and resistance to chemo and radiotherapy. Although melanoma is capable of eliciting an immune response, the disease progresses and the overall results of immunotherapeutic clinical studies are not satisfactory. Recently, we have developed a novel genetic platform for improving an induction of peptide-specific CD8(+) T cells by dendritic cell (DC) based on membrane-anchored beta2 microglobulin (beta2m) linked to a selected antigenic peptide at the N-terminus and to the cytosolic domain of TLR4 at the C-terminus. In vitro transcribed mRNA transfection of antigen-presenting cells (APCs) resulted in an efficient coupling of peptide presentation and cell activation. In this research, we utilize the chimeric platform to induce an immune response in ret transgenic mice that spontaneously develop malignant skin melanoma and to examine its effect on the overall survival of tumor-bearing mice. Following immunization with chimeric construct system, we observe a significantly prolonged survival of tumor-bearing mice as compared to the control group. Moreover, we see elevations in the frequency of CD62L(hi)CD44(hi) central and CD62L(lo)CD44(hi) effector memory CD8(+) T-cell subsets. Importantly, we do not observe any changes in frequencies of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the vaccinated groups. Our data suggest that this novel vaccination approach could be efficiently applied for the immunotherapy of malignant melanoma. PMID- 27471630 TI - Evaluation of innate and adaptive immunity contributing to the antitumor effects of PD1 blockade in an orthotopic murine model of pancreatic cancer. AB - Despite the clinical success of anti-PD1 antibody (alpha-PD1) therapy, the immune mechanisms contributing to the antineoplastic response remain unclear. Here, we describe novel aspects of the immune response involved in alpha-PD1-induced antitumor effects using an orthotopic Kras (G12D)/p53(R172H)/Pdx1-Cre (KPC) model of pancreatic ductal adenocarcinoma (PDA). We found that positive therapeutic outcome involved both the innate and adaptive arms of the immune system. Adoptive transfer of total splenocytes after short-term (3 d) but not long-term (28 d) PD1 blockade significantly extended survival of non-treated tumor-bearing recipient mice. This protective effect appeared to be mostly mediated by T cells, as adoptive transfer of purified natural killer (NK) cells and/or granulocyte receptor 1 (Gr1)(+) cells or splenocytes depleted of Gr1(+) cells and NK cells did not exhibit transferrable antitumor activity following short-term PD1 blockade. Nevertheless, splenic and tumor-derived CD11b(+)Gr1(+) cells and NK cells showed significant persistence of alpha-PD1 bound to these cells in the treated primary recipient mice. We observed that short-term inhibition of PD1 signaling modulated the profiles of multifunctional cytokines in the tumor immune infiltrate, including downregulation of vascular endothelial growth factor A (VEGF-A). Altogether, the data suggest that systemic blockade of PD1 results in rapid modulation of antitumor immunity that differs in the tumor microenvironment (TME) when compared to the spleen. These results demonstrate a key role for early immune-mediated events in controlling tumor progression in response to alpha-PD1 treatment and warrant further investigation into the mechanisms governing responses to the therapy at the innate-adaptive immune interface. PMID- 27471631 TI - Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response. AB - We have previously reported that intermediate monocytes (CD14(++)/CD16(+)) were increased in colorectal cancer (CRC) patients, while the subset of pro-angiogenic TIE2-expressing monocytes (TEMs) was not significantly elevated. This study was designed to evaluate changes in frequency and function of intermediate monocytes and TEMs during chemotherapy and anti-angiogenic cancer treatment and their relation to treatment response. Monocyte populations were determined by flow cytometry in 60 metastasized CRC (mCRC) patients who received neoadjuvant chemotherapy with or without bevacizumab. Blood samples were taken before treatment, after two therapy cycles, at the end of neoadjuvant therapy and immediately before surgical resection of liver metastases. Neoadjuvant treatment resulted in a significant increase in circulating intermediate monocytes which was most pronounced after two cycles and positively predicted tumor response (AUC = 0.875, p = 0.005). With a cut-off value set to 1% intermediate monocytes of leukocytes, this parameter showed a predictive sensitivity and specificity of 75% and 88%. Anti-angiogenic therapy with bevacizumab had no impact on monocyte populations including TEMs. In 15 patients and six healthy controls, the gene expression profile and the migratory behavior of monocyte subsets was evaluated. The profile of intermediate monocytes suggested functions in antigen presentation, inflammatory cytokine production, chemotaxis and was remarkably stable during chemotherapy. Intermediate monocytes showed a preferential migratory response to tumor-derived signals in vitro and correlated with the level of CD14(+)/CD16(+) monocytic infiltrates in the resected tumor tissue. In conclusion, the rapid rise of intermediate monocytes during chemotherapy may offer a simple marker for response prediction and a timely change in regimen. PMID- 27471632 TI - Tumor-infiltrating HLA-matched CD4(+) T cells retargeted against Hodgkin and Reed Sternberg cells. AB - Hodgkin lymphoma (HL) presents with a unique histologic pattern. Pathognomonic Hodgkin and Reed-Sternberg (HRS) cells usually account for less than 1% of the tumor and are embedded in a reactive infiltrate mainly comprised of CD4(+) T cells. HRS cells induce an immunosuppressive microenvironment and thereby escape antitumor immunity. To investigate the impact of interactions between HRS cells and T cells, we performed long-term co-culture studies that were further translated into a xenograft model. Surprisingly, we revealed a strong antitumor potential of allogeneic CD4(+) T cells against HL cell lines. HRS and CD4(+) T cells interact by adhesion complexes similar to immunological synapses. Tumor cell killing was likely based on the recognition of allogeneic major histocompatibility complex class II (MHC-II) receptor, while CD4(+) T cells from MHC-II compatible donors did not develop any antitumor potential in case of HL cell line L428. However, gene expression profiling (GEP) of co-cultured HRS cells as well as tumor infiltration of matched CD4(+) T cells indicated cellular interactions. Moreover, matched CD4(+) T cells could be activated to kill CD30(+) HRS cells when redirected with a CD30-specific chimeric antigen receptor. Our work gives novel insights into the crosstalk between HRS and CD4(+) T cells, suggesting the latter as potent effector cells in the adoptive cell therapy of HL. PMID- 27471633 TI - Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment. AB - Hippo is a tumor-suppressor pathway that negatively regulates the oncoproteins TAZ and YAP. Moreover, Hippo affects the biology of a variety of non-neoplastic cells in the tumor microenvironment, even including immune cells. We herein assessed the predictive role of TAZ and YAP, assessed by immunohistochemistry, in 50 cervical cancer patients prevalently treated with neoadjuvant chemotherapy. Tumors were classified as positive or negative according to the percentage of tumor-expressing cells and cellular localization. TAZ/YAP were also evaluated in non-neoplastic cells, namely endothelial cells, non-lymphocytic stromal cells and tumor-infiltrating lymphocytes (TILs). TAZ expression in cancer cells (TAZ(pos)) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZ(TIL+) and YAP(TIL+)) seemed to be associated with increased pCRs (p = 0.083 and p = 0.018, respectively). When testing the predictive significance of the concomitant expression of TAZ in cancer cells and its absence in TILs (TAZ(pos)/TAZ(TIL-)), patients with TAZ(pos)/TAZ(TIL-) showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZ(pos)/TAZ(TIL-): OR 8.67, 95% CI: 2.31-32.52, p = 0.001). Sensitivity analysis carried out in the 41 patients treated with neoadjuvant chemotherapy yielded comparable results (TAZ(pos)/TAZ(TIL-): OR 11.0, 95% CI: 2.42-49.91, p = 0.002). Internal validation carried out with two different procedures confirmed the robustness of this model. Overall, we found evidence on the association between TAZ expression in cervical cancer cells and reduced pCR rate. Conversely, the expression of the Hippo transducers in TILs may predict increased treatment efficacy, possibly mirroring the activation of a non canonical Hippo/MST pathway necessary for T-cells activation and survival. PMID- 27471634 TI - CD137 signaling in Hodgkin and Reed-Sternberg cell lines induces IL-13 secretion, immune deviation and enhanced growth. AB - CD137 and its ligand, CD137L, are expressed on activated T cells and antigen presenting cells (APC), respectively, and are powerful inducers of cellular, type 1 immune responses. CD137 is ectopically expressed by Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells in Hodgkin lymphoma (HL). Here we report that CD137 transmits signals into HRS cells, which induce the secretion of IL-13. IL 13 in conditioned supernatants of HRS cell lines inhibits the secretion of IFNgamma by peripheral blood mononuclear cells (PBMC). Since IFNgamma is essential for the development of a type 1 immune response, CD137-induced IL-13 secretion facilitates escape from immune surveillance. Further, CD137-induced IL 13 enhances the growth of HRS cell lines. CD137, IL-13 double-positive cells could be detected in the majority (58%) of HL patient samples, providing clinical evidence for a role of IL-13 induction by CD137 during HL pathogenesis. This study validates CD137 as a candidate target for immunotherapy of HL. PMID- 27471635 TI - Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate. AB - Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2alpha; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4(+), CD8(+), CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3. LC3B puncta positively correlated with the infiltration of metastases by CD163(+) macrophages, while expression of HMGB1 correlated with infiltration by FOXP3(+) regulatory T cells and CD56(+) lymphocytes. eIF2alpha phosphorylation was associated with an augmentation of nuclear diameters, reflecting an increase in ploidy. Interestingly, therapeutic vaccination led to a reduction of eIF2alpha phosphorylation suggestive of immunoselection against cells bearing this sign of endoplasmic reticulum (ER) stress. None of the stress/death-related biomarkers had a significant prognostic impact, contrasting with the major prognostic effect of the ratio of cytotoxic T lymphocytes (CTL) over immunosuppressive FOXP3(+) and CD163(+) cells. Altogether, these results support the idea of a mutual dialog between, on one hand, melanoma cells with their cell-intrinsic stress pathways and, on the other hand, immune effectors. Future work is required to understand the detailed mechanisms of this interaction. PMID- 27471636 TI - CXCL16-positive dendritic cells enhance invariant natural killer T cell-dependent IFNgamma production and tumor control. AB - Crosstalk interactions between dendritic cells (DCs) and invariant natural killer T (iNKT) cells are important in regulating antitumor responses elicited by glycolipid antigens. iNKT cells constitutively express the chemokine receptor CXCR6, while cytokine-activated DCs upregulate the transmembrane chemokine ligand, CXCL16. This study examined the co-stimulatory role of CXCR6/CXCL16 interactions in glycolipid-dependent iNKT cell activation and tumor control. Spleen and liver DCs in wild-type mice, but not iNKT cell deficient (Jalpha18(-/ )) mice, transiently upregulated surface CXCL16 following in vivo administration of the glycolipid antigen alpha-galactosylceramide. Recombinant CXCL16 did not directly induce iNKT cell activation in vitro but enhanced interferon (IFN)-gamma production when mouse or human iNKT cells were stimulated with plate-bound anti CD3. Compared with glycolipid-loaded CXCL16(neg) DCs, CXCL16(hi) DCs induced higher levels of IFNgamma production in iNKT cell cultures and following adoptive transfer in vivo. The number of IFNgamma(+) iNKT cells and expansion of T-bet(+) iNKT cells were reduced in vivo when CXCL16(-/-) DCs were used to activate iNKT cells. Enhanced IFNgamma production in vivo was not dependent on CXCR6 expression on natural killer (NK) cells. Adoptive transfer of glycolipid-loaded CXCL16(hi) DCs provided superior protection against tumor metastasis compared to CXCL16(neg) DC transfers. Similarly, wild-type DCs provided superior protection against metastasis compared with CXCL16(-/-) DCs. These experiments implicate an important role for CXCR6/CXCL16 interactions in regulating iNKT cell IFNgamma production and tumor control. The selective use of CXCL16(hi) DCs in adoptive transfer immunotherapies may prove useful for enhancing T helper (Th) type 1 responses and clinical outcomes in cancer patients. PMID- 27471637 TI - Natural killer cells require monocytic Gr-1(+)/CD11b(+) myeloid cells to eradicate orthotopically engrafted glioma cells. AB - Malignant gliomas are resistant to natural killer (NK) cell immune surveillance. However, the mechanisms used by these cancers to suppress antitumor NK cell activity remain poorly understood. We have recently reported on a novel mechanism of innate immune evasion characterized by the overexpression of the carbohydrate binding protein galectin-1 by both mouse and rat malignant glioma. Here, we investigate the cytokine profile of galectin-1-deficient GL26 cells and describe the process by which these tumors are targeted by the early innate immune system in RAG1(-/-) and C57BL/6J mice. Our data reveal that galectin-1 knockdown in GL26 cells heightens their inflammatory status leading to the rapid recruitment of Gr 1(+)/CD11b(+) myeloid cells and NK1.1(+) NK cells into the brain tumor microenvironment, culminating in tumor clearance. We show that immunodepletion of Gr-1(+) myeloid cells in RAG1(-/-) mice permits the growth of galectin-1 deficient glioma despite the presence of NK cells, thus demonstrating an essential role for myeloid cells in the clearance of galectin-1-deficient glioma. Further characterization of tumor-infiltrating Gr-1(+)/CD11b(+) cells reveals that these cells also express CCR2 and Ly-6C, markers consistent with inflammatory monocytes. Our results demonstrate that Gr-1(+)/CD11b(+) myeloid cells, often referred to as myeloid-derived suppressor cells (MDSCs), are required for antitumor NK cell activity against galectin-1-deficient GL26 glioma. We conclude that glioma-derived galectin-1 represents an important factor in dictating the phenotypic behavior of monocytic Gr-1(+)/CD11b(+) myeloid cells. Galectin-1 suppression may be a valuable treatment approach for clinical glioma by promoting their innate immune-mediated recognition and clearance through the concerted effort of innate myeloid and lymphoid cell lineages. PMID- 27471638 TI - Role of IL-2 in cancer immunotherapy. AB - Interleukin-2 (IL-2) is one of the key cytokines with pleiotropic effects on immune system. It has been approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Recent progress has been made in our understanding of IL-2 in regulating lymphocytes that has led to exciting new directions for cancer immunotherapy. While improved IL-2 formulations might be used as monotherapies, their combination with other anticancer immunotherapies, such as adoptive cell transfer regimens, antigen-specific vaccination, and blockade of immune checkpoint inhibitory molecules, for example cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) mono antibodies, would held the promise of treating metastatic cancer. Despite the comprehensive studies of IL-2 on immune system have established the application of IL-2 for cancer immunotherapy, a number of poignant obstacles remain for future research. In the present review, we will focus on the key biological features of IL-2, current applications, limitations, and future directions of IL 2 in cancer immunotherapy. PMID- 27471639 TI - Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma. AB - Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and decreasing the number and function of myeloid-derived suppressor cells (MDSC). Collectively, these data imply further testing of other epigenetic modulators with immunotherapy and provide a strong basis for clinical testing of anti-GD2 plus Vorinostat combination therapy in NBL patients. PMID- 27471640 TI - Identification of a novel human memory T-cell population with the characteristics of stem-like chemo-resistance. AB - High-dose chemotherapy may kill not only tumor cells but also immunocytes, and frequently induces severe lymphocytopenia. On the other hand, patients who recover from the nadir maintain immunity against infection, suggesting the existence of an unknown memory T-cell population with stress resistance, long living capacity, proliferation and differentiation. Recently, the differentiation system of T-cell memory has been clarified using mouse models. However, the human T-cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. Here we report a novel human T-cell memory population, "young memory" T (TYM) cells. TYM cells are defined by positive expression of CD73, which represents high aldehyde dehydrogenase 1 (ALDH1) activity and CXCR3 among CD8(+)CD45RA(+)CD62L(+) T cells. TYM proliferate upon TCR stimulation, with differentiation capacity into TCM and TEM and drug resistance. Moreover, TYM are involved in memory function for viral and tumor-associated antigens in healthy donors and cancer patients, respectively. Regulation of TYM might be very attractive for peptide vaccination, adoptive cell-transfer therapy and hematopoietic stem cell transplantation. PMID- 27471641 TI - Antitumor vaccination of prostate cancer patients elicits PD-1/PD-L1 regulated antigen-specific immune responses. AB - We have previously reported that tumor antigen-specific DNA vaccination in mice led to an increase in IFNgamma-secreting T cells and an increase in tumor expression of PD-L1. Further, we demonstrated that increasing the encoded antigen's MHC-binding affinity led to increased PD-1 expression on antigen specific CD8(+) T cells. Together these phenomena provided resistance to antitumor immunization that was abrogated with PD-1/PD-L1 blockade. We consequently sought to determine whether similar regulation occurred in human patients following antitumor immunization. Using clinical samples from prostate cancer patients who were previously immunized with a DNA vaccine, we analyzed changes in checkpoint receptor expression on antigen-specific CD8(+) T cells, the effect of PD-1 blockade on elicited immune responses, and for changes in checkpoint ligand expression on patients' circulating tumor cells (CTCs). We observed no significant changes in T-cell expression of PD-1 or other checkpoint receptors, but antigen-specific immune responses were detected and/or augmented with PD-1 blockade as detected by IFNgamma and granzyme B secretion or trans vivo DTH testing. Moreover, PD-L1 expression was increased on CTCs following vaccination, and this PD-L1 upregulation was associated with the development of sustained T-cell immunity and longer progression-free survival. Finally, similar results were observed with patients treated with sipuleucel-T, another vaccine targeting the same prostate antigen. These findings provide in-human rationale for combining anticancer vaccines with PD-1 blocking antibodies, particularly for the treatment of prostate cancer, a disease for which vaccines have demonstrated benefit and yet PD-1 inhibitors have shown little clinical benefit to date as monotherapies. PMID- 27471642 TI - A plant-expressed conjugate vaccine breaks CD4(+) tolerance and induces potent immunity against metastatic Her2(+) breast cancer. AB - Passive antibody therapy for cancer is an effective but costly treatment modality. Induction of therapeutically potent anticancer antibodies by active vaccination is an attractive alternative but has proven challenging in cancer due to tolerogenic pressure in patients. Here, we used the clinically relevant cancer target Her2, known to be susceptible to targeting by antibody therapy, to demonstrate how potent antibody can be induced by vaccination. A novel 44kD Her2 protein fragment was generated and found to be highly effective at inducing anti Her2 antibody including trastuzumab-like reactivities. In the tolerant and spontaneous BALB-neuT mouse model of metastatic breast cancer this Her2-targeting vaccine was only effective if the fragment was conjugated to a foreign immunogenic carrier; Fragment C of tetanus toxin. Only the conjugate vaccine induced high affinity anti-Her2 antibody of multiple isotypes and suppressed tumor development. The magnitude of CD4(+) T-cell help and breadth of cytokines secreted by the CD4(+) T helper (Th) cells induced to the foreign antigen was critical. We used a highly efficient plant-based bio-manufacturing process for protein antigens, magnICON, for vaccine expression, to underpin feasibility of future clinical testing. Hence, our novel Her2-targeting conjugate vaccine combines preclinical efficacy with clinical deliverability, thus setting the scene for therapeutic testing. PMID- 27471643 TI - Epithelial NF-kappaB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment. AB - Several studies have demonstrated that NF-kappaB activation is common in lung cancer; however, the mechanistic links between NF-kappaB signaling and tumorigenesis remain to be fully elucidated. We investigated the function of NF kappaB signaling in epidermal growth factor receptor (EGFR)-mutant lung tumors using a transgenic mouse model with doxycycline (dox)-inducible expression of oncogenic EGFR in the lung epithelium with or without a dominant inhibitor of NF kappaB signaling. NF-kappaB inhibition resulted in a significant reduction in tumor burden in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant tumors. However, NF-kappaB inhibition did not alter epithelial cell survival in vitro or in vivo, and no changes were detected in activation of EGFR downstream signaling pathways. Instead, we observed an influx of inflammatory cells (macrophages and neutrophils) in the lungs of mice with oncogenic EGFR expression that was blocked in the setting of NF-kappaB inhibition. To investigate whether inflammatory cells play a role in promoting EGFR-mutant lung tumors, we depleted macrophages and neutrophils during tumorigenesis and found that neutrophil depletion had no effect on tumor formation, but macrophage depletion caused a significant reduction in tumor burden. Together, these data suggest that epithelial NF-kappaB signaling supports carcinogenesis in a non-cell autonomous manner in EGFR-mutant tumors through recruitment of pro-tumorigenic macrophages. PMID- 27471644 TI - Stereotaxic administrations of allogeneic human Vgamma9Vdelta2 T cells efficiently control the development of human glioblastoma brain tumors. AB - Glioblastoma multiforme (GBM) represents the most frequent and deadliest primary brain tumor. Aggressive treatment still fails to eliminate deep brain infiltrative and highly resistant tumor cells. Human Vgamma9Vdelta2 T cells, the major peripheral blood gammadelta T cell subset, react against a wide array of tumor cells and represent attractive immune effector T cells for the design of antitumor therapies. This study aims at providing a preclinical rationale for immunotherapies in GBM based on stereotaxic administration of allogeneic human Vgamma9Vdelta2 T cells. The feasibility and the antitumor efficacy of stereotaxic Vgamma9Vdelta2 T cell injections have been investigated in orthotopic GBM mice model using selected heterogeneous and invasive primary human GBM cells. Allogeneic human Vgamma9Vdelta2 T cells survive and patrol for several days within the brain parenchyma following adoptive transfer and can successfully eliminate infiltrative GBM primary cells. These striking observations pave the way for optimized stereotaxic antitumor immunotherapies targeting human allogeneic Vgamma9Vdelta2 T cells in GBM patients. PMID- 27471645 TI - CMRF-56(+) blood dendritic cells loaded with mRNA induce effective antigen specific cytotoxic T-lymphocyte responses. AB - There are numerous transcriptional, proteomic and functional differences between monocyte-derived dendritic cells (Mo-DC) and primary blood dendritic cells (BDC). The CMRF-56 monoclonal antibody (mAb) recognizes a cell surface marker, which is upregulated on BDC following overnight culture. Given its unique ability to select a heterogeneous population of BDC, we engineered a human chimeric (h)CMRF 56 IgG4 mAb to isolate primary BDC for potential therapeutic vaccination. The ability to select multiple primary BDC subsets from patients and load them with in vitro transcribed (IVT) mRNA encoding tumor antigen might circumvent the issues limiting the efficacy of Mo-DC. After optimizing and validating the purification of hCMRF-56(+) BDC, we showed that transfection of hCMRF-56(+) BDC with mRNA resulted in efficient mRNA translation and antigen presentation by myeloid BDC subsets, while preserving superior DC functions compared to Mo-DC. Immune selected and transfected hCMRF-56(+) BDC migrated very efficiently in vitro and as effectively as cytokine matured Mo-DC in vivo. Compared to Mo-DC, hCMRF-56(+) BDC transfected with influenza matrix protein M1 displayed superior MHC peptide presentation and generated potent antigen specific CD8(+) T-cell recall responses, while Wilms tumor 1 (WT1) transfected CMRF-56(+) BDC generated effective primary autologous cytotoxic T-cell responses. The ability of the combined DC subsets within hCMRF-56(+) BDC to present mRNA delivered tumor antigens merits phase I evaluation as a reproducible generic platform for the next generation of active DC immune therapies. PMID- 27471647 TI - Successful engineering of a highly potent single-chain variable-fragment (scFv) bispecific antibody to target disialoganglioside (GD2) positive tumors. AB - Engineering potent bispecific antibodies from single-chain variable fragments (scFv) remains difficult due to the inherent instability and insufficient binding of scFv's compared to their parental immunoglobulin format. Previously, we described a scFv-based bispecific antibody (scBA) against disialoganglioside (GD2) based on the anti-GD2 murine 5F11-scFv and the anti-CD3 huOKT3-scFv (5F11 scBA). In this study, we substituted the 5F11-scFv with the higher affinity (13 fold) hu3F8-scFv to form hu3F8-scBA. With this modification, hu3F8-scBA redirected T cells to kill GD2(+) cancer cell lines with up to 5,000-fold higher potency (femtomolar EC50) compared with 5F11-scBA (picomolar EC50) in cytotoxicity assays, even against target cells with low GD2 densities. Furthermore, hu3F8-scBA induced stronger T-cell activation than 5F11-scBA, as measured by Ca(2+) flux and cytokine release. Additionally, in vivo, hu3F8-scBA suppressed tumor growth and prolonged mice survival much more effectively than 5F11-scBA, in both neuroblastoma and melanoma xenograft models. We conclude that the functional properties of scBA's can be increased substantially by relatively modest increases in antigen affinity. PMID- 27471646 TI - The immune network in thyroid cancer. AB - The immune system plays critical roles in tumor prevention, but also in its initiation and progression. Tumors are subjected to immunosurveillance, but cancer cells generate an immunosuppressive microenvironment that favors their escape from immune-mediated elimination. During chronic inflammation, immune cells can contribute to the formation and progression of tumors by producing mitogenic, prosurvival, proangiogenic and lymphangiogenic factors. Thyroid cancer is the most frequent type of endocrine neoplasia and is the most rapidly increasing cancer in the US. In this review, we discuss recent findings on how different immune cells and mediators can contribute to thyroid cancer development and progression. PMID- 27471648 TI - SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade. AB - Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody(r): IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses. PMID- 27471649 TI - Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy. AB - Tumor immune escape has been a major problem for developing effective immunotherapy. The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule whose primary function is to protect the fetus from the mother's immune system. While HLA-G is hardly found in normal adult tissues, various tumor cells are known to express it, aiding their escape from the immune system. Thus, HLA-G is an attractive immunotherapy target. CD4(+) helper T lymphocytes (HTLs) play an important role in the immune reaction against tumors by assisting in the generation and persistence of CD8(+) cytotoxic T lymphocytes (CTLs) or by displaying direct antitumor effects. We report here that HLA-G expression in breast cancer significantly correlates with a poor prognosis. Also, we describe that the MHC class II-binding peptide HLA-G26-40 was effective in eliciting tumor reactive CD4(+) T cell responses. Furthermore, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased HLA-G expression in tumors and subsequently enhanced recognition by HLA-G26-40-specific HTLs. These findings predict that a combination immunotherapy targeting HLA-G together with a DNA methyltransferase inhibitor could be useful against some cancers. PMID- 27471650 TI - IL-7 signaling imparts polyfunctionality and stemness potential to CD4(+) T cells. AB - The functional status of CD4(+) T cells is a critical determinant of antitumor immunity. Polyfunctional CD4(+) T cells possess the ability to concomitantly produce multiple Th1-type cytokines, exhibiting a functional attribute desirable for cancer immunotherapy. However, the mechanisms by which these cells are induced are neither defined nor it is clear if these cells can be used therapeutically to treat cancer. Here, we report that CD4(+) T cells exposed to exogenous IL-7 during antigenic stimulation can acquire a polyfunctional phenotype, characterized by their ability to simultaneously express IFNgamma, IL 2, TNFalpha and granzyme B. This IL-7-driven polyfunctional phenotype was associated with increased histone acetylation in the promoters of the effector genes, indicative of increased chromatin accessibility. Moreover, forced expression of a constitutively active (CA) form of STAT5 recapitulated IL-7 in inducing CD4(+) T-cell polyfunctionality. Conversely, the expression of a dominant negative (DN) form of STAT5 abolished the ability of IL-7 to induce polyfunctional CD4(+) T cells. These in-vitro-generated polyfunctional CD4(+) T cells can traffic to tumor and expand intratumorally in response to immunization. Importantly, adoptive transfer of polyfunctional CD4(+) T cells following lymphodepletive chemotherapy was able to eradicate large established tumors. This beneficial outcome was associated with the occurrence of antigen epitope spreading, activation of the endogenous CD8(+) T cells and persistence of donor CD4(+) T cells exhibiting memory stem cell attributes. These findings indicate that IL-7 signaling can impart polyfunctionality and stemness potential to CD4(+) T cells, revealing a previously unknown property of IL-7 that can be exploited in adoptive T-cell immunotherapy. PMID- 27471651 TI - A novel role of breast cancer-derived hyaluronan on inducement of M2-like tumor associated macrophages formation. AB - Microenvironmental signals determine the differentiation types and distinct functions of macrophages. Tumor-associated macrophages (TAM) constitute major infiltrates around solid tumor cells and accelerate tumor progression due to their immunosuppressive functions. However, the mechanisms through which tumor microenvironment modulates macrophages transition are not completely elucidated. Hyaluronan (HA), a prominent component in tumor microenvironment, is a notable immunoregulator and its high level is often related to poor prognosis. Herein, we found that the number of M2 macrophages was highly correlated with HA expression in tumor tissues from breast cancer patients. Experimental data showed that breast cancer-derived HA stimulated M2-like TAM formation in a mouse model and had multiple effects on macrophages transformation in vitro, including upregulating CD204, CD206, IL-10 and TGF-beta, activating STAT3 signal, and suppressing killing capacity. These data indicate that HA derived from breast cancer activates macrophages in an alternative manner. Further mechanism study revealed that HA-CD44-ERK1/2-STAT3 pathway served as an important regulator in M2 like TAM formation. Therefore, targeting TAM by abrogating HA-CD44 interaction may be a potential strategy for breast cancer immunotherapy. PMID- 27471652 TI - Murine mesothelioma induces locally-proliferating IL-10(+)TNF-alpha(+)CD206( )CX3CR1(+) M3 macrophages that can be selectively depleted by chemotherapy or immunotherapy. AB - We used a murine model to monitor changes to myeloid cell subsets, i.e., myeloid derived suppressor cells (MDSCs), M1 macrophages that secrete pro-inflammatory cytokines and express CD40 and CD80 and suppressive M2 macrophages that secrete anti-inflammatory cytokines and express CD206 and CX3CR1, during mesothelioma progression and during chemotherapy or immunotherapy-induced tumor regression. In vitro studies showed that mesothelioma-conditioned media generated CD206( )CX3CR1(+)MCP-1(+)TGF-beta(+) macrophages that induced T cell proliferation but prevented T cell IFNgamma production. In vivo studies showed that co-inoculation of macrophages with mesothelioma cells led to faster tumor growth, and depleting macrophages using anti-F4/80 antibody induced tumor regression. Flow cytometry revealed increasing levels of different suppressive myeloid cells in lymphoid organs: MDSCs dominated bone marrow (BM) and spleens, M2 macrophages dominated tumor-draining lymph nodes (DLN) and a mixed IL-10(+)TNF-alpha(+)CD206( )CX3CR1(+) M1/M2 (M3) macrophage subset dominated the mesothelioma microenvironment. Ki67 staining and cell cycle analysis showed that tumor associated M1 and M3, but not M2, macrophages were proliferating in situ, with M1 cells arrested in the G1 phase while M3 cells progressed to mitosis. Immunohistochemistry showed that M1 and M3 cells were co-located supporting the hypothesis that M1 cells transition to M3 cells during proliferation. Gemcitabine reduced tumor-associated M3 and MDSCs, but not M2 macrophages, the latter likely contributing to the tumor outgrowth seen following treatment cessation. In contrast, IL-2/agonist anti-CD40 antibody therapy reduced M3 cells and polarized macrophages into M1 cells coinciding with tumor regression. These data show that myeloid cells, particularly M3 cells, represent a therapeutic target for the generation of antitumor immunity. PMID- 27471653 TI - Positive impact of autophagy in human breast cancer cells on local immunosurveillance. AB - In human breast cancer cells, the presence of cytoplasmic dots positive for microtubule-associated proteins 1A/1B light chain 3B (LC3B) indicates enhanced autophagic flux and favorable prognosis. LC3B(+) puncta within malignant cells positively correlate with the intratumoral abundance of CD8(+) cytotoxic T lymphocytes, yet negatively correlate with the frequency of local FOXP3(+) regulatory T cells and CD68(+) tumor-associated macrophages, resulting in an improvement of CD8(+)/FOXP(+) or CD8(+)/CD68(+) ratios. PMID- 27471655 TI - Erratum. AB - [This corrects the article DOI: 10.1080/2162402X.2015.1057674.]. PMID- 27471654 TI - Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity. AB - Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients' immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology, targetable tumor associated antigens (TAA) are identified and exploited for engineered T-cell therapy. Here, the specific recognition and lytic potential of transgenic allo restricted CD8(+) T cells, directed against the ES-associated antigen 6 transmembrane epithelial antigen of the prostate 1 (STEAP1), was examined. Following repetitive STEAP1(130) peptide-driven stimulations with HLA-A*02:01(+) dendritic cells (DC), allo-restricted HLA-A*02:01(-) CD8(+) T cells were sorted with HLA-A*02:01/peptide multimers and expanded by limiting dilution. After functional analysis of suitable T cell clones via ELISpot, flow cytometry and xCELLigence assay, T cell receptors' (TCR) alpha- and beta-chains were identified, cloned into retroviral vectors, codon optimized, transfected into HLA A*02:01(-) primary T cell populations and tested again for specificity and lytic capacity in vitro and in a Rag2(-/-)gammac(-/-) mouse model. Initially generated transgenic T cells specifically recognized STEAP1(130)-pulsed or transfected cells in the context of HLA-A*02:01 with minimal cross-reactivity as determined by specific interferon-gamma (IFNgamma) release, lysed cells and inhibited growth of HLA-A*02:01(+) ES lines more effectively than HLA-A*02:01(-) ES lines. In vivo tumor growth was inhibited more effectively with transgenic STEAP1(130)-specific T cells than with unspecific T cells. Our results identify TCRs capable of recognizing and inhibiting growth of STEAP1-expressing HLA-A*02:01(+) ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1-expressing tumors. PMID- 27471656 TI - Corrigendum. AB - [This corrects the article DOI: 10.1080/2162402X.2014.1002721.]. PMID- 27471657 TI - Influences on Adoption of Greenhouse Gas Reduction Targets among US States, 1998 2008. AB - While the United States has not established federal regulations for greenhouse gas (GHG) reduction targets, many US states have adopted their own standards and guidelines. In this study we examine state adoption of targets for GHG reductions during the ten-year period of 1998-2008, and identify factors that explain variation in target adoption. Potential influences are drawn from research from the public policy formulation and diffusion literature, and from studies specific to climate policy adoption. Potential influences on GHG reduction efforts among US states include socioeconomic attributes of residents, political and ideological orientations of citizens and state government, interest group activities, environmental pressures, and proximity to other states that have adopted GHG reduction targets. The findings of the multinomial logistic regression analysis indicate that states are more likely to adopt GHG reduction targets if they share a border with another state with a similar climate program and if their citizens are more ideologically liberal. Other factors including socioeconomic resources and interest group activities were not found to be associated with policy adoption. The findings yield insights into the conditions under which states are more likely to take action to reduce GHG's, and are relevant both to state policy makers and residents with an interest in climate planning, and for researchers attempting to estimate future greenhouse gas reduction scenarios. PMID- 27471658 TI - Implementation and comparison of kernel-based learning methods to predict metabolic networks. AB - Metabolic pathways can be conceptualized as the biological equivalent of a data pipeline. In living cells, series of chemical reactions are carried out by different proteins called enzymes in a stepwise manner. However, many pathways remain incompletely characterized, and in some of them, not all enzyme components have been identified. Kernel methods are useful in many difficult problem areas, such as document classification and bioinformatics. Specifically, kernel methods have been used recently to predict biological networks, such as protein-protein interaction networks and metabolic networks. In this paper, we implement and compare different methods and types of data to predict metabolic networks. The methods are Penalized Kernel Matrix Regression (PKMR) and pairwise Support Vector Machine (pSVM). We develop several experiments using these methods with sequence, non-sequence, and combined data. We obtain better accuracy when the sequence data are used in both methods. Whereas when the methods are compared using the same type of data, the pSVM approach shows better accuracy. The best results are obtained with pSVM using all combined kernels. PMID- 27471659 TI - Testing the hypothesis of preferential attachment in social network formation. AB - The hypothesis of preferential attachment (PA) - whereby better connected individuals make more connections - is hotly debated, particularly in the context of epidemiological networks. The simplest models of PA, for example, are incompatible with the eradication of any disease through population-level control measures such as random vaccination. Typically, evidence has been sought for the presence or absence of preferential attachment via asymptotic power-law behaviour. Here, we present a general statistical method to test directly for evidence of PA in count data and apply this to data for contacts relevant to the spread of respiratory diseases. We find that while standard methods for model selection prefer a form of PA, careful analysis of the best fitting PA models allows for a level of contact heterogeneity that in fact allows control of respiratory diseases. Our approach is based on a flexible but numerically cheap likelihood-based model that could in principle be applied to other integer data where the hypothesis of PA is of interest. PMID- 27471660 TI - Open source data reveals connection between online and on-street protest activity. AB - There is enormous interest in inferring features of human behavior in the real world from potential digital footprints created online - particularly at the collective level, where the sheer volume of online activity may indicate some changing mood within the population regarding a particular topic. Civil unrest is a prime example, involving the spontaneous appearance of large crowds of otherwise unrelated people on the street on a certain day. While indicators of brewing protests might be gleaned from individual online communications or account content (e.g. Twitter, Facebook) societal concerns regarding privacy can make such probing a politically delicate issue. Here we show that instead, a simple low-level indicator of civil unrest can be obtained from online data at the aggregate level through Google Trends or similar tools. Our study covers countries across Latin America during 2011-2014 in which diverse civil unrest events took place. In each case, we find that the combination of the volume and momentum of searches from Google Trends surrounding pairs of simple keywords, tailored for the specific cultural setting, provide good indicators of periods of civil unrest. This proof-of-concept study motivates the search for more geographically specific indicators based on geo-located searches at the urban level. PMID- 27471661 TI - Quantifying social contacts in a household setting of rural Kenya using wearable proximity sensors. AB - : Close proximity interactions between individuals influence how infections spread. Quantifying close contacts in developing world settings, where such data is sparse yet disease burden is high, can provide insights into the design of intervention strategies such as vaccination. Recent technological advances have enabled collection of time-resolved face-to-face human contact data using radio frequency proximity sensors. The acceptability and practicalities of using proximity devices within the developing country setting have not been investigated. We present and analyse data arising from a prospective study of 5 households in rural Kenya, followed through 3 consecutive days. Pre-study focus group discussions with key community groups were held. All residents of selected households carried wearable proximity sensors to collect data on their close (<1.5 metres) interactions. Data collection for residents of three of the 5 households was contemporaneous. Contact matrices and temporal networks for 75 individuals are defined and mixing patterns by age and time of day in household contacts determined. Our study demonstrates the stability of numbers and durations of contacts across days. The contact durations followed a broad distribution consistent with data from other settings. Contacts within households occur mainly among children and between children and adults, and are characterised by daily regular peaks in the morning, midday and evening. Inter household contacts are between adults and more sporadic when measured over several days. Community feedback indicated privacy as a major concern especially regarding perceptions of non-participants, and that community acceptability required thorough explanation of study tools and procedures. Our results show for a low resource setting how wearable proximity sensors can be used to objectively collect high-resolution temporal data without direct supervision. The methodology appears acceptable in this population following adequate community engagement on study procedures. A target for future investigation is to determine the difference in contact networks within versus between households. We suggest that the results from this study may be used in the design of future studies using similar electronic devices targeting communities, including households and schools, in the developing world context. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1140/epjds/s13688-016-0084-2) contains supplementary material. PMID- 27471663 TI - The Next Generation of ABA Providers. AB - The imbalance of supply and demand for behavior analytic services will change in the near future. Behavior analysts, who want to survive in an increasing competitive marketplace, will need to show quality results and better results than the next behavior analyst. Trumpet Behavioral Health is a company designed to infuse scientific research with clinical practices. In the years ahead, look to companies like Trumpet as role models of the next generation of autism service providers. PMID- 27471666 TI - Editorial. PMID- 27471665 TI - Editor Profile: Guest Editors of the Special Issue "Functional Materials, Nanocarriers, and Formulations for Targeted Therapy". PMID- 27471667 TI - Charge-reversal nanoparticles: novel targeted drug delivery carriers. AB - Spurred by significant progress in materials chemistry and drug delivery, charge reversal nanocarriers are being developed to deliver anticancer formulations in spatial-, temporal- and dosage-controlled approaches. Charge-reversal nanoparticles can release their drug payload in response to specific stimuli that alter the charge on their surface. They can elude clearance from the circulation and be activated by protonation, enzymatic cleavage, or a molecular conformational change. In this review, we discuss the physiological basis for, and recent advances in the design of charge-reversal nanoparticles that are able to control drug biodistribution in response to specific stimuli, endogenous factors (changes in pH, redox gradients, or enzyme concentration) or exogenous factors (light or thermos-stimulation). PMID- 27471662 TI - Calcium orthophosphates (CaPO4): occurrence and properties. AB - The present overview is intended to point the readers' attention to the important subject of calcium orthophosphates (CaPO4). This type of materials is of the special significance for the human beings because they represent the inorganic part of major normal (bones, teeth and antlers) and pathological (i.e., those appearing due to various diseases) calcified tissues of mammals. For example, atherosclerosis results in blood vessel blockage caused by a solid composite of cholesterol with CaPO4, while dental caries and osteoporosis mean a partial decalcification of teeth and bones, respectively, that results in replacement of a less soluble and harder biological apatite by more soluble and softer calcium hydrogenorthophosphates. Therefore, the processes of both normal and pathological calcifications are just an in vivo crystallization of CaPO4. Similarly, dental caries and osteoporosis might be considered as in vivo dissolution of CaPO4. In addition, natural CaPO4 are the major source of phosphorus, which is used to produce agricultural fertilizers, detergents and various phosphorus-containing chemicals. Thus, there is a great significance of CaPO4 for the humankind and, in this paper, an overview on the current knowledge on this subject is provided. PMID- 27471669 TI - Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. AB - Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles; exosomes are non-immunogenic in nature due to similar composition as body's own cells. In this article, the origin and structure of exosomes as well as their biological functions are outlined. We will then focus on specific applications of exosomes as drug delivery systems in pharmaceutical drug development. An overview of the advantages and challenges faced when using exosomes as a pharmaceutical drug delivery vehicles will also be discussed. PMID- 27471668 TI - Progress and perspectives on targeting nanoparticles for brain drug delivery. AB - Due to the ability of the blood-brain barrier (BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood-brain tumor barrier (BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed. PMID- 27471670 TI - Targeted and effective photodynamic therapy for cancer using functionalized nanomaterials. AB - Photodynamic therapy (PDT) is an emerging, non-invasive therapeutic strategy that involves photosensitizer (PS) drugs and external light for the treatment of diseases. Despite the great progress in PS-mediated PDT, their clinical applications are still hampered by poor water solubility and tissue/cell specificity of conventional PS drugs. Therefore, great efforts have been made towards the development of nanomaterials that can tackle fundamental challenges in conventional PS drug-mediated PDT for cancer treatment. This review highlights recent advances in the development of nano-platforms, in which various functionalized organic and inorganic nanomaterials are integrated with PS drugs, for significantly enhanced efficacy and tumor-selectivity of PDT. PMID- 27471672 TI - Self-enhanced targeted delivery of a cell wall- and membrane-active antibiotics, daptomycin, against staphylococcal pneumonia. AB - Considering that some antibacterial agents can identify the outer structure of pathogens like cell wall and/or cell membrane, we explored a self-enhanced targeted delivery strategy by which a small amount of the antibiotic molecules were modified on the surface of carriers as targeting ligands of certain bacteria while more antibiotic molecules were loaded inside the carriers, and thus has the potential to improve the drug concentration at the infection site, enhance efficacy and reduce potential toxicity. In this study, a novel targeted delivery system against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia was constructed with daptomycin, a lipopeptide antibiotic, which can bind to the cell wall of S. aureus via its hydrophobic tail. Daptomycin was conjugated with N hydroxysuccinimidyl-polyethylene glycol-1,2-distearoyl-sn-glycero-3 phosphoethanolamine to synthesize a targeting compound (Dapt-PEG-DSPE) which could be anchored on the surface of liposomes, while additional daptomycin molecules were encapsulated inside the liposomes. These daptomycin-modified, daptomycin-loaded liposomes (DPD-L[D]) showed specific binding to MRSA as detected by flow cytometry and good targeting capabilities in vivo to MRSA infected lungs in a pneumonia model. DPD-L[D] exhibited more favorable antibacterial efficacy against MRSA than conventional PEGylated liposomal daptomycin both in vitro and in vivo. Our study demonstrates that daptomycin modified liposomes can enhance MRSA-targeted delivery of encapsulated antibiotic, suggesting a novel drug delivery approach for existing antimicrobial agents. PMID- 27471671 TI - Influence of physical properties of carrier on the performance of dry powder inhalers. AB - Dry powder inhalers (DPIs) offer distinct advantages as a means of pulmonary drug delivery and have attracted much attention in the field of pharmaceutical science. DPIs commonly contain micronized drug particles which, because of their cohesiveness and strong propensity to aggregate, have poor aerosolization performance. Thus carriers with a larger particle size are added to address this problem. However, the performance of DPIs is profoundly influenced by the physical properties of the carrier, particularly their particle size, morphology/shape and surface roughness. Because these factors are interdependent, it is difficult to completely understand how they individually influence DPI performance. The purpose of this review is to summarize and illuminate how these factors affect drug-carrier interaction and influence the performance of DPIs. PMID- 27471673 TI - Preparation and evaluation of a phospholipid-based injectable gel for the long term delivery of leuprolide acetaterrh. AB - A phospholipid-based injectable gel was developed for the sustained delivery of leuprolide acetate (LA). The gel system was prepared using biocompatible materials (SPME), including soya phosphatidyl choline (SPC), medium chain triglyceride (MCT) and ethanol. The system displayed a sol state with low viscosity in vitro and underwent in situ gelation in vivo after subcutaneous injection. An in vitro release study was performed using a dialysis setup with different release media containing different percentages of ethanol. The stability of LA in the SPME system was investigated under different temperatures and in the presence of various antioxidants. In vivo studies in male rats were performed to elucidate the pharmacokinetic profiles and pharmacodynamic efficacy. A sustained release of LA for 28 days was observed without obvious initial burst in vivo. The pharmacodynamic study showed that once-a-month injection of LA loaded SPME (SPME-LA) led to comparable suppression effects on the serum testosterone level as observed in LA solution except for the onset time. These findings demonstrate excellent potential for this novel SPME system as a sustained release delivery system for LA. PMID- 27471674 TI - Folate-conjugated polyspermine for lung cancer-targeted gene therapy. AB - Biodegradable polyamines have long been studied as potential recombinant viral gene vectors. Spermine (SPE) is an endogenous tetra-amine with excellent biocompatibility yet poor gene condensation capacity. We have previously synthesized a polyspermine based on SPE and poly(ethylene glycol) (PEG) diacrylate (SPE-alt-PEG) for enhanced transfection performance, but the synthesized SPE-alt-PEG still lacked specificity towards cancer cells. In this study, folic acid (FA) was incorporated into SPE-alt-PEG to fabricate a targeted gene delivery vector (FA-SPE-PEG) via an acylation reaction. FA-SPE-PEG exhibited mild cytotoxicity in both cancer cells and normal cells. FA-SPE-PEG possessed higher transfection efficiency than PEI 25 K and Lipofectamine((r)) 2000 in two tested cancer cell lines at functional weight ratios, and its superiority over untargeted SPE-alt-PEG was prominent in cells with overexpressed folate receptors (FRs). Moreover, in vivo delivery of green fluorescent protein (GFP) with FA-SPE PEG resulted in highest fluorescent signal intensity of all investigated groups. FA-SPE-PEG showed remarkably enhanced specificity towards cancer cells both in vivo and in vitro due to the interaction between FA and FRs. Taken together, FA SPE-PEG was demonstrated to be a prospective targeted gene delivery vector with high transfection capacity and excellent biocompatibility. PMID- 27471675 TI - Sodium dodecyl sulfate/beta-cyclodextrin vesicles embedded in chitosan gel for insulin delivery with pH-selective release. AB - In an answer to the challenge of enzymatic instability and low oral bioavailability of proteins/peptides, a new type of drug-delivery vesicle has been developed. The preparation, based on sodium dodecyl sulfate (SDS) and beta cyclodextrin (beta-CD) embedded in chitosan gel, was used to successfully deliver the model drug-insulin. The self-assembled SDS/beta-CD vesicles were prepared and characterized by particle size, zeta potential, appearance, microscopic morphology and entrapment efficiency. In addition, both the interaction of insulin with vesicles and the stability of insulin loaded in vesicles in the presence of pepsin were investigated. The vesicles were crosslinked into thermo sensitive chitosan/beta-glycerol phosphate solution for an in-situ gel to enhance the dilution stability. The in vitro release characteristics of insulin from gels in media at different pH values were investigated. The insulin loaded vesicles chitosan hydrogel (IVG) improved the dilution stability of the vesicles and provided pH-selective sustained release compared with insulin solution-chitosan hydrogel (ISG). In vitro, IVG exhibited slow release in acidic solution and relatively quick release in neutral solutions to provide drug efficacy. In simulated digestive fluid, IVG showed better sustained release and insulin protection properties compared with ISG. Thus IVG might improve the stability of insulin during its transport in vivo and contribute to the bioavailability and therapeutic effect of insulin. PMID- 27471676 TI - Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides. AB - Brain delivery of macromolecular therapeutics (e.g., proteins) remains an unsolved problem because of the formidable blood-brain barrier (BBB). Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs, new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. In order to overcome the barriers and take advantage of available pathways (e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion), a low molecular weight protamine (LMWP) cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides (CPP) have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP-proteins are able to effectively penetrate into the brain after intranasal administration. The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases. PMID- 27471677 TI - Thoracoscopic Esophageal Atresia with Tracheoesophageal Fistula Repair: The First Iranian Group Report, Passing the Learning Curve. AB - BACKGROUND: Thoracoscopic treatment of esophageal atresia and tracheoesophageal fistula (EA+TEF) is accepted as a superior technique at least in cosmetic point of view but it is considered as an advance endoscopic procedure that needs a learning curve to be performed perfectly. This is the first report of Iranian group pediatric surgeons in thoracoscopic approach to EA. METHODS AND MATERIALS: Since 2010, twenty four cases with EA+TEF underwent thoracoscopic approach in Sarvar Children Hospital (Mashhad -Iran). During the first 6 months, thoracoscopic approach to 6 cases of EA+TEF was converted to open procedure because of technical and instrumental problems. The first case of successful thoracoscopic EA repair was accomplished in 2010 and since then, 10 cases of EA+ TEF among 18 patients were treated successfully with thoracoscopic approach RESULTS: Overall conversion rate was 58.3% but conversion rate after the primary learning curve period, was 35.7%. The main conversion causes include difficulties in esophageal anastomosis, limited exposure and deteriorating the patient's condition. Anastomotic leak and stenosis were observed in 20% and 40% respectively. Overall mortality rate was 4.2%. CONCLUSION: Thoracoscopic repair of esophageal atresia seems feasible and safe with considerable superiorities to the conventional method although acceptable results needs a prolonged learning curve and advanced endoscopic surgical skill. Clear judgment about the best surgical intervention for EA according to all cosmetic and functional outcomes needs further studies. PMID- 27471678 TI - Metabolic Imaging to Assess Treatment Response to Cytotoxic and Cytostatic Agents. AB - For several decades, cytotoxic chemotherapeutic agents were considered the basis of anticancer treatment for patients with metastatic tumors. A decrease in tumor burden, assessed by volumetric computed tomography and magnetic resonance imaging, according to the response evaluation criteria in solid tumors (RECIST), was considered as a radiological response to cytotoxic chemotherapies. In addition to RECIST-based dimensional measurements, a metabolic response to cytotoxic drugs can be assessed by positron emission tomography (PET) using (18)F fluoro-thymidine (FLT) as a radioactive tracer for drug-disrupted DNA synthesis. The decreased (18)FLT-PET uptake is often seen concurrently with increased apparent diffusion coefficients by diffusion-weighted imaging due to chemotherapy induced changes in tumor cellularity. Recently, the discovery of molecular origins of tumorogenesis led to the introduction of novel signal transduction inhibitors (STIs). STIs are targeted cytostatic agents; their effect is based on a specific biological inhibition with no immediate cell death. As such, tumor size is not anymore a sensitive end point for a treatment response to STIs; novel physiological imaging end points are desirable. For receptor tyrosine kinase inhibitors as well as modulators of the downstream signaling pathways, an almost immediate inhibition in glycolytic activity (the Warburg effect) and phospholipid turnover (the Kennedy pathway) has been seen by metabolic imaging in the first 24 h of treatment. The quantitative imaging end points by magnetic resonance spectroscopy and metabolic PET (including 18F-fluoro-deoxy-glucose, FDG, and total choline) provide an early treatment response to targeted STIs, before a reduction in tumor burden can be seen. PMID- 27471679 TI - Edwardsiella tarda-Induced Inhibition of Apoptosis: A Strategy for Intracellular Survival. AB - Edwardsiella tarda is a Gram-negative bacterial pathogen that can infect a wide range of freshwater and marine fish. One salient feature of E. tarda is the ability to survive and replicate in various host cells. In this study, we observed that E. tarda replicated robustly in the zebrafish cell line ZF4, and that E. tarda-infected cells exhibited no detectable signs of apoptosis. Global transcriptome analysis and quantitative real-time RT-PCR revealed that E. tarda infection generally significantly downregulated pro-apoptotic genes and upregulated anti-apoptotic genes. To investigate the role of apoptosis in E. tarda infection, two upregulated anti-apoptotic genes (Fech and Prx3) and two downregulated pro-apoptotic genes (Brms1a and Ivns1a) were overexpressed in zebrafish. Subsequent infection study showed that Fech and Prx3 overexpression significantly promoted E. tarda dissemination in and colonization of fish tissues, while Brms1a and Ivns1a overexpression significantly reduced E. tarda dissemination and colonization. Consistently, when Fech and Prx3 were knocked down in zebrafish, E. tarda infection was significantly inhibited, whereas Brms1a and Ivns1a knockdown significantly enhanced E. tarda infection. These results indicate for the first time that E. tarda prevents apoptosis in teleost as a strategy for intracellular survival, and that some putative apoptotic genes of teleost function in the apoptosis pathway probably in a manner similar to that in mammalian systems. PMID- 27471680 TI - Effect size of contributory factors on adverse events: an analysis of RCA series in a teaching hospital. AB - BACKGROUND: One of the most important concerns of health care systems in the world is the patient safety issues. Root Cause Analysis is a systematic process for identifying root causes and contributory factors of problems or events. The objective of this study is to review RCA reports to determine the effect size of contributory factors on adverse events through an organizational perspective. METHODS: This study was conducted in a tertiary care teaching hospital in 2014. The process of root cause analysis was taken from National Patient Safety Agency framework. We calculated descriptive statistics to determine the frequency distribution of contributory factors on each adverse event. RESULTS: Having the process of 16 adverse events reviewed, 38 care or service delivery problems were identified which showed that 317 contributory factors and underlying causes had led to these problems. Accordingly, the most important contributory factors included the following: Task factors (20 %), education and training factors (16 %), communication factors (14 %), and team and social factors (13 %). CONCLUSIONS: RCA is an effective method of problem solving used for identifying the root causes of initial errors and finding ways to prevent the recurrences. In this study, lack of effective communication skills of nurses and other clinical staff when interacting with colleague and communicating with patients, failure to comply with health care provision standards, lack of adequate supervision on implementation of clinical guidelines and issues related to the organizational culture were the main determining factors which have been considered for implementing preventive measures with regard to the hospital specifications. PMID- 27471681 TI - Cancer as an immune-mediated disease. AB - The link between oncology and immunology has a long history and its development is forced by the necessity to develop innovative and highly efficient modalities for immunological destruction of malignant cells. The limited efficacy of surgery, chemotherapy and radiation also exemplify these issues, as these treatments do not eliminate all cancerous cells, do not address the immunosuppressive nature of the disease and can further impair the patient's immune response weakening patient's resistance to the cancer. Multidisciplinary analysis of the interaction between the immune system and cancer in preclinical and clinical settings suggests that the immune system is closely intertwined with both cancer pathogenesis and treatment. On the one hand, cancer is a manifestation of malfunctions in immunity, as malignant cells manage to escape recognition and elimination by the immune system. Chronic infections and inflammation associated with limited or polarized immune responses also contribute to carcinogenesis and tumor progression. The tumor immunoenvironment represents specific conditions and elements that support cancerous cell survival, proliferation and spreading. On the other hand, the specificity and strength of antitumor immunity is a powerful and efficient tool that can be used to recognize and destroy neoplastic cells or their supporting microenvironment. Understanding the role of the immune system in controlling and supporting tumor initiation, formation, growth and progression has crucial implications for cancer therapy and will therefore guide the future development of cancer immunotherapy and its combination with conventional therapies to achieve optimal antitumor effects in patients with different types of cancer. PMID- 27471682 TI - T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor-stimulated macrophages. AB - Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor-alpha (TNF-alpha), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion was not induced by low concentrations of TLR agonists that readily produced TNF-alpha. We subsequently stimulated lymphocytes with anti-CD3 antibody in the presence of media from macrophages activated with higher doses of TLR agonists and observed suppression of interferon gamma release. Use of both IL 10 knockout macrophages and IL-10 small-interfering RNA (siRNA) ablated this suppressive effect. Finally, IL-10 siRNA was successfully used to suppress CpG induced IL-10 production in vivo. We conclude that TLR-mediated APC stimulation can induce a paradoxical inhibitory effect on T-cell activation mediated by IL 10. PMID- 27471683 TI - Immunotherapy in the management of melanoma: current status. AB - As the rate of melanoma continues to increase, so does the need for more effective and durable therapies. Despite considerable research, the management of advanced disease remains challenging. Numerous therapies are being investigated, many of which aim at upregulating the immune system's innate ability to attack the tumor. Cytotoxic T lymphocyte antigen 4 antibodies are immune stimulants that act as negative regulators of the immune system by modifying an antitumor T-cell response. Ipilimumab, one such cytotoxic T lymphocyte antigen 4 antibody, and vemurafenib, a BRAF competitive inhibitor, were approved as first-line therapies in 2011 due to improved survival rates versus standard chemotherapy. Allovectin-7 is a lipid plasmid that encodes for major histone compatibility complex DNA sequences. It has led to increases in cytotoxic T-cell production, which subsequently attacks the tumor. OncoVEX, an oncolytic herpes virus, and PV-10, a chemoablative agent, have yielded promising results in metastatic lesions and have demonstrated a unique "bystander" phenomenon. In this paper we review the basics of melanoma from the pathophysiology, risk factors, signs, diagnostic approaches, and current status of immunologic management of melanoma. PMID- 27471684 TI - Cancer testis antigen and immunotherapy. AB - The identification of cancer testis (CT) antigens has been an important advance in determining potential targets for cancer immunotherapy. Multiple previous studies have shown that CT antigen vaccines, using both peptides and dendritic cell vaccines, can elicit clinical and immunologic responses in several different tumors. This review details the expression of melanoma antigen family A, 1 (MAGE A1), melanoma antigen family A, 3 (MAGE-A3), and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) in various malignancies, and presents our current understanding of CT antigen based immunotherapy. PMID- 27471685 TI - Update on immunopathogenesis and immunotherapy in multiple sclerosis. AB - Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Both genetic and environmental factors are believed to contribute to the pathogenesis of the disease. Histopathological findings suggest that multiple sclerosis is an immune-mediated disease, involving both the cellular and humoral immune systems. Within the last 20 years, several disease-modifying therapies for the treatment of multiple sclerosis were established. Moreover, promising new substances are currently being tested in clinical trials and will likely broaden the therapeutic opportunities available within the upcoming years. PMID- 27471686 TI - The association between Lambert-Eaton myasthenic syndrome and small cell lung carcinoma. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder mediated by autoantibodies to voltage-gated calcium channels. The disorder is diagnosed clinically on the basis of a triad of symptoms (proximal muscle weakness, hyporeflexia, and autonomic disturbance), supported by electrophysiological findings and the presence of autoantibodies. Between 40% and 62% of patients diagnosed with LEMS are found to have small-cell lung cancer (SCLC), almost all of whom develop neurological symptoms before their cancer is diagnosed. Prompt identification of LEMS and appropriate screening for SCLC is key to improving the outcome of both conditions. Here we review the pathophysiology and clinical management of LEMS, focusing particularly on the relationship with SCLC. PMID- 27471687 TI - Update on the challenges and recent advances in cancer immunotherapy. AB - This overview provides an analysis of some of the immunotherapies currently in use and under investigation, with a special focus on the tumor microenvironment, which we believe is a major factor responsible for the general failure of immunotherapy to date. It is our expectation that combining immunotherapy with methods of altering the tumor microenvironment and targeting regulatory T cells and myeloid cells will yield favorable results. PMID- 27471688 TI - Immunotargeting in the management of psoriasis. AB - The treatment of psoriasis has been revolutionized since the introduction of biologic therapies. Prior to their introduction, it was unclear if psoriasis was primarily a keratinocyte signaling dysfunction or an autoimmune T-cell mediated pathway. Nonspecific T-cell targeting treatments had been used with some success, but they were limited by a narrow therapeutic index. The nonspecific nature of these agents was fraught with side effects, and the efficacy of these treatments pales in comparison to current treatments. The initial biologic molecules, alefacept and efalizumab, were not specific for any T-cell driven pathway, and neither are currently available in the USA. The successors to these early therapies have shown high efficacy and low side effects in psoriasis and other autoimmune diseases through the specific targeting of tumor necrosis factor-alpha (TNF-alpha). Since the initial use of antitumor necrosis factor agents, a renaissance in our understanding of psoriasis has been underway, leading to the elucidation of the T-helper 17 (Th17) from the Th1 pathway. With each new treatment, the pathogenesis for psoriasis continues to be more defined, allowing for improved targeted therapies and the ability to achieve new milestones in efficacy. PMID- 27471689 TI - Allergen immunotherapy: routes, safety, efficacy, and mode of action. AB - Allergic rhinitis, allergic conjunctivitis, and allergic asthma have been steadily increasing in prevalence in recent years. These allergic diseases have a major impact on quality of life and are a major economic burden in the US. Although allergen avoidance and pharmacotherapy are currently the mainstays of therapy, they are not always successful in treating patients' symptoms effectively. If a patient fails allergen avoidance and medical therapy, immunotherapy may be indicated. Furthermore, immunotherapy is the only therapy that may change the course of the disease and induce long-term remission. Though subcutaneous administration has been the standard route for immunotherapy for many decades, there are several other routes of administration that have been and are currently being studied. The goal of utilizing alternative routes of immunotherapy is to improve safety without decreasing the efficacy of treatment. This paper will review the novel routes of immunotherapy, including sublingual, oral, local nasal, epicutaneous, and intralymphatic. PMID- 27471691 TI - Identification, characterization, and synthesis of peptide epitopes and a recombinant six-epitope protein for Trichomonas vaginalis serodiagnosis. AB - There is a need for a rapid, accurate serodiagnostic test useful for both women and men infected by Trichomonas vaginalis, which causes the number one sexually transmitted infection (STI). Women and men exposed to T. vaginalis make serum antibody to fructose-1,6-bisphosphate aldolase (ALD), alpha-enolase (ENO), and glyceraldehyde-3-phosphate dehydrogenase (GAP). We identified, by epitope mapping, the common and distinct epitopes of each protein detected by the sera of women patients with trichomonosis and by the sera of men highly seropositive to the immunogenic protein alpha-actinin (positive control sera). We analyzed the amino acid sequences to determine the extent of identity of the epitopes of each protein with other proteins in the databanks. This approach identified epitopes unique to T. vaginalis, indicating these peptide-epitopes as possible targets for a serodiagnostic test. Individual or combinations of 15-mer peptide epitopes with low to no identity with other proteins were reactive with positive control sera from both women and men but were unreactive with negative control sera. These analyses permitted the synthesis of a recombinant His6 fusion protein of 111 amino acids with an Mr of ~13.4 kDa, which consisted of 15-mer peptides of two distinct epitopes each for ALD, ENO, and GAP. This recombinant protein was purified by affinity chromatography. This composite protein was detected by enzyme-linked immunosorbent assay (ELISA), dot blots, and immunoblots, using positive control sera from women and men. These data indicate that it is possible to identify epitopes and that either singly, in combination, or as a composite protein represent targets for a point-of-care serodiagnostic test for T. vaginalis. PMID- 27471690 TI - Metastatic renal cell carcinoma: update on epidemiology, genetics, and therapeutic modalities. AB - The treatment of advanced renal cell carcinoma (RCC) remains a major therapeutic challenge for clinicians. Despite advances in the understanding of the immunobiology of RCC and the availability of several novel targeted agents, there has been little improvement in the survival of patients with metastatic RCC. This review will focus on the recent understanding of risk factors and treatment options and outcomes of metastatic RCC, in particular, targeted therapeutic agents that inhibit vascular endothelial growth factor and mammalian target of rapamycin pathways. Prospective studies are required to determine whether sequential targeted therapy will further improve progression-free survival in RCC. Ongoing research to develop novel agents with better tolerability and enhanced efficacy in the treatment of metastatic RCC is required. PMID- 27471692 TI - Therapeutic vaccines in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) unfortunately carries a very poor prognosis. Patients usually do not become symptomatic, and therefore do not seek treatment, until the cancer is advanced and it is too late to employ curative treatment options. New therapeutic options are urgently needed for NSCLC, because even current targeted therapies cure very few patients. Active immunotherapy is an option that is gaining more attention. A delicate and complex interplay exists between the tumor and the immune system. Solid tumors utilize a variety of mechanisms to evade immune detection. However, if the immune system can be stimulated to recognize the tumor as foreign, tumor cells can be specifically eliminated with little systemic toxicity. A number of vaccines designed to boost immunity against NSCLC are currently undergoing investigation in phase III clinical trials. Belagenpumatucel-L, an allogeneic cell vaccine that decreases transforming growth factor (TGF-beta) in the tumor microenvironment, releases the immune suppression caused by the tumor and it has shown efficacy in a wide array of patients with advanced NSCLC. Melanoma-associated antigen A3 (MAGE-A3), an antigen-based vaccine, has shown promising results in MAGE-A3(+) NSCLC patients who have undergone complete surgical resection. L-BLP25 and TG4010 are both antigenic vaccines that target the Mucin-1 protein (MUC-1), a proto-oncogene that is commonly mutated in solid tumors. CIMAVax is a recombinant human epidermal growth factor (EGF) vaccine that induces anti-EGF antibody production and prevents EGF from binding to its receptor. These vaccines may significantly improve survival and quality of life for patients with an otherwise dismal NSCLC prognosis. This review is intended to give an overview of the current data and the most promising studies of active immunotherapy for NSCLC. PMID- 27471693 TI - Hyaluronidase facilitated subcutaneous immunoglobulin in primary immunodeficiency. AB - Immunoglobulin (Ig)-replacement therapy represents the mainstay of treatment for patients with primary antibody deficiency and is administered either intravenously (IVIg) or subcutaneously (SCIg). While hyaluronidase has been used in clinical practice for over 50 years, the development of a high-purity recombinant form of this enzyme (recombinant human hyaluronidase PH20) has recently enabled the study of repeated and more prolonged use of hyaluronidase in facilitating the delivery of SC medicines. It has been used in a wide range of clinical settings to give antibiotics, local anesthetics, insulin, morphine, fluid replacement, and larger molecules, such as antibodies. Hyaluronidase has been used to help overcome the limitations on the maximum volume that can be delivered into the SC space by enabling dispersion of SCIg and its absorption into lymphatics. The rate of facilitated SCIg (fSCIg) infusion is equivalent to that of IVIg, and the volume administered at a single site can be greater than 700 mL, a huge increase over conventional SCIg, at 20-40 mL. The use of fSCIg avoids the higher incidence of systemic side effects of IVIg, and it has higher bioavailability than SCIg. Data on the long-term safety of this approach are currently lacking, as fSCIg has only recently become available. fSCIg may help several areas of patient management in primary antibody deficiency, and the extent to which it may be used in future will depend on long-term safety data and cost-benefit analysis. PMID- 27471694 TI - T cell immunoglobulin domain and mucin domain-3 as an emerging target for immunotherapy in cancer management. AB - Cancer-induced immunosuppression significantly impacts tumors, rendering them the ability to acquire aggressive and treatment-resistant phenotypes. The recent clinical success of drugs targeting the immunosuppressive machinery of tumors highlights the importance of identifying novel drugs that effectively augment antitumor immunity and elicit clinical remission in advanced tumors. T cell immunoglobulin domain and mucin domain-3 (TIM-3) is a critical immunoregulatory molecule that links pattern recognition-mediated innate sensing with antigen specific immune responses. Recent evidence has elucidated the potential utility of drugs targeting TIM-3 in inducing antitumor responses, particularly in synergy with conventional anticancer regimens. Herein, we provide a comprehensive overview, as well as future perspectives, regarding the role of TIM-3 as an emerging target that may improve clinical responses for cancer patients. PMID- 27471695 TI - Emerging treatments in management of prostate cancer: biomarker validation and endpoints for immunotherapy clinical trial design. AB - The rapidly emerging field of immunotherapy and the development of novel immunologic agents that have been approved in melanoma and successfully studied in lung cancer, kidney cancer, and prostate cancer have mandated that there be uniformity in clinical trial analysis beyond conventional survival endpoints and imaging. This includes some measure of determining whether the immunologic target is hit and how the treatment has impacted on the immune system in toto. While melanoma is leading the field towards these ends, there is some doubt that not all of the recent successes with immune therapies, for example, checkpoint inhibitors, will be effective for every cancer, and that the toxicities may also be different depending on the malignancy. This review serves to elucidate the current issues facing clinical investigators who perform immunologic trials targeted at patients with prostate cancer and discusses the challenges in assessing the right immunologic endpoints to demonstrate biologic/immunologic targeting leading to clinical benefit. PMID- 27471696 TI - Implications of chemokine receptors and inflammatory lipids in cancer. AB - Inflammatory lipids receive much attention due to their important biological activities. Knowledge of the chemokine system has also reached a level that makes it interesting in clinics, which prompted clinical trials into compounds manipulating chemokines or their receptors. However, little attention has been devoted to understand the relations between these two systems. Here, we will review the role of inflammatory lipids and chemokines in innate and adaptive immunity with an attempt to link the two systems and with emphasis on their importance in cancer development. PMID- 27471697 TI - Immunotherapy for the treatment of Alzheimer's disease: amyloid-beta or tau, which is the right target? AB - Alzheimer's disease (AD) is characterized by the presence of amyloid plaques composed mainly of amyloid-beta (Abeta) protein. Overproduction or slow clearance of Abeta initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Abeta, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Abeta raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Abeta peptide and tau protein, as well as future directions. PMID- 27471698 TI - B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292. AB - Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatable, the majority of CLL patients will die of complications of their disease. Recent advances in the understanding of the importance of the B cell receptor (BCR) pathway in CLL have led to the development of a number of agents targeting this pathway. In this review, we discuss recent developments in the targeting of the BCR pathway, with a focus on CC-292. CC-292 covalently binds to Bruton's tyrosine kinase, a key mediator of BCR signaling, and has demonstrated preclinical and clinical activity in CLL, with acceptable tolerability. Based on the success of CC-292 and other inhibitors of the BCR pathway, these agents are being investigated in combination with standard therapy, with the hope that they will increase the depth and length of response, without significant toxicity. PMID- 27471699 TI - Interleukin-17 and type 17 helper T cells in cancer management and research. AB - Since their recent discovery, T helper 17 (Th17) cells have been frequently detected in the tumor microenvironment of many malignancies, but their clinical implications remain largely unknown. Interleukin-17 (IL-17) detection is commonly related with poor outcomes in colorectal cancers, yet its presence is associated with antitumor responses in ovarian carcinomas. Numerous experimental models illustrate the divergent roles of Th17 cells in tumor immunity, which appears to be mainly dependent on the tumor context (type, location, and stage of cancer). It is recognized that IL-17 is produced by a variety of cell types and that Th17 cells are endowed with a unique functional plasticity. Therefore, when trying to elucidate potential immune biomarkers and immunotargets, it is extremely important to make a clear dissociation between strategies targeting Th17 versus its hallmark cytokine, IL-17. In this review, we will summarize the data regarding the detection of IL-17 and Th17 in human cancers, consider the experimental evidence on their respective roles in antitumor activity, and discuss the potential of IL-17 as an immune target for therapeutic interventions. PMID- 27471700 TI - Dendritic cell vaccination for glioblastoma multiforme: review with focus on predictive factors for treatment response. AB - Glioblastoma multiforme (GBM) is the most common and most aggressive type of primary brain cancer. Since median overall survival with multimodal standard therapy is only 15 months, there is a clear need for additional effective and long-lasting treatments. Dendritic cell (DC) vaccination is an experimental immunotherapy being tested in several Phase I and Phase II clinical trials. In these trials, safety and feasibility have been proven, and promising clinical results have been reported. On the other hand, it is becoming clear that not every GBM patient will benefit from this highly personalized treatment. Defining the subgroup of patients likely to respond to DC vaccination will position this option correctly amongst other new GBM treatment modalities, and pave the way to incorporation in standard therapy. This review provides an overview of GBM treatment options and focuses on the currently known prognostic and predictive factors for response to DC vaccination. In this way, it will provide the clinician with the theoretical background to refer patients who might benefit from this treatment. PMID- 27471701 TI - Antigen-based immunotherapy for the treatment of acute lymphoblastic leukemia: the emerging role of blinatumomab. AB - Acute lymphoblastic leukemia (ALL) arises from immature B and T lymphoblasts. An increasing array of cytogenetic and molecular markers have been identified in ALL, which allows for increasingly sophisticated prognostication, as well as identification of potential new targets for therapy. The treatment of ALL in children has shown astounding success in the last 50 years, with more than 90% of children now able to be cured of their ALL. In adults, these success rates have not been duplicated. However, the use of pediatric-intensive regimens in young adults has shown increasing success. The use of monoclonal antibodies conjugated to drugs, immunotoxins, and cells also has shown early success and promises to enhance the outcome of newly diagnosed patients. Blinatumomab, a bispecific T cell engager antibody, brings a malignant B cell in proximity to a T cell with redirected lysis. This antibody construct has shown promising results in patients with relapsed and refractory disease and is entering randomized clinical trials in newly diagnosed patients. The addition of monoclonal antibody therapy to chemotherapy in adults promises to enhance outcomes while hopefully not increasing toxicity. After many years of stagnation, it appears that the therapy of adults with ALL is showing significant improvement. PMID- 27471702 TI - Clinical potential of apremilast in the treatment of psoriatic arthritis. AB - Psoriatic arthritis (PsA) is a frequent chronic inflammatory disease characterized by joint and skin involvement, and by typical extra-articular manifestations. Although the pathogenesis of PsA is still under investigation, the available evidence suggests the importance of the patient's genetic background, microbial or environmental triggers, and an imbalance in the adaptive and acquired immune system, resulting in the production of inflammatory mediators. New therapeutic approaches have been proposed, among them the use of modulators of intracellular signals and gene transcription such as PDE4 inhibiting compounds, which are able to modulate the activity of transcription factors such as CREB and NF-kappaB and therefore the synthesis of inflammatory mediators, resulting in immunoregulation. This paper summarizes the mechanism of action of apremilast, a PDE4 inhibitor, and the clinical data available on its clinical efficacy and safety profile in the treatment of PsA patients. PMID- 27471703 TI - Hairy cell leukemia - immunotargets and therapies. AB - Hairy cell leukemia (HCL) is an indolent low-grade B-cell lymphoproliferative disorder that is reasonably sensitive to standard first-line purine analog therapy. However, in many cases, repeat relapses occur, requiring multiple courses of purine analog therapy, promoting eventual drug resistance. This, coupled with the concerning side effects of repeated purine analog exposure, has prompted the search for alternative targets and therapies that may provide deeper remissions. Novel strategies employing immune-mediated targeting via monoclonal antibody therapies and recombinant immunotoxins appear promising in HCL and are currently under investigation. More recently, the concept of targeted kinase inhibition using small-molecule inhibitors in HCL has emerged as another potentially viable option. As a deeper understanding of the aberrant molecular pathways contributing to the pathogenesis of HCL develops, the landscape of management for HCL, particularly in the relapse setting, may change significantly in the future as a result of these promising immunotargets and therapies. PMID- 27471704 TI - Nanocarrier-based immunotherapy in cancer management and research. AB - Research in cancer immunotherapy has gained momentum in the last two decades, with many studies and clinical trials showing positive therapeutic outcomes. Immunotherapy can elicit not only a strong anticancer immune response which could even control metastases, but could also induce immunological memory, resulting in long-lasting protection in the prophylactic setting and protection against possible recurrence. Nanocarriers offer an attractive means for delivery of a multitude of therapeutic immunomodulators which are readily taken up by immune cells and can initiate a particular arm of an immunostimulatory cascade leading to tumor cell killing. This review focuses on recent advances in nanocarrier mediated immunotherapy for the treatment of cancer. Both in vitro and in vivo studies as well as clinical progress are discussed in various sections. Description of the specific role of nanoparticle technology in immunotherapy highlights the way particles can be tailor-made in terms of size, structure, payload, and surface properties for active targeting to antigen-presenting cells and/or enhanced accumulation in the solid tumor. PMID- 27471705 TI - Therapeutic cancer vaccines and combination immunotherapies involving vaccination. AB - Recent US Food and Drug Administration approvals of Provenge((r)) (sipuleucel-T) as the first cell-based cancer therapeutic factor and ipilimumab (Yervoy((r))/anticytotoxic T-lymphocyte antigen-4) as the first "checkpoint blocker" highlight recent advances in cancer immunotherapy. Positive results of the clinical trials evaluating additional checkpoint blocking agents (blockade of programmed death [PD]-1, and its ligands, PD-1 ligand 1 and 2) and of several types of cancer vaccines suggest that cancer immunotherapy may soon enter the center stage of comprehensive cancer care, supplementing surgery, radiation, and chemotherapy. This review discusses the current status of the clinical evaluation of different classes of therapeutic cancer vaccines and possible avenues for future development, focusing on enhancing the magnitude and quality of cancer specific immunity by either the functional reprogramming of patients' endogenous dendritic cells or the use of ex vivo-manipulated dendritic cells as autologous cellular transplants. This review further discusses the available strategies aimed at promoting the entry of vaccination-induced T-cells into tumor tissues and prolonging their local antitumor activity. Finally, the recent improvements to the above three modalities for cancer immunotherapy (inducing tumor-specific T cells, prolonging their persistence and functionality, and enhancing tumor homing of effector T-cells) and rationale for their combined application in order to achieve clinically effective anticancer responses are addressed. PMID- 27471707 TI - Antigen-based immunotherapy for autoimmune disease: current status. AB - Autoimmune diseases are common chronic disorders that not only have a major impact on the quality of life but are also potentially life-threatening. Treatment modalities that are currently favored have conferred significant clinical benefits, but they may have considerable side effects. An optimal treatment strategy for autoimmune disease would specifically target disease associated antigens and limit systemic side effects. Similar to allergen-specific immunotherapy for allergic rhinitis, antigen-specific immunotherapy for autoimmune disease aims to induce immune deviation and promote tolerance to specific antigens. In this review, we present the current status of studies and clinical trials in both human and animal hosts that use antigen-based immunotherapy for autoimmune disease. PMID- 27471706 TI - Harnessing immunosurveillance: current developments and future directions in cancer immunotherapy. AB - Despite improved methods of cancer detection and disease management over the last few decades, cancer remains a major public health problem in many societies. Conventional therapies, such as chemotherapy, radiation, and surgery, are not usually sufficient to prevent disease recurrence. Therefore, efforts have been focused on developing novel therapies to manage metastatic disease and to prolong disease-free and overall survival, by modulating the immune system to alleviate immunosuppression, and to enhance antitumor immunity. This review discusses protumor mechanisms in patients that circumvent host immunosurveillance, and addresses current immunotherapy modalities designed to target these mechanisms. Given the complexity of cancer immunosuppressive mechanisms, we propose that identification of novel disease biomarkers will drive the development of more targeted immunotherapy. Finally, administration of different classes of immunotherapy in combination regimens, will be the ultimate route to impact low survival rates in advanced cancer patients. PMID- 27471708 TI - The role of autophagy in microbial infection and immunity. AB - The autophagy pathway represents an evolutionarily conserved cell recycling process that is activated in response to nutrient deprivation and other stress signals. Over the years, it has been linked to an array of cellular functions. Equally, a wide range of cell-intrinsic, as well as extracellular, factors have been implicated in the induction of the autophagy pathway. Microbial infections represent one such factor that can not only activate autophagy through specific mechanisms but also manipulate the response to the invading microbe's advantage. Moreover, in many cases, particularly among viruses, the pathway has been shown to be intricately involved in the replication cycle of the pathogen. Conversely, autophagy also plays a role in combating the infection process, both through direct destruction of the pathogen and as one of the key mediating factors in the host defense mechanisms of innate and adaptive immunity. Further, the pathway also plays a role in controlling the pathogenesis of infectious diseases by regulating inflammation. In this review, we discuss various interactions between pathogens and the cellular autophagic response and summarize the immunological functions of the autophagy pathway. PMID- 27471709 TI - Alzheimer's disease and immunotherapy: what is wrong with clinical trials? AB - Alzheimer's disease (AD) is characterized by progressive neurodegeneration and is the most common cause of dementia. Immunotherapy has recently been regarded as a potential treatment for AD. This stems from the fact that the clinical and pathological findings from the active AD vaccine trial suggests that such vaccine therapy may be effective for AD. However, this trial was halted because of the occurrence of meningoencephalitis in some patients. Avoiding excessive immune reaction is necessary for the success of vaccine therapy. For this purpose, adjuvant-free vaccine therapies (eg, passive immunization or DNA vaccines) are currently under investigation. However, the results of clinical trials employing both active and passive anti-amyloid-beta immunotherapy have been unsatisfactory. In this article, we will analyze the reasons for the limited efficacy of currently available immunotherapies and discuss the effectiveness of new vaccine therapies. Finally, we will speculate on the possibility of its clinical application. PMID- 27471710 TI - Development of antibody-based c-Met inhibitors for targeted cancer therapy. AB - Signaling pathways mediated by receptor tyrosine kinases (RTKs) and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. PMID- 27471712 TI - Management of patients with non-Hodgkin's lymphoma: focus on adoptive T-cell therapy. AB - Non-Hodgkin's lymphoma (NHL) represents a heterogeneous group of malignancies with high diversity in terms of biology, clinical responses, and prognosis. Standard therapy regimens produce a 5-year relative survival rate of only 69%, with the critical need to increase the treatment-success rate of this patient population presenting at diagnosis with a median age of 66 years and many comorbidities. The evidence that an impaired immune system favors the development of NHL has opened the stage for new therapeutics, and specifically for the adoptive transfer of ex vivo-expanded antigen-specific T-cells. In this review, we discuss how T-cells specific for viral-associated antigens, nonviral associated antigens expressed by the tumor, T-cells redirected through the expression of chimeric antigen receptors, and transgenic T-cell receptors against tumor cells have been developed and used in clinical trials for the treatment of patients with NHLs. PMID- 27471711 TI - Current perspectives on natural killer cell education and tolerance: emerging roles for inhibitory receptors. AB - Natural killer (NK) cells are regulated through the coordinated functions of activating and inhibitory receptors. These receptors can act during the initial engagement of an NK cell with a target cell, or in subsequent NK cell engagements to maintain tolerance. Notably, each individual possesses a sizable minority population of NK cells that are devoid of inhibitory receptors that recognize the surrounding MHC class I (ie, self-MHC). Since these NK cells cannot perform conventional inhibition, they are rendered less responsive through the process of NK cell education (also known as licensing) in order to reduce the likelihood of auto-reactivity. This review will delineate current views on NK cell education, clarify various misconceptions about NK cell education, and, lastly, discuss the relevance of NK cell education in anti-cancer therapies. PMID- 27471713 TI - Emerging role of Natural killer cells in oncolytic virotherapy. AB - Natural killer (NK) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. The ability of NK cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. Therapies with NK cells involve activation of endogenous NK cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. To exploit the diverse functional abilities of NK cells for cancer immunotherapy, it is important to understand NK cell biology and the underlying regulatory mechanisms. The state of immune suppression prevalent in malignancies creates the need for innovative therapies. Oncolytic viruses are novel anticancer agents showing selective tropism for tumor cells and lacking pathogenicity in humans, but the use of oncolytic virotherapy (OVT) presents multiple challenges. An increasing body of evidence suggests that the host immune response may critically influence the outcome of OVT. Classically, the immune system is thought to limit the efficacy of therapy through virus clearance mediated by innate immune effectors or through adaptive antiviral immune responses eliminating infected cells. Effective strategies do need to be designed in OVT to circumvent the early antiviral activity of NK cells and to augment late NK-cell-mediated antitumor responses. The intrinsic immunostimulating capacity of oncolytic viruses and the possibility of engineering them to express heterologous immunostimulatory molecules (eg, cytokines) support the use of these agents to enhance antitumor immune responses besides inducing direct oncolytic effects. OVT has indeed shown promising therapeutic outcomes in various clinical trials. Here, we review the biology of NK cells, strategies involving NK cells for achieving cancer therapy, and, more particularly, the emerging role of NK cells in OVT. PMID- 27471714 TI - Update on use of aldesleukin for treatment of high-risk metastatic melanoma. AB - High-dose interleukin-2 has been used for the treatment of metastatic melanoma since 1998 based on data proving durable complete responses in up to 10% of treated patients. The immunomodulatory effects of this critical cytokine have been instrumental in the development of immunotherapy for melanoma and other cancers. However, with the advent of new therapies, its use as a front-line agent has come into question. Nonetheless, there is still a role for interleukin-2 as monotherapy, as well as in combination with other agents and in clinical trials. In this article, we review preclinical and clinical data regarding interleukin-2, its pharmacology and mechanism of action, its toxicity profile, and its use in ongoing and planned clinical trials. We also explore the future of this agent within the treatment landscape for melanoma. PMID- 27471715 TI - Enhancement of antibody-dependent cell mediated cytotoxicity: a new era in cancer treatment. AB - The therapeutic efficacy of some anti-tumor monoclonal antibodies (mAbs) depends on the capacity of the mAb to recognize the tumor-associated antigen and induce cytotoxicity via a network of immune effector cells. This process of antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells is triggered by the interaction of the fragment crystallizable (Fc) portion of the mAb with the Fc receptors on effector cells like natural killer cells, macrophages, gammadelta T cells, and dendritic cells. By augmenting ADCC, the antitumor activity of mAbs can be significantly increased. Currently, identifying and developing therapeutic agents that enhance ADCC is a growing area of research. Combining existing tumor targeting mAbs and ADCC-promoting agents that stimulate effector cells will translate to greater clinical responses. In this review, we discuss strategies for enhancing ADCC and emphasize the potential of combination treatments that include US Food and Drug Administration-approved mAbs and immunostimulatory therapeutics. PMID- 27471716 TI - Emerging roles for HMGB1 protein in immunity, inflammation, and cancer. AB - High-mobility group box 1 (HMGB1) protein is a member of the highly conserved non histone DNA binding protein family. First identified in 1973, as one of a group of chromatin-associated proteins with high acidic and basic amino acid content, it was so named for its characteristic rapid mobility in polyacrylamide gel electrophoresis. HMGB1 was later discovered to have another function. It is released from a variety of cells into the extracellular milieu to act on specific cell-surface receptors. In this latter role, HMGB1 is a proinflammatory cytokine that may contribute to many inflammatory diseases, including sepsis. Therefore, HMGB1 regulates intracellular cascades influencing immune cell functions, including chemotaxis and immune modulation. The bioactivity of the HMGB1 is determined by specific posttranslational modifications that regulate its role in inflammation and immunity. During tumor development, HMGB1 has been reported to play paradoxical roles in promoting both cell survival and death by regulating multiple signaling pathways. In this review, we focus on the role of HMGB1 in physiological and pathological responses, as well as the mechanisms by which it contributes to immunity, inflammation, and cancer progression. PMID- 27471718 TI - Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy. AB - Obesity is a medical condition caused by accumulated excess body fat with negative impact on patients' health, including decreased life expectancy. It has become a major health problem in most developed and developing countries, since the worldwide prevalence of obesity nearly doubled during the last 30 years. Consequently, novel treatments focusing on obesity are being investigated. Potential targets include several pathophysiological mechanisms involved in appetite control affecting multiple organ systems, like adipose tissue; some cell types in the stomach and gut; pancreas; thyroid gland; several hypothalamic areas; and centers located in the brainstem. One of the most important orexigenic neuropeptides is ghrelin, which is produced and secreted primarily by ghrelin cells located in the stomach and duodenum. In humans, plasma ghrelin levels rise when the stomach is empty and fall shortly after meal ingestion. In fat tissue, ghrelin increases fat storage. In the brain, it exerts its orexigenic action through activation of NPY/AgRP neurons in the arcuate nucleus. From the pharmacological point of view, it seems that opposing ghrelin activity could be used as a therapeutic principle in treating obesity. The principal idea of antiobesity drugs is to augment anorexigenic and lipolytic signaling, or to block orexigenic and lipogenic mediators. Recent studies have shown that therapeutic vaccines could be a new approach in the development of antiobesity medications. A vaccine should provoke an immune response to a specific causal factor for a particular disease. Several types of anti-ghrelin vaccines have been developed so far, with significant immune response in terms of rising anti-ghrelin antibodies. However, in the only clinical trial performed yet, the results were disappointing, showing no additional weight loss in the study group. Until now, several studies have demonstrated the "proof of concept", but more studies are required to develop prophylactic and therapeutic vaccines to prevent and/or cure obesity. PMID- 27471717 TI - CD28 co-stimulation in T-cell homeostasis: a recent perspective. AB - T-cells play a key role within the adaptive immune system mediating cellular immunity and orchestrating the immune response as a whole. Their activation requires not only recognition of antigen/major histocompatibility complexes by the T-cell receptor but in addition co-stimulation via the CD28 molecule through binding to CD80, CD86, or as recently discovered, inducible co-stimulator ligand expressed by antigen-presenting cells. Apart from tight control of the co stimulatory signal by the T-cell receptor complex, expression of the inhibitory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) sharing its ligands with CD28 is required to avoid inappropriate or prolonged T-cell activation. CD4(+) Foxp3(+) regulatory T (Treg) cells, which are crucial inhibitors of autoimmunity, add another level of complexity in that they differ from conventional non regulatory CD4(+) T-cells by strongly depending on CD28 signaling for their generation and homeostasis. Moreover, CTLA-4 is constitutively expressed by Treg cells where it serves as a key mediator of suppression, while conventional CD4(+) T-cells express CTLA-4 only after activation. Here, we discuss recent insights into the molecular events underlying CD28-mediated co-stimulation, its impact on gene regulation, and the differential role of CD28 expression on Treg cells versus conventional CD4(+) and CD8(+) T-cells. Moreover, we summarize the exciting therapeutic options which have arisen from our current understanding of T-cell co-stimulation. Some of these have already been translated into the clinic, while others are expected to follow soon due to promising preclinical results. In particular, we discuss the failed 2006 trial of the CD28 superagonist TGN1412, and the return of this potent T-cell activator to clinical development. PMID- 27471719 TI - Novel perspectives on non-canonical inflammasome activation. AB - Inflammasomes are cytosolic multi-protein complexes that regulate the secretion of the proinflammatory cytokines, IL-1beta and IL-18, and induce pyroptosis, an inflammatory form of cell death. The NLRP3 inflammasome is the most well characterized member of this family and functions by sensing intracellular pathogen- and damage-associated molecular patterns and activating caspase-1, which processes the biologically inactive IL-1beta and IL-18 precursors into active cytokines. Recent studies have identified an alternative mechanism of inflammasome activation, termed the non-canonical inflammasome, which is triggered by cytosolic sensing of lipopolysaccharide (LPS) derived from bacteria that have escaped phagolysosomes. This pathway is independent of Toll-like receptor 4 (TLR4), the well-known extracellular receptor for LPS, but instead depends on the inflammatory protease, caspase-11. Although our understanding of caspase-11 activation is still in its infancy, it appears to be an essential mediator of septic shock and attenuates intestinal inflammation. In this review, we bring together the latest data on the roles of caspase-11 and the mechanisms underlying caspase-11-mediated activation of the non-canonical inflammasome, and consider the implications of this pathway on TLR4-independent immune responses to LPS. PMID- 27471720 TI - The hygiene hypothesis: current perspectives and future therapies. AB - Developed countries have experienced a steady increase in atopic disease and disorders of immune dysregulation since the 1980s. This increase parallels a decrease in infectious diseases within the same time period, while developing countries seem to exhibit the opposite effect, with less immune dysregulation and a higher prevalence of infectious disease. The "hygiene hypothesis", proposed by Strachan in 1989, aimed to explain this peculiar generational rise in immune dysregulation. However, research over the past 10 years provides evidence connecting the commensal and symbiotic microbes (intestinal microbiota) and parasitic helminths with immune development, expanding the hygiene hypothesis into the "microflora" and "old friends" hypotheses, respectively. There is evidence that parasitic helminths and commensal microbial organisms co-evolved with the human immune system and that these organisms are vital in promoting normal immune development. Current research supports the potential for manipulation of the bacterial intestinal microbiota to treat and even prevent immune dysregulation in the form of atopic disease and other immune-mediated disorders (namely inflammatory bowel disease and type 1 diabetes). Both human and animal model research are crucial in understanding the mechanistic links between these intestinal microbes and helminth parasites, and the human immune system. Pro-, pre-, and synbiotic, as well as treatment with live helminth and excretory/secretory helminth product therapies, are all potential therapeutic options for the treatment and prevention of these diseases. In the future, therapeutics aimed at decreasing the prevalence of inflammatory bowel disease, type 1 diabetes, and atopic disorders will likely involve personalized microbiota and/or helminth treatments used early in life. PMID- 27471722 TI - Place in therapy of rituximab in the treatment of granulomatosis with polyangiitis and microscopic polyangiitis. AB - Granulomatosis with polyangiitis and microscopic polyangiitis are small vessel vasculitides characterized by circulating antineutrophil circulating antibodies. Standard treatment for active severe disease has consisted of cyclophosphamide with glucocorticoids with or without plasmapheresis, which achieves approximately 75% sustained remission, but carries significant adverse effects such as malignancy, infertility, leukopenia, and infections. The role of B cells in the pathogenesis of anti-neutrophil circulating antibodies-associated vasculitis has been established, and as such, rituximab, a monoclonal anti-CD20 antibody, has been studied in treatment of active granulomatosis with polyangiitis and microscopic polyangiitis (induction) and in maintaining remission. Rituximab has been shown to be effective in inducing remission in several retrospective studies in patients with refractory disease or cyclophosphamide intolerance. The RAVE and RITUXVAS trials demonstrated rituximab is a noninferior alternative to standard cyclophosphamide-based therapy; however, its role in elderly patients and patients with severe renal disease warrants further investigation. Rituximab has been compared with azathioprine for maintaining remission in the MAINRITSAN trial and may be more efficacious in maintaining remission in patients treated with cyclophosphamide induction. Rituximab is not without risks and carries a similar adverse event risk rate as cyclophosphamide in randomized control trials. However, its use can be considered over cyclophosphamide in patients who have relapsing or refractory disease or in young patients seeking to preserve fertility. PMID- 27471724 TI - Ventricular Function in Congenital Heart Defects. PMID- 27471723 TI - Current perspective on the role of the interleukin-23/interleukin-17 axis in inflammation and disease (chronic arthritis and psoriasis). AB - TH17 is a lymphocyte subset, which is characterized by its polarization to secrete interleukin (IL)-17. IL-23 is the pivotal mediator responsible for TH17 differentiation and the IL-23/IL-17 axis has been strongly implicated in the pathogenesis of several immune mediated diseases, in particular chronic arthritis and skin psoriasis. This review will summarize the basic immunology and the new monoclonal antibodies, which antagonize this pathway allowing a new therapeutic approach. PMID- 27471721 TI - The role of regulatory T cells in cancer immunology. AB - Regulatory T cells (Treg) are generally considered to be significant contributors to tumor escape from the host immune system. Emerging evidence suggests, however, that in some human cancers, Treg are necessary to control chronic inflammation, prevent tissue damage, and limit inflammation-associated cancer development. The dual role of Treg in cancer and underpinnings of Treg diversity are not well understood. This review attempts to provide insights into the importance of Treg subsets in cancer development and its progression. It also considers the role of Treg as potential biomarkers of clinical outcome in cancer. The strategies for monitoring Treg in cancer patients are discussed as is the need for caution in the use of therapies which indiscriminately ablate Treg. A greater understanding of molecular pathways operating in various tumor microenvironments is necessary for defining the Treg impact on cancer and for selecting immunotherapies targeting Treg. PMID- 27471725 TI - A Detailed Protocol to Enable Safe-Handling, Preemptive Detection, and Systematic Surveillance of Rat-Vectored Pathogens in the Urban Environment. AB - We detail a five-stage protocol to address physical barriers and experimental limitations that have hindered routine pathogen monitoring of wild rats in urban settings. New York City potentially harbors from 2 to 32 million rats among its 8 million people. However, at a time, when people are most vulnerable to disease from over-crowdedness brought on by increased urbanization of society, the difficulty of studying wild rats has led to a paucity of ecological and epidemiological research. Challenges of safely handling animals and the difficulties of identifying individual animals and the emergence of their respective pathogen loads (timing of infection) have impeded progress. We previously reported a method using radio frequency identification paired with load cell and camera traps to enable the identification of individual animals and subsequent monitoring of the animals' weights (an indicator of health). However, efficient pathogen surveillance requires repeated captures of the same individual in order to isolate and document the emergence of new pathogens, or variations in pathogen load, over time. Most of these barriers are now addressed in our protocol, which is aided by the use of a mobile, outdoor laboratory, followed by incorporation of pheromone-based lures to attract individuals back to active sensors, within a camera trap. This approach allows for the assessment of individual animal health, behaviors under camera, and changing pathogen loads and weights in most urban environments (e.g., financial district, docks, sewers, and residential). Five phases are described and presented: (1) site selection and urban trapping, (2) anesthetization, (3) serological and ectoparasite collection, (4) microchip implantation, and (5) retrapping and luring animals back to active remote sensors. In order to fulfill the unmet call for preemptive pathogen surveillance, public health officials and researchers may wish to adapt, or modify, similar protocols to ensure early detection and monitoring of rat-borne zoonoses, before they become problematic. PMID- 27471726 TI - Dairy Tool Box Talks: A Comprehensive Worker Training in Dairy Farming. AB - Today's dairies are growing rapidly, with increasing dependence on Latino immigrant workers. This requires new educational strategies for improving milk quality and introduction to state-of-the-art dairy farming practices. It also creates knowledge gaps pertaining to the health of animals and workers, mainly due to the lack of time and language barriers. Owners, managers, and herdsmen assign training duties to more experienced employees, which may not promote "best practices" and may perpetuate bad habits. A comprehensive and periodic training program administered by qualified personnel is currently needed and will enhance the sustainability of the dairy industry. Strategic management and employee satisfaction will be achieved through proper training in the employee's language, typically Spanish. The training needs to address not only current industry standards but also social and cultural differences. An innovative training course was developed following the same structure used by the engineering and construction industries, giving farm workers basic understanding of animal care and handling, cow comfort, and personal safety. The "Dairy Tool Box Talks" program was conducted over a 10-week period with nine sessions according to farm's various employee work shifts. Bulk milk bacterial counts and somatic cell counts were used to evaluate milk quality on the three dairy farms participating in the program. "Dairy Tool Box Talks" resulted in a general sense of employee satisfaction, significant learning outcomes, and enthusiasm about the topics covered. We conclude this article by highlighting the importance of educational programs aimed at improving overall cross-cultural training. PMID- 27471727 TI - Discovering miRNA Regulatory Networks in Holt-Oram Syndrome Using a Zebrafish Model. AB - MicroRNAs (miRNAs) are small non-coding RNAs that play an important role in the post-transcriptional regulation of gene expression. miRNAs are involved in the regulation of many biological processes such as differentiation, apoptosis, and cell proliferation. miRNAs are expressed in embryonic, postnatal, and adult hearts, and they have a key role in the regulation of gene expression during cardiovascular development and disease. Aberrant expression of miRNAs is associated with abnormal cardiac cell differentiation and dysfunction. Tbx5 is a member of the T-box gene family, which acts as transcription factor involved in the vertebrate heart development. Alteration of Tbx5 level affects the expression of hundreds of genes. Haploinsufficiency and gene duplication of Tbx5 are at the basis of the cardiac abnormalities associated with Holt-Oram syndrome (HOS). Recent data indicate that miRNAs might be an important part of the regulatory circuit through which Tbx5 controls heart development. Using high-throughput technologies, we characterized genome-widely the miRNA and mRNA expression profiles in WT- and Tbx5-depleted zebrafish embryos at two crucial developmental time points, 24 and 48 h post fertilization (hpf). We found that several miRNAs, which are potential effectors of Tbx5, are differentially expressed; some of them are already known to be involved in cardiac development and functions, such as miR-30, miR-34, miR-190, and miR-21. We performed an integrated analysis of miRNA expression data with gene expression profiles to refine computational target prediction approaches by means of the inversely correlation of miRNA-mRNA expressions, and we highlighted targets, which have roles in cardiac contractility, cardiomyocyte proliferation/apoptosis, and morphogenesis, crucial functions regulated by Tbx5. This approach allowed to discover complex regulatory circuits involving novel miRNAs and protein coding genes not considered before in the HOS such as miR-34a and miR-30 and their targets. PMID- 27471728 TI - Adhesive Capsulitis in Eight Dogs: Diagnosis and Management. AB - OBJECTIVE: To describe clinical and diagnostic findings as well as management of adhesive capsulitis in dogs. BACKGROUND: Adhesive capsulitis, also known as frozen shoulder, is a syndrome defined by loss of range of motion of the shoulder and may be the end-stage manifestation of several primary conditions. EVIDENTIARY VALUE: This is a case series report of eight dogs with chronic forelimb lameness diagnosed with adhesive capsulitis. METHODS: Medical records (June 1, 2010 September 1, 2015) including, physical examination findings, radiographic findings, magnetic resonance imaging (MRI) findings, arthroscopy findings, and treatment plans were reviewed. RESULTS: All dogs presented with a chronic, grade III-VI/VI forelimb lameness. On orthopedic examination, all dogs had moderate to significant discomfort on shoulder extension and flexion and severe restriction of range of motion. Six of the eight dogs had evidence of bone remodeling and sclerosis in the affected shoulder on radiographs. Six of the dogs had an initial diagnostic ultrasound performed, which revealed evidence of fibrous scar tissue. Five dogs had MRI performed that revealed moderate shoulder effusion and enhancement of the synovial lining of the shoulder. Arthroscopy was performed in five of the eight patients. Three were noted to have significant contracture, adhesions, and fibrous scar tissue of the joint capsule. Severe inflammation was noted throughout the synovium of two patients. All eight patients tried conservative management consisting of oral medications and rehabilitation therapy. Five of the eight patients received extracorporeal shockwave therapy. Three patients received regenerative medicine treatment in the affected supraspinatus and shoulder. Regardless of the treatment elected, none of the dogs were reported to have significant improvement. CONCLUSION: Adhesive capsulitis is an uncommon cause of chronic forelimb lameness. Further investigation is needed to describe the etiology and pathogenesis of adhesive capsulitis in dogs to evaluate the effectiveness of both non-surgical and surgical treatment modalities, establish treatment protocols, and evaluate short- and long-term clinical outcome of patients. APPLICATION: Adhesive capsulitis should be considered in patients with chronic forelimb lameness and moderate to significant discomfort and restriction on shoulder range of motion. PMID- 27471729 TI - Transcriptional Suppression of Renal Antioxidant Enzyme Systems in Guinea Pigs Exposed to Polymerized Cell-Free Hemoglobin. AB - Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and plasma volume-expanding therapeutics though their potential to promote oxidative tissue injury has raised safety concerns. Using a guinea pig exchange transfusion model, we examined the effects of polymerized bovine hemoglobin (HbG) on the transcriptional regulation, activity, and expression of the renal antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). HbG infusion downregulated the mRNA levels for genes encoding SOD isoforms 1-3, GPx1, GPx3, GPx4, and CAT. This transcriptional suppression correlated with decreased enzymatic activities for SOD, CAT, and GPx. Immunostaining revealed decreased protein expression of SOD1, CAT, and GPx1 primarily in renal cortical tubules. DNA methylation analyses identified CpG hypermethylation in the gene promoters for SOD1-3, GPx1, GPx3, and GPx4, suggesting an epigenetic-based mechanism underlying the observed gene repression. HbG also induced oxidative stress as evidenced by increased renal lipid peroxidation end-products and 4-HNE immunostaining, which could be the result of the depleted antioxidant defenses and/or serve as a trigger for increased DNA methylation. Together, these findings provide evidence that the renal exposure to HbG suppresses the function of major antioxidant defense systems which may have relevant implications for understanding the safety of hemoglobin-based products. PMID- 27471730 TI - Full-Length cDNA, Prokaryotic Expression, and Antimicrobial Activity of UuHb-F-I from Urechis unicinctus. AB - Hemoglobin, which widely exists in all vertebrates and in some invertebrates, is possibly a precursor of antimicrobial peptides (AMPs). However, AMPs in the hemoglobin of invertebrates have been rarely investigated. This study is the first to report the full-length cDNA, prokaryotic expression, and antimicrobial activity of UuHb-F-I from Urechis unicinctus. The full-length cDNA sequence of UuHb-F-I was 780 bp with an open-reading frame of 429 bp encoding 142 amino acids. MALDI-TOF-MS suggested that the recombinant protein of UuHb-F-I (rUuHb-F I) yielded a molecular weight of 15,168.01 Da, and its N-terminal amino acid sequence was MGLTGAQIDAIK. rUuHb-F-I exhibited different antimicrobial activities against microorganisms. The lowest minimum inhibitory concentration against Micrococcus luteus was 2.78-4.63 MUM. Our results may help elucidate the immune defense mechanism of U. unicinctus and may provide insights into new AMPs in drug discovery. PMID- 27471732 TI - Use of Moringa oleifera Flower Pod Extract as Natural Preservative and Development of SCAR Marker for Its DNA Based Identification. AB - The use of Moringa oleifera as natural food preservative has been evaluated in the present study. In addition, for quality assurance, the study has also been focused on the shelf life of product to authenticate the identification of plant by development of DNA based marker. Among the different extracts prepared from flower pods of Moringa oleifera, methanol and aqueous extract exhibited high antibacterial and antioxidant activity, respectively. The high phenolic contents (53.5 +/- 0.169 mg GAE/g) and flavonoid contents (10.9 +/- 0.094 mg QE/g) were also recorded in methanol and aqueous extract, respectively. Due to instability of bioactive compounds in aqueous extract, methanol extract is considered as potent natural preservative. The shelf life of methanol extract was observed for two months at 4 degrees C under dark conditions. The developed SCAR primers (MOF217/317/MOR317) specifically amplified a fragment of 317 bp from DNA of Moringa oleifera samples collected from different regions of Punjab province of Pakistan. The methanol extract of Moringa oleifera flower pods has great potential to be used as natural preservative and nutraceutical in food industry. PMID- 27471731 TI - In Vivo and In Vitro Genotoxic and Epigenetic Effects of Two Types of Cola Beverages and Caffeine: A Multiassay Approach. AB - The aim of this work was to assess the biological and food safety of two different beverages: Classic Coca ColaTM (CCC) and Caffeine-Free Coca Cola (CFCC). To this end, we determined the genotoxicological and biological effects of different doses of lyophilised CCC and CFCC and Caffeine (CAF), the main distinctive constituent. Their toxic/antitoxic, genotoxic/antigenotoxic, and chronic toxicity (lifespan assay) effects were determined in vivo using the Drosophila model. Their cytotoxic activities were determined using the HL-60 in vitro cancer model. In addition, clastogenic DNA toxicity was measured using internucleosomal fragmentation and SCGE assays. Their epigenetic effects were assessed on the HL-60 methylation status using some repetitive elements. The experimental results showed a slight chemopreventive effect of the two cola beverages against HL-60 leukaemia cells, probably mediated by nonapoptotic mechanisms. Finally, CCC and CAF induced a global genome hypomethylation evaluated in LINE-1 and Alu M1 repetitive elements. Overall, we demonstrated for the first time the safety of this famous beverage in in vivo and in vitro models. PMID- 27471734 TI - Monocular Deprivation in Mice. AB - Monocular deprivation is an experimental technique to study the ocular dominance plasticity during critical period (Hubel and Wiesel, 1963). Generally one eye of an animal is sutured during critical period, and the sutured eye is re-opened after either less than three days (short term) or more than three days (long term). Here we describe a detailed protocol for short-term and long-term monocular deprivation in mouse (Ma et al., 2013). PMID- 27471733 TI - Insulin Resistance and Obesity Affect Lipid Profile in the Salivary Glands. AB - In today's world wrong nutritional habits together with a low level of physical activity have given rise to the development of obesity and its comorbidity, insulin resistance. More specifically, many researches indicate that lipids are vitally involved in the onset of a peripheral tissue (e.g., skeletal muscle, heart, and liver) insulin resistance. Moreover, it seems that diabetes can also induce changes in respect of lipid composition of both the salivary glands and saliva. However, judging by the number of research articles, the salivary glands lipid profile still has not been sufficiently explored. In the current study we aim to assess the changes in the main lipid fractions, namely, triacylglycerols, phospholipids, free fatty acids, and diacylglycerols, in the parotid and the submandibular salivary glands of rats exposed to a 5-week high fat diet regimen. We observed that the high caloric fat diet caused a significant change in the salivary glands lipid composition, especially with respect to PH and TG, but not DAG or FFAs, classes. The observed reduction in PH concentration is an interesting phenomenon frequently signifying the atrophy and malfunctions in the saliva secreting organs. On the other hand, the increased accumulation of TG in the glands may be an important clinical manifestation of metabolic syndrome and type 2 diabetes mellitus. PMID- 27471735 TI - Making a diagnosis of hypertension and defining treatment threshold in very low birth weight infants' need revision? AB - INTRODUCTION: Recent evidence suggests that preterm birth is a possible risk factor for high blood pressure (BP) in later life. The most widely quoted blood pressure centiles for very low birth weight (VLBW, <=1500 g birth weight) infants at corrected term gestation is based on a cohort with mostly late preterm or term infants (Zubrow curves). OBJECTIVES: The objective of this study was to determine the clinical utility of the Zubrow curves in diagnosis of hypertension in VLBW infants at their term corrected gestational age (CGA). PATIENTS AND METHODS: In a case-control study, we compared BP in 75 VLBW infants at 40 weeks CGA (cases) to 69 full term infants admitted to neonatal intensive care unit (NICU) (controls). RESULTS: In spite of having lower weights, VLBW infants compared to term infants (2612.8 +/- 546 vs. 3308.2 +/- 373 g, P <= 0.001) had higher average systolic (88.8 +/- 7.6 vs. 82.33 +/- 8.5 mm Hg; P <= 0.001) and mean BP (61.2 +/- 6.6 vs. 57.61 +/- 6.9, P = 0.01). Although 41% (31/75) VLBW infants would have met the criteria for hypertension according to Zubrow curves only 4% (3/75) were diagnosed with hypertension. CONCLUSION: Since Zubrow BP centiles were based on a heterogeneous population of infants including preterm and term infants, new BP centiles based on chronological data from VLBW infants would allow a better definition of hypertension in these infants and identify the threshold BP for initiating treatment. PMID- 27471736 TI - Prognostic indicators of adverse renal outcome and death in acute kidney injury hospital survivors. AB - INTRODUCTION: Data regarding prognostic factors of post-discharge mortality and adverse renal function outcome in acute kidney injury (AKI) hospital survivors are scarce and controversial. OBJECTIVES: We aimed to identify predictors of post discharge mortality and adverse renal function outcome in AKI hospital survivors. PATIENTS AND METHODS: The study group consisted of 84 AKI hospital survivors admitted to the tertiary medical center during 2-year period. Baseline clinical parameters, with renal outcome 3 months after discharge and 6-month mortality were evaluated. According survival and renal function outcome, patients were divided into two groups. RESULTS: Patients who did not recover renal function were statistically significantly older (P < 0.007) with higher Charlson comorbidity index (CCI) score (P < 0.000) and more likely to have anuria and oliguria (P = 0.008) compared to those with recovery. Deceased AKI patients were statistically significantly older (P < 0.000), with higher CCI score (P < 0.000), greater prevalence of sepsis (P =0.004), higher levels of C-reactive protein (CRP) (P < 0.017) and ferritin (P < 0.051) and lower concentrations of albumin (P<0.01) compared to survivors. By multivariate analysis, independent predictors of adverse renal outcome were female gender (P =0.033), increasing CCI (P =0.000), presence of pre-existing chronic kidney disease (P =0.000) and diabetes mellitus (P =0.019) as well as acute decompensated heart failure (ADHF) (P =0.032), while protective factor for renal function outcome was higher urine output (P =0.009). Independent predictors of post-discharge mortality were female gender (P =0.04), higher CCI score (P =0.001) and sepsis (P =0.034). CONCLUSION: Female AKI hospital survivors with increasing burden of comorbidities, diagnosis of sepsis and ADHF seem to be at high-risk for poor post-discharge outcome. PMID- 27471737 TI - Suitable intravenous fluid for preventing dysnatremia in children with gastroenteritis; a randomized clinical trial. AB - INTRODUCTION: Gastroenteritis (GE) is one of the most common pediatric diseases. Hyponatremia commonly occurs by administering hypotonic fluids to GE and hospitalized children. Yet, there is no consensus on the ideal method of treatment. OBJECTIVES: we aimed to assess suitable intravenous (IV) fluid for preventing dysnatremia in children with GE. PATIENTS AND METHODS: This is a double blind randomized clinical trial, which was conducted on infants of 6 months up to 14 years children with GE. Children were randomly assigned in 2 different groups. Group A; received 20 cc/kg 0.9% isotonic saline as a bolus, and 0.45% hypotonic saline as sum of maintenance fluid and volume deficit. Group B was treated with the same bolus and 0.9% isotonic saline with 20 mEq/L KCl as sum of maintenance fluid and volume deficit. Blood and urine samples were taken at admission, 4 and 24 hours. Data were analyzed by independent t test, Mann-Whitney U test, Friedmann test, chi-square and 2-tailed repeated measurements by SPSS version 19. RESULTS: Baseline hyponatremia and isonatremia were detected in 24 (31.5%) and 51 (67.1%) patients, respectively. Mean level of sodium at T0, T4 and T 24 mentioned no significant difference between groups. No hypernatremia was noted by administering isotonic saline. RESULTS showed that 4 and 24 hours after administration isotonic saline, the mean plasma sodium differed significantly in baseline hyponatremic patients. However, no significant difference was noted after 4 and 24 hours in group A. CONCLUSION: According to the considerable effect of isotonic saline on hyponatremic patients, it seems that administering isotonic fluids regardless of the types of dysnatremia can be recommended to lessen clinicians' conflicting decision-making in selecting an appropriate fluid. PMID- 27471738 TI - Tempol effects on diabetic nephropathy in male rats. AB - INTRODUCTION: Diabetic nephropathy (DN) is the most common cause of the chronic kidney disease in the world. Oxidative stress on the other hand has a major and well known role in its pathophysiology. OBJECTIVES: The aim of the study is to figure out if tempol, a synthetic antioxidant agent, modifies DN and to determine its relevance to changes of serum oxidative biomarkers. MATERIALS AND METHODS: Twenty-seven male rats were equally divided in to 4 groups (7 rats for each group). Group I (control or C), group II (diabetic or D), groups III (Tempol) which were given tempol (100 mg/kg/day) by gavages for 28 days and group IV (D&T) which includes diabetic rats that also received same dose of tempol. After treatment, blood samples were isolated. Enzymatic scavengers including catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, lipid peroxidation (LPO), total antioxidant capacity (TAC) and total thiol molecules (TTM) were measured. Blood urea nitrogen (BUN), creatinine (Cr) an albumin/Cr ratio were evaluated as well. Statistical differences were assessed with one-way analysis of variance (ANOVA) by SPSS followed by Tukey t test. RESULTS: Oxidative stress biomarkers modified and Alb/Cr ratio increased in diabetic group (II), however, they were altered to normal in group IV (D&T) compared with diabetic group (D). CONCLUSION: Tempol can modify oxidative stress biomarkers and presumably nephropathy in diabetic rats. PMID- 27471739 TI - Association of metabolic syndrome with serum fibroblast growth factor 21 in kidney transplanted patients. AB - INTRODUCTION: Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose and lipid homeostasis and insulin sensitivity. OBJECTIVES: The aim of this study was to investigate the relation between the serum level of FGF21 with and metabolic syndrome (MS) in kidney transplant recipients. PATIENTS AND METHODS: We performed a cross-sectional study on 86 stable renal transplant recipients to detect possible relation between serum FGF21 level and MS during October 2014 and Mach 2015. Patients with past history of diabetes mellitus were excluded. RESULTS: There were 43 patients in each group with and without MS. Totally, they were 52 (60.5%) male and 34 (39.5%) female. The mean age of the MS group was significantly higher than that of non-MS group. There was not significant difference between mean serum creatinine level and glomerular filtration rate (GFR) between two groups (P > 0.05). The MS patients had higher weight and body mass index (BMI) (P < 0.05). The prevalence of BMI >25 kg/m(2) in MS group was 25 (58.8%) versus non-MS group that only 10 (23.3%) had this condition (P < 0.05). The mean of FGF21 level in MS and non-MS groups was 1.23 +/- 0.67 ng/l and 1.18 +/- 0.71 ng/l, respectively (P > 0.05). There was not significant difference of serum FGF21 level between MS and non-MS patients (P > 0.05). CONCLUSION: While the elevated serum FGF21 level was found in subjects with insulin resistant states, however, this study revealed that serum FGF21 levels were not significantly increased in renal transplanted recipients with MS as compared with non-MS group. PMID- 27471740 TI - The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients. AB - INTRODUCTION: It is known that cytomegalovirus (CMV) infection is a common problem among kidney transplant patients. This infection can be increased morbidity and decreased graft survival. This problem has been associated with acute rejection too. PATIENTS AND METHODS: One hundred and thirty renal transplant patients were included in a prospective, case-control study. The renal transplant patients were divided into two groups; patients group with CMV infection and control group without CMV infection. Serum CMV-IgG in all patients was positive (donor and recipients). None of patients had received anti-thymocyte globulin and thymoglobulin. CMV infection was diagnosed by quantitative CMV-PCR (polymerase chain reaction) test (more than 500 copies/MUg). Rejection episode was defined by kidney isotope scan or biopsy. RESULTS: In the group of 66 CMV infection patients (41 male [62.1%] and 25 female [37.9%]) the incidence of graft rejection was 36%, however in the group of 64 control patients the incidence of graft rejection was 9.4 % (P < 0.005). CONCLUSION: CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation. The results of this study suggests that the control of CMV infection could decrease episodes of acute kidney rejection. PMID- 27471741 TI - Predictive factors of restless leg syndrome in hemodialysis patients. AB - INTRODUCTION: The restless leg syndrome (RLS) is a neurologic disorder suffering the hemodialysis patients. Although the pathophysiology of this syndrome remains unknown yet, an investigation of the parameters pertinent to it may help to develop the related medical knowledge and to improve the therapeutic-care interventions in this regard. OBJECTIVES: The correlation between the RLSs on individual, clinical, and laboratory indices in patients undergoing hemodialysis. PATIENTS AND METHODS: This descriptive-analytic study was conducted on 104 hemodialysis patients. Diagnosis of RLS was made using the International RLS Standard Questionnaire. The data on individual, clinical, and laboratory indices were obtained from patients' recorded files and interviews. RESULTS: Based on our findings, 28.8% of the patients undergoing hemodialysis were affected with mild RLS, 41.7% with moderate RLS, and 29.5% with severe RLS. There was a statistically significant correlation between affliction with RLS on the one hand, and age and gender, on the other (P < 0.05). However, there was no significant correlation between RLS and education level, occupation, length of hemodialysis, fasting blood sugar (FBS), hepatitis B and C, serum blood urea nitrogen (BUN), creatinine (Cr), iron, hemoglobin (Hb) level and also KT/Vor URR (P < 0.05). CONCLUSION: Regarding the high prevalence of RLS among the hemodialysis patients, there is the necessity for taking more care of these patients to reduce the somatic complications of the RLS especially among the elderly and female patients and to control the blood sugar of these patients at the normal level. PMID- 27471742 TI - Bioimpacts of dialyzer variety on phosphorus level in Iranian hemodialysis patients. AB - INTRODUCTION: Cardiovascular events are the major cause of death in patients with chronic renal failure. About half of dialysis patients because of reduced phosphorus clearance have hyperphosphatemia. Hyperphosphatemia and following secondary hyperparathyroidism lead to some cardiovascular changes. Hemodialysis (HD) partly removes phosphorus during each dialysis session. OBJECTIVES: Presented study was designed to evaluate dialyzer variation effect on phosphorus level as a prognostic factor after dialysis using. MATERIALS AND METHODS: Six kinds of dialyzer were used for dialysis; low flux (LF) dialyzer (F7 and F8), high flux (HF) dialyzer (F70 and F80) and finally hollow-fiber dialyzers including polyethersulfone (PES) 130 HF and polysulfone (PS) 13 LF. Fifty-seven patients were divided into 6 matched groups included three groups of 10 people and 3 groups of 9 persons in groups: A (F70), B (F80), C (F7), D (F8), E (PES 130 HF) and F (PS 13 LF). Patients were treated for one month with these dialyzers. At the end of the month, blood samples were taken again for phosphorus level before dialysis handling. RESULTS: The mean pre-dialysis serum phosphorus was 5.03, 5.4, 5.2, 4.6, 4.95 and 5.1 mg/dl and the mean phosphorus was 5.43, 5.01, 4.9, 4.18, 4.17 and 5.3 mg/dl after one month of dialysis, respectively in groups A to F without any statistically differences between pre- and after one month dialysis values respectively. DISCUSSION: The findings indicate dialyzer type in the control of serum phosphorus has not been effective in the short-term HD. We suggest a study with more duration time. PMID- 27471743 TI - Role of plasma neutrophil gelatinase-associated lipocalin as an emerging biomarker of acute renal failure following kidney transplantation and its correlation with plasma creatinine. AB - INTRODUCTION: Graft function early after kidney transplantation is an important parameter in determining the outcome of operation. Urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin protein family, has been advocated as a sensitive, early biomarker for predicting early renal graft after transplantation. The functions of NGAL appears to be expressed in stress conditions and in tissues undergoing involution. It rapidly accumulates in the kidney tubules and urine after nephrotoxic and ischemic insults. OBJECTIVES: This study aimed to examine the prognostic role of NGAL early after renal transplantation. PATIENTS AND METHODS: A total of 37 kidney recipients were enrolled from a teaching centre in Tabriz within a 6-month period of time. Plasma NGAL was measured immediately before and at 6 and 12 hours post-transplantation. Changes of serum creatinine were documented daily within the first week post operation. Acute kidney injury (AKI)/graft rejection during the first week after transplantation was the outcome variable. RESULTS: There were 22 males (59.5%) and 15 females (40.5%) with the mean age of 34.93 +/- 14.97 years (range: 12-59) in the study group. AKI/graft rejection developed in 12 patients (32.4%). The mean post-transplantation plasma NGAL levels and serum creatinine at all time points were significantly higher in patients with AKI/graft rejection. The best prognostic role was found for plasma NGAL at 12 hours (sensitivity = 100%, specificity = 92%; cut-off value = 309 ng/ml), far better than the prognostic accuracy of corresponding serum creatinine (sensitivity = 66.7%, specificity = 61.9%). CONCLUSION: Plasma NGAL, particularly 12 hours after transplantation, is a very sensitive and specific biomarker for predicting acute renal injury. PMID- 27471745 TI - Damage Location and Quantification Indices of Shear Structures Based on Changes in the First Two or Three Natural Frequencies. AB - This study proposes damage detection algorithms for multistory shear structures that only need the first two or three natural frequencies. The methods are able to determine the location and severity of damage on the basis of damage location indices (DLI) and damage quantification indices (DQI) consisting of the changes in the first few squared natural frequencies of the undamaged and damaged states. The damage is assumed to be represented by a reduction in stiffness. This stiffness reduction causes a shift in the natural frequencies of the structure. The uncertainty associated with system identification methods for obtaining natural frequencies is also carefully considered. The methods are accurate and cost-effective means only requiring the changes in the natural frequencies. PMID- 27471744 TI - A study on the association of serum fibroblast growth factor-23 with various indices of chronic kidney disease patients not yet on dialysis. AB - INTRODUCTION: Fibroblast growth factor-23 (FGF23) is found as a bone derived hormone which can influence the serum levels of parathormone, phosphorous and 1, 25-dihydroxyvitamin D. FGF23 may be a cardiovascular biomarker in patients with chronic kidney disease (CKD). While, FGF23 is inversely correlated with serum adiponectin level, thus it is possible that FGF23 is correlated to fat mass and related to dyslipidemia in CKD. OBJECTIVES: In this investigation, we studied the association of serum levels of FGF23 with serum lipid profile, body mass index (BMI), and various cardiovascular risk factors in patients with CKD. PATIENTS AND METHODS: This is a cross-sectional study, which was conducted on 80 non-dialysis patients (glomerular filtration rate [GFR] <60 cc/min) with CKD. Laboratory results and demographic information recorded in pre-defined data sheets and their relationship with FGF23 were analyzed. RESULTS: Eighty patients were studied. Mean +/- standard deviation (SD) of serum creatinine and FGF23 were 2.18 +/- 0.73 mg/dl and 15.028 +/- 20.20 RU/ml respectively. The correlation between FGF23, low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), ApoA, ApoB, intact parathyroid hormone (iPTH), calcium, phosphorous, alkaline phosphatase, 25-hydroxyvitamin D, BMI, waist girth, serum triglyceride and cholesterol was not significant (P > 0.05). In this study, the correlations of FGF23, with serum albumin (P = 0.036) and systolic blood pressure (P = 0.001) were significant. CONCLUSION: Our study showed that there are not any significant correlations among FGF23, BMI and lipid profile. There are not any significant correlations between FGF23 and age, sex, and level of calcium, phosphorous, vitamin D. However, the relationships between FGF23 and serum albumin was negatively significant. Additionally we detected a positive significant correlation of FGF23 with level of systolic blood presure. PMID- 27471746 TI - Exploring the Impact of Prostitution on HIV/AIDS Transmission. AB - HIV/AIDS has been somehow linked to prostitution for decades now. A mathematical model is presented to assess the link between prostitution and HIV transmission. The epidemic thresholds known as the reproduction numbers and equilibria for the model are determined and stabilities analyzed. Analysis of the reproduction numbers suggests that HIV/AIDS control using antiretroviral therapy is more effective in the absence of prostitution. Numerical simulations further show high levels of HIV/AIDS when percentage of prostitutes in the community is high. Results from this study suggest that effectively controlling HIV/AIDS requires strategies that address both prostitution and HIV/AIDS transmission. Addressing HIV/AIDS through condom use and antiretroviral therapy may not be enough to stem HIV/AIDS in the community as some drug/alcohol misusing prostitutes may not be able to negotiate for safe sex while they are in drunken stupor. Furthermore, prostitutes are likely to get infected by different HIV strains some of which may be resistant to the antiretroviral therapy regimen in use. PMID- 27471747 TI - On the System of High Order Rational Difference Equations. AB - This paper is concerned with the boundedness, persistence, and global asymptotic behavior of positive solution for a system of two rational difference equations x n+1 = A + (x n /? i=1 (k) y n-i ), y n+1 = B + (y n /? i=1 (k) x n-i ), n = 0,1,..., k ? {1,2,...}, where A, B ? (0, infinity), x -i ? (0, infinity), and y i ? (0, infinity), i = 0,1, 2,..., k. PMID- 27471748 TI - Modelling Furrow Irrigation-Induced Erosion on a Sandy Loam Soil in Samaru, Northern Nigeria. AB - Assessment of soil erosion and sediment yield in furrow irrigation is limited in Samaru-Zaria. Data was collected in 2009 and 2010 and was used to develop a dimensionless model for predicting furrow irrigation-induced erosion (FIIE) using the dimensional analyses approach considering stream size, furrow length, furrow width, soil infiltration rate, hydraulic shear stress, soil erodibility, and time flow of water in the furrows as the building components. One liter of water sediment samples was collected from the furrows during irrigations from which sediment concentrations and soil erosion per furrow were calculated. Stream sizes Q (2.5, 1.5, and 0.5 l/s), furrow lengths X (90 and 45 m), and furrow widths W (0.75 and 0.9 m) constituted the experimental factors randomized in a split plot design with four replications. Water flow into and out of the furrows was measured using cutthroat flumes. The model produced reasonable predictions relative to field measurements with coefficient of determination R (2) in the neighborhood of 0.8, model prediction efficiency NSE (0.7000), high index of agreement (0.9408), and low coefficient of variability (0.4121). The model is most sensitive to water stream size. The variables in the model are easily measurable; this makes it better and easily adoptable. PMID- 27471749 TI - Radioligand saturation binding for quantitative analysis of ligand-receptor interactions. AB - The reversible combination of a ligand with specific sites on the surface of a receptor is one of the most important processes in biochemistry. A classic equation with a useful simple graphical method was introduced to obtain the equilibrium constant, Kd, and the maximum density of receptors, Bmax. The entire 125I-labeled ligand binding experiment includes three parts: the radiolabeling, cell saturation binding assays and the data analysis. The assay format described here is quick, simple, inexpensive, and effective, and provides a gold standard for the quantification of ligand-receptor interactions. Although the binding assays and quantitative analysis have not changed dramatically compared to the original methods, we integrate all the parts to calculate the parameters in one concise protocol and adjust many details according to our experience. In every step, several optional methods are provided to accommodate different experimental conditions. All these refinements make the whole protocol more understandable and user-friendly. In general, the experiment takes one person less than 8 h to complete, and the data analysis could be accomplished within 2 h. PMID- 27471751 TI - Erratum for Sarwar et al., GcsR, a TyrR-Like Enhancer-Binding Protein, Regulates Expression of the Glycine Cleavage System in Pseudomonas aeruginosa PAO1. AB - [This corrects the article DOI: 10.1128/mSphere.00020-16.]. PMID- 27471752 TI - Temporal drift in Raman signal intensity during SERS measurements performed on analytes in liquid solutions. AB - In this communication, we report one factor that could limit the quantitative analysis by SERS, which has not yet been discussed in the literature. Our results show that SERS experiments performed with the substrate immersed in liquid solutions are subjected to a temporal drift in the Raman signal intensity. Measurements were performed using gold nanoparticle suspensions and gold-covered nanostructured ITO surfaces as SERS substrates, immersed in analyte solutions of crystal violet and 4-mercaptobenzoic acid. Depending on the substrate and the conditions used for measurements, the Raman signal can take between 30 min and several hours to stabilize. This effect, if not taken into account, could have a negative impact on the results of the quantitative chemical analysis by SERS performed in situ in liquid solutions. PMID- 27471750 TI - Transcriptomic Analysis of the Activity of a Novel Polymyxin against Staphylococcus aureus. AB - Polymyxin B and colistin are exclusively active against Gram-negative pathogens and have been used in the clinic as a last-line therapy. In this study, we investigated the antimicrobial activity of a novel polymyxin, FADDI-019, against Staphylococcus aureus. MIC and time-kill assays were employed to measure the activity of FADDI-019 against S. aureus ATCC 700699. Cell morphology was examined with scanning electron microscopy (SEM), and cell membrane polarity was measured using flow cytometry. Transcriptome changes caused by FADDI-019 treatment were investigated using transcriptome sequencing (RNA-Seq). Pathway analysis was conducted to examine the mechanism of the antibacterial activity of FADDI-019 and to rationally design a synergistic combination. Polymyxin B and colistin were not active against S. aureus strains with MICs of >128 mg/liter; however, FADDI-019 had a MIC of 16 mg/liter. Time-kill assays revealed that no S. aureus regrowth was observed after 24 h at 2* to 4* MIC of FADDI-019. Scanning electron microscopy (SEM) and flow cytometry results indicated that FADDI-019 treatment had no effect on cell morphology but caused membrane depolarization. The vancomycin resistance genes vraRS, as well as the VraRS regulon, were activated by FADDI-019. Virulence determinants controlled by SaeRS and the expression of enterotoxin genes yent2, sei, sem, and seo were significantly downregulated by FADDI-019. Pathway analysis of transcriptomic data was predictive of a synergistic combination comprising FADDI-019 and sulfamethoxazole. Our study is the first to examine the mechanism of the killing of a novel polymyxin against S. aureus. We also show the potential of transcriptomic and pathway analysis as tools to design synergistic antibiotic combinations. IMPORTANCE S. aureus is currently one of the most pervasive multidrug-resistant pathogens and commonly causes nosocomial infections. Clinicians are faced with a dwindling armamentarium to treat infections caused by S. aureus, as resistance develops to current antibiotics. This accentuates the urgent need for antimicrobial drug discovery. In the present study, we characterized the global gene expression profile of S. aureus treated with FADDI-019, a novel synthetic polymyxin analogue. In contrast to the concentration-dependent killing and rapid regrowth in Gram-negative bacteria treated with polymyxin B and colistin, FADDI-019 killed S. aureus progressively without regrowth at 24 h. Notably, FADDI-019 activated several vancomycin resistance genes and significantly downregulated the expression of a number of virulence determinants and enterotoxin genes. A synergistic combination with sulfamethoxazole was predicted by pathway analysis and demonstrated experimentally. This is the first study revealing the transcriptomics of S. aureus treated with a novel synthetic polymyxin analog. PMID- 27471754 TI - Factor structure and psychometric properties of a French and German shortened version of the Behavioural Inhibition System/Behavioural Activation System scales. AB - The Behavioural Inhibition System/Behavioural Activation System scales (BIS/BAS scales) constitute one of the most prominent questionnaires to assess individual differences in sensitivity to punishment and reward. However, some studies questioned its validity, especially that of the French and German translations. The aim of the present study was to re-evaluate the psychometric characteristics of the BIS/BAS scales in a large sample of French- and German-speaking young Swiss men (N = 5872). Results showed that factor structures previously found in the literature did not meet the standards of fit. Nine items had to be removed to achieve adequate fit statistics in confirmatory factor analysis, yielding a shortened version with four factors: one BIS factor comprising five items and three BAS factors, namely Reward Reactivity, Drive and Fun Seeking, each comprising two items. Convergent validity and group invariance analyses suggest that the shortened BIS/BAS scales constitute a valid and reliable instrument. Researchers interested in assessing individual differences in BIS and BAS reactivity in French- and German-speaking individuals should avoid using the BIS/BAS scales as originally specified. The shortened version may be a sound alternative at least in samples of young adults. Its shorter format may be particularly suited for surveys with constraints on questionnaire length. PMID- 27471753 TI - The active site architecture in peroxiredoxins: a case study on Mycobacterium tuberculosis AhpE. AB - Peroxiredoxins catalyze the reduction of peroxides, a process of vital importance to survive oxidative stress. A nucleophilic cysteine, also known as the peroxidatic cysteine, is responsible for this catalytic process. We used the Mycobacterium tuberculosis alkyl hydroperoxide reductase E (MtAhpE) as a model to investigate the effect of the chemical environment on the specificity of the reaction. Using an integrative structural (R116A - PDB ; F37H - PDB ), kinetic and computational approach, we explain the mutational effects of key residues in its environment. This study shows that the active site residues are specifically oriented to create an environment which selectively favours a reaction with peroxides. PMID- 27471756 TI - CardioPulse: The 2015 Arrigo Recordati International Prize for Scientific Research. PMID- 27471755 TI - CardioPulse: Gold medallists as ESC Congress 2015. PMID- 27471757 TI - CardioPulse: EHJ CardioPulse meets Professor Patrick W. Serruys MD in our series profiling the world's most influential cardiologists. PMID- 27471758 TI - CardioPulse: 'Ten Commandments' of 2015 European Society of Cardiology Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation (NSTE-ACS). PMID- 27471759 TI - CardioPulse: Quality measures in acute coronary syndromes. PMID- 27471760 TI - CardioPulse: Cyclosporine to reduce myocardial infarction injury? PMID- 27471761 TI - CardioPulse: Hearts in sight. PMID- 27471762 TI - CardioPulse: Exercise and stop smoking to improve depression after myocardial infarction. PMID- 27471763 TI - CardioPulse: Angina pectoris revisited. PMID- 27471764 TI - In Memorium: Kenneth W. Wear. PMID- 27471765 TI - Ti-Sheng Chang, M.D., 1916 to 2015. PMID- 27471766 TI - Collaborations: Partners in knowledge. PMID- 27471767 TI - Freedom to range. PMID- 27471768 TI - Cerebral small vessel disease and incident parkinsonism: the RUN DMC study. PMID- 27471769 TI - Cerebral small vessel disease and incident parkinsonism: the RUN DMC study. PMID- 27471770 TI - Introduction. PMID- 27471771 TI - TASKFORCE LOOKS TO END VIOLENCE AND AGGRESSION AGAINST NURSES. PMID- 27471772 TI - Meroterpenoids with New Skeletons from Myrtus communis and Structure Revision of Myrtucommulone K. AB - Five sesquiterpene-based meroterpenoids with three kinds of new skeletons [1, 2, 3, (+)-4, and (-)-4] were isolated from the leaves of Myrtus communis. Compound 1 featured a new carbon skeleton with an unprecedented octahydrospiro[bicyclo[7.2.0]undecane-2,2'-chromene] tetracyclic ring system, which possessed two preferred conformations detected by variable-temperature NMR spectroscopy experiments. In addition, the structure of reported myrtucommulone K was revised to be compound 3. The plausible biosynthetic pathways of these meroterpenoids and their cytotoxicities are discussed. PMID- 27471773 TI - Cytochrome and sulfotransferase gene variation in north African populations. AB - AIM: To describe the diversity of four cytochrome and four sulfotransferase polymorphisms in six north African samples. Scarce data have been compiled for these samples despite the rich genetic background of north African populations. MATERIALS & METHODS: CYP3A4*1B, CYP3A4*17, CYP3A4*3, CYP3A5*3, SULT1A1*2, SULT1A2*2, SULT1A2*3 and SULT1E1*2 polymorphisms were explored in 556 individuals from Morocco, Algeria, Tunisia and Libya. RESULTS: Allele frequencies in our samples largely exceeded the variation ranges described for European populations, especially for CYP3A4*1B, SULT1A1*2 and SULT1A2*3. CONCLUSION: North African populations are heterogeneous, genetically diverse and show a considerable sub Saharan African contribution for markers associated with increased risk of prostate cancer and with differential drug metabolism. PMID- 27471774 TI - Buckling-Based Method for Measuring the Strain-Photonic Coupling Effect of GaAs Nanoribbons. AB - The ability to continuously and reversibly tune the band gap and the strain photonic coupling effect in optoelectronic materials is highly desirable for fundamentally understanding the mechanism of strain engineering and its applications in semiconductors. However, optoelectronic materials (i.e., GaAs) with their natural brittleness cannot be subject to direct mechanical loading processes, such as tension or compression. Here, we report a strategy to induce continuous strain distribution in GaAs nanoribbons by applying structural buckling. Wavy GaAs nanoribbons are fabricated by transfer printing onto a prestrained soft substrate, and then the corresponding photoluminescence is measured to investigate the strain-photonic coupling effect. Theoretical analysis shows the evolution of the band gap due to strain and it is consistent with the experiments. The results demonstrate the potential application of a buckling configuration to delicately measure and tune the band gap and optoelectronic performance. PMID- 27471775 TI - Structural Determinants of Improved Fluorescence in a Family of Bacteriophytochrome-Based Infrared Fluorescent Proteins: Insights from Continuum Electrostatic Calculations and Molecular Dynamics Simulations. AB - Using X-ray crystallography, continuum electrostatic calculations, and molecular dynamics simulations, we have studied the structure, protonation behavior, and dynamics of the biliverdin chromophore and its molecular environment in a series of genetically engineered infrared fluorescent proteins (IFPs) based on the chromophore-binding domain of the Deinococcus radiodurans bacteriophytochrome. Our study suggests that the experimentally observed enhancement of fluorescent properties results from the improved rigidity and planarity of the biliverdin chromophore, in particular of the first two pyrrole rings neighboring the covalent linkage to the protein. We propose that the increases in the levels of both motion and bending of the chromophore out of planarity favor the decrease in fluorescence. The chromophore-binding pocket in some of the studied proteins, in particular the weakly fluorescent parent protein, is shown to be readily accessible to water molecules from the solvent. These waters entering the chromophore region form hydrogen bond networks that affect the otherwise planar conformation of the first three rings of the chromophore. On the basis of our simulations, the enhancement of fluorescence in IFPs can be achieved either by reducing the mobility of water molecules in the vicinity of the chromophore or by limiting the interactions of the nearby protein residues with the chromophore. Finally, simulations performed at both low and neutral pH values highlight differences in the dynamics of the chromophore and shed light on the mechanism of fluorescence loss at low pH. PMID- 27471776 TI - Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets. AB - Type 1 diabetes (T1DM) results from destruction of most insulin-secreting pancreatic beta-cells. The persistence of beta-cells decades after the onset of the disease indicates that the resistance of individual cells to the autoimmune insult is heterogeneous and might depend on the metabolic status of a cell at a given moment. The aim of this study is to investigate whether activation of nicotinic acetylcholine receptors (nACh-Rs) could increase beta-cell resistance against the adverse environment prevailing at the onset of T1DM. Here, we show that nACh-R activation by nicotine and choline, 2 agonists of the receptor, decreases murine and human beta-cell apoptosis induced by proinflammatory cytokines known to be present in the islet environment at the onset of T1DM. The protective mechanism activated by nicotine and choline involves attenuation of mitochondrial outer membrane permeabilization via modulation of endoplasmic reticulum stress, of the activity of B-cell lymphoma 2 family proteins and cytoplasmic calcium levels. Local inflammation and endoplasmic reticulum stress being key determinants of beta-cell death in T1DM, we conclude that pharmacological activation of nACh-R could represent a valuable therapeutic option in the modulation of beta-cell death in T1DM. PMID- 27471777 TI - Correlations of Optical Absorption, Charge Trapping, and Surface Roughness of TiO2 Photoanode Layer Loaded with Neat Ag-NPs for Efficient Perovskite Solar Cells. AB - We systematically investigated the effect of silver nanoparticles (Ag-NPs) on the power conversion efficiency (PCE) of perovskite solar cells (PSCs). Neat, spherical Ag-NPs at loading levels of 0.0, 0.5, 1.0, and 2.0 wt % were embedded into the titanium dioxide (TiO2) photoanode layer. The plasmonic effect of the Ag NPs strongly enhanced the incident light absorption over a wide range of the visible wavelength region in addition to the inherent absorbance of the perovskite sensitizer. The low conduction energy level of the Ag-NPs compared to that of TiO2 provides trap sites for free charge carriers. Thus, the correlation between the enhancement of the optical absorption and the number of charge traps provided by the Ag-NPs is critical to determine the device performance, especially current density (Jsc) and PCE. This is confirmed by the quantitative comparison of the incident light absorption and the time-resolved photoluminescence decay according to the loading levels of the Ag-NPs in the TiO2 layer. The absorption enhancement from 380 to 750 nm in the UV-visible spectrum is proportional to the increase in the loading levels of the Ag-NPs. However, the Jsc increases with the device with 0.5 wt % Ag-NPs and gradually decreases with increases in the loading level above 0.5 wt % because of the different contributions to the absorbance and the charge trapping by different Ag-NP loading levels. In addition, the suppression of the surface roughness with dense packing by the Ag-NPs helps to improve the Jsc and the following PCE. Consequently, the PCE of the PSC with 0.5 wt % Ag-NPs is increased to 11.96%. These results are attributed to the balance between increased absorbance by the localized surface plasmon resonance and the decreased charge trapping as well as the decreased surface roughness of the TiO2 layer with the Ag-NPs. PMID- 27471779 TI - Are regions of the lumbar multifidus differentially activated during walking at varied speed and inclination? AB - PURPOSE: Lumbar multifidus is a complex muscle with multi-fascicular morphology shown to be differentially controlled in healthy individuals during sagittal plane motion. The normal behaviour of multifidus muscle regions during walking has only received modest attention in the literature. This study aimed to determine activation patterns for deep and superficial multifidus in young adults during walking at different speeds and inclination. METHODS: This observational cohort study evaluated ten healthy volunteers in their twenties (three women, seven men) as they walked on a treadmill in eight conditions; at 2km/h and 4km/h, each at 0, 1, 5, and 10% inclination. Intramuscular EMG was recorded from the deep and superficial multifidus unilaterally at L5. Activity was characterized by: amplitude of the peak of activation, position of peak within the gait cycle (0-100%), and duration relative to the full gait cycle. RESULTS: Across all conditions superficial multifidus showed higher normalised EMG amplitude (p<0.01); superficial multifidus peak amplitude was 232+/-115% higher when walking at 4km/h/10%, versus only 172+/-77% higher for deeper region (p<0.01). The percentage of the gait cycle where peak EMG amplitude was detected did not differ between regions (49+/-13%). Deep multifidus duration of activation was longer when walking at the faster vs slower speed at all inclinations (p<0.01), which was not evident for superficial multifidus (p<0.05). Thus, a significantly longer activation of deep multifidus was observed compared to superficial multifidus when walking at 4km/h (p<0.05). CONCLUSIONS: Differential activation within lumbar multifidus was shown in young adults during walking. The prolonged, more tonic activation of deep relative to superficial regions of multifidus during gait supports a postural function of deeper fibres. PMID- 27471778 TI - High Level of Perforin Expression Is Required for Effective Correction of Hemophagocytic Lymphohistiocytosis. AB - Perforin-1 mutations result in a potentially fatal hemophagocytic lymphohistiocytosis (HLH) with heightened immune activation, hypercytokinemia, pancytopenia, and end-organ damage. At present, hematopoietic stem cell (HSC) transplantation is curative, but limited by donor availability and associated mortality, making gene therapy an attractive alternative approach for HLH. We reported that perforin expression driven by cellular promoters in lentiviral (LV) vectors resulted in significant, albeit partial, correction of the inflammatory features in a murine model of HLH. We hypothesized that the level of perforin expression achieved per cell from ectopic moderate-strength cellular promoters (phosphoglycerate kinase gene/perforin-1 gene) is inadequate and thus engineered an LV vector using a viral promoter (MND; a modified Moloney murine leukemia virus long terminal repeat with myeloproliferative sarcoma virus enhancer) containing microRNA126 target sequences to restrict perforin expression in HSCs. We show here that the MND-LV vector restored perforin expression to normal levels in a perforin-deficient human natural killer cell line and perforin gene corrected Perforin1-/- transplant recipients, whereas cellular promoters drove only partial correction. On lymphocytic choriomeningitis virus challenge, the clinical scores and survival improved only with the MND-LV vector, but inflammatory markers and cytotoxicity were improved with all LV vectors. Our studies suggest that although moderate levels of expression can result in partial amelioration of the HLH phenotype, high levels of perforin expression per cell are required for complete correction of HLH. PMID- 27471780 TI - The effect of repetitive ankle perturbations on muscle reaction time and muscle activity. AB - The use of a tilt platform to simulate a lateral ankle sprain and record muscle reaction time is a well-established procedure. However, a potential caveat is that repetitive ankle perturbation may cause a natural attenuation of the reflex latency and amplitude. This is an important area to investigate as many researchers examine the effect of an intervention on muscle reaction time. Muscle reaction time, peak and average amplitude of the peroneus longus and tibialis anterior in response to a simulated lateral ankle sprain (combined inversion and plantar flexion movement) were calculated in twenty-two physically active participants. The 40 perturbations were divided into 4 even groups of 10 dominant limb perturbations. Within-participants repeated measures analysis of variance (ANOVA) tests were conducted to assess the effect of habituation over time for each variable. There was a significant reduction in the peroneus longus average amplitude between the aggregated first and last 10 consecutive ankle perturbations (F2.15,45.09=3.90, P=0.03, np(2)=0.16). Authors should implement no more than a maximum of 30 consecutive ankle perturbations (inclusive of practice perturbations) in future protocols simulating a lateral ankle sprain in an effort to avoid significant attenuation of muscle activity. PMID- 27471781 TI - Modelling impacts of climate change on arable crop diseases: progress, challenges and applications. AB - Combining climate change, crop growth and crop disease models to predict impacts of climate change on crop diseases can guide planning of climate change adaptation strategies to ensure future food security. This review summarises recent developments in modelling climate change impacts on crop diseases, emphasises some major challenges and highlights recent trends. The use of multi model ensembles in climate change modelling and crop modelling is contributing towards measures of uncertainty in climate change impact projections but other aspects of uncertainty remain largely unexplored. Impact assessments are still concentrated on few crops and few diseases but are beginning to investigate arable crop disease dynamics at the landscape level. PMID- 27471782 TI - Early Intervention to Encourage Physical Activity in Infants and Toddlers: A Randomized Controlled Trial. AB - INTRODUCTION: Few physical activity interventions have been undertaken in infants and toddlers, despite concerns that they are insufficiently active. The Prevention of Overweight in Infancy trial encouraged parents to be physically active with their child from birth, including prone-based play ("tummy time"), while reducing time spent restrained in car seats and "strollers." METHODS: A total of 802 women, recruited in late pregnancy, were randomized to a physical activity intervention, which provided information antenatally, and active group sessions with their infant at 3, 9, and 18 months of age. Questionnaires were completed at multiple time points, and toddlers wore Actical accelerometers for 5 d at 24 months of age. RESULTS: Attendance at intervention sessions was high in infancy but declined by 18 months to 66%. Almost all parents placed their infant prone to play at least once a day (90%-95%, overall median 25 min.d), with no intervention differences observed (P = 0.445 and P = 0.350 at 4 and 6 months, respectively). Few differences were observed in other measures of restraint or parental activity at any time point. At 2 yr, children spent approximately 8 h.d in sedentary time while awake and 3.6 h in light-to-vigorous activity. However, no group differences were apparent in counts per minute (P = 0.759) or time in light-to-vigorous activity (P = 0.960). CONCLUSION: An early life intervention targeting improvements in child and parent physical activity as part of a wider obesity prevention initiative had little effect on physical activity at 2 yr of age. PMID- 27471783 TI - Allometrically Scaled Children's Clinical and Free-Living Ambulatory Behavior. AB - PURPOSE: This study aimed to compare clinical and free-living walking cadence in school-age children and to examine how the allometric scaling of leg length variability affects objective ambulatory activity assessment. METHODS: A total of 375 children (154 boys and 221 girls, 9-11 yr old) completed GAITRite-determined slow, normal, and fast walks and wore accelerometers for 1 wk. Dependent variables from clinical assessment included gait speed, cadence, and step length, whereas steps per day, peak 1-min cadence, and peak 60-min cadence were assessed during free living. Analogous allometrically scaled variables were used to account for leg length differences. Free-living times above clinically determined individualized slow, normal, and fast cadence values were calculated. Differences in dependent variables between sex and sex-specific leg length tertiles were assessed. RESULTS: Clinically assessed cadence (mean +/- SD) was 90.9 +/- 15.2 (slow), 113.8 +/- 12.9 (normal), and 148.9 +/- 20.9 (fast) steps per minute, respectively. During free living, participants accumulated 8651 +/- 2259 steps per day. Peak 1-min cadence was 113.4 +/- 12.4 steps per minute and peak 60-min cadence was 60.1 +/- 11.4 steps per minute. Allometrically scaling gait variables to leg length eliminated the previously significant leg length effect observed in both clinical and free-living gait variables but did not affect the observation that girls exhibited lower levels of free-living ambulatory behavior measured by mean steps per day. On average, all groups spent <15 min.d above clinically determined slow cadence; this was unaffected by leg length. CONCLUSION: Allometrically scaling gait variables to leg length significantly affected the assessment of ambulatory behavior, such that different leg length groups appear to walk in a dynamically similar manner. Leg length effects on free-living ambulatory behavior were also eliminated by implementing estimates of time spent above individualized cadence cut points derived from clinical gait assessment. PMID- 27471784 TI - Is Concurrent Training Efficacious Antihypertensive Therapy? A Meta-analysis. AB - : : Aerobic exercise training and, to a lesser degree, dynamic resistance training, are recommended to lower blood pressure (BP) among adults with hypertension. Yet the combined influence of these exercise modalities, termed concurrent exercise training (CET), on resting BP is unclear. PURPOSE: This study aimed to meta-analyze the literature to determine the efficacy of CET as antihypertensive therapy. METHODS: Electronic databases were searched for trials that included the following: adults (>19 yr), controlled CET interventions, and BP measured pre- and postintervention. Study quality was assessed with a modified Downs and Black Checklist. Analyses incorporated random-effects assumptions. RESULTS: Sixty-eight trials yielded 76 interventions. Subjects (N = 4110) were middle- to older-age (55.8 +/- 14.4 yr), were overweight (28.0 +/- 3.6 kg.m), and had prehypertension (systolic BP [SBP]/diastolic BP [DBP] = 134.6 +/- 10.9/80.7 +/- 7.5 mm Hg). CET was performed at moderate intensity (aerobic = 55% maximal oxygen consumption, resistance = 60% one-repetition maximum), 2.9 +/- 0.7 d.wk for 58.3 +/- 20.1 min per session for 19.7 +/- 17.8 wk. Studies were of moderate quality, satisfying 60.7% +/- 9.4% of quality items. Overall, CET moderately reduced SBP (db = -0.32, 95% confidence interval [CI] = -0.44 to -0.20, -3.2 mm Hg) and DBP (db = -0.35, 95% CI = -0.47 to -0.22, -2.5 mm Hg) versus control (P < 0.01). However, greater SBP/DBP reductions were observed among samples with hypertension in trials of higher study quality that also examined BP as the primary outcome (-9.2 mm Hg [95% CI = -12.0 to -8.0]/-7.7 mm Hg [95% CI = -14.0 to -8.0]). CONCLUSIONS: Among samples with hypertension in trials of higher study quality, CET rivals aerobic exercise training as antihypertensive therapy. Because of the moderate quality of this literature, additional randomized controlled CET trials that examine BP as a primary outcome among samples with hypertension are warranted to confirm our promising findings. PMID- 27471786 TI - Effects of Standing and Light-Intensity Walking and Cycling on 24-h Glucose. AB - PURPOSE: This study aimed to compare 24-h and postprandial glucose responses to incremental intervals of standing (STAND), walking (WALK), and cycling (CYCLE) to a sit-only (SIT) condition. METHODS: Nine overweight/obese (body mass index = 29 +/- 3 kg.m) adults (30 +/- 15 yr) participated in this randomized crossover full factorial study, with each condition performed 1 wk apart. STAND, CYCLE, and WALK intervals increased from 10 to 30 min.h (2.5 h total) during an 8-h workday. WALK (1.0 mph) and STAND were matched for upright time, and WALK and CYCLE were matched for energy expenditure (~2 METs). Continuous interstitial glucose monitoring was performed for 24 h to include the 8-h workday (LAB), after-work evening hours (EVE), and sleep (SLEEP). Three 2-h postprandial periods were also analyzed. Linear mixed models were used to test for condition differences. RESULTS: Compared with SIT (5.7 +/- 1.0 mmol.L), mean 24-h glucose during STAND (5.4 +/- 0.9 mmol.L) and WALK (5.3 +/- 0.9 mmol.L) were lower, and CYCLE (5.1 +/- 1.0 mmol.L) was lower than all other conditions (all P < 0.001). During LAB and EVE, mean glucose was lower for STAND, WALK, and CYCLE compared with SIT (P < 0.001). During SLEEP, the mean glucose for CYCLE was lower than all other conditions (P < 0.001). Compared with SIT, cumulative 6-h postprandial mean glucose was 5%-12% lower (P < 0.001) during STAND, WALK, and CYCLE, and 6-h postprandial glucose integrated area under the curve was 24% lower during WALK (P < 0.05) and 44% lower during CYCLE (P < 0.001). CONCLUSIONS: Replacing sitting with regular intervals of standing or light-intensity activity during an 8-h workday reduces 24-h and postprandial glucose. These effects persist during evening hours, with CYCLE having the largest and most sustained effect. PMID- 27471785 TI - Four-Year Physical Activity Levels among Intervention Participants with Type 2 Diabetes. AB - : Physical activity (PA) has numerous health benefits, particularly for those with diabetes. However, rates of long-term PA participation are often poor. PURPOSE: This study examined the effect of an intensive lifestyle intervention (ILI) on objectively assessed PA for a 4-yr period among older adults with type 2 diabetes. METHODS: Data from 2400 participants (age = 59.3 +/- 6.9 yr, body mass index = 36.1 +/- 5.9 kg.m) with accelerometry data from the Look AHEAD trial were included in the analyses. Participants randomized to ILI were instructed to reduce caloric intake and progress to >=175 min.wk of moderate-to-vigorous intensity PA (MVPA), whereas those randomized to Diabetes Support and Education (DSE) served as the control group. PA was measured at baseline, year 1, and year 4 using an RT3 accelerometer, and bout-related MVPA (PA >=3 METs, accumulated in bouts of >=10 min in duration) was calculated. RESULTS: Despite no differences at baseline (ILI = 93.4 +/- 152.7 vs DSE = 88.4 +/- 143.6 min.wk), bout-related MVPA was significantly greater in ILI compared with DSE at year 1 (151.0 +/- 213.5 vs 87.5 +/- 145.1 min.wk, P < 0.0001) and year 4 (102.9 +/- 195.6 vs 73.9 +/- 267.5 min.wk, P < 0.001), and more ILI participants achieved >=175 min.wk at year 1 (29.1% vs 16.3%, P < 0.001) and year 4 (18.3% vs 10.0%, P < 0.001). Forty-one percent of ILI participants who achieved >=175 min.wk at year 1 maintained this threshold of PA at year 4. However, the majority of ILI participants never achieved the >=175 min.wk threshold. CONCLUSIONS: When measured objectively and compared with DSE, ILI engaged in significantly more bout-related MVPA for a 4-yr period. However, future intervention strategies should target the large percentage of individuals who fail to reach the MVPA goal as result of a lifestyle intervention. PMID- 27471787 TI - Athletes Do Not Condition Inspired Air More Effectively than Nonathletes during Hyperpnea. AB - : Endurance athletes have a high prevalence of airway diseases, some possibly representing adaptive mechanisms to the need of conditioning large volumes of inspired air during high ventilation in specific environments. The aim of this study is to assess the ability to condition (warm and humidify) inspired air in athletes by measuring the difference between inhaled and exhaled air temperature (DeltaT) during and after eucapnic voluntary hyperpnea (EVH) test. METHODS: Twenty-three endurance athletes from various sports, 12 with airway hyperresponsiveness (AHR) and/or exercise-induced bronchoconstriction (EIB) (A+), 11 without AHR and/or EIB (A-), 12 nonathletes with AHR and/or EIB (C+), and 11 nonathletes without AHR and/or EIB (C-) were recruited. All subjects attended the laboratory on three occasions, twice for baseline characterization, including questionnaires, pulmonary function, methacholine bronchoprovocation, allergy skin prick tests, exhaled nitric oxide measurement, and a standard EVH, and once to perform a modified EVH to assess DeltaT. Inspired and expired air temperatures were measured with a high-precision probe during EVH and at regular intervals until 30 min after the end of the test. RESULTS: The global DeltaT during the EVH was +5.8 degrees C +/- 1.5 degrees C and +4.7 degrees C +/- 1.5 degrees C during the 30 min after the EVH. No difference was found between groups for either the DeltaT or the slope of DeltaT, during and after the EVH. CONCLUSION: This study shows no evidence of improved capacity to condition inspired air in endurance athletes, which could have suggested an increased bronchial blood flow or another adaptive mechanism. The absence of an adaptive mechanism could therefore contribute to airway damage observed in athletes in allowing colder but mainly dryer air to penetrate deeper in the lung. PMID- 27471788 TI - Slower Walking Speed in Older Men Improves Triceps Surae Force Generation Ability. AB - PURPOSE: Older adults walk slower than young adults, but it is not known why. Previous research suggests that ankle plantarflexors may have a crucial role in the reduction of walking speed. The purpose of this study was to investigate age related differences in triceps surae muscle-tendon function during walking to further investigate the role of plantarflexors in the age-related reduction of walking speed. METHODS: Medial gastrocnemius and soleus muscle fascicle lengths were measured using ultrasound imaging during walking from 13 young (25 +/- 4 yr) men at preferred walking speed and from 13 older (73 +/- 5 yr) men at preferred speed and at the young men's preferred speed. Muscle-tendon unit lengths were calculated from joint kinematics, and tendinous tissue lengths were calculated by subtracting muscle lengths from muscle-tendon unit lengths. In addition, ground reaction forces and electromyographic activity of medial gastrocnemius and soleus were measured. RESULTS: In both medial gastrocnemius and soleus, it was observed that at preferred walking speed, older men used a narrower muscle fascicle operating range and lower shortening velocity at the estimated time of triceps surae peak force generation compared with young men. Fascicles also accounted for a lower proportion of muscle-tendon unit length changes during the stance phase in older compared with young men. Significant differences in triceps surae muscle function were not observed between age groups when compared at matched walking speed. CONCLUSIONS: In older men, walking at preferred speed allows triceps surae muscles to generate force with more favorable shortening velocity and to enhance use of tendinous tissue elasticity compared with walking at young men's preferred speed. The results suggest that older men may prefer slower walking speeds to compensate for decreased plantarflexor strength. PMID- 27471789 TI - The Experience of Forming a Therapeutic Relationship from the Client's Perspective: A Metasynthesis ?. AB - OBJECTIVE: This review aimed to synthesize qualitative research exploring clients' perspectives of forming a therapeutic relationship with their therapist or counsellor. METHOD: Noblit and Hare's meta-ethnographic approach was used to guide the synthesis of 13 studies meeting inclusion criteria. The quality of each study was rated using the Critical Appraisal Skills Programme quality rating checklist. RESULTS: Findings demonstrated that clients create a hierarchy of desired therapist characteristics to assess how well the therapy can meet their needs (theme 1: assessing client-therapist match). The formation of the therapeutic relationship is facilitated by an openness from both the therapist and client (theme 2: facilitating openness) and helps to develop a connection through which the client can be fundamentally understood (theme 3: connecting on a deeper level). Displays of disrespectful or disempowering behaviour generate barriers in the formation of a therapeutic relationship (theme 4: empowerment through respect). CONCLUSIONS: The meta-ethnographic approach extended the findings from each individual study to highlight some significant discoveries, including that clients across different settings created a hierarchy of therapist characteristics which were of varying importance to them depending on their perceived needs. Additionally, clients reported that they preferred their therapists to disclose information in order to facilitate the therapeutic relationship. PMID- 27471791 TI - Adoption of new technology. PMID- 27471790 TI - Review of perforator flaps in head and neck cancer surgery. AB - PURPOSE OF REVIEW: Perforator flaps are increasingly being used to reconstruct head and neck defects. They offer several advantages over nonperforator-based flaps with lower donor site morbidity and a versatile range of reconstructive options. The anterolateral thigh flap is well established in the head and neck and is a good example of a reliable perforator free flap. With the increasing use of both free and regional perforator-based flaps, it is timely to review their anatomy, clinical applications, and role in head and neck reconstruction. We also discuss increasingly popular perforator flaps such as the submental flap for the head and neck. RECENT FINDINGS: The anterolateral thigh flap is now commonly used to reconstruct a wide variety of head and neck defects. The submental flap fills a niche role for reconstruction of intraoral defects. SUMMARY: Perforator flaps are now mainstream reconstructive options in the head and neck surgeon's armamentarium. PMID- 27471792 TI - Bias because of selective inclusion and reporting of outcomes and analyses in systematic reviews of randomized trials of healthcare interventions. PMID- 27471793 TI - Molecular Isomer Identification of Titan's Tholins Organic Aerosols by Photoelectron/Photoion Coincidence Spectroscopy Coupled to VUV Synchrotron Radiation. AB - The chemical composition of Titan organic haze is poorly known. To address this issue, laboratory analogues named tholins are synthesized and analyzed by methods often requiring an extraction process in a carrier solvent. These methods exclude the analysis of the insoluble tholins' fraction and assume a hypothetical chemical equivalence between soluble and insoluble fractions. In this work, we present a powerful complementary analysis method recently developed on the DESIRS VUV synchrotron beamline at SOLEIL. It involves soft pyrolysis of tholins at ~230 degrees C and electron/ion coincidence analysis of the emitted volatile compounds photoionized by tunable synchrotron radiation. By comparison with reference photoelectron spectra (PES), the spectral information collected on the detected molecules yields their isomeric structure. The method is more readily applied to light species (m/z <= 69), while for heavier ones, the number of possibilities and the lack of PES reference spectra in the literature limit its analysis. A notable pattern in the analyzed tholins is the presence of species containing adjacent doubly bonded N atoms, which might be a signature of heterogeneous incorporation of N2 in tholins. PMID- 27471794 TI - Monitoring of bacterial contamination on chicken meat surface using a novel narrowband spectral index derived from hyperspectral imagery data. AB - This study presents a novel narrowband spectral index for monitoring bacterial contamination on chicken meat surface. Fresh chicken meats were prepared and stored aerobically in a refrigerator at 4 degrees C for 11d. Hyperspectral images and the total viable count (TVC) of bacteria for meat samples were obtained every 24h. A new two band freshness index (TBFI) method was proposed for developing the bacteria prediction models. Results indicated that the model with the TBFI based on the wavelengths 650 and 700nm achieved the optimal estimation of TVC (R(2)=0.6833). The TBFI value for each image pixel was calculated using the above two wavelengths, and then used to predict the TVC for the corresponding pixel on the image. Finally, the predicted TVC were visualized to illustrate the temporal variation and spatial distribution of viable bacteria on meat surface over storage. The results demonstrate the promising potential of the developed TBFI for the detection of viable bacteria contamination on chicken meat surface. PMID- 27471795 TI - Physicochemical, microbiological and sensory evaluation of beef patties incorporated with destoned olive cake powder. AB - The biological efficacy of different concentrations (2%, 4%, and 6%) of destoned olive cake (DOC) as improvers of the quality, storability, and safety of beef patties was investigated. Increasing the percentage of DOC in the patties improved (P<=0.05) the protein and fat contents, cooking yield, moisture and fat retention, total phenolic, and DPPH radical scavenging activity, while the dimensional shrinkage and TBARS showed a progressive reduction. The pH of the patties decreased gradually with the storage time. DOC-incorporated patties showed significantly (P<=0.05) lower total plate count than untreated. Surface color values of raw beef patties were decreased gradually with the storage time. Throughout the storage period, all the sensory traits of non-formulated patties were significantly (P<=0.05) reduced, whereas the formulated patties revealed considerable stability of all characters. Overall, this study identified antioxidant and antimicrobial potentiality of DOC, which could pave the way for its use as an extender of the shelf life of the patties. PMID- 27471796 TI - Drought stress differentially regulates the expression of small open reading frames (sORFs) in Arabidopsis roots and shoots. AB - Characterizing the molecular mechanisms governing the response of plant roots and shoots to drought stress could aid the development of strategies aiming to ameliorate drought stress. Small open reading frames (sORFs), putatively encoding small peptides, may play a significant role in the response to different abiotic stresses. Microarray analyses revealed that after 5, 7 and 9 d of a drought treatment, 2, 77, and 104 sORFs were up-regulated in roots, respectively; while the number of upregulated sORFs in shoots was 12, 45, and 158, respectively. RT qPCR analysis confirmed the up-regulated expression of ATRIKEN29196 and ATRIKEN32280 specifically in roots. The identified upregulated sORFs, particularly those in roots, may contribute to drought stress tolerance. PMID- 27471797 TI - Structure and target interaction of a G-quadruplex RNA-aptamer. AB - G-quadruplexes have recently moved into focus of research in nucleic acids, thereby evolving in scientific significance from exceptional secondary structure motifs to complex modulators of gene regulation. Aptamers (nucleic acid based ligands with recognition properties for a specific target) that form Gquadruplexes may have particular potential for therapeutic applications as they combine the characteristics of specific targeting and Gquadruplex mediated stability and regulation. We have investigated the structure and target interaction properties of one such aptamer: AIR-3 and its truncated form AIR-3A. These RNA aptamers are specific for human interleukin-6 receptor (hIL-6R), a key player in inflammatory diseases and cancer, and have recently been exploited for in vitro drug delivery studies. With the aim to resolve the RNA structure, global shape, RNA:protein interaction site and binding stoichiometry, we now investigated AIR-3 and AIR-3A by different methods including RNA structure probing, Small Angle X-ray scattering and microscale thermophoresis. Our findings suggest a broader spectrum of folding species than assumed so far and remarkable tolerance toward different modifications. Mass spectrometry based binding site analysis, supported by molecular modeling and docking studies propose a general Gquadruplex affinity for the target molecule hIL-6R. PMID- 27471798 TI - Choosing wisely in daily practice: a mixed methods study on determinants of antinuclear antibody testing by rheumatologists. AB - OBJECTIVES: To explore the relationship between antinuclear antibody (ANA) overuse and rheumatologist-related factors before and after an intervention aimed at reducing ANA overuse. METHOD: In this mixed methods study we performed surveys among rheumatologists (n = 20) before and after the ANA intervention (education and feedback). We identified clinician-related determinants of ANA overuse (demographic characteristics, cognitive bias, numeracy, personality, thinking styles, and knowledge) by multivariate analysis. Two focus group meetings with rheumatologists were held 6 months after the intervention to explore self reported determinants. RESULTS: Questionnaires were completed by all rheumatologists and eight participated in the focus groups. Rheumatologists with more work experience and a less extravert personality ordered more ANA tests before the intervention [beta = 0.01, 95% confidence interval (CI) 0.003 to 0.02, p = 0.01 and beta = -0.11, 95% CI -0.21 to -0.01, p = 0.04, respectively; R2 = 47%]. After the intervention, female rheumatologists changed less than their male colleagues with regard to the number of ANA tests ordered (beta = 0.15, 95% CI 0.03-0.26, p = 0.02; R2 = 25%). During the focus groups, seven themes were identified that influenced improvement in ANA overuse: determinants related to the intervention and the study, individual health professionals, patients, professional interactions, incentives and resources, capacity for organizational change, and social, political, and legal factors. CONCLUSIONS: We identified several determinants that together explained a sizable part of the variance observed in the ANA outcomes at baseline and in the change in ANA outcomes afterwards. Furthermore, the focus groups yielded additional factors suggesting a complex interplay of determinants influencing rheumatologists' ANA ordering behaviour. PMID- 27471799 TI - Synthesis and structural diversity of trivalent rare-earth metal diisopropylamide complexes. AB - A series of rare-earth metal diisopropylamide complexes has been obtained via salt metathesis employing LnCl3(THF)x and lithium (LDA) or sodium diisopropylamide (NDA) in n-hexane. Reactions with AM : Ln ratios >=3 gave ate complexes (AM)Ln(NiPr2)4(THF)n (n = 1, 2; Ln = Sc, Y, La, Lu; AM = Li, Na) in good yields. For smaller rare-earth metal centres such as scandium and lutetium, a Li : Ln ratio = 2.5 accomplished ate-free tris(amido) complexes Ln(NiPr2)3(THF). The chloro-bridged dimeric derivatives [Ln(NiPr2)2(MU-Cl)(THF)]2 (Ln = Sc, Y, La, Lu) could be obtained in high yields for Li : Ln = 1.6-2. The product resulting from the Li : La = 1 : 1.6 reaction revealed a crystal structure containing two different molecules in the crystal lattice, [La(NiPr2)2(THF)(MU-Cl)]2.La(NiPr2)3(THF)2. Recrystallization of the chloro bridged dimers led to the formation of the monomeric species Ln(NiPr2)2Cl(THF)2 (Ln = Sc, Lu) and La(NiPr2)3(THF)2. The reaction of YCl3 and LDA with Li : Y = 2 in the absence of THF gave a bimetallic ate complex LiY(NiPr2)4 with a chain-like structure. For scandium, the equimolar reactions with LDA or NDA yielded crystals of tetrametallic mono(amido) species, {[Sc(NiPr2)Cl2(THF)]2(LiCl)}2 and [Sc(NiPr2)Cl2(THF)]4, respectively. Depending on the Ln(iii) size, AM, and presence of a donor solvent, ate complexes (AM)Ln(NiPr2)4(THF)n show distinct dynamic behaviour as revealed by variable temperature NMR spectroscopy. The presence of weak LnCH(iPr) beta-agostic interactions, as indicated by Ln-N-C angles <105 degrees , is corroborated by DFT calculations and NBO analysis. PMID- 27471801 TI - Do We Really Know the Prevalence of MIH? AB - AIM: To analyze the existing variability on molar incisor hypomineralization prevalence in the literature; to distinguish the various molar incisor hypomineralization prevalence rates in different countries, areas, and regions of the world; and to know the valid diagnostic criteria used for the correct identification of molar incisor hypomineralization prevalence. STUDY DESIGN: A literature review from Medline and Cochrane Library online databases was performed using five terms individually or in combination. Articles not reporting diagnostic criteria employed and articles not written English were excluded. The results were analyzed by country, region, year of study, sample size, range of age, and prevalence rate. RESULTS: A total of 37 articles in English were selected from 1987 to 2014 and from those only 14 employed the EAPD's 2003 diagnostic criteria. The reported age range varied from 5.5 to 17 years; the most frequently range used was 7 to 9 years. A wide prevalence range from 2.8% to 44% was found and 82.61% of the articles reported calibrated examiners. CONCLUSIONS: Comparison among the results of the studies is difficult due to the use of different indexes and diagnostic criteria, the analysis variability, selection methods, and different age groups. In reality, we are probably far from knowing the real MIH prevalence. PMID- 27471800 TI - Near-Infrared Intraoperative Chemiluminescence Imaging. AB - Intraoperative imaging technologies recently entered the operating room, and their implementation is revolutionizing how physicians plan, monitor, and perform surgical interventions. In this work, we present a novel surgical imaging reporter system: intraoperative chemiluminescence imaging (ICI). To this end, we have leveraged the ability of a chemiluminescent metal complex to generate near infrared light upon exposure to an aqueous solution of Ce(4+) in the presence of reducing tissue or blood components. An optical camera spatially resolves the resulting photon flux. We describe the construction and application of a prototype imaging setup, which achieves a detection limit as low as 6.9 pmol cm( 2) of the transition-metal-based ICI agent. As a proof of concept, we use ICI for the in vivo detection of our transition metal tracer following both systemic and subdermal injections. The very high signal-to-noise ratios make ICI an interesting candidate for the development of new intraoperative imaging technologies. PMID- 27471802 TI - CAD/CAM Endocrown Fabrication from a Polymer-Infiltrated Ceramic Network Block for Primary Molar: A Case Report. AB - OBJECTIVE: The aim of this case report is to describe the treatment of a primary molar with a deep carious lesion by pulpotomy and placement of a ceramic endocrown. CLINICAL CASE: A 7-year-old male patient with profound caries in tooth number 85 was referred to our clinic and underwent a pulpotomy. As the final treatment in tooth restoration, placement of an endocrown was planned, because little more than half of the tooth structure remained. After an additional request from the patient's parents for an advanced and prompt restoration, a computer-aided design/computer-aided manufacturing (CAD/CAM) polymer-infiltrated ceramic network (PICN) block was chosen. A three-dimensional model of the arch was obtained after scanning the dental cast, and the endocrown was designed digitally according to the model. When the design was complete, the endocrown was fabricated with a milling machine. Finally, the endocrown was cemented with self adhesive resin cement. RESULTS: Over the 9-month follow-up period, no pulpal or periradicular pathology was observed on radiographs. Regarding the crown, the marginal fit was excellent, the anatomical form was protected, and no discoloration occurred. CONCLUSION: During follow-up, the CAD/CAM PICN block endocrown proved to be a good material for the short- to long-term treatment of a primary tooth. However, more clinical cases and follow-up are required to investigate the long-term effects of antagonistic tooth wear. PMID- 27471803 TI - Efficacy and Stability of Two in-Office Bleaching Agents in Adolescents: 12 Months Follow-Up. AB - OBJECTIVE: Although there are several clinical studies on in office vital bleaching in adults, there are no Randomized Clinical Trials for the efficacy of this application in adolescents. The aim the study was to evaluate the efficiency of two bleaching systems on adolescents for twelve-months follow-up. STUDY DESIGN: Twenty-eight volunteers, aged between 13-18, randomly divided into two groups. Two commercial in-office bleaching systems were used: G1 (n=14): Zoom2 25 % HP with UV light and G2 (n=14): Beaming White 36% HP with LED light in a single 3 x 15 minute procedure. The color assessment was made with a spectrophometer; before and after bleaching; 48 hours; 1, 6 and 12 months later. Color enhancement and maintenance of two techniques over 12 months were compared by two ways ANOVA and Student's t test. Sensitivity was evaluated on a scale with Wilcoxon test. RESULTS: Both groups demonstrated similar and significant tooth color enhancement and did not reveal any statistically significant differences between them. However, a relapse of the tooth shade was observed with the low concentration agent/ultraviolet light system. No sensitivity was observed in any patients. CONCLUSION: Two in-office bleaching systems can be used successfully on young permanent teeth. For long-term successful results, high concentration/LED light may be more effective. PMID- 27471804 TI - Control of White Spot Lesions with Use of Fluoride Varnish or Chlorhexidine Gel During Orthodontic Treatment A Randomized Clinical Trial. AB - OBJECTIVE: To compare the effectiveness of fluoride varnish and 2% chlorhexidine gel for controlling active white spot lesions (WSLs) adjacent to orthodontic brackets. STUDY DESIGN: Thirty-five orthodontic patients (17.2 +/- 2.3 years old) presenting 60 WSLs adjacent to orthodontic brackets were enrolled in this randomized, blind, 3-armed and controlled clinical trial. The patients were randomly allocated to 1 of 3 arms: (1) two applications of 5% NaF varnish- F, with one-week interval, (2) two applications of 2% chlorhexidine gel-CHX, with one-week interval and (3) usual home care-control (CO). The WSLs were scored by using a DIAGNOdent pen. An independent examiner scored the surfaces using Nyvad criteria for caries assessment. RESULTS: A total of thirty patients presenting 51 lesions completed the study. All treatments reduced the fluorescence values during the experimental period; however, F induced faster remineralization than CHX. After 3 months, 70.58 % were inactive considering all groups. DIAGNOdent pen and Nyvad presented a significant correlation. CONCLUSION: After 3 months of treatment, F, CHX and CO were capable of controlling the WSLs adjacent to the orthodontic brackets. However, the treatment with F was capable of controlling the progression of the WSLs in a shorter period of time. PMID- 27471805 TI - Association between S. mutans and S. sanguinis in Severe Early childhood Caries and Caries-Free Children A Quantitative Real-Time PCR Analysis. AB - OBJECTIVES: To identify S. mutans and S. sanguinis in initial and overnight plaque between 2 groups and to analyze the association between them and caries related factors. STUDY DESIGN: Collected supra gingival plaque from 140 Thai children aged 2-6 years old (S-ECC = 68, caries-free=72). Recorded plaque and gingival indices, dmft score, salivary mutans streptococci level, pH and buffer capacity. Firstly, the overnight plaque was collected, then, 4 hrs. after a thorough prophylaxis, the initial plaque was collected. Accessed parent's attitude and behavior in children's oral hygiene care and diet practice using a questionnaire. A quantitative real-time PCR was performed. RESULTS: For initial plaque, S. sanguinis was higher in caries-free. S. mutans (0.011) and S. mutans/S. sanguinis ratio (0.005) were higher in S-ECC. S. sanguinis amount was inverse correlated with dmft (0.00), gingival index (0.044), and plaque index (0.011). For overnight plaque, S. mutans (0.00) and S. mutans/S. sanguinis ratio (0.005) were also higher in S-ECC. S. mutans, S. mutans/S. sanguinis ratio were positive correlated to dmft (0.00). Parent education levels (0.004) and bottle feeding (0.011) between 2 groups were different. CONCLUSION: S. sanguinis, S. mutans and their ratio in initial and overnight plaque, low family income and bottle feeding are strongly associated with S-ECC. PMID- 27471807 TI - Effect of Restoring Carious Teeth on Occlusal Bite Force in Children. AB - BACKGROUND: Bite force is one of the components of masticatory function. Poor dental health impacts on quality of life as a whole due to a number of different elements, dental caries being one of them. Functional impairment is a negative sequel of caries. AIM: to assess the impact of comprehensive dental treatment on occlusal bite forces in children. STUDY DESIGN: The sample comprised of forty children of both genders, aged 6-9 years, with dental caries in primary molars. Occlusal bite force was recorded using a hydraulic occlusal force gauge, in the region of primary molars before and following the restorations in primary molars. The obtained data was subjected to statistical analysis. RESULTS: Children with caries in all quadrants showed a significant increase in mean maximum bite force following restoration of their decayed teeth. In children with unilateral caries, either on right or left sides, a similar increase in occlusal bite force was seen in relation to the teeth that were restored. The contralateral sound teeth in these groups also showed an improvement in bite force. CONCLUSION: The mean occlusal bite force was seen to increase significantly following dental restoration of primary teeth. PMID- 27471806 TI - Fluoride Content of Bottled Waters in Hong Kong and Qatar. AB - OBJECTIVES: To determine the F concentration of bottled waters that was available in Hong Kong and Qatar. STUDY DESIGN: The F concentrations of bottled waters collected from Hong Kong (n=81) and Qatar (n=32) were analysed. The F ion selective electrode method was used to measure the F concentration in the samples. Three measurements were obtained for every sample to ensure reproducibility and appropriate statistical analyses were employed. RESULTS: Qatar group: F concentrations ranged from 0.06 ppm to 3.0 ppm with a mean value of 0.8 ppm. The F concentrations displayed on the labels of the samples (60%) were significantly lower than the measured F concentration (p < 0.0001). Hong Kong group: F concentrations ranged from 0.04 ppm to 2.52 ppm with a mean value of 0.44 ppm. The F concentrations displayed on the samples (16%) were significantly lower than the measured F concentration (p< 0.0001). CONCLUSION: Wide variations exist in the F concentration among the different brands of bottled water available in Hong Kong and Qatar. The F concentrations displayed on the labels were not consistent with the measured F concentrations. PMID- 27471808 TI - Evaluation of Buccal Infiltration with Articaine and Inferior Alveolar Nerve Block with Lignocaine for Pulp Therapy in Mandibular Primary Molars. AB - OBJECTIVE: Failure of inferior alveolar nerve block in achieving profound anesthesia of the pulp due to various reasons has led to the introduction of more potent local anesthetic agents like articaine. This study was conducted to compare the efficacy of buccal infiltration with articaine in achieving pulpal anesthesia of primary molars as compared to inferior alveolar nerve block with lignocaine. STUDY DESIGN: 30 patients (4-8 years) with indication of pulp therapy in at least two mandibular primary molars were selected. Patients were randomly assigned to receive nerve block with lignocaine or infiltration with articaine on first appointment and the other solution on second appointment. All the pulpotomies and pulpectomies were performed by a pediatric dentist. Two researchers standing at a distance of 1.5 m recorded the Pain Scores and Sound, Eye, Motor (SEM) scores. After the completion of procedure, the patient was asked to record the Facial Image score and Heft-Parker Visual Analogue Score (HP-VAS). RESULTS: Pain Score recorded at the time of injection showed significantly more movements with block as compared to infiltration (p<0.001). SEM scores at time of pulp extirpation were also higher for block than infiltration (p<0.001). CONCLUSION: Articaine infiltration has the potential to replace inferior alveolar nerve block for primary mandibular molars. PMID- 27471809 TI - Dental Anxiety of Parents in an Israeli Kibbutz Population and their Prediction of their Children's Behavior in the Dental Office. AB - BACKGROUND: Previous studies have suggested that a child's dental anxiety is mainly influenced by the maternal dental anxiety. As modern society evolves the conventional structure of the family changes and both parents take equal part in the child's upbringing. AIM: The aims of the present study were: 1. To evaluate and compare the levels of dental anxiety among kibbutz-bred and city-bred parents, whose children were dentally treated.; 2. To examine the effect of selected sociodemographic variables on parental attitudes toward the dental situation on their dental anxiety; 3. To assess the parents' ability to evaluate their children's future behavior at the dental office. STUDY DESIGN: seventy-four parents, 44 from a kibbutz and 31 that live in a city comprised the study population. Dental anxiety was assessed by using Corah's Dental Anxiety Scale and Kleinknecht's Dental Fear Survey. The future behavior of the parent's child in the dental office was evaluated by Parental assessment of child's behavior. RESULTS: No significant difference was found in the level of dental anxiety between kibbutz-member parents and city parents. Gender had no significant influence on the levels of dental anxiety among parents. CONCLUSIONS: The old axiom that dental anxiety is more prevalent among women is questioned. Dental anxiety of children may be equally influenced by both parents. PMID- 27471810 TI - Eugenol Toxicity in Human Dental Pulp Fibroblasts of Primary Teeth. AB - OBJECTIVE: The aim of the study was to determine the eugenol concentrations at which toxicity occurs in human dental pulp fibroblasts of primary teeth. STUDY DESIGN: Samples of primary dental pulp tissue were taken. Tissue samples were seeded by means of explant technique and used in the 4(th)-5th pass. Single Cell Gel Electrophoresis (Comet), phenazine MeThoSulfate (MTS), LIVE/DEAD Cell Viability/Toxicity and trypan blue assays for evaluation of the cytotoxicity of increasing concentrations of eugenol (0.06 to 810 MUM) were performed. RESULTS: The results of toxicity tests showed toxic effects on dental pulp fibroblasts, even at very low concentrations of eugenol (0.06 MUM). Very low concentrations of eugenol produce high toxicity in human dental pulp fibroblasts. CONCLUSIONS: All of the concentrations of eugenol that we evaluated produced high toxicity in human dental pulp fibroblasts of primary teeth. PMID- 27471811 TI - An Alternative Method to Treat Ankyloglossia. AB - Ankyloglossia entails short lingual frenum, impairing satisfactory tongue movement and leading to problems related to deglutition, feeding and diction. This clinical report uses laser technology, rather than traditional surgical procedure with scalpel, to perform a lingual frenulotomy on a 9-year old child diagnosed with ankyloglossia, aiming to investigate more conservative and less traumatic dental procedures. Due to the many advantages of the laser device, such as bloodless surgical field, absence of sutures, minimal swelling and post surgical pain, the high intensity diode laser is a viable alternative technique in soft tissue surgeries. PMID- 27471812 TI - Management of Multiple Mandibular Fractures in a Child with Osteogenesis Imperfecta Using Arch Bar Retained Thermoformed Splints: A Novel Technique. AB - Osteogenesis Imperfecta (OI) is a heterogeneous group of autosomal dominant and recessive inherited disorders of type I collagen metabolism. Clinical features of OI include multiple bone fractures, muscle weakness, joint laxity, skeletal deformities, blue sclerae, hearing loss, and dentinogenesis imperfecta. This report presents a challenging case of multiple mandibular fractures in a five years old child with OI, which was successfully treated with a new, minimally invasive technique of closed reduction with arch bar retained thermoformed splint. PMID- 27471813 TI - Anterior Open Bite In 27 Months Old Children after Use of a Novel Pacifier - A Cohort Study. AB - OBJECTIVES: The aim of the present cohort study was to evaluate the influence of a novel pacifier on the first formation of malocclusion, the anterior open bite in children. STUDY DESIGN: 129 newborn children whose parents had decided to use pacifiers were randomly attributed to two experimental groups (D=Dentistar, n=56, Novatex, Pattensen, Germany; N=NUK, n=73, Mapa, Zeven, Germany). Children (n=42) who did not use a pacifier were not randomized and served as reference (C). Primary outcome was the presence of anterior open bite. It was hypothesized that D would result in lower incidence when compared to N. At the age of 27 months the children were examined with respect to anterior open bite. Fisher's exact test served to detect significant differences between groups D and N (SPSS 22.0). RESULTS: 121 children with a mean age of 26.7 months were included in the final analysis (D: n=45; N: n=42; C: n=34). In group D three children (6.7%) showed an anterior open bite. The respective values were 21 (50.0%) for N and 0 for C. The results for group D compared to N were significantly different (chi(2)-test, p<0.001). CONCLUSION: In comparison to a commonly used pacifier the novel one causes significantly less anterior open bites. PMID- 27471814 TI - Initial Stresses induced in Permanent Maxillary First Molar in Mixed Dentition under Normal Masticatory Forces: A Finite Element Study. AB - OBJECTIVE: The cross-arch space maintainers are used to prevent mesio-distal movement of teeth under physiologic forces, contrary to adult orthodontics where these are used as anchorage against orthodontic forces. Stresses in periodontal ligaments (PDL) are supposed to be different in pediatric dentistry and need to be studied. This study aimed to create mathematical model and calculated the initial stresses generated in the PDL and the behavior of movement in developing permanent maxillary first molar under masticatory forces using 3D finite element analyses (FEA). STUDY DESIGN: Data acquisition, image processing, geometric modeling followed by FE analyses was done under vertical load of 70N. The generated stress and tooth displacement were observed with or without primary second molar, mesial to permanent maxillary first molar. RESULTS: Masticatory forces resulted in insignificant initial PDL stresses and mesial displacement of permanent maxillary first molar in the intact arch. In the case of missing primary second molar, maximum stresses were on the palatal root and the tooth showed greater mesial displacement with mesio-palatal rotation. CONCLUSIONS: Any space maintainer preventing mesio-palatal rotation of permanent maxillary first molar, under physiologic masticatory loadings, may be inserted in case of multiple tooth loss. PMID- 27471815 TI - Efficacy and safety of tabalumab plus standard of care in Japanese patients with active systemic lupus erythematosus: Subgroup analyses of the ILLUMINATE-1 study. AB - OBJECTIVE: To assess the efficacy and safety of tabalumab, an anti-B cell activating factor (BAFF) antibody, in combination with standard of care (SoC) therapy in Japanese patients with active systemic lupus erythematosus (SLE). METHODS: A subgroup analysis was conducted in Japanese patients (n = 45) enrolled in ILLUMINATE-1, a phase III global trial in SLE patients (N = 1164). Patients received SoC plus tabalumab or placebo, starting with a loading dose (240 mg) at week 0, followed by 120 mg every 4 weeks (120 Q4W, n = 15), 120 mg every 2 weeks (120 Q2W, n = 15), or placebo Q2W (n = 15). The primary endpoint was proportion achieving SLE Responder Index-5 (SRI-5) improvement at week 52. RESULTS: A numerically greater SRI-5 response rate was achieved with 120 Q2W (46.7%; p = 0.059 vs. placebo) compared with 120 Q4W (20.0%) and placebo Q2W (13.3%). The proportion of patients with severe SLE flare was lower for 120 Q2W (0%) and 120 Q4W (6.7%) than for placebo (26.7%). The rates of serious adverse events (AEs) and treatment-emergent AEs were similar across treatments. CONCLUSION: In Japanese SLE patients, tabalumab 120 Q2W improved SRI-5 response rate and reduced the frequency of severe flares compared with placebo. Safety profiles were similar with tabalumab and placebo. PMID- 27471816 TI - "Consent is Good, Joyous, Sexy": A banner campaign to market consent to college students. AB - OBJECTIVE: This study assessed the recall of, reaction to, and understanding of a brief campus banner campaign promoting consent in sexual relationships, and determined whether campaign exposure was associated with subsequent engagement in activities related to sexual assault education, awareness, and prevention. PARTICIPANTS: A stratified random sample of 1,200 undergraduates was recruited during fall of 2010; 628 (52.3%) participated. METHODS: To account for history and maturation, an experimental research design was employed with an online survey. RESULTS: Direct and indirect campaign exposure was associated with increased action. Students expressed primarily positive reactions to and appeared to understand the consent message. The campaign appealed to and was associated with increased activity among a wide range of students with one exception: a negative effect was observed for business students. CONCLUSIONS: Colorful banners with pithy, upbeat messages hold promise for engaging undergraduates in conversations and proactive activities related to sexual assault prevention. PMID- 27471817 TI - Cheating and sports: history, diagnosis and treatment. AB - This paper focuses on "cheating" in modern day athletics from youth through professional sports. We briefly summarize a history of cheating in the sports world. We examine the current role cheating plays in sports as well as its causes including, psychodynamic issues, the development of personality disorders and how personality traits become pathological resulting in deception, dishonesty, and underhandedness. We describe management and treatment including psychotherapeutic intervention as well as medication. Finally we discuss a systems approach involving outreach to coaches, families, and related sports organizations (like FIFA, WADA, etc) or the professional leagues which have institutional control and partial influence on the athlete. PMID- 27471818 TI - Is it confirmed the presence of neurological soft signs in children with Neurofibromatosis type 1? AB - BACKGROUND: Neurofibromatosis type 1 is a common neurogenetic disorder affecting nervous system, caused by germiline mutations of the NF1 gene. Although the clinical diagnosis of NF1 is defined by presence of cafe-au-laits spots, freckling and benign tumours (neurofibromatosis), neurocognitive impairment and neuropsychiatric disorders are reported in comorbidity. Children with NF1 show higher incidence of executive deficits, such attention, response inhibition, executive planning and problem solving, working memory, and learning impairment. In our study we examine the presence of neurological soft signs and planning function in subjects with NF1. The NSS are minor motor and sensory abnormalities without focal brain damage. METHODS: Eleven drug naive children between 7-15 years with clinical and molecular diagnosis of NF are matched to 11 healthy controls to ass the presence of neurological soft signs and planning executive functions. NSS were assessed using Physical and Neurological Examination for Subtle Signs and the Tower of London task is performance test to assess the capacity of planning, organization and execution of a work. RESULTS: Our results revealed highest rate of NSS and planning deficit in children with NF1 compared to healthy controls. CONCLUSIONS: The motor abnormalities and planning deficit are possible markers to confirm that NF1 could be considering a neurodevelopmental disorder. PMID- 27471819 TI - Association between meal frequency with anthropometric measures and blood pressure in Iranian children and adolescents. AB - BACKGROUND: This study aimed to assess the association of meal frequency with anthropometric measures and blood pressure in Iranian children and adolescents. METHODS: In this national survey, 14,880 students with 6-18 years of age were selected by stratified multistage sampling method from urban and rural regions of 30 provinces of Iran. Meal frequency was assessed by a questionnaire prepared based on global school-based student health survey .Physical measurements included height, weight, waist circumference, systolic blood pressure (SBP), and diastolic blood pressure (DBP). RESULTS: The participation rate was 90.6% including 49.24% girls and 75.5% urban residents. Skipping breakfast and dinner were more frequent in girls than in boys (71.6% vs. 64.1%, 91.2% vs. 86.9%, respectively, P<0.05). Overweight, obesity, and abdominal obesity were more prevalent in those who had 2meals, 1 meal or very low intake (P-value < 0.001) than those had 3 meals. There were no significant differences in SBP, DBP, and blood pressure across to different meal frequency groups (P-value >0.05). Students who had very low intake and 1 meal per week had more risk of abdominal obesity compared with those who had 3 meals (OR 1.7, CI 95%: 1.3-2.3, and OR 1.6, CI 95%: 1.4-2.0, respectively). CONCLUSIONS: An inverse significant association between higher meal frequency and anthropometric indices was observed. Therefore, encouraging children and adolescents for regular meal intake should be considered as a health priority in the pediatric population. PMID- 27471820 TI - Ventilator graphics. AB - Providing optimal mechanical ventilation to critically-ill children remains a challenge. Patient-ventilator dyssynchrony results frequently with numerous deleterious consequences on patient outcome including increased requirement for sedation, prolonged duration of ventilation, and greater imposed work of breathing. Most currently used ventilators have real-time, continuously-displayed graphics of pressure, volume, and flow versus time (scalars) as well as pressure, and flow versus volume (loops). A clear understanding of these graphics provides a lot of information about the mechanics of the respiratory system and the patient ventilator interaction in a dynamic fashion. Using this information will facilitate tailoring the support provided and the manner in which it is provided to best suit the dynamic needs of the patient. This paper starts with a description of the scalars and loops followed by a discussion of the information that can be obtained from each of these graphics. A review will follow, on the common types of dyssynchronous interactions and how each of these can be detected on the ventilator graphics. The final section discusses how graphics can be used to optimize the ventilator support provided to patients. PMID- 27471821 TI - Mahogunin-mediated regulation of Galphai localisation during mitosis and its effect on spindle positioning. AB - Mahogunin RING Finger 1 (MGRN1) is a ubiquitin E3 ligase known to affect spindle tilt in mitotic cells by regulating alpha-tubulin ubiquitination and polymerization. In cell culture systems we have found that expressing truncated mutants of MGRN1 leads to various other mitotic anomalies, such as lateral and angular spindle displacements. This seems to be independent of the MGRN1 ligase activity. Our experiments suggest that MGRN1 regulates the balance between the lower molecular weight monomeric Galphai and larger trimeric G-protein complex, along with its abundance in the ternary complex that regulates spindle positioning. The cytosolic isoforms of MGRN1 lead to the enrichment of monomeric Galphai in the cytosol and its subsequent recruitment at the plasma membrane. Excess Galphai at the cell cortex results in an imbalance in the assembly of the ternary complex regulating spindle positioning during mitosis. These observations seem independent of the ligase activity of MGRN1, although we cannot exclude the involvement of an intermediate player that acts as a substrate for MGRN1, and in turn, regulates Galphai. PMID- 27471822 TI - Metal-Free, Multicomponent Synthesis of Pyrrole-Based pi-Conjugated Polymers from Imines, Acid Chlorides, and Alkynes. AB - Multicomponent coupling reactions (MCRs) are becoming increasingly used in the synthesis of macromolecules, as they can allow the rapid generation of libraries of materials as a method to tune properties. MCRs could prove particularly useful in the synthesis of pi-conjugated polymers in which structural changes are necessary for fine-tuning of electronic properties. We describe here the first metal-free multicomponent approach to conjugated polymers. This reaction exploits the coupling of imines, acid chlorides, and (catechyl)PPh to generate phospha munchnone-containing polymers, which can be converted to poly(pyrroles) via cycloaddition. The platform allows for the efficient synthesis of families of high molecular weight polymers in one step from readily available monomers. PMID- 27471823 TI - An Electronic Health Record Investigation of Lenticulostriate Vasculopathy Features. AB - Objective Lenticulostriate vasculopathy (LSV) is characterized by linear hyperechogenicities in the basal ganglia found on the head ultrasounds of infants. We reviewed electronic health records of infants with and without LSV to investigate whether physician dictations indicated symptoms which could reflect subtle basal ganglia injury. Study Design In a case-control study, we analyzed data from 46 infants with LSV and 127 controls. Infants were stratified between term and preterm birth. Odds ratios (ORs) and 95% confidence intervals were calculated for tone abnormalities, apnea, feeding difficulties, seizures, and movement abnormalities in the presence of LSV. Results Both term and preterm infants with LSV showed elevated risks for tone abnormalities (OR: 3.6 and 2.9, respectively). Term infants with LSV showed elevated risks for hypotonia (OR: 4.3), apnea (OR: 2.9), and feeding difficulties (OR: 4.1). Preterm infants with LSV showed elevated risks for truncal hypotonia (OR: 3.9) and hyperreflexia (OR: 3.9). Conclusion Our findings provide some evidence that LSV is associated with an increased risk of early signs of abnormal development, possibly relating to signs of subtle basal ganglia injury. Historically LSV has been considered incidental. The associations identified here suggest that LSV findings are worthy of further study. PMID- 27471824 TI - 25-GAUGE TROCAR CANNULA FOR ACUTE ENDOPHTHALMITIS-RELATED IN-OFFICE VITREOUS TAP AND INJECTION: Patient Comfort and Physician Ease of Use. AB - PURPOSE: To assess comfort and procedural facility using a 25-gauge trocar cannula as a port to diagnose and treat acute endophthalmitis compared with a standard vitreous tap and injection technique. METHODS: Eighteen consecutive patients with acute endophthalmitis were randomized into two treatment arms: 1) Standard vitreous tap and injection technique, and 2) A technique where a valved 25-gauge trocar cannula is inserted through the pars plana as done in sutureless vitrectomy surgery and subsequent vitreous sampling and injections are performed through the port. A standardized anesthetic protocol was used and subjects were masked to the technique performed. Primary outcomes measured were patient comfort using a Wong-Baker pain scale and standardized physician ease-of-use scoring scale. Secondary outcomes included vitreous sampling success rate and volume of vitreous sample. RESULTS: No significant differences were found when comparing patient comfort (P = 0.340), physician ease-of-use scores (P = 0.796), vitreous sample volume (P = 0.149), successful vitreous taps (P = 0.620), and microbiologic yield (P = 1.000) between treatment arms. There were no adverse events. CONCLUSION: The 25-gauge trocar technique provides a safe, well tolerated, and equally effective alternative to the standard vitreous tap and injection technique for delivery of intravitreal antibiotics, and procuring of vitreous sample, requiring a single sharp penetration. PMID- 27471825 TI - AQUEOUS HUMOR CYTOKINE LEVELS AS BIOMARKERS OF DISEASE SEVERITY IN DIABETIC MACULAR EDEMA. AB - PURPOSE: To determine whether aqueous cytokine levels correlate with disease severity in diabetic macular edema. METHODS: A prospective cross-sectional study of 49 adults with diabetes mellitus, centre-involving diabetic macular edema and central subfield macular thickness >=310 MUm on spectral domain optical coherence tomography. Clinical examination and aqueous sampling were carried out before an initial injection of ranibizumab. Multiplex immunoassay of sample was carried out for vascular endothelial growth factor, placental growth factor, transforming growth factor beta, intercellular adhesion molecule-1, interleukin (IL)-2, IL-3, IL-6, IL-8, IL-10, IL-17, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and epidermal growth factor. Multivariate robust regression models were constructed, and adjusted for age, lens status, or severity of retinopathy, and size of foveal avascular zone. RESULTS: Spectral domain optical coherence tomography macular volume was an excellent measure of disease severity, correlating strongly with central subfield macular thickness (P < 0.001), best-corrected Snellen visual acuity (P < 0.001), and baseline diabetic retinopathy severity (P = 0.01). Elevated aqueous intercellular adhesion molecule 1 correlated with greater macular volume (P = 0.002). No aqueous cytokine, including VEGF, correlated with central subfield macular thickness. There was an association between IL-10 levels and best-corrected Snellen visual acuity (P = 0.03). CONCLUSION: Aqueous intercellular adhesion molecule-1 correlates with disease severity as measured by macular volume on spectral domain optical coherence tomography, and IL-10 is associated with BCVA. Intercellular adhesion molecule-1 may be a clinically useful biomarker for diabetic macular edema severity. PMID- 27471826 TI - REAL-LIFE STUDY IN DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE IMPLANT: The Reldex Study. AB - PURPOSE: To evaluate the efficacy and safety of intravitreal implant of dexamethasone (Ozurdex) in diabetic macular edema in real-life practice. METHODS: In this bicentric retrospective study, the authors reviewed 128 eyes of 89 patients. Main outcome measures included changes in best-corrected visual acuity, central macular thickness, time to retreatment, and incidence of adverse effects. Linear mixed-effects models were used to study changes in best-corrected visual acuity and central macular thickness over the 3-year follow-up. RESULTS: Best corrected visual acuity increased by a mean of 3.6 letters at Month 2 (P = 0.005), 4.2 letters at Month 12 (P = 0.006), 5.3 at Month 24 (P = 0.007), and 9.5 letters at Month 36 (P = 0.023). The proportion of eyes achieving at least a 15 letter improvement from baseline was 25.4% at Month 36. Central macular thickness decreased from 451 MUm to 289 MUm at Month 2 (P < 0.001), 370 MUm at Month 12 (P < 0.001), 377 MUm at Month 24 (P = 0.004), and 280 MUm at Month 36 (P = 0.001). A mean of 3.6 injections were administered over the 3-year follow-up. Ten percent of eyes developed a transient increase in intraocular pressure (IOP >= 25 mmHg), and cataract was removed from 47% of phakic eyes. CONCLUSION: This large case series study showed favorable 3-year outcomes when using Ozurdex to treat diabetic macular edema. Intravitreal Ozurdex provides substantial long-term benefits in the treatment of diabetic macular edema in real-life. PMID- 27471827 TI - RANIBIZUMAB FOR MACULAR EDEMA AFTER BRANCH RETINAL VEIN OCCLUSION: One Initial Injection Versus Three Monthly Injections. AB - PURPOSE: To compare the 12-month-efficacy of 1 initial intravitreal ranibizumab injection (IVR) followed by pro re nata (PRN) dosing with that of three initial monthly IVR followed by PRN dosing in patients with macular edema (ME) after branch retinal vein occlusion. DESIGN: Prospective, interventional study. METHODS: Of 81 eyes, 42 received 1 initial IVR injection (1+PRN group) and 39 eyes received 3 monthly IVRs (3+PRN). Pro re nata injections were performed when fovea exudative changes were evident. RESULTS: At Month 12, the visual acuity (VA) changes from baseline were -0.245 +/- 0.227 and -0.287 +/- 0.222, in the 1+PRN and 3+PRN groups, respectively; there were no significant difference between groups (P = 0.728). The stratified analysis showed that patients with better VA (baseline VA >20/40) had similar significant improvement in VA at Month 12 (P < 0.001) to that of those with poorer VA (<=20/40). Better VA at Month 12 was significantly associated with younger age, better baseline VA, and thinner baseline central foveal thickness (P = 0.003, < 0.001, and < 0.001, respectively). Mean total number of IVR injections in the 1+PRN and 3+PRN groups were 3.8 +/- 1.8 and 4.6 +/- 1.4, respectively (P = 0.060). In both groups, shorter durations to the first PRN injection were associated with greater total PRN injection number (1+PRN, P = 0.006; 3+PRN; group, P < 0.001). CONCLUSION: In IVR treatment for ME after branch retinal vein occlusion, 1+PRN and 3+PRN regimens achieved similar 12-month functional outcomes. Patients with shorter durations to initial PRN injection may require more PRN treatments. PMID- 27471828 TI - Managing Optic Pit. The Right Stuff! PMID- 27471830 TI - Unraveling Cold Molecular Collisions: Stark Decelerators in Crossed-Beam Experiments. AB - In the last two decades, enormous progress has been made in the manipulation of molecular beams. In particular, molecular decelerators have been developed with which advanced control over neutral molecules in a beam can be achieved. By using arrays of inhomogeneous and time-varying electric (or magnetic) fields, bunches of molecules can be produced with a tunable velocity, narrow velocity spreads, and almost perfect quantum-state purity. These monochromatic or "tamed" molecular beams are ideally suited to be used in crossed-molecular-beam scattering experiments. Here, we review the first generation of these "cold and controlled" scattering experiments that have been conducted in the last decade and discuss the prospects for this emerging field of research in the years to come. PMID- 27471829 TI - DIABETES ALTERS THE MAGNITUDE OF VITREOMACULAR ADHESION. AB - PURPOSE: To quantify the changes in vitreomacular interactions that occur with aging in diabetic eyes in comparison with age-matched control eyes. METHODS: Spectral-domain optical coherence tomography (Spectralis; Heidelberg Engineering) foveal scans of diabetic patients, without evidence of cystoid macular edema, were included. Twenty-five raster foveal scans were performed on every subject. Area of vitreomacular adhesion was delineated using the Spectralis drawing tool and calculated in square millimeter. Data collected included gender, race, best corrected visual acuity, and posterior vitreous detachment status. Subjects were divided into age groups according to decade of life. RESULTS: Spectral-domain optical coherence tomography scans from 141 diabetic patients were analyzed. Area of vitreomacular adhesion (mm) showed a hyperbolic decline in diabetic patients (35.5 +/- 0, 35.0 +/- 3, 34.0 +/- 3, 33.9 +/- 5, 33.7 +/- 6, 29.0 +/- 11, 23 +/- 15, 13 +/- 15). With aging, incidence of posterior vitreous detachment increased and incidence of complete attachment decreased. CONCLUSION: Diabetes affects the magnitude of attachment of the vitreous gel to the macula that results in stronger and longer lasting attachment of the gel throughout life. Gender differences were not noticed in diabetic patients, suggesting that vitreomacular adhesion remains robust in both genders in diabetes despite aging. PMID- 27471831 TI - Sequence analysis of the pyruvylated galactan sulfate-derived oligosaccharides by negative-ion electrospray tandem mass spectrometry. AB - Five sulfated oligosaccharide fragments, F1-F5, were prepared from a pyruvylated galactan sulfate from the green alga Codium divaricatum, by partial depolymerization using mild acid hydrolysis and purification with gel-permeation chromatography. Negative-ion electrospray tandem mass spectrometry with collision induced dissociation (ES-CID-MS/MS) is attempted for sequence determination of the sulfated oligosaccharides. The sequence of F1 with homogeneous disaccharide composition was first characterized to be Galp-(4SO4)-(1 -> 3)-Galp by detailed nuclear magnetic resonance spectroscopic analyses. The fragmentation pattern of F1 in the product ion spectra was established on the basis of negative-ion ES-CID MS/MS, which was then applied to sequence analysis of other sulfated oligosaccharides. The sequences of F2 and F3 were deduced to be Galp-(4SO4)-(1 -> 3)-Galp-(1 -> 3)-Galp-(1 -> 3)-Galp and 3,4-O-(1-carboxyethylidene)-Galp-(6SO4) (1 -> 3)-Galp, respectively. The sequences of major fragments in F4 and F5 were also deduced. The investigation demonstrated that negative-ion ES-CID-MS/MS was an efficient method for the sequence analysis of the pyruvylated galactan sulfate derived oligosaccharides which revealed the patterns of substitution and glycosidic linkages. The pyruvylated galactan sulfate-derived oligosaccharides were novel sulfated oligosaccharides different from other algal polysaccharide derived oligosaccharides. PMID- 27471832 TI - 1,3-Dipolar cycloaddition of a cyclic nitrone derived from 2-deoxy-D-ribose to alpha,beta-unsaturated lactones: An entry to carbapenem antibiotics. AB - 1,3-Dipolar cycloadditions of 2-deoxy-D-ribose-derived L-threo five-membered cyclic nitrone to alpha,beta-unsaturated gamma- and delta-lactones were investigated. Cycloadducts obtained from delta-lactones, after NO bond cleavage, opening of the lactone ring, and protection of hydroxyl groups were subjected to beta-lactam ring formation by using Mukaiyama's salt. Cycloadducts from gamma lactones subjected to the same reaction sequence undergo beta-elimination of a water molecule to provide pyrrolidine-substituted unsaturated gamma-lactones. PMID- 27471833 TI - Recipient-derived angiogenesis with short term immunosuppression increases bone remodeling in bone vascularized composite allotransplantation: A pilot study in a swine tibial defect model. AB - Current vascularized composite allotransplantation (VCA) transplantation protocols rely upon life-long immune modulation to maintain tissue perfusion. Alternatively, bone-only VCA viability may be maintained in small animal models using surgical angiogenesis from implanted autogenous vessels to develop a neoangiogenic bone circulation that will not be rejected. This study tests the method's efficacy in a large animal model as a bridge to clinical practice, quantifying the remodeling and mechanical properties of porcine tibial VCAs. A segmental tibial defect was reconstructed in Yucatan miniature swine by transplantation of a matched tibia segment from an immunologically mismatched donor. Microsurgical repair of nutrient vessels was performed in all pigs, with simultaneous intramedullary placement of an autogenous arteriovenous (AV) bundle in Group 2. Group 1 served as a no-angiogenesis control. All received 2 weeks of immunosuppression. After 16 weeks, micro-CT and histomorphometric analyses were used to evaluate healing and remodeling. Axial compression and nanoindentation studies evaluated bone mechanical properties. Micro-CT analysis demonstrated significantly more new bone formation and bone remodeling at the distal allotransplant/recipient junction and on the endosteal surfaces of Group 2 tibias (p = 0.03). Elastic modulus and hardness were not adversely affected by angiogenesis. The combination of 2 weeks of immunosuppression and autogenous AV bundle implantation within a microsurgically transplanted tibial allotransplant permitted long-term allotransplant survival over the study period of 16 weeks in this large animal model. Angiogenesis increased bone formation and remodeling without adverse mechanical effects. The method may allow future composite-tissue allotransplantation of bone without the risks associated with long-term immunosuppression. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1242-1249, 2017. PMID- 27471834 TI - Outcome and complications of combined liver and pancreas resections: a retrospective analysis. AB - BACKGROUND: Combined resections of the liver and pancreas are related to high complication and mortality rates. The present study assessed the outcome of these procedures and identified specific risk factors for morbidity and mortality. METHODS: Between January 2001 and April 2012, 28 combined liver/pancreas resections were performed at our institution. All patients were retrospectively analysed using a database with regards to baseline characteristics, surgical procedures, complications and survival. RESULTS: Among the pancreatic resections, there were 12 (42.9%) Kausch-Whipple (KW), 9 (32.1%) pylorus-preserving pancreaticoduodenectomy (PPPD), 6 (21.4%) distal pancreatectomies (DP) and 1 (3.6%) total pancreaticoduodenectomy (TPD). In 12 (48.9%) cases, major complications (grade IIIb-V) were observed. Overall survival was 35 months (SD = 40.5) and the 3-year survival rate was 35.7% (1-year survival rate: 50%). DISCUSSION: Combined resections of the liver and pancreas are associated with high complication rates, especially if major liver resections are performed. Therefore, it is mandatory to do a thorough evaluation of potential patients. PMID- 27471835 TI - Molecular simulation of the thermophysical properties and phase behaviour of impure CO2 relevant to CCS. AB - Impurities from the CCS chain can greatly influence the physical properties of CO2. This has important design, safety and cost implications for the compression, transport and storage of CO2. There is an urgent need to understand and predict the properties of impure CO2 to assist with CCS implementation. However, CCS presents demanding modelling requirements. A suitable model must both accurately and robustly predict CO2 phase behaviour over a wide range of temperatures and pressures, and maintain that predictive power for CO2 mixtures with numerous, mutually interacting chemical species. A promising technique to address this task is molecular simulation. It offers a molecular approach, with foundations in firmly established physical principles, along with the potential to predict the wide range of physical properties required for CCS. The quality of predictions from molecular simulation depends on accurate force-fields to describe the interactions between CO2 and other molecules. Unfortunately, there is currently no universally applicable method to obtain force-fields suitable for molecular simulation. In this paper we present two methods of obtaining force-fields: the first being semi-empirical and the second using ab initio quantum-chemical calculations. In the first approach we optimise the impurity force-field against measurements of the phase and pressure-volume behaviour of CO2 binary mixtures with N2, O2, Ar and H2. A gradient-free optimiser allows us to use the simulation itself as the underlying model. This leads to accurate and robust predictions under conditions relevant to CCS. In the second approach we use quantum-chemical calculations to produce ab initio evaluations of the interactions between CO2 and relevant impurities, taking N2 as an exemplar. We use a modest number of these calculations to train a machine-learning algorithm, known as a Gaussian process, to describe these data. The resulting model is then able to accurately predict a much broader set of ab initio force-field calculations at comparatively low numerical cost. Although our method is not yet ready to be implemented in a molecular simulation, we outline the necessary steps here. Such simulations have the potential to deliver first-principles simulation of the thermodynamic properties of impure CO2, without fitting to experimental data. PMID- 27471836 TI - Multicentre study to evaluate the clinical effects of laparoscopic uterine artery occlusion in combination with myomectomy to treat symptomatic uterine leiomyomas. AB - OBJECTIVE: Uterine artery occlusion is often used to treat symptomatic uterine myomas, as this is a minimally invasive approach. However, alternative methods for uterus-sparing therapy are in development. This study aimed to compare the clinical effects of laparoscopic uterine artery occlusion (LUAO) in combination with laparoscopic myomectomy (LM) with LM alone for the management of symptomatic uterine leiomyomas. STUDY DESIGN: This multicentre study was a retrospective controlled investigation. In total, 618 patients with symptomatic uterine myomas from six hospitals in Eastern China underwent LUAO+LM or LM alone between June 2011 and December 2012. Operative time, blood loss, transfusion, highest temperature, postoperative hospital stay, complications and follow-up results were compared between the two groups. RESULTS: Complete clinical data were available for 504 patients. Among these, 324 patients underwent LUAO+LM and 180 patients underwent LM alone. Mean+/-standard deviation blood loss, transfusion, highest peri-operative temperature and duration of hospital stay were significantly lower in the LUAO+LM group compared with the LM group (83.61+/ 53.70ml vs 109+/-58.43ml, 1.85% vs 6.11%, 37.6+/-0.40 degrees C vs 37.9+/-0.45 degrees C and 5.11+/-0.62 days vs 6.10+/-0.83 days, respectively). The mean duration of follow-up was 38.97+/-5.82 months in the LUAO+LM group and 37.30+/ 2.25 months in the LM group (p>0.05). The relief of abnormal uterine bleeding, reduction of uterine volume and recurrence of myomas were more remarkable in the LUAO+LM group than the LM group (97.22% vs 83.75%, 62.42% vs 51.83% and 3.47% vs 10.63%, respectively). CONCLUSIONS: LUAO in combination with LM was associated with higher surgical quality, greater relief of abnormal symptoms and less recurrence of myomas compared with LM alone. LUAO in combination with LM is recommended for women with symptomatic uterine myomas who wish to preserve their uterus. PMID- 27471837 TI - The DGAT1 inhibitor pradigastat does not induce photosensitivity in healthy human subjects: a randomized controlled trial using three defined sunlight exposure conditions. AB - The DGAT1 inhibitor, pradigastat, demonstrated a mild phototoxicity signal in preclinical studies. Therefore, this clinical trial was conducted to assess the risk of photosensitivity in humans. 47 healthy adults were randomized to part A (double-blind, placebo-controlled; 3 : 1 pradigastat : placebo) or part B (open label positive control ciprofloxacin, investigator blind). Three irradiation conditions (1. full range UVB/UVA, 2. UVA only, 3. 1/2 MED from UVB/UVA + 16 J cm(-2) UVA) were applied to simulate different sunlight exposure conditions. Photosensitizing potential was assessed by determining the minimum erythemal dose (MED) and calculating the photosensitivity index (PI) at 1 and 24 h. Local skin reactions were recorded as a secondary endpoint. Following full UVB/UVA irradiation, there were no significant differences in MED or PI between groups. With UVA-only, no changes in MED or PI were observed for the pradigastat or placebo groups. For ciprofloxacin, there was a significant reduction in MED at 24 h (-32%, vs. 24 h baseline), which correlated to a PI of 1.61. The difference in mean PI between ciprofloxacin-pradigastat, and ciprofloxacin-placebo, was significant at 24 h (p < 0.001). Local skin erythema scores were comparable between pradigastat and placebo, but higher with ciprofloxacin. Pradigastat was not shown to induce photosensitivity reactions, while significant responses were seen with the positive control. These results strongly suggest that pradigastat will not induce photosensitivity reactions in individuals administered doses up to 40 mg per day, which is the highest intended clinical dose. Furthermore, the design of this clinical trial may serve as a prototype for future regulatory clinical photosensitivity studies. PMID- 27471838 TI - House dust mite sublingual tablet is effective and safe in patients with allergic rhinitis. AB - BACKGROUND: House dust mite (HDM) is the major indoor allergen for allergic diseases such as allergic rhinitis (AR) and asthma. Although sublingual immunotherapy is a curative treatment for HDM-induced AR, data from large-scale studies are limited. We evaluated the efficacy and safety of HDM tablets in adolescent and adult patients (aged 12-64 years) with HDM-induced AR with or without intermittent asthma. METHODS: In a double-blind trial in Japan, 968 subjects were randomized 1 : 1 : 1 to 300 index of reactivity (IR), 500 IR, or placebo groups. The primary endpoint was the Average Adjusted Symptom Score (AASS) in the last eight weeks of the 52-week treatment. Secondary endpoints included individual nasal and ocular symptom scores, rescue medication use, and the Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) scores. RESULTS: The AASS in the last eight weeks of treatment significantly improved in both the 300 IR and the 500 IR groups compared to that in the placebo group (P < 0.001). In the 300 IR group, the onset of action occurred at week 8-10. All four nasal symptoms significantly improved in both active treatment groups; rescue medication use and JRQLQ outcome improved in the 300 IR group. Most adverse events (AEs) were mild, and 16 serious AEs (SAEs) were reported; however, none of them were drug-related. CONCLUSIONS: One-year treatment with 300 IR and 500 IR HDM tablets was effective without major safety concerns. The recommended therapeutic dose for AR is 300 IR. PMID- 27471840 TI - Prophylactic Mesh Placement During Formation of an End-colostomy Reduces the Rate of Parastomal Hernia: Short-term Results of the Dutch PREVENT-trial. AB - OBJECTIVE: The aim of this study was to investigate the incidence of parastomal hernias (PSHs) after end-colostomy formation using a polypropylene mesh in a randomized controlled trial versus conventional colostomy formation. BACKGROUND: A PSH is the most frequent complication after stoma formation. Symptoms may range from mild abdominal pain to life-threatening obstruction and strangulation. The treatment of a PSH is notoriously difficult and recurrences up to 20% have been reported despite the use of mesh. This has moved surgical focus toward prevention. METHODS: Augmentation of the abdominal wall with a retro-muscular lightweight polypropylene mesh was compared with the traditional formation of a colostomy. In total, 150 patients (1:1 ratio) were included. The incidence of a PSH, morbidity, mortality, quality of life, and cost-effectiveness was measured after 1 year of follow-up. RESULTS: There was no difference between groups regarding demographics and predisposing factors for PSH. Three out of 67 patients (4.5%) in the mesh group and 16 out of 66 patients (24.2%) in the nonmesh group developed a PSH (P = 0.0011). No statistically significant difference was found in infections, concomitant hernias, SF-36 questionnaire, Von Korff pain score, and cost-effectiveness between both study groups. CONCLUSION: Prophylactic augmentation of the abdominal wall with a retromuscular lightweight polypropylene mesh at the ostomy site significantly reduces the incidence of PSH without a significant difference in morbidity, mortality, quality of life, or cost effectiveness. PMID- 27471839 TI - A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity. AB - OBJECTIVE: To develop a plasma-based microRNA (miRNA) diagnostic assay specific for colorectal neoplasms, building upon our prior work. BACKGROUND: Colorectal neoplasms [colorectal cancer (CRC) and colorectal advanced adenoma (CAA)] frequently develop in individuals at ages when other common cancers also occur. Current screening methods lack sensitivity, specificity, and have poor patient compliance. METHODS: Plasma was screened for 380 miRNAs using microfluidic array technology from a "Training" cohort of 60 patients, (10 each) control, CRC, CAA, breast cancer, pancreatic cancer, and lung cancer. We identified uniquely dysregulated miRNAs specific for colorectal neoplasia (P < 0.05, false discovery rate: 5%, adjusted alpha = 0.0038). These miRNAs were evaluated using single assays in a "Test" cohort of 120 patients. A mathematical model was developed to predict blinded sample identity in a 150 patient "Validation" cohort using repeat sub-sampling validation of the testing dataset with 1000 iterations each to assess model detection accuracy. RESULTS: Seven miRNAs (miR-21, miR-29c, miR-122, miR-192, miR-346, miR-372, and miR-374a) were selected based upon P value, area under the curve (AUC), fold change, and biological plausibility. Area under the curve (+/-95% confidence interval) for "Test" cohort comparisons were 0.91 (0.85 0.96) between all neoplasia and controls, 0.79 (0.70-0.88) between colorectal neoplasia and other cancers, and 0.98 (0.96-1.0) between CRC and colorectal adenomas. In our "Validation" cohort, our mathematical model predicted blinded sample identity with 69% to 77% accuracy, 67% to 76% accuracy, and 86% to 90% accuracy for each comparison, respectively. CONCLUSIONS: Our plasma miRNA assay and prediction model differentiate colorectal neoplasia from patients with other neoplasms and from controls with higher sensitivity and specificity compared with current clinical standards. PMID- 27471841 TI - PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model. AB - OBJECTIVE: The purpose of the current study is to determine the efficacy of a PI3K/mTOR dual inhibitor, LY3023414, on established EAC in an in vivo model. BACKGROUND: Esophageal adenocarcinoma (EAC) is a highly lethal cancer with limited treatment options. The PI3K/mTOR pathway is upregulated in EAC and may be a target for novel therapies. METHODS: Esophagojejunostomy was performed on Sprague-Dawley rats to induce carcinogenesis, and LY3023414 was cyclically administered intraperitoneally between 32 and 40 weeks postsurgery to treatment animals. Magnetic resonance imaging (MRI) and histology were used to determine clinical response. Immunohistochemistry, immunofluorescence, and Western blot were used to validate apoptosis by cleaved caspase-3, proliferation by Ki67, and pathway inhibition, respectively. RESULTS: Mean MRI tumor volume increased by 109.2% in controls (n = 32) and decreased by 56.8% in treatment animals (n=17) (P < 0.01). Treatment with LY3023414 demonstrated tumor volume increase in 0% (control = 46.4%) (P < 0.01), decrease in 58.8% (control = 7.1%) (P < 0.01), and stable volume in 41.2% (control = 46.4%) (P = 0.77). EAC prevalence in controls increased by 25%; whereas, prevalence in treatment animals decreased by 29.4% (P < 0.01). Approximately, 75% of treatment animals presenting with residual masses on MRI had a histological response >50%. Increased apoptosis by cleaved caspase-3 (P = 0.03) and decreased proliferation by Ki67 (P < 0.01) were demonstrated in the treatment arm, when compared with the control arm. On Western blot analysis of pathway checkpoints, p-mTOR (p=0.03) and PI3K-alpha (P = 0.04) were downregulated in treatment responsive residual tumors, when compared with controls. CONCLUSIONS: LY3023414 demonstrates efficacy against EAC in a preclinical model, establishing the rationale for clinical testing. PMID- 27471842 TI - Childhood adversity and depressive symptoms following retirement in the Gazel cohort. AB - BACKGROUND: Only a few studies have examined whether specific moderators may impact the magnitude of the relationship between retirement and depression. The aim of this study was to examine the potential moderating role of adverse childhood life events (ACLE) on changes in depressive symptoms following retirement in the GAZEL cohort. METHODS: 9242 participants, followed up since 1989, completed the Center of Epidemiologic Studies Depression scale (CESD) every three years and were asked in 2004 to answer an ACLE questionnaire. Subjects were classed according to 6 clusters by Two-Step Cluster Analysis (no ACLE: cluster 1; increasing material deprivation: clusters 2 to 4; history of early separation: cluster 5 and history of conflicts or violence: cluster 6), and then stratified for sex. Analyses were based on general linear models with the CESD variation between, before and after retirement as dependent variable. All results were adjusted according to age, marital status, occupational status, alcohol consumption, self-rated health and CESD score before retirement. RESULTS: The association between exposure to ACLE and changes in depressive symptoms following retirement was significant in both men (F = 6.929; p < 0.001; eta(2) = 0.005) and women (F = 6.890; p < 0.001; eta(2) = 0.016). Exposure to early separation or history of conflicts or violence during childhood was associated with less improvement in both men and women, whereas early exposure to material deprivation only affected results in men. CONCLUSIONS: Programs aimed at facilitating retirement transition may focus on subjects at risk of not experiencing the expected benefits of retirement, which is the case for those with a history of ACLE. PMID- 27471843 TI - Marginal adaptation of composite resins under two adhesive techniques. AB - In the present research, different adhesive techniques were used to set up fillings with composite resins. After the application of etch and rinse or self etch adhesive technique, marginal adaptation of composite fillings was estimated by the length of margins without gaps, and by the microretention of resin in enamel and dentin. The study material consisted of 40 extracted teeth. Twenty Class V cavities were treated with 35% phosphorous acid and restored after rinsing by Adper Single Bond 2 and Filtek Ultimate-ASB/FU 3M ESPE composite system. The remaining 20 cavities were restored by Adper Easy One-AEO/FU 3M ESPE composite system. Marginal adaptation of composite fillings was examined using a scanning electron microscope (SEM). The etch and rinse adhesive technique showed a significantly higher percentage of margin length without gaps (in enamel: 92.5%, in dentin: 57.3%), compared with the self-etch technique with lower percentage of margin length without gaps, in enamel 70.4% (p < .001), and in dentin-22.6% (p < .05). In the first technique, microretention was composed of adhesive and hybrid layers as well as resin tugs in interprismatic spaces of enamel, while the dentin microretention was composed of adhesive and hybrid layers with resin tugs in dentin canals. In the second technique, resin tugs were rarely seen and a microgap was dominant along the border of restoration margins. The SEM analysis showed a better marginal adaptation of composite resin to enamel and dentin with better microretention when the etch and rinse adhesive procedure was applied. PMID- 27471844 TI - Loop-driven conformational transition between the alternative and collapsed form of prethrombin-2: targeted molecular dynamics study. AB - Two distinct crystal structures of prethrombin-2, the alternative and collapsed forms, are elucidated by X-ray crystallogrphy. We analyzed the conformational transition from the alternative to the collapsed form employing targeted molecular dynamics (TMD) simulation. Despite small RMSD difference in the two X ray crystal structures, some hydrophobic residues (W60d, W148, W215, and F227) show a significant difference between the two conformations. TMD simulation shows that the four hydrophobic residues undergo concerted movement from dimer to trimer transition via tetramer state in the conformational change from the alternative to the collapsed form. We reveal that the concerted movement of the four hydrophobic residues is controlled by movement of specific loop regions behind. In this paper, we propose a sequential scenario for the conformational transition from the alternative form to the collapsed form, which is partially supported by the mutant W148A simulation. PMID- 27471845 TI - Interventions for treating oral leukoplakia to prevent oral cancer. AB - BACKGROUND: Oral leukoplakia is a relatively common oral lesion that, in a small proportion of people, precedes the development of oral cancer. Most leukoplakias are asymptomatic; therefore, the primary objective of treatment should be to prevent onset of cancer. This review updates our previous review, published in 2006. OBJECTIVES: To assess the effectiveness, safety and acceptability of treatments for leukoplakia in preventing oral cancer. SEARCH METHODS: We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 16 May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 4), MEDLINE Ovid (1946 to 16 May 2016), Embase Ovid (1980 to 16 May 2016) and CancerLit via PubMed (1950 to 16 May 2016). We searched the metaRegister of Controlled Trials (to 10 February 2015), ClinicalTrials.gov (to 16 May 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (to 16 May 2016). We placed no restrictions on the language or date of publication when searching electronic databases. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled people with a diagnosis of oral leukoplakia and compared any treatment versus placebo or no treatment. DATA COLLECTION AND ANALYSIS: We collected data using a data extraction form. Oral cancer development, demonstrated by histopathological examination, was our primary outcome. Secondary outcomes were clinical resolution of the lesion, improvement of histological features and adverse events. We contacted trial authors for further details when information was unclear. When valid and relevant data were available, we conducted a meta-analysis of the data using a fixed-effect model when we identified fewer than four studies with no heterogeneity. For dichotomous outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). We assessed risk of bias in studies by using the Cochrane tool. We assessed the overall quality of the evidence by using standardised criteria (Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE)). MAIN RESULTS: We included 14 studies (909 participants) in this review. Surgical interventions, including laser therapy and cryotherapy, have never been studied by means of an RCT that included a no treatment or placebo arm. The included trials tested a range of medical and complementary treatments, in particular, vitamin A and retinoids (four studies); beta carotene or carotenoids (three studies); non-steroidal anti-inflammatory drugs (NSAIDs), specifically ketorolac and celecoxib (two studies); herbal extracts (four studies), including tea components, a Chinese herbal mixture and freeze-dried black raspberry gel; bleomycin (one study); and Bowman-Birk inhibitor (one study).We judged one study to be at low risk of bias, seven at unclear risk and six at high risk. In general, we judged the overall quality of the evidence to be low or very low, so findings are uncertain and further research is needed.Five studies recorded cancer incidence, only three of which provided useable data. None of the studies provided evidence that active treatment reduced the risk of oral cancer more than placebo: systemic vitamin A (RR 0.11, 95% CI 0.01 to 2.05; 85 participants, one study); systemic beta carotene (RR 0.71, 95% CI 0.24 to 2.09; 132 participants, two studies); and topical bleomycin (RR 3.00, 95% CI 0.32 to 27.83; 20 participants, one study). Follow-up ranged between two and seven years.Some individual studies suggested effectiveness of some proposed treatments, namely, systemic vitamin A, beta carotene and lycopene, for achieving clinical resolution of lesions more often than placebo. Similarly, single studies found that systemic retinoic acid and lycopene may provide some benefit in terms of improvement in histological features. Some studies also reported a high rate of relapse.Side effects of varying severity were often described; however, it seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups. AUTHORS' CONCLUSIONS: Surgical treatment for oral leukoplakia has not been assessed in an RCT that included a no treatment or placebo comparison. Nor has cessation of risk factors such as smoking been assessed. The available evidence on medical and complementary interventions for treating people with leukoplakia is very limited. We do not currently have evidence of a treatment that is effective for preventing the development of oral cancer. Treatments such as vitamin A and beta carotene may be effective in healing oral lesions, but relapses and adverse effects are common. Larger trials of longer duration are required to properly evaluate the effects of leukoplakia treatments on the risk of developing oral cancer. High-quality research is particularly needed to assess surgical treatment and to assess the effects of risk factor cessation in people with leukoplakia. PMID- 27471846 TI - N-Oxides rescue Ru(v) in catalytic Griffith-Ley (TPAP) alcohol oxidations. AB - The redox and ligand exchange reactions of oxido-ruthenium complexes are central to the function of the Sharpless and Griffith-Ley one-step alcohol oxidation protocols. However, their mechanisms have not been elucidated. Cyclic voltammetry and UV-vis spectroelectrochemical analysis of [RuO4](-) has provided new insight into the key ruthenium oxidation states involved in catalysis. Furthermore, the oxidation states sensitive to the presence of the N-oxide co-oxidant N methylmorpholine N-oxide (NMO), and its role in catalysis, have been determined. PMID- 27471847 TI - Statin therapy prevents the onset of Parkinson disease in patients with diabetes. AB - OBJECTIVE: We studied the association between the statin dosage and the risk of Parkinson disease (PD) in diabetic patients in Taiwan. METHODS: One million patients were randomly sampled from a National Health Insurance (NHI) database and followed from 2001 to 2008. Diabetic patients were screened by diagnosis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and statin dosage was determined according to the NHI pharmacy database. PD was diagnosed on the basis of ICD-9-CM codes and anti-Parkinson medication use. Statin users was classified by statin dose-duration-day > 28 and matched with nonusers of statins using a coarsened exact matching method. There were 50,432 patients, and half of them were statin users. We examined the risk of PD between statin users and nonusers of statins and further tested the trends of the relative risk between the statin dosage and PD. RESULTS: The PD incidence rate was lower in statin users than in nonusers of statins. The crude hazard ratio of PD incidence in statin users was 0.65 (95% confidence interval [CI] = 0.57-0.74) in females and 0.60 (95% CI = 0.51-0.69) in males compared with nonusers of statins. After Cox regression analysis, all statins except lovastatin exerted protective effects on PD incidence and had a significant dose-dependent trend. INTERPRETATION: In Taiwanese diabetic patients, the risk of PD is lower in statin users than in nonusers of statins. Statin users, except lovastatin users, are dose-dependently associated with a decreased incidence of PD compared with nonusers of statins. This finding provides a new indication for statin beyond lipid control and cardiovascular events in diabetic patients. Ann Neurol 2016;80:532-540. PMID- 27471848 TI - Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound. AB - RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14). Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9) or control RNA (n = 8) during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3) confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23+/-7% and 33+/-7% of control mice, p<0.01 and p = 0.03, respectively). Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease. PMID- 27471849 TI - Effects of Sodium Butyrate Treatment on Histone Modifications and the Expression of Genes Related to Epigenetic Regulatory Mechanisms and Immune Response in European Sea Bass (Dicentrarchus Labrax) Fed a Plant-Based Diet. AB - Bacteria that inhabit the epithelium of the animals' digestive tract provide the essential biochemical pathways for fermenting otherwise indigestible dietary fibers, leading to the production of short-chain fatty acids (SCFAs). Of the major SCFAs, butyrate has received particular attention due to its numerous positive effects on the health of the intestinal tract and peripheral tissues. The mechanisms of action of this four-carbon chain organic acid are different; many of these are related to its potent regulatory effect on gene expression since butyrate is a histone deacetylase inhibitor that play a predominant role in the epigenetic regulation of gene expression and cell function. In the present work, we investigated in the European sea bass (Dicentrarchus labrax) the effects of butyrate used as a feed additive on fish epigenetics as well as its regulatory role in mucosal protection and immune homeostasis through impact on gene expression. Seven target genes related to inflammatory response and reinforcement of the epithelial defense barrier [tnfalpha (tumor necrosis factor alpha) il1beta, (interleukin 1beta), il-6, il-8, il-10, and muc2 (mucin 2)] and five target genes related to epigenetic modifications [dicer1(double-stranded RNA specific endoribonuclease), ehmt2 (euchromatic histone-lysine-N-methyltransferase 2), pcgf2 (polycomb group ring finger 2), hdac11 (histone deacetylase-11), and jarid2a (jumonji)] were analyzed in fish intestine and liver. We also investigated the effect of dietary butyrate supplementation on histone acetylation, by performing an immunoblotting analysis on liver core histone extracts. Results of the eight-week-long feeding trial showed no significant differences in weight gain or SGR (specific growth rate) of sea bass that received 0.2% sodium butyrate supplementation in the diet in comparison to control fish that received a diet without Na-butyrate. Dietary butyrate led to a twofold increase in the acetylation level of histone H4 at lysine 8, but showed no effect on the histone H3 at Lys9. Moreover, two different isoforms of histone H3 that might correspond to the H3.1 and H3.2 isoforms previously found in terrestrial animals were separated on the immunoblots. The expression of four (il1 beta, il8, irf1, and tnfalpha) out of seven analyzed genes related to mucosal protection and inflammatory response was significantly different between the two analyzed tissues but only il10 showed differences in expression due to the interaction between tissue and butyrate treatment. In addition, butyrate caused significant changes in vivo in the expression of genes related to epigenetic regulatory mechanisms such as hdac11, ehmt2, and dicer1. Statistical analysis by two-way ANOVA for these genes showed not only significant differences due to the butyrate treatment, but also due to the interaction between tissue and treatment. PMID- 27471850 TI - Health Seeking Behaviours among Caretakers of Children with Nodding Syndrome in Pader District - Northern Uganda: A Mixed Methods Study. AB - BACKGROUND: Nodding syndrome is a neurological disorder which had affected about 3000 children with over 170 deaths in northern Uganda by 2012. With limited data on health seeking, the study aimed to assess the health seeking behavior and associated factors among caretakers of children with nodding syndrome in Pader district. METHODS: A mixed methods cross sectional study was conducted in July 2013 among 249 caretakers of children with nodding syndrome in three sub-counties of Pader. Respondents were consecutively interviewed using semi-structured questionnaires. Eleven key informants were additionally interviewed. We determined the associations of various factors with health care seeking and obtained adjusted odds ratios and 95% confidence intervals using logistic regression model. Quantitative data was analysed using Stata version 12 while qualitative data was analysed manually and quotes reported. RESULTS: Most caretakers, 78.3% (195/249) sought care first from a health facility, 12.9% (32/249) visited traditional healers and 8.8% (22/249) self-medicated. Of those who sought care from a health facility, 50% sought care after a month. Factors associated with improved care seeking included: Time taken to reach care 1-3 hours; adjusted odds ratio = 6.4 (95% CI = 2.96-14.03), time spent in care above five years; adjusted odds ratio = 12.0 (95% CI: 1.24-117.73) and changed care seeking place; adjusted odds ratio = 17.2 (95% CI: 3.64-81.67). CONCLUSION/ RECOMMENDATION: Caretakers sought care from multiple places. One in five caretakers still sought care outside a formal health facility. Many respondents who sought care first from health facilities went late, at least one month after symptoms onset. Factors associated with health seeking included distance, duration in treatment and not having changing care provider. There is need for massive sensitization of community to enhance prompt care seeking. More research is needed to elucidate the cause, thus finding the treatment for nodding syndrome, to prevent "wandering in hope". PMID- 27471851 TI - The Differential Response of Proteins to Macromolecular Crowding. AB - The habitat in which proteins exert their function contains up to 400 g/L of macromolecules, most of which are proteins. The repercussions of this dense environment on protein behavior are often overlooked or addressed using synthetic agents such as poly(ethylene glycol), whose ability to mimic protein crowders has not been demonstrated. Here we performed a comprehensive atomistic molecular dynamic analysis of the effect of protein crowders on the structure and dynamics of three proteins, namely an intrinsically disordered protein (ACTR), a molten globule conformation (NCBD), and a one-fold structure (IRF-3) protein. We found that crowding does not stabilize the native compact structure, and, in fact, often prevents structural collapse. Poly(ethylene glycol) PEG500 failed to reproduce many aspects of the physiologically-relevant protein crowders, thus indicating its unsuitability to mimic the cell interior. Instead, the impact of protein crowding on the structure and dynamics of a protein depends on its degree of disorder and results from two competing effects: the excluded volume, which favors compact states, and quinary interactions, which favor extended conformers. Such a viscous environment slows down protein flexibility and restricts the conformational landscape, often biasing it towards bioactive conformations but hindering biologically relevant protein-protein contacts. Overall, the protein crowders used here act as unspecific chaperons that modulate the protein conformational space, thus having relevant consequences for disordered proteins. PMID- 27471853 TI - A Landscape Approach to Invasive Species Management. AB - Biological invasions are not only a major threat to biodiversity, they also have major impacts on local economies and agricultural production systems. Once established, the connection of local populations into metapopulation networks facilitates dispersal at landscape scales, generating spatial dynamics that can impact the outcome of pest-management actions. Much planning goes into landscape scale invasive species management. However, effective management requires knowledge on the interplay between metapopulation network topology and management actions. We address this knowledge gap using simulation models to explore the effectiveness of two common management strategies, applied across different extents and according to different rules for selecting target localities in metapopulations with different network topologies. These management actions are: (i) general population reduction, and (ii) reduction of an obligate resource. The reduction of an obligate resource was generally more efficient than population reduction for depleting populations at landscape scales. However, the way in which local populations are selected for management is important when the topology of the metapopulation is heterogeneous in terms of the distribution of connections among local populations. We tested these broad findings using real world scenarios of European rabbits (Oryctolagus cuniculus) infesting agricultural landscapes in Western Australia. Although management strategies targeting central populations were more effective in simulated heterogeneous metapopulation structures, no difference was observed in real-world metapopulation structures that are highly homogeneous. In large metapopulations with high proximity and connectivity of neighbouring populations, different spatial management strategies yield similar outcomes. Directly considering spatial attributes in pest-management actions will be most important for metapopulation networks with heterogeneously distributed links. Our modelling framework provides a simple approach for identifying the best possible management strategy for invasive species based on metapopulation structure and control capacity. This information can be used by managers trying to devise efficient landscape-oriented management strategies for invasive species and can also generate insights for conservation purposes. PMID- 27471852 TI - Canine-Based Strategies for Prevention and Control of Visceral Leishmaniasis in Brazil. AB - Visceral leishmaniasis (VL) is a zoonosis found worldwide. Its incidence has increased in Brazil in recent years, representing a serious public and animal health problem. The strategies applied in Brazil are questionable and are not sufficient to control the disease. Thus, we have compared the efficacy of some of the currently available strategies focused on dogs to prevent and control zoonotic VL in endemic areas by optimizing a mathematical model. The simulations showed that the elimination of seropositive dogs, the use of insecticide impregnated dog collars, and the vaccination of dogs significantly contribute to reducing the prevalence of infection in both canines and humans. The use of insecticide-impregnated collars presented the highest level of efficacy mainly because it directly affected the force of infection and vector-dog contact. In addition, when used at a coverage rate of 90%, insecticide-impregnated collar was able to decrease the prevalence of seropositive dogs and humans to zero; moreover, because of the easy application and acceptance by the targeted population, these collars may be considered the most feasible for inclusion in public policies among the three simulated measures. Vaccination and euthanasia were efficacious, but the latter method is strongly criticized on ethical grounds, and both methods present difficulties for inclusion in public policies. When we compared the use of euthanasia and vaccination at coverages of 70 and 90%, respectively, the proportion of infected populations were similar. However, on evaluating the implications of both of these methods, particularly the negative aspects of culling dogs and the proportion of animals protected by vaccination, the latter measure appears to be the better option if the total cost is not significantly higher. The comparison of complications and advantages of different control strategies allows us to analyze the optimal measure and offer strategies to veterinary and public health authorities for making decisions to prevent and control zoonotic VL. Hence, improvements in both public and animal health can be achieved in regions with scenarios similar to that considered in the present study; such scenarios are characteristically found in some areas of Brazil and other countries. PMID- 27471854 TI - Keeping the Beat: A Large Sample Study of Bouncing and Clapping to Music. AB - The vast majority of humans move in time with a musical beat. This behaviour has been mostly studied through finger-tapping synchronization. Here, we evaluate naturalistic synchronization responses to music-bouncing and clapping-in 100 university students. Their ability to match the period of their bounces and claps to those of a metronome and musical clips varying in beat saliency was assessed. In general, clapping was better synchronized with the beat than bouncing, suggesting that the choice of a specific movement type is an important factor to consider in the study of sensorimotor synchronization processes. Performance improved as a function of beat saliency, indicating that beat abstraction plays a significant role in synchronization. Fourteen percent of the population exhibited marked difficulties with matching the beat. Yet, at a group level, poor synchronizers showed similar sensitivity to movement type and beat saliency as normal synchronizers. These results suggest the presence of quantitative rather than qualitative variations when losing the beat. PMID- 27471855 TI - Granular Formation during Apoptosis in Blastocystis sp. Exposed to Metronidazole (MTZ). AB - The role and function of the granular life cycle stage in Blastocystis sp, remains uncertain despite suggestions being made that the granules are metabolic, reproductive and lipid in nature. This present study aims to understand granular formation by triggering apoptosis in Blastocystis sp. by treating them with metronidazole (MTZ). Blastocystis sp.cultures of 4 sub-types namely 1, 2, 3 and 5 when treated with 0.01 and 0.0001 mg/ml of metronidazole (MTZ) respectively showed many of the parasites to be both viable and apoptotic (VA). Treated subtype 3 isolates exhibited the highest number of granular forms i.e. 88% (p<0.001) (0.0001 mg/ml) and 69% (p<0.01) (0.01 mg/ml) respectively at the 72 h in in vitro culture compared to other subtypes. These VA forms showed distinct granules using acridine orange (AO) and 4',6-diamino-2-phenylindole (DAPI) staining with a mean per cell ranging from 5 in ST 5 to as high as 16 in ST 3. These forms showed intact mitochondria in both viable apoptotic (VA) and viable non-apoptotic (VNA) cells with a pattern of accumulation of lipid droplets corresponding to viable cells. Granular VA forms looked ultra-structurally different with prominent presence of mitochondria-like organelle (MLO) and a changed mitochondrial trans-membrane potential with thicker membrane and a highly convoluted inner membrane than the less dense non-viable apoptotic (NVA) cells. This suggests that granular formation during apoptosis is a self-regulatory mechanism to produce higher number of viable cells in response to treatment. This study directs the need to search novel chemotherapeutic approaches by incorporating these findings when developing drugs against the emerging Blastocystis sp. infections. PMID- 27471857 TI - Editors' Note. PMID- 27471856 TI - Evaluation of the uptake and impact of neonatal vitamin A supplementation delivered through the Lady Health Worker programme on neonatal and infant morbidity and mortality in rural Pakistan: an effectiveness trial. AB - BACKGROUND: Despite evidence for the benefits of vitamin A supplementation (VAS) among children 6 to 59 months of age, the feasibility of introduction and potential benefit of VAS in the neonatal period in public health programmes is uncertain. OBJECTIVE: The primary objective was to evaluate the feasibility and effectiveness of early neonatal VAS (single dose of 50 000 international units within 48-72 hours after birth) delivered through the public sector Lady Health Worker (LHW) programme in rural Pakistan and to document its association with a reduction in mortality at 6 months of age. METHODS: A community-based, cluster randomised, placebo-controlled trial was undertaken in two districts of rural Pakistan. LHWs dispensed vitamin A/placebo in identical capsules to newborn infants within 48-72 hours of birth. Follow-up visits were undertaken at 1 week of age and every 4 weeks thereafter until 6 months of age. RESULTS: Of a total of 15 433 consecutive pregnancies among eligible women of reproductive age, 13 225 pregnancies were registered, 12 218 live births identified and 11 028 newborn infants reached by LHWs. Of these, 5380 (49%) received neonatal VAS and 5648 (51%) placebo. The LHWs successfully delivered the capsules to 79% of newborns within 72 hours of birth with no significant adverse effects. Although the proportion of days observed with symptoms of fever, diarrhoea or rapid breathing were lower with neonatal VAS, these differences were not statistically significant. Mortality rates in the two groups were comparable at 6 months of age. CONCLUSIONS: While our study demonstrated that neonatal VAS was safe and could be feasibly delivered by LHWs in Pakistan as part of their early postnatal visits, the overall lack of benefit on neonatal and 6-month morbidity and mortality in our population suggests the need for further evaluation of this intervention in populations at risk. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00674089. PMID- 27471858 TI - CME Statement. PMID- 27471859 TI - Spinal Cord Injury (SCI) 2016 Facts and Figures at a Glance. PMID- 27471860 TI - Development of Solid-State Emissive Materials Based on Multifunctional o Carborane-Pyrene Dyads. AB - The molecular design based on o-carborane dyads is described for preparing multifunctional luminescent molecules such as dual emissions, aggregation and crystallization-induced emission enhancements, and luminescent color changes. The pyrene-substituted o-carborane dyads were synthesized via the insertion reaction between decaborane and 1-ethynylpyrene in the presence of Lewis base in a good yield. Finally, extremely bright luminescent compounds with solid-state emission properties (PhiPL > 0.99) were obtained. PMID- 27471861 TI - Flexible Proton-Gated Oxide Synaptic Transistors on Si Membrane. AB - Ion-conducting materials have received considerable attention for their applications in fuel cells, electrochemical devices, and sensors. Here, flexible indium zinc oxide (InZnO) synaptic transistors with multiple presynaptic inputs gated by proton-conducting phosphorosilicate glass-based electrolyte films are fabricated on ultrathin Si membranes. Transient characteristics of the proton gated InZnO synaptic transistors are investigated, indicating stable proton gating behaviors. Short-term synaptic plasticities are mimicked on the proposed proton-gated synaptic transistors. Furthermore, synaptic integration regulations are mimicked on the proposed synaptic transistor networks. Spiking logic modulations are realized based on the transition between superlinear and sublinear synaptic integration. The multigates coupled flexible proton-gated oxide synaptic transistors may be interesting for neuroinspired platforms with sophisticated spatiotemporal information processing. PMID- 27471862 TI - Highly Tunable Colloidal Perovskite Nanoplatelets through Variable Cation, Metal, and Halide Composition. AB - Colloidal perovskite nanoplatelets are a promising class of semiconductor nanomaterials-exhibiting bright luminescence, tunable and spectrally narrow absorption and emission features, strongly confined excitonic states, and facile colloidal synthesis. Here, we demonstrate the high degree of spectral tunability achievable through variation of the cation, metal, and halide composition as well as nanoplatelet thickness. We synthesize nanoplatelets of the form L2[ABX3]n 1BX4, where L is an organic ligand (octylammonium, butylammonium), A is a monovalent metal or organic molecular cation (cesium, methylammonium, formamidinium), B is a divalent metal cation (lead, tin), X is a halide anion (chloride, bromide, iodide), and n-1 is the number of unit cells in thickness. We show that variation of n, B, and X leads to large changes in the absorption and emission energy, while variation of the A cation leads to only subtle changes but can significantly impact the nanoplatelet stability and photoluminescence quantum yield (with values over 20%). Furthermore, mixed halide nanoplatelets exhibit continuous spectral tunability over a 1.5 eV spectral range, from 2.2 to 3.7 eV. The nanoplatelets have relatively large lateral dimensions (100 nm to 1 MUm), which promote self-assembly into stacked superlattice structures-the periodicity of which can be adjusted based on the nanoplatelet surface ligand length. These results demonstrate the versatility of colloidal perovskite nanoplatelets as a material platform, with tunability extending from the deep-UV, across the visible, into the near-IR. In particular, the tin-containing nanoplatelets represent a significant addition to the small but increasingly important family of lead- and cadmium-free colloidal semiconductors. PMID- 27471863 TI - Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B. AB - The dramatic increase in the prevalence of antibiotic-resistant bacteria has necessitated a search for new antibacterial agents against novel targets. Moiramide B is a natural product, broad-spectrum antibiotic that inhibits the carboxyltransferase component of acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid synthesis. Herein, we report the 2.6 A resolution crystal structure of moiramide B bound to carboxyltransferase. An unanticipated but significant finding was that moiramide B bound as the enol/enolate. Crystallographic studies demonstrate that the (4S)-methyl succinimide moiety interacts with the oxyanion holes of the enzyme, supporting the notion that an anionic enolate is the active form of the antibacterial agent. Structure-activity studies demonstrate that the unsaturated fatty acid tail of moiramide B is needed only for entry into the bacterial cell. These results will allow the design of new antibacterial agents against the bacterial form of carboxyltransferase. PMID- 27471864 TI - Randomized phase III trial of consolidation therapy with bortezomib-lenalidomide Dexamethasone (VRd) vs bortezomib-dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen. PMID- 27471866 TI - Thrombotic microangiopathy during carfilzomib use: case series in Singapore. PMID- 27471865 TI - Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia. AB - The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD. PMID- 27471867 TI - New investigational drugs with single-agent activity in multiple myeloma. AB - The treatment of multiple myeloma (MM) is rapidly evolving. In the United States, four drugs (panobinostat, ixazomib, daratumumab and elotuzumab) were approved for the treatment of MM in 2015. As a result of improved diagnosis and therapy, there has been a dramatic improvement in the outcome of MM in the last decade, probably more than any other malignancy. Numerous agents continue to be studied in preclinical models and in clinical trials, with many demonstrating clinical efficacy that appears promising enough to have a trajectory for regulatory approval. The purpose of this article is to summarize the current data and provide perspective on new investigational agents with promising single-agent activity in MM. The agents reviewed include Isatuximab, an anti-CD38 monoclonal antibody; marizomib, a new proteasome inhibitor; oprozomib, an oral proteasome inhibitor; filanesib (ARRY-520), a kinesin spindle protein inhibitor; dinaciclib, a cyclin-dependent kinase inhibitor; venetoclax (ABT-199), a selective BCL-2 inhibitor; and LGH-447, pan PIM kinase inhibitor. PMID- 27471868 TI - First-line therapy of peripheral T-cell lymphoma: extension and long-term follow up of a study investigating the role of autologous stem cell transplantation. AB - Current guidelines recommend consolidation with autologous stem cell transplantation (autoSCT) after induction chemotherapy for most patients with peripheral T-cell lymphoma (PTCL). This assumption is based on five prospective phase II studies, three of which included <50 patients with limited follow-up. Here we present the final analysis of the prospective German study. The treatment regimen consisted of four to six cycles of CHOP chemotherapy followed by mobilizing therapy and stem cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemo(radio)therapy and autoSCT. From January 2001 to July 2010, 111 patients were enrolled in the study. The main subgroups were PTCL not specified (n=42) and angioimmunoblastic T-cell lymphoma (n=37). Seventy-five (68%) of the 111 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent to-treat analysis, the complete response rate after myeloablative therapy was 59%. The estimated 5-year overall survival, disease-free survival and progression free survival rates were 44%, 54% and 39%, respectively. The results of this study confirm that upfront autoSCT can result in long-term remissions in patients with all major subtypes of PTCL and therefore should be part of first-line therapy whenever possible. PMID- 27471871 TI - A Protocol for the Preparation of 2,5-Diaryl Fulleropyrrolidines: Thermal Reaction of [60]Fullerene with Aromatic Aldehydes and Arylmethanamines. AB - Thermal reaction of [60]fullerene with various arylmethanamines in the presence of aromatic aldehydes under air conditions afforded a series of rare 2,5-diaryl fulleropyrrolidines. Intriguingly, the obtained fulleropyrrolidines exhibited different stereoselectivity. N-unsubstituted arylmethanamines exclusively produced 2,5-diaryl fulleropyrrolidines as cis isomers, while N-substituted arylmethanamines with rare exceptions always gave 2,5-diaryl fulleropyrrolidines as trans isomers. Theoretical calculations at the level of B3LYP/6-31G (d,p) were employed to elucidate the stereoselectivity of N-substituted 2,5-diaryl fulleropyrrolidines as trans isomers by investigating the transition-state structures of different cycloaddition pathways. PMID- 27471869 TI - Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling defined high-risk multiple myeloma. AB - Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance. PMID- 27471870 TI - Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma. AB - We studied 190 patients with smoldering multiple myeloma (SMM) at our institution between 1973 and 2014. Evolving change in monoclonal protein level (eMP) was defined as ?10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ?3 g/dl) and/or ?25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig. Evolving change in hemoglobin (eHb) was defined as ?0.5 g/dl decrease within 12 months of diagnosis. A total of 134 patients (70.5%) progressed to MM over a median follow-up of 10.4 years. On multivariable analysis adjusting for factors known to predict for progression to MM, bone marrow plasma cells ?20% (odds ratio (OR)=3.37 (1.30 8.77), P=0.013), eMP (OR=8.20 (3.19-21.05), P<0.001) and eHb (OR=5.86 (2.12 16.21), P=0.001) were independent predictors of progression within 2 years of SMM diagnosis. A risk model comprising these variables was constructed, with median time to progression of 12.3, 5.1, 2.0 and 1.0 years among patients with 0-3 risk factors respectively. The 2-year progression risk was 81.5% in individuals who demonstrated both eMP and eHb, and 90.5% in those with all three risk factors. PMID- 27471872 TI - A Concise Total Synthesis of Dictyodendrins F, H, and I Using Aryl Ynol Ethers as Key Building Blocks. AB - We report a concise total synthesis of dictyodendrin F and the first total syntheses of dictyodendrins H and I in six steps. In these syntheses, aryl ynol ethers were employed as the key building blocks to introduce aryl and heteroaryl rings in the dictyodendrins. This rapid synthesis utilized a novel hetero-[2 + 2] cycloaddition reaction between two aryl ynol ethers to yield a cyclobutenone ring. The cyclobutenone was sequentially converted into a highly substituted carbazole via a retro-4pi/6pi-electrocyclization-N-acylation cascade reaction to provide the dictyodendrin core. Consecutive intramolecular oxidative coupling and deprotection gave dictyodendrins F, H, and I. PMID- 27471874 TI - Toward Biomarker Development in Large Clinical Cohorts: An Integrated High Throughput 96-Well-Plate-Based Sample Preparation Workflow for Versatile Downstream Proteomic Analyses. AB - We describe a cheap, robust, fast, high-throughput, and flexible proteomic sample processing method based on a regular 96-well plate by acetone precipitation under low centrifuge speed (96PACS), which enables predigestion processing of 96 samples within 2 h. Tested on a complex Huh-7 total lysate, 96PACS produced comparable proteome coverage and even showed better reproducibility than FASP. Quantitative performance of 96PACS was further tested using data-independent acquisition and parallel reaction monitoring quantitation in a set of 6 benchmark samples consisting of 6 serial dilutions of BSA spiked in complex E. coli proteome background. The protocol was also successfully modified for automation and was validated in a comparative label-free proteomic study to develop serum markers for early detection of liver fibrosis and necroinflammation in patients chronically infected with hepatitis B virus. PMID- 27471875 TI - Coracoid Process: The Lighthouse of the Shoulder. AB - The coracoid process is a hook-shaped bone structure projecting anterolaterally from the superior aspect of the scapular neck. Surgeons often refer to the coracoid process as the "lighthouse of the shoulder" given its proximity to major neurovascular structures such as the brachial plexus and the axillary artery and vein, its role in guiding surgical approaches, and its utility as a landmark for other important structures in the shoulder. The coracoid also serves as a critical anchor for many tendinous and ligamentous attachments. These include the tendons of the pectoralis minor, coracobrachialis, and short head of the biceps brachii muscles, and the coracoclavicular, coracohumeral, coracoacromial, and transverse scapular ligaments. Consequently, the coracoid and its associated structures are linked to numerous shoulder pathologic conditions. This article will detail the anatomy of the coracoid and its associated structures and review the clinical and radiologic findings of corresponding pathologic conditions in this region with original illustrations and multimodality imaging examples. Highlighted in this article are the coracoclavicular joint, the classification and management of coracoid fractures, subcoracoid impingement, the coracoacromial arch and subacromial impingement, the coracohumeral ligament and the biceps pulley, the coracoclavicular ligament and its surgical reconstruction, adhesive capsulitis, the suprascapular notch and suprascapular notch impingement, subcoracoid bursitis, coracoid transfer procedures, and coracoid tumors. A brief summary of the pathophysiology, potential causes, and management options for each of the pathologic entities will also be discussed. (c)RSNA, 2016. PMID- 27471873 TI - Image quality of a novel light-emitting diode (LED)-illuminated colonoscope. AB - BACKGROUND AND STUDY AIMS: Light-emitting diodes (LEDs) are used widely for their high luminous efficiency and durability. We developed a novel prototype high definition endoscope with white LEDs and evaluated the image quality it produced against a commercial endoscope with conventional light source. PATIENTS AND METHODS: The specifications of both colonoscopes were identical, except for the LED light source at the tip of the prototype. We examined 20 patients with rectal or sigmoid colon lesions and the image quality was evaluated in 40 images (one image from the LED colonoscope and one from the conventional colonoscope for each lesion) by three endoscopists. We additionally evaluated the 17 videos recorded with the LED colonoscope that were available. Image quality, mucosal and vascular color, and luminous distribution and intensity were scored on a 5-point scale. RESULTS: The mean score for vascular color given by one evaluator was significantly higher using the LED colonoscope than using the conventional colonoscope. The mean scores for mucosal color and luminous intensity from another evaluator were significantly lower with the LED colonoscope than with the conventional colonoscope. There were no significant differences in the luminous distribution scores for any of the evaluators. The image quality of the videos was evaluated as being similar with both colonoscopes. CONCLUSIONS: Image quality from the LED and conventional colonoscopes were similar, although the luminous intensity of the LEDs is inferior to that of the conventional light source at the present time. PMID- 27471876 TI - Impact of CT-apelin and NT-proBNP on identifying non-responders to cardiac resynchronization therapy. AB - CONTEXT: Assessment of response to cardiac resynchronization therapy (CRT) is essential. OBJECTIVE: To assess the predictive value of CT-apelin together with NT-proBNP in patients undergoing CRT. METHODS: Serum CT-apelin and NT-proBNP were measured by ELISA before, and six months after CRT. Primary endpoint was non response (<4% increase in LVEF) after six months. RESULTS: From 81 patients, 15 proved to be non-responders. Six-month CT-apelin was superior compared to NT proBNP in identifying non-responders by multivariate ROC (CT-apelin: p = 0.01, NT proBNP: p = 0.13) and by logistic regression (CT-apelin: p = 0.01, NT-proBNP: p = 0.41) analyses. CONCLUSION: Six-month CT-apelin might be a valuable novel biomarker in identifying non-responders to CRT that was superior to NT-proBNP. PMID- 27471877 TI - Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice. AB - Weight regain frequently follows interventions that reduce body weight, leading to a failure in long-term obesity treatment. Inhibitory proteins of the leptin signaling pathway, such as the suppressor of cytokine signaling 3 (SOCS3), have been studied in conditions that predispose animals to obesity. However, whether SOCS3 modulates postrestriction hyperphagia and weight regain remains unknown. Mice lacking SOCS3 protein specifically in leptin receptor (LepR)-expressing cells (LepR SOCS3 knockout [KO]) were generated and studied in fasting and refeeding conditions. LepR SOCS3 KO mice exhibited increased leptin sensitivity in the hypothalamus. Notably, LepR SOCS3 KO males and females showed attenuated food intake and weight regain after 48 hours of fasting. Postrestriction hyperleptinemia was also prevented in LepR SOCS3 KO mice. Next, we studied possible mechanisms and neural circuits involved in the SOCS3 effects. SOCS3 deletion did not prevent fasting- or refeeding-induced c-Fos expression in the arcuate nucleus of the hypothalamus (ARH) nor fasting-induced increased excitability of ARH LepR-expressing cells. On the other hand, SOCS3 ablation reduced the mRNA levels of hypothalamic orexigenic neuropeptides during fasting (neuropeptide Y, agouti-related protein, orexin, and melanin-concentrating hormone). In summary, our findings suggest that increased leptin sensitivity contributes to the maintenance of a reduced body weight after food deprivation. In addition, the attenuated postrestriction food intake observed in mutant mice was not explained by fasting-induced changes in the activity of ARH neurons but exclusively by a lower transcription of orexigenic neuropeptides during fasting. These results indicate a partial dissociation between the regulation of neuronal activity and gene expression in ARH LepR-expressing cells. PMID- 27471878 TI - Corrigendum: Biocidal activity of chicken defensin-9 against microbial pathogens. PMID- 27471879 TI - The effects of a pedometer-based intervention on first-year university students: A randomized control trial. AB - OBJECTIVES: To assess the effects of a 12-week pedometer-based intervention on the physical activity behavior, health-related quality of life (HRQOL), and psychological well-being of first-year university students. PARTICIPANTS: First year university students (N = 184) were recruited during September 2012 and randomly assigned to an intervention or a control group. METHODS: Intervention participants were provided with a pedometer, monthly tracking logs, and follow-up e-mails. Control participants received no intervention. Physical activity, HRQOL, and psychological well-being were measured at baseline and post intervention. Data were analyzed using multivariate/univariate analysis of variance (MANOVA/ANOVA). RESULTS: All participants experienced an increase in mild physical activity (p < .01) from baseline to follow-up. The intervention failed to produce significant differences between groups for physical activity (p = .28), HRQOL (p = .80), or psychological well-being (p = .72). Psychological well being (p < .001), vigorous physical activity (p = .04), and mental health status (p < .001) decreased across the duration of the study. CONCLUSIONS: More intensive interventions may be required to elicit physical activity behavior change. PMID- 27471880 TI - Corrigendum. PMID- 27471881 TI - The diagnostic importance of the bronchoalveolar lavage in lymphocytic alveolitis. AB - Multidisciplinary concertation is mandatory in order to assess interstitial pneumonias. The study of the bronchoalveolar lavage helps evoking a diagnosis according to the lavage profile. In lymphocytic alveolitis, immunocytochemistry, or in flux cytometry are necessary in order to identify the different clusters of lymphocytes implicated. Our objective was to evaluate the profile of 31 lymphocytic alveolitis using 2 different techniques which are the immunocytochemistry and the in flow cytometry in order to evaluate the efficacy of each technique and to compare the different results to the final diagnoses. We describe a retrospective study about 31 patients admitted to our hospital in order to explore an interstitial pneumonia between January and July 2014. Bronchial endoscopy and bronchoalveolar lavage were performed in all cases. The sensitivity of the in flow cytometry was estimated to 53% and its specificity reached 33%. On the other hand, the immunocytochemistry presented a specificity of 42.8% and a sensitivity of 42.8%. The final diagnoses retained consisted in sarcoidosis in 12 cases, infectious pneumonia in 10 cases, hypersensitivity pneumonia in 3 cases, cryptogenic pneumonia in 3 cases, idiopathic fibrosis in 2 cases, and adenocarcinoma in 1 case. The relevance of both techniques depends on many factors. They necessitate an available material, well-trained technicians, and experimented pathologists. PMID- 27471882 TI - Stump appendicitis 10 years after appendectomy, a rare, but serious complication of appendectomy, a case report. AB - We describe a case of stump appendicitis with the formation of abdominal abscesses in a 41-year-old patient 10 years prior appendectomy. The patient consulted with fever (38.1 degrees C) and abdominal pain, located at the right iliac fossa. Imaging studies showed signs of abscesses, located at the right iliac fossa, without clear origin of these abscesses. The abscesses were drained through diagnostic laparoscopy, no bowel perforation or clear origin of the abscedation was found during laparoscopy. During postoperative stay, the inflammatory parameters rose and the abscesses reoccurred. Re-laparoscopy was performed, the abscesses were drained and on careful inspection and adhesiolysis, a perforated stump appendicitis was revealed, covered underneath layers of fibrous tissue. Stump appendicitis is a rare complication seen after appendectomy and is generally not considered a possible etiology in patients presenting with fever and right iliac fossa abdominal pain with a history of appendectomy. This often delays the correct diagnosis and results in an associated increased incidence of complications. We describe a case of stump appendicitis occurring 10 years after initial appendectomy. PMID- 27471883 TI - First report of two new antioxidative meroterpeno 2H-pyranoids from short-necked yellow-foot clam Paphia malabarica (family: Veneridae) with bioactivity against pro-inflammatory cyclooxygenases and lipoxygenase. AB - Two new meroterpeno 2H-pyranoids were isolated from the EtOAc:MeOH extract of yellow-foot clam Paphia malabarica. The structures of these newly reported compounds were elucidated based on spectroscopic interpretations. This is the first report of biogenic 2H-pyrans bearing decadienyl and allyloxy-(isopentanyl) cyclohexene skeletons from marine biota. The extended C18 sesquiterpenoid with prenylated irregular farnesene framework was characterised as 2-((E)-deca-1,8 dien-10-yl)-11,12-dihydro-13-propyl-2H-pyran (1). The compound 2, 1'-((10E)-10 (10-(pentan-4-yl)-cyclohex-4-enyl)-allyloxy)-tetrahydro-2',2'-dimethyl-2H-pyran represents the first example of naturally occurring C21 prenylated bisabolene type meroterpenoid, whereas tetrahydro-2',2'-dimethyl-2H-pyran remains attached at C-2' position of rearranged bisabolene framework formed by allyloxy linkage. The antioxidant activities (DPPH/ABTS+) of 1 and 2 were comparable (IC50 < 1.0 mg/mL) with alpha-tocopherol. In addition, these compounds exhibited greater activity against cyclooxygenase-2 than COX-1, and the selectivity indices were significantly lesser (~1.1). No significant differences in anti-5-lipoxygenase activity of 1 and 2 (IC50 1.02-1.06 mg/mL) than ibuprofen (IC50 0.93 mg/mL) indicated the potential anti-inflammatory properties of title compounds. PMID- 27471884 TI - Attenuation of Carbon Tetrachloride-Induced Hepatic Toxicity by a Dietary Supplement. AB - Advanced liver disease (ALD) is often characterized with overt malnutrition and liver fibrosis. In this study, a dietary supplement (DS) was first developed, including branch chain amino acids, fat soluble vitamins, zinc, medium chain triglycerides, soy lecithin, L-carnitine, and n-3 polyunsaturated fatty acids. Benefits of DS were then tested using an ALD rat model treated with carbon tetrachloride (CCl4) for 6, 8, and 10 weeks, respectively. Our study showed that CCl4-induced drop of serum albumin and ratio of branch chain to aromatic amino acids were significantly prevented at all three time points. DS also mitigated CCl4-induced elevation of classical liver function markers (alanine aminotransferase, aspartate aminotransferase, and bilirubin) at certain time points, depending on specific liver function markers. Moreover, CCl4-induced liver fibrosis was strongly inhibited at all three time points in a transforming growth factor beta (TGF-beta) independent manner. These findings indicated multi faceted benefits of DS in this animal model, suggesting that it could be a useful adjunctive treatment of ALD in clinic. PMID- 27471885 TI - There's a cream for that: A textual analysis of beauty and body-related advertisements aimed at middle-aged women. AB - This article explores the magazine advertising strategies and tactics used by health and beauty products to target middle-aged women. Advertisements found in the April 2013 issues of Shape, Fitness, and Women's Health were analyzed using intersectionality to determine how these advertisements are presenting messages pertaining to age, gender, and sexuality and how these messages can "other" and marginalize certain identities. The findings suggest that advertisement strategies implement pseudoscience, heteronormativity, hegemonic beauty, and body ideals to establish an idealized version of middle-aged womanhood. PMID- 27471886 TI - Reevaluation of the plant "gemstones": Calcium oxalate crystals sustain photosynthesis under drought conditions. AB - Land plants face the perpetual dilemma of using atmospheric carbon dioxide for photosynthesis and losing water vapors, or saving water and reducing photosynthesis and thus growth. The reason behind this dilemma is that this simultaneous exchange of gases is accomplished through the same minute pores on leaf surfaces, called stomata. In a recent study we provided evidence that pigweed, an aggressive weed, attenuates this problem exploiting large crystals of calcium oxalate as dynamic carbon pools. This plant is able to photosynthesize even under drought conditions, when stomata are closed and water losses are limited, using carbon dioxide from crystal decomposition instead from the atmosphere. Abscisic acid, an alarm signal that causes stomatal closure seems to be implicated in this function and for this reason we named this path "alarm photosynthesis." The so-far "enigmatic," but highly conserved and widespread among plant species calcium oxalate crystals seem to play a crucial role in the survival of plants. PMID- 27471887 TI - Effect of atorvastatin on resolution of chronic subdural hematoma: a prospective observational study [RETRACTED]. AB - OBJECTIVE Chronic subdural hematoma (CSDH) is prevalent in the aged population and is commonly treated with bur hole drainage. This treatment, however, can lead to various surgical complications. Atorvastatin may cure CSDH via its antiinflammatory and proangiogenesis effects, but not all patients treated with this medication can avoid surgery. The authors' aim was to investigate the effect of atorvastatin and identify characteristics of patients with CSDH sensitive to atorvastatin therapy. METHODS A prospective, placebo-controlled observational study was conducted in 80 patients with evidence of CSDH. The patients were enrolled between February 2012 and August 2014 and were randomly assigned to either atorvastatin treatment (atorvastatin group) or placebo (control group). Patients were followed up for 12 months after initiation of treatment. Clinically relevant data were collected and compared between the 2 groups. The atorvastatin group was subdivided into patients who required surgery and those who did not, and characteristics of these subgroups were also compared. The relationship between atorvastatin treatment and need for surgery was investigated by means of multiple regression analysis using the following variables as predictors: age, sex, admission Markwalder grade, level of dependency in activities of daily living (ADL) as assessed with the modified Barthel Index, presence of hemiparesis, and hematoma volume. RESULTS The proportion of patients who required surgical intervention during the follow-up period was significantly lower in the atorvastatin group than in the control group (p = 0.001), and the mean time to surgery was longer in the atorvastatin group (p = 0.018). Within the atorvastatin group, there was a significant difference with respect to Markwalder grades, degree of dependency in ADL, percentage of patients with hemiparesis, and mean hematoma volume between the patients who required surgery during the follow-up period and those who did not (p = 0.002, p = 0.001, p = 0.001, and p = 0.012, respectively). The results of the logistic regression analysis showed that atorvastatin significantly reduced the probability of surgery and that female sex and favorable admission Markwalder grades and favorable dependency status with respect to ADL (independent, slightly dependent, or moderately dependent) were independent predictors of not requiring surgery. CONCLUSIONS Atorvastatin administration can promote the resolution of CSDH, especially for women with favorable Markwalder grades and favorable ADL dependency status at admission. PMID- 27471888 TI - The clinical significance of persistent trigeminal nerve contrast enhancement in patients who undergo repeat radiosurgery. AB - OBJECTIVE Contrast enhancement of the retrogasserian trigeminal nerve on MRI scans frequently develops after radiosurgical ablation for the management of medically refractory trigeminal neuralgia (TN). The authors sought to evaluate the clinical significance of this imaging finding in patients who underwent a second radiosurgical procedure for recurrent TN. METHODS During a 22-year period, 360 patients underwent Gamma Knife stereotactic radiosurgery (SRS) as their first surgical procedure for TN at the authors' center. The authors retrospectively analyzed the data from 59 patients (mean age 72 years, range 33-89 years) who underwent repeat SRS for recurrent pain at a median of 30 months (range 6-146 months) after the first SRS. The isocenter was 4 mm, and the median maximum doses for the first and second procedures were 80 Gy and 70 Gy, respectively. A neuroradiologist and a neurosurgeon blinded to the treated side evaluated the presence of nerve contrast enhancement on MRI series at the time of the repeat procedure. The authors correlated the presence of this imaging change with clinical outcomes. Pain outcomes and development of trigeminal sensory dysfunction were evaluated with the Barrow Neurological Institute (BNI) Pain Scale and BNI Numbness Scale, respectively. The mean length of follow-up after the second SRS was 58 months (95% CI 49-68 months). RESULTS At the time of the repeat SRS, contrast enhancement of the trigeminal nerve on MRI scans was observed in 31 patients (53%). Five years after the SRS, patients with this enhancement had lower actuarial rates of complete pain relief after the repeat SRS (27% [95% CI 7%-47%]) than patients without the enhancement (76% [95% CI 58% 94%]) (p < 0.001). At the 5-year follow-up, patients with the contrast enhancement also had a higher risk for trigeminal sensory loss after repeat SRS (75% [95% CI 59%-91%]) than patients without contrast enhancement (26% [95% CI 10%-42%]) (p = 0.001). Dysesthetic pain after repeat SRS was observed for 8 patients with and for 2 patients without contrast enhancement. CONCLUSIONS Trigeminal nerve contrast enhancement on MRI scans observed at the time of a repeat SRS for TN was associated with less satisfactory pain control and more frequently detected facial sensory loss. Residual contrast enhancement at the time of a repeat SRS may warrant consideration of dose reduction or further separation of the radiosurgical targets. PMID- 27471889 TI - Blunt cerebrovascular injuries in severe traumatic brain injury: incidence, risk factors, and evolution. AB - OBJECTIVE Blunt cerebrovascular injuries (BCVIs) affect approximately 1% of patients with blunt trauma. An antithrombotic or anticoagulation therapy is recommended to prevent the occurrence or recurrence of neurovascular events. This treatment has to be carefully considered after severe traumatic brain injury (TBI), due to the risk of intracranial hemorrhage expansion. Thus, the physician in charge of the patient is confronted with a hemorrhagic and ischemic risk. The main objective of this study was to determine the incidence of BCVI after severe TBI. METHODS The authors conducted a prospective, observational, single-center study including all patients with severe TBI admitted in the trauma center. Diagnosis of BCVI was performed using a 64-channel multidetector CT. Characteristics of the patients, CT scan results, and outcomes were collected. A multivariate logistic regression model was developed to determine the risk factors of BCVI. Patients in whom BCVI was diagnosed were treated with systemic anticoagulation. RESULTS In total, 228 patients with severe TBI who were treated over a period of 7 years were included. The incidence of BCVI was 9.2%. The main risk factors were as follows: motorcycle crash (OR 8.2, 95% CI 1.9-34.8), fracture involving the carotid canal (OR 11.7, 95% CI 1.7-80.9), cervical spine injury (OR 13.5, 95% CI 3.1-59.4), thoracic trauma (OR 7.3, 95% CI 1.1-51.2), and hepatic lesion (OR 13.3, 95% CI 2.1-84.5). Among survivors, 82% of patients with BCVI received systemic anticoagulation therapy, beginning at a median of Day 1.5. The overall stroke rate was 19%. One patient had an intracranial hemorrhagic complication. CONCLUSIONS Blunt cerebrovascular injuries are frequent after severe TBI (incidence 9.2%). The main risk factors are high-velocity lesions and injuries near cervical arteries. PMID- 27471890 TI - Erratum: Interpretation of the causes of instability of flash visual evoked potentials in intraoperative monitoring and proposal of a recording method for reliable functional monitoring of visual evoked potentials using a light-emitting device. PMID- 27471891 TI - Stereotactic radiosurgery for recurrent vestibular schwannoma after previous resection. AB - OBJECTIVE The goal of this retrospective cohort study was to assess long-term outcomes in patients with vestibular schwannoma (VS) who underwent stereotactic radiosurgery (SRS) after initial microsurgical resection. METHODS From the authors' database of 1770 patients with VS, the authors retrospectively analyzed data from 173 Gamma Knife SRS procedures for VS after 1 (128 procedures) or multiple (45 procedures) microsurgical resections. The median length of the interval between the last resection and SRS was 42 months (range 2-329 months). The median length of clinical follow-up was 74 months (range 6-285 months). Progression-free survival after SRS was determined with Kaplan-Meier analysis. RESULTS At the time of SRS, the hearing of 161 patients (93%) was Gardner Robertson Class V, and 81 patients (47%) had facial neuropathy (i.e., facial function with House-Brackmann [HB] grades of III-VI), 87 (50%) had trigeminal neuropathy, and 71 (41%) reported imbalance or disequilibrium disorders. The median tumor volume was 2.7 cm3 (range 0.2-21.6 cm3), and the median dose to the tumor margin was 13 Gy (range 11-20 Gy). Radiosurgery controlled growth of 163 (94%) tumors. Progression-free survival after SRS was 97% at 3 years, 95% at 5 years, and 90% at 10 years. Four patients with delayed tumor progression underwent repeat SRS at a median of 35 months (range 23-64 months) after the first SRS. Four patients (2.3%) with tumor progression underwent repeat resection at a median of 25 months (range 19-33 months). Among the patients with any facial dysfunction (indicated by HB grades of II-VI), 19% had improvement in this condition after SRS, and 5.5% with some facial function (indicated by HB grades of I-V) developed more facial weakness. Among patients with trigeminal neuropathy, 20% had improvement in this condition, and 5.8% developed or had worsened trigeminal neuropathy after SRS. CONCLUSIONS Stereotactic radiosurgery offered a safe and effective long-term management strategy for VS patients whose tumors remained or recurred after initial microsurgery. PMID- 27471892 TI - Direct versus indirect revascularization procedures for moyamoya disease: a comparative effectiveness study. AB - OBJECTIVE Moyamoya disease (MMD) is a chronic cerebrovascular disease that can lead to devastating neurological outcomes. Surgical intervention is the definitive treatment, with direct, indirect, and combined revascularization procedures currently employed by surgeons. The optimal surgical approach, however, remains unclear. In this decision analysis, the authors compared the effectiveness of revascularization procedures in both adult and pediatric patients with MMD. METHODS A comprehensive literature search was performed for studies of MMD. Using complication and success rates from the literature, the authors constructed a decision analysis model for treatment using a direct and indirect revascularization technique. Utility values for the various outcomes and complications were extracted from the literature examining preferences in similar clinical conditions. Sensitivity analysis was performed. RESULTS A structured literature search yielded 33 studies involving 4197 cases. Cases were divided into adult and pediatric populations. These were further subdivided into 3 different treatment groups: indirect, direct, and combined revascularization procedures. In the pediatric population at 5- and 10-year follow-up, there was no significant difference between indirect and combination procedures, but both were superior to direct revascularization. In adults at 4-year follow-up, indirect was superior to direct revascularization. CONCLUSIONS In the absence of factors that dictate a specific approach, the present decision analysis suggests that direct revascularization procedures are inferior in terms of quality-adjusted life years in both adults at 4 years and children at 5 and 10 years postoperatively, respectively. These findings were statistically significant (p < 0.001 in all cases), suggesting that indirect and combination procedures may offer optimal results at long-term follow-up. PMID- 27471893 TI - Editorial: Direct versus indirect bypass for moyamoya disease: ongoing controversy. PMID- 27471894 TI - Letter to the Editor: Comparison between surgery and Gamma Knife radiosurgery for brain AVMs. PMID- 27471896 TI - Editorial: Effect of atorvastatin. PMID- 27471895 TI - Endoscopic versus microscopic microvascular decompression for trigeminal neuralgia: equivalent pain outcomes with possibly decreased postoperative headache after endoscopic surgery. AB - OBJECTIVE Endoscopic surgery has revolutionized surgery of the ventral skull base but has not yet been widely adopted for use in the cerebellopontine angle. Given the relatively normal anatomy of the cerebellopontine angle in patients with trigeminal neuralgia (TN), the authors hypothesized that a fully endoscopic microvascular decompression (E-MVD) might provide pain outcomes equivalent to those of microscopic MVD (M-MVD) but with fewer complications. METHODS The authors conducted a single-institution, single-surgeon retrospective study with patients treated in the period of 2006-2013. Before surgery, all patients completed a questionnaire that included a validated multidimensional pain-outcome tool, the Penn Facial Pain Scale (PFPS, formerly known as Brief Pain Inventory Facial), an 11-point scale that measures pain intensity, interference with general activities of daily living (ADLs), and facial-specific ADLs. Using a standardized script, independent research assistants conducted follow-up telephone interviews. RESULTS In total, 167 patients were available for follow ups (66.5% female; 93 patients underwent M-MVD and 74 underwent E-MVD). Preoperative characteristics (i.e., TN classification, PFPS components, and medication use) were similar for the 2 surgical groups except for 2 variables. Patients in the M-MVD group had slightly higher incidence of V3 pain, and the 2 groups differed in the date of surgery and hence in the length of follow-up (2.4 years for the M-MVD group and 1.3 years for the E-MVD group, p < 0.05). There was a trend toward not finding neurovascular conflict at the time of surgery more frequently in the M-MVD than in the E-MVD group (11% vs 7%, p = 0.052). Internal neurolysis was more often performed in the E-MVD group (26% vs 7%, p = 0.001). The 2 groups did not significantly differ in the length of the MVD procedure (approximately 2 hours). Self-reported headaches at 1 month postoperatively were present in 21% of the patients in the M-MVD group versus 7% in the E-MVD group (p = 0.01). Pain outcomes at the most recent followup were equivalent, with patients reporting a 5- to 6-point (70%-80%) improvement in pain intensity, a 5-point (85%) improvement in pain interference with ADLs, and a 6-point (85%) improvement in interference with facial-specific ADLs. Actuarial freedom from pain recurrence was equivalent in the 2 groups, with 80% pain control at 3 years. CONCLUSIONS Both the fully endoscopic MVD and the conventional M-MVD appear to provide patients with equivalent pain outcomes. Complication rates were also similar between the groups, with the exception of the rate of headaches, which was significantly lower in the E-MVD group 1 month postoperatively. PMID- 27471897 TI - Transcranial Doppler sonography during acute 80 degrees head-down tilt (HOT) for the assessment of cerebral autoregulation in humans. AB - Cerebrovascular hemodynamics during postural changes have been sparsely Investigated despite the fact that abnormal responses may contribute to the risk of stroke. The aim of this study was to determine the effect of acute 80 degrees head-down tilt (HDT) on cerebrovascular hemodynamics in humans using transcranial Doppler sonography (TCD). In 13 healthy volunteers (2 female, 7 1 male, age 19-37 years, mean age 26.8 years) left midcerebral artery blood flow velocities (CBFVs) were continuously monitored using TCD during 180 sec in horizontal position and during 60 sec of 80 degrees HDT. Simultaneously, systolic, diastolic, mean CBFVs, pulsatility index (PI), heart rate, beat-to-beat blood pressure (BP) and transcutaneous pC02 were measured. In five volunteers, the procedure was repeated the next day to test the repeatability of the results. Mean BP increased slightly, but not significantly during tilt (from 80.5+/- 7.7 mmHg to 85.9 +/ 14.1 mmHg; p < 0.05). Heart rate decreased significantly during the first 20sec of HDT (from 66.8+/- 9.9 min-1 to 60+/- 11 min-1; p> 0.05). Transcutaneous pC02 was within physiological ranges during the whole procedure (mean pC02 minimum 39.5+/-2.9 mmHg, mean pC02 maximum 42.2+/-3.3 mmHg). Mean CBFV did not change significantly during tilt (from 70.1 +/- 7 9.1 cm sec-1 to 66.6 +/- 14.1 cm sec 1; p < 0.05). PI, however, increased significantly with a more pronounced increase during the first 20 sec than the last 40sec of tilt (Plsupine 0.92+/ 0.11; Pltnt(0-20sec) 1.15+/-0.18; Pltnt(2i~6o sec) 1-03+/-0.16; p = 0.001; p = 0.017). The HDT results were found to be reproducible in the five volunteers. During 80 degrees -HDT mean BP and pC02 did not change significantly. This observation combined with the significant decrease in heart rate during the first 20 sec of HDT, suggests that there is no sympathetic activation. The significant PI increase during HDT indicates a vasoconstriction of the cerebral resistance vessels. We assume that this vasoconstriction is due to the myogenic mechanism of cerebrovascular autoregulation triggered by a rapid, passive intracranial blood volume influx during HDT. [Neurol Res 1999; 21: 457-462]. PMID- 27471898 TI - Therapeutic collaboration and the assimilation of problematic experiences in emotion-focused therapy for depression: Comparison of two cases. AB - OBJECTIVE: The Assimilation model argues that therapists should work responsively within the client's therapeutic zone of proximal development (TZPD). This study analyzed the association between the collaborative processes assessed by the Therapeutic Collaboration Coding System (TCCS) and advances in assimilation, as assessed by the Assimilation of Problematic Experiences Scale (APES). METHOD: Sessions 1, 4, 8, 12, and 16 of two contrasting cases, Julia and Afonso (pseudonyms), drawn from a clinical trial of 16-sessions emotion-focused therapy (EFT) for depression, were coded according to the APES and the TCCS. Julia met criteria for reliable and clinically significant improvement, whereas Afonso did not. RESULTS: As expected, Julia advanced farther along the APES than did Afonso. Both therapists worked mainly within their client's TZPD. However, Julia's therapist used a balance of supporting and challenging interventions, whereas Afonso's therapist used mainly supporting interventions. Setbacks were common in both cases. CONCLUSIONS: This study supports the theoretical expectation that EFT therapists work mainly within their client's TZPD. Therapeutic exchanges involving challenging interventions may foster client change if they occur in an overall climate of safety. PMID- 27471899 TI - Trabeculectomy with or without Anterior Chamber Maintainer: A Study on Intraocular Pressure, Endothelial Cells, and Central Corneal Thickness. AB - PURPOSE: To compare the impact of trabeculectomy and trabeculectomy with an anterior chamber (AC) maintainer on intraocular pressure (IOP), endothelial cell density (ECD), and central corneal thickness (CCT) in patients with primary open angle glaucoma (POAG). METHODS: The two groups consisted of 36 (trabeculectomy, Group A) and 42 (trabeculectomy with AC maintainer, Group B) patients with POAG. IOP, CCT, and ECD were measured one day prior to surgery, one month, six months, and 12 months postoperatively. RESULTS: No complications were observed. The mean decrease of mean IOP from baseline to 12 months was statistically significant for both groups (all p < 0.0001), but more significant in Group B (p = 0.01). ECD decrease was significant in both Groups (all p < 0.01), but more significant in Group A (p < 0.0001). CCT decrease was also greater in Group A (p < 0.0001). The surgical procedure's duration was significantly longer in Group B than in Group A (p < 0.0001). CONCLUSIONS: Both techniques seem to be effective and safe options for patients with POAG. Using an AC maintainer might add some safety for the ECD and a bit greater IOP reduction; however, the classic technique, which is of less complexity and less time-consuming, has comparable results. PMID- 27471900 TI - Management of Spinal Deformity in Adult Patients With Neuromuscular Disease. AB - A wide range of neuromuscular diseases, including Parkinson disease, cerebral palsy, multiple sclerosis, and myopathy, are associated with spinal deformities. The most common postural deformities include anterocollis, Pisa syndrome (pleurothotonus), scoliosis, and camptocormia. Nonsurgical management of spinal deformity in patients with neuromuscular disease centers on maximizing the medical management of the underlying neurodegenerative pathology before surgical intervention is contemplated. Surgical management can include decompression alone, or decompression and fusion with short or long fusion constructs. Patients with neuromuscular disease are susceptible to postoperative medical complications, such as delirium, epidural hematomas, pulmonary emboli, and cardiac events. Compared with outcomes in the typical patient with spinal deformity, postoperative outcomes in patients with neuromuscular disease have higher rates of surgical complications, such as instrumentation failure, proximal junctional kyphosis, loss of correction, and the need for revision surgery, regardless of the magnitude of surgical treatment. PMID- 27471901 TI - Prevalence of Obesity in Patients With Legg-Calve-Perthes Disease. AB - INTRODUCTION: Children with Legg-Calve-Perthes disease classically have been described as thin, small, and socioeconomically disadvantaged. Despite the obesity epidemic, no study has determined the prevalence of obesity in this patient population and its effect on treatment. METHODS: This is a retrospective study of 150 patients (172 hips) with Legg-Calve-Perthes disease seen between 2009 and 2014. Patients were grouped based on body mass index at the initial visit. This cohort was analyzed on the basis of the treatment received and socioeconomic status. RESULTS: Of 150 patients with Legg-Calve-Perthes disease, 16% were overweight and 32% were obese. Patients who were obese had a 2.8 lower likelihood of receiving a bony operation (confidence interval: 1.1 to 7.7). Obesity in patients with the disease was associated with later Waldenstrom stage at presentation (P = 0.003), lower median household income by zip code (P < 0.001), and greater use of government-funded health insurance (P < 0.001). DISCUSSION: Obesity is common in patients with Legg-Calve-Perthes disease and is associated with a later stage of disease presentation. LEVEL OF EVIDENCE: Level III. PMID- 27471902 TI - Celebrating the Yellow Journal. PMID- 27471904 TI - Neuropsychological functioning and health-related quality of life in pediatric liver disease: the sum of our perspectives is greater than each alone. AB - PURPOSE OF REVIEW: The review will discuss current data on neuropsychological and health-related quality of life (HRQOL) outcomes in children with liver disease. Research has trickled in over the past 30 years, mostly in small, single-center studies with observational or retrospective design. As medical treatment has advanced, survival has improved dramatically, with the majority now living into adulthood. The focus is shifting toward more systematic exploration of functional outcomes. RECENT FINDINGS: Contemporary cohorts provide evidence for increased prevalence of IQ deficits despite overall average means in children with end stage liver disease and long after transplant. Recent studies explore specific neurocognitive domains and populations, such as pediatric acute liver failure and metabolic disorders. HRQOL is reduced in pediatric liver transplant recipients, even years later. Current research examines HRQOL in pediatric acute liver failure, infants with chronic liver disease, and specific diseases. A major psychosocial concern is the transition from pediatric to adult care, and the challenges in assessing transfer readiness. SUMMARY: As research in functional outcomes becomes more sophisticated (more prospective, controlled, and multisite studies), richer data are available. The most comprehensive understanding of how children with liver disease fare is achieved by integrating perspectives into one picture painted by many. PMID- 27471903 TI - Central oxytocin receptor stimulation attenuates the orexigenic effects of butorphanol tartrate. AB - Butorphanol tartrate (BT), a mixed u/kappa/delta opioid receptor agonist, is one of the most potent orexigens known to date. The central mechanisms through which BT causes hyperphagia are largely unknown. Interestingly, BT suppresses meal-end activation of neurons synthesizing anorexigenic neuropeptide, oxytocin (OT), which suggests that BT promotes hyperphagia by silencing OT-derived satiety signaling. As OT terminates consumption by acting by distinct hindbrain and forebrain circuits, we investigated whether stimulation of the OT receptor in the forebrain or the hindbrain [through lateral ventricular (LV) and fourth ventricular (4V) OT injections] leads to termination of food intake induced by BT. We established effective doses of BT on chow intake in ad-libitum-fed and overnight-deprived rats as well as effective doses of LV and 4V OT in deprived animals. Then, we determined doses of LV and 4V OT that reduce hyperphagia produced by BT in sated and deprived rats. Finally, we assessed whether OT's effects on BT-induced feeding can be suppressed by an OT receptor antagonist. 4 mg/kg BT increased intake in ad-libitum-fed and overnight-deprived rats, whereas LV and 4V OT at 1 MUg caused a decrease in deprived rats. BT-induced chow intake in hungry and sated animals was suppressed by a very low, 0.1 MUg dose of 4V OT, whereas 1 MUg OT was effective LV. The effect of OT was attenuated by OT receptor antagonist, L-368 899. Reduced activity of the OT circuit, especially its hindbrain component, is a critical factor in shaping the magnitude of consumption in response to BT treatment. PMID- 27471905 TI - The hand that 'sees' to grasp. AB - New findings advance our understanding of how vision is used to guide the hand during object grasping. PMID- 27471906 TI - An Approach for Determining the Absolute Configuration of C-2 in 2-Oxygenated Phenylethanoid Glycosides by (1)H NMR Spectroscopy. AB - The absolute configurations of 2-oxygenated phenylethanoid glycosides were conveniently determined by (1)H NMR spectroscopy. A comparison of the chemical shift differences (Deltadelta) of the diastereotopic methylene protons (H-1) demonstrate that a large chemical shift difference corresponds to an R configuration and a small chemical shift difference indicates S for the 2-alkoxy form. However, the situation is contrary to that of the 2-hydroxy form. Furthermore, the mechanism underlying this result is discussed based on the visualized conformations of such compounds. PMID- 27471907 TI - Water-Soluble Nonconjugated Polymer Nanoparticles with Strong Fluorescence Emission for Selective and Sensitive Detection of Nitro-Explosive Picric Acid in Aqueous Medium. AB - Water-soluble nonconjugated polymer nanoparticles (PNPs) with strong fluorescence emission were prepared from hyperbranched poly(ethylenimine) (PEI) and d-glucose via Schiff base reaction and self-assembly in aqueous phase. Preparation of the PEI-d-glucose (PEI-G) PNPs was facile (one-pot reaction) and environmentally friendly under mild conditions. Also, PEI-G PNPs showed a high fluorescence quantum yield in aqueous solution, and the fluorescence properties (such as concentration- and solvent-dependent fluorescence) and origin of intrinsic fluorescence were investigated and discussed. PEI-G PNPs were then used to develop a fluorescent probe for fast, selective, and sensitive detection of nitro explosive picric acid (PA) in aqueous medium, because the fluorescence can be easily quenched by PA whereas other nitro-explosives and structurally similar compounds only caused negligible quenching. A wide linear range (0.05-70 MUM) and a low detection limit (26 nM) were obtained. The fluorescence quenching mechanism was carefully explored, and it was due to a combined effect of electron transfer, resonance energy transfer, and inner filter effect between PA and PEI-G PNPs, which resulted in good selectivity and sensitivity for PA. Finally, the developed sensor was successfully applied to detection of PA in environmental water samples. PMID- 27471908 TI - Frequency Scale Factors for Some Double-Hybrid Density Functional Theory Procedures: Accurate Thermochemical Components for High-Level Composite Protocols. AB - In the present study, we have obtained geometries and frequency scale factors for a number of double-hybrid density functional theory (DH-DFT) procedures. We have evaluated their performance for obtaining thermochemical quantities [zero-point vibrational energies (ZPVE) and thermal corrections for 298 K enthalpies (DeltaH298) and 298 K entropies (S298)] to be used within high-level composite protocols (using the W2X procedure as a probe). We find that, in comparison with the previously prescribed protocol for optimization and frequency calculations (B3-LYP/cc-pVTZ+d), the use of contemporary DH-DFT methods such as DuT-D3 and DSD type procedures leads to a slight overall improved performance compared with B3 LYP. A major strength of this approach, however, lies in the better robustness of the DH-DFT methods in that the largest deviations are notably smaller than those for B3-LYP. In general, the specific choices of the DH-DFT procedure and the associated basis set do not drastically change the performance. Nonetheless, we find that the DSD-PBE-P86/aug'-cc-pVTZ+d combination has a very slight edge over the others that we have examined, and we recommend its general use for geometry optimization and vibrational frequency calculations, in particular within high level composite methods such as the higher-level members of the WnX series of protocols. The scale factors determined for DSD-PBE-P86/aug'-cc-pVTZ+d are 0.9830 (ZPVE), 0.9876 (DeltaH298), and 0.9923 (S298). PMID- 27471909 TI - Bottom-up Approach Design, Band Structure, and Lithium Storage Properties of Atomically Thin gamma-FeOOH Nanosheets. AB - As a novel class of soft matter, two-dimensional (2D) atomic nanosheet-like crystals have attracted much attention for energy storage devices due to the fact that nearly all of the atoms can be exposed to the electrolyte and involved in redox reactions. Herein, atomically thin gamma-FeOOH nanosheets with a thickness of ~1.5 nm are synthesized in a high yield, and the band and electronic structures of the gamma-FeOOH nanosheet are revealed using density-functional theory calculations for the first time. The rationally designed gamma-FeOOH@rGO composites with a heterostacking structure are used as an anode material for lithium-ion batteries (LIBs). A high reversible capacity over 850 mAh g(-1) after 100 cycles at 200 mA g(-1) is obtained with excellent rate capability. The remarkable performance is attributed to the ultrathin nature of gamma-FeOOH nanosheets and 2D heterostacking structure, which provide the minimized Li(+) diffusion length and buffer zone for volume change. Further investigation on the Li storage electrochemical mechanism of gamma-FeOOH@rGO indicates that the charge discharge processes include both conversion reaction and capacitive behavior. This synergistic effect of conversion reaction and capacitive behavior originating from 2D heterostacking structure casts new light on the development of high-energy anode materials. PMID- 27471910 TI - Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor. AB - The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described. PMID- 27471911 TI - Pilot plant test of the advanced flash stripper for CO2 capture. AB - Alternative stripping processes have been proposed to reduce energy use for CO2 capture, but only a few have been applied to pilot-scale experiments. This paper presents the first pilot plant test results of one of the most promising stripper configurations, the advanced flash stripper with cold and warm rich solvent bypass. The campaign using aqueous piperazine was carried out at UT Austin in 2015. The advanced flash stripper improves the heat duty by over 25% compared to previous campaigns using the two-stage flash, achieving 2.1 GJ per tonne CO2 of heat duty and 32 kJ mol-1 CO2 of total equivalent work. The bypass control strategy proposed minimized the heat duty. The test successfully demonstrated the remarkable energy performance and the operability of this advanced system. An Aspen Plus(r) model was validated using the pilot plant data and used to explore optimum operating and design conditions. The irreversibility analysis showed that the pilot plant performance has attained 50% thermodynamic efficiency and further energy improvement should focus on the absorber and the cross exchanger by increasing absorption rate and solvent capacity. PMID- 27471912 TI - Intersection of Chemokine and TSH Receptor Pathways in Human Fibrocytes: Emergence of CXCL-12/CXCR4 Cross Talk Potentially Relevant to Thyroid-Associated Ophthalmopathy. AB - Fibrocytes are monocyte progenitor cells that have been implicated in normal and pathological tissue remodeling. Among the prominent chemokine receptors expressed by these cells is CXC motif receptor 4 (CXCR4), which, with its cognate ligand CXCL motif ligand 12 (CXCL-12), directs fibrocytes to sites of fibrosis. Fibrocytes have been implicated in the pathogenesis of thyroid-associated ophthalmopathy, the ocular manifestation of Graves' disease (GD), by virtue of their unique accumulation as CD34+ orbital fibroblasts (OFs). Fibrocytes also express high levels of functional TSH receptor (TSHR). Here, we determined CXCL 12 and CXCR4 expression in fibrocytes and GD-OF and whether that pathway interacts with TSHR. CXCL-12 is highly expressed in GD-OF, whereas CXCR4 levels are dramatically higher in fibrocytes. Levels of these proteins are differentially regulated by TSH in a cell type-specific manner. Further, CXCL-12 enhances the induction by TSH of IL-6 in fibrocytes but attenuates this induction in GD-OF. In contrast, in pure CD34+ OF, the interplay between TSH and CXCL-12 reverts to that observed in fibrocytes. Our results indicate that CXCL-12 enhances TSH actions in fibrocytes but inhibits them in GD-OF, a dichotomy imposed by factors emanating from CD34- OF. They also suggest a potentially important modulatory role for CD34- OF in determining the factors that influence pathological TSHR signaling in the TAO orbit. PMID- 27471913 TI - Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators. AB - The implication of iron in the pathophysiology of colorectal cancer is documented at both the biochemical and epidemiological levels. Iron chelators are therefore useful molecular tools for the study and potential treatment of this type of cancer characterized by high incidence and mortality rates. We report a novel prochelation strategy that utilizes a disulfide redox switch to connect a thiosemicarbazone iron-binding unit with carbohydrate moieties targeting the increased expression of glucose transporters in colorectal cancer cells. We synthesized three glycoconjugates (GA2TC4, G6TC4, and M6TC4) with different connectivity and/or carbohydrate moieties, as well as an aglycone analog (ATC4). The sugar conjugates present increased solubility in neutral aqueous solutions, and the ester-linked conjugates M6TC4 and G6TC4 compete as effectively as d glucose for transporter-mediated cellular uptake. The glycoconjugates show improved selectivity compared to the aglycone analog and are 6-11 times more toxic in Caco-2 colorectal adenocarcinoma cells than in normal CCD18-co colon fibroblasts. PMID- 27471914 TI - The Competing Mechanisms of Phosphate Monoester Dianion Hydrolysis. AB - Despite the numerous experimental and theoretical studies on phosphate monoester hydrolysis, significant questions remain concerning the mechanistic details of these biologically critical reactions. In the present work we construct a linear free energy relationship for phosphate monoester hydrolysis to explore the effect of modulating leaving group pKa on the competition between solvent- and substrate assisted pathways for the hydrolysis of these compounds. Through detailed comparative electronic-structure studies of methyl phosphate and a series of substituted aryl phosphate monoesters, we demonstrate that the preferred mechanism is dependent on the nature of the leaving group. For good leaving groups, a strong preference is observed for a more dissociative solvent-assisted pathway. However, the energy difference between the two pathways gradually reduces as the leaving group pKa increases and creates mechanistic ambiguity for reactions involving relatively poor alkoxy leaving groups. Our calculations show that the transition-state structures vary smoothly across the range of pKas studied and that the pathways remain discrete mechanistic alternatives. Therefore, while not impossible, a biological catalyst would have to surmount a significantly higher activation barrier to facilitate a substrate-assisted pathway than for the solvent-assisted pathway when phosphate is bonded to good leaving groups. For poor leaving groups, this intrinsic preference disappears. PMID- 27471915 TI - Life Cycle Greenhouse Gas Emissions from Uranium Mining and Milling in Canada. AB - Life cycle greenhouse gas (GHG) emissions from the production of nuclear power (in g CO2e/kWh) are uncertain due partly to a paucity of data on emissions from individual phases of the nuclear fuel cycle. Here, we present the first comprehensive life cycle assessment of GHG emissions produced from the mining and milling of uranium in Canada. The study includes data from 2006-2013 for two uranium mine-mill operations in northern Saskatchewan (SK) and data from 1995 2010 for a third SK mine-mill operation. The mine-mill operations were determined to have GHG emissions intensities of 81, 64, and 34 kg CO2e/kg U3O8 at average ore grades of 0.74%, 1.54%, and 4.53% U3O8, respectively. The production-weighted average GHG emission intensity is 42 kg CO2e/kg U3O8 at an average ore grade of 3.81% U3O8. The production-weighted average GHG emission intensity drops to 24 kg CO2e/kg U3O8 when the local hydroelectric GHG emission factor (7.2 g CO2e/kWh) is substituted for the SK grid-average electricity GHG emission factor (768 g CO2e/kWh). This results in Canadian uranium mining-milling contributing only 1.1 g CO2e/kWh to total life cycle GHG emissions from the nuclear fuel cycle (0.7 g CO2e/kWh using the local hydroelectric emission factor). PMID- 27471916 TI - Lignicolous fungi hydrodistilled extracts may represent a promising source of natural phenolics. AB - In vitro evaluation of total phenolic contents and antiradical activities of the lignicolous fungi Fomes fomentarius and Schizophyllum commune hydrodistilled extracts was the subject of this study. This preliminary screening included four free radical species evaluated by UV-vis (DPPH*, ABTS* and *NO) and EPR (Asc*), respectively. According to the experimental data obtained, both F. fomentarius and S. commune hydrodistilled extracts may be considered as promising sources of phenolic natural products (157 and 138 mg GAE/g d.e., respectively) and other bioactives showing good anti-DPPH (1.31 MUg/mL) and anti-Asc (70.40%) radical activities, respectively, at in vitro conditions. PMID- 27471917 TI - Middle cerebral artery blood flow velocity, end-tidal pC02 and blood pressure in patients with obstructive sleep apnea and in healthy subjects during continuous positive airway pressure breathing. AB - There is conflicting evidence in the literature as to the potential effect of continuous positive airway pressure (CPAP) on cerebral perfusion. Compromising cerebral perfusion could possibly outweigh the benefit of improved oxygenation. Patients with the obstructive sleep apnea syndrome (OSAS) have been claimed to have a higher cerebrovascular reactivity to changes in end-tidal pC02. In this study, we investigated 23 patients with OSAS and 7 6 healthy young adults in the waking state. Both groups performed a series of lOmin of normal breathing, 20min with 9 cmH20 nasal CPAP, and then TOmin of normal breathing while wearing a nasal CPAP mask. The following parameters were assessed: bilateral transcranial Doppler signal of the middle cerebral artery, systolic and diastolic blood pressure assessed manually, and cerebrovascular reactivity to changes in pC02 during hyperventilation and rebreathing into an airbag. Continuous end-tidal pC02 measurements were performed in 74 subjects. As compared with normal breathing middle cerebral artery blood flow velocity and pC02 remained unchanged during CPAP. Systolic and diastolic blood pressure increased slightly by 1.2mmHg (p = 0.015) and 1.1 mmHg (p = 0.007), respectively. Cerebrovascular reactivity did not differ in the two groups. Nasal CPAP of 9 cmH20 is a safe treatment with respect to the maintenance of cerebral blood flow. Our study gives further evidence for the autoregulation's capacity to maintain cerebral blood flow velocity constant during different levels of intrathoracic pressure and different cerebral perfusion pressures. We could not demonstrate any difference in cerebrovascular reactivity between patients with OSAS and healthy persons. [Neurol Res 1999; 21: 737-741]. PMID- 27471918 TI - In-hospital contact investigation among health care workers after exposure to pulmonary tuberculosis in an intermediate tuberculosis prevalence area: A prospective study. AB - We carried out in-hospital contact investigations of patients with pulmonary tuberculosis and analyzed the prevalence of latent tuberculosis infection (LTBI) among health care workers (HCWs) after TB exposure. A prospective study was conducted of 872 HCWs who were exposed to 55 index cases diagnosed with active pulmonary TB. HCWs after TB exposure were evaluated both TST and chest X-ray at the time of enrollment and 12 weeks after exposure; 625 HCWs (71.6%) underwent both initial assessments; 41 HCWs (6.6%) had a positive TST result. After 12 weeks, 71.1% of HCWs with initial negative TST (n = 415) underwent a second assessment. Ten HCWs had TST conversion. One HCW (0.2%) developed active pulmonary TB. In multivariable analysis, age over 30 years was associated with TST conversion (p = .02). Point prevalence of latent TB was 6.6%, and incidence of LTBI was estimated as 2.4 per 100 HCWs. Strict infection control measures should be emphasized in intermediate TB-burden, BCG-vaccinated countries, especially in HCWs with high risk for TB exposure. PMID- 27471919 TI - Energy Drink Consumption and Cardiac Complications: A Case for Caution. AB - We present a case of atrial fibrillation with rapid ventricular response in a 28 year-old previously healthy man in the context of daily consumption of 2 Monster energy drinks and 2 to 3 beers. We have obtained consent from this patient to present his case. Our observation adds to the developing literature describing an association between highly caffeinated drinks and adverse cardiovascular events. The previous cases in the literature and the proposed underlying mechanisms of this association are briefly discussed in this article. With the rising popularity of energy drinks, clinicians should be aware of their arrhythmogenic potential and consider screening for these products in patients who present with otherwise unexplained arrhythmias. PMID- 27471920 TI - When Added to Opioid Agonist Treatment, Psychosocial Interventions do not Further Reduce the Use of Illicit Opioids: A Comment on Dugosh et al. AB - This commentary reviews the limitations of the recent literature review by that examined the role of psychosocial interventions with medication for opioid addiction treatment. The commonly held belief that opioid agonist treatment alone is inferior treatment to such treatment combined with 'psychosocial' treatment (which many will understand to mean counseling) is not supported by the research evidence and it results in limitations on the use of these effective medications. PMID- 27471921 TI - Response to Schwartz Commentary on Dugosh et al. PMID- 27471922 TI - Statistics Failures Make Lawyer Addiction Estimates Worthless. PMID- 27471924 TI - Society News: ASAM Magazine. PMID- 27471923 TI - Author's Response to Statistics Failures Make Lawyer Addiction Estimates Worthless. PMID- 27471925 TI - Heat shock proteins in the context of photodynamic therapy: autophagy, apoptosis and immunogenic cell death. AB - Photodynamic therapy (PDT) is an anti-tumor treatment administered for the elimination of early-stage malignancies and the palliation of symptoms in patients with late-stage tumors, which involves the activation of a photosensitizer (PS) using light of a specific wavelength, which also generates singlet oxygen and other reactive oxygen species (ROS) that cause tumor cell death. Several mechanisms are involved in the protective responses to PDT including the expression of chaperone/heat shock proteins (HSPs). The HSPs are a family of proteins that are induced by cells in response to exposure to stressful conditions. In the last few decades, it has been discovered that HSPs can play an important role in cell survival, due to the fact that they are responsible for many cytoprotective mechanisms. These proteins have different functions depending on their intracellular or extracellular location. In general, intracellular HSPs have been related to an anti-apoptotic function and recently, HSP-induced autophagy has shown to have a protective role in these chaperones. In contrast, extracellular HSPs or membrane-bound HSPs mediate immunological functions. In the present article, we attempt to review the current knowledge concerning the role of HSPs in the outcome of PDT in relation to autophagy and apoptosis mediated resistance to photodynamic treatment. We will also discuss how certain PDT protocols optimally stimulate the immune system through HSPs. PMID- 27471926 TI - Owning Medical Professionalism. PMID- 27471927 TI - The Importance of Fostering Ownership During Medical Training. AB - There is a need to consider the impact of the new resident-hours regulations on the variety of aspects of medical education and patient care. Most existing literature about this subject has focused on the role of fatigue in resident performance, education, and health care delivery. However, there are other possible consequences of these new regulations, including a negative impact on decision ownership. Our main assumption of is that increased shift work in medicine can decrease ownership of treatment decisions and impact negatively on quality of care. We review some potential components of decision ownership in treatment context and suggest possible ways in which the absence of decision ownership may decrease the quality of medical decision making. The article opens with the definition of decision ownership and the overview of some contextual factors that may contribute to the development of ownership in medical residency. The following section discusses decision ownership in medical care from the perspective of "diffusion of responsibility." We question the quality of choices made within narrow decisional frames. We also compare isolated and interrelated choices, assuming that residents make more isolated decisions during their shifts. Lastly, we discuss the consequences of decreased decision ownership impacting the delivery of health care. PMID- 27471928 TI - To Leave or to Lie: Duty Hour Restrictions and Patient Ownership. PMID- 27471929 TI - White (Coat) Lies: Bending the Truth to Stay Faithful to Patients. PMID- 27471930 TI - The Importance of Fostering Ownership During Medical Training: Working 9-5 Isn't the Only Issue. PMID- 27471931 TI - Anesthesia Intraoperative Handoffs: Is Decision Ownership Compatible With Transitions of Care Providers? PMID- 27471932 TI - Evidence-Based Practice and Policy: ACGME Resident Duty Hours-More Harm Than Help. PMID- 27471933 TI - Watching the Responsibility Clock: Medical Care, Ethics, and Medical Shift Work. PMID- 27471934 TI - Patient Ownership and the Millennial Learner. PMID- 27471935 TI - Four Roles of Ethical Theory in Clinical Ethics Consultation. AB - When clinical ethics committee members discuss a complex ethical dilemma, what use do they have for normative ethical theories? Members without training in ethical theory may still contribute to a pointed and nuanced analysis. Nonetheless, the knowledge and use of ethical theories can play four important roles: aiding in the initial awareness and identification of the moral challenges, assisting in the analysis and argumentation, contributing to a sound process and dialogue, and inspiring an attitude of reflexivity. These four roles of ethical theory in clinical ethics consultation are described and their significance highlighted, while an example case is used as an illustration throughout. PMID- 27471936 TI - Ethical Theory as Part of Clinical Ethics Support Practice. PMID- 27471937 TI - Ethical Theory and Clinical Ethics Consultation: Toward Understanding the Relationship. PMID- 27471938 TI - Clinical Ethics Consultation and the Challenge to Implement What Is Right. PMID- 27471939 TI - Ethical Theories: The More, the Better? PMID- 27471940 TI - A MacIntyrean Critique of Theoretical Pluralism in Applied Ethics. PMID- 27471941 TI - Do We Need Ethical Theory to Achieve Quality Critical Engagement in Clinical Ethics? PMID- 27471942 TI - Should We Worry About the Possible Framing Effect of Ethical Theories? PMID- 27471943 TI - The Poverty of Value Clarification: Using Ethical Theory to Critique and Transcend the "Givens" of Clinical Ethics Consultation. PMID- 27471944 TI - Do Not Try To Run Before You Can Walk: Empirical and Meta-Ethical Presuppositions of Using Ethical Theory in Clinical Ethics Consultation. PMID- 27471946 TI - On the Curious Range of Responses to Our Curious Case: Response to Open Peer Commentaries on "The Curious Case of the De-ICD: Negotiating the Dynamics of Autonomy and Paternalism in Complex Clinical Relationships". PMID- 27471947 TI - The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief. The brains of AD patients are characterized by the deposition of amyloid-beta and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation. The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-beta production and tau hyperphosphorylation in vitro. CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties. CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy. Thus, this review will present a brief introduction to AD biology and current treatment options before outlining comprehensively CBD biology and pharmacology, followed by in-vitro and in-vivo evidence for the therapeutic potential of CBD. We will also discuss the role of the endocannabinioid system in AD before commenting on the potential future of CBD for AD therapy (including safety aspects). PMID- 27471948 TI - EQ-5D health utilities: exploring ways to improve upon responsiveness in psoriasis. AB - AIMS: To determine if EuroQoL 5-Dimension Health Questionnaire (EQ-5D) health utility scores were able to discriminate among different levels of improvement in psoriasis severity following therapy. MATERIALS AND METHODS: Data were from three placebo-controlled phase 3 ixekizumab studies (UNCOVER-1, UNCOVER-2, and UNCOVER 3) with patients who had baseline Dermatology Life Quality Index scores >10 (DLQI >10). Psoriasis severity (Psoriasis Area and Severity Index [PASI]), general health utility (EQ-5D), and psoriasis-specific utility (EQ-PSO, UNCOVER-3 only) were assessed. EQ-5D-5L utility scores were generated using the England EQ-5D-5L value set, a crosswalk applied to the EQ-5D-3L United States (US) and United Kingdom (UK) value sets, and a regression-based exploratory scoring function for the EQ-PSO (UK). Analysis of variance was used to estimate change in EQ-5D-5L from baseline to Week 12 per PASI improvement level: PASI <50, PASI 50 to <75, PASI 75 to <90, PASI 90 to <100, and PASI 100. Missing data were imputed using the last observation carried forward method. Value sets for the UK, England, and the US were applied. RESULTS: In total, 2085 patients across UNCOVER-1, UNCOVER 2, and UNCOVER-3 had baseline DLQI >10 and available utility scores. At Week 12, mean EQ-5D utility scores increased with increasing PASI improvement levels (p < 0.001, all analyses). Mean health utilities for PASI 90 to <100 and PASI 100 were similar when based on the generic classifier, whereas a clear differentiation between PASI 90 to <100 and PASI 100 was observed for EQ-PSO mean scores (UNCOVER 3 only, n = 645; PASI 90 to <100: 0.141, PASI 100: 0.200; adjusted p = 0.043). LIMITATIONS: EQ-5D-5L index-based scores have limited ability to differentiate among psoriasis patients at the highest PASI improvement levels. ConclusionsL Adding psoriasis-specific EQ-PSO dimensions to the EQ-5D may enhance responsiveness to improvement in skin clarity at the highest PASI levels, and, therefore, generate utility scores that better reflect treatment benefit in cost utility models. PMID- 27471949 TI - Skew Deviation: Case Report and Review of the Literature. AB - OBJECTIVE: To present a patient with a sudden onset ocular tilt reaction (OTR) and review recent knowledge and evolving insights of the underlying pathophysiological mechanisms of skew deviation and OTR. METHODS: A middle-aged hypertensive man who had previously suffered stroke with good recovery presented with sudden-onset double vision, slurred speech, ataxia, and a head tilt. Romberg test was positive. The patient denied having disturbances of visual acuity, eye pain, or recent trauma. The right eyeball was pushed upward. The patient complained of double vision in any gaze direction. Movements of the extraocular muscles (EOMs) in the horizontal plane were normal, whereas vertical version and convergence were not possible. We administered a Hess-Lancaster test, cover test, fundoscopic examination, Parks-Bielschowsky three-step test, upright-supine test, brain magnetic resonance imaging (MRI), transcranial doppler (TCD) ultrasonography, electrocardiogram (ECG), Holter monitor (24 h), and echocardiography. RESULTS: The Hess-Lancaster test showed superior rectus muscle and inferior obliquus muscle palsy to the left and rectus inferior muscle and superior obliquus muscle palsy to the right. The right eyeball fell behind when looking downward and the left eyeball when looking upward. Cover alternating test was positive from vertical, R/L. Examination of the ocular fundus showed incyclotorsion of elevated right eye and excyclotorsion of depressed eye. The Parks-Bielschowsky three-step test was negative. A brain MRI with gadolinium revealed a small zone of diffusion restriction in the medial portion of the right cerebral peduncle and right thalamus. There was a gradual improvement in the patient's neurological status following treatment. CONCLUSION: Skew deviation, a not uncommon clinical condition, should be promptly recognized when binocular vertical diplopia cannot be interpreted by trochlearis and oculomotor nerve lesion, myasthenia gravis, or orbital pathology. Maddox rod, cover test, Parks Bielschowsky three-step, and other tests should help to establish the diagnosis. The prognosis depends on etiology, but it is commonly favorable; the majority of patients recover spontaneously after less than a year. More invasive management options should be discussed thereafter. PMID- 27471950 TI - Long-term outcomes of children with transanal endorectal pull-through and a review of the literature. AB - INTRODUCTION: The transanal endorectal pull-through (TERPT) procedure, the latest advancement in the surgical treatment of Hirschsprung's disease, has replaced most other surgical techniques in the last decade. PATIENTS AND METHODS: Between October 2002 and March 2014, a total of 22 patients diagnosed with Hirschsprung's disease underwent a one-stage TERPT operation. RESULTS: Resected segments included the rectosigmoid (seven patients), the descending colon (10 patients), and the transverse colon (five patients). The minimum length of the resected segments was 15 cm and the maximum length was 65 cm. The mean length was 39.18 +/ 12.05 cm. Following surgery, the start of oral ingestion was 1-8 days (mean 3 +/ 1.69 days) and the hospital stay after the operation lasted 4-11 days (mean 7.04 +/- 2.05 days). The mean follow-up period was 48 +/- 6 months (range of 24-166 months). Out of 22 patients, three patients had an anal stricture, which responded to anal dilatations; three patients had an enterocolitis episode that required hospitalization; two patients experienced constipation; and two patients had incontinence/soiling. CONCLUSION: Our data suggest that the TERPT operation can be safely performed in terms of long-term complications. PMID- 27471951 TI - CACNA1S expression in mouse retina: Novel isoforms and antibody cross-reactivity with GPR179. AB - Cacna1s encodes the alpha1S subunit (Cav1.1) of voltage-dependent calcium channels, and is required for normal skeletal and cardiac muscle function, where it couples with the ryanodine receptor to regulate muscle contraction. Recently CACNA1S was reported to be expressed on the tips of retinal depolarizing bipolar cells (DBCs) and colocalized with metabotropic glutamate receptor 6 (mGluR6), which is critical to DBC signal transduction. Further, in mGluR6 knockout mice, expression at this location is down regulated. We examined RNAseq data from mouse retina and found expression of a novel isoform of Cacna1s. To determine if CACNA1S was a functional component of the DBC signal transduction cascade, we performed immunohistochemistry to visualize its expression in several mouse lines that lack DBC function. Immunohistochemical staining with antibodies to CACNA1S show punctate labeling at the tips of DBCs in wild type (WT) retinas that are absent in Gpr179 nob5 mutant retinas and decreased in Grm6 -/- mouse retinas. CACNA1S and transient receptor potential cation channel, subfamily M, member 1 (TRPM1) staining also colocalized in WT retinas. Western blot analyses for CACNA1S of either retinal lysates or proteins after immunoprecipitation with the CACNA1S antibody failed to show the presence of bands expected for CACNA1S. Mass spectrometric analysis of CACNA1S immunoprecipitated proteins also failed to detect any peptides matching CACNA1S. Immunohistochemistry and western blotting after expression of GPR179 in HEK293T cells indicate that the CACNA1S antibody used here and in the retinal studies published to date, cross-reacts with GPR179. These data suggest caution should be exercised in conferring a role for CACNA1S in DBC signal transduction based solely on immunohistochemical staining. PMID- 27471952 TI - PI-RADS Version 2: A Pictorial Update. AB - The Prostate Imaging Reporting and Data System (PI-RADS) is the result of an extensive international collaborative effort. PI-RADS provides a comprehensive yet practical set of guidelines for the interpretation and reporting of prostate multiparametric magnetic resonance (MR) imaging that will promote the use of this modality for detecting clinically significant prostate cancer. The revised PI RADS version (PI-RADS version 2) introduces important changes to the original system used for assessing the level of suspicion for clinically significant cancer with multiparametric MR imaging. For peripheral zone abnormalities in PI RADS version 2, the score obtained from the apparent diffusion coefficient (ADC) map in combination with diffusion-weighted imaging (DWI) performed with high b values (>=1400 sec/mm(2)) is the dominant parameter for determining the overall level of suspicion for clinically significant cancer. For transition zone abnormalities, the score obtained from T2-weighted MR imaging is dominant for overall lesion assessment. Dynamic contrast material-enhanced MR imaging has ancillary roles in the characterization of peripheral zone lesions considered equivocal for clinically significant cancer on the basis of the DWI-ADC combination and in the detection of lesions missed with other multiparametric MR pulse sequences. Assessment with dynamic contrast-enhanced MR imaging is also simplified, being considered positive or negative on the basis of qualitative evaluation for a focal area of rapid enhancement matching an abnormality on DWI ADC or T2-weighted MR images. In PI-RADS version 2, MR spectroscopic imaging is not incorporated into lesion assessment. In this article, a pictorial overview is provided of the revised PI-RADS version 2 assessment categories for the likelihood of clinically significant cancer. PI-RADS version 2 is expected to evolve with time, with updated versions being released as experience in the use of PI-RADS version 2 increases and as new scientific evidence and technologies emerge. ((c))RSNA, 2016. PMID- 27471953 TI - Caspase-mediated degradation of host cortactin that promotes influenza A virus infection in epithelial cells. AB - Influenza A virus (IAV) is well-known to exploit host factors to its advantage. Here, we report that IAV exploits host cortactin, an actin filament-stabilising protein for infection in epithelial cells. By using RNA interference-mediated knockdown and overexpression approach, we demonstrate that cortactin promotes IAV infection. However, cortactin polypeptide undergoes the degradation during late IAV infection. By perturbing the lysosome and proteasome, two main compartments governing the degradation of mammalian proteins, we demonstrate that a lysosome associated apoptotic pathway mediates the degradation of cortactin in IAV infected cells. However, we could not detect cleaved cortactin fragments by western blotting using the antibodies recognising either N-terminal/Central or C terminal cortactin regions, which suggested the presence of multiple caspase cleavage sites. Indeed, CaspDB, a recently-described database predicted up to 35 caspase cleavage motifs present across cortactin polypeptide. The data presented indicate that host cortactin potentially has a dual but contrasting role during IAV infection. PMID- 27471955 TI - Impact of increased mutagenesis on adaptation to high temperature in bacteriophage Qbeta. AB - RNA viruses replicate with very high error rates, which makes them more sensitive to additional increases in this parameter. This fact has inspired an antiviral strategy named lethal mutagenesis, which is based on the artificial increase of the error rate above a threshold incompatible with virus infectivity. A relevant issue concerning lethal mutagenesis is whether incomplete treatments might enhance the adaptive possibilities of viruses. We have addressed this question by subjecting an RNA virus, the bacteriophage Qbeta, to different transmission regimes in the presence or the absence of sublethal concentrations of the mutagenic nucleoside analogue 5-azacytidine (AZC). Populations obtained were subsequently exposed to a non-optimal temperature and analyzed to determine their consensus sequences. Our results show that previously mutagenized populations rapidly fixed a specific set of mutations upon propagation at the new temperature, suggesting that the expansion of the mutant spectrum caused by AZC has an influence on later evolutionary behavior. PMID- 27471954 TI - A robust method for the rapid generation of recombinant Zika virus expressing the GFP reporter gene. AB - Zika virus (ZIKV) infection is a major public health problem with severe human congenital and neurological anomalies. The screening of anti-ZIKV compounds and neutralizing antibodies needs reliable and rapid virus-based assays. Here, we described a convenient method leading to the rapid production of molecular clones of ZIKV. To generate a molecular clone of ZIKV strain MR766(NIID), the viral genome was directly assembled into Vero cells after introduction of four overlapping synthetic fragments that cover the full-length genomic RNA sequence. Such strategy has allowed the production of a recombinant ZIKV expressing the GFP reporter gene that is stable over two culturing rounds on Vero cells. Our data demonstrate that the ZIKV reporter virus is a very reliable GFP-based tool for analyzing viral growth and measuring the neutralizing antibody as well as rapid screening of antiviral effect of different classes of inhibitors. PMID- 27471956 TI - Uveitis in Children and Adolescents. PMID- 27471957 TI - Targeting Resistance. PMID- 27471958 TI - Brain Exploration, Off the Beaten Path. AB - Model organisms, such as rodents, monkeys, or Drosophila, have driven much of recent research in neuroscience. However, studies in other, more unusual systems have broadened the types of questions that are being asked and have revealed the diverse ways in which species tackle common problems. Cell editor Mirna Kvajo talked with Nachum Ulanovsky, Gilles Laurent, and Anthony Leonardo about their research and how studying bats, reptiles, and dragonflies informs big questions in neuroscience. An annotated excerpt of the conversation appears below, and the full conversation is available with the article online. PAPERCLIP. PMID- 27471959 TI - Big Questions in Evolution. PMID- 27471960 TI - In Praise of Descriptive Science: A Breath of Fresh AIRE. AB - Meyer et al. find that subjects lacking the AIRE gene, critical for self tolerance in T lymphocytes, show a broad range of autoantibody specificities, which can have extremely high affinities. The data also suggest that some of these autoantibodies can, surprisingly, prevent some types of autoimmunity, particularly type I diabetes. PMID- 27471961 TI - Broadening Horizons: New Antibodies Against Influenza. AB - Seasonal influenza vaccine formulation efforts struggle to keep up with viral antigenic variation. Two studies now report engineered or naturally occurring human antibodies targeting the influenza hemagglutinin (HA) stem, with exceptional neutralizing breadth (Joyce et al., 2016; Kallewaard et al., 2016). Antibodies with similar structural features are elicited in multiple subjects, suggesting that modified vaccine regimens could provide broad protection. PMID- 27471962 TI - Baby Nuclear Pores Grow Up Faster All the Time. AB - Annulate lamellae (AL) are stacked ER-derived membranes containing nuclear pore complex-like structures whose fate and function have remained a mystery. During the short interphase of early embryonic cells, AL are rapidly delivered into the nuclear envelope through fenestrations, highlighting the remarkable dynamics of the nuclear envelope. PMID- 27471963 TI - A Biomarker Harvest from One Thousand Cancer Cell Lines. AB - Identifying molecular biomarkers that predict cancer drug efficacy is crucial for the advancement of precision medicine. In this issue of Cell, Iorio et al. nominate hundreds of potential genetic and epigenetic biomarkers through high throughput drug screening in ~1,000 molecularly annotated cancer cell lines. PMID- 27471964 TI - The Genetics of Transcription Factor DNA Binding Variation. AB - Most complex trait-associated variants are located in non-coding regulatory regions of the genome, where they have been shown to disrupt transcription factor (TF)-DNA binding motifs. Variable TF-DNA interactions are therefore increasingly considered as key drivers of phenotypic variation. However, recent genome-wide studies revealed that the majority of variable TF-DNA binding events are not driven by sequence alterations in the motif of the studied TF. This observation implies that the molecular mechanisms underlying TF-DNA binding variation and, by extrapolation, inter-individual phenotypic variation are more complex than originally anticipated. Here, we summarize the findings that led to this important paradigm shift and review proposed mechanisms for local, proximal, or distal genetic variation-driven variable TF-DNA binding. In addition, we discuss the biomedical implications of these findings for our ability to dissect the molecular role(s) of non-coding genetic variants in complex traits, including disease susceptibility. PMID- 27471965 TI - Mitochondria and Cancer. AB - Mitochondria are bioenergetic, biosynthetic, and signaling organelles that are integral in stress sensing to allow for cellular adaptation to the environment. Therefore, it is not surprising that mitochondria are important mediators of tumorigenesis, as this process requires flexibility to adapt to cellular and environmental alterations in addition to cancer treatments. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation, including mitochondrial biogenesis and turnover, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. Thus, understanding mechanisms of mitochondrial function during tumorigenesis will be critical for the next generation of cancer therapeutics. PMID- 27471967 TI - The Synchronization of Replication and Division Cycles in Individual E. coli Cells. AB - Isogenic E. coli cells growing in a constant environment display significant variability in growth rates, division sizes, and generation times. The guiding principle appears to be that each cell, during one generation, adds a size increment that is uncorrelated to its birth size. Here, we investigate the mechanisms underlying this "adder" behavior by mapping the chromosome replication cycle to the division cycle of individual cells using fluorescence microscopy. We have found that initiation of chromosome replication is triggered at a fixed volume per chromosome independent of a cell's birth volume and growth rate. Each initiation event is coupled to a division event after a growth-rate-dependent time. We formalize our findings in a model showing that cell-to-cell variation in division timing and cell size is mainly driven by variations in growth rate. The model also explains why fast-growing cells display adder behavior and correctly predict deviations from the adder behavior at slow growth. PMID- 27471966 TI - Amyloid-like Self-Assembly of a Cellular Compartment. AB - Most vertebrate oocytes contain a Balbiani body, a large, non-membrane-bound compartment packed with RNA, mitochondria, and other organelles. Little is known about this compartment, though it specifies germline identity in many non mammalian vertebrates. We show Xvelo, a disordered protein with an N-terminal prion-like domain, is an abundant constituent of Xenopus Balbiani bodies. Disruption of the prion-like domain of Xvelo, or substitution with a prion-like domain from an unrelated protein, interferes with its incorporation into Balbiani bodies in vivo. Recombinant Xvelo forms amyloid-like networks in vitro. Amyloid like assemblies of Xvelo recruit both RNA and mitochondria in binding assays. We propose that Xenopus Balbiani bodies form by amyloid-like assembly of Xvelo, accompanied by co-recruitment of mitochondria and RNA. Prion-like domains are found in germ plasm organizing proteins in other species, suggesting that Balbiani body formation by amyloid-like assembly could be a conserved mechanism that helps oocytes function as long-lived germ cells. PMID- 27471968 TI - Systemic Spread of Sequence-Specific Transgene RNA Degradation in Plants Is Initiated by Localized Introduction of Ectopic Promoterless DNA. PMID- 27471969 TI - A Viral Movement Protein Prevents Spread of the Gene Silencing Signal in Nicotiana benthamiana. PMID- 27471970 TI - Ordered Recruitment of Transcription and Chromatin Remodeling Factors to a Cell Cycle- and Developmentally Regulated Promoter. PMID- 27471971 TI - LINE-1 Activity in Facultative Heterochromatin Formation during X Chromosome Inactivation. PMID- 27471972 TI - SnapShot: Neuronal Regulation of Aging. AB - Aging is characterized by loss of homeostasis across multiple tissues. The nervous system governs whole-body homeostasis by communicating external and internal signals to peripheral tissues. Here, we highlight neuronal mechanisms and downstream outputs that regulate aging and longevity. Targeting these neuronal pathways may be a novel strategy to promote healthy aging. To view this SnapShot, open or download the PDF. PMID- 27471973 TI - Carotid Artery Angioplasty and Stenting Without Distal Embolic Protection Devices. AB - BACKGROUND: Embolic protection devices are used during carotid artery stenting procedures to reduce risk of distal embolization. Although this is a standard procedural recommendation, no studies have shown superiority of these devices over unprotected stenting procedures. OBJECTIVE: To assess the periprocedural outcome and durability of carotid artery stenting without embolic protection devices and poststent angioplasty. METHODS: We performed a retrospective chart review of 174 carotid angioplasty stent procedures performed at our institution. One hundred sixty-six patients underwent angioplasty and stenting without distal protection devices or poststent angioplasty. Complications related to stenting, including procedural complications, postoperative stroke and/or myocardial infarction, and stent restenosis were analyzed. RESULTS: One hundred thirty-five stents (78%) were performed in symptomatic patients, whereas 22% of stents were placed for asymptomatic internal carotid artery stenosis. The degree of stenosis was 80% or greater in 75% of patients and 90% or greater in 55% of patients. Following the stenting procedure, the 24-hour and 30-day rate of transient ischemic attack, intracranial hemorrhage, or ischemic stroke was 0. Three (2%) patients had a perioperative, non-ST elevation myocardial infarction. Five patients (2.8%) required treatment for restenosis (>50% stenosis from baseline), 1 of which was symptomatic. CONCLUSION: Our data show that carotid artery stenting without the use of embolic protection devices and without postangioplasty stenting, in experienced hands, can be performed safely. Furthermore, this technique does not result in a higher degree of in-stent restenosis than series in which poststenting angioplasty is performed. PMID- 27471975 TI - Lower Risk of Intracranial Arteriovenous Malformation Hemorrhage in Patients With Hereditary Hemorrhagic Telangiectasia. PMID- 27471976 TI - Letter: Meta-analysis Does Not Support Lower Complication Rates in Minimally Invasive Transforaminal Lumbar Interbody Fusion. PMID- 27471977 TI - Imaging of Intracranial Pressure Disorders. AB - Intracranial pressure (ICP) is the pressure inside the bony calvarium and can be affected by a variety of processes, such as intracranial masses and edema, obstruction or leakage of cerebrospinal fluid, and obstruction of venous outflow. This review focuses on the imaging of 2 important but less well understood ICP disorders: idiopathic intracranial hypertension and spontaneous intracranial hypotension. Both of these ICP disorders have salient imaging findings that are important to recognize to help prevent their misdiagnosis from other common neurological disorders. PMID- 27471978 TI - In Reply: Meta-analysis Does Not Support Lower Complication Rates in Minimally Invasive Transforaminal Lumbar Interbody Fusion. PMID- 27471979 TI - Overview on relative importance of house dust ingestion in human exposure to polybrominated diphenyl ethers (PBDEs): International comparison and Korea as a case. AB - Human exposure studies to polybrominated diphenyl ethers (PBDEs) have reached different results about the relative importance of diet intake and house dust ingestion. In the present study, concentrations of PBDEs in Korean house dust (n=15) from geographically different cities were measured, which were in agreement with a previous result, and compared with those for 22 countries of five continents collected from the most recent scientific literature. Compared with other exposure pathways, diet intake was the most important contributor to total PBDEs exposure of Korean adults (i.e., 71% of overall intake). On global comparison, total PBDE levels in house dust differed by two to three orders of magnitude among the countries investigated, with a significant relationship with gross domestic product (GDP). Whereas, dietary daily intakes exhibited a narrow difference within one order of magnitude worldwide and no relationship with GDP. Consequently, the relative importance of major two pathways depended on the contamination extent of PBDEs in house dust, which may be associated with the amount of PBDE products in use. In most countries except for UK and USA, the contribution of house dust ingestion was less important than diet intake in the current and are expected to much more mitigate in the future. However, how fast the effect of regulation will be reflected to house dust and human exposure is necessary to be monitored steadily. PMID- 27471980 TI - A bio-economic analysis of a sustainable agricultural transition using green biorefinery. AB - Traditional pig production often relies on cereal-based feed, which has adverse environmental effects, e.g. nitrogen leaching and greenhouse gas (GHG) emissions. Alternative production systems are therefore sought to improve the sustainability of pig production. A promising alternative is to use proteinaceous feed from grass, produced in a green bio-refinery (GBR), to substitute part of the cereals in the feed. Cultivation of grass on arable land can reduce nitrogen leaching and pesticide application, and increase carbon storage. The GBR using grass as feedstock also produces valuable byproducts, e.g. fibre and biogas. In this study we combine a life-cycle analysis (LCA) and a cost-benefit analysis to compare the economic and environmental effects of producing the pig feed to produce 1ton of pork using two feeding systems. We apply this approach to the intensive Danish pork production as a case study. The results show that compared with traditional cereal-based feeding system for producing a ton of pork, using proteinaceous concentrate from small-scale GBR will (1) decrease the average feed cost by 5.01%; (2) produce a profit of 96? before tax in the GBR; and (3) decrease the nitrogen leaching (NO3-N) by 28.2%. However, in most of the scenarios (except for G2), the nitrogen emissions into the air (N2O-N) will also increase because of the increased N fertilizer application compared to a cereal-based system. In most of the scenarios (except for S1 and G1), the energy and land use will also be saved. However, some important factors, e.g. the soil characteristics, pressed juice fraction in fresh biomass and scale of GBR, could subvert the conclusion about energy and land use saving in the alternative feeding system. PMID- 27471981 TI - Total and speciated urinary arsenic levels in the Spanish population. AB - BACKGROUND: Very few studies exist on urinary arsenic exposure in Spain. OBJECTIVE: To evaluate total and speciated urinary arsenic (As) levels in a Spanish population sample. METHODS: Demographic, lifestyle and dietary data was collected for 124 volunteers (aged 20-76years; 88 women and 36 men), who were tested for total arsenic and five arsenic species using high-performance liquid chromatography-inductively coupled plasma mass spectrometry. RESULTS: Arsenobetaine (AB) and dimethylarsinic acid (DMA) were detected in 96.8% of the study participants (limit of detection (LOD) 1.0MUg/L for AB and 1.9MUg/L for DMA). Monomethylarsonic acid (MMA) and arsenous acid (As(III)) were detected in 5.6% (LOD 1.8MUg/L) and 1.6% (LOD 1.4MUg/L) of the participants, respectively; arsenic acid (As(V)) was not detected (LOD 1.4MUg/L). AB and DMA (geometric mean (GM) 29.1MUg/L and 7.5MUg/L, respectively) were the main contributors to total urinary arsenic levels. Urinary DMA was positively associated with AB. CONCLUSION: Total arsenic levels observed in the Spanish population sample were higher than those reported by other European studies. The most recurrent urinary arsenic species was AB, followed by DMA, probably attributable to the high Spanish consumption of seafood. We recommend using inorganic As+MMA as the two main urinary biomarkers for inorganic As exposure. Our results provide reference data for analysing arsenic speciation results and assessing human exposure. PMID- 27471982 TI - Assessing levels of POPs in air over the South Atlantic Ocean off the coast of South America. AB - The occurrence of persistent organic pollutants (POPs) in the atmosphere of the near-coast South Atlantic Ocean was studied. Air samples were collected using a high-volume air sampler (filter and polyurethane foam) on board the Argentinean research cruise R/V Puerto Deseado (CONICET). Samples were analyzed for 50 polychlorinated biphenyl (PCBs), 22 organochlorine pesticides (OCPs) and 14 polybrominated diphenyl ethers (PBDEs). These POPs classes showed a trend of decreasing levels from near-shore to open ocean sites. OCPs and PCBs were in the same order of magnitude (2.71-87.1pg/m(3) and 9.56-130pg/m(3), respectively) while PBDEs levels were significantly lower (0.69-2.58pg/m(3)). Dichlorodiphenyltrichloroethanes (DDTs), endosulfans, chlordanes, hexachlorocyclohexanes (HCHs) and heptachlors were between 0.20 and 17.8pg/m(3), while drines and hexachlorobenzene (HCB) were at lower levels (0.28-3.71pg/m(3)). The most frequently detected PCBs were congeners 32, 28, 44, 52, 95, representing >50% of the total. The PBDEs congener pattern was dominated by congener 209 (70%), followed by 47 and 99 (16% and 7%, respectively). Air parcel back trajectories for the study period provided few insights as trajectories mainly stemmed from the open ocean with limited inputs from continental sources. These results indicate that the concentration of POPs (namely PCBs, OCPs, and PBDEs) in air remain elevated in the near-shore environment and then drop-off substantially beyond a distance of about 400km. This has implications for the loading of POPs and delivery to the marine environment in the near coastal zone. PMID- 27471983 TI - Recent climatic events controlling the hydrological and the aquifer dynamics at arid areas: The case of Huasco River watershed, northern Chile. AB - The investigation assesses the influence of recent climatic events in the water resources and the aquifer dynamics in the Huasco watershed by means of the analysis of precipitation, streamflow and piezometric levels during the last 50years. These hydrological and hydrogeological parameters were evaluated by an exploratory geostatistical analysis (semivariogram) and a spectral analysis (periodogram). Specifically, the hydrological and hydrogeological data analyses are organized according to three sub-basins, the Del Carmen River (Section I), the El Transito River (Section II), and the Huasco River (Section III). Data ranges for rainfall are from 1961 to 2015, for streamflow from 1964 to 2015, and for groundwater levels from 1969 to 2014, available from Water Authority of Chile. The analyses allowed the identification of cycles in the hydrological and hydrogeological records. The study area is located in a transient climatic fringe where the convergence of several climatic systems can be identified in the hydrological and hydrogeological records. Results indicate that the nival areas and the small glaciers are especially important to the recharge processes in the Huasco watershed during the spring-summer snowmelting. Water reservoirs in the main aquifer (Section III) and in the Santa Juana dam are highly sensitive to ENSO oscillation climatic patterns. The main climatic events that control this record are the El Nino and La Nina events. In addition, the climatic influence of the westerlies and the SE extratropical moisture were also identified. Spectral analysis identified the presence of a 22.9-yearcycle in piezometric levels of the alluvial aquifer of the Huasco River. This cycle is consistent with the 22-year Hale solar cycle, suggesting the existence of a solar forcing controlling the ENSO oscillations. Moreover, semivariogram and spectral analysis identified a 10.65-yearcycle and a 9.2-yearcycle in groundwater, respectively, which were attributed to the strong mode of ENSO oscillations. PMID- 27471984 TI - A comparison between thermal-optical transmittance elemental carbon measured by different protocols in PM2.5 samples. AB - Although controlled procedures for the determination of carbonaceous fractions are of importance for any air quality measurements, currently no reference method for elemental carbon (EC) and organic carbon (OC) analysis is established yet in Europe. The implementation of the different thermal evolution protocols available in the literature, differing in temperature and duration of the heating ramps, affects the results and can result in a wide variation of EC and OC values. In this study three different protocols for thermal-optical-transmittance analysis of EC and OC were compared, namely He-870 (a variation of the NIOSH protocol), He 550 (a proxy of the IMPROVE protocol), and EUSAAR_2. Measurements were carried out on PM2.5 samples collected on Quartz fibre filters in three sites of different typology: urban background and urban traffic in Florence (Italy) and regional background in Livorno (Italy). The samples were analysed before and after a washing procedure to remove possible water-soluble organic compounds (WSOC), which may enhance the charring process, complicating the EC quantification. This study evidenced a very good agreement for TC measurement (at 2-3% level) and some discrepancies in EC measurement (up to 40%), as expected. WSOC and Pyrolitic Carbon (PyC) present a good correlation, independently of site typology, demonstrating that water soluble compound can be responsible of charring mechanism during the He phase. PMID- 27471985 TI - Biochar decreased microbial metabolic quotient and shifted community composition four years after a single incorporation in a slightly acid rice paddy from southwest China. AB - While numerous studies both in laboratory and field have showed short term impacts of biochar on soil microbial community, there have been comparatively few reports addressing its long term impacts particular in field condition. This study investigated the changes of microbial community activity and composition in a rice paddy four years after a single incorporation of biochar at 20 and 40t/ha. The results indicated that biochar amendment after four years increased soil pH, soil organic C (SOC), total N and C/N ratio and decreased bulk density, particularly for the 40t/ha treatment compared to the control (0t/ha). Though no significant difference was observed in soil basal respiration, biochar amendment increased soil microbial biomass C and resulted in a significantly lower metabolic quotient. Besides, dehydrogenase and beta-glucosidase activities were significantly decreased under biochar amendment relative to the control. The results of Illumina Miseq sequencing showed that biochar increased alpha diversity of bacteria but decreased that of fungi and changed both bacterial and fungal community structures significantly. Biochar did not change the relative abundances of majority of bacteria at phylum level with the exception of a significant reduction of Actinobacteria, but significantly changed most of bacterial groups at genus level, particularly at 40t/ha. In contrast, biochar significantly decreased the relative abundances of Ascomycota and Basidiomycota by 11% and 66% and increased the relative abundances of Zygomycota by 147% at 40t/ha compared to the non-amended soil. Redundancy analysis (RDA) indicated that biochar induced changes in soil chemical properties, such as pH, SOC and C/N, were important factors driving community composition shifts. This study suggested that biochar amendment may increase microbial C use efficiency and reduce some microorganisms that are capable of decomposing more recalcitrant soil C, which may help stabilization of soil organic matter in paddy soil in long term. PMID- 27471986 TI - Total Synthesis of the Proposed Structure of Maltepolide C. AB - The first total synthesis of the proposed structure of cytotoxic macrolide maltepolide C has been achieved via an E-selective intramolecular Heck cyclization as a key step. Other key features of the synthesis are Z-selective Wittig olefination, Sharpless asymmetric dihydroxylation followed by Williamson type cyclo-etherification, Brown asymmetric allylation, and Noyori reduction of an alkynone. Detailed NMR study confirms the structure and stereochemistry of the synthetic maltepolide C unambiguously. However, the deviation of the spectra of the synthetic maltepolide C from those of the natural maltepolide C indicates a possible error in the original structural assignment. PMID- 27471987 TI - Gender differences and bleeding complications after PCI on first and second generation DES. AB - BACKGROUND: The aim of this study was to evaluate gender differences in the long term clinical outcomes and safety of patients treated with first- and second generation DES. METHODS: The Katowice-Zabrze Registry included 1916 consecutive patients treated with either first or second generation DES. We evaluated major adverse cardiac and cerebrovascular events (MACCE) [composite of death, myocardial infarction (MI), stroke and target vessel revascularization (TVR)] at 12-month follow-up. Safety end point was bleeding complications and stent thrombosis. RESULTS: Registry included [unstable angina (UA) 1500(78%), non-ST segment elevation myocardial infarction (NSTEMI) 285 (15%), ST-segment elevation myocardial infarction/left bundle branch block (STEMI/LBBB) 131 (7%)]. There were 35.5% females and 64.5% males. Women were older and had higher prevalence of comorbidities. Males more often had multivessel disease and higher Syntax score when comparable to females. We did not observed difference in acute and subacute stent thrombosis in our data, however, females had more in-hospital bleeding complications. Univariable Cox regression analysis revealed that women had similar outcomes when compared to men in terms of a risk of death, MI, TVR, stroke and MACCE at 1-year follow-up. There were no differences between males and females in MACCE when first- and second generation DES were analyzed separately. CONCLUSION: Despite higher risk profile, women treated with DES have similar outcomes as males in 1-year follow-up. However there is, an increased risk of in hospital bleedings in women. PMID- 27471988 TI - Non-intercourse and intercourse hookup intentions, drinking expectancies, and college students' heavy drinking. AB - BACKGROUND: The current study tested the associations between college students' intentions to hookup (i.e., specifically intending to go out and engage in sexual behavior with a non-romantic partner) and self-reported heavy drinking. Further, social and sexual enhancement drinking expectancies were tested as moderators of those associations. METHODS: College students (N = 235) reported (a) if they had specifically intended to hookup (reported separately for non-intercourse and intercourse hookup intentions) in the past 6 months; (b) social and sexual enhancement drinking expectancies; and (c) heavy drinking (a composite of past-30 day drinking frequency, typical amount consumed per drinking occasion, and how many times they got drunk). Data were analyzed using a hierarchical multiple regression (HMR), controlling for demographic variables. RESULTS: Non-intercourse hookup intentions were positively associated with heavy drinking, but intercourse hookup intentions were not. Sexual but not social enhancement drinking expectancies moderated the associations between both types of hookup intentions and heavy drinking. Among those who had intended a non-intercourse hookup, heavy drinking was greater when they also reported high (+1 SD) sexual enhancement drinking expectancies. For intercourse hookup intentions, higher (+1 SD) sexual enhancement drinking expectancies were associated with less heavy drinking. CONCLUSIONS: Pursuing non-intercourse hookups appears to be associated with heavy drinking, but intercourse hookup intention is not. Sexual enhancement drinking expectancies moderated those associations. Thus, an interest in some types of casual sexual experiences may promote heavy drinking among college students. PMID- 27471989 TI - Facile and efficient formation and dissociation of a pseudo[2]rotaxane by a slippage approach using pillar[5]arene-based cyclic host liquid and solvent. AB - A pillar[5]arene-based pseudo[2]rotaxane was synthesized using a slippage method by only heating an axle with bulky valine derivative ends in a cyclic host liquid (CHL), which is liquid at room temperature. The pseudo[2]rotaxane synthesized in a CHL can be converted back to the starting components, i.e., the pillar[5]arene wheel and the axle, by heating in a solvent. PMID- 27471990 TI - Ocfentanil overdose fatality in the recreational drug scene. AB - This paper describes the first reported death involving ocfentanil, a potent synthetic opioid and structure analogue of fentanyl abused as a new psychoactive substance in the recreational drug scene. A 17-year-old man with a history of illegal substance abuse was found dead in his home after snorting a brown powder purchased over the internet with bitcoins. Acetaminophen, caffeine and ocfentanil were identified in the powder by gas chromatography mass spectrometry and reversed-phase liquid chromatography with diode array detector. Quantitation of ocfentanil in biological samples was performed using a target analysis based on liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry. In the femoral blood taken at the external body examination, the following concentrations were measured: ocfentanil 15.3MUg/L, acetaminophen 45mg/L and caffeine 0.23mg/L. Tissues sampled at autopsy were analyzed to study the distribution of ocfentanil. The comprehensive systematic toxicological analysis on the post-mortem blood and tissue samples was negative for other compounds. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of death was an acute intoxication with ocfentanil. The manner of death was assumed to be accidental after snorting the powder. PMID- 27471991 TI - Chemical characterization of synthetic cannabinoids by electrospray ionization FT ICR mass spectrometry. AB - The synthetic cannabinoids (SCs) represent the most recent advent of the new psychotropic substances (NPS) and has become popularly known to mitigate the effects of the Delta(9)-THC. The SCs are dissolved in organic solvents and sprayed in a dry herbal blend. However, little information is reported on active ingredients of SCs as well as the excipients or diluents added to the herbal blend. In this work, the direct infusion electrospray ionization Fourier transform ion cyclotron mass spectrometry technique (ESI-FT-ICR MS) was applied to explore the chemical composition of nine samples of herbal extract blends, where a total of 11 SCs (UR-144, JWH-073, XLR-11, JWH-250, JWH-122, AM-2201, AKB48, JWH-210, JWH-081, MAM-2201 and 5F-AKB48) were identified in the positive ionization mode, ESI(+), and other 44 chemical species (saturated and unsaturated fatty acids, sugars, flavonoids, etc.) were detected in the negative ionization mode, ESI(-). Additionally, CID experiments were performed, and fragmentation pathways were proposed to identify the connectivity of SCs. Thus, the direct infusion ESI-FT-ICR MS technique is a powerful tool in forensic chemistry that enables the rapid and unequivocal way for the determination of molecular formula, the degree of unsaturation (DBE-double bond equivalent) and exact mass (<1ppm) of a total of 55 chemical species without the prior separation step. PMID- 27471992 TI - Role of surgical consolidation in metastatic urothelial carcinoma. AB - PURPOSE OF REVIEW: Since the development of systemic combination chemotherapy, postchemotherapy extirpation has been performed in selected patients mainly with locally advanced and/or initially unresectable bladder cancer, and, in very selected patients, surgical consolidation for visceral metastases has also been performed. The purpose of this article was to review and summarize the current evidence for the role of surgical consolidation in metastatic urothelial carcinoma. RECENT FINDINGS: The role of metastasectomy has not yet been examined in a randomized setting. In terms of locally advanced and/or node-positive bladder cancer, studies further support the benefit of surgical consolidation, especially after a favorable response to systemic chemotherapy. Regarding metastasectomy for visceral metastasis, recent evidence suggested that lung metastases (ideally small solitary lesions) are a good indication. SUMMARY: Patients with a good response to chemotherapy, limited nodal/pulmonary disease, and a favorable performance status are good candidates for surgical consolidation. Careful patient selection is mandatory. PMID- 27471993 TI - Metastasis therapies for renal cancer. AB - PURPOSE OF REVIEW: Although novel targeted therapies for metastatic renal cell carcinoma (RCC) are emerging, metastasectomy still remains the only potentially curable intervention and plays an important role both in disease control, cancer specific survival (CSS) and overall survival (OS). A systematic review was conducted in 2014 by the European Association of Urology RCC guidelines panel to summarize evidence on the subject at hand. The purpose of this review is to update the current evidence base. RECENT FINDINGS: A total of 17-19% of initially nonmetastatic patients with later RCC metastasis are potentially curable. Complete metastasectomy still remains the sole curative option, continues to show improved OS and CSS and is suggested to defer time to palliative targeted therapy. Resectability, long time to recurrence, good performance status and oligometastatic disease have better benefit of metastasectomy. Stereotactic radiotherapy remains an excellent option for local tumor control and symptom control in patients with RCC brain and bone metastases. Minimal-invasive options such as thermal ablation are evolving, albeit the evidence base is small. Novel trials are investigating sequencing of metastasectomy and targeted therapy with results pending. SUMMARY: Metastasectomy continues to be supported as beneficial for OS, CSS and progression-free survival in patients with good prognostic factors. PMID- 27471995 TI - Multifunctional Photonic Molecular Logic Gate Based On A Biphotochromic Dyad With Reduced Energy Transfer. AB - Using molecular logic gates (MLGs) for information processing attracts attention due to perspectives of creating molecular computers. Biphotochromic dyads are suitable models of photonic MLGs. However, they suffer from one weakness: the activity of one of the photochromes is often quenched because of Forster resonance energy transfer (FRET). Herein, we designed a dyad with reduced FRET, in which both photochromes keep their photoactivity thanks to spectral and spatial separation, allowing MLG switching between different states. This novel dyad reproduces the functionality of the full set of 16 two-input gates, as well a reversible gate-dual inverter, all gates are photonic. PMID- 27471994 TI - Immunotherapy in genitourinary malignancies. AB - PURPOSE OF REVIEW: Active investigation suggests immune checkpoint inhibitor therapy and therapeutic cancer vaccines provide clinical benefit for genitourinary malignancies including prostate cancer, renal cell carcinoma, and bladder cancer. Recent developments in the utility of immune checkpoint inhibitor and vaccine therapy for the management of genitourinary malignancies are highlighted in this review. RECENT FINDINGS: Dramatic responses to checkpoint inhibitor therapy have been demonstrated in renal cell carcinoma and bladder cancer with recent Food and Drug Administration approvals in both indications. No benefit to checkpoint inhibitor therapy has yet been shown for the management of prostate cancer. Therapeutic cancer vaccines have also shown benefit in the treatment of genitourinary malignancies, specifically in the treatment of prostate cancer. Despite advances in these therapeutic modalities, benefit is limited to a subset of patients. SUMMARY: Current evidence supports the use of immune checkpoint inhibitor therapy and therapeutic cancer vaccines for the management of genitourinary malignancies. Further development of biomarkers for predicting response and study of combination therapy is required to achieve optimal efficacy with these therapeutic interventions. PMID- 27471996 TI - Molecular digital pathology: progress and potential of exchanging molecular data. AB - Many of the demands to perform next generation sequencing (NGS) in the clinical laboratory can be resolved using the principles of telepathology. Molecular telepathology can allow facilities to outsource all or a portion of their NGS operation such as cloud computing, bioinformatics pipelines, variant data management, and knowledge curation. Clinical pathology laboratories can electronically share diverse types of molecular data with reference laboratories, technology service providers, and/or regulatory agencies. Exchange of electronic molecular data allows laboratories to perform validation of rare diseases using foreign data, check the accuracy of their test results against benchmarks, and leverage in silico proficiency testing. This review covers the emerging subject of molecular telepathology, describes clinical use cases for the appropriate exchange of molecular data, and highlights key issues such as data integrity, interoperable formats for massive genomic datasets, security, malpractice and emerging regulations involved with this novel practice. PMID- 27471997 TI - [No neurexit please]. PMID- 27471998 TI - [Practical Use of the Levodopa Pump]. AB - Patients with advanced Parkinson's disease and motor complications undergoing optimized oral therapy can significantly benefit from continuous intrajejunal levodopa/carbidopa infusion applied by means of a medication pump. However, this requires a correctly positioned PEG-J tube and finely adjusted pump settings. Although this method is a routine procedure in specialist centers, no standard procedure has been defined up to now. For this reason, an expert recommendation regarding the practical application has been developed in order to standardize the procedure and facilitate patient access to this treatment option. PMID- 27472000 TI - [German Translation and Validation of the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's disease (SEND-PD)]. AB - OBJECTIVE: The aim of the present study was to validate and provide a German version of the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's disease (SEND-PD) of Martinez-Martin et al. (2012). METHOD: The German version of the SEND-PD was evaluated in a sample consisting of 96 patients with Parkinson's disease (PD) (mean age: 65.3 years +/- 9.6, 29 female). This scale includes 12 items, representing the domains psychotic symptoms, mood/apathy and impulse control disorders. Reliability and validity analyses were conducted. RESULTS: The examined patients presented a few neuropsychiatric symptoms. Explorative factor analyses identified the proposed three dimensions solution. The items of the mood/apathy domain were homogenous and selective, and the domain showed acceptable internal consistency. For the other two domains, the values were only partially acceptable. Convergent, discriminate and construct validity were shown. CONCLUSION: The German version of the SEND-PD is sufficiently reliable and valid to be adopted in German speaking countries. However, since patients showed only a few symptoms in the dimensions of psychotic symptoms and impulse control disorders, these two domains can be evaluated only to a limited extent. PMID- 27471999 TI - [The Therapeutic Dilemma in Treatment of Intracranial Infectious Aneurysm in Patients with Infective Endocarditis: Proposal for a Patient-Centered, Interdisciplinary Treatment Concept]. AB - Intracranial infectious aneurysms are rare but hazardous complications of an infective endocarditis. To date, there are no evidence-based recommendations for the treatment of patients with this condition. Therefore, it remains an interdisciplinary challenge to decide which treatment steps are required and in which order they should be carried out. To illustrate the interdisciplinary dilemma in the treatment of these patients, we here present a case of a 23-year old, drug-addicted woman with infectious endocarditis. While antibiotic treatment of the streptococcus-mitis-induced endocarditis stabilized the overall status of the patient, rupture of a basilar artery aneurysm caused her sudden death. We discuss the decision-making processes of the treatment, potential difficulties and dilemmas when dealing with patients suffering from infectious endocarditis and infectious intracranial aneurysm. Based upon case reports, studies and reviews, we present the options and risks of conservative, neurosurgical, endovascular, and cardiosurgical treatment of intracranial infectious aneurysms, and propose a patient-centered, interdisciplinary treatment concept. PMID- 27472001 TI - [The Value of Neuropsychological Legal Evaluations]. AB - In the context of neurological assessment, neuropsychological deficits, in particular of attention and memory functions, usually require additional neuropsychological evaluation. Clinical neuropsychology also has at its disposal an inventory of validated and standardized tests for assessing symptom validity. Procedure, test selection, quality criteria and limitations of neuropsychological expert medical evaluations are presented. Independent expert evaluations should be conducted by a qualified clinical neuropsychologist. PMID- 27472003 TI - [Not Available]. PMID- 27472002 TI - [Mental disorders in women: Natural course during premenstrual phases, peripartum period and perimenopause]. AB - Epidemiological studies indicate sex-specific differences in prevalence rates and the natural course of mental disorders. Affective, anxiety, somatoform and eating disorders are more prevalent in women than men, whereas substance use disorders occur more commonly in men, and some disorders are equally distributed in both sexes (e. g. psychotic disorders). The aim of this review is to depict the natural course of mental disorders during the reproductive stages (premenstrual phases, peripartum period, perimenopause) in women, including also neuroendocrine features associated with the menstrual cycle, pregnancy, puerperium and perimenopause. Recommendations for sex-specific diagnostic and therapeutic procedures are provided. PMID- 27472004 TI - pi-Stacking attraction vs. electrostatic repulsion: competing supramolecular interactions in a tpphz-bridged Ru(ii)/Au(iii) complex. AB - The synthesis and characterization of a mixed metal ruthenium(ii)/gold(iii) complex bridged by tetrapyridophenazine (tpphz) are described. It is isostructural and isoelectronic to the well-known photocatalysts with palladium(ii) or platinum(ii). Concentration dependent (1)H-NMR spectroscopy and XRD studies show that the electrostatic repulsion between the gold(iii) moieties exceeds the attractive pi-stacking interaction. Theoretical calculations based on the new structural data confirm an increased positive charge on the bridging ligand as well as significantly altered orbital symmetry as compared to the previously investigated palladium(ii) complex. This is the first example of a tpphz ruthenium(ii) complex where pi-stacking is completely inhibited. The detailed investigation of the solid-state structure showed for the first time in bimetallic tpphz bridged complexes no significant torsion within the bridging ligand itself. Although catalytic performance for proton reduction by gold(iii) is naturally not observed, its photochemical decomposition in colloidal gold particles could be shown by TEM and DLS. PMID- 27472005 TI - Fluoride mouthrinses for preventing dental caries in children and adolescents. AB - BACKGROUND: Fluoride mouthrinses have been used extensively as a caries preventive intervention in school-based programmes and by individuals at home. This is an update of the Cochrane review of fluoride mouthrinses for preventing dental caries in children and adolescents that was first published in 2003. OBJECTIVES: The primary objective is to determine the effectiveness and safety of fluoride mouthrinses in preventing dental caries in the child and adolescent population.The secondary objective is to examine whether the effect of fluoride rinses is influenced by:* initial level of caries severity;* background exposure to fluoride in water (or salt), toothpastes or reported fluoride sources other than the study option(s); or* fluoride concentration (ppm F) or frequency of use (times per year). SEARCH METHODS: We searched the following electronic databases: Cochrane Oral Health's Trials Register (whole database, to 22 April 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 3), MEDLINE Ovid (1946 to 22 April 2016), Embase Ovid (1980 to 22 April 2016), CINAHL EBSCO (the Cumulative Index to Nursing and Allied Health Literature, 1937 to 22 April 2016), LILACS BIREME (Latin American and Caribbean Health Science Information Database, 1982 to 22 April 2016), BBO BIREME (Bibliografia Brasileira de Odontologia; from 1986 to 22 April 2016), Proquest Dissertations and Theses (1861 to 22 April 2016) and Web of Science Conference Proceedings (1990 to 22 April 2016). We undertook a search for ongoing trials on the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform. We placed no restrictions on language or date of publication when searching electronic databases. We also searched reference lists of articles and contacted selected authors and manufacturers. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials where blind outcome assessment was stated or indicated, comparing fluoride mouthrinse with placebo or no treatment in children up to 16 years of age. Study duration had to be at least one year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces in permanent teeth (D(M)FS). DATA COLLECTION AND ANALYSIS: At least two review authors independently performed study selection, data extraction and risk of bias assessment. We contacted study authors for additional information when required. The primary measure of effect was the prevented fraction (PF), that is, the difference in mean caries increments between treatment and control groups expressed as a percentage of the mean increment in the control group. We conducted random-effects meta-analyses where data could be pooled. We examined potential sources of heterogeneity in random-effects metaregression analyses. We collected adverse effects information from the included trials. MAIN RESULTS: In this review, we included 37 trials involving 15,813 children and adolescents. All trials tested supervised use of fluoride mouthrinse in schools, with two studies also including home use. Almost all children received a fluoride rinse formulated with sodium fluoride (NaF), mostly on either a daily or weekly/fortnightly basis and at two main strengths, 230 or 900 ppm F, respectively. Most studies (28) were at high risk of bias, and nine were at unclear risk of bias.From the 35 trials (15,305 participants) that contributed data on permanent tooth surface for meta-analysis, the D(M)FS pooled PF was 27% (95% confidence interval (CI), 23% to 30%; I(2) = 42%) (moderate quality evidence). We found no significant association between estimates of D(M)FS prevented fractions and baseline caries severity, background exposure to fluorides, rinsing frequency or fluoride concentration in metaregression analyses. A funnel plot of the 35 studies in the D(M)FS PF meta-analysis indicated no relationship between prevented fraction and study precision (no evidence of reporting bias). The pooled estimate of D(M)FT PF was 23% (95% CI, 18% to 29%; I2 = 54%), from the 13 trials that contributed data for the permanent teeth meta-analysis (moderate quality evidence).We found limited information concerning possible adverse effects or acceptability of the treatment regimen in the included trials. Three trials incompletely reported data on tooth staining, and one trial incompletely reported information on mucosal irritation/allergic reaction. None of the trials reported on acute adverse symptoms during treatment. AUTHORS' CONCLUSIONS: This review found that supervised regular use of fluoride mouthrinse by children and adolescents is associated with a large reduction in caries increment in permanent teeth. We are moderately certain of the size of the effect. Most of the evidence evaluated use of fluoride mouthrinse supervised in a school setting, but the findings may be applicable to children in other settings with supervised or unsupervised rinsing, although the size of the caries preventive effect is less clear. Any future research on fluoride mouthrinses should focus on head-to-head comparisons between different fluoride rinse features or fluoride rinses against other preventive strategies, and should evaluate adverse effects and acceptability. PMID- 27472006 TI - The Renaissance of Metal-Pyrimidine Nucleobase Coordination Chemistry. AB - The significance of metal ions for the function and properties of DNA and RNA, long seen primarily under biological aspects and medicinal uses, has recently gained a renewed momentum. This is a consequence of the advent of novel applications in the fields of materials science, biotechnology, and analytical sensor chemistry that relate to the designed incorporation of transition metal ions into nucleic acid base pairs. Ag(+) and Hg(2+) ions, binding to pyrimidine (pym) nucleobases, represent major players in this development. Interestingly, these metal ions were the ones that some 60 years ago started the field! At the same time, the mentioned metal ions had demonstrated a "special relationship" with the pym nucleobases cytosine, thymine, and uracil! Parallel work conducted with oligonucleotides and model nucleobases fostered numerous significant details of these interactions, in particular when X-ray crystallography was involved, correcting earlier views occasionally. Our own activities during the past three to four decades have focused on, among others, the coordination chemistry of transition and main-group metal ions with pym model nucleobases, with an emphasis on Pt(II) and Pd(II). It has always been our goal to deduce, if possible, the potential relevance of our findings for biological processes. It is interesting to put our data, in particular for trans-a2Pt(II) (a = NH3 or amine), into perspective with those of other metal ions, notably Ag(+) and Hg(2+). Irrespective of major differences in kinetics and lability/inertness between d(8) and d(10) metal ions, there is also a lot of similarity in structural aspects as a result of the preferred linear coordination geometry of these species. Moreover, the apparent clustering of metal ions to the pym nucleobases, which is presumably essential for the formation of nanoclusters on oligonucleotide scaffolds, is impressively reflected in model systems, as are reasons for inter nucleobase cross-links containing more than a single metal ion. The present understanding of these interrelationships is a consequence of intensive research carried out during the last 60 years by numerous laboratories. For space restrictions in this Account, it was impossible to adequately highlight the valuable contributions of all of the researchers in the field of metal-pym nucleobase interactions. Explicitly this refers to colleagues not cited in the references, e.g., R. Stuart Tobias, Robert Bau, R. Bruce Martin, Colin J. L. Lock, Katsuyuki Aoki, Helmut Sigel, and Michael J. Clarke, among others. PMID- 27472008 TI - Techniques for Accurate Sizing of Gold Nanoparticles Using Dynamic Light Scattering with Particular Application to Chemical and Biological Sensing Based on Aggregate Formation. AB - Gold nanoparticles (AuNPs) have found broad applications in chemical and biological sensing, catalysis, biomolecular imaging, in vitro diagnostics, cancer therapy, and many other areas. Dynamic light scattering (DLS) is an analytical tool used routinely for nanoparticle size measurement and analysis. Due to its relatively low cost and ease of operation in comparison to other more sophisticated techniques, DLS is the primary choice of instrumentation for analyzing the size and size distribution of nanoparticle suspensions. However, many DLS users are unfamiliar with the principles behind the DLS measurement and are unware of some of the intrinsic limitations as well as the unique capabilities of this technique. The lack of sufficient understanding of DLS often leads to inappropriate experimental design and misinterpretation of the data. In this study, we performed DLS analyses on a series of citrate-stabilized AuNPs with diameters ranging from 10 to 100 nm. Our study shows that the measured hydrodynamic diameters of the AuNPs can vary significantly with concentration and incident laser power. The scattered light intensity of the AuNPs has a nearly sixth order power law increase with diameter, and the enormous scattered light intensity of AuNPs with diameters around or exceeding 80 nm causes a substantial multiple scattering effect in conventional DLS instruments. The effect leads to significant errors in the reported average hydrodynamic diameter of the AuNPs when the measurements are analyzed in the conventional way, without accounting for the multiple scattering. We present here some useful methods to obtain the accurate hydrodynamic size of the AuNPs using DLS. We also demonstrate and explain an extremely powerful aspect of DLS-its exceptional sensitivity in detecting gold nanoparticle aggregate formation, and the use of this unique capability for chemical and biological sensing applications. PMID- 27472007 TI - Heterogeneity in ADHD: Neurocognitive predictors of peer, family, and academic functioning. AB - Childhood attention-deficit/hyperactivity disorder (ADHD) is associated with impairments in peer, family, and academic functioning. Although impairment is required for diagnosis, children with ADHD vary significantly in the areas in which they demonstrate clinically significant impairment. However, relatively little is known about the mechanisms and processes underlying these individual differences. The current study examined neurocognitive predictors of heterogeneity in peer, family, and academic functioning in a well-defined sample of 44 children with ADHD aged 8-13 years (M = 10.31, SD = 1.42; 31 boys, 13 girls; 81% Caucasian). Reliable change analysis indicated that 98% of the sample demonstrated objectively-defined impairment on at least one assessed outcome measure; 65% were impaired in two or all three areas of functioning. ADHD children with quantifiable deficits in academic success and family functioning performed worse on tests of working memory (d = 0.68 to 1.09), whereas children with impaired parent-reported social functioning demonstrated slower processing speed (d = 0.53). Dimensional analyses identified additional predictors of peer, family, and academic functioning. Working memory abilities were associated with individual differences in all three functional domains, processing speed predicted social functioning, and inhibitory control predicted family functioning. These results add to a growing literature implicating neurocognitive abilities not only in explaining behavioral differences between ADHD and non-ADHD groups, but also in the substantial heterogeneity in ecologically-valid functional outcomes associated with the disorder. PMID- 27472009 TI - Stratifying the NHS Diabetic Eye Screening Programme: into the unknown? PMID- 27472010 TI - Retrieving GPCR data from public databases. AB - Improvements in databases have already impacted GPCR research. The purpose of the review is to give a snapshot of the GPCR data available and provide utility examples. Consequently, this review covers a small set of major databases, including UniProt for proteins, Ensembl for genes, ChEMBL for bioactive chemistry and SureChEMBL for patents. In addition, two portals are outlined, GPCRdb and the IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb) that are based on expert annotation. The former has an emphasis on structures, sequences, point mutations, analysis tools and visualisation. The latter focuses on endogenous GPCR ligands, pharmacological modulation, approved drugs, clinical candidates and tool compounds. Since data growth is accelerating, those embarking on GPCR projects should not only check databases but also recent journal and patent publications. PMID- 27472011 TI - Measuring and Predicting the Internal Structure of Semiconductor Nanocrystals through Raman Spectroscopy. AB - Nanocrystals composed of mixed chemical domains have diverse properties that are driving their integration in next-generation electronics, light sources, and biosensors. However, the precise spatial distribution of elements within these particles is difficult to measure and control, yet profoundly impacts their quality and performance. Here we synthesized a unique series of 42 different quantum dot nanocrystals, composed of two chemical domains (CdS:CdSe), arranged in 7 alloy and (core)shell structural classes. Chemometric analyses of far-field Raman spectra accurately classified their internal structures from their vibrational signatures. These classifications provide direct insight into the elemental arrangement of the alloy as well as an independent prediction of fluorescence quantum yield. This nondestructive, rapid approach can be broadly applied to greatly enhance our capacity to measure, predict and monitor multicomponent nanomaterials for precise tuning of their structures and properties. PMID- 27472013 TI - CORRECTION. PMID- 27472012 TI - AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITYEXECUTIVE SUMMARYComplete Guidelines available at https://www.aace.com/publications/guidelines. AB - OBJECTIVE: Development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and the American College of Endocrinology (ACE) Board of Trustees and adheres to published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS: Recommendations are based on diligent review of clinical evidence with transparent incorporation of subjective factors. RESULTS: There are 9 broad clinical questions with 123 recommendation numbers that include 160 specific statements (85 [53.1%] strong [Grade A], 48 [30.0%] intermediate [Grade B], and 11 [6.9%] weak [Grade C], with 16 [10.0%] based on expert opinion [Grade D]) that build a comprehensive medical care plan for obesity. There were 133 (83.1%) statements based on strong (best evidence level [BEL] 1 = 79 [49.4%]) or intermediate (BEL 2 = 54 [33.7%]) levels of scientific substantiation. There were 34 (23.6%) evidence-based recommendation grades (Grades A-C = 144) that were adjusted based on subjective factors. Among the 1,788 reference citations used in this CPG, 524 (29.3%) were based on strong (evidence level [EL] 1), 605 (33.8%) were based on intermediate (EL 2), and 308 (17.2%) were based on weak (EL 3) scientific studies, with 351 (19.6%) based on reviews and opinions (EL 4). CONCLUSION: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life. The detailed evidence-based recommendations allow for nuanced clinical decision making that addresses real-world medical care of patients with obesity, including screening, diagnosis, evaluation, selection of therapy, treatment goals, and individualization of care. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientific approach to management that optimizes health outcomes and safety. ABBREVIATIONS: A1C = hemoglobin A1c AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology AMA = American Medical Association BEL = best evidence level BMI = body mass index CCO = Consensus Conference on Obesity CPG = clinical practice guideline CSS = cross-sectional study CVD = cardiovascular disease EL = evidence level FDA = Food and Drug Administration GERD = gastroesophageal reflux disease HDL-c = high-density lipoprotein cholesterol IFG = impaired fasting glucose IGT = impaired glucose tolerance LDL-c = low-density lipoprotein cholesterol MNRCT = meta-analysis of non-randomized prospective or case-controlled trials NE = no evidence PCOS = polycystic ovary syndrome RCT = randomized controlled trial SS = surveillance study U.S = United States. PMID- 27472014 TI - In situ studies of materials for high temperature CO2 capture and storage. AB - Carbon capture and storage (CCS) offers a possible solution to curb the CO2 emissions from stationary sources in the coming decades, considering the delays in shifting energy generation to carbon neutral sources such as wind, solar and biomass. The most mature technology for post-combustion capture uses a liquid sorbent, amine scrubbing. However, with the existing technology, a large amount of heat is required for the regeneration of the liquid sorbent, which introduces a substantial energy penalty. The use of alternative sorbents for CO2 capture, such as the CaO-CaCO3 system, has been investigated extensively in recent years. However there are significant problems associated with the use of CaO based sorbents, the most challenging one being the deactivation of the sorbent material. When sorbents such as natural limestone are used, the capture capacity of the solid sorbent can fall by as much as 90 mol% after the first 20 carbonation-regeneration cycles. In this study a variety of techniques were employed to understand better the cause of this deterioration from both a structural and morphological standpoint. X-ray and neutron PDF studies were employed to understand better the local surface and interfacial structures formed upon reaction, finding that after carbonation the surface roughness is decreased for CaO. In situ synchrotron X-ray diffraction studies showed that carbonation with added steam leads to a faster and more complete conversion of CaO than under conditions without steam, as evidenced by the phases seen at different depths within the sample. Finally, in situ X-ray tomography experiments were employed to track the morphological changes in the sorbents during carbonation, observing directly the reduction in porosity and increase in tortuosity of the pore network over multiple calcination reactions. PMID- 27472015 TI - Advanced colonic neoplasia in the first degree relatives of colon cancer patients: A colonoscopy-based study. AB - We aimed to determine the risk of advanced neoplasms among a cohort of asymptomatic first degree relatives (FDRs) of patients with sporadic colorectal cancer (CRC) compared with matched controls. Data for patients with a diagnosis of CRC made between September 2013 and August 2014 were obtained from a population-based cancer registry system in Tehran. Screening colonoscopies were done for 342 FDRs and the findings were compared to those from 342 age- and gender-matched healthy controls without a family history of CRC. We reported the association as conditional Odds Ratio (OR) using Mantel Hazel and Logistic regression. The prevalence of advanced neoplasia was 13.2% among FDRs and 3.8% in controls (matched OR [mOR], 4.0, 95% confidence interval [CI], 2.1 - 7.6; p < 0.001). In FDRs aged 40-49 years, the prevalence of advanced neoplasia was significantly higher than in their matched controls (mOR, 6.8, 95% CI, 1.5-31.4; p = 0.01). Family history of CRC in at least one FDR was the strongest predictor of advanced neoplasia (adjusted OR, 4.0, 95% CI: 2.1-7.6; p < 0.001). The age of the index case at diagnosis did not predict the presence of advanced colonic neoplasms in their FDRs. Our study indicates a high risk of advanced neoplasia in FDRs of CRC cases, where only eight colonoscopies are needed to detect one advanced neoplasia. Our data suggest that all FDRs, regardless of the age of CRC diagnosis in their index case, should be considered for a targeted early screening. PMID- 27472016 TI - Anharmonic Theoretical Vibrational Spectroscopy of Polypeptides. AB - Because of the size of polypeptides and proteins, the quantum-chemical prediction of their vibrational spectra presents an exceptionally challenging task. Here, we address one of these challenges, namely, the inclusion of anharmonicities. By performing the expansion of the potential energy surface in localized-mode coordinates instead of the normal-mode coordinates, it becomes possible to calculate anharmonic vibrational spectra of polypeptides efficiently and reliably. We apply this approach to calculate the infrared, Raman, and Raman optical activity spectra of helical alanine polypeptides consisting of up to 20 amino acids. We find that while anharmonicities do not alter the band shapes, simple scaling procedures cannot account for the different shifts found for the individual bands. This closes an important gap in theoretical vibrational spectroscopy by making it possible to quantify the anharmonic contributions and opens the door to a first-principles calculation of multidimensional vibrational spectra. PMID- 27472017 TI - Crossing the threshold: can outcome data from food challenges be used to predict risk of anaphylaxis in the community? PMID- 27472019 TI - Hydroformylation of Olefinic Derivatives of Isosorbide and Isomannide. AB - The first time application of hydroformylation on olefinic derivatives of isosorbide and isomannide is shown by which a new carbon-carbon bond is formed. Depending on the ligand and reaction conditions used, the C6 regioisomer a can be obtained in 4:1 ratio and excellent yield, whereas C5 isomer b is achieved in almost complete regioselectivity (46:1) and good yield. In the majority of cases only the exo orientation is observed for the obtained aldehydes, and the method is easily applicable also on a 1 g scale. PMID- 27472020 TI - The impact of badminton on health markers in untrained females. AB - The purpose of the study was to examine the health effects of 8 weeks of recreational badminton in untrained women. Participants were matched for maximal oxygen uptake (VO2max) and body fat percentage and assigned to either a badminton (n = 14), running (n = 14) or control group (n = 8). Assessments were conducted pre- and post-intervention with physiological, anthropometric, motivation to exercise and physical self-esteem data collected. Post-intervention, VO2max increased (P < 0.05) by 16% and 14% in the badminton and running groups, respectively, and time to exhaustion increased (P < 0.05) by 19% for both interventions. Maximal power output was increased (P < 0.05) by 13% in the badminton group only. Blood pressure, resting heart rate and heart rate during submaximal running were lower (P < 0.05) in both interventions. Perceptions of physical conditioning increased (P < 0.05) in both interventions. There were increases (P < 0.05) in enjoyment and ill health motives in the running group only, whilst affiliation motives were higher (P < 0.05) for the badminton group only. Findings suggest that badminton should be considered a strategy to improving the health and well-being of untrained females who are currently not meeting physical activity guidelines. PMID- 27472021 TI - Perineal pseudocontinent colostomy for ultra-low rectal adenocarcinoma: the muscular graft as a pseudosphincter. AB - BACKGROUND AND STUDY AIM: The aim of this study was to analyze objectively the role of the muscular graft in the continence using manometric study in the patients who underwent pseudocontinent perineal colostomy after abdominoperineal resection for rectal adenocarcinoma. PATIENTS AND METHODS: This was a retrospective study including all the patients from January 2002 to December 2009 who underwent an abdominoperineal resection followed by perineal pseudocontinent colostomy for ultra-low rectal adenocarcinoma and agreed to perform the manometric evaluation of the muscular graft. RESULTS: Fifteen patients were included, six males and nine females, with a mean age of 50 years. According to Kirwan's classification, 2 (13.3%) patients had normal continence (Stage A) had 10 (66.6%) no soiling (stage B) and 3 (20%) patients had minimal soiling (Stage C). The manometric evaluation was performed after a median period of 12 months post-surgery. The mean maximal resting and squeeze pressures were respectively 41 cmH2O and 59 cmH2O and the mean colonic sensory volume was 12 ml. CONCLUSION: This study showed that the musculae graft of Pseudocontinent Perineal colostomy acted as a hypotonic sphincter that pressure can increase during the voluntary squeeze. These data may help to clarify the functional outcomes of this technique after APR for ultra-low rectal adenocarcinoma. PMID- 27472025 TI - Current state and challenges for dynamic metabolic modeling. AB - While the stoichiometry of metabolism is probably the best studied cellular level, the dynamics in metabolism can still not be well described, predicted and, thus, engineered. Unknowns in the metabolic flux behavior arise from kinetic interactions, especially allosteric control mechanisms. While the stoichiometry of enzymes is preserved in vitro, their activity and kinetic behavior differs from the in vivo situation. Next to this challenge, it is infeasible to test the interaction of each enzyme with each intracellular metabolite in vitro exhaustively. As a consequence, the whole interacting metabolome has to be studied in vivo to identify the relevant enzymes properties. In this review we discuss current approaches for in vivo perturbation experiments, that is, stimulus response experiments using different setups and quantitative analytical approaches, including dynamic carbon tracing. Next to reliable and informative data, advanced modeling approaches and computational tools are required to identify kinetic mechanisms and their parameters. PMID- 27472026 TI - Sensing new chemicals with bacterial transcription factors. AB - Bacteria rely on allosteric transcription factors (aTFs) to sense a wide range of chemicals. The variety of effectors has contributed in making aTFs the most used input system in synthetic biological circuits. Considering their enabling role in biotechnology, an important question concerns the size of the chemical space that can potentially be detected by these biosensors. From digging into the ever changing repertoire of natural regulatory circuits, to advances in aTF engineering, we review here different strategies that are pushing the boundaries of this chemical space. We also review natural and synthetic cases of indirect sensing, where aTFs work in combination with metabolism to enable detection of new molecules. PMID- 27472027 TI - System-level genome editing in microbes. AB - The release of the first complete microbial genome sequences at the end of the past century opened the way for functional genomics and systems-biology to uncover the genetic basis of various phenotypes. The surge of available sequence data facilitated the development of novel genome editing techniques for system level analytical studies. Recombineering allowed unprecedented throughput and efficiency in microbial genome editing and the recent discovery and widespread use of RNA-guided endonucleases offered several further perspectives: (i) previously recalcitrant species became editable, (ii) the efficiency of recombineering could be elevated, and as a result (iii) diverse genomic libraries could be generated more effectively. Supporting recombineering by RNA-guided endonucleases has led to success stories in metabolic engineering, but their use for system-level analysis is mostly unexplored. For the full exploitation of opportunities that are offered by the genome editing proficiency, future development of large scale analytical procedures is also vitally needed. PMID- 27472028 TI - Effect of copper contaminated food on the life cycle and secondary production of Daphnia laevis. AB - In aquatic environments, copper (Cu) plays important physiological roles in planktonic food chain, such as electron transfer in photosynthesis and constituting proteins that transport oxygen in some arthropods, while at higher concentrations it is toxic on these organisms and higher trophic levels. The combined effects of natural (e.g. volcanic activity) and anthropogenic sources (e.g. mining waste) contribute to the increase in copper pollution in different ecosystems and regions around the world. In the present study, we evaluated the bioaccumulation and effect of Cu on Raphidocelis subcapitata (freshwater algae), and the influence of Cu-contaminated food (algae) on Daphnia laevis (tropical cladoceran). The amount of copper accumulated in microalgae and cladoceran was quantified, and life-history parameters of D. laevis such as growth, reproduction and longevity were measured. The cell density of Cu exposed R. subcapitata declined, and cladoceran fed with contaminated food had lower longevity, production of eggs and neonates, and reduced secondary production. A concentration dependent increase in Cu accumulation was observed in the microalgae, while the opposite occurred in the animal, indicating a cellular metal regulatory mechanism in the latter. However, this regulation seems not to be sufficient to avoid metal induced damages in the cladoceran such as decreased longevity and reproduction. We conclude that diet is an important metal exposure route to this cladoceran, and the assessment of chronic contamination during the complete life cycle of cladoceran provides results that are similar to those observed in natural environments, especially when native organisms are investigated. PMID- 27472029 TI - The use of a Weight-of-Evidence approach to address sediment quality in the Odiel River basin (SW, Spain). AB - The fluvial systems of the Iberian Pyrite Belt (SW Iberian Peninsula) are affected by acid mine drainage (a lixiviate residue product of mining activities derived from sulfide oxidation). The high acidity and high concentrations of sulfates and metal(loid)s are the main causes of the environmental degradation of the Odiel River basin. The use of weight of evidence approach in areas of the Odiel River basin implies the integration of different lines of evidence (chemistry, toxicity and bioaccumulation) using the freshwater clam Corbicula fluminea as target species. The integration of the results from the application of the different lines of evidence showed that the index of pollution was higher downvalley (Ptriad=12,312), moderate after mining effluent discharges (Ptriad=13.9) and very low where the Odiel River sources (Ptriad=6.31). The multivariate analysis indicated that variables and chemicals were associated with geochemical matrix and background levels (% of fines and toxic metal(loid) concentrations), toxic effects, and metal(loid) bioaccumulation reflecting the geographical distribution of the contamination towards the estuary. Metal(loid) thresholds were calculated for the study area as site-specific values of interim freshwater sediment quality values: As>=171; Cd>=0.48; Co>=8.82; Cr>=38.4; Cu>=451; Ni>=18.4; Pb>=377; Sb>=17.7; Zn>=221mg/kg of freshwater fluvial dry sediment. These results revealed the possibility of using the TEL values proposed by the USEPA and the NOAA for sediments from this site, and proposed lower PEL values for the Iberian Pyrite Belt as result of toxicity effects found in the Asian clam due to the combination of extreme acidity and high metal(loid) concentrations. PMID- 27472030 TI - Letters to the Editor: Re: The Literature That Shaped Modern Periodontology. PMID- 27472031 TI - Letters to the Editor: Re: Platelet-Rich Fibrin With 1% Metformin for the Treatment of Intrabony Defects in Chronic Periodontitis: A Randomized Controlled Clinical Trial. PMID- 27472032 TI - Letters to the Editor: Authors' Response. PMID- 27472033 TI - ManLMN is a glucose transporter and central metabolic regulator in Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a common colonizer of the human nasopharynx and a leading cause of bacterial pneumonia and otitis media, among other invasive diseases. During both colonization and invasive disease S. pneumoniae ferments host-derived carbohydrates as its primary means of generating energy. This pathogen is adept at transporting and metabolizing a wide variety of carbohydrates. We found the highly conserved PTS ManLMN contributes to growth on glucose and is also essential for growth on a variety of nonpreferred carbohydrates, suggesting it is a multisubstrate transporter. Exploration of this phenotype revealed ManLMN is required for inducing expression of downstream metabolic genes in response to carbohydrate stimuli. We further demonstrate that ManLMN's role as a constitutively expressed transporter is likely unique and integral to pneumococcus's strategy of carbon catabolite repression (CCR). Using a selection for suppressors, we explored how ManLMN is integrated into the CCR regulatory framework in S. pneumoniae. We identified two hypothetical small proteins and the virulence regulator SmrC as potential mediators of CCR in connection with ManLMN. Characterization of these two hypothetical proteins revealed they influence transcriptional regulation of carbohydrate transporters. We propose a model unifying these observations in which ManLMN is a versatile surveyor of available carbohydrates in S. pneumoniae. PMID- 27472034 TI - Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma post-autologous stem cell transplant: a cost-effectiveness analysis in Scotland. AB - OBJECTIVE: To evaluate cost-effectiveness of brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma who have received autologous stem cell transplantation, from a Scottish healthcare payer perspective. METHODS: A Microsoft Excel-based partitioned survival model comprising three health states (progression-free survival [PFS], post-progression survival, and death) was developed. Relevant comparators were chemotherapy with or without radiotherapy (C/R) and C/R with intent to allogeneic hematopoietic stem cell transplantation (alloSCT). Data were obtained from the pivotal phase II single-arm trial in 102 patients (SG035-0003; NCT00848926), a systematic literature review and clinical expert opinions (where empirical evidence was unavailable). PFS and overall survival for brentuximab vedotin were estimated using 5-year follow-up data from SG035-0003, and extrapolated using event rates observed for comparator treatments from published survival data. Resource use included drug acquisition and administration; alloSCT; treatment of adverse events; and long-term follow-up. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the impact of uncertainty. RESULTS: In the base case, the incremental cost effectiveness ratio (ICER) for brentuximab vedotin was L38,769 per quality adjusted life year (QALY) vs C/R, whereas C/R with intent to alloSCT was dominated by brentuximab vedotin. ICERs for brentuximab vedotin generated by the deterministic sensitivity analysis ranged between L32,000-L54,000 per QALY. Including productivity benefits reduced the ICER to L28,881 per QALY. LIMITATIONS: Limitations include lack of comparative data from this single arm study and the heterogeneous population. Inconsistent baseline characteristic reporting across studies prevented complete assessment of heterogeneity and the extent of potential bias in clinical and cost-effectiveness estimates. CONCLUSIONS: Although the base case ICER is above the threshold usually applied in Scotland, it is relatively low compared with other orphan drugs, and lower than the ICER generated using a previous data cut of SG035-0003 that informed a positive recommendation from the Scottish Medicines Consortium, under its decision-making framework for assessment of ultra-orphan medicines. PMID- 27472035 TI - Typing pictures: Linguistic processing cascades into finger movements. AB - The present study investigated the effect of psycholinguistic variables on measures of response latency and mean interkeystroke interval in a typewritten picture naming task, with the aim to outline the functional organization of the stages of cognitive processing and response execution associated with typewritten word production. Onset latencies were modulated by lexical and semantic variables traditionally linked to lexical retrieval, such as word frequency, age of acquisition, and naming agreement. Orthographic variables, both at the lexical and sublexical level, appear to influence just within-word interkeystroke intervals, suggesting that orthographic information may play a relevant role in controlling actual response execution. Lexical-semantic variables also influenced speed of execution. This points towards cascaded flow of activation between stages of lexical access and response execution. PMID- 27472036 TI - The early emergence and puzzling decline of relational reasoning: Effects of knowledge and search on inferring abstract concepts. AB - We explore the developmental trajectory and underlying mechanisms of abstract relational reasoning. We describe a surprising developmental pattern: Younger learners are better than older ones at inferring abstract causal relations. Walker and Gopnik (2014) demonstrated that toddlers are able to infer that an effect was caused by a relation between two objects (whether they are the same or different), rather than by individual kinds of objects. While these findings are consistent with evidence that infants recognize same-different relations, they contrast with a large literature suggesting that older children tend to have difficulty inferring these relations. Why might this be? In Experiment 1a, we demonstrate that while younger children (18-30-month-olds) have no difficulty learning these relational concepts, older children (36-48-month-olds) fail to draw this abstract inference. Experiment 1b replicates the finding with 18-30 month-olds using a more demanding intervention task. Experiment 2 tests whether this difference in performance might be because older children have developed the general hypothesis that individual kinds of objects are causal - the high initial probability of this alternative hypothesis might override the data that favors the relational hypothesis. Providing additional information falsifying the alternative hypothesis improves older children's performance. Finally, Experiment 3 demonstrates that prompting for explanations during learning also improves performance, even without any additional information. These findings are discussed in light of recent computational and algorithmic theories of learning. PMID- 27472037 TI - Do 18F-FDG PET/CT findings have a relationship with histopathological and immunohistochemical factors of breast cancer in men? AB - PURPOSE: We aimed to investigate the relationship between histopathological and immunohistochemical features of male breast cancer (MBC) and comprehensive fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) parameters. METHODS: Fifteen male patients with newly diagnosed breast cancer who underwent F FDG PET/CT were included in the study. Maximum and average standardized uptake value (SUVmax and SUVavg), metabolic total volume, and total lesion glycolysis (TLG) were compared with the histopathological and immunohistochemical findings of patients. In addition, metabolic tumor-node-metastases (TNM) staging was performed following the determination of metastatic axillary lymph nodes and tumor size by F-FDG PET/CT and verified by histopathological evaluation. RESULTS: There were no significant differences between all groups classified on the basis of histopathological and immunohistochemical parameters for SUVmax, SUVavg, TLG, and metabolic total volume. The only difference was found in patients with distant metastases and stage IV. SUVmax, SUVavg, and TLG were higher in patients with distant metastases compared with patients without distant metastases (P: 0.005, 0.011, and 0.042, respectively). Strong correlations were found between metabolic TNM staging and histopathological TNM staging (for T stage; r: 0.590, P: 0.021, N stage; r: 0.694, P: 0.002, TNM stage; r: 0.835, P: 0.002). In addition, no differences were found with any metabolic F-FDG PET/CT parameters in survival. CONCLUSION: Although no correlation was found between metabolic parameters and groups categorized on the basis of histopathological or immunohistochemical features, F-FDG PET/CT is a reliable imaging modality to determine tumor size, axillary lymph node involvement, and metabolic TNM staging of MBC. In addition, none of those metabolic F-FDG PET/CT parameters predicted survival in MBC. PMID- 27472038 TI - Fractional flow reserve using computed tomography for assessing coronary artery disease: a meta-analysis. AB - AIMS: Noninvasive fractional flow reserve (FFR) measurement with computed tomography (FFRCT) is a newly described method for assessing functional significance of coronary disease. The objective of this meta-analysis is to determine the diagnostic performance of FFRCT in the assessment of hemodynamically significant coronary artery stenosis. METHODS: PubMed and the Cochrane Center Register of Controlled Trials were searched from January 2000 through February 2015. Six original studies were found comparing FFRCT to invasive FFR in evaluating hemodynamic significance of coronary lesions (1354 vessels; 812 patients). Lesions were considered hemodynamically significant if invasive FFR was 0.80 or less. FFRCT used the same cutoff as invasive FFR to be considered as a positive test. Sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio were calculated. RESULTS: One-third of the lesions (n = 443) were hemodynamically significant. The pooled per-vessel analysis showed that the sensitivity, specificity, negative and positive likelihood ratios, and diagnostic odds ratio of FFRCT to diagnose hemodynamically significant coronary disease were 0.84 [95% confidence interval (CI): 0.80-0.87], 0.76 (95% CI: 0.73-0.79), 0.22 (95% CI: 0.17-0.29), 3.48 (95% CI: 2.21-5.47), and 16.82 (95% CI: 8.20-34.49), respectively. CONCLUSION: The results of this meta analysis demonstrate that FFRCT results correlate closely with invasive coronary angiography and FFR measurement. It is a feasible noninvasive method to assess hemodynamic significance of coronary lesions in patients with stable coronary artery disease. PMID- 27472039 TI - Sleep in Adolescents With Bipolar I Disorder: Stability and Relation to Symptom Change. AB - Sleep disturbances are common features of bipolar disorder (BD), yet little is known about trajectories of sleep disturbances in youth with BD. Using longitudinal data, this study assessed the stability of sleep disturbances and their ability to predict symptom progression in adolescents diagnosed with BD compared to controls. Thirteen- to 19-year-olds meeting diagnostic criteria for BD I (n = 19, 16.2 +/- 1.75 years, 57.9 % female, 68.4% Caucasian) and psychiatrically healthy age-comparable controls (n = 21, 15.7 +/- 1.48 years. 52.4% female, 57.1% Caucasian) were assessed for sleep onset latency, number of awakenings, and wake time, separately for weekdays and weekends using a self report questionnaire. Sleep indices and symptoms of mania (Young Mania Rating Scale) and depression (Children's Depression Rating Scale) were assessed at two time points, T1 and T2, approximately 12 months apart. Correlations were used to examine stability of sleep indices across time points and regression models to examine the effects of T1 sleep on T2 symptoms. Adolescents with BD showed low stability on most sleep indices, whereas controls showed high stability on all sleep indices. After controlling for T1 depression symptoms, more T1 weekend awakenings and weekend wake time predicted significantly greater T2 depression symptoms in youth with BD but not in controls. No significant associations were found between T1 sleep and T2 mania symptoms. These findings suggest that increased awakenings and wakefulness on weekends may represent an important therapeutic target for reducing depression in adolescents with BD. PMID- 27472040 TI - Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-kappaB. AB - Although certain evidence has indicated a role for angiogenesis in the pathophysiology of hematopoietic malignancies, its role in chronic lymphocytic leukemia (CLL) prognosis is yet to be defined. To our knowledge, the effects of CLL plasma on cell culture have not been addressed. Therefore, we investigated the effects of CLL plasma on cell cycle regulation and von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs). Since nuclear factor-kappa B (NF-kappaB) transcription factor has been a therapeutic target for treatment of cancer, we inhibited NF-kappaB using small interfering RNA to clarify if there is a role for this factor in probable effects. The cells were treated with the plasma of patients with CLL. Subsequently, cell cycle phase distribution, vWF secretion, expression, and storage were detected using ELISA, flow cytometry, and immunohistochemical staining. In addition, NF-kappaB was inhibited using small interfering RNA. Plasma treatment promoted cell cycle progression by decreasing the cell number in G1 phase, while increasing the cell number in S phase and G2M phase. A significant increase of vWF expression, secretion, and storage was found, associated with the vWF levels of patients' plasma. We found that induction of cell cycle promotion, but not vWF expression and secretion, was partially suppressed by this inhibition. We found that endothelial cell cycle and vWF expression and secretion affected by CLL plasma and NF-kappaB play a role in the former. These findings would be useful for understanding the prognostic importance of plasma angiogenic factor levels in CLL. PMID- 27472044 TI - An assessment of olfactory function in patients with laryngopharyngeal reflux disease. AB - CONCLUSIONS: The results reported here indicate that there was a statistically significant difference in the olfactory functions of laryngopharyngeal reflux patients vs the healthy group. To the best of the authors' knowledge, this study is the first to evaluate the olfactory function of patients diagnosed with laryngopharyngeal reflux using an objective method, 24-h pH monitoring. OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate olfactory functions in laryngopharyngeal reflux (LPR) patients and compare the results with healthy controls. METHODS: A total of 60 participants; 30 men and women with a diagnosis of laryngopharyngeal reflux and 30 healthy controls, were included in the study. Patients in the laryngopharyngeal reflux group were evaluated by the Reflux Symptom Index (RSI), Reflux Finding Scores (RFS), and finally 24-h pH monitoring to confirm the diagnosis of laryngopharyngeal reflux. The Sniffin' Sticks olfactory test results of the laryngopharyngeal reflux and control groups were compared, and the relationship between the study findings and the olfactory parameters were evaluated. RESULTS: The odor threshold, odor discrimination, odor identification, and TDI scores of the laryngopharyngeal reflux group were significantly lower than those of the control group. Also there was a statistically significant negative correlation detected between the olfactory test and some symptom and finding scores. PMID- 27472046 TI - Corrigendum. PMID- 27472045 TI - Fate and Characterization Factors of Nanoparticles in Seventeen Subcontinental Freshwaters: A Case Study on Copper Nanoparticles. AB - The lack of characterization factors (CFs) for engineered nanoparticles (ENPs) hampers the application of life cycle assessment (LCA) methodology in evaluating the potential environmental impacts of nanomaterials. Here, the framework of the USEtox model has been selected to solve this problem. On the basis of colloid science, a fate model for ENPs has been developed to calculate the freshwater fate factor (FF) of ENPs. We also give the recommendations for using the hydrological data from the USEtox model. The functionality of our fate model is proved by comparing our computed results with the reported scenarios in North America, Switzerland, and Europe. As a case study, a literature survey of the nano-Cu toxicology values has been performed to calculate the effect factor (EF). Seventeen freshwater CFs of nano-Cu are proposed as recommended values for subcontinental regions. Depending on the regions and the properties of the ENPs, the region most likely to be affected by nano-Cu is Africa (CF of 11.11 * 10(3) CTUe, comparative toxic units) and the least likely is north Australia (CF of 3.87 * 10(3) CTUe). Furthermore, from the sensitivity analysis of the fate model, 13 input parameters (such as depth of freshwater, radius of ENPs) show vastly different degrees of influence on the outcomes. The characterization of suspended particles in freshwater and the dissolution rate of ENPs are two significant factors. PMID- 27472047 TI - An Evaluation of Benchmarks for Esthetic Orientation of the Occlusal Plane. AB - PURPOSE: This patient study was designed to measure the validity of both the horizontal and Camper's planes, which are used as benchmarks to reestablish the sagittal orientation of the occlusal plane angles in dental rehabilitation. MATERIALS AND METHODS: Profile digital photographs were made of the first 100 consenting dentate patients as they closed on an occlusal plane analyzer while maintaining natural head posture. Using a digital screen protractor, three angles were measured: the occlusal plane angle relative to the horizontal plane, and the angle between the occlusal plane and Camper's plane from both the superior and inferior borders of the tragus of the ear. RESULTS: The angle between the occlusal plane and the horizontal reference plane for the 100 patients ranged from -8.72 degrees to +18.08 degrees (mean +3.25 degrees ); the angle between the occlusal plane and Camper's plane, from the superior border of the tragus to the ala of the nose demonstrated a range from -8.49 degrees to +15.16 degrees (mean +3.03 degrees ); and the angle between Camper's plane, from the inferior border of the tragus to the ala of the nose and the occlusal plane demonstrated a range from -15.57 degrees to +9.15 degrees (mean -4.09 degrees ). CONCLUSIONS: Occlusal plane angles measured in this patient population with natural dentitions demonstrated a relatively small mean deviation from both the horizontal plane and Camper's plane when using the superior border of the tragus as the distal reference point, but the range was quite broad and could result in unacceptable occlusal plane angles in many patients undergoing dental rehabilitation. CLINICAL IMPLICATIONS: Both Camper's plane and the horizontal reference plane may be acceptable initial reference planes for oral rehabilitation, but additional anatomic and esthetic parameters are required for verification of an esthetically pleasing occlusal plane angle. PMID- 27472048 TI - (129)Xe NMR Relaxation-Based Macromolecular Sensing. AB - We report a (129)Xe NMR relaxation-based sensing approach that exploits changes in the bulk xenon relaxation rate induced by slowed tumbling of a cryptophane based sensor upon target binding. The amplification afforded by detection of the bulk dissolved xenon allows sensitive detection of targets. The sensor comprises a xenon-binding cryptophane cage, a target interaction element, and a metal chelating agent. Xenon associated with the target-bound cryptophane cage is rapidly relaxed and then detected after exchange with the bulk. Here we show that large macromolecular targets increase the rotational correlation time of xenon, increasing its relaxation rate. Upon binding of a biotin-containing sensor to avidin at 1.5 MUM concentration, the free xenon T2 is reduced by a factor of 4. PMID- 27472049 TI - Waste recycling by vermicomposting: Maturity and quality assessment via dehydrogenase enzyme activity, lignin, water soluble carbon, nitrogen, phosphorous and other indicators. AB - Present study aims to examine the dynamics of maturation and qualification indicators in various vermicompost treatments and selection of the best treatment along with best maturation time in this regard. In this empirical study, dynamics of chemical (pH, electrical conductivity (EC), total nitrogen (TN), phosphorous, lignin, water soluble carbon (WSC), C/N, NH4/NO3) and biological (dehydrogenase enzyme (DEH) and DEH/WSC) properties were investigated in four various treatments, including various ratios of compost produced from municipal solid waste (MSW) and carbonaceous materials (50:50, 70:30, 85:15 and 100:0) over 100 days. Results showed a significant fluctuation in EC, DEH and DEH/WSC proportions over the process. In addition, a noticeable increase was observed for the dynamics of TN, phosphorous and lignin. In contrast, the C/N, NH4/NO3 and WSC values gradually decreased during the process. Moreover, it was observed that the length of 75 days for the process is an appropriate time for maturation of all treatments. However, the first and second treatments resulted in better outcomes compared with the other types of treatments. From the point of view of quality obtained vermicompost was nitrogen enriched product in all treatments. Whereas, for the phosphorous elements this method is appropriate for the first treatment only. PMID- 27472050 TI - Carbon-cryogel hierarchical composites as effective and scalable filters for removal of trace organic pollutants from water. AB - Effective technologies are required to remove organic micropollutants from large fluid volumes to overcome present and future challenges in water and effluent treatment. A novel hierarchical composite filter material for rapid and effective removal of polar organic contaminants from water was developed. The composite is fabricated from phenolic resin-derived carbon microbeads with controllable porous structure and specific surface area embedded in a monolithic, flow permeable, poly(vinyl alcohol) cryogel. The bead-embedded monolithic composite filter retains the bulk of the high adsorptive capacity of the carbon microbeads while improving pore diffusion rates of organic pollutants. Water spiked with organic contaminants, both at environmentally relevant concentrations and at high levels of contamination, was used to determine the purification limits of the filter. Flow through tests using water spiked with the pesticides atrazine (32 mg/L) and malathion (16 mg/L) indicated maximum adsorptive capacities of 641 and 591 mg pollutant/g carbon, respectively. Over 400 bed volumes of water contaminated with 32 mg atrazine/L, and over 27,400 bed volumes of water contaminated with 2 MUg atrazine/L, were treated before pesticide guideline values of 0.1 MUg/L were exceeded. High adsorptive capacity was maintained when using water with high total organic carbon (TOC) levels and high salinity. The toxicity of water filtrates was tested in vitro with human epithelial cells with no evidence of cytotoxicity after initial washing. PMID- 27472051 TI - Priority substances in sediments of the "Carska Bara" special nature reserve, a natural scientific research area on the UNESCO list. AB - Surface sediments were subject to systematic long-term monitoring (2002-2014) in the Republic of Serbia (Province of Vojvodina). Eight heavy metals (Ni, Zn, Cd, Cr, Cu, Pb, As and Hg), mineral oils (total petroleum hydrocarbons), 16 EPA PAHs, selected pesticides and polychlorinated biphenyls (PCB) were monitored. As part of this research, this paper presents a sediment contamination spatial and temporal trend study of diverse pollution sources and the ecological risk status of the alluvial sediments of Carska Bara at three representative sampling sites (S1S3), in order to establish the status of contamination and recommend substances of interest for more widespread future monitoring. Multivariate statistical methods including factor analysis of principal component analysis (PCA/FA), Pearson correlation and several synthetic indicators were used to evaluate the extent and origin of contamination (anthropogenic or natural, geogenic sources) and potential ecological risks. Hg, Cd, As, mineral oils and PAHs (dominated by dibenzo(a,h)anthracene and benzo(a)pyrene, contributing 85.7% of the total) are derived from several anthropogenic sources, whereas Ni, Cu, Cr and Zn are convincingly of geogenic origin, and exhibit dual origins. Cd and Hg significantly raise the levels of potential ecological risk for all sampling locations, demonstrating the effect of long-term bioaccumulation and biomagnification. Pb is isolated from the other parameters, implying unique sources. This research suggests four heavy metals (Zn, Cr, Cu and As) and dibenzo(a,h)anthracene be added to the list of priority pollutants within the context of the application of the European Water Framework Directive (WFD), in accordance with significant national and similar environmental data from countries in the region. PMID- 27472052 TI - Valorization of CH4 emissions into high-added-value products: Assessing the production of ectoine coupled with CH4 abatement. AB - This study assessed an innovative strategy for the valorization of dilute methane emissions based on the bio-conversion of CH4 (the second most important greenhouse gas (GHG)) into ectoine by the methanotrophic ectoine-producing strain Methylomicrobium alcaliphilum 20 Z. The influence of CH4 (2-20%), Cu(2+) (0.05-50 MUM) and NaCl (0-9%) concentration as well as temperature (25-35 degrees C) on ectoine synthesis and specific CH4 biodegradation rate was evaluated for the first time. Concentrations of 20% CH4 (at 3% NaCl, 0.05 MUM Cu(2+), 25 degrees C) and 6% NaCl (at 4% CH4, 0.05 MUM Cu(2+), 25 degrees C) supported the maximum intra-cellular ectoine production yield (31.0 +/-1.7 and 66.9 +/-4.2 mg g biomass(-1), respectively). On the other hand, extra-cellular ectoine concentrations of up to 4.7 +/- 0.1 mg L(-1) were detected at high Cu(2+)concentrations (50 MUM), despite this methanotroph has not been previously classified as an ectoine-excreting strain. This research demonstrated the feasibility of the bio-conversion of dilute emissions of methane into high-added value products in an attempt to develop a sustainable GHG bioeconomy. PMID- 27472053 TI - Changes in grass plant populations and temporal soil seed bank dynamics in a semi arid African savanna: Implications for restoration. AB - The re-colonization or recovery of grass species after disappearance due to heavy grazing depends on the presence of persistent soil seed banks that might be accumulated over time from the aboveground vegetation. Moreover, successful plant recruitment is a function of seed production, seed germination and seedling survival, which can be mechanistically understood through studying the life cycle processes of grass species populations under field conditions. Therefore, we studied the number of germinable seeds, species richness and life-forms in the soil seed banks under light and heavy grazing conditions, and the changes in grass species populations in a semi-arid savanna of Ethiopia. Accordingly, a total of 103 species (15 perennial and 29 annual grasses, 6 legumes, 52 forbs and 1 woody species) emerged from the soil samples collected. Lightly grazed sites had a higher seed density compared with heavily grazed sites. The seed density increased over the first three months of soil sampling and decreased thereafter. Perennial grasses dominated the light grazing sites, whereas annual species dominated the heavily grazed sites, indicating that perennial grasses were replaced by annual species in the soil seed bank through grazing. The mean mortality rate from the seedling stage to adult plants was 65%. The seed-to seedling stage was found to be the most critical transitional stage for grass survival. High seedling mortality in the aboveground vegetation and depletion of seeds in the soil seed banks as a result of sustained heavy grazing can lead to local extinction and disappearance of perennial grasses in semi-arid Ethiopian savannas. PMID- 27472054 TI - Impact of elevated carbon dioxide on soil heat storage and heat flux under unheated low-tunnels conditions. AB - Suboptimal regimes of air and soil temperature usually occur under unheated low tunnels during winter crop cycles. CO2 is one of the most important gases linked to climate change and posing challenge to the current agricultural productivity. Field experiment was conducted in unheated low-tunnels (10.0 m long, 1.5 m wide and 1.0 m high) during winter and spring periods to evaluate the increasing CO2 concentration (352, 709, 1063, 1407, and 1761 ppm) on net radiation budget, soil air thermal regime and pepper plants growth development and yield. CO2 was injected into each hollow space of the tunnel double-layer transparent polyethylene covers. Recorded integral net longwave radiation increased from 524.81 to 1111.84 Wm(-2) on January when CO2 concentration increased from 352 to 1761 ppm. A similar trend was recorded on February. Moreover, minimum soil surface and air temperatures were markedly increased from -1.3 and -6.8 degrees C to 3.4 and 0.6 degrees C, when CO2 concentration increased from 352 to 1761 ppm. Additionally, soil heat flux as well as soil heat storage increased with increasing CO2 concentrations accordingly. Increasing the tunnel minimum air and soil temperatures with the CO2 concentration treatments 1063, 1407 and 1761 ppm reflected in a significant pepper yield (3.19, 5.06 and 6.13 kg m(-2)) due to the modification of the surrounding plants microenvironment and prevented pepper plants from freezing and the accelerated the plant growth. On the contrary, the drop of minimum air and soil temperatures to freezing levels with the CO2 concentration treatments 352 and 709 ppm resulted in the deterioration of pepper plants development during the early growth stages on January. PMID- 27472055 TI - Structural and Catalytic Characterization of a Fungal Baeyer-Villiger Monooxygenase. AB - Baeyer-Villiger monooxygenases (BVMOs) are biocatalysts that convert ketones to esters. Due to their high regio-, stereo- and enantioselectivity and ability to catalyse these reactions under mild conditions, they have gained interest as alternatives to chemical Baeyer-Villiger catalysts. Despite their widespread occurrence within the fungal kingdom, most of the currently characterized BVMOs are from bacterial origin. Here we report the catalytic and structural characterization of BVMOAFL838 from Aspergillus flavus. BVMOAFL838 converts linear and aryl ketones with high regioselectivity. Steady-state kinetics revealed BVMOAFL838 to show significant substrate inhibition with phenylacetone, which was more pronounced at low pH, enzyme and buffer concentrations. Para substitutions on the phenyl group significantly improved substrate affinity and increased turnover frequencies. Steady-state kinetics revealed BVMOAFL838 to preferentially oxidize aliphatic ketones and aryl ketones when the phenyl group are separated by at least two carbons from the carbonyl group. The X-ray crystal structure, the first of a fungal BVMO, was determined at 1.9 A and revealed the typical overall fold seen in type I bacterial BVMOs. The active site Arg and Asp are conserved, with the Arg found in the "in" position. Similar to phenylacetone monooxygenase (PAMO), a two residue insert relative to cyclohexanone monooxygenase (CHMO) forms a bulge within the active site. Approximately half of the "variable" loop is folded into a short alpha-helix and covers part of the active site entry channel in the non-NADPH bound structure. This study adds to the current efforts to rationalize the substrate scope of BVMOs through comparative catalytic and structural investigation of different BVMOs. PMID- 27472056 TI - Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease. AB - Ciliopathies are genetic disorders arising from dysfunction of microtubule-based cellular appendages called cilia. Different cilia types possess distinct stereotypic microtubule doublet arrangements with non-motile or 'primary' cilia having a 9+0 and motile cilia have a 9+2 array of microtubule doublets. Primary cilia are critical sensory and signaling centers needed for normal mammalian development. Defects in their structure/function result in a spectrum of clinical and developmental pathologies including abnormal neural tube and limb patterning. Altered patterning phenotypes in the limb and neural tube are due to perturbations in the hedgehog (Hh) signaling pathway. Motile cilia are important in fluid movement and defects in motility result in chronic respiratory infections, altered left-right asymmetry, and infertility. These features are the hallmarks of Primary Ciliary Dyskinesia (PCD, OMIM 244400). While mutations in several genes are associated with PCD in patients and animal models, the genetic lesion in many cases is unknown. We assessed the in vivo functions of Growth Arrest Specific 8 (GAS8). GAS8 shares strong sequence similarity with the Chlamydomonas Nexin-Dynein Regulatory Complex (NDRC) protein 4 (DRC4) where it is needed for proper flagella motility. In mammalian cells, the GAS8 protein localizes not only to the microtubule axoneme of motile cilia, but also to the base of non-motile cilia. Gas8 was recently implicated in the Hh signaling pathway as a regulator of Smoothened trafficking into the cilium. Here, we generate the first mouse with a Gas8 mutation and show that it causes severe PCD phenotypes; however, there were no overt Hh pathway phenotypes. In addition, we identified two human patients with missense variants in Gas8. Rescue experiments in Chlamydomonas revealed a subtle defect in swim velocity compared to controls. Further experiments using CRISPR/Cas9 homology driven repair (HDR) to generate one of these human missense variants in mice demonstrated that this allele is likely pathogenic. PMID- 27472058 TI - Effect of Codend Circumference on the Size Selection of Square-Mesh Codends in Trawl Fisheries. AB - It is well established that increasing mesh number in the circumference of a diamond-mesh trawl codend can reduce size selection for round fish, whereas selection for flat fish species is unaffected. This effect has also been documented in Mediterranean trawl fisheries. In contrast, no information is available with regard to the effect of increasing mesh number in the circumference of square-mesh codends on the size selection of round fish and flat fish species. A field study was devised to bridge this gap and formulate proposals aimed at improving trawl fishery management. Size selection data were collected for a round fish species, red mullet (Mullus barbatus), and two flat fish species, Mediterranean scaldfish (Arnoglossus laterna) and solenette (Buglossidium luteum). Fishing trials were conducted in the Adriatic Sea (Central Mediterranean) using three square-mesh codends that differed only in mesh number around the circumference. Results demonstrated that increasing the number of meshes from 107 to 213 reduced the 50% retention length (L50) for red mullet by 2.5 cm but did not affect size selection for the two flat fish species. In some fisheries, regulatory provisions regarding the number of meshes in the circumference should therefore be carefully considered both for diamond- and square-mesh codends. PMID- 27472057 TI - Identification of TENP as the Gene Encoding Chicken Egg White Ovoglobulin G2 and Demonstration of Its High Genetic Variability in Chickens. AB - Ovoglobulin G2 (G2) has long been known as a major protein constituent of chicken egg white. However, little is known about the biochemical properties and biological functions of G2 because the gene encoding G2 has not been identified. Therefore, the identification of the gene encoding G2 and an analysis of its genetic variability is an important step toward the goal of understanding the biological functions of the G2 protein and its utility in poultry production. To identify and characterize the gene encoding G2, we separated G2 from egg white using electrophoresis on a non-denaturing polyacrylamide gel. Two polymorphic forms of G2 protein (G2A and G2B), with different mobilities (fast and slow respectively), were detected by staining. The protein band corresponding to G2B was electro-eluted from the native gel, re-electrophoresed under denaturing conditions and its N-terminal sequence was determined by Edman degradation following transfer onto a membrane. Sequencing of the 47 kDa G2B band revealed it to be identical to TENP (transiently expressed in neural precursors), also known as BPI fold-containing family B, member 2 (BPIFB2), a protein with strong homology to a bacterial permeability-increasing protein family (BPI) in mammals. Full-length chicken TENP cDNA sequences were determined for 78 individuals across 29 chicken breeds, lines, and populations, and consequently eleven non-synonymous substitutions were detected in the coding region. Of the eleven non-synonymous substitutions, A329G leading to Arg110Gln was completely associated with the noted differential electrophoretic mobility of G2. Specifically G2B, with a slower mobility is encoded by A329 (Arg110), whereas G2A, with a faster mobility, is encoded by G329 (Gln110). The sequence data, derived from the coding region, also revealed that the gene encoding G2 demonstrates significant genetic variability across different chicken breeds/lines/populations. These variants, and how they correlate with egg white properties, may allow us to understand further G2's functions. PMID- 27472059 TI - The Effect of Altered Loading on Mandibular Condylar Cartilage. AB - OBJECTIVE: The purpose of this study was to delineate the cellular, mechanical and morphometric effects of altered loading on the mandibular condylar cartilage (MCC) and subchondral bone. We hypothesized that altered loading will induce differentiation of cells by accelerating the lineage progression of the MCC. MATERIALS AND METHODS: Four-week-old male Dkk3 XCol2A1XCol10A1 mice were randomly divided into two groups: (1) Loaded-Altered loading of MCC was induced by forced mouth opening using a custom-made spring; (2) Control-served as an unloaded group. Mice were euthanized and flow cytometery based cell analysis, micro-CT, gene expression analysis, histology and morphometric measurements were done to assess the response. RESULTS: Our flow cytometery data showed that altered loading resulted in a significant increase in a number of Col2a1-positive (blue) and Col10a1-positive (red) expressing cells. The gene expression analysis showed significant increase in expression of BMP2, Col10a1 and Sox 9 in the altered loading group. There was a significant increase in the bone volume fraction and trabecular thickness, but a decrease in the trabecular spacing of the subchondral bone with the altered loading. Morphometric measurements revealed increased mandibular length, increased condylar length and increased cartilage width with altered loading. Our histology showed increased mineralization/calcification of the MCC with 5 days of loading. An unexpected observation was an increase in expression of tartrate resistant acid phosphatase activity in the fibrocartilaginous region with loading. CONCLUSION: Altered loading leads to mineralization of fibrocartilage and drives the lineage towards differentiation/maturation. PMID- 27472060 TI - DNA Damage Responses Are Induced by tRNA Anticodon Nucleases and Hygromycin B. AB - Previous studies revealed DNA damage to occur during the toxic action of PaT, a fungal anticodon ribonuclease (ACNase) targeting the translation machinery via tRNA cleavage. Here, we demonstrate that other translational stressors induce DNA damage-like responses in yeast as well: not only zymocin, another ACNase from the dairy yeast Kluyveromyces lactis, but also translational antibiotics, most pronouncedly hygromycin B (HygB). Specifically, DNA repair mechanisms BER (base excision repair), HR (homologous recombination) and PRR (post replication repair) provided protection, whereas NHEJ (non-homologous end-joining) aggravated toxicity of all translational inhibitors. Analysis of specific BER mutants disclosed a strong HygB, zymocin and PaT protective effect of the endonucleases acting on apurinic sites. In cells defective in AP endonucleases, inactivation of the DNA glycosylase Ung1 increased tolerance to ACNases and HygB. In addition, Mag1 specifically contributes to the repair of DNA lesions caused by HygB. Consistent with DNA damage provoked by translation inhibitors, mutation frequencies were elevated upon exposure to both fungal ACNases and HygB. Since polymerase zeta contributed to toxicity in all instances, error-prone lesion bypass probably accounts for the mutagenic effects. The finding that differently acting inhibitors of protein biosynthesis induce alike cellular responses in DNA repair mutants is novel and suggests the dependency of genome stability on translational fidelity. PMID- 27472062 TI - Activation of beta-Catenin Signaling in CD133-Positive Dermal Papilla Cells Drives Postnatal Hair Growth. AB - The hair follicle dermal papilla (DP) contains a unique prominin-1/CD133-positive (CD133+) cell subpopulation, which has been shown to possess hair follicle inducing capability. By assaying for endogenous CD133 expression and performing lineage tracing using CD133-CreERT2; ZsGreen1 reporter mice, we find that CD133 is expressed in a subpopulation of DP cells during the growth phase of the murine hair cycle (anagen), but is absent at anagen onset. However, how CD133+ DP cells interact with keratinocytes to induce hair regenerative growth remains unclear. Wnt/beta-catenin has long been recognized as a major signaling pathway required for hair follicle morphogenesis, development, and regeneration. Nuclear Wnt/beta catenin activity is observed in the DP during the hair growth phase. Here we show that induced expression of a stabilized form of beta-catenin in CD133+ DP cells significantly accelerates spontaneous and depilation-induced hair growth. However, hair follicle regression is not affected in these mutants. Further analysis indicates that CD133+ DP-expressed beta-catenin increases proliferation and differentiation of epithelial matrix keratinocytes. Upregulated Wnt/beta catenin activity in CD133+ DP cells also increases the number of proliferating DP cells in each anagen follicle. Our data demonstrate that beta-catenin signaling potentiates the capability of CD133+ DP cells to promote postnatal hair growth. PMID- 27472061 TI - Analysis of the Bile Salt Export Pump (ABCB11) Interactome Employing Complementary Approaches. AB - The bile salt export pump (BSEP, ABCB11) plays an essential role in the formation of bile. In hepatocytes, BSEP is localized within the apical (canalicular) membrane and a deficiency of canalicular BSEP function is associated with severe forms of cholestasis. Regulation of correct trafficking to the canalicular membrane and of activity is essential to ensure BSEP functionality and thus normal bile flow. However, little is known about the identity of interaction partners regulating function and localization of BSEP. In our study, interaction partners of BSEP were identified in a complementary approach: Firstly, BSEP interaction partners were co-immunoprecipitated from human liver samples and identified by mass spectrometry (MS). Secondly, a membrane yeast two-hybrid (MYTH) assay was used to determine protein interaction partners using a human liver cDNA library. A selection of interaction partners identified both by MYTH and MS were verified by in vitro interaction studies using purified proteins. By these complementary approaches, a set of ten novel BSEP interaction partners was identified. With the exception of radixin, all other interaction partners were integral or membrane-associated proteins including proteins of the early secretory pathway and the bile acyl-CoA synthetase, the second to last, ER associated enzyme of bile salt synthesis. PMID- 27472065 TI - Quality-assured cancer surgery for Wilms tumour: What is the role of the clinical trials groups? PMID- 27472063 TI - Transcriptional control of non-apoptotic developmental cell death in C. elegans. AB - Programmed cell death is an essential aspect of animal development. Mutations in vertebrate genes that mediate apoptosis only mildly perturb development, suggesting that other cell death modes likely have important roles. Linker cell type death (LCD) is a morphologically conserved cell death form operating during the development of Caenorhabditis elegans and vertebrates. We recently described a molecular network governing LCD in C. elegans, delineating a key role for the transcription factor heat-shock factor 1 (HSF-1). Although HSF-1 functions to protect cells from stress in many settings by inducing expression of protein folding chaperones, it promotes LCD by inducing expression of the conserved E2 ubiquitin-conjugating enzyme LET-70/UBE2D2, which is not induced by stress. Following whole-genome RNA interference and candidate gene screens, we identified and characterized four conserved regulators required for LCD. Here we show that two of these, NOB-1/Hox and EOR-1/PLZF, act upstream of HSF-1, in the context of Wnt signaling. A third protein, NHR-67/TLX/NR2E1, also functions upstream of HSF 1, and has a separate activity that prevents precocious expression of HSF-1 transcriptional targets. We demonstrate that the SET-16/mixed lineage leukemia 3/4 (MLL3/4) chromatin regulation complex functions at the same step or downstream of HSF-1 to control LET-70/UBE2D2 expression. Our results identify conserved proteins governing LCD, and demonstrate that transcriptional regulators influence this process at multiple levels. PMID- 27472066 TI - Melting of gelatin gels confined to silica nanopores. AB - Nanoconfinement is a way to create materials whose properties differ from the bulk. For the first time, this research explores the effect of nanoconfinement on the thermodynamics and kinetics of gel melting. Differential scanning calorimetry has been employed to study gelatin gels prepared inside 4, 6, 15, and 30 nm pores of a silica matrix. It has been found that with decreasing the pore size the heat of melting decreases from 3.5 J g-1 in bulk to 0.6 J g-1 in 6 nm pores, which is linked to a decrease in crosslinks formed via hydrogen bonding. Despite decreases in crosslink formation, the melting temperature for gels confined to 6 nm pores increased nearly 10 degrees C compared to bulk gel. In 4 nm pores, no gel melting was observed. Isoconversional kinetic analysis of the melting data has revealed that the increase in thermal stability is associated with a decrease in the pre-exponential factor that occurs upon nanoconfinement. The origins of the effect have been linked to diminished molecular mobility of the gelatin chains confined inside the nanopores, which leads to enhanced restoration of broken crosslinks. PMID- 27472064 TI - IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells. AB - Severe or prolonged inflammatory response caused by infection or biomaterials leads to delayed healing or bone repair failure. This study investigated the important roles of the proinflammatory cytokines of the interleukin-12 (IL-12) family, namely, IL-12 and IL-23, in the inflammation-mediated inhibition of bone formation in vivo. IL-12p40-/- mice lacking IL-12 and IL-23 exhibited enhanced bone formation. IL-12 and IL-23 indirectly inhibited bone marrow mesenchymal stem cell (BMMSC) differentiation by stimulating CD4+ T cells to increase interferon gamma (IFN-gamma) and IL-17 levels. Mechanistically, IL-17 synergistically enhanced IFN-gamma-induced BMMSC apoptosis. Moreover, INF-gamma and IL-17 exerted proapoptotic effects by upregulating the expression levels of Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as by activating the caspase cascade in BMMSCs. IL-12p40 depletion in mice could promote ectopic bone formation. Thus, IL-12p40 is an attractive therapeutic target to overcome the inflammation-mediated inhibition of bone formation in vivo. PMID- 27472067 TI - Predictors of late virologic failure after initial successful suppression of HIV replication on efavirenz-based antiretroviral therapy. AB - BACKGROUND: Practical issues, including cost, hinder implementing virologic monitoring of patients on antiretroviral therapy (ART) in resource-limited settings. We evaluated factors that might guide monitoring frequency and efforts to prevent treatment failure after initial virologic suppression. METHODS: Participants were the 911 HIV-infected antiretroviral-naive adults with CD4 count <300 cells/MUL who started efavirenz-based ART in the international A5175/PEARLS trial and achieved HIV-1 RNA <1000 copies/mL at 24 weeks. Participant report of ART adherence was evaluated using a structured questionnaire in monthly interviews. Adherence and readily available clinical and laboratory measures were evaluated as predictors of late virologic failure (late VF: confirmed HIV-1 RNA >=1000 copies/mL after 24 weeks). RESULTS: During median follow-up of 3.5 years, 82/911 participants (9%) experienced late VF. Of 516 participants reporting missed doses during the first 24 weeks of ART, 55 (11%) experienced late VF, compared with 27 (7%) of 395 participants reporting no missed doses (hazard ratio: 1.73; 95% CI: 1.08, 2.73). This difference persisted in multivariable analysis, in which lower pre-ART hemoglobin and absence of Grade >=3 laboratory results prior to week 24 were also associated with higher risk of late VF. DISCUSSION: In this clinical trial, the late VF rate after successful suppression was very low. If achievable in routine clinical practice, virologic monitoring involving infrequent (e.g. annual) measurements might be considered; the implications of this for development of resistance need evaluating. Patients reporting missed doses early after ART initiation, despite achieving initial suppression, might require more frequent measurement and/or strategies for promoting adherence. PMID- 27472068 TI - Synthetic Applications of Proton-Coupled Electron Transfer. AB - Redox events in which an electron and proton are exchanged in a concerted elementary step are commonly referred to as proton-coupled electron transfers (PCETs). PCETs are known to operate in numerous important biological redox processes, as well as recent inorganic technologies for small molecule activation. These studies suggest that PCET catalysis might also function as a general mode of substrate activation in organic synthesis. Over the past three years, our group has worked to advance this hypothesis and to demonstrate the synthetic utility of PCET through the development of novel catalytic radical chemistries. The central aim of these efforts has been to demonstrate the ability of PCET to homolytically activate a wide variety of common organic functional groups that are energetically inaccessible using known molecular H atom transfer catalysts. To do so, we made use of a simple formalism first introduced by Mayer and co-workers that allowed us to predict the thermodynamic capacity of any oxidant/base or reductant/acid pair to formally add or remove H. from a given substrate. With this insight, we were able to rationally select catalyst combinations thermodynamically competent to homolyze the extraordinarily strong E H sigma-bonds found in many common protic functional groups (BDFEs > 100 kcal/mol) or to form unusually weak bonds to hydrogen via the reductive action of common organic pi-systems (BDFEs < 35 kcal/mol). These ideas were reduced to practice through the development of new catalyst systems for reductive PCET activations of ketones and oxidative PCET activation of amide N-H bonds to directly furnish reactive ketyl and amidyl radicals, respectively. In both systems, the reaction outcomes were found to be successfully predicted using the effective bond strength formalism, suggesting that these simple thermochemical considerations can provide useful and actionable insights into PCET reaction design. The ability of PCET catalysis to control enantioselectivity in free radical processes has also been established. Specifically, multisite PCET requires the formation of a pre-equilibrium hydrogen bond between the substrate and a proton donor/acceptor prior to charge transfer. We recognized that these H bond interfaces persist following the PCET event, resulting in the formation of noncovalent complexes of the nascent radical intermediates. When chiral proton donors/acceptors are employed, this association can provide a basis for asymmetric induction in subsequent bond-forming steps. We discuss our efforts to capitalize on this understanding via the development of a catalytic protocol for enantioselective aza-pinacol cyclizations. Lastly, we highlight an alternative PCET mechanism that exploits the ability of redox-active metals to homolytically weaken the bonds in coordinated ligands, enabling nominally strong bonds (BDFEs ~ 100 kcal) to be abstracted by weak H atom acceptors with concomitant oxidation of the metal center. This "soft homolysis" mechanism enables the generation of metalated intermediates from protic substrates under completely neutral conditions. The first example of this form of catalysis is presented in the context of a catalytic C-N bond forming reaction jointly mediated by bulky titanocene complexes and the stable nitroxyl radical TEMPO. PMID- 27472069 TI - The interaction of a model active pharmaceutical with cationic surfactant and the subsequent design of drug based ionic liquid surfactants. AB - Interactions of active pharmaceutical ingredients (API) with surfactants remain an important research area due to the need to improve drug delivery systems. In this study, UV-Visible spectrophotometry was used to investigate the interactions between a model low molecular weight hydrophilic drug sodium valproate (SV) and cationic surfactant cetyltrimethylammonium bromide (CTAB). Changes in the spectra of SV were observed in pre- and post-micellar concentrations of CTAB. The binding constant (Kb) values and the number of drug molecules encapsulated per micelle were calculated, which posed the possibility of mixed micelle formation and strong complexation between SV and CTAB. These results were compared to those of a novel room temperature surface active ionic liquid, which was synthesized by the removal of inorganic counterions from a 1:1 mixture of CTAB and SV. In this new compound the drug now constitutes a building block of the carrier and, as such, has considerably different surfactant properties to its building blocks. In addition, enhanced solubility in a range of solvents, including simulated gastric fluid, was observed. The study provides valuable experimental evidence concerning the performance of drug based surfactant ionic liquids and how their chemical manipulation, without altering the architecture of the API, leads to control of surfactant behavior and physicochemical properties. In turn, this should feed through to improved and controlled drug release rates and delivery mechanisms, and the prevention of precipitation or formation of polymorphs typical of crystalline form APIs. PMID- 27472070 TI - Characterization of a new toxin from the entomopathogenic fungus Metarhizium anisopliae: the ribotoxin anisoplin. AB - Metarhizium anisopliae is an entomopathogenic fungus relevant in biotechnology with applications like malaria vector control. Studies of its virulence factors are therefore of great interest. Fungal ribotoxins are toxic ribonucleases with extraordinary efficiency against ribosomes and suggested as potential insecticides. Here we describe this ribotoxin characteristic activity in M. anisopliae cultures. Anisoplin has been obtained as a recombinant protein and further characterized. It is structurally similar to hirsutellin A, the ribotoxin from the entomopathogen Hirsutella thompsonii. Moreover, anisoplin shows the ribonucleolytic activity typical of ribotoxins and cytotoxicity against insect cells. How Metarhizium uses this toxin and possible applications are of interest. PMID- 27472072 TI - Clinical features of patients with game-induced seizures in the Chinese population. AB - PURPOSE: To study the clinical characteristics of patients with game-induced seizures in the Chinese population. METHOD: We assessed 51 patients with various game-induced epileptic seizures. Based on whether they had spontaneous seizures, these 51 patients were classified as two groups. Twenty-seven patients who had both game-induced and spontaneous seizures were referred to as Group I, whereas twenty-four patients that had experienced seizures exclusively while playing specific games were assigned to Group II. All of the related clinical data of the patients was collected and evaluated. RESULTS: The patients in Group I presented with adolescent-onset and related to photosensitive idiopathic generalized epilepsy (IGE), were responsive to valproic acid (VPA) or magnesium valproate (VPA-Mg) therapy, and presented a major seizure-precipitating factor in response to electronic games. While patients in Group II were adult onset and not associated with IGE, showed uncertain responses to VPA and a benign prognosis, and presented major seizure-precipitating factors in response to non-electronic games. CONCLUSION: There are obvious genetic differences between patients with game-induced epilepsy. It is necessary to differentiate between various types of game-induced seizures and select the corresponding treatment. PMID- 27472071 TI - Bedside quantitative electroencephalography improves assessment of consciousness in comatose subarachnoid hemorrhage patients. AB - OBJECTIVE: Accurate behavioral assessments of consciousness carry tremendous significance in guiding management, but are extremely challenging in acutely brain-injured patients. We evaluated whether electroencephalography (EEG) and multimodality monitoring parameters may facilitate assessment of consciousness in patients with subarachnoid hemorrhage. METHODS: A retrospective analysis was performed of 83 consecutively treated adults with subarachnoid hemorrhage. All patients were initially comatose and had invasive brain monitoring placed. Behavioral assessments were performed during daily interruption of sedation and categorized into 3 groups based on their best examination as (1) comatose, (2) arousable (eye opening or attending toward a stimulus), and (3) aware (command following). EEG features included spectral power and complexity measures. Comparisons were made using bootstrapping methods and partial least squares regression. RESULTS: We identified 389 artifact-free EEG clips following behavioral assessments. Increasing central gamma, posterior alpha, and diffuse theta-delta oscillations differentiated patients who were arousable from those in coma. Command following was characterized by a further increase in central gamma and posterior alpha, as well as an increase in alpha permutation entropy. These EEG features together with basic neurological examinations (eg, pupillary light reflex) contributed heavily to a linear model predicting behavioral state, whereas brain physiology measures (eg, brain oxygenation), structural injury, and clinical course added less. INTERPRETATION: EEG measures of behavioral states provide distinctive signatures that complement behavioral assessments of patients with subarachnoid hemorrhage shortly after the injury. Our data support the hypothesis that impaired connectivity of cortex with both central thalamus and basal forebrain underlies decreasing levels of consciousness. Ann Neurol 2016;80:541-553. PMID- 27472073 TI - Dealing with microcarcinoma of the thyroid gland. PMID- 27472074 TI - Non-equilibrium passive sampling of hydrophobic organic contaminants in sediment pore-water: PCB exchange kinetics. AB - This study investigates the isotropic exchange kinetics of PCBs for polyethylene (PE) passive samplers in quiescent sediment and develops a novel non-equilibrium passive sampling method using PE with multiple thicknesses. The release and uptake kinetics of PCBs in quiescent sediment are reproduced by a 1-D diffusion model using sediment diffusion parameters fitted with the data from actual measurements. From the sediment diffusion parameters observed for uptake and release kinetics, it is seen that the uptake kinetics are distinctly slower than the release kinetics, most likely because of the sorption-desorption hysteresis of PCBs in the study sediment. Despite the presence of the anisotropic PCB exchange kinetics, a performance reference compound (PRC)-based method, which is grounded on the assumption of isotropic exchange kinetics, estimated the freely dissolved aqueous concentrations (Cfree) of PCBs in sediment pore-water with less than a factor of two error for the study sediment. The novel method developed in this study using PE with multiple thicknesses also gives reasonable estimates of Cfree, demonstrating its potential as another option for non-equilibrium passive sampling for hydrophobic organic contaminants in sediment pore-water. PMID- 27472075 TI - RhoA Signaling and Synaptic Damage Occur Within Hours in a Live Pig Model of CNS Injury, Retinal Detachment. AB - PURPOSE: The RhoA pathway is activated after retinal injury. However, the time of onset and consequences of activation are unknown in vivo. Based on in vitro studies we focused on a period 2 hours after retinal detachment, in pig, an animal whose retina is holangiotic and contains cones. METHODS: Under anesthesia, retinal detachments were created by subretinal injection of a balanced salt solution. Two hours later, animals were sacrificed and enucleated for GTPase activity assays and quantitative Western blot and confocal microscopy analyses. RESULTS: RhoA activity with detachment was increased 1.5-fold compared to that in normal eyes or in eyes that had undergone vitrectomy only. Increased phosphorylation of myosin light chain, a RhoA effector, also occurred. By 2 hours, rod cells had retracted their terminals toward their cell bodies, disrupting the photoreceptor-to-bipolar synapse and producing significant numbers of spherules with SV2 immunolabel in the outer nuclear layer of the retina. In eyes with detachment, distant retina that remained attached also showed significant increases in RhoA activity and synaptic disjunction. Increases in RAC1 activity and glial fibrillary acidic protein (GFAP) were not specific for detachment, and sprouting of bipolar dendrites, reported for longer detachments, was not seen. The RhoA kinase inhibitor Y27632 significantly reduced axonal retraction by rod cells. CONCLUSIONS: Activation of the RhoA pathway occurs quickly after injury and promotes synaptic damage that can be controlled by RhoA kinase inhibition. We suggest that retinal detachment joins the list of central nervous system injuries, such as stroke and spinal cord injury, that should be considered for rapid therapeutic intervention. PMID- 27472076 TI - Swept-Source OCT Angiography Imaging of the Foveal Avascular Zone and Macular Capillary Network Density in Diabetic Retinopathy. AB - PURPOSE: We compared the area of the foveal avascular zone (FAZ) and macular capillary network density at different retinal layers using swept-source optical coherence tomography angiography (OCT-A) in normal individuals and patients with diabetic retinopathy (DR). METHODS: Images (a 3 * 3 mm cube centered on the fovea) were acquired in 40 eyes of 22 normal individuals and 28 eyes of 18 patients with varying levels of DR using a swept-source OCT-A device (central wavelength 1050 nm; A-scan-rate of 100,000 scans per second). En face images of the retinal vasculature were generated from the superficial and deep retinal layers (SRL/DRL). Quantitative analysis of the vessel density (VD) and FAZ area was performed. Vessel density was assessed as the ratio of the retinal area occupied by vessels. RESULTS: Among the DR subjects (mean age, 72 years; 61% male), 35.7% of the eyes had mild, 35.7% moderate, and 7.1% severe nonproliferative DR (NPDR), and 21.4% and proliferative DR (PDR). The mean FAZ area in patients with DR and in normal individuals was 0.518 and 0.339 mm2, respectively, for the SRL (P = 0.003), and 0.615 and 0.358 mm2, respectively, for the DRL (P < 0.001). The mean VD (ratio) at the SRL and DRL was statistically significantly lower in patients with DR (SRL, P < 0.001; DRL, P = 0.028). CONCLUSIONS: Swept-source OCT-A of the microcirculation in eyes of patients with DR can be used to quantitatively demonstrate alterations in the FAZ and VD in the SRL/DRL of the macula compared to normal eyes. Future longitudinal studies may use these metrics to evaluate changes over time or in response to treatment. PMID- 27472077 TI - Evidence of Dual Mechanisms of Glutathione Uptake in the Rodent Lens: A Novel Role for Vitreous Humor in Lens Glutathione Homeostasis. AB - PURPOSE: Lens glutathione synthesis knockout (LEGSKO) mouse lenses lack de novo glutathione (GSH) synthesis but still maintain >1 mM GSH. We sought to determine the source of this residual GSH and the mechanism by which it accumulates in the lens. METHODS: Levels of GSH, glutathione disulfide (GSSG), and GSH-related compounds were measured in vitro and in vivo using isotope standards and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. RESULTS: Wild-type (WT) lenses could accumulate GSH from gamma-glutamylcysteine and glycine or from intact GSH, but LEGSKO lenses could only accumulate GSH from intact GSH, indicating that LEGSKO lens GSH content is not due to synthesis by a salvage pathway. Uptake of GSH in cultured lenses occurred at the same rate for LEGSKO and WT lenses, could not be inhibited, and occurred primarily through cortical fiber cells. In contrast, uptake of GSH from aqueous humor could be competitively inhibited and showed an enhanced Km in LEGSKO lenses. Mouse vitreous had >1 mM GSH, whereas aqueous had <20 MUM GSH. Testing physiologically relevant GSH concentrations for uptake in vivo, we found that both LEGSKO and WT lenses could obtain GSH from the vitreous but not from the aqueous. Vitreous rapidly accumulated GSH from the circulation, and depletion of circulating GSH reduced vitreous but not aqueous GSH. CONCLUSIONS: The above data provide, for the first time, evidence for the existence of dual mechanisms of GSH uptake into the lens, one mechanism being a passive, high-flux transport through the vitreous exposed side of the lens versus an active, carrier-mediated uptake mechanism at the anterior of the lens. PMID- 27472078 TI - Erratum. PMID- 27472079 TI - Erratum. PMID- 27472080 TI - Tear Interferometric Patterns Reflect Clinical Tear Dynamics in Dry Eye Patients. AB - PURPOSE: We investigated whether the tear interferometric pattern was able to identify differences in tear film kinetics among clinical subtypes of dry eye. METHODS: A total of 138 eyes of 76 subjects (38 men and 38 women; mean age +/- SD, 61.6 +/- 16.2 years) with or without dry eye who visited Itoh Clinic from May to August 2015 were enrolled in a cross-sectional study. Clinical diagnosis of dry eye subtype was based on tear film parameters. The pattern of tear film kinetics determined by interferometry was classified as 0 (monotonous gray or multicolor interferometric fringe with a noninvasive breakup time [NIBUT] of >=5 seconds), 1 (multicolor interferometric fringe with a NIBUT of <5 seconds), or 2 (grayish amorphous interferometric fringe with a NIBUT of <5 seconds), and reliability of classification was evaluated. Lipid layer thickness (LLT) for the tear film was also determined by interferometry. RESULTS: Interrater kappa values for evaluation of interferometric patterns ranged from 0.57 to 0.94 for both physicians and nonphysicians with reference to a dry eye expert, the latter of whom showed an intrarater reliability of 0.90. The distribution of eyes among interferometric patterns 0, 1, and 2 coincided well with the clinical subgroups of normal tear condition, non-Sjogren syndrome aqueous-deficient dry eye, and meibomian gland dysfunction, respectively. A multicolor interferometric fringe was essentially observed only at an LLT of >70 nm. CONCLUSIONS: Tear interferometry was able to reliably distinguish clinical subtypes of dry eye by reflecting the balance between the lipid and aqueous layers of the tear film. PMID- 27472081 TI - Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases. AB - PURPOSE: Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5 phosphate 4-kinases (PI5P4Kalpha and -beta) abrogates proliferation of p53 deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kalpha and -beta and whether suppression of PI5P4Kalpha and -beta would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR). METHODS: PI5P4Kalpha and beta encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and 2B. In addition, we rescued expression of PI5P4Kalpha and -beta by re-expressing mouse PIP4K2A and -2B in the PI5P4Kalpha and -beta knocked-down ARPE-19 cells. Expression of PI5P4Kalpha and -beta was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection. RESULTS: We found that vitreous enhanced expression of PI5P4Kalpha and -beta in RPE cells and that knocking down PI5P4Kalpha and -beta abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4Kalpha and -beta in the human PI5P4Kalpha and -beta knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4Kalpha and -beta abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4Kalpha and -beta was abundant in epiretinal membranes from PVR grade C patients. CONCLUSIONS: The findings from this study indicate that PI5P4Kalpha and -beta could be novel therapeutic targets for the treatment of PVR. PMID- 27472082 TI - Comparative Evaluation of the Chemical Composition, Antioxidant and Antimicrobial Activities of the Volatile Oils of Hawk Tea from Six Botanical Origins. AB - In this study, volatile oils of six Hawk tea varieties were studied for their chemical composition, antioxidant and antimicrobial activities to screen the most suitable botanical origins of Hawk tea. A total of 72 components were separated and identified from the six oils. The major constituents of the volatile oils were: alpha-pinene, camphene, limonene, 1,8-cineole, linalool, cis-nerolidol, and germacrene B. Moreover, the volatile oils were evaluated for antioxidant potential and antimicrobial activities. The results showed that all volatile oils exhibited acceptable antioxidant and antimicrobial activities, which suggested that these volatile oils may serve as natural alternatives to synthetic antioxidants and preservatives to be applied in food and pharmaceutical industries. Principal component analysis results denoted that some major compounds may be closely related to the antioxidant and antimicrobial activities. It also showed that the volatile oils from Litsea coreana var. lanuginosa and Litsea pungens Hemsl. were characterized by positive values of first two principal components, indicating higher active chemical compounds and antioxidant and antimicrobial activities compared with other species. Thus, they were temporarily considered as good sources of Hawk tea. PMID- 27472083 TI - Highly Sensitive and Selective Detection of Nanomolar Ferric Ions Using Dopamine Functionalized Graphene Quantum Dots. AB - The good stability, low cytotoxicity, and excellent photoluminescence property of graphene quantum dots (GQDs) make them an emerging class of promising materials in various application fields ranging from sensor to drug delivery. In the present work, the dopamine-functionalized GQDs (DA-GQDs) with stably bright blue fluorescence were successfully synthesized for low level Fe(3+) ions detection. The as-synthesized GQDs are uniform in size with narrow-distributed particle size of 4.5 +/- 0.6 nm and high quantum yield of 10.2%. The amide linkage of GQDs with dopamine, confirmed by using XPS and FTIR spectra, results in the specific interaction between Fe(3+) and catechol moiety of dopamine at the interfaces for highly sensitive and selective detection of Fe(3+). A linear range of 20 nM to 2 MUM with a detection limit of 7.6 nM is obtained for Fe(3+) detection by DA-GQDs. The selectivity of DA-GQDs sensing probe is significantly excellent in the presence of other interfering metal ions. In addition, the reaction mechanism for Fe(3+) detection based on the complexation and oxidation of dopamine has been proposed and validated. Results obtained in this study clearly demonstrate the superiority of surface functionalized GQDs to Fe(3+) detection, which can pave an avenue for the development of high performance and robust sensing probes for detection of metal ions and other organic metabolites in environmental and biomedical applications. PMID- 27472085 TI - Grape skin extract mitigates tissue degeneration, genotoxicity, and oxidative status in multiple organs of rats exposed to cadmium. AB - The aim of this study was to investigate whether grape skin extract can mitigate the noxious activities induced by cadmium exposure in multiple organs of rats. For this purpose, histopathological analysis for the liver, genotoxicity, and oxidative status in the blood and liver were investigated in this setting. A total of 20 Wistar rats weighing 250 g, on average, and 8 weeks of age were distributed into four groups (n=5) as follows: control group (nontreated group); cadmium group (Cd); and grape skin extract groups (Cd+GS) at 175 or 350 mg/l. Histopathological analysis in liver showed that animals treated with grape skin extract showed improved tissue degeneration induced by cadmium intoxication. Genetic damage was reduced in blood and hepatocytes as indicated by comet and micronucleus assays in animals treated with grape skin extract. Copper-zinc superoxide dismutase and cytochrome c gene expression increased in groups treated with grape skin extract in liver cells. Grape skin extract also reduced the 8 hydroxy-2'-deoxyguanosine levels in liver cells compared with the cadmium group. Taken together, our results indicate that grape skin extract can mitigate tissue degeneration, genotoxicity, and oxidative stress induced by cadmium exposure in multiple organs of Wistar rats. PMID- 27472084 TI - Elevated intracellular pH appears in aged oocytes and causes oocyte aneuploidy associated with the loss of cohesion in mice. AB - Increases in the aneuploidy rate caused by the deterioration of cohesion with increasing maternal age have been well documented. However, the molecular mechanism for the loss of cohesion in aged oocytes remains unknown. In this study, we found that intracellular pH (pHi) was elevated in aged oocytes, which might disturb the structure of the cohesin ring to induce aneuploidy. We observed for the first time that full-grown germinal vesicle (GV) oocytes displayed an increase in pHi with advancing age in CD1 mice. Furthermore, during the in vitro oocyte maturation process, the pHi was maintained at a high level, up to ~7.6, in 12-month-old mice. Normal pHi is necessary to maintain protein localization and function. Thus, we put forward a hypothesis that the elevated oocyte pHi might be related to the loss of cohesion and the increased aneuploidy in aged mice. Through the in vitro alkalinization treatment of young oocytes, we observed that the increased pHi caused an increase in the aneuploidy rate and the sister inter kinetochore (iKT) distance associated with the strength of cohesion and caused a decline in the cohesin subunit SMC3 protein level. Young oocytes with elevated pHi exhibited substantially the increase in chromosome misalignment. PMID- 27472086 TI - Cancer mortality in Europe, 1970-2009: an age, period, and cohort analysis. AB - The aim of this study was to interpret long-term trends in cancer mortality. We analyzed age, period of death, and cohort of birth effects for 18 major cancer sites and all neoplasms combined in the European Union and 16 European countries over the period 1970-2009 using data from the WHO mortality database. We used a log-linear Poisson model with a likelihood penalizing function to solve the identifiability problem. The present comprehensive analysis confirms the appreciable declines of cancer mortality since the late 1980s in most European countries. For several major sites, the declines were appreciably greater for cohort effects than for period ones. This reflects - besides the inherent characteristics of the model used - a major impact of tobacco smoking on total cancer mortality, particularly in men, as the role of tobacco in mortality of subsequent generations is largely - although not totally - a cohort effect. For neoplasms largely affected by improvements in management and therapy (e.g. testis, Hodgkin lymphoma, leukemia, but also breast and colorectal cancer), a favorable period effect is evident. However, there is also a cohort effect as the advancements have been generally greater in younger generations. For several cancer sites, there were considerable differences in cohort and period effects across Europe, and particularly high age-specific estimates were observed in eastern countries. PMID- 27472087 TI - [Documentation Time and Effort and Associated Resources for Patients with Primary Breast Cancer from Diagnosis to End of Follow-Up - Results of a Multicentre Validation]. PMID- 27472088 TI - Exploring a Role for IL-7-Induced Homeostatic Reconstitution of Regulatory T Cells Postbasiliximab Therapy: Implications for Transplantation Tolerance. PMID- 27472090 TI - An Exciting New Era in Donor Organ Preservation and Transplantation: Assess, Condition, and Repair! PMID- 27472091 TI - Donor-Transmitted Atherosclerosis Associated With Worsening Cardiac Allograft Vasculopathy After Heart Transplantation: Serial Volumetric Intravascular Ultrasound Analysis. AB - BACKGROUND: The influence of preexisting donor-transmitted atherosclerosis (DA) on cardiac allograft vasculopathy (CAV) development remains unclear. METHODS: We performed 3-dimensional intravascular ultrasound (3D-IVUS) analysis in 42 heart transplantation (HTx) recipients at 2.1 +/- 0.9 months (baseline) and 12.2 +/- 0.4 months post-HTx, as well as consecutive 3D-IVUS analyses up to 3 years post HTx in 35 of the 42 recipients. Donor-transmitted atherosclerosis was defined as a maximal intimal thickness of 0.5 mm or greater at baseline. Changes in volumetric IVUS parameters were compared in recipients with (DA group) and without DA (DA-free group) at baseline, 1 year, and 3 years post-HTx. RESULTS: Donor-transmitted atherosclerosis was observed in 57.1% of 42 recipients. The DA group exhibited a significantly greater increase in plaque volume at 1 year post HTx (P < 0.001), leading to increased percent plaque volume (plaque volume/vessel volume, [%]) (P < 0.001) and decreased luminal volume (P = 0.021). Donor transmitted atherosclerosis was independently associated with a greater increase in percent plaque volume during the first post-HTx year (P = 0.011). From 1 to 3 years post-HTx, the DA group underwent continuous reduction in luminal volume (P = 0.022). These changes resulted in a higher incidence of angiographic CAV at 3 years post-HTx in the DA group (58.8% vs 5.6%, P = 0.002). CONCLUSIONS: This volumetric IVUS study suggests that DA correlates with the worsening change in CAV several years post-HTx. Donor-transmitted atherosclerosis recipients may require more aggressive treatment to prevent subsequent CAV progression. PMID- 27472093 TI - Updated Manufacturer and European Medicines Agency Recommendations on the Use of Mycophenolate Acid: Balancing the Risks for Male Allograft Recipients. PMID- 27472092 TI - Increased CD40 Ligation and Reduced BCR Signalling Leads to Higher IL-10 Production in B Cells From Tolerant Kidney Transplant Patients. AB - BACKGROUND: An increased percentage of peripheral transitional B cells producing IL-10 has been observed in patients tolerant to kidney allografts. In healthy volunteers, the balance between the CD40 and B-cell receptor (BCR) signalling modulated IL-10 production by B cells, with stimulation via the BCR decreasing CD40-mediated IL-10 production. In this study, we evaluate whether in tolerant kidney transplant patients, the increased IL-10 production by B cells was due to an altered CD40 and/or BCR signalling. METHODS: B cells obtained from a new cohort of tolerant renal transplant recipients and those from age- and sex matched healthy volunteers were activated via CD40 and BCR, either alone or in combination. RESULTS: In tolerant patients, we observed higher percentages of B cells producing IL-10 after CD40 ligation and higher expression of CD40L on activated T cells compared with healthy controls. Furthermore, B cells from tolerant recipients had reduced extracellular signal-regulated kinase signalling after BCR-mediated activation compared with healthy controls. In keeping with this, combining BCR signalling with CD40 ligation did not reduce IL-10 secretion as was observed in healthy control transitional B cells. CONCLUSIONS: Altogether, our data suggest that the altered response of B cells in tolerant recipients may contribute to long-term stable graft acceptance. PMID- 27472096 TI - Criteria for and Appropriateness of Renal Transplantation in Elderly Patients With End-Stage Renal Disease: A Literature Review and Position Statement on Behalf of the European Renal Association-European Dialysis and Transplant Association Descartes Working Group and European Renal Best Practice. AB - During the last 20 years, waiting lists for renal transplantation (RT) have grown significantly older. However, elderly patients (ie >=65 years of age) are still more rarely referred or accepted to waiting lists and, if enlisted, have less chances of actually receiving a kidney allograft, than younger counterparts. In this review, we looked at evidence for the benefits and risks of RT in the elderly trying to answer the following questions: Should RT be advocated for elderly patients? What should be the criteria to accept elderly patients on the waiting list for RT? What strategies might be used to increase the rate of RT in waitlisted elderly candidates? For selected elderly patients, RT was shown to be superior to dialysis in terms of patient survival. Virtually all guidelines recommend that patients should not be deemed ineligible for RT based on age alone, although a short life expectancy generally might preclude RT. Concerning the assessment of comorbidities in the elderly, special attention should be paid to cardiac evaluation and screening for malignancy. Comorbidity scores and frailty assessment scales might help the decision making on eligibility. Psychosocial issues should also be evaluated. To overcome the scarcity of organ donors, elderly RT candidates should be encouraged to consider expanded criteria donors and living donors, as alternatives to deceased standard criteria donors. It has been demonstrated that expanded criteria donor RT in patients 60 years or older is associated with higher survival rates than remaining on dialysis, whereas living donor RT is superior to all other options. PMID- 27472094 TI - Costimulation Blockade in Kidney Transplantation: An Update. AB - In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending. PMID- 27472097 TI - A Novel Predictor of Posttransplant Portal Hypertension in Adult-To-Adult Living Donor Liver Transplantation: Increased Estimated Spleen/Graft Volume Ratio. AB - BACKGROUND: In adult living donor liver transplantation (ALDLT), graft-to recipient weight ratio of less than 0.8 is incomplete for predicting portal hypertension (>20 mm Hg) after reperfusion. We aimed to identify preoperative factors contributing to portal venous pressure (PVP) after reperfusion and to predict portal hypertension, focusing on spleen volume-to-graft volume ratio (SVGVR). METHODS: In 73 recipients with ALDLT between 2002 and 2013, first we analyzed survival according to PVP of 20 mm Hg as the threshold, evaluating the efficacy of splenectomy. Second, we evaluated various preoperative factors contributing to portal hypertension after reperfusion. RESULTS: All of the recipients with PVP greater than 20 mm Hg (n = 19) underwent PVP modulation by splenectomy, and their overall survival was favorable compared with 54 recipients who did not need splenectomy (PVP <= 20 mm Hg). Graft-to-recipient weight ratio had no correlation with PVP.Multivariate analysis revealed that estimated graft and spleen volume were significant factors contributing to PVP after reperfusion (P < 0.0001 and P < 0.0001, respectively). Furthermore, estimated SVGVR showed a significant negative correlation to PVP after reperfusion (R = 0.652), and the best cutoff value for portal hypertension was 0.95. CONCLUSIONS: In ALDLT, preoperative assessment of SVGVR is a good predictor of portal hypertension after reperfusion can be used to indicate the need for splenectomy before reperfusion. PMID- 27472098 TI - Treatment of Type 2 diabetes mellitus in Chongqing of China: unaffordable care for the poor. AB - AIM: This study aims to investigate the medical expenditure of people with Type 2 diabetes mellitus in Chongqing, China; to explore factors that contribute to the expenditure; and to examine the financial burden placed on households, particularly poor households. METHODS: A cross sectional survey was conducted with a sample of people diagnosed with Type 2 diabetes mellitus in 2014. Of the 664 people eligible, 76% were interviewed. Descriptive statistics and log-linear regression were used to examine respondents' age, sex and level education, location of residence, income and type of health insurance associated with out-of pocket expenditure on accessing diabetes mellitus care. RESULTS: In a year, average out-of-pocket expenditure on the purchase of drugs from pharmacies and having outpatient care were US $333 and US $310, respectively. The average out-of pocket expenditure on accessing inpatient care was 3.7 times (US $1159) that of accessing outpatient care. After adjusting for age and sex, out-of-pocket expenditure on diabetes care was significantly higher for people covered by the Urban Employee Basic Medical Insurance programme and those enrolled in the identified priority diseases reimbursement programme, which provided higher reimbursement rates for outpatient and (or) inpatient care. Out-of-pocket expenditures on the purchase of drugs from pharmacies, having outpatient and inpatient care, respectively, were 9.8%, 16.2% and 62.6% of annual household income in low-income group. CONCLUSION: Even with health insurance coverage, poor people with Type 2 diabetes mellitus suffered from significant financial hardship. This has significant implications for models of care and healthcare financing in China with the growing burden of diabetes. PMID- 27472099 TI - Multiplexed site-specific electrode functionalization for multitarget biosensors. AB - Multitarget biosensors hold great promise to improve point-of-care diagnostics as they enable simultaneous detection of different biomolecular markers. Multiplexed detection of different markers, like genes, proteins, or a combination of both, propels advancement in numerous fields such as genomics, medical diagnosis and therapy monitoring. The functionalization of these biosensors, however, necessitates patterned immobilization of different bioreceptors, which remains challenging and time-consuming. We demonstrate a simple method for the patterned multiplexing of bioreceptors on a multi-electrode chip. By using the lithographically defined electrodes for surface functionalization, additional patterning steps become obsolete. Using the electrodes for self-aligned immobilization provides a spatial resolution that is limited by the electrode patterning process and that cannot be easily obtained by alternative dispensing or coating techniques. Via electrochemical reduction of diazonium salts combined with click chemistry, we achieved site-specific immobilization of two different ssDNA probes side by side on a single chip. This method was experimentally verified by cyclic voltammetry (CV), Fourier transform infrared spectroscopy (ATR FTIR) and X-ray photoelectron spectroscopy (XPS), and specific target recognition was visualized by fluorescence microscopy. The combination of the electroaddressability of electrografting with the chemoselectivity of click chemistry, offers a versatile platform for highly efficient site-specific functionalization of multitarget biosensors. PMID- 27472100 TI - Overcoming the minimum image constraint using the closest point search. AB - Finding the set of nearest images of a point in a simulation cell with periodic (torus) boundary conditions is of central importance for molecular dynamics algorithms. To compute all pairwise distances closer than a given cutoff in linear time requires region-based neighbor-listing algorithms. Available algorithms encounter increasing difficulties when the cutoff distance exceeds half the shortest cell length. This work provides details on two ways to directly and efficiently generate region-region interaction lists in n-dimensional space, free from the minimum image restriction. The solution is based on a refined version of existing algorithms solving the closest vector problem. A self contained discussion of lattice reduction methods for efficient higher dimensional searches is also provided. In the MD setting, these reduction criteria provide useful guidelines for lattice compaction. PMID- 27472101 TI - Reparameterization of an Accurate, Few-Parameter Implicit Solvation Model for Quantum Chemistry: Composite Method for Implicit Representation of Solvent, CMIRS v. 1.1. AB - CMIRS (composite method for implicit representation of solvent) is a relatively new implicit solvation model that adds terms representing solute-solvent dispersion, Pauli repulsion, and hydrogen bonding to a continuum treatment of electrostatics. A small error in the original implementation of the dispersion term, but one that can modify dispersion energies by up to 8 kcal/mol in some cases, necessitates refitting the parameters in the model, which we do here. We refer to the modified implementation and parameter set as CMIRS v. 1.1. While the dispersion energies change in nontrivial ways, an increase in the attractive dispersion term in the new implementation is largely offset by an increase in the Pauli repulsion during the fitting process, such that overall statistical errors are virtually unchanged with respect to v. 1.0 of the model, for a large database of experimental solvation free energies for molecules and ions. Overall, we obtain mean unsigned errors of <0.7 kcal/mol when the solvent is cyclohexane or benzene, <1.5 kcal/mol for water, and <2.8 kcal/mol for dimethyl sulfoxide and acetonitrile, despite using no more than five empirical parameters per solvent. For the important but difficult case of ionic solutes in water, mean unsigned errors are <2.9 kcal/mol. PMID- 27472102 TI - Critical Examination of Incoherent Operations and a Physically Consistent Resource Theory of Quantum Coherence. AB - Considerable work has recently been directed toward developing resource theories of quantum coherence. In this Letter, we establish a criterion of physical consistency for any resource theory. This criterion requires that all free operations in a given resource theory be implementable by a unitary evolution and projective measurement that are both free operations in an extended resource theory. We show that all currently proposed basis-dependent theories of coherence fail to satisfy this criterion. We further characterize the physically consistent resource theory of coherence and find its operational power to be quite limited. After relaxing the condition of physical consistency, we introduce the class of dephasing-covariant incoherent operations as a natural generalization of the physically consistent operations. Necessary and sufficient conditions are derived for the convertibility of qubit states using dephasing-covariant operations, and we show that these conditions also hold for other well-known classes of incoherent operations. PMID- 27472103 TI - Secret Sharing of a Quantum State. AB - Secret sharing of a quantum state, or quantum secret sharing, in which a dealer wants to share a certain amount of quantum information with a few players, has wide applications in quantum information. The critical criterion in a threshold secret sharing scheme is confidentiality: with less than the designated number of players, no information can be recovered. Furthermore, in a quantum scenario, one additional critical criterion exists: the capability of sharing entangled and unknown quantum information. Here, by employing a six-photon entangled state, we demonstrate a quantum threshold scheme, where the shared quantum secrecy can be efficiently reconstructed with a state fidelity as high as 93%. By observing that any one or two parties cannot recover the secrecy, we show that our scheme meets the confidentiality criterion. Meanwhile, we also demonstrate that entangled quantum information can be shared and recovered via our setting, which shows that our implemented scheme is fully quantum. Moreover, our experimental setup can be treated as a decoding circuit of the five-qubit quantum error-correcting code with two erasure errors. PMID- 27472104 TI - Adaptive Heat Engine. AB - A major limitation of many heat engines is that their functioning demands on-line control and/or an external fitting between the environmental parameters (e.g., temperatures of thermal baths) and internal parameters of the engine. We study a model for an adaptive heat engine, where-due to feedback from the functional part the engine's structure adapts to given thermal baths. Hence, no on-line control and no external fitting are needed. The engine can employ unknown resources; it can also adapt to results of its own functioning that make the bath temperatures closer. We determine resources of adaptation and relate them to the prior information available about the environment. PMID- 27472105 TI - Analytical Limit Distributions from Random Power-Law Interactions. AB - Nature is full of power-law interactions, e.g., gravity, electrostatics, and hydrodynamics. When sources of such fields are randomly distributed in space, the superposed interaction, which is what we observe, is naively expected to follow a Gauss or Levy distribution. Here, we present an analytic expression for the actual distributions that converge to novel limits that are in between these already-known limit distributions, depending on physical parameters, such as the concentration of field sources and the size of the probe used to measure the interactions. By comparing with numerical simulations, the origin of non-Gauss and non-Levy distributions are theoretically articulated. PMID- 27472106 TI - Complex Squeezing and Force Measurement Beyond the Standard Quantum Limit. AB - A continuous quantum field, such as a propagating beam of light, may be characterized by a squeezing spectrum that is inhomogeneous in frequency. We point out that homodyne detectors, which are commonly employed to detect quantum squeezing, are blind to squeezing spectra in which the correlation between amplitude and phase fluctuations is complex. We find theoretically that such complex squeezing is a component of ponderomotive squeezing of light through cavity optomechanics. We propose a detection scheme called synodyne detection, which reveals complex squeezing and allows the accounting of measurement backaction. Even with the optomechanical system subject to continuous measurement, such detection allows the measurement of one component of an external force with sensitivity only limited by the mechanical oscillator's thermal occupation. PMID- 27472107 TI - Detection of Zeptojoule Microwave Pulses Using Electrothermal Feedback in Proximity-Induced Josephson Junctions. AB - We experimentally investigate and utilize electrothermal feedback in a microwave nanobolometer based on a normal-metal (Au_{x}Pd_{1-x}) nanowire with proximity induced superconductivity. The feedback couples the temperature and the electrical degrees of freedom in the nanowire, which both absorbs the incoming microwave radiation, and transduces the temperature change into a radio-frequency electrical signal. We tune the feedback in situ and access both positive and negative feedback regimes with rich nonlinear dynamics. In particular, strong positive feedback leads to the emergence of two metastable electron temperature states in the millikelvin range. We use these states for efficient threshold detection of coherent 8.4 GHz microwave pulses containing approximately 200 photons on average, corresponding to 1.1*10^{-21} J~7.0 meV of energy. PMID- 27472108 TI - Hints for Leptonic CP Violation or New Physics? AB - One of the major open questions in the neutrino sector is the issue of leptonic CP violation. Current global oscillation data show a mild preference for a large, potentially maximal value for the Dirac CP phase in the neutrino mixing matrix. In this Letter, we point out that new physics in the form of neutral-current-like nonstandard interactions with real couplings would likely yield a similar conclusion even if CP in the neutrino sector were conserved. Therefore, the claim for a discovery of leptonic CP violation will require a robust ability to test new physics scenarios. PMID- 27472111 TI - Detecting Chirality in Molecules by Linearly Polarized Laser Fields. AB - A new scheme for enantiomer differentiation of chiral molecules using a pair of linearly polarized intense ultrashort laser pulses with skewed mutual polarization is presented. The technique relies on the fact that the off-diagonal anisotropic contributions to the electric polarizability tensor for two enantiomers have different signs. Exploiting this property, we are able to excite a coherent unidirectional rotation of two enantiomers with a pi phase difference in the molecular electric dipole moment. The approach is robust and suitable for relatively high temperatures of molecular samples, making it applicable for selective chiral analysis of mixtures, and to chiral molecules with low barriers between enantiomers. As an illustration, we present nanosecond laser-driven dynamics of a tetratomic nonrigid chiral molecule with short-lived chirality. The ultrafast time scale of the proposed technique is well suited to study parity violation in molecular systems in short-lived chiral states. PMID- 27472114 TI - Anomalous Refraction of Acoustic Guided Waves in Solids with Geometrically Tapered Metasurfaces. AB - The concept of a metasurface opens new exciting directions to engineer the refraction properties in both optical and acoustic media. Metasurfaces are typically designed by assembling arrays of subwavelength anisotropic scatterers able to mold incoming wave fronts in rather unconventional ways. The concept of a metasurface was pioneered in photonics and later extended to acoustics while its application to the propagation of elastic waves in solids is still relatively unexplored. We investigate the design of acoustic metasurfaces to control elastic guided waves in thin-walled structural elements. These engineered discontinuities enable the anomalous refraction of guided wave modes according to the generalized Snell's law. The metasurfaces are made out of locally resonant toruslike tapers enabling an accurate phase shift of the incoming wave, which ultimately affects the refraction properties. We show that anomalous refraction can be achieved on transmitted antisymmetric modes (A_{0}) either when using a symmetric (S_{0}) or antisymmetric (A_{0}) incident wave, the former clearly involving mode conversion. The same metasurface design also allows achieving structure embedded planar focal lenses and phase masks for nonparaxial propagation. PMID- 27472110 TI - Holographic Quark Matter and Neutron Stars. AB - We use a top-down holographic model for strongly interacting quark matter to study the properties of neutron stars. When the corresponding equation of state (EOS) is matched with state-of-the-art results for dense nuclear matter, we consistently observe a first-order phase transition at densities between 2 and 7 times the nuclear saturation density. Solving the Tolman-Oppenheimer-Volkov equations with the resulting hybrid EOSs, we find maximal stellar masses in excess of two solar masses, albeit somewhat smaller than those obtained with simple extrapolations of the nuclear matter EOSs. Our calculation predicts that no quark matter exists inside neutron stars. PMID- 27472112 TI - Diverging Fluctuations of the Lyapunov Exponents. AB - We show that in generic one-dimensional Hamiltonian lattices the diffusion coefficient of the maximum Lyapunov exponent diverges in the thermodynamic limit. We trace this back to the long-range correlations associated with the evolution of the hydrodynamic modes. In the case of normal heat transport, the divergence is even stronger, leading to the breakdown of the usual single-function Family Vicsek scaling ansatz. A similar scenario is expected to arise in the evolution of rough interfaces in the presence of suitably correlated background noise. PMID- 27472113 TI - Convert Acoustic Resonances to Orbital Angular Momentum. AB - We use acoustic resonances in a planar layer of half-wavelength thickness to twist wave vectors of an in-coming plane wave into a spiral phase dislocation of an outgoing vortex beam with orbital angular momentum (OAM). The mechanism is numerically and experimentally demonstrated by producing an airborne Bessel-like vortex beam. Our acoustic resonance-based OAM production differs from existing means for OAM production by enormous phased spiral sources or by elaborate spiral profiles. Our study can advance the capability of generating phase dislocated wave fields for further applications of acoustic OAM. PMID- 27472115 TI - Inverse Saffman-Taylor Experiments with Particles Lead to Capillarity Driven Fingering Instabilities. AB - Using air to displace a viscous fluid contained in a Hele-Shaw cell can create a fingering pattern at the interface between the fluids if the capillary number exceeds a critical value. This Saffman-Taylor instability is revisited for the inverse case of a viscous fluid displacing air when partially wettable hydrophilic particles are lying on the walls. Though the inverse case is otherwise stable, the presence of the particles results in a fingering instability at low capillary number. This capillary-driven instability is driven by the integration of particles into the interface which results from the minimization of the interfacial energy. Both axisymmetric and rectangular geometries are considered in order to quantify this phenomenon. PMID- 27472116 TI - Nanoscale Electron Bunching in Laser-Triggered Ionization Injection in Plasma Accelerators. AB - Ionization injection is attractive as a controllable injection scheme for generating high quality electron beams using plasma-based wakefield acceleration. Because of the phase-dependent tunneling ionization rate and the trapping dynamics within a nonlinear wake, the discrete injection of electrons within the wake is nonlinearly mapped to a discrete final phase space structure of the beam at the location where the electrons are trapped. This phenomenon is theoretically analyzed and examined by three-dimensional particle-in-cell simulations which show that three-dimensional effects limit the wave number of the modulation to between >2k_{0} and about 5k_{0}, where k_{0} is the wave number of the injection laser. Such a nanoscale bunched beam can be diagnosed by and used to generate coherent transition radiation and may find use in generating high-power ultraviolet radiation upon passage through a resonant undulator. PMID- 27472117 TI - Measurement of Hydrodynamic Growth near Peak Velocity in an Inertial Confinement Fusion Capsule Implosion using a Self-Radiography Technique. AB - First measurements of hydrodynamic growth near peak implosion velocity in an inertial confinement fusion (ICF) implosion at the National Ignition Facility were obtained using a self-radiographing technique and a preimposed Legendre mode 40, lambda=140 MUm, sinusoidal perturbation. These are the first measurements of the total growth at the most unstable mode from acceleration Rayleigh-Taylor achieved in any ICF experiment to date, showing growth of the areal density perturbation of ~7000*. Measurements were made at convergences of ~5 to ~10* at both the waist and pole of the capsule, demonstrating simultaneous measurements of the growth factors from both lines of sight. The areal density growth factors are an order of magnitude larger than prior experimental measurements and differed by ~2* between the waist and the pole, showing asymmetry in the measured growth factors. These new measurements significantly advance our ability to diagnose perturbations detrimental to ICF implosions, uniquely intersecting the change from an accelerating to decelerating shell, with multiple simultaneous angular views. PMID- 27472118 TI - Using Inertial Fusion Implosions to Measure the T+^{3}He Fusion Cross Section at Nucleosynthesis-Relevant Energies. AB - Light nuclei were created during big-bang nucleosynthesis (BBN). Standard BBN theory, using rates inferred from accelerator-beam data, cannot explain high levels of ^{6}Li in low-metallicity stars. Using high-energy-density plasmas we measure the T(^{3}He,gamma)^{6}Li reaction rate, a candidate for anomalously high ^{6}Li production; we find that the rate is too low to explain the observations, and different than values used in common BBN models. This is the first data directly relevant to BBN, and also the first use of laboratory plasmas, at comparable conditions to astrophysical systems, to address a problem in nuclear astrophysics. PMID- 27472119 TI - Ionization-Induced Multiwave Mixing: Terahertz Generation with Two-Color Laser Pulses of Various Frequency Ratios. AB - Ultrafast strong-field ionization is shown to be accompanied by atypical multiwave mixing with the number of mixed waves defined by the dependence of the ionization rate on the field strength. For two-color laser pulses of various frequency ratios, this results in the excitation of a free-electron current at laser combination frequencies and possibly in the excitation of the zero frequency (residual) current responsible for terahertz (THz) generation in a formed plasma. The high-order nature of ionization-induced wave mixing may cause THz generation with uncommon laser frequency ratios (such as 2:3 and 3:4) to be virtually as effective as that with the commonly used frequency ratio of 1:2. PMID- 27472120 TI - Nanoscale Ultradense Z-Pinch Formation from Laser-Irradiated Nanowire Arrays. AB - We show that ultradense Z pinches with nanoscale dimensions can be generated by irradiating aligned nanowires with femtosecond laser pulses of relativistic intensity. Using fully three-dimensional relativistic particle-in-cell simulations, we demonstrate that the laser pulse drives a forward electron current in the area around the wires. This forward current induces return current densities of ~0.1 GA per MUm^{2} through the wires. The resulting strong, quasistatic, self-generated azimuthal magnetic field pinches the nanowires into hot plasmas with a peak electron density of >9*10^{24} cm^{-3}, exceeding 1000 times the critical density. Arrays of these new ultradense nanopinches can be expected to lead to efficient microfusion and other applications. PMID- 27472121 TI - Emergence of a Metallic Quantum Solid Phase in a Rydberg-Dressed Fermi Gas. AB - We examine possible low-temperature phases of a repulsively Rydberg-dressed Fermi gas in a three-dimensional free space. It is shown that the collective density excitations develop a roton minimum, which is softened at a wave vector smaller than the Fermi wave vector when the particle density is above a critical value. The mean field calculation shows that, unlike the insulating density wave states often observed in conventional condensed matters, a self-assembled metallic density wave state emerges at low temperatures. In particular, the density wave state supports a Fermi surface and a body-centered-cubic crystal order at the same time with the estimated critical temperature being about one tenth of the noninteracting Fermi energy. Our results suggest the emergence of a fermionic quantum solid that should be observable in the current experimental setup. PMID- 27472122 TI - Statistics and Properties of Low-Frequency Vibrational Modes in Structural Glasses. AB - Low-frequency vibrational modes play a central role in determining various basic properties of glasses, yet their statistical and mechanical properties are not fully understood. Using extensive numerical simulations of several model glasses in three dimensions, we show that in systems of linear size L sufficiently smaller than a crossover size L_{D}, the low-frequency tail of the density of states follows D(omega)~omega^{4} up to the vicinity of the lowest Goldstone mode frequency. We find that the sample-to-sample statistics of the minimal vibrational frequency in systems of size Linfinity model shows a tendency towards condensation of magnon bound states preceding the plateau phase. PMID- 27472137 TI - Ferromagnetic Quantum Critical Point Avoided by the Appearance of Another Magnetic Phase in LaCrGe_{3} under Pressure. AB - The temperature-pressure phase diagram of the ferromagnet LaCrGe_{3} is determined for the first time from a combination of magnetization, muon-spin rotation, and electrical resistivity measurements. The ferromagnetic phase is suppressed near 2.1 GPa, but quantum criticality is avoided by the appearance of a magnetic phase, likely modulated, AFM_{Q}. Our density functional theory total energy calculations suggest a near degeneracy of antiferromagnetic states with small magnetic wave vectors Q allowing for the potential of an ordering wave vector evolving from Q=0 to finite Q, as expected from the most recent theories on ferromagnetic quantum criticality. Our findings show that LaCrGe_{3} is a very simple example to study this scenario of avoided ferromagnetic quantum criticality and will inspire further study on this material and other itinerant ferromagnets. PMID- 27472138 TI - Three-dimensional Character of the Magnetization Dynamics in Magnetic Vortex Structures: Hybridization of Flexure Gyromodes with Spin Waves. AB - Three-dimensional linear spin-wave eigenmodes of a vortex-state Permalloy disk are studied by micromagnetic simulations based on the Landau-Lifshitz-Gilbert equation. The simulations confirm that the increase of the disk thickness leads to the appearance of additional exchange-dominated so-called gyrotropic flexure modes having nodes along the disk thickness, and eigenfrequencies that decrease when the thickness is increased. We observe the formation of a gap in the mode spectrum caused by the hybridization of the first flexure mode with one of the azimuthal spin-wave modes of the disk. A qualitative change of the transverse profile of this azimuthal mode is found, demonstrating that in a thick vortex state disk the influence of the "transverse" and the "azimuthal" coordinates cannot be separated. The three-dimensional character of the eigenmodes is essential to explain the recently observed asymmetries in an experimentally obtained phase diagram of vortex-core reversal in relatively thick Permalloy disks. PMID- 27472139 TI - Low-Energy Spin Dynamics of the Honeycomb Spin Liquid Beyond the Kitaev Limit. AB - We investigate the generic features of the low energy dynamical spin structure factor of the Kitaev honeycomb quantum spin liquid perturbed away from its exact soluble limit by generic symmetry-allowed exchange couplings. We find that the spin gap persists in the Kitaev-Heisenberg model, but generally vanishes provided more generic symmetry-allowed interactions exist. We formulate the generic expansion of the spin operator in terms of fractionalized Majorana fermion operators according to the symmetry enriched topological order of the Kitaev spin liquid, described by its projective symmetry group. The dynamical spin structure factor displays power-law scaling bounded by Dirac cones in the vicinity of the Gamma, K, and K^{'} points of the Brillouin zone, rather than the spin gap found for the exactly soluble point. PMID- 27472140 TI - Inversion of Ferrimagnetic Magnetization by Ferroelectric Switching via a Novel Magnetoelectric Coupling. AB - Although several multiferroic materials or heterostructures have been extensively studied, finding strong magnetoelectric couplings for the electric field control of the magnetization remains challenging. Here, a novel interfacial magnetoelectric coupling based on three components (ferroelectric dipole, magnetic moment, and antiferromagnetic order) is analytically formulated. As an extension of carrier-mediated magnetoelectricity, the new coupling is shown to induce an electric-magnetic hysteresis loop. Realizations employing BiFeO_{3} bilayers grown along the [111] axis are proposed. Without involving magnetic phase transitions, the magnetization orientation can be switched by the carrier modulation driven by the field effect, as confirmed using first-principles calculations. PMID- 27472141 TI - Probing the Metal-Insulator Transition in BaTiO_{3} by Electrostatic Doping. AB - The metal-to-insulator transition in BaTiO_{3} is investigated using electrostatic doping, which avoids effects from disorder and strain that would accompany chemical doping. SmTiO_{3}/BaTiO_{3}/SrTiO_{3} heterostructures are doped with a constant sheet carrier density of 3*10^{14} cm^{-2} that is introduced via the polar SmTiO_{3}/BaTiO_{3} interface. Below a critical BaTiO_{3} thickness, the structures exhibit metallic behavior with high carrier mobilities at low temperatures, similar to SmTiO_{3}/SrTiO_{3} interfaces. Above this thickness, data indicate that the BaTiO_{3} layer becomes ferroelectric. The BaTiO_{3} lattice parameters increase to a value consistent with a strained, tetragonal unit cell, the structures are insulating below ~125 K, and the mobility drops by more than an order of magnitude, indicating self-trapping of carriers. The results shed light on the interplay between charge carriers and ferroelectricity. PMID- 27472142 TI - Single-File Escape of Colloidal Particles from Microfluidic Channels. AB - Single-file diffusion is a ubiquitous physical process exploited by living and synthetic systems to exchange molecules with their environment. It is paramount to quantify the escape time needed for single files of particles to exit from constraining synthetic channels and biological pores. This quantity depends on complex cooperative effects, whose predominance can only be established through a strict comparison between theory and experiments. By using colloidal particles, optical manipulation, microfluidics, digital microscopy, and theoretical analysis we uncover the self-similar character of the escape process and provide closed formula evaluations of the escape time. We find that the escape time scales inversely with the diffusion coefficient of the last particle to leave the channel. Importantly, we find that at the investigated microscale, bias forces as tiny as 10^{-15} N determine the magnitude of the escape time by drastically reducing interparticle collisions. Our findings provide crucial guidelines to optimize the design of micro- and nanodevices for a variety of applications including drug delivery, particle filtering, and transport in geometrical constrictions. PMID- 27472143 TI - Effective Dynamics of Microorganisms That Interact with Their Own Trail. AB - Like ants, some microorganisms are known to leave trails on surfaces to communicate. We explore how trail-mediated self-interaction could affect the behavior of individual microorganisms when diffusive spreading of the trail is negligible on the time scale of the microorganism using a simple phenomenological model for an actively moving particle and a finite-width trail. The effective dynamics of each microorganism takes on the form of a stochastic integral equation with the trail interaction appearing in the form of short-term memory. For a moderate coupling strength below an emergent critical value, the dynamics exhibits effective diffusion in both orientation and position after a phase of superdiffusive reorientation. We report experimental verification of a seemingly counterintuitive perpendicular alignment mechanism that emerges from the model. PMID- 27472144 TI - Auditory Power-Law Activation Avalanches Exhibit a Fundamental Computational Ground State. AB - The cochlea provides a biological information-processing paradigm that we are only beginning to understand in its full complexity. Our work reveals an interacting network of strongly nonlinear dynamical nodes, on which even a simple sound input triggers subnetworks of activated elements that follow power-law size statistics ("avalanches"). From dynamical systems theory, power-law size distributions relate to a fundamental ground state of biological information processing. Learning destroys these power laws. These results strongly modify the models of mammalian sound processing and provide a novel methodological perspective for understanding how the brain processes information. PMID- 27472145 TI - How Far from Equilibrium Is Active Matter? AB - Active matter systems are driven out of thermal equilibrium by a lack of generalized Stokes-Einstein relation between injection and dissipation of energy at the microscopic scale. We consider such a system of interacting particles, propelled by persistent noises, and show that, at small but finite persistence time, their dynamics still satisfy a time-reversal symmetry. To do so, we compute perturbatively their steady-state measure and show that, for short persistent times, the entropy production rate vanishes. This endows such systems with an effective fluctuation-dissipation theorem akin to that of thermal equilibrium systems. Last, we show how interacting particle systems with viscous drags and correlated noises can be seen as in equilibrium with a viscoelastic bath but driven out of equilibrium by nonconservative forces, hence providing energetic insight into the departure of active systems from equilibrium. PMID- 27472146 TI - Evolutionary Phase Transitions in Random Environments. AB - We present analytical results for long-term growth rates of structured populations in randomly fluctuating environments, which we apply to predict how cellular response networks evolve. We show that networks which respond rapidly to a stimulus will evolve phenotypic memory exclusively under random (i.e., nonperiodic) environments. We identify the evolutionary phase diagram for simple response networks, which we show can exhibit both continuous and discontinuous transitions. Our approach enables exact analysis of diverse evolutionary systems, from viral epidemics to emergence of drug resistance. PMID- 27472147 TI - Vacuum extraction in fetal macrosomia and risk of neonatal complications: a population-based cohort study. AB - INTRODUCTION: High birthweight is associated with complicated childbirth. The aim of the present study was to investigate the association between birthweight, mode of delivery, and neonatal complications among infants born at term with a birthweight >=3000 g. MATERIAL AND METHODS: This population-based cohort study used data from the Swedish Medical Birth Register from 1999 to 2012, including 1 030 775 births at >36 completed weeks. Exposure was mode of delivery, categorized into non-instrumental vaginal delivery (VD), emergency cesarean section (CS), vacuum extraction (VE) or cesarean section following attempted vacuum extraction (VE + CS), and birthweight was divided into five categories (3000-3999 g, 4000 4499 g, 4500-4999 g, and >=5000 g). The following outcomes were assessed: 5-min Apgar score <7, neonatal convulsions, intracranial hemorrhage, and brachial plexus injury. Infants born after VD with a birthweight of 3000-3999 g were used as reference in the logistic regression analysis. RESULTS: The odds ratios for all complications increased at higher birthweights among infants born after VE/VE + CS and VD. The highest risks were seen after VE/VE + CS with an adjusted odds ratio for neonatal convulsions of 2.6 (95% CI 2.1-3.2) in the reference birthweight group and 6.3 (95% CI 4.3-9.2) among infants with a birthweight of >=4500 g. The corresponding adjusted odds ratios for intracranial hemorrhage were 2.6 (95% CI 1.7-3.9) and 6.7 (95% CI 3.3-13.6) and for brachial plexus injury 4.0 (95% CI 3.3-4.9) and 88.4 (95% CI 71.9-108.4). CONCLUSION: Vacuum extraction is a risk factor for serious neonatal complications, in particular when used in macrosomic fetuses. PMID- 27472148 TI - Protocol for Ultralow-Temperature Ceramic Sintering: An Integration of Nanotechnology and the Cold Sintering Process. AB - The sintering process is an essential step in taking particulate materials into dense ceramic materials. Although a number of sintering techniques have emerged over the past few years, the sintering process is still performed at high temperatures. Here we establish a protocol to achieve dense ceramic solids at extremely low temperatures (<200 degrees C) via integrating the particle nanotechnology into the recently developed cold sintering process (CSP). The sintering path has been appropriately tailored via effectively utilizing the large surface-to-volume ratio of nanoparticles. BaTiO3 ceramics have been used for the illustration, given its importance in extensive electronic device applications, as well as its scientific interest, being a model material for many of the ferroelectric materials. Together with detailed experimental studies, the trends are also analyzed with a fundamental thermodynamic consideration. Such an impactful technique could have widespread application prospects in a wide variety of materials and would also provide a clear roadmap to guide future studies on ultralow-temperature ceramic sintering, ceramic materials related integration, and sustainable manufacturing practices. PMID- 27472149 TI - Generally representative is generally representative: comment on Shuttleworth Edwards. AB - OBJECTIVE: The aim of this paper is to provide comment on Shuttleworth-Edwards' criticism of the general population norms created for the South African adaptation of the WAIS-IV. In her criticism, she states that the norms are not applicable for any groups in South Africa, based on the fact that the norms were not stratified according to quality of education. METHOD: A discussion of some of the key issues that impact on the creation of general population norms in the South African context is provided. Demographic characteristics such as education level, quality of education, urban and rural demarcations, and home language are all considered. RESULTS: While the utility of within-group norms is not denied, the adoption of these without reference to the general population is not advised. To recommend that practitioners simply dispense with the general population norm without evidence that it creates misclassification or does not function effectively for the intended population lacks scientific merit at the current time. CONCLUSIONS: The need for clinical studies and further predictive validity research using the South African adaptation of the WAIS-IV is crucial to demonstrate the continued utility of the test in the South African context. Additional reference groups will improve the amount of comparative information available for clinicians to be able to make better informed decisions for diagnosis, but the general population norms will be an important starting point in this process. PMID- 27472150 TI - Synchronous Generation of Nano- and Microscaled Hierarchical Porous Polyelectrolyte Multilayers for Superwettable Surfaces. AB - We created both a superhydrophilic polymer surface and a superhydrophobic surface by using the poly(acrylic acid) (PAA)/poly(allylamine hydrochloride) (PAH) multilayers with the synchronously generated hierarchical porous surface structures. The formation of surface and pore structures induced at acidic pH values is subject to the composition, distribution, and molecular weights of polyelectrolytes in the layer-by-layer (LbL) assembled film, leading to a variety of unique surface topographies and porous structures located on different scales. During the porous induction at pH 2.0, both nano- and microscaled features synchronously developed on the surface as a result of the unique combination of high-molecular-weight PAH (900K g/mol) and low molecular weight PAA (15K g/mol), along with a much reduced deposition time of 1 min. Although thermally cross linked, the porous surface with hierarchical structure could achieve superhydrophilicity due to the remaining free amine and carboxylate groups on the porous structures. A complete switch from the superhydrophilic to the superhydrophobic surface was achieved via a simple chemical vapor deposition of trichloro(1H,1H,2H,2H-perfluoro-octyl)silane. In this work, the effects of molecular weight of polyelectrolytes (15K-900K g/mol), deposition time (10-900 s) during the LbL assembly, and pH (1.8 to 2.4) for the porous induction on the surface topography, pore structures, and wetting behavior were investigated in detail. A variety of unique porous surface structures on different length scales were systematically studied by controlling the above parameters. PMID- 27472151 TI - Hydrogen peroxide activation by fluorophilic polyoxotungstates for fast and selective oxygen transfer catalysis. AB - Fluorophilic polyoxotungstates perform the selective epoxidations of internal and terminal double bonds by hydrogen peroxide (H2O2) activation in 1,1,1,3,3,3 hexafluoro-2-propanol (HFIP), under mild temperature conditions. A hybrid synergy of supramolecular interactions, involving the inorganic cluster and the fluorinated solvent, is envisaged to boost H2O2 activation and the oxygen transfer mechanism. 1,2-Epoxides have been obtained with >99% selectivity and 98% yield at T = 40-70 degrees C. PMID- 27472152 TI - 'Out-of-the-box' thinking to help stop the spread of antibiotic resistance. PMID- 27472153 TI - Macroporous Hydrogels Composed Entirely of Synthetic Polypeptides: Biocompatible and Enzyme Biodegradable 3D Cellular Scaffolds. AB - Synthetic polypeptides are a class of bioinspired polymers with well demonstrated biocompatibility, enzyme biodegradability, and cell adhesive properties, making them promising materials for the preparation of macroporous hydrogels as 3D cellular scaffolds. Three-dimensional macroporous hydrogels composed entirely of biocompatible and enzyme biodegradable synthetic polypeptides have thus been prepared. Under cryoconditions, macroporous hydrogels in the form of macroporous cryogels were prepared using a single copolymer component through direct EDC/sulfo-NHS zero-length cross-linking between poly(l-glutamic acid) (PLG) and poly(l-lysine) (PLL) residues on a PLG-r-PLL random copolypeptide chain. The resulting macroporous cryogels were found to contain large interconnected pores (>=100 MUm) highly suitable for tissue engineering applications. Tuning the relative ratios of the amino acid components could result in cryogels with very different pore structures, swelling, and mechanical properties, suitable for developing gels for a range of possible soft tissue engineering applications. These cryogels were shown to be enzymatically biodegradable and demonstrated excellent biocompatibility, cell attachment and cell proliferation profiles with mammalian fibroblast (NIH-3T3) cells, demonstrating the appeal of these novel cryogels as highly suitable cellular scaffolds. PMID- 27472154 TI - Supplementation with Cashew Nut and Cottonseed Meal to Modify Fatty Acid Content in Lamb Meat. AB - This study evaluates the effect of cashew nut meal (CNM), whole cottonseed (WCS), and calcium salts of long-chain fatty acids (Ca-LCFA) on the fatty acid profiles of meat from hair lambs. Thirty-five 60-d-old, male, noncastrated Santa Ines lambs with an initial average body weight of 13.00 +/- 1.80 kg were used in a randomized complete-block design with 7 blocks and 5 treatments. The experimental treatments consisted of a control diet (CON) without supplemental lipids and 4 test diets with different lipid supplements that were selected according to the degree of protection from ruminal hydrogenation and their polyunsaturated fatty acid richness. The tests diets included the following modifications: supplementation with WCS, supplementation with CNM, supplementation with both cottonseed and CNM (CSCNM), and supplementation with Ca-LCFA. The C18:1n9c content was highest in the meat of the animals fed the CNM diet (42.00%). The meat from lambs fed the WCS and Ca-LCFA diets had higher C18:0 contents (25.23 and 22.80%, respectively). The C16:1 content was higher in the meat from the animals fed the CNM and CON diets (1.54 and 1.49%, respectively). C18:2c9t11 concentration was higher in the meat from the animals fed the Ca-LCFA and CNM diets. The estimated enzyme activity of Delta9-desaturase C18 was highest in the muscles of the lambs fed the CON, CNM, and CSCNM diets. The use of cashew nuts in the diet resulted in an increase in the C18:2c9t11 content of the lamb meat, which improved the nutritional characteristics of the fat. PMID- 27472155 TI - Kinetics of carbonate mineral dissolution in CO2-acidified brines at storage reservoir conditions. AB - We report experimental measurements of the dissolution rate of several carbonate minerals in CO2-saturated water or brine at temperatures between 323 K and 373 K and at pressures up to 15 MPa. The dissolution kinetics of pure calcite were studied in CO2-saturated NaCl brines with molalities of up to 5 mol kg-1. The results of these experiments were found to depend only weakly on the brine molality and to conform reasonably well with a kinetic model involving two parallel first-order reactions: one involving reactions with protons and the other involving reaction with carbonic acid. The dissolution rates of dolomite and magnesite were studied in both aqueous HCl solution and in CO2-saturated water. For these minerals, the dissolution rates could be explained by a simpler kinetic model involving only direct reaction between protons and the mineral surface. Finally, the rates of dissolution of two carbonate-reservoir analogue minerals (Ketton limestone and North-Sea chalk) in CO2-saturated water were found to follow the same kinetics as found for pure calcite. Vertical scanning interferometry was used to study the surface morphology of unreacted and reacted samples. The results of the present study may find application in reactive-flow simulations of CO2-injection into carbonate-mineral saline aquifers. PMID- 27472156 TI - Prognostic value of baseline seric Syndecan-1 in initially unresectable metastatic colorectal cancer patients: a simple biological score. AB - In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab based chemotherapy in two independent prospective clinical trials (development set: n = 126, validation set: n = 51, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p = 0.0066) and log-CD138 high level (p = 0.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS= 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p < 0.0001). This score had a good discrimination ability (C-index = 0.63). These results were externally confirmed in the validation set. Our study provides robust evidence in favor of the additional baseline soluble CD138 prognostic value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values. PMID- 27472157 TI - HEALTH TECHNOLOGY ASSESSMENT, DELIBERATIVE PROCESS, AND ETHICALLY CONTESTED ISSUES. AB - Healthcare technology assessment (HTA) aims to support decisions as to which technologies should be used in which situations to optimize value. Because such decisions will create winners and losers, they are bound to be controversial. HTA, then, faces a dilemma: should it stay away from such controversies, remaining a source of incomplete advice and risking an important kind of marginalization, or should it enter the controversy? The question is a challenging one, because we lack agreement on principles that are fine grained enough to tell us what choices we should make. In this study, we will argue that HTA should take a stand on ethical issues raised by the technology that is being investigated. To do so, we propose adding a form of procedural justice to HTA to arrive at decisions that the public can regard as legitimate and fair. A fair process involves deliberation about the reasons, evidence, and rationales that are considered relevant to meeting population-health needs fairly. One important way to make sure that there is real deliberation about relevant reasons is to include a range of stakeholders in the deliberative process. To illustrate how such deliberation might work, we use the case of cochlear implants for deaf children. PMID- 27472158 TI - DETERMINANTS OF THE INTENTION TO USE TELEMEDICINE: EVIDENCE FROM PRIMARY CARE PHYSICIANS. AB - OBJECTIVES: While most studies have focused on analyzing the results of telemedicine use, it is crucial to consider the determinants of its use to fully understand the issue. This article aims to provide evidence on the determinants of telemedicine use in clinical practice. METHODS: The survey targeted a total population of 398 medical professionals from a healthcare institution in Spain. The study sample was formed by the ninety-three primary care physicians who responded. Using an extended Technology Acceptance Model and microdata for the ninety-six physicians, binary logistic regression analysis was carried out. RESULTS: The analysis performed confirmed the model's goodness-of-fit, which allowed 48.1 percent of the dependent variable's variance to be explained. The outcomes revealed that the physicians at the healthcare institution placed greater importance on telemedicine's potential to reduce costs, and on its usefulness to the medical profession. The perception of medical information security and confidentiality and the patients' predisposition toward telemedicine were the second explanatory factors in order of importance. A third set of moderating effects would appear to corroborate the importance of the physicians' own opinions. CONCLUSIONS: These results have revealed the need for a dynamic approach to the design of telemedicine use, especially when it targets a variety of end-users. Hence, the importance of conducting studies before using telemedicine, and attempting to identify which of the above-mentioned predictors exert an influence and how. PMID- 27472159 TI - CHALLENGES IN CONTEMPORARY HEALTH TECHNOLOGY ASSESSMENT: A VIEW FROM THE OUTSIDE ERRATUM. AB - Owing to a copyediting error, Marjukka Makela was incorrectly listed as an author in the editorial by Oortwijn & van der Wilt (1) in February/April 2016 issue of International Journal of Technology Assessment in Health Care. The publisher apologizes to the author and readers for this error. The original article has been corrected online to rectify this error. PMID- 27472160 TI - Ultrafast Scavenging of the Precursor of H(*) Atom, (e(-), H3O(+)), in Aqueous Solutions. AB - Picosecond pulse radiolysis measurements have been performed in several highly concentrated HClO4 and H3PO4 aqueous solutions containing silver ions at different concentrations. Silver ion reduction is used to unravel the ultrafast reduction reactions observed at the end of a 7 ps electron pulse. Solvated electrons and silver atoms are observed by the pulse (electron beam)-probe (supercontinuum light) method. In highly acidic solutions, ultrafast reduction of silver ions is observed, a finding that is not compatible with a reaction between the H(*) atom and silver ions, which is known to be thermally activated. In addition, silver ion reduction is found to be even more efficient in phosphoric acid solution than that in neutral solution. In the acidic solutions investigated here, the species responsible for the reduction of silver atoms is considered to be the precursor of the H(*) atom. This precursor, denoted (e(-), H3O(+)), is a pair constituting an electron (not fully solvated) and H3O(+). Its structure differs from that of the pair of a solvated electron and a hydronium ion (es(-), H3O(+)), which absorbs in the visible region. The (e(-), H3O(+)) pair , called the pre-H(*) atom here, undergoes ultrafast electron transfer and can, like the presolvated electron, reduce silver ions much faster than the H(*) atom. Moreover, it is found that with the same concentration of H3O(+) the reduction reaction is favored in the phosphoric acid solution compared to that in the perchloric acid solution because of the less-efficient electron solvation process. The kinetics show that among the three reducing species, (e(-), H3O(+)), (es(-), H3O(+)), and H(*) atom, the first one is the most efficient. PMID- 27472161 TI - Challenges to acellular biological scaffold mediated skeletal muscle tissue regeneration. AB - Volumetric muscle loss (VML) injuries present a complex and heterogeneous clinical problem that results in a chronic loss of muscle tissue and strength. The primary limitation to muscle tissue regeneration after VML injury is the frank loss of all native muscle constituents in the defect, especially satellite cells and the basal lamina. Recent advancements in regenerative medicine have set forth encouraging and emerging translational and therapeutic options for these devastating injuries including the surgical implantation of acellular biological scaffolds. While these biomaterials can modulate the wound environment, the existing data do not support their capacity to promote appreciable muscle fiber regeneration that can contribute to skeletal muscle tissue functional improvements. An apparent restriction of endogenous satellite cell (i.e., pax7(+)) migration to acellular biological scaffolds likely underlies this deficiency. This work critically evaluates the role of an acellular biological scaffold in orchestrating skeletal muscle tissue regeneration, specifically when used as a regenerative medicine approach for VML injury. PMID- 27472163 TI - Biomaterials trigger endothelial cell activation when co-incubated with human whole blood. AB - Endothelial cell activation resulting from biomaterial contact or biomaterial induced blood activation may in turn also affect hemostasis and inflammatory processes in the blood. Current in vitro hemocompatibility assays typically ignore these modulating effects of the endothelium. This study describes a co incubation system of human whole blood, biomaterial and endothelial cells (ECs) that was developed to overcome this limitation. First, human endothelial cells were characterized in terms of their expression of coagulation- and inflammation relevant markers in response to various activators. Subsequently, their capacity to regulate hemostasis as well as complement and granulocyte activation was monitored in a hemocompatibility assay. After blood contact, quiescent ECs exhibited anticoagulant and anti-inflammatory properties. When they were co incubated with surfaces exhibiting pro-coagulant or pro-inflammatory characteristics, the ECs down-regulated coagulation but not complement or leukocyte activation. Analysis of intracellular levels of the endothelial activation markers E-selectin and tissue factor showed that co-incubation with model surfaces and blood significantly increased the activation state of ECs. Finally, the coagulation- and inflammation-modulating properties of the ECs were tested after blood/biomaterial exposure. Pre-activation of ECs by biomaterials in the blood induced a pro-coagulant and pro-inflammatory state of the ECs, wherein the pro-coagulant response was higher for biomaterial/blood pre-activated ECs than for TNF-alpha-pre-activated cells. This work provides evidence that biomaterials, even without directly contacting the endothelium, affect the endothelial activation state with and have consequences for plasmatic and cellular reactions in the blood. PMID- 27472165 TI - The effects of player grip on the dynamic behaviour of a tennis racket. AB - The aim of this article is to characterise the extent to which the dynamic behaviour of a tennis racket is dependent on its mechanical characteristics and the modulation of the player's grip force. This problem is addressed through steps involving both experiment and modelling. The first step was a free boundary condition modal analysis on five commercial rackets. Operational modal analyses were carried out under "slight", "medium" and "strong" grip force conditions. Modal frequencies and damping factors were then obtained using a high-resolution method. Results indicated that the dynamic behaviour of a racket is not only determined by its mechanical characteristics, but is also highly dependent on the player's grip force. Depending on the grip force intensity, the first two bending modes and the first torsional mode frequencies respectively decreased and increased while damping factors increased. The second step considered the design of a phenomenological hand-gripped racket model. This model is fruitful in that it easily predicts the potential variations in a racket's dynamic behaviour according to the player's grip force. These results provide a new perspective on the player/racket interaction optimisation by revealing how grip force can drive racket dynamic behaviour, and hence underlining the necessity of taking the player into account in the racket design process. PMID- 27472162 TI - iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes. AB - Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel polymersomes for intraperitoneal treatment of peritoneal carcinomatosis. PMID- 27472164 TI - Gene regulation with carbon-based siRNA conjugates for cancer therapy. AB - We report fluorescent carbon nanoparticle (FCN)-based small interfering RNA (siRNA) conjugates (C-siRNA) for gene regulation and cancer therapy. The C-siRNA has a core of chitosan-derived FCN and a shell of siRNA, and can down-regulate the expression of polo-like kinase-1 (Plk1), a master regulator of mitosis, via siRNA targeting Plk1 (siPlk1), for cancer therapy. The required amount of the FCNs is only ~1/30 of that of the gold nanoparticles in delivering equal amount of siRNA. The C-siPlk1 led to ~80% knockdown of cellular Plk1 mRNA in A375 cells, and induced apoptosis of the A375 cells (31.9%) and MCF-7 cells (20.33%), much higher than those by commercial nonviral gene delivery vectors, such as Lipofectamine 2000 in both cell lines (apoptosis rate < 10%). After the C-siPlk1 was administrated to A375 tumor-bearing mice intravenously, the tumor volume was less than 1/11 of the control groups. The C-siRNA can thus be powerful tools for gene delivery and gene therapy. PMID- 27472166 TI - Your word is my command: Oxytocin facilitates the understanding of appeal in verbal communication. AB - The hormone oxytocin is known to facilitate positive communication behaviors. In the current study, we aimed to examine how it affects the interpretation of verbal information during communication. We predicted oxytocin to promote the understanding of the socially most effortful dimension of appeal. After intranasal administration of oxytocin or a placebo, participants responded to a "four-ear communication" questionnaire. Results revealed that participants under oxytocin not only chose the dimension of appeal as first choice significantly more often than participants under placebo but also preferred it over most of the other dimensions of interpretation. The findings add to our knowledge of oxytocin as a facilitator of social approach and indicate how oxytocin might work in communicative settings. PMID- 27472167 TI - Ventricular septal rupture: successful delayed repair. AB - Ventricular septal rupture (VSR) occurs in approximately 1% of the patients who experience an acute myocardial infarction. The operative mortality of VSR repair decreases if surgery can be delayed until the infarct has healed and tissue strength improved. Because of heart failure or impending cardiogenic shock, surgical treatment can often not be delayed. We present a case in which a delayed repair of a VSR was possible. The patient was initially stabilized with an intra aortic balloon pump. She was discharged and readmitted 5 weeks later for definitive repair. Repair was performed, according to the Daggett technique, using a bovine pericardial patch and a mitral annuloplasty was carried out to correct for the regurgitation. Recovery was uneventful. Cardiac ultrasound examination at discharge showed no residual defect. PMID- 27472170 TI - Raman spectroscopy detection of biomolecules in biocrusts from differing environmental conditions. AB - Lichens and cyanobacteria colonize inhospitable places covering a wide climate range due to their different survival strategies, such as the synthesis of protective biomolecules. The effect of ecological factors on the synthesis of biomolecules has not been widely analysed. This study aimed to assess the effects of four factors (species, microclimate, seasonality and hydration state) and their interactions on the biomolecule frequency detected by Raman Spectroscopy. We included cyanobacterial biocrusts, and the lichens Diploschistes diacapsis, Squamarina lentigera, and Lepraria isidiata; two contrasted microclimates (typical and marginal), two contrasted seasons (hot and dry vs cool and wet) and two hydration states (dry and wet). "Species" was the most influential factor in the identity and frequency of the main biomolecules. Microclimatic differences in the range of the local specific habitats only influenced the biomolecules in cyanobacteria. There was a quadruple interaction among the factors, the effects being different mainly depending on the species. At D. diacapsis, the production of their main biomolecules depended on microclimate, although it also depended on seasonality. Nevertheless, in L. isidiata and S. lentigera microclimatic differences did not significantly affect the production of biomolecules. In the lichen species, the microhabitats exposed to relatively larger incident radiation did not show significantly larger relative frequency of photoprotective biomolecules. No clear connection between higher production of oxalates and drier microhabitats was found, suggesting that the synthesis of oxalates is not related to water reserve strategy. The pros and cons of monitor biomolecules in biocrust by Raman spectrometry were also discussed. PMID- 27472169 TI - Social anxiety as a potential mediator of the association between attachment and depression. AB - OBJECTIVE: The study represents a conceptual replication of the study by Eng et al. (2001) in a sample of adult patients diagnosed with social anxiety disorder as primary diagnosis. METHODS: Two different attachment questionnaires (Bielefeld Questionnaire of Client Expectations (BQCE) and Experiences in Close Relationships (ECR-RD)) were applied to examine whether the effect of attachment on depression (measured by the BDI) is mediated by social anxiety (measured by the LSAS) in a cross-sectional study. RESULTS: The data confirms such a mediation. The effect of attachment measured with the BQCE on depression was completely mediated, whereas the effect of both scales of the ECR-RD (attachment related avoidance and anxiety) on depression was only partially mediated by social anxiety disorder. CONCLUSION: The study supports the association of attachment, social anxiety, and depressive symptoms and the need to consider different perspectives on attachment. PMID- 27472171 TI - The perceived risk of pregnancy as a mediator of the association between prenatal maternal self-efficacy and postnatal subjective well-being. AB - The present study examined the mediating role of a mother's appraisal of the risk of being pregnant in the association between prenatal maternal self-efficacy and postnatal subjective well-being, regardless of actual objective risk. Recruited through public health funds, 582 Israeli women filled out self-reported questionnaires during the third trimester of their pregnancy and about eight weeks postnatal. Results confirmed a mediating effect, implying that health professionals treating pregnant women, have the ability to impact maternal subjective well-being, beyond their physical condition, through their regular pregnancy monitoring checkups. The results are discussed in light of Transactional Stress Theory. PMID- 27472172 TI - Shared versus distinct genetic contributions of mental wellbeing with depression and anxiety symptoms in healthy twins. AB - Mental wellbeing and mental illness symptoms are typically conceptualized as opposite ends of a continuum, despite only sharing about a quarter in common variance. We investigated the normative variation in measures of wellbeing and of depression and anxiety in 1486 twins who did not meet clinical criteria for an overt diagnosis. We quantified the shared versus distinct genetic and environmental variance between wellbeing and depression and anxiety symptoms. The majority of participants (93%) reported levels of depression and anxiety symptoms within the healthy range, yet only 23% reported a wellbeing score within the "flourishing" range: the remainder were within the ranges of "moderate" (67%) or "languishing" (10%). In twin models, measures of wellbeing and of depression and anxiety shared 50.09% of variance due to genetic factors and 18.27% due to environmental factors; the rest of the variance was due to unique variation impacting wellbeing or depression and anxiety symptoms. These findings suggest that an absence of clinically-significant symptoms of depression and anxiety does not necessarily indicate that an individual is flourishing. Both unique and shared genetic and environmental factors may determine why some individuals flourish in the absence of symptoms while others do not. PMID- 27472173 TI - Candidate gene study reveals DRD1 and DRD2 as putative interacting risk factors for youth depression. AB - Alterations in the monoaminergic neurotransmission systems are suspected to be involved in the etiology of neuropsychiatric disorders, including depression. The role of these pathways in the risk of developing depressive symptoms during childhood or adolescence is still not completely clear. This study sought to identify putative genetic factors in genes of serotonergic and dopaminergic systems modulating the level of manifestation of depressive symptoms in children and adolescents. We analyzed 170 single nucleotide polymorphisms (SNPs) in 21 candidate dopaminergic and serotonergic genes in a non-clinical sample of 410 Costa Rican participants of ages between 7 and 18 years, assessing the severity of depressive symptoms through the Child Depression Inventory (CDI). Genotypic and haplotypic associations, as well as epistatic effects, were examined. A significant interaction effect was detected between rs1039089 in conjunction with rs877138 located upstream of the dopamine D1 receptor (DRD1) and the dopamine D2 receptor (DRD2) genes respectively, although no evidence was found for any single variant or haplotype related to a differential liability. This newly described genetic interaction among putative regulatory regions of dopamine receptors could affect the level of manifestation of depressive symptoms through an imbalance of D1-D2 heteromers and modulation of cognitive processes. PMID- 27472175 TI - The Once and Future Care Manager. PMID- 27472174 TI - Analysis of non-derivatised bacteriohopanepolyols by ultrahigh-performance liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Traditional investigation of bacteriohopanepolyols (BHPs) has relied on derivatisation by acetylation prior to gas chromatography/mass spectrometry (GC/MS) or liquid chromatography/MS (LC/MS) analysis. Here, modern chromatographic techniques (ultrahigh-performance liquid chromatography (UPLC)) and new column chemistries were tested to develop a method for BHP analysis without the need for derivatisation. METHODS: Bacterial culture and sedimentary lipid extracts were analysed using a Waters Acquity Xevo TQ-S triple quadrupole mass spectrometer in positive ion atmospheric pressure chemical ionisation (APCI) mode. Waters BEH C18 and ACE Excel C18 were the central columns evaluated using a binary solvent gradient with 0.1% formic acid in the polar solvent phase in order to optimise performance and selectivity. RESULTS: Non-amine BHPs and adenosylhopane showed similar performance on each C18 column; however, BHP containing terminal amines were only identified eluting from the ultra-inert ACE Excel C18 column. APCI-MS/MS product ion scans revealed significant differences in fragmentation pathways from previous methods for acetylated compounds. The product ions used for targeted multiple reaction monitoring (MRM) are summarised. CONCLUSIONS: UPLC/MS/MS analysis using an ACE Excel C18 column produced superior separation for amine-containing BHPs and reduced run times from 60 to 9 min compared with previous methods. Unexpected variations in fragmentation pathways between structural subgroups must be taken into account when optimising MRM transitions for future quantitative studies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27472176 TI - Essentials of Advocacy in Case Management: Part 2: Client Advocacy Model and Case Manager's Advocacy Strategies and Competencies. AB - PURPOSE/OBJECTIVES: This article describes a client advocacy model for use by case managers. It delineates necessary competencies for the case manager and shares important strategies for effective client advocacy. PRIMARY PRACTICE SETTING(S): All practice settings across the continuum of health and human services and case managers of diverse professional backgrounds. FINDINGS AND CONCLUSION: Advocacy is a primary role and necessary competency of professional case managers functioning in various care settings. It is rooted in ethical theory and principles. Successful case managers apply ethical principles of advocacy at every step of the case management process and in the decisions they make. Part II of this two-part article presents a client advocacy model for case managers to apply in their practice, describes the role of advocacy in client engagement, and identifies important strategies and a set of essential competencies for effective case management advocacy. Part I already explored the ethical theories and principles of advocacy, the perception of case management related professional organizations of advocacy, and the common types of advocacy based on scope, complexity, impact, and reach. IMPLICATIONS FOR CASE MANAGEMENT: Acquiring foundational knowledge, skills, and competencies in what advocacy is and how to effectively enact its related behaviors is essential for success of case managers and for achieving desired outcomes for both the clients and health care agencies/providers alike. Case management leaders are urged to use the knowledge shared in this article to develop advocacy training and competency management programs for their case managers. PMID- 27472177 TI - A 30-Year Retrospective: Degrees of Difficulty in Decreasing LOS. AB - PURPOSE: In an attempt to avoid future revisionist history, the author offers a 30-year retrospective (1986-2016) on the evolution of strategies to reduce length of stay (LOS). She and her colleagues have been involved from the onset by developing tools such as critical paths, roles such as clinical case management, and operational systems for managing measureable outcome-driven care from the bedside to the boardroom. PRIMARY PRACTICE SETTING: Acute care hospitals. FINDINGS/CONCLUSIONS: The LOS for all inpatients has changed dramatically from 1970 (average LOS = 7.8 days) through solidly between 2005 and 2012 (average LOS = 4.5 days in 2012) despite a significant increase in the average age of hospital inpatients (; ). For patients 65 years and older, who comprised 38% of all inpatients, the decrease has been more drastic: from 12.6 days in 1970 to 5.5 days in 2005-2010 ().With the exception of hospitalists and case management staff, acute care hospitals have essentially doubled productivity without adding additional direct care full-time equivalents! Described in terms of "low-hanging" to "high-hanging" fruit, this article outlines the classic methods used to reduce LOS and concludes with some implications of LOS for health care reform. The U.S. health system could not have accomplished this feat without case managers and social workers. IMPLICATIONS FOR CASE MANAGEMENT: Acute care services should be very proud of their achievements and use their reputation to empower their work for the next frontier, which will be reducing cost per case, especially in risk contracts. Everything old seems new again. PMID- 27472178 TI - Contracts and Contracting: A Primer. AB - PURPOSE/OBJECTIVES: The underlying guiding principles of case management services and practices of the Case Management Body of Knowledge include the following: "Case managers must possess the education, skills, knowledge, competencies, and experiences needed to effectively render appropriate, safe, and quality services to clients/support systems" and "Case management services are offered according to the clients' benefits as stipulated in their health insurance plans (http://www.cmbodyofknowledge.com/content/case-management-knowledge-2). Fulfilling these principles requires that the case manager engage in negotiating and contract execution.This article explores the concepts of negotiation and some of the many ways case managers contribute to the contracting process. PRIMARY PRACTICE SETTING: Acute care hospitals, individual practice, managed care. FINDINGS AND CONCLUSIONS: Case managers can provide valuable information during the contracting process, in many settings. In the managed care arena, case management can help identify the types of services needed by the population the organization serves. The same understanding of data can assist during the payer contracting process in the acute care setting and ensure that the hospital is fairly reimbursed by third party payers. The independent practitioners will, undoubtedly, face the need to negotiate for themselves as well as their clients. IMPLICATIONS FOR CASE MANAGEMENT: The case manager, regardless of the setting, benefits from an understanding of the principles and processes associated with negotiation and contracting. PMID- 27472179 TI - The Addict's Last Ally. PMID- 27472180 TI - Title Protection for Professional Case Managers: What's in a Name? PMID- 27472181 TI - Straight Talk About Case Manager Burnout. PMID- 27472182 TI - Retail Clinics: Bringing Health Care to the Neighborhood. PMID- 27472183 TI - Essentials of Advocacy in Case Management: Part 2: Client Advocacy Model and Case Manager's Advocacy Strategies and Competencies. PMID- 27472184 TI - A 30-Year Retrospective: Degrees of Difficulty in Decreasing LOS. PMID- 27472187 TI - Effects of Maternal Diet During Pregnancy on the Risk of Childhood Acute Lymphoblastic Leukemia: A Systematic Review. AB - Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children that can be affected by maternal diet. The aim of this study was to evaluate maternal dietary risk factors of ALL. We searched MEDLINE, Cochrane Library, Springer Link, Wiley Online, Science Direct, Mosby, ISI Web of Science, OVID, ProQuest, and Scopus from database inception until February 2, 2016. Two reviewers scanned titles, abstracts, and keywords of articles after excluding duplicates. We included case-control studies evaluating the relationship between maternal diet during pregnancy and childhood ALL. The search resulted in 2,940 papers, of which 11 full-text articles met the criteria for inclusion in the review and were analyzed. The finding of these studies suggest that maternal diet composed largely of vegetables, fruits, and protein sources before and during pregnancy can reduce the risk of ALL in offspring. Maternal alcohol intake had no effect. Nevertheless, inherent limitations of case-control studies like measurement error, random error, recall bias, and selection bias preclude conclusive evidence. Persuading pregnant women to follow a healthy diet rich in fruits, vegetables, and protein may reduce the risk of childhood ALL. Avoiding alcohol intake seems prudent. PMID- 27472185 TI - 20/40 or Better Visual Acuity After Optic Neuritis: Not as Good as We Once Thought? AB - BACKGROUND: Although patients with acute optic neuritis (ON) recover high contrast visual acuity (HCVA) to 20/40 or better in 95% of affected eyes, patients with a history of ON continue to note subjective abnormalities of vision. Furthermore, substantial and permanent thinning of the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) is now known to occur early in the course of ON. We measured vision-specific quality of life (QOL) in patients with a history of acute ON and recovery of VA to 20/40 or better in their affected eyes to determine how these QOL scores relate to RNFL and GCL thickness and low-contrast letter acuity (LCLA) across the spectrum of visual recovery. METHODS: Data from an ongoing collaborative study of visual outcomes in multiple sclerosis and ON were analyzed for this cross-sectional observational cohort. Patients and disease-free control participants completed the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, as well as VA and LCLA testing for each eye separately and binocularly. Optical coherence tomography measures for each eye included peripapillary RNFL thickness and macular GCL + inner plexiform layer (GCL + IPL) thickness. RESULTS: Patients with a history of acute ON and recovery to 20/40 or better VA (n = 113) had significantly reduced scores for the NEI-VFQ-25 (83.7 +/- 15.4) and 10-Item Neuro-Ophthalmic Supplement (74.6 +/- 17.4) compared with disease-free controls (98.2 +/- 2.1 and 96.4 +/- 5.2, P < 0.001, linear regression models, accounting for age and within-patient, intereye correlations). Most patients with 20/40 or better visual recovery (98/112, 88%) had monocular HCVA in their affected eye of 20/20 or better. Although patients with 20/50 or worse HCVA recovery demonstrated the worst performance on low contrast acuity, affected eye RNFL and GCL + IPL thickness, and QOL scales, these measures were also significantly reduced among those with 20/40 or better HCVA recovery compared with controls. CONCLUSIONS: Patients with a history of ON and "good" visual recovery, defined in the literature as 20/40 or better HCVA, are left with clinically meaningful reductions in vision-specific QOL. Such patient observed deficits reflect the underlying significant degrees of retinal axonal and neuronal loss and visual dysfunction that are now known to characterize ON even in the setting of maximal HCVA recovery. There remains an unmet therapeutic need for patients with ON. PMID- 27472188 TI - Psychometric Properties of the Chinese Version of the Acceptance of Chronic Health Conditions (Stoma) Scale for Patients With Stoma. AB - BACKGROUND: Formation of a stoma is a common outcome in surgical treatment of colorectal cancer. A higher acceptance of stoma was shown to improve quality of life of patients. No instrument in Chinese is available that can be used to measure the acceptance of stoma among patients with colorectal cancer. OBJECTIVES: The aims of this study were to translate and test the psychometric properties of Chinese version of Acceptance of Chronic Health Conditions (ACHC) (Stoma) scale. METHODS: A sample of 100 Chinese-speaking patients with stoma was recruited from a public tertiary care hospital in Singapore. The scale was translated into Chinese and reviewed by an expert panel for semantic equivalence and content validity testing. Convergent validity was established by exploring correlations between scores of the Chinese version of the ACHC (Stoma) scale and those of the 5-level version of European Quality of Life Questionnaire-5 Dimensions. Reliability was assessed by internal consistency and test-retest reliability. RESULTS: The newly translated scale had high content validity (content validity index = 94%) and acceptable internal consistency (Cronbach's alpha = .846). The test-retest reliability was satisfactory with an intraclass coefficient of 0.997. A positive correlation was found between both scores on ACHC (Stoma) scale and EQ-5D utility score (r = 0.63, P < .01) and EQ-5D global visual analog scale (r = 0.70, P < .01). CONCLUSIONS: The Chinese version of the ACHC (Stoma) scale demonstrated satisfactory content validity, good convergent validity, and adequate internal consistency and stability. IMPLICATIONS FOR PRACTICE: This scale can be used as a convenient screening tool in clinical settings to assess the level of acceptance in Chinese-speaking patients with stoma. PMID- 27472190 TI - Knowledge and Beliefs Regarding Breast and Cervical Cancer Screening Among Mexican-Heritage Latinas. AB - BACKGROUND: Lower participation rates in mammography and Papanicolaou test are common among Latinas compared with other ethnic groups. Suboptimal screening rates are attributed to lack of knowledge, access to services, and cultural influences. OBJECTIVE: The purpose of this study is to qualitatively examine an alternative framework for examining cultural influences on Mexican-heritage Latinas' understandings of breast and cervical cancer screening and how to leverage their beliefs to positively influence screening practices. METHODS: The study is based on the analysis of 4 focus groups with 47 Latinas residing in greater Phoenix, Arizona. RESULTS: Iterative qualitative analyses identified 5 major themes: (1) knowledge and beliefs about cancer cause and risk in general, (2) knowledge and beliefs specific to breast and cervical cancer screening, (3) experiences with breast and cervical cancer screening, (4) facilitators and barriers to breast and cervical screening, and (5) desired information about cancer and screening. CONCLUSIONS: Rather than focusing on Latinas' knowledge and/or misconceptions of breast and cervical cancer in screening-related education, researchers must examine what Latinas believe and leverage those convictions to expand their perceptions and behaviors related to breast and cervical cancer prevention practices. IMPLICATIONS FOR PRACTICE: Practitioners should recognize that Latinas may differ in beliefs from other minorities, and that even within-group, there may be cultural differences that influence cancer screening behaviors. PMID- 27472189 TI - Benefit Finding and Quality of Life in Caregivers of Childhood Cancer Survivors: The Moderating Roles of Demographic and Psychosocial Factors. AB - BACKGROUND: Benefit finding, or finding positive outcomes in the face of adversity, may play a role in predicting quality of life (QoL) among caregivers, but mixed results suggest that other factors may moderate this relationship. OBJECTIVE: This study examined demographic and psychosocial moderators of the association between benefit finding and QoL among caregivers of childhood cancer survivors. METHODS: Caregivers of childhood cancer survivors (n = 83) completed measures of benefit finding, QoL, coping, optimism, social support, caregiving demand, posttraumatic stress, and demographics. RESULTS: The relationship between benefit finding and QoL was moderated by caregiver age, marital status, socioeconomic status, geographic location, acceptance and emotion-focused coping, optimism, caregiving demand, and posttraumatic stress. Benefit finding was more strongly related to QoL among caregivers with fewer demographic/psychosocial resources. CONCLUSIONS: Results suggest that finding benefits in the cancer experience may have a greater positive impact for caregivers with relatively fewer demographic and psychosocial resources and may have less of an impact for caregivers with relatively greater resources. Findings further point to the complex nature of QoL among caregivers of childhood cancer survivors. IMPLICATIONS FOR PRACTICE: Results may aid clinicians in identifying caregivers at particular risk for low QoL. They may be counseled to find benefits in their experience or provided with resources to strengthen other factors that impact QoL. PMID- 27472192 TI - Rethinking Sensitized Luminescence in Lanthanide Coordination Polymers and MOFs: Band Sensitization and Water Enhanced Eu Luminescence in [Ln(C15H9O5)3(H2O)3]n (Ln = Eu, Tb). AB - A coordination polymer [Ln(C15H9O9)3(H2O)3]n (1-Ln = Eu(III), Tb(III)) assembled from benzophenonedicarboxylate was synthesized and characterized. The organic component is shown to sensitize lanthanide-based emission in both compounds, with quantum yields of 36% (Eu) and 6% (Tb). Luminescence of lanthanide coordination polymers is currently described from a molecular approach. This methodology fails to explain the luminescence of this system. It was found that the band structure of the organic component rather than the molecular triplet state was able to explain the observed luminescence. Deuterated (Ln(C15H9O9)3(D2O)3) and dehydrated (Ln(C15H9O9)3) analogues were also studied. When bound H2O was replaced by D2O, lifetime and emission increased as expected. Upon dehydration, lifetimes increased again, but emission of 1-Eu unexpectedly decreased. This reduction is reasoned through an unprecedented enhancement effect of the compound's luminescence by the OH/OD oscillators in the organic-to-Eu(III) energy transfer process. PMID- 27472191 TI - Symptom Clusters and Impact of Fatigue and Sleep Disturbance on Symptom Experiences of Hepatoma Patients in Taiwan. AB - BACKGROUND: Hepatoma is the second leading cause of cancer mortality among patients with cancer in Taiwan. Patients with cancer simultaneously experience multiple symptoms in clusters. Relevant studies have generally focused on a single hepatoma symptom. OBJECTIVES: The aim of this study is to explore the prevalence of symptom clusters and the impact of fatigue and sleep on symptom experiences of patients with hepatoma. METHODS: The Taiwanese version of the M.D. Anderson Symptom Inventory was administered to a sample of 100 patients. Data were analyzed using descriptive statistics, Pearson correlation, and regression, factor, and hierarchical cluster analyses. RESULTS: The results showed that fatigue and sleep disturbance were the most severe symptoms experienced by patients with hepatoma. Patients with hepatoma who concurrently experienced fatigue and sleep disturbance experienced more symptoms and more severe symptoms than did those who experienced either symptom or no symptom. This study identified 2 clusters: 1 cluster comprised 8 symptoms and the other cluster comprised 5 symptoms. Factor analysis revealed the following 3 factors: pain-, gastrointestinal-, and sensation-related symptoms. CONCLUSIONS: Patients with hepatoma who concurrently experienced fatigue and sleep disturbance experienced more symptoms and more severe symptoms than did those who experienced either symptom or no symptom. This study identified 2 clusters experienced by patients with hepatoma. IMPLICATIONS FOR PRACTICE: Our results provide implications for further research on managing the most common co-occurring symptoms to reduce symptom clusters and improve the quality of life of hepatoma patients. PMID- 27472193 TI - The role of human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. AB - CONCLUSION: HPV + HNSCC patients have improved Overall Survival (OS), Disease Specific Survival (DSS), Disease Free Survival (DFS), and Progression Free Survival (PFS). The radiotherapy treatment can't improve the Survival of the HPV negative HNSCC patients. OBJECTIVE: To investigate the role of Human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. METHODS: A search in PubMed and Chinese CNKI (2000-2015) was performed. This meta analysis was done using RevMan 5.1 software. Outcomes included OS, DSS, DFS, PFS, and Treatment responses rates (RR). RESULTS: A total of 2620 patients in 10 studies were included. The Positive detective rates of HPV and P16 are 32.5% (425/1309) and 42.5% (526/1239). OS and PFS were improved in HPV + patients compared to HPV - patients (HR = 0.48; 95% CI = 0.37-0.62, p < 0.0001) and (HR = 0.49; 95% CI = 0.31-0.78, p < 0.0001). The survival benefit was similar in HPV-16 + patients (adjusted HR = 0.39; 95% CI = 0.21-0.60, p < 0.0001). The DFS of P16 + patients improved (HR = 0.70; 95% CI = 0.55-0.89, p < 0.0001). The treatment response of p16 + patients didn't significantly improve compared with p16- patients (HR = 1.44; 95% CI = 1.01-2.05, p = 0.05). PMID- 27472194 TI - The caring concept, its behaviours and obstacles: perceptions from a qualitative study of undergraduate nursing students. AB - Developing caring competences is considered to be one of the most important aims of undergraduate nursing education and the role of clinical placement is recognised as special in this regard. Students' reflection on caring, their experience and obstacles in being caring is recommended as a key strategy in the process of teaching and studying the nursing discipline. Therefore, the aim of this study was to describe the concept of caring, its manifestations and possible obstacles while caring, as perceived by first-year nursing students before and after their first clinical placement. Qualitative content analysis of 15 Polish students' narratives written before and after their clinical experience in the form of text-diaries was undertaken. The findings revealed that students entered their nursing education with a deep humanistic vision of caring both on theoretical and practical levels and the first clinical placement has enriched this vision. Expressive caring was more appreciated by students than the instrumental one and their concept of caring was coherent with the caring behaviours as described in their narratives. Several internal and external obstacles for caring have been reported by students, indicating a specific tension between their ideal of caring and their practical experience of caring in the clinical reality. PMID- 27472195 TI - Biomimetic Approach to the Catalytic Enantioselective Synthesis of Flavonoids. AB - Herein is reported the direct asymmetric addition of phenol nucleophiles to benzopyrylium salts as a means to produce enantioenriched flavonoid-like compounds. This enantioselective C-C bond construction was achieved through a chiral anion phase-transfer strategy that mimics the proposed biosynthesis of this structurally diverse set of natural products. The utility of this methodology was demonstrated in enantioselective synthesis of a 2,8 dioxabicyclo[3.3.1]nonane and a 2,4-diarylbenzopyran. PMID- 27472196 TI - Altered Concentrations in Dyslipidemia Evidence a Role for ANGPTL8/Betatrophin in Lipid Metabolism in Humans. AB - CONTEXT: Angiopoietin-like protein 8 (ANGPTL8)/betatrophin is a secreted protein initially involved in beta-cell replication. Recent data in humans and mice models suggest that ANGPTL8/betatrophin is more related to lipid metabolism. OBJECTIVE: The aim of the present study was to compare the circulating concentrations of ANGPTL8/betatrophin in individuals with dyslipidemia defined as having high or low levels of high-density lipoprotein (HDL)-cholesterol or triglycerides, respectively. DESIGN, SETTING, AND PARTICIPANTS: Serum concentrations of ANGPTL8/betatrophin were measured by an ELISA in 177 subjects. We studied two different selected case-control dyslipidemic cohorts including individuals with high (n = 43) or low (n = 46) circulating concentrations of HDL cholesterol or with low (n = 48) or high (n = 40) levels of triglycerides. RESULTS: Circulating concentrations of ANGPTL8/betatrophin were significantly lower in individuals with dyslipidemia (P < .001) in both males (controls 27.8 +/ 15.2 vs dyslipidemic 17.0 +/- 11.2 ng/mL) and females (controls 50.0 +/- 22.2 vs dyslipidemic 27.0 +/- 16.5 ng/mL). The magnitude of the differences was higher in dyslipidemic patients with low HDL-cholesterol than in those with high triglyceride concentrations. ANGPTL8/betatrophin levels were lower in subjects with type 2 diabetes (P < .001), but the impact of type 2 diabetes vanished (P = .257) when the effect of dyslipidemia was included in the analysis. CONCLUSIONS: We conclude that serum ANGPTL8/betatrophin concentrations are altered in human dyslipidemia. ANGPTL8/betatrophin emerges as a potential player in dyslipidemia with a strong association with HDL-cholesterol and a potential therapeutic tool for the treatment of dyslipidemia. PMID- 27472197 TI - Local Intramedullary Delivery of Vancomycin Can Prevent the Development of Long Bone Staphylococcus aureus Infection. AB - Current treatments for methicillin-resistant Staphylococcus aureus (MRSA) infections require intravenously delivered vancomycin; however, systemically delivered vancomycin has its problems. To determine the feasibility and safety of locally delivering vancomycin hydrochloride (~25 mg/Kg) to the medullary canal of long bones, we conducted a pharmacokinetics study using a rat tibia model. We found that administering the vancomycin intraosseously resulted in very low concentrations of vancomycin in the blood plasma and the muscle surrounding the tibia, reducing the risk for systemic toxicity, which is often seen with traditional intravenous administration of vancomycin. Additionally, we were able to inhibit the development of osteomyelitis in the tibia if the treatment was administered locally at the same time as a bacterial inoculum (i.e., Log10 7.82 CFU/mL or 6.62x107 CFU/mL), when compared to an untreated group. These findings suggest that local intramedullary vancomycin delivery can achieve sufficiently high local concentrations to prevent development of osteomyelitis while minimizing systemic toxicity. PMID- 27472199 TI - Bioassays as one of the Green Chemistry tools for assessing environmental quality: A review. AB - For centuries, mankind has contributed to irreversible environmental changes, but due to the modern science of recent decades, scientists are able to assess the scale of this impact. The introduction of laws and standards to ensure environmental cleanliness requires comprehensive environmental monitoring, which should also meet the requirements of Green Chemistry. The broad spectrum of Green Chemistry principle applications should also include all of the techniques and methods of pollutant analysis and environmental monitoring. The classical methods of chemical analyses do not always match the twelve principles of Green Chemistry, and they are often expensive and employ toxic and environmentally unfriendly solvents in large quantities. These solvents can generate hazardous and toxic waste while consuming large volumes of resources. Therefore, there is a need to develop reliable techniques that would not only meet the requirements of Green Analytical Chemistry, but they could also complement and sometimes provide an alternative to conventional classical analytical methods. These alternatives may be found in bioassays. Commercially available certified bioassays often come in the form of ready-to-use toxkits, and they are easy to use and relatively inexpensive in comparison with certain conventional analytical methods. The aim of this study is to provide evidence that bioassays can be a complementary alternative to classical methods of analysis and can fulfil Green Analytical Chemistry criteria. The test organisms discussed in this work include single celled organisms, such as cell lines, fungi (yeast), and bacteria, and multicellular organisms, such as invertebrate and vertebrate animals and plants. PMID- 27472198 TI - Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function. AB - Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures. PMID- 27472201 TI - Surgery for sight: outcomes of congenital and developmental cataracts operated in Durban, South Africa. PMID- 27472200 TI - Responses of Rapid Viscoanalyzer Profile and Other Rice Grain Qualities to Exogenously Applied Plant Growth Regulators under High Day and High Night Temperatures. AB - High-temperature stress degrades the grain quality of rice; nevertheless, the exogenous application of plant growth regulators (PGRs) might alleviate the negative effects of high temperatures. In the present study, we investigated the responses of rice grain quality to exogenously applied PGRs under high day temperatures (HDT) and high night temperatures (HNT) under controlled conditions. Four different combinations of ascorbic acid (Vc), alpha-tocopherol (Ve), brassinosteroids (Br), methyl jasmonates (MeJA) and triazoles (Tr) were exogenously applied to two rice cultivars (IR-64 and Huanghuazhan) prior to the high-temperature treatment. A Nothing applied Control (NAC) was included for comparison. The results demonstrated that high-temperature stress was detrimental for grain appearance and milling qualities and that both HDT and HNT reduced the grain length, grain width, grain area, head rice percentage and milled rice percentage but increased the chalkiness percentage and percent area of endosperm chalkiness in both cultivars compared with ambient temperature (AT). Significantly higher grain breakdown, set back, consistence viscosity and gelatinization temperature, and significantly lower peak, trough and final viscosities were observed under high-temperature stress compared with AT. Thus, HNT was more devastating for grain quality than HDT. The exogenous application of PGRs ameliorated the adverse effects of high temperature in both rice cultivars, and Vc+Ve+MejA+Br was the best combination for both cultivars under high temperature stress. PMID- 27472202 TI - Ophthalmologic manifestations of Hallermann-Streiff-Francois syndrome: report of four cases. AB - PurposeHallermann-Streiff-Francois syndrome (HSS) is a rare genetic disorder characterised by ocular and craniofacial anomalies. The purpose of this report is to highlight the ophthalmological features in four such patients and outcomes of cataract surgery.Patients and methodsRetrospective review of medical records of patients with cataract and/or microcornea due to HSS was done. Presenting features, ocular findings, ocular motility and visual outcomes were noted.ResultsWe identified four children with microcornea/cataract who had associated clinical features suggestive of HSS. Mean age at presentation was 25.5+/-27.8 months. Three children presented with poor vision in both eyes and one with strabismus. All patients had a microcornea and microphthalmos. Three patients had a membranous cataract. Horizontal corneal diameter ranged from 5.5 to 10.5 mm and axial length ranged from 12 to 18 mm. Three patients had associated strabismus. Three patients underwent lens extraction and two underwent strabismus surgery. Best corrected visual acuity (BCVA) improved from fixing, following light to a median post-operative BCVA of 20/380. One eye developed retinal detachment.ConclusionChildren with HSS present with membranous cataracts, microcornea and microphthalmos and present surgical challenges. Though the patients were mostly left aphakic, all showed moderate visual improvement. PMID- 27472203 TI - Changing trend in the utilisation rate of donated corneas for keratoplasty in the UK: The North East England Study. AB - PurposeTo report the changing trend in the utilisation rate of donated corneas for keratoplasty and to examine the reasons for unutilised corneas in the North East of England.MethodsRelevant data were retrospectively collected from a local eye retrieval database and the UK Transplant Registry for two separate years; namely, 2006 and 2010.ResultsThe utilisation rate of donated corneas for keratoplasty improved from 57% (52/92) in 2006 to 71% (220/312) in 2010 (P=0.012). Over the same period, there was a marked reduction of failed serological test results from 24% (22/92) to 5% (14/312) (P<0.001). The leading reasons for unutilised corneas were failed serological test results (22/92, 24%) in 2006 and inadequate tissue quality (23/312, 7%) in 2010. The rate of tissue contamination remained similar between 2006 (4%) and 2010 (6%) (P=0.80). Eleven (4%) corneas were not transplanted due to recipient-related factors in 2010. Donor corneas of inadequate tissue quality were associated with older age (P=0.04) but not with gender, donation site, consent method, death-to-enucleation interval, death-to-processing interval, and storage time in the eye bank.ConclusionThere was a substantial improvement in the utilisation rate of corneas donated in the North East of England between 2006 and 2010. The principal reason was a reduction in failed serological test results. High donor age was associated with increased chance of corneas not being used. Utilisation rate of corneas can be further improved if potential modifiable factors are addressed, such as recipient-related factors and microbial contamination. PMID- 27472204 TI - Vision, eye disease, and art. PMID- 27472205 TI - Congenital cataract associated with persistent fetal vasculature: findings from IoLunder2. AB - PurposeTo describe the frequency, characteristics, and treatment outcome of persistent fetal vasculature (PFV) in children undergoing surgery for congenital and infantile cataract in the first 2 years of life.Patients and methodsObservational population-based cohort study with case identification through active surveillance and standardised data collection via a national clinical network, the British Isles Congenital Cataract Interest Group (BCCIG).ResultsThe IoLunder2 cohort comprises 246 children undergoing surgery for bilateral and unilateral congenital and infantile cataract in the first 2 years of life. A total of 58/246 (24%) children had PFV (%): overall, 46/95 (46%) with unilateral cataract, and 12/141 (8%) with bilateral disease. Anterior segment vascular remnants were more common in bilateral than unilateral disease (75 vs 11%, P=0.01). At 1 year after surgery, 20% of children with bilateral PFV and 24% with unilateral had achieved normal vision for age within the operated eye. The prevalence of post-operative glaucoma was 9% (of children with bilateral disease) and 4% (unilateral).ConclusionPFV is significantly more common than previously reported, and outcomes are comparable to that for congenital and infantile cataract overall. PMID- 27472206 TI - Response to: 'Cotton wool spots and migraine: a case series of three patients'. PMID- 27472207 TI - Effectiveness of the present ROP screening protocol. PMID- 27472208 TI - Second intraocular surgery after primary pediatric cataract surgery: indications and outcomes during long-term follow-up at a tertiary eye care center. AB - PurposeAlthough pediatric cataract surgery has become standardized and safe, further surgical interventions are not uncommon. The purpose of this study was to analyze the incidence of complications in children who required an intraocular intervention.MethodsA retrospective review of medical records of children (<7 years) with cataract who underwent cataract surgery with or without primary posterior chamber intraocular lens (IOL) placement between January 2006 and December 2014 was carried out. Data were collected regarding visual axis opacification (VAO), glaucoma, IOL decentration, intraocular infections, and other indications that required a second intraocular surgery.ResultsOut of 814 (570 pseudophakic and 244 aphakic) eyes of 620 operated children, 45 eyes of 40 children (5.5%, 45/814) needed a second surgery. The most common indication being VAO (2.9%, 24/814), followed by glaucoma (0.73%, 6/814). Incidence of complications was higher in children <1 year (VAO 6.1%, 19/308 and glaucoma 6%, 6/308). Among all children, repeat interventions and VAO were slightly less frequent in pseudophakics (4.91%, 28/570) vs aphakics (6.91%, 17/244) (P=0.31). As VAO was more common in pseudophakic eyes in infants, glaucoma was equally common in both groups. Best-corrected visual acuity improved from 1.6+/-0.56 LogMAR preoperatively to 0.80+/-0.50 LogMAR postoperatively.ConclusionsOur study suggests that overall incidence of second intraocular surgery is low after primary pediatric cataract surgery. VAO remains the most common indication followed by secondary glaucoma. Incidence of complications is higher in children <1 year of age at initial surgery. PMID- 27472209 TI - Globe size and bevacizumab treatment in retinopathy of prematurity: should we adjust the dose? PMID- 27472210 TI - Strabismus developing after unilateral and bilateral cataract surgery in children. AB - PurposeTo evaluate the prevalence and risk factors of strabismus in children undergoing surgery for unilateral or bilateral cataract with or without intraocular lens implantation.MethodsMedical records of pediatric patients were evaluated from 2000 to 2011. Children undergoing surgery for unilateral or bilateral cataract with at least 1 year of follow-up were included. Children with ocular trauma, prematurity, or co-existing systemic disorders were excluded. The following data were evaluated: strabismus pre- and post-operation; age at surgery; post-operative aphakia or pseudophakia; and visual acuity.ResultsNinety patients were included, 40% had unilateral and 60% had bilateral cataracts. Follow-up was on average 51 months (range: 12-130 months). Strabismus was found preoperatively in 34.4% children, and in 43.3% children at last follow-up. Strabismus developed in 46.2% of children who were orthotropic preoperatively, whereas 32.3% of children who had strabismus before surgery became orthotropic. Strabismus occurred after unilateral or bilateral cataract surgery in 63.9% and 29.6% children, respectively. At the last follow-up, strabismus was found in 46.7% of aphakic and 58.7% of pseudophakic children (P=0.283). Children who developed strabismus were generally operated at a younger age as compared with those without strabismus (mean of 25.9 vs 52.7 months, P<0.001). Final visual acuity was inversely correlated with prevalence of strabismus.ConclusionStrabismus is a frequent complication after cataract surgery in children. Risk factors include unilateral cases and young age at surgery. No correlation was found between prevalence of strabismus and use of intraocular lens. Strabismus was more common in children with poor final visual acuity. PMID- 27472211 TI - Twenty-four-hour intraocular pressure and ocular perfusion pressure characteristics in newly diagnosed patients with normal tension glaucoma. AB - PurposeTo determine the mean 24-h intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) characteristics of newly diagnosed, previously untreated, Caucasian, normal tension glaucoma (NTG) patients and to identify relationships between these features and visual field (VF) loss at diagnosis.MethodsConsecutive newly diagnosed NTG patients underwent 24-h habitual IOP and blood pressure (BP) monitoring. Parameters from pooled measurements obtained in the sitting (0800-2200 hours) and supine (1200-0600 hours) positions were compared and associations were sought with VF mean deviation (MD) and pattern standard deviation (PSD).ResultsSixty-two Caucasian NTG patients (24 men and 38 women) successfully completed circadian IOP and BP monitoring. In habitual position, 8 subjects (12.9%) exhibited a diurnal acrophase, 42 subjects (67.7%) demonstrated a nocturnal acrophase, one subject (1.6%) showed a flat rhythm and 11 patients (17.7%) revealed a biphasic/polyphasic rhythm. Nighttime MOPP values (supine position) were significantly greater than diurnal values (sitting position); (P<0.001). No association could be demonstrated between glaucomatous damage, as indicated by VF parameters, and either mean habitual 24-h IOP (P=0.20 and P=0.12 for MD and PSD, respectively), or habitual 24-h MOPP (P=0.96 and 0.29, for MD and PSD, respectively).ConclusionsIn this cohort of Caucasian NTG patients, most patients exhibited a nocturnal IOP acrophase when evaluated in a habitual position. No association was found between 24-h IOP or MOPP and VF damage. PMID- 27472212 TI - Reply to 'Response to: Cotton wool spots and migraine: a case series of three patients'. PMID- 27472213 TI - Strategies to improve follow-up of children after surgery for cataract: findings from Child Eye Health Tertiary Facilities in sub-Saharan Africa and South Asia. AB - PurposeWe sought to conduct a systematic literature review on follow-up of children with ocular surgical management (primarily childhood cataract) in developing countries. Second, we sought to determine the current practices regarding follow-up for clinical, optical, low vision, rehabilitation, and educational placement among children receiving surgical services at Child Eye Health Tertiary Facilities (CEHTF) in sub-Saharan Africa (SSA) and South Asia.MethodsA systematic literature review was conducted. Separately, we conducted a cross-sectional study among CEHTF in SSA and South Asia (India, Nepal, and Bangladesh) to assess current capacities and practices related to follow-up and educational placement.ResultsThe articles that met the systematic review eligibility criteria could be grouped into two areas: factors and strategies to improve post-operative follow-up and educational placement of children after surgery. Among the 106 CEHTF in SSA and South Asia, responses were provided by 75 CEHTF. Only 59% of CEHTF reported having a Childhood Blindness and Low Vision Coordinator; having a coordinator was associated with having appropriate follow-up mechanisms in place. Educational referral practices were associated with having a low-vision technician, having low-vision devices, and having donor support for these services.ConclusionsThe systematic literature review revealed evidence of poor follow-up after surgical interventions for cataract and other conditions, but also showed that follow-up could be improved significantly if specific strategies were adopted. Approaches to follow-up are generally inadequate at most facilities and there is little external support for follow-up. Findings suggest that funding and supporting a coordinator would assist in ensuring that good practices for follow-up (cell phone reminders, patient tracking, and reimbursement of transport) were followed. PMID- 27472215 TI - Optical coherence tomography characteristics of different types of big bubbles seen in deep anterior lamellar keratoplasty by the big bubble technique. AB - PurposeTo define optical coherence tomography (OCT) characteristics of type-1, type-2, and mixed big bubbles (BB) seen in deep anterior lamellar keratoplasty.MethodsHuman sclero-corneal discs were obtained from UK (30) and Canada (16) eye banks. Air was injected into corneal stroma until a BB formed. UK samples were fixed in formalin before scanning with Fourier-domain (FD-OCT). One pair of each type of BB was scanned fresh. All BB obtained from Canada were scanned fresh with time-domain (TD-OCT). For each OCT machine used, type-1 BB from which Descemets membrane (DM) was partially peeled, were also scanned. The morphological characteristics of the scans were studied.ResultsFD-OCT of the posterior wall of type-1 (Dua's layer (DL) with DM) and type-2 BB (DM alone) both revealed a double-contour hyper-reflective curvilinear image with a hypo reflective zone in between. The anterior line of type-2 BB was thinner than that seen with type-1 BB. In mixed BB, FD-OCT showed two separate curvilinear images. The anterior image was a single hyper-reflective line (DL), whereas the posterior image, representing the posterior wall of type-2 BB (DM) was made of two hyper reflective lines with a dark space in between. TD-OCT images were similar with less defined component lines, but the entire extent of the BB could be visualised.ConclusionOn OCT examination the DM and DL present distinct features, which can help identify type-1, type-2, and mixed BB. These characteristics will help corneal surgeons interpret intraoperative OCT during lamellar corneal surgery. PMID- 27472214 TI - Paediatric intraocular lens implants: accuracy of lens power calculations. AB - PurposeThis study aims to evaluate the accuracy of lens prediction formulae on a paediatric population.MethodsA retrospective case-note review was undertaken of patients under 8 years old who underwent cataract surgery with primary lens implantation in a regional referral centre for paediatric ophthalmology, excluding those whose procedure was secondary to trauma. Biometric and refractive data were analysed for 43 eyes, including prediction errors (PE). Statistical measures used included mean absolute error (MAE), median absolute error (MedAE), Student's t-test and Lin's correlation coefficient.ResultsThe mean PE using the SRK-II formula was +0.96 D (range -2.47D to +2.41 D, SD 1.33 D, MAE 1.38 D, MedAE 1.55, n=15). The mean PE was smaller using SRK/T (-0.18 D, range -3.25 D to +3.95 D, SD 1.70 D, MAE 1.30 D, MedAE 1.24, n=27). We performed an analysis of the biometry data using four different formula (Hoffer Q, Holladay 1, SRK-II and SRK/T). Hoffer Q showed a smaller MedAE than other formulae but also a myopic bias.ConclusionOur clinical data suggest SRK/T was more accurate in predicting post-operative refraction in this cohort of paediatric patients undergoing cataract surgery. Hoffer Q may have improved accuracy further. PMID- 27472216 TI - Factors associated with stereopsis and a good visual acuity outcome among children in the Infant Aphakia Treatment Study. AB - PurposeTo identify factors associated with stereopsis in children with good visual acuity after unilateral congenital cataract surgery in the Infant Aphakia Treatment Study.Patients and methodsInfants with a unilateral congenital cataract (n=114) were randomized to IOL implantation or contact lens correction after cataract surgery. At age 4.5 years, a masked examiner assessed HOTV acuity and stereopsis. Adherence to patching was assessed using 48-h recall telephone interviews and 7-day diaries throughout the first 5 years of life. Ocular motility was evaluated at age 5 years. Baseline, postoperative, and adherence findings were compared between patients with 20/40 or better acuity in their treated eyes with or without stereopsis.ResultsThirty (27%) of 112 patients who were evaluated at age 4.5 years had 20/40 or better acuity in their treated eye. Stereopsis was present on one or more tests in 15 of these 30 (50%) children. Baseline characteristics and postoperative findings did not differ between patients with or without stereopsis. Children with stereopsis were more likely to be orthotropic at distance (P=0.003) and were patched for fewer hours per day throughout the first 5 years of life and the difference increased over time (P<0.001). On average children with stereopsis were patched for 3.4 h/day during the first year of life and patching steadily decreased to 1.8 h/day by age 4 years.ConclusionAmong children with good vision following unilateral congenital cataract surgery, orthophoria and fewer hours of patching, particularly during years 2, 3, and 4, are associated with some evidence of stereopsis. PMID- 27472217 TI - Visual acuity and its predictors after surgery for bilateral cataracts in children. AB - PurposeThe objective of this study was to investigate preoperative factors associated with postoperative visual acuity outcomes and to develop a model to predict visual acuity prognosis.MethodsA retrospective study was conducted by reviewing clinical charts of pediatric patients who underwent bilateral cataract surgery by a single surgeon (MEW) at the Storm Eye Institute. A multiple logistic regression model was constructed to predict the odds of poor postoperative visual acuity, that is, worse than 20/40, based on age at surgery, gender, primary intraocular lens (IOL) placement, ethnicity, and preoperative nystagmus.ResultsA sample size of 157 children (314 eyes) was investigated with median duration of follow-up of 6.4 years. A total of 78% of children with bilateral cataract had postoperative visual acuity of 20/40 or better. The presence of preoperative nystagmus was highly correlated with poor postoperative visual acuity (OR=6.0; 95% CLs, 2.5-14.1; P-value<0.0001). Children of age <1 year at time of cataract extraction (OR=3.2; 95% CLs, 1.4-7.6; P-value=0.0073), male gender (OR=2.3; 95% CLs, 1.1-4.5; P-value=0.02), the absence of primary IOL placement (OR=3.0; 95% CLs, 1.05-8.4; P-value=0.04), and non-Caucasian ethnicity (OR=2.0; 95% CLs, 1.02 4.03; P-value 0.0447) were associated with poor visual acuity postoperatively.ConclusionsSatisfactory visual outcomes occurred in 78% of children operated on for bilateral cataracts. Preoperative nystagmus, age <1 year at time of cataract extraction, absence of primary IOL placement, male gender, and non-Caucasian ethnicity, were all factors associated with poor postoperative visual acuity. PMID- 27472218 TI - Screening for retinopathy of prematurity can be started in postmenstrual week 31 in very premature babies! PMID- 27472219 TI - Hepatocyte Nuclear Factor 4alpha (HNF4alpha) Is a Transcription Factor of Vertebrate Fatty Acyl Desaturase Gene as Identified in Marine Teleost Siganus canaliculatus. AB - Rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the capability of biosynthesizing long-chain polyunsaturated fatty acids (LC PUFA) from C18 precursors, and to possess a Delta4 fatty acyl desaturase (Delta4 Fad) which was the first report in vertebrates, and is a good model for studying the regulatory mechanisms of LC-PUFA biosynthesis in teleosts. In order to understand regulatory mechanisms of transcription of Delta4 Fad, the gene promoter was cloned and characterized in the present study. An upstream sequence of 1859 bp from the initiation codon ATG was cloned as the promoter candidate. On the basis of bioinformatic analysis, several binding sites of transcription factors (TF) including GATA binding protein 2 (GATA-2), CCAAT enhancer binding protein (C/EBP), nuclear factor 1 (NF-1), nuclear factor Y (NF-Y), hepatocyte nuclear factor 4alpha (HNF4alpha) and sterol regulatory element (SRE), were identified in the promoter by site-directed mutation and functional assays. HNF4alpha and NF-1 were confirmed to interact with the core promoter of Delta4 Fad by gel shift assay and mass spectrometry. Moreover, over-expression of HNF4alpha increased promoter activity in HEK 293T cells and mRNA level of Delta4 Fad in rabbitfish primary hepatocytes, respectively. The results indicated that HNF4alpha is a TF of rabbitfish Delta4 Fad. To our knowledge, this is the first report on promoter structure of a Delta4 Fad, and also the first demonstration of HNF4alpha as a TF of vertebrate Fad gene involved in transcription regulation of LC-PUFA biosynthesis. PMID- 27472220 TI - Correction: microRNA-122 Dependent Binding of Ago2 Protein to Hepatitis C Virus RNA Is Associated with Enhanced RNA Stability and Translation Stimulation. AB - [This corrects the article DOI: 10.1371/journal.pone.0056272.]. PMID- 27472221 TI - Glaucoma and Driving: On-Road Driving Characteristics. AB - PURPOSE: To comprehensively investigate the types of driving errors and locations that are most problematic for older drivers with glaucoma compared to those without glaucoma using a standardized on-road assessment. METHODS: Participants included 75 drivers with glaucoma (mean = 73.2+/-6.0 years) with mild to moderate field loss (better-eye MD = -1.21 dB; worse-eye MD = -7.75 dB) and 70 age-matched controls without glaucoma (mean = 72.6 +/- 5.0 years). On-road driving performance was assessed in a dual-brake vehicle by an occupational therapist using a standardized scoring system which assessed the types of driving errors and the locations where they were made and the number of critical errors that required an instructor intervention. Driving safety was rated on a 10-point scale. Self-reported driving ability and difficulties were recorded using the Driving Habits Questionnaire. RESULTS: Drivers with glaucoma were rated as significantly less safe, made more driving errors, and had almost double the rate of critical errors than those without glaucoma. Driving errors involved lane positioning and planning/approach, and were significantly more likely to occur at traffic lights and yield/give-way intersections. There were few between group differences in self-reported driving ability. CONCLUSIONS: Older drivers with glaucoma with even mild to moderate field loss exhibit impairments in driving ability, particularly during complex driving situations that involve tactical problems with lane-position, planning ahead and observation. These results, together with the fact that these drivers self-report their driving to be relatively good, reinforce the need for evidence-based on-road assessments for evaluating driving fitness. PMID- 27472222 TI - Unmanned Aerial Vehicles for High-Throughput Phenotyping and Agronomic Research. AB - Advances in automation and data science have led agriculturists to seek real time, high-quality, high-volume crop data to accelerate crop improvement through breeding and to optimize agronomic practices. Breeders have recently gained massive data-collection capability in genome sequencing of plants. Faster phenotypic trait data collection and analysis relative to genetic data leads to faster and better selections in crop improvement. Furthermore, faster and higher resolution crop data collection leads to greater capability for scientists and growers to improve precision-agriculture practices on increasingly larger farms; e.g., site-specific application of water and nutrients. Unmanned aerial vehicles (UAVs) have recently gained traction as agricultural data collection systems. Using UAVs for agricultural remote sensing is an innovative technology that differs from traditional remote sensing in more ways than strictly higher resolution images; it provides many new and unique possibilities, as well as new and unique challenges. Herein we report on processes and lessons learned from year 1-the summer 2015 and winter 2016 growing seasons-of a large multidisciplinary project evaluating UAV images across a range of breeding and agronomic research trials on a large research farm. Included are team and project planning, UAV and sensor selection and integration, and data collection and analysis workflow. The study involved many crops and both breeding plots and agronomic fields. The project's goal was to develop methods for UAVs to collect high-quality, high-volume crop data with fast turnaround time to field scientists. The project included five teams: Administration, Flight Operations, Sensors, Data Management, and Field Research. Four case studies involving multiple crops in breeding and agronomic applications add practical descriptive detail. Lessons learned include critical information on sensors, air vehicles, and configuration parameters for both. As the first and most comprehensive project of its kind to date, these lessons are particularly salient to researchers embarking on agricultural research with UAVs. PMID- 27472223 TI - A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems. AB - A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1alpha subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs. PMID- 27472224 TI - Preoperative systemic levels of VEGFA, IL-7, IL-17A, and TNF-beta delineate two distinct groups of children with brain tumors. AB - BACKGROUND: Primary brain tumors are the most common solid tumors in children. Increasing evidence demonstrates diverse intratumoral immune signatures, which are tentatively reflected in peripheral blood. PROCEDURE: Twenty cytokines were analyzed in preoperative plasma samples from five healthy children and 45 children with brain tumors, using a multiplex platform (MesoScale Discovery V PLEX(r) ). Tumor types included medulloblastoma (MB), ependymoma, sarcoma, high grade glioma, pilocytic astrocytoma, and other low-grade gliomas. RESULTS: A panel of four cytokines [VEGFA, interleukin (IL)-7, IL-17A, and tumor necrosis factor (TNF)-beta] delineated two distinct patient groups, identified as VEGFAhigh IL-7high IL-17Alow TNF-betalow (Group A) and VEGFAlow IL-7low IL 17Ahigh TNF-betahigh (Group B). Healthy controls and the vast majority of patients with MB were found within Group A, whereas patients with other tumor types were equally distributed between the two groups. Unrelated to A/B affiliation, we detected trends toward increased IL-10 and decreased IL-12/23 and TNF-alpha in several tumor types. Finally, a small number of patients displayed evidence of enhanced systemic immune activation, including elevated levels of interferon-gamma, granulocyte monocyte colony-stimulating factor, IL-6, IL-12/23, and TNF-alpha. Following tumor resection, cytokine levels in a MB patient approached the levels of healthy controls. CONCLUSIONS: We identify common features and individual differences in the systemic immune profiles of children with brain tumors. Overall, patients with MB displayed a uniform cytokine profile, whereas other tumor diagnoses did not predict systemic immunological status in single patients. Future characterization and monitoring of systemic immune responses in children with brain tumors will have important implications for the development and implementation of immunotherapy. PMID- 27472225 TI - Critical theory and the scholarship of medical education. PMID- 27472226 TI - Controlling the Interface Areas of Organic/Inorganic Semiconductor Heterojunction Nanowires for High-Performance Diodes. AB - A new method of in situ electrically induced self-assembly technology combined with electrochemical deposition has been developed for the controllable preparation of organic/inorganic core/shell semiconductor heterojunction nanowire arrays. The size of the interface of the heterojunction nanowire can be tuned by the growing parameter. The heterojunction nanowires of graphdiyne/CuS with core/shell structure showed the strong dependence of rectification ratio and perfect diode performance on the size of the interface. It will be a new way for controlling the structures and properties of one-dimensional heterojunction nanomaterials. PMID- 27472228 TI - First-Line Immune Therapy-Implications for Pathologists. PMID- 27472229 TI - In Reply. PMID- 27472230 TI - HER2 Immunohistochemistry-Guided Targeted Fluorescence In Situ Hybridization Analysis Does Not Help Identify Intratumoral Heterogeneity in Breast Cancer. PMID- 27472231 TI - Reports of the Death of the Microscope Have Been Greatly Exaggerated. PMID- 27472232 TI - Insights on the "Why, When, and How" of Integrating Molecular Testing in Anatomic Pathology Practice: Dedicated to the Memory of Gregory J. Naus, MD (1951-2015). PMID- 27472233 TI - The Ever-Changing Landscape of Drug-Induced Injury of the Lower Gastrointestinal Tract. AB - CONTEXT: -There is an ever-growing armamentarium of pharmacologic agents that can cause gastrointestinal (GI) mucosal injury, the most common symptoms being diarrhea, constipation, nausea, and vomiting. These are often self-limiting and without serious sequelae, but some symptoms are of greater concern, like drug induced mucosal ulceration that can manifest as GI hemorrhage, stricture formation, and even perforation. Histologically, there is significant overlap between drug-induced injuries and various disease entities. A single type of medication may cause multiple patterns of injury, which can involve the entire GI tract or just some parts of it. OBJECTIVE: -To review the most common drug induced injury patterns affecting the colon, which may be recognized by the surgical pathologist on colonic mucosal biopsies. This review does not address the injuries occurring in the upper GI tract. DATA SOURCES: -A PubMed review of English-language literature, up to December 2015, on drug-induced injury of GI tract was performed. CONCLUSIONS: -There are numerous drugs that damage the colonic mucosa. The most common drugs are included in this review according to their histologic pattern of injury. It is important for the pathologist to keep in mind that a single drug type can induce many histologic patterns of mucosal injury that can mimic many disease entities. Although there are some histologic clues helpful in the diagnosis of drug-induced colonic injury, correlation with clinical history and especially medication history is essential to improve diagnostic accuracy. PMID- 27472234 TI - Practical Strategies to Improve the Clinical Utility of the Dermatopathology Report. AB - CONTEXT: -Dermatologists and subspecialty dermatopathologists, working together over many years, develop a common understanding of clinical information provided on the requisition and of terminology used in the pathology report. Challenges arise for pathologists without additional subspecialty training in dermatology/dermatopathology, and for any pathologist reporting skin biopsies for nondermatologists such as general practitioners or surgeons. OBJECTIVE: -To provide practical strategies to improve efficiency of dermatopathology sign-out, at the same time providing the clinician with clear diagnostic and prognostic information to guide patient management. DATA SOURCES: -The information outlined in this review is based on our own experiences with routine dermatopathology and dermatology practice, and review of English-language articles related to the selected topics discussed. CONCLUSIONS: -Using generic diagnoses for some benign lesions, listing pertinent negatives in the pathology report, and using logical risk management strategies when reporting on basal cell carcinoma, partial biopsies, or specimens with incomplete clinical information allow the pathologist to convey relevant and useful diagnostic information to the treating clinician. PMID- 27472235 TI - Immunohistochemistry as a Practical Tool in Molecular Pathology. AB - CONTEXT: -Molecular genetics is playing an increasingly important role in patient care and pathology practice. Immunohistochemistry (IHC) is a valuable and practical tool employed by most pathologists on a regular basis. OBJECTIVE: -To highlight select examples of how IHC may be used in the realm of molecular diagnostics. DATA SOURCES: -Select sources on IHC relating to tumor subtyping, hereditary cancer screening, and treatment-response prediction are reviewed. These represent some of the areas in which IHC can be employed by anatomic pathologists to optimize patient care and further inform molecular testing. CONCLUSION: -In the emerging era of personalized medicine, IHC continues to serve a valuable function, complementing and enhancing other molecular techniques. PMID- 27472236 TI - Practical Considerations in Breast Papillary Lesions: A Review of the Literature. AB - CONTEXT: -Diagnosis of papillary breast lesions, especially in core biopsies, is challenging for most pathologists, and these lesions pose problems for patient management. Distinction between benign, premalignant, and malignant components of papillary lesions is challenging, and the diagnosis of invasion is problematic in lesions that have circumscribed margins. Obtaining a balance between overtreatment and undertreatment of these lesions is also challenging. OBJECTIVES: -To provide a classification and a description of the histologic and immunohistochemical features and the differential diagnosis of papillary breast lesions, to provide an update on the molecular pathology of papillary breast lesions, and to discuss the recommendations for further investigation and management of papillary breast lesions. This review provides a concise description of the histologic and immunohistochemical features of the different papillary lesions of the breast. DATA SOURCES: -The standard pathology text books on breast pathology and literature on papillary breast lesions were reviewed with the assistance of the PubMed database ( http://www.ncbi.nlm.nih.gov/pubmed ). CONCLUSIONS: -Knowledge of the clinical presentation, histology, immunoprofile, and behavior of papillary breast lesions will assist pathologists with the diagnosis and optimal management of patients with papillary breast lesions. PMID- 27472238 TI - Invasive Micropapillary Carcinoma of the Breast: An Update. AB - CONTEXT: -Invasive micropapillary carcinoma (IMPC) is a distinct variant of mammary carcinoma in which tumor cells are arranged in morulelike clusters devoid of fibrovascular cores and situated within empty stromal spaces. Identification of IMPC can be achieved by the assessment of morphologic features in conjunction with the characteristic "inside-out" staining pattern of epithelial membrane antigen and sialyl Lewis X highlighted by immunohistochemical analysis. Although recognizing micropapillary architecture is often not challenging, the criteria for distinguishing between mixed and pure IMPC remain imprecise. Some mucin producing carcinomas can also have micropapillary histology, but there is no consensus on whether these tumors are variants of IMPC or mucinous carcinomas. The molecular genetic studies demonstrate that IMPCs have distinct molecular genetic profiles, supporting the theory that they constitute distinct pathologic entities. However, genomic analyses have not identified any specific genomic aberration that may explain the distinctive morphology and clinical behavior of IMPC. OBJECTIVE: -To provide an overview on the current concepts in the diagnosis and pathogenesis of IMPC of the breast, incorporating recent molecular genetic advances and prognosis-based reclassification. DATA SOURCES: -PubMed search and the cited references were reviewed. CONCLUSIONS: -The recent evolution of prognosis-based reclassification and molecular genetic advances has enhanced our knowledge of the pathogenesis of IMPC of the breast. Additional studies might reveal consistent molecular alterations that underlie the formation of the inside out growth pattern, and they might elucidate the molecular mechanisms responsible for the unfavorable clinical behavior of IMPC. PMID- 27472239 TI - Immunohistochemical Surrogates for Molecular Classification of Breast Carcinoma: A 2015 Update. AB - CONTEXT: -The pioneering works on molecular classification (MC) by Perou and Sorlie et al in the early 2000s using global gene expression profiling identified 5 intrinsic subtypes of invasive breast cancers (IBCs): luminal A, luminal B, normal breast-like, HER2-enriched, and basal-like subtypes, each unique in incidence, survival, and response to therapy. Because the application of gene expression profiling in daily practice is not economical or practical at the present time, many investigators have studied the use of immunohistochemical (IHC) surrogates as a substitute for determining the MC of IBC. OBJECTIVE: -To discuss the continuing efforts that have been made to develop clinically significant and readily available IHC surrogates for the MC of IBC. DATA SOURCES: -Data were obtained from pertinent peer-reviewed English-language literature. CONCLUSIONS: -The most commonly used IHC surrogates are estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), dividing IBC into luminal, HER2, and triple-negative subtypes. The addition of Ki 67, cytokeratin 5, and epidermal growth factor receptor (EGFR) separates luminal B from luminal A subtypes, and basal-like subtype from triple-negative breast cancer. More recently, biomarkers such as androgen receptor and p53 have been shown to further stratify these molecular subtypes. Although many studies of IHC based MC have shown clinical significance similar to gene expression profiling defined MC, its critical limitations are: (1) a lack of standardization in terminology, (2) a lack of standardization in biomarkers used for each subtype, and (3) the lack of a uniform cutoff for each biomarker. A panel of IHC surrogates for each subtype of IBC is proposed. PMID- 27472237 TI - Sentinel Lymph Nodes for Breast Carcinoma: A Paradigm Shift. AB - CONTEXT: -Sentinel lymph node biopsy has been established as the new standard of care for axillary staging in most patients with invasive breast carcinoma. Historically, all patients with a positive sentinel lymph node biopsy result underwent axillary lymph node dissection. Recent trials show that axillary lymph node dissection can be safely omitted in women with clinically node negative, T1 or T2 invasive breast cancer treated with breast-conserving surgery and whole breast radiotherapy. This change in practice also has implications on the pathologic examination and reporting of sentinel lymph nodes. OBJECTIVE: -To review recent clinical and pathologic studies of sentinel lymph nodes and explore how these findings influence the pathologic evaluation of sentinel lymph nodes. DATA SOURCES: -Sources were published articles from peer-reviewed journals in PubMed (US National Library of Medicine) and published guidelines from the American Joint Committee on Cancer, the Union for International Cancer Control, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network. CONCLUSIONS: -The main goal of sentinel lymph node examination should be to detect all macrometastases (>2 mm). Grossly sectioning sentinel lymph nodes at 2-mm intervals and evaluation of one hematoxylin-eosin-stained section from each block is the preferred method of pathologic evaluation. Axillary lymph node dissection can be safely omitted in clinically node-negative patients with negative sentinel lymph nodes, as well as in a selected group of patients with limited sentinel lymph node involvement. The pathologic features of the primary carcinoma and its sentinel lymph node metastases contribute to estimate the extent of non-sentinel lymph node involvement. This information is important to decide on further axillary treatment. PMID- 27472240 TI - Molecular Testing in Breast Cancer: A Guide to Current Practices. AB - CONTEXT: -Molecular diagnostics play a role in the management of many cancers, including breast cancer. OBJECTIVE: -To provide an update on molecular testing in current clinical practice, targeted at practicing pathologists who are not breast cancer specialists. DATA SOURCES: -This study is a narrative literature review. CONCLUSIONS: -In addition to routine hormone (estrogen and progesterone) receptor testing, new and recurrent tumors are tested for HER2 amplification by in situ hybridization or overexpression by immunohistochemistry. Intrinsic subtyping of tumors represents a fundamental advance in our understanding of breast cancer biology, but currently it has an indirect role in patient management. Clinical next-generation sequencing (tumor profiling) is increasingly used to identify potentially actionable mutations in tumor tissue. Multianalyte assays with algorithmic analysis, including MammaPrint, Oncotype DX, and Prosigna, play a larger role in breast cancer than in many other malignancies. Given that a proportion of breast cancers are familial, testing of nontumor tissue for cancer predisposition mutations also plays a role in breast cancer care. PMID- 27472241 TI - Pleuroparenchymal Fibroelastosis of the Lung: A Review. AB - Described in Japan by Amitani et al in 1992, the entity of idiopathic upper lobe fibrosis was subsequently given the name pleuroparenchymal fibroelastosis (PPFE) in the English-speaking world. Pleuroparenchymal fibroelastosis is believed to be a rare disease characterized by a fibrosing process affecting the pleura and the subpleural lung parenchyma, with a predilection for the upper lobes. Uniquely, the fibrosing process is elastotic in nature, being associated with intra alveolar fibrosis. The etiology of PPFE is unclear at this juncture, with many cases being considered as idiopathic forms of the disease. Conditions associated with PPFE include infections, bone marrow transplantation, and autoimmunity. In this review, we explore the clinical, radiologic, and pathologic features associated with PPFE in light of current understanding of the disease. Recent studies implicated that PPFE may not be as uncommon as claimed. The various differential diagnoses and implications of diagnosing PPFE are discussed. PMID- 27472242 TI - Cytomegalovirus Colitis: An Uncommon Mimicker of Common Colitides. AB - Cytomegalovirus latency, though ubiquitous in the human population, is known to cause colitis in both immunocompromised and immunocompetent hosts. Furthermore, the clinical, endoscopic, and histologic appearance of cytomegalovirus colitis can mimic that of inflammatory bowel disease, an extremely well-documented disease. In this context, though many reports have looked at inflammatory bowel disease with superimposed cytomegalovirus infection, less attention has been paid to cytomegalovirus as a primary cause of isolated colitis. Owing to the rarity of this phenomenon, it is important to consider this diagnosis and implement proper testing to avoid misdiagnosis and mismanagement. PMID- 27472243 TI - Corrigendum. PMID- 27472244 TI - Depression and physical functioning among older Americans with diabesity: NHANES 2009-2010. AB - BACKGROUND: Caring for older adults with diabesity can be challenging for primary care nurse practitioners. The purpose of this study was to examine whether there would be an additive effect of diabesity on depressive symptoms and physical functioning of older adults. We hypothesized that there is an additive effect of diabesity on depressive symptoms and physical functioning among older adults with one or neither condition. METHODS: We performed a cross-sectional analysis of data from National Health and Nutrition Examination Surveys collected from African-American and Caucasian adults aged 65 and over between 2009 and 2010. Multivariate linear regression models were utilized. The sample consisted of 918 participants. In covariate-adjusted models, participants with diabesity reported more depressive symptoms than people with neither condition. Individuals with diabesity and those with obesity alone reported significantly more difficulty with physical function when compared to participants with neither condition. CONCLUSION: Findings suggest that diabesity was more burdensome to older adults than either condition alone. More research is needed to understand the interplay between depression, physical function, and diabesity. IMPLICATIONS FOR PRACTICE: To disrupt the adverse effects of diabesity burden, increased nurse practitioner awareness of this phenomenon may be beneficial in improving and maintaining physical and mental health among older adults. PMID- 27472245 TI - Stereotype-based faultlines and out-group derogation in diverse teams: The moderating roles of task stereotypicality and need for cognition. AB - Alignment of individuals on more than one diversity attribute (i.e., faultlines) may lead to intergroup biases in teams, disrupting the efficiency expectancies. Research has yet to examine if this can be a consequence of a stereotypical consistency between social and information attributes of diversity. The present study tests the hypothesis that, in a team with a stereotype-based faultline (a stereotypical consistency between gender and skills), there is increased out group derogation compared to a team with a stereotype-inconsistent faultline. Furthermore, the study proposes that tasks can activate stereotypes, and the need for cognition dictates whether stereotypes are applied. The findings confirm the hypothesis and additionally provide evidence that tasks that activate gender stereotypes emphasize out-group derogation, especially for team members with low need for cognition. PMID- 27472109 TI - Search for Narrow Resonances in Dijet Final States at sqrt[s]=8 TeV with the Novel CMS Technique of Data Scouting. AB - A search for narrow resonances decaying into dijet final states is performed on data from proton-proton collisions at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 18.8 fb^{-1}. The data were collected with the CMS detector using a novel technique called data scouting, in which the information associated with these selected events is much reduced, permitting collection of larger data samples. This technique enables CMS to record events containing jets at a rate of 1 kHz, by collecting the data from the high-level-trigger system. In this way, the sensitivity to low-mass resonances is increased significantly, allowing previously inaccessible couplings of new resonances to quarks and gluons to be probed. The resulting dijet mass distribution yields no evidence of narrow resonances. Upper limits are presented on the resonance cross sections as a function of mass, and compared with a variety of models predicting narrow resonances. The limits are translated into upper limits on the coupling of a leptophobic resonance Z_{B}^{'} to quarks, improving on the results obtained by previous experiments for the mass range from 500 to 800 GeV. PMID- 27472246 TI - Physical Properties and Stabilization of Microcapsules Containing Thyme Oil by Complex Coacervation. AB - The aim of this study was to produce and characterize microcapsules of thyme oil and finally appraise the extent of stability improvement. The optimum process conditions obtained from orthogonal tests were as follows: ratio of core material to wall 0.5, temperature 40 degrees C, pH value 3.0 and time 20 min, where the practical encapsulation efficiency was 85.17+/-1.35%. The microcapsules belong to the nanometric range as the average particle diameter was 531.17+/-77.12 nm. The results from structural analysis indicated that no significant chemical bond occurred during the encapsulation process and the microcapsules remained stable when the encapsulation was conducted at a temperature below 53.1 degrees C. Especially, the retention rate of thyme oil in microcapsules remained 39.21% at 4 degrees C, 36.99% at 25 degrees C and 33.80% at 40 degrees C after 30 d of storage. Moreover, protection from light exposure presented a positive impact on the storage stability of thyme oil microcapsules. PMID- 27472249 TI - Involvement of Sub-Bandgap States in Subpicosecond Exciton and Biexciton Dynamics of Ternary AgInS2 Nanocrystals. AB - We have synthesized three AgxInS2 (AIS) ternary nanocrystals (NCs), where x varies from 0.25 to 1, and reported their biexcitonic feature which depends on the stoichiometry ratio of Ag/In. The broadening of absorption band and dual photoluminescence in different AIS NCs indicates the existence of Ag-related sub bandgap (S-states) and antisite states. Ultrafast charge carrier dynamics in AIS NCs that involve multiple states like higher excited state, band-edge, Ag-related sub-bandgap, and antisite states have been carried out by employing femtosecond transient absorption spectroscopy, which strongly depends on Ag/In ratio. The probe-induced biexcitonic feature that originated from antisite state has been observed in these AIS NCs even at low pump fluency ( = ~0.2). The enhancement of binding energy of biexciton and slow down of electron cooling dynamics has been demonstrated by gradual increment of pump fluence as well as with different stoichiometry of Ag and In. PMID- 27472250 TI - Interfacial Microstructure and Enhanced Mechanical Properties of Carbon Fiber Composites Caused by Growing Generation 1-4 Dendritic Poly(amidoamine) on a Fiber Surface. AB - In an attempt to improve the mechanical properties of carbon fiber composites, propagation of poly(amidoamine) (PAMAM) dendrimers by in situ polymerization on a carbon fiber surface was performed. During polymerization processes, PAMAM was grafted on carbon fiber by repeated Michael addition and amidation reactions. The changes in surface microstructure and the chemical composition of carbon fibers before and after modification were investigated by atomic force microscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy. All the results indicated that PAMAM was successfully grown on the carbon fiber surface. Such propagation could significantly increase the surface roughness and introduce sufficient polar groups onto the carbon fiber surface, enhancing the surface wettability of carbon fiber. The fractured surface of carbon fiber-reinforced composites showed a great enhancement of interfacial adhesion. Compared with those of desized fiber composites, the interlaminar shear strength and interfacial shear strength of PAMAM/fiber-reinforced composites showed increases of 55.49 and 110.94%, respectively. PMID- 27472248 TI - Functionalized phosphonates as building units for multi-dimensional homo- and heterometallic 3d-4f inorganic-organic hybrid-materials. AB - Using the multifunctional ligand H4L (2,2'-bipyridinyl-5,5'-diphosphonic acid), a new family of inorganic-organic hybrid-materials was prepared. The ligand shows a very high flexibility regarding the coordination mode, leading to a large structural diversity. The compounds 1a, 1b ([M(H2L)(H2O)4].2.5H2O; M = Co(2+) (a), Ni(2+) (b)), 2 ([Gd2(H2H'L)2(H2H'2L)(H2O)6]Cl4.14H2O), 3a, 3b, 3c ([MCo(iii)(H2L)3(H2O)2].6.5H2O; M = Gd(3+) (a), Dy(3+) (b) and Tb(3+) (c)), and 4 ([GdNi(ii)(H2L)3(H2O)3]NaCl.6H2O) were isolated and characterized with single crystal X-ray diffraction. Depending on the used metal ions and on the stoichiometry, either discrete entities (0D), extended 2D layers or 3D frameworks were obtained. In contrast to the general approach in phosphonate chemistry, the compounds were prepared without hydrothermal synthesis, but under ambient pressure. Variable temperature magnetic measurements were carried out to determine the magnetic properties. PMID- 27472247 TI - What are the Newer Applications for Therapeutic Apheresis in Nephrology?: Current Indications for Therapeutic Plasma Exchange in Nephrology. PMID- 27472251 TI - Clinical Impact of Accurate Point-of-Care Glucose Monitoring for Tight Glycemic Control in Severely Burned Children. AB - OBJECTIVES: The goal of this study was to retrospectively evaluate the clinical impact of an accurate autocorrecting blood glucose monitoring system in children with severe burns. Blood glucose monitoring system accuracy is essential for providing appropriate intensive insulin therapy and achieving tight glycemic control in critically ill patients. Unfortunately, few comparison studies have been performed to evaluate the clinical impact of accurate blood glucose monitoring system monitoring in the high-risk pediatric burn population. DESIGN: Retrospective analysis of an electronic health record system. SETTING: Pediatric burn ICU at an academic medical center. PATIENTS: Children (aged < 18 yr) with severe burns (>= 20% total body surface area) receiving intensive insulin therapy guided by either a noncorrecting (blood glucose monitoring system-1) or an autocorrecting blood glucose monitoring system (blood glucose monitoring system 2). MEASUREMENTS AND MAIN RESULTS: Patient demographics, insulin rates, and blood glucose monitoring system measurements were collected. The frequency of hypoglycemia and glycemic variability was compared between the two blood glucose monitoring system groups. A total of 122 patient charts from 2001 to 2014 were reviewed. Sixty-three patients received intensive insulin therapy using blood glucose monitoring system-1 and 59 via blood glucose monitoring system-2. Patient demographics were similar between the two groups. Mean insulin infusion rates (5.1 +/- 3.8 U/hr; n = 535 paired measurements vs 2.4 +/- 1.3 U/hr; n = 511 paired measurements; p < 0.001), glycemic variability, and frequency of hypoglycemic events (90 vs 12; p < 0.001) were significantly higher in blood glucose monitoring system-1-treated patients. Compared with laboratory measurements, blood glucose monitoring system-2 yielded the most accurate results (mean +/- SD bias: -1.7 +/- 6.9 mg/dL [-0.09 +/- 0.4 mmol/L] vs 7.4 +/- 13.5 mg/dL [0.4 +/- 0.7 mmol/L]). Blood glucose monitoring system-2 patients achieve glycemic control more quickly (5.7 +/- 4.3 vs 13.1 +/- 6.9 hr; p< 0.001) and stayed within the target glycemic control range longer compared with blood glucose monitoring system-1 patients (85.2% +/- 13.9% vs 57.9% +/- 29.1%; p < 0.001). CONCLUSIONS: Accurate autocorrecting blood glucose monitoring system optimizes intensive insulin therapy, improves tight glycemic control, and reduces the risk of hypoglycemia and glycemic variability. The use of an autocorrecting blood glucose monitoring system for intensive insulin therapy may improve glycemic control in severely burned children. PMID- 27472252 TI - A Randomized Controlled Comparison of the Internal Jugular Vein and the Subclavian Vein as Access Sites for Central Venous Catheterization in Pediatric Cardiac Surgery. AB - OBJECTIVES: To compare internal jugular vein and subclavian vein access for central venous catheterization in terms of success rate and complications. DESIGN: A 1:1 randomized controlled trial. SETTING: Baskent University Medical Center. PATIENTS: Pediatric patients scheduled for cardiac surgery. INTERVENTIONS: Two hundred and eighty children undergoing central venous catheterization were randomly allocated to the internal jugular vein or subclavian vein group during a period of 18 months. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the first-attempt success rate of central venous catheterization through either approach. The secondary outcomes were the rates of infectious and mechanical complications. The central venous catheterization success rate at the first attempt was not significantly different between the subclavian vein (69%) and internal jugular vein (64%) groups (p = 0.448). However, the overall success rate was significantly higher through the subclavian vein (91%) than the internal jugular vein (82%) (p = 0.037). The overall frequency of mechanical complications was not significantly different between the internal jugular vein (25%) and subclavian vein (31%) (p = 0.456). However, the rate of arterial puncture was significantly higher with internal jugular vein (8% vs 2%; p = 0.03) and that of catheter malposition was significantly higher with subclavian vein (17% vs 1%; p < 0.001). The rates per 1,000 catheter days for both positive catheter-tip cultures (26.1% vs 3.6%; p < 0.001) and central-line bloodstream infection (6.9 vs 0; p < 0.001) were significantly higher with internal jugular vein. There were no significant differences between the groups in the length of ICU and hospital stays or in-hospital mortality rates (p > 0.05 for all). CONCLUSIONS: Central venous catheterization through the internal jugular vein and subclavian vein was not significantly different in terms of success at the first attempt. Although the types of mechanical complications were different, the overall rate was similar between internal jugular vein and subclavian vein access. The risk of infectious complications was significantly higher with internal jugular vein access. PMID- 27472253 TI - Ketosis After Cardiopulmonary Bypass in Children Is Associated With an Inadequate Balance Between Oxygen Transport and Consumption. AB - OBJECTIVES: Hyperglycemia after cardiac surgery and cardiopulmonary bypass in children has been associated with worse outcome; however, causality has never been proven. Furthermore, the benefit of tight glycemic control is inconsistent. The purpose of this study was to describe the metabolic constellation of children before, during, and after cardiopulmonary bypass, in order to identify a subset of patients that might benefit from insulin treatment. DESIGN: Prospective observational study, in which insulin treatment was initiated when postoperative blood glucose levels were more than 12 mmol/L (216 mg/dL). SETTING: Tertiary PICU. PATIENTS: Ninety-six patients 6 months to 16 years old undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Metabolic tests were performed before anesthesia, at the end of cardiopulmonary bypass, at PICU admission, and 4 and 12 hours after PICU admission, as well as 4 hours after initiation of insulin treatment. Ketosis was present in 17.9% patients at the end of cardiopulmonary bypass and in 31.2% at PICU admission. Young age was an independent risk factor for this condition. Ketosis at PICU admission was an independent risk factor for an increased difference between arterial and venous oxygen saturation. Four hours after admission (p = 0.05). Insulin corrected ketosis within 4 hours. CONCLUSIONS: In this study, we found a high prevalence of ketosis at PICU admission, especially in young children. This was independently associated with an imbalance between oxygen transport and consumption and was corrected by insulin. These results set the basis for future randomized controlled trials, to test whether this subgroup of patients might benefit from increased glucose intake and insulin during surgery to avoid ketosis, as improving oxygen transport and consumption might improve patient outcome. PMID- 27472254 TI - Platelet Transfusions in Pediatric Intensive Care. AB - OBJECTIVES: To characterize the determinants of platelet transfusion in a PICU and determine whether there exists an association between platelet transfusion and adverse outcomes. DESIGN: Prospective observational single center study, combined with a self-administered survey. SETTING: PICU of Sainte-Justine Hospital, a university-affiliated tertiary care institution. PATIENTS: All children admitted to the PICU from April 2009 to April 2010. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Among 842 consecutive PICU admissions, 60 patients (7.1%) received at least one platelet transfusion while in PICU. In the univariate analysis, significant determinants for platelet transfusion were admission Pediatric Risk of Mortality Score greater than 10 (odds ratio, 6.80; 95% CI, 2.5-18.3; p < 0.01) and Pediatric Logistic Organ Dysfunction scores greater than 20 (odds ratio, 26.9; 95% CI, 8.88-81.5; p < 0.01), history of malignancy (odds ratio, 5.08; 95% CI, 2.43-10.68; p < 0.01), thrombocytopenia (platelet count, < 50 * 10/L or < 50,000/mm) (odds ratio, 141; 95% CI, 50.4 394.5; p < 0.01), use of heparin (odds ratio, 3.03; 95% CI, 1.40-6.37; p < 0.01), shock (odds ratio, 5.73; 95% CI, 2.85-11.5; p < 0.01), and multiple organ dysfunction syndrome (odds ratio, 10.41; 95% CI, 5.89-10.40; p < 0.01). In the multivariate analysis, platelet count less than 50 * 10/L (odds ratio, 138; 95% CI, 42.6-449; p < 0.01) and age less than 12 months (odds ratio, 3.06; 95% CI, 1.03-9.10; p = 0.02) remained statistically significant determinants. The attending physicians were asked why they gave a platelet transfusion; the most frequent justification was prophylactic platelet transfusion in presence of thrombocytopenia with an average pretransfusion platelet count of 32 +/- 27 * 10/L (median, 21), followed by active bleeding with an average pretransfusion platelet count of 76 +/- 39 * 10/L (median, 72). Platelet transfusions were associated with the subsequent development of multiple organ dysfunction syndrome (odds ratio, 2.53; 95% CI, 1.18-5.43; p = 0.03) and mortality (odds ratio, 10.1; 95% CI, 4.48-22.7; p < 0.01). CONCLUSIONS: Among children, 7.1% received at least one platelet transfusion while in PICU. Thrombocytopenia and active bleeding were significant determinants of platelet transfusion. Platelet transfusions were associated with the development of multiple organ dysfunction syndrome and increased mortality. PMID- 27472255 TI - Risk Factors of Acute Kidney Injury in Critically Ill Children. AB - OBJECTIVES: Acute kidney injury may be promoted by critical illness, preexisting medical conditions, and treatments received both before and during ICU admission. We aimed to estimate the frequency of acute kidney injury during ICU treatment and to determine factors, occurring both before and during the ICU stay, associated with the development of acute kidney injury. DESIGN: Cohort study of critically ill children. SETTING: University-affiliated PICU. PATIENTS: Eligible patients were admitted to the ICU between January 2006 and June 2009. We excluded those admitted with known primary renal failure, chronic renal failure or postrenal transplant, conditions with known renal complications, or metabolic conditions treated with dialysis. Patients were also excluded if they had a short ICU stay (< 6 hr) and those who had no creatinine or urine output measurements during their ICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 3,865 pediatric patients who met the inclusion criteria, 915 (23.7%) developed acute kidney injury, as classified by the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria, during their ICU stay. Patients at high risk for development of acute kidney injury included those urgently admitted to the ICU (adjusted odds ratio, 1.88), those who developed respiratory dysfunction during their ICU care (adjusted odds ratio, 2.90), and those who treated with extracorporeal membrane oxygenation (adjusted odds ratio, 2.72). The single greatest risk factor for acute kidney injury was the administration of nephrotoxic medications during ICU admission (adjusted odds ratio, 3.37). CONCLUSIONS: This study, the largest evaluating the incidence of RIFLE-defined acute kidney injury in critically ill children, found that one-quarter of patients admitted to the ICU developed acute kidney injury. We identified a number of potentially modifiable risk factors, the largest of which was the administration of nephrotoxic medication. The results of this study may be used to inform targeted interventions to reduce acute kidney injury and improve the outcomes of critically ill children. PMID- 27472256 TI - Oligomerized backbone pilin helps piliated Lactococcus lactis to withstand shear flow. AB - The present work focuses on the role of pili present at the cell surface of Lactococcus lactis in bacterial adhesion to abiotic (hydrophobic polystyrene) and biotic (mucin-coated polystyrene) surfaces. Native pili-displaying strains and isogenic derivatives in which pilins or sortase C structural genes had been modified were used. Surface physico-chemistry, morphology and shear-flow-induced detachment of lactococcal cells were evaluated. The involvement of pili in L. lactis adhesion was clearly demonstrated, irrespective of the surface characteristics (hydrophobic/hydrophilic, presence or not of specific binding sites). The accessory pilin, PilC, and the backbone pilin, PilB, were revealed to play a major role in adhesion, provided that the PilB was present in its polymerized form. Within the population fraction that remained attached to the surface under increasing shear flow, different association behaviors were observed, showing that pili could serve as anchoring sites thus hampering the effect of shear flow on cell orientation and detachment. PMID- 27472257 TI - Insulin storage in hot climates without refrigeration: temperature reduction efficacy of clay pots and other techniques. AB - AIM: Insulin loses potency when stored at high temperatures. Various clay pots part-filled with water, and other evaporative cooling devices, are used in less resourced countries when home refrigeration is unavailable. This study examined the cooling efficacy of such devices. METHODS: Thirteen devices used in Sudan, Ethiopia, Tanzania, Mali, India, Pakistan and Haiti (10 clay pots, a goat skin, a vegetable gourd and a bucket filled with wet sand), and two identical commercially manufactured cooling wallets were compared. Devices were maintained according to local instructions. Internal and ambient temperature and ambient humidity were measured by electronic loggers every 5 min in Khartoum (88 h), and, for the two Malian pots, in Bamako (84 h). Cooling efficacy was assessed by average absolute temperature difference (internal vs. ambient), and % maximal possible evaporative cooling (allowing for humidity). RESULTS: During the study period, mean ambient temperature and humidity were 31.0 degrees C and 32.0% in Khartoum and 32.9 degrees C and 39.8% in Bamako. All devices reduced the temperature (P < 0.001) with a mean (sd) reduction from 2.7 +/- 0.5 degrees C to 8.3 +/- 1.0 degrees C, depending on the device. When expressed as % maximal cooling, device efficacy ranged from 20.5% to 71.3%. On cluster analysis, the most efficacious devices were the goat skin, two clay pots (from Ethiopia and Sudan) and the suspended cooling wallet. CONCLUSIONS: Low-cost devices used in less-resourced countries reduce storage temperatures. With more efficacious devices, average temperatures at or close to standard room temperature (20-25 degrees C) can be achieved, even in hot climates. All devices are more efficacious at lower humidity. Further studies are needed on insulin stability to determine when these devices are necessary. PMID- 27472258 TI - Atrial fibrillation and chronic kidney disease requiring hemodialysis - Does warfarin therapy improve the risks of this lethal combination? AB - INTRODUCTION: Warfarin therapy for stroke prevention is recommended for patients with AF, but its value in patients with chronic kidney disease on HD is unknown. METHODS: The anticoagulation regimens of patients with a prior history of AF hospitalized for initiation of chronic HD, and of patients receiving chronic HD who had a new diagnosis of AF between 2009 and 2012 were reviewed. Exclusions were renal transplant, peritoneal dialysis, rheumatic valve disease, prosthetic heart valve, GI bleeding, malignancy with chemotherapy in last 6months or still undergoing treatment, a history of AF ablation, a history of ICD implantation, or those receiving warfarin for non-AF indications. RESULTS: Among 302 patients included in the study, 119 (39%) were prescribed warfarin and 183 (61%) were not. The two groups were similar regarding demographics, and prevalence of comorbidities including diabetes, heart failure, coronary artery disease, hypertension, use of antiplatelet agents and prior stroke. Warfarin use did not lower risk for ischemic stroke (HR 0.93; 95% CI 0.49-1.82, P=0.88) or improve overall survival (HR 1.02; 95% CI 0.91-1.15, P=0.62), but trended toward higher risk of bleeding complications (HR 1.53; 95% CI 0.94-2.51, P=0.086) after adjusting for potential confounders. CONCLUSION: Warfarin use was not associated with reduction in stroke risk or mortality in patients with AF on chronic HD, but trended toward greater bleeding risk. The benefit of warfarin therapy in these patients may be outweighed by its risks. PMID- 27472259 TI - Role of vincristine in the inhibition of angiogenesis in glioblastoma. AB - OBJECTIVE: Vincristine, a microtubule-destabilizing drug, was found to exhibit anti-angiogenic effects and anti-tumoral activity. However, the precise mechanism by which vincristine inhibits angiogenesis in glioblastomas is not well understood. Our aim was to investigate whether vincristine affects vascular endothelial growth factor (VEGF) expression in glioblastoma cells and determine whether it is mediated by the downregulation of hypoxia-inducible factor-1alpha (HIF-1alpha). METHODS: We investigated the expression of HIF-1alpha in glioblastoma tissues resected from patients and in human glioblastoma cell lines using immunohistochemistry, Western blot analysis, and immunocytochemistry. In addition to an MTT assay assessing the effect of vincristine on cell proliferation and viability, the effects of vincristine on VEGF mRNA expression and HIF-1alpha protein were examined using real-time RT-PCR and Western blot analysis under 1% O2 (hypoxia). RESULTS: HIF-1alpha was expressed in the majority of glioblastoma tissues and was detected mainly in the nucleus. Strong immunoreactivity for HIF- 1 alpha was found often in the hypercellular zones. Under hypoxic conditions, HIF-1alpha protein levels in the glioblastoma cell lines increased, primarily localizing into the nucleus similar to glioblastoma tissues. Exposure of glioblastoma cells to vincristine resulted in enrichment of the G2-M fraction of the cell cycle, which suggests that vincristine-mediated growth inhibition of glioblastoma is correlated with mitotic inhibition. Using doses lower than those found to reduce the viability and proliferation of cells by 50% (IC50), vincristine decreased both the expression of VEGF mRNA and the level of HIF-1alpha protein in hypoxic glioblastoma cells. In addition, following exposure to vincristine, the expression of VEGF mRNA was correlated with HIF 1alpha protein levels. CONCLUSIONS: Our results suggest that the mechanism by which vincristine elicits an anti-angiogenic effect in glioblastomas under hypoxic conditions might be mediated, in part, by HIF-1alpha inhibition. PMID- 27472260 TI - From Model Hamiltonians to ab Initio Hamiltonians and Back Again: Using Single Excitation Quantum Chemistry Methods To Find Multiexciton States in Singlet Fission Materials. AB - Due to the promise of significantly enhanced photovoltaic efficiencies, significant effort has been directed toward understanding and controlling the singlet fission mechanism. Although accurate quantum chemical calculations would provide a detail-rich view of the singlet fission mechanism, this is complicated by the multiexcitonic nature of one of the key intermediates, the (1)(TT) state. Being described as two simultaneous and singlet-coupled triplet excitations on a pair of nearest neighbor monomers, the (1)(TT) state is inherently a multielectronic excitation. This fact renders most single-reference ab initio quantum chemical methods incapable of providing accurate results. This paper serves two purposes: (1) to demonstrate that the multiexciton states in singlet fission materials can be described using a spin-only Hamiltonian and with each monomer treated as a biradical and (2) to propose a very simple procedure for extracting the values for this Hamiltonian from single-reference calculations. Numerical examples are included for a number of different systems, including dimers, trimers, tetramers, and a cluster comprised of seven chromophores. PMID- 27472261 TI - Protective effects of carnosine on dehydroascorbate-induced structural alteration and opacity of lens crystallins: important implications of carnosine pleiotropic functions to combat cataractogenesis. AB - The high level of dehydroascorbic acid (DHA) in the lenticular tissue is an important risk factor for the development of age-related cataracts. In this study, the effects of DHA on structure and function of lens crystallins were studied in the presence of carnosine using gel mobility shift assay, different spectroscopic techniques, and lens culture analysis. The DHA-induced unfolding and aggregation of lens proteins were largely prevented by this endogenous dipeptide. The ability of carnosine to preserve native protein structure upon exposure to DHA suggests the essential role of this dipeptide in prevention of the senile cataract development. Although the DHA-modified alpha-crystallin was characterized by altered chaperone activity, functionality of this protein was significantly restored in the presence of carnosine. The increased proteolytic instability of DHA-modified lens proteins was also attenuated in the presence of carnosine. Furthermore, the assessment of lens culture suggested that DHA can induce significant lens opacity which can be prevented by carnosine. These observations can be explained by the pleiotropic functions of this endogenous and pharmaceutical compound, notably by its anti-glycation and anti-aggregation properties. In summary, our study suggests that carnosine may have therapeutic potential in preventing senile cataracts linked with the increased lenticular DHA generation, particularly under pathological conditions associated with the oxidative stress. PMID- 27472262 TI - Anharmonic Calculation of the Structure, Vibrational Frequencies, and Intensities of the NH3...cis-HONO and NH3...cis-DONO Complexes. AB - The geometrical parameters, the frequencies, and absolute intensities for transitions between vibrational states of NH3...cis-HONO and NH3...cis-DONO hydrogen-bonded complexes are calculated using the approach earlier tested in calculations of isolated molecules of nitrous acid and the NH3...trans-HONO and NH3..trans-DONO complexes. Vibrational wave functions and energy values of the complexes are derived from variational solutions of anharmonic equations in one to four dimensions. The equilibrium nuclear configuration and potential energy surfaces are calculated by the MP2/aug-cc-pVTZ method with the basis set superposition error taken into account. Comparison of the obtained results with the analogous data calculated in the same approximation for isolated cis- and trans-HONO (DONO) molecules and the NH3...trans-HONO (DONO) complexes provides information about the changes in the spectroscopic and geometrical parameters of nitrous acid upon cis-trans transition, H/D substitution, and H-bond formation. PMID- 27472263 TI - Photoluminescence study of time- and spatial-dependent light induced trap de activation in CH3NH3PbI3 perovskite films. AB - Organometal halide perovskite-based solar cells have rapidly achieved high efficiency in recent years. However, many fundamental recombination mechanisms underlying the excellent performance are still not well understood. Here we apply confocal photoluminescence microscopy to investigate the time and spatial characteristics of light-induced trap de-activation in CH3NH3PbI3 perovskite films. Trap de-activation is characterized by a dramatic increase in PL emission during continuous laser illumination accompanied by a lateral expansion of the PL enhancement far beyond the laser spot. These observations are attributed to an oxygen-assisted trap de-activation process associated with carrier diffusion. To model this effect, we add a trap de-activation term to the standard semiconductor carrier recombination and diffusion models. With this approach we are able to reproduce the observed temporal and spatial dependence of laser induced PL enhancement using realistic physical parameters. Furthermore, we experimentally investigate the role of trap diffusion in this process, and demonstrate that the trap de-activation is not permanent, with the traps appearing again once the illumination is turned off. This study provides new insights into recombination and trap dynamics in perovskite films that could offer a better understanding of perovskite solar cell performance. PMID- 27472265 TI - Toward in Situ Measurement of the Density of Liquid Benzene Using Optical Kerr Effect Spectroscopy. AB - The high-frequency portion of the optical Kerr effect (OKE) spectrum of benzene shifts to higher frequency with decreasing temperature at constant pressure. This behavior has been interpreted previously in terms of an increase in librational frequencies due to the decrease in free volume with liquid densification. However, decreasing temperature also provides less access to the more repulsive portion of the intermolecular potential, which would cause the blue edge of the spectrum to red-shift. To explore the relative importance of these phenomena, molecular dynamics simulations of benzene are used to isolate the effects of temperature and density on the spectrum. The simulations show that, at constant density, the high-frequency portion of the spectrum shifts to lower frequency with decreasing temperature. In contrast, at constant temperature, the high frequency portion of the spectrum shifts to higher frequency with increasing density. These results indicate that density plays a greater role in determining the position of the blue edge of the low-frequency Raman spectrum of benzene than does temperature. Empirical fits show that the effects of changing density or temperature are similar in experimental and simulated OKE spectra. Furthermore, line-shape analysis of simulated spectra under isochoric and isothermal conditions shows that the effects of density and temperature are separable, suggesting that OKE spectroscopy is a viable technique for in situ measurement of the density of van der Waals liquids. PMID- 27472264 TI - Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis. AB - Schwannomatosis is a genetic disorder characterized by the occurrence of multiple peripheral schwannomas. Segmental schwannomatosis is diagnosed when schwannomas are restricted to 1 extremity and is thought to be caused by genetic mosaicism. We studied 5 patients with segmental schwannomatosis through microstructural magnetic resonance neurography and mutation analysis of NF2, SMARCB1, and LZTR1. In 4 of 5 patients, subtle fascicular nerve lesions were detected in clinically unaffected extremities. Two patients exhibited LZTR1 germline mutations. This appears contrary to a simple concept of genetic mosaicism and suggests more complex and heterogeneous mechanisms underlying the phenotype of segmental schwannomatosis than previously thought. Ann Neurol 2016;80:625-628. PMID- 27472266 TI - The Case for Smaller Diameter Implants. PMID- 27472267 TI - Ambient-Temperature Spin-State Switching Achieved by Protonation of the Amino Group in [Fe(H2Bpz2)2(bipy-NH2)]. AB - Magnetism of a complex [Fe(H2Bpz2)2(bipy-NH2)] (H2Bpz2 = dihydrobis(1 pyrazolyl)borate, bipy-NH2 = 4,4'-diamino-2,2'-bipyridine) has been altered from paramagnetic to spin-crossover (SCO) behavior, through protonation of one amino group of bipy-NH2 with CF3SO3H. Complete SCO transition, both in solid state and in solution, occurs at ambient temperature. PMID- 27472268 TI - Spatial Control of Gene Expression by Nanocarriers Using Heparin Masking and Ultrasound-Targeted Microbubble Destruction. AB - We developed a method to spatially control gene expression following nonviral delivery of DNA. This method includes surface-modifying DNA nanocarriers with heparin to inhibit passive gene transfer in both the target and the off-target tissues and using ultrasound-targeted microbubble destruction (UTMD) to selectively activate heparin-inhibited gene transfer at the target site. We observed that the engraftment of heparin onto the surface of cationic liposomes reduced off-target gene expression in the liver, a major site of nanoplex accumulation, by more than 700-fold compared to the nonheparinized PEGylated liposomes. We further observed that tumor-directed UTMD increased gene transfer with heparin-modified nanoplexes by more than 10-fold. This method augmented tumor-to-liver selectivity of gene expression by 4000-fold compared to controls. We conclude that heparinization of DNA nanocarriers in conjunction with localized activation of gene transfer by UTMD may enable greater spatial control over genetic therapy. PMID- 27472269 TI - Modeled ecohydrological responses to climate change at seven small watersheds in the northeastern United States. AB - A cross-site analysis was conducted on seven diverse, forested watersheds in the northeastern United States to evaluate hydrological responses (evapotranspiration, soil moisture, seasonal and annual streamflow, and water stress) to projections of future climate. We used output from four atmosphere ocean general circulation models (AOGCMs; CCSM4, HadGEM2-CC, MIROC5, and MRI CGCM3) included in Phase 5 of the Coupled Model Intercomparison Project, coupled with two Representative Concentration Pathways (RCP 8.5 and 4.5). The coarse resolution AOGCMs outputs were statistically downscaled using an asynchronous regional regression model to provide finer resolution future climate projections as inputs to the deterministic dynamic ecosystem model PnET-BGC. Simulation results indicated that projected warmer temperatures and longer growing seasons in the northeastern United States are anticipated to increase evapotranspiration across all sites, although invoking CO2 effects on vegetation (growth enhancement and increases in water use efficiency (WUE)) diminish this response. The model showed enhanced evapotranspiration resulted in drier growing season conditions across all sites and all scenarios in the future. Spruce-fir conifer forests have a lower optimum temperature for photosynthesis, making them more susceptible to temperature stress than more tolerant hardwood species, potentially giving hardwoods a competitive advantage in the future. However, some hardwood forests are projected to experience seasonal water stress, despite anticipated increases in precipitation, due to the higher temperatures, earlier loss of snow packs, longer growing seasons, and associated water deficits. Considering future CO2 effects on WUE in the model alleviated water stress across all sites. Modeled streamflow responses were highly variable, with some sites showing significant increases in annual water yield, while others showed decreases. This variability in streamflow responses poses a challenge to water resource management in the northeastern United States. Our analyses suggest that dominant vegetation type and soil type are important attributes in determining future hydrological responses to climate change. PMID- 27472270 TI - The Inflammatory Bowel Disease-Disability Index: validation of the Portuguese version according to the COSMIN checklist. AB - BACKGROUND AND AIM: Recently, the Inflammatory Bowel Disease-Disability Index (IBD-DI) was developed to assess disability in inflammatory bowel disease (IBD). Our aim was to validate the Portuguese version of IBD-DI according to the COnsensus-based Standards for the selection of the health Measurement INstruments (COSMIN) recommendations. MATERIALS AND METHODS: After translation into Portuguese, the IBD-DI was administered by two interviewers to IBD patients at baseline and after 4 weeks and 4 months. We evaluated reliability (internal consistency, test-retest, and inter-rater reliability and measurement error), construct validity, responsiveness, and interpretability. RESULTS: At baseline, 129 patients (73=Crohn's disease; 56=ulcerative colitis) completed the IBD-DI. After 4 weeks and 4 months, 118 and 89 patients repeated the questionnaire, respectively. Factor analysis confirmed the unidimensionality of the scale and reduced the final version to 14 items. The Cronbach's alpha was 0.88. The intraclass correlation coefficients were 0.87 and 0.99 for test-retest (baseline and 4 weeks) and inter-rater reliability, respectively. The smallest detectable change was 18.64 at the individual level and 1.87 at the group level. IBD-DI scores correlated negatively with the total, physical, and mental scores of Short Form-36 items. The change score of IBD-DI between baseline and 4 months correlated negatively with the clinical evolution of patients. The minimal important change was 16.96. IBD-DI scores ranged from 0 to 78.6, with a mean of 21.8+/-18.1. Female sex, professional inactivity, and clinical disease activity were associated with higher IBD-DI scores. CONCLUSION: The Portuguese version of IBD-DI obtained is a reliable, valid, responsive, and interpretable (at the group level) tool to assess disability in Portuguese IBD patients. PMID- 27472272 TI - Symptoms and biomarkers associated with celiac disease: evaluation of a population-based screening program in adults. AB - OBJECTIVES: To identify possible early predictors (symptoms and biomarkers) of celiac disease, compare symptoms before and after screening, and evaluate the diagnostic efficacy of serologic screening for celiac disease in an adult Danish population. METHODS: This cross-sectional population-based study was based on the 5-year follow-up of the Health2006 cohort, where 2297 individuals were screened for celiac disease; 56 were antibody positive and thus invited to clinical evaluation. Eight were diagnosed with biopsy-verified celiac disease. A follow-up questionnaire was sent to antibody-positive individuals 19 months after the clinical evaluation to obtain information on their symptoms and their experience with participation in the screening. RESULTS: Before screening, participants subsequently diagnosed with celiac disease did not differ from the rest of the population with respect to symptoms, but had significantly lower total cholesterol. Tissue transglutaminase IgA antibodies with a cut-off of 10 U/ml had a positive predictive value of 88%. The majority of participants were satisfied with their participation in the screening program. Individuals with celiac disease were generally satisfied with having been diagnosed and 71% felt better on a gluten-free diet. CONCLUSION: There were no differences in the prevalence of symptoms between participants with and without screening-detected celiac disease, confirming that risk stratification in a general population by symptoms is difficult. The majority of participants diagnosed with celiac disease felt better on a gluten-free diet despite not reporting abdominal symptoms before diagnosis and participants in the clinical evaluation were generally satisfied with participation in the screening program. PMID- 27472271 TI - Use of complementary and alternative medicine in Swedish patients with inflammatory bowel disease: a controlled study. AB - BACKGROUND: There is an increasing interest in complementary and alternative medicine (CAM) in patients with chronic diseases, including those with inflammatory bowel disease (IBD). Patients may turn to CAM when conventional therapies are inadequate or associated with side effects for symptomatic relief or to regain control over their disease. The objectives were to explore CAM use and perceived effects in IBD patients in comparison with a control group. METHODS: A cross-sectional, multicenter, controlled study was carried out. IBD patients were invited from 12 IBD clinics in Sweden. Controls were selected randomly from a residence registry. A study-specific questionnaire was used for data collection. RESULTS: Overall, 48.3% of patients with IBD had used some kind of CAM during the past year compared with 53.5% in controls (P=0.025, adjusted for age, sex, geographic residence, and diet). The most frequently used CAM among IBD patients was massage (21.3%), versus controls (31.4%) (adjusted P=0.0003). The second most used CAM was natural products, 18.7% in IBD patients versus 22.3% of the controls (unadjusted P=0.018). In all, 83.1% of the patients experienced positive effects from CAM and 14.4% experienced negative effects. CONCLUSION: Overall, 48.3% of Swedish IBD patients used some kind of CAM and controls used CAM significantly more. Natural products were used by one-fifth of the patients and even more by controls. This is notable from a patient safety perspective considering the possible risks of interactions with conventional medication. In all, 40% of the patients reported adverse events from conventional medicine. Patients experienced predominantly positive effects from CAM, and so did controls. PMID- 27472273 TI - Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports. AB - BACKGROUND: Three checkpoint inhibitor drugs have been approved by the US Food and Drug Administration for use in specific types of cancers. While the results are promising, severe immunotherapy-related adverse events (irAEs) have been reported. OBJECTIVES: To conduct a systematic review of case reports describing the occurrence of irAEs in patients with cancer following checkpoint blockade therapy, primarily to identify potentially unrecognized or unusual clinical findings and toxicity. DATA SOURCES: We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no restriction through August 2015. STUDY SELECTION: Studies reporting cases of cancer develop irAEs following treatment with anti CTLA-4 (ipilimumab) or anti PD-1 (nivolumab or pembrolizumab) antibodies were included. DATA EXTRACTION: We extracted data on patient characteristics, irAEs characteristics, how irAEs were managed, and their outcomes. DATA SYNTHESIS: 191 publications met inclusion criteria, reporting on 251 cases. Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab. LIMITATIONS: Our study is limited by information available in the original reports. CONCLUSIONS: Evidence from case reports shows that cancer patients develop irAEs following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases. While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported. PMID- 27472275 TI - Linking Retinal Microvasculature Features With Severity of Diabetic Retinopathy Using Optical Coherence Tomography Angiography. AB - PURPOSE: To correlate retinal vascular features with severity and systemic indicators of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA). METHODS: A total of 209 eyes of 122 type 2 diabetes mellitus patients with DR and 60 eyes of 31 normal Indian subjects underwent OCTA imaging. The diabetic retinopathy patients were graded as having either nonproliferative diabetic retinopathy (NPDR: mild, moderate, and severe NPDR using Early Treatment Diabetic Retinopathy Study classification) or proliferative diabetic retinopathy (PDR). Local fractal analysis was applied to the superficial and deep retinal OCTA images. Foveal avascular zone area (FAZ in mm2); vessel density (%); spacing between large vessels (%); and spacing between small vessels (%) were analyzed. Sensitivity and specificity of vascular parameters were assessed with receiver operating characteristics (ROC) curve. RESULTS: Normal eyes had a significantly lower FAZ area, higher vessel density, and lower spacing between large and small vessels compared with DR grades (P < 0.001). In the superficial layer, PDR and severe NPDR had higher spacing between large vessels than mild and moderate NPDR (P = 0.04). However, mild NPDR had higher spacing between the small vessels (P < 0.001). Spacing between the large vessels in the superficial retinal layer correlated positively with HbA1c (r = 0.25, P = 0.03); fasting (r = 0.23, P = 0.02); and postprandial (r = 0.26, P = 0.03) blood sugar. The same spacing in the deep retinal vascular plexus had the highest area under the ROC curve (0.99 +/- 0.01) and was uniformly elevated in all diabetic eyes (P > 0.05). CONCLUSIONS: Spacing between the large vessels in the superficial and deep retinal layers had superior diagnostic performance than overall vessel density. PMID- 27472274 TI - Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection. AB - Chromosomal instability is a well-defined hallmark of tumor aggressiveness and metastatic progression in colorectal cancer. The magnitude of genetic heterogeneity among distinct liver metastases from the same patient at the copy number level, as well as its relationship with chemotherapy exposure and patient outcome, remains unknown. We performed high-resolution DNA copy number analyses of 134 liver metastatic deposits from 45 colorectal cancer patients to assess: (i) intra-patient inter-metastatic genetic heterogeneity using a heterogeneity score based on pair-wise genetic distances among tumor deposits; and (ii) genomic complexity, defined as the proportion of the genome harboring aberrant DNA copy numbers. Results were analyzed in relation to the patients' clinical course; previous chemotherapy exposure and outcome after surgical resection of liver metastases. We observed substantial variation in the level of intra-patient inter metastatic heterogeneity. Heterogeneity was not associated with the number of metastatic lesions or their genomic complexity. In metachronous disease, heterogeneity was higher in patients previously exposed to chemotherapy. Importantly, intra-patient inter-metastatic heterogeneity was a strong prognostic determinant, stronger than known clinicopathological prognostic parameters. Patients with a low level of heterogeneity (below the median level) had a three year progression-free and overall survival rate of 23% and 66% respectively, versus 5% and 18% for patients with a high level (hazard ratio0.4, 95% confidence interval 0.2-0.8, P = 0.01; and hazard ratio0.3,95% confidence interval 0.1-0.7, P = 0.007). A low patient-wise level of genomic complexity (below 25%) was also a favorable prognostic factor; however, the prognostic association of intra-patient heterogeneity was independent of genomic complexity in multivariable analyses. In conclusion, intra-patient inter-metastatic genetic heterogeneity is a pronounced feature of metastatic colorectal cancer, and the strong prognostic association reinforces its clinical relevance and places it as a key feature to be explored in future patient cohorts. PMID- 27472276 TI - Evaluating Polypoidal Choroidal Vasculopathy With Optical Coherence Tomography Angiography. AB - PURPOSE: We observed and analyzed the morphologic characteristics of polypoidal lesions and abnormal branching vascular network (BVN) in patients with polypoidal choroidal vasculopathy (PCV) by optical coherence tomography angiography (OCTA). METHODS: A retrospective observational case series was done of patients with PCV. All patients were scanned with a 70-kHz spectral-domain OCT system using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm to distinguish blood flow from static tissue. The OCTA images of these patients were compared to those from indocyanine green angiography (ICGA). Semiautomated segmentation was used to further analyze the polypoidal lesion and the BVN. RESULTS: We studied 13 eyes of 13 patients 51 to 69 years old. A total of 11 patients were treatment-naive. Two patients had multiple anti-VEGF injections and one underwent photodynamic therapy (PDT). Optical coherence tomography angiography was able to detect the BVN in all cases. Using cross-sectional OCTA, BVN locations were shown to be in the space between the RPE and Bruch's membrane. Using en face OCTA, the BVN vascular pattern could be shown more clearly than by ICGA. Polypoidal lesions showed high flow signals in different patterns in 12 cases in the outer retina slab. Using cross-sectional OCTA, the polyps were shown to be just below the top of the pigment epithelial detachment (PED). In one case, the polypoidal lesion was not detectable at the outer retina slab. CONCLUSIONS: Optical coherence tomography angiography is a noninvasive imaging tool for detecting vascular changes in PCV. Branching vascular networks showed more clearly on OCTA than on ICGA. Polypoidal lesions had variable patterns on OCTA and were not always detected. The OCTA patterns of the polypoidal lesions and the BVN are helpful in understanding the pathology of PCV. PMID- 27472277 TI - 3D Imaging of Retinal Pigment Epithelial Cells in the Living Human Retina. AB - PURPOSE: Dysfunction of the retinal pigment epithelium (RPE) underlies numerous retinal pathologies, but biomarkers sensitive to RPE change at the cellular level are limited. In this study, we used adaptive optics optical coherence tomography (AO-OCT) in conjunction with organelle motility as a novel contrast mechanism to visualize RPE cells and characterize their 3-dimensional (3D) reflectance profile. METHODS: Using the Indiana AO-OCT imaging system (lambdac = 790 nm), volumes were acquired in the macula of six normal subjects (25-61 years). Volumes were registered in 3D with subcellular accuracy, layers segmented, and RPE and photoreceptor en face images extracted and averaged. Voronoi and two-dimensional (2D) power spectra analyses were applied to the images to quantify RPE and cone packing and cone-to-RPE ratio. RESULTS: Adaptive optics OCT revealed two distinct reflectance patterns at the depth of the RPE. One is characterized by the RPE interface with rod photoreceptor tips, the second by the RPE cell nuclei and surrounding organelles, likely melanin. Increasing cell contrast by averaging proved critical for observing the RPE cell mosaic, successful in all subjects and retinal eccentricities imaged. Retinal pigment epithelium mosaic packing and cell thickness generally agreed with that of histology and in vivo studies using other imaging modalities. CONCLUSIONS: We have presented, to our knowledge, the first detailed characterization of the 3D reflectance profile of individual RPE cells and their relation to cones and rods in the living human retina. Success in younger and older eyes establishes a path for testing aging effects in larger populations. Because the technology is based on OCT, our measurements will aid in interpreting clinical OCT images. PMID- 27472278 TI - Incorporating and Compensating Cerebrospinal Fluid in Surface-Based Forward Models of Magneto- and Electroencephalography. AB - MEG/EEG source imaging is usually done using a three-shell (3-S) or a simpler head model. Such models omit cerebrospinal fluid (CSF) that strongly affects the volume currents. We present a four-compartment (4-C) boundary-element (BEM) model that incorporates the CSF and is computationally efficient and straightforward to build using freely available software. We propose a way for compensating the omission of CSF by decreasing the skull conductivity of the 3-S model, and study the robustness of the 4-C and 3-S models to errors in skull conductivity. We generated dense boundary meshes using MRI datasets and automated SimNIBS pipeline. Then, we built a dense 4-C reference model using Galerkin BEM, and 4-C and 3-S test models using coarser meshes and both Galerkin and collocation BEMs. We compared field topographies of cortical sources, applying various skull conductivities and fitting conductivities that minimized the relative error in 4 C and 3-S models. When the CSF was left out from the EEG model, our compensated, unbiased approach improved the accuracy of the 3-S model considerably compared to the conventional approach, where CSF is neglected without any compensation (mean relative error < 20% vs. > 40%). The error due to the omission of CSF was of the same order in MEG and compensated EEG. EEG has, however, large overall error due to uncertain skull conductivity. Our results show that a realistic 4-C MEG/EEG model can be implemented using standard tools and basic BEM, without excessive workload or computational burden. If the CSF is omitted, compensated skull conductivity should be used in EEG. PMID- 27472279 TI - Circulating Levels of Irisin in Hypopituitary and Normal Subjects. AB - CONTEXT: The recently identified myokine irisin conveys some of the benefits of exercise. Hypopituitarism with adult growth hormone deficiency (HP) is a situation characterized by decreased GH secretion and an altered body composition. OBJECTIVE: Our aim was to study the skeletal muscle hormone irisin in HP, and compare the results with a similar group of normal subjects. PARTICIPANTS AND METHODS: Seventeen HP patients and fifty-one normal subjects of similar age and sex were studied. The diagnosis of GH deficiency was confirmed by the presence of pituitary disease and a peak GH secretion below 3 MUg/L after an insulin tolerance test. The patients were adequately treated for all pituitary hormone deficits, except for GH. Fasting serum irisin was measured with an enzyme immunoassay, and HOMA-IR, QUICKI and HOMA-beta were calculated. RESULTS: Fasting irisin levels (ng/ml) were similar in normal [208.42 (168.44-249.23)] and HP patients [195.13 (178.44-241.44)]. In the control group there were moderate significant positive correlations between irisin and BMI, waist circumference, leptin, fasting insulin, HOMA-IR, HOMA-beta, triglycerides, and cholesterol. In the control group there were moderate significant negative correlations between irisin and IGF-I and QUICKI. In the hypopituitary group there were moderate significant positive correlations between irisin and body fat and HOMA-beta. CONCLUSIONS: We found similar irisin levels in GH deficiency hypopituitary patients when compared with normal subjects. The correlation between irisin and adiposity related factors suggests that that in the case of this clinical model, irisin is regulated by adiposity and not by GH. PMID- 27472280 TI - Revisiting the Heterogeneous IFN-gamma Response of Bacille of Calmette-Guerin (BCG)-Revaccinated Healthy Volunteers in a Randomized Controlled Trial: Effect of the Body Mass Index and of the IFNG+874 A/T Polymorphism. AB - In trials evaluating the immune responses to Bacille of Calmette-Guerin (BCG), the genetic background and the nutritional status are host-related factors that could affect the heterogeneity in these parameters. The IFNG+874 A/T (rs 62559044) polymorphism has been reported to influence the IFN-gamma production by BCG-vaccinated individuals challenged in vitro with mycobacterial antigens. The body mass index (BMI) is a proxy for the nutritional status and has been associated both with the susceptibility to tuberculosis and with the IFN-gamma response. We show that although the IFNG+874 A/T polymorphism was not associated with the heterogeneity of IFN-gamma production in a randomized controlled trial that evaluated long-term immune responses to BCG revaccination previously conducted in Salvador, Bahia, Brazil, the effect of this polymorphism on the observed increase in IFN-gamma production among revaccinated subjects was adjusted in individuals with a low BMI. PMID- 27472281 TI - Enhancement of Oral Tolerance Induction in DO11.10 Mice by Lactobacillus gasseri OLL2809 via Increase of Effector Regulatory T Cells. AB - Food allergy is a serious problem for infants and young children. Induction of antigen-specific oral tolerance is one therapeutic strategy. Enhancement of oral tolerance induction by diet is a promising strategy to prevent food allergy in infants. Thus, in this study, we evaluate the effect of probiotic Lactobacillus gasseri OLL2809 (LG2809) on oral tolerance induction in a mouse model. The degree of oral tolerance induction was evaluated by measuring the proliferation and level of IL-2 production of splenic CD4+ T cells from DO11.10 mice fed ovalbumin (OVA) alone or OVA with LG2809. Oral administration of LG2809 significantly decreased the rate of proliferation and IL-2 production by CD4+ T cells from OVA fed mice. LG2809 increased a ratio of CD4+ T-cell population, producing high levels of IL-10 and having strong suppressive activity. Moreover, LG2809 increased a ratio of plasmacytoid dendritic cells (pDCs) among the lamina propria (LP) in small intestine. When used as antigen presenting cells to naive CD4+ T cells from DO11.10 mice, LP cells from BALB/c mice fed LG2809 induced higher IL 10 production and stronger suppressive activity than those from non-treated mice. These results suggest that oral administration of LG2809 increases the population of pDCs in the LP, resulting in the enhancement of oral tolerance induction by increasing the ratio of effector regulatory T cells. LG2809 could, therefore, act as a potent immunomodulator to prevent food allergies by promoting oral tolerance. PMID- 27472283 TI - Anti-HSV-1 and HSV-2 Flavonoids and a New Kaempferol Triglycoside from the Medicinal Plant Kalanchoe daigremontiana. AB - Kalanchoe daigremontiana (Crassulaceae) is a medicinal plant native to Madagascar. The aim of this study was to investigate the flavonoid content of an aqueous leaf extract from K. daigremontiana (Kd), and assess its antiherpetic potential. The major flavonoid, kaempferol 3-O-beta-d-xylopyranosyl-(1 -> 2) alpha-l-rhamnopyranoside (1), was isolated from the AcOEt fraction (Kd-AC). The BuOH-soluble fraction afforded quercetin 3-O-beta-d-xylopyranosyl-(1 -> 2)-alpha l-rhamnopyranoside (2) and the new kaempferol 3-O-beta-d-xylopyranosyl-(1 -> 2) alpha-l-rhamnopyranoside-7-O-beta-d-glucopyranoside (3), named daigremontrioside. The crude extract, Kd-AC fraction, flavonoids 1 and 2 were evaluated using acyclovir-sensitive strains of HSV-1 and HSV-2. Kd-AC was highly active against HSV-1 (EC50 = 0.97 MUg/ml, SI > 206.1) and HSV-2 (EC50 = 0.72 MUg/ml, SI > 277.7). Flavonoids 1 and 2 showed anti-HSV-1 (EC50 = 7.4 MUg/ml; SI > 27 and EC50 = 5.8 MUg/ml; SI > 8.6, respectively) and anti-HSV-2 (EC50 = 9.0 MUg/ml; SI > 22.2 and EC50 = 36.2 MUg/ml; SI > 5.5, respectively) activities, suggesting the contribution of additional substances to the antiviral activity. PMID- 27472282 TI - Clinical Relevance of Pathogens Detected by Multiplex PCR in Blood of Very-Low Birth Weight Infants with Suspected Sepsis - Multicentre Study of the German Neonatal Network. AB - INTRODUCTION: In the German Neonatal Network (GNN) 10% of very-low-birth weight infants (VLBWI) suffer from blood-culture confirmed sepsis, while 30% of VLBWI develop clinical sepsis. Diagnosis of sepsis is a difficult task leading to potential over-treatment with antibiotics. This study aims to investigate whether the results of blood multiplex-PCR (SeptiFast(r)) for common sepsis pathogens are relevant for clinical decision making when sepsis is suspected in VLBWI. METHODS: We performed a prospective, multi-centre study within the GNN including 133 VLBWI with 214 episodes of suspected late onset sepsis (LOS). In patients with suspected sepsis a multiplex-PCR (LightCycler SeptiFast MGRADE-test(r)) was performed from 100 MUl EDTA blood in addition to center-specific laboratory biomarkers. The attending neonatologist documented whether the PCR-result, which was available after 24 to 48 hrs, had an impact on the choice of antibiotic drugs and duration of therapy. RESULTS: PCR was positive in 110/214 episodes (51%) and blood culture (BC) was positive in 55 episodes (26%). Both methods yielded predominantly coagulase-negative staphylococci (CoNS) followed by Escherichia coli and Staphylococcus aureus. In 214 BC-PCR paired samples concordant results were documented in 126 episodes (59%; n = 32 were concordant pathogen positive results, n = 94 were negative in both methods). In 65 episodes (30%) we found positive PCR results but negative BCs, with CoNS being identified in 43 (66%) of these samples. Multiplex-PCR results influenced clinical decision making in 30% of episodes, specifically in 18% for the choice of antimicrobial therapy and in 22% for the duration of antimicrobial therapy. CONCLUSIONS: Multiplex-PCR results had a moderate impact on clinical management in about one third of LOS-episodes. The main advantage of multiplex-PCR was the rapid detection of pathogens from micro-volume blood samples. In VLBWI limitations include risk of contamination, lack of resistance testing and high costs. The high rate of positive PCR results in episodes of negative BC might lead to overtreatment of infants which is associated with risk of mortality, antibiotic resistance, fungal sepsis and NEC. PMID- 27472285 TI - Interfacial Symmetry Control of Emergent Ferromagnetism at the Nanoscale. AB - The emergence of complex new ground states at interfaces has been identified as one of the most promising routes to highly tunable nanoscale materials. Despite recent progress, isolating and controlling the underlying mechanisms behind these emergent properties remains among the most challenging materials physics problems to date. In particular, generating ferromagnetism localized at the interface of two nonferromagnetic materials is of fundamental and technological interest. Moreover, the ability to turn the ferromagnetism on and off would shed light on the origin of such emergent phenomena and is promising for spintronic applications. We demonstrate that ferromagnetism confined within one unit cell at the interface of CaRuO3 and CaMnO3 can be switched on and off by changing the symmetry of the oxygen octahedra connectivity at the boundary. Interfaces that are symmetry-matched across the boundary exhibit interfacial CaMnO3 ferromagnetism while the ferromagnetism at symmetry-mismatched interfaces is suppressed. We attribute the suppression of ferromagnetic order to a reduction in charge transfer at symmetry-mismatched interfaces, where frustrated bonding weakens the orbital overlap. Thus, interfacial symmetry is a new route to control emergent ferromagnetism in materials such as CaMnO3 that exhibit antiferromagnetism in bulk form. PMID- 27472284 TI - Viral/Nonviral Chimeric Nanoparticles To Synergistically Suppress Leukemia Proliferation via Simultaneous Gene Transduction and Silencing. AB - Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of chronic myelogenous leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic antileukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and interlinked pathological pathways. PMID- 27472286 TI - CCL2, CCL5, IL4 and IL15 Gene Polymorphisms in Women with Gestational Diabetes Mellitus. AB - Gestational diabetes mellitus (GDM) is a glucose intolerance that occurs during pregnancy. Several studies suggest that inflammation contributes to pregnancy induced insulin resistance and the development of glucose intolerance. The aim of this study is to examine the association between the CCL2, CCL5, IL4 and IL15 gene polymorphisms and the development of GDM. This study included 411 pregnant women who underwent a 75 g oral glucose tolerance test at 24-28 weeks of gestation. Participants were categorised into 2 groups according to results of the oral glucose tolerance test (OGTT). The GDM group included 204 pregnant women who were diagnosed with GDM. The normal glucose tolerance group included 207 pregnant women with normal values in the OGTT. To discriminate the CCL2 rs1024611 and rs4586, CCL5 rs2107538, IL4 rs2243250, IL15 rs2857261 and rs2254514 alleles, TaqMan(r) Pre-Designed SNP Genotyping Assays were used. GDM was significantly associated with genotypes and alleles of the CCL2 rs1024611 and rs4586 polymorphisms, while there was no statistically significant association between the CCL5 rs2107538, IL4 rs2243250, IL15 rs2857261, and rs2254514 gene polymorphisms and GDM. In a multivariate regression analysis, age and BMI before pregnancy were independent significant predictors of a higher risk of GDM, while a lower number of G alleles CCL2 rs1024611 was protective against GDM. Moreover, women with the GG CCL2 rs1024611 and CC rs4586 genotype tended to have lower body mass and BMI increases during pregnancy, as well as lower newborn body mass. The results of our study suggest an association between CCL2 gene polymorphisms and GDM. PMID- 27472287 TI - Second Trimester Fetal and Maternal Epicardial Fat Thickness in Gestational Diabetic Pregnancies. AB - Our aim was to evaluate the association between gestational diabetes mellitus and sonographically measured fetal epicardial fat thickness between 24-28 weeks' gestation. This was a cross-sectional study that included 40 pregnancies with gestational diabetes mellitus, matched with 40 normal pregnancies with similar maternal age, body-mass index, gestational age, fetal gender, and fetal abdominal circumference on ultrasound. Fetal epicardial fat thickness was measured and recorded during ultrasonography at 24-28 weeks of gestation. Maternal evaluation included measurement of maternal epicardial fat thickness, using echocardiography. Fetal and maternal epicardial fat thickness values were compared across the groups. Ultrasound views of fetal epicardial fat thickness were evaluated independently by 3 perinatology fellows to determine inter- and intra-observer variability. Partial and intraclass correlation analyses were used. Fetal and maternal epicardial fat thickness measurements were moderately correlated (r=0.63). Mean fetal and maternal epicardial fat thickness values were higher in gestational diabetes mellitus pregnancies (p=0.004 and p<0.0001, respectively) compared to controls. Fetal epicardial fat thickness was positively correlated (r=0.43) with postchallenge 2-h glucose values. Inter- and intra observer agreement was high, demonstrated by strong correlations (r=0.99 and r=0.99, respectively) across fetal epicardial fat thickness measurements of the examiners. Fetuses from gestational diabetes mellitus pregnancies have significantly higher fetal and maternal epicardial fat thickness values compared to nongestational diabetes mellitus pregnancies. Fetal epicardial fat thickness obtained during second trimester fetal anatomy ultrasound may potentially be a reliable indicator for gestational diabetes mellitus. However, clinical validation studies are needed. PMID- 27472288 TI - Correction: Can Nocturnal Flight Calls of the Migrating Songbird, American Redstart, Encode Sexual Dimorphism and Individual Identity? AB - [This corrects the article DOI: 10.1371/journal.pone.0156578.]. PMID- 27472289 TI - Chikugunya and zika virus dissemination in the Americas: different arboviruses reflecting the same spreading routes and poor vector-control policies. AB - PURPOSE OF REVIEW: This review gathers the most recent investigations about chikungunya and zika viruses in America and would help in creating new research approaches. RECENT FINDINGS: Clinical descriptions of chikungunya fever have been performed in the American outbreak observing that fever, polyarthalgia, myalgia and rash are the most common symptoms in the acute phase, while chronic arthralgia has persisted in 37-90% of small cohorts. The Asian origin of American strains of chikungunya virus (CHIKV) and zika virus (ZIKV) evidences a dissemination route in common and both are being transmitted by Aedes aegypti. Regarding zika fever, the association of congenital malformations with previous ZIKV exposure of pregnant women and potential sexual transmission of ZIKV are the most important discoveries in the New World. SUMMARY: Massive outbreaks of chikungunya fever in 2014 and then followed by zika fever epidemics of lower magnitude in the next year throughout the American continent have their origins in Asia but may have used Pacific Islands as a path of dissemination. Reports of chronic arthralgia have been little described in the continent and more research is needed to measure the economic and health impact in patients who contracted CHIKV before. On the contrary, zika is menacing newborns' health because of its link with congenital microcephaly and sexual health by prolonged presence of viral particles in semen and urine. PMID- 27472290 TI - HIV and diarrhoea: what is new? AB - PURPOSE OF REVIEW: The review examines the changing causes and the investigation of infectious and noninfectious diarrhoea in individuals with HIV. RECENT FINDINGS: Despite the excellent prognosis conferred by combination antiretroviral therapy, diarrhoea is still common in HIV-positive individuals and is associated with reduced quality of life and survival. There is increasing interest in the importance of Th17 and Th22 T cells in the maintenance of mucosal immunity within the gut, and in the role of the gut microbiome in gut homeostasis. Bacterial causes of HIV-associated diarrhoea continue to be important in resource-poor settings. In other settings, sexually transmitted enteric infections such as lymphogranuloma venereum and shigellosis are increasingly reported in men who have sex with men. HIV increases the risk of such infections and the presence of antimicrobial resistance. Parasitic causes of diarrhoea are more common in individuals with uncontrolled HIV and low CD4 counts. Noninfectious causes of diarrhoea include all classes of antiretroviral therapy, which is under recognised as a cause of poor treatment adherence. Pancreatic dysfunction is remediable and the diagnostic workup of HIV-related diarrhoea should include faecal elastase measurements. New antimotility agents such as crofelemer may be useful in managing secretory diarrhoea symptoms. SUMMARY: Clinicians looking after patients with HIV should ask about diarrhoeal symptoms, which are under reported and may have a remediable infectious or noninfectious cause. PMID- 27472292 TI - The organisational stressors encountered by athletes with a disability. AB - Organisational stressors have been found to be prevalent and problematic for sport performers, with research identifying demographic differences in the stressors encountered. Nevertheless, extant sport psychology research on the topic of stress has generally focused on able-bodied athletes; whilst that which has been conducted on performers with a disability has typically recruited relatively small samples to explore a narrow selection of organisational stressors, or examined other components of the stress process. The purpose of the present study was to explore the various organisational stressors that athletes with a disability encounter. The sample comprised 18 elite athletes with a disability (10 male, 8 female) who had a classified disability and experience of competing at a major championships in their sport (e.g., Paralympic Games, World Championships). Participants took part in a semi-structured interview which was analysed by drawing from grounded theory procedures. A total of 316 organisational stressors were identified, which were abstracted into 31 concepts and four, previously conceptualised, exploratory schemes: leadership and personnel issues, cultural and team issues, logistical and environmental issues, and performance and personal issues. This study not only provides the first illustration of the prevalence of organisational stressors for athletes with a disability, but also significantly points to salient similarities and distinct differences between the stress experiences of performers with and without a disability. PMID- 27472291 TI - Menopause, Reproductive Life, Hormone Replacement Therapy, and Bone Phenotype at Age 60-64 Years: A British Birth Cohort. AB - CONTEXT: Previous studies of menopausal age and length of reproductive life on bone are limited by retrospective reproductive histories, being cross-sectional, or lacking gold standard bone technologies or information on hormone replacement therapy (HRT) or surgical treatment. OBJECTIVE: The objective of the study was to investigate age at menopause, length of reproductive life, and HRT use in relation to volumetric and areal bone mineral density (vBMD, aBMD), bone size, and strength in women aged 60-64 years. DESIGN: This was a birth cohort study that followed up for 64 years with prospective measures of age at menarche and menopause and monthly HRT histories. SETTING: The study was conducted in England, Scotland, and Wales. PARTICIPANTS: Participants included 848 women with a known type of menopause and bone measures at 60-64 years. MAIN OUTCOME MEASURES: Peripheral quantitative computed tomography measurements of the distal radius total and trabecular vBMD were measured. Diaphyseal radius total and medullary cross-sectional area, cortical vBMD, and polar strength strain index (SSI); dual energy x-ray absorptiometry measurements of aBMD at the lumbar spine and total hip were also measured. RESULTS: A 10-year increase in age at natural (but not surgical) menopause was associated with 8.2% (95% confidence interval [CI] 1.3% 15.1%, P = .02) greater trabecular vBMD and a 6.0% (95% CI 0.51%-11.5%, P = .03) greater total vBMD; findings were similar for length of reproductive life. A 10 year difference in HRT use was associated with a 6.0% (95% CI 2.6%-9.3%, P < .001) greater polar SSI and a 0.9% (95% CI 0.4%-1.5%, P = .001) greater cortical vBMD. These estimates changed little on adjustment. Estimates for aBMD were consistent with those for peripheral quantitative computed tomography. CONCLUSIONS: The positive effects on trabecular vBMD of later natural menopause and longer reproductive life persisted into early old age. HRT use was associated with greater radius cortical vBMD and polar SSI and aBMD. PMID- 27472293 TI - Hydrogen sulfide improves colonic barrier integrity in DSS-induced inflammation in Caco-2 cells and mice. AB - Intestinal barrier involves in the pathogeny of inflammatory bowel disease (IBD) and hydrogen sulfide (H2S) has been reported to improve intestinal barrier integrity. Thus, this study investigated the effects of GYY4137, a slow-release H2S donor, on DSS-induced inflammation and intestinal dysfunction. In vitro model, cellular permeability was significantly increased and expression of tight junctions (ZO-1, Cauldin4, and Occludin) was downregulated in Caco-2 cells. GYY4137 treatment markedly attenuated DSS-induced inflammation and barrier dysfunction. Cystathionine beta-synthase (CBS)-siRNA transfection further demonstrated that endogenous H2S system involves in DSS-induced inflammation and mediates barrier function. In vivo model, DSS exposure caused colonic inflammation and injury in mice and GYY4137 injection alleviated inflammatory response and improved intestinal barrier via reducing intestinal permeability and upregulating of tight junctions. In conclusion, endogenous H2S system involves in DSS-induced inflammation and H2S addition alleviated inflammation and intestinal dysfunction in vitro and in vivo. PMID- 27472294 TI - Epigallocatechin gallate potentially abrogates fluoride induced lung oxidative stress, inflammation via Nrf2/Keap1 signaling pathway in rats: An in-vivo and in silico study. AB - BACKGROUND: Since this Nrf2-dependent cellular defense response is able to protect multi-organs, including cancer, neurodegenerative diseases, cardiovascular diseases, inflammation and chronic lung injury. The antioxidant and anti-inflammatory potential of Epigallocatechin gallate (EGCG) and Nrf2/Keap1 signaling mechanisms in pulmonary toxicity have not been clarified. In the present study, we demonstrated that protective efficacy of EGCG against fluoride (Fl) induced oxidative stress mediated lung injury in rats. METHODS: The animals were divided in to four groups. Group 1: Control rats received normal saline; Group 2 rats received EGCG (40mg/kg/bw) alone for four weeks; Group 3 rats received Fl (25mg/kg/bw) alone for four weeks, Group 4 rats received EGCG (90min before administration) along with Fl for four weeks. RESULTS: Oral administration of Fl (25mg/kg/bw) significantly (p<0.05) increased the ROS, inflammatory cytokines, lung edema, melonaldehyde (MDA) and myeloperoxidase (MPO) in rats. In addition, upon administration of Fl significantly (p<0.05) decreased the antioxidant status, Nrf2, and HO-1 with increased Keap1 protein. Histological and immunohistochemical (iNOS) study also revealed the Fl induced significant (p<0.05) changes in the lung tissue of rats. Pre-administration of EGCG significantly (p<0.05) improved the antioxidant status, and inhibited the oxidative stress, inflammatory cytokines, and Keap1 protein via the activation of Nrf2 translocation in to the nucleus. Moreover, the molecular docking studies also support the antioxidant potential of EGCG and Nrf2 activation. CONCLUSION: Taken together, our data indicate that EGCG potentially abrogates Fl induced oxidative lung injury by activation of the Nrf2/Keap1 pathway in rats. PMID- 27472297 TI - 'Open access' and the International Journal of Audiology. PMID- 27472295 TI - Effect of connexin 43 inhibition by the mimetic peptide Gap27 on corneal wound healing, inflammation and neovascularization. AB - BACKGROUND AND PURPOSE: The connexin 43 (Cx43) mimetic peptide Gap27 was designed to transiently block the function of this gap junction. This study was undertaken to investigate the effect of Gap27 on corneal healing, inflammation and neovascularization. EXPERIMENTAL APPROACH: The effect of Gap27 on wound healing, inflammation and vascularization was assessed in primary human corneal epithelial cells (HCEC) in vitro and whole human corneas ex vivo, and in an in vivo rat wound healing model. KEY RESULTS: Gap27 enhanced the wound closure of HCEC in vitro and accelerated wound closure and stratification of epithelium in human corneas ex vivo, but did not suppress the corneal release of inflammatory mediators IL-6 or TNF-alpha in vivo. In human corneas ex vivo, F4/80 positive macrophages were observed around the wound site. In vivo, topical Gap27 treatment enhanced the speed and density of early granulocyte infiltration into rat corneas. After 7 days, the expressions of TNF-alpha and TGFbeta1 were elevated and correlated with inflammatory cell accumulation in the tissue. Additionally, Gap27 did not suppress VEGF release in organotypic culture, nor did it suppress early or late VEGFA expression or neovascularization in vivo. CONCLUSIONS AND IMPLICATIONS: Gap27 can be effective in promoting the healing of superficial epithelial wounds, but in deep stromal wounds it has the potential to promote inflammatory cell migration and accumulation in the tissue and does not suppress the subsequent neovascularization response. These results support the proposal that Gap27 acts as a healing agent in the transient, early stages of corneal epithelial wounding. PMID- 27472296 TI - Sera of patients with recurrent miscarriages containing anti-trophoblast antibodies (ATAB) reduce hCG and progesterone production in trophoblast cells in vitro. AB - PROBLEM: Reproductive failure including RM has been suggested to correlate with antibodies that cross react with HLA-negative syncytiotrophoblasts and we have reported that 17% of women with 2 or more miscarriages and 34% of women with 3 or more miscarriages express anti-trophoblast antibodies (ATAB). Until now, the mechanism, how ATAB interfere with pregnancy success is not known. HCG and progesterone both play fundamental roles in supporting human pregnancy. Therefore we investigated the effects of sera of RM patients containing ATAB on the hCG and progesterone production of cells of the choriocarcinoma cell line JEG-3. METHOD OF STUDY: In vitro study to investigate effects of patient sera with and without ATAB on hCG and progesterone secretion of JEG-3 cells. The presence of ATAB was detected as described earlier. Effects of sera from ATAB positive and ATAB negative RM patients on hCG and progesterone secretion by JEG-3 cells were analysed 12 and 24h after plating. Sera of women without pregnancy pathologies served as controls. RESULTS: Sera of ATAB-positive RM patients significantly inhibit hCG secretion of JEG-3 cells for 12h after plating compared to sera of healthy controls (p=0.019) and significantly reduce progesterone production for 12h (p=0.046) and 24h (p=0.027) of co-culture. Sera of ATAB-negative RM patient show no significant effect on progesterone secretion. CONCLUSIONS: Inhibition of hCG and progesterone production might point to a mechanism, how ATAB interfere with early pregnancies. PMID- 27472298 TI - Lycopene Consumption and Risk of Colorectal Cancer: A Meta-Analysis of Observational Studies. AB - A number of epidemiological studies have explored the association between lycopene or lycopene-rich food intake and the risk of colorectal cancer, but the results of these studies have not been consistent. We conducted a systematic review and meta-analysis of studies published in the PubMed and EMBASE databases to quantitatively assess the association between lycopene consumption and the risk of colorectal cancer. A total of 15 studies were included in the meta analysis, and the summary relative risk (RR) for highest versus lowest category indicated no significant association between lycopene consumption and the risk of colorectal cancer [RR = 0.94, 95% confidence interval (CI): 0.80-1.10]. However, a significant inverse association was observed between lycopene consumption and the site of cancer in the colon (RR = 0.88, 95% CI: 0.81-0.96). We also found that the incidence of colon cancer and lycopene intake did not exhibit dose response relationships. The Grades of Recommendations Assessment, Development and Evaluation (GRADE) quality in our study was very low. In conclusion, this meta analysis indicates that lycopene consumption is not associated with the risk of colorectal cancer. Further research will be needed in this area to provide conclusive evidence. PMID- 27472299 TI - Use of a mid-scala and a lateral wall electrode in children: insertion depth and hearing preservation. AB - CONCLUSIONS: Atraumatic insertion of the HiFocusTM Mid-Scala (HFMS) electrode via the round window was successfully achieved in seven children. Residual hearing 6 months post-operatively was preserved to within 10 dB HL of the pre-operative audiogram at 500 Hz for six children, indicating minimal initial insertion trauma to the cochlea. OBJECTIVES: The objectives were to document the clinical experience and evaluate differences between HFMS and HiFocusTM 1j (HF1j) by means of insertion depth and hearing preservation results. METHOD: Nineteen children were prospectively recruited and consecutively implanted with the HF1j electrode (n = 12) or the HFMS electrode (n = 7) via the round window. Average median angular insertion depths and the amount of residual hearing preserved at 6 months post-operatively were compared between the two electrode groups. RESULTS: The median angular insertion depth for the HF1j was 439 degrees and for the HFMS 435 degrees . Preservation of residual hearing at 500 Hz was assessed in seven HFMS subjects and 11 HF1j subjects. Based on the Skarzynski formula, three out of seven subjects (42%) in the HFMS group had their residual hearing completely preserved at 500 Hz. In the control group, no subjects had complete hearing preservation and five subjects had a complete loss of residual hearing. PMID- 27472300 TI - Physicochemical properties and digestibility of eleven Vietnamese rice starches with varying amylose contents. AB - The physicochemical properties of eleven Vietnamese rice starches with apparent amylose contents ranging from 0.2% to 28.4% were investigated to identify the interplaying factors contributing to the in vitro digestibility of starch: in uncooked, cooked in excess water and under limited water conditions. The amylose content of rice starches governed the physicochemical properties of starch such as swelling power, pasting and gelatinization of starch which strongly correlated with raw starch digestibility. Amylopectin predominantly contributed to the crystallinity of starches both in short range and long range orders (observed by FT-IR and X-ray diffraction respectively). This study found that cooking destructively changed the molecular structure of starch that lead to an increase in the rate of starch digestion. Cooking in excess water resulted in a higher rate of starch digestion at least by 2 fold in all examined starches, suggesting that under these cooking conditions, factors that would normally limit the rate of digestion were eliminated. Cooking in limited water that was similar to domestic cooking conditions, seemed to allow rice starch granules to rearrange and interact together and limited the rate of digestion compared to cooking in excess water. It can be concluded that the physicochemical properties of starch can predict the digestibility of raw starches only but not cooked starches. The digestion of rice starch cooked in limited water cannot be predicted by just studying the uncooked starches or cooking in excess water. PMID- 27472301 TI - Modular Attachment of Appended Boron Lewis Acids to a Ruthenium Pincer Catalyst: Metal-Ligand Cooperativity Enables Selective Alkyne Hydrogenation. AB - A new series of bifunctional Ru complexes with pendent Lewis acidic boranes were prepared by late-stage modification of an active hydrogen-transfer catalyst. The appended boranes modulate the reactivity of a metal hydride as well as catalytic hydrogenations. After installing acidic auxiliary groups, the complexes become multifunctional and catalyze the cis-selective hydrogenation of alkynes with higher rates, conversions, and selectivities compared with the unmodified catalyst. PMID- 27472302 TI - Characterization of 2,3-diarylxanthones by electrospray mass spectrometry: gas phase chemistry versus known antioxidant activity properties. AB - RATIONALE: Xanthones (XH) are a class of heterocyclic compounds widely distributed in nature that hold numerous noteworthy biological and antioxidant activities. Therefore, it is of utmost importance to achieve relevant detailed structural information to understand and assist prediction of their biological properties. The potential relationship between radical-mediated xanthone chemistry in the gas phase and their promising antioxidant activities has not been previously explored. METHODS: Protonated xanthones XH1-9 were generated in the gas phase by electrospray ionization (ESI) and the main fragmentation pathways of the protonated XH1-9 formed due to collision-induced dissociation (CID) were investigated. RESULTS: In the CID-MS/MS spectra of [M+H](+) ions of XH1, XH2 and XH4 the product ions formed due to H2 O elimination corresponding to the base peak of the spectra. For the remaining six xanthones (XH3, XH5-9), showing the most promising biological profile, the product ion produced with the highest relative abundance (RA) corresponded to the one formed through concomitant loss of H2 O plus CO. Indicative of an inexistent or lower biological activity is the combined loss of CO plus O unique to the CID-MS/MS spectra of XH1, XH2, XH4, and XH5. The product ion formed by loss of 64 Da (concomitant loss of two molecules of H2 O plus CO) is only observed for xanthones containing a catechol unit (XH3 and XH6-9). This product ion has the highest RA for the most potent scavenger of reactive oxygen and nitrogen species XH9 that contains two of these catechol moieties. CONCLUSIONS: A strong relationship between some of the biological activities of the studied 2,3-diarylxanthones and their ESI-MS/MS fragmentation spectra was found. The multivariate statistical analysis results suggest that the selected MS features are related to the important biological features. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27472303 TI - A Systematic Approach for the Determination of B-Group Vitamins in Multivitamin Dietary Supplements by High-Performance Liquid Chromatography with Diode-Array Detection and Mass Spectrometry. AB - This paper describes a practical approach using an LC diode-array detector (DAD) and MS for the quantitation of B-group vitamins (thiamine, riboflavin, nicotinamide, pantothenic acid, pyridoxine, biotin, folic acid, and cyanocobalamin) in multivitamin supplements. The purpose of this study was to optimize the extraction and chromatographic conditions without application of internal standards to determine B-group vitamins in multivitamins. Chromatographic separation on a C18 column was optimized on the basis of chromatographic behavior depending on pH variation of the mobile phase. The optimized methods showed good r values, with RSD values lower than 2.44 and 3.09% for most of the B-group vitamins (except cyanocobalamin) using LC-DAD and LC-MS, respectively. The methods were also proved to be reproducible, with RSD values of 0.96 and 2.48% being obtained with LC-DAD and LC-MS, respectively. In addition, the developed analytical methods for B-group vitamins were validated using certified reference materials and were applied to commercially available multivitamin tablets. PMID- 27472304 TI - Hexagonal beta-NaYF4:Yb(3+), Er(3+) Nanoprism-Incorporated Upconverting Layer in Perovskite Solar Cells for Near-Infrared Sunlight Harvesting. AB - Hexagonal beta-NaYF4:Yb(3+), Er(3+) nanoprisms, successfully prepared using a hydrothermal method, were incorporated into CH3NH3PbI3 perovskite solar cells (PSCs) as an upconverting mesoporous layer. Due to their near-infrared (NIR) sunlight harvesting, the PSCs based on the upconverting mesoporous layer exhibited a power conversion efficiency of 16.0%, an increase of 13.7% compared with conventional TiO2 nanoparticle-based PSCs (14.1%). This result suggests that the hexagonal beta-NaYF4:Yb(3+), Er(3+) nanoprisms expand the absorption range of the PSC via upconversion photoluminescence, leading to an enhancement of the photocurrent. PMID- 27472305 TI - Significant Heterogeneity and Slow Dynamics of the Unfolded Ubiquitin Detected by the Line Confocal Method of Single-Molecule Fluorescence Spectroscopy. AB - The conformation and dynamics of the unfolded state of ubiquitin doubly labeled regiospecifically with Alexa488 and Alexa647 were investigated using single molecule fluorescence spectroscopy. The line confocal fluorescence detection system combined with the rapid sample flow enabled the characterization of unfolded proteins at the improved structural and temporal resolutions compared to the conventional single-molecule methods. In the initial stage of the current investigation, however, the single-molecule Forster resonance energy transfer (sm FRET) data of the labeled ubiquitin were flawed by artifacts caused by the adsorption of samples to the surfaces of the fused-silica flow chip and the sample delivery system. The covalent coating of 2-methacryloyloxyethyl phosphorylcholine polymer to the flow chip surface was found to suppress the artifacts. The sm-FRET measurements based on the coated flow chip demonstrated that the histogram of the sm-FRET efficiencies of ubiquitin at the native condition were narrowly distributed, which is comparable to the probability density function (PDF) expected from the shot noise, demonstrating the structural homogeneity of the native state. In contrast, the histogram of the sm-FRET efficiencies of the unfolded ubiquitin obtained at a time resolution of 100 MUs was distributed significantly more broadly than the PDF expected from the shot noise, demonstrating the heterogeneity of the unfolded state conformation. The variety of the sm-FRET efficiencies of the unfolded state remained even after evaluating the moving average of traces with a window size of 1 ms, suggesting that conformational averaging of the heterogeneous conformations mostly occurs in the time domain slower than 1 ms. Local structural heterogeneity around the labeled fluorophores was inferred as the cause of the structural heterogeneity. The heterogeneity and slow dynamics revealed by the line confocal tracking of sm FRET might be common properties of the unfolded proteins. PMID- 27472306 TI - Neoadjuvant chemoradiation treatment followed by surgery for esophageal cancer: there is much more than the mandard tumor regression score. AB - OBJECTIVE: Tumor regression grading (TRG) systems categorize residual tumor volume on the primary tumor after neoadjuvant treatment. Aim was to evaluate the impact of Mandard TRG, residual tumor depth (ypT) and residual lymph node status (ypN) and extent (ELNI) i.e. intracapsular versus extracapsular involvement on overall (OS) and disease-free survival (DFS) in esophageal carcinoma. METHODS: Between 2005 and 2014, 344 patients receiving R0-esophagectomy after neoadjuvant chemoradiation therapy (nCRT) were selected. Mandard TRG, ypTN and ELNI were prospectively recorded. RESULTS: Mandard TRG1 was found in 110 (32%); TRG2 in 120 (35%); TRG3 in 53 (15%); TRG4 in 54 (16%) and TRG5 in 7 (2%) patients. Both OS and DFS showed no significant difference between TRG1 and 2 (p = 0.059 and 0.105, respectively). Therefore, TRG1/2 was classified together as 'major response', TRG3/4 as 'minor response' and TRG5 as 'no response'. Multivariate analysis showed two independent prognosticators for OS (tumor regression response (TRR) and number of positive lymph nodes) and three independent prognosticators for DFS (TRR, ypT and ELNI). CONCLUSION: After nCRT followed by surgery for esophageal carcinoma, number of residual positive lymph nodes as well as TRR are prognosticators for OS. Minor TRR, ypT and extracapsular lymph node invasion are prognosticators for recurrence. PMID- 27472307 TI - Different Flavonoids Can Shape Unique Gut Microbiota Profile In Vitro. AB - The impact of flavonoids has been discussed on the relative viability of bacterial groups in human microbiota. This study was aimed to compare the modulation of various flavonoids, including quercetin, catechin and puerarin, on gut microbiota culture in vitro, and analyze the interactions between bacterial species using fructo-oligosaccharide (FOS) as carbon source under the stress of flavonoids. Three plant flavonoids, quercetin, catechin, and puerarin, were added into multispecies culture to ferment for 24 h, respectively. The bacterial 16S rDNA amplicons were sequenced, and the composition of microbiota community was analyzed. The results revealed that the tested flavonoids, quercetin, catechin, and puerarin, presented different activities of regulating gut microbiota; flavonoid aglycones, but not glycosides, may inhibit growth of certain species. Quercetin and catechin shaped unique biological webs. Bifidobacterium spp. was the center of the biological web constructed in this study. PMID- 27472308 TI - Capsaicin: From Plants to a Cancer-Suppressing Agent. AB - Capsaicinoids are plant secondary metabolites, capsaicin being the principal responsible for the pungency of chili peppers. It is biosynthesized through two pathways involved in phenylpropanoid and fatty acid metabolism. Plant capsaicin concentration is mainly affected by genetic, environmental and crop management factors. However, its synthesis can be enhanced by the use of elicitors. Capsaicin is employed as food additive and in pharmaceutical applications. Additionally, it has been found that capsaicin can act as a cancer preventive agent and shows wide applications against various types of cancer. This review is an approach in contextualizing the use of controlled stress on the plant to increase the content of capsaicin, highlighting its synthesis and its potential use as anticancer agent. PMID- 27472310 TI - Green Tea Leaves Extract: Microencapsulation, Physicochemical and Storage Stability Study. AB - Green tea polyphenols have been reported to possess many biological properties. Despite the many potential benefits of green tea extracts, their sensitivity to high temperature, pH and oxygen is a major disadvantage hindering their effective utilization in the food industry. Green tea leaves from the Cameron Highlands Malaysia were extracted using supercritical fluid extraction (SFE). To improve the stability, green tea extracts were encapsulated by spray-drying using different carrier materials including maltodextrin (MD), gum arabic (GA) and chitosan (CTS) and their combinations at different ratios. Encapsulation efficiency, total phenolic content and antioxidant capacity were determined and were found to be in the range of 71.41%-88.04%, 19.32-24.90 (g GAE/100 g), and 29.52%-38.05% respectively. Further analysis of moisture content, water activity, hygroscopicity, bulk density and mean particles size distribution of the microparticles were carried out and the results ranged from; 2.31%-5.11%, 0.28 0.36, 3.22%-4.71%, 0.22-0.28 g/cm3 and 40.43-225.64 um respectively. The ability of the microparticles to swell in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) was determined as 142.00%-188.63% and 207.55%-231.77%, respectively. Release of catechin polyphenol from microparticles in SIF was higher comparable to that of SGF. Storage stability of encapsulated catechin extracts under different temperature conditions was remarkably improved compared to non-encapsulated extract powder. This study showed that total catechin, total phenolic content (TPC) and antioxidant activity did not decrease significantly (p >= 0.05) under 4 degrees C storage conditions. The half-life study results were in the range of 35-60, 34-65 and 231-288 weeks at storage temperatures of 40 degrees C, 25 degrees C and 4 degrees C respectively, therefore, for improved shelf-life stability we recommend that microparticles should be stored at temperatures below 25 degrees C. PMID- 27472309 TI - Immobilization of Chlamydomonas reinhardtii CLH1 on APTES-Coated Magnetic Iron Oxide Nanoparticles and Its Potential in the Production of Chlorophyll Derivatives. AB - Recombinant Chlamydomonas reinhardtii chlorophyllase 1 (CrCLH1) that could catalyze chlorophyll hydrolysis to chlorophyllide and phytol in vitro was successfully expressed in Escherichia coli. The recombinant CrCLH1 was immobilized through covalent binding with a cubic (3-aminopropyl) triethoxysilane (APTES) coating on magnetic iron oxide nanoparticles (MIONPs), which led to markedly improved enzyme performance and decreased biocatalyst costs for potential industrial application. The immobilized enzyme exhibited a high immobilization yield (98.99 +/- 0.91 mg/g of gel) and a chlorophyllase assay confirmed that the immobilized recombinant CrCLH1 retained enzymatic activity (722.3 +/- 50.3 U/g of gel). Biochemical analysis of the immobilized enzyme, compared with the free enzyme, showed higher optimal pH and pH stability for chlorophyll-a hydrolysis in an acidic environment (pH 3-5). In addition, compared with the free enzyme, the immobilized enzyme showed higher activity in chlorophyll-a hydrolysis in a high temperature environment (50-60 degrees C). Moreover, the immobilized enzyme retained a residual activity of more than 64% of its initial enzyme activity after 14 cycles in a repeated-batch operation. Therefore, APTES-coated MIONP-immobilized recombinant CrCLH1 can be repeatedly used to lower costs and is potentially useful for the industrial production of chlorophyll derivatives. PMID- 27472311 TI - Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. AB - Methylxanthines are a group of phytochemicals derived from the purine base xanthine and obtained from plant secondary metabolism. They are unobtrusively included in daily diet in common products as coffee, tea, energetic drinks, or chocolate. Caffeine is by far the most studied methylxanthine either in animal or epidemiologic studies. Theophylline and theobromine are other relevant methylxanthines also commonly available in the aforementioned sources. There are many disseminated myths about methylxanthines but there is increased scientific knowledge to discuss all the controversy and promise shown by these intriguing phytochemicals. In fact, many beneficial physiologic outcomes have been suggested for methylxanthines in areas as important and diverse as neurodegenerative and respiratory diseases, diabetes or cancer. However, there have always been toxicity concerns with methylxanthine (over)consumption and pharmacologic applications. Herein, we explore the structure-bioactivity relationships to bring light those enumerated effects. The potential shown by methylxanthines in such a wide range of conditions should substantiate many other scientific endeavors that may highlight their adequacy as adjuvant therapy agents and may contribute to the advent of functional foods. Newly designed targeted molecules based on methylxanthine structure may originate more specific and effective outcomes. PMID- 27472312 TI - Efficient Double Suzuki Cross-Coupling Reactions of 2,5-Dibromo-3-hexylthiophene: Anti-Tumor, Haemolytic, Anti-Thrombolytic and Biofilm Inhibition Studies. AB - The present study describes several novel 2,5-biaryl-3-hexylthiophene derivatives (3a-i) synthesized via a Pd(0)-catalyzed Suzuki cross-coupling reaction in moderate to good yields. The novel compounds were also analyzed for their anti thrombolytic, haemolytic, and biofilm inhibition activities. In addition, the anti-tumor activity was also evaluated in vitro for newly-synthesized compounds, where 3-hexyl-2,5-bis(4-(methylthio)phenyl)thiophene exhibited the best anti tumor activity against 4T1 cells with IC50 value of 16 MUM. Moreover, 2,5-bis(4 methylphenyl)-3-hexylthiophene showed the highest activity against MCF-7 cells with an IC50 value of 26.2 MUM. On the other hand, the compound 2,5-bis(4 chloropheny)-3-hexylthiophene exhibited excellent biofilm inhibition activity. Furthermore, the compound 2,5-bis(3-chloro-4-fluorophenyl)-3-hexylthiophene also exhibited better anti-thrombolytic and hemolytic activity results as compared to the other newly-synthesized compounds. PMID- 27472313 TI - Corynoline Isolated from Corydalis bungeana Turcz. Exhibits Anti-Inflammatory Effects via Modulation of Nfr2 and MAPKs. AB - Corydalis bungeana Turcz. is an anti-inflammatory medicinal herb used widely in traditional Chinese medicine for upper respiratory tract infections. It is demonstrated that corynoline is its active anti-inflammatory component. The nuclear factor-erythroid-2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and the mitogen-activated protein kinase (MAPK) pathway play important roles in the regulation of inflammation. In this study, we investigated the potential anti-inflammatory mechanism of corynoline through modulation of Nfr2 and MAPKs. Lipopolysaccharide (LPS)-activated RAW264.7 cells were used to explore modulatory role of NO production and the activation of signaling proteins and transcription factors using nitrite assay, Western bloting and qPCR. Treatment with corynoline reduced production of nitric oxide (NO) and the protein and mRNA levels of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) Treatment also significantly increased the expression of Nrf2, quinone oxidoreductase 1 (NQO1) and hemeoxygenase-1 (HO-1) at the mRNA and protein levels, which demonstrated that corynoline may protect cells from inflammation through the Nrf2/ARE pathway In addition, corynoline suppressed the expression of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), at the mRNA and protein levels. Furthermore, molecular data revealed that corynoline inhibited lipopolysaccharide-stimulated phosphorylation of c-jun NH2-terminal kinase (JNK) and p38. Taken together, these results suggest that corynoline reduces the levels of pro-inflammatory mediators, such as iNOS, COX-2, TNF-alpha and IL-1beta, by suppressing extracellular signal regulated kinase 1/2 (ERK) and p38 phosphorylation in RAW264.7 cells, which is regulated by the Nrf2/ARE pathway. These findings reveal part of the molecular basis for the anti-inflammatory properties of corynoline. PMID- 27472314 TI - Hybrid Molecules Containing a 7-Chloro-4-aminoquinoline Nucleus and a Substituted 2-Pyrazoline with Antiproliferative and Antifungal Activity. AB - Twenty-four new hybrid analogues (15-38) containing 7-chloro-4-aminoquinoline and 2-pyrazoline N-heterocyclic fragments were synthesized. Twelve of the new compounds were evaluated against 58 human cancer cell lines by the U.S. National Cancer Institute (NCI). Compounds 25, 30, 31, 36, and 37 showed significant cytostatic activity, with the most outstanding GI50 values ranging from 0.05 to 0.95 uM. The hybrid compounds (15-38) were also evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. From the obtained results some structure-activity relationships were outlined. PMID- 27472315 TI - Inhibitory Effect of Camptothecin against Rice Bacterial Brown Stripe Pathogen Acidovorax avenae subsp. avenae RS-2. AB - Camptothecin (CPT) has anticancer, antiviral, and antifungal properties. However, there is a dearth of information about antibacterial activity of CPT. Therefore, in this study, we investigated the inhibitory effect of CPT on Acidovorax avenae subsp. avenae strain RS-2, the pathogen of rice bacterial brown stripe, by measuring cell growth, DNA damage, cell membrane integrity, the expression of secretion systems, and topoisomerase-related genes, as well as the secretion of effector protein Hcp. Results indicated that CPT solutions at 0.05, 0.25, and 0.50 mg/mL inhibited the growth of strain RS-2 in vitro, while the inhibitory efficiency increased with an increase in CPT concentration, pH, and incubation time. Furthermore, CPT treatment affected bacterial growth and replication by causing membrane damage, which was evidenced by transmission electron microscopic observation and live/dead cell staining. In addition, quantitative real-time PCR analysis indicated that CPT treatment caused differential expression of eight secretion system-related genes and one topoisomerase-related gene, while the up regulated expression of hcp could be justified by the increased secretion of Hcp based on the ELISA test. Overall, this study indicated that CPT has the potential to control the bacterial brown stripe pathogen of rice. PMID- 27472316 TI - Genome-Wide Identification and Expression Analysis of Two-Component System Genes in Tomato. AB - The two-component system (TCS), which comprises histidine kinases (HKs), phosphotransfers (HPs), and response regulator proteins (RRs), plays pivotal roles in regulating plant growth, development, and responses to biotic and abiotic stresses. TCS genes have been comprehensively identified and investigated in various crops but poorly characterized in tomato. In this work, a total of 65 TCS genes consisting of 20 HK(L)s, six HPs, and 39 RRs were identified from tomato genome. The classification, gene structures, conserved domains, chromosome distribution, phylogenetic relationship, gene duplication events, and subcellular localization of the TCS gene family were predicted and analyzed in detail. The amino acid sequences of tomato TCS family members, except those of type-B RRs, are highly conserved. The gene duplication events of the TCS family mainly occurred in the RR family. Furthermore, the expansion of RRs was attributed to both segment and tandem duplication. The subcellular localizations of the selected green fluorescent protein (GFP) fusion proteins exhibited a diverse subcellular targeting, thereby confirming their predicted divergent functionality. The majority of TCS family members showed distinct organ- or development-specific expression patterns. In addition, most of TCS genes were induced by abiotic stresses and exogenous phytohormones. The full elucidation of TCS elements will be helpful for comprehensive analysis of the molecular biology and physiological role of the TCS superfamily. PMID- 27472317 TI - Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure. AB - The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) kappa opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs. PMID- 27472318 TI - Chicken-Specific Kinome Array Reveals that Salmonella enterica Serovar Enteritidis Modulates Host Immune Signaling Pathways in the Cecum to Establish a Persistence Infection. AB - Non-typhoidal Salmonella enterica induces an early, short-lived pro-inflammatory response in chickens that is asymptomatic of clinical disease and results in a persistent colonization of the gastrointestinal (GI) tract that transmits infections to naive hosts via fecal shedding of bacteria. The underlying mechanisms that control this persistent colonization of the ceca of chickens by Salmonella are only beginning to be elucidated. We hypothesize that alteration of host signaling pathways mediate the induction of a tolerance response. Using chicken-specific kinomic immune peptide arrays and quantitative RT-PCR of infected cecal tissue, we have previously evaluated the development of disease tolerance in chickens infected with Salmonella enterica serovar Enteritidis (S. Enteritidis) in a persistent infection model (4-14 days post infection). Here, we have further outlined the induction of an tolerance defense strategy in the cecum of chickens infected with S. Enteritidis beginning around four days post-primary infection. The response is characterized by alterations in the activation of T cell signaling mediated by the dephosphorylation of phospholipase c-gamma1 (PLCG1) that inhibits NF-kappaB signaling and activates nuclear factor of activated T-cells (NFAT) signaling and blockage of interferon-gamma (IFN-gamma) production through the disruption of the JAK-STAT signaling pathway (dephosphorylation of JAK2, JAK3, and STAT4). Further, we measured a significant down-regulation reduction in IFN-gamma mRNA expression. These studies, combined with our previous findings, describe global phenotypic changes in the avian cecum of Salmonella Enteritidis-infected chickens that decreases the host responsiveness resulting in the establishment of persistent colonization. The identified tissue protein kinases also represent potential targets for future antimicrobial compounds for decreasing Salmonella loads in the intestines of food animals before going to market. PMID- 27472319 TI - Liposomes Loaded with Hydrophobic Iron Oxide Nanoparticles: Suitable T2 Contrast Agents for MRI. AB - There has been a recent surge of interest in the use of superparamagnetic iron oxide nanoparticles (SPIONs) as contrast agents (CAs) for magnetic resonance imaging (MRI), due to their tunable properties and their low toxicity compared with other CAs such as gadolinium. SPIONs exert a strong influence on spin-spin T2 relaxation times by decreasing the MR signal in the regions to which they are delivered, consequently yielding darker images or negative contrast. Given the potential of these nanoparticles to enhance detection of alterations in soft tissues, we studied the MRI response of hydrophobic or hydrophilic SPIONs loaded into liposomes (magnetoliposomes) of different lipid composition obtained by sonication. These hybrid nanostructures were characterized by measuring several parameters such as size and polydispersity, and number of SPIONs encapsulated or embedded into the lipid systems. We then studied the influence of acyl chain length as well as its unsaturation, charge, and presence of cholesterol in the lipid bilayer at high field strength (7 T) to mimic the conditions used in preclinical assays. Our results showed a high variability depending on the nature of the magnetic particles. Focusing on the hydrophobic SPIONs, the cholesterol containing samples showed a slight reduction in r2, while unsaturation of the lipid acyl chain and inclusion of a negatively charged lipid into the bilayer appeared to yield a marked increase in negative contrast, thus rendering these magnetoliposomes suitable candidates as CAs, especially as a liver CA. PMID- 27472322 TI - Characterization and Discrimination of Ancient Grains: A Metabolomics Approach. AB - Hulled, or ancient, wheats were the earliest domesticated wheats by mankind and the ancestors of current wheats. Their cultivation drastically decreased during the 1960s; however, the increasing demand for a healthy and equilibrated diet led to rediscovering these grains. Our aim was to use a non-targeted metabolomic approach to discriminate and characterize similarities and differences between ancient Triticum varieties. For this purpose, 77 hulled wheat samples from three different varieties were collected: Garfagnana T. turgidum var. dicoccum L. (emmer), ID331 T. monococcum L. (einkorn) and Rouquin T. spelta L. (spelt). The ultra high performance liquid chromatography coupled to high resolution tandem mass spectrometry (UHPLC-QTOF) metabolomics approach highlighted a pronounced sample clustering according to the wheat variety, with an excellent predictability (Q2), for all the models built. Fifteen metabolites were tentatively identified based on accurate masses, isotopic pattern, and product ion spectra. Among these, alkylresorcinols (ARs) were found to be significantly higher in spelt and emmer, showing different homologue composition. Furthermore, phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPC) levels were higher in einkorn variety. The results obtained in this study confirmed the importance of ARs as markers to distinguish between Triticum species and revealed their values as cultivar markers, being not affected by the environmental influences. PMID- 27472320 TI - Aquaporins in Health and Disease: An Overview Focusing on the Gut of Different Species. AB - Aquaporins (AQPs) play a pivotal role in gut homeostasis since their distribution and function is modulated both in physiological and in pathophysiological conditions. The transport of water and solutes through gut epithelia is essential for osmoregulation and digestive and absorptive functions. This passage is regulated by different AQP isoforms and characterized by their peculiar distribution in the gastrointestinal tract. To date, AQP localization has been identified in the gut and associated organs of several mammalian species by different techniques (immunohistochemical, western blotting, and RT-PCR). The present review describes the modulation of AQP expression, distribution, and function in gut pathophysiology. At the same time, the comparative description of AQP in animal species sheds light on the full range of AQP functions and the screening of their activity as transport modulators, diagnostic biomarkers, and drug targets. Moreover, the phenotype of knockout mice for several AQPs and their compensatory role and the use of specific AQP inhibitors have been also reviewed. The reported data could be useful to design future research in both basic and clinical fields. PMID- 27472321 TI - Design of Phosphonated Imidazolium-Based Ionic Liquids Grafted on gamma-Alumina: Potential Model for Hybrid Membranes. AB - Imidazolium bromide-based ionic liquids bearing phosphonyl groups on the cationic part were synthesized and grafted on gamma-alumina (gamma-Al2O3) powders. These powders were prepared as companion samples of conventional mesoporous gamma alumina membranes, in order to favor a possible transfer of the results to supported membrane materials, which could be used for CO2 separation applications. Effective grafting was demonstrated using energy dispersive X-ray spectrometry (EDX), N2 adsorption measurements, fourier transform infrared spectroscopy (FTIR), and special attention was paid to (31)P and (13)C solid state nuclear magnetic resonance spectroscopy (NMR). PMID- 27472323 TI - Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy. AB - Acute generalized exanthematous pustulosis (AGEP) is a severe, usually drug related reaction, characterized by an acute onset of mainly small non-follicular pustules on an erythematous base and spontaneous resolution usually within two weeks. Systemic involvement occurs in about 20% of cases. The course is mostly benign, and only in rare cases complications lead to life-threatening situations. Recent studies highlight the importance of genetic variations in interleukin-36 receptor antagonist gene (IL-36RN) in the pathogenesis of this disease. The physiopathology of AGEP remains unclear, but an involvement of innate and acquired immune cells together with resident cells (keratinocytes), which recruit and activate neutrophils via production of cytokines/chemokines such as IL-17, IL 36, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFalpha) and chemokine (C-X-C motif) ligand 8 (CXCL8)/IL-8, has been postulated. Treatment is based on the removal of the causative drug, supportive care, infection prevention and use of potent topical or systemic steroids. PMID- 27472324 TI - Glutathione Transferases Superfamily: Cold-Inducible Expression of Distinct GST Genes in Brassica oleracea. AB - Plants, as sessile organisms, can suffer serious growth and developmental consequences under cold stress conditions. Glutathione transferases (GSTs, EC 2.5.1.18) are ubiquitous and multifunctional conjugating proteins, which play a major role in stress responses by preventing oxidative damage by reactive oxygen species (ROS). Currently, understanding of their function(s) during different biochemical and signaling pathways under cold stress condition remain unclear. In this study, using combined computational strategy, we identified 65 Brassica oleracea glutathione transferases (BoGST) and characterized them based on evolutionary analysis into 11 classes. Inter-species and intra-species duplication was evident between BoGSTs and Arabidopsis GSTs. Based on localization analyses, we propose possible pathways in which GST genes are involved during cold stress. Further, expression analysis of the predicted putative functions for GST genes were investigated in two cold contrasting genotypes (cold tolerance and susceptible) under cold condition, most of these genes were highly expressed at 6 h and 1 h in the cold tolerant (CT) and cold susceptible (CS) lines, respectively. Overall, BoGSTU19, BoGSTU24, BoGSTF10 are candidate genes highly expressed in B. oleracea. Further investigation of GST superfamily in B. oleracea will aid in understanding complex mechanism underlying cold tolerance in plants. PMID- 27472326 TI - The Impact of Nonalcoholic Fatty Liver Disease on Renal Function in Children with Overweight/Obesity. AB - The association between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease has attracted interest and attention over recent years. However, no data are available in children. We determined whether children with NAFLD show signs of renal functional alterations, as determined by estimated glomerular filtration rate (eGFR) and urinary albumin excretion. We studied 596 children with overweight/obesity, 268 with NAFLD (hepatic fat fraction >=5% on magnetic resonance imaging) and 328 without NAFLD, and 130 healthy normal-weight controls. Decreased GFR was defined as eGFR < 90 mL/min/1.73 m2. Abnormal albuminuria was defined as urinary excretion of >=30 mg/24 h of albumin. A greater prevalence of eGFR < 90 mL/min/1.73 m2 was observed in patients with NAFLD compared to those without liver involvement and healthy subjects (17.5% vs. 6.7% vs. 0.77%; p < 0.0001). The proportion of children with abnormal albuminuria was also higher in the NAFLD group compared to those without NAFLD, and controls (9.3% vs. 4.0% vs. 0; p < 0.0001). Multivariate logistic regression analysis revealed that NAFLD was associated with decreased eGFR and/or microalbuminuria (odds ratio, 2.54 (confidence interval, 1.16-5.57); p < 0.05) independently of anthropometric and clinical variables. Children with NAFLD are at risk for early renal dysfunction. Recognition of this abnormality in the young may help to prevent the ongoing development of the disease. PMID- 27472325 TI - One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling. AB - Cancer cell metabolism differs significantly from the metabolism of non transformed cells. This altered metabolic reprogramming mediates changes in the uptake and use of nutrients that permit high rates of proliferation, growth, and survival. The androgen receptor (AR) plays an essential role in the establishment and progression of prostate cancer (PCa), and in the metabolic adaptation that takes place during this progression. In its role as a transcription factor, the AR directly affects the expression of several effectors and regulators of essential catabolic and biosynthetic pathways. Indirectly, as a modulator of the one-carbon metabolism, the AR can affect epigenetic processes, DNA metabolism, and redox balance, all of which are important factors in tumorigenesis. In this review, we focus on the role of AR-signaling on one-carbon metabolism in tumorigenesis. Clinical implications of one-carbon metabolism and AR-targeted therapies for PCa are discussed in this context. PMID- 27472327 TI - A Machine Learning Approach for Hot-Spot Detection at Protein-Protein Interfaces. AB - Understanding protein-protein interactions is a key challenge in biochemistry. In this work, we describe a more accurate methodology to predict Hot-Spots (HS) in protein-protein interfaces from their native complex structure compared to previous published Machine Learning (ML) techniques. Our model is trained on a large number of complexes and on a significantly larger number of different structural- and evolutionary sequence-based features. In particular, we added interface size, type of interaction between residues at the interface of the complex, number of different types of residues at the interface and the Position Specific Scoring Matrix (PSSM), for a total of 79 features. We used twenty-seven algorithms from a simple linear-based function to support-vector machine models with different cost functions. The best model was achieved by the use of the conditional inference random forest (c-forest) algorithm with a dataset pre processed by the normalization of features and with up-sampling of the minor class. The method has an overall accuracy of 0.80, an F1-score of 0.73, a sensitivity of 0.76 and a specificity of 0.82 for the independent test set. PMID- 27472328 TI - Stage-Related Defense Response Induction in Tomato Plants by Nesidiocoris tenuis. AB - The beneficial effects of direct predation by zoophytophagous biological control agents (BCAs), such as the mirid bug Nesidiocoris tenuis, are well-known. However, the benefits of zoophytophagous BCAs' relation with host plants, via induction of plant defensive responses, have not been investigated until recently. To date, only the females of certain zoophytophagous BCAs have been demonstrated to induce defensive plant responses in tomato plants. The aim of this work was to determine whether nymphs, adult females, and adult males of N. tenuis are able to induce defense responses in tomato plants. Compared to undamaged tomato plants (i.e., not exposed to the mirid), plants on which young or mature nymphs, or adult males or females of N. tenuis fed and developed were less attractive to the whitefly Bemisia tabaci, but were more attractive to the parasitoid Encarsia formosa. Female-exposed plants were more repellent to B. tabaci and more attractive to E. formosa than were male-exposed plants. When comparing young- and mature-nymph-exposed plants, the same level of repellence was obtained for B. tabaci, but mature-nymph-exposed plants were more attractive to E. formosa. The repellent effect is attributed to the signaling pathway of abscisic acid, which is upregulated in N. tenuis-exposed plants, whereas the parasitoid attraction was attributed to the activation of the jasmonic acid signaling pathway. Our results demonstrate that all motile stages of N. tenuis can trigger defensive responses in tomato plants, although these responses may be slightly different depending on the stage considered. PMID- 27472329 TI - Substrate and Passivation Techniques for Flexible Amorphous Silicon-Based X-ray Detectors. AB - Flexible active matrix display technology has been adapted to create new flexible photo-sensing electronic devices, including flexible X-ray detectors. Monolithic integration of amorphous silicon (a-Si) PIN photodiodes on a flexible substrate poses significant challenges associated with the intrinsic film stress of amorphous silicon. This paper examines how altering device structuring and diode passivation layers can greatly improve the electrical performance and the mechanical reliability of the device, thereby eliminating one of the major weaknesses of a-Si PIN diodes in comparison to alternative photodetector technology, such as organic bulk heterojunction photodiodes and amorphous selenium. A dark current of 0.5 pA/mm2 and photodiode quantum efficiency of 74% are possible with a pixelated diode structure with a silicon nitride/SU-8 bilayer passivation structure on a 20 um-thick polyimide substrate. PMID- 27472330 TI - Short-Range Noncontact Sensors for Healthcare and Other Emerging Applications: A Review. AB - Short-range noncontact sensors are capable of remotely detecting the precise movements of the subjects or wirelessly estimating the distance from the sensor to the subject. They find wide applications in our day lives such as noncontact vital sign detection of heart beat and respiration, sleep monitoring, occupancy sensing, and gesture sensing. In recent years, short-range noncontact sensors are attracting more and more efforts from both academia and industry due to their vast applications. Compared to other radar architectures such as pulse radar and frequency-modulated continuous-wave (FMCW) radar, Doppler radar is gaining more popularity in terms of system integration and low-power operation. This paper reviews the recent technical advances in Doppler radars for healthcare applications, including system hardware improvement, digital signal processing, and chip integration. This paper also discusses the hybrid FMCW-interferometry radars and the emerging applications and the future trends. PMID- 27472331 TI - Design of a New Built-in UHF Multi-Frequency Antenna Sensor for Partial Discharge Detection in High-Voltage Switchgears. AB - In this study a new built-in ultrahigh frequency (UHF) antenna sensor was designed and applied in a high-voltage switchgear for partial discharge (PD) detection. The casing of the switchgear was initially used as the ground plane of the antenna sensor, which integrated the sensor into the high-voltage switchgear. The Koch snowflake patch was adopted as the radiation patch of the antenna to overcome the disadvantages of common microstrip antennas, and the feed position and the dielectric layer thickness were simulated in detail. Simulation results show that the antenna sensor possessed four resonant points with good impedance matching from 300 MHz to 1000 MHz, and it also presented good multi-frequency performance in the entire working frequency band. PD detection experiments were conducted in the high-voltage switchgear, and the fabricated antenna sensor was effectively built into the high-voltage switchgear. In order to reflect the advantages of the built-in antenna sensor, another external UHF antenna sensor was used as a comparison to simultaneously detect PD. Experimental results demonstrated that the built-in antenna sensor possessed high detection sensitivity and strong anti-interference capacity, which ensured the practicability of the design. In addition, it had more high-voltage switchgear PD detection advantages than the external sensor. PMID- 27472332 TI - A Spray-On Carbon Nanotube Artificial Neuron Strain Sensor for Composite Structural Health Monitoring. AB - We present a nanocomposite strain sensor (NCSS) to develop a novel structural health monitoring (SHM) sensor that can be easily installed in a composite structure. An NCSS made of a multi-walled carbon nanotubes (MWCNT)/epoxy composite was installed on a target structure with facile processing. We attempted to evaluate the NCSS sensing characteristics and benchmark compared to those of a conventional foil strain gauge. The response of the NCSS was fairly good and the result was nearly identical to the strain gauge. A neuron, which is a biomimetic long continuous NCSS, was also developed, and its vibration response was investigated for structural damage detection of a composite cantilever. The vibration response for damage detection was measured by tracking the first natural frequency, which demonstrated good result that matched the finite element (FE) analysis. PMID- 27472333 TI - Computing the Deflection of the Vertical for Improving Aerial Surveys: A Comparison between EGM2008 and ITALGEO05 Estimates. AB - Recent studies on the influence of the anomalous gravity field in GNSS/INS applications have shown that neglecting the impact of the deflection of vertical in aerial surveys induces horizontal and vertical errors in the measurement of an object that is part of the observed scene; these errors can vary from a few tens of centimetres to over one meter. The works reported in the literature refer to vertical deflection values based on global geopotential model estimates. In this paper we compared this approach with the one based on local gravity data and collocation methods. In particular, denoted by xi and eta, the two mutually perpendicular components of the deflection of the vertical vector (in the north and east directions, respectively), their values were computed by collocation in the framework of the Remove-Compute-Restore technique, applied to the gravity database used for estimating the ITALGEO05 geoid. Following this approach, these values have been computed at different altitudes that are relevant in aerial surveys. The (xi, eta) values were then also estimated using the high degree EGM2008 global geopotential model and compared with those obtained in the previous computation. The analysis of the differences between the two estimates has shown that the (xi, eta) global geopotential model estimate can be reliably used in aerial navigation applications that require the use of sensors connected to a GNSS/INS system only above a given height (e.g., 3000 m in this paper) that must be defined by simulations. PMID- 27472335 TI - Recent Progress on Cellulose-Based Electro-Active Paper, Its Hybrid Nanocomposites and Applications. AB - We report on the recent progress and development of research into cellulose-based electro-active paper for bending actuators, bioelectronics devices, and electromechanical transducers. The cellulose electro-active paper is characterized in terms of its biodegradability, chirality, ample chemically modifying capacity, light weight, actuation capability, and ability to form hybrid nanocomposites. The mechanical, electrical, and chemical characterizations of the cellulose-based electro-active paper and its hybrid composites such as blends or coatings with synthetic polymers, biopolymers, carbon nanotubes, chitosan, and metal oxides, are explained. In addition, the integration of cellulose electro-active paper is highlighted to form various functional devices including but not limited to bending actuators, flexible speaker, strain sensors, energy harvesting transducers, biosensors, chemical sensors and transistors for electronic applications. The frontiers in cellulose paper devices are reviewed together with the strategies and perspectives of cellulose electro-active paper and cellulose nanocomposite research and applications. PMID- 27472336 TI - Fuzzy Adaptive Cubature Kalman Filter for Integrated Navigation Systems. AB - This paper presents a sensor fusion method based on the combination of cubature Kalman filter (CKF) and fuzzy logic adaptive system (FLAS) for the integrated navigation systems, such as the GPS/INS (Global Positioning System/inertial navigation system) integration. The third-degree spherical-radial cubature rule applied in the CKF has been employed to avoid the numerically instability in the system model. In processing navigation integration, the performance of nonlinear filter based estimation of the position and velocity states may severely degrade caused by modeling errors due to dynamics uncertainties of the vehicle. In order to resolve the shortcoming for selecting the process noise covariance through personal experience or numerical simulation, a scheme called the fuzzy adaptive cubature Kalman filter (FACKF) is presented by introducing the FLAS to adjust the weighting factor of the process noise covariance matrix. The FLAS is incorporated into the CKF framework as a mechanism for timely implementing the tuning of process noise covariance matrix based on the information of degree of divergence (DOD) parameter. The proposed FACKF algorithm shows promising accuracy improvement as compared to the extended Kalman filter (EKF), unscented Kalman filter (UKF), and CKF approaches. PMID- 27472334 TI - Distributed Fiber-Optic Sensors for Vibration Detection. AB - Distributed fiber-optic vibration sensors receive extensive investigation and play a significant role in the sensor panorama. Optical parameters such as light intensity, phase, polarization state, or light frequency will change when external vibration is applied on the sensing fiber. In this paper, various technologies of distributed fiber-optic vibration sensing are reviewed, from interferometric sensing technology, such as Sagnac, Mach-Zehnder, and Michelson, to backscattering-based sensing technology, such as phase-sensitive optical time domain reflectometer, polarization-optical time domain reflectometer, optical frequency domain reflectometer, as well as some combinations of interferometric and backscattering-based techniques. Their operation principles are presented and recent research efforts are also included. Finally, the applications of distributed fiber-optic vibration sensors are summarized, which mainly include structural health monitoring and perimeter security, etc. Overall, distributed fiber-optic vibration sensors possess the advantages of large-scale monitoring, good concealment, excellent flexibility, and immunity to electromagnetic interference, and thus show considerable potential for a variety of practical applications. PMID- 27472337 TI - Autonomous Underwater Navigation and Optical Mapping in Unknown Natural Environments. AB - We present an approach for navigating in unknown environments while, simultaneously, gathering information for inspecting underwater structures using an autonomous underwater vehicle (AUV). To accomplish this, we first use our pipeline for mapping and planning collision-free paths online, which endows an AUV with the capability to autonomously acquire optical data in close proximity. With that information, we then propose a reconstruction pipeline to create a photo-realistic textured 3D model of the inspected area. These 3D models are also of particular interest to other fields of study in marine sciences, since they can serve as base maps for environmental monitoring, thus allowing change detection of biological communities and their environment over time. Finally, we evaluate our approach using the Sparus II, a torpedo-shaped AUV, conducting inspection missions in a challenging, real-world and natural scenario. PMID- 27472338 TI - Robust Decentralized Nonlinear Control for a Twin Rotor MIMO System. AB - This article presents the design of a novel decentralized nonlinear multivariate control scheme for an underactuated, nonlinear and multivariate laboratory helicopter denominated the twin rotor MIMO system (TRMS). The TRMS is characterized by a coupling effect between rotor dynamics and the body of the model, which is due to the action-reaction principle originated in the acceleration and deceleration of the motor-propeller groups. The proposed controller is composed of two nested loops that are utilized to achieve stabilization and precise trajectory tracking tasks for the controlled position of the generalized coordinates of the TRMS. The nonlinear internal loop is used to control the electrical dynamics of the platform, and the nonlinear external loop allows the platform to be perfectly stabilized and positioned in space. Finally, we illustrate the theoretical control developments with a set of experiments in order to verify the effectiveness of the proposed nonlinear decentralized feedback controller, in which a comparative study with other controllers is performed, illustrating the excellent performance of the proposed robust decentralized control scheme in both stabilization and trajectory tracking tasks. PMID- 27472339 TI - High-Accuracy Self-Calibration for Smart, Optical Orbiting Payloads Integrated with Attitude and Position Determination. AB - A high-accuracy space smart payload integrated with attitude and position (SSPIAP) is a new type of optical remote sensor that can autonomously complete image positioning. Inner orientation parameters (IOPs) are a prerequisite for image position determination of an SSPIAP. The calibration of IOPs significantly influences the precision of image position determination of SSPIAPs. IOPs can be precisely measured and calibrated in a laboratory. However, they may drift to a significant degree because of vibrations during complicated launches and on-orbit functioning. Therefore, laboratory calibration methods are not suitable for on orbit functioning. We propose an on-orbit self-calibration method for SSPIAPs. Our method is based on an auto-collimating dichroic filter combined with a micro electro-mechanical system (MEMS) point-source focal plane. A MEMS procedure is used to manufacture a light transceiver focal plane, which integrates with point light sources and a complementary metal oxide semiconductor (CMOS) sensor. A dichroic filter is used to fabricate an auto-collimation light reflection element. The dichroic filter and the MEMS point light sources focal plane are integrated into an SSPIAP so it can perform integrated self-calibration. Experiments show that our method can achieve micrometer-level precision, which is good enough to complete real-time calibration without temporal or spatial limitations. PMID- 27472341 TI - Near-Space TOPSAR Large-Scene Full-Aperture Imaging Scheme Based on Two-Step Processing. AB - Free of the constraints of orbit mechanisms, weather conditions and minimum antenna area, synthetic aperture radar (SAR) equipped on near-space platform is more suitable for sustained large-scene imaging compared with the spaceborne and airborne counterparts. Terrain observation by progressive scans (TOPS), which is a novel wide-swath imaging mode and allows the beam of SAR to scan along the azimuth, can reduce the time of echo acquisition for large scene. Thus, near space TOPS-mode SAR (NS-TOPSAR) provides a new opportunity for sustained large scene imaging. An efficient full-aperture imaging scheme for NS-TOPSAR is proposed in this paper. In this scheme, firstly, two-step processing (TSP) is adopted to eliminate the Doppler aliasing of the echo. Then, the data is focused in two-dimensional frequency domain (FD) based on Stolt interpolation. Finally, a modified TSP (MTSP) is performed to remove the azimuth aliasing. Simulations are presented to demonstrate the validity of the proposed imaging scheme for near space large-scene imaging application. PMID- 27472340 TI - Microfluidic Surface Plasmon Resonance Sensors: From Principles to Point-of-Care Applications. AB - Surface plasmon resonance (SPR) is a label-free, highly-sensitive, and real-time sensing technique. Conventional SPR sensors, which involve a planar thin gold film, have been widely exploited in biosensing; various miniaturized formats have been devised for portability purposes. Another type of SPR sensor which utilizes localized SPR (LSPR), is based on metal nanostructures with surface plasmon modes at the structural interface. The resonance condition is sensitive to the refractive index change of the local medium. The principles of these two types of SPR sensors are reviewed and their integration with microfluidic platforms is described. Further applications of microfluidic SPR sensors to point-of-care (POC) diagnostics are discussed. PMID- 27472342 TI - All-Fiber Configuration Laser Self-Mixing Doppler Velocimeter Based on Distributed Feedback Fiber Laser. AB - In this paper, a novel velocimeter based on laser self-mixing Doppler technology has been developed for speed measurement. The laser employed in our experiment is a distributed feedback (DFB) fiber laser, which is an all-fiber structure using only one Fiber Bragg Grating to realize optical feedback and wavelength selection. Self-mixing interference for optical velocity sensing is experimentally investigated in this novel system, and the experimental results show that the Doppler frequency is linearly proportional to the velocity of a moving target, which agrees with the theoretical analysis commendably. In our experimental system, the velocity measurement can be achieved in the range of 3.58 mm/s-2216 mm/s with a relative error under one percent, demonstrating that our novel all-fiber configuration velocimeter can implement wide-range velocity measurements with high accuracy. PMID- 27472343 TI - Defect Detection in Textures through the Use of Entropy as a Means for Automatically Selecting the Wavelet Decomposition Level. AB - This paper presents a robust method for defect detection in textures, entropy based automatic selection of the wavelet decomposition level (EADL), based on a wavelet reconstruction scheme, for detecting defects in a wide variety of structural and statistical textures. Two main features are presented. One of the new features is an original use of the normalized absolute function value (NABS) calculated from the wavelet coefficients derived at various different decomposition levels in order to identify textures where the defect can be isolated by eliminating the texture pattern in the first decomposition level. The second is the use of Shannon's entropy, calculated over detail subimages, for automatic selection of the band for image reconstruction, which, unlike other techniques, such as those based on the co-occurrence matrix or on energy calculation, provides a lower decomposition level, thus avoiding excessive degradation of the image, allowing a more accurate defect segmentation. A metric analysis of the results of the proposed method with nine different thresholding algorithms determined that selecting the appropriate thresholding method is important to achieve optimum performance in defect detection. As a consequence, several different thresholding algorithms depending on the type of texture are proposed. PMID- 27472344 TI - Revealing Nucleic Acid Mutations Using Forster Resonance Energy Transfer-Based Probes. AB - Nucleic acid mutations are of tremendous importance in modern clinical work, biotechnology and in fundamental studies of nucleic acids. Therefore, rapid, cost effective and reliable detection of mutations is an object of extensive research. Today, Forster resonance energy transfer (FRET) probes are among the most often used tools for the detection of nucleic acids and in particular, for the detection of mutations. However, multiple parameters must be taken into account in order to create efficient FRET probes that are sensitive to nucleic acid mutations. In this review; we focus on the design principles for such probes and available computational methods that allow for their rational design. Applications of advanced, rationally designed FRET probes range from new insights into cellular heterogeneity to gaining new knowledge of nucleic acid structures directly in living cells. PMID- 27472347 TI - Incorporating Environmental Justice into Second Generation Indices of Multiple Deprivation: Lessons from the UK and Progress Internationally. AB - Second generation area-based indices of multiple deprivation have been extensively used in the UK over the last 15 years. They resulted from significant developments in political, technical, and conceptual spheres for deprivation data. We review the parallel development of environmental justice research and how and when environmental data was incorporated into these indices. We explain the transfer of these methods from the UK to Germany and assess the progress internationally in developing such indices. Finally, we illustrate how billions of pounds in the UK was allocated by using these tools to tackle neighbourhood deprivation and environmental justice to address the determinants of health. PMID- 27472346 TI - Sinularin Induces Apoptosis through Mitochondria Dysfunction and Inactivation of the pI3K/Akt/mTOR Pathway in Gastric Carcinoma Cells. AB - Sinularin is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigated the effects of sinularin on two human gastric cancer cell lines, AGS and NCI-N87. Our results demonstrated that sinularin suppressed the proliferation of gastric cancer cells in a dose dependent manner and induced apoptosis. In addition, the loss of mitochondrial membrane potential, the release of cytochrome C, the activation of Bax, Bad and caspase-3/9, and the suppression of p-Bad, Bcl-xL and Bcl-2 were observed in the cells treated with sinularin. This finding suggests that sinularin-induced apoptosis is associated with mitochondria-mediated apoptosis and occurs through caspase-dependent pathways. Furthermore, sinularin inhibited the phosphoinositol 3-kinase/Akt/mechanistic target of the rapamycin signaling pathway. Taken together, our results show that sinularin-induced apoptosis is mediated by activation of the caspase cascade and mitochondrial dysfunction. Our findings suggest that sinularin merits further evaluation as a chemotherapeutic agent for human gastric cancer. PMID- 27472348 TI - Hot of Not: Physiological versus Meteorological Heatwaves-Support for a Mean Temperature Threshold. AB - The aim of this study was to determine whether a revised heat warning threshold provides an enhanced predictive tool for increases in Emergency Department heat related presentations in Canberra, Australia. All Emergency Department triage records containing the word "heat", as well as those diagnosing a heat related illness for the summer periods 2013/2014, 2014/2015, and 2015/2016 were searched. Then a medical record review was conducted to confirm that the patient's presentation was related to environmental heat, which was defined by the final clinical diagnosis, presentation complaint and details of the patient's treatment. Researchers then compared this presentation data, to a mean threshold formula. The mean threshold formula included the past three consecutive daily mean temperatures and the last measured temperature upon presentation. This formula was designed to take into account the variance of night-time lows, with concurrent daily ambient temperatures, and was used to determine whether there was a correlation between heat-related presentations and increasing mean temperatures. Heat-related presentations appeared to occur when the mean threshold temperature reached 25 degrees C (77 degrees F), with significant increases when the mean threshold reached 30 degrees C (86 degrees F). These results confirm that a mean temperature of 30 degrees C corresponds to a relevant local public health heat-related threat. PMID- 27472345 TI - Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation. AB - Neutrophils are widely recognized to play an important role in acute inflammatory responses, and recent evidence has expanded their role to modulating chronic inflammatory and autoimmune diseases. Reactive oxygen species (ROS) and microbicidal compounds released from neutrophils that are recruited to the site of inflammation contribute to the pathogenesis of multiple inflammation associated diseases such as chronic obstructive pulmonary disease, atherosclerosis, and hepatitis. Marine organisms are a valuable source of bioactive compounds with potential for industrial and pharmaceutical application. Marine natural products that inhibit neutrophil activation could be used as drugs for the treatment of inflammatory diseases. Numerous studies investigating marine natural products have reported novel anti-inflammatory agents. Nevertheless, the detailed mechanisms underlying their actions, which could facilitate our understanding of the molecular events occurring in neutrophils, have not been reported in most of the associated research studies. Therefore, in this review, we will present marine products that inhibit neutrophil-associated inflammation. Furthermore, we will be limiting the detailed discussion to agents with well investigated molecular targets. PMID- 27472349 TI - Impact of Partial and Comprehensive Smoke-Free Regulations on Indoor Air Quality in Bars. AB - In Korea, smoke-free regulations have been gradually implemented in bars based on venue size. Smoking bans were implemented in 2013 for bars >=150 m2, in 2014 for bars >=100 m2, and in 2015 for bars of all sizes. The purpose of this study was to determine indoor fine particle (PM2.5) concentrations in bars before and after implementation of the smoke-free policies based on venue size. Indoor PM2.5 concentrations were measured with real-time aerosol monitors at four time points: (1) pre-regulation (n = 75); (2) after implementing the ban in bars >=150 m2 (n = 75); (3) after implementing the ban in bars >=100 m2 (n = 107); and (4) when all bars were smoke-free (n = 79). Our results showed that the geometric mean of the indoor PM2.5 concentrations of all bars decreased from 98.4 MUg/m3 pre-regulation to 79.5, 42.9, and 26.6 MUg/m3 after the ban on smoking in bars >=150 m2, >=100 m2, and all bars, respectively. Indoor PM2.5 concentrations in bars of each size decreased only after the corresponding regulations were implemented. Although smoking was not observed in Seoul bars after smoking was banned in all bars, smoking was observed in 4 of 21 bars in Changwon. Our study concludes that the greatest decrease in PM2.5 concentrations in bars was observed after the regulation covering all bars was implemented. However, despite the comprehensive ban, smoking was observed in bars in Changwon. Strict compliance with the regulations is needed to improve indoor air quality further. PMID- 27472350 TI - Olives and Bone: A Green Osteoporosis Prevention Option. AB - Skeletal degeneration due to aging, also known as osteoporosis, is a major health problem worldwide. Certain dietary components confer protection to our skeletal system against osteoporosis. Consumption of olives, olive oil and olive polyphenols has been shown to improve bone health. This review aims to summarize the current evidence from cellular, animal and human studies on the skeletal protective effects of olives, olive oil and olive polyphenols. Animal studies showed that supplementation of olives, olive oil or olive polyphenols could improve skeletal health assessed via bone mineral density, bone biomechanical strength and bone turnover markers in ovariectomized rats, especially those with inflammation. The beneficial effects of olive oil and olive polyphenols could be attributed to their ability to reduce oxidative stress and inflammation. However, variations in the bone protective, antioxidant and anti-inflammatory effects between studies were noted. Cellular studies demonstrated that olive polyphenols enhanced proliferation of pre-osteoblasts, differentiation of osteoblasts and decreased the formation of osteoclast-like cells. However, the exact molecular pathways for its bone health promoting effects are yet to be clearly elucidated. Human studies revealed that daily consumption of olive oil could prevent the decline in bone mineral density and improve bone turnover markers. As a conclusion, olives, olive oil and its polyphenols are potential dietary interventions to prevent osteoporosis among the elderly. PMID- 27472351 TI - Dietary Fluoride Intake and Associated Skeletal and Dental Fluorosis in School Age Children in Rural Ethiopian Rift Valley. AB - An observational study was conducted to determine dietary fluoride intake, diet, and prevalence of dental and skeletal fluorosis of school age children in three fluorosis endemic districts of the Ethiopian Rift Valley having similar concentrations of fluoride (F) in drinking water (~5 mg F/L). The duplicate plate method was used to collect foods consumed by children over 24 h from 20 households in each community (n = 60) and the foods, along with water and beverages, were analyzed for fluoride (F) content. Prevalence of dental and skeletal fluorosis was determined using presence of clinical symptoms in children (n = 220). Daily dietary fluoride intake was at or above tolerable upper intake level (UL) of 10 mg F/day and the dietary sources (water, prepared food and beverages) all contributed to the daily fluoride burden. Urinary fluoride in children from Fentale and Adamitulu was almost twice (>5 mg/L) the concentration found in urine from children from Alaba, where rain water harvesting was most common. Severe and moderate dental fluorosis was found in Alaba and Adamitulu, the highest severity and prevalence being in the latter district where staple foods were lowest in calcium. Children in all three areas showed evidence of both skeletal and non-skeletal fluorosis. Our data support the hypothesis that intake of calcium rich foods in addition to using rain water for household consumption and preparation of food, may help in reducing risk of fluorosis in Ethiopia, but prospective studies are needed. PMID- 27472353 TI - Seasonality and Trend Forecasting of Tuberculosis Prevalence Data in Eastern Cape, South Africa, Using a Hybrid Model. AB - BACKGROUND: Tuberculosis (TB) is a deadly infectious disease caused by Mycobacteria tuberculosis. Tuberculosis as a chronic and highly infectious disease is prevalent in almost every part of the globe. More than 95% of TB mortality occurs in low/middle income countries. In 2014, approximately 10 million people were diagnosed with active TB and two million died from the disease. In this study, our aim is to compare the predictive powers of the seasonal autoregressive integrated moving average (SARIMA) and neural network auto-regression (SARIMA-NNAR) models of TB incidence and analyse its seasonality in South Africa. METHODS: TB incidence cases data from January 2010 to December 2015 were extracted from the Eastern Cape Health facility report of the electronic Tuberculosis Register (ERT.Net). A SARIMA model and a combined model of SARIMA model and a neural network auto-regression (SARIMA-NNAR) model were used in analysing and predicting the TB data from 2010 to 2015. Simulation performance parameters of mean square error (MSE), root mean square error (RMSE), mean absolute error (MAE), mean percent error (MPE), mean absolute scaled error (MASE) and mean absolute percentage error (MAPE) were applied to assess the better performance of prediction between the models. RESULTS: Though practically, both models could predict TB incidence, the combined model displayed better performance. For the combined model, the Akaike information criterion (AIC), second-order AIC (AICc) and Bayesian information criterion (BIC) are 288.56, 308.31 and 299.09 respectively, which were lower than the SARIMA model with corresponding values of 329.02, 327.20 and 341.99, respectively. The seasonality trend of TB incidence was forecast to have a slightly increased seasonal TB incidence trend from the SARIMA-NNAR model compared to the single model. CONCLUSIONS: The combined model indicated a better TB incidence forecasting with a lower AICc. The model also indicates the need for resolute intervention to reduce infectious disease transmission with co-infection with HIV and other concomitant diseases, and also at festival peak periods. PMID- 27472352 TI - Hemoglobin Status and Externalizing Behavioral Problems in Children. AB - BACKGROUND: Still considered one of the most prevalent nutritional problems in the world, anemia has been shown in many studies to have deleterious effects on neurobehavioral development. While most research efforts have focused on investigating the effects of anemia on social and emotional development of infants by using a cross-sectional design, research is still needed to investigate whether early childhood anemia, beyond infantile years, is linked with behavioral problems. OBJECTIVE: This study assessed whether (1) hemoglobin (Hb) levels in early childhood are associated with externalizing behavior; and (2) this relationship is confounded by social adversity. METHODS: Hemoglobin levels were taken from children (N = 98) of the China Jintan Cohort Study at age 4 years, and externalizing behaviors (attention and aggression) were assessed with the Child Behavior Checklist (ASEBA-CBCL) at age 6 years (mean age 5.77 +/- 0.39 years old). RESULTS: Compared with other children in the sample, children with relatively lower Hb levels at age 4 had more behavioral problems in both attention and aggression at age 6, independent of social adversity. For boys, this association was significant for attention problems, which did not interact with social adversity. For girls, the association was significant for aggression, which interacted with social adversity. While girls on average exhibited higher social adversity than boys, the main effect of Hb was only significant in girls with low social adversity. CONCLUSIONS: These results indicate that there is an inverse association between hemoglobin levels and later behavioral problems. Findings of this study suggest that regular monitoring of children's hemoglobin levels and appropriate intervention may help with early identification of behavioral problems. PMID- 27472354 TI - Risk Factors Associated with Peer Victimization and Bystander Behaviors among Adolescent Students. AB - Despite the prevalence of the phenomena of peer victimization and bystander behaviors, little data has generated to describe their relationships and risk factors. In this paper, a self-administered survey using a cross-sectional cluster-random sampling method in a sample of 5450 participants (2734 girls and 2716 boys) between 4th and 11th grades was conducted at six schools (two primary schools and four middle schools) located in Shantou, China. Self-reported peer victimization, bystander behaviors and information regarding parents' risky behaviors and individual behavioral factors were collected. Multinomial logistic regression analysis was applied to evaluate risk factors affecting peer victimization and bystander behaviors. The results indicated that urban participants were more likely to become bullying victims but less likely to become passive bystanders. Contrarily, bullying victimization was related to the increasing of passive bystander behaviors. Father drinking and mother smoking as independent factors were risk factors for peer victimization. Participants who were smoking or drinking had a tendency to be involved in both peer victimization and passive bystander behaviors. This study suggested that bystander behaviors, victims' and parents' educations play a more important role in peer victimization than previously thought. PMID- 27472355 TI - Association of Perceived Stress with Atopic Dermatitis in Adults: A Population Based Study in Korea. AB - Atopic dermatitis (AD) is a widely prevalent skin disease that affects both children and adults. The aim of the study was to assess the association of perceived stress (single-item, self-reported) with AD (self-reported) in a sample of Korean adults using a cross-sectional research design. A cross-sectional study was conducted using data from 33,018 adults aged 20 years and older collected in the 2007-2012 Korea National Health and Nutrition Examination Surveys (KNHANES). An increased level of self-reported stress was positively associated with an increased prevalence of AD in Korean adults (p for trend <0.001). After adjusting for covariates, the odds ratios (ORs) of AD among participants reporting high and very high levels of stress were 1.81 (95% confidence interval (CI): 1.22, 2.67) and 2.17 (95% CI: 1.38, 3.42), respectively, compared with those who reported low levels of stress. This study found a statistically significant association between perceived stress and AD among Korean adults. PMID- 27472356 TI - Mortality from Unspecified Unintentional Injury among Individuals Aged 65 Years and Older by U.S. State, 1999-2013. AB - INTRODUCTION: Recent changes in unspecified unintentional injury mortality for the elderly by U.S. state remain unreported. This study aims to examine U.S. state variations in mortality from unspecified unintentional injury among Americans aged 65+, 1999-2013; METHODS: Using mortality rates from the U.S. CDC's Web-based Injury Statistics Query and Reporting System (WISQARSTM), we examined unspecified unintentional injury mortality for older adults aged 65+ from 1999 to 2013 by state. Specifically, the proportion of unintentional injury deaths with unspecified external cause in the data was considered. Linear regression examined the statistical significance of changes in proportion of unspecified unintentional injury from 1999 to 2013; RESULTS: Of the 36 U.S. states with stable mortality rates, over 8-fold differences were observed for both the mortality rates and the proportions of unspecified unintentional injury for Americans aged 65+ during 1999-2013. Twenty-nine of the 36 states showed reductions in the proportion of unspecified unintentional injury cause, with Oklahoma (-89%), Massachusetts (-86%) and Oregon (-81%) displaying the largest changes. As unspecified unintentional injury mortality decreased, mortality from falls in 28 states and poisoning in 3 states increased significantly. Mortality from suffocation in 15 states, motor vehicle traffic crashes in 12 states, and fire/burn in 8 states also decreased; CONCLUSIONS: The proportion of unintentional injuries among older adults with unspecified cause decreased significantly for many states in the United States from 1999 to 2013. The reduced proportion of unspecified injury has implications for research and practice. It should be considered in state-level trend analysis during 1999-2013. It also suggests comparisons between states for specific injury mortality should be conducted with caution, as large differences in unspecified injury mortality across states and over time could create bias for specified injury mortality comparisons. PMID- 27472357 TI - Breakfast Consumption and Its Associations with Health-Related Behaviors among School-Aged Adolescents: A Cross-Sectional Study in Zhejiang Province, China. AB - Evidence indicates that breakfast consumption is associated with a cluster of health-related behaviors, yet studies in mainland China are scarce. This study is conducted to describe the frequency of breakfast consumption among Chinese adolescents and examine its associations with other dietary, physical activity, sedentary, sleep, cigarette-smoking, and alcohol-drinking behaviors. Breakfast consumption and other health-related behaviors data was collected via a self administered questionnaire in a cross-sectional study in Zhejiang Province, China. A total of 19,542 school-aged adolescents were recruited in this survey. The associations between breakfast consumption and other health-related behaviors were examined using logistic regression models. A significantly higher prevalence of daily breakfast consumption was found among students who were younger (p for trend <0.001), from urban schools (p < 0.001), and academic high schools (p < 0.001). More frequent vegetable and milk consumption, greater physical activity, and longer sleep duration were positively associated with daily breakfast consumption, while soft drinks and fast food consumption, computer use, cigarette smoking and alcohol-drinking behaviors were inversely associated. The prevalence of irregular breakfast consumption was relatively high among Chinese adolescents in Zhejiang Province. Daily breakfast consumption was associated with a constellation of health-related behaviors. PMID- 27472359 TI - Comparison of a Powdered, Acidified Liquid, and Non-Acidified Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants. AB - We previously compared infant outcomes between a powdered human milk fortifier (P HMF) vs. acidified liquid HMF (AL-HMF). A non-acidified liquid HMF (NAL-HMF) is now commercially available. The purpose of this study is to compare growth and outcomes of premature infants receiving P-HMF, AL-HMF or NAL-HMF. An Institutional Review Board (IRB) approved retrospective chart review compared infant outcomes (born < 2000 g) who received one of three HMF. Growth, enteral nutrition, laboratory and demographic data were compared. 120 infants were included (P-HMF = 46, AL-HMF = 23, NAL-HMF = 51). AL-HMF infants grew slower in g/day (median 23.66 vs. P-HMF 31.27, NAL-HMF 31.74 (p < 0.05)) and in g/kg/day, median 10.59 vs. 15.37, 14.03 (p < 0.0001). AL-HMF vs. NAL-HMF infants were smaller at 36 weeks gestational age (median 2046 vs. 2404 g, p < 0.05). However AL-HMF infants received more daily calories (p = 0.21) and protein (p < 0.0001), mean 129 cal/kg, 4.2 g protein/kg vs. P-HMF 117 cal/kg, 3.7 g protein/kg , NAL HMF 120 cal/kg, 4.0 g protein/kg. AL-HMF infants exhibited lower carbon dioxide levels after day of life 14 and 30 (p < 0.0001, p = 0.0038). Three AL-HMF infants (13%) developed necrotizing enterocolitis (NEC) vs. no infants in the remaining groups (p = 0.0056). A NAL-HMF is the most optimal choice for premature human milk-fed infants in a high acuity neonatal intensive care unit (NICU). PMID- 27472360 TI - Letter to the Editor Re: Nissensohn M. et al.; Nutrients 2016, 8, 232. AB - Dear Editor, We read with interest the recently published original article entitled "Beverage Consumption Habits and Association with TotalWater and Energy Intakes in the Spanish Population: Findings of the ANIBES Study" by Nissensohn et al. [1] in Nutrients.[...]. PMID- 27472358 TI - Exploring the Dietary Patterns of Young New Zealand Women and Associations with BMI and Body Fat. AB - Examining dietary patterns provides an alternative approach to investigating dietary behaviors related to excess adiposity. The study aim was to investigate dietary patterns and body composition profiles of New Zealand European (NZE) women, participating in the women's EXPLORE (Examining the Predictors Linking Obesity Related Elements) study. Post-menarche, pre-menopausal NZE women (16-45 years) (n = 231) completed a validated 220-item, self-administrated, semi quantitative food frequency questionnaire. Body mass index (BMI) was calculated using measured height (cm) and weight (kg); body fat percentage (BF%) was measured using air displacement plethysmography (BodPod). Dietary patterns were identified using principal component factor analysis. Associations between dietary patterns, age, BMI and BF% were investigated. Four dietary patterns were identified: snacking; energy-dense meat; fruit and vegetable; healthy, which explained 6.9%, 6.8%, 5.6% and 4.8% of food intake variation, respectively. Age (p = 0.012) and BMI (p = 0.016) were positively associated with the "energy-dense meat" pattern. BF% (p = 0.016) was positively associated with the "energy-dense meat" pattern after adjusting for energy intake. The women following the identified dietary patterns had carbohydrate intakes below and saturated fat intakes above recommended guidelines. Dietary patterns in NZE women explain only some variations in body composition. Further research should examine other potential factors including physical activity and socioeconomic status. PMID- 27472361 TI - The Effect of Casein Protein Prior to Sleep on Fat Metabolism in Obese Men. AB - We have previously shown that ingesting protein at night before sleep is either beneficial or non-detrimental to metabolism, health, and body composition in obese women. However, the overnight protein-induced lipolytic actions and mechanism for improved metabolism and body composition have not been fully established. Therefore, in a crossover design, twelve obese men (age, 27.0 +/- 2.2 years) were randomly assigned to ingest (within 30 min of sleep) casein protein (CAS, 120 kcal) or a non-nutritive placebo (PLA) before going to sleep. Markers of fat metabolism (lipolysis, substrate utilization, growth hormone), insulin, glucose, resting energy expenditure (REE), and appetite (questionnaire and ghrelin) were measured. During sleep and the next morning, interstitial glycerol from the subcutaneous abdominal adipose tissue (SCAAT) was measured using microdialysis. There were no differences in SCAAT glycerol (overnight: CAS, 177.4 +/- 26.7; PLA, 183.8 +/- 20.2 MUmol/L; morning: CAS, 171.6 +/- 19.1; PLA, 161.5 +/- 18.6 MUmol/L), substrate utilization, REE, or any blood markers between CAS and PLA. Desire to eat was greater for CAS compared to baseline (p = 0.03), but not different from PLA (baseline: 39 +/- 6, CAS: 62 +/- 8, PLA: 55 +/- 5 mm). CAS consumption before sleep did not affect fat or glucose metabolism, REE, or suppress appetite in hyperinsulemic obese men. CAS may be consumed before sleep without impeding overnight or morning fat metabolism in young, obese men. PMID- 27472362 TI - Susceptibility of Broiler Chickens to Coccidiosis When Fed Subclinical Doses of Deoxynivalenol and Fumonisins-Special Emphasis on the Immunological Response and the Mycotoxin Interaction. AB - Deoxynivalenol (DON) and fumonisins (FB) are the most frequently encountered mycotoxins produced by Fusarium species in livestock diets. The effect of subclinical doses of mycotoxins in chickens is largely unknown, and in particular the susceptibility of birds to pathogenic challenge when fed these fungal metabolites. Therefore, the present study reports the effects of DON and FB on chickens challenged with Eimeria spp, responsible for coccidiosis. Broilers were fed diets from hatch to day 20, containing no mycotoxins, 1.5 mg DON/kg, 20 mg FB/kg, or both toxins (12 pens/diet; 7 birds/pen). At day 14, six pens of birds per diet (half of the birds) were challenged with a 25*-recommended dose of coccidial vaccine, and all birds (challenged and unchallenged) were sampled 6 days later. As expected, performance of birds was strongly affected by the coccidial challenge. Ingestion of mycotoxins did not further affect the growth but repartitioned the rate of reduction (between the fraction due to the change in maintenance and feed efficiency), and reduced apparent nitrogen digestibility. Intestinal lesions and number of oocysts in the jejunal mucosa and feces of challenged birds were more frequent and intense in the birds fed mycotoxins than in birds fed control feed. The upregulation of cytokines (interleukin (IL) IL 1beta, IL-6, IL-8 and IL-10) following coccidial infection was higher in the jejunum of birds fed mycotoxins. Further, the higher intestinal immune response was associated with a higher percentage of T lymphocytes CD4+CD25+, also called Tregs, observed in the cecal tonsils of challenged birds fed mycotoxins. Interestingly, the increase in FB biomarker of exposure (sphinganine/sphingosine ratio in serum and liver) suggested a higher absorption and bioavailability of FB in challenged birds. The interaction of DON and FB was very dependent on the endpoint assessed, with three endpoints reporting antagonism, nine additivity, and two synergism. In conclusion, subclinical doses of DON and FB showed little effects in unchallenged chickens, but seem to result in metabolic and immunologic disturbances that amplify the severity of coccidiosis. PMID- 27472363 TI - CD8 T Cell-Independent Antitumor Response and Its Potential for Treatment of Malignant Gliomas. AB - Malignant brain tumors continue to represent a devastating diagnosis with no real chance for cure. Despite an increasing list of potential salvage therapies, standard-of-care for these patients has not changed in over a decade. Immunotherapy has been seen as an exciting option, with the potential to offer specific and long lasting tumor clearance. The "gold standard" in immunotherapy has been the development of a tumor-specific CD8 T cell response to potentiate tumor clearance and immunological memory. While many advances have been made in the field of immunotherapy, few therapies have seen true success. Many of the same principles used to develop immunotherapy in tumors of the peripheral organs have been applied to brain tumor immunotherapy. The immune-specialized nature of the brain should call into question whether this approach is appropriate. Recent results from our own experiments require a rethinking of current dogma. Perhaps a CD8 T cell response is not sufficient for an organ as immunologically unique as the brain. Examination of previously elucidated principles of the brain's immune specialized status and known immunological preferences should generate discussion and experimentation to address the failure of current therapies. PMID- 27472364 TI - Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan. AB - We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan. PMID- 27472365 TI - Dry/Wet Cycling and the Thermodynamics and Kinetics of Prebiotic Polymer Synthesis. AB - The endoergic nature of protein and nucleic acid assembly in aqueous media presents two questions that are fundamental to the understanding of life's origins: (i) how did the polymers arise in an aqueous prebiotic world; and (ii) once formed in some manner, how were they sufficiently persistent to engage in further chemistry. We propose here a quantitative resolution of these issues that evolved from recent accounts in which RNA-like polymers were produced in evaporation/rehydration cycles. The equilibrium Nm + Nn <-> Nm+n + H2O is endoergic by about 3.3 kcal/mol for polynucleotide formation, and the system thus lies far to the left in the starting solutions. Kinetic simulations of the evaporation showed that simple Le Chatelier's principle shifts were insufficient, but the introduction of oligomer-stabilizing factors of 5-10 kcal/mol both moved the process to the right and respectively boosted and retarded the elongation and hydrolysis rates. Molecular crowding and excluded volume effects in present-day cells yield stabilizing factors of that order, and we argue here that the crowded conditions in the evaporites generate similar effects. Oligomer formation is thus energetically preferred in those settings, but the process is thwarted in each evaporation step as diffusion becomes rate limiting. Rehydration dissipates disordered oligomer clusters in the evaporites, however, and subsequent dry/wet cycling accordingly "ratchets up" the system to an ultimate population of kinetically trappedthermodynamically preferred biopolymers. PMID- 27472367 TI - Stress and Withdrawal from Chronic Ethanol Induce Selective Changes in Neuroimmune mRNAs in Differing Brain Sites. AB - Stress is a strong risk factor in alcoholic relapse and may exert effects that mimic aspects of chronic alcohol exposure on neurobiological systems. With the neuroimmune system becoming a prominent focus in the study of the neurobiological consequences of stress, as well as chronic alcohol exposure proving to be a valuable focus in this regard, the present study sought to compare the effects of stress and chronic ethanol exposure on induction of components of the neuroimmune system. Rats were exposed to either 1 h exposure to a mild stressor (restraint) or exposure to withdrawal from 15 days of chronic alcohol exposure (i.e., withdrawal from chronic ethanol, WCE) and assessed for neuroimmune mRNAs in brain. Restraint stress alone elevated chemokine (C-C motif) ligand 2 (CCL2), interleukin-1-beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and toll like receptor 4 (TLR4) mRNAs in the cerebral cortex within 4 h with a return to a control level by 24 h. These increases were not accompanied by an increase in corresponding proteins. Withdrawal from WCE also elevated cytokines, but did so to varying degrees across different cytokines and brain regions. In the cortex, stress and WCE induced CCL2, TNFalpha, IL-1beta, and TLR4 mRNAs. In the hypothalamus, only WCE induced cytokines (CCL2 and IL-1beta) while in the hippocampus, WCE strongly induced CCL2 while stress and WCE induced IL-1beta. In the amygdala, only WCE induced CCL2. Finally-based on the previously demonstrated role of corticotropin-releasing factor 1 (CRF1) receptor inhibition in blocking WCE-induced cytokine mRNAs-the CRF1 receptor antagonist CP154,526 was administered to a subgroup of stressed rats and found to be inactive against induction of CCL2, TNFalpha, or IL-1beta mRNAs. These differential results suggest that stress and WCE manifest broad neuroimmune effects in brain depending on the cytokine and brain region, and that CRF inhibition may not be a relevant mechanism in non-alcohol exposed animals. Overall, these effects are complex in terms of their neuroimmune targets and neuroanatomical specificity. Further investigation of the differential distribution of cytokine induction across neuroanatomical regions, individual cell types (e.g., neuronal phenotypes and glia), severity of chronic alcohol exposure, as well as across differing stress types may prove useful in understanding differential mechanisms of induction and for targeting select systems for pharmacotherapeutic intervention in alcoholism. PMID- 27472368 TI - Reliability and Variability of tDCS Induced Changes in the Lower Limb Motor Cortex. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is emerging as a promising adjuvant to enhance motor function. However, there has been increasing reservations about the reliability and variability of the neuromodulatory effects evoked by tDCS. OBJECTIVE/HYPOTHESIS: The main purpose of this study was to explore the test-retest reliability and inter-individual variability of tDCS of the lower limb M1 and the relationship between transcranial magnetic stimulation (TMS)-related measures and tDCS-induced changes. METHODS: Fifteen healthy participants received anodal tDCS of the lower limb M1 either when performing a lower limb motor task or when the limb was at rest. Each condition was tested twice. tDCS induced changes in corticomotor excitability of the tibialis anterior muscle were measured using TMS. A repeated measures ANOVA was performed to examine efficacy of tDCS between the two task conditions. Intraclass correlation coefficients (ICC) and variance component analyses were performed to examine reliability and variability respectively. RESULTS: A significant increase in in corticomotor excitability was noted for the tDCS-task condition at 140% active motor threshold (AMT) and when comparing recruitment curve slopes, but not at 120% and 130% AMT. Overall, ICC values between testing days for each stimulation condition ranged from 0.6-0.9. Higher ICCs were seen for higher TMS intensities (140% AMT) and recruitment curve slopes. Inter-individual variability contributed to 34% of the exhibited variance. CONCLUSIONS: Our data suggest that the TMS related measure used to assess neuromodulation after tDCS has an effect on its perceived test-retest reliability and inter-individual variability. Importantly, we noticed that a high reliability and low variability does not necessarily indicate clinical efficacy of tDCS as some participants showed little to no modulation of corticomotor excitability consistently. PMID- 27472366 TI - Maternal Malnutrition in the Etiopathogenesis of Psychiatric Diseases: Role of Polyunsaturated Fatty Acids. AB - Evidence from human studies indicates that maternal metabolic state and malnutrition dramatically influence the risk for developing psychiatric complications in later adulthood. In this regard, the central role of polyunsaturated fatty acids (PUFAs), and particularly n-3 PUFAs, is emerging considering that epidemiological evidences have established a negative correlation between n-3 PUFA consumption and development of mood disorders. These findings were supported by clinical studies indicating that low content of n-3 PUFAs in diet is linked to an increased susceptibility to psychiatric disorders. PUFAs regulate membrane fluidity and exert their central action by modulating synaptogenesis and neurotrophic factor expression, neurogenesis, and neurotransmission. Moreover, they are precursors of molecules implicated in modulating immune and inflammatory processes in the brain. Importantly, their tissue concentrations are closely related to diet intake, especially to maternal consumption during embryonal life, considering that their synthesis from essential precursors has been shown to be inefficient in mammals. The scope of this review is to highlight the possible mechanisms of PUFA functions in the brain during pre- and post-natal period and to evaluate their role in the pathogenesis of psychiatric diseases. PMID- 27472369 TI - The Role of Copper Chaperone Atox1 in Coupling Redox Homeostasis to Intracellular Copper Distribution. AB - Human antioxidant protein 1 (Atox1) is a small cytosolic protein with an essential role in copper homeostasis. Atox1 functions as a copper carrier facilitating copper transfer to the secretory pathway. This process is required for activation of copper dependent enzymes involved in neurotransmitter biosynthesis, iron efflux, neovascularization, wound healing, and regulation of blood pressure. Recently, new cellular roles for Atox1 have emerged. Changing levels of Atox1 were shown to modulate response to cancer therapies, contribute to inflammatory response, and protect cells against various oxidative stresses. It has also become apparent that the activity of Atox1 is tightly linked to the cellular redox status. In this review, we summarize biochemical information related to a dual role of Atox1 as a copper chaperone and an antioxidant. We discuss how these two activities could be linked and contribute to establishing the intracellular copper balance and functional identity of cells during differentiation. PMID- 27472370 TI - Immunological Evaluation of Recent MUC1 Glycopeptide Cancer Vaccines. AB - Aberrantly glycosylated mucin 1 (MUC1) is a recognized tumor-specific antigen on epithelial cell tumors. A wide variety of MUC1 glycopeptide anti-cancer vaccines have been formulated by many research groups. Some researchers have used MUC1 alone as an immunogen whereas other groups used different antigenic carrier proteins such as bovine serum albumin or keyhole limpet hemocyanin for conjugation with MUC1 glycopeptide. A variety of adjuvants have been used with MUC1 glycopeptides to improve their immunogenicity. Fully synthetic multicomponent vaccines have been synthesized by incorporating different T helper cell epitopes and Toll-like receptor agonists. Some vaccine formulations utilized liposomes or nanoparticles as vaccine delivery systems. In this review, we discuss the immunological evaluation of different conjugate or synthetic MUC1 glycopeptide vaccines in different tumor or mouse models that have been published since 2012. PMID- 27472372 TI - A Review of the Multidisciplinary Diagnosis of Interstitial Lung Diseases: A Retrospective Analysis in a Single UK Specialist Centre. AB - The accurate diagnosis and management of individuals with interstitial lung diseases (ILDs) poses an interesting challenge in clinical practice. A multidisciplinary team (MDT) approach is considered the gold standard. This is a single-centre retrospective review spanning a five-year period. We assessed the accuracy of prior ILD diagnosis, the methodology used to establish a correct diagnosis and how an MDT approach affected subsequent management. Our data supports an MDT approach in an experienced specialist ILD centre. We have demonstrated that diagnosis is often changed after an MDT review and that this impacts the subsequent management. Our results demonstrate that an MDT approach to diagnosis can establish a diagnosis in the majority of cases when prior diagnosis is uncertain (76%). We also show that a prior diagnosis of idiopathic pulmonary fibrosis is deemed inaccurate in over 50% of cases after MDT discussion. We have shown that during diagnostic uncertainty the considered gold standard of proceeding to a lung biopsy is not always feasible due to disease severity and comorbidities. In these circumstances, an MDT approach to diagnosis of ILDs combines clinical data with serial lung function and disease behavior, with or without responses to previous treatment trials to establish an accurate expert diagnosis. PMID- 27472371 TI - Leptin-Induced JAK/STAT Signaling and Cancer Growth. AB - Growth factor and cytokine signaling can influence the development of several cancer types. One of the key players in the development of cancer is the Janus kinas (JAK) signal transducer of activators of transcription (STAT) signaling pathway. The majority of growth factors and cytokine interactions with their membrane-bound receptors trigger JAK-STAT activation. The influential relationship between obesity and cancer is a fact. However, there is a complex sequence of events contributing to the regulation of this mechanism to promote tumor growth, yet to be fully elucidated. The JAK-STAT pathway is influenced by obesity-associated changes that have been shown to impact cancer growth and progression. This intricate process is highly regulated by a vast array of adipokines and cytokines that exert their pleiotropic effects on cancer cells to enhance metastasis to distant target sites. Leptin is a cytokine, or more precise, an adipokine secreted mainly by adipose tissue that requires JAK-STAT activation to exert its biological functions. Leptin is the central regulator of energy balance and appetite. Leptin binding to its receptor OB-R in turn activates JAK-STAT, which induces proliferation, angiogenesis, and anti-apoptotic events in normal cells and malignant cells expressing the receptor. Leptin also induces crosstalk with Notch and IL-1 (NILCO), which involves other angiogenic factors promoting tumor growth. Therefore, the existence of multiple novel classes of therapeutics that target the JAK/STAT pathway has significant clinical implications. Then, the identification of the signaling networks and factors that regulate the obesity-cancer link to which potential pharmacologic interventions can be implemented to inhibit tumor growth and metastasis. In this review, we will discuss the specific relationship between leptin-JAK-STAT signaling and cancer. PMID- 27472374 TI - In Response to Michael Wininger's Commentary: Common Roadblocks for Biomaterials Metrologists. AB - I welcome Wininger's commentary [1], and I would like to take the opportunity to address some of the issues raised.[...]. PMID- 27472373 TI - Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. AB - A new application for omega-3 fatty acids has recently emerged, concerning the treatment of several mental disorders. This indication is supported by data of neurobiological research, as highly unsaturated fatty acids (HUFAs) are highly concentrated in neural phospholipids and are important components of the neuronal cell membrane. They modulate the mechanisms of brain cell signaling, including the dopaminergic and serotonergic pathways. The aim of this review is to provide a complete and updated account of the empirical evidence of the efficacy and safety that are currently available for omega-3 fatty acids in the treatment of psychiatric disorders. The main evidence for the effectiveness of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been obtained in mood disorders, in particular in the treatment of depressive symptoms in unipolar and bipolar depression. There is some evidence to support the use of omega-3 fatty acids in the treatment of conditions characterized by a high level of impulsivity and aggression and borderline personality disorders. In patients with attention deficit hyperactivity disorder, small-to-modest effects of omega-3 HUFAs have been found. The most promising results have been reported by studies using high doses of EPA or the association of omega-3 and omega-6 fatty acids. In schizophrenia, current data are not conclusive and do not allow us either to refuse or support the indication of omega-3 fatty acids. For the remaining psychiatric disturbances, including autism spectrum disorders, anxiety disorders, obsessive-compulsive disorder, eating disorders and substance use disorder, the data are too scarce to draw any conclusion. Concerning tolerability, several studies concluded that omega-3 can be considered safe and well tolerated at doses up to 5 g/day. PMID- 27472375 TI - Deciphering the Duality of Clock and Growth Metabolism in a Cell Autonomous System Using NMR Profiling of the Secretome. AB - Oscillations in circadian metabolism are crucial to the well being of organism. Our understanding of metabolic rhythms has been greatly enhanced by recent advances in high-throughput systems biology experimental techniques and data analysis. In an in vitro setting, metabolite rhythms can be measured by time dependent sampling over an experimental period spanning one or more days at sufficent resolution to elucidate rhythms. We hypothesized that cellular metabolic effects over such a time course would be influenced by both oscillatory and circadian-independent cell metabolic effects. Here we use nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling of mammalian cell culture media of synchronized U2 OS cells containing an intact transcriptional clock. The experiment was conducted over 48 h, typical for circadian biology studies, and samples collected at 2 h resolution to unravel such non-oscillatory effects. Our data suggest specific metabolic activities exist that change continuously over time in this settting and we demonstrate that the non-oscillatory effects are generally monotonic and possible to model with multivariate regression. Deconvolution of such non-circadian persistent changes are of paramount importance to consider while studying circadian metabolic oscillations. PMID- 27472376 TI - Treatment of hemophilia: A qualitative study of mothers' perspectives. AB - BACKGROUND: In Norway, boys with hemophilia usually begin treatment after their first bleeding episode. Boys with severe hemophilia usually start prophylactic treatment around 18-24 months. Health professionals administer factor concentrate initially, but when boys are around 4 years old most parents start treating their children at home. There is a lack of research on how parents, and especially how carrier mothers, experience the medical treatment for their sons' hemophilia. Our aim was to investigate how carrier mothers experience this treatment in the hospital setting and at home. METHODS: In this qualitative study, we interviewed 16 mothers of boys or men with hemophilia A or B. Data were collected via semistructured interviews and analyzed using an inductive thematic analytical approach. RESULTS: Mothers experienced both practical and emotional challenges in relation to their sons' treatment, and repeated venipuncture was especially difficult emotionally. Parents preferred home treatment to hospital treatment because it was less time-consuming, less disruptive to family life, and provided a greater sense of control. Encountering healthcare professionals who were unfamiliar with hemophilia was a second major stress factor, especially when parents felt that health professionals lacked competence and were unwilling to seek advice. CONCLUSION: While home treatment for hemophilia enables freedom, flexibility, and autonomy for the boys as well as for the family, mothers may experience treatment of hemophilia as a burden. Health professionals should provide tailored practical and emotional support to parents by probing into their experiences with treating their sons' hemophilia. PMID- 27472377 TI - Antibiotic perturbation of the preterm infant gut microbiome and resistome. AB - The gut microbiota plays important roles in nutrient absorption, immune system development, and pathogen colonization resistance. Perturbations early in life may be detrimental to host health in the short and the long-term. Antibiotics are among the many factors that influence the development of the microbiota. Because antibiotics are heavily administered during the first critical years of gut microbiota development, it is important to understand the effects of these interventions. Infants, particularly those born prematurely, represent an interesting population because they receive early and often extensive antibiotic therapy in the first months after birth. Gibson et al. recently demonstrated that antibiotic therapy in preterm infants can dramatically affect the gut microbiome. While meropenem, ticarcillin-clavulanate, and cefotaxime treatments were associated with decreased species richness, gentamicin and vancomycin had variable effects on species richness. Interestingly, the direction of species richness response could be predicted based on the abundance of 2 species and 2 genes in the microbiome prior to gentamicin or vancomycin treatment. Nonetheless, all antibiotic treatments enriched the presence of resistance genes and multidrug resistant organisms. Treatment with different antibiotics further resulted in unique population shifts of abundant organisms and selection for different sets of resistance genes. In this addendum, we provide an extended discussion of these recent findings, and outline important future directions for elucidating the interplay between antibiotics and preterm infant gut microbiota development. PMID- 27472379 TI - Modeling Electronic-Nuclear Interactions for Excitation Energy Transfer Processes in Light-Harvesting Complexes. AB - An accurate approach for computing intermolecular and intrachromophore contributions to spectral densities to describe the electronic-nuclear interactions relevant for modeling excitation energy transfer processes in light harvesting systems is presented. The approach is based on molecular dynamics (MD) calculations of classical correlation functions of long-range contributions to excitation energy fluctuations and a separate harmonic analysis and single-point gradient quantum calculations for electron-intrachromophore vibrational couplings. A simple model is also presented that enables detailed analysis of the shortcomings of standard MD-based excitation energy fluctuation correlation function approaches. The method introduced here avoids these problems, and its reliability is demonstrated in accurate predictions for bacteriochlorophyll molecules in the Fenna-Matthews-Olson pigment-protein complex, where excellent agreement with experimental spectral densities is found. This efficient approach can provide instantaneous spectral densities for treating the influence of fluctuations in environmental dissipation on fast electronic relaxation. PMID- 27472378 TI - Changing caring behaviours in rehabilitation after a hip fracture - A tool for empowerment? AB - Different rehabilitation programs after surgery have been presented to improve the outcome for patients with a hip fracture. Empowerment has been suggested as useful, but requires a change in the caring behaviours of health professionals. The aim with this study was to evaluate if training and supervision of the nursing staff could alter caring behaviours. A case-control study of nursing staff treating hip fracture patients was performed at a hospital with two sites. Training and supervision was given to the nursing staff at the intervention site. The intervention focused on creating positive care interaction by using eight guidelines. The evaluation was performed with recordings of a constructed caring situation before training, and observations of care situations at the ward before and after intervention. The results showed no differences at baseline between the two sites in the caring behaviours. After intervention, significant effects of caring behaviours were seen in seven out of eight guidelines, the effect sizes ranged from medium to large. The findings indicate that the nursing staff can change caring behaviours and facilitate the empowerment of patients with a hip fracture. PMID- 27472380 TI - Systematic evaluation of heteronuclear spin decoupling in solid-state NMR at the rotary-resonance conditions in the regime of fast magic-angle spinning. AB - The performance of heteronuclear spin decoupling sequences in solid-state NMR severely degrades when the proton radiofrequency (RF) nutation frequencies (nu1) are close to or at multiples of magic-angle spinning (MAS) frequency (nur) that are referred to as rotary-resonance recoupling conditions (nu1=n.nur). Recently, two schemes, namely, PISSARRO and rCW(ApA), have been shown to be less affected by the problem of MAS and RF interference, specifically at the n=2 rotary resonance recoupling condition, especially in the fast MAS regime. Here, we systematically evaluate the loss in intensity of several heteronuclear spin decoupling sequences at the n=1, 2 conditions compared to high-power decoupling in the fast-MAS regime. We propose that in the fast-MAS regime (above 40kHz) the entire discussion about RF and MAS interference can be avoided by using appropriate low-power decoupling sequences which give comparable performance to decoupling sequences with high-power (1)H irradiation of ca.195kHz. PMID- 27472381 TI - High affinity nanobodies against human epidermal growth factor receptor selected on cells by E. coli display. AB - Most therapeutic antibodies (Abs) target cell surface proteins on tumor and immune cells. Cloning of Ab gene libraries in E. coli and their display on bacteriophages is commonly used to select novel therapeutic Abs binding target antigens, either purified or expressed on cells. However, the sticky nature of bacteriophages renders phage display selections on cells challenging. We previously reported an E. coli display system for expression of VHHs (i.e., nanobodies, Nbs) on the surface of bacteria and selection of high-affinity clones by magnetic cell sorting (MACS). Here, we demonstrate that E. coli display is also an attractive method for isolation of Nbs against cell surface antigens, such as the epidermal growth factor receptor (EGFR), upon direct selection and screening of Ab libraries on live cells. We employ a whole cell-based strategy using a VHH library obtained by immunization with human tumor cells over expressing EGFR (i.e., A431), and selection of bacterial clones bound to murine fibroblast NIH-3T3 cells transfected with human EGFR, after depletion of non specific clones on untransfected cells. This strategy resulted in the isolation of high-affinity Nbs binding distinct epitopes of EGFR, including Nbs competing with the ligand, EGF, as characterized by flow cytometry of bacteria displaying the Nbs and binding assays with purified Nbs using surface plasmon resonance. Hence, our study demonstrates that E. coli display of VHH libraries and selection on cells enables efficient isolation and characterization of high-affinity Nbs against cell surface antigens. PMID- 27472383 TI - An Empirical Orthogonal Function-Based Algorithm for Estimating Terrestrial Latent Heat Flux from Eddy Covariance, Meteorological and Satellite Observations. AB - Accurate estimation of latent heat flux (LE) based on remote sensing data is critical in characterizing terrestrial ecosystems and modeling land surface processes. Many LE products were released during the past few decades, but their quality might not meet the requirements in terms of data consistency and estimation accuracy. Merging multiple algorithms could be an effective way to improve the quality of existing LE products. In this paper, we present a data integration method based on modified empirical orthogonal function (EOF) analysis to integrate the Moderate Resolution Imaging Spectroradiometer (MODIS) LE product (MOD16) and the Priestley-Taylor LE algorithm of Jet Propulsion Laboratory (PT JPL) estimate. Twenty-two eddy covariance (EC) sites with LE observation were chosen to evaluate our algorithm, showing that the proposed EOF fusion method was capable of integrating the two satellite data sets with improved consistency and reduced uncertainties. Further efforts were needed to evaluate and improve the proposed algorithm at larger spatial scales and time periods, and over different land cover types. PMID- 27472382 TI - The Arabidopsis KINbetagamma Subunit of the SnRK1 Complex Regulates Pollen Hydration on the Stigma by Mediating the Level of Reactive Oxygen Species in Pollen. AB - Pollen-stigma interactions are essential for pollen germination. The highly regulated process of pollen germination includes pollen adhesion, hydration, and germination on the stigma. However, the internal signaling of pollen that regulates pollen-stigma interactions is poorly understood. KINbetagamma is a plant-specific subunit of the SNF1-related protein kinase 1 complex which plays important roles in the regulation of plant development. Here, we showed that KINbetagamma was a cytoplasm- and nucleus-localized protein in the vegetative cells of pollen grains in Arabidopsis. The pollen of the Arabidopsis kinbetagamma mutant could not germinate on stigma, although it germinated normally in vitro. Further analysis revealed the hydration of kinbetagamma mutant pollen on the stigma was compromised. However, adding water to the stigma promoted the germination of the mutant pollen in vivo, suggesting that the compromised hydration of the mutant pollen led to its defective germination. In kinbetagamma mutant pollen, the structure of the mitochondria and peroxisomes was destroyed, and their numbers were significantly reduced compared with those in the wild type. Furthermore, we found that the kinbetagamma mutant exhibited reduced levels of reactive oxygen species (ROS) in pollen. The addition of H2O2 in vitro partially compensated for the reduced water absorption of the mutant pollen, and reducing ROS levels in pollen by overexpressing Arabidopsis CATALASE 3 resulted in compromised hydration of pollen on the stigma. These results indicate that Arabidopsis KINbetagamma is critical for the regulation of ROS levels by mediating the biogenesis of mitochondria and peroxisomes in pollen, which is required for pollen-stigma interactions during pollination. PMID- 27472384 TI - Pollination Mode and Mating System Explain Patterns in Genetic Differentiation in Neotropical Plants. AB - We studied genetic diversity and differentiation patterns in Neotropical plants to address effects of life history traits (LHT) and ecological attributes based on an exhaustive literature survey. We used generalized linear mixed models (GLMMs) to test the effects as fixed and random factors of growth form, pollination and dispersal modes, mating and breeding systems, geographical range and habitat on patterns of genetic diversity (HS, HeS, pi and h), inbreeding coefficient (FIS), allelic richness (AR) and differentiation among populations (FST) for both nuclear and chloroplast genomes. In addition, we used phylogenetic generalized least squares (pGLS) to account for phylogenetic independence on predictor variables and verify the robustness of the results from significant GLMMs. In general, GLMM revealed more significant relationships among LHTs and genetic patterns than pGLS. After accounting for phylogenetic independence (i.e., using pGLS), FST for nuclear microsatellites was significantly related to pollination mode, mating system and habitat. Plants specifically with outcrossing mating system had lower FST. Moreover, AR was significantly related to pollination mode and geographical range and HeS for nuclear dominant markers was significantly related to habitat. Our findings showed that different results might be retrieved when phylogenetic non-independence is taken into account and that LHTs and ecological attributes affect substantially the genetic pattern in Neotropical plants, hence may drive key evolutionary processes in plants. PMID- 27472385 TI - Novel Method for Differentiating Histological Types of Gastric Adenocarcinoma by Using Confocal Raman Microspectroscopy. AB - Gastric adenocarcinoma, a single heterogeneous disease with multiple epidemiological and histopathological characteristics, accounts for approximately 10% of cancers worldwide. It is categorized into four histological types: papillary adenocarcinoma (PAC), tubular adenocarcinoma (TAC), mucinous adenocarcinoma (MAC), and signet ring cell adenocarcinoma (SRC). Effective differentiation of the four types of adenocarcinoma will greatly improve the treatment of gastric adenocarcinoma to increase its five-year survival rate. We reported here the differentiation of the four histological types of gastric adenocarcinoma from the molecularly structural viewpoint of confocal Raman microspectroscopy. In total, 79 patients underwent laparoscopic or open radical gastrectomy during 2008-2011: 21 for signet ring cell carcinoma, 21 for tubular adenocarcinoma, 14 for papillary adenocarcinoma, 6 for mucinous carcinoma, and 17 for normal gastric mucosas obtained from patients underwent operation for other benign lesions. Clinical data were retrospectively reviewed from medical charts, and Raman data were processed and analyzed by using principal component analysis (PCA) and linear discriminant analysis (LDA). Two-dimensional plots of PCA and LDA clearly demonstrated that the four histological types of gastric adenocarcinoma could be differentiated, and confocal Raman microspectroscopy provides potentially a rapid and effective method for differentiating SRC and MAC from TAC or PAC. PMID- 27472386 TI - Impact of oxidative and osmotic stresses on Candida albicans biofilm formation. AB - Candida albicans possesses an ability to grow under different host-driven stress conditions by developing robust protective mechanisms. In this investigation the focus was on the impact of osmotic (2M NaCl) and oxidative (5 mM H2O2) stress conditions during C. albicans biofilm formation. Oxidative stress enhanced extracellular DNA secretion into the biofilm matrix, increased the chitin level, and reduced virulence factors, namely phospholipase and proteinase activity, while osmotic stress mainly increased extracellular proteinase and decreased phospholipase activity. Fourier transform infrared and nuclear magnetic resonance spectroscopy analysis of mannan isolated from the C. albicans biofilm cell wall revealed a decrease in mannan content and reduced beta-linked mannose moieties under stress conditions. The results demonstrate that C. albicans adapts to oxidative and osmotic stress conditions by inducing biofilm formation with a rich exopolymeric matrix, modulating virulence factors as well as the cell wall composition for its survival in different host niches. PMID- 27472387 TI - Corrigendum. PMID- 27472388 TI - Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133+ tumor initiating cells. AB - Chemoresistance in pancreatic cancer has been attributed to tumor-initiating cells (TICs), a minor sub-population of tumor cells. However, the mechanism of chemo-resistance in these cells is still unclear.In the current study, immunohistochemical analysis of LSL-KrasG12D; LSL-Trp53R172H;PdxCre (KPC) murine tumors indicated that hypoxic regions developed through tumor progression. This hypoxic "niche" correlated with increased CD133+ population that had an increased HIF1A activity. Consistent with this observation, CD133+ cells had increased glucose uptake and activity of glycolytic pathway enzymes compared to CD133- cells. Mass spectrometric analysis (UPLC-TQD) following metabolic labeling of CD133+ cells with [13C]-U6 glucose confirmed this observation. Furthermore, although both populations had functionally active mitochondria, CD133+ cells had low mitochondrial complex I and complex IV activity and lesser accumulation of ROS in response to standard chemotherapeutic compounds like paclitaxel, 5FU and gemcitabine. CD133+ cells also showed increased resistance to all three chemotherapeutic compounds and treatment with Glut1 inhibitor (STF31) reversed this resistance, promoting apoptotic death in these cells similar to CD133- cells.Our study indicates that the altered metabolic profile of CD133+ pancreatic TIC protects them against apoptosis, by reducing accumulation of ROS induced by standard chemotherapeutic agents, thereby confering chemoresistance. Since resistance to existing chemotherapy contributes to the poor prognosis in pancreatic cancer, our study paves the way for identifying novel therapeutic targets for managing chemoresistance and tumor recurrence in pancreatic cancer. PMID- 27472390 TI - Prognostic significance of preoperative aspartate aminotransferase to neutrophil ratio index in patients with hepatocellular carcinoma after hepatic resection. AB - OBJECTIVES: Various inflammation-based prognostic scores have been associated with poor survival in patients with hepatocellular carcinoma (HCC), and neutrophils display important roles. However, few studies have illuminated the relationship between preoperative aspartate aminotransferase (AST) to neutrophil ratio index (ANRI) and poor prognosis of HCC. We aimed to clarify the prognostic value of ANRI and evaluate the ability of different inflammation-based prognostic scores such as ANRI, AST to lymphocyte ratio index (ALRI) ,AST to platelet count ratio index (APRI), neutrophil-lymphocyte ratio index (NLR), and platelet lymphocyte ratio index (PLR). METHODS: Data were collected retrospectively from 303 patients who underwent curative resection for HCC. Preoperative ANRI, ALRI, APRI,NLR, PLR and clinico-pathological variables were analyzed. Univariate, multivariate and Kaplan-Meier analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS). RESULTS: ANRI was correlated with presence of HBsAg, AST, presence of cirrhosis, tumor size, PVTT, cancer of the liver Italian program (CLIP) score ,recurrence. Univariate analysis showed ANRI, ALRI, APRI, NLR, PLR were significantly associated with DFS and OS in HCC patients with curative resection. After multivariate analysis, ANRI was demonstrated to be superior to ALRI, APRI, NLR, PLR, which were independently correlated with DFS and OS. Survival analysis showed that preoperative ANRI > 7.8 predicted poor prognosis of patients with HCC after hepatectomy. preoperative ANRI also showed different prognostic value in various subgroups of HCC. Furthermore, the predictive range was expanded by the combination of ANRI and NLR. CONCLUSIONS: preoperative ANRI is an independent effective predictor of prognosis for patients with HCC, higher levels of ANRI predict poorer outcomes and the combining ANRI and NLR increases the prognostic accuracy of testing. PMID- 27472391 TI - TRPC1/TRPC3 channels mediate lysophosphatidylcholine-induced apoptosis in cultured human coronary artery smooth muscles cells. AB - The earlier study showed that lysophosphatidylcholine (lysoPC) induced apoptosis in human coronary artery smooth muscle cells (SMCs); however, the related molecular mechanisms are not fully understood. The present study investigated how lysoPC induces apoptosis in cultured human coronary artery SMCs using cell viability assay, flow cytometry, confocal microscopy, and molecular biological approaches. We found that lysoPC reduced cell viability in human coronary artery SMCs by eliciting a remarkable Ca2+ influx. The effect was antagonized by La3+, SKF-96365, or Pyr3 as well as by silencing TRPC1 or TRPC3. Co-immunoprecipitation revealed that TRPC1 and TRPC3 had protein-protein interaction. Silencing TRPC1 or TRPC3 countered the lysoPC-induced increase of Ca2+ influx and apoptosis, and the pro-apoptotic proteins Bax and cleaved caspase-3 and decrease of the anti apoptotic protein Bcl-2 and the survival kinase pAkt. These results demonstrate the novel information that TRPC1/TRPC3 channels mediate lysoPC-induced Ca2+ influx and apoptosis via activating the pro-apoptotic proteins Bax and cleaved caspase-3 and inhibiting the anti-apoptotic protein Bcl-2 and the survival kinase pAkt in human coronary artery SMCs, which implies that TRPC1/TRC3 channels may be the therapeutic target of lysoPC-induced disorders such as atherosclerosis. PMID- 27472392 TI - Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation. AB - Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. The receptor tyrosine kinase MET has been implicated as an oncogene in numerous cancer subtypes, including non-small cell lung cancer (NSCLC). Here we explore the therapeutic potential of savolitinib (volitinib, AZD6094, HMPL-504), a potent and selective MET inhibitor, in NSCLC. In vitro, savolitinib inhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo, savolitinib causes inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinib resistance in MET-amplified NSCLC cell lines and analyzed individual clones. We found that upregulation of MYC and constitutive mTOR pathway activation is a conserved feature of resistant clones that can be overcome by knockdown of MYC or dual mTORC1/2 inhibition. Lastly, we demonstrate that mechanisms of resistance are heterogeneous, arising via a switch to EGFR dependence or by a requirement for PIM signaling. This work demonstrates the efficacy of savolitinib in NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic. PMID- 27472393 TI - Role of SATB2 in human pancreatic cancer: Implications in transformation and a promising biomarker. AB - SATB2 (special AT-rich binding protein-2), a transcription factor and chromatin modulator, regulates the expression of genes required for maintaining pluripotency and self-renewal. The molecular mechanisms by which human pancreatic normal ductal epithelial cells are transformed to cancer cells are not well understood. The main goal of the paper is to examine the molecular mechanisms by which SATB2 regulates transformation of human pancreatic normal ductal epithelial (HPNE) cells, and assess whether transformed HPNE cells gained the phenotypes of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in pancreatic CSCs, primary tissues and cell lines, but not in HPNE cells. SATB2 induces cellular transformation, stemness and epithelial to mesenchymal transition in HPNE cells, and inhibition of its expression suppresses these activities. Overexpression of SATB2 in HPNE cells resulted in induction of stem cell markers (CD44, CD24 and CD133), and transcription factors (Oct4, Sox2 and Nanog). SATB2 can directly bind to promoters of Bcl-2, Bsp, Nanog, c-Myc, XIAP, Klf4 and Hoxa2, suggesting the role of SATB2 in pluripotency, cell survival and proliferation. SATB2-overexpressing HPNE cells (HPNE/SATB2) formed tumors in Balb C nude mice, whereas HPNE/Empty vector cells did not form any tumor. Since SATB2 is highly expressed in human pancreatic cancer tissues and cell lines, but not in HPNE cells and normal pancreatic tissue, it can drive pancreatic cancer growth and metastasis. Our findings suggest that SATB2 can induce dedifferentiation by inducing stemness and may have a role in pancreatic carcinogenesis, and can be used as a diagnostic biomarker. PMID- 27472394 TI - c-CBL regulates melanoma proliferation, migration, invasion and the FAK-SRC-GRB2 nexus. AB - Melanoma is one of the most aggressive and lethal forms of skin cancer. Despite recent improvements in targeted therapies, many patients with advanced disease fail to achieve lasting tumor regression. Therefore, it is important to develop novel druggable targets that can be exploited to improve clinical outcome. Here, we studied the role of Casitas B-lineage lymphoma (c-CBL), an E3 ubiquitin ligase, in human melanoma. Employing quantitative real-time PCR and Western blot analysis in a panel of human melanoma cell lines (A375, G361, Hs-294T, SK-Mel-2, SK-Mel-28 and 451Lu), we found that c-CBL is strongly expressed in human melanoma cells at the mRNA and protein levels. Further, we determined c-CBL levels in clinical samples of melanomas and benign melanocytic nevi, using quantitative Nuance multispectral imaging. Compared to benign nevi, melanomas showed an overlapping range of c-CBL immunoreactivity. Small interfering RNA (siRNA) mediated knockdown of c-CBL resulted in decreased proliferation, clonogenic survival and migration of melanoma cells. Furthermore, it also resulted in decreased cellular invasion in a 3D spheroid assay system. C-CBL and FAK are regulated by SRC, and FAK binds SRC and GRB2. C-CBL E3 ligase domain regulates receptor tyrosine kinase internalization through ubiquitination and its ring finger domain stabilizes the FAK-SRC-actin cytoskeleton thereby promoting cellular motility. C-CBL knockdown was associated with decreased protein and/or mRNA levels of SRC, FAK and GRB2. Taken together, we have provided evidence that c-CBL plays a role in melanoma cell proliferation, migration and invasion as well as inhibition of the FAK-GRB2-SRC nexus. Our findings indicate that additional studies are warranted to further dissect the role of c-CBL in melanoma and determine the therapeutic potential of its inhibition. PMID- 27472395 TI - IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin. AB - The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-related kinase (ATR). We also observed a clear induction of DDR in cells that were exposed to IGF-1R TKIs (BMS-754807 and OSI-906) as indicated by accumulation of gamma-H2AX, and phosphorylated Chk1. Combination of the IGF-1R/IR TKIs with an ATR kinase inhibitor VE-821 resulted in additive to synergistic cytotoxicity compared to either drug alone. In MCF-7 cells with stably acquired resistance to the IGF-1R TKI (MCF-7-R), DNA damage was also observed, and again, dual inhibition of the ATR kinase and IGF-1R/IR kinase resulted in synergistic cytotoxicity. Interestingly, dual inhibition of ATR and IGF-1R was more effective in MCF-7-R cells than parental cells. IGF-1R TKIs also potentiated the effects of cisplatin in a panel of breast cancer cell lines. Overall, our findings identify induction of DDR by IGF-1R kinase inhibition as a rationale for co-targeting the IGF-1R with ATR kinase inhibitors or cisplatin, particularly in cells with acquired resistance to TKIs. PMID- 27472396 TI - Targeting XBP1-mediated beta-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues. AB - Conventional chemotherapy is commonly used for advanced stages of transitional cell carcinoma (TCC) with modest success and high morbidity; however, TCC eventually develops resistance. Muscle invasive bladder cancer (MIBC) is recognized as a lethal disease due to its poor response to traditional chemotherapy. Numerous studies have implicated beta-catenin, a critical effector in Wnt-mediated pathway associated with epithelial-mesenchymal transition and cancer stem cell, is involved in TCC progression, and furthermore closely associated with chemo-resistance. In this study, we discovered a novel natural product analogue CYD 6-17 that has a potent inhibitory effect on TCC cells exhibiting drug resistance to various chemotherapeutics, with an IC50 at nM range. Delivery of CYD 6-17 significantly inhibited the tumor growth using xenograft model but without detectable side effects. Mechanistically, it targeted beta-catenin gene transcription by decreasing the binding of XBP1 to the promoter region, which appeared to be a new regulatory mechanism for beta-catenin gene expression. Clinically, XBP1 expression correlated with the poor overall survival of patients. Overall, this study unveils unique mechanism of beta-catenin gene regulation in advanced TCC and also offers a potential rational therapeutic regimen to MIBC. PMID- 27472397 TI - Ethnic Differences in Arterial Wave Reflection Are Mostly Explained by Differences in Body Height - Cross-Sectional Analysis of the HELIUS Study. AB - BACKGROUND: Differences in arterial wave reflection and central blood pressure (BP) have been associated with cardiovascular disease (CVD) in various populations and may contribute to ethnic differences in CVD. Whether ethnic differences in wave reflection and central BP can be explained by conventional risk factors for CVD or may result from physiological differences remains undetermined. METHODS: We examined ethnic differences in augmentation index (AIx) and central systolic BP and their determinants in a large multi-ethnic cohort study in Amsterdam, the Netherlands. A total of 8812 (46% male) participants aged 18-70 years of Dutch, South-Asian Surinamese, African Surinamese and Ghanaian origin were included. AIx and central BP were measured in duplicate using the Arteriograph system. RESULTS: AIx and central systolic BP were significantly higher in South-Asian Surinamese (35+/-17%, 126+/-22 mmHg), African Surinamese (33+/-17%, 129+/-23 mmHg) and Ghanaian (33+/-16%, 135+/-24 mmHg) as compared with Dutch (27+/-17%, 118+/-20 mmHg, all p<0.001). Correction for cardiovascular risk factors only slightly reduced the difference in AIx, whereas correction for body height attenuated age and gender corrected ethnic differences in AIx the most. Differences in central systolic BP were primarily determined by differences in AIx for South-Asian Surinamese and by differences in peripheral systolic BP for subjects of African origin. CONCLUSIONS: Substantial differences in AIx and central BP exist across different ethnic groups that cannot be explained by differences in conventional risk factors for CVD. These findings may explain part of the underestimation of cardiovascular risk observed in populations of African and South-Asian descent. PMID- 27472398 TI - Experience Playing a Musical Instrument and Overnight Sleep Enhance Performance on a Sequential Typing Task. AB - The smooth, coordinated fine motor movements required to play a musical instrument are not only highly valued in our society; they also predict academic success in areas that generalize beyond the motor domain, including reading and math readiness, and verbal abilities. Interestingly, motor skills that overlap with those required to play a musical instrument (e.g., sequential finger tapping) markedly improve (get faster) over a night of sleep, but not after a day spent awake. Here we studied whether individuals who play musical instruments that require fine finger motor skill are better able to learn and consolidate a simple motor skill task compared to those who do not play an instrument, and whether sleep-specific motor skill benefits interact with those imparted by musical experience. We used the motor sequence task (MST), which taps into a core skill learned and used by musicians, namely, the repetition of learned sequences of key presses. Not surprisingly, we found that musicians were faster than non musicians throughout the learning session, typing more correct sequences per 30 sec trial. In the 12hrs that followed learning we found that sleep and musical experience both led to greater improvement in performance. Surprisingly, musicians retested after a day of wake performed slightly better than non musicians who had slept between training and retest, suggesting that musicians have the capacity to consolidate a motor skill across waking hours, while non musicians appear to lack this capacity. These findings suggest that the musically trained brain is optimized for motor skill consolidation across both wake and sleep, and that sleep may simply promote a more effective use of this machinery. In sum, there may be something special about musicians, perhaps a neurophysiological advantage, that leads to both the expected-greater motor speed at learning-and the surprising-greater motor skill improvement over time. PMID- 27472399 TI - Two Distinct Cardiolipin Synthases Operate in Agrobacterium tumefaciens. AB - Cardiolipin (CL) is a universal component of energy generating membranes. In most bacteria, it is synthesized via the condensation of two molecules phosphatidylglycerol (PG) by phospholipase D-type cardiolipin synthases (PLD-type Cls). In the plant pathogen and natural genetic engineer Agrobacterium tumefaciens CL comprises up to 15% of all phospholipids in late stationary growth phase. A. tumefaciens harbors two genes, atu1630 (cls1) and atu2486 (cls2), coding for PLD-type Cls. Heterologous expression of either cls1 or cls2 in Escherichia coli resulted in accumulation of CL supporting involvement of their products in CL synthesis. Expression of cls1 and cls2 in A. tumefaciens is constitutive and irrespective of the growth phase. Membrane lipid profiling of A. tumefaciens mutants suggested that Cls2 is required for CL synthesis at early exponential growth whereas both Cls equally contribute to CL production at later growth stages. Contrary to many bacteria, which suffer from CL depletion, A. tumefaciens tolerates large changes in CL content since the CL-deficient cls1/cls2 double mutant showed no apparent defects in growth, stress tolerance, motility, biofilm formation, UV-stress and tumor formation on plants. PMID- 27472400 TI - Disproportionate longer-term opioid use among U.S. adults with mood disorders. AB - Adults with mood disorders frequently use prescription opioids. The factors associated with this increased use remain unclear. We used the Medical Expenditure Panel Surveys from 2005 to 2011 to measure the association of mood disorders with new opioid use and the transition to longer-term opioid use for a variety of pain conditions before and after controlling for patient characteristics and clinical disability. We analyzed 33,450 adults with likely acute or potentially chronic pain conditions who were not using opioids at baseline. Among respondents with likely acute pain conditions, those with mood disorders initiated opioids more frequently for that pain condition compared with those without mood disorders (19.3%, vs 17.2%, P = 0.01). After initiation, they also transitioned to longer-term opioid therapy more frequently (11.7% vs 5.3%, P < 0.01). Among respondents with potentially chronic pain conditions, adults with mood disorders initiated opioid therapy more frequently for their chronic pain condition (11.5% vs 9.2%, P < 0.01) and transitioned to longer-term therapy more frequently (36.8% vs 19.9%, P < 0.01). After adjusting for sociodemographics and clinical disability, there was no association between mood disorders and new opioid use for likely acute (adjusted odds ratio [aOR] 1.05 [0.92-1.20]) or potentially chronic pain (aOR 0.91 [0.80-1.03]). However, there remained a strong association between mood disorders and the transition to longer-term opioid use for likely acute (aOR 1.77 [1.15-2.72]) and potentially chronic pain (aOR 1.95 [1.42-2.68]). Targeting the transition to longer-term opioid use may help clinicians reduce potentially inappropriate opioid prescriptions in this high risk population. PMID- 27472401 TI - A novel and simple fluorescence probe for detecting main group magnesium ion in HeLa cells and Arabidopsis. AB - A simple-molecule fluorescence probe L has been designed, synthesized and characterized, which shows high selectivity and sensitivity for the main group magnesium ion through fluorescence "turn-on" response in ethanol solution, and no interference from calcium ion in particular. Detection limit of probe L is 1.47*10(-6) M and the rapid response could reach about 15-20s. The recognition mechanism has been established by fluorescence spectra, (1)H NMR study. Moreover, probe L presents a great photostability, low toxicity and cellular permeability, then we have carried out fluorescent bio-imaging of the probe L for magnesium ions in HeLa cells, which showed that probe L could be utilized to detect the intracellular magnesium ion. Furthermore, it is successfully used as a magnesium ion developer in plant tissues, which shows that it not only can be well tracking the transport of magnesium ion but also make a corresponding fluorescence response to different concentrations magnesium ion. These results would make this probe a great potential application for detecting Mg(2+) in biological system. PMID- 27472402 TI - Spatial-resolved electrochemiluminescence ratiometry based on bipolar electrode for bioanalysis. AB - Herein, a spatial-resolved electrochemiluminescene (ECL) ratiometry based on a closed biopolar electrode (BPE) is reported for the highly sensitive detection of prostate specific antigen (PSA). Au@g-C3N4 NCs as one ECL emitter were firstly coated on the cathode of BPE, while the anode of the BPE served for calibration via another ECL substance, Ru(bpy)3(2+). The electroneutrality across the BPE makes the reactions on each pole of BPE electrically coupled. Thus one electrochemical sensing reaction at one pole of BPE could be quantified at both ends. A composite, Pt-PAMAM-DNAzyme was assembled on the surface of cathode via DNA hybridization between probe DNA and PSA aptamer. It acted as an ECL quencher of g-C3N4 via resonance energy transfer (RET) and catalyzing the reduction of O2, the co-reactant of g-C3N4. Meanwhile, it could promote the ECL of Ru(bpy)3(2+) at anode, since the catalytic reduction of O2 at the cathode increased the faradiac current flowing through the BPE. Based on this signal composite, an ECL "off-on" phenomenon was observed at the cathode, after Pt-PAMAM-DNAzyme was "peeled off" by PSA. Conversely, at the anode, an "on-off" ECL changing was obtained. Therefore, a sensitive ratiometry for PSA detection was achieved with a linear range from 0.10 to 200ng/mL. Since the two ECL emitters were physically separated, the ratiometric system was relatively simple and neither optical filters nor spectrometer were required. The strategy combining the ECL ratiometry and BPE broadens the applications of BPE-ECL and shows good perspective in clinical application. PMID- 27472403 TI - Detection of Hepatitis C core antibody by dual-affinity yeast chimera and smartphone-based electrochemical sensing. AB - Yeast cell lines were genetically engineered to display Hepatitis C virus (HCV) core antigen linked to gold binding peptide (GBP) as a dual-affinity biobrick chimera. These multifunctional yeast cells adhere to the gold sensor surface while simultaneously acting as a "renewable" capture reagent for anti-HCV core antibody. This streamlined functionalization and detection strategy removes the need for traditional purification and immobilization techniques. With this biobrick construct, both optical and electrochemical immunoassays were developed. The optical immunoassays demonstrated detection of anti-HCV core antibody down to 12.3pM concentrations while the electrochemical assay demonstrated higher binding constants and dynamic range. The electrochemical format and a custom, low-cost smartphone-based potentiostat ($20 USD) yielded comparable results to assays performed on a state-of-the-art electrochemical workstation. We propose this combination of synthetic biology and scalable, point-of-care sensing has potential to provide low-cost, cutting edge diagnostic capability for many pathogens in a variety of settings. PMID- 27472404 TI - Carbohydrate-enriched diet predispose to anxiety and depression-like behavior after stress in mice. AB - OBJECTIVES: Obesity is a chronic disease frequently associated with serious co morbidities, such as diabetes type II, metabolic syndrome, and psychiatric disorders. Little is known, however, regarding the behavioral consequences of modified diet constituents and the propensity to development of stress related disorders. Thus, the aim of this study was to verify whether chronic exposure to a normocaloric/high-carbohydrate diet will modify the animal's behavior after different stressful stimuli. METHODS: BALB/c mice were fed for 12 weeks with a standard chow diet or high refined carbohydrate-containing diet (HC). Following this period, independent groups of animals were exposed to different stress paradigms: 1 - two hours of restraint stress followed by exposure to the Elevated Plus Maze test (EPM) 24 hours later; 2 - The contextual fear conditioning (CFC) test and 3 - the tail suspension test (TST). RESULTS: Despite no change on total body weight, animals fed with HC diet showed increase in serum leptin levels and higher adiposity compared to diet control group. In behavioral tests, animals from HC diet group displayed reduction in the percentage of entries into the open arms of the EPM, evaluated 24 hours after restraint stress, suggesting an anxiogenic-like effect. It is also observed increase in aversive memory in the CFC test and depressive-like behavior in TST. DISCUSSION: Our results suggest that a moderate obesity, induced by high refined carbohydrate diet, may facilitate the development of anxiety and depressive-like behaviors after the stress. The mechanisms responsible for such effects remain to be elucidated. PMID- 27472405 TI - Effectiveness of cognitive-behavioural therapy on glycaemic control and psychological outcomes in adults with diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. AB - AIM: Diabetes is a chronic progressive condition presenting physical, social and psychological challenges that increase the risk of comorbid mental health problems. Cognitive-behavioural therapy (CBT) is effective in treating a variety of psychological disorders, and may potentially improve glycaemic control and psychological outcomes in diabetes. This systematic review and meta-analysis aims to establish the effectiveness of CBT on glycaemic control and comorbid diabetes related distress, depression, anxiety and quality of life in the short, medium and longer term among adults with diabetes. METHOD: An electronic search was conducted in PubMed, Embase, MEDLINE, PsycINFO, CINAHL, Web of Knowledge, Cochrane Central Register of Controlled Trials and references in reviews. Twelve randomized controlled trials (RCTs) were identified that evaluated the effectiveness of CBT on at least one of: glycaemic control, diabetes-related distress, anxiety, depression or quality of life in adults with Type 1 or Type 2 diabetes. The Cochrane Risk of Bias Tool and Review Manager version 5.3 were used for risk of bias assessment and meta-analysis, respectively. RESULTS: CBT is effective in reducing short-term and medium-term glycaemic control, although no significant effect was found for long-term glycaemic control. CBT improved short- and medium-term anxiety and depression, and long-term depression. Mixed results were found for diabetes-related distress and quality of life. CONCLUSION: CBT is beneficial in improving depression for adults with diabetes. It may have benefits for improving glycaemic control and other aspects of psychological health, although the findings are inconclusive. PMID- 27472406 TI - Plaque angiogenesis and its relation to inflammation and atherosclerotic plaque destabilization. AB - PURPOSE OF REVIEW: The review discusses the recent literature on plaque angiogenesis and its relation to inflammation and plaque destabilization. Furthermore, it discusses how plaque angiogenesis can be used to monitor atherosclerosis and serve as a therapeutic target. RECENT FINDINGS: Histopathologic studies have shown a clear relationship between plaque angiogenesis, intraplaque hemorrhage (IPH), plaque vulnerability, and cardiovascular events. Hypoxia is a main driver of plaque angiogenesis and the mechanism behind angiogenesis is only partly known. IPH, as the result of immature neovessels, is associated with increased influx of inflammatory cells in the plaques. Experimental models displaying certain features of human atherosclerosis such as plaque angiogenesis or IPH are developed and can contribute to unraveling the mechanism behind plaque vulnerability. New imaging techniques are established, with which plaque angiogenesis and vulnerability can be detected. Furthermore, antiangiogenic therapies in atherosclerosis gain much attention. SUMMARY: Plaque angiogenesis, IPH, and inflammation contribute to plaque vulnerability. Histopathologic and imaging studies together with specific experimental studies have provided insights in plaque angiogenesis and plaque vulnerability. However, more extensive knowledge on the underlying mechanism is required for establishing new therapies for patients at risk. PMID- 27472407 TI - Role of noncoding RNA in vascular remodelling. AB - PURPOSE OF REVIEW: Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are becoming fundamentally important in the pathophysiology relating to injury-induced vascular remodelling. We highlight recent studies that demonstrate the involvement of ncRNAs in vein graft disease, in in-stent restenosis and in pulmonary arterial hypertension, with a particular focus on endothelial cell and vascular smooth muscle cell function. We also briefly discuss the emerging role of exosomal-derived ncRNAs and how this mechanism impacts on vascular function. RECENT FINDINGS: ncRNAs have been described as novel regulators in the pathophysiology of vascular injury, inflammation, and vessel wall remodelling. In particular, several studies have demonstrated that manipulation of miRNAs can reduce the burden of pathological vascular remodelling. Such studies have also shown that exosomal miRNA-mediated, cell-to-cell communication between endothelial cells and vascular smooth muscle cells is critical in the disease process. In addition to miRNAs, lncRNAs are emerging as regulators of vascular function in health and disease. Although lncRNAs are complex in both their sheer numbers and mechanisms of action, identifying their contribution to vascular disease is essential. SUMMARY: Given the important roles of ncRNAs in vascular injury and remodelling together will their capacity for cell-to-cell communication, manipulating ncRNA might provide novel therapeutic interventions. PMID- 27472409 TI - The central role of arterial retention of cholesterol-rich apolipoprotein-B containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. AB - PURPOSE OF REVIEW: Today, it is no longer a hypothesis, but an established fact, that increased plasma concentrations of cholesterol-rich apolipoprotein-B (apoB) containing lipoproteins are causatively linked to atherosclerotic cardiovascular disease (ASCVD) and that lowering plasma LDL concentrations reduces cardiovascular events in humans. Here, we review evidence behind this assertion, with an emphasis on recent studies supporting the 'response-to-retention' model - namely, that the key initiating event in atherogenesis is the retention, or trapping, of cholesterol-rich apoB-containing lipoproteins within the arterial wall. RECENT FINDINGS: New clinical trials have shown that ezetimibe and anti PCSK9 antibodies - both nonstatins - lower ASCVD events, and they do so to the same extent as would be expected from comparable plasma LDL lowering by a statin. These studies demonstrate beyond any doubt the causal role of apoB-containing lipoproteins in atherogenesis. In addition, recent laboratory experimentation and human Mendelian randomization studies have revealed novel information about the critical role of apoB-containing lipoproteins in atherogenesis. New information has also emerged on mechanisms for the accumulation in plasma of harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoproteins in states of overnutrition. Like LDL, these harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoprotein remnants become retained and modified within the arterial wall, causing atherosclerosis. SUMMARY: LDL and other cholesterol-rich, apoB-containing lipoproteins, once they become retained and modified within the arterial wall, cause atherosclerosis. This simple, robust pathophysiologic understanding may finally allow us to eradicate ASCVD, the leading killer in the world. PMID- 27472408 TI - Dipeptidyl peptidase-4 inhibition: insights from the bench and recent clinical studies. AB - PURPOSE OF REVIEW: Atherosclerosis is the leading cause of death globally. The pathophysiology of atherosclerosis is not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. Recent advances in the understanding of DPP4 function in atherosclerosis will be discussed in this review. RECENT FINDINGS: Multiple preclinical and clinical studies suggest DPP4/glucagon-like peptide-1 axis is involved in the development of atherosclerotic disease. However, several recent trials assessing the cardiovascular effects of DPP4 inhibition indicate enzymatic inhibition of DPP4 lacks beneficial effects on cardiovascular disease. SUMMARY: Catalytic inhibition of DPP4 with DPP4 inhibitors alters pathways that could favor cardioprotection. Glucagon-like peptide-1 receptor-independent aspects of DPP4 function may contribute to the overall neutral effects on cardiovascular outcome seen in the outcome trials. PMID- 27472410 TI - Novel B-cell subsets in atherosclerosis. AB - PURPOSE OF REVIEW: The number of deaths associated with cardiovascular disease remains high, despite great advances in treating the associated high levels of cholesterol. The main underlying pathology of cardiovascular disease is atherosclerosis, which is recognized as a chronic autoimmune-like inflammatory disease. Hence, there is a pressing need to shed light on the immune pathways associated with atherosclerosis. B cells have long been thought to have a general protective effect in atherosclerosis. However, findings in the last decade have challenged this paradigm, showing that it is crucial to differentiate between the various B-cell subsets when assessing their role/effect on atherosclerosis. RECENT FINDINGS: It has become increasingly recognized lately that B cells can have significant effects on the immune system independent of antibody production. The understanding that B cells form a major source of cytokines and can directly influence T-cell responses via surface markers, have led to the identification of novel B-cell subsets. These subsets are important modulators of autoimmune disorders but have not yet been fully investigated in atherosclerosis. SUMMARY: Here we review the current known roles of B-cell subsets and the putative effects of recently identified B cells on atherosclerosis. PMID- 27472411 TI - Depression among migrant workers in Al-Qassim, Saudi Arabia. AB - BACKGROUND: Mental disorders are common among migrant workers. There is no data on depression in Saudi Arabia among them; although, they are a third of the population. OBJECTIVE: To determine the prevalence of depression and to assess its relationship with duration of stay and living condition in a sample of migrant workers. METHODS: A cross-sectional survey of 400 migrant workers was conducted in Al-Qassim region of Saudi Arabia. Exposure and covariate factors were assessed with a standardized questionnaire, depression with the CES-D (Center for Epidemiological Studies on Depression) scale, and physical indices (e.g. weight, height, and blood pressure) with a general examination. Logistic regression was used to identify significant correlates of depression. RESULTS: Depression prevalence was 20%; it did not vary by duration of stay or living condition but by age, stress, and self-reported health. In the multivariate model, those who reported 'moderate' or 'high' levels of stress were 1.7 (95% CI: 0.9, 3.1) and 3.9 (95% CI: 1.7, 9.1) times more likely to have depression (reference ='low' level), respectively. Similarly, those who rated their health either 'good' or 'fair to very poor' were 3.4 (95% CI: 1.9, 6.1) and 4.8 (95% CI: 2.3, 10.1) times more likely to have depression (reference ='excellent/very good'), respectively. LIMITATIONS: The data were collected from one company and pertained to only male participants, and the study design could not establish temporal sequence between the exposure and outcome variables. CONCLUSION: Depression is considerably high in this population; a large-scale and nationally representative survey is needed to validate the findings. PMID- 27472413 TI - Corpus callosum integrity is affected by mood disorders and also by the suicide attempt history: A diffusion tensor imaging study. AB - BACKGROUND: Some MRI studies have noted alterations in the corpus callosum (CC) white matter integrity of individuals with mood disorders and also in patients with suicidal behavior. We investigated the specific impact of suicidal behavior on CC integrity in mood disorders. METHODS: CC structural changes were assessed by diffusion tensor imaging (DTI) in 121 women 18-50-year-old): 41 with bipolar disorder (BD), 50 with major depressive disorder (MDD) and 30 healthy controls (HC). Fractional anisotropy (FA) and DTI metrics were calculated for the genu, body and splenium of CC and compared in the three groups by MANCOVA. Then, they were re-analyzed relative to the suicide attempt history within the MDD and BD groups and to the suicide number/severity. RESULTS: FA values for the CC genu and body were lower in non-suicide attempters with BD than with MDD and in HC. Conversely, FA values for all CC regions were significantly lower in suicide attempters with BD than in HC. Finally, higher number of suicide attempts (>2) and elevated Suicidal Intent Scale score were associated with significant splenium alterations. LIMITATIONS: Limitations include the cross-sectional design (non-causal study), the potential influence of medications and concerns about the generalizability to men. CONCLUSION: Genu and body are altered in non-suicide attempters with BD, while splenium is specifically altered in suicide attempters, independently from their psychiatric status. History of suicide attempts may be a source of heterogeneity in the association between CC alterations and BD and may partially explain the variable results of previous studies. PMID- 27472412 TI - Parental and comorbid migraine in individuals with bipolar disorder: A nationwide register study. AB - BACKGROUND: Genetic studies imply a shared genetic etiology between bipolar disorder (BD) and migraine. Epidemiological studies have demonstrated elevated comorbidity between these disorders, but haven't controlled for parental psychopathology. No previous nationally representative studies exist on familial clustering of BD and migraine. This study examines the association between parental and comorbid migraine and BD, controlling for potential confounders. METHODS: We identified 1861 cases aged <=25 years, 3643 matched controls, and their parents from Finnish national registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) and two-sided significance limits of p<0.05. RESULTS: Parental migraine, controlling for parental BD, was associated with offspring BD diagnosed at age >=18 years (OR 1.52, 95%CI: 1.08-2.14). Associations between BD and comorbid migraine persisted following adjustment for parental BD and parental migraine in all subjects (OR=2.46, 95% CI: 1.76-3.42), both age groups of BD-diagnosis (<18 years,>=18 years) and both sexes. LIMITATIONS: The diagnoses were register-based, not directly ascertained. CONCLUSIONS: This study indicates that parental migraine, even in the absence of parental BD, is a risk factor for offspring BD. Thus, a genetic link between BD and migraine could potentially explain some of the elevated comorbidity between these disorders. However, BD shows a stronger association with comorbid migraine than with parental migraine, suggesting that much of the elevated comorbidity is related to non-genetic factors. Increased understanding of mechanisms underlying the comorbidity of BD and migraine is important since it is associated with poorer health-related outcomes compared with BD alone. PMID- 27472414 TI - Distress intolerance as a moderator of the relationship between daily stressors and affective symptoms: Tests of incremental and prospective relationships. AB - BACKGROUND: Distress intolerance (DI) is conceptualized as an individual difference reflective of the ability to tolerate aversive psychological states. Although high DI has demonstrated cross-sectional associations with multiple forms of psychopathology, few studies have tested key facets of its theoretical conceptualization. Specifically, little research has been conducted on DI's theorized role as an incrementally valid prospective moderator of the relationship between daily stressful events and affective symptoms reflective of preoccupation with aversive internal (e.g., depression, worry) rather than external stimuli (e.g., social anxiety). METHOD: A non-clinical sample (N = 147; 77% female; M age = 19.32) in which high DI individuals were oversampled was recruited. Participants completed baseline measures of DI and trait negative affect followed by six diary entries over a two-week period in which participants reported on daily stressors, negative affect, worry, depressive, and social anxiety symptoms. RESULTS: Hierarchical linear models revealed that DI positively predicted depressive and worry, but not social anxiety symptoms, independent of daily stressors and negative affect. Further, a significant interaction effect was found such that the positive association between daily stressor(s) occurrence and daily worry was significant at high, but not low DI, and a similar trend level interaction effect was observed for depressive symptoms. The interaction for social anxiety symptoms was non-significant LIMITATIONS: Utilization of a non clinical sample precludes generalization of results to clinical samples. Only self-reported DI was assessed, limiting conclusions to perceived as opposed to behaviorally-indexed DI. CONCLUSIONS: Results largely supported DI's theoretical conceptualization as an incrementally valid moderator of stress responding with relevance to particular affective symptoms. PMID- 27472415 TI - Cyclic Incrementality in Competitive Coevolution: Evolvability through Pseudo Baldwinian Switching-Genes. AB - Coevolving systems are notoriously difficult to understand. This is largely due to the Red Queen effect that dictates heterospecific fitness interdependence. In simulation studies of coevolving systems, master tournaments are often used to obtain more informed fitness measures by testing evolved individuals against past and future opponents. However, such tournaments still contain certain ambiguities. We introduce the use of a phenotypic cluster analysis to examine the distribution of opponent categories throughout an evolutionary sequence. This analysis, adopted from widespread usage in the bioinformatics community, can be applied to master tournament data. This allows us to construct behavior-based category trees, obtaining a hierarchical classification of phenotypes that are suspected to interleave during cyclic evolution. We use the cluster data to establish the existence of switching-genes that control opponent specialization, suggesting the retention of dormant genetic adaptations, that is, genetic memory. Our overarching goal is to reiterate how computer simulations may have importance to the broader understanding of evolutionary dynamics in general. We emphasize a further shift from a component-driven to an interaction-driven perspective in understanding coevolving systems. As yet, it is unclear how the sudden development of switching-genes relates to the gradual emergence of genetic adaptability. Likely, context genes gradually provide the appropriate genetic environment wherein the switching-gene effect can be exploited. PMID- 27472416 TI - WebAL Comes of Age: A Review of the First 21 Years of Artificial Life on the Web. AB - We present a survey of the first 21 years of web-based artificial life (WebAL) research and applications, broadly construed to include the many different ways in which artificial life and web technologies might intersect. Our survey covers the period from 1994-when the first WebAL work appeared-up to the present day, together with a brief discussion of relevant precursors. We examine recent projects, from 2010-2015, in greater detail in order to highlight the current state of the art. We follow the survey with a discussion of common themes and methodologies that can be observed in recent work and identify a number of likely directions for future work in this exciting area. PMID- 27472417 TI - Open-Ended Evolution: Perspectives from the OEE Workshop in York. AB - We describe the content and outcomes of the First Workshop on Open-Ended Evolution: Recent Progress and Future Milestones (OEE1), held during the ECAL 2015 conference at the University of York, UK, in July 2015. We briefly summarize the content of the workshop's talks, and identify the main themes that emerged from the open discussions. Two important conclusions from the discussions are: (1) the idea of pluralism about OEE-it seems clear that there is more than one interesting and important kind of OEE; and (2) the importance of distinguishing observable behavioral hallmarks of systems undergoing OEE from hypothesized underlying mechanisms that explain why a system exhibits those hallmarks. We summarize the different hallmarks and mechanisms discussed during the workshop, and list the specific systems that were highlighted with respect to particular hallmarks and mechanisms. We conclude by identifying some of the most important open research questions about OEE that are apparent in light of the discussions. The York workshop provides a foundation for a follow-up OEE2 workshop taking place at the ALIFE XV conference in Cancun, Mexico, in July 2016. Additional materials from the York workshop, including talk abstracts, presentation slides, and videos of each talk, are available at http://alife.org/ws/oee1 . PMID- 27472420 TI - Reasons to be fussy about cultural evolution. AB - This discussion paper responds to two recent articles in Biology and Philosophy that raise similar objections to cultural attraction theory, a research trend in cultural evolution putting special emphasis on the fact that human minds create and transform their culture. Both papers are sympathetic to this idea, yet both also regret a lack of consilience with Boyd, Richerson and Henrich's models of cultural evolution. I explain why cultural attraction theorists propose a different view on three points of concern for our critics. I start by detailing the claim that cultural transmission relies not chiefly on imitation or teaching, but on cognitive mechanisms like argumentation, ostensive communication, or selective trust, whose evolved or habitual function may not be the faithful reproduction of ideas or behaviours. Second, I explain why the distinction between context biases and content biases might not always be the best way to capture the interactions between culture and cognition. Lastly, I show that cultural attraction models cannot be reduced to a model of guided variation, which posits a clear separation between individual and social learning processes. With cultural attraction, the same cognitive mechanisms underlie both innovation and the preservation of traditions. PMID- 27472419 TI - Epidermal growth factor preserves myelin and promotes astrogliosis after intraventricular hemorrhage. AB - Intraventricular hemorrhage (IVH) leads to reduced myelination and astrogliosis of the white matter in premature infants. No therapeutic strategy exists to minimize white matter injury in survivors with IVH. Epidermal growth factor (EGF) enhances myelination, astrogliosis, and neurologic recovery in animal models of white matter injury. Here, we hypothesized that recombinant human (rh) EGF treatment would enhance oligodendrocyte precursor cell (OPC) maturation, myelination, and neurological recovery in preterm rabbits with IVH. In addition, rhEGF would promote astrogliosis by inducing astroglial progenitor proliferation and GFAP transcription. We tested these hypotheses in a preterm rabbit model of IVH and evaluated autopsy samples from human preterm infants. We found that EGF and EGFR expression were more abundant in the ganglionic eminence relative to the cortical plate and white matter of human infants and that the development of IVH reduced EGF levels, but not EGFR expression. Accordingly, rhEGF treatment promoted proliferation and maturation of OPCs, preserved myelin in the white matter, and enhanced neurological recovery in rabbits with IVH. rhEGF treatment inhibited Notch signaling, which conceivably contributed to OPC maturation. rhEGF treatment contributed to astrogliosis by increasing astroglial proliferation and upregulating GFAP as well as Sox9 expression. Hence, IVH results in a decline in EGF expression; and rhEGF treatment preserves myelin, restores neurological recovery, and exacerbates astrogliosis by inducing proliferation of astrocytes and enhancing transcription of GFAP and Sox9 in pups with IVH. rhEGF treatment might improve the neurological outcome of premature infants with IVH. GLIA 2016;64:1987-2004. PMID- 27472421 TI - Barriers and Recommended Interventions to Prevent Melioidosis in Northeast Thailand: A Focus Group Study Using the Behaviour Change Wheel. AB - BACKGROUND: Melioidosis, an often fatal infectious disease in Northeast Thailand, is caused by skin inoculation, inhalation or ingestion of the environmental bacterium, Burkholderia pseudomallei. The major underlying risk factor for melioidosis is diabetes mellitus. Recommendations for melioidosis prevention include using protective gear such as rubber boots and gloves when in direct contact with soil and environmental water, and consuming bottled or boiled water. Only a small proportion of people follow such recommendations. METHODS: Nine focus group discussions were conducted to evaluate barriers to adopting recommended preventive behaviours. A total of 76 diabetic patients from northeast Thailand participated in focus group sessions. Barriers to adopting the recommended preventive behaviours and future intervention strategies were identified using two frameworks: the Theoretical Domains Framework and the Behaviour Change Wheel. RESULTS: Barriers were identified in the following five domains: (i) knowledge, (ii) beliefs about consequences, (iii) intention and goals, (iv) environmental context and resources, and (v) social influence. Of 76 participants, 72 (95%) had never heard of melioidosis. Most participants saw no harm in not adopting recommended preventive behaviours, and perceived rubber boots and gloves to be hot and uncomfortable while working in muddy rice fields. Participants reported that they normally followed the behaviour of friends, family and their community, the majority of whom did not wear boots while working in rice fields and did not boil water before drinking. Eight intervention functions were identified as relevant for the intervention: (i) education, (ii) persuasion, (iii) incentivisation, (iv) coercion, (v) modeling, (vi) environmental restructuring, (vii) training, and (viii) enablement. Participants noted that input from role models in the form of physicians, diabetic clinics, friends and families, and from the government via mass media would be required for them to change their behaviours. CONCLUSION: There are numerous barriers to the adoption of behaviours recommended for melioidosis prevention. We recommend that a multifaceted intervention at community and government level is required to achieve the desired behaviour changes. PMID- 27472422 TI - Performance Investigation of Proteomic Identification by HCD/CID Fragmentations in Combination with High/Low-Resolution Detectors on a Tribrid, High-Field Orbitrap Instrument. AB - The recently-introduced Orbitrap Fusion mass spectrometry permits various types of MS2 acquisition methods. To date, these different MS2 strategies and the optimal data interpretation approach for each have not been adequately evaluated. This study comprehensively investigated the four MS2 strategies: HCD-OT (higher energy-collisional-dissociation with Orbitrap detection), HCD-IT (HCD with ion trap, IT), CID-IT (collision-induced-dissociation with IT) and CID-OT on Orbitrap Fusion. To achieve extensive comparison and identify the optimal data interpretation method for each technique, several search engines (SEQUEST and Mascot) and post-processing methods (score-based, PeptideProphet, and Percolator) were assessed for all techniques for the analysis of a human cell proteome. It was found that divergent conclusions could be made from the same dataset when different data interpretation approaches were used and therefore requiring a relatively fair comparison among techniques. Percolator was chosen for comparison of techniques because it performs the best among all search engines and MS2 strategies. For the analysis of human cell proteome using individual MS2 strategies, the highest number of identifications was achieved by HCD-OT, followed by HCD-IT and CID-IT. Based on these results, we concluded that a relatively fair platform for data interpretation is necessary to avoid divergent conclusions from the same dataset, and HCD-OT and HCD-IT may be preferable for protein/peptide identification using Orbitrap Fusion. PMID- 27472423 TI - Chemodiversity of Epicuticular n-Alkanes and Morphological Traits of Natural Populations of Satureja subspicata Bartl. ex Vis. along Dinaric Alps - Ecological and Taxonomic Aspects. AB - Morphological characters and the composition of epicuticular leaf n-alkanes of two Satureja subspicata Bartl. ex Vis. subspecies (subsp. liburnica Silic and subsp. subspicata) from nine natural populations along Dinaric Alps range were studied. Morphological characters were chosen based on Silic's subspecies separation. Seventeen n-alkane homologues (C19 - C35 ) were identified using gas chromatography/mass spectrometry (GC/MS) and GC/flame ionisation detector (FID). The most abundant n-alkane in all populations was n-nonacosane (C29 ), followed by n-hentriacontane (C31 ), with the exception of Divaca population where these two alkanes were co-dominant. Diversity and variability of n-alkane patterns and morphological characters and their relation to different geographic and bioclimatic parameters, including exposure, were analysed by several statistical multivariate methods (PCA, HCA, Discriminant Analysis, Mantel test). These tests showed clear separation of subsp. liburnica from subsp. subspicata, even though population Velebit showed separation from other subsp. liburnica populations based on phytochemical characters. Mantel test showed high correlation with geographical distribution in both investigated data sets. High correlation between morphological and phytochemical characters was also established. However, exposure can influence n-alkane profile, suggesting precaution while taking samples from natural habitats. PMID- 27472424 TI - Perioperative Coagulation Management in a Patient with Congenital Afibrinogenemia during Revision Total Hip Arthroplasty. PMID- 27472425 TI - Thrombolysis and Thrombectomy for Acute Ischemic Stroke: Strengths and Synergies. AB - Acute ischemic stroke is responsible for around 80% of all strokes and is a leading cause of disability and death globally. There are two potential treatment strategies: restoring blood flow (reperfusion) and preventing cellular injury (neuroprotection). As yet, all the successful trials have involved reperfusion with numerous failures of neuroprotectants. There are two proven reperfusion strategies. Intravenous thrombolysis with alteplase was first demonstrated to reduce disability with publication of the National Institute of Neurological Disorders and Stroke tissue plasminogen activator trial in 1995. Since that time further trials have solidified the evidence base and demonstrated benefit when alteplase is administered within 4.5 hours of stroke onset. Exploration of potentially more effective thrombolytics is still underway with tenecteplase but others, such as desmoteplase, have been unsuccessful in clinical trials. The second proven reperfusion strategy is endovascular clot retrieval. This has been practiced for several years but came of age with the publication of five strongly positive trials in 2015. This review discusses the evidence for intravenous and intra-arterial reperfusion strategies and the advantages, disadvantages, and synergies of the two approaches. PMID- 27472426 TI - Monitoring Therapy during Treatment of von Willebrand Disease. AB - von Willebrand factor (VWF) is an adhesive plasma protein that primarily acts to bridge platelets to sites of vascular injury and thus prevent bleeding. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by deficiency and/or defects of VWF, leading to low levels of plasma VWF or dysfunctional VWF. Factor VIII (FVIII) is also reduced in many patients with VWD, since VWF stabilizes and protects FVIII from degradation. Treatment of VWD primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail use of VWF/FVIII concentrates, and/or desmopressin (1 deamino-8-d-arginine vasopressin) to release endogenous VWF in some patients. Adjunct therapies include antifibrinolytics and hormonal therapies in women. Optimal treatment of VWD entails measuring the effects of treatment, either as a trial before surgery or during therapeutic management. This is usually accomplished by performance of the same tests that are used to help diagnose VWD, although additional monitoring (clinically and/or by laboratory testing) may also be performed. The current review provides an overview of the treatment of VWD but is primarily focused on the monitoring of such therapy. PMID- 27472427 TI - Decreased Plasma Fibrinolytic Potential As a Risk for Venous and Arterial Thrombosis. AB - It has been well established that inherited or acquired hypercoagulability is a risk factor for venous thrombosis. In addition, hypercoagulability may contribute to the risk of arterial events. Much less is known regarding the role of the fibrinolytic system in the risk of thrombotic disease, which partly relates to the lack of validated assays. A plasma-based global fibrinolysis assay, which is sensitive to plasma levels of plasminogen, regulators of fibrinolysis, and proteins involved in coagulation, has been used in large epidemiological studies to assess the role of fibrinolysis in thrombosis. It has been demonstrated that a hypofibrinolytic state increases the risk of a first venous thrombosis, but not of a recurrence. This increased risk of venous thrombosis associated with plasma hypofibrinolysis appears primarily driven by elevated plasma levels of thrombin activatable fibrinolysis inhibitor and plasminogen activator inhibitor type 1. The combination of hypercoagulability and hypofibrinolysis synergistically enhances the risk of a first venous event. Plasma hypofibrinolysis may constitute a risk factor for the postthrombotic syndrome. Decreased fibrinolytic potential is also associated with an increased risk of arterial thrombosis, but only in individuals younger than 55 years. The association between hypofibrinolysis and myocardial infarction appears primarily driven by elevated levels of alpha2 antiplasmin. Although recent studies have clearly demonstrated a role of the fibrinolytic system in thrombotic disease, the clinical utility of plasma-based clot lysis assays is probably limited. PMID- 27472429 TI - Evidence-based strategies to create a culture of cybercivility in health professions education. PMID- 27472428 TI - alpha2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke. AB - Thrombotic vascular occlusion is the leading cause of ischemic stroke. High blood levels of alpha2-antiplasmin (a2AP), an ultrafast, covalent inhibitor of plasmin, have been linked in humans to increased risk of ischemic stroke and failure of tissue plasminogen activator (tPA) therapy. Consistent with these observations, a2AP neutralizes the therapeutic benefit of tPA therapy in experimental stroke. In addition, a2AP has deleterious, dose-related effects on ischemic brain injury in the absence of therapy. Experimental therapeutic inactivation of a2AP markedly reduces microvascular thrombosis, ischemic brain injury, brain swelling, brain hemorrhage, and death after thromboembolic stroke. These data provide new insights into the critical importance of a2AP in the pathogenesis of ischemic brain injury and suggest that transiently inactivating a2AP may have therapeutic value in ischemic stroke. PMID- 27472431 TI - Label-Free Electrical Detection of Enzymatic Reactions in Nanochannels. AB - We report label-free electrical detection of enzymatic reactions using 2-D nanofluidic channels and investigate reaction kinetics of enzymatic reactions on immobilized substrates in nanoscale-confined spaces. Trypsin proteolysis is chosen for demonstration of the detection scheme. When trypsin cleaves poly-l lysine coated on the surface of silica nanochannels, the resulting change of surface charge density can be detected by monitoring the ionic conductance of the nanochannels. Our results show that detection of such surface enzymatic reactions is faster than detection of surface binding reactions in nanochannels for low concentration analytes. Furthermore, the nanochannel sensor has a sensitivity down to 5 ng/mL, which statistically corresponds to a single enzyme per nanochannel. Our results also suggest that enzyme kinetics in nanochannels is fundamentally different from that in bulk solutions or plain surfaces. Such enzymatic reactions form two clear self-propagating reaction fronts inside the nanochannels, and the reaction fronts follow square-root time dependences at high enzyme concentrations due to significant nonspecific adsorption. However, at low enzyme concentrations when nonspecific adsorption is negligible, the reaction fronts propagate linearly with time, and the corresponding propagation speed is related to the channel geometry, enzyme concentration, catalytic reaction constant, diffusion coefficient, and substrate surface density. Optimization of this nanochannel sensor could lead to a quick-response, highly sensitive, and label-free sensor for enzyme assay and kinetic studies. PMID- 27472433 TI - Flexible heterostructured supercapacitor electrodes based on alpha-Fe2O3 nanosheets with excellent electrochemical performances. AB - In this paper, two kinds of hybrid alpha-Fe2O3@Co3O4 and alpha-Fe2O3@MnCo2O4 composites with high yield have been successfully synthesized on a flexible carbon cloth via simple solution methods. These as-obtained products serve as supercapacitor electrodes without the use of any adscititious surfactants and binders. These two hybrid electrode architectures make full use of the synergistic effects between alpha-Fe2O3 frameworks and coated Co3O4 or MnCo2O4 layers. They exhibit obviously enhanced discharge areal capacitance of 490 mF cm( 2) and 1073 mF cm(-2) for alpha-Fe2O3@Co3O4 and alpha-Fe2O3@MnCo2O4 composites at 1 mA cm(-2) with an identical potential voltage of 0-0.9 V. Long-life cycling stability with capacitance retention of 74.6% for alpha-Fe2O3@Co3O4 and 77.8% for alpha-Fe2O3@MnCo2O4 are presented after 6000 charge/discharge cycles, respectively. Such prominent electrochemical performances are mainly ascribed to the hybrid composites, which can provide a large reaction surface area, fast ion and electron transfer and good structure combination stability. The as synthesized flexible hybrid composites might have promising applications in micro/nanoscale energy storage devices. PMID- 27472432 TI - Between GERD and NERD: the relevance of weakly acidic reflux. AB - Nonerosive reflux disease (NERD) is a common condition and the most frequent phenotype of gastroesophageal reflux disease (GERD). NERD is extremely heterogeneous and includes patients with negative endoscopy but abnormal esophageal acid exposure and/or positive reflux-symptom association analysis (hypersensitive esophagus). This segregation is only possible owing to the use of impedance-pH monitoring. Indeed, weakly acidic reflux represents one of the most common causes of refractory symptoms in patients evaluated off antisecretory therapy and, more importantly, during antisecretory drug treatment. Patients with heartburn who do not have any type of reflux underlying their symptoms (functional heartburn) must be excluded from the category of GERD. The drawbacks of impedance-pH are mainly due to the day-to-day variability of the test and the fact that the accuracy of the symptom-reflux correlation scores is often far from perfect. Some histopathological characteristics, such as dilated intercellular spaces, can be helpful in distinguishing patients with NERD through esophageal biopsies. Patients with NERD in whom acid is the main pathogenetic factor respond successfully to proton pump inhibitor therapy, while those with hypersensitive esophagus to weakly acidic reflux could be treated with reflux inhibitors or surgery, although further controlled studies are required. PMID- 27472434 TI - Getting on with persistent pollutants: Decreasing trends of perfluoroalkyl acids (PFAAs) in sewage sludge. AB - Sewage sludge can be a relevant source of perfluoroalkyl acids (PFAAs) for the environment. In order to reduce emissions from this source, Bavarian authorities enforced in 2008 an analysis of PFAAs from sewage sludge derived from municipal wastewater treatment plants (WWTPs). 4981 sludge samples from 1165 different WWTPs were analyzed between 2008 and 2013 for 11 PFAAs compounds. During this period, 71 WWTPs exceeded the precautionary limit of 125 MUg kg(-1) dm of total PFAAs in sludge samples at least once with a decreasing tendency. The yearly exceedances of the investigated WWTPs decreased from 6% in 2008 to 0.8% in 2013. At the same time, the percentage of uncontaminated WWTPs increased from 33% to 65%. Perfluorooctane sulfonic acid (PFOS) was the predominant compound found in 41% of all sludge samples. Perfluorodecanoic acid (PFDA) was detected in 19% and Perfluorooctanoic acid (PFOA) in 7%. Very high PFAAs concentrations (>500 MUg kg( 1) dm) in sewage sludge were generally caused by firefighting foams containing PFAAs or emissions from PFAAs-using industries including metal plating, textile, leather or paper industries. Trend analyses of the six year period show that PFAAs contamination in sewage sludge clearly decreased for 47% of the WWTPs. However, for 16% of the WWTPs an increasing trend was detected, even though the concentration levels were below the precautionary limit. During the six years of investigation the load of total PFAAs in sewage sludge was reduced by more than 90%, from 17 t a(-1) in 2008 to 1.5 t a(-1) in 2013. PMID- 27472435 TI - Glutathione-mediated regulation of nitric oxide, S-nitrosothiol and redox homeostasis confers cadmium tolerance by inducing transcription factors and stress response genes in tomato. AB - Glutathione (GSH) plays a critical role in plant growth, development and responses to stress. However, the mechanism by which GSH regulates tolerance to cadmium (Cd) stress still remains unclear. Here we show that inhibition of GSH biosynthesis by buthionine sulfoximine (BSO) aggravated Cd toxicity by increasing accumulation of reactive oxygen species (ROS) and reducing contents of nitric oxide (NO) and S-nitrosothiol (SNO) in tomato roots. In contrast, exogenous GSH alleviated Cd toxicity by substantially minimizing ROS accumulation and increasing contents of NO and SNO, and activities of antioxidant enzymes that eventually reduced oxidative stress. GSH-induced enhancement in Cd tolerance was closely associated with the upregulation of transcripts of several transcription factors such as ETHYLENE RESPONSIVE TRANSCRIPTION FACTOR 1 (ERF1), ERF2, MYB1 TRANSCRIPTION FACTOR- AIM1 and R2R3-MYB TRANSCRIPTION FACTOR- AN2, and some stress response genes. In addition, GSH modulated the cellular redox balance through maintaining increased GSH: GSSG and AsA: DHA ratios, and also increased phytochelatins contents. Nonetheless, GSH-induced alleviation of Cd phytotoxicity was also associated with increased sequestration of Cd into cell walls and vacuoles but not with Cd accumulation. Under Cd stress, while treatment with BSO slightly decreased vacuolar fraction of Cd, combined treatment with BSO and GSH noticeably increased that fraction. Our results suggest that GSH increases tomato tolerance to Cd stress not only by promoting the chelation and sequestration of Cd but also by stimulating NO, SNO and the antioxidant system through a redox dependent mechanism. PMID- 27472436 TI - A state of limbo: the politics of waiting in neo-liberal Latvia. AB - This article presents an ethnographic study of politics of waiting in a post Soviet context. While activation has been explored in sociological and anthropological literature as a neo-liberal governmental technology and its application in post-socialist context has also been compellingly documented, waiting as a political artefact has only recently been receiving increased scholarly attention. Drawing on ethnographic fieldwork at a state-run unemployment office in Riga, this article shows how, alongside activation, state welfare policies also produce passivity and waiting. Engaging with the small but developing field of sociological literature on the politics of waiting, I argue that, rather than interpreting it as a clash between 'neo-liberal' and 'Soviet' regimes, we should understand the double-move of activation and imposition of waiting as a key mechanism of neo-liberal biopolitics. This article thus extends the existing theorizations of the temporal politics of neo-liberalism. PMID- 27472437 TI - Prosocial Behavior and Subjective Insecurity in Violent Contexts: Field Experiments. AB - Subjective insecurity is a key determinant of different forms of prosocial behavior. In Study 1, we used field experiments with farmers in Colombian villages exposed to different levels of violence to investigate how individual perceptions of insecurity affect cooperation, trust, reciprocity and altruism. To do so, we developed a cognitive-affective measure of subjective insecurity. We found that subjective insecurity has a negative effect on cooperation but influences trust and altruism positively. In Study 2, carried out three years after Study 1, we repeated the initial design with additional measures of victimization. Our goal was to relate subjective insecurity with actual victimization. The findings of Study 2 support the initial results, and are robust and consistent for cooperative behavior and trust when including victimization as a mediator. Different indicators of victimization are positively correlated with subjective insecurity and an aggregate index of victimization has a negative direct effect on cooperation and trust. PMID- 27472438 TI - Three-dimensional mapping of the orientation of collagen corneal lamellae in healthy and keratoconic human corneas using SHG microscopy. AB - Keratoconus is an eye disorder that causes the cornea to take an abnormal conical shape, thus impairing its refractive functions and causing blindness. The late diagnosis of keratoconus is among the principal reasons for corneal surgical transplantation. This pathology is characterized by a reduced corneal stiffness in the region immediately below Bowman's membrane, probably due to a different lamellar organization, as suggested by previous studies. Here, the lamellar organization in this corneal region is characterized in three dimensions by means of second-harmonic generation (SHG) microscopy. In particular, a method based on a three-dimensional correlation analysis allows to probe the orientation of sutural lamellae close to the Bowman's membrane, finding statistical differences between healthy and keratoconic samples. This method is demonstrated also in combination with an epi-detection scheme, paving the way for a potential clinical ophthalmic application of SHG microscopy for the early diagnosis of keratoconus. SHG image acquired with sagittal optical sectioning (A) of a healthy cornea and (B) of a keratoconic cornea. Scale bars: 30 MUm. PMID- 27472439 TI - DFT Calculations on the Mechanism of Transition-Metal-Catalyzed Reaction of Diazo Compounds with Phenols: O-H Insertion versus C-H Insertion. AB - The reaction of diazo compounds with transition-metal carbenes is an efficient way to achieve the functionalization of chemical bonds in organic molecules, especially for the C-H and O-H bonds. However, the selective mechanisms of C-H and O-H bond insertions by various metal carbenes such as Rh and Cu complexes are not quite clear. In this work, we performed a comprehensively theoretical investigation of the phenol C-H and O-H bonds inserted by Rh and Cu carbenes by using DFT calculations. The calculated results reveal that the nucleophilic additions of phenols to the Rh and Cu carbenes in the C-H bond insertions are the rate-determining steps of whole reactions, which are higher than the barriers in the O-H insertions. In the process of intramolecular [1,3]-H transfer, the Rh and Cu ligands in their carbenes tend to dissociate into solution rather than the intramolecular migration due to their weak metal-carbon bonds. A deeply theoretical analysis of the electronic structures of Rh, Cu, and Au carbenes as well as their complexes elucidated their differences in the chemoselectivity of C H and O-H insertion products, which agrees with the experimental observations well. PMID- 27472440 TI - Atomic-Scale Observations of (010) LiFePO4 Surfaces Before and After Chemical Delithiation. AB - The ability to view directly the surface structures of battery materials with atomic resolution promises to dramatically improve our understanding of lithium (de)intercalation and related processes. Here we report the use of state-of-the art scanning transmission electron microscopy techniques to probe the (010) surface of commercially important material LiFePO4 and compare the results with theoretical models. The surface structure is noticeably different depending on whether Li ions are present in the topmost surface layer or not. Li ions are also found to migrate back to surface regions from within the crystal relatively quickly after partial delithiation, demonstrating the facile nature of Li transport in the [010] direction. The results are consistent with phase transformation models involving metastable phase formation and relaxation, providing atomic-level insights into these fundamental processes. PMID- 27472441 TI - Quantity and quality of interaction between staff and older patients in UK hospital wards: A descriptive study. AB - BACKGROUND: The quality of staff-patient interactions underpins the overall quality of patient experience and can affect other important outcomes. However no studies have been identified that comprehensively explore both the quality and quantity of interactions in general hospital settings. AIMS & OBJECTIVES: To quantify and characterise the quality of staff-patient interactions and to identify factors associated with negative interaction ratings. SETTING: Data were gathered at two acute English NHS hospitals between March and April 2015. Six wards for adult patients participated including medicine for older people (n=4), urology (n=1) and orthopaedics (n=1). METHODS: Eligible patients on participating wards were randomly selected for observation. Staff-patient interactions were observed using the Quality of Interactions Schedule. 120h of care were observed with each 2h observation session determined from a balanced random schedule (Monday-Friday, 08:00-22:00h). Multilevel logistic regression models were used to determine factors associated with negative interactions. RESULTS: 1554 interactions involving 133 patients were observed. The median length of interaction was 36s with a mean of 6 interactions per patient per hour. Seventy three percent of interactions were categorized as positive, 17% neutral and 10% negative. Forty percent of patients had at least one negative interaction (95% confidence interval 32% to 49%). Interactions initiated by the patient (adjusted Odds Ratio [OR] 5.30), one way communication (adjusted OR 10.70), involving two or more staff (adjusted OR 5.86 for 2 staff, 6.46 for 3+ staff), having a higher total number of interactions (adjusted OR 1.09 per unit increase), and specific types of interaction content were associated with increased odds of negative interaction (p<0.05). In the full multivariable model there was no significant association with staff characteristics, skill mix or staffing levels. Patient agitation at the outset of interaction was associated with increased odds of negative interaction in a reduced model. There was no significant association with gender, age or cognitive impairment. There was substantially more variation at ward level (variance component 1.76) and observation session level (3.49) than at patient level (0.09). CONCLUSION: These findings present a unique insight into the quality and quantity of staff-patient interactions in acute care. While a high proportion of interactions were positive, findings indicate that there is scope for improvement. Future research should focus on further exploring factors associated with negative interactions, such as workload and ward culture. PMID- 27472442 TI - Social discrimination and social justice. PMID- 27472443 TI - Increased Frequency of Hormone Negative and Polyhormonal Endocrine Cells in Lean Individuals With Type 2 Diabetes. AB - CONTEXT: It has been suggested that beta cell loss in type 2 diabetes (T2D) may be due to beta cell degranulation and/or altered cell identity. While shown to have a minor role in obese T2D, this has not been evaluated in lean T2D. OBJECTIVE: To establish the contribution of altered beta cell identity in lean T2D and, using a rodent model of lean T2D, whether changes in beta cell identity precede hyperglycemia. DESIGN, SETTING, AND PARTICIPANTS: We investigated the frequency of chromogranin A positive hormone negative (CPHN) and polyhormonal endocrine cells in pancreas from 10 lean nondiabetic and 10 lean T2D subjects and in pancreas from wild-type and human IAPP transgenic rats at the prediabetic and diabetic stages. RESULTS: CPHN cells and polyhormonal-expressing cells were comparably increased in lean T2D and human IAPP transgenic rats, in the latter both before and at onset of diabetes. However, the extent of these cells could only account for approximately 2% of beta cell loss. CONCLUSION: Degranulation and altered identity play at most a minor role in the beta cell deficit in lean T2D. Because the increase in CPHN and polyhormonal cells precede diabetes onset, these changes are likely a response to stress rather than hyperglycemia, and may reflect attempted regeneration. PMID- 27472444 TI - Integrated Approach To Producing High-Purity Trehalose from Maltose by the Yeast Yarrowia lipolytica Displaying Trehalose Synthase (TreS) on the Cell Surface. AB - An alternative strategy that integrated enzyme production, trehalose biotransformation, and bioremoval in one bioreactor was developed in this study, thus simplifying the traditional procedures used for trehalose production. The trehalose synthase gene from a thermophilic archaea, Picrophilus torridus, was first fused to the YlPir1 anchor gene and then inserted into the genome of Yarrowia lipolytica, thus yielding an engineered yeast strain. The trehalose yield reached 73% under optimal conditions. The thermal and pH stabilities of the displayed enzyme were improved compared to those of its free form purified from recombinant Escherichia coli. After biotransformation, the glucose byproduct and residual maltose were directly fermented to ethanol by a Saccharomyces cerevisiae strain. Ethanol can be separated by distillation, and high-purity trehalose can easily be obtained from the fermentation broth. The results show that this one pot procedure is an efficient approach to the economical production of trehalose from maltose. PMID- 27472445 TI - Anticancer Activity of Buttermilk Against SW480 Colon Cancer Cells is Associated with Caspase-Independent Cell Death and Attenuation of Wnt, Akt, and ERK Signaling. AB - Buttermilk is a rich source of milk fat globule membrane (MFGM) fragments assembled from bioactive polar lipids and proteins that originate from bovine mammary epithelial cells. The objective of this study was to examine growth modulatory effects of experimental buttermilks varying in sphingolipid and phospholipid composition on a colon cancer cell line of human origin. Buttermilks were prepared from washed and unwashed cream using gravity or centrifugation. Compositional analysis showed that sphingomyelin (SM) (10.4-29.5%) and lactosylceramide (LacCer) (1.2-44.3%) were the predominant sphingolipids detected. Experimental samples inhibited in vitro growth of SW480 colon cancer cells in a dose-dependent manner. Antiproliferative activity was selective toward cancer cells. A fraction enriched in LacCer (44.3%), obtained by microfiltration induced caspase-independent cell death as evident by phosphatidylserine externalization, increased percentage of degraded DNA, and loss of mitochondrial membrane potential in SW480 cells. This fraction downregulated growth-signaling pathways mediated by beta-catenin, phosphorylated Akt (serine/threonine-specific protein kinase), ERK1/2 (extracellular signal-regulated kinase), and c-myc. This study is to our knowledge the first to screen buttermilk samples that vary in polar lipid composition for antiproliferative activity in vitro. PMID- 27472446 TI - Prednisolone Delivery Platforms: Capsules and Beads Combination for a Right Timing Therapy. AB - In this work, a platform of alginate beads loaded with Prednisolone in hypromellose/gellan gum capsules (F6/Cps) able to delay steroidal anti inflammatory drug (SAID) release as needed for chronotherapy of rheumatoid arthritis is proposed. Rheumatoid arthritis, showing a worsening in symptoms in the morning upon waking, is a pathology that can benefit from chronotherapy. With the aim to maximize prednisolone therapeutic action allowing the right timing of glucocorticoid therapy, different engineered microparticles (gel-beads) were manufactured using prilling (laminar jet break-up) as micro-encapsulation technique and Zn-alginate as gastroresistant carrier. Starting from various feed solutions and process parameters, the effect of the variables on particles size, morphology, solid state properties and drug release was studied. The optimization of operative and prilling/ionotropic gelation variables led to microspheres with almost spherical shape and a narrow dimensional range. The feed solution with the highest alginate (2.5% w/v) amount and drug/polymer ratio (1:5 w/w) gave rise to the highest encapsulation efficiency (78.5%) as in F6 formulation. As to drug release, F6 exhibited an interesting dissolution profile, releasing about 24% of the drug in simulated gastric fluid followed by a more sustained profile in simulated intestinal fluid. #F6, acting as a gastro-resistant and delayed release formulation, was selected for in vivo studies on male Wistar rats by means of a carrageenan-induced oedema model. Finally, this efficacious formulation was used as core material for the development of a final dosage form: F6/Cps allowed to significantly reduce prednisolone release in simulated gastric fluid (12.6%) and delayed drug release up to about 390 minutes. PMID- 27472447 TI - Boundedness and convergence analysis of weight elimination for cyclic training of neural networks. AB - Weight elimination offers a simple and efficient improvement of training algorithm of feedforward neural networks. It is a general regularization technique in terms of the flexible scaling parameters. Actually, the weight elimination technique also contains the weight decay regularization for a large scaling parameter. Many applications of this technique and its improvements have been reported. However, there is little research concentrated on its convergence behavior. In this paper, we theoretically analyze the weight elimination for cyclic learning method and determine the conditions for the uniform boundedness of weight sequence, and weak and strong convergence. Based on the assumed network parameters, the optimal choice for the scaling parameter can also be determined. Moreover, two illustrative simulations have been done to support the theoretical explorations as well. PMID- 27472448 TI - Corrigendum: The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. PMID- 27472450 TI - Liquid-Phase Synthesis of Ba2V2O7 Phosphor Powders and Films Using Immiscible Biphasic Organic-Aqueous Systems. AB - A liquid-phase synthesis of inorganic phosphor materials at a moderate temperature was proposed by using immiscible liquid-liquid biphasic systems. A self-activated Ba2V2O7 phosphor was actually synthesized from vanadium alkoxide dissolved in an organic solution and barium acetate in an aqueous solution. A mild hydrolysis reaction of the alkoxide started at the organic-inorganic interface, and an intermediate compound, Ba(VO3)2.H2O, was initially formed. Ba2V2O7 powders were then obtained by the conversion from Ba(VO3)2.H2O promoted in the aqueous solution. Ba2V2O7 films were obtained on surface-modified silica glass substrates through the similar chemical reactions. Factors such as the surface state of substrates, the kind of organic solvents, and the volume of aqueous solutions were examined to improve the film deposition behavior. The resultant Ba2V2O7 materials showed broad-band visible photoluminescence upon irradiation with ultraviolet light based on the charge transfer transition in the VO4(3-) units existing as dimers. PMID- 27472449 TI - Electronic Health Record Based Algorithm to Identify Patients with Autism Spectrum Disorder. AB - OBJECTIVE: Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co occurrence patterns of medical comorbidities in ASD. METHODS: We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children's Hospital (BCH) (N = 150) and Cincinnati Children's Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups. RESULTS: The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children's Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters. CONCLUSIONS: In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD. PMID- 27472451 TI - Effect of Mir-122 on Human Cholangiocarcinoma Proliferation, Invasion, and Apoptosis Through P53 Expression. AB - BACKGROUND Bile duct carcinoma is a common digestive tract tumor with high morbidity and mortality. As a kind of important non-coding RNA, microRNA (miR) plays an important role in post-transcriptional regulation. MiR-122 is the most abundant miR in the liver. Multiple studies have shown that miR-122 level is reduced in a variety of liver tumors and can be used as a specific marker for liver injury. P53 is a classic tumor suppressor gene that can induce tumor cell apoptosis through various pathways. Whether miR-122 affects p53 in bile duct carcinoma still needs investigation. MATERIAL AND METHODS miR inhibitor or mimics was transfected to bile duct carcinoma cells to evaluate its function on proliferation, invasion, apoptosis, and p53 expression. RESULTS MiR-122 overexpression reduced cell invasion and migration ability, and inhibited cell apoptosis and p53 expression. Inhibiting miR-122 caused the opposite results. CONCLUSIONS Upregulating miR-122 can suppress bile duct carcinoma cell proliferation and induce apoptosis. MiR-122 could be used as a target for bile duct carcinoma treatment, which provides a new strategy for cholangiocarcinoma patients. PMID- 27472452 TI - Cognitive behaviour therapy for specific phobia of vomiting (Emetophobia): A pilot randomized controlled trial. AB - : This is the first randomised controlled trial to evaluate a protocol for cognitive behaviour therapy (CBT) for a Specific Phobia of Vomiting (SPOV) compared with a wait list and to use assessment scales that are specific for a SPOV. METHOD: 24 participants (23 women and 1 man) were randomly allocated to either 12 sessions of CBT or a wait list. RESULTS: At the end of the treatment, CBT was significantly more efficacious than the wait list with a large effect size (Cohen's d=1.53) on the Specific Phobia of Vomiting Inventory between the two groups after 12 sessions. Six (50%) of the participants receiving CBT achieved clinically significant change compared to 2 (16%) participants in the wait list group. Eight (58.3%) participants receiving CBT achieved reliable improvement compared to 2 (16%) participants in the wait list group. CONCLUSIONS: A SPOV is a condition treatable by CBT but further developments are required to increase efficacy. PMID- 27472453 TI - Polymer-associated liposomes for the oral delivery of grape pomace extract. AB - The pomaces from red grapes were used as a source of phenolic antioxidants, which are known to have health-promoting effects. Environmentally-friendly extraction strategies were investigated to improve the rate and recovery of an extract with high phenolic content and antioxidant activity, which were evaluated by the Folin Ciocalteu, DPPH, ABTS(+), CUPRAC and FRAP assays. The extract was incorporated in liposomes, which were stabilized by the addition of a natural polysaccharide, sodium alginate or arabic gum, widely used in pharmaceutical and food industries as thickeners and stabilizers. Results showed that the polymer-associated liposomes were approximately 300nm in size, spherical in shape, and with high entrapment efficiency. The polymers prevented vesicle degradation in the gastric environment, and played a key role in improving liposomes' performances, especially arabic gum. The polymer-associated liposomes were biocompatible and protected Caco-2 cells against oxidative stress. The achieved results suggest a potential application of the polymer-associated liposomes loaded with the grape pomace extract in the nutraceutical field. PMID- 27472454 TI - The influence of environmentally friendly pesticide - Eucalyptol - alone and in combination with terpinen-4-ol - on model bacterial membranes. AB - Eucalyptus oil is known from antimicrobial properties and due to natural origin and low toxicity it can be applied as a green pesticide. This plant extract is a mixture of compounds among which Eucalyptol prevails strongly over the number of minor components including terpinen-4-ol. However, antimicrobial effect of total extract is stronger than the effect of its major component. The mechanism of action of essential oils involves their incorporation into membrane of pathogenic cell. To investigate the effect of eucalyptus oil components on bacterial membrane in this work the influence of Eucalyptol on model lipid systems of various compositions was studied and then compared with the effect induced by the mixture of Eucalyptol and terpinen-4-ol. The analysis of the lipid monolayer properties modified by the presence of the essential oils evidenced that Eucalyptol reduces the lipids packing and decreases membrane rigidity, however, its influence is determined both by the concentration of this terpene and by the composition of lipid film. As indicated the results of calculation of the surface excess values Eucalyptol molecules tend to adsorb at the interface, however, at higher concentration in the subphase, the molecules undergo desorption at membrane-related surface pressure. By mixing of Eucalyptol and terpinen-4-ol stronger monolayer fluidization and destabilization can be achieved as well as stronger adsorption, even at higher surface pressures, occurs. However, these effects are also determined by the composition of model system. The collected data suggest that these compounds may act by penetrating bacterial membrane. Moreover, it can be proposed that although Eucalyptol is a major component of the Eucalyptus oil the antimicrobial effect of total extract is generated also by a minor component. This may explain stronger antimicrobial effect of Eucalyptus oil as compared to sole Eucalyptol confirmed in biological studies. PMID- 27472455 TI - Aminoglycoside-derived amphiphilic nanoparticles for molecular delivery. AB - The development of effective drug carriers can lead to improved outcomes in a variety of disease conditions. Aminoglycosides have been used as antibacterial therapeutics, and are attractive as monomers for the development of polymeric materials in various applications. Here, we describe the development of novel aminoglycoside-derived amphiphilic nanoparticles for drug delivery, with an eye towards ablation of cancer cells. The aminoglycoside paromomycin was first cross linked with resorcinol diglycidyl ether leading to the formation of a poly (amino ether), PAE. PAE molecules were further derivatized with methoxy-terminated poly(ethylene glycol) or mPEG resulting in the formation of mPEG-PAE polymer, which self-assembled to form nanoparticles. Formation of the mPEG-PAE amphiphile was characterized using (1)H NMR, (13)C NMR, gel permeation chromatography (GPC) and FTIR spectroscopy. Self-assembly of the polymer into nanoparticles was characterized using dynamic light scattering, zeta potential analyses, atomic force microscopy (AFM) and the pyrene fluorescence assay. mPEG-PAE nanoparticles were able to carry significant amounts of doxorubicin (DOX), presumably by means of hydrophobic interactions between the drug and the core. Cell-based studies indicated that mPEG-PAE nanoparticles, loaded with doxorubicin, were able to induce significant loss in viabilities of PC3 human prostate cancer, MDA-MB-231 human breast cancer, and MB49 murine bladder cancer cells; empty nanoparticles resulted in negligible losses of cell viability under the conditions investigated. Taken together, our results indicate that the mPEG-PAE nanoparticle platform is attractive for drug delivery in different applications, including cancer. PMID- 27472457 TI - Polycatenar Ligand Control of the Synthesis and Self-Assembly of Colloidal Nanocrystals. AB - Hydrophobic colloidal nanocrystals are typically synthesized and manipulated with commercially available ligands, and surface functionalization is therefore typically limited to a small number of molecules. Here, we report the use of polycatenar ligands derived from polyalkylbenzoates for the direct synthesis of metallic, chalcogenide, pnictide, and oxide nanocrystals. Polycatenar molecules, branched structures bearing diverging chains in which the terminal substitution pattern, functionality, and binding group can be independently modified, offer a modular platform for the development of ligands with targeted properties. Not only are these ligands used for the direct synthesis of monodisperse nanocrystals, but nanocrystals coated with polycatenar ligands self-assemble into softer bcc superlattices that deviate from conventional harder close-packed structures (fcc or hcp) formed by the same nanocrystals coated with commercial ligands. Self-assembly experiments demonstrate that the molecular structure of polycatenar ligands encodes interparticle spacings and attractions, engineering self-assembly, which is tunable from hard sphere to soft sphere behavior. PMID- 27472456 TI - Multivalent Interactions between an Aromatic Helical Foldamer and a DNA G Quadruplex in the Solid State. AB - Quinoline-based oligoamide foldamers have been identified as a potent class of ligands for G-quadruplex DNA. Their helical structure is thought to target G quadruplex loops or grooves and not G-tetrads. We report a co-crystal structure of the antiparallel hairpin dimeric DNA G-quadruplex (G4 T4 G4 )2 with tetramer 1 a helically folded oligo-quinolinecarboxamide bearing cationic side chains-that is consistent with this hypothesis. Multivalent foldamer-DNA interactions that modify the packing of (G4 T4 G4 )2 in the solid state are observed. PMID- 27472458 TI - Impact of a Mesoporous Titania-Perovskite Interface on the Performance of Hybrid Organic-Inorganic Perovskite Solar Cells. AB - We report on the optimization of the interfacial properties of titania in mesoscopic CH3NH3PbI3 solar cells. Modification of the mesoporous TiO2 film by TiCl4 treatment substantially reduced the surface traps, as is evident from the sharpness of the absorption edge with a significant reduction in Urbach energy (from 320 to 140 meV) determined from photothermal deflection spectroscopy, and led to an order of magnitude enhancement in the bulk electron mobility and corresponding decrease in the transport activation energy (from 170 to 90 meV) within a device. After optimization of the photoanode-perovskite interface using various sizes of TiO2 nanoparticles, the best photovoltaic efficiency of 16.3% was achieved with the mesoporous TiO2 composed of 36 nm sized nanoparticles. The improvement in device performance can be attributed to the enhanced charge collection efficiency that is driven by improved charge transport in the mesoporous TiO2 layer. Also, the decreased recombination at the TiO2-perovskite interface and better perovskite coverage play important roles. PMID- 27472459 TI - Crosstalk among the proteome, lysine phosphorylation, and acetylation in romidepsin-treated colon cancer cells. AB - Romidepsin (FK228) is one of the most promising histone-deacetylase inhibitors due to its potent antitumor activity, and has been used as a practical option for cancer therapy. However, FK228-induced changes in protein modifications and the crosstalk between different modifications has not been reported. To better understand the underlying mechanisms of FK228-related cancer therapy, we investigated the acetylome, phosphorylation, and crosstalk between modification datasets in colon cancer cells treated with FK228 by using stable-isotope labeling with amino acids in cell culture and affinity enrichment, followed by high-resolution liquid chromatography tandem mass spectrometry analysis. In total, 2728 protein groups, 1175 lysine-acetylation sites, and 4119 lysine phosphorylation sites were quantified. When the quantification ratio thresholds were set to > 2.0 and < 0.5, respectively, a total of 115 and 38 lysine acetylation sites in 85 and 32 proteins were quantified as increased and decreased targets, respectively, and 889 and 370 lysine-phosphorylation sites in 599 and 289 proteins were quantified as increased and decreased targets, respectively. Furthermore, we identified 274 proteins exhibiting both acetylation and phosphorylation modifications. These findings indicated possible involvement of these proteins in FK228-related treatment of colon cancer, and provided insight for further analysis of their biological function. PMID- 27472460 TI - EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis. AB - Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain the silenced state of genes. EZH2 is the catalytic core and one of the most important components of the polycomb repressive complex 2 (PRC2). In non small cell lung cancer (NSCLC) cells and primary lung tumors, we found that PRC2 components, including EZH2, are overexpressed. High levels of EZH2 protein were associated with worse overall survival rate in NSCLC patients. RNA interference mediated attenuation of EZH2 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that, in the suppression of EZH2, p53 upregulated modulator of apoptosis (PUMA) expression was concomitantly induced. This is achieved through EZH2 directly binds to the Puma promoter thus epigenetic repression of PUMA expression. Furthermore, cisplatin-induced apoptosis of EZH2-knocking down NSCLC cells was elevated as a consequence of increased PUMA expression. Our work reveals a novel epigenetic regulatory mechanism controlling PUMA expression and suggests that EZH2 offers a candidate molecular target for NSCLC therapy and EZH2 regulated PUMA induction would synergistically increase the sensitivity to platinum agents in non-small cell lung cancers. PMID- 27472461 TI - Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells. AB - Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, immune evasion and increased invasion. Despite clinical relevance, effective/selective therapeutic targeting strategies for GSCs do not exist, potentially due to the lack of a definitive understanding of key regulators of GSCs. Consequently, there is a pressing need to identify therapeutic targets and novel options to effectively target this therapy-resistant cell population. The precise roles of GSCs in governing GBM development, progression and prognosis are under intense scrutiny, but key upstream regulatory genes remain speculative. MDA-9/Syntenin (SDCBP), a scaffold protein, regulates tumor pathogenesis in multiple cancers. Highly aggressive cancers like GBM express elevated levels of MDA-9 and contain increased populations of GSCs. We now uncover a unique function of MDA-9 as a facilitator and determinant of glioma stemness and survival. Mechanistically, MDA 9 regulates multiple stemness genes (Nanog, Oct4 and Sox2) through activation of STAT3. MDA-9 controls survival of GSCs by activating the NOTCH1 pathway through phospho-Src and DLL1. Once activated, cleaved NOTCH1 regulates C-Myc expression through RBPJK, thereby facilitating GSC growth and proliferation. Knockdown of MDA-9 affects the NOTCH1/C-Myc and p-STAT3/Nanog pathways causing a loss of stemness and initiation of apoptosis in GSCs. Our data uncover a previously unidentified relationship between MDA-9 and GSCs, reinforcing relevance of this gene as a potential therapeutic target in GBM. PMID- 27472463 TI - Activation of proinflammatory signaling by 4-hydroxynonenal-Src adducts in aged kidneys. AB - In our previous study, reactive 4-hydroxy-2-nonenal (4-HNE) was shown to activate Src (a non-receptor tyrosine kinase) by forming an adduct on binding with a specific residue of Src, leading to the activation of proinflammatory signaling pathways in cultured cells. However, to date, the deleterious roles of 4-HNE in inflammatory signaling activation in kidneys during aging have not been explored. The purpose of the present study was to document the mechanisms by which 4-HNE induces inflammation in the kidney during aging. Initial experiments revealed that activated nuclear factor-kappaB (NF-kappaB) expression was caused by 4-HNE activation, which suppressed transcriptional activity in the aged kidney. Treatment of human umbilical vein endothelial cells with 4-HNE revealed that Src caused senescence via NF-kappaB activation. Furthermore, our immunohistochemistry data showed that 4-HNE-adducted Src significantly increased in aged kidney tissues. The data showed age-related upregulation of downstream signaling molecules such as mitogen activated protein kinases (MAPKs), activator protein-1 (AP-1), NF-kappaB, and COX-2 in a cell culture cell system.Taken together, the results of this study show that the formation of adducts between 4-HNE and Src activates inflammatory signaling pathways in the aged kidney, contributing to age related nephropathy. PMID- 27472462 TI - Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations. AB - Although endocrine therapy is successfully used to treat patients with estrogen receptor (ER) positive breast cancer, a substantial proportion of this population will relapse. Several mechanisms of acquired resistance have been described including activation of the mTOR pathway, increased activity of CDK4 and activating mutations in ER. Using a patient derived xenograft model harboring a common activating ER ligand binding domain mutation (D538G), we evaluated several combinatorial strategies using the selective estrogen receptor degrader (SERD) fulvestrant in combination with chromatin modifying agents, and CDK4/6 and mTOR inhibitors. In this model, fulvestrant binds WT and MT ER, reduces ER protein levels, and downregulated ER target gene expression. Addition of JQ1 or vorinostat to fulvestrant resulted in tumor regression (41% and 22% regression, respectively) though no efficacy was seen when either agent was given alone. Interestingly, although the CDK4/6 inhibitor palbociclib and mTOR inhibitor everolimus were efficacious as monotherapies, long-term delayed tumor growth was only observed when co-administered with fulvestrant. This observation was consistent with a greater inhibition of compensatory signaling when palbociclib and everolimus were co-dosed with fulvestrant. The addition of fulvestrant to JQ1, vorinostat, everolimus and palbociclib also significantly reduced lung metastatic burden as compared to monotherapy. The combination potential of fulvestrant with palbociclib or everolimus were confirmed in an MCF7 CRISPR model harboring the Y537S ER activating mutation. Taken together, these data suggest that fulvestrant may have an important role in the treatment of ER positive breast cancer with acquired ER mutations. PMID- 27472464 TI - Inhibition of heat shock protein 90 improves pulmonary arteriole remodeling in pulmonary arterial hypertension. AB - While the molecular chaperone heat shock protein 90 (HSP90) is involved in a multitude of physiological and pathological processes, its role relating to pulmonary arterial hypertension (PAH) remains unclear. In the present study, we investigated the effect in which HSP90 improves pulmonary arteriole remodeling, and explored the therapeutic utility of targeting HSP90 as therapeutic drug for PAH. By Elisa and immunohistochemistry, HSP90 was found to be increased in both plasma and membrane walls of pulmonary arterioles from PAH patients. Moreover, plasma HSP90 levels positively correlated with mean pulmonary arterial pressure and C-reactive protein. In a monocrotaline-induced rat model of PH, we found that 17-AAG, a HSP90-inhibitor, alleviated the progress of PH, demonstrated by lower pulmonary arterial pressure and absence of right ventricular hypertrophy. Immunohistochemical staining demonstrated that 17-AAG improved pulmonary arteriole remodeling on the basis of reduced wall thickness and wall area. The inflammatory response attributed to PH could be attenuated by 17-AAG through reduction of NF-kappaB signaling. Moreover, 17-AAG was found to suppress PDGF stimulated proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through induction of cell cycle arrest in the G1 phase. In conclusion, HSP90 inhibitor 17-AAG could improve pulmonary arteriole remodeling via inhibiting the excessive proliferation of PASMCs, and inhibition of HSP90 may represent a therapeutic avenue for the treatment of PAH. PMID- 27472465 TI - Memo interacts with c-Src to control Estrogen Receptor alpha sub-cellular localization. AB - Understanding the complex interaction between growth factor and steroid hormone signaling pathways in breast cancer is key to identifying suitable therapeutic strategies to avoid progression and therapy resistance. The interaction between these two pathways is of paramount importance for the development of endocrine resistance. Nevertheless, the molecular mechanisms behind their crosstalk are still largely obscure. We previously reported that Memo is a small redox-active protein that controls heregulin-mediated migration of breast cancer cells. Here we report that Memo sits at the intersection between heregulin and estrogen signaling, and that Memo controls Estrogen Receptor alpha (ERalpha) sub-cellular localization, phosphorylation, and function downstream of heregulin and estrogen in breast cancer cells. Memo facilitates ERalpha and c-Src interaction, ERalpha Y537 phosphorylation, and has the ability to control ERalpha extra-nuclear localization. Thus, we identify Memo as an important key mediator between the heregulin and estrogen signaling pathways, which affects both breast cancer cell migration and proliferation. PMID- 27472467 TI - Peripheral mRNA expression of pluripotency markers in bipolar disorder and the effect of long-term lithium treatment. AB - BACKGROUND: The aim was to evaluate the peripheral mRNA expression of pluripotency master transcriptional factors such as octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2) and homeobox protein Nanog, in patients with bipolar disorder (BD), and the effect of long-term lithium treatment. METHODS: Fifteen BD patients (aged 53+/-7years) not treated with lithium, with duration of illness>10years, 15 BD patients (aged 55+/-6years) treated with lithium for 8-40 years (mean 16years) and 15 control subjects (aged 50+/-5years) were included. Assessment of the mRNA levels of pluripotency markers (Oct-4, Sox 2 and Nanog) was performed, using the Real-time quantitative reverse transcription PCR (RQ-PCR) procedure, and the number of CD34+ very small embryonic-like stem cells (VSELs) was measured by flow cytometric analysis. RESULTS: In those BD patients not treated with lithium the expression of all three pluripotency genes was significantly higher than that in the control subjects. Oct-4, Sox2 and Nanog also positively correlated with the number of CD34+ VSELs/[ul] in this group. In the lithium-treated patients the mRNA levels of Nanog were significantly higher than in the control individuals and correlated with the number and % of CD34+ VSELs. CONCLUSIONS: The overexpression of the pluripotency master transcriptional factors in patients with a long duration of BD not treated with lithium, may contribute to the pathogenesis of the illness and make them potential biological markers of BD. Long-term lithium treatment may attenuate these excessive regenerative processes, especially in relation to the transcription factors Oct-4 and Sox2. PMID- 27472466 TI - Royal jelly promotes DAF-16-mediated proteostasis to tolerate beta-amyloid toxicity in C. elegans model of Alzheimer's disease. AB - Numerous studies have demonstrated that dietary intervention may promote health and help prevent Alzheimer's disease (AD). We recently reported that bee products of royal jelly (RJ) and enzyme-treated royal jelly (eRJ) were potent to promote healthy aging in C. elegans. Here, we examined whether RJ/eRJ consumption may benefit to mitigate the AD symptom in the disease model of C. elegans. Our results showed that RJ/eRJ supplementation significantly delayed the body paralysis in AD worms, suggesting the beta-amyloid (Abeta) toxicity attenuation effects of RJ/eRJ. Genetic analyses suggested that RJ/eRJ-mediated alleviation of Abeta toxicity in AD worms required DAF-16, rather than HSF-1 and SKN-1, in an insulin/IGF signaling dependent manner. Moreover, RJ/eRJ modulated the transactivity of DAF-16 and dramatically improved the protein solubility in aged worms. Given protein solubility is a hallmark of healthy proteostasis, our findings demonstrated that RJ/eRJ supplementation improved proteostasis, and this promotion depended on the transactivity of DAF-16. Collectively, the present study not only elucidated the possible anti-AD mechanism of RJ/eRJ, but also provided evidence from a practical point of view to shed light on the extensive correlation of proteostasis and the prevention of neurodegenerative disorders. PMID- 27472468 TI - Atypical teratoid/rhabdoid tumor arising in a malignant glioma. AB - Atypical teratoid/rhabdoid tumor (AT/RT), a highly malignant brain tumor in young children, usually arises de novo and has only rarely been described as a secondary malignancy. Here, we present a case of a child with glioblastoma, who was treated postoperatively by a combination of temozolomide, irradiation, and bevacizumab. AT/RT was diagnosed as a secondary tumor, 2.5 years following primary diagnosis. The child died 13 months after the diagnosis of AT/RT. This case demonstrates that malignant gliomas may give rise to AT/RT. It also emphasizes the diagnostic value of a repeated tumor biopsy in the recurrence setting. PMID- 27472469 TI - The role of arabidopsis WDR protein in plant growth and defense strategies. AB - Evidence indicates that the mechanisms controlling photosynthesis efficiency also regulate plant response to biotic and abiotic stress. Light-induced cell death is genetically maintained for the control of innate immunity. In a recent study we showed that the expression of AtWDR26 was induced by light, multiple plant hormones, and abiotic stress; increased AtWDR26 strongly upregulated gene groups related to chloroplast metabolism, disease resistance, and abiotic stress tolerance. Gain- and loss-of-function analyses in transgenic plants demonstrated the involvement of AtWDR26 in signaling pathways; these controls were osmotic as well as salt stress tolerance. More detailed transcriptome evidence suggested that AtWDR26 was a powerful inducer of gene expression associated with chloroplast metabolism. This included the electron transport chain of the photosystem, carbohydrate synthesis, and enzymatic activity involved in photorespiration. Moreover, genes in auxin synthesis (and perception) constituted a significant portion of those that were upregulated. Gene expression involved in disease resistance, control of cell wall flexibility, Zn uptake, and AP2/ERF transcription factors was also be upregulated. We concluded that AtWDR26 is one component in the regulatory network between light-regulated plant growth and the adaptation response to disease resistance and abiotic stress. Auxin signal acts downstream for AtWDR26 regulation and the adaptation response to biotic and abiotic stress: this occurs through modulating cell wall flexibility, Zn homeostasis, and controlling stress-related transcription factors. PMID- 27472470 TI - plantMirP: an efficient computational program for the prediction of plant pre miRNA by incorporating knowledge-based energy features. AB - MicroRNAs are a predominant type of small non-coding RNAs approximately 21 nucleotides in length that play an essential role at the post-transcriptional level by either RNA degradation, translational repression or both through an RNA induced silencing complex. Identification of these molecules can aid the dissecting of their regulatory functions. The secondary structures of plant pre miRNAs are much more complex than those of animal pre-miRNAs. In contrast to prediction tools for animal pre-miRNAs, much less effort has been contributed to plant pre-miRNAs. In this study, a set of novel knowledge-based energy features that has very high discriminatory power is proposed and incorporated with the existing features for specifically distinguishing the hairpins of real/pseudo plant pre-miRNAs. A promising performance area under a receiver operating characteristic curve of 0.9444 indicates that 5 knowledge-based energy features have very high discriminatory power. The 10-fold cross-validation result demonstrates that plantMirP with full features has a promising sensitivity of 92.61% and a specificity of 98.88%. Based on various different datasets, it was found that plantMirP has a higher prediction performance by comparison with miPlantPreMat, PlantMiRNAPred, triplet-SVM, and microPred. Meanwhile, plantMirP can greatly balance sensitivity and specificity for real/pseudo plant pre-miRNAs. Taken together, we developed a promising SVM-based program, plantMirP, for predicting plant pre-miRNAs by incorporating knowledge-based energy features. This study shows it to be a valuable tool for miRNA-related studies. PMID- 27472472 TI - Is reaction time an index of white matter connectivity during training? AB - Voelker et al. (this issue) discuss the idea of linking white matter (WM) plasticity to improved reaction time (RT) during training. While compelling, this argument has important confounds and should be taken with cautions. RT is constrained not only by the speed of signal transmission in WM, but also by the properties of synaptic and neural processing in cortical gray matter. It is still unclear to what extent RT variability could be explained by WM plasticity and cortical plasticity. Future studies should examine both WM plasticity and cortical plasticity in relation to RT changes, to fully understand the brain mechanisms underlying RT improvement during training. PMID- 27472473 TI - Complementary and Alternative Medicine in Pediatric Gastroenterology. PMID- 27472471 TI - Towards longitudinal mapping of extracellular pH in gliomas. AB - Biosensor imaging of redundant deviation in shifts (BIRDS), an ultrafast chemical shift imaging technique, requires infusion of paramagnetic probes such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis methylene phosphonate (DOTP(8-) ) complexed with thulium (Tm(3+) ) ion (i.e. TmDOTP(5-) ), where the pH-sensitive resonances of hyperfine-shifted non-exchangeable protons contained within the paramagnetic probe are detected. While imaging extracellular pH (pHe ) with BIRDS meets an important cancer research need by mapping the intratumoral-peritumoral pHe gradient, the surgical intervention used to raise the probe's plasma concentration limits longitudinal scans on the same subject. Here we describe using probenecid (i.e. an organic anion transporter inhibitor) to temporarily restrict renal clearance of TmDOTP(5-) , thereby facilitating molecular imaging by BIRDS without surgical intervention. Co-infusion of probenecid with TmDOTP(5-) increased the probe's distribution into various organs, including the brain, compared with infusing TmDOTP(5-) alone. In vivo BIRDS data using the probenecid TmDOTP(5-) co-infusion method in rats bearing RG2, 9 L, and U87 brain tumors showed intratumoral-peritumoral pHe gradients that were unaffected by the probe dose. This co-infusion method can be used for pHe mapping with BIRDS in preclinical models for tumor characterization and therapeutic monitoring, given the possibility of repeated scans with BIRDS (e.g. over days and even weeks) in the same subject. The longitudinal pHe readout by the probenecid-TmDOTP(5-) co infusion method for BIRDS adds translational value in tumor assessment and treatment. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27472474 TI - Biliary Dyskinesia in Children: A Systematic Review. AB - Cholecystectomy rates for biliary dyskinesia in children are rising in the United States, but not in other countries. Biliary dyskinesia is a validated functional gallbladder disorder in adults, requiring biliary colic in the diagnosis. In contrast, most studies in children require upper abdominal pain, absent gallstones on ultrasound, and an abnormal gallbladder ejection fraction (GBEF) on cholecystokinin-stimulated cholescintigraphy for diagnosis. We aimed to systematically review existing literature in biliary dyskinesia in children, determine the validity and reliability of diagnostic criteria, GBEF, and to assess outcomes following cholecystectomy. We performed a systematic review following the PRISMA checklist and searched 7 databases including PubMed, Scopus, Embase, Ovid, MEDLINE, ProQuest, Web of Science, and the Cochrane library. Bibliographies of articles were screened for additional studies. Our search terms yielded 916 articles of which 28 were included. Three articles were manually added from searched references. We reviewed 31 peer-reviewed publications, all retrospective chart reviews. There was heterogeneity in diagnostic criteria and GBEF values. Outcomes after laparoscopic cholecystectomy varied from 34% to 100% success, and there was no consensus concerning factors influencing outcomes. The observational, retrospective study designs that comprised our review limited interpretation of safety and efficacy of the investigations and treatment in biliary dyskinesia in children. Symptoms of biliary dyskinesia overlapped with functional dyspepsia. There is a need for consensus on symptoms defining biliary dyskinesia, validation of testing required for diagnosis of biliary dyskinesia, and randomized controlled trials comparing medical versus surgical management in children with upper abdominal pain. PMID- 27472476 TI - Promotion of Epithelial Barrier Integrity Via Probiotic-derived Products. PMID- 27472477 TI - Duodenitis in Children. PMID- 27472479 TI - Highlights of the ESPEN-ESPGHAN-ECFS Guidelines on Nutrition Care for Infants and Children With Cystic Fibrosis. PMID- 27472478 TI - Partly Fermented Infant Formulae With Specific Oligosaccharides Support Adequate Infant Growth and Are Well-Tolerated. AB - OBJECTIVE: Fermented formulae (FERM) and a specific mixture of 90% short-chain galacto-oligosaccharides and 10% long-chain fructo-oligosaccharides (scGOS/lcFOS; 9:1) have a potential beneficial effect on gastrointestinal function and microbiota development in infants. The present study assessed the safety and tolerance of the combination of partly fermented infant milk formulae and scGOS/lcFOS compared with either 1 feature, in healthy term infants. METHODS: Four hundred thirty-two infants were enrolled before 28 days of age and followed up to 17 weeks of age and assigned to 1 of the 4 groups: (i) formula with scGOS/lcFOS, (ii) scGOS/lcFOS + 15% FERM, (iii) scGOS/lcFOS + 50% FERM, or (iv) 50% fermented formula (50% FERM). Primary outcome was daily weight gain during intervention (equivalence criterion: difference in daily weight gain <=3 g/day). Infants' anthropometrics, formula intake, number, and type of (serious) AEs were monitored monthly. Stool samples were collected at baseline and after 17 weeks for analysis of physiological and microbiological parameters. RESULTS: Equivalence of weight gain per day was demonstrated in both the intention-to treat and per-protocol population, with a mean weight gain (SD) of 29.7 (6.1), 28.2 (4.8), 28.5 (5.0), and 28.7 (5.9) g/day for the groups i to iv respectively. No differences were observed in other growth parameters, formula intake, and the number or severity of AEs. In all scGOS/lcFOS-containing formulae, a beneficial effect of scGOS/lcFOS was observed, indicated by the lower pH, lower Clostridium difficile levels, and higher secretory immunoglobulin A levels. CONCLUSIONS: The partly fermented infant milk formulae containing the specific mixture scGOS/lcFOS were well-tolerated and resulted in normal growth in healthy infants. PMID- 27472480 TI - Medical death certification by forensic physicians in the Netherlands: Validity and interdoctorvariation. AB - The aim of the study was to assess interdoctorvariation and validity in death certification by forensic physicians using 19 written scenarios. The scenarios described typical cases from forensic-medical practice. Physicians were asked to determine the manner of death (natural/unnatural) and to provide an ICD-10 code for the cause of death. In contrast to most studies on this topic, the measure of agreement among physicians was chance-corrected and a standard was used to assess the correctness of the assigned cause and manner of death. Forty-seven physicians participated in the survey. The study demonstrated that forensic physicians varied widely in their conclusions. With respect to manner of death, adequate agreement (defined as kappa>0.70) was achieved in six scenarios (32% of all scenarios). Concerning the underlying cause of death, adequate agreement was reached in three cases (16% of all scenarios). Furthermore, predictors for the correctness of manner and cause of death were studied using logistic regression. Years of experience as a forensic physician significantly predicted the correctness of cause of death (p < 0.05). Other predictors remained insignificant. With regard to manner of death, none of the studied predictors proved to be significant. To conclude, there appears to be a lack of consistency among forensic physicians regarding death certification. The ICD-10 coding of causes of death applied by forensic physicians is questionable. Less experienced physicians need supervision by more experienced colleagues when making judgments concerning the cause of death. Altogether, there is an urgent need to work out consensus-based guidelines for forensic physicians on how to certify deaths. PMID- 27472481 TI - A MnO2/Graphene Oxide/Multi-Walled Carbon Nanotubes-Sulfur Composite with Dual Efficient Polysulfide Adsorption for Improving Lithium-Sulfur Batteries. AB - Lithium-sulfur batteries can potentially be used as a chemical power source because of their high energy density. However, the sulfur cathode has several shortcomings, including fast capacity attenuation, poor electrochemical activity, and low Coulombic efficiency. Herein, multi-walled carbon nanotubes (CNTs), graphene oxide (GO), and manganese dioxide are introduced to the sulfur cathode. A MnO2/GO/CNTs-S composite with a unique three-dimensional (3D) architecture was synthesized by a one-pot chemical method and heat treatment approach. In this structure, the innermost CNTs work as a conducting additive and backbone to form a conducting network. The MnO2/GO nanosheets anchored on the sidewalls of CNTs have a dual-efficient absorption capability for polysulfide intermediates as well as afford adequate space for sulfur loading. The outmost nanosized sulfur particles are well-distributed on the surface of the MnO2/GO nanosheets and provide a short transmission path for Li+ and the electrons. The sulfur content in the MnO2/GO/CNTs-S composite is as high as 80 wt %, and the as-designed MnO2/GO/CNTs-S cathode displays excellent comprehensive performance. The initial specific capacities are up to 1500, 1300, 1150, 1048, and 960 mAh g-1 at discharging rates of 0.05, 0.1, 0.2, 0.5, and 1 C, respectively. Moreover, the composite cathode shows a good cycle performance: the specific capacity remains at 963.5 mAh g-1 at 0.2 C after 100 cycles when the area density of sulfur is 2.8 mg cm-2. PMID- 27472482 TI - Vaccination of Sheep with a Methanogen Protein Provides Insight into Levels of Antibody in Saliva Needed to Target Ruminal Methanogens. AB - Methane is produced in the rumen of ruminant livestock by methanogens and is a major contributor to agricultural greenhouse gases. Vaccination against ruminal methanogens could reduce methane emissions by inducing antibodies in saliva which enter the rumen and impair ability of methanogens to produce methane. Presently, it is not known if vaccination can induce sufficient amounts of antibody in the saliva to target methanogen populations in the rumen and little is known about how long antibody in the rumen remains active. In the current study, sheep were vaccinated twice at a 3-week interval with a model methanogen antigen, recombinant glycosyl transferase protein (rGT2) formulated with one of four adjuvants: saponin, Montanide ISA61, a chitosan thermogel, or a lipid nanoparticle/cationic liposome adjuvant (n = 6/formulation). A control group of sheep (n = 6) was not vaccinated. The highest antigen-specific IgA and IgG responses in both saliva and serum were observed with Montanide ISA61, which promoted levels of salivary antibodies that were five-fold higher than the second most potent adjuvant, saponin. A rGT2-specific IgG standard was used to determine the level of rGT2-specific IgG in serum and saliva. Vaccination with GT2/Montanide ISA61 produced a peak antibody concentration of 7 * 1016 molecules of antigen-specific IgG per litre of saliva, and it was estimated that in the rumen there would be more than 104 molecules of antigen-specific IgG for each methanogen cell. Both IgG and IgA in saliva were shown to be relatively stable in the rumen. Salivary antibody exposed for 1-2 hours to an in vitro simulated rumen environment retained approximately 50% of antigen-binding activity. Collectively, the results from measuring antibody levels and stablility suggest a vaccination based mitigation strategy for livestock generated methane is in theory feasible. PMID- 27472484 TI - Interpreting Visual Cultures of Science. PMID- 27472483 TI - The application of a clinical prediction rule for patients with neck pain likely to benefit from cervical traction: A case report. AB - PURPOSE: Cervical traction is a commonly utilized intervention in the treatment of patients with neck pain. In 2009, a clinical prediction rule (CPR) was developed as a way to assist clinicians in determining the patient population most likely to respond to cervical traction, though this CPR has yet to be validated. The purpose of this case report is to demonstrate the application of that CPR. CASE DESCRIPTION: The patient was a 46-year-old female with a four-week history of right-sided neck and shoulder pain, with numbness and tingling of her thumb and index finger. Treatment consisted of five sessions provided over 3 weeks. The plan of care included home mechanical cervical traction, exercise, and manual therapy. OUTCOMES: The patient achieved pain-free cervical range of motion. Neck disability index scores decreased from 28% to 6%, and the Patient Specific Functional Scale average score improved from 5.5 to 10 out of 10. DISCUSSION: This case report demonstrates the application of a CPR to assist in deciding if cervical traction is an appropriate intervention. Further research is needed to validate the CPR and to establish the optimal mode of delivery for traction. PMID- 27472485 TI - A model of muscle contraction based on the Langevin equation with actomyosin potentials. AB - We propose a muscle contraction model that is essentially a model of the motion of myosin motors as described by a Langevin equation. This model involves one dimensional numerical calculations wherein the total force is the sum of a viscous force proportional to the myosin head velocity, a white Gaussian noise produced by random forces and other potential forces originating from the actomyosin structure and intra-molecular charges. We calculate the velocity of a single myosin on an actin filament to be 4.9-49 MUm/s, depending on the viscosity between the actomyosin molecules. A myosin filament with a hundred myosin heads is used to simulate the contractions of a half-sarcomere within the skeletal muscle. The force response due to a quick release in the isometric contraction is simulated using a process wherein crossbridges are changed forcibly from one state to another. In contrast, the force response to a quick stretch is simulated using purely mechanical characteristics. We simulate the force-velocity relation and energy efficiency in the isotonic contraction and adenosine triphosphate consumption. The simulation results are in good agreement with the experimental results. We show that the Langevin equation for the actomyosin potentials can be modified statistically to become an existing muscle model that uses Maxwell elements. PMID- 27472487 TI - Impact of imagery rescripting on adverse self-defining memories and post-recall working selves in a non-clinical sample: a pilot study. AB - Imagery rescripting (ImRS) effectively targets intrusive images and symptoms in a number of disorders, but the mechanisms of change behind it are not yet clear. This study investigated the impact of ImRS on the characteristics of adverse self defining memories and post-recall working selves in a non-clinical sample. In the first session, participants recalled an adverse memory and completed state self and affect measures. Then they attended an ImRS session and a follow-up session one week later. Participants rated their memory as less negative, less distressing and less important for their sense of self at follow-up compared to the first session. They also reported higher state self-esteem and positive affect, as well as reduced negative affect and anxiety after recalling the memory. Results suggest that, by modifying the meaning of adverse memories, ImRS may facilitate their integration with individuals' sense of self and reduce the negative impact that they have on individuals' online representation of the self when retrieved. An implication of these findings is that cognitive-behavioural therapy may need to conceptualise the self in broader terms, moving beyond core beliefs. To complement this, research could focus on changes in patients' sense of self in order to understand the mechanisms through which interventions like ImRS work. PMID- 27472488 TI - FDA Advisory Panel Votes to Recommend Non-Adjunctive Use of Dexcom G5 Mobile CGM. PMID- 27472486 TI - Irritable bowel syndrome, the microbiota and the gut-brain axis. AB - Irritable bowel syndrome is a common functional gastrointestinal disorder and it is now evident that irritable bowel syndrome is a multi-factorial complex of changes in microbiota and immunology. The bidirectional neurohumoral integrated communication between the microbiota and the autonomous nervous system is called the gut-brain-axis, which integrates brain and GI functions, such as gut motility, appetite and weight. The gut-brain-axis has a central function in the perpetuation of irritable bowel syndrome and the microbiota plays a critical role. The purpose of this article is to review recent research concerning the epidemiology of irritable bowel syndrome, influence of microbiota, probiota, gut brain-axis, and possible treatment modalities on irritable bowel syndrome. PMID- 27472489 TI - The Complete Genome Sequence of Plodia Interpunctella Granulovirus: Evidence for Horizontal Gene Transfer and Discovery of an Unusual Inhibitor-of-Apoptosis Gene. AB - The Indianmeal moth, Plodia interpunctella (Lepidoptera: Pyralidae), is a common pest of stored goods with a worldwide distribution. The complete genome sequence for a larval pathogen of this moth, the baculovirus Plodia interpunctella granulovirus (PiGV), was determined by next-generation sequencing. The PiGV genome was found to be 112, 536 bp in length with a 44.2% G+C nucleotide distribution. A total of 123 open reading frames (ORFs) and seven homologous regions (hrs) were identified and annotated. Phylogenetic inference using concatenated alignments of 36 baculovirus core genes placed PiGV in the "b" clade of viruses from genus Betabaculovirus with a branch length suggesting that PiGV represents a distinct betabaculovirus species. In addition to the baculovirus core genes and orthologues of other genes found in other betabaculovirus genomes, the PiGV genome sequence contained orthologues of the bidensovirus NS3 gene, as well as ORFs that occur in alphabaculoviruses but not betabaculoviruses. While PiGV contained an orthologue of inhibitor of apoptosis-5 (iap-5), an orthologue of inhibitor of apoptosis-3 (iap-3) was not present. Instead, the PiGV sequence contained an ORF (PiGV ORF81) encoding an IAP homologue with sequence similarity to insect cellular IAPs, but not to viral IAPs. Phylogenetic analysis of baculovirus and insect IAP amino acid sequences suggested that the baculovirus IAP-3 genes and the PiGV ORF81 IAP homologue represent different lineages arising from more than one acquisition event. The presence of genes from other sources in the PiGV genome highlights the extent to which baculovirus gene content is shaped by horizontal gene transfer. PMID- 27472490 TI - Following up infant bronchiolitis patients provided new evidence for and against the united airway disease hypothesis. AB - AIM: The united airway disease (UAD) hypothesis suggests that allergic rhinitis and asthma develop together. We evaluated the evidence for and against the UAD hypothesis at five to seven years of age after hospitalisation for bronchiolitis at less than six months. METHODS: This study used prospective follow-up data for 102 children hospitalised for bronchiolitis under the age of six months. We included the presence of previous and current asthma, prolonged rhinitis and skin prick tests (SPT) to common inhaled allergens and lung function by impulse oscillometry (IOS) at five to seven years of age. Bronchial hyper-reactivity (BHR) was assessed using the exercise challenge test and bronchodilation test. RESULTS: Current asthma, but not previous transient asthma, was associated with prolonged rhinitis and a positive SPT. BHR, which reflected reactive airways, but not lung function, was associated with respiratory allergy, namely the combination of current asthma, prolonged rhinitis and a positive SPT. CONCLUSION: This post-bronchiolitis follow-up study suggested an association between respiratory allergy and reactive airways at five to seven years of age, which supported the UAD hypothesis. However, previous transient asthma and a reduction in lung function reduction did not support the hypothesis. PMID- 27472491 TI - Corrigendum. PMID- 27472492 TI - Effect of tetracycline on the growth and nutrient removal capacity of Chlamydomonas reinhardtii in simulated effluent from wastewater treatment plants. AB - The aim of this work was to study the effect of tetracycline, which is on the growth, physiological characteristics, and contaminants removal by Chlamydomonas reinhardtii. The results showed that the biomass and photosynthetic pigment concentration of C. reinhardtii exposed to tetracycline were lower than those of the control, while the superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities, and the malondialdehyde (MDA) content, were higher than those of the control. Additionally, when the tetracycline concentration reached 0.25mg/L, the removal of total nitrogen (TN), total phosphorus (TP), and chemical oxygen demand (COD) decreased from 80.8 to 55.0%, 100 to 92.5%, and 36.5 to 11.5%, respectively. Thus, tetracycline concentrations of 0-0.25mg/L are expected to have a significant effect on the growth and nutrient removal of C. reinhardtii in recycled water from wastewater treatment plants. PMID- 27472493 TI - Diplosphaera sp. MM1 - A microalga with phycoremediation and biomethane potential. AB - This study evaluated the potential of a microalga Diplosphaera sp. MM1 for its ability to generate energy through biomass production from wastewater remediation. 33% dairy wastewater and 50% winery wastewater demonstrated as promising alternative media for cultivating Diplosphaera sp. MM1 biomass. Interestingly, the alga cultivated in 50% winery wastewater with limited nitrogen produced the highest lipid content (43.07% total solid) and the lowest carbohydrate content (9.35% TS). On the contrary, the lowest lipid content (16.98% TS) and the highest carbohydrate content (29.39% TS) were exhibited by the alga cultivated in 33% dairy wastewater. The results from anaerobic digestion processes in terms of biochemical methane potential of the alga cultivated in BG 11 medium, 33% dairy wastewater and 50% winery wastewater were 197.39, 129.75 and 218.51NmLg(-1)VS, respectively. Further, this study demonstrates the potential of winery wastewater as a candidate to increase the lipid content of algae and enhance biofuel production of algal biomass. PMID- 27472494 TI - Cultivation of Nannochloropsis oceanica biomass rich in eicosapentaenoic acid utilizing wastewater as nutrient resource. AB - The eicosapentaenoic acid rich marine eustigmatophyte Nannochloropsis oceanica was grown in wastewaters sampled from four different industries (i.e. pesticides industry, pharmaceutical industry, activated sludge treatment plant of municipality sewage and petroleum (oil) industry). Under the wastewater based growth conditions used in this study, the biomass productivity ranged from 21.78+/-0.87 to 27.78+/-0.22mgL(-1)d(-1) in relation to freeze dried biomass, while the lipid productivity varied between 5.59+/-0.02 and 6.81+/-0.04mgL(-1)d( 1). Although comparatively higher biomass, lipid and EPA productivity was observed in Conway medium, the %EPA content was similarly observed in pesticides industry and municipal effluents. The results highlight the possibility of selectively using wastewater as a growth medium, demonstrating the elevated eicosapentaenoic acid content and biodiesel properties, that complies with the European standards for biodiesel. PMID- 27472495 TI - Pleiotropic effects of 5-aminolevulinic acid in mouse brain. AB - 5-Aminolevulinic acid (ALA) seems to be responsible for the neuropsychiatric manifestations of acute intermittent porphyria (AIP). Our aim was to study the effect of ALA on the different metabolic pathways in the mouse brain to enhance our knowledge about the action of this heme precursor on the central nervous system. Heme metabolism, the cholinergic system, the defense enzyme system, and nitric oxide metabolism were evaluated in the encephalon of CF-1 mice receiving a single (40 mg/kg body mass) or multiple doses of ALA (40 mg/kg, every 48 h for 14 days). We subsequently found ALA accumulation in the encephalon of the mice. ALA also altered the brain cholinergic system. After one dose of ALA, a decrease in superoxide dismutase activity and a reduction in glutathione levels were detected, whereas malondialdehyde levels and catalase activity were increased. Heme oxygenase was also increased as an antioxidant response to protect the encephalon against injury. All nitric oxide synthase isoforms were induced by ALA, these changes were more significant for the inducible isoform in glial cells. In conclusion, ALA affected several metabolic pathways in mouse encephalon. Data indicate that a rapid response to oxidative stress was developed; however, with long-term intoxication, the redox balance was probably restored, thereby minimizing oxidative damage. PMID- 27472496 TI - Action adaptation during natural unfolding social scenes influences action recognition and inferences made about actor beliefs. AB - When observing another individual's actions, we can both recognize their actions and infer their beliefs concerning the physical and social environment. The extent to which visual adaptation influences action recognition and conceptually later stages of processing involved in deriving the belief state of the actor remains unknown. To explore this we used virtual reality (life-size photorealistic actors presented in stereoscopic three dimensions) to see how visual adaptation influences the perception of individuals in naturally unfolding social scenes at increasingly higher levels of action understanding. We presented scenes in which one actor picked up boxes (of varying number and weight), after which a second actor picked up a single box. Adaptation to the first actor's behavior systematically changed perception of the second actor. Aftereffects increased with the duration of the first actor's behavior, declined exponentially over time, and were independent of view direction. Inferences about the second actor's expectation of box weight were also distorted by adaptation to the first actor. Distortions in action recognition and actor expectations did not, however, extend across different actions, indicating that adaptation is not acting at an action-independent abstract level but rather at an action-dependent level. We conclude that although adaptation influences more complex inferences about belief states of individuals, this is likely to be a result of adaptation at an earlier action recognition stage rather than adaptation operating at a higher, more abstract level in mentalizing or simulation systems. PMID- 27472497 TI - Dyslexics' usage of visual priors is impaired. AB - Human perception benefits substantially from familiarity, via the formation of effective predictions of the environment's pattern of stimulation. Basic stimulation characteristics are automatically retrieved and integrated into our perception. A quantitatively measurable manifestation of the integration of priors is known as "contraction to the mean"; i.e., perception is biased toward the experienced mean. We previously showed that in the context of auditory discrimination, the magnitude of this bias is smaller among dyslexic individuals than among good readers matched for age and general reasoning skills. Here we examined whether a similarly reduced contraction characterizes dyslexics' behavior on serial visual tasks. Using serial spatial frequency discrimination tasks, we found that dyslexics' bias toward the experiment's mean spatial frequency was smaller than that observed for the controls. Thus, dyslexics' difficulties in automatic detection and integration of stimulus statistics are domain-general. These difficulties are likely to impede the acquisition of reading expertise. PMID- 27472498 TI - Visual field restorative rehabilitation after brain injury. AB - About 20%-30% of patients undergoing neurological rehabilitation report visual field defects, one of the most frequent of which is homonymous hemianopsia (loss of the same half of the visual field in both eyes). There is still no consensus as to whether homonymous hemianopsia is best treated in a restorative or compensatory manner. The aim of this review is to describe the effects of restorative rehabilitation, whose long-term efficacy is still being debated. We analyzed 56 articles describing the use of various techniques used to promote visual field recovery but concentrating on two approaches: "border training," which involves exercising vision at the edge of the damaged visual field, and "blindsight training," which is based on exercising unconscious perceptual functions in the mild of the blind hemifield where the scotoma is deep. Both techniques have been supported by functional imaging studies showing evidence of cortical rearrangement (plasticity) after rehabilitation. Although no formal meta analysis was possible, the results of a semiquantitative evaluation suggested that the improvement in visual skills obtained is related to the type of training used: Border rehabilitation seems to improve the detection of visual stimuli, whereas blindsight rehabilitation seems to improve their processing. Finally, the addition of transcranial direct current stimulation seems to enhance the effects of visual field rehabilitation. PMID- 27472500 TI - Corrections. PMID- 27472499 TI - Corrections. PMID- 27472501 TI - Spatiotemporal properties of multiple-color channels in the human visual system. AB - Psychophysical and neurophysiological evidence argues for neural channels in V1 selectively sensitive to intermediate hues between the cardinal axes of opponent color space. The present study examined if these multiple-color channels are selective for other visual features analyzed by V1 such as orientation, spatial frequency, and motion direction. Using a conventional masking paradigm, we measured detection thresholds for an isoluminant grating modulated along a particular hue angle either in the presence or absence of a bandpass noise mask that varied in hue angle, orientation, spatial frequency, and motion direction. In line with previous studies, thresholds for the test grating were selectively elevated by noise masks with hue angles similar to that of the test. Hue selective masking was substantially reduced if test and mask were oriented orthogonally or differed in spatial frequency, but thresholds remained elevated if the mask drifted in the direction opposite to that of the test. Masking also revealed components selective for hue angle, but not for orientation. The results support the notion that multiple-color channels partly involve visual units selective for orientation and spatial frequency but largely nonselective for motion direction. PMID- 27472502 TI - Effective signaling of surface boundaries by L-vertices reflect the consistency of their contrast in natural images. AB - An L-vertex, the point at which two contours coterminate, provides highly reliable evidence that a surface terminates at that vertex, thus providing the strongest constraint on the extraction of shape from images (Guzman, 1968). Such vertices are pervasive in our visual world but the importance of a statistical regularity about them has been underappreciated: The contours defining the vertex are (almost) always of the same direction of contrast with respect to the background (i.e., both darker or both lighter). Here we show that when the two contours are of different directions of contrast, the capacity of the L-vertex to signal the termination of a surface, as reflected in object recognition, is markedly reduced. Although image statistics have been implicated in determining the connectivity in the earliest cortical visual stage (V1) and in grouping during visual search, this finding provides evidence that such statistics are involved in later stages where object representations are derived from two dimensional images. PMID- 27472503 TI - Emerging Roles of Transforming Growth Factor beta Signaling in Diabetic Retinopathy. AB - Diabetic retinopathy (DR) is a serious complication of diabetes mellitus affecting about one third of diabetic adults. Despite its prevalence, treatment options are limited and often implemented only in the later stages of the disease. To date, the pathogenesis of DR has been extensively characterized in the context of elevated glucose, insulin, and VEGF signaling, although a growing number of other growth factors and molecules, including transforming growth factor beta (TGF-beta) are being recognized as important contributors and/or therapeutic targets. Here, we review the complex roles of TGF-beta signaling in DR pathogenesis and progression. J. Cell. Physiol. 232: 486-489, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27472504 TI - Neural Correlates of Trait Rumination During an Emotion Interference Task in Women With PTSD. AB - Rumination, defined as repetitive, negative, self-focused thinking, is hypothesized to be a transdiagnostic factor that is associated with depression, anxiety, and posttraumatic stress disorder (PTSD). Theory has suggested that in individuals with PTSD, rumination serves as a cognitive avoidance factor that contributes to the maintenance of symptoms by inhibiting the cognitive and emotional processing of the traumatic event, subsequently interfering with treatment engagement and outcome. Little is known about the neural correlates of rumination in women with PTSD. The current study utilized functional magnetic resonance imaging (fMRI) to examine neural correlates during an emotion interference task of self-reported rumination in women with PTSD. Women with PTSD (39 participants) were recruited at a university-based trauma clinic and completed a clinical evaluation that included measures of PTSD symptoms, rumination, and depressive symptoms, as well as a neuroimaging session in which the participants were administered an emotion interference task. There was a significant relationship between self-reported rumination and activity in the right orbital frontal cortex, BA 11; t(37) = 5.62, p = .004, k = 46 during the task. This finding suggested that women with PTSD, who had higher levels of rumination, may experience greater difficulty inhibiting negative emotional stimuli compared to women with lower levels of rumination. PMID- 27472505 TI - Advances in modeling and treating spinal muscular atrophy. AB - PURPOSE OF REVIEW: Spinal muscular atrophy (SMA) is an inherited childhood neurodegenerative disorder caused by ubiquitous deficiency of the survival motor neuron (SMN) protein - the hallmarks of which are the selective loss of motor neurons and skeletal muscle atrophy. Here, we highlight recent progress in the understanding of SMA pathology and in the development of therapeutic approaches for its treatment. RECENT FINDINGS: Phenotypic characterization of mouse models of the disease, combined with analysis of SMN restoration or depletion in a spatially and temporally controlled manner, has yielded key insights into the normal requirement of SMN and SMA pathophysiology. Increasing evidence indicates a higher demand for SMN during neuromuscular development and extends the pathogenic effects of SMN deficiency beyond motor neurons to include additional cells both within and outside the nervous system. These findings have been paralleled by preclinical development of powerful approaches for increasing SMN expression through gene therapy or splicing modulation that are now in human trials. SUMMARY: Along with the availability of SMN-upregulating drugs, identification of the specific cell types in which SMN deficiency induces the disease and delineation of the window of opportunity for effective treatment are key advances in the ongoing path to SMA therapy. PMID- 27472506 TI - Congenital myasthenic syndromes: recent advances. AB - PURPOSE OF REVIEW: Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins essential for the integrity of neuromuscular transmission. This review updates the reader on recent findings that have expanded the phenotypic spectrum and suggested improved treatment strategies. RECENT FINDINGS: The use of next generation sequencing is continuing to unearth new genes in which mutations can give rise to defective neuromuscular transmission. The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. Notably, mutations in series of genes encoding presynaptic proteins are being identified. Further work on mutations found in the AGRN-MUSK acetylcholine receptor clustering pathway has helped characterize the role of LRP4 and broadened the phenotypic spectrum for AGRN mutations. Mutations in another extracellular matrix protein, collagen 13A1 and in GMPPB have also been found to cause a CMS. Finally, there are an increasing number of reports for the beneficial effects of treatment with beta2 adrenergic receptor agonists. SUMMARY: Recent studies of the CMS illustrate the increasing complexity of the genetics, pathophysiological mechanisms and the need to tailor therapy for the genetic disorders of the neuromuscular junction. PMID- 27472507 TI - Characteristics of Sexually Abused Children and Their Nonoffending Mothers Followed by Child Welfare Services: The Role of a Maternal History of Child Sexual Abuse. AB - Considering the importance of mother's support in the adaptation of a sexually abused child, it is relevant to determine if the mothers and children involved in an intergenerational cycle of child sexual victimization differ from dyads in which only the child has been abused. The purpose of this study was to compare mother-child dyads with sexually abused children according to whether the mother had herself been victim of child sexual abuse. The sample included 87 dyads with sexually abused children aged 3-18 years old and their mothers (44 reporting maternal and child abuse), followed by social welfare services of the province of Quebec (Canada). The two groups of mothers were compared on their past family abuse experiences and past family relations, their mental health history, their current psychological distress, their parenting behaviors, and their current levels of family functioning. Children were compared on their adaptation. Multivariate analyses indicated that mothers reporting child sexual abuse were more likely to report more other maltreatments in their childhood and greater prevalence of lifetime history of alcohol abuse disorders, dysthymia, and panic disorder compared with mothers who had not experienced CSA. Compared to children whose mothers had not experienced CSA, those whose mothers had experienced CSA showed higher rates of problems behaviors and were more likely to report having been sexually abused by a trusted person. These results highlight the specific clinical needs for the assessment and treatment for sexually abused children whose mothers experienced child sexual abuse. PMID- 27472508 TI - Teachers' Knowledge and Beliefs About Child Sexual Abuse. AB - Child sexual abuse is one of the main types of abuse still to be addressed within the field of education, yet the education system itself can serve as a primary tool for its prevention. A better understanding of teachers' knowledge and beliefs about child sexual abuse will allow us to establish key starting points from which to utilize the system for prevention. Four hundred and fifty teachers participated in this study, completing a questionnaire regarding their knowledge and beliefs about child sexual abuse. The study revealed that over half the teachers, 65.3% (n = 294), had never received any type of training in child sexual abuse education and that the majority were not familiar with methods of identifying child sexual abuse, 90.7% (n = 279). Various mistaken beliefs were identified among the participating teachers, such as pathological profiles of abusers, that the vast majority of child sexual abuse implies violent behavior, and that there cannot be abusers the same age as the victim. These results indicate that knowledge deficiencies do exist about child sexual abuse among teachers and highlight the need for training in this field. PMID- 27472509 TI - Children's Experiences of Completing a Computer-Based Violence Survey: Finnish Child Victim Survey Revisited. AB - The involvement of children as research subjects requires special considerations with regard to research practices and ethics. This is especially true concerning sensitive research topics such as sexual victimization. Prior research suggests that reflecting these experiences in a survey can cause negative feelings in child participants, although posing only a minimal to moderate risk. Analyzing only predefined, often negative feelings related to answering a sexual victimization survey has dominated the existing literature. In this article children's free-text comments about answering a victimization survey and experiences of sexual victimization are analyzed together to evaluate the effects of research participation in relation to this sensitive issue. Altogether 11,364 children, aged 11-12 and 15-16, participated in the Finnish Child Victim Survey in 2013. Of these, 69% (7,852) reflected on their feelings about answering the survey. Results indicate that both clearly negative and positive feelings are more prevalent among victimized children compared to their nonvictimized peers. Characteristics unique to sexual victimization as well as differences related to gender and age are also discussed. The study contributes to the important yet contradictory field of studying the effects of research participation on children. PMID- 27472510 TI - Behavioural Differences Between Online Sexual Groomers Approaching Boys and Girls. AB - This study focused on the behavior of convicted offenders who had approached profiles of boys and girls online for offline sexual encounters. A detailed coding scheme was designed to code and analyze offenders' grooming behaviors in transcripts of conversational interactions between convicted offenders and 52 volunteer workers purporting to be girls and 49 volunteer workers who masqueraded as boys. Behavioral differences and commonalities associated with the gender of the groomed child decoys were examined. Results showed that offenders approaching boys were significantly older and pretended to be younger than offenders approaching girls. When compared to offenders grooming boy decoys, offenders grooming girl decoys typically built more rapport, were less sexually explicit, and approached sexual topics carefully and indirectly. Offenders also used more strategies to conceal contact with girls than with boys. PMID- 27472511 TI - A Summary of Selective Experimental Research on Psychosocial Interventions for Sexually Abused Children. AB - This study was conducted to explore current trends in psychosocial interventions for sexually abused children through a review of recent research. Our comprehensive review is limited to published (quasi) experimental studies in the English language over a period of 2000-2013. It provides a detailed analysis of the final 18 articles that met our inclusion criteria, from the 670 potentially relevant articles that were identified. Reviewers analyzed candidate articles to determine whether they met inclusion or exclusion criteria. The retrieved studies reported positive results with respect to improvements in the negative psychosocial sequelae of child sexual abuse following the use of a diverse set of treatment strategies. Of the various interventions, cognitive behavioral therapy was shown to be the most promising type of intervention for sexually abused children. In this review, we discuss some of the implications of psychosocial interventions for victims of child sexual abuse, citing both the methodological and ethical issues that should be considered. PMID- 27472512 TI - PURTSCHER RETINOPATHY AS A MANIFESTATION OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. AB - PURPOSE: The authors describe a woman diagnosed with hemophagocytic lymphohistiocytosis and found to have retinal examination findings consistent with Purtscher retinopathy. METHODS: A 52-year-old woman underwent multimodal imaging, including color fundus photography and spectral-domain optical coherence tomography, to confirm the diagnosis. RESULTS: The ophthalmic examination and imaging confirmed the findings of Purtscher retinopathy with significant inner retinal thickening on spectral-domain optical coherence tomography. Throughout a hospital course complicated by multi-organ failure, she continued to have profoundly limited visual acuity, likely resulting from inner retinal ischemia affecting the posterior pole of both eyes. CONCLUSION: The authors describe a patient with hemophagocytic lymphohistiocytosis, a disease characterized by disruption of normal natural killer cell activity with subsequent uncontrolled cytokine release, who presented with Purtscher retinopathy confirmed with spectral-domain optical coherence tomography. PMID- 27472513 TI - INTRAVITREAL RANIBIZUMAB AS AN ADJUNCTIVE TREATMENT FOR COATS DISEASE (6-YEAR FOLLOW-UP). AB - PURPOSE: To evaluate the effectiveness of intravitreal ranibizumab in combination with laser photocoagulation in the management of Coats disease. METHOD: Six intravitreal injections of 0.5 mg (0.05 mL) ranibizumab were performed, each 4 weeks apart. Correspondence to therapy was evaluated using visual acuity measurements and optical coherence tomography images. Six months after the initiation of treatment, laser photocoagulation was applied on the telangiectasias and on the surrounding ischemic areas, followed by a single intravitreal ranibizumab injection. Three months later, laser photocoagulation was repeated in purpose to prevent recurrence. RESULTS: In the sixth month, no improvement in visual acuity was recorded, as thick circinate hard exudates still remained in the submacular space. Nevertheless, retinal detachment had completely subsided, and fluorescein angiography showed a significant decrease of leakage from the telangiectatic vessels. At the 12-month follow-up visit, an impressive improvement was recorded, with total absorption of the submacular exudate and visual acuity being 20/30. At the 20-month follow-up visit, his visual acuity was 20/20 and the retina was flat with no signs of macular edema or exudates. At the 6-year follow-up visit, the patient was absolutely stable. DISCUSSION: Elevated vascular endothelial growth factor levels have been demonstrated in Coats disease. Anti-vascular endothelial growth factor agents assist to the decrease of vascular permeability of the capillary endothelial cells, thus increasing the efficiency of laser application. PMID- 27472514 TI - SUCCESSFUL TREATMENT OF REFRACTORY PROLIFERATIVE RETINOPATHY OF INCONTINENTIA PIGMENTI BY INTRAVITREAL RANIBIZUMAB AS ADJUNCT THERAPY IN A 4-YEAR-OLD CHILD. AB - PURPOSE: To describe a case of incontinentia pigmenti with proliferative retinopathy successfully treated by combination of repeated retinal laser photocoagulation and intravitreal ranibizumab injection. METHODS: Single interventional case report of a 4-year-old girl, known case of incontientia pigmenti, first screened at the age of two, presented with proliferative retinopathy. Sole treatment by panretinal laser photocoagulation failed to control the progression of retinal neovascularization. Intravitreal ranibizumab injections were used as an adjunct therapy. RESULTS: The proliferative retinopathy was brought under control and halted till this date with repeated intravitreal ranibizumab and panretinal photocoagulation. No systemic side effect was noted. CONCLUSION: Intravitreal ranibizumab can be considered as an adjunct therapy in proliferative retinopathy secondary to incontinentia pigmenti when monotherapy with panretinal photocoagulation fails. Intravitreal ranibizumab may quickly inhibit the intraocular vascular endothelial growth factor and may prevent devastating complications like tractional retinal detachment. Extra caution has to be taken in adopting different dosages and injection regimes especially in pediatric cases. PMID- 27472515 TI - TARANTULA HAIR ASSOCIATED PANUVEITIS TREATED WITH SUSTAINED-RELEASE INTRAVITREAL DEXAMETHASONE IMPLANT. AB - PURPOSE: To report a case of tarantula hair-induced panuveitis treated with sustained-release intravitreal dexamethasone implant and followed by sequential spectral domain optical coherence tomography imaging. METHODS: Findings on clinical examination, anterior segment optical coherence tomography, corneal in vivo confocal microscopy, color fundus photos, fluorescein angiography, and retinal spectral domain optical coherence tomography are presented. Sequential optical coherence tomography images demonstrated the course of the chorioretinal lesions before and after sustained-release intravitreal dexamethasone implant. RESULTS: A 19-year-old female presented with localized temporal episcleritis and scleritis that incompletely resolved despite multiple courses of topical and oral corticosteroids. She subsequently developed focal vitritis and chorioretinitis, and was found to have tarantula hair-induced panuveitis. Anterior segment optical coherence tomography and in vivo confocal microscopy confirmed the presence of tarantula hairs embedded in the anterior corneal stroma. There was only transient improvement with posterior sub-Tenon's Kenalog injection. After treatment with sustained-release intravitreal dexamethasone implant, her symptoms improved and the chorioretinal lesions became inactive. Sequential spectral domain optical coherence tomography images revealed hyperreflective inner retina lesions that progressed to involve the outer retina, and then flattened to near resolution after therapy. CONCLUSION: This is the first case showing positive clinical outcomes supported by sequential retinal spectral domain optical coherence tomography using a sustained-release intravitreal dexamethasone implant to treat ophthalmia nodosa-induced by tarantula hairs. PMID- 27472516 TI - Pharmacoeconomic analysis of biological disease modifying antirheumatic drugs in patients with rheumatoid arthritis based on real-world data from the IORRA observational cohort study in Japan. AB - OBJECTIVES: To evaluate the cost-effectiveness of biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: We used a state-transition model and parameters were determined from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study on 421 patients who had failed at least one DMARD and started either 1 of 4 bDMARDs (bDMARD group; adalimumab, etanercept, infliximab, and tocilizumab) or methotrexate (control group). bDMARD group was evaluated as two groups: sequence of any 1 of 4 bDMARDs with and without tocilizumab. The incremental cost-effectiveness ratios (ICERs) for bDMARD group were estimated using base-case analysis, probabilistic sensitivity analysis (PSA) and scenario sensitivity analyses. RESULTS: ICERs of bDMARD group with or without tocilizumab were $38,179 and $48,855, respectively. By PSA, these sequences had respective probabilities of 86.8% and 75.1% of falling below the assumed cost-effectiveness threshold of $50,000 in Japan. Scenario sensitivity analyses showed that the best population for initiating bDMARD was RA patients less than 50 years old with Japanese version of HAQ between 1.1 and 1.6 and using tocilizumab as the bDMARD. CONCLUSION: bDMARDs were cost-effective for RA patients based on a real-world setting in Japan. PMID- 27472517 TI - The Anisakis Transcriptome Provides a Resource for Fundamental and Applied Studies on Allergy-Causing Parasites. AB - BACKGROUND: Food-borne nematodes of the genus Anisakis are responsible for a wide range of illnesses (= anisakiasis), from self-limiting gastrointestinal forms to severe systemic allergic reactions, which are often misdiagnosed and under reported. In order to enhance and refine current diagnostic tools for anisakiasis, knowledge of the whole spectrum of parasite molecules transcribed and expressed by this parasite, including those acting as potential allergens, is necessary. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we employ high throughput (Illumina) sequencing and bioinformatics to characterise the transcriptomes of two Anisakis species, A. simplex and A. pegreffii, and utilize this resource to compile lists of potential allergens from these parasites. A total of ~65,000,000 reads were generated from cDNA libraries for each species, and assembled into ~34,000 transcripts (= Unigenes); ~18,000 peptides were predicted from each cDNA library and classified based on homology searches, protein motifs and gene ontology and biological pathway mapping. Using comparative analyses with sequence data available in public databases, 36 (A. simplex) and 29 (A. pegreffii) putative allergens were identified, including sequences encoding 'novel' Anisakis allergenic proteins (i.e. cyclophilins and ABA-1 domain containing proteins). CONCLUSIONS/SIGNIFICANCE: This study represents a first step towards providing the research community with a curated dataset to use as a molecular resource for future investigations of the biology of Anisakis, including molecules putatively acting as allergens, using functional genomics, proteomics and immunological tools. Ultimately, an improved knowledge of the biological functions of these molecules in the parasite, as well as of their immunogenic properties, will assist the development of comprehensive, reliable and robust diagnostic tools. PMID- 27472518 TI - New Cell Adhesion Molecules in Human Ischemic Cardiomyopathy. PCDHGA3 Implications in Decreased Stroke Volume and Ventricular Dysfunction. AB - BACKGROUND: Intercalated disks are unique structures in cardiac tissue, in which adherens junctions, desmosomes, and GAP junctions co-localize, thereby facilitating cardiac muscle contraction and function. Protocadherins are involved in these junctions; however, their role in heart physiology is poorly understood. We aimed to analyze the transcriptomic profile of adhesion molecules in patients with ischemic cardiomyopathy (ICM) and relate the changes uncovered with the hemodynamic alterations and functional depression observed in these patients. METHODS AND RESULTS: Twenty-three left ventricular tissue samples from patients diagnosed with ICM (n = 13) undergoing heart transplantation and control donors (CNT, n = 10) were analyzed using RNA sequencing. Forty-two cell adhesion genes involved in cellular junctions were differentially expressed in ICM myocardium. Notably, the levels of protocadherin PCDHGA3 were related with the stroke volume (r = -0.826, P = 0.003), ejection fraction (r = -0.793, P = 0.004) and left ventricular end systolic and diastolic diameters (r = 0.867, P = 0.001; r = 0.781, P = 0.005, respectively). CONCLUSIONS: Our results support the importance of intercalated disks molecular alterations, closely involved in the contractile function, highlighting its crucial significance and showing gene expression changes not previously described. Specifically, altered PCDHGA3 gene expression was strongly associated with reduced stroke volume and ventricular dysfunction in ICM, suggesting a relevant role in hemodynamic perturbations and cardiac performance for this unexplored protocadherin. PMID- 27472520 TI - High load of Merkel cell polyomavirus DNA detected in the normal skin of Japanese patients with Merkel cell carcinoma. AB - BACKGROUND: Although Merkel cell polyomavirus (MCPyV) has the potential to cause Merkel cell carcinoma (MCC), it is also found in the normal skin of healthy individuals. However, the mechanism for transformation of MCPyV to an oncogenic form is unknown. OBJECTIVES: To investigate the levels of MCPyV infection in the normal skin patients with MCC compared with those in a control cohort. STUDY DESIGN: We studied a total of six Japanese patients with cutaneous MCC. Sun exposed and sun-unexposed skin swabs were obtained and analyzed for MCPyV loads using quantitative real-time polymerase chain reaction. RESULTS: At first, we found a patient with MCC carrying an extremely high load of MCPyV DNA in normal skin. This unique case prompted us to further explore the levels of MCPyV as skin microbiota in patients with MCC. We showed that MCPyV DNA levels were significantly higher in swabs obtained from normal skin samples of six patients with MCC compared with those from 30 age-matched healthy individuals and 19 patients with other cutaneous cancers. Whereas MCPyV strains obtained from the normal skin of patients with MCC had gene sequences without structural alterations, sequences of the tumor-derived strains showed truncating mutations or deletions. CONCLUSIONS: Although the number of patients with MCC studied was small, our findings suggest that MCC may occur with a background of high MCPyV load in the skin, and are expected to stimulate further studies on whether such skin virome levels could be one of predictive markers for the development of MCC. PMID- 27472519 TI - Genotypic resistance test in proviral DNA can identify resistance mutations never detected in historical genotypic test in patients with low level or undetectable HIV-RNA. AB - BACKGROUND: Beyond the detection of resistant HIV strains found in plasma samples, archival HIV-DNA in peripheral blood mononuclear cells (PBMCs) might represent a reservoir of additional resistance. OBJECTIVE: To characterize the HIV-1 resistance in PBMCs from patients with suppressed or low-level viremia (50 1000 copies/mL) and evaluate its added value compared to the resistance detected in previous plasma genotypic resistance tests (GRTs). STUDY DESIGN: HIV-1 infected patients selected for treatment change despite low/undetectable viremia were tested. Number and type of primary resistance mutations (PRMs) detected in PBMCs were compared to those detected in previous plasma GRTs. Logistic regression assessed factors associated with presence of at least one PRM in PBMCs. RESULT: 468 patients with a PBMC GRT were analyzed; 149 of them had at least 2 plasma GRTs performed before PBMC genotyping. 42.3% of patients showed at least one PRM in PBMCs. The highest proportion of PRMs in PBMCs was observed for NRTI class (30.6%), followed by NNRTI (22.2%), PI (14.1%) and INI (4.9%). In 20.1% of patients, PRMs were detected only in PBMCs and not in any of the plasma GRT previously performed. By using multivariable analysis, a higher number of previous regimens, injecting drug-use route and a lower nadir CD4 were associated with significantly higher risk of detecting PRMs in PBMCs. CONCLUSION: Our findings support the usage of PBMC GRT in addition to the current recommended plasma RNA test, especially when therapeutic and/or resistance information is not available. PMID- 27472521 TI - Temporomandibular Disorder Diagnostic Groups Affect Outcomes Independently of Treatment in Patients at Risk for Developing Chronicity: A 2-Year Follow-Up Study. AB - AIMS: To evaluate whether a biobehavioral intervention would be more effective than a self-care intervention or no intervention in reducing psychosocial distress, reducing pain, and improving functioning in patients with an acute myofascial temporomandibular disorder (m-TMD). METHODS: Participants (n = 435) were from community dental clinics in the Dallas-Fort Worth Metroplex who were seeking treatment for their acute TMD symptoms and were recruited between 2008 and 2013. The participants were diagnosed using the Research Diagnostic Criteria for TMD (RDC/TMD) and assigned to a biobehavioral intervention, self-care intervention, or no intervention. Three outcomes were assessed: psychosocial distress, pain, and functioning; and treatment effectiveness was assessed according to TMD diagnosis. Outcome evaluations were conducted immediately postintervention as well as at 1 and 2 years postintervention. Analyses were conducted using two-level hierarchical multilevel linear models (MLMs). RESULTS: Contrary to expectations, patients did not respond differently to the intervention based on their TMD diagnosis. Acute m-TMD patients, especially those with other comorbid TMD diagnoses, reported the highest levels of pain and pain related symptoms and disability. They also exhibited poorer jaw functioning, especially if they were at high risk for chronic TMD. CONCLUSION: This study indicates that acute m-TMD tends to result in more severe symptom presentations, particularly if diagnosed in combination with other TMD comorbidities. Additionally, patients do not appear to respond better to biobehavioral or self care intervention on the basis of their TMD diagnosis. PMID- 27472523 TI - The Effectiveness of Physiotherapy in the Management of Temporomandibular Disorders: A Systematic Review and Meta-analysis. AB - AIMS: To analyze the methodologic quality, summarize the findings, and perform a meta-analysis of the results from randomized controlled trials that assessed the effects of physiotherapy management of temporomandibular disorders. METHODS: A literature review was performed using the electronic databases PubMed, Science Direct, and EBSCO. Each article was independently assessed by two investigators using the Physiotherapy Evidence Database (PEDro), Jadad scales, and the Cochrane Risk of Bias tool. A meta-analysis was conducted by using the DerSimonian-Laird random-effects method to obtain summary estimates of the standardized mean differences (SMD) and the corresponding 95% confidence intervals (95% CI). Between-study heterogeneity was computed and publication bias was assessed. RESULTS: Seven articles met the inclusion criteria and were used in the analysis, corresponding to nine estimates of SMD. The meta-analysis showed that for pain reduction, the summary SMD favored physiotherapy (SMD = -0.63; 95% CI: -0.95 to 0.31; number of studies = 8; I2 = 0.0%), while for active range of movement (ROM) the differences between the intervention and control groups were not statistically significant (SMD = 0.33; 95% CI: -0.07 to 0.72; number of studies = 9; I2 = 61.9%). CONCLUSION: Physiotherapy seems to lead to decreased pain and may improve active ROM. However, the results are not definitive and further studies and meta-analyses are needed before these results can be considered fully generalizable. PMID- 27472524 TI - Coincidence and Awareness of the Relationship Between Temporomandibular Disorders and Jaw Injury, Orthodontic Treatment, and Third Molar Removal in University Students. AB - AIMS: To determine whether there is an association between temporomandibular disorders (TMD) and a history of facial/jaw injury (FJI), orthodontic treatment (OT), or third molar removal (TMR) in university students, and to evaluate the students' awareness of a possible relationship between jaw pain or other TMD symptoms, FJI, OT, and TMR, and the presence of TMD. METHODS: This cross sectional study involved 1,381 Oporto District university students. The Portuguese version of the Research Diagnostic Criteria for TMD was used for TMD diagnosis. FJI, OT, and TMR histories were evaluated by questionnaire. Univariate associations between categorical variables were tested by using chi-square tests. Multivariate logistic regression was applied to predict independent factors associated with TMD. RESULTS: Of the 1,381 students (mean age +/- standard deviation [SD]: 21.7 +/- 3.9 years), 39.3% had TMD, 23.2% had a history of FJI, 44.5% had undergone OT, and 26.2% had undergone TMR. Univariate analyses showed significant associations between OT and TMD (P = .044) and between TMR and TMD (P = .003). Multivariate regression analyses using FJI, OT, TMR, OT * TMR interaction, sex, and age in the first step showed TMR (Odds Ratio [OR] = 1.30; P = .041), sex (OR = 1.59; P = .001), and age (OR = 1.04; P = .013) as significant. A positive correlation between TMD and awareness of the relationship between jaw pain or TMD symptoms and a history of FJI or OT (P < .001 and P = .002, respectively) was documented. CONCLUSION: TMR, female sex, and older age were risk factors independently associated with TMD. The results also suggest that patients' awareness of potential risk factors for TMD should be taken into account on an individual basis. PMID- 27472522 TI - Circulating Omentin-1 and Chronic Painful Temporomandibular Disorders. AB - AIMS: To investigate the relationship between omentin-1 levels and painful temporomandibular disorders (TMD). METHODS: In a case-control design, chronic painful TMD cases (n = 90) and TMD-free controls (n = 54) were selected from participants in the multisite OPPERA study (Orofacial Pain: Prospective Evaluation and Risk Assessment). Painful TMD case status was determined by examination using established Research Diagnostic Criteria for TMD (RDC/TMD). Levels of omentin-1 in stored blood plasma samples were measured by using an enzyme linked immunosorbent assay. Binary logistic regression was used to calculate the odds ratios (ORs) and 95% confidence limits (CLs) for the association between omentin-1 and painful TMD. Models were adjusted for study site, age, sex, and body mass index. RESULTS: The unadjusted association between omentin-1 and chronic painful TMD was statistically nonsignificant (P = .072). Following adjustment for covariates, odds of TMD pain decreased 36% per standard deviation increase in circulating omentin-1 (adjusted OR = 0.64; 95% CL: 0.43, 0.96; P = .031). CONCLUSION: Circulating levels of omentin-1 were significantly lower in painful TMD cases than controls, suggesting that TMD pain is mediated by inflammatory pathways. PMID- 27472525 TI - Transient Pain Following Orthodontic Fixed Appliances Induces Sensitization of Gingival and Periodontal Tissues. AB - AIMS: To evaluate the transient effects of orthodontic treatment on the mechanical detection threshold (MDT) and mechanical pain threshold (MPT) of the buccal attached gingiva and the pressure pain threshold (PPT) of the buccal attached gingiva and of the teeth in two directions (perpendicular and parallel). METHODS: A total of 20 patients (15 females and 5 males) aged 18 to 30 years participated in the study. Perceived pain on a 0- to 10-cm visual analog scale (VAS) and MDT, MPT, and PPT scores were evaluated at two time points at the masseter muscle, gingiva, teeth, and hand (control) prior to orthodontic treatment (T0) and 24 hours after the first archwire placement (T1). Mean values and SEMs were calculated for all continuous variables. The differences between T0 and T1 of MDT, MPT, and PPT were analyzed by means of a paired Student t test. RESULTS: The pain intensity as assessed on the VAS was 4.2 +/- 1.8 cm. No significant changes in MDT or MPT were found at the hand and buccal attached gingiva (P > .06). The PPTs at the buccal attached gingiva of teeth 21, 23, 24, and 34, at teeth 21, 23, 24, and 34 (perpendicular) and at teeth 21 and 23 (parallel) were lower (ie, more sensitive) at T1 compared with T0 (P < .04). CONCLUSION: This study indicates for the first time that pain following insertion of an archwire causes sensitization to blunt-pressure stimuli both in the attached gingiva and in the periodontal ligament. Quantitative assessment of mechanical sensitivity may provide more insights into procedural pain and allow for better monitoring and evaluation of the effects of orthodontic treatment in the future. PMID- 27472526 TI - The Effects of Mandibular Advancement Device on Pressure Pain Threshold of Masticatory Muscles: A Prospective Controlled Cohort Study. AB - AIMS: To determine if pressure pain thresholds (PPTs) of masticatory and neck muscles change after the application of a mandibular advancement device (MAD) in patients with obstructive sleep apnea (OSA). METHODS: A prospective study was conducted in a sample of 27 OSA patients (24 males and 3 females; mean age +/- standard deviation [SD]: 54.8 +/- 11.8, mean apnea-hypopnea index +/- SD: 23.5 +/ 13.3) and 27 age- and sex-matched healthy controls. Exclusion criteria were signs and symptoms of temporomandibular disorders (TMD), metabolic diseases, and use of antidepressants, analgesics, or anti-inflammatory drugs. A calibrated examiner evaluated PPTs of seven head and neck muscles bilaterally by using a Fischer algometer. In the OSA group, PPTs were recorded immediately before the MAD application (T0), after 15 days (T1), and after 6 months (T2) of therapy; in the control group, PPTs were recorded at the same time intervals. PPT differences at baseline and over time within each group and between OSA and control groups were analyzed by Friedman and Mann-Whitney tests. RESULTS: There were no PPT differences between groups at baseline. In the OSA group, PPTs of temporalis and masseter muscles decreased significantly at T1 compared with T0 (P < .05), but no differences were found at T2. No significant PPT differences were found in the neck muscles or over time in the control group. CONCLUSION: MAD application induces a decrease of PPTs of masticatory muscles at the beginning of the therapy, but a physiologic adaptation occurs by 6 months. PMID- 27472527 TI - Ipsilateral Molar Clenching Induces Less Pain and Discomfort than Contralateral Molar Clenching in Patients with Unilateral Anterior Disc Displacement of the Temporomandibular Joint. AB - AIMS: To assess the influence of clenching side and location (ie, tooth) on the bite force necessary to induce pain or discomfort in patients with unilateral anterior disc displacement (ADD) of the temporomandibular joint (TMJ). METHODS: A total of 17 patients with unilateral ADD diagnosed clinically and with magnetic resonance imaging were included. A bite force meter was positioned at each of four experimental positions: the mandibular first premolars and first molars, bilaterally. Subjects were instructed to clench on the bite force meter until they felt pain or discomfort in the orofacial area and to report the location of the pain. Differences in pain location (ADD side versus contralateral side) and in the bite force thresholds for eliciting pain or discomfort were assessed by means of the paired t test and Wilcoxon signed-rank test. RESULTS: Only 18% of subjects (3 out of 17) reported pain in the TMJ with ADD during clenching at the ipsilateral molar, whereas 65% (11 out of 17) reported joint pain during clenching on the contralateral molar (P = .005). At the molars, the mean +/- standard deviation bite force necessary to induce pain was 241.2 +/- 135.5 N on the side with ADD and 160.9 +/- 78.0 N on the contralateral side. The mean molar bite force necessary to induce pain on the side with ADD was significantly higher than that on the contralateral side (P = .002). CONCLUSION: Patients with unilateral ADD had fewer reports of TMJ pain and discomfort when they were molar clenching on the ipsilateral side compared to molar clenching on the contralateral side. PMID- 27472528 TI - Assessment of Anxiety and Coping Features in Bruxers: A Portable Electromyographic and Electrocardiographic Study. AB - AIMS: To determine whether there is a correlation between any psychological features and sleep bruxism (SB). METHODS: A total of 36 healthy volunteers underwent an in-home evaluation with a portable device combining electromyographic (EMG) and electrocardiographic (ECG) recordings for the diagnosis of SB. They were administered questionnaires that assessed state and trait anxiety levels and coping strategies. The study hypothesis was that the SB index was significantly correlated with an individual's anxiety and coping. Correlation between SB index and psychological features was assessed and a comparison between SB prevalences in subjects with different psychological scores was carried out. RESULTS: Correlation analysis showed that the SB index was not correlated with any of the psychological scales; however, there were some significant correlations (r values range from 0.393 to 0.458) between the SB index and specific items from the trait anxiety and coping scales. Crosstabulations of subjects with SB and with high (overmedian) or low (undermedian) scores for the various psychological measures revealed significant correlations between the prevalence of SB in higher-scoring subjects for state anxiety scores (Phi coefficient = .456; P = .006), trait anxiety scores (Phi = 0.369; P = .027), and social support coping strategy (Phi = 0.387; P = .020). CONCLUSION: These findings support the study hypothesis only in part and confirm the absence of a clear-cut relationship between SB and psychological features. PMID- 27472529 TI - Systematic Review and Meta-analysis of the Efficacy of Oral Medications Compared with Placebo Treatment in the Management of Postherpetic Neuralgia. AB - AIMS: To conduct a systematic review to determine the efficacy of oral medications for the management of postherpetic neuralgia (PHN). METHODS: Three electronic databases were searched: Cochrane Library (up to 7 July 2015), MEDLINE via PubMed (from 1950 to 7 July 2015), and Web of Science (1864 to 7 July 2015). Studies were limited to double-blind, placebo controlled, randomized controlled trials on oral medications used to treat PHN. Risk of bias was independently assessed in duplicate. RESULTS: A total of 256 abstracts were screened by two independent reviewers and 26 full-text articles were assessed for eligibility. A total of 11 relevant articles were selected for inclusion. These 11 articles were included in a qualitative synthesis and 8 were included in a meta-analysis; however, all the included studies had a high or unclear risk of bias and the interventions were heterogenous. In a subgroup analysis of five studies, anticonvulsants (gabapentin, pregabalin, and divalproex sodium) were found to improve short-term pain intensity (standardized mean difference [SMD] = -0.484, 95% confidence interval [CI] = -0.622 to -0.346, P < .001). In a second subgroup analysis of five studies, it was found that patients taking anticonvulsants were 2.5 times as likely to have a 50% or more reduction in pain after treatment than patients taking placebo. CONCLUSION: This review has provided favorable but low quality evidence to support the use of anticonvulsants for PHN. Although statistically significant effects were observed for posttreatment pain and the percent of responders, the number of studies in each subgroup analysis for anticonvulsants was small and the included studies had high or unclear risk of bias. Further high-quality methodologic studies are needed to explore the effects of orally administered anticonvulsants for PHN. PMID- 27472530 TI - Trigeminal Neuralgia Induced by Sour and Spicy Foods: What Is the Underlying Mechanism? A Case Report. AB - This article is a case report of a female patient in whom sour and spicy foods evoked trigeminal neuralgia (TN). An attempt to reveal the underlying pain mechanism is described and discussed. The 81-year-old woman had been suffering from classical TN since the age of 50. Attacks occurred spontaneously or in response to mechanical stimuli. In addition, sour and spicy foods also evoked TN attacks and were therefore avoided for years. Medical treatment was initially effective, but two radiofrequency ablations of the gasserian ganglion were required later on and yielded good, albeit incomplete, pain relief. Sensory examination consisted of application of a mechanical stimulus and sweet, salty, sour, and spicy solutions to the anterior part of the tongue and the mandibular mucosa on both sides. Mechanical stimuli were felt but produced no pain. When applied to the tongue, the tastes of all solutions were identified but produced no pain. When applied to the mucogingival line, none of the solutions was identified but the sour and the spicy solutions provoked TN immediately following their application. These findings suggest that in this patient, sour and spicy solutions may have evoked TN attacks by direct activation of trigeminal C nociceptors, possibly via interactions with transient receptor potential vanilloid 1 receptors. PMID- 27472531 TI - Mesoporous LixMn2O4 Thin Film Cathodes for Lithium-Ion Pseudocapacitors. AB - Charge storage devices with high energy density and enhanced rate capabilities are highly sought after in today's mobile world. Although several high-rate pseudocapacitive anode materials have been reported, cathode materials operating in a high potential range versus lithium metal are much less common. Here, we present a nanostructured version of the well-known cathode material, LiMn2O4. The reduction in lithium-ion diffusion lengths and improvement in rate capabilities is realized through a combination of nanocrystallinity and the formation of a 3-D porous framework. Materials were fabricated from nanoporous Mn3O4 films made by block copolymer templating of preformed nanocrystals. The nanoporous Mn3O4 was then converted via solid-state reaction with LiOH to nanoporous LixMn2O4 (1 < x < 2). The resulting films had a wall thickness of ~15 nm, which is small enough to be impacted by inactive surface sites. As a consequence, capacity was reduced by about half compared to bulk LiMn2O4, but both charge and discharge kinetics as well as cycling stability were improved significantly. Kinetic analysis of the redox reactions was used to verify the pseudocapacitive mechanisms of charge storage and establish the feasibility of using nanoporous LixMn2O4 as a cathode in lithium-ion devices based on pseudocapacitive charge storage. PMID- 27472534 TI - Biochemical magnetic resonance imaging of knee articular cartilage: T1rho and T2 mapping as cartilage degeneration biomarkers. AB - Osteoarthritis (OA) is a disease whose hallmark is the degeneration of articular cartilage. There is a worsening epidemic of OA in the United States today, with considerable economic costs. In order to develop more effective treatments for OA, noninvasive biomarkers that permit early diagnosis and treatment monitoring are necessary. T1rho and T2 mapping are two magnetic resonance imaging techniques that have shown great promise as noninvasive biomarkers of cartilage degeneration. Each of the two techniques is endowed with advantages and disadvantages: T1rho can discern earlier biochemical changes of OA than T2 mapping, while T2 mapping is more widely available and can be incorporated into existing imaging protocols in a more time-efficient manner than T1rho. Both techniques have been applied in numerous instances to study how cartilage is affected by OA risk factors, such as age and exercise. Additionally, both techniques have been repeatedly applied to the study of posttraumatic OA in patients with torn anterior cruciate ligaments. PMID- 27472535 TI - Contrasting coordination behavior of Group 12 perchlorate salts with an acyclic N3O2 donor ligand by X-ray crystallography and (1)H NMR. AB - An unbranched N3O2 ligand 2,6-bis[((2-pyridinylmethyl)oxy)methyl]pyridine (L1) was used to prepare new mononuclear heteroleptic Group 12 perchlorate complexes characterized by IR, (1)H NMR and X-ray crystallography. Racemic complexes with pentadentate L1 and one to four oxygens from either water or perchlorate bound to a metal ion were structurally characterized. Octahedral [Zn(L1)(OH2)](ClO4)2 (1) and pentagonal bipyramidal [Cd(L1)(OH2)(OClO3)]ClO4 (2) structures were found with lighter congeners. The polymorphic forms of [Hg(L1)(ClO4)2] characterized (3 in P1[combining macron] and 4 in P21/c) had a mix of monodentate, anisobidentate and bidentate perchlorates, providing the first examples of a tricapped trigonal prismatic Hg(ii) coordination geometry, as well as additional examples of a rare square antiprismatic Hg(ii) coordination geometry. Solution state (1)H NMR characterization of the Group 12 complexes in CD3CN indicated intramolecular reorganization remained rapid under conditions where intermolecular M-L1 exchange was slow on the chemical shift time scale for Zn(ii) and on the J(M(1)H) time scale for Cd(ii) and Hg(ii). Solution studies with more than one equivalent of ligand also suggested that a complex with a 1 : 2 ratio of M : L1 contributed significantly to solution equilibria with Hg(ii) but not the other metal ions. The behavior of related linear pentadentate ligands with Group 12 perchlorate salts is discussed. PMID- 27472536 TI - Improved multi-stage neonatal seizure detection using a heuristic classifier and a data-driven post-processor. AB - OBJECTIVE: After identifying the most seizure-relevant characteristics by a previously developed heuristic classifier, a data-driven post-processor using a novel set of features is applied to improve the performance. METHODS: The main characteristics of the outputs of the heuristic algorithm are extracted by five sets of features including synchronization, evolution, retention, segment, and signal features. Then, a support vector machine and a decision making layer remove the falsely detected segments. RESULTS: Four datasets including 71 neonates (1023h, 3493 seizures) recorded in two different university hospitals, are used to train and test the algorithm without removing the dubious seizures. The heuristic method resulted in a false alarm rate of 3.81 per hour and good detection rate of 88% on the entire test databases. The post-processor, effectively reduces the false alarm rate by 34% while the good detection rate decreases by 2%. CONCLUSION: This post-processing technique improves the performance of the heuristic algorithm. The structure of this post-processor is generic, improves our understanding of the core visually determined EEG features of neonatal seizures and is applicable for other neonatal seizure detectors. SIGNIFICANCE: The post-processor significantly decreases the false alarm rate at the expense of a small reduction of the good detection rate. PMID- 27472537 TI - Early TMS evoked potentials in epilepsy: A pilot study. AB - OBJECTIVE: To explore if the TMS evoked potential is different in patients with epilepsy compared to healthy subjects. METHODS: Eighteen healthy subjects and thirteen epilepsy patients participated in this study. Single TMS pulses were applied to the left and right motor cortex. For each target we applied 75 pulses at 110% of the resting motor threshold (RMT), and continuously measured the EEG. Resting motor threshold and the TMS evoked potential (TEP) were compared between patients and healthy subjects. RESULTS: Epilepsy patients had a higher left RMT than healthy subjects (88.5% vs. 81.8%, p=0.048). For left motor cortex stimulation, the N100 was larger in amplitude in epilepsy patients than in healthy subjects (p=0.0073). For right motor cortex stimulation, the P180 was larger in amplitude in epilepsy patients than in healthy subjects (p=0.006). The differences in these late TEP components were localized in the centro-parietal areas. No significant differences were found for other TEP components. CONCLUSIONS: In this pilot study, we found a significant higher MT and higher TEP amplitudes in epilepsy patients compared to healthy subjects. SIGNIFICANCE: Changes in cortical excitability may assist in epilepsy diagnostics or evaluation of the efficacy of anti-epileptic drugs. PMID- 27472538 TI - What is the optimal task difficulty for reinforcement learning of brain self regulation? AB - OBJECTIVE: The balance between action and reward during neurofeedback may influence reinforcement learning of brain self-regulation. METHODS: Eleven healthy volunteers participated in three runs of motor imagery-based brain machine interface feedback where a robot passively opened the hand contingent to beta-band modulation. For each run, the beta-desynchronization threshold to initiate the hand robot movement increased in difficulty (low, moderate, and demanding). In this context, the incentive to learn was estimated by the change of reward per action, operationalized as the change in reward duration per movement onset. RESULTS: Variance analysis revealed a significant interaction between threshold difficulty and the relationship between reward duration and number of movement onsets (p<0.001), indicating a negative learning incentive for low difficulty, but a positive learning incentive for moderate and demanding runs. Exploration of different thresholds in the same data set indicated that the learning incentive peaked at higher thresholds than the threshold which resulted in maximum classification accuracy. CONCLUSION: Specificity is more important than sensitivity of neurofeedback for reinforcement learning of brain self regulation. SIGNIFICANCE: Learning efficiency requires adequate challenge by neurofeedback interventions. PMID- 27472539 TI - Effect of sampling rate and filter settings on High Frequency Oscillation detections. AB - OBJECTIVE: High Frequency Oscillations (HFOs) are being studied as a biomarker of epilepsy, yet it is unknown how various acquisition parameters at different centers affect detection and analysis of HFOs. This paper specifically quantifies effects of sampling rate (FS) and anti-aliasing filter (AAF) positions on automated HFO detection. METHODS: HFOs were detected on intracranial EEG recordings (17 patients) with 5kHz FS. HFO detection was repeated on downsampled and/or filtered copies of the EEG data, mimicking sampling rates and low-pass filter settings of various acquisition equipment. For each setting, we compared the HFO detection sensitivity, HFO features, and ability to identify the ictal onset zone. RESULTS: The relative sensitivity remained above 80% for either FS ?2kHz or AAF ?500Hz. HFO feature distributions were consistent (AUROC<0.7) down to 1kHz FS or 200Hz AAF. HFO rate successfully identified ictal onset zone over most settings. HFO peak frequency was highly variable under most parameters (Spearman correlation<0.5). CONCLUSIONS: We recommend at least FS ?2kHz and AAF ?500Hz to detect HFOs. Additionally, HFO peak frequency is not robust at any setting: the same HFO event can be variably classified either as a ripple (<200Hz) or fast ripple (>250Hz) under different acquisition settings. SIGNIFICANCE: These results inform clinical centers on requirements to analyze HFO rates and features. PMID- 27472540 TI - Ictal time-irreversible intracranial EEG signals as markers of the epileptogenic zone. AB - OBJECTIVE: To show that time-irreversible EEG signals recorded with intracranial electrodes during seizures can serve as markers of the epileptogenic zone. METHODS: We use the recently developed method of mapping time series into directed horizontal graphs (dHVG). Each node of the dHVG represents a time point in the original intracranial EEG (iEEG) signal. Statistically significant differences between the distributions of the nodes' number of input and output connections are used to detect time-irreversible iEEG signals. RESULTS: In 31 of 32 seizure recordings we found time-irreversible iEEG signals. The maximally time irreversible signals always occurred during seizures, with highest probability in the middle of the first seizure half. These signals spanned a large range of frequencies and amplitudes but were all characterized by saw-tooth like shaped components. Brain regions removed from patients who became post-surgically seizure-free generated significantly larger time-irreversibilities than regions removed from patients who still had seizures after surgery. CONCLUSIONS: Our results corroborate that ictal time-irreversible iEEG signals can indeed serve as markers of the epileptogenic zone and can be efficiently detected and quantified in a time-resolved manner by dHVG based methods. SIGNIFICANCE: Ictal time irreversible EEG signals can help to improve pre-surgical evaluation in patients suffering from pharmaco-resistant epilepsies. PMID- 27472541 TI - Motor unit number estimation based on high-density surface electromyography decomposition. AB - OBJECTIVE: To advance the motor unit number estimation (MUNE) technique using high density surface electromyography (EMG) decomposition. METHODS: The K-means clustering convolution kernel compensation algorithm was employed to detect the single motor unit potentials (SMUPs) from high-density surface EMG recordings of the biceps brachii muscles in eight healthy subjects. Contraction forces were controlled at 10%, 20% and 30% of the maximal voluntary contraction (MVC). Achieved MUNE results and the representativeness of the SMUP pools were evaluated using a high-density weighted-average method. RESULTS: Mean numbers of motor units were estimated as 288+/-132, 155+/-87, 107+/-99 and 132+/-61 by using the developed new MUNE at 10%, 20%, 30% and 10-30% MVCs, respectively. Over 20 SMUPs were obtained at each contraction level, and the mean residual variances were lower than 10%. CONCLUSIONS: The new MUNE method allows a convenient and non invasive collection of a large size of SMUP pool with great representativeness. It provides a useful tool for estimating the motor unit number of proximal muscles. SIGNIFICANCE: The present new MUNE method successfully avoids the use of intramuscular electrodes or multiple electrical stimuli which is required in currently available MUNE techniques; as such the new MUNE method can minimize patient discomfort for MUNE tests. PMID- 27472542 TI - Automatic detection of high frequency oscillations during epilepsy surgery predicts seizure outcome. AB - OBJECTIVE: High frequency oscillations (HFOs) and in particular fast ripples (FRs) in the post-resection electrocorticogram (ECoG) have recently been shown to be highly specific predictors of outcome of epilepsy surgery. FR visual marking is time consuming and prone to observer bias. We validate here a fully automatic HFO detector against seizure outcome. METHODS: Pre-resection ECoG dataset (N=14 patients) with visually marked HFOs were used to optimize the detector's parameters in the time-frequency domain. The optimized detector was then applied on a larger post-resection ECoG dataset (N=54) and the output was compared with visual markings and seizure outcome. The analysis was conducted separately for ripples (80-250Hz) and FRs (250-500Hz). RESULTS: Channel-wise comparison showed a high association between automatic detection and visual marking (p<0.001 for both FRs and ripples). Automatically detected FRs were predictive of clinical outcome with positive predictive value PPV=100% and negative predictive value NPV=62%, while for ripples PPV=43% and NPV=100%. CONCLUSIONS: Our automatic and fully unsupervised detection of HFO events matched the expert observer's performance in both event selection and outcome prediction. SIGNIFICANCE: The detector provides a standardized definition of clinically relevant HFOs, which may spread its use in clinical application. PMID- 27472543 TI - Reduced prefrontal MEG alpha-band power in mild traumatic brain injury with associated posttraumatic stress disorder symptoms. AB - OBJECTIVE: To determine if changes in cortical alpha-band power in patients with mild traumatic brain injury (mTBI) are associated with the severity of their post traumatic stress disorder (PTSD) symptoms, and if injury severity and level of exposure to psychologically traumatic events are predictors of these electrophysiological changes. METHODS: Resting-state magnetoencephalographic recordings were analyzed in 32 patients with mTBI. Alpha-band power was estimated for each patient in 68 cortical regions and was compared between groups of patients with low versus high PTSD symptoms severity. RESULTS: Participants with high PTSD symptom severity showed reduced alpha-band power bilaterally in the superior and middle frontal gyri and frontal poles, and in the left inferior frontal gyrus. Alpha-band power in bilateral middle frontal gyri and frontal poles was negatively correlated with scores reflecting symptoms of emotional numbing. Loss of consciousness (LOC) associated with mTBI and level of exposure to psychologically traumatic events were predictors of decreased prefrontal alpha band power in some of these regions. CONCLUSION: Altered prefrontal alpha-band activity, shown to be partly explained by mTBI-related LOC, is associated with PTSD symptoms severity. SIGNIFICANCE: Our findings will guide future studies addressing the electrophysiological mechanisms underlying a higher incidence of PTSD in patients with mTBI. PMID- 27472544 TI - Late and progressive alterations of sleep dynamics following central thalamic deep brain stimulation (CT-DBS) in chronic minimally conscious state. PMID- 27472546 TI - Cathodal tDCS improves task performance in participants high in Coldheartedness. AB - OBJECTIVE: It is investigated whether personality-related inter-individual differences modulate tDCS effects on response inhibition. Psychopathic personality traits have been associated with a reduced ability to inhibit prepotent responses and as such it is likely that these traits may modulate the effect tDCS has on response inhibition. This study represents the first investigation into the effect of psychopathic traits on tDCS effects in the context of response inhibition, and based on previous research, the psychopathic traits Blame Externalization and Coldheartedness were elected as potential candidates for modulating tDCS effects to right dorsolateral prefrontal cortex. METHODS: Eighteen healthy participants underwent tDCS stimulation (sham, anodal, cathodal) before completing a response inhibition task, the parametric Go/No-go task. This task measures response inhibition under conditions of low and high cognitive load. TDCS stimulation was applied to F4 (international 10-20 system), corresponding to right dorsolateral prefrontal cortex, for 20min with an intensity of 1.5mA. Analysis of covariance was performed to assess how changes in response inhibition performance across difficulty level and stimulation condition were related to individual differences in psychopathy scores as measured via the Psychopathic Personality Inventory-Revised questionnaire. RESULTS: A positive relationship was found between greater scores on the Psychopathic Personality Inventory-Revised subscale of Coldheartedness and improvement in Go/No-go task performance after application of cathodal tDCS. This effect specifically related to the high load condition of the Go/No-go task. CONCLUSION: The psychopathic personality trait Coldheartedness may represent an imbalance of excitatory and inhibitory inputs to dlPFC. Improvement in functioning on inhibitory tasks after cathodal tDCS may be a result of a shift of excitatory glutamate levels to a more optimal level. SIGNIFICANCE: The current results demonstrate the utility of tDCS as a tool to assess how differences in cortical responsivity are associated with specific personality traits. Additionally, this study represents the first investigation into the influence of psychopathic traits on tDCS effects on dlPFC, and we observed beneficial changes in response inhibition as a result of, especially, cathodal stimulation in participants scoring high on Coldheartedness. PMID- 27472545 TI - Cortical activity during cued picture naming predicts individual differences in stuttering frequency. AB - OBJECTIVE: Developmental stuttering is characterized by fluent speech punctuated by stuttering events, the frequency of which varies among individuals and contexts. Most stuttering events occur at the beginning of an utterance, suggesting neural dynamics associated with stuttering may be evident during speech preparation. METHODS: This study used EEG to measure cortical activity during speech preparation in men who stutter, and compared the EEG measures to individual differences in stuttering rate as well as to a fluent control group. Each trial contained a cue followed by an acoustic probe at one of two onset times (early or late), and then a picture. There were two conditions: a speech condition where cues induced speech preparation of the picture's name and a control condition that minimized speech preparation. RESULTS: Across conditions stuttering frequency correlated to cue-related EEG beta power and auditory ERP slow waves from early onset acoustic probes. CONCLUSIONS: The findings reveal two new cortical markers of stuttering frequency that were present in both conditions, manifest at different times, are elicited by different stimuli (visual cue, auditory probe), and have different EEG responses (beta power, ERP slow wave). SIGNIFICANCE: The cue-target paradigm evoked brain responses that correlated to pre-experimental stuttering rate. PMID- 27472547 TI - Effects of chronic neck-shoulder pain on normalized mutual information analysis of surface electromyography during functional tasks. AB - OBJECTIVE: To investigate the effects neck-shoulder pain on the connectivity of surface electromyography (SEMG) signals during functional tasks. METHODS: Twenty adults suffering from chronic neck-shoulder pain and 20 healthy controls were recruited. The SEMG signals from the left and right proximal cervical erector spinae, upper trapezius, lower trapezius and distal extensor carpi radialis, extensor digitorum, flexor digitorum superficialis and, abductor pollicis brevis were recorded during three functional tasks: unilateral and bilateral texting on a smart-phone and computer typing. Normalized mutual information (NMI) values were computed between homonymous proximal and distal muscle pairs as an index of the functional connectivity between muscles pairs. RESULTS: NMI among homonymous muscles pairs as well as among proximal and distal muscles pairs were lower among cases compared with controls. Moreover, NMI values in homonymous proximal muscles were higher during texting compared with computer typing with both hands. CONCLUSIONS: Our results show for the first time that chronic neck-shoulder pain affects the functional connectivity of muscle pairs. SIGNIFICANCE: The study furnishes novel information about the effects of chronic neck-shoulder pain on the interplay of muscle pairs during functional tasks. PMID- 27472548 TI - Reversed cortical over-activity during movement imagination following neurofeedback treatment for central neuropathic pain. AB - OBJECTIVE: One of the brain signatures of the central neuropathic pain (CNP) is the theta band over-activity of wider cortical structures, during imagination of movement. The objective of the study was to investigate whether this over activity is reversible following the neurofeedback treatment of CNP. METHODS: Five paraplegic patients with pain in their legs underwent from twenty to forty neurofeedback sessions that significantly reduced their pain. In order to assess their dynamic cortical activity they were asked to imagine movements of all limbs a week before the first and a week after the last neurofeedback session. Using time-frequency analysis we compared EEG activity during imagination of movement before and after the therapy and further compared it with EEG signals of ten paraplegic patients with no pain and a control group of ten able-bodied people. RESULTS: Neurofeedback treatment resulted in reduced CNP and a wide spread reduction of cortical activity during imagination of movement. The reduction was significant in the alpha and beta band but was largest in the theta band. As a result cortical activity became similar to the activity of other two groups with no pain. CONCLUSIONS: Reduction of CNP is accompanied by reduced cortical over activity during movement imagination. SIGNIFICANCE: Understanding causes and consequences mechanism through which CNP affects cortical activity. PMID- 27472549 TI - Remodeling of cortical activity for motor control following upper limb loss. AB - OBJECTIVE: Upper extremity loss presents immediate and lasting challenges for motor control. While sensory and motor representations of the amputated limb undergo plasticity to adjacent areas of the sensorimotor homunculus, it remains unclear whether laterality of motor-related activity is affected by neural reorganization following amputation. METHODS: Using electroencephalography, we evaluated neural activation patterns of formerly right hand dominant persons with upper limb loss (amputees) performing a motor task with their residual right limb, then their sound left limb. We compared activation patterns with left- and right-handed persons performing the same task. RESULTS: Amputees have involvement of contralateral motor areas when using their sound limb and atypically increased activation of posterior parietal regions when using the affected limb. When using the non-amputated left arm, patterns of activation remains similar to right handed persons using their left arm. CONCLUSIONS: A remodeling of activations from traditional contralateral motor areas into posterior parietal areas occurs for motor planning and execution when using the amputated limb. This may reflect an amputation-specific adaptation of heightened visuospatial feedback for motor control involving the amputated limb. SIGNIFICANCE: These results identify a neuroplastic mechanism for motor control in amputees, which may have great relevance to development of motor rehabilitation paradigms and prosthesis adaptation. PMID- 27472550 TI - 4h versus 1h-nap-video-EEG monitoring in an Epileptology Unit. AB - OBJECTIVE: To compare the performance of 4h-video EEG monitoring (VEEG) and 1h nap-VEEG in an Epileptology Unit. METHODS: We examined short-term VEEG data from 196 patients admitted to characterize their: (i) clinical events; (ii) epileptic syndromes or (iii) state after status epilepticus or surgery. We compared the 4h VEEG and 1h-nap-VEEG performances using three measures: (i) the capability to detect epileptic seizures (ES), psychogenic non-epileptic seizures (PNES), interictal epileptiform abnormalities (IEA) and sleep-related IEA; (ii) the usefulness to answer questions on referral; (iii) the sensitivity for the final diagnosis. RESULTS: The 4h-VEEG test recorded clinical events in 53.6% of 196 patients, IEA in 41.3%, sleep-related IEA in 34.7%, and was judged as useful in 66.8%. The 4h-VEEG was compared to the 1h-nap-VEEG in 129 patients. 4h-VEEG had a better capability to record clinical events (50.3% vs. 6.2%, p<0.001), a higher usefulness (63.5% vs. 37.2%, p<0.001), and a higher sensitivity for both ES (69.3% vs. 49.3%, p=0.0035) and PNES (61.3% vs. 15.4%, p=0.0014) than nap-EEG. CONCLUSIONS: This work found 4h-VEEG records were superior to the 1h-nap-VEEG test on the basis of three complementary measures, capability, usefulness and sensitivity. SIGNIFICANCE: 4h-VEEG is a useful alternative investigation tool in an Epileptology Unit. PMID- 27472551 TI - Single and paired pulse transcranial magnetic stimulation in drug naive epilepsy. AB - Transcranial magnetic stimulation (TMS) measures cortical excitability and is therefore potentially suitable as an additional tool for epilepsy diagnostics and therapy evaluation. In this review we discuss the application of TMS in epilepsy research and systematically analyze single and paired pulse TMS outcomes from 31 drug naive patient studies. Despite a large variety in used TMS protocols, there was no relation between specific protocol aspects and the occurrence of significant results. Protocols were often not in accordance with latest guidelines and recommendations. Cortical excitability, as measured by TMS, was increased in drug naive epilepsy patients, being most prominent for generalized epilepsy. Single pulse TMS indicated a trend towards a lower resting motor threshold (rMT) and a prolonged cortical silent period (CSP) for generalized epilepsy, while inconclusive results were found for focal epilepsy. The paired pulse TMS outcomes, short intracortical inhibition (SICI) and long intracortical inhibition (LICI), showed the most consistent significant increase in cortical excitability in generalized and focal epilepsy patients. Future epilepsy research should especially focus on the interstimulus intervals 2 and 5ms for SICI, and 250 and 300ms for LICI. Furthermore, combining TMS with electroencephalography (EEG) may contribute to analysis on an individual patient level. PMID- 27472552 TI - Detection of the mild emphysema by quantification of lung respiratory airways with hyperpolarized xenon diffusion MRI. AB - PURPOSE: To demonstrate the feasibility to quantify the lung respiratory airway in vivo with hyperpolarized xenon diffusion magnetic resonance imaging (MRI), which is able to detect mild emphysema in the rat model. MATERIALS AND METHODS: The lung respiratory airways were quantified in vivo using hyperpolarized xenon diffusion MRI (7T) with eight b values (5, 10, 15, 20, 25, 30, 35, 40 s/cm2 ) in five control rats and five mild emphysematous rats, which were induced by elastase. The morphological results from histology were acquired and used for comparison. RESULTS: The parameters DL (longitudinal diffusion coefficient), r (internal radius), h (alveolar sleeve depth), Lm (mean linear intercept), and S/V (surface area to lung volume ratio) derived from the hyperpolarized xenon diffusion MRI in the emphysematous group showed significant differences from those in the control group (P < 0.05). Additionally, these parameters correlated well with the Lm obtained by the traditional histological sections (Pearson's correlation coefficients >0.8). CONCLUSION: The lung respiratory airways can be quantified by hyperpolarized xenon diffusion MRI, showing the potential for mild emphysema diagnosis. Also, the study suggested that the hyperpolarized xenon DL is more sensitive than DT (transverse diffusion coefficient) to detect mild emphysema. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:879-888. PMID- 27472553 TI - Impact of Cultivation Conditions, Ethylene Treatment, and Postharvest Storage on Selected Quality and Bioactivity Parameters of Kiwifruit "Hayward" Evaluated by Analytical and Chemometric Methods. AB - Organic, semiorganic, and conventional "Hayward" kiwifruits, treated with ethylene for 24 h and stored during 10 days, were assessed by UV spectrometry, fluorometry, and chemometrical analysis for changes in selected characteristics of quality (firmness, dry matter and soluble solid contents, pH, and acidity) and bioactivity (concentration of polyphenols via Folin-Ciocalteu and p hydroxybenzoic acid assays). All of the monitored qualitative parameters and characteristics related to bioactivity were affected either by cultivation practices or by ethylene treatment and storage. Results obtained, supported by statistical evaluation (Friedman two-way ANOVA) and chemometric analysis, clearly proved that the most significant impact on the majority of the evaluated parameters of quality and bioactivity of "Hayward" kiwifruit had the ethylene treatment followed by the cultivation practices and the postharvest storage. Total concentration of polyphenols expressed via p-hydroxybenzoic acid assay exhibited the most significant sensitivity to all three evaluated parameters, reaching a 16.5% increase for fresh organic compared to a conventional control sample. As a result of postharvest storage coupled with ethylene treatment, the difference increased to 26.3%. Three-dimensional fluorescence showed differences in the position of the main peaks and their fluorescence intensity for conventional, semiorganic, and organic kiwifruits in comparison with ethylene nontreated samples. PMID- 27472554 TI - Educational software usability: Artifact or Design? AB - Online educational technologies and e-learning tools are providing new opportunities for students to learn worldwide, and they continue to play an important role in anatomical sciences education. Yet, as we shift to teaching online, particularly within the anatomical sciences, it has become apparent that e-learning tool success is based on more than just user satisfaction and preliminary learning outcomes-rather it is a multidimensional construct that should be addressed from an integrated perspective. The efficiency, effectiveness and satisfaction with which a user can navigate an e-learning tool is known as usability, and represents a construct which we propose can be used to quantitatively evaluate e-learning tool success. To assess the usability of an e learning tool, usability testing should be employed during the design and development phases (i.e., prior to its release to users) as well as during its delivery (i.e., following its release to users). However, both the commercial educational software industry and individual academic developers in the anatomical sciences have overlooked the added value of additional usability testing. Reducing learner frustration and anxiety during e-learning tool use is essential in ensuring e-learning tool success, and will require a commitment on the part of the developers to engage in usability testing during all stages of an e-learning tool's life cycle. Anat Sci Educ 10: 190-199. (c) 2016 American Association of Anatomists. PMID- 27472556 TI - Nickel-Catalyzed Reductive Cross-Coupling of Aryl Bromides with Alkyl Bromides: Et3N as the Terminal Reductant. AB - Reductive cross-coupling has emerged as a direct method for the construction of carbon-carbon bonds. Most cobalt-, nickel-, and palladium-catalyzed reductive cross-coupling reactions to date are limited to stoichiometric Mn(0) or Zn(0) as the reductant. One nickel-catalyzed cross-coupling paradigm using Et3N as the terminal reductant is reported. By using this photoredox catalysis and nickel catalysis approach, a direct Csp(2)-Csp(3) reductive cross-coupling of aryl bromides with alkyl bromides is achieved under mild conditions without stoichiometric metal reductants. PMID- 27472557 TI - Discrimination, poor mental health, and mental illness. AB - Discrimination is a major public health issue. Discrimination is known and well recognized to be associated with poor physical and mental health, as well as creating social divisions and fear that undermines the success of society and economic progress. Policies to eradicate discrimination and prejudice in the public sphere, and in public life, need thoughtful and careful planning and engagement by all public institutions and in the way they conduct their business. This forms the basis of social justice. Employers, politicians, and public servants, as well as other stakeholders, irrespective of their professional status, all have ethical responsibilities to uphold such actions and policies, values, and supporting behaviours, as a core principle of successful societies. PMID- 27472555 TI - A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages. AB - Orientia (O.) tsutsugamushi-induced scrub typhus is endemic across many regions of Asia and the Western Pacific, where an estimated 1 million cases occur each year; the majority of patients infected with O. tsutsugamushi end up with a cytokine storm from a severe inflammatory response. Previous reports have indicated that blocking tumor necrosis factor (TNF)-alpha reduced cell injury from a cytokine storm. Since TNF-alpha production is known to be associated with intracellular Ca2+ elevation, we examined the effect of store-operated Ca2+ entry (SOCE) inhibitors on TNF-alpha production in O. tsutsugamushi-infected macrophages. We found that 2-aminoethoxydiphenyl borate (2-APB), but not SKF96365, facilitates the suppression of Ca2+ mobilization via the interruption of Orai1 expression in O. tsutsugamushi-infected macrophages. Due to the decrease of Ca2+ elevation, the expression of TNF-alpha and its release from macrophages was repressed by 2-APB. In addition, a novel role of 2-APB was found in macrophages that causes the upregulation of heat shock protein 70 (HSP70) expression associated with ERK activation; upregulated TNF-alpha production in the case of knockdown HSP70 was inhibited with 2-APB treatment. Furthermore, elevated HSP70 formation unexpectedly did not help the cell survival of O. tsutsugamushi-infected macrophages. In conclusion, the parallelism between downregulated Ca2+ mobilization via SOCE and upregulated HSP70 after treatment with 2-APB against TNF-alpha production was found to efficiently attenuate an O. tsutsugamushi-induced severe inflammatory response. PMID- 27472558 TI - Pairwise Kinship Analysis by the Index of Chromosome Sharing Using High-Density Single Nucleotide Polymorphisms. AB - We developed a new approach for pairwise kinship analysis in forensic genetics based on chromosomal sharing between two individuals. Here, we defined "index of chromosome sharing" (ICS) calculated using 174,254 single nucleotide polymorphism (SNP) loci typed by SNP microarray and genetic length of the shared segments from the genotypes of two individuals. To investigate the expected ICS distributions from first- to fifth-degree relatives and unrelated pairs, we used computationally generated genotypes to consider the effect of linkage disequilibrium and recombination. The distributions were used for probabilistic evaluation of the pairwise kinship analysis, such as likelihood ratio (LR) or posterior probability, without allele frequencies and haplotype frequencies. Using our method, all actual sample pairs from volunteers showed significantly high LR values (i.e., >= 108); therefore, we can distinguish distant relationships (up to the fifth-degree) from unrelated pairs based on LR. Moreover, we can determine accurate degrees of kinship in up to third-degree relationships with a probability of > 80% using the criterion of posterior probability >= 0.90, even if the kinship of the pair is totally unpredictable. This approach greatly improves pairwise kinship analysis of distant relationships, specifically in cases involving identification of disaster victims or missing persons. PMID- 27472559 TI - Tuning Electron Delocalization and Transfer Rates in Mixed-Valent Ru3O Complexes through "Push-Pull" Effects. AB - Electron transfer rates in a series of oxo-centered triruthenium clusters featuring an extended aromatic ancillary ligand of the type [Ru3(OAc)6(MU3 O)(CO)(L)(pep)], where L = 4-cyanopyridine (cpy), pyridine (py), or 4 (dimethylamino)pyridine (dmap) and pep = 4-(phenylethynyl)pyridine were investigated. The electron self-exchange rate constants for the 0/- couple were determined by (1)H NMR line broadening experiments and found to range from 4.3 to 9.2 (* 10(7) M(-1) s(-1)) in deuterated acetonitrile (ACN-d3). Relative rates of self-exchange can be rationalized on the basis of increased contact area between self-exchanging pairs, and a push-pull modulation of electron density between the pep vs ancillary pyridine ligands. Faster self-exchange was observed with increasing electron-donating character of the ancillary pyridine ligand substituent (dmap > py > cpy), and this was attributed to increased orbital overlap between self-exchanging pairs. These results are supported by trends observed in (1)H NMR contact shifts of the pep ligand that were found to depend on the electron-donating or -withdrawing nature of the ancillary pyridine ligand. PMID- 27472561 TI - Effect of External Electric Field on Substrate Transport of a Secondary Active Transporter. AB - Substrate transport across a membrane accomplished by a secondary active transporter (SAT) is essential to the normal physiological function of living cells. In the present research, a series of all-atom molecular dynamics (MD) simulations under different electric field (EF) strengths was performed to investigate the effect of an external EF on the substrate transport of an SAT. The results show that EF both affects the interaction between substrate and related protein's residues by changing their conformations and tunes the timeline of the transport event, which collectively reduces the height of energy barrier for substrate transport and results in the appearance of two intermediate conformations under the existence of an external EF. Our work spotlights the crucial influence of external EFs on the substrate transport of SATs and could provide a more penetrating understanding of the substrate transport mechanism of SATs. PMID- 27472560 TI - Pilot Randomised Controlled Trial of a Web-Based Intervention to Promote Healthy Eating, Physical Activity and Meaningful Social Connections Compared with Usual Care Control in People of Retirement Age Recruited from Workplaces. AB - BACKGROUND: Lifestyle interventions delivered during the retirement transition might promote healthier ageing. We report a pilot randomised controlled trial (RCT) of a web-based platform (Living, Eating, Activity and Planning through retirement; LEAP) promoting healthy eating (based on a Mediterranean diet (MD)), physical activity (PA) and meaningful social roles. METHODS: A single blinded, two-arm RCT with individual allocation. Seventy-five adult regular internet users living in Northeast England, within two years of retirement, were recruited via employers and randomised in a 2:1 ratio to receive LEAP or a 'usual care' control. Intervention arm participants were provided with a pedometer to encourage self-monitoring of PA goals. Feasibility of the trial design and procedures was established by estimating recruitment and retention rates, and of LEAP from usage data. At baseline and 8-week follow-up, adherence to a MD derived from three 24-hour dietary recalls and seven-day PA by accelerometry were assessed. Healthy ageing outcomes (including measures of physiological function, physical capability, cognition, psychological and social wellbeing) were assessed and acceptability established by compliance with measurement protocols and completion rates. Thematically analysed, semi-structured, qualitative interviews assessed acceptability of the intervention, trial design, procedures and outcome measures. RESULTS: Seventy participants completed the trial; 48 (96%) participants in the intervention and 22 (88%) in the control arm. Participants had considerable scope for improvement in diet as assessed by MD score. LEAP was visited a median of 11 times (range 1-80) for a mean total time of 2.5 hours (range 5.5 min- 8.3 hours). 'Moving more', 'eating well' and 'being social' were the most visited modules. At interview, participants reported that diet and PA modules were important and acceptable within the context of healthy ageing. Participants found both trial procedures and outcome assessments acceptable. CONCLUSIONS: The trial procedures and the LEAP intervention proved feasible and acceptable. Effectiveness and cost-effectiveness of LEAP to promote healthy lifestyles warrant evaluation in a definitive RCT. TRIAL REGISTRATION: ClinicalTrials.gov NCT02136381. PMID- 27472562 TI - Endodontic Treatment of Primary Molars with Antibiotic Paste: A Report of 38 Cases. AB - OBJECTIVE: This study presents 38 cases of primary molars with necrotic pulps treated with antibiotics-based paste. CASE REPORT: The technique consisted of necrotic tissue removal of the pulp chamber, using spoons excavators and low speed drills. Pulp cavity was washed with saline solution and dried with sterile cotton balls. Then an antibiotic paste composed of chloramphenicol, tetracycline, zinc oxide and eugenol - CTZ paste - was inserted at the entrance of root canals. Patients were evaluated clinically and radiographically at different times. The criteria that defined clinical success were the lack of periapical abscess and mobility compatible with chronological age. Radiographic assessments consisted in absence of radiolucency in the region of root bifurcation and pathological bone resorption. CONCLUSION: There were 100% and 93% of clinical and radiographic success, respectively. The results suggest that the CTZ paste is an optional therapy for pulp of primary molars. PMID- 27472563 TI - Effect of Infant Formula on Streptococcus Mutans Biofilm Formation. AB - OBJECTIVE: This study investigated the effect that infant formula had on biofilm growth of Streptococcus mutans. Specifically, it compared biofilm growth in media containing lactose-based and sucrose-based formulas. It also analyzed biofilm formation with formulas of varying iron content. Biofilm growth was tested with the specific infant formula components sucrose, lactose, and ferric chloride. The study was designed to determine if these types of infant formulas and components affected S. mutans biofilm formation differently. STUDY DESIGN: A 24-hour culture of S. mutans was treated with various concentrations of infant formula diluted in bacteriological media. To test for biofilm formation, S. mutans was cultured with and without the infant formula and formula components. The biofilms were washed, fixed, and stained with crystal violet. The absorbance was measured to evaluate biofilm growth and total absorbance. RESULTS: Sucrose-based formulas provided significant increases in biofilm growth when compared to lactose-based formulas at two dilutions (1:5, 1:20). Similac Sensitive RS (sucrose-based) at most dilutions provided the most significant increase in biofilm growth when compared to the control. Sucrose tested as an individual component provided more of a significant increase on biofilm growth than lactose or iron when compared to the control. A low iron formula provided a significant increase in biofilm growth at one dilution (1:5) when compared to formula containing a normal iron content. There was no significant difference in biofilm growth when comparing high iron formula to normal iron formula or low iron formula. There was no significant difference when comparing Similac PM 60/40 (low iron formula) to Similac PM 60/40 with additional ferric chloride. CONCLUSION: The results of this study demonstrated that sucrose-based formula provided more of a significant increase in biofilm growth compared to lactose-based formula. Sucrose alone provided a significant increase of biofilm growth at more dilutions when compared to the control than lactose and iron. The amount of iron in formula had a significant effect on biofilm formation only when comparing low iron formula to normal iron formula at the highest concentration (1:5). There was no significant difference in biofilm growth when iron was added to the low iron formula. The information obtained expands current knowledge regarding the influence of infant formula on the primary dentition and reinforces the importance of oral hygiene habits once the first tooth erupts. PMID- 27472564 TI - Dental Caries and its Socio-Behavioral Predictors- An Exploratory Cross-Sectional Study. AB - OBJECTIVES: To assess dental caries status and oral health related behavior of 12 year old school children in relation to urbanization and gender; to analyze the effect of socio-demographic and behavioral variables on dental caries experience. STUDY DESIGN: Study sample comprised 831, 12 year old school children in, India. Caries status was assessed by Decayed, missing, filled teeth (DMFT) index and a 16 item closed ended questionnaire was administered to children for assessing their oral health related knowledge, beliefs and behavior. RESULTS: Mean caries experience and prevalence was 1.94 and 64.9% respectively. Decay was the dominant component of DMFT. Greater proportion of female and urban children presented better oral health knowledge, beliefs and practices. Boys were more liable (OR=1.2, 95% CI=1.10-1.96) for having caries than girls. Children living in rural areas and whose parents were not professionals or semiprofessionals were more likely to experience caries. Children whose mothers were unskilled or house wives were more than twice likely to present caries (OR=2.14, 95% CI-2.03-2.45) than those children whose mothers were skilled or semi-skilled. Children of illiterate fathers and mothers were 1.09 (95% CI, 1.02-1.49) and 1.98 (95% CI, 1.13-1.99) times more likely to have dental caries than those children whose parents had greater than 10 years of education. Children, those who cleaned their teeth less than once a day presented an odds ratio of 1.36 (CI-1.17-1.86) also higher odds of dental caries was observed in children consuming sweets or soft drinks more than once a day. CONCLUSIONS: The prevalence and severity of dental caries was low among urban children and girls than their rural and boy counterparts. In general, oral health knowledge, beliefs and practices were low, predominantly in rural and male children. Caries experience was significantly associated with gender, location of residence, brushing frequency, frequency of consumption of soft drinks and sweets, parents' occupation and education. PMID- 27472566 TI - Association between Optimism, Psychosocial Well Being and Oral Health: A Cross Sectional Study. AB - OBJECTIVE: The aim of the study was to assess the association of optimism and psychosocial well being of school going children on their oral health status. STUDY DESIGN: The study included 12- to 15-year-old school going children (N = 2014) from Tamilnadu, India. Optimism was measured using the revised version of the Life Orientation Test (LOT-R). A questionnaire was sent to the parents regarding their child's psychosocial behavior which included shyness, feeling inferiority, unhappiness and friendliness. Clinical examination for each child was done to assess the DMFT score and OHI-S score. The data obtained were statistically analyzed using Pearson Chi-Square test, Mann-Whitney test and Kruskal-Wallis test with the aid of SPSS software (version 17). Odds Ratio (OR) was calculated with 95% Confidence Interval (CI). The p value <= 0.05 was considered statistically significant. RESULTS: Boys with high optimism had significantly lesser DMFT score than the boys with low optimism (p=0.001). Girls with high optimism had significantly higher DMFT score (p=0.001). In psychosocial outcomes, inferiority (p=0.002) and friendliness (p=0.001) showed significant association with DMFT score. Among the boys, children who felt less inferior (p=0.001), less unhappy (p=0.029) and more friendly (p=0.001) had lesser DMFT score. CONCLUSION: Among the psychosocial outcomes assessed, inferiority and friendliness had significant association with oral health of the children and hence, can be used as a proxy measures oral health. PMID- 27472565 TI - Intraligamentary and Supraperiosteal Anesthesia Efficacy Using a Computer Controlled Delivery System in Mandibular Molars. AB - PURPOSE: The purpose of this study was to compare pain, efficacy and postoperative complications of anesthesia in first primary mandibular molars anesthetized with either intraligamentary (IL) or supraperiosteal (SP) anesthesia using a computer-controlled delivery system (CCDS). STUDY DESIGN: This randomized, controlled-crossover, blind clinical trial was conducted with 90 children requiring bilateral extraction, pulpotomy or restorative treatment of first mandibular primary molars. A CCDS was used to deliver IL anesthesia to 1 deciduous tooth and SP anesthesia to the contralateral tooth in each patient. Severity of pain and efficacy of anesthesia during the treatments were evaluated using the Wong-Baker Faces Pain Rating Scale (PRS) and comfort and side effects were assessed using post-injection and post-treatment questionnaires. Data were analyzed using chi2 and Mann-Whitney U tests. RESULTS: According to PRS scores, pain levels during extraction were significantly higher with IL when compared to SP. Patients reported significantly less pain during needle insertion with SP when compared to IL; however, rates of postoperative complications were significantly higher with SP when compared to IL. CONCLUSIONS: CCDS-administered IL anesthesia and SP anesthesia were similarly effective when used during restorative treatment and pulpotomy of primary mandibular molars; however, SP was more effective than IL when used during extraction procedures. PMID- 27472567 TI - Effect of Fluoride Varnish on Enamel Remineralization in Anterior Teeth with Molar Incisor Hypomineralization. AB - OBJECTIVE: The objective of this study was to investigate the effect of fluoride varnish on remineralization of anterior teeth affected by Molar-Incisor Hypomineralization (MIH) by means of Quantitative Light-Induced Fluorescence- QLF. STUDY DESIGN: Fifty-one healthy 9 - 12- year-old children were selected according to different clinically diagnosed levels of MIH, proposed by the European Academy of Pediatric Dentistry (2003) (considering the most severe lesion per patient, n= 51 lesions), and randomly divided into two groups: (1) four applications of 5% NaF varnish, with one-week interval, and (2) usual home care- control. At each visit, the mean change in fluorescence and area of lesion were measured by QLF. The data were analyzed by repeated measures ANOVA and Tukey's test. RESULTS: All patients showed enamel alterations in first permanent molars and incisors, frequently with two molars affected by MIH (41.1%). There was no statically significant difference in the mean of fluorescence and area of lesion between groups over the studied time. CONCLUSION: We observed no favorable effect on the remineralization of MIH lesions in anterior teeth after four applications of fluoride varnish. PMID- 27472568 TI - The Role of Vitamin D Receptor Polymorphisms on Dental Caries. AB - OBJECTIVE: To determine the association between the ApaI, FokI, Cdx2 and TaqI polymorphisms of vitamin D receptor (VDR) gene in caries-active (high-moderate) and caries-free children. STUDY DESIGN: A hundred and fifty children (75 males, 75 females, mean age: 10.19 +/- 1.61 years) were included in the study. The subjects were divided into three groups as high caries risk group (DMFT, dft>4)(n=55), moderate caries risk group (DMFT, dft=1-4)(n=57) and caries-free group (n=38). From each individual, blood samples were collected and DNA was extracted. The VDR gene was genotyped for the polymorphisms ApaI, FokI, Cdx2 and TaqI using polymerase chain reaction and restriction fragment length polymorphism methods. All data were analyzed by chi-square test, Fisher's exact test and t test. RESULTS: There was statistically significant difference in the frequency of TaqI genotypes (tt) between caries-active and caries-free children (p=0.029). No statistically significant differences were detected between ApaI, FokI, Cdx2 genotypes and dental caries. CONCLUSION: In the future, VDR gene polymorphisms may be used as a marker for the identification of patients with high caries risk. PMID- 27472569 TI - In Vitro Assessment of Enamel Permeability in Primary Teeth with and without Early Childhood Caries Using Laser Scanning Confocal Microscope. AB - OBJECTIVE: To compare the permeability of the enamel of primary teeth from individuals free of Early Childhood Caries (ECC) with that from individuals affected with ECC by assessment of dye penetration using Laser Scanning Confocal Microscope (LSCM). STUDY DESIGN: Experimental in vitro study. Exfoliated primary maxillary anterior teeth (n = 44) were collected and divided into two groups (n=22 per group): samples with ECC (Group 1) and without ECC (Group 2). The samples were immersed in Rhodamine B dye solution for 1 day, cut longitudinally into 3 sections, observed using LSCM. Dye penetration depths in the incisal, middle, cervical thirds and on labial, lingual surfaces were recorded. Data were analyzed by the Mann-Whitney test (alpha = 5%, p < .005). RESULTS: The overall mean penetration depth for group 1 (100.6 MUm +/- 58.48 MUm) was significantly higher than that of group 2 (31.55 MUm +/- 23.40 MUm, p < .000). Mean penetration depth in the incisal, middle, and cervical thirds and on the labial and lingual surfaces of group 1 also presented significantly higher scores than in group 2 (p < .005). CONCLUSION: There was significantly more dye penetration in the ECC group than in the non-ECC group. This could be related to a higher level of enamel permeability in teeth affected with ECC. PMID- 27472570 TI - Effectiveness of Air Drying and Magnification Methods for Detecting Initial Caries on Occlusal Surfaces Using Three Different Diagnostic Aids. AB - Objective-The aim of this study was to assess the effect of magnification and air drying on detection of carious lesion. Study Design-44 human extracted premolars were selected with sound occlusal surfaces without frank cavitation. The Diagnostic techniques used were Unaided visual examination, Magnifying Loupes (4.2*) and Stereomicroscope (10*, before and after air-drying) and then the teeth were sectioned bucco-lingually and both the surfaces were examined under Stereomicroscope (50*) to assess the presence or absence of carious lesion in the pit and fissures. The scores were compared to obtain Cohen's kappa coefficient (Reproducibility) and subjected to the Friedman Test and Paired t test. Sensitivity, specificity and positive predictive value used to assess accuracy. Results-On Statistical analysis, visual examination before and after air drying had highest specificity but lowest sensitivity compared to different diagnostic techniques. Magnifying loupes after air-drying had highest sensitivity and lowest specificity compared to other diagnostic techniques. Conclusion-Air drying combined with magnifying aids are cost-effective, reliable method for detection of early carious lesion. If used in pediatric clinical practice, any undesirable pain and discomfort to the patient due to invasive procedures and helps in employing preventive measures. PMID- 27472571 TI - Radiographic Assessment of Dental Maturation in Children With Dental Agenesis. AB - BACKGROUND: Dental agenesis is the most common developmental anomaly in humans, frequently associated with disorders in dental development and maturation. AIM: The purpose of this study is to determine radiographic variations in dental maturation in a group of Venezuelan children with dental agenesis. STUDY DESIGN: 1,188 panoramic radiographs, from healthy patients ages 5 to 12 years old were studied for agenesis of permanent teeth. Dental maturation was assessed by relative eruption and dental age according to Nolla, comparing children affected with dental agenesis to a stratified control group selected from the same population, excluding children with premature loss of primary teeth in the left quadrants and unclear radiographs. Descriptive analysis, and differences between means and medians (Student t test, Kruskall-Wallis p=0.05) were performed. RESULTS: Medians for Nolla stages were similar between groups, with delay in tooth formation in the agenesis group for second molars (p<0.05) and maxillary lateral incisors and second premolars. Dental age was significantly underestimated for both groups, -0.89 (+/-0.78) for the control group and -1.20 (+/-0.95) for the study group. Tooth eruption was similar between groups. CONCLUSION: Dental age was significantly delayed in Venezuelan children with dental agenesis, with variable significance for tooth formation of studied teeth. PMID- 27472573 TI - Orthodontic Consideration in Patients with Beta-Thalassemia Major: Case Report and Literature Review. AB - OBJECTIVE: Beta Thalassemia (betaT) patients present a unique facial appearance and specific craniofacial, jaw and dental patterns. Although this anomaly often requires orthodontic management, betaT patients have received scant attention in the orthodontic and dental literature over the past 50 years. The aim of this article is to review the characteristic craniofacial and dental manifestation pattern of betaT patients and to emphasize their preferred orthodontic management protocol by presenting a betaT orthodontic treated patient. CASE REPORT: A 10 year old patient presented with a complaint of severe esthetic and functional disorders due to her diagnosis of betaT. We initiated orthodontic treatment including a combined orthopedic and functional treatment modality to improve facial appearance. RESULTS: Maxillary restraint and increased mandibular size during treatment along with an increase in the vertical dimension were achieved. The patient presented with Angle class I molar relationship, with reduction of the excessive overjet and deep overbite. CONCLUSION: Orthodontic treatment comprised of maxillary orthopedic treatment directed especially toward premaxilla with light forces, and mandibular modification by functional appliance along with fixed orthodontic treatment is recommended in betaT patients. PMID- 27472574 TI - Severe Anterior Open Bite during Mixed Dentition Treated with Palatal Spurs. AB - Deleterious oral habits, such as non-nutritive sucking or tongue thrusting, if not intercepted at an early stage can cause complex malocclusions. This manuscript describes a clinical case report of a successful interception of a severe anterior dental open bite caused by thumb sucking and tongue thrusting habits. The case involved a six-year-old female patient treated with the use of palatal spurs and maxillary removable crib followed by monitoring the development of dental occlusion. At the end of the interceptive phase acceptable results were achieved, showing the efficacy of the treatment undertaken as well the importance of an early intervention to remove harmful oral habits. PMID- 27472572 TI - Intra Operative Use of Anti Emetic Drugs for Children Undergoing Full Dental Rehabilitation under General Anesthesia. A Double Blind Randomized Clinical Trial. AB - BACKGROUND: Postoperative Nausea and Vomiting (PONV) is a common complication following dental treatment under general anesthesia (DGA) that may lead to unplanned hospitalization, increased costs and dissatisfaction of parents. AIM: To investigate the incidence of Postoperative Vomiting (POV) on children who underwent dental rehabilitation under general anesthesia and to compare possible preventive effect of Dexamethasone and Ondansetron on occurrences of POV. STUDY DESIGN: A double blind randomized parallel clinical trial was carried out on 352 ASA I children who underwent DGA in a private Saudi hospital in Jeddah. Children were allocated randomly to four groups. Group D of 91 children, received Dexamethasone PONV prophylaxis, group O of 87 children received Ondansetron, group DO of 93 children received combination of the two drugs and group C the control group of 81 children. The three groups were investigated by blinded dental staff for POV episodes, number of times analgesia was needed and post anesthesia care unit time (PACUT). RESULTS: There was a no significant difference between the two drugs on POV. There was a significant difference in POV between control group and groups D, O, and DO. There was significant reduction in need for analgesia in the Dexamethasone groups. The three groups, which had PONV prophylaxis, showed significant reduction in PACUT compared to control group. CONCLUSIONS: Antiemetic drugs are useful adjuncts in DGA. Some dental procedures may have higher emetic potential than others. The type of dental procedures done is to be considered when deciding the drug profile in children undergoing DGA. PMID- 27472575 TI - Line of Sight in Hominoids. AB - OBJECTIVES: It remains unclear how the realignments of the face and basicranium that characterize humans were acquired, both phylogenetically and ontogenetically. The developmentally constrained nature of the skull has been previously demonstrated in other primates using Donald H. Enlow's mammalian craniofacial architectural relationships. Here, we compare crania of our closest relatives to gain greater understanding of how and why the relationship of the face and cranial base is developmentally constrained in order to inform instances of abnormal growth and clinical intervention. STUDY DESIGN: A method for evaluating these fundamental architectural relationships using 3D landmark data was developed, thereby taking overall size and the geometric relationships among points into account. A sample of cone-beam computed tomography scans derived from humans and extant apes were analyzed (n=10 and n=6, respectively), as well as fossil hominid crania (n=7). Landmarks for 23 craniofacial architectural points were identified and recorded. RESULTS AND CONCLUSIONS: Principal components analyses reveal that despite the similarities in craniofacial architecture between humans, extant apes and fossil hominids, appreciable trends in variation between the extant species suggest that the repositioning of the foramen magnum was only one of a constellation of traits that realigned the basicranium and face during the transition to bipedalism. PMID- 27472576 TI - Nanoscale TiO2 dielectric resonator absorbers. AB - We demonstrate a narrow-band plasmonic absorber based on a uniform array of nanoscale cylindrical dielectric resonators (DRs) on a metallic substrate at visible frequencies. Under a normally incident plane-wave excitation, the DRs resonate in their horizontal magnetic dipolar mode, which can be seen as localized plasmonic hot spots. Such a localized resonance also couples incident waves into surface plasmon polaritons (SPPs) bidirectionally, and perfect absorption is achieved by creating SPP standing waves. The simulation shows perfect absorption at 633 nm and 1.8% relative bandwidth with >90% absorption, while the measurement demonstrates maximum absorption of 90% at 636 nm. Both simulation and measurement results are analyzed with coupled mode theory. An additional numerical study elaborates on the dependence of absorption on the resonator size, period, and incidence angle. PMID- 27472577 TI - 42 W femtosecond Yb:Lu2O3 regenerative amplifier. AB - We report on a femtosecond high-power regenerative amplifier based on Yb:Lu2O3. Exploiting the excellent thermo-mechanical properties of this material, we were able to achieve up to 64.5 W in continuous wave regime, limited only by the available pump power. In pulsed operation, 42 W of average output power at a repetition rate of 500 kHz with 780 fs long pulses could be demonstrated, resulting in a pulse peak power of ~100 MW. The spectrum was centered at 1034 nm with an FWHM of 2.4 nm, potentially allowing for even shorter pulses. At the maximum output power the beam was nearly TEM00, with an M2 value of 1.2 in both axes. PMID- 27472578 TI - Polycrystalline metasurface perfect absorbers fabricated using microsphere photolithography. AB - Microsphere photolithography (MPL) is a practical, cost-effective nanofabrication technique. It uses self-assembled microspheres in contact with the photoresist as microlenses. The microspheres focus incident light to a sub-diffraction limited array of photonic jets in the photoresist. This Letter explores the MPL technique to pattern metal-insulator-metal metasurfaces with near-perfect absorption at mid wave infrared (MWIR) frequencies. Experimental results are compared to electromagnetic simulations of both the exposure process and the metasurface response. The microsphere self-assembly technique results in a polycrystalline metasurface; however, the metal-insulator-metal structure is shown to be defect tolerant. While the MPL approach imposes geometric constraints on the metasurface design, once understood, the technique can be used to create functional devices. In particular, the ability to tune the resonant wavelength with the exposure dose raises the potential of hierarchical structures. PMID- 27472579 TI - Multilayer deformation planarization by substrate pit suturing. AB - In the pursuit of 1064 nm high-power laser resistance dielectric coatings in the nanosecond region, a group of HfO2/SiO2 high reflectors with and without suture layers were prepared on prearranged fused silica substrates with femtosecond laser pits. Surface morphology, global coating stress, and high-resolution cross sections were characterized to determine the effects of substrate pit suturing. Laser-induced damage resistance was investigated for samples with and without suture layers. Our results indicate considerable stability in terms of the nanosecond 1064 nm laser-induced damage threshold for samples having a suture layer, due to decreased electronic field (e field) deformation with simultaneous elimination of internal cracks. In addition, a suture layer formed by plasma ion-assisted deposition could effectively improve global mechanical stress of the coatings. By effectively reducing the multilayer deformation using a suture layer, electron-beam high-reflective coatings, whose laser-induced damage resistance was not influenced by the substrate pit, can be prepared. PMID- 27472580 TI - Beam quality measure for vector beams. AB - Vector beams have found a myriad of applications, from laser materials processing to microscopy, and are now easily produced in the laboratory. They are usually differentiated from scalar beams by qualitative measures, for example, visual inspection of beam profiles after a rotating polarizer. Here we introduce a quantitative beam quality measure for vector beams and demonstrate it on cylindrical vector vortex beams. We show how a single measure can be defined for the vector quality, from 0 (purely scalar) to 1 (purely vector). Our measure is derived from a quantum toolkit, which we show applies to classical vector beams. PMID- 27472581 TI - Laser irradiation precipitation from nonlinear optical KH2PO4 crystal. AB - Structural stability of KH2PO4 (KDP) crystal under laser irradiation is a great challenge to nonlinear optical devices. Herein, the dependency of structural stability on the propagated laser wavelength was established. Separated precipitations with different morphologies, including irregular fusion, elongated prism, and quasi-equiaxial particles were irradiated from the KDP crystal surface by a laser with different wavelengths, including 0.103, 355, and 785 nm. All the precipitations induced by laser irradiation were identified to be the same KDP phase as its parent phase examined by electron diffraction. Noticeably, the stacked periodicity degree at (001) planes of precipitations becomes irregular somehow. It is believed that our research findings might have new implications and inspirations in constructing KDP devices with better stability. PMID- 27472582 TI - Versatile digital micromirror device-based method for the recording of multilevel optical diffractive elements in photosensitive chalcogenide layers (AMTIR-1). AB - A new alternative and versatile method for the production of diffractive optical elements (DOEs) with up to four phase levels in AMTIR-1 (Ge33As12Se55) layers is demonstrated. The developed method proposes the use of the photosensitive properties of the layers and a specific in situ optical monitoring coupled with a reverse engineering algorithm to control the trigger points of the writing of the different diffractive patterns. Examples of various volume DOEs are presented. PMID- 27472583 TI - Theory and measurement of the soliton self-frequency shift and efficiency in optical microcavities. AB - Dissipative Kerr cavity solitons experience a so-called self-frequency shift (SFS) as a result of Raman interactions. The frequency shift has been observed in several microcavity systems. The Raman process has also been shown numerically to influence the soliton pumping efficiency. Here, a perturbed Lagrangian approach is used to derive simple analytical expressions for the SFS and the soliton efficiency. The predicted dependences of these quantities on soliton pulse width are compared with measurements in a high-Q silica microcavity. The Raman time constant in silica is also inferred. Analytical expressions for the Raman SFS and soliton efficiency greatly simplify the prediction of soliton behavior over a wide range of microcavity platforms. PMID- 27472584 TI - High refractive index Fresnel lens on a fiber fabricated by nanoimprint lithography for immersion applications. AB - In this Letter, we present a Fresnel lens fabricated on the end of an optical fiber. The lens is fabricated using nanoimprint lithography of a functional high refractive index material, which is suitable for mass production. The main advantage of the presented Fresnel lens compared to a conventional fiber lens is its high refractive index (n=1.68), which enables efficient light focusing even inside other media, such as water or an adhesive. Measurement of the lens performance in an immersion liquid (n=1.51) shows a near diffraction limited focal spot of 810 nm in diameter at the 1/e2 intensity level for a wavelength of 660 nm. Applications of such fiber lenses include integrated optics, optical trapping, and fiber probes. PMID- 27472585 TI - Generation of axially modulated plasma waveguides using a spatial light modulator. AB - We demonstrate the generation of axially modulated plasma waveguides using spatially patterned high-energy laser pulses. A spatial light modulator (SLM) imposes transverse phase front modulations on a low-energy (10 mJ) laser pulse which is interferometrically combined with a high-energy (130-450 mJ) pulse, sculpting its intensity profile. This enables dynamic and programmable shaping of the laser profile limited only by the resolution of the SLM and the intensity ratio of the two pulses. The plasma density profile formed by focusing the patterned pulse with an axicon lens is likewise dynamic and programmable. Centimeter-scale, axially modulated plasmas of varying shape and periodicity are demonstrated. PMID- 27472586 TI - Low-coherence wavelength shifting interferometry for high-speed quantitative phase imaging. AB - We propose low-coherence wavelength shifting interferometry and demonstrate its application to quantitative phase imaging of dynamic specimens. By shifting the source wavelength, multiple interferograms of the sample can be acquired at different spectral bands. A sample phase is thus encoded in the phase step between consecutive acquisitions. For the particular case of four-band imaging, we show that the phase can be extracted with a modified Carre algorithm. We describe signal demodulation in detail and discuss its implication on system implementation. A swept laser-based Mach-Zehnder interferometer is used to demonstrate the technique for real-time imaging of live sperm cells at 62.5 Hz. The dynamic dry mass of the sperm head is measured with a full-scale error of +/ 2%, validating the technique's capability for high-sensitivity, high-speed quantitative phase imaging. PMID- 27472587 TI - Transverse and longitudinal characterization of electron beams using interaction with optical near-fields. AB - We demonstrate an experimental technique for both transverse and longitudinal characterization of bunched femtosecond free electron beams. The operation principle is based on monitoring of the current of electrons that obtained an energy gain during the interaction with the synchronized optical near-field wave excited by femtosecond laser pulses. The synchronous accelerating/decelerating fields confined to the surface of a silicon nanostructure are characterized using a highly focused sub-relativistic electron beam. Here the transverse spatial resolution of 450 nm and femtosecond temporal resolution of 480 fs (sub-optical cycle temporal regime is briefly discussed) achievable by this technique are demonstrated. PMID- 27472588 TI - 1 kW 1 mJ eight-channel ultrafast fiber laser. AB - An ultrafast fiber chirped-pulse amplifier comprising eight coherently combined amplifier channels is presented. The laser delivers 1 kW average power at 1 mJ pulse energy and 260 fs pulse duration. Excellent beam quality and low-noise performance are confirmed. The laser has proven suitable for demanding scientific applications. Further power scaling is possible right away using even more amplifier channels. PMID- 27472589 TI - Controlling leakage losses in subwavelength grating silicon metamaterial waveguides. AB - Subwavelength gratings (SWG) are photonic structures with a period small enough to suppress diffraction, thereby acting as artificial dielectric materials, also called all-dielectric metamaterials. This property has been exploited in many high-performance photonic integrated devices in the silicon-on-insulator (SOI) platform. While SWG waveguides are theoretically lossless, they may exhibit leakage penalty to the substrate due to a combination of reduced modal confinement and finite thickness of the buried oxide (BOX) layer. In this Letter, for the first time, to the best of our knowledge, we analyze substrate leakage losses in SWG waveguides. We establish a direct relation between the effective index of the waveguide mode and the leakage losses which, remarkably, is independent of the geometric parameters of the SWG waveguide. This universal relation is demonstrated both numerically and experimentally, and it provides practical design guidelines to mitigate leakage losses. For BOX thicknesses of 2 and 3 MUm, we find negligible leakage losses when the mode effective index is higher than 1.65 and 1.55, respectively. PMID- 27472590 TI - Experimental demonstration of a 200-Gbit/s free-space optical link by multiplexing Laguerre-Gaussian beams with different radial indices. AB - We demonstrate a 200-Gbit/s space-division multiplexing system using two Laguerre Gaussian (LG) beams with different radial indices (LGl=0,p=0 and LGl=0,p=1). With a proper design of the radial change of the demultiplexing pattern, the channel crosstalk could be minimized and both channels could achieve a bit error rate of 3.8*10-3. Moreover, the multiplexing of four LG beams with different azimuthal indices and different radial indices (e.g., LGl=0,p=0, LGl=0,p=1, LGl=1,p=0, and LGl=1,p=1 beams) is also demonstrated with a <-12 dB channel crosstalk, potentially enabling a 400-Gbit/s data transmission. PMID- 27472591 TI - Analog optical computing based on a dielectric meta-reflect array. AB - In this Letter, we realize the concept of analog computing using an engineered gradient dielectric meta-reflect-array. The proposed configuration consists of individual subwavelength silicon nanobricks, in combination with a fused silica spacer and silver ground plane, realizing a reflection beam with full phase coverage of 2pi degrees, as well as an amplitude range of 0 to 1. Spectrally overlapping electric and magnetic dipole resonances, such high-index dielectric metasurfaces can locally and independently manipulate the amplitude and phase of the incident electromagnetic wave. This practically feasible structure overcomes substantial limitations imposed by plasmonic metasurfaces such as absorption losses and low polarization conversion efficiency in the visible range. Using such CMOS-compatible and easily integrable platforms promises highly efficient ultrathin planar wave-based computing systems that circumvent the drawbacks of conventional bulky lens-based signal processors. Based on these key properties and the general concept of spatial Fourier transformation, we design and realize broadband mathematical operators such as the differentiator and integrator in the telecommunication wavelengths. PMID- 27472592 TI - Double moire structured illumination microscopy with high-index materials. AB - Structured illumination microscopy utilizes illumination of periodic light patterns to allow reconstruction of high spatial frequencies, conventionally doubling the microscope's resolving power. This Letter presents a structured illumination microscopy scheme with the ability to achieve 60 nm resolution by using total internal reflection of a double moire pattern in high-index materials. We propose a realization that provides dynamic control over relative amplitudes and phases of four coherently interfering beams in gallium phosphide and numerically demonstrate its capability. PMID- 27472593 TI - Observation of photonic paramagnetic to spin-glass transition in a specially designed TiO2 particle-based dye-colloidal random laser. AB - Colloidal-based random lasers (RLs) are highly efficient and have been exploited in a wide range of geometries. However, in the particular case of ethanol solutions of rhodamines and TiO2 particles, the RL behavior is quite unstable due to the fast precipitation of the particles. In this Letter, specially designed amorphous TiO2 particles were synthesized by a sol gel method, preventing the degradation of the RL for long operating lifetimes of over 105 shots. As a consequence, this modified colloidal RL allowed the observation of a clear replica-symmetry-breaking phase transition from the paramagnetic fluorescent to spin-glass RL behavior, which has not been observed in the system with nonfunctionalized TiO2 particles. PMID- 27472594 TI - Femtosecond laser direct writing of microholes on roughened ZnO for output power enhancement of InGaN light-emitting diodes. AB - A significant enhancement of light extraction efficiency from InGaN light emitting diodes (LEDs) with microhole arrays and roughened ZnO was experimentally demonstrated. The roughened ZnO was fabricated using an Ar and H2 plasma treatment of ZnO films pre-coated on a p-GaN layer. When followed by a femtosecond laser direct writing technique, a periodic array of microholes could be added to the surface. The diameter of the microhole was varied by changing the output power of the femtosecond laser. Compared to conventional LEDs on the same wafer, the output power of LEDs with roughened ZnOs and a microhole (diameter of 2 MUm) array was increased by 58.4% when operated with an injection current of 220 mA. Moreover, it was found that LEDs fabricated with roughened ZnO and the microhole array had similar current-voltage (I-V) characteristics to those of conventional LEDs and no degrading effect was observed. PMID- 27472595 TI - Analog computing by Brewster effect. AB - Optical computing has emerged as a promising candidate for real-time and parallel continuous data processing. Motivated by recent progresses in metamaterial-based analog computing [Science343, 160 (2014)SCIEAS0036-807510.1126/science.1242818], we theoretically investigate the realization of two-dimensional complex mathematical operations using rotated configurations, recently reported in [Opt. Lett.39, 1278 (2014)OPLEDP0146-959210.1364/OL.39.001278]. Breaking the reflection symmetry, such configurations could realize both even and odd Green's functions associated with spatial operators. Based on such an appealing theory and by using the Brewster effect, we demonstrate realization of a first-order differentiator. Such an efficient wave-based computation method not only circumvents the major potential drawbacks of metamaterials, but also offers the most compact possible device compared to conventional bulky lens-based optical signal and data processors. PMID- 27472596 TI - Digital generation of partially coherent vortex beams. AB - We present an experimental technique to generate partially coherent vortex beams with an arbitrary azimuthal index using only a spatial light modulator. Our approach is based on digitally simulating the intrinsic randomness of broadband light passing through a spiral phase plate. We illustrate the versatility of the technique by generating partially coherent beams with different coherence lengths and orbital angular momentum content, without any moving optical device. Consequently, we study its cross-correlation function in a wavefront folding interferometer. The comparison with theoretical predictions yields excellent agreement. PMID- 27472597 TI - Femtosecond supercontinuum generation in water in the vicinity of absorption bands. AB - We show that it is possible to overcome the perceived limitations caused by absorption bands in water so as to generate supercontinuum (SC) spectra in the anomalous dispersion regime that extend well beyond 2000 nm wavelength. By choosing a pump wavelength within a few hundred nanometers above the zero dispersion wavelength of 1048 nm, initial spectral broadening extends into the normal dispersion regime and, in turn, the SC process in the visible strongly benefits from phase-matching and matching group velocities between dispersive radiation and light in the anomalous dispersion regime. Some of the SC spectra are shown to encompass two and a half octaves. PMID- 27472598 TI - Angle-resolved multioctave supercontinua from mid-infrared laser filaments. AB - Angle-resolved spectral analysis of a multioctave high-energy supercontinuum output of mid-infrared laser filaments is shown to provide a powerful tool for understanding intricate physical scenarios behind laser-induced filamentation in the mid-infrared. The ellipticity of the mid-infrared driver beam breaks the axial symmetry of filamentation dynamics, offering a probe for a truly (3+1) dimensional spatiotemporal evolution of mid-IR pulses in the filamentation regime. With optical harmonics up to the 15th order contributing to supercontinuum generation in such filaments alongside Kerr-type and ionization induced nonlinearities, the output supercontinuum spectra span over five octaves from the mid-ultraviolet deep into the mid-infrared. Full (3+1)-dimensional field evolution analysis is needed for an adequate understanding of this regime of laser filamentation. Supercomputer simulations implementing such analysis articulate the critical importance of angle-resolved measurements for both descriptive and predictive power of filamentation modeling. Strong enhancement of ionization-induced blueshift is shown to offer new approaches in filamentation assisted pulse compression, enabling the generation of high-power few- and single cycle pulses in the mid-infrared. PMID- 27472599 TI - Single-shot afocal three-dimensional microscopy. AB - Fourier-basis agile structured illumination sensing (F-BASIS) employs acousto optically synthesized moving interference patterns, sparse RF-encoded aperture synthesis, nonredundant spatiotemporal frequency multiplexing, and single-pixel detection to measure dense clouds of three-dimensional (3D) Fourier samples without scanning, enabling high-speed focus-free volume microscopy. We present 3D fluorescence imaging results using F-BASIS, including an unprecedented wide-field single-shot volumetric measurement in under 10 ms. The unique capabilities provided by F-BASIS could prove instrumental for capturing fleeting dynamic processes such as neuron signaling in 3D. PMID- 27472600 TI - Explicit expressions for the elementary polarization properties of a weakly anisotropic, homogeneous medium. AB - We derive the relationships between the elementary polarization properties describing a homogeneous medium within the framework of the differential Jones and Mueller formalisms from transmission polarimetry, and the permittivity tensor of the medium, assumed to be weakly anisotropic. The expressions are illustrated on selected examples and allowed to physically interpret experimental polarimetry data. PMID- 27472601 TI - Light scattering by irregular particles much larger than the wavelength with wavelength-scale surface roughness. AB - We simulate light scattering by random irregular particles that have dimensions much larger than the wavelength of incident light at the size parameter of X=200 using the discontinuous Galerkin time domain method. A comparison of the DGTD solution for smoothly faceted particles with that obtained with a geometric optics model shows good agreement for the scattering angle curves of intensity and polarization. If a wavelength-scale surface roughness is introduced, diffuse scattering at rough interface results in smooth and featureless curves for all scattering matrix elements which is consistent with the laboratory measurements of real samples. PMID- 27472602 TI - Optimal parameters of monolithic high-contrast grating mirrors. AB - In this Letter a fully vectorial numerical model is used to search for the construction parameters of monolithic high-contrast grating (MHCG) mirrors providing maximal power reflectance. We determine the design parameters of highly reflecting MHCG mirrors where the etching depth of the stripes is less than two wavelengths in free space. We analyze MHCGs in a broad range of real refractive index values corresponding to most of the common optoelectronic materials in use today. Our results comprise a complete image of possible highly reflecting MHCG mirror constructions for potential use in optoelectronic devices and systems. We support the numerical analysis by experimental verification of the high reflectance via a GaAs MHCG designed for a wavelength of 980 nm. PMID- 27472603 TI - Lateral spin transport in paraxial beams of light. AB - We investigate the lateral transport of (longitudinal) spin angular momentum in a special polarization tailored light beam composed of a superposition of a y polarized zero-order and an x-polarized first-order Hermite-Gaussian mode. This phenomenon is linked to the relative Gouy phase shift between the individual modes upon propagation, but can also be interpreted as a geometric phase effect. Experimentally, we demonstrate the implementation of such a mode and measure the spin density upon propagation. PMID- 27472604 TI - High speed optical holography of retinal blood flow. AB - We performed noninvasive video imaging of retinal blood flow in a pigmented rat by holographic interferometry of near-infrared laser light backscattered by retinal tissue, beating against an off-axis reference beam sampled at a frame rate of 39 kHz with a high throughput camera. Local Doppler contrasts emerged from the envelopes of short-time Fourier transforms and the phase of autocorrelation functions of holograms rendered by Fresnel transformation. This approach permitted imaging of blood flow in large retinal vessels (~30 microns diameter) over 400*400 pixels with a spatial resolution of ~8 microns and a temporal resolution of ~6.5 ms. PMID- 27472605 TI - Direct laser writing of a low-loss waveguide with independent control over the transverse dimension and the refractive index contrast between the core and the cladding. AB - In this Letter, we present the realization of a low-loss waveguide in a chalcogenide glass by direct laser writing technique in a particular configuration that allows the independent control over the diameter of the core and the magnitude of the refractive index contrast with the cladding. The waveguide is of multicore type and composed of 19 channels arranged on a hexagonal lattice. Each channel is obtained by stacking voxels of refractive index variation obtained by static exposure to femtosecond laser pulse burst. The distance between the channels can be used to vary the diameter of the waveguide, while the duration of laser burst controls the magnitude of the effective index and the propagation loss. We demonstrate that it can be reduced down to 0.11 dB/cm. PMID- 27472606 TI - Field demonstration of a continuous-variable quantum key distribution network. AB - We report on what we believe is the first field implementation of a continuous variable quantum key distribution (CV-QKD) network with point-to-point configuration. Four QKD nodes are deployed on standard communication infrastructures connected with commercial telecom optical fiber. Reliable key exchange is achieved in the wavelength-division-multiplexing CV-QKD network. The impact of a complex and volatile field environment on the excess noise is investigated, since excess noise controlling and reduction is arguably the major issue pertaining to distance and the secure key rate. We confirm the applicability and verify the maturity of the CV-QKD network in a metropolitan area, thus paving the way for a next-generation global secure communication network. PMID- 27472607 TI - Controlling formation and suppression of fiber-optical rogue waves. AB - Fiber-optical rogue waves appear as rare but extreme events during optical supercontinuum generation in photonic crystal fibers. This process is typically initiated by the decay of a high-order fundamental soliton into fundamental solitons. Collisions between these solitons as well as with dispersive radiation affect the soliton trajectory in frequency and time upon further propagation. Launching an additional dispersive wave at carefully chosen delay and wavelength enables statistical manipulation of the soliton trajectory in such a way that the probability of rogue wave formation is either enhanced or reduced. To enable efficient control, parameters of the dispersive wave have to be chosen to allow trapping of dispersive radiation in the nonlinear index depression created by the soliton. Under certain conditions, direct manipulation of soliton properties is possible by the dispersive wave. In other more complex scenarios, control is possible via increasing or decreasing the number of intersoliton collisions. The control mechanism reaches a remarkable efficiency, enabling control of relatively large soliton energies. This scenario appears promising for highly dynamic all optical control of supercontinua. PMID- 27472608 TI - Octave-spanning supercontinuum generation in hybrid silver metaphosphate/silica step-index fibers. AB - We reveal the potential of step-index fibers consisting of a metaphosphate glass core and a silica cladding as an ultrafast octave-spanning supercontinuum source. The hybrid waveguide was fabricated by pressure-assisted melt filling and possesses a sophisticated dispersion behavior with two zero-dispersion points in the proximity of the Erbium laser bands. The fiber generates an octave-spanning supercontinuum from 0.7 to 2.4 MUm if pumped at 1.56 MUm with 30 fs pulses and energies as low as 300 pJ. Numerical simulations reveal soliton fission and double dispersive wave generation as the dominant broadening effect. This study highlights phosphate glasses as a promising new candidate for the next generation of broadband photonic devices, as they allow for high rare earth-doping levels and dispersion posttuning via plasmonic nanoparticle growth. PMID- 27472609 TI - On-chip plasmonic spectrometer. AB - We report a numerical and experimental study of an on-chip optical spectrometer, utilizing propagating surface plasmon polaritons in the telecom spectral range. The device is based on two holographic gratings, one for coupling, and the other for decoupling free-space radiation with the surface plasmons. This 800 MUm*100 MUm on-chip spectrometer resolves 17 channels spectrally separated by 3.1 nm, spanning a freely tunable spectral window, and is based on standard lithography fabrication technology. We propose two potential applications for this new device; the first employs the holographic control over the amplitude and phase of the input spectrum, for intrinsically filtering unwanted frequencies, like pump radiation in Raman spectroscopy. The second prospect utilizes the unique plasmonic field enhancement at the metal-dielectric boundary for the spectral analysis of very small samples (e.g., Mie scatterers) placed between the two gratings. PMID- 27472610 TI - Femtosecond damage resistance of femtosecond multilayer and hybrid mirrors. AB - Improving the laser-induced damage threshold of optical components is a basic endeavor in femtosecond technology. By testing more than 30 different femtosecond mirrors with 42 fs laser pulses at 1 kHz repetition rate, we found that a combination of high-bandgap dielectric materials and improved design and coating techniques enable femtosecond multilayer damage thresholds exceeding 2 J/cm2 in some cases. A significant *2.5 improvement in damage resistance can also be achieved for hybrid Ag-multilayer mirrors exhibiting more than 1 J/cm2 threshold with a clear anticorrelation between damage resistance and peak field strength in the stack. Slight dependence on femtosecond pulse length and substantial decrease for high (megahertz) repetition rates are also observed. PMID- 27472611 TI - Extended field-of-view in a lensless endoscope using an aperiodic multicore fiber. AB - We investigate lensless endoscopy using coherent beam combining and aperiodic multicore fibers (MCF). We show that diffracted orders, inherent to MCF with periodically arranged cores, dramatically reduce the field-of-view (FoV), and that randomness in MCF core positions can increase the FoV up to the diffraction limit set by a single fiber core, while maintaining a MCF experimental feasibility. We demonstrate experimentally pixelation-free lensless endoscopy imaging over a 120 MUm FoV with an aperiodic MCF designed with widely spaced cores. We show that this system is suitable to perform beam scanning imaging by simply applying a tilt to the proximal wavefront. PMID- 27472612 TI - Tunable orbital angular momentum generation in optical fibers. AB - We present a method in this Letter to generate optical vortices with tunable orbital angular momentum (OAM) in optical fibers. The tunable OAM optical vortex is produced by combining different vector modes HE2,meven (HE2,modd) and TE0,m (TM0,m) when l=1 or combining HEl+1,meven (HEl+1,modd) and EHl-1,modd (EHl-1,meven) when l>1 with a pi/2 phase shift. The vortex can be regarded as a result of overlapping two orthogonal optical vortex beams of equal helicity but opposite chirality with a pi/2 phase shift. We have experimentally demonstrated the smooth variation of OAM from l=-1 to l=+1 by adjusting a polarizer at the output end of the fiber. PMID- 27472613 TI - Subwavelength focusing of terahertz waves in silicon hyperbolic metamaterials. AB - We theoretically demonstrate the subwavelength focusing of terahertz (THz) waves in a hyperbolic metamaterial (HMM) based on a two-dimensional subwavelength silicon pillar array microstructure. The silicon microstructure with a doping concentration of at least 1017 cm-3 offers a hyperbolic dispersion at terahertz frequency range and promises the focusing of terahertz Gaussian beams. The results agree with the simulation based on effective medium theory. The focusing effect can be controlled by the doping concentration, which determines the real part of the out-of-plane permittivity and, therefore, the refraction angles in HMM. The focusing property in the HMM structure allows the propagation of terahertz wave through a subwavelength aperture. The silicon-based HMM structure can be realized using microfabrication technologies and has the potential to advance terahertz imaging with subwavelength resolution. PMID- 27472614 TI - Monolithically mode division multiplexing photonic integrated circuit for large capacity optical interconnection. AB - We propose and fabricate an on-chip mode division multiplexed (MDM) photonic interconnection system. Such a monolithically photonic integrated circuit (PIC) is composed of a grating coupler, two micro-ring modulators, mode multiplexer/demultiplexer, and two germanium photodetectors. The signals' generation, multiplexing, transmission, demultiplexing, and detection are successfully demonstrated on the same chip. Twenty Gb/s MDM signals are successfully processed with clear and open eye diagrams, validating the feasibility of the proposed circuit. The measured power penalties show a good performance of the MDM link. The proposed on-chip MDM system can be potentially used for large-capacity optical interconnection in future high-performance computers and big data centers. PMID- 27472615 TI - Two-dimensional fluorescence spectroscopy of laser-produced plasmas. AB - We use a two-dimensional laser-induced fluorescence spectroscopy technique to measure the coupled absorption and emission properties of atomic species in plasmas produced via laser ablation of a solid aluminum target at atmospheric pressure. Emission spectra from the Al I 394.4 nm and Al I 396.15 nm transitions are measured while a frequency-doubled, continuous wave (cw) Ti:sapphire laser is tuned across the Al I 396.15 nm transition. The resulting two-dimensional spectra show the energy coupling between the two transitions via increased emission intensity for both transitions during resonant absorption of the cw laser at one transition. Time-delayed, gated detection of the emission spectrum is used to isolate resonantly excited fluorescence emission from thermally excited emission from the plasma. In addition, the tunable cw laser measures the absorption spectrum of the Al transition with ultrahigh resolution after the plasma has cooled, resulting in narrower spectral linewidths than observed in emission spectra. Our results highlight that fluorescence spectroscopy employing cw laser re-excitation after pulsed laser ablation combines benefits of both traditional emission and absorption spectroscopic methods. PMID- 27472616 TI - Efficient way to convert propagating waves into guided waves via gradient wire structures. AB - We propose a method for the design of gradient wire structures that are capable of converting propagating waves into guided waves along the wire. The conversion process is achieved by imposing an additional wave vector to the scattered waves via the gradient wire structure, such that the wave vector of scattered waves is beyond the wave number in the background medium. Thus, the scattered waves turn into evanescent waves. We demonstrate that two types of gradient wire structures, with either a gradient permittivity and a fixed radius, or a gradient radius and a fixed permittivity, can both be designed to realize such a wave conversion effect. The principle demonstrated in our work has potential applications in various areas including nanophotonics, silicone photonics, and plasmonics. PMID- 27472618 TI - Multi-wavelength Yb:YAG/Nd3+:YVO4 continuous-wave microchip Raman laser. AB - Multi-wavelength continuous-wave (CW) Raman lasers in a laser diode pumped Yb:YAG/Nd3+:YVO4 microchip Raman laser have been demonstrated for the first time to our best knowledge. The multi-wavelength laser of the first Stokes radiation around 1.08 MUm has been achieved with a Raman shift of 261 cm-1 for a-cut Nd:YVO4 crystal corresponding to the fundamental wavelength at 1.05 MUm. Multi-wavelength laser operation simultaneously around 1.05 and 1.08 MUm has been achieved under the incident pump power between 1.5 and 1.7 W. Multi-wavelength Raman laser with frequency separation of 1 THz around 1.08 MUm has been obtained when the incident pump power is higher than 1.7 W. The maximum Raman laser output power of 260 mW at 1.08 MUm is obtained and the corresponding optical-to-optical conversion efficiency is 4.2%. Elliptically polarized fundamental laser and linearly polarized Raman laser were observed in an Yb:YAG/Nd:YVO4 CW microchip Raman laser. The experimental results of linearly polarized, multi-wavelength Yb:YAG/Nd:YVO4 CW microchip Raman laser with adjustable frequency separation provide a novel approach for developing potential compact laser sources for Terahertz generation. PMID- 27472619 TI - Q-factor and absorption enhancement for plasmonic anisotropic nanoparticles. AB - We investigate the scattering and absorption properties of anisotropic metal dielectric core-shell nanoparticles. It is revealed that the radially anisotropic dielectric layer can accelerate the evanescent decay of the localized resonant surface modes, leading to Q-factor and absorption rate enhancement. Moreover, the absorption cross section can be maximized to reach the single resonance absorption limit. We further show that such artificial anisotropic cladding materials can be realized by isotropic layered structures, which may inspire many applications based on scattering and absorption of plasmonic nanoparticles. PMID- 27472617 TI - Injection-induced, tunable all-optical gating in a two-state quantum dot laser. AB - We demonstrate a tunable all-optical gating phenomenon in a single-section quantum dot laser. The free-running operation of the device is emission from the excited state. Optical injection into the ground state of the material can induce a switch to emission from the ground state with complete suppression of the excited state. If the master laser is detuned from the ground-state emitting frequency, a periodic train of ground-state dropouts can be obtained. These dropouts act as gates for excited-state pulsations: during the dropout, the gate is opened and gain is made available for the excited state, and the gate is closed again when the dropout ends. Numerical simulations using a rate equation model are in excellent agreement with experimental results. PMID- 27472620 TI - Powerful 100-fs-scale Kerr-lens mode-locked thin-disk oscillator. AB - We have recently demonstrated a simple power scaling procedure for Kerr-lens mode locked thin-disk oscillators. Here we report on the extension of this scheme to a broadband high-peak-power thin-disk oscillator, delivering 140-fs pulses with a peak and average power of 62 MW and 155 W, respectively. This result shows that reaching the emission bandwidth of the gain material in Kerr-lens mode-locked thin-disk oscillators is feasible without sacrificing output power, efficiency, or stability by relying on high intracavity nonlinearities. PMID- 27472621 TI - Holographic optical assembly and photopolymerized joining of planar microspheres. AB - The aim of this research is to demonstrate a holographically driven photopolymerization process for joining colloidal particles to create planar microstructures fixed to a substrate, which can be monitored with real-time measurement. Holographic optical tweezers (HOT) have been used to arrange arrays of microparticles prior to this work; here we introduce a new photopolymerization process for rapidly joining simultaneously handled microspheres in a plane. Additionally, we demonstrate a new process control technique for efficiently identifying when particles have been successfully joined by measuring a sufficient reduction in the particles' Brownian motion. This technique and our demonstrated joining approach enable HOT technology to take critical steps toward automated additive fabrication of microstructures. PMID- 27472622 TI - Lithography-free wide-angle antireflective self-cleaning silicon nanocones. AB - Low-cost, wideband, and wide-angle antireflective layers are of prime importance to photovoltaic and other optoelectronic applications. We report a novel fabrication methodology of random textured silicon nanocones (SiNCs) array through metal-assisted chemical etching combined with oxidation. The optical properties of the fabricated structure are studied theoretically and experimentally. The random textured SiNCs array showed very promising broadband antireflective properties through the entire visible wavelength range at different incident angles up to +/-60 degrees . In addition, the nanostructures inherently could become self-cleaning due to the high contact angle. This random cheap textured SiNCs array increases the absorption efficiency of photodetectors and reduces its cost. PMID- 27472623 TI - Single-step optical realization of bio-inspired dual-periodic motheye and gradient-index-array photonic structures. AB - This Letter demonstrates a single-step optical realization method for hexagonal and square lattice-based dual periodic motheye and gradient-index-array photonic structures over large areas. Computed phase mask of gradient interference patterns are used as inputs to a phase-only spatial light modulator (SLM), and the first-order diffracting beams are coherently superposed with the help of a 2f 2f Fourier filtering setup to avoid complex optical geometry for generation and control of individual beams. The simulated interference patterns are verified experimentally through a CMOS camera. The fabricated micro-structures on a positive photoresist are shown to have a major periodicity of 638 MUm and minor periodicity of 25.2 MUm, with the air hole diameter varying from 22.7 to 6.9 MUm along the X and Y axes. The depth of the fabricated structure gradually varies from 4.203 MUm at the center to 1.818 MUm at the corner. These structures may be scaled down to submicron features that can show improved anti-reflection properties for solar energy harvesting and GRIN lens for optical wavelength region. PMID- 27472624 TI - High power multi-color OPCPA source with simultaneous femtosecond deep-UV to mid IR outputs. AB - Many experimental investigations demand synchronized pulses at various wavelengths, ideally with very short pulse duration and high repetition rate. Here we describe a femtosecond multi-color optical parametric chirped pulse amplifier (OPCPA) with simultaneous outputs from the deep-UV to the mid-IR with optical synchronization. The high repetition rate of 160 kHz is well suited to compensate for low interaction probability or low cross section in strong-field interactions. Our source features high peak powers in the tens to hundreds of MW regime with pulse durations below 110 fs, which is ideal for pump-probe experiments of nonlinear and strong-field physics. We demonstrate its utility by strong-field ionization experiments of xenon in the near- to mid-IR. PMID- 27472625 TI - Polymer-clad silica fibers for tailoring modal area and dispersion. AB - We demonstrate higher-order-mode (Aeff up to ~2000 MUm2) propagation in a 100 MUm outer diameter pure-silica fiber with a low-index polymer jacket commonly used for fiber laser pump guidance. This simple structure obviates the need for complex designs deemed necessary for realizing large-mode area fibers. Modes ranging from HE1,12 to HE1,22 were found to propagate stably over 15 m in this fiber. The index step is approximately 4 times larger than that obtained with fluorine down doping; thus the fiber supports even higher-order modes, which may have implications for building rare earth-doped fiber lasers or achieving enhanced dispersion tunability for high energy fiber nonlinear phenomena. PMID- 27472626 TI - Broadband orbital angular momentum transmission using a hollow-core photonic bandgap fiber. AB - We present the viability of exploiting a current hollow-core photonic bandgap fiber (HC-PBGF) to support orbital angular momentum (OAM) states. The photonic bandgap intrinsically provides a large refractive index spacing for guiding light, leading to OAM transmission with low crosstalk. From numerical simulations, a broad OAM+/-1 mode transmission window with satisfied effective index separations between vector modes (>10-4) and low confinement loss (<3 dB/km) covering 240 nm bandwidth is observed. The OAM purity (defined as normalized power weight for OAM mode) is found to be affected by the modal effective area. Simulation results also show HC-PBGF based OAM transmission is immune to fabrication inaccuracies near the hollow core. This work illustrates that HC-PBGF is a competitive candidate for high-capacity communication harnessing OAM multiplexing. PMID- 27472627 TI - Effect of a magnetic field on intersubband polaritons in a quantum well: strong to weak coupling conversion. AB - We investigate theoretically the effect of a magnetic field on intersubband polaritons in an asymmetric quantum well placed inside an optical resonator. It is demonstrated that the field-induced diamagnetic shift of electron subbands in the well increases the broadening of optical lines corresponding to intersubband electron transitions. As a consequence, the magnetic field can switch the polariton system from the regime of strong light-matter coupling to the regime of a weak one. This effect paves a way for the effective control of polaritonic devices with a magnetic field. PMID- 27472628 TI - Broadband tunable microwave photonic phase shifter with low RF power variation in a high-Q AlN microring. AB - An all-optically tunable microwave photonic phase shifter is demonstrated based on an epitaxial aluminum nitride (AlN) microring with an intrinsic quality factor of 3.2*106. The microring adopts a pedestal structure, which allows overcoupling with 700 nm gap size and facilitates the fabrication process. A phase shift for broadband signals from 4 to 25 GHz is demonstrated by employing the thermo-optic effect and the separate carrier tuning technique. A phase tuning range of 0 degrees -332 degrees is recorded with a 3 dB radio frequency (RF) power variation and 48 mW optical power consumption. In addition, AlN exhibits intrinsic second-order optical nonlinearity. Thus, our work presents a novel platform with a low propagation loss and the capability of electro-optic modulation for applications in integrated microwave photonics. PMID- 27472629 TI - Fabrication of a microtoroidal resonator with picometer precise resonant wavelength. AB - Fabricating an optical microresonator with precise resonant wavelength is of significant importance for fundamental research and practical applications. Here, we develop an effective method to fabricate ultra-high Q microtoroid with picometer-precise resonant wavelength. Our method adds a tuning reflow process, using low-power CO2 laser pulses, to the traditional fabrication process. It can tailor resonant wavelength to a red or blue direction by choosing a proper laser power. Also, this shift can be controlled by the exposure time. Meanwhile, quality factor remains nearly unchanged during this tailoring process. Our method can greatly reduce the difficulties of experiments where precise resonances are required. PMID- 27472630 TI - Rise in power of Yb:YCOB for green light generation by self-frequency doubling. AB - Spectroscopic properties and self-frequency-doubling laser performance are presented for Yb:YCa4O(BO3)3 (Yb:YCOB) crystals oriented for type I second-harmonic generation in the ZX plane. In a plane concave cavity 10 cm long, up to 330 mW of green light (544.5 nm) is obtained for 14.7 W of laser diode incident pump power. Broad emission bands and weak anisotropy in the 1060-1100 nm range between the two eigenstates of polarization may explain the instability of the self-frequency-doubled output power. PMID- 27472631 TI - Anomalous nonlinear absorption in epsilon-near-zero materials: optical limiting and all-optical control. AB - We investigate nonlinear absorption in films of epsilon-near-zero materials. The combination of large local electric fields at the fundamental frequency and material losses at the harmonic frequencies induce unusual intensity-dependent phenomena. We predict that the second-order nonlinearity of a low-damping, epsilon-near-zero slab produces an optical limiting effect that mimics a two photon absorption process. Anomalous absorption profiles that depend on low permittivity values at the pump frequency are also predicted for third-order nonlinearities. These findings suggest new opportunities for all-optical light control and novel ways to design reconfigurable and tunable nonlinear devices. PMID- 27472633 TI - Vector plasmonic lattice solitons in nonlinear graphene-pair arrays. AB - We investigate the vector plasmonic lattice solitons (PLSs) in nonlinear graphene pair arrays (GPAs) consisting of periodically arranged double graphene sheets, which are spatially separated. There are two dispersion bands for the Bloch modes in the array due to the coupling of surface plasmon polaritons (SPPs) between the graphene pairs. The vector PLSs composed of two components originate from the nonlinear interaction of Bloch modes in different bands. Both components undergo mutual self-trapping through the balance between diffraction and self-focusing nonlinearity of graphene. Thanks to the strong confinement of SPPs, the vector PLSs can be squeezed into a lateral width of ~lambda/100. The study provides a promising approach to all-optical control on a deep-subwavelength scale. PMID- 27472632 TI - Scattering detection of a solenoidal Poynting vector field. AB - The Poynting vector S plays a central role in electrodynamics as it is directly related to the power and the momentum carried by an electromagnetic wave. In the presence of multiple electromagnetic waves with different polarizations and propagation directions, the Poynting vector may exhibit solenoidal components which are not associated to any power flow. Here, we demonstrate theoretically and experimentally that the presence of such solenoidal components has physical consequences, and it is not a mere artifact of the gauge invariance of S. In particular, we identify a simple field configuration displaying solenoidal components of S and theoretically show that a judiciously designed scatterer can act as a "Poynting vector detector" which when immersed in such field distribution would experience a transverse optical force orthogonal to the incidence plane. We experimentally validate our theoretical predictions by observing a pronounced asymmetry in the scattering pattern of a spherical nanoparticle. PMID- 27472634 TI - Second harmonic generation in graphene-coated nanowires. AB - We study second harmonic generation in a pair of graphene-coated nanowires. We show that the phase matching condition for harmonic generation can be engineered in a wide range of frequencies by tuning the spacing between graphene nanowires. We derive coupled mode equations describing the process of second harmonic generation using an unconjugated Lorentz reciprocity theorem. We show that the highest harmonic generation efficiency can be achieved by phase matching the fundamental mode with the two lowest order symmetric modes at the second harmonic frequency. Despite losses in graphene, we predict that the efficiency can be further enhanced by reducing the radius of nanowires due to larger mode overlap and lower propagation loss. PMID- 27472635 TI - Micropatterning of silver nanoclusters embedded in polyvinyl alcohol films. AB - Direct laser writing has been utilized to fabricate highly photostable fluorescent nanocluster microstructures in an organic polymer poly(methacrylic acid), where the carboxyl functional group is reported to play a vital role in nanocluster stabilization. In this Letter, we demonstrate that not only the polymer containing the carboxyl functional group, but also the polymer comprising the hydroxyl group, namely polyvinyl alcohol (PVA), can act as an appropriate stabilizer matrix for laser-induced synthesis and patterning of silver nanoclusters. The as-formed nanoclusters in the PVA film exhibit broadband emission and photostability comparable to the nanoclusters formed in the poly(methacrylic acid) polymer. As PVA is a widely used, nontoxic, biocompatible and biodegradable polymer, the technique of patterning fluorescent nanoclusters in PVA thin films is expected to find numerous applications in fields like fluorescence imaging, biolabeling, and sensing. PMID- 27472636 TI - Coma aberrations in combined two- and three-dimensional STED nanoscopy. AB - Stimulated emission depletion (STED) microscopes, like all super-resolution methods, are sensitive to aberrations. Of particular importance are aberrations that affect the quality of the depletion focus, which requires a point of near zero intensity surrounded by strong illumination. We present analysis, modeling, and experimental measurements that show the effects of coma aberrations on depletion patterns of two-dimensional (2D) and three-dimensional (3D) STED configurations. Specifically, we find that identical coma aberrations create focal shifts in opposite directions in 2D and 3D STED. This phenomenon could affect the precision of microscopic measurements and has ramifications for the efficacy of combined 2D/3D STED systems. PMID- 27472637 TI - Laser-induced excited-state crossover and spectral variation of Cr3+ in the high-crystal-field environment of CaGa2O4. AB - We have studied a wide-bandgap oxide semiconductor, CaGa1.99Cr0.01O4, which possesses high crystal field strength and develops deep traps. These traps efficiently store electric charges after excitation with ultraviolet light. Stimulation of trap charges using infrared radiation (both coherent and incoherent) gives wideband emission of Cr3+ in the red-infrared region, which is similar to the photon upconversion process in lanthanides. Under laser excitation, high photon density and local heating pronounce the coupling of E2 and T24 states and causes an excited state crossover of the population from the E2 to T24 state. This expands the emission band-width of Cr3+ up to 900 nm. PMID- 27472638 TI - High power and high SFDR frequency conversion using sum frequency generation in KTP waveguides. AB - We characterize the intermodulation distortion of high power and efficient frequency conversion of modulated optical signals based on sum frequency generation (SFG) in a periodically poled potassium titanyl phosphate (KTP) waveguide. Unwanted frequency two-tone spurs are generated near the converted signal via a three-step cascaded three-wave mixing process. Computer simulations describing the process are presented along with the experimental measurements. High-conversion efficiencies and large spur-free dynamic range of the converted optical signal are demonstrated. PMID- 27472639 TI - High spatial resolution, low-noise Brillouin dynamic gratings reflectometry based on digital pulse compression. AB - Digital pulse compression was used to enhance the performance of optical time domain reflectometry, employing Brillouin dynamic gratings (BDGs) in polarization maintaining fibers. The fundamental and unique issues in BDG field-reflection are addressed, and rules for proper selection of the coding and detection techniques are formulated. While coding in BDG applications generally requires coherent processing of the reflection, conditions are established for use of direct detection. A 256-bit Golay complementary unipolar probe code is used to demonstrate an eightfold signal-to-noise ratio enhancement in the measurement of the Brillouin gain spectrum (BGS), with a spatial resolution of 2 cm and a full BGS acquisition rate of 1331/3 kHz, resulting in an equivalent reduction in the estimation error of small Brillouin frequency shifts. PMID- 27472640 TI - Birefringent Fourier transform imaging spectrometer with a rotating retroreflector. AB - A birefringent Fourier transform imaging spectrometer with a new lateral shearing interferometer is presented. The interferometer includes a Wollaston prism and a retroreflector. It splits an incident light beam into two shearing parallel parts to obtain interference fringe patterns of an imaging target, which is well established as an aid in reducing problems associated with optical alignment and manufacturing precision. Continuously rotating the retroreflector enables the spectrometer to acquire two-dimensional spectral images without spatial scanning. This technology, with a high work efficiency and low complexity, is inherently compact and robust. The effectiveness of the proposed method is demonstrated by the experimental results. PMID- 27472641 TI - Low control-power wavelength conversion on a silicon chip. AB - We demonstrate controlled wavelength conversion on a silicon chip based on four wave mixing Bragg scattering (FWM-BS). A total conversion efficiency of 5% is achieved with strongly unbalanced pumps and a controlling peak power of 55 mW, while the efficiency is over 15% when using less asymmetric pumps. The numerical simulation agrees with the experimental results. Both time domain and spectral domain noise measurements show as low as 2 dB signal-to-noise ratio (SNR) penalty because of the strong pump noise, two-photon absorption, and free-carrier absorption in silicon. We discuss how the scheme can be used to implement an all optically controlled high-speed switch. PMID- 27472642 TI - Air and dielectric bands photonic crystal microringresonator for refractive index sensing. AB - We present the experimental and numerical analysis of a microring resonator with an integrated one-dimensional photonic crystal fabricated on a silicon-on insulator platform and show its applicability in bulk refractive index sensing. The photonic crystal is formed by periodically patterned, partially etched cylindrical perforations, whose induced photonic bandgap is narrower than the range of measurable wavelengths (1520-1620 nm). Of particular interest is that the microring operates in both air and dielectric bands, and the sensitivities of the resonances on both edges of the bandgap were investigated. We showed that a higher field localization inside the volume of the perforations for the air band mode leads to an increase in sensitivity. PMID- 27472643 TI - Optical single sideband modulation based on a high-order birefringent filter using cascaded Solc-Sagnac and Lyot-Sagnac loops. AB - We propose and experimentally demonstrate a simple and flexible photonic approach to implementing single sideband (SSB) modulation based on optical spectral filtering. The high-order birefringent filter is realized through the cascaded Solc-Sagnac and Lyot-Sagnac loops. By adjusting the rotation angle of the polarization controller (PC), the notch position to remove undesired sidebands changes. The frequency for SSB modulation varies accordingly. The periodical response of the filter spectrum allows both the carrier wavelength and the optical carrier to sideband ratio (OCSR) to be tunable. SSB modulation over a frequency range from 5 to 40 GHz and tunable OCSR ranging from -9.174 to 34.408 dB are obtained. The significant merits of the proposed approach are the simple structure, easy operation, large frequency range, tunable OCSR, and wavelength independence. The approach has potential applications in optimizing the transmission performance of photonic microwave signal processing systems. PMID- 27472644 TI - Cell identification using single beam lensless imaging with pseudo-random phase encoding. AB - In this Letter, we propose a novel compact optical system for automated cell identification. Our system employs pseudo-random encoding of the light modulated by the cells under inspection to capture the unique opto-biological signature of the micro-organisms by an image sensor and without using a microscope objective lens to magnify the object beam. The proposed instrument can be fabricated using a compact light source, a thin diffuser, and an image sensor connected to computational hardware; thus, it can be compact and cost effective. Experiments are presented using the proposed system to identify and classify various micro objects and demonstrate proof of concept. The captured opto-biological signature pattern can be attributed to the micro-object's morphology, size, sub-cellular complex structure, index of refraction, internal material composition, etc. Using the captured signature of the micro-object, we extract statistical features such as mean, variance, skewness, kurtosis, entropy, and correlation coefficients for cell identification using the random forest classifier. For comparison, similar identification experiments were repeated with a digital shearing interferometer. To the best of our knowledge, this is the first report on automated cell identification using the proposed approach. PMID- 27472645 TI - Widely tunable in the mid-IR BaGa4Se7 optical parametric oscillator pumped at 1064 nm. AB - A BaGa4Se7 nanosecond optical parametric oscillator (OPO) shows extremely wide idler tunability in the mid-IR (2.7-17 MUm) under 1.064 MUm pumping. The ~10 ns pulses at ~7.2 MUm have an energy of 3.7 mJ at 10 Hz. The pump-to-idler conversion efficiency for this wavelength reaches 5.9% with a slope of 6.5% corresponding to a quantum conversion efficiency or pump depletion of 40%. PMID- 27472646 TI - Optical vector analysis based on double-sideband modulation and stimulated Brillouin scattering. AB - A high-resolution and high-accuracy optical vector analysis based on optical double-sideband modulation and stimulated Brillouin scattering is proposed and experimentally demonstrated. Different from the conventional OVA based on optical single-sideband modulation, in which the measurement range is limited by the bandwidth of the microwave and optoelectronic components, and the measurement accuracy is restricted by the high-order sidebands, the proposed technique measures the magnitude and phase responses by making use of both +/-1st-order sidebands without spectrum response aliasing. As a result, the measurement range is doubled, and the high-order, sideband-induced errors only appear at specific frequencies that are predictable and removable. A proof-of-concept experiment is carried out. The transmission response of a fiber Bragg grating, in a range of 80 GHz, is measured with a resolution of less than 667 kHz by using 40 GHz microwave components. PMID- 27472647 TI - Clonal analysis of stem cells in differentiation and disease. AB - Tracking the fate of individual cells and their progeny by clonal analysis has redefined the concept of stem cells and their role in health and disease. The maintenance of cell turnover in adult tissues is achieved by the collective action of populations of stem cells with an equal likelihood of self-renewal or differentiation. Following injury stem cells exhibit striking plasticity, switching from homeostatic behavior in order to repair damaged tissues. The effects of disease states on stem cells are also being uncovered, with new insights into how somatic mutations trigger clonal expansion in early neoplasia. PMID- 27472650 TI - Neurogenic Differentiation of Mesenchymal Stem Cells Induces Alterations in Extracellular Nucleotides Metabolism. AB - The presented results show for the first time that the neurogenic transdifferentiation of hUC-MSCs considerably changes the elements of purinergic signaling profile. Although, it has been demonstrated in the literature that extracellular nucleotides and nucleosides determine the fate of mesenchymal and neural stem cells, there is lack of comprehensive studies on the activity of ecto enzymes metabolizing nucleotides on the surface of neurogenically induced cells. Our study shows that human UC-MSCs sense the microenvironment and adjust their response to the environmental signals for example, adenine nucleotides and nucleosides. Nucleotides, and not adenosine, signaling alters the biological potential of MSCs-decreases their proliferation rate, increases the neurogenic transdifferentiation efficiency expressed as the number of positively labeled NCAM+ and A2B5+ cells and simultaneously increases the ecto-nucleotidases activity on neural- and glial-committed precursors. Purines implication in the proliferative and neurogenic potential of hUC-MSCs is of strong importance for the in vitro propagation of hUC-MSCs and for their successive therapeutic applications. J. Cell. Biochem. 118: 478-486, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27472648 TI - Systematic versus on-demand early palliative care: results from a multicentre, randomised clinical trial. AB - BACKGROUND: Early palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined. METHODS: This prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive 'standard cancer care plus on-demand EPC' (n = 100) or 'standard cancer care plus systematic EPC' (n = 107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy - Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated. FINDINGS: The mean changes in TOI score and HCS score between T0 and T1 were -4.47 and -0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10-7.57) (p = 0.041), and -2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40-4.61, p = 0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p = 0.022) and 52.0 versus 48.2 (p = 0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms. INTERPRETATIONS: Systematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC. PMID- 27472651 TI - Importance of a Conserved Lys/Arg Residue for Ligand/PDZ Domain Interactions as Examined by Protein Semisynthesis. AB - PDZ domains are ubiquitous small protein domains that are mediators of numerous protein-protein interactions, and play a pivotal role in protein trafficking, synaptic transmission, and the assembly of signaling-transduction complexes. In recent years, PDZ domains have emerged as novel and exciting drug targets for diseases (in the brain in particular), so understanding the molecular details of PDZ domain interactions is of fundamental importance. PDZ domains bind to a protein partner at either a C-terminal peptide or internal peptide motifs. Here, we examined the importance of a conserved Lys/Arg residue in the ligand-binding site of the second PDZ domain of PSD-95, by employing a semisynthetic approach. We generated six semisynthetic PDZ domains comprising different proteogenic and nonproteogenic amino acids representing subtle changes of the conserved Lys/Arg residue. These were tested with four peptide interaction partners, representing the two different binding modes. The results highlight the role of a positively charged amino acid in the beta1-beta2 loop of PDZ domains, and show subtle differences for canonical and noncanonical interaction partners, thus providing additional insight into the mechanism of PDZ/ligand interaction. PMID- 27472649 TI - Diffuse malignant peritoneal mesothelioma: Evaluation of systemic chemotherapy with comprehensive treatment through the RENAPE Database: Multi-Institutional Retrospective Study. AB - PURPOSE: Diffuse malignant peritoneal mesothelioma (DMPM) is a severe disease with mainly locoregional evolution. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the reported treatment with the longest survival. The aim of this study was to evaluate the impact of perioperative systemic chemotherapy strategies on survival and postoperative outcomes in patients with DMPM treated with curative intent with CRS-HIPEC, using a multi-institutional database: the French RENAPE network. PATIENTS AND METHODS: From 1991 to 2014, 126 DMPM patients underwent CRS-HIPEC at 20 tertiary centres. The population was divided into four groups according to perioperative treatment: only neoadjuvant chemotherapy (NA), only adjuvant chemotherapy (ADJ), perioperative chemotherapy (PO) and no chemotherapy before or after CRS-HIPEC (NoC). RESULTS: All groups (NA: n = 42; ADJ: n = 16; PO: n = 16; NoC: n = 48) were comparable regarding clinicopathological data and main DMPM prognostic factors. After a median follow-up of 61 months, the 5-year overall survival (OS) was 40%, 67%, 62% and 56% in NA, ADJ, PO and NoC groups, respectively (P = 0.049). Major complications occurred for 41%, 45%, 35% and 41% of patients from NA, ADJ, PO and NoC groups, respectively (P = 0.299). In multivariate analysis, NA was independently associated with worse OS (hazard ratio, 2.30; 95% confidence interval, 1.07-4.94; P = 0.033). CONCLUSION: This retrospective study suggests that adjuvant chemotherapy may delay recurrence and improve survival and that NA may impact negatively the survival for patients with DMPM who underwent CRS-HIPEC with curative intent. Upfront CRS and HIPEC should be considered when achievable, waiting for stronger level of scientific evidence. PMID- 27472652 TI - Are letters to the editor really useful? PMID- 27472653 TI - EF4 reveals the energy barrier for tRNA back-translocation in the peptidyl transferase center. AB - In the translating ribosomal complex, transfer RNA (tRNA) is stabilized in the ribosome by its anticodon stem-loop (ASL) and 3'-CCA end through base-pairing interactions with mRNA codon on the small subunit and rRNA in the peptidyl transferase center (PTC) of large subunit, respectively.Elongation factor 4 (EF4), a highly conserved translational GTPase, has been identified to trigger back-translocation. Early this year, we reported high resolution cryo-EM structures of EF4 in complex with Escherichia coli 70S ribosome in pre- and post translocational states with direct observations that EF4 disrupts the base pairs between the 3'-end of peptidyl-tRNA and the P-loop of rRNA in PTC. Here, we focus on the novel molecular mechanism how EF4 catalyzes back-translocation, and discuss the common and specific energy barriers for forward- and back translocation. PMID- 27472654 TI - Optical studies of high-temperature superconducting cuprates. AB - The optical studies of high-temperature superconducting cuprates (HTSC) are reviewed. From the doping dependence of room temperature spectra, a dramatic change of the electronic state from a Mott (charge transfer) insulator to a Fermi liquid has been revealed. Additionally, the unusual 2D nature of the electronic state has been found. The temperature dependence of the optical spectra provided a rich source of information on the pseudogap, superconducting gap, Josephson plasmon, transverse Josephson plasma mode and precursory superconductivity. Among these issues, Josephson plasmons and transverse Josephson plasma mode were experimentally discovered by optical measurements, and thus are unique to HTSC. The effect of the spin/charge stripe order is also unique to HTSC, reflecting the conducting nature of the stripe order in this system. The pair-breaking due to the stripe order seems stronger in the out-of-plane direction than in the in plane one. PMID- 27472655 TI - Mortality due to Vegetation Fire-Originated PM2.5 Exposure in Europe-Assessment for the Years 2005 and 2008. AB - BACKGROUND: Vegetation fires can release substantial quantities of fine particles (PM2.5), which are harmful to health. The fire smoke may be transported over long distances and can cause adverse health effects over wide areas. OBJECTIVE: We aimed to assess annual mortality attributable to short-term exposures to vegetation fire-originated PM2.5 in different regions of Europe. METHODS: PM2.5 emissions from vegetation fires in Europe in 2005 and 2008 were evaluated based on Moderate Resolution Imaging Spectroradiometer (MODIS) satellite data on fire radiative power. Atmospheric transport of the emissions was modeled using the System for Integrated modeLling of Atmospheric coMposition (SILAM) chemical transport model. Mortality impacts were estimated for 27 European countries based on a) modeled daily PM2.5 concentrations and b) population data, both presented in a 50 * 50 km2 spatial grid; c) an exposure-response function for short-term PM2.5 exposure and daily nonaccidental mortality; and d) country-level data for background mortality risk. RESULTS: In the 27 countries overall, an estimated 1,483 and 1,080 premature deaths were attributable to the vegetation fire originated PM2.5 in 2005 and 2008, respectively. Estimated impacts were highest in southern and eastern Europe. However, all countries were affected by fire originated PM2.5, and even the lower concentrations in western and northern Europe contributed substantially (~ 30%) to the overall estimate of attributable mortality. CONCLUSIONS: Our assessment suggests that air pollution caused by PM2.5 released from vegetation fires is a notable risk factor for public health in Europe. Moreover, the risk can be expected to increase in the future as climate change proceeds. This factor should be taken into consideration when evaluating the overall health and socioeconomic impacts of these fires. Citation: Kollanus V, Prank M, Gens A, Soares J, Vira J, Kukkonen J, Sofiev M, Salonen RO, Lanki T. 2017. Mortality due to vegetation fire-originated PM2.5 exposure in Europe-assessment for the years 2005 and 2008. Environ Health Perspect 125:30-37; http://dx.doi.org/10.1289/EHP194. PMID- 27472656 TI - Effects of near-infrared LED therapy on experimental tooth replantation in rats. AB - BACKGROUND/AIM: Dental avulsion damages periodontal tissues and may induce dentoalveolar ankylosis and root resorption after replantation. The aim of this work was to evaluate the effects of light-emitting diode (LED) therapy after tooth replantation. MATERIAL AND METHODS: The upper right incisors of 36 male Wistar rats were extracted and replanted after 15 min. The control group (Co, n = 18) was submitted to replantation and the LED group (n = 18) was submitted to replantation and LED therapy (940 nm, 4 J cm-2 ) for three consecutive days (0, 24, and 48 h). Six animals from each group were euthanized at 7, 14, and 21 days for histological analysis. The upper left incisors were used as a negative control. Data were compared using the Fisher exact test, considering P < 0.05. RESULTS: After 7 days, the Co (73.3%) and LED (72.2%) groups presented areas of periodontal ligament necrosis. However, periodontal ligament necrosis was more frequent in the LED group at 14 (70%, P < 0.05) and 21 days (43.2%, P < 0.05) in relation to the Co group (33 and 21.6%). Inflammatory cell infiltration was more frequent in the Co group at 7 days (100%) than the LED group (24.4%, P < 0.05), but increased in the LED group after 21 days (83.3%, P < 0.05). Bone necrosis was more frequent in the LED group after 14 (79%, P < 0.05) and 21 days (60%, P < 0.005) than in the Co group (45% and 20%). Bone repair was evident in the Co group at 14 days. All of the replanted teeth had pulp necrosis. CONCLUSION: The results suggest that the application of LED therapy up to 48 h after tooth replantation may delay periodontal ligament repair. PMID- 27472657 TI - Warming and Acidification Effects on Planktonic Heterotrophic Pico- and Nanoflagellates in a Mesocosm Experiment. AB - We studied the response of the heterotrophic flagellate (HF) community to the combined impact of warming and ocean acidification in a mesocosm experiment with a plankton community from the western Baltic Sea. We performed a quantitative analysis of the response at the level of total biomass and size classes and a semi-quantitative one at the level of individual taxa. Total biomass of HF was significantly lower under higher temperatures while there was no significant effect of CO2. The mean biomass of the picoflagellates did not respond to temperature while the three nanoflagellate size classes (class limits 3, 5, 8, 15MUm) responded negatively to warming while not responding to CO2. The taxon level results indicate that heterotrophic flagellates do not form a homogenous trophic guild, as often assumed in pelagic food web studies. Instead, the heterotrophic flagellates formed a "food web within the food web". There was a pronounced succession of flagellates leading from a dominance of bacterivores and colloidal matter feeders before the phytoplankton bloom to omnivorous feeders preying upon phytoplankton and heterotrophic flagellates during and after the bloom. This complex intraguild predation patterns probably dampened the response to experimental treatments. PMID- 27472658 TI - Bayesian Inference of Forces Causing Cytoplasmic Streaming in Caenorhabditis elegans Embryos and Mouse Oocytes. AB - Cellular structures are hydrodynamically interconnected, such that force generation in one location can move distal structures. One example of this phenomenon is cytoplasmic streaming, whereby active forces at the cell cortex induce streaming of the entire cytoplasm. However, it is not known how the spatial distribution and magnitude of these forces move distant objects within the cell. To address this issue, we developed a computational method that used cytoplasm hydrodynamics to infer the spatial distribution of shear stress at the cell cortex induced by active force generators from experimentally obtained flow field of cytoplasmic streaming. By applying this method, we determined the shear stress distribution that quantitatively reproduces in vivo flow fields in Caenorhabditis elegans embryos and mouse oocytes during meiosis II. Shear stress in mouse oocytes were predicted to localize to a narrower cortical region than that with a high cortical flow velocity and corresponded with the localization of the cortical actin cap. The predicted patterns of pressure gradient in both species were consistent with species-specific cytoplasmic streaming functions. The shear-stress distribution inferred by our method can contribute to the characterization of active force generation driving biological streaming. PMID- 27472659 TI - The broad roles of CBF genes: From development to abiotic stress. AB - Cold acclimation is an important adaptive response of plants from temperate regions to increase their freezing tolerance after being exposed to low nonfreezing temperatures. The three CBF genes are well known to be involved in cold acclimation. As the 3 CBF genes are linked tandemly in the Arabidopsis genome, it is almost impossible to obtain cbf triple mutants using traditional genetic methods. Recently, using the CRISPR/Cas9 technology, we generated cbf single, double, and triple mutants. Our results showed that the cbf triple mutants are extremely sensitive to freezing stress. In addition, the cbf triple mutants are defective in early development and salt tolerance. Interestingly, the cbf1 cbf3 double mutants show increased expression of the CBF2 gene and some downstream cold-responsive genes and display increased freezing tolerance, compared to the wild type, revealing that CBF1 and CBF3 negatively regulate CBF2 expression. PMID- 27472661 TI - Comparative proteomics of cucurbit phloem indicates both unique and shared sets of proteins. AB - Cucurbits are well-studied models for phloem biology but unusually possess both fascicular phloem (FP) within vascular bundles and additional extrafascicular phloem (EFP). Although the functional differences between the two systems are not yet clear, sugar analysis and limited protein profiling have established that FP and EFP have divergent compositions. Here we report a detailed comparative proteomics study of FP and EFP in two cucurbits, pumpkin and cucumber. We re examined the sites of exudation by video microscopy, and confirmed that in both species, the spontaneous exudate following tissue cutting derives almost exclusively from EFP. Comparative gel electrophoresis and mass spectrometry-based proteomics of exudates, sieve element contents and microdissected stem tissues established that EFP and FP profiles are highly dissimilar, and that there are also species differences. Searches against cucurbit databases enabled identification of more than 300 FP proteins from each species. Few of the detected proteins (about 10%) were shared between the sieve element contents of FP and EFP, and enriched Gene Ontology categories also differed. To explore quantitative differences in the proteomes, we developed multiple reaction monitoring methods for cucumber proteins that are representative markers for FP or EFP and assessed exudate composition at different times after tissue cutting. Based on failure to detect FP markers in exudate samples, we conclude that FP is blocked very rapidly and therefore makes a minimal contribution to the exudates. Overall, the highly divergent contents of FP and EFP indicate that they are substantially independent vascular compartments. PMID- 27472660 TI - Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions. AB - Today much is known about cytochrome P450 (P450) enzymes and their catalytic specificity, but the range of reactions catalyzed by each still continues to surprise. Historically, P450s had been considered to be involved in either the metabolism of xenobiotics or endogenous chemicals, in the former case playing a generally protective role and in the latter case a defined physiological role. However, the line of demarcation is sometimes blurred. It is difficult to be completely specific in drug design, and some P450s involved in the metabolism of steroids and vitamins can be off-targets. In a number of cases, drugs have been developed that act on some of those P450s as primary targets, e.g., steroid aromatase inhibitors. Several of the P450s involved in the metabolism of endogenous substrates are less specific than once thought and oxidize several related structures. Some of the P450s that primarily oxidize endogenous chemicals have been shown to oxidize xenobiotic chemicals, even in a bioactivation mode. PMID- 27472662 TI - Structural and mechanistic diversity of multidrug transporters. AB - Covering: 2009 to mid 2016Multidrug transporters are common and prevalent in all orders of life, having diverse functions from the removal of toxins, resistance to cytotoxins, and the transport of specific eluents. In addition, multidrug transporters pose a significant threat to modern medicine. Able to transport structurally diverse small molecule drugs, these transporters are implicated in antibiotic resistant strains of bacteria, as well as chemotherapeutic-resistance cancer cells. Although important in such resistance, a relatively small number of multidrug transporters have been structurally characterized, primarily due to the difficulty in purifying and crystallizing active membrane proteins and protein complexes. This review will cover recent structural breakthroughs in the past six years that have led to increased knowledge of the mechanisms of multidrug transporter chemistry, and the role of these transporters in exporting secondary metabolites. PMID- 27472663 TI - Climate Change Research in View of Bibliometrics. AB - This bibliometric study of a large publication set dealing with research on climate change aims at mapping the relevant literature from a bibliometric perspective and presents a multitude of quantitative data: (1) The growth of the overall publication output as well as (2) of some major subfields, (3) the contributing journals and countries as well as their citation impact, and (4) a title word analysis aiming to illustrate the time evolution and relative importance of specific research topics. The study is based on 222,060 papers (articles and reviews only) published between 1980 and 2014. The total number of papers shows a strong increase with a doubling every 5-6 years. Continental biomass related research is the major subfield, closely followed by climate modeling. Research dealing with adaptation, mitigation, risks, and vulnerability of global warming is comparatively small, but their share of papers increased exponentially since 2005. Research on vulnerability and on adaptation published the largest proportion of very important papers (in terms of citation impact). Climate change research has become an issue also for disciplines beyond the natural sciences. The categories Engineering and Social Sciences show the strongest field-specific relative increase. The Journal of Geophysical Research, the Journal of Climate, the Geophysical Research Letters, and Climatic Change appear at the top positions in terms of the total number of papers published. Research on climate change is quantitatively dominated by the USA, followed by the UK, Germany, and Canada. The citation-based indicators exhibit consistently that the UK has produced the largest proportion of high impact papers compared to the other countries (having published more than 10,000 papers). Also, Switzerland, Denmark and also The Netherlands (with a publication output between around 3,000 and 6,000 papers) perform top-the impact of their contributions is on a high level. The title word analysis shows that the term climate change comes forward with time. Furthermore, the term impact arises and points to research dealing with the various effects of climate change. The discussion of the question of human induced climate change towards a clear fact (for the majority of the scientific community) stimulated research on future pathways for adaptation and mitigation. Finally, the term model and related terms prominently appear independent of time, indicating the high relevance of climate modeling. PMID- 27472664 TI - Changes in water content in response to an acute bout of eccentric loading in a patellar tendon with a history of tendinopathy: A case report. AB - OBJECTIVE: This case-based report assessed resting water content and exercise driven water exchange within a tendon with a history of tendinopathy and compared the response to that of a healthy uninvolved tendon. DESIGN: Case Report. SETTING: University imaging center. PARTICIPANT: The participant was a 27-year old female basketball player 39 months following knee trauma. Patellar tendinopathy developed 12 months after the injury episode and was treated with eccentric exercises. Eighteen months from the beginning of the first eccentric training bout, the participant reported full resolution of symptoms and returned to her pre-injury sport participation without symptoms. INTERVENTION: Eccentric decline squat exercise. MAIN OUTCOME MEASURES: Tendon water content obtained from magnetic resonance imaging (MRI). RESULTS: MRI acquired 39 months post-injury demonstrated increased resting water content of the involved tendon (involved: 91.1% vs. uninvolved: 84.6%). Immediately after the eccentric squat maneuver, water content decreased on both involved and uninvolved tendons (involved: 89.5% vs. uninvolved: 83.3%). CONCLUSIONS: Elevated resting water content of the involved tendon found in this report may be indicative of reduced tendon stiffness. A similar amount of water content reduction was observed on both sides following mechanical loading, suggesting that the involved tendon may respond to the eccentric exercise similarly to the uninvolved tendon. Future investigations are needed to study the relationships among tendon water exchanges, mechanical properties, patient symptoms, and tissue injuries. PMID- 27472665 TI - Medically resistant pediatric insular-opercular/perisylvian epilepsy. Part 2: outcome following resective surgery. AB - OBJECTIVE Seizure onset in the insular cortex as a cause of refractory epilepsy is underrepresented in the pediatric population, possibly due to difficulties localizing seizure onset in deep anatomical structures and limited surgical access to the insula, a complex anatomical structure with a rich overlying vascular network. Insular seizure semiology may mimic frontal, temporal, or parietal lobe semiology, resulting in false localization, incomplete resection, and poor outcome. METHODS The authors retrospectively reviewed the records of all pediatric patients who underwent insular cortical resections for intractable epilepsy at Miami Children's Hospital from 2009 to 2015. Presurgical evaluation included video electroencephalography monitoring and anatomical/functional neuroimaging. All patients underwent excisional procedures utilizing intraoperative electrocorticography or extraoperative subdural/depth electrode recording. RESULTS Thirteen children (age range 6 months-16 years) with intractable focal epilepsy underwent insular-opercular resection. Seven children described symptoms that were suggestive of insular seizure origin. Discharges on scalp EEG revealed wide fields. Four patients were MRI negative (i.e., there were no insular or brain abnormalities on MRI), 4 demonstrated insular signal abnormalities, and 5 had extrainsular abnormalities. Ten patients had insular involvement on PET/SPECT. All patients underwent invasive investigation with insular sampling; in 2 patients resection was based on intraoperative electrocorticography, whereas 11 underwent surgery after invasive EEG monitoring with extraoperative monitoring. Four patients required an extended insular resection after a failed initial surgery. Postoperatively, 2 patients had transient hemiplegia. No patients had new permanent neurological deficits. At the most recent follow-up (mean 43.8 months), 9 (69%) children were seizure free and 1 had greater than 90% seizure reduction. CONCLUSIONS Primary insular seizure origin should be considered in children with treatment-resistant focal seizures that are believed to arise within the perisylvian region based on semiology, widespread electrical field on scalp EEG, or insular abnormality on anatomical/functional neuroimaging. There is a reasonable chance of seizure freedom in this group of patients, and the surgical risks are low. PMID- 27472666 TI - Neurological findings in pediatric penetrating head injury at a university teaching hospital in Durban, South Africa: a 23-year retrospective study. AB - OBJECTIVES Penetrating traumatic brain injuries (TBIs) can be divided into gunshot wounds or stab wounds based on the mechanisms of injury. Pediatric penetrating TBIs are of major concern as many parental and social factors may be involved in the causation. The authors describe the penetrating cranial injuries in pediatric patient subgroups at risk and presenting to the Department of Neurosurgery at the University of KwaZulu-Natal, by assessment of the Glasgow Coma Scale (GCS) score and review of the common neurological manifestations including cranial nerve abnormalities. METHODS The authors performed a retrospective chart review of children who presented with penetrating TBIs between 1985 and 2007 at a university teaching hospital. Descriptive statistical analysis with univariate and multivariate logistic regression was used to assess the variables. RESULTS Out of 223 children aged 16 years and younger with penetrating TBIs seen during the study period, stab wounds were causal in 127 (57%) of the patients, while gunshot injuries were causal in 96 (43%). Eighty four percent of the patients were male. Apart from abnormal GCS scores, other neurological abnormalities were noted in 109 (48.9%) of the patients, the most common being cranial nerve deficits (22.4%) and hemiparesis. There was a strong correlation between left-sided stab wounds and development of seizures. The mean age of patients with neurological abnormalities was 11.72 years whereas that of patients with no neurological abnormalities was 8.96 years. CONCLUSIONS Penetrating head injuries in children are not as uncommon as previously thought. There was no correlation between the age group of the patients and the mechanism of injury, which implies that stab or gunshot injuries could occur in any of our pediatric population with the same frequency. While gunshot injuries accounted for 56% of the patient population, stab injuries still accounted for 44%. Following penetrating head injuries, neurological abnormalities tend to occur in the older subgroup of the pediatric patients. The most common neurological abnormalities were hemiparesis followed by cranial nerve deficits. Facial nerve deficits were the most commonly seen cranial nerve abnormality. Immediate convulsions were a significant feature in patients with stab injuries to the head compared to those with gunshot injuries. PMID- 27472667 TI - Medically resistant pediatric insular-opercular/perisylvian epilepsy. Part 1: invasive monitoring using the parasagittal transinsular apex depth electrode. AB - OBJECTIVE Insular lobe epilepsy (ILE) is an under-recognized cause of extratemporal epilepsy and explains some epilepsy surgery failures in children with drug-resistant epilepsy. The diagnosis of ILE usually requires invasive investigation with insular sampling; however, the location of the insula below the opercula and the dense middle cerebral artery vasculature renders its sampling challenging. Several techniques have been described, ranging from open direct placement of orthogonal subpial depth and strip electrodes through a craniotomy to frame-based stereotactic placement of orthogonal or oblique electrodes using stereo-electroencephalography principles. The authors describe an alternative method for sampling the insula, which involves placing insular depth electrodes along the long axis of the insula through the insular apex following dissection of the sylvian fissure in conjunction with subdural electrodes over the lateral hemispheric/opercular region. The authors report the feasibility, advantages, disadvantages, and role of this approach in investigating pediatric insular-opercular refractory epilepsy. METHODS The authors performed a retrospective analysis of all children (< 18 years old) who underwent invasive intracranial studies involving the insula between 2002 and 2015. RESULTS Eleven patients were included in the study (5 boys). The mean age at surgery was 7.6 years (range 0.5-16 years). All patients had drug-resistant epilepsy as defined by the International League Against Epilepsy and underwent comprehensive noninvasive epilepsy surgery workup. Intracranial monitoring was performed in all patients using 1 parasagittal insular electrode (1 patient had 2 electrodes) in addition to subdural grids and strips tailored to the suspected epileptogenic zone. In 10 patients, extraoperative monitoring was used; in 1 patient, intraoperative electrocorticography was used alone without extraoperative monitoring. The mean number of insular contacts was 6.8 (range 4 8), and the mean number of fronto-parieto-temporal hemispheric contacts was 61.7 (range 40-92). There were no complications related to placement of these depth electrodes. All 11 patients underwent subsequent resective surgery involving the insula. CONCLUSIONS Parasagittal transinsular apex depth electrode placement is a feasible alternative to orthogonally placed open or oblique-placed stereotactic methodologies. This method is safe and best suited for suspected unilateral cases with a possible extensive insular-opercular epileptogenic zone. PMID- 27472668 TI - Correlation between intraoperative ultrasound and postoperative MRI in pediatric tumor surgery. AB - OBJECTIVE Malignant disease of the CNS is the primary etiology for deaths resulting from cancer in the pediatric population. It has been well documented that outcomes of pediatric neurosurgery rely on the extent of tumor resection. Therefore, techniques that improve surgical results have significant clinical implications. Intraoperative ultrasound (IOUS) offers real-time surgical guidance and a more accurate means for detecting residual tumor that is inconspicuous to the naked eye. The objective of this study was to evaluate the correlation of extent of resection between IOUS and postoperative MRI. The authors measured the correlation of extent of resection, negative predictive value, and sensitivity of IOUS and compared them with those of MRI. METHODS This study consisted of a retrospective review of the medical charts of all pediatric patients who underwent neurosurgical treatment of a tumor between August 2009 and July 2015 at Albany Medical Center. Included were patients who were aged <= 21 years, who underwent brain or spinal tumor resection, for whom IOUS was used during the tumor resection, and for whom postoperative MRI (with and without contrast) was performed within 1 week of surgery. RESULTS Sixty-two patients met inclusion criteria for the study (33 males, mean age 10.0 years). The IOUS results very significantly correlated with postoperative MRI results (phi = 0.726; p = 0.000000011; negative predictive value 86.3% [95% CI 73.7%-94.3%]). These results exemplify a 71% overall gross-total resection rate and 80% intended gross-total resection rate with the use of IOUS (i.e., excluding cases performed only for debulking purposes). CONCLUSIONS The use of IOUS may play an important role in achieving a greater extent of resection by providing real-time information on tumor volume and location in the setting of brain shift throughout the course of an operation. The authors support the use of IOUS in pediatric CNS tumor surgery to improve clinical outcomes at low cost with minimal additional operating-room time and no identified additional risk. PMID- 27472669 TI - Pediatric occipitocervical fusion: long-term radiographic changes in curvature, growth, and alignment. AB - OBJECTIVE The authors assessed the rate of vertebral growth, curvature, and alignment for multilevel constructs in the cervical spine after occipitocervical fixation (OCF) in pediatric patients and compared these results with those in published reports of growth in normal children. METHODS The authors assessed cervical spine radiographs and CT images of 18 patients who underwent occipitocervical arthrodesis. Measurements were made using postoperative and follow-up images available for 16 patients to determine cervical alignment (cervical spine alignment [CSA], C1-7 sagittal vertical axis [SVA], and C2-7 SVA) and curvature (cervical spine curvature [CSC] and C2-7 lordosis angle). Seventeen patients had postoperative and follow-up images available with which to measure vertebral body height (VBH), vertebral body width (VBW), and vertical growth percentage (VG%-that is, percentage change from postoperative to follow-up). Results for cervical spine growth were compared with normal parameters of 456 patients previously reported on in 2 studies. RESULTS Ten patients were girls and 8 were boys; their mean age was 6.7 +/- 3.2 years. Constructs spanned occiput (Oc)-C2 (n = 2), Oc-C3 (n = 7), and Oc-C4 (n = 9). The mean duration of follow-up was 44.4 months (range 24-101 months). Comparison of postoperative to follow-up measures showed that the mean CSA increased by 1.8 +/- 2.9 mm (p < 0.01); the mean C2-7 SVA and C1-7 SVA increased by 2.3 mm and 2.7 mm, respectively (p = 0.3); the mean CSC changed by -8.7 degrees (p < 0.01) and the mean C2-7 lordosis angle changed by 2.6 degrees (p = 0.5); and the cumulative mean VG% of the instrumented levels (C2-4) provided 51.5% of the total cervical growth (C2-7). The annual vertical growth rate was 4.4 mm/year. The VBW growth from C2-4 ranged from 13.9% to 16.6% (p < 0.001). The VBW of C-2 in instrumented patients appeared to be of a smaller diameter than that of normal patients, especially among those aged 5 to < 10 years and 10-15 years, with an increased diameter at the immediately inferior vertebral bodies compensating for the decreased width. No cervical deformation, malalignment, or detrimental clinical status was evident in any patient. CONCLUSIONS The craniovertebral junction and the upper cervical spine continue to present normal growth, curvature, and alignment parameters in children with OCF constructs spanning a distance as long as Oc-C4. PMID- 27472670 TI - Estimation of direct medical cost related to the management of chronic hepatitis C and its complications in South Korea. AB - BACKGROUND: This study aimed to estimate the direct medical costs of managing chronic hepatitis C (CHC) and its complications based on health-care resources in South Korea. METHODS: The study design was multicenter, retrospective, non interventional, and observational. Between September 2013 and April 2014, health care resource data from patients chronically infected with hepatitis C virus, regardless of genotype, were collected from 8 institutions, including data related to outpatient management, emergency care, and hospitalization. The observation period was between January 2011 and December 2012. The disease state was classified as CHC, compensated cirrhosis (CC), decompensated cirrhosis (DC), or hepatocellular carcinoma (HCC). RESULTS: A total of 445 patients were recruited and mean age was 60.1 +/- 12.3 years. Among 155 patients with reported outcomes of antiviral therapy, 107 (69%) had sustained virologic response (SVR). The rate of patients who did not receive antiviral therapy was 52.8% (n = 235). The distribution of disease state was CHC in 307 patients (69.0%), CC in 75 (16.9%), HCC in 45 (10.1%), and DC in 18 (4.0%). All direct medical costs, whether reimbursed or nonreimbursed by the National Health Insurance System, were included. After excluding patients whose observational period was <1 month for each disease status, the mean costs per month increased as disease state progressed (CHC: 77 +/- 80 USD; CC: 98 +/- 94 USD; DC: 512 +/- 1115 USD; HCC: 504 +/- 717 USD). The mean total costs per person were 3590 +/- 8783 USD, and approximately 72% of patients were reimbursed. When 44 patients with an observation period <1 month were excluded, the mean medical costs per month for patients with CHC who achieved SVR (n = 69) were significantly lower than for those (n = 215) who did not (42 +/- 16 vs 79 +/- 83 USD, P < 0.001). The cost also tended to be lower for patients with CC with SVR (n = 8) than for those without SVR (n = 70; 48 +/- 20 vs 95 +/- 96 USD, P = 0.177). The cost of antiviral therapy (pegylated interferon and ribavirin) corresponded to 19.0% of total medical costs and 53.7% of prescription/pharmacy. CONCLUSION: The direct medical costs increased as disease state progressed from CHC to cirrhosis or HCC. The achievement of SVR by antiviral therapy would decrease the costs. PMID- 27472672 TI - Accuracy of endoscopic ultrasonography for diagnosing ulcerative early gastric cancers. AB - Although endoscopic ultrasonography (EUS) is the first-choice imaging modality for predicting the invasion depth of early gastric cancer (EGC), the prediction accuracy of EUS is significantly decreased when EGC is combined with ulceration.The aim of present study was to compare the accuracy of EUS and conventional endoscopy (CE) for determining the depth of EGC. In addition, the various clinic-pathologic factors affecting the diagnostic accuracy of EUS, with a particular focus on endoscopic ulcer shapes, were evaluated.We retrospectively reviewed data from 236 consecutive patients with ulcerative EGC. All patients underwent EUS for estimating tumor invasion depth, followed by either curative surgery or endoscopic treatment. The diagnostic accuracy of EUS and CE was evaluated by comparing the final histologic result of resected specimen. The correlation between accuracy of EUS and characteristics of EGC (tumor size, histology, location in stomach, tumor invasion depth, and endoscopic ulcer shapes) was analyzed. Endoscopic ulcer shapes were classified into 3 groups: definite ulcer, superficial ulcer, and ill-defined ulcer.The overall accuracy of EUS and CE for predicting the invasion depth in ulcerative EGC was 68.6% and 55.5%, respectively. Of the 236 patients, 36 patients were classified as definite ulcers, 98 were superficial ulcers, and 102 were ill-defined ulcers, In univariate analysis, EUS accuracy was associated with invasion depth (P = 0.023), tumor size (P = 0.034), and endoscopic ulcer shapes (P = 0.001). In multivariate analysis, there is a significant association between superficial ulcer in CE and EUS accuracy (odds ratio: 2.977; 95% confidence interval: 1.255-7.064; P = 0.013).The accuracy of EUS for determining tumor invasion depth in ulcerative EGC was superior to that of CE. In addition, ulcer shape was an important factor that affected EUS accuracy. PMID- 27472671 TI - Renal denervation, adjusted drugs, or combined therapy for resistant hypertension: A meta-regression. AB - The objective of this study is to systematically evaluate the efficacy of renal denervation (RD), adjusted drugs, or combined therapy for resistant hypertension (RH) through a systematic review and meta-analysis of controlled studies.Publications were comprehensively searched. Studies that investigated the effects of RD and/or adjusted drugs in lowering blood pressure (BP) were included. After quality assessment and data extraction, subgroup analyzes were first performed according to blinding method. Meta-regression and inverted funnel plots were also conducted.A total of 13 studies containing 1604 RH patients were included. Compared with control, the meta-analysis showed that RD significantly reduced office-based BP and ambulatory BP in 6 months in the unblinded studies, while no significant difference was found in the blinded studies. Meta-regression demonstrated the significant influence of blinding method on BP reduction, and further analysis revealed a significant BP reduction compared with baseline even in the control arm of blinded studies. RD had similar effects compared with adjusted drugs, and combined therapy seemed to further reduce the level of BP.The efficacy of RD was different between blinded and unblinded studies, and our data revealed a significant BP-lowering effect in the control arm of blinded studies, which was helpful to explain this finding. Furthermore, RD seemed to be equivalent to adjusted drugs, and also we suggested a potential advantage of combined therapy of RD and adjusted drugs compared with monotherapy for RH. However, more studies are warranted to better address the issue. PMID- 27472674 TI - Comparison of the prognostic values of the 2010 WHO classification, AJCC 7th edition, and ENETS classification of gastric neuroendocrine tumors. AB - The ability of the European Neuroendocrine Tumor Society (ENETS) system, 2010 World Health Organization (WHO) grading system, and American Joint Committee on Cancer (AJCC) staging system to predict survival after gastric neuroendocrine tumor (NET) resection has not yet been validated.We retrospectively evaluated 175 gastric NETs from 1996 to 2014. WHO grade 3 (G3) patients (n = 66) had a lower survival rate than grade 1 (G1) (n = 39) or grade 2 (G2) (n = 13) patients, with similar high survival rates for G1 and G2 patients. G3 patients had a lower survival rate than mixed-type patients (n = 57). Using the AJCC classification, most of the G1/2 NETs (86.6%) were confined to T1/T2, N0 tumor, and stage I/IIa, but the survival rate was not well distributed. In contrast, G3/mixed tumors were well distributed in terms of T, N, stage, and survival. Using the ENETS classification, 64.6% of the tumors were T2 and only 8.6% were T3. In addition, 49.7% were stage IIIb and only 1.9% was IIa, with poor survival distribution.Our findings strongly suggested that the WHO and ENETS classification systems have shown a low prognostic value. The AJCC TNM system showed a low prognostic value for well-differentiated NETs (G1 or G2). In contrast, the AJCC TNM system had a high prognostic value for G3 or mixed tumors. PMID- 27472673 TI - Discriminative analysis of schizophrenia using support vector machine and recursive feature elimination on structural MRI images. AB - Structural abnormalities in schizophrenia (SZ) patients have been well documented with structural magnetic resonance imaging (MRI) data using voxel-based morphometry (VBM) and region of interest (ROI) analyses. However, these analyses can only detect group-wise differences and thus, have a poor predictive value for individuals. In the present study, we applied a machine learning method that combined support vector machine (SVM) with recursive feature elimination (RFE) to discriminate SZ patients from normal controls (NCs) using their structural MRI data. We first employed both VBM and ROI analyses to compare gray matter volume (GMV) and white matter volume (WMV) between 41 SZ patients and 42 age- and sex matched NCs. The method of SVM combined with RFE was used to discriminate SZ patients from NCs using significant between-group differences in both GMV and WMV as input features. We found that SZ patients showed GM and WM abnormalities in several brain structures primarily involved in the emotion, memory, and visual systems. An SVM with a RFE classifier using the significant structural abnormalities identified by the VBM analysis as input features achieved the best performance (an accuracy of 88.4%, a sensitivity of 91.9%, and a specificity of 84.4%) in the discriminative analyses of SZ patients. These results suggested that distinct neuroanatomical profiles associated with SZ patients might provide a potential biomarker for disease diagnosis, and machine-learning methods can reveal neurobiological mechanisms in psychiatric diseases. PMID- 27472675 TI - Migraine and breast cancer risk: a meta-analysis of observational studies based on MOOSE compliant. AB - It has long been speculated that migraine may contribute to an increased risk of breast cancer; however, results from previous studies have been inconclusive. To definitively interrogate this issue, we performed a meta-analysis to assess the correlation between these 2 diseases.Medline and PubMed were searched to identify relevant studies that had been published until October 2015. Based on a random effects model, relative risk (RR) and the corresponding 95% confidence interval (CI) were used to evaluate the pooled risk.A total of 7 studies involving 17,776 cases and 162,954 participants were included. Our study revealed that there was an inverse relationship between migraine and total breast cancer risk, with RR (95%CI) was 0.78 (0.66, 0.92). In subgroup-analysis, such an inverse relationship was also identified in the ductal and lobular carcinoma, case-control studies, and the ER/PR breast cancer. Little evidence indicative of a publication bias was uncovered.In conclusion, our study implicates a statistically significant inverse association between migraine and the risk of breast cancer. However, larger prospective cohort studies concerning other geographic populations to assess the association between migraine and the breast cancer risk are warranted. PMID- 27472676 TI - Reduced local diffusion homogeneity as a biomarker for temporal lobe epilepsy. AB - In the present study, we adopted a novel method-local diffusion homogeneity (LDH) to characterize the structure feature in mesial temporal lobe epilepsy (MTLE). Diffusion-weighted images were acquired from 11 left MTLE patients, 16 right MTLE patients, and 20 healthy controls from May 2014 to January 2015. Local diffusion homogeneity was compared among patient groups and controls by 2 sample t test. The discriminative value of LDH abnormalities was examined by receiver operating characteristic (ROC) curve analysis. Correlations with disease duration and onset age in both patient groups were assessed using Pearson's coefficient. Both patient groups exhibited lower LDH in the anterior corpus callosum (P < 0.05, corrected), and this regional anomaly exhibited excellent classification performance in left MTLE patients (sensitivity = 82%, specificity = 100%), right MTLE patients (sensitivity = 81%, specificity = 90%), and the entire patient cohort (sensitivity = 82%, specificity = 95%). In summary, left and right MTLE patients show common pathological changes in the anterior corpus callosum. This regional LDH abnormality is a potential quantitative biomarker for MTLE. PMID- 27472677 TI - Increased risk of herpes zoster in children with cancer: A nationwide population based cohort study. AB - Herpes zoster is rare in healthy children, but immunocompromised persons have an increased risk of herpes zoster and severe diseases. Considering the very limited information on herpes zoster in children with cancer, we performed a nationwide population-based cohort study to estimate the incidence of herpes zoster in children with cancer and to explore the association between the 2 diseases.Data were obtained from the National Health Research Institutes Database in Taiwan. A total of 4432 children with newly diagnosed cancer between 2000 and 2007 were identified as the cancer cohort, and 17,653 children without cancer frequency matched by sex and age at entry were considered the noncancer cohort. The association between herpes zoster and childhood cancer was determined.Children with cancer had a higher risk of herpes zoster. The incidence rate of herpes zoster was higher in the cancer cohort than in the noncancer cohort (20.7 vs 2.4 per 10,000 person-years; IRR = 8.6; 95% CI = 4.8-15.6). The cumulative incidence was significantly higher in the cancer cohort (P < 0.0001). Leukemia, lymphoma, and solid tumor were all associated with the increased risk, and leukemia had the highest magnitude of strength of association.This nationwide population-based cohort study demonstrated that children with cancer were associated with an increased risk of herpes zoster. In addition to early antiviral treatment, vaccination with heat-treated zoster vaccine or adjuvanted subunit vaccine could be an appropriate policy to decrease the incidence in children with cancer. PMID- 27472678 TI - Serum lipocalin-2 levels are positively associated with not only total body fat but also visceral fat area in Chinese men. AB - Serum lipocalin-2 (LCN2) plays an important role in the regulation of the obesity associated dysmetabolic state and cardiovascular disease. However, relatively little is known about the relationship between serum LCN2 levels and body fat content and distribution. We examined the associations of total body fat content and abdominal fat distribution with serum LCN2 levels in Chinese men.The study was based on a cross-sectional analysis of data for 1203 Chinese men aged 22 to 78 years from the Shanghai Obesity Study. Body fat percentage (fat%) was assessed by bioelectrical impedance analysis, and magnetic resonance imaging was adopted to quantify the visceral fat area (VFA) and subcutaneous fat area (SFA). Serum levels of LCN2 were measured with a standard enzyme-linked immunosorbent assay method.Subjects with a high fat% had higher serum LCN2 levels than those with a normal fat% regardless of their body mass index category (<25 and >=25 kg/m). The frequency of isolated high VFA was increased with increasing quintiles of serum LCN2 levels (P < 0.001), but the frequency of isolated high SFA did not differ between quintiles of serum LCN2 levels. A trend of increasing VFA was observed with increasing serum LCN2 levels (P < 0.001). Multiple stepwise regression analysis showed that VFA was positively associated with serum LCN2 levels, independent of overall obesity and other confounding factors (standardized beta = 0.082, P = 0.008).Serum LCN2 levels are positively correlated with body fat content and independently associated with VFA in Chinese men. PMID- 27472679 TI - Clinical efficacy maintains patients' positive attitudes toward fecal microbiota transplantation. AB - Few studies have been conducted on the attitudes of patients seeking fecal microbiota transplantation (FMT). This study aimed to investigate the reasons for patients with Crohn's disease (CD) seeking FMT and their attitude changes after FMT.In this prospective study, all included patients were diagnosed with CD for at least 6 months and intended to receive FMT. A questionnaire was designed to investigate the history of medical visits and patients' attitudes toward FMT. Only refractory patients who failed to clinically respond to previous treatment were selected for undergoing FMT. Three months after the first FMT, patients were required to complete the second questionnaire on attitudes toward the first FMT.A total of 207 patients with CD were included for questionnaire survey. In 118 refractory patients, 94.07% sought FMT because they had no other choice. In 89 nonrefractory patients, 78.65% sought FMT for the reason that they wanted to achieve better clinical results or even a cure, although the current treatment was effective for them. In all, 118 refractory patients received FMT. Three months after the first FMT, 88.98% (105/118) patients completed the questionnaire on patients' attitudes toward FMT. Of these 105 patients, 56.19% reported to have satisfactory clinical efficacy and 74.29% were willing to receive the second FMT. Moreover, 89.52% (94/105) showed their willingness to recommend FMT to other patients.In conclusion, this study at least first time demonstrated that patients with CD were willing to accept FMT due to its efficacy. PMID- 27472680 TI - Treatment efficacy of anti-hypertensive drugs in monotherapy or combination: ATOM systematic review and meta-analysis of randomized clinical trials according to PRISMA statement. AB - BACKGROUND: The relative efficacy of antihypertensive drugs/combinations is not well known. Identifying the most effective ones and the patients' characteristics associated with best performance of the drugs will improve management of hypertensive patients. OBJECTIVE: To assess the blood pressure (BP) reduction attributed to antihypertensive drugs and identify characteristics associated with BP decrease. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials from inception through July 2012 and selected papers. STUDY ELIGIBILITY CRITERIA: Double-blind, randomized clinical trials whose main result was the reduction in BP by antihypertensive treatment, with study population >=50 or >=25 if the study was a crossover, follow-up of at least 8 weeks, and available required data. STUDY APPRAISAL AND SYNTHESIS METHODS: Study data were independently extracted by multiple observers and introduced in an electronic database. Inconsistencies were resolved by discussion and referral back to the original articles. Meta-analysis was performed according to PRISMA statement and using a Bayesian framework. MAIN OUTCOME(S) AND MEASURE(S): Mean decrease in systolic (SBP) and diastolic blood pressure (DBP) achieved by each drug or combination. RESULTS: Two hundred eight trials including 94,305 patients were identified. In monotherapy, most drugs achieved 10 to 15 mm Hg SBP and 8 to 10 mm Hg DBP decreases.Olmesartan/amlodipine, olmesartan/hydrochlorothiazide, felodipine/metoprolol, and valsartan/hydrochlorothiazide were the combinations leading to the greatest mean SBP reductions (>20 mm Hg). Female sex and body mass index >25 kg/m were associated with more pronounced SBP and DBP reductions, whereas Afro-American ethnicity was associated with BP reductions smaller than the median. Results were adjusted by study duration, cardiovascular disease, and diabetes mellitus. Still, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats. LIMITATIONS: Data corresponded to those obtained in each of the included trials; the analysis of the combinations was limited to the most recent ones; estimations were performed using the mean administered doses. CONCLUSIONS AND IMPLICATIONS: Certain drug combinations achieve BP reductions ranging from 20 to 25/10 to 15 mm Hg. Sex, ethnicity, and obesity are associated with antihypertensive response. This information can contribute to better selection of the antihypertensive drug, depending on the magnitude of pretreatment BP elevation. Guidelines should be revised. PMID- 27472681 TI - Multiple epithelioid hemangioedothelioma of the skull in a child: A case report. AB - INTRODUCTION: Epithelioid hemangioedothelioma (EHE) is a rare vascular tumor characterized by neoplastic proliferation of epithelioid or histiocytoid epithelial cells. EHE of bone constitutes <1% of primary malignant bone tumor. EHE in the skull is an extremely rare case. Here, we report a case of multiple neoplasm of the skull in a 15-month-old boy who presented with gradual facial swelling for 2 months. On computed tomography (CT) scan, multiple irregular osteolytic lesions were seen on the right maxillary, sphenoid, left zygoma, and roof of the left orbit. Excisional surgery of the lesion was planned. Histopathological and immunohistochemical examination of excised specimen suggest it to be epithelioid hemangioedothelioma. Follow-up for 6 months showed no recurrence. CONCLUSION: Epithelioid hemangioedothelioma is a locally aggressive tumor with metastatic potential. CT imaging could help in assessment of lesion, but final diagnosis is possible only with histopathology. Complete surgical resection at the early stage of the disease is the most effective treatment with better prognosis. PMID- 27472683 TI - Approach an appropriate decision on fetus with endocardial fibroelastosis in collaboration with cardiovascular profile score: A case report. AB - INTRODUCTION: Fetal endocardial fibroelastosis (EFE) is a kind of rare fetal cardiac malformation characterized by the diffuse thickening of the ventricular endocardium. The diagnosis of fetal EFE depends on the echocardiographic features which are still confused that how to make an appropriate pregnant decision due to the conflict between high prenatal mortality and acceptable prognosis once after birth. Here, we seriously built a 4-gradation recommendation system based on cardiovascular profile score (CVPS) to supply a prediction of clarified pregnant outcomes with EFE and provide a practical way to offer optimal medical consultation. CLINICAL PROCEDURE: A suspected case of fetal EFE has been aware at 24th gestational week by fetal echocardiography. The CVPS of this affected fetus dropped to 6 out of 10 points, which indicated a severe heart condition along with the fetus and predicted an adverse fetal prognosis according to our recommendation system. After fully informed consent, the prospective parents determined to terminate pregnancy. Following the induced abortion, postmortem pathological findings confirmed the echocardiographic suspicion of EFE. CONCLUSION: According to our experience and previous researches, we could reach a relative clear prediction of the outcomes of the EFE fetuses based on the CVPS of such suspected fetuses, which should lead to approach an appropriate pregnant decision for such fetuses. PMID- 27472682 TI - Early-onset status epilepticus in patients with acute encephalitis. AB - Status epilepticus (SE) is a common complication of acute encephalitis, but its determinants and prognostic value in this setting are not known.Risk factors for early-onset SE (within 48 hours of intensive care unit [ICU] admission) in consecutive adult patients with all-cause encephalitis admitted to the medical ICU of a university hospital (1991-2013) were evaluated by multivariate logistic regression analysis. To examine the prognostic value of SE, patients were classified into 3 groups: no SE, nonrefractory SE (NRSE), and refractory SE (RSE). Poor neurologic outcome was defined by a modified Rankin score of 4 to 6.Among the 290 patients, 58 (20%, 95% CI: 15%-25%) developed early-onset SE, comprising 44 patients with NRSE and 14 patients with RSE. Coma (adjusted odds ratio [OR]: 3.1, 95% CI: 1.5-6.3), cortical lesions on neuroimaging (adjusted OR: 3.7, 95% CI: 1.8-7.8), and nonneurologic organ failure(s) (adjusted OR: 13.6, 95% CI: 4.9-37.7) were found to be independent risk factors for SE. By contrast, a bacterial etiology had a protective effect (adjusted OR: 0.3, 95% CI: 0.1-0.7). Age, body temperature, and blood sodium levels were not independently associated with SE. Poor neurologic outcomes were observed at day 90 in respectively 23% (95% CI: 17%-28%), 23% (95% CI: 10%-35%), and 71% (95% CI: 48%-95%) of no SE, NRSE, and RSE patients (P < 0.01). After adjusting for confounders, RSE, but not NRSE, remained independently associated with 90-day mortality (adjusted OR: 6.0, 95% CI: 1.5-23.3).Coma, cortical involvement on neuroimaging, and nonneurologic organ failure(s) are independent risk factors for SE in patients with acute encephalitis. Conversely, a bacterial etiology is associated with a lower risk of SE.These findings may help identify patients who may benefit from prophylactic antiepileptic drugs. PMID- 27472684 TI - Positron emission tomography and computed tomography angiography for the diagnosis of giant cell arteritis: A real-life prospective study. AB - The use of 18F-fluoro-deoxyglucose positron emission tomography scan (FDG-PET) and computed tomography angiography (CTA) to improve accuracy of diagnosis of giant cell arteritis (GCA) is a very important clinical need. We aimed to compare the diagnostic performance of FDG-PET and CTA in patients with GCA.FDG-PET and CTA were acquired in all consecutive patients suspected for GCA. Results of FDG PET and CTA were compared with the final diagnosis based on clinical judgment, temporal artery biopsy (TAB) findings, and ACR criteria. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each method.Twenty-four patients suspected for GCA were included. Fifteen (62.5%) were ultimately diagnosed as having GCA. Among them, all fulfilled ACR criteria and 6 had biopsy-proven GCA. Strong FDG uptake in large vessels was found in 10 patients who all had GCA. Mean maximal standard uptake values (SUVmax) per patient measured at all the arterial territories were of 3.7 (range: 2.8-4.7). FDG uptake was negative in 14 patients including 9 and 5 patients without and with GCA, respectively. Mural thickening suggestive of aortitis or branch vessel arteritis was observed on CTA in 11 patients with and 2 patients without GCA. No mural thickening was observed in 11 patients including 7 patients without and 4 patients with GCA. Overall, sensitivity was 66.7% and 73.3%, specificity was 100% and 84.6%, NPV was 64.3% and 64.6%, and PPV was 100% and 84.6% of FDG-PET and CTA, respectively.Both FDG-PET and CTA have a strong diagnostic yield for the diagnosis of GCA. FDG-PET appeared to have a higher PPV as compared to CTA and may be the preferred noninvasive technique to explore patients with suspected GCA. PMID- 27472685 TI - Postoperative aspartate aminotransferase to platelet ratio index change predicts prognosis for hepatocellular carcinoma. AB - An elevated preoperative aspartate aminotransferase (AST) to platelet ratio index (APRI) is reported to be a prognostic factor for patients with hepatocellular carcinoma (HCC) after treatment. However, delta APRI (DeltaAPRI), which represents the change from preoperative to postoperative APRI, has received little attention. The present study was designed to evaluate the prognostic value of DeltaAPRI in patients with small HCC after liver resection.A retrospective cohort study analyzing 244 patients with small HCC who had undergone liver resection was conducted. Medical data were retrieved from our prospectively maintained database. Patients were divided into 2 groups according to DeltaAPRI as follows: group A (DeltaAPRI >=0.02) and group B (DeltaAPRI <0.02). The association of demographic and clinical data, overall survival (OS), and recurrence-free survival (RFS) were statistically compared in the 2 groups, and a multivariate analysis was used to identify prognostic factors.The 1, 3, and 5 year OS of patients in group A were 94.2%, 79.5%, and 62.3%, respectively, and 95.1%, 87.9%, and 84.6%, respectively, for patients in group B (P = 0.001). The corresponding 1, 3, and 5-year RFS was 69.0%, 44.7 %, and 28.1%, and 77.4%, 57.0%, and 54.2% for patients in the 2 groups, respectively (P = 0.009). The results of a multivariate analysis indicated that DeltaAPRI was an independent prognostic factor for both OS (P = 0.001, hazard ratio 3.115, 95% confidence interval 1.642-5.912) and RFS (P = 0.006, hazard ratio 1.689, 95% confidence interval 1.163-2.452).A positive DeltaAPRI after liver resection predicts decreased OS and RFS in patients with small HCC. PMID- 27472686 TI - Hand-carried ultrasound use in clinical nephrology: Case report. AB - BACKGROUND: Correctly assessing and managing volume status are critical elements of daily care for patients managed by nephrologists. However, intravascular volume is difficult to assess by physical examination alone. METHODS: We present vignettes illustrating the potential for using hand-carried ultrasound (HCU) to improve volume assessment in common clinical scenarios faced by the renal consultant in the hospital setting. These include patients with acute kidney injury and patients treated with hemodialysis. RESULTS: We used HCU to provide essential information about volume status which is otherwise not readily available. HCU allowed objective assessment of volume status, helping with clinical management of hospitalized patients and potentially avoiding harm. CONCLUSION: HCU can complement physical examination for volume assessment in hospitalized patients with acute kidney injury or those on hemodialysis. Our report highlights the need for systematic research in this area. PMID- 27472687 TI - The outcome and prognostic factors of 248 elderly patients with acute myeloid leukemia treated with standard-dose or low-intensity induction therapy. AB - The prognosis of elderly patients with acute myeloid leukemia (AML) is poor, and the recommendation of standard-dose or low-intensity induction regimen for these patients remains controversial. We retrospectively analyzed treatment outcome and prognostic factors of elderly AML patients who had received either standard-dose or low-intensity induction regimens.Two hundred forty-eight elderly AML patients with good Eastern Cooperative Oncology Group performance status (ECOG PS <= 2) received one of three regimens for induction in this study: standard-dose cytarabine plus idarubicin (IA; n = 144) or daunorubicin (DA; n = 42); low intensity cytarabine, aclarubicin, and granulocyte colony-stimulating factor (G CSF) (CAG; n = 62).After first induction treatment cycle, the overall complete remission (CR) rate was 42.7%. Patients in IA group had a higher CR rate than in DA or CAG group (49.3%, 35.7%, and 32.3%, respectively; P = 0.046). The 1-year, 3 year, and 5-year overall survival (OS) rates were 42.2%, 18.9%, and 13.5% for these 248 patients, with median survival of 9.2 months. Long-term survival of IA group was better than DA or CAG group. The 1-year, 3-year, and 5-year OS rates of IA group were 45.9%, 23.5%, and 19.4%, respectively, as compared to 39.8%, 8.3%, and estimated 2.4% in DA group, and 34.9%, 15.9%, and 6.3% in CAG group, respectively. Early induction mortality and 2-year relapse rates showed no difference among 3 groups. Univariate analysis and multivariate analysis identified lactic dehydrogenase (LDH) more than two times of upper normal limit at diagnosis and nonremission after first induction cycle as adverse prognostic factors for OS. A simple and valid scoring model was constructed for risk stratification and prediction of long-term survival of elderly AML patients.Standard-dose IA regimen could improve the prognosis of elderly AML patients with good performance status compared with standard-dose DA or low intensity CAG regimen. All prognostic factors and risk assessment should be considered to ensure that each patient receives the suitable individualized treatment. PMID- 27472688 TI - Selective reoperation after primary resection as a feasible and safe treatment strategy for recurrent pancreatic cancer. AB - Local recurrence frequently occurs in patients with pancreatic cancer after intended curative resections. However, no treatment strategies have been established for isolated local recurrence. Several series have demonstrated a survival benefit for reoperation in selected pancreatic recurrence cases. This study compares the difference in overall survival (OS) between surgery and nonsurgery groups in recurrent pancreatic cancer.All patients from 1990 to 2014 with recurrent pancreatic cancer who underwent curative resections were investigated and retrospectively reviewed. Clinicopathological features and OS were compared.A total of 332 patients were recruited in this series. The majority had histologically pancreatic adenocarcinoma (289 patients, 87.0%). Fourteen of 332 patients (4.2%) with recurrent pancreatic cancer received subsequent resection. Most of these patients underwent curative surgery (R0 resection, 13 patients, 92.9%), and only 1 patient (7.1%) had microscopic residual tumor (R1 resection). Disease-free survival (DFS), OS, and postrecurrence survival (PRS) were all significantly longer in the surgery group (DFS 10.6 vs 6.1 months, P = 0.044; OS 57.8 vs 14.0 months, P < 0.001; PRS 14.1 vs 6.0 months, P < 0.001). The median survival times were comparable in patients with recurrent pancreatic adenocarcinoma who received surgery and those who did not (DFS 10.6 vs 6.1 months, P = 0.226; OS 23.7 vs 14.0 months, P = 0.074; PRS 8.9 vs 5.8 months, P = 0.183). However, the OS and PRS were superior in the patients who did not display adenocarcinoma histologically but underwent operation for recurrence (OS 97.2 vs 16.9 months, P = 0.016; PRS 65.7 vs 6.9 months, P = 0.010). Notably, DFS levels were similar (16.0 vs 7.0 months, P = 0.265).Surgery can feasibly and safely provide survival benefits in selective recurrent pancreatic cancer. In patients who are histologically negative for adenocarcinoma, survival is prolonged when the operation is performed with R0 resection. Patients with isolated recurrent pancreatic adenocarcinoma need multidisciplinary therapy. In addition to operation, chemoradiotherapy and intraoperative radiotherapy may also be considered; their roles should be further investigated. PMID- 27472689 TI - Understanding the diagnostic yield of current endoscopic biopsy for gastric neoplasm: A prospective single-center analysis based on tumor characteristics stratified by biopsy number and site. AB - Although there are general guidelines on endoscopic biopsy for diagnosing gastric neoplasms, they are predominantly based on outdated literature obtained with fiberscopes without analyses specific to tumor characteristics.This study aims to comprehensively characterize the contemporary endoscopic biopsy by determining the diagnostic yield across different lesion morphologies and histological stages, especially exploring how the number and site of biopsy may influence the overall yield.Biopsy samples from suspected gastric neoplasms were collected prospectively from May 2011 to August 2014 in a tertiary care medical center. A standardized methodology was used to obtain a total of 6 specimens from 2 defined sites per lesion. Rate of positive diagnosis based on the biopsy number and site was assessed for specific gastric lesion morphologies and histological stages.A total of 1080 biopsies from 180 pathologically diagnosed neoplastic lesions in 176 patients were obtained during the study. For depressed/ulcerative and polypoid lesions, the yield was already >99% by the fourth biopsy without further gain from additional biopsies. Lower overall yield was observed for infiltrative lesions (57.1% from 4 biopsies). The site of biopsy did not influence the diagnostic yield except for with infiltrative lesions in which biopsies from thickened mucosal folds were of higher yield than erosive regions.Obtaining 4 specimens may be sufficient for accurate diagnosis of a depressed/ulcerative or polypoid gastric lesion regardless of its histological stage. For infiltrative lesions, at least 5 to 6 biopsies per lesion with more representative sampling from thickened mucosal folds may be preferable. PMID- 27472690 TI - Risk factors of gender for renal progression in patients with early chronic kidney disease. AB - Risk factors for chronic kidney disease (CKD), such as hypertension, hyperglycemia, albuminuria, renal structure, and sex hormones, have been reported to have different effects on males and females. Thus, CKD progression may differ depending on sex. In addition to CKD management, treatment at earlier stages can reduce complications and prevent disease progression as well as high medical expenses at late stages. We examined the differences in predictive risk factors for renal progression between male and female patients with early CKD.This case cohort study recruited patients aged 18 years or older treated in the outpatient departments of 8 hospitals in Taiwan between August 2008 and September 2014. In total, 1530 patients were included in the analysis. Renal progression was defined as >=25% decline based on baseline estimated glomerular filtration rate. To examine the predictive risk factors for renal progression, we constructed a subset multivariate logistic model with stepwise variable selection by using P < 0.10 for variable retention.The numbers of male and female patients with CKD exhibiting renal progression were 100 (11.64%) and 84 (12.52%), respectively. After adjusting for all the potential confounders, stepwise logistic regression analysis showed that main independent predictive risk factors for the male patients- (C statistic = 0.72) were proteinuria (odds ratio [OR] 2.20; 95% confidence interval [CI] 1.26-3.84), age (OR 1.04; 95% CI 1.02-1.06), anemia (OR 2.75; 95% CI 1.20-6.30), and poor control of blood pressure (OR 1.84; 95% CI 1.05 3.22). However, the main independent predictive factors for the female patients were (C statistic = 0.75) poor glycemic control (OR 2.28; 95% CI 1.22-4.25), poor blood pressure control (OR 1.93; 95% CI 1.06-3.50), and family income (OR 2.51; 95% CI 1.01-6.20).In conclusion, this study demonstrated that proteinuria was the most crucial risk factor for male patients, whereas poor glycemic control was the main risk factor for female patients. Poor blood pressure control was a shared risk factor for male and female patients. PMID- 27472691 TI - Estimating the rate of retinal ganglion cell loss to detect glaucoma progression: An observational cohort study. AB - This study aimed to evaluate the relationship between glaucoma progression and estimates of the retinal ganglion cells (RGCs) obtained by combining structural and functional measurements in patients with glaucoma.In the present observational cohort study, we examined 116 eyes of 62 glaucoma patients. Using Cirrus optical coherence tomography (OCT), a minimum of 5 serial retinal nerve fiber layer (RNFL) measurements were performed in all eyes. There was a 3-year separation between the first and last measurements. Visual field (VF) testing was performed on the same day as the RNFL imaging using the Swedish Interactive Threshold Algorithm Standard 30-2 program of the Humphrey Field Analyzer. Estimates of the RGC counts were obtained from standard automated perimetry (SAP) and OCT, with a weighted average then used to determine a final estimate of the number of RGCs for each eye. Linear regression was used to calculate the rate of the RGC loss, and trend analysis was used to evaluate both serial RNFL thicknesses and VF progression.Use of the average RNFL thickness parameter of OCT led to detection of progression in 14 of 116 eyes examined, whereas the mean deviation slope detected progression in 31 eyes. When the rates of RGC loss were used, progression was detected in 41 of the 116 eyes, with a mean rate of RGC loss of -28,260 +/- 8110 cells/year.Estimation of the rate of RGC loss by combining structural and functional measurements resulted in better detection of glaucoma progression compared to either OCT or SAP. PMID- 27472692 TI - Risk factors for cardiac events in patients with Brugada syndrome: A PRISMA compliant meta-analysis and systematic review. AB - INTRODUCTION: Inconsistent results have been reported about the risk stratification of patients with Brugada syndrome. We have summarized the evidence regarding the strength of association between 6 risk factors (family history of sudden cardiac death [SCD] or syncope, inducible ventricular arrhythmias on electrophysiology study [EPS], spontaneous type 1 Brugada electrocardiogram [ECG], male sex, family history of SCD, and sodium voltage-gated channel alpha subunit 5 [SCN5A] gene mutation) and subsequent cardiac events in Brugada syndrome patients. METHODS: Pubmed, Ovid, Embase, and the Cochrane Library were searched for studies published between January 1992 and March 2016. Only prospective studies (27 studies, 4494 patients) that reported estimates with 95% confidence intervals (CIs) of cardiac events for the 6 risk factors were included. RESULTS: Family history of SCD or syncope (risk ratio [RR] 4.97, 95% CI 3.96-6.23, P < 0.001), inducible ventricular arrhythmia on EPS (RR 3.56, 95% CI 1.30-9.74, P = 0.01), and spontaneous type 1 Brugada ECG (RR 4.07, 95% CI 2.23 7.41, P < 0.001) were associated with an increased risk of future cardiac events. Spontaneous type 1 Brugada ECG was associated with an elevated risk of future cardiac events in patients without a family history of SCD. CONCLUSIONS: Inducible ventricular arrhythmias on EPS, spontaneous type 1 Brugada ECG, and family history of SCD or syncope indicate a high risk of future cardiac events in patients with Brugada syndrome. Spontaneous type 1 Brugada ECG significantly increased the risk of future cardiac events in patients without family history of SCD. PMID- 27472693 TI - Response to crizotinib in a lung adenocarcinoma patient harboring EML4-ALK translocation with adnexal metastasis: A Case Report. AB - BACKGROUND: Lung cancer with ovarian metastasis or adnexal metastasis harboring anaplastic lymphoma kinase (ALK) gene translocation is rare. Crizotinib, a novel ALK tyrosine kinase inhibitor, has already shown an impressive single-agent activity in ALK positive lung cancer. METHODS: To summarize the case of clinical data and treatment of a 33-year-old woman with pelvic adnexal metastasis NSCLC. RESULTS: Histological examination of the tumors showed lung adenocarcinoma. The right lung biopsy tissue and left adnexal mass biopsy tissue both revealed the presence of an ALK rearrangement by Ventana (D5F3) ALK immunohistochemistry assay (Ventana Medical Systems, Roche, Inc., Tuscon, AZ). The patient experienced a remarkable tumor response to crizotinib treatment. CONCLUSION: Although the adnexal location is an uncommon metastasis site from lung cancer, oncologists should be aware of the possibility of such metastasis for female patients with ALK rearrangement NSCLC. Considering this remarkable response, we conclude that the presence of adnexal metastasis in NSCLC patients with ALK rearrangement should be attentive. PMID- 27472694 TI - Altered directional connectivity between emotion network and motor network in Parkinson's disease with depression. AB - Depression is common in patients with Parkinson's disease (PD), which can make all the other symptoms of PD much worse. It is thus urgent to differentiate depressed PD (DPD) patients from non-depressed PD (NDPD).The purpose of the present study was to characterize alterations in directional brain connectivity unique to Parkinson's disease with depression, using resting state functional magnetic resonance imaging (rs-fMRI).Sixteen DPD patients, 20 NDPD patients, 17 patients with major depressive disorder (MDD) and 21 healthy control subjects (normal controls [NC]) underwent structural MRI and rs-fMRI scanning. Voxel-based morphometry and directional brain connectivity during resting-state were analyzed. Analysis of variance (ANOVA) and 2-sample t tests were used to compare each pair of groups, using sex, age, education level, structural atrophy, and/or HAMD, unified PD rating scale (UPDRS) as covariates.In contrast to NC, DPD showed significant gray matter (GM) volume abnormalities in some mid-line limbic regions including dorsomedial prefrontal cortex and precuneus, and sub-cortical regions including caudate and cerebellum. Relative to NC and MDD, both DPD and NDPD showed significantly increased directional connectivity from bilateral anterior insula and posterior orbitofrontal cortices to left inferior temporal cortex. As compared with NC, MDD and NDPD, alterations of directional connectivity in DPD were specifically observed in the pathway from bilateral anterior insula and posterior orbitofrontal cortices to right basal ganglia.Resting state directional connectivity alterations were observed between emotion network and motor network in DPD patients after controlling for age, sex, structural atrophy. Given that these alterations are unique to DPD, it may provide a potential differential biomarker for distinguishing DPD from NC, NDPD, and MDD. PMID- 27472695 TI - Thalidomide for inflammatory bowel disease: Systematic review. AB - BACKGROUND: Thalidomide is an immunomodulatory drug used in the experimental treatment of refractory Crohn disease and ulcerative colitis. We aimed to review the existing evidence on the efficacy and safety of thalidomide in the treatment of inflammatory bowel diseases. METHODS: CENTRAL, MEDLINE, LILACS, POPLINE, CINHAL, and Web of Science were searched in March 2016. Manual search included conference and reference lists. All types of studies, except single case reports, were included. Outcomes evaluated were: induction of remission; maintenance of remission; steroid reduction; effect on penetrating Crohn disease; endoscopic remission; adverse events. RESULTS: The research strategies retrieved 722 papers. Two randomized controlled trials and 29 uncontrolled studies for a total of 489 patients matched the inclusion criteria. Thalidomide induced a clinical response in 296/427 (69.3%) patients. Clinical remission was achieved in 220/427 (51.5%) cases. Maintenance of remission was reported in 128/160 (80.0%) patients at 6 months and in 96/133 (72.2%) at 12 months. Reduction in steroid dosage was reported in 109/152 (71.7%) patients. Fistulas improved in 49/81 (60.5%) cases and closed in 28/81 (34.6%). Endoscopic improvement was observed in 46/66 (69.7%) and complete mucosal healing in 35/66 (53.0%) patients. Cumulative incidence of total adverse events and of those leading to drug suspension was 75.6 and 19.7/1000 patient-months, respectively. Neurological disturbances accounted for 341/530 (64.3%) adverse events and were the most frequent cause of drug withdrawal. CONCLUSION: Existing evidence suggests that thalidomide may be a valid treatment option for patients with inflammatory bowel diseases refractory to other first- and second-line treatments. PMID- 27472696 TI - A giant ancient schwannoma mimicking an adnexal mass: Case report. AB - INTRODUCTION: Ancient schwannoma is a rare tumor of the peripheral nerve sheath. As degenerative properties are defined histologically, it can be wrongly interpreted as malignant. CASE PRESENTATION: The case presented here is of a giant ancient schwannoma with a pelvic retroperitoneal location, which was mimicking an adnexal mass. CONCLUSION: In the rarely seen cases in the retroperitoneum, it may reach very large dimensions. PMID- 27472697 TI - Participation in cancer screening among female migrants and non-migrants in Germany: A cross-sectional study on the role of demographic and socioeconomic factors. AB - In many European countries, migrants utilize cancer screening less often than non migrants. In Germany, in contrast, higher rates of utilization among migrants as compared with non-migrants have been reported. The role of demographic and socioeconomic factors potentially confounding the association between migration status and participation in screening, however, could not be studied. The present study aims to investigate the utilization of cancer screening among migrant and nonmigrant women residing in Germany, adjusting for potential confounders.We used self-reported information from women surveyed on whether they have ever participated in screening for cancer (n = 11,709). The data was collected as part of a cross-sectional representative telephone survey conducted by the Robert Koch Institute in 2010. We distinguished between three groups of women: (1) respondents of non-German nationality, those who had immigrated to Germany after their birth or those who have two foreign-born parents ("migrants with two-sided migration background"), (2) respondents who only have one foreign-born parent ("migrant with one-sided migration background"), and (3) all others ("non migrants").To account for confounders, logistic regression analysis was performed. Only individuals proficient in German were included in the survey, allowing to control for a bias arising from poor language proficiency.84.9% of nonmigrant women, 82.1% of women with a one-sided, and 70.5% of women with a two sided migration background had utilized screening for cancer at least once in their lifetime before the survey. The adjusted odds ratios (OR) as compared with nonmigrant women were 0.99 (95% confidence interval [95% CI]: 0.77-1.27) and 0.55 (95% CI: 0.47-0.64), respectively.The study shows that migrant women with a two sided migration background residing in Germany utilize screening for cancer less often than nonmigrant women-independently of demographic and socioeconomic factors. This is in line with findings from other countries. Likely, barriers that migrant women encounter limit them from taking informed choices. These barriers need to be identified and appropriate measures aiming to enhance informed decision making must be implemented. PMID- 27472698 TI - Parenchymal lung involvement in adult-onset Still disease: A STROBE-compliant case series and literature review. AB - Parenchymal lung involvement (PLI) in adult-onset Still's disease (AOSD) has seldom, if ever, been studied. We examine here retrospective cohort AOSD cases and present a review of the literature (1971-2014) on AOSD-related PLI cases.Patients with PLI were identified in 57 AOSD cases. For inclusion, the patients had to fulfill Yamaguchi or Fautrel classification criteria, show respiratory symptoms, and have imaging evidence of pulmonary involvement, and data allowing exclusion of infectious, cardiogenic, toxic, or iatrogenic cause of PLI should be available. This AOSD + PLI group was compared with a control group (non-PLI-complicated AOSD cases from the same cohort).AOSD + PLI was found in 3 out of the 57 patients with AOSD (5.3%) and the literature mentioned 27 patients. Among these 30 AOSD + PLI cases, 12 presented an acute respiratory distress syndrome (ARDS) and the remaining 18 another PLI. In the latter, a nonspecific interstitial pneumonia computed tomography pattern prevailed in the lower lobes, pulmonary function tests showed a restrictive lung function, the alveolar differential cell count was neutrophilic in half of the cases, and the histological findings were consistent with bronchiolitis and nonspecific interstitial pneumonia. Corticosteroids were fully efficient in all but 3 patients. Ten out of 12 ARDS cases occurred during the first year of the disease course. All ARDS-complicated AOSD cases received corticosteroids with favorable outcomes in 10 (2 deceased). Most PLIs occurred during the systemic onset of AOSD.PLI may occur in 5% of AOSDs, of which ARDS is the most severe. Very often, corticosteroids are efficient in controlling this complication. PMID- 27472699 TI - Impact of hepatic function on serum procalcitonin for the diagnosis of bacterial infections in patients with chronic liver disease: A retrospective analysis of 324 cases. AB - Although procalcitonin (PCT) is a valid marker for early diagnosis of bacterial infections, it is unclear whether its accuracy in predicting bacterial infections is affected by impaired liver function. This study aimed to assess the impact of compromised liver function on the diagnostic value of PCT.This retrospective study was conducted between January 2013 and May 2015. A total of 324 patients with chronic liver disease were enrolled. Routine laboratory measurements and PCT were performed. Patients were divided into 3 groups according to clinical diagnosis: chronic hepatitis (group 1), decompensated cirrhosis (group 2), and acute-on-chronic liver failure/chronic liver failure (group 3). The correlation between PCT and liver function was analyzed. The area under the receiver operating characteristic (AUCROC) curve of PCT was analyzed according to infection status and liver function.PCT was more accurate than white blood cell count (P < 0.001) and percentage of neutrophils (P < 0.001) in detecting bacterial infections in patients with impaired liver function. In patients without infection, PCT had a moderate positive correlation with serum total bilirubin (TBIL) (r = 0.592), and a weak correlation with model for end-stage liver disease score (r = 0.483) and international normalized ratio (r = 0.389). The AUCROC and optimum thresholds of PCT and for predicting bacterial infections at different levels of TBIL were 0.907 (95% CI 0.828-0.958) and 0.38 ng/mL, respectively, for TBIL <5 mg/dL, 0.927 (95% CI 0.844-0.974) and 0.54 ng/mL (5 mg/dL <=TBIL<10 mg/dL), 0.914 (95% CI 0.820-0.968) and 0.61 ng/mL (10 mg/dL <=TBIL<20 mg/dL), 0.906 (95% CI 0.826-0.958) and 0.94 ng/mL (TBIL >=20 mg/dL), respectively.This study demonstrated that PCT was a valuable marker of bacterial infection in patients with chronic liver diseases. TBIL affected PCT threshold, so different cut-offs should be used according to different TBIL values. PMID- 27472700 TI - Outcome in noncritically ill patients with acute kidney injury requiring dialysis: Effects of differing medical staffs and organizations. AB - Acute kidney injury requiring dialysis (AKI-D) treatment has significantly increased in incidence over the years, with more than 400 new cases per million population/y, 2/3 of which concern noncritically ill patients. In these patients, there are little data on mortality or on information of care organization and its impact on outcome. Specialty training and integrated teams, as well as a high volume of activity, seem to be linked to better hospital outcome. The study investigates mortality of patients admitted to and in-care of nephrology (NEPHROpts), a closed-staff organization, and to other medical wards (MEDpts), representing a model of open-staff organization.This is a single center, case control cohort study derived from a prospective epidemiology investigation on patients with AKI-D admitted to or in-care of the Hospital of Perugia during the period 2007 to 2014. Noncritically ill AKI-D patients were analyzed: inclusion and exclusion criteria were defined to avoid possible bias on the cause of hospital admittance and comorbidities, and a propensity score (PS) matching was performed.Six hundred fifty-four noncritically ill patients were observed and 296 fulfilled inclusion/exclusion criteria. PS matching resulted in 2 groups: 100 NEPHROpts and 100 MEDpts. Characteristics, comorbidities, acute kidney injury causes, risk-injury-failure acute kidney injury criteria, and simplified acute physiology score (SAPS 2) were similar. Mortality was 36%, and a difference was reported between NEPHROpts and MEDpts (20% vs 52%, chi = 23.2, P < 0.001). Patients who died differed in age, serum creatinine, blood urea nitrogen/s.Creatinine ratio, dialysis urea reduction rate (URR), SAPS 2 and Charlson score; they presented a higher rate of heart disease, and a larger proportion required noradrenaline/dopamine for shock. After correction for mortality risk factors, multivariate Cox analysis revealed that site of treatment (medical vs nephrology wards) represents an independent risk factor of mortality (relative risk = 2.13, 95% confidence interval = 1.25, 3.63; P < 0.01). Other independent risk factors were age, URR, s.Creatinine at hemodialysis beginning, and SAPS 2 score.In our context, we have documented that noncritically ill AKI-D patients, who represented 2/3 of the population, had high in-hospital mortality (36%), and that a closed-staff specialty medical organization, such as a Nephrology team, seems to guarantee a better outcome than general medical organizations. The significance in healthcare system organization and resource allocation could be important. PMID- 27472701 TI - Concomitant etoposide and cisplatin provided improved survival compared with docetaxel and cisplatin in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy. AB - Presently, there is no consensus regarding which chemotherapy regimen is best to administer with radiotherapy in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). Herein, our aim was to compare the outcome of patients treated with either etoposide-cisplatin (EP) or docetaxel-cisplatin (DP) in this curative setting.Patients treated with either EP or DP and concurrent radiotherapy from 2004 to2012 were identified and their detailed medical records and follow-up information were obtained for analysis in this retrospective study. Survival rates were compared using Cox proportional hazards regression models with adjustments for confounding parameters provided by propensity score methods.A total of 105 patients were treated with concurrent chemoradiotherapy for LA-NSCLC (stage IIB-IIIA-IIIB). The median ages were 54 years (range, 32-70 years) and 55 years (range, 37-73 years) in the EP (n = 50) and DP (n = 55) groups, respectively. The median follow-up time was 27 months (range, 1-132 months) in the EP group and 19 months (range, 1-96 months) in DP group. There was no significant difference in baseline clinicopathologic features including age, sex, performance status, histologic subtype, and clinical TNM stages between groups. In the univariate analysis, the median overall survival of patients treated with EP was higher than that of patients treated with DP (41 vs. 20 months, P = 0.003). Multivariate analysis further revealed a survival advantage with EP compared with DP (hazard ratio [HR], 0.46; 95% confidence interval: 0.25 0.83; P = 0.009). The toxicity profile of the 2treatment groups was similar except that pulmonary toxicity was higher in the DP group (grade 3-4: 0% vs. 6%, P = 0.024).Concurrent chemoradiotherapy with EP may provide more favorable outcomes than DP and with an acceptable safety profile. PMID- 27472702 TI - Factors affecting poor nutritional status after small bowel resection in patients with Crohn disease. AB - In Crohn disease, bowel-preserving surgery is necessary to prevent short bowel syndrome due to repeated operations. This study aimed to determine the remnant small bowel length cut-off and to evaluate the clinical factors related to nutritional status after small bowel resection in Crohn disease.We included 394 patients (69.3% male) who underwent small bowel resection for Crohn disease between 1991 and 2012. Patients who were classified as underweight (body mass index < 17.5) or at high risk of nutrition-related problems (modified nutritional risk index < 83.5) were regarded as having a poor nutritional status. Preliminary remnant small bowel length cut-offs were determined using receiver operating characteristic curves. Variables associated with poor nutritional status were assessed retrospectively using Student t tests, chi-squared tests, Fisher exact tests, and logistic regression analyses.The mean follow-up period was 52.9 months and the mean patient ages at the time of the last bowel surgery and last follow up were 31.2 and 35.7 years, respectively. The mean remnant small bowel length was 331.8 cm. Forty-three patients (10.9%) underwent ileostomy, 309 (78.4%) underwent combined small bowel and colon resection, 111 (28.2%) had currently active disease, and 105 (26.6%) underwent at least 2 operations for recurrent disease. The mean body mass index and modified nutritional risk index were 20.6 and 100.8, respectively. The independent factors affecting underweight status were remnant small bowel length <=240 cm (odds ratio: 4.84, P < 0.001), ileostomy (odds ratio: 4.70, P < 0.001), and currently active disease (odds ratio: 4.16, P < 0.001). The independent factors affecting high nutritional risk were remnant small bowel length <=230 cm (odds ratio: 2.84, P = 0.012), presence of ileostomy (odds ratio: 3.36, P = 0.025), and currently active disease (odds ratio: 4.90, P < 0.001).Currently active disease, ileostomy, and remnant small bowel length <=230 cm are risk factors affecting the poor nutritional status of patients with Crohn disease after small bowel resection. PMID- 27472703 TI - An investigation of crosstalk between Wnt/beta-catenin and transforming growth factor-beta signaling in androgenetic alopecia. AB - BACKGROUND: Wnt and transforming growth factor-beta (TGF-beta) signaling pathways are known to be involved in the pathogenesis of androgenetic alopecia (AGA). However, the way that Wnt and TGF-beta signaling is altered in patients with AGA and whether there exists a crosstalk between them in pathogenetic process of AGA remain unclear. OBJECTIVES: To investigate the expression of Wnt and TGF-beta signaling and the crosstalk between these 2 signaling pathways in AGA. METHODS: Fifteen male patients with AGA were recruited for our research. Fifteen scalp specimens of the balding were collected from frontal areas, and 9 nonbalding were collected from occipital areas. We analyzed the expression and activation of downstream Wnt and TGF-beta signaling molecules in both balding and nonbalding hair follicles isolated from scalp specimens. Furthermore, we evaluated the activation of Wnt and TGF-beta signaling after either of them was blocked with the inhibitor in balding and nonbalding dermal papilla (DP) cells. RESULTS: Compared with the nonbalding counterparts, the mRNA level of Wnt10a and LEF1 was decreased. But TbetaRI and TbetaRII, and the protein expression of TGF-beta1 was elevated in balding hair follicles. To investigate the crosstalk between Wnt and TGF-beta signaling, we used SB431542 to inhibit the TGF-beta signaling in balding DP cells and found that SB431542 significantly attenuated the phosphorylation of Smad2 and Akt. However, the mRNA level of Wnt10a, LEF1, and the nuclear translocation of beta-catenin was increased. On the other hand, we suppressed the Wnt signaling by XAV939 in nonbalding DP cells, which displayed that the level of beta-catenin and LEF1 was significantly inhibited; however, the level of active TGF-beta1 and the phosphorylation of Smad2 and Akt were up-regulated. CONCLUSIONS: These data indicate that crosstalk between Wnt/beta-catenin and TGF beta signaling pathways may exist as one of the important mechanisms contributing to AGA. PMID- 27472704 TI - Association of beta-blocker therapy with long-term clinical outcomes in patients with coronary chronic total occlusion. AB - There are limited data regarding the efficacy of beta-blockers for secondary prevention in patients with coronary chronic total occlusion (CTO). Therefore, we investigated the association of beta-blocker therapy with long-term clinical outcomes in CTO patients. From March 2003 to February 2012, a total of 2024 CTO patients treated with either medical therapy alone or revascularization were enrolled in the study. We assessed 1596 patients with stable ischemic heart disease and divided them into the beta-blocker group (n = 932) and the no-beta blocker group (n = 664). The primary outcome was all-cause death. The median follow-up duration was 3.9 (interquartile range: 2.0-6.2) years. All-cause death occurred in 11.6% patients in the beta-blocker group and 13.6% patients in the no beta-blocker group (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.61 1.08; P = 0.15). In the propensity score-matched population (570 pairs), all cause death occurred in 12.3% patients in the beta-blocker group and 12.8% patients in the no-beta-blocker group (HR: 0.93, 95% CI: 0.67-1.29; P = 0.66). In subgroup analysis, beta-blocker therapy was associated with better outcome, in terms of all-cause death, in patients with CTO of the left anterior descending coronary artery and Synergy Between PCI with Taxus and Cardiac Surgery (SYNTAX) score >=23 (P for interaction = 0.01 and 0.02, respectively). In conclusion, beta blocker therapy was not associated with favorable long-term clinical outcomes in stable CTO patients, regardless of treatment strategy. However, beta-blocker therapy might be beneficial in a highly selective group of CTO patients with a high ischemic burden. PMID- 27472705 TI - Acute thrombosis of a transplanted renal artery after gastric ulcer bleeding in a patient with a long-term well-functioning renal allograft: A case report and literature review. AB - BACKGROUND: Acute thrombosis of a transplanted renal artery is a serious vascular complication following renal allograft transplantation, which usually occurs within the first month after transplantation and often results in graft loss. It rarely occurs beyond the first month, except in a rejected kidney or in a kidney with high-grade transplant renal artery stenosis. RESULT: A 65-year-old male with a history of type 2 diabetes mellitus, hypertension, pulmonary tuberculosis, and end-stage renal disease was previously treated with hemodialysis (HD). He received a kidney transplant and had a well-functioning graft for 2 years. He presented to our emergency department with gastric ulcer bleeding and received treatment involving an endoscopic submucosal epinephrine injection, a proton pump inhibitor, and blood transfusions. Nine days later, he complained of sudden lower abdominal pain and had acute anuric kidney failure. Renal ultrasonography revealed an absence of blood flow to the allograft kidney. Renal artery angiogram demonstrated complete occlusion of the transplanted renal artery. After thrombectomy and percutaneous transluminal angioplasty (PTA) with stent placement, 60% stenosis of the proximal renal artery with distal perfusion was noted. However, his graft function did not improve, and he received HD again. Histopathology of the transplanted kidney revealed ischemic tubular nephropathy with focal infarction without rejection. CONCLUSION: This is the first case of acute thrombosis of the transplanted renal artery following gastric ulcer bleeding in a patient with a long-term well-functioning graft kidney. PMID- 27472706 TI - Inversion of the Vdelta1 to Vdelta2 gammadelta T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion. AB - Common variable immunodeficiency (CVID) is defined by low levels of IgG and IgA, but perturbations in T cells are also commonly found. However, there is limited information on gammadelta T cells in CVID patients. Newly diagnosed CVID patients (n = 15) were enrolled before and after intravenous IgG (IVIg) replacement therapy. Cryopreserved peripheral blood mononuclear cells were then used to study gammadelta T cells and CVID patients were compared to healthy controls (n = 22). The frequency and absolute count of Vdelta1 gammadelta T cells was found to be increased in CVID (median 0.60% vs 2.64%, P <0.01 and 7.5 vs 39, P <0.01 respectively), while they were decreased for Vdelta2 gammadelta T cells (median, 2.36% vs 0.74%, P <0.01 and 37.8 vs 13.9, P <0.01 respectively) resulting in an inversion of the Vdelta1 to Vdelta2 ratio (0.24 vs 1.4, P <0.001). Markers of immune activation were elevated on all subsets of gammadelta T cells, and HLA-DR expression was associated with an expansion of Vdelta1 gammadelta T cells (r = 0.73, P = 0.003). Elevated PD-1 expression was found only on Vdelta2 gammadelta T cells (median 1.15% vs 3.08%, P <0.001) and was associated with the decrease of Vdelta2 gammadelta T cells (r = -0.67, P = 0.007). IVIg had no effect on the frequency of Vdelta1 and Vdelta2 gammadelta T cells or HLA-DR expression, but alleviated CD38 expression on Vdelta1 gammadelta T cells (median MFI 965 vs 736, P <0.05). These findings suggest that immunological perturbations of gammadelta T cells are a general feature associated with CVID and are only partially reversed by IVIg therapy. PMID- 27472707 TI - Acquired reactive perforating collagenosis: A report of a typical case. AB - BACKGROUND: Reactive perforating collagenosis (RPC) is a rare form of transepithelial elimination, in which altered collagen is extruded through the epidermis. There are 2 types of RPC, acquired RPC (ARPC) and inherited RPC, while the latter is extremely rare. Here we report on 1 case of ARPC. METHODS: A 73 year-old female was presented with strongly itchy papules over her back and lower limbs for 3 months. She denied the history of oozing or vesiculation. A cutaneous examination showed diffusely distributed multiple well-defined keratotic papules, 4 to 10 mm in diameter, on the bilateral lower limbs and back as well as a few papules on her chest and forearm. Scratching scars were over the resolved lesions while Koebner phenomenon was negative. The patient had a history of type 2 diabetes for 15 years. Laboratory examinations showed elevated blood glucose level. Skin lesion biopsy showed a well-circumscribed area of necrosis filled with a keratotic plug. Parakeratotic cells and lymphocytic infiltration could be seen in the necrosed area. In dermis, sparse fiber bundles were seen perforating the epidermis. These degenerated fiber bundles were notarized as collagen fiber by elastic fiber stain, suggesting a diagnosis of RPC. RESULTS: Then a diagnosis of ARPC was made according to the onset age and the history of diabetes mellitus. She was treated with topical application of corticosteroids twice a day and oral antihistamine once a day along with compound glycyrrhizin tablets 3 times a day. And the blood glucose was controlled in a satisfying range. Two months later, a significant improvement was seen in this patient. CONCLUSION: Since there is no efficient therapy to RPC, moreover, ARPC is considered to be associated with some systemic diseases, the management of the coexisting disease is quite crucial. The patient in this case received a substantial improvement due to the control of blood glucose and application of compound glycyrrhizin tablets. PMID- 27472708 TI - Association between anti-HBc positivity and hepatocellular carcinoma in HBsAg negative subjects with chronic liver disease: A meta-analysis. AB - A meta-analysis was performed to ascertain to what extent hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core (anti-HBc)-positive subjects with chronic liver disease are at a higher risk of developing hepatocellular carcinoma (HCC) than the anti-HBc-negative.All studies included had to fulfill the following characteristics and inclusion criteria: they investigated the relationship between HBsAg-negative/anti-HBc-positive serology and the occurrence of HCC, whether a case-control or cohort study, they provided relative risk (RR) or odds ratios (ORs) and 95% confidence intervals (CIs), were available as a full text written in English, and were published and indexed up to April 2015.Twenty six original studies met the inclusion criteria, allowing a meta-analysis on 44,553 patients. The risk of HCC among the 9986 anti-HBc-positive subjects was 67% higher than in the 34,567 anti-HBc-negative (95% CI = 1.44-1.95, P < 0.0001). The results were similar when groups of patients with a different stage of liver disease (patients with chronic liver disease, patients with cirrhosis), with different ethnicity (Asian and non-Asian) and etiology (HCV and non-HCV) were considered. The risk of HCC was significantly higher in the 651 anti-HBs/anti-HBc positive patients (RR = 1.36; 95% CI = 1.17-1.58, P = 0.03) and in the 595 anti HBs-negative/anti-HBc-positive subjects (RR = 2.15; 95% CI = 1.58-2.92, P < 0.0001) than in the 1242 anti-HBs/anti-HBc negative. However, the RR from 8 studies indicated that the risk of HCC was 35% lower among the anti-HBs/anti-HBc positive subjects compared to the anti-HBs-negative/anti-HBc-positive (RR = 0.65; 95% CI = 0.52-0.8, P < 0.0001).This meta-analysis shows that in HBsAg-negative subjects with chronic liver disease, anti-HBc positivity is strongly associated with the presence of HCC, an association observed in all subgroups according to the stage of the disease, etiology, and ethnicity. PMID- 27472709 TI - Hemorrhagic, calcified, and ossified benign retroperitoneal schwannoma: First case report. AB - BACKGROUND: Schwannomas are mesenchymal tumors arising from the neural sheaths of peripheral nerves. They can almost develop in any part of the body, while head, neck and extremities are the most common sites. Occurrence in the retroperitoneum is rare. Schwannomas can show secondary degenerative changes including cyst formation, hyalinization, hemorrhage, and calcification, whereas the ossified retroperitoneal schwannoma was only reported in a malignant one. CASE SUMMARY: We first present a benign ossified retroperitoneal schwannoma in a 61-year-old female. The mass was found by a routine health examination. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a well-defined mass in the area among duodenum, right liver, and kidney. Definitive preoperative diagnosis of the mass was difficult. By laparotomy, the mass was found in the retroperitoneum. We completely removed the tumor and gross specimen showed a mass with a capsule and 6 * 6 * 4.8 cm in size. Microscopic examination showed the tumor is composed of spindle-shaped cells with degenerative changes of hemorrhage, calcification, and ossification. Immunohistochemically, S-100 protein was strongly positive. Finally, the mass was diagnosed as a hemorrhagic, calcified, and ossified benign schwannoma in the retroperitoneum. The patient was followed up for a period of 21 months, during which she was well with no evidence of recurrence. CONCLUSION: We report the first case of a benign retroperitoneal schwannoma with secondary degenerative changes including hemorrhage, calcification, and ossification. Precise preoperative diagnosis of the tumor is challenging even with multiple preoperative imaging modalities. After complete resection, patients with benign retroperitoneal schwanommas generally have good prognosis. PMID- 27472710 TI - Integrative exploration of genomic profiles for triple negative breast cancer identifies potential drug targets. AB - BACKGROUND: Triple negative breast cancer (TNBC) is high-risk due to its rapid drug resistance and recurrence, metastasis, and lack of targeted therapy. So far, no molecularly targeted therapeutic agents have been clinically approved for TNBC. It is imperative that we discover new targets for TNBC therapy. OBJECTIVES: A large volume of cancer genomics data are emerging and advancing breast cancer research. We may integrate different types of TNBC genomic data to discover molecular targets for TNBC therapy. DATA SOURCES: We used publicly available TNBC tumor tissue genomic data in the Cancer Genome Atlas database in this study. METHODS: We integratively explored genomic profiles (gene expression, copy number, methylation, microRNA [miRNA], and gene mutation) in TNBC and identified hyperactivated genes that have higher expression, more copy numbers, lower methylation level, or are targets of miRNAs with lower expression in TNBC than in normal samples. We ranked the hyperactivated genes into different levels based on all the genomic evidence and performed functional analyses of the sets of genes identified. More importantly, we proposed potential molecular targets for TNBC therapy based on the hyperactivated genes. RESULTS: Some of the genes we identified such as FGFR2, MAPK13, TP53, SRC family, MUC family, and BCL2 family have been suggested to be potential targets for TNBC treatment. Others such as CSF1R, EPHB3, TRIB1, and LAD1 could be promising new targets for TNBC treatment. By utilizing this integrative analysis of genomic profiles for TNBC, we hypothesized that some of the targeted treatment strategies for TNBC currently in development are more likely to be promising, such as poly (ADP-ribose) polymerase inhibitors, while the others are more likely to be discouraging, such as angiogenesis inhibitors. LIMITATIONS: The findings in this study need to be experimentally validated in the future. CONCLUSION: This is a systematic study that combined 5 different types of genomic data to molecularly characterize TNBC and identify potential targets for TNBC therapy. The integrative analysis of genomic profiles for TNBC could assist in identifying potential new therapeutic targets and predicting the effectiveness of a targeted treatment strategy for TNBC therapy. PMID- 27472711 TI - Giant bladder stone in a male patient: A case report. AB - BACKGROUND: In recent years, bladder stones are increasing in China. However, a giant bladder stone is rarely found nowadays. METHODS: A case of a 54-year-old man who presented with a >9-year history of urinary frequency and urgency and macrohematuria for the past 3 days, was examined by ultrasound scan, kidney ureter-bladder x-ray, and computed tomography. Then, the patient received a cystolithotomy. RESULTS: His suprapubic area was hard when palpated. An ultrasound scan showed hydronephrosis of both kidneys and expanded ureters. A kidney-ureter-bladder x-ray showed a large stone within the bladder, and computed tomography revealed that the stone occupied most of the bladder. A large bladder stone composed of magnesium ammonium phosphate, weighing 1048 g, and measuring 13.3*8.0*9.7cm in size was removed. CONCLUSION: This rare case is, to the best of our knowledge, the largest bladder stone case reported to date in China. For patients with only Lower urinary tract symptoms, bladder stone should be taken into consideration when other signs occur, such as recurrent urinary tract infection and hematuria. PMID- 27472712 TI - The BTNL2 G16071A gene polymorphism increases granulomatous disease susceptibility: A meta-analysis including FPRP test of 8710 participants. AB - OBJECTIVE: The butyrophilin-like 2 (BTNL2) G16071A gene polymorphism has been implicated in the susceptibility to granulomatous diseases, but the results were inconclusive. The objective of the current study was to precisely explore the relationship between BTNL2 G16071A gene polymorphism and granulomatous disease susceptibility by the meta-analysis including false-positive report probability (FPRP) test. METHODS: A systematic literature search in the PubMed, Embase, and Wanfang databases, China National Knowledge Internet, and commercial Internet search engines was conducted to identify studies published up to April 1, 2016. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the effect size. Statistical analysis was conducted using the STATA 12.0 software and FPRP test sheet. RESULTS: In total, all 4324 cases and 4386 controls from 14 eligible studies were included in the current meta-analysis. By the overall meta analysis, we found a significant association between BTNL2 G16071A gene polymorphism and granulomatous disease susceptibility (A vs G: OR = 1.25, 95% CI = 1.07-1.45, P = 0.005). The meta-regression analyses showed that a large proportion of the between-study heterogeneity was significantly attributed to the ethnicity (A vs G, P = 0.013) and the types of granulomatous diseases (A vs G, P = 0.002). By the subgroup meta-analysis, the BTNL2 G16071A gene polymorphism was associated with granulomatous disease susceptibility in Caucasians (A vs G: OR = 1.37, 95% CI = 1.18-1.58, P < 0.001). Moreover, a significant relationship between the BTNL2 G16071A gene polymorphism and sarcoidosis susceptibility (A vs G: OR = 1.52, 95% CI = 1.39-1.66, P < 0.001) was found. However, to avoid the "false-positive report," we further investigated the significant associations observed in the present meta-analysis by the FPRP test. Interestingly, the results of FPRP test indicated that the BTNL2 G16071A gene polymorphism was truly associated with sarcoidosis susceptibility (A vs G, FPRP < 0.001). Additionally, the FPRP test confirmed that the BTNL2 G16071A gene polymorphism was associated only with granulomatous disease susceptibility among Caucasians (A vs G, FPRP < 0.001) at the level of a prior probability, which was 0.001. CONCLUSION: The meta analysis indicated that BTNL2 G16071A gene polymorphism may as a likelihood factor contributed to granulomatous disease susceptibility, especially increasing the sarcoidosis susceptibility. In addition, the polymorphism may be greatly associated with likelihood of granulomatous diseases among Caucasians. PMID- 27472713 TI - Elevated expression of growth-regulated oncogene-alpha in tumor and stromal cells predicts unfavorable prognosis in pancreatic cancer. AB - Growth-regulated oncogene-alpha (GRO-alpha) has been reported to be over expressed in a series of human cancers including colorectal cancer, melanoma, gastric cancer, hepatocellular carcinoma, and ovarian cancer and was known to regulate multiple biologic activities associated with tumor progression. But the role in human pancreatic cancer remains unclear. To examine the expression of GRO alpha and its clinical significance in pancreatic cancer (PC), a total of 12 fresh PC specimens and 12 surrounding normal tissues to detect GRO-alpha mRNA expression were measured by quantitative real-time polymerase chain reaction (qRT PCR). Immunohistochemical analysis of GRO-alpha protein was performed in 160 formalin-fixed, paraffin-embedded PC tissue samples and 68 control specimens, including 37 matched normal surgical margins and 31 benign pancreatic lesions. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of PC patients.Expression of GRO-alpha mRNA in PC tissues was significantly compared with that in adjacent normal tissues (1.399 +/- 0.165 vs. 0.870 +/- 0.103 t = 1.75, P = 0.012), GRO-alpha protein expression in cytoplasm of cancer cells and stroma was detected in 41.88% and 40.63% PC specimens, respectively, and was significantly higher than that in corresponding normal tissues (P = 0.008, P = 0.002, respectively). High GRO-alpha expression in the cytoplasm of cancer cells was related to tumor location (P = 0.047), tumor status (T classification; P = 0.001), distant metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P < 0.001). High GRO-alpha expression in the stroma correlated with perineural invasion (P = 0.010), T classification (P = 0.006) and TNM stage (P = 0.004), and was marginally associated with metastasis (P = 0.056). Elevated expression of GRO-alpha in cytoplasm of cancer cells (hazard ratio [HR] = 5.730, P = 0.007) and stroma (HR = 3.120, P = 0.022) were independent prognostic factors of pancreatic cancer. T classification (HR = 2.130, P = 0.023), lymphatic metastasis (HR = 4.211, P = 0.009) and TNM classification (HR = 0.481, P = 0.031) were also prognostic predictors in PC patients.GRO-alpha expression was elevated in pancreatic cancer tissues and might be a potential therapeutic target and prognostic marker in patients with pancreatic cancer. PMID- 27472714 TI - Diagnosis of hepatitis C virus infection in pregnant women in the healthcare system in Poland: Is it worth the effort? AB - The hepatitis C virus (HCV) is globally recognized as a serious public health concern. Current statistics indicate that approximately 2% of people worldwide and 1.9% of people in Poland suffer from HCV infection.This study was conducted to assess the anti-HCV seroprevalence in pregnant women in Poland and subsequently provide recommendations on the rationale for obligatory screening.A total of 42,274 women participated in our study, of which 16,130 were pregnant. We were granted access to their health data stored in the form of electronic medical records kept by the network of outpatient clinics throughout Poland.The lowest rate of positive anti-HCV test results was found in women ages 25 to 34 (0.73%); however, younger and older age groups had similar rates (15-24 = 0.86%; 35-44 = 0.84%). Additional analysis of data from the period between 2011 and 2014 revealed a downward trend in the proportion of positive anti-HCV tests among pregnant women (mean positive anti-HCV = -0.001 * year + 1.9451; R = 0.7274). Regardless of the gradual increase in the number of female patients undergoing screening between 2004 and 2015, there has been a constant decrease in the rate of positive cases. The rate of pregnant women potentially infected with HCV was twice as lower than that in a control group of women undergoing tests for other medical circumstances: 0.76% vs 1.67% (P < 0.0001).Analysis of real-world data of female patients in Poland provides evidence that screening based on an individual's medical history and behavioral risk factors in clinical circumstances would be more effective than obligatory testing of all pregnant women. PMID- 27472715 TI - Functional mitral regurgitation: predictor for atrial substrate remodeling and poor ablation outcome in paroxysmal atrial fibrillation. AB - Functional mitral regurgitation (FMR) is not uncommon in atrial fibrillation (AF) patients. We sought to investigate the association between FMR and atrial substrate remodeling as well as the ablation outcome in paroxysmal AF (PAF) patients.We retrospectively analyzed a prospectively enrolled cohort of 132 patients (age 55.1 +/- 9.6 years, 75.8% male) with symptomatic PAF who underwent initial ablation in our institute. Functional mitral regurgitation was defined as regurgitation jet area to left atrium (LA) area ratio >= 0.1 without any primary valvular disease. Voltage mapping of LA was performed under sinus rhythm. Low voltage zones (LVZs) were semi-quantitatively estimated and presented as low voltage index. Follow-up for AF recurrence >= 12 months was performed.In total, 40 patients (29.6%) were detected with FMR, who were older than the non-FMR patients (P = 0.007) and had larger LA diameters (P = 0.02). Left atrium LVZs were observed in 64.9% of patients with FMR versus 22.1% patients without FMR (P < 0.001). Functional mitral regurgitation independently predicted the presence of LVZs (OR 7.286; 95% CI 3.023-17.562; P < 0.001). During a mean follow-up of 22.9 +/- 6.5 months, 38 patients (28.8%) experienced AF recurrence. The recurrence rate was 60.0% and 19.5% in FMR and non-FMR cohort, respectively (log rank P < 0.001). Multivariate analysis showed that FMR was an independent predictor for AF recurrence (HR 2.291; 95% CI 1.062-4.942; P = 0.03).Functional mitral regurgitation was strongly associated with atrial substrate remodeling. Furthermore, patients with FMR have substantial risk for AF recurrence post ablation. PMID- 27472716 TI - Socioeconomic status in relation to Parkinson's disease risk and mortality: A population-based prospective study. AB - Little is known about the role of socioeconomic status in relation to Parkinson's disease (PD) risk, and no study has investigated whether the impact of socioeconomic status on all-cause mortality differs between individuals with and without PD.In this population-based prospective study, over 4.6 million Swedish inhabitants who participated in the Swedish census in 1980 were followed from 1981 to 2010. The incidence rate of PD and incidence rate ratio were estimated for the association between socioeconomic status and PD risk. Age-standardized mortality rate and hazard ratio (HR) were estimated for the association between socioeconomic status and all-cause mortality for individuals with and without PD.During follow-up, 66,332 incident PD cases at a mean age of 76.0 years were recorded. Compared to individuals with the highest socioeconomic status (high nonmanual workers), all other socioeconomic groups (manual or nonmanual and self employed workers) had a lower PD risk. All-cause mortality rates were higher in individuals with lower socioeconomic status compared with high nonmanual workers, but relative risks for all-cause mortality were lower in PD patients than in non PD individuals (e.g., for low manual workers, HR: 1.12, 95% confidence interval [CI]: 1.09-1.15 for PD patients; HR: 1.36, 95% CI: 1.35-1.36 for non-PD individuals).Individuals with lower socioeconomic status had a lower PD incidence compared to the highest socioeconomic group. Lower socioeconomic status was associated with higher all-cause mortality among individuals with and without PD, but such impact was weaker among PD patients. PMID- 27472717 TI - Obturator internus pyomyositis manifested as sciatica in a patient with subacute bacterial endocarditis: A rare case report. AB - Pyomyositis is a pyogenic infection of the skeletal muscles causing myalgia and fever in patients. Hematogenous seeding engendered by persistent bacteremia and septic embolism is usually the underlying cause of the disease. Trauma, intravenous drug use, and immunodeficiency are the main predisposing factors.Obturator internus pyomyositis with sciatica has not previously been reported. We report a rare case of a patient with subacute bacterial endocarditis presenting with left buttock pain and sciatica.Computed tomography confirmed the diagnosis of obturator internus pyomyositis. The patient was discharged uneventfully after successful antibiotic treatment.The mortality rate of patients who have pyomyositis comorbid with another condition or disease is extremely high. Early diagnosis and aggressive management are imperative. PMID- 27472718 TI - Plasma growth differentiation factor 15 predicts first-ever stroke in hypertensive patients. AB - Growth differentiation factor 15 (GDF-15) is a relatively new biomarker that predicts adverse stroke outcomes. However, the association of GDF-15 with first ever stroke in hypertensive patients has not yet been evaluated. The objective of this study was to evaluate the clinical implications of plasma GDF-15 on the development of first-ever stroke in patients with hypertension.In total, 254 patients with hypertension without a history of stroke were included from March 2010 to August 2010 and followed up until June 2013. The baseline circulating GDF 15 was determined by enzyme-linked immunosorbent assays.During a follow-up of 3.0 +/- 0.6 years, 22 (8.7%) first-ever strokes were identified, including 12 ischemic strokes and 10 intracerebral hemorrhages (ICH). According to tertiles of GDF-15, survival free of first-ever stroke was lower in the highest tertile of GDF-15 (log-rank P = 0.001). By backward stepwise Cox-regression analysis, adjusted for age, gender, diabetes mellitus, hyperlipidemia, hypertension stage, body mass index, cigarette smoking, anti-hypertensive drugs, and uric acid, every 100 pg/mL-increase in plasma of GDF-15 predicted an 11% greater risk of first ever stroke (hazard ratios [HR]: 1.11, 95% confidence interval [CI]: 1.03-1.20, P = 0.010) and an 18% increase in ischemic stroke risk (HR: 1.18, 95% CI: 1.07 1.30, P = 0.001). Receiver operating characteristic analysis indicated that GDF 15 had reasonable accuracy to predict first-ever stroke (area under curve = 0.73, 95% CI: 0.62-0.83, P < 0.001).This study identifies that GDF-15 is an independent predictor of first-ever stroke, especially for ischemic stroke in the patients with hypertension. PMID- 27472719 TI - Autograft versus sterilized allograft for lateral calcaneal lengthening osteotomies: Comparison of 50 patients. AB - Sterilized allografts may be less resistant to collapse and prone to nonunion leading to loss of correction in open wedge osteotomies. These adverse events usually occur at early time points (i.e., < 9 months postoperatively). The goal of this study was to compare sterilized allografts to autologous grafts in respect to secondary loss of hindfoot alignment and graft incorporation after lateral calcaneal lengthening osteotomies.Fifty patients (22 F/ 28 M, age: 16-69 years) who had undergone 50 lateral calcaneal lengthening osteotomies for adult flatfoot deformity were included in this retrospective study. Cortical sterilized allografts were used in 25 patients, autologous grafts in the remaining 25. Patients' preoperative, 6 and 12 weeks, and 6 to 9 months follow-up weight bearing radiographs of the affected foot were analyzed by 2 blinded radiologists: on each radiograph, graft incorporation, the talo-first metatarsal angle (TFMA), the talo-navicular coverage angle (TNCA), and the calcaneal pitch angle (CPA) were assessed. Loss of hindfoot alignment was defined as an increase of the TFMA or the TNCA or a decrease of the CPA, each by 5 degrees .Inter- and intraclass correlation coefficients for TFMA, TNCA, and CPA measurements ranged from 0.93 to 0.99. At all follow-up visits, the ratio of patients with loss of hindfoot alignment and graft incorporation was not significantly different between the allograft and autograft group. However, loss of correction was associated with failure of graft incorporation.Compared with autografts, sterilized allografts do not increase the risk for loss of hindfoot alignment in lateral column lengthening of the calcaneus. With respect to mechanical resistance, allografts thus mean an equal and valid alternative without risk of donor site morbidities. PMID- 27472720 TI - Five known tagging DLL3 SNPs are not associated with congenital scoliosis: A case control association study in a Chinese Han population. AB - Genetic etiology hypothesis is widely accepted in the development of congenital scoliosis (CS). The delta-like 3 (DLL3) gene, a member of the Notch signaling pathway, was implicated to contribute to human CS. In this study, a case-control association study was conducted to determine the association of single nucleotide polymorphism (SNP) in the DLL3 gene with CS in a Chinese Han Population. Five known tagging SNPs of the DLL3 gene were genotyped among 270 Chinese Han subjects (128 nonsyndromic CS patients and 142 matched controls). CS patients were divided into 3 types: type I-failure of formation (29 cases), type II-failure of segmentation (50 cases), and type III-mixed defects (49 cases). The 5 SNPs were analyzed by the allelic and genotypic association analysis, genotype-phenotype association analysis, and haplotype analysis. Allele frequencies of 5 tagging SNPs (SNP1: rs1110627, SNP2: rs3212276, SNP3: rs2304223, SNP4: rs2304222, and SNP5: rs2304214) in CS cases and controls were comparable and there were no available inheritance models. The SNPs were not associated with clinical phenotypes. Moreover, the 5 makers in the DLL3 gene were found to be in strong linkage disequilibrium (LD). Both global haplotype and individual haplotype analyses showed that the haplotypes of SNP1/SNP2/SNP3/SNP4/SNP5 did not correlate with the disease (P >0.05). Together, these data suggest that genetic variants of the DLL3 gene are not associated with CS in the Chinese Han population. PMID- 27472721 TI - Epithelioid hemangioendothelioma in the thorax: Clinicopathologic, CT, PET, and prognostic features. AB - Little is known about prognostic factors in epithelioid hemangioendothelioma (EHE). We aimed to identify prognostic factors among various clinicopathologic and imaging features of thoracic EHEs.Forty-two patients (male:female = 20:22; median age, 49 years) of EHEs with (n = 19) and without (n = 23) thoracic involvement were included. We reviewed electronic medical records for clinical information and computed tomography (CT) features for thoracic involvement. Differences in demographics and survival outcomes of patients with and without thoracic involvement were assessed. We also estimated overall survival.The most common pattern of thoracic involvement was multiple pulmonary nodules (n = 10), followed by parenchymal tumor with pleural invasion (n = 4), reticulonodular opacities (n = 3), and diffuse pleural thickening (n = 2). No significant difference in survival was found between the thoracic EHE group and nonthoracic EHE group (P = 0.68). Among 4 different thoracic involvement types, the lung multinodular pattern tended to demonstrate longer median survival (8.5 months) than other patterns, whereas the shortest median survival (1 month) was observed for the nodule/mass with pleural involvement pattern (P = 0.038).CT manifestations of thoracic EHEs are classified into 4 patterns, of which lung multinodular pattern is associated with longer survival. Survival is not different between patients with and without thoracic involvement. PMID- 27472722 TI - Nasolacrimal recanalization as an alternative to external dacryocystorhinostomy for treating failed nasolacrimal duct intubation. AB - To compare the surgical duration and clinical outcomes of nasolacrimal recanalization versus external dacryocystorhinostomy (DCR) in the treatment of failed nasolacrimal duct intubation.This is a retrospective, comparative, and interventional study. We evaluated the outcomes of 66 consecutive patients undergoing either nasolacrimal recanalization (n = 32) or DCR (n = 34) in a tertiary lacrimal disease referral center. Length of surgical duration, clinical outcomes, and rate of recurrence at 18 months postoperatively were compared.The mean surgical duration was 18.5 minutes (range, 15-25 minutes) for nasolacrimal recanalization and 48.2 minutes (range, 45-61 minutes) for DCR, respectively (P < 0.001). The rate of success was 84.4% in the recanalization group and 85.3% in the DCR group, respectively (P = 0.91). The time to recurrence was 2.6 +/- 1.1 months in the recanalization group and 5.6 +/- 2.1 months in the DCR group (P < 0.001). Five failed cases in each group received a secondary DCR surgery with the same resolution rate (40%). The absence of ocular discharge at baseline was a significant predictor for a successful outcome in the recanalization group (P = 0.04) but not in the DCR group (P = 0.63).Nasolacrimal recanalization is an effective, safe, and time-saving alternative to DCR for the treatment of failed nasolacrimal duct intubation. Clinicians should be cautious in patients with discharge. PMID- 27472723 TI - Retrospective study: The diagnostic accuracy of conventional forceps biopsy of gastric epithelial compared to endoscopic submucosal dissection (STROBE compliant). AB - Conventional forceps biopsy (CFB) is the most popular way to screen for gastric epithelial neoplasia (GEN) and adenocarcinoma of gastric epithelium. The aim of this study was to compare the diagnostic accuracy between conventional forceps biopsy and endoscopic submucosal dissection (ESD).Four hundred forty-four patients who finally undertook ESD in our hospital were enrolled from Jan 1, 2009 to Sep 1, 2015. We retrospectively assessed the characteristics of pathological results of CFB and ESD.The concordance rate between CFB and ESD specimens was 68.92% (306/444). Men showed a lower concordance rate (63.61% vs 79.33%; P = 0.001) and concordance patients were younger (P = 0.048). In multivariate analysis, men significantly had a lower concordance rate (coefficient -0.730, P = 0.002) and a higher rate of pathological upgrade (coefficient -0.648, P = 0.015). Locations of CFB did not influence the concordance rate statistically.The concordance rate was relatively high in our hospital. According to our analysis, old men plus gastric fundus or antrum of CFB were strongly suggested to perform ESD if precancerous lesions were found. And young women with low-grade intraepithelial neoplasia could select regular follow-up. PMID- 27472724 TI - The prevalence of tic disorders for children in China: A systematic review and meta-analysis. AB - BACKGROUND: Tic disorders (TD) are common neuropsychiatric disorders among children and adolescents. Still, there is great uncertainty regarding their epidemiology in China. We aim to depict the prevalence of TD for children in China and explore the influence of sex, age, geographic distribution, and diagnostic criteria on the prevalence rates. METHODS: We searched PubMed, EMBASE, four Chinese electronic databases, and relevant lists. Two reviewers independently selected trials, assessed trial quality, and extracted the data. RESULTS: We included 13 studies investigating 269,571 participants. The sample size ranged from 563 to 216,005 participants. The age of participants ranged from 3 to 16 years. The meta-analysis of the prevalence of TD was 6.1% [95% CI: 0.036 0.100, I = 49.7%]. The prevalence of transient tic disorder (TTD), chronic tic disorder (CTD), and Tourette syndrome (TS) was 1.7% [95% CI = 0.009-0.031, I = 49%], 1.2% [95% CI = 0.007-0.022, I = 48.3%], and 0.3% [95% CI = 0.001-0.008, I = 49.5%], respectively. The prevalence of TD in boys [5.1%, 95% CI = 0.026-0.098, I = 49.3%] was higher than that in girls [2.4%, 95% CI = 0.009-0.065, I = 49.4%]. The prevalence of TD in urban area [2.6%, 95% CI = 0.019-0.034, I = 35.5%] was higher than that in rural area [2.2%, 95% CI = 0.016-0.030, I = 33.9%]. The prevalence of TD in central China [10.7%, 95% CI = 0.043-0.242, I = 49.2%] was higher than that in North China [7.8%, 95% CI = 0.007-0.522, I = 49.9%] and East China [4.4%, 95% CI = 0.015-0.120, I = 49.8%]. CONCLUSION: TD is a common disease in China, with prevalence differing based on sex, age, and region. PMID- 27472725 TI - Longitudinal comparison of quality of life in patients undergoing laparoscopic Toupet fundoplication versus magnetic sphincter augmentation: Observational cohort study with propensity score analysis. AB - Only a minority of patients with gastro-esophageal reflux disease (GERD) are offered a surgical option. This is mostly due to the fear of potential side effects, the variable success rate, and the extreme alteration of gastric anatomy with the current gold standard, the laparoscopic Nissen fundoplication. It has been reported that laparoscopic Toupet fundoplication (LTF) and laparoscopic sphincter augmentation using a magnetic device (LINX) can treat reflux more physiologically and with a lower incidence of side-effects and reoperation rate. We present the first comparing quality of life in patients undergoing LTF versus LINX.Observational cohort study. Consecutive patients undergoing LTF or LINX over the same time period were compared by using the propensity score full matching method and generalized estimating equation. Criteria of exclusion were >3 cm hiatal hernia, grade C-D esophagitis, ineffective esophageal motility, body mass index >35, and previous upper abdominal surgery. The primary study outcome was quality of life measured with the Gastro-Esophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) questionnaire. Secondary outcomes were proton pump inhibitors (PPI) use, presence of gas-related symptoms or dysphagia, and reoperation-free probability.Between March 2007 and July 2014, 238 patients with GERD met the criteria of inclusion in the study. Of these, 103 underwent an LTF and 135 a LINX procedure. All patients had a minimum 1-year follow-up. Over time, patients in both groups had similar GERD-HRQL scores (odds ratio [OR] 1.04, confidence interval [CI] 0.89-1.27; P = 0.578), PPI use (OR 1.18, CI 0.81-1.70; P = 0.388), gas-related symptoms (OR 0.69, CI 0.21-2.28; P = 0.542), dysphagia (OR 0.62, CI 0.26-1.30; P = 0.241), and reoperation-free probability (stratified log rank test = 0.556).In 2 concurrent cohorts of patients with early stage GERD undergoing LTF or LINX and matched by propensity score analysis, health-related quality of life significantly improved and GERD-HRQL scores had a similar decreasing trend over time up to 7 years of follow-up. We conclude that LTF and LINX provide similar disease-specific quality of life over time in patients with early stage GERD. PMID- 27472726 TI - Impact of anastomotic leakage on long-term oncologic outcome and its related factors in rectal cancer. AB - Anastomotic leakage (AL) is a well-known cause of morbidity after low anterior resection (LAR) for rectal cancer, but its impact on oncologic outcome is not well understood. The aim of this study is to investigate the impact of AL on long term oncologic outcome and to identify factors associated with AL that may affect prognosis after LAR for rectal cancer.A retrospective analysis of patients who underwent curative resection for rectal cancer without diverting stoma was performed. To investigate AL related factors that may be associated with oncologic outcome, Clavien-Dindo grades, prognostic nutritional indices (PNI) and inflammatory indices were included.One hundred and one patients out of a total of 1258 patients developed postoperative AL, giving an AL rate of 8.0%. Patients with AL showed poorer disease-free survival (DFS), than patients without AL (hazard ratio [HR] = 1.6; 95% confidence intervals [CI]: 1.1-2.5; P = 0.01). In patients who developed AL, age over 60 (HR = 2.2; 95% CI: 1.1-4.7; P = 0.033), advanced pathologic stage (HR = 2.4; 95% CI: 1.4-4.0; P = 0.001), suppressed neutrophil-proportion (<=80%) (HR = 2.6; 95% CI: 1.2-5.8; P = 0.019) and PNI <36 (HR = 3.5; 95% CI: 1.2-9.6; P = 0.018) were associated with poorer DFS.AL was associated with poorer DFS. In patients with AL, a suppressed neutrophil proportion and decreased PNI below 36 were associated with tumor recurrence. PMID- 27472727 TI - Awakening arterial blood and end-tidal concentrations of isoflurane in female surgical patients. AB - Delayed extubation occurs after isoflurane anesthesia, especially following prolonged surgical duration. We aimed to determine the arterial blood concentrations of isoflurane and the correlation with end-tidal concentrations for predicting emergence from general anesthesia.Thirty-four American Society of Anesthesiologists physical status class I-II gynecologic patients were included. General anesthesia was maintained with a fixed 2% inspiratory isoflurane in 6 L/minute oxygen, which was discontinued after surgery. One milliliter of arterial blood was obtained for the determination of isoflurane concentration by gas chromatography at 20 and 10 minutes before and 0, 5, 10, 15, and 20 minutes after discontinuation, in addition to the time of eye opening to verbal command, defined as awakening. Inspiratory and end-tidal concentrations were simultaneously detected by an infrared analyzer.The mean awakening arterial blood concentration of isoflurane was 0.20%, which was lower than the simultaneous end tidal concentration 0.23%. The differences between arterial and end-tidal concentrations during emergence fell into an acceptable range (+/-1.96 standard deviation). After receiving a mean time of 108-minute general anesthesia, the time to eye opening after discontinuing isoflurane was 18.5 minutes (range 11-30, median 18 minutes), without statistical significance with anesthesia duration (P = 0.078) and body mass index (P = 0.170).We demonstrated the awakening arterial blood concentration of isoflurane in female patients as 0.20%. With well-assisted ventilation, the end-tidal concentration could be an indicator for the arterial blood concentration to predict emergence from shorter duration of isoflurane anesthesia. PMID- 27472728 TI - Catheter ablation versus medical rate control for persistent atrial fibrillation in patients with heart failure: A PRISMA-compliant systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND: The effectiveness of restoring the sinus rhythm by catheter ablation relative to that of medical rate control for persistent atrial fibrillation (AF) patients with heart failure (HF) remains to be defined. METHODS: We systematically searched Embase, Pubmed, the Cochrane Library, and ClinicalTrials.gov for articles that compared the outcomes of interest between catheter ablation and medical rate control therapy in persistent AF patients with HF and left ventricular systolic dysfunction (LVSD). The primary endpoint was the change in the left ventricular ejection fraction (LVEF) following catheter ablation or medical rate control therapy relative to baseline. Other endpoints included changes in cardiac function and exercise capacity, including the New York Heart Association (NYHA) class, the brain natriuretic peptide (BNP) level, the peak oxygen consumption (peak VO2), the 6-minute walk test (6MWT) results, and quality of life (QOL). RESULTS: Three randomized controlled trials (RCTs) with 143 patients were included. At the overall term follow-up, catheter ablation significantly improved the LVEF (mean difference [MD]: 6.22%; 95% confidence interval [CI]: 0.7-11.74, P = 0.03) and peak VO2 (MD: 2.81 mL/kg/min; 95% CI: 0.78-4.85, P = 0.007) and reduced the NYHA class (MD: 0.9; 95% CI: 0.59-1.21, P < 0.001) and the Minnesota Living with Heart Failure Questionnaires (MLHFQ) scores (MD: -11.05; 95% CI: -19.45 - -2.66, P = 0.01) compared with the medical rate control for persistent AF patients with HF. Alterations in parameters, such as the BNP level, 6MWT, and Short Form-36 (SF-36) questionnaire scores also revealed trends that favored catheter ablation therapy, although these differences were not significant. CONCLUSION: Catheter ablation resulted in improved LVEF, cardiac function, exercise capacity, and QOL for persistent AF patients with HF compared with the medical rate control strategy. PMID- 27472729 TI - Short-term surgical outcomes of preterm infants with necrotizing enterocolitis: A single-center experience. AB - The purpose of this study was to analyze the nature of the disease, the surgical procedures, complications, and survival of preterm infants with necrotizing enterocolitis (NEC) at our institution.Medical records of 34 preterm (gestational age <37 weeks) infants with surgical NEC were retrospectively analyzed from January 2010 to December 2014. Patients were divided into 2 groups: low birth weight (LBW, <2500 g, n = 27) and normal birth weight (NBW, >=2500 g, n = 7).The LBW and NBW groups differed dramatically in gestational age (31.2 +/- 2.2 vs. 36.3 +/- 0.5 weeks), and respiratory support (55.5% vs. 0%). The median age of NEC onset was 12 and 5 postnatal days respectively. There was an inverse association between gestational age and day of NEC onset (r = -0.470). Pneumoperitoneum, positive paracentesis, and progressive clinical deterioration were the indications for laparotomy. There was no difference in the extent of disease, in the bowel involvement, in the surgical procedures, and in the postoperative complication rates between the 2 groups. The choice of procedure has often depended upon the extent of disease (enterostomy was performed in most localized and multifocal infants, simple drainage was used in 83.3% pan intestinal patients, P < 0.001). Postoperative complications occurred in 70.5% patients. The most common complications were sepsis, intestinal stricture, and short bowel syndrome. The median hospital stay was significantly longer in the LBW group (65 vs. 19 days, P = 0.004). The overall postoperative 180-day survival rate was 70.6% (70.4% vs. 71.5%, P = 0.890, log rank test). The severity of illness was the main risk factor for mortality (8.3% in localized, 18.7% in multifocal, and 100% in pan-intestinal, P < 0.001).The short-term outcomes for surgical NEC are grave. The high mortality and postoperative complications in this study mandate urgent improvements in early recognition, expeditious operation, and better perioperative care. PMID- 27472730 TI - Developing a simple preinterventional score to predict hospital mortality in adult venovenous extracorporeal membrane oxygenation: A pilot study. AB - Despite gaining popularity, venovenous extracorporeal membrane oxygenation (VV ECMO) remains a controversial therapy for acute respiratory failure (ARF) in adult patients due to its equivocal survival benefits. The study was aimed at identifying the preinterventional prognostic predictors of hospital mortality in adult VV-ECMO patients and developing a practical mortality prediction score to facilitate clinical decision-making.This retrospective study included 116 adult patients who received VV-ECMO for severe ARF in a tertiary referral center, from 2007 to 2015. The definition of severe ARF was PaO2/ FiO2 ratio < 70 mm Hg under advanced mechanical ventilation (MV). Preinterventional variables including demographic characteristics, ventilatory parameters, and severity of organ dysfunction were collected for analysis. The prognostic predictors of hospital mortality were generated with multivariate logistic regression and transformed into a scoring system. The discriminative power on hospital mortality of the scoring system was presented as the area under receiver operating characteristic curve (AUROC).The overall hospital mortality rate was 47% (n = 54). Pre-ECMO MV day > 4 (OR: 4.71; 95% CI: 1.98-11.23; P < 0.001), pre-ECMO sequential organ failure assessment (SOFA) score >9 (OR: 3.16; 95% CI: 1.36-7.36; P = 0.01), and immunocompromised status (OR: 2.91; 95% CI: 1.07-7.89; P = 0.04) were independent predictors of hospital mortality of adult VV-ECMO. A mortality prediction score comprising of the 3 binary predictors was developed and named VV-ECMO mortality score. The total score was estimated as follows: VV-ECMO mortality score = 2 * (Pre-ECMO MV day > 4) + 1 * (Pre-ECMO SOFA score >9) + 1 * (immunocompromised status). The AUROC of VV-ECMO mortality score was 0.76 (95% CI: 0.67-0.85; P < 0.001). The corresponding hospital mortality rates to VV-ECMO mortality scores were 18% (Score 0), 35% (Score 1), 56% (Score 2), 75% (Score 3), and 88% (Score 4), respectively.Duration of MV, severity of organ dysfunction, and immunocompromised status were important preinterventional prognostic predictors for adult VV-ECMO. The 3 prognostic predictors could also constitute a practical prognosticating tool in patients requiring this advanced respiratory support. Physicians in ECMO institutions are encouraged to perform external validations of this prognosticating tool and make contributions to score optimization. PMID- 27472731 TI - Emphysematous epididymo-orchitis as a camouflage of prostate invasion secondary to rectum cancer: A case report. AB - INTRODUCTION: Emphysematous epididymo-orchitis is a rare cause of acute scrotum pain characterized by gas formation within the tissue. Diabetes mellitus and recto-seminal fistula secondary to sigmoid diverticulitis are generally accepted as being responsible for this disease. However, prostate invasion secondary to rectal cancer may be considered to be a newly identified pathogenetic mechanism. Herein, we report this rare case and illustrate the pathogenesis. CASE PRESENTATION: A 69-year-old man arrived at our emergency department presenting with sepsis and acute scrotal pain. Emphysematous epididymo-orchitis was diagnosed by scrotal sonography initially; however, advanced rectal cancer with prostate invasion was diagnosed by CT after a recurrent episode. An exploratory laparotomy with abdominoperineal resection and radical prostectomy were performed after neoadjuvant chemoradiotherapy. Histopathologic analysis confirmed the previous diagnosis. Emphysematous epididymo-orchitis caused by advanced rectal cancer is very rare, and our case is the first to be reported according to a literature search. Neoadjuvant chemoradiotherapy plus extended surgery can achieve a good oncological outcome. CONCLUSION: This case indicated that the very rare presentation as emphysematous epididymo-orchitis caused by locally advanced colorectal cancer. PMID- 27472732 TI - Blood flow speed of the gastric conduit assessed by indocyanine green fluorescence: New predictive evaluation of anastomotic leakage after esophagectomy. AB - Anastomotic leakage is considered as an independent risk factor for postoperative mortality after esophagectomy, and an insufficient blood flow in the reconstructed conduit may be a risk factor of anastomotic leakage. We investigated the clinical significance of blood flow visualization by indocyanine green (ICG) fluorescence in the gastric conduit as a means of predicting the leakage of esophagogastric anastomosis after esophagectomy.Forty patients who underwent an esophagectomy with gastric conduit reconstruction were prospectively investigated. ICG fluorescence imaging of the gastric conduit was detected by a near-infrared camera system during esophagectomy and correlated with clinical parameters or surgical outcomes.In 25 patients, the flow speed of ICG fluorescence in the gastric conduit wall was simultaneous with that of the greater curvature vessels (simultaneous group), whereas in 15 patients this was slower than that of the greater curvature vessels (delayed group). The reduced speed of ICG fluorescence stream in the gastric conduit wall was associated with intraoperative blood loss (P = 0.008). Although anastomotic leakage was not found in the simultaneous group, it occurred in 7 patients of the delayed group (P < 0.001). A flow speed of ICG fluorescence in the gastric conduit wall of 1.76 cm/s or less was determined by a receiver operating characteristic (ROC) curve, identified as a significant independent predictor of anastomotic leakage after esophagectomy (P = 0.004).This preliminary study demonstrates that intraoperative evaluation of blood flow speed by ICG fluorescence in the gastric conduit wall is a useful means to predict the risk of anastomotic leakage after esophagectomy. PMID- 27472733 TI - Natural conception in HIV-serodiscordant couples with the infected partner in suppressive antiretroviral therapy: A prospective cohort study. AB - The potential of antiretroviral treatment (ART) to prevent the sexual transmission of HIV has increased the number of serodiscordant couples who are considering natural conception. We aim to describe the results of a protocol for reproductive counseling aimed at HIV serodiscordant couples who desire natural conception, in which the infected partner, the index case, is receiving suppressive antiretroviral treatment.A prospective cohort included all HIV serodiscordant couples attended a counseling program in the period 2002 to 2013 who opted for natural conception and met the following criteria: index case on ART with persistent plasma viral suppression for at least the previous 6 months, ART compliance over 95%, preserved immune status, undetectable HIV viral and proviral load in semen in male index cases, and absence of genitourinary infections and fertility problems in both members of the couple.Of the 161 HIV serodiscordant couples included, 133 with male index cases, 66% achieved at least 1 pregnancy, 18% a second one, and 5% a third pregnancy. A total of 144 natural pregnancies occurred and 107 babies were born. The pregnancy rate was 1.9 for each 100 acts of vaginal intercourse, and the mean time to conception was 6.1 months, both independently of the sex of the index case. No case of sexual or vertical HIV transmission occurred.In the absence of fertility problems and under controlled conditions, natural conception might be a safe and effective reproductive method for those HIV serodiscordant couples who choose this reproductive option. PMID- 27472734 TI - Students' perception and experience of intimate area examination and sexual history taking during undergraduate clinical skills training: A study from two Saudi medical colleges. AB - This study explores the experiences of Saudi undergraduate medical students about intimate-area examination (IAE) and sexual history taking (SHT) skills and assesses the barriers and their impacts on students' learning. This survey-based study was performed at 2 Saudi university medical colleges and revealed that most of the students never performed IAE, that is, female breast, male genital, female genital, female pelvic, male rectal, and female rectal. We found that 42.3% students had never taken any sexual history during their course. Both, male and female students reported barriers of patient refusal, mismatched sex, cultural background, ethical factors, lack of supervision, lack of training, and lack of skills. Among the currently used pedagogical techniques, majority of the students were satisfied with real patient-based learning, followed by video and manikin based learning. The study indicates that Saudi students do not have sufficient experience of IAE and SHT because of above-mentioned barriers along with religious issues. This study suggests that teachers provide positive support to students and that they develop novel, competent teaching-and-learning techniques to meet the skills training of students without compromising on religious, sociocultural, and ethical values of the kingdom. PMID- 27472735 TI - Leiomyoma originating from axilla: A rare case report and differential diagnosis. AB - INTRODUCTION: Leiomyoma is a form of benign tumor originated in hypertrophy of the smooth muscles, which is most prevalent in the uterus and gastrointestinal tract. However, Leiomyoma originating from smooth muscle at the vessels lying on deep soft tissue is very rare. CASE REPORT: Our case was a rare case of leiomyoma originating from the axillary region, which was initially diagnosed as a fibroadenoma on radiological examination. The mass was separated from surrounding tissues and totally resected. Pathologically, hematoxylin-eosin-stained biopsy tissue showed the typical findings of leiomyoma. Postoperative follow-up observation was done for 1 year, without any complications or recurrence. CONCLUSION: Notably, a leiomyoma in the axillary region is difficult to differentiate from other benign or malignant tumors on preoperative radiological examinations such as ultrasonography or computed tomgraphy. Therefore, when an indefinite asymptomatic mass that is not lymphadenopathy or common benign tumor is identified in the axillary region, leiomyoma can be considered as one of the differential diagnoses. PMID- 27472736 TI - Relative and combined effects of socioeconomic status and diabetes on mortality: A nationwide cohort study. AB - Both low socioeconomic status (SES) and diabetes mellitus (DM) are important risk factors for mortality. However, little is known about their combined effects and relative contribution to the mortality risk.From a nationwide cohort provided by the National Health Insurance Service in Korea, 153,075 subjects who were over 30 years of age from 2003 to 2004 were followed-up until 2010. The SESs of the subjects in the DM and non-DM (NDM) groups were categorized into 3 groups (highest 30% as S1, middle 40% as S2, and lowest 30% as S3) based on the subjects' income levels.During the 7.9-year follow-up, 3933 deaths occurred. When the subjects were stratified into 6 groups by their socioeconomic and diabetes status, a linearly increasing pattern of the hazard ratio (HR) of mortality from the higher SES without diabetes group (NDM-S1, as a reference) to the lower SES with diabetes group (DM-S3; HR, 2.04, 95% confidence interval (CI), 1.80-2.36) was observed (P for trend < 0.001). Notably, subjects with DM in the highest SES group (DM-S1) had a significantly higher mortality risk than did non-DM subjects in the lowest SES group (NDM-S3). This pattern was maintained in cause-specific mortality but was more prominent in cardiovascular disease (CVD) and less prominent in cancer mortality. The association was not affected by gender; however, in individuals <60 years of age, the combined effects of SES and DM on mortality were more prominent (DM-S3; HR, 3.68, 95% CI, 2.95-4.60) than in those >=60 years of age.Low SES and DM were major determinants of mortality and synergistically increased the risks of all-cause, CVD, and cancer mortality. PMID- 27472737 TI - Improving risk assessment and familial aggregation of age at onset in schizophrenia using minor physical anomalies and craniofacial measures. AB - Age at onset is the most important feature of schizophrenia that could indicate its origin. Minor physical anomalies (MPAs) characterize potential marker indices of disturbances in early neurodevelopment. However, the association between MPAs and age at onset of schizophrenia is still unclear. We aimed to compare risk assessment and familial aggregation in patients with early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) with MPAs and craniofacial measures.We estimated the risk assessment of MPAs among patients with EOS (n = 68), patients with AOS (n = 183), nonpsychotic relatives (n = 147), and healthy controls (n = 241) using 3 data-mining algorithms. In addition, we assessed the magnitude of familial aggregation of MPAs with respect to the age at onset of schizophrenia.The performance of EOS was superior to that of AOS, with discrimination accuracies of 89% and 76%, respectively. Combined MPA scores as the risk assessment were significantly higher in all schizophrenia subgroups and the nonpsychotic relatives of EOS patients than in the healthy controls. The recurrence risk ratio for familial aggregation of the MPA scores of EOS families (odds ratio 9.27) was substantially higher than that of AOS families (odds ratio 2.47).The results highlight that EOS improves risk assessment and has a severe magnitude of familial aggregation of MPAs. These findings indicate that EOS might result from a stronger genetic susceptibility to neurodevelopmental deficits. PMID- 27472738 TI - Increased risk of systemic lupus erythematosus in pregnancy-induced hypertension: A nationwide population-based retrospective cohort study. AB - Dysregulation of the immune system plays a role in the pathogenesis of both, pregnancy-induced hypertension (PIH) and systemic lupus erythematosus (SLE). It is well known that SLE predisposes to be complicated with PIH. However, few studies have attempted to investigate whether PIH increased subsequent SLE risk.The objectives of this study were to assess the association between PIH and subsequent SLE risk and identify predictive risk factors.Patients with newly diagnosed PIH were selected from the Taiwan National Health Insurance Research Database (NHIRD) and compared with a matched cohort without PIH based on age and the year of delivery. The incidence of new-onset SLE was evaluated in both cohorts. The overall observational period was from January 1, 2000 to December 31, 2013.Among the 23.3 million individuals registered in the NHIRD, 29,091 patients with PIH and 116,364 matched controls were identified. The incidence of SLE was higher among patients with PIH than in the matched controls (incidence rate ratio [IRR] = 4.02, 95% confidence interval [CI] 3.98-4.05, P < 0.0001). The IRR for subsequent SLE development remained significantly higher in all stratifications during the follow-up years. The multivariate Cox regression model was performed and the results showed that PIH may be an independent risk factors for the development of subsequent SLE (hazard ratio [HR] = 2.87, 95% CI 2.07 3.98, P < 0.0001). Moreover, multivariate Cox regression model was used again among the PIH cohort only in order to identify the possible risk factors for subsequent SLE in the population with PIH.Patients with PIH may have higher risk of developing newly diagnosed SLE than those without PIH. In addition, among individuals who have experienced PIH, those younger than 30 years, having experienced preeclampsia/eclampsia, single parity, preterm birth, or chronic kidney disease, may display an increased subsequent risk of SLE. PMID- 27472739 TI - 18F-FDG uptake for prediction EGFR mutation status in non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are a response to EGFR-tyrosine kinase inhibitor. However, a lack of sufficient tumor tissue has been a limitation for determining EGFR mutation status in clinical practice. The objective of this study was to predict EGFR mutation status in NSCLC patients based on a model including maximum standardized uptake value (SUVmax) and clinical features.We retrospectively reviewed NSCLC patients undergoing EGFR mutation testing and pretreatment positron emission tomography/computed tomography between March 2009 and December 2013. The relationships of EGFR mutations with both SUVmax and patient characteristics were evaluated, and a multivariate logistic regression analysis was performed. The model was assessed by area under the receiver-operating characteristic curve (AUC) and was prospectively validated during January to June 2014.Three hundred and sixteen patients meeting the criteria were enrolled for model construction. The SUVmax values were significantly lower for EGFR mutations (mean, 9.5 +/- 5.74) than for EGFR wild-type (mean, 12.7 +/- 6.43; P < 0.001). ROC curve analysis showed that the SUVmax cutoff point was 8.1, for which the AUC was 0.65 (95% confidence interval [CI], 0.60-0.72). In addition, multivariate analysis also showed that low SUVmax (<=8.1) was a predictor of EGFR mutations, for which the AUC was 0.77, combining nonsmoking history and primary tumor size (<=5 cm). Eighty-five patients were enrolled to validate the predictive model, and the overall accuracy, sensitivity, and specificity were 77.6%, 64.6% (95% CI 40.7 82.8), and 82.5% (95% CI 70.9-91.0), respectively.The specific FDG uptake value could be considered to effectively predict EGFR mutation status of NSCLC patients by considering smoking history and primary tumor size when genetic tests are not available. PMID- 27472740 TI - Outcomes of thoracoscopy versus thoracotomy for esophageal atresia with tracheoesophageal fistula repair: A PRISMA-compliant systematic review and meta analysis. AB - BACKGROUND: A thoracoscopic approach for repair of esophageal atresia (EA) with tracheoesophageal fistula (TEF) has become a standard procedure in many pediatric surgical centers. However, whether thoracotomy or thoracoscopy offer advantages in terms of surgical outcomes is not known. METHODS: To evaluate the efficacy and safety of thoracoscopic repair (TR) versus conventional open repair (COR) for EA with TEF.PubMed, Cochrane Library, and EMBASE were searched to identify relevant literature until 2016.Studies comparing surgical outcomes of patients undergoing TR versus COR for EA with TEF were reviewed.The quality of each included study was assessed using the Newcastle-Ottawa scale score. A fixed or random-effect model was applied depending on heterogeneity tests. RESULTS: Eight observational clinical studies involving 452 patients were included in this meta-analysis. The meta-analysis of 2 major postoperative complications (leaks and strictures) did not show significant differences between TR and COR. Overall estimates of the odds ratio (OR) of TR versus COR for leaks and strictures were: 1.57 (95% confidence interval [CI], 0.77-3.20; P = 0.22) and 0.90 (95% CI, 0.27-2.97; P = 0.86), respectively. However, meta-analysis of operation time (OR = 19.59, 95% CI = 0.77-38.40, P = 0.04), timing of extubation (OR = -2.50, 95% CI = -3.39 to 1.62, P < 0.001), time to 1st oral feeding (OR = -2.58, 95% CI = -3.79 to -1.36, P < 0.001), and duration of hospital stay (OR = -10.76, 95% CI = -16.39 to -5.12, P < 0.001) showed significant differences.No randomized controlled trial was included, and most studies had small sample sizes and were based on retrospective analysis. CONCLUSION: TR and COR show a similar complication rates of leaks and strictures for EA/TEF repair. Although associated with a longer operative time, TR has the advantages of an earlier time to extubation and 1st oral feeding, and shorter hospital stay. PMID- 27472741 TI - Multiple T-cell responses are associated with better control of acute HIV-1 infection: An observational study. AB - Cytotoxic T lymphocyte (CTL) responses play pivotal roles in controlling the replication of human immunodeficiency virus type 1 (HIV-1), but the correlation between CTL responses and the progression of HIV-1 infection are controversial on account of HIV immune escape mutations driven by CTL pressure were reported.The acute HIV-1-infected patients from Beijing were incorporated into our study to investigate the effects of CTL response on the progression of HIV-1 infection.A longitudinal study was performed on acute HIV-1-infected patients to clarify the kinetic of T-cell responses, the dynamic of escape mutations, as well as the correlation between effective T-cell response and the progression of HIV infection.Seven human leukocyte antigen-B51+ (HLA-B51+) individuals were screened from 105 acute HIV-1 infectors. The detailed kinetic of HLA-B51-restricted CTL responses was described through blood sampling time points including seroconversion, 3 and 6 months after HIV-1 infection in the 7 HLA-B51+ individuals, by using 16 known HLA-B51 restricted epitopes. Pol743-751 (LPPVVAKEI, LI9), Pol283-289 (TAFTIPSI, TI8), and Gag327-3459 (NANPDCKTI, NI9) were identified as 3 dominant epitopes, and ranked as starting with LI9, followed by TI8 and NI9 in the ability to induce T-cell responses. The dynamics of escape mutations in the 3 epitopes were also found with the same order as T-cell response, by using sequencing for viral clones on blood sampling at seroconversion, 3 and 6 months after HIV-1 infection.We use solid evidence to demonstrate the correlation between T-cell response and HIV-1 mutation, and postulate that multiple T-cell responses might benefit the control of HIV-1 infection, especially in acute infection phase. PMID- 27472742 TI - Complement activation and effect of eculizumab in scleroderma renal crisis. AB - BACKGROUND: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill defined, but a growing body of evidence suggests that activation of the complement system may be involved. METHODS: Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the kidney, in the absence of genetic defect of the complement system. RESULTS: Immunofluorescence studies on kidney biopsy showed significant deposits of C1q and C4d in the endothelium of renal arterioles, pointing toward activation of the classical pathway. Because of the dramatic clinical and histological severity, and the lack of response to early treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers and plasma exchange, the patient was treated with the specific C5 blocker eculizumab.Contrarily to conventional treatment, eculizumab efficiently blocked C5b-9 deposition ex vivo and maintained hematological remission. Unfortunately, the patient died from heart failure a few weeks later. Postmortem examination of the heart showed diffuse patchy interstitial fibrosis, the typical lesion of systemic sclerosis-related cardiomyopathy, but normal coronary arteries and myocardial microvasculature. CONCLUSION: SRC may lead to complement system activation through the classical pathway. Early administration of C5 inhibitor eculizumab may have therapeutic potential in patients with life-threatening SRC refractory to conventional treatment using angiotensin-converting enzyme inhibitors. PMID- 27472745 TI - Erratum: Expandable cylindrical cages in the cervical spine: a review of 22 cases. PMID- 27472744 TI - Neurological outcomes and surgical complications in 221 spinal nerve sheath tumors. AB - OBJECTIVE Among all primary spinal neoplasms, approximately two-thirds are intradural extramedullary lesions; nerve sheath tumors, mainly neurofibromas and schwannomas, comprise approximately half of them. Given the rarity of these lesions, reports of surgical complications are limited. The aim of this study was to identify the rates of new or worsening neurological deficits and surgical complications associated with the resection of spinal nerve sheath tumors and the potential factors related to these outcomes. METHODS Patients were identified through a search of an institutional neuropathology database and a separate review of current procedural terminology (CPT) codes. Age, sex, clinical presentation, presence of neurofibromatosis (NF), tumor type, tumor location, extent of resection characterized as gross total or subtotal, use of intraoperative neuromonitoring, surgical complications, presence of neurological deficit, and clinical follow-up were recorded. RESULTS Two hundred twenty-one tumors in 199 patients with a mean age of 45 years were identified. Fifty-three tumors were neurofibromas; 163, schwannomas; and 5, malignant peripheral nerve sheath tumors (MPNSTs). There were 70 complications in 221 cases, a rate of 32%, which included 34 new or worsening sensory symptoms (15%), 12 new or worsening motor deficits (5%), 10 CSF leaks or pseudomeningoceles (4%), 11 wound infections (5%), 5 cases of spinal deformity (2%), and 6 others (2 spinal epidural hematomas, 1 nonoperative cranial subdural hematoma, 1 deep venous thrombosis, 1 case of urinary retention, and 1 recurrent laryngeal nerve injury). Complications were more common in cervical (36%) and lumbosacral (38%) tumors than in thoracic (18%) lesions (p = 0.021). Intradural and dumbbell lesions were associated with higher rates of CSF leakage, pseudomeningocele, and wound infection. Complications were present in 18 neurofibromas (34%), 50 schwannomas (31%), and 2 MPNSTs (40%); the differences in frequency were not significant (p = 0.834). Higher complication rates were observed in patients with NF than in patients without (38% vs 30%, p = 0.189), although rates were higher in NF Type 2 than in Type 1 (64% vs 31%). There was no difference in the use of intraoperative neuromonitoring when comparing cases with surgical complications and those without (67% vs 69%, p = 0.797). However, the use of neuromonitoring was associated with a significantly higher rate of gross-total resection (79% vs 66%, p = 0.022). CONCLUSIONS Resection is a safe and effective treatment for spinal nerve sheath tumors. Approximately 30% of patients developed a postoperative complication, most commonly new or worsening sensory deficits. This rate probably represents an inevitable complication of nerve sheath tumor surgery given the intimacy of these lesions with functional neural elements. PMID- 27472746 TI - Lateral pectoral nerve transfer for spinal accessory nerve injury. AB - Spinal accessory nerve (SAN) injury results in loss of motor function of the trapezius muscle and leads to severe shoulder problems. Primary end-to-end or graft repair is usually the standard treatment. The authors present 2 patients who presented late (8 and 10 months) after their SAN injuries, in whom a lateral pectoral nerve transfer to the SAN was performed successfully using a supraclavicular approach. PMID- 27472747 TI - Structured Approach Therapy for Combat-Related PTSD in Returning U.S. Veterans: Complementary Mediation by Changes in Emotion Functioning. AB - To address the impact of combat-related posttraumatic stress disorder (PTSD) on U.S. Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans, the investigators developed a 12-session manualized PTSD treatment for couples called structured approach therapy (SAT). A randomized controlled trial had shown that 29 OEF/OIF veterans with combat-related PTSD who had participated in SAT showed significantly greater reductions in PTSD compared to 28 veterans receiving a 12-session PTSD family education intervention (Sautter, Glynn, Cretu, Senturk, & Vaught, 2015). We conducted supplemental follow-up and mediation analyses, which tested the hypothesis that changes in emotion functioning play a significant role in the decreases in PTSD symptoms primarily observed in veterans who had received SAT. Veterans assigned to the SAT condition showed significantly greater decreases than those assigned to PTSD family education in emotion regulation problems (p < .001, Cohen's f(2) = .18) and fear of intense emotions (p < .001, Cohen's f(2) = .152). Decreases in both emotion regulation problems (mediated effect:ab= .36), and fear of intense emotions (mediated effect:ab = .24) were found to be complementary mediators of reductions in PTSD symptoms greater with SAT. These findings suggest that SAT may aid veterans in improving their ability to regulate trauma-related emotions. PMID- 27472748 TI - The use of fermentation liquid of wastewater primary sedimentation sludge as supplemental carbon source for denitrification based on enhanced anaerobic fermentation. AB - Wastewater primary sedimentation sludge was prepared into fermentation liquid as denitrification carbon source, and the main components of fermentation liquid was short-chain volatile fatty acids. Meanwhile, the acetic acid and propionic acid respectively accounted for about 29.36% and 26.56% in short-chain volatile fatty acids. The performance of fermentation liquid, methanol, acetic acid, propionic acid and glucose used as sole carbon source were compared. It was found that the denitrification rate with fermentation liquid as carbon source was 0.17mgNO3(-) N/mg mixed liquor suspended solid d, faster than that with methanol, acetic acid, and propionic acid as sole carbon source, and lower than that with glucose as sole carbon source. For the fermentation liquid as carbon source, the transient accumulation of nitrite was insignificantly under different initial total nitrogen concentration. Therefore, the use of fermentation liquid for nitrogen removal could improve denitrification rate, and reduce nitrite accumulation in denitrification process. PMID- 27472749 TI - Effect of sludge retention time on continuous-flow system with enhanced biological phosphorus removal granules at different COD loading. AB - The effect of sludge retention time (SRT) on the continuous-flow system with enhanced biological phosphorus removal (EBPR) granules at different COD loading was investigated during the operation of more than 220days. And the results showed that when the system operated at long SRT (30days) and low COD loading (200mg.L(-1)), it could maintain excellent performance. However, long SRT and high COD loading (300mg.L(-1)) deteriorated the settling ability of granules and the performance of system and resulted in the overgrowth of filamentous bacteria. Meanwhile, the transformation of poly-beta-hydroxyalkanoates (PHAs) and glycogen in metabolism process was inhibited. Moreover, the results of pyrosequencing indicated that filamentous bacteria had a competitive advantage over polyphosphate-accumulating organisms (PAOs) at high COD loading and long SRT. The PAOs specious of Candidatus_Accumlibater and system performance increased obviously when the SRT was reduced to 20days at high COD loading. PMID- 27472750 TI - Organ Doses From Diagnostic Medical Radiography-Trends Over Eight Decades (1930 to 2010). AB - This study provides a retrospective assessment of doses to 13 organs for the most common radiographic examinations conducted between the 1930s and 2010, taking into account typical technical parameters used for radiography during those years. This study is intended to be a resource on changes in medical diagnostic radiation exposure over time with a specific purpose of supporting retrospective epidemiological studies of radiation health risks. The authors derived organ doses to the brain, esophagus, thyroid, red bone marrow, lungs, breast, heart, stomach, liver, colon, urinary bladder, ovaries, and testes based on 14 common radiographic procedures and compared, when possible, with doses reported in the literature. These dose estimates were based on radiographic exposure parameters described in textbooks widely used by radiologic technologists in training from 1939 to 2010. The derived estimated doses presented here are believed to be representative of typical organs for an average-size adult who might be considered to be similar to the reference person. There were large variations in organ doses noted among the different types of radiographic examinations. Doses were highest in organs within the area imaged and next highest in organs in close proximity to the area imaged. Estimated organ doses have declined substantially [overall 22-fold (+/-38)] over time as a consequence of changes in technology, imaging protocols and protective measures. For some examinations, only slight differences were observed in doses for the decades of the 1960s, 1970s, and 1980s due to minor changes in technical parameters. Substantial dose reductions were observed in the 1990s and 2000s. PMID- 27472751 TI - Radiochemical Characterization of Algae Products Commercialized for Human Consumption. AB - Natural radionuclides and Cs were determined by alpha (U, U, Th,Po,Th, and Th) and gamma spectrometry (Cs, K, Ra, Pb, and Ra via Ac) in 14 dried seaweeds commercialized for human nutrition in Italy. The study was carried out in order to provide information on the concentrations of natural and artificial radionuclides. Cesium-137 (Cs) concentrations in all analyzed samples were always <2.0 Bq kg (dry weight), while the naturally occurring radionuclide concentrations were detectable in all the samples and significantly different in the analyzed seaweeds. Potassium-40 (K) showed a mean activity of 894 Bq kg with a range of 14.1-3,256 Bq kg. The mean of activity for Po was 5.1 Bq kg with a range of 1.5-13.6 Bq kg. The mean of activity for Pb was 8.9 Bq kg with a range of 2.9-25.7 Bq kg. The mean of U and Ra activity concentration was 4.7 and 8.4 Bq kg with a range of 0.1-27.7 and 3.2-24.6 Bq kg, respectively. The mean activity concentrations for Th, Th, and Ra were 0.69, 3.0, and 6.6 Bq kg with ranges of 0.05-3.39, 0.24-15.7, and 0.5-35.6 Bq kg, respectively. Radionuclide activity concentrations were within ranges reported in the scientific literature. The committed effective dose due to all the radionuclides analyzed, from ingestion of 1 kg y of seaweeds, accounts for 0.66% of the natural radiation exposure in Italy. PMID- 27472752 TI - Assessment of Natural Radioactivity and Radiological Hazards in Brick Samples Used in Tiruvannamalali District, Tamilnadu, India, With a Statistical Approach. AB - The activity concentration of Ra, Th and K in brick samples used in Tiruvannamalai District of Tamilnadu has been determined using gamma ray spectrometry. The activity concentration ranges from BDL to 16.02 Bq kg, 17.86 to 120.19 Bq kg, 240.09 to 481.35 Bq kg for Ra, Th, and K, respectively. The concentration of these radionuclides is compared with reported data from other countries. The radium equivalent activity (Raeq), absorbed gamma dose rate (DR), annual effective dose rate (HR), annual gonadal dose equivalent (AGDE), criteria formula (CF), representative level index (RLI), activity utilization index (AUI), gamma index (Igamma), alpha index (Ialpha), the external hazard (Hex), and internal hazard (Hin) indices are calculated for the measured samples to assess the radiation hazards due to the use of these materials in the construction of dwellings. Multivariate statistical techniques (Pearson correlation, principal component analysis and cluster analysis) are used to study the relation between radionuclides and radiation hazards. The treatment of 14 radioactive variables sampled at 32 bricks by the factor and cluster analyses provided a possible interpretation of the collective data. The spatial distribution pattern of radionuclides has been depicted through the Kriging method using MapInfo software. PMID- 27472753 TI - Radon Levels Measured at a Touristic Thermal Spa Resort in Montagu (South Africa) and Associated Effective Doses. AB - Radon activity concentrations (in water and in air) were measured at 13 selected locations at the Avalon Springs thermal spa resort in Montagu (Western Cape, South Africa) to estimate the associated effective dose received by employees and visitors. A RAD-7 detector (DURRIDGE), based on alpha spectrometry, and electret detectors (E-PERM(r)Radelec) were used for these radon measurements. The primary source of radon was natural thermal waters from the hot spring, which were pumped to various locations on the resort, and consequently a range of radon in-water analyses were performed. Radon in-water activity concentration as a function of time (short term and long term measurements) and spatial distributions (different bathing pools, etc.) were studied. The mean radon in-water activity concentrations were found to be 205 +/- 6 Bq L (source), 112 +/- 5 Bq L (outdoor pool) and 79 +/- 4 Bq L (indoor pool). Radon in-air activity concentrations were found to range between 33 +/- 4 Bq m (at the outside bar) to 523 +/- 26 Bq m (building enclosing the hot spring's source). The most significant potential radiation exposure identified is that due to inhalation of air rich in radon and its progeny by the resort employees. The annual occupational effective dose due to the inhalation of radon progeny ranges from 0.16 +/- 0.01 mSv to 0.40 +/- 0.02 mSv. For the water samples collected, the Ra in-water activity concentrations from samples collected were below the lower detection limit (~0.7 Bq L) of the gamma-ray detector system used. No significant radiological health risk can be associated with radon and progeny from the hot spring at the Avalon Springs resort. PMID- 27472754 TI - Some Analysis of Integrated-count Processing for Fixed-filter Continuous Particulate Air Monitors. AB - A calculation for estimating concentrations of long-lived airborne particulate radioactivity using fixed-filter continuous air monitors is given in an ISO standard. The method uses counts integrated over relatively long time intervals, rather than the 'instantaneous' count rates that in digital systems are evaluated using much shorter time intervals and some form of variance-reduction filtering. This article presents three ways of deriving and interpreting this calculation, based on previously published mathematical models that were derived from first principles. The method is also extended here to apply for short-lived activity. Some statistical properties of the estimator are discussed, including its time dependent variance and the presence of strong autocorrelation in the concentration estimates. An interactive simulation was used to examine the performance of the concentration estimation, using physically plausible concentration time-dependence profiles; example plots are provided. The conclusion of these studies is that the method, as modified herein, can perform remarkably well in providing periodic average-concentration estimates for both long- and short-lived activity, and it should be considered an appropriate method in those situations where the tracking of a time-dependent concentration is deemed necessary. PMID- 27472755 TI - A Closer Look at the Thresholds of Thermal Damage: Workshop Report by an ICNIRP Task Group. AB - The International Commission on Non-Ionizing Radiation Protection issued guidelines in 1998 for limiting public and occupational exposure to radiofrequency electromagnetic fields (100 kHz to 300 GHz). As part of the process of updating this advice, a 2-d workshop titled "A closer look at the thresholds of thermal damage" was held from 26-28 May 2015 in Istanbul to re examine the thermal basis of the guidelines and to provide further information on heat-related effects and thresholds of thermal damage. Overall, the workshop provided much useful information relevant to revision of the guidelines. Participants indicated that the effects of heating from radiofrequency fields are consistent with those from other sources, and that the information derived from those studies can be applied to radiofrequency-induced heating. Another conclusion was that absolute temperature of tissues was more important for thermal damage than temperature change. The discussion suggested that the 6-min averaging time used in international guidelines was valid for whole-body exposures but with a large uncertainty: 30 min may be a more appropriate averaging time for localized exposures, and less than 1 min for implanted medical devices. The duration of whole-body radiofrequency exposure is a critical parameter that often determines the effect threshold, but this will be affected by other, ongoing thermoregulation, which is dependant on many factors. The thresholds for localized radiofrequency exposure were difficult to determine because of the potential range of exposure conditions and the possibility of radiofrequency-induced local hotspots. Suggestions for future dose metrics and further research were discussed and are included in this report. PMID- 27472756 TI - Response to "Urgent Change Needed to Radiation Protection Policy". PMID- 27472757 TI - Response to Beyea. PMID- 27472761 TI - Cytomegalovirus Infection of the Rat Developing Brain In Utero Prominently Targets Immune Cells and Promotes Early Microglial Activation. AB - BACKGROUND: Congenital cytomegalovirus infections are a leading cause of neurodevelopmental disorders in human and represent a major health care and socio economical burden. In contrast with this medical importance, the pathophysiological events remain poorly known. Murine models of brain cytomegalovirus infection, mostly neonatal, have brought recent insights into the possible pathogenesis, with convergent evidence for the alteration and possible involvement of brain immune cells. OBJECTIVES AND METHODS: In order to confirm and expand those findings, particularly concerning the early developmental stages following infection of the fetal brain, we have created a model of in utero cytomegalovirus infection in the developing rat brain. Rat cytomegalovirus was injected intraventricularly at embryonic day 15 (E15) and the brains analyzed at various stages until the first postnatal day, using a combination of gene expression analysis, immunohistochemistry and multicolor flow cytometry experiments. RESULTS: Rat cytomegalovirus infection was increasingly seen in various brain areas including the choroid plexi and the ventricular and subventricular areas and was prominently detected in CD45low/int, CD11b+ microglial cells, in CD45high, CD11b+ cells of the myeloid lineage including macrophages, and in CD45+, CD11b- lymphocytes and non-B non-T cells. In parallel, rat cytomegalovirus infection of the developing rat brain rapidly triggered a cascade of pathophysiological events comprising: chemokines upregulation, including CCL2-4, 7 and 12; infiltration by peripheral cells including B-cells and monocytes at E17 and P1, and T-cells at P1; and microglia activation at E17 and P1. CONCLUSION: In line with previous findings in neonatal murine models and in human specimen, our study further suggests that neuroimmune alterations might play critical roles in the early stages following cytomegalovirus infection of the brain in utero. Further studies are now needed to determine which role, whether favorable or detrimental, those putative double-edge swords events actually play. PMID- 27472762 TI - Platelet-Lymphocyte Ratio as a Useful Predictor of the Therapeutic Effect of Neoadjuvant Chemotherapy in Breast Cancer. AB - BACKGROUND: The peripheral blood platelet-lymphocyte ratio (PLR) has been proposed as an indicator for evaluating systemic inflammatory responses in cancer bearing patients. While some reports suggest a correlation between PLR and prognosis, few studies have examined the relationship between PLR and sensitivity to chemotherapy. We conducted a study on whether PLR could serve as a predictor of the therapeutic effects of neoadjuvant chemotherapy (NAC). METHODS: PLR was evaluated in 177 breast cancer patients treated with the NAC 5-fluorouracil, epirubicin and cyclophosphamide, followed by weekly paclitaxel and subsequent curative surgery. The correlation between PLR and prognosis, and between PLR and the efficacy of NAC, were evaluated retrospectively. RESULTS: The low PLR group had significantly more patients > 56 years old (p = 0.001) and postmenopausal women (p = 0.001) than the high PLR group. The low PLR group also had a higher pathologic complete response (pCR) rate (p = 0.019). On examining the correlation with prognosis, the low-PLR group was found to have significantly longer disease free survival (p = 0.004) and overall survival (p = 0.032) than the high PLR group. Multivariate analysis also revealed that lymph node metastasis (p = 0.043, hazard ratio = 4.40) and a high PLR (p = 0.005, hazard ratio = 2.84) were independent, unfavorable prognostic factors. CONCLUSIONS: For patients with breast cancer treated with NAC, a low PLR indicated high chemotherapy sensitivity, suggesting that PLR could serve as a predictive marker of the therapeutic effect of NAC. PMID- 27472763 TI - Chondrocyte Morphology in Stiff and Soft Agarose Gels and the Influence of Fetal Calf Serum. AB - Changes to chondrocyte volume/morphology may have deleterious effects on extracellular matrix (ECM) metabolism potentially leading to cartilage deterioration and osteoarthritis (OA). The factors controlling chondrocyte properties are poorly understood, however, pericellular matrix (PCM) weakening may be involved. We have studied the density, volume, morphology, and clustering of cultured bovine articular chondrocytes within stiff (2% w/v) and soft (0.2% w/v) three-dimensional agarose gels. Gels with encapsulated chondrocytes were cultured in Dulbecco's Modified Eagle's Medium (DMEM; fetal calf serum (FCS) 1 10%;380 mOsm) for up to 7 days. Chondrocytes were fluorescently labeled after 1, 3, and 7 days with 5-chloromethylfluorescein-diacetate (CMFDA) and propidium iodide (PI) or 1,5-bis{[2-(di-methylamino)ethyl]amino}-4,8-dihydroxyanthracene 9,10-dione (DRAQ5) to identify cytoplasmic space or DNA and imaged by confocal laser scanning microscopy (CLSM). Chondrocyte density, volume, morphology, and clustering were quantified using VolocityTM software. In stiff gels after 7 d with 10% FCS, chondrocyte density remained unaffected and morphology was relatively normal with occasional cytoplasmic processes. However, in soft gels by day 1, chondrocyte volume increased (P = 0.0058) and by day 7, density increased (P = 0.0080), along with the percentage of chondrocytes of abnormal morphology (P < 0.0001) and enhanced clustering (P < 0.05), compared to stiff gels. FCS exacerbated changes to density (P < 0.01), abnormal morphology (P < 0.001) and clustering (P < 0.01) compared to lower concentrations at the same gel strength. Reduced gel stiffness and/or increased FCS concentrations promoted chondrocyte proliferation and clustering, increased cell volume, and stimulated abnormal morphology, producing similar changes to those occurring in OA. The increased penetration of factors in FCS into soft gels may be important in the development of these abnormal chondrocyte properties. J. Cell. Physiol. 232: 1041-1052, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27472764 TI - Multiscale mechanical integrity of human supraspinatus tendon in shear after elastin depletion. AB - Human supraspinatus tendon (SST) exhibits region-specific nonlinear mechanical properties under tension, which have been attributed to its complex multiaxial physiological loading environment. However, the mechanical response and underlying multiscale mechanism regulating SST behavior under other loading scenarios are poorly understood. Furthermore, little is known about the contribution of elastin to tendon mechanics. We hypothesized that (1) SST exhibits region-specific shear mechanical properties, (2) fiber sliding is the predominant mode of local matrix deformation in SST in shear, and (3) elastin helps maintain SST mechanical integrity by facilitating force transfer among collagen fibers. Through the use of biomechanical testing and multiphoton microscopy, we measured the multiscale mechanical behavior of human SST in shear before and after elastase treatment. Three distinct SST regions showed similar stresses and microscale deformation. Collagen fiber reorganization and sliding were physical mechanisms observed as the SST response to shear loading. Measures of microscale deformation were highly variable, likely due to a high degree of extracellular matrix heterogeneity. After elastase treatment, tendon exhibited significantly decreased stresses under shear loading, particularly at low strains. These results show that elastin contributes to tendon mechanics in shear, further complementing our understanding of multiscale tendon structure function relationships. PMID- 27472766 TI - Fiduciary considerations in the physician-patient relationship. PMID- 27472765 TI - The effect of images on item statistics in multiple choice anatomy examinations. AB - Although multiple choice examinations are often used to test anatomical knowledge, these often forgo the use of images in favor of text-based questions and answers. Because anatomy is reliant on visual resources, examinations using images should be used when appropriate. This study was a retrospective analysis of examination items that were text based compared to the same questions when a reference image was included with the question stem. Item difficulty and discrimination were analyzed for 15 multiple choice items given across two different examinations in two sections of an undergraduate anatomy course. Results showed that there were some differences item difficulty but these were not consistent to either text items or items with reference images. Differences in difficulty were mainly attributable to one group of students performing better overall on the examinations. There were no significant differences for item discrimination for any of the analyzed items. This implies that reference images do not significantly alter the item statistics, however this does not indicate if these images were helpful to the students when answering the questions. Care should be taken by question writers to analyze item statistics when making changes to multiple choice questions, including ones that are included for the perceived benefit of the students. Anat Sci Educ 10: 68-78. (c) 2016 American Association of Anatomists. PMID- 27472767 TI - Perspectives and Approaches to the Dynamic and Developmental Issues in Adolescent Health Care. PMID- 27472768 TI - Providing Confidential Care to Adolescents in Healthcare Settings. PMID- 27472769 TI - Patient Engagement for Youth in Multiple Facets of Healthcare in Rhode Island. AB - Health reform strives to be patient-centered but often emphasizes institutional and financial well-being at the expense of patient responsiveness. Rhode Island is a pioneer, with innovative youth engagement programs in health care. The Youth Advisory Board of the Adolescent Patient-Centered Medical Home (PCMH) Initiative at Brown Family Medicine has brought together adolescents to gather feedback about participants' preferences for their health care and bring that feedback to health care providers. The Adolescent Leadership Council (TALC) of Hasbro Children's Hospital is comprised of adolescents with chronic medical illnesses and serves as an advisory group. The Rhode Island Department of Health's Office of Special Needs offers Dare to Dream, a youth leadership development program, a youth advisory council and a healthy lifestyles program. These youth engagement programs allow youth to help shape the health care system to meet their needs and contribute to youth empowerment in the state. [Full article available at http://rimed.org/rimedicaljournal-2016-08.asp, free with no login]. PMID- 27472770 TI - Transitions to Adult Care for Rhode Island Youth with Special Healthcare Needs. AB - The transitioning of youth from pediatric to adult care systems is often fraught with discontinuity, miscommunication and gaps in care. This is most significant for youth with special health care needs. A panel discussion on transitioning youth to adult care systems that was part of a learning collaborative held by The RI Care Transformation Collaborative (CTC) is presented here, illustrated by a pertinent case of a youth with type 1 diabetes. [Full article available at http://rimed.org/rimedicaljournal-2016-08.asp, free with no login]. PMID- 27472771 TI - Here, There and Nowhere: Following Adult Survivors of Childhood Cancer A Case Report of Recurrent Osteosarcoma in a Young Adult. AB - Approximately 1 in 285 children in the United States (US) will be diagnosed with cancer before the age of 20.1 More than 80% of children diagnosed with cancer will become long-term survivors.2 As of January, 2010, there are more than 380,000 adult survivors of childhood cancer in the US.3 More than two-thirds of survivors will develop chronic conditions.4 Professional organizations have advocated for specialized risk-based care of survivors.5 Locally and nationally, lack of transition services and insurance coverage are barriers to care of these adult survivors.6 We describe one such case to illustrate these challenges and their impact. [Full article available at http://rimed.org/rimedicaljournal-2016 08.asp, free with no login]. PMID- 27472772 TI - The Refugee Community Health Worker Initiative (RCHWI) in Rhode Island: A Pilot Program. PMID- 27472773 TI - Student-Driven Approaches to Undergraduate Medical Research: A Peer-Led Symposium. AB - Exposure to research early in medical school facilitates the development of physician-scientists and competent clinicians. In the last decade, institutions have established programs and policies to address the physician- scientist shortage. However, student-led initiatives to promote medical student engagement in research remain unexplored. This paper presents the design and results of the third iteration of a symposium in which senior medical students provided guidance and advice to preclinical students interested in research. It also reviews the lessons learned from three years of conducting the symposium. [Full article available at http://rimed.org/rimedicaljournal-2016-08.asp, free with no login]. PMID- 27472774 TI - Cocaine-induced diffuse alveolar hemorrhage: A case report and review of the literature. AB - Cocaine is one of the most commonly abused drugs in the United States. Ingestion of cocaine may result in a wide array of disease processes due to its stimulant properties, contaminants, or to downstream effects, such as myo- cardial infarction, stroke, or cardiac arrest. Pulmonary complaints are common in patients seeking treatment for cocaine-associated medical problems and include acute eosinophilic pneumonia, pneumothorax, pneumomediastium, diffuse alveolar hemorrhage (DAH), pulmonary hypertension and granulomatosis. We present a case of DAH due to cocaine abuse and rapid resolution with mechanical ventilation and supportive care. [Full article available at http://rimed.org/rimedicaljournal 2016-08.asp, free with no login]. PMID- 27472775 TI - Metastatic Prostate Cancer Presenting as Acute Appendicitis: A Case Report. PMID- 27472776 TI - Left Ventricular Free Wall Rupture. PMID- 27472777 TI - Peeping Painless Proptosis. PMID- 27472778 TI - Exploring the co-occurrence of bullying victimization, homophobic teasing and teen dating violence: Implications for prevention programs. PMID- 27472779 TI - Shared Decision Making or Paternalism? PMID- 27472780 TI - Regarding the Idiopathic Intracranial Hypertension Treatment Trial. PMID- 27472781 TI - An Improved System for Generation of Diploid Cloned Porcine Embryos Using Induced Pluripotent Stem Cells Synchronized to Metaphase. AB - Pigs provide outstanding models of human genetic diseases due to their striking similarities with human anatomy, physiology and genetics. Although transgenic pigs have been produced using genetically modified somatic cells and nuclear transfer (SCNT), the cloning efficiency was extremely low. Here, we report an improved method to produce diploid cloned embryos from porcine induced pluripotent stem cells (piPSCs), which were synchronized to the G2/M stage using a double blocking method with aphidicolin and nocodazole. The efficiency of this synchronization method on our piPSC lines was first tested. Then, we modified our traditional SCNT protocol to find a workable protocol. In particular, the removal of a 6DMAP treatment post-activation enhanced the extrusion rate of pseudo-second polar bodies (p2PB) (81.3% vs. 15.8%, based on peak time, 4hpa). Moreover, an immediate activation method yielded significantly more blastocysts than delayed activation (31.3% vs. 16.0%, based on fused embryos). The immunofluorescent results confirmed the effect of the 6DMAP treatment removal, showing remarkable p2PB extrusion during a series of nuclear transfer procedures. The reconstructed embryos from metaphase piPSCs with our modified protocol demonstrated normal morphology at 2-cell, 4-cell and blastocyst stages and a high rate of normal karyotype. This study demonstrated a new and efficient way to produce viable cloned embryos from piPSCs when synchronized to the G2/M phase of the cell cycle, which may lead to opportunities to produce cloned pigs from piPSCs more efficiently. PMID- 27472782 TI - Physiological effects of the herbicide glyphosate on the cyanobacterium Microcystis aeruginosa. AB - Glyphosate has been used extensively for weed control in agriculture in many countries. However, glyphosate can be transported into the aquatic environment and might cause adverse effects on aquatic life. This study investigated the physiological characteristics of cyanobacteria Microcystis aeruginosa (M. aeruginosa) after exposure to glyphosate, and the results showed that changes in cell density production, chlorophyll a and protein content are consistent. In M. aeruginosa, oxidative stress caused by glyphosate indicated that 48h of exposure increased the concentration of malondialdehyde (MDA) and enhanced the activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD). To further investigate the toxicity of glyphosate on M. aeruginosa, the viability of treated cells was monitored and the toxin release was determined. The results indicated that glyphosate induced apoptosis of and triggered toxin release in M. aeruginosa. These results are helpful for understanding the toxic effects of glyphosate on cyanobacteria, which is important for environmental assessment and protection. These results are also useful for guidance on the application of this type of herbicide in agricultural settings. PMID- 27472783 TI - Tributyltin affects shoaling and anxiety behavior in female rare minnow (Gobiocypris rarus). AB - Effects of tributyltin (TBT) on reproduction are well established in many fish species. However, few studies report the effects of TBT on non-reproductive behaviors, which is a novel aspect of endocrine disruption in fish. Thus, the present study used rare minnow (Gobiocypris rarus) to investigate the effects of TBT, at environmental concentrations of 1, 10 and 100ng/L, on shoaling and anxiety behaviors. The results showed that fish exposed to TBT had less group cohesion during the course of the 10-min observation period as compared with the control fish. Further, TBT altered the shoaling in the Novel tank test, where shoaling is determined as the tendency to leave a shoal of littermates trapped behind a Plexiglas barrier at one end of the test tank. Fish exposed to TBT had shorter latency before leaving shoal mates and spent more time away from shoal than control fish. In addition, we also used Novel tanks to study the anxiety behavior as the tendency to stay at the bottom when introduced into an unfamiliar environment. The fish exposed to TBT showed increased anxiety, manifested as increased latency to enter the upper half and decreased time in upper half when compared with the control fish. TBT exposure increased the levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid, and decreased the levels of 5 hydroxytryptamine and its metabolite 5-hydroxy indole acetic acid in the brain. Thus, the hypofunction of the dopaminergic system or of the serotoninergic system or the combination of the two may underlie the observed behavioral change, which might affect the fitness of fish in their natural environment. PMID- 27472784 TI - Effects and mechanisms of waterborne copper exposure influencing ovary development and related hormones secretion in yellow catfish Pelteobagrus fulvidraco. AB - The present study was conducted to determine the effects and mechanism of waterborne copper (Cu) exposure influencing ovary development and related hormones secretion in yellow catfish Pelteobagrus fulvidraco. To this end, two experiments were conducted. In Exp. 1, the partial cDNA sequences of three steroidogenesis-related genes (androgen receptor (ar), steroidogenic factor 1 (sf 1) and steroidogenic acute regulatory protein (star)) were firstly characterized from P. fulvidraco. The predicted amino acid sequences for the P. fulvidraco ar, sf-1 and star contained the main structural features characteristic in other species. In Exp. 2, P. fulvidraco were exposed to three waterborne Cu concentrations (control, 30MUg/l and 60MUg/l, respectively) for 56days. Sampling occurred on day 28 and day 56, respectively. On day 28, the levels of serum sex steroid hormones (FSH and LH) and the mRNA levels of steroidogenesis-related genes (3beta-hsd, cyp11a1, cyp17, cyp19a, sf-1 and star) were significantly increased in ovary of P. fulvidraco exposed to 30MUg Cu/l. The immunohistochemical analysis showed the positive reaction of ER, VTG and aromatase in low dose exposure group. These indicated that in low dose and relative short-term exposure, Cu was beneficial. In contrast, 60MUg Cu/l exposure significantly reduced the levels of serum FSH, LH, E2 and P, and the mRNA levels of ovarian 20beta-hsd, cyp19a and eralpha in P. fulvidraco. On day 56, waterborne Cu concentration exposure reduced the levels of serum gonadotropins and sex hormones, and down-regulated the mRNA levels of steroidogenesis-related genes, indicating long-term Cu exposure had toxic effect on the secretion of sex-steroid hormone in P. fulvidraco. For the first time, our study cloned cDNA sequences of ar, sf-1 and star in P. fulvidraco, and demonstrated the effects and mechanism of waterborne Cu exposure influencing hormones secretion and synthesis in dose- and time-dependent manner in P. fulvidraco, which will help to understand the Cu induced reproductive toxicity at both protein and transcriptional levels in fish. PMID- 27472786 TI - Professional Virtue. PMID- 27472785 TI - Anticipation of Monetary Reward Can Attenuate the Vigilance Decrement. AB - Motivation and reward can have differential effects on separate aspects of sustained attention. We previously demonstrated that continuous reward/punishment throughout a sustained attention task improves overall performance, but not vigilance decrements. One interpretation of these findings is that vigilance decrements are due to resource depletion, which is not overcome by increasing overall motivation. However, an alternative explanation is that as one performs a continuously rewarded task there are less potential gains/losses as the task progresses, which could decrease motivation over time, producing a vigilance decrement. This would predict that keeping future gains/losses consistent throughout the task would reduce the vigilance decrement. In the current study, we examined this possibility by comparing two versions (continuous-small loss vs. anticipate-large loss) of a 10-minute gradual onset continuous performance task (gradCPT), a challenging go/no-go sustained attention task. Participants began each task with the potential to keep $18. In the continuous-small-loss version, small monetary losses were accrued continuously throughout the task for each error. However, in the anticipate-large-loss version, participants lost all $18 if they erroneously responded to one target that always appeared toward the end of the vigil. Typical vigilance decrements were observed in the continuous-small loss condition. In the anticipate-large-loss condition, vigilance decrements were reduced, particularly when the anticipate-large loss condition was completed second. This suggests that the looming possibility of a large loss can attenuate the vigilance decrement and that this attenuation may occur most consistently after sufficient task experience. We discuss these results in the context of current theories of sustained attention. PMID- 27472787 TI - Justice, Courage, and Truthfulness: Virtues That Medical Trainees Can and Must Learn. AB - BACKGROUND: Medical educators and powerful physician organizations agree on the importance of professionalism for the formation of good physicians. However, the many definitions of professionalism found in the literature lack content and differ significantly, undermining attempts to describe and implement professionalism curricula. The work of the contemporary moral philosopher Alasdair MacIntyre on the virtues may help provide some of the content that the concept of professionalism currently lacks. MacIntyre shows the importance of the virtues, particularly justice, courage, and truthfulness, for the success of any "practice," defined as a form of cooperative human activity. Medicine fits his definition of a practice, and accordingly, medical trainees require these virtues, among others, to succeed. This analysis may provide a foundation for a new form of ethical instruction, in which excellent clinician-educators model the virtues for students and residents, thereby combating the "hidden curriculum" that sometimes corrodes these values. This educational model resembles the way in which masters of other practices, such as music, teach their students and help them become lifelong learners. Such an approach requires leaders at academic medical centers to commit to the establishment of communities in which the virtues flourish. Instruction in the virtues could supplement the emphasis on principles and rule following that predominates in medical education. It would also allow physicians and students to engage with the various cultural and religious traditions in which virtue ethics has flourished, enriching the diversity of medical ethics education and promoting trainees' professional development. PMID- 27472788 TI - Developing a Family Medicine Postgraduate Training Program in Zambia. AB - BACKGROUND AND OBJECTIVES: The last decade has seen a number of educational programs in family medicine begin throughout the African region as many countries have recognized that family medicine offers an efficient way to meet the growing health demands of their country. Zambia's health situation is similar to many countries in sub-Saharan Africa by having a wide array of compelling health demands and a health sector with a limited capacity to meaningfully respond. This paper describes the efforts to begin Zambia's first post-graduate training program for family medicine. Several different methods were used to assist with the launch of Zambia's first postgraduate training program in family medicine: developing a logistical framework, regional site visits, building consensus among stakeholders, defining family medicine specifically for Zambia, and the development of a curriculum. Significant outputs achieved during the start-up period include: changes to the organizational structure of the medical school, budget reconciliation, and recruitment of the teaching faculty. Challenges that remain for the near-term include identifying appropriate district-level teaching facilities and the recruitment and retention of qualified faculty. Zambia's experience in developing family medicine may prove useful to other academic medical institutions throughout the region or in comparable socioeconomic circumstances as they look to address similar health sector challenges. PMID- 27472789 TI - Influence of Provider Communication on Women's Delivery Expectations and Birth Experience Appraisal: A Qualitative Study. AB - BACKGROUND AND OBJECTIVES: Although current research suggests that patient provider prenatal communication and expectation-setting affects women's outcomes, more needs to be understood about the kinds of communication experiences that shape women's expectations, the nature of expectations that women hold, and how those expectations influence their appraisal of labor and delivery. The goal of this study is to draw connections between provider communication, birth experience expectations, and birth experience appraisals. METHODS: Recently delivered mothers (n=36) were recruited at a mid-Atlantic community hospital. Using a grounded theory approach, interviews were systematically analyzed to uncover how participants perceived provider communication during their prenatal care, how participants described their expectations of the birth experience, and how expectations affected appraisals of the experience. RESULTS: Mothers recognize providers' use of patient-centered communication in messages of empowerment, emotional support, explanation, decision making, and elicitation. Findings posit that it is the inflexibility or flexibility of expectations that may determine mothers' appraisals of the birth experience. CONCLUSIONS: Mothers continue to rely on providers as partners in health care. Through patient centered communication, providers can help mothers develop flexible expectations of the birth experience, which in turn can result in positive appraisals of delivery. PMID- 27472790 TI - Global Health in Family Medicine Residency Programs: A Nationwide Survey of US Residency Directors: A CERA Study. AB - BACKGROUND AND OBJECTIVES: Interest in global health (GH) has increased significantly among medical trainees in the past 3 decades. Despite the potential for family medicine to be a major contributor to GH, there are no recent, large scale studies of GH education and experiences in family medicine training. This study was designed to assess current opportunities, educational activities, resident interest, perceived program benefits, and barriers to international and domestic GH training in US family medicine residencies. METHODS: Data for this study were elicited as part of a 2015 survey conducted by the Council of Academic Family Medicine (CAFM) Educational Research Alliance (CERA). The nationwide, web based survey was sent to 452 family medicine residency program directors. RESULTS: A total of 257 program directors completed the GH portion of the survey. A total of 74.3% of programs offered international or domestic GH experiences. Program directors identified preparing physicians to practice underserved medicine and teaching community medicine or public health as primary goals for GH training. Program directors also reported that GH opportunities were important for attracting future residents. Programs offered a variety of preparatory activities to their residents. Funding and time constraints were identified as the primary barriers to GH training in residency. CONCLUSIONS: Global health continues to be a focus of interest in the training of family medicine residents while attracting the passion of student applicants and residents. PMID- 27472791 TI - Impact of a Psychological Opioid-Risk Evaluation on Opioid Prescribing in Primary Care. AB - BACKGROUND AND OBJECTIVES: The misuse and abuse of opioids has increased across the United States in recent years, associated with a rise in opioid-related overdose deaths. Physicians report having difficulty discerning substance abuse or drug diversion, which can lead to over- or under-prescribing of opioids and poor pain management. Additionally, research suggests that patient characteristics (eg, sex, ethnicity/race, age) may unduly influence the pain management decisions of health care providers. This investigation aimed to assist in physicians' prescribing decisions and reduce prescribing bias through the assistance of mental health professionals. METHODS: This study utilized 151 chronic pain patients being considered for chronic opioid therapy to determine if a psychological opioid-risk evaluation influenced physicians' opioid prescribing. The evaluation resulted in an opioid-risk level (ie, low, moderate, high) being assigned to each patient representing their potential risk for misusing or abusing opioid medication. A record review was conducted on each patient, abstracting information about opioid prescribing, and several other factors, which were included in logistic regression analyses. RESULTS: Risk status and substance abuse history significantly predicted opioid prescribing, with a lower risk status associated with greater likelihood of opioid prescribing and those with a history of substance abuse being less likely to be prescribed an opioid; however, substance abuse did not significantly improve the overall model and was removed. Demographic variables were not significant predictors of prescribing contrary to findings in other studies. CONCLUSIONS: These findings suggest that providing physicians with additional information about their patients' opioid abuse potential aids in prescribing decisions and may reduce prescribing bias based on demographic factors. PMID- 27472792 TI - Differential Experience With Men's and Women's Health Care Visits Between Male and Female Family Medicine Residents. AB - BACKGROUND AND OBJECTIVES: Few studies have addressed whether male family medicine residents have more exposure to men's health issues than their female colleagues. Additionally, the association between panel demographics or continuity of care and the differential experience with gender-specific health care is unclear. METHODS: Between July 1, 2011, and June 30, 2014, all residents in the family medicine program had their gender, the number of women's and men's health care visits, the total number of male and female visits, and the number of visits with patients assigned to their primary care panel recorded each academic year. To determine which visits pertained to men's or women's health care, Clinical Classification Software developed by the Agency for Healthcare Research and Quality (AHRQ) was used to map ICD9 billing codes into a useful ontology. RESULTS: Female residents had significantly more women's health visits (229 versus 123) while male residents had significantly more men's health visits (89 versus 49) than colleagues of the opposite gender. There were no significant differences in continuity, the gender distribution of panels, nor the mean age of panels. However, female residents saw a greater percentage of female visits overall (60.6% versus 53.3%). CONCLUSIONS: Both male and female resident physicians acquire more experience with same-gender health care visits during training. Panel demographics and continuity do not explain the differential experience. Patient preferences and/or biased scheduling selection may explain why residents accumulate same-gender health care visits at twice the rate of opposite-gender health care visits. PMID- 27472793 TI - Student-Led Training Day Increases Student Confidence in Women's Primary Care Skills. AB - BACKGROUND AND OBJECTIVES: Medical students are often apprehensive in approaching basic women's health concepts, including wellness exams, reproductive health concerns, and patient counseling. This study evaluates a novel student-developed and student-run Women's Health Training Day (WHTD) as a means of cultivating medical student confidence in women's primary care early in medical training. METHODS: Sixty-six first-year medical students participated in WHTD, a voluntary 6-hour weekend day of interactive workshops. Students were divided into groups of six to eight students that rotated together through five workshops focused on the breast exam, pelvic exam, microscopy, family planning, and patient interviews. Before participating in WHTD, students completed surveys indicating their confidence in performing skills related to women's health on a 5-point Likert scale. Students completed an identical survey after participating in all of the WHTD workshops. Changes in pre- and post-training day confidence scores were assessed. RESULTS: Students reported increased confidence in all of the composite sessions that were assessed. The specific skillsets demonstrating the greatest increases in student confidence were speculum handling during pelvic examinations, detecting abnormal breast masses, and recognizing the clinical presentations of common sexually transmitted infections. All but one of the evaluated skills, using a microscope, demonstrated a significant increase in student confidence. CONCLUSIONS: These results indicate that the student implemented and student-run Women's Health Training Day increases student confidence in women's primary care skills. Further studies are needed to determine whether this perceived increase in confidence is associated with increased objective knowledge pertaining to primary care and women's health. PMID- 27472794 TI - Training Requirements and Curriculum Content for Primary Care Providers Delivering Preventive Oral Health Services to Children Enrolled in Medicaid. AB - BACKGROUND AND OBJECTIVES: Despite the emphasis on delivery of preventive oral health services in non-dental settings, limited information exists about state Medicaid policies and strategies to educate practicing physicians in the delivery of these services. This study aims to determine: (1) training requirements and policies for reimbursement of oral health services, (2) teaching delivery methods used to train physicians, and (3) curricula content available to providers among states that reimburse non-dental providers for oral health services. METHODS: Using Web-based Internet searches as the primary data source, and a supplemental e-mail survey of all states offering in-person training, we assessed training requirements, methods of delivery for training, and curriculum content for states with Medicaid reimbursement to primary care providers delivering preventive oral health services. RESULTS of descriptive analyses are presented for information collected and updated in 2014. RESULTS: Forty-two states provide training sessions or resources to providers, 34 requiring provider training before reimbursement for oral health services. Web-based training is the most common CME delivery method. Only small differences in curricular content were reported by the 11 states that use in-person didactic sessions as the delivery method. CONCLUSIONS: Although we found that most states require training and curricular content is similar, training was most often delivered using Web-based courses without any additional delivery methods. Research is needed to evaluate the impact of a mixture of training methods and other quality improvement methods on increased adoption and implementation of preventive oral health services in medical practices. PMID- 27472796 TI - Inside the Lines. PMID- 27472795 TI - Big Pharma on the Farm: Students Are Exposed to Pharmaceutical Marketing More Often in Rural Clinics. AB - BACKGROUND AND OBJECTIVES: Pharmaceutical marketing techniques are effective in changing the behavior of health care providers in ways that deviate from evidence based practices. To mitigate the influence of pharmaceutical marketing on learners, academic medical centers (AMCs) have adopted policies to limit student/industry interaction. Many clinical experiences occur outside of the AMC. The purpose of this study was to compare medical students' exposure to pharmaceutical marketing in off-campus rural and urban underserved clinical sites. METHODS: The University of Washington School of Medicine Rural and Underserved Opportunities Program (RUOP) places rising second-year medical students in underserved clinical sites in five northwestern states. We surveyed RUOP students to evaluate their exposure to pharmaceutical marketing. RESULTS: Of 120 students, 86 (72%) completed surveys. Sixty-five (76%) did their RUOP rotation in rural areas. Students in rural locations were more likely to report exposure to pharmaceutical marketing. Distribution of free drug samples was reportedly three times higher in rural than urban sites (54% versus 15%). Doctors meeting with sales representatives were reported as four times higher in rural clinics (40% versus 10%). CONCLUSIONS: Students at rural sites reported exposure to pharmaceutical marketing more than those in urban settings. Rural medical educators should provide faculty development for community clinicians on the influences of pharmaceutical marketing on learners. Medical schools must review local clinic and institution-wide policies to limit pharmaceutical marketing exposure to learners in the rural learning environment. PMID- 27472797 TI - My Family Medicine Story. PMID- 27472798 TI - Transformations: Reflections on a Longitudinal, Relationship-Centered Medical School Curriculum. PMID- 27472800 TI - Medicine in the Mist. PMID- 27472799 TI - He Up and Died: The Challenge of Living Without an Answer. PMID- 27472801 TI - How to Be a Rock Star Doctor, The Complete Guide to Taking Back Control of Your Life and Your Profession. PMID- 27472802 TI - What Every Medical Writer Needs to Know: Questions and Answers for the Serious Medical Author. PMID- 27472803 TI - Clinical Uncertainty in Primary Care: The Challenge of Collaborative Engagement. PMID- 27472806 TI - PhyloBot: A Web Portal for Automated Phylogenetics, Ancestral Sequence Reconstruction, and Exploration of Mutational Trajectories. AB - The method of phylogenetic ancestral sequence reconstruction is a powerful approach for studying evolutionary relationships among protein sequence, structure, and function. In particular, this approach allows investigators to (1) reconstruct and "resurrect" (that is, synthesize in vivo or in vitro) extinct proteins to study how they differ from modern proteins, (2) identify key amino acid changes that, over evolutionary timescales, have altered the function of the protein, and (3) order historical events in the evolution of protein function. Widespread use of this approach has been slow among molecular biologists, in part because the methods require significant computational expertise. Here we present PhyloBot, a web-based software tool that makes ancestral sequence reconstruction easy. Designed for non-experts, it integrates all the necessary software into a single user interface. Additionally, PhyloBot provides interactive tools to explore evolutionary trajectories between ancestors, enabling the rapid generation of hypotheses that can be tested using genetic or biochemical approaches. Early versions of this software were used in previous studies to discover genetic mechanisms underlying the functions of diverse protein families, including V-ATPase ion pumps, DNA-binding transcription regulators, and serine/threonine protein kinases. PhyloBot runs in a web browser, and is available at the following URL: http://www.phylobot.com. The software is implemented in Python using the Django web framework, and runs on elastic cloud computing resources from Amazon Web Services. Users can create and submit jobs on our free server (at the URL listed above), or use our open-source code to launch their own PhyloBot server. PMID- 27472807 TI - Tunable Ambipolar Polarization-Sensitive Photodetectors Based on High-Anisotropy ReSe2 Nanosheets. AB - Atomically thin 2D-layered transition-metal dichalcogenides have been studied extensively in recent years because of their intriguing physical properties and promising applications in nanoelectronic devices. Among them, ReSe2 is an emerging material that exhibits a stable distorted 1T phase and strong in-plane anisotropy due to its reduced crystal symmetry. Here, the anisotropic nature of ReSe2 is revealed by Raman spectroscopy under linearly polarized excitations in which different vibration modes exhibit pronounced periodic variations in intensity. Utilizing high-quality ReSe2 nanosheets, top-gate ReSe2 field-effect transistors were built that show an excellent on/off current ratio exceeding 10(7) and a well-developed current saturation in the current-voltage characteristics at room temperature. Importantly, the successful synthesis of ReSe2 directly onto hexagonal boron nitride substrates has effectively improved the electron motility over 500 times and the hole mobility over 100 times at low temperatures. Strikingly, corroborating with our density-functional calculations, the ReSe2-based photodetectors exhibit a polarization-sensitive photoresponsivity due to the intrinsic linear dichroism originated from high in-plane optical anisotropy. With a back-gate voltage, the linear dichroism photodetection can be unambiguously tuned both in the electron and hole regime. The appealing physical properties demonstrated in this study clearly identify ReSe2 as a highly anisotropic 2D material for exotic electronic and optoelectronic applications. PMID- 27472808 TI - Identification of MEF2B and TRHDE Gene Polymorphisms Related to Growth Traits in a New Ujumqin Sheep Population. AB - 2 SNPs were discovered in our previous genome-wide association study (GWAS): s58995.1 (rs420767326 A>G) in MEF2B gene and OAR3_115712045.1 (rs401775061 A>C) in TRHDE gene, which were significantly associated with post-weaning gain in sheep. Herein, we performed a replication experiment to investigate single nucleotide polymorphisms (SNPs) within the MEF2B and TRHDE gene exons, the 5'untranslated regions (within 1000bp), the 3' untranslated regions (within 1000bp) and their associations with Ujumqin sheep growth traits in 4-month age and 6-month age, respectively. Finally,3 SNPs were selected to be investigated including 1 SNP in 3'untranslated regions in MEF2B gene (rs417014745 A>G) and 2 SNPs in TRHDE gene (rs426980328 T>C and rs430810656 G>A).The chi2 test showed all the 3 variations were in Hardy-Weinberg equilibrium (P>0.05) status. Association analysis suggested that rs426980328 T>C was significantly associated with body weight and chest girth in 4-month age (P<0.05). rs430810656 G>A exhibited extremely significant association with body weight and chest girth in 4-month age (P<0.01). rs417014745 A>G was extremely significantly associated with body weight and chest girth in 4-month age and chest girth in 6-month age (P<0.01), and it was also significantly associated with body weight in 6-month age (P<0.05). Combined effect analysis indicated significant associations between the combinations of rs426980328-rs417014745, rs430810656-rs417014745 and several growth traits (P<0.05). These results suggested MEF2B and TRHDE genes affected growth traits in Ujumqin sheep and the combination effect of the two genes also played a significant effective role. These SNPs might have potential value as genetic markers for growth traits and it could be used in Ujumqin sheep breeding in future. Further studies are necessary to confirm our findings. PMID- 27472809 TI - Endometrial Polyps - When Should Hysteroscopic Resection Be Performed? PMID- 27472810 TI - Comparison between Slow Freezing and Vitrification in Terms of Ovarian Tissue Viability in a Bovine Model. AB - Objective To assess the viability of bovine ovarian tissue after cryopreservation through either slow freezing or vitrification, and to compare it to that of control tissue by performing morphological analyses. Methods The study included 20 bovine ovarian cortex fragments that were divided into control, vitrification, and slow freezing groups. Each group consisted of four fragments of the same ovary, two fixed without cultivation, and two fixed with cultivation. Tissues were evaluated based on follicular morphology immediately after heating and after 7 days of culture, and compared with the control group. Results A total of 240 fragments were analyzed, generating a sample of 1,344 follicles without cultivation and 552 with cultivation. When the non-cultivated samples were classified as non-atretic follicles, 572 were found in the control group, 289 in the vitrification group, and 373 in the slow freezing group, showing no significant differences. When classified as atretic, 46 follicles were found in the control group, 23 in the vitrification group, and 41 in the slow freezing group, also showing no statistical difference. In the post-culture sample, an evolution of the follicular stages could be observed. This finding was important to support that the follicles considered non-atretic in the non-cultivated group were actually viable in the morphological evaluation. Conclusion With no differences between the protocols, vitrification was shown to be an advanced and alternative method for patients who will undergo treatments that carry the risk of ovarian failure, as the method is less expensive, faster, and more adaptable to laboratory routine. PMID- 27472811 TI - Quality of Life in Women with Polycystic Ovary Syndrome after a Program of Resistance Exercise Training. AB - Purpose Aerobic exercises may improve quality of life (QoL) in women with polycystic ovary syndrome (PCOS). However, there is no data on the effect of resistance exercise training (RET) programs on the QoL of women with PCOS. Thus, this study aimed to assess the effect of a 16-week RET program on QoL in PCOS women. Methods This 16-week case-control study enrolled 43 women with PCOS (PCOS group, PCOSG) and 51 healthy pre-menopausal controls aged 18 to 37 years (control group, CG). All women underwent a supervised RET program for 16 weeks, and were evaluated in two different occasions: week-0 (baseline), and week-16 (after RET). Quality of life was assessed using the 36-Item Short Form Health Survey (SF-36). Results Testosterone reduced significantly in both groups after RET (p < 0.01). The PCOSG had improvements in functional capacity at week-16 relative to week-0 (p = 0.02). The CG had significant improvements in vitality, social aspects, and mental health at week-16 relative to week-0 (p <= 0.01). There was a weak correlation between social aspects of the SF-36 domain and testosterone levels in PCOS women. Conclusion A 16-week RET program modestly improved QoL in women with PCOS. PMID- 27472812 TI - Mesh Surgery for Anterior Vaginal Wall Prolapse: A Meta-analysis. AB - Purpose Pelvic organ prolapse (POP) is a major health issue worldwide, affecting 6-8% of women. The most affected site is the anterior vaginal wall. Multiple procedures and surgical techniques have been used, with or without the use of vaginal meshes, due to common treatment failure, reoperations, and complication rates in some studies. Methods Systematic review of the literature and meta analysis regarding the use of vaginal mesh in anterior vaginal wall prolapse was performed. A total of 115 papers were retrieved after using the medical subject headings (MESH) terms: 'anterior pelvic organ prolapse OR cystocele AND surgery AND (mesh or colporrhaphy)' in the PubMed database. Exclusion criteria were: follow-up shorter than 1 year, use of biological or absorbable meshes, and inclusion of other vaginal wall prolapses. Studies were put in a data chart by two independent editors; results found in at least two studies were grouped for analysis. Results After the review of the titles by two independent editors, 70 studies were discarded, and after abstract assessment, 18 trials were eligible for full text screening. For final screening and meta-analysis, after applying the Jadad score (> 2), 12 studies were included. Objective cure was greater in the mesh surgery group (odds ratio [OR] = 1,28 [1,07-1,53]), which also had greater blood loss (mean deviation [MD] = 45,98 [9,72-82,25]), longer surgery time (MD = 15,08 [0,48-29,67]), but less prolapse recurrence (OR = 0,22 [01,3 0,38]). Dyspareunia, symptom resolution and reoperation rates were not statistically different between groups. Quality of life (QOL) assessment through the pelvic organ prolapse/urinary incontinence sexual questionnaire (PISQ-12), the pelvic floor distress inventory (PFDI-20), the pelvic floor impact questionnaire (PFIQ-7), and the perceived quality of life scale (PQOL) was not significantly different. Conclusions Anterior vaginal prolapse mesh surgery has greater anatomic cure rates and less recurrence, although there were no differences regarding subjective cure, reoperation rates and quality of life. Furthermore, mesh surgery was associated with longer surgical time and greater blood loss. Mesh use should be individualized, considering prior history and risk factors for recurrence. PMID- 27472813 TI - Skin provocation tests may help to diagnose atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a common skin disorder. Its diagnosis relies on clinical judgment. Mild and untypical manifestations may cause diagnostic difficulties. Biomarkers for the differential diagnostic workup of AD are needed. OBJECTIVE: To test whether the results of skin provocation with cowhage, an established model of histamine-independent pruritus, and histamine are different in AD patients and healthy subjects and whether these tests may be used as diagnostic markers of AD. METHODS: Twenty-two AD patients and 18 healthy controls were subjected to topical cowhage provocation and skin prick testing with histamine and assessed for differences in the quality, intensity, and persistence of itch, for wheal diameter, volume, and flare size and intensity. RESULTS: Patients with AD, compared with healthy controls, exhibited significantly smaller histamine-induced flares (P < 0.01) and markedly longer itch persistence after provocation with cowhage (P < 0.01). Both parameters showed good diagnostic properties for AD (area under the receiver operating characteristic (ROC) curve 0.78 and 0.80, respectively). The persistence of cowhage-induced itch for at least 30 min and a histamine-induced flare of less than 2 cm in diameter were reliable thresholds for the diagnosis of AD. If combinations of the results of both tests were used, their sensitivity and specificity of diagnosing AD were up to 91% and 94%, respectively. CONCLUSION: The clinical benefit of cowhage and histamine skin provocation tests should be investigated in further studies. Long persistence of cowhage-induced itch and diminished histamine-induced flare in nonlesional skin may support diagnosis of AD. PMID- 27472814 TI - MAGED1 is a novel regulator of a select subset of bHLH PAS transcription factors. AB - Transcription factors of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) family generally have critical and nonredundant biological roles, but some bHLH PAS proteins compete for common cofactors or recognise similar DNA elements. Identifying factors that regulate function of bHLH PAS proteins, particularly in cells where multiple family members are coexpressed, is important for understanding bHLH PAS factor biology. This study identifies and characterises a novel interaction between melanoma-associated antigen D1 (MAGED1) and select members of the bHLH PAS transcription factor family. MAGED1 binds and positively regulates the transcriptional activity of family members SIM1, SIM2, NPAS4 and ARNT2, but does not interact with AhR, HIF1alpha and ARNT. This interaction is mediated by PAS repeat regions which also form the interface for bHLH PAS dimerisation, and accordingly MAGED1 is not found in complex with bHLH PAS dimers. We show that MAGED1 does not affect bHLH PAS protein levels and cannot be acting as a coactivator of transcriptionally active heterodimers, but rather appears to interact with nascent bHLH PAS proteins in the cytoplasm to enhance their function prior to nuclear import. As a selective regulator, MAGED1 may play an important role in the biology of these specific factors and in general bHLH PAS protein dynamics. PMID- 27472815 TI - Influential factors of red-light running at signalized intersection and prediction using a rare events logistic regression model. AB - Red light running (RLR) has become a major safety concern at signalized intersection. To prevent RLR related crashes, it is critical to identify the factors that significantly impact the drivers' behaviors of RLR, and to predict potential RLR in real time. In this research, 9-month's RLR events extracted from high-resolution traffic data collected by loop detectors from three signalized intersections were applied to identify the factors that significantly affect RLR behaviors. The data analysis indicated that occupancy time, time gap, used yellow time, time left to yellow start, whether the preceding vehicle runs through the intersection during yellow, and whether there is a vehicle passing through the intersection on the adjacent lane were significantly factors for RLR behaviors. Furthermore, due to the rare events nature of RLR, a modified rare events logistic regression model was developed for RLR prediction. The rare events logistic regression method has been applied in many fields for rare events studies and shows impressive performance, but so far none of previous research has applied this method to study RLR. The results showed that the rare events logistic regression model performed significantly better than the standard logistic regression model. More importantly, the proposed RLR prediction method is purely based on loop detector data collected from a single advance loop detector located 400 feet away from stop-bar. This brings great potential for future field applications of the proposed method since loops have been widely implemented in many intersections and can collect data in real time. This research is expected to contribute to the improvement of intersection safety significantly. PMID- 27472817 TI - Improving the robustness of cobalt porphyrin water oxidation catalysts by chlorination of aryl groups. AB - The water oxidation (WO) activity of a chlorinated cobalt tetraphenylporphyrin (CoClPS), possessing Cl atoms on the 2,6-positions of the aryl groups, shows higher resistance to attack by singlet oxygen, in situ generated during photochemical WO using Ru(bpy)3(2+) and S2O8(2-) with the turnover frequency (TOF) and turnover number (TON) reaching 1.7 s(-1) and 836, respectively. PMID- 27472816 TI - Time-to-contact estimation errors among older drivers with useful field of view impairments. AB - Previous research indicates that useful field of view (UFOV) decline affects older driver performance. In particular, elderly drivers have difficulty estimating oncoming vehicle time-to-contact (TTC). The objective of this study was to evaluate how UFOV impairments affect TTC estimates in elderly drivers deciding when to make a left turn across oncoming traffic. TTC estimates were obtained from 64 middle-aged (n=17, age=46+/-6years) and older (n=37, age=75+/ 6years) licensed drivers with a range of UFOV abilities using interactive scenarios in a fixed-base driving simulator. Each driver was situated in an intersection to turn left across oncoming traffic approaching and disappearing at differing distances (1.5, 3, or 5s) and speeds (45, 55, or 65mph). Drivers judged when each oncoming vehicle would collide with them if they were to turn left. Findings showed that TTC estimates across all drivers, on average, were most accurate for oncoming vehicles travelling at the highest velocities and least accurate for those travelling at the slowest velocities. Drivers with the worst UFOV scores had the least accurate TTC estimates, especially for slower oncoming vehicles. Results suggest age-related UFOV decline impairs older driver judgment of TTC with oncoming vehicles in safety-critical left-turn situations. Our results are compatible with national statistics on older driver crash proclivity at intersections. PMID- 27472818 TI - Protein Aggregate-Ligand Binding Assays Based on Microfluidic Diffusional Separation. AB - The measurement of molecular interactions with pathological protein aggregates, including amyloid fibrils, is of central importance in the context of the development of diagnostic and therapeutic strategies against protein misfolding disorders. Probing such interactions by conventional methods can, however, be challenging because of the supramolecular nature of protein aggregates, their heterogeneity, and their often dynamic nature. Here we demonstrate that direct measurement of diffusion on a microfluidic platform enables the determination of affinity and kinetics data for ligand binding to amyloid fibrils in solution. This method yields rapid binding information from only microlitres of sample, and is therefore a powerful technique for identifying and characterising molecular species with potential therapeutic or diagnostic application. PMID- 27472819 TI - In vitro and in vivo assays on egg white/polyvinyl alcohol/clay nanocomposite hydrogel wound dressings. AB - Novel nanocomposite hydrogel wound dressings on the basis of egg white and polyvinyl alcohol, as matrix, and natural Na-montmorillonite clay, as reinforcing agent, were prepared and their performances on wound healing investigated in vitro and in vivo. In vitro cytotoxicity assay revealed non-cytotoxic activity and excellent biocompatibility level of prepared nanocomposite hydrogel wound dressings. The bacterial penetration assay showed the prepared nanocomposite hydrogel wound dressings are excellent barriers against microorganisms and could protect the wound from infection during the wound healing. In vivo animal study showed that the wound healing process was considerably faster in wounds covered with nanocomposite hydrogel wound dressings compared to the conventional wound dressing, i.e. sterile gauze, due to creation of a moist environment on the wound surface and faster migration rate of the epidermal cells. The mechanical properties of healed wounds with nanocomposite hydrogel wound dressings were better than those control wounds covered with sterile gauze due to their better collagen formation ability as a result of created moist healing condition as well as the presence of egg white, as a source of proteins, in their structures. PMID- 27472821 TI - Mechanical and neuromuscular changes with lateral trunk lean gait modifications. AB - Lateral trunk lean (LTL) is a proposed intervention for knee osteoarthritis but increased muscular demands have not been considered. The objective was to compare lower extremity and trunk muscle activation and joint mechanics between normal and increased LTL gait in healthy adults. Participants (n=20, mean age 22 years) were examined under two gait conditions: normal and increased LTL. A motion capture system and force plates sampled at 100 and 2000Hz respectively were used to determine joint angles and external moments including LTL angle and external knee adduction moment (KAM). Surface electromyography, sampled at 2000Hz, measured activation of six trunk/hip muscles bilaterally. Peak LTL angle, peak KAM, gait speed, and mean values from electromyography waveforms were compared between normal and LTL conditions using paired t-tests or 2-way analysis of variance. There was a significant (p<0.05) increase in peak LTL angle, decrease in first but not second peak KAM, and decrease in gait speed during LTL gait. There were significant (p<0.01) increases in external oblique and iliocostalis muscle activation during LTL gait. There was no change in activation for internal oblique, rectus abdominis, longissimus, and gluteus medius. LTL gait decreased early/mid-stance KAM demonstrating its ability to decrease medial compartment knee loading. Increases in external oblique and iliocostalis activation were present but small to moderate in size and unlikely to lead to short term injury. Longitudinal studies should evaluate the effectiveness of increased LTL for knee osteoarthritis and if the increase in muscular demands leads to negative long term side effects. PMID- 27472820 TI - Standardised surveillance of Clostridium difficile infection in European acute care hospitals: a pilot study, 2013. AB - Clostridium difficile infection (CDI) remains poorly controlled in many European countries, of which several have not yet implemented national CDI surveillance. In 2013, experts from the European CDI Surveillance Network project and from the European Centre for Disease Prevention and Control developed a protocol with three options of CDI surveillance for acute care hospitals: a 'minimal' option (aggregated hospital data), a 'light' option (including patient data for CDI cases) and an 'enhanced' option (including microbiological data on the first 10 CDI episodes per hospital). A total of 37 hospitals in 14 European countries tested these options for a three-month period (between 13 May and 1 November 2013). All 37 hospitals successfully completed the minimal surveillance option (for 1,152 patients). Clinical data were submitted for 94% (1,078/1,152) of the patients in the light option; information on CDI origin and outcome was complete for 94% (1,016/1,078) and 98% (294/300) of the patients in the light and enhanced options, respectively. The workload of the options was 1.1, 2.0 and 3.0 person days per 10,000 hospital discharges, respectively. Enhanced surveillance was tested and was successful in 32 of the hospitals, showing that C. difficile PCR ribotype 027 was predominant (30% (79/267)). This study showed that standardised multicountry surveillance, with the option of integrating clinical and molecular data, is a feasible strategy for monitoring CDI in Europe. PMID- 27472822 TI - Timed Up and Go test: Comparison of kinematics between patients with chronic stroke and healthy subjects. AB - Understanding locomotor behavior is important to guide rehabilitation after stroke. This study compared lower-limb kinematics during the walking and turning sub-tasks of the Timed Up and Go (TUG) test in stroke patients and healthy subjects. We also determined the parameters which explain TUG sub-task performance time in healthy subjects. Biomechanical parameters were recorded during the TUG in standardized conditions in 25 healthy individuals and 29 patients with chronic stroke using a 3D motion-analysis system. Parameters were compared between groups and a stepwise regression was used to indicate parameters which explained performance time in the healthy subjects. The percentage difference in step length between the last and first steps was calculated, during walking sub-tasks for each group. Speed, cadence, step length, percentage paretic single support phase, percentage non-paretic swing phase, peak hip extension, knee flexion and ankle dorsiflexion were significantly reduced in the Stroke group compared to the Healthy group (p<0.05). In the Healthy group, step length and cadence explained 91% of variance for Go and 86% for Return (walking sub tasks), and none of the parameters explained the Turn. Previous study in patients with stroke showed that the same parameters explained the variance during the walking sub-tasks and balance-related parameters explained the Turn. The present results showed that step length was differently modulated in each group. Thus the locomotor behavior of patients with stroke during obstacle circumvention is quite specific in light of the results obtained in healthy subjects. PMID- 27472823 TI - Long-term effects of adolescent concussion history on gait, across age. AB - The aim of this study was to examine the possible long-term effects of high school concussion history on gait performance across the lifespan. Individuals with and without a concussion history were grouped into 20-year-old (yo) (n=40), 40yo (n=19), and 60yo (n=18) age groups. Participants completed five trials of four walking conditions: a normal walk, a dual task walk, an obstructed walk, and an obstructed, dual task walk. Spatiotemporal gait parameters for gait analyses during single and dual task conditions. Gait velocity, step width, stride length, percent of time in double support, and obstacle toe clearance were the gait variables assessed along with number correct from dual task. Gait was analyzed via optical motion capture. Data were analyzed by two-factor, multivariate ANOVAs and significant interactions were explored using post hoc contrasts. A significant (F=2.62, p=0.03) interaction was observed for the obstructed walk condition. Further analyses yielded no significant concussion history and control group differences, within age. The data indicate that an adolescent concussion history has a non-observable effect on gait across the lifespan. PMID- 27472824 TI - Performance of ZnSe(Te) as fiberoptic dosimetry detector. AB - Fiberoptic dosimetry (FOD) is an experimental technique suitable for in-vivo, real time dosimetry in radiotherapy treatments. FOD relies on using a small scintillator coupled to one end of a long optical fiber. The scintillator is placed at the point where the dose rate is to be determined whereas a light detector at the other end of the fiber measures the intensity of the radioluminescence emitted by the scintillator. One of the problems hampering the straightforward application of this technique in clinics is the presence of Cherenkov radiation generated in the fiber by the ionizing radiation, which adds to the scintillating light and introduces a bias in the dose measurement. Since Cherenkov radiation is more important in short wavelength range of the visible spectrum, using red-emitting scintillators as FOD detectors permits to reduce the Cherenkov contribution by using optical filters. In this work, the performance of red-emitting tellurium-doped zinc selenide crystal as FOD detector is evaluated and compared to the response of an ion-chamber. PMID- 27472825 TI - Production of scandium-43 and -47 from a powdery calcium oxide target via the (nat/44)Ca(alpha,x)-channel. AB - We produced (43)Sc and (47)Sc via the (nat/44)Ca(alpha,x)-channel using a vertical beam coupled with a ceramic target box. After activation, the powdery CaO target material was dissolved in HCl in the target box in situ and remotely recovered as a radio-Sc solution. The respective yields of (43)Sc and (47)Sc following isolation via a precipitation method with a typical 0.22um sterile filter were 54.8MBq/uAh (1.48mCi/uAh) and 780kBq/uAh (21.1uCi/uAh) at the end of separation (approximately 1.5h from the EOB). In addition, we discuss the recycling of target Ca. PMID- 27472826 TI - A pioneer experience in Malaysia on In-house Radio-labelling of (131)I-rituximab in the treatment of Non-Hodgkin's Lymphoma and a case report of high dose (131)I rituximab-BEAM conditioning autologous transplant. AB - Radioimmunotherapy is an established treatment modality in Non-Hodgkin's lymphoma. The only two commercially available radioimmunotherapies - (90)Y ibritumomab tiuxetan is expensive and (131)I-tositumomab has been discontinued from commercial production. In resource limited environment, self-labelling (131)I-rituximab might be the only viable practical option. We reported our pioneer experience in Malaysia on self-labelling (131)I-rituximab, substituting autologous haematopoietic stem cell transplantation (HSCT) and a patient, the first reported case, received high dose (131)I-rituximab (6000MBq/163mCi) combined with BEAM conditioning for autologous HSCT. PMID- 27472827 TI - Diffusion tensor imaging MR neurography for the detection of polyneuropathy in type 1 diabetes. AB - PURPOSE: To evaluate if diffusion tensor imaging MR neurography (DTI-MRN) can detect lesions of peripheral nerves in patients with type 1 diabetes. MATERIALS AND METHODS: Eleven type 1 diabetic patients with polyneuropathy (DPN), 10 type 1 diabetic patients without polyneuropathy (nDPN), and 10 healthy controls (HC) were investigated with a 3T MRI scanner. Clinical examinations, nerve-conduction studies, and vibratory-perception thresholds determined the presence of DPN. DTI MRN (voxel size: 1.4 * 1.4 * 3 mm3 ; b-values: 0, 800 s/mm2 ) covered proximal (sciatic nerve) and distal regions of the lower extremity (tibial nerve). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated and compared to T2 -relaxometry and proton-spin density obtained from a multiecho turbo spin echo (TSE) sequence. Furthermore, we evaluated DTI reproducibility, repeatability, and diagnostic accuracy. RESULTS: DTI-MRN could accurately discriminate between DPN, nDPN, and HC. The proximal FA was lowest in DPN (DPN 0.37 +/- 0.06; nDPN 0.47 +/- 0.03; HC 0.49 +/- 0.06; P < 0.01). In addition, distal FA was lowest in DPN (DPN 0.31 +/- 0.05; nDPN 0.41 +/- 0.07; HC 0.43 +/- 0.08; P < 0.01). Likewise, proximal ADC was highest in DPN (DPN 1.69 +/- 0.25 * 10-3 mm2 /s; nDPN 1.50 +/- 0.06 * 10-3 mm2 /s; HC 1.42 +/- 0.12 * 10-3 mm2 /s; P < 0.01) as was distal ADC (DPN 1.87 +/- 0.45 * 10-3 mm2 /s; nDPN 1.59 +/- 0.19 * 10-3 mm2 /s; HC 1.57 +/- 0.26 * 10-3 mm2 /s; P = 0.09). The combined interclass-correlation (ICC) coefficient of DTI reproducibility and repeatability was high in the sciatic nerve (ICC: FA = 0.86; ADC = 0.85) and the tibial nerve (ICC: FA = 0.78; ADC = 0.66). T2 -relaxometry and proton-spin-density did not enable detection of neuropathy. CONCLUSION: DTI-MRN accurately detects DPN by lower nerve FA and higher ADC. These alterations are likely to reflect proximal and distal nerve fiber pathology. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:1125-1134. PMID- 27472828 TI - Hydrogen bond competition in the ethanol-methanol dimer. AB - Previous theoretical work on the ethanol-methanol dimer has been inconclusive in predicting the preferred hydrogen bond donor/acceptor configuration. Here, we report the microwave spectrum of the dimer using a chirped pulse Fourier transform microwave spectrometer from 8-18 GHz. In an argon-backed expansion, 50 transitions have been assigned to a trans-ethanol-acceptor/methanol-donor structure that is likely stabilized by a secondary weak C-HO hydrogen bond. A higher energy conformer was observed in a helium-backed expansion and tentatively assigned to a gauche-ethanol-acceptor/methanol-donor structure. No ethanol donor/methanol-acceptor dimers have been found, suggesting such interactions are energetically disfavored. A preliminary analysis of the A-E splitting due to the internal rotation of the methanol methyl group in the ground state species is also presented. We find evidence of the Ubbelohde effect in the measured A-E splittings of three deuterated isotopologues and the normal species of this conformer. PMID- 27472829 TI - Microscopic gastrointestinal stromal tumours: a clinical and molecular study of 13 cases. AB - AIMS: Recent literature suggests that clinically silent, microscopic gastrointestinal stromal tumours (micro-GISTs) are common incidental findings. The aim of this study was to examine the histological, immunohistochemical and molecular characteristics of these tumours, which we have defined as measuring <=20 mm, in order to determine whether the rate and spectrum of mutations are similar to those of clinically symptomatic gastrointestinal stromal tumours (GISTs). METHODS AND RESULTS: Thirteen micro-GISTs identified as incidental findings in patients undergoing management of concomitant disease were tested for KIT/PDGFRA mutations. Ten micro-GISTs (77%) were located in the stomach, two (15%) in the duodenum, and one (8%) in the rectum. The mean tumour size was 9.3 mm (range 2-19 mm). All tumours were well-circumscribed lesions showing a predominantly spindle-cell morphology and a very low mitotic rate. Twelve of 13 (92%) tumours carried mutations in either KIT (83%) or PDGFRA (17%), a rate higher than in other published series. A high mutation rate (80%) was also seen in lesions measuring <=5 mm. CONCLUSIONS: Our results suggest that KIT/PDGFRA mutation is a very common early event in GIST development, that tumour size does not reliably predict the presence of mutation, and that one or more subsequent mutations are required for clinical manifestation. PMID- 27472830 TI - Intact NYN/PIN-Like Domain is Crucial for the Degradation of Inflammation-Related Transcripts by ZC3H12D. AB - ZC3H12D belongs to a recently discovered family of proteins containing four members of which the most studied and best described is the RNase ZC3H12A (MCPIP1/Regnase-1). ZC3H12A is a crucial negative regulator of inflammation. It accelerates the turnover of transcripts of a spectrum of proinflammatory cytokines, as well as its own mRNA. The biological role of ZC3H12D is less clear, although it was shown that this member of ZC3H12 family is also involved in the regulation of inflammation. Here, we show that ZC3H12A and ZC3H12D recognize a set of common target mRNAs encoding proteins that play important roles in the course of the inflammation. Similarly to ZC3H12A, ZC3H12D participates in the 3'UTR-dependent regulation of the turnover of mRNAs encoding interleukin-6 (IL 6), tumor necrosis factor (TNF), and immediate early response 3 gene (IER3). The ZC3H12A mRNA is also among the identified ZC3H12D targets. Using the combination of immunofluorescence with single molecule RNA fluorescence in situ hybridization (smRNA FISH) we have shown that ZC3H12D protein interacts with the ZC3H12A transcript. The direct binding of these two molecules in vivo was further confirmed by RNA immunoprecipitation. Simultaneously, overexpression of ZC3H12D increases the turnover rate of transcripts containing ZC3H12A 3'UTR. Using reporter gene assays we have confirmed that the Asp95 residue present in the NYN/PIN-like domain is crucial for ZC3H12D biological activity. We have also revealed that ZC3H12D recognizes the same structural elements present in the 3'UTRs of the investigated transcripts, as ZC3H12A. J. Cell. Biochem. 118: 487 498, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27472831 TI - Manual dexterity: Functional lateralisation patterns and motor efficiency. AB - Manual tasks are an important goal-directed ability. In this EEG work, we studied how handedness affects the hemispheric lateralisation patterns during performance of visually-driven movements with either hand. The neural correlates were assessed by means of EEG coherence whereas behavioural output was measured by motor error. The EEG data indicated that left- and right-handers showed distinct recruitment patterns. These involved local interactions between brain regions as well as more widespread associations between brain systems. Despite these differences, brain-behaviour correlations highlighted that motor efficiency depended on left-sided brain regions across groups. These results suggest that skilled hand motor control relies on different neural patterns as a function of handedness whereas behavioural efficiency is linked with the left hemisphere. In conclusion, the present findings add to our understanding about principles of lateralised organisation as a function of handedness. PMID- 27472832 TI - [Evolution of education in nursing]. AB - PURPOSE: This study focuses on investigating the evolution of nursing studies in order to know how much this transformation has contributed to the development of the nursing profession. METHODS: Literature review with data sources from different national and international databases. These sources provide an update on the ongoing evolution of nursing studies and the progress of this profession as a result of change. CONCLUSIONS: The competencies and skills that add value to the nursing profession are: an evidence-based practice; empathic communication; and other broad-range skills such as critical thinking. All are necessary in order to develop the profession alongside the constant changes in the health systems and the improvement of quality care. These competencies and skills should be evaluated and their achievement is being reached through the "portfolio". Innovations that enable the development of these skills can be found in education, strategies and tools used by educators and institutions. PMID- 27472833 TI - Discovery and functional identification of fecundity-related genes in the brown planthopper by large-scale RNA interference. AB - Recently, transcriptome and proteome data have increasingly been used to identify potential novel genes related to insect phenotypes. However, there are few studies reporting the large-scale functional identification of such genes in insects. To identify novel genes related to fecundity in the brown planthopper (BPH), Nilaparvata lugens, 115 genes were selected from the transcriptomic and proteomic data previously obtained from high- and low-fecundity populations in our laboratory. The results of RNA interference (RNAi) feeding experiments showed that 91.21% of the genes were involved in the regulation of vitellogenin (Vg) expression and may influence BPH fecundity. After RNAi injection experiments, 12 annotated genes were confirmed as fecundity-related genes and three novel genes were identified in the BPH. Finally, C-terminal binding protein (CtBP) was shown to play an important role in BPH fecundity. Knockdown of CtBP not only led to lower survival, underdeveloped ovaries and fewer eggs laid but also resulted in a reduction in Vg protein expression. The novel gene resources gained from this study will be useful for constructing a Vg regulation network and may provide potential target genes for RNAi-based pest control. PMID- 27472834 TI - Efficient electrochemical water oxidation in neutral and near-neutral systems with a nanoscale silver-oxide catalyst. AB - In electrocatalytic water splitting systems pursuing for renewable energy using sunlight, developing robust, stable and easily accessible materials operating under mild chemical conditions is pivotal. We present here a unique nanoparticulate type silver-oxide (AgOx-NP) based robust and highly stable electrocatalyst for efficient water oxidation. The AgOx-NP is generated in situ in a HCO3(-)/CO2 system under benign conditions. Micrographs show that they exhibit a nanoscale box type squared nano-bipyramidal configuration. The oxygen generation is initiated at low overpotential, and a sustained O2 evolution current density of >1.1 mA cm(-2) is achieved during prolonged-period water electrolysis. The AgOx-NP electrocatalyst performs exceptionally well in metal ion free neutral or near-neutral carbonate, phosphate and borate buffers relative to recently reported Co-oxide and Ni-oxide based heterogeneous electrocatalysts, which are unstable in metal-ion free electrolytes and tend to deactivate with time and lose catalytic performance during long-term experimental tests. PMID- 27472835 TI - IL-33 Drives Augmented Responses to Ozone in Obese Mice. AB - BACKGROUND: Ozone increases IL-33 in the lungs, and obesity augments the pulmonary effects of acute ozone exposure. OBJECTIVES: We assessed the role of IL 33 in the augmented effects of ozone observed in obese mice. METHODS: Lean wildtype and obese db/db mice were pretreated with antibodies blocking the IL-33 receptor, ST2, and then exposed to ozone (2 ppm for 3 hr). Airway responsiveness was assessed, bronchoalveolar lavage (BAL) was performed, and lung cells harvested for flow cytometry 24 hr later. Effects of ozone were also assessed in obese and lean mice deficient in gammadelta T cells and their wildtype controls. RESULTS AND DISCUSSION: Ozone caused greater increases in BAL IL-33, neutrophils, and airway responsiveness in obese than lean mice. Anti-ST2 reduced ozone-induced airway hyperresponsiveness and inflammation in obese mice but had no effect in lean mice. Obesity also augmented ozone-induced increases in BAL CXCL1 and IL-6, and in BAL type 2 cytokines, whereas anti-ST2 treatment reduced these cytokines. In obese mice, ozone increased lung IL-13+ innate lymphoid cells type 2 (ILC2) and IL-13+ gammadelta T cells. Ozone increased ST2+ gammadelta T cells, indicating that these cells can be targets of IL-33, and gammadelta T cell deficiency reduced obesity-related increases in the response to ozone, including increases in type 2 cytokines. CONCLUSIONS: Our data indicate that IL-33 contributes to augmented responses to ozone in obese mice. Obesity and ozone also interacted to promote type 2 cytokine production in gammadelta T cells and ILC2 in the lungs, which may contribute to the observed effects of IL-33. Citation: Mathews JA, Krishnamoorthy N, Kasahara DI, Cho Y, Wurmbrand AP, Ribeiro L, Smith D, Umetsu D, Levy BD, Shore SA. 2017. IL-33 drives augmented responses to ozone in obese mice. Environ Health Perspect 125:246-253; http://dx.doi.org/10.1289/EHP272. PMID- 27472836 TI - Validation of Deleterious Mutations in Vorderwald Cattle. AB - In Montbeliarde cattle two candidate mutations on bovine chromosomes 19 and 29 responsible for embryonic lethality have been detected. Montbeliarde bulls have been introduced into Vorderwald cattle to improve milk and fattening performance. Due to the small population size of Vorderwald cattle and the wide use of a few Montbeliarde bulls through artificial insemination, inbreeding on Montbeliarde bulls in later generations was increasing. Therefore, we genotyped an aborted fetus which was inbred on Montbeliarde as well as Vorderwald x Montbeliarde crossbred bulls for both deleterious mutations. The abortion was observed in an experimental herd of Vorderwald cattle. The objectives of the present study were to prove if one or both lethal mutations may be assumed to have caused this abortion and to show whether these deleterious mutations have been introduced into the Vorderwald cattle population through Montbeliarde bulls. The aborted fetus was homozygous for the SLC37A2:g.28879810C>T mutation (ss2019324563) on BTA29 and both parents as well as the paternal and maternal grandsire were heterozygous for this mutation. In addition, the parents and the paternal grandsire were carriers of the MH2-haplotype linked with the T-allele of the SLC37A2:g.28879810C>T mutation. For the SHBG:g.27956790C>T mutation (rs38377500) on BTA19 (MH1), the aborted fetus and its sire were heterozygous. Among all further 341 Vorderwald cattle genotyped we found 27 SLC37A2:g.28879810C>T heterozygous animals resulting in an allele frequency of 0.0396. Among the 120 male Vorderwald cattle, there were 12 heterozygous with an allele frequency of 0.05. The SLC37A2:g.28879810C>T mutation could not be found in further nine cattle breeds nor in Vorderwald cattle with contributions from Ayrshire bulls. In 69 Vorderwald cattle without genes from Montbeliarde bulls the mutated allele of SLC37A2:g.28879810C>T could not be detected. The SHBG:g.27956790C>T mutation appeared unlikely to be responsible for the present case of abortion and, in addition, we observed this mutation in a homozygous state in a living animal. In conclusion, we could demonstrate the first case of an aborted fetus carrying the deleterious SLC37A2:g.28879810C>T mutation homozygous and show that this deleterious mutation had been introduced through Montbeliarde bulls into Vorderwald cattle. PMID- 27472837 TI - Opioid treatment failure in cancer patients: the role of clinical and genetic factors. AB - AIM: To identify clinical and genetic factors associated with outcome of opioid treatment. PATIENTS & METHODS: We performed an exploratory analysis in a cohort of 353 patients treated with fentanyl, morphine, oxycodone and/or hydromorphone for cancer-related pain, exploring selected clinical and pharmacogenetic factors for a correlation with treatment failure for all and per type of opioid. RESULTS: Use of adjuvant pain medication, intensity of pain at rest and age were associated with treatment failure in the various cohorts. Only the genetic variants rs12948783 (RHBDF2) and rs7016778 (OPRK1) correlated statistically significant in univariate, but not in multivariable analysis. CONCLUSION: Several clinical and genetic factors were identified that warrant further study to clarify their role and use in opioid treatment. PMID- 27472838 TI - Correction: Measurement of the Absolute Magnitude and Time Courses of Mitochondrial Membrane Potential in Primary and Clonal Pancreatic Beta-Cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0159199.]. PMID- 27472840 TI - Heterogeneous phase fibrinolysis rates by damped oscillation rheometry. AB - BACKGROUND: Devices gauging viscoelastic properties of blood during coagulation like the thromboelastograph support fundamental research as well as point of care needs. Associated fibrinolysis data are based on endogenous species or plasminogen activator added to a homogeneous sample prior to clot formation. Digestion in a monolithic structure differs from the physical situation of thrombolytic therapy where surface reactions dominate. OBJECTIVE: This study aims to develop rheological testing for heterogeneous phase fibrinolysis. METHOD: Fibrinolysis rates were determined by phase change of a solid clot induced by autologous plasma/streptokinase (SK) in a rheometer sensitive to viscous damping. RESULTS: Initial slope or overall change in the logarithmic damping factor indicated fibrinolytic rates. Rates depended on clot geometry, phase volumes, clot composition and SK concentration. CONCLUSION: The damped oscillation rheometer can be adapted to determine relative rates of heterogeneous fibrinolysis in vitro. PMID- 27472841 TI - Relationship between arterial blood pressure and blood viscosity in spontaneously hypertensive rats treated with pentoxifylline. AB - BACKGROUND: Systemic arterial pressure (AP) depends on two physiological variables: cardiac output (CO) and total peripheral resistance (TPR). The latter depends on vascular hindrance and blood viscosity (BV). However, the relative contributions of the vascular and rheological factors to TPR remain unclear. OBJECTIVE: The aim of our work was to study the haemodynamic and haemorheologic effects of a treatment course with pentoxifylline (PTX) in SHRs in an effort to assess the impact of the rheological factor on TPR and AP. METHODS: The effects of the treatment course with PTX (100 mg/kg/day p.o. for six weeks) on BV, plasma viscosity, haematocrit, erythrocyte aggregation and deformability, mean AP (MAP), stroke volume (SV), CO, and TPR were studied in SHRs and in control Wistar Kyoto (WKY) rats. RESULTS: PTX-treated SHRs had a lower BV, lower erythrocyte aggregation, and higher erythrocyte deformability index compared with the controls. The TPR level was higher by 43% compared with that in WKY rats and did not differ from the values obtained from control SHRs. In SHRs, moderate and strong positive correlations were found between BV and MAP and between BV and TPR. PTX-treated SHRs did not have any significant correlations between the above mentioned parameters. CONCLUSIONS: Treatment with PTX attenuated whole blood viscosity, but did not affect the AP and hemodynamic parameters in the experimental SHRs compared with the control SHRs. The magnitude of the rheologic effects of PTX was insufficient to cause appreciable decreases in TPR and AP. PMID- 27472842 TI - Rheological effects of macromolecular interactions in synovial fluid. AB - The rheological properties of synovial fluid (SF) are largely attributed to the presence of high molecular weight hyaluronan (HA). However, rheological differences between SF and pure HA solutions suggest that SF proteins actively contribute towards the bulk viscoelasticity of this biological fluid. Due to various experimental challenges involved with the rheometry of low-viscosity biological fluids, the macromolecular interactions in SF and their relative rheological importance are still a matter of active discussion. Interestingly however, recent evidence suggests that the concentration and structure of proteoglycan 4 (PRG4, also known as lubricin) can directly modulate the viscoelastic properties of HA-PRG4 solutions. The objective of this review is to highlight recent rheological studies that examine the macromolecular interactions between HA and proteins in SF. First, a general overview of the chemical composition of SF and the molecular structure of its key constituents HA and PRG4 is provided. Subsequently, diverse rheological experimental techniques that have been developed to characterize HA solutions are discussed. Finally, rheological investigations of macromolecular interactions between HA, serum proteins, and PRG4 are examined. This review illustrates how diverse rheological techniques can expand our understanding of the composition-structure-function relationships in SF. PMID- 27472843 TI - Large artery biomechanical, geometrical, and structural remodeling elicited by long-term propranolol administration in an animal model. AB - BACKGROUND: Limited attention has been paid to the role of beta-adrenergic blocking agents on large artery function/structure, despite being clinically useful for treating many forms of cardiovascular disease. OBJECTIVE: To assess long-term consequences of beta-blocker administration on the biomechanical properties, geometry, and histological structure of two major elastic arteries. METHODS: Healthy male rats received water with their food, while beta-blockade was produced in rats by adding propranolol in their drinking water. The thoracic aorta and carotid artery were resected after three months for biomechanical (failure and inflation-extension) testing along with geometrical and histological evaluation. RESULTS: The thoracic aorta presented increased strength longitudinally in propranolol-treated than untreated rats, resulting from increased adventitial collagen content. The distensibility of carotid artery increased in propranolol-treated rats at low-to-physiologic pressures, resulting from decreased medial collagen content. Structural remodeling was characterized by reduced lumen diameter, wall mass, and thickness-to-radius ratio. The latter, together with the greater resorption of the media than adventitia, related with the measured opening angle decrease in propranolol-treated rats. CONCLUSIONS: The geometrical/biomechanical remodeling was mediated by the hemodynamic effects of propranolol treatment, namely the reduced blood flow, and served to normalize in vivo hoop stresses as well as vessel compliance. PMID- 27472844 TI - Image enhancement for on-site X-ray nondestructive inspection of reinforced concrete structures. AB - The use of portable and high-energy X-ray system can provide a very promising approach for on-site nondestructive inspection of inner steel reinforcement of concrete structures. However, the noise properties and contrast of the radiographic images for thick concrete structures do often not meet the demands. To enhance the images, we present a simple and effective method for noise reduction based on a combined curvelet-wavelet transform and local contrast enhancement based on neighborhood operation. To investigate the performance of this method for our X-ray system, we have performed several experiments with using simulated and experimental data. With comparing to other traditional methods, it shows that the proposed image enhancement method has a better performance and can significantly improve the inspection performance for reinforced concrete structures. PMID- 27472845 TI - Modulating transcallosal and intra-hemispheric brain connectivity with tDCS: Implications for interventions in Aphasia. AB - BACKGROUND/OBJECTIVE: Transcranial direct current stimulation (tDCS) can enhance or diminish cortical excitability levels depending on the polarity of the stimulation. One application of non-invasive brain-stimulation has been to modulate a possible inter-hemispheric disinhibition after a stroke. This disinhibition model has been developed mainly for the upper extremity motor system, but it is not known whether the language/speech-motor system shows a similar inter-hemispheric interaction. We aimed to examine physiological evidence of inter- and intra-hemispheric connectivity changes induced by tDCS of the right inferior frontal gyrus (IFG) using arterial-spin labeling (ASL) MRI. METHODS: Using an MR-compatible DC-Stimulator, we applied anodal stimulation to the right IFG region of nine healthy adults while undergoing non-invasive cerebral blood flow imaging with arterial-spin labeling (ASL) before, during, and after the stimulation. All ASL images were then normalized and timecourses were extracted in regions of interest (ROIs), which were the left and right IFG regions, and the right supramarginal gyrus (SMG) in the inferior parietal lobule. Two additional ROIs (the right occipital lobe and the left fronto-orbital region) were taken as control regions. RESULTS: Using regional correlation coefficients as a surrogate marker of connectivity, we could show that inter-hemispheric connectivity (right IFG with left IFG) decreased significantly (p < 0.05; r-scores from 0.67 to 0.53) between baseline and post-stimulation, while the intra-hemispheric connectivity (right IFG with right SMG) increased significantly (p < 0.05;r-scores from 0.74 to 0.81). A 2 * 2 ANOVA found a significant main effect of HEMISPHERE (F(8) = 6.83, p < 0.01) and a significant HEMISPHERE-by-TIME interaction (F(8) = 4.24, p < 0.05) in connectivity changes. The correlation scores did not change significantly in the control region pairs (right IFG with right occipital and right IFG with left fronto-orbital) over time. CONCLUSION: Using an MR-compatible DC stimulator we showed that ASL-MRI can detect tDCS-induced modulation of brain connectivity within and between hemispheres. These findings might affect trial designs focusing on modulating the non-dominant hemisphere to enhance language/speech-motor functions. PMID- 27472846 TI - Treadmill vs Cycling in Parkinson's disease rehabilitation: Commentary on "Intensive cycle ergometer training improves gait speed and endurance in patients with Parkinson's disease: A comparison with treadmill training" by Arcolin et al., 2016. PMID- 27472847 TI - Reply to Commentary by Miguel Fernandez-del-Olmo on "Intensive cycle ergometer training improves gait speed and endurance in patients with Parkinson's disease: A comparison with treadmill training" by Arcolin et al., 2016. PMID- 27472848 TI - Neuroplasticity in the language system: Reorganization in post-stroke aphasia and in neuromodulation interventions. PMID- 27472849 TI - Polydimethylsiloxane pressure sensors for force analysis in tension band wiring of the olecranon. AB - BACKGROUND: Several different surgical techniques are used in the treatment of olecranon fractures. Tension band wiring is one of the most preferred options by surgeons worldwide. The concept of this technique is to transform a tensile force into a compression force that adjoins two surfaces of a fractured bone. Currently, little is known about the resulting compression force within a fracture. OBJECTIVE: Sensor devices are needed that directly transduce the compression force into a measurement quality. This allows the comparison of different surgical techniques. Ideally the sensor devices ought to be placed in the gap between the fractured segments. METHODS: The design, development and characterization of miniaturized pressure sensors fabricated entirely from polydimethylsiloxane (PDMS) for a placement within a fracture is presented. The pressure sensors presented in this work are tested, calibrated and used in an experimental in vitro study. RESULTS: The pressure sensors are highly sensitive with an accuracy of approximately 3 kPa. A flexible fabrication process for various possible applications is described. The first in vitro study shows that using a single-twist or double-twist technique in tension band wiring of the olecranon has no significant effect on the resulting compression forces. CONCLUSIONS: The in vitro study shows the feasibility of the proposed measurement technique and the results of a first exemplary study. PMID- 27472850 TI - Darknet and bitcoin, the obscure and anonymous side of the internet in healthcare. AB - Illegal activities prosecutable by law in the real life can be committed on the internet alike. In the healthcare domain, we refer mainly to selling of illegal and counterfeit drugs, exchange of pedo-pornographic material and marketing of stolen medical records. These illegal activities are made easier by recent developments of the Internet that medical community must be aware of: darknet and bitcoin. The first allows anonymous surfing and the last anonymous financial transactions. After discussing which healthcare areas are affected by these technological developments of the Internet and the deriving consequences, then the Authors express their opinion on what actions can be taken to protect internet community. PMID- 27472851 TI - Attitudes towards personal and shared space during the flight. AB - BACKGROUND: Aircraft passenger comfort experience was previously defined based on its underlying thematic components representing passengers' perception of the environmental elements and their link to their concerns. OBJECTIVE: This paper aims to 1) identify aircraft passengers' attitudes towards their personal and shared space in the cabin environment during the flight which are linked to their comfort experience and 2) highlight passenger concerns associated with those attitudes. METHOD: A sample involving 16 participants was conducted, collecting full accounts of their real-time flight experiences onboard commercial aircrafts, using questionnaires. RESULTS: Four types of attitudes were identified in reaction to participants' personal and shared space during the flight. Those were described as adjust, avoid, approach, and shield. Passengers' concerns associated with those attitudes were respectively: control, privacy, connectedness and tolerance. CONCLUSIONS: It is concluded that passenger comfort can be improved once the identified concerns and attitudes are addressed in the design of the aircraft seat and interior. Design recommendations are provided accordingly. PMID- 27472852 TI - Occupancy and patient care quality benefits of private room relative to multi-bed patient room designs for five different children's hospital intensive and intermediate care units. AB - BACKGROUND: Prior research documents occupancy and patient care quality (OPCQ) benefits for private room (PR) relative to multi-bed (MB) designs in neonatal intensive care units (NICUs). OBJECTIVE: To extend this research design to four additional types of children's hospital units: a cardiovascular care center (CVCC), an infant care center (ICC), a medical/surgical unit (Med/Surg), and a pediatric intensive care unit (PICU). METHODS: Staff comments, task activities, patient care demands, and perceptual survey rankings for twelve major indicators of OPCQ were assessed with nursing staff on these units plus an NICU. RESULTS: With the PR designs, for 38 of 48 pairwise comparisons for the twelve major OPCQ indicators, CVCC staff rankings are significantly lower than those by staff on the other four units. For 47 of 48 pairwise comparisons for the twelve major OPCQ indicators, NICU, ICC, Med/Surg, and PICU staff rankings for PR designs do not differ significantly from those for MB designs. Comments by staff on all five units target numerous PR OPCQ defects. CONCLUSION: Design, operation and management of the patient care environments on the five different PR units evaluated in this research confront a challenge in realizing OPCQ benefits that match experience with PR NICU designs in other contexts. PMID- 27472853 TI - Functional customization: Value creation by individual storage elements in the car interior. AB - BACKGROUND: Mobility demands change due to differing life stages of car owners. Car sharing and retail markets seldom offer a possibility for customization by the user in contrast to the freedom of choice of an initial owner of a car. OBJECTIVE: The value creation of functional customization is investigated. Prior to a test with a concept design, different use case scenarios of car drivers are identified regarding the preferred storage location of their personal belongings in different situations. METHODS: A study with 70 subjects was conducted in order to evaluate the value added by functional customization. Storage habits of users were investigated in general and in relation to a concept design offering the possibility for flexible storage. RESULTS: Smartphones, supplies, beverages and wallets were the most relevant belongings in all driving situations (commuting, leisure, vacation and special occasions) complemented by sports equipment. Smartphones and other valuables are stored within reach and sight of the user. The emotional responses, recorded before and after the test, subdivided in attraction, hope and joy indicated positive feedback. CONCLUSIONS: The ease of use and the design proved to be crucial product characteristics of individually adaptable storage solutions. Positive emotions are contributing factors for a user's purchasing decision. PMID- 27472854 TI - Exploring communication processes in workplace meetings: A mixed methods study in a Swedish healthcare organization. AB - BACKGROUND: An efficient team and a good organizational climate not only improve employee health but also the health and safety of the patients. Building up trust, a good organizational climate and a healthy workplace requires effective communication processes. In Sweden, workplace meetings as settings for communication processes are regulated by a collective labor agreement. However, little is known about how these meetings are organized in which communication processes can be strengthened. OBJECTIVE: The aim of this study was to explore communication processes during workplace meetings in a Swedish healthcare organization. METHODS: A qualitatively driven, mixed methods design was used with data collected by observations, interviews, focus group interviews and mirroring feedback seminars. Data were analyzed using descriptive statistics and conventional content analysis. RESULTS: The communication flow and the organization of the observed meetings varied in terms of physical setting, frequency, time allocated and duration. The topics for the workplace meetings were mainly functional with a focus on clinical processes. Overall, the meetings were viewed not only as an opportunity to communicate information top down but also a means by which employees could influence decision-making and development at the workplace. CONCLUSIONS: Workplace meetings have very distinct health promoting value. It emerged that information and the opportunity to influence decisions related to workplace development are important to the workers. These aspects also affect the outcome of the care provided. PMID- 27472855 TI - The clinical and EMG assessment of the effects of stabilization exercise on nonspecific chronic neck pain: A randomized controlled trial. AB - BACKGROUND: Neck pain is an important cause of disability. In spite of its high prevalence rate, treatment of the disorder is a challenging topic. Stabilization exercise has been the topic of many studies. OBJECTIVE: To compare the effects of stabilization and routine exercises on chronic neck pain. METHODS: Forty patients were randomly assigned into either stabilization or routine exercise groups and undertook a 10-week training program. Electromyographic (EMG) activity was recorded from Sternocleidomastoid (SCM), Anterior Scalene (AS) and Splenius Capitis (SC) muscles bilaterally. Endurance time of deep flexor muscles was measured by chronometer.Pain and disability were measured using Visual Analogue Scale (VAS) and neck disability index (NDI) questionnaire, respectively before and after training period. RESULTS: Findings revealed significant decreased pain and disability in both groups after intervention (P< 0/001). Flexor muscles endurance of stabilization group was significantly increased compared with that of routine (P< 0/001). Also EMG activity of SCM, AS and SC muscles were significantly decreased in stabilization group compared with routine (P< 0/001). CONCLUSION: Increased deep flexor endurance and decreased EMG activity of SCM, AS and SC muscles suggest an important role for stabilizing exercises on reducing the activity of superficial muscles in chronic neck pain. PMID- 27472856 TI - Effects of weighted and un-weighted pendulum exercises on ultrasonographic acromiohumeral distance in patients with subacromial impingement syndrome. AB - BACKGROUND: Although functional results of combined rehabilitation programs are reported, there have been no reports studying the effects of solo pendulum exercises on ultrasonographic measurements of acromiohumeral distance (AHD). OBJECTIVE: To investigate the effects of weighted and un-weighted pendulum exercises on ultrasonographic AHD and clinical symptoms in patients with subacromial impingement syndrome. METHODS: Patients with subacromial impingement syndrome were randomized to performing weighted (1.5 kilograms hand held dumbbell, N= 18) or un-weighted (free of weight, N= 16) pendulum exercises for 4 weeks, 3 sessions/day. Exercises were repeated for each direction of shoulder motion in each session (ten minutes). Clinical situation was evaluated by Constant score and Shoulder Pain Disability Index (SPADI). Ultrasonographic measurements of AHD at 0 degrees , 30 degrees and 60 degrees shoulder abduction were performed. All clinical and ultrasonographic evaluations were performed at the beginning of the exercise program and at end of 4 weeks of exercise program. RESULTS: Thirty-four patients (23 females, 11 males; mean age 41.7 +/- 8.9 years) were evaluated. Significant clinical improvements were detected in both exercise groups between pre and post-treatment evaluations (p < 0.05). There was no significant difference for pre and post-treatment AHD measurements at 0 degrees , 30 degrees , and 60 degrees shoulder abduction between groups (p > 0.05). There was no significant difference for pre and post-treatment narrowing of AHD (narrowing of 0 degrees -30 degrees , and 0 degrees -60 degrees ) between groups (p > 0.05). CONCLUSION: While significant clinical improvements were achieved with both weighted and un-weighted solo pendulum exercises, no significant difference was detected for ultrasonographic AHD measurements between exercise groups. PMID- 27472857 TI - Validity and reliability of a Turkish Brief Pain Inventory Short Form when used to evaluate musculoskeletal pain. AB - BACKGROUND: The Brief Pain Inventory (BPI) is both a questionnaire and an outcome measure that is used widely in clinical trials to assess pain associated with many conditions. The BPI Short Form has been extensively translated into foreign languages. The aim of this study was to assess the validity and reliability of a Turkish Brief Pain Inventory Short Form (BPI-TR) to evaluate musculoskeletal pain. METHODS: In total, 297 patients with musculoskeletal pain participated in the study. Demographic characteristics and brief medical histories were recorded. Pain intensity was assessed using a visual analogue scale (VAS) and quality-of life was assessed using the Short Form 36 (SF-36). Pain was evaluated using the BPI-TR in all patients. Internal consistency and test-retest analysis were used to assess reliability. The internal consistency of the scale items was assessed by calculating Cronbach's alpha value, which was expected to be > 0.7. The criterion validity of the BPI-TR was assessed by correlation with VAS scores. RESULTS: Pain intensity, pain interference, and other components of the Turkish version were consistent with validity thereof. Cronbach's alpha was 0.84 for pain intensity and 0.89 for pain interference. The extent of BPI-TR and VAS correlation was statistically significant. CONCLUSIONS: The BPI-TR may be used for assessment of musculoskeletal pain. PMID- 27472858 TI - The effects of two different low level laser therapies in the treatment of patients with chronic low back pain: A double-blinded randomized clinical trial. AB - OBJECTIVE: The purpose of this study was to compare the effectiveness of two different laser therapy regimens on pain, lumbar range of motions (ROM) and functional capacity in patients with chronic low back pain (CLBP). METHODS: Forty nine patients with CLBP were randomly assigned into two groups. Group 1 (n= 20) received hot-pack + laser therapy 1 (wavelength of 850 nm Gallium-Aluminum Arsenide (Ga-Al-As) laser); group 2 (n= 29) received hot-pack + laser therapy 2 (wavelength of 650 nm Helyum-Neon (He-Ne), 785 ve 980 nm Gal-Al-As combined plaque laser) for 15 sessions. Pain severity, patient's and physician's global assessments were evaluated with visual analogue scale (VAS). Modified Schober test, right and left lateral flexion measurements were done. Modified Oswestry Disability Questionnaire (MODQ) was used for evaluation of functional disability. Measurements were done before and after the treatment. RESULTS: After treatment there were statistically significant improvements in pain severity, patient's and physician's global assessment, ROM and MODQ scores in both groups (P< 0.05). After the treatment there were statistically significant differences between the groups in lateral flexion measurements and MODQ scores (P< 0.05) except in pain severity, Modified Schober test, patient's and physician's global assessments (P> 0.05) in favor of those patients who received combined plaque laser therapy (group 2). CONCLUSION: Laser therapy applied with combined He-Ne and Ga-Al-As provides more improvements in lateral flexion measurements and disability of the patients, however no superiority of the two different laser devices to one another were detected on pain severity. PMID- 27472859 TI - Acute effect of different time periods of passive static stretching on the hamstring flexibility. AB - BACKGROUND: Several factors are associated with the presence of chronic low back pain; one of them is the flexibility of the hamstring muscles that influences the posture of the pelvic spine. OBJECTIVE: Investigate the influence of two different time periods of passive static stretching on the flexibility of the hamstring. METHODS: Forty-six physiotherapy students were divided into two groups performing stretching exercises: 30 s and 60 s duration. The collections consisted of: (1) pre-test: evaluation of the flexibility of the hip and knee, using a manual goniometer by means of the following tests: Straight Leg Raise Test (SLR), Passive Hip Flexion Test (PHFT) and Modified Knee Extension Test (MKET), (2) intervention: stretching with different runtimes, (3) post-test: reappraisal of flexibility, conducted immediately after the intervention. RESULTS: Significant difference was observed intra groups, group that did stretching exercises lasting 30 seconds (G30) (SLR p = 0.000. PHFT p = 0.003 and MKET p = 0.000) and group that did stretching exercises lasting 60 seconds (G60) (SLR p = 0.000. PHFT p = 0.001 and MKET p = 0.002). Comparing the groups, no significant difference was found (SLR p = 0.307; PHFT p = 0.904; MKET p = 0.132). CONCLUSION: Thus it can be inferred that 30 seconds are sufficient for increased flexibility of young women. Therefore the time-treatment sessions can be optimized. Only the acute effect of stretching was observed; further investigation of the long-term effect is required. PMID- 27472860 TI - Plant expression systems for early stage discovery and development of lead therapeutic antibodies. AB - BACKGROUND: Antibodies for human clinical applications are predominantly produced in mammalian expression systems, with Chinese hamster ovary (CHO) cells being the gold standard. CHO cells are ideal for the manufacturing of the IgG class of antibodies, but not for the production of complex antibodies like secretory IgAs (SIgAs) and IgMs, which remain unavailable for clinical use. In contrast, plant seeds and leaves hold the promise to produce SIgAs, IgMs and similar complex antibody formats to scalable amounts. Using transient transformation of Nicotiana benthamiana leaves, complex antibody formats can be produced up to milligram amounts in less than a month. OBJECTIVE: Based on these merits, we propose a model for early-phase exploration and designing of innovative antibody formats for therapeutic application. Further in this essay, we elaborate how the model was followed during the selection of novel antibodies for seed-based production. RESULT: This exploratory model led to the engineering of novel light-chain devoid porcinized-llama antibodies (VHH-Fc) of the IgG (VHH-IgG) and IgA (VHH-IgA) isotypes and also tetravalent dimeric and SIgAs. CONCLUSION: The proposed strategy may lead to plant-based rapid engineering of innovative antibodies more apt and efficacious for therapy, and in the coarse also add to the understanding of their mode of action. PMID- 27472861 TI - Glycosylation of plant produced human antibodies. AB - Human immunoglobulins circulate as highly heterogeneously glycosylated mixture of otherwise homogeneous protein backbones. A series of studies, mainly on IgG, have unequivocally proven that antibodies modulate their effector function through sugars present in the Fc domain. However, our limited technology in producing complex proteins such as antibodies, with defined glycan structures hamper in depths studies. This review introduces a plant based expression platform enabling engineering of antibody glycans. The procedure is based on the simultaneous delivery of appropriate constructs, carrying cDNAs of target proteins (e.g. heavy and light chain of antibodies) in combination with human glycosylation enzymes into plant leaves. Harvesting of recombinant proteins one week post construct delivery allows high speed and flexibility. Major achievements include the production of functional active slialylated pentameric IgMs in tobacco leaves. The system provides a viable approach to the generation of antibodies with defined glycoforms on demand, contributing to studies on antibody glycans and the development of novel antibody based drugs. PMID- 27472862 TI - The emergence of antibody therapies for Ebola. AB - This review describes the history of Ebola monoclonal antibody (mAb) development leading up to the recent severe Ebola outbreak in West Africa. The Ebola virus has presented numerous perplexing challenges in the long effort to develop therapeutic antibody strategies. Since the first report of a neutralizing human anti-Ebola mAb in 1999, the straightforward progression from in vitro neutralization resulting in in vivo protection and therapy has not occurred. A number of mAbs, including the first reported, failed to protect non-human primates (NHPs) in spite of protection in rodents. An appreciation of the role of effector functions to antibody efficacy has contributed significantly to understanding mechanisms of in vivo protection. However a crucial contribution, as measured by post-exposure therapy of NHPs, involved the comprehensive testing of mAb cocktails. This effort was aided by the use of plant production technology where various combinations of mAbs could be rapidly produced and tested. Introduction of appropriate modifications, such as specific glycan profiles, also improved therapeutic efficacy. The resulting cocktail, ZMappTM, consists of three mAbs that were identified from numerous mAb candidates. ZMappTM ? is now being evaluated in human clinical trials but has already played a role in bringing awareness to the potential of antibody therapy for Ebola. PMID- 27472864 TI - Licensed monoclonal antibodies and associated challenges. AB - Monoclonal antibodies (mAbs) are the leading class of targeted therapeutics and remarkably effective in addressing autoimmune diseases, inflammations, infections, and various types of cancer. Several mAbs approved by US food and drug administration (FDA), are available on the market and a number are pending for approval. Luckily, FDA approved mAbs have played a pivotal role in the treatment and prevention of lethal diseases. However, claiming that licensed mAbs are 100% safe is still debatable, because infections, malignancies, anaphylactoid, and anaphylactic reactions are the more frequently associated adverse events. To evaluate benefit to risk ratio of mAbs, it is important for the clinical research staff or physicians to monitor and follow-up the patients who are receiving mAbs dozes. It is recommended that patients, physicians, biopharmaceutical companies, and researchers should keep in touch to highlight and resolve antibody-based adverse events. In this review we underscore the associated challenges of mAbs, approved by FDA from 2007-2014. PMID- 27472863 TI - Prevalence of Hepatitis B surface antigen among biomedical students of African descent in Usmanu Danfodiyo University, Sokoto, Nigeria. AB - BACKGROUND: Hepatitis B (HB) is a serious global public health problem that put health professionals particularly at risk. OBJECTIVE: The aim of this study was to investigate the prevalence of Hepatitis B surface antigen (HBsAg) among Biomedical Students of African descent attending Usmanu Danfodiyo University Sokoto in North-Western Nigeria. METHODS: The Onsite HBsAg (CTK Biotech, USA) was used to detect the presence of hepatitis B surface antigen. RESULTS: We tested 186 consecutively-recruited students consisting of 147 males and 39 females aged 18-35 years (mean age 26 +/- 2.0 years). Of the 186 students tested, 25 (13.4%) were positive for HBsAg. The prevalence of HBsAg was significantly higher among students in the 21-25 years age group. Hepatitis B vaccination uptake among students was 7%. Majority of subjects were single 173(93.1%) compared to married 13 (6.9%). Ethnic distribution of the subjects indicated that 104(55.9%) were Hausa compared to Yoruba 32 (17.2%), other ethnic groups 21(11.3%), Fulani 20(10.8%) and Igbo 9(4.8%). CONCLUSIONS: This study indicates a high prevalence of hepatitis B virus infection among Biomedical students in Sokoto, North Western, Nigeria. Finding from this study is enough justification for the implementation of a policy to routinely test students entering into the biomedical professions for Hepatitis B virus infection. There is the need to provide hepatitis B vaccination universally to all those who are found negative prior to commencement of their biomedical training. There is also need to educate students entering biomedical professions and healthcare workers on the modes of transmission and prevention, importance of being compliant with protective vaccination as well as the need to observe universal precaution and infection control guidelines during their training and future professional practice. PMID- 27472867 TI - Keyword Index Volume 23 (2014/2015). PMID- 27472865 TI - Design and construction of immune phage antibody library against Tetanus neurotoxin: Production of single chain antibody fragments. AB - BACKGROUND: Tetanus neurotoxin (TeNT) is composed of a light (LC) and heavy chain (HC) polypeptides, released by anaerobic bacterium Clostridium tetani and can cause fatal life-threatening infectious disease. Toxin HC and LC modules represents receptor binding and zinc metalloprotease activity, respectively. The passive administration of animal-derived antibodies against tetanus toxin has been considered as the mainstay therapy for years. However, this treatment is associated with several adverse effects due to the presence of anti-isotype antibodies. OBJECTIVE: In the present study, we have produced the fully human single chain antibody fragments (HuScFv) from two human antibody phage display libraries. MATERIAL AND METHODS: Twenty-four different HuscFvs were isolated from two anti TeNT immune libraries. Our produced human ScFv (HuScFv) were converted to IgG platform and analyzed regarding their specific reactivity to TeNT. RESULTS: All of the selected scFvs have the same VL but different VH. Three HuscFvs from the first library (TTX15, 51, 75) and two HuscFvs from the second library (TTX16, 20) were chosen to convert to IgG1 using pOptiVEC and pcDNA3.3 systems. Production of IgG1 from transfected DG44 and binding capacity of them to tetanus toxin and toxoid were measured by ELISA. ELISA results showed no detectable production of TTX16 and TTX20 IgG1. Although, TTX51 and TTX75 were converted and produced as IgG1, no reactivity to tetanus toxin and toxoid was observed. However, TTX15 was successfully produced as whole IgG1 platform with reactivity to both tetanus toxin and toxoid. The latter would be an appropriate replacement for conventional polyclonal antibodies if would meet the further characterization including specificity determination, affinity measurement and toxin neutralizing assays. CONCLUSION: Our results demonstrated production of functional IgG1 derived from TTX15 scFv and might be an appropriate replacement for polyclonal Tetabulin but it needs further characterization. PMID- 27472868 TI - High-resolution analysis of the B cell repertoire before and after polyethylene glycol fusion reveals preferential fusion of rare antigen-specific B cells. AB - OBJECTIVE: The hybridoma technology is one of the most important advances in clinical immunology. Little is known about the differences between the antibodies produced during the in vivo immune response and those recovered in hybridoma libraries. Here, we investigate a potential fusion bias inherent to the hybridoma production process. METHODS: Transgenic rats carrying human Ig heavy and light chain loci were immunized with measles virus (MV) to generate human mAbs. Usin g high-throughput sequencing of IgH mRNA, we compared the IgH repertoire of lymph nodes and the derived hybridoma library using the sequences of the MV-specific hybridoma clones as a reference set with known specificity. RESULTS: We observed that large clonotypes from the lymph nodes were not represented in the hybridoma library, but low-frequency B cell populations became highly enriched and most hybridoma clones were derived from these. Our data also showed that identical CDR3s evolved from diverse VDJ recombinations, indicating convergence of different B cells subpopulations towards expression of antibodies with similar paratopes. CONCLUSION: The efficient generation of mAbs results from a fusion process highly selective for rare antigen-specific B cells rather than in vivo expanded populations. Antibodies of particular interest may therefore be missed during classical hybridoma production. PMID- 27472869 TI - Frequency of viral infections and environmental factors in multiple sclerosis. AB - OBJECTIVES: Multiple sclerosis (MS) is a complicated disease which occurs due to relationship between genes and environmental factors that causes tissue damage by autoimmune mechanisms.We investigated and illustrated the hypotheses correlated to the evidence of several putative environmental risk factors for MS onset and progression in this part of Iran. MATERIALS AND METHODS: Univariate logistic regression was used to detect the effects of environmental factors on the risk of MS. Data were analyzed using SPSS version 16. RESULTS: The childhood history of patients with rubella, measles and chickenpox increased the risk of MS significantly. Moreover, low consumption of dairy products, avoidance of seafood consumption, cigarette smoking and exposure to tobacco smoke, stress, anxiety disorders, depress and disturbing thoughts, negative and disturbing thoughts, developing a sudden shock upon hearing bad news, having obsessive-compulsive and being depressed increased the risk of MS significantly. CONCLUSIONS: The results of the current research partially solved the puzzling question of complex interplay between environmental factors and MS disease in this part of Iran. Incorporating these factors enables more powerful and accurate detection of novel risk factors with diagnostic and prognostic methods. PMID- 27472870 TI - Investigation of the correlation between some immune system and biochemical indicators in patients with type 2 diabetes. AB - AIMS/INTRODUCTION: Since changes in some immune system indicators such as leukocyte count and neutrophil to lymphocyte ratio in the blood and Inflammation is directly in relation with the pathogenesis of type 2 diabetes, metabolic syndrome and atherosclerosis, measuring these indicators in patients with type 2 diabetes and comparing them with control group can be a suitable indicator of Inflammation and prognosis of the disease. MATERIALS AND METHODS: The current study was done on 75 patients with type 2 diabetes and 72 healthy individuals as patient and healthy group respectively. The selected groups have been matched for age and sex. Fasting blood sugar, lipid profile including triglycerides, total cholesterol, HDL, LDL, as well as the number of white blood cells, neutrophils, lymphocytes, neutrophils to lymphocytes ratio were measured and analyzed in both groups. RESULTS: The results demonstrated that there is a significant relationship between the number of white blood cells and increase in blood sugar and also between the neutrophil to lymphocyte ratio and increase in Fasting blood sugar and triglycerides parameters. Furthermore, the average of fasting blood sugar, triglycerides, total cholesterol, LDL and neutrophil to lymphocyte ratio in patient with type 2 diabetes is significantly higher than control group. CONCLUSION: Considering the findings of current study, we showed the inflammation and the pathogenesis caused by type 2 diabetes can be attributed to neutrophil to lymphocyte ratio. PMID- 27472871 TI - TRAIL gene expression analysis in multiple sclerosis patients. AB - BACKGROUND: Multiple sclerosis (MS) as an autoimmune disorder in which the insulating covers of neurons in the Central Nervous System are destructed. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an immunomodulatory molecule to protect against T cells hyper activation. METHODS: In this Case control study, we compare TRAIL gene expression in peripheral blood between 50 relapse remitting MS patients and 50 healthy controls by TaqMan Real time PCR. All the patients were negative for HLA-DRB1*15 susceptible allele, normal serum vitamin D, responder to Interferon beta. All the health individuals were matched to patients. Also, we tried to find correlation between TRAIL gene expression and clinical characteristics of patients. RESULTS: No statistically significant difference was found in TRAIL mRNA expression between MS patients and controls (p> 0.05). There was no correlation in the TRAIL expression and age of onset, disease duration and Expanded Disability Status Scale of Kurtzke (EDSS). As IFN-b may have stimulatory effects on immunoregulatory function of TRAIL and all of our patients were treated with interferon beta and were responder, it lead to no significant change in TRAIL expression. We suggest comparing between responders and non-responders should be investigated. PMID- 27472872 TI - A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders. AB - BACKGROUND: Late life depression is a prodromal feature and a risk factor for Alzheimer's disease (AD) and mild cognitive impairment (MCI). We identified five items in the Geriatric Depression scale (DepE) that are important as a risk for MCI and AD: memory problems, feeling blue, crying, feeling worthless, and trouble concentrating. OBJECTIVE: Our goal was to examine the relationship between DepE and cognition in a cohort of Mexican Americans. METHODS: Data from 317 Mexican Americans from the HABLE study were analyzed. DepE scores were dichotomized into two groups: endorsement of 1 item or less, and endorsement of 2 or more items. Cognition was assessed via neuropsychological tests, and diagnosis was based on consensus review. We utilized linear regression to examine the association between DepE and cognitive performance, and logistic regression to examine the utility of DepE in predicting MCI. To examine the impact of DepE on memory over 12 months, we performed ANOVA analysis. RESULTS: Elevated DepE scores were associated with poorer performance on various measures of memory and cognition, but not executive or visual spatial skills. Over 12 months, we found a decline in immediate memory among women but not men. Those with high scores were 4 times more likely to have MCI. ANOVA of total scores revealed differences between groups on immediate memory (p < 0.05) in women, with no significant differences on delay recall in either gender. CONCLUSION: DepE can be utilized in Mexican Americans to identify those at risk of memory related cognitive decline. PMID- 27472873 TI - Streptozotocin Induces Mild Cognitive Impairment at Appropriate Doses in Mice as Determined by Long-Term Potentiation and the Morris Water Maze. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease, and effective therapeutic drugs in the clinic are still lacking. Ideally, AD progression could be stopped at an early stage, such as at the mild cognitive impairment (MCI) stage. MCI refers to the clinical condition between normal aging and dementia. Patients with MCI experience memory loss but do not meet the criteria for the diagnosis of clinically probable AD. However, few MCI animal models have been established. Here, we used in vivo long-term potentiation (LTP) recording and the Morris water maze (MWM) to evaluate the effects of intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. We found a relationship between cognitive behavior and LTP in vivo and determined the appropriate doses of STZ for a putative MCI animal model. Animals that received>=150MUg of STZ exhibited cognitive impairment in the MWM test, and few changes in behavior tests were observed in animals receiving less than 150MUg of STZ. In vivo LTP recordings revealed that the induction of LTP decreased significantly in STZ-treated animals, even at the lowest dose (25MUg/mouse), in a dose-dependent manner. Pathology analysis revealed STZ-induced neuron loss in a dose-dependent manner, both in the cortex and in the hippocampus, as evidenced by a significantly decreased neuronal number in the cohort treated with 75MUg of STZ/mouse. Our study indicated that a low dose (25MUg/mouse) of STZ impaired neural plasticity; at a higher dose of 75MUg/mouse STZ, further LTP deficits were noted along with induced neuronal loss in both the cortex and the hippocampus, which could be considered a possible MCI or pre-MCI animal model; and finally, at 150MUg/mouse STZ, dementia was induced, feasibly indicating a state of AD. PMID- 27472874 TI - Mortality in Mild Cognitive Impairment: A Longitudinal Study in Memory Clinics. AB - BACKGROUND: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival. OBJECTIVE: To identify predictors of mortality in patients with MCI. METHODS: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline. RESULTS: 55 (30%) patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality. CONCLUSION: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients' risk. PMID- 27472875 TI - Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. AB - In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-beta1-42 (Abeta1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE E4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Abeta1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE E4 carriers, who had lower levels of Abeta1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE E4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Abeta1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping. PMID- 27472876 TI - Biofunctionalized Silica Nanoparticles: Standards in Amyloid-beta Oligomer-Based Diagnosis of Alzheimer's Disease. AB - Amyloid-beta (Abeta) oligomers represent a promising biomarker for the early diagnosis of Alzheimer's disease (AD). However, state-of-the-art methods for immunodetection of Abeta oligomers in body fluids show a large variability and lack a reliable and stable standard that enables the reproducible quantitation of Abeta oligomers. At present, the only available standard applied in these assays is based on a random aggregation process of synthetic Abeta and has neither a defined size nor a known number of epitopes. In this report, we generated a highly stable standard in the size range of native Abeta oligomers that exposes a defined number of epitopes. The standard consists of a silica nanoparticle (SiNaP), which is functionalized with Abeta peptides on its surface (Abeta SiNaP). The different steps of Abeta-SiNaP synthesis were followed by microscopic, spectroscopic and biochemical analyses. To investigate the performance of Abeta-SiNaPs as an appropriate standard in Abeta oligomer immunodetection, Abeta-SiNaPs were diluted in cerebrospinal fluid and quantified down to a concentration of 10 fM in the sFIDA (surface-based fluorescence intensity distribution analysis) assay. This detection limit corresponds to an Abeta concentration of 1.9 ng l-1 and lies in the sensitivity range of currently applied diagnostic tools based on Abeta oligomer quantitation. Thus, we developed a highly stable and well-characterized standard for the application in Abeta oligomer immunodetection assays that finally allows the reproducible quantitation of Abeta oligomers down to single molecule level and provides a fundamental improvement for the worldwide standardization process of diagnostic methods in AD research. PMID- 27472877 TI - PKC Activation Counteracts ADAM10 Deficit in HuD-Silenced Neuroblastoma Cells. AB - Neuronal ELAV/Hu (nELAV) are RNA-binding proteins that mainly regulate gene expression by increasing the stability and/or translation rate of target mRNAs bearing ARE (adenine and uracil-rich elements) sequences. Among nELAV target transcripts there is ADAM10, an alpha-secretase involved in the non-amyloidogenic processing of the amyloid-beta protein precursor (AbetaPP) which leads to the production of the neuroprotective sAbetaPPalpha peptide. The aim of this study was to evaluate if nELAV depletion affects ADAM10 expression in human SH-SY5Y neuroblastoma cells. We also studied the effects of Bryostatin-1, a molecule able to activate nELAV protein cascade. The specific HuD/nELAV gene silencing decreased both nELAV and ADAM10 protein contents; similar results were obtained by Abeta40 treatment in wild-type SH-SY5Y cells. In HuD-silenced cells, the exposure to Bryostatin-1 counteracted both nELAV and ADAM10 proteins downregulation, by restoring nELAV/ADAM10 basal levels. We also found that sAbetaPPalpha release, which seemed not to be compromised by Abeta40 challenge or HuD-silencing, was favored by Bryostatin-1. Overall, these findings strongly suggest that a deficiency in nELAV content negatively affects ADAM10 expression and may play a role in neurodegenerative diseases, which may benefit by molecules activating ELAV cascade. PMID- 27472878 TI - Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial. AB - There is evidence to suggest the efficacy of Crocus (saffron) in the management of cognitive decline. This study examined the efficacy of Crocus in patients with amnesic and multi domain MCI (aMCImd). The participants included 17 patients on Crocus and 18 on a waiting list, who were examined with a short neuropsychological battery, MRI 3T, while some patients were examined via 256 channel electroencephalogram (HD-EEG) at baseline and after 12 months. The results showed that patients on Crocus had improved Mini-Mental State Examination scores (p = 0.015), while the control group deteriorated. Also, MRI, EEG, and ERP showed improvement in specific domains. This led us to conclude that Crocus is a good choice for management of aMCImd. PMID- 27472879 TI - Chronic Traumatic Encephalopathy Presenting as Alzheimer's Disease in a Retired Soccer Player. AB - The relationship between soccer and chronic traumatic encephalopathy (CTE) is not well established. We report clinicopathological correlations in an 83-year-old retired center-back soccer player, with no history of concussion, manifesting typical Alzheimer-type dementia. Examination revealed mixed pathology including widespread CTE, moderate Alzheimer's disease, hippocampal sclerosis, and TDP-43 proteinopathy. This case adds to a few CTE cases described in soccer players. Furthermore, it corroborates that CTE may present clinically as typical Alzheimer type dementia. Further studies investigating the extent to which soccer is a risk for CTE are needed. PMID- 27472880 TI - Longitudinal Alteration of Intrinsic Brain Activity in the Striatum in Mild Cognitive Impairment. AB - The striatum is a critical functional hub in understanding neurological disorders. However, the Alzheimer's disease (AD)-associated striatal change is unclear, as is the relationship between striatal change and AD pathology. Three year resting-state fMRI data from 15 healthy control (HC) and 20 mild cognitive impairment (MCI) participants were obtained. We analyzed the amplitude of low frequency fluctuations (ALFF) (0.01-0.08 Hz) and two subdivided bands (slow 4:0.027-0.073 Hz; slow-5:0.01-0.027 Hz). We calculated Abeta/pTau ratio using baseline cerebrospinal fluid pTau and Abeta1-42 to represent AD pathology. Compared to HC, MCI participants showed greater decline in right putaminal ALFF, including the slow-4 band. Greater decline of ALFF in the right putamen was significantly related to the memory decline over time and lower baseline Abeta/pTau ratio regardless of age or group. The slow-4 band, relative to slow-5 band, showed a stronger correlation between Abeta/pTau ratio and decline of ALFF in the right putamen. The results suggest that the putaminal function declines early in the AD-associated neurodegeneration. The continuous decline in putaminal ALFF, especially slow-4 band, may be a sensitive marker of AD pathology such as Abeta/pTau ratio regardless of clinical diagnosis. PMID- 27472883 TI - Parkinsonism Differentiates Idiopathic Normal Pressure Hydrocephalus from Its Mimics. AB - BACKGROUND: Parkinsonism is frequent in neurological conditions affecting gait and cognition, such as idiopathic normal pressure hydrocephalus (iNPH) and iNPH mimics, but its discriminating value between these two groups is still unidentified. OBJECTIVE: This study aims to compare the prevalence of parkinsonism between iNPH and iNPH mimics and its discriminating value. METHODS: Among 141 patients with suspicion of iNPH (75.7+/-7.1 years; 31.2% women), seventy-nine presented a possible or probable iNPH according to standardized diagnostic criteria and the remaining sixty-two were classified as iNPH mimics. Presence of parkinsonism and other seminal clinical symptoms of iNPH were systematically evaluated by a board-certified neurologist. Covariates include age, gender, comorbidities, and white matter disease burden using the age-related white matter changes scale. Logistic regressions were used to assess the association between parkinsonism and diagnostic groups. RESULTS: Parkinsonism was present in 40.3% of iNPH mimics and 20.3% of iNPH (p-value: 0.015). The presence of parkinsonism, but not iNPH symptoms, was associated with the diagnosis of mimics in the adjusted model (adjusted odds ratio: 2.28; 95% CI: 1.06-4.93), even when age-related white matter changes were accounted for. CONCLUSION: Compared to iNPH, the increased prevalence of parkinsonism in patients with iNPH mimics in the absence of significant white matter disease suggest an underlying neurodegenerative mechanism. PMID- 27472882 TI - Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers. AB - Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2-isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2-isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD). Smoking and non-smoking CN (n = 83), MCI (n = 164), and probable AD (n = 101) were compared on cerebrospinal fluid (CSF) iPF2alpha-III and 8,12, iso-iPF2alpha-VI F2-isoprostane concentrations. Associations between F2-isoprostane levels and hippocampal volumes were also evaluated. In CN and AD, smokers had higher iPF2alpha-III concentration; overall, smoking AD showed the highest iPF2alpha-III concentration across groups. Smoking and non-smoking MCI did not differ on iPF2alpha-III concentration. No group differences were apparent on 8,12, iso-iPF2alpha-VI concentration, but across AD, higher 8,12, iso-iPF2alpha-VI level was related to smaller left and total hippocampal volumes. Results indicate that active cigarette smoking in CN and probable AD is associated with increased central nervous system OxS. Further investigation of factors mediating/moderating the absence of smoking effects on CSF F2-isoprostane levels in MCI is warranted. In AD, increasing magnitude of OxS appeared to be related to smaller hippocampal volume. This study contributes additional novel information to the mounting body of evidence that cigarette smoking is associated with adverse effects on the human central nervous system across the lifespan. PMID- 27472881 TI - Dysregulation of Autophagy, Mitophagy, and Apoptotic Genes in the Medial Temporal Lobe Cortex in an Ischemic Model of Alzheimer's Disease. AB - Ischemic brain damage is a pathological incident that is often linked with medial temporal lobe cortex injury and finally its atrophy. Post-ischemic brain injury associates with poor prognosis since neurons of selectively vulnerable ischemic brain areas are disappearing by apoptotic program of neuronal death. Autophagy has been considered, after brain ischemia, as a guardian against neurodegeneration. Consequently, we have examined changes in autophagy (BECN 1), mitophagy (BNIP 3), and apoptotic (caspase 3) genes in the medial temporal lobe cortex with the use of quantitative reverse-transcriptase PCR following transient 10-min global brain ischemia in rats with survival 2, 7, and 30 days. The intense significant overexpression of BECN 1 gene was noted on the 2nd day, while on days 7-30 the expression of this gene was still upregulated. BNIP 3 gene was downregulated on the 2nd day, but on days 7-30 post-ischemia, there was a significant reverse tendency. Caspase 3 gene, associated with apoptotic neuronal death, was induced in the same way as BNIP 3 gene after brain ischemia. Thus, the demonstrated changes indicate that the considerable dysregulation of expression of BECN 1, BNIP 3, and caspase 3 genes may be connected with a response of neuronal cells in medial temporal lobe cortex to transient complete brain ischemia. PMID- 27472884 TI - All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity. AB - BACKGROUND: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. OBJECTIVE: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). METHODS: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. RESULTS: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. CONCLUSIONS: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia. PMID- 27472885 TI - ABCA7 Mediates Phagocytic Clearance of Amyloid-beta in the Brain. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-beta in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-beta plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain that is related to phagocytic clearance of amyloid-beta. We isolated microglia and macrophages from Abca7-/- and wild type mice and tested them for their capacity to phagocytose amyloid-beta oligomers. We found that the phagocytic clearance of amyloid-beta was substantially reduced in both microglia and macrophages from Abca7-/- mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-beta oligomers in the hippocampus was reduced in Abca7-/- mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-beta pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-beta in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD. PMID- 27472886 TI - The Identification of Aluminum in Human Brain Tissue Using Lumogallion and Fluorescence Microscopy. AB - Aluminum in human brain tissue is implicated in the etiologies of neurodegenerative diseases including Alzheimer's disease. While methods for the accurate and precise measurement of aluminum in human brain tissue are widely acknowledged, the same cannot be said for the visualization of aluminum. Herein we have used transversely-heated graphite furnace atomic absorption spectrometry to measure aluminum in the brain of a donor with Alzheimer's disease, and we have developed and validated fluorescence microscopy and the fluor lumogallion to show the presence of aluminum in the same tissue. Aluminum is observed as characteristic orange fluorescence that is neither reproduced by other metals nor explained by autofluorescence. This new and relatively simple method to visualize aluminum in human brain tissue should enable more rigorous testing of the aluminum hypothesis of Alzheimer's disease (and other neurological conditions) in the future. PMID- 27472887 TI - hTERT gene polymorphism correlates with the risk and the prognosis of thyroid cancer. AB - OBJECTIVES: The study explored the association between rs10069690C/T and rs2736100G/T of human telomerase reverse transcriptase (hTERT) gene, and the prognosis of thyroid cancer. METHODS: The study had 452 thyroid cancer patients recruited as case group who hospitalized in Jingzhou Central Hospital from January 2001 to June 2004 and 452 healthy people recruited as control group at the same area. The hTERT gene polymorphisms at rs10069690 C/T and rs2736100 G/T were tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between patients' life quality and hTERT gene polymorphisms six months after surgery was evaluated based on the Cancer patients' quality of life index rating scale. RESULTS: There were statistical differences in genotype and allele frequencies of rs10069690 C/T between the case group and control group (both P < 0.05). An association between rs10069690C/T polymorphism and an increased risk of thyroid cancer was shown by logistic regression analysis (CT vs. CC, OR = 1.333, 95%CI = 1.006-1.766, P = 0.045; TT vs. CC, OR = 1.910, 95%CI = 1.084-3.367, P = 0.023; CT + TT vs. CC, OR = 2.246, 95%CI = 1.078-1.840, P = 0.006; T vs. C, OR = 1.376, 95%CI = 1.104-1.715, P = 0.004). Genotype frequency of rs2736100G/T between the two groups had no statistical differences (P > 0.05). After stratification according to age, T stage, tumor size and tumor node metastasis (TNM) stage, the distribution frequencies of CC genotype and CT + TT genotype of rs10069690C/T showed significant difference (P < 0.05). The life quality of patients with CC genotype was better than that of patients with CT $+$ TT genotype. The results of Cox regression model multifactor analysis showed that age, T stage, tumor size and rs10069690C/T were independent risk factors of thyroid cancer prognosis. CONCLUSIONS: hTERT gene polymorphism at rs10069690C/T is associated with the risk and prognosis of thyroid cancer, but hTERT gene polymorphism at rs2736100G/T is not. PMID- 27472888 TI - Choosing an Advanced Therapy in Parkinson's Disease; is it an Evidence-Based Decision in Current Practice? AB - BACKGROUND: In advanced Parkinson's disease (PD), neurologists and patients face a complex decision for an advanced therapy. When choosing a treatment, the best available evidence should be combined with the professional's expertise and the patient's preferences. OBJECTIVE: The objective of this study was to explore current decision-making in advanced PD. METHODS: We conducted focus group discussions and individual interviews with patients (N = 20) who had received deep brain stimulation, Levodopa-Carbidopa intestinal gel, or subcutaneous apomorphine infusion, and with their caregivers (N = 16). Furthermore, we conducted semi-structured interviews with neurologists (N = 7) and PD nurse specialists (N = 3) to include the perspectives of all key players in this decision-making process. Data were analyzed by two researchers using a qualitative thematic analysis approach. RESULTS: Four themes representing current experiences with the decision-making process were identified: 1) information and information needs, 2) factors influencing treatment choice and individual decision strategies, 3) decision-making roles, and 4) barriers and facilitators to shared decision-making (SDM). Patient preferences were taken into account, however patients were not always provided with adequate information. The professional's expertise influenced the decision-making process in both positive and negative ways. Although professionals and patients considered SDM essential for the decision of an advanced treatment, they mentioned several barriers for the implementation in current practice. CONCLUSIONS: In this study we found several factors explaining why in current practice, evidence-based decision making in advanced PD is not optimal. An important first step would be to develop objective information on all treatment options. PMID- 27472889 TI - Synthesis and Single-Molecule Conductance Study of Redox-Active Ruthenium Complexes with Pyridyl and Dihydrobenzo[b]thiophene Anchoring Groups. AB - The ancillary ligands 4'-(4-pyridyl)-2,2':6',2''-terpyridine and 4'-(2,3 dihydrobenzo[b]thiophene)-2,2'-6',2"-terpyridine were used to synthesize two series of mono- and dinuclear ruthenium complexes differing in their lengths and anchoring groups. The electrochemical and single-molecular conductance properties of these two series of ruthenium complexes were studied experimentally by means of cyclic voltammetry and the scanning tunneling microscopy-break junction technique (STM-BJ) and theoretically by means of density functional theory (DFT). Cyclic voltammetry data showed clear redox peaks corresponding to both the metal- and ligand-related redox reactions. Single-molecular conductance demonstrated an exponential decay of the molecular conductance with the increase in molecular length for both the series of ruthenium complexes, with decay constants of betaPY =2.07+/-0.1 nm(-1) and betaBT =2.16+/-0.1 nm(-1) , respectively. The contact resistance of complexes with 2,3-dihydrobenzo[b]thiophene (BT) anchoring groups is found to be smaller than the contact resistance of ruthenium complexes with pyridine (PY) anchors. DFT calculations support the experimental results and provided additional information on the electronic structure and charge transport properties in those metal|ruthenium complex|metal junctions. PMID- 27472890 TI - Molecular cloning and functional characterization of DkMATE1 involved in proanthocyanidin precursor transport in persimmon (Diospyros kaki Thunb.) fruit. AB - Persimmon fruits accumulate a large amount of proanthocyanidins (PAs) in "tannin cells" during development that cause the sensation of astringency due to coagulation of oral proteins. Pollination-constant non-astringent (PCNA) is a spontaneous mutant persimmon phenotype that loses its astringency naturally on the tree at maturity; while the more common non-PCNA fruits remain rich in PAs until they are fully ripened. Here, we isolated a DkMATE1 gene encoding a Multidrug And Toxic Compound Extrusion (MATE) family protein from the Chinese PCNA (C-PCNA) 'Eshi 1'. Expression patterns of DkMATE1 were positively correlated with the accumulation of PAs in different types of persimmons fruits during fruit development. An analysis of the inferred amino acid sequences and phylogenetic relationships indicated that DkMATE1 is a putative PA precursor transporter, and subcellular localization assays revealed that DkMATE1 is localized in the vacuolar membrane. Ectopic expression of the DkMATE1 in Arabidopsis tt12 mutant supported that DkMATE1 could complement its biological function in transporting epicatechin 3'-O-glucoside as a PAs precursor from the cytoplasm to vacuole. Furthermore, the transient over-expression and silencing of DkMATE1 in 'Mopanshi' persimmon leaves resulted in a significant increase and a decrease in PA content, respectively. The analysis of cis-elements in DkMATE1 promoter regions indicated that DkMATE1 might be regulated by DkMYB4, another well-known structural gene in persimmon. Overall, our results show that DkMATE1 may be an essential PA precursor membrane transporter that plays an important role in PA biosynthesis in persimmon. PMID- 27472891 TI - On Belonging: The American Adolescent of Arab Descent. AB - Although American families of Arab origin come from 22 countries and from varied backgrounds and cultures, reports suggest that they suffer equally from acculturation stress, stereotyping, discrimination, and the reverberations of the aftermath of September 11 as well as global affairs. However, because children and adolescents from these families, particularly those who are newly arrived immigrants, tend to do well in school, they are rarely targeted by research or policy. This article uses the narratives of 5 middle school age male students from Arab descent who were in a support group that met for 3 years (2004-2007), beginning shortly after President George W. Bush's declaration of the war on the "axis of evil." I used vignettes from this group to illustrate the stressors this population faces. The final section suggests an option for supporting this population. PMID- 27472892 TI - New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief-access taste aversion experiments. AB - Pharmacodynamic (PD) count data can exhibit bimodality and nonequidispersion complicating the inclusion of drug effect. The purpose of this study was to explore four different mixture distribution models for bimodal count data by including both drug effect and distribution truncation. An example dataset, which exhibited bimodal pattern, was from rodent brief-access taste aversion (BATA) experiments to assess the bitterness of ascending concentrations of an aversive tasting drug. The two generalized Poisson mixture models performed the best and was flexible to explain both under and overdispersion. A sigmoid maximum effect (Emax ) model with logistic transformation was introduced to link the drug effect to the data partition within each distribution. Predicted density-histogram plot is suggested as a model evaluation tool due to its capability to directly compare the model predicted density with the histogram from raw data. The modeling approach presented here could form a useful strategy for modeling similar count data types. PMID- 27472893 TI - Effects of the length of central cancer registry operations on identification of subsequent cancers and on survival estimates. AB - BACKGROUND: Population-based cancer survival analyses have traditionally been based on the first primary cancer. Recent studies have brought this practice into question, arguing that varying registry reference dates affect the ability to identify earlier cancers, resulting in selection bias. We used a theoretical approach to evaluate the extent to which the length of registry operations affects the classification of first versus subsequent cancers and consequently survival estimates. METHODS: Sequence number central was used to classify tumors from the New York State Cancer Registry, diagnosed 2001-2010, as either first primaries (value=0 or 1) or subsequent primaries (>=2). A set of three sequence numbers, each based on an assumed reference year (1976, 1986 or 1996), was assigned to each tumor. Percent of subsequent cancers was evaluated by reference year, cancer site and age. 5-year relative survival estimates were compared under four different selection scenarios. RESULTS: The percent of cancer cases classified as subsequent primaries was 15.3%, 14.3% and 11.2% for reference years 1976, 1986 and 1996, respectively; and varied by cancer site and age. When only the first primary was included, shorter registry operation time was associated with slightly lower 5-year survival estimates. When all primary cancers were included, survival estimates decreased, with the largest decreases seen for the earliest reference year. CONCLUSIONS: Registry operation length affected the identification of subsequent cancers, but the overall effect of this misclassification on survival estimates was small. Survival estimates based on all primary cancers were slightly lower, but might be more comparable across registries. PMID- 27472894 TI - Dual roles of calpain in facilitating Coxsackievirus B3 replication and prompting inflammation in acute myocarditis. AB - BACKGROUND: Viral myocarditis (VMC) treatment has long been lacking of effective methods. Our former studies indicated roles of calpain in VMC pathogenesis. This study aimed at verifying the potential of calpain in Coxsackievirus B3 (CVB3) induced myocarditis treatment. METHODS: A transgenic mouse overexpressing the endogenous calpain inhibitor, calpastatin, was introduced in the study. VMC mouse model was established via intraperitoneal injection of CVB3 in transgenic and wild mouse respectively. Myocardial injury was assayed histologically (HE staining and pathology grading) and serologically (myocardial damage markers of CK-MB and cTnI). CVB3 replication was observed in vivo and in vitro via the capsid protein VP1 detection or virus titration. Inflammation/fibrotic factors of MPO, perforin, IFNgamma, IL17, Smad3 and MMP2 were evaluated using western blot or immunohistology stain. Role of calpain in regulating fibroblast migration was studied in scratch assays. RESULTS: Calpastatin overexpression ameliorated myocardial injury induced by CVB3 infection significantly in transgenic mouse indicated by reduced peripheral CK-MB and cTnI levels and improved histology injury. Comparing with CVB3-infected wild type mouse, the transgenic mouse heart tissue carried lower virus load. The inflammation factors of MPO, perforin, IFNgamma and IL17 were down-regulated accompanied with fibrotic agents of Smad3 and MMP2 inhibition. And calpain participated in the migration of fibroblasts in vitro, which further proves its role in regulating fibrosis. CONCLUSION: Calpain plays dual roles of facilitating CVB3 replication and inflammation promotion. Calpain inhibition in CVB3-induced myocarditis showed significant treatment effect. Calpain might be a novel target for VMC treatment in clinical practices. PMID- 27472896 TI - N-Heterocyclic olefins as ancillary ligands in catalysis: a study of their behaviour in transfer hydrogenation reactions. AB - The Ir(i) complexes [Ir(cod)(kappaP,C,P'-NHO(PPh2))]PF6 and [IrCl(cod)(kappaC NHO(OMe))] (cod = 1,5-cyclooctadiene, NHO(PPh2) = 1,3-bis(2 (diphenylphosphanyl)ethyl)-2-methyleneimidazoline) and NHO(OMe) = 1,3-bis(2 (methoxyethyl)-2-methyleneimidazoline), both featuring an N-heterocyclic olefin ligand (NHO), have been tested in the transfer hydrogenation reaction; this representing the first example of the use of NHOs as ancillary ligands in catalysis. The pre-catalyst [Ir(cod)(kappaP,C,P'-NHO(PPh2))]PF6 has shown excellent activities in the transfer hydrogenation of aldehydes, ketones and imines using (i)PrOH as a hydrogen source, while [IrCl(cod)(kappaC-NHO(OMe))] decomposes throughout the reaction to give low yields of the hydrogenated product. Addition of one or two equivalents of a phosphine ligand to the latter avoids catalyst decomposition and significantly improves the reaction yields. The reaction mechanism has been investigated by means of stoichiometric studies and theoretical calculations. The formation of the active species ([Ir(kappaP,C,P' NHO(PPh2))((i)PrO)]) has been proposed to occur via isopropoxide coordination and concomitant COD dissociation. Moreover, throughout the catalytic cycle the NHO moiety behaves as a hemilabile ligand, thus allowing the catalyst to adopt stable square planar geometries in the transition states, which reduces the energetic barrier of the process. PMID- 27472895 TI - Improvement in Protein Domain Identification Is Reached by Breaking Consensus, with the Agreement of Many Profiles and Domain Co-occurrence. AB - Traditional protein annotation methods describe known domains with probabilistic models representing consensus among homologous domain sequences. However, when relevant signals become too weak to be identified by a global consensus, attempts for annotation fail. Here we address the fundamental question of domain identification for highly divergent proteins. By using high performance computing, we demonstrate that the limits of state-of-the-art annotation methods can be bypassed. We design a new strategy based on the observation that many structural and functional protein constraints are not globally conserved through all species but might be locally conserved in separate clades. We propose a novel exploitation of the large amount of data available: 1. for each known protein domain, several probabilistic clade-centered models are constructed from a large and differentiated panel of homologous sequences, 2. a decision-making protocol combines outcomes obtained from multiple models, 3. a multi-criteria optimization algorithm finds the most likely protein architecture. The method is evaluated for domain and architecture prediction over several datasets and statistical testing hypotheses. Its performance is compared against HMMScan and HHblits, two widely used search methods based on sequence-profile and profile-profile comparison. Due to their closeness to actual protein sequences, clade-centered models are shown to be more specific and functionally predictive than the broadly used consensus models. Based on them, we improved annotation of Plasmodium falciparum protein sequences on a scale not previously possible. We successfully predict at least one domain for 72% of P. falciparum proteins against 63% achieved previously, corresponding to 30% of improvement over the total number of Pfam domain predictions on the whole genome. The method is applicable to any genome and opens new avenues to tackle evolutionary questions such as the reconstruction of ancient domain duplications, the reconstruction of the history of protein architectures, and the estimation of protein domain age. Website and software: http://www.lcqb.upmc.fr/CLADE. PMID- 27472897 TI - A host basal transcription factor is a key component for infection of rice by TALE-carrying bacteria. AB - Transcription activator-like effectors (TALEs) are sequence-specific DNA binding proteins found in a range of plant pathogenic bacteria, where they play important roles in host-pathogen interactions. However, it has been unclear how TALEs, after they have been injected into the host cells, activate transcription of host genes required for infection success. Here, we show that the basal transcription factor IIA gamma subunit TFIIAgamma5 from rice is a key component for infection by the TALE-carrying bacterium Xanthomonas oryzae pv. oryzae, the causal agent for bacterial blight. Direct interaction of several TALEs with TFIIAgamma5 is required for activation of disease susceptibility genes. Conversely, reduced expression of the TFIIAgamma5 host gene limits the induction of susceptibility genes and thus decreases bacterial blight symptoms. Suppression or mutation of TFIIAgamma5 can also reduce bacterial streak, another devastating disease of rice caused by TALE-carrying X. oryzae pv. oryzicola. These results have important implications for formulating a widely applicable strategy with which to improve resistance of plants to TALE-carrying pathogens. PMID- 27472898 TI - Antiparallel protocadherin homodimers use distinct affinity- and specificity mediating regions in cadherin repeats 1-4. AB - Protocadherins (Pcdhs) are cell adhesion and signaling proteins used by neurons to develop and maintain neuronal networks, relying on trans homophilic interactions between their extracellular cadherin (EC) repeat domains. We present the structure of the antiparallel EC1-4 homodimer of human PcdhgammaB3, a member of the gamma subfamily of clustered Pcdhs. Structure and sequence comparisons of alpha, beta, and gamma clustered Pcdh isoforms illustrate that subfamilies encode specificity in distinct ways through diversification of loop region structure and composition in EC2 and EC3, which contains isoform-specific conservation of primarily polar residues. In contrast, the EC1/EC4 interface comprises hydrophobic interactions that provide non-selective dimerization affinity. Using sequence coevolution analysis, we found evidence for a similar antiparallel EC1-4 interaction in non-clustered Pcdh families. We thus deduce that the EC1-4 antiparallel homodimer is a general interaction strategy that evolved before the divergence of these distinct protocadherin families. PMID- 27472899 TI - Tagging motor memories with transcranial direct current stimulation allows later artificially-controlled retrieval. AB - We demonstrate that human motor memories can be artificially tagged and later retrieved by noninvasive transcranial direct current stimulation (tDCS). Participants learned to adapt reaching movements to two conflicting dynamical environments that were each associated with a different tDCS polarity (anodal or cathodal tDCS) on the sensorimotor cortex. That is, we sought to determine whether divergent background activity levels within the sensorimotor cortex (anodal: higher activity; cathodal: lower activity) give rise to distinct motor memories. After a training session, application of each tDCS polarity automatically resulted in the retrieval of the motor memory corresponding to that polarity. These results reveal that artificial modulation of neural activity in the sensorimotor cortex through tDCS can act as a context for the formation and recollection of motor memories. PMID- 27472902 TI - Are embryonic developing modes determinant in the acquisition and levels of photoprotective compounds in slipper limpets of the Crepipatella genus? AB - The type of embryonic development (mixed and direct) and its influence on the accumulation and translocation of photoprotective compounds from the mother to the encapsulated embryo was studied in the intertidal gastropods Crepipatella peruviana and Crepipatella dilatata during their reproductive peak. HPLC/MS was used to determine type and levels of sunscreen compounds (total carotenoids; TC/and mycosporine-like amino acid; MAA) in brooding females, capsule walls and early and pre-hatching embryos of both species. Photoprotective compounds were only quantified in nurse eggs of C. dilatata. Our results indicate that females of both species can accumulate TC and MAA at different levels, and they are able to transfer them selectively to capsule walls, embryos and nurse eggs. Palythine serine (MW=244Da; lambdamax=320nm) and MAA-330 (MW=234Da; lambdamax=330nm) constitute total MAA pool in brooding females, whereas brooded embryos incorporate palythine (MW=244Da; lambdamax=320nm) to the MAA pool. Although TC was transferred from the mother to the embryo through the yolk in both species, MAA trespass showed differences. Females of C. peruviana transfer MAA to their embryos through the embryonic yolk; C. dilatata can transfer MAA only through their nurse eggs, which are consumed by embryos during the terminal stages of intracapsular development. Differences between mixed and direct embryonic development, as well as environmental UV-R levels, which the recently hatched larvae and juveniles of C. peruviana and C. dilatata are exposed to, would determine levels of sunscreen compounds in each species. Higher TC and MAA levels in pre-hatching larvae of C. peruviana compared to C. dilatata, indicate a necessity of C. peruviana for protection against UV-R radiation during approximately 15days when their veliger larvae remain in the water column before metamorphosis is complete. Conversely, low photoprotective levels in pre-hatching juveniles of C. dilatata could be related to low UV-R exposure levels due to the direct incorporation to the benthos and the presence of a protective shell. PMID- 27472901 TI - The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L. AB - Epithelial cells that lose attachment to the extracellular matrix undergo a specialized form of apoptosis called anoikis. Here, using large-scale RNA interference (RNAi) screening, we find that KDM3A, a histone H3 lysine 9 (H3K9) mono- and di-demethylase, plays a pivotal role in anoikis induction. In attached breast epithelial cells, KDM3A expression is maintained at low levels by integrin signaling. Following detachment, integrin signaling is decreased resulting in increased KDM3A expression. RNAi-mediated knockdown of KDM3A substantially reduces apoptosis following detachment and, conversely, ectopic expression of KDM3A induces cell death in attached cells. We find that KDM3A promotes anoikis through transcriptional activation of BNIP3 and BNIP3L, which encode pro apoptotic proteins. Using mouse models of breast cancer metastasis we show that knockdown of Kdm3a enhances metastatic potential. Finally, we find defective KDM3A expression in human breast cancer cell lines and tumors. Collectively, our results reveal a novel transcriptional regulatory program that mediates anoikis. PMID- 27472903 TI - Spectroscopic and dynamic properties of arachidonoyl serotonin- beta lactoglobulin complex: A molecular modeling and chemometric study. AB - UV-Vis absorption data of beta-lactoglobulin (BLG) and arachidonoyl serotonin (AA 5HT) in BLG complex were examined and analyzed using chemometrics method. Analysis of the spectral data matrices by using the multivariate curve resolution alternating least squares (MCR-ALS) algorithm resulted to the pure concentration calculation and spectral profiles resolution of the chemical constituents and the values of (6.433+/-0.019)*10(4)M(-1), (4.532+/-0.007)*10(4)M(-1), (3.364+/ 0.010)*10(4)M(-1) and (2.977+/-0.013)*10(4)M(-1) as estimated equilibrium constants at 288, 293, 298 and 303K, respectively. The number of chemical constituents involved in the interaction which was extracted by PCA method were free and bound BLG. The spontaneity of the binding process and critical role of hydrogen bonding and van der Waals interactions in stabilizing protein-ligand complex have been designated by negative values of Gibbs free energy, entropy and enthalpy changes. Molecular docking study showed that AA-5HT binds to Val(41), Leu(39), Leu(54), Ile(71), Phe(82), Asn(90), Val(92), Phe(105), Met(107), Glu(108) with the free binding energy of -37.478kJ/mol. Computational studies predicted that in spite of serotonin (5HT) which anchors to the outer surface of BLG by hydrogen bonds, AA-5HT is situated in the calyx pose and stayed there during the entire time of simulation. This binding is accompanying with no apparent influence on secondary structure and partially destabilization of tertiary structure of BLG which pointed the suitability of this protein as drug carrier for AA-5HT. PMID- 27472900 TI - Trisomy 21 consistently activates the interferon response. AB - Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits. PMID- 27472904 TI - Ultra-weak photon emission of hands in aging prediction. AB - Aging has been one of the several topics intensely investigated during recent decades. More scientists have been scrutinizing mechanisms behind the human aging process. Ultra-weak photon emission is known as one type of spontaneous photon emission that can be detected with a highly sensitive single photon counting photomultiplier tube (PMT) from the surface of human bodies. It may reflect the body's oxidative damage. Our aim was to examine whether ultra-weak photon emission from a human hand is able to predict one's chronological age. Sixty subjects were recruited and grouped by age. We examined four areas of each hand: palm side of fingers, palm side of hand, dorsum side of fingers, and dorsum side of hand. Left and right hand were measured synchronously with two independent PMTs. Mean strength and Fano factor values of photon counts were utilized to compare the UPE patterns of males and females of different age groups. Subsequently, we utilized UPE data from the most sensitive PMT to develop an age prediction model. We randomly picked 49 subjects to construct the model, whereas the remaining 11 subjects were utilized for validation. The results demonstrated that the model was a good regression compared to the observed values (Pearson's r=0.6, adjusted R square=0.4, p=9.4E-7, accuracy=49/60). Further analysis revealed that the average difference between the chronological age and predicted age was only 7.6+/-0.8years. It was concluded that this fast and non-invasive photon technology is sufficiently promising to be developed for the estimation of biological aging. PMID- 27472905 TI - Comparison of total-etch, self-etch, and selective etching techniques on class V composite restorations prepared by Er:YAG laser and bur: a scanning electron microscopy study. AB - The purpose of this study was to compare total-etch, self-etch, and selective etching techniques on the marginal microleakage of Class V composite restorations prepared by Er:YAG laser and bur. Class V cavities prepared on both buccal and lingual surfaces of 30 premolars by Er:YAG laser or bur and divided into six groups. The occlusal margins were in enamel, and the cervical margins were in cementum. Group-1: bur preparation(bp)+Adper Single Bond 2 (ASB)+Filtek Z550 (FZ); Group-2: laser preparation(lp)+(ASB)+(FZ); Group-3: bp + Clearfil S3 Bond Plus (CSBP)+(FZ); Group-4: lp+(CSBP) (FZ); Group-5: bp + acid etching+(CSBP)+(FZ); Group-6: lp + acid etching+(CSBP)+(FZ). All teeth were stored in distilled water at 37 degrees C for 24 hr, and then thermocycled 1000 times (5-55 degrees C). Five teeth from each group were chosen for the microleakage investigation, and two teeth for the scanning electron microscope evaluation. Teeth which were prepared for the microleakage test were immersed in .5% methylene blue dye for 24 hr. After immersion, the teeth were sectioned and observed under a stereomicroscope for dye penetration. Data were analyzed using Kruskal-Wallis and Mann-Whitney U tests (p < .05). More microleakage was observed in the cervical regions compared to the occlusal regions in Groups 3, 5, and 6, respectively (p < .05). There is no statistically significant difference in Groups 1, 2, and 4, in terms of cervical regions versus occlusal regions (p > .05). No significant differences were observed among any groups in terms of occlusal and cervical surfaces, separately (p > .05). Different etching techniques did not influence microleakage of Class V restorations prepared by Er:YAG laser and bur. PMID- 27472906 TI - Identification of Highly Potent Protein Kinase C-Related Kinase 1 Inhibitors by Virtual Screening, Binding Free Energy Rescoring, and in vitro Testing. AB - Despite the considerable interest in protein kinase C-related kinase 1 (PRK1) as a target in cancer research, there is still a lack of PRK1 inhibitors with suitable selectivity profiles and physicochemical properties. To identify new PRK1 inhibitors we applied a virtual screening approach, which combines ensemble docking, minimization of the protein-ligand complex, binding free energy calculations, and application of quantitative structure-activity relationship (QSAR) models for predicting in vitro activity. The developed approach was then applied in a prospective manner to screen available libraries of kinase inhibitors from Selleck and GlaxoSmithKline (GSK). Compounds that showed favorable prediction were then tested in vitro for PRK1 inhibition. Some of the hits were found to inhibit PRK1 in the low-nanomolar range. Three in vitro hits were additionally tested in a mass-spectrometry-based cellular kinase profiling assay to examine selectivity. Our findings show that nanomolar and drug-like inhibitors can be identified by the virtual screening approach presented herein. The identified inhibitors are valuable tools for gaining a better understanding of PRK1 inhibition, and the identified hits can serve as starting points for further chemical optimization. PMID- 27472907 TI - Adipokines induce pro-inflammatory factors in activated Cd4+ T cells from osteoarthritis patient. AB - Osteoarthritis (OA) is a chronic systemic musculoskeletal disorder involving inflammation, immunity, and metabolic alterations. OA is commonly regarded as non inflammatory disease; still inflammation is recognized as contributing to the symptoms and progression of OA. New evidence suggests that adipokines are involved in the pathophysiology of OA and might modulate the production of inflammatory mediators including in immune cells. However, the role of immune component in osteoarthritis is still poorly investigated. To gain further insights into the interaction of immune cells in OA and the role of adipokines on these cells, we performed experiments aimed to determine the cytokine profile in activated CD4+ T cells from OA patients. For completeness, we also explored the cross talk between T lymphocytes and chondrocytes in OA by co-culturing human primary chondrocytes with activated CD4+ T cells in two ways: the first by incubating the cells by direct contact (D.C.) or by transwell system. Our results show that the exposure of activated CD4+ T cells to adipokines modulates IL-6, IL 8, and CCL-3 production. In addition, the production of key macromolecules of ECM (aggrecan and collagen-2) and matrix metalloproteinase 13 (MMP-13) in co-cultured chondrocytes with activated CD4+ T cells was altered. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1299-1303, 2017. PMID- 27472908 TI - Risk assessment of noroviruses and human adenoviruses in recreational surface waters. AB - In the interest of public health and safety, this study aimed to quantify risks associated with the presence of noroviruses (NoV) and human adenoviruses (HAdV) in an urban catchment area in Singapore. Enteric viruses were quantified using QPCR. NoV were more prevalent in water samples than HAdV, and presented higher associated illness risks across all exposure scenarios. For primary contact recreation of adults and children, mean probability of illness were 0.0061 and 0.0089 for NoV, and 0.0028 and 0.0048 for HAdV. For secondary contact recreation, mean probability of illness were 0.0016 for NoV and 0.00068 for HAdV. Therefore, owing to their prevalence and associated risks, NoV are better suited as reference pathogens in recreational waters in Singapore. PMID- 27472909 TI - Kinetics and modeling of sulfonamide antibiotic degradation in wastewater and human urine by UV/H2O2 and UV/PDS. AB - Sulfonamide antibiotics have been frequently detected in the aquatic environment and are of emerging concern due to their adverse bio-effect and potential of inducing antibiotic resistance. This study investigated the degradation kinetics of sulfonamide antibiotics in synthetic wastewater and hydrolyzed human urine by low pressure (LP) UV, UV/H2O2 and UV/peroxydisulfate (PDS). Direct photolysis rates of sulfonamide antibiotics varied and depended on the structures. Sulfonamides with a five-membered heterocyclic group underwent faster direct photolysis. For indirect photolysis processes, second-order rate constants of sulfonamide antibiotics with hydroxyl radical, sulfate radical and carbonate radical were determined, which were (6.21-9.26) * 10(9), (0.77-16.1) * 10(10) and (1.25-8.71) * 10(8) M(-1) s(-1), respectively. A dynamic model was applied and successfully predicted the degradation kinetics of sulfonamides in different water matrices. In synthetic wastewater, carbonate radical contributed to approximately 10% of the overall removal, whereas in synthetic hydrolyzed urine, carbonate radical was the dominant reactive species to degrade sulfonamides. Sulfonamide antibiotics were eliminated more efficiently in synthetic hydrolyzed urine than in synthetic wastewater and UV/PDS was more efficient than UV/H2O2 to degrade most sulfonamides. Energy evaluation showed that UV/PDS costs less energy than LPUV and UV/H2O2 under the experimental conditions applied in this study, particularly for sulfonamides whose indirect photolysis overweighed direct photolysis. By varying UV dose and oxidant dose, the UV/H2O2 process can be optimized to achieve higher efficiency than the UV/PDS process in synthetic wastewater. PMID- 27472910 TI - Low incidence of pneumocystis pneumonia utilizing PCR-based diagnosis in patients with B-cell lymphoma receiving rituximab-containing combination chemotherapy. AB - Recent literature has demonstrated concern over the risk of Pneumocystis jirovecii pneumonia (PJP) when administering rituximab with combination chemotherapy such as in R-CHOP; however, the exact risk and potential need for prophylaxis is unknown. We sought to determine the incidence of PJP infection following R-CHOP administration in patients with B-cell lymphoma. Consecutive patients diagnosed with B-cell lymphoma receiving R-CHOP were evaluated from chemotherapy initiation until 180 days after the last administration. The primary outcome was cumulative incidence of PJP infection. Secondary endpoints included the association of rituximab, prednisone and subsequent chemotherapy with PJP infection risk. A total of 689 patients (53% male, median age 66 years) were included. Seventy-three percent of patients completed at least 6 cycles of R-CHOP treatment. Median rituximab and prednisone cumulative doses were 3950 mg and 5325 mg, respectively. Median daily prednisone dose through end of treatment was 45 mg (range 7.6 mg to 119 mg). The cumulative incidence of PJP was 1.51% (95% CI 0.57 2.43, at maximum follow-up of 330 days), below 3.5%, the conventional threshold for prophylaxis. Univariate analysis did not detect a statistically significant association between PJP and rituximab, steroids, or receipt of additional chemotherapy in this patient population. Our results demonstrate a low occurrence of Pneumocystis pneumonia during R-CHOP treatment of B-cell lymphoma and argue against universal anti-Pneumocystis prophylaxis in this setting. Further investigations should focus on targeted anti-Pneumocystis prophylaxis for patients presenting with high-risk baseline characteristics or when receiving rituximab-inclusive intensive combination chemotherapy regimens as treatment for other aggressive lymphoma subtypes. Am. J. Hematol. 91:1113-1117, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27472911 TI - Long-Term Exposure to Traffic-Related Air Pollution and Risk of Incident Atrial Fibrillation: A Cohort Study. AB - BACKGROUND: Atrial fibrillation is the most common sustained arrhythmia and is associated with cardiovascular morbidity and mortality. The few studies conducted on short-term effects of air pollution on episodes of atrial fibrillation indicate a positive association, though not consistently. OBJECTIVES: The aim of this study was to evaluate the long-term impact of traffic-related air pollution on incidence of atrial fibrillation in the general population. METHODS: In the Danish Diet, Cancer, and Health cohort of 57,053 people 50-64 years old at enrollment in 1993-1997, we identified 2,700 cases of first-ever hospital admission for atrial fibrillation from enrollment to end of follow-up in 2011. For all cohort members, exposure to traffic-related air pollution assessed as nitrogen dioxide (NO2) and nitrogen oxides (NOx) was estimated at all present and past residential addresses from 1984 to 2011 using a validated dispersion model. We used Cox proportional hazard model to estimate associations between long-term residential exposure to NO2 and NOx and risk of atrial fibrillation, after adjusting for lifestyle and socioeconomic position. RESULTS: A 10 MUg/m3 higher 10-year time-weighted mean exposure to NO2 preceding diagnosis was associated with an 8% higher risk of atrial fibrillation [incidence rate ratio: 1.08; 95% confidence interval (CI): 1.01, 1.14] in adjusted analysis. Though weaker, similar results were obtained for long-term residential exposure to NOx. We found no clear tendencies regarding effect modification of the association between NO2 and atrial fibrillation by sex, smoking, hypertension or myocardial infarction. CONCLUSION: We found long-term residential traffic-related air pollution to be associated with higher risk of atrial fibrillation. Accordingly, the present findings lend further support to the demand for abatement of air pollution. Citation: Monrad M, Sajadieh A, Christensen JS, Ketzel M, Raaschou-Nielsen O, Tjonneland A, Overvad K, Loft S, Sorensen M. 2017. Long-term exposure to traffic related air pollution and risk of incident atrial fibrillation: a cohort study. Environ Health Perspect 125:422-427; http://dx.doi.org/10.1289/EHP392. PMID- 27472912 TI - Sequence-sensitive exemplar and decision-bound accounts of speeded-classification performance in a modified Garner-tasks paradigm. AB - Among the most fundamental results in the area of perceptual classification are the "correlated facilitation" and "filtering interference" effects observed in Garner's (1974) speeded categorization tasks: In the case of integral-dimension stimuli, relative to a control task, single-dimension classification is faster when there is correlated variation along a second dimension, but slower when there is orthogonal variation that cannot be filtered out (e.g., by attention). These fundamental effects may result from participants' use of a trial-by-trial bypass strategy in the control and correlated tasks: The observer changes the previous category response whenever the stimulus changes, and maintains responses if the stimulus repeats. Here we conduct modified versions of the Garner tasks that eliminate the availability of a pure bypass strategy. The fundamental facilitation and interference effects remain, but are still largely explainable in terms of pronounced sequential effects in all tasks. We develop sequence sensitive versions of exemplar-retrieval and decision-bound models aimed at capturing the detailed, trial-by-trial response-time distribution data. The models combine assumptions involving: (i) strengthened perceptual/memory representations of stimuli that repeat across consecutive trials, and (ii) a bias to change category responses on trials in which the stimulus changes. These models can predict our observed effects and provide a more complete account of the underlying bases of performance in our modified Garner tasks. PMID- 27472914 TI - Electrical Detection of Single Graphene Plasmons. AB - Plasmons-the collective oscillations of electrons in conducting materials-play a pivotal role in nanophotonics because of their ability to couple electronic and photonic degrees of freedom. In particular, plasmons in graphene-the atomically thin carbon material-offer strong spatial confinement and long lifetimes, accompanied by extraordinary optoelectronic properties derived from its peculiar electronic band structure. Understandably, this material has generated great expectations for its application to enhanced integrated devices. However, an efficient scheme for detecting graphene plasmons remains a challenge. Here we show that extremely compact graphene nanostructures are capable of realizing on chip electrical detection of single plasmons. Specifically, we predict a 2-fold increase in the electrical current across a graphene nanostructure junction caused by the excitation of a single plasmon. This effect, which is due to the increase in electron temperature following plasmon decay, should persist during a picosecond time interval characteristic of electron-gas relaxation. We further show that a broad spectral detection range is accessible either by electrically doping the junction or by varying the size of the nanostructure. The proposed graphene plasmometer could find application as a basic component of future optics free integrated nanoplasmonic devices. PMID- 27472913 TI - Evidence of selection for an accessible nucleosomal array in human. AB - BACKGROUND: Recently, a physical model of nucleosome formation based on sequence dependent bending properties of the DNA double-helix has been used to reveal some enrichment of nucleosome-inhibiting energy barriers (NIEBs) nearby ubiquitous human "master" replication origins. Here we use this model to predict the existence of about 1.6 millions NIEBs over the 22 human autosomes. RESULTS: We show that these high energy barriers of mean size 153 bp correspond to nucleosome depleted regions (NDRs) in vitro, as expected, but also in vivo. On either side of these NIEBs, we observe, in vivo and in vitro, a similar compacted nucleosome ordering, suggesting an absence of chromatin remodeling. This nucleosomal ordering strongly correlates with oscillations of the GC content as well as with the interspecies and intraspecies mutation profiles along these regions. Comparison of these divergence rates reveals the existence of both positive and negative selections linked to nucleosome positioning around these intrinsic NDRs. Overall, these NIEBs and neighboring nucleosomes cover 37.5 % of the human genome where nucleosome occupancy is stably encoded in the DNA sequence. These 1 kb sized regions of intrinsic nucleosome positioning are equally found in GC-rich and GC-poor isochores, in early and late replicating regions, in intergenic and genic regions but not at gene promoters. CONCLUSION: The source of selection pressure on the NIEBs has yet to be resolved in future work. One possible scenario is that these widely distributed chromatin patterns have been selected in human to impair the condensation of the nucleosomal array into the 30 nm chromatin fiber, so as to facilitate the epigenetic regulation of nuclear functions in a cell-type-specific manner. PMID- 27472915 TI - Determinants of breastfeeding initiation and cessation among employed mothers: a prospective cohort study. AB - BACKGROUND: The U.S. continues to have one of the lowest breastfeeding rates in the industrialized world. Studies have shown that full-time employment and early return to work decreased breastfeeding duration, but little is known about the relationship between leave policies and breastfeeding initiation and cessation. This study aimed to identify workplace-related barriers and facilitators associated with breastfeeding initiation and cessation in the first 6 months postpartum. METHODS: A prospective cohort study design was utilized to recruit 817 Minnesota women aged 18 and older while hospitalized for childbirth. Selection criteria included English-speaking, employed mothers with a healthy, singleton birth. These women were followed up using telephone interviews at 6 weeks, 12 weeks, and 6 months after childbirth. The main study outcomes were breastfeeding initiation, measured during hospital enrollment, and breastfeeding cessation by 6 months postpartum. RESULTS: Women were 30 years old; 86 % were White, and 73 % were married. Breastfeeding rates were 81 % at childbirth, 67 % at 6 weeks, 49 % at 12 weeks, and 33 % at 6 months postpartum. Logistic regression revealed the odds of breastfeeding initiation were higher for women who: held professional jobs, were primiparae, had graduate degree, did not smoke prenatally, had no breastfeeding problems, and had family or friends who breastfeed. Survival analyses showed the hazard for breastfeeding cessation by 6 months was: higher for women who returned to work at any time during the 6 months postpartum versus those who did not return, lower for professional workers, higher among single than married women, higher for every educational category compared to graduate school, and higher for those with no family or friends who breastfeed. CONCLUSIONS: While employer paid leave policy did not affect breastfeeding initiation or cessation, women who took shorter leaves were more likely to stop breastfeeding in the first 6 months postpartum. Future research should examine women's awareness of employer policies regarding paid and unpaid leave. PMID- 27472916 TI - Perception of quality of health delivery and health insurance subscription in Ghana. AB - BACKGROUND: National health insurance schemes (NHIS) in developing countries and perhaps in developed countries as well is a considered a pro-poor intervention by helping to bridge the financial burden of access to quality health care. Perceptions of quality of health service could have immense impacts on enrolment. This paper shows how perception of service quality under Ghana's insurance programme contributes to health insurance subscription. METHODS: The study used the 2014 Ghana Demographic and Health Survey (GDHS) dataset. Both descriptive proportions and binary logistic regression techniques were applied to generate results that informed the discussion. RESULTS: Our results show that a high proportion of females (33 %) and males (35 %) felt that the quality of health provided to holders of the NHIS card was worse. As a result, approximately 30 % of females and 22%who perceived health care as worse by holding an insurance card did not own an insurance policy. While perceptions of differences in quality among females were significantly different (AOR = 0.453 [95 % CI = 0.375, 0.555], among males, the differences in perceptions of quality of health services under the NHIS were independent in the multivariable analysis. Beyond perceptions of quality, being resident in the Upper West region was an important predictor of health insurance ownership for both males and females. CONCLUSION: For such a social and pro-poor intervention, investing in quality of services to subscribers, especially women who experience enormous health risks in the reproductive period can offer important gains to sustaining the scheme as well as offering affordable health services. PMID- 27472917 TI - CicerTransDB 1.0: a resource for expression and functional study of chickpea transcription factors. AB - BACKGROUND: Transcription factor (TF) databases are major resource for systematic studies of TFs in specific species as well as related family members. Even though there are several publicly available multi-species databases, the information on the amount and diversity of TFs within individual species is fragmented, especially for newly sequenced genomes of non-model species of agricultural significance. DESCRIPTION: We constructed CicerTransDB (Cicer Transcription Factor Database), the first database of its kind, which would provide a centralized putatively complete list of TFs in a food legume, chickpea. CicerTransDB, available at www.cicertransdb.esy.es , is based on chickpea (Cicer arietinum L.) annotation v 1.0. The database is an outcome of genome-wide domain study and manual classification of TF families. This database not only provides information of the gene, but also gene ontology, domain and motif architecture. CONCLUSION: CicerTransDB v 1.0 comprises information of 1124 genes of chickpea and enables the user to not only search, browse and download sequences but also retrieve sequence features. CicerTransDB also provides several single click interfaces, transconnecting to various other databases to ease further analysis. Several webAPI(s) integrated in the database allow end-users direct access of data. A critical comparison of CicerTransDB with PlantTFDB (Plant Transcription Factor Database) revealed 68 novel TFs in the chickpea genome, hitherto unexplored. Database URL: http://www.cicertransdb.esy.es. PMID- 27472918 TI - Flavihumibacter sediminis sp. nov., isolated from tidal flat sediment. AB - A yellow, Gram-staining-positive, aerobic, rod-shaped and non-motile bacterial strain, designated CJ663T, was isolated from the tidal flat sediment in Ganghwa do, South Korea. Strain CJ663T grew optimally on R2A at 30 degrees C and pH 7.0 and did not require NaCl for growth. Phylogenetic analysis based on 16S rRNA gene sequence similarity showed that strain CJ663T belonged to the genus Flavihumibacter within the family Chitinophagaceae and was most closely related to Flavihumibacter cheonanensis KACC 17467T (98.3 % similarity), followed by Flavihumibacter solisilvae KACC 17917T (97.4 %). DNA-DNA relatedness levels of strain CJ663T were 42.9 % to F. cheonanensis KACC 17467T and 48.6 % to F. solisilvae KACC 17917T. The major isoprenoid quinone was menaquinone 7 (MK-7). The predominant polar lipids were phosphatidylethanolamine, aminophospholipid and two unidentified lipids. The major cellular fatty acids of strain CJ663T were iso C15 : 0, anteiso-C15 : 0 and iso-C17 : 0 3-OH. The G+C content of the genomic DNA was 47.7 mol%. On the basis of data from this polyphasic taxonomic study, strain CJ663T represents a novel species in the genus Flavihumibacter, for which name Flavihumibacter sediminis sp. nov. is proposed; the type strain is CJ663T (=KACC 18874T=JCM 31431T). PMID- 27472919 TI - Factors associated with improved survival following surgical treatment for metastatic prostate cancer in the spine: retrospective analysis of 29 patients in a single center. AB - BACKGROUND: Prostate cancer (PCa) is very common and frequently metastasizes to the spine. However, PCa spinal metastases were rarely reported in the literature. In this study, the outcome of therapies and prognostic factors affecting surgical outcomes for patients with PCa spinal metastases are discussed to select the best candidates for aggressive surgical resection. METHODS: All patients affected by the spinal metastatic PCa surgically treated at our spine tumor center were reviewed. Overall survival was analyzed from the time of spinal surgery. A univariate survival analysis and a multivariate Cox proportional hazard analysis to identify independent prognostic factors were carried out. The survival rate was estimated by the Kaplan-Meier method, and differences were analyzed by the log-rank test. Factors with P values of 0.1 or less were subjected to multivariate analysis for survival rate by multivariate Cox proportional hazard analysis. RESULTS: A total of 31 consecutive patients were identified. Of these, 29 underwent surgical resection. The median survival time of all patients after their spinal surgery was 44.0 months. Visceral metastases, revised Tokuhashi scores (0-8/9-11/12-15), Tomita scores (7-10/2-6), hormone status, and bisphosphonate treatment were suggested as the potential prognostic factors through univariate analysis. As they were submitted to the multivariate Cox regression model, visceral metastases and Tomita score were found as independent prognostic factors. CONCLUSIONS: Patients without visceral metastases and a Tomita score no more than 6 are favorable prognostic factors for PCa metastases in the mobile spine. PMID- 27472920 TI - Structural and functional characterization of a novel gene, Hc-daf-22, from the strongylid nematode Haemonchus contortus. AB - BACKGROUND: The strongylid nematode Haemonchus contortus is a parasite of major concern for modern livestock husbandry because hostile environmental conditions may induce diapause in the early fourth-stage larvae. METHODS: A new gene Hc-daf 22 was identified which is the homologue of Ce-daf-22 and human SCPx. Genome walking and RACE were performed to obtain the whole cDNA and genomic sequence of this gene. Using qRT-PCR with all developmental stages as templates to explore the transcription level and micro-injection was applied to confirm the promoter activity of the 5'-flanking region. Overexpression, rescue and RNA interference experiments were performed in N2, daf-22 mutant (ok 693) strains of C. elegans to study the gene function of Hc-daf-22. RESULTS: The full length gene of Hc-daf-22 (6,939 bp) contained 16 exons separated by 15 introns, and encoded a cDNA of 1,602 bp (533 amino acids, estimated at about 59.3 kDa) with a peak in L3 and L4 in transcriptional level. The Hc-DAF-22 protein was consisted of a 3-oxoacyl-CoA thiolase domain and a SCP2 domain and evolutionarily conserved. The 1,548 bp fragment upstream of the 5'-flanking region was confirmed to have promoter activity compared with 5'-flanking region of Ce-daf-22. The rescue experiment by micro-injection of daf-22 (ok693) mutant strain showed significant increase in body size and brood size in the rescued worms with significantly reduced or completely absent fat granules confirmed by Oil red O staining, indicating that Hc-daf-22 could partially rescue the function of Ce-daf-22. Furthermore, RNAi with Hc-daf-22 could partially silence the endogenous Ce-daf-22 in N2 worms and mimic the phenotype of daf-22 (ok693) mutants. CONCLUSION: The gene Hc-daf-22 was isolated and its function identified using C. elegans as a model organism. Our results indicate that Hc-daf-22 shared similar characteristics and function with Ce-daf-22 and may play an important role in peroxisomal beta-oxidation and the development in H. contortus. PMID- 27472921 TI - Association between motor timing and treatment outcomes in patients with alcohol and/or cocaine use disorder in a rehabilitation program. AB - BACKGROUND: Individuals with Substance Use Disorders (SUDs) have disruptions in the brain's dopaminergic (DA) system and the functioning of its target neural substrates (striatum and prefrontal cortex). These substrates are important for the normal processing of reward, inhibitory control and motivation. Cognitive deficits in attention, impulsivity and working memory have been found in individuals with SUDs and are predictors of poor SUD treatment outcomes and relapse in alcohol and cocaine dependence specifically. Furthermore, the DA system and accompanying neural substrates play a key role in the timing of motor acts (motor timing). Motor timing deficits have been found in DA system related disorders and more recently also in individuals with SUDs. Motor timing is found to correlate with attention, impulsivity and working memory deficits. To our knowledge motor timing, with regards to treatment outcome and relapse, has not been investigated in populations with SUDs. METHODS/DESIGN: This study aims to investigate motor timing and its relation to treatment response (at 8 weeks) and relapse (at 12 months) in cocaine and/or alcohol dependent individuals. The tested sensitivity values of motor timing parameters will be compared to a battery of neurocognitive tests, owing to the novelty of the motor task battery, the confounding effects of attention and working memory on motor timing paradigms, and high impulsivity levels found in individuals with SUDs. DISCUSSION: This research will contribute to current knowledge of neuropsychological deficits associated with treatment response in SUDs and possibly provide an opportunity to individualize and modify currently available treatments through the possible prognostic value of motor task performance in cocaine and/or alcohol dependent individuals. PMID- 27472922 TI - Bmi1 (+) cardiac progenitor cells contribute to myocardial repair following acute injury. AB - BACKGROUND: The inability of the adult mammalian heart to replace cells lost after severe cardiac injury compromises organ function. Although the heart is one of the least regenerative organs in the body, evidence accumulated in recent decades indicates a certain degree of renewal after injury. We have evaluated the role of cardiac Bmi1 (+) progenitor cells (Bmi1-CPC) following acute myocardial infarction (AMI). METHODS: Bmi1 (Cre/+);Rosa26 (YFP/+) (Bmi1-YFP) mice were used for lineage tracing strategy. After tamoxifen (TM) induction, yellow fluorescent protein (YFP) is expressed under the control of Rosa26 regulatory sequences in Bmi1 (+) cells. YFP(+) cells were tracked following myocardial infarction. Additionally, whole transcriptome analysis of isolated YFP(+) cells was performed in unchallenged hearts and after myocardial infarction. RESULTS: Deep-sequencing analysis of Bmi1-CPC from unchallenged hearts suggests that this population expresses high levels of pluripotency markers. Conversely, transcriptome evaluation of Bmi1-CPC following AMI shows a rich representation of genes related to cell proliferation, movement, and cell cycle. Lineage-tracing studies after cardiac infarction show that the progeny of Bmi1-expressing cells contribute to de novo cardiomyocytes (CM) (13.8 +/- 5 % new YFP(+) CM compared to 4.7 +/- 0.9 % in age-paired non-infarcted hearts). However, apical resection of TM-induced day 1 Bmi1-YFP pups indicated a very minor contribution of Bmi1-derived cells to de novo CM. CONCLUSIONS: Cardiac Bmi1 progenitor cells respond to cardiac injury, contributing to the generation of de novo CM in the adult mouse heart. PMID- 27472923 TI - Potentiation of synaptic transmission in Rat anterior cingulate cortex by chronic itch. AB - Itch and pain share similar mechanisms. It has been well documented that the anterior cingulate cortex (ACC) is important for pain-related perception. ACC has also been approved to be a potential pruritus-associated brain region. However, the mechanism of sensitization in pruriceptive neurons in the ACC is not clear. In current study, a chronic itch model was established by diphenylcyclopropenone (DCP) application. We found that both the frequency and amplitude of miniature excitatory postsynaptic currents in the ACC were enhanced after the formation of chronic itch. The paired-pulse ratio in ACC neurons recorded from the DCP group were smaller than those recorded in control group at the 50-ms interval. We also observe a significant increase in the AMPA/NMDA ratio in the DCP group. Moreover, an increased inward rectification of AMPARs in ACC pyramidal neurons was observed in the DCP group. Interestingly, the calculated ratio of silent synapses was significantly reduced in the DCP group compared with controls. Taken together, we conclude that a potentiation of synaptic transmission in the ACC can be induced by chronic itch, and unsilencing silent synapses, which probably involved recruitment of AMPARS, contributed to the potentiation of postsynaptic transmission. PMID- 27472924 TI - Glycoside rich fraction from Spondias pinnata bark ameliorate iron overload induced oxidative stress and hepatic damage in Swiss albino mice. AB - BACKGROUND: Iron in the overloaded condition in liver promotes the overproduction of free radicals that lead to oxidative stress and ultimately hepatic damage. The present study was designed to evaluate the ameliorating potential from iron overloaded hepatotoxicity by the glycosidic fraction from Spondious pinnata bark (SPW1) along with its antioxidant property. METHODS: The fraction was tested for its in vitro antioxidant, free radical scavenging property and iron chelation potential via standard biochemical assays. Iron overload condition was generated by the intraperitoneal administration of iron dextran in mice. The levels of serum enzymes, antioxidant enzymes in liver, markers of hepatic damage, liver iron, and ferritin content were measured in response to the oral treatment of SPW1. Histopathology of the liver sections was performed for visual confirmation of the amelioration potential of SPW1. RESULTS: The fraction exhibited excellent in vitro antioxidant as well as free radical scavenging potential against both reactive oxygen species and reactive nitrogen species. Administration of SPW1 significantly normalized the disturbed levels of antioxidant enzymes, liver iron, lipid peroxidation, liver fibrosis, serum enzyme and ferritin better than standard desirox which were also supported by the morphological study of the liver sections. Phytochemical analysis as well as HPLC study, confirmed that the fraction mainly consisted of glycosidic phenolics and flavonoids that attributed to its biological activities. CONCLUSIONS: The above results suggested that beneficial effects of SPW1 on iron overload induced hepatotoxicity that can be considered as a possible candidate against iron overload diseases. PMID- 27472925 TI - A modified and enhanced test setup for biomechanical investigations of the hindfoot, for example in tibiotalocalcaneal arthrodesis. AB - BACKGROUND: Tibiotalocalcaneal arthrodesis (TTCA) using intramedullary nails is a salvage procedure for many diseases in the ankle and subtalar joint. Despite "newly described intramedullary nails" with specific anatomical shapes there still remain major complications regarding this procedure. The following study presents a modified biomechanical test setup for investigations of the hindfoot. METHODS: Nine fresh-frozen specimens from below the human knee were anaysed using the Hindfoot Arthrodesis Nail (Synthes) instrument. Quasi-static biomechanical testing was performed for internal/external rotation, varus/valgus and dorsal/plantar flexion using a modified established setup (physiological load entrance point, sledge at lever arm to apply pure moments). Additionally, a 3D optical measurement system was added to allow determination of interbony movements. RESULTS: The mean torsional range of motion (ROM) calculated from the actuator data of a material testing machine was 10.12 degrees (SD 0.6) compared to 10 degrees (SD 2.83) as measured with the Optotrak(r) system (between tibia and calcaneus). The Optotrak showed 40 % more rotation in the talocrural joint. Mean varus/valgus ROM from the material testing flexion machine was seen to be 5.65 degrees (SD 1.84) in comparison to 2.82 degrees (SD 0.46) measured with the Optotrak. The subtalar joint showed a 70 % higher movement when compared to the talocrural joint. Mean ROM in the flexion test was 5.3 degrees (SD 1.45) for the material testing machine and 2.1 degrees (SD 0.39) for the Optotrak. The movement in the talocrural joint was 3 times higher compared to the subtalar joint. CONCLUSION: The modified test setup presented here for the hindfoot allows a physiological biomechanical loading. Moreover, a detailed characterisation of the bone-implant constructs is possible. PMID- 27472926 TI - A combined approach of generalized additive model and bootstrap with small sample sets for fault diagnosis in fermentation process of glutamate. AB - BACKGROUND: Glutamate is of great importance in food and pharmaceutical industries. There is still lack of effective statistical approaches for fault diagnosis in the fermentation process of glutamate. To date, the statistical approach based on generalized additive model (GAM) and bootstrap has not been used for fault diagnosis in fermentation processes, much less the fermentation process of glutamate with small samples sets. RESULTS: A combined approach of GAM and bootstrap was developed for the online fault diagnosis in the fermentation process of glutamate with small sample sets. GAM was first used to model the relationship between glutamate production and different fermentation parameters using online data from four normal fermentation experiments of glutamate. The fitted GAM with fermentation time, dissolved oxygen, oxygen uptake rate and carbon dioxide evolution rate captured 99.6 % variance of glutamate production during fermentation process. Bootstrap was then used to quantify the uncertainty of the estimated production of glutamate from the fitted GAM using 95 % confidence interval. The proposed approach was then used for the online fault diagnosis in the abnormal fermentation processes of glutamate, and a fault was defined as the estimated production of glutamate fell outside the 95 % confidence interval. The online fault diagnosis based on the proposed approach identified not only the start of the fault in the fermentation process, but also the end of the fault when the fermentation conditions were back to normal. The proposed approach only used a small sample sets from normal fermentations excitements to establish the approach, and then only required online recorded data on fermentation parameters for fault diagnosis in the fermentation process of glutamate. CONCLUSIONS: The proposed approach based on GAM and bootstrap provides a new and effective way for the fault diagnosis in the fermentation process of glutamate with small sample sets. PMID- 27472927 TI - Synergistic antitumor activity of triple-regulated oncolytic adenovirus with VSTM1 and daunorubicin in leukemic cells. AB - V-set and transmembrane domain-containing 1 (VSTM1), which is downregulated in bone marrow cells from leukemia patients, may provide a diagnostic and treatment target. Here, a triple-regulated oncolytic adenovirus was constructed to carry a VSTM1 gene expression cassette, SG611-VSTM1, and contained the E1a gene with a 24 nucleotide deletion within the CR2 region under control of the human telomerase reverse transcriptase promoter, E1b gene directed by the hypoxia response element, and VSTM1 gene controlled by the cytomegalovirus promoter. Real-time quantitative PCR and Western blot analyses showed that SG611-VSTM1 expressed VSTM1 highly efficiently in the human leukemic cell line K562 compared with SG611. In Cell Counting Kit-8 and flow cytometric assays, SG611-VSTM1 exhibited more potent anti-proliferative and pro-apoptotic effects in leukemic cells compared with SG611 and exerted synergistic cytotoxicity with low-dose daunorubicin (DNR) in vitro. In xenograft models, SG611-VSTM1 intratumorally injected at a dose of 1 * 10(9) plaque forming units combined with intraperitoneally injected low-dose DNR displayed significantly stronger antitumor effects than either treatment alone. Histopathologic examination revealed that SG611-VSTM1 induced apoptosis of leukemic cells. These results implicate an important role for VSTM1 in the pathogenesis of leukemia, and SG611 VSTM1 may be a promising agent for enhancing chemosensitivity in leukemia therapy. PMID- 27472928 TI - Response to comment on: Thomson et al. Muscle strength gains during resistance exercise training are attenuated with soy compared with dairy or usual protein intake in older adults: A randomized controlled trial. Clinical Nutrition 35:27 33, 2016. PMID- 27472929 TI - A randomized controlled trial of 130 g/day low-carbohydrate diet in type 2 diabetes with poor glycemic control. AB - BACKGROUND & AIMS: The usefulness of low-carbohydrate diet (LCD) for Japanese patients with type 2 diabetes mellitus (T2DM) has not been fully investigated. Therefore, we compared the effectiveness and safety of LCD with calorie restricted diet (CRD). METHODS: This prospective, randomized, open-label, comparative study included 66 T2DM patients with HbA1c >7.5% even after receiving repeated education programs on CRD. They were randomly allocated to either the 130g/day LCD group (n = 33) or CRD group (n = 33). Patients received personal nutrition education of CRD or LCD for 30 min at baseline, 1, 2, 4, and 6 months. Patients of the CRD group were advised to maintain the intake of calories and balance of macronutrients (28* ideal body weight calories per day). Patients of the LCD group were advised to maintain the intake of 130 g/day carbohydrate without other specific restrictions. Several parameters were assessed at baseline and 6 months after each intervention. The primary endpoint was a change in HbA1c level from baseline to the end of the study. RESULTS: At baseline, BMI and HbA1c were 26.5 (24.6-30.1) and 8.3 (8.0-9.3), and 26.7 (25.0-30.0) kg/m2 and 8.0 (7.6 8.9) %, in the CRD and LCD, respectively. At the end of the study, HbA1c decreased by -0.65 (-1.53 to -0.10) % in the LCD group, compared with 0.00 (-0.68 to 0.40) % in the CRD group (p < 0.01). Also, the decrease in BMI in the LCD group [-0.58 (-1.51 to -0.16) kg/m2] exceeded that observed in the CRD group (p = 0.03). CONCLUSIONS: Our study demonstrated that 6-month 130 g/day LCD reduced HbA1c and BMI in poorly controlled Japanese patients with T2DM. LCD is a potentially useful nutrition therapy for Japanese patients who cannot adhere to CRD. This trial was registered at http://www.umin.ac.jp/english/ (University Hospital Medical Information Network: study ID number 000010663). PMID- 27472931 TI - Behavioral Health Integration: Challenges and Opportunities for Academic Medical Centers. PMID- 27472930 TI - Degenerative and regenerative features of myofibers differ among skeletal muscles in a murine model of muscular dystrophy. AB - Skeletal muscle myofibers constantly undergo degeneration and regeneration. Histopathological features of 6 skeletal muscles (cranial tibial [CT], gastrocnemius, quadriceps femoris, triceps brachii [TB], lumbar longissimus muscles, and costal part of the diaphragm [CPD]) were compared using C57BL/10ScSn Dmd mdx (mdx) mice, a model for muscular dystrophy versus control, C57BL/10 mice. Body weight and skeletal muscle mass were lower in mdx mice than the control at 4 weeks of age; these results were similar at 6-30 weeks. Additionally, muscular lesions were observed in all examined skeletal muscles in mdx mice after 4 weeks, but none were noted in the controls. Immunohistochemical staining revealed numerous paired box 7-positive satellite cells surrounding the embryonic myosin heavy chain-positive regenerating myofibers, while the number of the former and staining intensity of the latter decreased as myofiber regeneration progressed. Persistent muscular lesions were observed in skeletal muscles of mdx mice between 4 and 14 weeks of age, and normal myofibers decreased with age. Number of muscular lesions was lowest in CPD at all ages examined, while the ratio of normal myofibers was lowest in TB at 6 weeks. In CT, TB, and CPD, Iba1-positive macrophages, the main inflammatory cells in skeletal muscle lesions, showed a significant positive correlation with the appearance of regenerating myofibers. Additionally, B220-positive B-cells showed positive and negative correlation with regenerating and regenerated myofibers, respectively. Our data suggest that degenerative and regenerative features of myofibers differ among skeletal muscles and that inflammatory cells are strongly associated with regenerative features of myofibers in mdx mice. PMID- 27472933 TI - How the Principles of Improvisational Theater Can Set Your Educational Potential Free! PMID- 27472932 TI - Has the Time Come for a Cultural Psychiatry Fellowship in the USA? PMID- 27472934 TI - Preparing Residents and Fellows to Address Ethical Issues in the Use of Mobile Technologies in Clinical Psychiatry. PMID- 27472936 TI - The gravid uterus: MR imaging and reporting of abnormal placentation. AB - Appropriate placentation is critical to maternal and fetal outcomes. Abnormal placentation, including placenta previa and morbidly adherent placenta, is increasing in incidence and is associated with multiple risk factors including advanced maternal age and history of prior cesarean delivery. Magnetic resonance imaging (MRI) is increasingly used in assessing the type and extent of abnormal placentation, often leading to modifications in surgical approach. Here, we review the MRI features and appropriate reporting of placenta previa and the placenta accreta spectrum. PMID- 27472937 TI - Radiological appearances of corpus luteum cysts and their imaging mimics. AB - PURPOSE: To review the radiological appearances of corpus luteum cysts and their imaging mimics. CONCLUSION: Corpus luteum cysts are normal post-ovulatory structures seen in the ovaries through the second half of the menstrual cycle and the first trimester of pregnancy. The typical appearance, across all modalities, is of a 1- to 3-cm cyst with a thick crenulated vascularized wall. Occasionally, similar imaging findings may be seen with endometrioma, ectopic pregnancy, tuboovarian abscess, red degeneration of a fibroid, and ovarian neoplasia. In most cases, imaging findings are distinctive and allow for a confident and accurate diagnosis that provides reassurance for patients and referring physicians and avoids costly unnecessary follow-up. PMID- 27472935 TI - Determinants of stunting in Indonesian children: evidence from a cross-sectional survey indicate a prominent role for the water, sanitation and hygiene sector in stunting reduction. AB - BACKGROUND: Stunting in early life has considerable human and economic costs. The purpose of the study was to identify factors associated with stunting among children aged 0-23 months in Indonesia to inform the design of appropriate policy and programme responses. METHODS: Determinants of child stunting, including severe stunting, were examined in three districts in Indonesia using data from a cross-sectional survey conducted in 2011. A total of 1366 children were included. The analysis used multiple logistic regression to determine unadjusted and adjusted odds ratios. RESULTS: The prevalence of stunting and severe stunting was 28.4 % and 6.7 %, respectively. The multivariate analysis on determinants of stunting identified a significant interaction between household sanitary facility and household water treatment (P for interaction = 0.007) after controlling for potential covariates: in households that drank untreated water, the adjusted odds on child stunting was over three times higher if the household used a unimproved latrine (adjusted odds ratio 3.47, 95 % confidence interval 1.73-7.28, P <0.001); however, in households that drank treated water, the adjusted odds on child stunting was not significantly higher if the household used an unimproved latrine (adjusted odds ratio 1.27, 95 % confidence interval 0.99-1.63, P = 0.06). Other significant risk factors included male sex, older child age and lower wealth quintile. The risk factors for severe stunting included male sex, older child age, lower wealth quintile, no antenatal care in a health facility, and mother's participation in decisions on what food was cooked in the household. CONCLUSIONS: The combination of unimproved latrines and untreated drinking water was associated with an increased odds on stunting in Indonesia compared with improved conditions. Policies and programmes to address child stunting in Indonesia must consider water, sanitation and hygiene interventions. Operational research is needed to determine how best to converge and integrate water, sanitation and hygiene interventions into a broader multisectoral approach to reduce stunting in Indonesia. PMID- 27472938 TI - Early Peribiliary Hyperenhancement on MRI in Patients with Primary Sclerosing Cholangitis: Significance and Association with the Mayo Risk Score. AB - The aims of this study are to assess any relationship between peribiliary hyperenhancement on MRI in patients with primary sclerosing cholangitis (PSC) and their Mayo risk score and to assess which timing of peribiliary hyperenhancement correlates best with the Mayo risk score. In this HIPAA-compliant, IRB-approved retrospective study, 101 patients who underwent MRI for known or suspected PSC were identified. Of those, 62 patients (mean age 48 years; 40 males) were diagnosed with PSC by a hepatologist based on findings on MRI, ERCP, and/or liver biopsy, and comprise the final cohort. Data were recorded on whether peribiliary hyperenhancement was present, the post-contrast phase and the extent of involvement. The components to calculate the Mayo risk score were recorded. Statistical analysis was performed using the student T test, Fisher's exact test, and the Kaplan-Meier estimate. Of 62 patients, 41 (66.1%) patients had a low-Mayo risk score (<0), 14 (22.6%) had an intermediate-risk score (<=2 and >0), and 7 (11.3%) had a high-risk score (>2). On MRI, 29 (46.8%) patients demonstrated arterial peribiliary hyperenhancement. Both the presence and extent of peribiliary hyperenhancement showed significant associations with Mayo risk score (p < 0.01). Using the combined end point of liver transplantation or death, there was a statistically significant difference in survival times between those with and those without arterial peribiliary hyperenhancement (p < 0.05). The presence of arterial peribiliary hyperenhancement in patients with PSC on MRI is associated with higher Mayo risk scores and may suggest a poorer prognosis. PMID- 27472939 TI - Response to Letter to the Editor: Mercury Human Exposure in Populations Living Around Lake Tana (Ethiopia). PMID- 27472940 TI - Analysis of Relations Between the Level of Mg, Zn, Ca, Cu, and Fe and Depressiveness in Postmenopausal Women. AB - Numerous observations suggest a possible connection between the levels of Mg, Zn, Fe, and Zn and the incidence of depressive symptoms. Depression is two to three times more common in women than in men. The menopausal period is extremely conducive to depressive disorders. The aim of this study was to assess the severity of depressive symptoms in postmenopausal women depending on the levels of Mg, Zn, Ca, Cu, and Fe. The study included 198 healthy postmenopausal women at the average age of 56.26 +/- 5.55 years. In the first part of the study, standardized research tools were used, namely the Primary Care Evaluation of Mental Disorders (PRIME-MD) and the Beck Depression Inventory (BDI). The second part involved biochemical analysis of Mg, Zn, Ca, Cu, and Fe levels in blood serum. The lowest Cu levels were observed in women without depressive symptoms (1.07 +/- 0.22 mg/l) and the highest in those with severe depressive symptoms (1.19 +/- 0.17 mg/l), (p <= 0.05). The lowest Mg levels were observed in women with depressive symptoms (14.28 +/- 2.13 mg/l), and the highest in women without depressive symptoms (16.30 +/- 3.51 mg/l), (p <= 0.05). The average serum Mg levels (15.75 +/- 3.23 mg/l) decreased compared to the reference values (18.77-24 mg/l). What is striking is a potential relation between the levels of Mg and Cu and depressiveness. Our results indicate to a higher vulnerability to depression in a group of women with lower levels of Mg and higher levels of Cu. PMID- 27472941 TI - Differential Tissue Accumulation of Copper, Iron, and Zinc in Bycatch Fish from the Mexican Pacific. AB - In order to ascertain if Cu, Fe, and Zn are differentially accumulated in fish tissues, metal concentrations were measured in the muscle and liver of bycatch fish from the states of Sinaloa (189 specimens, 7 species) and Guerrero (152 individuals, 8 species) in the Mexican Pacific Coast during March and November 2011. Additionally, metal levels were compared with the maximum allowable limits set by international legislation and contrasted with similar ichthyofauna from other regions. Liver had more elevated concentrations of Cu (Sinaloa 28.3, Guerrero 16.3 MUg g-1), Fe (Sinaloa 1098, Guerrero 636 MUg g-1), and Zn (Sinaloa 226, Guerrero 186 MUg g-1) than the muscle in fish from both studied areas. The relative abundances of analyzed metals in both tissues was Fe > Zn > Cu. As far as limits set by international legislation (Australia, India, New Zealand, Zambia), measured concentrations of Cu in the edible portion of fish were not found to be above the set values. In the case of Zn, the maximum allowable limits set by international legislation were exceeded by the Peruvian mojarra Diapterus peruvianus from Guerrero state (Mexican Pacific). No limits exist for Fe in the edible portion of fishery products in the national and international legislations. PMID- 27472942 TI - Does performance-based financing increase value for money in low- and middle- income countries? A systematic review. AB - Governments of low- and middle-income countries (LMICs) are widely implementing performance-based financing (PBF) to improve healthcare services. However, it is unclear whether PBF provides good value for money compared to status quo or other interventions aimed at strengthening the healthcare system in LMICs. The objective of this systematic review is to identify and synthesize the existing literature that examines whether PBF represents an efficient manner of investing resources. We considered PBF to be efficient when improved care quality or quantity was achieved with equal or lower costs, or alternatively, when the same quality of care was achieved using less financial resources. A manual search of the reference lists of two recent systematic reviews on economic evaluations of PBF was conducted to identify articles that met our inclusion and exclusion criteria. Subsequently, a search strategy was developed with the help of a librarian. The following databases and search engines were used: PubMed, EconLit, Google Scholar and Google. Experts on economic evaluations were consulted for validation of the selected studies. A total of seven articles from five LMICs were selected for this review. We found the overall strength of the evidence to be weak. None of the articles were full economic evaluations; they did not make clear connections between the costs and effects of PBF. Only one study reported using a randomized controlled trial, but issues with the randomization procedure were reported. Important alternative interventions to strengthen the capacities of the healthcare system have not been considered. Few studies examined the costs and consequences of PBF in the long term. Important costs and consequences were omitted from the evaluations. Few LMICs are represented in the literature, despite wide implementation. Lastly, most articles had at least one author employed by an organization involved in the implementation of PBF, thereby resulting in potential conflicts of interest. Stronger empirical evidence on whether PBF represents good value for money in LMICs is needed. PMID- 27472943 TI - What, who and when? Incorporating a discrete choice experiment into an economic evaluation. AB - BACKGROUND: Economic evaluation focuses on Quality-Adjusted-Life-Years (QALYs) as the main valuation method. However, it is well known that factors beyond health related quality of life are important to patients and the public. Whilst discrete choice-experiments (DCE) have been extensively used to value such factors, their incorporation within an economic evaluation framework is limited. This study is the first to incorporate patient preferences for factors beyond QALYs into an economic evaluation and compare results with the standard cost-per-QALY approach, using randomised-controlled-trial (RCT) participants. METHODS: Costings, clinical effectiveness (appropriateness-of-treatment), QALYs and patient satisfaction data were collected at baseline and 12-month follow-up for a new pharmacy-service within a randomised-controlled-trial. Trial participants who replied to the follow-up survey and had not subsequently withdrawn from the study were mailed a DCE questionnaire at 24-months. WTP for the standard and new service was derived from the DCE. Results from QALYs and the DCE were compared. RESULTS: At 12 months, costs, clinical-effectiveness and QALYs did not differ between the intervention and control; however there was a significant increase in satisfaction in the intervention. The DCE valued this increased satisfaction in the intervention (positive net-benefit). The longer the time patients experienced the new service the greater the reported net-benefit. CONCLUSION: When incorporating a DCE into an economic evaluation a number of questions are raised: what factors should be valued, whose values (trial-groups vs. all-trial population) and when should they be elicited (still-receiving-the-intervention or afterwards). Consideration should also be given to status quo bias. PMID- 27472944 TI - Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-beta (Abeta) and alpha- and beta-cleaved soluble forms of amyloid precursor protein (sAPPalpha and sAPPbeta). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery. METHODS: Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month follow-up after surgery using the iNPH scale. Lumbar puncture was performed pre operatively. CSF samples were analyzed for neurofilament light (NFL), Abeta isoforms Abeta38, Abeta40 and Abeta42, sAPPalpha, sAPPbeta, APLP1 beta-derived peptides APL1beta25, APL1beta 27 and APL1beta 28 and YKL40 by immunochemical methods. RESULTS: The concentrations of all soluble forms of APP, all Abeta isoforms and APL1beta28 were lower, whilst APL1beta25 and APL1beta27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged. CONCLUSIONS: The reduced CSF concentrations of Abeta38, Abeta40, Abeta42, sAPPalpha and sAPPbeta suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1beta25 and APL1beta27 in combination with a slight decreased APL1beta28 could be caused by more available gamma secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness. PMID- 27472945 TI - Modelling the concentrations of dissolved contaminants (Cd, Cu, Ni, Pb, Zn) in floodplain soils. AB - Central European floodplain soils are often contaminated with potentially toxic metals. The prediction of their aqueous concentrations is a prerequisite for an assessment of environmental concerns. We tested the aqueous concentrations of cadmium (Cd), copper (Cu), nickel (Ni), lead (Pb) and zinc (Zn) derived from multi-surface adsorption modelling (on hydrous iron, aluminum and manganese oxides, clay and soil organic matter) against those analyzed in situ in the soil solution of four horizons of floodplain soils at the Elbe River, Germany. The input data for the reactive metals were derived from a seven-step sequential extraction scheme or from extraction with 0.43 M nitric acid (HNO3) and evaluated in four modelling scenarios. In all scenarios, measured and modelled concentrations were positively related, except partially for Pb. Close reproduction of the measured data was obtained using measured data of accompanying cations and anions together with amounts of reactive metals from both the sequential extraction or from 0.43 M HNO3 extraction, except for Cu, which was often strongly overestimated, and partially Cd. We recommend extraction with 0.43 M HNO3 to quantify reactive metals in soil because the modelling results were metal-specific with better or equal results using the single extractant, the application of which is also less laborious. Approximations of ion concentrations and water contents yielded similar results. Modelled solid phase speciation of metals varied with pH and differed from that from sequential extraction. Multi-surface modelling may be an effective tool to predict both aqueous concentrations and solid-phase speciation of metals in soil. PMID- 27472946 TI - [Psychological comorbidities in patients with psychosomatic disorders of micturition]. AB - Many patients with chronic urological diseases report a long-term suffering. Because of previous failure to recognize the psychosomatic diagnosis they are inefficiently treated or even suffer from complications of unsuccessful therapy attempts, which in retrospect were not indicated. The patients are desperate and put all their hopes and expectations in every new doctor, which is why they put us urologists under tremendous pressure to perform and are a challenge for our diagnostic and therapeutic expertise. Knowledge of psychological comorbidities and their effect on the urogenital tract are essential for the differential diagnostics of the urological complaints and for a purposeful therapy. PMID- 27472948 TI - NHS trust stands by doctors who set up clinic for private work. PMID- 27472947 TI - A 'busy day' effect on perinatal complications of delivery on weekends: a retrospective cohort study. AB - OBJECTIVE: To evaluate whether busy days on a labour and delivery unit are associated with maternal and neonatal complications of childbirth in California hospitals, accounting for weekday/weekend births. DESIGN: This is a population based retrospective cohort study. SETTING: Linked vital statistics/patient discharge data for California births between 2009 and 2010 from the Office of Statewide Health Planning and Development. PARTICIPANTS: All singleton, cephalic, non-anomalous California births between 2009 and 2010 (N=724 967). MAIN OUTCOMES: The key exposure was high daily obstetric volume, defined as giving birth on a day when the number of births exceeded the hospital-specific 75th percentile of daily delivery volume. Outcomes were a range of maternal and neonatal complications. RESULTS: Several maternal and neonatal complications were increased on high-volume days and weekends following adjustment for maternal demographics, annual hospital birth volume and teaching hospital status. For example, compared with low-volume weekdays, the odds of Apgar <7 on low-volume weekend days and high-volume weekend days were 11% (adjusted OR (aOR) 1.11, CI 1.03 to 1.21) and 29% higher (aOR 1.29, CI 1.10 to 1.52), respectively. High volume was associated with increased odds of neonatal seizures on weekdays (aOR 1.33, CI 1.01 to 1.71) and haemorrhage on weekends (aOR 1.11, CI 1.01 to 1.22). After accounting for between-hospital variation, weekend delivery remained significantly associated with increased odds of Apgar score <7, neonatal intensive care unit admission, prolonged maternal length of stay and the odds of neonatal seizures remained increased on high-volume weekdays. CONCLUSIONS: Our findings suggest that weekend delivery is a consistent risk factor for a range of perinatal complications and there may be variability in how well hospitals handle surges in volume. PMID- 27472949 TI - Efficacy and safety of tribendimidine against Opisthorchis viverrini: two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials. AB - BACKGROUND: Treatment of the liver fluke infection Opisthorchis viverrini relies exclusively on praziquantel. Tribendimidine could be an alternative treatment option. We aimed to assess the efficacy and safety of ascending single, oral doses of tribendimidine in patients with O viverrini infection. METHODS: We did two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials in children (aged 8-14 years) and adults and adolescents (>=15 years) in three O viverrini endemic villages in Champasack province, southern Laos. Patients with O viverrini infection were randomly assigned, via a computer-generated central block-randomisation procedure, with block sizes of three (study 1) and four, eight, and 12 (study 2), to receive oral tribendimidine at doses of 200 mg, 400 mg, or 600 mg in a 1:1:1 ratio (adults and adolescents in study 1); 25 mg, 50 mg, 100 mg, or 200 mg (four 50 mg tablets) in a 1:1:1:1 ratio (adults and adolescents in study 2); or 100 mg, 200 mg, or 400 mg in a 1:1:1 ratio (children in study 1). One non-randomised group of children received tribendimidine 50 mg (study 2). Participants, investigators, and laboratory technicians doing the diagnostic assessments were masked to group assignment, but the investigator administering treatment could have recognised the treatment group based on the number of tablets. The primary objective was to estimate the dose-response relation in terms of cure rate and egg reduction rate. We did available-case analysis of all patients with primary endpoint data. We predicted dose-response associations with Emax models. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN96948551. FINDINGS: Between Oct 25, 2012, and Nov 5, 2013, 318 adolescents and adults were randomly assigned to seven tribendimidine dose groups: 200 mg (n=51), 400 mg (n=49), or 600 mg (n=47) in study 1, and 25 mg (n=39), 50 mg (n=47), 100 mg (n=44), or 200 mg (four 50 mg tablets; n=41) in study 2. 128 children were randomly assigned to receive tribendimidine 100 mg (n=44), 200 mg (n=40), or 400 mg (n=44) in study 1; 39 children were enrolled and received tribendimidine 50 mg in study 2. In adolescents and adults, the number of patients cured increased with increasing tribendimidine doses up to 100 mg: ten of 39 patients (25.6%, 95% CI 13.0-42.1) were cured in the 25 mg group, 20 of 47 patients (42.6%, 28.3-57.8) were cured in the 50 mg group, and 34 of 44 patients (77.3%, 62.2-88.5) were cured in the 100 mg group; geometric mean egg reduction rates were 86.9% (95% CI 74.8-93.4), 95.9% (92.7-97.7), and 99.1% (98.2-99.7), respectively. The 200 mg dose resulted in cure in 40 of 47 (83.0%, 69.2-92.5) adolescents and adults given the 200 mg tablet and 25 of 41 (61.0%, 95% CI 44.5-75.8) of those given four 50 mg tablets; the 400 mg dose resulted in cure in 43 of 47 patients (91.5%, 79.6-97.6) and the 600 mg dose resulted in cure in 36 of 45 patients (80.0%, 65.4-90.4). Corresponding egg reduction rates were 99.8% (95% CI 99.7-100.0) with one 200 mg tablet, 97.9% (95.9-99.2) with four 50 mg tablets, 99.9% (99.8-100.0) with 400 mg, and 99.8% (99.6-99.9) with 600 mg. The Emax model predicted an egg reduction rate of 99.0% (95% CI 95.7-99.8) at 111 mg in adolescents and adults. 50 mg tribendimidine had moderate efficacy in children, with cure recorded in 16 of 39 patients (41.0%, 95% CI 25.6-57.9). The 100 mg dose resulted in cure in 40 of 44 children (98.9%, 95% CI 78.3-97.5) and an egg reduction rate of 99.7% (95% CI 99.0-100.0), with no increased efficacy at higher doses. The Emax model predicted an egg reduction rate of 99.0% (95% CI 92.2-99.9) at 215 mg. Few adverse events were reported and were mostly mild, with few moderate and no serious events. The most common adverse events 3 h after treatment in adolescents and adults were vertigo (n=35 [11%]), headache (n=9 [3%]), nausea (n=6 [2%]), and fatigue (n=4 [1%]), and in children were headache (n=3 [2%]), vertigo (n=2 [1%]), and fatigue (n=2 [1%]). INTERPRETATION: Tribendimidine has excellent efficacy and tolerability at doses of 100 mg and above. Our study included mainly adults and children with low-intensity O viverrini infection; future studies should assess the efficacy of tribendimidine in patients with infections of moderate and high intensity. FUNDING: Department for International Development, Medical Research Council, Wellcome Trust Joint Global Health Trials Scheme. PMID- 27472950 TI - Tribendimidine: great expectations. PMID- 27472953 TI - An episomal CRISPR/Cas9 system to derive vector-free gene modified mammalian cells. PMID- 27472952 TI - Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer. AB - Oxaliplatin is a key drug in chemotherapy of colorectal cancer (CRC). However, its efficacy is unsatisfied due to drug resistance of cancer cells. In this study, we tested whether a natural agent, ursolic acid, was able to enhance the efficacy of oxaliplatin for CRC. Four CRC cell lines including SW480, SW620, LoVo, and RKO were used as in vitro models, and a SW620 xenograft mouse model was used in further in vivo study. We found that ursolic acid inhibited proliferation and induced apoptosis of all four cells and enhanced the cytotoxicity of oxaliplatin. This effect was associated with down-regulation of Bcl-xL, Bcl-2, survivin, activation of caspase-3, 8, 9, and inhibition of KRAS expression and BRAF, MEK1/2, ERK1/2, p-38, JNK, AKT, IKKalpha, IkappaBalpha, and p65 phosphorylation of the MAPK, PI3K/AKT, and NF-kappaB signaling pathways. The two agents also showed synergistic effects against tumor growth in vivo. In addition, ursolic acid restored liver function and body weight of the mice treated with oxaliplatin. Thus, we concluded that ursolic acid could enhance the therapeutic effects of oxaliplatin against CRC both in vitro and in vivo, which offers an effective strategy to minimize the burden of oxaliplatin-induced adverse events and provides the groundwork for a new clinical strategy to treat CRC. PMID- 27472951 TI - Structural characterization of coatomer in its cytosolic state. AB - Studies on coat protein I (COPI) have contributed to a basic understanding of how coat proteins generate vesicles to initiate intracellular transport. The core component of the COPI complex is coatomer, which is a multimeric complex that needs to be recruited from the cytosol to membrane in order to function in membrane bending and cargo sorting. Previous structural studies on the clathrin adaptors have found that membrane recruitment induces a large conformational change in promoting their role in cargo sorting. Here, pursuing negative-stain electron microscopy coupled with single-particle analyses, and also performing CXMS (chemical cross-linking coupled with mass spectrometry) for validation, we have reconstructed the structure of coatomer in its soluble form. When compared to the previously elucidated structure of coatomer in its membrane-bound form we do not observe a large conformational change. Thus, the result uncovers a key difference between how COPI versus clathrin coats are regulated by membrane recruitment. PMID- 27472955 TI - An assessment of early colonisation of implant-abutment metal surfaces by single species and co-cultured bacterial periodontal pathogens. AB - OBJECTIVE: Numerous studies have proposed that smooth metal surfaces reduce initial bacterial attachment in the establishment of an early biofilm formation. However, these studies have largely examined single bacterial species, which are not always relevant as pathogens identified as initiators of inflammatory peri implantitis. This study investigated the adherence of four periodontally-relevant bacterial species to implant and abutment surfaces in current clinical use. METHODS: Discs of polished cobalt chromium (CoCr-polished) and milled titanium (Ti-milled), representing two clinically relevant surfaces, were prepared and surfaces were characterised. Bacterial species Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia and Aggregatibacter actinomycetemcomitans were cultured to mid-log or stationary growth phase. Co cultures of P. gingivalis, F. nucleatum and P. gingivalis, F. nucleatum, Pr. intermedia were similarly prepared. Bacteria were inoculated onto discs for 2h, stained with a live/dead fluorescent stain and percentage bacterial coverage was calculated by confocal microscopy and image analysis. RESULTS: CoCr-polished discs had smooth surfaces with gentle valley structures, whilst Ti-milled discs had sharp edged peaks. Both discs demonstrated a partial wetting ability capable of initiating bacterial adhesion. P. gingivalis, F. nucleatum and co-cultures, at both mid-log and stationary concentrations, demonstrated equally high coverage of both the smooth CoCr-polished and the rougher Ti-milled metal surfaces. Pr. intermedia and A. actinomycetemcomitans demonstrated lower surface coverage which was slightly higher for Ti-milled. CONCLUSION: Variability was noted in the adherence potential for the respective periodontal pathogens examined. Particularly high adherence was noted for P. gingivalis and F. nucleatum, despite the manufacture of a smooth surface. CLINICAL SIGNIFICANCE: Both surfaces studied may be used at implant-abutment junctions and both possess an ability to establish a bacterial biofilm containing a periodontally-relevant species. These surfaces are thus able to facilitate the apical migration of bacteria associated with peri-implantitis. PMID- 27472956 TI - Bonding performance of experimental bioactive/biomimetic self-etch adhesives doped with calcium-phosphate fillers and biomimetic analogs of phosphoproteins. AB - OBJECTIVES: This study examined the bonding performance and dentin remineralization potential of an experimental adhesive containing calcium phosphate (Ca/P) micro-fillers, and self-etching primers doped with phosphoprotein biomimetic analogs (polyacrylic acid-(PAA) and/or sodium trimetaphosphate-(TMP)). METHODS: Experimental self-etching primers doped with biomimetic analogs (PAA and/or TMP), and an adhesive containing Ca(2+), PO4(-3) releasing micro-fillers (Ca/P) were formulated. Sound human dentin specimens were bonded and cut into sticks after aging (24h or 6 months) under simulated pulpal pressure (20cm H2O), and tested for microtensile bond strength (MUTBS). Results were analyzed using two-way ANOVA and Tukey's test (p<0.05). Interfacial silver nanoleakage was assessed using SEM. Remineralization of EDTA-demineralized dentin was assessed through FTIR and TEM ultrastructural analysis. RESULTS: Application of the Ca/P-doped adhesive with or without dentin pre-treatments with the primer containing both biomimetic analogs (PAA and TMP) promoted stable MUTBS over 6 months. Conversely, MUTBS of the control primer and filler-free adhesive significantly decreased after 6 months. Nanoleakage decreased within the resin dentin interfaces created using the Ca/P-doped adhesives. EDTA-demineralized dentin specimens treated the Ca/P-doped adhesive and the primer containing PAA and TMP showed phosphate uptake (FTIR analysis), as well as deposition of needle like crystallites at intrafibrillar level (TEM analysis). SIGNIFICANCE: The use of Ca/P-doped self-etching adhesives applied in combination with analogs of phosphoproteins provides durable resin-dentin bonds. This approach may represent a suitable bonding strategy for remineralization of intrafibrillar dentin collagen within the resin-dentin interface. PMID- 27472954 TI - Three-dimensional biofilm properties on dental bonding agent with varying quaternary ammonium charge densities. AB - OBJECTIVES: Tooth-restoration interfaces are the weak link with secondary caries causing restoration failure. The objectives of this study were to develop an antimicrobial bonding agent with dimethylaminododecyl methacrylate (DMAHDM), and investigate the effects of quaternary amine charge density on three-dimensional (3D) biofilms on dental resin for the first time. METHODS: DMAHDM was synthesized and incorporated into Scotchbond Multi-Purpose bonding agent at mass fractions of 0% (control), 2.5%, 5%, 7.5% and 10%. Streptococcus mutans bacteria were inoculated on the polymerized resin and cultured for two days to form biofilms. Confocal laser scanning microscopy was used to measure biofilm thickness, live and dead biofilm volumes, and live bacteria percentage in 3D biofilm vs. distance from resin surface. RESULTS: Charge density of the resin had a significant effect on the antibacterial efficacy (p<0.05). Biofilms on control resin had the greatest thicknesses. Biofilm thickness and live biofilm volume decreased with increasing surface charge density (p<0.05). There were significant variations in bacterial viability along the 3D biofilm thickness (p<0.05). At 2.5% and 5% DMAHDM, the bacterial inhibition was the greatest on or near the resin surface, and the killing effect decreased away from the resin surface. At 10% DMAHDM, the entire 3D biofilm was dead and the percentage of live bacteria was nearly 0% throughout the biofilm thickness. CONCLUSIONS: Adding new antibacterial monomer DMAHDM into dental bonding agent yielded a strong antimicrobial activity, substantially decreasing the 3D biofilm thickness, live biofilm volume, and percentage of live bacteria on cross-sections through the biofilm thickness. SIGNIFICANCE: Novel DMAHDM-containing bonding agent with capability of inhibiting 3D biofilms is promising for a wide range of dental restorative and preventive applications to inhibit biofilms at the tooth-restoration margins and prevent secondary caries. PMID- 27472957 TI - A randomized controlled trial of various MTA materials for partial pulpotomy in permanent teeth. AB - OBJECTIVES: The aim of this study was to evaluate and compare the clinical applicability of various MTA materials as partial pulpotomy materials in permanent teeth. METHODS: Partial pulpotomy was performed on 104 permanent teeth from 82 people (mean 29.3+/-14.8years old), who met the inclusion criteria in randomized clinical trial. The teeth were divided into three groups: ProRoot MTA (n=33), OrthoMTA (n=36), RetroMTA (n=35). Clinical examination and radiographic comparison were carried out at 1, 3, 6 and 12 months after the treatment. Survival analysis was performed using the Kaplan-Meier survival curves and log rank tests. RESULTS: Partial pulpotomy sustained a high success rate up to 1year with no significant differences in the outcomes treated with three MTA materials: ProRoot MTA, 96.0%; OrthoMTA, 92.8%; RetroMTA, 96.0%. The Kaplan-Meier survival function curves showed no significant differences among three groups concerning clinical and radiographic cumulative survival rates. In addition, no potential prognostic factors related to the success rate of partial pulpotomy among age, sex, tooth type, root apex status, the site and type of pulp exposure, and the type of restoration were observed in log rank analysis. CONCLUSIONS: Partial pulpotomy with ProRoot MTA, OrthoMTA and RetroMTA had favorable results and clinical and radiographic results were not significantly different in three groups after 1year. PMID- 27472958 TI - The Density Awakens: A Reply to Blonder. PMID- 27472959 TI - Phylogenetic analyses of the subgenus Mollienesia (Poecilia, Poeciliidae, Teleostei) reveal taxonomic inconsistencies, cryptic biodiversity, and spatio temporal aspects of diversification in Middle America. AB - The subgenus Mollienesia is a diverse group of freshwater fishes, including species that have served as important models across multiple biological disciplines. Nonetheless, the taxonomic history of this group has been conflictive and convoluted, in part because the evolutionary relationships have not been rigorously resolved. We conducted a comprehensive molecular phylogenetic analysis of the subgenus Mollienesia to identify taxonomic discrepancies and potentially identify undescribed species, estimate ancestral areas of origin and estimate dates of divergence, as well as explore biogeographical patterns. Our findings confirm the presence of three main clades composed of the P. latipinna, P. sphenops, and P. mexicana species complexes. Unlike previously hypothesized morphology-based analyses, species found on the Caribbean Islands are not part of Mollienesia, but are more closely related to species of the subgenus Limia. Our study also revealed several taxonomic inconsistencies and distinct lineages in the P. mexicana species complex that may represent undescribed species. The diversity in the subgenus Mollienesia is a result of dynamic geologic activity leading to vicariant events, dispersal across geologic blocks, and ecological speciation. PMID- 27472960 TI - Criterion-related validity of the short form of the international physical activity questionnaire in adults who are Deaf. AB - BACKGROUND: To implement appropriate programs for promoting physical activity (PA) in people who are Deaf, it is important to have valid instruments for assessing PA in this population. OBJECTIVE: The main purpose of this study was to examine the criterion validity of the short form of the International Physical Activity Questionnaire (IPAQ-S) in Deaf adults. METHOD: This study included 44 adults (18-65 years) of both genders (63.6% were females) who met the inclusion criteria. Objective measures of PA were collected using accelerometers, which were worn by each participant during one week. After using the accelerometer, the IPAQ-S was applied to assess participants' physical activity during the last 7 days. RESULTS: There was no significant correlation between the average time spent in moderate to vigorous physical activity (MVPA) as measured by the accelerometer (40.1 +/- 24.5 min/day) and by the IPAQ-S (41.3 +/- 57.5 min/day). The IPAQ-S significantly underestimated the time spent in sedentary behavior (7.6 +/- 2.7 h/day vs. 10.1 +/- 1.6 h/day). Sedentary behavior and MVPA as measured by the accelerometer and the IPAQ-S showed limited agreement. CONCLUSIONS: Our results show some limitations on the use of IPAQ-S for quantifying PA among adults who are Deaf. The IPAQ-S tends to overestimate the MVPA and to underestimate sedentary behavior in adults who are Deaf. PMID- 27472961 TI - Characterizing polymorphic inversions in human genomes by single-cell sequencing. AB - Identifying genomic features that differ between individuals and cells can help uncover the functional variants that drive phenotypes and disease susceptibilities. For this, single-cell studies are paramount, as it becomes increasingly clear that the contribution of rare but functional cellular subpopulations is important for disease prognosis, management, and progression. Until now, studying these associations has been challenged by our inability to map structural rearrangements accurately and comprehensively. To overcome this, we coupled single-cell sequencing of DNA template strands (Strand-seq) with custom analysis software to rapidly discover, map, and genotype genomic rearrangements at high resolution. This allowed us to explore the distribution and frequency of inversions in a heterogeneous cell population, identify several polymorphic domains in complex regions of the genome, and locate rare alleles in the reference assembly. We then mapped the entire genomic complement of inversions within two unrelated individuals to characterize their distinct inversion profiles and built a nonredundant global reference of structural rearrangements in the human genome. The work described here provides a powerful new framework to study structural variation and genomic heterogeneity in single cell samples, whether from individuals for population studies or tissue types for biomarker discovery. PMID- 27472963 TI - Oxidized LDL at the crossroads of immunity in non-alcoholic steatohepatitis. AB - Non-alcoholic steatohepatitis (NASH) is viewed as the hepatic manifestation of the metabolic syndrome and is a condition hallmarked by lipid accumulation in the liver (steatosis) along with inflammation (hepatitis). Currently, the etiology and mechanisms leading to obesity-induced hepatic inflammation are not clear and, as a consequence, strategies to diagnose or treat NASH in an accurate manner do not exist. In the current review, we put forward the concept of oxidized lipids as a significant risk factor for NASH. We will focus on the contribution of the different types of oxidized lipids as part of the oxidized low-density lipoprotein (oxLDL) to the hepatic inflammatory response. Furthermore, we will elaborate on the underlying mechanisms linking oxLDL to inflammatory responses in the liver and on how these cascades can be used as therapeutic targets to combat NASH. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder. PMID- 27472962 TI - Single nucleotide polymorphism rs13042395 in the SLC52A3 gene as a biomarker for regional lymph node metastasis and relapse-free survival of esophageal squamous cell carcinoma patients. AB - BACKGROUND: SLC52A3 was recently identified as a susceptibility gene for esophageal squamous cell carcinoma (ESCC). However, associations between the single nucleotide polymorphisms (SNPs) rs13042395 (C > T) and rs3746803 (G > A) in SLC52A3 and risk, tumor characteristics and survival of ESCC patients remain inconclusive and of unknown prognostic significance. METHODS: Analyses of the association between SNPs in SLC52A3 and ESCC risk were performed on 479 ESCC cases, together with 479 controls, in a case-control study. Blood samples for cases and controls were collected and genotyped by real-time polymerase chain reaction (PCR) using TaqMan assays. Among the 479 ESCC cases, 343 cases with complete clinical data were used to investigate the association between SNPs and ESCC clinical characteristics; 288 cases with complete clinical data and 5-year follow-up data were used to analyze the association between SNPs and prognosis. Dual luciferase reporter assays and electrophoretic mobility shift assays (EMSAs) were used to investigate the biological function of rs13042395. RESULTS: No association was found between SLC52A3 rs3746803 and susceptibility, tumor characteristics or survival of ESCC patients. For rs13042395, TT genotype carriers were likely to have reduced lymph node metastasis (odds ratio (OR) = 0.55, 95 % confidence interval (CI), 0.31-0.98) and longer relapse-free survival time (P = 0.03) . Also, both rs13042395 (hazard ratio (HR) = 0.62, 95 % CI, 0.38 0.99) and regional lymph node metastasis (HR = 2.06, 95 % CI, 1.36-3.13 for N1 vs. N0; HR = 2.88, 95 % CI, 1.70-4.86 for N2 vs. N0; HR = 2.08, 95 % CI, 1.01 4.30 for N3 vs. N0) were independent factors affecting relapse-free survival for ESCC patients who underwent surgery. Dual luciferase reporter assays and EMSAs suggested that the CC genotype of rs13042395 enhanced SLC52A3 expression, probably via binding with specific transcription factors. CONCLUSIONS: The rs13042395 polymorphism in SLC52A3 is associated with regional lymph node metastasis and relapse-free survival in ESCC patients. PMID- 27472965 TI - Guideline conflict of interest management and methodology heavily impacts on the strength of recommendations: comparison between two iterations of the American College of Chest Physicians Antithrombotic Guidelines. PMID- 27472964 TI - The Cognitive Remediation in Bipolar (CRiB) pilot study: study protocol for a randomised controlled trial. AB - BACKGROUND: People with bipolar disorder often show difficulties with cognitive functioning, and though these difficulties are identified as important targets for intervention, few treatment options are available. Preliminary evidence suggests that cognitive remediation therapy (a psychological treatment proven beneficial for people diagnosed as having schizophrenia) is helpful for people with bipolar disorders. We are conducting a pilot trial to determine whether individual, computerised, cognitive remediation therapy (CRT) for people with bipolar disorder 1) increases cognitive function; 2) improves global functioning, goal attainment and mood symptoms; 3) is acceptable and feasible for participants; and 4) can be addressed in a comprehensive, larger, randomised, controlled trial. METHODS/DESIGN: The study is designed as a two-arm, randomised, controlled trial comparing cognitive remediation therapy with treatment-as-usual (TAU) for euthymic bipolar patients. Participants are eligible to take part if aged between 18 and 65 with a diagnosis of bipolar disorder (type I) and currently in euthymic state, and no neurological, substance or personality disorder diagnoses. Sixty participants will be recruited (mainly through secondary and tertiary care) and will be block-randomised to receive either treatment-as-usual alone or in addition to a 12-week course of cognitive remediation therapy totalling 20-40 therapy hours. The intervention will comprise regular sessions with a therapist and computer-based training. Research assessments will take place before and after the intervention period and at a 12 week follow-up, and will include evaluation of neuropsychological, symptom related, demographic and social factors, as well as collecting qualitative data regarding CRT expectations and satisfaction. Intention-to-treat analyses will examine the efficacy of cognitive remediation therapy primarily on cognition and additionally on functioning, quality of life and mood symptoms. Furthermore, we will examine the acceptability of CRT and undertake a preliminary health economics analysis to ascertain the cost of delivering the intervention. DISCUSSION: The results of this trial will provide valuable information about whether cognitive remediation therapy may be beneficial for people diagnosed with bipolar disorder in a euthymic state. TRIAL REGISTRATION: ISRCTN registry, ISRCTN32290525 . Registered on 2 March 2016. PMID- 27472966 TI - Prenatal exposure to di(2-ethylhexyl) phthalate impairs development of the mouse neocortex. AB - Di(2-ethylhexyl) phthalate (DEHP) is currently the most commonly used phthalate for the production of flexible polyvinyl chloride. Phthalates including DEHP have been labeled as potential endocrine disruptors. The effect on the development of the neocortex, however, is unknown. To evaluate the neurodevelopmental effects of prenatal DEHP exposure at 1 and 100mg/kg/day or 100 and 500mg/kg/day in fetal and newborn mice, we performed a detailed histologic analysis of the developing dorsal telencephalon and neocortex. The observation of fetuses exposed to DEHP revealed reductions of proliferation and neurogenesis (1 and 100mg/kg) and an increase in cell death (500mg/kg). In addition, the newborns prenatally exposed to DEHP showed an abnormal neuronal distribution and a decrease in neurons. These findings suggest that prenatal DEHP exposure induces neurodevelopmental toxicity associated with the neural stem cell niche and corticogenesis. PMID- 27472967 TI - The Power of Affiliation. PMID- 27472969 TI - A Few Minutes With Rebecca M. Patton. PMID- 27472968 TI - Credentialing for Perioperative Nurse Leaders. PMID- 27472970 TI - Strategies for Successful Perioperative Orientation. AB - The successful orientation of new employees facilitates their transition to the complex and demanding world of perioperative nursing. Whether a nurse is a recent graduate or an experienced nurse who has recently joined the facility or department, a new nurse benefits from a transition period during which new skills, processes, and concepts can be learned. Training should offer new employees the opportunity to develop competency, experience, collegial relationships, clinical judgment, and, overall, specialized knowledge for application in the clinical setting. Concerns surrounding orientation and training include the initial costs for training and the possibility of new employees leaving after the completion of training. The associated costs can be staggering, but adopting perioperative nurse residency programs may be a way to provide quality, high-level training and improve retention rates while minimizing long-term costs. PMID- 27472971 TI - Effective Perioperative Communication to Enhance Patient Care. AB - Breakdowns in health care communication are a significant cause of sentinel events and associated patient morbidity and mortality. Effective communication is a necessary component of a patient safety program, which enables all members of the interdisciplinary health care team to effectively manage their individual roles and responsibilities in the perioperative setting; set expectations for safe, high-reliability care; and measure and assess outcomes. To sustain a culture of safety, effective communication should be standardized, complete, clear, brief, and timely. Executive leadership and support helps remove institutional barriers and address challenges to support the engagement of patients in health care communication, which has been shown to improve outcomes, reduce costs, and improve the patient experience. PMID- 27472973 TI - Perioperative Nurse Leaders and Professionalism. AB - Professionalism in nursing leadership encompasses key elements that include a common body of knowledge, autonomous practice, self-regulation through education and licensure, a set code of ethics, and a commitment to altruism. Perioperative nurse leaders also must embrace collaboration, vision, accountability, and patient and staff member advocacy based on established ethics, values, and standards of care. Nurse leaders who are committed to professional development through pursuit of higher degrees, application of evidence-based practice, collaboration with colleagues, and certification show a strong commitment to their profession and serve as role models for staff members. This article discusses professionalism in nursing and offers information specific to perioperative nurse leaders. PMID- 27472972 TI - Improving OR Efficiency. AB - The high-cost/high-revenue environment of the OR requires special attention from managers to scrutinize and reduce costs. In the OR, nonlabor cost savings (ie, no staff member will be laid off or reclassified to realize cost savings) can typically be identified most readily. Operational costs in the OR are affected by start times, turnover times, cancellation rates, and adequate supplies, equipment, and staffing. Inefficiency in the OR can increase costs and lead to dissatisfied patients, physicians, and staff members. This article describes concepts that contribute to efficiency in the OR and illustrates the importance of staff member engagement in achieving desired outcomes. PMID- 27472974 TI - Using a Checklist in Robotic-Assisted Laparoscopic Radical Prostatectomy Procedures. AB - Robotic surgical systems are relatively new in New Zealand and have been used mainly for laparoscopic radical prostatectomy. Checklists are successfully used in other industries and health care facilities, so we developed a checklist for use during robotic-assisted laparoscopic radical prostatectomy (RALRP) procedures. After a two-month trial using the checklist, we calculated the completeness of each phase of the checklist as a percentage of the number of completed checklists versus total number of compliant checklists in that phase. Operating room personnel participated in an audiotaped focus group and discussed their perceptions about using the RALRP checklist. We collected, transcribed, and reviewed the focus group discussion and thematically analyzed the responses, which confirmed that the checklist served as a guideline and reminder during the setup. Additionally, staff members associated the checklist with improved OR readiness, minimized workflow interruption, improved efficiency, and positive changes in confidence and teamwork. PMID- 27472975 TI - Leadership and Management Roles: Challenges and Success Strategies. PMID- 27472976 TI - Perioperative Nurse Leaders and Their Role in Patient Safety. PMID- 27472977 TI - Clinical Issues-August 2016. AB - Assessing discharge risks for infants and toddlers who have undergone moderate sedation Key words: patient discharge, pediatric, caregiver, moderate sedation. Assessing a child for sleep apnea Key words: pediatric, obstructive sleep apnea, moderate sedation. Using a frailty index to assess surgical patients Key words: frailty, surgical complications, older adult, Braden Scale, Fried Frailty Criteria. Determining the need for IV access in patients undergoing local anesthesia Key words: local anesthesia, IV, preoperative assessment. PMID- 27472978 TI - Evidence appraisal of Salzwedel C, Bartz HJ, Kuhnelt I, et al. The effect of a checklist on the quality of post-anaesthesia patient handover: a randomized controlled trial.: Int J Qual Health Care. 2013;25(2):176-181. PMID- 27472979 TI - Two Wrongs Don't Make a Right (Kidney). PMID- 27472980 TI - Impact of antiseptics on Chlamydia trachomatis growth. AB - Bacterial vaginosis is a frequent dysbiosis, where the normal lactobacillus dominated flora is replaced by an anaerob/aerob polymicrobial flora. Bacterial vaginosis increases the risk of acquiring sexually transmitted infections (STI) including the most frequent Chlamydia trachomatis infections. Intravaginal antiseptics are part of the bacterial vaginosis treatment, and ideally they should also inhibit the bacterial vaginosis-related STI. Therefore, we tested the antichlamydial activity of four antiseptics: iodine aqueous solution, povidone iodine, chlorhexidine and borax. First, we measured the impact of antiseptics on the viability of the HeLa cervical epithelial cells, and calculated the maximum nontoxic concentrations. Next, we infected the cells with C. trachomatis preincubated for 1 h with the particular antiseptic. The chlamydial growth was measured by direct quantitative PCR (qPCR) of the infected cells. The minimal inhibitory concentrations (MIC) of chlorhexidine and povidone-iodine were 3.91 and 97 MUg ml(-1) respectively; however, the MIC of chlorhexidine was close to its maximum nontoxic concentration. The iodine aqueous solution and the borax showed no antichlamydial activity. Our in vitro studies showed that chlorhexidine and particularly povidone-iodine are potentially able to limit the bacterial vaginosis-related C. trachomatis infection. SIGNIFICANCE AND IMPACT OF THE STUDY: We measured the antichlamydial effects of various antiseptics. These antiseptics are being used for the treatment of bacterial vaginosis, but their effect on the bacterial vaginosis-related sexually transmitted infections, particularly the most frequent Chlamydia trachomatis (C. trachomatis) infections has not been investigated. We showed that povidone-iodine (Betadine) inhibited the chlamydial growth in concentrations that was not toxic to the epithelial cells. We concluded that due to its additional antichlamydial effect, povidone-iodine could be a preferable antiseptic in bacterial vaginosis treatment. PMID- 27472981 TI - An often neglected area in crooked nose: middle turbinate pneumatization. AB - INTRODUCTION: Crooked or deviated nose is a deviation of the nose from the straight vertical position of the face. Extensive pneumatization of the middle turbinate, also called concha bullosa or bullous middle turbinate (BMT) is known to be one of the possible etiologic factors in nasal obstruction, recurrent sinusitis, and headache. There is no study concerning a link between BMT and crooked nose. OBJECTIVE: To investigate the association between crooked nose and the presence of a BMT. METHODS: A total of 199 patients who underwent open septorhinoplasty were retrospectively analyzed. Preoperative paranasal Computerized Tomography (CT) findings, preoperative photodocumentation, and anterior rhinoscopic examination findings were documented. Of the 199 patients, 169 were found to meet the criteria and were included in the study. CT scans were examined to note the presence of BMT, inferior turbinate hypertrophy, and septum deviation (SD). SDs and crooked noses were classified. RESULTS: Ninety-four of 169 patients (56%) presented a crooked nose deformity and seventy-five of 169 patients (44%) presented a straight nose. While 49 (52%) crooked nose patients had a bulbous and extensive BMT, 20 patients with straight nose (26.6%) had a BMT. A statistically significant relationship was found between the presence of crooked nose and BMT, regardless of the side of the disease (p=0.011). CONCLUSION: This study revealed a link between crooked nose and BMT. PMID- 27472982 TI - Medical adherence to intranasal corticosteroids in adult patients. AB - INTRODUCTION: The adherence to medical treatment in allergic rhinitis is poorly evaluated in clinical practice. OBJECTIVES: To evaluate adherence to intranasal corticosteroids in the treatment of allergic rhinitis patients. METHODS: This prospective study was conducted on adult patients who were admitted to the outpatient clinic of the otolaryngology department tertiary hospital. Patients diagnosed with moderate to severe persistent AR and who had not used any nasal sprays were enrolled in the study. The patients were provided with mometasone furoate nasal sprays. On the 30th day, all participants filled out a questionnaire regarding the factors that may have influenced their adherence to the treatment. Afterwards, each patient filled out the Turkish-language-validated Morisky Medical Adherence Scale (MMAS-8) form. Each factor that may have affected adherence to the prescribed medication was evaluated according to the MMAS-8 score and all variables were analyzed statistically. RESULTS: Fifty-nine adult patients with a mean age of 32.5 years (range 21-52 years) were included in the study. The mean overall MMAS-8 score was 3.64. Two factors were significantly related to low adherence: number of dependent children (p=0.001) and benefit from the medication (p=0.001). In addition, patients with higher education levels seemed to be more adherent than the rest of the group. CONCLUSION: Clinicians must keep in mind the factors related to non-adherence in order to achieve better treatment outcomes. Therefore, based on our results, patients must be informed that medications should be taken properly regardless of the benefit, and the treatment should be scheduled with respect to daily activities, particularly for patients caring for more than two children. PMID- 27472983 TI - Treatment of large persistent tracheoesophageal peristomal fistulas using silicon rings. AB - INTRODUCTION: Tracheoesophageal peristomal fistulae can often be solved by reducing the size of the fistula or replacing the prosthesis; however, even with conservative techniques, leakage around the fistula may continue in total laryngectomy patients. Also, several techniques have been developed to overcome this problem, including injections around the fistula, fistula closure with local flaps, myofascial flaps, or free flaps and fistula closure using a septal perforation silicon button. OBJECTIVE: To present the results of the application of silicon ring expanding the voice prosthesis in patients with large and persistent peri-prosthetic fistula. METHODS: A voice prosthesis was fitted to 42 patients after total laryngectomy. Leakage was detected around the prosthesis in 18 of these 42 patients. Four patients demonstrated improvement with conservative methods. Eight of 18 patients who couldn't be cured with conservative methods were treated by using primary suture closure and 4 patients were treated with local flaps. As silicon ring was applied as a primary treatment in the 2 remaining patients and also, applied to 2 patients who had recurrence after suture repair and to 2 patients who had recurrence after local flap implementation. Silicon rings were used in a total of 6 patients due to the secondary trachea-esophageal fistula. Patients were treated with provox-1 initially and later with provox-2. At the time of leakage around the fistula, 6 patients had provox-2. RESULTS: Fistulae were treated successfully in 6 patients, and effective speech of patients was preserved. Patients experienced no adaptation problem. Prosthesis changing time was not different between silicon rings expanded and normal prosthesis applied patients. Silicon ring combined voice prosthesis was used 26 times; there was no recurrence in fistula complication during 29+/-6 months follow up. CONCLUSION: Silicon rings for modified expanded voice prosthesis seems to be an effective treatment for persistent peri-prosthetic leakage, for both, fistula closure and preserving the patients speech. PMID- 27472984 TI - The importance of clinical monitoring for compliance with Continuous Positive Airway Pressure. AB - INTRODUCTION: Obstructive sleep apnea syndrome is currently a public health problem of great importance. When misdiagnosed or improperly treated, it can lead to serious consequences on patients' quality of life. The gold standard treatment for cases of obstructive sleep apnea syndrome, especially in mild to severe and symptomatic cases, is continuous positive airway pressure therapy. Compliance with continuous positive airway pressure therapy is directly dependent on the active participation of the patient, which can be influenced by several factors. OBJECTIVE: The objective of this study is to describe the factors related to compliance with continuous positive airway pressure therapy, and to analyze which associated factors directly influence the efficiency of the treatment. METHODS: Patients who received continuous positive airway pressure therapy through the Municipal Health Department of the city of Ribeirao Preto were recruited. A structured questionnaire was administered to the patients. Compliance with continuous positive airway pressure therapy was assessed by average hours of continuous positive airway pressure therapy usage per night. Patients with good compliance (patients using continuous positive airway pressure therapy >=4h/night) were compared to those with poor compliance (patients using <4h/night). RESULTS: 138 patients were analyzed: 77 (55.8%) were considered compliant while 61 (44.2%) were non-compliant. The comparison between the two groups showed that regular monitoring by a specialist considerably improved compliance with continuous positive airway pressure therapy (odds ratio, OR=2.62). CONCLUSION: Compliance with continuous positive airway pressure therapy is related to educational components, which can be enhanced with continuous and individualized care to patients with obstructive sleep apnea syndrome. PMID- 27472985 TI - Diphenyl diselenide supplementation in infected mice by Toxoplasma gondii: Protective effect on behavior, neuromodulation and oxidative stress caused by disease. AB - The aim of this study was to evaluate the effect of subcutaneous administration of diphenyl diselenide (PhSe)2 on animal behavior and activities of acetylcholinesterase (AChE), adenylate kinase (AK), and creatine kinase (CK) in the brain of mice infected by Toxoplasma gondii. In addition, thiobarbituric acid reactive species (TBARS) levels and glutathione (GR, GPx and GST) activity were also evaluated. For the study, 40 female mice were divided into four groups of 10 animals each: group A (uninfected and untreated), group B (uninfected and treated with (PhSe)2), group C (infected and untreated) and group D (infected and treated with (PhSe)2). The mice were inoculated with 50 cysts of the ME49 strain of T. gondii. After infection the animals of the groups B and D were treated on days 1 and 20 post-infection (PI) with 5.0 MUmol/kg of (PhSe)2 subcutaneously. Behavioral tests were conducted on days 29 PI to assess memory loss (object recognition), anxiety (elevated plus maze), locomotor and exploratory activity (Open Field) and it was found out that infected and untreated animals (group C) had developed anxiety and memory impairment, and the (PhSe)2 treatment did not reverse these behavioral changes on infected animals treated with (PhSe)2 (group D). The results showed an increase on AChE activity (P < 0.01) in the brain of infected and untreated animals (group C) compared to the uninfected and untreated animals (group A). The AK and CK activities decreased in infected and untreated animals (group C) compared to the uninfected and untreated animals (group A) (P < 0.01), however the (PhSe)2 treatment did not reverse these alterations. Infected and untreated animals (group C) showed increased TBARS levels and GR activity, and decreased GPx and GST activities when compared to uninfected and untreated animals (group A). Infected animals treated with (PhSe)2 (group D) decreased TBARS levels and GR activity, while increased GST activity when compared to infected and untreated animals (group C). It was concluded that (PhSe)2 showed antioxidant activity, but the dose used had no anti-inflammatory effect and failed to reverse the behavioral changes caused by the parasite. PMID- 27472987 TI - Ten pearls every dermatologist should know about the appropriate use of relaxers. AB - Chemical relaxers are products marketed to straighten the hair and have been principally used by African Americans since the early twentieth century. They contain alkaline agents that break and reform hydrogen and disulfide bonds, leaving hair permanently straightened. Relaxers cause loss of tensile strength and increased fragility of the hair shaft that lead to increased risk of hair breakage and thinning. When used improperly, they can also cause local irritant contact dermatitis and chemical burns to the scalp and hairline that can potentially lead to a scarring alopecia. After interviewing several cosmetology educators in the field and reviewing the literature, we generated a list of ten pearls that all dermatologists should know about relaxers to provide professional guidance to their patients. PMID- 27472986 TI - Infant hair cortisol: associations with salivary cortisol and environmental context. AB - Early chronic stress has enduring implications for physical and mental health outcomes. Hair cortisol concentration (HCC) has emerged as a marker of cumulative cortisol exposure, yet HCC in infants is not well understood. We examined how infant HCC relates to widely used basal salivary cortisol measures, maternal HCC, and environmental context in 111 infants assessed at 6 and 12 months of age. Maternal HCC at 6 and 12 months was correlated with infant HCC at 12 months. At 12 months, infant HCC was positively associated with waking salivary cortisol concentration (SCC), evening SCC, and area under the curve (AUC), but was independent of diurnal slope. Breastfeeding was associated with lower HCC, whereas increased sleep disruption was related to flatter slope. Reduced nighttime sleep duration was related both to higher HCC and to flatter slope. A person-focused analysis indicated that the combination of high HCC and flattened slope was associated with more environmental risks, highlighting the importance of investigating the interplay between HCC and diurnal cortisol slope. Results support the validity of HCC as a marker of cumulative cortisol exposure in infancy, while emphasizing the value of including multiple cortisol measures assessing distinct aspects of hypothalamic-pituitary-adrenal (HPA) function. PMID- 27472989 TI - Point of Care Ultrasound: A WFUMB Position Paper. AB - Over the last decade, the use of portable ultrasound scanners has enhanced the concept of point of care ultrasound (PoC-US), namely, "ultrasound performed at the bedside and interpreted directly by the treating clinician." PoC-US is not a replacement for comprehensive ultrasound, but rather allows physicians immediate access to clinical imaging for rapid and direct solutions. PoC-US has already revolutionized everyday clinical practice, and it is believed that it will dramatically change how ultrasound is applied in daily practice. However, its use and teaching are different from continent to continent and from country to country. This World Federation for Ultrasound in Medicine and Biology position paper discusses the current status and future perspectives of PoC-US. Particular attention is given to the different uses of PoC-US and its clinical significance, including within emergency and critical care medicine, cardiology, anesthesiology, rheumatology, obstetrics, neonatology, gynecology, gastroenterology and many other applications. In the future, PoC-US will be more diverse than ever and be included in medical student training. PMID- 27472988 TI - Clinical efficacy of adalimumab in Crohn's disease: a real practice observational study in Japan. AB - BACKGROUND: There are few reports of the efficacy of adalimumab (ADA) for clinical remission and preventing postoperative recurrence in Crohn's disease (CD) in Asian real practice settings. We conducted a Japanese multicenter retrospective observational study. METHODS: We evaluated patients with CD who were treated with ADA at 11 medical institutions in Japan to investigate the clinical efficacy of remission up to 52 weeks and the associated factors to achieve remission with a CD Activity Index (CDAI) < 150. The effects of preventing postoperative recurrence were also evaluated. RESULTS: In 62 patients, the remission rates were 33.9, 74.2, 75.8, 77.4, and 66.1 % at 0, 4, 12, 26, and 52 weeks, respectively. Although 10 patients discontinued treatment due to primary nonresponse, secondary nonresponse, or adverse events, the ongoing treatment rate at 52 weeks was 83.9 %. Comparison of remission and non-remission on univariate analysis identified colonic type and baseline CDAI value as significant associated factors (P < 0.05). In 16 patients who received ADA to prevent postoperative recurrence, the clinical remission maintenance rate was 93.8 % and the mucosal healing rate was 64.3 % during a mean postoperative follow up period of 32.3 months. CONCLUSIONS: ADA effectively induced remission and prevented postoperative recurrence in patients with CD in a real practice setting. PMID- 27472990 TI - The latent structure of Acute Stress Disorder symptoms in trauma-exposed children and adolescents. AB - BACKGROUND: The revision of Acute Stress Disorder (ASD) in the DSM-5 (DSM-5, 2013) proposes a cluster-free model of ASD symptoms in both adults and youth. Published evaluations of competing models of ASD clustering in youth have rarely been examined. METHODS: We used Confirmatory Factor Analysis (combined with multigroup invariance tests) to explore the latent structure of ASD symptoms in a trauma-exposed sample of children and young people (N = 594). The DSM-5 structure was compared with the previous DSM-IV conceptualization (4-factor), and two alternative models proposed in the literature (3-factor; 5-factor). Model fit was examined using goodness-of-fit indices. We also established DSM-5 ASD prevalence rates relative to DSM-IV ASD, and the ability of these models to classify children impaired by their symptoms. RESULTS: Based on both the Bayesian Information Criterion, the interfactor correlations and invariance testing, the 3 factor model best accounted for the profile of ASD symptoms. DSM-5 ASD led to slightly higher prevalence rates than DSM-IV ASD and performed similarly to DSM IV with respect to categorising children impaired by their symptoms. Modifying the DSM-5 ASD algorithm to a 3+ or 4+ symptom requirement was the strongest predictor of impairment. CONCLUSIONS: These findings suggest that a uni-factorial general-distress model is not the optimal model of capturing the latent structure of ASD symptom profiles in youth and that modifying the current DSM-5 9+ symptom algorithm could potentially lead to a more developmentally sensitive conceptualization. PMID- 27472993 TI - Methadone analgesia in the critically ill. PMID- 27472991 TI - Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan. AB - BACKGROUND: Little evidence supports anticoagulant therapy as effective adjuvant therapy to reduce mortality overall in sepsis. However, several studies suggest that anticoagulant therapy may reduce mortality in specific patients. This study aimed to identify a subset of patients with high benefit profiles for anticoagulant therapy against sepsis. METHODS: This post hoc subgroup analysis of a nationwide multicentre retrospective registry was conducted in 42 intensive care units in Japan. Consecutive adult patients with sepsis were included. Treatment effects of anticoagulants, e.g. antithrombin, recombinant thrombomodulin, heparin, and protease inhibitors, were evaluated by stratifying patients according to disseminated intravascular coagulation (DIC) and Sequential Organ Failure Assessment (SOFA) score. Intervention effects of anticoagulant therapy on in-hospital mortality and bleeding complications were analysed using Cox regression analysis stratified by propensity scores. RESULTS: Participants comprised 2663 consecutive patients with sepsis; 1247 patients received anticoagulants and 1416 received none. After adjustment for imbalances, anticoagulant administration was significantly associated with reduced mortality only in subsets of patients diagnosed with DIC, whereas similar mortality rates were observed in non-DIC subsets with anticoagulant therapy. Favourable associations between anticoagulant therapy and mortality were observed only in the high-risk subset (SOFA score 13-17; adjusted hazard ratio 0.601; 95 % confidence interval 0.451, 0.800) but not in the subsets of patients with sepsis with low to moderate risk. Although the differences were not statistically significant, there was a consistent tendency towards an increase in bleeding related transfusions in all SOFA score subsets. CONCLUSIONS: The analysis of this large database indicates anticoagulant therapy may be associated with a survival benefit in patients with sepsis-induced coagulopathy and/or very severe disease. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000012543 ). Registered on 10 December 2013. PMID- 27472994 TI - Measurement properties of instruments evaluating self-care and related concepts in people with chronic obstructive pulmonary disease: A systematic review. AB - The use of valid and reliable instruments for assessing self-care is crucial for the evaluation of chronic obstructive pulmonary disease (COPD) management programs. The aim of this review is to evaluate the measurement properties and theoretical foundations of instruments for assessing self-care and related concepts in people with COPD. A systematic review was conducted of articles describing the development and validation of self-care instruments. The methodological quality of the measurement properties was assessed using the COSMIN checklist. Ten studies were included evaluating five instruments: three for assessing self-care and self-management and two for assessing self-efficacy. The COPD Self-Efficacy Scale was the most studied instrument, but due to poor study methodological quality, evidence about its measurement properties is inconclusive. Evidence from the COPD Self-Management Scale is more promising, but only one study tested its properties. Due to inconclusive evidence of their measurement properties, no instrument can be recommended for clinical use. PMID- 27472995 TI - A case of papillary tumor of the pineal region with a long clinical history: molecular characterization and therapeutic consideration with review of the literature. PMID- 27472992 TI - EQ-5D in Central and Eastern Europe: 2000-2015. AB - OBJECTIVE: Cost per quality-adjusted life year data are required for reimbursement decisions in many Central and Eastern European (CEE) countries. EQ 5D is by far the most commonly used instrument to generate utility values in CEE. This study aims to systematically review the literature on EQ-5D from eight CEE countries. METHODS: An electronic database search was performed up to 1 July 2015 to identify original EQ-5D studies from the countries of interest. We analysed the use of EQ-5D with respect to clinical areas, methodological rigor, population norms and value sets. RESULTS: We identified 143 studies providing 152 country specific results with a total sample size of 81,619: Austria (n = 11), Bulgaria (n = 6), Czech Republic (n = 18), Hungary (n = 47), Poland (n = 51), Romania (n = 2), Slovakia (n = 3) and Slovenia (n = 14). Cardiovascular (21 %), neurologic (17 %), musculoskeletal (15 %) and endocrine, nutritional and metabolic diseases (13 %) were the most frequently studied clinical areas. Overall, 112 (78 %) of the studies reported EQ VAS results and 86 (60 %) EQ-5D index scores, of which 27 (31 %) did not specify the applied tariff. Hungary, Poland and Slovenia have population norms. Poland and Slovenia also have a national value set. CONCLUSIONS: Increasing use of EQ-5D is observed throughout CEE. The spread of health technology assessment activities in countries seems to be reflected in the number of EQ-5D studies. However, improvement in informed use and methodological quality of reporting is needed. In jurisdictions where no national value set is available, in order to ensure comparability we recommend to apply the most frequently used UK tariff. Regional collaboration between CEE countries should be strengthened. PMID- 27472997 TI - [Perinatal palliative care in France: Who? Why? How?]. AB - Severe congenital or morphologic anomalies are one of the main causes of infant morbidity and mortality. Some of these prenatally-diagnosed pathologies are incompatible with postnatal survival. In this context, some women choose to continue with pregnancy. Subsequently, perinatal palliative care seems to be a constructive answer to offer in such situations. At international level, this is a new clinical practice where decision dilemmas exist (prognostic uncertainty, prolonged survival, and attachment to the infant). It might be necessary to identify the factors that can affect these ethical tensions. With no national data, we explored the perceptions and professional practices that may influence parental requests for continuing with pregnancy, despite the uncertainty corresponding to the postnatal condition of a newborn with a lethal pathology. This exploration aims to question and debate current norms, especially in medical termination of pregnancy, discussing the dilemmas and divergences that affect decision-making and professional practices in neonatal palliative care. Reflection is also necessary on how to find an answer that can make sense within a request for continuation of pregnancy, despite the uncertainty inherent in the postnatal period in case of live birth of a newborn with a lethal abnormality. PMID- 27472996 TI - Predictors of Breastfeeding Confidence in the Early Postpartum Period. AB - OBJECTIVE: To identify factors related to breastfeeding self-efficacy, an important psychological variable in sustained breastfeeding, in the postpartum period. DESIGN: Descriptive correlational study. SETTING: Data were collected on the mother-baby unit of an academic medical center in the Northeastern United States. PARTICIPANTS: This convenience sample (N = 107) was composed of women in the first 4 days postpartum and included nearly equal numbers of primiparas (49.5%, n = 53) and multiparas (50.5%, n = 54). METHODS: Participants completed the Perceived Stress Scale-10, Birth Satisfaction Scale-Revised, Breastfeeding Self-Efficacy Scale-Short Form, and a demographic questionnaire. Descriptive and inferential statistics were used to analyze the data. RESULTS: Breastfeeding self efficacy was positively correlated with birth satisfaction, number of children, partner support of breastfeeding, intention to breastfeed, intention to breastfeed exclusively for 6 months, and feeling prepared for birth. Breastfeeding self-efficacy was greater in women with previous breastfeeding experience and lower in mothers of newborns who received in-hospital formula supplementation. A standard multiple linear regression explained approximately 38.5% of the variance in self-efficacy scores. CONCLUSION: Nurses can apply our findings to inform strategies to increase breastfeeding confidence, such as promoting birth satisfaction, involving partners in breastfeeding education, and limiting the use of in-hospital formula supplementation. PMID- 27472998 TI - The obligate respiratory supercomplex from Actinobacteria. AB - Actinobacteria are closely linked to human life as industrial producers of bioactive molecules and as human pathogens. Respiratory cytochrome bcc complex and cytochrome aa3 oxidase are key components of their aerobic energy metabolism. They form a supercomplex in the actinobacterial species Corynebacterium glutamicum. With comprehensive bioinformatics and phylogenetic analysis we show that genes for cyt bcc-aa3 supercomplex are characteristic for Actinobacteria (Actinobacteria and Acidimicrobiia, except the anaerobic orders Actinomycetales and Bifidobacteriales). An obligatory supercomplex is likely, due to the lack of genes encoding alternative electron transfer partners such as mono-heme cyt c. Instead, subunit QcrC of bcc complex, here classified as short di-heme cyt c, will provide the exclusive electron transfer link between the complexes as in C. glutamicum. Purified to high homogeneity, the C. glutamicum bcc-aa3 supercomplex contained all subunits and cofactors as analyzed by SDS-PAGE, BN-PAGE, absorption and EPR spectroscopy. Highly uniform supercomplex particles in electron microscopy analysis support a distinct structural composition. The supercomplex possesses a dimeric stoichiometry with a ratio of a-type, b-type and c-type hemes close to 1:1:1. Redox titrations revealed a low potential bcc complex (Em(ISP)=+160mV, Em(bL)=-291mV, Em(bH)=-163mV, Em(cc)=+100mV) fined-tuned for oxidation of menaquinol and a mixed potential aa3 oxidase (Em(CuA)=+150mV, Em(a/a3)=+143/+317mV) mediating between low and high redox potential to accomplish dioxygen reduction. The generated molecular model supports a stable assembled supercomplex with defined architecture which permits energetically efficient coupling of menaquinol oxidation and dioxygen reduction in one supramolecular entity. PMID- 27472999 TI - Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management. AB - Genitourinary syndrome of menopause, a new term for a condition more renowned as atrophic vaginitis, is a hypoestrogenic condition with external genital, urological, and sexual implications that affects >50% of postmenopausal women. Due to sexual embarrassment and the sensitive nature of discussing symptoms, genitourinary syndrome of menopause is greatly underdiagnosed. The most up-to date literature pertaining to clinical manifestations, pathophysiology, etiology, evaluation, and management of genitourinary syndrome of menopause is comprehensively reviewed. Early detection and individually tailored pharmacologic (eg, estrogen therapy, selective estrogen receptor modulator, synthetic steroid, oxytocin, and dehydroepiandrosterone) and/or nonpharmacologic (eg, laser therapies, moisturizers and lubricants, homeopathic remedies, and lifestyle modifications) treatment is paramount for not only improving quality of life but also for preventing exacerbation of symptoms in women with this condition. PMID- 27473000 TI - Medical evacuation of the uterus and subsequent preterm labor. PMID- 27473001 TI - Reply. PMID- 27473003 TI - Accreta placentation: a systematic review of prenatal ultrasound imaging and grading of villous invasiveness. AB - BACKGROUND: Determining the depth of villous invasiveness before delivery is pivotal in planning individual management of placenta accreta. We have evaluated the value of various ultrasound signs proposed in the international literature for the prenatal diagnosis of accreta placentation and assessment of the depth of villous invasiveness. OBJECTIVE: We undertook a PubMed and MEDLINE search of the relevant studies published from the first prenatal ultrasound description of placenta accreta in 1982 through March 30, 2016, using key words "placenta accreta," "placenta increta," "placenta percreta," "abnormally invasive placenta," "morbidly adherent placenta," and "placenta adhesive disorder" as related to "sonography," "ultrasound diagnosis," "prenatal diagnosis," "gray scale imaging," "3-dimensional ultrasound", and "color Doppler imaging." STUDY DESIGN: The primary eligibility criteria were articles that correlated prenatal ultrasound imaging with pregnancy outcome. A total of 84 studies, including 31 case reports describing 38 cases of placenta accreta and 53 series describing 1078 cases were analyzed. Placenta accreta was subdivided into placenta creta to describe superficially adherent placentation and placenta increta and placenta percreta to describe invasive placentation. RESULTS: Of the 53 study series, 23 did not provide data on the depth of villous myometrial invasion on ultrasound imaging or at delivery. Detailed correlations between ultrasound findings and placenta accreta grading were found in 72 cases. A loss of clear zone (62.1%) and the presence of bridging vessels (71.4%) were the most common ultrasound signs in cases of placenta creta. In placenta increta, a loss of clear zone (84.6%) and subplacental hypervascularity (60%) were the most common ultrasound signs, whereas placental lacunae (82.4%) and subplacental hypervascularity (54.5%) were the most common ultrasound signs in placenta percreta. No ultrasound sign or a combination of ultrasound signs were specific of the depth of accreta placentation. CONCLUSION: The wide heterogeneity in terminology used to describe the grades of accreta placentation and differences in study design limits the evaluation of the accuracy of ultrasound imaging in the screening and diagnosis of placenta accreta. This review emphasizes the need for further prospective studies using a standardized evidence-based approach including a systematic correlation between ultrasound signs of placenta accreta and detailed clinical and pathologic examinations at delivery. PMID- 27473002 TI - Use of antimullerian hormone to predict the menopausal transition in HIV-infected women. AB - BACKGROUND: HIV infection has been associated with early menopausal onset, which may have adverse long-term health consequences. Antimullerian hormone, a biomarker of ovarian reserve and gonadal aging, is reduced in HIV-infected women. OBJECTIVE: We sought to assess the relationship of antimullerian hormone to age of menopause onset in HIV-infected women. STUDY DESIGN: We used antimullerian hormone levels measured in plasma in 2461 HIV-infected participants from the Women's Interagency HIV Study to model the age at final menstrual period. Multivariable normal mixture models for censored data were used to identify factors associated with age at final menstrual period. RESULTS: Higher antimullerian hormone at age 40 years was associated with later age at final menstrual period, even after multivariable adjustment for smoking, CD4 cell count, plasma HIV RNA, hepatitis C infection, and history of clinical AIDS. Each doubling of antimullerian hormone was associated with a 1.5-year increase in the age at final menstrual period. Median age at final menstrual period ranged from 45 years for those in the 10th percentile of antimullerian hormone to 52 years for those in the 90th percentile. Other factors independently associated with earlier age at final menstrual period included smoking, hepatitis C infection, higher HIV RNA levels, and history of clinical AIDS. CONCLUSION: Antimullerian hormone is highly predictive of age at final menstrual period in HIV-infected women. Measuring antimullerian hormone in HIV-infected women may enable clinicians to predict risk of early menopause, and potentially implement individualized treatment plans to prevent menopause-related comorbidities and to aid in interpretation of symptoms. PMID- 27473004 TI - Antidepressant efficacy of high and low frequency transcranial magnetic stimulation in the FSL/FRL genetic rat model of depression. AB - Repetitive Magnetic Stimulation (rTMS) has appeared to be a potential non invasive antidepressant method, which implies non-convulsive focal stimulation of the brain through a time varying magnetic field. The antidepressant potential of rTMS has been supported by animal studies showing a number of interesting similarities between magnetic stimulation and electroconvulsive stimulation (ECS). Despite these positive results, this method still contains many unknown issues. Importantly, there are fundamental uncertainties concerning the optimal combination of stimulus parameters (frequency, intensity, duration, and number of pulses) to obtain an antidepressant effect. Therefore, the present study aimed to qualify the choice of rTMS stimulus frequency in a well-validated genetic animal model of depression, the FSL/FRL rats. We compared the antidepressant effect of low frequency, high frequency rTMS and ECS to sham treatment in FRL and FSL rats using 6 parallel groups. We used the Forced Swim Test and the Open Field Test to screen the depression-like state in rats. We found that both the high frequency and the low frequency rTMS resulted in a significant antidepressant effect. However, this effect was inferior to the effect of ECS. The low frequency and high frequency groups, which received the same total impulse load and stimulus intensity, did not differ with respect to antidepressant efficacy in this study. In conclusion, this study provides robust evidence that both rTMS interventions are efficacious, although not as efficient as ECS. PMID- 27473006 TI - Two Creams, Three Sugars. PMID- 27473005 TI - The CareFirst Patient-Centered Medical Home Program: Cost and Utilization Effects in Its First Three Years. AB - BACKGROUND: Enhanced primary care models have diffused slowly and shown uneven results. Because their structural features are costly and challenging for small practices to implement, they offer modest rewards for improved performance, and improvement takes time. OBJECTIVE: To test whether a patient-centered medical home (PCMH) model that significantly rewarded cost savings and accommodated small primary care practices was associated with lower spending, fewer hospital admissions, and fewer emergency room visits. DESIGN: We compared medical care expenditures and utilization among adults who participated in the PCMH program to adults who did not participate. We computed difference-in-difference estimates using two-part multivariate generalized linear models for expenditures and negative binomial models for utilization. Control variables included patient demographics, county, chronic condition indicators, and illness severity. PARTICIPANTS: A total of 1,433,297 adults aged 18-64 years, residing in Maryland, Virginia, and the District of Columbia, and insured by CareFirst for at least 3 consecutive months between 2010 and 2013. INTERVENTION: CareFirst implemented enhanced fee-for-service payments to the practices, offered a large retrospective bonus if annual cost and quality targets were exceeded, and provided information and care coordination support. MEASURES: Outcomes were quarterly claims expenditures per member for all covered services, inpatient care, emergency care, and prescription drugs, and quarterly inpatient admissions and emergency room visits. RESULTS: By the third intervention year, annual adjusted total claims payments were $109 per participating member (95 % CI: -$192, -$27), or 2.8 % lower than before the program and compared to those who did not participate. Forty-two percent of the overall decline in spending was explained by lower inpatient care, emergency care, and prescription drug spending. Much of the reduction in inpatient and emergency spending was explained by lower utilization of services. CONCLUSIONS: A PCMH model that does not require practices to make infrastructure investments and that rewards cost savings can reduce spending and utilization. PMID- 27473007 TI - Capsule Commentary on Raghavan et al., Incident Type 2 Diabetes Risk is Influenced by Obesity and Diabetes in Social Contacts: A Social Network Analysis. PMID- 27473008 TI - Single incision laparoscopic 90 % pancreatectomy for the treatment of persistent hyperinsulinemic hypoglycemia of infancy. AB - Single incision laparoscopic surgery as a surgical approach in treatment of pancreatic disease has recently been reported in adults. However, its application in persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in children is limited. In this article, we report single incision laparoscopic 90 % pancreatectomy for the treatment of persistent hyperinsulinemic hypoglycemia of infancy. Between July 2011 and February 2015, the single incision laparoscopic 90 % pancreatectomy was performed in three children with PHHI. All patients underwent (18)F-FDOPA PET/CT before the surgeries. The scans showed diffuse physiologic (18)F-FDOPA activity in entire pancreas. All patients were followed up. The levels of blood sugar and insulin were recorded postoperatively. The time required for surgery was 120-230 min, and blood loss was minimal. The hospital stay was 6 days. The duration of postoperative abdominal drainage was 4-5 days. The levels of fasting blood glucose after surgery were higher than those before surgery (4.38-8.9 vs. 0.54-1.8 mmol/L). The levels of fasting insulin after surgery were lower than those before surgery (2.4-5.5 vs. 14-33.3 uU/ml). The duration of follow-up was 4-46 months. During follow-up, the levels of blood glucose and insulin were normal in three patients. There was no recurrence of hypoglycemia after operation in all patients. Single incision laparoscopic 90 % pancreatectomy for children with PHHI is feasible and safe in well-selected cases in the experienced centers. PMID- 27473009 TI - Anaplastic histology Wilms' tumors registered to the Japan Wilms' Tumor Study Group are less aggressive than that in the National Wilms' Tumor Study 5. AB - PURPOSE: To evaluate the clinical features and treatment results of anaplastic histology (AH) Wilms' tumor (WT) patients registered in the Japan Wilms' Tumor Study (JWiTS) group to elucidate the clinical characteristics of AH in the Japanese population. PATIENTS AND METHODS: Of 344 WT patients who were enrolled in JWiTS between 1995 and 2013, 17 had AH. Treatment using the JWiTS protocols was similar to the fifth National Wilms' Tumor Study 5 (NWTS-5) protocols. Clinical characteristics and mutation status of TP53 gene were evaluated and compared with those in NWST-5 study. RESULTS: AH incidences in JWiTS were 4.9 %, lower than that in NWTS-5. Seven tumors had focal AH and 10 had diffuse AH. Clinical stages of AH patients were stage I in seven, stage II in three, stage III in five, stage IV in one and unknown in one. Four-year event-free survival and overall survival rates were 90.9 and 86.7 %, respectively. Two patients with diffuse AH and none with focal AH had TP53 mutation. CONCLUSION: Japanese patients presented with higher incidence, earlier stages and may have better outcomes than American patients, indicating a possible biological heterogeneity of AH WT. Further analysis is necessary to elucidate the different characteristic of AH WT between Japanese and American populations. PMID- 27473010 TI - Prophylactic efficacy of enteral miconazole administration for neonatal intestinal perforation and its potential mechanism. AB - PURPOSE: Intestinal perforation (IP) is a fatal complication in extremely low birth weight infants (ELBWI). We started administrating enteral miconazole (MCZ) to ELBWI in 2002. Since then, the incidence of IP has significantly decreased. The aim of this study was to elucidate the prophylactic effect of MCZ for the treatment of neonatal IP, and to establish a new prophylactic concept for this disease. METHODS: In in vivo experiments, the effects of MCZ were examined histopathologically using a mouse model of intestinal ischemia. In in vitro experiments, the cytoprotective effect of MCZ against hypoxia was evaluated using Caco-2 intestinal cells, and its anti-inflammatory potential using a co-culture model of Caco-2 and HL60 cells. RESULTS: MCZ showed a tissue protective effect against intestinal ischemia. MCZ reduced high mobility group-box 1 (HMGB1) release in Caco-2 cells under hypoxic stress and attenuated the potential to activate co-cultured HL60 leukocytes with Caco-2 cells by suppressing interleukin 8 (IL-8). CONCLUSION: MCZ may have preventive roles in the clinical management of IP in ELBWI by the suppression of IL-8 and HMGB-1. PMID- 27473011 TI - Improved outcomes after technical modifications in tubularized incised plate urethroplasty for mid-shaft and proximal hypospadias. AB - PURPOSE: To investigate and compare the outcomes after tubularized incised plate (TIP) urethroplasty in mid-shaft and proximal hypospadias using a standard and a modified technique. METHODS: We conducted a retrospective study in 104 consecutive children who underwent mid-shaft or proximal TIP repairs from Jan 2007 to Sept 2015. Patients in Cohort One had dorsal dartos (DD) neourethral coverage while patients in Cohort Two had either de-epithelialized split preputial (DESP) or tunica vaginalis (TV) flap coverage. TV flap was used only when DESP flap was not sufficient to cover the neourethra. RESULTS: There were 52 patients each in Cohort One (DD, n = 52) and Cohort Two (DESP, n = 38; TV, n = 14) with no difference in ratio of mid-shaft/proximal between the two cohorts. At a median follow-up of 28 months, 36 patients (34.6 %) developed 47 complications including fistula (n = 19; 18.3 %) and neourethral dehiscence (n = 4; 3.8 %). Cohort One patients had significantly more fistula (28.8 vs 7.7 %; p = 0.005) and neourethral dehiscence (7.7 vs 0 %; p = 0.04) than Cohort Two. There was no difference between the two cohorts in the complication rates of meatal stenosis, recurrent ventral curvature and neourethral stricture. CONCLUSIONS: Both DESP and TV flap appear to be superior to DD in preventing fistula and neourethral dehiscence in non-distal TIP repairs. PMID- 27473012 TI - Identification of a secretory phospholipase A2 from Papaver somniferum L. that transforms membrane phospholipids. AB - The full-length sequence of a new secretory phospholipase A2 was identified in opium poppy seedlings (Papaver somniferum L.). The cDNA of poppy phospholipase A2, denoted as pspla2, encodes a protein of 159 amino acids with a 31 amino acid long signal peptide at the N-terminus. PsPLA2 contains a PLA2 signature domain (PA2c), including the Ca(2+)-binding loop (YGKYCGxxxxGC) and the catalytic site motif (DACCxxHDxC) with the conserved catalytic histidine and the calcium coordinating aspartate residues. The aspartate of the His/Asp dyad playing an important role in animal sPLA2 catalysis is substituted by a serine residue. Furthermore, the PsPLA2 sequence contains 12 conserved cysteine residues to form 6 structural disulfide bonds. The calculated molecular weight of the mature PsPLA2 is 14.0 kDa. Based on the primary structure PsPLA2 belongs to the XIB group of PLA2s. Untagged recombinant PsPLA2 obtained by expression in Escherichia coli, renaturation from inclusion bodies and purification by cation-exchange chromatography was characterized in vitro. The pH optimum for activity of PsPLA2 was found to be pH 7, when using mixed micelles of 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC) and Triton X-100. PsPLA2 specifically cleaves fatty acids from the sn-2 position of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and shows a pronounced preference for PC over phosphatidyl ethanolamine, -glycerol and -inositol. The active recombinant enzyme was tested in vitro against natural phospholipids isolated from poppy plants and preferably released the unsaturated fatty acids, linoleic acid and linolenic acid, from the naturally occurring mixture of substrate lipids. PMID- 27473013 TI - Lack of TAK1 in dendritic cells inhibits the contact hypersensitivity response induced by trichloroethylene in local lymph node assay. AB - Trichloroethylene (TCE) is a ubiquitous environmental contaminant. Occupational TCE exposure has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder. The development of CHS depends on innate and adaptive immune functions. Transforming growth factor-beta activated kinase-1 (TAK1) controls the survival of dendritic cells (DCs) that affect the immune system homeostasis. We aimed to investigate the role of TAK1 activity in DC on TCE-induced CHS response. Control mice and DC-specific TAK1 deletion mice were treated with 80% (v/v) TCE using local lymph node assay (LLNA) to establish a TCE induced CHS model. The draining lymph nodes (DLNs) were excised and the lymphocytes were measure for proliferation by BrdU-ELISA, T-cell phenotype analysis by flow cytometry and signaling pathway activation by western blot. The ears were harvested for histopathological analysis. Control mice in the 80% TCE group displayed an inflammatory response in the ears, increased lymphocyte proliferation, elevated regulatory T-cell and activated T-cell percentages, and more IFN-gamma producing CD8(+) T cells in DLNs. In contrast to control mice, DC specific TAK1 deletion mice in the 80% TCE group showed an abolished CHS response and this was associated with defective T-cell expansion, activation and IFN-gamma production. This effect may occur through Jnk and NF-kappaB signaling pathways. Overall, this study demonstrates a pivotal role of TAK1 in DCs in controlling TCE induced CHS response and suggests that targeting TAK1 function in DCs may be a viable approach to preventing and treating TCE-related occupational health hazards. PMID- 27473014 TI - A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. AB - Physiologically based pharmacokinetic (PBPK) modeling was applied to investigate the effects of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. Successful construction of both rat and human models was achieved by fitting model outputs to published nicotine concentration time course data in the blood and in the brain. Key parameters presumed to have the most effect on the ability of these antibodies to prevent nicotine from entering the brain were selected for investigation using the human model. These parameters, which included antibody affinity for nicotine, antibody cross-reactivity with cotinine, and antibody concentration, were broken down into different, clinically derived in silico treatment levels and fed into the human PBPK model. Model predictions suggested that all three parameters, in addition to smoking status, have a sizable impact on anti-nicotine antibodies' ability to prevent nicotine from entering the brain and that the antibodies elicited by current human vaccines do not have sufficient binding characteristics to reduce brain nicotine concentrations. If the antibody binding characteristics achieved in animal studies can similarly be achieved in human studies, however, nicotine vaccine efficacy in terms of brain nicotine concentration reduction is predicted to meet threshold values for alleviating nicotine dependence. PMID- 27473015 TI - TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer. AB - Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2 dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters. PMID- 27473016 TI - Why mistreatment of medical students is not reported in clinical settings: perspectives of trainees. AB - Mistreatment of medical students is a major source of stress for them. Studies indicate a high incidence of such mistreatment, especially in clinical settings. In most cases, students who have been mistreated do not report it to the authorities. This study investigated factors related to the failure to report mistreatment. This was a cross-sectional study carried out in Kerman Medical School, Iran. All students in the internship and clerkship stages, as well as residents, were selected through the census method. Experiences of mistreatment and the reasons for not reporting them were evaluated using a questionnaire. The data were analysed with SPSS 19. Ninety-three per cent of the participants experienced mistreatment, but less than half of them reported it. Residents and interns reported emotional and academic mistreatment, respectively, more than other groups. The most common reason for not reporting mistreatment was that the students did not think reporting would accomplish anything. Our study showed that the experience of mistreatment in the clinical setting is common, but the cases reported to the authorities are far fewer than the actual number of cases. Educational systems should make extensive efforts to detect and prevent mistreatment to improve the teaching-learning environment. PMID- 27473017 TI - Regulation of oncogenes and gap junction intercellular communication during the proliferative response of zearalenone in TM3 cells. AB - Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin produced by Fusarium species. The exposure risk to humans and animals is the consumption of contaminated food and animal feeds. The aim of this study was to investigate ZEA induced effects and its tumorigenic mechanism in TM3 cells (mouse Leydig cells). Cell proliferation, apoptosis, and gap junction intercellular communication (GJIC) were assessed in this study. Results showed that low concentrations of ZEA could significantly promote the growth of TM3 cells. The percentage of cell distribution was decreased significantly in G1/G0 phase and was increased significantly in S phase with 10 and 20 MUg/L of ZEA for 72 h ( p < 0.05, p < 0.01). The expressions of cyclin D1 and Cdk4 were significantly increased in the exposure groups compared with the control group ( p < 0.05, p < 0.01). Compared with the control group, the apoptosis was significantly decreased in 10 and 20 MUg/L groups ( p < 0.01), and the ratio of Bax/Bcl-2 protein level was significantly decreased in a dose-dependent manner. The protein levels of proto oncogene c-Myc, c-Jun, and c-Fos were significantly elevated and the protein levels of anti-oncogene p53 and phosphatase and tensin homolog (PTEN) were decreased obviously compared with the control group ( p < 0.05, p < 0.01). ZEA affected the expressions of connexins and inhibited the activity of GJIC. These results demonstrated that ZEA can disturb the dynamic balance between proliferation and apoptosis and causes abnormal regulation of oncogenes, GJIC, and connexins in TM3 cells, which may easily induce the translation of normal cells into tumor cells. PMID- 27473018 TI - Impact of di-(2-ethylhexyl) phthalate on the uterus of adult Wistar rats. AB - Di-(2-ethylhexyl) phthalate (DEHP) is the most common plasticizer used in polyvinyl chloride-based plastics. DEHP is not covalently bound to the plastics and is easily released to the environment, resulting in human exposure. In this study, the adult rats were exposed to DEHP and its effects on the uterus was evaluated. Healthy adult female rats were treated with DEHP orally (with dose level 0, 1, 10, and 100 mg/kg body weight/day) for 30 days. No significant changes in the body weight and wet uterine weight were observed. Ovarian hormones and their receptor levels in the uterus were increased. Histological studies exhibited the structural abnormalities such as decrease in diameter, thinning of the layers and disruption in the glandular epithelium. PMID- 27473019 TI - Resident simulation training in endoscopic endonasal surgery utilizing haptic feedback technology. AB - Simulated practice may improve resident performance in endoscopic endonasal surgery. Using the NeuroTouch haptic simulation platform, we evaluated resident performance and assessed the effect of simulation training on performance in the operating room. First- (N=3) and second- (N=3) year residents were assessed using six measures of proficiency. Using a visual analog scale, the senior author scored subjects. After the first session, subjects with lower scores were provided with simulation training. A second simulation served as a task-learning control. Residents were evaluated in the operating room over six months by the senior author-who was blinded to the trained/untrained identities-using the same parameters. A nonparametric bootstrap testing method was used for the analysis (Matlab v. 2014a). Simulation training was associated with an increase in performance scores in the operating room averaged over all measures (p=0.0045). This is the first study to evaluate the training utility of an endoscopic endonasal surgical task using a virtual reality haptic simulator. The data suggest that haptic simulation training in endoscopic neurosurgery may contribute to improvements in operative performance. Limitations include a small number of subjects and adjudication bias-although the trained/untrained identity of subjects was blinded. Further study using the proposed methods may better describe the relationship between simulated training and operative performance in endoscopic Neurosurgery. PMID- 27473020 TI - Review of systems questionnaire helps differentiate psychogenic nonepileptic seizures from epilepsy. AB - We investigated the utility of a very brief review of system (ROS) questionnaire in differentiating psychogenic nonepileptic seizures (PNES) from epilepsy. In this retrospective study, we investigated all patients with PNES admitted to Jefferson Comprehensive Epilepsy Center from October 2013 through April 2015. Patients with a confirmed diagnosis of PNES or epilepsy based on video-EEG monitoring were included. These were matched with respect to age and sex. All patients had a brief ROS questionnaire in their electronic charts. The questionnaire included 10 general yes/no questions about the presence or absence of any abnormality in body systems. Thirty patients with PNES and 30 patients with epilepsy were investigated. The mean of ROS responses for the presence of any abnormality (+/-standard deviation) for the PNES group was 2.43 (+/-1.33) and for the epilepsy group was 1.50 (+/-0.94) (p=0.01). Cut-off point of three positive ROS was able to differentiate these two conditions from each another (p=0.01; OR: 6, 95% confidence interval: 1.48-24.29). Presence of multiple complaints in the ROS questionnaire argues in favor of PNES compared with epilepsy. This brief and easy to apply ROS questionnaire may be used as a valuable ancillary tool to differentiate PNES from epilepsy during the initial screening visit. This may help prevent the delay in making the diagnosis. PMID- 27473021 TI - Muscle biopsy findings in a child with NALCN gene mutation. AB - Mutation in NALCN (Sodium leak channel, non-selective) gene in humans has been shown to present with a wide spectrum of clinical manifestations including neurodevelopmental impairment, hypotonia and congenital contractures. Distinctive features including episodic ataxia and neuroaxonal dystrophy have also been reported. In this case report, we describe the muscle biopsy findings of a 3-year old boy who presented with congenital arthrogryposis, hypotonia and developmental delay who has a heterozygous de novo C.965T>C (p.1332T) variant in the NALCN gene found by expanded whole exome sequencing (WES). Distal arthrogryposis and ulnar deviation of hands were prominent findings, which have been shown to be associated with de novo heterozygous mutations in this gene. He also presented with brief paroxysmal episodes of tremulousness; however, he has not clearly had episodes of episodic ataxia. Initial work-up including extensive genetic and metabolic tests was normal except for mildly elevated multiple metabolites in urine, suggestive of mild dysfunction of multiple mitochondrial enzymes. Muscle biopsy findings revealed ragged red fiber changes on trichrome staining and an increased number of mitochondria with non-specific crystalloid like inclusions ultrastructurally. The biochemical and muscle biopsy findings are suggestive of a possible mitochondrial bioenergetic dysfunction. The association of NALCN gene with secondary mitochondrial dysfunction remains unclear. PMID- 27473022 TI - Addition of instrumented fusion after posterior decompression surgery suppresses thickening of ossification of the posterior longitudinal ligament of the cervical spine. AB - Laminoplasty (LMP) is a widely accepted surgical procedure for ossification of the posterior longitudinal ligament (OPLL) of the cervical spine. Progression of OPLL can occur in the long term after LMP. The aim of the present study was to determine whether addition of the instrumented fusion, (posterior decompression with instrumented fusion [PDF]), can suppress progression of OPLL or not. The present study included 50 patients who underwent LMP (n=23) or PDF (n=27) for OPLL of the cervical spine. We performed open door laminoplasty. PDF surgery was performed by double-door laminoplasty followed by instrumented fusion. We observed the non-ossified segment of the OPLL and measured the thickness of the OPLL at the thickest segment with pre- and postoperative sagittal CT multi-planar reconstruction images. Postoperative CT scan revealed fusion of the non-ossified segment of the OPLL was obtained in 4/23 patients (17%) in the LPM group and in 23/27 patients (85%) in the PDF group, showing a significant difference between both groups (p=0.003). Progression of the thickness of the OPLL in the PDF group (-0.1+/-0.4mm) was significantly smaller than in the LMP group (0.6+/-0.7mm, p=0.0002). The proportion of patients showing the decrease in thickness of OPLL was significantly larger in the PDF group (6/27 patients; 22%) than in the LMP group (0/23 patients; 0%, p=0.05). In conclusion, PDF surgery can suppress the thickening of OPLL. PMID- 27473023 TI - Rapid, spontaneous obliteration of intracranial arteriovenous malformation. AB - A 35-year-old male presented with headaches and was found to have a Spetzler Martin grade 2 right occipital arteriovenous malformation (AVM) with single, superficial draining vein. The patient opted to undergo embolization for possible cure with resection scheduled in the event complete obliteration was not achieved. Three weeks later, angiography during his embolization procedure revealed that the AVM had spontaneously obliterated; no treatment was required. In conjunction with prior case reports/series, this patient highlights the need for current imaging prior to proceeding with intervention to confirm that spontaneous obliteration has not occurred between diagnosis and treatment. PMID- 27473025 TI - Visual cortex hyperexcitability contributes to the pathophysiology of the photoparoxysmal response. PMID- 27473024 TI - CT-guided thoracic sympathetic blockade for palmar hyperhidrosis: Immediate results and postoperative quality of life. AB - The purpose of this study was to evaluate the results, complications, and degree of satisfaction among patients who underwent a CT-guided percutaneous puncture thoracic sympathetic blockade. A total of 186 patients underwent CT-guided thoracic sympathetic blockade based on case histories and a prospective pre- and postoperative questionnaire survey. The study sample was composed of 93 patients with an age range from 18 to 34years and a diagnosis with primary palmar hyperhidrosis (severe in some patients). Percutaneous puncture thoracic sympathetic blockade guided by CT was performed under local anesthesia in all patients. Heart rate (HR), non-invasive blood pressure (NIBP), arterial oxygen saturation (SPO2), perfusion index (PI), and palmar temperature (T) were monitored before and after treatment. Follow-up included a questionnaire on life quality and degree of satisfaction. Ten minutes after treatment, the SPO2, PI, and temperature all raised remarkably ([92.75+/-2.02]% vs. [98.85+/-1.09]%, [1.55+/-0.69]% vs. [8.60+/-0.94]%, [30.95+/-1.27] degrees C vs. [35.75+/-0.55] degrees C, respectively, P<0.001). The therapeutic success rate was 96.7%. No operative mortality was recorded. No complications were observed, except transient bradycardia in one patient and transient injection site pain in 25 patients. Of the 89 patients who were monitored over a period of 6-12months through follow-up interviews and questionnaires, 46% developed compensatory hyperhidrosis, 87.6% reported improvement in their quality of life. CT-guided percutaneous puncture thoracic sympathetic blockade is a safe, effective, and minimally invasive technique for the treatment of palmar hyperhidrosis. Despite the high rate of compensatory hyperhidrosis, it produces a high rate of patient satisfaction. PMID- 27473026 TI - Seat belt repositioning and use of vehicle seat cushions is increased among older drivers aged 75 years and older with morbidities. AB - OBJECTIVE: Good seat belt fit and positioning is important for crash protection. Older drivers experience problems in achieving good seat belt fit and often reposition seat belts and/or use seat cushions. Comfort influences these behaviours. This work examines the impact of functional morbidities on belt positioning and accessory use and whether comfort mediates this relationship METHODS: Mediation analysis was used to examine the relationship between morbidities affecting physical function, comfort, belt repositions and seat cushion use among 380 drivers aged 75 years and older. RESULTS: Musculoskeletal morbidities increase the likelihood of seat belt repositioning (OR 1.37, 95% CI 1.12-1.67) and comfort partially mediates this relationship (P = 0.03). Morbidities of any type also increase the likelihood of seat cushion use (OR 1.15 95% CI 1.04-1.27), but comfort plays no role in this relationship (P = 0.87). CONCLUSION: Greater awareness among older drivers is needed, to ensure behavioural modifications do not impair their crash protection. PMID- 27473027 TI - Erythropoietin attenuates motor impairments induced by bilateral renal ischemia/reperfusion in rats. AB - Neurologic sequelae remain a common and destructive problem in patients with acute kidney injury. The objective of this study was to evaluate the possible neuroprotective effect of erythropoietin (EPO) on motor impairments following bilateral renal ischemia (BRI) in two time points after reperfusion: short term (24 h) and long term (1 week). Male Wistar rats underwent BRI or sham surgery. EPO or saline administration was performed 30 min before surgery (1000 U/kg, i.p.). Explorative behaviors and motor function of the rats were evaluated by open field, rotarod, and wire grip tests. Plasma concentrations of blood urea nitrogen (BUN) and creatinine (Cr) were significantly enhanced in BRI rats 24 h after reperfusion. BRI group had only an increased level of BUN but not Cr 1 week after reperfusion. Impairment of balance function by BRI was not reversed by EPO 24 h after reperfusion, but counteracted 7 days after renal ischemia. Muscle strength had no significant differences between the groups. BRI group had a decrease in locomotor activity, and EPO could not reverse this reduction in both time points of the experiment. Although EPO could not be offered as a potential neuroprotective agent in the treatment of motor dysfunctions induced by BRI, it could be effective against balance dysfunction 1 week after renal ischemia. PMID- 27473028 TI - minotaur: A platform for the analysis and visualization of multivariate results from genome scans with R Shiny. AB - Genome scans are widely used to identify 'outliers' in genomic data: loci with different patterns compared with the rest of the genome due to the action of selection or other nonadaptive forces of evolution. These genomic data sets are often high dimensional, with complex correlation structures among variables, making it a challenge to identify outliers in a robust way. The Mahalanobis distance has been widely used, but has the major limitation of assuming that data follow a simple parametric distribution. Here, we develop three new metrics that can be used to identify outliers in multivariate space, while making no strong assumptions about the distribution of the data. These metrics are implemented in the R package minotaur, which also includes an interactive web-based application for visualizing outliers in high-dimensional data sets. We illustrate how these metrics can be used to identify outliers from simulated genetic data and discuss some of the limitations they may face in application. PMID- 27473030 TI - Gut Inflammation in Mice Leads to Reduction in alphavbeta8 Integrin Expression on CD103+CD11b- Dendritic Cells. PMID- 27473029 TI - Sodium chloride-enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice. AB - BACKGROUND AND AIM: Environmental factors are supposed to play a decisive role in the pathogenesis of inflammatory bowel diseases [IBDs]. Increased dietary salt intake has been linked with the development of autoimmune diseases, but the impact of a salt-enriched diet on the course of IBD remains unknown. In this study, we examined whether high salt intake alters mucosal cytokine production and exacerbates colitis. METHODS: Normal intestinal lamina propria mononuclear cells [LPMCs] were activated with anti-CD3/CD28 in the presence or absence of increasing concentrations of sodium chloride [NaCl] and/or SB202190, a specific inhibitor of p38/MAP Kinase. For in vivo experiments, a high dose of NaCl was administered to mice 15 days before induction of trinitrobenzene-sulfonic acid [TNBS]-colitis or dextran sulfate sodium [DSS]-colitis. In parallel, mice were given SB202190 before induction of TNBS-colitis. Transcription factors and effector cytokines were evaluated by flow-cytometry and real-time PCR. RESULTS: IL-17A, IL-23R, TNF-alpha, and Ror-gammaT were significantly increased in human LPMCs following NaCl exposure, while there was no significant change in IFN gamma, T-bet or Foxp3. Pharmacologic inhibition of p38/MAPK abrogated the NaCl inducing effect on LPMC-derived cytokines. Mice receiving the high-salt diet developed a more severe colitis than control mice, and this effect was preventable by SB202190. CONCLUSIONS: Our data indicated that exposure of intestinal mononuclear cells to a high-NaCl diet enhanced effector cytokine production and contributed to the exacerbation of experimental colitis in mice. PMID- 27473032 TI - Calcific tendinitis of biceps femoris: an unusual site and cause for lateral knee pain. AB - A 37-year-old man presented to the acute knee and sports medicine clinic with atraumatic lateral knee pain. He had point tenderness over the lateral aspect of his knee which had not settled with anti-inflammatory medications. Imaging revealed a large opaque lesion lateral to the knee and although there was no clear mechanism, injury to the posterolateral corner was considered. An MRI subsequently revealed a rare case of calcific tendinitis to the biceps femoris tendon insertion. This condition was self-limiting and did not require interventions such as steroid injections. This is the first reported case of calcific tendinitis of biceps femoris as a cause of acute knee pain. PMID- 27473031 TI - Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study. AB - BACKGROUND: Late-onset Pompe disease is characterized by progressive skeletal myopathy followed by respiratory muscle weakness, typically leading to loss of ambulation and respiratory failure. In this population, enzyme replacement therapy (ERT) with alglucosidase alfa has been shown to stabilize respiratory function and improve mobility and muscle strength. Muscle pathology and glycogen clearance from skeletal muscle in treatment-naive adults after ERT have not been extensively examined. METHODS: This exploratory, open-label, multicenter study evaluated glycogen clearance in muscle tissue samples collected pre- and post- alglucosidase alfa treatment in treatment-naive adults with late-onset Pompe disease. The primary endpoint was the quantitative reduction in percent tissue area occupied by glycogen in muscle biopsies from baseline to 6months. Secondary endpoints included qualitative histologic assessment of tissue glycogen distribution, secondary pathology changes, assessment of magnetic resonance images (MRIs) for intact muscle and fatty replacement, and functional assessments. RESULTS: Sixteen patients completed the study. After 6months of ERT, the percent tissue area occupied by glycogen in quadriceps and deltoid muscles decreased in 10 and 8 patients, respectively. No changes were detected on MRI from baseline to 6months. A majority of patients showed improvements on functional assessments after 6months of treatment. All treatment-related adverse events were mild or moderate. CONCLUSIONS: This exploratory study provides novel insights into the histopathologic effects of ERT in late-onset Pompe disease patients. Ultrastructural examination of muscle biopsies demonstrated reduced lysosomal glycogen after ERT. Findings are consistent with stabilization of disease by ERT in treatment-naive patients with late-onset Pompe disease. PMID- 27473033 TI - Pregnancy complicated by haemorrhagic ascites in a woman with newly diagnosed HIV. AB - A young pregnant Zambian woman was referred from a district hospital in South Zambia to the university teaching hospital, Lusaka with severe anaemia and ascites. The ascites had developed over a month and the woman was currently 15 weeks pregnant. Further workup revealed that the patient was HIV-positive and the ascitic tap showed haemorrhagic fluid. After being reviewed by multiple doctors, the cause of the haemorrhagic ascites remained unclear; therefore, the decision was made to do a laparotomy. The laparotomy revealed haemoperitoneum and a large cyst attached to the liver containing 5 L of bloodstained fluid. The histopathology report revealed features consistent with a giant haemangioma. There were many barriers to accessing optimum healthcare in this case. These included limited access to blood, poor communication resulting in the patient being unaware of her HIV status and lack of patient education about HIV. PMID- 27473034 TI - Migration of peripherally inserted central catheter likely into the azygos vein: a conservative management. PMID- 27473035 TI - Impact of Increased Early Statin Administration on Ischemic Stroke Outcomes: A Multicenter Electronic Medical Record Intervention. AB - BACKGROUND: Statin administration early in ischemic stroke may influence outcomes. Our aim was to determine the clinical impact of increasing statin administration early in ischemic stroke hospitalization. METHODS AND RESULTS: This is a retrospective analysis of a multicenter electronic medical record (EMR) intervention to increase early statin administration in ischemic stroke across all 20 hospitals of an integrated healthcare delivery system. A stroke EMR order set was modified from an "opt-in" to "opt-out" mode of statin ordering. Outcomes were mortality by 90 days, discharge disposition, and increase in stroke severity. We examined the relationship between intervention and outcome using autoregressive integrated moving average (ARIMA) time-series modeling. The EMR intervention increased both overall in-hospital statin administration (from 87.2% to 90.7%, P<0.001) and early statin administration (from 16.9% to 26.3%, P<0.001). ARIMA models showed a small increase in the rate of survival (difference in probability [Pdiff]=0.02, P=0.016) and discharge to home or rehabilitation facility (Pdiff=0.04, P=0.034) associated with the intervention. The increase in statin administration <8 hours was associated with much larger increases in survival (Pdiff=0.17, P=0.033) and rate of discharge to home or rehabilitation (Pdiff=0.29, P=0.011), as well as a decreased rate of neurological deterioration in-hospital (Pdiff=-0.14, P=0.026). CONCLUSIONS: A simple EMR change increased early statin administration in ischemic stroke and was associated with improved clinical outcomes. This is, to our knowledge, the first EMR intervention study to show that a modification of an electronic order set resulted in improved clinical outcomes. PMID- 27473036 TI - Nitrite Therapy Ameliorates Myocardial Dysfunction via H2S and Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-Dependent Signaling in Chronic Heart Failure. AB - BACKGROUND: Bioavailability of nitric oxide (NO) and hydrogen sulfide (H2S) is reduced in heart failure (HF). Recent studies suggest cross-talk between NO and H2S signaling. We previously reported that sodium nitrite (NaNO2) ameliorates myocardial ischemia-reperfusion injury and HF. Nuclear factor-erythroid-2-related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H2S. We examined the NaNO2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia-induced chronic heart failure (CHF). METHODS AND RESULTS: Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO2 (165 MUg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic (LVEDD) and systolic dimensions (LVESD) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein-related assays. We found that NaNO2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia-induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO2-treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO2 therapy markedly increased expression of Cu,Zn-superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO2 upregulated the activity of Nrf2, as well as H2S-producing enzymes, and ultimately increased H2S bioavailability in ischemia-induced CHF in mice as compared with vehicle. CONCLUSIONS: Our results demonstrate that NaNO2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses. PMID- 27473037 TI - Mitogen-Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation-Induced Cardiac Hypertrophy. AB - BACKGROUND: The transient receptor potential vanilloid type 1 (TRPV1) is expressed in the cardiovascular system, and increased TRPV1 expression has been associated with cardiac hypertrophy. Nevertheless, the role of TRPV1 in the pathogenesis of cardiac hypertrophy and the underlying molecular mechanisms remain unclear. METHODS AND RESULTS: In cultured cardiomyocytes, activation of TRPV1 increased cell size and elevated expression of atrial natriuretic peptide mRNA and intracellular calcium level, which was reversed by TRPV1 antagonist capsazepine. Increased expression of phosphorylated calmodulin-dependent protein kinase IIdelta and mitogen-activated protein kinases were found in TRPV1 agonist capsaicin-treated cardiomyocytes. Selective inhibitor of calmodulin-dependent protein kinase IIdelta decreased phosphorylation of extracellular signal regulated kinases and p38. Capsaicin induced an increase in expression of ornithine decarboxylase protein, which is the key enzyme in polyamine biosynthesis in cardiomyocytes. Nevertheless, there was no obvious change of ornithine decarboxylase expression in TRPV1 knockdown cells after capsaicin treatment, and specific inhibitors of calmodulin-dependent protein kinase IIdelta or p38 downregulated the capsaicin-induced expression of ornithine decarboxylase. Capsazepine alleviated the increase in cross-sectional area of cardiomyocytes and the ratio of heart weight to body weight and improved cardiac function, including left ventricular internal end-diastolic and -systolic dimensions and ejection fraction and fractional shortening percentages, in mice treated with transverse aorta constriction. Capsazepine also reduced expression of ornithine decarboxylase and cardiac polyamine levels. Transverse aorta constriction induced increases in phosphorylated calmodulin-dependent protein kinase IIdelta and extracellular signal-regulated kinases, and p38 and Serca2a were attenuated by capsazepine treatment. CONCLUSIONS: This study revealed that the mitogen activated protein kinase signaling pathway and intracellular polyamines are essential for TRPV1 activation-induced cardiac hypertrophy. PMID- 27473040 TI - Primary school students' mental health in Uganda and its association with school violence, connectedness, and school characteristics: a cross-sectional study. AB - BACKGROUND: Few studies have explored risk factors for poor mental health in Ugandan primary schools. This study investigated whether individual- and contextual-level school-related factors including violence from school staff and other students, connectedness to school and peers, as well as school size and urban/rural location, were associated with mental health difficulties in Ugandan children. We also examined whether associations between violence exposure at school and mental health were mediated by connectedness as well as whether associations were different for boys and girls. METHODS: The analytic sample consisted of 3,565 students from 42 primary schools participating in the Good Schools Study. Data were collected through individual interviews conducted in June and July 2012. Mental health was measured using the Strengths and Difficulties Questionnaire. Multilevel logistic regression was applied to investigate factors associated with mental health difficulties. RESULTS: Experiences of violence from school staff and other students in the past week were strongly associated with mental health difficulties (OR = 1.58, 95 % CI 1.31 to 1.90 and 1.81, 1.47 to 2.23, respectively). Children with a low school connectedness had 1.43 times (1.11 to 1.83) the odds of mental health difficulties compared to those with a high school connectedness. The OR comparing children never feeling close to other students at their school with those always feeling close was 1.86 (1.18 to 2.93). The effect of violence on mental health was not mediated through the connectedness variables. School size was not related to mental health difficulties, but attending an urban school increased the odds of mental health difficulties after accounting for other factors. We did not find evidence that the effect of one or more of the exposures on the outcome differed between boys and girls. CONCLUSIONS: These findings suggest that violence in school and low connectedness to school and peers are independently associated with mental health difficulties and interventions should address both concurrently. Extra support may be needed for students in urban schools. TRIAL REGISTRATION: Clinicaltrials.gov NCT01678846 . Registered 24 August 2012. PMID- 27473041 TI - First-Line Chemotherapy for Ovarian Cancer: Inferences From Recent Studies. PMID- 27473039 TI - Pregnant women and infants as sentinel populations to monitor prevalence of malaria: results of pilot study in Lake Zone of Tanzania. AB - BACKGROUND: As malaria control interventions are scaled-up, rational approaches are needed for monitoring impact over time. One proposed approach includes monitoring the prevalence of malaria infection among pregnant women and children at the time of routine preventive health facility (HF) visits. This pilot explored the feasibility and utility of tracking the prevalence of malaria infection in pregnant women attending their first antenatal care (ANC) visit and infants presenting at 9-12 months of age for measles vaccination. METHODS: Pregnant women attending first ANC and infants nine to 12 months old presenting for measles vaccination at a non-probability sample of 54 HFs in Tanzania's Lake Zone (Mara, Mwanza and Kagera Regions) were screened for malaria infection using a malaria rapid diagnostic test (RDT) from December 2012 to November 2013, regardless of symptoms. Participants who tested positive were treated for malaria per national guidelines. Data were collected monthly. RESULTS: Overall 89.9 and 78.1 % of expected monthly reports on malaria infection prevalence were received for pregnant women and infants, respectively. Among 51,467 pregnant women and 35,155 infants attending routine preventive HF visits, 41.2 and 37.3 % were tested with RDT, respectively. Malaria infection prevalence was 12.8 % [95 % confidence interval (CI) 11.3-14.3] among pregnant women and 11.0 % (95 % CI 9.5 12.5) among infants, and varied by month. There was good correlation of the prevalence of malaria among pregnant women and infants at the HF level (Spearman rho = 0.6; p < 0.001). This approach is estimated to cost $1.28 for every person tested, with the RDT accounting for 72 % of the cost. CONCLUSIONS: Malaria infection was common and well correlated among pregnant women and infants attending routine health services. Routine screening of these readily accessible populations may offer a practical strategy for continuously tracking malaria trends, particularly seasonal variation. Positivity rates among afebrile individuals presenting for routine care offer an advantage as they are unaffected by the prevalence of other causes of febrile illness, which could influence positivity rates among febrile patients presenting to outpatient clinics. The data presented here suggest that in addition to contributing to clinical management, ongoing screening of pregnant women could be used for routine surveillance and detection of hotspots. PMID- 27473038 TI - Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure. AB - BACKGROUND: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) >=45%, diastolic dysfunction grade >=1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF >=45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. CONCLUSIONS: We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum. PMID- 27473042 TI - Evolution of Management and Outcomes in Waldenstrom Macroglobulinemia: A Population-Based Analysis. AB - INTRODUCTION: Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM) is a rare lymphoma affecting older patients. Its management largely relies on small phase II trials and it is unclear how their results translate into clinical practice in the community. METHOD: We evaluated changes in the presentation, management, and survival among 2,666 Medicare beneficiaries diagnosed with WM between 1994 and 2011, using Medicare claims linked to Surveillance, Epidemiology and End Results data. RESULTS: Prevalence of transfusions, anemia, thrombocytopenia, and neuropathy at diagnosis significantly increased over time, whereas the use of plasmapheresis was low (2.5%) and stable. The proportion of patients starting chemotherapy within 1 year of WM diagnosis increased from 39% in 1994 to 62% in 2011 (p < .0001). Treatments based on classic alkylators and purine analogs predominated in the 1990s, but were quickly replaced by rituximab containing regimens after 2000. Rituximab monotherapy has been prescribed for >50% of patients since 2004, and combination chemoimmunotherapy for a further 30%. Most patients initiating multiagent regimens in 2012-2013 received rituximab with bortezomib or bendamustine. These changes were accompanied by significant improvements in overall and WM-related survival, but also by a significant increase in cost of chemotherapy. Mean Medicare payments for chemotherapy drugs accrued in the first year of treatment rose from $9,464 in 1994-2000 to $29,490 after 2008. CONCLUSION: Hematologists have rapidly adopted innovative, expensive therapies for WM before completion of randomized trials. This underscores the need to assess the comparative value of such therapies in rare malignancies through a combination of clinical and observational data. IMPLICATIONS FOR PRACTICE: Most older patients with Waldenstrom macroglobulinemia currently treated in the U.S. receive rituximab as monotherapy or in combination with bortezomib or bendamustine. Newly designed trials should consider control arms aligned with this prevalent real-life standard. Compared with the 1990s, patients diagnosed according to current criteria are more likely to have anemia or neuropathy, or to receive early chemotherapy, but only 2.5% require plasmapheresis at diagnosis. The incremental clinical value of newly introduced agents needs to be assessed through a combination of clinical and health services research, taking into consideration their associated survival benefits, toxicities, and associated costs of care. PMID- 27473043 TI - Dramatic Response to Carboplatin, Paclitaxel, and Radiation in a Patient With Malignant Myoepithelioma of the Breast. PMID- 27473044 TI - Decline in Cognitive Function in Older Adults With Early-Stage Breast Cancer After Adjuvant Treatment. AB - BACKGROUND: The impact of chemotherapy on cognition among elderly patients has received little attention, although such patients are more prone to presenting with age-related cognitive deficits and/or cognitive decline during chemotherapy. The present study assessed the cognitive function in older adults treated for early-stage breast cancer (EBC). PATIENTS AND METHODS: The participants were newly diagnosed EBC patients aged >=65 years without previous systemic treatment or neurological or psychiatric disease and matched healthy controls. They underwent two assessments: before starting adjuvant therapy and after the end of chemotherapy (including doxorubicin +/- docetaxel [CT+ group], n = 58) or radiotherapy for patients who did not receive chemotherapy (CT- group, n = 61), and at the same interval for the healthy controls (n = 62). Neuropsychological and geriatric assessments were performed. Neuropsychological data were analyzed using the Reliable Change Index. RESULTS: Forty-nine percent of the patients (mean age, 70 +/- 4 years) had objective cognitive decline after adjuvant treatment that mainly concerned working memory. Among these patients, 64% developed a cognitive impairment after adjuvant treatment. Comorbidity was not associated with cognitive decline. No significant difference in objective cognitive decline was found between the two groups of patients; however, the CT+ group had more subjective cognitive complaints after treatment (p = .008). The oldest patients (aged 70-81 years) tended to have more objective decline with docetaxel (p = .05). CONCLUSION: This is the largest published study assessing cognitive function in older adults with EBC that included a group of patients treated with modern chemotherapy regimens. Approximately half the patients had objective cognitive decline after adjuvant treatment. The oldest patients were more likely to have cognitive decline with chemotherapy, particularly with docetaxel. IMPLICATIONS FOR PRACTICE: This is the largest published study assessing cognitive function in older adults with early-stage breast cancer that included a group of patients treated with modern chemotherapy regimens. Approximately half the patients had objective cognitive decline after adjuvant treatment. The oldest patients were more likely to have cognitive decline with chemotherapy, particularly with docetaxel. Cognitive deficits could affect patients' quality of life and their compliance to treatment. Assessing cognitive dysfunctions in the elderly cancer population is a challenge in clinical practice, but it could influence the choice of the most appropriate therapy, including the use of oral drugs. PMID- 27473045 TI - Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management. AB - : : Molecularly targeted cancer therapy has rapidly changed the landscape of oncologic care, often improving patients' prognosis without causing as substantial a quality-of-life decrement as cytotoxic chemotherapy does. Nevertheless, targeted agents can cause side effects that may be less familiar to medical oncologists and that require the attention and expertise of subspecialists. In this review, we focus on hyperglycemia, which can occur with use of new anticancer agents that interact with cell proliferation pathways. Key mediators of these pathways include the tyrosine kinase receptors insulin growth factor receptor 1 (IGF-1R) and epidermal growth factor receptor (EGFR), as well as intracellular signaling molecules phosphatidylinositol 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). We summarize available information on hyperglycemia associated with agents that inhibit these molecules within the larger context of adverse event profiles. The highest incidence of hyperglycemia is observed with inhibition of IGF-1R or mTOR, and although the incidence is lower with PI3K, AKT, and EGFR inhibitors, hyperglycemia is still a common adverse event. Given the interrelationships between the IGF-1R and cell proliferation pathways, it is important for oncologists to understand the etiology of hyperglycemia caused by anticancer agents that target those pathways. We also discuss monitoring and management approaches for treatment-related hyperglycemia for some of these agents, with a focus on our experience during the clinical development of the EGFR inhibitor rociletinib. IMPLICATIONS FOR PRACTICE: Treatment-related hyperglycemia is associated with several anticancer agents. Many cancer patients may also have preexisting or undiagnosed diabetes or glucose intolerance. Screening can identify patients at risk for hyperglycemia before treatment with these agents. Proper monitoring and management of symptoms, including lifestyle changes and pharmacologic intervention, may allow patients to continue benefiting from use of anticancer agents. PMID- 27473046 TI - A randomised trial of Acceptance and Commitment Therapy for Anorexia Nervosa after daycare treatment, including five-year follow-up. AB - BACKGROUND: No specific psychotherapy for adult anorexia nervosa (AN) has shown superior effect. Maintenance factors in AN (over-evaluation of control over eating, weight and shape) were addressed via Acceptance and Commitment Therapy (ACT). The study aimed to compare 19 sessions of ACT with treatment as usual (TAU), after 9 to 12 weeks of daycare, regarding recovery and risk of relapse up to five years. METHODS: Patients with a full, sub-threshold or partial AN diagnosis from an adult eating disorder unit at a hospital were randomized to ACT (n = 24) and TAU (n = 19). The staff at the hospital, as well as the participants, were unaware of the allocation until the last week of daycare. Primary outcome measures were body mass index (BMI) and specific eating psychopathology. Analyses included mixed model repeated measures and odds ratios. RESULTS: Groups did not differ regarding recovery and relapse using a metric of BMI and the Eating Disorder Examination Questionnaire (EDE-Q). There were only significant time effects. However, odds ratio indicated that ACT participants were more likely to reach good outcome. The study was underpowered due to unexpected low inflow of patients and high attrition. CONCLUSION: Longer treatment, more focus on established perpetuating factors and weight restoration integrated with ACT might improve outcome. Potential pitfalls regarding future trials on AN are discussed. Trial registration number ISRCTN 12106530. Retrospectively registered 08/06/2016. PMID- 27473047 TI - The impact of socioeconomic factors on the efficiency of voluntary toxoplasmosis screening during pregnancy: a population-based study. AB - BACKGROUND: Congenital toxoplasmosis is associated with severe complications. German state health insurance covers rubella, but not toxoplasmosis, immunity screening. We analysed the effect of socioeconomic factors on the efficiency of private toxoplasmosis screening during pregnancy. METHODS: Toxoplasmosis and rubella screening data (n = 5402 mothers) were collected within the population based Survey of Neonates in Pomerania (SNiP). RESULTS: At the first-trimester screening, 34.4 % (88.1 %) of expecting mothers were immune to toxoplasmosis (rubella). Susceptibility for toxoplasmosis (rubella) was observed in 39.6 % (8.9 %) and 25.8 % (2.95 %) were not tested. Data on a 2(nd) screening were available in a subgroup of women with negative immunity showing less than 45 % participation rate. Active toxoplasmosis (no rubella) infection was observed in 0.3 % (n = 17) of pregnant women. A multiple logistic regression model (AIC = 719.67; AUC = 0.725) revealed that the likelihood of participating in a second toxoplasmosis screening increased among women with a good level of education and a steady partnership and decreased with paternal unemployment and the absence of breastfeeding. The highest probability of non-participation in toxoplasmosis screening was found among women with temporal burden and family responsibilities. A cost-benefit analysis showed that covering general screening for toxoplasmosis with health insurance saved costs. CONCLUSION: Toxoplasmosis carried a substantial risk of infection during pregnancy. Although increased socioeconomic status was positively associated with the participation in toxoplasmosis screening, this was not the case when pregnant women had strong temporal burden and family responsibilities. This data supports the need for toxoplasmosis screening among pregnant women as a general healthcare benefit covered by insurance. PMID- 27473048 TI - Identification of combinatorial host-specific signatures with a potential to affect host adaptation in influenza A H1N1 and H3N2 subtypes. AB - BACKGROUND: The underlying strategies used by influenza A viruses (IAVs) to adapt to new hosts while crossing the species barrier are complex and yet to be understood completely. Several studies have been published identifying singular genomic signatures that indicate such a host switch. The complexity of the problem suggested that in addition to the singular signatures, there might be a combinatorial use of such genomic features, in nature, defining adaptation to hosts. RESULTS: We used computational rule-based modeling to identify combinatorial sets of interacting amino acid (aa) residues in 12 proteins of IAVs of H1N1 and H3N2 subtypes. We built highly accurate rule-based models for each protein that could differentiate between viral aa sequences coming from avian and human hosts. We found 68 host-specific combinations of aa residues, potentially associated to host adaptation on HA, M1, M2, NP, NS1, NEP, PA, PA-X, PB1 and PB2 proteins of the H1N1 subtype and 24 on M1, M2, NEP, PB1 and PB2 proteins of the H3N2 subtypes. In addition to these combinations, we found 132 novel singular aa signatures distributed among all proteins, including the newly discovered PA-X protein, of both subtypes. We showed that HA, NA, NP, NS1, NEP, PA-X and PA proteins of the H1N1 subtype carry H1N1-specific and HA, NA, PA-X, PA, PB1-F2 and PB1 of the H3N2 subtype carry H3N2-specific signatures. M1, M2, PB1-F2, PB1 and PB2 of H1N1 subtype, in addition to H1N1 signatures, also carry H3N2 signatures. Similarly M1, M2, NP, NS1, NEP and PB2 of H3N2 subtype were shown to carry both H3N2 and H1N1 host-specific signatures (HSSs). CONCLUSIONS: To sum it up, we computationally constructed simple IF-THEN rule-based models that could distinguish between aa sequences of avian and human IAVs. From the rules we identified HSSs having a potential to affect the adaptation to specific hosts. The identification of combinatorial HSSs suggests that the process of adaptation of IAVs to a new host is more complex than previously suggested. The present study provides a basis for further detailed studies with the aim to elucidate the molecular mechanisms providing the foundation for the adaptation process. PMID- 27473049 TI - Twenty-year trajectories of alcohol consumption during midlife and atherosclerotic thickening in early old age: findings from two British population cohort studies. AB - BACKGROUND: Epidemiological evidence indicates a protective effect of light moderate drinking on cardiovascular disease and an increased risk for heavier drinking. Nevertheless, the effect of alcohol on atherosclerotic changes in vessel walls is disputed. Most previous studies have only looked at the cross sectional relationship between alcohol and carotid intima media thickness (cIMT) a surrogate marker of atherosclerosis. Single measurements of alcohol assume that alcohol exposure is stable and ignore the possible cumulative effects of harm, leading to possibly incorrect inferences. METHODS: Data were retrieved from two UK population based cohort studies: the Whitehall II cohort of civil servants and the MRC National Survey of Health and Development (combined sample size of 5403 men and women). Twenty year-drinking trajectories during midlife were linked to measures of cIMT when participants were in early old age, and adjusted for age, sex, socioeconomic position, ethnicity and smoking. RESULTS: Those who consistently drank heavily had an increased cIMT compared to stable moderate drinkers (pooled difference in cIMT 0.021 mm; 95 % CI 0.002 to 0.039), after adjustment for covariates. This was not detected in cross-sectional analyses. Former drinkers also had an increased cIMT compared to moderate drinkers (pooled difference in cIMT 0.021; 95 % CI 0.005 to 0.037). There were no appreciable differences in cIMT between non-drinkers and consistent moderate drinkers. CONCLUSION: The drinking habits among adults during midlife affect the atherosclerotic process and sustained heavy drinking is associated with an increased cIMT compared to stable moderate drinkers. This finding was not seen when only using cross-sectional analyses, thus highlighting the importance of taking a life course approach. There was no evidence of a favourable atherosclerotic profile from stable moderate drinking compared to stable non drinking. PMID- 27473050 TI - Low tidal volume ventilation with low PEEP during surgery may induce lung inflammation. AB - BACKGROUND: Compared to conventional tidal volume ventilation, low tidal-volume ventilation reduces mortality in cased of acute respiratory distress syndrome. The aim of the present study is to determine whether low tidal-volume ventilation reduces the production of inflammatory mediators in the lungs and improves physiological status during hepatic surgery. METHODS: We randomly assigned patients undergoing hepatectomy into 2 groups: conventional tidal-volume vs. low tidal-volume (12 vs. 6 mL*kg(-1) ideal body weight) ventilation with a positive end-expiratory pressure of 3 cm H2O. Arterial blood and airway epithelial lining fluid were sampled immediately after intubation and every 3 h thereafter. RESULTS: Twenty-five patients were analyzed. No significant changes were found in hemodynamics or acid-base status during the study. Interleukin-8 was significantly elevated in epithelial lining fluid from the low tidal-volume group. Oxygenation evaluated immediately after admission to the post-surgical care unit was significantly worse in the low tidal-volume group. CONCLUSIONS: Low tidal-volume ventilation with low positive end-expiratory pressure may lead to pulmonary inflammation during major surgery such as hepatectomy. TRIAL REGISTRATION: The effect of ventilatory tidal volume on lung injury during hepatectomy that requires transient liver blood flow interruption. UMIN000021371 (03/07/2016); retrospectively registered. PMID- 27473051 TI - Development of training for medicines-oriented policymakers to apply evidence. AB - BACKGROUND: Health systems globally promote appropriate prescribing by healthcare providers and safe and effective medicine use by consumers. Rx for Change, a publicly available database, provides access to systematic reviews regarding best practices for prescribing and using medicines. Despite the value of the database for improving prescribing and medicine use, its use remains suboptimal. This study aimed to develop a training program for five medicine-focused organisations in Canada and Australia to facilitate the use and understanding of the Rx for Change database. METHODS: Four steps were undertaken: 1) key informant interviews were completed across all organisations to understand the knowledge user perspective; 2) a directed content analysis was completed of the interview transcripts and proposed training was developed; 3) a second round of feedback on the proposed training by knowledge users was gathered; and 4) feedback was integrated to develop the final training. RESULTS: Sixteen key informant interviews with knowledge users were conducted. Themes for training content included the scope of, navigation and strategies for using Rx for Change (generic content) and practical examples on incorporating evidence within their workplace context (tailored content). The final training consisted of an informational video, a 60-minute face-to-face workshop and two post-training reminders. CONCLUSIONS: A method of engaging knowledge users in the development of a training program to improve the use of an on-line database of systematic reviews was established and used to design training. Next steps include the delivery and evaluation of the training. PMID- 27473052 TI - Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients. AB - We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age corrected RTL (acRTL) was also obtained. The 36-month probability of treatment free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean +/- SD = 0.01 +/- 0.14 vs 0.20 +/- 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL <=0.09 (78.9 vs 30.8 %, p = 0.002). CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation. PMID- 27473053 TI - Health partnership research and the assessment of effectiveness. PMID- 27473054 TI - Erratum to: 'NETTAB 2014: From high-throughput structural bioinformatics to integrative systems biology'. PMID- 27473055 TI - Clausenidin induces caspase-dependent apoptosis in colon cancer. AB - BACKGROUND: Clausena excavata Burm.f. is a shrub traditionally used to treat cancer patients in Asia. The main bioactive chemical components of the plant are alkaloids and coumarins. In this study, we isolated clausenidin from the roots of C. excavata to determine its apoptotic effect on the colon cancer (HT-29) cell line. METHOD: We examined the effect of clausenidin on cell viability, ROS generation, DNA fragmentation, mitochondrial membrane potential in HT-29 cells. Ultrastructural analysis was conducted for morphological evidence of apoptosis in the treated HT-29 cells. In addition, we also evaluated the effect of clausenidin treatment on the expression of caspase 3 and 9 genes and proteins in HT-29 cells. RESULT: Clausenidin induced a G0/G1 cell cycle arrest in HT-29 cells with significant (p < 0.05) dose-dependent increase in apoptotic cell population. The DNA fragmentation assay also showed apoptotic features in the clausenidin-treated HT-29 cells. Clausenidin treatment had caused significant (p < 0.05) increases in the expression of caspase 9 protein and gene in HT-29 cells and mitochondrial ROS and mitochondrial membrane depolarization. The results suggest the involvement of the mitochondria in the caspase-dependent apoptosis in clausenidin-treated colon cancer cells. CONCLUSION: Clausenidin induces a caspase-dependent apoptosis in colon cancers through the stimulation of the mitochondria. The study demonstrates the potential of clausenidin for use in the treatment of colon cancers. PMID- 27473056 TI - Direct conversion of mouse embryonic fibroblasts into functional keratinocytes through transient expression of pluripotency-related genes. AB - The insufficient ability of specialized cells such as neurons, cardiac myocytes, and epidermal cells to regenerate after tissue damage poses a great challenge to treat devastating injuries and ailments. Recent studies demonstrated that a diverse array of cell types can be directly derived from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or somatic cells by combinations of specific factors. The use of iPSCs and direct somatic cell fate conversion, or transdifferentiation, holds great promise for regenerative medicine as these techniques may circumvent obstacles related to immunological rejection and ethical considerations. However, producing iPSC-derived keratinocytes requires a lengthy two-step process of initially generating iPSCs and subsequently differentiating into skin cells, thereby elevating the risk of cellular damage accumulation and tumor formation. In this study, we describe the reprogramming of mouse embryonic fibroblasts into functional keratinocytes via the transient expression of pluripotency factors coupled with directed differentiation. The isolation of an iPSC intermediate is dispensable when using this method. Cells derived with this approach, termed induced keratinocytes (iKCs), morphologically resemble primary keratinocytes. Furthermore they express keratinocyte-specific markers, downregulate mesenchymal markers as well as the pluripotency factors Oct4, Sox2, and Klf4, and they show important functional characteristics of primary keratinocytes. iKCs can be further differentiated by high calcium administration in vitro and are capable of regenerating a fully stratified epidermis in vivo. Efficient conversion of somatic cells into keratinocytes could have important implications for studying genetic skin diseases and designing regenerative therapies to ameliorate devastating skin conditions. PMID- 27473057 TI - Heat shock protein 70-2 (HSP70-2) is a novel therapeutic target for colorectal cancer and is associated with tumor growth. AB - BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer related deaths worldwide both in men and women. Our recent studies have indicated an association of heat shock protein 70-2 (HSP70-2) with bladder urothelial carcinoma. In the present study, we investigated the association of HSP70-2 with various malignant properties of colorectal cancer cells and clinic-pathological features of CRC in clinical specimens. METHODS: HSP70-2 mRNA and protein was investigated expression by RT-PCR, immunohistochemistry, immunofluorescence, flow cytometry and Western blotting in CRC clinical specimens and COLO205 and HCT116 cell lines. Plasmid-based gene silencing approach was employed to study the association of HSP70-2 with various malignant properties of COLO205 and HCT116 cells in in vitro and with tumor progression in in vivo COLO205 human xenograft mice model. RESULTS: HSP70-2 expression was detected in 78 % of CRC patients irrespective of various stages and grades by RT-PCR and IHC. Our analysis further revealed that HSP70-2 expression was detected in both COLO205 and HCT116 cell lines. Ablation of HSP70-2 expression resulted in reduced cellular growth, colony forming ability, migratory and invasive ability of CRC cells. In addition, ablation of HSP70-2 expression showed significant reduction in tumor growth in COLO205 human xenograft in in vivo mouse model. CONCLUSION: Collectively, our results indicate that HSP70-2 is associated with CRC clinical specimens. In addition, down regulation of HSP70-2 expression reduces cellular proliferation and tumor growth indicating that HSP70-2 may be a potential therapeutic target for CRC treatment. PMID- 27473058 TI - Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects. AB - BACKGROUND: Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. METHODS: Our case control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5 methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk. RESULTS: Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk. CONCLUSIONS: Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk. PMID- 27473059 TI - The efficacy of mirabegron additional therapy for lower urinary tract symptoms after treatment with alpha1-adrenergic receptor blocker monotherapy: prospective analysis of elderly men. AB - BACKGROUND: Mirabegron is a beta3-adrenoreceptor agonist developed for treatment of overactive bladder (OAB). alpha1-Adrenergic receptor blockers are effective for lower urinary tract symptoms (LUTS) in male patients. However, the efficacy of mirabegron additional treatment in elderly male patients with persistent male LUTS, especially in OAB after monotherapy with alpha1-adrenergic blockers, is not fully understood. METHODS: This study was conducted in male LUTS patients who were >= 65 years of age and had persistent OAB symptoms, regardless of whether they took an alpha1-adrenergic receptor blocker orally. Before and 12 weeks after mirabegron additional therapy (50 mg once daily), we evaluated the efficacy of this treatment using the Overactive Bladder Symptom Score (OABSS) and International Prostate Symptom Score (IPSS), and changes in the maximum flow rate (Qmax) and post-void residual urine volume (PVR). We evaluated patients overall and divided into two groups by age: young-old (from 65 to 74 years old) and old old (from 75 to 84 years old). RESULTS: Fifty men were enrolled in this study. Mirabegron additional therapy improved the total OABSS, total IPSS, and IPSS quality of life (QOL) score. The voided volume (VV) and Qmax improved after treatment in patients overall. However, there was no significant change in PVR. The total OABSS, total IPSS, and IPSS-QOL score significantly improved in both of the young-old and old-old groups. However, a significant increasing of VV was detected in the young-old group. There were no significant differences in the Qmax or PVR in either group. CONCLUSIONS: Mirabegron additional therapy was effective for male patients whose persistent LUTS and particularly OAB was not controlled with alpha1-adrenergic receptor blocker monotherapy, and mirabegron did not have negative effects on voiding function. Additionally, mirabegron additional therapy was considered effective regardless of patient age. TRIAL REGISTRATION: Trial registration number (TRN) trial registration number (TRN) and date of registration: ISRCTN16759097 in July 8, 2016. PMID- 27473060 TI - Models and impact of patient and public involvement in studies carried out by the Medical Research Council Clinical Trials Unit at University College London: findings from ten case studies. AB - BACKGROUND: Patient and public involvement (PPI) in studies carried out by the UK Medical Research Council Clinical Trials Unit (MRC CTU) at University College London varies by research type and setting. We developed a series of case studies of PPI to document and share good practice. METHODS: We used purposive sampling to identify studies representing the scope of research at the MRC CTU and different approaches to PPI. We carried out semi-structured interviews with staff and patient representatives. Interview notes were analysed descriptively to categorise the main aims and motivations for involvement; activities undertaken; their impact on the studies and lessons learned. RESULTS: We conducted 19 interviews about ten case studies, comprising one systematic review, one observational study and 8 randomised controlled trials in HIV and cancer. Studies were either open or completed, with start dates between 2003 and 2011. Interviews took place between March and November 2014 and were updated in summer 2015 where there had been significant developments in the study (i.e. if the study had presented results subsequent to the interview taking place). A wide range of PPI models, including representation on trial committees or management groups, community engagement, one-off task-focused activities, patient research partners and participant involvement had been used. Overall, interviewees felt that PPI had a positive impact, leading to improvements, for example in the research question; study design; communication with potential participants; study recruitment; confidence to carry out or complete a study; interpretation and communication of results; and influence on future research. CONCLUSIONS: A range of models of PPI can benefit clinical studies. Researchers should consider different approaches to PPI, based on the desired impact and the people they want to involve. Use of multiple models may increase the potential impacts of PPI in clinical research. PMID- 27473062 TI - Evo-Devo-EpiR: a genome-wide search platform for epistatic control on the evolution of development. AB - Evo-devo is a theory proposed to study how phenotypes evolve by comparing the developmental processes of different organisms or the same organism experiencing changing environments. It has been recognized that nonallelic interactions at different genes or quantitative trait loci, known as epistasis, may play a pivotal role in the evolution of development, but it has proven difficult to quantify and elucidate this role into a coherent picture. We implement a high dimensional genome-wide association study model into the evo-devo paradigm and pack it into the R-based Evo-Devo-EpiR, aimed at facilitating the genome-wide landscaping of epistasis for the diversification of phenotypic development. By analyzing a high-throughput assay of DNA markers and their pairs simultaneously, Evo-Devo-EpiR is equipped with a capacity to systematically characterize various epistatic interactions that impact on the pattern and timing of development and its evolution. Enabling a global search for all possible genetic interactions for developmental processes throughout the whole genome, Evo-Devo-EpiR provides a computational tool to illustrate a precise genotype-phenotype map at interface between epistasis, development and evolution. PMID- 27473061 TI - Quantitative assessment of the spatial heterogeneity of tumor-infiltrating lymphocytes in breast cancer. AB - BACKGROUND: Tumor-infiltrating lymphocyte (TIL) count in breast cancer carries prognostic information and represents a potential predictive marker for emerging immunotherapies. However, the distribution of the lymphocyte subpopulations is not well defined. The goals of this study were to examine intratumor heterogeneity in TIL subpopulation counts in different fields of view (FOV) within each section, in different sections from the same biopsy, and between biopsies from different regions of the same cancer using quantitative immunofluorescence (QIF). METHODS: We used multiplexed QIF to quantify cytokeratin-positive epithelial cells, and CD3-positive, CD8-positive and CD20 positive lymphocytes in tissue sections from multiple biopsies obtained from different areas of 31 surgically resected primary breast carcinomas (93 samples total). Log2-transformed QIF scores or concordance and variance component analyses with linear mixed-effects models were used. Cohen's kappa index [k] of high versus low scores, defined as above and below the median, was used to measure sample similarity between areas. RESULTS: We found a strong positive correlation between CD3 and CD8 levels across all patients (Pearson correlation coefficient [CC] = 0.827). CD3 and CD8 showed a weaker but significant association with CD20 (CC = 0.446 and 0.363, respectively). For each marker, the variation between different FOVs in the same section was higher than the variation between sections or between biopsies of the same cancer. The intraclass correlation coefficients (ICC) were 0.411 for CD3, 0.324 for CD8, and 0.252 for CD20. In component analysis, 66-69 % of the variance was attributable to differences between FOVs in the same section and 30-33 % was due to differences between biopsies from different areas of the same cancer. Section to section differences were negligible. Concordance for low versus high marker status assignment in single biopsies compared to all three biopsies combined yielded k = 0.705 for CD3, k = 0.655 for CD8, and k = 0.603 for CD20. CONCLUSIONS: T and B lymphocytes show more heterogeneity across the dimensions of a single section than between different sections or regions of a given breast tumor. This observation suggests that the average lymphocyte score from a single biopsy of a tumor is reasonably representative of the whole cancer. PMID- 27473063 TI - Comparative assessment of differential network analysis methods. AB - Differential network analysis (DiNA) denotes a recent class of network-based Bioinformatics algorithms which focus on the differences in network topologies between two states of a cell, such as healthy and disease, to identify key players in the discriminating biological processes. In contrast to conventional differential analysis, DiNA identifies changes in the interplay between molecules, rather than changes in single molecules. This ability is especially important in cases where effectors are changed, e.g. mutated, but their expression is not. A number of different DiNA approaches have been proposed, yet a comparative assessment of their performance in different settings is still lacking. In this paper, we evaluate 10 different DiNA algorithms regarding their ability to recover genetic key players from transcriptome data. We construct high quality regulatory networks and enrich them with co-expression data from four different types of cancer. Next, we assess the results of applying DiNA algorithms on these data sets using a gold standard list (GSL). We find that local DiNA algorithms are generally superior to global algorithms, and that all DiNA algorithms outperform conventional differential expression analysis. We also assess the ability of DiNA methods to exploit additional knowledge in the underlying cellular networks. To this end, we enrich the cancer-type specific networks with known regulatory miRNAs and compare the algorithms performance in networks with and without miRNA. We find that including miRNAs consistently and considerably improves the performance of almost all tested algorithms. Our results underline the advantages of comprehensive cell models for the analysis of -omics data. PMID- 27473064 TI - Deep learning in bioinformatics. AB - In the era of big data, transformation of biomedical big data into valuable knowledge has been one of the most important challenges in bioinformatics. Deep learning has advanced rapidly since the early 2000s and now demonstrates state-of the-art performance in various fields. Accordingly, application of deep learning in bioinformatics to gain insight from data has been emphasized in both academia and industry. Here, we review deep learning in bioinformatics, presenting examples of current research. To provide a useful and comprehensive perspective, we categorize research both by the bioinformatics domain (i.e. omics, biomedical imaging, biomedical signal processing) and deep learning architecture (i.e. deep neural networks, convolutional neural networks, recurrent neural networks, emergent architectures) and present brief descriptions of each study. Additionally, we discuss theoretical and practical issues of deep learning in bioinformatics and suggest future research directions. We believe that this review will provide valuable insights and serve as a starting point for researchers to apply deep learning approaches in their bioinformatics studies. PMID- 27473066 TI - Gene Ontology semantic similarity tools: survey on features and challenges for biological knowledge discovery. AB - Gene Ontology (GO) semantic similarity tools enable retrieval of semantic similarity scores, which incorporate biological knowledge embedded in the GO structure for comparing or classifying different proteins or list of proteins based on their GO annotations. This facilitates a better understanding of biological phenomena underlying the corresponding experiment and enables the identification of processes pertinent to different biological conditions. Currently, about 14 tools are available, which may play an important role in improving protein analyses at the functional level using different GO semantic similarity measures. Here we survey these tools to provide a comprehensive view of the challenges and advances made in this area to avoid redundant effort in developing features that already exist, or implementing ideas already proven to be obsolete in the context of GO. This helps researchers, tool developers, as well as end users, understand the underlying semantic similarity measures implemented through knowledge of pertinent features of, and issues related to, a particular tool. This should empower users to make appropriate choices for their biological applications and ensure effective knowledge discovery based on GO annotations. PMID- 27473065 TI - Indel detection from RNA-seq data: tool evaluation and strategies for accurate detection of actionable mutations. AB - Driver somatic mutations are a hallmark of a tumor that can be used for diagnosis and targeted therapy. Mutations are primarily detected from tumor DNA. As dynamic molecules of gene activities, transcriptome profiling by RNA sequence (RNA-seq) is becoming increasingly popular, which not only measures gene expression but also structural variations such as mutations and fusion transcripts. Although single-nucleotide variants (SNVs) can be easily identified from RNA-seq, intermediate long insertions/deletions (indels > 2 bases and less than sequence reads) cause significant challenges and are ignored by most RNA-seq analysis tools. This study evaluates commonly used RNA-seq analysis programs along with variant and somatic mutation callers in a series of data sets with simulated and known indels. The aim is to develop strategies for accurate indel detection. Our results show that the RNA-seq alignment is the most important step for indel identification and the evaluated programs have a wide range of sensitivity to map sequence reads with indels, from not at all to decently sensitive. The sensitivity is impacted by sequence read lengths. Most variant calling programs rely on hard evidence indels marked in the alignment and the programs with realignment may use soft-clipped reads for indel inferencing. Based on the observations, we have provided practical recommendations for indel detection when different RNA-seq aligners are used and demonstrated the best option with highly reliable results. With careful customization of bioinformatics algorithms, RNA seq can be reliably used for both SNV and indel mutation detection that can be used for clinical decision-making. PMID- 27473067 TI - Impact of recent regulatory notifications on an institutional ethics committee. AB - The Government of India came out with a slew of notifications to streamline clinical research in the beginning of 2013 in response to the Supreme Court's orders and a Parliamentary Standing Committee's report. The notifications greatly influenced the structure, review process, outcomes and administration of ethics committees across India. In this study, we attempted to objectively evaluate the impact of these notifications on our institutional ethics committee's (IEC) structure, review process, outcomes and administration. The results revealed that though the number of regulatory studies reviewed by our IEC remained the same, the number of studies actually approved decreased with an increase in the turnover time. The number of serious adverse events (SAEs) reported also fell, although the number of meetings held to discuss these SAEs increased significantly. The administrative workload rose with increased documentation. Though the annual income of the IEC fell marginally, the expenses shot up. We believe that the notifications definitely had an impact on the structure, review process, outcomes and administration of our IEC, although it remains to be seen whether they had a real impact on the research participants' safety and well being. PMID- 27473068 TI - Integrin alphaDbeta2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS). AB - BACKGROUND: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a potentially lethal complication of clinical malaria. Acute lung injury in MA-ARDS shares features with ARDS triggered by other causes, including alveolar inflammation and increased alveolar-capillary permeability, leading to leak of protein-rich pulmonary oedema fluid. Mechanisms and physiologic alterations in MA ARDS can be examined in murine models of this syndrome. Integrin alphaDbeta2 is a member of the leukocyte, or beta2 (CD18), sub-family of integrins, and emerging observations indicate that it has important activities in leukocyte adhesion, accumulation and signalling. The goal was to perform analysis of the lungs of mice wild type C57Bl/6 (a D (+/+) ) and Knockout C57Bl/6 (a D (-/-) ) with malaria-associated acute lung injury to better determine the relevancy of the murine models and investigate the mechanism of disease. METHODS: C57BL/6 wild type (a D (+/+) ) and deficient for CD11d sub-unit (a D (-/-) ) mice were monitored after infection with 10(5) Plasmodium berghei ANKA. CD11d subunit expression RNA was measured by real-time polymerase chain reaction, vascular barrier integrity by Evans blue dye (EBD) exclusion and cytokines by ELISA. Protein and leukocytes were measured in bronchoalveolar lavage fluid (BALF) samples. Tissue cellularity was measured by the point-counting technique, F4/80 and VCAM-1 expression by immunohistochemistry. Respiratory function was analysed by non-invasive BUXCO and mechanical ventilation. RESULTS: Alveolar inflammation, vascular and interstitial accumulation of monocytes and macrophages, and disrupted alveolar-capillary barrier function with exudation of protein-rich pulmonary oedema fluid were present in P. berghei-infected wild type mice and were improved in alphaDbeta2-deficient animals. Key pro-inflammatory cytokines were also decreased in lung tissue from alpha D (-/-) mice, providing a mechanistic explanation for reduced alveolar-capillary inflammation and leak. CONCLUSIONS: The results indicate that alphaDbeta2 is an important inflammatory effector molecule in P. berghei-induced MA-ARDS, and that leukocyte integrins regulate critical inflammatory and pathophysiologic events in this model of complicated malaria. Genetic deletion of integrin subunit alphaD in mice, leading to deficiency of integrin alphaDbeta2, alters lung inflammation and acute lung injury in a mouse model of MA-ARDS caused by P. berghei. PMID- 27473069 TI - The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds. AB - The production of fully functional insulin-secreting cells to treat diabetes is a major goal of regenerative medicine. In this article, I review progress towards this goal over the last 15 years from the perspective of a beta cell biologist. I describe the current state-of-the-art, and speculate on the general approaches that will be required to identify and achieve our ultimate goal of producing functional beta cells. The need for deeper phenotyping of heterogeneous cultures of stem cell derived islet-like cells in parallel with a better understanding of the heterogeneity of the target cell type(s) is emphasised. This deep phenotyping should include high-throughput single-cell analysis, as well as comprehensive 'omics technologies to provide unbiased characterisation of cell products and human beta cells. There are justified calls for more detailed and well-powered studies of primary human pancreatic beta cell physiology, and I propose online databases of standardised human beta cell responses to physiological stimuli, including both functional and metabolomic/proteomic/transcriptomic profiles. With a concerted, community-wide effort, including both basic and applied scientists, beta cell replacement will become a clinical reality for patients with diabetes. PMID- 27473070 TI - Personal and Financial Risk Typologies Among Women Who Engage in Sex Work in Mongolia: A Latent Class Analysis. AB - Women engaged in sex work bear a disproportionate burden of HIV infection worldwide, particularly in low- to middle-income countries. Stakeholders interested in promoting prevention and treatment programs are challenged to efficiently and effectively target heterogeneous groups of women. This problem is particularly difficult because it is nearly impossible to know how those groups are composed a priori. Although grouping based on individual variables (e.g., age or place of solicitation) can describe a sample of women engaged in sex work, selecting these variables requires a strong intuitive understanding of the population. Furthermore, this approach is difficult to quantify and has the potential to reinforce preconceived notions, rather than generate new information. We aimed to investigate groupings of women engaged in sex work. The data were collected from a sample of 204 women who were referred to an HIV prevention intervention in Ulaanbaatar, Mongolia. Latent class analysis was used to create subgroups of women engaged in sex work, based on personal and financial risk factors. This analysis found three latent classes, representing unique response pattern profiles of personal and financial risk. The current study approached typology research in a novel, more empirical way and provided a description of different subgroups, which may respond differently to HIV risk interventions. PMID- 27473071 TI - Devaluation of Safe Sex by Delay or Uncertainty: A Within-Subjects Study of Mechanisms Underlying Sexual Risk Behavior. AB - The value of safe sex may be discounted based on contextual factors associated with an opportunity for sex. College students in a within-subjects study selected hypothetical sexual partners from a set of pictures and classified them based on attractiveness and estimated chance of having an sexually transmitted infection (STI). In the Sexual Delay Discounting (SDD) task, participants rated their likelihood (0-100 %) of waiting for some period of time (e.g., 3 h) to have protected sex with their selected partners, when they could have immediate sex without protection. In the Sexual Probability Discounting (SPD) task, participants rated their likelihood of having protected sex if the opportunity was uncertain (e.g., 50 %), when they could have unprotected sex for sure (100 %). All participants included in the final analyses were aware of and had a positive attitude towards protection against STIs as they were likely to have immediate (or certain) protected sex. Results from 432 delay data in the SDD task and 488 probability data in the SPD task showed that participants' preference for safe sex systematically decreased as the delay to and odds against having safe sex increased. However, this preference was altered by the participants' perception of their partner's attractiveness and STI risk. PMID- 27473072 TI - Are Outness and Community Involvement Risk or Protective Factors for Alcohol and Drug Abuse Among Sexual Minority Women? AB - Sexual minority women (SMW) are at increased risk for substance abuse compared to heterosexual women. Two psychosocial factors that have been implicated in SMW's substance abuse are outness and LGBT community involvement, but findings have been mixed as to whether these are risk or protective factors. One possible explanation is that they may have different consequences for subgroups of SMW (lesbians, bisexual women, and queer women). While being open about one's sexual orientation and involved in the community may be protective for lesbians, discrimination against bisexual women may lead these same factors to contribute to substance abuse for bisexual women. It is unclear how these associations will operate for queer women, given limited research on this subpopulation. The current study examined whether sexual identity moderated the associations between outness and community involvement with alcohol and drug abuse. We also examined whether perceived discrimination would help explain why these associations may be different for subgroups of SMW. A sample of 288 self-identified SMW (113 lesbians, 106 bisexual women, and 69 queer women) completed an online survey. Higher outness was associated with higher alcohol and drug abuse for bisexual women, but not for lesbians or queer women. Similarly, higher community involvement was associated with higher drug abuse for bisexual women, but not for lesbians or queer women. Among bisexual women, the association between community involvement and drug abuse was mediated by perceived discrimination. Further, the association between outness and drug abuse was mediated by both community involvement and perceived discrimination. Findings demonstrate that outness and community involvement function as risk factors for substance abuse for bisexual women, in part due to their associations with discrimination. PMID- 27473073 TI - Changes in the Sexual Relationship and Relationship Adjustment Precede Extradyadic Sexual Involvement. AB - Extradyadic sexual involvement (ESI) is associated with negative consequences for individuals and threatens couple stability. Research on ESI in unmarried samples has been marked by methodological limitations, such as examining only mean levels of sexual satisfaction or frequency to predict later ESI as opposed to changes in various aspects of the sexual relationship over time. The current study compared linear trajectories of four aspects of the sexual relationship-sexual satisfaction, frequency of sex, comfort communicating about sex, and sexual closeness-between individuals in opposite-sex, unmarried relationships who subsequently engaged in ESI (ESI group; n = 183) compared to individuals who did not engage in ESI (non-ESI group; n = 603). Trajectories of relationship adjustment were also evaluated leading up to ESI as well as controlled for in models evaluating the sexual relationship. Results indicated that relationship adjustment declined for individuals preceding ESI, but did not change for the non ESI group. When controlling for relationship adjustment, comfort communicating about sex decreased for ESI women but increased for ESI men. Some results became nonsignificant after controlling for relationship adjustment, including that sexual satisfaction declined more steeply in the ESI group compared to the non ESI group, and ESI women significantly decreased in sexual closeness while ESI men demonstrated no significant change. Some mean level differences were also discovered directly before ESI. Conclusions include that changes in a couple's sexual relationship and relationship adjustment are associated with ESI behaviors, providing novel information regarding normative and risk trajectories. PMID- 27473074 TI - Early origins of mental disorder - risk factors in the perinatal and infant period. AB - BACKGROUND: There is increasing understanding of the significance of early neurodevelopment in establishing risk for the range of mental disorders. Models of the early aetiology of mental disorders are complex with a range of potential factors from genetic and epigenetic to environmental influencing neurological and psychological development. Whilst the mechanisms are not fully understood, this paper provides an overview of potential biological and neurobiological factors that might be involved. METHOD: An aetiological model is presented and discussed. The discussion includes a range of risk factors for mental disorder. Maternal anxiety disorder is presented and reviewed as an example of the interaction of placental, epigenetic and early parenting factors elevating risk of poor neonatal outcome. RESULTS: Available evidence points to the importance of in-utero influences as well as the role of early attachment and emotional care. Transgenerational mechanisms such as the impact of maternal mental disorder on foetal development are important models for examination of early risk. Maternal anxiety, as an example, is a significant risk factor for compromised mental health. CONCLUSIONS: Development of models for understanding the early origins of mental disorder is an important step in elaborating risk reduction strategies. Comprehensive early identification of risk raises the possibility of preventive interventions. PMID- 27473076 TI - Adopting a healthy lifestyle when pregnant and obese - an interview study three years after childbirth. AB - BACKGROUND: Obesity during pregnancy is increasing and is related to life threatening and ill-health conditions in both mother and child. Initiating and maintaining a healthy lifestyle when pregnant with body mass index (BMI) >= 30 kg/m(2) can improve health and decrease risks during pregnancy and of long-term illness for the mother and the child. To minimise gestational weight gain women with BMI >= 30 kg/m(2) in early pregnancy were invited to a lifestyle intervention including advice and support on diet and physical activity in Gothenburg, Sweden. The aim of this study was to explore the experiences of women with BMI >= 30 kg/m(2) regarding minimising their gestational weight gain, and to assess how health professionals' care approaches are reflected in the women's narratives. METHODS: Semi-structured interviews were conducted with 17 women who had participated in a lifestyle intervention for women with BMI >= 30 kg/m(2) during pregnancy 3 years earlier. The interviews were digitally recorded and transcribed in full. Thematic analysis was used. RESULTS: The meaning of changing lifestyle for minimising weight gain and of the professional's care approaches is described in four themes: the child as the main motivation for making healthy changes; a need to be seen and supported on own terms to establish healthy routines; being able to manage healthy activities and own weight; and need for additional support to maintain a healthy lifestyle. CONCLUSIONS: To support women with BMI >= 30 kg/m(2) to make healthy lifestyle changes and limit weight gain during pregnancy antenatal health care providers should 1) address women's weight in a non-judgmental way using BMI, and provide accurate and appropriate information about the benefits of limited gestational weight gain; 2) support the woman on her own terms in a collaborative relationship with the midwife; 3) work in partnership to give the woman the tools to self-manage healthy activities and 4) give continued personal support and monitoring to maintain healthy eating and regular physical activity habits after childbirth involving also the partner and family. PMID- 27473075 TI - Beta-glucan contamination of pharmaceutical products: How much should we accept? AB - Beta-glucans are large polysaccharides produced by a range of prokaryotic and eukaryotic organisms. They have potential immunostimulatory properties and have been used with therapeutic intent as anti-microbial and anti-tumour agents. A range of other potentially beneficial effects have been described, and oral forms of beta-glucans are widely available over-the-counter and online. Parenteral formulations are popular in parts of Asia and are the subject of ongoing trials, worldwide. Beta-glucans are also potential contaminants of pharmaceutical products, and high levels have been described in some blood products. However, little is known about the clinical effects of such contamination, considerable uncertainty exists over the level at which immunostimulation may occur, and there are no guidelines available on acceptable levels. We encountered beta-glucan contamination of one of our products, and we suspect that others may encounter similar issues since the origin of beta-glucan contamination includes commonly used filters and solutions applied in the manufacture of biotherapeutic agents. It is likely that regulators will increasingly enquire about beta-glucan levels in pharmaceutical products, especially those with an immunomodulatory mechanism of action. Here, we review the literature on beta-glucans in pharmaceutical products and propose an acceptable level for therapeutic agents for parenteral use. PMID- 27473077 TI - Recommendations for treatment of hypothyroidism with levothyroxine and levotriiodothyronine: a 2016 position statement of the Italian Society of Endocrinology and the Italian Thyroid Association. AB - Levothyroxine (L-T4) is recommended as lifelong replacement therapy for hypothyroidism. Recent clinical and experimental data support the addition of levotriiodothyronine (L-T3) treatment in some selected hypothyroid patients when their symptoms persist and their quality of life remains impaired despite adequate L-T4 monotherapy. An increase in L-T3 prescriptions has been recently observed in Italy due to availability of different L-T3 formulations, making it possible to clinicians to prescribe L-T3 alone or in combination with L-T4. The aim of the present position statement was to define the correct clinical indications, schedule, duration of treatment and contraindications of combined treatment with L-T4 and L-T3 in hypothyroid patients in an attempt to guide clinicians and to avoid potential adverse effects of overtreatment. PMID- 27473078 TI - New markers of insulin resistance in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder in women of reproductive age. The diagnostic criteria include two out of three features: hyperandrogenism, polycystic ovaries on ultrasound and menstrual irregularities (Rotterdam Criteria 2003). PCOS patients are more vulnerable to develop diabetes, cardiovascular diseases and metabolic syndrome. Insulin resistance (IR) is prevalent in women with PCOS independently of obesity and is critically involved in reproductive and metabolic complications of the syndrome. Several tests have been developed to measure IR, some very reliable but complex like the hyperinsulinemic euglycemic glucose clamp and others less precise but easier and less invasive like HOMA-IR. New markers are needed to reach a more reliable assessment of insulin resistance. To date, several surrogate markers have been proposed in the literature to facilitate and improve the determination of IR. Many new proteins are strongly involved with PCOS physiopathology and IR, such as some adipocytokines (adiponectin, visfatin, vaspin and apelin), copeptin, irisin, PAI-1 and zonulin. Many other proteins have been proposed as potential new markers of IR in PCOS, such as resistin, leptin, RBP4, kisspetin and ghrelin, but their role is still controversial. In this review, we provide a short characterization of these new markers, recently studied as indicators of metabolic state. PMID- 27473080 TI - Erratum to: Secretome of tumor-associated leukocytes augment epithelial mesenchymal transition in positive lymph node breast cancer patients via activation of EGFR/Tyr845 and NF-kB/p65 signaling pathway. PMID- 27473079 TI - The relationship between the expression of FOXA1 and GATA3 and the efficacy of neoadjuvant endocrine therapy. AB - BACKGROUND: Estrogen receptor (ER)/GATA3/Forkhead box A1 (FOXA1) network is necessary for the ERalpha functional signature. High FOXA1 expression indicates a good prognosis in ER-positive breast cancer. However, little is known about the significance of FOXA1 and GATA3 expression in neoadjuvant endocrine therapy (NAE). The aim of this study is to investigate their predictive potential for NAE and their expression changes after NAE. METHODS: FOXA1 and GATA3 expression was evaluated using immunohistochemistry in 66 patients with ER-positive/HER2 negative breast cancer who had been treated with NAE. The association between biological marker expressions and the efficacy of NAE and their expression changes after NAE were analyzed. RESULTS: The median pre-treatment FOXA1 and GATA3 expressions were 94.6 and 90 %. Pre-treatment FOXA1 expression was positively correlated with GATA3 (P = 0.0003) and progesterone receptor (PgR) (P = 0.0138). There was no correlation between pre- or post-treatment FOXA1 and GATA3 expressions and the efficacy of NAE. Post-treatment Ki67 expression was significantly lower in tumors with partial response (PR) (P = 0.0007). In terms of the changes of the expression, PgR, Ki67, and FOXA1 expression significantly decreased after NAE (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). CONCLUSIONS: FOXA1 and GATA3 expression was not correlated with the efficacy of NAE, but FOXA1 expression was significantly reduced after NAE. PMID- 27473081 TI - Genomic imbalances and microRNA transcriptional profiles in patients with mycosis fungoides. AB - Mycosis fungoides is the most common type of primary cutaneous T cell lymphoma. We have evaluated CDKN2A losses and MYC gains/amplifications by FISH analysis, as well as expression of miR-155 and members of the oncogenic cluster miR-17-92 (miR17, miR18a, miR19b, and miR92a) in MF patients with advanced disease. Formalin-fixed paraffin-embedded skin biopsies from 36 patients at diagnosis, 16 with tumoral MF (T-MF), 13 in histological transformation to a large T cell lymphoma (TR-MF), and 7 cases with folliculotropic variant (F-MF), were studied. Twenty cases showed genomic alterations (GAs): 8 (40 %) had CDKN2A deletion, 7 (35 %) showed MYC gain, and 5 (25 %) exhibited both alterations. GAs were more frequently observed in F-MF (p = 0.004) and TR-MF (p = 0.0001) than T-MF. GAs were significantly higher in cases presenting lesions in head, neck, and lower extremities compared to those observed in trunk and upper extremities (p = 0.03), when >=25 % neoplastic cells were CD30 positive (p = 0.016) as well as in cases with higher Ki-67 proliferation index (p = 0.003). Patients with GAs showed bad response to treatment (p = 0.02) and short survival (p = 0.04). Furthermore, MF patients showed higher miRNA expression compared to controls (p <= 0.0223). T-MF showed higher miR17 and miR-18a expression compared to F-MF and TR-MF (p <= 0.0387) while miR19b, miR92a, and miR-155 showed increased levels in F-MF and TR MF with respect to T-MF (p <= 0.0360). Increased expression of miR17 and miR19b in GA group compared to cases without alterations (p >= 0.0307) was also detected. Our results add new information about genomic imbalances in MF patients, particularly in F-MF, and extend the present view of miRNA deregulation in this disease. PMID- 27473082 TI - A novel VHLalpha isoform inhibits Warburg effect via modulation of PKM splicing. AB - Von Hippel-Lindau (VHL) is the most frequently mutated gene in clear cell renal carcinoma. Here, we identified a novel translational variant of VHL, termed VHLalpha, initiated from an alternative translational start site upstream and in frame with the ATG start codon. We showed that VHLalpha interacts with and regulates heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), which consequently modulates pyruvate kinase transcript splicing and reprograms cellular glucose metabolism. Our study demonstrated that a novel VHL isoform may function as a tumor suppressor through inhibiting the Warburg effect. PMID- 27473083 TI - High expression of apoptosis-inducing factor, mitochondrion-associated 3 (AIFM3) in human cholangiocarcinoma. AB - Prognosis of cholangiocarcinoma (CCA) patients is absolutely poor in spite of extensive efforts for the development of chemotherapy. Mitochondrial proteins play key roles in carcinogenesis of various cancers. Therefore, mitochondria are considered as the target organelles for chemotherapy of several cancers including CCA. The purpose of this study is to identify potential candidate proteins for chemotherapy using mitochondrial proteome analysis for CCA tissues. A shotgun proteomic approach using SDS-PAGE coupled with LC-MS/MS was applied to compare the expression of mitochondrial proteins in CCA and the adjacent non-cancerous tissues. Using the proteomic analysis for the pooled mitochondrial proteins purified from three each of papillary and non-papillary types of CCA and their adjacent tissues, 281 proteins were identified as mitochondrial proteins, and 105 of them have significantly different expression levels compared with the corresponding counterparts. Among the 105 proteins, apoptosis-inducing factor, mitochondrion-associated 3 (AIFM3) was a unique protein commonly over-expressed in both papillary and non-papillary types of CCA tissues but not in the adjacent non-cancerous tissues. In conclusion, AIFM3 was aberrantly expressed only in the mitochondria of CCA tissues. This finding suggests that AIFM3 could be a potential target molecule for CCA chemotherapy. PMID- 27473084 TI - ASPP2 suppresses stem cell-like characteristics and chemoresistance by inhibiting the Src/FAK/Snail axis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients' prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice. An expression profiling assay revealed that ASPP2 specifically repressed focal adhesion kinase (FAK)/Src/extracellular signal regulated kinase (ERK) signaling. ASPP2 does this by physically interacting with C-terminal Src kinase (CSK) and stimulating its kinase activity, which eventually leads to activator protein 1 (AP1)-mediated downregulation of Snail expression. In addition, pharmacologic inhibition of Src attenuated the effects of ASPP2 deficiency. Our findings present functional and mechanistic insight into the critical role of ASPP2 in the inhibition of HCC stemness and drug resistance and may provide a new strategy for therapeutic combinations to treat HCC. PMID- 27473085 TI - Prognostic value of mixed lineage kinase domain-like protein expression in the survival of patients with gastric caner. AB - The aim of this study was to detect mixed lineage kinase domain-like protein (MLKL) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse-transcriptase polymerase chain reaction were performed to detect MLKL tissue expression in 117 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of MLKL expression. The chi-square test was used to analyze the relationship between MLKL expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan-Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of MLKL mRNA was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.003). Clinicopathological analysis showed that MLKL expression was significantly correlated with age (P = 0.013), histologic type (P = 0.049), differentiation grade (P < 0.001), depth of invasion (P = 0.022), and lymph node metastasis (P = 0.003). Low MLKL expression was significantly associated with decreased overall survival (median 29 months vs. 56 months, P < 0.001). Multivariate analysis suggested that MLKL expression might be an independent prognostic indicator (HR = 0.645, 95 % CI, 0.446-1.165, P = 0.002) for GC patients. In conclusion, our findings provide evidence that MLKL might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC. PMID- 27473086 TI - Total and mutated EGFR quantification in cell-free DNA from non-small cell lung cancer patients detects tumor heterogeneity and presents prognostic value. AB - Mutation analysis of epidermal growth factor receptor (EGFR) gene is essential for treatment selection in non-small cell lung cancer (NSCLC). Analysis is usually performed in tumor samples. We evaluated the clinical utility of EGFR analysis in plasma cell-free DNA (cfDNA) from patients under treatment with EGFR inhibitors. We selected 36 patients with NSCLC and EGFR-activating mutations. Blood samples were collected at baseline and during treatment with EGFR inhibitors. Wild-type EGFR, L858R, delE746-A750, and T790M mutations were quantified in cfDNA by droplet digital PCR. Stage IV patients had higher total circulating EGFR copy levels than stage I (3523 vs. 1003 copies/mL; p < 0.01). There was high agreement for activating mutations between baseline cfDNA and tumor samples, especially for L858R mutation (kappa index = 0.679; p = 0.001). In 34 % of advanced NSCLC patients, we detected mutations in cfDNA not previously detected in tumor samples and double mutations in 17 %. Patients with baseline total EGFR copy levels above the median presented decreased overall survival (OS) (341 vs. 870 days, p < 0.05) and progression-free survival (PFS) (238 vs. 783 days; p < 0.05) compared with those with total EGFR copy levels below the median. Patients with baseline concentrations of activating mutations above the median (94 copies/mL) had lower OS (317 vs. 805 days; p < 0.05) and PFS (195 vs. 724 days; p < 0.05). During follow-up, T790M resistance mutation was detected in 53 % of patients. Total and mutated EGFR analysis in cfDNA seems a relevant tool to characterize the molecular profile and prognosis of NSCLC patients harboring EGFR mutations. PMID- 27473088 TI - Measuring transaminases in patients with rheumatoid arthritis on weekly methotrexate: does timing of blood testing matter? AB - The change in transaminase levels over a single week during therapy with methotrexate (MTX) has not been investigated or reported to date. In clinical practice, it is common to observe abnormal transaminase levels upon routine blood work for toxicity monitoring. Many have suggested that such lab abnormalities can sometimes be attributed to sampling blood for toxicity monitoring proximately following MTX dosing. The aim of our study was to evaluate changes in transaminase levels (AST/ALT) over 1 week after MTX administration in rheumatoid arthritis (RA) patients. In this small proof of concept study, we evaluated 13 patients with RA taking stable doses of methotrexate and background medications (e.g., NSAIDs and prednisone), but no other disease-modifying anti-rheumatic drugs (DMARDs). All patients were on a stable dose of folic acid. Patients received their usual doses of MTX administered at a specified time, and then sequential blood samples were obtained over the course of 7 days. Peripheral blood was obtained at each time point to measure serum transaminases. We did not observe any significant change in sequential transaminases over 1 week in relationship to MTX administration. It is possible that MTX therapy alone does not lead to significant weekly transaminase variations, contrary to our clinical expectations. The addition of other medications (i.e., NSAIDs) to stable MTX regimen may result in transaminase abnormalities. PMID- 27473087 TI - Growth inhibitory effect of rapamycin in Hodgkin-lymphoma cell lines characterized by constitutive NOTCH1 activation. AB - Growing evidence suggests that deregulation of signalling elements of Notch and mammalian target of rapamycin (mTOR) pathways contribute to tumorigenesis. These signals play important roles in cellular functions and malignancies. Their tumorigenic role in T-cell acute lymphoblastic leukaemia (T-ALL) is well known; however, their potential interactions and functions are poorly characterized in Hodgkin lymphoma (HL). The aim of our study was to characterize mTOR and Notch signalling elements in HL cell lines (DEV, L1236, KMH2) and human biopsies and to investigate their cross-talk in the tumorous process. High mTOR activity and constitutive NOTCH1 activation was confirmed in HL cell lines, without any known oncogenic mutations in key elements, including those common to both pathways. The anti-tumour effect of Notch inhibitors are well known from several preclinical models but resistance and side effects occur in many cases. Here, we tested mTOR and Notch inhibitors and their combinations in gamma-secretase inhibitor (GSI) resistant HL cells in vitro and in vivo. mTOR inhibitor alone or in combination was able to reduce tumour growth; furthermore, it was more effective in xenograft models in vivo. Based on these results, we suggest that constitutively activated NOTCH1 may be a potential target in HL therapy; furthermore, mTOR inhibitors may be effective for decreasing tumour growth if resistance to Notch inhibitors develop. PMID- 27473089 TI - Individualized Education Program Development Among Racially/Ethnically Diverse Children and Adolescents with Health Conditions. AB - Background Black, Hispanic, and low income children bear a greater burden of chronic health conditions compared to wealthier white counterparts. Under federal law, schools provide services to children when their health conditions impair learning. These school services, called individualized education programs (IEPs) can reduce disparities in school outcomes. This paper examines the extent to which children with health conditions have an IEP plan, an important first step in understanding service utilization. Method Andersen's Behavioral Model was used to examine IEP plan presence by using the 2012 National Survey of Children's Health. School aged children (6-17), with at least one health condition (N = 16,496) were examined using multivariable logistic regression analysis to understand predisposing (age, sex, race/ethnicity), enabling (family and neighborhood), and need (health related) factors as predictors of having an IEP plan. Race/ethnicity interaction terms tested for moderating effects of race/ethnicity on the relationship between predisposing, enabling and need factors and having an IEP plan. Results Hispanic children were 93.4 % (OR = .066) less likely and Black children were 87.9 % (OR = .121) less likely to have an IEP plan compared to White children. Black, Hispanic, and Multiracial children were more likely to have an IEP plan if they had more family and neighborhood resources (OR range 1.37-1.62) and greater health needs and health care needs (OR range 1.29-2.57). Conclusion The Behavioral Model was useful in predicting the presence of IEP plans among racially/ethnically diverse children with health conditions as an important step in understanding disparities in healthcare access in schools. PMID- 27473090 TI - Health Behaviors Among Women Using Fertility Treatment. AB - Objective To describe associated perinatal behaviors among women using fertility treatment. Methods Data were obtained for 12,197 Maryland women who delivered live neonates from 2004 to 2011 and completed the Pregnancy Risk Assessment Monitoring System survey postpartum. We conducted weighted descriptive and multivariable analyses. Results Among 1368 women using fertility treatments, 28.4 % did not take folic acid daily 1 month before pregnancy, 58.1 % consumed alcohol, 16.0 % were binge drinking, and 7.5 % smoked 3 months before pregnancy, and 12.9 % consumed alcohol and 3.7 % smoked during pregnancy. Additionally, among those who consumed alcohol and smoked before pregnancy, 36.0 % and 25.7 %, respectively, reported not receiving prenatal counseling about alcohol use and smoking. Lack of counseling for these women was higher than for women with unintended pregnancies who consumed alcohol (36.0 % vs. 26.3 %, P < .001) or smoked (25.7 % vs. 15.0 %, P < .001). Women using fertility treatments were less likely to have inadequate folic acid intake [adjusted odds ratio (aOR) 0.14, 95 % confidence interval (CI) 0.10-0.18), consume alcohol (aOR 0.52, 95 % CI 0.40 0.69), and smoke (aOR 0.35, 95 % CI 0.21-0.59) before pregnancy, and no statistically significant differences were found during pregnancy for alcohol consumption (aOR 0.89, 95 % CI 0.59-1.33) or smoking (aOR 0.64, 95 % CI 0.28 1.45) compared to women with unintended pregnancies. Conclusion A significant proportion of women using fertility treatments were not practicing recommended perinatal behaviors or receiving prenatal counseling on preventable risk factors. Ongoing counseling before and during pregnancy may be especially effective for optimizing healthy behaviors among these motivated women undergoing often stressful treatments for fertility. PMID- 27473091 TI - Recommend, but also Discuss: Different Patterns of Physician-Perceived Barriers to Discussing HPV Vaccination and Their Association with Vaccine Administration in 11-12 Year-Old Girls. AB - Objectives We examined variation in primary care physicians' (PCPs') perceptions of barriers to physician-initiated discussion of HPV vaccination, and how this is associated with the rates at which they discuss, initiate and continue to administer vaccination with 11-12 year-old girls. Methods We surveyed 301 PCPs using systematic random sampling. PCP variation in perceived barriers to discussing HPV vaccination was modeled using latent class analysis (LCA). The distinct PCP groups identified were compared with each other using three iterative logistic regression models to predict the likelihood of initiating vaccine discussion and the reported percentages of 11-12 year-old patients who initiated HPV vaccination and received follow-up shots. Results LCA revealed three groups of PCPs who perceived major, moderately significant and relatively minor barriers (17.9, 41.9 and 40.2 % of respondents, respectively). Pediatricians, PCPs who were female, had minority racial/ethnic status and who perceived only minor barriers had significantly higher odds of initiating discussion. PCPs were more likely to initiate HPV vaccination if they had initiated discussion and perceived minor or moderate communication barriers. Increased likelihood to administer follow-up HPV vaccine was associated with having initiated discussion, perceiving only minor barriers and working outside Deep South states, but not with having initiated vaccination. Conclusions for Practice PCPs who discuss HPV vaccination with girls aged 11-12 and their mothers are more likely to start and sustain vaccine administration. However, different PCPs perceive barriers to discussion in different ways. Interventions tailored to different groups of PCPs should assist them in overcoming barriers to discussing their recommendations when necessary. PMID- 27473092 TI - Effect of Planned Mode of Delivery in Women with Advanced Maternal Age. AB - OBJECTIVES: The purpose of this study was to determine the prognostic value of planned primary elective cesarean section versus planned vaginal delivery in women with advanced maternal age. METHODS: We conducted a population-based, retrospective cohort study using the United States' Health Care Cost and Utilization Project's Nationwide Inpatient Sample to evaluate maternal outcomes in women with advanced maternal age delivering from 2003 to 2012. Healthy women who underwent primary elective cesarean section constituted a surrogate for low risk planned cesarean delivery. Logistic regression was used to compare outcomes between women with planned cesarean and planned vaginal delivery. RESULTS: Among seven million births, we identified 442,067 deliveries in healthy women with advanced maternal age. The planned cesarean group comprised 7.96 % of women in the cohort. When compared to healthy women in the planned vaginal group, women in the planned cesarean group had a significantly higher mortality ratio (2.56/10,000 vs. 0.44/10,000, p < 0.01). The planned cesarean group was also at higher odds of numerous complications, including peripartum hysterectomy OR 1.81 (1.36-2.40), p < 0.01, cardiac arrest OR 5.39 (4.54-6.38), p < 0.01, acute renal failure OR 3.39 (1.78-6.46), p < 0.01 and sepsis OR 2.27 (1.25-4.14), p < 0.01. CONCLUSIONS FOR PRACTICE: Planned cesarean section is a key factor significantly influencing maternal morbidity and mortality in healthy women with advanced maternal age. When possible, planned cesarean deliveries should be avoided in this population. PMID- 27473093 TI - Fathers' Perceived Reasons for Their Underrepresentation in Child Health Research and Strategies to Increase Their Involvement. AB - Purpose Examine fathers' perceived reasons for their lack of inclusion in pediatric research and strategies to increase their participation. Description We conducted expert interviews with researchers and practitioners (N = 13) working with fathers to inform the development of an online survey. The survey-which measured fathers' perceived reasons for their underrepresentation in pediatric research, recommended recruitment venues, and research personnel and study characteristics valued by fathers-was distributed online and in-person to fathers. Assessment Respondents included 303 fathers. Over 80 % of respondents reported that fathers are underrepresented in pediatric research because they have not been asked to participate. Frequently recommended recruitment venues included community sports events (52 %), social service programs (48 %) and the internet (60 %). Compared with white fathers, more non-white fathers recommended public transit (19 % vs. 10 %, p = .02), playgrounds (16 % vs. 6 %, p = .007) and barber shops (34 % vs. 14 %, p < .0001) and fewer recommended doctors' offices (31 % vs. 43 %, p = .046) as recruitment venues. Compared with residential fathers (100 % resident with the target child), more non-residential fathers recommended social services programs (45 % vs. 63 %, p = .03) and public transit (10 % vs. 27 %, p = .001) and fewer recommended the workplace (17 % vs. 40 %, p = .002) as recruitment venues. Study brevity, perceived benefits for fathers and their families, and the credibility of the lead organization were valued by fathers. Conclusion Fathers' participation in pediatric research may increase if researchers explicitly invite father to participate, target father-focused recruitment venues, clearly communicate the benefits of the research for fathers and their families and adopt streamlined study procedures. PMID- 27473094 TI - Effects of Incentive-Based Smoking Cessation Program for Pregnant Women on Birth Outcomes. AB - Objectives Cigarette smoking during pregnancy is an important modifiable risk factor for poor birth outcomes. We evaluated whether participation in a statewide incentive-based smoking cessation program for pregnant women, the Baby & Me Tobacco Free (BMTF) program, was associated with improved birth outcomes. Methods Linked program and birth certificate data from 866 pregnant smokers who participated in the BMTF program and 11,568 pregnant smokers who were eligible for but did not enroll in the program were analyzed. The BMTF program consisted of 4 prenatal smoking cessation counselling sessions, 12 postpartum follow-up visits, breath carbon monoxide measurements to monitor smoking status, and rewards of diaper vouchers for quitting smoking. Logistic regression models were used to examine the associations of program participation with infant low birth weight and preterm birth. Results Participants who completed 3-4 prenatal smoking cessation sessions had a significantly lower rate of low birth weight than non participants (4.9 vs. 11.6 %). After adjustment for multiple potential confounders, the odds ratios for low birth weight were 0.51 (95 % confidence interval, 0.30-0.88) in those participants completing 3-4 sessions and 0.37 (95 % confidence interval, 0.17-0.79) in participants who quit smoking, as compared with non-participants. Although not statistically significant, a protective effect was also suggested for preterm birth. Conclusions We found for the first time that successful participation in the BMTF program, a unique incentive-based smoking cessation program for pregnant women implemented in community settings, was associated with significantly reduced odds of having a low birth weight infant. PMID- 27473095 TI - Alpha-1-antitrypsin interacts with gp41 to block HIV-1 entry into CD4+ T lymphocytes. AB - BACKGROUND: Study of a clinic case reveals that alpha-1-antitrypsin (AAT) deficiency is related to CD4+ T cell count decline and AIDS progression, suggesting that AAT might be an endogenous inhibitor of HIV/AIDS. Previous study shows that AAT inhibits HIV-1 replication in infected host cells and the C terminus fragment of AAT, VIRIP, interferes with HIV-1 infection. However, it is still unclear whether and how intact AAT inhibits HIV-1 infection. It is also unknown what the mechanism of AAT is and which critical step(s) are involved. RESULTS: In the present study, the C-terminus of AAT (C) was synthesized. C terminus-truncated AAT (DeltaAAT) was also prepared by digesting AAT with metalloproteinase. Primary CD4+ T cells were then co-cultured with HIV-1 with the presence or absence of AAT/C/DeltaAAT to detect cis-infection of HIV-1. The interaction between AAT/C/DeltaAAT and gp120/gp41 was also measured. Meanwhile, HIV-1 reverse transcriptase activity and viral DNA integration were also detected in these lymphocytes. The results demonstrated that AAT and C, not DeltaAAT, inhibited HIV-1 entry by directly interacting with gp41. Meanwhile, AAT, C and DeltaAAT could not directly interfere with the steps of viral RNA reverse transcription and viral DNA integration. CONCLUSION: AAT inhibits HIV-1 entry by directly interacting with gp41 through its C-terminus and thereby inhibits HIV-1 infection. PMID- 27473097 TI - Adrenal cryptococcosis in an immunosuppressed patient showing intensely increased metabolic activity on 18F-FDG PET/CT. AB - Disseminated cryptococcosis most commonly occurs in immunosuppressed patients and can rarely affect the adrenal glands. We report on a patient with biopsy proven bilateral adrenal cryptococcosis resulting in primary adrenal insufficiency, which was evaluated with whole-body positron emission tomography/computed tomography scan using 18F-FDG. Both enlarged adrenal glands presented intensely increased 18F-FDG activity in the periphery, while central necrotic regions were photopenic. Although diagnosis was established by adrenal gland biopsy, 18F-FDG positron emission tomography/computed tomography scan can significantly contribute to the assessment of disease activity and monitoring of treatment response. Furthermore, fungal infections should always be considered when encountering hypermetabolic adrenal masses, especially in the setting of immunodeficient patients. PMID- 27473096 TI - Antigen-based immunotherapies do not prevent progression of recent-onset autoimmune diabetes: a systematic review and meta-analysis. AB - We performed a systematic review and meta-analysis to assess the efficacy and safety of antigen-based immunotherapies in tertiary prevention of autoimmune diabetes. We searched for randomised controlled trials testing antigen-based immunotherapies in patients with recent-onset type 1 diabetes or latent autoimmune diabetes of adults in MEDLINE, COCHRANE and EMBASE databases, trial registries, conference proceedings and reference lists of pertinent records. Primary outcomes were fasting and stimulated C-peptide (after glucagon or mixed meal stimulation). Change in glycosylated haemoglobin (HbA1c), daily insulin needs and incidence of any or severe hypoglycaemic events or severe adverse events were secondary outcomes. Fifteen studies were included in the meta analysis. Overall, there was no difference in fasting [weighted mean difference (WMD) 0.01 nmol/L; 95 % confidence interval (CI) -0.09, 0.11; I 2 = 73 %] or mixed meal stimulated C-peptide (WMD 0.02 nmol/L/min; 95 % CI -0.08, 0.12; I 2 = 50 %) compared with placebo. Glucagon stimulated C-peptide was maintained higher (WMD 0.13 nmol/L/min; 95 % CI 0.05, 0.21; I 2 = 0 %) in patients treated with Diapep277. Moreover, there was no change in daily insulin needs (WMD 0.02 IU/kg; 95 % CI -0.04, 0.09; I 2 = 51 %) or HbA1c (WMD -0.06 %; 95 % CI -0.35, 0.23; I 2 = 42 %) vs. placebo. Finally, there was no effect on the incidence of severe hypoglycaemic events or overall serious adverse events [risk ratio 0.94, 95 % CI 0.62, 1.41; I 2 = 0 % and 0.87; 95 % CI 0.53, 1.44; I 2 = 0 %, respectively). Antigen-based immunotherapies are not effective in preventing the progression of autoimmune diabetes in newly diagnosed patients. PMID- 27473098 TI - Liquid and softgel levothyroxine use in clinical practice: state of the art. AB - Levothyroxine is recognized as the treatment of choice for hypothyroidism. So far, the tablet levothyroxine has been the formulation almost exclusively used, even though an optimal daily dose of levothyroxine has been unsuccessfully sought and a consensus not achieved. Due to progressive use of a more individually tailored levothyroxine dose, increasing evidence has instead displayed that many gastrointestinal disorders, polypharmacy, and food interference may raise the daily levothyroxine requirement. In recent years, alternative levothyroxine formulations have become available and have rapidly gained attention because of their pharmacokinetic properties. This study aims to provide an overview regarding the use of softgel capsule and/or liquid levothyroxine solution while performing a review of published studies about such topic. A comprehensive computer literature search of the PubMed/MEDLINE, Scopus, and Google Scholar databases has been conducted to find published articles on this topic. The search algorithm was based on the combinations of the following terms: "oral solution" or "soft gel" or "liquid", and "levothyroxine". The computer search resulted in 75 articles; through a critical review of such titles and abstracts and a screening of their references lists, the review included 18 original articles relating to 800 patients treated with alternative formulations. Despite some limits, the results obtained using softgel and liquid levothyroxine were consistent with each other. In selected categories of levothyroxine-treated patients (pediatric, suffering from hypo-achlorhydria, polypharmacy, undergone bariatric surgery, fed through enteric tube) these new formulations have shown promising attributes in improving a treatment that needs to be individually tailored. PMID- 27473099 TI - Effect of estrogen replacement therapy on bone and cardiovascular outcomes in women with turner syndrome: a systematic review and meta-analysis. AB - Patients with Turner syndrome have adverse bone and cardiovascular outcomes from chronic estrogen deficiency. Hence, long-term estrogen replacement therapy is the cornerstone treatment. The estimates of its effect and optimal use, however, remain uncertain. We aimed to summarize the benefits and harms of estrogen replacement therapy on bone, cardiovascular, vasomotor and quality of life outcomes in patients with Turner syndrome. A comprehensive search of four databases was performed from inception through January 2016. Randomized clinical trials and observational cohort studies studying the effect of estrogen replacement therapy in patients with Turner syndrome under the age of 40 were included. Independently and in duplicate reviewers selected studies, extracted data and assessed risk of bias. Subgroup analyses were based on route of administration and type of estrogen formulation. Twenty-five studies at moderate to high risk of bias (12 randomized trials, 13 cohort studies) with 771 patients were included. Using random-effects models, estrogen replacement therapy showed an increase in bone mineral density [weighted mean change from baseline 0.09 g/cm2 (0.04-0.14)] that differed by type of estrogen but not route of administration. Oral estrogen replacement therapy showed a higher increase in high density lipoprotein cholesterol levels when compared to transdermal [weighted mean difference 9.33 mg/dl (4.82-13.85)] with no significant effect on other lipid fractions. The current evidence suggests possible benefit of estrogen replacement therapy on bone mineral density and high density lipoprotein cholesterol. Whether this improvement translates into changes in patient important outcomes (cardiovascular events or fractures) remains uncertain. Larger randomized clinical trials with direct comparisons on patient important outcomes are necessary. PMID- 27473100 TI - Efficacy of protocols for induction of chronic hyperthyroidism in male and female mice. AB - Protocols for induction of hyperthyroidism in mice are highly variable and mostly involve short-term thyroid hormone (TH) treatment. In addition, little is known about a possible influence of sex on experimental TH manipulation. Here we analyzed the efficacy of intraperitoneal vs. oral levothyroxine (T4) administration to induce chronic hyperthyroidism in male and female mice and asked which T4 dosing intervals are required to achieve stable organ thyrotoxicosis. T4 was administered intraperitoneally or orally over a period of 6/7 weeks. Assessment included monitoring of body weight, TH serum concentrations, and serial quantitative TH target gene expression analysis in liver and heart. Our results show that both intraperitoneal and oral T4 treatment are reliable methods for induction of chronic hyperthyroidism in mice. Thereby T4 injection intervals should not exceed 48 h and oral levothyroxine should be administered continuously during experiments and up to sacrifice to ensure a hyperthyroid organ state. Furthermore, we found a sex-dependent variation in levothyroxine-induced TH serum state, with significantly higher T4 concentrations in female mice, while expression of investigated classical TH responsive genes in liver and heart did not vary with animal's sex. In summary, our study shows that common approaches for rendering rodents thyrotoxic can also be used for induction of chronic hyperthyroidism in male and female mice. Thereby T4 dosing intervals are critical as are read-out parameters to verify a chronic thyrotoxic organ state. PMID- 27473101 TI - Two-miRNA classifiers differentiate mutation-negative follicular thyroid carcinomas and follicular thyroid adenomas in fine needle aspirations with high specificity. AB - Diagnosis of thyroid by fine needle aspiration is challenging for the "indeterminate" category and can be supported by molecular testing. We set out to identify miRNA markers that could be used in a diagnostic setting to improve the discrimination of mutation-negative indeterminate fine needle aspirations. miRNA high-throughput sequencing was performed for freshly frozen tissue samples of 19 RAS and PAX8/PPARG mutation-negative follicular thyroid carcinomas, and 23 RAS and PAX8/PPARG mutation-negative follicular adenomas. Differentially expressed miRNAs were validated by quantitative polymerase chain reaction in a set of 44 fine needle aspiration samples representing 24 follicular thyroid carcinomas and 20 follicular adenomas. Twenty-six miRNAs characterized by a significant differential expression between follicular thyroid carcinomas and follicular adenomas were identified. Nevertheless, since no single miRNA had satisfactory predictive power, classifiers comprising two differentially expressed miRNAs were designed with the aim to improve the classification. Six two-miRNA classifiers were established and quantitative polymerase chain reaction validated in fine needle aspiration samples. Four out of six classifiers were characterized by a high specificity (>=94 %). The best two-miRNA classifier (miR-484/miR-148b-3p) identified thyroid malignancy with a sensitivity of 89 % and a specificity of 87 %. The high-throughput sequencing allowed the identification of subtle differences in the miRNA expression profiles of follicular thyroid carcinomas and follicular adenomas. While none of the differentially expressed miRNAs could be used as a stand-alone malignancy marker, the validation results for two-miRNA classifiers in an independent set of fine needle aspirations are very promising. The ultimate evaluation of these classifiers for their capability of discriminating mutation-negative indeterminate fine needle aspirations will require the evaluation of a sufficiently large number of fine needle aspirations with histological confirmation. PMID- 27473102 TI - Type 1 familial partial lipodystrophy: understanding the Kobberling syndrome. AB - Familial partial lipodystrophy are Mendelian disorders involving abnormal body fat distribution and insulin resistance. The current classification includes the Kobberling syndrome (type 1 familial partial lipodystrophy), characterized by fat loss in the lower limbs and abnormal fat accumulation in other areas. Type 1 familial partial lipodystrophy appears to be heritable, but little is known about it, including putative contributing mutations. We aimed to characterize this syndrome better by evaluating a group of women with phenotypic features of type 1 familial partial lipodystrophy. This is a case-controlled study in which 98 women with type 1 familial partial lipodystrophy that lacked classical mutations known to cause familial partial lipodystrophy were compared with 60 women without lipodystrophy and 25 patients with type 2 familial partial lipodystrophy (Dunnigan disease). Clinical course, body composition by dual-energy X-ray absorptiometry, HbA1c, lipid profile, insulin, leptin and family history were evaluated in all of the participants. Analyses of receiver-operating characteristic curve were performed for type 1 familial partial lipodystrophy diagnosis, comparing different truncal/limbs ratios. Among patients with type 1 familial partial lipodystrophy, 68 % developed recognizable lipodystrophy before adolescence, and most displayed an autosomal-dominant pattern (86 %). Women with type 1 familial partial lipodystrophy had less lower-limb adipose tissue than women without lipodystrophy, but significantly more than patients with Dunnigan disease. Moreover, metabolic disturbances occurred more frequently in the type 1 familial partial lipodystrophy group (81 %) than in the non-lipodystrophic group (30 %, p<0.05). The severity of metabolic disturbances was inversely proportional to the percentage of fat in the lower extremities and directly proportional to the amount of visceral adipose tissue. Metabolic profiles were worse in type 1 familial partial lipodystrophy than in Dunnigan disease. According to the receiver-operating characteristic curve analysis, the best ratio was subscapular/calf skinfolds (KoB index), with a cut-off value of 3.477 (sensitivity: 89 %; specificity: 84 %). Type 1 familial partial lipodystrophy was an early-onset, autosomal-dominant lipodystrophy, characterized by fat loss in the lower limbs and abnormal fat accumulation in the abdominal visceral region, associated to insulin resistance and metabolic disorders. A KoB index >3.477 is highly suggestive of this syndrome. PMID- 27473103 TI - Sex- and age-specific percentiles of body composition indices for Chinese adults using dual-energy X-ray absorptiometry. AB - PURPOSE: The aims of the study were to develop sex- and age-specific percentiles for lean mass index (LMI), appendicular LMI (aLMI), fat mass index (FMI), and body fat distribution indices in Chinese adults using dual-energy X-ray absorptiometry (DXA), and to compare those indices with those of other ethnicities using the US NHANES data. METHODS: Whole-body and regional lean mass and fat mass (FM) were measured using DXA in 5688 healthy males (n = 1693) and females (n = 3995) aged 20-90 years. Body fat distribution indices were expressed as % fat trunk/% fat legs, trunk/appendicular FM ratio (FMR), and android/gynoid FMR. Percentile curves of LMI, aLMI, FMI, and body fat distribution indices were obtained by the Lambda-Mu-Sigma method. RESULTS: The aLMI and LMI were negatively associated with age, decreasing from the fifth decade for males, but were not associated with age in females. Females had more total FM than males, whereas males had greater central adiposity (% fat trunk/% fat legs ratio, trunk/appendicular FMR, and android/gynoid FMR) than females. Moreover, FMI and body fat distribution indices consistently increased with age in both sexes, especially in women. In comparison with white, black, and Mexican populations in the USA, Chinese adults had lower total FM, but had greater central adiposity (% fat trunk/% fat legs ratio and trunk/appendicular FMR). Additionally, older white and Mexican populations showed greater decreases for aLMI and LMI than their Chinese counterparts. CONCLUSIONS: We present the sex- and age-specific percentiles for aLMI, LMI, FMI, and body fat distribution indices by DXA in Chinese adults, which may refine the individual assessment of the nutritional status of Chinese adults. PMID- 27473104 TI - Supplementation of Flemingia macrophylla and cassava foliage as a rumen enhancer on fermentation efficiency and estimated methane production in dairy steers. AB - Four rumen-fistulated dairy steers, 3 years old with 180 +/- 15 kg body weight (BW), were randomly assigned according to a 4 * 4 Latin square design to investigate on the effect of Flemingia macrophylla hay meal (FMH) and cassava hay meal (CH) supplementation on rumen fermentation efficiency and estimated methane production. The treatments were as follows: T1 = non-supplement, T2 = CH supplementation at 150 g/head/day, T3 = FMH supplementation at 150 g/head/day, and T4 = CH + FMH supplementation at 75 and 75 g/head/day. All steers were fed rice straw ad libitum and concentrate was offered at 0.5 % of BW. Results revealed that supplementation of CH and/or FMH did not affect on feed intake (P > 0.05) while digestibility of crude protein and neutral detergent fiber were increased especially in steers receiving FMH and CH+FMH (P < 0.05). Ruminal pH, temperature, and blood urea nitrogen were similar among treatments while ammonia nitrogen was increased in all supplemented groups (P < 0.05). Furthermore, propionic acid (C3) was increased while acetic acid (C2), C2:C3 ratio, and estimated methane production were decreased by dietary treatments. Protozoa and fungi population were not affected by dietary supplement while viable bacteria count increased in steers receiving FMH. Supplementation of FMH and/or FMH+CH increased microbial crude protein and efficiency of microbial nitrogen supply. This study concluded FMH (150 g/head/day) and/or CH+FMH (75 and 75 g/head/day) supplementation could be used as a rumen enhancer for increasing nutrient digestibility, rumen fermentation efficiency, and microbial protein synthesis while decreasing estimated methane production without adverse effect on voluntary feed intake of dairy steers fed rice straw. PMID- 27473105 TI - The biophysical and physiological basis for mitigated elevations in heart rate with electric fan use in extreme heat and humidity. AB - Electric fan use in extreme heat wave conditions has been thought to be disadvantageous because it might accelerate heat gain to the body via convection. However, it has been recently shown that fan use delays increases in heart rate even at high temperatures (42 degrees C) in young adults. We here assess the biophysical and physiological mechanisms underlying the apparently beneficial effects of fan use. Eight males (24 +/- 3 y; 80.7 +/- 11.7 kg; 2.0 +/- 0.1 m2) rested at either 36 degrees C or 42 degrees C, with (F) or without (NF) electric fan use (4.2 m/s) for 120 min while humidity increased every 7.5 min by 0.3 kPa from a baseline value of 1.6 kPa. Heart rate (HR), local sweat rate (LSR), cutaneous vascular conductance (CVC), core and mean skin temperatures, and the combined convective/radiative heat loss (C+R), evaporative heat balance requirements (Ereq) and maximum evaporative potential (Emax) were assessed. C+R was greater with fan use at 36 degrees C (F 8 +/- 6, NF 2 +/- 2 W/m2; P = 0.04) and more negative (greater dry heat gain) with fan use at 42 degrees C (F -78 +/ 4, NF -27 +/- 2 W/m2; P < 0.01). Consequently, Ereq was lower at 36 degrees C (F 38 +/- 16, NF 45 +/- 3 W/m2; P = 0.04) and greater at 42 degrees C (F 125 +/- 1, NF 74 +/- 3 W/m2; P < 0.01) with fan use. However, fan use resulted in a greater Emax at baseline humidity at both 36 degrees C (F 343 +/- 10, NF 153 +/- 5 W/m2; P < 0.01) and 42 degrees C (F 376 +/- 13, NF 161 +/- 4 W/m2; P < 0.01) and throughout the incremental increases in humidity. Within the humidity range that a rise in HR was prevented by fan use but not without a fan, LSR was higher in NF at both 36 degrees C (P = 0.04) and 42 degrees C (P = 0.05), and skin temperature was higher in NF at 42 degrees C (P = 0.05), but no differences in CVC or core temperatures were observed (all P > 0.05). These results suggest that the delayed increase in heart rate with fan use during extreme heat and humidity is associated with improved evaporative efficiency. PMID- 27473106 TI - Biases encountered in long-term monitoring studies of invertebrates and microflora: Australian examples of protocols, personnel, tools and site location. AB - Monitoring forms the basis for understanding ecological change. It relies on repeatability of methods to ensure detected changes accurately reflect the effect of environmental drivers. However, operator bias can influence the repeatability of field and laboratory work. We tested this for invertebrates and diatoms in three trials: (1) two operators swept invertebrates from heath vegetation, (2) four operators picked invertebrates from pyrethrum knockdown samples from tree trunk and (3) diatom identifications by eight operators in three laboratories. In each trial, operators were working simultaneously and their training in the field and laboratory was identical. No variation in catch efficiency was found between the two operators of differing experience using a random number of net sweeps to catch invertebrates when sequence, location and size of sweeps were random. Number of individuals and higher taxa collected by four operators from tree trunks varied significantly between operators and with their 'experience ranking'. Diatom identifications made by eight operators were clustered together according to which of three laboratories they belonged. These three tests demonstrated significant potential bias of operators in both field and laboratory. This is the first documented case demonstrating the significant influence of observer bias on results from invertebrate field-based studies. Examples of two long-term trials are also given that illustrate further operator bias. Our results suggest that long-term ecological studies using invertebrates need to be rigorously audited to ensure that operator bias is accounted for during analysis and interpretation. Further, taxonomic harmonisation remains an important step in merging field and laboratory data collected by different operators. PMID- 27473107 TI - Forest genetic monitoring: an overview of concepts and definitions. AB - Safeguarding sustainability of forest ecosystems with their habitat variability and all their functions is of highest priority. Therefore, the long-term adaptability of forest ecosystems to a changing environment must be secured, e.g., through sustainable forest management. High adaptability is based on biological variation starting at the genetic level. Thus, the ultimate goal of the Convention on Biological Diversity (CBD) to halt the ongoing erosion of biological variation is of utmost importance for forest ecosystem functioning and sustainability. Monitoring of biological diversity over time is needed to detect changes that threaten these biological resources. Genetic variation, as an integral part of biological diversity, needs special attention, and its monitoring can ensure its effective conservation. We compare forest genetic monitoring to other biodiversity monitoring concepts. Forest genetic monitoring (FGM) enables early detection of potentially harmful changes of forest adaptability before these appear at higher biodiversity levels (e.g., species or ecosystem diversity) and can improve the sustainability of applied forest management practices and direct further research. Theoretical genetic monitoring concepts developed up to now need to be evaluated before being implemented on a national and international scale. This article provides an overview of FGM concepts and definitions, discusses their advantages and disadvantages, and provides a flow chart of the steps needed for the optimization and implementation of FGM. FGM is an important module of biodiversity monitoring, and we define an effective FGM scheme as consisting of an assessment of a forest population's capacity to survive, reproduce, and persist under rapid environmental changes on a long-term scale. PMID- 27473108 TI - Relative importance of P and N in macrophyte and epilithic algae biomass in a wastewater-impacted oligotrophic river. AB - The role of nutrient loading on biomass growth in wastewater-impacted rivers is important in order to effectively optimize wastewater treatment to avoid excessive biomass growth in the receiving water body. This paper directly relates wastewater treatment plant (WWTP) effluent nutrients (including ammonia (NH3-N), nitrate (NO3-N) and total phosphorus (TP)) to the temporal and spatial distribution of epilithic algae and macrophyte biomass in an oligotrophic river. Annual macrophyte biomass, epilithic algae data and WWTP effluent nutrient data from 1980 to 2012 were statistically analysed. Because discharge can affect aquatic biomass growth, locally weighted scatterplot smoothing (LOWESS) was used to remove the influence of river discharge from the aquatic biomass (macrophytes and algae) data before further analysis was conducted. The results from LOWESS indicated that aquatic biomass did not increase beyond site-specific threshold discharge values in the river. The LOWESS-estimated biomass residuals showed a variable response to different nutrients. Macrophyte biomass residuals showed a decreasing trend concurrent with enhanced nutrient removal at the WWTP and decreased effluent P loading, whereas epilithic algae biomass residuals showed greater response to enhanced N removal. Correlation analysis between effluent nutrient concentrations and the biomass residuals (both epilithic algae and macrophytes) suggested that aquatic biomass is nitrogen limited, especially by NH3-N, at most sampling sites. The response of aquatic biomass residuals to effluent nutrient concentrations did not change with increasing distance to the WWTP but was different for P and N, allowing for additional conclusions about nutrient limitation in specific river reaches. The data further showed that the mixing process between the effluent and the river has an influence on the spatial distribution of biomass growth. PMID- 27473109 TI - The invasive species Ulex europaeus (Fabaceae) shows high dynamism in a fragmented landscape of south-central Chile. AB - Ulex europaeus (gorse) is an invasive shrub deemed as one of the most invasive species in the world. U. europaeus is widely distributed in the south-central area of Chile, which is considered a world hotspot for biodiversity conservation. In addition to its negative effects on the biodiversity of natural ecosystems, U. europaeus is one of the most severe pests for agriculture and forestry. Despite its importance as an invasive species, U. europaeus has been little studied. Although information exists on the potential distribution of the species, the interaction of the invasion process with the spatial dynamic of the landscape and the landscape-scale factors that control the presence or absence of the species is still lacking. We studied the spatial and temporal dynamics of the landscape and how these relate to U. europaeus invasion in south-central Chile. We used supervised classification of satellite images to determine the spatial distribution of the species and other land covers for the years 1986 and 2003, analysing the transitions between the different land covers. We used logistic regression for modelling the increase, decrease and permanence of U. europaeus invasion considering landscape variables. Results showed that the species covers only around 1 % of the study area and showed a 42 % reduction in area for the studied period. However, U. europaeus was the cover type which presented the greatest dynamism in the landscape. We found a strong relationship between changes in land cover and the invasion process, especially connected with forest plantations of exotic species, which promotes the displacement of U. europaeus. The model of gorse cover increase presented the best performance, and the most important predictors were distance to seed source and landscape complexity index. Our model predicted high spread potential of U. europaeus in areas of high conservation value. We conclude that proper management for this invasive species must take into account the spatial dynamics of the landscape within the invaded area in order to address containment, control or mitigation of the invasion. PMID- 27473110 TI - Assessment of surf zone environmental variables in a southwestern Atlantic sandy beach (Monte Hermoso, Argentina). AB - The aim of this study was to investigate the temporal dynamics (monthly/tidal) of water temperature, salinity, chlorophyll-a (chlo-a), suspended particulate matter (SPM), particulate organic carbon (POC), and dissolved nutrients in the surf zone of Monte Hermoso sandy beach, Argentina. We also aimed to understand the underlying mechanisms responsible for the observed variability. Sampling was carried out approximately monthly (September 2009-November 2010), and all samples were collected in a fixed station during high and low tide. Water temperature showed a clear seasonal variability (July: 9 degrees C-December: 26.5 degrees C) and a thermal amplitude of 17.5 degrees C. Salinity ranged from 33 to 37, without a pronounced seasonality. SPM (10-223 mg L(-1)) and POC concentrations (399-6445 mg C m(-3)) were high in surf zone waters. Chlo-a (0.05-9.16 MUg L(-1)) was low and did not evidence the occurrence of surf diatom accumulations. Dissolved nutrient concentration was quite fluctuating. None of the variables seemed to be affected by tidal stage. The results showed how fluctuating the physico-chemical and biological variables can be in this particular system. The observed variability can be related with local beach conditions but also with regional processes. The study area is highly influenced by a neighbor estuary and as a consequence, could be vulnerable to their seasonal and inter-annual dynamics. All of these characteristics must be considered for further studies and planning of the uses of natural resources and should be taken into account in any environmental monitoring program conducted in a similar beach system. PMID- 27473111 TI - Vitamin D3/VDR resists diet-induced obesity by modulating UCP3 expression in muscles. AB - BACKGROUND: The impact of vitamin D3 (VD3) on obesity has been reported in the past. Our study was aimed at investigating the possible mechanisms by which VD3 affects obesity induced by a high fat diet. METHODS: Eight-week-old C57BL/6 J male mice were fed a normal- or high-fat diet for 9 weeks and were treated with a gavage of vehicle (corn oil) or cholecalciferol (50 MUg/kg, daily). Body weight, white adipose tissue weight, blood lipid and glucose levels were measured. In addition, we investigated the expression of 1,25(OH)2D3 (calcitriol)/VDR regulated genes involved in energy and lipid metabolism, such as of uncoupling protein 3 (UCP3), by using qRT-PCR in the liver, adipose tissue, skeletal muscle and C2C12, L6, and H-EMC-SS cells. We also measured UCP3 promoter transcription in the same cell lines using a Dual Luciferase Assay. Furthermore, we analyzed the binding site consensus sequences of VDR on the UCP3 promoter. RESULTS: Mice consuming a high-fat diet treated with cholecalciferol had lower body weight and adipose tissue weight and higher expression of UCP3 compared to the other treatment groups. Changes in the expression of genes correlated with calcitriol/VDR. Luciferase activity was dose-dependently associated with calcitriol/VDR levels. We confirmed the functional VDR binding site consensus sequences at -2200, -1561, -634, and +314 bp in the UCP3 promoter region. CONCLUSION: We suggest that VD3/VDR inhibits weight gain by activating UCP3 in the muscles. PMID- 27473112 TI - Prognostic significance of APACHE II score and plasma suPAR in Chinese patients with sepsis: a prospective observational study. AB - BACKGROUND: Timely risk stratification is the key strategy to improve prognosis of patients with sepsis. Previous study has proposed to develop a powerful risk assessment rule by the combination of Acute Physiology and Chronic Health Evaluation II (APACHE II) score and plasma soluble urokinase plasminogen activator receptor (suPAR). That reaffirmation of suPAR as a prognostic marker in Chinese patients with severe sepsis is the aim of the study. METHODS: A total of 137 consecutive Chinese patients with sepsis were enrolled in a prospective study cohort. Demographic and clinical characteristics, conventional risk factors and important laboratory data were prospectively recorded. Sequential plasma suPAR concentrations were measured by an enzymeimmunoabsorbent assay on days 1, 3, and 7 after admission to the intensive care unit (ICU). Receiver operating characteristic (ROC) curves and Cox regression analysis were used to examine the performance of suPAR in developing a rule for risk stratification. RESULTS: The results showed that plasma suPAR concentrations remained relatively stable within survivors and non-survivors during the first week of disease course. Regression analysis indicated that APACHE II >=15 and suPAR >=10.82 ng/mL were independently associated with unfavorable outcome. With the above cutoffs of APACHE II and suPAR, strata of disease severity were determined. The mortality of each stratum differed significantly from the others. CONCLUSIONS: Combination of APACHE II score and suPAR may supply the powerful prognostic utility for the mortality of sepsis. PMID- 27473113 TI - A quasi-experimental examination of how school-based physical activity changes impact secondary school student moderate- to vigorous- intensity physical activity over time in the COMPASS study. AB - BACKGROUND: Adolescence is characterized by low moderate- to vigorous- intensity physical activity (MVPA) levels. Targeting the school setting can increase MVPA among a large proportion of adolescents. However, school-based physical activity interventions for adolescents remain largely ineffective. Therefore, the purpose of this study was to examine how naturally-occurring changes to school physical activity policy, recreational programming, public health resources, and the physical environment, impact adolescent MVPA over a 1-year period. METHODS: Quasi experimental longitudinal data from 18,777 grade 9-12 students (mean age = 15.1 +/- 0.02 years), and 86 principals from 86 schools, participating in year 2 (2013 2014) and year 3 (2014-2015) of the COMPASS study (Ontario and Alberta, Canada) was used. Total MVPA over the previous week was self-reported at both time points using the COMPASS Student Questionnaire and average daily MVPA was calculated. Changes to physical activity policies, recreational programming, public health resources, and the physical environment were self-reported by school principals. Changes to the number and condition of physical activity facilities were objectively measured during school audits using the COMPASS School Environment Application. Multi-level modeling was used to examine change in student MVPA between schools that made changes and schools that did not. Models were adjusted for several student and school level confounders. RESULTS: Over the 1-year period, 61 of 86 schools made physical activity related changes. Of these, 9 significantly changed student MVPA. However, only 4 of 9 schools' changes increased student MVPA, including opening the fitness centre at lunch (beta = 17.2, 95% CI: 2.6-31.7), starting an outdoor club (beta = 17.8, 95% CI:7.4-28.1), adding a bike rack (beta-14.9, 95% CI:0.7-29.1), and adding weightlifting and run/walk clubs, archery, figure skating, increased access to the sports field, and improved condition of the outdoor basketball court (beta = 15.5, 95% CI: 5.2 25.7). CONCLUSIONS: Changes such as adding or increasing access to facilities, and adding multiple recreational programs, seemed to be effective for increasing student MVPA over the 1-year period. However, given the specificity of results, a one-size fits all approach may not be effective for increasing MVPA. Instead, school principals need to consider the resources within and surrounding their school, and the interests of the students. PMID- 27473115 TI - Surfactant-assisted solvothermal synthesis of pure nickel submicron spheres with microwave-absorbing properties. AB - Pure metallic nickel submicron spheres (Ni-SSs), flower-like nickel nanoflakes, and hollow micrometer-sized nickel spheres/tubes were controllably synthesized by a facile and efficient one-step solvothermal method with no reducing agent. The characteristics of these nickel nanostructures include morphology, structure, and purification. Possible synthesis mechanisms were discussed in detail. The resultant Ni-SSs had a wide diameter distribution of 200~800 nm through the aggregation of small nickel nanocrystals. The ferromagnetic behaviors of Ni-SSs investigated at room temperature showed high coercivity values. Furthermore, the microwave absorption properties of magnetic Ni-SSs were studied in the frequency range of 0.5-18.0 GHz. The minimum reflection loss reached -17.9 dB at 17.8 GHz with a thin absorption thickness of 1.2 mm, suggesting that the submicron spherical structures could exhibit excellent microwave absorption properties. More importantly, this one-pot synthesize route provides a universal and convenient way for preparation of larger scale pure Ni-SSs, showing excellent microwave absorption properties. PMID- 27473114 TI - Familial Mediterranean fever is no longer a rare disease in Japan. AB - BACKGROUND: The aim of this study was to evaluate the clinical manifestations and prevalence of familial Mediterranean fever (FMF) in Japanese patients with unexplained fever and rheumatic manifestations. METHODS: We enrolled 601 patients with unexplained fever or suspected FMF throughout Japan between 2009 and 2015. Patients were divided into three groups according to Tel Hashomer criteria: sure FMF, probable FMF, and non-FMF patients, including definitive rheumatic diseases. Mutation detection in exons 1, 2, 3, and 10 of the FMF gene MEFV was performed by direct sequencing. RESULTS: A total of 192 patients (31.9 %) were diagnosed with FMF according to FMF diagnostic criteria. These could be divided into sure FMF (56.3 %, n = 108) and probable FMF (43.7 %, n = 84) patients. Fever, abdominal symptoms, and thoracic symptoms were significantly more common in FMF than non FMF patients. Among FMF patients, 26 (13.5 %) had concomitant rheumatic diseases. Most FMF patients (94.3 %, 181/192) carried at least one MEFV mutation. Allele frequencies of M694I (13.5 % vs 0 %) and E148Q (39.1 % vs 24.8 %) mutations were significantly higher in FMF compared with healthy subjects. Allele frequencies of common MEFV mutations in FMF patients were M694I (13.5 %), P369S (8.6 %), R408Q (8.1 %), G304R (2.9 %), R202Q (4.4 %), E148Q (39.1 %), L110P (11.7 %), and E84K (3.1 %). Patients with a sure FMF phenotype had a higher frequency of MEFV exon 10 mutation (M694I) and a lower frequency of MEFV exon 3 mutations (P369S, R408Q) compared with those with a probable FMF phenotype. CONCLUSION: The high prevalence of FMF in Japanese patients with unexplained fever was confirmed in the present study. FMF should be suspected in cases of unexplained fever or non specific rheumatic manifestations, and mutational analysis of MEFV could be useful to predict the clinical phenotypes of FMF in Japan. PMID- 27473116 TI - iLead-a transformational leadership intervention to train healthcare managers' implementation leadership. AB - BACKGROUND: Leadership is a key feature in implementation efforts, which is highlighted in most implementation frameworks. However, in studying leadership and implementation, only few studies rely on established leadership theory, which makes it difficult to draw conclusions regarding what kinds of leadership managers should perform and under what circumstances. In industrial and organizational psychology, transformational leadership and contingent reward have been identified as effective leadership styles for facilitating change processes, and these styles map well onto the behaviors identified in implementation research. However, it has been questioned whether these general leadership styles are sufficient to foster specific results; it has therefore been suggested that the leadership should be specific to the domain of interest, e.g., implementation. To this end, an intervention specifically involving leadership, which we call implementation leadership, is developed and tested in this project. The aim of the intervention is to increase healthcare managers' generic implementation leadership skills, which they can use for any implementation efforts in the future. METHODS/DESIGN: The intervention is conducted in healthcare in Stockholm County, Sweden, where first- and second-line managers were invited to participate. Two intervention groups are included, including 52 managers. Intervention group 1 consists of individual managers, and group 2 of managers from one division. A control group of 39 managers is additionally included. The intervention consists of five half-day workshops aiming at increasing the managers' implementation leadership, which is the primary outcome of this intervention. The intervention will be evaluated through a mixed-methods approach. A pre- and post-design applying questionnaires at three time points (pre-, directly after the intervention, and 6 months post-intervention) will be used, in addition to process evaluation questionnaires related to each workshop. In addition, interviews will be conducted over time to evaluate the intervention. DISCUSSION: The proposed intervention represents a novel contribution to the implementation literature, being the first to focus on strengthening healthcare managers' generic skills in implementation leadership. PMID- 27473117 TI - Sam68 reduces cisplatin-induced apoptosis in tongue carcinoma. AB - BACKGROUND: Resistance to anticancer agents is a major obstacle for successful chemotherapy in tongue squamous cancer. Sam68 is an oncogenic-related protein in oral tongue squamous cell carcinoma functions as a signaling molecule mediating apoptosis, whose over-expression is associated with the clinicopathologic characteristics and prognosis of patients. The present study was to examine the effect of Sam68 on chemotherapeutics-induced apoptosis in oral tongue squamous cell carcinoma, and its clinical significance in oral tongue squamous cell carcinoma progression. METHODS: The effect of Sam68 on apoptosis induced by cisplatin was examined both in vitro and in vivo, using Annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays. Real-time PCR and Western blotting analysis were used to detect mRNA and protein expression levels. RESULTS: Upregulation of Sam68 significantly inhibited cisplatin-induced apoptosis in oral tongue squamous cell carcinoma cells, associated with induction of anti-apoptotic proteins caspase-9, caspase-3, and PARP. In contrast, Silencing Sam68 expression significantly enhanced the sensitivity of oral tongue squamous cell carcinoma cells to apoptosis induced by cisplatin both in vitro and in vivo. CONCLUSIONS: The current study suggests that Sam68 could enhance the anti-apoptosis activity of oral tongue squamous cell carcinoma cells. Sam68 is a potential pharmacologic target for the treatment of oral tongue squamous cell carcinoma and inhibition of Sam68 expression might represent a novel strategy to sensitize oral tongue squamous cell carcinoma to chemotherapy. PMID- 27473118 TI - High-efficiency generation of induced pluripotent mesenchymal stem cells from human dermal fibroblasts using recombinant proteins. AB - BACKGROUND: Induced pluripotent mesenchymal stem cells (iPMSCs) are novel candidates for drug screening, regenerative medicine, and cell therapy. However, introduction of transcription factor encoding genes for induced pluripotent stem cell (iPSC) generation which could be used to generate mesenchymal stem cells is accompanied by the risk of insertional mutations in the target cell genome. METHODS: We demonstrate a novel method using an inactivated viral particle to package and deliver four purified recombinant Yamanaka transcription factors (Sox2, Oct4, Klf4, and c-Myc) resulting in reprogramming of human primary fibroblasts. Whole genome bisulfite sequencing was used to analyze genome-wide CpG methylation of human iPMSCs. Western blot, quantitative PCR, immunofluorescence, and in-vitro differentiation were used to assess the pluripotency of iPMSCs. RESULTS: The resulting reprogrammed fibroblasts show high level expression of stem cell markers. The human fibroblast-derived iPMSC genome showed gains in DNA methylation in low to medium methylated regions and concurrent loss of methylation in previously hypermethylated regions. Most of the differentially methylated regions are close to transcription start sites and many of these genes are pluripotent pathway associated. We found that DNA methylation of these genes is regulated by the four iPSC transcription factors, which functions as an epigenetic switch during somatic reprogramming as reported previously. These iPMSCs successfully differentiate into three embryonic germ layer cells, both in vitro and in vivo. Following multipotency induction in our study, the delivered transcription factors were degraded, leading to an improved efficiency of subsequent programmed differentiation. CONCLUSION: Recombinant transcription factor based reprogramming and derivatization of iPMSC offers a novel high-efficiency approach for regenerative medicine from patient-derived cells. PMID- 27473120 TI - Acacia honey accelerates in vitro corneal ulcer wound healing model. AB - BACKGROUND: The study aimed to evaluate the effects of Acacia honey (AH) on the migration, differentiation and healing properties of the cultured rabbit corneal fibroblasts. METHODS: Stromal derived corneal fibroblasts from New Zealand White rabbit (n = 6) were isolated and cultured until passage 1. In vitro corneal ulcer was created using a 4 mm corneal trephine onto confluent cultures and treated with basal medium (FD), medium containing serum (FDS), with and without 0.025 % AH. Wound areas were recorded at day 0, 3 and 6 post wound creation. Genes and proteins associated with wound healing and differentiation such as aldehyde dehydrogenase (ALDH), vimentin, alpha-smooth muscle actin (alpha-SMA), collagen type I, lumican and matrix metalloproteinase 12 (MMP12) were evaluated using qRT PCR and immunocytochemistry respectively. RESULTS: Cells cultured with AH enriched FDS media achieved complete wound closure at day 6 post wound creation. The cells cultured in AH-enriched FDS media increased the expression of vimentin, collagen type I and lumican genes and decreased the ALDH, alpha-SMA and MMP12 gene expressions. Protein expression of ALDH, vimentin and alpha-SMA were in accordance with the gene expression analyses. CONCLUSION: These results demonstrated AH accelerate corneal fibroblasts migration and differentiation of the in vitro corneal ulcer model while increasing the genes and proteins associated with stromal wound healing. PMID- 27473119 TI - Designing and conducting a cluster-randomized trial of ICU admission for the elderly patients: the ICE-CUB 2 study. AB - BACKGROUND: The benefit of ICU admission for elderly patients remains controversial. This report highlights the methodology, the feasibility of and the ethical and logistical constraints in designing and conducting a cluster randomized trial of intensive care unit (ICU) admission for critically ill elderly patients. METHODS: We designed an interventional open-label cluster randomized controlled trial in 24 centres in France. Clusters were healthcare centres with at least one emergency department (ED) and one ICU. Healthcare centres were randomly assigned either to recommend a systematic ICU admission (intervention group) or to follow standard practices regarding ICU admission (control group). Clusters were stratified by the number of ED annual visits (<44,616 or >44,616 visits), the presence or absence of a geriatric ward and the geographical area (Paris area vs other regions in France). All elderly patients (>=75 years of age) who got to the ED were assessed for eligibility. Patients were included if they had one of the pre-established critical conditions, a preserved functional status as assessed by an ADL scale >=4 (0 = very dependent, 6 = independent), a preserved nutritional status (subjectively assessed by physicians) and without active cancer. Exclusion criteria were an ED stay >24 h, a secondary referral to the ED and refusal to participate. The primary outcome was the mortality at 6 months calculated at the individual patient level. Secondary outcomes were ICU and hospital mortality, as well as ADL scale and quality of life (as assessed by the SF-12 Health Survey) at 6 months. RESULTS: Between January 2012 and April 2015, 3036 patients were included in the trial, 1518 patients in 11 clusters allocated to intervention group and 1518 patients in 13 clusters allocated to standard care. There were 51 protocol violations. CONCLUSIONS: The ICE-CUB 2 trial was deemed feasible and ethically acceptable. The ICE-CUB 2 trial will be the first cluster-randomized trial to assess the benefits of ICU admission for selected elderly patients on long-term mortality. Trial registration Clinical trials.gov identifier: NCT01508819. PMID- 27473121 TI - The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients. AB - BACKGROUND: Hyponatremia is prognostic of higher mortality in some cancers but has not been well studied in others. We used a longitudinal design to determine the incidence and prognostic importance of euvolemic and hypervolemic hyponatremia in patients following diagnosis with lymphoma, breast (BC), colorectal (CRC), small cell lung (SCLC), or non-small cell lung cancer (NSCLC). METHODS: Medical record and tumor registry data from two large integrated delivery networks were combined for patients diagnosed with lymphoma, BC, CRC, or lung cancers (2002-2010) who had >=1 administration of radiation/chemotherapy within 6 months of diagnosis and no evidence of hypovolemic hyponatremia. Hyponatremia incidence was measured per 1000 person-years (PY). Cox proportional hazard models assessed the prognostic value of hyponatremia as a time-varying covariate on overall survival (OS) and progression-free survival (PFS). RESULTS: Hyponatremia incidence (%, rate) was 76 % each, 1193 and 2311 per 1000 PY, among NSCLC and SCLC patients, respectively; 37 %, 169 in BC; 64 %, 637 in CRC, and 60 %, 395 in lymphoma. Hyponatremia was negatively associated with OS in BC (HR 3.7; P = <.01), CRC (HR 2.4; P < .01), lung cancer (HR 2.4; P < .01), and lymphoma (HR 4.5; P < .01). Hyponatremia was marginally associated with shorter PFS (HR 1.3, P = .07) across cancer types. CONCLUSIONS: The incidence of hyponatremia is higher than previously reported in lung cancer, is high in lymphoma, BC, and CRC and is a negative prognostic indicator for survival. Hyponatremia incidence in malignancy may be underestimated. The effects of hyponatremia correction on survival in cancer patients require further study. PMID- 27473123 TI - Anticipating and addressing event-specific alcohol consumption among adolescents. AB - BACKGROUND: Various specific events and celebrations are associated with excessive alcohol consumption and related harms. End-of-school celebrations such as Schoolies in Australia are of particular concern given high levels of documented harm among underage and young drinkers. The present study investigated high school students' expectations of their Schoolies celebrations to inform future interventions to reduce adverse outcomes among members of this vulnerable group and other young people involved in similar rites of passage. METHODS: A link to an online survey was distributed via high schools and Schoolies-related websites. The survey included qualitative questions that invited respondents to discuss (i) aspects of Schoolies they were looking forward to most and least and (ii) their perceptions of the likely consequences if they refrained from consuming alcohol during the event. In total, 435 students provided responses. RESULTS: Respondents discussed the role of Schoolies in marking their transition to adulthood. Their comments revealed a cross-temporal focus indicating that Schoolies is simultaneously symbolic of the past, present, and future. Through its ability to enhance social interaction, alcohol was perceived to have a vital role in realising the potential of this event to signify and facilitate this temporal progression. CONCLUSIONS: Results suggest interventions that treat Schoolies as an isolated event that occurs in specific locations may fail to appreciate the extent to which these events transcend time for those involved. Instead, harm reduction is likely to involve a reconceptualisation of the event among both participants and authority figures to facilitate the provision of alternative pastimes to drinking during Schoolies that yield similar social benefits. PMID- 27473124 TI - Erratum to: Environmental health and justice and the right to research: institutional review board denials of community-based chemical biomonitoring of breast milk. PMID- 27473122 TI - Elevated circulating irisin is associated with lower risk of insulin resistance: association and path analyses of obese Chinese adults. AB - BACKGROUND: Evidence on the role of irisin in insulin resistance is limited and controversial, and pathways between them remain unknown. We aimed to examine the independent effects of circulating irisin and different adiposity measurements, as well as their potential interactions, on insulin resistance. We also aimed to explore possible pathways among circulating irisin, adiposity, glucose and insulin levels and insulin resistance. METHODS: A cross-sectional study of 1,115 community- living obese Chinese adults, with data collection on clinical characteristics, glucose and lipid metabolic parameters and circulating irisin levels. RESULTS: Among the 1,115 subjects, 667 (59.8 %) were identified as insulin-resistance, and showed significantly decreased serum irisin than their controls (log-transformed irisin: 1.19 +/- 2.34 v.s. 1.46 +/- 2.05 ng/ml, p = 0.042). With adjustment for potential confounders, elevated circulating irisin was significantly associated with reduced risk of insulin resistance, with adjusted odds ratio per standard deviation increase of irisin of 0.871 (0.765 0.991, p = 0.036). As for different adiposity measurements, body fat percentage, but neither BMI nor waist, was significantly associated with increased risk of insulin resistance (OR: 1.152 (1.041-1.275), p = 0.006). No significant interaction effect between serum irisin and adiposity on insulin resistance was found. A one pathway model about the relationship between serum irisin and insulin resistance fits well (chi (2) = 44.09, p < 0.001; CFI-0.994; TLI =0.986; and RMSEA = 0.067), and shows that elevated circulating irisin might improve insulin resistance indirectly through lowering fasting insulin levels (standardized path coefficient = -0.046, p = 0.032). CONCLUSIONS: Elevated circulating irisin is associated with lower risk of insulin resistance indirectly through lowering fasting insulin. PMID- 27473125 TI - A comparative analysis of vaccine administration in urban and non-urban skilled nursing facilities. AB - BACKGROUND: The U.S. population is aging at an unprecedented rate, resulting in an increased demand for skilled nursing facilities (SNFs) and long-term care. Residents of these facilities are at a high risk for pneumococcal disease or severe influenza-related illnesses and death. For these reasons, the Centers for Medicare and Medicaid Services use influenza and pneumococcal vaccination rates as a quality measure in the assessment of SNFs, as complications related to these infections increase morbidity and mortality rates. METHODS: Disparities have been reported amongst vaccination with increased rates in urban areas as compared to their non-urban counterparts. Statistical analyses were performed to compare influenza and pneumococcal vaccination in urban and non-urban SNFs to determine variables that may influence vaccination status. RESULTS: Of the 15,639 nursing homes included in the study, 10,107 were in urban areas, while 5532 were considered non-urban. We found the percent of eligible and willing residents with up-to-date influenza and pneumococcal vaccinations increased with overall five star ratings of SNFs. Somewhat paradoxically, although urban SNFs had higher mean overall five-star ratings, they showed lower rates of influenza and pneumococcal vaccination compared to non-urban SNFs. Ordinary least squares regression analysis comparing overall ratings, type of ownership, and geographic location by region yielded statistically significant results in which the overall rating, ownership-type and certificate-type favored urban SNFs (p < 0.001). CONCLUSIONS: This is the first systematic and comparative analysis to use the Nursing Home Compare database to assess vaccine administration of urban and non-urban SNFs. The findings of this study may be used to encourage the development of programs to improve vaccination rates and the quality of care in these facilities. PMID- 27473126 TI - Attitudes and opinions regarding confirmatory adaptive clinical trials: a mixed methods analysis from the Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT) project. AB - BACKGROUND: Adaptive designs have been increasingly used in the pharmaceutical and device industries, but adoption within the academic setting has been less widespread - particularly for confirmatory phase trials. We sought to understand perceptions about understanding, acceptability, and scientific validity of adaptive clinical trials (ACTs). METHODS: We used a convergent mixed methods design using survey and mini-focus group data collection procedures to elucidate attitudes and opinions among "trial community" stakeholders regarding understanding, acceptability, efficiency, scientific validity, and speed of discovery with adaptive designs. Data were collected about various aspects of ACTs using self-administered surveys (paper or Web-based) with visual analog scales (VASs) with free text responses and with mini-focus groups of key stakeholders. Participants were recruited as part of an ongoing NIH/FDA-funded research project exploring the incorporation of ACTs into an existing NIH network that focuses on confirmatory phase clinical trials in neurological emergencies. "Trial community" representatives, namely, clinical investigators, biostatisticians, NIH officials, and FDA scientists involved in the planning of four clinical trials, were eligible to participate. In addition, recent and current members of a clinical trial-oriented NIH study section were also eligible. RESULTS: A total of 76 stakeholders completed the survey (out of 91 who were offered it, response rate 84 %). While the VAS attitudinal data showed substantial variability across respondents about acceptability and understanding of ACTs by various constituencies, respondents perceived clinicians to be less likely to understand ACTs and that ACTs probably would increase the efficiency of discovery. Textual and focus group responses emerged into several themes that enhanced understanding of VAS attitudinal data including the following: acceptability of adaptive designs depends on constituency and situation; there is variable understanding of ACTs (limited among clinicians, perceived to be higher at FDA); views about the potential for efficiency depend on the situation and implementation. Participants also frequently mentioned a need for greater education within the academic community. Finally, the empiric, non-quantitative selection of treatments for phase III trials based on limited phase II trials was highlighted as an opportunity for improvement and a potential explanation for the high number of neutral confirmatory trials. CONCLUSIONS: These data show considerable variations in attitudes and beliefs about ACTs among trial community representatives. For adaptive trials to be fully considered when appropriate and for the research enterprise to realize the full potential of adaptive designs will likely require extensive experience and trust building within the trial community. PMID- 27473127 TI - Heavy Metal Levels in Fish from Heilongjiang River and Potential Health Risk Assessment. AB - Concentrations of Cu, Zn, Cr, As, Cd, Pb and Hg were determined in 153 samples covering 18 fish species collected from Heilongjiang River, China, and the potential health risks to local residents through fish consumption were estimated. Results revealed that all metals were detected with Cd and Pb having considerably lower detection rate. There were 28.6 % of Lethenteron camtschaticum samples exceeding the limit of inorganic As content established by Chinese legislation. Metal bioaccumulation in fish were poorly correlated with fish sizes, and generally tended to increase with trophic levels. The hazard quotient values of all fish species were far below 1 for general population and fishermen. The carcinogenic risk of As in L. camtschaticum for the local fishermen exceeded the acceptable level of 10(-4) rise in cancer rates, but was considered safe given the migratory habits of the fish. PMID- 27473128 TI - The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement. AB - Vesicular protein sorting-associated proteins (VPS, including VPS11) are indispensable in the endocytic network, in particular the endosome-lysosome biogenesis. Exome sequencing revealed the homozygous variant p.Leu387_ Gly395del in the VPS11 gene in two siblings. On immunoblotting, the mutant VPS11 protein showed a distinctly reduced immunostaining intensity. The children presented with primary and severe developmental delay associated with myoclonic seizures, spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly. Neuro-imaging showed severe hypomyelination affecting cerebral and cerebellar white matter and corpus callosum, in the absence of a peripheral neuropathy. Electron microscopy of a skin biopsy revealed clusters of membranous cytoplasmic bodies in dermal unmyelinated nerve axons, and numbers of vacuoles in eccrine sweat glands, similar to what is seen in a classic lysosomal storage disease (LSD). Bone marrow cytology showed a high number of storage macrophages with a micro-vacuolated cytoplasm. Biochemically, changes in urinary glycosphingolipids were reminiscent of those in prosaposin deficiency (another LSD). The clinical and neuro-imaged features in our patients were almost identical to those in some recently reported patients with another variant in the VPS11 gene, p.Cys846Gly; underlining the presumed pathogenic potential of VPS11 defects. A new feature was the morphological evidence for lysosomal storage in VPS11 deficiency: This newly characterised disease can be viewed as belonging to the complex field of LSD. PMID- 27473129 TI - A Multicenter Predictive Score for Amputation-Free Survival for Patients Operated on with an Heparin-Bonded ePTFE Graft for Critical Limb Ischemia. AB - AIM OF THE STUDY: To retrospectively create a predictive score for estimating amputation-free survival (AFS) in patients with critical limb ischemia (CLI) operated on with the use of a heparin-bonded expanded polytetrafluoroethylene (ePTFE) bypass graft (Hb-ePTFE). METHODS: Over a 13-year period, ending in March 2015, a Hb-ePTFE graft was implanted in 683 patients undergoing below-knee revascularization for CLI in seven Italian vascular hospitals. Data concerning these interventions were retrospectively collected in a multicenter registry with a dedicated database. Univariate and multivariable analyses with Kaplan-Meier estimates were used to identify potential significant predictors of AFS at 5 years, and then a predictive risk score was constructed. A qualitative assessment of the Kaplan-Meier survival estimates for each integer score was performed, and subgroups of risk were stratified on the basis of the primary end point. RESULTS: Overall, estimated 5-year AFS rate was 48.3 % (SE 0.024). At multivariate analysis, older age, coronary artery disease, end-stage renal disease, tissue loss and poor runoff score were predictors of AFS. The integer score ranged from 0 to 11; Kaplan-Meier analysis for AFS in each score group identified three subgroups with significant differences at 5 years: low-risk subgroup (scores from 0 to 2, 67.7 %), medium-risk subgroup (scores 3 and 4, 49.2 %, p < 0.001 in comparison with low-risk subgroup) and high-risk subgroup (scores from 5 to 11, 25.2 %, p < 0.001 in comparison with either low-risk subgroup or medium-risk subgroup). CONCLUSIONS: A category of low-risk patients with CLI treated with the indexed graft does exist, thus suggesting a primary role for Hb-ePTFE in such patients. A prospective validation of such a score is necessary. PMID- 27473130 TI - Surgical Indications of Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Body/Tail Cancer. AB - BACKGROUND: The survival impact of distal pancreatectomy (DP) with celiac axis resection for locally advanced pancreatic body/tail cancer remains unclear. METHODS: A total of 16 patients underwent DP with celiac axis resection, while 76 underwent standard DP for pancreatic body/tail cancer. The indications for DP with celiac axis resection included: (a) tumor invasion of either the celiac axis or common hepatic artery or both [CA/CHA (+)] and (b) tumor invasion of the root of the splenic artery, which is difficult to dissect without securing an adequate surgical margin [CA/CHA (-)]. RESULTS: DP with celiac axis resection presented longer operative time and greater amount of blood loss than DP. The median survival time was 17.5 months in the DP with celiac axis resection group and 43.1 months in the DP group (p = 0.040). Among the patients who underwent DP with celiac axis resection, the median survival time was 35.1 months in the CA/CHA (-) group and 13.2 months in the CA/CHA (+) group (p = 0.001). Comparing the patients undergoing standard DP and DP with celiac axis resection with a CA/CHA (-) status, there were no significant differences in either disease-free or overall survival times. The CA19-9 value, CA/CHA (+) status, and microscopic venous infiltration were revealed independent significant prognostic factors. CONCLUSIONS: DP with celiac axis resection should therefore be indicated in patients with a CA/CHA (-) status. However, it is difficult to justify the use of DP with celiac axis resection in patients with CA/CHA (+) status due to the poor survival. PMID- 27473131 TI - Barriers to Surgical Care and Health Outcomes: A Prospective Study on the Relation Between Wealth, Sex, and Postoperative Complications in the Republic of Congo. AB - BACKGROUND: Approximately thirty percent of the global burden of disease is comprised of surgical conditions. However, five billion people lack access to surgery, with complex factors acting as barriers. We examined whether patient demographics predict barriers to care, and the relation between these factors and postoperative complications in a prospective cohort. METHODS: Participants included people presenting to a global charity in Republic of Congo with a surgical condition between August 2013 and May 2014. The outcomes were self reported barrier to care and postoperative complications documented by medical record. Logistic regression was used to adjust for covariates. RESULTS: Of 1237 patients in our study, 1190 (96.2 %) experienced a barrier to care and 126 (10.2 %) experienced a postoperative complication. The most frequently reported barrier was cost (73 %), followed by lack of provider (8.2 %). Greater wealth was associated with decreased odds of cost as a barrier (OR 0.72 [0.57, 0.90]). Greater wealth (OR 1.52 [1.03, 2.25]) and rural home location (OR 3.35 [1.16, 9.62]) were associated with increased odds of no surgeon being available. Cost as a barrier (OR 2.82 [1.02, 7.77]), female sex (OR 3.45 [1.62, 7.33]), and lack of surgeon (OR 5.62 [1.68, 18.77]) were associated with increased odds of postoperative complication. Patient wealth was not associated with odds of postoperative complication. CONCLUSIONS: Barriers to surgery were common in Republic of Congo. Patient wealth and home location may predict barriers to surgery. Addressing gender disparities, access to providers, and patient perception of barriers in addition to removal of barriers may help maximize patient health benefits. PMID- 27473132 TI - Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. AB - OBJECTIVE: To better understand cross-sectional relationships between CSF and PET measures of tau pathology, we compared regional and global measures of (18)F-T807 (AV-1451) PET to CSF protein levels of total tau (t-tau), phosphorylated tau (p tau), and beta-amyloid 1-42 (Abeta42). METHODS: T-tau, p-tau, and Abeta42 levels were assessed using INNOTEST xMAP immunoassays. Linear regression was used to compare regional and global measures of (18)F-T807 standardized uptake value ratios (SUVR) to CSF protein levels using data from 31 cognitively unimpaired elderly participants in the Harvard Aging Brain study. RESULTS: After controlling for sex and age, total cortical (18)F-T807 binding was significantly correlated with p-tau (partial r = 0.48; p < 0.01) and at trend level with t-tau (partial r = 0.30; p = 0.12). Regional (18)F-T807 measures were more strongly correlated with CSF protein levels than the global measure, with both t-tau and p-tau significantly correlated with (18)F-T807 SUVR in entorhinal, parahippocampal, and inferior temporal cortical regions (partial r = 0.53-0.73). Peak correlations between CSF and PET measures of tau were similar to those between CSF and PET measures of amyloid burden. Finally, we observed significantly higher temporal T807 SUVR in individuals with high amyloid burden. CONCLUSIONS: These data support the link between (18)F-T807 PET and CSF measures of tau pathology. In these cognitively normal individuals with (18)F-T807 binding largely restricted to the temporal lobe, (18)F-T807 SUVR in temporal regions appeared more reflective of CSF t-tau and p-tau than a total cortical measure. PMID- 27473133 TI - Looking for the "perfect" TIA risk score. PMID- 27473134 TI - GABA deficiency in NF1: A multimodal [11C]-flumazenil and spectroscopy study. AB - OBJECTIVE: To provide a comprehensive investigation of the gamma-aminobutyric acid (GABA) system in patients with neurofibromatosis type 1 (NF1) that allows understanding the nature of the GABA imbalance in humans at pre- and postsynaptic levels. METHODS: In this cross-sectional study, we employed multimodal imaging and spectroscopy measures to investigate GABA type A (GABAA) receptor binding, using [(11)C]-flumazenil PET, and GABA concentration, using magnetic resonance spectroscopy (MRS). Fourteen adult patients with NF1 and 13 matched controls were included in the study. MRS was performed in the occipital cortex and in a frontal region centered in the functionally localized frontal eye fields. PET and MRS acquisitions were performed in the same day. RESULTS: Patients with NF1 have reduced concentration of GABA+ in the occipital cortex (p = 0.004) and frontal eye fields (p = 0.026). PET results showed decreased binding of GABAA receptors in patients in the parieto-occipital cortex, midbrain, and thalamus, which are not explained by decreased gray matter levels. CONCLUSIONS: Abnormalities in the GABA system in NF1 involve both GABA concentration and GABAA receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement. PMID- 27473137 TI - Comment: Hormone therapy in the early postmenopausal stage-: Safe for the brain? PMID- 27473135 TI - Effects of hormone therapy on brain structure: A randomized controlled trial. AB - OBJECTIVE: To investigate the effects of hormone therapy on brain structure in a randomized, double-blinded, placebo-controlled trial in recently postmenopausal women. METHODS: Participants (aged 42-56 years, within 5-36 months past menopause) in the Kronos Early Estrogen Prevention Study were randomized to (1) 0.45 mg/d oral conjugated equine estrogens (CEE), (2) 50 MUg/d transdermal 17beta estradiol, or (3) placebo pills and patch for 48 months. Oral progesterone (200 mg/d) was given to active treatment groups for 12 days each month. MRI and cognitive testing were performed in a subset of participants at baseline, and at 18, 36, and 48 months of randomization (n = 95). Changes in whole brain, ventricular, and white matter hyperintensity volumes, and in global cognitive function, were measured. RESULTS: Higher rates of ventricular expansion were observed in both the CEE and the 17beta-estradiol groups compared to placebo; however, the difference was significant only in the CEE group (p = 0.01). Rates of ventricular expansion correlated with rates of decrease in brain volume (r = 0.58; p <= 0.001) and with rates of increase in white matter hyperintensity volume (r = 0.27; p = 0.01) after adjusting for age. The changes were not different between the CEE and 17beta-estradiol groups for any of the MRI measures. The change in global cognitive function was not different across the groups. CONCLUSIONS: Ventricular volumes increased to a greater extent in recently menopausal women who received CEE compared to placebo but without changes in cognitive performance. Because the sample size was small and the follow-up limited to 4 years, the findings should be interpreted with caution and need confirmation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that brain ventricular volume increased to a greater extent in recently menopausal women who received oral CEE compared to placebo. PMID- 27473136 TI - Association between diabetes mellitus and the occurrence and outcome of intracerebral hemorrhage. AB - OBJECTIVE: Whether diabetes mellitus (DM) is a risk factor for spontaneous intracerebral hemorrhage (ICH) and influences outcome after ICH remains unclear. METHODS: One reviewer searched Ovid MEDLINE and Embase 1980-2014 inclusive for studies investigating the associations between DM and ICH occurrence or DM and ICH case fatality. Two reviewers independently confirmed each study's eligibility, assessed risk of bias, and extracted data. One reviewer combined studies using random effects meta-analysis. RESULTS: Nineteen case-control studies involving 3,397 people with ICH and 5,747 people without ICH found an association between DM and ICH occurrence (unadjusted odds ratio [OR] 1.23, 95% confidence interval [CI] 1.04-1.45; I(2) = 22%), which did not differ between 17 hospital-based and 2 population-based studies (pdiff = 0.70), and was similar in the 16 studies that controlled for age and sex (unadjusted OR 1.15, 95% CI 0.95 1.40; I(2) = 14%). This association was not identified in 3 population-based cohort studies in which ICH occurred in 38 (0.66%) of 5,724 people with DM and 448 (0.57%) of 78,702 people without DM (unadjusted risk ratio [RR] 1.27, 95% CI 0.68-2.36; I(2) = 69%). DM was associated with a higher case fatality by 30 days or hospital discharge in 18 cohort studies involving 813 people with DM and 3,714 people without DM (unadjusted RR 1.52, 95% CI 1.28-1.81; I(2) = 49%). CONCLUSIONS: The findings suggest that there may be modest associations between DM and ICH occurrence and outcome, but further information from large, population based studies that account for confounding is required before the association can be confirmed. PMID- 27473139 TI - MTR recovery in brain lesions in the BECOME study of glatiramer acetate vs interferon beta-1b. AB - OBJECTIVE: To compare magnetization transfer changes in new brain MRI lesions identified during monthly imaging in patients with multiple sclerosis (MS) randomized to treatment with 250 MUg subcutaneous interferon-beta-1b (IFN-beta 1b) every other day or daily 20 mg glatiramer acetate (GA) in a post hoc study using data from the Betaseron Versus Copaxone for Relapsing Remitting or CIS Forms of MS Using Triple Dose Gad 3 T MRI (BECOME) trial. METHODS: T1-weighted images acquired with and without fat saturation pulses in the BECOME study were evaluated and found to exhibit magnetization transfer ratio (MTR) effects, and were used to compute MTR images (FSMTR). Forty-three participants who had the required imaging and new lesions, from the 75 originally randomized into the BECOME study, were included in this post hoc analysis and evaluated longitudinally during treatment to determine FSMTRDrop, an experimental measure of the completeness of FSMTR recovery in new lesions. Two sets of new brain MRI lesions were defined, one based on the appearance of gadolinium contrast enhancement (Gd lesions) and the other based on FSMTR decreases (DeltaFSMTR lesions). RESULTS: A total of 887 Gd lesions were identified in 43 participants (19 GA, 24 IFN-beta-1b) and 321 DeltaFSMTR lesions in 32 participants (16 GA, 16 IFN-beta-1b). Participants randomized to GA exhibited greater average postlesion FSMTR recovery than did those randomized to IFN-beta-1b in both Gd (p < 0.0001) and DeltaFSMTR (p < 0.0001) lesions. CONCLUSIONS: New brain lesions that developed during treatment with GA exhibited evidence of greater FSMTR recovery than during treatment with IFN-beta-1b. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that MTR recovery in patients with MS with new MRI brain lesions is greater with GA than with IFN-beta-1b. PMID- 27473138 TI - Predictive value of ABCD2 and ABCD3-I scores in TIA and minor stroke in the stroke unit setting. AB - OBJECTIVE: It is not clear whether risk scores for early stroke recurrence after TIA that have been mainly established in outpatient and emergency department settings are valid on the background of highly specialized stroke unit care. METHODS: ABCD2 and ABCD3-I scores have been prospectively documented in a cohort of patients admitted to Austrian stroke units within 24 hours of symptom onset with TIA or minor stroke (NIH Stroke Scale score <4). RESULTS: A total of 5,237 TIA and minor stroke patients met inclusion criteria, with 3-month follow-up data available on 2,457. Early and 3-month stroke were observed in 2.4% and 4.2% of the study population. The probability of early stroke during the stroke unit stay (median 2 [interquartile range 1-3] days) steadily increased from 0% to 4.8% and 0% to 16.7% with increasing ABCD2 and ABCD3-I score points, respectively. On 3 month follow-up, stroke risk increased from 0% to 8.0% and 0% to 23.8% with increasing ABCD2 and ABCD3-I score points, respectively. Of the individual score components, age, blood pressure, and diabetes were not related to early or 3 month stroke, whereas clinical presentation (C), symptom duration (D), and cerebral as well as carotid imaging (I) were and accounted for the information provided by the full scores. CONCLUSIONS: Standard ABCD2 and ABCD3-I scores are useful instruments to estimate the probability of early and 3-month stroke in TIA and minor stroke patients treated at specialized stroke units, with C, D, and I being the most important score components in this setting. PMID- 27473142 TI - Measurement of anti-DFS70 antibodies in patients with ANA-associated autoimmune rheumatic diseases suspicion is cost-effective. AB - The presence of antinuclear antibodies (ANA) is associated with a wide range of ANA-associated autoimmune rheumatic diseases (AARD). The most commonly method used for the detection of ANA is indirect immunofluorescence (IIF) on HEp-2 cells. This method is very sensitive but unspecific. As a consequence, ANA testing on HEp-2 substrates outside a proper clinical specialist framework may lead to inappropriate referrals to tertiary care specialists and, worst case inappropriate and potentially toxic therapy for the patient. Among ANA, isolated anti-DFS70 antibodies represent a potentially important biomarker that can be clinically used to discriminate AARD from non-AARD patients in ANA IIF positive individuals. Therefore, their presence may avoid unnecessary follow-up testing and referrals. In our study, we investigated if the implementation of a new ANA workup algorithm allowing for the identification of anti-DFS70 antibodies is cost effective through the reduction of both unnecessary follow-up testing and outpatient clinic visits generated by the clinical suspicion of a potential AARD. None of the 181 patients included with a positive monospecific anti-DFS70 antibody result developed SARD during the follow-up period of 10 years. The reduction in number of tests after ANA and anti-DFS70 positive results was significant for anti-ENA (230 vs. 114 tests; p < 0.001) and anti-dsDNA antibodies (448 vs. 114 tests; p < 0.001). In addition, the outpatient clinic visits decreased by 70 % (p < 0.001). In total, the adoption of the new algorithm including anti-DFS70 antibody testing resulted in a cost saving of 60869.53 ? for this pilot study. In conclusion, the use of anti-DFS70 antibodies was clearly cost-efficient in our setting. PMID- 27473140 TI - Trends in socioeconomic inequalities in mortality in small areas of 33 Spanish cities. AB - BACKGROUND: In Spain, several ecological studies have analyzed trends in socioeconomic inequalities in mortality from all causes in urban areas over time. However, the results of these studies are quite heterogeneous finding, in general, that inequalities decreased, or remained stable. Therefore, the objectives of this study are: (1) to identify trends in geographical inequalities in all-cause mortality in the census tracts of 33 Spanish cities between the two periods 1996-1998 and 2005-2007; (2) to analyse trends in the relationship between these geographical inequalities and socioeconomic deprivation; and (3) to obtain an overall measure which summarises the relationship found in each one of the cities and to analyse its variation over time. METHODS: Ecological study of trends with 2 cross-sectional cuts, corresponding to two periods of analysis: 1996-1998 and 2005-2007. Units of analysis were census tracts of the 33 Spanish cities. A deprivation index calculated for each census tracts in all cities was included as a covariate. A Bayesian hierarchical model was used to estimate smoothed Standardized Mortality Ratios (sSMR) by each census tract and period. The geographical distribution of these sSMR was represented using maps of septiles. In addition, two different Bayesian hierarchical models were used to measure the association between all-cause mortality and the deprivation index in each city and period, and by sex: (1) including the association as a fixed effect for each city; (2) including the association as random effects. In both models the data spatial structure can be controlled within each city. The association in each city was measured using relative risks (RR) and their 95 % credible intervals (95 % CI). RESULTS: For most cities and in both sexes, mortality rates decline over time. For women, the mortality and deprivation patterns are similar in the first period, while in the second they are different for most cities. For men, RRs remain stable over time in 29 cities, in 3 diminish and in 1 increase. For women, in 30 cities, a non-significant change over time in RR is observed. However, in 4 cities RR diminishes. In overall terms, inequalities decrease (with a probability of 0.9) in both men (RR = 1.13, 95 % CI = 1.12-1.15 in the 1st period; RR = 1.11, 95 % CI = 1.09-1.13 in the 2nd period) and women (RR = 1.07, 95 % CI = 1.05-1.08 in the 1st period; RR = 1.04, 95 % CI = 1.02-1.06 in the 2nd period). CONCLUSIONS: In the future, it is important to conduct further trend studies, allowing to monitoring trends in socioeconomic inequalities in mortality and to identify (among other things) temporal factors that may influence these inequalities. PMID- 27473143 TI - Interactions between the oomycete Pythium arrhenomanes and the rice root-knot nematode Meloidogyne graminicola in aerobic Asian rice varieties. AB - BACKGROUND: Aerobic rice fields are frequently infested by pathogenic oomycetes (Pythium spp.) and the rice root-knot nematode Meloidogyne graminicola. Here, the interaction between Pythium arrhenomanes and Meloidogyne graminicola was studied in rice roots of two aerobic rice varieties. In different experimental set-ups and infection regimes, plant growth, rice yield, Pythium colonization, as well as establishment, development and reproduction of M. graminicola were studied. RESULTS: In this study, it is shown that the presence of P. arrhenomanes delays the establishment, development and reproduction of M. graminicola compared to single nematode infected plants. The delay in establishment and development of M. graminicola becomes stronger with higher P. arrhenomanes infection pressure. CONCLUSIONS: Our data indicate that P. arrhenomanes antagonizes M. graminicola in the rice root and that the plant benefits from this antagonism as shown by the yield data, especially when either of the pathogens is present in high levels. PMID- 27473144 TI - REL2, A Gene Encoding An Unknown Function Protein which Contains DUF630 and DUF632 Domains Controls Leaf Rolling in Rice. AB - BACKGROUND: Rice leaves are important energy source for the whole plant. An optimal structure will be beneficial for rice leaves to capture light energy and exchange gas, thus increasing the yield of rice. Moderate leaf rolling and relatively erect plant architecture may contribute to high yield of rice, but the relevant molecular mechanism remains unclear. RESULTS: In this study, we identified and characterized a rolling and erect leaf mutant in rice and named it as rel2. Histological analysis showed that the rel2 mutant has increased number of bulliform cells and reduced size of middle bulliform cells. We firstly mapped REL2 to a 35-kb physical region of chromosome 10 by map-based cloning strategy. Further analysis revealed that REL2 encodes a protein containing DUF630 and DUF632 domains. In rel2 mutant, the mutation of two nucleotide substitutions in DUF630 domain led to the loss-of-function of REL2 locus and the function of REL2 could be confirmed by complementary expression of REL2 in rel2 mutant. Further studies showed that REL2 protein is mainly distributed along the plasma membrane of cells and the REL2 gene is relatively higher expressed in younger leaves of rice. The results from quantitative RT-PCR analysis indicated that REL2 functioning in the leaf shape formation might have functional linkage with many genes associated with the bulliform cells development, auxin synthesis and transport, etc. CONCLUSIONS: REL2 is the DUF domains contained protein which involves in the control of leaf rolling in rice. It is the plasma membrane localization and its functions in the control of leaf morphology might involve in multiple biological processes such as bulliform cell development and auxin synthesis and transport. PMID- 27473145 TI - Hypoxia-induced resistance to cisplatin-mediated apoptosis in osteosarcoma cells is reversed by gambogic acid independently of HIF-1alpha. AB - In vitro evidence of hypoxia-induced resistance to cisplatin (CDDP)-mediated apoptosis exists in human osteosarcoma (OS). Gambogic acid (GA) is a promising chemotherapeutic compound that could increase the chemotherapeutic effectiveness of CDDP in human OS cells by inducing cell cycle arrest and promoting apoptosis. This study examined whether GA could overcome OS cell resistance to CDDP. Hypoxia significantly reduced levels of CDDP-induced apoptosis in the OS cell lines MG63 and HOS. However, combined treatment with GA and CDDP revealed a strong synergistic action between these drugs, and higher protein levels of the apoptosis-related factor Fas, cleaved caspase-8 and cleaved caspase-3 and lower expression of hypoxia-inducible factor (HIF)-1alpha are detected in both cell lines. Meanwhile, drug resistance was not reversed by exposure to the HIF-1alpha inhibitor 2-methoxyestradiol. These findings strongly suggest that hypoxia induced resistance to CDDP is reversed by GA in OS cells independently of HIF 1alpha. Furthermore, in vivo studies using xenograft mouse models revealed that combination therapy with CDDP and GA exerted increased antitumor effects by inducing apoptosis. Taken together, our results demonstrate that GA may be a new potent therapeutic agent useful for targeting human OS cells. PMID- 27473146 TI - Induction of apoptosis and downregulation of ERalpha in DMBA-induced mammary gland tumors in Sprague-Dawley rats by synthetic 3,5-disubstituted isoxazole derivatives. AB - Isoxazole derivatives are an important group of chemotherapeutic prototypes. In the current study, we have synthesized few isoxazole derivatives and tested them for their antiproliferative properties in cancer cell lines such as MCF7 and HeLa. The lead compound, 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)isoxazole (2b), showed considerable inhibition of proliferation of MCF7 and HeLa cells with the IC50 values of 19.5 and 39.2 uM, respectively. Cell cycle analyses and annexin FITC staining in 2b-treated breast adenocarcinoma cells (MCF7) showed increased sub-G1 population and apoptosis. Furthermore, we tested the tumor inhibitory effect of 2b and estrogen receptor expression profile in DMBA-induced mammary tumors in Sprague-Dawley rats. The gross morphology of tumor studies was investigated by histopathology and ERalpha protein expression was evaluated by immunohistochemistry, which showed tumor regression and downregulation of ERalpha in tumor cells. The present results implicate that compound 2b could be used for the further derivatization for the treatment of breast cancer. PMID- 27473147 TI - The Roles for Prior Visual Experience and Age on the Extraction of Egocentric Distance. AB - OBJECTIVES: In a well-lit room, observers can generate well-constrained estimates of the distance to an object on the floor even with just a fleeting glimpse. Performance under these conditions is typically characterized by some underestimation but improves when observers have previewed the room. Such evidence suggests that information extracted from longer durations may be stored to contribute to the perception of distance at limited time frames. Here, we examined the possibility that this stored information is used differentially across age. Specifically, we posited that older adults would rely more than younger adults on information gathered and stored at longer glimpses to judge the distance of briefly glimpsed objects. METHOD: We collected distance judgments from younger and older adults after brief target glimpses. Half of the participants were provided 20-s previews of the testing room in advance; the other half received no preview. RESULTS: Performance benefits were observed for all individuals with prior visual experience, and these were moderately more pronounced for the older adults. DISCUSSION: The results suggest that observers store contextual information gained from longer viewing durations to aid in the perception of distance at brief glimpses, and that this memory becomes more important with age. PMID- 27473148 TI - The role of bone biopsy for the diagnosis of renal osteodystrophy: a short overview and future perspectives. AB - Chronic kidney disease (CKD) patients present specific bone and mineral metabolism disturbances, which account for important morbidity and mortality. The term renal osteodystrophy, classically used for the nomination of CKD-associated bone disorder, has been limited to the histologic description of bone lesions, requiring the use of bone biopsy. Biochemical markers and imaging tools do not adequately predict the complex bone changes that are observed in renal osteodystrophy. Parathyroid hormone, which is a universally used biomarker of bone turnover in clinical practice, lacks specificity and sensitivity. Therefore, tetracycline double-labelled transiliac bone biopsy, with bone histology and histomorphometric evaluation, remains the best clinical tool to discriminate bone turnover and to evaluate the other dimensions of renal osteodystrophy. This review will focus on the value of classic bone histomorphometric analysis of trabecular bone in CKD patients and unfold new perspectives of this diagnostic tool, including cortical bone evaluation and bone tissue immunohistochemistry. PMID- 27473151 TI - Fifteen-minute consultation: the child with systemic arterial hypertension. AB - Hypertension in children is a relatively uncommon condition but its prevalence is increasing with the rising rates of excess weight during childhood. It is important that hypertension is diagnosed early in children, particularly in those with symptoms, in those with secondary causes and in those with target organ damage. This article presents a systematic approach to the evaluation of a child with arterial hypertension, highlighting important points on history and examination, out-of-office monitoring and baseline investigations before consideration for more detailed investigations and treatment. PMID- 27473152 TI - Improved GP retainer scheme with increased funding is launched. PMID- 27473150 TI - Progress in the utilization of antenatal and delivery care services in Bangladesh: where does the equity gap lie? AB - BACKGROUND: Universal access to health care services does not automatically guarantee equity in the health system. In the post Millennium Development Goals (MDGs) era, the progress towards universal access to maternal health care services in a developing country, like Bangladesh requires an evaluation in terms of equity lens. This study, therefore, analysed the trend in inequity and identified the equity gap in the utilization of antenatal care (ANC) and delivery care services in Bangladesh between 2004 and 2011. METHODS: The data of this study came from the Bangladesh Demographic and Health Survey. We employed rate ratio, concentration curve and concentration index to examine the trend in inequity of ANC and delivery care services. We also used logistic regression models to analyse the relationship between socioeconomic factors and maternal health care services. RESULTS: The concentration index for 4+ ANC visits dropped from 0.42 in 2004 to 0.31 in 2011 with a greater decline in urban area. There was almost no change in the concentration index for ANC services from medically trained providers during this period. We also found a decreasing trend in inequity in the utilization of both health facility delivery and skilled birth assistance but this trend was again more pronounced in urban area compared to rural area. The concentration index for C-section delivery decreased by about 33 % over 2004-2011 with a similar rate in both urban and rural areas. Women from the richest households were about 3 times more likely to have 4+ ANC visits, delivery at a health facility and skilled birth assistance compared to women from the poorest households. Women's and their husbands' education were significantly associated with greater use of maternal health care services. In addition, women's exposure to mass media, their involvement in microcredit programs and autonomy in healthcare decision-making appeared as significant predictors of using some of these health care services. CONCLUSIONS: Bangladesh faces not only a persistent pro-rich inequity but also a significant rural-urban equity gap in the uptake of maternal health care services. An equity perspective in policy interventions is much needed to ensure safe motherhood and childbirth in Bangladesh. PMID- 27473149 TI - The phosphatase calcineurin regulates pathological TDP-43 phosphorylation. AB - Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90 % of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date, several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together, these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences. PMID- 27473153 TI - Identification of Salmonella enterica serovar Kentucky genes involved in attachment to chicken skin. AB - BACKGROUND: Regardless of sanitation practices implemented to reduce Salmonella prevalence in poultry processing plants, the problem continues to be an issue. To gain an understanding of the attachment mechanism of Salmonella to broiler skin, a bioluminescent-based mutant screening assay was used. A random mutant library of a field-isolated bioluminescent strain of Salmonella enterica serovar Kentucky was constructed. Mutants' attachment to chicken skin was assessed in 96-well plates containing uniform 6 mm diameter pieces of circular chicken skin. After washing steps, mutants with reduced attachment were selected based on reduced bioluminescence, and transposon insertion sites were identified. RESULTS: Attachment attenuation was detected in transposon mutants with insertion in genes encoding flagella biosynthesis, lipopolysaccharide core biosynthesis protein, tryptophan biosynthesis, amino acid catabolism pathway, shikimate pathway, tricarboxylic acid (TCA) cycle, conjugative transfer system, multidrug resistant protein, and ATP-binding cassette (ABC) transporter system. In particular, mutations in S. Kentucky flagellar biosynthesis genes (flgA, flgC, flgK, flhB, and flgJ) led to the poorest attachment of the bacterium to skin. CONCLUSIONS: The current study indicates that attachment of Salmonella to broiler skin is a multifactorial process, in which flagella play an important role. PMID- 27473154 TI - Does N-terminal pro-brain natriuretic peptide add prognostic value to the Mehran risk score for contrast-induced nephropathy and long-term outcomes after primary percutaneous coronary intervention? AB - PURPOSE: To evaluate the prognostic value of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) in relation to Mehran risk score (MRS) for contrast-induced nephropathy (CIN) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). METHODS: We prospectively enrolled 283 consecutive patients treated with PPCI for STEMI. NT-proBNP was measured, and the MRS was calculated. The primary end point was CIN, defined as an absolute increase in serum creatinine >=0.5 mg/dL from baseline within 48-72 h after contrast medium exposure. RESULTS: The incidence of CIN was 9.2 %. Patients with CIN had higher NT-proBNP and MRS than those without CIN. The value of NT-proBNP was similar to MRS for CIN (C statistics 0.760 vs. 0.793, p = 0.689). After adjustment for MRS, elevated NT-proBNP (defined as the best cutoff point) was significantly associated with CIN. The addition of elevated NT-proBNP to MRS did not significantly improve the C statistics, over that with the original MRS model (0.833 vs. 0.793, p = 0.256). In addition, similar results were observed for in hospital and long-term major adverse clinical events. CONCLUSIONS: Although NT proBNP did not add any prognostic value to the MRS model for CIN, NT-proBNP, as a simple biomarker, was similar to MRS, and may be another useful and rapid screening tool for CIN and death risk assessment, identifying subjects who need therapeutic measures to prevent CIN. PMID- 27473156 TI - A cross-sectional study in the USA of the epidemiology and quality of life of underactive bladder symptoms. AB - PURPOSE: To assess the prevalence, awareness, and quality of life (QOL) impact of symptoms suggestive of underactive bladder (UAB) in the USA. METHODS: A thirteen item paper survey was mailed to 25,000 individuals 60 years or older living in the USA. It aimed to collect information relating to demographics, familiarity with UAB, patient urinary symptoms, and QOL concerns. RESULTS: Nine hundred and seventy-seven survey participants were stratified into four groups based on the number of UAB symptoms (straining, retention, and difficulty emptying) present: zero, one, two, and three. As the number of reported UAB symptoms increased, there was an increase prevalence in nocturia, urge, and urinary frequency (p < 0.0001). Increased UAB symptoms were associated with an increased prevalence of concerns related to urgency, urge incontinence, nocturia, and overall urinary status (p < 0.0001). Urology visits were most common in individuals who reported the most UAB symptoms (p < 0.0001); however, there was no difference among groups with regard to UAB awareness. Women were less likely to report any UAB symptoms (p < 0.0001), symptoms of urge (p = 0.001), retention (p = 0.002), difficulty emptying their bladder (p < 0.0001), a history of catheter use for retention (P = 0.002), and urology visits in the past 3 years (p < 0.0001). This study is limited in its inability to differentiate UAB from disorders that may mimic UAB clinically, based on the survey questions asked. CONCLUSIONS: Underactive bladder symptoms are common and can have a significant impact on ones QOL, although awareness is still lacking among potentially affected individuals. More must be done to allow one to better differentiate between UAB and conditions that are clinically similar. PMID- 27473155 TI - Lowering dialysate sodium improves systemic oxidative stress in maintenance hemodialysis patients. AB - PURPOSE: The purpose of the current prospective study was to evaluate the effects of low sodium dialysate on oxidative stress parameters, blood pressure (BP) and endothelial dysfunction in maintenance hemodialysis (HD) patients. METHODS: After baseline measurements were taken, the dialysate sodium concentration was reduced from 140 to 137 mEq/L. Oxidative stress parameters and flow-mediated dilatation (FMD %) were measured before and after 6 months of HD with low sodium dialysate. Interdialytic weight gain (IDWG) and pre- and post-dialysis BP were monitored during the study. RESULTS: A total of 52 patients were enrolled and 41 patients completed the study. There was a significant reduction in systolic blood pressure at the end of the study [130.00 (90.00-190.00) vs. 120.00 (90.00-150.00), p < 0.001]. Similarly, there were significant improvements in IDWG [2670.00 (1670.00 4300.00) vs. 1986.00 (1099.00-3998.00), p < 0.001] and FMD % [7.26 (4.55-8.56) vs. 9.56 (6.55-12.05), p < 0.001]. Serum MDA levels (p < 0.001) were significantly decreased; serum SOD (p < 0.001) and GPx (p < 0.001) activities were significantly increased after low sodium HD compared to standard sodium HD. CONCLUSION: Our data seem to suggest a potential role of 137 mEq/L sodium dialysate for improving hemodynamic status, endothelial function and reducing oxidative stress than 140 mEq/L sodium dialysate in maintenance HD patients. PMID- 27473157 TI - Life expectancy of different ethnic groups using death records linked to population census data for 4.62 million people in Scotland. AB - BACKGROUND: Few countries record the data needed to estimate life expectancy by ethnic group. Such information is helpful in assessing the extent of health inequality. METHOD: Life tables were created using 3 years of deaths (May 2001 April 2004) linked to Scottish 2001 Census data for 4.62 million individuals with self-reported ethnicity. We created 8 ethnic groups based on the census definitions, each with at least 5000 individuals and 40 deaths. Life expectancy at birth was calculated using the revised Chiang method. RESULTS: The life expectancy of White Scottish males at birth was 74.7 years (95% CI 74.6 to 74.8), similar to Mixed Background (73.0; 70.2 to 75.8) and White Irish (75.0; 74.0 to 75.9), but shorter than Indian (80.9; 78.4 to 83.4), Pakistani (79.3; 76.9 to 81.6), Chinese (79.0; 76.5 to 81.5), Other White British (78.9; 78.6 to 79.2) and Other White (77.2; 76.4 to 78.1). The life expectancy of White Scottish females was 79.4 years (79.3 to 79.5), similar to mixed background (79.3; 76.6 to 82.0), but shorter than Pakistani (84.6; 82.0 to 87.3), Chinese (83.4; 81.1 to 85.7), Indian (83.3; 80.7 to 85.9), Other White British (82.6; 82.3 to 82.9), other White (82.0; 81.3 to 82.8) and White Irish (81; 80.2 to 81.8). CONCLUSIONS: Males and females in most of the larger ethnic minority groups in Scotland have longer life expectancies than the majority White Scottish population. PMID- 27473158 TI - Modulation of Immunologic Response by Preventive Everolimus Application in a Rat CPB Model. AB - Everolimus (EVL) is widely used in solid organ transplantation. It is known to have antiproliferative and immunosuppressive abilities via inhibition of the mTOR pathway. Preventive EVL administration may lower inflammation induced by cardiopulmonary bypass (CPB) and reduce systemic inflammatory response syndrome (SIRS). After oral loading with EVL 2.5 mg/kg/day (n = 11) or placebo (n = 11) for seven consecutive days, male Wistar rats (400-500 g) were connected to a miniaturised heart-lung-machine performing a deep hypothermic circulatory arrest protocol. White blood cells (WBC) were significantly reduced in EVL-pretreated animals before start of CPB with a preserved reduction by trend at all other time points. Ischemia/reperfusion led to decreased glucose levels. Application of EVL significantly increased glucose levels after reperfusion. In addition, potassium levels were significantly lower in EVL-treated animals at the end of reperfusion. Immunoblotting revealed increased S6 levels after CPB. EVL decreased phosphorylation of S6 in the heart and kidney, which indicates an inhibition of mTOR pathway. Moreover, EVL significantly modified phosphorylation of AKT, while decreasing IL2, IL6, RANTES, and TNFalpha (n = 6). Preventive application of EVL may modulate inflammation by inhibition of mammalian target of rapamycin (mTOR) pathway and reduction of proinflammatory cytokines. This may be beneficial to evade SIRS-related morbidities after CPB. PMID- 27473160 TI - Patients' perspective of a group intervention for perfectionism in anorexia nervosa: A qualitative study. AB - This study aimed to explore the experiences of adults with anorexia nervosa who took part in a perfectionism group intervention in an inpatient setting. Thematic analysis was used to explore patient feedback collected in focus groups. Patient feedback was generally positive and centred around three main themes: perceived benefits of the group, the content of the group and suggested improvements. The findings suggest that a brief perfectionism group intervention is an acceptable treatment with a range of perceived benefits for patients with severe anorexia nervosa. Understanding patients' experiences of the intervention can provide further important information to maximise therapeutic impact of the group in inpatient settings. PMID- 27473159 TI - The Effects of Dexamethasone and L-NAME on Acute Lung Injury in Rats with Lung Contusion. AB - The therapeutic efficiency of an anti-inflammatory agent, dexamethasone (DXM), and a nitric oxide synthase (NOS) inhibitor, Nitro-L-arginine methyl ester (L NAME), in lung tissue injury after lung contusion was investigated. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), YKL-40, an inflammatory peptide, inducible NOS (iNOS), and Clara cell protein 16 (CC-16) were evaluated. Immunohistochemical analyses were also performed, and the lung tissue was examined histopathologically. The study consisted of eight groups of Sprague-Dawley rats (n = 10 in each group), weighing 250-300 g: (1) control, (2) contusion, (3) control + DXM, (4) contusion + DXM, (5) control + L-NAME (6) contusion + L-NAME, (7) control + DXM + L-NAME, and (8) contusion + DXM + L-NAME. A previously developed lung contusion model was used, in addition to the control group. The rats were administered DXM and L-NAME intraperitoneally (i.p.) at doses of 15 and 60 mg/kg/day, respectively. DXM and L-NAME administration decreased the iNOS level in the contusion groups. DXM increased the levels of YKL 40 and IL-10 in both the control and contusion groups, with higher levels in the contusion groups. L-NAME increased the serum level of IL-10 in the lung contusion groups. DXM increased the synthesis of CC-16 in the control and contusion groups. The combined use of a high-dose steroid and NOS inhibitor resulted in the death of the rats. Steroids can increase the level of cytokines, such as YKL-40 and IL 10, and the synthesis of CC-16 and prevent pneumonia, ALI/ARDS, and sepsis in lung contusion. PMID- 27473161 TI - Autophagy is associated with cell fate in the process of macrophage-derived foam cells formation and progress. AB - BACKGROUND: Autophagy participates in plaque formation and progression; however, its association with foam cells' fate is unknown. To investigate autophagy features and its effect on the fate of different-stage macrophage foam cells (FCs). Different-stage FCs were obtained through incubation of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein LDL (oxLDL, 80 MUg/mL) for various durations (0-72 h). Autophagy in THP-1 macrophage FCs and in apoE-/- mice was regulated by Rapamycin (80 ug/mL) or 3-MA (10 mM). Lipid droplet accumulation, LC3 I/II, P62 expression level, and autophagic flux were measured. Vascular ultrasound, TUNEL, IHC, and DHE staining were used to detect the artery plaques in apoE-/- mice. RESULTS: In early-stage FCs, the amount of autophagosomes gradually increased, and autophagic flux intensity accelerated, but in mid-late stage FCs, autophagic flux was suppressed. For early stage FCs, treatment with autophagy activator rapamycin markedly decreased intracellular lipid content and prevented them from transforming into foam cells, while the autophagy inhibitor 3 MA considerably increased the intracellular lipid-droplet accumulation. During the process of foam cell development, upregulating autophagy not only reduced intracellular lipid-droplet accumulation, but also inhibited cell apoptosis through clearing dysfunctional mitochondria and lowering intracellular ROS level. The in vivo experiments produced consistent results that rapamycin administration in apoE-/- mice reduced the death rate of macrophages and delayed plaque progression. CONCLUSIONS: The fate of macrophage FCs was associated with autophagy. Early autophagy enhancement inhibits the formation and progression of macrophage FCs and prevents atherosclerosis. PMID- 27473162 TI - Phrenic nerve block caused by interscalene brachial plexus block: breathing effects of different sites of injection. AB - BACKGROUND: Interscalene brachial plexus (ISB) block is often associated with phrenic nerve block and diaphragmatic paresis. The goal of our study was to test if the anterior or the posterior ultrasound guided approach of the ISB is associated with a lower incidence of phrenic nerve blocks and impaired lung function. METHODS: This was a prospective, randomized and single-blinded study of 84 patients scheduled for elective shoulder surgery who fullfilled the inclusion and exclusion critereria. Patients were randomized in two groups to receive either the anterior (n = 42) or the posterior (n = 42) approach for ISB. Clinical data were recorded. In both groups patients received ISB with a total injection volume of 15 ml of ropivacaine 1 %. Spirometry was conducted at baseline (T0) and 30 min (T30) after accomplishing the block. Changes in spirometrical variables between T0 and T30 were investigated by Wilcoxon signed-rank test for each puncture approach. The temporal difference between the posterior and the anterior puncture approach groups were again analyzed by the Wilcoxon-Mann-Whitney test. RESULTS: The spirometric results showed a significant decrease in vital capacity, forced expiratory volume per second, and maximum nasal inspiratory breathing after the Interscalene brachial plexus block; indicating a phrenic nerve block (p <0.001, Wilcoxon signed-rank). A significant difference in the development of the spirometric parameters between the anterior and the posterior group could not be identified (Wilcoxon-Mann-Whitney test). Despite the changes in spirometry, no cases of dyspnea were reported. CONCLUSION: A different site of injection (anterior or posterior) did not show an effect in reducing the cervical block spread of the local anesthetic and the incidence of phrenic nerve blocks during during ultrasound guided Interscalene brachial plexus block. Clinical breathing effects of phrenic nerve blocks are, however, usually well compensated, and subjective dyspnea did not occur in our patients. TRIAL REGISTRATION: German Clinical Trials Register (DRKS number 00009908 , registered 26 January 2016). PMID- 27473163 TI - Differential tumor infiltration by T-cells characterizes intrinsic molecular subtypes in breast cancer. AB - BACKGROUND: Molecular subtypes of breast cancer and presence of tumor infiltrating immune cells have both been implicated as important predictive and prognostic factors for improved risk stratification and treatment individualization of breast cancer patients. Their association, however, has not been studied in detail. The aim of this study was to evaluate the expression of the T cell markers CD8, FoxP3, CD3 and zeta-chain in molecular subtypes of the invasive margin and tumor center of breast cancer and corresponding sentinel nodes and to deduct prognostic information from these findings. METHODS: Tumor and sentinel node sections from 177 patients with primary, invasive, unilateral early-stage breast cancer were stained by immunohistochemistry and T-cell phenotypes quantified manually. Clinical data were collected from medical records. RESULTS: The degree of T-cell infiltration and expression of all markers differed significantly among the molecular subtypes, being highest in non luminal, more aggressive tumors: more T-cell infiltration and higher expression of all markers were associated with hormone receptor negativity, higher proliferation and higher histological grades, but also with larger tumor size. Basal-like tumors, and most remarkably their tumor centers, hosted the highest number of FoxP3+ T-cells with an unfavorable ratio to cytotoxic CD8+ T-cells. T cell infiltration was generally higher in the invasive margin than the tumor center. A scoring system based on densities of CD3 and CD8 could significantly separate molecular subtypes (p < 0.001). CONCLUSIONS: Thus, immunological patterns with functional implications within each subtype are associated with prognostic factors. These findings should be further validated in studies using larger patient populations and longer follow-up. PMID- 27473165 TI - Virulence and resistance profiles of MRSA isolates in pre- and post-liver transplantation patients using microarray. AB - Methicillin-resistant Staphylococcus aureus (MRSA) screening plays a great role in preventing infections in surgical patients. This study aims to evaluate clonality, virulence and resistance of MRSA in pre- and post-liver transplantation (LT) patients. Nasal and groin swabs of 190 patients were collected. PCR for virulence genes and staphylococcal cassette chromosome mec (SCCmec) types, microarray, PFGE, multilocus sequence typing and MIC were performed. MRSA carriers were detected in 20.5 % (39/190) of the patients. However, only three colonized patients developed infections post-LT. Sixty-nine MRSA isolates were identified, and the most frequent SCCmec type was type II (29/69; 42.0 %). Most isolates (57/69; 82.6 %) were susceptible to trimethoprim sulfamethoxazole (TMP/SMX) and harboured the lukD, lukE, clf and fnbA genes as determined by PCR. Five sequence types (ST) were identified among nine clones; 36.2 % (25/69) isolates belonged to a predominant clone (ST105 and SCCmec type II) that was susceptible to TMP/SMX, mupirocin and chlorhexidine, which had 87.9 % similarity with the New York/Japan clone. The array showed virulence difference in isolates of the same clone and patients and that colonized isolates (pre-LT patients) were less virulent than those post-LT and those infected. Therefore, despite the high frequency of MRSA colonization, infection due to MRSA was uncommon in our LT unit. MRSA isolates presented great diversity. Isolates of the same clone expressed different virulence factors by array. Colonizing isolates pre-LT expressed less virulent factors than post-LT and infecting isolates. PMID- 27473164 TI - Resistance exercise improves physical fatigue in women with fibromyalgia: a randomized controlled trial. AB - BACKGROUND: Fibromyalgia (FM) affects approximately 1-3 % of the general population. Fatigue limits the work ability and social life of patients with FM. A few studies of physical exercise have included measures of fatigue in FM, indicating that exercise can decrease fatigue levels. There is limited knowledge about the effects of resistance exercise on multiple dimensions of fatigue in FM. The present study is a sub-study of a multicenter randomized controlled trial in women with FM. The purpose of the present sub-study was to examine the effects of a person-centered progressive resistance exercise program on multiple dimensions of fatigue in women with FM, and to investigate predictors of the potential change in fatigue. METHODS: A total of 130 women with FM (age 22-64 years) were included in this assessor-blinded randomized controlled multicenter trial examining the effects of person-centered progressive resistance exercise compared with an active control group. The intervention was performed twice a week for 15 weeks. Outcomes were five dimensions of fatigue measured with the Multidimensional Fatigue Inventory (MFI-20). Information about background was collected and the women also completed several health-related questionnaires. Multiple linear stepwise regression was used to analyze predictors of change in fatigue in the total population. RESULTS: A higher improvement was found at the post-treatment examination for change in the resistance exercise group, as compared to change in the active control group in the MFI-20 subscale of physical fatigue (resistance group Delta -1.7, SD 4.3, controls Delta 0.0, SD 2.7, p = 0.013), with an effect size of 0.33. Sleep efficiency was the strongest predictor of change in the MFI-20 subscale general fatigue (beta = -0.54, p = 0.031, R (2) = 0.05). Participating in resistance exercise (beta = 1.90, p = 0.010) and working fewer hours per week (beta = 0.84, p = 0.005) were independent significant predictors of change in physical fatigue (R (2) = 0.14). CONCLUSIONS: Person-centered progressive resistance exercise improved physical fatigue in women with FM when compared to an active control group. TRIAL REGISTRATION: ClinicalTrials.gov NCT01226784 . Registered 21 October 2010. PMID- 27473166 TI - Streptococcusmarmotae sp. nov., isolated from the respiratory tract of Marmota himalayana. AB - Five strains of a Gram-stain-positive, catalase-negative, alpha-haemolytic, coccus-shaped chain-forming organism were isolated separately from the lower respiratory tracts of five animals of Marmota himalayana in the endemic area of plague, the Qinghai-Tibet Plateau, China. Based on their morphological characteristics, biochemical features and molecular phylogenetic studies, the strains were placed as representing a new member of the genus Streptococcus. Comparative 16S rRNA gene sequence studies indicated that strain HTS5T shared 96.5, 96.2 and 96.0 % similarity with Streptococcus gallinaceus CCUG 42692T, Streptococcus parasanguinis ATCC 15912T and Streptococcus suis ATCC 43765T, respectively. Sequence analysis of its rpoB and sodA genes showed that strain HTS5T was most closely related to Streptococcus cuniculi CCUG 65085T with 9.2 and 10.9 % interspecies divergence, respectively. The whole genome phylogenetic tree based on 339 core genes of 65 Streptococcus genomes confirmed that HTS5T belongs to a distinct lineage that is well separated from recognized species of the genus Streptococcus. In silico DNA-DNA hybridization using 65 available genomes from GenBank showed that HTS5T displayed less than 70 % DNA-DNA relatedness with the other 65 species of the genus Streptococcus deposited in the GenBank database. The genome of strain HTS5T (2 322 791 bp) contained 2377 genes and had a G+C content of 41.6 mol%. Therefore, the five strains are considered to represent a novel species of the genus Streptococcus for which the name Streptococcusmarmotae sp. nov. is proposed. The type strain is HTS5T (=DSM 101995T=CGMCC 1.15534T). PMID- 27473167 TI - Monetary reward magnitude effects on behavior and brain function during goal directed behavior. AB - Reward may modulate the cognitive processes required for goal achievement, while individual differences in personality may affect reward modulation. Our aim was to test how different monetary reward magnitudes modulate brain activation and performance during goal-directed behavior, and whether individual differences in reward sensitivity affect this modulation. For this purpose, we scanned 37 subjects with a parametric design in which we varied the magnitude of monetary rewards (?0, ?0.01, ?0.5, ?1 or ?1.5) in a blocked fashion while participants performed an interference counting-Stroop condition. The results showed that the brain activity of left dorsolateral prefrontal cortex (DLPFC) and the striatum were modulated by increasing and decreasing reward magnitudes, respectively. Behavioral performance improved as the magnitude of monetary reward increased while comparing the non reward (?0) condition to any other reward condition, or the lower ?0.01 to any other reward condition, and this improvement was related with individual differences in reward sensitivity. In conclusion, the locus of influence of monetary incentives overlaps the activity of the regions commonly involved in cognitive control. PMID- 27473168 TI - Temporo-spatial cell-cycle kinetics in HeLa cells irradiated by Ir-192 high dose rate remote afterloading system (HDR-RALS). AB - BACKGROUND: Intracavitary irradiation plays a pivotal role in definitive radiotherapy for cervical cancer, and the Ir-192 high dose-rate remote afterloading system (HDR-RALS) is often used for this purpose. Under this condition, tumor tissues receive remarkably different absorption doses, with a steep gradient, depending on distance from the radiation source. To obtain temporo-spatial information regarding cell-cycle kinetics in cervical cancer following irradiation by Ir-192 HDR-RALS, we examined HeLa cells expressing the fluorescence ubiquitination-based cell cycle indicator (Fucci), which allowed us to visualize cell-cycle progression. METHODS: HeLa-Fucci cells, which emit red and green fluorescence in G1 and S/G2/M phases, respectively, were grown on 35-mm dishes and irradiated by Ir-192 HDR-RALS under normoxic and hypoxic conditions. A 6 French (Fr) catheter was used as an applicator. A radiation dose of 6 Gy was prescribed at hypothetical treatment point A, located 20 mm from the radiation source. Changes in Fucci fluorescence after irradiation were visualized for cells from 5 to 20 mm from the Ir-192 source. Several indices, including first green phase duration after irradiation (FGPD), were measured by analysis of time-lapse images. RESULTS: Cells located 5 to 20 mm from the Ir-192 source became green, reflecting arrest in G2, in a similar manner up to 12 h after irradiation; at more distant positions, however, cells were gradually released from the G2 arrest and became red. This could be explained by the observation that the FGPD was longer for cells closer to the radiation source. Detailed observation revealed that FGPD was significantly longer in cells irradiated in the green phase than in the red phase at positions closer to the Ir-192 source. Unexpectedly, the FGPD was significantly longer after irradiation under hypoxia than normoxia, due in large part to the elongation of FGPD in cells irradiated in the red phase. CONCLUSION: Using HeLa-Fucci cells, we obtained the first temporo-spatial information about cell-cycle kinetics following irradiation by Ir-192 HDR-RALS. Our findings suggest that the potentially surviving hypoxic cells, especially those arising from positions around point A, exhibit different cell-cycle kinetics from normoxic cells destined to be eradicated. PMID- 27473169 TI - Identification of new branch points and unconventional introns in Saccharomyces cerevisiae. AB - Spliced messages constitute one-fourth of expressed mRNAs in the yeast Saccharomyces cerevisiae, and most mRNAs in metazoans. Splicing requires 5' splice site (5'SS), branch point (BP), and 3' splice site (3'SS) elements, but the role of the BP in splicing control is poorly understood because BP identification remains difficult. We developed a high-throughput method, Branch seq, to map BPs and 5'SSs of isolated RNA lariats. Applied to S. cerevisiae, Branch-seq detected 76% of expressed, annotated BPs and identified a comparable number of novel BPs. We performed RNA-seq to confirm associated 3'SS locations, identifying some 200 novel splice junctions, including an AT-AC intron. We show that several yeast introns use two or even three different BPs, with effects on 3'SS choice, protein coding potential, or RNA stability, and identify novel introns whose splicing changes during meiosis or in response to stress. Together, these findings show unanticipated complexity of splicing in yeast. PMID- 27473170 TI - RNA-binding protein HuR and the members of the miR-200 family play an unconventional role in the regulation of c-Jun mRNA. AB - Post-transcriptional gene regulation is a fundamental step for coordinating cellular response in a variety of processes. RNA-binding proteins (RBPs) and microRNAs (miRNAs) are the most important factors responsible for this regulation. Here we report that different components of the miR-200 family are involved in c-Jun mRNA regulation with the opposite effect. While miR-200b inhibits c-Jun protein production, miR-200a tends to increase the JUN amount through a stabilization of its mRNA. This action is dependent on the presence of the RBP HuR that binds the 3'UTR of c-Jun mRNA in a region including the mir-200a binding site. The position of the binding site is fundamental; by mutating this site, we demonstrate that the effect is not micro-RNA specific. These results indicate that miR-200a triggers a microRNA-mediated stabilization of c-Jun mRNA, promoting the binding of HuR with c-Jun mRNA. This is the first example of a positive regulation exerted by a microRNA on an important oncogene in proliferating cells. PMID- 27473172 TI - RevEcoR: an R package for the reverse ecology analysis of microbiomes. AB - BACKGROUND: All species live in complex ecosystems. The structure and complexity of a microbial community reflects not only diversity and function, but also the environment in which it occurs. However, traditional ecological methods can only be applied on a small scale and for relatively well-understood biological systems. Recently, a graph-theory-based algorithm called the reverse ecology approach has been developed that can analyze the metabolic networks of all the species in a microbial community, and predict the metabolic interface between species and their environment. RESULTS: Here, we present RevEcoR, an R package and a Shiny Web application that implements the reverse ecology algorithm for determining microbe-microbe interactions in microbial communities. This software allows users to obtain large-scale ecological insights into species' ecology directly from high-throughput metagenomic data. The software has great potential for facilitating the study of microbiomes. CONCLUSIONS: RevEcoR is open source software for the study of microbial community ecology. The RevEcoR R package is freely available under the GNU General Public License v. 2.0 at http://cran.r project.org/web/packages/RevEcoR/ with the vignette and typical usage examples, and the interactive Shiny web application is available at http://yiluheihei.shinyapps.io/shiny-RevEcoR , or can be installed locally with the source code accessed from https://github.com/yiluheihei/shiny-RevEcoR . PMID- 27473171 TI - Altered gut microbiota in Rett syndrome. AB - BACKGROUND: The human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Rett syndrome (RTT), a progressive neurological disorder mainly caused by mutations in MeCP2 gene, is commonly associated with gastrointestinal dysfunctions and constipation, suggesting a link between RTT's gastrointestinal abnormalities and the gut microbiota. The aim of this study was to evaluate the bacterial and fungal gut microbiota in a cohort of RTT subjects integrating clinical, metabolomics and metagenomics data to understand if changes in the gut microbiota of RTT subjects could be associated with gastrointestinal abnormalities and inflammatory status. RESULTS: Our findings revealed the occurrence of an intestinal sub-inflammatory status in RTT subjects as measured by the elevated values of faecal calprotectin and erythrocyte sedimentation rate. We showed that, overall, RTT subjects harbour bacterial and fungal microbiota altered in terms of relative abundances from those of healthy controls, with a reduced microbial richness and dominated by microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida. We further observed that alterations of the gut microbiota do not depend on the constipation status of RTT subjects and that this dysbiotic microbiota produced altered short chain fatty acids profiles. CONCLUSIONS: We demonstrated for the first time that RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that impairments of MeCP2 functioning favour the establishment of a microbial community adapted to the costive gastrointestinal niche of RTT subjects. The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT subjects and contribute to RTT gastrointestinal physiopathology. PMID- 27473174 TI - Primary extramammary invasive Paget's vulvar disease: what is the standard, what are the challenges and what is the future for radiotherapy? AB - BACKGROUND: Primary invasive Extramammary Paget's vulvar disease is a rare tumor that is challenging to control. Wide surgical excision represents the standard treatment approach for Primary invasive Extramammary Paget's vulvar disease. The goal of the current study was to analyze the appropriate indications of radiotherapy in Primary invasive Extramammary Paget's vulvar disease because they are still controversial. DISCUSSION: We searched the Cochrane Gynecological Cancer Group Trials Register, Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE database up to September 2015. Radiotherapy was delivered as a treatment in various settings: i) Radical in 28 cases (range: 60-63 Gy), ii) Adjuvant in 25 cases (range: 39-60 Gy), iii) Salvage in recurrence of 3 patients (63 Gy) and iv) Neoadjuvant in one patient (43.3 Gy). A radiotherapy field that covered the gross tumor site with a 2-5 cm margin for the microscopic disease has been used. Radiotherapy of the inguinal, pelvic or para-aortic lymph node should be considered only for the cases with lymph node metastases within these areas. Radiotherapy alone is an alternative therapeutic approach for patients with extensive inoperable disease or medical contraindications. Definitive radiotherapy can be used in elderly patients and/or with medical contraindications. Adjuvant radiotherapy may be considered in presence of risk factors associated with local recurrence as dermal invasion, lymph node metastasis, close or positive surgical margins, perineal, large tumor diameter, multifocal lesions, extensive disease, coexisting histology of adenocarcinoma or vulvar carcinoma, high Ki-67 expression, adnexal involvement and probably in overexpression of HER-2/neu. Salvage radiotherapy can be given in inoperable loco regional recurrence and to those who refused additional surgery. PMID- 27473175 TI - alpha-Synuclein-carrying extracellular vesicles in Parkinson's disease: deadly transmitters. AB - Exosomes play a key role in delivery of various biological material and complex signals from one cell to another at long distances. These small extracellular vehicles are involved in mediating multiple physiological and pathogenic processes. In neurodegenerative diseases such as Parkinson's disease (PD), exosomes contribute to disease propagation through transferring misfolded proteins from affected cells to normal cells. In PD, progressive degeneration of neurons arises from the extensive accumulation of toxic forms of alpha-synuclein in the cytoplasm. alpha-Synuclein could exist in several forms, some of which (i.e., oligomeric and polymeric forms) are cytotoxic. Neuron-derived exosomes were found to transfer alpha-synuclein toxic forms between neuronal and non neuronal cells (such as astrocytes and microglia) thereby contributing to PD spreading. Deposition of alpha-synuclein in glial cells induces inflammation that could be further propagated to other glial cells and neurons. Neuroinflammation promotes degeneration of neurons and aggravates the pathogenesis of PD. PMID- 27473173 TI - An Integrated Process and Outcome Evaluation of a Web-Based Communication Tool for Patients With Malignant Lymphoma: Randomized Controlled Trial. AB - BACKGROUND: The complex nature of the medical dialogue and the often emotional context in cancer care present challenges to health care professionals (HCPs) and patients. Patients are increasingly expected to be informed participants and to be able to make conscious decisions, which they often find very difficult. In an attempt to support patients with malignant lymphoma in clinical communication, we developed a stand-alone, Web-based intervention called "PatientTIME." The development of PatientTIME was based on a participatory intervention mapping framework. Its primary aim is to boost patients' self-efficacy in patient professional communication (ie, their confidence when interacting with their HCP). Patients can use this intervention before their hospital visit to prepare for their clinical consultation. PatientTIME is fully automated and use is patient-initiated. OBJECTIVE: The aim of this study was to evaluate if and in what way patients benefit from PatientTIME and if it enhances their confidence in clinical communication. METHODS: The intervention was evaluated in a closed randomized controlled trial with continuous recruitment (using online and offline methods to reach potential participants) and data collection. In accordance with the Medical Research Council guidance, we started with a process evaluation. Subsequently, an outcome evaluation was performed focusing on the patients' perceived confidence in communication with their HCP, measured with the validated PEPPI questionnaire at baseline and at 3 months after participation. Process and outcome data were obtained through Web-based questionnaires, log files (automatically generated files mapping the interactions between program and users), and a logbook (comprising a record of actions and interactions kept by the researchers). Participants were not blinded. A total of 146 patients registered online, of whom 97 gave their informed consent and were assigned at random to the control group (N=34) or 1 of the 2 intervention groups (N=63). Ultimately 87/97 (90%) of these patients actually participated in the study, producing 87 datasets for analysis. RESULTS: More than half of the intervention group patients reported that the intervention helped them prepare for a clinical consultation; it created awareness about the importance of communication and reinforced their existing communication skills. In the postvisit test, the control group showed a small, nonsignificant improvement in perceived communication efficacy. The intervention group showed a significant improvement in perceived efficacy. However, the interaction effect was not significant, indicating that the improvement solely as a result of the intervention may not be significant. CONCLUSIONS: A considerable number of patients reported that PatientTIME did provide support. We found a trend indicating that in the long run, patients with access to PatientTIME scored better on the perceived efficacy scale than patients without access. However, at this stage we cannot conclude that PatientTIME improves patients' confidence when interacting with HCPs. CLINICALTRIAL: Netherlands National Trial Register (NTR): 3779; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3779 (archived by WebCite at http://www.webcitation.org/6iztxJ5Nt). PMID- 27473176 TI - Isolated IgG4-related hypertrophic pachymeningitis. PMID- 27473177 TI - The effect of periodontal therapy on glycemic control and fasting plasma glucose level in type 2 diabetic patients: systematic review and meta-analysis. AB - BACKGROUND: Diabetic mellitus and periodontal disease have bilateral associations. However, there is a dilemma on the effect of periodontal therapy on glycemic control and/or fasting plasma glucose level in type 2 diabetic patients with periodontitis. Therefore, this review aimed to assess the effectiveness of periodontal therapy versus no periodontal therapy on glycated hemoglobin (HbA1c) and fasting plasma glucose level in type 2 diabetic patients. METHODS: Article searching was done using four databases (MEDLINE, Cochrane library (CENTRAL), EMBASE and CINAHL) and a manual search (until December 2015). We included randomized controlled trials testing the effectiveness of periodontal therapy on glycated hemoglobin and fasting plasma glucose level in patients with type 2 Diabetes mellitus with periodontal disease. Studies published in English between 2005 and 2015 were included. Risk of bias was assessed regarding randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases. RESULTS: After the article selection process, seven Randomized controlled trials involving 940 participants with a primary outcome of change in glycated hemoglobin and/or fasting plasma glucose and having a minimum of 3 months follow-up were included. There was a reduction of glycated hemoglobin 0.48(95 % CI: 0.18-0.78) after 3 months follow-up and 0.53 (95 % CI: 0.24-0.81) at the end of the intervention period. There was also a significant reduction of fasting plasma glucose level, 8.95 mg/dl (95 % CI: 4.30 13.61) in the intervention group after the end of the intervention. The pooled analysis showed that patients with adjunctive antibiotic therapy and mouth wash had effect size of 0.51(0.03, 1.00, p = 0.04) and it was 0.53 (95 % CI: 0.19, 0.87; p = 0.002) in patients without adjunctive therapy. The publication bias of the studies was 0.066 according to Egger's test. CONCLUSION: In this systematic review and meta-analysis, there is a significant reduction of Glycated hemoglobin and Fasting plasma glucose level on type 2 diabetic and periodontal patients with non-surgical periodontal therapy. PMID- 27473178 TI - Development of a Rickettsia bellii-Specific TaqMan Assay Targeting the Citrate Synthase Gene. AB - Rickettsia bellii is a rickettsial species of unknown pathogenicity that infects argasid and ixodid ticks throughout the Americas. Many molecular assays used to detect spotted fever group (SFG) Rickettsia species do not detect R. bellii, so that infection with this bacterium may be concealed in tick populations when assays are used that screen specifically for SFG rickettsiae. We describe the development and validation of a R. bellii-specific, quantitative, real-time PCR TaqMan assay that targets a segment of the citrate synthase (gltA) gene. The specificity of this assay was validated against a panel of DNA samples that included 26 species of Rickettsia, Orientia, Ehrlichia, Anaplasma, and Bartonella, five samples of tick and human DNA, and DNA from 20 isolates of R. bellii, including 11 from North America and nine from South America. A R. bellii control plasmid was constructed, and serial dilutions of the plasmid were used to determine the limit of detection of the assay to be one copy per 4 ul of template DNA. This assay can be used to better determine the role of R. bellii in the epidemiology of tick-borne rickettsioses in the Western Hemisphere. PMID- 27473179 TI - Action of Ants on Vertebrate Carcasses and Blow Flies (Calliphoridae). AB - Forensic entomology is a science that uses insect fauna as a tool to assist in criminal investigations and civil proceedings. Although the most researched insects are the Diptera and Coleoptera, ants may be present in all stages of decomposition. The aim of this study was to evaluate the role of ants and their action on blow flies during the decomposition process. Experiments were performed in which four pig carcasses were exposed in the cold and dry season (November/2012 and March/2013) and four in the hot and wet season (May/2013 and August/2013). Flies were the first insects to detect and interact with the carcasses, and six species of the Calliphoridae family were identified. Ants (Hymenoptera: Formicidae) were the second group, with six subfamilies identified. Myrmycinae represented 42% of the species, followed by Formicinae (28%), Ectatominae and Ponerinae (both 10%), and Ecitoninae and Dolichoderinae (both 5%). The ants acted on the carcasses as predators of visiting species, omnivores, and necrophagous, in all cases significantly affecting the decomposition time, slowing it down when the ants preyed on adult and immature insects consuming the carcass, or accelerating it by consuming the carcass and creating holes that could serve as gateways for the action of other organisms. The ants also generated artifacts that could lead to forensic misinterpretation. PMID- 27473181 TI - Role of per-oral pancreatoscopy in the evaluation of suspected pancreatic duct neoplasia: a 13-year U.S. single-center experience. AB - BACKGROUND AND AIMS: The role of per-oral pancreatoscopy (POP) in the evaluation of occult pancreatic duct (PD) lesions remains limited to case series. The aim of this study was to evaluate the ability of POP to differentiate malignant from benign diseases of the PD. METHODS: Patients who underwent POP between 2000 and 2013 for the evaluation of indeterminate PD strictures, dilatations, or with suspected or known main duct intraductal papillary mucinous neoplasm were identified. Main outcome measurements were visual impression accuracy, POP tissue sampling, efficacy, and safety of POP. RESULTS: During the study period, 79 patients who underwent POP for the evaluation of pancreatic stricture or dilatation were identified. Technical success was achieved in 78 (97%). In the PD neoplasia group (n = 33), the final diagnosis was based on index confirmatory POP guided tissue sampling in 29 (88%). For the detection of PD neoplasia, POP visual impression had a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 87%, 86%, 83%, 91%, and 87%, respectively. When combined with POP-guided tissue sampling, the values were 91%, 95%, 94%, 93%, and 94%, respectively. Of 102 POPs performed, adverse events were noted in 12 (12%) cases. CONCLUSIONS: This study demonstrates a high technical success rate, visual impression accuracy, and tissue sampling capability of POP. Examinations were performed by endoscopists with expertise in pancreatoscopy interpretation, and the results may not be generalizable. PMID- 27473180 TI - Reducing violence and increasing condom use in the intimate partnerships of female sex workers: study protocol for Samvedana Plus, a cluster randomised controlled trial in Karnataka state, south India. AB - BACKGROUND: Female sex workers (FSWs) are at increased risk of HIV and STIs compared to women in the general population, and frequently experience violence in their working and domestic lives from a variety of perpetrators, which can enhance this risk. While progress has been made in addressing violence by police and clients, little work has been done to understand and prevent violence by intimate partners (IPs) among FSW populations. METHODS: Samvedana Plus is a multi level intervention programme that works with FSWs, their IPs, the sex worker community, and the general population, and aims to reduce violence and increase consistent condom use within these 'intimate' relationships. The programme involves shifting norms around the acceptability of beating as a form of discipline, challenging gender roles that give men authority over women, and working with men and women to encourage new relationship models based on gender equity and respect. The programme will aim to cover 800 FSWs and their IPs living in 47 villages in Bagalkot district, northern Karnataka. The study is designed to assess two primary outcomes: the proportion of FSWs who report: (i) physical or sexual partner violence; and (ii) consistent condom use in their intimate relationship, within the past 6 months. The evaluation will employ a cluster randomised controlled trial design, with 50 % of the village clusters (n = 24) randomly selected to receive the intervention for the first 24 months and the remaining 50 % (n = 23) receiving the intervention thereafter. Statisticians will be blinded to treatment arm allocation. The evaluation will use an adjusted, cluster-level intention to treat analysis, comparing outcomes in intervention and control villages at midline (12 months) and endline (24 months). The evaluation design will involve quantitative and qualitative assessments with (i) all FSWs who report an IP (ii) IPs; and process/ implementation monitoring. Baseline data collection was completed in April 2015, and endline data collection is anticipated in May 2017. CONCLUSIONS: This is an innovative intervention programme that aims to address violence by IPs as part of HIV prevention programming with FSWs. Reducing violence is expected to reduce vulnerability to HIV acquisition, and help women to work and live without fear of violence. TRIAL REGISTRATION: Clinical Trials NCT02807259 Jun 24 2016 (retrospectively registered). PMID- 27473182 TI - Effect of an endoscopic quality improvement program on adenoma detection rates: a multicenter cluster-randomized controlled trial in a clinical practice setting (EQUIP-3). AB - BACKGROUND: Colonoscopy is protective against colorectal cancer, but its quality and protective benefits can vary. Adenoma detection rate (ADR) is associated with quality and the degree of protection against colorectal cancer and death. In a previous, single academic center, randomized, controlled trial, we demonstrated that an endoscopic quality improvement program increased ADR (EQUIP-1) and that those increases were durable (EQUIP-2). We hypothesized that EQUIP training would increase ADR in a multicenter clinical practice setting. METHODS: Nine large clinical practice sites were recruited. After a baseline period (phase I), 5 sites were randomized to receive supplemental in-person EQUIP training with active feedback. After follow-up (phase II), the changes in ADRs at these sites were compared with the changes at 4 control sites that did not receive training or feedback until after study completion. RESULTS: Twenty-two thousand three hundred sixteen colonoscopies were included. There was a statistically significant increase in ADR at the training sites (odds ratio [OR], 1.28; P = .004) with a raw ADR of 31% in phase I and 42% in phase II after the intervention. However, raw ADRs also increased at the control sites (from 36% to 39%). As a result, there was limited evidence of a training effect (OR, 1.03; 95% confidence interval [CI], 0.84-1.25; P = .78). CONCLUSIONS: ADRs increased at the sites participating in the endoscopic quality improvement program. However it is not clear to what extent the training program is responsible for the changes, because raw ADRs also increased at the control sites but to a lesser extent. (Clinical Trials Registration number: NCT02325635.). PMID- 27473183 TI - "Dietaly": practical issues for the nutritional management of CKD patients in Italy. AB - Evidence exists that nutritional therapy induces favorable metabolic changes, prevents signs and symptoms of renal insufficiency, and is able to delay the need of dialysis. Currently, the main concern of the renal diets has turned from the efficacy to the feasibility in the daily clinical practice.Herewith we describe some different dietary approaches, developed in Italy in the last decades and applied in the actual clinical practice for the nutritional management of CKD patients.A step-wise approach or simplified dietary regimens are usually prescribed while taking into account not only the residual renal function and progression rate but also socio-economic, psychological and functional aspects.The application of the principles of the Mediterranean diet that covers the recommended daily allowances for nutrients and protein (0.8 g/Kg/day) exert a favorable effect at least in the early stages of CKD. Low protein (0.6 g/kg/day) regimens that include vegan diet and very low-protein (0.3-0.4 g/Kg/day) diet supplemented with essential amino acids and ketoacids, represent more opportunities that should be tailored on the single patient's needs.Rather than a structured dietary plan, a list of basic recommendations to improve compliance with a low-sodium diet in CKD may allow patients to reach the desired salt target in the daily eating.Another approach consists of low protein diets as part of an integrated menu, in which patients can choose the "diet" that best suits their preferences and clinical needs.Lastly, in order to allow efficacy and safety, the importance of monitoring and follow up of a proper nutritional treatment in CKD patients is emphasized. PMID- 27473184 TI - The potential of nuclear magnetic resonance to track lipids in planta. AB - Nuclear Magnetic Resonance (NMR) provides a highly flexible platform for non invasive analysis and imaging biological samples, since the manipulation of nuclear spin allows the tailoring of experiments to maximize the informativeness of the data. MRI is capable of visualizing a holistic picture of the lipid storage in living plant/seed. This review has sought to explain how the technology can be used to acquire functional and physiological data from plant samples, and how to exploit it to characterize lipid deposition in vivo. At the same time, we have referred to the current limitations of NMR technology as applied to plants, and in particular of the difficulty of transferring methodologies optimized for animal/medical subjects to plant ones. A forward look into likely developments in the field is included, anticipating its key future role in the study of living plant. PMID- 27473185 TI - Dietary arachidonic acid as a risk factor for age-associated neurodegenerative diseases: Potential mechanisms. AB - Alzheimer's disease and associated diseases constitute a major public health concern worldwide. Nutrition-based, preventive strategies could possibly be effective in delaying the occurrence of these diseases and lower their prevalence. Arachidonic acid is the second major polyunsaturated fatty acid (PUFA) and several studies support its involvement in Alzheimer's disease. The objective of this review is to examine how dietary arachidonic acid contributes to Alzheimer's disease mechanisms and therefore to its prevention. First, we explore the sources of neuronal arachidonic acid that could potentially originate from either the conversion of linoleic acid, or from dietary sources and transfer across the blood-brain-barrier. In a second part, a brief overview of the role of the two main agents of Alzheimer's disease, tau protein and Abeta peptide is given, followed by the examination of the relationship between arachidonic acid and the disease. Third, the putative mechanisms by which arachidonic acid could influence Alzheimer's disease occurrence and evolution are presented. The conclusion is devoted to what remains to be determined before integrating arachidonic acid in the design of preventive strategies against Alzheimer's disease and other neurodegenerative diseases. PMID- 27473186 TI - Mapping intra-urban malaria risk using high resolution satellite imagery: a case study of Dar es Salaam. AB - BACKGROUND: With more than half of Africa's population expected to live in urban settlements by 2030, the burden of malaria among urban populations in Africa continues to rise with an increasing number of people at risk of infection. However, malaria intervention across Africa remains focused on rural, highly endemic communities with far fewer strategic policy directions for the control of malaria in rapidly growing African urban settlements. The complex and heterogeneous nature of urban malaria requires a better understanding of the spatial and temporal patterns of urban malaria risk in order to design effective urban malaria control programs. In this study, we use remotely sensed variables and other environmental covariates to examine the predictability of intra-urban variations of malaria infection risk across the rapidly growing city of Dar es Salaam, Tanzania between 2006 and 2014. METHODS: High resolution SPOT satellite imagery was used to identify urban environmental factors associated malaria prevalence in Dar es Salaam. Supervised classification with a random forest classifier was used to develop high resolution land cover classes that were combined with malaria parasite prevalence data to identify environmental factors that influence localized heterogeneity of malaria transmission and develop a high resolution predictive malaria risk map of Dar es Salaam. RESULTS: Results indicate that the risk of malaria infection varied across the city. The risk of infection increased away from the city centre with lower parasite prevalence predicted in administrative units in the city centre compared to administrative units in the peri-urban suburbs. The variation in malaria risk within Dar es Salaam was shown to be influenced by varying environmental factors. Higher malaria risks were associated with proximity to dense vegetation, inland water and wet/swampy areas while lower risk of infection was predicted in densely built up areas. CONCLUSIONS: The predictive maps produced can serve as valuable resources for municipal councils aiming to shrink the extents of malaria across cities, target resources for vector control or intensify mosquito and disease surveillance. The semi-automated modelling process developed can be replicated in other urban areas to identify factors that influence heterogeneity in malaria risk patterns and detect vulnerable zones. There is a definite need to expand research into the unique epidemiology of malaria transmission in urban areas for focal elimination and sustained control agendas. PMID- 27473189 TI - Left pulmonary artery sling: A rare cause of congenital stridor. PMID- 27473187 TI - CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation. AB - : We studied the association between CYP2R1 genetic polymorphisms and circulating 25-hydroxyvitamin D [25(OH)D] before and after supplementation with vitamin D3 in 218 elderly. We found differences between 3 and 8 ng/ml in circulating levels at baseline in women but not in the response after 1 year of supplementation. INTRODUCTION: This study evaluated the association between polymorphisms in four single nucleotide polymorphisms (SNPs) of the CYP2R1 gene and 25(OH)D levels before and 1 year after supplementation with two different doses of vitamin D3 (600 IU daily or a dose equivalent to 3750 IU daily), in a cohort of 218 (96 men and 122 women) Lebanese elderly overweight subjects. METHODS: Genotyping was performed for rs12794714, rs10741657, rs1562902, and rs10766197 SNPs using real time PCR. The 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry. RESULTS: At baseline, the mean +/- SD age was 71.0 +/- 4.7 years, BMI 30.3 +/- 4.6 kg/m2, and 25(OH)D level was 20.5 +/- 7.6 ng/ml. There were significant differences in mean 25(OH)D levels between genotypes in women, but not in men. After adjustment for age, season, and BMI, the homozygous for the low frequency gene variant (HLV) of rs1562902 and rs10741657 SNPs had the highest mean 25(OH)D levels with difference of 7.6 ng/ml for rs1562902 SNP (p < 0.01) and of 5.9 ng/ml for rs10741657 (p = 0.05) compared to the homozygous for the major polymorphisms (HMPs). Conversely, for rs10766197 and rs12794714 SNPs, HMP had the highest mean 25(OH)D levels with difference of 6 ng/ml for rs10766197 (p = 0.003) and of 4.8 ng/ml (p = 0.02) for rs12794714, compared to the HLV. CYP2R1 genetic polymorphisms explained 4.8 to 9.8 % of variability in 25(OH)D in women. After 1 year, there was no difference in the response to vitamin D3 supplementation between genotypes in either gender. CONCLUSION: This study showed a difference in 25(OH)D levels between CYP2R1 genotypes that equates a daily supplementation of 400-800 IU vitamin D, depending on genotype. It underscores possible important genetic contributions for the high prevalence of hypovitaminosis D in the Middle East. PMID- 27473188 TI - Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1 randomized trials. AB - BACKGROUND: Chronic pain in older people is highly prevalent, often underestimated, and associated with adverse outcomes. Most available analgesic drugs are often either ineffective or not tolerated, with many side effects. Palmitoylethanolamide (PEA) is an endogenous widely distributed N acylethanolamina involved in neuroinflammation and pain-generating processes. Formulations containing ultra-micronized palmitoylethanolamide (um-PEA) are available but their effectiveness on chronic pain in highly heterogeneous geriatric patients is not clear and probably not generalizable. We planned to adopt the N-of-1 trial approach to test the effectiveness of um-PEA objectively at the individual level in our older outpatients. METHODS/DESIGN: Persons 65 years or older referring to the Geriatric Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan complaining of noncancer chronic pain of any origin will be eligible. Each trial will be a placebo-controlled randomized crossover trial including two um-PEA (600 mg twice a day) and placebo treatment pairs. The um-PEA or placebo 3-week periods will be separated by 2-week washout intervals to overcome possible carryover effects. Pain intensity, need of on demand analgesic medications, and impact on daily activities will be evaluated. Cognitively impaired patients will be eligible as long as an expression of pain can be recognized and its frequency assessed by a caregiver. Trial results will be discussed with the patient or caregiver and the treating physician to decide whether to continue the treatment. The impact of the N-of-1 approach on the physician's management plan and confidence will be assessed. We will secondarily meta-analyze the performed N-of-1 trials to obtain an estimate of the average effect of um-PEA compared with placebo using a frequentist and Bayesian approach. DISCUSSION: While pursuing an ultimate clinical objective, i.e. to empirically and objectively decide the best treatment choice for an individual older patient with chronic pain, these series of geriatric N-of-1 trials on PEA will bring the principles of evidence-based medicine into the care of patients not usually represented in conventional randomized controlled trials, and realize a patient centered outcome approach necessary to improve appropriate prescribing in elderly patients with multimorbidity and polypharmacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02699281 . Registered on 3 March 2016. PMID- 27473190 TI - Agreement studies in radiology research. AB - PURPOSE: The goal of this study was to estimate the frequency and the quality of agreement studies published in diagnostic imaging journals. MATERIALS AND METHODS: All studies published between January 2011 and December 2012 in four radiology journals were reviewed. Four trained readers evaluated agreement studies using a 24-item form that included the 15 items of the Guidelines for Reporting Reliability and Agreement Studies criteria. RESULTS: Of 2229 source titles, 280 studies (13%) reported agreement. The mean number of patients per study was 81+/-99 (SD) (range, 0-180). Justification for sample size was found in 9 studies (3%). The number of raters was<=2 in 226 studies (81%). No intra observer study was performed in 212 (76%) articles. Confidence intervals and interpretation of statistical estimates were provided in 98 (35%) and 147 (53%) of the studies, respectively. In 168 studies (60%), the agreement study was not mentioned in the discussion section. In 8 studies (3%), reporting of the agreement study was judged to be adequate. Twenty studies (7%) were dedicated to agreement. CONCLUSION: Agreement studies are preliminary and not adequately reported. Studies dedicated to agreement are infrequent. They are research opportunities that should be promoted. PMID- 27473191 TI - Surveillance of infectious diseases in the Arctic. AB - OBJECTIVES: This study reviews how social and environmental issues affect health in Arctic populations and describes infectious disease surveillance in Arctic Nations with a special focus on the activities of the International Circumpolar Surveillance (ICS) project. METHODS: We reviewed the literature over the past 2 decades looking at Arctic living conditions and their effects on health and Arctic surveillance for infectious diseases. RESULTS: In regards to other regions worldwide, the Arctic climate and environment are extreme. Arctic and sub-Arctic populations live in markedly different social and physical environments compared to those of their more southern dwelling counterparts. A cold northern climate means people spending more time indoors, amplifying the effects of household crowding, smoking and inadequate ventilation on the person-to-person spread of infectious diseases. The spread of zoonotic infections north as the climate warms, emergence of antibiotic resistance among bacterial pathogens, the re emergence of tuberculosis, the entrance of HIV into Arctic communities, the specter of pandemic influenza or the sudden emergence and introduction of new viral pathogens pose new challenges to residents, governments and public health authorities of all Arctic countries. ICS is a network of hospitals, public health agencies, and reference laboratories throughout the Arctic working together for the purposes of collecting, comparing and sharing of uniform laboratory and epidemiological data on infectious diseases of concern and assisting in the formulation of prevention and control strategies (Fig. 1). In addition, circumpolar infectious disease research workgroups and sentinel surveillance systems for bacterial and viral pathogens exist. CONCLUSIONS: The ICS system is a successful example of collaborative surveillance and research in an extreme environment. PMID- 27473192 TI - Allogeneic bone marrow transplantation for therapy-related acute lymphocytic leukemia after autologous hematopoietic stem cell transplantation for multiple myeloma. PMID- 27473193 TI - Pembrolizumab for relapsed anaplastic large cell lymphoma after allogeneic haematopoietic stem cell transplantation: efficacy and safety. PMID- 27473194 TI - Pembrolizumab and lenalidomide induced remission in refractory double-hit lymphoma. PMID- 27473195 TI - Adult-onset opsoclonus-myoclonus syndrome due to West Nile Virus treated with intravenous immunoglobulin. AB - A 63-year-old female with no significant past medical history was presented with a 5-day history of progressive opsoclonus-myoclonus, headaches, and fevers. Her workup was significant only for positive West-Nile Virus serum serologies. She received a 2-day course of intravenous immunoglobulin (IvIG). At an 8-week follow up, she had a complete neurological remission. Adult-onset opsoclonus-myoclonus syndrome is a rare condition for which paraneoplastic and infectious causes have been attributed. To our knowledge, this is the first case reported of opsoclonus myoclonus secondary to West-Nile Virus treated with intravenous immunoglobulin monotherapy. PMID- 27473196 TI - Proceedings from the NIMH symposium on "NeuroAIDS in Africa: neurological and neuropsychiatric complications of HIV". AB - Despite major advances in HIV-1 treatment, the prevalence of HIV-associated neurocognitive disorders (HAND) remains a problem, particularly as individuals on suppressive treatment continue to live longer. To facilitate discussion on emerging and future directions in HAND research, a meeting was held in Durban, South Africa in March 2015 as part of the Society of Neuroscientists of Africa (SONA) conference. The objective of the meeting was to assess the impact of HIV subtype diversity on HAND and immunological dysfunction. The meeting brought together international leaders in the area of neurological complications of HIV-1 infection with special focus on the African population. Research presentations indicated that HAND was highly prevalent and that inflammatory cytokines and immune-activation played important roles in progression of neurocognitive impairment. Furthermore, children on antiretroviral therapy were also at risk for developing neurocognitive impairment. With respect to the effect of HIV-1 subtype diversity, analyses of HIV-1 clade C infection among South Africans revealed that clade C infection induced cognitive impairment that was independent of the substitution in HIV-1 Trans-Activator of Transcription (Tat; C31S). At the cellular level, a Zambian study showed that clade C infection resulted in reduced brain cell death compared with clade B infection suggesting clade specific variations in mediating brain cell injury. Furthermore, ex vivo Tat protein from clade CRF02_AG, prevalent in West/ Central Africa, exhibited reduced disruption of brain endothelium compared with clade B Tat protein. Discussions shed light on future research directions aimed at understanding biomarkers and disease mechanisms critical for HAND. PMID- 27473197 TI - Ambient Light Modulation of Exogenous Attention to Threat. AB - Planet Earth's motion yields a 50 % day-50 % night yearly balance in every latitude or longitude, so survival must be guaranteed in very different light conditions in many species, including human. Cone- and rod-dominant vision, respectively specialized in light and darkness, present several processing differences, which are-at least partially-reflected in event-related potentials (ERPs). The present experiment aimed at characterizing exogenous attention to threatening (spiders) and neutral (wheels) distractors in two environmental light conditions, low mesopic (L, 0.03 lx) and high mesopic (H, 6.5 lx), yielding a differential photoreceptor activity balance: rod > cone and rod < cone, respectively. These distractors were presented in the lower visual hemifield while the 40 participants were involved in a digit categorization task. Stimuli, both targets (digits) and distractors, were exactly the same in L and H. Both ERPs and behavioral performance in the task were recorded. Enhanced attentional capture by salient distractors was observed regardless of ambient light level. However, ERPs showed a differential pattern as a function of ambient light. Thus, significantly enhanced amplitude to salient distractors was observed in posterior P1 and early anterior P2 (P2a) only during the H context, in late P2a during the L context, and in occipital P3 during both H and L contexts. In other words, while exogenous attention to threat was equally efficient in light and darkness, cone-dominant exogenous attention was faster than rod-dominant, in line with previous data indicating slower processing times for rod- than for cone-dominant vision. PMID- 27473198 TI - Mortality in Transition: Study Protocol of the PrivMort Project, a multilevel convenience cohort study. AB - BACKGROUND: Previous research using routine data identified rapid mass privatisation as an important driver of mortality crisis following the collapse of Communism in Central and Eastern Europe. However, existing studies on the mortality crisis relying on individual level or routine data cannot assess both distal (societal) and proximal (individual) causes of mortality simultaneously. The aim of the PrivMort Project is to overcome these limitations and to investigate the role of societal factors (particularly rapid mass privatisation) and individual-level factors (e.g. alcohol consumption) in the mortality changes in post-communist countries. METHODS: The PrivMort conducts large-sample surveys in Russia, Belarus and Hungary. The approach is unique in comparing towns that have undergone rapid privatisation of their key industrial enterprises with those that experienced more gradual forms of privatisation, employing a multi-level retrospective cohort design that combines data on the industrial characteristics of the towns, socio-economic descriptions of the communities, settlement-level data, individual socio-economic characteristics, and individuals' health behaviour. It then incorporates data on mortality of different types of relatives of survey respondents, employing a retrospective demographic approach, which enables linkage of historical patterns of mortality to exposures, based on experiences of family members. By May 2016, 63,073 respondents provided information on themselves and 205,607 relatives, of whom 102,971 had died. The settlement-level dataset contains information on 539 settlements and 12,082 enterprises in these settlements in Russia, 96 settlements and 271 enterprises in Belarus, and 52 settlement and 148 enterprises in Hungary. DISCUSSION: In addition to reinforcing existing evidence linking smoking, hazardous drinking and unemployment to mortality, the PrivMort dataset will investigate the variation in transition experiences for individual respondents and their families across settlements characterized by differing contextual factors, including industrial characteristics, simultaneously providing information about how excess mortality is distributed across settlements with various privatization strategies. PMID- 27473199 TI - Normal-weight obesity syndrome: diagnosis, prevalence, and clinical implications. AB - The growing concern about the impact of overweight on health has led to studies that shed light on types of obesity other than the classic model based on body mass index. Normal-weight obesity syndrome is characterized by excess body fat in individuals with adequate body mass index (18.5-24.9 kg/m(2)). This condition increases the risk of cardiovascular morbidity and mortality and other conditions associated with chronic diseases, such as insulin resistance, hypertension, and dyslipidemia. The aims of this review are to define the diagnostic criteria for normal-weight obesity syndrome and to examine the risks associated with this condition in order to promote preventive measures and early treatment for affected individuals. PMID- 27473200 TI - Diverse and Dynamic Interactions: A Model of Suicidal Men's Help Seeking as It Relates to Health Services. AB - There is a striking gender difference in suicide rates worldwide, with men accounting for approximately 80% of all suicide deaths. In contradictory public discussions, suicidal men are presented sometimes as victims of "poor" health services and sometimes as irremediable, "poor" help seekers. A more substantive theory of suicidal men's help seeking, which moves beyond homogenizing accounts to examine the complex interplay between help seeking and health services, is now required. Eighteen life history interviews were undertaken with men who had engaged in nonfatal suicide. Interviews were analyzed within a theoretical framework of gender relations. The findings challenge static and uniform notions of suicidal men's help seeking. While a few men actively avoided health services, others actively sought help, and in many cases help-seeking practices were triggered by unsolicited encounters with health services. Responsibility for help seeking behavior did not rest solely with suicidal men. Men's help-seeking practices could either be facilitated or blocked by the character of the professional support that was available. Men in this study overwhelmingly rejected services that framed emotional distress and suicidal behavior as mental illness. PMID- 27473201 TI - Reliable Entity Subtyping in Non-small Cell Lung Cancer by Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry on Formalin-fixed Paraffin embedded Tissue Specimens. AB - Histopathological subtyping of non-small cell lung cancer (NSCLC) into adenocarcinoma (ADC), and squamous cell carcinoma (SqCC) is of utmost relevance for treatment stratification. However, current immunohistochemistry (IHC) based typing approaches on biopsies are imperfect, therefore novel analytical methods for reliable subtyping are needed. We analyzed formalin-fixed paraffin-embedded tissue cores of NSCLC by Matrix-assisted laser desorption/ionization (MALDI) imaging on tissue microarrays to identify and validate discriminating MALDI imaging profiles for NSCLC subtyping. 110 ADC and 98 SqCC were used to train a Linear Discriminant Analysis (LDA) model. Results were validated on a separate set of 58 ADC and 60 SqCC. Selected differentially expressed proteins were identified by tandem mass spectrometry and validated by IHC. The LDA classification model incorporated 339 m/z values. In the validation cohort, in 117 cases (99.1%) MALDI classification on tissue cores was in accordance with the pathological diagnosis made on resection specimen. Overall, three cases in the combined cohorts were discordant, after reevaluation two were initially misclassified by pathology whereas one was classified incorrectly by MALDI. Identification of differentially expressed peptides detected well-known IHC discriminators (CK5, CK7), but also less well known differentially expressed proteins (CK15, HSP27). In conclusion, MALDI imaging on NSCLC tissue cores as small biopsy equivalents is capable to discriminate lung ADC and SqCC with a very high accuracy. In addition, replacing multislide IHC by an one-slide MALDI approach may also save tissue for subsequent predictive molecular testing. We therefore advocate to pursue routine diagnostic implementation strategies for MALDI imaging in solid tumor typing. PMID- 27473203 TI - Effects of rAAV-mediated FGF-2 gene transfer and overexpression upon the chondrogenic differentiation processes in human bone marrow aspirates. AB - BACKGROUND: Application of genetically modified bone marrow concentrates in articular cartilage lesions is a promising approach to enhance cartilage repair by stimulating the chondrogenic differentiation processes in sites of injury. METHOD: In the present study, we examined the potential benefits of transferring the proliferative and pro-chondrogenic basic fibroblast growth factor (FGF-2) to human bone marrow aspirates in vitro using the clinically adapted recombinant adeno-associated virus (rAAV) vectors to monitor the biological and chondrogenic responses over time to the treatment compared with control (lacZ) gene application. RESULTS: Effective, significant FGF-2 gene transfer and expression via rAAV was established in the aspirates relative to the lacZ condition (from ~ 97 to 36 pg rhFGF-2/mg total proteins over an extended period of 21 days). Administration of the candidate FGF-2 vector led to prolonged increases in cell proliferation, matrix synthesis, and chondrogenesis but also to hypertrophic and terminal differentiation in the aspirates. CONCLUSION: The present evaluation shows the advantages of rAAV-mediated FGF-2 gene transfer to conveniently modify bone marrow concentrates as a future approach to directly treat articular cartilage lesions, provided that expression of the growth factor is tightly regulated to prevent premature hypertrophy in vivo. PMID- 27473202 TI - Fungal Keratitis in North India: Spectrum of Agents, Risk Factors and Treatment. AB - To assess the prevalence of fungal keratitis, we conducted a retrospective study over 7 years (2005 through 2011) at a tertiary care center in North India. Effort has been made to analyze the disease burden, spectrum of agents and treatment history. The findings were compared with an earlier study at the same center for any change in the epidemiology of the disease. Microbiology records were screened at the Postgraduate Institute of Medical Education and Research, Chandigarh, India, to identify fungal keratitis cases, and available clinical records of those cases were analyzed. Of 2459 clinically suspected fungal keratitis cases, 765 (31 %) cases were direct microscopy confirmed. Of these microscopy-confirmed cases, fungi were isolated in 393 (51.4 %), with Aspergillus spp. ranked top (n = 187, 47.6 %), followed by melanized fungi (n = 86, 21.9 %) and Fusarium spp. (n = 64, 16 %). A male predominance of 78.7 % was noted with a peak in the incidence of fungal keratitis during post-monsoon season (September to November). A delay in diagnosis was significantly associated (p < 0.001) with keratitis cases due to melanized fungi. In comparison with an earlier study, higher isolation of melanized fungi was noted with a widening of the spectrum of agents identified. Thus, fungal keratitis due to Aspergillus spp. remains a serious ocular illness among the active male population in North India with relative rise of keratitis due to melanized fungi. The spectrum of agents causing fungal keratitis has broadened with many rare fungi that are implicated. PMID- 27473204 TI - Initial stability of a new cementless fixation method of a tibial component with polyaxial locking screws: a biomechanical in vitro examination. AB - INTRODUCTION: Cementless fixation of the tibial component is critical as reduced initial stability leads to implant failure. In this experimental in vitro study, a new fixation method of the tibial component using polyaxial locking screws is evaluated using Roentgen stereophotogrammetric analysis (RSA). MATERIALS AND METHODS: A special prototype of a tibial component with four polyaxial locking screws was tested on 10 fresh-frozen human tibia specimens. The components were tested with an axial load of 2000 N for 10,000 cycles. Radiographs in two views were performed before loading, after 1000 and after 10,000 cycles, respectively. Besides rotation and translation along the x-, y-, and z-axes, endpoints for RSA were maximum subsidence (MaxSub), maximum lift off (MaxLiftOff) and maximum total point motion (MTPM). RESULTS: MaxSub increased from -0.5 mm (SD = 0.2) after 1000 cycles to -0.9 mm (SD = 1.1). MaxLiftOff was 0.1 mm after 1000 cycles and did not increase after 10,000 cycles. The MTPM was 0.7 mm (SD = 0.3) after 1000 cycles and 1.1 mm (SD = 1.1) after 10,000 cycles. Two out of nine implants showed an MTPM >= 1.0 mm after 10,000 cycles. CONCLUSIONS: Polyaxial locking screws can potentially improve the initial stability of tibial components. The results of this study indicate that the use of such screws in total knee arthroplasty may be of interest in the future. Further experimental and clinical investigation is needed. PMID- 27473205 TI - Threat-level-dependent manipulation of signaled body size: dog growls' indexical cues depend on the different levels of potential danger. AB - Body size is an important feature that affects fighting ability; however, size related parameters of agonistic vocalizations are difficult to manipulate because of anatomical constraints within the vocal production system. Rare examples of acoustic size modulation are due to specific features that enable the sender to steadily communicate exaggerated body size. However, one could argue that it would be more adaptive if senders could adjust their signaling behavior to the fighting potential of their actual opponent. So far there has been no experimental evidence for this possibility. We tested this hypothesis by exposing family dogs (Canis familiaris) to humans with potentially different fighting ability. In a within-subject experiment, 64 dogs of various breeds consecutively faced two threateningly approaching humans, either two men or two women of different stature, or a man and a woman of similar or different stature. We found that the dogs' vocal responses were affected by the gender of the threatening stranger and the dog owner's gender. Dogs with a female owner, or those dogs which came from a household where both genders were present, reacted with growls of lower values of the Pitch-Formant component (including deeper fundamental frequency and lower formant dispersion) to threatening men. Our results are the first to show that non-human animals react with dynamic alteration of acoustic parameters related to their individual indexical features (body size), depending on the level of threat in an agonistic encounter. PMID- 27473206 TI - Kea cooperate better with sharing affiliates. AB - Controlled studies that focus on intraspecific cooperation tasks have revealed striking similarities, but also differences, in abilities across taxa as diverse as primates, fish, and birds. Such comparisons may provide insight into the specific socio-ecological selection pressures that led to the evolution of cooperation. Unfortunately, however, compared to primates data on birds remain relatively scarce. We tested a New Zealand psittaciform, the kea, in a dyadic cooperation task using the loose-string design. During trials our subjects were in separate compartments, but obtained a common reward that could be divided multiple ways, allowing the examination of reward division effects. Ten individuals were tested twice in 44 combinations of partners. Dyads with a high affiliation score attempted to cooperate more often and were also more often successful in doing so. Furthermore, dyads that shared rewards more equally seemed to be more likely to attempt cooperation in the next trial. Like other bird and some monkey species, but unlike, for example, chimpanzees, kea did not spontaneously show understanding of either the role of the partner or the mechanism behind the cooperation task. This may point to true disparities between species, but may also be due to differences in task design and/or the amount of exposure to similar tasks and individual skills of the subjects. PMID- 27473207 TI - New Cancer Drugs Fund is flawed without NICE reform, says Roche. PMID- 27473208 TI - Anterior Temporal Lobectomy for Refractory Status Epilepticus in Herpes Simplex Encephalitis. AB - BACKGROUND: Herpes simplex virus (HSV) is a common cause of viral encephalitis that can lead to refractory seizures. The primary treatment of HSV encephalitis is with acyclovir; however, surgery sometimes plays a role in obtaining tissue diagnosis or decompression in cases with severe mass effect. We report a unique case in which anterior temporal lobectomy was successfully used to treat refractory status epilepticus in HSV encephalitis. METHODS: Case report and review of the literature. RESULTS: We report a case of a 60-year-old man with HSV encephalitis, who presented with seizures originating from the right temporal lobe refractory to maximal medical management. Right anterior temporal lobectomy was performed for the purpose of treatment of refractory status epilepticus and obtaining tissue diagnosis, with ultimate resolution of seizures and excellent functional outcome. CONCLUSIONS: We suggest that anterior temporal lobectomy should be considered in cases of HSV encephalitis with refractory status epilepticus with clear unilateral origin. PMID- 27473209 TI - Derivation of a Predictive Score for Hemorrhagic Progression of Cerebral Contusions in Moderate and Severe Traumatic Brain Injury. AB - BACKGROUNDS: After traumatic brain injury (TBI), hemorrhagic progression of contusions (HPCs) occurs frequently. However, there is no established predictive score to identify high-risk patients for HPC. METHODS: Consecutive patients who were hospitalized (2008-2013) with non-penetrating moderate or severe TBI were studied. The primary outcome was HPC, defined by both a relative increase in contusion volume by >=30 % and an absolute increase by >=10 mL on serial imaging. Logistic regression models were created to identify independent risk factors for HPC. The HPC Score was then derived based on the final model. RESULTS: Among a total of 286 eligible patients, 61 (21 %) patients developed HPC. On univariate analyses, HPC was associated with older age, higher initial blood pressure, antiplatelet medications, anticoagulants, subarachnoid hemorrhage (SAH) subdural hematoma (SDH), skull fracture, frontal contusion, larger contusion volume, and shorter interval from injury to initial CT. In the final model, SAH (OR 6.33, 95 % CI, 1.80-22.23), SDH (OR 3.46, 95 % CI, 1.39-8.63), and skull fracture (OR 2.67, 95 % CI, 1.28-5.58) were associated with HPC. Based on these factors, the HPC Score was derived (SAH = 2 points, SDH = 1 point, and skull fracture = 1 point). This score had an area under the receiver operating curve of 0.77. Patients with a score of 0-2 had a 4.0 % incidence of HPC, while patients with a score of 3-4 had a 34.6 % incidence of HPC. CONCLUSIONS: A simple HPC Score was developed for early risk stratification of HPC in patients with moderate or severe TBI. PMID- 27473210 TI - Are hypertensive disorders in pregnancy associated with congenital malformations in offspring? Evidence from the WHO Multicountry cross sectional survey on maternal and newborn health. AB - BACKGROUND: Annually, around 7.9 million children are born with birth defects and the contribution of congenital malformations to neonatal mortality is generally high. Congenital malformations in children born to mothers with hypertensive disorders during pregnancy has marginally been explored. METHODS: Country incidence of congenital malformations was estimated using data on the 310 401 livebirths of the WHO Multicountry Survey which reported information from 359 facilities across 29 countries. A random-effect logistic regression model was utilized to explore the associations between six broad categories of congenital malformations and the four maternal hypertensive disorders "Chronic Hypertension", "Preeclampsia" and "Eclampsia" and "Chronic hypertension with superimposed preeclampsia". RESULTS: The occupied territories of Palestine presented the highest rates in all groups of malformation except for the "Lip/Cleft/Palate" category. Newborns of women with chronic maternal hypertension were associated with a 3.7 (95 % CI 1.3-10.7), 3.9 (95 % CI 1.7-9.0) and 4.2 (95 % CI 1.5-11.6) times increase in odds of renal, limb and lip/cleft/palate malformations respectively. Chronic hypertension with superimposed preeclampsia was associated with a 4.3 (95 % CI 1.3-14.4), 8.7 (95 % CI 2.5-30.2), 7.1 (95 % CI 2.1-23.5) and 8.2 (95 % CI 2.0-34.3) times increase in odds of neural tube/central nervous system, renal, limb and Lip/Cleft/Palate malformations. CONCLUSIONS: This study shows that chronic hypertension in the maternal period exposes newborns to a significant risk of developing renal, limb and lip/cleft/palate congenital malformations, and the risk is further exacerbate by superimposing eclampsia. Additional research is needed to identify shared pathways of maternal hypertensive disorders and congenital malformations. PMID- 27473211 TI - Impact of the surgical treatment for degenerative cervical myelopathy on the preoperative cervical sagittal balance: a review of prospective comparative cohort between anterior decompression with fusion and laminoplasty. AB - PURPOSE: Cervical sagittal balance has received increased attention as an important determinant of radiological and clinical outcomes. However, no prospective studies have compared the impact of cervical sagittal balance between anterior and posterior surgeries. We previously conducted a prospective study comparing anterior decompression with fusion (ADF) and laminoplasty (LAMP) for degenerative cervical myelopathy (DCM) and reported; however, analysis of cervical alignment within the concept of sagittal balance has yet to be performed, because that concept has recently been proposed. This study aimed to review this prospective cohort, specifically focusing on cervical sagittal balance. METHODS: We prospectively performed ADF or LAMP for DCM patients based on the year of enrollment: ADF was performed in odd-numbered years and LAMP in even-numbered years. Cervical lateral X-ray images taken in the neutral standing position were evaluated preoperatively and at a 1-year follow-up. The radiographic measurements included the following: (1) CL (cervical lordosis: C2-7 lordotic angle), (2) CGH (center of gravity of the head)-C7 SVA (sagittal vertical axis), and (3) C7 slope. The clinical results were evaluated using the Japanese Orthopedic Association scoring system for cervical myelopathy (C-JOA score). RESULTS: We analyzed the data for 66 patients (ADF n = 28, LAMP n = 38). While the CL and CGH-C7 SVA in the ADF were unchanged after the operation, those in the LAMP group worsened, especially in patients with preoperative cervical sagittal imbalance. The C7 slopes were not affected by the operation in either group. The postoperative decreases in the CL in the LAMP group correlated with the preoperative CGH-C7 SVA (r = 0.618, P < 0.01), but those in ADF group did not. In patients with preoperative cervical sagittal imbalance (CGH-C7 SVA >=40 mm), the recovery rate of the C-JOA score in the ADF group was superior to that in the LAMP group (67.3 vs. 39.8 %). In contrast, for patients without cervical sagittal imbalance, the recovery rate of the C-JOA score showed no significant difference between the ADF and LAMP groups (64.5 vs. 58.7 %). CONCLUSIONS: Postoperative cervical sagittal alignment and balance were maintained after ADF but deteriorated following LAMP, especially in patients with preoperative CGH-C7 SVA >=40 mm. In these patients, neurological recovery after LAMP was unsatisfactory. LAMP is not suitable for degenerative cervical myelopathy patients with preoperative cervical sagittal imbalance. PMID- 27473213 TI - Trade-off performance analysis of LTI system with channel energy constraint. AB - In this paper, the trade-off performance between tracking error, control input energy and channel input power is studied. By modelling the communication channel as the additive coloured Gaussian noise channel (ACGN) with limited bandwidth, a new performance index is proposed and minimized over all stabilizing two-degree of-freedom controllers. The results show that the trade-off performance is correlated to the intrinsic characteristics of the plant, including the locations and directions of the unstable pole, non-minimum phase zero. However it is unrelated to the non-minimum phase zeros of filter because of the two-degree-of freedom controller. We also demonstrated that ACGN may degenerate the tracking performance. Finally, a typical example is given to validate the theoretical results. PMID- 27473212 TI - The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. AB - AIMS/HYPOTHESIS: Potentiation of glucose-induced insulin secretion is the main mechanism of exenatide (EXE) antidiabetic action, however, increased glucose utilization by peripheral tissues has been also reported. We here studied the effect of EXE on glucose uptake by skeletal muscle cells. METHODS: 2-deoxy glucose (2DG) uptake and intracellular signal pathways were measured in rat L6 skeletal muscle myotubes exposed to 100 nmol/l EXE for up to 48 h. Mechanisms of EXE action were explored by inhibiting AMPK activity with compound C (CC, 40 MUmol/l) or siRNAs (2 MUmol/l). RESULTS: Time course experiments show that EXE increases glucose uptake up to 48 h achieving its maximal effect, similar to that induced by insulin, after 20 min (2- vs 2.5-fold-increase, respectively). Differently from insulin, EXE does not stimulate: (i) IR beta-subunit- and IRS1 tyrosine phosphorylation and binding to p85 regulatory subunit of PI-3kinase; (ii) AKT activation; and (iii) ERK1/2 and JNK1/2 phosphorylation. Conversely, EXE increases phosphorylation of alpha-subunit of AMPK at Thr172 by 2.5-fold (p < 0.01). Co-incubation of EXE and insulin does not induce additive effects on 2DG uptake. Inhibition of AMPK with CC, and reduction of AMPK protein expression by siRNA, completely abolish EXE-induced 2DG-uptake. Liraglutide, another GLP-1 receptor agonist, also stimulates AMPK phosphorylation and 2DG-uptake. Moreover, EXE stimulates 2DG-uptake also by L6 myotubes rendered insulin-resistant with methylglyoxal. Finally, EXE also induces glucose transporter Glut-4 translocation to the plasma membrane. CONCLUSIONS/INTERPRETATION: In L6 myotubes, EXE and liraglutide increase glucose uptake in an insulin-independent manner by activating AMPK. PMID- 27473214 TI - Function projective synchronization of complex networks with asymmetric coupling via adaptive and pinning feedback control. AB - The problem on function projective synchronization (FPS) is investigated for complex networks via hybrid control. In contrast to existing works, the asymmetric coupling matrix was considered. Based on adaptive and pinning feedback control methods, new FPS criteria are proposed. Finally, three examples are provided to illustrate the effectiveness of the proposed methods. PMID- 27473215 TI - How to reconstruct dynamic cardiac PET data? PMID- 27473216 TI - Diagnostic and prognostic roles of echocardiography and cardiac magnetic resonance. AB - Accurate prediction of sudden cardiac death due to ventricular arrhythmia remains challenging. Left ventricular ejection fraction has shown an association with increased risk of ventricular arrhythmias and is included in the recommendations for implantable cardioverter defibrillator as primary prevention. However, left ventricular ejection fraction may be normal in a large number of patients who are at risk of ventricular arrhythmias. Echocardiography remains the imaging technique of first choice to rule out the presence of structural heart disease and assess left and right ventricular function. Advances in strain echocardiography and cardiac magnetic resonance have provided important insights into the mechanisms of ventricular arrhythmias, and will be summarized in this review. PMID- 27473217 TI - Diagnosis and risk stratification of women with stable ischemic heart disease. AB - Although mortality rates for cardiovascular disease are on the decline, it remains the leading cause of death among men and women in the United States. Until recently, more women died of heart disease every year than men. Significant effort has been focused on increasing the awareness of cardiovascular disease among women, but ethnic disparities in awareness still exist. Early symptom recognition, risk assessment, and diagnosis of CAD are paramount in reducing cardiovascular morbidity and mortality in women. This review will highlight the unique risk factors for CAD in women, variability in clinical presentation for ischemic heart disease, and risk stratification for CAD in symptomatic women. PMID- 27473219 TI - The power of stress echocardiography and myocardial perfusion scintigraphy in predicting long-term outcome. Nothing lasts forever. PMID- 27473218 TI - Heart failure patients with prediabetes and newly diagnosed diabetes display abnormalities in myocardial metabolism. AB - BACKGROUND: In type 2 diabetes, a decrease in myocardial glucose uptake (MGU) may lower glucose oxidation and contribute to progression of chronic heart failure (CHF). However, it is unsettled whether CHF patients with prediabetes have abnormal MGU and myocardial blood flow (MBF) during normal physiological conditions. METHODS AND RESULTS: We studied 35 patients with CHF and reduced left ventricular ejections fraction (34 +/- 9%) without overt T2D (mean HbA1c: 40 +/- 4 mmol/mol) using echocardiography and quantitative measurements of MGU by 18F FDG-PET and perfusion by 15O-H2O-PET. An oral glucose tolerance test (OGTT) was performed during the FDG-PET, which identified 17 patients with abnormal and 18 patients with normal glucometabolic response. Global MGU was higher in patients with normal OGTT response (0.31 +/- 0.09 umol/g/min) compared with patients with abnormal OGTT response (0.25 +/- 0.09 umol/g/min) (P = 0.05). MBF (P = 0.22) and myocardial flow reserve (MFR) (P = 0.83) were similar in the study groups. The reduced MGU in prediabetic patients was attributable to reduced MGU in viable myocardium with normal MFR (P < 0.001). CONCLUSION: CHF patients with prediabetes have reduced MGU in segments with preserved MFR as compared to CHF patients with normal glucose tolerance. Whether reversal of these myocardial abnormalities can improve outcome needs to be investigated in large-scale studies. PMID- 27473220 TI - Off-pump mitral valved stent implantation: comparison of apical and subannular fixation techniques. AB - OBJECTIVES: A large cohort of patients suffering from severe mitral regurgitation does not meet the indications for conventional surgery and would greatly benefit from a transcatheter approach in the beating heart. Consequently, off-pump transcatheter mitral valve procedures have been the focus of recent research. The aim of this study was the in vivo evaluation and comparison of subannular versus apical fixation of mitral valved stents to show the feasibility of subannular anchorage. METHODS: Twenty-two pigs received a self-expanding valved stent in the mitral position in an off-pump procedure. The first design (design AP: n = 12) was anchored apically and served as the control group. The second design (design SA: n = 10) included additional sub-annular fixation elements. Echocardiographic and haemodynamic evaluations were conducted before and 1 h after stent implantation. RESULTS: Haemodynamic stability was achieved, and the capillary wedge pressure was within a normal range (AP: 11 +/- 4 mmHg, SA: 9 +/- 4 mmHg). Paravalvular leakages were trace or less in 19 of 20 cases. The mean gradients across the valved stent increased (P <= 0.014) but remained within a physiological range in both groups (AP: 1.2 +/- 0.6 mmHg, SA: 2.6 +/- 2.0 mmHg). The longitudinal heart function remained within a physiological normal range (AP: 0.95 +/- 0.1 cm, SA: 0.95 +/- 0.1 cm) but was reduced in group SA. The ejection fraction decreased after stent implantation (AP: 52 +/- 10%, SA: 48 +/- 4%). The mean survival time was higher in group AP compared with group SA. CONCLUSIONS: The proof-of-principle for the subannular fixation was shown with haemodynamic stability, low gradients and physiological longitudinal function. A decreased ejection fraction, survival time and fractures identify potential areas for improvement. With regard to the long-term outcome, the group with subannular fixation did not reach the results of the group with apical fixation in this study. PMID- 27473221 TI - Pf4 bacteriophage produced by Pseudomonas aeruginosa inhibits Aspergillus fumigatus metabolism via iron sequestration. AB - Pseudomonas aeruginosa (Pa) and Aspergillus fumigatus (Af) are major human pathogens known to interact in a variety of disease settings, including airway infections in cystic fibrosis. We recently reported that clinical CF isolates of Pa inhibit the formation and growth of Af biofilms. Here, we report that the bacteriophage Pf4, produced by Pa, can inhibit the metabolic activity of Af biofilms. This phage-mediated inhibition was dose dependent, ablated by phage denaturation, and was more pronounced against preformed Af biofilm rather than biofilm formation. In contrast, planktonic conidial growth was unaffected. Two other phages, Pf1 and fd, did not inhibit Af, nor did supernatant from a Pa strain incapable of producing Pf4. Pf4, but not Pf1, attaches to Af hyphae in an avid and prolonged manner, suggesting that Pf4-mediated inhibition of Af may occur at the biofilm surface. We show that Pf4 binds iron, thus denying Af a crucial resource. Consistent with this, the inhibition of Af metabolism by Pf4 could be overcome with supplemental ferric iron, with preformed biofilm more resistant to reversal. To our knowledge, this is the first report of a bacterium producing a phage that inhibits the growth of a fungus and the first description of a phage behaving as an iron chelator in a biological system. PMID- 27473223 TI - Anatomy and embryology of umbilicus in newborns: a review and clinical correlations. AB - Umbilicus is considered a mirror of the abdomen in newborns. Despite its importance, the umbilicus has been stated in literature and textbooks as discrete subjects with many body systems, such as the urinary, digestive, and cardiovascular ones. This article aimed to address the basic knowledge of the umbilicus in relation to clinical disorders under one integrated topic to aid physicians and surgeons in assessing newborns and infants. The umbilicus appears as early as the fourth week of fetal life when the folding of the embryonic plate occurs. The umbilicus appears initially as a primitive umbilical ring on the ventral aspect of the body. The primitive umbilicus contains the connecting stalk, umbilical vessels, vitelline duct and vessels, allantois, and loop of the intestine. Changes occur to form the definitive cord, which contains three umbilical vessels, namely, "one vein and two arteries," embedded in Wharton's jelly. After birth, the umbilical vessels inside the body obliterate and gradually form ligaments. Congenital disorders at the umbilicus include herniation, bleeding, and discharge of mucous, urine, or feces. Some of these disorders necessitate emergent surgical interference, whereas others may be managed conservatively. The umbilicus has many embryological remnants. Thus, the umbilicus is prone to various clinical disorders. Detecting these disorders as early as possible is essential to prevent or minimize possible complications. PMID- 27473224 TI - Desulfotomaculum aquiferis sp. nov. and Desulfotomaculum profundi sp. nov., isolated from a deep natural gas storage aquifer. AB - Two novel strictly anaerobic bacteria, strains Bs105T and Bs107T, were isolated from a deep aquifer-derived hydrocarbonoclastic community. The cells were rod shaped, not motile and had terminal spores. Phylogenetic affiliation and physiological properties revealed that these isolates belong to two novel species of the genus Desulfotomaculum. Optimal growth temperatures for strains Bs105T and Bs107T were 42 and 45 degrees C, respectively. The estimated G+C content of the genomic DNA was 42.9 and 48.7 mol%. For both strains, the major cellular fatty acid was palmitate (C16 : 0). Specific carbon fatty acid signatures of Gram positive bacteria (iso-C17 : 0) and sulfate-reducing bacteria (C17 : 0cyc) were also detected. An insertion was revealed in one of the two 16S rRNA gene copies harboured by strain Bs107T. Similar insertions have previously been highlighted among moderately thermophilic species of the genus Desulfotomaculum. Both strains shared the ability to oxidize aromatic acids (Bs105T: hydroquinone, acetophenone, para-toluic acid, 2-phenylethanol, trans-cinnamic acid, 4-hydroxybenzaldehyde, benzyl alcohol, benzoic acid 4-hydroxybutyl ester; Bs107T: ortho-toluic acid, benzoic acid 4-hydroxybutyl ester). The names Desulfotomaculum aquiferis sp. nov. and Desulfotomaculum profundi sp. nov. are proposed for the type strains Bs105T (=DSM 24088T=JCM 31386T) and Bs107T (=DSM 24093T=JCM 31387T). PMID- 27473222 TI - MicroRNA-125b-5p suppresses Brucella abortus intracellular survival via control of A20 expression. AB - BACKGROUND: Brucella may establish chronic infection by regulating the expression of miRNAs. However, the role of miRNAs in modulating the intracellular growth of Brucella remains unclear. RESULTS: In this study, we show that Brucella. abortus infection leads to downregulation of miR-125b-5p in macrophages. We establish that miR-125b-5p targets A20, an inhibitor of the NF-kB activation. Additionally, expression of miR-125b-5p decreases A20 expression in B. abortus-infected macrophages and leads to NF-kB activation and increased production of TNFalpha. Furthermore, B. abortus survival is attenuated in the presence of miR-125b-5p. CONCLUSIONS: These results uncover a role for miR-125b-5p in the regulation of B. abortus intracellular survival via the control of A20 expression. PMID- 27473225 TI - Depression and burden among the caregivers of visually impaired patients: a systematic review. AB - Caregiving has evolved as an important issue not only for those receiving care, but for those providing it as well. While caregiving allows those with disabilities to better adapt, it has been shown to take a toll on the caregiver on various levels, such as invoking depression and burden. The purpose of this study was to perform a systematic review of the literature pertaining to depression and burden among caregivers of patients with visual impairment. A comprehensive literature search using multiple databases was conducted to include all articles on burden of care or depression among the caregivers of the visually impaired. Nine studies were included in this review. There was demonstrable association of depression and burden with the caregivers of the visually impaired. Communication theory, emotional contagion, and care burden were cited as factors associated with depression in these studies. A number of other elements were also identified to play a role in depression and burden, such as providing greater hours of supervision to the patient, multiple chronic conditions in the patient or caregiver, patient not completing vision rehabilitation, and female gender of the caregiver. By identifying those at risk for decreased quality of life outcomes, health care providers may be able to alter the management of the visually impaired, such as advocating the use of vision rehabilitation clinics in order to minimize the caregiver burden and depression. PMID- 27473226 TI - The development of PubMed search strategies for patient preferences for treatment outcomes. AB - BACKGROUND: The importance of respecting patients' preferences when making treatment decisions is increasingly recognized. Efficiently retrieving papers from the scientific literature reporting on the presence and nature of such preferences can help to achieve this goal. The objective of this study was to create a search filter for PubMed to help retrieve evidence on patient preferences for treatment outcomes. METHODS: A total of 27 journals were hand searched for articles on patient preferences for treatment outcomes published in 2011. Selected articles served as a reference set. To develop optimal search strategies to retrieve this set, all articles in the reference set were randomly split into a development and a validation set. MeSH-terms and keywords retrieved using PubReMiner were tested individually and as combinations in PubMed and evaluated for retrieval performance (e.g. sensitivity (Se) and specificity (Sp)). RESULTS: Of 8238 articles, 22 were considered to report empirical evidence on patient preferences for specific treatment outcomes. The best search filters reached Se of 100 % [95 % CI 100-100] with Sp of 95 % [94-95 %] and Sp of 97 % [97-98 %] with 75 % Se [74-76 %]. In the validation set these queries reached values of Se of 90 % [89-91 %] with Sp 94 % [93-95 %] and Se of 80 % [79-81 %] with Sp of 97 % [96-96 %], respectively. CONCLUSIONS: Narrow and broad search queries were developed which can help in retrieving literature on patient preferences for treatment outcomes. Identifying such evidence may in turn enhance the incorporation of patient preferences in clinical decision making and health technology assessment. PMID- 27473227 TI - At last, a standardized laparoscopy curriculum for gynecology residents. PMID- 27473228 TI - The TGFbeta-SMAD3 pathway inhibits IL-1alpha induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration. AB - BACKGROUND: The most abundant cells in the extensive desmoplastic stroma of pancreatic adenocarcinomas are the pancreatic stellate cells, which interact with the carcinoma cells and strongly influence the progression of the cancer. Tumor stroma interactions induced by IL-1alpha/IL-1R1 signaling have been shown to be involved in pancreatic cancer cell migration. TGFbeta and its receptors are overexpressed in pancreatic adenocarcinomas. We aimed at exploring TGFbeta and IL 1alpha signaling and cross-talk in the stellate cell cancer cell interactions regulating pancreatic adenocarcinoma cell migration. METHODS: Human pancreatic stellate cells were isolated from surgically resected pancreatic adenocarcinomas and cultured in the presence of TGFbeta or pancreatic adenocarcinoma cell lines. The effects of TGFbeta were blocked by inhibitors or amplified by silencing the endogenous inhibitor of SMAD signaling, SMAD7. Pancreatic stellate cell responses to IL-1alpha or to IL-1alpha-expressing pancreatic adenocarcinoma cells (BxPC-3) were characterized by their ability to stimulate migration of cancer cells in a 2D migration model. RESULTS: In pancreatic stellate cells, IL-1R1 expression was found to be down-regulated by TGFbeta and blocking of TGFbeta signaling re established the expression. Endogenous inhibition of TGFbeta signaling by SMAD7 was found to correlate with the levels of IL-1R1, indicating a regulatory role of SMAD7 in IL-1R1 expression. Pancreatic stellate cells cultured in the presence of IL-1alpha or in co-cultures with BxPC-3 cells enhanced the migration of cancer cells. This effect was blocked after treatment of the pancreatic stellate cells with TGFbeta. Silencing of stellate cell expression of SMAD7 was found to suppress the levels of IL-1R1 and reduce the stimulatory effects of IL-1alpha, thus inhibiting the capacity of pancreatic stellate cells to induce cancer cell migration. CONCLUSIONS: TGFbeta signaling suppressed IL-1alpha mediated pancreatic stellate cell induced carcinoma cell migration. Depletion of SMAD7 upregulated the effects of TGFbeta and reduced the expression of IL-1R1, leading to inhibition of IL-1alpha induced stellate cell enhancement of carcinoma cell migration. SMAD7 might represent a target for inhibition of IL-1alpha induced tumor stroma interactions. PMID- 27473229 TI - 'The "schizophrenic" in the self-consciousness of schizophrenic patients', by Mari Nagai (1990). PMID- 27473230 TI - Return to work after cancer treatment of gynecologic cancer in Japan. AB - BACKGROUND: Gynecologic cancer is one of the most common malignant diseases in working-age women. This study investigated whether several characteristics influence return to work after treatment of gynecologic cancer. METHODS: We investigated the correlations between return to work and several other characteristics in 199 gynecologic cancer survivors. Questionnaires were distributed to patients with cancer (>=1 year after treatment and age of <65 years) who visited Okayama University. Logistic regression analysis and receiver operating characteristic curves were used to determine whether each characteristic influenced return to work (no return to work or job change) in these gynecologic cancer survivors. RESULTS: For all patients, the mean age at the time of diagnosis was 47.0 years, and the average number of years after treatment was 4.5. Forty-four patients (53.7 %) who were non-regular employees continued to be employed at the same workplace. Non-regular employment had a significantly higher area under the curve (AUC) (0.726) than other characteristics in terms of negatively affecting return to work. Additionally, non-regular employment tended to have a higher AUC (0.618) than other characteristics in terms of job changes. CONCLUSIONS: Non-regular employment was the variable most likely to negatively affect return to work and job changes in employed patients who underwent treatment for gynecologic cancer. PMID- 27473231 TI - Complete nucleotide sequences of dsRNA2 and dsRNA7 detected in the phytopathogenic fungus Sclerotium hydrophilum and their close phylogenetic relationship to a group of unclassified viruses. AB - Ten dsRNA segments were extracted from Sclerotium hydrophilum isolate (HZ11). The isolation of virus-like particles contained 10 dsRNA segments with the same number and migration as those extracted directly from the fungal mycelia. Two of these dsRNA segments, dsRNA2 and dsRNA7, were cloned and sequenced. They were 2121 and 1953 bp, respectively. The dsRNA2 encodes a RNA-dependent RNA polymerase. The dsRNA7 contains two open reading frames that encode putative proteins of unknown functions. Phylogenetic analysis of the putative proteins indicated that they are closely related to protein encoded by unclassified viruses, such as Cryphonectria parasitica bipartite mycovirus 1, Lactarius rufus RNA virus 1, Penicillium aurantiogriseum bipartite virus 1, and Curvularia thermal tolerance virus. The 5'- and 3'-untranslated regions of the two dsRNAs share significant sequence identity and contain conserved sequence stretches. It suggested that dsRNA2 and dsRNA7 have a common origin and a close phylogenetic relationship to a group of unclassified viruses. PMID- 27473255 TI - Genetic Diversity of HIV-1 in Tunisia. AB - In this study, the genetic diversity of HIV-1 in Tunisia was analyzed. For this, 193 samples were collected in different regions of Tunisia between 2012 and 2015. A protease and reverse transcriptase fragment were amplified and sequenced. Phylogenetic analyses were performed through maximum likelihood and recombination was analyzed by bootscanning. Six HIV-1 subtypes (B, A1, G, D, C, and F2), 5 circulating recombinant forms (CRF02_AG, CRF25_cpx, CRF43_02G, CRF06_cpx, and CRF19_cpx), and 11 unique recombinant forms were identified. Subtype B (46.4%) and CRF02_AG (39.4%) were the predominant genetic forms. A group of 44 CRF02_AG sequences formed a distinct Tunisian cluster, which also included four viruses from western Europe. Nine viruses were closely related to isolates collected in other African or in European countries. In conclusion, a high HIV-1 genetic diversity is observed in Tunisia and the local spread of CRF02_AG is first documented in this country. PMID- 27473256 TI - Immediate versus delayed loading of strategic mini dental implants for the stabilization of partial removable dental prostheses: a patient cluster randomized, parallel-group 3-year trial. AB - BACKGROUND: Acceptable short-term survival rates (>90 %) of mini-implants (diameter < 3.0 mm) are only documented for mandibular overdentures. Sound data for mini-implants as strategic abutments for a better retention of partial removable dental prosthesis (PRDP) are not available. METHODS/DESIGN: The purpose of this study is to test the hypothesis that immediately loaded mini-implants show more bone loss and less success than strategic mini-implants with delayed loading. In this four-center (one university hospital, three dental practices in Germany), parallel-group, controlled clinical trial, which is cluster randomized on patient level, a total of 80 partially edentulous patients with unfavourable number and distribution of remaining abutment teeth in at least one jaw will receive supplementary min-implants to stabilize their PRDP. The mini-implant are either immediately loaded after implant placement (test group) or delayed after four months (control group). Follow-up of the patients will be performed for 36 months. The primary outcome is the radiographic bone level changes at implants. The secondary outcome is the implant success as a composite variable. Tertiary outcomes include clinical, subjective (quality of life, satisfaction, chewing ability) and dental or technical complications. DISCUSSION: Strategic implants under an existing PRDP are only documented for standard-diameter implants. Mini implants could be a minimal invasive and low cost solution for this treatment modality. TRIAL REGISTRATION: The trial is registered at Deutsches Register Klinischer Studien (German register of clinical trials) under DRKS-ID: DRKS00007589 ( www.germanctr.de ) on January 13(th), 2015. PMID- 27473257 TI - Percutaneous nephrolithotomy in children with pediatric and adult-sized instruments. AB - OBJECTIVE: Pediatric stone disease is a significant health issue which has increased in incidence because of lifestyle changes, dietary habits, and obesity. The incidence of urolithiasis among pediatric age groups varies according to region and is high in Turkey. The management of stone disease in children has improved dramatically over the last two decades. The high success rate of percutaneous nephrolithotomy (PNL) have led modern researchers to suggest that it be used as a first-line treatment of kidney stones greater than 2 cm in size. This study compared the outcomes, including morbidity and success rates, of different groups of pediatric patients who underwent PNL via pediatric- and adult sized instruments. METHODS: Percutaneous nephrolithotomy was performed in 194 children in a clinical setting between the years 2000 and 2015. Patients were categorized into 2 groups (group 1: pediatric-sized devices used, n = 90 [46.4%]; group 2: adult-sized devices used, n = 104 [53.6%]). The children in group 2 were further divided into subgroups: a 24 F nephroscope was used for group 2a (n = 84 [43.3%]) and a 26 F nephroscope was used for group 2b (n = 20 [10.3%]) (Figure). RESULTS: For this study, a total of 194 pediatric patients (99 boys and 95 girls ranging from 8 months to 17 years of age, with a mean age of 9.43 years) underwent PNL for the removal of kidney stones in a clinical setting. Between the examined groups, there were no significant differences in patient height or weight, stone site or localization, pre- and post-operative creatinine levels, duration of nephrostomy, or hospitalization time. There was also no significant variation in minor complications such as fever or urinary infection. However, the stone burden was notably smaller in the group wherein pediatric-sized nephroscopes were used. Additionally, the incidence of hemorrhage was markedly lower in groups where a 17 F nephroscope was used than in groups where treatment was administered via 24 and 26 F nephroscopes. CONCLUSIONS: Stone disease is considered to be relatively rare in childhood, but recent studies have indicated that it presents a considerable health problem. According to some researchers, a decrease in instrument size has not meaningfully reduced complication rates. In contrast, some studies have reported that the use of smaller sized nephroscopes may reduce rates of morbidity and mortality. In this study, success rates of PNL were similar across all groups, regardless of nephroscope size. However, the use of a 17 F nephroscope significantly decreased the rate of hematocrit level reduction (p < 0.001). While instrument size does not affect the success of PNL, smaller instruments can be used to reduce various complications such as bleeding. PMID- 27473259 TI - Development of high-resolution cathodoluminescence system for STEM and application to plasmonic nanostructures. AB - A high-resolution cathodoluminescence (CL) system for scanning transmission electron microscope (STEM) has been developed by employing a field emission gun and a spherical aberration corrector, which realizes a probe size of 1 nm even at an accelerating voltage of 80 kV and beam current of the order of 1 nA. Angle resolved measurement of light emission from a sample in the STEM is possible by combining a parabolic mirror and position-controlled pinhole. CL spectra are successively acquired by a highly sensitive charge-coupled device while scanning the incident electron beam or pinhole, which enables various detection modes, i.e. (i) angle resolved spectral pattern, (ii) beam scan spectral image and (iii) photon map. In order to calibrate the acquired spectrum, the correction function is created from the comparison between the observed and theoretical spectra of the transition radiation. Furthermore, the modification of polarization by the parabolic mirror is discussed. Some examples of the applications of the STEM-CL system to plasmonics are presented to demonstrate the unique measurement features of the CL system, i.e. (i) multipole modes in silver nanoparticles, (ii) surface plasmon polariton modes in a 2D plasmonic crystal and (iii) localized surface plasmon modes in a gold bow tie nano-antenna. PMID- 27473258 TI - Responding to the health needs of survivors of human trafficking: a systematic review. AB - BACKGROUND: Despite the multiple physical and psychological health consequences associated with human trafficking, there is little evidence-based guidance available for health providers on assessing and meeting the health needs of trafficked people. We aimed to review literature that provided guidance or research on care provision for people who had been trafficked. METHODS: We conducted a systematic review and qualitative analysis of peer-reviewed and grey literature. Data sources included electronic databases, reference list screening, citation tracking, and expert recommendations. Documents were included if they reported on: 1) male or females (adults or children) who were currently or had previously been trafficked; 2) health interventions or service provision; 3) primary, secondary, tertiary or specialist post-trafficking services; and 4) World Bank high income countries. Two reviewers independently screened and quality appraised documents. Framework analysis was used to analyse extracted data. RESULTS: Forty-four documents were included, 19 of which reported findings of primary studies and nine of which exclusively addressed children. Evidence to inform the identification, referral and care of trafficked people is extremely limited. Within current literature on survivor identification, key indicators included signs of physical and sexual abuse, absence of documentation, and being accompanied by a controlling companion. Findings highlighted the importance of interviewing possible victims in private, using professional interpreters, and building trust. For provision of care, key themes included the importance of comprehensive needs assessments, adhering to principles of trauma-informed care, and cultural sensitivity. Further prominent themes were the necessity of multi agency working strategies and well-defined referral pathways. CONCLUSIONS: Human trafficking survivors require healthcare that is trauma-informed and culturally sensitive to their particular needs. Coordination is needed between health providers and statutory and voluntary organisations. Future research should generate empirical evidence to develop trafficking indicators for use by health providers, alongside validated screening tools, and evaluate the effectiveness of psychological interventions. PMID- 27473260 TI - Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development. AB - BACKGROUND: Recent meta-analyses of genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within/near 54 genes associated with lung function measures. Current understanding of the contribution of these genes to human lung development is limited. We set out to further define i) the expression profile of these genes during human lung development using a unique set of resources to examine both mRNA and protein expression and ii) the link between key polymorphisms and genes using expression quantitative trait loci (eQTL) approaches. METHODS: The mRNA expression profile of lung function associated genes across pseudoglandular and canalicular stages of lung development were determined using expression array data of 38 human fetal lungs. eQTLs were investigated for selected genes using blood cell and lung tissue data. Immunohistochemistry of the top 5 candidates was performed in a panel of 24 fetal lung samples. RESULTS: Twenty-nine lung function associated genes were differentially expressed during lung development at the mRNA level. The greatest magnitude of effect was observed for 5 genes; TMEM163, FAM13A and HHIP which had increasing expression and CDC123 and PTCH1 with decreased expression across developmental stages. Focussed eQTL analyses investigating SNPs in these five loci identified several cis-eQTL's. Protein expression of TMEM163 increased and CDC123 decreased with fetal lung age in agreement with mRNA data. Protein expression in FAM13A, HHIP and PTCH1 remained relatively constant throughout lung development. CONCLUSIONS: We have identified that > 50 % of lung function associated genes show evidence of differential expression during lung development and we show that in particular TMEM163 and CDC123 are differentially expressed at both the mRNA and protein levels. Our data provides a systematic evaluation of lung function associated genes in this context and offers some insight into the potential role of several of these genes in contributing to human lung development. PMID- 27473262 TI - Molecular Identification of the Western Drywood Termite (Isoptera: Kalotermitidae) by Loop-Mediated Isothermal Amplification of DNA from Fecal Pellets. AB - A rapid and technically simple molecular detection method was developed for the western drywood termite, Incisitermes minor (Hagen), which is among the most harmful pests of wooden architectures. The method features DNA extraction from fecal pellets and species-specific loop-mediated isothermal amplification (LAMP) of DNA. As drywood termites have low moisture requirements, they easily infest artificial wooden products, and are likely to spread by human transportation of infested wood and wooden products. Rapid detection and accurate identification are essential tools for termite eradication at new sites of introduction. Our molecular detection method exploits the detectability and accessibility of fecal pellets and the accuracy and rapidity of the LAMP assay. The methodology permits rapid detection and identification of various drywood termites by designing specific primers for each species, and will be applicable to regulatory applications. PMID- 27473261 TI - Cytotoxic effects of the anthraquinone derivatives 1'-deoxyrhodoptilometrin and (S)-(-)-rhodoptilometrin isolated from the marine echinoderm Comanthus sp. AB - We investigated cytotoxic effects of the anthraquinone derivatives 1' deoxyrhodoptilometrin (SE11) and (S)-(-)-rhodoptilometrin (SE16) isolated from the marine echinoderm Comanthus sp. in two tumor cell lines (C6 glioma, Hct116 colon carcinoma). Both compounds showed cytotoxic effects, with SE11 [IC50-value (MTT assay): 13.1 uM in Hct116 cells] showing a higher potency to induce apoptotic and necrotic cell death. No generation of oxidative stress was detectable (DCF assay), and also no modulation of Nrf2/ARE and NFkappaB signaling could be shown. Investigation of 23 protein kinases associated with cell proliferation, survival, metastasis, and angiogenesis showed that both compounds were potent inhibitors of distinct kinases, e.g., IGF1-receptor kinase, focal adhesion kinase, and EGF receptor kinase with SE11 being a more potent compound (IC50 values: 5, 18.4 and 4 uM, respectively). SE11 caused a decrease in ERK phosphorylation which may be a consequence of the inhibition of EGF receptor kinase by this compound. Since an inhibition of the EGF receptor/MAPK pathway is an important target for diverse cytostatic drugs, we suggest that the anthraquinone derivative 1'-deoxyrhodoptilometrin (SE11) may be an interesting lead structure for the development of new anticancer drugs. PMID- 27473263 TI - Comparative Responses of Anastrepha ludens and Anastrepha obliqua (Diptera: Tephritidae) to the Synthetic Attractant BioLure. AB - The responses of wild and sterile Anastrepha ludens (Loew) and Anastrepha obliqua (Mcquart) fruit flies to the synthetic attractant BioLure were determined by electroantennography (EAG), in field cage tests using MultiLure traps, and by release-recapture field experiments using sterile flies. In EAG bioassays, no differences were found between species, sexes, sterile and wild flies. There were only specific differences and interactions in dose responses. More A. ludens than A. obliqua individuals were captured in multilure traps in field cage test. In A. ludens, there was not significant difference between the number of females and males captured, whereas in A. obliqua more females than males were caught. Age showed a bimodal response in both species and both sexes, with peaks at 4 and 14 d old. In the release-recapture experiments, there were significant differences between species, sexes, and orchards and among the days after release. More individuals of A. ludens than A obliqua were recaptured. Only in A. obliqua the difference between the sexes was significant, with a 3.60:1 female:male ratio. Orchard conditions affected the recapture rate, but in both orchards the largest number of flies recaptured occurred during the first day after release (46 and 88% in each orchard). Our results show that the response to this synthetic lure is species-specific and contribute to better interpret trapping data. PMID- 27473264 TI - T1 high-grade bladder carcinoma outcome: the role of p16, topoisomerase-IIalpha, survivin, and E-cadherin. AB - High-grade papillary urothelial carcinoma with subepithelial connective tissue invasion (T1HG) is an aggressive disease at high risk of progression after transurethral resection/Bacillus Calmette-Guerin standardized therapy. The European Organization for Research and Treatment of Cancer has identified T1HG bladder carcinoma that is single and <=3 cm in the largest dimension at first diagnosis as a category in which the prognosis cannot be further stratified based on conventional criteria. This category may benefit from biomarker analysis as a valuable tool to determine the patient's outcome. To further the issue of biomarkers in predicting aggressiveness in single T1HG bladder carcinoma <=3 cm in greatest dimension at first diagnosis, we have conducted a validation study of the biomarker risk score set previously reported by our group. The study set included immunohistochemical detection of galectin-3, CD44, E-cadherin (E-CAD), CD138, p16, survivin, HYAL-1, and topoisomerase-IIalpha in 92 randomly selected specimens at participating institutions. Topoisomerase-IIalpha expression was identified as a predictor of disease-free survival. p16, survivin, and E-CAD expression predicted progression-free survival, but p16 and E-CAD also predicted overall survival. The current study validates a panel of immunohistochemical markers with the potential of being implemented in practice and supports the use of biomarkers in predicting aggressiveness in patients with first diagnosis of single T1HG bladder carcinoma <=3 cm in greatest dimension and therefore in identifying patients who need closer surveillance or earlier aggressive treatment. PMID- 27473265 TI - Loss of expression of Plag1 in malignant transformation from pleomorphic adenoma to carcinoma ex pleomorphic adenoma. AB - PLAG1 (pleomorphic adenoma gene 1) is frequently activated in pleomorphic adenoma (PA). Carcinoma ex pleomorphic adenoma (CXPA) arises in PA, and PLAG1 expression is believed to be maintained from PA to CXPA, as it can contribute to the carcinogenesis process. To evaluate if PLAG1 is a good marker of malignant transformation from PA to CXPA as well as to evaluate if PLAG1 expression is associated with progression and histopathologic subtype of CXPA. Forty PAs, 21 residual PAs (without malignant transformation), and 40 CXPAs were analyzed by immunohistochemistry with PLAG1 antibody. The proportion of positive neoplastic cells was assessed according to a 2-tiered scale: >10% to 50%, and >50% positive cells. The CXPA group was classified according to histopathologic subtype and invasiveness degree. Thirty-seven PAs (92.5%), 15 residual PAs (71%), and 14 CXPAs (35%) were positive for PLAG1. In relation to the CXPA group, among the intracapsular cases, myoepithelial carcinoma and epithelial-myoepithelial carcinoma showed the highest level of PLAG1 expression. PLAG1 expression is lost when PA undergoes malignant transformation, possibly due to other pathway activation and different clone cells. In addition, PLAG1 expression seems to be present mainly in low-grade carcinomas and in cases with early phase of invasion, due to its regulation of oncogene-induced cell senescence. In CXPA, PLAG1 expression was most associated with myoepithelial differentiation. This way, loss of PLAG1 expression can be considered a hallmark of CXPA carcinogenesis, mainly when there is only epithelial differentiation. PMID- 27473266 TI - PD-L1 expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung. AB - PD-1/PD-L1-targeted immunotherapy has emerged as a promising therapeutic strategy for pulmonary adenocarcinoma (pADC). Epithelial-to-mesenchymal transition (EMT) is involved in the progression and immune evasion of cancers. Therefore, we investigated the association between PD-L1 expression and EMT phenotype in pADC. Immunohistochemistry for E-cadherin (epithelial marker), ZEB1, SNAIL, SLUG, vimentin (mesenchymal markers), PD-L1, CD8, and PD-1 was performed on 477 cases of pADC. Cases were classified into epithelial, mesenchymal, epithelial mesenchymal, and unspecified types based on immunohistochemical results. PD-L1 expression was scored as 0 in 14.0% (n=67), 1 in 26.4% (n=126), 2 in 51.2% (n=244), and 3 in 8.4% (n=40). PD-L1 score was positively correlated with SNAIL and vimentin H scores (P<.001, both). After dichotomizing patients into PD-L1 negative and PD-L1-positive groups, PD-L1 positivity was significantly higher in patients with mesenchymal (71.2%; 84/118) and epithelial-mesenchymal (62.7%; 84/134) phenotypes compared with those with epithelial (50.6%; 44/87) and unspecified (50.0%; 35/70) phenotypes (P=.005). The significant association between PD-L1 expression and EMT phenotype was maintained in EGFR-mutated pADCs. Moreover, cases with EMT phenotype (ie, mesenchymal and epithelial-mesenchymal) were infiltrated by higher numbers of CD8+ and PD-1+ cells than those with epithelial and unspecified phenotypes in EGFR-mutated pADCs (P=.043 for CD8+ cells and P<.001 for PD-l+ cells). Particularly, cases with EMT phenotype and PD L1 expression showed the greatest amount of CD8+ and PD-1+ cells in EGFR-mutated cases (P=.043 for CD8+ cells and P=.005 for PD-1+ cells). This study demonstrates that EMT phenotype is related to PD-L1 overexpression in pADC cells and patients with EMT-phenotype pADC may benefit from PD-1/PD-L1-blocking immunotherapy. PMID- 27473267 TI - Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma. AB - Tumor-infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host antitumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 patients with primary melanoma to assess the association of absent, nonbrisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared with histology alone in 15% of the cohort. To assess for intergroup immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1241 primary melanomas, TILs were graded as absent (n=388, 31%), nonbrisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (P=.025) and overall survival (P=.006) compared with patients with nonbrisk and absent TILs, for which there were no differences in recurrence-free survival (P=.40) or overall survival (P=.41). TIL quantitation by immunohistochemistry did not improve prognostication compared with TIL grading on hematoxylin and eosin-stained sections. Melanomas with nonbrisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group, and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared with melanomas with nonbrisk or absent TILs. PMID- 27473268 TI - Prediction of bladder neck invasion and tumor extension to bladder neck margin by prostatic adenocarcinoma: a nomogram using biopsy data including transition zone tumor morphology. AB - Transition zone (TZ) prostatic adenocarcinoma can be identified on needle core biopsy based on tumor morphology, provided that the sample is preserved in a glutaraldehyde-based tissue fixative. TZ tumors have a propensity to grow larger than their peripheral counterparts without extraprostatic extension and finally to escape the gland by invading the bladder neck. We investigated the value of biopsy-determined parameters including TZ origin to predict the risk of isolated bladder neck invasion at radical prostatectomy. If reliable, this will enable urologists to expand their bladder neck dissection and avoid an isolated positive bladder neck margin. The study cohort consisted of 3942 patients with detailed pre operative biopsy information who underwent curative-intent radical prostatectomy between January 2010 and December 2015 in Western Australia. Multivariate logistic regression models were developed to predict isolated bladder neck invasion or isolated positive bladder neck margin. A predictive preoperative nomogram is presented. The predictive accuracy is shown in the calibration plot (the area under the curve: 0.777). The accuracy of the nomogram is dependent on the biopsy identification of transition zone cancer features, parameters only reliably interpretable after glutaraldehyde tissue fixation. PMID- 27473269 TI - Melatonin in Youth: N-of-1 trials in a stimulant-treated ADHD Population (MYNAP): study protocol for a randomized controlled trial. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurological disorder affecting 5 % of children worldwide. A prevalent problem for children with ADHD is initial insomnia. The gold standard treatment to manage ADHD symptoms is stimulant medications, which may exacerbate the severity of existing initial insomnia. Currently, no gold standard treatment option exists for initial insomnia for these children. Melatonin, a hormone and a popular natural health product, is commonly provided to children by parents and recommended by healthcare providers, but high quality pediatric evidence is lacking. METHODS/DESIGN: This trial is a multicenter randomized triple-blind, placebo-controlled, parallel-group, randomized, controlled trial (RCT), in which each participant is offered an N-of-1 trial. An N-of-1 trial is a multiple crossover, randomized, controlled trial conducted in a single individual. For the N-of-1 trial, each participant will undergo three pairs of treatment/placebo periods; each period is 1 week in length. Half the participants will have melatonin in the first period, the other half will start with placebo, and this will make up the parallel-group RCT. The primary outcome will be mean difference in sleep onset latency as measured by sleep diaries. A comparison of treatment effects yielded by the RCT data versus the aggregated N-of-1 trial data will also be assessed. DISCUSSION: This trial will provide rigorous evidence for the effectiveness of melatonin in children with ADHD on stimulants who experience initial insomnia. Further, this study will provide the first prospectively planned head-to-head comparison of RCT data with pooled data from a series of N of-1 trials. Aggregated N-of-1 trials may be a powerful tool to produce high quality clinical trial evidence. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov, NCT02333149 . Registered on 16 December 2014. Australian New Zealand Clinical Trials Registry, ACTRN12614000542695 . Registered on 21 May 2014. PMID- 27473270 TI - Individual level covariate adjusted conditional autoregressive (indiCAR) model for disease mapping. AB - BACKGROUND: Mapping disease rates over a region provides a visual illustration of underlying geographical variation of the disease and can be useful to generate new hypotheses on the disease aetiology. However, methods to fit the popular and widely used conditional autoregressive (CAR) models for disease mapping are not feasible in many applications due to memory constraints, particularly when the sample size is large. We propose a new algorithm to fit a CAR model that can accommodate both individual and group level covariates while adjusting for spatial correlation in the disease rates, termed indiCAR. Our method scales well and works in very large datasets where other methods fail. RESULTS: We evaluate the performance of the indiCAR method through simulation studies. Our simulation results indicate that the indiCAR provides reliable estimates of all the regression and random effect parameters. We also apply indiCAR to the analysis of data on neutropenia admissions in New South Wales (NSW), Australia. Our analyses reveal that lower rates of neutropenia admissions are significantly associated with individual level predictors including higher age, male gender, residence in an outer regional area and a group level predictor of social disadvantage, the socio-economic index for areas. A large value for the spatial dependence parameter is estimated after adjusting for individual and area level covariates. This suggests the presence of important variation in the management of cancer patients across NSW. CONCLUSIONS: Incorporating individual covariate data in disease mapping studies improves the estimation of fixed and random effect parameters by utilizing information from multiple sources. Health registries routinely collect individual and area level information and thus could benefit by using indiCAR for mapping disease rates. Moreover, the natural applicability of indiCAR in a distributed computing framework enhances its application in the Big Data domain with a large number of individual/group level covariates. CI NSW Study Reference Number: 2012/07/410. Dated: July 2012. PMID- 27473271 TI - A practical approach to a low protein diet in Brazil. AB - BACKGROUND: Chronic kidney disease (CKD) is an emerging health public problem in Brazil. Nutritional counseling with focus on protein restriction is a promising strategy to treatment of nondialysis CKD patients due its effects on slowing renal loss. However, Brazilian people have high protein intake, which is a challenge when low protein diet (LPD) should be prescribed. This review describes a practical approach to the dietetic management of nondialysis CKD patients in Brazil. DISCUSSION: Although Brazilian cuisine varies greatly by region, Brazil has current trends of incorporating Western dietary habits, including high intake of red meat. Traditional plant-based foods, such as rice and beans, are also important contributors to the high protein content to the Brazilian diet. Thus, a successful implementation of LPD requires adaptation of these dietary habits, with reduction of portion sizes and adequate food substitution options. Intensive nutritional counseling with specialized renal dietitians is also important to improve compliance to the LPD. Moreover, the precarious health system organization and economic problems are barriers to nutritional care, which could be solved with intensive and specialized perspectives of treatment. The adherence to protein restriction is important for better metabolic and clinical control of nondialysis CKD patients. Early dietetic attention, nutrition education strategies and intensive specialized nutritional counseling are essential to achieve diet habits that promote adherence to the LPD without excluding cultural characteristics of the Brazilian diet. PMID- 27473272 TI - Impact of hypofractionation and tangential beam IMRT on the acute skin reaction in adjuvant breast cancer radiotherapy. AB - BACKGROUND: The purpose of the study was to evaluate the impact of multiple prognostic factors on the acute skin reaction in adjuvant breast cancer radiotherapy, in particular the impact of hypofractionation (HF) compared to conventional fractionation (CF) and tangential beam (TB) IMRT compared to three dimensional conformal radiotherapy (3DCRT). METHODS: Two-hundred and sixty-six breast cancer patients with postoperative radiotherapy after breast conserving surgery or mastectomy were retrospectively evaluated. Patients were treated with HF (15 fractions of 2.67 Gy; n = 121) or CF (28 fractions of 1.8 Gy or 25 fractions of 2.0 Gy; n = 145) and TB-IMRT (n = 151) or 3DCRT (n = 115). The acute skin reactions were prospectively assessed using the CTCAE v4 grading scale. Ordinal regression analysis was used to assess the impact of possible prognostic factors on the maximal acute skin reaction. RESULTS: Grade 2 skin reactions were observed in 19 % of the patients treated with CF compared to 2 % treated with HF. On univariate analysis, the fractionation regimen, the PTV (breast versus chest wall), the volume of the PTV and the body mass index were significant prognostic factors for the maximum acute skin reaction. On multivariate analysis, the fractionation regimen (p < 0.00001) and the volume of the PTV (p = 0.0002) remained as independent significant factors. CONCLUSIONS: Our data suggest that HF is associated with a significantly reduced maximal acute skin reaction compared to CF. PMID- 27473273 TI - The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells. AB - PURPOSE: Cisplatin can cause a variety of DNA crosslink lesions including intra strand and inter-strand crosslinks (ICLs), which are associated with the sensitivity of cancer cells to cisplatin. Here, we aimed to assess the contribution of the Fanconi anemia (FA), homologous recombination (HR) and nucleotide excision repair (NER) pathways to cisplatin resistance in non-small cell lung cancer (NSCLC)-derived cells. METHODS: The expression of FA, HR and NER pathway-associated genes was assessed by RT-qPCR and Western blotting. siRNAs were used to knock down the expression of these genes. CCK-8 and flow cytometry assays were used to assess the viability and apoptotic rate of NSCLC-derived cells, respectively. Immunofluorescence and alkaline comet assays were used to assess the repair of ICLs. RESULTS: We found that acquired cisplatin-resistant NSCLC-derived A549/DR cells exhibited markedly enhanced FA and HR repair pathway capacities compared to its parental A549 cells and another independent NSCLC derived cell line, Calu-1, which possesses a moderate innate resistance to cisplatin. siRNA-mediated silencing of the FA-associated genes FANCL and RAD18 and the HR-associated genes BRCA1 and BRCA2 significantly potentiated the sensitivity of A549/DR cells to cisplatin compared to A549 and Calu-1 cells, suggesting that the acquired cisplatin resistance in A549/DR cells may be attributed to enhanced FA and HR pathway capacities responsible for ICL repair. Although we found that expression knockdown of the NER-associated genes XPA and ERCC1 sensitized the three NSCLC-derived cell lines to cisplatin, the sensitization effect was more significant in Calu-1 cells than in A549 and A549/DR cells, implying that the innate cisplatin resistance in Calu-1 cells may result from an increased NER activity. CONCLUSIONS: Our results indicate that the functional status of DNA repair pathways determine the sensitivity of NSCLC cells to cisplatin. Direct targeting of the pathway that is involved in cisplatin resistance may be an effective strategy to surmount cisplatin resistance in NSCLC. PMID- 27473274 TI - Caffeine intake inverts the effect of adenosine on myocardial perfusion during stress as measured by T1 mapping. AB - Caffeine intake before adenosine stress myocardial perfusion imaging may cause false negative findings. We hypothesized that the antagonistic effect of caffeine can be measured by T1 relaxation times in rest and adenosine stress cardiac magnetic resonance imaging (CMR), as T1 mapping techniques are sensitive to changes in myocardial blood volume. We prospectively analyzed 105 consecutive patients with adenosine stress perfusion CMR on a 1.5-T MRI system. Rest and stress T1 mapping was performed using Modified Look-Locker Inversion recovery. T1 reactivity was defined as difference in T1rest and T1stress (?T1). Fifteen patients drank coffee within 4 h of CMR (<4H caffeine group), and 10 patients had coffee the day before (>8H caffeine group). Comparison was made to patients without self-reported coffee intake: 50 with normal CMR (control group), 18 with myocardial ischemia, and 12 with myocardial infarction. The national review board approved the study; all patients gave written informed consent. The <4H caffeine group showed inverted ?T1 of -7.8 % (T1rest 975 +/- 42 ms, T1stress 898 +/- 51 ms, p < 0.0005). The >8H caffeine group showed reduced T1 reactivity (1.8 %; T1rest 979 ms, T1stress 997 ms) compared to the controls (4.3 %; T1rest 977 +/- 40 ms, T1stress 1018 +/- 40 ms), p < 0.0005. Ischemic and infarcted myocardium showed minimal T1 reactivity (0.2 and 0.3 %, respectively). Caffeine intake inverts the adenosine effect during stress perfusion CMR as measured by T1 mapping. T1 reactivity can assess the adequacy of adenosine-induced stress in perfusion CMR. PMID- 27473275 TI - Matrix and reservoir-type multipurpose vaginal rings for controlled release of dapivirine and levonorgestrel. AB - A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) - a lead candidate human immunodeficiency virus type 1 (HIV 1) microbicide compound - has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200mg DPV and 0, 16 or 32mg LNG, Day 1 daily DPV release values were between 4132 and 6113MUg while Day 60 values ranged from 284 to 454MUg. Daily LNG release ranged from 129 to 684MUg on Day 1 and 2-91MUg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180days, and maintained daily drug release rates within much narrower windows (either 75-131MUg/day or 37-66MUg/day for DPV, and either 96-150MUg/day or 37 57MUg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception. PMID- 27473276 TI - Displacement of itraconazole from cyclodextrin complexes in biorelevant media: In vitro evaluation of supersaturation and precipitation behavior. AB - Intestinal fluids contain several constituents with affinity for cyclodextrins that have the potential of displacing drugs from the cyclodextrin cavity by competition. In this study, the solubilizing capacity of 2-hydroxypropyl-beta cyclodextrin (HP-beta-CD) for itraconazole was studied in presence of selected bile salts and phosphatidylcholine. Despite the fact that these competing agents significantly lowered the solubility of itraconazole in presence of cyclodextrins, the addition of concentrated solutions of these bile constituents to a solution containing itraconazole solubilized by HP-beta-CD did not result in precipitation, even at bile salt and phospholipid concentrations where itraconazole precipitation would be anticipated based on solubility studies. This phenomenon was further investigated in more dynamic conditions via in vitro transfer studies, mimicking the gastrointestinal transfer of HP-beta-CD solutions saturated with itraconazole. Intestinal supersaturation upon transfer was observed for all conditions tested and a concentration dependent impact of bile salts and phospholipids on the precipitation behavior of itraconazole was demonstrated: high concentrations of bile salts and phospholipids generated the highest degrees of supersaturation shortly after the transfer step but also resulted in stronger itraconazole precipitation at later time points. These findings demonstrate the possible impact of the variable intestinal fluid composition on the behavior of cyclodextrin containing formulations. PMID- 27473277 TI - Influence of serum albumin on intracellular delivery of drug-loaded hyaluronan polymeric micelles. AB - Polymeric micelles are attractive drug delivery systems for intravenously administered nonpolar drugs. Although physical parameters like size, shape and loading capacity are considered as the most important for their efficiency, here we demonstrate that the effects of serum protein interaction and characteristics of loaded compound cannot be neglected during the micelle development and design of experimental set up. Polymeric micelles prepared from amphiphilic hyaluronic acid grafted with short (hexanoic) and long fatty acids (oleic) were tested after loading with two different hydrophobic models, Nile red and curcumin. The composition of micelles affected mainly the loading capacity. Both encapsulated compounds behaved differently in the in vitro cell uptake, which was also influenced by serum concentration, where serum albumin was found to be the primary destabilizing component. This destabilization was found to be influenced by polymeric micelle concentration. Thus, the chemical structure of micelle, the properties of non-covalently loaded substance and serum albumin/polymeric micelle ratio modulate the in vitro intracellular uptake of drugs loaded in nanocarriers. PMID- 27473278 TI - New multifunctional pharmaceutical excipient in tablet formulation based on citric acid-cyclodextrin polymer. AB - A beta-cyclodextrin (beta-CD) polymer obtained by crosslinking beta-CD with citric acid in its water-insoluble (PCD-I) and soluble (PCD-S) forms was used as a multifunctional direct compression excipient for tablet designing. PCD-I powder was obtained after grinding the solid fraction through a 200MUm grid. PCD-S powder was recovered after lyophilization or spray drying of the PCD-S aqueous solutions, eventually followed by a wet granulation step. Both PCD-I and PCD-S powders were characterized, separately and mixed in variable ratios, based on dynamic water vapor sorption, SEM, particle size distribution, tapped density, compressibility, and flowability. PCD-I and spray dried and lyophilized/wet granulated PCD-S, as well as the mixture PCD-I/PCD-S=90/10, presented optimal free flowing characteristics. Then, PCD-I or PCD-S powders - separately or mixed in variable ratios - were used for tablets preparation by direct compression without adding any other excipient (e.g. binder, lubricant, disintegrant etc). As PCD-I decreased, tablets resistance to crushing and disintegration time increased from 15s to 15min (against 30min for beta-CD), showing the improved disintegrant functionality of PCD-I, that rapidly swelled once in contact with water. Finally, PCD was force-fed to Sprague-Dawley rats (2g/kg) which were then observed during 14days for any clinical signs of toxicity. PMID- 27473279 TI - Solid Lipid Nanoparticle assemblies (SLNas) for an anti-TB inhalation treatment-A Design of Experiments approach to investigate the influence of pre-freezing conditions on the powder respirability. AB - For direct intramacrophagic antitubercular therapy, pulmonary administration through Dry Powder Inhaler (DPI) devices is a reasonable option. For the achievement of efficacious aerosolisation, rifampicin-loaded Solid Lipid Nanoparticle assemblies (SLNas) were developed using the melt emulsifying technique followed by freeze-drying. Indeed, this drying method can cause freezing or drying stresses compromising powder respirability. It is the aim of this research to offer novel information regarding pre-freezing variables. These included type and concentration of cryoprotectants, pre-freezing temperature, and nanoparticle concentration in the suspension. In particular, the effects of such variables were observed at two main levels. First of all, on SLNas characteristics - i.e., size, polydispersity index, zeta-potential, circularity, density, and drug loading. Secondly, on powder respirability, taking into account aerodynamic diameter, emitted dose, and respirable fraction. Considering the complexity of the factors involved in a successful respirable powder, a Design of Experiments (DoE) approach was adopted as a statistical tool for evaluating the effect of pre-freezing conditions. Interestingly, the most favourable impact on powder respirability was exerted by quick-freezing combined with a certain grade of sample dilution before the pre-freezing step without the use of cryoprotectants. In such conditions, a very high SLNas respirable fraction (>50%) was achieved, along with acceptable yields in the final dry powder as well as a reduction of powder mass to be introduced into DPI capsules with benefits in terms of administered drug dose feasibility. PMID- 27473280 TI - Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously. AB - Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. PMID- 27473281 TI - Total arterial revascularization: A superior method of cardiac revascularization. AB - For over 40 years, the left internal thoracic artery has been used as the gold standard for myocardial revascularization and anastomosis over the left anterior descending artery due to its excellent patency rates. However, the right internal thoracic artery behaves in the same manner as the left, also having excellent long-term patency. Hence, no patient should be deprived of the benefits of total arterial revascularization allowed by the bilateral use of both internal thoracic arteries. PMID- 27473282 TI - The progressive increase of the platelet count in a patient with acute severe pancreatitis. PMID- 27473283 TI - DISMISS: detection of stranded methylation in MeDIP-Seq data. AB - BACKGROUND: DNA methylation is an important regulator of gene expression and chromatin structure. Methylated DNA immunoprecipitation sequencing (MeDIP-Seq) is commonly used to identify regions of DNA methylation in eukaryotic genomes. Within MeDIP-Seq libraries, methylated cytosines can be found in both double stranded (symmetric) and single-stranded (asymmetric) genomic contexts. While symmetric CG methylation has been relatively well-studied, asymmetric methylation in any dinucleotide context has received less attention. Importantly, no currently available software for processing MeDIP-Seq reads is able to resolve these strand-specific DNA methylation signals. Here we introduce DISMISS, a new software package that detects strand-associated DNA methylation from existing MeDIP-Seq analyses. RESULTS: Using MeDIP-Seq datasets derived from Apis mellifera (honeybee), an invertebrate species that contains more asymmetric- than symmetric DNA methylation, we demonstrate that DISMISS can identify strand-specific DNA methylation signals with similar accuracy as bisulfite sequencing (BS-Seq; single nucleotide resolution methodology). Specifically, DISMISS is able to confidently predict where DNA methylation predominates (plus or minus DNA strands - asymmetric DNA methylation; plus and minus DNA stands - symmetric DNA methylation) in MeDIP-Seq datasets derived from A. mellifera samples. When compared to DNA methylation data derived from BS-Seq analysis of A. mellifera worker larva, DISMISS-mediated identification of strand-specific methylated cytosines is 80 % accurate. Furthermore, DISMISS can correctly (p <0.0001) detect the origin (sense vs antisense DNA strands) of DNA methylation at splice site junctions in A. mellifera MeDIP-Seq datasets with a precision close to BS-Seq analysis. Finally, DISMISS-mediated identification of DNA methylation signals associated with upstream, exonic, intronic and downstream genomic loci from A. mellifera MeDIP-Seq datasets outperforms MACS2 (Model-based Analysis of ChIP Seq2; a commonly used MeDIP-Seq analysis software) and closely approaches the results achieved by BS-Seq. CONCLUSIONS: While asymmetric DNA methylation is increasingly being found in growing numbers of eukaryotic species and is the predominant pattern observed in some invertebrate genomes, it has been difficult to detect in MeDIP-Seq datasets using existing software. DISMISS now enables more sensitive examinations of MeDIP-Seq datasets and will be especially useful for the study of genomes containing either low levels of DNA methylation or for genomes containing relatively high amounts of asymmetric methylation. PMID- 27473285 TI - Pharmacokinetics, safety, and tolerability of ceftolozane/tazobactam in healthy Japanese, Chinese, and white subjects. AB - Ceftolozane/tazobactam, a novel antibacterial with potent activity against Gram negative pathogens, was developed for treatment of complicated urinary tract infections, including pyelonephritis, and intra-abdominal infections. A phase 1 pharmacokinetic (PK) study of ceftolozane/tazobactam in healthy Japanese, Chinese, and white volunteers was conducted to assess the potential effect of ethnicity on PK. The PK of ceftolozane, tazobactam, and tazobactam metabolite M1 was compared after single 1.5- and 3-g intravenous doses of ceftolozane/tazobactam. Ten Japanese, nine Chinese, and ten white subjects were enrolled, and 27 completed all doses of study medication. Dose-normalized PK parameters for ceftolozane and tazobactam were similar among Japanese, Chinese, and white subjects (at 1.5-g and 3-g doses, ceftolozane area under the plasma concentration-time curve from zero to infinity [AUC0-infinity ] = 166.3, 165.9, and 185.5 h MUg/mL, respectively, and 157.7, 158.5, and 181.2 h MUg/mL, respectively; tazobactam AUC0-infinity = 48.5, 43.2, and 50.1 h MUg/mL, respectively, and 47.3, 43.7, and 50.0 h MUg/mL, respectively. The 90% CIs of their ratio estimates were within the range 0.80 to 1.25 with the exception of AUC0-infinity for ceftolozane after the 3-g dose (0.79). The cumulative amount of ceftolozane and tazobactam excreted in urine was similar among ethnic groups. For all groups, treatment-emergent adverse events (AEs) were mild; no deaths or serious AEs were reported. The PK of ceftolozane/tazobactam was approximately dose proportional (i.e. doubling the dose approximately doubles the exposure) and similar among the groups. No dosage adjustment is needed for ceftolozane/tazobactam in Japanese and Chinese patients. PMID- 27473284 TI - Latitude in sample handling and storage for infant faecal microbiota studies: the elephant in the room? AB - BACKGROUND: In this manuscript, we investigate the "stones best left unturned" of sample storage and preparation and their implications for the next-generation sequencing of infant faecal microbial communities by the 16S ribosomal ribonucleic acid (rRNA) gene. We present a number of experiments that investigate the potential effects of often overlooked methodology factors, establishing a "normal" degree of variation expected between replica sequenced samples. Sources of excess variation are then identified, as measured by observation of alpha diversity, taxonomic group counts and beta diversity magnitudes between microbial communities. RESULTS: Extraction of DNA from samples on different dates, by different people and even using varied sample weights results in little significant difference in downstream sequencing data. A key assumption in many studies is the stability of samples stored long term at -80 degrees C prior to extraction. After 2 years, we see relatively few changes: increased abundances of lactobacilli and bacilli and a reduction in the overall OTU count. Where samples cannot be frozen, we find that storing samples at room temperature does lead to significant changes in the microbial community after 2 days. Mailing of samples during this time period (a common form of sample collection from outpatients for example) does not lead to any additional variation. CONCLUSIONS: Important methodological standards can be drawn from these results; painstakingly created archives of infant faecal samples stored at -80 degrees C are still largely representative of the original community and varying factors in DNA extraction methodology have comparatively little effect on overall results. Samples taken should ideally be either frozen at -80 degrees C or extracted within 2 days if stored at room temperature, with mail samples being mailed on the day of collection. PMID- 27473286 TI - Altered tryptophan metabolism in human meningioma. AB - Meningiomas are the neoplasms that arise from the arachnoid cells of the meninges. It was reported that cancer cells escape from immune system through the metabolism of an aromatic essential amino acid tryptophan (TRP) via Kynurenine (KYN) pathway. However, the role of TRP metabolites such as, 5-Hydroxy tryptophan (5-HTP), 5-Hydroxy tryptamine (5-HT), N-acetyl serotonin (NAS), Melatonin (MEL), KYN, N-acetyl tryptamine, 5-Hydroxy indole acetic acid (5-HIAA) and 5-Methoxy indole acetic acid is not yet evaluated in human meningioma. Therefore, in the current study we have evaluated the levels of TRP and its metabolites in the progression of human meningioma using tumor biopsy samples and autopsy control meninges with Reverse Phase-HPLC. We here report that TRP metabolism favors towards KYN pathway in human meningioma and it could be due to increased indoleamine 2,3-dioxygenase 2 levels as we found its m-RNA levels to be up regulated in human meningioma. We observed significant increase in KYN and 5HIAA levels and significant decrease in TRP, 5-HTP, 5-HT, NAS and MEL levels in meningioma compared to control meninges. Since TRP metabolites regulate inducible nitric oxide synthase (INOS) gene expression and thereby nitric oxide (NO) production, we have also evaluated the INOS and NO levels. The INOS and NO levels were up regulated in human meningioma. The present data corroborates with existing data on TRP metabolism in tumor progression and may serve to target TRP metabolism as a therapeutic intervention. PMID- 27473287 TI - Activation of CO2-reducing methanogens in oil reservoir after addition of nutrient. AB - Nutrient addition as part of microbial enhanced oil recovery (MEOR) operations have important implications for more energy recovery from oil reservoirs, but very little is known about the in situ response of microorganisms after intervention. An analysis of two genes as biomarkers, mcrA encoding the key enzyme in methanogenesis and fthfs encoding the key enzyme in acetogenesis, was conducted during nutrient addition in oil reservoir. Clone library data showed that dominant mcrA sequences changed from acetoclastic (Methanosaetaceae) to CO2 reducing methanogens (Methanomicrobiales and Methanobacteriales), and the authentic acetogens affiliated to Firmicutes decreased after the intervention. Principal coordinates analysis (PCoA) and Jackknife environment clusters revealed evidence on the shift of the microbial community structure among the samples. Quantitative analysis of methanogens via qPCR showed that Methanobacteriales and Methanomicrobiales increased after nutrient addition, while acetoclastic methanogens (Methanosaetaceae) changed slightly. Nutrient treatment activated native CO2-reducing methanogens in oil reservoir. The high frequency of Methanobacteriales and Methanomicrobiales (CO2-reducers) after nutrient addition in this petroleum system suggested that CO2-reducing methanogenesis was involved in methane production. The nutrient addition could promote the methane production. The results will likely improve strategies of utilizing microorganisms in subsurface environments. PMID- 27473288 TI - Characterization of an O-methyltransferase specific to guaiacol-type benzenoids from the flowers of loquat (Eriobotrya japonica). AB - Volatile benzenoids, including methyl p-methoxybenzoate, p-anisaldehyde, and p anisalcohol, are responsible for the sweet and characteristic fragrance of loquat (Eriobotrya japonica, Rosaceae) flowers. Although the full pathway of volatile benzenoid synthesis has yet to be elucidated, their chemical structures suggest that O-methyltransferases are present in loquat and function in the methylation of the para-OH groups. In the present study, we used RNA-sequencing to identify four loquat genes (EjOMT1, EjOMT2, EjOMT3, and EjOMT4) that encode O methyltransferases. We found that EjOMT1 was highly expressed in floral tissues, with an expression pattern that coincided with changes in intracellular volatile benzenoids during flower development. Recombinant EjOMT1 protein expressed in Escherichia coli showed the highest activity towards guaiacol with a Km value of 35 MUM. Furthermore, the protein also showed lesser activities towards guaiacol type benzenoids including eugenol, isoeugenol, vanillin, and ferulic acid, in addition to much weaker activities towards catechol and p-hydroxybenzenoid derivatives. However, no activity was shown towards phenylpropenes without m methoxy substitution, t-anol and chavicol. Taken together, our findings indicate that EjOMT1 has a broad substrate specificity towards compounds with both para-OH and meta-OCH3 groups, unlike previously characterized O-methyltransferases for volatile benzenoid/phenylpropanoid biosynthesis. PMID- 27473289 TI - Cosynthesis of l-homophenylalanine and 2-phenylethanol by recombinant Saccharomyces cerevisiae expressing aspartate aminotransferase from Escherichia coli BL21(DE3). AB - The Escherichia coli aspartate aminotransferase gene was introduced into a high 2 phenylethanol (2-PEA) producing Saccharomyces cerevisiae YS58, and the recombinant strain of S. cerevisiae was utilized for the co-production of 2-PEA and l-homophenylalanine (L-HPA) via a fermentation process. The L-HPA productivity of the recombinant S. cerevisiae improved 78.9% in comparison to the wild-type S. cerevisiae. High yields of 43.7 mM L-HPA and 32.4 mM 2-PEA were achieved. As a result, the coupling of the biosynthesis process for these two products in the recombinant strain led to a more complete and efficient utilization of the substrate, l-phenylalanine. PMID- 27473290 TI - A study of SPECT/CT camera stability for quantitative imaging. AB - BACKGROUND: The purpose of this study was twofold: to evaluate the quantitative stability of a SPECT/CT gamma camera over time and to determine if daily flood acquisitions can reliably serve as calibration factors for quantitative SPECT. Using a cylindrical water phantom filled with measured amounts of (99m)Tc, factors were calculated to convert counts/cc to activity/cps. Measurements were made over an 18-month period. System sensitivity data calculated from (57)Co daily quality assurance (DQA) flood acquisitions were then compared to the (99m)Tc calibration factors to determine the relationship of the factors. RESULTS: The coefficient of variation is 2.7 % for the (99m)Tc cylinder conversion factors and 2.6 % for the (57)Co DQA flood data. The greatest difference between the cylinder conversion factors and the flood data is less than 3 %. CONCLUSIONS: Based on the results, the camera was stable within 3 % over an 18-month time period. The daily flood source acquisitions can be a reliable source for tracking camera stability and may provide information on updating the calibration factor for quantitative imaging. PMID- 27473291 TI - Using Personal Mobile Phones to Assess Dietary Intake in Free-Living Adolescents: Comparison of Face-to-Face Versus Telephone Training. AB - BACKGROUND: Traditional paper-based methods to assess food intake can be cumbersome for adolescents; use of mobile phones to track and photograph what they eat may be a more convenient, reliable, and compelling way to collect data. OBJECTIVE: Our aims were to determine (1) the feasibility of using personal mobile phones to send food records with digital images (FRDIs) among free-living adolescents and (2) whether the quality of food records differed between a high level intervention group (ie, face-to-face training plus real-time support) and a low-level intervention group (ie, telephone training plus next-day follow-up). METHODS: Adolescents (N=42, 11 males and 31 females) aged 12-18 years who had a mobile phone with camera enrolled in the study via consecutive sampling. The first group (n=21) received face-to-face training while the second group (n=21) was trained via telephone. Participants received a fiducial marker (FM) and completed a 1-day FRDI using their mobile phones. At every eating occasion, participants were to (1) take clear images of their meals/food with a correctly placed fiducial marker before eating, (2) send the image immediately to a designated email address, (3) right after completing a meal, send a text message listing the time and name of the meal, foods eaten, and amounts eaten, and (4) before sleep, send an "end" text message to indicate completion of food recording. Those who received face-to-face training received real-time support during reporting; those trained by telephone received next-day follow-up. Descriptive statistics and comparison tests were used to determine performance of the groups. RESULTS: All participants (N=42) who underwent training completed their 1-day FRDI. A significantly greater proportion of the low-level intervention group compared to the high-level intervention group placed their FM correctly in the image (95% vs 43%, P<.001), had complete information for each meal in their food record (95% vs 71%, P=.04), and had a higher overall score in meeting the criteria for food recording (4.3 vs 3.4 out of 5 points). Both groups had energy intake values that moderately correlated with their estimated energy requirements: low-intervention r=.55; high-intervention r=.51. CONCLUSIONS: Using personal mobile phones to report dietary intake via texting and digital images is feasible among free-living adolescents. Real-time support or high-level intervention does not guarantee better food recording quality among adolescents. PMID- 27473292 TI - Reply to the letter "A proposal for a level for parapharyngeal extension of parotid gland". PMID- 27473294 TI - Reply to the letter to the editor by Viroj Wiwanitkit concerning: 'Is neutrophil lymphocyte ratio associated with the severity of allergic rhinitis in children?'. PMID- 27473293 TI - Upper airway structural changes induced by CPAP in OSAS patients: a study using drug-induced sleep endoscopy. AB - We studied upper airway structural changes induced by continuous positive airway pressure (CPAP) in obstructive sleep apnea syndrome (OSAS) patients using drug induced sleep endoscopy (DISE). This prospective study was conducted at an academic secondary referral center. In total, 28 male OSAS patients (mean age 41.1 years) with only retropalatal level obstructions were enrolled. Measurements of the obstruction site were obtained in two steps: first a measurement was taken of the obstruction site in accordance with sleep apnea, then, a measurement was taken of the obstruction site in accordance with DISE-assisted CPAP titration, including quantitative changes in the occlusion site before and after CPAP in pixel format using an area calculation program. There was a tendency for persistent closing in cases of antero-posterior (AP) obstruction versus cases of lateral (Lat) obstruction in the CPAP titration. Lat obstructions showed a tendency to be wider than AP obstructions in the quantitative analysis. These results show that the pattern and degree of airway expansion after CPAP differ in accordance with the obstruction site. PMID- 27473295 TI - Reply to the letter to the editor by Satvinder Singh Bakshi concerning: 'Is neutrophil-lymphocyte ratio associated with the severity of allergic rhinitis in children?'. PMID- 27473296 TI - Promoting physical activity in a low-income neighborhood of the Paris suburb of Saint-Denis: effects of a community-based intervention to increase physical activity. AB - BACKGROUND: Physical activity (PA) is a key factor for facing the increasing prevalence of obesity and overweight, and should be part of every public health programs. In this context, a community-based public health program promoting PA was developed in a low-income neighborhood of the city of Saint-Denis (France). METHODS: This work aimed at assessing the effectiveness of a 2-year PA promotion program. A quasi-experimental study was carried out using a pre/post design, with an assessment before (2013) and after (2015) the program. The interviewees were selected using a stratified random cluster sampling. The primary outcome was the proportion of participants practicing sufficient PA (WHO guidelines), and was measured using the RPAQ questionnaire. External interventions (on both neighborhood environment and inhabitants) were listed. RESULTS: We collected 199 questionnaires at baseline and 217 in 2015. There was a majority of women in both samples: 64.3 % in 2013 and 58.2 % in 2015. The average age of participants was 38.1 years (+/-1.1) and 40.6 (+/-1.1) respectively. The proportion of people practicing sufficient PA was modified from 48.1 % in 2013 to 63.5 % in 2015 (p = 0.001). This was mainly driven by women whose level of PA, increased from 40.3 % to 60.3 % (p = 0.002), reaching the average national French estimation of PA level among adults (63.5 %). CONCLUSIONS: This work showed a significant increase of the proportion of people practicing PA in a disadvantaged neighborhood where a community-based program promoting PA was developed. Simultaneous external interventions contributed to the results, showing the necessity of synergic interventions to reach efficiency. PMID- 27473297 TI - Ling-Ling Chen: Linking Long Noncoding RNA Processing and Function to RNA Biology. PMID- 27473298 TI - Robot-assisted Surgery for Benign Ureteral Strictures: Experience and Outcomes from Four Tertiary Care Institutions. AB - BACKGROUND: Minimally invasive treatment of benign ureteral strictures is still challenging because of its technical complexity. In this context, robot-assisted surgery may overcome the limits of the laparoscopic approach. OBJECTIVE: To evaluate outcomes for robotic ureteral repair in a multi-institutional cohort of patients treated for ureteropelvic junction obstruction and ureteral stricture (US) at four tertiary referral centres. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study reports data for 183 patients treated with standard robot assisted pyeloplasty (PYP) and robotic uretero-ureterostomy (UUY) at four high volume centres from January 2006 to September 2014. SURGICAL PROCEDURE: Robotic PYP and robot-assisted UUY were performed according to previously reported surgical techniques. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Preoperative, intraoperative, and postoperative variables and outcomes were assessed. A descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: No robot assisted UUY cases required surgical conversion, while 2.8% of PYP cases were not completed robotically. The median operative time was 120 and 150min for robot assisted PYP and robot-assisted UUY, respectively. No intraoperative complications were reported. The overall complication rate for all procedures was 11% (n=20) and complications were mostly of low grade. The high-grade complication rate was 2.2% (n=4). At median follow-up of 24 mo, the overall success rate was >90% for both procedures. The study limitations include its retrospective nature and the heterogeneity of the study population. CONCLUSIONS: Robotic surgery for benign US is safe and effective, with limited risk of high grade complications and good intermediate-term results. PATIENT SUMMARY: In this study we review the use of robotic surgery at four different tertiary care centres in the treatment of patients affected by benign ureteral strictures. Our results demonstrate that robotic surgery is a safe alternative to the standard open approach in the treatment of ureteral strictures. PMID- 27473299 TI - Long-Term Outcomes and Longitudinal Changes of Neurogenic Bowel Management in Adults With Pediatric-Onset Spinal Cord Injury. AB - OBJECTIVES: To describe long-term outcomes of neurogenic bowel dysfunction (NBD), determine changes over time in the type of bowel program, and determine changes in psychosocial outcomes associated with NBD-related factors in adults with pediatric-onset spinal cord injury (SCI). DESIGN: Longitudinal cohort survey. Follow-up occurred annually for a total of 466 interviews, with most participants (75%) contributing to at least 3 consecutive interviews. SETTING: Community. PARTICIPANTS: Adults (N=131) who had sustained an SCI before the age of 19 years (men, 64.1%; tetraplegia, 58.8%; mean age +/- SD, 33.4+/-6.1y; mean time since injury +/- SD, 19.5+/-7.0y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Type and evacuation time of bowel management programs; standardized measures assessing life satisfaction, health perception, depressive symptoms, and participation. Generalized estimating equations were formulated to determine odds of change in outcomes over time. RESULTS: At first interview, rectal suppository/enema use was most common (51%). Over time, the likelihood of using manual evacuation (odds ratio [OR]=1.077; 95% confidence interval [CI], 1.023 1.134; P=.005), oral laxatives (OR=1.052; 95% CI, 1.001-1.107; P=.047), and colostomy (OR=1.071; 95% CI, 1.001-1.147; P=.047) increased, whereas the odds of rectal suppository use decreased (OR=.933; 95% CI, .896-.973; P=.001). Bowel evacuation times were likely to decrease over time in participants using manual evacuation (OR=.499; 95% CI, .256-.974; P=.042) and digital rectal stimulation (OR=.490; 95% CI, .274-.881; P=.017), but increase for rectal suppository/enema use (OR=1.871; 95% CI, 1.264-2.771; P=.002). When the level of injury was controlled for, participants using manual evacuation and digital rectal stimulation were more likely to have increases in community participation scores (P<.05). CONCLUSIONS: Changes in type of bowel program over time may be associated with the time required to complete bowel evacuation in this relatively young adult SCI population. PMID- 27473301 TI - The three-dimensional radiologic viewer and scientific publications in the new century. PMID- 27473300 TI - Relationship between dairy product intake during pregnancy and neonatal and maternal outcomes among Portuguese women. AB - BACKGROUND: The role played by dairy product intake during pregnancy on neonatal outcomes has raised interest in the last few years. However, studies on this association remain scarce. Thus, the aim of this study was to determine the association between dairy product consumption during pregnancy and neonatal and maternal outcomes. METHODS: A prospective study was conducted with 98 pregnant women, aged 18-40, from the city of Porto, Portugal. Socio-demographic and lifestyle characteristics were assessed through a questionnaire. Dairy product consumption was assessed with a three-day food diary completed during the first and second trimesters. Postpartum medical records were examined for neonatal and maternal outcomes. Multivariate linear regression analyses were performed to assess the association between dairy intake and neonatal and maternal outcomes, adjusting for dietary variables and maternal characteristics. RESULTS: Compared to the first trimester pregnant women had higher energy intake and lower calcium, iodine and yogurt intake in the second trimester (P<0.05). Total dairy and yogurt intake in the first trimester were positively associated with head circumference and placental weight (respectively beta=0.002, P=0.014, beta=0.333, P=0.012). Change in total dairy intake between the second and first trimester was negatively associated with maternal weight gain during pregnancy (beta=-0.007, P=0.020). CONCLUSION: The findings of this study suggest that dairy product intake during pregnancy may have an effect on neonatal head circumference, placental weight, and gestational weight gain. PMID- 27473302 TI - Facial onset sensory and motor neuronopathy. AB - Facial onset sensory and motor neuronopathy (FOSMN) is a recently defined slowly progressive motor neuron disorder. It is characterized by facial onset sensory abnormalities which may spread to the scalp, neck, upper trunk and extremities, followed by lower motor neuron deficits. Bulbar symptoms, such as dysarthria and dysphagia, muscle weakness, cramps and fasciculations, can present later in the course of the disease. We search the PubMed database for articles published in English from 2006 to 2016 using the term of "Facial onset sensory and motor neuronopathy". Reference lists of the identified articles were selected and reviewed. Only 38 cases of FOSMN have been reported in the Pubmed database since it was first reported in 2006. Typically, FOSMN present with slowly evolving numbness of the face followed by neck and arm weakness. Reduced or absent of corneal reflexes and blink reflex is the main pathognomonic features of FOSMN. In this review, we summarize the epidemiology, clinical presentation, auxiliary examination, and treatment of all the reported cases of FOSMN. Moreover, we discuss the pathogenesis of this rare disorder. In addition, we propose diagnostic criteria for FOSMN. PMID- 27473303 TI - Communication of support and critique in Swedish virtual community threads about prenatal diagnoses of fetal anomalies. AB - BACKGROUND: A prenatal diagnosis of a fetal anomaly involves acute grief and psychological distress. The Internet has the potential to provide virtual support following the diagnosis. The overall aim was to explore communication of support and critique in Swedish virtual community threads about prenatal diagnoses of fetal anomalies. METHODS: Systematic searches in Google resulted in 117 eligible threads. Fifteen of these were purposefully selected and subjected to deductive content analysis. RESULTS: The virtual support involved mainly emotional support (meaning units n = 1,992/3,688, 54 %) and was described as comforting and empowering. Posters with experience of a prenatal diagnosis appreciated the virtual support, including the opportunity to gain insight into other cases and to write about one's own experience. Critique of the decision to continue or terminate the pregnancy occurred, primarily against termination of pregnancy. However, it was met with defense. CONCLUSIONS: Peer support, mainly emotional, is provided and highly appreciated in threads about prenatal diagnoses of a fetal anomaly. Critique of the decision to terminate the pregnancy occurs in virtual community threads about prenatal diagnoses, but the norm is to not question the decision. Future studies need to investigate if virtual peer support promotes psychosocial function following a prenatal diagnosis and what medium would be most suitable for these types of supportive structures. PMID- 27473304 TI - Unaltered pneumococcal carriage prevalence due to expansion of non-vaccine types of low invasive potential 8years after vaccine introduction in Stockholm, Sweden. AB - OBJECTIVE: To evaluate the carriage prevalence, serotype distribution, and antibiotic resistance for pneumococcal carriage isolates collected 4-8years after introduction of pneumococcal conjugate vaccines (PCVs) in Stockholm, Sweden, and to identify risk factors for carriage and calculate the invasive disease potential for emerging serotypes. METHODS: Nasopharyngeal aspirates were collected from 3024 children aged 0-<5years at regular visits at 23 Child Health Centers in Stockholm County in 2011-2015, and from 787 parents in 2014-2015. The invasive disease potential was calculated for serotypes using invasive disease isolates from 824 patients of all ages identified in the Stockholm County during the same time period as the carriage isolates. RESULTS: A total carriage prevalence of 30% did not change during the study period. Non-vaccine types (NVT) dominated (94% by 2015) and the most common serotypes in descending order were 11A, 23B, 35F and 21. Risk factors for carriage were: age ?3months-<3years, having siblings, attending day-care and having travelled abroad the last 3months. Antibiotic resistance remained low. The invasive disease potential was high for NVT 8, 9N, 12F, and 22F, while low for a majority of emerging NVTs in carriage. CONCLUSION: The carriage prevalence remained the same 4-8years after vaccine introduction, but serotype replacement became almost complete. A majority of emerging NVTs in carriage showed a low invasive disease potential. Carriage studies are an important complement to invasive disease surveillance to understand the full effect of PCV vaccine programs. PMID- 27473305 TI - Prediction of influenza B vaccine effectiveness from sequence data. AB - Influenza is a contagious respiratory illness that causes significant human morbidity and mortality, affecting 5-15% of the population in a typical epidemic season. Human influenza epidemics are caused by types A and B, with roughly 25% of human cases due to influenza B. Influenza B is a single-stranded RNA virus with a high mutation rate, and both prior immune history and vaccination put significant pressure on the virus to evolve. Due to the high rate of viral evolution, the influenza B vaccine component of the annual influenza vaccine is updated, roughly every other year in recent years. To predict when an update to the vaccine is needed, an estimate of expected vaccine effectiveness against a range of viral strains is required. We here introduce a method to measure antigenic distance between the influenza B vaccine and circulating viral strains. The measure correlates well with effectiveness of the influenza B component of the annual vaccine in humans between 1979 and 2014. We discuss how this measure of antigenic distance may be used in the context of annual influenza vaccine design and prediction of vaccine effectiveness. PMID- 27473307 TI - Population pharmacokinetics, optimised design and sample size determination for rifampicin, isoniazid, ethambutol and pyrazinamide in the mouse. AB - The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug. The RIF, INH, EMB and PZA blood concentrations after single oral and IV doses and multiple-dose oral administrations based on the original designs were used in the PopPK analysis using NONMEM software. The final PopPK models described the data well. Stochastic simulation and estimation were used to optimise the designs. The relative bias and relative imprecision of each pharmacokinetic parameter for each drug were derived and assessed to choose the final designs. The final single-dose IV and oral designs included up to eight samples per mouse with a total of 24 mice required for RIF and EMB and 33 mice for INH and PZA. In the new multiple-dose (zipper) oral designs, the mice were divided into two groups of three per dose, and four samples were taken from each mouse to cover all seven or eight sampling time points. The final number of mice required for the multiple-dose oral designs was 30 for RIF, INH and EMB, 36 for PZA. The number of mice required in the new designs for RIF, INH and EMB was decreased by up to 7-fold and the relative bias and relative imprecision in the parameter estimates were at least similar to those in the original designs. PMID- 27473306 TI - High-dose influenza vaccine favors acute plasmablast responses rather than long term cellular responses. AB - High-dose (HD) influenza vaccine shows improved relative efficacy against influenza disease compared to standard-dose (SD) vaccine in individuals ?65years. This has been partially credited to superior serological responses, but a comprehensive understanding of cell-mediated immunity (CMI) of HD vaccine remains lacking. In the current study, a total of 105 participants were randomly administered HD or SD vaccine and were evaluated for serological responses. Subsets of the group (n=12-26 per group) were evaluated for B and T cell responses at days 0, 7, 14 and 28 post-vaccination by flow cytometry or ELISPOT assay. HD vaccine elicited significantly higher hemagglutination inhibition (HI) titers than SD vaccine at d28, but comparable titers at d365 post-vaccination. HD vaccine also elicited higher vaccine-specific plasmablast responses at d7 post vaccination than SD vaccine. However, long-lived memory B cell induction, cytokine-secreting T cell responses and persistence of serological memory were comparable regardless of vaccine dose. More strategies other than increased Ag amount may be needed to improve CMI in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01189123. PMID- 27473308 TI - Modified-chitosan nanoparticles: Novel drug delivery systems improve oral bioavailability of doxorubicin. AB - The efficacy of most anticancer drugs is highly limited in vivo due mainly to poor pharmacokinetics behavior including poor bioavailability after extravascular administration. We have developed novel chitosan-modified polymeric nanoparticles for oral as well as i.v. administration. Nanoparticles were developed utilizing the double emulsion solvent evaporation technique for sustained delivery of various anticancer drugs. Chitosan diacetate (CDA) and chitosan triacetate (CTA) polymers were previously modified in our laboratory and used as novel matrix. Nanoparticles, loaded with various anticancer drugs, were characterized for particle size using dynamic light scattering as well as transmission electron microscopy and net surface charge using dynamic light scattering. Particles size was below 100nm in diameter and zeta potential ranged - (25-30). Encapsulation efficiency of anticancer drugs varied considerably and was dependent on the physicochemical characteristics of the encapsulated drug. However, chitosan triacetate nanoparticles showed relatively higher encapsulation efficiency than chitosan diacetate nanoparticles. In vitro release of encapsulated drugs was sustained over a period of 14days. Nanoparticles enhanced cellular accumulation of encapsulated drugs, compared to the free drugs, in vitro in MCF-7 and Caco-II tumor cell lines. In conclusion, diacetate and triacetate chitosan are novel polymers that can be used to formulate nanoparticles which efficiently encapsulated anticancer drugs, and sustained the release and enhanced tumor cellular uptake of these drugs. Further, chitosan triacetate nanoparticles enhanced oral bioavailability of doxorubicin. CDA and CTA nanoparticles can be used to efficiently deliver anticancer drugs and improve their in vivo profile. PMID- 27473309 TI - Solubility, lipophilicity and membrane permeability of some fluoroquinolone antimicrobials. AB - Aqueous solubility and distribution of ciprofloxacin, enrofloxacin, norfloxacin and levofloxacin antimicrobials drugs in octanol/buffer system has been measured by the isothermal saturation method using buffer solutions pH2.0 and 7.4 in the temperature range of 293.15-313.15K. Thermophysical characteristics for the compounds have been determined by the DSC method. It has been established that the solubility of levofloxacin in these buffers is higher than that of the other fluoroquinolones. HYBOT descriptors for biologically active compounds have been calculated and the impact of the donor-acceptor capacity of the molecules on drugs solubility has been studied. According to the lipophilicity parameter fluoroquinolones are ranged in the following order: enrofloxacin>levofloxacin>ciprofloxacin>norfloxacin. The thermodynamic solubility and distribution functions of the studied compounds have been obtained. The permeability coefficients of the substances through an artificial phospholipid membrane were determined. The drugs with a lower aqueous solubility were estimated to have higher distribution coefficients and membrane permeability. PMID- 27473310 TI - Survey of Chinese Medicine Students to Determine Research and Evidence-Based Medicine Perspectives at Pacific College of Oriental Medicine. AB - CONTEXT: Research literacy and the practice of evidence-based medicine (EBM) are important initiatives in complementary and alternative medicine (CAM), which requires cultural change within educational institutions for successful implementation. OBJECTIVE: To determine the self-assessed research and EBM perspectives of Chinese medicine Masters degree students at Pacific College of Oriental Medicine, New York campus (PCOM-NY). DESIGN AND METHODS: A survey with 17 close-ended questions and one open-ended question was administered through Survey Monkey to students at PCOM-NY. RESULTS: The survey was sent to 420 Masters students and 176 (41.9%) responded. Students in all four years of the Masters degree indicated a generally high degree of interest in, and support for the value of research. However, increasing years (one to four years) in the program was associated with lower interest in post-graduation research participation and entering the doctoral program, and the fourth year students reported low levels of interest in having greater research content and training in their Masters degree programs. Students who responded to the open-ended question (23% of respondents) expressed enthusiasm for research and concerns about the relevance of research in Chinese medicine. CONCLUSIONS: Consistent with findings in similar studies at CAM colleges, interest in research, and EBM of the PCOM-NY Masters students appeared to decline with increasing years in the program. Concerns around paradigm and epistemological issues associated with research and EBM among Chinese medicine students and practitioners warrants further investigation, and may be an important challenge for integrative medicine. PMID- 27473311 TI - Beneficial Effect of Mindfulness-Based Art Therapy in Patients with Breast Cancer A Randomized Controlled Trial. AB - BACKGROUND: Mindfulness-based art therapy (MBAT) induces emotional relaxation in cancer patients and is a treatment known to improve psychological stability. The objective of this research was to evaluate the treatment effects of MBAT for breast cancer patients. METHODS: Overall, 24 breast cancer patients were selected as subjects of the study. Two groups, the MBAT group and control group with 12 patients each, were randomly assigned. The patients in the MBAT group were given 12 sessions of treatments. To measure depression and anxiety, low scales of the personality assessment inventory (PAI) was used. Health-related quality of life was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTCQLQ-C30). The treatment results were analyzed using analysis of covariance (ANCOVA) and two-way repeated measures analysis of variance (ANOVA). RESULTS: The results showed that depression and anxiety decreased significantly and health-related quality of life improved significantly in the MBAT group. In the control group, however, there was no significant change. CONCLUSIONS: MBAT can be seen as an effective treatment method that improves breast cancer patients' psychological stability and quality of life. Evaluation of treatment effects using program development and large scale research for future clinical application is needed. PMID- 27473312 TI - Osteopathic Manipulative Therapy for Preterm Infants, Acupuncture for Menopausal Symptoms, Mindfulness-Based Stress Reduction for Chronic Low Back Pain, Chocolate for Ischemic Heart Disease, Berberine for Irritable Bowel Syndrome. PMID- 27473313 TI - Killed surgeon at Berlin hospital had treated patient who shot him. PMID- 27473314 TI - The Evolution of the FT/TFL1 Genes in Amaranthaceae and Their Expression Patterns in the Course of Vegetative Growth and Flowering in Chenopodium rubrum. AB - The FT/TFL1 gene family controls important aspects of plant development: MFT-like genes affect germination, TFL1-like genes act as floral inhibitors, and FT-like genes are floral activators. Gene duplications produced paralogs with modified functions required by the specific lifestyles of various angiosperm species. We constructed the transcriptome of the weedy annual plant Chenopodium rubrum and used it for the comprehensive search for the FT/TFL1 genes. We analyzed their phylogenetic relationships across Amaranthaceae and all angiosperms. We discovered a very ancient phylogenetic clade of FT genes represented by the CrFTL3 gene of C. rubrum Another paralog CrFTL2 showed an unusual structural rearrangement which might have contributed to the functional shift. We examined the transcription patterns of the FT/TFL1 genes during the vegetative growth and floral transition in C. rubrum to get clues about their possible functions. All the genes except for the constitutively expressed CrFTL2 gene, and the CrFTL3 gene, which was transcribed only in seeds, exhibited organ-specific expression influenced by the specific light regime. The CrFTL1 gene was confirmed as a single floral activator from the FT/TFL1 family in C. rubrum Its floral promoting activity may be counteracted by CrTFL1 C. rubrum emerges as an easily manipulated model for the study of floral induction in weedy fast-cycling plants lacking a juvenile phase. PMID- 27473315 TI - Aspergillus fumigatus MADS-Box Transcription Factor rlmA Is Required for Regulation of the Cell Wall Integrity and Virulence. AB - The Cell Wall Integrity (CWI) pathway is the primary signaling cascade that controls the de novo synthesis of the fungal cell wall, and in Saccharomyces cerevisiae this event is highly dependent on the RLM1 transcription factor. Here, we investigated the function of RlmA in the fungal pathogen Aspergillus fumigatus We show that the DeltarlmA strain exhibits an altered cell wall organization in addition to defects related to vegetative growth and tolerance to cell wall perturbing agents. A genetic analysis indicated that rlmA is positioned downstream of the pkcA and mpkA genes in the CWI pathway. As a consequence, rlmA loss-of-function leads to the altered expression of genes encoding cell wall related proteins. RlmA positively regulates the phosphorylation of MpkA and is induced at both protein and transcriptional levels during cell wall stress. The rlmA was also involved in tolerance to oxidative damage and transcriptional regulation of genes related to oxidative stress adaptation. Moreover, the DeltarlmA strain had attenuated virulence in a neutropenic murine model of invasive pulmonary aspergillosis. Our results suggest that RlmA functions as a transcription factor in the A. fumigatus CWI pathway, acting downstream of PkcA MpkA signaling and contributing to the virulence of this fungus. PMID- 27473317 TI - Knee arthrodesis with a long intramedullary nail as limb salvage for complex periprosthetic infections. AB - BACKGROUND: Periprosthetic infection following total knee arthroplasty is a devastating complication, which is not always satisfactorily resolved by revision surgery. Arthrodesis is a salvage alternative to above-knee amputation or permanent resection arthroplasty. Fixation options include internal compression plating, external fixation, and intramedullary nails. METHODS: We retrospectively reviewed twelve consecutive cases (9 males, 3 females; mean age, 67 years) of knee arthrodesis with a long intramedullary nail, performed at a single institution between 2003 and 2014. Desired outcomes were the ability to mobilize without pain, solid radiographic fusion, and the eradication of infection. RESULTS: Mean follow-up was 48.5 months (range, 9-120 months). Eleven patients (92 %) demonstrated stable fusion, ten patients (83 %) were ambulatory without pain, and ten patients (83 %) remained without infection at most recent follow up. Eight patients (67 %) achieved union at an average of 12 months; three required repeat procedures, achieving union at an average of 9 months. There was a significant difference (P < 0.01) between the numbers of previous operations amongst the eight patients who initially achieved union (mean, 3.25) and three who subsequently required repeat procedures (mean, 8.33). CONCLUSIONS: In contrast to similar studies, we performed a single-stage exchange where possible, while comparable ambulatory and fusion rates were observed. Numerous previous attempts at revision arthroplasty, co-morbidities, and infections with highly resistant organisms have been associated with further complications. Although technically challenging, knee arthrodesis with a long intramedullary nail offers an acceptable limb salvage procedure for carefully selected patients with complex periprosthetic infections. PMID- 27473318 TI - Modulatory Effects of the Ipsi and Contralateral Ventral Premotor Cortex (PMv) on the Primary Motor Cortex (M1) Outputs to Intrinsic Hand and Forearm Muscles in Cebus apella. AB - The ventral premotor cortex (PMv) is a key node in the neural network involved in grasping. One way PMv can carry out this function is by modulating the outputs of the primary motor cortex (M1) to intrinsic hand and forearm muscles. As many PMv neurons discharge when grasping with either arm, both PMv within the same hemisphere (ipsilateral; iPMv) and in the opposite hemisphere (contralateral; cPMv) could modulate M1 outputs. Our objective was to compare modulatory effects of iPMv and cPMv on M1 outputs to intrinsic hand and forearm muscles. We used paired-pulse protocols with intracortical microstimulations in capuchin monkeys. A conditioning stimulus was applied in either iPMv or cPMv simultaneously or prior to a test stimulus in M1 and the effects quantified in electromyographic signals. Modulatory effects from iPMv were predominantly facilitatory, and facilitation was much more common and powerful on intrinsic hand than forearm muscles. In contrast, while the conditioning of cPMv could elicit facilitatory effects, in particular to intrinsic hand muscles, it was much more likely to inhibit M1 outputs. These data show that iPMv and cPMv have very different modulatory effects on the outputs of M1 to intrinsic hand and forearm muscles. PMID- 27473316 TI - Characterization of a Novel MMS-Sensitive Allele of Schizosaccharomyces pombe mcm4. AB - The minichromosome maintenance (MCM) complex is the conserved helicase motor of the eukaryotic replication fork. Mutations in the Mcm4 subunit are associated with replication stress and double strand breaks in multiple systems. In this work, we characterize a new temperature-sensitive allele of Schizosaccharomyces pombe mcm4+ Uniquely among known mcm4 alleles, this mutation causes sensitivity to the alkylation damaging agent methyl methanesulfonate (MMS). Even in the absence of treatment or temperature shift, mcm4-c106 cells show increased repair foci of RPA and Rad52, and require the damage checkpoint for viability, indicating genome stress. The mcm4-c106 mutant is synthetically lethal with mutations disrupting fork protection complex (FPC) proteins Swi1 and Swi3. Surprisingly, we found that the deletion of rif1+ suppressed the MMS-sensitive phenotype without affecting temperature sensitivity. Together, these data suggest that mcm4-c106 destabilizes replisome structure. PMID- 27473319 TI - Dissociable Fronto-Operculum-Insula Control Signals for Anticipation and Detection of Inhibitory Sensory Cue. AB - The ability to anticipate and detect behaviorally salient stimuli is important for virtually all adaptive behaviors, including inhibitory control that requires the withholding of prepotent responses when instructed by external cues. Although right fronto-operculum-insula (FOI), encompassing the anterior insular cortex (rAI) and inferior frontal cortex (rIFC), involvement in inhibitory control is well established, little is known about signaling mechanisms underlying their differential roles in detection and anticipation of salient inhibitory cues. Here we use 2 independent functional magnetic resonance imaging data sets to investigate dynamic causal interactions of the rAI and rIFC, with sensory cortex during detection and anticipation of inhibitory cues. Across 2 different experiments involving auditory and visual inhibitory cues, we demonstrate that primary sensory cortex has a stronger causal influence on rAI than on rIFC, suggesting a greater role for the rAI in detection of salient inhibitory cues. Crucially, a Bayesian prediction model of subjective trial-by-trial changes in inhibitory cue anticipation revealed that the strength of causal influences from rIFC to rAI increased significantly on trials in which participants had higher anticipation of inhibitory cues. Together, these results demonstrate the dissociable bottom-up and top-down roles of distinct FOI regions in detection and anticipation of behaviorally salient cues across multiple sensory modalities. PMID- 27473320 TI - Modulating Reward Induces Differential Neurocognitive Approaches to Sustained Attention. AB - Reward and motivation have powerful effects on cognition and brain activity, yet it remains unclear how they affect sustained cognitive performance. We have recently shown that a variety of motivators improve accuracy and reduce variability during sustained attention. In the current study, we investigate how neural activity in task-positive networks supports these sustained attention improvements. Participants performed the gradual-onset continuous performance task with alternating motivated (rewarded) and unmotivated (unrewarded) blocks. During motivated blocks, we observed increased sustained neural recruitment of task-positive regions, which interacted with fluctuations in task performance. Specifically, during motivated blocks, participants recruited these regions in preparation for upcoming targets, and this activation predicted accuracy. In contrast, during unmotivated blocks, no such advanced preparation was observed. Furthermore, during motivated blocks, participants had similar activation levels during both optimal (in-the-zone) and suboptimal (out-of-the-zone) epochs of performance. In contrast, during unmotivated blocks, task-positive regions were only engaged to a similar degree as motivated blocks during suboptimal (out-of the-zone) periods. These data support a framework in which motivated individuals act as "cognitive investors," engaging task-positive resources proactively and consistently during sustaining attention. When unmotivated, however, the same individuals act as "cognitive misers," engaging maximal task-positive resources only during periods of struggle. PMID- 27473321 TI - Synaptic Adhesion Molecules Regulate the Integration of New Granule Neurons in the Postnatal Mouse Hippocampus and their Impact on Spatial Memory. AB - Postnatal hippocampal neurogenesis induces network remodeling and may participate to mechanisms of learning. In turn, the maturation and survival of newborn neurons is regulated by their activity. Here, we tested the effect of a cell autonomous overexpression of synaptic adhesion molecules on the maturation and survival of neurons born postnatally and on hippocampal-dependent memory performances. Families of adhesion molecules are known to induce pre- and post synaptic assembly. Using viral targeting, we overexpressed three different synaptic adhesion molecules, SynCAM1, Neuroligin-1B and Neuroligin-2A in newborn neurons in the dentate gyrus of 7- to 9-week-old mice. We found that SynCAM1 increased the morphological maturation of dendritic spines and mossy fiber terminals while Neuroligin-1B increased spine density. In contrast, Neuroligin-2A increased both spine density and size as well as GABAergic innervation and resulted in a drastic increase of neuronal survival. Surprisingly, despite increased neurogenesis, mice overexpressing Neuroligin-2A in new neurons showed decreased memory performances in a Morris water maze task. These results indicate that the cell-autonomous overexpression of synaptic adhesion molecules can enhance different aspects of synapse formation on new neurons and increase their survival. Furthermore, they suggest that the mechanisms by which new neurons integrate in the postnatal hippocampus conditions their functional implication in learning and memory. PMID- 27473322 TI - A Hedonism Hub in the Human Brain. AB - Human values are abstract ideals that motivate behavior. The motivational nature of human values raises the possibility that they might be underpinned by brain structures that are particularly involved in motivated behavior and reward processing. We hypothesized that variation in subcortical hubs of the reward system and their main connecting pathway, the superolateral medial forebrain bundle (slMFB) is associated with individual value orientation. We conducted Pearson's correlation between the scores of 10 human values and the volumes of 14 subcortical structures and microstructural properties of the medial forebrain bundle in a sample of 87 participants, correcting for multiple comparisons (i.e.,190). We found a positive association between the value that people attach to hedonism and the volume of the left globus pallidus (GP).We then tested whether microstructural parameters (i.e., fractional anisotropy and myelin volume fraction) of the slMFB, which connects with the GP, are also associated to hedonism and found a significant, albeit in an uncorrected level, positive association between the myelin volume fraction within the left slMFB and hedonism scores. This is the first study to elucidate the relationship between the importance people attach to the human value of hedonism and structural variation in reward-related subcortical brain regions. PMID- 27473324 TI - fMRI-based Multivariate Pattern Analyses Reveal Imagery Modality and Imagery Content Specific Representations in Primary Somatosensory, Motor and Auditory Cortices. AB - Previous studies have shown that the early visual cortex contains content specific representations of stimuli during visual imagery, and that these representational patterns of imagery content have a perceptual basis. To date, there is little evidence for the presence of a similar organization in the auditory and tactile domains. Using fMRI-based multivariate pattern analyses we showed that primary somatosensory, auditory, motor, and visual cortices are discriminative for imagery of touch versus sound. In the somatosensory, motor and visual cortices the imagery modality discriminative patterns were similar to perception modality discriminative patterns, suggesting that top-down modulations in these regions rely on similar neural representations as bottom-up perceptual processes. Moreover, we found evidence for content-specific representations of the stimuli during auditory imagery in the primary somatosensory and primary motor cortices. Both the imagined emotions and the imagined identities of the auditory stimuli could be successfully classified in these regions. PMID- 27473323 TI - Retrosplenial Cortical Neurons Encode Navigational Cues, Trajectories and Reward Locations During Goal Directed Navigation. AB - The retrosplenial cortex (RSC) plays an important role in memory and spatial navigation. It shares functional similarities with the hippocampus, including the presence of place fields and lesion-induced impairments in spatial navigation, and the RSC is an important source of visual-spatial input to the hippocampus. Recently, the RSC has been the target of intense scrutiny among investigators of human memory and navigation. fMRI and lesion data suggest an RSC role in the ability to use landmarks to navigate to goal locations. However, no direct neurophysiological evidence of encoding navigational cues has been reported so the specific RSC contribution to spatial cognition has been uncertain. To examine this, we trained rats on a T-maze task in which the reward location was explicitly cued by a flashing light and we recorded RSC neurons as the rats learned. We found that RSC neurons rapidly encoded the light cue. Additionally, RSC neurons encoded the reward and its location, and they showed distinct firing patterns along the left and right trajectories to the goal. These responses may provide key information for goal-directed navigation, and the loss of these signals may underlie navigational impairments in subjects with RSC damage. PMID- 27473325 TI - Repression of phosphoglycerate dehydrogenase sensitizes triple-negative breast cancer to doxorubicin. AB - PURPOSE: Approximately 70 % of triple-negative breast cancer (TNBC) cell lines are identified to upregulate phosphoglycerate dehydrogenase (PHGDH), which regulates the intracellular synthesis of serine and glycine, and promotes tumor growth. In this work, the impact of this pathway on doxorubicin efficacy was evaluated. METHODS: MDA-MB-468, BT-20 and HCC70 cells were transfected with lentiviral vectors expressing short hairpin RNA (shRNA) against PHGDH. In response to doxorubicin treatment, cellular proliferation was measured, ROS were evaluated and intracellular levels of serine, glycine and glutathione (GSH) were determined using liquid chromatography-mass spectrometry. A TNBC orthotopic tumor model was used to examine the effect of PHGDH on doxorubicin efficacy in vivo. RESULTS: TNBC cells exposed to doxorubicin undergo metabolic remodeling, resulting in increased glucose flux for serine synthesis regulated by PHGDH. Serine is then converted into GSH, which counters doxorubicin-induced formation of ROS. Consequently, suppression of PHGDH by the use of the shRNA caused doxorubicin-induced oxidative stress and increased doxorubicin sensitivity. The enhancement of doxorubicin efficacy through simultaneous suppression of PHGDH was validated in a mouse tumor model. CONCLUSION: These results shed light on PHGDH that could be a promising target for increasing the effectiveness of chemotherapy in patients with TNBC. PMID- 27473326 TI - Impact of intra-operative cell salvage on blood coagulation in high-bleeding-risk patients undergoing cardiac surgery with cardiopulmonary bypass: a prospective randomized and controlled trial. AB - BACKGROUND: Intra-operative cell salvage (CS) was reported to have no impairment on blood coagulation in low-bleeding-risk cardiac surgery with cardiopulmonary bypass (CPB), but studies in high-bleeding-risk cardiac surgery are limited. The objective of this study is to evaluate the impact of CS on blood coagulation in high-bleeding-risk cardiac surgery with CPB. METHODS: One hundred and ten patients were randomly assigned to either with intra-operative CS group (Group CS) or without intra-operative CS group (Group C). Study endpoints included the incidence of impairment of blood coagulation during perioperative period (peri op) and the incidence of adverse events during postoperative period (post-op). Peri-op was defined as the period from beginning of anesthesia (anesthesia induction) to 24 h after end of surgery. Post-op was defined as the period from the end of surgery to 24 h after end of surgery. The types of impairment of blood coagulation included heparin residual, coagulopathy due to low PLT, coagulopathy due to low FIB, coagulopathy due to low coagulation factors, hyperfibrinolytic. The sum of above five types was total impairment of blood coagulation. Adverse events included excessive bleeding, resternotomy, etc. RESULTS: The incidence of heparin residual measured both at the end of surgery and during post-op were significantly higher in Group CS than in Group C (15.09 vs 4.00, 13.21 vs 2.00 %; p = 0.024, 0.010, respectively). Similarly, the incidence of total impairment of blood coagulation at the end of surgery and during post-op were significantly higher in Group CS than in Group C (32.08 vs 18.00, 26.42 vs 12.00 %; p = 0.043, 0.040, respectively). The incidence of excessive bleeding during post-op was 32.08 % in Group CS compared with 16.00 % in Group C (p = 0.038). Intriguingly, CS was associated with a significantly increase in the relative risk ratios for heparin residual and excessive bleeding (p = 0.034, 0.049, respectively). CONCLUSIONS: Intra-operative CS could impair blood coagulation in the scenario of high-risk-bleeding cardiac surgery with CPB. PMID- 27473327 TI - Balanced: a randomised trial examining the efficacy of two self-monitoring methods for an app-based multi-behaviour intervention to improve physical activity, sitting and sleep in adults. AB - BACKGROUND: Many adults are insufficiently physically active, have prolonged sedentary behaviour and report poor sleep. These behaviours can be improved by interventions that include education, goal setting, self-monitoring, and feedback strategies. Few interventions have explicitly targeted these behaviours simultaneously or examined the relative efficacy of different self-monitoring methods. METHODS/DESIGN: This study aims to compare the efficacy of two self monitoring methods in an app-based multi-behaviour intervention to improve objectively measured physical activity, sedentary, and sleep behaviours, in a 9 week 2-arm randomised trial. Participants will be adults (n = 64) who report being physically inactive, sitting >8 h/day and frequent insufficient sleep (>=14 days out of last 30). The "Balanced" intervention is delivered via a smartphone 'app', and includes education materials (guidelines, strategies to promote change in behaviour), goal setting, self-monitoring and feedback support. Participants will be randomly allocated to either a device-entered or user-entered self monitoring method. The device-entered group will be provided with a activity tracker to self-monitor behaviours. The user-entered group will recall and manually record behaviours. Assessments will be conducted at 0, 3, 6, and 9 weeks. Physical activity, sedentary behaviour and sleep-wake behaviours will be measured using the wrist worn Geneactiv accelerometer. Linear mixed models will be used to examine differences between groups and over time using an alpha of 0.01. DISCUSSION: This study will evaluate an app-based multi-behavioural intervention to improve physical activity, sedentary behaviour and sleep; and the relative efficacy of two different approaches to self-monitoring these behaviours. Outcomes will provide information to inform future interventions and self-monitoring targeting these behaviours. TRIAL REGISTRATION: ACTRN12615000182594 (Australian New Zealand Clinical Trials Registry. Registry URL: www.anzctr.org.au ; registered prospectively on 25 February 2015). PMID- 27473328 TI - Characterization of Staphylococcus aureus isolates from raw milk sources in Victoria, Australia. AB - BACKGROUND: Highly pathogenic strains of Staphylococcus aureus can cause disease in both humans and animals. In animal species, including ruminants, S. aureus may cause severe or sub-clinical mastitis. Dairy animals with mastitis frequently shed S. aureus into the milk supply which can lead to food poisoning in humans. The aim of this study was to use genotypic and immunological methods to characterize S. aureus isolates from milk-related samples collected from 7 dairy farms across Victoria. RESULTS: A total of 30 S. aureus isolates were collected from milk and milk filter samples from 3 bovine, 3 caprine and 1 ovine dairy farms across Victoria, Australia. Pulsed Field Gel Electrophoresis (PFGE) identified 11 distinct pulsotypes among isolates; all caprine and ovine isolates shared greater than 80 % similarity regardless of source. Conversely, bovine isolates showed higher diversity. Multi-Locus Sequence Typing (MLST) identified 5 different sequence types (STs) among bovine isolates, associated with human or ruminant lineages. All caprine and ovine isolates were ST133, or a single allele variant of ST133. Two new novel STs were identified among isolates in this study (ST3183 and ST3184). With the exception of these 2 new STs, eBURST analysis predicted all other STs to be founding members of their associated clonal complexes (CCs). Analysis of genetic markers revealed a diverse range of classical staphylococcal enterotoxins (SE) among isolates, with 11 different SEs identified among bovine isolates, compared with just 2 among caprine and ovine isolates. None of the isolates contained mecA, or were resistant to oxacillin. The only antibiotic resistance identified was that of a single isolate resistant to penicillin; this isolate also contained the penicillin resistance gene blaZ. Production of SE was observed at 16 degrees C and/or 37 degrees C in milk, however no SE production was detected at 12 degrees C. CONCLUSION: Although this study characterized a limited number of isolates, bovine-associated isolates showed higher genetic diversity than their caprine or ovine counterparts. This was also reflected in a more diverse SE repertoire among bovine isolates. Very little antibiotic resistance was identified among isolates in this study. These results suggest maintaining the milk cold chain will minimise any risk from SE production and highlights the need to prevent temperature abuse. PMID- 27473329 TI - Blocking sense-strand activity improves potency, safety and specificity of anti hepatitis B virus short hairpin RNA. AB - Hepatitis B virus (HBV) is a promising target for therapies based on RNA interference (RNAi) since it replicates via RNA transcripts that are vulnerable to RNAi silencing. Clinical translation of RNAi technology, however, requires improvements in potency, specificity and safety. To this end, we systematically compared different strategies to express anti-HBV short hairpin RNA (shRNA) in a pre-clinical immunocompetent hepatitis B mouse model. Using recombinant Adeno associated virus (AAV) 8 vectors for delivery, we either (i) embedded the shRNA in an artificial mi(cro)RNA under a liver-specific promoter; (ii) co-expressed Argonaute-2, a rate-limiting cellular factor whose saturation with excess RNAi triggers can be toxic; or (iii) co-delivered a decoy ("TuD") directed against the shRNA sense strand to curb off-target gene regulation. Remarkably, all three strategies minimised adverse side effects as compared to a conventional shRNA vector that caused weight loss, liver damage and dysregulation of > 100 hepatic genes. Importantly, the novel AAV8 vector co-expressing anti-HBV shRNA and TuD outperformed all other strategies regarding efficiency and persistence of HBV knock-down, thus showing substantial promise for clinical translation. PMID- 27473331 TI - An intravenous self-administration procedure for assessing the reinforcing effects of hallucinogens in nonhuman primates. AB - INTRODUCTION: Self-administration procedures are the gold standard for investigating the reinforcing effects of drugs. The notable exception to good correspondence between laboratory self-administration studies and human drug taking behavior has historically been the classic hallucinogens. METHOD: The present study used a well-established daily access procedure, followed by a novel intermittent access procedure, to investigate the reinforcing effects of LSD in baboons. RESULTS: Rates of self-injection in the daily access procedure were minimal. One baboon self-administered 0.001mg/kg and a second baboon self administered 0.0032mg/kg above vehicle levels, though rates of self-injection were clearly low and neither of the two remaining baboons self-administered any LSD dose tested in the daily access procedure. Rates of self-injection using an intermittent access procedure with discriminative stimuli resulted in two doses of LSD being self-administered above vehicle levels in two of three baboons tested (0.01 and 0.032mg/kg in one baboon; 0.0032 and 0.01mg/kg in a second). In addition, the number of self-injections at these doses was higher (range=3-6 injections) in the intermittent access procedure than in the daily access procedure (range=1-2 injections). DISCUSSION: The present study is the first to demonstrate LSD self-administration in a laboratory animal, and though the results are limited, they indicate intermittent access procedures with discriminative stimuli may provide a reliable and valid method for investigating the reinforcing effects of IV self-administered hallucinogens in laboratory animals. The usefulness of such procedures should be further evaluated in a larger number of subjects. PMID- 27473330 TI - Cross-shift study of exposure-response relationships between bioaerosol exposure and respiratory effects in the Norwegian grain and animal feed production industry. AB - OBJECTIVE: We have studied cross-shift respiratory responses of several individual bioaerosol components of the dust in the grain and feed industry in Norway. METHODS: Cross-shift changes in lung function and nasal congestion, as well as in respiratory and systemic symptoms of 56 exposed workers and 36 referents, were recorded on the same day as full-shift exposure to the inhalable aerosol fraction was assessed. Exposure-response associations were investigated by regression analysis. RESULTS: The workers were exposed on average to 1.0 mg/m(3) of grain dust, 440 EU/m(3) of endotoxin, 6 ug/m(3) of beta-1,3-glucans, 17*10(4)/m(3) of bacteria and 4*10(4)/m(3) of fungal spores during work. The exposure was associated with higher prevalence of self-reported eye and airway symptoms, which were related to the individual microbial components in a complex manner. Fatigue and nose symptoms were strongest associated with fungal spores, cough with or without phlegm was associated with grain dust and fungal spores equally strong and wheeze/tight chest/dyspnoea was strongest associated with grain dust. Bioaerosol exposure did not lead to cross-shift lung function decline, but several microbial components had influence on nose congestion. CONCLUSIONS: Exposure to fungal spores and dust showed stronger associations with respiratory symptoms and fatigue than endotoxin exposure. The associations with dust suggest that there are other components in dust than the ones studied that induce these effects. PMID- 27473332 TI - Prospective evaluation of five methods used to treat cesarean scar defects. AB - OBJECTIVE: To evaluate operative and nonoperative therapies for cesarean scar defects (CSDs). METHODS: A prospective study was conducted among patients who underwent treatment of CSDs at a hospital in Shanghai, China, between April 1, 2010, and December 31, 2014. Treatment included laparoscopy (group 1), vaginal surgery (group 2), hysteroscopy (group 3), combined oral contraceptives (group 4), and the levonorgestrel intrauterine system (group 5). RESULTS: Among 142 participants, 119 patients underwent surgical repair and 23 received nonsurgical (conservative) treatment. Operation time, blood loss, and length of hospital stay reported for patients in group 3 (n=19) were all lower than those reported for patients in group 1 (n=86) and group 2 (n=14; P<0.001 for all comparisons). Patients who underwent surgery and those in group 4 (n=18) experienced shortened menstrual periods after treatment (P<0.001 for all comparisons). For group 5 (n=5), the duration of menstruation was similar before and after therapy (P=0.89). All 32 women who desired fertility underwent laparoscopy; 12 (37.5%) became pregnant after this procedure. CONCLUSION: All treatments for CSDs other than the levonorgestrel intrauterine system shortened menstrual periods. Laparoscopic surgery was effective for patients with fertility requirements. PMID- 27473333 TI - Pitfalls in the diagnosis of tailgut cysts. PMID- 27473334 TI - Clinical, Sociobiological, and Cognitive Predictors of ADHD Persistence in Children Followed Prospectively Over Time. AB - With increasing awareness that ADHD is chronically disabling, a burgeoning literature has examined childhood clinical indicators of ADHD persistence. This study investigates whether childhood factors reflecting biological risk and cognitive reserve have additive predictive value for the persistence of ADHD that is unique beyond childhood indicators of disorder severity. One-hundred thirty children with ADHD (mean age = 8.9 years, 75 % male) were followed into adolescence (mean age = 14.0 years). Childhood ADHD and co-morbidities were assessed via interviews with parents and teachers; parental psychopathology was assessed via parent interview; exposure to neurobiological and psychosocial adversity were indexed by parent questionnaire; and cognitive reserve was evaluated through children's performance on measures of IQ and executive functioning. Univariate analyses identified childhood inattention and hyperactivity-impulsivity, co-morbid oppositional defiant disorder, overall impairment, and paternal anxiety and depression as more prevalent amongst adolescents with persistent compared with remitted ADHD. Only child-level predictors remained significant in a final multivariate model. These results suggest that children who are most likely to experience persistent ADHD have a more severe clinical presentation in childhood, reflected by increased levels of inattention, oppositional behavior, and impairment. They also are more likely to have fathers with internalizing concerns, but these concerns do not uniquely predict ADHD persistence beyond child-level factors. Contrary to expectations, childhood adversity and cognitive functioning did not predict the course of ADHD. PMID- 27473335 TI - beta-arrestin1 at the cross-road of endothelin-1 signaling in cancer. AB - The advent of targeted therapeutics in human cancer has begun to find novel druggable targets and, in this context, the endothelin-1 receptor (ET-1R), namely ETA receptor (ETAR) and ETB receptor, among the GPCR family represents a class of highly druggable molecules in cancer. ET-1R are aberrantly expressed in human malignancies, potentially representing prognostic factors. Their activation by ligand stimulation initiate signaling cascades activating different downstream effectors, allowing precise control over multiple signaling pathways. ET-1R regulates cell proliferation, survival, motility, cytoskeletal changes, angiogenesis, metastasis as well as drug resistance. The molecular events underlying these responses are the activation of transcriptional factors and coactivators, and downstream genes, acting as key players in tumor growth and progression. ET-1R represent crucial cancer targets that have been exploited for ET-1R therapeutics. Importantly, efforts to explore new information of ETAR in cancer have uncovered that their functions are crucially regulated by multifunctional scaffold protein beta-arrestins (beta-arrs) which orchestrate the multidimensionality of ETAR signaling into highly regulated and distinct signaling complexes, a property that is highly advantageous for tumor signaling. Moreover, the role of beta-arr1 in ET-1 signaling in cancer highlights why the pleiotropic effects of ET-1 and its dynamic signaling are more complex than previously recognized. In order to improve therapeutic strategies that interfere with the widespread effects of ET-1R, it is important to consider antagonists able to turn the receptors "off" selectively controlling beta-arr1-dependent signaling, highlighting the possibility that targeting ETAR/beta-arr1 may display a large therapeutic window in cancer. PMID- 27473336 TI - How do researchers determine the difference to be detected in superiority trials? Results of a survey from a panel of researchers. AB - BACKGROUND: There is currently no guidance for selecting a specific difference to be detected in a superiority trial. We explored 3 factors that in our opinion should influence the difference to be detected (type of outcome, patient age group, and presence of treatment side-effects), and 3 that should not (baseline level of risk, logistical difficulties, and cost of treatment). METHODS: We conducted an experimental survey using a factorial design among 380 corresponding authors of randomized controlled trials indexed in Medline. Two hypothetical vignettes were submitted to participants: one described a trial of a new analgesic in mild trauma injuries, the other described a trial of a new chemotherapy among cancer patients. The first vignette tested the baseline level of risk, patient age-group, patient recruitment difficulties, and treatment side effects. The second tested the baseline level of risk, patient age-group, type of outcome, and cost of treatment. The respondents were asked to select the smallest gain of effectiveness that should be detected by the trial. RESULTS: In vignette 1, respondents selected a median difference to be detected corresponding to an improvement of 7.0 % in pain control with the new treatment. In vignette 2, they selected a median difference to be detected corresponding to a reduction of 5.0 % in mortality or cancer recurrence with the new chemotherapy. In both vignettes, the difference to be detected decreased significantly with the baseline risk. The other factor influencing difference to be detected was the age group, but the impact of this factor was smaller. Cost, side-effects, outcome severity, or mention of logistical difficulties did not significantly impact the difference to be detected selected by participants. CONCLUSIONS: Three of the anticipated effects conformed to our expectations (the effect of patient age, and absence of effect of the cost of treatment and of patient recruitment difficulties) and the other three did not. These findings can guide future research in determining differences to be detected in trials that can translate to meaningful clinical decision-making. PMID- 27473337 TI - Can the Direct Peptide Reactivity Assay Be Used for the Identification of Respiratory Sensitization Potential of Chemicals? AB - Prospective identification of low molecular weight respiratory sensitizers is difficult due to the current lack of adequate test methods. The direct peptide reactivity assay (DPRA) seems to be a promising method to determine the sensitization potential of chemicals because it determines the intrinsic characteristic of sensitizers to bind to proteins. It is already applied in the field of skin sensitization, and adaptation to respiratory sensitization has started recently. This article further evaluates the ability of the DPRA to predict the respiratory sensitization potential of chemicals. In addition, the added value of applying High Performance Liquid Chromatography (HPLC)-MS and measurements after 20 minutes and 24 hours of incubation was evaluated. Eighteen respiratory sensitizers (10 haptens, 3 prehaptens, and 5 prohaptens) and 14 nonsensitizers were tested with 2-model peptides. Based on peptide depletion, a prediction model was proposed for the identification of (respiratory) sensitizers. Application of mass spectrometry and measurements at 2 time-points increased prediction accuracy of the assay by resolving discordant results. The prediction model correctly identified all haptens and prehaptens as sensitizers. The 5 prohaptens were not identified as sensitizers, most likely due to lack of metabolic activity in the DPRA. All but 1 nonsensitizer was correctly predicted. The model, therefore, shows an accuracy of 78% for the tested dataset. Unfortunately, this assay cannot be used to distinguish respiratory from skin sensitizers. To make this distinction, the DPRA needs to be combined with other test methods that are able to identify respiratory sensitizers. PMID- 27473338 TI - The Influence of Human Interindividual Variability on the Low-Dose Region of Dose Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells. AB - The influence of interindividual variability is not typically assessed in traditional toxicological studies. Given that chemical exposures occur in heterogeneous populations, this knowledge gap has the potential to cause undue harm within the realms of public health and industrial and municipal finances. A recent report from the National Research Council (NRC) suggests that when accounting for interindividual variation in responses, traditionally assumed nonlinear dose-response relationships (DRRs) for noncancer-causing endpoints would better be explained with a linear relationship within the low-dose region. To address this knowledge gap and directly test the NRC's assumption, this study focused on assessing the DRR between 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) exposure and immune suppression in a cohort of unique human donors. Human B cells were isolated from 51 individual donors and treated with logarithmically increasing concentrations of TCDD (0-30 nM TCDD). Two endpoints sensitive to TCDD were assessed: (1) number of IgM-secreting B cells and (2) quantity of IgM secreted. The results show that TCDD significantly suppressed both the number of IgM-secreting B cells and the quantity of IgM secreted (P < .05). Statistical model comparisons indicate that the low-dose region of the two DRRs is best explained with a nonlinear relationship. Rather than assuming low-dose linearity for all noncancer-causing DRRs, our study suggests the need to consider the specific mode of action of toxicants and pharmaceuticals during risk-management decision making. PMID- 27473339 TI - From the Cover: Alterations in Optineurin Expression and Localization in Pre clinical Parkinson's Disease Models. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease that affects ~5 million people around the world. PD etiopathogenesis is poorly understood and curative or disease modifying treatments are not available. Mechanistic studies have identified numerous pathogenic pathways that overlap with many other neurodegenerative diseases. Mutations in the protein optineurin (OPTN) have recently been identified as causative factors for glaucoma and amyotrophic lateral sclerosis. OPTN has multiple recognized roles in neurons, notably in mediating autophagic flux, which has been found to be disrupted in most neurodegenerative diseases. OPTN(+ )aggregates have preliminarily been identified in cytoplasmic inclusions in numerous neurodegenerative diseases, however, whether OPTN has a role in PD pathogenesis has yet to be tested. Thus, we chose to test the hypothesis that OPTN expression and localization would be modulated in pre-clinical PD models. To test our hypothesis, we characterized midbrain OPTN expression in normal rats and in a rat rotenone PD model. For the first time, we show that OPTN is enriched in dopamine neurons in the midbrain, and its expression is modulated by rotenone treatment in vivo Here, animals were sampled at time-points both prior to overt neurodegeneration and after severe behavioral deficits, where a lesion to the nigrostriatal dopamine system is present. The effect and magnitude of OPTN expression changes are dependent on duration of treatment. Furthermore, OPTN colocalizes with LC3 (autophagic vesicle marker) and alpha-synuclein positive puncta in rotenone-treated animals, potentially indicating an important role in autophagy and PD pathogenesis. PMID- 27473340 TI - A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From an In Vitro Estrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to the In Vivo Uterotrophic Assay Using Oral Exposure. AB - In vitro estrogen receptor assays are valuable tools for identifying environmental samples and chemicals that display estrogenic activity. However, in vitro potency cannot necessarily be extrapolated to estimates of in vivo potency because in vitro assays are currently unable to fully account for absorption, distribution, metabolism, and excretion. To explore this issue, we calculated relative potency factors (RPF), using 17alpha-ethinyl estradiol (EE2) as the reference compound, for several chemicals and mixtures in the T47D-KBluc estrogen receptor transactivation assay. In vitro RPFs were used to predict rat oral uterotrophic assay responses for these chemicals and mixtures. EE2, 17beta estradiol (E2), benzyl-butyl phthalate (BBP), bisphenol-A (BPA), bisphenol-AF (BPAF), bisphenol-C (BPC), bisphenol-S (BPS), and methoxychlor (MET) were tested individually, while BPS + MET, BPAF + MET, and BPAF + BPC + BPS + EE2 + MET were tested as equipotent mixtures. In vivo ED50 values for BPA, BPAF, and BPC were accurately predicted using in vitro data; however, E2 was less potent than predicted, BBP was a false positive, and BPS and MET were 76.6 and 368.3-fold more active in vivo than predicted from the in vitro potency, respectively. Further, mixture ED50 values were more accurately predicted by the dose addition model using individual chemical in vivo uterotrophic data (0.7-1.5-fold difference from observed) than in vitro data (1.4-86.8-fold). Overall, these data illustrate the potential for both underestimating and overestimating in vivo potency from predictions made with in vitro data for compounds that undergo substantial disposition following oral administration. Accounting for aspects of toxicokinetics, notably metabolism, in in vitro models will be necessary for accurate in vitro-to-in vivo extrapolations. PMID- 27473341 TI - Erratum to: Worldwide Argus II implantation: recommendations to optimize patient outcomes. PMID- 27473342 TI - TGF-beta signaling regulates resistance to parasitic nematode infection in Drosophila melanogaster. AB - Over the past decade important advances have been made in the field of innate immunity; however, our appreciation of the signaling pathways and molecules that participate in host immune responses to parasitic nematode infections lags behind that of responses to microbial challenges. Here we have examined the regulation and immune activity of Transforming Growth Factor-beta (TGF-beta) signaling in the model host Drosophila melanogaster upon infection with the nematode parasites Heterorhabditis gerrardi and H. bacteriophora containing their mutualistic bacteria Photorhabdus. We have found that the genes encoding the Activin and Bone Morphogenic Protein (BMP) ligands Dawdle (Daw) and Decapentaplegic (Dpp) are transcriptionally induced in flies responding to infection with the nematode parasites, containing or lacking their associated bacteria. We also show that deficient Daw or Dpp regulates the survival of D. melanogaster adults to the pathogens, whereas inactivation of Daw reduces the persistence of the nematodes in the mutant flies. These findings demonstrate a novel role for the TGF-beta signaling pathways in the host anti-nematode immune response. Understanding the molecular mechanisms of host anti-nematode processes will potentially lead to the development of novel means for the efficient control of parasitic nematodes. PMID- 27473343 TI - Immune response of macrophages induced by Porphyromonas gingivalis requires HmuY protein. AB - The main etiologic agent and a key pathogen responsible for initiation and progression of chronic periodontitis is Porphyromonas gingivalis. We examined the role of P. gingivalis, with particular interest to HmuY protein, in expression of genes involved in Toll-like receptor (TLR)-induced signaling pathways using cell based infection model. U937 and THP-1 cells differentiated toward macrophages by PMA treatment responded to P. gingivalis-caused infection in slightly different gene expression pattern, mainly by higher expression of genes encoding NF-kappaB, TLR7, TLR2, TLR8, pro-inflammatory cytokines (IL-1beta, IL-6, TNFalpha), anti inflammatory cytokine (IL-10), and chemokines (CCL3L1, CCL4, CXCL10, CXCL11, PTX3). P. gingivalis lacking functional hmuY gene stimulates immune response of macrophages, albeit in a different manner as compared with the wild-type strain, mainly by lower expression of genes encoding NF-kappaB, IL-1beta, IL-10, CD80, PTX3, and CCL31L. The purified HmuY protein alone induced expression of genes encoding IL-6, IL-10, TNFalpha, CCL3L1, and CCL4. We conclude that macrophages respond to P. gingivalis infection mostly by TLR7-induced pathway(s). Moreover, P. gingivalis HmuY is one of important virulence factors, which allows P. gingivalis for in vivo growth in the heme-limited host environment, resulting in efficient immune response of macrophages. PMID- 27473344 TI - The function and evolution of male and female genitalia in Phyllophaga Harris scarab beetles (Coleoptera: Scarabaeidae). AB - Genitalia diversity in insects continues to fuel investigation of the function and evolution of these dynamic structures. Whereas most studies have focused on variation in male genitalia, an increasing number of studies on female genitalia have uncovered comparable diversity among females, but often at a much finer morphological scale. In this study, we analysed the function and evolution of male and female genitalia in Phyllophaga scarab beetles, a group in which both sexes exhibit genitalic diversity. To document the interaction between male and female structures during mating, we dissected flash-frozen mating pairs from three Phyllophaga species and investigated fine-scale morphology using SEM. We then reconstructed ancestral character states using a species tree inferred from mitochondrial and nuclear loci to elucidate and compare the evolutionary history of male and female genitalia. Our dissections revealed an interlocking mechanism of the female pubic process and male parameres that appears to improve the mechanical fit of the copulatory position. The comparative analyses, however, did not support coevolution of male and female structures and showed more erratic evolution of the female genitalia relative to males. By studying a group that exhibits obvious female genitalic diversity, we were able to demonstrate the relevance of female reproductive morphology in studies of male genital diversity. PMID- 27473345 TI - Two-year Optical Coherence Tomography Findings after Balloon-Only Treatment of Bioresorbable Scaffold Restenosis in a Calcified Coronary Lesion: A Case Report. AB - We report a case of a 65-year-old female patient treated with an everolimus eluting bioresorbable scaffold (BRS) after rotational atherectomy of a severely calcified lesion of the left anterior descending coronary artery. The implanted BRS restenosed 10 months after implantation and was treated with a scoring balloon followed by drug-eluting balloons with good immediate and long-term results. To the best of our knowledge, this is the first report of a balloon-only treatment of a restenosis occurring more than 6 months after BRS implantation; angiographic and optical coherence tomography images after treatment and at two year follow-up are presented. PMID- 27473347 TI - Environmental exposure to endocrine-disrupting chemicals and miscarriage. AB - Establishment of early pregnancy is the result of complex biochemical interactions between the decidua and blastocyst. Any alteration in this chemical dialogue has the potential to result in adverse pregnancy outcomes including miscarriage. Sporadic miscarriage is the most common complication of pregnancy and can be caused by multiple factors. While the most common cause of miscarriage is genetic abnormalities in the fetus, other contributing factors certainly can play a role in early loss. One such factor is environmental exposure, in particular to endocrine-disrupting chemicals, which has the potential to interfere with endogenous hormone action. These effects can be deleterious, especially in early pregnancy when the hormonal milieu surrounding implantation is in delicate balance. The purpose of this paper is to review the current evidence on the role of environmental toxins in reproduction. PMID- 27473346 TI - Is emotion recognition the only problem in ADHD? effects of pharmacotherapy on face and emotion recognition in children with ADHD. AB - The objectives of this study were to evaluate both face and emotion recognition, to detect differences among attention deficit and hyperactivity disorder (ADHD) subgroups, to identify effects of the gender and to assess the effects of methylphenidate and atomoxetine treatment on both face and emotion recognition in patients with ADHD. The study sample consisted of 41 male, 29 female patients, 8 15 years of age, who were diagnosed as having combined type ADHD (N = 26), hyperactive/impulsive type ADHD (N = 21) or inattentive type ADHD (N = 23) but had not previously used any medication for ADHD and 35 male, 25 female healthy individuals. Long-acting methylphenidate (OROS-MPH) was prescribed to 38 patients, whereas atomoxetine was prescribed to 32 patients. The reading the mind in the eyes test (RMET) and Benton face recognition test (BFRT) were applied to all participants before and after treatment. The patients with ADHD had a significantly lower number of correct answers in child and adolescent RMET and in BFRT than the healthy controls. Among the ADHD subtypes, the hyperactive/impulsive subtype had a lower number of correct answers in the RMET than the inattentive subtypes, and the hyperactive/impulsive subtype had a lower number of correct answers in short and long form of BFRT than the combined and inattentive subtypes. Male and female patients with ADHD did not differ significantly with respect to the number of correct answers on the RMET and BFRT. The patients showed significant improvement in RMET and BFRT after treatment with OROS-MPH or atomoxetine. Patients with ADHD have difficulties in face recognition as well as emotion recognition. Both OROS-MPH and atomoxetine affect emotion recognition. However, further studies on the face and emotion recognition are needed in ADHD. PMID- 27473348 TI - Validation of the American Society for Reproductive Medicine guidelines/recommendations in white European men presenting for couple's infertility. AB - OBJECTIVE: To retrospectively validate the American Society for Reproductive Medicine (ASRM) guidelines/recommendations concerning endocrine evaluation in a cohort of white European men presenting for couple's infertility. DESIGN: Retrospective study. SETTING: Academic reproductive medicine outpatient clinic. PATIENT(S): Cohort of 1,056 consecutive infertile men (noninterracial infertile couples). INTERVENTION(S): Testicular volume was assessed with a Prader orchidometer. Serum hormones were measured (8-10 a.m.) in all cases. Hypogonadism was defined as total T < 3 ng/mL, according to the Endocrine Society definition. Semen analysis values were assessed based on the 2010 World Health Organisation reference criteria. MAIN OUTCOME MEASURE(S): ASRM indications for endocrine assessment in infertile men (sperm concentration <10 million/mL, impaired sexual function, and other clinical findings suggesting a specific endocrinopathy) were used to predict hypogonadism in our cohort. Moreover, a clinically user-friendly three-item nomogram was developed to predict hypogonadism and was compared to the ASRM guidelines assessment. RESULT(S): Biochemical hypogonadism was diagnosed in 156 (14.8%) men. Overall, 669 (63.4%) patients would have necessitated total T assessment according to the ASRM criteria; of these, only 119 (17.8%) were actually hypogonadal according to the Endocrine Society classification criteria. Conversely, 37 (23.7%) out of 156 patients with biochemical hypogonadism would have been overlooked. The overall predictive accuracy, sensitivity, and specificity of the ASRM guidelines was 58%, 76%, and 39%, respectively. Our nomogram was not reliable enough to predict hypogonadism, despite demonstrating a significantly higher predictive accuracy (68%) than the ASRM guidelines. CONCLUSION(S): The current findings show that the ASRM guidelines/recommendations for male infertility workup may not be suitable for application in white European infertile men. PMID- 27473349 TI - Caution: counseling patients with diminished ovarian reserve and recurrent pregnancy loss about in vitro fertilization with preimplantation genetic screening. PMID- 27473351 TI - Public support in the United States for elective oocyte cryopreservation. AB - OBJECTIVE: To determine whether public support for oocyte cryopreservation (OC) exists and if support varies by demographic factors. DESIGN: Cross-sectional electronic survey. SETTING: Not applicable. PATIENT(S): A nationally representative sample based on age, sex, and race of 1,064 people in the United States recruited by the company SurveyMonkey. INTERVENTIONS(S): Completion of an online questionnaire. MAIN OUTCOME MEASURE(S): Supporters of OC for various indications were compared with participants who were neutral or in opposition by means of log binomial regression to calculate risk ratios. Statistical models were adjusted for demographic characteristics, including sex, race, age, income, sexual orientation, education, marital status, state political party affiliation, and history of being a parent. RESULT(S): OC for cancer patients was the indication most supported (89%), followed by delayed childbearing for career advancement (72%), current lack of a partner (63%), and insufficient funds for child rearing (58%). Despite considerable support for OC, only 37% agreed employers should fund egg freezing for employees. Older age was associated with lower support for all indications of OC. Younger age, single status, never being a parent, identifying as a sexual minority, and atheist/agnostic religion were associated with the survey taker personally considering OC. Compared with women, men demonstrated lower support for women undergoing OC for "lack of a male partner," and for future use of cryopreserved oocytes without being married. CONCLUSION(S): In a nationally representative sample, the majority of respondents support elective OC. The indication for OC was associated with significant differences in support. PMID- 27473350 TI - Androgen responses to adrenocorticotropic hormone infusion among individual women with polycystic ovary syndrome. AB - OBJECTIVE: To compare androgen responses during ACTH infusion among women with polycystic ovary syndrome (PCOS) and healthy women. DESIGN: Cross-sectional study. SETTING: Academic medical center. PATIENT(S): Women with PCOS (n = 13) and healthy controls (n = 15). INTERVENTION(S): Blood samples were obtained frequently during a 6-hour dose-response ACTH infusion. MAIN OUTCOME MEASURE(S): Comparison of basal and stimulated levels of 17alpha-hydroxyprogesterone (17 OHP), androgens, and cortisol (F) during ACTH infusion with those after hCG injection within individual subjects. RESULT(S): In women with PCOS increased 17 OHP, androstenedione (A), and DHEA responses during ACTH infusion were comparable to those observed in healthy controls. The magnitude of responses was highly variable among women with PCOS. Within individual women with PCOS adrenal responses to ACTH and ovarian responses to hCG were significantly correlated. Cortisol responses to ACTH were similar in women with PCOS and healthy controls. CONCLUSION(S): Within individual women with PCOS, enhanced androgen responses to ACTH are accompanied by comparable androgen responsiveness to hCG. These findings suggest that dysregulated steroidogenesis leading to hyperandrogenemia in this disorder is likely present in both adrenal and ovarian tissues. CLINICAL TRIAL REGISTRATION NUMBER: NCT00747617. PMID- 27473352 TI - Perceived importance of childbearing and attitudes toward assisted reproductive technology among Chinese lesbians in Hong Kong: implications for psychological well-being. AB - OBJECTIVE: To assess the perceived importance of childbearing and attitudes toward assisted reproductive technology (ART) among Chinese lesbians and the impact on their psychological well-being. DESIGN: Survey-based study using a 39 item questionnaire. SETTING: Not applicable. PATIENT(S): A total of 438 Chinese lesbians between the ages of 18 and 35 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Perceived importance of childbearing; attitudes toward ART; and levels of anxiety and depression. RESULT(S): Perceived importance of childbearing to Chinese lesbians was negatively associated with age (r = -0.23), relationship length (r = -0.18), and full-time employment (F = 4.29). Compared to heterosexual childless women, Chinese lesbians thought childbearing was significantly less important (3.30 vs. 6.00 on a 1-10 scale, t = 14.6). Most lesbian respondents (92%) supported legalizing same-sex couples' access to ART, although less than half (41%) wanted to use it themselves to have children. Among lesbians who thought childbearing was important to their parents or their partners, not wanting ART was associated with higher anxiety levels. CONCLUSION(S): This is the first quantitative study of childbearing attitudes of lesbians in Asia. The data suggest that Chinese lesbians in the study who perceived childbearing as important to their parents or to their partners but did not want to seek ART reported higher anxiety levels. This study helps raise health care professionals' awareness of Chinese lesbians' attitudes toward childbearing as well as calls for a better delivery system of fertility and mental health services to address the psychological burden of Chinese lesbians in relation to reproductive issues. PMID- 27473353 TI - Aromatase, microRNA, and inflammation: a complex relationship. PMID- 27473354 TI - Appendectomy, tonsillectomy, and conceptions. PMID- 27473355 TI - Evidence-based research for weight management of the obese woman around the time of conception is not as simple as you think! PMID- 27473356 TI - Cell phone microscope for semen analysis. PMID- 27473357 TI - Comparison of a new visual isothermal nucleic acid amplification test with PCR and skin snip analysis for diagnosis of onchocerciasis in humans. AB - Accurate, simple and affordable diagnostics are needed to detect Onchocerca volvulus infection in humans. A newly developed colorimetric loop-mediated isothermal amplification (LAMP) assay was compared to PCR and skin snip analysis for diagnosis of onchocerciasis. The robustness and simplicity of the assay indicates that it may be a useful field tool for surveillance in endemic countries. PMID- 27473358 TI - Protective effect of fermented Cyclopia intermedia against UVB-induced damage in HaCaT human keratinocytes. AB - BACKGROUND: The fermented leaves and stems of Cyclopia intermedia are used to brew honeybush tea, a herbal tea indigenous to South Africa. The aim of this study was to evaluate the protective effect of fermented honeybush extracts (FH ex) and scale-up fermented honeybush extracts (SFH ex) against ultraviolet B (UVB)-induced damage in HaCaT keratinocytes. To this end, we examined UVB-induced cell viability, antioxidant enzymes, and inflammatory mediators in HaCaT cells. METHODS: UVB significantly decreased HaCaT cell viability, whereas FH ex and SFH ex did not exhibit cytotoxic effects and increased the viability of the HaCaT cells. To further investigate the protective effects of FH ex on UVB-induced oxidative stress in HaCaT cells, the activities of superoxide dismutase (SOD), catalase (CAT), matrix metalloproteinases (MMPs), pro-inflammatory cytokines and skin barrier function in terms of involucrin, filaggrin, and loricrin were analyzed. RESULTS: UVB-induced treatment reduced the activity of antioxidant enzymes and skin barrier function, while FH ex or SFH ex increased their activity. These results suggest that FH ex exerted cytoprotective activity against UVB-induced oxidative stress in HaCaT cells through stimulation of antioxidant enzymes activities. Furthermore, FH ex and SFH ex suppressed the UVB induced expression of inflammatory mediators, such as IL-1beta, IL-6, and IL-8, at mRNA level together with down regulation of matrix metalloproteinase (MMPs). In addition, FH ex and SFH ex reversed the phosphorylation of mitogen-activated protein kinase (MAPK) induced by UVB-irradiation. Notably, FH ex and SFH ex markedly inhibited UVB-induced activation of ERK, p38, and JNK. Thus, this agent exhibits anti-oxidative and -inflammatory effects via lowering ROS production, suppressing p38, ERK, and JNK activation, and down-regulating expression of MMPs. CONCLUSIONS: These findings suggest that FH ex and SFH ex can be used as a skin anti-photoaging agent. PMID- 27473359 TI - Future expenditure risk of silent members: a statistical analysis. AB - BACKGROUND: Silent-members are members of a medical health plan who submit no claims for healthcare services in a benefit year despite 12 months of continuous enrollment. This study was conducted to evaluate the future expenditure risk of commercial-insured members who avoid all medical care despite coverage. In order to determine if the silent-members were at greater risk, we compared them to members who received care in the anchor year (2009) but had low-expenditures. The low-expenditure members were assumed to represent persons without significant medical conditions and without care-avoidance behaviors. We examined the claims experience of a cohort of silent members in the 2 years after the silent year (2009) and compared it with the corresponding claims experience for a cohort of low-expenditure members from the same anchor year (2009). METHODS: Members of commercial health plans (BCBS of Texas) were selected based on continuous enrollment in 2009. Two sub-groups were identified based on annual claims expenditure: Care avoiders were members with 12 months continuous-enrollment and no medical claims, and are thus referred to as "silent members" in the insurance industry. Low-Expenditure members were those with 12 months continuous-enrollment and total PMPY (per member per year) annual medical claims expenditure in the lowest 10th percentile of members with claims experience. "Low-expenditure" members served as a comparison group to the "silent members", under the assumption that such claimants were using benefits for minor healthcare issues as needed. Key variables were enrollment and expenditures. Enrollment data identified demographics and continuous-enrollment. Medical claims data were used to calculate utilization and expenditures. All claims data were de-identified and no consent was required, as approved by the Institutional Review Board. No research involved human subjects. Multivariate logistic regression models were applied. RESULTS: Silent members who seek care in subsequent years have a greater probability of becoming high-expenditure claimants than those with low expenditure experience. CONCLUSIONS: For silent members who subsequently seek treatment, the probability of becoming high-expenditure is significantly greater than low-expenditure members from the anchor year. The implications of future high costs for silent members who become claimants may support the need for additional research to address the risks of care avoidance behaviors. PMID- 27473360 TI - Lacinutrix cladophorae sp. nov., a flavobacterium isolated from the green alga Cladophora stimpsonii, transfer of Flavirhabdus iliipiscaria Shakeela et al. 2015 to the genus Lacinutrix as Lacinutrix iliipiscaria comb. nov. and emended description of the genus Lacinutrix. AB - A strictly aerobic, Gram-stain-negative, rod-shaped, motile by gliding and yellow pigmented bacterium, designated strain 7Alg 4T, was isolated from the green alga Cladophora stimpsonii. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the novel strain was affiliated to the family Flavobacteriaceae of the phylum Bacteroidetes, and was most closely related to the recognized species of the genera Lacinutrixand Flavirhabdus, with 16S rRNA gene sequence similarities of 95.1-98.1 and 97.0 %, respectively. Strain 7Alg 4T grew in the presence of 1-5 % NaCl and at 4-32 degrees C, and hydrolysed aesculin, gelatin, starch and Tween 80. The prevalent fatty acids were iso-C15 : 1 G, iso-C15 : 0, iso-C17 : 0 3-OH, iso-C15 : 0 3-OH and C15 : 0. The polar lipid profile was characterized by the presence of phosphatidylethanolamine, three unidentified aminolipids and four unidentified lipids. The major respiratory quinone was MK-6. The DNA G+C content was 31.9 mol%. On the basis of the differences in 16S rRNA gene sequences, chemotaxonomic and phenotypic characteristics, it is suggested that strain 7Alg 4T represents a novel species of the genus Lacinutrix, for which the name Lacinutrixcladophorae sp. nov. is proposed. The type strain is 7Alg 4T (=KCTC 23036T=KMM 6381T). Reclassification of Flavirhabdus iliipiscaria as Lacinutrix iliipiscaria comb. nov. and an emend of the genus Lacinutrix are also proposed. PMID- 27473362 TI - Re-born in the USA: Another cholera vaccine for travellers. PMID- 27473361 TI - Single-Anastomosis Pylorus-Preserving Bariatric Procedures: Review of the Literature. AB - Single-anastomosis pylorus-preserving procedures (SAPPP) were recently introduced into bariatric surgery in order to combine the physiologic advantages of a post pyloric reconstruction with the technical advantages of an omega loop. Surgery consists of a sleeve gastrectomy that is performed first, followed by a duodeno enterostomy. Two main variants exist: proximal and distal SAPPP, with duodeno jejunostomy and duodeno-ileostomy, respectively. This review describes the SAPPP reported in the literature and analyzes their outcomes in comparison with the most frequently performed bariatric techniques. Preliminary results appear as promising in terms of both safety and effectiveness on weight loss and comorbidities improvement. PMID- 27473363 TI - Regulation of bone and cartilage by adenosine signaling. AB - There is growing recognition that bone serves important endocrine and immunologic functions that are compromised in several disease states. While many factors are known to affect bone metabolism, recent attention has focused on investigating the role of purinergic signaling in bone formation and regulation. Adenosine is a purine nucleoside produced intracellularly and extracellularly in response to stimuli such as hypoxia and inflammation, which then interacts with P1 receptors. Numerous studies have suggested that these receptors play a pivotal role in osteoblast, osteoclast, and chondrocyte differentiation and function. This review discusses the various ways by which adenosine signaling contributes to bone and cartilage homeostasis, while incorporating potential therapeutic applications of these signaling pathways. PMID- 27473364 TI - Low serum transferrin correlates with acute-on-chronic organ failure and indicates short-term mortality in decompensated cirrhosis. AB - BACKGROUND & AIMS: Iron represents an essential, but potentially harmful micronutrient, whose regulation has been associated with poor outcome in liver disease. Its homeostasis is tightly linked to oxidative stress, bacterial infections and systemic inflammation. To study the prognostic short-term significance of iron parameters in a cohort study of patients with decompensation of cirrhosis at risk of acute-on-chronic liver failure (ACLF). METHODS: Ferritin, transferrin, iron, transferrin saturation (TSAT) and hepcidin were determined in sera from 292 German patients hospitalized for decompensation of cirrhosis with ascites, of which 78 (27%) had ACLF. Short-term mortality was prospectively assessed 30 and 90 days after inclusion. RESULTS: Transferrin concentrations were significantly lower, whereas ferritin and TSAT were higher in patients with ACLF compared to patients without ACLF (P<=.006). Transferrin, TSAT and ferritin differentially correlated with the severity of organ failure, active alcoholism and surrogates of systemic inflammation and macrophage activation. As compared with survivors, 30-day non-survivors displayed lower serum transferrin (P=.0003) and higher TSAT (P=.003), whereas 90-day non-survivors presented with higher ferritin (P=.03) and lower transferrin (P=.02). Lower transferrin (continuous or dichotomized at 87 mg/dL) and consecutively higher TSAT (continuous or dichotomized >41%) indicated increased mortality within 30 days and remained significant after adjustment for organ failure and inflammation in multivariate regression models and across subgroups of patients. CONCLUSION: Among the investigated indicators of iron metabolism, serum transferrin concentration was the best indicator of organ failure and an independent predictor of short-term mortality at 30 days. PMID- 27473366 TI - The role of circulating thrombospondin-1 in patients with precapillary pulmonary hypertension. AB - BACKGROUND: The vasoconstrictive protein TSP-1 is released from endothelial cells upon increased shear stress and hypoxia. Both conditions are prevalent in pulmonary hypertension (PH). TSP-1 damages the local microcirculation by disrupting pathways, which are essential for specific medical therapeutics. Furthermore, TSP-1 induces excessive fibrosis and smooth muscle proliferation - a common finding in advanced PH - via TGF-beta and might promote disease progression. The prognostic impact of circulating TSP-1, influence on hemodynamic parameters and interaction with other biomarkers in patients with PH is incompletely understood. This study examines prospectively circulating TSP-1 in association with hemodynamic parameters, clinical variables and mortality. METHODS: Circulating TSP-1 was measured prospectively in 93 patients with precapillary PH undergoing right heart catheterization and in 19 subjects without PH. TSP-1 levels were determined by ELISA and examined in the context of hemodynamic variables. For evaluation of survival, patients were monitored for adverse events on a 3-monthly basis and contacted at the end of the study after 5 years. In addition, levels of big-endothelin and humoral cofactors of TSP-1 release were measured. RESULTS: Patients with PH had significantly increased TSP 1 levels compared to controls without PH (1114 +/- 136 ng/mL vs. 82.1 +/- 15.8 ng/mL, p < 0.05). Levels were correlated with mean pulmonary artery pressure (PAPm, r = -0.58, p < 0.001) and pulmonary vascular resistance (PVR, r = 0.33, p = 0.002). Survivors had lower TSP-levels as non-survivors and all cause mortality associated with TSP-1 plasma levels above 2051 ng/mL (p = 0.0002, HR 1.49). CONCLUSIONS: High plasma levels of TSP-1 are associated with increased PAPm, increased PVR and decreased survival. Due to its interaction with therapeutic pathways, studies are warranted to clarify the impact of TSP-1 on of specific medications for PH. PMID- 27473365 TI - Enhancing effect of menthol on nicotine self-administration in rats. AB - RATIONALE: Tobacco smoking is a leading preventable cause of premature death in the USA. Menthol is a significant flavoring additive in tobacco products. Clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. However, it is unclear whether menthol enhances the reinforcing actions of nicotine and thus facilitates nicotine consumption. This study employed a rat model of nicotine self-administration to examine the effects of menthol on nicotine-taking behavior. METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to press a lever for intravenous nicotine self administration under a fixed-ratio 5 schedule of reinforcement. In separate groups, rats self-administered nicotine at four different doses (0.0075, 0.015, 0.03, and 0.06 mg/kg/infusion). Five minutes prior to the two test sessions, menthol (5 mg/kg) or its vehicle was administered intraperitoneally in all rats in a counterbalanced design within each group. In separate rats that self administered 0.015 mg/kg/infusion nicotine, menthol dose-response function was determined. Menthol was also tested on food self-administration. RESULTS: An inverted U-shaped nicotine dose-response curve was observed. Menthol pretreatment shifted the nicotine dose-response curve to the left. The facilitating effect of menthol on the self-administration of 0.015 mg/kg/infusion nicotine was dose dependent, whereas it produced similar effects at doses above the threshold of 2.5 mg/kg. Menthol tended to suppress the self-administration of food pellets. CONCLUSIONS: These data demonstrate that menthol enhances the reinforcing effects of nicotine, and the effect of menthol was specific to nicotine. The findings suggest that menthol directly facilitates nicotine consumption, thereby contributing to tobacco smoking. PMID- 27473367 TI - Evaluation of gantry speed on image quality and imaging dose for 4D cone-beam CT acquisition. AB - BACKGROUND: This study investigates the effect of gantry speed on 4DCBCT image quality and dose for the Varian On-Board Imager(r). METHODS: A thoracic 4DCBCT protocol was designed using a 125 kVp spectrum. Image quality parameters were evaluated for 4DCBCT acquisition using Catphan(r) phantom with real-time position managementTM system for gantry speeds varying between 1.0 to 6.0 degrees /s. Superior-inferior motion of the phantom was executed using a sinusoidal waveform with five second period. Scans were retrospectively sorted into 4 phases (CBCT-4 ph) and 10 phases (CBCT-10 ph); average 4DCBCT (CBCT-ave), using all image data from the 4DCBCT acquisitions was also evaluated. The 4DCBCT images were evaluated using the following image quality metrics: spatial resolution, contrast-to-noise ratio (CNR), and uniformity index (UI). Additionally, Hounsfield unit (HU) sensitivity compared to a baseline CBCT and percent differences and RMS errors (RMSE) of excursion were also determined. Imaging dose was evaluated using an IBA CC13 ion chamber placed within CIRS Thorax phantom using the same sinusoidal motion and image acquisition settings as mentioned above. RESULTS: Spatial resolution decreased linearly from 5.93 to 3.82 lp/cm as gantry speed increased from 1.0 to 6.0 degrees /s. CNR decreased linearly from 4.80 to 1.82 with gantry speed increasing from 1.0 to 6.0 degrees /s, respectively. No noteworthy variations in UI, HU sensitivity, or excursion metrics were observed with changes in gantry speed. Ion chamber dose rates measured ranged from 2.30 (lung) to 5.18 (bone) E-3 cGy/mAs. CONCLUSIONS: A quantitative analysis of the Varian OBI's 4DCBCT capabilities was explored. Changing gantry speed changes the number of projections used for reconstruction, affecting both image quality and imaging dose if x-ray tube current is held constant. From the results of this study, a gantry speed between 2 and 3 degrees /s was optimal when considering image quality, dose, and reconstruction time. The future of 4DCBCT clinical utility relies on further investigation of image acquisition and reconstruction optimization. PMID- 27473368 TI - The impact of early environmental interventions on structural plasticity of the axon initial segment in neocortex. AB - Plasticity of the axon initial segment (AIS) is a newly discovered type of structural plasticity that regulates cell excitability. AIS plasticity has been reported to happen during normal development of neocortex and also in a few pathological conditions involving disruption of the inhibition/excitation balance. Here we report on the impact of early environmental interventions on structural plasticity of AIS in the mouse neocortex. C57BL/6 mice were raised in standard or enriched environment (EE) from birth up to the time of experiments and were injected with saline or MK-801 [N-Methyl-D-Aspartate (NMDA) receptor antagonist, 1 mg/kg] on postnatal days (P) 6-10. We used Ankyrin G immunoreactivity to mark the AIS of cortical neurons in two sub-regions of frontal cortex (frontal association area, FrA and secondary motor cortex, M2) and in the secondary visual cortex (V2). In 1-month-old mice, the mean AIS length differed between three areas, with the shortest AISs being observed in V2. Postnatal MK-801 or EE led to shortening of AIS only in the frontal areas. However, exposure to EE restored AIS shortening induced by MK-801. Chronic postnatal MK-801 results in structural plasticity of AIS exclusive to the frontal cortex. EE may modify underlying neuronal mechanisms resulting in restoration of AIS length. PMID- 27473369 TI - Corrigendum to 'Validation and improvement of a proposed scoring system to detect retained common bile duct stones in gallstone pancreatitis': Surgery 2015;157:1073-9. PMID- 27473370 TI - Meaningful use and good catches: More appropriate metrics for checklist effectiveness. AB - BACKGROUND: The benefit of utilizing surgical safety checklists has been recently questioned. We evaluated our checklist performance after implementing a program that includes checklist-related good catches. METHODS: Multifaceted interventions aimed at the preincision checklist and 5 prospective audits were conducted from 2011-2015. We documented adherence to the checklist (verbalization of each checkpoint), fidelity (meaningful performance of each checkpoint), and good catches (events with the potential to cause the patient harm but that were prevented from occurring). Good catches were divided into quality improvement based categories (processes, medication, safety, communication, and equipment). RESULTS: A total of 1,346 checklist performances were observed (range, 144 373/yr). Adherence to the preincision checklist improved from 30% to 95% (P < .001), while adherence to the preinduction and debriefing checklists decreased (71% to 56%, P = .002) and remained unchanged (76%), respectively. Preincision fidelity decreased from 86% to 76% (P = .012). Good catches were identified during 16% of preincision checklist performances; process issues were most common (32%) followed by issues of medication administration (30%) and safety (22%). CONCLUSION: Implementation of a systematic checklist program resulted in significant and sustainable improvement in performance. Meaningful use and associated good catches may be more appropriate metric than actual patient harm for measuring checklist effectiveness. Although not previously described, checklist-related good catches represent an unknown benefit of checklists. PMID- 27473371 TI - Hepatitis C - Assessment to Treatment Trial (HepCATT) in primary care: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Public Health England (PHE) estimates that there are upwards of 160,000 individuals in England and Wales with chronic hepatitis C virus (HCV) infection, but until now only around 100,000 laboratory diagnoses have been reported to PHE and of these 28,000 have been treated. Targeted case-finding in primary care is estimated to be cost-effective; however, there has been no robust randomised controlled trial evidence available of specific interventions. Therefore, this study aims to develop and conduct a complex intervention within primary care and to evaluate this approach using a cluster randomised controlled trial. METHODS/DESIGN: A total of 46 general practices in South West England will be randomised in a 1:1 ratio to receive either a complex intervention comprising: educational training on HCV for the practice; poster and leaflet display in the practice waiting rooms to raise awareness and encourage opportunistic testing; a HCV risk prediction algorithm based on information on possible risk markers in the electronic patient record run using Audit + software (BMJ Informatica). The audit will then be used to recall and offer patients a HCV test. Control practices will follow usual care. The effectiveness of the intervention will be measured by comparing number and rates of HCV testing, the number and proportion of patients testing positive, onward referral, rates of specialist assessment and treatment in control and intervention practices. Intervention costs and health service utilisation will be recorded to estimate the NHS cost per new HCV diagnosis and new HCV patient initiating treatment. Longer-term cost effectiveness of the intervention in improving quality-adjusted life years (QALYs) will be extrapolated using a pre-existing dynamic health economic model. Patients' and health care workers' experiences and acceptability of the intervention will be explored through semi-structured qualitative interviews. DISCUSSION: This trial has the potential to make an important impact on patient care and will provide high-quality evidence to help general practitioners make important decisions on HCV testing and onward referral. If found to be effective and cost-effective the intervention is readily scalable and can be used to support the implementation of NICE recommendations on HCV case-finding. TRIAL REGISTRATION: ISRCTN61788850 . Registered on 24 April 2015; Protocol Version: 2.0, 22 May 2015. PMID- 27473372 TI - Association between axial length and horizontal and vertical globe diameters. AB - PURPOSE: To assess relationships between axial length and the horizontal and vertical globe diameters. MATERIAL AND METHODS: The study consisted of enucleated human eyes. The horizontal, vertical, and sagittal diameters were measured. RESULTS: The study included 135 globes removed because of malignant uveal melanoma (111 globes) or end-stage painful glaucoma (n = 24 eyes). Mean axial, horizontal, and vertical diameters were 24.6 +/- 2.6 mm (range: 20-35 mm), 23.7 +/- 1.4 mm (range: 21-29 mm) and 23.7 +/- 1.4 mm (range: 20-29 mm) respectively. The horizontal diameter and vertical diameter did not differ significantly (P = 0.92), while both were significantly (P < 0.001) shorter than the axial diameter. The horizontal diameter was significantly and linearly correlated with the vertical globe diameter (P < 0.001; regression line: vertical globe diameter = 0.84 * horizontal globe diameter + 3.69). The axial diameter was significantly (P < 0.001) associated with the horizontal diameter and vertical diameters in a bipartite manner. In eyes with an axial length <=24 mm, horizontal and vertical diameters increased by 0.44 and 0.51 mm, respectively, for each mm increase in axial diameter, while in eyes with an axial length >24 mm, the horizontal and vertical globe diameter increased by a lower amount of 0.19 and 0.21 mm, respectively, for each mm increase in axial diameter. CONCLUSIONS: Myopic enlargement of the globe beyond an axial length of 24 mm takes place predominantly in the sagittal axis, leading to a change in the globe form from a sphere to an elongated form. It fits with the notion that myopic elongation may occur by an elongation of the eye walls in regions close to the globe's equator. PMID- 27473373 TI - Body image mediates the depressive effects of weight gain in new mothers, particularly for women already obese: evidence from the Norwegian Mother and Child Cohort Study. AB - BACKGROUND: Multiple studies show that obesity and depression tend to cluster in women. An "appearance concern" pathway has been proposed as one basic explanation of why higher weights might lead to depression. The transition to motherhood is a life phase in which women's body image, weight, and depressive risk are in flux, with average weight increasing overall during this period. Examination of how these factors interact from pre- to post-pregnancy provides a means to test how body image plays a key role, as proposed, in causally shaping women's depressive risk. METHODS: Tracking 39,915 pregnant women in the Norwegian Mother and Child (MoBA) Cohort Study forward 36 months after their deliveries, we test the moderating and mediating effects of body image concerns on the emergence of new mothers' depressive symptoms by using a binary logistic regression model with a discrete-time event history approach and mediation analysis with bootstrapping. RESULTS: For women with high pre-pregnancy body mass index (BMI), weight gain heightens their depressive symptoms over time. Body image concerns mediate the association between weight gain and the development of depressive symptoms regardless of weight status. However, the mediation effect is more evident for women with higher pre-pregnancy BMI. Conversely, better body image is highly protective against the transition to mild or more severe depressive symptoms among new mothers, but only for women who were not classified as obese prior to their pregnancies. CONCLUSIONS: These findings support a role for body image concerns in the etiology of depressive symptoms during the transition to motherhood. The findings suggest body image interventions before or during pregnancy could help reduce risks of depression in the early postpartum period and well beyond. PMID- 27473374 TI - Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells - evidence for a role in hepatocellular carcinoma growth in vivo. AB - BACKGROUND: Previous studies have established that proteinase-activated receptor 2 (PAR2) promotes migration and invasion of hepatocellular carcinoma (HCC) cells, suggesting a role in HCC progression. Here, we assessed the impact of PAR2 in HCC stromal cells on HCC growth using LX-2 hepatic stellate cells (HSCs) and Hep3B cells as model. METHODS: PAR2 expression and function in LX-2 cells was analysed by RT-PCR, confocal immunofluorescence, electron microscopy, and [Ca(2+)]i measurements, respectively. The impact of LX-2-expressed PAR2 on tumour growth in vivo was monitored using HCC xenotransplantation experiments in SCID mice, in which HCC-like tumours were induced by coinjection of LX-2 cells and Hep3B cells. To characterise the effects of PAR2 activation in LX-2 cells, various signalling pathways were analysed by immunoblotting and proteome profiler arrays. RESULTS: Following verification of functional PAR2 expression in LX-2 cells, in vivo studies showed that these cells promoted tumour growth and angiogenesis of HCC xenografts in mice. These effects were significantly reduced when F2RL1 (encoding PAR2) was downregulated by RNA interference (RNAi). In vitro studies confirmed these results demonstrating RNAi mediated inhibition of PAR2 attenuated Smad2/3 activation in response to TGF-beta1 stimulation in LX-2 cells and blocked the pro mitotic effect of LX-2 derived conditioned medium on Hep3B cells. Furthermore, PAR2 stimulation with trypsin or a PAR2-selective activating peptide (PAR2-AP) led to activation of different intracellular signalling pathways, an increased secretion of pro-angiogenic and pro-mitotic factors and proteinases, and an enhanced migration rate across a collagen-coated membrane barrier. Silencing F2RL1 by RNAi or pharmacological inhibition of Src, hepatocyte growth factor receptor (Met), platelet-derived growth factor receptor (PDGFR), p42/p44 mitogen activated protein kinase (MAPK) or matrix-metalloproteinases (MMPs) blocked PAR2 AP-induced migration. CONCLUSION: PAR2 in HSCs plays a crucial role in promoting HCC growth presumably by mediating migration and secretion of pro-angiogenic and pro-mitotic factors. Therefore, PAR2 in stromal HSCs may have relevance as a therapeutic target of HCC. PMID- 27473375 TI - Intensive social cognitive treatment (can do treatment) with participation of support partners in persons with relapsing remitting multiple sclerosis: observation of improved self-efficacy, quality of life, anxiety and depression 1 year later. AB - BACKGROUND: In persons with multiple sclerosis (MS) self-efficacy positively affects health-related quality of life (HRQoL) and physical activity. In a previous study we observed that 6 months after an intensive 3-day social cognitive treatment (Can Do treatment) with the participation of support partners, self-efficacy and HRQoL had improved in persons with relapsing remitting MS (RRMS). Given the chronic nature of the disease, it is important to know whether these beneficial changes may last. METHODS: Can Do treatment was given to 60 persons with MS and their support partners. At baseline and 12 months after treatment self-efficacy control, self-efficacy function, physical and mental HRQoL, anxiety, depression and fatigue were assessed via self-report questionnaires. Differences were tested via a paired t test. RESULTS: Of the 57 persons with MS that completed the baseline assessment and the 3-day treatment, 38 filled in the 12th month questionnaires (response rate 66.7 %), 22 with RRMS and 14 with progressive MS. In the RR group self-efficacy control had increased by 20.2 % and physical HRQoL by 15.0 %, and depression and anxiety had decreased by 29.8 and 25.9 %, respectively (all P < 0.05); the changes in mental HRQoL (+17 %) and fatigue (-20 %) failed to be statistically significant (P = 0.087, P = 0.080, respectively). In the progressive group no changes suggestive of improvement were seen. CONCLUSIONS: The findings suggest that a 3-day intensive social cognitive treatment (Can Do treatment) with the participation of support partners may have long lasting beneficial effects on the self-efficacy and HRQoL in persons with RRMS; and that improvements in anxiety and depression, not seen in the 6-month study, may yet develop at 12 months. PMID- 27473377 TI - Attentional capture for tool images is driven by the head end of the tool, not the handle. AB - Tools afford specialized actions that are tied closely to object identity. Although there is mounting evidence that functional objects, such as tools, capture visuospatial attention relative to non-tool competitors, this leaves open the question of which part of a tool drives attentional capture. We used a modified version of the Posner cueing task to determine whether attention is oriented towards the head versus the handle of realistic images of common elongated tools. We compared cueing effects for tools with control stimuli that consisted of images of fruit and vegetables of comparable elongation to the tools. Critically, our displays controlled for lower-level influences on attention that can arise from global shape asymmetries in the image cues. Observers were faster to detect low-contrast targets positioned near the head end versus the handle of tools. As expected, no lateralized performance bias was observed for the control stimuli. In a follow-up experiment, we confirmed that the bias towards tool heads was not due to inhibition of return as a result of early attentional orienting towards tool handles. Finally, we confirmed that real world exemplars of the tools in the cueing studies were associated more strongly with specific grasping patterns than the elongated fruits and vegetables. Together, our results demonstrate that affordance effects on attentional capture are driven by the head end of a tool. Prioritizing the head end of a tool is adaptive because it ensures that the most relevant region of the object takes priority in selecting an effective motor plan. PMID- 27473376 TI - French patients on daily hemodialysis: clinical characteristics and treatment trajectories. AB - BACKGROUND: Increasing the weekly frequency of hemodialysis sessions has positive effects, on the control of several biological data of patients. However, knowledge about Daily HemoDialysis (DHD) practices is limited in France. The aim of the present study was to describe the characteristics and treatment trajectories of all French patients undergoing DHD. METHODS: All patients older than 18 years who started DHD between 2003 and 2012 in France were included and followed until December 31, 2013. The patients' demographic and clinical characteristics and treatment modalities were extracted from the French Renal Epidemiological and Information Network (REIN) registry. RESULTS: During the inclusion period, 753 patients started DHD in France. Based on their median age (64 years), patients were classified in two groups: "old" group (>=64 years) and "young" group (<64 years). Patients in the old group had more comorbidities than in the young group: 48 % had diabetes (vs 29 % in the young group), 17 % an active malignancy (vs 10 %) and 80 % >=1 cardiovascular disease (vs 41 %). Concerning patients' treatment trajectories, 496 (66 %) patients started with another dialysis before switching to DHD and 257 (34 %) directly with DHD. At the end of the follow-up, 69 % of patients in the old group were dead (27.4 % in the young group) and kidney transplantation was more frequent in the young group (30.4 % vs 0.5 %). CONCLUSION: In France, DHD is proposed not only to young in rather good clinical conditions and waiting for kidney transplantation, but also to old and frail patients with higher mortality. PMID- 27473378 TI - Curcumin confers protection to irradiated THP-1 cells while its nanoformulation sensitizes these cells via apoptosis induction. AB - Protection against ionizing radiation (IR) and sensitization of cancer cells to IR are apparently contrasting phenomena. However, curcumin takes on these contrasting roles leading to either protection or enhanced apoptosis in different irradiated cells. Here we studied whether pretreatment with free curcumin or a novel dendrosomal nanoformulation of curcumin (DNC) could exert protective/sensitizing effects on irradiated THP-1 leukemia cells. We employed assays including MTT viability, clonogenic survival, DNA fragmentation, PI/Annexin V flow cytometry, antioxidant system (ROS, TBARS for lipid peroxidation, 8-OHdG and gammaH2AX for DNA damage, glutathione, CAT and GPx activity, enzymes gene expression), ELISA (NF-kappaB and Nrf2 binding, TNF-alpha release), caspase assay, siRNA silencing of caspase-3, and western blotting to illustrate the observed protective role of curcumin in comparison with the opposite sensitizing role of its nanoformulation at a similar 10 MUM concentration. The in vivo relevance of this concentration was determined via intraperitoneal administration in mice. Curcumin significantly enhanced the antioxidant defense, while DNC induced apoptosis and reduced viability as well as survival of irradiated THP-1 cells. Nrf2 binding showed an early rise and fall in DNC-treated cells, despite a gradual increase in curcumin-treated cells. We also demonstrated that DNC induced apoptosis in THP-1 cells via caspase-3 activation; whereas in combination with radiation, DNC alternatively employed a caspase independent apoptosis pathway involving cytochrome c release from mitochondria. PMID- 27473381 TI - Erratum to: A year for JCCS editorial changes and CCN3 KO mice at ICCNS. PMID- 27473380 TI - Perineal injuries and birth positions among 2992 women with a low risk pregnancy who opted for a homebirth. AB - BACKGROUND: Whether certain birth positions are associated with perineal injuries and severe perineal trauma (SPT) is still unclear. The objective of this study was to describe the prevalence of perineal injuries of different severity in a low-risk population of women who planned to give birth at home and to compare the prevalence of perineal injuries, SPT and episiotomy in different birth positions in four Nordic countries. METHODS: A population-based prospective cohort study of planned home births in four Nordic countries. To assess medical outcomes a questionnaire completed after birth by the attending midwife was used. Descriptive statistics, bivariate analysis and logistic regression were used to analyze the data. RESULTS: Two thousand nine hundred ninety-two women with planned home births, who birthed spontaneously at home or after transfer to hospital, between 2008 and 2013 were included. The prevalence of SPT was 0.7 % and the prevalence of episiotomy was 1.0 %. There were differences between the countries regarding all maternal characteristics. No association between flexible sacrum positions and sutured perineal injuries was found (OR 1.02; 95 % CI 0.86 1.21) or SPT (OR 0.68; CI 95 % 0.26-1.79). Flexible sacrum positions were associated with fewer episiotomies (OR 0.20; CI 95 % 0.10-0.54). CONCLUSION: A low prevalence of SPT and episiotomy was found among women opting for a home birth in four Nordic countries. Women used a variety of birth positions and a majority gave birth in flexible sacrum positions. No associations were found between flexible sacrum positions and SPT. Flexible sacrum positions were associated with fewer episiotomies. PMID- 27473383 TI - Antimicrobial Agent Dosing in Infants. AB - PURPOSE: The goal of this article was to review infant physiology and its effects on the pharmacokinetic properties of antimicrobial agents. METHODS: A review of the drug development process was performed. A literature search was conducted on the pharmacokinetics of various antimicrobial agents in infants. FINDINGS: The pharmacokinetic properties of antimicrobial agents in infants are most often affected by the renal maturation of premature infants. Hepatic metabolism and volume of distribution play a common role as well. IMPLICATIONS: The dosing and dosing intervals of various medications were reviewed and compared with details of adult dosing. It is vital to continue to gather pharmacokinetic data in infants to ensure adequate safety and dosing of medications. PMID- 27473382 TI - Exosomes in carcinogenesis: molecular palkis carry signals for the regulation of cancer progression and metastasis. AB - Exosomes, which act as biological cargo vessels, are cell-released, phospholipid enclosed vesicles. In eukaryotic cells, exosomes carry and exchange biological materials or signals for the benefit or detriment to the cells. Thereby, we consider exosomes to be molecular Palkis (carriers). Although exosomes are currently one of the most popularly researched cellular entities, they have remained largely enigmatic and warrant continued investigation into their structure and functions. These membraned vesicles are between 30 and 150 nm in diameter and are actively secreted by all cell types. While initially considered cellular "trash bags," recent years have revealed exosomes to be dynamic and multi-functional vesicles that may play a crucial role in cancer development, progression and metastasis. Thereby, they have the potential to be used in development of therapeutic modalities for cancer and other diseases. As more research studies emerge, it's becoming evident that exosomes are released by cells with a purpose and are representatives of certain cell types and disease conditions. Hence, they may also be used as biomarkers for the detection of cancer initiation, progression and organotropic metastatic growth of cancer cells. This review will focus on the recent developments achieved in identifying the role of exosomes in cancer development and progression as well as therapeutic implications. The review will also discuss the pitfalls of methodologies used for the extraction of exosomes. PMID- 27473379 TI - Pathogen-induced secretory diarrhea and its prevention. AB - Secretory diarrhea is a historically known serious health implication around the world which primarily originates through pathogenic microorganisms rather than immunological or genetical disorders. This review highlights infective mechanisms of non-inflammatory secretory diarrhea causing pathogens, known therapeutics and their efficacy against them. These non-inflammatory diarrheal pathogens breach cell barriers, induce inflammation, disrupt fluid secretion across the epithelium by alteration in ion transport by faulting cystic fibrosis transmembrane conductance regulator (CFTR), calcium activated chloride channels and ion exchanger functions. Currently, a variety of prevention strategies have been used to treat these symptoms like use of antibacterial drugs, vaccines, fluid and nutritional therapy, probiotics and prebiotics as adjuncts. In progression of the need for a therapy having quick physiological effects, withdrawing the symptoms with a wide and safe therapeutic index, newer antisecretory agents like potent inhibitors, agonists and herbal remedies are some of the interventions which have come into light through greater understanding of the mechanisms and molecular targets involved in intestinal fluid secretion. Although these therapies have their own pros and cons inside the host, the quest for new antisecretory agents has been a successful elucidation to reduce burden of diarrheal disease. PMID- 27473384 TI - Pharmacokinetic and Pharmacodynamic Equivalence of Epoetin Hospira and Epogen After Single Subcutaneous Doses to Healthy Male Subjects. AB - PURPOSE: The purpose of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of single 100 U/kg subcutaneous doses of Epoetin Hospira and Epogen in healthy male subjects as part of an overall program to demonstrate biosimilarity of Epoetin Hospira to the reference product Epogen. METHODS: This single-center, open-label, randomized, 2-period, crossover study was conducted in 81 healthy male subjects. Subjects were randomized to Sequence 1, in which they received 100 U/kg of Epoetin Hospira or to sequence 2, in which they received 100 U/kg Epogen subcutaneously in the first study period and the alternative treatment in the second study period. Blood was collected for determination of baseline-adjusted epoetin concentrations (BAECs) for pharmacokinetics and for determination of reticulocyte percentage of total erythrocytes for pharmacodynamics throughout both study periods. The primary PK end points were the geometric mean ratios (GMRs) of the 2 treatments for AUC0-t and Cmax based on the BAEC, and the primary PD end points were the GMRs of the 2 treatments for AUC0-t and Cmax for reticulocyte percentage. FINDINGS: The GMRs of Epoetin Hospira to Epogen for the BAEC-derived PK parameters were 1.05 for AUC0-t with a 90% CI of 1.01 to 1.11, and 1.09 for Cmax with a 90% CI of 1.01 to 1.18, with both 90% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. The GMRs (Epoetin Hospira/Epogen) for the reticulocyte percentage-derived PD parameters were 1.01 for AUC0-t with a 95% CI of 0.98 to 1.05, and 1.02 for Cmax with a 95% CI of 0.98 to 1.06, with both 95% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. Overall, the adverse events were of similar frequency (11.7% and 13.9% for Epoetin Hospira and Epogen, respectively) and severity between treatments. One subject had a positive anti- recombinant human erythropoietin antibody result by radioimmunoprecipitation assay before dosing and throughout the conduct of the study with negative neutralizing antibodies and with no evidence of clinical deterioration or impact on the pharmacokinetics, pharmacodynamics, or safety. IMPLICATIONS: The results of this study established the PK and PD equivalence of single 100 U/kg subcutaneous doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen in healthy male subjects and support the overall demonstration of biosimilarity of Epoetin Hospira and Epogen. PMID- 27473385 TI - Non-cytotoxic Concentration of Cisplatin Decreases Neuroplasticity-Related Proteins and Neurite Outgrowth Without Affecting the Expression of NGF in PC12 Cells. AB - Cisplatin is the most effective and neurotoxic platinum chemotherapeutic agent. It induces a peripheral neuropathy characterized by distal axonal degeneration that might progress to degeneration of cell bodies and apoptosis. Most symptoms occur nearby distal axonal branches and axonal degeneration might induce peripheral neuropathy regardless neuronal apoptosis. The toxic mechanism of cisplatin has been mainly associated with DNA damage, but cisplatin might also affect neurite outgrowth. Nevertheless, the neurotoxic mechanism of cisplatin remains unclear. We investigated the early effects of cisplatin on axonal plasticity by using non-cytotoxic concentrations of cisplatin and PC12 cells as a model of neurite outgrowth and differentiation. PC12 cells express NGF-receptors (trkA) and respond to NGF by forming neurites, branches and synaptic vesicles. For comparison, we used a neuronal model (SH-SY5Y cells) that does not express trkA nor responds to NGF. Cisplatin did not change NGF expression in PC12 cells and decreased neurite outgrowth in both models, suggesting a NGF/trkA independent mechanism. It also reduced axonal growth (GAP-43) and synaptic (synapsin I and synaptophysin) proteins in PC12 cells, without inducing mitochondrial damage or apoptosis. Therefore, cisplatin might affect axonal plasticity before DNA damage, NGF/trkA down-regulation, mitochondrial damage or neuronal apoptosis. This is the first study to show that neuroplasticity-related proteins might be early targets of the neurotoxic action of cisplatin and their role on cisplatin-induced peripheral neuropathy should be investigated in vivo. PMID- 27473386 TI - Apigenin Reduces Proteasome Inhibition-Induced Neuronal Apoptosis by Suppressing the Cell Death Process. AB - Impairment of proteasomal function has been shown to be implicated in neuronal cell degeneration. The compounds which have antioxidant and anti-inflammatory abilities appear to provide a neuroprotective effect. Flavone apigenin is known to exhibits antioxidant and anti-inflammatory effects. Nevertheless, the effect of apigenin on the proteasome inhibition-induced neuronal apoptosis has not been studied. Therefore, we assessed the effect of apigenin on the proteasome inhibition-induced apoptotic neuronal cell death using differentiated PC12 cells and human neuroblastoma SH-SY5Y cells. Apigenin attenuated the proteasome inhibitors (MG132 and MG115)-induced decrease in the levels of Bid and Bcl-2, increase in the levels of Bax and p53, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9 and -3), cleavage of PARP-1 and cell death in both cell lines. Apigenin attenuated the production of reactive oxygen species, the depletion and oxidation of glutathione, the formations of malondialdehyde and carbonyls in cell lines treated with proteasome inhibitors. The results show that apigenin appears to attenuate the proteasome inhibitor-induced apoptosis in differentiated PC12 cells and SH-SY5Y cells by suppressing the activation of the mitochondrial pathway, and of the caspase-8- and Bid-dependent pathways. The inhibitory effect of apigenin on the proteasome inhibitor-induced apoptosis appears to be attributed to the suppressive effect on the production of reactive oxygen species, the depletion and oxidation of glutathione and the formations of malondialdehyde and carbonyls. PMID- 27473387 TI - Effectiveness of Interventions to Decrease Emergency Department Visits by Adult Frequent Users: A Systematic Review. AB - OBJECTIVES: Frequent emergency department (ED) users are high-risk and high resource-utilizing patients. This systematic review evaluates effectiveness of interventions targeting adult frequent ED users in reducing visit frequency and improving patient outcomes. METHODS: An a priori protocol was published in PROSPERO. Two independent reviewers screened, selected, rated quality, and extracted data. Third-party adjudication resolved disagreements. Rate ratios of post- versus pre-intervention ED visits were calculated. Data sources were from a comprehensive search that included seven databases and the gray literature. Eligibility criteria for selecting studies included experimental studies assessing the effect of interventions on frequent users' ED visits and patient oriented outcomes. RESULTS: A total of 6,865 citations were identified and 31 studies included. Designs were noncontrolled (n = 21) and controlled (n = 4) before-after studies and randomized controlled trials (n = 6). Frequent user definitions varied considerably and risk of bias was moderate to high. Studies examined general frequent users or those with psychiatric comorbidities, chronic disease, or low socioeconomic status or the elderly. Interventions included case management (n = 18), care plans (n = 8), diversion strategies (n = 3), printout case notes (n = 1), and social work visits (n = 1). Post- versus pre-intervention rate ratios were calculated for 25 studies and indicated a significant visit decrease in 21 (84%) of these studies. The median rate ratio was 0.63 (interquartile range = 0.41 to 0.71), indicating that the general effect of the interventions described was to decrease ED visits post-intervention. Significant visit decreases were found for a majority of studies in subgroup analyses based on 6- or 12-month follow-up, definition thresholds, clinical frequent user subgroups, and intervention types. Studies reporting homelessness found consistent improvements in stable housing. Overall, interstudy heterogeneity was high. CONCLUSIONS: Interventions targeting frequent ED users appear to decrease ED visits and may improve stable housing. Future research should examine cost effectiveness and adopt standardized definitions. PMID- 27473388 TI - Characterization of European Yersinia enterocolitica 1A strains using restriction fragment length polymorphism and multilocus sequence analysis. AB - Yersinia enterocolitica is currently divided into two subspecies: subsp. enterocolitica including highly pathogenic strains of biotype 1B and subsp. palearctica including nonpathogenic strains of biotype 1A and moderately pathogenic strains of biotypes 2-5. In this work, we characterized 162 Y. enterocolitica strains of biotype 1A and 50 strains of biotypes 2-4 isolated from human, animal and food samples by restriction fragment length polymorphism using the HindIII restriction enzyme. Phylogenetic relatedness of 20 representative Y. enterocolitica strains including 15 biotype 1A strains was further studied by the multilocus sequence analysis of four housekeeping genes (glnA, gyrB, recA and HSP60). In all the analyses, biotype 1A strains formed a separate genomic group, which differed from Y. enterocolitica subsp. enterocolitica and from the strains of biotypes 2-4 of Y. enterocolitica subsp. palearctica. Based on these results, biotype 1A strains considered nonpathogenic should not be included in subspecies palearctica containing pathogenic strains of biotypes 2-5. SIGNIFICANCE AND IMPACT OF THE STUDY: Yersinia enterocolitica strains are currently divided into six biotypes and two subspecies. Strains of biotype 1A, which are phenotypically and genotypically very heterogeneous, are classified as subspecies palearctica. In this study, European Y. enterocolitica 1A strains isolated from both human and nonhuman sources were characterized using restriction fragment length polymorphism and multilocus sequence analysis. The European biotype 1A strains formed a separate group, which differed from strains belonging to subspecies enterocolitica and palearctica. This may indicate that the current division between the two subspecies is not sufficient considering the strain diversity within Y. enterocolitica. PMID- 27473389 TI - Visual outcomes and late complications in paediatric orbital rhabdomyosarcoma. AB - BACKGROUND: Orbital rhabdomyosarcoma is a rare but important malignancy for an ophthalmologist. We aimed to review the management and outcome, including late orbital complications and visual acuity over 25 years from a specialist paediatric ophthalmology department. DESIGN: This was a retrospective longitudinal case series. PARTICIPANTS: All patients presenting to our institution between December 1989 and December 2014 with a histopathological diagnosis of rhabdomyosarcoma originating from (primary) or invading into the orbit (paranasal) were included. METHODS: The oncology and ophthalmology databases were cross referenced to identify patients. MAIN OUTCOME MEASURES: Baseline demographics, chemotherapy, surgical and radiation dose, visual acuity, ocular and systemic complications, local and distant recurrence and mortality were recorded for each patient. Outcomes were reported with descriptive statistics. RESULTS: Eighteen patients were included. Median age was 4.3 years (range 4 months to 16 years) with average follow-up of 9 years. The 5-year disease-specific survival was 100% for the orbital group and 25% for the paranasal group; 29% of the orbital group maintained vision better than 6/12 in their treated eye, and the overall globe conservation rate was 71%. The most common ocular complications were cataract and keratopathy in both the orbital and paranasal groups. Other ocular complications included orbital hypoplasia or fat atrophy, eyelid malposition and lacrimal duct stenosis. CONCLUSIONS: Ophthalmic late effects are seen in a significant proportion of patients with orbital rhabdomyosarcoma. There is excellent survival in these patients, and continued efforts should be made to reduce the late effects of therapy. PMID- 27473390 TI - Helium ventilation for treatment of post-cardiac arrest syndrome: A safety and feasibility study. AB - AIM: Besides supportive care, the only recommended treatment for comatose patients after cardiac arrest is target temperature management. Helium reduces ischaemic injury in animal models, and might ameliorate neurological injury in patients after cardiac arrest. As no studies exist on the use of helium in patients after cardiac arrest we investigated whether this is safe and feasible. METHODS: The study was an open-label single arm intervention study in a mixed-bed academic intensive care unit. We included 25 patients admitted after circulatory arrest, with a presenting rhythm of ventricular fibrillation or pulseless tachycardia, return of spontaneous circulation within 30min and who were treated with hypothermia. Helium was administrated in a 1:1 mix with oxygen for 3h. A safety committee reviewed all ventilation problems, complications and causes of mortality. RESULTS: Helium ventilation was started 4:59+/-0:52 (mean+/-SD)h after circulatory arrest. In one patient, helium ventilation was discontinued prematurely due to oxygenation problems. This was caused by pre-existing pulmonary oedema, and imposed limitations to PEEP and FiO2 by the study protocol, rather than the use of helium ventilation. Sixteen (64%) patients had a favourable neurological outcome. CONCLUSIONS: We found that helium ventilation is feasible and can be used safely in patients treated with hypothermia after cardiac arrest. No adverse events related to the use of helium occurred during the three hours of administration. PMID- 27473391 TI - TopoICSim: a new semantic similarity measure based on gene ontology. AB - BACKGROUND: The Gene Ontology (GO) is a dynamic, controlled vocabulary that describes the cellular function of genes and proteins according to tree major categories: biological process, molecular function and cellular component. It has become widely used in many bioinformatics applications for annotating genes and measuring their semantic similarity, rather than their sequence similarity. Generally speaking, semantic similarity measures involve the GO tree topology, information content of GO terms, or a combination of both. RESULTS: Here we present a new semantic similarity measure called TopoICSim (Topological Information Content Similarity) which uses information on the specific paths between GO terms based on the topology of the GO tree, and the distribution of information content along these paths. The TopoICSim algorithm was evaluated on two human benchmark datasets based on KEGG pathways and Pfam domains grouped as clans, using GO terms from either the biological process or molecular function. The performance of the TopoICSim measure compared favorably to five existing methods. Furthermore, the TopoICSim similarity was also tested on gene/protein sets defined by correlated gene expression, using three human datasets, and showed improved performance compared to two previously published similarity measures. Finally we used an online benchmarking resource which evaluates any similarity measure against a set of 11 similarity measures in three tests, using gene/protein sets based on sequence similarity, Pfam domains, and enzyme classifications. The results for TopoICSim showed improved performance relative to most of the measures included in the benchmarking, and in particular a very robust performance throughout the different tests. CONCLUSIONS: The TopoICSim similarity measure provides a competitive method with robust performance for quantification of semantic similarity between genes and proteins based on GO annotations. An R script for TopoICSim is available at http://bigr.medisin.ntnu.no/tools/TopoICSim.R . PMID- 27473392 TI - Extremely rare persistent primitive artery passing through the jugular foramen with symptomatic ipsilateral carotid artery stenosis. AB - Primitive arteries are persistent fetal anastomoses between the carotid and vertebral-basilar circulation. Although rare, persistent primitive arteries can remain at birth. A 73-year-old woman presented with cerebral infarction to the posterior circulation caused by symptomatic common carotid artery stenosis with an unnamed and extremely rare persistent primitive artery. This anomalous vessel branched from the extracranial internal carotid artery and passed through the ipsilateral jugular foramen into the posterior cranial fossa and merged into the basilar artery. To our knowledge, this is the first case of a persistent primitive artery passing through the jugular foramen with symptomatic common carotid artery stenosis. PMID- 27473393 TI - Visualization of the normal pituitary gland during the endoscopic endonasal removal of pituitary adenoma by narrow band imaging. AB - BACKGROUND: Narrow band imaging (NBI) is an endoscopic technology that enhances the visualization of the superficial and submucosal vasculature. The aim of the present study was to evaluate the feasibility of NBI in visualizing the normal pituitary gland during the endoscopic endonasal removal of pituitary adenoma. METHODS: A total of 25 patients with pituitary adenoma underwent endoscopic endonasal transsphenoidal surgery using a rigid endoscope with conventional imaging. The NBI of the surgical field was conducted under air and/or continuous irrigation of artificial cerebrospinal fluid using a flexible videoscope before and/or after the gross removal of the tumor. RESULTS: The capillaries of the normal pituitary gland had a characteristic appearance that could be confirmed in 16 cases. In contrast, the adenomas exhibited no characteristic vascular enhancement under NBI. The reasons why NBI failed to visualize the pituitary gland included the presence of a blood clot or a certain amount of tumor obscuring the normal pituitary gland and difficulty in steering the videoscope within the sella to approach the assumed site of the residual pituitary gland. CONCLUSIONS: NBI observation during the endoscopic endonasal removal of pituitary adenoma may be useful for visualizing the normal pituitary gland after the gross removal of the tumor. The absence of a typical vascular pattern suggests the presence of a residual tumor, which may justify further exploration in cases where gross total removal is considered necessary. PMID- 27473394 TI - Flexible endoscope-assisted evacuation of chronic subdural hematomas. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurosurgical condition with an increasing incidence. Standard treatment of CSDHs is surgical evacuation. The objective of this study is to present a modification of standard burr-hole hematoma evacuation using a flexible endoscope and to assess the advantages and risks. METHODS: Prospectively, 34 consecutive patients diagnosed with CSDH were included in the study. Epidemiological, clinical and radiographical data were collected and reviewed. All patients underwent a burr-hole evacuation of CSDH. A flexible endoscope was inserted and subdural space inspected during surgery. The surgeon was looking specifically for the presence of septations, draining catheter position and acute bleeding. RESULTS: Thirty-four patients underwent 37 endoscope-assisted surgeries. Presenting symptoms were hemiparesis (79%), decreased level of consciousness (18%), gait disturbances (15%), headache (12%), aphasia (6%), cognitive disturbances (6%) and epileptic seizure (3%). Average operative time was 43 min, and the average increase in operative time due to the use of the endoscope was 6 min. Recurrence rate was 8.8%, and clinical outcome was favorable (defined as mRS <= 2) in 97% of the cases. CONCLUSIONS: To our knowledge, the present cohort of 34 patients is the largest group of patients with CSDH treated using an endoscope. This technique allows decent visualization of the hematoma cavity while retaining the advantages of a minimally invasive approach under a local anesthesia. The main advantages are correct positioning of the catheter under visual control, identification of septations and early detection of cortex or vessel injury during surgery. PMID- 27473396 TI - [Not Available]. PMID- 27473395 TI - Hospitals and birth centers remain safest setting for giving birth, US obstetricians say. PMID- 27473397 TI - Intravitreal ranibizumab for diabetic macular oedema in previously vitrectomized eyes. AB - PURPOSE: There is little information about the efficacy of intravitreal vascular endothelial growth factor (VEGF) inhibition in vitrectomized eyes. This study aimed to evaluate the efficacy of anti-VEGF (ranibizumab) on diabetic macular oedema in previously vitrectomized eyes. METHODS: A nationwide retrospective review of medical records from 2010 to 2013. RESULTS: We identified 33 previously vitrectomized eyes in 28 patients treated with ranibizumab injections for diabetic macular oedema. Median follow-up was 323 days (interquartile range 72 1404 days). Baseline mean visual acuity was 0.57 logMAR (95% CI 0.13-1.01) before injections. After an average of 4.7 injections (range 1-15), mean visual acuity remained stable at 0.54 logMAR (95% CI 0.13-0.95) with a mean improvement of 0.03 (p = 0. 45, 95% CI -0.12 to 0.06). In 12 eyes (36%), visual acuity improved 0.1 logMAR or more, in 12 eyes (36%), vision was unchanged (gain or loss of 0-0.05 logMAR), and in nine eyes (27%), vision decreased 0.1 logMAR or more. Mean central foveal thickness (CFT) on optical coherence tomography (OCT) scan was 412 MUm (95% CI 390-434 MUm) before injections. After injections, the mean CFT decreased to 352 MUm (95% CI 334-370 MUm). The mean reduction in CFT was 14% (95% CI 4-24%, p = 0.01). Sixteen eyes (48.5%) became devoid of oedema on the last OCT scan. Despite the significant reduction in CFT, the visual acuity remained unchanged. CONCLUSION: Intravitreal ranibizumab can be effective in previously vitrectomized eyes with diabetic macular oedema. However, the response is variable and should be carefully monitored. PMID- 27473398 TI - Some aspects of sex ratio studies. PMID- 27473399 TI - Buffering deleterious polymorphisms in highly constrained parts of HIV-1 envelope by flexible regions. AB - BACKGROUND: Covariation is an essential process that leads to coevolution of parts of proteins and genomes. In organisms subject to strong selective pressure, coevolution is central to keep the balance between the opposite requirements of antigenic variation and retention of functionality. Being the viral component most exposed to the external environment, the HIV-1 glycoprotein gp120 constitutes the main target of the immune response. Accordingly its more external portions are characterised by extensive sequence heterogeneity fostering constant antigenic variation. RESULTS: We report that a single polymorphism, present at the level of the viral population in the conserved internal region C2, was sufficient to totally abolish Env functionality when introduced in an exogenous genetic context. The prominent defect of the non-functional protein is a block occurring after recognition of the co-receptor CCR5, likely due to an interference with the subsequent conformational changes that lead to membrane fusion. We also report that the presence of compensatory polymorphisms at the level of the external and hypervariable region V3 fully restored the functionality of the protein. The functional revertant presents different antigenic profiles and sensitivity to the entry inhibitor TAK 779. CONCLUSIONS: Our data suggest that variable regions, besides harbouring intrinsic extensive antigenic diversity, can also contribute to sequence diversification in more structurally constrained parts of the gp120 by buffering the deleterious effect of polymorphisms, further increasing the genetic flexibility of the protein and the antigenic repertoire of the viral population. PMID- 27473401 TI - Clinical trials for pediatric MS should be prioritized to test only one or two of the most promising agents - YES. PMID- 27473402 TI - Clinical trials for pediatric MS should be prioritized to test only one or two of the most promising agents - NO. PMID- 27473400 TI - Protocol of the impact of alternative social assistance disbursement on drug related harm (TASA) study: a randomized controlled trial to evaluate changes to payment timing and frequency among people who use illicit drugs. AB - BACKGROUND: Government social assistance payments seek to alleviate poverty and address survival needs, but their monthly disbursement may cue increases in illicit drug use. This cue may be magnified when assistance is disbursed simultaneously across the population. Synchronized payments have been linked to escalations in drug use and unintended but severe drug-related harms, including overdose, as well as spikes in demand for health, social, financial and police services. METHODS/DESIGN: The TASA study examines whether changing payment timing and frequency can mitigate drug-related harm associated with synchronized social assistance disbursement. The study is a parallel arm multi-group randomized controlled trial in which 273 participants are randomly allocated for six assistance cycles to a control or one of two intervention arms on a 1:1:1 basis. Intervention arm participants receive their payments: (1) monthly; or (2) semi monthly, in each case on days that are not during the week when cheques are normally issued. The study partners with a community-based credit union that has developed a system to vary social assistance payment timing. The primary outcome is a 40 % increase in drug use during the 3 days beginning with cheque issue day compared to other days of the month. Bi-weekly follow-up interviews collect participant information on this and secondary outcomes of interest, including drug-related harm (e.g. non-fatal overdose), exposure to violence and health service utilization. Self-reported data will be supplemented with participant information from health, financial, police and government administrative databases. A longitudinal, nested, qualitative parallel process evaluation explores participant experiences, and a cost-effectiveness evaluation of different disbursement scenarios will be undertaken. Outcomes will be compared between control and intervention arms to identify the impacts of alternative disbursement schedules on drug-related harm resulting from synchronized income assistance. DISCUSSION: This structural RCT benefits from strong community partnerships, highly detailed outcome measurement, robust methods of randomization and data triangulation with third party administrative databases. The study will provide evidence regarding the potential importance of social assistance program design as a lever to support population health outcomes and service provision for populations with a high prevalence of substance use. TRIAL REGISTRATION: NCT02457949 Registered 13 May 2015. PMID- 27473403 TI - Clinical trials for pediatric MS should be prioritized to test only one or two of the most promising agents - Commentary. PMID- 27473404 TI - C. elegans screening strategies to identify pro-longevity interventions. AB - Drugs screenings in search of enhancers or suppressors of selected readout(s) are nowadays mainly carried out in single cells systems. These approaches are however limited when searching for compounds with effects at the organismal level. To overcome this drawback the use of different model organisms to carry out modifier screenings has exponentially grown in the past decade. Unique characteristics such as easy manageability, low cost, fast reproductive cycle, short lifespan, simple anatomy and genetic amenability, make the nematode Caenorhabditis elegans especially suitable for this purpose. Here we briefly review the different high throughput and high-content screenings which exploited the nematode to identify new compounds extending healthy lifespan. In this context, we describe our recently developed screening strategy to search for pro-longevity interventions taking advantage of the very reproducible phenotypes observed in C. elegans upon different degrees of mitochondrial stress. Indeed, in Mitochondrial mutants, the processes induced to cope with mild mitochondrial alterations during development, and ultimately extending animal lifespan, lead to reduced size and induction of specific stress responses. Instead, upon strong mitochondrial dysfunction, worms arrest their development. Exploiting these automatically quantifiable phenotypic readouts, we developed a new screening approach using the Cellomics ArrayScanVTI HCS Reader and identified a new pro-longevity drug. PMID- 27473405 TI - Accountability for improving maternal and newborn health. AB - In 2010, the United Nations (UN) launched the Global Strategy for Women's and Children's Health to accelerate progress on maternal and child health. A UN Commission on Information and Accountability, established to ensure oversight and accountability on women's and children's health, outlined a framework with three processes: monitor, review, and act. This paper assesses progress on these processes. Effective monitoring depends on a functional civil registration and vital statistics system. Review requires counting all deaths and identifying contributing factors. The final, critical step is action to prevent similar deaths. Maternal death surveillance and response includes these steps and strengthens accountability. Strategies are underway to improve accountability for severe maternal morbidity and perinatal mortality. The post-2015 agenda adds greater focus on reducing inequalities, increasing availability of quality, disaggregated data, and accountability for human rights. This agenda requires engagement with communities and health providers - the foundation of accountability for women's and children's health. PMID- 27473406 TI - Posterior reperfusion T-waves: Wellens' syndrome of the posterior wall. AB - BACKGROUND: Reperfusion after coronary occlusion (myocardial infarction, MI), as in Wellens' syndrome, is often represented on ECG as T-wave inversion in the leads overlying the affected myocardial wall(s). As an extension of this logic, reperfusion of the posterior wall should manifest on right precordial leads (which are opposite the posterior wall) as enlarged T-waves. OBJECTIVE: We sought to determine whether T-wave amplitude (TWa) in leads V2 and V3 after reperfusion in posterior MI (PMI) is greater than in patients without PMI. METHODS: Review of ECGs from patients with ST elevation MI of the left circumflex or right coronary artery with post-procedure thrombolysis in MI (TIMI) flow >0 between 2007 and 2009. Blinded experts reviewed admission ECGs to determine the presence of PMI and measure TWa before and after reperfusion. Maximum TWa in V2 and V3 and the difference between maximum and admission V2 and V3 TWa were compared between those with and without PMI. RESULTS: Of 72 patients, 48 had PMI. Values expressed are medians and IQRs. Maximum TWa after reperfusion was greater in PMI than in non-PMI in V2 (5.00 mm (3.5 to 8.25) vs 3.9 mm (2.75 to 5.5), p=0.04), but not in V3 (4.0 mm (2 to 5.5) vs 3.0 mm (1.75 to 4), p=0.09). The increase in TWa in V2 and V3 after reperfusion was greater in PMI compared with non-PMI: (V2, 3.4 mm (2 to 5.25) vs 1.25 mm (-0.25 to 2), p=0.0005; V3, 2 mm (-0.5 to 3.25) vs 0.25 mm ( 1 to 1.75), p=0.03). CONCLUSIONS: Reperfusion of the posterior wall results in higher right precordial TWa, and an even greater increase in TWa, as measured in leads V2 and V3. This observation has important implications for emergency physicians to accurately identify recent posterior infarction in patients who may be symptom free on presentation but at risk of reocclusion. PMID- 27473407 TI - Competing Principles for Allocating Health Care Resources. AB - We clarify options for conceptualizing equity, or what we refer to as justice, in resource allocation. We do this by systematically differentiating, expounding, and then illustrating eight different substantive principles of justice. In doing this, we compare different meanings that can be attributed to "need" and "the capacity to benefit" (CTB). Our comparison is sharpened by two analytical tools. First, quantification helps to clarify the divergent consequences of allocations commended by competing principles. Second, a diagrammatic approach developed by economists Culyer and Wagstaff offers a visual and conceptual aid. Of the eight principles we illustrate, only two treat as relevant both a person's initial health state and a person's CTB per resource unit expended: (1) allocate resources so as to most closely equalize final health states and (2) allocate resources so as to equally restore health states to population norms. These allocative principles ought to be preferred to the alternatives if one deems relevant both a person's initial health state and a person's CTB per resource unit expended. Finally, we examine some possibilities for conceptualizing benefits as relative to how badly off someone is, extending Parfit's thought on Prioritarianism (a prioritizing of the worst off). Questions arise as to how much intervention effects accruing to the worse off count for more and how this changes with improving health. We explicate some recent efforts to answer these questions, including in Dutch and British government circles. These efforts can be viewed as efforts to operationalize need as an allocative principle. Each effort seeks to maximize in the aggregate quanta of effect that are differentially valued in favor of the worst off. In this respect, each effort constitutes one type of Prioritarianism, which Parfit failed to differentiate from other types. PMID- 27473408 TI - Personal Responsibility and Lifestyle Diseases. AB - What does it take for an individual to be personally responsible for behaviors that lead to increased risk of disease? We examine three approaches to responsibility that cover the most important aspects of the discussion of responsibility and spell out what it takes, according to each of them, to be responsible for behaviors leading to increased risk of disease. We show that only what we call the causal approach can adequately accommodate widely shared intuitions to the effect that certain causal influences-such as genetic make-up or certain social circumstances-diminish, or undermine personal responsibility. However, accepting the causal approach most likely makes personal responsibility impossible. We therefore need either to reject these widely shared intuitions about what counts as responsibility-softening or undermining or to accept that personal responsibility for behaviors leading to increased risk of disease rests on premises so shaky that personal responsibility is probably impossible. PMID- 27473409 TI - The Misfortunes of Moral Enhancement. AB - In Unfit for the Future, Ingmar Persson and Julian Savulescu present a sophisticated argument in defense of the imperative of moral enhancement. They claim that without moral enhancement, the future of humanity is seriously compromised. The possibility of ultimate harm, caused by a dreadful terrorist attack or by a final unpreventable escalation of the present environmental crisis aggravated by the availability of cognitive enhancement, makes moral enhancement a top priority. It may be considered optimistic to think that our present moral capabilities can be successfully improved by means of moral education, moral persuasion, and fear of punishment. So, without moral enhancement, drastic restrictions on human freedom would become the only alternative to prevent those dramatic potential outcomes. In this article, I will try to show that we still have reason to be less pessimistic and that Persson & Savulescu's arguments are fortunately unconvincing. PMID- 27473410 TI - Bioethics and Moral Agency: On Autonomy and Moral Responsibility. AB - Two clusters of essays in this issue of The Journal of Medicine and Philosophy provide a critical gaze through which to explore central moral, phenomenological, ontological, and political concerns regarding human moral agency and personal responsibility. The first cluster challenges common assumptions in bioethics regarding the voluntariness of human actions. The second set turns the debate towards morally responsible choice within the requirements of distributive justice. The force of their collective analysis leaves us with a well-founded basis critically to approach any account of bioethics or health policy that is insufficiently attentive to the central challenges of human freedom and responsible free choice. PMID- 27473411 TI - Gliomatosis peritonei: a series of eight cases and review of the literature. AB - BACKGROUND: Gliomatosis peritonei (GP) is a rare condition characterized by mature glial tissue implants widespread in the peritoneum. The GP is often associated with ovarian teratoma. However, little is known about the characteristics and prognosis of GP. The purpose of this study was to describe the features, treatment, and prognosis of GP. Additionally, we review previously reported cases of GP, summarizing the presently known data. METHODS: From January 2000 to January 2016, cases of ovarian teratoma and GP treated at Peking Union Medical College Hospital were reviewed. We assessed the pathology, treatments, and outcomes along with prognostic information. Additionally, the literature regarding this clinical condition was also reviewed. RESULTS: Eight patients met the inclusion criteria. Patients had a median age of 20 (range, 15-25) years. GP was diagnosed as the primary tumor in 6 patients and at a secondary surgery in two patients. The primary ovarian tumor consisted of immature teratoma (n = 7) and mature teratoma (n = 1). Grades of immature ovarian teratoma were 2, grade 1; 3, grade 2; and 2, grade 3. Tumors mean had a size of 20.4 (range, 11-30) cm. The median follow-up time was 60.5 (range, 3-144) months. All cases had conservative surgery and seven of them had macroscopic residual disease postoperatively. During the study period, the eight patients remained alive and asymptomatic. Three patients in the study experienced spontaneous pregnancy. After reviewing the existing literature, a total of 14 patients with nodal gliomatosis were present and 10 of them were alive. According to the literature review, five articles reported more than five cases. Of a total of 67 patients, 60 of them remained alive. CONCLUSION: The prognosis of immature ovarian teratoma with GP is favorable. Complete resection of GP is often difficult. Residual peritoneal disease in GP can be asymptomatic and quiescent over a long period. A more conservative surgical approach may be carried out in patients with massive peritoneal spread after the presence of metastatic immature elements is excluded. Owing to the risk of recurrence and malignant transformation of GP, a long-term follow-up is necessary for patients with residual peritoneal disease. PMID- 27473413 TI - Evaluating the influence of initial magnetization conditions on extracted exchange parameters in NMR relaxation experiments: applications to CPMG and CEST. AB - Transient excursions of native protein states to functionally relevant higher energy conformations often occur on the MUs-ms timescale. NMR spectroscopy has emerged as an important tool to probe such processes using techniques such as Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion and Chemical Exchange Saturation Transfer (CEST). The extraction of kinetic and structural parameters from these measurements is predicated upon mathematical modeling of the resulting relaxation profiles, which in turn relies on knowledge of the initial magnetization conditions at the start of the CPMG/CEST relaxation elements in these experiments. Most fitting programs simply assume initial magnetization conditions that are given by equilibrium populations, which may be incorrect in certain implementations of experiments. In this study we have quantified the systematic errors in extracted parameters that are generated from analyses of CPMG and CEST experiments using incorrect initial boundary conditions. We find that the errors in exchange rates (k ex ) and populations (p E ) are typically small (<10 %) and thus can be safely ignored in most cases. However, errors become larger and cannot be fully neglected (20-40 %) as k ex falls near the lower limit of each method or when short CPMG/CEST relaxation elements are used in these experiments. The source of the errors can be rationalized and their magnitude given by a simple functional form. Despite the fact that errors tend to be small, it is recommended that the correct boundary conditions be implemented in fitting programs so as to obtain as robust estimates of exchange parameters as possible. PMID- 27473412 TI - Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge. AB - Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC). Recent studies of MBC development and function after protein immunization have uncovered significant MBC heterogeneity. To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice. Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M(+) (IgM(+)) and IgG(+) MBC subsets and an unmutated IgD(+) MBC population. Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium specific IgM(+) MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge. IgM(+) MBCs also gave rise to T cell-dependent IgM(+) and IgG(+)B220(+)CD138(+) plasmablasts or T cell-independent B220(-)CD138(+) IgM(+) plasma cells. Thus, even in competition with IgG(+) MBCs, IgM(+) MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies. PMID- 27473414 TI - Behavioural health consultants in integrated primary care teams: a model for future care. AB - BACKGROUND: Significant challenges exist within primary care services in the United Kingdom (UK). These include meeting current demand, financial pressures, an aging population and an increase in multi-morbidity. Psychological services also struggle to meet waiting time targets and to ensure increased access to psychological therapies. Innovative ways of delivering effective primary care and psychological services are needed to improve health outcomes. In this article we argue that integrated care models that incorporate behavioural health care are part of the solution, which has seldom been argued in relation to UK primary care. Integrated care involves structural and systemic changes to the delivery of services, including the co-location of multi-disciplinary primary care teams. Evidence from models of integrated primary care in the United States of America (USA) and other higher-income countries suggest that embedding continuity of care and collaborative practice within integrated care teams can be effective in improving health outcomes. The Behavioural Health Consultant (BHC) role is integral to this, working psychologically to support the team to improve collaborative working, and supporting patients to make changes to improve their health across management of long-term conditions, prevention and mental wellbeing. Patients' needs for higher-intensity interventions to enable changes in behaviour and self-management are, therefore, more fully met within primary care. The role also increases accessibility of psychological services, delivers earlier interventions and reduces stigma, since psychological staff are seen as part of the core primary care service. Although the UK has trialled a range of approaches to integrated care, these fall short of the highest level of integration. A single short pilot of integrated care in the UK showed positive results. Larger pilots with robust evaluation, as well as research trials are required. There are clearly challenges in adopting such an approach, especially for staff who must adapt to working more collaboratively with each other and patients. Strong leadership is needed to assist in this, particularly to support organisations to adopt the shift in values and attitudes towards collaborative working. CONCLUSIONS: Integrated primary care services that embed behavioural health as part of a multi-disciplinary team may be part of the solution to significant modern day health challenges. However, developing this model is unlikely to be straight-forward given current primary care structures and ways of working. The discussion, developed in this article, adds to our understanding of what the BHC role might consist off and how integrated care may be supported by such behavioural health expertise. Further work is needed to develop this model in the UK, and to evaluate its impact on health outcomes and health care utilisation, and test robustly through research trials. PMID- 27473415 TI - Unique pathology of colonic spirochaetosis characterised by mucosal eosinophilia is linked to diarrhoea and IBS. PMID- 27473417 TI - Causality Assessment in Premarketing Drug Clinical Trials: Regulatory Evolution in the USA and Ongoing Concerns. AB - Since 1993, how to assess the causality of serious adverse events in premarketing drug clinical trials has undergone sustained regulatory evolution in the USA. In that year, an investigational drug study for chronic hepatitis B virus infection was emergently stopped after a patient suddenly exhibited hepatic failure and lactic acidosis, which later developed, along with pancreatitis and peripheral neuropathy, in several others after drug discontinuation. Five patients eventually died, including three despite emergency liver transplantation. The drug's multisystem toxicity was not predicted by preclinical animal studies, with grave injury to human mitochondria subsequently implicated. A concerned US Food and Drug Administration (FDA) created a task force whose findings would have a lasting impact on the agency's thinking. In 1994, the FDA proposed to amend its investigational new drug reporting requirements largely based on task force recommendations for ways to enhance the likelihood that sponsors and investigators would consider investigational agents as a possible cause of serious adverse events mimicking the underlying disease or concomitant drug toxicity. Then, in its 1997 final rule for expedited safety reporting requirements for drugs and biologics, the FDA advised sponsors that such reporting of serious, unexpected clinical trial cases would be expected when "there is a reasonable suspected causal relationship between the investigational product and the adverse event (i.e., the causal relationship cannot be ruled out)." This last clause was codified into the suspected adverse drug reaction definition in the FDA's 2003 safety reporting requirements for drugs and biologics proposed rule. The negatively received suspected adverse drug reaction and proposed causality standard were not adopted in the FDA's 2010 finalized investigational new drug safety reporting regulations, the agency stating that "'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event." However, such new requirements as aggregate analysis of specific events and expedited reporting of animal or in vitro data suggesting significant harm to humans, and subsequent guidance that sponsors develop "a systematic approach" to premarketing safety assessment, are among the components of the FDA's efforts to enhance determination of a "reasonable possibility" of causality. They are also philosophically consistent with the 1993 task force recommendations, and a reminder of the inherent hazards associated with the use of investigational drugs, particularly in the early stages of human study. PMID- 27473416 TI - A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency. PMID- 27473419 TI - Characterization of the Fluorescent Spectra and Intensity of Dabigatran and Dabigatran Etexilate: Application to HPLC Analysis with Fluorescent Detection. AB - There is considerable interest in dabigatran etexilate (Pradaxa) and its major metabolite, dabigatran, which has been shown to be an important inhibitor of thrombin and clotting. In this study, the fluorescent excitation and emission spectra of dabigatran and dabigatran etexilate were characterized. In addition, a ultra performance liquid chromatography (UPLC) and high performance liquid chromatography (HPLC) method using fluorescent detection was developed for the analysis of dabigatran. Dabigatran and dabigatran etexilate were found to have excitation and emission maxima of 310 and 375 nm and 335 and 400 nm, respectively. UPLC analysis of dabigatran standards and plasma dabigatran samples were analyzed on a reversed phase C-18 column with methanol-water (70:30, v/v) as the mobile phase. The lower limit of quantitation for dabigatran was 10.0 ng/mL for both the standards and plasma samples. Standard curves were linear from 10.0 to 1000.0 ng/mL (R2 = 0.995). Within-day coefficient of variations of the fluorometric method at 50.0, 100.0 and 500.0 ng/mL were 1.38%, 4.83% and 2.31%, respectively. The intense fluorescent properties of dabigatran permit the sensitive and specific UPLC or HPLC fluorescent analysis of dabigatran. PMID- 27473418 TI - Magnetic Solid Phase Extraction Based on Oleic Acid Coated Fe3O4 for the Determination of Benzo[alpha]pyrene in Cigarette Smoke Coupled with High Performance Liquid Chromatography. AB - In this work, a simple and effective method based on magnetic solid-phase extraction combined with high-performance liquid chromatography was developed for the determination of benzo[alpha]pyrene (BaP) in cigarette smoke. Oleic acid coated Fe3O4 (Fe3O4-OA) was synthesized and directly used as an efficient sorbent for the first time in magnetic solid-phase extraction (MSPE) procedure for the clean-up of BaP in cigarette smoke extracts. The synthesized Fe3O4-OA was characterized by transmission electron microscopy, X-ray diffraction and Fourier transformed infrared spectroscopy. The extraction via Fe3O4-OA was dispersed in the extracts of cigarette smoke followed by the magnetic isolation, acetonitrile tetrahydrofuran (ACN-THF; v/v = 9:1) was used for desorption of the analyte. The effects of important parameters such as the amount of adsorbent, solution pH, the content of acetonitrile, temperature and sorption time were investigated. The method showed good linearity for the determination of BaP in the concentration range of 0.5-50 ng mL-1 with a regression coefficient (R2) of 0.9987. The limit of detection and limit of quantification for BaP were obtained to be 0.12 and 0.41 ng mL-1, respectively. The mean recoveries were in the range from 81.0% to 97.6% at low, medium, high spiked levels, and the relative standard deviations were in the range of 2.7-6.8%. Combined with high-performance liquid chromatography and fluorescence detection, a simple and effective method was developed for the analysis of BaP in cigarette smoke. PMID- 27473420 TI - Formula PSORI-CM01 eliminates psoriasis by inhibiting the expression of keratinocyte cyclin B2. AB - BACKGROUND: Psoriasis is a chronically recurrent inflammatory skin disease, modern medicine could achieve good therapeutic effect, but these treatments led to recurrence of the psoriasis, more severe symptoms due to damaging skin barrier. Traditional Chinese medicine is a useful alternative therapies. The purpose of this study was to explore the mechanism of PSORI-CM01, a Chinese medicine formula for psoriasis therapy, in eliminating psoriasis by studying its effects on inhibiting epidermal hyperplasia. METHODS: Imiquimod induced psoriasis form mice model was used to determine the efficacy of PSORICM-01 by assessing the improvement of hyperplasia in epidermal and dermal skin, cyclin B2 expression in skin was detected by immunochemistry. Human keratinocyte cell line HaCaT stimulated by LPS or not was used to research molecular mechanisms of PSORIMCM-01 as in vitro model. The inhibition of proliferation of HaCaT was determined by MTT assay, BrdU assay and real-time cell analysis (RTCA). Cell cycle distribution was detected by flow cytometry. Real-Time PCR and western blot analysis was performed to quantify the mRNA and protein expression levels, respectively. The ability of PSORICM-01 to inhibit proliferation of cyclin B2 overexpressed HaCaT cell were also investigated. RESULTS: PSORI-CM01 significantly inhibited epidermal hyperplasia in IMQ mice lesion skin, and reduced expression of epidermis cyclin B2. Serum containing PSORI-CM01 dramatically inhibited keratinocyte HaCaT cell proliferation, no matter stimulated by LPS or not. FACS analysis showed ability of PSORICM-01 to arrest cell cycle in the G2/M phase. Additionally, PSORI-CM01 significant downregulated mRNA and protein expression of cyclin B2, and over expression of cyclin B2 antagonized the anti-proliferative effect of PSORI-CM01 on HaCaT cells. CONCLUSIONS: PSORI-CM01 inhibits epidermal hyperplasia in imiquimod-induced mouse psoriasis-form model and reduces keratinocyte proliferation in vitro. Our results indicate that PSORI-CM01 may possess therapeutic potential for psoriasis by inhibiting keratinocyte proliferation through downregulation of cyclin B2. PMID- 27473421 TI - Searching for best practices of youth friendly services - a study protocol using qualitative comparative analysis in Sweden. AB - BACKGROUND: Swedish youth clinics constitute one of the most comprehensive and consolidated examples of a nationwide network of health care services for young people. However, studies evaluating their 'youth-friendliness' and the combination of factors that makes them more or less 'youth-friendly' have not been conducted. This protocol will scrutinise the current youth-friendliness of youth clinics in northern Sweden and identify the best combination of conditions needed in order to implement the criteria of youth-friendliness within Swedish youth clinics and elsewhere. METHODS/DESIGN: In this study, we will use qualitative comparative analysis to analyse the conditions that are sufficient and/or necessary to implement Youth Friendly Health Services in 20 selected youth clinics (cases). In order to conduct Qualitative Comparative Analysis, we will first identify the outcomes and the conditions to be assessed. The overall outcome - youth-friendliness - will be assessed together with specific outcomes for each of the five domains - accessible, acceptable, equitable, appropriate and effective. This will be done using a questionnaire to be applied to a sample of young people coming to the youth clinics. In terms of conditions, we will first identify what might be the key conditions, to ensure the youth friendliness of health care services, through literature review, interviews with professionals working at youth clinics, and with young people. The combination of conditions and outcomes will form the hypothesis to be further tested later on in the qualitative comparative analysis of the 20 cases. Once information on outcomes and conditions is gathered from each of the 20 clinics, it will be analysed using Qualitative Comparative Analysis. DISCUSSION: The added value of this study in relation to the findings is twofold: on the one hand it will allow a thorough assessment of the youth-friendliness of northern Swedish youth clinics. On the other hand, it will extract lessons from one of the most consolidated examples of differentiated services for young people. Methodologically, this study can contribute to expanding the use of Qualitative Comparative Analysis in health systems research. PMID- 27473423 TI - Arvibacter flaviflagrans gen. nov., sp. nov., isolated from forest soil. AB - During a study of the bacterial community in forest soil of Kyonggi University, Suwon, South Korea, a glistening yellow-pigmented, Gram-stain-negative, aerobic, motile and rod-shaped bacterium, designated strain C-1-16T, was isolated. This strain was non-sporulating, catalase-negative and oxidase-positive. It was able to grow at 20-42 degrees C, at pH 6.0-9.0 and with 0-0.5 % (w/v) NaCl. This strain was taxonomically characterized by a polyphasic approach. Based on the results of 16S rRNA gene sequence analysis, strain C-1-16T formed a lineage within the family Chitinophagaceae of the phylum Bacteroidetes and closely related to the genera Filimonas(93.53 % sequence similarity), Sediminibacterium(92.52-90.75 %), Lacibacter(91.99-91.19 %) and Parasegetibacter(91.88-91.78 %). Flexirubin-type pigment was present for strain C 1-16T. The only respiratory quinone was menaquinone-7 (MK-7) and the major polar lipid was phosphatidylethanolamine. The predominant fatty acids of strain C-1-16T were iso-C15 : 0, iso-C17 : 0 3-OH, iso-C15 : 1 G, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) and C16 : 0. The genomic DNA G+C content of this novel strain was 45.5 mol%. On the basis of phenotypic, genotypic and phylogenetic analysis, strain C-1-16T represents a novel species of a new genus in the family Chitinophagaceae, for which the name Arvibacter flaviflagrans gen. nov., sp. nov. is proposed. The type strain of Arvibacter flaviflagrans is C-1 16T (=KEMB 900-374T=KACC 18717T=JCM 31293T). PMID- 27473422 TI - Microbial diversity in individuals and their household contacts following typical antibiotic courses. AB - BACKGROUND: Antibiotics are a mainstay of treatment for bacterial infections worldwide, yet the effects of typical antibiotic prescriptions on human indigenous microbiota have not been thoroughly evaluated. We examined the effects of the two most commonly prescribed antibiotics (amoxicillin and azithromycin) in the USA to discern whether short-term antibiotic courses may have prolonged effects on human microbiota. RESULTS: We sampled the feces, saliva, and skin specimens from a cohort of unrelated, cohabitating individuals over 6 months. An individual in each household was given an antibiotic, and the other a placebo to discern antibiotic impacts on microbiota, as well as determine whether antibiotic use might reshape the microbiota of each household. We observed household specific patterns of microbiota on each body surface, which persevered despite antibiotic perturbations. While the gut microbiota within an individual became more dissimilar over time, there was no evidence that the use of antibiotics accelerated this process when compared to household members. There was a significant change in microbiota diversity in the gut and mouth in response to antibiotics, but analogous patterns were not observed on the skin. Those who received 7 days of amoxicillin generally had greater reductions in diversity compared to those who received 3 days, in contrast to those who received azithromycin. CONCLUSIONS: As few as 3 days of treatment with the most commonly prescribed antibiotics can result in sustained reductions in microbiota diversity, which could have implications for the maintenance of human health and resilience to disease. PMID- 27473424 TI - "One-way-street" streamlined admission of critically ill trauma patients reduces emergency department length of stay. AB - Emergency department (ED) overcrowding remains a significant problem in many hospitals, and results in multiple negative effects on patient care outcomes and operational metrics. We sought to test whether implementing a quality improvement project could decrease ED LOS for trauma patients requiring an ICU admission from the ED, specifically by directly admitting critically ill trauma patients from the ED CT scanner to an ICU bed. This was a retrospective study comparing patients during the intervention period (2013-2014) to historical controls (2011 2013). Critically ill trauma patients requiring a CT scan, but not the operating room (OR) or Interventional Radiology (IR), were directly admitted from the CT scanner to the ICU, termed the "One-way street (OWS)". Controls from the 2011 2013 Trauma Registry were matched 1:1 based on the following criteria: Injury Severity Score; mechanism of injury; and age. Only patients who required emergent trauma consult were included. Our primary outcome was ED LOS, defined in minutes. Our secondary outcomes were ICU LOS, hospital LOS and mortality. Paired t test or Wilcoxon signed rank test were used for continuous univariate analysis and Chi square for categorical variables. Logistic regression and linear regressions were used for categorical and continuous multivariable analysis, respectively. 110 patients were enrolled in this study, with 55 in the OWS group and 55 matched controls. Matched controls had lower APACHE II score (12 vs. 15, p = 0.03) and a higher GCS (14 vs. 6, p = 0.04). ED LOS was 229 min shorter in the OWS group (82 vs. 311 min, p < 0.0001). The time between CT performed and ICU disposition decreased by 230 min in the OWS arm (30 vs. 300 min, p < 0.001). There was no difference in ED arrival to CT time between groups. Following multivariable analysis, mortality was primarily predicted by the APACHE II score (OR 1.29, p < 0.001), and not ISS, mechanism of injury, or age. After controlling for APACHE II score, there was no difference in mortality between the two cohorts (OR = 0.49, p = 0.28). Expedited admission of critically ill trauma patients immediately following CT imaging significantly reduced ED LOS by 3.82 h (229 min), without a change in ICU LOS, hospital LOS, or mortality. Further studies are needed to assess the impact of expedited admission on morbidity and mortality. PMID- 27473426 TI - Synthesis and electrochemical detection of a thiazolyl-indole natural product isolated from the nosocomial pathogen Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen, capable of surviving in a broad range of natural environments and quickly acquiring resistance. It is associated with hospital-acquired infections, particularly in patients with compromised immunity, and is the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa is also of nosocomial importance on dairy farms and veterinary hospitals, where it is a key morbidity factor in bovine mastitis. P. aeruginosa uses a cell-cell communication system consisting of signalling molecules to coordinate bacterial secondary metabolites, biofilm formation, and virulence. Simple and sensitive methods for the detection of biomolecules as indicators of P. aeruginosa infection would be of great clinical importance. Here, we report the synthesis of the P. aeruginosa natural product, barakacin, which was recently isolated from the bovine ruminal strain ZIO. A simple and sensitive electrochemical method was used for barakacin detection using a boron-doped diamond (BDD) and glassy carbon (GC) electrodes, based on cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The influence of electrolyte pH on the peak potential and peak currents was also investigated. At pH 2.0, the peak current was linearly dependent on barakacin concentration (in the range used, 1-10 MUM), with correlation coefficients greater than 0.98 on both electrodes. The detection limit (S/N = 3) on the BDD electrode was 100-fold lower than that obtained on the GC electrode. The optimized method using the BDD electrode was extended to bovine (cow feces) and human (sputum of a CF patient) samples. Spiked barakacin was easily detected in these matrices at a limit of 0.5 and 0.05 MUM, respectively. Graphical abstract Electrochemical detection of barakacin. PMID- 27473425 TI - Lung ultrasound for monitoring cardiogenic pulmonary edema. AB - Several studies address the accuracy of lung ultrasound (LUS) in the diagnosis of cardiogenic pulmonary edema (CPE) evaluating the interstitial syndrome, which is characterized by multiple and diffuse vertical artifacts (B-lines), and correlates with extravascular lung water. We studied the potential role of LUS in monitoring CPE response to therapy, by evaluating the clearance of interstitial syndrome within the first 24 h after Emergency Department (ED) admission. LUS was performed at arrival (T0), after 3 (T3) and 24 (T24) hours. Eleven regions were evaluated in the antero-lateral chest; the B-lines burden was estimated in each region (0 = no B-lines, 1 = multiple B-lines, 2 = confluent B-lines/white lung) and a mean score (B-Score, range 0-2) was calculated. Patients received conventional CPE treatment. Blood chemistry, vital signs, blood gas analysis, diuresis at T0, T3, T24 were also recorded. A complete echocardiography was obtained during hospitalization. Forty-one patients were enrolled. Respiratory and hemodynamic parameters improved in all patients between T0 and T3 and between T3 and T24. Mean B-score significantly decreased at T3 (from 1.59 +/- 0.40 to 0.73 +/- 0.44, P < 0.001) and between T3 and T 24 (from 0.73 +/- 0.44 to 0.38 +/- 0.33, P < 0.001). B-score was higher in the lower pulmonary regions at any time. At final evaluation (T24) 75 % of apical and only 38 % of basal regions were cleared. LUS allows one to assess the clearance of interstitial syndrome and its distribution in the early hours of treatment of CPE, thus representing a possible tool to guide therapy titration. PMID- 27473427 TI - Profile and quantification of human stratum corneum ceramides by normal-phase liquid chromatography coupled with dynamic multiple reaction monitoring of mass spectrometry: development of targeted lipidomic method and application to human stratum corneum of different age groups. AB - Skin, the largest organ of the human body, serves as the primary barrier to the external environment. Ceramides are one of the main constituents of stratum corneum (SC), playing an important role in skin barrier function. Therefore, comprehensive profiling and quantification of SC ceramide is important. Herein, a new targeted lipidomic method for human SC ceramide profiling and quantification is presented and tested. Normal-phase high-performance liquid chromatography coupled with dynamic multiple reaction monitoring mass spectrometry (NP-HPLC-dMRM MS) was used to separate ceramides into subclasses and then characterize different ceramides within each subclass on the basis of their characteristics. In total, 483 ceramides were quantified in a single run within 20 min, covering 12 subclasses as well as some glycosylated ceramides not previously reported. Each subclass had typical standard substances (if available) that served to establish representative standard curves and were used for related substances with no standards. Linearity range, limit of quantification (LOQ), limit of detection (LOD), precision, accuracy, stability, and matrix effects were validated. dMRM increased sensitivity and accuracy greatly compared with common MRM (cMRM). This method was successfully applied to the study of human SC from different age groups. A total of 193 potential biomarkers were found to indicate age differences between children and adults. This method is an innovative approach for high-throughput quantification of SC ceramide. Graphical Abstract Method establishment (MRM spectra by the established method) and method application (score scatter plots of authentic samples). PMID- 27473428 TI - The development of plasma pseudotargeted GC-MS metabolic profiling and its application in bladder cancer. AB - Bladder cancer (BC) is a fatal malignancy with considerable mortality. BC urinary metabolomics has been extensively investigated for biomarker discovery, but few BC blood metabolomic studies have been performed. Hence, a plasma pseudotargeted metabolomic method based on gas chromatography-mass spectrometry with selected ion monitoring (GC-MS-SIM) was developed to study metabolic alterations in BC. The analytical performance of the developed method was compared with that of a nontargeted method. The relative standard deviation (RSD) values of 89 and 70.7 % of the peaks obtained using the pseudotargeted and nontargeted methods, respectively, were less than 20 %. The Pearson correlations of 90.7 and 78.3 % of the peaks obtained using the pseudotargeted and nontargeted methods, respectively, exceeded 0.90 in the linearity evaluation. Compared with the nontargeted method, the signal-to-noise ratios (S/N) of 97.9 and 69.3 % of the peaks increased two- and fivefold, respectively. The developed method was fully validated, with good precision, recovery, and stability of the trimethylsilyl (TMS) derivatives. The method was applied to investigate BC. Significant increases in the contents of metabolites involved in, for example, the pentose phosphate pathway (PPP) and nucleotide and fatty acid synthesis were found in the high-grade (HG) BC group compared to the healthy control (HC) group. These differences imply that the activated PPP may regulate BC cell proliferation by promoting lipid and nucleotide biosynthesis and the detoxification of reactive oxygen species (ROS). These results illustrate that the plasma pseudotargeted method is a powerful tool for metabolic profiling. Graphical abstract The plasma pseudotargeted metabolic profiling suggested the metabolic alterations in bladder cancer (BC) and the significantly differential metabolites for BC discrimination. PMID- 27473429 TI - Parallel-processing continuous-flow device for optimization-free polymerase chain reaction. AB - A parallel-processing four-station polymerase chain reaction (PCR) device has been developed, which performs continuous-flow PCR without optimization of the annealing temperature. Since the annealing temperature of each station can be controlled independently, the device covers an annealing temperature range of 50 68 degrees C, which is wide enough to perform PCR for any DNA fragment regardless of its optimum annealing condition. This arrangement lets us continuously obtain an amplified amount of a DNA fragment at least from one of the stations. The device consists of four identical cylindrical stations (diameter 20 mm, height 55 mm). A polytetrafluoroethylene capillary reactor (length 2 m, I.D. 100 MUm, O.D. 400 MUm) is wound helically up around each station. The whole assembly is designed to minimize the number of heating blocks (for providing temperatures of denaturation, annealing, and extension) to be seven and to shape a compact cube (height 55 mm, base 60 mm * 60 mm). The reproducibility for continuous-flow PCR is reasonably high (run-to-run and station-to-station relative standard deviation of their amplification is lower than 6 % and about 4 %, respectively). Performance on the optimization-free DNA amplification has been evaluated with four DNA samples with different annealing conditions and product sizes (323, 608, 828, and 1101 bp), which has demonstrated that in all cases, PCR is successful at least on one station. In addition, three DNA fragments with different lengths (323, 1101, and 2836 bp) have been successfully amplified in a segmented-flow mode without the carry-over contamination between segments. This result suggests that this device could serve as the PCR module of a continuous-flow high-throughput on-line total DNA analysis system integrating all necessary modules from cell lysis/DNA extraction to PCR product analysis. PMID- 27473430 TI - Multiwalled carbon nanotubes/gold nanocomposites-based electrochemiluminescent sensor for sensitive determination of bisphenol A. AB - An electrochemiluminescence (ECL) sensor for bisphenol A was proposed by using L cysteine-functionalized multiwalled carbon nanotubes/gold nanocomposites-modified glassy carbon electrode (MWCNTs-Au/GCE) based on ECL of peroxydisulfate solution. The ECL behaviors of peroxydisulfate solution had been investigated at the chitosan/MWCNTs-Au/GCE, and bisphenol A was found to have quenching effects on the ECL of peroxydisulfate solution. Both Au nanoparticles (AuNPs) and multiwalled CNTs could promote the electron transfer and synergetically amplify the ECL signal of peroxydisulfate solution. Under the optimized conditions, the ECL signal intensity was linear with the concentration of bisphenol A in the concentration range between 0.25 and 100 MUM (R = 0.9931) with a detection limit (S/N = 3) of 0.083 MUM. The constructed ECL sensor has the advantages of simplicity, sensitivity, good selectivity, and reproducibility, exhibiting a great potential application in the determination of bisphenol A. PMID- 27473431 TI - Effect of amino compounds on luminol-H2O2-gold nanoparticle chemiluminescence system. AB - In this work, the effect of amino compounds on the catalytic property of gold nanoparticles (AuNPs) in the luminol-H2O2 chemiluminescence (CL) system was systematically investigated. The experimental results showed that the catalytic ability of AuNPs on luminol-H2O2 system can be changed after AuNPs interacted with the amino compounds. It was found that two main aspects influence the catalytic property of AuNPs: (1) the electron density in conduction bands of AuNPs and (2) the surface negative charge density of AuNPs. Some amino compounds can decrease the electron density in the conduction bands of AuNPs after they reacted with AuNPs, resulting in a decrease of the catalytic property of AuNPs on luminol-H2O2 system. However, some amino compounds can cause AuNPs to aggregate after they reacted with AuNPs. The surface negative charge density of AuNPs would decrease, and zeta potentials were tested to verify the change of the surface negative charge density of AuNPs. As a result, the catalytic property of AuNPs on luminol-H2O2 system increased, and an enhanced CL signal can be obtained after the amino compounds reacted with AuNPs. This work will help people understand the catalytic mechanism of AuNPs and establish the CL method for the determination of amino compounds. Graphical Abstract Effects of amino compound on luminol-H2O2 AuNPs CL system. PMID- 27473432 TI - Understanding definitions of minimally verbal across instruments: evidence for subgroups within minimally verbal children and adolescents with autism spectrum disorder. AB - BACKGROUND: Minimally verbal (MV) children with autism spectrum disorder (ASD) are often assumed to be profoundly cognitively impaired and excluded from analyses due to challenges completing standardized testing protocols. A literature aimed at increasing understanding of this subgroup is emerging; however, the many methods used to define MV status make it difficult to compare studies. Understanding how different instruments and definitions used to identify MV children affect sample composition is critical to advance research on this understudied clinical population. METHOD: The MV status of 1,470 school-aged children was defined using five instruments commonly used in ASD research. MV sample composition was compared across instruments. Analyses examined the proportion of overlap across MV subgroups and the extent to which child characteristics varied across MV subgroups defined using different definitions or combinations of measures. RESULTS: A total of 257 children were classified as MV on at least one instrument. Proportion of overlap between definitions ranged from 3% to 100%. The stringency of definition (i.e. few-to-no vs. some words) was associated with differences in cognitive and adaptive functioning; more stringent definitions yielded greater consistency of MV status across instruments. Cognitive abilities ranged from profoundly impaired to average intelligence; 16% had NVIQ >= 70. Approximately half exhibited verbal skills commensurate with nonverbal cognitive ability, whereas half had verbal abilities significantly lower than their estimated NVIQ. CONCLUSIONS: Future studies of MV children must carefully consider the methods used to identify their sample, acknowledging that definitions including children with 'some words' may yield larger samples with a wider range of language and cognitive abilities. Broadly defined MV samples may be particularly important to delineate factors interfering with language development in the subgroup of children whose expressive impairments are considerably below their estimated nonverbal cognitive abilities. PMID- 27473433 TI - Potential risk factors for jaw osteoradionecrosis after radiotherapy for head and neck cancer. AB - INTRODUCTION: To identify potential risk factors for the development of jaw osteoradionecrosis (ORN) after 3D-conformal radiotherapy (3D-CRT) and intensity modulated radiotherapy (IMRT) among patients with newly diagnosed head and neck cancer. MATERIAL AND METHODS: This study included 776 patients who underwent 3D CRT or IMRT for head and neck cancer at the Department of Radiotherapy at the University Hospital Halle-Wittenberg between 2003 and 2013. Sex, dental status prior to radiotherapy, tumor site, bone surgery during tumor resection, concomitant chemotherapy, and the development of advanced ORN were documented for each patient. ORN was classified as grade 3, 4, or 5 according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer classification or grade 3 or 4 according to the late effects in normal tissues/subjective, objective, management, and analytic scale. The cumulative incidence of ORN was estimated. Cox regression analysis was used to identify prognostic risk factors for the development of ORN. RESULTS: Fifty-one patients developed advanced ORN (relative frequency 6.6 %, cumulative incidence 12.4 %). The highest risk was found in patients who had undergone primary bone surgery during tumor resection (hazard ratio [HR] = 5.87; 95 % confidence interval [CI]: 3.09-11.19) and in patients with tumors located in the oral cavity (HR = 4.69; 95 % CI: 1.33-16.52). Sex, dentition (dentulous vs. edentulous), and chemotherapy had no clinically relevant influence. DISCUSSION AND CONCLUSION: In contrast to most previous studies, we noted a low cumulative incidence of advanced ORN. Patients with tumors located in the oral cavity and those who undergo bone surgery during tumor resection prior to RT may be considered a high-risk group for the development of ORN. PMID- 27473434 TI - Dietary flavonoids advance timing of moult but do not affect redox status of juvenile blackbirds (Turdus merula). AB - Flavonoids are the most abundant plant polyphenols, widely occurring in fruits and berries, and show a strong antioxidant activity in vitro Studies of avian species feeding on berries suggest that dietary flavonoids have health-promoting effects and may enhance the expression of melanin-based plumage traits. These effects are probably mediated by the antioxidant activity of flavonoids. However, the effect of dietary flavonoids on oxidative status has never been investigated in any bird species. We analysed the effects of dietary flavonoids on blood non enzymatic antioxidants and protein oxidative damage of juvenile European blackbirds (Turdus merula). In addition, we analysed the effects of flavonoid enriched diet on body condition and on the timing of moult from juvenile to adult plumage. Dietary flavonoids did not significantly affect redox status but significantly advanced the onset of moult, hastening plumage development. Moulting birds showed higher protein oxidative damage compared with those that had not yet started moulting. The probability of initiating moult after 40 days of dietary treatment was higher for birds with low circulating levels of oxidizing agents and high glutathione concentration. The metabolization of flavonoids could have altered their redox potential, resulting in no net effects on redox status. However, flavonoid consumption before and during moult may contribute to enhance plumage development. Moreover, our findings suggest that moulting feathers may result in redox imbalance. Given their effect on moult and growth of melanin-rich feathers, fruit flavonoids may have contributed to shape plant fruiting time in relation to fruit consumption preferences by birds. PMID- 27473435 TI - Determinants of preferred ground clearance during swing phase of human walking. AB - During each step of human walking, the swing foot passes close to the ground with a small but (usually) non-zero clearance. The foot can occasionally scuff against the ground, with some risk of stumbling or tripping. The risk might be mitigated simply by lifting the foot higher, but presumably at increased effort, of unknown amount. Perhaps the normally preferred ground clearance is a trade-off between competing costs, one for lifting the foot higher and one for scuffing it. We tested this by measuring the metabolic energy cost of lifting and scuffing the foot, treating these apparently dissimilar behaviors as part of a single continuum, where scuffing is a form of negative foot lift. We measured young, healthy adults (N=9) lifting or scuffing the foot by various amounts mid-swing during treadmill walking, and observed substantial costs, each well capable of doubling the net metabolic rate for normal walking (gross cost minus that for standing). In relative terms, the cost for scuffing increased over twice as steeply as that for lifting. That relative difference means that the expected value of cost, which takes into account movement variability, occurs at a non zero mean clearance, approximately matching the preferred clearance we observed. Energy cost alone is only a lower bound on the overall disadvantages of inadvertent ground contact, but it is sufficient to show how human behavior may be determined not only by the separate costs of different trade-offs but also by movement variability, which can influence the average cost actually experienced in practice. PMID- 27473436 TI - Vertebral bending mechanics and xenarthrous morphology in the nine-banded armadillo (Dasypus novemcinctus). AB - The vertebral column has evolved to accommodate the broad range of locomotor pressures found across vertebrate lineages. Xenarthran (armadillos, sloths and anteaters) vertebral columns are characterized by xenarthrous articulations, novel intervertebral articulations located in the posterior trunk that are hypothesized to stiffen the vertebral column to facilitate digging. To determine the degree to which xenarthrous articulations impact vertebral movement, we passively measured compliance and range of motion during ventroflexion, dorsiflexion and lateral bending across the thoracolumbar region of the nine banded armadillo, Dasypus novemcinctus Patterns of bending were compared with changes in vertebral morphology along the column to determine which morphological features best predict intervertebral joint mechanics. We found that compliance was lower in post-diaphragmatic, xenarthrous vertebrae relative to pre xenarthrous vertebrae in both sagittal and lateral planes of bending. However, we also found that range of motion was higher in this region. These changes in mechanics are correlated with the transition from pre-xenarthrous to xenarthrous vertebrae, as well as with the transition from thoracic to lumbar vertebrae. Our results thus substantiate the hypothesis that xenarthrous articulations stiffen the vertebral column. Additionally, our data suggest that xenarthrous articulations, and their associated enlarged metapophyses, also act to increase the range of motion of the post-diaphragmatic region. We propose that xenarthrous articulations perform the dual role of stiffening the vertebral column and increasing mobility, resulting in passively stable vertebrae that are capable of substantial bending under appropriate loads. PMID- 27473437 TI - Aerodynamic consequences of wing morphing during emulated take-off and gliding in birds. AB - Birds morph their wings during a single wingbeat, across flight speeds and among flight modes. Such morphing may allow them to maximize aerodynamic performance, but this assumption remains largely untested. We tested the aerodynamic performance of swept and extended wing postures of 13 raptor species in three families (Accipitridae, Falconidae and Strigidae) using a propeller model to emulate mid-downstroke of flapping during take-off and a wind tunnel to emulate gliding. Based on previous research, we hypothesized that (1) during flapping, wing posture would not affect maximum ratios of vertical and horizontal force coefficients (CV:CH), and that (2) extended wings would have higher maximum CV:CH when gliding. Contrary to each hypothesis, during flapping, extended wings had, on average, 31% higher maximum CV:CH ratios and 23% higher CV than swept wings across all biologically relevant attack angles (alpha), and, during gliding, maximum CV:CH ratios were similar for the two postures. Swept wings had 11% higher CV than extended wings in gliding flight, suggesting flow conditions around these flexed raptor wings may be different from those in previous studies of swifts (Apodidae). Phylogenetic affiliation was a poor predictor of wing performance, due in part to high intrafamilial variation. Mass was only significantly correlated with extended wing performance during gliding. We conclude that wing shape has a greater effect on force per unit wing area during flapping at low advance ratio, such as take-off, than during gliding. PMID- 27473438 TI - Evidence for sex-specific genetic architectures across a spectrum of human complex traits. AB - BACKGROUND: Sex differences are a common feature of human traits; however, the role sex determination plays in human genetic variation remains unclear. The presence of gene-by-sex (GxS) interactions implies that trait genetic architecture differs between men and women. Here, we show that GxS interactions and genetic heterogeneity among sexes are small but common features of a range of high-level complex traits. RESULTS: We analyzed 19 complex traits measured in 54,040 unrelated men and 59,820 unrelated women from the UK Biobank cohort to estimate autosomal genetic correlations and heritability differences between men and women. For 13 of the 19 traits examined, there is evidence that the trait measured is genetically different between males and females. We find that estimates of genetic correlations, based on ~114,000 unrelated individuals and ~19,000 related individuals from the same cohort, are largely consistent. Genetic predictors using a sex-specific model that incorporated GxS interactions led to a relative improvement of up to 4 % (mean 1.4 % across all relevant phenotypes) over those provided by a sex-agnostic model. This further supports the hypothesis of the presence of sexual genetic heterogeneity across high-level phenotypes. CONCLUSIONS: The sex-specific environment seems to play a role in changing genotype expression across a range of human complex traits. Further studies of GxS interactions for high-level human traits may shed light on the molecular mechanisms that lead to biological differences between men and women. However, this may be a challenging endeavour due to the likely small effects of the interactions at individual loci. PMID- 27473439 TI - Chronic tarsal conjunctivitis. AB - BACKGROUND: Toxicity is rarely considered in the differential diagnosis of conjunctivitis, but we present here a new form of toxic conjunctivitis with unusual clinical features. Between 2010 and 2013, a new clinical presentation of chronic conjunctivitis unresponsive to normal treatment was noted within a Primary Care Ophthalmology Service. METHODS: Retrospective review of case records and histopathology results. RESULTS: A total of 55 adult patients, all females, presented with epiphora and stickiness. They did not complain of itch and had had symptoms for an average of 9 months. Clinical examination showed bilateral moderate to severe upper and lower tarsal conjunctival papillary reaction, without corneal or eyelid changes and mild bulbar conjunctival hyperaemia in a third of cases. Biopsies were taken in 15 cases to exclude an atypical infection or lymphoma. Histologically, there was a variable superficial stromal lymphocytic infiltrate, involving the epithelium in more severe cases. The majority of the cells were CD3 positive T-lymphocytes and follicle formation was not noted. The clinical history in all cases included prolonged use of eye make- up and other facial cosmetic products. Clinical symptoms of epiphora settled with topical steroid drops, but the clinical signs of chronic tarsal inflammation persisted until withdrawal of the facial wipes thought to contain the inciting agent, though the exact nature of this remains unclear. CONCLUSION: The presentation, appearances, histological features are consistent with a contact allergen-driven chronic conjunctivitis. Steroid treatment provided good relief of symptoms and patients were advised to avoid potential contact allergens. Management remains difficult. Further research into contact allergies of mucous membranes and identification of its allergens is required. PMID- 27473441 TI - Characterization of stochastic noise and post-irradiation density growth for reflective-type radiochromic film in therapeutic photon beam dosimetry. AB - The aim of this study is to investigate the dosimetric uncertainty of stochastic noise and the post-irradiation density growth for reflective-type radiochromic film to obtain the appropriate dose from the exactly controlled film density. Film pieces were irradiated with 6-MV photon beams ranging from 0 to 400cGy. The pixel values (PVs) of these films were obtained using a flatbed scanner at elapsed times of 1min to 120h between the end of irradiation and the film scan. The means and standard deviations (SDs) of the PVs were calculated. The SDs of the converted dose scale, usd, and the dose increases resulting from the PV increases per +/-29min at each elapsed time, utime, were computed. The combined dose uncertainties from these two factors, uc, were then calculated. A sharp increase in the PV occurred within the first 3h after irradiation, and a slight increase continued from 3h to 120h. usd was independent of post-irradiation elapsed time. Sharp decreases in utime were obtained within 1h after irradiation, and slight decreases in utime were observed from 1 to 24h after irradiation. uc first decreased 1h after irradiation and remained constant afterward. Assuming that the post-irradiation elapsed times of all of the related measurements are synchronized within +/-29min, the elapsed time should be at least 1h in our system. It is important to optimize the scanning protocol for each institution with consideration of the required measurement uncertainty and acceptable latency time. PMID- 27473440 TI - Effects of lifestyle intervention in BRCA1/2 mutation carriers on nutrition, BMI, and physical fitness (LIBRE study): study protocol for a randomized controlled trial. AB - BACKGROUND: Women with highly penetrant BRCA mutations have a 55-60 % lifetime risk for breast cancer and a 16-59 % lifetime risk of developing ovarian cancer. However, penetrance differs interindividually, indicating that environmental and behavioral factors may modify this risk. It is well documented that the risk for sporadic breast cancer disease can be modified by changing lifestyle factors that primarily include physical activity, dietary habits, and body weight. It can thus be hypothesized that the modification of these lifestyle factors may also influence the incidence and progression of cancer in BRCA mutation carriers. METHODS/DESIGN: This multicenter, interdisciplinary, prospective, two-armed, randomized (1:1) controlled trial aims to enroll a minimum of 600 BRCA1 and BRCA2 mutation carriers to partake in either a lifestyle intervention or usual care. The study primarily aims to demonstrate an improvement of nutritional behavior (adherence to the Mediterranean diet), body mass index, and physical fitness. Furthermore, the effects on quality of life, stress coping capacity, breast cancer incidence, and mortality will be investigated. The intervention group (IG) will receive a structured lifestyle intervention over 12 months, whereas the control group (CG) will only receive information regarding a healthy lifestyle. During the first 3 months, women in the IG will receive structured, individualized, and mainly supervised endurance training with a minimum of 18 MET h physical activity per week and nutrition education based on the Mediterranean diet. Over the following 9 months, IG monthly group training sessions and regular telephone contacts will motivate study participants. The CG will receive one general training session about healthy nutrition in accordance with the recommendations of the German Society of Nutrition (standard of care in Germany) and the benefits of regular physical activity on health status. At randomization and subsequent time points (3 and 12 months), cardiopulmonary fitness will be assessed by spiroergometry, and nutritional and psychological status will be assessed by validated questionnaires, interviews, and clinical examinations. DISCUSSION: As data on the role of lifestyle intervention in women with a hereditary risk for breast and ovarian cancer are currently lacking, this study will be of major importance from a scientific, as well as a practical advice viewpoint. It will investigate the optimal strategy to improve physical fitness, nutritional status, and psychological factors such as quality of life, perceived stress, optimism, as well as incidence and outcome of cancer in this selected group of women at high risk. If the study indicates a positive long-term outcome, a structured lifestyle intervention program could be added to health care prevention strategies for BRCA1 and BRCA2 mutation carriers. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02516540 . Registered on 22 July 2015. PMID- 27473442 TI - Using Milestones as Evaluation Metrics During an Emergency Medicine Clerkship. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education's (ACGME) Milestones presumes graduating medical students will enter residency proficient at Milestone level 1 for 23 skills. The Next Accreditation System now includes Milestones for each postgraduate specialty, and it is unlikely that schools will document every emergency medicine (EM) applicant's EM-specific skills in their performance evaluation. OBJECTIVES: The goals of this research were to determine if assessment of the Milestones was feasible during a medical student clerkship and examine the proportion of medical students performing at Milestone level 1. METHODS: This study was conducted at a center with Liaison Committee on Medical Education-approved medical training and a 4-year EM residency. Using traditional clerkship, we studied the feasibility of an ACGME EM Milestones-based clerkship assessment. Data led to redesign of the clerkship and its evaluation process, including all level 1 anchor(s) to add "occasionally" (>60%), "usually" (>80%), and "always" (100%) on a Likert scale to on-shift assessment forms. RESULTS: During the feasibility phase (2013-14), 75 students rotated though the clerkship; 55 evaluations were issued and 50 contained the Milestone summary. Eight deficiencies were noted in Milestone 12 and three in Milestone 14. After changes, 49 students rotated under the new evaluation rubric. Of 575 completed on-shift evaluations, 16 Milestone deficiencies were noted. Of 41 institutional evaluations issued, only one student had deficiencies noted, all of which pertained to patient care. All evaluations in this second cohort contained each student's Milestone proficiency. CONCLUSIONS: Assessment of the Milestones is feasible. Communication of ACGME EM Milestone proficiency may identify students who require early observation or remediation. The majority of students meet the anchors for the Milestones, suggesting that clerkship assessment with the ACGME EM Milestones does not adequately differentiate students. PMID- 27473443 TI - Risk of Delayed Intracranial Hemorrhage in Anticoagulated Patients with Mild Traumatic Brain Injury: Systematic Review and Meta-Analysis. AB - BACKGROUND: Delayed intracranial hemorrhage is a potential complication of head trauma in anticoagulated patients. OBJECTIVE: Our aim was to use a systematic review and meta-analysis to determine the risk of delayed intracranial hemorrhage 24 h after head trauma in patients who have a normal initial brain computed tomography (CT) scan but took vitamin K antagonist before injury. METHODS: EMBASE, Medline, and Cochrane Library were searched using controlled vocabulary and keywords. Retrospective and prospective observational studies were included. Outcomes included positive CT scan 24 h post-trauma, need for surgical intervention, or death. Pooled risk was estimated with logit proportion in a random effect model with 95% confidence intervals (CIs). RESULTS: Seven publications were identified encompassing 1,594 patients that were rescanned after a normal first head scan. For these patients, the pooled estimate of the incidence of intracranial hemorrhage on the second CT scan 24 h later was 0.60% (95% CI 0-1.2%) and the resulting risk of neurosurgical intervention or death was 0.13% (95% CI 0.02-0.45%). CONCLUSIONS: The present study is the first published meta-analysis estimating the risk of delayed intracranial hemorrhage 24 h after head trauma in patients anticoagulated with vitamin K antagonist and normal initial CT scan. In most situations, a repeat CT scan in the emergency department 24 h later is not necessary if the first CT scan is normal. Special care may be required for patients with serious mechanism of injury, patients showing signs of neurologic deterioration, and patients presenting with excessive anticoagulation or receiving antiplatelet co-medication. PMID- 27473444 TI - Xylazine Exposures Reported to Texas Poison Centers. AB - BACKGROUND: Xylazine is a sedative, analgesic, anesthetic, and central muscle relaxant approved for animals but not humans. Although xylazine is an emerging drug of abuse, there are limited data on potentially adverse exposures to the drug. OBJECTIVES: The intent of this study was to describe potentially adverse xylazine exposures reported to a large poison center system. METHODS: All xylazine exposures reported to Texas poison centers between 2000 and 2014 were included. The distribution of cases by select variables was determined. RESULTS: Of 76 total cases, 93% of the patients were >=20 years of age, and 54% were male. Fifty-one percent of the exposures occurred by injection, 28% by ingestion, 16% were dermal, 14% were ocular, and 3% by inhalation. Sixty-four percent of the exposures were unintentional, 32% were intentional, and 1% each was related to malicious use and adverse reaction. Sixty-seven percent of the patients were already at or en route to a health care facility when the poison center was contacted, 21% were managed on-site, and 9% were referred to a health care facility. The most common clinical effects were drowsiness or lethargy (47%), bradycardia (20%), hypotension (11%), hypertension (9%), puncture or wound (8%), and slurred speech (8%). CONCLUSION: Xylazine exposures tended to involve patients who were adult males, exposures were typically unintentional; and most often occurred by injection. Most of the patients were already at or en route to a health care facility when a poison center was contacted. The most frequently reported adverse effects were cardiovascular or neurologic in nature. PMID- 27473445 TI - Low-volume high-intensity swim training is superior to high-volume low-intensity training in relation to insulin sensitivity and glucose control in inactive middle-aged women. AB - PURPOSE: We tested the hypothesis that low-volume high-intensity swimming has a larger impact on insulin sensitivity and glucose control than high-volume low intensity swimming in inactive premenopausal women with mild hypertension. METHODS: Sixty-two untrained premenopausal women were randomised to an inactive control (n = 20; CON), a high-intensity low-volume (n = 21; HIT) or a low intensity high-volume (n = 21; LIT) training group. During the 15-week intervention period, HIT performed 3 weekly 6-10 * 30-s all-out swimming intervals (average heart rate (HR) = 86 +/- 3 % HRmax) interspersed by 2-min recovery periods and LIT swam continuously for 1 h at low intensity (average HR = 73 +/- 3 % HRmax). Fasting blood samples were taken and an oral glucose tolerance test (OGTT) was conducted pre- and post-intervention. RESULTS: After HIT, resting plasma [insulin] was lowered (17 +/- 34 %; P < 0.05) but remained similar after LIT and CON. Following HIT, 60-min OGTT plasma [insulin] and [glucose] was lowered (24 +/- 30 % and 10 +/- 16 %; P < 0.05) but remained similar after LIT and CON. Total area under the curve for plasma [glucose] was lower (P < 0.05) after HIT than LIT (660 +/- 141 vs. 860 +/- 325 mmol min L(-1)). Insulin sensitivity (HOMA-IR) had increased (P < 0.05) by 22 +/- 34 % after HIT, with no significant change after LIT or CON, respectively. Plasma soluble intracellular cell adhesion molecule 1 was lowered (P < 0.05) by 4 +/- 8 and 3 +/- 9 % after HIT and CON, respectively, while plasma soluble vascular cell adhesion molecule 1 had decreased (P < 0.05) by 8 +/- 23 % after HIT only. CONCLUSIONS: These findings suggest that low-volume high-intensity intermittent swimming is an effective and time-efficient training strategy for improving insulin sensitivity, glucose control and biomarkers of vascular function in inactive, middle-aged mildly hypertensive women. PMID- 27473446 TI - The impact of repetition mechanics on the adaptations resulting from strength-, hypertrophy- and cluster-type resistance training. AB - PURPOSE: The purpose of this study was to examine the acute and chronic training responses to strength-, hypertrophy- and cluster-type resistance training. METHODS: Thirty-four trained males were assigned to a strength [STR: 4 * 6 repetitions, 85 % of one repetition maximum, (1RM), 900 s total rest], hypertrophy (HYP: 5 * 10 repetitions, 70 % 1RM, 360 s total rest), cluster 1 (CL 1: 4 * 6/1 repetitions, 85 % 1RM, 1400 s total rest), and cluster 2 (CL-2: 4 * 6/1 repetitions, 90 % 1RM, 1400 s total rest) regimens which were performed twice weekly for a 6-week period. Measurements were taken before, during and following the four workouts to investigate the acute training stimulus, whilst similar measurements were employed to examine the training effects before and after the intervention. RESULTS: The improvements in 1RM strength were significantly greater for the STR (12.09 +/- 2.75 %; p < 0.05, d = 1.106) and CL-2 (13.20 +/- 2.18 %; p < 0.001, d = 0.816) regimens than the HYP regimen (8.13 +/- 2.54 %, d = 0.453). In terms of the acute responses, the STR and CL-2 workouts resulted in greater time under tension (TUT) and impulse generation in individual repetitions than the HYP workout (p < 0.05). Furthermore, the STR (+3.65 +/- 2.54 mmol/L(-1)) and HYP (+6.02 +/- 2.97 mmol/L(-1)) workouts resulted in significantly greater elevations in blood lactate concentration (p < 0.001) than the CL-1 and CL-2 workouts. CONCLUSION: CL regimens produced similar strength improvements to STR regimens even when volume load was elevated (CL-2). The effectiveness of the STR and CL-2 regimens underlines the importance of high loads and impulse generation for strength development. PMID- 27473447 TI - Does knee joint cooling change in vivo patellar tendon mechanical properties? AB - PURPOSE: This study aimed to assess the influence of knee joint cooling on the in vivo mechanical properties of the patellar tendon. METHODS: Twenty young, healthy women volunteered for the study. B-mode ultrasonography was used to record patellar tendon elongation during isometric ramp contraction of the knee extensors (5-7 s, 90 degrees knee angle) and calculate tendon stiffness. Skin temperature was measured by infrared thermometry. Data were acquired before and after 30 min of local icing of the knee joint and compared by paired samples t tests. RESULTS: After cold exposure, skin temperature as measured over the patellar tendon dropped by 16.8 +/- 2.0 degrees C. Tendon stiffness increased from 2189 +/- 551 to 2705 +/- 902 N mm(-1) (+25 %, p = 0.007). Tendon strain decreased by 9 % (p = 0.004). A small, albeit significant reduction in maximum tendon force was observed (-3.3 %, p = 0.03). CONCLUSIONS: Knee cooling is associated with a significant increase in patellar tendon stiffness. The observed tendon stiffening may influence the operating range of sarcomeres, possibly limiting the maximal force generation capacity of knee extensor muscles. In addition, a stiffer tendon might benefit rate of force development, thus countering the loss in explosiveness typically described for cold muscles. PMID- 27473448 TI - Mechanical work and efficiency of 5 + 5 m shuttle running. AB - PURPOSE: Acceleration and deceleration phases characterise shuttle running (SR) compared to constant speed running (CR); mechanical work is thus expected to be larger in the former compared to the latter, at the same average speed (v mean). The aim of this study was to measure total mechanical work (W tot (+) , J kg(-1) m(-1)) during SR as the sum of internal (W int (+) ) and external (W ext (+) ) work and to calculate the efficiency of SR. METHODS: Twenty males were requested to perform shuttle runs over a distance of 5 + 5 m at different speeds (slow, moderate and fast) to record kinematic data. Metabolic data were also recorded (at fast speed only) to calculate energy cost (C, J kg(-1) m(-1)) and mechanical efficiency (eff(+) = W tot (+) C (-1)) of SR. RESULTS: Work parameters significantly increased with speed (P < 0.001): W ext (+) = 1.388 + 0.337 v mean; W int (+) = -1.002 + 0.853 v mean; W tot (+) = 1.329 v mean. At the fastest speed C was 27.4 +/- 2.6 J kg(-1) m(-1) (i.e. about 7 times larger than in CR) and eff(+) was 16.2 +/- 2.0 %. CONCLUSIONS: W ext (+) is larger in SR than in CR (2.5 vs. 1.4 J kg(-1) m(-1) in the range of investigated speeds: 2-3.5 m s( 1)) and W int (+) , at fast speed, is about half of W tot (+) . eff(+) is lower in SR (16 %) than in CR (50-60 % at comparable speeds) and this can be attributed to a lower elastic energy reutilization due to the acceleration/deceleration phases over this short shuttle distance. PMID- 27473449 TI - Increased risk of aortic aneurysm (AA) in relation to the severity of psoriasis: A national population-based matched-cohort study. AB - BACKGROUND: Inflammation of systemic and vascular tissues besides the skin in psoriasis is associated with cardiovascular morbidity and mortality. OBJECTIVE: We sought to investigate whether or not patients with psoriasis have an increased risk of aortic aneurysm (AA). METHODS: This population-based cohort study identified 34,301 patients with psoriasis in the Taiwan National Health Insurance Research Database during 2004 to 2006, who were matched for age and sex with 137,204 control subjects without psoriasis from the Taiwan Longitudinal Health Insurance Database 2000. Each individual was individually followed up for 5 years to identify those who subsequently developed AA. RESULTS: After adjusting for medical history and medication use, patients with psoriasis were at increased overall risk of AA (adjusted hazard ratio [HR] 1.80; 95% confidence interval 1.25 2.61). The risk for AA increased with the severity of psoriasis. The adjusted HRs were higher for male than female patients (adjusted HR 1.84 vs 1.56), and for patients younger than 50 years versus older patients (adjusted HR 2.81 vs 1.64). LIMITATIONS: There is a lack of information regarding patients' Psoriasis Area and Severity Index score, daily tobacco use, or alcohol consumption. CONCLUSION: Patients with psoriasis are predisposed to developing AA: this risk increases with psoriasis severity and is independent of established cardiovascular risk factors. PMID- 27473451 TI - Correction. PMID- 27473450 TI - Incidence and prevalence of basal cell carcinoma (BCC) and locally advanced BCC (LABCC) in a large commercially insured population in the United States: A retrospective cohort study. AB - BACKGROUND: Accurate evaluation of basal cell carcinoma (BCC) in the United States was not possible before the 2011 release of BCC-specific International Classification of Diseases, Ninth Revision, Clinical Modification codes. OBJECTIVE: We sought to describe BCC (including locally advanced BCC [LABCC]) incidence/prevalence and the characteristics of patients in a commercially insured US population. METHODS: This retrospective cohort study used Truven Health MarketScan database insurance claims. Patients, aged 18 years or older with 2 or more BCC claims at least 30 days apart from October 1, 2011, to September 30, 2012, were continuously enrolled in medical and pharmacy benefits for 12 months before and after the index claim. A specific algorithm was used to classify patients with LABCC. RESULTS: A total of 56,987 patients with BCC were identified (39,035 incident cases; 17,952 prevalent cases). Age-adjusted BCC incidence and prevalence were 226.09 and 342.64 per 100,000 persons, respectively. These values project to 542,782 patients (incidence) and 822,593 patients (prevalence) in the 2012 US population. LABCC was uncommon (471 cases identified; projected US incidence and prevalence: 4399 and 7940 patients, respectively). LIMITATIONS: Use of medical claims data and retrospective analysis are limitations. CONCLUSION: In a study designed to distinguish patients with LABCC from the general BCC population based on BCC-specific International Classification of Diseases, Ninth Revision, Clinical Modification codes, 0.8% were found to have LABCC, the majority having pre-existing disease. PMID- 27473452 TI - The infliximab biosimilar in the treatment of moderate to severe plaque psoriasis. AB - BACKGROUND: The infliximab originator's patent recently expired, leading to the production of biosimilar versions of the drug. The biosimilars' efficacy was not tested on patients with psoriasis but most regulatory authorities approved their use in psoriasis because of an extrapolation of data from studies conducted in other diseases. OBJECTIVE: We sought to describe the use of the infliximab biosimilar (Remsima; CT-P13) in patients with psoriasis. METHODS: Objective (Psoriasis Area and Severity Index) and subjective (visual analog pain scale) measurements of disease activity were collected in 2 cohorts of patients with moderate to severe plaque psoriasis: cohort 1 patients switched from the infliximab originator to the infliximab biosimilar; and cohort 2 patients were infliximab-naive and started on the infliximab biosimilar. RESULTS: We observed no changes of Psoriasis Area and Severity Index and visual analog pain scale scores in 30 patients who switched from the infliximab originator to the biosimilar. Four of 5 infliximab-naive patients who started infliximab biosimilar treatment achieved 75% improvement or better from baseline Psoriasis Area and Severity Index score at the end of the induction phase. LIMITATIONS: Number of patients and length of follow-up was limited. CONCLUSIONS: Patients with psoriasis taking infliximab originator treatment can switch to the infliximab biosimilar without experiencing a significant change in clinical response or additional adverse events. The use of the infliximab biosimilar could reduce the growing pressure on health care budgets. PMID- 27473453 TI - Clinical and immunologic features of recurrent herpes zoster (HZ). AB - BACKGROUND: Recurrent herpes zoster (HZ) is thought to be rare, but there have been few large-scale studies of recurrent HZ. OBJECTIVE: We conducted a large scale prospective cohort study to characterize recurrent HZ. METHODS: We examined 12,522 participants aged 50 years or older in Shozu County and followed them up for 3 years. We compared the incidence of HZ and postherpetic neuralgia, severity of skin lesions and acute pain, cell-mediated immunity, and varicella-zoster virus-specific antibody titer between primary and recurrent HZ. RESULTS: A total of 401 participants developed HZ: 341 with primary HZ and 60 with recurrent HZ. Skin lesions and acute pain were significantly milder and the incidence of postherpetic neuralgia was lower in patients aged 50 to 79 years with recurrent HZ than in those with primary HZ. Varicella-zoster virus skin test induced a stronger reaction in patients aged 50 to 79 years with recurrent HZ than in those with primary HZ. LIMITATIONS: Information on previous HZ episodes was self reported by participants, so it could not be confirmed that they actually had a history of HZ. CONCLUSION: Recurrent HZ was associated with milder clinical symptoms than primary HZ, probably because of stronger varicella-zoster virus specific cell-mediated immunity in the patients with recurrence. PMID- 27473454 TI - Clinical features, causes, treatments, and outcomes of peristomal pyoderma gangrenosum (PPG) in 44 patients: The Mayo Clinic experience, 1996 through 2013. AB - BACKGROUND: There are limited large case series of peristomal pyoderma gangrenosum (PPG), an uncommon cause of recalcitrant peristomal ulceration. OBJECTIVE: We sought to further characterize the clinical features, causes, treatments, and outcomes of PPG. METHODS: We conducted a retrospective chart review of patients with PPG seen at Mayo Clinic from January 1996 to July 2013. RESULTS: A total of 44 patients had PPG (mean age, 46 years; 32 women [73%]); 41 (93%) had inflammatory bowel disease. Mean time to PPG onset after stoma surgery was 5.2 months (excluding 1 outlier). Systemic therapies included corticosteroids (66%), immunosuppressants (41%), biologics (36%), and a combination of systemic treatments (36%). Mean time to reach a complete response was 10.7 weeks. Stoma closure had the greatest complete response (4 of 4 patients, no recurrences). Recurrence after any treatment was documented in 23 of 38 (61%) patients. Stoma relocation/revision recurred in 10 of 15 (67%) patients. Remission occurred in 29 of 31 (94%) patients. LIMITATIONS: Small sample size and retrospective study design are limitations. CONCLUSION: PPG is strongly associated with inflammatory bowel disease, is predominant in women, and has a prolonged time to onset and high recurrence rate. Systemic corticosteroid or combination therapies and surgical closure can be effective treatments. Timely recognition and management are paramount to achieving early remission. PMID- 27473456 TI - The use of Mohs micrographic surgery (MMS) for melanoma in situ (MIS) of the trunk and proximal extremities. AB - BACKGROUND: Evaluation of the entire surgical margin results in high rates of complete excision, low local recurrence rates, and maximal tissue conservation. Although well recognized for melanoma of the head and neck, few studies have focused exclusively on the trunk and proximal extremities. OBJECTIVE: We sought to evaluate the efficacy of Mohs micrographic surgery for melanoma in situ (MIS) of the trunk and proximal extremities, and determine adequate excision margins for MIS when total margin evaluation is not used. METHODS: Long-term outcomes in 882 cases of MIS treated with Mohs micrographic surgery were analyzed and compared with historical controls. Rates of complete excision were determined for increasing surgical margin intervals. RESULTS: One local recurrence occurred in our cohort (0.1%). Only 83% of MIS were excised with a 6-mm margin. Margins of 9 mm were needed to excise 97% of MIS, statistically equivalent to thin melanomas. LIMITATIONS: We used a nonrandomized, single-institution, retrospective design. CONCLUSION: Mohs micrographic surgery may cure the 17% of MIS that exceed traditional excision margins of 5 mm and is a valuable option for these patients. Surgical margins of at least 0.9 cm should be considered for MIS of the trunk and extremities when total margin evaluation is not used. PMID- 27473455 TI - Multivariate analysis of potential risk factors for lymph node metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. AB - BACKGROUND: The current knowledge about potential risk factors for lymph node (LN) metastasis in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) is primarily based on studies that lack adjustment for confounding variables. OBJECTIVES: We sought to identify independent risk factors for LN metastasis in patients with HNcSCC and to evaluate the impact of LN metastasis on prognosis. METHODS: Patients with primary HNcSCC were retrospectively included. Potential risk factors were analyzed by univariate and multivariate Cox regression models. Survival was compared using the Kaplan-Meier method. RESULTS: Three hundred thirty-six patients with 545 primary HNcSCCs were included. The median follow-up period was 43 months (range, 1-176 months). LN metastasis occurred in 55 patients (16.4%). The following independent risk factors of HNcSCC for the development of LN metastasis were identified: location on the ear, tumor diameter >50 mm, moderate and poor differentiation, and tumor thickness >2 mm. There was a significant decline in disease-specific survival and overall survival in patients with LN metastasis compared to patients without LN metastasis. LIMITATIONS: The retrospective study design. CONCLUSION: LN metastases from HNcSCC are common with diminished survival rates. This study confirmed some well known risk factors, but also found moderate differentiation as an independent risk factor for LN metastasis. PMID- 27473457 TI - Onychotillomania: An underrecognized disorder. AB - Onychotillomania is an uncommon and likely underreported condition in which patients repetitively manipulate the different constituents of the nail unit. Onychotillomania is characterized by a range of nonspecific findings, including bizarre morphology of the nail plate and damage to the nail bed and periungual skin. Histopathological changes are also nonspecific, but may be viewed as analogous to lichen simplex chronicus and prurigo nodularis of the skin. Clinical history is essential to making this diagnosis, as effective treatment modalities may focus on behavioral therapies and psychiatric medications. PMID- 27473460 TI - [Wishes for the future of science: an analysis of dementia and ageing on The National Research Agenda (NWA)]. AB - INTRODUCTION: The National Research Agenda (NWA) assembles topics on which scientist can focus in the coming years. A study carried out by de Radboudumc in Nijmegen examined how many questions are put to the NWA on dementia and ageing. What priority does society give to this research field and who ask questions about this? With the method of the NWA as reference frame a supplementary route on dementia/ageing was proposed. RESULTS: Of the 11.700 questions submitted to the NWA almost 2.5% is about dementia/ageing. Compared to other medical issues this is a relatively high percentage. This analysis provides 21 research questions which give a good idea of the questions that where asked about the themes of ageing and dementia. Half of the questions came from citizens, therefore we can speak of a socially supported agenda in this area. However, most of the valid questions came from professional organizations involved in dementia. CONCLUSION: In the Netherlands a relatively high priority is given by authors of questions for the NWA to research on dementia and ageing. Questions from professionals are complemented by citizens who ask other relevant questions that provide a new perspective and are an addition to the knowledge questions from scientists. PMID- 27473458 TI - A systematic review on the clustering and co-occurrence of multiple risk behaviours. AB - BACKGROUND: Risk behaviours, such as smoking and physical inactivity account for up to two-thirds of all cardiovascular deaths, and are associated with substantial increased mortality in many conditions including cancer and diabetes. As risk behaviours are thought to co-occur in individuals we conducted a systematic review of studies addressing clustering or co-occurrence of risk behaviours and their predictors. As the main aim of the review was to inform public health policy in England we limited inclusion to studies conducted in the UK. METHODS: Key databases were searched from 1990 to 2016. We included UK based cross-sectional and longitudinal studies that investigated risk behaviours such as smoking, physical inactivity, unhealthy diet. High heterogeneity precluded meta-analyses. RESULTS: Thirty-seven studies were included in the review (32 cross-sectional and five longitudinal). Most studies investigated unhealthy diet, physical inactivity, alcohol misuse, and smoking. In general adult populations, there was relatively strong evidence of clustering between alcohol misuse and smoking; and unhealthy diet and smoking. For young adults, there was evidence of clustering between sexual risk behaviour and smoking, sexual risk behaviour and illicit drug use, and sexual risk behaviour and alcohol misuse. The strongest associations with co-occurrence and clustering of multiple risk behaviours were occupation (up to 4-fold increased odds in lower SES groups) and education (up to 5-fold increased odds in those with no qualifications). CONCLUSIONS: Among general adult populations, alcohol misuse and smoking was the most commonly identified risk behaviour cluster. Among young adults, there was consistent evidence of clustering found between sexual risk behaviour and substance misuse. Socio-economic status was the strongest predictor of engaging in multiple risk behaviours. This suggests the potential for interventions targeting multiple risk behaviours either sequentially or concurrently particularly where there is evidence of clustering. In addition, there is potential for intervening at the social or environmental level due to the strong association with socio-economic status. PMID- 27473459 TI - First-episode psychosis in a 15 year-old female with clinical presentation of anti-NMDA receptor encephalitis: a case report and review of the literature. AB - BACKGROUND: Anti-NMDA receptor encephalitis is an autoimmune disease that was identified in 2007, and manifests in a stepwise manner with psychiatric, neurological and autonomic symptoms. The disease is caused by autoantibodies against NMDA receptors. It can have a paraneoplastic origin, mainly secondary to ovarian teratomas, but it can also be unrelated to the tumor. This disease can affect both sexes and all ages. CASE PRESENTATION: Here, we present a case of a 15 year-old female adolescent with first-episode psychosis with anti-NMDA receptor encephalitis not related to tumor, which manifested with delusion, hallucinations, panic attacks, agitation, and neurological symptoms, and later with autonomic instability. She was treated with immunotherapy and psychiatric medication resulting in improvement of her main psychiatric and neurological symptoms. CONCLUSION: Our main objective in presenting this case is to alert clinicians to this challenging and recent disease that has a clinical presentation that might resemble a functional psychiatric condition and can be underdiagnosed in the context of child and adolescent psychiatry. PMID- 27473461 TI - Deformation pattern and predictive value of right ventricular longitudinal strain in children with pulmonary arterial hypertension. AB - BACKGROUND: Right ventricular function has been identified as an important prognostic factor in children with pulmonary arterial hypertension. The aim of the study was to assess the deformation pattern and prognostic value of right ventricular longitudinal strain in children with pulmonary arterial hypertension. METHODS: We prospectively evaluated 46 children (25 with pulmonary arterial hyperetension and 21 age and sex matched controls) using conventional and speckle tracking echocardiography, brain natriuretic peptide levels and clinical status expressed by WHO functional class and 6-min walking test. According to the clinical status after 12 months of follow-up, the pulmonary arterial hypertension patients were divided in two groups: non-worsening (13) and worsening (12). RESULTS: Right ventricular free wall longitudinal strain and strain rate were significantly lower in children with PAH compared with controls (-24.72 +/- 3.48 vs -15.60 +/- 3.40, p = 0.0001 and -1.44 +/- 0.09 vs -1.09 +/- 0.15, p = 0.0001, respectively). There was a more expressed decrease of basal than apical region of right ventricular free wall longitudinal strain/strain rate in pulmonary arterial hypertension patients compared with controls (strain: p = 0.0001 vs p = 0.07 and strain rate: p = 0.0001 vs p = 0.002). Comparing worsening and non-worsening pulmonary arterial hypertension patients there was a significant difference in Mid right ventricular free wall longitudinal strain (-14.00 +/- 3.13 vs. -20.76 +/- 4.62, p = 0.0001). In multivariable logistic regression analysis Mid right ventricular free wall longitudinal strain was an independent predictor of worsening in pulmonary arterial hypertension children (OR 0.45; 95 % CI: 0.21 0.96, p = 0.041). In ROC curve analysis a cut-off value of Mid right ventricular free wall longitudinal strain of -18.50 % predicted clinical worsening in pulmonary arterial hypertension children, with a sensitivity and specificity of 91.7 and 30.8 %, respectively (area under curve = 0.88 +/- 0.06, 95 % CI: 0.75 1.00, p = 0.001). CONCLUSIONS: Two-dimensional speckle-tracking echocardiography is a complementary non-invasive tool for assessment of right ventricular function in children with severe pulmonary arterial hypertension, allowing also clinical prediction and segmental analysis of right ventricular myocardial performance in these patients. PMID- 27473462 TI - Overcoming Barriers: Adolescents' Experiences Using a Mobile Phone Dietary Assessment App. AB - BACKGROUND: The use of new technology has the potential to increase participation rates in dietary studies and improve the validity of collected dietary data. However, to evaluate the usability of developed dietary methods, qualitative studies of participants' experiences and perceptions are needed. OBJECTIVE: To explore adolescents' experiences using a newly developed mobile phone dietary assessment app, with a focus on factors that could affect their recording of dietary intake. METHODS: Focus group interviews were conducted with 75 participants who had used a newly developed mobile phone dietary assessment app in a quantitative evaluation study. The interviews were analyzed using qualitative content analysis and the theoretical framework of Self Determination Theory was applied. RESULTS: The adolescents' use of the mobile phone dietary assessment app was characterized by their struggle to overcome several perceived barriers. Facilitators that helped adolescents complete the method were also identified. Motivation was found to be an important facilitator, and intrinsically motivated participants completed the method because they found it fun to use. The autonomous extrinsically motivated participants completed the method for the greater good, in order to contribute to the study. The controlled extrinsically motivated participants completed the method to get a reward or avoid punishment. Amotivated participants did not complete the method. More motivated participants were assumed to be more able to overcome barriers and needed less facilitators. CONCLUSIONS: Future studies that examine the recording of food intake should include systematic efforts that aim to minimize identified barriers and promote identified facilitators. Further research should specifically aim at studying methods for (and effects of) increasing intrinsic motivation by supporting autonomy, competence, and relatedness among adolescents asked to participate in dietary studies. PMID- 27473464 TI - [Presentation]. PMID- 27473465 TI - [Part I. Fibrates in primary and secondary prevention]. PMID- 27473463 TI - The Sounds of Sentences: Differentiating the Influence of Physical Sound, Sound Imagery, and Linguistically Implied Sounds on Physical Sound Processing. AB - Both the imagery literature and grounded models of language comprehension emphasize the tight coupling of high-level cognitive processes, such as forming a mental image of something or language understanding, and low-level sensorimotor processes in the brain. In an electrophysiological study, imagery and language processes were directly compared and the sensory associations of processing linguistically implied sounds or imagined sounds were investigated. Participants read sentences describing auditory events (e.g., "The dog barks"), heard a physical (environmental) sound, or had to imagine such a sound. We examined the influence of the 3 sound conditions (linguistic, physical, imagery) on subsequent physical sound processing. Event-related potential (ERP) difference waveforms indicated that in all 3 conditions, prime compatibility influenced physical sound processing. The earliest compatibility effect was observed in the physical condition, starting in the 80-110 ms time interval with a negative maximum over occipital electrode sites. In contrast, the linguistic and the imagery condition elicited compatibility effects starting in the 180-220 ms time window with a maximum over central electrode sites. In line with the ERPs, the analysis of the oscillatory activity showed that compatibility influenced early theta and alpha band power changes in the physical, but not in the linguistic and imagery, condition. These dissociations were further confirmed by dipole localization results showing a clear separation between the source of the compatibility effect in the physical sound condition (superior temporal area) and the source of the compatibility effect triggered by the linguistically implied sounds or the imagined sounds (inferior temporal area). Implications for grounded models of language understanding are discussed. PMID- 27473466 TI - [Part II. Combination statin plus fibrate regimens (free and fixed)]. PMID- 27473467 TI - [Part III. Clinical control of fenofibrate therapy]. PMID- 27473468 TI - [Part IV. Non-lipid effects of fenofibrate therapy]. PMID- 27473469 TI - Risk factors for new-onset diabetes mellitus after living donor kidney transplantation in Korea - a retrospective single center study. AB - BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) is a serious complication following renal transplantation. The aim of this study was to identify the risk factors for the development of NODAT in Korean transplant patients. METHODS: Recipients who underwent living donor kidney transplantation between January 2009 and April 2012 at Asan Medical Center were reviewed. Diagnosis of NODAT was defined according to the American Diabetes Association criteria. RESULTS: A total of 418 patients were enrolled. NODAT was diagnosed in 85 (20.4 %) patients within 1 year. By multivariate analysis, old age (odds ratio [OR], 1.05; 95 % Confidence interval [CI]: 1.01-1.08), family history of diabetes mellitus (OR, 2.48; 95 % CI: 1.04-5.94), pre-transplant high serum glucose level (OR, 1.04; 95 % CI: 1.01-1.08), and obesity (OR, 3.46; 95 % CI: 1.55-7.73) were independent risk factors for NODAT. CONCLUSION: Old age, family history of diabetes, pre-transplant high plasma glucose level, and obesity are independent factors associated with the development of diabetes after renal transplantation. In contrast, serum magnesium levels and the use of tacrolimus are not associated with the development of NODAT. PMID- 27473471 TI - From policy to practice in the Affordable Care Act: Training center for New York State's health insurance programs. AB - BACKGROUND: The United States currently faces the large, logistical undertaking of enrolling millions of Americans into a complex Affordable Care Act (ACA) system within a short period of time. One way states have addressed this implementation challenge is through the development of consumer assistance programs. In these programs, health care professionals-known as "Assistors"-are trained in insurance enrollment services to help consumers navigate the complex application and plan selection process, with the ultimate goal of optimizing enrollment rates. ORGANIZATIONAL CONTEXT: Cicatelli Associates Inc. (CAI), a non profit capacity building organization, has served as the Statewide Training Center for New York's Health Insurance Program Initiative since 2013, before the ACA Marketplace roll-out occurred. This article presents a narrative of CAI's experiences and promising practices related to training and developing of the Assistor workforce in New York State (NYS). SOLUTIONS IDENTIFIED THROUGH TRAINING AND DEVELOPMENT: By the end of the second enrollment period (February 2015), NYS trained and certified over 11,000 Assistors (1); CAI trained fifteen percent of this total workforce. As a result of this intensive workforce training effort, NYS observed extremely high rates of facilitated enrollment, and overall success with the roll-out process. LESSONS FROM THE FIELD: Through this initiative, CAI has garnered key insights for other organizations that engage in similar work, as well as state policymakers considering how to integrate and bolster the Assistor programs in their states. These lessons include: the necessity of ensuring that Assistors are armed with all technical concepts and messages; ensuring that Assistors are motivated to work through a change process; the constructive feedback process that can occur when these Assistors directly communicate issues to the state; and the transformation of public opinion that can occur when Assistors provide good customer service and can effectively promote statewide and federal ACA policies and benefits. PMID- 27473470 TI - RLIP76 Depletion Enhances Autophagic Flux in U251 Cells. AB - Our previous study showed that RalA-binding protein 1 (RLIP76) is overexpressed in gliomas and is associated with higher tumour grade and decreased patient survival. Furthermore, RLIP76 downregulation increases chemosensitivity of glioma cells to temozolomide by inducing apoptosis. However, other mechanisms underlying RLIP76-associated chemoresistance are unknown. In this study, we investigated the effect of RLIP76 depletion on autophagy. RLIP76 was knocked down in U251 glioma cells using shRNA and autophagy-related proteins, and PI3K/Akt signalling components were evaluated. RLIP76 depletion significantly increased cell autophagy as demonstrated by a significant increase in LC3 II, autophagy protein 5 (ATG-5), and Beclin1, and a decrease in p62 expression levels. Furthermore, RLIP76 knockdown increased autophagic flux in U251 cells as autolysosome numbers increased relative to autophagosome numbers. Autophagy induced by RLIP76 knockdown resulted in increased apoptosis that was independent of temozolomide treatment. Moreover, RLIP76 knockdown decreased PI3K and Akt activation. RLIP76 depletion also resulted in decreased levels of the anti-apoptotic protein Bcl2. LY294002, a PI3K/Akt pathway inhibitor, led to increased autophagy and apoptosis in U251 RLIP76-depleted cells. Therefore, RLIP76 knockdown increased autophagic flux and apoptosis in U251 glioma cells, possibly through inhibition of the PI3K/Akt pathway. Thus, this study provides a novel mechanism for the role of RLIP76 in glioma pathogenesis and chemoresistance. PMID- 27473472 TI - Challenges in patient safety improvement research in the era of electronic health records. AB - Electronic health record (EHR) data repositories contain large volumes of aggregated, longitudinal clinical data that could allow patient safety researchers to identify important safety issues and conduct comprehensive evaluations of health care delivery outcomes. However, few health systems have successfully converted this abundance of data into useful information or knowledge for safety improvement. In this paper, we use a case study involving a project on missed/delayed follow-up of test results to discuss real-world challenges in using EHR data for patient safety research. We identify three types of challenges that pose as barriers to advance patient safety improvement research: 1) gaining approval to access/review EHR data; 2) interpreting EHR data; 3) working with local IT/EHR personnel. We discuss the complexity of these challenges, all of which are unlikely to be unique to this project, and outline some key next steps that must be taken to support research that uses EHR data to improve safety. We recognize that all organizations face competing priorities between clinical operations and research. However, to leverage EHRs and their abundant data for patient safety improvement research, many current data access and security policies and procedures must be rewritten and standardized across health care organizations. These efforts are essential to help make EHRs and EHR data useful for progress in our journey to safer health care. PMID- 27473474 TI - The Current State and Path Forward For Enterprise Image Viewing: HIMSS-SIIM Collaborative White Paper. AB - Clinical specialties have widely varied needs for diagnostic image interpretation, and clinical image and video image consumption. Enterprise viewers are being deployed as part of electronic health record implementations to present the broad spectrum of clinical imaging and multimedia content created in routine medical practice today. This white paper will describe the enterprise viewer use cases, drivers of recent growth, technical considerations, functionality differences between enterprise and specialty viewers, and likely future states. This white paper is aimed at CMIOs and CIOs interested in optimizing the image-enablement of their electronic health record or those who may be struggling with the many clinical image viewers their enterprises may employ today. PMID- 27473473 TI - AURORA: bariatric surgery registration in women of reproductive age - a multicenter prospective cohort study. AB - BACKGROUND: The expansion of the obesity epidemic is accompanied with an increase in bariatric procedures, in particular in women of reproductive age. The weight loss induced by the surgery is believed to reverse the negative impact of overweight and obesity on female reproduction, however, research is limited to in particular retrospective cohort studies and a growing number of small case-series and case-(control) studies. METHODS/DESIGN: AURORA is a multicenter prospective cohort study. The main objective is to collect long-term data on reproductive outcomes before and after bariatric surgery and in a subsequent pregnancy. Women aged 18-45 years are invited to participate at 4 possible inclusion moments: 1) before surgery, 2) after surgery, 3) before 15 weeks of pregnancy and 4) in the immediate postpartum period (day 3-4). Depending on the time of inclusion, data are collected before surgery (T1), 3 weeks and 3, 6, 12 or x months after surgery (T2-T5) and during the first, second and third trimester of pregnancy (T6-T8), at delivery (T9) and 6 weeks and 6 months after delivery (T10-T11). Online questionnaires are send on the different measuring moments. Data are collected on contraception, menstrual cycle, sexuality, intention of becoming pregnant, diet, physical activity, lifestyle, psycho-social characteristics and dietary supplement intake. Fasting blood samples determine levels of vitamin A, D, E, K, B-1, B-12 and folate, albumin, total protein, coagulation parameters, magnesium, calcium, zinc and glucose. Participants are weighted every measuring moment. Fetal ultrasounds and pregnancy course and complications are reported every trimester of pregnancy. Breastfeeding is recorded and breast milk composition in the postpartum period is studied. DISCUSSION: AURORA is a multicenter prospective cohort study extensively monitoring women before undergoing bariatric surgery until a subsequent pregnancy and postpartum period. TRIAL REGISTRATION: Retrospectively registered (July 2015 - NCT02515214 ). PMID- 27473475 TI - Rare primary leiomyosarcoma of the internal jugular vein with cervical extravascular extension. AB - Leiomysarcoma of intravascular origin is a rare malignant tumour of the soft tissue. We present what is, to our knowledge, the first example of one that has arisen from the wall of the internal jugular vein. PMID- 27473476 TI - Brittle Hair, Photosensitivity, Brain Hypomyelination and Immunodeficiency: Clues to Trichothiodystrophy. PMID- 27473477 TI - Chemical and Instrumental Approaches for Capillary Electrophoresis (CE) Fluorescence Analysis of Proteins. AB - Capillary electrophoresis (CE) coupled to fluorescence detection is an invaluable technique for the quantitative analysis of proteins of interest in the field of clinical diagnosis and quality control of novel biotechnology products. The various chemical and instrumental approaches that have been reported to carry out such sensitive analysis are described in this paper. To illustrate the contribution of CE to the analysis of therapeutic proteins, a detailed protocol for impurities profiling of a recombinant antibody sample using CE-LEDIF is given. PMID- 27473478 TI - Discrimination of Glycoproteins from Unglycosylated Proteins in Capillary Electrophoresis: Two-Color LIF Detection Coupled with Post-column Derivatization. AB - Glycosylation is one of the most important posttranslational modifications (PTMs) which lead to the functionalization of proteins. Here, we describe one method for discriminating glycosylated proteins from unglycosylated ones in their mixture sample by capillary electrophoretic separation and two-color laser-induced fluorescence detection coupled with post-column derivatization. Two lasers emitting at 450 and 532 nm permit the detection of amino groups of proteins derivatized by naphthalene-2,3-dicarboxaldehyde and a fluorescently labeled lectin, tetramethylrhodamine-labeled concanavalin A (Rh-Con A), respectively. When a protein mixture react with Rh-Con A, the glycoproteins bound with Rh-Con A exhibit signals at the same migration time in two electropherograms obtained by 450- and 532-nm lasers whereas unbound proteins show a signal only in the electropherogram of the 450-nm laser. So, when one protein is glycosylated it is detected at the same migration time in the electropherograms obtained by two lasers. PMID- 27473479 TI - Capillary Zone Electrophoresis-Mass Spectrometry of Intact Proteins. AB - Capillary electrophoresis (CE) coupled with mass spectrometry (MS) has proven to be a powerful analytical tool for the characterization of intact proteins. It combines the high separation efficiency, short analysis time, and versatility of CE with the mass selectivity and sensitivity offered by MS detection. This chapter focuses on important practical considerations when applying CE-MS for the analysis of intact proteins. Technological aspects with respect to the use of CE MS interfaces and application of noncovalent capillary coatings preventing protein adsorption are treated. Critical factors for successful protein analysis are discussed and four typical CE-MS systems are described demonstrating the characterization of different types of intact proteins by CE-MS. These methodologies comprise the use of sheath-liquid and sheathless CE-MS interfaces, and various types of noncovalent capillary coatings allowing efficient and reproducible protein separations. The discussion includes the analysis of lysozyme-drug conjugates and the therapeutic proteins human growth hormone, human interferon-beta-1a, and human erythropoietin. PMID- 27473480 TI - Screening of Small Intact Proteins by Capillary Electrophoresis Electrospray Ionization-Mass Spectrometry (CE-ESI-MS). AB - Capillary electrophoresis (CE) has been shown to be a suitable separation technique for complex samples. Combined with electrospray ionization-mass spectrometry (ESI-MS), it is a powerful tool offering the opportunity of high selectivity and sensitivity combined with the possibility to identify and characterize intact proteins. In this protocol, we demonstrate a screening method for intact proteins based on capillary zone electrophoresis (CZE) separation coupled with online mass spectrometric detection. In order to avoid protein-wall interactions, a neutral coated capillary is used to create a universal method for proteins with both low and high electrophoretic mobilities. In addition, we show the successful validation and application of this screening method for a set of eight standard proteins and the glycoprotein erythropoietin. PMID- 27473481 TI - Online Capillary IsoElectric Focusing-ElectroSpray Ionization Mass Spectrometry (CIEF-ESI MS) in Glycerol-Water Media for the Separation and Characterization of Hydrophilic and Hydrophobic Proteins. AB - Capillary isoelectric focusing (CIEF) is a high-resolution technique for the separation of ampholytes, such as proteins, according to their isoelectric point. CIEF coupled online with MS is regarded as a promising alternative to 2-D PAGE for fast proteome analysis with high-resolving capabilities and enhanced structural information without the drawbacks of conventional slab-gel electrophoresis. However, online coupling has been rarely described, as it presents some difficulties. A new methodology for the online coupling of CIEF with electrospray ionization mass spectrometry (ESI-MS) has been developed in glycerol-water media. This new integrated methodology provides a mean for the characterization of a large number of hydrophilic and hydrophobic proteins. PMID- 27473482 TI - On-Line Solid-Phase Extraction Capillary Electrophoresis Mass Spectrometry for Preconcentration and Clean-Up of Peptides and Proteins. AB - One of the major drawbacks of capillary electrophoresis (CE) and other microscale separation techniques, for the analysis of low abundant peptides and proteins in complex samples, are the poor concentration limits of detection. Several strategies have been developed to improve CE sensitivity. Here, we describe an on line solid-phase extraction capillary electrophoresis mass spectrometry method with a commercial C18 sorbent for clean-up and preconcentration of neuropeptides from highly diluted biological samples. PMID- 27473483 TI - Affinity Monolith-Integrated Microchips for Protein Purification and Concentration. AB - Affinity chromatography is a valuable method to purify and concentrate minute amount of proteins. Monoliths with epoxy groups for affinity immobilization were prepared by direct in-situ photopolymerization of glycidyl methacrylate and ethylene glycol dimethacrylate in porogenic solvents consisting of 1-dodecanol and cyclohexanol. By integrating affinity monoliths onto a microfluidic system, targeted biomolecules can be captured and retained on affinity column, while other biomolecules having no specific interactions toward the immobilized ligands flow through the microchannel. Therefore, proteins which remain on the affinity column are purified and concentrated, and then eluted by appropriate solutions and finally, separated by microchip capillary electrophoresis. This integrated microfluidic device has been applied to the purification and separation of specific proteins (FITC-labeled human serum albumin and IgG) in a mixture. PMID- 27473484 TI - Analysis of Somatropin by Double-Injection Capillary-Zone Electrophoresis in Polybrene/Chondroitin Sulfate A Double-Coated Capillaries. AB - Purity determination of somatropin as a recombinant protein is important to ensure its safety and quality. This is carried out by capillary zone electrophoresis in double-injection mode using polybrene/chondroitin sulfate A double-coated capillaries. Modification of the capillary wall eliminates protein wall interactions which results in improved accuracy and precision of the determinations. In the double-injection mode two somatropin samples are analyzed within a single electrophoretic run. Prior to the second injection, the first injected plug is electrophoresed for a predetermined time period in order to adjust the inter-plug distance. Here, the principle for the separation of somatropin charge variants is described. PMID- 27473485 TI - Poly(N,N-Dimethylacrylamide)-Based Coatings to Modulate Electroosmotic Flow and Capillary Surface Properties for Protein Analysis. AB - Capillary electrophoresis (CE) is one of the most powerful techniques for the separation of biomolecules. However, the separation efficiency of proteins in CE is often compromised by their tendency to interact with the silanol groups on the surface of the inner capillary and by an uncontrolled electroosmotic flow. Herein, we report on the use of novel hydrophilic polymeric coatings that can modulate the properties of the capillary walls. The novelty of these poly(N,N dimethylacrylamide)-based copolymers relies on the simultaneous presence of chemically reactive groups (N-acryloyloxysuccinimide and glycidyl methacrylate) and silane groups in the backbone, which results in highly stable films due to the covalent reaction between the polymer and the glass silanols. A careful optimization of monomer concentration confers anti-fouling properties to the polymer coatings, and thus allows for highly efficient acidic and alkaline protein separations. Furthermore, the presence of these monomers makes it possible to modulate the electroosmotic flow from negligible to reduced values, depending on the desired application. PMID- 27473486 TI - Measurement of Inflammatory Chemokines in Micro-dissected Tissue Biopsy Samples by Chip-Based Immunoaffinity Capillary Electrophoresis. AB - To aid in the biochemical analysis of human skin biopsies, a chip-based immunoaffinity capillary electrophoresis (ICE) system has been developed for measuring inflammatory chemokines in micro-dissected areas of the biopsy. Following isolation of the areas of interest, the tissue was solubilized and the analytes of interest were isolated by the immunoaffinity disk within the chip. The captured analytes were labeled in situ with a 635 nm light-emitting laser dye and electro-eluted into the chip separation channel. Electrophoretic separation of all of the analytes was achieved in 2.5 min with quantification of each peak being performed by online LIF detection and integration of each peak area. The degree of accuracy and precision achieved by the chip-based system is comparable to conventional immunoassays and the system is robust enough to be applied to the analysis of clinical samples. Further, with the expanding array of antibodies that are commercially available, this chip-based system can be applied to a wide variety of different biomedical and clinical analyses. PMID- 27473487 TI - Separation of Recombinant Therapeutic Proteins Using Capillary Gel Electrophoresis and Capillary Isoelectric Focusing. AB - Detailed step-by-step methods for protein separation techniques based on capillary electrophoresis (CE) are described in this chapter. Focus is placed on two techniques, capillary gel electrophoresis (CGE) and capillary isoelectric focusing (cIEF). CGE is essentially gel electrophoresis, performed in a capillary, where a hydrogel is used as a sieving matrix to separate proteins or peptides based on size. cIEF separates proteins or peptides based on their isoelectric point (pI), the pH at which the protein or peptide bears no charges. Detailed protocols and steps (including capillary preparation, sample preparation, CE separation conditions, and detection) for both CGE and cIEF presented so that readers can follow the described methods in their own labs. PMID- 27473488 TI - Characterization of Chemical and Physical Modifications of Human Serum Albumin by Capillary Zone Electrophoresis. AB - Therapeutic proteins can easily undergo chemical or physical changes during their manufacturing, purification, and storage. These modifications might change or reduce their biological activity. Therefore, it is important to have analytical methodologies that are able to reliably detect, characterize, and quantify degradation products in formulations. Capillary Zone Electrophoresis (CZE) is very well suited for the analysis of proteins due to its relatively easiness of implementation, separation efficiency, and resolving power. We describe here a CZE method that allows separating more than nine forms in therapeutic albumin, including oxidized, glycated, and truncated forms. This method uses a polyethylene oxide (PEO) coating and a buffer composed of HEPES and SDS at physiological pH. The method is reproducible (RSD < 0.5 and 4 % for migration times and peak areas, respectively) and allows quantitation of albumin forms in pharmaceutical preparations. PMID- 27473489 TI - Capillary Electrophoresis Method for the Assessment of Erythropoiesis-Stimulating Agents in Final Formulations. AB - Capillary electrophoresis (CE) comprises several separation modes that can be used to characterize proteins in terms of physico-chemical properties such as isoelectric point or molecular weight, or in terms of purity/heterogeneity for the presence of charge or size variants. In glycoproteins the heterogeneity occurring as a consequence of variable amounts of terminal sialic acid residues on glycan moieties can be detected by CE. As such, a capillary zone electrophoresis (CZE) method was found suitable for the detection of isoforms of several erythropoiesis-stimulating agents (Bietlot and Girard, J Chromatogr A 759:177-184, 1997; Boucher et al., J Pharm Biomed Anal 71:207-213, 2012). In particular, the method can be used to analyze finished products containing erythropoietin-alpha, erythropoietin-beta, or darbepoetin-alpha regardless of the formulation and without the need for sample pretreatment. The major excipients encountered in the various formulations included polysorbate 80, polysorbate 20, or human serum albumin. The ability of the method to resolve isoforms of the active ingredient in finished product enables the comparison of the isoform profile with that of the corresponding drug substance, allowing the assessment of the structural integrity and content of the active ingredients in finished products. PMID- 27473490 TI - Quality Control of Therapeutic Monoclonal Antibodies at the Hospital After Their Compounding and Before Their Administration to Patients. AB - Monoclonal antibodies (mAbs) are widely used in cancer therapy and recently many new mAbs have gained EMA and FDA approvals for oncology indications. Here we describe a highly reproducible CZE method, relying on a cationic coating allowing separation and identification of a complex mixture of four compounded mAbs widely used in cancer therapy (cetuximab, rituximab, bevacizumab, and trastuzumab). PMID- 27473491 TI - Capillary Electrophoresis-Ultraviolet-Mass Spectrometry (CE-UV-MS) for the Simultaneous Determination and Quantification of Insulin Formulations. AB - This chapter describes a CE-UV-MS method for the identification and quantification of insulin in pharmaceutical formulations in a single run. The CE conditions are optimized to avoid the adsorption of the protein onto the capillary wall. Particular attention is paid regarding the choice of the internal standard. A strategy based on multiple injections is applied to correct both ionization and injection variabilities. The methodology is validated according to international guidelines and the obtained accuracy profile demonstrates the ability of the CE-UV-MS method to quantify insulin in pharmaceutical formulations within a +/-5 % acceptance range. This strategy can be implemented in the field of quality control, as well as in the detection of counterfeits. PMID- 27473492 TI - Applications of an Automated and Quantitative CE-Based Size and Charge Western Blot for Therapeutic Proteins and Vaccines. AB - Capillary Electrophoresis (CE) is a versatile and indispensable analytical tool that can be applied to characterize proteins. In recent years, labor-intensive SDS-PAGE and IEF slab gels have been replaced with CE-SDS (CGE) and CE-IEF methods, respectively, in the biopharmaceutical industry. These two CE-based methods are now an industry standard and are an expectation of the regulatory agencies for biologics characterization. Another important and traditional slab gel technique is the western blot, which detects proteins using immuno-specific reagents after SDS-PAGE separation. This technique is widely used across industrial and academic laboratories, but it is very laborious, manual, time consuming, and only semi-quantitative. Here, we describe the applications of a relatively new CE-based western blot technology which is automated, fast, and quantitative. We have used this technology for both charge- and size-based CE westerns to analyze biotherapeutic and vaccine products. The size-based capillary western can be used for fast antibody screening, clone selection, product titer, identity, and degradation while the charge-based capillary western can be used to study product charge heterogeneity. Examples using this technology for monoclonal antibody (mAb), Enbrel, CRM197, and Clostridium difficile (C. difficile) vaccine proteins are presented here to demonstrate the utility of the capillary western techniques. Details of sample preparation and experimental conditions for each capillary western mode are described in this chapter. PMID- 27473493 TI - Affinity Capillary Electrophoresis Applied to Investigation of Valinomycin Complexes with Ammonium and Alkali Metal Ions. AB - This chapter deals with the application of affinity capillary electrophoresis (ACE) to investigation of noncovalent interactions (complexes) of valinomycin, a macrocyclic dodecadepsipeptide antibiotic ionophore, with ammonium and alkali metal ions (lithium, sodium, potassium, rubidium, and cesium). The strength of these interactions was characterized by the apparent binding (stability, association) constants (K b) of the above valinomycin complexes using the mobility shift assay mode of ACE. The study involved measurements of effective electrophoretic mobility of valinomycin at variable concentrations of ammonium or alkali metal ions in the background electrolyte (BGE). The effective electrophoretic mobilities of valinomycin measured at ambient temperature and variable ionic strength were first corrected to the reference temperature 25 degrees C and constant ionic strength (10 or 25 mM). Then, from the dependence of the corrected valinomycin effective mobility on the ammonium or alkali metal ion concentration in the BGE, the apparent binding constants of the valinomycin ammonium or valinomycin-alkali metal ion complexes were determined using a nonlinear regression analysis. Logarithmic form of the binding constants (log K b) were found to be in the range of 1.50-4.63, decreasing in the order Rb(+) > K(+) > Cs(+) > > Na(+) > NH4 (+) ~ Li(+). PMID- 27473494 TI - Glycine Polymerization on Oxide Minerals. AB - It has long been suggested that mineral surfaces played an important role in peptide bond formation on the primitive Earth. However, it remains unclear which mineral species was key to the prebiotic processes. This is because great discrepancies exist among the reported catalytic efficiencies of minerals for amino acid polymerizations, owing to mutually different experimental conditions. This study examined polymerization of glycine (Gly) on nine oxide minerals (amorphous silica, quartz, alpha-alumina and gamma-alumina, anatase, rutile, hematite, magnetite, and forsterite) using identical preparation, heating, and analytical procedures. Results showed that a rutile surface is the most effective site for Gly polymerization in terms of both amounts and lengths of Gly polymers synthesized. The catalytic efficiency decreased as rutile > anatase > gamma alumina > forsterite > alpha- alumina > magnetite > hematite > quartz > amorphous silica. Based on reported molecular-level information for adsorption of Gly on these minerals, polymerization activation was inferred to have arisen from deprotonation of the NH3+ group of adsorbed Gly to the nucleophilic NH2 group, and from withdrawal of electron density from the carboxyl carbon to the surface metal ions. The orientation of adsorbed Gly on minerals is also a factor influencing the Gly reactivity. The examination of Gly-mineral interactions under identical experimental conditions has enabled the direct comparison of various minerals' catalytic efficiencies and has made discussion of polymerization mechanisms and their relative influences possible Further systematic investigations using the approach reported herein (which are expected to be fruitful) combined with future microscopic surface analyses will elucidate the role of minerals in the process of abiotic peptide bond formation. PMID- 27473496 TI - Corrigendum to "depletion of the "gamma-type carbonic anhydrase-like" subunits of complex I affects central mitochondrial metabolism in Arabidopsis thaliana" [Biochim. Biophys. Acta 1857 (2016) 60-71]. PMID- 27473495 TI - Mitochondrial dysfunction in peripheral blood mononuclear cells in early experimental and clinical acute pancreatitis. AB - BACKGROUND/OBJECTIVES: Mitochondrial dysfunction occurs in vital organs in experimental acute pancreatitis (AP) and may play an important role in determining severity of AP. However, obtaining vital organ biopsies to measure mitochondrial function (MtF) in patients with AP poses considerable risk of harm. Being able to measure MtF from peripheral blood will bypass this problem. Furthermore, whether mitochondrial dysfunction is detectable in peripheral blood in mild AP is unknown. Therefore, the objective was to evaluate peripheral blood MtF in experimental and clinical AP. METHOD: Mitochondrial respiration was measured using high resolution oxygraphy in an experimental study in caerulein induced AP and in a separate study, in patients with mild AP. Superoxide, cytochrome c, mitochondrial membrane potential (DeltaPsi) and adenine triphosphate (ATP) were also measured as other markers of MtF. RESULTS: Even though some states of mitochondrial respiration were increased in both experimental and clinical AP, this did not lead to an increase in net ATP in patients with AP. The increased leak respiration in both studies was further proof of dyscoupled mitochondria. In the clinical study there were also features of mitochondrial dysfunction with increased leak flux control ratio, superoxide, DeltaPsi and decreased cytochrome c. CONCLUSION: There is evidence of mitochondrial dysfunction with dyscoupled mitochondria, increased superoxide and decreased cytochrome c in patients with mild acute pancreatitis. Further studies should now determine whether mitochondrial function alters with severity in AP and whether mitochondrial dysfunction responds to treatments. PMID- 27473497 TI - Retraction notice to - Sirtuin-4 modulates sensitivity to induction of the mitochondrial permeability transition pore. PMID- 27473498 TI - Widely distributed and regionally isolated! Drivers of genetic structure in Gammarus fossarum in a human-impacted landscape. AB - BACKGROUND: The actual connectivity between populations of freshwater organisms is largely determined by species biology, but is also influenced by many area- and site-specific factors, such as water pollution and habitat fragmentation. Therefore, the prediction of effective gene flow, even for well-studied organisms, is difficult. The amphipod crustacean Gammarus fossarum is a key invertebrate in freshwater ecosystems and contains many cryptic species. One of these species is the broadly distributed G. fossarum clade 11 (type B). In this study, we tested for factors driving the genetic structure of G. fossarum clade 11 in a human-impacted landscape at local and regional scales. To determine population structure, we analyzed the mitochondrial cytochrome c oxidase 1 (CO1) gene of 2,086 specimens from 54 sampling sites and microsatellite loci of 420 of these specimens from ten sites. RESULTS: We detected strong overall genetic differentiation between populations at regional and local scales with both independent marker systems, often even within few kilometers. Interestingly, we observed only a weak correlation of genetic distances with geographic distances or catchment boundaries. Testing for factors explaining the observed population structure revealed, that it was mostly the colonization history, which has influenced the structure rather than any of the chosen environmental factors. Whereas the number of in-stream barriers did not explain population differentiation, the few large water reservoirs in the catchment likely act as dispersal barriers. CONCLUSIONS: We showed that populations of Gammarus fossarum clade 11 are strongly isolated even at local scales in the human-impacted region. The observed genetic structure was best explained by the effects of random genetic drift acting independently on isolated populations after historical colonization events. Genetic drift in isolated populations was probably further enhanced by anthropogenic impacts, as G. fossarum is sensitive to many anthropogenic stressors. These findings highlight the importance of small-scale genetic studies to determine barriers restricting gene flow to prevent further loss of genetic diversity and maintain intact freshwater ecosystems. PMID- 27473499 TI - C9ORF72 repeat expansions in Chinese patients with Parkinson's disease and multiple system atrophy. AB - The hexanucleotide repeat expansions in the C9ORF72 gene has been found in some patients with atypical Parkinsonism. A number of hexanucleotide repeats were examined in a Chinese population, including 619 patients with Parkinson's disease (PD), 381 patients with multiple system atrophy (MSA), and 632 healthy controls. We did not identify any pathogenic repeat expansions in either patients or controls, and any associations between repeats number and disease risk. C9ORF72 expansions are not involved the wider spectrum of Parkinsonism. PMID- 27473500 TI - Phenotypic and genotypic characterisation of multiple antibiotic-resistant Staphylococcus aureus exposed to subinhibitory levels of oxacillin and levofloxacin. AB - BACKGROUND: The emergence and spread of multidrug resistant methicillin-resistant Staphylococcus aureus (MDR-MRSA) has serious health consequences in the presence of sub-MIC antibiotics. Therefore, this study was designed to evaluate beta lactamase activity, efflux activity, biofilm formation, and gene expression pattern in Staphylococcus aureus KACC 10778, S. aureus ATCC 15564, and S. aureus CCARM 3080 exposed to sublethal concentrations of levofloxacin and oxacillin. RESULTS: The decreased MICs were observed in S. aureus KACC and S. aureus ATCC when exposed to levofloxacin and oxacillin, while and S. aureus CCARM remained resistance to streptomycin (512 MUg/mL) in the presence of levofloxacin and imipenem (>512 MUg/mL) in the presence of oxacillin. The considerable increase in extracellular and membrane-bound beta-lactamase activities was observed in S. aureus ATCC exposed to oxacillin (>26 MUmol/min/mL). The antibiotic susceptibility of all strains exposed to EPIs (CCCP and PAbetaN) varied depending on the classes of antibiotics. The relative expression levels of adhesion-related genes (clfA, clfB, fnbA, fnnB, and icaD), efflux-related genes (norB, norC, and qacA/B), and enterotoxin gene (sec) were increased more than 5-fold in S. aureus CCARM. The eno and qacA/B genes were highly overexpressed by more than 12- and 9 folds, respectively, in S. aureus CCARM exposed to levofloxacin. The antibiotic susceptibility, lactamase activity, biofilm-forming ability, efflux activity, and gene expression pattern varied with the intrinsic antibiotic resistance of S. aureus KACC, S. aureus ATCC, and S. aureus CCARM exposed to levofloxacin and oxacillin. CONCLUSIONS: This study would provide useful information for better understating of combination therapy related to antibiotic resistance mechanisms and open the door for designing effective antibiotic treatment protocols to prevent excessive use of antibiotics in clinical practice. PMID- 27473501 TI - Plasticity in bilateral superior temporal cortex: Effects of deafness and cochlear implantation on auditory and visual speech processing. AB - While many individuals can benefit substantially from cochlear implantation, the ability to perceive and understand auditory speech with a cochlear implant (CI) remains highly variable amongst adult recipients. Importantly, auditory performance with a CI cannot be reliably predicted based solely on routinely obtained information regarding clinical characteristics of the CI candidate. This review argues that central factors, notably cortical function and plasticity, should also be considered as important contributors to the observed individual variability in CI outcome. Superior temporal cortex (STC), including auditory association areas, plays a crucial role in the processing of auditory and visual speech information. The current review considers evidence of cortical plasticity within bilateral STC, and how these effects may explain variability in CI outcome. Furthermore, evidence of audio-visual interactions in temporal and occipital cortices is examined, and relation to CI outcome is discussed. To date, longitudinal examination of changes in cortical function and plasticity over the period of rehabilitation with a CI has been restricted by methodological challenges. The application of functional near-infrared spectroscopy (fNIRS) in studying cortical function in CI users is becoming increasingly recognised as a potential solution to these problems. Here we suggest that fNIRS offers a powerful neuroimaging tool to elucidate the relationship between audio-visual interactions, cortical plasticity during deafness and following cochlear implantation, and individual variability in auditory performance with a CI. PMID- 27473502 TI - The effect of progressive hearing loss on the morphology of endbulbs of Held and bushy cells. AB - Studies of congenital and early-onset deafness have demonstrated that an absence of peripheral sound-evoked activity in the auditory nerve causes pathological changes in central auditory structures. The aim of this study was to establish whether progressive acquired hearing loss could lead to similar brain changes that would degrade the precision of signal transmission. We used complementary physiologic hearing tests and microscopic techniques to study the combined effect of both magnitude and duration of hearing loss on one of the first auditory synapses in the brain, the endbulb of Held (EB), along with its bushy cell (BC) target in the anteroventral cochlear nucleus. We compared two hearing mouse strains (CBA/Ca and heterozygous shaker-2+/-) against a model of early-onset progressive hearing loss (DBA/2) and a model of congenital deafness (homozygous shaker-2-/-), examining each strain at 1, 3, and 6 months of age. Furthermore, we employed a frequency model of the mouse cochlear nucleus to constrain our analyses to regions most likely to exhibit graded changes in hearing function with time. No significant differences in the gross morphology of EB or BC structure were observed in 1-month-old animals, indicating uninterrupted development. However, in animals with hearing loss, both EBs and BCs exhibited a graded reduction in size that paralleled the hearing loss, with the most severe pathology seen in deaf 6-month-old shaker-2-/- mice. Ultrastructural pathologies associated with hearing loss were less dramatic: minor changes were observed in terminal size but mitochondrial fraction and postsynaptic densities remained relatively stable. These results indicate that acquired progressive hearing loss can have consequences on auditory brain structure, with prolonged loss leading to greater pathologies. Our findings suggest a role for early intervention with assistive devices in order to mitigate long-term pathology and loss of function. PMID- 27473503 TI - Cortical reorganization in postlingually deaf cochlear implant users: Intra-modal and cross-modal considerations. AB - With the advances of cochlear implant (CI) technology, many deaf individuals can partially regain their hearing ability. However, there is a large variation in the level of recovery. Cortical changes induced by hearing deprivation and restoration with CIs have been thought to contribute to this variation. The current review aims to identify these cortical changes in postlingually deaf CI users and discusses their maladaptive or adaptive relationship to the CI outcome. Overall, intra-modal and cross-modal reorganization patterns have been identified in postlingually deaf CI users in visual and in auditory cortex. Even though cross-modal activation in auditory cortex is considered as maladaptive for speech recovery in CI users, a similar activation relates positively to lip reading skills. Furthermore, cross-modal activation of the visual cortex seems to be adaptive for speech recognition. Currently available evidence points to an involvement of further brain areas and suggests that a focus on the reversal of visual take-over of the auditory cortex may be too limited. Future investigations should consider expanded cortical as well as multi-sensory processing and capture different hierarchical processing steps. Furthermore, prospective longitudinal designs are needed to track the dynamics of cortical plasticity that takes place before and after implantation. PMID- 27473504 TI - Capturing contextual effects in spectro-temporal receptive fields. AB - Spectro-temporal receptive fields (STRFs) are thought to provide descriptive images of the computations performed by neurons along the auditory pathway. However, their validity can be questioned because they rely on a set of assumptions that are probably not fulfilled by real neurons exhibiting contextual effects, that is, nonlinear interactions in the time or frequency dimension that cannot be described with a linear filter. We used a novel approach to investigate how a variety of contextual effects, due to facilitating nonlinear interactions and synaptic depression, affect different STRF models, and if these effects can be captured with a context field (CF). Contextual effects were incorporated in simulated networks of spiking neurons, allowing one to define the true STRFs of the neurons. This, in turn, made it possible to evaluate the performance of each STRF model by comparing the estimations with the true STRFs. We found that currently used STRF models are particularly poor at estimating inhibitory regions. Specifically, contextual effects make estimated STRFs dependent on stimulus density in a contrasting fashion: inhibitory regions are underestimated at lower densities while artificial inhibitory regions emerge at higher densities. The CF was found to provide a solution to this dilemma, but only when it is used together with a generalized linear model. Our results therefore highlight the limitations of the traditional STRF approach and provide useful recipes for how different STRF models and stimuli can be used to arrive at reliable quantifications of neural computations in the presence of contextual effects. The results therefore push the purpose of STRF analysis from simply finding an optimal stimulus toward describing context-dependent computations of neurons along the auditory pathway. PMID- 27473505 TI - Atypical white-matter microstructure in congenitally deaf adults: A region of interest and tractography study using diffusion-tensor imaging. AB - Considerable research documents the cross-modal reorganization of auditory cortices as a consequence of congenital deafness, with remapped functions that include visual and somatosensory processing of both linguistic and nonlinguistic information. Structural changes accompany this cross-modal neuroplasticity, but precisely which specific structural changes accompany congenital and early deafness and whether there are group differences in hemispheric asymmetries remain to be established. Here, we used diffusion tensor imaging (DTI) to examine microstructural white matter changes accompanying cross-modal reorganization in 23 deaf adults who were genetically, profoundly, and congenitally deaf, having learned sign language from infancy with 26 hearing controls who participated in our previous fMRI studies of cross-modal neuroplasticity. In contrast to prior literature using a whole-brain approach, we introduce a semiautomatic method for demarcating auditory regions in which regions of interest (ROIs) are defined on the normalized white matter skeleton for all participants, projected into each participants native space, and manually constrained to anatomical boundaries. White-matter ROIs were left and right Heschl's gyrus (HG), left and right anterior superior temporal gyrus (aSTG), left and right posterior superior temporal gyrus (pSTG), as well as one tractography-defined region in the splenium of the corpus callosum connecting homologous left and right superior temporal regions (pCC). Within these regions, we measured fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and white-matter volume. Congenitally deaf adults had reduced FA and volume in white matter structures underlying bilateral HG, aSTG, pSTG, and reduced FA in pCC. In HG and pCC, this reduction in FA corresponded with increased RD, but differences in aSTG and pSTG could not be localized to alterations in RD or AD. Direct statistical tests of hemispheric asymmetries in these differences indicated the most prominent effects in pSTG, where the largest differences between groups occurred in the right hemisphere. Other regions did not show significant hemispheric asymmetries in group differences. Taken together, these results indicate that atypical white matter microstructure and reduced volume underlies regions of superior temporal primary and association auditory cortex and introduce a robust method for quantifying volumetric and white matter microstructural differences that can be applied to future studies of special populations. PMID- 27473506 TI - Acoustic input impedance of the avian inner ear measured in ostrich (Struthio camelus). AB - In both mammals and birds, the mechanical behavior of the middle ear structures is affected by the mechanical impedance of the inner ear. In this study, the aim was to quantify the acoustic impedance of the avian inner ear in the ostrich, which allows us to determine the effect on columellar vibrations and middle ear power flow in future studies. To determine the inner ear impedance, vibrations of the columella were measured for both the quasi-static and acoustic stimulus frequencies. In the frequency range of 0.3-4 kHz, we used electromagnetic stimulation of the ossicle and a laser Doppler vibrometer to measure the vibration response. At low frequencies, harmonic displacements were imposed on the columella using piezo stimulation and the resulting force response was measured with a force sensor. From these measurement data, the acoustic impedance of the inner ear could be determined. A simple RLC model in series of the impedance measurements resulted in a stiffness reactance of KIE = 0.20.10(12) Pa/m3, an inertial impedance of MIE = 0.652.10(6) Pa s(2)/m3, and a resistance of RIE = 1.57.10(9) Pa s/m. We found that values of the inner ear impedance in the ostrich are one to two orders in magnitude smaller than what is found in mammal ears. PMID- 27473507 TI - Seasonal variations in auditory processing in the inferior colliculus of Eptesicus fuscus. AB - Eptesicus fuscus is typical of temperate zone bats in that both sexes undergo marked seasonal changes in behavior, endocrine status, and reproductive status. Acoustic communication plays a key role in many seasonal behaviors. For example, males emit specialized vocalizations during mating in the fall, and females use different specialized vocalizations to communicate with infants in late spring. Bats of both sexes use echolocation for foraging during times of activity, but engage in little sound-directed behavior during torpor and hibernation in winter. Auditory processing might be expected to reflect these marked seasonal changes. To explore the possibility that seasonal changes in hormonal status could drive functional plasticity in the central auditory system, we examined responses of single neurons in the inferior colliculus throughout the year. The average first spike latency in females varied seasonally, almost doubling in spring compared to other times of year. First spike latencies in males remained relatively stable throughout the year. Latency jitter for both sexes was higher in winter and spring than in summer or fall. Females had more burst responders than other discharge patterns throughout the year whereas males had more transient responders at all times of year except fall, when burst responses were the predominant type. The percentage of simple discharge patterns (sustained and transient) was higher in males than females in the spring and higher in females than males in the fall. In females, the percentage of shortpass duration-tuned neurons doubled in summer and remained elevated through fall and early winter. In males, the percentage of shortpass duration-tuned cells increased in spring and the percentage of bandpass duration-tuned cells doubled in the fall. These findings suggest that there are clear seasonal changes in basic response characteristics of midbrain auditory neurons in Eptesicus, especially in temporal response properties and duration sensitivity. Moreover, the pattern of changes is different in males and females, suggesting that hormone-driven plasticity adjusts central auditory processing to fit the characteristics of vocalizations specific to seasonal behavioral patterns. PMID- 27473508 TI - Effect of epithelial cell type on in vitro invasion of non-typeable Haemophilus influenzae. AB - Non-typeable Haemophilus influenzae (NTHi) have been shown to have variable ability for in vitro invasion with a range of epithelial cells, and increased invasion of BEAS-2B cells has been associated with altered penicillin binding protein3 (PBP3), which is concerning as these strains are increasing worldwide. The aim of the study was to investigate the effect of respiratory cell type and the presence of altered PBP3 on the in vitro invasion of NTHi. A collection of 16 clinical NTHi isolates was established, 7 had normal PBP3, and 9 had altered PBP3 as defined by an N526K substitution. The isolates were tested for invasion of BEAS-2B, NHBE, A549 and NCI-H292 respiratory epithelial cells in vitro using a gentamicin survival assay, with invasion measured as the percentage of intracellular organisms relative to the initial inoculum. The overall median invasion for the 16 NTHi isolates for cell types BEAS-2B, NHBE, A549 and NCI-H292 cells were 3.17, 2.31, 0.11 and 1.52 respectively. The differences were statistically significant for BEAS-2B compared to A549 (P=0.015) and A549 compared to NCI-H292 (P=0.015), and there were also very marked differences in invasion for some individual isolates depending on the cell type used. There was a consistent bias for invasion of isolates with normal versus abnormal PBP3: and this was statistically significant for BEAS-2B (0.07 to 9.90, P=0.031) and A549 cells (0.02 to 1.68, P=0.037). These results show that NTHi invasion of respiratory epithelial cells in vitro is both strain dependant and influenced significantly by the cell line used, and that the association between altered PBP3 and increased invasion is conserved across multiple cell lines. PMID- 27473509 TI - Ocular surface microbiome in meibomian gland dysfunction. AB - BACKGROUND: To investigate the ocular microbiome in meibomian gland dysfunction in Auckland, New Zealand. DESIGN: Prospective, cross-sectional, observational, university-based study. PARTICIPANTS: Participants resident in New Zealand for >=2 years (n = 157) were classified as normal (n = 66), mild (n = 41) or moderate to-severe meibomian gland dysfunction (n = 50). Contact lens wear and anterior blepharitis status were recorded, as well as symptoms and clinical features. METHODS: Bacteria collected from lid margin swabs, before and after gland expression, were isolated and identified by conventional microbiological culture techniques. Aerobic isolates were identified in all 157 participants, and both aerobic and anaerobic bacteria isolated in a subset of 87 subjects. MAIN OUTCOME MEASURES: Bacterial incidence according to meibomian gland dysfunction status RESULTS: Symptoms, bulbar hyperaemia, conjunctival staining, lipid layer grade and tear film stability, but not corneal staining, showed moderate association with meibomian gland dysfunction severity. Participants with and without meibomian gland dysfunction showed a similar microbiome, unaffected by gland expression. Anterior blepharitis, a common co-morbidity, was not an independent predictor of the microbiome. Sterile cultures were more common in contact lens wearers than non-wearers. The incidence of Staphylococcus aureus was higher than anticipated across all severity groups, and that of coagulase-negative Staphylococcus, Corynebacterium and streptococci was lower. CONCLUSIONS: Modest differences in relative proportions of bacteria compared with other studies support climatic variations in the ocular surface microbiome. Similarity in microbiome profile, irrespective of meibomian gland dysfunction severity, anterior blepharitis presence or contact lens wear, suggests potential for commonality in treatment. PMID- 27473510 TI - Quasi-targeted analysis of hydroxylation-related metabolites of polycyclic aromatic hydrocarbons in human urine by liquid chromatography-mass spectrometry. AB - Metabolite identification is crucial for revealing metabolic pathways and comprehensive potential toxicities of polycyclic aromatic hydrocarbons (PAHs) in human body. In this work, a quasi-targeted analysis strategy was proposed for metabolite identification of monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) in human urine using liquid chromatography triple quadruple mass spectrometry (LC-QqQ-MS/MS) combined with liquid chromatography high resolution mass spectrometry (LC-HRMS). Potential metabolites of OH-PAHs were preliminarily screened out by LC-QqQ-MS/MS in association with filtering in a self-constructed information list of possible metabolites, followed by further identification and confirmation with LC-HRMS. The developed method can provide more reliable and systematic results compared with traditional untargeted analysis using LC-HRMS. In addition, data processing for LC-HRMS analysis were greatly simplified. This quasi-targeted analysis method was successfully applied to identifying phase I and phase II metabolites of OH-PAHs in human urine. Five metabolites of hydroxynaphthalene, seven of hydroxyfluorene, four of hydroxyphenanthrene, and three of hydroxypyrene were tentatively identified. Metabolic pathways of PAHs in human body were putatively revealed based on the identified metabolites. The experimental results will be valuable for investigating the metabolic processes of PAHs in human body, and the quasi-targeted analysis strategy can be expanded to the metabolite identification and profiling of other compounds in vivo. PMID- 27473511 TI - Rapid determination of cocamidopropyl betaine impurities in cosmetic products by core-shell hydrophilic interaction liquid chromatography-tandem mass spectrometry. AB - Cocamidopropyl betaine (CAPB) is a common surfactant widely used in personal care products. Dimethylaminopropylamine (DMAPA) and lauramidopropyldimethylamine (LAPDMA) are two chemicals present as impurities in CAPB and have been reported as skin sensitizers. A rapid and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method, using a core shell hydrophilic interaction liquid chromatography (HILIC) column, has been developed to quantify DMAPA and LAPDMA in cosmetic products. Corresponding stable isotopically labeled analogues of the above native compounds were used as internal standards to compensate for matrix effect and for loss of recovery. Each sample was first screened to determine whether the sample needed to be diluted to minimize matrix effects as well as to fit the calibration range. The concept of matrix effect factor (MEF) was introduced to quantitatively evaluate each sample with a unique matrix using the internal standards. Recoveries at three spiking levels of low, medium, and high concentrations ranged from 98.4 to 112% with RSDs less than 5%. This method has been validated and is the first UHPLC-MS/MS method, which uses core shell HILIC column and stable isotopically labeled internal standards to simultaneously determine these two CAPB impurities in cosmetic products. PMID- 27473512 TI - The use of chemometrics to study multifunctional indole alkaloids from Psychotria nemorosa (Palicourea comb. nov.). Part I: Extraction and fractionation optimization based on metabolic profiling. AB - Extraction methods evaluation to access plants metabolome is usually performed visually, lacking a truthful method of data handling. In the present study the major aim was developing reliable time- and solvent-saving extraction and fractionation methods to access alkaloid profiling of Psychotria nemorosa leaves. Ultrasound assisted extraction was selected as extraction method. Determined from a Fractional Factorial Design (FFD) approach, yield, sum of peak areas, and peak numbers were rather meaningless responses. However, Euclidean distance calculations between the UPLC-DAD metabolic profiles and the blank injection evidenced the extracts are highly diverse. Coupled with the calculation and plotting of effects per time point, it was possible to indicate thermolabile peaks. After screening, time and temperature were selected for optimization, while plant:solvent ratio was set at 1:50 (m/v), number of extractions at one and particle size at <=180MUm. From Central Composite Design (CCD) results modeling heights of important peaks, previously indicated by the FFD metabolic profile analysis, time was set at 65min and temperature at 45 degrees C, thus avoiding degradation. For the fractionation step, a solid phase extraction method was optimized by a Box-Behnken Design (BBD) approach using the sum of peak areas as response. Sample concentration was consequently set at 150mg/mL, % acetonitrile in dichloromethane at 40% as eluting solvent, and eluting volume at 30mL. Summarized, the Euclidean distance and the metabolite profiles provided significant responses for accessing P. nemorosa alkaloids, allowing developing reliable extraction and fractionation methods, avoiding degradation and decreasing the required time and solvent volume. PMID- 27473513 TI - Residual on column host cell protein analysis during lifetime studies of protein A chromatography. AB - Capacity reduction in protein A affinity chromatography with extended cycling during therapeutic antibody manufacture is well documented. Identification of which residual proteins remain from previous cycles during the lifetime of these adsorbent materials is required to understand their role in this ageing process, but represents a significant metrological challenge. Scanning electron microscopy (SEM) and liquid chromatography mass spectrometry (LC-MS/MS) are combined to detect and map this phenomenon of protein carry-over. We show that there is a morphological change at the surface of the agarose resin, revealing deposits on the polymer fibres increasing with cycle number. The amount of residual host cell proteins (HCPs) by LC-MS/MS present on the resin is shown to increase 10-fold between 50 and 100 cycles. During this same period the functional class of the predominant HCPs associated with the resin increased in diversity, with number of proteins identified increasing 5-fold. This ageing is observed in the context of the product quality of the eluate HCP and protein A leachate concentration remaining constant with cycle number. PMID- 27473514 TI - Liquid chromatographic enantioseparations on crown ether-based chiral stationary phases. AB - Various liquid chromatographic chiral stationary phases (CSPs) have been developed for the resolution of racemic compounds. In particular, CSPs based on chiral crown ethers have been known to be useful in the resolution of racemic compounds containing a primary amino group. In this paper, the development of two types of CSPs based on the chiral crown ethers containing 1,1'-binaphthyl unit(s) or tartaric acid units as chiral barrier(s) and their applications to the resolution of various racemic compounds were reviewed. The structural characteristics of eleven CSPs and their chromatographic behaviors for the resolution of racemic primary amino and non-primary amino compounds were included. PMID- 27473515 TI - Antiangiogenic effect of betaine on pathologic retinal neovascularization via suppression of reactive oxygen species mediated vascular endothelial growth factor signaling. AB - Reactive oxygen species (ROS) as well as vascular endothelial growth factor (VEGF) play important roles in pathologic retinal neovascularization. We investigated whether betaine inhibits pathologic retinal neovascularization in a mouse model of oxygen induced retinopathy (OIR). Betaine was intravitreally injected in OIR mice at postnatal day (P) 14. At P17, the neovascular tufts area in OIR retina was analyzed. Intravitreal injection of betaine (200MUM) effectively reduced the neovascular tufts area in OIR retina (68.0+/-6.7% of the control eyes, P<0.05). Even in a high concentration (2mM), betaine never induced any retinal toxicity or cytotoxicity. Betaine significantly inhibited VEGF induced proliferation, migration, and tube formation in human retinal microvascular endothelial cells (HRMECs). Betaine suppressed VEGF-induced VEGFR 2, Akt and ERK phosphorylation in HRMECs. In human brain astrocytes, betaine reduced tBH-induced ROS production, and subsequently attenuated tBH-induced VEGFA mRNA transcription via suppression of ROS. Our data suggest that betaine has an anti-angiogenic effect on pathologic retinal neovascularization via suppression of ROS mediated VEGF signaling. Betaine could be a potent anti-angiogenic agent to treat pathologic retinal neovascularization. PMID- 27473516 TI - Apigenin and naringenin ameliorate PKCbetaII-associated endothelial dysfunction via regulating ROS/caspase-3 and NO pathway in endothelial cells exposed to high glucose. AB - Endothelial dysfunction is a key event in the progression of atherosclerosis with diabetes. Increasing cell apoptosis may lead to endothelial dysfunction. Apigenin and naringenin are two kinds of widely used flavones. In the present study, we investigated whether and how apigenin and naringenin reduced endothelial dysfunction induced by high glucose in endothelial cells. We showed that apigenin and naringenin protected against endothelial dysfunction via inhibiting phosphorylation of protein kinase C betaII (PKCbetaII) expression and downstream reactive oxygen species (ROS) production in endothelial cells exposed to high glucose. Furthermore, we demonstrated that apigenin and naringenin reduced high glucose-increased apoptosis, Bax expression, caspase-3 activity and phosphorylation of NF-kappaB in endothelial cells. Moreover, apigenin and naringenin effectively restored high glucose-reduced Bcl-2 expression and Akt phosphorylation. Importantly, apigenin and naringenin significantly increased NO production in endothelial cells subjected to high glucose challenge. Consistently, high glucose stimulation impaired acetylcholine (ACh)-mediated vasodilation in the rat aorta, apigenin and naringenin treatment restored the impaired endothelium-dependent vasodilation via dramatically increasing eNOS activity and nitric oxide (NO) level. Taken together, our results manifest that apigenin and naringenin can ameliorate endothelial dysfunction via regulating ROS/caspase-3 and NO pathway. PMID- 27473517 TI - Common position of indels that cause deviations from canonical genome organization in different measles virus strains. AB - BACKGROUND: The canonical genome organization of measles virus (MV) is characterized by total size of 15 894 nucleotides (nts) and defined length of every genomic region, both coding and non-coding. Only rarely have reports of strains possessing non-canonical genomic properties (possessing indels, with or without the change of total genome length) been published. The observed mutations are mutually compensatory in a sense that the total genome length remains polyhexameric. Although programmed and highly precise pseudo-templated nucleotide additions during transcription are inherent to polymerases of all viruses belonging to family Paramyxoviridae, a similar mechanism that would serve to non randomly correct genome length, if an indel has occurred during replication, has so far not been described in the context of a complete virus genome. METHODS: We compiled all complete MV genomic sequences (64 in total) available in open access sequence databases. Multiple sequence comparisons and phylogenetic analyses were performed with the aim of exploring whether non-recombinant and non-evolutionary linked measles strains that show deviations from canonical genome organization possess a common genetic characteristic. RESULTS: In 11 MV sequences we detected deviations from canonical genome organization due to short indels located within homopolymeric stretches or next to them. In nine out of 11 identified non canonical MV sequences, a common feature was observed: one mutation, either an insertion or a deletion, was located in a 28 nts long region in F gene 5' untranslated region (positions 5051-5078 in genomic cDNA of canonical strains). This segment is composed of five tandemly linked homopolymeric stretches, its consensus sequence is G6-7C7-8A6-7G1-3C5-6. Although none of the mononucleotide repeats within this segment has fixed length, the total number of nts in canonical strains is always 28. These nine non-canonical strains, as well as the tenth (not mutated in 5051-5078 segment), can be grouped in three clusters, based on their passage histories/epidemiological data/genetic similarities. There are no indications that the 3 clusters are evolutionary linked, other than the fact that they all belong to clade D. CONCLUSIONS: A common narrow genomic region was found to be mutated in different, non-related, wild type strains suggesting that this region might have a function in non-random genome length corrections occurring during MV replication. PMID- 27473518 TI - Neonatal Plasma Transfusion: An Evidence-Based Review. AB - Several clinical scenarios for plasma transfusion are repeatedly identified in audits, including treatment of bleeding in association with laboratory evidence of coagulopathy, correction of disseminated intravascular coagulation, prevention of intraventricular hemorrhage, management of critically ill neonates (eg, during sepsis or as a volume expander), or correction of markers of prolonged coagulation in the absence of bleeding. The findings of at least one national audit of transfusion practice indicated that almost half of plasma transfusions are given to neonates with abnormal coagulation values with no evidence of active bleeding, despite the limited evidence base to support the effectiveness of this practice. Plasma transfusions to neonates should be considered in the clinical context of bleeding (eg, vitamin K dependent), disseminated intravascular coagulation, and very rare inherited deficiencies of coagulation factors. There seems to be no role for prophylactic plasma to prevent intraventricular hemorrhage or for use as a volume expander. PMID- 27473519 TI - Spillover effects of HIV testing policies: changes in HIV testing guidelines and HCV testing practices in drug treatment programs in the United States. AB - BACKGROUND: To examine the extent to which state adoption of the Centers for Disease Control and Prevention (CDC) 2006 revisions to adult and adolescent HIV testing guidelines is associated with availability of other important prevention and medical services. We hypothesized that in states where the pretest counseling requirement for HIV testing was dropped from state legislation, substance use disorder treatment programs would have higher availability of HCV testing services than in states that had maintained this requirement. METHODS: We analyzed a nationally representative sample of 383 opioid treatment programs from the 2005 and 2011 National Drug Abuse Treatment System Survey (NDATSS). Data were collected from program directors and clinical supervisors through telephone surveys. Multivariate logistic regression models were used to measure associations between state adoption of CDC recommended guidelines for HIV pretest counseling and availability of HCV testing services. RESULTS: The effects of HIV testing legislative changes on HCV testing practices varied by type of opioid treatment program. In states that had removed the requirement for HIV pretest counseling, buprenorphine-only programs were more likely to offer HCV testing to their patients. The positive spillover effect of HIV pretest counseling policies, however, did not extend to methadone programs and did not translate into increased availability of on-site HCV testing in either program type. CONCLUSIONS: Our findings highlight potential positive spillover effects of HIV testing policies on HCV testing practices. They also suggest that maximizing the benefits of HIV policies may require other initiatives, including resources and programmatic efforts that support systematic integration with other services and effective implementation. PMID- 27473520 TI - Culture-sensitive psychotraumatology. AB - BACKGROUND: Although there is some evidence of the posttraumatic stress disorder (PTSD) construct's cross cultural validity, trauma-related disorders may vary across cultures, and the same may be true for treatments that address such conditions. Experienced therapists tailor psychotherapy to each patient's particular situation, to the nature of the patient's psychopathology, to the stage of therapy, and so on. In addition, culture-sensitive psychotherapists try to understand how culture enhances the meaning of their patient's life history, the cultural components of their illness and help-seeking behaviors, as well as their expectations with regard to treatment. We cannot take for granted that all treatment-seeking trauma survivors speak our language or share our cultural values. Therefore, we need to increase our cultural competencies. METHODS: The authors of this article are clinicians and/or researchers from across the globe, working with trauma survivors in various settings. Each author focused on one or more specific cultural aspects of working with trauma survivors and highlighted the following aspects. RESULTS: As a result of culture-specific individual and collective meanings linked to trauma and trauma-related disorders survivors may be exposed to (self-)stigma in the aftermath of trauma. Patients who are reluctant to talk about their traumatic experiences may instead be willing to write or use other ways of accessing the painful memories such as drawing. In other cultures, community and family cohesion are crucial elements of recovery. While awareness of culture-specific aspects is important, we also need to beware of premature cultural stereotyping. When disseminating empirically supported psychotherapies for PTSD across cultures, a number of additional challenges need to be taken into account: many low and middle income countries have very limited resources available and suffer from a poor health infrastructure. CONCLUSIONS: In summary, culture-sensitive psychotraumatology means assuming an empathic and non judgmental attitude, trying to understand each individual's cultural background. PMID- 27473521 TI - Right temporal cortical hypertrophy in resilience to trauma: an MRI study. AB - BACKGROUND: In studies employing physiological measures such as magnetic resonance imaging (MRI), it is often hard to distinguish what constitutes risk resilience factors to posttraumatic stress disorder (PTSD) following trauma exposure and what the effects of trauma exposure and PTSD are. OBJECTIVE: We aimed to investigate whether there were observable morphological differences in cortical and sub-cortical regions of the brain, 7-8 years after a single potentially traumatic event. METHODS: Twenty-four participants, who all directly experienced the 2004 Indian Ocean Tsunami, and 25 controls, underwent structural MRI using a 3T scanner. We generated cortical thickness maps and parcellated sub cortical volumes for analysis. RESULTS: We observed greater cortical thickness for the trauma-exposed participants relative to controls, in a right lateralized temporal lobe region including anterior fusiform gyrus, and superior, middle, and inferior temporal gyrus. CONCLUSIONS: We observed greater thickness in the right temporal lobe which might indicate that the region could be implicated in resilience to the long-term effects of a traumatic event. We hypothesize this is due to altered emotional semantic memory processing. However, several methodological and confounding issues warrant caution in interpretation of the results. PMID- 27473522 TI - Assessment of Efficacy, Safety, and Quality of Life of 124 Patients Treated With Axitinib as Second-Line Therapy for Metastatic Renal-Cell Carcinoma: Experience in Real-World Clinical Practice in Japan. AB - PURPOSE: To comprehensively analyze the efficacy of axitinib for metastatic renal cell carcinoma (mRCC) patients. PATIENTS AND METHODS: This study included 124 consecutive Japanese patients treated with axitinib as second-line systemic therapy for mRCC in a routine clinical setting. RESULTS: In addition to 4 indeterminate patients (3.2%), 0 (0%), 21 (16.9%), 87 (70.2%), and 12 (9.7%) were judged to show complete response, partial response, stable disease, and progressive disease, respectively, as the best responses to axitinib. The median progression-free survival (PFS) and overall survival (OS) after initiating treatment with axitinib were 9.3 and 27.0 months, respectively. Multivariate analyses of several parameters identified the following independent predictors of PFS and OS: Memorial Sloan Kettering Cancer Center (MSKCC) classification and C reactive protein level for PFS; and MSKCC classification, C-reactive protein level, bone metastasis, and liver metastasis for OS. Common grade 3 or higher adverse events associated with axitinib were hypertension in 41 (33.1%), proteinuria in 14 (11.3%), and hand-foot syndrome in 14 (11.3%). Quality-of-life analysis using the Medical Outcomes Study 36-Item Short Form showed that 2 scores were significantly improved 12 weeks after the administration of axitinib, while there were no significant differences in the remaining 6 scores between surveys administered before and 12 weeks after the treatment with axitinib. CONCLUSION: Favorable disease control could be achieved with acceptable tolerability by introducing axitinib as second-line systemic therapy, resulting in improvement of the prognosis and quality of life of Japanese patients with mRCC. PMID- 27473524 TI - Burdened by obligation: Recognising the caring roles of people with motor neurone disease. PMID- 27473523 TI - Tyrosine Kinase and Mammalian Target of Rapamycin Inhibitors in the Treatment of Advanced Renal Cell Carcinoma: Practical Clinical Implications of Pharmacologic Features. AB - The development of multiple vascular endothelial growth factor- and mammalian target of rapamycin-targeted therapies in advanced renal cell carcinoma has resulted in significant clinical benefit. However, the availability of multiple treatment options has led to a more complicated clinical decision-making process. Prognostic factors have been incorporated into the inclusion criteria for pivotal clinical trials and have thus provided some guidance regarding the selection and sequencing of therapy. Even within a given patient risk group and particular line of therapy, questions remain regarding the optimal choice of a targeted agent. The present review provides a practical, clinician-oriented assessment of pharmacologic factors that should be considered when a receptor tyrosine kinase or mammalian target of rapamycin kinase inhibitor is used to treat patients with advanced or metastatic renal cell carcinoma. Although these 2 classes of agents have different mechanisms of action, they are metabolized by similar pathways, resulting in broadly similar pharmacokinetic and drug-drug interaction profiles. To further individualize therapy and optimize clinical benefit, an enhanced understanding of the key pharmacologic features that differentiate these agents is important. PMID- 27473525 TI - A novel arrangement of zinc finger nuclease system for in vivo targeted genome engineering: the tomato LEC1-LIKE4 gene case. AB - KEY MESSAGE: A selection-free, highly efficient targeted mutagenesis approach based on a novel ZFN monomer arrangement for genome engineering in tomato reveals plant trait modifications. How to achieve precise gene targeting in plants and especially in crops remains a long-sought goal for elucidating gene function and advancing molecular breeding. To address this issue, zinc finger nuclease (ZFN) based technology was developed for the Solanum lycopersicum seed system. A ZFN architecture design with an intronic sequence between the two DNA recognition sites was evaluated for its efficiency in targeted gene mutagenesis. Custom engineered ZFNs for the developmental regulator LEAFY-COTYLEDON1-LIKE4 (L1L4) coding for the beta subunit of nuclear factor Y, when transiently expressed in tomato seeds, cleaved the target site and stimulated imperfect repair driven by nonhomologous end-joining, thus, introducing mutations into the endogenous target site. The successful in planta application of the ZFN platform resulted in L1L4 mutations which conferred heterochronic phenotypes during development. Our results revealed that sequence changes upstream of the DNA binding domain of L1L4 can lead to phenotypic diversity including fruit organ. These results underscore the utility of engineered ZFN approach in targeted mutagenesis of tomato plant which may accelerate translational research and tomato breeding. PMID- 27473526 TI - Upregulation of LINC-AP2 is negatively correlated with AP2 gene expression with Turnip crinkle virus infection in Arabidopsis thaliana. AB - KEY MESSAGE: A long intergenic noncoding RNA LINC - AP2 is upregulated and negatively correlated with AP2 gene expression with Turnip crinkle virus infection in Arabidopsis. Plant vegetative growth and floral reproductive structure were severely retarded and distorted in Turnip crinkle virus (TCV) infected Arabidopsis thaliana. Compared to mock-inoculated plants, the stamen filaments were shorter in flowers of TCV-infected plants. However, TCV-infected plants can still produce normal seeds through artificial pollination, indicating both its pollen and stigma were biologically functional. From our high-throughput RNA-Seq transcriptome analysis, a floral structure-related APETALA2 (AP2) gene was found to be downregulated and its neighboring long intergenic noncoding RNAs (lincRNA), At4NC069370 (named LINC-AP2 in this study), were upregulated significantly in TCV-infected plants. This LINC-AP2 was further confirmed for its existence using 5'RACE technology. LINC-AP2 overexpression (LINC-AP2 OE) transgenic Arabidopsis plants were generated to compare with TCV-infected WT plants. TCV-infected LINC-AP2 OE plants which contained lower AP2 gene expression displayed more severe symptoms (including floral structure distortion) and higher TCV-CP gene transcript and coat protein levels. Furthermore, compared to TCV infected WT plants, TCV-infected ap2 mutant plants failed to open their flower buds and displayed more severe viral symptoms. In conclusion, upregulation of LINC-AP2 is negatively correlated with AP2 gene expression with TCV infection in Arabidopsis. PMID- 27473527 TI - An improved immunofluorescence staining method for chloroplast proteins. AB - KEY MESSAGE: An improved immunofluorescence staining method significantly facilitates the visualization of the subcellular localization of interested proteins in chloroplasts. As an important technical approach, immunofluorescence staining is widely used in the subcellular localization study of interested proteins. During the study of the functions of chloroplast division proteins, immunofluorescence staining was frequently adopted. Previously, a method has been developed to study the localization of a chloroplast division protein, FtsZ. However, it is laborious and time-consuming. In this study, we report a modified immunofluorescence staining method, in which protoplasts were isolated from leaf tissues, and then fixed for immunofluorescence staining. The time of the experiment was significantly reduced to several hours. Furthermore, we used correction pen in the fixation procedure and a new way to coat the slide, which greatly saved the cost of the experiment. With the chloroplast division protein ARC6 as an example, we can get a good fluorescence signal. Moreover, the localization of ARC6 in two chloroplast division mutants, arc3 and arc5, and three other plant species, such as cabbage, radish and pea, was also successfully analyzed with our new method. Overall, the immunofluorescence staining method we reported here is very practical, and it significantly facilitates the visualization of the subcellular localization of interested proteins in plant cells. PMID- 27473528 TI - More than 50 UK Zika cases are reported in people returning from abroad so far this year. PMID- 27473529 TI - The role of boundary spanners in delivering collaborative care: a process evaluation. AB - BACKGROUND: On average, people with schizophrenia and psychosis die 13-30 years sooner than the general population (World Psychiatry 10 (1):52-77, 2011). Mental and physical health care is often provided by different organisations, different practitioners and in different settings which makes collaborative care difficult. Research is needed to understand and map the impact of new collaborative ways of working at the primary/secondary care interface (PloS One 7 (5); e36468). The evaluation presented in this paper was designed to explore the potential of a Community and Physical Health Co-ordinator role (CPHC) (CPHCs were previously Care Co-ordinators within the Community Mental Health Team, Community in the title CPHC refers to Community Mental Health) and Multi-Disciplinary Team (MDT) meetings across primary and community care, with the aim of improving collaboration of mental and physical health care for service users with Severe Mental Illness (SMI). METHODS: Data collection took place across five general practices (GPs) and a Community Mental Health Team (CMHT) in the Northwest of England, as part of a process evaluation. Semi-structured interviews were conducted with a purposive sample of GP staff (n= 18) and CMHT staff (n=4), a focus group with CMHT staff (n=8) and a survey completed by 13 CMHT staff, alongside cardiovascular risk data and MDT actions. Framework analysis was used to manage and interpret data. RESULTS: The results from the evaluation demonstrate that a CPHC role and MDT meetings are effective mechanisms for improving the collaboration and co-ordination of physical health care for SMI service users. The findings highlight the importance of embedding and supporting the CPHC role, with an emphasis on protected time and continuing professional roles and integrating multiple perspectives through MDT meetings. Considering the importance of physical health care for SMI service users and the complex environment, these are important findings for practitioners, researchers and policy makers in the field of primary care and mental health. CONCLUSION: There is an increasing focus on integration and collaborative working to ensure the delivery of quality care across the whole patient pathway, with a growing need for professionals to work together across service and professional boundaries. The introduction of a two pronged approach to collaboration has shown some important improvements in the management of physical health care for service users with SMI. PMID- 27473530 TI - Oral exposure to commercially available coal tar-based pavement sealcoat induces murine genetic damage and mutations. AB - Coal tar (CT) is a thick black liquid produced as a by-product of coal carbonization to produce coke or manufactured gas. It is comprised a complex mixture of polycyclic aromatic compounds, including a wide range of polycyclic aromatic hydrocarbons (PAHs), many of which are genotoxic and carcinogenic. CT is used in some pavement sealants (also known as sealcoat), which are applied to pavement in order to seal and beautify the surface. Human exposure is known to occur not only during application, but also as a result of the weathering process, as elevated levels of PAHs have been found in settled house dust in residences adjacent to CT-sealed surfaces. In this study we examined the genotoxicity of an extract of a commercially available CT-based sealcoat in the transgenic MutaTMMouse model. Mice were orally exposed to 3 doses of sealcoat extract daily for 28 days. We evaluated genotoxicity by examining: (1) stable DNA adducts and (2) lacZ mutations in bone marrow, liver, lung, small intestine, and glandular stomach, as well as (3) micronucleated red blood cells. Significant increases were seen for each endpoint and in all tissues. The potency of the response differed across tissues, with the highest frequency of adducts occurring in liver and lung, and the highest frequency of mutations occurring in small intestine. The results of this study are the first demonstration of mammalian genotoxicity following exposure to CT-containing pavement sealcoat. This work provides in vivo evidence to support the contention that there may be adverse health effects in mammals, and potentially in humans, from exposure to coal tar. Environ. Mol. Mutagen. 57:535-545, 2016. (c) 2016 Her Majesty the Queen in Right of Canada. PMID- 27473531 TI - Incidence of second hip fractures and associated mortality in Taiwan: A nationwide population-based study of 95,484 patients during 2006-2010. AB - OBJECTIVES: The aim of the study is was to determine the incidence and mortality of second hip fracture using a nationwide database. PATIENTS AND METHODS: A nationwide epidemiological study was conducted using the Taiwan National Health Insurance Research Database from 2001 to 2011. Patients older than 50 years with hip fractures from 2006 to 2011 were included in the study. A total of 95,484 hip fractures were identified, with subsequent second hip fracture occurred in 4102 of them. RESULTS: The incidence rate ratio of second hip fracture showed a 7.13 fold of risk of further hip fracture in 3 months, 5.21 fold in one year, and remained more than 2 fold in the end of 6th year when compared with the general population. The 6-year cumulative incidence of a second hip fracture was higher in female (8.0%) than in male (6.2%). A significantly higher 1-year mortality rate was seen after a second hip fracture (18.8%) compared to the first hip fracture (14.1%) (p < 0.05). Men had higher 1- and 5-year mortality rates after second hip fractures (12.1% and 41.2%, respectively) than women (17.4% and 47.3%, respectively). CONCLUSIONS: Patients with hip fractures would have a 2-7 fold of risk of a second fracture within 6 years. Women were more prone to a second hip fracture than men but men had a higher mortality rate. PMID- 27473532 TI - Obstructive sleep apnoea in patients with epilepsy: a meta-analysis. AB - PURPOSE: The aim of this study was to accurately determine the prevalence of obstructive sleep apnoea (OSA) in patients with epilepsy (PWE) and to evaluate the efficacy of seizure control after treating OSA. METHODS: Articles were identified through a search of both MEDLINE and Embase. The articles were collected and data were extracted independently by two authors. OSA was described using the following terms: Apnoea/hypopnoea index (AHI) and respiratory disturbance index (RDI). The variables were calculated using DerSimonian and Laird's random-effects model and odds ratio (OR). RESULTS: The prevalence of mild to-severe OSA in PWE was determined to be 33.4 % (95 % CI 20.8-46.1 %), and PWE are more susceptible to OSA as compared to healthy controls (OR 2.36; 95 % CI 1.33-4.18). Males were shown to be more susceptible to OSA than females (OR 3.00; 95 % CI 2.25-3.99). The results also indicated that the prevalence of OSA in patients with refractory epilepsy is not higher than the prevalence of OSA in PWE overall (17.5 vs 33.4 %). The prevalence of OSA was not found to be significantly different for different seizure types or in the number of antiepileptic drugs (AEDs). Patients that had been treated with continuous positive airway pressure (CPAP) were shown to have better seizure control than those untreated (OR 5.26; 95 % CI 2.04-13.5). CONCLUSIONS: The prevalence of OSA in PWE is higher than in the general population. Additionally, the results of our study suggest that CPAP treatment results in a reduction of seizures. PMID- 27473534 TI - Phylogeographical Analysis Reveals Distinct Sources of HIV-1 and HCV Transmitted to Former Blood Donors in China. AB - Historically, coinfection of HIV and hepatitis C virus (HCV) was frequent among Chinese former blood donors (FBDs). This is largely due to ignorance/lack of education regarding appropriate sterilizing techniques and/or the availability of single-use needles and equipment. Although HCV shares identical transmission routes with HIV, the source of HCV in the Chinese blood donor population still remains unknown. In this study, we investigated the evolution and transmission of HCV and HIV in the Chinese FBD group. Similar to previous reports, two HCV subtypes (HCV 1b and 2a) and one HIV subtype (Thai-B) were identified in FBDs. The HCV 1b subtype had a similar evolutionary rate of 1.9 * 10-3 substitutions/site/year to that of HIV (2.06 * 10-3 substitutions/site/year), while the HCV 2a subtype had a faster evolutionary rate of 3.8 * 10-3 substitutions/site/year. Phylogeographical analysis indicated that the introduction of HCV 1b into FBDs was estimated to be earlier than that of HCV 2a and HIV (late 1970s vs. late 1980s). Bayesian Skyline Plot (BSP) analysis further confirmed our findings, showing that HCV 1b infections breached a fast exponential growth from 1991 to 1998, while the HCV 2a infections had a fast exponential growth that occurred in around 1996-2001. Overall, this investigation helps to better understand HCV transmission in China and supports improvements of HCV prevalence control. PMID- 27473533 TI - Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection. AB - Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment-limiting side effects and its additive toxicity with interferon, the search for interferon- and ribavirin-free regimens has been underway. The recent approvals of all-oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co-administered with all-oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all-oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups. PMID- 27473535 TI - Mitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics. AB - Skeletal muscle insulin resistance in obesity associates with mitochondrial dysfunction, but the causality of this association is controversial. This review evaluates mitochondrial models of nutrient-induced muscle insulin resistance. It transpires that all models predict that insulin resistance arises as a result of imbalanced cellular bioenergetics. The nature and precise origin of the proposed insulin-numbing molecules differ between models but all species only accumulate when metabolic fuel supply outweighs energy demand. This observation suggests that mitochondrial deficiency in muscle insulin resistance is not merely owing to intrinsic functional defects, but could instead be an adaptation to nutrient induced changes in energy expenditure. Such adaptive effects are likely because muscle ATP supply is fully driven by energy demand. This market-economic control of myocellular bioenergetics offers a mechanism by which insulin-signalling deficiency can cause apparent mitochondrial dysfunction, as insulin resistance lowers skeletal muscle anabolism and thus dampens ATP demand and, consequently, oxidative ATP synthesis. PMID- 27473536 TI - Hepatoprotective activity of ethanolic extract of Salix subserrata against CCl4 induced chronic hepatotoxicity in rats. AB - BACKGROUND: The liver performs diverse functions that are essential for life. In the absence of reliable liver protective drugs, a large number of natural medicinal preparations are used for the treatment of liver diseases. Therefore the present study aims to investigate the hepatoprotective effects of Salix subserrata Willd flower ethanolic extract (SFEE) against carbon tetrachloride (CCl4)-induced liver damage. METHODS: Rats were divided into 4 groups of 10 animals each. Group I served as the normal healthy control, groups II rats were intoxicated with CCl4 i.p. (0.8 ml/kg body weight CCl4/olive oil, twice weekly for 9 weeks), group III rats received CCl4 i.p. and SFEE orally (150 mg/kg daily) and group IV rats received CCl4 i.p. and Silymarin orally (100 mg/kg, daily). The hepatoprotective potential of SFEE in rats was evaluated by measuring the protein levels of two inflammatory biomarkers; tumor necrosis factor-alpha (TNF-alpha) and nuclear factor kappa-B (NF-kB) in addition to other liver biomarkers. Histopathological changes in the liver were assessed using hematoxylin and eosin staining (HE). RESULTS: The administration of SFEE showed hepatic protection at an oral dose of 150 mg/kg. SFEE significantly reduced the elevated serum levels of intracellular liver enzymes as well as liver biomarkers in comparison to CCl4- intoxicated group. Notably, SFEE significantly reduced the expression levels of TNF-alpha and NFkB proteins compared to their levels in CCl4 intoxicated group. These findings were confirmed with the histopathological observations, where SFEE was capable of reversing the toxic effects of CCl4 on liver cells compared to that observed in CCl4-intoxicated animals. CONCLUSION: Our results show that SFEE has potential hepatoprotective effects at 150 mg/kg. These effects can be regarded to the antioxidant and anti-inflammatory properties of the extract. PMID- 27473537 TI - Management of Hyperglycemia in Patients With Acromegaly Treated With Pasireotide LAR. AB - Pasireotide (Signifor((r))) long-acting release (LAR) is a next-generation somatostatin receptor ligand (SRL) approved for treatment of patients with acromegaly who have had an inadequate response to surgery or for whom surgery is not an option. Pasireotide LAR has been shown to be more effective than other SRLs in providing biochemical control in patients with acromegaly. However, hyperglycemia-related adverse events were more frequent in patients treated with pasireotide LAR than in those treated with other SRLs. Given the effectiveness of pasireotide LAR, it is important to understand whether these hyperglycemia related events are manageable and, if so, the appropriate steps to take to manage them. In patients treated with pasireotide LAR, levels of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) increased in the first 1-3 months and stabilized for as long as 26 months thereafter. In phase III trials of patients with acromegaly, only 3.4-3.8 % discontinued pasireotide LAR because of hyperglycemia-related adverse events. In cases in which pasireotide LAR was discontinued, FPG and HbA1c levels returned to baseline. Frequent monitoring of glucose levels is recommended, especially immediately after initiating and discontinuing pasireotide LAR. The treatment strategies suggested herein are made on the basis of available clinical data from healthy volunteers and post hoc analyses of phase III trials. Data from several clinical trials indicate a predictable and possibly reversible hyperglycemic effect that is manageable with proactive monitoring and available antidiabetic medications. PMID- 27473538 TI - Sertoli - Leydig cell tumor with retiform areas and overgrowth of rhabdomyosarcomatous elements: case report and literature review. AB - BACKGROUND: Sertoli - Leydig cell tumors (SLCTs) are sex-cord stromal tumors that account less than 0.5 % of primary ovarian neoplasms. They are mostly benign and occur in reproductive age women. Variants with heterologous mesenchymal elements are exceptionaly rare. The usual presentation of SLCTs is with signs of androgen excess as majority of them produce androgens. CASE PRESENTATION: We present a case of a SLCT occurring in a 70 year old woman. Her presenting complaint was abdominal distension and pain. She had no signs of androgen or estrogen excess. Transvaginal ultrasound (TVUS) and CT scan showed a multilocular adnexal tumor and level of CA 125 was raised. A complete cytoreduction was achieved with surgical procedure. Histopathological examination revealed moderately differentiated SLCT with retiform areas and owergrowth of heterologous component in form of embrional rhabdomyosarcoma (RMS). She returned 7 months after the surgery with a large abdominal mass, ascites, right- sided hydronephrosis and massive pulmonary embolism. Due to the widespread disease and her poor general condition, she received only palliative care. She died 15 days after the admission. No autopsy was performed. CONCLUSIONS: Due to the rarity of SLCTs, especially those with retiform areas and heterologous elements, their management remains challenging. There is no firm evidence that adjuvant chemotherapy is effective in improving survival in SLCTs with malignant heterologous elements. Further studies with a higher number of cases and a longer follow-up are needed to better predicting the prognosis and determine the role of chemotherapy in such cases. PMID- 27473539 TI - Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24. AB - Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation. PMID- 27473540 TI - Is quantum entanglement in homeopathy a reality? PMID- 27473541 TI - The publication in Homeopathy of studies involving animal experimentation. PMID- 27473542 TI - Homeopathic therapy in pediatric atopic diseases: short- and long-term results. AB - AIM: To study the outcomes of atopic diseases in children treated with homeopathy at the Homeopathic Clinic of Lucca (Italy) and related long-term results after approximately an 8-year period. MATERIALS AND METHODS: Our data derive from an observational longitudinal study carried out on 857 pediatric patients who consecutive visited from 1998 to 2014. Children with atopic diseases were 325 (37.9%), 126 (39%) suffered from atopic dermatitis, 72 (22%) from allergic rhinitis, and 127 (39%) from asthma. Moreover, a long-term study was conducted on a subset of 107/165 patients, consecutively visited from 1998 to 2006, and with >=5 years follow-up. The study also investigated the evolution of overall symptoms in those patients with a complex atopic symptomatology. RESULTS: 75.8% of atopic children had moderate or major improvement (67.1% with asthma as the primary disease; 84.2% rhinitis; 84.2% dermatitis). At re-evaluation after 5-10 years, complete remission of atopic symptoms was obtained in 70.1% of the children: 84.2% in dermatitis; 48.1% in allergic rhinitis; 71.4% in asthma. Children with two or three atopic diseases at the first visit were completely cured in 40% of cases. CONCLUSION: The results seem to confirm that homeopathic medicine produces positive therapeutic response in atopic children. PMID- 27473543 TI - Preparation, standardization and in vitro safety testing of Mycobacterium nosodes (Emtact- polyvalent nosode). AB - BACKGROUND: Most of the nosodes in the homeopathic pharmacopeia have been sourced from obscure pathological material over a century ago; of which no scientific documentation is available. METHOD: A method for preparation and standardization of univalent and polyvalent Mycobacterium nosodes (labeled as Emtact), using different strains of Mycobacterium tuberculosis was developed. The committee comprising microbiologists, scientist, pharmacist, homeopaths and clinicians had reviewed and approved the method of preparation of nosode. Preparation of the nosode was based on the reference in the Homeopathy Pharmacopoeia of India (HPI), group N-IV. Strains of M. tuberculosis viz. Standard strain H37Rv, multi-drug resistant (MDR) M. tuberculosis, Mycobacterium bovis (BCG vaccine) and Mycobacterium avium were identified, procured and documented. Twenty billion viable cells for each strain were taken for Original Stock Nosode (OSN). The original stock was prepared by suspending the microbial cells into water for injection (WFI) (1 ml). As per the Indian Pharmacopoeia (IP) monograph, sterility testing was done for different potencies. Polymerase Chain Reaction (PCR) was performed for 30c potency for detection of any DNA material of the source organisms. RESULT: A polyvalent (multi-strain) and univalent M. tuberculosis nosodes were prepared for research and clinical use. No growth of Mycobacterium was observed in any of the samples above 5c potency. The in-vitro testing for nosode (30c) was found to be free from any organism and DNA material. CONCLUSION: Mycobacterium nosodes sourced from individual strain and polyvalent Emtact nosode in vitro testing results found to be satisfactory for its handling and utilization. The nosode seems to be safe and may be tested further in vivo to explore its therapeutic application. PMID- 27473544 TI - Survey on hand gestures relevance in patient practitioner communication: a homeopathic example. AB - BACKGROUND: Gestures play an important role in medical communication. METHODS: 94 homeopaths (Mean age 49.6 years, 20% male) completed a 20-item questionnaire on utilization and relevance of gestures in patients' symptom description. RESULTS: After excluding nine items due to low validity (n = 4) or low item total correlation (n = 5), factor analysis of the questionnaire resulted in the following three dimensions explaining 66.6% of variance: 'Hand gestures in relation to verbal expressions' (5 items; Cronbach's alpha = 0.81), 'Hand Gestures describing the experience of bodily and mental symptoms' (4 items; Cronbach's alpha = 0.74) and 'practitioners' behavior and active attitude in observing hand gestures' (2 items; Cronbach's alpha = 0.86). CONCLUSION: The survey shows how homeopathic therapists view patients' hand gestures, whether they use these diagnostically and how this relates to their homeopathic practice. Practitioners with only homeopathic influence on this topic are highly congruent to findings on hand gestures from other domains. PMID- 27473545 TI - Protocol of randomized controlled trial of potentized estrogen in homeopathic treatment of chronic pelvic pain associated with endometriosis. AB - BACKGROUND: Endometriosis is a chronic inflammatory disease that causes difficult to-treat pelvic pain. Thus being, many patients seek help in complementary and alternative medicine, including homeopathy. The effectiveness of homeopathic treatment for endometriosis is controversial due to the lack of evidences in the literature. The aim of the present randomized controlled trial is to assess the efficacy of potentized estrogen compared to placebo in the treatment of chronic pelvic pain associated with endometriosis. METHODS/DESIGN: The present is a randomized, double-blind, placebo-controlled trial of a homeopathic medicine individualized according to program 'New Homeopathic Medicines: use of modern drugs according to the principle of similitude' (http://newhomeopathicmedicines.com). Women with endometriosis, chronic pelvic pain and a set of signs and symptoms similar to the adverse events caused by estrogen were recruited at the Endometriosis Unit of Division of Clinical Gynecology, Clinical Hospital, School of Medicine, University of Sao Paulo (Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo - HCFMUSP). The participants were selected based on the analysis of their medical records and the application of self-report structured questionnaires. A total of 50 women meeting the eligibility criteria will be randomly allocated to receive potentized estrogen or placebo. The primary clinical outcome measure will be severity of chronic pelvic pain. Statistical analysis will be performed on the intention-to-treat and per-protocol approaches comparing the effect of the homeopathic medicine versus placebo after 24 weeks of intervention. DISCUSSION: The present study was approved by the research ethics committee of HCFMUSP and the results are expected in 2016. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: https://clinicaltrials.gov/ct2/show/NCT02427386. PMID- 27473546 TI - A morphometric and molecular study of the apoptosis observed on tadpoles' tail explants under the exposition of triiodothyronine in different homeopathic dilutions. AB - BACKGROUND: As a therapeutic system, homeopathy is supported by: i) similitude and experimentation in healthy individuals, ii) potentization. A challenge for researchers consists in looking for signals in water (or vehicle) to explain the storage of information in extremely high dilutions and the transfer of such information to the living systems. Anuran amphibian metamorphosis is controlled by thyroid hormones (TH), including the resorption of the tadpole tail. Apoptosis is a genetically regulated form of cell death that can be triggered by various extracellular and intracellular stimuli resulting in coordinated activation of a family of cysteine proteases called caspases. METHODS: This study was blind and randomized. It performed in three stages: I) the identification of the most effective T3 homeopathic dilution to induce apoptotic reactions in Rana (Lithobates) catesbeianus tadpole tail explants stimulated by T3 in substantial, II) study of different controls and III) detection in explants under the action of the most effective dilution of T3, as established in Stage I. RESULTS: There was no statistically significant difference between tail macroscopic dimensions between the groups. T3 10cH decreased the expression of caspase 3/7 mRNA, in explants treated with T3 20 nM. CONCLUSION: The present experiment is in agreement with the hypothesis that T3, at a 10cH homeopathic dilution, changes the metamorphosis molecular network. PMID- 27473547 TI - Homeopathic treatments modify inflammation but not behavioral response to influenza antigen challenge in BALB/c mice. AB - BACKGROUND: Influenza affects thousands of people worldwide every year, motivating the development of new therapies. In this work, the effects of two homeopathic preparations (influenza biotherapies and thymulin) were chosen following two different rationales: isotherapy and endo-isotherapy models. The homeopathic effects were evaluated individually considering the inflammatory and behavioral responses against influenza virus antigen were studied in BALB/c mice. METHODS: Male adult mice were treated orally and blindly for 21 days with highly diluted influenza virus or with thymulin, and were divided in two sets of experiments. The first series of experiments aimed to describe their behavior, using an open field (OF) device. In the second series, mice were challenged subcutaneously with influenza hemagglutinin antigen (7 MUg/200 MUl) at day 21. At day 42, behavior and inflammation response were evaluated. RESULTS: No behavioral changes were seen in OF tests at any time point after treatments. Flow cytometry and morphometry revealed significant changes in T and B cell balance after influenza antigen challenge, varying according to treatment. CONCLUSION: The results show that both homeopathic treatments induced subtle changes in acquired immune anti-viral response regulation. A deeper understanding of the mechanism could elucidate their possible use in influenza epidemiological situations. PMID- 27473549 TI - First evidence of Beauvais' hypothesis in a plant model. AB - INTRODUCTION: Beauvais presented the application of a so-called 'quantum-like model of homeopathy' by introducing the idea of a type of randomization/unblinding which he called 'in situ'. He predicted that randomized studies based on this type of randomization/unblinding lead to more pronounced effects in placebo controlled randomized homeopathic trials. We designed an experiment regarding wheat germination and stalk length to investigate Beauvais' idea of 'in situ randomization/unblinding' using a homeopathic dilution of sulphur (LM VI) as compared to placebo as well as to water. AIM AND METHOD: The primary aim of this double-blind randomized controlled experiment was to investigate whether there are differences of 'in situ randomization/unblinding' vs 'central randomization/unblinding' with respect to the effect of a homeopathic substance compared to placebo. The secondary aim of our study was to examine possible differences between the sulphur and the placebo group in the 'in situ' arm regarding germination and/or stalk growth of wheat seedlings measured after a seven days exposure. Wheat was treated either with sulphur LM VI, placebo, or water. The wheat grains were placed on glass lids and treatment was performed following the 'in situ randomization/unblinding' as well as 'central randomization/unblinding' method. Germination was measured and classified into three categories. RESULTS: Under 'in situ' randomization/unblinding the odds of a seed not to germinate is 40% lower if treated with sulphur compared to placebo (p=0.004). In contrast, these odds are practically equal in the 'central' meta group (OR=1.01, p=0.954). Under 'in situ' randomization/unblinding the odds of a seed to germinate with a length >=1mm is practically equal if treated with sulphur or with placebo (OR=0.96, p=0.717). In contrast, these odds are 21% higher under sulphur compared to placebo in the 'central' meta-group (OR=1.21, p=0.062). In summary, we found a sulphur effect that is significantly different between 'in situ' and 'central' randomization/unblinding relating to all three stages of germination. PMID- 27473548 TI - In vitro assessment of anticytotoxic and antigenotoxic effects of CANOVA((r)). AB - BACKGROUND: CANOVA((r)) (CA) is a homeopathic immunomodulator. It contains several homeopathic medicines prepares according to the Brazilian Pharmacopoeia. CA is indicated in clinical conditions in which the immune system is impaired and against tumors. N-methyl-N-nitrosourea (NMU) is an N-nitroso compound, with genotoxic/mutagenic properties. Although several studies have shown promising results in the use of CA, there are no studies reporting possible antigenotoxic effects. METHOD: This study evaluated the in vitro antigenotoxic and anticytotoxic effects of CA in human lymphocytes exposed to NMU. Samples of human lymphocytes that were subjected to different concentrations of a mixture containing CA and NMU were used. The genotoxicity/antigenotoxicity of CA was evaluated by the comet assay, anticytotoxicity was assessed by quantification of apoptosis and necrosis using acridine orange/ethidium bromide. RESULTS: CA significantly reduced DNA damage induced by NMU and reduced significantly the frequency of NMU-induced apoptosis after 24 h of treatment. CONCLUSION: CA has an important cytoprotective effect significantly reducing the DNA damage and apoptosis induced by the carcinogen NMU. PMID- 27473550 TI - Explanatory models for homeopathy: from the vital force to the current paradigm. AB - Facing claims for and against the scientific status of homeopathy, one is entitled to ask: is there a scientific model for homeopathy? In this study we reconstructed the model put forward by Hahnemann. The results showed that it was essentially based on the assumption of a 'vital force' exclusive to living beings. While the vital force was a basic element of 18th-century science, the existence of such a sui generis force of nature was refuted with the formulation of the law of the conservation of energy by mid-19th century. As a function of that fact for homeopathic theory, we discuss the history of the rise and demise of the theory of the vital force from the last quarter of the 18th century to 1830. Finally, we call the attention to the paradigm shift biology underwent starting at the end of the 19th century as the framework for contemporary views on the functioning of living beings and consequently, of the effects of pharmacological agents on them. PMID- 27473551 TI - Reply to Letter to the Editor regarding recurrent sebaceous carcinoma of the eyelid: Outcome after postoperative reirradiation. PMID- 27473552 TI - Computed Tomography Use for Adults With Head Injury: Describing Likely Avoidable Emergency Department Imaging Based on the Canadian CT Head Rule. AB - BACKGROUND: Millions of head computed tomography (CT) scans are ordered annually, but the extent of avoidable imaging is poorly defined. OBJECTIVES: The objective was to determine the prevalence of likely avoidable CT imaging among adults evaluated for head injury in 14 community emergency departments (EDs) in Southern California. METHODS: We conducted an electronic health record (EHR) database and chart review of adult ED trauma encounters receiving a head CT from 2008 to 2013. The primary outcome was discordance with the Canadian CT Head Rule (CCHR) high risk criteria; the secondary outcome was use of a neurosurgical intervention in the discordant cohort. We queried systemwide EHRs to identify CCHR discordance using criteria identifiable in discrete data fields. Explicit chart review of a subset of discordant CTs provided estimates of misclassification bias and assessed the low-risk cases who actually received an intervention. RESULTS: Among 27,240 adult trauma head CTs, EHR data classified 11,432 (42.0%) discordant with CCHR recommendation. Subsequent chart review showed that the designation of discordance based on the EHR was inaccurate in 12.2% (95% confidence interval [CI] = 5.6% to 18.8%). Inter-rater reliability for attributing CCHR concordance was 95% (kappa = 0.86). Thus, we estimate that 36.8% of trauma head CTs were truly likely avoidable (95% CI = 34.1% to 39.6%). Among the likely avoidable CT group identified by EHR, only 0.1% (n = 13) received a neurosurgical intervention. Chart review showed none of these were actually "missed" by the CCHR, as all 13 were misclassified. CONCLUSION: About one-third of head CTs currently performed on adults with head injury may be avoidable by applying the CCHR. Avoidance of CT in such patients is unlikely to miss any important injuries. PMID- 27473553 TI - Wukongibacter baidiensis gen. nov., sp. nov., an anaerobic bacterium isolated from hydrothermal sulfides, and proposal for the reclassification of the closely related Clostridium halophilum and Clostridium caminithermale within Maledivibacter gen. nov. and Paramaledivibacter gen. nov., respectively. AB - An anaerobic, Gram-stain-positive, spore-forming bacterium, designated DY30321T, was isolated from a sample of mixed hydrothermal sulfides collected during cruise DY30 of R/V Da Yang Yi Hao. Cells of strain DY30321T were rod-shaped with rounded ends, and were not motile. Strain DY30321T grew optimally at pH 8.0, at 30 degrees C and at a salinity (sea salts) of 30-40 g l-1. The principal fatty acids of strain DY30321T were C14 : 0 and summed feature 1 (comprising iso H-C15 : 1/C13 : 0 3-OH). The predominant polar lipids of strain DY30321T were diphosphatidylglycerol, phosphatidylcholine and phosphatidylethanolamine. No respiratory quinone was detected. The G+C content of the genomic DNA of strain DY30321T was 33.4 mol%. Phylogenetically, strain DY30321T branched within the family Peptostreptococcaceae, with (misclassified) Clostridium halophilum M1T being its closest phylogenetic relative (94.6 % 16S rRNA gene sequence similarity), followed by (misclassified) Clostridium caminithermale DVird3T (92.1 %). These strains showed very low 16S rRNA gene sequence similarity (<84 %) to Clostrdium butyricum ATCC 19398T, the type species of the genus Clostridium sensu stricto. On the basis of its phenotypic, phylogenetic and chemotaxonomic characteristics, strain DY30321T (=KCTC 15549T=MCCC 1A01532T) is considered as the type strain of a novel species of a new genus in the family Peptostreptococcaceae, for which the name Wukongibacterbaidiensis gen. nov., sp. nov. is proposed. Maledivibacter gen. nov. is proposed to accommodate Clostridium halophilum as Maledivibacter halophilus comb. nov. (type species of the genus), and Paramaledivibacter gen. nov. to accommodate Clostridium caminithermale as Paramaledivibacter caminithermalis comb. nov. (type species of the genus). PMID- 27473554 TI - Fabrication and biological evaluation of chitosan coated hyaluronic acid docetaxel conjugate nanoparticles in CD44(+) cancer cells. AB - BACKGROUND: Hyaluronic acid (HA) has been used for target-specific drug delivery because of strong affinity to CD44, a marker in which overexpressed in cancer cells and cancer stem cells. Conjugation of HA to the cytotoxic agents via active targeting can improve efficacy, biodistribution, and water solubility. To be able to benefit from passive targeting as well, a nanoparticulate system by counter ion using a polycation like chitosan may lead to a perfect delivery system. METHODS: Water soluble Hyaluronic acid-Docetaxel (HA-DTX) conjugate was prepared and used to formulate chitosan-coated HA-DTX nanoparticles by polyelectrolyte complex (PEC) method and optimized using Box-Behnken design. Biological evaluation of nanoparticles was done in CD44+ cancer cells. RESULTS AND DISCUSSION: Biological evaluation of optimized formula showed IC50 of nanoparticles for 4 T1 and MCF-7 cell lines were 45.34 MUM and 354.25 MUM against 233.8 MUM and 625.9 MUM for DTX, respectively with increased cellular uptake showed by inverted confocal microscope. CONCLUSION: Chitosan-coated HA-DTX nanoparticles were more effective against CD44+ cells than free DTX. Chitosan coated hyaluronic acid-docetaxel conjugate nanoparticles fabricated and evaluated in CD44+ cancer cells. PMID- 27473555 TI - Correlation of ASA Grade and the Charlson Comorbidity Index With Complications in Patients After Transurethral Resection of Prostate. AB - OBJECTIVE: To re-assess the Charlson Comorbidity Index (CCI) and the American Society of Anesthesiologists Physical Status Classification System (ASA grade) as predictive factors of complications after transurethral resection of prostate. METHODS: This study retrospectively included and analyzed consecutive patients undergoing transurethral resection of the prostate at Peking University First Hospital between 1992 and 2013. A multivariate analysis was conducted to evaluate the connection of the ASA and CCI grades with the incidence of complications. RESULTS: This paper studied 2326 cases in total. The CCI and ASA grades were significantly correlated, with a Spearman rho of 0.245 (P <.001). No considerable differences among the patient cohorts with different CCI or ASA grades were observed in terms of day of catheter removal, surgical time, and prostate size. In addition, no considerable differences were observed in the different modified Clavien classification system scores of complications among patient cohorts with different grades of CCI. CONCLUSION: The majority of complications (86.9%) were of grades I, II, and III, whereas grade IV was less frequent (12.1%), and, after transurethral resection of the prostate, grade V was rare (1%). Males with an ASA grade >=3 and higher CCI scores were more likely to demonstrate a higher incidence of morbidity than males with a lower grade. However, ASA grades and CCI scores were not independent predictors of complications because of the experience of the surgeon and progress in perioperative management and operative techniques. Therefore, for patients with more comorbidities and higher CCI scores or ASA grades, active surgical intervention is still suggested. PMID- 27473556 TI - Complete Azoospermia Factor b Deletion of Y Chromosome in an Infertile Male With Severe Oligoasthenozoospermia: Case Report and Literature Review. AB - OBJECTIVE: To report on a male patient with complete deletion of azoospermia factor b (AZFb) who presented with severe oligoasthenozoospermia, but who successfully fathered a child via intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: Karyotype analysis of peripheral blood lymphocytes was performed by standard G-banding. Y chromosome microdeletions were detected by multiplex polymerase chain reaction amplification using AZF-specific, sequence tagged site markers. The ICSI procedure was performed using ejaculated motile spermatozoa. RESULTS: Cytogenetic analysis of the patient revealed a normal male karyotype, 46,XY. Multiplex polymerase chain reaction screening showed complete deletion of AZFb demonstrated by the absence of specific sequence-tagged site markers sY121, sY127, sY134, and sY143. Following successful ICSI, an ultrasound scan of the patient's partner revealed a single pregnancy with cardiac activity. A healthy boy was born by cesarean section at 38 weeks of gestation. Genetic testing 2 years later revealed that the infant had inherited his father's AZFb deletion. CONCLUSION: Evidence from this case supports the fact that carriers of AZFb deletions can sometimes produce spermatozoa and father a son with the same AZFb deletion. This possibility reinforces the need for genetic counseling in patients with Y chromosome microdeletions. PMID- 27473557 TI - The Decline of the Open Ureteral Reimplant in the United States: National Data From 2003 to 2013. AB - OBJECTIVE: To examine trends in the number of cases of primary vesicoureteral reflux managed by ureteral reimplantation nationally over the last decade. Substantial changes have occurred in management of vesicoureteral reflux (VUR) over time, but trends in use of ureteral reimplantation have yet to be investigated on a national scale with annualized data. MATERIALS AND METHODS: Using the Premier Healthcare Database, we extracted hospital discharge data for pediatric patients (age <= 18 years) with a procedure code for ureteroneocystostomy (International Classification of Diseases, Ninth Revision, 56.74) between January 1, 2003 and December 31, 2013. We excluded patients with secondary VUR. The presence of a temporal trend in reimplantation was examined via regression using generalized estimating equations. RESULTS: In 4301 cases of primary VUR (23,602 weighted), there was a substantial decrease in the number of reimplantations performed, with an estimated decline in the rate of 0.239 cases per attending per year (P = .006). Average patient age declined 1.2 months in each year (P < .0001) due largely to a decline in reimplantation in those over age 2, which fell by 0.15 reimplantations per attending per year (P = .026). There was no difference between rates of decline in reimplantation for children with and without reflux nephropathy (P = .21) CONCLUSION: Nationally there has been a marked decrease in the incidence of ureteral reimplantation among children with primary VUR. The potential factors contributing to this are broad, including changes in diagnostic patterns, treatment recommendations, and the rise of endoscopic intervention. PMID- 27473558 TI - Exogenous fibroblast growth factor 9 attenuates cartilage degradation and aggravates osteophyte formation in post-traumatic osteoarthritis. AB - OBJECTIVE: The aim of the present study is to investigate the effects of exogenous fibroblast growth factor (FGF)9 on the progression of post-traumatic osteoarthritis (OA). DESIGN: The expression of FGF9 in articular cartilage with OA is detected by immunohistochemistry (IHC). The effects of intra-articular exogenous FGF9 injection on post-traumatic OA induced by the destabilization of the medial meniscus (DMM) surgery are evaluated. Cartilage changes and osteophyte formation in knee joints are investigated by histological analysis. Changes in subchondral bone are evaluated by microcomputed tomography (micro-CT). The effect of exogenous FGF9 on an interleukin-1beta (IL-1beta)-induced ex vivo OA model of human articular cartilage tissues is also evaluated. RESULTS: FGF9 expression was down-regulated in articular chondrocytes of OA but ectopically induced at sites of osteophyte formation. Intra-articular injection of exogenous FGF9 attenuated articular cartilage degradation in mice after DMM surgery. Exogenous FGF9 suppressed collagen X and MMP13 expressions in OA cartilage, while promoted collagen II expression. Similar results were observed in IL-1beta-induced ex vivo OA model. Intra-articular injection of FGF9 had no significant effect on the subchondral bone of knee joints after DMM surgery, but aggravated osteophyte formation. The expressions of SOX9 and collagen II, and cell proliferation were up-regulated at sites of initial osteophyte formation in mice with exogenous FGF9 treatment. CONCLUSIONS: Intra-articular injection of exogenous FGF9 delays articular cartilage degradation in post-traumatic OA, while aggravates osteophyte formation. PMID- 27473559 TI - Tendon and ligament as novel cell sources for engineering the knee meniscus. AB - OBJECTIVE: The application of cell-based therapies in regenerative medicine is hindered by the difficulty of acquiring adequate numbers of competent cells. For the knee meniscus in particular, this may be solved by harvesting tissue from neighboring tendons and ligaments. In this study, we have investigated the potential of cells from tendon and ligament, as compared to meniscus cells, to engineer scaffold-free self-assembling fibrocartilage. METHOD: Self-assembling meniscus-shaped constructs engineered from a co-culture of articular chondrocytes and either meniscus, tendon, or ligament cells were cultured for 4 weeks with TGF beta1 in serum-free media. After culture, constructs were assessed for their mechanical properties, histological staining, gross appearance, and biochemical composition including cross-link content. Correlations were performed to evaluate relationships between biochemical content and mechanical properties. RESULTS: In terms of mechanical properties as well as biochemical content, constructs engineered using tenocytes and ligament fibrocytes were found to be equivalent or superior to constructs engineered using meniscus cells. Furthermore, cross-link content was found to be correlated with engineered tissue tensile properties. CONCLUSION: Tenocytes and ligament fibrocytes represent viable cell sources for engineering meniscus fibrocartilage using the self-assembling process. Due to greater cross-link content, fibrocartilage engineered with tenocytes and ligament fibrocytes may maintain greater tensile properties than fibrocartilage engineered with meniscus cells. PMID- 27473560 TI - A convergent approach to side-chain homologated derivatives of 1alpha,25 dihydroxyergocalciferol. AB - As part of our program on search for vitamin D analogs with selective biological properties, such as low or negligible calcemic action, we describe here an efficient and versatile synthetic approach to derivatives of 1alpha,25 dihydroxyvitamin D2 with homologated side-chains and substitution at C24 for biological evaluation. PMID- 27473561 TI - CYP2R1 mutations causing vitamin D-deficiency rickets. AB - CYP2R1 is the principal hepatic 25-hydroxylase responsible for the hydroxylation of parent vitamin D to 25-hydroxyvitamin D [25(OH)D]. Serum concentrations of 25(OH)D reflect vitamin D status, because 25(OH)D is the major circulating metabolite of vitamin D. The 1alpha-hydroxylation of 25(OH)D in the kidney by CYP27B1 generates the fully active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D). The human CYP2R1 gene, located at 11p15.2, has five exons, coding for an enzyme with 501 amino acids. In Cyp2r1-/- knockout mice, serum 25(OH)D levels were reduced by more than 50% compared wild-type mice. Genetic polymorphisms of CYP2R1 account for some of the individual variability of circulating 25(OH)D values in the population. We review the evidence that inactivating mutations in CYP2R1 can lead to a novel form of vitamin D-deficiency rickets resulting from impaired 25-hydroxylation of vitamin D. We sequenced the promoter, exons and intron-exon flanking regions of the CYP2R1 gene in members of 12 Nigerian families with rickets in more than one family member. We found missense mutations (L99P and K242N) in affected members of 2 of 12 families. The L99P mutation had previously been reported as a homozygous defect in an unrelated child of Nigerian origin with rickets. In silico analyses predicted impaired CYP2R1 folding or reduced interaction with substrate vitamin D by L99P and K242N mutations, respectively. In vitro studies of the mutant CYP2R1 proteins in HEK293 cells confirmed normal expression levels but completely absent or markedly reduced 25-hydroxylase activity by the L99P and K242N mutations, respectively. Heterozygous subjects had more moderate biochemical and clinical features of vitamin D deficiency than homozygous subjects. After an oral bolus dose of 50,000 IU of vitamin D2 or vitamin D3, heterozygous subjects had lower increases in serum 25(OH)D than control subjects, and homozygous subjects had minimal increases, supporting a semidominant inheritance of these mutations. No CYP2R1 mutations were found in 27 Nigerian children with sporadic rickets, a cohort of 50 unrelated Nigerian subjects, or in 628 unrelated subjects in the 1000 Genomes Project. We conclude that mutations in CYP2R1 are responsible for an atypical form of vitamin D-deficiency rickets, which has been classified as vitamin D dependent rickets type 1B (VDDR1B, MIM 600081). PMID- 27473562 TI - Plant sterol ester diet supplementation increases serum plant sterols and markers of cholesterol synthesis, but has no effect on total cholesterol levels. AB - This double-blind, randomized, placebo-controlled, cross-over intervention-study was conducted in healthy volunteers to evaluate the effects of plant sterol ester supplemented margarine on cholesterol, non-cholesterol sterols and oxidative stress in serum and monocytes. Sixteen volunteers, average age 34 years, with no or mild hypercholesterolemia were subjected to a 4 week period of daily intake of 3g plant sterols per day supplied via a supplemented margarine on top of regular eating habits. After a wash-out period of one week, volunteers switched groups. Compared to placebo, a diet supplementation with plant sterols increased serum levels of plant sterols such as campesterol (+0.16+/-0.19mg/dL, p=0.005) and sitosterol (+0.27+/-0.18mg/dL, p<0.001) and increased markers of cholesterol synthesis such as desmosterol (+0.05+/-0.07mg/dL, p=0.006) as well as lathosterol (+0.11+/-0.16mg/dL, p=0.012). Cholesterol serum levels, however, were not changed significantly (+18.68+/-32.6mg/dL, p=0.052). These findings could not be verified in isolated circulating monocytes. Moreover, there was no effect on monocyte activation and no differences with regard to redox state after plant sterol supplemented diet. Therefore, in a population of healthy volunteers with no or mild hypercholesterolemia, consumption of plant sterol ester supplemented margarine results in increased concentrations of plant sterols and cholesterol synthesis markers without affecting total cholesterol in the serum, activation of circulating monocytes or redox state. PMID- 27473563 TI - JAK2 V617F stimulates proliferation of erythropoietin-dependent erythroid progenitors and delays their differentiation by activating Stat1 and other nonerythroid signaling pathways. AB - JAK2 V617F is a mutant-activated JAK2 kinase found in most polycythemia vera (PV) patients; it skews normal proliferation and differentiation of hematopoietic stem and progenitor cells and simulates aberrant expansion of erythroid progenitors. JAK2 V617F is known to activate some signaling pathways not normally activated in mature erythroblasts, but there has been no systematic study of signal transduction pathways or gene expression in erythroid cells expressing JAK2 V617F undergoing erythropoietin (Epo)-dependent terminal differentiation. Here we report that expression of JAK2 V617F in murine fetal liver Epo-dependent progenitors allows them to divide approximately six rather than the normal approximately four times in the presence of Epo, delaying their exit from the cell cycle. Over time, the number of red cells formed from each Epo-dependent progenitor increases fourfold, and these cells eventually differentiate into normal enucleated reticulocytes. We report that purified fetal liver Epo dependent progenitors express many cytokine receptors additional to the EpoR. Expression of JAK2 V617F triggers activation of Stat5, the only STAT normally activated by Epo, as well as activation of Stat1 and Stat3. Expression of JAK2 V617F also leads to transient induction of many genes not normally activated in terminally differentiating erythroid cells and that are characteristic of other hematopoietic lineages. Inhibition of Stat1 activation blocks JAK2 V617F hyperproliferation of erythroid progenitors, and we conclude that Stat1-mediated activation of nonerythroid signaling pathways delays terminal erythroid differentiation and permits extended cell divisions. PMID- 27473564 TI - Longitudinal analyses of leukemia-associated antigen-specific CD8+ T cells in patients after allogeneic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Graft versus leukemia (GVL) effects, which are exerted by donor T cells directed against leukemic-associated antigens (LAAs), are considered to play a crucial role in disease eradication. Although the expansion of cytotoxic T lymphocytes (CTLs) specific for cytomegalovirus (CMV) in response to an infection has been shown in multiple studies, data on CTLs mediating GVL effects are limited. To evaluate a potential increase or decrease of T lymphocytes specific for LAAs in the setting of allogeneic HSCT, we monitored leukemia-specific CD8+ T cells throughout the first year after HSCT in 18 patients using streptamer technology. A broad panel of promising LAAs was selected: Wilms tumor protein, proteinase 3, receptor for hyaluronan acid-mediated motility, apoptosis regulator Bcl-2, survivin, nucleophosmin, and fibromodulin. T cells specifically directed against AML- or CLL-associated antigens were found at very low frequencies in peripheral blood. Substantial frequencies of LAA-specific T cells could not be measured at any time point by flow cytometry. In contrast, abundant CMV-pp65 specific T cells were detected in CMV-seropositive patient-recipient pairs and an increase prompted by CMV infection could be demonstrated. In conclusion, T lymphocytes with specificities for the aforementioned LAAs can only be detected in minimal quantities in the early phase after allogeneic HSCT. PMID- 27473565 TI - Complement cascade gene expression defines novel prognostic subgroups of acute myeloid leukemia. AB - The involvement of the complement pathway in cancer is supported by a growing body of evidence, and yet its role in acute myeloid leukemia (AML) has not been extensively studied. We examined the expression of 87 genes in the complement, coagulation, and fibrinolysis-proteolytic pathways in 374 cytogenetically normal AML samples and observed that these samples can be divided into subgroups on the basis of complement gene expression. Three complement regulatory genes were linked to poor outcome as individual factors in a multivariate analysis (CFH, CFD, and SERPING1) in multiple cohorts. The combined expression of these genes was significantly associated with poorer overall survival in two cohorts of patients <60 years of age, independent of other factors (p <= 0.0004). For patients with an intermediate molecular risk, this three-gene risk marker enabled stratification of patients into prognostic subgroups with survival ranging from 17.4% to 44.1%. Thus, the expression of complement pathway genes is linked to outcome in AML, and a three-gene risk marker may improve the risk assessment of patients. PMID- 27473566 TI - Tunneling nanotubes mediate the transfer of stem cell marker CD133 between hematopoietic progenitor cells. AB - Deciphering all mechanisms of intercellular communication used by hematopoietic progenitors is important, not only for basic stem cell research, but also in view of their therapeutic relevance. Here, we investigated whether these cells can produce the thin F-actin-based plasma membrane protrusions referred to as tunneling nanotubes (TNTs), which are known to bridge cells over long distances without contact with the substratum and transfer cargo molecules along them in various biological processes. We found that human primary CD34+ hematopoietic progenitors and leukemic KG1a cells develop such structures upon culture on primary mesenchymal stromal cells or specific extracellular-matrix-based substrata. Time-lapse video microscopy revealed that cell dislodgement is the primary mechanism responsible for TNT biogenesis. Surprisingly, we found that, among various cluster of differentiation (CD) markers, only the stem cell antigen CD133 is transferred between cells. It is selectively and directionally transported along the surface of TNTs in small clusters, such as cytoplasmic phospho-myosin light chain 2, suggesting that the latter actin motor protein might be implicated in this process. Our data provide new insights into the biology of hematopoietic progenitors that can contribute to our understanding of all facets of intercellular communication in the bone marrow microenvironment under healthy or cancerous conditions. PMID- 27473567 TI - PARP-inhibitor-induced synthetic lethality for acute myeloid leukemia treatment. AB - Genomic instability is one of the most common and critical characteristics of cancer cells. The combined effect of replication stress and DNA damage repair defects associated with various oncogenic events drives genomic instability and disease progression. However, these DNA repair defects found in cancer cells can also provide unique therapeutic opportunities and form the basis of synthetic lethal targeting of solid tumors carrying BRCA mutations. Although the idea of utilizing synthetic lethality as a therapy strategy has been gaining momentum in various solid tumors, its application in leukemia still largely lags behind. In this article, we review recent advances in understanding the roles of the DNA damage response in acute myeloid leukemia and examine the potential therapeutic avenues of using poly (ADP-ribose) polymerase (PARP) inhibitors in AML treatment. PMID- 27473568 TI - Improving the safety of T-Cell therapies using an inducible caspase-9 gene. AB - Adoptive transfer of T cells can be an effective anticancer treatment. However, uncontrolled or unpredictable immediate or persistent toxic effects are a source of concern. The ability to conditionally eliminate aberrant cells in vivo is therefore becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently in human T cells without impairing phenotype, function, or antigen specificity. This system is based on the fusion of human caspase-9 to a modified human FK-binding protein, allowing conditional dimerization in the presence of an otherwise bio-inert small molecule drug. When exposed to the synthetic dimerizing drug, the inducible caspase-9 becomes activated, resulting in the rapid apoptosis of cells expressing this construct. We have illustrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant. Here we review the benefits and limitations of the approach. PMID- 27473569 TI - Depression Screening and Education: Options to Reduce Barriers to Treatment (DESEO): protocol for an educational intervention study. AB - BACKGROUND: Barriers to depression treatment among Hispanic populations include persistent stigma, inadequate doctor patient communication (DPC) and resultant sub-optimal use of anti-depressant medications. Stigma is primarily perpetuated due to inadequate disease literacy and cultural factors. Common concerns about depression treatments among Hispanics include fears about the addictive and harmful properties of antidepressants, worries about taking too many pills, and the stigma attached to taking psychotropic medications. The current manuscript presents the study protocol for the Depression Screening and Education: Options to Reduce Barriers to Treatment (DESEO) study funded by the Center for Medicare and Medicaid Services (CMS) Grants to Support the Hispanic Health Services Research Grant Program. METHODS/DESIGN: DESEO will implement universal screening with a self-report depression screening tool (the 9-item Patient Health Questionnaire (PHQ-9)) that is presented through a customized web application and a Depression Education Intervention (DEI) designed to increase disease literacy, and dispel myths about depression and its treatment among Hispanic patients thus reducing stigma and increasing treatment engagement. This project will be conducted at one community health center whose patient population is majority Hispanic. The target enrollment for recruitment is 350 patients over the 24-month study period. A one-group, pretest-posttest design will be used to asses knowledge of depression and its treatment and related stigma before, immediately after, and one month post intervention. DISCUSSION: Primary care settings often are the gateway to identifying undiagnosed mental health disorders, particularly for people with comorbid physical health conditions. This study is unique in that it aims to examine the specific role of patient education as an intervention to increase engagement in depression treatment. By participating in the DEI, it is expected that patients will have time to understand treatment options, participate in shared decision-making with their provider, and increase engagement in treatment of depression which might lead to improved overall health. It is also expected that implementation of the iPad Depression Screening application will increase provider awareness of the incidence and prevalence of depression in their own practice and improve the performance and care the clinic provides. TRIAL REGISTRATION: The study was registered with: NCT02491034 July 2, 2015. PMID- 27473570 TI - Chronic impalement- Case report of a knitting needle 33 years' ascension. AB - BACKGROUND: We report the case of a 72-year-old female complaining of hemoptysis due to a thoracic-abdominal knitting needle inserted 33 years ago for self induced abortion. CASE PRESENTATION: The PA/LL chest x-ray showed a metallic foreign body on thorax extending into the abdomen. An CT examination confirmed the transdiaphragmatic knitting needle extending from liver into right upper lobe. CONCLUSIONS: Surgical removal of the foreign body and wedge resection were performed with good follow-up results. PMID- 27473571 TI - Asthma self-management model: randomized controlled trial. AB - Information for patients provided by the pharmacist is reflected in adhesion to treatment, clinical results and patient quality of life. The objective of this study was to assess an asthma self-management model for rational medicine use. This was a randomized controlled trial with 60 asthmatic patients assigned to attend five modules presented by a pharmacist (intervention group) and 59 patients in the control group. Data collection was performed before and after this 4-month intervention and included an evaluation of asthma knowledge, lifestyle, inhaler techniques, adhesion to treatment, pulmonary function and quality of life. An economic viability analysis was also performed. The intervention group obtained an increase in asthma knowledge scores of 58.3-79.5% (P < 0.001). In this group, there was also an increase in the number of individuals who practiced physical exercise (36-43%), in the number of correct replies regarding the use of inhalers, in the percentage of adherent patients, and in quality of life scores for all domains. We concluded that this asthma self management model was effective in improving the quality of life of asthma patients. PMID- 27473573 TI - Acute myeloid leukemia following etoposide therapy for EBV-associated hemophagocytic lymphohistiocytosis: a case report and a brief review of the literature. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder characterized by prolonged fever, cytopenia, hepatosplenomegaly, rash, icterus, and other neurological symptoms. Successful treatment of HLH by etoposide has improved outcomes for children with HLH. However, the development of treatment-related acute myeloid leukemia (t-AML) after the usage of this drug is a concern. CASE PRESENTATION: We report a case of acquired EBV-triggered HLH with progression to t-AML following etoposide therapy with cytogenetic abnormality for t (11; 19) (q23; p13) resulting in MLL gene fusion. The development of t-AML was detected 23 months after HLH diagnosis. CONCLUSIONS: Although the successful treatment of HLH by etoposide has improved outcomes for children with HLH, t-AML is a serious complication of topoisomerase II inhibitor therapy and is characterized by the presence of gene rearrangement. This study suggests that HLH patients undergoing therapy with HLH-2004 protocol need monitoring for future malignancy, especially in the initial 2 to 3 years. PMID- 27473572 TI - The role of Arabidopsis Actin-Related Protein 3 in amyloplast sedimentation and polar auxin transport in root gravitropism. AB - Gravitropism is vital for shaping directional plant growth in response to the forces of gravity. Signals perceived in the gravity-sensing cells can be converted into biochemical signals and transmitted. Sedimentation of amyloplasts in the columella cells triggers asymmetric auxin redistribution in root tips, leading to downward root growth. The actin cytoskeleton is thought to play an important role in root gravitropism, although the molecular mechanism has not been resolved. DISTORTED1 (DIS1) encodes the ARP3 subunit of the Arabidopsis Actin-Related Protein 2/3 (ARP2/3) complex, and the ARP3/DIS1 mutant dis1-1 showed delayed root curvature after gravity stimulation. Microrheological analysis revealed that the high apparent viscosity within dis1-1 central columella cells is closely associated with abnormal movement trajectories of amyloplasts. Analysis using a sensitive auxin input reporter DII-VENUS showed that asymmetric auxin redistribution was reduced in the root tips of dis1-1, and the actin-disrupting drug Latrunculin B increased the asymmetric auxin redistribution. An uptake assay using the membrane-selective dye FM4-64 indicated that endocytosis was decelerated in dis1-1 root epidermal cells. Treatment and wash-out with Brefeldin A, which inhibits protein transport from the endoplasmic reticulum to the Golgi apparatus, showed that cycling of the auxin-transporter PIN-FORMED (PIN) proteins to the plasma membrane was also suppressed in dis1-1 roots. The results reveal that ARP3/DIS1 acts in root gravitropism by affecting amyloplast sedimentation and PIN-mediated polar auxin transport through regulation of PIN protein trafficking. PMID- 27473574 TI - Loss of AZGP1 as a Superior Predictor of Relapse in Margin-Positive Localized Prostate Cancer. AB - BACKGROUND: Positive surgical margins (PSMs) in localized prostate cancer (PC) confer a two- to three-fold increased risk of biochemical relapse (BR). Absent/weak AZGP1 expression and Gleason grade >=4 at the margin are each independent predictors of BR in patients with PSMs. Our study aimed to determine whether the biomarkers AZGP1 expression and Gleason grade at the site of a PSM are significant independent markers of biochemical and clinical relapse (CR) when modeled together and whether one of these biomarkers may be superior in its capacity to predict outcome. METHODS: A cohort of 275 consecutive patients with margin-positive localized PC following surgery were assessed for Gleason grade and AZGP1 expression at the PSM. BR-free survival was the primary end-point, while CR-free survival and PC-specific death were secondary endpoints. Kaplan Meier Analysis and Cox Proportional Hazards Modeling were performed. RESULTS: Absent AZGP1 expression was significantly associated with increased risk of BR (P = 0.001) and PC-specific death (P = 0.02). Gleason grade >=4 at PSM was associated with BR (P = 0.02), CR (P = 0.003), and PC-specific death (P = 0.004). On multivariable analysis, absent AZGP1 expression remained an independent predictor of BR (HR 2.4, 95%CI 1.5-3.9, P < 0.001) when modeled with Gleason grade at margin (HR 1.3, 95%CI 0.9-1.9, P = 0.16), preoperative PSA (P = 0.002), seminal vesicle involvement (P = 0.002), extraprostatic extension (P = 0.001), Gleason score (P = 0.01), adjuvant treatment (P = 0.75), linear length of the involved margin (P = 0.001) and margin number (P = 0.09). CONCLUSION: Absent AZGP1 expression is an independent predictor of BR in margin-positive localized PC and is associated with increased PC-specific mortality in a Phase II study. Absent AZGP1 expression was superior to Gleason grade at PSM in predicting relapse and should be incorporated into subsequent clinical trials of post operative radiotherapy in men with margin-positive PC. Prostate 76:1491-1500, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27473575 TI - Sleep and diabetic retinopathy. AB - PURPOSE: To investigate the association between sleep duration and diabetic retinopathy (DR). METHODS: A population-based cross-sectional study using a nation-wide, systemically stratified, multistage, clustered sampling method included a total of 1670 subjects aged >=40 years with diabetes who participated in the Korean National Health and Nutrition Examination Survey during 2008-2012. All participants performed standardized interviews, including self-reported sleep duration, and comprehensive ophthalmic examinations. Seven standard retinal fundus photographs were obtained from both eyes after pupil dilatation. Diabetic retinopathy (DR) was graded and classified as any DR and vision-threatening DR. Participants were stratified into men and women. RESULTS: The mean sleep duration was 6.71 hr/day. In men, adjusted OR of any DR was 1.88 [95% confidence interval (OR), 1.01-3.59] in those with <=5 hr sleep, and 2.19 (95% CI, 1.01-4.89) in those with >=9 hr sleep, compared to in subjects with 6-8 hr sleep, after adjusting for potential confounders including age, body mass index (BMI), diabetes duration, fasting glucose level, haemoglobin A1c levels and hypertension. In women, however, no significant association between sleep duration and DR was found. The vision-threatening DR was not significantly associated with sleep duration in either men or women. CONCLUSIONS: Short and long sleep was associated with high prevalence of DR in men. Sleep deprivation may be involved in the pathogenesis of DR development. PMID- 27473577 TI - Trainee competence in thoracoscopic esophagectomy in the prone position: evaluation using cumulative sum techniques. AB - PURPOSE: Minimally invasive esophagectomy (MIE) has less morbidity than the open approach. In particular, thoracoscopic esophagectomy in the prone position (TEP) has been performed worldwide. Using the cumulative sum control chart (CUSUM) method, this study aimed to confirm whether a trainee surgeon who learned established standards would become skilled in TEP with a shorter learning curve than that of the mentoring surgeon. METHODS: Surgeon A performed TEP in 100 patients; the first 22 patients comprised period 1. His learning curve, defined based on the operation time (OT) of the thoracic procedure, was evaluated using the CUSUM method, and short-term outcomes were assessed. Another 22 patients underwent TEP performed by surgeon B, with outcomes compared to those of surgeon A's period 1. RESULTS: Using the CUSUM chart, the peak point of the thoracic procedure OT occurred at the 44th case in surgeon A's experience of 100 cases. With surgeon A's first 22 cases (period 1), the peak point of the thoracic procedure OT could not be confirmed and graph is expanding soaring at CUSUM chart. The CUSUM chart of surgeon B's experience of 22 cases clearly indicated that the peak point of the thoracic procedure OT occurred at the 17th case. The rate of recurrent laryngeal nerve palsy for surgeon B (9 %) was significantly lower than for surgeon A in period 1 (36 %) (p = 0.0266). CONCLUSIONS: There is some possibility for a trainee surgeon to attain the required basic skills to perform TEP in a relatively short period of time using a standardized procedure developed by a mentoring surgeon. The CUSUM method should be useful in evaluating trainee competence during an initial series of procedures, by assessing the learning curve defined by OT. PMID- 27473576 TI - A practical description and student perspective of the integration of radiology into lower limb musculoskeletal anatomy. AB - BACKGROUND: Anatomy educators are increasing their utilisation of radiology in anatomy education in line with growing requirements for undergraduate radiology competency and clinical need. AIMS: We aimed to evaluate student perceptions of radiology and to outline the technical and academic considerations underlying the integration of radiology into musculoskeletal practical anatomy sessions. MATERIALS AND METHODS: The formal integration of radiology into anatomy practical sessions took place over a 5-week period during the lower limb musculoskeletal component of the anatomy course taught to first-year medical students. During practical sessions, students were required to rotate between aligned audio-visual radiology presentations, osteology/anatomical models, and prosection/dissection learning stations. After completing the course, students were invited to complete a survey to establish their opinions on radiology as a mode of learning and their satisfaction with radiological integration in anatomical practical sessions. RESULTS: Most students were not familiar with radiology prior to attending our university. All our students agreed or strongly agreed that learning to read radiographs in anatomy is important and most agreed that radiology is a valid assessment tool. Sixty percent stated that radiology facilitated their understanding of anatomy. The majority believed that radiology was best suited to clinically relevant anatomy and X-rays were their preferred learning tool. CONCLUSIONS: The practical approach to integrating radiology into undergraduate musculoskeletal anatomy described here did not place strain on existing academic resources. Most students agreed that radiology should be increased in anatomy education and that learning to understand radiographs in anatomy was important for clinical practice. PMID- 27473578 TI - Patients infected by tuberculosis and human immunodeficiency virus facing their disease, their reactions to disease diagnosis and its implication about their families and communities, in Burkina Faso: a mixed focus group and cross sectional study. AB - BACKGROUND: Patients facing tuberculosis (TB) and human immunodeficiency virus (HIV) infection receive particular care. Despite efforts in the care, misconceptions about TB and HIV still heavily impact patients, their families and communities. This situation severely limits achievement of TB and HIV programs goals. This study reports current situation of TB patients and patients living with HIV/AIDS (PLWHA) facing their disease and its implications, by comparing results from both qualitative and quantitative study design. METHODS: Cross sectional study using mixed methods was used and excluded patients co-infected by TB and HIV. Focus group included 96 patients (6 patients per group) stratified by setting, disease profile and gender; from rural (Orodara Health District) and urban (Bobo Dioulasso) areas, all from Hauts-Bassins region in Burkina Faso. Quantitative study included 862 patients (309 TB patients and 553 PLWHA) attending TB and HIV care facilities in two main regions (Hauts-Bassins and Centre) of Burkina Faso. RESULTS: A content analysis of reports found TB patients and PLWHA felt discriminated and stigmatized because of misconceptions with its aftermaths (rejection, emotional and financial problems), mainly among PLWHA and women patients. PLWHA go to healers when facing limited solutions in health system. There are fewer associations for TB patients, and less education and sensitization sessions to give them opportunity for sharing disease status and learning from other TB patients. TB patients and PLWHA still need to better understand their disease and its implication. Access to care (diagnosis and treatment) remains one of the key issues in health system, especially for PLWHA. Individual counseling is centered among PLWHA but not for TB patients. With research progress and experiences sharing, TB patients and PLWHA have some hope to implement their life project, and to receive psychosocial and nutritional support. CONCLUSION: Despite international aid, TB patients and PLWHA are facing misconceptions effects. There is a need to reinforce health education towards patients and healers, inside community, health centers and associations, and for specific settings. International aid must be adapted to specific targets and strategies implementing programs. Maintaining psychosocial and nutritional support is crucial for better outcomes of medication adherence. Individual counseling has to be centered among TB patients and PLWHA. PMID- 27473579 TI - Impact of a public media event on the use of statins in the French population. AB - BACKGROUND: In February 2013, a retired French professor of medicine published a book denying the benefits of statins for cardiovascular prevention. The book was the subject of extensive media coverage and multiple public discussions and debate. AIMS: To investigate the impact of this media event on use of statins among regular users. METHODS: This repeated cohort study used the French claims database sample Echantillon generaliste des beneficiaires to identify regular statin users and quantify the number who discontinued statins after February 2013, compared to discontinuation patterns in previous years (2011 and 2012). Discontinuation was defined as a gap of at least 2months without statin exposure. RESULTS: In 2013, 30,725 regular statin users were identified; 29,517 in 2012 and 28,272 in 2011. Statin discontinuation at 9-month follow-up in 2013 was 11.9% (95% confidence interval [CI] 11.5-12.2), compared with 8.5% (95% CI 8.2-8.8) in 2012 and 8.5% (95% CI 8.2-8.8) in 2011. Discontinuation varied according to cardiovascular risk: 19.4% (95% CI 18.2-20.6) in low risk, 11.6% (95% CI 11.1 12.0) in moderate risk, and 7.4% (95% CI 6.8-8.1) in high risk for the 2013 cohort. These discontinuation rates were, respectively, 1.53 (95% CI 1.36-1.72), 1.40 (95% CI 1.31-1.49), and 1.25 (95% CI 1.08-1.46) times higher in 2013 than in 2012 for low risk, moderate risk, or high risk patients. CONCLUSIONS: The rate of statin discontinuation, overall and in each cardiovascular risk group, was greater in 2013 after the media event than in previous years. The clinical impact of the increased discontinuation could be important. PMID- 27473580 TI - Feelings of familiarity and false memory for specific associations resulting from mugshot exposure. AB - This research reveals that mugshot viewing accompanied by questions about an action can cause young adults to associate the pictured person and the queried action, leading to later false recollection of having seen that person perform that action. In contrast, mugshot viewing in older adults can lead to vague feelings of familiarity for the pictured person, encouraging older adults to later falsely recognize the pictured person performing any familiar action. Participants viewed events involving actors performing different actions and then were asked verbal questions about which actor had performed each action, with each question accompanied by mugshots of potential "perpetrators" of the action. In a later recognition test, older adults were more likely to falsely recognize a novel conjunction of a familiar actor and action if they had seen a mugshot of that actor, regardless of whether the mugshot had accompanied a question about that action. In contrast, young adults were more likely to falsely recognize a conjunction event only if it involved an actor whose mugshot had accompanied a question about that particular action. This effect remained when the analysis was limited to trials involving actors whose mugshots had not been previously selected, implicating false recollection rather than commitment effects. PMID- 27473581 TI - Calcium Phosphate Crystals from Uremic Serum Promote Osteogenic Differentiation in Human Aortic Smooth Muscle Cells. AB - Recent study demonstrated that calcium phosphate (CaP) crystals isolated from high phosphate medium were a key contributor to arterial calcification. The present study further investigated the effects of CaP crystals induced by uremic serum on calcification of human aortic smooth muscle cells. This may provide a new insight for the development of uremic cardiovascular calcification. We tested the effects of uremic serum or normal serum on cell calcification. Calcification was visualized by staining and calcium deposition quantified. Expression of various bone-calcifying genes was detected by real-time PCR, and protein levels were quantified by western blotting or enzyme-linked immunosorbent assays. Pyrophosphate was used to investigate the effects of CaP crystals' inhibition. Finally, CaP crystals were separated from uremic serum to determine its specific pro-calcification effects. Uremic serum incubation resulted in progressively increased calcification staining and increased calcium deposition in HASMCs after 4, 8 and 12 days (P vs 0 day <0.001 for all). Compared to cells incubated in control serum, uremic serum significantly induced the mRNA expression of bone morphogenetic factor-2, osteopontin and RUNX2, and increased their protein levels as well (P < 0.05 for all). Inhibition of CaP crystals with pyrophosphate incubation prevented calcium deposition and bone-calcifying gene over-expression increased by uremic serum. CaP crystals, rather than the rest of uremic serum, were responsible for these effects. Uremic serum accelerates arterial calcification by mediating osteogenic differentiation. This effect might be mainly attributed to the CaP crystal content. PMID- 27473582 TI - The role of plasma exchange in treating post-transplant focal segmental glomerulosclerosis: A systematic review and meta-analysis of 77 case-reports and case-series. AB - BACKGROUND: Evidence on the role of plasma exchange for treating recurrent post transplant focal segmental glomerulosclerosis (FSGS) comes largely from individual cases and uncontrolled series. We conducted a systematic review and meta-analysis to estimate the remission rate after treatment with plasma exchange, and to determine if remission varied with patient or treatment characteristics. METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, and the Conference Proceedings Citation Index (Science and BIOSIS) for studies of patients with post-transplant recurrent FSGS who were treated with plasma exchange after recurrence (1950-2012). Of 678 studies screened, 77 met our inclusion criteria: 34 case reports (45 patients) and 43 case series (378 patients). We extracted patient-level data from each study and used random effects models to calculate remission, defined as proteinuria <3.5 g/day (partial) or <0.5 g/day (complete). RESULTS: The overall remission rate in 423 patients with outcome data was 71 % (95 % CI: 66 % to 75 %). In 235 patients with data on age, remission was similar for adults and children: 69.1 % (95 % CI: 59.6 % to 77.2 %) and 70.2 % (95 % CI: 61.1 % to 77.9 %). Males were more likely to achieve remission (OR = 2.85; 95 % CI: 1.44 to 5.62) and patients treated within 2 weeks of recurrence showed a trend towards higher likelihood of remission (OR = 2.16; 95 % CI: 0.93 to 5.01). Proteinuria >7 g/day at recurrence was inversely associated with remission (OR = 0.43; 95 % CI: 0.19 to 0.97). Age and type of kidney transplant (living vs. deceased) did not associate with remission. CONCLUSION: In this systematic review of patients with recurrent post-transplant FSGS, 71 % of patients achieved full or partial remission after treatment with plasma exchange; however, extensive missing data and lack of a control group limit any conclusions on causality. PMID- 27473583 TI - Mothers' Early Depressive Symptoms and Preschoolers' Behavioral Problems: The Moderating Role of Genetic Influences. AB - As a stressful environment in families, mothers' depressive symptoms might increase children's risks of developing behavioral problems by exacerbating genetic influences. Using data from the nationally representative Early Childhood Longitudinal Study-Birth Cohort data of approximately 750 pairs of twins, we examined whether genetic influences on preschoolers' behavioral problems depended upon mothers' depressive symptoms. Results indicated that the genetic etiology for both internalizing and externalizing behaviors varied with maternal depressive symptoms at 9-months child age. Genetic effects on externalizing behaviors increased as mothers' depressive symptoms increased; however, genetics effects on internalizing behaviors increased when depressive symptoms either increased or decreased from the median level. These different patterns of interactive effects suggest potentially different mechanisms for the etiology of children's externalizing and internalizing behaviors. PMID- 27473584 TI - Recruiting faith- and non-faith-based schools, adolescents and parents to a cluster randomised sexual-health trial: experiences, challenges and lessons from the mixed-methods Jack Feasibility Trial. AB - BACKGROUND: The move toward evidence-based education has led to increasing numbers of randomised trials in schools. However, the literature on recruitment to non-clinical trials is relatively underdeveloped, when compared to that of clinical trials. Recruitment to school-based randomised trials is, however, challenging, even more so when the focus of the study is a sensitive issue such as sexual health. This article reflects on the challenges of recruiting post primary schools, adolescent pupils and parents to a cluster randomised feasibility trial of a sexual-health intervention, and the strategies employed to address them. METHODS: The Jack Trial was funded by the UK National Institute for Health Research. It comprised a feasibility study of an interactive film-based sexual-health intervention entitled If I Were Jack, recruiting over 800 adolescents from eight socio-demographically diverse post-primary schools in Northern Ireland. It aimed to determine the facilitators and barriers to recruitment and retention to a school-based sexual-health trial and identify optimal multi-level strategies for an effectiveness study. As part of an embedded process evaluation, we conducted semi-structured interviews and focus groups with principals, vice-principals, teachers, pupils and parents recruited to the study as well as classroom observations and a parents' survey. RESULTS: With reference to social learning theory, we identified a number of individual-, behavioural- and environmental-level factors that influenced recruitment. Commonly identified facilitators included perceptions of the relevance and potential benefit of the intervention to adolescents, the credibility of the organisation and individuals running the study, support offered by trial staff, and financial incentives. Key barriers were prior commitment to other research, lack of time and resources, and perceptions that the intervention was incompatible with pupil or parent needs or the school ethos. CONCLUSIONS: Reflecting on the methodological challenges of recruiting to a school-based sexual-health feasibility trial, this study highlights pertinent general and trial-specific facilitators and barriers to recruitment, which will prove useful for future trials with schools, adolescent pupils and parents. TRIAL REGISTRATION: ISRCTN 11632300 . Registered on 19 December 2014. PMID- 27473586 TI - Erratum to: The shocking consequences of hybrid epigenomes. PMID- 27473585 TI - Increased sensitivity of African American triple negative breast cancer cells to nitric oxide-induced mitochondria-mediated apoptosis. AB - BACKGROUND: Breast cancer is a complex heterogeneous disease where many distinct subtypes are found. Younger African American (AA) women often present themselves with aggressive form of breast cancer with unique biology which is very difficult to treat. Better understanding the biology of AA breast tumors could lead to development of effective treatment strategies. Our previous studies indicate that AA but not Caucasian (CA) triple negative (TN) breast cancer cells were sensitive to nitrosative stress-induced cell death. In this study, we elucidate possible mechanisms that contribute to nitric oxide (NO)-induced apoptosis in AA TN breast cancer cells. METHODS: Breast cancer cells were treated with various concentrations of long-acting NO donor, DETA-NONOate and cell viability was determined by trypan blue exclusion assay. Apoptosis was determined by TUNEL and caspase 3 activity as well as changes in mitochondrial membrane potential. Caspase 3 and Bax cleavage, levels of Cu/Zn superoxide dismutase (SOD) and Mn SOD was assessed by immunoblot analysis. Inhibition of Bax cleavage by Calpain inhibitor, and levels of reactive oxygen species (ROS) as well as SOD activity was measured in NO-induced apoptosis. In vitro and in vivo effect of NO treatment on mammary cancer stem cells (MCSCs) was assessed. RESULTS AND DISCUSSION: NO induced mitocondria-mediated apoptosis in all AA but not in CA TN breast cancer cells. We found significant TUNEL-positive cells, cleavage of Bax and caspase-3 activation as well as depolarization mitochondrial membrane potential only in AA TN breast cancer cells exposed to NO. Inhibition of Bax cleavage and quenching of ROS partially inhibited NO-induced apoptosis in AA TN cells. Increase in ROS coincided with reduction in SOD activity in AA TN breast cancer cells. Furthermore, NO treatment of AA TN breast cancer cells dramatically reduced aldehyde dehydrogenase1 (ALDH1) expressing MCSCs and xenograft formation but not in breast cancer cells from CA origin. CONCLUSIONS: Ethnic differences in breast tumors dictate a need for tailoring treatment options more suited to the unique biology of the disease. PMID- 27473587 TI - Clinical Significance of Histone Demethylase NO66 in Invasive Colorectal Cancer. AB - BACKGROUND: Targeting epigenetic regulators is a promising therapeutic strategy against cancer. However, because of the broad spectrum of targets, selective inhibition of cancer-associated genes remains a major challenge. To address this issue, we focused on the oncogene-regulated histone demethylase, nucleolar protein 66 (NO66 [C14orf169/MAPJD]), which is known to work coordinately with the well-characterized oncogene, c-MYC. METHODS: To investigate expression patterns and clinical significance of NO66 in colorectal cancer (CRC), we performed immunohistochemical staining in 114 CRC cases. We performed functional analysis of NO66 to evaluate its contribution to proliferation and migration ability in CRC cells in vitro. RESULTS: NO66 was selectively expressed in CRC tissues. Furthermore, high expression levels of NO66 were associated with cancer metastatic potential, including lymphatic duct invasion (p = 0.047), venous invasion (p = 0.033), and lymph node metastasis (p = 0.015). Multivariate analysis indicated that NO66 was an independent prognostic factor for overall survival. In vitro assays revealed that NO66 expression is closely associated with malignant potential, including proliferation, migration and anti-apoptotic activity. CONCLUSIONS: NO66 is an independent prognostic factor in CRC. The cancer-selective expression patterns and its involvement in metastatic phenotypes suggest that NO66 is not only a crucial biomarker but is also a promising therapeutic target in CRC. PMID- 27473588 TI - Pragmatics of the Development of Personal Identity in Adolescents in the Latin American Context. AB - The present work proposes a pragmatic perspective of the development of personal identity. Such perspective is based on a unifying vision that incorporates the contribution of communicative pragmatics and becomes aware of the contribution of semiotics to psychology, without leaving aside the eriksonian point of view and other significant contributions in the field. The article defines identity in adolescence from a development approach, and adopts a systemic perspective concerning the insertion of adolescents in their context of formation as individuals. It then proposes a way to understand identity from a pragmatic communicative perspective. Finally, it introduces two communicative use contexts from which personal identity can emerge, showing the importance of communication and language in the formation and development of identity. PMID- 27473589 TI - Causal inferences on the effectiveness of complex social programs: Navigating assumptions, sources of complexity and evaluation design challenges. AB - This paper explores avenues for navigating evaluation design challenges posed by complex social programs (CSPs) and their environments when conducting studies that call for generalizable, causal inferences on the intervention's effectiveness. A definition is provided of a CSP drawing on examples from different fields, and an evaluation case is analyzed in depth to derive seven (7) major sources of complexity that typify CSPs, threatening assumptions of textbook recommended experimental designs for performing impact evaluations. Theoretically supported, alternative methodological strategies are discussed to navigate assumptions and counter the design challenges posed by the complex configurations and ecology of CSPs. Specific recommendations include: sequential refinement of the evaluation design through systems thinking, systems-informed logic modeling; and use of extended term, mixed methods (ETMM) approaches with exploratory and confirmatory phases of the evaluation. In the proposed approach, logic models are refined through direct induction and interactions with stakeholders. To better guide assumption evaluation, question-framing, and selection of appropriate methodological strategies, a multiphase evaluation design is recommended. PMID- 27473590 TI - The genetic variants in 3' untranslated region of voltage-gated sodium channel alpha 1 subunit gene affect the mRNA-microRNA interactions and associate with epilepsy. AB - BACKGROUND: mRNA expression in a cell or subcellular organelle is precisely regulated for the purpose of gene function regulation. The 3' untranslated region (3'UTR) of mRNA is the binding target of microRNA and RNA binding proteins. Their interactions regulate mRNA level in specific subcellular regions and determine the intensity of gene repression. The mutations in the coding region of voltage gated sodium channel alpha 1 subunit gene, SCN1A, were identified in epileptic patients and confirmed as causative factors of epilepsy. We investigated if there were genetic variants in 3'UTR of SCN1A, affecting the microRNA-mRNA 3'UTR interaction and SCN1A gene repression, potentially associated with epilepsy. RESULTS: In this case-control study, we identified twelve variants, NM_001202435.1:n.6277A > G, n.6568_6571del, n.6761C > T, n.6874A > T, n.6907 T > C, n.6978A > G, n.7065_7066insG, n.7282 T > C, n.7338_7344del, n.7385 T > A, n.7996C > T, and n.8212C > T in 3'UTR of SCN1A gene. We found that the variant of n.6978A > G in all our samples was completely mutated (G/G). In male group, T allele in n.7282 T > C was associated with epilepsy, while C allele was significantly less frequent in epileptic patients than in normal males (OR 0.424). Consequently, the haplotype "CTTACATGACGA" / "CTCTA" was significantly less frequent in male epileptic patients (0.173) than in normal males (0.305). The frequency of haplotype block found in females, "TTTAACA", "TTCAACA", and "CTTAACA" was 0.499, 0.254 and 0.234 respectively. Within STarMir model analysis, the "CTCTA" haplotype showed significantly higher site accessibility to microRNA targeting and higher downstream sequence accessibility for nonconserved binding than that of other haplotypes. Overall, the male genotypes have the higher accessibility of the downstream 30nt block of nonconserved site than the female genotypes. CONCLUSIONS: NM_001202435.1:n.7282 T > C is the genetic variant associated with epilepsy in males, and the related haplotype "CTTACATGACGA" / "CTCTA" in the region of chr2: 165991297-165989081, which has high site accessibility for microRNA binding, is the genetic protective factor against epilepsy in males. In female subset, the frequencies of haplotype block "TTTAACA", "TTCAACA", and "CTTAACA" were 0.499,0.254 and 0.234 respectively. Alleles and haplotypes distribution did not differ in female cases in comparison to female controls. PMID- 27473591 TI - MicroRNA 433 regulates nonsense-mediated mRNA decay by targeting SMG5 mRNA. AB - BACKGROUND: Nonsense-mediated mRNA decay (NMD) is a RNA quality surveillance system for eukaryotes. It prevents cells from generating deleterious truncated proteins by degrading abnormal mRNAs that harbor premature termination codon (PTC). However, little is known about the molecular regulation mechanism underlying the inhibition of NMD by microRNAs. RESULTS: The present study demonstrated that miR-433 was involved in NMD pathway via negatively regulating SMG5. We provided evidence that (1) overexpression of miR-433 significantly suppressed the expression of SMG5 (P < 0.05); (2) Both mRNA and protein expression levels of TBL2 and GADD45B, substrates of NMD, were increased when SMG5 was suppressed by siRNA; (3) Expression of SMG5, TBL2 and GADD45B were significantly increased by miR-433 inhibitor (P < 0.05). These results together illustrated that miR-433 regulated NMD by targeting SMG5 mRNA. CONCLUSIONS: Our study highlights that miR-433 represses nonsense mediated mRNA decay. The miR-433 targets 3'-UTR of SMG5 and represses the expression of SMG5, whereas NMD activity is decreased when SMG5 is decreased. This discovery provides evidence for microRNA/NMD regulatory mechanism. PMID- 27473592 TI - Stress-responsive gene RsICE1 from Raphanus sativus increases cold tolerance in rice. AB - The ICE1 transcription factor plays a critical role in plant cold tolerance via triggering CBF/DREB1 cold-regulated signal networks. In this work, a novel MYC type ICE1-like gene, RsICE1, was isolated from radish (Raphanus sativus L.), and its function in cold tolerance was characterized in rice. The RsICE1 gene was expressed constitutively with higher transcriptional levels in the roots and stems of radish seedlings. The NaCl, cold, and ABA treatments could significantly upregulate RsICE1 expression levels, but dehydration stress had a weak effect on its expression. Ectopic expression of the RsICE1 gene in rice conferred enhanced tolerance to low-temperature stress grounded on a higher survival rate, higher accumulation of soluble sugars and free proline content, a decline in electrolyte leakage and MDA levels, and higher chlorophyll levels relative to control plants. OsDREBL and OsTPP1, downstream cold-regulated genes, were remarkably upregulated at transcription levels in rice overexpressing RsICE1 under low-temperature stress, which indicated that RsICE1 was involved in CBF/DREB1 cold-regulated signal networks. Overall, the above data showed that RsICE1 played an active role in improving rice cold tolerance, most likely resulting from the upregulation of OsDREBL and OsTPP1 expression levels by interacting with the RsICE1 gene under low-temperature stress. PMID- 27473593 TI - A lack of information engagement among colorectal cancer screening non-attenders: cross-sectional survey. AB - BACKGROUND: The NHS Cancer Screening Programmes in England now operate a policy of 'informed choice' about participation in cancer screening. Engagement with written information about screening is important to facilitate informed choice, although the degree to which the screening-eligible public engages with the available information is unknown. We examined the association between reading of the standard informational booklet ('Bowel Cancer Screening: The Facts') and participation in the nationally organised NHS Bowel Cancer Screening Programme in England. METHODS: Face-to-face interviews were conducted with 1307 adults who were age-eligible for nationally organised colorectal cancer (CRC; also called bowel cancer) in a population-based survey in England in 2014. Respondents were shown an image of 'The Facts' booklet and were asked how much of it they had read when they received their screening invitation ('none', 'a little', 'some', 'most', 'almost all', or 'all'). Logistic regression was used to estimate the associations between screening uptake status ('never' vs. 'ever') and self reported reading of 'The Facts' booklet (dichotomised to 'none vs. 'any'), adjusting for age, sex, ethnicity, educational attainment, and occupation-based social grade. RESULTS: Overall, 69 % of the sample (908/1307) had participated in CRC screening at least once ('ever' screeners). One-fifth of the sample reported that they had read 'none' of 'The Facts' booklet (22 %; 287/1307), while half reported having read 'all' of it (52 %; 680/1307). Reading of the booklet was strongly differential according to screening uptake status: nearly two-thirds of 'never' screeners had read none of 'The Facts' booklet (63 %; 251/399), compared to less than one in twenty 'ever' screeners (4 %; 36/908); adjusted OR = 39.0; 95 % CI: 26.2-58.1 for reading 'none' in 'never' vs. 'ever' screeners. CONCLUSIONS: Although 'The Facts' booklet is intended to support informed choices about CRC screening, the majority of unscreened individuals report that they have read none of it. The degree to which public engagement with the decision-making process about cancer screening is socially unequal must be better understood so that comprehensive and equitable public communication strategies can be developed. PMID- 27473594 TI - Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights. AB - Depression is common but underdiagnosed in epilepsy. A quarter of patients meet criteria for a depressive disorder, yet few receive active treatment. We hypothesize that the presentation of depression is less recognizable in epilepsy because the symptoms are heterogeneous and often incorrectly attributed to the secondary effects of seizures or medication. Extending the ILAE's new phenomenological approach to classification of the epilepsies to include psychiatric comorbidity, we use data-driven profiling of the symptoms of depression to perform a preliminary investigation of whether there is a distinctive symptom-based phenotype of depression in epilepsy that could facilitate its recognition in the neurology clinic. The psychiatric and neuropsychological functioning of 91 patients with focal epilepsy was compared with that of 77 healthy controls (N=168). Cluster analysis of current depressive symptoms identified three clusters: one comprising nondepressed patients and two symptom-based phenotypes of depression. The 'Cognitive' phenotype (base rate=17%) was characterized by symptoms taking the form of self-critical cognitions and dysphoria and was accompanied by pervasive memory deficits. The 'Somatic' phenotype (7%) was characterized by vegetative depressive symptoms and anhedonia and was accompanied by greater anxiety. It is hoped that identification of the features of these two phenotypes will ultimately facilitate improved detection and diagnosis of depression in patients with epilepsy and thereby lead to appropriate and timely treatment, to the benefit of patient wellbeing and the potential efficacy of treatment of the seizure disorder. This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy". PMID- 27473595 TI - The arrector pili muscle, the bridge between the follicular stem cell niche and the interfollicular epidermis. AB - Proximally, the arrector pili muscle (APM) attaches to the follicular stem cell niche in the bulge, but its distal properties are comparatively unclear. In this work, a novel method employing an F-actin probe, phalloidin, was employed to visualize the APM anatomy. Phalloidin staining of the APM was validated by comparison with conventional antibodies/stains and by generating three dimensional reconstructions. The proximal attachment of the APM to the bulge in 8 patients with androgenic alopecia was studied using Masson's trichrome stain. Phalloidin visualized extensive branching of the APM. The distal end of the human APM exhibits a unique "C"-shaped structure connecting to the dermal-epidermal junction. The proximal APM attachment was observed to be lost or extremely miniaturized in androgenic alopecia. The unique shape, location, and attachment sites of the APM suggest a significant role for this muscle in maintaining follicular integrity. Proximally, the APM encircles the follicular unit and only attaches to the primary hair follicle in the bulge; this attachment is lost in irreversible hair loss. The APM exhibits an arborized morphology as it ascends toward the epidermis, and anchors to the basement membrane. PMID- 27473597 TI - A Comparison of Web and Telephone Responses From a National HIV and AIDS Survey. AB - BACKGROUND: Response differences to survey questions are known to exist for different modes of questionnaire completion. Previous research has shown that response differences by mode are larger for sensitive and complicated questions. However, it is unknown what effect completion mode may have on HIV and AIDS survey research, which addresses particularly sensitive and stigmatized health issues. OBJECTIVES: We seek to compare responses between self-selected Web and telephone respondents in terms of social desirability and item nonresponse in a national HIV and AIDS survey. METHODS: A survey of 2085 people in Canada aged 18 years and older was conducted to explore public knowledge, attitudes, and behaviors around HIV and AIDS in May 2011. Participants were recruited using random-digit dialing and could select to be interviewed on the telephone or self complete through the Internet. For this paper, 15 questions considered to be either sensitive, stigma-related, or less-sensitive in nature were assessed to estimate associations between responses and mode of completion. Multivariate regression analyses were conducted for questions with significant (P<=.05) bivariate differences in responses to adjust for sociodemographic factors. As survey mode was not randomly assigned, we created a propensity score variable and included it in our multivariate models to control for mode selection bias. RESULTS: A total of 81% of participants completed the questionnaire through the Internet, and 19% completed by telephone. Telephone respondents were older, reported less education, had lower incomes, and were more likely from the province of Quebec. Overall, 2 of 13 questions assessed for social desirability and 3 of 15 questions assessed for item nonresponse were significantly associated with choice of mode in the multivariate analysis. For social desirability, Web respondents were more likely than telephone respondents to report more than 1 sexual partner in the past year (fully adjusted odds ratio (OR)=3.65, 95% CI 1.80 7.42) and more likely to have donated to charity in the past year (OR=1.63, 95% CI 1.15-2.29). For item nonresponse, Web respondents were more likely than telephone respondents to have a missing or "don't know" response when asked about: the disease they were most concerned about (OR=3.02, 95% CI 1.67-5.47); if they had ever been tested for HIV (OR=8.04, 95% CI 2.46-26.31); and when rating their level of comfort with shopping at grocery store if the owner was known to have HIV or AIDS (OR=3.11, 95% CI 1.47-6.63). CONCLUSION: Sociodemographic differences existed between Web and telephone respondents, but for 23 of 28 questions considered in our analysis, there were no significant differences in responses by mode. For surveys with very sensitive health content, such as HIV and AIDS, Web administration may be subject to less social desirability bias but may also have greater item nonresponse for certain questions. PMID- 27473596 TI - Health-related quality of life in Hodgkin lymphoma: a systematic review. AB - PURPOSE: Hodgkin Lymphoma (HL) is highly curable with well-established treatment regimens; however, the impact on patient's health-related quality of life (HRQL) from diagnosis through survivorship is unclear. This systematic review aimed to describe the available literature on HRQL in HL, assess the quality of these studies, identify gaps in the literature and recommend further areas of research. METHODS: Following PRISMA guidelines, we performed a systematic review to include studies assessing the HRQL in HL patients. Articles identified through database searches were screened and data extracted. Quality was evaluated using a 6-point scale, adapted from published HRQL systematic reviews. RESULTS: Sixty five articles published between 1986 and 2015 met inclusion criteria. These included 53 (82 %) cross-sectional studies; 12 (18 %) longitudinal studies, including three embedded in randomized trials; and three additional longitudinal studies that began assessment at diagnosis. Study sample sizes of HL patients varied considerably with only five (42 %) longitudinal studies including more than 50 patients. Multidimensional HRQL was assessed in 45 studies, single HRQL domains in 22 studies, and symptoms, including fatigue, in 28 studies. CONCLUSIONS: The majority of studies employed a cross-sectional design, enrolling HL survivors at least 10 years after the completion of therapy. Emphasis on HRQL following therapy may inform initial treatment decisions and long-term survivorship goals. We recommend that future research include prospective, longitudinal randomized designs across both treatment and time. PMID- 27473599 TI - Pregabalin use disorder and secondary nicotine dependence in a woman with no substance abuse history. AB - This is an addictovigilance report of a pregabalin use disorder case in a young female patient who secondarily presented a tobacco use disorder after smoking initiation combined with pregabalin intake. Pregabalin was first prescribed for anxiety. Concomitant use of pregabalin with tobacco led to a synergic effect of both substances. She presented a craving behavior for pregabalin, with a tolerance phenomenon and a withdrawal syndrome between pregabaline intakes. The patient had a history of depressive disorder, personality disorder and anorexia, but never had any history of substance use disorder. This case report is noteworthy for 3 reasons: 1: this is one of the first report of pregabalin use disorder in a patient without any substance abuse disorder (licit or illicit), with the exception of a personal vulnerability factors to substance abuse; 2: the patient presented characteristics of pregabalin use disorder at usual dose (below 300mg per day), with drug-seeking behavior, tolerance phenomenon and intense craving with these moderate doses; 3: concomitant use of pregabalin with tobacco led to a synergic effect of both substances. PMID- 27473598 TI - Diagnostic performance of the Luminex xTAG gastrointestinal pathogens panel to detect rotavirus in Ghanaian children with and without diarrhoea. AB - BACKGROUND: Rotavirus is one of the leading causes of childhood diarrhoea worldwide. The highest disease burden is seen in resource-constrained settings of sub-Saharan Africa. Recently, commercial multiplex PCR panels proved their accuracy to diagnose infectious gastroenteritis in Europe and the USA. However, data on their performance using samples from tropical regions in general and to detect rotavirus in particular remains scant. We aimed to analyse the diagnostic performance of the Luminex xTAG gastrointestinal pathogens panel, a multiplex PCR, to detect rotavirus in stool samples from Ghanaian children. METHODS: A total of 682 stool samples were collected in the Ashanti region of Ghana between 2007 and 2008. Of these, 341 were from cases (children with diarrhoea), and another 341 from controls (children without diarrhoea). All samples were analysed using the Luminex xTAG assay and compared to a rotavirus quantitative reverse transcription PCR (reference assay). Rotavirus reference assay positive samples were P and G genotyped by sequencing the rotavirus VP4 and VP7 genes. RESULTS: Overall agreement between the Luminex xTAG and the reference assay was excellent (kappa 0.93). The sensitivity and specificity was 88.2 % (95 % confidence interval [CI] 78.2-94.1) and 100 % (95 % CI 99.2-100), respectively. Of 76 rotavirus reference assay positive samples, 64 were successfully genotyped and the Luminex xTAG assay was able to detect all rotavirus genotypes present in the study. CONCLUSION: The Luminex xTAG assay proved a sensitive and highly specific tool to detect rotavirus and may aid clinicians and public health authorities in the diagnosis and surveillance of rotavirus. PMID- 27473601 TI - Pathological, Immunohistochemical and Molecular Findings Associated with Senecavirus A-Induced Lesions in Neonatal Piglets. AB - This study investigated the cause of the mortality of piglets with cutaneous, enteric and neurological disorders from seven pig farms located in different geographical regions of Brazil. Twelve 1- to 5-day-old piglets were submitted for pathological evaluation. The principal gross findings included faint rib impressions on the pleural surface of the lungs (n = 9), diphtheritic glossitis (n = 6) and ulcerative lesions at the coronary band (n = 5). Histopathology revealed interstitial pneumonia (n = 12), myocarditis (n = 6), diphtheritic glossitis (n = 3), encephalitis (n = 3) and atrophy of intestinal villi with vacuolation of the superficial epithelial cells (n = 6). Immunohistochemistry with monoclonal antibodies specific for Senecavirus A (SenV-A) demonstrated immunoreactivity of the choroid plexus of the cerebrum, degenerate epithelium of ulcerative lesions of the tongue, the urothelium of the kidney and urinary bladder, and the superficial cells of the intestine. Reverse transcriptase polymerase chain reaction (PCR), PCR and/or quantitative PCR assays were used to investigate viral agents associated with vesicular and/or enteric diseases. Antigens and RNA of SenV-A were identified in multiple tissues of all piglets; molecular assays for all other viruses evaluated yielded negative results. These findings confirm the participation of SenV-A in the multiple lesions observed in these piglets. Several theories are proposed: SenV-A may be eliminated via the urinary system, neurological disease may occur due to initial invasion of choroid plexus, enteric disease may be related to atrophy and fusion of villi of the small intestine, and vertical transmission could be a form of dissemination. PMID- 27473600 TI - Endophenotype best practices. AB - This review examines the current state of electrophysiological endophenotype research and recommends best practices that are based on knowledge gleaned from the last decade of molecular genetic research with complex traits. Endophenotype research is being oversold for its potential to help discover psychopathology relevant genes using the types of small samples feasible for electrophysiological research. This is largely because the genetic architecture of endophenotypes appears to be very much like that of behavioral traits and disorders: they are complex, influenced by many variants (e.g., tens of thousands) within many genes, each contributing a very small effect. Out of over 40 electrophysiological endophenotypes covered by our review, only resting heart, a measure that has received scant advocacy as an endophenotype, emerges as an electrophysiological variable with verified associations with molecular genetic variants. To move the field forward, investigations designed to discover novel variants associated with endophenotypes will need extremely large samples best obtained by forming consortia and sharing data obtained from genome wide arrays. In addition, endophenotype research can benefit from successful molecular genetic studies of psychopathology by examining the degree to which these verified psychopathology relevant variants are also associated with an endophenotype, and by using knowledge about the functional significance of these variants to generate new endophenotypes. Even without molecular genetic associations, endophenotypes still have value in studying the development of disorders in unaffected individuals at high genetic risk, constructing animal models, and gaining insight into neural mechanisms that are relevant to clinical disorder. PMID- 27473603 TI - A GWA study reveals genetic loci for body conformation traits in Chinese Laiwu pigs and its implications for human BMI. AB - Pigs share numerous physiological and phenotypic similarities with human and thus have been considered as a good model in nonrodent mammals for the study of genetic basis of human obesity. Researches on candidate genes for obesity traits have successfully identified some common genes between humans and pigs. However, few studies have assessed how many similarities exist between the genetic architecture of obesity in pigs and humans by large-scale comparative genomics. Here, we performed a genome-wide association study (GWAS) using the porcine 60 K SNP Beadchip for BMI and other four conformation traits at three different ages in a Chinese Laiwu pig population, which shows a large variability in fat deposition. In total, 35 SNPs were found to be significant at Bonferroni corrected 5 % chromosome-wise level (P = 2.13 * 10-5) and 88 SNPs had suggestive (P < 10-4) association with the conformation traits. Some SNPs showed age dependent association. Intriguingly, out of 32 regions associated with BMI in pigs, 18 were homologous with the loci for BMI in humans. Furthermore, five closest genes to GWAS peaks including HIF1AN, SMYD3, COX10, SLMAP, and GBE1 have been already associated with BMI in humans, which makes them very promising candidates for these QTLs. The result of GO analysis provided strong support to the fact that mitochondria and synapse play important roles in obesity susceptibility, which is consistent with previous findings on human obesity, and it also implicated new gene sets related to chromatin modification and Ig-like C2 type 5 domain. Therefore, these results not only provide new insights into the genetic architecture of BMI in pigs but also highlight that humans and pigs share the significant overlap of obesity-related genes. PMID- 27473604 TI - Dosha phenotype specific Ayurveda intervention ameliorates asthma symptoms through cytokine modulations: Results of whole system clinical trial. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Over the past few decades, there have been significant scientific advances leading to improved understanding of asthma as a disease and treatment providing immediate relief. However, prevention of recurrent attacks, exacerbations and disease cure remains a challenge. Ayurveda refers to bronchial asthma as Tamaka Swasa and it is well explained in Charaka Samhita. Management of asthma in Ayurveda includes removal of vitiated Kapha through Shodhana, Shamana procedures, herbal and herbomineral formulations in addition to advising a healthy lifestyle and diet. Several clinical trials on Ayurvedic formulations for treatment of asthma are reported, however, whole system management of asthma has rarely been studied in the manner in which it is actually being practiced. Ayurveda therapeutics provides Dosha specific approaches, which needs biological investigation. AIM OF THE STUDY: The objective of our study was to investigate lung functions and cytokine changes in Asthmatic individuals in response to Ayurvedic intervention. METHODS: The study design was approved by the Institutional Ethics Committee of Tilak Ayurveda Mahavidyalaya (TAMV) & Sheth Tarachand Ramnath Charitable Ayurveda Hospital and followed guidelines of the Declaration of Helsinki and Tokyo for humans. It was conducted as a whole system individualized pragmatic clinical trial and written consent of patients was collected before enrollment. One hundred and fifteen patients with mild-to-moderate asthma were divided into 2 sub-groups depending on their disease subsets and administered phenotype specific ayurvedic interventions. Seventy six asthma patients completed the treatment. Serum IgE levels, blood eosinophil counts, spirometry and blood cytokine levels were measured before the start of treatment and six months at the end of treatment. Age and sex matched healthy participants (n=69) were recruited in the study for comparison of cytokines levels. RESULTS: Significant improvements in FEV1(% predicted) (p<0.0001) and FVC (% predicted) (p=0.0001) was observed in asthmatic patients who underwent Ayurvedic treatment. Circulating levels of IgE (p<0.03) and eosinophil numbers (p=0.001) reduced significantly in the asthmatics after Ayurvedic treatment. This was associated with significant reduction in levels of circulating cytokines. Levels of Th2, Th1 and inflammatory cytokines in the peripheral blood were higher than healthy control participants at baseline (p values <0.0001) and reduced significantly after ayurvedic intervention. CONCLUSION: This proof of concept study highlights the potential benefits and possible mechanism of Ayurvedic interventions in patients with mild-to-moderate asthma. The interventions significantly reduced IgE and eosinophil count, also improved lung function and reduced levels of circulating Th2 cytokines. PMID- 27473602 TI - S-Nitrosylation Induces Structural and Dynamical Changes in a Rhodanese Family Protein. AB - S-Nitrosylation is well established as an important post-translational regulator in protein function and signaling. However, relatively little is known about its structural and dynamical consequences. We have investigated the effects of S nitrosylation on the rhodanese domain of the Escherichia coli integral membrane protein YgaP by NMR, X-ray crystallography, and mass spectrometry. The results show that the active cysteine in the rhodanese domain of YgaP is subjected to two competing modifications: S-nitrosylation and S-sulfhydration, which are naturally occurring in vivo. It has been observed that in addition to inhibition of the sulfur transfer activity, S-nitrosylation of the active site residue Cys63 causes an increase in slow motion and a displacement of helix 5 due to a weakening of the interaction between the active site and the helix dipole. These findings provide an example of how nitrosative stress can exert action at the atomic level. PMID- 27473606 TI - International collaboration for sexual and reproductive health. PMID- 27473605 TI - The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bacopa monnieri (L) Wettst (common name, bacopa) is a medicinal plant used in Ayurveda, the traditional system of medicine of India, as a nootropic. It is considered to be a "medhya rasayana", an herb that sharpens the mind and the intellect. Bacopa is an important ingredient in many Ayurvedic herbal formulations designed to treat conditions such as memory loss, anxiety, poor cognition and loss of concentration. It has also been used in Ayurveda to treat inflammatory conditions such as arthritis. In modern biomedical studies, bacopa has been shown in animal models to inhibit the release of the pro inflammatory cytokines TNF-alpha and IL-6. However, less is known regarding the anti-inflammatory activity of Bacopa in the brain. AIM OF THE STUDY: The current study examines the ability of Bacopa to inhibit the release of pro-inflammatory cytokines from microglial cells, the immune cells of the brain that participate in inflammation in the CNS. The effect of Bacopa on signaling enzymes associated with CNS inflammatory pathways was also studied. MATERIALS AND METHODS: Various extracts of Bacopa were prepared and examined in the N9 microglial cell line in order to determine if they inhibited the release of the proinflammatory cytokines TNF-alpha and IL-6. Extracts were also tested in cell free assays as inhibitors of caspase-1 and matrix metalloproteinase-3 (enzymes associated with inflammation) and caspase-3, which has been shown to cleave protein Tau, an early event in the development of Alzheimer's disease. RESULTS: The tea, infusion, and alkaloid extracts of bacopa, as well as Bacoside A significantly inhibited the release of TNF-alpha and IL-6 from activated N9 microglial cells in vitro. In addition, the tea, infusion, and alkaloid extracts of Bacopa effectively inhibited caspase 1 and 3, and matrix metalloproteinase-3 in the cell free assay. CONCLUSIONS: Bacopa inhibits the release of inflammatory cytokines from microglial cells and inhibits enzymes associated with inflammation in the brain. Thus, Bacopa can limit inflammation in the CNS, and offers a promising source of novel therapeutics for the treatment of many CNS disorders. PMID- 27473607 TI - Prevalence and predictors of hyperprolactinemia in subclinical hypothyroidism. AB - BACKGROUND AND AIMS: Hyperprolactinemia has been reported in 0-57% of primary hypothyroidism. Data on hyperprolactinemia in subclinical hypothyroidism (ScH) is scant and inconsistent. This study aimed to determine the prevalence and predictors of hyperprolactinemia in ScH. METHODS: Consecutive patients diagnosed to have normal thyroid function, ScH or overt primary hypothyroidism underwent serum prolactin, gonadotropins, testosterone and estradiol estimation. Patients with pregnancy, pituitary adenomas, secondary hypothyroidism, hyperthyroidism, comorbid states and drug-induced hyperprolactinemia were excluded. RESULTS: From initially screened 4950 patients, hormonal data from 2848 individuals who fulfilled all criteria were analyzed. The occurrence of hyperprolactinemia (females:males) was highest in primary hypothyroidism (42.95%:39.53%) (n=192), followed by ScH (35.65%:31.61%) (n=770) and euthyroid individuals (2.32%:2.02%) (n=1886) (P<0.001). Hyperprolactinemia in ScH with TSH 5-7.5, 7.5-10 and >10mIU/L (females: males) was 25.56%:20.73%, 49.07%:50% and 61.43%:35.71% respectively (P<0.001). Significant positive correlation between TSH and prolactin was noted in ScH and primary hypothyroidism. In females, testosterone was lowest in patients with primary hypothyroidism. In males, serum estradiol was significantly higher, and testosterone significantly lower in men with ScH and primary hypothyroidism. Regression analysis revealed serum TSH followed by free T4, to be best predictors of serum prolactin in both sexes. CONCLUSION: Hyperprolactinemia is common in ScH, especially in those with TSH>7.5mIU/L. ROC analysis confirmed that TSH>=7.51mIU/L in females and >=8.33mIU/L in males had a sensitivity of ~50% with a very high specificity of >90% in detecting hyperprolactinemia. Prolactin screening may be warranted in ScH with TSH>7.5mIU/L, and may form an indication for treating ScH. PMID- 27473608 TI - [Pityriasis versicolor mimicking trichostasis spinulosa]. PMID- 27473609 TI - Partially shared consensus decision making and distributed leadership in vervet monkeys: older females lead the group to forage. AB - OBJECTIVES: Group living can be advantageous, but for motile organisms, collective movements become necessary. We are just beginning to understand the many ways that animal groups make movement decisions and maintain cohesion. We examined start attempts and success in leading collective group movements in vervet monkeys (Chlorocebus pygerythrus) characterized by matrilineal groups and territoriality. MATERIALS AND METHODS: We recorded 179 start attempts in a single group of vervets at Lake Nabugabo, Uganda and examined individual success in three situations (departing from sleeping site, moving to forage, returning to sleeping site) relative to dominance rank, age, and sex. RESULTS: Sex and age were associated with both the number of start attempts and success in leading group movements, but there was no effect of dominance rank. Older females were most successful at leading group movements, especially toward foraging sites, while adult and subadult males almost always led the group out of the sleeping site. DISCUSSION: Collective group movements in vervet monkeys appear to be based on distributed leadership and partially shared consensus decision making. Older females may be repositories of ecological knowledge, resulting in their success at leading the group to forage. Male motivation to lead the way out of the sleeping site appeared related to accessing human food sources before other group members. Young natal males achieved some success leading group progressions because they were motivated to make many initiations, which may be related to their life-stage. These results give us a better understanding of the processes underlying collective movements in cohesive animal groups. PMID- 27473610 TI - Fentanyl and a Novel Synthetic Opioid U-47700 Masquerading as Street "Norco" in Central California: A Case Report. AB - In 2013 and 2014, more than 700 deaths were attributed to fentanyl and fentanyl analogues in the United States. Of recent concern is the cluster of unintentional fentanyl overdoses because of tablets thought to be "Norco" purchased on the street in Northern California. U-47700 (trans-3,4-dichloro-N-[2-(dimethyl amino)cyclohexyl]-N-methylbenz-amide) is a nonfentanyl-based synthetic opioid with 7.5 times the binding affinity of morphine to MU-opioid. We report a case of fentanyl and U-47700 intoxication from what was thought to be illicitly purchased Norco. A 41-year-old woman presented to the emergency department (ED) for altered mental status shortly after ingesting 3 beige Norco pills bearing a Watson imprint. She had pinpoint pupils and respiratory depression, which reversed after 0.4 mg naloxone administration intravenously. She had complete recovery and was discharged from the ED after a 4-hour observation period. Serum testing with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC 1260 QTOF/MS 6550; Agilent, Santa Clara, CA) confirmed the presence of the medications the patient reported receiving, and additionally fentanyl (15.2 ng/mL) and U 47700 (7.6 ng/mL). In this case report, street Norco purchased in Central California resulted in altered mental status requiring naloxone reversal because of fentanyl and the novel synthetic opioid U-47700. Because these compounds are not detected by routine urine drug testing and physical examination findings are similar to those of a traditional opioid toxidrome, emergency providers should use the patient's history and other circumstantial details to aid in diagnosis. In cases with suspicion of opioid or opioid analogue cause, we recommend that emergency providers contact their local poison control center, medical toxicologist, or public health department to aid in the investigation. PMID- 27473611 TI - Ca2+ signaling and emesis: Recent progress and new perspectives. AB - Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2+)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca2+ signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca2+ elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo((r))) with >85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broad spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca2+ involvement in the emetic process; discuss the relationship between Ca2+ signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca2+-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca2+-signaling blockers/inhibitors in the treatment of nausea and vomiting. PMID- 27473612 TI - Advising vaccinations for the elderly: a cross-sectional survey on differences between general practitioners and physician assistants in Germany. AB - BACKGROUND: In Germany, the coverage of officially recommended vaccinations for the elderly is below a desirable level. It is known that advice provided by General Practitioners and Physician Assistants influences the uptake in patients >=60 years. Therefore, the predictors of advice-giving behavior by these professions should be investigated to develop recommendations for possible actions for improvement. METHODS: We conducted a postal cross-sectional survey on knowledge, attitudes and advice - giving behavior regarding vaccinations in the elderly among General Practitioners and Physician Assistants in 4995 practices in Germany. To find specific predictors, we performed logistic regressions with non advising on any officially recommended vaccination or on three specific vaccinations as four separate outcomes, first using all participants, then only General Practitioners and lastly only Physician Assistants as our study population. RESULTS: Participants consisted of 774 General Practitioners and 563 Physician Assistants, of whom overall 21 % stated to have not advised an officially recommended vaccination in elderly patients. The most frequent explanation was having forgotten about it. The habit of not counselling on vaccinations at regular intervals was associated with not advising any vaccination (OR: 2.8), influenza vaccination (OR: 2.3), and pneumococcal vaccination (OR: 3.1). While more General Practitioners than Physician Assistants felt sufficiently informed (90 % vs. 79 %, p < 0.001), General Practitioners displayed higher odds to not advise specific vaccinations (ORs: 1.8-2.8). CONCLUSIONS: To reduce the high risk of forgetting to advice on vaccinations, we recommend improving and promoting standing recall-systems, encouraging General Practitioners and Physician Assistants to counsel routinely at regular intervals regarding vaccinations, and providing Physician Assistants with better, tailor made information on official recommendations and their changes. PMID- 27473613 TI - Examining reach, dose, and fidelity of the "Girls on the Move" after-school physical activity club: a process evaluation. AB - BACKGROUND: After-school programs represent a promising opportunity to assist adolescent girls' in attaining adequate physical activity. Although evaluating the process of intervention implementation is important for determining if an intervention was delivered and received as intended, comprehensive information about process evaluation methods and results are rarely reported. The purpose of this article was to evaluate the reach, dose, and fidelity of a 90-minute after school physical activity club offered 3 days a week. The club is 1 of 3 components included in a 17-week intervention designed for 5th-8th grade girls, the majority of whom were of minority and/or low socioeconomic status. METHODS: A total of 24 schools (12 intervention; 12 control) and 56-67 girls per school (total N = 1519 girls) were included in the Girls on the Move group randomized controlled trial. At the beginning of each of 3 academic years (2012-2015), 8 schools per year were randomized to receive either the intervention (n = 4) or control condition (n = 4). To evaluate the club, data collected via surveys from girls, club coaches and managers, and process evaluators were analyzed. To evaluate the opportunity for physical activity provided by the coaches and managers, process evaluators used an observation tool based on the System for Observing Fitness Instruction Time and Academic Learning Time - Physical Education. Girls wore accelerometers every other week during the club time. RESULTS: Mean attendance was 41 % with the average attendance in year 3 being higher than rates for years 1 or 2. Mean moderate-to-vigorous physical activity time was 21.85 minutes measured via accelerometry and 21.81 minutes observed by process evaluators. Satisfaction with the intervention was high. For the most part, process evaluators perceived the club was delivered as planned and reflected constructs of the Health Promotion Model and Self-Determination Theory. Areas contributing to success included using incentives and offering a variety of activities. Issues negatively impacting implementation included managing behavioral problems, having limited space for moderate-to-vigorous physical activity, dealing with inclement weather, and getting coaches to actively participate in all physical activities with the girls. CONCLUSIONS: This process evaluation provides important information to guide future school-based physical activity intervention delivery. Barriers to implementation have been identified. Ways to overcome them warrant consideration when designing physical activity interventions. Research is needed to test innovative approaches for enhancing attendance and increasing girls' moderate-to-vigorous physical activity in after school programs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01503333 . Registered 23 December, 2011. PMID- 27473614 TI - Concentrations and identification of culturable airborne fungi in underground stations of the Seoul metro. AB - The purpose of this study was to measure the culturable airborne fungi (CAF) concentrations in the underground subway stations of Seoul, Korea at two time points. This study measured the CAF concentrations in enclosed environments at 16 underground stations of the Seoul Metro in 2006 and 2013 and investigated the effects of various environmental factors, including the presence of platform screen doors, temperature, relative humidity, and number of passengers. CAF concentrations at the stations in 2006 were significantly higher than that at the same stations in 2013 (p < 0.001). Furthermore, there was a significant correlation between CAF concentration and relative humidity (r = 0.311, p < 0.05). Geotrichum and Penicillium were the predominant genera. The CAF concentrations in stations with an operating supply air were significantly higher than that in stations with no supply air (p < 0.001). Therefore, it is recommended that special attention be given to stations with clean supplied air to improve the indoor air quality of these subway stations. PMID- 27473615 TI - Implications of climate change damage for agriculture: sectoral evidence from Pakistan. AB - This paper gives a projection of the possible damage of climate change on the agriculture sector of Pakistan for the period 2012-2037, based on a dynamic approach, using an environment-related applied computable general equilibrium model (CGE). Climate damage projections depict an upward trend for the period of review and are found to be higher than the global average. Further, the damage to the agricultural sector exceeds that for the overall economy. By sector, climatic damage disproportionately affects the major and minor crops, livestock and fisheries. The largest losses following climate change, relative to the other agricultural sectors, are expected for livestock. The reason for this is the orthodox system of production for livestock, with a low adaptability to negative shocks of climate change. Overall, the findings reveal the high exposure of the agriculture sector to climate damage. In this regard, policymakers in Pakistan should take seriously the effects of climate change on agriculture and consider suitable technology to mitigate those damages. PMID- 27473616 TI - Characterization of freshwater changes in lakes of Nahuel Huapi National Park produced by the 2011 Puyehue-Cordon Caulle eruption. AB - This work supplies a characterization of the chemical properties, including data of dissolved major and minor components in surface and pore water collected in Argentinean lakes surrounding the impacted area of Puyehue-Cordon Caulle volcanic complex, in the 2011 eruption. The principal component analysis and Pollution Load Index were used for the identification of water changes by volcanic ashes deposited throughout 1 year of eruption. The element content between water column and pore water provided a direct evidence of the potential dissolution of the element. Many chemical transformations, after the pyroclastic material contacted with the freshwater, were observed such as large pH changes from 3.2 to 8.1, electrical conductivity of 28.9 to 457 MUs/cm, and redox potential of 171 to 591 mV. The maximum concentrations measured of F, Al, and Hg were 600, 40, and 0.0382 MUg/L respectively. These concentrations in water column were lower than the limit of aquatic life protection for chronic toxicity. The Pollution Load Index indicated very low pollution for sites far away from the volcano and moderated pollution in closely sites. The processes were stabilized at the end of the monitoring, 1 year after the eruption. PMID- 27473617 TI - Awasthi, A. K., Zeng, X., & Li, J. (2016). Relationship between e-waste recycling and human health risk in India: a critical review. Environmental Science and Pollution Research, 1-24. PMID- 27473618 TI - Cd-induced production of glomalin by arbuscular mycorrhizal fungus (Rhizophagus irregularis) as estimated by monoclonal antibody assay. AB - Glomalin is a specific fungal glycoprotein produced by arbuscular mycorrhizal (AM) fungi belonging to the Glomerales which could efficiently sequestrate heavy metals. The glomalin has been introduced as a heat shock protein and there are evidences that increasing levels of heavy metals could enhance its production. We examined the influence of Cd concentrations on glomalin production by AM fungus, as well as its contribution to the sequestration of Cd in both pot and in vitro culture conditions. Pot experiment was carried out using pure sand with Trifolium repens L. as host plant, mycorrhized by Rhizophagus irregularis and treated with Cd levels of 0, 15, 30, and 45 MUM. In vitro experiment was performed in two compartment plates containing the transformed carrot roots mycorrhized with the same fungus and treated with Cd levels of 0, 0.001, 0.01, and 0.1 mM. The immunoreactive and Bradford reactive glomalin contents in both experiments increased as so raising Cd concentration. Total Cd sequestrated by hyphal glomalin in both cultures was significantly increased as the levels of Cd increased. The highest contents of Cd sequestration in pot (75.78 MUg Cd/mg glomalin) and in vitro (11.44 MUg Cd/mg glomalin) cultures were recorded at the uppermost levels of Cd, which significantly differed with other levels. Our results suggested that under Cd-induced stress, stimulated production of glomalin by AM fungus may be a protective mechanism against the toxic effect of Cd. PMID- 27473619 TI - A field study on the dynamic uptake and transfer of heavy metals in Chinese cabbage and radish in weak alkaline soils. AB - Vegetables and crops can take up heavy metals when grown on polluted lands. The concentrations and dynamic uptake of heavy metals vary at different growth points for different vegetables. In order to assess the safe consumption of vegetables in weak alkaline farmlands, Chinese cabbage and radish were planted on the farmlands of Baiyin (polluted site) and Liujiaxia (relatively unpolluted site). Firstly, the growth processes of two vegetables were recorded. The growth curves of the two vegetables observed a slow growth at the beginning, an exponential growth period, and a plateau towards the end. Maximum concentrations of copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) were presented at the slow growth period and showed a downtrend except the radish shoot. The concentrations of heavy metals (Cu, Zn, and Cd) in vegetables of Baiyin were higher than those of Liujiaxia. In the meanwhile, the uptake contents continued to increase during the growth or halted at maximum at a certain stage. The maximum uptake rates were found on the maturity except for the shoot of radish which took place at the exponential growth stages of root. The sigmoid model could simulate the dynamic processes of growth and heavy metals uptake of Chinese cabbage and radish. Conclusively, heavy metals have higher bioaccumulation tendency for roots in Chinese cabbage and for shoots in radish. PMID- 27473620 TI - Decolorization and degradation of reactive yellow HF aqueous solutions by electrochemical advanced oxidation processes. AB - Textile manufacturing is the one responsible for water bodies' contamination through the discharge of colored wastes. This work presents the study of reactive yellow HF (RYHF) dye degradation under two different electrochemical advanced oxidation processes (EAOP), namely anodic oxidation (AO) and electro-Fenton (EF)/boron-doped diamond (BDD) process. For the AO, 100 and 300 mg/L solutions using Pt and BDD as anodes in a 100 mL stirred tank cell were used, with a supporting electrolyte of 0.05 mol/L of Na2SO4 at pH 3 under 30 and 50 mA/cm2 current density. The EF/BDD process was carried out in a flow reactor at 4 and 7 L/min to degrade 100, 200, and 300 mg/L RYHF solutions under 50 and 80 mA/cm2. UV Vis determinations were used for decolorization evaluation, while high performance liquid chromatography (HPLC) method provided information on dye degradation rate. PMID- 27473621 TI - Immune competence assessment in marine medaka (Orzyias melastigma)-a holistic approach for immunotoxicology. AB - Many anthropogenic pollutants in coastal marine environments can induce immune impairments in wild fish and reduce their survival fitness. There is a pressing need to establish sensitive and high throughput in vivo tools to systematically evaluate the immunosuppressive effects of contaminants in marine teleosts. This study reviewed a battery of in vivo immune function detection technologies established for different biological hierarchies at molecular (immune function pathways and genes by next generation sequencing (NGS)), cellular (leukocytes profiles by flow cytometry), tissues/organ system (whole adult histo-array), and organism (host resistance assays (HRAs)) levels, to assess the immune competence of marine medaka Oryzias melastigma. This approach enables a holistic assessment of fish immune competence under different chemical exposure or environmental scenarios. The data obtained will also be useful to unravel the underlying immunotoxic mechanisms. Intriguingly, NGS analysis of hepatic immune gene expression profiles (male > female) are in support of the bacterial HRA findings, in which infection-induced mortality was consistently higher in females than in males. As such, reproductive stages and gender-specific responses must be taken into consideration when assessing the risk of immunotoxicants in the aquatic environment. The distinct phenotypic sexual dimorphism and short generation time (3 months) of marine medaka offer additional advantages for sex-related immunotoxicological investigation. PMID- 27473622 TI - Effect of dry mycelium of Penicillium chrysogenum fertilizer on soil microbial community composition, enzyme activities and snap bean growth. AB - The dry mycelium fertilizer (DMF) was produced from penicillin fermentation fungi mycelium (PFFM) following an acid-heating pretreatment to degrade the residual penicillin. In this study, it was applied into soil as fertilizer to investigate its effects on soil properties, phytotoxicity, microbial community composition, enzyme activities, and growth of snap bean in greenhouse. As the results show, pH, total nitrogen, total phosphorus, total potassium, and organic matter of soil with DMF treatments were generally higher than CON treatment. In addition, the applied DMF did not cause heavy metal and residual drug pollution of the modified soil. The lowest GI values (<0.3) were recorded at DMF8 (36 kg DMF/plat) on the first days after applying the fertilizer, indicating that severe phytotoxicity appeared in the DMF8-modified soil. Results of microbial population and enzyme activities illustrated that DMF was rapidly decomposed and the decomposition process significantly affected microbial growth and enzyme activities. The DMF modified soil phytotoxicity decreased at the late fertilization time. DMF1 was considered as the optimum amount of DMF dose based on principal component analysis scores. Plant height and plant yield of snap bean were remarkably enhanced with the optimum DMF dose. PMID- 27473623 TI - Influence of an iron-rich amendment on chemical lability and plant (Raphanus sativus L.) availability of two metallic elements (As and Pb) on mine-impacted agricultural soils. AB - Variation of the chemical extractability and phytoavailability of two metallic elements (e.g., As and Pb) on amendment-treated soils was investigated. Four mine impacted agricultural soils contaminated with both As (174-491 mg kg-1) and Pb (116-357 mg kg-1) were amended with an iron-rich sludge at the rate of 5 % (w/w). After a 4-, 8-, and 16-week incubation, the extractability of metallic elements was assessed by sequential extraction procedure (SEP; F1-F5). The control without amendment was also run. In amended soils, the labile element mass (i.e., F1 + F2) promptly decreased (15-48 % of As and 5-10 % of Pb) in 4 weeks, but the decrement was continued over 16 weeks up to 70 and 28 % for As and Pb, respectively. The labile mass decrement was quantitatively corresponded with the increment of F3 (bound to amorphous metal oxides). In plant test assessed by radish (Raphanus sativus) grown on the 16-week soils, up to 57 % of As and 28 % of Pb accumulation was suppressed and 10-43 % of growth (i.e., shoot/root elongation and fresh weight) was improved. For both the control and amended soils, element uptake by plant was well correlated with their labile soil concentrations (r 2 = 0.799 and 0.499 for As and Pb, respectively). The results confirmed that the iron-rich material can effectively suppress element uptake during R. sativus seedling growth, most likely due to the chemical stabilization of metallic elements in growth medium. PMID- 27473624 TI - The 5th World Symposium for Lymphedema Surgery. PMID- 27473626 TI - Characterizing Drug-Induced Liver Injury With Autoimmune Features. PMID- 27473625 TI - Evaluation of antioxidant, anti-hemolytic and anticancer activity of various solvent extracts of Acacia hydaspica R. Parker aerial parts. AB - BACKGROUND: Acacia hydaspica R. Parker, family leguminosae, is a medicinally important plant. Different plant parts are used in various ailments in folk medicine. The current study aimed at investigating the in vitro antioxidant, anti hemolytic and anticancer activity of A. hydaspica. METHODS: Antioxidant potential was assessed using DPPH, ABTS and *OH, scavenging of H2O2, inhibition of lipid peroxidation and beta-carotene bleaching inhibition assays. Anti-hemolytic activity was assessed using H2O2 induced hemolysis of RBCs. Anticancer potential was assessed using MTT assay. Spectrometric methods and HPLC-DAD analysis was performed for phytochemical screening. RESULTS: EC50 values based on reduction of DPPH, ABTS and *OH, scavenging of H2O2, inhibition of lipid peroxidation and beta carotene bleaching for AHB, AHE and AHM were generally lower manifesting potential antiradical capacities. The fractions also exhibited significant (P <0.001) anti-hemolytic potential. Regarding IC50 values for anticancer activity against HCC-38 and MDA-MB-361 cancer cell lines; AHB, AHE and AHM exhibited significant (P <0.001) cyto-selection indices. Plant extracts showed no cytotoxicity against normal Vero cells (IC50 > 250 MUg/ml). While significant (P <0.001) cytotoxicity was elicited by these extract/fractions against cancer cell lines. AHE was the most effective and IC50 was found to be 29.9 +/- 0.909 MUg/ml (SI = 9.83) and 39.5 +/- 0.872 MUg/ml (SI = 7.44) against MDA-MB-361 and HCC-38 cancer cells respectively. Higher amounts of TPC and TFC were exhibited by AHE and AHB as compared to other fractions. Gallic acid, catechin and myricetin were identified in AHE whereas gallic acid and catechin were identified in AHB by HPLC. CONCLUSION: The presence of bioactive constituents in AHE and AHB might be responsible for antioxidant, anti-hemolytic and anticancer activities. PMID- 27473627 TI - A System to Assess the Competency for Interpretation of Esophageal Manometry Identifies Variation in Learning Curves. AB - BACKGROUND & AIMS: Quality esophageal high-resolution manometry (HRM) studies require competent interpretation of data. However, there is little understanding of learning curves, training requirements, or measures of competency for HRM. We aimed to develop and use a competency assessment system to examine learning curves for interpretation of HRM data. METHODS: We conducted a prospective multicenter study of 20 gastroenterology trainees with no experience in HRM, from 8 centers, over an 8-month period (May through December 2015). We designed a web based HRM training and competency assessment system. After reviewing the training module, participants interpreted 50 HRM studies and received answer keys at the fifth and then at every second interpretation. A cumulative sum procedure produced individual learning curves with preset acceptable failure rates of 10%; we classified competency status as competency not achieved, competency achieved, or competency likely achieved. RESULTS: Five (25%) participants achieved competence, 4 (20%) likely achieved competence, and 11 (55%) failed to achieve competence. A minimum case volume to achieve competency was not identified. There was no significant agreement between diagnostic accuracy and accuracy for individual HRM skills. CONCLUSIONS: We developed a competency assessment system for HRM interpretation; using this system, we found significant variation in learning curves for HRM diagnosis and individual skills. Our system effectively distinguished trainee competency levels for HRM interpretation and contrary to current recommendations, found that competency for HRM is not case-volume specific. PMID- 27473629 TI - The Combination of IV and Perineural Dexamethasone Prolongs the Analgesic Duration of Intercostal Nerve Blocks Compared with IV Dexamethasone Alone. AB - Objective: The use of multiple-level, single-injection intercostal nerve blocks for pain control following video-assisted thorascopic surgery (VATS) is limited by the analgesic duration of local anesthetics. This study examines whether the combination of perineural and intravenous (IV) dexamethasone will prolong the duration of intraoperatively placed intercostal nerve blocks following VATS compared with IV dexamethasone and a perineural saline placebo. Design: Prospective, double-blind, randomized placebo-controlled trial. Setting: Single level-1 academic trauma center. Subjects: Forty patients undergoing a unilateral VATS under the care of a single surgeon. Methods: Patients were randomly assigned to two groups and received an intercostal nerve block containing 1) 0.5% bupivacaine with epinephrine and 1 ml of 0.9% saline or 2) 0.5% bupivacaine with epinephrine and 1 ml of a 4 mg/ml dexamethasone solution. All patients received 8 mg of IV dexamethasone. Results: Group 2 had lower NRS-11 scores at post operative hours 8 (5.05, SD = 2.13 vs 3.50, SD = 2.50; p = 0.04), 20 (4.30, SD = 2.96 vs 2.26, SD = 2.31; p = 0.02), and 24 (4.53, SD = 1.95 vs 2.26, SD = 2.31; p = 0.02). Equianalgesic opioid requirement was decreased in group 2 at 32 hours (5.78 mg, SD = 5.77 vs 1.67 mg, SD = 3.49; p = 0.02). Group 2 also had greater FEV1 measured at 8, 12, 24, and 44 hours; greater FVC at 24 hours; greater PEF at 28 through 48 hours; and greater FEV1/FVC at 8 and 36 hours. Conclusions: The combination of IV and perineural dexamethasone prolonged the duration of a single injection bupivacaine intercostal nerve block as measured by NRS-11 compared with IV dexamethasone alone at 24 hours. Reduced NRS-11 at other times, reduced opioid requirements, and increased PFTs were observed in group 2. PMID- 27473633 TI - Morning Versus Evening Bright Light Treatment at Home to Improve Function and Pain Sensitivity for Women with Fibromyalgia: A Pilot Study. AB - Objective: To test the feasibility, acceptability, and effects of a home-based morning versus evening bright light treatment on function and pain sensitivity in women with fibromyalgia. Design: A single blind randomized study with two treatment arms: 6 days of a 1 hour morning light treatment or 6 days of a 1 hour evening light treatment. Function, pain sensitivity, and circadian timing were assessed before and after treatment. Setting: Participants slept at home, except for two nights in Sleep Center. Participants: Ten women meeting the American College of Rheumatology's diagnostic criteria for fibromyalgia, including normal blood test results. Methods: Self-reported function was assessed with the Fibromyalgia Impact Questionnaire (FIQ). Pain sensitivity was assessed using a heat stimulus that gave measures of threshold and tolerance. Circadian timing was assessed with the dim light melatonin onset. Results: Both morning and evening light treatments led to improvements in function and pain sensitivity. However, only the morning light treatment led to a clinically meaningful improvement in function (>14% reduction from baseline FIQ) and morning light significantly increased pain threshold more than evening light ( P < 0.05). Phase advances in circadian timing were associated with an increase in pain tolerance (r = 0.67, P < 0.05). Conclusions: Bright light treatment appears to be a feasible and acceptable adjunctive treatment to women with fibromyalgia. Those who undergo morning light treatment may show improvements in function and pain sensitivity. Advances in circadian timing may be one mechanism by which morning light improves pain sensitivity. Findings can inform the design of a randomized controlled trial. PMID- 27473634 TI - Physiological and Behavioral Responses to Calibrated Noxious Stimuli Among Individuals with Cerebral Palsy and Intellectual Disability. AB - Objective: As individuals with intellectual disability (ID) due to cerebral palsy (CP) are at high risk of experiencing pain, measuring their pain is crucial for adequate treatment. While verbal reports are the gold standard in pain measurements, they may not be sufficient in ID. The aim was to detect behavioral/autonomic responses that may indicate the presence and intensity of pain in individuals with CP and ID, using calibrated stimuli, here for the first time. Subjects: Thirteen adults with CP and ID (CPID), 15 healthy controls (HC), and 5 adults with CP with no ID (CPNID). Methods: Subjects received pressure stimuli of various intensities. Self-reports (using a pyramid scale), facial expressions (retrospectively analyzed with Facial Action Coding System = FACS), and autonomic function (heart rate, heart rate variability, pulse, galvanic skin response) were analyzed. Results: Self-reports and facial expressions but not the autonomic function exhibited stimulus-response relationship to pressure stimulation among all groups. The CPID group had increased pain ratings and facial expressions compared with controls. In addition, the increase in facial expressions along the increase in noxious stimulation was larger than in controls. Freezing in response to pain was frequent in CPID. Conclusions: 1) Individuals with CP and ID have increased responses to pain; 2) facial expressions and self-reports, but not autonomic variables can reliably indicate their pain intensity; 3) the pyramid scale is suitable for self-report in this population. Although facial expressions may replace verbal reports, increased facial expressions at rest among these individuals may mask pain, especially at lower intensities. PMID- 27473635 TI - Isometric Back Exercise Has Different Effect on Pressure Pain Thresholds in Healthy Men and Women. AB - Objective: Isometric exercises produce an acute decrease in the pain sensitivity, known as exercise-induced hypoalgesia (EIH). Existing EIH paradigms use exercises at the extremities with more pronounced EIH at local compared to remote body sites, indicating local inhibition in addition to central inhibitory mechanisms. So far the results on EIH in patients with low back pain (LBP) are equivocal and no studies have investigated an EIH paradigm targeting the lower back in order to assess EIH in patients with LBP. Thus, the aim of this pilot study was to assess pressure pain sensitivity at local and remote assessment sites, before and after an isometric back exercise in healthy women and men. Methods: In a pre-posttest design, pressure pain thresholds (PPT) were assessed at the lower back, biceps femoris muscle, and hand in 29 healthy subjects (17 women) before and after 120 seconds of the isometric Biering-Soerensen back extension test. Results: After exercise, PPT increased significantly at the hand in women, but not in men ( P = 0.027). Moreover, PPT at the leg increased independently of sex ( P < 0.004). The increase in PPT at the lower back after exercise approached significance ( P = 0.07). Conclusions: The results of this pilot study indicate that isometric back exercise produces local and remote hypoalgesia. Remote EIH was only demonstrated in women, supporting the influence of sex in the hypoalgesic response after exercise. The effect of isometric back exercise on pain sensitivity in patients with low back pain should be investigated in future studies. PMID- 27473636 TI - Maximizing resources in the local treatment of prostate cancer: A summary of cost effectiveness studies. AB - OBJECTIVES: Prostate cancer is a common diagnosis with several treatment options for the newly diagnosed patient, including radiation, surgery, active surveillance, and watchful waiting. Although tailoring of treatment to individual patient needs is an important goal, the recent passage of the Affordable Care Act has placed renewed interest in cost containment and cost-effectiveness. We sought to conduct a literature review of recent US-based studies to analyze the cost effectiveness of initial local treatments for localized prostate cancer. METHODS: We conducted a systematic literature search through PubMed, the Cost Effectiveness Analysis Registry, and manual cross-referencing of articles. We identified US-based studies with cost analyses starting in 2005 that studied the cost-effectiveness of initial local treatments for localized prostate cancer (surgery, radiation, or observation). RESULTS: There were eight studies that met our inclusion and exclusion criteria. Most studies took the cost perspective of Medicare, and two studies also considered the societal cost in terms of lost patient time. Most studies also used a Markov model with inputs based on the available literature for the effectiveness and toxicity of the different treatment options. The radiation-focused studies tended to find brachytherapy (BT) or stereotactic body radiation therapy (SBRT) to be more cost-effective than intensity-modulated radiation therapy or proton beam therapy. These findings were primarily based on the lower cost of SBRT or BT with roughly equal efficacy and toxicity. The two studies focused on surgery found surgery to be more cost effective than intensity-modulated radiation therapy, at least for low-risk disease, and one study found BT to be more cost-effective than surgery, and watchful waiting to be the most cost-effective option overall. CONCLUSION: Cost effectiveness analysis is important because it helps patients, physicians, and policymakers make quantitatively-based decisions, which balance treatment efficacy, toxicity, and costs. Significant methodological heterogeneity in the studies we found limit the ability to compare their results directly, but most found that for favorable-risk prostate cancer, shorter or simpler treatments tended to be more cost-effective, including no treatment (watchful waiting) in one study. PMID- 27473637 TI - Is linking research, teaching and practice in communication in health care the way forward? AB - This paper is based on the keynote lecture given at the ICCH conference in New Orleans in October 2015. With as background the observation that even though research and teaching of communication have been receiving attention for some time now, patients still encounter many problems when they visit clinicians because of health problems, it subsequently touches upon research on integration of communication with correct medical content, person centered communication and the role of placebo on outcomes. For teaching it emphasizes methods working best to teach clinical communication skills and lead to behavior changes in professionals: experiential teaching methods but taking care of a balance with cognitive methods. It then discusses the challenge of transfer to clinical practice and what is needed to overcome these challenges: learning from reflecting on undesired outcomes in clinical practice, feedback from clinicians who are open to communication and support learners with effective feedback in that specific context. It adds suggestions about where linking more between research, teaching and clinical practice could help moving communication in health care forward and builds the case for involving policymakers and members of hospital boards to help manage the necessary climate change in clinical settings. PMID- 27473638 TI - Are nutrition messages lost in transmission? Assessing the quality and consistency of diabetes guideline recommendations on the delivery of nutrition therapy. AB - AIM: To provide an overview of (1) the consistency of Type 2 Diabetes Clinical Practice Guidelines recommendations on the delivery of nutrition therapy and (2) Clinical Practice Guideline quality. METHODS: Large international clinical practice guideline repositories, diabetes organisation websites, and electronic databases (Pubmed, Scopus), were searched to identify Clinical Practice Guidelines for adults with type 2 diabetes published 2005 to August 2014. Recommendations on the delivery of nutrition therapy were extracted and inductive content analysis was used to analyse consistency. Two researchers independently assessed guideline quality using the AGREE II tool. RESULTS: Nine topics were identified from the recommendations. Overall the consistency of the recommendations was related to guideline type. Compared with nutrition-specific guidelines, the broad ones had a broader focus and included more patient-focused recommendations. The ten Clinical Practice Guidelines assessed included six broad guidelines and four nutrition specific guidelines. Based on AGREE II analysis, the broad guidelines were higher quality than nutrition-specific ones. CONCLUSIONS: Broad Clinical Practice Guidelines were higher quality and included more patient-focused recommendations than nutrition-specific ones. PRACTICE IMPLICATIONS: Our findings suggest a need for nutrition-specific guidelines to be modified to include greater patient-focus, or for practitioners delivering nutrition therapy to adopt broad Clinical Practice Guidelines. PMID- 27473639 TI - Engaging patients and consumers in research evidence: Applying the conceptual model of patient and family engagement. AB - OBJECTIVE: This essay discusses applying the Conceptual Framework for Patient and Family Engagement to partnerships with patients and consumers to increase their use of research evidence in healthcare decisions. The framework's foundational principles hold that engagement occurs on a continuum across all levels of healthcare-from direct care to policymaking-with patients and healthcare professionals working in full partnership and sharing responsibility for achieving a safe, high-quality, efficient, and patient-centered healthcare system. DISCUSSION: Research evidence can serve as a critical decision-making tool in partnerships between patients and health professionals. However, as the framework suggests, without patient and consumer engagement in the design, planning, interpretation, and dissemination of research findings, it is unlikely that the broader consumer population will find research evidence useful, much less use it, to guide their healthcare decisions. Understanding what factors influence patient and consumer engagement can lead to effective strategies that enable meaningful partnerships between patients and researchers. CONCLUSION: Understanding patient and consumer perspectives of research evidence is critical to engaging them in meaningful partnerships that produce actionable research findings that they can in turn use in partnership with health professionals to improve their own health and the healthcare system as a whole. PMID- 27473640 TI - The Pharmacoeconomic Evaluation Process in Ireland. AB - BACKGROUND: In Ireland, all new drugs are considered for a formal pharmacoeconomic evaluation (PE) prior to a reimbursement decision. All evaluations are conducted by the National Centre for Pharmacoeconomics (NCPE). The objectives of this study were to describe the evaluation process and to examine the movement of drugs through the process. METHODS: The movement of all drugs submitted to the NCPE (from January 2010 to December 2015 inclusive) was investigated. RESULTS: A total of 230 Rapid Review submissions (each pertaining to one drug for one indication) were made. The Rapid Review process determines the requirement for a full PE. A full PE was deemed unnecessary in 108 cases (47 %). A positive reimbursement recommendation was made in 100 of these (a price reductions was advised in 25 cases and a recommendation to restrict/monitor usage was made in 35). The requirement for a full PE was recognised in 122 cases (53 %). In 12, subsequent payer-led price negotiations negated the requirement for a full PE, and reimbursement was recommended. In 24 cases, a timely full submission was not made; cost effectiveness could not be established. Fifteen interventions are currently going through the submission process. To date, 71 full PEs have been completed by the NCPE. Reimbursement was recommended in 19 and was not recommended in eight. Reimbursement was not recommended 'at the submitted price' in 44. Of these, reimbursement was subsequently approved in 34 (77 %) following price negotiations. To date, negotiations are on-going in a further six cases. In all, negotiations have been informed by the NCPE. A negative recommendation was reached in the remaining four. CONCLUSIONS: Over the study period, the NCPE evaluated 230 drugs for which reimbursement was sought. In total, a positive reimbursement recommendation has been made in 165 cases (72 % of all drugs submitted, or 79 % when drugs currently undergoing the process are excluded). A price reduction was deemed necessary in 71 (43 %) of the 165 cases, and a recommendation to restrict/monitor usage was made in 35 cases (21 %). PMID- 27473641 TI - Refined clothespin relocation test and assessment of motion. AB - BACKGROUND: Advancements in upper limb prosthesis design have focused on providing increased degrees of freedom for the end effector through multiple articulations of a prosthetic hand, wrist and elbow. Measuring improvement in patient function with these devices requires development of appropriate assessment tools. OBJECTIVES: This study presents a refined clothespin relocation test for measuring performance and assessing compensatory motion between able bodied subjects and subjects with upper limb impairments. STUDY DESIGN: Comparative analysis. METHODS: Trunk and head motions of 13 able-bodied subjects who performed the refined clothespin relocation test were compared to the motion of a transradial prosthesis user with a single degree of freedom hand. RESULTS: There were observable differences between the prosthesis user and the able-bodied group. The assessment used provided a clear indication of the differences in motion through analysis of compensatory motion. CONCLUSION: The refined clothespin relocation test provides additional benefits over the standard clothespin assessment and makes identification of compensatory motions easily identifiable to the researcher. While this article establishes the method for the new assessment, further validation will need to be performed with more users. Clinical relevance The refined test provides a more defined structure for the trajectory of the hand/terminal device than the standard protocol for the clothespin relocation test. This will help researchers interested in motion studies of limb segments to efficiently compare and analyse motion between able bodied and prosthesis user groups. PMID- 27473642 TI - Categorization of compensatory motions in transradial myoelectric prosthesis users. AB - BACKGROUND: Prosthesis users perform various compensatory motions to accommodate for the loss of the hand and wrist as well as the reduced functionality of a prosthetic hand. OBJECTIVES: Investigate different compensation strategies that are performed by prosthesis users. STUDY DESIGN: Comparative analysis. METHODS: A total of 20 able-bodied subjects and 4 prosthesis users performed a set of bimanual activities. Movements of the trunk and head were recorded using a motion capture system and a digital video recorder. Clinical motion angles were calculated to assess the compensatory motions made by the prosthesis users. The video recording also assisted in visually identifying the compensations. RESULTS: Compensatory motions by the prosthesis users were evident in the tasks performed (slicing and stirring activities) as compared to the benchmark of able-bodied subjects. Compensations took the form of a measured increase in range of motion, an observed adoption of a new posture during task execution, and prepositioning of items in the workspace prior to initiating a given task. CONCLUSION: Compensatory motions were performed by prosthesis users during the selected tasks. These can be categorized into three different types of compensations. Clinical relevance Proper identification and classification of compensatory motions performed by prosthesis users into three distinct forms allows clinicians and researchers to accurately identify and quantify movement. It will assist in evaluating new prosthetic interventions by providing distinct terminology that is easily understood and can be shared between research institutions. PMID- 27473643 TI - Paenibacillus methanolicus sp. nov., a xylanolytic, methanol-utilizing bacterium isolated from the phyllosphere of bamboo (Pseudosasa japonica). AB - Strain BL24T, isolated from bamboo phyllosphere collected in Coimbatore, India, was studied for taxonomic classification. Cells of the strain were aerobic, Gram stain-positive, motile, catalase- and oxidase-positive rods and grew on media containing methanol. In 16S rRNA gene sequence analysis, strain BL24Tshowed the highest sequence similarities with Paenibacillus phyllosphaeraeKACC 11473T (97.8 %) and Paenibacillus sacheonensisSY01 (95.1 %). DNA-DNA hybridization with P. phyllosphaerae KACC 11473T, phylogenetically the most closely related species, was 21.6 %; this value showed that strain BL24Tbelonged to a different species. The cell-wall peptidoglycan was found to possess meso-diaminopimelic acid and the G+C content of genomic DNA was 52.1 mol %. It contained menaquinone (MK)-7 as the predominant respiratory quinone and the major cellular fatty acids are C16 : 0, anteiso-C15 : 0, iso-C16 : 0, and anteiso-C17 : 0. Based on the molecular and chemotaxonomic markers and physiological properties, strain BL24T (=NRRL B 51698T=CCM 7577T) is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillusmethanolicusis proposed. PMID- 27473645 TI - Impulse control disorders in Parkinson's disease: Predominant role of psychological determinants. AB - OBJECTIVES: Impulse Control Disorders (ICDs) in Parkinson's disease (PD) have previously almost exclusively been considered to result from anti-parkinsonian medication. However, this biomedical perspective has failed to achieve a full understanding of the phenomenon and it is argued that a failure to consider psychological factors is a critical omission. DESIGN: The present study examined the predictive relationship between ICDs in PD and a range of psychological measures, whilst controlling for a number of biomedical determinants. MAIN OUTCOME MEASURES: One hundred participants with idiopathic PD completed questionnaires that assessed demographic and clinical characteristics, psychological measures and the presence of ICDs (QUIP-RS). RESULTS: Increased use of a 'negative' coping strategy, stronger illness identity, more emotional illness representations and stress were found to be significant predictors of ICDs, and different psychological predictors were associated with different ICDs. Medication was not found to predict ICDs in the presence of psychological factors, either when total treatment levels were considered or when agonist dose was considered alone. CONCLUSIONS: This study provides the first quantitative evidence of a predominant predictive relationship between psychological factors and ICDs in PD. The results suggest that psychological interventions may have useful therapeutic role to play for ICDs in PD. PMID- 27473644 TI - "I Don't Want to Be an Ostrich": Managing Mothers' Uncertainty during BRCA1/2 Genetic Counseling. AB - Families who face genetic disease risk must learn how to grapple with complicated uncertainties about their health and future on a long-term basis. Women who undergo BRCA 1/2 genetic testing describe uncertainty related to personal risk as well as their loved ones', particularly daughters', risk. The genetic counseling setting is a prime opportunity for practitioners to help mothers manage uncertainty in the moment but also once they leave a session. Uncertainty Management Theory (UMT) helps to illuminate the various types of uncertainty women encounter and the important role of communication in uncertainty management. Informed by UMT, we conducted a thematic analysis of 16 genetic counseling sessions between practitioners and mothers at risk for, or carriers of, a BRCA1/2 mutation. Five themes emerged that represent communication strategies used to manage uncertainty: 1) addresses myths, misunderstandings, or misconceptions; 2) introduces uncertainty related to science; 3) encourages information seeking or sharing about family medical history; 4) reaffirms or validates previous behavior or decisions; and 5) minimizes the probability of personal risk or family members' risk. Findings illustrate the critical role of genetic counseling for families in managing emotionally challenging risk-related uncertainty. The analysis may prove beneficial to not only genetic counseling practice but generations of families at high risk for cancer who must learn strategic approaches to managing a complex web of uncertainty that can challenge them for a lifetime. PMID- 27473646 TI - Prognostic relevance of miR-137 in patients with hepatocellular carcinoma. AB - BACKGROUND & AIMS: Cancer stem cells (CSCs) play a pivotal role in progression, metastasis and recurrence of cancer. Therefore, it is clinically useful to identify the relevant CSC marker that is associated with prognosis of hepatocellular carcinoma (HCC) and clarify its genetic and biological characteristics. METHODS: Expression of four CSC markers, CD13, EpCAM, CD44 and CD44v9, was examined in 99 HCC patients. Biological and cDNA/miRNA microarray data were compared among CD44-positive/-negative HCC cells and normal hepatic cells. The significance of the representative miRNAs was examined with regard to prognosis of additional 110 HCC patients. RESULTS: CD44-positive HuH7 cells proliferated faster and showed a greater sphere forming ability than CD44 negative HuH7 cells. CD44-positive HuH7 cells exhibited higher expression of specific genes involved in resistance to reactive oxygen species, anticancer drugs and tumour invasion than CD44-negative HCC cells. Higher expression of six miRNAs was observed in CD44-positive HuH7 cells, CD44-negative HuH7 cells, and human normal hepatic cells in that order. Of the six miRNAs, miR-137 was closely associated with overall and cancer-specific survivals, as well as with invasion of hepatic vein, hepatic artery, portal vein and bile duct, and alpha foetoprotein in additional 110 HCC patients. CONCLUSIONS: miR-137 may serve as a prognostic marker in patients with HCC and may be a potential target for the elimination of liver CSCs. PMID- 27473647 TI - Evaluation and Management of Tolosa-Hunt Syndrome in Children: A Clinical Update. AB - BACKGROUND: Tolosa-Hunt syndrome is a painful ophthalmoplegia caused by an inflammatory process of unknown etiology in the region of the cavernous sinus, orbital apex, or superior orbital fissure. This disease is rare in the pediatric population. The objective of this study was to provide a clinical framework for the evaluation and treatment of children with this disorder. A systematic approach to the diagnosis of painful ophthalmoplegia in children is proposed. METHODS: We present a 15-year-old girl whose clinical presentation and neuroradiological findings support a diagnosis of Tolosa-Hunt syndrome as defined by the 2013 International Classification of Headache Disorders (Third Edition, ICHD-3 beta) diagnostic criteria. An exhaustive systematic literature search based on these criteria yielded 15 additional cases of Tolosa-Hunt syndrome in children. Clinical, demographic, and radiological features were retrospectively analyzed. The results and statistical analyses are reported. RESULTS: A total of 16 individuals were included in the final analysis. This review summarizes the current knowledge and recommendations for the diagnosis and management of pediatric Tolosa-Hunt syndrome. It highlights demographic, clinical, and radiological features of this disease in children and underscores areas of the literature where evidence is still lacking. CONCLUSIONS: Overall, Tolosa-Hunt syndrome seems to follow a similar course in children compared to adults. The diagnostic approach and treatment require specific considerations. New observations and possible features of pediatric Tolosa-Hunt syndrome are discussed. Further research is needed to optimize clinical detection and medical management of this disease. PMID- 27473648 TI - Quality of Life in Pediatric Moyamoya Disease. AB - BACKGROUND: Moyamoya disease (MMD) is a progressive intracranial arteriopathy with high risk of stroke. Its impact on quality of life is unstudied. We surveyed children with moyamoya disease and compared their quality of life to chronically ill children and children with stroke to better understand the impact of this diagnosis. METHODS: Children with moyamoya disease aged seven to 17 years from Stanford's Moyamoya Clinic between June 2014 and March 2015 were included. Children with syndromic neurodevelopmental diagnoses were excluded. Patients were surveyed using the Pediatric Quality of Life 4.0, in addition to the Pediatric Stroke Outcome Measure or Recovery Recurrence Questionnaire. Mean scores were compared to normative data sets. Linear regression models compared total quality of life scores in patients with and without stroke, after adjusting for confounders. RESULTS: This cross-sectional study included 30 children with moyamoya disease; ten were male, and the median age was 13.5 years (range, 7 to 17 years). Twenty children (67%) had a stroke, and 14 of these had good neurological outcome (70%). Mean parent-proxy Pediatric Quality of Life scores were lower in all domains compared to healthy controls (P < 0.05), and all scores were comparable to chronically ill children and children with non-moyamoya disease stroke. There was no significant difference in total quality of life between patients with and without stroke. CONCLUSIONS: Even in the absence of stroke, children with moyamoya disease have lower quality of life than healthy controls and a similar quality of life to chronically ill children and those with non-moyamoya disease stroke. Children with moyamoya disease would benefit from mental health support beyond what a mild physical presentation may indicate. PMID- 27473649 TI - Neonatal Brachial Plexus Palsy in Children Aged 0 to 2.5 Years; Parent-Perceived Family Impact, Quality of Life, and Upper Extremity Functioning. AB - BACKGROUND: To investigate whether parents perceive impact of neonatal brachial plexus palsy on family and quality of life and upper extremity functioning in children less than 2.5 years. METHODS: This cross-sectional study used the PedsQL Family Impact Module (36 items/one total/four scales/scores 0 to 100), TNO-AZL (Dutch Organisation of Applied Natural Science and Academic Hospital Leiden) Preschool Children Quality of Life (43 items/12 scales/scores 0 to 100) and 21 upper extremity functioning questions. Associations between neonatal brachial plexus palsy/patient characteristics and family impact, perceived quality of life, and upper extremity functioning were investigated using regression analysis. RESULTS: Parents of 59 children (median age, 18 months) participated, 49 with C5-C6/C5-C7 lesions. Median Family Impact Module and TNO-AZL Preschool Children Quality of Life scores were 81.3 to 100.0/100.0 and 78.6 to 100.0/100.0. TNO-AZL Preschool Children Quality of Life scores did not differ significantly to healthy references except for stomach, skin, communication, and motor functioning problems. Parents reported around three upper extremity functioning problems. Greater lesion extent, lower age, still being in follow-up, and right-sided lesions were associated with greater family impact (P < 0.01 to P < 0.1). No clinically relevant associations were found for perceived quality of life. Greater lesion extent and nerve surgery history were associated with more upper extremity functioning problems (P < 0.01). Problems were associated with parental worrying (P < 0.05). CONCLUSIONS: Parents perceive having a child with neonatal brachial plexus palsy as impacting on their family depending on the side and severity of the lesion, treatment history, still being in follow-up, and age. They perceive the child's quality of life as relatively normal and not significantly different to healthy peers. However, parents noticed upper extremity functioning problems which increased parental worrying. Health care specialists should take these findings into account to better inform or counsel parents in an early stage during treatment. PMID- 27473650 TI - Fellowship Training in the Emerging Fields of Fetal-Neonatal Neurology and Neonatal Neurocritical Care. AB - BACKGROUND: Neonatal neurocritical care is a growing and rapidly evolving medical subspecialty, with increasing numbers of dedicated multidisciplinary clinical, educational, and research programs established at academic institutions. The growth of these programs has provided trainees in neurology, neonatology, and pediatrics with increased exposure to the field, sparking interest in dedicated fellowship training in fetal-neonatal neurology. OBJECTIVES: To meet this rising demand, increasing numbers of training programs are being established to provide trainees with the requisite knowledge and skills to independently deliver care for infants with neurological injury or impairment from the fetal care center and neonatal intensive care unit to the outpatient clinic. This article provides an initial framework for standardization of training across these programs. RESULTS: Recommendations include goals and objectives for training in the field; core areas where clinical competency must be demonstrated; training activities and neuroimaging and neurodiagnostic modalities which require proficiency; and programmatic requirements necessary to support a comprehensive and well-rounded training program. CONCLUSIONS: With consistent implementation, the proposed model has the potential to establish recognized standards of professional excellence for training in the field, provide a pathway toward Accreditation Council for Graduate Medical Education certification for program graduates, and lead to continued improvements in medical and neurological care provided to patients in the neonatal intensive care unit. PMID- 27473651 TI - The Clinical Predictors That Facilitate a Clinician's Decision to Order Genetic Testing for Rett Syndrome. AB - BACKGROUND: Rett syndrome is a common genetic cause of intellectual disability in girls caused by a mutation in the MECP2 gene. Diagnosis is based on clinical criteria. The aim was to compare the frequencies of the clinical criteria in patients with and without MECP2 mutations. METHODS: We performed a retrospective review at a children's hospital of patients who underwent MECP2 testing from 2008 to 2013. Logistic regression was performed to determine which criteria were most predictive of MECP2 status. RESULTS: Of 169 patients who met inclusion criteria, 46 (27.2%) were MECP2 positive. Loss of language skills (MECP2+ 100% versus MECP2 87.8%; P = 0.012) was the most common finding among both groups. Other main criteria were more common in MECP2 patients: gait abnormalities (84.8% versus 27.6%; P < 0.0001); stereotypic hand movements (76.1% versus 15.5%; P < 0.0001); loss of hand skills (71.7% versus 4.9%; P < 0.0001). Logistic regression analysis including all four criteria demonstrated language loss was not predictive. CONCLUSIONS: Loss of hand skills resulted in the highest odds of having a positive genetic test. Gait abnormalities and stereotypic hand movements were also strong predictors of MECP2+ testing. Many individuals with language delay had genetic testing; however, this is the least specific of the major criteria. These findings have implications for which patients should have genetic testing. PMID- 27473652 TI - Vitamin B12 Deficiency Presenting with Neurological Dysfunction in an Adolescent. AB - BACKGROUND: Vitamin B12 deficiency is classically encountered in the adult Caucasian population and manifests as a subacute combined degeneration in the presence or absence of macrocytic anemia. However, B12 deficiency is extremely rare in children in developed countries, and pernicious anemia is even rarer etiology of this deficiency. The clinical presentation of B12 deficiency in children is not as easily recognizable or well-characterized and may result in missed or delayed diagnosis. PATIENT DESCRIPTION: We describe a previously healthy adolescent girl who presented with emotional lability, mental status changes, hyperreflexia, and ataxia. She was found to have megaloblastic anemia and subacute combined degeneration secondary to B12 deficiency caused by pernicious anemia. CONCLUSION: Though B12 deficiency is uncommon in pediatrics, it is important to maintain a high index of suspicion because early recognition and treatment of B12 deficiency are key to preventing long-term neurological sequelae. PMID- 27473653 TI - The reliability of a maximal isometric hip strength and simultaneous surface EMG screening protocol in elite, junior rugby league athletes. AB - OBJECTIVES: Firstly to describe the reliability of assessing maximal isometric strength of the hip abductor and adductor musculature using a hand held dynamometry (HHD) protocol with simultaneous wireless surface electromyographic (sEMG) evaluation of the gluteus medius (GM) and adductor longus (AL). Secondly, to describe the correlation between isometric strength recorded with the HHD protocol and a laboratory standard isokinetic device. DESIGN: Reliability and correlational study. METHODS: A sample of 24 elite, male, junior, rugby league athletes, age 16-20 years participated in repeated HHD and isometric Kin-Com (KC) strength testing with simultaneous sEMG assessment, on average (range) 6 (5-7) days apart by a single assessor. Strength tests included; unilateral hip abduction (ABD) and adduction (ADD) and bilateral ADD assessed with squeeze (SQ) tests in 0 and 45 degrees of hip flexion. RESULTS: HHD demonstrated good to excellent inter-session reliability for all outcome measures (ICC(2,1)=0.76-0.91) and good to excellent association with the laboratory reference KC (ICC(2,1)=0.80 0.88). Whilst intra-session, inter-trial reliability of EMG activation and co activation outcome measures ranged from moderate to excellent (ICC(2,1)=0.70 0.94), inter-session reliability was poor (all ICC(2,1)<0.50). CONCLUSIONS: Isometric strength testing of the hip ABD and ADD musculature using HHD may be measured reliably in elite, junior rugby league athletes. Due to the poor inter session reliability of sEMG measures, it is not recommended for athlete screening purposes if using the techniques implemented in this study. PMID- 27473654 TI - Endogenous occurrence of protein S-guanylation in Escherichia coli: Target identification and genetic regulation. AB - 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a nitrated cGMP derivative formed in response to nitric oxide (NO) and reactive oxygen species (ROS). It can cause a post-translational modification (PTM) of protein thiols through cGMP adduction (protein S-guanylation). Accumulating evidence has suggested that, in mammals, S-guanylation of redox-sensor proteins may implicate in regulation of adaptive responses against ROS-associated oxidative stress. Occurrence as well as protein targets of S-guanylation in bacteria remained unknown, however. Here we demonstrated, for the first time, the endogenous occurrence of protein S-guanylation in Escherichia coli (E. coli). Western blotting using anti-S-guanylation antibody clearly showed that multiple proteins were S-guanylated in E. coli. Interestingly, some of those proteins were more intensely S-guanylated when bacteria were cultured under static culture condition than shaking culture condition. It has been known that E. coli is deficient of guanylate cyclase, an enzyme indispensable for 8-nitro-cGMP formation in mammals. We found that adenylate cyclase from E. coli potentially catalyzed 8-nitro-cGMP formation from its precursor 8-nitroguanosine 5'-triphosphate. More importantly, E. coli lacking adenylate cyclase showed significantly reduced formation of S guanylated proteins. Our S-guanylation proteomics successfully identified S guanylation protein targets in E. coli, including chaperons, ribosomal proteins, and enzymes which associate with protein synthesis, redox regulation and metabolism. Understanding of functional impacts for protein S-guanylation in bacterial signal transduction is necessary basis for development of potential chemotherapy and new diagnostic strategy for control of pathogenic bacterial infections. PMID- 27473656 TI - The Salmonella effector SopB prevents ROS-induced apoptosis of epithelial cells by retarding TRAF6 recruitment to mitochondria. AB - Microbial pathogens enter host cells by injecting effector proteins of the Type III secretion system (T3SS), which facilitate pathogen translocation across the host cell membrane. These effector proteins exert their effects by modulating a variety of host innate immune responses, thereby facilitating bacterial replication and systemic infection. Salmonella enterica serovar typhimurium (S.typhimurium) is a clinically important pathogen that causes food poisoning and gastroenteritis. The SopB effector protein of S. typhimurium, encoded by Salmonella pathogenicity islands (SPI)-1 T3SS, protects host epithelial cells from infection-induced apoptosis. However, how SopB influences apoptosis induction remains unclear. Here, we investigated the mechanism of SopB action in host cells. We found that SopB inhibits infection-induced apoptosis by attenuating the production of reactive oxygen species (ROS) in mitochondria, the crucial organelles for apoptosis initiation. Further investigation revealed that SopB binds to cytosolic tumor necrosis factor receptor associated factor 6 (TRAF6) and forms a trap preventing the mitochondrial recruitment of TRAF6, an essential event for ROS generation within mitochondria. By studying the response of Traf6(+/+) and Traf6(-/-)mouse embryonic fibroblasts to S. typhimurium infection, we found that TRAF6 promoted apoptosis by increasing ROS accumulation, which led to increased Bax/Bcl-2 ratio, Bax recruitment to mitochondrial membrane, and release of Cyt c into the cytoplasm. These findings show that SopB suppresses host cell apoptosis by binding to TRAF6 and preventing mitochondrial ROS generation. PMID- 27473655 TI - In vitro selection of bispecific diabody fragments using covalent bicistronic DNA display. AB - Bispecific antibodies with two different antigen-binding sites have been widely used for a variety of medical applications. The activity and stability of antibody fragments can be improved by in vitro evolution. Although the affinity and stability of small bispecific antibody fragments such as diabodies can be further optimized by in vitro display technologies, cell-free display of bispecific antibody fragments has not been reported. In this study, we applied a covalent bicistronic DNA display for the in vitro selection of heterodimeric diabodies. First, we confirmed the antigen-binding activities of a diabody synthesized by an in vitro transcription and translation system. However, when we performed DNA-display selection of a model diabody library in a proof-of principle experiment, no enrichment of the diabody gene was observed, likely due to a low yield of the diabody heterodimer. To overcome this issue, we introduced cysteine residues at the VH-VL interface of the diabody heterodimer. Using the disulfide-stabilized diabodies, we successfully enriched the diabody gene from a model library. Our results indicate that the covalent bicistronic DNA display technique could be useful for improving the stability and affinity of bispecific diabody fragments. PMID- 27473657 TI - Mouse D1Pas1, a DEAD-box RNA helicase, is required for the completion of first meiotic prophase in male germ cells. AB - D1Pas1 is a mouse autosomal DEAD-box RNA helicase expressed predominantly in the testis. To assess its possible function, we generated D1Pas1-deficient mice using embryonic stem cells with a targeted D1Pas1 allele. Deletion of D1Pas1 did not cause noticeable embryonic defects or death, indicating that D1Pas1 is not essential for embryogenesis. Whereas homozygous knockout female mice showed normal reproductive performance, homozygous knockout male mice were completely sterile. The seminiferous epithelium of D1Pas1-deficient males contained no spermatids or spermatozoa because of spermatogenic arrest at the late pachytene stage. Upregulation of retrotransposons such as LINE-1 was not found in D1Pas1 deficient males, unlike males lacking Mvh, another testicular DEAD-box RNA helicase. Meiotic chromosome behavior in developing spermatocytes of D1Pas1 deficient males was indistinguishable from that in wild-type males, at least until synaptonemal complex formation. Thus, mouse D1Pas1 is the first-identified DEAD-box RNA helicase that plays critical roles in the final step of the first meiotic prophase in male germ cells. PMID- 27473658 TI - Differential elastic responses to barrier-altering agonists in two types of human lung endothelium. AB - Vascular integrity is primarily determined by endothelial cell (EC) cytoskeletal structure that is differentially regulated by various stimuli. In this study, atomic force microscopy (AFM) was used to characterize structural and mechanical properties in the cytoskeleton of cultured human pulmonary artery EC (HPAEC) and human lung microvascular EC (HLMVEC) by determining elastic properties (Young's modulus) in response to endogenous barrier protective agents sphingosine 1 phosphate (S1P) and hepatocyte growth factor (HGF), or the barrier disruptive molecule thrombin. Initial studies in unstimulated cells indicate higher baseline peripheral elastic modulus values in HPAEC (mean 2.9 KPa) than in HLMVEC (1.8 KPa). After 30 min of stimulation, S1P induced the highest Young's modulus increase (6.1 KPa) compared to the other barrier enhancing stimuli, HGF (5.8 KPa) and the pharmaceutical agent and S1P analog FTY720 (4.1 KPa). In contrast, the barrier disruptive agent thrombin decreased values from 2.5 KPa to 0.7 KPa depending on the cell type and treatment time. AFM topographical imaging supports these quantitative biophysical data regarding differential peripheral elastic properties in EC. Overall, these AFM studies provide novel insights into the biomechanical properties of human lung EC that regulate vascular barrier function and have potential applicability to pathophysiologic vascular leak syndromes such as acute lung injury. PMID- 27473659 TI - A global perspective on the use, occurrence, fate and effects of anti-diabetic drug metformin in natural and engineered ecosystems. AB - Metformin is the most commonly used anti-diabetic drug in the world. When consumed, this unmetabolised pharmaceutical compound is excreted by the body and eventually enters the environment through a variety of pathways. Based on its high consumption and excretion rates, high concentrations of metformin have been detected in influents of wastewater treatment plants. Metformin and its transformation product, guanylurea, are also expected to be present in other aquatic environments based on their physico-chemical properties. Not surprisingly, guanylurea has also been detected in surface water, groundwater, and drinking water. Available information on ecotoxicological effects of metformin suggests that metformin is a potential endocrine disruptor and thus further emphasising the threat this drug could pose to our environment. This review provides a comprehensive overview of metformin and critically discusses available literature data with respect to its global use/demand, occurrence, fate and ecotoxicity in treatment facilities equipped with conventional and advanced treatment technologies, and its degradation/removal mechanisms. Final section highlights the existing knowledge gaps regarding its ultimate fate under the natural and engineered ecosystems and identifies some important research areas requiring urgent attention from regulatory makers and scientific community. PMID- 27473660 TI - The release of wastewater contaminants in the Arctic: A case study from Cambridge Bay, Nunavut, Canada. AB - The treatment of municipal wastewater in the Arctic is challenging due to a variety of financial, operational, climatic and technical issues. To better understand the efficacy of current wastewater treatment in this region and the hazard posed to receiving waters, we assessed the occurrence of nutrients and contaminants (i.e., pharmaceuticals, antibiotic resistance genes) as they moved through a lagoon-based treatment system in Cambridge Bay, Nunavut, Canada. Wastewater treatment in this community is performed by the use of a lagoon-tundra wetland system that is discharged into the marine environment and is representative of current common practices throughout the region. In 2014, samples were collected before and during lagoon discharge from two locations in the main lagoon, one location downstream from the lagoon effluent and three locations offshore. Grab samples were collected to measure nutrients (e.g., total nitrogen and phosphorus) and the presence of antibiotic resistance gene-bearing microbes, and Polar Organic Chemical Integrative Samplers (POCIS) were deployed to collect passively organic contaminants in all locations. A total of six pharmaceuticals were detected from a screen of twenty-eight analytes during the study: atenolol, carbamazepine, clarithromycin, metoprolol, sulfamethoxazole and trimethoprim. The greatest concentrations of nutrients, antibiotic resistance genes (ARGs), and pharmaceuticals were found in sampling locations within the treatment lagoon. Offshore of the release point, we observed limited to no detection of pharmaceuticals and ARGs, but no change in total nitrogen and phosphorus from pre-release. We conclude that the current concentrations of monitored pharmaceuticals do not pose a significant hazard at this time to aquatic organisms in Cambridge Bay. PMID- 27473661 TI - Which skills boost service provider confidence when managing people presenting with psychiatric emergencies? AB - The way service seekers interact with the staff at emergency services has been shown to influence the standard of care, especially in the case of certain psychiatric manifestations. Staff reactions to psychiatric complaints have been linked to their comfort dealing with these types of service users as well as their competencies understanding the illness. It is therefore vital to understand which skills increase confidence in treating psychiatric emergencies. Twenty-six open-ended convergent interviews were conducted with staff working in a psychiatric emergency department. Thematic analysis was used to analyze the data. Participants reported several non-technical skills which developed from exclusively serving people with psychiatric emergencies: 1) Vigilance allowed staff to be sensitive to minor changes in behavior which precede psychiatric emergencies. 2) The ability to negotiate and find tangible solutions was particularly important when dealing with psychiatric complaints which may not have tangible resolutions. 3) The ability to appraise social support networks allowed staff to plan follow-up actions and ensure continuity of care when support was available. 4) The ability to self-reflect allowed participants to learn from their experience and avoid burnout, frustration, and fatigue. Participants also reported several other clinical skills which they gained during training, including teamwork, de-escalating techniques and risk assessment. Tentatively speaking, these skills improve staff's confidence when treating psychiatric emergencies. Certain skills may be generalized to staff working in medical emergency departments who frequently encounter psychiatric complaints. PMID- 27473662 TI - Technical analysis, contestation and politics in policy agenda setting and implementation: the rise and fall of primary care maternal services from Ghana's capitation policy. AB - BACKGROUND: Why issues get on the policy agenda, move into policy formulation and implementation while others drop off in the process is an important field of enquiry to inform public social policy development and implementation. This paper seeks to advance our understanding of health policy agenda setting, formulation and implementation processes in Ghana, a lower middle income country by exploring how and why less than three months into the implementation of a pilot prior to national scale up; primary care maternal services that were part of the basket of services in a primary care per capita national health insurance scheme provider payment system dropped off the agenda. METHODS: We used a case study design to systematically reconstruct the decisions and actions surrounding the rise and fall of primary care maternal health services from the capitation policy. Data was collected from July 2012 and August 2014 through in-depth interviews, observations and document review. The data was analysed drawing on concepts of policy resistance, power and arenas of conflict. RESULTS: During the agenda setting and policy formulation stages; predominantly technical policy actors within the bureaucratic arena used their expertise and authority for consensus building to get antenatal, normal delivery and postnatal services included in the primary care per capita payment system. Once policy implementation started, policy makers were faced with unanticipated resistance. Service providers, especially the private self-financing used their professional knowledge and skills, access to political and social power and street level bureaucrat power to contest and resist various aspects of the policy and its implementation arrangements - including the inclusion of primary care maternal health services. The context of intense public arena conflicts and controversy in an election year added to the high level political anxiety generated by the contestation. The President and Minister of Health responded and removed antenatal, normal delivery and postnatal care from the per capita package. CONCLUSION: The tensions and complicated relationships between technical considerations and politics and bureaucratic versus public arenas of conflict are important influences that can cause items to rise and fall on policy agendas. PMID- 27473663 TI - ROHHAD syndrome and evolution of sleep disordered breathing. AB - BACKGROUND: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare disease with a high mortality rate. Although nocturnal hypoventilation (NH) is central to ROHHAD, the evolution of sleep disordered breathing (SDB) is not well studied. The aim of the study was to assess early manifestations of SDB and their evolution in ROHHAD syndrome. METHODS: Retrospective study of children with ROHHAD at two Canadian centers. All children with suspected ROHHAD at presentation underwent polysomnography (PSG) to screen for nocturnal hypoventilation. PSG findings at baseline and follow-up were collected. Interventions and diagnostic test results were recorded. RESULTS: Six children were included. The median age of rapid onset obesity and nocturnal hypoventilation (NH) was 3.5 and 7.2 years respectively. On initial screening for ROHHAD 4/6 (66.7 %) children had obstructive sleep apnea (OSA), 1/6 (16.7 %) had NH and 1/6 (16.7 %) had both OSA and NH. Follow up PSGs were performed in 5/6 children as one child died following a cardiorespiratory arrest. All children at follow up had NH and required non-invasive positive pressure ventilation. Additionally, 3/6 (50 %) children demonstrated irregular breathing patterns during wakefulness. CONCLUSIONS: Children with ROHHAD may initially present with OSA and only develop NH later as well as dysregulation of breathing during wakefulness. The recognition of the spectrum of respiratory abnormalities at presentation and over time may be important in raising the index of suspicion of ROHHAD. Early recognition and targeted therapeutic interventions may limit morbidity and mortality associated with ROHHAD. PMID- 27473664 TI - Influence of Aspergillus fumigatus conidia viability on murine pulmonary microRNA and mRNA expression following subchronic inhalation exposure. AB - BACKGROUND: Personal exposure to fungal bioaerosols derived from contaminated building materials or agricultural commodities may induce or exacerbate a variety of adverse health effects. The genomic mechanisms that underlie pulmonary immune responses to fungal bioaerosols have remained unclear. OBJECTIVE: The impact of fungal viability on the pulmonary microRNA and messenger RNA profiles that regulate murine immune responses was evaluated following subchronic inhalation exposure to Aspergillus fumigatus conidia. METHODS: Three groups of naive B6C3F1/N mice were exposed via nose-only inhalation to A. fumigatus viable conidia, heat-inactivated conidia (HIC), or HEPA-filtered air twice a week for 13 weeks. Total RNA was isolated from whole lung 24 and 48 h postfinal exposure and was further processed for gene expression and microRNA array analysis. The molecular network pathways between viable and HIC groups were evaluated. RESULTS: Comparison of data sets revealed increased Il4, Il13 and Il33 expression in mice exposed to viable vs. HIC. Of 415 microRNAs detected, approximately 50% were altered in mice exposed to viable vs. HIC 48 h postexposure. Significantly down regulated (P <= 0.05) miR-29a-3p was predicted to regulate TGF-beta3 and Clec7a, genes involved in innate responses to viable A. fumigatus. Also significantly down-regulated (P <= 0.05), miR-23b-3p regulates genes involved in pulmonary IL 13 and IL-33 responses and SMAD2, downstream of TGF-beta signalling. Using Ingenuity Pathway Analysis, a novel interaction was identified between viable conidia and SMAD2/3. CONCLUSIONS AND CLINICAL RELEVANCE: Examination of the pulmonary genetic profiles revealed differentially expressed genes and microRNAs following subchronic inhalation exposure to A. fumigatus. MicroRNAs regulating genes involved in the pulmonary immune responses were those with the greatest fold change. Specifically, germinating A. fumigatus conidia were associated with Clec7a and were predicted to interact with Il13 and Il33. Furthermore, altered microRNAs may serve as potential biomarkers to evaluate fungal exposure. PMID- 27473665 TI - The impact of neighborhood on physical activity in the Jackson Heart Study. AB - Physical inactivity is an independent risk factor for many diseases. Most research has focused on individual-level factors for physical activity (PA), but evidence suggests that neighborhood is also important. We examined baseline data collected between 2000 and 2004 from 5236 participants in the Jackson Heart Study to determine the effects of neighborhood on 2 types of PA: Active Living (AL), and Sports and Exercise (Sport) in an all-African American cohort. Participants were georeferenced and data from individual baseline questionnaires and US Census were analyzed using descriptive, bivariate, and multilevel models. In both types of PA, neighborhood factors had an independent and additive effect on AL and Sport. Living in an urban (p=0.003) or neighborhood with a higher percentage of residents with less than a high school education (p<0.001) was inversely associated with AL. There was an inverse interaction effect between individual and lower neighborhood education (p=0.01), as well as between age and urban neighborhoods (p=0.02) on AL. Individual level education (OR=1.30) and per capita income (OR=1.07) increased the odds of moderate-to-high sports. Future studies should focus on what contextual aspects of urban or less educated neighborhoods are influential in determining PA, as well as longitudinal multilevel analyses of neighborhood effects on PA. PMID- 27473666 TI - Utility of nonblood-based risk assessment for predicting type 2 diabetes mellitus: A meta-analysis. AB - OBJECTIVE: Nonblood-based risk assessment for type 2 diabetes mellitus (T2DM) that depends on data based on a questionnaire and anthropometry is expected to avoid unnecessary diagnostic testing and overdiagnosis due to blood testing. This meta-analysis aims to assess the predictive ability of nonblood-based risk assessment for future incident T2DM. METHODS: Electronic literature search was conducted using EMBASE and MEDLINE (from January 1, 1997 to October 1, 2014). Included studies had to use at least 3 predictors for T2DM risk assessment and allow reproduction of 2*2 contingency table data (i.e., true positive, true negative, false positive, false negative) to be pooled with a bivariate random effects model and hierarchical summary receiver-operating characteristic model. Considering the importance of excluding individuals with a low likelihood of T2DM from diagnostic blood testing, we especially focused on specificity and LR-. RESULTS: Eighteen eligible studies consisting of 184,011 participants and 7038 cases were identified. The pooled estimates (95% confidence interval) were as follows: sensitivity=0.73 (0.66-0.79), specificity=0.66 (0.59-0.73), LR+=2.13 (1.81-2.50), and LR-=0.41 (0.34-0.50). CONCLUSIONS: Nonblood-based assessment of risk of T2DM could produce acceptable results although the feasibility of such a screener needs to be determined in future studies. PMID- 27473667 TI - Epitope analysis of DQ6-reactive antibodies in sera from a DQ6-positive transplant candidate sensitized during pregnancy. AB - This case report describes DQ6-reactive serum antibody reactivity in a patient who types as DQ6. DNA typing showed DQB1*06:09 on the antibody producer and serum reactivity with DQB1*06:01, *06:02 and *06:03 but not with *06:04 and *06:09. HLAMatchmaker serum analysis showed antibody reactivity with a new antibody verified 85VA eplet on DQB but additional reactivity with DQB1*02:01 could not be readily interpreted. After applying the nonself-self algorithm of HLA immunogenicity we have identified a new DQB epitope structurally described as 140A2+130R+135D and shared by DQB1*02:01 and DQB1*05:01 and DQB1*06:02 of the immunizer. PMID- 27473668 TI - Macroscopic Sertoli cell nodule of the testis containing numerous spermatogonia. AB - Sertoli cell nodule consists of clusters of seminiferous tubules composed of immature Sertoli cells and, in some cases, spermatogonia. We report a case of macroscopic Sertoli cell nodule that occurred in the descended left testis of a 26-year-old man. The nodule was centrally located and measured 1.7cm in greatest dimension, the largest such lesion reported to date. Spermatogonia were prominent, a feature that is particularly common in the larger nodules. Macroscopic Sertoli cell nodules (greater than 0.5cm) typically occur in a descended testis. The age range of patients in cases reported since the year 2000 is 19-36 years. Unlike incidental Sertoli cell nodules, macroscopic Sertoli cell nodules containing numerous germ cells can be mistaken for several other Sertoli cell and germ cell lesions and neoplasms. PMID- 27473670 TI - Activity-dependent synapse to nucleus signaling. AB - The unique polarity of neurons requires that synaptic inputs are relayed to the nucleus to trigger changes in gene expression. This long distance signaling process is crucial for the function and survival of neuronal circuits. To that end, neurons have developed multiple modes of signal transmission from the synapse to the nucleus. In this review, we summarize the latest research on activity-dependent movement and nuclear import of postsynaptic proteins that modulate neuronal plasticity. We also focus on the mechanism of active transport as well as the role of importins in mediating nuclear import of the postsynaptic proteins. Finally, we briefly discuss the role of synapse to nucleus signaling in the context of transcription-dependent plasticity and conclude by describing future challenges in this field of research. PMID- 27473669 TI - P63 expression as a biomarker discriminating giant cell tumor of bone from other giant cell-rich bone lesions. AB - INTRODUCTION: Giant cell tumor of bone (GCTOB) is a locally aggressive neoplasm that accounts for 5% of all primary bone tumors. This tumor overlaps in histopathologic and radiographic presentations with different malignant, benign, and metabolic giant cell-rich lesions. The purpose of this study is to evaluate p63 expression status in giant cell tumor of bone in comparison with other giant cell-rich lesions. MATERIALS AND METHODS: In a cross-sectional study we examined immunohistochemical expression of p63 in a series of 100 giant cell-rich bone lesions, including 31 giant cell tumors of bone, 14 osteosarcomas (including 3 giant cell-rich variants), 18 aneurysmal bone cysts (including one solid variant), 8 non-ossifying fibromas, 17 chondroblastomas, 8 tenosynovial giant cell tumors, and 4 brown tumors. RESULTS: Immunohistochemical analysis showed p63 nuclear expression in 96.8% of giant cell tumors of bone, 14.3% of osteosarcomas, 50% of non-ossifiying fibromas, 22.2% of aneurysmal bone cysts, 68.7% of chondroblastomas, 75.0% of brown tumors and none of the tenosynovial giant cell tumors. Taking into account the intensity of staining, we identified strong staining in 48.4% of giant cell tumors of bone, 35.3% of chondroblastomas and 7.1% of osteosarcomas (in 2 cases which were both giant cell-rich variants). Considering extent of staining, extensive staining was only observed in 58.0% of giant cell tumors of bone, 23.5% of chondroblastomas and 14.3% of osteosarcomas. CONCLUSION: A large number of giant cell tumors of bone (96.8%) are positive for p63, which is considerably more than any other giant cell-rich lesion. However, positive staining for p63 is not specific for GCTOB and may be seen in other lesions such as chondroblastoma, non-ossifying fibroma, brown tumor, and giant cell-rich osteosarcoma. P63 is a sensitive (96.8%) and relatively specific marker for discriminating GCTOB from other types of giant cell-rich lesions. We suggest a combined scoring method for p63 IHC staining interpretation in GC-rich lesions, considering both intensity and extent of reaction, with a 2+ cut off as a more accurate marker for the diagnosis of GCTOB within the appropriate clinical context. PMID- 27473671 TI - The dipeptide Pro-Asp promotes IGF-1 secretion and expression in hepatocytes by enhancing JAK2/STAT5 signaling pathway. AB - It has been implicated that IGF-1 secretion can be regulated by dietary protein. However, whether the dipeptides, one of digested products of dietary protein, have influence on IGF-1 secretion remain largely unknown. Our study aimed to investigate the effects of the dipeptide Pro-Asp on IGF-1 secretion and expression in hepatocytes and to explore the possible underlying mechanisms. Our findings demonstrated that Pro-Asp promoted the secretion and gene expression of IGF-1 in HepG2 cells and primary porcine hepatocytes. Meanwhile, Pro-Asp activated the ERK and Akt signaling pathways, downstream of IGF-1. In addition, Pro-Asp enhanced GH-mediated JAK2/STAT5 signaling pathway, while inhibition of JAK2/STAT5 blocked the promotive effect of Pro-Asp on IGF-1 secretion and expression. Moreover, acute injection of Pro-Asp stimulated IGF-1 expression and activated JAK2/STAT5 signaling pathway in mice liver. Together, these results suggested that the dipeptide Pro-Asp promoted IGF-1 secretion and expression in hepatocytes by enhancing GH-mediated JAK2/STAT5 signaling pathway. PMID- 27473673 TI - Letter to the Editor regarding recurrent sebaceous carcinoma of the eyelid: Outcome after postoperative reirradiation. PMID- 27473672 TI - Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model. AB - BACKGROUND: Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). METHODS: JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. RESULTS: JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. CONCLUSIONS: Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the treatment of AR-overexpressed CRPC driven by AR splice variants that are not clinically actionable at present. Prostate 76:1536 1545, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27473674 TI - Does the physiatrist replicate the functions of the neurologist or orthopedist? PMID- 27473675 TI - Factors associated with different types of birth attendants for home deliveries: an analysis of the cross-sectional 2010 South Sudan household survey. AB - BACKGROUND: In South Sudan, birth deliveries attended by unskilled birth attendants put the mothers and their newborns at increased risk of perinatal morbidity and mortality. The aim of this study was to identify factors associated with delivery by unskilled birth attendants or by unassisted delivery. DESIGN: We examined data for 2,767 (weighted total) women aged 15-49 years who delivered at home 2 years prior to the South Sudan Household Health Survey 2010. Multinomial logistic regression analyses were used to identify factors associated with delivery by unskilled birth attendants or by unassisted delivery. RESULTS: The prevalence of delivery by unskilled birth attendants was 19% [95% confidence interval (CI) 17.0, 20.5], by skilled birth attendants (SBAs) was 45% (95% CI 42.4, 47.0), and by unassisted delivery was 36% (95% CI 34.2, 38.6). After adjusting for potential confounders, the following factors were associated with the increased odds for unassisted delivery or delivery by an unskilled birth attendant: mothers with no schooling, who did not attend antenatal care (ANC) during pregnancy, who had lower quality of ANC services, from poor households, or who had no prior knowledge about obstetric danger signs. CONCLUSIONS: We found that non-utilization of maternal health care services, such as ANC, was significantly associated with unattended birth delivery or delivery by unskilled health providers. The increased uptake of SBAs at delivery will require easier access to ANC services, health promotion on the importance and benefits of SBAs for delivery, targeting both mothers and their families, and the training and deployment of more SBAs across the country. PMID- 27473676 TI - Impact of a peer-counseling intervention on breastfeeding practices in different socioeconomic strata: results from the equity analysis of the PROMISE-EBF trial in Uganda. AB - BACKGROUND: Undernutrition is highly prevalent among infants in Uganda. Optimal infant feeding practices may improve nutritional status, health, and survival among children. OBJECTIVE: Our study evaluates the socioeconomic distribution of exclusive breastfeeding (EBF) and growth outcomes among infants included in a trial, which promoted EBF by peer counselors in Uganda. DESIGN: Twenty-four clusters comprising one to two communities in Uganda were randomized into intervention and control arms, including 765 mother-infant pairs (PROMISE-EBF trial, 200608, ClinicalTrials.gov no. NCT00397150). Intervention clusters received the promotion of EBF by peer counselors in addition to standard care. Breastfeeding and growth outcomes were compared according to wealth quintiles and intervention/control arms. Socioeconomic inequality in breastfeeding and growth outcomes were measured using the concentration index 12 and 24 weeks postpartum. We used the decomposition of the concentration index to identify factors contributing to growth inequality at 24 weeks. RESULTS: EBF was significantly concentrated among the poorest in the intervention group at 24 weeks postpartum, concentration index -0.060. The control group showed a concentration of breastfeeding among the richest part of the population, although not statistically significant. Stunting, wasting, and underweight were similarly significantly concentrated among the poorest in the intervention group and the total population at 24 weeks, but showing non-significant concentrations for the control group. CONCLUSION: This study shows that EBF can be successfully promoted among the poor. In addition, socioeconomic inequality in growth outcomes starts early in infancy, but the breastfeeding intervention was not strong enough to counteract this influence. PMID- 27473677 TI - A case report of ocular chemical injury secondary to ozone gas. PMID- 27473678 TI - LBW and IUGR temporal trend in 4 population-based birth cohorts: the role of economic inequality. AB - BACKGROUND: Low/medium income countries, with health inequalities present high rates of neonates having low birthweight and/or are small for the gestational age. This study aims to analyze the absolute and relative income inequality in the occurrence of low birthweight and small size for gestational age among neonates in four birth cohorts from southern Brazil in 1982, 1993, 2004, and 2011. METHODS: The main exhibit was monthly family income. The outcomes were birth with low birthweight or small for the gestational age. The inequalities were calculated using the Slope Index of Inequality and the Relative Index of Inequality adjusted for maternal skin color, schooling, age, and marital status. RESULTS: In all birth cohorts, poorer mothers were at greater odds of having neonates with low birthweight or small for the gestational age. There was a tendency to decrease the prevalence of small for gestational age in poorer families associated with the reduction of inequalities over the past decades, which was not observed regarding low birthweight. CONCLUSIONS: Economic inequalities occurred in neonates with low birthweight and with intrauterine growth restriction in the four studies, with a higher incidence of inadequate neonatal outcomes in the poorer families. PMID- 27473679 TI - Hypersensitivity Pneumonitis Due to Metalworking Fluid Aerosols. AB - PURPOSE OF REVIEW: This review summarises the clinical knowledge of hypersensitivity pneumonitis in workers exposed to aerosols of metalworking fluid, reviewing published outbreaks and clinical cases. RECENT FINDINGS: Metalworking fluid exposure has become the commonest recognised cause of occupational hypersensitivity pneumonitis, having been rare before 2000. There are many possible agents in the metalworking fluid which may be the cause of disease including bacteria, mycobacteria, fungae, biocides, emulsifiers, reodorants and dissolved chrome and cobalt. Causes are likely to be different in different outbreaks. Mycobacteria growing in the metalworking fluid have generated immune responses in some workers, but their role in disease causation is not yet established. Many outbreaks have been identified in large workplaces using common sumps. It is not possible to prevent microbial contamination of metalworking fluids in use. Disease prevention should focus on stopping inhalation of aerosols, particularly by re-engineering to remove recirculation. PMID- 27473680 TI - Genome-wide identification and expression analysis of sulfate transporter (SULTR) genes in potato (Solanum tuberosum L.). AB - MAIN CONCLUSION: Solanum tuberosum genome analysis revealed 12 StSULTR genes encoding 18 transcripts. Among genes annotated at group level ( StSULTR I-IV), group III members formed the largest SULTRs-cluster and were potentially involved in biotic/abiotic stress responses via various regulatory factors, and stress and signaling proteins. Employing bioinformatics tools, this study performed genome wide identification and expression analysis of SULTR (StSULTR) genes in potato (Solanum tuberosum L.). Very strict homology search and subsequent domain verification with Hidden Markov Model revealed 12 StSULTR genes encoding 18 transcripts. StSULTR genes were mapped on seven S. tuberosum chromosomes. Annotation of StSULTR genes was also done as StSULTR I-IV at group level based mainly on the phylogenetic distribution with Arabidopsis SULTRs. Several tandem and segmental duplications were identified between StSULTR genes. Among these duplications, Ka/Ks ratios indicated neutral nature of mutations that might not be causing any selection. Two segmental and one-tandem duplications were calculated to occur around 147.69, 180.80 and 191.00 million years ago (MYA), approximately corresponding to the time of monocot/dicot divergence. Two other segmental duplications were found to occur around 61.23 and 67.83 MYA, which is very close to the origination of monocotyledons. Most cis-regulatory elements in StSULTRs were found associated with major hormones (such as abscisic acid and methyl jasmonate), and defense and stress responsiveness. The cis-element distribution in duplicated gene pairs indicated the contribution of duplication events in conferring the neofunctionalization/s in StSULTR genes. Notably, RNAseq data analyses unveiled expression profiles of StSULTR genes under different stress conditions. In particular, expression profiles of StSULTR III members suggested their involvement in plant stress responses. Additionally, gene co expression networks of these group members included various regulatory factors, stress and signaling proteins, and housekeeping and some other proteins with unknown functions. PMID- 27473681 TI - Recent global trends in the prevalence and incidence of dementia, and survival with dementia. AB - BACKGROUND: Current projections of the scale of the coming dementia epidemic assume that the age- and sex-specific prevalence of dementia will not vary over time, and that population ageing alone (increasing the number of older people at risk) drives the projected increases. The basis for this assumption is doubtful, and secular trends (that is, gradual decreases or increases in prevalence over long-term periods) are perfectly plausible. METHODS: We carried out a systematic review of studies of trends in prevalence, incidence and mortality for people with dementia, conducted since 1980. RESULTS: We identified nine studies that had tracked dementia prevalence, eight that had tracked dementia incidence, and four that had tracked mortality among people with dementia. There was some moderately consistent evidence to suggest that the incidence of dementia may be declining in high-income countries. Evidence on trends in the prevalence of dementia were inconsistent across studies and did not suggest any clear overall effect. Declining incidence may be balanced by longer survival with dementia, although mortality trends have been little studied. There is some evidence to suggest increasing prevalence in East Asia, consistent with worsening cardiovascular risk factor profiles, although secular changes in diagnostic criteria may also have contributed. CONCLUSIONS: We found no evidence to suggest that the current assumption of constant age-specific prevalence of dementia over time is ill founded. However, there remains some uncertainty as to the future scale of the dementia epidemic. Population ageing seems destined to play the greatest role, and prudent policymakers should plan future service provision based upon current prevalence projections. Additional priorities should include investing in brain health promotion and dementia prevention programs, and monitoring the future course of the epidemic to chart the effectiveness of these measures. PMID- 27473682 TI - Do the EMA accelerated assessment procedure and the FDA priority review ensure a therapeutic added value? 2006-2015: a cohort study. AB - PURPOSE: The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have both implemented procedures in order to shorten review time for marketing authorizations with potential therapeutic added value, called priority review and accelerated assessment procedure, respectively. The aim of this study is to compare the new molecular entities (NME) assessed in shorter review time by both agencies and to investigate whether granting a shorter review time status subsequently predicts its therapeutic value attributed by a health technology assessment agency, the French Haute Autorite de Sante (HAS). METHODS: All NME approved by the EMA and the FDA with a therapeutic added value between 2007 and June 30, 2015 were extracted. We assessed the sensibility, the positive predictive value, and the EMA review time. RESULTS: One hundred seventy-eight NME were approved by the FDA and the EMA and a therapeutic value was available for 160 NME. Eighty-eight (55.0 %) NME were on FDA priority review, 24 (15.0 %) on EMA accelerated procedure and 43 (26.9 %) were considered of high clinical added value. The sensibility was 86.0 % for the FDA and 30.2 % for the EMA. The positive predictive value was, respectively, 42.0 and 54.2 %. Twenty-five NME on FDA priority review and of high therapeutic added value were not on EMA accelerated assessment procedure, leading to a supplementary mean EMA review time of 146 days. CONCLUSION: The EMA was restrictive to grant a shorten review time status for products with therapeutic interest during the study period. PMID- 27473683 TI - Perceived causality, force, and resistance in the absence of launching. AB - In the launching effect, a moving object (the launcher) contacts a stationary object (the target), and upon contact, the launcher stops and the target begins moving in the same direction and at the same or slower velocity as previous launcher motion (Michotte, 1946/1963). In the study reported here, participants viewed a modified launching effect display in which the launcher stopped before or at the moment of contact and the target remained stationary. Participants rated perceived causality, perceived force, and perceived resistance of the launcher on the target or the target on the launcher. For launchers and for targets, increases in the size of the spatial gap between the final location of the launcher and the location of the target decreased ratings of perceived causality and ratings of perceived force and increased ratings of perceived resistance. Perceived causality, perceived force, and perceived resistance exhibited gradients or fields extending from the launcher and from the target and were not dependent upon contact of the launcher and target. Causal asymmetries and force asymmetries reported in previous studies did not occur, and this suggests that such asymmetries might be limited to typical launching effect stimuli. Deviations from Newton's laws of motion are noted, and the existence of separate radii of action extending from the launcher and from the target is suggested. PMID- 27473684 TI - Predialysis nephrology care and dialysis-related health outcomes among older adults initiating dialysis. AB - BACKGROUND: Predialysis nephrology care is associated with lower mortality and rates of hospitalization following chronic dialysis initiation. Whether more frequent predialysis nephrology care is associated with other favorable outcomes for older adults is not known. METHODS: Retrospective cohort study of patients >=66 years who initiated chronic dialysis in 2000-2001 and were eligible for VA and/or Medicare-covered services. Nephrology visits in VA and/or Medicare during the 12-month predialysis period were identified and classified by low intensity (<3 visits), moderate intensity (3-6 visits), and high intensity (>6 visits). Outcome measures included very low estimated glomerular filtration rate, severe anemia, use of peritoneal dialysis, and receipt of permanent vascular access at dialysis initiation and death and kidney transplantation within two years of initiation. Generalized linear models with propensity score weighting were used to examine the association between nephrology care and outcomes. RESULTS: Among 58,014 patients, 46 % had none, 22 % had low, 13 % had moderate, and 19 % had high intensity predialysis nephrology care. Patients with a greater intensity of predialysis nephrology care had more favorable outcomes (all p < 0.001). In adjusted models, patients with high intensity predialysis nephrology care were less likely to have severe anemia (RR = 0.70, 99 % CI: 0.65-0.74) and more likely to have permanent vascular access (RR = 3.60, 99 % CI: 3.42-3.79) at dialysis initiation, and less likely to die within two years of dialysis initiation (RR = 0.80, 99 % CI: 0.77-0.82). CONCLUSION: In a large cohort of older adults treated with chronic dialysis, greater intensity of predialysis nephrology care was associated with more favorable outcomes. PMID- 27473685 TI - A Longitudinal Study of Financial Difficulties and Mental Health in a National Sample of British Undergraduate Students. AB - Previous research has shown a relationship between financial difficulties and poor mental health in students, but most research is cross-sectional. To examine longitudinal relationships over time between financial variables and mental health in students. A national sample of 454 first year British undergraduate students completed measures of mental health and financial variables at up to four time points across a year. Cross-sectional relationships were found between poorer mental health and female gender, having a disability and non-white ethnicity. Greater financial difficulties predicted greater depression and stress cross-sectionally, and also predicted poorer anxiety, global mental health and alcohol dependence over time. Depression worsened over time for those who had considered abandoning studies or not coming to university for financial reasons, and there were effects for how students viewed their student loan. Anxiety and alcohol dependence also predicted worsening financial situation suggesting a bi directional relationship. Financial difficulties appear to lead to poor mental health in students with the possibility of a vicious cycle occurring. PMID- 27473686 TI - [Recurrence of drug eruption after renewed injection of iodinated contrast medium in patients with known allergic contraindications]. AB - BACKGROUND: Iodinated contrast media (ICM) are used extensively by both radiologists and cardiologists. Injection of such products can induce immediate hypersensitivity reactions, some of which are IgE-mediated, and delayed hypersensitivity reaction with all types of drug eruptions being reported. Allergy tests, whether patch-tests or intradermal tests, are useful to confirm whether patients are allergic. At the end of these tests, depending on the reaction (chronology and clinical symptoms) and the results of the skin tests, patients are given an allergy card as well as a detailed certificate indicating the various ICM contraindicated and those allowed. OBSERVATIONS: We report herein three cases of patients experiencing a confirmed allergic eruption after injection of ICM, and whose recommendations and contraindication were not taken into consideration, leading to recurrence of eruption after renewed ICM injection. DISCUSSION: The three cases we report herein underscore the lack of knowledge concerning eruptions induced by ICM, particularly among radiologists. Better dissemination of information about the existence of such reactions appears necessary amongst the medical professionals concerned. PMID- 27473687 TI - The impact of body mass index on treatment outcomes for patients with low intermediate risk prostate cancer. AB - BACKGROUND: Little is known about the relationship between preoperative body mass index and need for adjuvant radiation therapy (RT) following radical prostatectomy. The goal of this study was to evaluate the utility of body mass index in predicting adverse clinical outcomes which require adjuvant RT among men with organ-confined prostate cancer (PCa). METHODS: We used a prospective cohort of 1,170 low-intermediate PCa risk men who underwent radical prostatectomy and evaluated the effect of body mass index on adverse pathologic features and freedom from biochemical failure (FFbF). Clinical and pathologic variables were compared across the body mass index groups using an analysis of variance model for continuous variables or chi(2) for categorical variables. Factors related to adverse pathologic features were examined using logistic regression models. Time to biochemical recurrence was compared across the groups using a log-rank survivorship analysis. Multivariable analysis predicting biochemical recurrence was conducted with a Cox proportional hazards model. RESULTS: Patients with elevated body mass index (defined as body mass index >=25 kg/m(2)) had greater extraprostatic extension (p = 0.004), and positive surgical margins (p = 0.01). Elevated body mass index did not correlate with preoperative risk groupings (p = 0.94). However, when compared with non-obese patients (body mass index <30 kg/m(2)), obese patients (body mass index >=30 kg/m(2)) were much more likely to have higher rate of adverse pathologic features (p = 0.006). In patients with low and intermediate- risk disease, obesity was strongly associated with rate of pathologic upgrading of tumors (p = 0.01 and p = 0.02), respectively. After controlling for known preoperative risk factors, body mass index was independently associated with >=2 adverse pathologic features (p = 0.002), an indicator for adjuvant RT as well as FFbF (p = 0.001). CONCLUSIONS: Body mass index of >=30 kg/m(2) is independently associated with adverse pathologic features, which is an indicator for additional RT, particularly in patients with low-intermediate risk disease. Future studies may determine if this select group of patients may be best treated with definitive RT to reduce toxicity from additional RT following radical prostatectomy. We propose including body mass index in clinical decision-making for appropriate treatment recommendation for patients with low-intermediate risk PCa. PMID- 27473689 TI - Alpha proteobacterial ancestry of the [Fe-Fe]-hydrogenases in anaerobic eukaryotes. AB - Eukaryogenesis, a major transition in evolution of life, originated from the symbiogenic fusion of an archaea with a metabolically versatile bacterium. By general consensus, the latter organism belonged to alpha proteobacteria, subsequently evolving into the mitochondrial organelle of our cells. The consensus is based upon genetic and metabolic similarities between mitochondria and aerobic alpha proteobacteria but fails to explain the origin of several enzymes found in the mitochondria-derived organelles of anaerobic eukaryotes such as Trichomonas and Entamoeba. These enzymes are thought to derive from bacterial lineages other than alpha proteobacteria, e.g., Clostridium - an obligate anaerobe. [FeFe]-hydrogenase constitues the characteristic enzyme of this anaerobic metabolism and is present in different types also in Entamoeba and other anaerobic eukaryotes. Here we show that alpha proteobacteria derived from metagenomic studies possess both the cytosolic and organellar type of [FeFe] hydrogenase, as well as all the proteins required for hydrogenase maturation. These organisms are related to cultivated members of the Rhodospirillales order previously suggested to be close relatives of mitochondrial ancestors. For the first time, our evidence supports an alpha proteobacterial ancestry for both the anaerobic and the aerobic metabolism of eukaryotes. REVIEWERS: This article was reviewed by William Martin and Nick Lane, both suggested by the Authors. PMID- 27473690 TI - Non-human Primate Total-body Irradiation Model with Limited and Full Medical Supportive Care Including Filgrastim for Biodosimetry and Injury Assessment. AB - An assessment of multiple biomarkers from radiation casualties undergoing limited or full-supportive care including treatment with filgrastim is critical to develop rapid and effective diagnostic triage strategies. The efficacy of filgrastim with full-supportive care was compared with results with limited supportive care by analyzing survival, necropsy, histopathology and serial blood samples for hematological, serum chemistry and protein profiles in a non-human primate (Macaca mulatta, male and female) model during 60-d post-monitoring period following sham- and total-body irradiation with 6.5 Gy 60Co gamma-rays at 0.6 Gy min-1 Filgrastim (10 MUg kg-1) was administered beginning on Day 1 post exposure and continued daily until neutrophil counts were >=2,000 MUL-1 for two consecutive days. Filgrastim and full-supportive care significantly decreased the pancytopenia duration and resulted in improved animal survival and recovery compared to animals with a limited-supportive care. These findings also identified and validated a multiparametric biomarker panel to support radiation diagnostic device development. PMID- 27473688 TI - Cognitive behavioral therapy program for cannabis use cessation in first-episode psychosis patients: study protocol for a randomized controlled trial. AB - BACKGROUND: The high rate of cannabis use among patients with first-episode psychosis (FEP), as well as the associated negative impact on illness course and treatment outcomes, underlines the need for effective interventions in these populations. However, to date, there have been few clinical treatment trials (of pharmacological or psychological interventions) that have specifically focused on addressing comorbid cannabis use among these patients. The aim of this paper is to describe the design of a study protocol for a randomized controlled trial in which the objective is to assess the efficacy of a specific cognitive behavioral therapy program for cannabis cessation in patients with FEP compared to standard treatment (psychoeducation). METHODS/DESIGN: This is a single-blind randomized study with 1 year of follow-up. Patients are to be randomly assigned to one of two treatments: (1) specific cognitive behavioral therapy for cannabis cessation composed of 1-hour sessions once a week for 16 weeks, in addition to pharmacological treatment scheduled by the psychiatrist, or (2) a control group (psychoeducation + pharmacological treatment) following the same format as the experimental group. Participants in both groups will be evaluated at baseline (pre-treatment), at 16 weeks (post-treatment), and at 3 and 6 months and 1 year of follow-up. The primary outcome will be that patients in the experimental group will have greater cannabis cessation than patients in the control group at post treatment. The secondary outcome will be that the experimental group will have better clinical and functional outcomes than the control group. DISCUSSION: This study provides the description of a clinical trial design based on specific cognitive behavioral therapy for cannabis cessation in FEP patients, aiming to improve clinical and functional outcome, as well as tackling the addictive disorder. TRIAL REGISTRATION: NCT02319746 ClinicalTrials.gov Identifier. ClinicalTrials.gov Protocol and Results Registration System (PRS) Receipt Release Date: 15 December 2014. PMID- 27473691 TI - INITIAL AND PRESENT SITUATION OF FOOD CONTAMINATION IN JAPAN AFTER THE ACCIDENT AT THE FUKUSHIMA DAI-ICHI NUCLEAR POWER PLANT. AB - The accident at the Fukushima Dai-ichi Nuclear Power Plant (NPP) in March 2011 affected not only the terrestrial environment of Fukushima prefecture and the surrounding area, but also the marine area facing the NPP. Our present study is focused on the concentrations of radionuclides in agricultural products of Fukushima and sea-foods collected off Fukushima after the accident. The regulation value for radiocesium in vegetables, meat and fish was revised from 500 Bq/kg-wet to 100 Bq/kg-wet on 1 April 2012. The overall activity of radiocesium in these products was found to be within the limit of tolerance in respect to Japanese and also international regulations, but there is still radiocesium found at activities greater than this level in edible wild plants, wild mushrooms and game such as boar meat. Although the activities of radionuclides exceeding the regulatory limits were not detected in marine products collected off Fukushima after April 2015, the commercial marine fishery has not received approval in the affected areas except for certain species. We learned from the Fukushima accident that long-term kinetic studies of radionuclides in terrestrial and marine environments is extremely important for prevention of internal contamination, since contamination with radionuclides occurs via the food chain in the environment. PMID- 27473692 TI - Communicating Radiation Risk to the Population of Fukushima. AB - Radiological specialists from Nagasaki University have served on the medical relief team organized at Fukushima Medical University Hospital (Fukushima City) ever since the accident at the Fukushima Dai-ichi nuclear power plant. Furthermore, we have conducted the radiation crisis communication efforts by spreading correct information on the health effects of radiation as 'advisors on radiation health risk control'. Nagasaki University has been assisting the reconstruction efforts of Kawauchi Village in Fukushima Prefecture, which was the first village to declare that residents could safely return to their homes because radiation doses were found to be at comparatively low levels. In April 2013, Nagasaki University and the Kawauchi government office concluded an agreement concerning comprehensive cooperation toward reconstruction of the village. As a result, we established a satellite facility of the university in the village. In conclusion, training of specialists who can take responsibility for long-term risk communication regarding the health effects of radiation as well as crisis communication in the initial phase of the accident is an essential component of all such recovery efforts. Establishment of a training system for such specialists will be very important both for Japan and other countries worldwide. PMID- 27473693 TI - Factors Affecting the Quality of Tooth Enamel for In Vivo EPR-Based Retrospective Biodosimetry. AB - In vivo electron paramagnetic resonance biodosimetry on tooth enamel is likely to be an important technology for triage of overexposed individuals after a major radiological incident. The accuracy and robustness of the technique relies on various properties of the enamel such as the geometry of the tooth, the presence of restorations, whitening treatments or exposition to sunlight. Those factors are reviewed, and their influence on dosimetry specifically for triage purposes is discussed. PMID- 27473694 TI - Biodosimetry: Medicine, Science, and Systems to Support the Medical Decision Maker Following a Large Scale Nuclear or Radiation Incident. AB - The public health and medical response to a radiological or nuclear incident requires the capability to sort, assess, treat, triage and to ultimately discharge, refer or transport people to their next step in medical care. The size of the incident and scarcity of resources at the location of each medical decision point will determine how patients are triaged and treated. This will be a rapidly evolving situation impacting medical responders at regional, national and international levels. As capabilities, diagnostics and medical countermeasures improve, a dynamic system-based approach is needed to plan for and manage the incident, and to adapt effectively in real time. In that the concepts and terms can be unfamiliar and possibly confusing, resources and a concept of operations must be considered well in advance. An essential underlying tenet is that medical evaluation and care will be managed by healthcare professionals with biodosimetry assays providing critical supporting data. PMID- 27473695 TI - Automatic Detection of Mitosis and Nuclei From Cytogenetic Images by CellProfiler Software for Mitotic Index Estimation. AB - Mitotic Index (MI) estimation expressed as percentage of mitosis plays an important role as quality control endpoint. To this end, MI is applied to check the lot of media and reagents to be used throughout the assay and also to check cellular viability after blood sample shipping, indicating satisfactory/unsatisfactory conditions for the progression of cell culture. The objective of this paper was to apply the CellProfiler open-source software for automatic detection of mitotic and nuclei figures from digitized images of cultured human lymphocytes for MI assessment, and to compare its performance to that performed through semi-automatic and visual detection. Lymphocytes were irradiated and cultured for mitosis detection. Sets of images from cultures were analyzed visually and findings were compared with those using CellProfiler software. The CellProfiler pipeline includes the detection of nuclei and mitosis with 80% sensitivity and more than 99% specificity. We conclude that CellProfiler is a reliable tool for counting mitosis and nuclei from cytogenetic images, saves considerable time compared to manual operation and reduces the variability derived from the scoring criteria of different scorers. The CellProfiler automated pipeline achieves good agreement with visual counting workflow, i.e. it allows fully automated mitotic and nuclei scoring in cytogenetic images yielding reliable information with minimal user intervention. PMID- 27473697 TI - Local Radiolesion in X-Ray Inspection Specialists. AB - As a result of some deviations in the installation of the X-ray inspection plant 'Extravolt-225/1600' two workers of an X-ray inspection laboratory were exposed to the radiation in a dose enough to cause an acute local radiolesions (LRs). The first patient was diagnosed with an acute LR of the hands of severe and extremely severe degree. The second patient was diagnosed with a mild LR of her right hand. The first patient received a surgical treatment followed by subcutaneous introduction of the autologous mesenchymal stem cells. The second patient received only conservative treatment. The complete epithelization of the traumatic surface was achieved. Modeling the incident with the following EPR analysis of the compact substance of the ablated bone structures made it possible to specify the spatial-temporal properties of the exposure. PMID- 27473696 TI - NORMAL TISSUE REACTIONS TO CHRONIC RADIATION EXPOSURE IN MAN. AB - This paper presents an overview of radiobiological dependences governing the occurrence of tissue (organ) reactions that determine the outcomes of chronic exposure to low-LET ionizing radiation (IR) in humans. The mechanisms involved in the development of tissue reactions (TRs) to long-term exposures to IR and radioadaptation are considered. The overview describes the reactions of the haematopoietic, immune, nervous, reproductive and endocrine systems, lungs, skin and crystalline lens to chronic radiation exposure, which are of fundamental importance in view of radiation protection. It is shown that the individual's physiological tissue (organ) reserve, and also that induced by radiation exposure at low-dose rates are of great significance in the context of TR development. PMID- 27473698 TI - EXTERNAL AND INTERNAL EXPOSURE TO FUKUSHIMA RESIDENTS. AB - The Great East Japan Earthquake of 11 March 2011, caused the Fukushima Daiichi Nuclear Power Plant Accident, which resulted in the release of a large amount of radioactive materials into the environment, and there is a serious concern about the radiation effects on the health of residents living in the affected areas. The evaluation of exposure dose is fundamental for the estimation of health effects, and whenever possible, the exposure dose should be evaluated by actual measurements as opposed to estimations. Here, the outline of the exposure doses of residents estimated from surveys or obtained by measurements is described. Fukushima Health Management Survey reported the results for 460 408 residents during the first 4 months after the accident; 66.3% received doses <1 mSv, 94.9% received <2 mSv, 99.7% received <5 mSv and the maximum dose was 25 mSv. Thus, it was demonstrated that the results from personal dosemeter measurements were comparable to the estimations. The dose assessment of internal exposure of 184 205 residents conducted by Fukushima Prefecture by using whole body counter showed that 99.986% received <1 mSv, with the maximum dose being 3 mSv. Regarding exposure of the thyroid, there is not enough data for the Fukushima accident, but it is presumed that thyroid doses are much lower than those from Chernobyl. The outline of exposure doses of residents in result of the accident is still being clarified, questions and uncertainties in dose assessment remain and further efforts for more accurate dosimetry are required continuously. PMID- 27473699 TI - Radiation Exposure and Thyroid Cancer Risk After the Fukushima Nuclear Power Plant Accident in Comparison with the Chernobyl Accident. AB - The actual implementation of the epidemiological study on human health risk from low dose and low-dose rate radiation exposure and the comprehensive long-term radiation health effects survey are important especially after radiological and nuclear accidents because of public fear and concern about the long-term health effects of low-dose radiation exposure have increased considerably. Since the Great East Japan earthquake and the Fukushima Daiichi Nuclear Power Plant accident in Japan, Fukushima Prefecture has started the Fukushima Health Management Survey Project for the purpose of long-term health care administration and medical early diagnosis/treatment for the prefectural residents. Especially on a basis of the lessons learned from the Chernobyl accident, both thyroid examination and mental health care are critically important irrespective of the level of radiation exposure. There are considerable differences between Chernobyl and Fukushima regarding radiation dose to the public, and it is very difficult to estimate retrospectively internal exposure dose from the short-lived radioactive iodines. Therefore, the necessity of thyroid ultrasound examination in Fukushima and the intermediate results of this survey targeting children will be reviewed and discussed in order to avoid any misunderstanding or misinterpretation of the high detection rate of childhood thyroid cancer. PMID- 27473700 TI - EPR DOSIMETRY STUDY FOR POPULATION RESIDING IN THE VICINITY OF FALLOUT TRACE FOR NUCLEAR TEST ON 7 AUGUST 1962. AB - The method of electron paramagnetic resonance (EPR) dosimetry using extracted teeth has been applied to human tooth enamel to obtain individual absorbed doses of residents of settlements in the vicinity of the central axis of radioactive fallout trace from the contaminating surface nuclear test on 7 August 1962. Most of the settlements (Kurchatov, Akzhar, Begen, Buras, Grachi, Mayskoe, Semenovka) are located from 70 to 120 km to the North-East from the epicenter of the explosion at the Semipalatinsk Nuclear Test Site (SNTS). This region is basically an agricultural region. A total of 57 teeth samples were collected from these sites. Eight teeth from residents of the Kokpekty settlement, which was not subjected to any radioactive contamination and located 400 km to the Southeast from SNTS, were chosen as a control. The principal findings, using this method, were that the average excess dose obtained after subtraction of the natural background radiation was 13 mGy and ranged up to about 100 mGy all for residents in this region. PMID- 27473701 TI - Review of Cytogenetic analysis of restoration workers for Fukushima Daiichi nuclear power station accident. AB - Japan faced with the nuclear accident of the Fukushima Daiichi Nuclear Power Station (NPS) caused by the combined disaster of the Great East Japan Earthquake and the subsequent tsunamis on 11 March 2011. National Institute of Radiological Sciences received all nuclear workers who were engaged in emergency response tasks at the NPS and suspected of being overexposed to acute radiation. Biological dosimetry by dicentric chromosome assay was helpful for medical triage and management of the workers. PMID- 27473702 TI - Multiple Methods for Assessing the Dose to Skin Exposed to Radioactive Contamination. AB - There is the possibility for a worker at a nuclear installation, such as a nuclear power reactor, a fuel production facility or a medical facility, to come in contact with radioactive contaminants. When such an event occurs, the first order of business is to care for the worker by promptly initiating a decontamination process. Usually, the radiation protection personnel performs a G M pancake probe measurement of the contamination in situ and collects part or all of the radioactive contamination for further laboratory analysis. The health physicist on duty must then perform, using the available information, a skin dose assessment that will go into the worker's permanent dose record. The contamination situations are often complex and the dose assessment can be laborious. This article compares five dose assessment methods that involve analysis, new technologies and new software. The five methods are applied to 13 actual contamination incidents consisting of direct skin contact, contamination on clothing and contamination on clothing in the presence of an air gap between the clothing and the skin. This work shows that, for the cases studied, the methods provided dose estimates that were usually within 12% (1sigma) of each other, for those cases where absolute activity information for every radionuclide was available. One method, which relies simply on a G-M pancake probe measurement, appeared to be particularly useful in situations where a contamination sample could not be recovered for laboratory analysis. PMID- 27473703 TI - Electron Spin Resonance Dating of Toxodon Tooth from Upper Ribeira Valley, Sao Paulo, Brazil. AB - Electron spin resonance (ESR) dating was applied to date a sample of fossil tooth found in Ribeira Valley, Sao Paulo, Brazil. This region is characterized by abundant fossil records of Pleistocene-Holocene South American megafauna belonging to different faunistic moments related to climate changes during the quaternary. As the number of fossils dated is not too large, the dating of materials from this region will provide important information to better understand the events associated with the presence and extinction of these species. The equivalent dose (De) was determined using single exponential fitting resulting in (24 +/- 1)Gy. The De was converted to age using ROSY ESR Dating program and the concentration of radioisotopes present in the sample and soil determined through neutron activation analysis. The ages cover the range of 25-34 ka. This information is important to contextualize other findings in the region from different sites and to help obtain better information about the climate changes in this region. PMID- 27473704 TI - A MONTE CARLO STUDY OF SIMULATED MEASUREMENTS OF RADIONUCLIDES IN BONE. AB - When measuring the internally deposited activity in the bone of a subject, the placement of the detector is critical. This study reports the simulated counting efficiencies for three counting geometries, the skull, knee and shin, using 13 different voxel phantoms. It shows that the range of counting efficiencies for a given geometry is large for the studied phantoms, especially at low energies. Skull counting offers higher efficiency for low energies such as the 17 keV compared to knee counting or shin counting, but this advantage disappears when the energy is higher such as at 185 keV. This work also shows that the calibration phantom may greatly impact the accuracy of the activity estimate in bone counting, with uncertainties increasing greatly as the photon energy is reduced. Estimating the activity of a radionuclide in bone from direct counting has large uncertainties, and the dose calculated from a skeleton measurement would need careful analysis and, if possible, supporting data from other bioassay measurements. PMID- 27473705 TI - The Application and Distribution of Magnetic Field Modulation in the Detection Apertures of X-band EPR Cavities for In Vivo Tooth Dosimetry. AB - In vivo electron paramagnetic resonance tooth dosimetry could be a practical and ideal tool for quick mass triage of victims in the rescue following a disaster event involving irradiation radiation. Magnetic field modulation is an important issue to improve the sensitivity of X-band in vivo tooth dosimetry. We designed a couple of trapezoidal modulation coil sets fixed on the magnet poles that could be used to apply sufficient magnet field modulation into the detection aperture of the resonant cavity. Measurements of irradiated teeth with such coil sets demonstrated significant radiation-induced signals. The modulation generation efficiencies and magnetic field distributions in apertures with different cavity geometries were analytically calculated, simulated by a finite element method and evaluated by measurements of a free radical point sample to study the influences caused by the geometries of the apertures and other factors. PMID- 27473706 TI - Variables Affecting Fusion Rates in the Rat Posterolateral Spinal Fusion Model with Autogenic/Allogenic Bone Grafts: A Meta-analysis. AB - The rat posterolateral spinal fusion model with autogenic/allogenic bone graft (rat PFABG) has been increasingly utilized as an experimental model to assess the efficacy of novel fusion treatments. The objective of this study was to investigate the reliability of the rat PFABG model and examine the effects of different variables on spinal fusion. A web-based literature search from January, 1970 to September, 2015, yielded 26 studies, which included 40 rat PFABG control groups and 449 rats. Data regarding age, weight, sex, and strain of rats, graft volume, graft type, decorticated levels, surgical approach, institution, the number of control rats, fusion rate, methods of fusion assessment, and timing of fusion assessment were collected and analyzed. The primary outcome variable of interest was fusion rate, as evaluated by manual palpation. Fusion rates varied widely, from 0 to 96%. The calculated overall fusion rate was 46.1% with an I 2 value of 62.4, which indicated moderate heterogeneity. Weight >300 g, age >14 weeks, male rat, Sprague-Dawley strain, and autogenic coccyx grafts increased fusion rates with statistical significance. Additionally, an assessment time point >=8 weeks had a trend towards statistical significance (p = 0.070). Multi regression analysis demonstrated that timing of assessment and age as continuous variables, as well as sex as a categorical variable, can predict the fusion rate with R 2 = 0.82. In an inter-institution reliability analysis, the pooled overall fusion rate was 50.0% [44.8, 55.3%], with statistically significant differences among fusion outcomes at different institutions (p < 0.001 and I 2 of 72.2). Due to the heterogeneity of fusion outcomes, the reliability of the rat PFABG model was relatively limited. However, selection of adequate variables can optimize its use as a control group in studies evaluating the efficacy of novel fusion therapies. PMID- 27473707 TI - Additive Biomanufacturing: An Advanced Approach for Periodontal Tissue Regeneration. AB - Periodontitis is defined as a chronic inflammatory condition, characterized by destruction of the periodontium, composed of hard (i.e. alveolar bone and cementum) and soft tissues (i.e. gingiva and periodontal ligament) surrounding and supporting the teeth. In severe cases, reduced periodontal support can lead to tooth loss, which requires tissue augmentation or procedures that initiate a repair, yet ideally a regenerative response. However, mimicking the three dimensional complexity and functional integration of the different tissue components via scaffold- and/or matrix-based guided tissue engineering represents a great challenge. Additive biomanufacturing, a manufacturing method in which objects are designed and fabricated in a layer-by-layer manner, has allowed a paradigm shift in the current manufacturing of medical devices and implants. This shift from design-to-manufacture to manufacture-to-design, seen from a translational research point of view, provides the biomedical engineering and periodontology communities a technology with the potential to achieve tissue regeneration instead of repair. In this review, the focus is put on additively biomanufactured scaffolds for periodontal applications. Besides a general overview of the concept of additive biomanufacturing within this field, different developed scaffold designs are described. To conclude, future directions regarding advanced biomaterials and additive biomanufacturing technologies for applications in regenerative periodontology are highlighted. PMID- 27473708 TI - A change in behaviour: getting the balance right for research and policy. AB - Behaviour change interventions offer clinical pharmacists many opportunities to optimise the use of medicines. 'MINDSPACE' is a framework used by a Government affiliated organisation in the United Kingdom to communicate an approach to changing behaviour through policy. The Theoretical Domains Framework (TDF) organises constructs of psychological theories that are most relevant to behaviour change into 14 domains. Both frameworks offer a way of identifying what drives a change in behaviour, providing a target for an intervention. This article aims to compare and contrast MINDSPACE and the TDF, and serves to inform pharmacy practitioners about the potential strengths and weaknesses of using either framework in a clinical pharmacy context. It appears that neither framework can deliver evidence-based interventions that can be developed and implemented with the pace demanded by policy and practice-based settings. A collaborative approach would ensure timely development of acceptable behaviour change interventions that are grounded in evidence. PMID- 27473709 TI - Development of an algorithm for analysing the electronic measurement of medication adherence in routine HIV care. AB - Background Medication adherence is crucial for successful treatment. Various methods exist for measuring adherence, including electronic drug monitoring, pharmacy refills, pill count, and interviews. These methods are not equivalent, and no method can be considered as the gold standard. A combination of methods is therefore recommended. Objective To develop an algorithm for the management of routinely collected adherence data and to compare persistence and implementation curves using post-algorithm data (reconciled data) versus raw electronic drug monitoring data. Setting A community pharmacy located within a university medical outpatient clinic in Lausanne, Switzerland. Methods The algorithm was developed to take advantage of the strengths of each available adherence measurement method, with electronic drug monitoring as a cornerstone to capture the dynamics of patient behaviour, pill count as a complementary objective method to detect any discrepancy between the number of openings measured by electronic monitoring and the number of pills ingested per opening, and annotated interviews to interpret the discrepancy. The algorithm was tested using data from patients taking lopinavir/r and having participated in an adherence-enhancing programme for more than 3 months. Main outcome measure Adherence was calculated as the percentage of persistent patients (persistence) and the proportion of days with correct dosing over time (implementation) from inclusion to the end of the median follow-up period. Results A 10-step algorithm was established. Among 2041 analysed inter-visit periods, 496 (24 %) were classified as inaccurate, among which 372 (75 %) could be reconciled. The average implementation values were 85 % (raw data) and 91 % (reconciled data) (p < 0.0001). At day 544, persistence values were 68 % (raw) and 82 % (reconciled) (p = 0.11), and adherence values were 74 % (raw) and 82 % (reconciled) (p < 0.0001). Conclusion Combining electronic drug monitoring, pill count and patient interviews is possible within the setting of a medication adherence clinic. Electronic drug monitoring underestimates medication adherence, affecting subsequent analysis of routinely collected adherence data. To ensure a set of reliable electronic drug monitoring data, structured and timely electronic drug monitoring management should be reinforced. PMID- 27473710 TI - Controversy and consensus on a clinical pharmacist in primary care in the Netherlands. AB - Background Controversy about the introduction of a non-dispensing pharmacist in primary care practice hampers implementation. Objective The aim of this study is to systematically map the debate on this new role for pharmacists amongst all stakeholders to uncover and understand the controversy and consensus. SETTING: Primary health care in the Netherlands. Method Q methodology. 163 participants rank-ordered statements on issues concerning the integration of a non-dispensing pharmacist in primary care practice. MAIN OUTCOME MEASURE: Stakeholder perspectives on the role of the non-dispensing pharmacist and pharmaceutical care in primary care. Results This study identified the consensus on various features of the non-dispensing pharmacist role as well as the financial, organisational and collaborative aspects of integrating a non-dispensing pharmacist in primary care practice. Q factor analysis revealed four perspectives: "the independent community pharmacist", "the independent clinical pharmacist", "the dependent clinical pharmacist" and "the medication therapy management specialist". These four perspectives show controversies to do with the level of professional independency of the non-dispensing pharmacist and the level of innovation of task performance. Conclusion Despite the fact that introducing new professional roles in healthcare can lead to controversy, the results of this Q study show the potential of a non-dispensing pharmacist as a pharmaceutical care provider and the willingness for interprofessional collaboration. The results from the POINT intervention study in the Netherlands will be an important next step in resolving current controversies. PMID- 27473711 TI - A focus group based study of the perspectives of the Maltese population and healthcare professionals on medication wastage. AB - Background The World Health Organization states that globally more than half of all medication is inappropriately prescribed, dispensed or sold with a need to implement wastage reduction strategies. Developing processes which include behaviour change theories, such as the Theoretical Domains Framework (TDF), significantly impacts the positive implementation of evidence into healthcare practice. Objective To describe and understand the beliefs and behaviours regarding medication wastage of the Maltese public and healthcare professionals (HCPs) and to explore potential solutions. SETTING: Malta. Method Five 90 min audio recorded focus groups (2 public and 3 HCPs) were conducted with a purposive sample who responded to a previous survey study and were willing to participate in focus groups in Malta. The guide was based upon the TDF with interview questions derived from findings of the questionnaire phase. Focus groups were audio recorded and transcribed verbatim. Analysis was carried using the framework approach. Main outcome measure Beliefs and behaviours regarding medication wastage and potential solutions to reduce medication wastage. Results A total of eleven pharmacists, six doctors and six members of the public consented to participate. Focus groups conducted with HCPs and the general public identified the following four key themes aligned with the TDF domains to address proposed solutions to minimise medication wastage: (1) practitioner effects; (2) patients effects; (3) political effects; (4) societal effects. Conclusion This study has employed a theoretical framework to obtain a better understanding of facilitators which require attention as part of strategic development. PMID- 27473712 TI - Exploring discharge prescribing errors and their propagation post-discharge: an observational study. AB - Background Discharge prescribing error is common. Little is known about whether it persists post-discharge. Objective To explore the relationship between discharge prescribing error and post-discharge medication error. Setting This was a prospective observational study (March-May 2013) at an adult academic hospital in Ireland. Method Patients using three or more chronic medications pre admission, with a clinical pharmacist documented gold-standard pre-admission medication list, having a chronic medication stopped or started in hospital and discharged to home were included. Within 10-14 days after discharge a gold standard discharge medication was prepared and compared to the discharge prescription to identify differences. Patients were telephoned to identify actual medication use. Community pharmacists, general practitioners and hospital prescribers were contacted to corroborate actual and intended medication use. Post-discharge medication errors were identified and the relationship to discharge prescribing error was explored. Main outcome measured Incidence, type, and potential severity of post-discharge medication error, and the relationship to discharge prescribing. Results Some 36 (43 %) of 83 patients experienced post discharge medication error(s), for whom the majority (n = 31, 86 %) were at risk of moderate harm. Most (58 of 66) errors were discharge prescribing errors that persisted post-discharge. Unintentional prescription of an intentionally stopped medication; error in the dose, frequency or formulation and unintentional omission of active medication are the error types most likely to persist after discharge. Conclusion There is a need to implement discharge medication reconciliation to support medication optimisation post-hospitalisation. PMID- 27473713 TI - Knowledge and perceptions of the risks of non-steroidal anti-inflammatory drugs among orthopaedic patients in Thailand. AB - Background There is a high incidence of adverse effects from non-steroidal antiinflammatory drugs (NSAIDs) in Thailand, but patients' perceptions and knowledge of NSAID risks is unknown. Objective This study aims to assess patients' perceptions and knowledge of NSAID risks and factors affecting them. Setting University hospital in North-East of Thailand. Method A Cross-sectional study conducted over 4 months, using a self-administered questionnaire. Patients prescribed NSAIDs for at least one month duration from orthopaedic clinic were recruited using systematic random sampling. Main outcome measure Patients' perceptions on NSAID risks, knowledge on risk factors, and their associated factors. Results A total of 474 questionnaires were assessed. Overall perceptions of risks was low (scoring below five on a 0-10 visual analogue scale), with risks associated with the renal system scoring highest. Perceived risk of gastrointestinal problems differed between patients using non-selective and selective NSAIDs (3.47 +/- 2.75 vs 2.06 +/- 2.98; P < 0.001). Receiving side effect information from a health professional was associated with higher risk perception. Most patients (80 %) identified high doses, renal disease and gastrointestinal ulcer increased risks of NSAIDs, but fewer than half recognized that use in the elderly, multiple NSAID use, drinking, hypertension and cardiovascular disease also increased risk of adverse events. Having underlying diseases and receiving side effect information were associated with 1.6-2.0 fold increased knowledge of NSAID risks. Conclusion Perceptions and knowledge concerning NSAID risks was generally low in Thai patients, but higher in those who had received side effect information. Risk-related information should be widely provided, especially in high-risk patients. PMID- 27473714 TI - Association of asthma diagnosis with leptin and adiponectin: a systematic review and meta-analysis. AB - There is some evidence which shows that higher levels of serum leptin and lower levels of serum adiponectin are associated with the diagnosis of asthma. This meta-analysis evaluated the association of serum leptin and adiponectin levels with the diagnosis of asthma. We searched the MEDLINE, Cochrane, EMBASE and CINAHL Plus databases up to July 2015. Eligible studies were randomized controlled trials, prospective studies, retrospective studies, case-control studies and cohort studies. 13 studies with 3642 patients were included in the study. The meta-analysis found that in the overall study population, the diagnosis of asthma was associated with higher levels of leptin (pooled standardized difference in means=0.867, 95% CI 0.416 to 1.318, p<0.001) and lower levels of adiponectin (pooled standardized difference in means=-0.371, 95% CI 0.728 to -0.014, p=0.042) in patients with asthma compared with controls. Subgroup analysis found that higher leptin levels were associated with asthma both in adults (standardized difference in means=1.374, 95% CI 0.621 to 2.126, p<0.001) and children (standardized difference in means=0.302, 95% CI 0.010 to 0.594, p=0.042). However, borderline association of adiponectin with asthma was seen in adults (p=0.05), but not in children (p=0.509). Sensitivity analysis indicated that the findings for leptin were robust. Our findings are consistent with higher levels of serum leptin being associated with asthma regardless of age, and low adiponectin levels being associated with asthma in adults only. PMID- 27473715 TI - Circadian clock control of hepatic lipid metabolism: role of small heterodimer partner (Shp). AB - Hepatic steatosis, the accumulation of triglyceride droplets in the hepatocytes, is a common hepatic pathology seen in subjects with obesity/metabolic syndrome and those with excessive alcohol use. The pathogenesis underlying hepatic steatosis is complex. Recent studies have shown the specific role played by the molecular clock mechanism in the control of lipid metabolism and that the disruption of these tissue clocks may lead to the disturbances in lipid homeostasis. This review reports a novel role of small heterodimer partner in maintaining triglyceride and lipoprotein homeostasis through neuronal PAS domain protein 2. PMID- 27473716 TI - Time trends in leisure time physical activity, smoking, alcohol consumption and body mass index in Danish adults with and without COPD. AB - BACKGROUND: Promotion of a healthy lifestyle and non-pharmacological interventions in the treatment of chronic obstructive pulmonary disease (COPD) has received great attention in recent decades. The aim of this study was to investigate trends in leisure time physical activity (PA), smoking, alcohol consumption and body mass index (BMI) from 2000 to 2010 in Danish individuals with and without COPD. METHODS: Analyses were based on data provided by The Danish Health and Morbidity's three cross-sectional surveys from 2000, 2005 and 2010. Data compromised level of leisure time PA, smoking, alcohol consumption, BMI and sociodemographic characteristics. Participants aged 25 years or older with and without COPD were included in the analyses. RESULTS: In multiple logistic regression analyses, odds ratio (OR) of being physically active in the leisure time in 2010 compared to 2000 was 1.70 (95 % CI: 1.28-2.26), p < 0.001, and 1.32 (1.22-1.43), p < 0.001, in participants with and without COPD, respectively. Being a non-smoker in 2010 compared to 2000 was associated with an OR of 1.41 (1.07-1.85), p = 0.015, and 1.73 (1.63-1.85), p < 0.001, in participants with and without COPD. The OR of not exceeding national recommended alcohol limits was 0.64 (0.45-0.93), p = 0.020, and 1.19 (1.09-1.29), p < 0.001, in participants with and without COPD. In a multiple linear regression analysis, the time frame from 2000 to 2010 was associated with an increased BMI of 1.18 kg . m(-2) (0.52-1.84), p < 0.001, and 0.74 kg . m(-2) (0.63-0.86), p < 0.001, in participants with and without COPD. The COPD participants with higher levels of education and/or living in a marriage or a relationship were more likely to be physically active, non-smoking and not exceeding the recommended alcohol limits. CONCLUSION: From the 2000 to 2010, Danish individuals aged 25 years with and without COPD, increased their leisure time PA level and reduced smoking. Lower socioeconomic status was associated with a reduced level of PA, smoking and an increased alcohol intake. Future national health campaigns and treatment strategies need to target this socioeconomic impact. The reported increased PA level and reduced smoking may have important implications in relation to a reduced morbidity and mortality risk in Danish patients with COPD. PMID- 27473717 TI - Microsatellite markers from tea green leafhopper Empoasca (Matsumurasca) onukii: a powerful tool for studying genetic structure in tea plantations. AB - BACKGROUND: Tea green leafhopper is one of the most dominant pests in Chinese tea plantations. Recent evidence, including morphological and molecular data, revealed that tea green leafhopper in China is the same species as in Japan, Empoasca (Matsumurasca) onukii Matsuda. Previous morphological study that revealed variation in the structure of the male genitalia within and among populations of this species suggested that there may be significant population level genetic variation. To provide powerful molecular markers to explore the population genetic diversity and population genetic structure of this pest in China, microsatellite markers were obtained by AFLP of sequences containing repeats (FIASCO). RESULTS: Eighteen polymorphic markers were evaluated for five populations of E. (M.) onukii, Two related empoascine leafhopper species were selected to test the transferability of the markers. Population genetic structure of E. (M.) onukii was detected using Structure analysis, principal coordinate analysis (PCoA) and variance analysis. The identified markers were polymorphic with total number of alleles ranging from 6 to 24 per locus, observed and expected heterozygosity ranged from 0.133 to 0.9 and 0.183 to 0.926, respectively, and the polymorphic information content value over all populations varied from 0.429 to 0.911. CONCLUSIONS: This is the first study to demonstrate that microsatellite markers provide valuable information for genetic structure of E. (M.) onukii in Chinese tea plantations. There is obvious genetic differentiation between the two populations in the Southwest tea area. These microsatellite markers will be the powerful tools for genetic studies of E. (M.) onukii and improve understanding of the microevolution of this species. PMID- 27473718 TI - Correlation of cognitive and masticatory function in Alzheimer's disease. AB - OBJECTIVES: This study investigated chewing function in elderly individuals with Alzheimer's disease (AD) and correlated chewing function with cognitive status. MATERIALS AND METHODS: Sixteen elderly individuals with mild AD (mean age 76.7 +/ 6.3 years; 8 men, 8 women) and 16 age and gender-matched healthy controls (mean age 75.23 +/- 4.4 years; 8 men, 8 women) were included in this study. All volunteers wore removable prostheses: 11 were totally edentulous and five were partially edentulous in each group. Chewing function was evaluated via masticatory performance (MP) using Optocal chewable test material and a sieve fractionation method. Cognitive functioning was assessed by the Mini Mental State Exam (MMSE), administered by a trained examiner. Data were analyzed by non-paired t test and Pearson's correlation with alpha = 0.05. RESULTS: Compared to controls, mild AD patients had decreased MP (P < 0.01) and MMSE (P = 0.01). MP showed a moderate negative correlation with MMSE (r = -0.69). CONCLUSIONS: Mild AD was associated with impaired chewing function. CLINICAL RELEVANCE: Knowledge that mild AD has an impact on chewing is important for dental professionals in decision-making related to prosthetics and general dental treatment. PMID- 27473719 TI - Monitoring waste anesthetic gas in the pediatric postanesthesia care unit. PMID- 27473720 TI - Transesophageal lung ultrasonography: a novel technique for investigating hypoxemia. AB - BACKGROUND: Acute deterioration in respiratory status commonly occurs in patients who cannot be transported for imaging studies, particularly during surgical procedures and in critical care settings. Transthoracic lung ultrasonography has been developed to allow rapid diagnosis of respiratory conditions at the bedside. Nevertheless, the thorax is not always accessible, especially in the perioperative setting. Transesophageal lung ultrasonography (TELU) can be used to circumvent this problem. PURPOSE: The aim of this narrative review is to provide a complete description of the TELU technique by summarizing the existing literature on the subject and describing our own experience that extrapolates from transthoracic lung ultrasonography. PRINCIPAL FINDINGS: The use of TELU can provide point-of-care real-time information for quickly establishing the etiology of acute hypoxemia. The transesophageal probe is placed in close proximity to the posterior regions of the lungs where lung consolidation and pleural effusions are most often seen; however, most of the artefacts relied on by transthoracic ultrasound have yet to be validated with TELU. Moreover, the relative invasiveness of TELU compared with transthoracic ultrasonography may limit its use to specific situations when the probe is already in place, as during cardiac anesthesia or when the anterior thorax is inaccessible. The main advantage of TELU may lie in the ability to integrate both cardiac and pulmonary assessments in one single examination. CONCLUSION: Anesthesiologists and intensivists who already use transesophageal echocardiography on a regular basis should consider adding TELU to their clinical assessment of hypoxemia and related pulmonary pathologies. Nevertheless, the literature specifically supporting TELU is relatively limited, and further validation studies are needed. PMID- 27473721 TI - Inhaled milrinone for pulmonary hypertension in high-risk cardiac surgery: silver bullet or just part of a broader management strategy? PMID- 27473722 TI - Perioperative visual loss following transurethral resection surgery: not always a transurethral resection syndrome. PMID- 27473723 TI - Transesophageal lung ultrasound: to boldly go.... PMID- 27473724 TI - A novel rodent Chapparvovirus in feces of wild rats. AB - Chapparvovirus, a recently determined new genus in the family Parvoviridae, can infect many species of animals including bats, chickens, and pigs. Here, using viral metagenomics method, we identified a novel Chapparvovirus from feces of wild rats and designated it as rat parvovirus 2 (RPV2). The nearly complete genome of RPV2 is 4222-nt long and includes two ORFs encoding a 654-aa nonstructural protein 1 (NS1) and a 472-aa capsid protein (VP), respectively. Phylogenetic analysis over the amino acid sequence of the NS1 showed that RPV2 clustered with Eidolon helvum parvovirus 2 (EHPV2), porcine parvovirus 7 (PPV7), and turkey parvovirus 1 (TP1), forming a separate clade. Sequence analysis indicated that the NS1 protein of RPV2 shared the highest amino acid sequence identity (51 %) with that of EHPV2. According to the genetic distance-based criteria, RPV2 identified here belongs to a novel species of Chapparvovirus. PMID- 27473725 TI - Prognostic factors after pulmonary metastasectomy of colorectal cancers: influence of liver metastasis. AB - BACKGROUND: Our objective was to evaluate the influence of liver metastasis on survival after pulmonary metastasectomy in patients with colorectal cancer (CRC). METHODS: We retrospectively reviewed a total of 524 patients and were classified into two groups based on the presence of liver metastasis. Group HM + PM (n = 106) included patients who previously received a hepatic metastasectomy and then received pulmonary metastasectomy. Group PM (n = 418) included patients who only received pulmonary metastasectomy with no liver metastasis. RESULTS: There were more male patients (70 vs. 57 %; P = 0.02) and more patients with colon cancer (60 vs. 42 %, P = 0.001) in group HM + PM than in group PM. Otherwise, there was no significant difference between the two groups in clinicopathologic characteristics and extent of surgery. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 58 and 31 %, respectively. There was no significant difference in OS (group HM + PM, 54 % vs. group PM, 59 %; P = 0.085) and in DFS (group HM + PM, 28 % vs. group PM, 32 %; P = 0.12). For the entire patient cohort, a multivariate analysis revealed that the presence of liver metastasis, CRC T and N stages, disease-free interval, and number and size of lung metastases were significantly associated with OS and DFS. CONCLUSIONS: Our findings suggest that previous or present liver metastasis should not exclude a patient from pulmonary metastasectomy. When lung metastasis is detected in patients with a history of hepatic metastasectomy, pulmonary metastasectomy is still a viable treatment option especially in patients with a long disease-free interval and a small number of lung metastases. PMID- 27473726 TI - Impact of Elimination or Reduction of Dietary Animal Proteins on Cancer Progression and Survival: Protocol of an Online Pilot Cohort Study. AB - BACKGROUND: Current evidence suggests that the incidence of cancer is low in vegan populations, and experimental studies have revealed a significant role of dietary proteins in cancer development and progression. However, little data currently exists regarding the effect of a plant-based diet on the progression of diagnosed cancer. OBJECTIVE: The main objective of this study is to determine if a reduction or total elimination of animal protein from the diet can positively influence the outcome of an existing cancer and, in addition to standard oncological therapies, increase remission rates. METHODS: The primary aim of this online study is to test the effect on remission rates in cancer patients (primary outcome) with distinct self-selected dietary patterns (omnivore, lacto-ovo vegetarian, vegan), and allow for an estimation of the effect size. Secondary outcomes are tumor behavior, relapse-free interval, therapies, therapy tolerability and side-effects, comorbidities, medication, quality of life, acceptance, and feasibility of the selected diet. Safety concerns exist for vegan diets (especially in cancer patients) and the study will carefully monitor for deterioration of health, tumor progression, or malnutrition. Furthermore, the study will evaluate the online portal as a study platform (technical and safety aspects, and sequence of displayed questionnaires) as well as the validity of self-reported and online-generated data. RESULTS: The study was performed between April, 2015 and June, 2016, and a preliminary evaluation of safety aspects was undertaken after June, 2016. Primary and secondary outcomes will be evaluated when the final patients complete the study in December, 2016. CONCLUSIONS: This study will reveal information about the effects of dietary patterns on cancer disease and progression. The methodology of the study addresses several aspects and limitations of nutrition studies in cancer patients, such as precision of nutrition data, acceptance criteria, online methodology, and safety aspects. CLINICALTRIAL: Clinicaltrials.gov NCT02437474; https://clinicaltrials.gov/ct2/show/NCT02437474 (Archived by WebCite at http://www.webcitation.org/6jL7UUCVq). PMID- 27473727 TI - Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism. AB - Selenocysteine is the 21st proteinogenic amino acid in mammals. The human genome contains 25 genes encoding selenoproteins, and their significance for human health is increasingly recognized through the identification of patients with inborn errors in selenoprotein biosynthetic factors or in individual selenoproteins. Mutations in selenoprotein N (SEPN1) lead to a spectrum of disorders collectively called SEPN1-related myopathy, and mutations in glutathione peroxidase 4 (GPX4) cause respiratory failure and bone defects, and mutations in thioredoxin reductase 2 (TXNRD2) are associated with familial glucocorticoid deficiency. Pathogenic mutations in selenocysteine synthase (SEPSECS) cause neurodevelopmental disorders, but also other factors epistatic to selenoprotein biosynthesis, such as SECIS-binding protein 2 (SECISBP2) and tRNA[Ser]Sec, are known to cause complex disorders. Mutations in the latter 2 genes involve impaired metabolism and action of thyroid hormones, which lead to delayed bone growth and maturation. Mutations in SECISBP2 sometimes affect nervous system development, muscle, inner ear, skin, and immune system function, underlining the significance of selenoproteins for the organism. Mouse models helped to delineate the functions of selenoproteins and explain pathomechanisms. For brevity, this review is focused on human genetic disorders associated with selenoprotein deficiency and only briefly touches on health effects of nutritional selenium deficiency.-Schweizer, U., Fradejas-Villar, N. Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism. PMID- 27473729 TI - Joseph Maxwell on mediumistic personifications. AB - The study of mediumship received much impetus from the work of psychical researchers. This included ideas about the phenomena of personation, or changes in attitudes, dispositions and behaviours shown by some mediums that supposedly indicated discarnate action. The aim of this Classic Text is to reprint passages about this topic from the writings of French psychical researcher Joseph Maxwell (1858-1938), which were part of the contributions of some psychical researchers to reconceptualize the manifestations in psychological terms. Maxwell suggested these changes in mediums were a production of their subconscious mind. His ideas are a reflection of previous theorization about secondary personalities and a particular example of the contributions of psychical researchers to understand the psychology of mediumship. PMID- 27473728 TI - Responses to elevated CO2 exposure in a freshwater mussel, Fusconaia flava. AB - Freshwater mussels are some of the most imperiled species in North America and are particularly susceptible to environmental change. One environmental disturbance that mussels may encounter that remains understudied is an increase in the partial pressure of CO2 (pCO2). The present study quantified the impacts of acute (6 h) and chronic (up to 32 days) exposures to elevated pCO2 on genes associated with shell formation (chitin synthase; cs) and the stress response (heat shock protein 70; hsp70) in Fusconaia flava. Oxygen consumption (MO2) was also assessed over the chronic CO2 exposure period. Although mussels exhibited an increase in cs following an acute exposure to elevated pCO2, long-term exposure resulted in a decrease in cs mRNA abundance, suggesting that mussels may invest less in shell formation during chronic exposure to elevated pCO2. In response to an acute elevation in pCO2, mussels increased hsp70 mRNA abundance in mantle and adductor muscle and a similar increase was observed in the gill and adductor muscle in response to a chronic elevation in pCO2. A chronic elevation in pCO2 also increased mussel MO2. This overall increase in hsp70 mRNA levels and MO2 in F. flava indicates that exposure to elevated pCO2 initiates activation of the general stress response and an increased energy demand. Together, the results of the present study suggest that freshwater mussels respond to elevated pCO2 by increasing processes necessary to 'deal with' the stressor and, over the long term, may reduce their investment in non-essential processes such as shell growth. PMID- 27473734 TI - S. Shamdasani and the 'serial exemplarity of mediumship' in Jung's work: a critique (received 8 February 2016). PMID- 27473735 TI - Response by the author (received 19 April 2016). PMID- 27473736 TI - Overview of Thoracic Oncology Trials in Cooperative Groups Around the Globe. AB - Survival rates of patients with either early and advanced stage non-small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015. PMID- 27473737 TI - Challenges of Maintaining Good Clinical Laboratory Practices in Low-Resource Settings: A Health Program Evaluation Framework Case Study From East Africa. AB - OBJECTIVES: Using a clinical research laboratory as a case study, we sought to characterize barriers to maintaining Good Clinical Laboratory Practice (GCLP) services in a developing world setting. METHODS: Using a US Centers for Disease Control and Prevention framework for program evaluation in public health, we performed an evaluation of the Kilimanjaro Christian Medical Centre-Duke University Health Collaboration clinical research laboratory sections of the Kilimanjaro Clinical Research Institute in Moshi, Tanzania. Laboratory records from November 2012 through October 2014 were reviewed for this analysis. RESULTS: During the 2-year period of study, seven instrument malfunctions suspended testing required for open clinical trials. A median (range) of 9 (1-55) days elapsed between instrument malfunction and biomedical engineer service. Sixteen (76.1%) of 21 suppliers of reagents, controls, and consumables were based outside Tanzania. Test throughput among laboratory sections used a median (range) of 0.6% (0.2%-2.7%) of instrument capacity. Five (55.6%) of nine laboratory technologists left their posts over 2 years. CONCLUSIONS: These findings demonstrate that GCLP laboratory service provision in this setting is hampered by delays in biomedical engineer support, delays and extra costs in commodity procurement, low testing throughput, and high personnel turnover. PMID- 27473738 TI - Serum Free Light Chain Assay and kappa/lambda Ratio Performance in Patients Without Monoclonal Gammopathies: High False-Positive Rate. AB - OBJECTIVES: Serum free light chain assay is a recommended screening test for monoclonal gammopathies. Anecdotal observations indicated a high rate of false positive abnormal kappa/lambda ratios. This study was undertaken to ascertain the magnitude of the false-positive rate and factors contributing to the error rate. METHODS: Results of serum protein electrophoresis, serum free light chains, and related tests, usually done for investigation of suspected monoclonal gammopathy, were reviewed retrospectively for 270 patients and 297 observations. RESULTS: Using the conventional kappa/lambda ratio, 36.4% of the ratios were abnormal, in the absence of monoclonal gammopathy. When the renal kappa/lambda ratio was used, the rate of abnormal kappa/lambda ratios was 30.1%. In patients with a gamma globulin concentration of 1.6 g/dL or more, the usual kappa/lambda ratio was abnormal in 54.8% of the patients. Urine protein electrophoresis was used in 53 (19.6%) instances, whereas bone marrow examination was done in 65 (24.1%) cases. CONCLUSIONS: Usual kappa/lambda ratio was abnormal in 36.4% of the observations in patients without evidence of monoclonal gammopathy, and an abnormal kappa/lambda ratio should not be used as the sole indicator for diagnosis of neoplastic proliferation of the lympho-plasmacytic system. Hypergammaglobulinemia is associated with a higher rate of false-positive abnormal kappa/lambda ratios. Examination of urine for monoclonal immunoglobulins may be underused, and recommendations by some to use serum free light chain assay in place of, rather than as an adjunct to, urine electrophoresis are not warranted. PMID- 27473739 TI - A Review of Outcomes for Stage Ta Bladder Tumors. AB - OBJECTIVES: Using data from former reports, this study reviews and analyzes the outcomes of tumor recurrence, tumor progression, and tumor-specific survival of patients with stage Ta bladder tumors. METHODS: Data were collected from 19 longitudinal studies of outcomes after the first diagnosis of tumor and collected as individual patient results, that is, as failure times from the first tumor to any of the three outcomes. Altogether, there were 14,252 patients, including 4,050 for the outcome of tumor recurrence, 2,937 for the outcome of tumor progression, and 11,595 for the outcome of disease-specific survival (some patients were available for more than one outcome). RESULTS: In these data, the mean time to additional tumors was 7.8 years, the mean time to an invasive tumor was 19.5 years, and the mean tumor-specific survival time was 27.2 years. All three outcomes were significantly related to the 2004 World Health Organization (WHO) tumor grades. CONCLUSIONS: Although greater than 50% of those with stage Ta bladder tumors have additional bladder tumors, approximately 80% appear to follow a benign course without developing invasive tumors or dying of bladder cancer. The 2004 WHO grading scheme accounts for some but not all of the prognostic information. PMID- 27473740 TI - Preventing Genetic Testing Order Errors With a Laboratory Utilization Management Program. AB - OBJECTIVES: To characterize error rates for genetic test orders between medical specialties and in different settings by examining detailed order information. METHODS: We performed a retrospective analysis of a detailed utilization management case database, comprising 2.5 years of data and almost 1,400 genetic test orders. After review by multiple reviewers, we categorized order modifications and cancellations, quantified rates of positive results and order errors, and compared genetics with nongenetics providers and inpatient with outpatient orders. RESULTS: High cost or problems with preauthorization were the most common reasons for modification and cancellation, respectively. The cancellation rate for nongenetics providers was three times the rate for geneticists, but abnormal result rates were similar between the two groups. The approval rate for inpatient orders was not significantly lower than outpatient orders, and abnormal result rates were similar for these two groups as well. Order error rates were approximately 8% among tests recommended by genetics providers in the inpatient setting, and tests ordered or recommended by nongeneticists had error rates near 5% in both inpatient and outpatient settings. CONCLUSIONS: Clinicians without specialty training in genetics make genetic test order errors at a significantly higher rate than geneticists. A laboratory utilization management program prevents these order errors from becoming diagnostic errors and reaching the patient. PMID- 27473741 TI - Artificial Neural Network Approach in Laboratory Test Reporting: Learning Algorithms. AB - OBJECTIVES: In the field of laboratory medicine, minimizing errors and establishing standardization is only possible by predefined processes. The aim of this study was to build an experimental decision algorithm model open to improvement that would efficiently and rapidly evaluate the results of biochemical tests with critical values by evaluating multiple factors concurrently. METHODS: The experimental model was built by Weka software (Weka, Waikato, New Zealand) based on the artificial neural network method. Data were received from Dokuz Eylul University Central Laboratory. "Training sets" were developed for our experimental model to teach the evaluation criteria. After training the system, "test sets" developed for different conditions were used to statistically assess the validity of the model. RESULTS: After developing the decision algorithm with three iterations of training, no result was verified that was refused by the laboratory specialist. The sensitivity of the model was 91% and specificity was 100%. The estimated kappa score was 0.950. CONCLUSIONS: This is the first study based on an artificial neural network to build an experimental assessment and decision algorithm model. By integrating our trained algorithm model into a laboratory information system, it may be possible to reduce employees' workload without compromising patient safety. PMID- 27473743 TI - Prozone Effect in the Diagnosis of Lupus Anticoagulant for the Lupus Anticoagulant-Hypoprothrombinemia Syndrome. AB - OBJECTIVES: The main clinical sequela of a lupus anticoagulant is increased thrombosis risk. However, bleeding due to lupus anticoagulant-hypoprothrombinemia syndrome is a rare but well-described manifestation of antiphospholipid syndrome. The association of acute acquired hypoprothrombinemia is caused by a lupus anticoagulant's specificity to prothrombin, which results in clearance of prothrombin and bleeding due to hypoprothrombinemia (usually <10% of normal). Severe life-threatening bleeding is most frequently reported in children with systemic lupus erythematosus or in healthy children after viral infection. In such cases, steroid therapy is usually effective in controlling the bleeding problems and improving prothrombin levels. METHODS: We report one pediatric patient with a lupus anticoagulant who had acute hemorrhagic diathesis. RESULTS: The diagnosis in this case was complicated by the presence of a prozone effect in lupus anticoagulant testing. The prozone effect (also known as hook effect) refers to situations where very high concentrations of antibody mask detection, typically in antigen-antibody reactions, which depend on visualization of agglutination. Decreasing the antibody/antigen ratio results in detectable antigen-antibody complexes. CONCLUSIONS: We report for the first time a variation on this theme in a patient with a lupus anticoagulant-type antiphospholipid antibody and hypoprothrombinemia, which corrected with immunosuppression and restoration of normal prothrombin levels. PMID- 27473742 TI - The Crossmatch/Issue Ratio: Use of a Novel Quality Indicator and Results of an International Survey on RBC Crossmatching and Issuing Practices. AB - OBJECTIVES: To understand the worldwide scope of RBC crossmatching and issuing practices and measure efficiency using a novel quality indicator, the crossmatch/issue (C/I) ratio. METHODS: An electronic survey was disseminated to hospital transfusion services collecting details about RBC crossmatching and issuing practices. Respondents were asked to enumerate the number of RBCs crossmatched and issued at their institutions during the 2014 calendar year to calculate the C/I ratio. RESULTS: Fifty-two survey responses were received, mostly from North American transfusion services (28/52, 54%). The electronic crossmatch was the most common technique (n = 29), and most respondents performed the crossmatch at the time that an order for RBCs was received in the transfusion service (even if an order to issue the RBCs was not received). Data to calculate the C/I ratio were supplied by 22 respondents, and the mean +/- SD was 1.30 +/- 0.34. There was no difference in C/I ratios between services that use the electronic or serologic crossmatch techniques (P = .49). The ratio was the same at the four sites that crossmatch RBCs at the time of issue compared with the time of order receipt (mean +/- SD, 1.11 +/- 0.09 vs. 1.35 +/- 0.36, respectively; P = .19). CONCLUSIONS: Electronic crossmatching is common, and the C/I ratio can be an indicator of efficiency. PMID- 27473744 TI - Successful ABO-Incompatible Renal Transplantation: Blood Group A1B Donor Into A2B Recipient With Anti-A1 Isoagglutinins. AB - OBJECTIVES: Transplantation of the blood group A2B in a recipient was successfully performed in the setting of receiving a deceased donor kidney from an "incompatible" A1B donor. METHODS: The donor and recipient were both typed for ABO blood group, including ABO genotyping. The donor and recipient were tested for ABO, non-ABO, and human leukocyte antigen (HLA) antibodies. The donor and recipient were typed for HLA antigens, including T- and B-flow cytometry crossmatch tests. RESULTS: The recipient's RBCs were negative with A1 lectin, and immunoglobulin G anti-A1 was demonstrated in the recipient's plasma. The donor recipient pair was a four-antigen HLA mismatch, but final T- and B-flow cytometry crossmatch tests were compatible. The transplant procedure was uneventful; the patient experienced immediate graft function with no episodes of rejection or readmissions more than 2 years later. CONCLUSIONS: It may be safe to transplant across the A1/A2 blood group AB mismatch barrier in the setting of low titer anti A1 isoagglutinins without the need for pretransplant desensitization even if the antibody produced reacts with anti-human globulin. PMID- 27473746 TI - Acute Headache Presentations to the Emergency Department: A Statewide Cross sectional Study. AB - OBJECTIVES: The objective of this study was to describe demographic and clinical characteristics including features that were consistent with subarachnoid hemorrhage (SAH), use of diagnostic tests, emergency department (ED) discharge diagnoses, and disposition of adult patients presenting with an acute headache to EDs statewide across Queensland, Australia. In addition, potential variations in the presentation and diagnostic workup between principal-referral and city regional hospitals were examined. METHODS: A prospective cross-sectional study was conducted over 4 weeks in September 2014. All patients >= 18 years presenting to one of 29 public and five private hospital EDs across the state with an acute headache were included. The headache had to be the principal presenting complaint and nontraumatic. The 34 study sites attend to about 90% of all ED presentations statewide. The treating doctor collected clinical information at the time of the ED visit including the characteristics of the headache and investigations performed. A study coordinator retrieved results of investigations, ED discharge diagnoses, and disposition from state databases. Variations in presentation, investigations, and diagnosis between city-regional and principal-referral hospitals were examined. RESULTS: There were 847 headache presentations. Median (range) age was 39 (18-92) years, 62% were female, and 31% arrived by ambulance. Headache peaked instantly in 18% and <= 1 hour in 44%. It was "worst ever" in 37%, 10/10 in severity in 23%, and associated with physical activity in 7.4%. Glasgow Coma Scale score was < 15 in 4.1%. Neck stiffness was noted on examination in 4.8%. Neurologic deficit persisting in the ED was found in 6.5%. A computed tomography (CT) head scan was performed in 38% (318/841, 95% CI = 35% to 41%) and an lumbar puncture in 4.7% (39/832, 95% CI = 3.4% to 6.3%). There were 18 SAH, six intraparenchymal hemorrhages, one subdural hematoma, one newly diagnosed brain metastasis, and two bacterial meningitis. Migraine was diagnosed in 23% and "primary headache not further specified" in 45%. CT head scans were more likely to be performed in principal-referral hospitals (41%) compared to city-regional hospitals (33%). The headache in patients presenting to the latter was less likely to be instantly peaking or associated with activity, but was no less severe in intensity and was more frequently accompanied by nausea and vomiting. Their diagnosis was more likely to be a benign primary headache. Variations in CT scanning could thus be due to differences in the case mix. The median (interquartile range) ED length of stay was 3.1 (2.2 to 4.5) hours. Patients was discharged from the ED or admitted to the ED short-stay unit prior to discharge in 57 and 23% of cases, respectively. CONCLUSIONS: The majority of patients had a benign diagnosis, with intracranial hemorrhage and bacterial meningitis accounting for only 3% of the diagnoses. There are variations in the proportion of patients receiving CT head scans between city-regional and principal-referral hospitals. As 38% of headache presentations overall underwent CT scanning, there is scope to rationalize diagnostic testing to rule out life threatening conditions. PMID- 27473745 TI - Experiences of nurse practitioners and medical practitioners working in collaborative practice models in primary healthcare in Australia - a multiple case study using mixed methods. AB - BACKGROUND: In 2010 policy changes were introduced to the Australian healthcare system that granted nurse practitioners access to the public health insurance scheme (Medicare) subject to a collaborative arrangement with a medical practitioner. These changes facilitated nurse practitioner practice in primary healthcare settings. This study investigated the experiences and perceptions of nurse practitioners and medical practitioners who worked together under the new policies and aimed to identify enablers of collaborative practice models. METHODS: A multiple case study of five primary healthcare sites was undertaken, applying mixed methods research. Six nurse practitioners, 13 medical practitioners and three practice managers participated in the study. Data were collected through direct observations, documents and semi-structured interviews as well as questionnaires including validated scales to measure the level of collaboration, satisfaction with collaboration and beliefs in the benefits of collaboration. Thematic analysis was undertaken for qualitative data from interviews, observations and documents, followed by deductive analysis whereby thematic categories were compared to two theoretical models of collaboration. Questionnaire responses were summarised using descriptive statistics. RESULTS: Using the scale measurements, nurse practitioners and medical practitioners reported high levels of collaboration, were highly satisfied with their collaborative relationship and strongly believed that collaboration benefited the patient. The three themes developed from qualitative data showed a more complex and nuanced picture: 1) Structures such as government policy requirements and local infrastructure disadvantaged nurse practitioners financially and professionally in collaborative practice models; 2) Participants experienced the influence and consequences of individual role enactment through the co-existence of overlapping, complementary, traditional and emerging roles, which blurred perceptions of legal liability and reimbursement for shared patient care; 3) Nurse practitioners' and medical practitioners' adjustment to new routines and facilitating the collaborative work relied on the willingness and personal commitment of individuals. CONCLUSIONS: Findings of this study suggest that the willingness of practitioners and their individual relationships partially overcame the effect of system restrictions. However, strategic support from healthcare reform decision-makers is needed to strengthen nurse practitioner positions and ensure the sustainability of collaborative practice models in primary healthcare. PMID- 27473747 TI - Differences in perceived fairness and health outcomes in two injury compensation systems: a comparative study. AB - BACKGROUND: Involvement in a compensation process following a motor vehicle collision is consistently associated with worse health status but the reasons underlying this are unclear. Some compensation systems are hypothesised to be more stressful than others. In particular, fault-based compensation systems are considered to be more adversarial than no-fault systems and associated with poorer recovery. This study compares the perceived fairness and recovery of claimants in the fault-based compensation system in New South Wales (NSW) to the no-fault system in Victoria, Australia. METHODS: One hundred eighty two participants were recruited via claims databases of the compensation system regulators in Victoria and NSW. Participants were > 18 years old and involved in a transport injury compensation process. The crash occurred 12 months (n = 95) or 24 months ago (n = 87). Perceived fairness about the compensation process was measured by items derived from a validated organisational justice questionnaire. Health outcome was measured by the initial question of the Short Form Health Survey. RESULTS: In Victoria, 84 % of the participants considered the claims process fair, compared to 46 % of NSW participants (chi(2) = 28.54; p < .001). Lawyer involvement and medical assessments were significantly associated with poorer perceived fairness. Overall perceived fairness was positively associated with health outcome after adjusting for demographic and injury variables (Adjusted Odds Ratio = 2.8, 95 % CI = 1.4 - 5.7, p = .004). CONCLUSION: The study shows large differences in perceived fairness between two different compensation systems and an association between fairness and health. These findings are politically important because compensation processes are designed to improve recovery. Lower perceived fairness in NSW may have been caused by potential adversarial aspects of the scheme, such as liability assessment, medical assessments, dealing with a third party for-profit insurance agency, or financial insecurity due to lump sum payments at settlement. This study should encourage an evidence informed discussion about how to reduce anti-therapeutic aspects in the compensation process in order to improve the injured person's health. PMID- 27473748 TI - Computer-based tools for assessing micro-longitudinal patterns of cognitive function in older adults. AB - Patterns of cognitive change over micro-longitudinal timescales (i.e., ranging from hours to days) are associated with a wide range of age-related health and functional outcomes. However, practical issues of conducting high-frequency assessments make investigations of micro-longitudinal cognition costly and burdensome to run. One way of addressing this is to develop cognitive assessments that can be performed by older adults, in their own homes, without a researcher being present. Here, we address the question of whether reliable and valid cognitive data can be collected over micro-longitudinal timescales using unsupervised cognitive tests.In study 1, 48 older adults completed two touchscreen cognitive tests, on three occasions, in controlled conditions, alongside a battery of standard tests of cognitive functions. In study 2, 40 older adults completed the same two computerized tasks on multiple occasions, over three separate week-long periods, in their own homes, without a researcher present. Here, the tasks were incorporated into a wider touchscreen system (Novel Assessment of Nutrition and Ageing (NANA)) developed to assess multiple domains of health and behavior. Standard tests of cognitive function were also administered prior to participants using the NANA system.Performance on the two "NANA" cognitive tasks showed convergent validity with, and similar levels of reliability to, the standard cognitive battery in both studies. Completion and accuracy rates were also very high. These results show that reliable and valid cognitive data can be collected from older adults using unsupervised computerized tests, thus affording new opportunities for the investigation of cognitive. PMID- 27473749 TI - Using auriculotherapy for osteoarthritic knee among elders: a double-blinded randomised feasibility study. AB - BACKGROUND: Osteoarthritic knee (OA knee) is a common condition in the elderly. Exploration of non-invasive complementary therapies for OA knee is warranted given the limitations of pharmacologic therapies. Auriculotherapy (AT) is a therapeutic method in which specific points on the auricle are stimulated to treat various disorders of the body, and the therapeutic value and synergistic effect of laser auriculotherapy (LAT) when combined with magneto-auriculotherapy (MAT) merits further investigation. METHODS: This study adopted a double-blinded four-arm randomized placebo design. The aims of study are (1) to assess the feasibility of AT among elders with OA knee in a future large-scale study, including the use of blinding in subjects and evaluators, acceptance of treatment protocol, and estimating the effect size and attrition rate; and (2) to evaluate the preliminary effect of AT in elders with OA knee. Subjects were randomly divided into four groups with different modes of AT with/without placebo objects. A total of 43 subjects completed the 6-week intervention and post-assessment. Assessments included a numerical rating scale of pain (NRS), the timed-up-and-go test (TUGT), and standard goniometer measurements during knee flexion and extension, Kruskal-Wallis test was used to evaluate differences among groups, and Wilcoxon sign-ranked test for examining within-group comparison. RESULTS: Preliminary results indicated the absence of differences in the NRS, TUGT, and active/passive knee flexion and extension at baseline, as well as post-therapy, between the four groups. Even though the differences of these parameters between groups were not significant, the relative differences of NRS and TUGT in subjects who received combined MAT plus LAT were higher than those treated with MAT or LAT alone, or the placebo group. Four of the six parameters demonstrated significant within group differences in subjects who received MAT and/or LAT, whereas no significant differences were found in the placebo group. CONCLUSION: This study demonstrates that the AT protocol adopted in this study for elders with OA knee is feasible and could be applied in future larger-scale study. Larger sample size should be considered in a future trial to determine the causal relationship between treatment and effect. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02352636 . Registered on 23 January 2015. PMID- 27473750 TI - Dead space in acute respiratory distress syndrome: more than a feeling! PMID- 27473751 TI - Enhanced pregenomic RNA levels and lowered precore mRNA transcription efficiency in a genotype A hepatitis B virus genome with C1766T and T1768A mutations obtained from a fulminant hepatitis patient. AB - The viral factors associated with the development of fulminant hepatitis B are not fully understood. We recently found four unique mutations [G to A at nucleotide 1742 (G1742A), C1766T, T1768A and T1809C] in the basal core promoter (BCP) region of a genotype A hepatitis B virus (HBV) strain (FH) obtained from a 53-year-old man with fatal fulminant hepatitis. To elucidate the association of the mutations of the FH genome with the disease, we constructed a 1.3-fold FH genome and its five variants by replacing one or two mutated nucleotides with wild-type nucleotide(s) via site-directed mutagenesis, and transfected human hepatoma cells (HepG2/C3A) with the constructs. There were no discernible differences between FH and two variants (FH_A1742G and FH_C1809T) with regard to viral replication and protein expression. However, in comparison to three other variants (FH_T1766C, FH_A1768T and FH_T1766C/A1768T) with wild-type nucleotide(s) at 1766 and/or 1768, the FH genome exhibited a 2.5-5-fold enhancement of viral replication by heightened pregenomic RNA synthesis and a 1.5-2.5-fold reduction in the hepatitis B e antigen (HBeAg) synthesis by the downregulation of the precore mRNA level. An immunofluorescence analysis revealed the increased and predominant cytoplasmic localization of the core protein in the FH genome. The present study demonstrates that the C1766T/T1768A mutations in the BCP region of genotype A HBV enhance viral replication, downregulate HBeAg expression and are responsible for the predominant localization of the core protein in the cytoplasm, which are likely associated with the development of fulminant hepatitis. PMID- 27473752 TI - Human Papillomavirus Vaccine Uptake in Texas Pediatric Care Settings: A Statewide Survey of Healthcare Professionals. AB - The purpose of this study was to identify barriers to and facilitators of human papillomavirus (HPV) vaccination in children aged 9-17 years across Texas. A literature review informed the development of a web-based survey designed for people whose work involves HPV vaccination in settings serving pediatric patients. The survey was used to examine current HPV vaccine recommendation practices among healthcare providers, barriers to HPV vaccination, reasons for parent/caregiver vaccine refusal, staff and family education practices, utilization of reminder and recall systems and status of vaccine administration (payment, ordering and stocking). 1132 responses were received representing healthcare providers, administrative and managerial staff. Respondents identified perceived barriers to HPV vaccination as parental beliefs about lack of necessity of vaccination prior to sexual debut, parental concerns regarding safety and/or side effects, parental perceptions that their child is at low risk for HPV related disease, and parental lack of knowledge that the vaccine is a series of three shots. Of responding healthcare providers, 94 % (n = 582) reported they recommend the vaccine for 9-12 year olds; however, same-day acceptance of the vaccine is low with only 5 % (n = 31) of providers reporting the HPV vaccine is "always" accepted the same day the recommendation is made. Healthcare providers and multidisciplinary care teams in pediatric care settings must work to identify gaps between recommendation and uptake to maximize clinical opportunities. Training in methods to communicate an effective HPV recommendation and patient education tailored to address identified barriers may be helpful to reduce missed opportunities and increase on-time HPV vaccinations. PMID- 27473753 TI - Epidemiology of lung cancer and approaches for its prediction: a systematic review and analysis. AB - BACKGROUND: Owing to the use of tobacco and the consumption of alcohol and adulterated food, worldwide cancer incidence is increasing at an alarming and frightening rate. Since the last decade of the twentieth century, lung cancer has been the most common cancer type. This study aimed to determine the global status of lung cancer and to evaluate the use of computational methods in the early detection of lung cancer. METHODS: We used lung cancer data from the United Kingdom (UK), the United States (US), India, and Egypt. For statistical analysis, we used incidence and mortality as well as survival rates to better understand the critical state of lung cancer. RESULTS: In the UK and the US, we found a significant decrease in lung cancer mortalities in the period of 1990-2014, whereas, in India and Egypt, such a decrease was not much promising. Additionally, we observed that, in the UK and the US, the survival rates of women with lung cancer were higher than those of men. We observed that the data mining and evolutionary algorithms were efficient in lung cancer detection. CONCLUSIONS: Our findings provide an inclusive understanding of the incidences, mortalities, and survival rates of lung cancer in the UK, the US, India, and Egypt. The combined use of data mining and evolutionary algorithm can be efficient in lung cancer detection. PMID- 27473754 TI - Current irritability associated with hastened depressive recurrence and delayed depressive recovery in bipolar disorder. AB - BACKGROUND: Current irritability is associated with greater retrospective and current bipolar disorder (BD) illness severity; less is known about prospective longitudinal implications of current irritability. We examined relationships between current irritability and depressive recurrence and recovery in BD. METHODS: Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form during follow-up during up to 2 years of naturalistic treatment. Prevalence and clinical correlates of any current irritability in depressed and recovered (euthymic >=8 weeks) BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between current irritability and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators. RESULTS: Recovered BD outpatients with vs. without current irritability had significantly higher rates of 13/19 (68.4 %) other baseline unfavorable illness characteristics/current mood symptoms and hastened depressive recurrence (Log-Rank p = 0.020), driven by lifetime history of anxiety disorder and prior year rapid cycling, and attenuated by history of psychosis. Depressed BD outpatients with vs. without current irritability had significantly higher rates of 7/19 (36.8 %) other unfavorable illness characteristics/current mood symptoms and delayed depressive recovery (Log-Rank p = 0.034), NOT mediated by any assessed parameter. LIMITATIONS: Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample. CONCLUSIONS: Current irritability was associated with hastened depressive recurrence and delayed depressive recovery in BD. Treatment studies targeting irritability may yield strategies to mitigate increased longitudinal depressive burden. PMID- 27473755 TI - A qualitative study examining healthcare managers and providers' perspectives on participating in primary care implementation research. AB - BACKGROUND: Primary care reforms should be supported by high-quality evidence across the entire life cycle of research. Front-line healthcare providers play an increasing role in implementation research. We recently evaluated two interventions for people with type 2 diabetes (T2D) in partnership with four Primary Care Networks (PCNs) in Alberta, Canada. Here, we report healthcare professionals perspectives on participating in primary care implementation research. METHODS: Guided by the RE-AIM framework, we collected qualitative data before, during, and after both interventions. We conducted 34 in-person or telephone interviews with 17 individual PCN professionals. We used content analysis to identify emerging codes and concepts. RESULTS: Two major themes emerged from the data. First, healthcare managers were eager to conduct implementation research in a primary care setting. Second, regardless of willingness to conduct research, there were challenges to implementing experimental study designs for both interventions. PCN professionals presumed the interventions were better than usual care, expressed role conflict, and reported administrative burdens related to research participation. Perceptions of patient vulnerability and an obligation to intervene exacerbated these issues. CONCLUSIONS: Healthcare professionals with limited practical research experience might not foresee the challenges in implementing experimental study designs in primary care settings to generate high-quality evidence. These issues are intensified when healthcare professionals perceive target patient populations as vulnerable and in need of intervention based on the presenting illness. Possible solutions include further research training, involving healthcare professionals in study design development, and using non-clinical staff to conduct research activities, particularly among acutely unwell patient populations. PMID- 27473756 TI - Caloric restriction and the precision-control of autophagy: A strategy for delaying neurodegenerative disease progression. AB - Caloric restriction (CR) is known to extend lifespan in most organisms, indicating that nutrient and energy regulatory mechanisms impact aging. The greatest risk factor for neurodegeneration is age; thus, the antiaging effects of CR might attenuate progressive cell death and avert the aggregation of abnormal proteins associated with neurodegenerative diseases. CR is a potent inducer of autophagy, a tightly regulated intracellular process that facilitates recycling of abnormal protein aggregates and damaged organelles into bioenergetic and biosynthetic materials to maintain homeostasis. Thus, dysregulated autophagy can lead to cellular dysfunction, abnormal protein accumulation, proteotoxicity and subsequently the onset of several neurodegenerative diseases. Therefore, the targeted and precision-controlled activation of autophagy represents a promising therapeutic strategy. Non-pharmacological therapeutic interventions that delay aging by modulating specific stages of autophagy might be beneficial against premature aging, neurodegeneration and its associated ailments. However, the dynamic and often compensatory cross-talk that exists between the protein degradation pathways makes clinical translational approaches challenging. Here we review the primary autophagy pathways in the context of age-related neurodegenerative diseases, focusing on compensatory mechanisms and pathway failure. By critically assessing each underlying molecular machinery, we reveal their impact on aging and unmask the role of caloric restriction in changing cellular fate by delayed aging through stimulation of autophagy. This may point towards novel and better targeted interventions that exploit the autophagic machinery in the treatment of neurodegenerative diseases. PMID- 27473758 TI - Correction for The alternate AP-1 adaptor subunit Apm2 interacts with the Mil1 regulatory protein and confers differential cargo sorting. PMID- 27473759 TI - Retraction for Lectin-deficient Calreticulin Retains Full Functionality as a Chaperone for Class I Histocompatibility Molecules. PMID- 27473757 TI - Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF. AB - BACKGROUND: Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease. OBJECTIVES: To obtain information about genetic predisposition to CM in Ticino, the southern region of Switzerland, a zone with moderate-to-high CM incidence. METHODS: We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first- or second-degree relatives. Healthy blood donors (n = 146) were included as a control group. RESULTS: From July 2010 to July 2012, 57 patients (41 pedigrees) were included. Twenty-six were melanoma-prone families (with at least two cases) and 15 had multiple CMs. Pancreatic cancer was found in six families. The CDKN2A mutation p.V126D was identified in seven patients (four families) with a founder effect, whereas CDKN2A A148T was detected in seven cases (five families) and seven healthy donors (odds ratio 2.76, 95% confidence interval 0.83-9.20). At least one MC1R melanoma-associated polymorphism was detected in 32 patients (78%) and 97 healthy donors (66%), with more than one polymorphism in 12 patients (29%) and 25 healthy donors (17%). The MITF variant p.E318K was identified in four patients from three additional pedigrees (7%) and one healthy control (0.7%). CONCLUSIONS: Inclusion criteria for the Ticino population for genetic assessment should follow the rule of two (two affected individuals in a family or a patient with multiple CMs), as we detected a CDKN2A mutation in almost 10% of our pedigrees (four of 41), MITF p.E318K in 7% (three of 41) and a higher number of MC1R variants than in the control population. PMID- 27473761 TI - Sedation quality in intensive care: which interventions work? PMID- 27473760 TI - Staff education, regular sedation and analgesia quality feedback, and a sedation monitoring technology for improving sedation and analgesia quality for critically ill, mechanically ventilated patients: a cluster randomised trial. AB - BACKGROUND: Optimal sedation of patients in intensive care units (ICUs) requires the avoidance of pain, agitation, and unnecessary deep sedation, but these outcomes are challenging to achieve. Excessive sedation can prolong ICU stay, whereas light sedation can increase pain and frightening memories, which are commonly recalled by ICU survivors. We aimed to assess the effectiveness of three interventions to improve sedation and analgesia quality: an online education programme; regular feedback of sedation-analgesia quality data; and use of a novel sedation-monitoring technology (the Responsiveness Index [RI]). METHODS: We did a cluster randomised trial in eight ICUs, which were randomly allocated to receive education alone (two ICUs), education plus sedation-analgesia quality feedback (two ICUs), education plus RI monitoring technology (two ICUs), or all three interventions (two ICUs). Randomisation was done with computer-generated random permuted blocks, stratified according to recruitment start date. A 45 week baseline period was followed by a 45 week intervention period, separated by an 8 week implementation period in which the interventions were introduced. ICU and research staff were not masked to study group assignment during the intervention period. All mechanically ventilated patients were potentially eligible. We assessed patients' sedation-analgesia quality for each 12 h period of nursing care, and sedation-related adverse events daily. Our primary outcome was the proportion of care periods with optimal sedation-analgesia, defined as being free from excessive sedation, agitation, poor limb relaxation, and poor ventilator synchronisation. Analysis used multilevel generalised linear mixed modelling to explore intervention effects in a single model taking clustering and patient level factors into account. A concurrent mixed-methods process evaluation was undertaken to help understand the trial findings. The trial is registered with ClinicalTrials.gov, number NCT01634451. FINDINGS: Between June 1, 2012, and Dec 31, 2014, we included 881 patients (9187 care periods) during the baseline period and 591 patients (6947 care periods) during the intervention period. During the baseline period, optimal sedation-analgesia was present for 5150 (56%) care periods. We found a significant improvement in optimal sedation-analgesia with RI monitoring (odds ratio [OR] 1.44 [95% CI 1.07-1.95]; p=0.017), which was mainly due to increased periods free from excessive sedation (OR 1.59 [1.09-2.31]) and poor ventilator synchronisation (OR 1.55 [1.05-2.30]). However, more patients experienced sedation-related adverse events (OR 1.91 [1.02-3.58]). We found no improvement in overall optimal sedation-analgesia with education (OR 1.13 [95% CI 0.86-1.48]), but fewer patients experienced sedation-related adverse events (OR 0.56 [0.32-0.99]). The sedation-analgesia quality data feedback did not improve quality (OR 0.74 [95% CI 0.54-1.00]) or sedation-related adverse events (OR 1.15 [0.61-2.15]). The process evaluation suggested many clinicians found the RI monitoring useful, but it was often not used for decision making as intended. Education was valued and considered useful by staff. By contrast, sedation analgesia quality feedback was poorly understood and thought to lack relevance to bedside nursing practice. INTERPRETATION: Combination of RI monitoring and online education has the potential to improve sedation-analgesia quality and patient safety in mechanically ventilated ICU patients. The RI monitoring seemed to improve sedation-analgesia quality, but inconsistent adoption by bedside nurses limited its impact. The online education programme resulted in a clinically relevant improvement in patient safety and was valued by nurses, but any changes to behaviours did not seem to alter other measures of sedation-analgesia quality. Providing sedation-analgesia quality feedback to ICUs did not appear to improve any quality metrics, probably because staff did not think it relevant to bedside practice. FUNDING: Chief Scientist Office, Scotland; GE Healthcare. PMID- 27473763 TI - Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis. AB - Chloroquine (CQ) is a widely used antimalarial drug with emerging potential in anticancer therapies due to its apparent inhibitory effects on CXCR4 chemokine receptor, autophagy, and cholesterol metabolism. This study reports on polymeric CQ (pCQ) as a macromolecular drug with antimetastatic activity. The pCQ polymers were synthesized by copolymerization of methacryloylated hydroxy-CQ (HCQ) and N (2-hydroxypropyl)methacrylamide (HPMA). The results show that pCQ is significantly more effective in inhibiting cancer cell migration and invasion when compared with the parent HCQ. The proposed mechanism of action at least partially relies on the ability of pCQ to inhibit cell migration mediated by the CXCR4/CXCL12 pathway. The pCQ also demonstrates superior inhibitory activity over HCQ when tested in a mouse model of experimental lung metastasis. Lastly, pCQ shows the ability to efficiently translocate to the cytoplasm while exhibiting lower cytotoxicity than HCQ. Overall, this study supports pCQ as a promising polymeric drug platform suitable for use in combination antimetastatic strategies and potential use in cytoplasmic drug delivery. PMID- 27473762 TI - Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study. AB - BACKGROUND: The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom. METHODS: We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA. RESULTS: Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo /dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups. CONCLUSIONS: Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment. PMID- 27473765 TI - Local arterial wall drug delivery using balloon catheter system. AB - Balloon-based drug delivery systems allow localized application of drugs to a vascular segment to reduce neointimal hyperplasia and restenosis. Drugs are coated onto balloons using excipients as drug carriers to facilitate adherence and release of drug during balloon inflation. Drug-coated balloon delivery system is characterized by a rapid drug transfer that achieves high drug concentration along the vessel wall surface, intended to correspond to the balloon dilation induced vascular injury and healing processes. The balloon catheter system allows homogenous drug delivery to the vessel wall, such that the drug release per unit surface area is kept constant along balloons of different lengths. Optimization of the balloon coating matrix is essential for efficient drug transfer and tissue retention until the artery remodels to a normal set point. Challenges in the development of balloon-based drug delivery to the arterial wall include finding suitable excipients for drug formulation to enable drug release to a targeted lesion site effectively, maintain coating integrity during transit, prolong tissue retention and reduce particulate generation. This review highlights various factors involved in the successful design of balloon-based delivery systems, including drug release kinetics, matrix coating transfer, transmural drug partitioning, dissolution rate and release of unbound active drug. PMID- 27473764 TI - Intra- and trans-cellular delivery of enzymes by direct conjugation with non multivalent anti-ICAM molecules. AB - Intercellular adhesion molecule 1 (ICAM-1) is a cell-surface protein overexpressed in many diseases and explored for endocytosis and transcytosis of drug delivery systems. All previous evidence demonstrating ICAM-1-mediated transport of therapeutics into or across cells was obtained using nanocarriers or conjugates coupled to multiple copies of anti-ICAM antibodies or peptides. Yet, transport of therapeutics linked to non-multivalent anti-ICAM ligands has never been shown, since multivalency was believed to be necessary to induce transport. Our goal was to explore whether non-multivalent binding to ICAM-1 could drive endocytosis and/or transcytosis of model cargo in different cell types. We found that anti-ICAM was specifically internalized by all tested ICAM-1-expressing cells, including epithelial, fibroblast and neuroblastoma cells, primary or established cell lines. Uptake was inhibited at 4 degrees C and in the presence of an inhibitor of the ICAM-1-associated pathway, rather than inhibitors of the clathrin or caveolar routes. We observed minimal transport of anti-ICAM to lysosomes, yet prominent and specific transcytosis across epithelial monolayers. Finally, we coupled a model cargo (the enzyme horseradish peroxidase (HRP)) to anti-ICAM and separated a 1:2 antibody:enzyme conjugate for non-multivalent ICAM 1 targeting. Similar to anti-ICAM, anti-ICAM-HRP was specifically internalized and transported across cells, which rendered intra- and trans-cellular enzyme activity. Therefore, non-multivalent ICAM-1 targeting also provides transport of cargoes into and across cells, representing a new alternative for future therapeutic applications via this route. PMID- 27473767 TI - Geometrical envelopes: Extending graphical contemporary niche theory to communities and eco-evolutionary dynamics. AB - Contemporary niche theory is a powerful structuring framework in theoretical ecology. First developed in the context of resource competition, it has been extended to encompass other types of regulating factors such as shared predators, parasites or inhibitors. A central component of contemporary niche theory is a graphical approach popularized by Tilman that illustrates the different outcomes of competition along environmental gradients, like coexistence and competitive exclusion. These food web modules have been used to address species sorting in community ecology, as well as adaptation and coexistence on eco-evolutionary time scales in adaptive dynamics. Yet, the associated graphical approach has been underused so far in the evolutionary context. In this paper, we provide a rigorous approach to extend this graphical method to a continuum of interacting strategies, using the geometrical concept of the envelope. Not only does this approach provide community and eco-evolutionary bifurcation diagrams along environmental gradients, it also sheds light on the similarities and differences between those two perspectives. Adaptive dynamics naturally merges with this ecological framework, with a close correspondence between the classification of singular strategies and the geometrical properties of the envelope. Finally, this approach provides an integrative tool to study adaptation between levels of organization, from the individual to the ecosystem. PMID- 27473766 TI - Sustained release of stromal cell derived factor-1 from an antioxidant thermoresponsive hydrogel enhances dermal wound healing in diabetes. AB - Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus. Altered cell migration due to microcirculatory deficiencies as well as excessive and prolonged reactive oxygen species production are implicated in the delayed healing of DFUs. The goal of this research was to assess whether sustained release of SDF-1, a chemokine that promotes endothelial progenitor cell homing and angiogenesis, from a citrate-based antioxidant thermoresponsive polymer would significantly improve impaired dermal wound healing in diabetes. Poly (polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) was synthesized via sequential polycondensation and free radical polymerization reactions. SDF-1 was entrapped via gelation of the PPCN+SDF-1 solution above its lower critical solution temperature (LCST) and its release and bioactivity was measured. The effect of sustained release of SDF-1 from PPCN (PPCN+SDF-1) versus a bolus application of SDF-1 in phosphate buffered saline (PBS) on wound healing was evaluated in a diabetic murine splinted excisional dermal wound model using gross observation, histology, immunohistochemistry, and optical coherence tomography microangiography. Increasing PPCN concentration decreased SDF-1 release rate. The time to 50% wound closure was 11days, 16days, 14days, and 17days for wounds treated with PPCN+SDF-1, SDF-1 only, PPCN only, and PBS, respectively. Wounds treated with PPCN+SDF-1 had the shortest time for complete healing (24days) and exhibited accelerated granulation tissue production, epithelial maturation, and the highest density of perfused blood vessels. In conclusion, sustained release of SDF-1 from PPCN is a promising and easy to use therapeutic strategy to improve the treatment of chronic non-healing DFUs. PMID- 27473768 TI - Nature lessons: The whitefly bacterial endosymbiont is a minimal amino acid factory with unusual energetics. AB - Reductive genome evolution is a universal phenomenon observed in endosymbiotic bacteria in insects. As the genome reduces its size and irreversibly losses coding genes, the functionalities of the cell system, including the energetics processes, are more restricted. Several energetic pathways can also be lost. How do these reduced metabolic networks sustain the energy needs of the system? Among the bacteria with reduced genomes Candidatus Portiera aleyrodidarum, obligate endosymbiont of whiteflies, represents an extreme case since lacks several key mechanisms for ATP generation. Thus, to analyze the cell energetics in this system, a genome-scale metabolic model of this endosymbiont was constructed, and its energy production capabilities dissected using stoichiometric analysis. Our results suggest that energy generation is coupled to the synthesis of essential amino acids and carotenoids, crucial metabolites in the symbiotic association. A deeper insight showed that ATP production via carotenoid synthesis is also connected with amino acid production. This unusual association of energy production with anabolism suggests that, although minimized, endosymbiont metabolic networks maintain a remarkable biosynthetic potential. PMID- 27473769 TI - Carbapenem-resistant gram-negative bacilli in Tripoli, Libya. PMID- 27473770 TI - Intra-family differences in efficacy of inactivation of small, non-enveloped viruses. AB - The use of specific model viruses for validating viral purification process steps and for assessing the efficacies of viral disinfectants is based, in part, on the assumption that viral susceptibilities to such treatments will be similar for different members, including different genera, within a given viral family. This assumption is useful in cases where cell-based infectivity assays or laboratory strains for the specific viruses of interest might not exist. There are some documented cases, however, where exceptions to this assumption exist. In this paper, we discuss some of the more striking cases of intra-family differences in susceptibilities to inactivation steps used for downstream viral purification steps in biologics manufacture (e.g. heat inactivation, low pH, and guanidinium hydrochloride inactivation) and to specific viral disinfectants (e.g. alcohols, hydrogen peroxide, and quaternary ammonium-containing disinfectants) that might be employed for facility/equipment disinfection. The results suggest that care should be taken when extrapolating viral inactivation susceptibilities from specific model viruses to different genera or even to different members of the same genus. This should be taken into consideration by regulatory agencies and biologics manufacturers designing viral clearance and facility disinfection validation studies, and developers and evaluators of viral disinfectants. PMID- 27473771 TI - Factors driving changes in freshwater mussel (Bivalvia, Unionida) diversity and distribution in Peninsular Malaysia. AB - Freshwater mussels (Bivalvia, Unionida) fulfil important ecosystem functions and are one of the most threatened freshwater taxa globally. Knowledge of freshwater mussel diversity, distribution and ecology in Peninsular Malaysia is extremely poor, and the conservation status of half of the species presumed to occur in the region has yet to be assessed. We conducted the first comprehensive assessment of Peninsular Malaysia's freshwater mussels based on species presence/absence and environmental data collected from 155 sites spanning all major river catchments and diverse habitat types. Through an integrative morphological-molecular approach we recognised nine native and one widespread non-native species, i.e. Sinanodonta woodiana. Two species, i.e. Pilsbryoconcha compressa and Pseudodon cambodjensis, had not been previously recorded from Malaysia, which is likely a result of morphological misidentifications of historical records. Due to their restriction to single river catchments and declining distributions, Hyriopsis bialata, possibly endemic to Peninsular Malaysia, Ensidens ingallsianus, possibly already extinct in the peninsula, and Rectidens sumatrensis, particularly require conservation attention. Equally, the Pahang, the Perak and the north-western river catchments are of particular conservation value due to the presence of a globally unique freshwater mussel fauna. Statistical relationships of 15 water quality parameters and mussel presence/absence identified acidification and nutrient pollution (eutrophication) as the most important anthropogenic factors threatening freshwater mussel diversity in Peninsular Malaysia. These factors can be linked to atmospheric pollution, deforestation, oil-palm plantations and a lack of functioning waste water treatment, and could be mitigated by establishing riparian buffers and improving waste water treatment for rivers running through agricultural and residential land. PMID- 27473773 TI - Impact of climate change on soil thermal and moisture regimes in Serbia: An analysis with data from regional climate simulations under SRES-A1B. AB - We considered temporal and spatial variations to the thermal and moisture regimes of the most common RSGs (Reference Soil Groups) in Serbia under the A1B scenario for the 2021-2050 and 2071-2100 periods, with respect to the 1961-1990 period. We utilized dynamically downscaled global climate simulations from the ECHAM5 model using the coupled regional climate model EBU-POM (Eta Belgrade University Princeton Ocean Model). We analysed the soil temperature and moisture time series using simple statistics and a Kolmogorov complexity (KC) analysis. The corresponding metrics were calculated for 150 sites. In the future, warmer and drier regimes can be expected for all RSGs in Serbia. The calculated soil temperature and moisture variations include increases in the mean annual soil temperature (up to 3.8 degrees C) and decreases in the mean annual soil moisture (up to 11.3%). Based on the KC values, the soils in Serbia are classified with respect to climate change impacts as (1) less sensitive (Vertisols, Umbrisols and Dystric Cambisols) or (2) more sensitive (Chernozems, Eutric Cambisols and Planosols). PMID- 27473772 TI - Reducing nutrient impacts from shrimp effluents in a subtropical coastal lagoon. AB - Shrimp farm aquaculture causes environmental impacts, notably decreased water quality due to the release of nutrient-rich effluents. Pond wastewater is usually discharged without treatment, and tidal conditions are not taken into account in the management plans. However, natural variability of nutrients makes difficult field evaluation and attribution of impacts. Here we implemented a three dimensional coupled hydrodynamic-biogeochemical model (spatial resolution=50m*50m, time resolution=4s) in order to evaluate the dispersion conditions under specific tidal conditions of nutrient discharges from a semi intensive shrimp farm during spring and neap tide. Ammonia was quickly assimilated by plankton and its concentration recovered initial levels 10days after the beginning of the harvest. Due to the higher salinity of the pond effluents, shrimp farm discharges accumulate in waters and sediments of the upper lagoon creeks, mostly affecting the benthos, thus implying a potential risk of shrimp farm self-contamination. Maximum concentrations of most biogeochemical tracers occurred when the harvest ends and the ponds are fully emptied. We show that maximum nutrient concentrations can be reduced by ~10% when the harvest ends during spring tides compared to harvests ending during neap tides. This work may be useful to improve the management of shrimp farm effluents by reducing, easily and at little cost, nutrient impacts on tropical and sub-tropical receiving ecosystems. PMID- 27473774 TI - New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation. AB - PURPOSE: Smad3 is a critical signaling protein in renal fibrosis. Proteolysis targeting chimeric molecules (PROTACs) are small molecules designed to degrade target proteins via ubiquitination. They have three components: (1) a recognition motif for E3 ligase; (2) a linker; and (3) a ligand for the target protein. We aimed to design a new PROTAC to prevent renal fibrosis by targeting Smad3 proteins and using hydroxylated pentapeptide of hypoxia-inducible factor-1alpha as the recognition motif for von Hippel-Lindau (VHL) ubiquitin ligase (E3). METHODS: Computer-aided drug design was used to find a specific ligand targeting Smad3. Surface plasmon resonance (SPR) was used to verify and optimize screening results. Synthesized PROTAC was validated by two-stage mass spectrometry. The PROTAC's specificity for VHL (E3 ligase) was proved with two human renal carcinoma cell lines, 786-0 (VHL(-)) and ACHN (VHL(+)), and its anti-fibrosis effect was tested in renal fibrosis cell models. RESULTS: Thirteen small molecular compounds (SMCs) were obtained from the Enamine library using GLIDE molecular docking program. SPR results showed that #8 SMC (EN300-72284) combined best with Smad3 (KD=4.547*10(-5)M). Mass spectrometry showed that synthesized PROTAC had the correct peptide molecular weights. Western blot showed Smad3 was degraded by PROTAC with whole-cell lysate of ACHN but not 786-0. Degradation, but not ubiquitination, of Smad3 was inhibited by proteasome inhibitor MG132. The upregulation of fibronectin and Collagen I induced by TGF-beta1 in both renal fibroblast and mesangial cells were inhibited by PROTAC. CONCLUSION: The new PROTAC might prevent renal fibrosis by targeting Smad3 for ubiquitination and degradation. PMID- 27473775 TI - Repair of ruptured abdominal aortic aneurysm after cardiac arrest. AB - OBJECTIVE: Cardiac arrest in patients with ruptured abdominal aortic aneurysm (rAAA) is not uncommon and associated with significantly increased mortality. Although it has been suggested as a contraindication to aortic repair, the prognostic implications of preoperative cardiac arrest in the face of rAAA are controversial. The purpose of this structured review is to analyze the reported outcomes of patients with rAAA and preoperative cardiac arrest. METHODS: English language single- and multi-institutional series reporting outcomes of patients with rAAA and cardiac arrest were identified by systematic literature search and review. An aggregate analysis and structured review of outcomes after subsequent aortic repair was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. The primary outcome was short term overall mortality. RESULTS: Sixteen studies involving 2669 patients with rAAA were analyzed, including 334 (13%) with preoperative cardiac arrest. Cardiac arrest was associated with significantly increased mortality compared with patients with rAAA without arrest (86% vs 44%; P < .0001), although cardiac arrest in isolation was poorly predictive of mortality. Four patients were treated by endovascular aortic repair, and all survived. Shorter resuscitation times and return of signs of life prior to aortic repair are associated with improved survival, and long-term functional outcomes among survivors have been reported. CONCLUSIONS: Mortality among patients with rAAA and preoperative cardiac arrest is high but not prohibitive. Aortic repair should not be withheld from such patients who are otherwise reasonable candidates for intervention, provided resources for emergent aortic repair are available. PMID- 27473776 TI - Meta-analysis of posterior versus medial approach for popliteal artery aneurysm repair. AB - BACKGROUND: Popliteal artery aneurysm is an uncommon vascular disease but one that can cause significant morbidity, the most severe being limb loss reported in 20% to 59% of cases. Two approaches to repair are described in the literature, the posterior and the medial; however, the "gold standard" method of repair remains controversial. METHODS: A systematic review of electronic information sources was undertaken to identify papers comparing outcomes of posterior repair vs medial repair. The methodologic quality of the papers was assessed using the Newcastle-Ottawa Scale. Fixed-effect or random-effects models were applied to synthesize data. RESULTS: The search yielded seven articles eligible for inclusion. The total population comprised 1427 patients; 338 had posterior repair and 1089 had medial repair. There was no difference in the two groups in terms of postoperative nerve damage (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.24-4.2) and 30-day postoperative complications (OR, 0.87; 95% CI, 0.43-1.77). Limb loss at 30 days occurred more frequently in the medial approach group, but the difference was not statistically significant (risk difference [RD], 0.02; 95% CI, -0.04 to 0.00). Thirty-day primary patency was not statistically different between groups (RD, -0.01; 95% CI, -0.04 to 0.02), but the 30-day secondary patency suggested superiority of the posterior approach (RD, 0.05; 95% CI, 0.02 0.07). Long-term primary and secondary patency both favored the posterior approach (OR, 1.61 [95% CI, 1.06-2.43] and OR, 1.73 [95% CI, 0.91-3.30], respectively). Aneurysm exclusion was also superior with the posterior approach (OR, 4.20; 95% CI, 1.40-12.60). The rate of reoperation favored the posterior approach (OR, 0.26; 95% CI, 0.09-0.72). Long-term risk of limb loss favored posterior repair, but no statistically significant difference was found (OR, 0.32; 95% CI, 0.43-1.77). CONCLUSIONS: High-level comparative data comparing posterior and medial repair for popliteal artery aneurysms are not available. Within the parameters of this review, however, superiority of the posterior approach for primary and secondary patency, aneurysm exclusion, and need for reoperation was noted. High-level evidence from randomized clinical trials is required to define the relative benefits of the posterior approach over the medial approach in selected patients. PMID- 27473777 TI - The impact of vascular surgery wound complications on quality of life. AB - OBJECTIVE: In addition to traditional surgical outcomes, perioperative quality of life is being scrutinized as a patient-centric metric. As part of a prospective study in a contemporary surgical cohort, subjective health states were examined in context of postoperative wound complications (WCs). We hypothesized that WCs negatively affect quality of life. METHODS: The EuroQol (EQ)-5D subjective health state data, comprising five domains with 1 (good) to 3 (poor) ordinal scoring, plus visual analog score, were collected at the day of surgery and at 2 and 4 weeks of follow-up in a study evaluating silver-eluting dressings in 500 patients at three centers. A preference-weighted index was calculated. Groups were defined by no complication (NC) or presence of one or more postoperative WCs. RESULTS: Patients (72% male) were a mean age of 67.6 years. Primary indications included critical limb ischemia (41.4%), claudication (31.6%), and abdominal aortic aneurysm (11.2%; open groin access for endovascular aneurysm repair). At least one WC occurred in 148 patients (29.6%). Baseline demographics were similar except mean age (NC group, 67.9 years; WC group, 65.7 years; P = .042) and body mass index (NC group, 27.0 kg/m2; WC group, 28.2 kg/m2). WCs were associated with use of conduit for reconstruction (P = .002), below-knee incisions (P = .002), and incision length (P < .001). Compared with the NC group, there was a decrement in quality-of-life scores in the WC group at 2 weeks (mean change, -0.217; P = .001) but not at 4 weeks (mean change, +0.044; P = .065) postoperatively. Subgroup analysis showed quality-of-life change after WC was most significant in the claudication group (P = .008). The EQ-5D visual analog scale score was lowest in groups with rest pain (57.0) and tissue loss (55.1) and highest in the abdominal aortic aneurysm cohort (71.8). CONCLUSIONS: EQ-5D identified a significantly decreased quality-of-life score 2 weeks after WCs in a cohort undergoing elective infrainguinal arterial surgery. This effect was not present 4 weeks postoperatively. PMID- 27473778 TI - Prevention of abdominal aortic aneurysm progression by oral administration of green tea polyphenol in a rat model. AB - OBJECTIVE: Inflammation-mediated elastin destruction in the aortic medial layer is related to progression of abdominal aortic aneurysm (AAA). Epigallocatechin-3 gallate (EGCG), a major component of green tea polyphenols, reportedly increases elastin synthesis in vitro and may possess anti-inflammatory effects. We used a rat model to investigate whether EGCG could prevent AAA progression. METHODS: AAA was induced with administration of intraluminal elastase and extraluminal CaCl2 in male rats. Rats were randomly divided into a control group (n = 30) and an EGCG group (n = 30). In the EGCG group, an EGCG solution (20 mg/d) was administered orally to each rat from 2 weeks before AAA induction and continued 4 weeks beyond induction. RESULTS: The abdominal aortic diameter was significantly smaller in the EGCG group than in the control group on day 28 (2.9 +/- 0.2 vs 2.3 +/- 0.1 mm; P < .0001). The medial layer wall thickness and elastin content were significantly greater in the EGCG group than in the control group on day 28 (68.4 +/- 13.6 vs 46.7 +/- 13.4 MUm [P < .001] and 20.3 +/- 4.6 vs 9.5 +/- 3.6% [P < .0001], respectively). Gene expression levels of tropoelastin and lysyl oxidase were significantly higher in the EGCG group immediately before AAA induction, indicating promoted elastoregeneration by EGCG administration (tropoelastin: 0.59 +/- 0.36 control vs 1.24 +/- 0.36 EGCG [P < .05], lysyl oxidase: 0.77 +/- 0.45 control vs 1.34 +/- 0.4 EGCG [P < .05]) (fold increase). Gene expression levels of inflammatory cytokines, including tumor necrosis factor-alpha and interleukin 1beta, were significantly downregulated in the EGCG group (1.82 +/- 0.71 vs 0.97 +/- 0.59 [P < .05] and 3.91 +/- 3.24 vs 0.89 +/- 0.59 [P < .05], respectively). On day 7, gene expression levels and gelatinolytic activity of matrix metalloproteinase 9 were significantly lower in the EGCG group (1.41 +/- 0.86 vs 0.51 +/- 0.42 [P < .05] and 1.00 +/- 0.17 vs 0.29 +/- 0.12 [P < .0001], respectively), whereas gene expression levels of tissue inhibitors of metalloproteinase-1 were significantly higher in the EGCG group (0.96 +/- 0.11 vs 1.14 +/- 0.09; P < .05). CONCLUSIONS: EGCG attenuated AAA progression in a rat model by preserving the aortic thickness and elastin content of the medial layer through regeneration of elastin, as mediated by anti-inflammatory effects, and subsequent reduction of matrix metalloproteinase activity. PMID- 27473779 TI - Current status and future perspectives of bioresorbable stents in peripheral arterial disease. AB - BACKGROUND: Endovascular treatment of peripheral arterial disease (PAD) still yields unsatisfactory patency rates. Recent new developments include the use of bioresorbable stents. The objective of this study was to provide an overview of currently available data on the use of bioresorbable stents in lower limb PAD and to summarize the needs for future research focus. METHODS: A systematic search in the databases of MEDLINE, Embase, and the Cochrane Library was performed. Studies using predefined inclusion and exclusion criteria were included and critically appraised by two independent reviewers. Inclusion criteria were (1) original data on (2) bioresorbable stents in (3) lower limb arteries including the iliac tract. Primary end points were safety and feasibility of bioresorbable stents, including 30-day adverse events. Secondary end points included radial force, bioresorption process, long-term primary and secondary patency, and clinical outcomes, such as amputation rate, Rutherford category, and ankle-brachial index improvement. RESULTS: Seven published studies with a total of 316 patients were included, and five conference abstracts including 272 patients were assessed. Median follow-up time was 12 months. Overall technical success rate was 99% (range, 95.0%-100%). The 30-day adverse event rates were reported in 5.0% of patients (range, 0% 13.3%); these included one death, two major amputations, and seven reinterventions. Mean primary patency rate was 61.6% in the femoral arteries (range, 32.1%-80.0%) after 6 to 12 months compared with 50.3% in below-the-knee lesions (range, 31.8%-92.9%). Secondary patency rates were 91.5% (range, 84% 97.1%) and 72.1% (range, 62.9%-100%), respectively. The 1-year amputation rate was 3.0% in the whole group (range, 0%-12.4%). CONCLUSIONS: Experience with the use of bioresorbable stents in PAD is still limited and is investigated only in small studies. The use of bioresorbable stents in PAD appears to be feasible and safe. With current published results, we are unable to fully answer all of the questions about the future use of bioresorbable stents in PAD, and use should be limited to study-related cases in PAD. PMID- 27473780 TI - Genetic diversity of bats coronaviruses in the Atlantic Forest hotspot biome, Brazil. AB - Bats are notorious reservoirs of genetically-diverse and high-profile pathogens, and are playing crucial roles in the emergence and re-emergence of viruses, both in human and in animals. In this report, we identified and characterized previously unknown and diverse genetic clusters of bat coronaviruses in the Atlantic Forest Biome, Brazil. These results highlight the virus richness of bats and their possible roles in the public health. PMID- 27473781 TI - Phylogenetic and geographic patterns of bartonella host shifts among bat species. AB - The influence of factors contributing to parasite diversity in individual hosts and communities are increasingly studied, but there has been less focus on the dominant processes leading to parasite diversification. Using bartonella infections in bats as a model system, we explored the influence of three processes that can contribute to bartonella diversification and lineage formation: (1) spatial correlation in the invasion and transmission of bartonella among bats (phylogeography); (2) divergent adaptation of bartonellae to bat hosts and arthropod vectors; and (3) evolutionary codivergence between bats and bartonellae. Using a combination of global fit techniques and ancestral state reconstruction, we found that codivergence appears to be the dominant process leading to diversification of bartonella in bats, with lineages of bartonellae corresponding to separate bat suborders, superfamilies, and families. Furthermore, we estimated the rates at which bartonellae shift bat hosts across taxonomic scales (suborders, superfamilies, and families) and found that transition rates decrease with increasing taxonomic distance, providing support for a mechanism that can contribute to the observed evolutionary congruence between bats and their associated bartonellae. While bartonella diversification is associated with host sympatry, the influence of this factor is minor compared to the influence of codivergence and there is a clear indication that some bartonella lineages span multiple regions, particularly between Africa and Southeast Asia. Divergent adaptation of bartonellae to bat hosts and arthropod vectors is apparent and can dilute the overall pattern of codivergence, however its importance in the formation of Bartonella lineages in bats is small relative to codivergence. We argue that exploring all three of these processes yields a more complete understanding of bat-bartonella relationships and the evolution of the genus Bartonella, generally. Application of these methods to other infectious bacteria and viruses could uncover common processes that lead to parasite diversification and the formation of host-parasite relationships. PMID- 27473782 TI - Molecular signature of extended spectrum beta-lactamase producing Klebsiella pneumoniae isolated from bovine milk in eastern and north-eastern India. AB - The present study reports on 23 extended spectrum beta-lactamase producing Klebsiella pneumoniae (KP), isolated from milk samples (n=340) of healthy cows (n=129) and cows with subclinical (n=159) and clinical (n=52) mastitis, from three different states of India viz. West Bengal, Jharkhand and Mizoram. Seven of them were AmpC type beta-lactamase producers, as well. The ESBL producing KP were significantly (P=0.006, chi2=10.04, df=2) and more frequently detected in milk samples of mastitic cows than healthy ones. The beta-lactamase genes - blaCTX-M, blaTEM and blaSHV were detected in 19, 8 and 3 isolates, respectively. In all but one CTX-M positive isolates, the genetic platform - ISEcp1-blaCTX-M-orf477 was detected. Ten of the isolates carried plasmid mediated quinolone resistance gene qnrS and 1 isolate possessed qnrB. Again 11 of them were found to have sulfonamide resistance gene - sul1 and 12 possessed class I integron. Sequencing of the class 1 integron revealed the presence of dfrA12/dfrA17 and aadA2/aadA5 gene cassettes conferring resistance to trimethoprim and aminoglycosides, respectively. All the isolates, characterized by enterobacterial repetitive intergenic consensus (ERIC) PCR, yielded distinct fingerprinting profile. However, most of the isolates from Jharkhand were clustered along with two isolates each from West Bengal and Mizoram indicating their clonal relatedness even though isolated from geographically different areas. Isolation of ESBL producing KP from bovine milk samples implies its public health significance; as such pathogens may enter the human food chain causing severe health hazards. PMID- 27473783 TI - Spontaneous resolution of left bundle branch block and biventricular stimulation lead to reverse remodeling in dyssynchronopathy. AB - Left bundle branch block (LBBB) is considered a marker of underlying structural cardiac disease. To determine whether LBBB is cause or consequence of deterioration of left ventricular (LV) function is difficult as both are often diagnosed concomitantly. We discuss a patient where reversal of LBBB and subsequent normalization of LV function was observed after 2 different therapies, first after start of heart failure medication, and years later after implantation of a cardiac resynchronization device. This indicates that LBBB per se may result in the development of non-ischemic cardiomyopathy and that LBBB resolution can lead to reverse remodeling in dyssynchronopathy. PMID- 27473784 TI - The role of porcine reproductive and respiratory syndrome virus infection in immune phenotype and Th1/Th2 balance of dendritic cells. AB - The aim of this study was to characterize the immune response of dendritic cells derived from monocytes (Mo-DCs) in the porcine peripheral blood following infection with porcine reproductive and respiratory syndrome virus (PRRSV). Viral load assays indicated that PRRSV efficiently infected Mo-DCs but failed to replicate, whereas PRRSV infection of Mo-DCs decreased the expression of SLA-I, SLA-II, CD80 and CD40 compared with those of mock Mo-DCs. Furthermore, we analyzed the cytokine profiles using quantitative RT-PCR and ELISA. Results indicated apparent changes in IL-10 and IL-12 p40 expression but not in IFN-gamma and TNF-alpha among Mo-DCs infected with PRRSV and uninfected Mo-DCs. Additionally, flow cytometry analysis of the altered Mo-DCs together with IL-4 and GM-CSF induction for 7days revealed the typical morphology and phenotype with 91.73% purity before infection with PRRSV. Overall, our data demonstrate that PRRSV impaired the normal antigen presentation of Mo-DCs and led to inadequate adaptive immune response by down-regulating the expression of SLA-I,SLA-II, CD80 and CD40. Enhanced Th2 -type cytokine IL-10 secretion and reduced Th1-type cytokines IL-12p40,IFN-gamma and TNF-alpha secretion results in Th1/Th2 imbalance. PMID- 27473785 TI - Hyperglycemia Induces Bioenergetic Changes in Adipose-Derived Stromal Cells While Their Pericytic Function Is Retained. AB - Diabetic retinopathy (DR) is a hyperglycemia (HG)-mediated microvascular complication. In DR, the loss of pericytes and subsequently endothelial cells leads to pathologic angiogenesis in retina. Adipose-derived stromal cells (ASC) are a promising source of therapeutic cells to replace lost pericytes in DR. To date, knowledge of the influence of HG on the bioenergetics and pericytic function of ASC is negligible. Human ASC were cultured in normoglycemia medium (5 mM d-glucose) or under HG (30 mM d-glucose) and assessed. Our data showed that HG increased the level of apoptosis and reactive oxygen species production in ASC, yet their proliferation rate was not affected. HG induced alterations in mitochondrial function and morphology in ASC. HG also strongly affected the bioenergetic status of ASC in which both the maximum oxygen consumption rate and extracellular acidification rate were decreased. This was corroborated by a reduced uptake of glucose under HG. In spite of these observations, in vitro, ASC promoted the formation of vascular-like networks of human umbilical vein endothelial cells on monolayers of ASC under HG with minimally affected. PMID- 27473787 TI - [Pathological advances in renal, prostatic, bladder and testis neoplasia]. AB - INTRODUCTION: The ISUP (International Society of Urological Pathology) Consensus Conferences between 2012 and 2015 made recommendations regarding the classification, staging, prognostic factors of adult tumors from kidney, prostate, bladder and testis. The main points of these recommendations are highlighted in this article. MATERIALS AND METHODS: This article is based on a systematic literature search by using different keywords "cancer, kidney, prostate, bladder, testis, pathology, classification" from Pubmed database. Only publications between 2012 and 2015 were retained. RESULTS: The different Consensus conferences since 2012 in uropathology have provided international guidelines for the classification, grading and staging of tumors in kidney, bladder, prostate and testis. We identified in this article the main points of these new guidelines that are about to be published in the new 2016 WHO classification of urogenital tract tumors in adult. CONCLUSION: New pathological guidelines in urogenital tumors have to be taken into account for a better diagnosis and therapy. PMID- 27473786 TI - [Cancer genetic screening for patient with multiple renal tumors: What is the current practice for what results?]. AB - AIM: To evaluate in a high volume center the practice and the performance of cancer genetic screening for patients with multiple renal tumors without a predisposition to kidney tumors known at the time of surgery. METHOD: All patients treated for multiple renal tumors from January 2000 to December 2013 in our center were included. Patients with a family history of renal cell carcinoma, a kidney disease or a genetic predisposition to renal cancer known at the time of surgery were excluded from the analysis. Our list of patients was retrospectively compared to the records from PREDIR (PREDisposition to Kidney Tumors) center of Ile-de-France, which regionally centralizes the care of patients with kidney tumors associated with a genetic predisposition. RESULTS: One hundred and thirty six patients were included. Twenty-six patients of 136 (19%) were referred to PREDIR center: 23 followed the screening and 3 did not show up in consultation. Of the 23 patients screened, three genetic predispositions to kidney tumors were identified (13%). Of the 95 patients with synchronous tumors, 48% with more than 3 tumors benefited from cancer genetics investigation against 13% of those presenting only two tumors. CONCLUSION: Our study shows that cancer genetic investigations are not routinely offered to patients with multiple kidney tumors, conversely to existing guidelines. Urologists must be aware of this screening. LEVEL OF EVIDENCE: 4. PMID- 27473788 TI - [Rigid cystoscopy versus retrovision for adjustable peri-urethral balloons guidance: Comparison of precision thanks to a surgical navigation system]. AB - OBJECTIVES: The main goal of our phantom study was to compare the precision of adjustable periurethral balloons positioning depending whether the guidance was obtained by retrovision or rigid cystoscopy. MATERIAL AND METHODS: A navigation guidance system was used to localize the introduction mandrel which was equipped with tracking targets. Two ideal sites of implantation were predefined and recorded into the navigation system. The two points were placed symmetrically to the phantom reproducing the urethra. Four different users were asked to position the tip of the introduction mandrel as close as possible to the ideal site of implantation with the help of each method of guidance. For each attempt, the distance (mm) between the tip of the introduction mandrel and the ideal position was recorded by the navigation system. RESULTS: For each method of guidance, a total of 20 attempts on each side were made by direct puncture on one side and a symmetrical contralateral puncture. For direct puncture, the median distances were 5.20 (+/-3.96) and 4.38 (+/-1.55) mm with rigid cystoscopy and retrovision respectively (P=0.29). For symmetrical contralateral puncture, the median distance were 7,19 (+/-3,78) and 6,86 (+/-2,76) mm with rigid cystoscopy and retrovision respectively (P=0,32) CONCLUSION: This study could not demonstrate any significant difference between the two guidance systems. Nevertheless, it showed that navigation guidance system could be used to compare the precision of surgical interventions. LEVEL OF EVIDENCE: 4. PMID- 27473789 TI - Cell fusion and nuclear fusion in plants. AB - Eukaryotic cells are surrounded by a plasma membrane and have a large nucleus containing the genomic DNA, which is enclosed by a nuclear envelope consisting of the outer and inner nuclear membranes. Although these membranes maintain the identity of cells, they sometimes fuse to each other, such as to produce a zygote during sexual reproduction or to give rise to other characteristically polyploid tissues. Recent studies have demonstrated that the mechanisms of plasma membrane or nuclear membrane fusion in plants are shared to some extent with those of yeasts and animals, despite the unique features of plant cells including thick cell walls and intercellular connections. Here, we summarize the key factors in the fusion of these membranes during plant reproduction, and also focus on "non gametic cell fusion," which was thought to be rare in plant tissue, in which each cell is separated by a cell wall. PMID- 27473790 TI - Reply to Letter to the Editor - Targeted Treatments for Pulmonary Arterial Hypertension: Interpreting Outcomes by Network Meta-Analysis. PMID- 27473791 TI - Cow's milk allergy guidelines: a quality appraisal with the AGREE II instrument. AB - BACKGROUND: The appropriate diagnosis and management of cow's milk allergy (CMA) is challenging. OBJECTIVE: To systematically review the quality of the existing guidelines on CMA. METHODS: The Cochrane Library, MEDLINE, and EMBASE databases were searched from 2010 to November 2015. The methodological rigour, quality, and transparency of relevant guidelines were assessed with the use of the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. RESULTS: Of the 15 included guidelines, two, both developed by recognized scientific organizations, achieved the highest score (100%). Eight others were considered to be of high quality (i.e., overall quality scores >60%). The quality scores for each domain varied. Of all the domains, clarity and presentation had the highest mean score, and applicability had the lowest mean score. The scores (mean +/- SD) for individual domains were as follows: domain 1 (score and purpose) 62 +/- 36%; domain 2 (stakeholder involvement) 56 +/- 33%; domain 3 (rigor of development) 55 +/- 38%; domain 4 (clarity of presentation) 71 +/- 29%; domain 5 (applicability) 44 +/- 33%; and domain 6 (editorial independence) 60 +/- 36%. One guideline had the maximum possible score of 100% for all AGREE II domains. CONCLUSION AND CLINICAL RELEVANCE: A number of guidelines on CMA are available; however, their quality varies. Overall, the guidelines developed by recognized professional/scientific organizations were of the highest quality. These guidelines should be recommended for use. Still, the methodological quality of CMA guidelines may be improved. PMID- 27473792 TI - Use of anti-vascular endothelial growth factor in the management of pterygium. AB - The rising success of anti-vascular endothelial growth factor (VEGF) therapies in ocular disease has stimulated the use of such treatments in the surgical management of pterygium. We reviewed the literature to better understand the safety and efficacy of the adjunctive role of anti-VEGF treatments for pterygium excision. Without surgery, anti-VEGF alone may favourably alter symptoms and vascularity, but does not cause pterygium regression. Some evidence supports the use of anti-VEGF as an adjuvant therapy to surgery, especially when using a higher dose and a more frequent dosing regimen. Overall, anti-VEGF is generally safe and well tolerated in patients with pterygium. Currently, the evidence does not conclusively support the use of anti-VEGF in pterygium surgery. However, further research may guide unanswered questions regarding the interaction between VEGF and other factors responsible for pterygium growth. In addition, the optimal route and dosage of anti-VEGF administration is not yet known. PMID- 27473793 TI - A History of Bariatric Surgery: The Maturation of a Medical Discipline. AB - This article examines the progression of bariatric surgery since its creation more than 60 years ago with a focus on the effect of surgery on weight loss, comorbidity reduction, and safety. The success has been remarkable. It is possible to cure severe obesity, type 2 diabetes, and hyperlipidemia in addition to the many other manifestations of the metabolic syndrome with remarkable safety. Equally important are the opportunities for research afforded by the surgery and its outcomes. Until better treatments become available, bariatric surgery is the therapy of choice for patients with morbid obesity for weight control and comorbidity improvement. PMID- 27473794 TI - The Socioeconomic Impact of Morbid Obesity and Factors Affecting Access to Obesity Surgery. AB - Bariatric surgery has been shown in many studies to be the most effective long term treatment for severe obesity and obesity-related comorbidities. Economic analysis has demonstrated cost-effectiveness as well as cost-savings in select subgroups of patients. Despite the health and economic benefits of bariatric surgery, relatively few eligible patients receive this treatment. This disparity in access to care must be addressed by health policy decision-makers. PMID- 27473795 TI - Obesity, Type 2 Diabetes, and the Metabolic Syndrome: Pathophysiologic Relationships and Guidelines for Surgical Intervention. AB - Several gastrointestinal (GI) operations originally developed for the treatment of severe obesity (bariatric surgery) promote sustained weight loss as well as dramatic, durable improvements of insulin-resistant states, most notably type 2 diabetes mellitus (T2DM). Experimental evidence shows that some rearrangements of GI anatomy can directly affect glucose homeostasis, insulin sensitivity, and inflammation, supporting the idea that the GI tract is a biologically rational target for interventions aimed at correcting pathophysiologic aspects of cardiometabolic disorders. This article reviews the pathophysiology of metabolic disease and the role of bariatric/metabolic surgery in current clinical guidelines for the treatment of obesity and T2DM. PMID- 27473796 TI - The Effects of Metabolic Surgery on Fatty Liver Disease and Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is an under-recognized but increasingly important manifestation of the metabolic syndrome. Bariatric surgery, both through direct weight loss and more indirect effects on insulin resistance and improvements in inflammatory proteins, can have a profound effect on NAFLD, resulting in improvement or resolution of even high-grade liver disease. PMID- 27473797 TI - Resolution of Comorbidities and Impact on Longevity Following Bariatric and Metabolic Surgery. AB - Bariatric surgery is the most effective and durable treatment of severe obesity. In addition to weight loss, these operations result in significant improvement or resolution of many obesity-related comorbid diseases. There are now numerous studies demonstrating that bariatric surgery decreases all-cause mortality long term compared with cohorts of patients who did not undergo surgery. Decreases in cancer, diabetes, and cardiovascular-related mortality are major contributors to this overall effect on life expectancy after bariatric surgery. PMID- 27473798 TI - Patient Safety and Quality Improvement Initiatives in Contemporary Metabolic and Bariatric Surgical Practice. AB - Patient safety and quality improvement have been part of bariatric surgery since its inception, and there have been significant improvements in outcomes of bariatric surgery over the past 2 decades. A strong accreditation program exists. This program defines 2 tiers of accredited centers: low-acuity and comprehensive centers similar to the trauma systems. Accreditation has been shown to have a favorable impact on outcomes of bariatric surgery. Bariatric surgery lends itself well to improvements in processes and use of perioperative protocols, such as ulcer and thromboembolic prophylaxis prevention or gallstone prevention and management. PMID- 27473800 TI - Laparoscopic Sleeve Gastrectomy: Surgical Technique and Perioperative Care. AB - Laparoscopic sleeve gastrectomy is a bariatric surgical procedure created for long-term weight loss and improvement of metabolic syndrome abnormalities in morbidly obese patients. It has been shown to demonstrate durable results compared with other bariatric procedures. This article aims to describe the surgical technique and perioperative care for patients undergoing laparoscopic sleeve gastrectomy based on current scientific literature and best standard practices. PMID- 27473799 TI - Patient Selection and Surgical Management of High-Risk Patients with Morbid Obesity. AB - Bariatric surgery is the most effective way to improve comorbidities related to obesity. Since the introduction of minimally invasive laparoscopic surgery in the bariatric surgery techniques, the number of procedures has increased substantially; advances in techniques and the transition from open to minimally invasive procedures have decreased morbidity and mortality. Multidisciplinary teams in charge of the operative planning, surgical act, and postoperative recovery are determinant in the success of the management of high-risk bariatric patients; careful identification and preoperative management of these higher-risk patients is crucial in decreasing complications after weight loss surgery. PMID- 27473801 TI - Laparoscopic Roux-en-Y Gastric Bypass: Surgical Technique and Perioperative Care. AB - Obesity is a global epidemic with multiple associated comorbid conditions. The laparoscopic Roux-en-Y gastric bypass is the gold standard operation in the fight against obesity. This review outlines the common technical aspects of the procedure, as well as the evidence based recommendations for preoperative and postoperative care. PMID- 27473802 TI - Update on Treatment of Morbid Obesity with Adjustable Gastric Banding. AB - Laparoscopic adjustable gastric banding (LAGB) is considered the simplest of the bariatric operations. Although studies have confirmed the effectiveness of the LAGB in terms of weight loss and resolution of comorbidities, concerns have developed over its long-term efficacy and safety. Reports have described a high incidence of complications and need for reintervention. These reports and the availability of other effective and well-tolerated procedures have determined a significant decrease in the number of LAGBs performed. This article reviews key historic milestones, fundamental changes in the design and technique, and potential reasons that determined a quick rise and a progressive fall of LAGB's popularity. PMID- 27473803 TI - Biliopancreatic Diversion with Duodenal Switch: Surgical Technique and Perioperative Care. AB - The goal of this article is to present an overview of selection criteria, surgical technique, and perioperative outcomes of biliopancreatic diversion with duodenal switch. The standard follow-up requirements, including vitamin supplementation, and long-term risks associated with metabolic surgery are also discussed. Most of the data reported here are based on the authors' experience with 4000 biliopancreatic diversions with duodenal switch performed in their institution since 1990. PMID- 27473804 TI - Revisional Bariatric Surgery. AB - Revisional bariatric procedures are increasingly common. With more primary procedures being performed to manage severe obesity and its complications, 5% to 8% of these procedures will fail, requiring revisional operation. Reasons for revisional bariatric surgery are either primary inadequate weight loss, defined as less than 25% excess body weight loss, or weight recidivism, defined as a gain of more than 10 kg based on the nadir weight; however, each procedure also has inherit specific complications that can also be indications for revision. This article reviews the history of each primary bariatric procedure, indications for revision, surgical options, and subsequent outcomes. PMID- 27473805 TI - Management and Prevention of Surgical and Nutritional Complications After Bariatric Surgery. AB - Bariatric surgery is well-recognized for its effects on health, beyond weight loss. It underwent a revolution recently with the growing performance of laparoscopic procedures, leading to enhanced recovery and a reduction in procedural risk. However, surgical complications, although rare, do develop. It is important to recognize the complications, and ideally prevent them from happening. This article reviews the risks of the four most commonly performed bariatric procedures, with an emphasis on technique and management in the intraoperative and postoperative period. The nutritional aspect of bariatric surgery is of the utmost importance, because catastrophic consequences have been linked to malnutrition and vitamin deficiencies. PMID- 27473806 TI - Novel Endoscopic and Surgical Techniques for Treatment of Morbid Obesity: A Glimpse into the Future. AB - The burden of obesity and weight-related comorbid disease is significant. Existing laparoscopic techniques show excellent efficacy and safety. New endoscopic and laparoscopic procedures offer different approaches, as primary and revisional techniques, to treat obesity and associated metabolic disease. PMID- 27473807 TI - Body Contouring Surgery in the Massive Weight Loss Patient. AB - Plastic surgeons subspecializing in body contouring are meeting the challenge of postbariatric surgery massive weight loss patients. With an appreciation of the magnitude of the surface deformity, and altered metabolism, nutrition, and psychological makeup of these patients, innovative plastic surgeons have forged an organized approach to preparation, operative technique, and postoperative care. Patients at greatest risk for complications are identified, appraised, and either their condition improved or they are counselled to reduce expectations. Beyond the removal of excess skin and adipose tissue, advanced gender-specific techniques have improved aesthetics. PMID- 27473808 TI - Foreword. PMID- 27473809 TI - Obesity-The Epidemic Crisis of Our Time. PMID- 27473810 TI - Bloodless medicine: current strategies and emerging treatment paradigms. AB - BACKGROUND: Advances in our understanding of the risks associated with allogeneic blood transfusions (ABTs) and the growing number of patients who wish to avoid ABTs have led to the emergence of new treatment paradigms for "bloodless" medicine and surgery. STUDY DESIGN AND METHODS: Here, we review prior studies and summarize current strategies for bloodless care used at our institution. We advocate three basic principles: 1) diagnosing and aggressively treating anemia, 2) minimizing blood loss from laboratory testing and invasive procedures, and 3) identifying and managing bleeding diatheses. Anemia is treated with erythropoiesis-stimulating agents as well as iron, folate, and B12 when indicated. Low-volume phlebotomy tubes are used for laboratory testing. Autologous blood salvage is used for childbirth and surgical patients who have the potential for substantial bleeding. RESULTS: Although there have been few retrospective studies and no prospective studies to guide management, prior studies suggest that outcomes for surgical patients managed without ABTs are comparable to those of historic controls. CONCLUSIONS: Given the emerging evidence that patients who avoid ABTs do as well if not better than patients who accept ABTs, further efforts are needed to determine whether all patients could benefit from bloodless strategies. Bloodless approaches in selected patients could reduce risks, improve outcomes, and decrease costs for all patients. PMID- 27473811 TI - Common Iliac Aneurysm 30 Years After Open Abdominal Aortic Aneurysm Repair. PMID- 27473812 TI - How to Engage in Trainee-led Multicentre Collaborative Vascular Research: The Vascular and Endovascular Research Network (VERN). PMID- 27473813 TI - Patterns and Timing of Failure for Diffuse Large B-Cell Lymphoma After Initial Therapy in a Cohort Who Underwent Autologous Bone Marrow Transplantation for Relapse. AB - PURPOSE: To evaluate the location and timing of initial recurrence in patients with diffuse large B-cell lymphoma (DLBCL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplant (HDC/ASCT), to direct approaches for disease surveillance, elucidate the patterns of failure of contemporary treatment strategies, and guide adjuvant treatment decisions. METHODS AND MATERIALS: We analyzed consecutive patients with DLBCL who underwent HDC/ASCT between May 1992 and March 2014 at our institution. Of the 187 evaluable patients, 8 had incomplete data, and 79 underwent HDC/ASCT as a component of initial treatment for de novo or refractory DLBCL and were excluded from further analysis. RESULTS: The median age was 50.8 years; the median time to relapse was 1.3 years. Patients were segregated according to the initial stage at diagnosis, with early stage (ES) defined as stage I/II and advanced stage (AS) defined as stage III/IV. In total, 40.4% of the ES and 75.5% of the AS patients relapsed in sites of initial disease; 68.4% of those with ES disease and 75.0% of those with AS disease relapsed in sites of initial disease only. Extranodal relapses were common (44.7% in ES and 35.9% in AS) and occurred in a variety of organs, although gastrointestinal tract/liver (n=12) was most frequent. CONCLUSIONS: Most patients with DLBCL who relapse and subsequently undergo HDC/ASCT initially recur in the previously involved disease site(s). Time to recurrence is brief, suggesting that frequency of screening is most justifiably greatest in the early posttherapy years. (c) 2016 Elsevier Inc. PMID- 27473814 TI - The Pattern of Use of Hypofractionated Radiation Therapy for Early-Stage Breast Cancer in New South Wales, Australia, 2008 to 2012. AB - PURPOSE: Increasing phase 3 evidence has been published about the safety and efficacy of hypofractionated radiation therapy, in comparison with standard fractionation, in early-stage, node-negative breast cancer. However, uptake of hypofractionation has not been universal. The aim of this study was to investigate the hypofractionation regimen variations in practice across public radiation oncology facilities in New South Wales (NSW). METHODS AND MATERIALS: Patients with early breast cancer registered in the NSW Clinical Cancer Registry who received radiation therapy for early-stage breast cancer in a publicly funded radiation therapy department between 2008 and 2012 were identified. Data extracted and analyzed included dose and fractionation type, patient age at first fraction, address (for geocoding), year of diagnosis, year of treatment, laterality, and department of treatment. A logistic regression model was used to identify factors associated with fractionation type. RESULTS: Of the 5880 patients fulfilling the study criteria, 3209 patients (55%) received standard fractionation and 2671 patients (45%) received hypofractionation. Overall, the use of hypofractionation increased from 37% in 2008 to 48% in 2012 (range, 7%-94% across departments). Treatment facility and the radiation oncologist prescribing the treatment were the strongest independent predictors of hypofractionation. Weaker associations were also found for age, tumor site laterality, year of treatment, and distance to facility. CONCLUSIONS: Hypofractionated regimens of whole breast radiation therapy have been variably administered in the adjuvant setting in NSW despite the publication of long-term trial results and consensus guidelines. Some factors that predict the use of hypofractionation are not based on guideline recommendations, including lower rates of left-sided treatment and increasing distance from a treatment facility. PMID- 27473815 TI - Phase 1 Study of Preoperative Chemoradiation Therapy With Temozolomide and Capecitabine in Patients With Locally Advanced Rectal Cancer. AB - PURPOSE: Preoperative chemoradiation therapy (CRT) with capecitabine is a standard treatment strategy in patients with locally advanced rectal cancer (LARC). Temozolomide improves the survival of patients with glioblastoma with hypermethylated O(6)-methylguanine DNA methyltransferase (MGMT); MGMT hypermethylation is one of the colorectal carcinogenesis pathways. We aimed to determine the dose-limiting toxicity (DLT) and recommended dose (RD) of temolozomide in combination with capecitabine-based preoperative CRT for LARC. METHODS AND MATERIALS: Radiation therapy was delivered with 45 Gy/25 daily fractions with coned-down boost of 5.4 Gy/3 fractions. Concurrent chemotherapy comprised fixed and escalated doses of capecitabine and temozolomide, respectively. The MGMT hypermethylation was evaluated in pretreatment tumor samples. This trial is registered with ClinicalTrials.gov with the number NCT01781403. RESULTS: Twenty-two patients with LARC of cT3-4N0 or cTanyN1-2 were accrued. Dose level 3 was chosen as the RD because DLT was noticeably absent in 10 patients treated up to dose level 3. An additional 12 patients were recruited in this group. Grade III adverse events were noted, and pathologic complete response (pCR) was observed in 7 patients (31.8%); MGMT hypermethylation was detected in 16. The pCR rate was 37.5% and 16.7% in the hypermethylated and unmethylated MGMT groups, respectively (P=.616). CONCLUSIONS: There was a tendency toward higher pCR rates in patients with hypermethylated MGMT. Future randomized studies are therefore warranted. PMID- 27473816 TI - Predictors of Dysgeusia in Patients With Oropharyngeal Cancer Treated With Chemotherapy and Intensity Modulated Radiation Therapy. AB - OBJECTIVE(S): Dysgeusia is a significant factor reducing quality of life and worsening dysphagia in patients receiving chemoradiation therapy for head and neck cancer. The factors affecting dysgeusia severity are uncertain. We investigated the effects on patient-reported dysgeusia of doses to the oral cavity, salivary output (required to dissolve food particles), and patient reported xerostomia. METHODS AND MATERIALS: Seventy-three patients with stage III to IV oropharyngeal cancer (OPC) (N=73) receiving definitive intensity modulated radiation therapy concurrently with chemotherapy participated in a prospective, longitudinal study of quality of life (QOL), including assessment of patient reported gustatory function by taste-related questions from the Head and Neck QOL instrument (HNQOL) and the University of Washington Head and Neck-related QOL instrument (UWQOL), before therapy and periodically after treatment. At these intervals, patients also completed a validated xerostomia-specific questionnaire (XQ) and underwent unstimulated and stimulated major salivary gland flow rate measurements. RESULTS: At 1, 3, 6, and 12 months after treatment, dysgeusia improved over time: severe dysgeusia was reported by 50%, 40%, 22%, and 23% of patients, respectively. Significant associations were found between patient reported severe dysgeusia and radiation dose to the oral cavity (P=.005) and tongue (P=.019); normal tissue complication probability for severe dysgeusia at 3 months showed mean oral cavity D50 doses 53 Gy and 57 Gy in the HNQOL and WUQOL questionnaires, respectively, with curve slope (m) of 0.41. Measured salivary output was not statistically significantly correlated with severe taste dysfunction, whereas patient-reported XQ summary scores and xerostomia while eating scores were correlated with severe dysgeusia in the UWQOL tool (P=.04). CONCLUSIONS: Taste impairment is significantly correlated with mean radiation dose to the oral cavity. Patient-reported xerostomia, but not salivary output, was correlated with severe dysgeusia in 1 of the 2 QOL questionnaires. Reduction in oral cavity doses is likely to improve dysgeusia. PMID- 27473817 TI - Geographic Disparity in the Use of Hypofractionated Radiation Therapy Among Elderly Women Undergoing Breast Conservation for Invasive Breast Cancer. AB - PURPOSE: To evaluate geographic heterogeneity in the delivery of hypofractionated radiation therapy (RT) for breast cancer among Medicare beneficiaries across the United States. METHODS AND MATERIALS: We identified 190,193 patients from the Centers for Medicare and Medicaid Services Chronic Conditions Warehouse. The study included patients aged >65 years diagnosed with invasive breast cancer treated with breast conservation surgery followed by radiation diagnosed between 2000 and 2012. We analyzed data by hospital referral region based on patient residency ZIP code. The proportion of women who received hypofractionated RT within each region was analyzed over the study period. Multivariable logistic regression models identified predictors of hypofractionated RT. RESULTS: Over the entire study period we found substantial geographic heterogeneity in the use of hypofractionated RT. The proportion of women receiving hypofractionated breast RT in individual hospital referral regions varied from 0% to 61%. We found no correlation between the use of hypofractionated RT and urban/rural setting or general geographic region. The proportion of hypofractionated RT increased in regions with higher density of radiation oncologists, as well as lower total Medicare reimbursements. CONCLUSIONS: This study demonstrates substantial geographic heterogeneity in the use of hypofractionated RT among elderly women with invasive breast cancer treated with lumpectomy in the United States. This heterogeneity persists despite clinical data from multiple randomized trials proving efficacy and safety compared with standard fractionation, and highlights possible inefficiency in health care delivery. PMID- 27473818 TI - Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma. AB - PURPOSE: To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma. METHODS AND MATERIALS: After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT. RESULTS: Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P=.01). There was also a trend toward inferior local control with MYCN amplified tumors or serum lactate dehydrogenase >=1500 U/L (P=.09 and P=.06, respectively). CONCLUSION: After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR. PMID- 27473820 TI - Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. AB - The Janus kinase (JAK) family of non-receptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase-2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that regulates the adjacent protein kinase domain (JH1). JAK1/2 and TYK2 are ubiquitously expressed whereas JAK3 is found predominantly in hematopoietic cells. The Janus kinase family is regulated by numerous cytokines including interleukins, interferons, and hormones such as erythropoietin, thrombopoietin, and growth hormone. Ligand binding to cytokine and hormone receptors leads to the activation of associated Janus kinases, which then mediate the phosphorylation of the receptors. The SH2 domain of STATs (signal transducers and activators of transcription) binds to the receptor phosphotyrosines thereby promoting STAT phosphorylation by the Janus kinases and consequent activation. STAT dimers are translocated to the nucleus where they participate in the regulation of the expression of thousands of proteins. JAK-STAT dysregulation results in autoimmune disorders such as rheumatoid arthritis, ulcerative colitis, and Crohn disease. JAK-STAT dysregulation also plays a role in the pathogenesis of myelofibrosis, polycythemia vera, and other myeloproliferative illnesses. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and in a lower percentage of people with other neoplasms. JAK1/3 signaling participates in the pathogenesis of inflammatory afflictions while JAK1/2 signaling participates in the development of several malignancies including leukemias and lymphomas as well as myeloproliferative neoplasms. Tofacitinib is a pan-JAK inhibitor that is approved by the FDA for the treatment of rheumatoid arthritis and ruxolitinib is a JAK1/2 inhibitor that is approved for the treatment of polycythemia vera and myelofibrosis. PMID- 27473819 TI - Strawberry tannins inhibit IL-8 secretion in a cell model of gastric inflammation. AB - In the present study we chemically profiled tannin-enriched extracts from strawberries and tested their biological properties in a cell model of gastric inflammation. The chemical and biological features of strawberry tannins after in vitro simulated gastric digestion were investigated as well. The anti inflammatory activities of pure strawberry tannins were assayed to get mechanistic insights. Tannin-enriched extracts from strawberries inhibit IL-8 secretion in TNFalpha-treated human gastric epithelial cells by dampening the NF kappaB signaling. In vitro simulated gastric digestion slightly affected the chemical composition and the biological properties of strawberry tannins. By using pure compounds, we found that casuarictin may act as a pure NF-kappaB inhibitor while agrimoniin inhibits IL-8 secretion also acting on other biological targets; in our system procyanidin B1 prevents the TNFalpha-induced effects without interfering with the NF-kappaB pathway. We conclude that strawberry tannins, even after in vitro simulated gastric digestion, exert anti inflammatory activities at nutritionally relevant concentrations. PMID- 27473821 TI - Histamine prevents radiation-induced mesenchymal changes in breast cancer cells. AB - Radiotherapy is a prime option for treatment of solid tumors including breast cancer though side effects are usually present. Experimental evidence shows an increase in invasiveness of several neoplastic cell types through conventional tumor irradiation. The induction of epithelial to mesenchymal transition is proposed as an underlying cause of metastasis triggered by gamma irradiation. Experiments were conducted to investigate the role of histamine on the ionizing radiation-induced epithelial to mesenchymal transition events in breast cancer cells with different invasive phenotype. We also evaluated the potential involvement of Src phosphorylation in the migratory capability of irradiated cells upon histamine treatment. MCF-7 and MDA-MB-231 mammary tumor cells were exposed to a single dose of 2Gy of gamma radiation and five days after irradiation mesenchymal-like phenotypic changes were observed by optical microscope. The expression and subcellular localization of E-cadherin, beta catenin, vimentin and Slug were determined by immunoblot and indirect immunofluorescence. There was a decrease in the epithelial marker E-cadherin expression and an increase in the mesenchymal marker vimentin after irradiation. E-cadherin and beta-catenin were mainly localized in cytoplasm. Slug positive nuclei, matrix metalloproteinase-2 activity and cell migration and invasion were significantly increased. In addition, a significant enhancement in Src phosphorylation/activation could be determined by immunoblot in irradiated cells. MCF-7 and MDA-MB-231 cells also received 1 or 20MUM histamine during 24h previous to be irradiated. Notably, pre-treatment of breast cancer cells with 20MUM histamine prevented the mesenchymal changes induced by ionizing radiation and also reduced the migratory behavior of irradiated cells decreasing phospho-Src levels. Collectively, our results suggest that histamine may block events related to epithelial to mesenchymal transition in irradiated mammary cancer cells and open a perspective for the potential use of histamine to improve radiotherapy efficacy. PMID- 27473822 TI - Synthesis and evaluation of new steroidal lactam conjugates with aniline mustards as potential antileukemic therapeutics. AB - Alkylating agents are still nowadays one of the most important classes of cytotoxic drugs, which display a wide range of therapeutic use for the treatment of various cancers. We have synthesized and tested four hybrid homo-azasteroidal alkylating esters for antileukemic activity against five sensitive to alkylating agents human leukemia cell lines in vitro and against P388 murine leukemia in vivo. Comparatively, melphalan and 3-(4-(bis(2 chloroethyl)amino)phenoxy)propanoic acid (POPAM) were also examined. All the homo aza-steroidal alkylators showed relatively lower acute toxicity, very promising and antileukemic activity both in vitro and in vivo. PMID- 27473823 TI - P144, a Transforming Growth Factor beta inhibitor peptide, generates antitumoral effects and modifies SMAD7 and SKI levels in human glioblastoma cell lines. AB - Glioblastoma (GBM) is the most prevalent malignant primary brain tumor, accounting for 60-70% of all gliomas. Current median patient survival time is 14 16 months after diagnosis. Numerous efforts in therapy have not significantly altered the nearly uniform lethality of this malignancy. The Transforming Growth Factor beta (TGF-beta) signaling pathway plays a key role in GBM and is implicated in proliferation, invasion and therapy resistance. Several inhibitors of the TGF-beta pathway have entered clinical trials or are under development. In this work, the therapeutic potential of P144, a TGF-beta inhibitor peptide, was analyzed. P144 decreased proliferation, migration, invasiveness, and tumorigenicity in vitro, whereas apoptosis and anoikis were significantly increased for GBM cell lines. SMAD2 phosphorylation was reduced, together with a downregulation of SKI and an upregulation of SMAD7 at both transcriptional and translational levels. Additionally, P144 was able to impair tumor growth and increase survival in an in vivo flank model. Our findings suggest a potential effect of P144 in vitro and in vivo that is mediated by regulation of transcriptional target genes of the TGF-beta pathway, suggesting a therapeutic potential of P144 for GBM treatment. PMID- 27473825 TI - Regulation of RNA polymerase II-mediated transcriptional elongation: Implications in human disease. AB - Expression of protein-coding genes is primarily regulated at the level of transcription. Most of the earlier studies focussed on understanding the assembly of the pre-initiation complex at the promoter of genes and subsequent initiation of transcription as the regulatory steps in transcription. However, research over the last decade has demonstrated the significance of regulating transcription of genes at the elongation stage. Several new proteins have been identified that control this step and our knowledge about their functions is expanding rapidly. Moreover, an increasing body of evidence suggests that a dysfunction of these transcription elongation factors is related to several diseases. Here, we review the latest advances in our understanding about the in vivo roles of the transcription elongation factors and their link with diseases. (c) 2016 IUBMB Life, 68(9):709-716, 2016. PMID- 27473824 TI - Dual targeting and enhanced cytotoxicity to HER2-overexpressing tumors by immunoapoptotin-armored mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are promising vehicles for the delivery of anticancer agents in cancer therapy. However, the tumor targeting of loaded therapeutics is essential. Here, we explored a dual-targeting strategy to incorporate tumor-tropic MSC delivery with HER2-specific killing by the immunoapoptotin e23sFv-Fdt-tBid generated in our previous studies. The MSC engineering allowed simultaneous immunoapoptotin secretion and bioluminescence detection of the modified MSCs. Systemic administration of the immunoapoptotin engineered MSCs was investigated in human HER2-reconstituted syngeneic mouse models of orthotopic and metastatic breast cancer, as well as in a xenograft nude mouse model of orthotopic gastric cancer. In vivo dual tumor targeting was confirmed by local accumulation of the bioluminescence-imaged MSCs and persistence of His-immunostained immunoapoptotins in tumor sites. The added tumor preference of MSC-secreted immunoapoptotins resulted in a significantly stronger antitumor effect compared with purified immunoapoptotins and Jurkat-delivered immunoapoptotins. This immunoapoptotin-armored MSC strategy provides a rationale for its use in extended malignancies by combining MSC mobility with redirected immunoapoptotins against a given tumor antigen. PMID- 27473826 TI - Quantification of 10 elements in human cerebrospinal fluid from chronic pain patients with and without spinal cord stimulation. AB - Neuropathic pain affects 1-10% of the general population and is caused by a lesion or disease of the somatosensory nervous system. Spinal cord stimulation (SCS), a method where implanted electrodes stimulate the spinal cord, has been successfully used to treat drug-resistant neuropathic pain, but the mechanism of action is largely unknown. Studies show that SCS changes the protein levels in CSF (cerebrospinal fluid) of pain patients. Several neurological conditions have been shown to alter the elemental composition of CSF. Therefore changes in the levels of ions and trace elements in the CSF may correspond to SCS use. This study used ICP-MS (Inductively coupled plasma mass spectrometry) and ICP-AES (Inductively coupled plasma atomic emission spectroscopy) to quantify 10 elements in CSF from chronic neuropathic pain patients using SCS. The element concentrations in CSF from patients with SCS treatment on/off, were measured. No effect on the element concentrations in CSF from treatment with SCS could be detected. Also, the elemental concentrations in pooled CSF from patients without chronic neuropathic pain was determined and compared to the patients using SCS. The concentration of the elements Ca, Sr, Na, K, P, Mg and Ti were, significantly higher in patients compared to the CSF-control. PMID- 27473827 TI - The relationship between mercury and autism: A comprehensive review and discussion. AB - The brain pathology in autism spectrum disorders (ASD) indicates marked and ongoing inflammatory reactivity with concomitant neuronal damage. These findings are suggestive of neuronal insult as a result of external factors, rather than some type of developmental mishap. Various xenobiotics have been suggested as possible causes of this pathology. In a recent review, the top ten environmental compounds suspected of causing autism and learning disabilities were listed and they included: lead, methyl-mercury, polychorinated biphenyls, organophosphate pesticides, organochlorine pesticides, endocrine disruptors, automotive exhaust, polycyclic aromatic hydrocarbons, polybrominated diphenyl ethers, and perfluorinated compounds. This current review, however, will focus specifically on mercury exposure and ASD by conducting a comprehensive literature search of original studies in humans that examine the potential relationship between mercury and ASD, categorizing, summarizing, and discussing the published research that addresses this topic. This review found 91 studies that examine the potential relationship between mercury and ASD from 1999 to February 2016. Of these studies, the vast majority (74%) suggest that mercury is a risk factor for ASD, revealing both direct and indirect effects. The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD. PMID- 27473828 TI - Short repeats in the heme oxygenase 1 gene promoter is associated with increased levels of inflammation, ferritin and higher risk of type-2 diabetes mellitus. AB - OBJECTIVE: We evaluated the relationship between the HO1 genotype, ferritin levels and the risk of type-2 diabetes and inflammation. RESEARCH METHODS: Eight hundred thirty-five individuals were evaluated and classified according to their nutritional status and the presence of type-2 diabetes: 153 overweight (OW); 62 obese (OB); 55 type-2 diabetes mellitus (DM); 202 OWDM; 239 OBDM and 124 controls (C). We studied biochemical (glycemia, insulin, lipid profile, liver enzyme, creatinine, hsCRP), hematological (hemoglobin, free erythrocyte protoporphyrin, transferrin receptor and serum Fe and ferritin) and oxidative stress (SOD, GHS and TBARS) parameters. We determined heme oxygenase activity and the (GT)n polymorphism in its gene promoter. RESULTS: Individuals with diabetes, independent of nutritional status, showed high levels of ferritin and HO activity compared to control subjects. Allelic frequency was not different between the groups (Chi(2), NS) however, genotypes were different (Chi(2), P<0.001). The SS (short-short) genotype was higher in all DM individuals compared to controls and MM was higher in controls. SM (short-medium) genotype was an independent risk factor for DM in logistic regression analysis. We observed high risk for type-2 diabetes mellitus in the presence of SM genotype and high levels of ferritin (OR adjusted: 2.7; 1.9-3.6; p<0.001; compared to control group). It was also significantly related to inflammation. CONCLUSION: The SM genotype in HO1 gene promoter and ferritin levels were associated with higher risk for type-2 diabetes and for having a higher marker of inflammation, which is the main risk factor for the development of chronic diseases. PMID- 27473829 TI - Investigating the intra-individual variability in the human metabolic profile of urinary selenium. AB - Selenium is an essential micronutrient widely present in our diet. It plays its role through the selenoproteins. Previous reports have shown marked variation between individuals in the excretion of this trace element, but the intra individual variability in selenium excretion has not been specifically investigated. The present study investigates the intra-individual variation in the urinary excretion of selenium in a group of healthy volunteers. We also discuss inter-individual variability trends. Urine samples were collected from healthy volunteers without selenium supplementation twice a day for 7 days and then once a week for an additional 7 weeks. A total of 168 urine samples were collected and analyzed for total selenium and individual selenium species using elemental mass spectrometry and HPLC/mass spectrometry, respectively. We found only modest day-to-day and week-to-week intra-individual variation of selenium excretion. Two commonly reported urine metabolites, selenosugar 1 and selenosugar 3, were detected in all urine samples, and our data suggest that selenosugar 3 is a deacetylated product of selenosugar 1 produced in a manner dependent on selenium intake. Trimethylselenonium displayed no intra-individual variability but considerable inter-individual variability in agreement with the involvement of genetic polymorphisms, as recently reported. Se-methylselenoneine was consistently detected in the urine of all volunteers and was a significant metabolite in one volunteer contributing up to 24% of total urinary selenium. Our data indicate that selenium urinary excretion is consistent within an individual, and that intra-individual variation in selenium excretion is unlikely to complicate future inter-individual variation studies. PMID- 27473830 TI - Comparison of mercury sulfides with mercury chloride and methylmercury on hepatic P450, phase-2 and transporter gene expression in mice. AB - Zuotai (mainly beta-HgS) and Zhusha (also called as cinnabar, mainly alpha-HgS) are used in traditional medicines in combination with herbs or even drugs in the treatment of various disorders, while mercury chloride (HgCl2) and methylmercury (MeHg) do not have known medical values but are highly toxic. This study aimed to compare the effects of mercury sulfides with HgCl2 and MeHg on hepatic drug processing gene expression. Mice were orally administrated with Zuotai (beta-HgS, 30mg/kg), alpha-HgS (HgS, 30mg/kg), HgCl2 (33.6mg/kg), or MeHg (3.1mg/kg) for 7days, and the expression of genes related to phase-1 drug metabolism (P450), phase-2 conjugation, and phase-3 (transporters) genes were examined. The mercurials at the dose and duration used in the study did not have significant effects on the expression of cytochrome P450 1-4 family genes and the corresponding nuclear receptors, except for a slight increase in PPARalpha and Cyp4a10 by HgCl2. The expressions of UDP-glucuronosyltransferase and sulfotransferase were increased by HgCl2 and MeHg, but not by Zuotai and HgS. HgCl2 decreased the expression of organic anion transporter (Oatp1a1), but increased Oatp1a4. Both HgCl2 and MeHg increased the expression of multidrug resistance-associated protein genes (Mrp1, Mrp2, Mrp3, and Mrp4). Zuotai and HgS had little effects on these transporter genes. In conclusion, Zuotai and HgS are different from HgCl2 and MeHg in hepatic drug processing gene expression; suggesting that chemical forms of mercury not only affect their disposition and toxicity, but also affect their effects on the expression of hepatic drug processing genes. PMID- 27473831 TI - Selenium levels and Glutathione peroxidase activity in the plasma of patients with type II diabetes mellitus. AB - Selenium, an essential trace element, is involved in the complex system of defense against oxidative stress through selenium-dependent glutathione peroxidases (GPx) and other selenoproteins. Because of its antioxidant properties, selenium or its selenospecies at appropriate levels could hinder oxidative stress and so development of diabetes. In this vein, quantitative speciation of selenium in human plasma samples from healthy and diabetic patients (controlled and non-controlled) was carried out by affinity chromatography (AF) coupled on-line to inductively coupled plasma mass spectrometry (ICP-MS) and isotope dilution analysis (IDA). Similarly, it is well known that patients with diabetes who exhibit poor control of blood glucose show a decreased total antioxidant activity. Thus, we evaluated the enzymatic activity of GPx in diabetic and healthy individuals, using the Paglia and Valentine enzymatic method, observing a significant difference (p<0.05) between the three groups of assayed patients (healthy (n=24): 0.61+/-0.11U/ml, controlled diabetic (n=38): 0.40+/-0.12U/ml and non-controlled diabetic patients (n=40): 0.32+/-0.09U/ml). Our results show that hyperglycemia induces oxidative stress in diabetic patients compared with healthy controls. What is more, glycation of GPx experiments demonstrated that it is the degree of glycation of the selenoenzyme (another species of the Se protein) what actually modulates its eventual activity against ROS in type II diabetes mellitus patients. PMID- 27473832 TI - Radiotherapy-associated dental extractions and osteoradionecrosis. AB - BACKGROUND: Preradiotherapy dental extractions often form a part of the management plan for patients treated with radiotherapy for head and neck cancers in order to prevent complications, such as osteoradionecrosis. There is contention about whether these extractions should be performed and the timing of such extractions. The purpose of this study was to determine if pre-RT extractions were associated with the development of osteoradionecrosis of the jaws. METHODS: Retrospective data on patients treated with RT for oropharyngeal cancer were pooled with a cross-sectional survey. RESULTS: Pre-radiotherapy dental extractions were associated with a statistically significant increase in the risk of developing ORN. CONCLUSION: Pre-radiotherapy dental extractions do not protect against the development of osteoradionecrosis. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 128-132, 2017. PMID- 27473833 TI - A World-Wide Awareness of Pediatric Pain. PMID- 27473834 TI - Survival prediction of high-risk outborn neonates with congenital diaphragmatic hernia from capillary blood gases. AB - BACKGROUND: The extent of lung hypoplasia in neonates with congenital diaphragmatic hernia (CDH) can be assessed from gas exchange. We examined the role of preductal capillary blood gases in prognosticating outcome in patients with CDH. METHODS: We retrospectively reviewed demographic data, disease characteristics, and preductal capillary blood gases on admission and within 24 h following admission for 44 high-risk outborn neonates. All neonates were intubated after delivery due to acute respiratory distress, and were emergently transferred via ground ambulance to our unit between 1/2000 and 12/2014. The main outcome measure was survival to hospital discharge and explanatory variables of interest were preductal capillary blood gases obtained on admission and during the first 24 h following admission. RESULTS: Higher ratio of preductal partial pressure of oxygen to fraction of inspired oxygen (PcO2/FIO2) on admission predicted survival (AUC = 0.69, P = 0.04). However, some neonates substantially improve PcO2/FIO2 following initiation of treatment. Among neonates who survived at least 24 h, the highest preductal PcO2/FIO2 achieved in the initial 24 h was the strongest predictor of survival (AUC = 0.87, P = 0.002). Nonsurvivors had a mean admission preductal PcCO2 higher than survivors (91 +/- 31 vs. 70 +/- 25 mmHg, P = 0.02), and their PcCO2 remained high during the first 24 h of treatment. CONCLUSION: The inability to achieve adequate gas exchange within 24 h of initiation of intensive care treatment is an ominous sign in high-risk outborn neonates with CDH. We suggest that improvement of oxygenation during the first 24 h, along with other relevant clinical signs, should be used when making decisions regarding treatment options in these critically ill neonates. PMID- 27473835 TI - Retrospective study of human cystic echinococcosis over the past decade in France, using a nationwide hospital medical information database. AB - No specific surveillance system of cystic echinococcosis infections in humans exists in France. The incidence and trends over time have not been documented since the last decade of the twentieth century. We performed the current analysis to assess human cystic echinococcosis epidemiology over a 10-year period in France (including the island of Corsica but excluding the overseas territories) using a nationwide hospital medical information database. A total number of 2629 patients were identified in this database between 2005 and 2014. The average annual incidence rate was 0.42 hospitalized cases/100,000 inhabitants. It was highest in the Island of Corsica (1.76 cases/100,000) and in the region Provence Alpes-Cote d'Azur (0.85 cases/100,000). This retrospective analysis of hospital records provides a population-based estimate of cystic echinococcosis incidence and trends over a 10-year period at a national level. It indicates a significant decrease of the incidence between 2005 and 2014 at the national level and in the area that reported the highest incidence. It stresses the fact that in France, cystic echinococcosis is not re-emerging and that the incidence remains low in comparison with similar studies in other Mediterranean countries. PMID- 27473836 TI - Species composition and infection dynamics of ascaridoid nematodes in Barents Sea capelin (Mallotus villosus) reflecting trophic position of fish host. AB - Capelin (Mallotus villosus) is among the most abundant fish species in the Barents Sea, and represents a critical food source for many predators in the area including Atlantic cod and harp seal. In Norway, the fish is of economic importance since whole capelin and roe are valuable export products. Despite its economic and ecological importance, the parasites of Barents Sea capelin are poorly known. However, the presence of parasites in the edible parts may adversely affect product quality and consumer safety. During the main annual catching seasons of 2009-2012, we investigated the diversity and infection dynamics of ascaridoid nematodes in capelin (n = 620) from the southern Barents Sea. Three anisakid species were identified by genetic or molecular methods; Anisakis simplex (s.s.), Contracaecum osculatum sp. B, and Hysterothylacium aduncum, with C. osculatum sp. B as the most prevalent and abundant species. The present findings suggest that the ascaridoid species composition in capelin reflects its trophic position in the Barents Sea ecosystem. There appears to be a link between infection level of the nematode species and the preferred prey organisms of the different developmental phases of capelin. Thus, the higher abundance of C. osculatum sp. B compared to A. simplex (s.s.) and H. aduncum may be related to more extensive feeding on calanoid copepods over a wider ontogenetic size range including adolescence, while the main intermediate hosts of the latter nematode species, i.e. euphausiids and amphipods, appear to be the preferred prey of larger capelin. PMID- 27473837 TI - Prebiotic inulin supplementation modulates the immune response and restores gut morphology in Giardia duodenalis-infected malnourished mice. AB - Malnutrition induces a state of growth retardation and immunologic depression, enhancing the host susceptibility to various infections. In the present study, it was observed that prebiotic supplementation either prior or simultaneously with Giardia infection in malnourished mice significantly reduced the severity of giardiasis and increased the body and small intestine mass, along with increased lactobacilli counts in faeces compared with malnourished-Giardia-infected mice. More specifically, prebiotic supplementation significantly increased the levels of anti-giardial IgG and IgA antibodies and anti-inflammatory cytokines IL-6 and IL-10 and reduced the pro-inflammatory cytokine TNF-alpha, along with increased levels of nitric oxide in both the serum and intestinal fluid of malnourished prebiotic-Giardia-infected mice compared with malnourished-Giardia-infected mice. Histopathology and scanning electron microscopy of the small intestine also revealed less cellular and mucosal damage in the microvilli of prebiotic supplemented malnourished-Giardia-infected mice compared with severely damaged mummified and blunted villi of malnourished-Giardia-infected mice. This is the first study to report that prebiotic supplementation modulated the gut morphology and improved the immune status even in malnourished-Giardia-infected mice. PMID- 27473838 TI - Differential diagnosis and molecular characterization of Hymenolepis nana and Hymenolepis diminuta (Cestoda: Cyclophyllidea: Hymenolepididae) based on nuclear rDNA ITS2 gene marker. AB - Given the widespread distribution and medical implication of members of the genus Hymenolepis, specific identification of the aetiological agent becomes imperative. For precise diagnosis of the species, molecular techniques such as PCR and RFLP of the nuclear ribosomal internal transcribed spacer 2 (rDNA-ITS2) gene marker were carried out. The results showed distinct restriction patterns for both Hymenolepis nana and Hymenolepis diminuta when digested with either of the enzymes RsaI, HaeIII or HhaI. The annotated rDNA-ITS2 sequences from the two species revealed differences in the length; the folded secondary structure also depicted clear demarcation between the two species with variations in length of the helices, pyrimidine-pyrimidine mismatches and sites where motifs occur. In phylogenetic analysis of the evolutionary relationship between the two species as well as with other members of the family Hymenolepididae, the species causing human hymenolepiasis were found to be distantly related as they diverged independently from the ancestral lineage. PMID- 27473840 TI - Vascular tortuosity in relationship with hypertension and posterior fossa volume in hemifacial spasm. AB - BACKGROUND: Hemifacial spasm (HFS) is a disabling neurological condition. Vascular tortuosity in HFS patients has not been quantified objectively and its relationship with hypertension and posterior fossa volume (PF) is unknown. In a case control magnetic resonance imaging and angiographic (MRI/A) study, we quantified and compared the vascular tortuosity in HFS and controls, and evaluated its relationship with hypertension and PF. METHODS: Using a commercially available vessel probe tool, an index of tortuosity based on vessel over chord length was employed to quantify vascular tortuosity of the vertebral (VA) and basilar arteries (BA) in 79 subjects (40 HFS, 39 controls). RESULTS: The tortuosity index of the BA (1.09 vs 1.16, p = 0.26, 95 % CI 1.07, 1.23), RVA (1.15 vs 1.15, p = 0.83, 95 % CI 1.06, 1.38) and LVA (1.14 vs 1.288, p = 0.16, 95 % CI 1.14, 1.44) was not different between HFS and controls, with adjustments for PF volume and hypertension. CONCLUSIONS: Contrary to popular belief, our study showed that taking into account hypertension and PF volume, vascular tortuosity of the vertebrobasilar arteries is unlikely to be a major etiologic factor in HFS, though its role in select individuals cannot be excluded. The complex interplay of facial nerve hyperexcitability, genetic predisposition, vascular tortuosity, posterior fossa volume and hypertension needs to be further evaluated. PMID- 27473839 TI - Exploring anterograde memory: a volumetric MRI study in patients with mild cognitive impairment. AB - BACKGROUND: The aim of this volumetric study was to explore the neuroanatomical correlates of the Free and Cued Selective Reminding Test (FCSRT) and the Delayed Matching-to-Sample-48 items (DMS-48), two tests widely used in France to assess verbal and visual anterograde memory. We wanted to determine to what extent the two tests rely on the medial temporal lobe, and could therefore be predictive of Alzheimer's disease, in which pathological changes typically start in this region. METHODS: We analysed data from a cohort of 138 patients with mild cognitive impairment participating in a longitudinal multicentre clinical research study. Verbal memory was assessed using the FCSRT and visual recognition memory was evaluated using the DMS-48. Performances on these two tests were correlated to local grey matter atrophy via structural MRI using voxel-based morphometry. RESULTS: Our results confirm the existence of a positive correlation between the volume of the medial temporal lobe and the performance on the FCSRT, prominently on the left, and the performance on the DMS-48, on the right, for the whole group of patients (family-wise error, P < 0.05). Interestingly, this region remained implicated only in the subgroup of patients who had deficient scores on the cued recall of the FCSRT, whereas the free recall was associated with prefrontal aspects. For the DMS-48, it was only implicated for the group of patients whose performances declined between the immediate and delayed trial. Conversely, temporo-parietal cortices were implicated when no decline was observed. Within the medial temporal lobe, the parahippocampal gyrus was prominently involved for the FCSRT and the immediate trial of the DMS-48, whereas the hippocampus was solely involved for the delayed trial of the DMS-48. CONCLUSIONS: The two tests are able to detect an amnestic profile of the medial temporal type, under the condition that the scores remain deficient after the cued recall of the FCSRT or decline on the delayed recognition trial of the DMS 48. Strategic retrieval as well as perceptual/attentional processes, supported by prefrontal and temporo-parietal cortices, were also found to have an impact on the performances. Finally, the implication of the hippocampus appears time dependent, triggered by a longer delay than the parahippocampus, rather than determined by the sense of recollection or the encoding strength associated with the memory trace. PMID- 27473841 TI - Coffee consumption and the risk of malignant melanoma in the Norwegian Women and Cancer (NOWAC) Study. AB - BACKGROUND: Coffee contains biologically-active substances that suppress carcinogenesis in vivo, and coffee consumption has been associated with a lower risk of malignant melanoma. We studied the impact of total coffee consumption and of different brewing methods on the incidence of malignant melanoma in a prospective cohort of Norwegian women. METHODS: We had baseline information on total coffee consumption and consumption of filtered, instant, and boiled coffee from self-administered questionnaires for 104,080 women in the Norwegian Women and Cancer (NOWAC) Study. We also had follow-up information collected 6-8 years after baseline. Multiple imputation was used to deal with missing data, and multivariable Cox regression models were used to calculate hazard ratios (HR) for malignant melanoma by consumption category of total, filtered, instant, and boiled coffee. RESULTS: During 1.7 million person-years of follow-up, 762 cases of malignant melanoma were diagnosed. Compared to light consumers of filtered coffee (<=1 cup/day), we found a statistically significant inverse association with low-moderate consumption (>1-3 cups/day, HR = 0.80; 95 % confidence interval [CI] 0.66-0.98) and high-moderate consumption of filtered coffee (>3-5 cups/day, HR = 0.77; 95 % CI 0.61-0.97) and melanoma risk (p trend = 0.02). We did not find a statistically significant association between total, instant, or boiled coffee consumption and the risk of malignant melanoma in any of the consumption categories. CONCLUSIONS: The data from the NOWAC Study indicate that a moderate intake of filtered coffee could reduce the risk of malignant melanoma. PMID- 27473842 TI - Happy Family Kitchen II: a cluster randomized controlled trial of a community based positive psychology family intervention for subjective happiness and health related quality of life in Hong Kong. AB - BACKGROUND: Most positive psychology interventions conducted in the West have been focused on the individual. Family relationships are highly valued in the Chinese collectivist culture, and it is of interest to know whether family focused interventions can improve the well-being of Chinese people. We have previously reported the effectiveness of a positive psychology family intervention in terms of family well-being. Based on the data derived from the Happy Family Kitchen II project, this paper examines the effectiveness of a community-based positive psychology family intervention on subjective happiness and health-related quality of life. METHODS: Thirty-one social service units and schools organized intervention programs for 2070 participants in Hong Kong. In a cluster randomized controlled trial, participants were randomly assigned on the basis of computer-generated numbers into the intervention group or the control group. The intervention programs emphasized one of five positive psychology themes: joy, gratitude, flow, savoring, and listening. The control group engaged in activities unrelated to the intervention, such as arts and crafts workshops. Subjective happiness and mental and physical quality of life were assessed at baseline and at 4 weeks and 12 weeks postintervention. RESULTS: Data of 1261 participants were analyzed. The results showed that the intervention was more effective than the control condition in improving subjective happiness, with a small effect size, at 12 weeks postintervention (beta = .15, p = .020, Cohen's d = .16). However, there were no improvements in mental and physical quality of life in the intervention group compared with the control group at 4 weeks (beta = .39, p = .494, d = .05; beta = -.10, p = 1.000, d = -.01, respectively) and 12 weeks postintervention (beta = .71, p = .233, d = .08; beta = -.05, p = 1.000, d = -.01, respectively). Furthermore, the booster session was no more effective than the tea gathering session in improving subjective happiness (beta = .00, p = .990, d = .00) or mental (beta = 1.20, p = 1.000, d = -.04) and physical quality of life (beta = .15, p = 1.000, d = -.01). CONCLUSIONS: The analyses extend previous findings of salutary effects on family well-being by showing that positive psychology family interventions can improve subjective happiness. Suggestions for future research are proposed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01796275 . Retrospectively registered 19 February 2013. PMID- 27473843 TI - Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial. AB - BACKGROUND: Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid beta (Abeta, coded on chromosome 21) deposition and, therefore, delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs) on this issue. Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults. METHODS: TOP-COG was a feasibility/pilot, double-blind RCT of 12 months simvastatin 40 mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E (APOE) epsilon4 allele status, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre randomisation and at 12 months post randomisation. Blood Abeta40/Abeta42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework Approach to determine recruitment motivators/barriers, and participation experience. RESULTS: We identified 181 (78 %) of the likely eligible Down syndrome population, and recruited 21 (11.6 %), from an area with a general population size of 3,135,974. Recruitment was highly labour-intensive. Thirteen (62 %) participants completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Individuals with Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Abeta40 levels changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part. CONCLUSION: A full-scale RCT is feasible. It will need 37 % UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population. TRIAL REGISTRATION: ISRCTN67338640 . PMID- 27473844 TI - Food Decision-Making: Effects of Weight Status and Age. AB - Food decisions determine energy intake. Since overconsumption is the main driver of obesity, the effects of weight status on food decision-making are of increasing interest. An additional factor of interest is age, given the rise in childhood obesity, weight gain with aging, and the increased chance of type 2 diabetes in the elderly. The effects of weight status and age on food preference, food cue sensitivity, and self-control are discussed, as these are important components of food decision-making. Furthermore, the neural correlates of food anticipation and choice and how these are affected by weight status and age are discussed. Behavioral studies show that in particular, poor self-control may have an adverse effect on food choice in children and adults with overweight and obesity. Neuroimaging studies show that overweight and obese individuals have altered neural responses to food in brain areas related to reward, self-control, and interoception. Longitudinal studies across the lifespan will be invaluable to unravel the causal factors driving (changes in) food choice, overconsumption, and weight gain. PMID- 27473845 TI - Conditions for homogeneous preparation of stable monomeric and oligomeric forms of activated Vip3A toxin from Bacillus thuringiensis. AB - Bacillus thuringiensis vegetative insecticidal proteins like Vip3A have been used for crop protection and to delay resistance to existing insecticidal Cry toxins. However, little is known about Vip3A's behavior or its mechanism of action, and a structural model is required. Herein, in an effort to facilitate future crystallization and functional studies, we have used the orthogonal biophysical techniques of light scattering and sedimentation to analyze the aggregation behavior and stability of trypsin-activated Vip3A toxin in solution. Both scattering and sedimentation data suggest that at pH 10 the toxin is monomeric and adopts an elongated shape, but after overnight incubation aggregation was observed at all pH values tested (5-12). The narrowest size distribution was observed at pH 7, but it was consistent with large oligomers of ~50 nm on average. The addition of beta-D-glucopyranoside (OG) helped in achieving preparations that were stable and with a narrower particle size distribution. In this case, scattering was consistent with a 4-nm monomeric globular Vip3A form. After OG dialysis, 40-nm particles were detected, with a molecular weight consistent with homotetramers. Therefore, OG is proposed as the detergent of choice to obtain a Vip3A crystal for structural studies, either before (monomers) or after dialysis (tetramers). PMID- 27473846 TI - Fractal and multifractal analysis of PET/CT images of metastatic melanoma before and after treatment with ipilimumab. AB - BACKGROUND: PET/CT with F-18-fluorodeoxyglucose (FDG) images of patients suffering from metastatic melanoma have been analysed using fractal and multifractal analysis to assess the impact of monoclonal antibody ipilimumab treatment with respect to therapy outcome. RESULTS: Thirty-one cases of patients suffering from metastatic melanoma have been scanned before and after two and after four cycles of treatment. For each patient, we calculated the fractal and multifractal dimensions using the box-counting method on the digitalised PET/CT images of all three studies to assess the therapeutic outcome. We modelled the spreading of malignant cells in the body via kinetic Monte Carlo simulations to address the dynamical evolution of the metastatic process and to predict the spatial distribution of malignant lesions. Our analysis shows that the fractal dimensions which describe the tracer dispersion in the body decrease consistently with the deterioration of the patient's therapeutic outcome condition. In 20 out of 24 cases, the fractal analysis results match those of the treatment outcome as defined by the oncologists, while 7 cases are considered as special cases because the patients had non-tumour-related findings or side effects which affect the results. The decrease in the fractal dimensions with the deterioration of the patient conditions (in terms of disease progression) is attributed to the hierarchical localisation of the tracer which accumulates in the affected lesions and does not spread homogeneously throughout the body. Fractality emerges as a result of the migration patterns which the malignant cells follow for propagating within the body (circulatory system, lymphatic system). Analysis of the multifractal spectrum complements and supports the results of the fractal analysis. In the kinetic Monte Carlo modelling of the metastatic process, a small number of malignant cells diffuse through a fractal medium representing the blood circulatory network. Along their way, the malignant cells engender random metastases (colonies) with a small probability and, as a result, fractal spatial distributions of the metastases are formed similar to the ones observed in the PET/CT images. CONCLUSIONS: The Monte Carlo-generated spatial distribution of metastases changes with time approaching values close to the ones recorded in the metastatic patients. Thus, we propose that fractal and multifractal analyses have potential applications in quantification of the evaluation of PET/CT images to monitor the disease evolution as well as the response to different medical treatments. The proposed approach, being operator independent, can offer new diagnostic tools in parallel to the visual location of the lesions and may improve multiparameter assessment of FDG PET/CT studies. PMID- 27473848 TI - Transfer Entails Communication: The Public Understanding of (Social) Science as a Stage and a Play for Implementing Evidence-Based Prevention Knowledge and Programs. AB - Many social science-based interventions entail the transfer of evidence-based knowledge to the "target population," because the acquisition and the acceptance of that knowledge are necessary for the intended improvement of behavior or development. Furthermore, the application of a certain prevention program is often legitimated by a reference to science-based reasons such as an evaluation according to scientific standards. Hence, any implementation of evidence-based knowledge and programs is embedded in the public understanding of (social) science. Based on recent research on such public understanding of science, we shall discuss transfer as a process of science communication. PMID- 27473847 TI - The bovine endometrial epithelial cells promote the differentiation of trophoblast stem-like cells to binucleate trophoblast cells. AB - Endometrial epithelial cells (EECs) cultured in vitro are valuable tools for investigating embryo implantation and trophoblast differentiation. In this study, we have established the bovine EECs and trophoblast stem-like (TS) coculture system, and used it to investigate the binucleate cell formation of ungulates. The EECs was derived from the uterine horn ipsilateral to the corpus luteum by using collagenase I and deoxyribonuclease I, which exhibited typical epithelial morphology and were expressing bovine uterine epithelial marker such as IFNAR1, IFNAR2, Eralpha, PGR, ESR1 and KRT18. The cells immunostained positively by epithelial and trophectoderm marker cytokeratin 18 (KRT18) and stromal marker vimentin antibodies, and the KRT18 positive cells reached 99 %. The EECs can be cultured for up to 20 passages in vitro with no significant morphology changes and uterine epithelial marker gene expression alteration. The bTS cells were established in a dual inhibitor system and exhibited typical trophoblast stem cell characteristics. When bTS cells were cultured with EECs, the bTS cells adhered to the EECs as adhering to feeder cells. Binucleate cells began appearing on day 4 of coculture and reached approximately 18.47 % of the differentiated cells. Quantitative real-time PCR or immunofluorescence analyses were performed on bTS cells cocultured at day 6 and day 12. The results showed that the expression level of KRT18 was down-regulated while the expression level of trophoblast differentiation marker MASH2, HAND1, GCM1 and CDX2 was up-regulated in bTS cells. In conclusion, bovine EECs can be obtained from the uterine horn ipsilateral to the corpus luteum via treatment with collagenase I and deoxyribonuclease I, and the EECs-bTS cells coculture system presents an ideal tool for studying the differentiation of bTS cells to trophoblast binucleate cells. PMID- 27473849 TI - A case of defibrillator-associated infective endocarditis due to Campylobacter fetus. AB - Campylobacter spp. are Gram-negative, spiral motile bacteria. Infections caused by Campylobacter fetus are frequently of invasive character, but they are very rare. The described case of infection of a cardioverter defibrillator implantation site was effectively cured with antibiotics, but it required removal of the cardioverter defibrillator. PMID- 27473850 TI - Identification of two novel powdery mildew resistance loci, Ren6 and Ren7, from the wild Chinese grape species Vitis piasezkii. AB - BACKGROUND: Grapevine powdery mildew Erysiphe necator is a major fungal disease in all grape growing countries worldwide. Breeding for resistance to this disease is crucial to avoid extensive fungicide applications that are costly, labor intensive and may have detrimental effects on the environment. In the past decade, Chinese Vitis species have attracted attention from grape breeders because of their strong resistance to powdery mildew and their lack of negative fruit quality attributes that are often present in resistant North American species. In this study, we investigated powdery mildew resistance in multiple accessions of the Chinese species Vitis piasezkii that were collected during the 1980 Sino-American botanical expedition to the western Hubei province of China. RESULTS: A framework genetic map was developed using simple sequence repeat markers in 277 seedlings of an F1 mapping population arising from a cross of the powdery mildew susceptible Vitis vinifera selection F2-35 and a resistant accession of V. piasezkii DVIT2027. Quantitative trait locus analyses identified two major powdery mildew resistance loci on chromosome 9 (Ren6) and chromosome 19 (Ren7) explaining 74.8 % of the cumulative phenotypic variation. The quantitative trait locus analysis for each locus, in the absence of the other, explained 95.4 % phenotypic variation for Ren6, while Ren7 accounted for 71.9 % of the phenotypic variation. Screening of an additional 259 seedlings of the F1 population and 910 seedlings from four pseudo-backcross populations with SSR markers defined regions of 22 kb and 330 kb for Ren6 and Ren7 in the V. vinifera PN40024 (12X) genome sequence, respectively. Both R loci operate post-penetration through the induction of programmed cell death, but vary significantly in the speed of response and degree of resistance; Ren6 confers complete resistance whereas Ren7 confers partial resistance to the disease with reduced colony size. A comparison of the kinetics of induction of powdery mildew resistance mediated by Ren6, Ren7 and the Run1 locus from Muscadinia rotundifolia, indicated that the speed and strength of resistance conferred by Ren6 is greater than that of Run1 which, in turn, is superior to that conferred by Ren7. CONCLUSIONS: This is the first report of mapping powdery mildew resistance in the Chinese species V. piasezkii. Two distinct powdery mildew R loci designated Ren6 and Ren7 were found in multiple accessions of this Chinese grape species. Their location on different chromosomes to previously reported powdery mildew resistance R loci offers the potential for grape breeders to combine these R genes with existing powdery mildew R loci to produce grape germplasm with more durable resistance against this rapidly evolving fungal pathogen. PMID- 27473851 TI - Value of peripheral blood eosinophil markers to predict severity of asthma. AB - BACKGROUND: Asthma represents a significant clinical and economic burden to the US healthcare system. Along with other clinical manifestations of the disease, elevated sputum and blood eosinophil levels are observed in patients experiencing asthma exacerbations. The aim of this study was to evaluate the association between blood eosinophil levels and asthma severity defined using Expert Panel Report 3 guidelines. METHODS: Patients with asthma diagnosis between 2004 and 2011 were extracted from the EMRClaims+ database (eMAX Health, White Plains, NY) containing electronic medical records linked to insurance claims for over 675,000 patients. The date of first asthma diagnosis was defined as the 'index date'. Patients were required to have at least 1 peripheral eosinophil test (elevated defined as >= 400 cells/MUL) in the 12 month 'assessment' period following the index date. We classified patients as those with mild asthma and moderate-to severe asthma based on the pattern of medication use, as recommended by the 2007 National Institutes of Health Expert Panel Report. Logistic regression models were used to determine if patients with moderate-to-severe asthma had increased likelihood of an elevated peripheral eosinophil count, after accounting for demographics and comorbidities. RESULTS: Among 1,144 patients with an asthma diagnosis, 60 % were classified as having moderate-to-severe asthma. Twenty four percent of patients with moderate-to-severe asthma and 19 % of patients with mild asthma had an elevated peripheral eosinophil count (p = 0.053). Logistic regression showed that moderate-to-severe asthma was associated with 38 % increased odds of elevated eosinophil level (OR 1.38, 95 % CI: 1.02 to 1.86, p = 0.04). CONCLUSION: Patients with moderate-severe asthma are significantly more likely to have an elevated peripheral eosinophil count than patients with mild asthma. PMID- 27473852 TI - Description of the male and the larva of Ixodes ariadnae Hornok, 2014. AB - Ixodes ariadnae is a tick species of bats so far reported only in Central Europe, with its description based on the female and nymph. This study describes the male and larva in order to complete the description of the species. Male ticks collected from cave walls in Hungary showed a different morphology from those of I. vespertilionis and I. simplex. Molecular analysis of the cytochrome oxidase subunit I (COI) gene of these ticks verified them as conspecific to I. ariadnae. In addition, a larva of I. ariadnae was removed from a Daubenton's bat (Myotis daubentonii Kuhl, 1817). The male of I. ariadnae is characterized by long legs (7 8mm; I. vespertilionis: 8-10mm; I. simplex: 2-2.2mm), relatively short palpal setae (30-100MUm; I. vespertilionis: 100-200MUm; I. simplex: 20-50MUm) and straight lateral edge of palps, the genital aperture (enclosed by a line of sclerotization) situated anteriorly to second intercoxal space and rounded coxae. The larva of I. ariadnae has long legs (2-2.2mm; I. vespertilionis: 1.6-1.8mm; I. simplex: 1mm), broad palps (length*width: 200*90MUm; I. vespertilionis: 200*70MUm; I. simplex: 140*60MUm), pentagonal and posteriorly reverse bell-shaped scutum. These features allow to distinguish the male and the larva of I. ariadnae from those of I. vespertilionis (of which the male has longer palpal setae and curved lateral edge of palps, the genital aperture is situated posterior to the second intercoxal space, and the second coxae are squared; the larva of I. vespertilionis has narrower palps and posteriorly triangular scutum) and I. simplex (of which the male and the larva have considerably shorter legs, palps). PMID- 27473853 TI - First report of Rickettsia raoultii and Rickettsia helvetica in Dermacentor reticulatus ticks from the Czech Republic. AB - Tick-borne rickettsioses nowadays present a significant health threat among emerging tick-borne infections. In the study, we screened a total of 997 questing adult Dermacentor reticulatus ticks (576 females and 421 males) collected in Southern Moravia (Czech Republic) from April to September of 2010 and 2011 for the presence of human pathogenic rickettsiae. Here we provide the first evidence on the occurrence of human pathogenic Rickettsia raoultii in the local D. reticulatus population indicating possible future emergence of Dermacentor-borne necrotic erythema and lymphadenopathy (DEBONEL) in the region. PMID- 27473854 TI - Erratum to: Highly diverse nirK genes comprise two major clades that harbour ammonium-producing denitrifiers. PMID- 27473855 TI - Aluminum Exposure at Human Dietary Levels for 60 Days Reaches a Threshold Sufficient to Promote Memory Impairment in Rats. AB - Aluminum (Al) is a significant environmental contaminant. While a good deal of research has been conducted on the acute neurotoxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses for comparison with a model of exposure known to produce neurotoxicity in rats. Three-month-old male Wistar rats were divided into two major groups: (1) low aluminum levels, and (2) a high aluminum level. Group 1 rats were treated orally by drinking water for 60 days as follows: (a) control received ultrapure drinking water; (b) aluminum at 1.5 mg/kg b.w., and (c) aluminum at 8.3 mg/kg b.w. Group 2 rats were treated through oral gavages for 42 days as follows: (a) control-received ultrapure water; (b) aluminum at 100 mg/kg b.w. We analyzed cognitive parameters, biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in hippocampus and prefrontal cortex. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing. Moreover, Al increased hippocampal reactive oxygen species and lipid peroxidation, reduced antioxidant capacity, and decreased AChE activity. Our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote memory impairment and neurotoxicity. The elevation of oxidative stress and cholinergic dysfunction highlight pathways of toxic actions for this metal. PMID- 27473857 TI - From being a nurse to becoming a 'different' doctor. AB - Using interpretative phenomenological analysis to make meaning of the experiences of three highly qualified registered nurses who had enrolled in an undergraduate medical programme, this study provides insight into their personal journeys of wanting to become 'different' doctors. In so doing, they conceptualised their future selves as adding clinical reasoning and diagnostic skills to the patient centred caring ethic of their nursing practice, becoming a multi-skilled community member or helping to fix the health care culture. By customising their identities, e.g. by splinting (aligning with their stronger nursing identity), by enriching current nursing practice with newly acquired theory as medical students or by patching a perceived deficiency (i.e. patient-centredness) in medicine, they tailored their identities. Their journeys had, however, not been the natural progression they had anticipated, threatened by perceived and/or real intrinsic (e.g. working as nurses whilst studying medicine) and extrinsic (e.g. interprofessional rivalry) factors. Rather than being accepted as legitimate newcomers to the medical profession, the women sometimes felt like intruders. Some nursing colleagues accused them of desertion. In response, they generally withheld their identities as nurses or medical students, compartmentalising their group membership. This study has highlighted the role of personal (e.g. prior experience; agency; resilience; personality) and contextual factors in 'becoming' a doctor. A recommendation emerging from this study is the need for interprofessional learning in the medical curriculum to cultivate a health care culture of collaboration rather than competition. Future research is required in terms of how allied health professionals transition to medicine. PMID- 27473856 TI - Flavivirus NS1: a multifaceted enigmatic viral protein. AB - Flaviviruses are emerging arthropod-borne viruses representing an immense global health problem. The prominent viruses of this group include dengue virus, yellow fever virus, Japanese encephalitis virus, West Nile virus tick borne encephalitis virus and Zika Virus. These are endemic in many parts of the world. They are responsible for the illness ranging from mild flu like symptoms to severe hemorrhagic, neurologic and cognitive manifestations leading to death. NS1 is a highly conserved non-structural protein among flaviviruses, which exist in diverse forms. The intracellular dimer form of NS1 plays role in genome replication, whereas, the secreted hexamer plays role in immune evasion. The secreted NS1 has been identified as a potential diagnostic marker for early detection of the infections caused by flaviviruses. In addition to the diagnostic marker, the importance of NS1 has been reported in the development of therapeutics. NS1 based subunit vaccines are at various stages of development. The structural details and diverse functions of NS1 have been discussed in detail in this review. PMID- 27473858 TI - Effects of lacosamide "a novel antiepileptic drug" in the early stages of chicken embryo development. AB - INTRODUCTION: Antiepileptic drugs (AEDs) are teratogens and confer a risk of congenital malformation. The estimated prevalence of major congenital malformations such as cardiac defects, facial clefts, hypospadias, and neural tube defects in epileptic women is 4-10 %, which represents a two- to fourfold increase in pregnant women compared to the general population. However, there are no clear data for newer drugs. Lacosamide (LCM), a novel AED, is the first of the third-generation AEDs to be approved as adjunctive therapy for the treatment of partial-onset seizures. There are no data on the pharmacokinetics of LCM during pregnancy, and only some published data have reported on its effects during pregnancy. METHODS: In this study, three different doses of LCM (0.12, 0.5, and 1.60 mg in 0.18 mL) were applied under the embryonic disks of specific pathogen free Leghorn chicken embryos after a 30-h incubation. Incubation was continued for 80 h, at which time all embryos were evaluated macroscopically and microscopically. RESULTS: There was growth retardation in all of the LCM-treated groups. Major malformations increased in a dose-dependent manner and were mostly observed in the supratherapeutic group. CONCLUSION: Based on our data, LCM may cause growth retardation or major congenital malformations. Nevertheless, more extensive investigations of its reliability are needed. PMID- 27473859 TI - Metastatic rectal adenocarcinoma in the mandibular gingiva: a case report. AB - BACKGROUND: Oral metastatic tumor from a rectal adenocarcinoma is very uncommon. The primary site is usually assumed based on the past clinical history. In the case of oral metastatic tumors, they commonly have a poor prognosis because often they have already spread to other sites. CASE PRESENTATION: We present the case of a 64-year-old male patient with secondary metastasis to the mandibular gingiva via lung metastasis after the surgical resection of a primary rectal adenocarcinoma. The gingival lesion grossly appeared as a swollen mass, making mastication difficult. The patient received palliative radiotherapy for the mandibular mass lesion. However, tumor reduction was accompanied by the development of pneumonia and deterioration of the patient's cachexia. Thus, the radiotherapy was discontinued but the patient died 2 months postradiotherapy. In the long term after its primary resection, the rectal adenocarcinoma was deduced to have finally metastasized to the oral region. CONCLUSIONS: In this case, we consider a distant secondary metastasis to the oral region from a rectal malignancy. In such cases, careful clinical and pathologic evaluations are necessary, with careful consideration of the inclusion of palliative treatment in the therapeutic management. PMID- 27473860 TI - Integrated care: theory to practice. AB - 'Integrated care' is pitched as the solution to current health system challenges. In the literature, what integrated care actually involves is complex and contested. Multi-disciplinary team case management is frequently the primary focus of integrated care when implemented internationally. We examine the practical application of integrated care in the NHS in England to exemplify the prevalence of the case management focus. We look at the evidence for effectiveness of multi-disciplinary team case management, for the focus on high risk groups and for integrated care more generally. We suggest realistic expectations of what integration of care alone can achieve and additional research questions. PMID- 27473861 TI - Human brainnetome atlas: a new chapter of brain cartography. PMID- 27473862 TI - Hydropericardium syndrome outbreak caused by fowl adenovirus serotype 4 in China in 2015. AB - There have been many outbreaks of hydropericardium syndrome (HPS), which is characterized by pericardial effusion and hepatitis, in Chinese chicken farms since June 2015. HPS was mainly found in miscellaneous meat-type chickens, Ma chickens, layer chicks and Three-yellow chickens, while it was occasionally found in white broilers. To determine the specific causative pathogen and pathogenicity of HPS in chickens, we collected 25 suspected cases and performed clinical pathology and aetiology analyses. The results showed that the 25 cases exhibited multifocal hepatitis with intra-nuclear inclusion bodies and 70 nm-latticed viral particles in the cell nuclei. All samples were positive for fowl adenovirus (FAdV), and sequencing results showed that the hexon gene shared the highest nucleotide similarities with the hexon gene of group 1 serotype 4 (FAdV-4). FAdV 4 was highly pathogenic to embryos and specific pathogen-free chickens, causing 100 and 70 % mortality rates, respectively. Thus, FAdV-4 is associated with HPS outbreaks in China. PMID- 27473863 TI - Serum Bilirubin Levels and the Presence and Progression of Abdominal Aortic Aneurysms. AB - The relationship between bilirubin levels and peripheral artery disease has been documented. Our aim was to demonstrate the possible relationship between serum bilirubin levels and abdominal aortic aneurysms (AAAs). The study included 219 patients, 110 had a previous diagnosis of AAA and 109 patients were normal controls. Only patients with AAAs which had a size of 40 to 54 mm were included in the study. Baseline laboratory values and 2 computerized tomographic measurements 12 months apart were recorded. Patients with AAA had significantly higher white blood cell (WBC) counts and neutrophil-lymphocyte ratio (NLR) but lower total and direct bilirubin levels compared with the control patients ( P < .05). Multivariate logistic regression analysis showed that WBC, NLR, and total and direct bilirubin levels were independent predictors of the presence of an AAA ( P = .03, P = .001, P = .001, and P = .001, respectively). White blood cells and total bilirubin level were independent predictors of a rapidly enlarging AAA (>10 mm/y, P = .002 and P < .001, respectively). This study demonstrated that increased WBC and decreased total bilirubin levels were independent predictors of an AAA, especially the subgroup in which the AAA was rapidly expanding. PMID- 27473864 TI - Platelet-to-Lymphocyte Ratio Predicts Contrast-Induced Acute Kidney Injury in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. AB - We aimed to investigate the relationship between platelet-to-lymphocyte ratio (PLR) and contrast-induced acute kidney injury (CI-AKI) in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). A total of 2563 patients diagnosed with STEMI and underwent primary pPCI were retrospectively included in the study. Levels of PLR and creatinine were measured before and at 72 hours after pPCI. Patients were divided into 2 groups: non-CI-AKI group and CI-AKI group. Contrast-induced acute kidney injury occurred in 6.4% of the overall study population. Patients in the CI-AKI group had significantly higher PLR than those in the non-CI-AKI group (169.18 +/- 81.01 vs 149.49 +/- 74.54, P < .001). In logistic regression analysis, PLR was an independent predictor of CI-AKI (odds ratio [OR]: 1.774, 95% CI: 1.243-2.532, P = .002), along with age, use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prior to the procedure, preprocedural creatinine level, amount of contrast material used during the procedure, and hypertension. Increased PLR levels are independently associated with a greater risk of CI-AKI in patients undergoing primary PCI for STEMI. PMID- 27473865 TI - Childhood adiposity trajectories are associated with late adolescent blood pressure: birth to twenty cohort. AB - BACKGROUND: Elevated blood pressure in childhood is a risk factor for adult hypertension which is a global health problem. Excess adiposity in childhood creates a predisposition to develop adult hypertension. Our aim was to explore distinct sex-specific adiposity trajectories from childhood to late adolescence and examined their association with blood pressure. METHODS: Latent Class Growth Mixture Modeling (LCGMM) on longitudinal data was used to derive sex-specific and distinct body mass index (BMI: kg/m(2)) trajectories. We studied 1824 black children (boys = 877, girls = 947) from the Birth to Twenty (Bt20) cohort from Soweto, South Africa, and obtained BMI measures at ages 5 through 18 years. Participants with at least two age-point BMI measures, were included in the analysis. Analysis of variance (ANOVA), chi-square test, multivariate linear and standard logistic regressions were used to test study characteristics and different associations. RESULTS: We identified three (3) and four (4) distinct BMI trajectories in boys and girls, respectively. The overall prevalence of elevated blood pressure (BP) was 34.9 % (39.4 % in boys and 30.38 % in girls). Boys and girls in the early onset obesity or overweight BMI trajectories were more likely to have higher BP values in late adolescence. Compared to those in the normal weight BMI trajectory, girls in early onset obesity trajectories had an increased risk of elevated BP with odds ratio (OR) of 2.18 (95 % confidence interval 1.31 to 4.20) and 1.95 (1.01 to 3.77). We also observed the weak association for boys in early onset overweight trajectory, (p-value = 0.18 and odds ratio of 2.39 (0.67 to 8.57)) CONCLUSIONS: Distinct weight trajectories are observed in black South African children from as early as 5 years. Early onset adiposity trajectories are associated with elevated BP in both boys and girls. It is important to consider individual patterns of early-life BMI development, so that intervention strategies can be targeted to at-risk individuals. PMID- 27473866 TI - Context-Awareness Based Personalized Recommendation of Anti-Hypertension Drugs. AB - The World Health Organization estimates that almost one-third of the world's adult population are suffering from hypertension which has gradually become a "silent killer". Due to the varieties of anti-hypertensive drugs, patients are interested in how these drugs can be selected to match their respective conditions. This study provides a personalized recommendation service system of anti-hypertensive drugs based on context-awareness and designs a context ontology framework of the service. In addition, this paper introduces a Semantic Web Rule Language (SWRL)-based rule to provide high-level context reasoning and information recommendation and to overcome the limitation of ontology reasoning. To make the information recommendation of the drugs more personalized, this study also devises three categories of information recommendation rules that match different priority levels and uses a ranking algorithm to optimize the recommendation. The experiment conducted shows that combining the anti hypertensive drugs personalized recommendation service context ontology (HyRCO) with the optimized rule reasoning can achieve a higher-quality personalized drug recommendation service. Accordingly this exploratory study of the personalized recommendation service for hypertensive drugs and its method can be easily adopted for other diseases. PMID- 27473867 TI - Butyrate inhibits interleukin-17 and generates Tregs to ameliorate colorectal colitis in rats. AB - BACKGROUND: Butyrate is an energy source for colonocytes that is formed by bacterial fermentation of dietary fiber in the colon and that exerts broad anti inflammatory activities. Although the administration of butyrate improves homeostasis in patients and ameliorates IBD (Inflammatory Bowel Disease)-related lesions and symptoms, the anti-inflammatory mechanisms of butyrate still remain unclear. To explore the impact of butyrate on Treg (Regulatory T cell)/Th17 (T helper 17 cell) differentiation and colitis in rats. METHODS: The effect of butyrate on the expression of markers related to both Tregs and Th17 cells were determined in human monocytes as well as a rat model of colitis induced by 2,4,6 trinitrobenzene sulfonic acid. Rats were treated with butyrate in vivo, whereas the rat splenocytes and human monocytes were treated in vitro. RESULTS: We found that butyrate administration increased peripheral blood Treg cell levels as well as plasma levels of anti-Th17 cytokines (IL-10 and IL-12). Butyrate administration further suppressed IL-17 levels in both plasma and colonic mucosa, and ameliorated colonic colitis lesions in rats. This promotion of Treg activity and inhibition of IL-17 release was also observed in human venous monocytes and rat splenocytes in vitro. CONCLUSIONS: Our results suggest that butyrate plays a key role in regulating the Treg/Th17 balance and ultimately protects the colon mucosa against the development of IBD. PMID- 27473869 TI - Chromatin remodeling factor LSH affects fumarate hydratase as a cancer driver. AB - Cancer metabolism and epigenetic alteration are two critical mechanisms for tumorigenesis and cancer progression; however, the dynamic interplay between them remains poorly understood. As reported in the article entitled "Chromatin remodeling factor LSH drives cancer progression by suppressing the activity of fumarate hydratase," which was recently published in Cancer Research, our group examined the physiological role of lymphocyte-specific helicase (LSH) in nasopharyngeal carcinoma (NPC) by focusing on cancer progression and the tricarboxylic acid cycle. We found that LSH was overexpressed in NPC, and its expression associated with Epstein-Barr virus infection. We also found that LSH directly suppressed fumarate hydratase (FH), a key component of the tricarboxylic acid cycle, in combination with euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a. Depletion of FH promoted epithelial-mesenchymal transition (EMT). Moreover, LSH controlled expression of tricarboxylic acid cycle intermediates that promote cancer progression, including EMT, through activation by inhibitor of nuclear factor kappa-B kinase alpha (IKKalpha), a chromatin modifier and transcriptional activator. Our study showed that LSH plays a critical role in cancer progression, which has important implications for the development of novel strategies to treat NPC. PMID- 27473868 TI - Guidewire exchange vs new site placement for temporary dialysis catheter insertion in ICU patients: is there a greater risk of colonization or dysfunction? AB - BACKGROUND: Intensive care unit (ICU) patients require dialysis catheters (DCs) for renal replacement therapy (RRT). They carry a high risk of developing end stage renal disease, and therefore their vascular access must be preserved. Guidewire exchange (GWE) is often used to avoid venipuncture insertion (VPI) at a new site. However, the impact of GWE on infection and dysfunction of DCs in the ICU is unknown. Our aim was to compare the effect of GWE and VPI on DC colonization and dysfunction in ICU patients. METHODS: Using data from the ELVIS randomized controlled trial (RCT) (1496 ICU adults requiring DC for RRT or plasma exchange) we performed a matched-cohort analysis. Cases were DCs inserted by GWE (n = 178). They were matched with DCs inserted by VPI. Matching criteria were participating centre, simplified acute physiology score (SAPS) II +/-10, insertion site (jugular or femoral), side for jugular site, and length of ICU stay before DC placement. We used a marginal Cox model to estimate the effect of DC insertion (GWE vs. VPI) on DC colonization and dysfunction. RESULTS: DC colonization rate was not different between GWE-DCs and VPI-DCs (10 (5.6 %) for both groups) but DC dysfunction was more frequent with GWE-DCs (67 (37.6 %) vs. 28 (15.7 %); hazard ratio (HR), 3.67 (2.07-6.49); p < 0.01). Results were similar if analysis was restricted to DCs changed for dysfunction. CONCLUSIONS: GWE for DCs in ICU patients, compared with VPI did not contribute to DC colonization or infection but was associated with more than twofold increase in DC dysfunction. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT00563342 . Registered 2 April 2009. PMID- 27473870 TI - Crucial conversations about weight management with healthcare providers: patients' perspectives and experiences. AB - PURPOSE: To elicit patient experiences of weight management discussions with providers and provide recommendations for future weight-related discussions. METHODS: 1000 patients who recently saw their provider for non-weight specific appointments were mailed measures of demographics, self-reported height and weight, activity level, adherence, perceptions of and recommendations for weight related discussions, and internalized weight bias. This study was primarily descriptive and utilized a mixed method design including collection of quantitative and qualitative data. RESULTS: 242 patients responded (24 % response rate); 32.4 % overweight (N = 72), 41.9 % obese (N = 93). 47 % of overweight and 71 % of obese patients recalled that their provider discussed weight; 92 % were motivated to follow recommendations and 89 % felt confident doing so. Most patients (75 %) would like their provider to be "very direct/straightforward" when discussing weight, and 52 % would be "not at all offended" if they were diagnosed as "overweight/obese." Most patients (63 %) reported being "extremely comfortable" discussing weight with providers. Patients with higher BMI had higher levels of internalized weight bias (p < .001) and wanted their provider to "discuss weight sensitively" (p < .05). CONCLUSION: This study suggests that patients have important preferences that providers should be mindful of when discussing weight. While these discussions can be challenging, most patients report that they would be comfortable having these conversations directly and most would have enhanced motivation and confidence following these conversations. Communicating about weight is needed and desired by patients; doing so sensitively with those at higher weight is essential. PMID- 27473871 TI - Effect of beta-sitosterol against methyl nitrosourea-induced mammary gland carcinoma in albino rats. AB - BACKGROUND: The present study was in quested to study the effects of beta sitosterol on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. METHODS: Animals were randomized and divided into four groups of eight animals each. Group I (sham control 1 % CMC in normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v); Group III (MNU 47 mg/kg, i.v + beta sitosterol, 10 mg/kg, p.o); Group IV (MNU 47 mg/kg, i.v + beta-sitosterol, 20 mg/kg, p.o). Toxicity was induced by single i.v. injection of MNU followed by beta-sitosterol supplementation therapy for 115 days at the dose mentioned above. RESULTS: Treatment with beta-sitosterol evidenced decrease in the alveolar bud and lobule score in the whole mount of the mammary gland. beta-sitosterol exhibited diminishing effect on oxidative stress through synchronizing lipid and enzymatic antioxidant defense. A significant decrease in the saturated and unsaturated fatty acid was evident with the MNU treatment and beta-sitosterol demonstrated a marked effect on it. Pgp 9.5 expression was dose dependently upregulated by beta-sitosterol treatment in comparison to MNU treatment. On the contrary, downregulated NF-kB expression was perceived, when beta-sitosterol was concomitantly administered with MNU. CONCLUSION: beta-sitosterol afforded significant protection against the deleterious effects of MNU. PMID- 27473872 TI - Systematic review of factors influencing length of stay in ICU after adult cardiac surgery. AB - BACKGROUND: Intensive care unit (ICU) care is associated with costly and often scarce resources. In many parts of the world, ICUs are being perceived as major bottlenecks limiting downstream services such as operating theatres. There are many clinical, surgical and contextual factors that influence length of stay. Knowing these factors can facilitate resource planning. However, the extent at which this knowledge is put into practice remains unclear. The aim of this systematic review was to identify factors that impact the duration of ICU stay after cardiac surgery and to explore evidence on the link between understanding these factors and patient and resource management. METHODS: We conducted electronic searches of Embase, PubMed, ISI Web of Knowledge, Medline and Google Scholar, and reference lists for eligible studies. RESULTS: Twenty-nine papers fulfilled inclusion criteria. We recognised two types of objectives for identifying influential factors of ICU length of stay (LOS) among the reviewed studies. These were general descriptions of predictors and prediction of prolonged ICU stay through statistical models. Among studies with prediction models, only two studies have reported their implementation. Factors most commonly associated with increased ICU LOS included increased age, atrial fibrillation/ arrhythmia, chronic obstructive pulmonary disease (COPD), low ejection fraction, renal failure/ dysfunction and non-elective surgery status. CONCLUSION: Cardiac ICUs are major bottlenecks in many hospitals around the world. Efforts to optimise resources should be linked to patient and surgical characteristics. More research is needed to integrate patient and surgical factors into ICU resource planning. PMID- 27473874 TI - Low-dose propranolol for infantile hemangioma of the head and neck: Analysis of 23 consecutive patients. AB - BACKGROUND: More and more infantile hemangiomas (IH) are being treated with propranolol, but the effectiveness, dosage, and treatment course are still in dispute. The aim of this observational study was to describe the therapeutic response, tolerance, and safety of low-dose propranolol in 23 children with IH of the head and neck. METHODS: Data were collected from the medical charts of patients treated with low-dose propranolol from December 2009 through November 2011. Oral dose was 1-1.5 mg/kg once per day. Blood pressure and heart rate were monitored during the first 24 h of treatment. In the absence of side-effects, treatment was continued at home and the child was re-evaluated every month. RESULTS: All patients had a good response, even if treated with corticosteroid previously. Color and growth changes within 1 week were noted. Treatment continued for a mean total duration of 6 months until the IH had totally disappeared or stabilized. There were no severe adverse reactions. Side-effects were limited and mild, including blood pressure decrease, somnolence, and nausea. No relapse was noted. CONCLUSIONS: Low-dose propranolol appears to be effective and safe for IH, especially for those patients previously treated with corticosteroid and who had no response or severe side-effects. PMID- 27473873 TI - Altered skeletal muscle (mitochondrial) properties in patients with mitochondrial DNA single deletion myopathy. AB - BACKGROUND: Mitochondrial myopathy severely affects skeletal muscle structure and function resulting in defective oxidative phosphorylation. However, the major pathomechanisms and therewith effective treatment approaches remain elusive. Therefore, the aim of the present study was to investigate disease-related impairments in skeletal muscle properties in patients with mitochondrial myopathy. Accordingly, skeletal muscle biopsies were obtained from six patients with moleculargenetically diagnosed mitochondrial myopathy (one male and five females, 53 +/- 9 years) and eight age- and gender-matched healthy controls (two males and six females, 58 +/- 14 years) to determine mitochondrial respiratory capacity of complex I-V, mitochondrial volume density and fiber type distribution. RESULTS: Mitochondrial volume density (4.0 +/- 0.5 vs. 5.1 +/- 0.8 %) as well as respiratory capacity of complex I-V were lower (P < 0.05) in mitochondrial myopathy and associated with a higher (P < 0.001) proportion of type II fibers (65.2 +/- 3.6 vs. 44.3 +/- 5.9 %). Additionally, mitochondrial volume density and maximal oxidative phosphorylation capacity correlated positively (P < 0.05) to peak oxygen uptake. CONCLUSION: Mitochondrial myopathy leads to impaired mitochondrial quantity and quality and a shift towards a more glycolytic skeletal muscle phenotype. PMID- 27473875 TI - Outcomes Following Complete Surgical Metastasectomy for Patients with Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. AB - PURPOSE: The benefit of complete surgical metastasectomy for patients with metastatic renal cell carcinoma remains controversial due to limited outcome data. We performed a systematic review and meta-analysis to determine whether complete surgical metastasectomy confers a survival benefit compared to incomplete or no metastasectomy for patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: Ovid Embase(r), MEDLINE(r), Cochrane and Scopus(r) databases were searched for studies evaluating complete surgical metastasectomy for metastatic renal cell carcinoma through January 19, 2016. Only comparative studies reporting adjusted hazard ratios (aHRs) for all cause mortality of incomplete surgical metastasectomy vs complete surgical metastasectomy were included in the analysis. Generic inverse variance with random effects models was used to determine the pooled aHR. Risk of bias was assessed with the Newcastle-Ottawa Scale. RESULTS: Eight published cohort studies with a low or moderate potential for bias were included in the final analysis. The studies reported on a total of 2,267 patients (958 undergoing complete surgical metastasectomy and 1,309 incomplete surgical metastasectomy). Median overall survival ranged between 36.5 and 142 months for those undergoing complete surgical metastasectomy, compared to 8.4 to 27 months for incomplete surgical metastasectomy. Complete surgical metastasectomy was associated with a reduced risk of all cause mortality compared with incomplete surgical metastasectomy (pooled aHR 2.37, 95% CI 2.03-2.87, p <0.001), with low heterogeneity (I2 = 0%). Complete surgical metastasectomy remained independently associated with a reduction in mortality across a priori subgroup and sensitivity analyses, and regardless of whether we adjusted for performance status. CONCLUSIONS: Complete surgical metastasectomy for metastatic renal cell carcinoma is associated with improved survival compared with incomplete surgical metastasectomy based on meta analysis of observational data. Consideration should be given to performing complete surgical metastasectomy, when technically feasible, in patients with metastatic renal cell carcinoma who are surgical candidates. PMID- 27473876 TI - Characterization of the POU5F1 Homologue in Nile Tilapia: From Expression Pattern to Biological Activity. AB - POU5F1 (OCT4) is a crucial transcription factor for induction and maintenance of cellular pluripotency, as well as survival of germ cells in mammals. However, the homologues of POU5F1 in teleost fish, including zebrafish and medaka, now named Pou5f3, exhibit considerable differences in expression pattern and pluripotency maintaining activity. To what extent the POU5F1 homologues are conserved in vertebrates has been unclear. In this study, we report that the POU5F1 homologue from the Nile tilapia (Oreochromis niloticus), OnPou5f3, displays an expression pattern and biological activity somewhat different from those in zebrafish or medaka. The expression of Onpou5f3 at both mRNA and protein levels was abundant in early development embryos until blastula stages, barely detectable as proceeding, and then displayed a transiently strong expression domain in the brain region during neurula stages similar to zebrafish but not medaka. Afterward, OnPou5f3 appeared as germline-restricted (including primordial germ cells and female and male gonad germ cells) expression just like medaka. Notably, OnPou5f3 depletion through morpholino oligos caused blastula blockage or lethality and failure of survival and proliferation of blastula cell-derived cells. These findings indicate that equivalent POU5F1-like expression and activity of Pou5f3 might be conserved accompanying with species-specific expression pattern during evolution. Our study provides insight into the evolutionary conservation of the POU5F1 homologues across vertebrates. PMID- 27473877 TI - Expressing sexuality in nursing homes. The experience of older women: A qualitative study. AB - In nursing homes, a number of barriers to the expression of sexuality exist, such as the lack of privacy, certain attitudes on behalf of the staff and the family, the lack of a sexual partner, and physical limitations. The aim of this study was to describe the lived experience of sexuality in elderly Spanish women residing in nursing homes. A qualitative phenomenological approach was followed. Data were collected over an 18-month period between 2013 and 2015. Purposeful sampling was conducted with Spanish residents in nursing homes in Madrid. Data were collected using unstructured and semi-structured interviews. The data were analyzed using thematic analysis. Twenty female residents participated. Three main themes emerged from the data: a) expressing sexuality, b) sexuality as a duty and c) respecting vows. Female residents reported key elements influencing how they manage their sexuality in Nursing Homes. These results serve to improve our understanding regarding the expression of sexuality in older female nursing home residents. PMID- 27473878 TI - Predicting long-term nursing home transfer from MI choice waiver program. AB - This study aimed to identify characteristics of elderly participants in the Michigan Home and Community-Based Waiver Program that are associated with high risk of long-term nursing home (LT-NH) placement. We identified 8172 waiver clients aged 65 and older during 10/1/2010-9/30/2014. A proportional cause specific hazards regression model was used to analyze risk factors of waiver elderly for LT-NH placement. Waiver elderly participants who were white (HR (white vs. black): 2.76, with 95% CI (1.91, 4.00); HR (white vs. other races): 1.77, with 95% CI (1.05, 2.97)), had a history of long-term care use (HR: 1.42, 95% CI (1.14, 1.76)), mental disorders (HR: 1.51, 95% CI (1.23, 1.86)), bathing dependency (HR: 1.43, 95% CI (1.07, 1.89)), and finance management dependency (HR: 1.73, 95% CI (1.15, 2.60)) had greater hazards of LT-NH placement. Our study can be useful for policy makers to develop relevant support to reduce LT-NH placement. PMID- 27473879 TI - Older adults' personal routine at time of hospitalization. AB - This study is the first to explore whether hospitalization disrupts the daily routines of dependent and independent older adults. Data were collected as part of a prospectively designed study from 330 hospitalized older adults age 70+. Patients reported prehospitalization frequency, duration, and timing of basic activities of daily living and leisure activities at hospital admission. Hospital routine was assessed on day of discharge. Results indicated that frequency and duration of most basic activities decreased during hospitalization; the sharpest decrease was in frequency of getting dressed. Showering occurred 2 h earlier in the hospital setting, and getting dressed occurred an hour and a half later. For dependent respondents, the greatest change was in duration; for independent respondents, the greatest change was in frequency. Given the importance of routine maintenance to health and well-being, understanding the dynamics of its disruption in the hospital setting is imperative. PMID- 27473880 TI - Umbilical Cord Pseudocyst in a Newborn. PMID- 27473881 TI - Chest Radiograph as Diagnostic Clue in a Floppy Infant. PMID- 27473882 TI - The Influence of Brand Equity Characters on Children's Food Preferences and Choices. AB - OBJECTIVES: To assess the influence of brand equity characters displayed on food packaging on children's food preferences and choices, 2 studies were conducted. Brand equity characters are developed specifically to represent a particular brand or product. Despite existing literature suggesting that promotional characters influence children's food choices, to date, no research has assessed the influence of brand equity characters specifically. STUDY DESIGN: We recruited 209 children 4-8 years of age from schools and childcare centers in the UK. In a mixed-measures design, the children were asked to rate their taste preferences and preferred snack choice for 3 matched food pairs, presented either with or without a brand equity character displayed on packaging. Study 1 addressed congruent food-character associations and study 2 addressed incongruent associations. Participants were also asked to rate their recognition and liking of characters used. Wilcoxon signed-rank tests and chi(2) analyses were used where appropriate. RESULTS: Children were significantly more likely to show a preference for foods with a brand equity character displayed on the packaging compared with a matched food without a brand equity character, for both congruent and incongruent food-character associations. The presence of a brand equity character also significantly influenced the children's within-pair preferences, within-pair choices, and overall snack choice (congruent associations only). CONCLUSIONS: Displaying brand equity characters promotes unhealthy food choices in children. The findings are consistent with those of studies exploring other types of promotional characters. In the context of a childhood obesity epidemic, the use of brand equity characters in the promotion of foods high in fat, salt, and sugar to children should be restricted. PMID- 27473883 TI - There Is No "I" in Team: New Challenges for Career Development in the Era of Team Science. PMID- 27473884 TI - A 17-year experience in perioperative anaphylaxis 1998-2015: harmonizing optimal detection of mast cell mediator release. AB - BACKGROUND: Sheffield NARCOS (National Adverse Reactions Advisory Service) investigates suspected perioperative anaesthetic reactions using serial tryptase, urinary methylhistamine (UMH) and clinical information. Further recommendations for additional allergy clinic assessment are provided. OBJECTIVE: To establish a robustly measurable protocol for identifying mast cell mediator (MMR) release in this cohort. To compare these thresholds with previously suggested thresholds and algorithms. METHOD: A review of 3455 NARCOS cases referred with a suspected perioperative allergic reaction. Tryptase, UMH and clinical details were analysed. A total of 1746 cases were graded using the Ring and Messmer scale. Reaction grade, tryptase and UMH changes were compared with statistical and graphical presentations appropriate to non-normally distributed measurements using Analyse-IT software. RESULTS: Sensitive strategies such as 3 MUg/L or 20% are measurable and translatable and would substantially increase detection of potentially relevant changes in tryptases. Adequate quality assurance for low level measurement is needed. An incremental threshold of 20% would identify potential MMR in an additional 14% of cases with peak tryptase (Tp) between 5 and 14 MUg/L and a further 15% with Tp below 5 MUg/L. Further work is required to establish the diagnostic performance characteristics of this more sensitive approach. UMH also identified up to 120 further cases of potential MMR in the absence of tryptase increments. CONCLUSIONS AND CLINICAL RELEVANCE: Future studies should establish and compare the predictive performance characteristics of each strategy against clinical phenotypes. A single agreed definition of positive serial tryptases is needed to enable robust evaluation of diagnostic strategies. This could serve as a harmonized standard for comparative studies of case series from different centres. PMID- 27473886 TI - Development of model for prediction of Leachate Pollution Index (LPI) in absence of leachate parameters. AB - Leachate pollution index (LPI) is an environmental index which quantifies the pollution potential of leachate generated in landfill site. Calculation of Leachate pollution index (LPI) is based on concentration of 18 parameters present in leachate. However, in case of non-availability of all 18 parameters evaluation of actual values of LPI becomes difficult. In this study, a model has been developed to predict the actual values of LPI in case of partial availability of parameters. This model generates eleven equations that helps in determination of upper and lower limit of LPI. The geometric mean of these two values results in LPI value. Application of this model to three landfill site results in LPI value with an error of +/-20% for ?inwi?0.6. PMID- 27473885 TI - Associations of dietary polychlorinated biphenyls and long-chain omega-3 fatty acids with stroke risk. AB - BACKGROUND: Little is known about joint exposure to polychlorinated biphenyls (PCBs) and long-chain omega-3 fatty acids [eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)], through fish consumption, on cerebrovascular disease risk. OBJECTIVE: To explore associations of dietary PCB exposure and EPA-DHA intake with risk of different stroke subtypes. METHODS: This was assessed in the prospective population-based Cohort of Swedish Men including 39,948, middle-aged and elderly men, who were free of cardiovascular disease and cancer at baseline in 1997. Validated estimates of dietary PCBs and EPA-DHA were obtained via a food frequency questionnaire. RESULTS: During 12years of follow-up, 2286 and 474 incident cases of ischemic stroke and hemorrhagic stroke, respectively, were ascertained through register linkage. Dietary PCB exposure and EPA-DHA intake were associated with hemorrhagic stroke but not ischemic stroke. Men in the highest quartile of dietary PCB exposure (median 412ng/day) had a multivariable- and EPA-DHA-adjusted RR of hemorrhagic stroke of 2.77 [95% confidence interval (CI), 1.48-5.19] compared with men in the lowest quartile (median 128ng/day; p for trend <0.01). The corresponding RRs in men with and without hypertension were 5.45 (95% CI, 1.34-22.1) and 2.37 (95% CI 1.17-4.79), respectively. The multivariable- and PCB-adjusted RR of hemorrhagic stroke for the highest quartile of EPA-DHA intake (median 0.73g/day) versus the lowest quartile (median 0.18g/day) was 0.42 (95% CI, 0.22-0.79). CONCLUSION: Dietary PCB exposure was associated with an increased risk of hemorrhagic stroke, whereas a protective association was observed for dietary EPA-DHA intake. PMID- 27473887 TI - The malfunction of peroxisome has an impact on the oxidative stress sensitivity in Candida albicans. AB - The peroxisome plays an essential role in eukaryotic cellular metabolism, including beta-oxidation of fatty acids and detoxification of hydrogen peroxide. However, its functions in the important fungal pathogen, C. albicans, remain to be investigated. In this study, we identified a homologue of Saccharomyces cerevisiae peroxisomal protein Pex1 in this pathogen, and explored its functions in stress tolerance. Fluorescence observation revealed that C. albicans Pex1 was localized in the peroxisomes, and its loss led to the defect in peroxisome formation. Interestingly, the pex1Delta/Delta mutant had increased tolerance to oxidative stress, which was neither associated with the Cap1 pathway, nor related to the altered distribution of catalase. However, under oxidative stress, the pex1Delta/Delta mutant showed increased expression of autophagy-related genes, with enhanced cytoplasm-to-vacuole transport and degradation of the autophagy markers Atg8 and Lap41. Moreover, the double mutants pex1Delta/Deltaatg8Delta/Delta and pex1Delta/Deltaatg1Delta/Delta, both of which were defective in autophagy and peroxisome formation, showed remarkable attenuated tolerance to oxidative stress. These results indicated that autophagy is involved in resistance to oxidative stress in pex1Delta/Delta mutant. Taken together, this study provides evidence that the peroxisomal protein Pex1 regulates oxidative stress tolerance in an autophagy-dependent manner in C. albicans. PMID- 27473889 TI - Radium-223 in prostate cancer: emitting the right signals. PMID- 27473888 TI - Radium-223 and concomitant therapies in patients with metastatic castration resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. AB - BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223. METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012 000075-16. FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7.5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA). INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials. FUNDING: Pharmaceutical Division of Bayer. PMID- 27473890 TI - Quality of life and pain multidimensional aspects in individuals with HTLV-1. AB - HTLV-1 creates a chronic health condition that involves moderate to severe pain with a negative impact on quality of life (QoL). There is no consensus on which attitudes to pain are more related to the worsening of QoL in HTLV-1 infected patients. The aim of this study was to investigate the correlation between QoL and multidimensional aspects of pain in patients with HTLV-1. A cross-sectional study was conducted in Salvador, Bahia, Brazil. The study included individuals diagnosed with HTLV-1. The Short Form 36 Questionnaire was used to analyze QoL, and the Brief Pain Inventory was used to assess multidimensional aspects of pain. The mean pain intensity was 4.88+/-3.06 on the visual pain scale, and the average impact on QoL corresponded to a loss of approximately 40%. Moderate to high correlations between pain intensity and all domains of QoL were observed and compared reaction attitudes for general activity, mood, ability to walk, ability to work, relationships, sleep, and ability to enjoy life (r>0.40; p<0.05). Moderate correlations were found between all domains of QoL, pain intensity, and reactive attitudes to pain. The greatest pain intensity impacts involved difficulty to walk and to work, and interpersonal relationships in the emotional aspect of QoL. PMID- 27473891 TI - Cutaneous mucormycosis in advanced HIV disease. AB - Angionvasive mucormycosis is an emerging fungal disease known to affect mainly diabetics or subjects with profound neutropenia. Infection usually occurs through the inhalation route, but cutaneous inoculation may occur after trauma or burns. However, mucormycosis remains unusual in HIV infection. We report a fatal case of cutaneous mucormycosis due to Rhizopus arrhizus involving the scalp following herpes zoster infection. The patient was a 42-year-old man with advanced AIDS failing on salvage antiretroviral therapy. The fungus was diagnosed on the basis of histopathology and culture. Our case emphasizes the need to consider mucormycosis in the differential diagnosis of necrotic cutaneous lesions in patients with late-stage HIV disease. PMID- 27473892 TI - The fast transmission of infectious diseases around the world - a new concern to the public health. PMID- 27473893 TI - Ventilator-associated pneumonia: the influence of bacterial resistance, prescription errors, and de-escalation of antimicrobial therapy on mortality rates. AB - Ventilator-associated pneumonia is the most prevalent nosocomial infection in intensive care units and is associated with high mortality rates (14-70%). AIM: This study evaluated factors influencing mortality of patients with Ventilator associated pneumonia (VAP), including bacterial resistance, prescription errors, and de-escalation of antibiotic therapy. METHODS: This retrospective study included 120 cases of Ventilator-associated pneumonia admitted to the adult adult intensive care unit of the Federal University of Uberlandia. The chi-square test was used to compare qualitative variables. Student's t-test was used for quantitative variables and multiple logistic regression analysis to identify independent predictors of mortality. FINDINGS: De-escalation of antibiotic therapy and resistant bacteria did not influence mortality. Mortality was 4 times and 3 times higher, respectively, in patients who received an inappropriate antibiotic loading dose and in patients whose antibiotic dose was not adjusted for renal function. Multiple logistic regression analysis revealed the incorrect adjustment for renal function was the only independent factor associated with increased mortality. CONCLUSION: Prescription errors influenced mortality of patients with Ventilator-associated pneumonia, underscoring the challenge of proper Ventilator-associated pneumonia treatment, which requires continuous reevaluation to ensure that clinical response to therapy meets expectations. PMID- 27473894 TI - Antinociceptive effect induced by a combination of opioid and neurotensin moieties vs. their hybrid peptide [Ile(9)]PK20 in an acute pain treatment in rodents. AB - Hybrid compounds are suggested to be a more effective remedy for treatment of various diseases than combination therapy, since the attenuation or total disappearance of side effects, typically induced by a single moiety, can be observed. This is of great importance, especially when we consider problems resulting from the use of opioid analgesics. However, although it seems that such compounds can be valuable therapeutic tools, the lack of conviction among the public as to the appropriateness of their use still remains; therefore patients are commonly treated with polypharmacy. Thus, in the presented paper we show a comparison of the antinociceptive effect between a novel opioid-neurotensin chimera called [Ile(9)]PK20 and a mixture of its structural elements, delivered intrathecally and systemically. Additionally, motor coordination was assessed in the rotarod test. The results clearly indicate that spinal administration of the examined compounds, resulted in a long-lasting, dose- and time-dependent antinociceptive effect. Although the mixture of both pharmacophores was found to be more active than [Ile(9)]PK20, motor impairments surfaced as a side effect. This in turn illustrates the advantageous use of hybrid structures over drug cocktails. PMID- 27473895 TI - Increased expression of suppressor of cytokine signaling 2 in the subventricular zone after transient focal cerebral ischemia in adult rats. AB - Suppressor of cytokine signaling 2 (SOCS2) is a well-established negative regulator of growth hormone signaling that acts on adult hippocampal neurogenesis during ischemic insults. To explore whether SCOS2 is involved in poststroke neurogenesis, we studied the temporal expression of SOCS2 mRNA in the subventricular zone (SVZ) of rats after transient focal cerebral ischemia. We found that SOCS2 expression was upregulated in the SVZ of the infarcted hemisphere. The number of SOCS2-expressing cells was significantly increased in the ipsilateral SVZ compared with that on the contralateral side on days 7-10 after reperfusion, and SOCS2-expressing cells were highly proliferative, coinciding both spatially and temporally with stroke-induced neurogenesis. Almost all SOCS2-expressing cells in the SVZ were colabeled with the neural stem cell markers nestin and musashi1 and the neural/glial progenitor transcription factor Sox-2. In addition, SOCS2 was highly expressed in newly generated neurons that were immunoreactive for polysialic acid-neural cell adhesion molecule, indicating that SOCS2 expression may be persistent during neuronal differentiation. Thus, our data demonstrated that SOCS2 mRNA was highly expressed in proliferating neural stem/precursor cells and postmitotic migratory neuroblasts in the SVZ niche after focal cerebral ischemia, suggesting that SOCS2 may be actively involved in regulating adult neurogenesis induced by ischemic stroke. PMID- 27473896 TI - Lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFalpha) blunt the response of Neuropeptide Y/Agouti-related peptide (NPY/AgRP) glucose inhibited (GI) neurons to decreased glucose. AB - A population of Neuropeptide Y (NPY) neurons which co-express Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARC) are inhibited at physiological levels of brain glucose and activated when glucose levels decline (e.g. glucose-inhibited or GI neurons). Fasting enhances the activation of NPY/AgRP-GI neurons by low glucose. In the present study we tested the hypothesis that lipopolysaccharide (LPS) inhibits the enhanced activation of NPY/AgRP-GI neurons by low glucose following a fast. Mice which express green fluorescent protein (GFP) on their NPY promoter were used to identify NPY/AgRP neurons. Fasting for 24h and LPS injection decreased blood glucose levels. As we have found previously, fasting increased c-fos expression in NPY/AgRP neurons and increased the activation of NPY/AgRP-GI neurons by decreased glucose. As we predicted, LPS blunted these effects of fasting at the 24h time point. Moreover, the inflammatory cytokine tumor necrosis factor alpha (TNFalpha) blocked the activation of NPY/AgRP-GI neurons by decreased glucose. These data suggest that LPS and TNFalpha may alter glucose and energy homeostasis, in part, due to changes in the glucose sensitivity of NPY/AgRP neurons. Interestingly, our findings also suggest that NPY/AgRP-GI neurons use a distinct mechanism to sense changes in extracellular glucose as compared to our previous studies of GI neurons in the adjacent ventromedial hypothalamic nucleus. PMID- 27473897 TI - The effects of ivacaftor on CF fatty acid metabolism: An analysis from the GOAL study. AB - BACKGROUND: Ivacaftor has produced significant improvement in certain individuals with cystic fibrosis (CF), though the full metabolic effects of treatment remain unknown. Abnormalities in fatty acid metabolism have previously been shown to be a characteristic of CFTR dysfunction. We hypothesized that as a reflection of this clinical improvement, ivacaftor would improve plasma fatty acid levels and decrease urine prostaglandin E metabolite levels. METHODS: This study analyzed plasma fatty acid levels and urine prostaglandin E metabolites (PGE-M) in 40 subjects with CF participating in the G551D observational (GOAL) study who demonstrated response to the medication by a significant decrease in sweat Cl levels. Paired samples were analyzed before and after 6months of ivacaftor treatment. RESULTS: Linoleic acid and docosahexaenoic acid levels, which are typically low in individuals with CF, did not significantly increase with ivacaftor treatment. However, arachidonic acid levels did decrease with ivacaftor treatment and there was a significant decrease in the arachidonic acid metabolite PGE-M as measured in the urine [median: before treatment 17.03ng/mg Cr; after treatment 9.06ng/mg Cr; p<0.001]. Furthermore, there were fatty acid age differences observed, including pediatric participants having significantly greater linoleic acid levels at baseline. CONCLUSION: Ivacaftor reduces inflammatory PGE without fully correcting the plasma fatty acid abnormalities of CF. Age-related differences in fatty acid levels were observed, that may be a result of other clinical factors, such as diet, clinical care, or drug response. PMID- 27473898 TI - Adherence to therapies for secondary prevention of cardiovascular disease: a focus on aspirin. AB - AIM: Suboptimal adherence to medications taken chronically for secondary prevention of cardiovascular disease (CVD, e.g., aspirin) continues to burden the healthcare system despite the well-established benefits of prevention. We conducted a literature search to examine patient adherence to medications for secondary prevention of CVD-as evaluated by prescription refill data, electronic medication monitors, pill counts, and physiologic markers-to better identify an unmet need for measures to improve patient adherence to these therapies. METHODS: English-language articles were obtained from the PubMed database using the following key words or combinations thereof "adherence," "compliance," "secondary prevention," and "cardiovascular disease." Publications that provided adherence data only for primary prevention, lacked data on medication adherence (e.g., focus on guideline adherence), emphasized quality-of-care outcomes, or focused on outcomes of acute interventions were excluded. RESULTS: Multiple patient-, disease-, and treatment-related factors may contribute to poor adherence to treatment regimens, and therefore, a multifactorial approach will likely be needed to improve compliance with prescribed treatments for CVD. Although no magic bullet exists to assure full adherence, adherence programs coupled with patient counseling and education (inclusive of over-the-counter therapies), along with treatments that are less complex or avoid bothersome adverse effects, are more likely to be associated with successful outcomes. CONCLUSION: Given the burden of CVD to the community and the healthcare system, nonadherence to CVD preventative medications such as aspirin remains a substantial area of unmet need and represents a key opportunity for the development of quality-of-care enhancement programs to improve health outcomes in this patient population. PMID- 27473899 TI - Prevalence of Potentially Inappropriate Medication Use in Older Adults Living in Nursing Homes: A Systematic Review. AB - IMPORTANCE: As older adults living in nursing homes are at a high risk of adverse drug-related events, medications with a poor benefit/risk ratio or with a safer alternative should be avoided. OBJECTIVES: To systematically evaluate the prevalence of potentially inappropriate medication use in nursing home residents. EVIDENCE REVIEW: We searched in PubMed and EMBASE databases (1990-2015) for studies reporting the prevalence of potentially inappropriate medication use in people >=60 years of age living in nursing homes. The risk of bias was assessed with an adapted version of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. FINDINGS: A total of 91 articles were assessed for eligibility, and 48 met our inclusion criteria. These articles reported the findings from 43 distinct studies, of which 26 presented point prevalence estimates of potentially inappropriate medication use (227,534 nursing home residents). The overall weighted point prevalence of potentially inappropriate medication use in nursing homes was 43.2% [95% confidence interval (CI) 37.3%-49.1%], increasing from 30.3% in studies conducted during 1990-1999 to 49.8% in studies conducted after 2005 (P < .001). Point prevalence estimates reported in European countries were found to be higher (49.0%, 95% CI 42.5-55.5) than those reported in North America (26.8%, 95% CI 16.5-37.1) or in other countries (29.8%, 95% CI 19.3-40.3). In addition, 18 studies accounting for 326,562 nursing home residents presented 20 distinct period prevalence estimates ranging from 2.3% to 50.3%. The total number of prescribed medications was consistently reported as the main driving factor for potentially inappropriate medications use. CONCLUSIONS AND RELEVANCE: This systematic review shows that almost one-half of nursing home residents are exposed to potentially inappropriate medications and suggests an increase prevalence over time. Effective interventions to optimize drug prescribing in nursing home facilities are, therefore, needed. PMID- 27473900 TI - The nonopisthokont septins: How many there are, how little we know about them, and how we might learn more. AB - We have confirmed and extended previous reports of a wide distribution of septin proteins in the eukaryotic phylogeny. It now appears that septins are present in at least some representatives of every eukaryotic supergroup, with the possible exception of the Excavata. Presently, almost nothing is known of the structure, assembly, and biological roles of septins outside of the opisthokonts (animals, fungi, and their close relatives). Thus, studies of the septins in the highly diverse and distantly related nonopisthokont groups present a major opportunity to gain a much deeper understanding of septin core function and evolution, and we discuss briefly the excellent prospects for capitalizing on this opportunity in the next few years. PMID- 27473901 TI - Preparing recombinant yeast septins and their analysis by electron microscopy. AB - Septins are highly conserved and essential eukaryotic cytoskeletal proteins that interact with the inner plasma membrane. They are involved in essential functions requiring cell membrane remodeling and compartmentalization, such as cell division and dendrite morphogenesis, and have been implicated in numerous diseases. Depending on the organisms and on the type of tissue, a specific set of septins genes are expressed, ranging from 2 to 13. Septins self-assemble into linear, symmetric rods that can further organize into linear filaments several microns in length. Only a subset of human septins has been described at high resolution by X-ray crystallography (Sirajuddin et al., 2007). Electron microscopy (EM) has proven to be a method of choice for analyzing the molecular organization of septins. It is possible to localize each septin subunit within the rod complex using genetic tags, such as maltose-binding protein or green fluorescent protein, to generate a visible label of a specific septin subunit in EM images that are processed using single-particle EM methodology. In this chapter we present, in detail, the methods that we have used to analyze the molecular organization of budding yeast septins (Bertin et al., 2008). These methods include purification of septin complexes, sample preparation for EM, and image processing procedures. Such methods can be generalized to analyze the organization of septins from any organism. PMID- 27473903 TI - In vitro reconstitution of septin assemblies on supported lipid bilayers. AB - Septins are polymerizing eukaryotic proteins that play conserved roles in cell cortex organization and are essential in many cell types. How septin dynamics and protein-protein interactions determine their function at the plasma membrane remains a mystery. Here, we present a method for recapitulating septin polymerization and lipid interaction utilizing supported lipid bilayers to mimic the eukaryotic plasma membrane. Septins on supported lipid bilayers can be visualized with single-molecule sensitivity using total internal reflective fluorescence microscopy. Microscopy-based in vitro assays have revolutionized our understanding of actin, microtubules, and bacterial cytoskeletal systems, and will likely immediately advance our understanding of the septin proteins. As such, we hope that this technique will be adopted and widely utilized by those interested in uncovering septin properties and functions of septin interacting proteins. PMID- 27473902 TI - A FRET-based method for monitoring septin polymerization and binding of septin associated proteins. AB - Much about septin function has been inferred from in vivo studies using mainly genetic methods, and much of what we know about septin organization has been obtained through examination of static structures in vitro primarily by electron microscopy. Deeper mechanistic insight requires real-time analysis of the dynamics of the assembly of septin-based structures and how other proteins associate with them. We describe here a Forster resonance energy transfer (FRET) based approach for measuring in vitro the rate and extent of filament formation from septin complexes, binding of other proteins to septin structures, and the apparent affinities of these interactions. FRET is particularly well suited for interrogating protein-protein interactions, especially on a rapid timescale; the spectral change provides an unambiguous indication of whether two elements within the system under study are associating and serves as a molecular-level "ruler" because it is very sensitive to the separation between the donor and acceptor fluorophores over biologically relevant distances (<=10nm). The necessary procedures involve generation of appropriate cysteine-less and single cysteine containing septin variants, expression and purification of the heterooctameric complexes containing them, efficient labeling of the purified complexes with desired fluorophores, fluorimetric measurement of FRET, and appropriate safeguards and controls in data acquisition and analysis. Our methods can be used to interrogate the effects of buffer conditions, small molecules, and septin binding proteins on septin filament assembly or stability; determine the effect of alternative septin subunits, mutational alterations, or posttranslational modifications on assembly; and, delineate the location of septin-binding proteins. PMID- 27473904 TI - Visualization of in vivo septin ultrastructures by platinum replica electron microscopy. AB - Septins are cytoskeletal proteins involved in diverse biological processes including cytokinesis, cell morphogenesis, motility, and ciliogenesis. Septins form various filamentous structures in vitro and in vivo, but the higher-order architecture of septin structures in vivo remains poorly defined. The best understood system in this respect is the budding yeast Saccharomyces cerevisiae, where septins form a ring structure that undergoes multiple stages of remodeling during the cell cycle. In this chapter, we describe a method for visualizing supramolecular septin structures in yeast at high spatial resolution using platinum replica electron microscopy. This approach can be applied to further understand the regulation of assembly and remodeling of septin higher-order structures, as well as the relationship between septin architecture and function. PMID- 27473905 TI - Assays for genetic dissection of septin filament assembly in yeast, from de novo folding through polymerization. AB - In Saccharomyces cerevisiae, septin mutations have severe effects on colony forming ability, particularly at high temperatures, allowing the full variety of genetic tools available in this model organism to be applied to the study of septin biology. Although many details of septin function remain unknown, one can exploit a small number of easily scored phenotypes-proliferation capacity, cell morphology, septin localization, and septin ring integrity-as sensitive readouts of properly assembled septin filaments. Accordingly, this chapter focuses on genetic approaches targeted toward understanding the molecular mechanisms of de novo septin folding, heterooligomerization, and polymerization into filaments. The same general methods can be used to interrogate septin function, although interpretation of results can be more complicated. As genetic-based methodologies are technically simple but particularly dependent on interpretation, here I focus on the logic underlying the most common interpretations of results using septin mutants. PMID- 27473906 TI - Investigation of septins using infection by bacterial pathogens. AB - Investigation of the host cytoskeleton during infection by bacterial pathogens has significantly contributed to our understanding of cell biology and host defense. Work has shown that septins are recruited to the phagocytic cup as collarlike structures and enable bacterial entry into host cells. In the cytosol, septins can entrap actin-polymerizing bacteria in cage-like structures for targeting to autophagy, a highly conserved intracellular degradation process. In this chapter, we describe methods to investigate septin assembly and function during infection by bacterial pathogens. Use of these methods can lead to in depth understanding of septin biology and suggest therapeutic approaches to combat infectious disease. PMID- 27473907 TI - In vivo analysis of septin heteropolymer rods and higher-order structures in filamentous fungi. AB - Individual septins from separate phylogenetic groups assemble into heteropolymer rods with defined compositions. Heteropolymer rods can in turn assemble into larger higher-order structures (HOS). Using a combination of immunoprecipitation and fluorescence microscopy in Aspergillus nidulans wild-type and septin-mutant strains, we have shown that even when septin HOS are not visible by fluorescence microscopy, heteropolymer rods can still be present and that a septin found largely in filamentous fungi is required for a subset of HOS. We raise several factors that are important for analysis of heteropolymer rods and HOS. PMID- 27473908 TI - Live cell imaging of septin dynamics in Ustilago maydis. AB - Septins are highly conserved cytoskeletal proteins involved in a variety of biological processes such as cell polarization and cytokinesis. In humans, functional defects in these proteins have been linked to cancer and neuronal diseases. In recent years, substantial progress has been made in studying the structure of septin subunits and the formation of defined heteromeric building blocks. These are assembled into higher-order structures at distinct subcellular sites. An important microscopic approach in studying septin assembly and dynamics is the use of septins tagged with fluorescent proteins. This revealed, eg, that septins form rings during cytokinesis and that septins build extended filaments partially colocalizing with actin cables and microtubules. Here, we describe extensive live cell imaging of septins in the model microorganism Ustilago maydis. We present techniques to study dynamic localization of protein and septin mRNA on shuttling endosomes as well as colocalization of proteins at these highly motile units. Moreover, FLIM-FRET experiments for analyzing local protein interactions are presented. Importantly, these imaging approaches transfer well to other fungal and animal model systems for in vivo analysis of septin dynamics. PMID- 27473909 TI - Ashbya gossypii as a model system to study septin organization by single-molecule localization microscopy. AB - Heteromeric complexes of GTP-binding proteins from the septin family assemble into higher order structures that are essential for cell division in many organisms. The correct organization of the subunits into filaments, gauzes, and rings is the basis of septin function in this process. Electron microscopy and polarization fluorescence microscopy contributed greatly to the understanding of the dynamics and organization of such structures. However, both methods show technical limitations in resolution and specificity that do not allow the identification of individual septin complexes in assemblies in intact cells. Single-molecule localization-based fluorescence superresolution microscopy methods combine the resolution of cellular structures at the nanometer level with highest molecular specificity and excellent contrast. Here, we provide a protocol that enables the investigation of the organization of septin complexes in higher order structures in cells by combining advantageous features of the model organism Ashbya gossypii with single-molecule localization microscopy. Our assay is designed to investigate the general assembly mechanism of septin complexes in cells and is applicable to many cell types. PMID- 27473910 TI - Visualizing septins in early Drosophila embryos. AB - Functional studies in Drosophila have been key for establishing a role for the septin family of proteins in animal cell division and thus extending for the first time observations from the budding yeast to animal cells. Visualizing the distribution of specific septins in different Drosophila tissues and, in particular, in the Drosophila embryo, together with biochemical and mutant phenotype data, has contributed important advances to our understanding of animal septin biology, suggesting roles in processes other than in cytokinesis. Septin localization using immunofluorescence assays has been possible due to the generation of antibodies against different Drosophila septins. The recent availability of lines expressing fluorescent protein fusions of specific septins further promises to facilitate studies on septin dynamics. Here, we provide protocols for preparing early Drosophila embryos to visualize septins using immunofluorescence assays and live fluorescence microscopy. The genetic tractability of the Drosophila embryo together with its amenability to high resolution fluorescence microscopy promises to provide novel insights into animal septin structure and function. PMID- 27473911 TI - Purification of recombinant human and Drosophila septin hexamers for TIRF assays of actin-septin filament assembly. AB - Septins are guanine nucleotide-binding proteins that are conserved from fungi to humans. Septins assemble into heterooligomeric complexes and higher-order structures with key roles in various cellular functions including cell migration and division. The mechanisms by which septins assemble and interact with other cytoskeletal elements like actin remain elusive. A powerful approach to address this question is by cell-free reconstitution of purified cytoskeletal proteins combined with fluorescence microscopy. Here, we describe procedures for the purification of recombinant Drosophila and human septin hexamers from Escherichia coli and reconstitution of actin-septin coassembly. These procedures can be used to compare assembly of Drosophila and human septins and their coassembly with the actin cytoskeleton by total internal reflection fluorescence microscopy. PMID- 27473912 TI - Investigation of septin biology in vivo using zebrafish. AB - The zebrafish (Danio rerio) is an important animal model to study cell biology in vivo. Benefits of the zebrafish include a fully annotated reference genome, an easily manipulable genome (for example, by morpholino oligonucleotide or CRISPR Cas9), and transparent embryos for noninvasive, real-time microscopy using fluorescent transgenic lines. Zebrafish have orthologues of most human septins, and studies using larvae were used to investigate the role of septins in vertebrate development. The zebrafish larva is also an established model to study the cell biology of infection and has recently been used to visualize septin assembly during bacterial infection in vivo. Here, we describe protocols for the study of septins in zebrafish, with emphasis on techniques used to investigate the role of septins in host defense against bacterial infection. PMID- 27473913 TI - Fluorescence microscopy of actin- and microtubule-associated septins in mammalian cells. AB - Septins are a major component of the mammalian cytoskeleton. Septins associate with filamentous actin (F-actin) and microtubules, but the nature and significance of these interactions are not well understood. Fluorescence microscopy of F-actin- and microtubule-associated septins in fixed and living cells has been instrumental in uncovering septin functions in cellular morphogenesis and cytoskeleton-dependent processes (eg, cell division, cell migration). Here, we provide a detailed methodology for the visualization of endogenous septins by immunofluorescence microscopy, discussing sample preparation and reagents that are critical for optimal staining. In addition, we review approaches for the construction and expression of fluorescent septins and their time-lapse imaging with F-actin and microtubules. The recommended methodology is adaptable for high- and superresolution imaging of mammalian cells with various instrumentation, including wide-field and confocal microscopy as well as total internal reflection fluorescence and structured illumination microscopy. PMID- 27473914 TI - Immunofluorescent staining of septins in primary cilia. AB - Primary cilia are cellular antennae that receive and transduce extracellular cues. These microtubule-rich structures are comprised of at least three distinct ciliary compartments: basal bodies, transition zone, and axoneme. Septins have been implicated in cilia function at the transition zone, but accumulating evidence suggests that they localize predominantly within the axoneme. Here, we describe three fixation conditions that preserve the substructure of primary cilia and demonstrate known ciliary proteins that localize to these distinct ciliary substructures. Finally, we show immunostaining and live microscopy methods to detect septins within the axoneme. PMID- 27473915 TI - Methods for immunoblot detection and electron microscopic localization of septin subunits in mammalian nervous systems. AB - The minimal functional units of the mammalian septin system are diverse heterooligomers of SEPT1-14 subunits, which are most abundantly and differentially expressed in postmitotic neurons and glia. The subunit compositions of such heterooligomers are thought to differentiate their affinity for other proteins and lipids, and subcellular localization. Thus, high-precision quantification and mapping of each subunit is necessary to understand their subcellular functions and physiological roles. However, systematic information on the localization of individual septin subunits in the mammalian nervous system is limited. Here, we present our experimental workflows for the study of septin expression and localization in the rodent brain by immunoblot and serial section immunoelectron microscopy. Our protocols, based on standard methods, have been rigorously optimized and simplified for universality and reproducibility to aid non-experts in the field. PMID- 27473916 TI - Visualizing septin and cell dynamics in mammalian brain slices. AB - Correct neuronal migration is crucial for the brain architecture and function. During brain development, excitatory and inhibitory neurons generated in the ventricular zone (VZ) of the dorsal telencephalon and ganglionic medial eminence, respectively, move to their final destinations in tightly regulated spatiotemporal manners. While a variety of morphological methods have been applied to neurobiology, in utero electroporation (IUE) technique is one of the most powerful tools for rapid gain- and loss-of-function studies of brain development. This method enables us to introduce genes of interest into VZ progenitor and stem cells of rodent embryos, and to observe resulting phenotypes such as proliferation, migration, and cell morphology at later stages. In this chapter, we first summarize basic immunohistochemistry methods that are foundations for any advanced methods and showed data on the distribution of Sept6, Sept9, and Sept14 as examples. Then, IUE method is described where functional analyses of Sept14 during brain development are used as examples. We subsequently refer to the in vivo electroporation (IVE)-mediated gene transfer, which is conceptually the same method as IUE, into granule cells of hippocampal dentate gyrus in neonatal mice. Finally, an IUE-based time-lapse imaging method is explained as an advanced technique for the analyses of cortical neuron migration. IUE and IVE methods and the application would contribute greatly to the morphological analyses of septins as well as other molecules to elucidate their neuronal functions and pathophysiological roles in various neurological and psychiatric disorders. PMID- 27473917 TI - Small molecule perturbations of septins. AB - Progress on the study of the molecular and cellular biology of septins would be greatly accelerated by the development of small molecules that directly inhibit higher-order septin assembly in vivo. By comparison, molecules like latrunculin, paclitaxil, benomyl, etc. allow researchers to acutely perturb the actin or tubulin cytoskeletal networks. Two small molecules, forchlorfenuron (FCF; N-(2 chloro-4pyridyl)-N-phenylurea) and 1-ethyl-3-(4-methoxyphenyl)-6 methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione (PubChem CID 906558), have documented effects on septin localization and/or function, although for each molecule there is also strong evidence for off-target effects. In this chapter we provide a summary of ways to utilize FCF to alter higher-order septin assembly properties in living cells. PMID- 27473918 TI - Septin crystallization for structural analysis. AB - Septins are filament-forming proteins found in many eukaryotes. Despite being important components of the cytoskeleton, only recently details of their macromolecular assemblies and crystal structures have started to appear in the literature. These are of fundamental importance to the understanding of cytoskeleton dynamics, membrane barrier formation, and bacterial caging, as well as essential cellular processes such as cell division, exocytosis, and vesicle trafficking. However, obtaining this data is frequently hindered by several experimental difficulties common to the majority of septin samples. Here we provide an overview of the current approaches to circumvent or minimize the experimental complications observed in septin crystallography focusing mainly, but not exclusively, on the choice of the septin construct and how to best prepare the sample itself. PMID- 27473919 TI - Etoposide induces pancreatic beta-cells cytotoxicity via the JNK/ERK/GSK-3 signaling-mediated mitochondria-dependent apoptosis pathway. AB - Etoposide is widely used in the treatment of the different types of tumors such as pancreatic cancer. However, etoposide also causes several unwanted side effects in normal viable cells, including pancreatic beta-cells, which are vulnerable to chemical-induced injuries, and the molecular mechanisms underlying etoposide-induced apoptosis are still unclear. Here, the results showed that in RIN-m5F cells (a beta-cell-derived cell line), the number of viable cells was significantly decreased after 24h of etoposide treatment and underwent mitochondria-dependent apoptotic signals accompanied by mitochondrial dysfunction, and increases in the population of sub-G1 hypodiploid cells and apoptotic cells, caspase-3 activity, and the activation of caspase cascades. Etoposide also increased the phosphorylation levels of glycogen synthase kinase (GSK)-3alpha/beta in treated RIN-m5F cells. Pretreatment with LiCl, a GSK-3 inhibitor, prevented etoposide-induced mitochondria-dependent apoptosis and GSK-3 protein phosphorylation in RIN-m5F cells. Furthermore, exposure of the cells to etoposide induced the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK)1/2 but not p38-MAPK, which was suppressed by the specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059), respectively. Additionally, pretreatment with both SP600125 and PD98059 effectively suppressed etoposide-induced beta-cell cytotoxicity, apoptosis, and GSK-3 protein phosphorylation; however, LiCl did not reverse JNK and ERK1/2 phosphorylation. Taken together, these results suggest that etoposide is capable of causing cytotoxicity on pancreatic beta-cells by inducing apoptosis through the JNK/ERK-mediated GSK-3 downstream-triggered mitochondria-dependent signaling pathway. PMID- 27473921 TI - Comparison of Treatment Outcome After Collagenase and Needle Fasciotomy for Dupuytren Contracture: A Randomized, Single-Blinded, Clinical Trial With a 1-Year Follow-Up. AB - PURPOSE: This study compared the efficacy of collagenase treatment and needle fasciotomy for contracture of the metacarpophalangeal (MCP) joint in Dupuytren disease. METHODS: This is a prospective, single-blinded, randomized study with follow-up 1 week and 1 year after treatment. One hundred and forty patients with an MCP contracture of 20 degrees or more in a single finger were enrolled, of whom 69 patients were randomized to collagenase treatment and 71 patients to needle fasciotomy. The patients were followed at 1 week and were examined by a physiotherapist after 1 year. Measurements of joint movement and grip strength were recorded as well as patient-perceived outcomes measured by the Unite Rhumatologique des Affections de la Main (URAM) questionnaire and a visual analog scale (VAS) for the estimation of procedural pain and subjective treatment efficacy. RESULTS: Eighty-eight percent of the patients in the collagenase group and 90% of the patients in the needle fasciotomy group had a reduction in their MCP contracture to less than 5 degrees 1 week after treatment, and the median gains in passive MCP movement were 48 degrees and 46 degrees , respectively. The median VAS score for procedural pain was 4.9 of 10 in the collagenase group and 2.7 of 10 in the needle fasciotomy group. After 1 year, 90% of the patients in both groups had full extension of the treated MCP joint. One patient in each group had a recurrence of the contracture. The median improvement in URAM score was 8 units in both groups and the VAS estimation of treatment efficacy by the patients was 8.7 of 10 in both groups. CONCLUSIONS: There was no significant difference between the treatment outcomes after collagenase and needle fasciotomy treatment after 1 year. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 27473920 TI - [Breast cancer screening: On our way to the future]. AB - Breast cancer remains a potentially lethal disease, which requires aggressive treatments and is associated with long-term consequences. Its prognosis is linked to both tumor biology and burden at diagnosis. Although treatments have allowed important improvements in prognosis over the past 20 years, breast cancer screening remains necessary. Mammographic screening allows earlier stage diagnoses and a decrease of breast cancer specific mortality. However, breast cancer screening modalities should be revised with the objective to address demonstrated limitations of mammographic screening (limited benefit, imperfect sensitivity and specificity, overdiagnoses, radiation-induced morbidity). Furthermore, both objective and perceived performances of screening procedures should be improved. Numerous large international efforts are ongoing, leading to scientific progresses that should have rapid clinical implications in this area. Among them is improvement of imaging techniques performance, development of real time diagnosis, and development of new non radiological screening techniques such as the search for circulating tumor DNA, development of biomarkers able to allow precise risk evaluation and stratified screening. As well, overtreatment is currently addressed by biomarker-based de-escalation clinical trials. These advances need to be associated with strong societal support, as well as major paradigm changes regarding the way health and cancer prevention is perceived by individuals. PMID- 27473922 TI - A Longitudinal Study of Predictors of Housing Stability, Housing Quality, and Mental Health Functioning Among Single Homeless Individuals Staying in Emergency Shelters. AB - The current study examined risk and resilience factors at multiple levels that affect homeless individuals' ability to exit homelessness and achieve housing stability. It also examined the relationship between housing status, housing quality and mental health functioning. The methodology is a longitudinal study of single homeless individuals staying in emergency shelters in a medium-sized Canadian city who were followed for a 2 year period. Data were collected from participants at a baseline interview when they were homeless and at a 2-year follow-up. There were 329 participants interviewed at baseline and 197 (59.9%) participants interviewed at follow-up. Results from a structural equation modelling analysis found that having interpersonal and community resources were predictive of achieving housing stability. Specifically, having a larger social support network, access to subsidized housing, and greater income was related to achieving housing stability. On the other hand, having a substance use problem was a risk factor associated with a failure to achieving housing stability. Being female, feeling personally empowered, having housing that is perceived of being of higher quality were directly predictive of mental health functioning at follow up. Findings are discussed in the context of previous research and their policy implications. PMID- 27473924 TI - A randomized controlled trial of an early-intervention, computer-based literacy program to boost phonological skills in 4- to 6-year-old children. AB - BACKGROUND: Many school-based interventions are being delivered in the absence of evidence of effectiveness (Snowling & Hulme, 2011, Br. J. Educ. Psychol., 81, 1). AIMS: This study sought to address this oversight by evaluating the effectiveness of the commonly used the Lexia Reading Core5 intervention, with 4- to 6-year-old pupils in Northern Ireland. SAMPLE: A total of 126 primary school pupils in year 1 and year 2 were screened on the Phonological Assessment Battery 2nd Edition (PhAB-2). Children were recruited from the equivalent year groups to Reception and Year 1 in England and Wales, and Pre-kindergarten and Kindergarten in North America. METHODS: A total of 98 below-average pupils were randomized (T0) to either an 8-week block (x- = 647.51 min, SD = 158.21) of daily access to Lexia Reading Core5 (n = 49) or a waiting-list control group (n = 49). Assessment of phonological skills was completed at post-intervention (T1) and at 2-month follow up (T2) for the intervention group only. RESULTS: Analysis of covariance which controlled for baseline scores found that the Lexia Reading Core5 intervention group made significantly greater gains in blending, F(1, 95) = 6.50, p = .012, partial eta2 = .064 (small effect size) and non-word reading, F(1, 95) = 7.20, p = .009, partial eta2 = .070 (small effect size). Analysis of the 2-month follow up of the intervention group found that all group treatment gains were maintained. However, improvements were not uniform among the intervention group with 35% failing to make progress despite access to support. Post-hoc analysis revealed that higher T0 phonological working memory scores predicted improvements made in phonological skills. CONCLUSIONS: An early-intervention, computer-based literacy program can be effective in boosting the phonological skills of 4- to 6 year-olds, particularly if these literacy difficulties are not linked to phonological working memory deficits. PMID- 27473925 TI - Trends in scientific publications related to the field of onco-urology over the past 10 years. PMID- 27473926 TI - Visfatin stimulates endometrial cancer cell proliferation via activation of PI3K/Akt and MAPK/ERK1/2 signalling pathways. AB - OBJECTIVE: Endometrial carcinoma is one of the most common malignancies of the female reproductive system, but the aetiology and pathogenesis are not well understood, although adipokines such as visfatin may be involved. Our study provides insight into the mechanism underlying the tumorigenic effects of visfatin in endometrial carcinoma. METHODS: We investigated the effect of visfatin on endometrial carcinoma cell proliferation, cell cycle, and apoptosis using well-differentiated Ishikawa cells and poorly differentiated KLE cells. We also assessed the effect of visfatin on tumour growth in vivo. RESULTS: Visfatin stimulated the proliferation of both Ishikawa and KLE cells, and visfatin treatment promoted G1/S phase progression and inhibited endometrial carcinoma cell apoptosis. Visfatin promoted endometrial carcinoma tumour growth in BALB/c nu mice. Transplanted tumour tissues from an endometrial carcinoma mouse model were analysed using immunohistochemical staining, which revealed much stronger positive signals for Ki-67 with over-abundant visfatin. Western blot analysis revealed that insulin receptor (IR), insulin receptor substrate (IRS)1/2 and key components of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 signalling pathways were highly expressed in endometrial carcinoma cells exposed to visfatin. Treated cells showed increased C-MYC and cyclin D1 and reduced caspase 3 expression. The effects of visfatin on proliferation and apoptosis were abrogated by treatment with the PI3K inhibitor LY294002 and MEK inhibitor U0126. CONCLUSIONS: Visfatin promotes the malignant progression of endometrial carcinoma via activation of IR and PI3K/Akt and MAPK/ERK signalling. Visfatin may serve as a therapeutic target in the treatment of endometrial carcinoma. PMID- 27473927 TI - Improvising a Posterior Nasal Pack with Equipment in a Basic First Aid Kit. AB - Posterior epistaxis is a serious condition that can be difficult to treat in a wilderness setting. The initial standard of care involves packing the affected nostril with a 7 to 9 cm nasal pack to tamponade the bleed. These packs are often unavailable outside of the emergency or operating room. This study set out to determine whether a posterior nasal pack could be constructed from the supplies present in a basic first aid kit in order to control massive nasal hemorrhage in a wilderness setting. A basic first aid kit was utilized to construct a posterior nasal pack that was inserted into an anatomical model and visibly compared with the Rapid Rhino (Posterior, 7.5 cm; Smith & Nephew, Austin, TX) nasal packing. The shape, size, and anatomical areas of compression (ie, into nasopharynx and posterior aspect of inferior turbinate) of this pack was similar to the commercially available posterior nasal pack. Placement in an anatomical model appears to provide similar compression as the commercially available posterior pack. This technique may provide short-term hemorrhage control in cases of serious posterior nasal hemorrhage where standard treatment options are not available. PMID- 27473923 TI - Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling. AB - Severe noise-induced damage to the inner ear leads to auditory nerve fiber degeneration thereby reducing the neural input to the cochlear nucleus (CN). Paradoxically, this leads to a significant increase in spontaneous activity in the CN which has been linked to tinnitus, hyperacusis and ear pain. The biological mechanisms that lead to an increased spontaneous activity are largely unknown, but could arise from changes in glutamatergic or GABAergic neurotransmission or neuroinflammation. To test this hypothesis, we unilaterally exposed rats for 2h to a 126dB SPL narrow band noise centered at 12kHz. Hearing loss measured by auditory brainstem responses exceeded 55dB from 6 to 32kHz. The mRNA from the exposed CN was harvested at 14 or 28days post-exposure and qRT-PCR analysis was performed on 168 genes involved in neural inflammation, neuropathic pain and glutamatergic or GABAergic neurotransmission. Expression levels of mRNA of Slc17a6 and Gabrg3, involved in excitation and inhibition respectively, were significantly increased at 28days post-exposure, suggesting a possible role in the CN spontaneous hyperactivity associated with tinnitus and hyperacusis. In the pain and inflammatory array, noise exposure upregulated mRNA expression levels of four pain/inflammatory genes, Tlr2, Oprd1, Kcnq3 and Ntrk1 and decreased mRNA expression levels of two more genes, Ccl12 and Il1beta. Pain/inflammatory gene expression changes via Ntrk1 signaling may induce sterile inflammation, neuropathic pain, microglial activation and migration of nerve fibers from the trigeminal, cuneate and vestibular nuclei into the CN. These changes could contribute to somatic tinnitus, hyperacusis and otalgia. PMID- 27473928 TI - [Inferior alveolar nerve reconstruction after segmental resection of the mandible]. AB - INTRODUCTION: The sacrifice of inferior alveolar nerve (IAN) is usual in case of resection of mandibular tumors and is responsible for disabling sensory disorders, drooling and lip incompetence. We report the case of a reconstruction of the IAN by means of an autologous nerve graft after segmental resection of the mandible. OBSERVATION: A 27-year-old man presented with a recurrence of mandibular ameloblastoma. Treatment consisted in segmental mandibulectomy with resection of the IAN. Bone reconstruction was performed with a fibula free flap and IAN reconstruction was obtained by mean of a 7-cm nerve graft obtained from the greater auricular nerve (GAN). At the 6th postoperative month, the patient had recovered a normal sensitivity of his lower lip and chin. Latency of somatosensory evoked potentials was similar for both sides. DISCUSSION: The repair of the IAN by nerve autograft is a simple procedure that allows for good sensitive rehabilitation. The use of the GAN is well suited from its anatomy and from the moderate ear sensory sequelae. PMID- 27473929 TI - Temporomandibular joint ankylosis after condylar dislocation into the middle cranial fossa: A case report. AB - INTRODUCTION: Dislocation of the mandibular condyle into the middle cranial fossa after a trauma is a rare event. The lack of appropriate treatment can lead to ankylosis of the temporomandibular joint (TMJ). We report about a case of TMJ ankylosis following intracranial dislocation of the mandibular condyle through the roof of the articular fossa. CASE REPORT: A 9-year-old patient was referred for a severe limitation of mouth opening that began progressively one year before. A history of chin injury due to an accidental fall was found. Preoperative CT scan showed a TMJ ankylosis on the right side combined with a dislocation of the mandibular condyle into the middle cranial fossa. Treatment consisted in an intracranial resection of the mandibular condyle, partial removal of the ankylosis block and TMJ arthroplasty. DISCUSSION: Our case is the second case of TMJ ankylosis following intracranial dislocation of the mandibular condyle and treated with arthroplasty alone published in the English literature. There is no consensus regarding the pathophysiology of TMJ ankylosis and regarding the attitude towards the ankylosis block. In our case, no recurrence was noticed after a one-year follow-up. An interdisciplinary approach is needed, including maxillofacial surgeon, neurosurgeon, physiotherapist and orthodontist. PMID- 27473930 TI - Brainstem-mediated sniffing and respiratory modulation during odor stimulation. AB - The trigeminal and olfactory systems interact during sensory processing of odor. Here, we investigate odor-evoked modulations of brainstem respiratory networks in a decerebrated perfused brainstem preparation of rat with intact olfactory bulbs. Intranasal application of non-trigeminal odors (rose) did not evoke respiratory modulation in absence of cortico-limbic circuits. Conversely, trigeminal odors such as menthol or lavender evoked robust respiratory modulations via direct activation of preserved brainstem circuits. Trigeminal odors consistently triggered short phrenic nerve bursts (fictive sniff), and the strong trigeminal odor menthol also triggered a slowing of phrenic nerve frequency. Phrenic and vagal nerve recordings reveal that fictive sniffs transiently interrupted odor evoked tonic postinspiratory vagal discharge. This motor pattern is significantly different from normal (eupneic) respiratory activity. In conclusion, we show for the first time the direct involvement of brainstem circuits in primary odor processing to evoke protective sniffs and respiratory modulation in the complete absence of forebrain commands. PMID- 27473931 TI - Virus-inspired nucleic acid delivery system: Linking virus and viral mimicry. AB - Targeted delivery of nucleic acids into disease sites of human body has been attempted for decades, but both viral and non-viral vectors are yet to meet our expectations. Safety concerns and low delivery efficiency are the main limitations of viral and non-viral vectors, respectively. The structure of viruses is both ordered and dynamic, and is believed to be the key for effective transfection. Detailed understanding of the physical properties of viruses, their interaction with cellular components, and responses towards cellular environments leading to transfection would inspire the development of safe and effective non viral vectors. To this goal, this review systematically summarizes distinctive features of viruses that are implied for efficient nucleic acid delivery but not yet fully explored in current non-viral vectors. The assembly and disassembly of viral structures, presentation of viral ligands, and the subcellular targeting of viruses are emphasized. Moreover, we describe the current development of cationic material-based viral mimicry (CVM) and structural viral mimicry (SVM) in these aspects. In light of the discrepancy, we identify future opportunities for rational design of viral mimics for the efficient delivery of DNA and RNA. PMID- 27473932 TI - Towards Objective Voice Assessment: The Diplophonia Diagram. AB - OBJECTIVES: Diplophonia is an often misinterpreted symptom of disordered voice, and needs objectification. An audio signal processing algorithm for the detection of diplophonia is proposed. Diplophonia is produced by two distinct oscillators, which yield a profound physiological interpretation. The algorithm's performance is compared with the clinical standard parameter degree of subharmonics (DSH). STUDY DESIGN: This is a prospective study. METHODS: A total of 50 dysphonic subjects with (28 with diplophonia and 22 without diplophonia) and 30 subjects with euphonia were included in the study. From each subject, up to five sustained phonations were recorded during rigid telescopic high-speed video laryngoscopy. A total of 185 phonations were split up into 285 analysis segments of homogeneous voice qualities. In accordance to the clinical group allocation, the considered segmental voice qualities were (1) diplophonic, (2) dysphonic without diplophonia, and (3) euphonic. The Diplophonia Diagram is a scatter plot that relates the one-oscillator synthesis quality (SQ1) to the two-oscillator synthesis quality (SQ2). Multinomial logistic regression is used to distinguish between diplophonic and nondiplophonic segments. RESULTS: Diplophonic segments can be well distinguished from nondiplophonic segments in the Diplophonia Diagram because two-oscillator synthesis is more appropriate for imitating diplophonic signals than one-oscillator synthesis. The detection of diplophonia using the Diplophonia Diagram clearly outperforms the DSH by means of positive likelihood ratios (56.8 versus 3.6). CONCLUSIONS: The diagnostic accuracy of the newly proposed method for detecting diplophonia is superior to the DSH approach, which should be taken into account for future clinical and scientific work. PMID- 27473933 TI - Evaluation of Voice Acoustics as Predictors of Clinical Depression Scores. AB - OBJECTIVE: The aim of the present study was to determine if acoustic measures of voice, characterizing specific spectral and timing properties, predict clinical ratings of depression severity measured in a sample of patients using the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory (BDI-II). STUDY DESIGN: This is a prospective study. METHODS: Voice samples and clinical depression scores were collected prospectively from consenting adult patients who were referred to psychiatry from the adult emergency department or primary care clinics. The patients were audio-recorded as they read a standardized passage in a nearly closed-room environment. Mean Absolute Error (MAE) between actual and predicted depression scores was used as the primary outcome measure. RESULTS: The average MAE between predicted and actual HAMD scores was approximately two scores for both men and women, and the MAE for the BDI-II scores was approximately one score for men and eight scores for women. Timing features were predictive of HAMD scores in female patients while a combination of timing features and spectral features was predictive of scores in male patients. Timing features were predictive of BDI-II scores in male patients. CONCLUSION: Voice acoustic features extracted from read speech demonstrated variable effectiveness in predicting clinical depression scores in men and women. Voice features were highly predictive of HAMD scores in men and women, and BDI-II scores in men, respectively. The methodology is feasible for diagnostic applications in diverse clinical settings as it can be implemented during a standard clinical interview in a normal closed room and without strict control on the recording environment. PMID- 27473934 TI - [Lower bodylift after massive weight loss: Retrospective study of satisfaction, complications and quality of life. About 76 patients over 4years]. AB - INTRODUCTION: Massive weight loss leads to important cutaneous deformities with physical and psychological repercussions for patients. Lower bodylift is a procedure, which can restore the body contour. The aim of this study is to evaluate satisfaction and quality of life in patients who underwent lower bodylift and to review the complications of these procedures. MEANS AND METHODS: This is a retrospective study of 76 patients who underwent lower bodylift between 2012 and 2016. We reviewed the complications of these procedures. Satisfaction and quality of life were assessed using Body-QoL questionnaire. RESULTS: Seventy six patients were included with a mean age of 39.2years. The average body mass index was 27.6kg/m2 with a mean weight of 71.2kg at the time of surgery and a mean weight loss of 48.6kg. Twenty-three patients developed one complication: 22 minor and 1 major. Forty-eight patients answered the questionnaire. Satisfaction was rated "very good" by 41 patients (85.4%) and "good" by 5 patients (10.4%). The Body-QoL questionnaire's analysis showed an improvement of quality of life socially, sexually, in the body regard and in physical symptoms. CONCLUSIONS: Lower bodylift is the only procedure, which can restore circumferential body contour. Despite the minor complications reviewed, the degree of satisfaction of the patients is very high. The quality of life of these patients, after massive weight loss, is also highly improved by these procedures. With the worldwide development of obesity and bariatric surgery, this study demonstrated that the operation should be proposed to patients with massive weight loss to improve quality of life. PMID- 27473935 TI - The neural mechanisms of hallucinations: A quantitative meta-analysis of neuroimaging studies. AB - Activation likelihood estimation meta-analysis of functional neuroimaging data was used to investigate the neural mechanisms underlying auditory-verbal and visual hallucinations (AVHs and VHs). Consistent activation across studies during AVHs, but not VHs, in Wernicke's and Broca's areas is consistent with involvement of speech and language processes in the experience of hearing voices when none are present. Similarly, greater activity in auditory cortex during AVHs and in visual cortex during VHs supports models proposing over-stimulation of sensory cortices in the generation of these perceptual anomalies. Activation across studies in the medial temporal lobe highlights a role for memory intrusions in the provision of content for AVHs, whereas insula activation may relate to the involvement of awareness and self-representation. Finally, activation in the paracingulate region of medial prefrontal cortex during AVHs is consistent with models implicating reality monitoring impairment in the misattribution of self generated information as externally perceived. In the light of the results, the need for unified theoretical frameworks that account for the full range of hallucinatory experiences is discussed. PMID- 27473936 TI - Stress and the adolescent brain: Amygdala-prefrontal cortex circuitry and ventral striatum as developmental targets. AB - Adolescence is a time in development when significant changes occur in affective neurobiology. These changes provide a prolonged period of plasticity to prepare the individual for independence. However, they also render the system highly vulnerable to the effects of environmental stress exposures. Here, we review the human literature on the associations between stress-exposure and developmental changes in amygdala, prefrontal cortex, and ventral striatal dopaminergic systems during the adolescent period. Despite the vast differences in types of adverse exposures presented in his review, these neurobiological systems appear consistently vulnerable to stress experienced during development, providing putative mechanisms to explain why affective processes that emerge during adolescence are particularly sensitive to environmental influences. PMID- 27473939 TI - Right ventricular end-diastolic stiffness heralds right ventricular failure in monocrotaline-induced pulmonary hypertension. AB - Recent studies suggest right ventricular (RV) stiffness is important in pulmonary hypertension (PH) prognosis. Smaller stroke volume (SV) variation after a certain RV end-diastolic pressure (EDP) respiratory variation as assessed by spectral transfer function (STF) may identify RV stiffness. Our aim was to evaluate RV stiffness in monocrotaline (MCT)-induced PH progression and to validate STF gain between EDP and SV as marker of stiffness. Seven-week-old male Wistar rats randomly injected with 60 mg/kg MCT or vehicle were divided into three groups (n = 12 each) according to cardiac index (CI): controls (Ctrl), preserved CI (MCT pCI), and reduced CI (MCT rCI). All underwent RV pressure-volume (PV) evaluation 24-34 days after MCT, under halogenate anesthesia and constant positive-pressure ventilation. End-diastolic stiffness (betai), end-systolic elastance (Eesi), arterial elastance for indexed volumes (Eai), and preload recruitable stroke work (PRSW) were obtained and beat-to-beat fluctuations during ventilation assessed by STF. Eai was the strongest determinant of CI, alongside betai but not PRSW. MCT rCI showed impaired ventricular-vascular coupling (VVC) and higher betai, along with low end-diastolic pressure (EDP) and stroke volume index (SVi) STF gain, denoting impaired preload reserve. On multivariate analysis betai and not Eesi correlated with EDP-SVi STF gain (P < 0.001). Receiver-operating characteristics (ROC) curve analysis of EDP-SVi STF gain showed an area under curve of 0.84 for betai prediction (P = 0.002). Afterload, impaired VVC and RV stiffness are major players in RV failure. RV stiffness can be assessed by STF gain analysis of respiratory fluctuations between EDP and SVi, which may constitute a prognostic tool in PH. PMID- 27473940 TI - In with the new and out with the old: enter multivariate wavelet decomposition, exit transfer function. PMID- 27473938 TI - Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications. AB - Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications. PMID- 27473941 TI - Reduced serum concentrations of brain-derived neurotrophic factor (BDNF) in transsexual Brazilian men. AB - Serum BDNF levels are significantly decreased in transsexual Brazilian women when compared to cis-sexual men. Since transsexual men are also exposed to chronic social stress and have a high prevalence of associated psychopathologies, it is plausible to inquire if BDNF serum levels are altered in transsexual men as well. Therefore, our objective was to evaluate differences in BDNF serum level of transsexual men when compared to cis-sexual men and women. Our sample comprises 27 transsexual men, 31 cis-sexual women and 30 cis-sexual men recruited between 2011 and 2015. We observed that BDNF serum concentration is decreased in transsexual men comparing to cis-sexual men and women. Cross-sex hormone treatment, chronic social stress or long-term gender dysphoria (GD) could explain the variation found in BDNF serum levels. PMID- 27473937 TI - Associations of rare nicotinic cholinergic receptor gene variants to nicotine and alcohol dependence. AB - Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF) <0.05) at CHRN genes and nicotine dependence, and alcohol dependence were tested. The mRNA expression of all Chrn genes in whole mouse brain and 10 specific brain areas was investigated. All CHRN genes except the muscle-type CHRNB1, including eight genomic regions containing 11 neuronal CHRN genes and three genomic regions containing four muscle-type CHRN genes, were significantly associated with ND, and/or AD. All of these genes were expressed in the mouse brain. We conclude that CHRNs are associated with ND (mainly) and AD, supporting the hypothesis that the full catalog of ND/AD risk genes may contain most neuronal nAChRs-encoding genes. (c) 2016 Wiley Periodicals, Inc. PMID- 27473942 TI - Significance of aberrant glial cell phenotypes in pathophysiology of amyotrophic lateral sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) is a paradigmatic neurodegenerative disease, characterized by progressive paralysis of skeletal muscles associated with motor neuron degeneration. It is well-established that glial cells play a key role in ALS pathogenesis. In transgenic rodent models for familial ALS reactive astrocytes, microglia and oligodendrocyte precursors accumulate in the degenerating spinal cord and appear to contribute to primary motor neuron death through a non-cell autonomous pathogenic mechanism. Furthermore in rats expressing the ALS-linked SOD1G93A mutation, rapid spread of paralysis coincides with emergence of neurotoxic and proliferating aberrant glia cells with an astrocyte-like phenotype (AbA cells) that are found surrounding damaged motor neurons. AbAs simultaneously express astrocytic markers GFAP, S100beta and Connexin-43 along with microglial markers Iba-1, CD11b and CD163. Studies with cell cultures have shown that AbAs originate from inflammatory microglial cells that undergo phenotypic transition. Because AbAs appear only after paralysis onset and exponentially increase in parallel with disease progression, they appear to actively contribute to ALS progression. While several reviews have been published on the pathogenic role of glial cells in ALS, this review focuses on emergence and pro-inflammatory activity of AbAs as part of an increasingly complex neurodegenerative microenvironment during ALS disease development. PMID- 27473943 TI - High levels of brain-derived neurotrophic factor are associated with treatment adherence among crack-cocaine users. AB - Due to the complexity of crack -cocaine addiction treatment, the identification of biological markers that could help determining the impact or outcome of drug use has become a major subject of study. Therefore, we aim to evaluate the association of Brain-Derived Neurotrophic Factor (BDNF) and Thiobarbituric Acid Reactive Substances (TBARS) levels in crack -cocaine users with treatment adherence and with drug addiction severity. A sample of 47 male inpatient crack- cocaine users were recruited in a treatment unit, and blood samples were collected at admission and discharge in order to measure BDNF and TBARS serum levels. Subjects were split into 2 groups: treatment non-completers (n=23) and treatment completers (n=24). The completer group had a tendency of higher levels of BDNF than non-completers at admission (16.85+/-3.24 vs. 14.65+/-5.45, p=0.10), and significant higher levels at discharge (18.10+/-4.88 vs. 13.91+/-4.77, p=0.001). A negative correlation between BDNF levels at admission and years of crack use was observed. We did not find significant changes in TBARS levels during inpatient treatment, although the completer group tended to decrease these levels while non-completers tend to increase it. These findings suggest an association between higher levels of BDNF and better clinical outcomes in crack- cocaine users after detoxification. We believe that the variation in BDNF and TBARS found here add evidence to literature data that propose that such biomarkers could be used to better understand the physiopathology of crack- cocaine addiction. PMID- 27473945 TI - Imbalance of circulating CD4(+)CXCR5(+)FOXP3(+) Tfr-like cells and CD4(+)CXCR5(+)FOXP3(-) Tfh-like cells in myasthenia gravis. AB - Follicular regulatory T (Tfr) cells are defined as a specialized subset of regulatory T cells (Tregs) that act to control the overactivation of follicular helper T (Tfh) cells and B cells in germinal centers. Accumulating evidence has demonstrated that the dysregulation of either Tfr cells or Tfh cells results in abnormal germinal center responses that contribute to the pathogenesis of autoimmune diseases. However, the role that Tfr cells and Tfh cells play in myasthenia gravis (MG) remains unclear. This study revealed a significantly decreased frequency of CD4(+)CXCR5(+)FOXP3(+) Tfr-like cells and an increased frequency of CD4(+)CXCR5(+)FOXP3(-) Tfh-like cells in the peripheral blood of MG patients compared with healthy controls. Moreover, the Tfr-like/Tfh-like ratio was inversely correlated with the clinical severity of the MG patients. Interestingly, glucocorticoid (GC) treatment can restore the imbalance of circulating Tfr-like/Tfh-like cells, and this restoration is accompanied by reduced clinical symptoms. These results suggested, for the first time, that an imbalance of circulating Tfr-like and Tfh-like cells may be involved in the immunopathogenesis of MG and may provide novel insight for the development of MG therapies. PMID- 27473946 TI - Editorial. PMID- 27473944 TI - Association between theta power in 6-month old infants at rest and maternal PTSD severity: A pilot study. AB - Compared to infants born to mothers without PTSD, infants born to mothers with active PTSD develop poorer behavioral reactivity and emotional regulation. However, the association between perinatal maternal PTSD and infant neural activation remains largely unknown. This pilot study (N=14) examined the association between perinatal PTSD severity and infant frontal neural activity, as measured by MEG theta power during rest. Results indicated that resting left anterior temporal/frontal theta power was correlated with perinatal PTSD severity (p=0.004). These findings suggest delayed cortical maturation in infants whose mothers had higher perinatal PTSD severity and generate questions regarding perinatal PTSD severity and infant neurophysiological consequences. PMID- 27473947 TI - Evaluation of a programme for 'Rapid Assessment of Febrile Travelers' (RAFT): a clinic-based quality improvement initiative. AB - BACKGROUND: Fever in the returned traveller is a potential medical emergency warranting prompt attention to exclude life-threatening illnesses. However, prolonged evaluation in the emergency department (ED) may not be required for all patients. As a quality improvement initiative, we implemented an algorithm for rapid assessment of febrile travelers (RAFT) in an ambulatory setting. METHODS: Criteria for RAFT referral include: presentation to the ED, reported fever and travel to the tropics or subtropics within the past year. Exclusion criteria include Plasmodium falciparum malaria, and fulfilment of admission criteria such as unstable vital signs or significant laboratory derangements. We performed a time series analysis preimplementation and postimplementation, with primary outcome of wait time to tropical medicine consultation. Secondary outcomes included number of ED visits averted for repeat malaria testing, and algorithm adherence. RESULTS: From February 2014 to December 2015, 154 patients were seen in the RAFT clinic: 68 men and 86 women. Median age was 36 years (range 16-78 years). Mean time to RAFT clinic assessment was 1.2+/-0.07 days (range 0-4 days) postimplementation, compared to 5.4+/-1.8 days (range 0-26 days) prior to implementation (p<0.0001). The RAFT clinic averted 132 repeat malaria screens in the ED over the study period (average 6 per month). Common diagnoses were: traveller's diarrhoea (n=27, 17.5%), dengue (n=12, 8%), viral upper respiratory tract infection (n=11, 7%), chikungunya (n=10, 6.5%), laboratory-confirmed influenza (n=8, 5%) and lobar pneumonia (n=8, 5%). CONCLUSIONS: In addition to provision of more timely care to ambulatory febrile returned travellers, we reduced ED bed-usage by providing an alternate setting for follow-up malaria screening, and treatment of infectious diseases manageable in an outpatient setting, but requiring specific therapy. PMID- 27473948 TI - Cross-sectional study of patients with type 2 diabetes in OR Tambo district, South Africa. AB - OBJECTIVES: South Africa has pledged to the sustainable development goal of promoting good health and well-being to all residents. While this is laudable, paucity of reliable epidemiological data for different regions on diabetes and treatment outcomes may further widen the inequalities of access and quality of healthcare services across the country. This study examines the sociodemographic and clinical determinants of uncontrolled type 2 diabetes mellitus (T2DM) in individuals attending primary healthcare in OR Tambo district, South Africa. DESIGN: A cross-sectional analytical study. SETTING: Primary healthcare setting in OR Tambo district, South Africa. PARTICIPANTS: Patients treated for T2DM for 1 or more years (n=327). PRIMARY OUTCOME MEASURE: Prevalence of uncontrolled T2DM. SECONDARY OUTCOME MEASURE: Determinants of uncontrolled T2DM (glycosylated haemoglobin (HbA1c) >=7%). RESULTS: Out of the 327 participants, 274 had HbA1c>=7% (83.8%). Female sex (95% CI 1.3 to 4.2), overweight/obesity (95% CI 1.9 to 261.2), elevated low-density lipoprotein cholesterol (95% CI 4.4 to 23.8), sedentary habits (95% CI 7.2 to 61.3), lower monthly income (95% CI 1.3 to 6.5), longer duration of T2DM (95% CI 4.4 to 294.2) and diabetes information from non health workers (95% CI 1.4 to 7.0) were the significant determinants of uncontrolled T2DM. There was a significant positive correlation of uncontrolled T2DM with increasing duration of T2DM, estimated glomerular filtration rate and body mass index. However, a significant negative correlation exists between monthly income and increasing HbA1c. CONCLUSIONS: We found a significantly high prevalence (83.8%) of uncontrolled T2DM among the patients, possibly attributable to overweight/obesity, sedentary living, lower income and lack of information on diabetes. Addressing these determinants will require re-engineering of primary healthcare in the district. PMID- 27473949 TI - Retrospective observational study to assess the clinical management and outcomes of hospitalised patients with complicated urinary tract infection in countries with high prevalence of multidrug resistant Gram-negative bacteria (RESCUING). AB - INTRODUCTION: The emergence of multidrug resistant (MDR) Gram-negative bacteria (GNB), including carbapenemase-producing strains, has become a major therapeutic challenge. These MDR isolates are often involved in complicated urinary tract infection (cUTI), and are associated with poor clinical outcomes. The study has been designed to gain insight into the epidemiology, clinical management, outcome and healthcare cost of patients with cUTI, especially in countries with high prevalence of MDR GNB. METHODS AND ANALYSIS: This multinational and multicentre observational, retrospective study will identify cases from 1 January 2013 to 31 December 2014 in order to collect data on patients with cUTI as a cause of hospital admission, and patients who develop cUTI during their hospital stay. The primary end point will be treatment failure defined as the presence of any of the following criteria: (1) signs or symptoms of cUTI present at diagnosis that have not improved by days 5-7 with appropriate antibiotic therapy, (2) new cUTI related symptoms that have developed within 30 days of diagnosis, (3) urine culture taken within 30 days of diagnosis, either during or after completion of therapy, that grows >=10(4) colony-forming unit/mL of the original pathogen and (4) death irrespective of cause within 30 days of the cUTI diagnosis. SAMPLE SIZE: 1000 patients afford a power of 0.83 (alpha=0.05) to detect an absolute difference of 10% in the treatment failure rate between MDR bacteria and other pathogens. This should allow for the introduction of about 20 independent risk factors (or their interaction) in a logistic regression model looking at risk factors for failure. ETHICS AND DISSEMINATION: Approval will be sought from all relevant Research Ethics Committees. Publication of this study will be considered as a joint publication by the participating investigator leads, and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). TRIAL REGISTRATION NUMBER: NCT02641015; Pre-results. PMID- 27473950 TI - Association between passive smoking and mental distress in adult never-smokers: a cross-sectional study. AB - OBJECTIVE: Many studies have suggested exposure to secondhand smoke (SHS) is a risk factor for various somatic diseases, but only few studies based on small sample size or specific groups have explored the association between passive smoking and mental distress. We performed this study to examine the relationship between passive smoking and mental distress in adult never-smokers of north-east China. METHODS: Multistage, stratified random cluster sampling design was used in this cross-sectional study in 2012. A total of 12 978 never-smokers from Jilin, north-east China, were included. Data on passive smoking and baseline characteristics were collected by face-to-face interviews. The 12-item General Health Questionnaire (GHQ-12) was used to measure mental health status. Rao-Scott chi(2) tests were used to compare the prevalence between different groups; multivariable logistic regression was used to assess the association between passive smoking and mental distress, and Spearman rank analysis was employed to assess the correlation between passive smoking and GHQ-12 scores. RESULTS: The estimated prevalence of mental distress among never-smokers in Jilin province is 24.5%, and the estimated prevalence of passive smoking among the mental distressing group is 65.0%. After adjusting for gender, age, region, body mass index (BMI), occupation, marriage, education, drinking status and family monthly income per capita, passive smoking conferred a risk for mental distress (adjusted OR=1.26, 95% CI 1.13 to 1.40). A high proportion of adults, especially women, were passive smokers at home, but for men, passive smoking was more common at workplace. The more frequently participants exposed to SHS, the higher GHQ-12 scores they got. CONCLUSIONS: Passive smoking is an important risk factor for mental distress in never-smokers of Jilin province, which reminds Chinese government of increasing the awareness of public health and take measure to prevent SHS, especially with regard to SHS exposure at home and workplace. PMID- 27473951 TI - Assessing sex-differences and the effect of timing of vaccination on immunogenicity, reactogenicity and efficacy of vaccines in young children: study protocol for an individual participant data meta-analysis of randomised controlled trials. AB - INTRODUCTION: Disease incidence differs between males and females for some infectious or inflammatory diseases. Sex-differences in immune responses to some vaccines have also been observed, mostly to viral vaccines in adults. Little evidence is available on whether sex-differences occur in response to immunisation in infancy even though this is the age group in which most vaccines are administered. Factors other than sex, such as timing or coadministration of other vaccines, can also influence the immune response to vaccination. METHODS AND ANALYSIS: Individual participant data meta-analysis of randomised controlled trials of vaccines in healthy infants and young children will be conducted. Fully anonymised data from ~170 randomised controlled trials of vaccines for diphtheria, tetanus, Bordetella pertussis, polio, Haemophilus influenzae type B, hepatitis B, Streptococcus pneumoniae, Neisseria meningitidis, measles, mumps, rubella, varicella and rotavirus will be combined for analysis. Outcomes include measures of immunogenicity (immunoglobulins), reactogenicity, safety and disease specific clinical efficacy. Data from trials of vaccines containing similar components will be combined in hierarchical models and the effect of sex and timing of vaccinations estimated for each outcome separately. ETHICS AND DISSEMINATION: Systematic reviews of published estimates of sex-differences cannot adequately answer questions in this field since such comparisons are never the main purpose of a clinical trial, thus a large degree of reporting bias exists in the published literature. Recent improvements in the widespread availability of individual participant data from randomised controlled trials makes it feasible to conduct extensive individual participant data meta-analyses which were previously impossible, thereby reducing the effect of publication or reporting bias on the understanding of the infant immune response.Preliminary results will be available in 2016 with final results available in 2019. No ethics review is required for secondary analyses of anonymised data. PMID- 27473952 TI - Pharmacological interventions to improve sleep in hospitalised adults: a systematic review. AB - OBJECTIVES: Patients often suffer from disturbed sleep in hospital. Poor-quality sleep in hospitalised patients has been associated with significant morbidity and pharmacological sleep aids are often prescribed. The objective of this systematic review is to evaluate the comparative efficacy and safety of pharmacological interventions used for sleep in hospitalised patients. SETTING/PARTICIPANTS: We searched MEDLINE, Embase, the Cochrane database and grey literature for prospective studies that evaluated sleep in hospitalised adults after a pharmacological intervention. PRIMARY AND SECONDARY OUTCOME MEASURES: Two reviewers assessed studies for inclusion and extracted data for efficacy outcomes, including sleep efficiency, sleep latency, sleep fragmentation and objectively measured sleep stage distribution. Risk of bias was assessed and meta analyses were planned contingent upon homogeneity of the included studies. RESULTS: After screening 1920 citations, 15 studies involving 861 patients were included. Medications studied included benzodiazepines, nonbenzodiazepine sedatives, melatonin, propofol and dexmedetomidine. Five studies were deemed to be of high quality. Heterogeneity and variable outcome reporting precluded meta analysis in most cases. No consistent trends with respect to sleep efficiency, quality or interruptions were observed identifying a drug or drug class as superior to another or no treatment. Benzodiazepines appeared to be better than no treatment with respect to sleep latency, but this was not consistently demonstrated across all studies. Sleep stage distribution shows that sleep in hospital is dominated by stages N1 and N2. CONCLUSIONS: There is insufficient evidence to suggest that pharmacotherapy improves the quality or quantity of sleep in hospitalised patients suffering from poor sleep. No drug class or specific drug was identified as superior even when compared to placebo or no treatment. Although 15 studies were included, the quality of evidence was limited by their quality and size. Larger, better-designed trials in hospitalised adults are needed. PMID- 27473953 TI - Kaizen practice in healthcare: a qualitative analysis of hospital employees' suggestions for improvement. AB - OBJECTIVES: Kaizen, or continuous improvement, lies at the core of lean. Kaizen is implemented through practices that enable employees to propose ideas for improvement and solve problems. The aim of this study is to describe the types of issues and improvement suggestions that hospital employees feel empowered to address through kaizen practices in order to understand when and how kaizen is used in healthcare. METHODS: We analysed 186 structured kaizen documents containing improvement suggestions that were produced by 165 employees at a Swedish hospital. Directed content analysis was used to categorise the suggestions into following categories: type of situation (proactive or reactive) triggering an action; type of process addressed (technical/administrative, support and clinical); complexity level (simple or complex); and type of outcomes aimed for (operational or sociotechnical). Compliance to the kaizen template was calculated. RESULTS: 72% of the improvement suggestions were reactions to a perceived problem. Support, technical and administrative, and primary clinical processes were involved in 47%, 38% and 16% of the suggestions, respectively. The majority of the kaizen documents addressed simple situations and focused on operational outcomes. The degree of compliance to the kaizen template was high for several items concerning the identification of problems and the proposed solutions, and low for items related to the test and implementation of solutions. CONCLUSIONS: There is a need to combine kaizen practices with improvement and innovation practices that help staff and managers to address complex issues, such as the improvement of clinical care processes. The limited focus on sociotechnical aspects and the partial compliance to kaizen templates may indicate a limited understanding of the entire kaizen process and of how it relates to the overall organisational goals. This in turn can hamper the sustainability of kaizen practices and results. PMID- 27473954 TI - Dietary intake in young adults born small or appropriate for gestational age: data from the Haguenau cohort. AB - OBJECTIVES: Compare the dietary intake of young adults born small for gestational age (SGA) versus those born appropriate for gestational age (AGA). DESIGN: Cross sectional analysis. SETTING: Data at the 8-year follow-up Haguenau cohort (France). Data from 229 AGA-born adults and 172 SGA-born adults with available dietary information are presented. METHODS: Dietary intake was based on a food questionnaire including 19 items. The chi(2) test was run to compare intake between SGA-born and AGA-born individuals. An a priori score was calculated based on the adherence to recommendations from the French Nutrition and Health Program and included 8 components with the lowest value indicating a lower adherence to recommendations. The score was then divided into quartiles. Relative risks and 95% CIs, controlling for age and sex in multivariate analysis, were calculated in order to determine the risk of belonging to the first versus the second to the fourth quartiles in SGA-born and AGA-born individuals. RESULTS: Intakes of SGA born adults indicated that they consumed more meat, sugar and less fish than AGA born individuals (all p<0.05). Multivariate analyses with adjustment for age and sex showed that the relative risk of belonging to the first quartile versus the other three quartiles did not disclose any significant difference in SGA-born versus AGA-born participants: RR=0.92 (95% CI 0.65 to 1.30). CONCLUSIONS: Aside from the differences found by univariate analyses, no significant differences were obtained in multivariate analyses. Findings suggest that parameters of fetal programming are more associated with the development of metabolic syndrome in adulthood rather than dietary patterns. PMID- 27473955 TI - The basis of clinical tribalism, hierarchy and stereotyping: a laboratory controlled teamwork experiment. AB - OBJECTIVES: To examine the basis of multidisciplinary teamwork. In real-world healthcare settings, clinicians often cluster in profession-based tribal silos, form hierarchies and exhibit stereotypical behaviours. It is not clear whether these social structures are more a product of inherent characteristics of the individuals or groups comprising the professions, or attributable to a greater extent to workplace factors. SETTING: Controlled laboratory environment with well appointed, quiet rooms and video and audio equipment. PARTICIPANTS: Clinical professionals (n=133) divided into 35 groups of doctors, nurses and allied health professions, or mixed professions. INTERVENTIONS: Participants engaged in one of three team tasks, and their performance was video-recorded and assessed. PRIMARY AND SECONDARY MEASURES: Primary: teamwork performance. Secondary, pre experimental: a bank of personality questionnaires designed to assess participants' individual differences. Postexperimental: the 16-item Mayo High Performance Teamwork Scale (MHPTS) to measure teamwork skills; this was self assessed by participants and also by external raters. In addition, external, arm's length blinded observations of the videotapes were conducted. RESULTS: At baseline, there were few significant differences between the professions in collective orientation, most of the personality factors, Machiavellianism and conservatism. Teams generally functioned well, with effective relationships, and exhibited little by way of discernible tribal or hierarchical behaviours, and no obvious differences between groups (F (3, 31)=0.94, p=0.43). CONCLUSIONS: Once clinicians are taken out of the workplace and put in controlled settings, tribalism, hierarchical and stereotype behaviours largely dissolve. It is unwise therefore to attribute these factors to fundamental sociological or psychological differences between individuals in the professions, or aggregated group differences. Workplace cultures are more likely to be influential in shaping such behaviours. The results underscore the importance of culture and context in improvement activities. Future initiatives should factor in culture and context as well as individuals' or professions' characteristics as the basis for inducing more lateral teamwork or better interprofessional collaboration. PMID- 27473956 TI - Protective effect of the extract of Yi-Qi-Fu-Mai preparation on hypoxia-induced heart injury in mice. AB - Yi-Qi-Fu-Mai (YQFM) is extensively used clinically to treat cardiovascular diseases in China. To explore the anti-hypoxia effect of the extract of YQFM preparation (EYQFM), the EYQFM (1.4, 2.8, and 5.5 g.kg(-1).d(-1)) was assessed for its heart-protective effect in a chronic intermittent hypoxia (CIH) animal model (oxygen pressure 7%-8%, 20 min per day) for 28 days of treatment. Betaloc (0.151 6 g.kg(-1).d(-1)) was used as a positive control. The histopathological analyses of heart in CIH mice were conducted. Several cardiac state parameters, such as left ventricular ejection fractions (EF), stroke volume (SV), expression of creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. The results showed that treatment with EYQFM markedly reversed swelling of the endothelial cells and vacuolization in the heart when compared with the model group. Further study demonstrated that EYQFM significantly improved ventricular myocardial contractility by increasing EF and SV. In addition, EYQFM inhibited the activity of CK, LDH, decreased the level of MDA and improved SOD activity. The results demonstrated that EYQFM significantly improved the tolerability of myocardium to hypoxia and ameliorated the cardiac damage in the CIH model. PMID- 27473957 TI - Isoquercitrin suppresses the expression of histamine and pro-inflammatory cytokines by inhibiting the activation of MAP Kinases and NF-kappaB in human KU812 cells. AB - Mast cells and basophils are multifunctional effector cells that contain abundant secretory granules in their cytoplasm. Both cell types are involved in a variety of inflammatory and immune events, producing an array of inflammatory mediators, such as cytokines. The aim of the study was to examine whether isoquercitrin modulates allergic and inflammatory reactions in the human basophilic KU812 cells and to elucidate its influence on the phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB activation. The KU812 cells were stimulated with phorbol-12-myristate 13-acetate plus the calcium ionophore A23187 (PMACI). The inhibitory effects of isoquercitrin on the productions of histamine and pro-inflammatory cytokines in the stimulated KU812 cells were measured using cytokine-specific enzyme-linked immunosorbent (ELISA) assays. Western blotting analysis was used to assess the effects of isoquercitrin on the MAPKs and NF-kappaB protein levels. Our results indicated that the isoquercitrin treatment of PMACI-stimulated KU812 cells significantly reduced the production of histamine and the pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-1beta, and tumor necrosis factor (TNF)-alpha. The treated cells exhibited decreased phosphorylation of extracellular signal-regulated kinase (ERK), revealing the role of ERK MAPK in isoquercitrin-mediated allergy inhibition. Furthermore, isoquercitrin suppressed the PMACI-mediated activation of NF-kappaB in the human basophil cells. In conclusion, the results from the present study provide insights into the potential therapeutic use of isoquercitrin for the treatment of inflammatory and allergic reactions. PMID- 27473958 TI - Estrogenic activity of osthole and imperatorin in MCF-7 cells and their osteoblastic effects in Saos-2 cells. AB - There is an increasing interest in phytoestrogens due to their potential medical usage in hormone replacement therapy (HRT). The present study was designed to investigate the in vitro effects of estrogen-like activities of two widespread coumarins, osthole and imperatorin, using the MCF-7 cell proliferation assay and their alkaline phosphatase (ALP) activities in osteoblasts Saos-2 cells. The two compounds were found to strongly stimulate the proliferation of MCF-7 cells. The estrogen receptor-regulated ERalpha, progesterone receptor (PR) and PS2 mRNA levels were increased by treatment with osthole and imperatorin. All these effects were significantly inhibited by the specific estrogen receptor antagonist ICI182, 780. Cell cycle analysis revealed that their proliferation stimulatory effect was associated with a marked increase in the number of MCF-7 cells in S phase, which was similar to that observed with estradiol. It was also observed that they significantly increased ALP activity, which was reversed by ICI182,780. These results suggested that osthole and imperatorin could stimulate osteoblastic activity by displaying estrogenic properties or through the ER pathway. In conclusion, osthole and imperatorin may represent new pharmacological tools for the treatment of osteoporosis. PMID- 27473959 TI - An optimized micro-assay of myosin II ATPase activity based on the molybdenum blue method and its application in screening natural product inhibitors. AB - Myosin II plays multiple roles in physiological and pathological functions through its ATPase activity. The present study was designed to optimize a micro assay of myosin II ATPase activity based on molybdenum blue method, using a known myosin II ATPase inhibitor, blebbistatin. Several parameters were observed in the enzymatic reaction procedure, including the concentrations of the substrate (ATP) and calcium chloride, pH, and the reaction and incubation times. The proportion of coloration agent was also investigated. The sensitivity of this assay was compared with the malachite green method and bioluminescence method. Additionally, 20 natural compounds were studied for myosin II ATPase inhibitory activity using the optimized method. Our results showed that ATP at the concentration of 5 mmol.L(-1) and ammonium molybdate : stannous chloride at the ratio of 15 : 1 could greatly improve the sensitivity of this method. The IC50 of blebbistatin obtained by this method was consistent with literature. Compound 8 was screened with inhibitory activity on myosin II ATPase. The optimized method showed similar accuracy, lower detecting limit, and wider linear range, which could be a promising approach to screening myosin II ATPase inhibitors in vitro. PMID- 27473960 TI - Cranberry extract supplementation exerts preventive effects through alleviating Abeta toxicity in Caenorhabditis elegans model of Alzheimer's disease. AB - Cranberry extract (CBE) rich in polyphenols are potent to delay paralysis induced by alleviating beta-amyloid (Abeta) toxicity in C. elegans model of Alzheimer's disease (AD). In order to better apply CBE as an anti-AD agent efficiently, we sought to deterrmine whether preventive or therapeutic effect contributes more prominently toward CBE's anti-AD activity. As the level of Abeta toxicity and memory health are two major pathological parameters in AD, in the present study, we compared the effects of CBE on Abeta toxicity and memory health in the C. elegans AD model treated with preventive and therapeutic protocols. Our results revealed that CBE prominently showed the preventive efficacy, providing a basis for further investigation of these effects in mammals. PMID- 27473961 TI - Gingerol activates noxious cold ion channel TRPA1 in gastrointestinal tract. AB - TRPA1 channels are non-selective cation channels that could be activated by plant derived pungent products, including gingerol, a main active constituent of ginger. Ginger could improve the digestive function; however whether ginger improves the digestive function through activating TRPA1 receptor in gastrointestinal tract has not been investigated. In the present study, gingerol was used to stimulate cell lines (RIN14B or STC-1) while depletion of extracellular calcium. TRPA1 inhibitor (rethenium red) and TRPA1 gene silencing via TRPA1-specific siRNA were also used for mechanistic studies. The intracellular calcium and secretion of serotonin or cholecystokinin were measured by fura-2/AM and ELISA. Stimulation of those cells with gingerol increased intracellular calcium levels and the serotonin or cholecystokinin secretion. The gingerol-induced intracellular calcium increase and secretion (serotonin or cholecystokinin) release were completely blocked by ruthenium red, EGTA, and TRPA1-specific siRNA. In summary, our results suggested that gingerol derived from ginger might improve the digestive function through secretion releasing from endocrine cells of the gut by inducing TRPA1-mediated calcium influx. PMID- 27473962 TI - Reproductive toxicity of brazilein in ICR mice. AB - Brazilein is an active small molecular compound extracted from Caesalpinia sappan L. with favorable pharmacological properties on immune system, cardiovascular system, and nervous system. C. sappan has been used as a traditional medicine in China for hundreds of years for various diseases. However, the general reproductive toxicity of brazilein is still unknown. The purpose of the present study was to thoroughly evaluate the general reproductive toxicity of brazilein in ICR mice to support the future drug development and modernization of this potent traditional Chinese medicine. The results showed that, although no apparent toxicity on the reproducibility of the male was observed, brazilein might cause considerable risks to the fetuses and females as indicated by the ratios of dead fetuses and reabsorptions. In conclusion, our results from the present study provided some useful insights about the safety profile of brazilein, suggesting that brazilein should be used with caution in pregnant women. PMID- 27473963 TI - Bofutsushosan ameliorates obesity in mice through modulating PGC-1alpha expression in brown adipose tissues and inhibiting inflammation in white adipose tissues. AB - The inducible co-activator PGC-1alpha plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity. Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P < 0.05), including blood glucose (Glu), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1alpha and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1alpha and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT. PMID- 27473964 TI - Two new cyclic bisbibenzyl derivatives from Hebertus dicranus. AB - In the present study, two new cyclic bisbibenzyls (1, 2) co-occuring with a known compound, isoplagiochins C (3) were isolated from Hebertus dicranus. The structures were determined mainly by extensive 1D and 2D NMR experiments, and the absolute configurations of 1 and 2 were established by the circular dichroism spectrum. Furthermore, all these three rare compounds were tested in vitro for inhibitory activity against the growth of human cancer cell lines (A549, HCT116, MDA-MB-231, and BEL7404) by the MTT assay, and compound 2 exhibited moderately inhibitory activity with IC50 values ranging from 13.89 to 31.62 MUmol.L(-1). In conclusion, our results provided a basis for future development and modification of these compounds for cancer therapy. PMID- 27473965 TI - Synthesis and cytotoxicity evaluation of 3-amino-2-hydroxypropoxyisoflavone derivatives. AB - Soy isoflavones exert a wide variety of biological activities, such as antioxidant, anti-inflammatory and anti-cancer properties. Nuclear factor erythroid 2-related factor 2 (Nrf2), a bZip transcription factor, plays a key role in soy isoflavones induced protection against oxidative stress and cancer. To obtain more effective isofavones, a series of 7,4'-bis-(3-amino-2 hydroxypropoxy), 7 or 4'-(3-amino-2-hydroxypropoxy) isoflavone derivatives have been synthesized as potential antitumor agents and Nrf2/ARE (antioxidant response element) activators. The cytotoxicity of these compounds in human cancer cell lines MDA-MB-231, HT-29, HCT116, HepG2 and 7402 was tested by MTT assay. In this study, the cytotoxicity of compound 3b exhibited highest cytotoxic activity and at the safety dose range, it also strongly up-regulated antioxidant response element (ARE)-luciferase reporter activity. In addition, compound 3b induced Nrf2 nuclear translocation and upregulated its downstream target genes NQO-1 and HO-1 at protein level. Taken together, our results suggest that compound 3b could be a potential agent for cancer themotherapy or cancer chemoprevention. PMID- 27473966 TI - Quantitation of ligupurpurosides B and C in rat plasma using HPLC-MS/MS. AB - The present study was designed to develop a sensitive and selective specific high performance liquid chromatography (HPLC)-tandem mass spectrometric method (MS/MS) for the determination of ligupurpurosides B and C in rat plasma. The samples were prepared after protein precipitation and analyzed by liquid chromatography equipped with a C18 column interfaced with a triple quadrupole tandem mass spectrometer using ESI as the ionization source in the negative ion mode. The mobile phase consisted of water (0.01 % formic acid)-methanol (57 : 43, V/V) at the flow rate of 0.3 mL.min(-1). The analytes and internal standard acteoside were both detected by use of multiple reaction monitoring mode. The total run time was 6.0 min. The method was linear in the concentration range of 2.5-500.0 ng.mL(-1) and the lower limit of quantifiation (LLOQ) was 2.5 ng.mL(-1). The intra-day and inter-day relative standard deviations across three validation runs over the entire concentration range were less than 9.8 %. The accuracy determined at three concentrations was within +/- 6.1% in terms of relative error. In conclusion, this assay offers advantages in terms of expediency and suitability for the analysis of ligupurpuroside B and ligupurpuroside C in various biological fluids. PMID- 27473967 TI - Involvement of toll-like receptors 3 and 7/8 in the neuropathogenesis of bovine herpesvirus types 1 and 5. AB - Bovine herpesvirus types 1 (BoHV-1) and 5 (BoHV-5) are closely related alpha herpesviruses. BoHV-5 is the causal agent of non-suppurative meningoencephalitis in calves. BoHV-1 causes respiratory disease, abortions, genital disorders and, occasionally, encephalitis in cattle. Both viruses are neurotropic and they share similar biological properties. Nevertheless, they differ in their ability to cause neurological disease. Toll-like receptors (TLRs) are involved in the innate immune response to pathogens. In this study, the variations in the expression levels of TLRs were evaluated in different regions of the bovine central nervous system during the acute infection and reactivation of BoHV-1 and BoHV-5- infected cattle. With the exception of TLR9, significant up-regulation of all TLRs was detected following primary infection of neural tissues by both bovine alpha herpesviruses. Furthermore, the stages of acute infection and reactivation were characterized by a distinguishable TLR expression pattern. Important differences in TLR expression upon infection of the central nervous system by BoHV-1 or BoHV 5 were not detected. The striking differences in TLR mRNA levels during acute infection and reactivation provide evidence that the innate immune response may be involved in the clinical outcomes observed at each stage. Further research is required to analyze the mechanisms that initiate TLR activation and the signaling cascade mediated by each TLR to elucidate the precise role these receptors play in bovine herpesvirus encephalitis. PMID- 27473968 TI - Histopathological changes and mRNA expression in lungs of horses after inhalation anaesthesia with different ventilation strategies. AB - Inappropriate mechanical ventilation can lead to ventilator-induced lung injury (VILI). Aim of this study was to evaluate the effects of inhalation anaesthesia and ventilation with and without recruitment (RM) and PEEP titration on alveolar integrity in horses. Twenty-three horses were divided into 4 groups (group OLC ventilated with OLC, group IPPV ventilated with intermittent positive pressure ventilation, group NV non-ventilated, and group C non-anaesthetized control group). After sedation with xylazine and induction with diazepam and ketamine anaesthetized horses were under isoflurane anaesthesia for 5.5h. The horses were euthanized and tissue samples of the dependent and non-dependent lung areas were collected. Histopathological examinations of the lung tissue as well as relative quantification of mRNA of IL-1beta, IL-6, iNOS, MMP1 and MMP9 by PCR were performed. Horses of group OLC had significantly less alveolar congestion and atelectasis but greater alveolar overdistension compared to groups NV and IPPV. In groups OLC and group IPPV an increase in IL-1beta/6 and MMP1/9 was detected compared to groups NV and C. In conclusion, in breathing spontaneously or IPPV ventilated horses a higher degree of atelectasis was detected, whereas in OLC ventilated horses a higher degree of overdistention was present. Elevated levels in IL and MMP might be early signs of VILI in ventilated horses. PMID- 27473970 TI - Towards entire male pigs in Europe: A perspective from the Spanish supply chain. PMID- 27473969 TI - Obesity-driven prepartal hepatic lipid accumulation in dairy cows is associated with increased CD36 and SREBP-1 expression. AB - We investigated the hypothesis that obesity in dairy cows enhanced expression of proteins involved in hepatic fatty acid uptake and metabolism. Sixteen Holstein Friesian close-up cows were divided into 2 equal groups based on their body condition score (BCS) as optimal (3.25<=BCS<=3.5) and high (4.0<=BCS<=4.25). Intravenous glucose tolerance test (GTT) and liver biopsies were carried out at day 10 before calving. Blood samples were collected before (basal) and after glucose infusion, and glucose, insulin and non-esterified fatty acid (NEFA) levels were determined at each sample point. In addition, beta-hydroxybutyrate and triglycerides levels were measured in the basal samples. The liver biopsies were analyzed for total lipid content and protein expression of insulin receptor beta (IRbeta), fatty acid translocase (FAT/CD36) and sterol regulatory element binding protein-1 (SREBP-1). Basal glucose and insulin were higher in high-BCS cows, which coincided with higher circulating triglycerides and hepatic lipid content. Clearance rate and AUC for NEFA during GTT were higher in optimal-BCS cows. The development of insulin resistance and fatty liver in obese cows was paralleled by increased hepatic expression of the IRbeta, CD36 and SREBP-1. These results suggest that increased expression of hepatic CD36 and SREBP-1 is relevant in the obesity-driven lipid accumulation in the liver of dairy cows during late gestation. PMID- 27473971 TI - First report of a spermatic granuloma and varicocele in a marsupial: A Koala (Phascolarctos cinereus) Case Study. AB - This study reports the first documented clinical case of a spermatic granuloma and varicocele in a marsupial. Initial clinical presentation included gross morphological changes in the left scrotal cord, epididymis and testis. Ultrasonography of the scrotum and spermatic cord, and gross and histopathological examination after hemicastration, confirmed the condition as a spermatic granuloma affecting the left caput epididymis, with a varicocele in the left proximal spermatic cord, which was causing azoospermia and infertility. Semen quality and serum testosterone secretion following a GnRH challenge was assessed prior to, and following surgery. After hemi-castration, an increase in androgen secretion to within normal reference ranges for the koala was observed with a subsequent increase in semen production and sperm quality resulting in the sire of a pouch young, 12months later. PMID- 27473972 TI - Combination of competitive exclusion and immunisation with a live Salmonella vaccine in newly hatched chickens: Immunological and microbiological effects. AB - In addition to evaluating the efficacy potential of a combined use of vaccination and competitive exclusion (CE) against Salmonella exposure in chicks at 3-days of age, a live Salmonella Enteritidis vaccine (SE-LV) and a CE culture were tested for their ability to induce parameters of the innate immunity. Whereas the invasive SE-LV induced an influx of granulocytes and macrophages as well as an increased transcription of several cytokines in the caecal mucosa, the CE culture did not demonstrate any differences in these parameters compared to controls. It is therefore highly probable that the effects observed with CE cultures are not due to the rapid stimulation of the immune system. The combined use of both preparations did not result in an additive intestinal exclusion effect of the challenge strain more pronounced than that after single administration of the CE culture. The combined use of the Salmonella live vaccine and the CE culture resulted in an additive protective effect and prevented completely the systemic dissemination of the Salmonella challenge strain. To exploit the potential of combined use of CE and vaccination further and most effectively, live Salmonella vaccines are needed that are despite their attenuation in virulence still capable to induce both intestinal colonisation- and invasion-inhibition effects against Salmonella exposure. PMID- 27473973 TI - Dynamic computed tomography of the pituitary gland using a single slice scanner in dogs with pituitary-dependent hypercortisolism. AB - Selective removal of the pituitary adenoma has not been advocated in dogs with pituitary-dependent hypercortisolism because the pituitary adenoma is usually not visualized on routine computed tomography (CT). Dynamic pituitary CT scanning is aimed at the detection of the pituitary flush and, indirectly, at the presence and position of the adenoma. The first aim of this retrospective study was to compare findings of a multiple slice dynamic scanning protocol with those of a single slice dynamic protocol using a single slice CT scanner. The second aim was to compare the CT findings with surgical findings, and surgical findings with histopathological findings. Computed tomography with single and multiple slice dynamic scanning protocols was performed in 86 dogs with pituitary-dependent hypercortisolism. Thirty dogs underwent transsphenoidal hypophysectomy and pituitary specimens were collected as tumor, normal, mixed and neurohypophyseal samples and processed for histology. The pituitary flush was not detected more frequent in multiple slice dynamic scanning series than in single slice dynamic scanning series. However, in non-enlarged pituitaries, the flush was seen significantly more frequently than in enlarged pituitaries. Prediction of the nature of the tissue during hypophysectomy by the surgeon was inconclusive. In conclusion, when using a single slice CT scanner, both single or multiple slice dynamic scanning protocols can be used for localization of the neurohypophyseal flush, and, indirectly, the adenoma. However, based on this study, the aim of surgery in dogs with pituitary-dependent hypercortisolism remains total adenohypophysectomy, and when the neurophypophysis is recognized, it may be left in situ. PMID- 27473974 TI - Safety and protective efficacy of a spiC and crp deletion mutant of Salmonella gallinarum as a live attenuated vaccine for fowl typhoid. AB - With an aim to develop a safe, immunogenic fowl typhoid (FT) vaccine, the safety and efficacy of 1009DeltaspiCDeltacrp, a spiC and crp deletion mutant of Salmonella gallinarum, were evaluated in chickens. Three-day-old chickens were intramuscularly immunized with 1009DeltaspiCDeltacrp (1*10(7)CFU) and boosted 7days later (at 10-days old) with the same dose and via the same route (vaccinated group). The vaccinated group showed no clinical symptoms and no differences in body weight compared to the unvaccinated control group. 1009DeltaspiCDeltacrp bacteria colonized and persisted in the liver and spleen of vaccinated chickens for >14days, and significant specific humoral and cellular immune responses were induced. Vaccinated chickens were challenged with S. gallinarum strain SG9 at 21days post-immunization (24-day-old chickens), and efficient protection was observed based on the mortality and clinical symptoms, as compared to those in the control group. These results demonstrate that 1009DeltaspiCDeltacrp can be used as a live attenuated vaccine. PMID- 27473975 TI - Maternal and foetal cytokine production in dams naturally and experimentally infected with Neospora caninum on gestation day 110. AB - In the present study, IFN-gamma (Th1), IL-17A (Th17) and IL-4 (Th2) concentrations in response to concanavalin (ConA) and Neospora caninum antigen (Nc-1) stimulation were determined in cultures of cells from control uninfected (n=4), naturally N. caninum-infected (n=3) and experimentally N. caninum-infected (n=6) pregnant dams and their foetuses. Experimental animals were infected at 110days of gestation and euthanized 6weeks post-infection. In culture supernatants from the dams, significantly higher IFN-gamma and IL-4 levels were found in the experimentally-infected animals compared to the control or naturally infected dams. However, among the experimentally-infected dams no significant differences in IFN-gamma production were observed regardless of the incidence of live or aborted/dead foetuses, though spleen cultures of dams carrying live foetuses showed the highest levels of IFN-gamma. IL-17A production was very low and occasional in the dams infected with N. caninum and did not seem to be a major regulator of IFN-gamma production in this model. Experimentally infected dams with live foetuses showed higher IL-4 levels and accordingly IFN-gamma/IL-4 ratios were significantly lower than ratios recorded for cows with aborted/dead foetuses. In the infected foetuses of these dams, only spleen cultures showed high levels of IFN-gamma and IL-4 after Nc-1 antigen and ConA stimulation, respectively. No IL-17A was detected in the foetuses. As conclusion, although we could not clearly relate a protective immune response against N. caninum abortion only to IFN-gamma levels in cell cultures, our results highlight the important role of an inverse IFN-gamma/IL-4 balance in conferring protection against abortion induced by this parasite. PMID- 27473976 TI - Immune response to oligopeptide permease A (OppA) protein in pigs naturally and experimentally infected with Haemophilus parasuis. AB - Haemophilus parasuis is an important swine pathogen that causes Glasser's disease, characterized by pneumonia, polyserositis and meningitis. Protection against H. parasuis infection is associated with the presence of homologous antibodies in serum. However, a H. parasuis antigen that can elicit a protective immune response against all H. parasuis strains has yet to be found. A novel immunogenic and species-specific H. parasuis protein was identified by screening H. parasuis whole cell proteins using swine convalescent sera. One protein of 52kDa was clearly immunodominant and conserved among different H. parasuis strains. This protein was further identified as an oligopeptide permease A (OppA). Because OppA elicited a specific antibody response in pigs that recovered from H. parasuis infection, we investigated its potential role in diagnostics and protective immunity. An ELISA test using recombinant OppA (rOppA) as its coating antigen was further developed and tested. H. parasuis specific antibodies to rOppA were detected in serum from convalescent pigs but not in serum from specific pathogen free (SPF) or conventional pigs. Pigs immunized with rOppA protein had robust serological responses. However, the antibodies were not protective against challenge infection. We conclude that OppA is a universal species-specific H. parasuis immunogen, and a good marker for previous systemic infection with H. parasuis. PMID- 27473977 TI - Effects of feed supplementation with glycine chelate and iron sulfate on selected parameters of cell-mediated immune response in broiler chickens. AB - Because little is known about the impact of chelated (Fe-Gly, Fe-Gly+F) and inorganic (FeSO4, FeSO4+F) iron products on immune response parameters in broiler chickens, the objective of the study was to determine the effects of inorganic and organic forms of iron on selected parameters of the cell-mediated immune response in broiler chickens by assessing the percentage of CD3(+)CD4(+), CD3(+)CD8(+), CD25(+), and MHC Class II lymphocytes, as well as the CD4(+)/CD8(+) ratio and IL-2 concentration in the peripheral blood. The experiments were conducted using 50day-old Ross 308 roosters. The test material was peripheral blood. Flow cytometry was used to determine selected cell-mediated immune response parameters. The results obtained indicate that the use of iron chelates in the diet of broiler chickens may stimulate cellular defense mechanisms. As a result of the experiment an increase was observed in the percentage of Th1, mainly T CD4(+) and T CD8(+). It was also noted that application of chelated iron can increase production of T CD8(+) cytotoxic cells and IL-2, which promotes the body's natural response to developing inflammation. There were no changes in T CD4(+), T CD8(+), T CD25(+) or MHC II lymphocyte subpopulations in the chickens following application of the inorganic form of iron. PMID- 27473978 TI - Feather conditions and clinical scores as indicators of broilers welfare at the slaughterhouse. AB - The objective of this study was to evaluate the welfare of 64 different broiler farms on the basis of feather conditions and clinical scores measures collected at the slaughterhouse. A 3-point scale (0, 1 or 2) was used to classify dirty feathers, footpad dermatitis and hock burns measures, and a 2-point scale (present or absent) was used to classify breast burns, breast blisters and breast ulcer measures. Flocks were allocated into three body weight (BW) classes (A, B, C): class A (light) >=1.43 and <=1.68kg, class B (medium) >=1.69 and <=1.93kg; class C (heavy) >=1.94 and <=2.41kg. The absence of hock burns was more common in class A, while mild hock burns was more common in class B flocks. Breast ulcer was observed in class C flocks. The association observed for mild hock burns, breast burns and severe footpad dermatitis can indicate a simultaneous occurrence of these painful lesions. Very dirty feathers and severe footpad dermatitis relationship suggest litter humidity to be the common underlying cause. In conclusion, it was shown that clinical indicators can be used at the slaughterhouse to identify welfare problems. In the studied flocks, footpad dermatitis, feather conditions and hock burns were the main restrictions for good welfare and should be considered significant welfare indicators of the on-farm rearing conditions. PMID- 27473979 TI - Prostaglandin E2 exerts the proapoptotic and antiproliferative effects on bovine NK cells. AB - The aim of this research was to determine whether prostaglandin E2 (PGE2) affects bovine NK cells in respect of their counts, apoptosis and proliferation, and if it does, then which of the PGE2 receptor (EP) subtype(s) mediate(s) these effects. We here report that long-term, but not short-term, exposure of bovine peripheral blood mononuclear cells to PGE2 at 10(-5)M, 10(-6)M and 10(-7)M, but not at 10(-8)M, caused a significant increase in the percentage of early apoptotic cells among NK cell subset. Moreover, PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, induced a considerable decrease in the absolute count of NK cells. The magnitude of these effects increased with an increasing concentration of PGE2. The blockade of EP1, EP2, EP3 and EP4 receptors did not prevent the PGE2-induced apoptosis and depletion of NK cells. The results suggest that the proapoptotic effect of PGE2 is secondary in character and the induction of this effect is not mediated through EP receptors. Furthermore, the studies demonstrated that PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, highly significantly reduced the percentage of proliferating NK cells. The EP1, EP1/2 and EP3 receptor antagonists were unable to block this effect significantly, whereas the selective blockade of EP4 receptors prevented the PGE2 induced inhibition of NK cells proliferation. These results indicate that PGE2 at certain concentrations may impair the proliferation of NK cells and this effect is mediated via the EP4 receptor. PMID- 27473980 TI - Evaluation of the survival of bone marrow-derived mononuclear cells and the growth factors produced upon intramedullary transplantation in rat models of acute spinal cord injury. AB - Intramedullary bone marrow-derived mononuclear cell (BM-MNC) transplantation has demonstrated neuroprotective effects in the chronic stage of spinal cord injury (SCI). However, no previous study has evaluated its effects in the acute stage, even though cell death occurs mainly within 1week after injury in all neuronal cells. Moreover, the mechanism underlying these effects remains unclear. We aimed to investigate the survival of intramedullary transplanted allogeneic BM-MNCs and the production of growth factors after transplantation to clarify the therapeutic potential of intramedullary transplanted BM-MNCs and their protective effects in acute SCI. Sprague-Dawley rats were subjected to traumatic SCI and received intramedullary transplantation of EGFP(+)BM-MNCs (n=6), BM-MNCs (n=10), or solvent (n=10) immediately after injury. To evaluate the transplanted BM-MNCs and their therapeutic effects, immunohistochemical evaluations were performed at 3 and 7days post-injury (DPI). BM-MNCs were observed at the injected site at both 3 (683+/-83 cells/mm(2)) and 7 DPI (395+/-64 cells/mm(2)). The expression of hepatocyte growth factor was observed in approximately 20% transplanted BM-MNCs. Some BM-MNCs also expressed monocyte chemotactic protein-1 or vascular endothelial growth factor. The demyelinated area and number of cleaved caspase-3 positive cells were significantly smaller in the BM-MNC-transplanted group at 3 DPI. Hindlimb locomotor function was significantly improved in the BM-MNC transplanted group at 7 DPI. These results suggest that intramedullary transplantation of BM-MNCs is an efficient method for introducing a large number of growth factor-producing cells that can induce neuroprotective effects in the acute stage of SCI. PMID- 27473981 TI - One-pot fabrication of silver nanocrystals using Nicandra physalodes: A novel route for mosquito vector control with moderate toxicity on non-target water bugs. AB - Mosquitoes (Diptera: Culicidae) as vectors for important diseases and parasites causing millions of deaths every year. The use of synthetic pesticides against Culicidae leads to resistance and environmental concerns. Therefore, eco-friendly control tools are a priority. In this research, Nicandra physalodes-mediated synthesis of silver nanoparticles (Ag NPs) was conducted, in order to control larval populations of three important mosquito vectors, Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus. Biofabricated Ag NPs were characterized using UV-vis spectrophotometry, XRD, FTIR spectroscopy, SEM, and TEM analyses. Ag NPs were highly toxic against the three mosquito vectors. Maximum efficacy was detected against A. stephensi (LC50=12.39MUg/mL), followed by Ae. aegypti (LC50=13.61MUg/mL) and Cx. quinquefasciatus (LC50=14.79MUg/mL). Interestingly, Ag NPs were safer for the non-target aquatic organism Diplonychus indicus sharing the same aquatic habitats of mosquito larvae. LC50 and LC90 values were 1032.81 and 19,076.59MUg/mL, respectively. Overall, our results highlight that N. physalodes-fabricated Ag NPs are a promising for development of eco-friendly larvicides against mosquito vectors, with negligible toxicity against non-target aquatic water bugs. PMID- 27473982 TI - Sex difference in the survival rate of wild brushtail possums (Trichosurus vulpecula) experimentally challenged with bovine tuberculosis. AB - The main wildlife reservoir of bovine tuberculosis (TB) in New Zealand is the introduced brushtail possum (Trichosurus vulpecula), with spillover of infection from possums to livestock being regarded as the largest barrier to eradicating TB from the country. Past studies have experimentally challenged possums with Mycobacterium bovis (the causative agent of TB) to quantify infection parameters. However, the challenge models used are invariably non-representative of natural infection due to their resulting in much faster rates, and different clinical patterns of disease progression. We monitored the survival of 16 wild free-living possums, fitted with VHF mortality collars and experimentally challenged with a new model, out to six months post-challenge. The aim was to assess whether the new model does indeed result in an ongoing pathogenesis trajectory that is more reflective of natural TB in possums. The mean survival period of challenged possums (~4.6months) did not differ from that estimated for wild free-living possums with naturally acquired TB. In addition, and unexpectedly, infected males survived on average for five weeks longer than females. This significant difference has not been previously observed in experimental trials with other TB/possum challenge models. If this is reflective of natural disease (as is the survival period produced by the percutaneous challenge model), TB infected males in the wild may be generating more secondary cases of infection than infected females. This insight has important implications for understanding the dynamics of, and managing, the disease in its New Zealand wildlife reservoir. PMID- 27473983 TI - A chimeric protein composed of the binding domains of Clostridium perfringens phospholipase C and Trueperella pyogenes pyolysin induces partial immunoprotection in a mouse model. AB - Trueperella pyogenes and Clostridium perfringens are two kinds of conditional pathogens frequently associated with wound infections and succeeding lethal complications in various economic livestock. Pyolysin (PLO) and phospholipase C (PLC) are the key virulence factors of these two pathogens, respectively. In our study, a chimeric protein called rPC-PD4, which is composed of the binding regions of PLO and PLC, was synthesized. The toxicity of rPC-PD4 was evaluated. Results revealed that rPC-PD4 is a safe chimeric molecule that can be used to develop vaccines. Immunizing BALB/c mice with rPC-PD4 induced high titers of serum antibodies that could efficiently neutralize the hemolytic activity of recombinant PLO and PLC. After the challenge with T. pyogenes or C. perfringens was performed through the intraperitoneal route, we observed that rPC-PD4 immunization could provide partial immunoprotection and reduce lung, intestine, and liver tissue damage to mice. This work demonstrated the efficacy of the rationally designed rPC-PD4 chimeric protein as a potential vaccine candidate against C. perfringens and T. pyogenes. PMID- 27473984 TI - Generation of virus like particles for epizootic hemorrhagic disease virus. AB - Epizootic hemorrhagic disease virus (EHDV) is a distinct species within the genus Orbivirus, within the family Reoviridae. The epizootic hemorrhagic disease virus genome comprises ten segments of linear, double stranded (ds) RNA, which are packaged within each virus particle. The EHDV virion has a three layered capsid structure, generated by four major viral proteins: VP2 and VP5 (outer capsid layer); VP7 (intermediate, core-surface layer) and VP3 (innermost, sub-core layer). Although EHDV infects cattle sporadically, several outbreaks have recently occurred in this species in five Mediterranean countries, indicating a potential threat to the European cattle industry. EHDV is transmitted by biting midges of the genus Culicoides, which can travel long distances through wind-born movements (particularly over water), increasing the potential for viral spread in new areas/countries. Expression systems to generate self-assembled virus like particles (VLPs) by simultaneous expression of the major capsid-proteins, have been established for several viruses (including bluetongue virus). This study has developed expression systems for production of EHDV VLPs, for use as non infectious antigens in both vaccinology and serology studies, avoiding the risk of genetic reassortment between vaccine and field strains and facilitating large scale antigen production. Genes encoding the four major-capsid proteins of a field strain of EHDV-6, were isolated and cloned into transfer vectors, to generate two recombinant baculoviruses. The expression of these viral genes was assessed in insect cells by monitoring the presence of specific viral mRNAs and by western blotting. Electron microscopy studies confirmed the formation and purification of assembled VLPs. PMID- 27473985 TI - Carprofen neither reduces postoperative facial expression scores in rabbits treated with buprenorphine nor alters long term bone formation after maxillary sinus grafting. AB - In connection with bilateral maxillary sinus augmentation, the acute effects of the nonsteroidal anti-inflammatory drug carprofen on facial expressions and long term effects on bone formation were evaluated in 18 male New Zealand White rabbits. A 10*10mm bone window was drilled in the maxilla, the sinus membrane elevated and a titanium mini-implant inserted. One of two test materials was randomly inserted unilaterally and bovine bone chips (control) on the contralateral side in the created space. Rabbits were randomly allocated to receive buprenorphine plus carprofen (n=9) or buprenorphine plus saline (n=9) postoperatively. Buprenorphine was administered subcutaneously every 6h for 3days in a tapered dose (0.05-0.01mg/kg) and carprofen (5mg/kg) or saline administered subcutaneously 1h before, and daily for 4days postoperatively. To assess pain, clinical examination, body weight recording and scoring of facial expressions from photos taken before, and 6-13h after surgery were performed. Twelve weeks after surgery the rabbits were euthanized and sections of maxillary bones and sinuses were analysed with histomorphometry and by qualitative histology. Carprofen had no effect on mean facial expression scores, which increased from 0.0 to 3.6 (carprofen) and 4.3 (saline), of a maximum of 8.0. Neither did carprofen have an effect on bone formation or implant incorporation, whereas the test materials had. In conclusion, treatment with 5mg/kg carprofen once daily for 5days did not reduce facial expression scores after maxillary sinus augmentation in buprenorphine treated rabbits and did not affect long term bone formation. PMID- 27473986 TI - Recombinant porcine reproductive and respiratory syndrome virus expressing luciferase genes provide a new indication of viral propagation in both permissive and target cells. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has a condensed single-stranded positive-sense RNA genome that contains several overlapping regions. The transcription regulatory sequence (TRS) is the important cis-acting element participating in PRRSV discontinuous transcription process. Based on reverse genetic system of type 2 highly pathogenic PRRSV cell-passage attenuated strain pHuN4-F112, firefly luciferase or Renilla luciferase genes were inserted between ORF1b and ORF2. An extra TRS6 was embedded behind the foreign luciferase genes. pA-Fluc and pA-Rluc were constructed and successfully rescued in MARC-145 cells. The phenotypical characteristics of the progeny virus were indistinguishable from those of vHuN4-F112 and were genetically stable for at least 25 cell passages. Mutant virus-infected cells were lysed at different time points to assess luciferase activities and measure foreign gene expression levels. The results showed identical variations in the luciferase activities of the recombinants in MARC-145 cells, indicating that they were suitable for monitoring viral propagation in PRRSV-permissive cell cultures. They were also used to infect pulmonary alveolar macrophages, which yielded similar variations in luciferase activities. Therefore, vA-Fluc and vA-Rluc present powerful new tools to monitor PRRSV propagation in both passaged and target cells. PMID- 27473987 TI - Comparison between ultrasonographic findings of benign and malignant canine mammary gland tumours using B-mode, colour Doppler, power Doppler and spectral Doppler. AB - The aim of this study was to evaluate whether the comparison between the ultrasonographic features of canine mammary tumours, assessed by B-Mode, colour Doppler, power Doppler, spectral Doppler, and histopathologic features, would help to differentiate if a tumour is benign or malignant. Ultrasonographic examinations of 104 tumours were performed. Volume, margins, presence of a capsule, echotexture and presence and distribution of the vascular flow of the tumours were evaluated. All the tumours were surgically removed, submitted for histopathologic examination and classified in two groups: Group I (benign tumours) and Group II (malignant tumours). Echotexture was the only parameter evaluated by B-Mode ultrasonography where significant differences were found (p<0.01), with tumours in Group I being homogeneous and tumours in Group II presenting greater heterogeneity. Presence of vascular flow was observed in most of the tumours from both groups and no differences between them were found. Regarding flow distribution, significant differences were observed between groups (p<0.05). In benign tumours, the most common vascular pattern was the peripheral, showing significant differences (p<0.05) compared to mixed and central patterns. In malignant tumours the mixed pattern was the most frequent. Also significant differences among other patterns (peripheral and central) were found. Concerning vascular resistivity and pulsatility indexes, there were no significant differences between the two groups. The echotexture and type of vascular flow pattern of canine mammary gland tumours may help, in a first examination of the tumour, to differentiate between benign and malignant tumours; however to reach a definitive diagnosis histological study is required. PMID- 27473988 TI - Activation of c-Jun N-terminal kinase by Akabane virus is required for apoptosis. AB - Akabane virus (AKAV) belongs to the Simbu serogroup of the genus Orthobunyavirus in the family Bunyaviridae. It has been shown that AKAV induces apoptosis in mammalian cells. It is necessary to understand the signaling pathways involved in AKAV-induced apoptosis to further elucidate the molecular virology of AKAV. c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) are mediators of apoptosis; therefore, we investigated the roles of JNK and p38 MAPK cascades in AKAV-infected cells. We found that JNK and p38 MAPK as well as their downstream substrates, c-Jun and heat shock protein 27 (HSP27), were phosphorylated in response to AKAV infection. A JNK inhibitor (SP600125) inhibited AKAV-mediated apoptosis whereas a p38 MAPK inhibitor (SB203580) did not. We conclude that AKAV infection activates the JNK and p38 MAPK signaling pathways, and the JNK cascade plays a crucial role in AKAV-induced apoptosis in vitro. PMID- 27473989 TI - Impact of two different colistin dosing strategies on healthy piglet fecal microbiota. AB - Colistin is often used in piglets but underdosing and overdosing are frequent. The impact of such administrations on fecal microbiota was studied. Piglets were given either underdoses of colistin by oral gavage for five days or overdoses by in-feed medication for 14days. The composition of fecal microbiota was studied by quantitative PCR, 16S rRNA sequencing, culture of Enterobacteriaceae, and quantification of short-chain fatty acids (SCFAs). The mean colistin concentrations during the treatment for underdosed and overdosed groups were 14.4MUg/g and 64.9MUg/g of feces respectively. Whatever the piglet and the sampling day, the two main phyla were Firmicutes and Bacteroidetes, The main families were Lactobacillaceae, Clostridiales, Lachnospiraceae and Ruminococcaceae. The main perturbation was the significant but transitory decrease in the Escherichia coli population during treatment, yet all the E. coli isolates were susceptible to colistin. Moreover, colistin did not affect the production of SCFAs. These results show that under- or overdoses of colistin do not result in any major disturbance of piglet fecal microbiota and rarely select for chromosomal resistance in the dominant E. coli population. PMID- 27473990 TI - Expression of bovine non-classical major histocompatibility complex class I proteins in mouse P815 and human K562 cells. AB - Major histocompatibility complex class I (MHC-I) proteins can be expressed as cell surface or secreted proteins. To investigate whether bovine non-classical MHC-I proteins are expressed as cell surface or secreted proteins, and to assess the reactivity pattern of monoclonal antibodies with non-classical MHC-I isoforms, we expressed the MHC proteins in murine P815 and human K562 (MHC-I deficient) cells. Following antibiotic selection, stably transfected cell lines were stained with H1A or W6/32 antibodies to detect expression of the MHC-I proteins by flow cytometry. Two non-classical proteins (BoLA-NC1*00501 and BoLA NC3*00101) were expressed on the cell surface in both cell lines. Surprisingly, the BoLA-NC4*00201 protein was expressed on the cell membrane of human K562 but not mouse P815 cells. Two non-classical proteins (BoLA-NC1*00401, which lacks a transmembrane domain, and BoLA-NC2*00102) did not exhibit cell surface expression. Nevertheless, Western blot analyses demonstrated expression of the MHC-I heavy chain in all transfected cell lines. Ammonium-sulfate precipitation of proteins from culture supernatants showed that BoLA-NC1*00401 was secreted and that all surface expressed proteins where shed from the cell membrane by the transfected cells. Interestingly, the surface expressed MHC-I proteins were present in culture supernatants at a much higher concentration than BoLA NC1*00401. This comprehensive study shows that bovine non-classical MHC-I proteins BoLA-NC1*00501, BoLA-NC3*00101, and BoLA-NC4*00201 are expressed as surface isoforms with the latter reaching the cell membrane only in K562 cells. Furthermore, it demonstrated that BoLA-NC1*00401 is a secreted isoform and that significant quantities of membrane associated MHC-I proteins can be shed from the cell membrane. PMID- 27473991 TI - Development of renal atrophy in murine 2 kidney 1 clip hypertension is strain independent. AB - The murine 2-kidney 1-clip (2K1C) model has been used to identify mechanisms underlying chronic renal disease in human renovascular hypertension. Although this model recapitulates many of the features of human renovascular disease, strain specific variability in renal outcomes and animal-to-animal variation in the degree of arterial stenosis are well recognized limitations. In particular, the C57BL/6J strain is considered to be resistant to chronic renal damage in other models. Our objectives were to determine strain dependent variations in renal disease progression and to identify parameters that predict renal atrophy in murine 2K1C hypertension. We used a 0.20mm polytetrafluoroethylene cuff to establish RAS in 3 strains of mice C57BL/6J (N=321), C57BLKS/J (N=177) and129Sv (N=156). The kidneys and hearts were harvested for histopathologic analysis after 3days or after 1, 2, 4, 6, 7, 11 or 17weeks. We performed multivariate analysis to define associations between blood pressure, heart and kidney weights, ratio of stenotic kidney/contralateral kidney (STK/CLK) weight, percent atrophy (% atrophy) and plasma renin content. The STK of all 3 strains showed minimal histopathologic alterations after 3days, but later developed progressive interstitial fibrosis, tubular atrophy, and inflammation. The STK weight negatively correlated with maximum blood pressure and % atrophy, and positively correlated with STK/CLK ratio. RAS produces severe chronic renal injury in the STK of all murine strains studied, including C57BL/6J. Systolic blood pressure is negatively associated with STK weight, STK/CLK ratio and positively with atrophy and may be used to assess adequacy of vascular stenosis in this model. PMID- 27473992 TI - Chicken parvovirus and its associations with malabsorption syndrome. AB - Malabsorption syndrome (MAS) is a multifactorial syndrome which is characterized by enteric disorders and reduced growth rates of broilers. Such condition is responsible for significant economic losses to the poultry industry. A possible association between chicken parvovirus (ChPV) infections and the occurrence of MAS has been proposed. However, such association has not to date been elucidated in view that ChPV has been detected in healthy as well as in MAS-affected chickens. This study aimed to detect and quantify ChPV loads in sera and tissues of MAS-affected, as well as in healthy broilers. Fifty nine, 39-day-old broilers (50 diseased, 9 healthy birds), obtained from the same flocks, were examined. The highest ChPV DNA loads were detected in MAS-affected broilers, particularly in fecal samples and intestinal tissues (~5500 genomic copies/300ng of total DNA). The average viral genome load in serum in MAS-affected birds was 1134copies/mL, whereas no viral DNA was found in sera and thymus tissues from healthy animals. These findings reveal that MAS-affected broilers consistently carry ChPV DNA is serum, whereas healthy animals do not. In addition, viral loads in tissues (bursa of Fabricius, spleen, intestine and liver) of MAS-affected birds were significantly higher in comparison to the same tissues from healthy broilers. Although preliminary, the results obtained here indicate an association between the detection of ChPV DNA in serum, in addition to high ChPV viral loads in tissues, and the occurrence of MAS in broilers. Further experiments should be performed to confirm such results. PMID- 27473993 TI - RAPD analysis and sequencing of ITS1/5.8S rRNA/ITS2 and Fe-hydrogenase as tools for genetic classification of potentially pathogenic isolates of Trichomonas gallinae. AB - Trichomonas gallinae is a worldwide parasite that causes oropharyngeal avian trichomonosis. During eight years, 60 axenic isolates were obtained from different bird species and characterized by three molecular methods: RAPD analysis and PCR-sequencing of ITS1/5.8S rRNA/ITS2 fragment and Fe-hydrogenase gene. We have found two genotypes of ITS1/5.8S rRNA/ITS2 widely distributed among bird populations, a new variant and also two sequences with mixed pattern. Genotype ITS-OBT-Tg-1 was associated with the presence of gross lesions in birds. We have found eight genotypes of the Fe-hydrogenase (A1, A2, C2, C2.1, C4, C5, C6 and C7), three of them are new reports (C5, C6 and C7), and also three sequences with mixed pattern. Subtype A1 of the Fe-hydrogenase was also related with the presence of lesions. RAPD analyses included most of the strains isolated from animals with lesions in one of the sub-clusters. Potentially pathogenic isolates of T. gallinae obtained in this study fulfill the following criteria with one exception: isolated from lesions+ITS-OBT-Tg-1 genotype+FeHyd A1+RAPD sub-cluster I2. PMID- 27473995 TI - Zoonotic Enterocytozoon bieneusi genotypes found in brazilian sheep. AB - The presence of Enterocytozoon bieneusi in sheep has been reported in only three countries worldwide. The present study has found E. bieneusi in Brazilian sheep for the first time; in 24/125 (19.2%) fecal samples by PCR and on 8/10 (80%) farms from three diverse locations. A significantly greater number of lambs (34.1%) were found infected than older sheep (11.1%) (P=0.0036); most of the lambs were less than 6months of age. Farms with an intensive production system had a lower infection rate (10.5%) of infection than semi-intensive farms (23%), but this difference was not statistically significant. Sequencing analysis of the internal transcribed spacer (ITS) region of the rRNA gene revealed four known E. bieneusi genotypes (BEB6, BEB7, I, and LW1) and two novel genotypes (BEB18 and BEB19). Genotypes LW1 and BEB19 clustered within designated zoonotic Group 1 while genotypes BEB6, BEB7, I, and BEB18, and clustered within Group 2. BEB6 was the most prevalent (45.8%), followed by BEB7 (33.3%). Genotypes BEB6, I, and LW1 are zoonotic and can pose a risk to human health for immunocompromised individuals. PMID- 27473994 TI - Toll-like receptors, IFN-gamma and IL-12 expression in bovine leukemia virus infected animals with low or high proviral load. AB - Bovine leukemia virus (BLV) infection is widespread mainly in dairy cattle and 5 10% of infected animals will die due to lymphosarcoma; most cattle remain asymptomatic but 30% develop persistent lymphocytosis (PL). BLV transmission depends on infected cell exchange and thus, proviral load is determinant. Understanding the mechanisms which govern the control of viral dissemination will be desirable for the design of effective therapeutic or preventive strategies for BLV. The development of high proviral load (HPL) or low proviral load (LPL) might be associated to genetic factors and humoral immune responses, however cellular responses are not fully described. We aimed to characterize cytokines and toll like receptors (TLR) expression related to the proviral load profiles. IFN-gamma and IL-12 mRNA expression level was significantly higher in PBMC from infected cattle (LPL n=6 and HPL n=7) compared to uninfected animals (n=5). While no significant differences were observed in IL-12 expression between LPL and HPL group, IFN-gamma expression was significantly higher in LPL animals. Infected cattle exhibited higher expression levels of TLR3, 7-9. Animals with HPL had significantly higher expression of TLR7/8 than uninfected cattle. TLR8 and TLR9 were up-regulated in HPL group, and TLR3 was up-regulated in LPL group. This is the first report related to TLR gene expression in BLV infected cattle and represents evidence of the involvement of these receptors in BLV recognition. Further studies on different subpopulations of immune cells may help clarify their role in response to BLV and its consequences on viral dissemination. PMID- 27473996 TI - Blood concentrations of remifentanil during and after infusion in horses anesthetized with isoflurane and dexmedetomidine. AB - OBJECTIVE: To determine blood remifentanil concentration in isoflurane anesthetized horses during and after a 1h remifentanil and dexmedetomidine infusion. STUDY DESIGN: Prospective study. ANIMALS: Six adult mixed breed horses with (mean+/-SD) bodyweight of 507+/-61kg and 14+/-4years of age. METHODS: Following sedation with xylazine IV, anesthesia was induced with ketamine IV mixed with diazepam IV. Anesthesia was maintained with isoflurane in oxygen. After 52+/-7min for instrumentation, dexmedetomidine (0.25MUgkg(-1) followed by 1.0MUg(-1)kg(-1)h(-1)) and remifentanil infusions (6MUgkg(-1)h(-1)) were administered for a minimum of 60min and horses recovered from anesthesia. Drug infusions were administered into the left jugular vein. Blood was sampled (4mL) from the right jugular vein at predefined intervals before and during administration of remifentanil infusion. Following catheter flush, blood was sampled from the left jugular vein after the infusion was terminated while the horse was recovering from anesthesia. Blood was placed into tubes containing sodium heparin with citric acid, flash frozen in liquid nitrogen, and stored at 80 degrees C until analysis. Blood remifentanil concentration was measured using high performance liquid chromatography and tandem mass spectrometry. RESULTS: Mean peak remifentanil concentration was 7.14etagmL(-1) at 50min after start of infusion. Mean volume of distribution was 268+/-40mLkg(-1) and mean half-life was 12.8min. Blood concentration decreased to 1etagmL(-1) 27min after termination of infusion. Limit of quantification was 0.2etagmL(-1). PMID- 27473997 TI - Fluctuation of neutrophil counts around parturition in Holstein dairy cows with and without retained placenta. AB - Retained placenta (RP) is often diagnosed in high-yielding dairy cows and can negatively affect reproductive performances. The objective of the present study was to investigate the hematological and biochemical profile of cows with RP before and immediately after parturition, with particular emphasis on neutrophil counts, since a previous study demonstrated the presence of peripheral neutropenia in dairy cows with RP sampled a few days after parturition. Results from 12 Holstein cows affected by RP and from 17 clinically healthy controls sampled one week pre-partum, within 12h after calving and between 48 and 72h after parturition were compared between groups and over time. Compared with controls, cows with RP had lower lymphocyte counts before parturition, lower leukocyte and neutrophil counts at parturition, lower monocyte counts at all times, and higher beta-hydroxybutyrate before and after parturition. Erythroid and biochemical parameters were similar over time in both groups, whereas RP cows did not show the increase of neutrophil counts that occurs in controls at parturition. Hence, the finding of a lower neutrophil count in a routinely hemogram performed at parturition could be used as an alarm signal suggesting to monitor the affected animals. Moreover, although the underlying pathogenetic mechanism should be better investigated, the present study describes for the first time the association between altered blood leukocyte concentrations at parturition in RP compared to control cows. PMID- 27473998 TI - Oral health correlates of captivity. AB - The predominant diet fed to captive carnivores in North America consists of ground meat formulated to provide full nutritional requirements. However, this ground meat diet completely lacks the mechanical properties (i.e., toughness and hardness) of the foods these animals would consume in the wild. The goal of this study is to evaluate the effect of captivity on oral health by comparing the prevalence of periodontal disease and dental calculus accumulation in wild and captive lions and tigers (Panthera leo and Panthera tigris), and to also correlate oral health with cranial morphology in these specimens. To achieve this, 34 adult lion and 29 adult tiger skulls were scored for the presence and extent of dental calculus and periodontal disease. These oral health scores were also compared to cranial deformations examined in a previous study. We found that the occurrence and severity of calculus buildup and periodontal disease was significantly higher in captive felids compared to their wild counterparts. Further, higher calculus accumulation occurred on the posterior teeth when compared to the anterior teeth, while an opposite trend for periodontal disease was observed. We also found a significant correlation between oral health and cranial morphology of lions and tigers. The results suggest that food mechanical properties are significant factors contributing to oral health in felids. PMID- 27473999 TI - Evaluation of protective immune response against fowl typhoid in chickens vaccinated with the attenuated strain Salmonella Gallinarum DeltacobSDeltacbiA. AB - Salmonella enterica serovar Gallinarum biovar Gallinarum (SG) causes fowl typhoid in chickens, a septicemic infection which results in high mortality rates. This disease causes high economic impact to the poultry industry worldwide because of the mortality or elimination of positive flocks to control bacterial dissemination. Live vaccines are used in the fields, however the characterization of immune mechanisms important for protection are being studied to improve the efficacy of vaccination schemes. In this study, we evaluated the immune response in brown layer-hens, vaccinated or not, during the most critical period of infection. Cellular and humoral immunity were extensively evaluated until 7 days post-infection (DPI), by flow cytometry and ELISA, respectively. Furthermore, we evaluated the expression of important pro-inflammatory cytokines after infection of bone marrow derived macrophages (BMDMs) with the live attenuated SG vaccine and with the wild SG strain. The results showed an increasing production of IgG and IgM during the first week post-infection, in vaccinated layer-hens, which was absent in unvaccinated birds. The population of CD8(+)CD44(+) and CD4(+)CD44(+) T cells in spleen and cecal tonsils constantly decreased in unvaccinated birds in comparison with vaccinated layers. The expression of IFN-gamma and TNF-alpha in BMDMs was induced by both SG strains (attenuated and wild) at similar levels (p>0.05). Vaccination with live SG vaccine reduced systemic infection by challenge strain of SG and prevented the mortality rate of 85% that occurred in unvaccinated layer-hens during 30 dpi. Furthermore, the immunization enhanced the proliferation of effector CD4(+) and CD8(+) T cells after challenge. PMID- 27474000 TI - Seroprevalence of tuberculosis in domesticated elk (Cervus canadensis) in Korea. AB - Tuberculosis is a contagious disease in animals, primarily cattle, although it also affects wild animals and humans. There are few data on the state of tuberculosis in domesticated elk (Cervus canadensis) in Korea. In order to investigate tuberculosis in elk, the effectiveness of an enzyme linked immunosorbent assay (ELISA) using MPB70 and MPB83 antigens was compared with the tuberculin skin test (TST), and seroprevalence was measured with this assay using serum samples collected from domesticated elk herds in Korea. The respective sensitivities of the MPB70 and MPB83 ELISAs were 51.9% (95% CI 42.0-61.6) and 49.1% (95% CI 39.3-58.9), and their specificities were 100.0% (95% CI 92.6-100.0) and 97.9% (95% CI 88.9-100.0), respectively, in comparison with the TST. The herd prevalence ranged from 50 to 80% and the mean herd seropositive rate was 67.7% (21 of 31). Of 819 serum samples, 163 (19.9%) were seropositive, and the within region prevalence ranged from 18.5-58.0%. In conclusion, the ELISA using the MPB70 and MPB83 antigens showed moderate sensitivity and high specificity compared to TST in elk, and tuberculosis was assumed to be fairly prevalent in domesticated elk in Korea. PMID- 27474001 TI - Risk factors for failure to detect bovine tuberculosis in cattle from infected herds across Northern Ireland (2004-2010). AB - Correctly identifying animals that are truly infected with a pathogen using ante mortem tests is the cornerstone of any disease eradication programme. Failure to identify all infected animals will impede the progress towards controlling and eradicating disease and may also have unforeseen consequences when specific prevention measures are in place to avoid animal-to-animal transmission. In the case of bovine tuberculosis (bTB), the screening ante-mortem test, the Single Comparative Intradermal Tuberculin Test (SCITT), can exhibit moderate sensitivity which can result in a "hidden burden" of infection residing within the population. Using an animal-level dataset relating to the disclosure of infected cattle with Mycobacterium bovis, the causative agent of bTB within infected herds in Northern Ireland, we investigated what factors influenced the probability of an animal being a false-negative when truly infected (using post-mortem (PM) microbiological culture confirmation results to assess infection status). We found that different risk factors affected the probability of a test-negative outcome on infected animals depending on the ante-mortem test or their combination (SICTT and/or interferon gamma (IFN-gamma) testing). Using multivariable models, SCITT disclosure performance varied significantly by age, location (region), and production type. The IFN-gamma tests were significantly affected by region or season, but these effects depended on the cut-off used during interpretation of the test which affected the tests characteristics. Parallel use of SCITT and IFN-gamma tests resulted in the least number of false negatives, and their disclosure was affected by season and age-class. Understanding the factors that lead to the non-disclosure of infected animals is essential to optimise large-scale bTB disease eradication programmes. PMID- 27474002 TI - Effect of tibial tuberosity advancement on cranial tibial subluxation in the feline cranial cruciate deficient stifle joint: An ex vivo experimental study. AB - The effects of Tibial Tuberosity Advancement (TTA) on Cranial Tibial Subluxation (CTS) and Tibial Rotation Angle (TRA) were evaluated in a model of feline Cranial Cruciate Ligament (CrCL)-deficient stifle joint. Ten hindlimbs of adult cats were used. Quadriceps and gastrocnemius muscles were simulated using cables, turnbuckles and a spring. An axial load of 30% body weight was applied. The stifle and talocrural joint angles were adjusted to 120 degrees . Patellar tendon angle (PTA), CTS and TRA were measured radiographically before and after CrCL section, after TTA and after additional advancement by 1 and 2mm. CrCL section resulted in a CTS of 8.1+/-1.5mm and a TRA of 18.4+/-5.7 degrees . After TTA, PTA was significantly decreased from 99.1+/-1.7 degrees to 89.1+/-0.7 degrees ; CTS and TRA did not change significantly (7.8+/-1.0mm and 15.9+/-5.7 degrees respectively). Additional advancement of the tibial tuberosity by 1mm did not significantly affect CTS and TRA. Additional advancement of the tibial tuberosity by 2mm significantly reduced the PTA to 82.9+/-0.9 degrees . A significant decrease of CTS (6.9+/-1.3mm) and TRA (14.7+/-3.6 degrees ) was also observed. A lack of stabilization of the CrCL deficient stifle was observed after TTA in this model of the feline stifle. Even though the validity of the model can be questioned, simple transposition of the technique of TTA from the cat to the dog appeared hazardous. PMID- 27474003 TI - Dairy cows affected by ketosis show alterations in innate immunity and lipid and carbohydrate metabolism during the dry off period and postpartum. AB - The objective of this investigation was to search for alterations in blood variables related to innate immunity and carbohydrate and lipid metabolism during the transition period in cows affected by ketosis. One hundred multiparous Holstein dairy cows were involved in the study. Blood samples were collected at 8, -4, week of disease diagnosis (+1 to +3weeks), and +4weeks relative to parturition from 6 healthy cows (CON) and 6 cows with ketosis and were analyzed for serum variables. Results showed that cows with ketosis had greater concentrations of serum beta-hydroxybutyric acid (BHBA), interleukin (IL)-6, tumor necrosis factor (TNF), serum amyloid A (SAA), and lactate in comparison with the CON animals. Serum concentrations of BHBA, IL-6, TNF, and lactate were greater starting at -8 and -4weeks prior to parturition in cows with ketosis vs those of CON group. Cows with ketosis also had lower DMI and milk production vs CON cows. Milk fat also was lower in ketotic cows at diagnosis of disease. Cows affected by ketosis showed an activated innate immunity and altered carbohydrate and lipid metabolism several weeks prior to diagnosis of disease. Serum IL-6 and lactate were the strongest discriminators between ketosis cows and CON ones before the occurrence of ketosis, which might be useful as predictive biomarkers of the disease state. PMID- 27474004 TI - Infection of mice with oocysts of Toxoplasma gondii by oral route showed differences of virulence from Brazilian RFLP genotypes BrI and BrIII. AB - South American strains of Toxoplasma gondii present higher genetic diversity than classical European strains. We compared the virulence of two non-archetypal Brazilian genotypes of T. gondii to mice. Oocysts of four isolates, two genotype BrI (TgCatBr71 and TgShBr11) and two BrIII (TgCatBr74 and TgCatBr60) were obtained from cats fed experimentally infected mice. After sporulation, 5.0*10(1) and 1.0*10(2) oocysts were orally administrated to Swiss albine mice in Experiments #1 and #2, respectively (4-10 mice/group). Humoral response from dead and surviving mice was analyzed on days 9 to 35 post-infection. Microscopic observations of lungs and brains were performed for tachyzoites and cysts visualization in fresh preparations. Negative results were tested by PCR. Virulence after infection with oocysts is dose dependent for genotype BrIII isolates, but not for BrI. Differences in mortality were observed among isolates from genotype BrIII on Experiment #1. Intra-genotype phenotypic variation related to the parasite stage of infection was demonstrated and this characteristic should be further studied and may influence future work regarding the role of virulence amid hosts. PMID- 27474005 TI - Characterization of the T-cell receptor gamma chain gene rearrangements as an adjunct tool in the diagnosis of T-cell lymphomas in the gastrointestinal tract of cats. AB - Feline alimentary lymphoma is the most common hematopoietic neoplasia in cats. It affects mainly the small intestines and is most frequently of T-cell origin. Evaluation of a fine needle aspirate is often the first step in the diagnostic work-up. Differentiation between a resident mature lymphocyte population as encountered in inflammatory bowel disease and small cell lymphoma cannot be achieved by cytology alone. Even full thickness biopsies evaluated by histopathology can be inconclusive. These cases warrant the application of complementary tools like PCR-based T-cell receptor (TCR) clonality testing for confirmation. The aim of this study was to optimize the DNA extraction protocol for formalin fixed and paraffin embedded tissues (FFPE) and to establish a heteroduplex analysis to enhance resolution of the PCR fragments of the T-cell receptor gamma (TCRG) V-J gene. The new protocols resulted in improved quantity and quality of the extracted DNA. Heteroduplex analysis of the samples improved the resolution of the electrophoresis results so that rules for interpretation of the different patterns could be established. Application of this improved setup detected clonal rearrangements in at least one TCRG primer reaction in 31 of 36 of our feline intestinal lymphoma samples after DNA quality testing. PMID- 27474006 TI - Lidocaine decreases the xylazine-evoked contractility in pregnant cows. AB - The objective of this in vitro study was to evaluate and compare the effects of xylazine on basal uterine contractility of bovine pregnant uterine strips and that of lidocaine on xylazine-sensitized bovine pregnant uterine strips, at different stages of pregnancy. Basal contractility was evaluated in an isolated organ bath and the functionality of the strips throughout the experiment was evaluated using a dose of carbachol (10(-5)M). Uterine motility, expressed with amplitude, frequency of contractions as well as the area under the curve, was recorded in different stages of pregnancy and data were collected at 15-min intervals (5-min before and 5-min after xylazine administration and 5-min after lidocaine addition on the plateau contraction induced by xylazine). Uterine motility increased in all the stages of pregnancy after xylazine addition and gradually decreased after treatment with lidocaine. These data suggest that lidocaine might decrease the tonic effect induced by xylazine on bovine pregnant uteri. PMID- 27474007 TI - Daily rhythms of physiological parameters in the dromedary camel under natural and laboratory conditions. AB - Camels are well adapted to hot arid environments and can contribute significantly to the economy of developing countries in arid regions of the world. Full understanding of the physiology of camels requires understanding of the internal temporal order of the body, as reflected in daily or circadian rhythms. In the current study, we investigated the daily rhythmicity of 20 physiological variables in camels exposed to natural oscillations of ambient temperature in a desert environment and compared the daily temporal courses of the variables. We also studied the rhythm of core body temperature under experimental conditions with constant ambient temperature in the presence and absence of a light-dark cycle. The obtained results indicated that different physiological variables exhibit different degrees of daily rhythmicity and reach their daily peaks at different times of the day, starting with plasma cholesterol, which peaks 24min after midnight, and ending with plasma calcium, which peaks 3h before midnight. Furthermore, the rhythm of core body temperature persisted in the absence of environmental rhythmicity, thus confirming its endogenous nature. The observed delay in the acrophase of core body temperature rhythm under constant conditions suggests that the circadian period is longer than 24h. Further studies with more refined experimental manipulation of different variables are needed to fully elucidate the causal network of circadian rhythms in dromedary camels. PMID- 27474009 TI - Fibroblast activation in cancer: when seed fertilizes soil. AB - In solid cancers, activated fibroblasts acquire the capacity to provide fertile soil for tumor progression. Specifically, cancer-associated fibroblasts (CAFs) establish a strong relationship with cancer cells. This provides advantages to both cell types: whereas cancer cells initiate and sustain CAF activation, CAFs support cancer cell growth, motility and invasion. This results in tumor progression, metastasis and chemoresistance. Numerous studies have detailed the mechanisms involved in fibroblast activation and cancer progression, some of which are reviewed in this article. Cancer cells and CAFs are "partners in crime", and their interaction is supported by inflammation. An understanding of the enemy, the cancer cell population and its "allies" should provide novel opportunities for targeted-drug development. Graphical Abstract Molecular mechanism of fibroblast activation. a Normal fibroblasts are the most common cell type in the extracellular matrix and are responsible for the synthesis of collagens and fibrilar proteins. Under normal conditions, fibroblasts maintain tissue homeostasis and contribute to proper cell communication and function. Fibroblasts can be activated by a diverse set of factors secreted from cancer or immune cells. Not only growth factors such as TGF-beta, PDGF, HGF and FGF but also interleukins, metalloproteinases and reactive oxygen species can promote activation. Likewise, transcriptional factors such as NF-kappaB and HSF-1 play an important role, as do the gene family of metalloproteinase inhibitors, Timp and the NF-kappaB subunit, p62. Interestingly, fibroblasts themselves can stimulate cancer cells to support activation further. b Once activated, fibroblasts undergo a phenotype switch and become cancer-associated fibroblasts (CAFs) expressing various markers such as alpha-SMA, FSP1, vimentin and periostatin. c Recently, the LIF/GP130/IL6-R pathway has been identified as a signaling cascade involved in fibroblast activation. Upon LIF stimulation, JAK is phosphorylated and further activates STAT3, a transcriptional factor that is then translocated into the nucleus where it promotes the transcription of genes responsible for cell growth, differentiation, proliferation and apoptosis. Ruxolitinib can inhibit JAK and prevent STAT3 activation. Further on, the maintenance of JAK activation is supported by epigenetical changes and post-translational modifications. Once pSTAT3 is acetylated by histon acetyltransferase, p300, it leads to the loss of expression of SHP-1, which is a negative regulator of the JAK/STAT pathway. Silencing of SHP-1 steers the constitutive activation of JAK and STAT3. PMID- 27474008 TI - Use of a structured functional evaluation process for independent medical evaluations of claimants presenting with disabling mental illness: rationale and design for a multi-center reliability study. AB - BACKGROUND: Work capacity evaluations by independent medical experts are widely used to inform insurers whether injured or ill workers are capable of engaging in competitive employment. In many countries, evaluation processes lack a clearly structured approach, standardized instruments, and an explicit focus on claimants' functional abilities. Evaluation of subjective complaints, such as mental illness, present additional challenges in the determination of work capacity. We have therefore developed a process for functional evaluation of claimants with mental disorders which complements usual psychiatric evaluation. Here we report the design of a study to measure the reliability of our approach in determining work capacity among patients with mental illness applying for disability benefits. METHODS/DESIGN: We will conduct a multi-center reliability study, in which 20 psychiatrists trained in our functional evaluation process will assess 30 claimants presenting with mental illness for eligibility to receive disability benefits [Reliability of Functional Evaluation in Psychiatry, RELY-study]. The functional evaluation process entails a five-step structured interview and a reporting instrument (Instrument of Functional Assessment in Psychiatry [IFAP]) to document the severity of work-related functional limitations. We will videotape all evaluations which will be viewed by three psychiatrists who will independently rate claimants' functional limitations. Our primary outcome measure is the evaluation of claimant's work capacity as a percentage (0 to 100 %), and our secondary outcomes are the 12 mental functions and 13 functional capacities assessed by the IFAP-instrument. Inter-rater reliability of four psychiatric experts will be explored using multilevel models to estimate the intraclass correlation coefficient (ICC). Additional analyses include subgroups according to mental disorder, the typicality of claimants, and claimant perceived fairness of the assessment process. DISCUSSION: We hypothesize that a structured functional approach will show moderate reliability (ICC >= 0.6) of psychiatric evaluation of work capacity. Enrollment of actual claimants with mental disorders referred for evaluation by disability/accident insurers will increase the external validity of our findings. Finding moderate levels of reliability, we will continue with a randomized trial to test the reliability of a structured functional approach versus evaluation-as-usual. PMID- 27474010 TI - Diagnosis and follow-up of posterior inferior cerebellar artery dissection complicated with ischemic stroke assisted by T1-VISTA: a report of two cases. AB - BACKGROUND: Volume isotropic turbo spin-echo acquisition (VISTA) is a new method similar to the 3D black-blood imaging method that enables visualization of a intramural hematoma. T1-VISTA has recently been applied in the diagnosis of intracranial arterial dissection. However, the identification of an intramural hematoma in posterior inferior cerebellar dissection (PICA-D) by T1-VISTA has only rarely been reported. CASE PRESENTATION: We herein report two patients who suffered from PICA-D complicated with ischemic stroke. Initial magnetic resonance arteriography was not informative, however, T1-VISTA depicted high-intensity signal areas suggesting an intramural hematoma of PICA-D in both cases. The high intensity signal areas gradually reduced and finally disappeared at 4 months and 5 months after the onset, respectively. CONCLUSION: Our cases demonstrate that T1 VISTA was able to assist in the diagnosis and follow-up of PICA-D. PMID- 27474012 TI - Fully Capitated Payment Breakeven Rate for a Mid-Size Pediatric Practice. AB - BACKGROUND AND OBJECTIVES: Payers are implementing alternative payment models that attempt to align payment with high-value care. This study calculates the breakeven capitated payment rate for a midsize pediatric practice and explores how several different staffing scenarios affect the rate. METHODS: We supplemented a literature review and data from >200 practices with interviews of practice administrators, physicians, and payers to construct an income statement for a hypothetical, independent, midsize pediatric practice in fee-for-service. The practice was transitioned to full capitation to calculate the breakeven capitated rate, holding all practice parameters constant. Panel size, overhead, physician salary, and staffing ratios were varied to assess their impact on the breakeven per-member per-month (PMPM) rate. Finally, payment rates from an existing health plan were applied to the practice. RESULTS: The calculated breakeven PMPM was $24.10. When an economic simulation allowed core practice parameters to vary across a broad range, 80% of practices broke even with a PMPM of $35.00. The breakeven PMPM increased by 12% ($3.00) when the staffing ratio increased by 25% and increased by 23% ($5.50) when the staffing ratio increased by 38%. The practice was viable, even with primary care medical home staffing ratios, when rates from a real-world payer were applied. CONCLUSIONS: Practices are more likely to succeed in capitated models if pediatricians understand how these models alter practice finances. Staffing changes that are common in patient centered medical home models increased the breakeven capitated rate. The degree to which team-based care will increase panel size and offset increased cost is unknown. PMID- 27474011 TI - Comparison of a xeno-free and serum-free culture system for human embryonic stem cells with conventional culture systems. AB - BACKGROUND: Elimination of all animal components during derivation and long-term culture of human embryonic stem cells (hESCs) is necessary for future applications of hESCs in clinical cell therapy. METHODS: In this study, we established the culture system of xeno-free human foreskin fibroblast feeders (XF HFF) in combination with chemically defined medium (CDM). XF-HFF/CDM was compared with several conventional culture systems. The hESCs cultured in different media were further characterized through karyotype analysis, pluripotency gene expression, and cell differentiation ability. RESULTS: The hESCs in the XF HFF/CDM maintained their characteristics including typical morphology and stable karyotype. In addition, hESCs were characterized by fluorescent immunostaining of pluripotent markers and teratoma formation in vivo. RT-PCR analysis shown that the stem cell markers OCT3/4, hTERT, SOX2, and Nanog were present in the cell line hESC-1 grown on XF-HFF/CDM. Furthermore, the results of cell growth and expression of bFGF, Oct-4, and hTERT indicated that XF-HFF/CDM had better performance than human serum-matrix/CDM and XF-HFF/human serum. CONCLUSION: The comparison of different xeno-free culture conditions will facilitate clarifying the key features of self-renewal, pluripotency, and derivation and will shed light on clinic applications of hESCs. PMID- 27474014 TI - Tieder JS, Bonkowsky JL, Etzel RA, et al. Clinical Practice Guideline: Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants. Pediatrics. 2016;137(5):e20160590. PMID- 27474013 TI - RE: Overall Postneonatal Mortality and Rates of SIDS. PMID- 27474015 TI - Wong et al. Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study. Pediatrics. 2016:137(4):e20151888. PMID- 27474016 TI - Linear Growth and Child Development in Burkina Faso, Ghana, and Malawi. AB - OBJECTIVES: We aimed to produce quantitative estimates of the associations between 4 domains of child development and linear growth during 3 periods: before birth, early infancy, and later infancy. We also aimed to determine whether several factors attenuated these associations. METHODS: In 3700 children in Burkina Faso, Ghana, and Malawi, growth was measured several times from birth to age 18 months. At 18 months, language, motor, socioemotional, and executive function development were assessed. In Burkina Faso (n = 1111), personal-social development was assessed rather than the latter 2 domains. RESULTS: Linear growth was significantly associated with language, motor, and personal-social development but not socioemotional development or executive function. For language, the pooled adjusted estimate of the association with length-for-age z score (LAZ) at 6 months was 0.13 +/- 0.02 SD, and with DeltaLAZ from 6 to 18 months it was 0.11 +/- 0.03 SD. For motor, these estimates were 0.16 +/- 0.02 SD and 0.22 +/- 0.03 SD, respectively. In 1412 children measured at birth, estimates of the association with LAZ at birth were similar (0.07-0.16 SD for language and 0.09-0.18 SD for motor development). These associations were weaker or absent in certain subsets of children with high levels of developmental stimulation or mothers who received nutritional supplementation. CONCLUSIONS: Growth faltering during any period from before birth to 18 months is associated with poor development of language and motor skills. Interventions to provide developmental stimulation or maternal supplementation may protect children who are faltering in growth from poor language and motor development. PMID- 27474017 TI - Tieder JS, Bonkowsky JL, Etzel RA, et al. Clinical Practice Guideline: Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants: Executive Summary. Pediatrics. 2016:137(5):e20160591. PMID- 27474018 TI - Author's Response: RE: Overall Postneonatal Mortality and Rates of SIDS. PMID- 27474019 TI - RE: Overall Postneonatal Mortality and Rates of SIDS. PMID- 27474020 TI - Countrywide serological evaluation of canine prevalence for Anaplasma spp., Borrelia burgdorferi (sensu lato), Dirofilaria immitis and Ehrlichia canis in Mexico. AB - BACKGROUND: Canine vector-borne diseases (CVBD) have become a major concern for canine and human public health. The aim of the study described here is to add epidemiological data regarding four pathogens responsible for CVBD, namely anaplasmosis, borreliosis, dirofilariosis and ehrlichiosis in a national survey conducted in Mexico. METHODS: Seventy-four veterinary centres located in 21 federal Mexican states were asked to test dogs with clinical signs suspect for CVBD and healthy dogs, for detection of Dirofilaria immitis antigen and antibodies against Anaplasma spp., Borrelia burgdorferi (sensu lato) and Ehrlichia canis using the SNAP(r) 4DX(r) from IDEXX(r) Laboratories. RESULTS: A total of 1706 dogs were tested, including 943 apparently healthy and 722 CVBD suspect dogs. Infected dogs were 36.7 %. The highest percentages of infection with E. canis (51.0 %) and Anaplasma spp. (16.4 %) were obtained in the northwestern region, while D. immitis was most frequently found in the northeastern region of the country (8.9 %). Four dogs from the northwestern, northeastern, eastern and southeastern regions, respectively, were positive for B. burgdorferi (sensu lato). Northcentral regions showed lowest overall prevalence of infection (2.4 %). Co-infections were detected in 8.8 % of the dogs tested. Statistically significant lower positivity was found among dogs aged less than one year (23.2 %) and small-sized dogs (27.6 %), while higher prevalence of infection was found in dogs living outdoors (42.0 %), dogs with detectable tick infestation (43.3 %) and dogs that received treatment for tick-transmitted infections (58.8 %). Seropositivity was a risk factor for the presence of clinical signs as follows: Anaplasma spp. (OR = 2.63; 95 % CI: 1.88-3.67; P < 0.0001), D. immitis (OR = 2.52; 95 % CI: 1.61-3.95; P < 0.0001), E. canis (OR = 3.58; 95 % CI: 2.88-4.45; P < 0.0001), mixed infections (OR = 4.08; 95 % CI: 2.79 5.96; P < 0.0001), one or more agents (OR = 3.58; 95 % CI: 2.91-4.42; P < 0.0001). CONCLUSIONS: Canine serological evidence supports that dogs from Mexico are at risk of acquiring Anaplasma spp., D. immitis and/or E. canis, while B. burgdorferi (sensu lato) transmission is minimal in the country. Practitioners play a fundamental role in the detection and control of these diseases to protect dogs and humans. PMID- 27474022 TI - Enrichment and characteristics of mixed methane-oxidizing bacteria from a Chinese coal mine. AB - In methane-rich environments, methane-oxidizing bacteria usually occur predominantly among consortia including other types of microorganisms. In this study, artificial coal bed gas and methane gas were used to enrich mixed methanotrophic cultures from the soil of a coal mine in China, respectively. The changes in microbial community structure and function during the enrichment were examined. The microbial diversity was reduced as the enrichment proceeded, while the capacity for methane oxidation was significantly enhanced by the increased abundance of methanotrophs. The proportion of type II methanotrophs increased greatly from 7.84 % in the sampled soil to about 50 % in the enrichment cultures, due to the increase of methane concentration. After the microbial community of the cultures got stable, Methylomonas and Methylocystis became the dominant type I and type II methanotrophs, while Methylophilus was the prevailing methylotroph. The sequences affiliated with pigment-producing strains, Methylomonas rubra, Hydrogenophaga sp. AH-24, and Flavobacterium cucumis, could explain the orange appearance of the cultures. Comparing the two cultures, the multi-carbon sources in the artificial coal bed gas caused more variety of non-methanotrophic bacteria, but did not help to maintain the diversity or to increase the quantity and activity of methanotrophs. The results could help to understand the succession and interaction of microbial community in a methane-driven ecosystem. PMID- 27474021 TI - Randomized controlled trials: who fails run-in? AB - BACKGROUND: Early identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability. METHODS: We conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two group randomization (N = 666). RESULTS: Overall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13 fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF. CONCLUSIONS: There were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00153816 . Registered September 2005. PMID- 27474023 TI - Content and Temporal Order Memory for Performed Activities in Parkinson's Disease. AB - OBJECTIVE: This study examined content and temporal order memory for subject performed activities in an incidental learning condition in cognitively healthy individuals with Parkinson's disease (PD) (N = 20) and controls (N = 20). METHOD: Participant's free recall of activities provided a measure of content memory. Temporal order memory was assessed with a reconstruction task of activities. Self and informant-reports of everyday memory were used to examine the relationship between everyday memory, and content and temporal order memory. RESULTS: Individuals with PD recalled fewer activities although recognition memory was intact. Temporal order memory was also impaired for individuals with PD. For the PD group, both self- and informant-reports of changes in current memory abilities were strongly associated with temporal order memory but not content memory for activities. CONCLUSIONS: These findings suggest that there is a strong link between everyday memory abilities and temporal order memory for activities, and support the need for additional study of temporal order memory abilities in PD. PMID- 27474024 TI - Evaluating Potential Guardians for Adults Adjudicated Incompetent. AB - Despite the considerable interest from psychology and law in how to assess and conceptualized competency issues, relatively little has been written about guardianship, particularly how to best evaluate guardianship candidates. This is problematic because a guardian is assigned once an individual is adjudicated incompetent and decision-making about this is difficult in some cases. As psychologists have much to offer the court in making recommendations about a suitable guardian, the purpose of this article is to provide specific recommendation in domains to assess in an interview with a potential guardian. Domains that should be assessed include the following: relationship with proposed ward, knowledge and insight about proposed ward, guardianship plans, decision making style, and suitability for guardianship. Recommendations are also provided for especially difficult cases such as when working with families in conflict, the presence of undue influence, and when a family member or friend is pitted against a disinterested public agency. PMID- 27474025 TI - Introduction to the Special Section on Civil Capacities in Clinical Neuropsychology. PMID- 27474026 TI - Neuropsychological Assessment of Driving Capacity. AB - Clinicians are increasingly requested to make determinations regarding patients' driving capacity in the context of neurological injury/conditions and a growing cohort of older drivers. The capability to drive safely involves a number of cognitive, physical, and sensorimotor abilities that may be impacted by injury, illness, or substances that influence alertness. Neuropsychological measures are an important component of a multidisciplinary approach for evaluation of driving capacity. Clinicians should become familiar with measures that have the best predictive validity so they may incorporate a patient's neurocognitive strengths and weaknesses in decisions about driving ability. PMID- 27474027 TI - Addenbrooke's Cognitive Examination-Revised: Effects of Education and Age. Normative Data for the Spanish Speaking Population. AB - OBJECTIVE: Addenbrooke's Cognitive Examination-Revised is a brief test battery for the detection and classification of mild cognitive impairment and dementia. The aims were to investigate the influence of age and education on the Spanish version of the ACE-R and to propose normative data for the Spanish speaking population. METHOD: Three hundred thirty-four normal healthy volunteers were included in the study. They were classified in three age groups (48-64, 65-75, and 75-89 years of age) and four educational level groups (<=3; 4-8; 9-12, and >=13 years of education). They were assessed with the version of ACE-R validated in Argentina with some modifications in order to adapt it to the Spanish population. RESULTS: Significant differences were obtained between all age groups in Total ACE-R, Memory, Fluency, and Language indexes. Differences were observed among the 48-64 and 76-89 age groups in the Attention-Orientation and Visuospatial indexes. Regarding education, significant difference between <=3 years of education and the remaining groups were obtained in Total ACE-R and in all the indexes. Additionally, the group of 4-8 years of education performed significantly worse than the 9-12 and >=13 groups in Total, Memory, Fluency, and Language indexes. Adjusted scores by education were obtained and percentiles for each age group were calculated. CONCLUSIONS: The results show that both age and education have an important effect on ACE-R performance. Consequently, age and education should be taken into account when interpreting results in ACE-R to improve diagnostic accuracy. PMID- 27474028 TI - Osteonecrosis of the Jaw-a Bone Site-Specific Effect of Bisphosphonates. AB - A known complication that can occur in patients using bisphosphonates (BPs) is osteonecrosis of the jaw (ONJ). ONJ features bone exposure that may be associated with severe pain, swelling, local infection, and pathological fracture of the jaw. Current literature indicates that a complex combination of factors is necessary to induce ONJ. Several hypotheses about the pathophysiology of ONJ were previously reported. Here, we review these hypotheses and introduce new ideas and suggestions on this topic, focusing on bone site-specific cells, and the effect that BPs and other anti-resorptive drugs have on those cells. Gaining more insight into bone site-specific effects may help to better understand the pathogenesis ONJ, and contribute to the development of new bone site-specific anti-resorptive drugs. PMID- 27474029 TI - The Patient's Guide to Psoriasis Treatment. Part 1: UVB Phototherapy. AB - BACKGROUND: Psoriasis is a chronic immune-mediated disease that affects 2-3% of the world population. Ultraviolet B (UVB) phototherapy is an effective treatment for psoriasis compared to other systemic treatments. Currently there is a lack of easily accessible online patient educational material regarding this form of treatment. OBJECTIVE: To present a freely available online guide and video on UVB treatment that is informative to patients and increases the success and compliance of patients starting this therapy. METHODS: The UVB treatment protocol used at the University of California-San Francisco Psoriasis and Skin Treatment Center as well as available information from the literature was reviewed to design a comprehensive guide for patients receiving UVB treatment. RESULTS: We created a printable guide and video resource that reviews the fundamentals of UV light, UVB safety considerations, flow of treatment, side effects, and post phototherapy skin care. CONCLUSION: This guide serves as a valuable resource for patients preparing for UVB phototherapy, the clinicians who treat them, and trainees wishing to learn more about this form of therapy. PMID- 27474030 TI - The Patient's Guide to Psoriasis Treatment. Part 2: PUVA Phototherapy. AB - BACKGROUND: PUVA treatment is photochemotherapy for psoriasis that combines psoralen with UVA radiation. Although PUVA is a very effective treatment option for psoriasis, there is an absence of patient resources explaining and demonstrating the process of PUVA. Studies have shown that patients who viewed videos explaining the treatment procedures for various medical conditions had a greater understanding of their treatment and were more active participants in their health. OBJECTIVE: To present a freely available online guide and video on PUVA treatment designed for patient education on PUVA. METHODS: The PUVA treatment protocol used at the University of California-San Francisco Psoriasis and Skin Treatment Center as well as available information from the literature was reviewed to design a comprehensive guide for patients receiving PUVA treatment. RESULTS: We created a printable guide and video resource that reviews the benefits and risks of PUVA, discusses the three types of PUVA (hand-foot soak, full body soak, and systemic), demonstrates the PUVA process, and provides practical tips for safe use. CONCLUSION: Online media and video delivers material in a way that is flexible and often familiar to patients. This new format is beneficial for prospective patients planning to undergo PUVA treatment, health care providers, and trainees who want to learn more about this treatment. PMID- 27474031 TI - The Patient's Guide to Psoriasis Treatment. Part 3: Biologic Injectables. AB - BACKGROUND: An increasing number of injectable biologics are now available for the treatment of psoriasis. However, for individuals who have never received this therapy, the process of performing a self-injection can be daunting. There is lack of patient educational material on how to perform and optimize this treatment. OBJECTIVE: The objective of this study is to present a freely available online guide and video on biologic injections that is informative to patients and increases the success and compliance of patients starting this therapy. METHODS: The self-injection technique taught at the University of California-San Francisco Psoriasis and Skin Treatment Center as well as available information from the literature were reviewed to design a practical guide for patients receiving biologic injections. RESULTS: We created a printable guide and video resource that describes how to improve the injection process, pain management, travel planning, and common concerns with biologic injectables. CONCLUSION: This guide is beneficial for patients who wish to improve their experience with biologic self-injections, for healthcare providers who prescribe these treatments, and for trainees learning about this modality. PMID- 27474032 TI - The Patient's Guide to Psoriasis Treatment. Part 4: Goeckerman Therapy. AB - BACKGROUND: The Goeckerman regimen remains one of the oldest, most reliable treatment options for patients with moderate to severe psoriasis. Goeckerman therapy currently consists of exposure to ultraviolet B light and application of crude coal tar. The details of the procedure can be confusing and challenging to understand for the first-time patient or provider. OBJECTIVE: To present a freely available online guide and video on Goeckerman treatment that explains the regimen in a patient-oriented manner. METHODS: The Goeckerman protocol used at the University of California-San Francisco Psoriasis and Skin Treatment Center as well as available information from the literature were reviewed to design a comprehensive guide for patients receiving Goeckerman treatment. RESULTS: We created a printable guide and video resource that covers the supplies needed for Goeckerman regimen, the treatment procedure, expected results, how to monitor for adverse events, and discharge planning. CONCLUSION: This new resource is beneficial for prospective patients planning to undergo Goeckerman treatment, healthcare providers, and trainees who want to learn more about this procedure. Online media and video delivers material in a way that is flexible and often familiar to patients. PMID- 27474033 TI - Sunitinib-induced sudden hearing loss. PMID- 27474034 TI - Risk factors for back pain in marines; a prospective cohort study. AB - BACKGROUND: It is recognised that back pain (BP) is a debilitating medical problem in the soldier community, which limits operational readiness as well as work ability. As such, identification of risk factors is a necessity for effective preventive actions, but also regarded as important from a safety perspective. The aim of this prospective cohort study was therefore to identify risk factors for back pain and BP limiting work ability in active duty marines within a 6 and 12-month period. METHODS: Demographic characteristics, health related factors and occupational exposure information, as gathered from questionnaires, as well as clinical test of movement control among 137 Swedish marines were regressed with multivariable logistic regressions, and strength of associations was presented as odds ratio (OR) with 95 % confidence intervals (CI). BP within 6 and 12 months were used as primary outcomes, whereas BP limiting work ability within 6 and 12 months served as secondary outcomes. RESULTS: Previous BP and tall body height (>=1.86 m) emerged as risk factors for back pain within 6 months (OR 2.99, 95 % CI 1.22-7.30; OR 2.81, 95 % CI 1.16- 6.84, respectively), and 12 months (OR 6.75, 95 % CI 2.30-19.80; 2.75, 95 % CI 1.21-6.29, respectively). Previous BP was also identified as risk factor for BP limiting work ability within 12 months (OR 6.64, 95 % CI 1.78-24.78), and tall body height emerged as a risk within both six (OR 4.30, 95 % CI 1.31-14.13) and 12 months (OR 4.55, 95 % CI 1.53-13.57) from baseline. CONCLUSIONS: Marines with a history of BP are at risk of further BP episodes, which, thus, emphasise the importance of early BP preventive actions. Tall body height also emerged as an important risk which may reflect that personal equipment and work tasks are not adapted for the tallest marines. While this should be considered when introducing new work equipment, further studies are warranted to clarify the underlying mechanism of this association. PMID- 27474035 TI - Influence of pH Modulation on Dynamic Behavior of Gel Layer and Release of Weakly Basic Drug from HPMC/Wax Matrices, Controlled by Acidic Modifiers Evaluated by Multivariate Data Analysis. AB - The solubility of weakly basic drugs in passage through gastrointestinal tract leads to their pH-dependent release from extended release formulations and to lower drug absorption and bioavailability. The aim of this study was to modulate the micro-environmental pH of hypromellose/montanglycol wax matrices and to observe its influence on the release of weakly basic drug verapamil hydrochloride (VH) with a pH-dependent solubility with respect to gel layer formation and its dynamics. For this study, malic and succinic acids differing in their solubility and pKa were selected as pH modifiers. The dissolution studies were performed by the method of changing pH. Within the same conditions, pH, thickness, and penetration force of the gel layer were measured as well. From the PCA sub-model, it is evident that a higher acid concentration ensured lower gel pH and conditions for higher drug solubility, thus creating larger gel layer with smaller rigidity, resulting in higher VH release during the dissolution test. Incorporation of stronger and more soluble malic acid (100 mg/tablet) created the most acidic and the thickest gel layer through which a total of 74% of VH was released. Despite having lower strength and solubility, matrices containing succinic acid (100 mg/tablet) released a comparable 71% of VH in a manner close to zero-order kinetics. The thinner and less rigid gel layers of the succinic acid matrices allowed an even slightly faster VH release at pH 6.8 than from matrices containing malic acid. Thus acid solubility is more parametrically significant than acid pKa for drug release at pH 6.8. PMID- 27474036 TI - Pharmacokinetics of Abamectin/Levamisole Combination in a Medium Chain Mono and Diglyceride-Based Vehicle and an In Vitro Release and In Vitro In Vivo Correlation Study for Levamisole. AB - A combination of lipophilic and hydrophilic drugs in a single solution is a challenge due to their different physicochemical properties. In vitro and in vivo release studies are useful to optimize this solution. The in vitro (Franz diffusion cell) release rate of levamisole phosphate from an isotropic vehicle of medium chain mono and diglycerides (MCMDG) was significantly slower than the release from water. The injectable solution of the isotropic MCMDG-based system was prepared with 13.65% of levamisole phosphate and 0.5% of abamectin. Two milliliters/50 kg (0.04 ml/kg) was injected subcutaneously into five healthy adult sheep. None of the animals showed the signs of inflammation at injection site. Both drugs were assayed using validated HPLC methods. The absorption rates for levamisole (0.71 +/- 0.32 h-1) and abamectin (0.24 +/- 0.08 day-1) from the MCMDG-based formulation were considerably slower than those of other studies conducted on the commercial products. The tmax was delayed for levamisole (2.20 +/- 0.45 h) and abamectin (4.20 +/- 1.64 days) compared with those in published studies. Longer MRT values for levamisole (6.14 +/- 1.14 h) and abamectin (8.80 +/- 1.39 days) were found in this study compared to those reported. A correlation was observed between in vivo fraction absorbed and in vitro fraction released for levamisole phosphate in the MCMDG-based formulation. The injection vehicle of isotropic MCMDG-based system delayed the subcutaneous absorption of levamisole phosphate and abamectin compared to the commercial subcutaneous injection products for levamisole and abamectin. Notably, this isotropic MCMDG-based vehicle system is prepared with a combination of two drugs with different physicochemical properties. PMID- 27474037 TI - Antioxidant and Carbohydrate-Hydrolysing Enzymes Potential of Sechium edule (Jacq.) Swartz (Cucurbitaceae) Peel, Leaves and Pulp Fresh and Processed. AB - Sechum edule peel, leaves and pulp were investigated for their chemical composition (total phenol, flavonoid, carotenoid and vitamin C content), and for antioxidant activity and carbohydrate-hydrolysing enzymes (alpha-amylase and alpha-glucosidase) inhibition. In order to evaluate the incidence of cooking process on retention of healthy phytochemicals, the pulp was subjected to different treatments (grill roasting, domestic oven baking, microwave cooking, blanching and steaming). Cooking processes reduced the total phenol content (58.5 mg/g extract for fresh pulp vs 26.3 and 29.3 mg/g extract for roasted and steamed samples, respectively). Pulp was found to be the most active in 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS) (IC50 of 0.1 mg/mL), whereas peel showed the highest activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH) test (IC50 of 0.4 mg/mL). Moreover, peel exhibited the highest inhibitory activity against alpha-amylase with an IC50 of 0.2 mg/mL, except for steamed cooking process, which drastically influenced the bioactivity against both enzymes. PMID- 27474038 TI - Seamless editing of the chloroplast genome in plants. AB - BACKGROUND: Gene editing technologies enable the precise insertion of favourable mutations and performance enhancing trait genes into chromosomes whilst excluding all excess DNA from modified genomes. The technology gives rise to a new class of biotech crops which is likely to have widespread applications in agriculture. Despite progress in the nucleus, the seamless insertions of point mutations and non-selectable foreign genes into the organelle genomes of crops have not been described. The chloroplast genome is an attractive target to improve photosynthesis and crop performance. Current chloroplast genome engineering technologies for introducing point mutations into native chloroplast genes leave DNA scars, such as the target sites for recombination enzymes. Seamless editing methods to modify chloroplast genes need to address reversal of site-directed point mutations by template mediated repair with the vast excess of wild type chloroplast genomes that are present early in the transformation process. RESULTS: Using tobacco, we developed an efficient two-step method to edit a chloroplast gene by replacing the wild type sequence with a transient intermediate. This was resolved to the final edited gene by recombination between imperfect direct repeats. Six out of 11 transplastomic plants isolated contained the desired intermediate and at the second step this was resolved to the edited chloroplast gene in five of six plants tested. Maintenance of a single base deletion mutation in an imperfect direct repeat of the native chloroplast rbcL gene showed the limited influence of biased repair back to the wild type sequence. The deletion caused a frameshift, which replaced the five C-terminal amino acids of the Rubisco large subunit with 16 alternative residues resulting in a ~30-fold reduction in its accumulation. We monitored the process in vivo by engineering an overlapping gusA gene downstream of the edited rbcL gene. Translational coupling between the overlapping rbcL and gusA genes resulted in relatively high GUS accumulation (~0.5 % of leaf protein). CONCLUSIONS: Editing chloroplast genomes using transient imperfect direct repeats provides an efficient method for introducing point mutations into chloroplast genes. Moreover, we describe the first synthetic operon allowing expression of a downstream overlapping gene by translational coupling in chloroplasts. Overlapping genes provide a new mechanism for co-ordinating the translation of foreign proteins in chloroplasts. PMID- 27474040 TI - A Review of Studies on the System-Wide Implementation of Evidence-Based Psychotherapies for Posttraumatic Stress Disorder in the Veterans Health Administration. AB - Since 2006, the Veterans Health Administration (VHA) has instituted policy changes and training programs to support system-wide implementation of two evidence-based psychotherapies (EBPs) for posttraumatic stress disorder (PTSD). To assess lessons learned from this unprecedented effort, we used PubMed and the PILOTS databases and networking with researchers to identify 32 reports on contextual influences on implementation or sustainment of EBPs for PTSD in VHA settings. Findings were initially organized using the exploration, planning, implementation, and sustainment framework (EPIS; Aarons et al. in Adm Policy Ment Health Health Serv Res 38:4-23, 2011). Results that could not be adequately captured within the EPIS framework, such as implementation outcomes and adopter beliefs about the innovation, were coded using constructs from the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework (Glasgow et al. in Am J Public Health 89:1322-1327, 1999) and Consolidated Framework for Implementation Research (CFIR; Damschroder et al. in Implement Sci 4(1):50, 2009). We highlight key areas of progress in implementation, identify continuing challenges and research questions, and discuss implications for future efforts to promote EBPs in large health care systems. PMID- 27474041 TI - Correlation-based feature selection and classification via regression of segmented chromosomes using geometric features. AB - The genetic defects in the humans are uncovered by studying the chromosomes, as they are the genetic information carriers. They are non-rigid objects and they appear in different orientations when they are imaged. To find out the genetic defects, the chromosomes are pre-processed so that they are not touching, overlapping, and bent, and the noise is also discarded. The presence of bends, overlaps, or touches makes it difficult to uncover the genetic abnormalities. So there is a need for development of an efficient technique to classify the segmented chromosomes into different types and then pre-process them in order to correct their orientation. In this work, a hybrid classification technique based upon correlation-based feature selection and classification via regression approach, which will classify the segmented chromosomes into five categories viz; straight, overlapping, bent, touching, or noise is presented. The performance evaluation has been done using 1592 segmented chromosomes from Advance Digital Imaging Research data set. The over-all accuracy of 94.78 % has been obtained for the five class problem. The performance of the proposed classifier has been compared with Bayes Net, Naive Bayes, Radial Bias Feed Forward Network, and k nearest-neighbour classifiers. Based upon this categorization, different pre processing techniques will be applied to correct the orientation of the chromosomes. PMID- 27474039 TI - Differences in molecular evolutionary rates among microRNAs in the human and chimpanzee genomes. AB - BACKGROUND: The rise of the primate lineage is accompanied by an outstanding emergence of microRNAs, small non-coding RNAs with a prominent role in gene regulation. In spite of their biological importance little is known about the way in which natural selection has influenced microRNAs in the human lineage. To study the recent evolutionary history of human microRNAs and to analyze the signatures of natural selection in genomic regions harbouring microRNAs we have investigated the nucleotide substitution rates of 1,872 human microRNAs in the human and chimpanzee lineages. RESULTS: We produced a depurated set of microRNA alignments of human, chimpanzee and orang-utan orthologs combining BLAT and liftOver and selected 1,214 microRNA precursors presenting optimal secondary structures. We classified microRNAs in categories depending on their genomic organization, duplication status and conservation along evolution. We compared substitution rates of the aligned microRNAs between human and chimpanzee using Tajima's Relative Rate Test taking orang-utan as out-group and found several microRNAs with particularly high substitution rates in either the human or chimpanzee branches. We fitted different models of natural selection on these orthologous microRNA alignments and compared them using a likelihood ratio test that uses ancestral repeats and microRNA flanking regions as neutral sequences. We found that although a large fraction of human microRNAs is highly conserved among the three species studied, significant differences in rates of molecular evolution exist among microRNA categories. Particularly, primate-specific microRNAs, which are enriched in isolated and single copy microRNAs, more than doubled substitution rates of those belonging to older, non primate-specific microRNA families. CONCLUSIONS: Our results corroborate the remarkable conservation of microRNAs, a proxy of their functional relevance, and indicate that a subset of human microRNAs undergo nucleotide substitutions at higher rates, which may be suggestive of the action of positive selection. PMID- 27474042 TI - The Role of Online Communication in Long-Term Cyberbullying Involvement Among Girls and Boys. AB - Digital media, especially mobile communication technologies, enable adolescents to explore and experiment with each other with only limited adult control. Conflicts between peers can be easily staged since nearly everybody can be reached at any time under the radar of authorities. Therefore, involvement in conflicts and bullying might depend on how adolescents use and behave online. In the present study, we provide a comprehensive picture of the role aspects of online communication play in long-term involvement in cyberbullying. We focused on a gender-specific perspective, as girls and boys were found to differ not only according to their online communication but also in their cyberbullying involvement. Using a two-wave panel survey of 1817 adolescents between 13 and 17 years (56 % female), we found that girls' cyberbullying involvement (perpetration and victimization) could be traced back to more intensive online social activities and a higher amount of online contact with strangers. In contrast, for boys, only higher exposure to antisocial media content predicted higher levels of victimization over time. The findings indicate that certain patterns of online communication increase the cyberbullying risk over time. However, it needs to be noted that these risk factors vary between girls and boys. PMID- 27474044 TI - Thyroid-Like Follicular Carcinoma of the Kidney. AB - Thyroid-like follicular carcinoma of the kidney (TLFCK) is a rare but emerging renal neoplasm that morphologically mimics follicular carcinoma of the thyroid but lacks immunohistochemical expression of thyroid markers such as TTF-1 and thyroglobulin. Here, a case of an incidentally discovered TLFCK in a 27-year-old man is reported. Histologic evaluation demonstrated an encapsulated proliferation of variably sized thyroid follicle-like epithelial-lined spaces filled with colloid-like eosinophilic secretions. Immunohistochemical analysis confirmed lack of expression of the thyroid markers TTF-1 and thyroglobulin with expression of PAX8 and CD10, confirming a neoplasm of renal origin, which correlated to the clinical and radiographic absence of thyroid pathology. In this report, this case is described with an emphasis on the differential diagnosis. PMID- 27474055 TI - Are the Animal Welfare Acts achieving their full potential? AB - A decade has passed since the Animal Welfare Act 2006 and the Animal Health and Welfare (Scotland) Act 2006 became law. A session at this year's Animal Welfare Foundation Discussion Forum examined the successes and limitations of the Acts and whether they are working to their full potential. Further discussions centred on the keeping of non-traditional companion animals as pets and whether greater regulation of the pet trade is needed. Laura Honey reports. PMID- 27474043 TI - Omega-3 fatty acids control productions of superoxide and nitrogen oxide and insulin content in INS-1E cells. AB - Omega-3 fatty acids have multiple effects in peripheral tissues and pancreatic beta cell function. Dietary depletion of omega-3 fatty acids is associated with pancreatic islet dysfunction and insulin resistance in rats. Herein, the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on pancreatic beta cell redox state and function were investigated. INS-1E insulin-secreting cells were incubated with EPA and DHA in combination with palmitic acid, and productions of reactive oxygen species (ROS), nitric oxide (NO) and insulin were measured. The involvement of the NADPH oxidase complex in ROS production and expression of the antioxidant enzymes was also investigated. After incubation for 1 or 48 h, productions of superoxide (by hydroethidine method), nitric oxide (by 4,5-diaminofluorescein diacetate-DAF-2DA assay), insulin (by radioimmunoassay), and expressions (by western blot analysis) of glutathione peroxidase (GPx-1) and gp91PHOX were measured. EPA and DHA reduced superoxide production after 1-h incubation. After 48 h, palmitic acid reduced superoxide production that was normalized by EPA treatment. Palmitic acid increased NO production that was reverted by EPA and DHA. Palmitic acid increased insulin secretion after 48 h, whereas both omega-3 fatty acids increased intracellular insulin content. EPA and DHA enhanced GPx-1 expression as well as gp91PHOX glycosylated form. In conclusion, EPA and DHA increased intracellular insulin content and antioxidant enzymatic defense capacity and decreased pro-oxidant generating activities that are associated with maintenance of pancreatic beta cell redox state in response to palmitic acid. PMID- 27474045 TI - Macroporous mesh of nanoporous gold in electrochemical monitoring of superoxide release from skeletal muscle cells. AB - Real-time monitoring of metabolically relevant biochemicals released in minuscule amounts is of utmost diagnostic importance. Superoxide anion as a primary member of reactive oxygen species, has physiological and pathological effects that depend on its concentration and release rate. Here we present fabrication and successfully testing of a highly sensitive electrochemical biosensor featuring a three-dimensional macroporous mesh of nanoporous gold tailored to measure the dynamics of extracellular superoxide concentration. Wide and accessible surface of the mesh combined with high porosity of the thin nanoporous gold coating enables capturing the analyte in pico- to nano-molar ranges. The mesh is functionalized with cytochrome-c (cyt-c) and incorporated as a working electrode to measure the release rate of drug-induced superoxides from C2C12 cells through a porous membrane. The device displays a considerably improved superoxide sensitivity of 7.29nAnM-1cm-2 and a low level of detection of 70pM. Such sensitivity is orders of magnitude higher than any similar enzyme-based electrochemical superoxide sensor and is attributed to the facile diffusion of the analyte through the well-spread nanofeatured gold skin. Superoxide generation rates captured from monolayer myoblast cultures containing about 4*104 cells, varied from 1.0 to 9.0nMmin-1 in a quasi-linear fashion as a function of drug concentration. This work provides a platform for the development of highly sensitive molecular electrochemical biosensors. PMID- 27474056 TI - Working with GM vaccines: engaging the public. AB - The UK Veterinary Vaccinology Network was among the sponsors of this year's Cheltenham Science Festival, which took place from June 7 to 12. During the festival, Adrian Hill and Andrew Pollard, of the Jenner Institute, and Bryan Charleston, of the Pirbright Institute, represented the network and discussed the development of genetically modified vaccines and the issues surrounding them in animal and human health. Madeleine Clark sums up their presentation. PMID- 27474057 TI - Equine disease surveillance: quarterly summary. AB - National and international disease outbreaksAfrican horse sickness in South AfricaRising EHV-1 abortion cases in the UKSummary of surveillance testing, January to March 2016 These are among matters discussed in the most recent quarterly equine disease surveillance report, prepared by Defra, the Animal Health Trust and the British Equine Veterinary Association. PMID- 27474058 TI - Vesicular stomatitis. AB - More than 800 premises in eight states in the USA have recently reported cases of vesicular stomatitis in their horses. Here, Peter Timoney, of the Gluck Equine Research Center in Kentucky, discusses this zoonotic disease in more detail. PMID- 27474059 TI - Chronic wasting disease of deer - is the battle to keep Europe free already lost? PMID- 27474060 TI - Correction. PMID- 27474061 TI - Correction. PMID- 27474062 TI - Developing vaccines against African horse sickness. PMID- 27474063 TI - Reflecting on CPD. PMID- 27474064 TI - Jumping into equine practice. AB - Lesley Barwise-Munro is an equine practitioner in Northumberland and the senior vet at Newcastle Racecourse. She is currently in Rio de Janeiro for the Olympic Games. PMID- 27474065 TI - Ten-minute chat. AB - Alastair Porter became secretary and Registrar of the Royal College of Veterinary Surgeons in 1966. Here, he recalls the first of his 25 years in office. PMID- 27474066 TI - Anti-inflammatory and antiedematogenic activity of the Ocimum basilicum essential oil and its main compound estragole: In vivo mouse models. AB - The genus Ocimum are used in cooking, however, their essential oils are utilized in traditional medicine as aromatherapy. The present study was carried out to investigate the chemical composition and systemic anti-inflammatory activity of the Ocimum basilicum essential oil (EOOB) and its major component estragole, as well as its possible mechanisms of action. The Ocimum basilicum essential oil was obtained by hydrodistillation and analyzed by GC-MS. The anti-inflammatory action was verified using acute and chronic in vivo tests as paw edema, peritonitis, and vascular permeability and granulomatous inflammation model. The anti-inflammatory mechanism of action was analyzed by the participation of histamine and arachidonic acid pathways. The chemical profile analysis identified fourteen components present in the essential oil, within them: estragole (60.96%). The in vivo test results show that treatment with EOOB (100 and 50 mg/kg) and estragole (60 and 30 mg/kg) significantly reduced paw edema induced by carrageenan and dextran. The smallest doses of EOOB (50 mg/kg) and estragole (30 mg/kg) showed efficacy in the reduction of paw edema induced by histamine and arachidonic acid, vascular permeability inhibition and leukocyte emigration in the peritoneal fluid. Theses doses were capable of reducing the chronic inflammatory process. The results observed between the EOOB and estragole demonstrate efficacy in anti inflammatory activity, however, the essential oil is more efficacious in the acute and chronic anti-inflammatory action. This study confirms the therapeutic potential of this plant and reinforces the validity of its use in popular medicine. PMID- 27474067 TI - Luteolin exerts pro-apoptotic effect and anti-migration effects on A549 lung adenocarcinoma cells through the activation of MEK/ERK signaling pathway. AB - An increasing amount of evidence suggests that luteolin, a common dietary flavonoid that is widely distributed in plants and foods, has been shown to be protective against cancer. However, the precise underlying mechanisms of its action against lung cancer are still poorly understood. In the present study, we investigated whether luteolin exhibits the anti-cancer effect in lung cancer through the induction of cell apoptosis and inhibition of cell migration, and whether mitogen-activated protein kinases (MAPKs) and Akt signaling pathways are required. Results revealed that luteolin exerted an anti-proliferation effect in a dose- and time-dependent manner in A549 lung adenocarcinoma cells, and induced apoptosis with a concomitant increase in the activation of caspases-3 and -9, diminution of Bcl-2, elevation in Bax expression, and the phosphorylation of MEK and its down-stream kinase ERK, as well as the activation of Akt. Luteolin also dramatically inhibited cell motility and migration in A549 cells. The inhibitor of MEK-ERK pathway protected against luteolin-induced cell death and suppressed the apoptosis-inducing and anti-migratory effects of luteolin, suggesting MEK-ERK signaling pathway plays an important role in mediating the pro-apoptotic effect and anti-migration effects of luteolin. Taken together, this study provides a new insight into the mode of action of luteolin on lung cancer. PMID- 27474069 TI - Attenuation of gastric mucosal damage by artesunate in rat: Modulation of oxidative stress and NFkappaB mediated signaling. AB - A number of factors like alcohol consumption, stress, use of non steroidal anti inflammatory drugs and acidity are well known to increase the risk of development of gastric ulcers. The present study was carried out to investigate the protective effect of artesunate against gastric injury induced in rats by oral administration of ethanol and by pylorus ligation in independent sets of experiments. The groups included in each set (n = 6 per group) were normal control, experimental control and drug treated groups: artesunate 50 and 150 mg/kg (ART 50 and ART 150) and famotidine 20 mg/kg (FAM 20). Artesunate and famotidine were given orally 1 h before induction of gastric ulceration and the macroscopic changes, median ulcer score, gastric juice parameters (volume, pH and acidity), markers of oxidative stress and inflammation (GSH, SOD, TBARS and MPO) and tissue histology were evaluated in both the models. The study was extended further for determination of tissue levels of TNF-alpha and expression of IL 1beta, IL-6 and NFkappaB (p65) in ethanol induced gastric ulcer model. The results of the present study show that pretreatment with artesunate significantly decreased hemorrhagic lesions and mucosal damage with marked reduction in median ulcer score in both the models. The protective effect of artesunate was concomitant with dose-dependent normalization of gastric juice parameters, markers of oxidative stress and lipid peroxidation. The ameliorative effect of artesunate was also supported by restoration of histological architecture. Furthermore, artesunate pretreatment also alleviated the gastric mucosal inflammation as revealed by significant decrease in the tissue level of pro inflammatory cytokine TNF-alpha (p < 0.01) and tissue expression of IL-1beta, IL 6 and NFkappaB (p65). The protective effect of artesunate was found to be comparable to that of famotidine. Conclusively, artesunate afforded significant gastroprotection in rat due to its anti-oxidant and anti-inflammatory properties with transcription factor NFkappaB(p65) and its downstream inflammatory cascade as a plausible target for its action. PMID- 27474068 TI - Anti-inflammatory effects of 6'-O-acetyl mangiferin from Iris rossii Baker via NF kappab signal blocking in lipopolysaccharide-stimulated RAW 264.7 cells. AB - A series of acylated xanthone C-glucosides were identified from the methanolic extract of whole Iris rossii Baker. The major constituent was characterized as 6' O-acetyl mangiferin (OAM), and complete structure elucidation was carried out using 2D NMR (COSY, HSQC, and HMBC) and LC-IT-TOF-MS analyses. The present study is the first to report the anti-inflammatory effects of 6'-O-acetyl mangiferin from Iris rossii Baker on the lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 macrophage cells. OAM strongly suppressed protein expression of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2), thereby inhibiting the production of nitric oxide (NO), prostaglandin E2 (PGE2), and cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6). Furthermore, OAM inhibited the LPS-induced phosphorylation of ERK, JNK, and p38, which led to the blockade of nuclear factor-kappa B (NF kappaB) and inhibitor kappa B (IkappaB)-alpha activation. These results suggest that the anti-inflammatory effects of OAM may be attributed to the downregulation of COX-2 and iNOS via the suppression of NF-kappaB and the MAPK signaling pathway in RAW264.7 macrophages. PMID- 27474070 TI - Profile of fall injury in the New South Wales older adult population. AB - BACKGROUND: A previous report from the New South Wales (NSW) Trauma Registry identified falls and increasing age of severely injured patients as highly prevalent, but detailed injury and demographic profiles, outcomes and their predictors are poorly reported. This study describes the fall-injury profile in the older adult major trauma patient in NSW. METHODS: A retrospective registry based study between 2010 and 2014 on patients aged 55 years and over who sustained a moderate to critical injury from a fall, examining mortality and length of stay using regression analyses. RESULTS: There were 4263 major trauma falls between 2010 and 2014, most occurring at home (55.4%), on the same level (46.7%) and resulting in head injury (63.2%). Significant predictors for mortality following a fall were increased age, male gender, falls in residential care institutions, isolated head injuries and injury classified as critical (ISS 41-75). CONCLUSIONS: The outcomes of falls in the older adult are very poor and a focused prospective study is required to identify areas for intervention and prevention. The predictors of mortality following a fall identified in this study can be used with existing research to develop tools and design care pathways for implementation in the emergency context to improve patient care and outcomes. PMID- 27474071 TI - Bimodal Expansion of the Lymphatic Vessels Is Regulated by the Sequential Expression of IL-7 and Lymphotoxin alpha1beta2 in Newly Formed Tertiary Lymphoid Structures. AB - Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)betaR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTalpha1beta2/LTbetaR pathway in TLS associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis. PMID- 27474072 TI - Prolonged PD1 Expression on Neonatal Vdelta2 Lymphocytes Dampens Proinflammatory Responses: Role of Epigenetic Regulation. AB - A successful pregnancy depends on the maintenance of tolerance at the fetal maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections. Human Vdelta2 T cells mount innate-like responses to a broad range of microorganisms and are poised for Th1 responses before birth. In infants they likely play a key role in protection against pathogens by exerting early Th1 effector functions, improving function of other innate cells, and promoting Th1 polarization of adaptive responses. However, their propensity to release Th1 mediators may require careful regulation during fetal life to avoid exaggerated proinflammatory responses. We investigated molecules with the potential to act as a rheostat for fetal Vdelta2 cells. Programmed death 1 (PD1) is a negative regulator of T cell responses and a determinant of tolerance, particularly at the fetal-maternal interface. Neonatal Vdelta2 cells upregulate PD1 shortly after activation and, unlike their adult counterparts, express this molecule for at least 28 d. Engagement of PD1 by one of its ligands, PDL1, effectively dampens TCR-mediated responses (TNF-alpha production and degranulation) by neonatal Vdelta2 cells and may thus help maintain their activity within safe limits. PD1 expression by neonatal Vdelta2 cells is inversely associated with promoter DNA methylation. Prolonged PD1 expression may be part of a functional program to control Vdelta2 cell inflammatory responses during fetal life. PMID- 27474073 TI - DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum. AB - The chronic course of lepromatous leprosy may be interrupted by acute inflammatory episodes known as erythema nodosum leprosum (ENL). Despite its being a major cause of peripheral nerve damage in leprosy patients, the immunopathogenesis of ENL remains ill-defined. Recognized by distinct families of germline-encoded pattern recognition receptors, endogenous and pathogen-derived nucleic acids are highly immunostimulatory molecules that play a major role in the host defense against infections, autoimmunity, and autoinflammation. The aim of this work was to investigate whether DNA sensing via TLR-9 constitutes a major inflammatory pathway during ENL. Flow cytometry and immunohistochemistry analysis showed significantly higher TLR-9 expression in ENL when compared with nonreactional lepromatous patients, both locally in the skin lesions and in circulating mononuclear cells. The levels of endogenous and pathogen-derived TLR 9 ligands in the circulation of ENL patients were also higher. Furthermore, PBMCs isolated from the ENL patients secreted higher levels of TNF, IL-6, and IL-1beta in response to a TLR-9 agonist than those of the nonreactional patients and healthy individuals. Finally, E6446, a TLR-9 synthetic antagonist, was able to significantly inhibit the secretion of proinflammatory cytokines by ENL PBMCs in response to Mycobacterium leprae lysate. Our data strongly indicate that DNA sensing via TLR-9 constitutes a major innate immunity pathway involved in the pathogenesis and evolution of ENL. Thus, the use of TLR-9 antagonists emerges as a potential alternative to more effectively treat ENL aiming to prevent the development of nerve injuries and deformities in leprosy. PMID- 27474075 TI - In Vivo Expansion of Activated Foxp3+ Regulatory T Cells and Establishment of a Type 2 Immune Response upon IL-33 Treatment Protect against Experimental Arthritis. AB - IL-33 is strongly involved in several inflammatory and autoimmune disorders with both pro- and anti-inflammatory properties. However, its contribution to chronic autoimmune inflammation, such as rheumatoid arthritis, is ill defined and probably requires tight regulation. In this study, we aimed at deciphering the complex role of IL-33 in a model of rheumatoid arthritis, namely, collagen induced arthritis (CIA). We report that repeated injections of IL-33 during induction (early) and during development (late) of CIA strongly suppressed clinical and histological signs of arthritis. In contrast, a late IL-33 injection had no effect. The cellular mechanism involved in protection was related to an enhanced type 2 immune response, including the expansion of eosinophils, Th2 cells, and type 2 innate lymphoid cells, associated with an increase in type 2 cytokine levels in the serum of IL-33-treated mice. Moreover, our work strongly highlights the interplay between IL-33 and regulatory T cells (Tregs), demonstrated by the dramatic in vivo increase in Treg frequencies after IL-33 treatment of CIA. More importantly, Tregs from IL-33-treated mice displayed enhanced capacities to suppress IFN-gamma production by effector T cells, suggesting that IL-33 not only favors Treg proliferation but also enhances their immunosuppressive properties. In concordance with these observations, we found that IL-33 induced the emergence of a CD39(high) Treg population in a ST2L dependent manner. Our findings reveal a powerful anti-inflammatory mechanism by which IL-33 administration inhibits arthritis development. PMID- 27474074 TI - Leishmania major Infection-Induced VEGF-A/VEGFR-2 Signaling Promotes Lymphangiogenesis That Controls Disease. AB - Cutaneous leishmaniasis causes a spectrum of diseases from self-healing to severe nonhealing lesions. Defining the factors contributing to lesion resolution may help in developing new therapies for those patients with chronic disease. We found that infection with Leishmania major increases the expression of vascular endothelial growth factor-A and vascular endothelial growth factor receptor (VEGFR)-2 and is associated with significant changes in the blood and lymphatic vasculature at the site of infection. Ab blockade of VEGFR-2 during infection led to a reduction in lymphatic endothelial cell proliferation and simultaneously increased lesion size without altering the parasite burden. These data show that L. major infection initiates enhanced vascular endothelial growth factor-A/VEGFR 2 signaling and suggest that VEGFR-2-dependent lymphangiogenesis is a mechanism that restricts tissue inflammation in leishmaniasis. PMID- 27474076 TI - Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells. AB - Although the mechanisms governing the innate recognition of pathogen-associated molecular patterns have been well defined, how allogeneic cellular stimuli evoke innate responses remains less so. In this article, we report that upon i.v. transfer (to avoid major iatrogenic interference), allogeneic but not syngeneic leukocytes could induce a rapid (after 1 d) accumulation of host monocyte-derived dendritic cells (moDCs) without any increase in conventional DCs. This occurred in various donor-host strain combinations, did not require MHC mismatch, and could be induced by various donor cell types including B cells, T cells, or NK cells. Using RAG(-/-)gammac(-/-) and scid gammac(-/-)mice with different MHC, we found that the presence of either donor or host lymphoid cells was required. Alloinduced moDC accumulation was significantly reduced when splenocytes from mice deficient in NK cells by genetic ablation were used as donors. A major component of this moDC accumulation appears to be recruitment. Our findings provide new insights into how the innate and adaptive immune system may interact during allogeneic encounters and thus transplant rejection. PMID- 27474079 TI - Size mismatch in liver transplantation. AB - Size mismatch is an unique and inevitable but critical issue in live donor liver transplantation. Unmatched metabolic demand of recipient as well as physiologic mismatch aggravates the damage to liver graft, inevitably leading to graft failure on recipient. Also, an excessive resection of liver graft for better recipient outcome in live donor liver transplant may jeopardize the healthy donor well-being and even put donor life in danger. There is a fine balance between resected graft volume required to meet the recipient's metabolic demand and residual graft volume required for donor safety. The obvious clinical necessity of finding that balance has prompted a clinical need and promoted the improvement of knowledge and development of management strategies for size-mismatched transplants. The development of the size-matching methodology has significantly improved graft outcome and recipient survival in live donor liver transplants. On the other hand, the effect of size mismatch in cadaveric transplants has never been observed as being so pronounced. The importance of matching of the donor recipient size has been unrecognized in cadaveric liver transplant. In this review, we attempt to summarize the current most updated knowledge on the subject, particularly addressing the definition and complications of size mismatched cadaveric liver transplant, as well as management strategies. PMID- 27474077 TI - NADPH Oxidase-Derived Superoxide Provides a Third Signal for CD4 T Cell Effector Responses. AB - Originally recognized for their direct induced toxicity as a component of the innate immune response, reactive oxygen species (ROS) can profoundly modulate T cell adaptive immune responses. Efficient T cell activation requires: signal 1, consisting of an antigenic peptide-MHC complex binding with the TCR; signal 2, the interaction of costimulatory molecules on T cells and APCs; and signal 3, the generation of innate immune-derived ROS and proinflammatory cytokines. This third signal, in particular, has proven essential in generating productive and long lasting immune responses. Our laboratory previously demonstrated profound Ag specific hyporesponsiveness in the absence of NADPH oxidase-derived superoxide. To further examine the consequences of ROS deficiency on Ag-specific T cell responses, our laboratory generated the OT-II.Ncf1(m1J) mouse, possessing superoxide-deficient T cells recognizing the nominal Ag OVA323-339 In this study, we demonstrate that OT-II.Ncf1(m1J) CD4 T cells displayed a severe reduction in Th1 T cell responses, in addition to blunted IL-12R expression and severely attenuated proinflammatory chemokine ligands. Conversely, IFN-gamma synthesis and IL-12R synthesis were rescued by the addition of exogenous superoxide via the paramagnetic superoxide donor potassium dioxide or superoxide-sufficient dendritic cells. Ultimately, these data highlight the importance of NADPH oxidase derived ROS in providing a third signal for adaptive immune maturation by modulating the IL-12/IL-12R pathway and the novelty of the OT-II.Ncf1(m1J) mouse model to determine the role of redox-dependent signaling on effector responses. Thus, targeting ROS represents a promising therapeutic strategy in dampening Ag specific T cell responses and T cell-mediated autoimmune diseases, such as type 1 diabetes. PMID- 27474080 TI - Pretreatment Serum Folate Levels and Toxicity/Efficacy in Colorectal Cancer Patients Treated With 5-Fluorouracil and Folinic Acid. AB - BACKGROUND: 5-Fluorouracil (5-FU) chemotherapy is associated with severe and unpredictable toxicity in a significant proportion of patients. 5,10 Methylenetetrahydrofolate and 5-fluorodeoxyuridine monophosphate bind to thymidylate synthase and together inhibit its function, resulting in cytotoxicity. We hypothesized that susceptibility to 5-FU toxicity might be related to individual differences in the serum components of folate metabolism affecting intracellular 5,10-methylenetetrahydrofolate levels. PATIENTS AND METHODS: A prospective cohort of chemotherapy-naive colorectal cancer patients scheduled to receive intravenous 5-FU and folinic acid for 5 consecutive days every 4 weeks in both adjuvant and palliative settings was studied. Pretreatment clinical and laboratory data were collected. Biochemical data associated with folate metabolism were also collected. The primary endpoint was the occurrence of grade >= 3 toxicity and/or toxicity mandating dose delay or reduction. RESULTS: For the 78 eligible patients studied, multivariable analyses identified only a greater pretreatment serum folate level as an independent predictor of grade >= 3 toxicity and/or mandating schedule modification (P = .016). Comparing the patient cohorts among the folate quartile groups revealed increasing toxicity trends in the highest quartile with an odds ratio of 2.58 (P = .19) compared with the combined lower quartiles, and superior relapse-free and overall survival for patients treated in the adjuvant setting. Log-rank analysis showed a significant association between higher folate levels and relapse-free and overall survival. CONCLUSION: The pretreatment serum folate level did not conclusively influence 5 FU toxicity and antitumor efficacy. However, high folate levels showed a trend toward a greater incidence of severe toxicities but also lower rates of disease recurrence and mortality. These results provide promising hypothesis-generating data warranting further investigation. The predictive value of pretreatment folate status should be a priority for study in cancer patients receiving 5-FU based chemotherapy and should be considered a potentially confounding factor in clinical trials and a modifiable parameter in treatment. PMID- 27474078 TI - Antibodies That Efficiently Form Hexamers upon Antigen Binding Can Induce Complement-Dependent Cytotoxicity under Complement-Limiting Conditions. AB - Recently, we demonstrated that IgG Abs can organize into ordered hexamers after binding their cognate Ags expressed on cell surfaces. This process is dependent on Fc:Fc interactions, which promote C1q binding, the first step in classical pathway complement activation. We went on to engineer point mutations that stimulated IgG hexamer formation and complement-dependent cytotoxicity (CDC). The hexamer formation-enhanced (HexaBody) CD20 and CD38 mAbs support faster, more robust CDC than their wild-type counterparts. To further investigate the CDC potential of these mAbs, we used flow cytometry, high-resolution digital imaging, and four-color confocal microscopy to examine their activity against B cell lines and primary chronic lymphocytic leukemia cells in sera depleted of single complement components. We also examined the CDC activity of alemtuzumab (anti CD52) and mAb W6/32 (anti-HLA), which bind at high density to cells and promote substantial complement activation. Although we observed little CDC for mAb opsonized cells reacted with sera depleted of early complement components, we were surprised to discover that the Hexabody mAbs, as well as ALM and W6/32, were all quite effective at promoting CDC in sera depleted of individual complement components C6 to C9. However, neutralization studies conducted with an anti-C9 mAb verified that C9 is required for CDC activity against cell lines. These highly effective complement-activating mAbs efficiently focus activated complement components on the cell, including C3b and C9, and promote CDC with a very low threshold of MAC binding, thus providing additional insight into their enhanced efficacy in promoting CDC. PMID- 27474081 TI - Diagnostics and Resistance Profiling of Bacterial Pathogens. AB - Worldwide infectious disease is one of the leading causes of death. Despite improvements in technology and healthcare services, morbidity and mortality due to infections have remained unchanged over the past few decades. The high and increasing rate of antibiotic resistance is further aggravating the situation. Growing resistance hampers the use of conventional antibiotics, and substantial higher mortality rates are reported in patients given ineffective empiric therapy mainly due to resistance to the agents used. These infections cause suffering, incapacity, and death and impose an enormous financial burden on both healthcare systems and on society in general. The accelerating development of multidrug resistance is one of the greatest diagnostic and therapeutic challenges to modern medicine. The lack of new antibiotic options underscores the need for optimization of current diagnostics, therapies, and prevention of the spread of multidrug-resistant organisms. The so-called -omics technologies (genomics, transcriptomics, proteomics, and metabolomics) have yielded large-scale datasets that advanced the search for biomarkers of infectious diseases in the last decade. One can imagine that in the future the implementation of biomarker-driven molecular test systems will transform diagnostics of infectious diseases and will significantly accelerate the identification of the bacterial pathogens at the infected host site. Furthermore, molecular tests based on the identification of markers of antibiotic resistance will dramatically change resistance profiling. The replacement of culturing methods by molecular test systems for early diagnosis will provide the basis not only for a prompt and targeted therapy, but also for a much more effective stewardship of antibiotic agents and a reduction of the spread of multidrug resistance as well as the appearance of new antibiotic resistances. PMID- 27474082 TI - Rhizobium gei sp. nov., a bacterial endophyte of Geum aleppicum. AB - A bacterial strain, designated as ZFJT-2T, was isolated from the stem of Geum aleppicum Jacq. collected from Taibai Mountain in Shaanxi Province, north-west China. Cells of strain ZFJT-2T were Gram-stain-negative, strictly aerobic, rod shaped and motile by means of a single polar flagellum. The major fatty acids were summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c), C16 : 0, 11-methyl C18 : 1omega7c and summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), and the DNA G+C content was 58.3 mol% (HPLC). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain ZFJT-2T was a member of the genus Rhizobium and was most closely related to Rhizobium giardinii KACC 10720T (98.6 % similarity) and Rhizobium herbae CCBAU 83011T (98.5 %). The low levels of sequence similarity found between the atpD, recA and glnII gene sequences of strain ZFJT-2T and those of recognized species of the genus Rhizobium (no more than 94.4, 87.2 and 89.5 %, respectively) indicated that it may represent a separate species of the genus Rhizobium. The DNA-DNA relatedness values for strain ZFJT-2T with respect to R. giardinii KACC 10720T and R. herbae CCBAU 83011T were 17.6 and 41.9 %, respectively. On the basis of phenotypic, phylogenetic and genotypic data, strain ZFJT-2T is considered to represent a novel species of the genus Rhizobium, for which the name Rhizobium gei sp. nov. is proposed. The type strain is ZFJT-2T (=CCTCC AB 2013015T=KCTC 32301T=LMG 27603T). PMID- 27474083 TI - The metabolic consequences of repeated anoxic stress in the western painted turtle, Chrysemys picta bellii. AB - The painted turtle is known for its extreme tolerance to anoxia, but it is unknown whether previous experience with anoxic stress might alter physiological performance during or following a test bout of anoxia. Repeatedly subjecting 25 degrees C-acclimated painted turtles to 2h of anoxic stress every other day for 19days (10 submergence bouts total) caused resting levels of liver glycogen to decrease by 17% and liver citrate synthase (CS) and cytochrome oxidase (COX) activities to increase by 33% and 112%, respectively. When the repeatedly submerged turtles were studied during a subsequent anoxic stress test, liver COX and CS activities decreased during anoxia to the same levels of naive turtles, which were unchanged, and remained there throughout metabolic recovery. There were no effects of the repeated anoxia treatment on any of the other measured variables, which included lactate dehydrogenase and phosphofructokinase activities in liver, skeletal muscle, and ventricle, blood acid-base status, hemoglobin, hematocrit and plasma ion (Na, K, Ca, Mg, Cl) and metabolite concentrations (lactate, glucose, free-fatty acids), before, during, or after the anoxic stress test. We conclude that although painted turtles can show a physiological reaction to repeated anoxic stress, the changes appear to have no measurable effect on anaerobic physiological performance or ability to recover from anoxia. PMID- 27474084 TI - Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment. AB - It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions. PMID- 27474085 TI - Can Babies Remember Trauma? Symbolic Forms of Representation in Traumatized Infants. AB - Three important areas of current inquiry concerning early trauma-the respective roles of reality and fantasy, age-related capacity for the symbolic representation of trauma, and attachment status-are approached through clinical case reports of three children seen initially at very early ages. The findings are relevant to the issue of whether preverbal infants can experience traumatic events that later are available to interpretation. The focus is for the most part on event traumas-single harrowing, life-threatening experiences-occurring at quite early ages. Three main points are emphasized. First, toddlers and infants (including neonates) can experience intense pain and show symptoms of traumatization. They are capable of experiencing an event as harrowing and life threatening. Second, these events are capable of being memorialized or symbolically represented, that is, stored in memory in a way that can affect later behavior and learning. Third, how that traumatization resolves itself, or fails to, can be decisively affected by the functioning of the attachment system. PMID- 27474086 TI - The Relevance of Bionian Thinking to the Treatment of PTSD Patients. AB - Analysts who conduct trauma-focused treatments have much to learn from Wilfred Bion's contributions to the understanding and treatment of PTSD. Concepts such as catastrophe and catastrophic change can illuminate the subjective experience of PTSD patients, the beta screen concept sheds light on dissociative phenomena, and, as shown in a clinical vignette, the analyst can use his alpha function to transform the patient's fragmented raw material into alpha elements. A second clinical vignette shows how during a cognitive intervention the analyst can impart this alpha function to the patient and use his reverie to help the patient assimilate previously intolerable fragments into a coherent narrative. Finally, the idea of knowing mental pain (Bion's K) is discussed in relation to the processing of traumatic memories. PMID- 27474087 TI - Nationwide survey on volunteers' training in hospice and palliative care in Poland. AB - BACKGROUND: Volunteers working in hospice and palliative care facilities in Poland undertake various activities which are performed in accordance with legal regulations and the individual policies of each hospice. The aim of this study was to explore the roles and training of volunteers working in hospice and palliative care settings. METHODS: A cross-sectional survey was carried out that investigated the services performed by volunteers and their preparation for work within residential hospices. Questionnaires were distributed to volunteers and hospice representatives, and the responses obtained underwent statistical analysis. PARTICIPANTS: A total of 180 volunteers and 28 hospice representatives from 29 residential hospices participated in this survey. RESULTS: All hospices surveyed were supported by volunteers. 79% of volunteers worked alongside patients and performed the following services: accompanying patients (76%), feeding patients (61%), cleaning rooms (48%), dressing and bathing (42%) and organising leisure time (40%). Fewer volunteers were involved in activities outside of patient support-for example, charity work and fundraising (34%), cleaning hospice buildings (23%) as well as providing information and education (22%). According to volunteers, prior to undertaking their duties, 64% participated in theoretical training and 37% took part in a practical course. The majority attended courses relating to general knowledge of hospice and palliative care (64%) and volunteer rights and duties (55%). CONCLUSIONS: Overall, proper training was an essential requirement needed to be fulfilled by volunteers, particularly when involved in direct patient support. Most volunteers were simultaneously involved in various areas of service; therefore, their training should be comprehensive. PMID- 27474088 TI - [The practice of neonatal umbilical blood gas analysis in the "Alsace" regional French perinatal network]. AB - OBJECTIVE: The assessment of neonatal well-being is paramount in delivery rooms. For that purpose, it is recommended in France to carry out a systematic neonatal umbilical cord blood gas analysis. The aim of this study is to evaluate how umbilical cord blood gas sampling is realised, analysed and interpreted by midwives in a French regional perinatal network. MATERIALS AND METHODS: We conducted a survey focused on randomly selected midwives partitioning in different maternities that constitute the "Alsace" regional perinatal network. A questionnaire concerning the modalities of umbilical cord blood sampling, its analysis and the interpretation of results was used during interviews with included midwives. RESULTS: Fifty-one midwives were included in the study (15.8% of whom were working in delivery rooms). Only 13% of maternities constituting the perinatal network did not realise systematic neonatal umbilical cord blood analysis. Among interviewed midwives, 78.4% reported umbilical cord clamping after the first breath of the child. Among the midwives included, 86.3% of them realise sampling from the umbilical artery and 29.4% from both umbilical artery and vein. For 86.3% of interviewed midwives, the leitmotif of realising umbilical blood sampling was medico-legal. More than two third of included midwives interpret blood gas taking into account two parameters (either pH and base excess, or lactate). They settled at 7.0-7.2, the limit below which a newborn might present sequelae. DISCUSSION AND CONCLUSION: This study shows that the neonatal umbilical cord blood gas analysis at birth is almost systematic in this regional French perinatal network. It is realised primarily for medico-legal purpose. However, there are significant variations in sampling procedures and interpretation. This should lead to the establishment within each maternity of a neonatal umbilical cord blood gas sampling protocol along with a midwifery training program. PMID- 27474089 TI - Influences of innate immunity, autophagy, and fibroblast activation in the pathogenesis of lung fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by accumulation of extracellular matrix (ECM) and impaired gas exchange. The pathobiological mechanisms that account for disease progression are poorly understood but likely involve alterations in innate inflammatory cells, epithelial cells, and fibroblasts. Thus we seek to review the most recent literature highlighting the complex roles of neutrophils and macrophages as both promoters of fibrosis and defenders against infection. With respect to epithelial cells and fibroblasts, we review the data suggesting that defective autophagy promotes the fibrogenic potential of both cell types and discuss new evidence related to matrix metalloproteinases, growth factors, and cellular metabolism in the form of lactic acid generation that may have consequences for promoting fibrogenesis. We discuss potential cross talk between innate and structural cell types and also highlight literature that may help explain the limitations of current IPF therapies. PMID- 27474092 TI - Dr Peter Edward Baldry. PMID- 27474091 TI - Protection from interferon-beta-induced neuronal apoptosis through stimulation of muscarinic acetylcholine receptors coupled to ERK1/2 activation. AB - BACKGROUND AND PURPOSE: Although clinically useful for their immunomodulatory, antiproliferative and antiviral properties, type I interferons (IFNs) are involved in the pathogenesis of several neurodegenerative/neuroinflammatory diseases. In the present study, we investigated the ability of cholinergic stimulation to protect from IFN-beta-induced neuronal apoptosis. EXPERIMENTAL APPROACH: The effects of the ACh receptor agonist carbachol (CCh) on IFN-beta induced apoptosis of human SH-SY5Y neuroblastoma cells were examined by using western blots, immunofluorescence and cytofluorimetry. The involvement of muscarinic acetylcholine receptors (mAChRs) was assessed by using selective antagonists and siRNA transfection. Pharmacological inhibitors and overexpression of ERK2 and an ERK2 constitutively active form (ERK2-CA) were employed to study ERK1/2 signalling. The effects of oxotremorine-M (Oxo-M) on IFN-beta-induced apoptosis of mouse hippocampal neurons were examined by measuring cleaved caspase 3 expression. KEY RESULTS: In SH-SY5Y cells, CCh inhibited IFN-beta-induced mitochondrial cytochrome c release, activation of caspases 9, 7 and 3, PARP cleavage and DNA fragmentation. The anti-apoptotic effect of CCh was mediated by M3 receptors, blocked by Gq/11 antagonist YM254890 and PKC inhibitor Go 6983, impaired by inhibition of ERK1/2 pathway, potentiated by overexpression of ERK2 and mimicked by ERK2-CA. Blockade of JNK activation enhanced the CCh anti apoptotic response. IFN-beta inhibited JNK activation and up-regulated CCh induced ERK1/2 signalling. In hippocampal neurons, Oxo-M reduced IFN-beta-induced apoptosis; this effect was antagonized by blockade of M1 /M3 receptors and ERK1/2. CONCLUSIONS AND IMPLICATIONS: Stimulation of mAChRs counteracted IFN-beta induced neuronal apoptosis through the activation of ERK1/2 signalling. The data indicate that activation of ERK1/2-coupled mAChRs may be an effective strategy for preventing IFNs neurotoxicity. PMID- 27474093 TI - Opioid Treatment of Migraine: Risk Factors and Behavioral Issues. AB - Migraine can impact every aspect of a person's functioning. Psychological comorbidities, cognitive constructs, and behavioral responses to pain greatly impact the perception of migraine pain, treatment efficacy and outcome, and overall quality of life and functioning. Current considerations for migraine treatment emphasize the utility of the biopsychosocial model in understanding and treating migraine, noting both the importance of addressing psychological factors such as cognitive beliefs as well as psychiatric comorbidities. The guidelines for migraine treatment implicate opioid therapy as a second or third tier treatment. Guidelines and recommendations for the safe use of opioid medications among patients with chronic pain emphasize the importance of screening prior to prescribing opioid medications. Chronic opioid therapy has been shown to further levels of disability, decrease quality of life, and correlate to psychiatric comorbidities, concerns that are already present in migraine patients. While opioid treatment provides an alternative for persons with contraindications for alternative migraine treatments, it is critical that opioids be used sparingly and exclusively in conjunction with comprehensive assessment and integration of psychological treatment. PMID- 27474090 TI - Trafficking and function of the cystic fibrosis transmembrane conductance regulator: a complex network of posttranslational modifications. AB - Posttranslational modifications add diversity to protein function. Throughout its life cycle, the cystic fibrosis transmembrane conductance regulator (CFTR) undergoes numerous covalent posttranslational modifications (PTMs), including glycosylation, ubiquitination, sumoylation, phosphorylation, and palmitoylation. These modifications regulate key steps during protein biogenesis, such as protein folding, trafficking, stability, function, and association with protein partners and therefore may serve as targets for therapeutic manipulation. More generally, an improved understanding of molecular mechanisms that underlie CFTR PTMs may suggest novel treatment strategies for CF and perhaps other protein conformational diseases. This review provides a comprehensive summary of co- and posttranslational CFTR modifications and their significance with regard to protein biogenesis. PMID- 27474095 TI - Evaluation and Management of SCI-Associated Pain. AB - Traumatic spinal cord injury (SCI) is a devastating neurological condition. Treatment of SCI-related pain is challenging for the treating physician, as normal neural pathways are disrupted. Patients with SCI consistently rate pain as one of the most difficult problems associated with their injury. SCI-related pain can be refractory and complete relief is often not possible. The multidimensional nature of SCI-related pain affects the neural system including autonomic nervous system deregulation and can alter metabolic and biochemical processes throughout the body. Co-morbid psychological illnesses such as depression and adjustment disorder are seen in a significant percentage of patients. Despite a better understanding of the underlying pain mechanisms and advances in procedural, pharmacologic, and non-pharmacologic therapies, treatment of pain after SCI remains elusive. This manuscript reviews the current evidence-based evaluation and management of the SCI patient with the overarching goal of providing appropriate and effective management of their pain. In particular, additional well-designed studies are needed to help elucidate effective treatments for SCI related neuropathic pain in an effort to help provide these patients with better management of their pain and improve their quality of life. PMID- 27474096 TI - Editorial overview: Immunomodulation: Exploiting the circle between emotions and immunity: impact on pharmacological treatments. PMID- 27474094 TI - Neuroimaging in the Diagnostic Evaluation of Eye Pain. AB - Ocular or eye pain is a frequent complaint encountered not only by eye care providers but neurologists. Isolated eye pain is non-specific and non-localizing; therefore, it poses significant differential diagnostic problems. A wide range of neurologic and ophthalmic disorders may cause pain in, around, or behind the eye. These include ocular and orbital diseases and primary and secondary headaches. In patients presenting with an isolated and chronic eye pain, neuroimaging is usually normal. However, at the beginning of a disease process or in low-grade disease, the eye may appear "quiet," misleading a provider lacking familiarity with underlying disorders and high index of clinical suspicion. Delayed diagnosis of some neuro-ophthalmic causes of eye pain could result in significant neurologic and ophthalmic morbidity, conceivably even mortality. This article reviews some recent advances in imaging of the eye, the orbit, and the brain, as well as research in which neuroimaging has advanced the discovery of the underlying pathophysiology and the complex differential diagnosis of eye pain. PMID- 27474097 TI - Re: "Evaluation of Moderate Alcohol Use With QT Interval and Heart Rate Using Mendelian Randomization Analysis Among Older Southern Chinese Men in the Guangzhou Biobank Cohort Study". PMID- 27474099 TI - Cervical Esophago-Gastric Tubes for Patients with Malignant Ascites. AB - Patients with chronic small bowel obstruction and malignant ascites from diffuse peritoneal carcinomatosis have limited options for gastrointestinal decompression as part of end-of-life palliation. Insertion of a percutaneous gastrostomy tube is relatively contraindicated in patients with ascites. Alternatively, nasogastric tube placement often leads to significant discomfort to patients and necessitates hospitalization during their last days of life. Here, we demonstrate how placing a percutaneous cervical esophago-gastric tube can allow adequate gastrointestinal decompression for terminal patients with malignant small bowel obstruction. This palliative measure allows them to remain in the comfort of their own homes after the procedure. PMID- 27474098 TI - Water-Soluble Enema Prior to Ileostomy Closure in Patients Undergoing Low Anterior Resection: Is It Necessary? AB - BACKGROUND: Diverting ileostomy is recommended in patients undergoing neoadjuvant chemoradiotherapy and low anterior resection for low-rectal cancer. Prior to ileostomy reversal, water-soluble enema is performed to assess the low colorectal anastomosis. The aim of this study was to assess whether performance of routine water-soluble enema prior to ileostomy takedown is necessary. MATERIALS AND METHODS: All mid-low rectal cancer patients who underwent low anterior resection with temporary diverting ileostomy after neoadjuvant chemoradiotherapy, between 2006 and 2013, were identified, retrospectively. The colorectal anastomosis prior to ileostomy takedown was evaluated by digital rectal exam, rigid proctoscopy, and water-soluble enema. The rectal exam and proctoscopy findings were compared to those of the water-soluble enema. The efficacy of routine water-soluble enema was assessed. RESULTS: Three hundred and twelve (184 male) patients (mean age 62.2 +/- 17 years) met the inclusion criteria. Ten patients (3 %) experienced a contained anastomotic leak in the early postoperative period, of whom six had a positive intraoperative air leak test at the index operation. At follow-up, 12 patients (4 %) presented with anastomotic stricture, which was diagnosed by rectal exam and proctoscopy. In 11 of them, water-soluble enema showed anastomotic stricture. In terms of anastomotic defects, sinus was documented in two patients (0.6 %), yet digital rectal exam and proctoscopy were normal. No late septic complications related to the colorectal anastomosis after ileostomy closure were reported. The sensitivity of rectal exam, and proctoscopy for the diagnosis of anastomotic stricture was 100 %, while its negative predictive value for the diagnosis of anastomotic defect was 99 %. CONCLUSION: Routine water soluble enema for the evaluation of colorectal anastomosis before ileostomy takedown does not provide additional information that changes patient management. The efficacy of this test in patients after neoadjuvant chemoradiotherapy and low anterior resection should be reassessed. PMID- 27474100 TI - Association of FOXE1 polyalanine repeat region with thyroid cancer is dependent on tumour size. AB - OBJECTIVE: Polymorphisms in the thyroid transcription factor forkhead factor E1 (FOXE1) gene have been implicated in the genetic susceptibility to differentiated thyroid cancer, but little is known about their effect on tumour characteristics. The objective of this study was to determine the contribution of the FOXE1 polyalanine repeat region to the susceptibility to thyroid cancer and to its clinical characteristics. DESIGN, PATIENTS AND MEASUREMENTS: A total of 500 patients with sporadic thyroid cancer (440 papillary and 60 follicular thyroid carcinoma) and 502 healthy controls were included in this case-control association study. The number of FOXE1 alanine repeats in each subject was determined by PCR and multiplex fragment analysis by capillary electrophoresis. FOXE1 genotype and allele frequencies among groups were compared by logistic regression and adjusted for sex and age at diagnosis. Data were analysed according to cancer subtype, tumour size and the presence of lymph node or distant metastasis. RESULTS: FOXE1 alleles with 16 or more alanine repeats were more frequent in patients with tumour size > 1 cm compared to tumour size <= 1 cm (adjusted OR 1.44; 95% CI 1.05-1.88; P = 0.019). Genotypes containing at least one allele with 16 or more alanine repeats were associated with larger tumour size (adjusted OR 1.71; 95% CI 1.15-2.57; P = 0.009). No significant differences were observed between cancer subtypes or the presence/absence of metastasis. CONCLUSIONS: FOXE1 polyalanine repeat polymorphisms are associated with thyroid cancer, but only for tumours larger than 1 cm, suggesting a role in disease progression. PMID- 27474101 TI - A unified powerful set-based test for sequencing data analysis of GxE interactions. AB - The development of next-generation sequencing technologies has allowed researchers to study comprehensively the contribution of genetic variation particularly rare variants to complex diseases. To date many sequencing analyses of rare variants have focused on marginal genetic effects and have not explored the potential role environmental factors play in modifying genetic risk. Analysis of gene-environment interaction (GxE) for rare variants poses considerable challenges because of variant rarity and paucity of subjects who carry the variants while being exposed. To tackle this challenge, we propose a hierarchical model to jointly assess the GxE effects of a set of rare variants for example, in a gene or regulatory region, leveraging the information across the variants. Under this model, GxE is modeled by two components. The first component incorporates variant functional information as weights to calculate the weighted burden of variant alleles across variants, and then assess their GxE interaction with the environmental factor. Since this information is a priori known, this component is fixed effects in the model. The second component involves residual GxE effects that have not been accounted for by the fixed effects. In this component, the residual GxE effects are postulated to follow an unspecified distribution with mean 0 and variance [Formula: see text] We develop a novel testing procedure by deriving two independent score statistics for the fixed effects and the variance component separately. We propose two data-adaptive combination approaches for combining these two score statistics and establish the asymptotic distributions. An extensive simulation study shows that the proposed approaches maintain the correct type I error and the power is comparable to or better than existing methods under a wide range of scenarios. Finally we illustrate the proposed methods by a exome-wide GxE analysis with NSAIDs use in colorectal cancer. PMID- 27474102 TI - Modeling and testing maternal and newborn care mHealth interventions: a pilot impact evaluation and follow-up qualitative study in Guatemala. AB - Objective: To develop a descriptive model of structural characteristics of mHealth in the context of newborn nutrition, and to assess the effects of illustrative interventions through a mixed-methods study consisting of an impact evaluation and a qualitative assessment. Materials and Methods: We conducted a 23 week intervention with 100 mothers in rural Guatemala in 2013 and 2014. In group 1 ( n = 24), participants received health-promoting text messages. In group 2 ( n = 32), peer-to-peer groups were formed. In group 3 ( n = 30), peer-to-peer groups were formed, a health professional participated in the discussions, and participants received health-promoting messages. In the control group ( n = 14), participants were simply given a mobile phone. We measured changes in knowledge and self-reported behavior. Four focus groups in 2015 showed the perceptions of 44 additional women and the potential of the previously tested interventions in other marginalized areas. Results: Significant relationships were found between group membership and changes in knowledge ( P < .001), and between changes in knowledge and self-reported behavior ( P = .010). Within peer-to-peer groups, 3665 text messages were shared; discussions covered topics such as breastfeeding practices, health concerns, and emotional issues. Focus groups revealed a deficit of support for mothers, a precariousness of public services, different cultural barriers affecting access to care, and the potential for scaling up. Discussion: The complementarity of structural arrangements of mHealth interventions can play an important role in helping to encourage recommended breastfeeding attitudes along with providing rich information about challenges in rural areas. Conclusion: A mixed-methods study was appropriate to compare the effects and assess the potential of mHealth strategies in a complex rural setting. PMID- 27474103 TI - A tumor profile in Edwards syndrome (trisomy 18). AB - Constitutional trisomy 18 causes Edwards syndrome, which is characterized by intellectual disability and a particular set of malformations. Although this condition carries high mortality during prenatal and early postnatal life, some of the rare infants who survive the first months develop benign and malignant tumors. To determine the tumor profile associated with Edwards syndrome, we performed a systematic review of the literature. This review reveals a tumor profile differing from those of Down (trisomy 21) and Patau (trisomy 13) syndromes. The literature covers 45 malignancies: 29 were liver cancers, mainly hepatoblastomas found in Japanese females; 13 were kidney tumors, predominantly nephroblastomas; 1 was neuroblastoma; 1 was a Hodgkin disease; and 1 was acute myeloid leukemia in an infant with both trisomy 18 and type 1 neurofibromatosis. No instances of the most frequent malignancies of early life-cerebral tumors, germ cell tumors, or leukemia--are reported in children with pure trisomy 18. Tumor occurrence does not appear to correlate with body weight, tissue growth, or cancer genes mapping to chromosome 18. Importantly, the most recent clinical histories report successful treatment; this raises ethical concerns about cancer treatment in infants with Edwards syndrome. In conclusion, knowledge of the Edwards' syndrome tumor profile will enable better clinical surveillance in at risk organs (i.e., liver, kidney). This knowledge also provides clues to understanding oncogenesis, including the probably reduced frequency of some neoplasms in infants and children with this genetic condition. (c) 2016 Wiley Periodicals, Inc. PMID- 27474104 TI - Use of an Objective Structured Assessment of Technical Skill After a Sports Medicine Rotation. AB - PURPOSE: The purpose of this study was to determine if the use of an Objective Structured Assessment of Technical skill (OSATS), using dry models, would be a valid method of assessing residents' ability to perform sports medicine procedures after training in a competency-based model. METHODS: Over 18 months, 27 residents (19 junior [postgraduate year (PGY) 1-3] and 8 senior [PGY 4-5]) sat the OSATS after their rotation, in addition to 14 sports medicine staff and fellows. Each resident was provided a list of 10 procedures in which they were expected to show competence. At the end of the rotation, each resident undertook an OSATS composed of 6 stations sampled from the 10 procedures using dry models faculty used the Arthroscopic Surgical Skill Evaluation Tool (ASSET), task specific checklists, as well as an overall 5-point global rating scale (GRS) to score each resident. Each procedure was videotaped for blinded review. RESULTS: The overall reliability of the OSATS (0.9) and the inter-rater reliability (0.9) were both high. A significant difference by year in training was seen for the overall GRS, the total ASSET score, and the total checklist score, as well as for each technical procedure (P < .001). Further analysis revealed a significant difference in the total ASSET score between junior (mean 18.4, 95% confidence interval [CI] 16.8 to 19.9) and senior residents (24.2, 95% CI 22.7 to 25.6), senior residents and fellows (30.1, 95% CI 28.2 to 31.9), as well as between fellows and faculty (37, 95% CI 36.1 to 27.8) (P < .05). CONCLUSIONS: The results of this study show that an OSATS using dry models shows evidence of validity when used to assess performance of technical procedures after a sports medicine rotation. However, junior residents were not able to perform as well as senior residents, suggesting that overall surgical experience is as important as intensive teaching. CLINICAL RELEVANCE: As postgraduate medical training shifts to a competency-based model, methods of assessing performance of technical procedures become necessary. PMID- 27474105 TI - Arthroscopic Partial Meniscectomy or Conservative Treatment for Nonobstructive Meniscal Tears: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - PURPOSE: To conduct a meta-analysis of randomized controlled trials comparing the outcome of arthroscopic partial meniscectomy (APM) with conservative treatment in adults with nonobstructive meniscal tears and to recommend a treatment of choice. METHODS: We systematically searched the databases of MEDLINE, Excerpta Medica Database, Cochrane, the National Health Service Centre for Reviews and Dissemination, and Physiotherapy Evidence Database from inception to May 2, 2016. Two authors independently searched the literature and selected eligible studies. The meta-analyses used a random-effects model. The primary outcome was physical function, measured by knee-specific patient-reported outcomes. Secondary outcomes included knee pain, activity level, the progression of osteoarthritis, adverse events, general health, and quality of life. RESULTS: We included 6 randomized controlled trials, with a total of 773 patients, of whom 378 were randomized to APM and 395 were randomized to the control treatment. After pooling the data of 5 studies, we found small significant differences in favor of the APM group for physical function at 2 to 3 months (mean difference [MD] = 3.31; 95% confidence interval [CI] = 0.69-5.93; P = .01; I(2) = 0% [Lysholm knee score]), and at 6 months (MD = 3.56; 95% CI = 0.24-6.88; P = .04; I(2) = 0% (Knee injury and Osteoarthritis Outcome Score [KOOS] and Western Ontario and McMaster Universities Osteoarthritis Index); standardized MD = 0.17; 95% CI = 0.01-0.32; P = .03; I(2) = 0% [Lysholm knee score, KOOS, and Western Ontario and McMaster Universities Osteoarthritis Index]). We also found small significant differences for pain at 6 months (MD = 3.56; 95% CI = 0.18-6.95; P = .04; I(2) = 0% [KOOS] and MD = 0.56; 95% CI = 0.28-0.83; P <= .0001; I(2) = 0% [visual analog scale and numeric rating scale]). We found no significant differences after 12 and 24 months. CONCLUSIONS: We found small, although statistically significant, favorable results of APM up to 6 months for physical function and pain. However, we found no differences at longer follow-up. LEVEL OF EVIDENCE: Level I, systematic review and meta-analysis of Level I studies. PMID- 27474106 TI - Outcomes of Arthroscopic Decompression of Spinoglenoid Cysts Through a Subacromial Approach. AB - PURPOSE: To describe a spinoglenoid cyst decompression technique through a subacromial approach and its clinical outcomes after 2 years of follow-up. METHODS: From March 2008 to October 2013, 26 patients underwent arthroscopic decompression of a spinoglenoid ganglion cyst with and/or without superior labral anterior to posterior repair, and patients who were available for minimum of 2 years of follow-up were included. For functional assessments, the visual analog scale (VAS) pain score, subjective shoulder value (SSV), University of California at Los Angeles (UCLA) shoulder score, American Shoulder and Elbow Surgeon (ASES) score, and shoulder active range of motion were used to compare preoperative and postoperative follow-up values. Follow-up magnetic resonance arthrography was taken at 6 months postoperatively to evaluate incomplete decompression or recurrence of the cyst. RESULTS: In total, 21 patients were included in this study. At the 2-year follow-up, the VAS, SSV, ASES, and UCLA shoulder scores significantly improved compared with preoperative values (P < .001): VAS improved from 3.5 to 0.7 (P < .001); SSV improved from 62.9 to 93.1 (P < .001); ASES score improved from 64.3 to 94.4 (P < .001); UCLA shoulder score improved from 21.6 to 32.9 (P < .001). Also, active forward flexion improved from 153 degrees to 158 degrees (P = .014), and external rotation improved from 55 degrees to 57 degrees (P = .042) significantly, with the exception of internal rotation. The follow-up magnetic resonance arthrography was performed in 18 patients (86%), and there was no recurrence of the spinoglenoid notch cyst. CONCLUSIONS: For spinoglenoid cyst decompression, the subacromial approach was found to be effective, yielding satisfactory clinical outcomes without recurrence. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 27474108 TI - Is a Picture Worth a Thousand Words? The Graphical Abstract. PMID- 27474109 TI - Concomitant Pyoderma Gangrenosum and Erythema Nodosum in a Patient With Ulcerative Colitis. PMID- 27474107 TI - Evaluation of Nestin Expression in the Developing and Adult Mouse Inner Ear. AB - Adult stem cells are undifferentiated cells with the capacity to proliferate and form mature tissue-specific cell types. Nestin is an intermediate filament protein used to identify cells with stem cell characteristics. Its expression has been observed in a population of cells in developing and adult cochleae. In vitro studies using rodent cochlear tissue have documented the potential of nestin expressing cells to proliferate and form hair and supporting cells. In this study, nestin coupled to green fluorescent protein (GFP) transgenic mice were used to provide a more complete characterization of the spatial and temporal expression of nestin in the inner ear, from organogenesis to adulthood. During development, nestin is expressed in the spiral ganglion cell region and in multiple cell types in the organ of Corti, including nascent hair and supporting cells. In adulthood, its expression is reduced but persists in the spiral ganglion, in a cell population medial to and below the inner hair cells, and in Deiters' cells in the cochlear apex. Moreover, nestin-expressing cells can proliferate in restricted regions of the inner ear during development shown by coexpression with Ki67 and MCM2 and by 5-ethynyl-2'-deoxyuridine incorporation. Results suggest that nestin may label progenitor cells during inner ear development and may not be a stem cell marker in the mature organ of Corti; however, nestin-positive cells in the spiral ganglion exhibit some stem cell characteristics. Future studies are necessary to determine if these cells possess any latent stem cell-like qualities that may be targeted as a regenerative approach to treat neuronal forms of hearing loss. PMID- 27474110 TI - Improvement in extracellular protease production by the marine antarctic yeast Rhodotorula mucilaginosa L7. AB - Microorganisms from extreme and restrictive eco systems, such as the Antarctic continent, are of great interest due to their ability to synthesize products of commercial value. Among these, enzymes from psychrotolerant and psychrophilic microorganisms offer potential economical benefits due to their high activity at low and moderate temperatures. The cold adapted yeast Rhodotorula mucilaginosa L7 was selected out of 97 yeasts isolated from Antarctica as having the highest extracellular proteolytic activity in preliminary tests. The present study was aimed at evaluating the effects of nutrient composition (peptone, rice bran extract, ammonium sulfate, sodium chloride) and physicochemical parameters (temperature and pH) on its proteolytic activity. A 26-2 fractional factorial design experiment followed by a central composite design (CCD 23) was performed to optimize the culture conditions and improve the extracellular proteolytic activity. The results indicated that the presence of peptone in the medium was the most influential factor in protease production. Enzymatic activity was enhanced by the interaction between low glucose and peptone concentrations. The optimization of culture conditions with the aid of mathematical modeling enabled a c. 45% increase in proteolytic activity and at the same time reduced the amount of glucose and peptone required for the culture. Thus culture conditions established in this work may be employed in the biotechnological production of this protease. PMID- 27474111 TI - Status of market, regulation and research of genetically modified crops in Chile. AB - Agricultural biotechnology and genetically modified (GM) crops are effective tools to substantially increase productivity, quality, and environmental sustainability in agricultural farming. Furthermore, they may contribute to improving the nutritional content of crops, addressing needs related to public health. Chile has become one of the most important global players for GM seed production for counter-season markets and research purposes. It has a comprehensive regulatory framework to carry out this activity, while at the same time there are numerous regulations from different agencies addressing several aspects related to GM crops. Despite imports of GM food/feed or ingredients for the food industry being allowed without restrictions, Chilean farmers are not using GM seeds for farming purposes because of a lack of clear guidelines. Chile is in a rather contradictory situation about GM crops. The country has invested considerable resources to fund research and development on GM crops, but the lack of clarity in the current regulatory situation precludes the use of such research to develop new products for Chilean farmers. Meanwhile, a larger scientific capacity regarding GM crop research continues to build up in the country. The present study maps and analyses the current regulatory environment for research and production of GM crops in Chile, providing an updated overview of the current status of GM seeds production, research and regulatory issues. PMID- 27474112 TI - Correlation of Oxidative Stress Parameters and Inflammatory Markers in Ischemic Stroke Patients. AB - BACKGROUND: Ischemic stroke (IS) usually initiates inflammation and oxidative stress leading to neuronal death. Diabetes and impaired fasting glucose are associated with incidence of cerebrovascular and cardiovascular diseases. METHODS: In the present study, we assessed the relationship of fasting glucose with antioxidative parameters (erythrocyte glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities) and inflammatory markers (high-sensitivity C-reactive protein [hs-CRP] and fibrinogen) in IS patients with and without type 2 diabetes mellitus (T2DM). In addition, we determined factors associated with the risk of IS among these patients. Antioxidative, inflammatory, and lipid parameters were measured in 196 patients with IS (117diabetics and 79 nondiabetics). RESULTS: After adjustment of covariates, multiple logistic regression analysis showed that SOD and GPx significantly decreased the risk of IS among patients with and without T2DM. However, hs-CRP increased the risk of IS. For the diabetic patients, fasting glucose was positively correlated with hs CRP and fibrinogen and was negatively correlated with GPx and SOD levels. In addition, fasting glucose and hemoglobin A1c or glycosylated hemoglobin (HbA1c) have been shown to increase the risk of IS in diabetic patients. CONCLUSIONS: These data suggest that the antioxidant activity of plasma may be an important factor that provides protection from IS. hs-CRP concentrations can be used as a clinical screening tool to identify individuals with higher risk of IS. Finally, fasting glucose and HbA1c may also be useful indicators for cerebrovascular risk in diabetic patients that may be mediated by low levels of antioxidative defense markers and high inflammation status. PMID- 27474113 TI - Proactive and Brief Smoking Cessation Intervention for Smokers at Outdoor Smoking "Hotspots" in Hong Kong. AB - Increased outdoor smoking is a common phenomenon after indoor smoking bans were in place. A series of observational studies were conducted to evaluate a novel, proactive, and brief smoking cessation intervention at outdoor smoking "hotspots," i.e., outdoor public areas where ashtrays were available and smokers clustered to smoke. The number of smokers at 26 selected hotspots were observed and counted for two consecutive days. Further observations of the smokers' characteristics and brief smoking cessation intervention were conducted at ten of the hotspots with the greatest number of smokers. Responses of the smokers to the brief intervention, including a leaflet and brief smoking cessation advice using AWAR protocol delivered by trained smoking cessation ambassadors, were assessed. A total of 24,034 smokers were observed within 464 h, which equals 51.8 smokers per hour. Of the 5070 pedestrians observed at the ten hotspots during the intervention sessions, 1228 (24.2 %) were smokers. In the 1228 smokers who were approached during our intervention sessions, about two thirds were willing to receive the self-help leaflet on smoking cessation whereas about half received the brief smoking cessation advice. Recruiting smokers and delivering brief smoking cessation interventions at smoking hotspots are feasible and likely effective to reach large numbers of smokers. Studies to evaluate the effectiveness of using this approach for smoking cessation are warranted. PMID- 27474114 TI - Design and Success of a 21st Century Cancer Education Program at the University of Louisville. AB - Cancer incidence, morbidity, and mortality in the Commonwealth of Kentucky are among the highest in the nation. The University of Louisville was the recipient of a National Cancer Institute (NCI)-funded cancer education program grant in 1975 under the leadership of Dr. Norbert Burzynski. A new and totally redesigned performance-based University of Louisville Cancer Education Program was funded by NCI in 2011 to recruit and motivate outstanding undergraduate and health professional students to pursue further training and careers in cancer research. Here, we describe the strategy, design, methods, implementation, and accomplishments of our twenty-first century performance-based cancer education program. Our program will meet or exceed all of its 5-year performance goals, including the total number students (n = 156) and under-represented minorities (n = 53) who successfully completed the program under the mentorship of cancer research-intensive faculty members of the James Graham Brown Cancer Center (JGBCC). The mentored research program is complemented with professional development and enhancement activities, including cancer research seminars presented by faculty members actively engaged in research centered on the diagnosis, treatment or prevention of cancer, creation of individual career development plans, exploration of cancer research careers, and acquisition of professionalism skills. Student interests towards cancer research significantly increased after completion of the program compared to baseline (P = 0.02). Based on quantitative and qualitative analysis of various components of the curricula, the trainees favor practical, engaging, and interactive activities aligned within professional career goals and objectives. For instance, the trainees prefer two 30-min small group discussions on "Navigating Careers in Cancer Research" with faculty, professional students, and program alumni. Future updates to the program include new activities that capitalize on the cross-disciplinary background of our mentors and trainees as well as a team-based approach to professional development. Our cancer education program will continue to enhance the professional development of the next generation of cancer scientists and clinicians. PMID- 27474117 TI - Relationship between perceived limit-setting abilities, autism spectrum disorder severity, behaviour problems and parenting stress in mothers of children with autism spectrum disorder. AB - Parenting stress in mothers of children with autism spectrum disorder (ASD) is high and impacts perceptions about parenting. This study examined the relationship between parenting stress and observer-perceived limit-setting ability. Participants' perceptions of other parents' limit-setting ability were assessed by showing participants video clips of parenting behaviours. Mothers of 93 children with autism spectrum disorder completed an online survey regarding the severity of their own child's autism spectrum disorder (Social Communication Questionnaire), their child's behaviour problems (Strengths and Difficulties Questionnaire) and their own levels of parenting stress (Questionnaire on Resources and Stress). They were shown five videos of other parents interacting with children with autism spectrum disorder and were asked to rate the limit setting abilities observed in each video using the Parent-Child Relationship Inventory. Higher parenting stress negatively related to judgements about others' limit-setting skills. This mirrors the literature regarding the relationship between self-reported parenting stress and rating child behaviour more negatively. It suggests that stress negatively impacts a wide range of judgements and implies that caution may be required when interpreting the results of studies in which parenting skills are assessed by self-report. PMID- 27474115 TI - Class I and II Small Heat Shock Proteins Together with HSP101 Protect Protein Translation Factors during Heat Stress. AB - The ubiquitous small heat shock proteins (sHSPs) are well documented to act in vitro as molecular chaperones to prevent the irreversible aggregation of heat sensitive proteins. However, the in vivo activities of sHSPs remain unclear. To investigate the two most abundant classes of plant cytosolic sHSPs (class I [CI] and class II [CII]), RNA interference (RNAi) and overexpression lines were created in Arabidopsis (Arabidopsis thaliana) and shown to have reduced and enhanced tolerance, respectively, to extreme heat stress. Affinity purification of CI and CII sHSPs from heat-stressed seedlings recovered eukaryotic translation elongation factor (eEF) 1B (alpha-, beta-, and gamma-subunits) and eukaryotic translation initiation factor 4A (three isoforms), although the association with CI sHSPs was stronger and additional proteins involved in translation were recovered with CI sHSPs. eEF1B subunits became partially insoluble during heat stress and, in the CI and CII RNAi lines, showed reduced recovery to the soluble cell fraction after heat stress, which was also dependent on HSP101. Furthermore, after heat stress, CI sHSPs showed increased retention in the insoluble fraction in the CII RNAi line and vice versa. Immunolocalization revealed that both CI and CII sHSPs were present in cytosolic foci, some of which colocalized with HSP101 and with eEF1Bgamma and eEF1Bbeta. Thus, CI and CII sHSPs have both unique and overlapping functions and act either directly or indirectly to protect specific translation factors in cytosolic stress granules. PMID- 27474118 TI - Diagnostic stability of autism spectrum disorder in toddlers prospectively identified in a community-based setting: Behavioural characteristics and predictors of change over time. AB - Autism spectrum disorder diagnoses in toddlers have been established as accurate and stable across time in high-risk siblings and clinic-referred samples. Few studies have investigated diagnostic stability in children prospective identified in community-based settings. Furthermore, there is a dearth of evidence on the individual behaviours that predict diagnostic change over time. The stability and change of autism spectrum disorder diagnoses were investigated from 24 to 48 months in 77 children drawn from the Social Attention and Communication Study. Diagnostic stability was high, with 88.3% overall stability and 85.5% autism spectrum disorder stability. The behavioural markers at 24 months that contributed to diagnostic shift off the autism spectrum by 48 months included better eye contact, more directed vocalisations, the integration of gaze and directed vocalisations/gestures and higher non-verbal developmental quotient. These four variables correctly predicted 88.7% of children into the autism spectrum disorder-stable and autism spectrum disorder-crossover groups overall, with excellent prediction for the stable group (96.2%) and modest prediction for the crossover group (44.4%). Furthermore, non-verbal developmental quotient at 24 months accounted for the significant improvement across time in 'Social Affect' scores on the Autism Diagnostic Observation Schedule for both groups and was the only unique predictor of diagnostic crossover. These findings contribute to the body of evidence on the feasibility of diagnoses at earlier ages to facilitate children's access to interventions to promote positive developmental outcomes. PMID- 27474116 TI - Evidence for an Early Origin of Vernalization Responsiveness in Temperate Pooideae Grasses. AB - The ability of plants to match their reproductive output with favorable environmental conditions has major consequences both for lifetime fitness and geographic patterns of diversity. In temperate ecosystems, some plant species have evolved the ability to use winter nonfreezing cold (vernalization) as a cue to ready them for spring flowering. However, it is unknown how important the evolution of vernalization responsiveness has been for the colonization and subsequent diversification of taxa within the northern and southern temperate zones. Grasses of subfamily Pooideae, including several important crops, such as wheat (Triticum aestivum), barley (Hordeum vulgare), and oats (Avena sativa), predominate in the northern temperate zone, and it is hypothesized that their radiation was facilitated by the early evolution of vernalization responsiveness. Predictions of this early origin hypothesis are that a response to vernalization is widespread within the subfamily and that the genetic basis of this trait is conserved. To test these predictions, we determined and reconstructed vernalization responsiveness across Pooideae and compared expression of wheat vernalization gene orthologs VERNALIZATION1 (VRN1) and VRN3 in phylogenetically representative taxa under cold and control conditions. Our results demonstrate that vernalization responsive Pooideae species are widespread, suggesting that this trait evolved early in the lineage and that at least part of the vernalization gene network is conserved throughout the subfamily. These results are consistent with the hypothesis that the evolution of vernalization responsiveness was important for the initial transition of Pooideae out of the tropics and into the temperate zone. PMID- 27474120 TI - Successful cyclophosphamide desensitization in a pediatric patient with systemic lupus erythematosus and anaphylaxis after initial exposure. PMID- 27474119 TI - Systemic mastocytosis presenting as occupational IgE-mediated anaphylaxis to pine processionary caterpillar. PMID- 27474121 TI - Clinical trial data access: Opening doors with TrialShare. PMID- 27474122 TI - The skin microbiome is different in pediatric versus adult atopic dermatitis. PMID- 27474123 TI - Rhinovirus and serum IgE are associated with acute asthma exacerbation severity in children. PMID- 27474124 TI - Peripheral blood gene expression predicts clinical benefit from anti-IL-13 in asthma. PMID- 27474125 TI - Impact of p16 expression in oropharyngeal cancer in the postoperative setting: the necessity of re-evaluating traditional risk stratification. AB - OBJECTIVE: To evaluate the impact of p16 expression as a surrogate marker of human papillomavirus status in oropharyngeal squamous cell carcinoma patients underwent surgery followed by postoperative radiotherapy. METHODS: We identified 126 consecutive patients with histologically confirmed, newly diagnosed oropharyngeal squamous cell carcinoma who received surgery followed by radiotherapy and had p16 expression data available. All patients were treated between 2001 and 2011. Patients with high-risk factors (positive surgical margin and/or extracapsular extension) or other risk factors (multiple positive lymph nodes, perineural/lymphovascular invasion) were offered postoperative radiotherapy with or without concurrent chemotherapy. RESULTS: One hundred and four (82.5%) patients were p16-positive (p16 (+)) and 22 (17.5%) were p16 negative (p16 (-)). With a median follow-up of 56 months, patients with p16 (+) oropharyngeal squamous cell carcinoma exhibited a significantly better 5-year disease-free survival (80.7% vs. 57.6%, P < 0.001) and overall survival (84.9% vs. 59.1%, P < 0.001) than those with p16 (-) tumors. The p16 (+) oropharyngeal squamous cell carcinoma with high-risk factors (n = 64) showed no difference in disease-free survival (79.7% vs. 68.3%; P = 0.531) and overall survival (82.1% vs. 76.2%; P = 0.964) between postoperative radiotherapy and postoperative radiotherapy with concurrent chemotherapy. CONCLUSIONS: Expression of p16 is a strong independent prognostic factor of survival in the postoperative setting of oropharyngeal squamous cell carcinoma. The favorable prognosis of p16 (+) oropharyngeal squamous cell carcinoma suggests a need to re-examine traditional risk stratification for determining optimal adjuvant treatment. PMID- 27474127 TI - Incidence rates for colon cancer of Japanese in Japan and in the United States from the Cancer Incidence in Five Continents. PMID- 27474126 TI - Chemoradiotherapy with weekly low-dose docetaxel and cisplatin concurrent with radiation for patients with locally advanced nasopharyngeal carcinoma, followed by adjuvant chemotherapy for selected patients. AB - OBJECTIVE: We investigated the efficacy and safety of concurrent chemoradiotherapy using weekly low-dose docetaxel and cisplatin in patients with locally advanced nasopharyngeal carcinoma. METHODS: This was a retrospective analysis of 31 patients who were treated with this regimen from 2001 to 2014. Concurrent chemoradiotherapy consisted of radiotherapy with a total dose of 59.4 70.2 Gy plus weekly administration of docetaxel (5-10 mg/m2) and cisplatin (20 mg/m2), up to six cycles. At least two cycles of platinum-based adjuvant chemotherapy were prescribed for Stage IV and Stage III patients with partial response or stable disease after concurrent chemoradiotherapy. RESULTS: Of the 31 patients, 28 (90%) completed concurrent chemoradiotherapy as planned. The overall complete response and partial response rates were 42% and 52%, respectively. Seventeen of the 21 patients who were prescribed adjuvant chemotherapy underwent it. After a median follow-up of 39.1 months for the 23 surviving patients, 9 (29%) developed locoregional recurrence or progression and 6 patients (19%) developed distant metastasis. The 3-year overall survival and progression-free survival rates were 76% and 56%, respectively. Univariate analyses revealed that clinical stage was a significant predictor of complete response, overall survival and progression-free survival. The most serious adverse events were mucositis during concurrent chemoradiotherapy and neutropenia during adjuvant chemotherapy. CONCLUSIONS: This concurrent chemoradiotherapy protocol showed practical efficacy with high feasibility and acceptable toxicity. To improve the progression-free survival of patients with Stage IV disease who are treated by this protocol, changes to their treatment strategy should be considered. PMID- 27474128 TI - CRAC channels are required for [Ca(2+)]i oscillations and c-fos gene expression after muscarinic acetylcholine receptor activation in leukemic T cells. AB - AIMS: T lymphocytes express muscarinic acetylcholine receptors (mAChRs) involved in regulating their proliferation, differentiation and cytokine release. Activation of M1, M3 or M5 mAChRs increases the intracellular Ca(2+) concentration ([Ca(2+)]i) through inositol-1,4,5-phosphate (IP3)-mediated Ca(2+) release from endoplasmic reticulum Ca(2+) stores. In addition, T lymphocytes express Ca(2+)-release activated Ca(2+) (CRAC) channels to induce Ca(2+) influx and to regulate diverse immune functions. Our aim in the present study was to assess the role of CRAC channels during mAChR activation in the Ca(2+)-dependent transduction that contributes to the regulation of T cell function. MAIN METHODS: Changes in [Ca(2+)]i following mAChR activation on human leukemic T cells, CCRF CEM (CEM), were monitored using fura-2, based on the ratio of 510nm fluorescences elicited by excitation at 340nm and 380nm (R340/380). KEY FINDINGS: We demonstrate that CEM cells express mainly M3 and M5 mAChRs, but little the M1 subtype, and that oxotremorine-M (Oxo-M), an mAChR agonist, induces an initial transient increase in [Ca(2+)]i followed by repetitive [Ca(2+)]i oscillations. Removing extracellular Ca(2+) or pharmacological blockade of CRAC channels abolished the [Ca(2+)]i oscillations without affecting the initial [Ca(2+)]i transient induced by Oxo-M. Moreover, CRAC channel blockade also suppressed Oxo-M induced c-fos and interleukin-2 expression. SIGNIFICANCE: These results suggest that upon M3 or M5 mAChR activation, IP3-mediated Ca(2+) release induces extracellular Ca(2+) influx through CRAC channels, which generates repetitive [Ca(2+)]i oscillations and, in turn, enhances c-fos gene expression in T lymphocytes. PMID- 27474129 TI - Selective activation of CB2 receptor improves efferocytosis in cultured macrophages. AB - AIMS: Recent evidence indicates that the defective ability to clear apoptotic cells by macrophages (efferocytosis) and the resultant apoptotic cells accumulation in atherosclerotic plaques play an important role during the progression of unstable plaques. The cannabinoid type 2 receptor (CB2), has recently been emerging as a new target to reduce vulnerability and promote stability of plaques, however, the underlying mechanisms have not been studied in detail. In the present study, we investigated whether selective activation of CB2 improves efferocytosis of macrophages. MAIN METHODS: RAW264.7 macrophage line and primary-isolated peritoneal lavage macrophages from C57bl/6J mice were cultured. The efferocytosis of macrophages was analyzed by using flow cytometry or confocal microscopy; and the possible mechanisms involved in regulation of efferocytosis were also explored by using molecular biology methods. KEY FINDINGS: We found that JWH-133 and HU-308, selective agonists of CB2 receptor, concentration dependently increased the phagocytosis of apoptotic cells in normal-cultured and oxidative low density lipoprotein (OxLDL) -loaded RAW264.7 and primary macrophages. JWH-133 and HU-308 also up-regulated expressions of tyrosine kinase family phagocytic receptors MerTK, Tyro3 and Axl, reduced levels of TNF-alpha and reactive oxygen species (ROS) induced by OxLDL, and inhibited activation of RhoA GTPase. SIGNIFICANCE: The selective activation of CB2 improves efferosytosis of normal-cultured and OxLDL-loaded macrophages, which might provide a novel mechanism on how CB2 activation reduces vulnerability and promotes stability of atherosclerotic plaques. PMID- 27474130 TI - A network management approach to sleep apnea-hypopnea syndrome: Healthcare units. PMID- 27474131 TI - You'll Never Guess Who Wrote That: 78 Surprising Authors of Psychological Publications. AB - One can find psychological authors in the most unexpected places. We present a capsule summary of scholarly publications of psychological interest authored or coauthored by 78 surprising individuals, most of whom are celebrities or relatives of celebrities, historical figures, or people who have otherwise achieved visibility in academic circles, politics, religion, art, and diverse realms of popular culture. Still other publications are authored by individuals who are far better known for their contributions to popular than to academic psychology. The publications, stretching across more than two centuries, encompass a wide swath of domains of psychological inquiry and highlight the intersection of psychology with fields that fall outside its traditional borders, including public health, economics, law, neurosurgery, and even magic. Many of these scholarly contributions have enriched psychology and its allied disciplines, such as psychiatry, in largely unappreciated ways, and they illustrate the penetration of psychological knowledge into multiple scientific disciplines and everyday life. At the same time, our author list demonstrates that remarkable intellectual accomplishments in one scientific domain, such as physics, do not necessarily translate into success in psychology and underscores the distinction between intelligence, on the one hand, and critical thinking and wisdom, on the other. PMID- 27474132 TI - An Overly Permissive Extension. AB - In this article, I describe how the current practice of classifying as a stressor any event that is accompanied by a change in any of a number of biological or behavioral measures-even when it is not accompanied by a long-term compromise in an organism's health or capacity to cope with daily challenges-has limited the utility of this concept. This permissive posture, which began with Selye's writings more than 65 years ago, is sustained by the public's desire for a simple term that might explain the tension generated by the threat of terrorists, growing economic inequality, increased competiveness in the workplace or for admission to the best universities, rogue nuclear bombs, and media reports of threats to health in food and water. I believe that the concept stress should be limited to select events that pose a serious threat to an organism's well-being or discarded as too ambiguous to be theoretically useful. PMID- 27474133 TI - Response to Jerome Kagan's Essay on Stress (2016). AB - To be useful, the concept of stress needs to be defined in biological terms linked to a broader framework of allostasis and its role in the adaptation of brain and body to positive and negative life experiences. A clear biological framework helps connect and organize animal and human research on stress. In particular, the concepts of "toxic stress" and "allostatic load and overload" highlight those experiences and situations that, as Kagan says, "compromise an organism's health and capacity to cope with daily challenges" (p. 442). A deeper understanding is needed of the epigenetic influences throughout the life course that contribute both to these negative outcomes and to positive ones. PMID- 27474134 TI - A Stage Model of Stress and Disease. AB - In this article, we argued that the term stress has served as a valuable heuristic, helping researchers to integrate traditions that illuminate different stages of the process linking stressful life events to disease. We provided a short history of three traditions in the study of stress: the epidemiological, psychological, and biological. The epidemiological tradition focuses on defining which circumstances and experiences are deemed stressful on the basis of consensual agreement that they constitute threats to social or physical well being. The psychological tradition focuses on individuals' perceptions of the stress presented by life events on the basis of their appraisals of the threats posed and the availability of effective coping resources. The biological tradition focuses on brain-based perturbations of physiological systems that are otherwise essential for normal homeostatic regulation and metabolic control. The foci of these three traditions have informed elements of a stage model of disease, wherein events appraised as stressful are viewed as triggering affective states that in turn engender behavioral and biological responses having possible downstream implications for disease. PMID- 27474135 TI - Why Stress Remains an Ambiguous Concept: Reply to McEwen & McEwen (2016) and Cohen et al. (2016). AB - This reply to the commentaries by Cohen, Giannaros, and Manuck (2016, this issue) and McEwen and McEwen (2016, this issue) acknowledges investigators' reluctance to relinquish the term stress, despite the lack of agreement on its meaning and the evidence that is a sign of its presence. This brief reply urges scientists studying the exemplars of this ambiguous concept to search for robust relations that specify the type of event, the properties of the agent, the agent's circumstances, and the behavioral or biological consequences. The accumulation of these relations will reveal that the word stress adds little to our understanding. PMID- 27474136 TI - Shared-Reality Development in Childhood. AB - Many significant changes occur during human childhood, including cognitive, social-cognitive, and socioemotional changes. This article reviews some key phenomena associated with some of these changes and attempts to capture them within a single conceptual umbrella-changes in children's shared realities with others Shared reality is the experience that you have an inner state about something (e.g., a feeling or belief or concern about something) that is shared by others (a person or group). Four phases of shared-reality development are proposed: Phase 1 (6-12 months) shared feelings; Phase 2 (18-24 months) shared practices; Phase 3 (3-5 years) shared self-guides; Phase 4 (9-13 years) shared coordinated roles In each phase, a new way that children interact with and relate to others emerges, and the emergence of each new shared-reality mode has significant self-regulatory and social consequences. These consequences include both major benefits for children and potential costs-trade-offs of being human. PMID- 27474137 TI - Adaptive Memory: The Evolutionary Significance of Survival Processing. AB - A few seconds of survival processing, during which people assess the relevance of information to a survival situation, produces particularly good retention. One interpretation of this benefit is that our memory systems are optimized to process and retain fitness-relevant information. Such a "tuning" may exist, in part, because our memory systems were shaped by natural selection, using a fitness-based criterion. However, recent research suggests that traditional mnemonic processes, such as elaborative processing, may play an important role in producing the empirical benefit. Boundary conditions have been demonstrated as well, leading some to dismiss evolutionary interpretations of the phenomenon. In this article, we discuss the current state of the evolutionary account and provide a general framework for evaluating evolutionary and purportedly nonevolutionary interpretations of mnemonic phenomena. We suggest that survival processing effects are best viewed within the context of a general survival optimization system, designed by nature to help organisms deal with survival challenges. An important component of survival optimization is the ability to simulate activities that help to prevent or escape from future threats which, in turn, depends in an important way on accurate retrospective remembering of survival-relevant information. PMID- 27474139 TI - Changing the Context Is Important and Necessary, but Not Sufficient, for Reducing Adolescent Risky Sexual Behavior: A Reply to Steinberg (2015). AB - Starting school later, keeping adolescents busy with structured programming, and making free condoms available, as Steinberg (2015) suggests, are important and necessary steps, but they are simply not sufficient if the goal is reducing sexually transmitted infections and unplanned pregnancy. We agree that the current state of affairs, which in many schools involves sexuality education using programs that are not empirically supported, is unacceptable. However, abandoning sexuality education entirely would leave adolescents ill equipped to protect themselves. Despite the fact that current intervention technology is neither perfect nor optimally effective, there are empirically supported, school based sexual risk reduction interventions that teach these skills and are readily available. In addition, even though we agree that structured afternoon programs for school-aged adolescents would reduce the opportunity for sexual risk behavior during the school years, such programs would not address the demographic reality of sexual risk that continues for adolescents and emerging adults far past the end of traditional secondary education. We believe Steinberg's suggestions are an excellent start and ought to be implemented. But complementary to this approach should be the use of existing empirically supported sexual risk reduction interventions and research into the development of even more effective interventions. PMID- 27474138 TI - Working Memory Training Does Not Improve Performance on Measures of Intelligence or Other Measures of "Far Transfer": Evidence From a Meta-Analytic Review. AB - It has been claimed that working memory training programs produce diverse beneficial effects. This article presents a meta-analysis of working memory training studies (with a pretest-posttest design and a control group) that have examined transfer to other measures (nonverbal ability, verbal ability, word decoding, reading comprehension, or arithmetic; 87 publications with 145 experimental comparisons). Immediately following training there were reliable improvements on measures of intermediate transfer (verbal and visuospatial working memory). For measures of far transfer (nonverbal ability, verbal ability, word decoding, reading comprehension, arithmetic) there was no convincing evidence of any reliable improvements when working memory training was compared with a treated control condition. Furthermore, mediation analyses indicated that across studies, the degree of improvement on working memory measures was not related to the magnitude of far-transfer effects found. Finally, analysis of publication bias shows that there is no evidential value from the studies of working memory training using treated controls. The authors conclude that working memory training programs appear to produce short-term, specific training effects that do not generalize to measures of "real-world" cognitive skills. These results seriously question the practical and theoretical importance of current computerized working memory programs as methods of training working memory skills. PMID- 27474140 TI - What Should Researchers Expect When They Replicate Studies? A Statistical View of Replicability in Psychological Science. AB - A recent study of the replicability of key psychological findings is a major contribution toward understanding the human side of the scientific process. Despite the careful and nuanced analysis reported, the simple narrative disseminated by the mass, social, and scientific media was that in only 36% of the studies were the original results replicated. In the current study, however, we showed that 77% of the replication effect sizes reported were within a 95% prediction interval calculated using the original effect size. Our analysis suggests two critical issues in understanding replication of psychological studies. First, researchers' intuitive expectations for what a replication should show do not always match with statistical estimates of replication. Second, when the results of original studies are very imprecise, they create wide prediction intervals-and a broad range of replication effects that are consistent with the original estimates. This may lead to effects that replicate successfully, in that replication results are consistent with statistical expectations, but do not provide much information about the size (or existence) of the true effect. In this light, the results of the Reproducibility Project: Psychology can be viewed as statistically consistent with what one might expect when performing a large scale replication experiment. PMID- 27474141 TI - Introduction to a Registered Replication Report on Ego Depletion. PMID- 27474143 TI - Misguided Effort With Elusive Implications. PMID- 27474142 TI - A Multilab Preregistered Replication of the Ego-Depletion Effect. AB - Good self-control has been linked to adaptive outcomes such as better health, cohesive personal relationships, success in the workplace and at school, and less susceptibility to crime and addictions. In contrast, self-control failure is linked to maladaptive outcomes. Understanding the mechanisms by which self control predicts behavior may assist in promoting better regulation and outcomes. A popular approach to understanding self-control is the strength or resource depletion model. Self-control is conceptualized as a limited resource that becomes depleted after a period of exertion resulting in self-control failure. The model has typically been tested using a sequential-task experimental paradigm, in which people completing an initial self-control task have reduced self-control capacity and poorer performance on a subsequent task, a state known as ego depletion Although a meta-analysis of ego-depletion experiments found a medium-sized effect, subsequent meta-analyses have questioned the size and existence of the effect and identified instances of possible bias. The analyses served as a catalyst for the current Registered Replication Report of the ego depletion effect. Multiple laboratories (k = 23, total N = 2,141) conducted replications of a standardized ego-depletion protocol based on a sequential-task paradigm by Sripada et al. Meta-analysis of the studies revealed that the size of the ego-depletion effect was small with 95% confidence intervals (CIs) that encompassed zero (d = 0.04, 95% CI [-0.07, 0.15]. We discuss implications of the findings for the ego-depletion effect and the resource depletion model of self control. PMID- 27474144 TI - Sifting Signal From Noise With Replication Science. PMID- 27474145 TI - Serologically Confirmed Zika-Related Unilateral Acute Maculopathy in an Adult. PMID- 27474146 TI - Martinique Crinkled Retinal Pigment Epitheliopathy: Clinical Stages and Pathophysiologic Insights. AB - PURPOSE: To reappraise the autosomal dominant Martinique crinkled retinal pigment epitheliopathy (MCRPE) in light of the knowledge of its associated mutated gene mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3), an actor in the p38 mitogen-activated protein kinase pathway. DESIGN: Clinical and molecular study. PARTICIPANTS: A total of 45 patients from 3 generations belonging to a family originating from Martinique with an autosomal dominant MCRPE were examined. METHODS: Best-corrected visual acuity, fundus photographs, and spectral-domain optical coherence tomography (SD OCT) of all clinically affected patients and carriers for the causal mutation were reviewed at the initial visit and 4 years later for 10 of them. Histologic retinal lesions of Mapkapk3(-/-) mice were compared with those of the human disease. MAIN OUTCOME MEASURES: The MCRPE natural history in view of MAPKAPK3 function and Mapkapk3(-/ ) mouse retinal lesions. RESULTS: Eighteen patients had the c.518T>C mutation. One heterozygous woman aged 20 years was asymptomatic with normal fundus and SD OCT (stage 0). All c.518T>C heterozygous patients older than 30 years of age had the characteristic dried-out soil fundus pattern (stages 1 and 2). Complications (stage 3) were observed in 7 cases, including polypoidal choroidal vasculopathy (PCV) and macular fibrosis or atrophy. One patient was homozygous and had a form with severe Bruch's membrane (BM) thickening and macular exudation with a dried out soil pattern in the peripheral retina. The oldest heterozygous patient, who was legally blind, had peripheral nummular pigmentary changes (stage 4). After 4 years, visual acuity was unchanged in 6 of 10 patients. The dried-out soil elementary lesions radically enlarged in patients with a preferential macular extension and confluence. These findings are in line with the progressive thickening of BM noted with age in the mouse model. During follow-up, there was no occurrence of PCV. CONCLUSIONS: MCRPE is an autosomal dominant, fully penetrant retinal dystrophy with a preclinical stage, an onset after the age of 30 years, and a preserved visual acuity until occurrence of macular complications. The natural history of MCRPE is in relation to the role of MAPKAPK3 in BM modeling, vascular endothelial growth factor activity, retinal pigment epithelial responses to aging, and oxidative stress. PMID- 27474147 TI - The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma. AB - A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a well-developed stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents. Mol Cancer Ther; 15(10); 2455-64. (c)2016 AACR. PMID- 27474148 TI - Mechanism-Based Drug Combinations with the DNA Strand-Breaking Nucleoside Analog CNDAC. AB - CNDAC (2'-C-cyano-2'-deoxy-1-beta-d-arabino-pentofuranosyl-cytosine, DFP10917) and its orally bioavailable prodrug, sapacitabine, are undergoing clinical trials for hematologic malignancies and solid tumors. The unique action mechanism of inducing DNA strand breaks distinguishes CNDAC from other deoxycytidine analogs. To optimize the clinical potentials of CNDAC, we explored multiple strategies combining CNDAC with chemotherapeutic agents targeting distinct DNA damage repair pathways that are currently in clinical use. The ability of each agent to decrease proliferative potential, determined by clonogenic assays, was determined in paired cell lines proficient and deficient in certain DNA repair proteins. Subsequently, each agent was used in combination with CNDAC at fixed concentration ratios. The clonogenicity was quantitated by median effect analysis, and a combination index was calculated. The c-Abl kinase inhibitor imatinib had synergy with CNDAC in HCT116 cells, regardless of p53 status. Inhibitors of PARP1 that interfere with homologous recombination (HR) repair or base excision repair (BER) and agents such as temozolomide that cause DNA damage repaired by the BER pathway were also synergistic with CNDAC. The toxicity of the nitrogen mustards bendamustine and cytoxan, or of platinum compounds, which generate DNA adducts repaired by nucleotide excision repair and HR, was additive with CNDAC. An additive cell killing was also achieved by the combination of CNDAC with taxane mitotic inhibitors (paclitaxel and docetaxel). At concentrations that allow survival of the majority of wild-type cells, the synergistic or additive combination effects were selective in HR-deficient cells. This study provides mechanistic rationales for combining CNDAC with other active drugs. Mol Cancer Ther; 15(10); 2302-13. (c)2016 AACR. PMID- 27474149 TI - Wedelolactone, an Anti-inflammatory Botanical, Interrupts c-Myc Oncogenic Signaling and Synergizes with Enzalutamide to Induce Apoptosis in Prostate Cancer Cells. AB - The c-Myc gene encodes an oncoprotein transcription factor that is frequently upregulated in almost all cancer types and is the subject of intense investigation for management of cancer because of its pleiotropic effects controlling a spectrum of cellular functions. However, due of its nonenzymatic nature, development of suitable strategies to block its protein-protein or protein-DNA interaction is challenging. Thus, c-Myc has been recognized as an elusive molecular target for cancer control, and various approaches are in development to inhibit c-Myc transcriptional activity. We observed that wedelolactone (WDL), an anti-inflammatory botanical compound, severely downregulates the expression of c-Myc mRNA in prostate cancer cells. Moreover, WDL dramatically decreases the protein level, nuclear accumulation, DNA-binding, and transcriptional activities of c-Myc. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and is critical for maintaining their transformed phenotype. Interestingly, WDL was found to strongly affect the viability of Myc-activated prostate cancer cells and completely block their invasion as well as soft agar colony formation in vitro WDL was also found to downregulate c-Myc in vivo in nude mice xenografts. Moreover, WDL synergizes with enzalutamide to decrease the viability of androgen-sensitive prostate cancer cells via induction of apoptosis. These findings reveal a novel anticancer mechanism of the natural compound WDL, and suggest that the oncogenic function of c-Myc in prostate cancer cells can be effectively downregulated by WDL for the development of a new therapeutic strategy against Myc-driven prostate cancer. Mol Cancer Ther; 15(11); 2791-801. (c)2016 AACR. PMID- 27474151 TI - In Vivo Antitumor Activity of a Recombinant IL7/IL15 Hybrid Cytokine in Mice. AB - Both IL7 and IL15 have become important candidate immunomodulators for cancer treatment. However, IL7 or IL15 used alone suffers from shortcomings, such as short serum half-life and limited antitumor effect. We have cloned and expressed a recombinant (r) IL7/IL15 fusion protein in which IL7 and IL15 are linked by a flexible linker. We then compared the antitumor effect of rIL7/IL15 with the individual factors rIL7 and/or rIL15. We show here that rIL7/IL15 has a higher antitumor activity than the combination of the individual factors in both murine B16F10 melanoma and CT-26 colon cancer models. This was associated with a significant increase in tumor infiltration of T cells, DCs, and NK cells and a decrease in regulatory T cells (Tregs). In addition, rIL7/IL15-treated DCs had higher expression of costimulatory molecules CD80 and CD86. The higher antitumor activity of rIL7/IL15 is likely due to its longer in vivo half-life and different effects on immune cells. Our results suggest that rIL7/IL15 may offer a new tool to enhance antitumor immunity and treat cancer. Mol Cancer Ther; 15(10); 2413-21. (c)2016 AACR. PMID- 27474150 TI - FLIP: A Targetable Mediator of Resistance to Radiation in Non-Small Cell Lung Cancer. AB - Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor FLIP is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were downregulated by RNAi, IR-induced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the antitumor activity of IR in vivo Therefore, FLIP downregulation induced by HDAC inhibitors is a potential clinical strategy to radiosensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. Mol Cancer Ther; 15(10); 2432-41. (c)2016 AACR. PMID- 27474152 TI - ERBB2 Overexpression Establishes ERBB3-Dependent Hypersensitivity of Breast Cancer Cells to Withaferin A. AB - The catalytically deficient ERBB3 strongly synergizes with the receptor tyrosine kinase ERBB2, and elevated levels represent an overall risk factor for unfavorable disease outcomes in breast cancer. Although itself not a target of pan-ERBB kinase inhibitors, it contributes to resistance in ERBB2-targeted treatment regiments. The steroidal lactone Withaferin A (WA) has established broad anticancer properties through several modes of action and was shown to be effective against triple-negative breast cancers at elevated concentrations. We found that ERBB2 overexpression does render cells hypersensitive to WA. Although ERBB2 downregulation is one aspect of WA treatment at high concentrations, it is not causal for the elevated sensitivity at lower dosages. Instead, WA targets the ability of ERBB3 to amplify ERBB2 signaling. ERBB3 receptor levels, constitutive phosphorylation of both ERBB3 and ERBB2, as well as signaling through AKT are eliminated by WA treatment. By targeting ERBB2/ERBB3 as a functional unit, it is also effective in cases in which ERBB2-directed inhibitors, such as lapatinib, alone show reduced potency. Hence, WA or derivatives thereof may present a low toxicity addition to ERBB2-targeting therapeutics, especially in cases in which ERBB3 involvement is driving resistance or reduced overall sensitivity. Mol Cancer Ther; 15(11); 2750-7. (c)2016 AACR. PMID- 27474154 TI - Effects of Endurance-Focused Physical Activity Interventions on Brain Health: A Systematic Review. AB - Physical activity intervention studies that focus on improving cognitive function in older adults have increasingly used magnetic resonance imaging (MRI) measures in addition to neurocognitive measures to assess effects on the brain. The purpose of this systematic review was to identify the effects of endurance focused physical activity randomized controlled trial (RCT) interventions on the brain as measured by MRI in community-dwelling middle-aged or older adults without cognitive impairment. Five electronic databases were searched. The final sample included six studies. None of the studies reported racial or ethnic characteristics of the participants. All studies included neurocognitive measures in addition to MRI. Five of the six interventions included laboratory-based treadmill or supervised bike exercise sessions, while one included community based physical activity. Physical activity measures were limited to assessment of cardiorespiratory fitness and, in one study, pedometer. Due to the lack of adequate data reported, effect sizes were calculated for only one study for MRI measures and two studies for neurocognitive measures. Effect sizes ranged from d = .2 to .3 for MRI measures and .2 to .32 for neurocognitive measures. Findings of the individual studies suggest that MRI measures may be more sensitive to the effects of physical activity than neurocognitive measures. Future studies are needed that include diverse, community-based participants, direct measures of physical activity, and complete reporting of MRI and neurocognitive findings. PMID- 27474153 TI - Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs. AB - Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First- and second-line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O6-chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links are supposed to be converted into DNA double strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement, and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacologic inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes, and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggest that pharmacologic inhibition of HR, for example by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs. Mol Cancer Ther; 15(11); 2665-78. (c)2016 AACR. PMID- 27474155 TI - Long-term complications of different porous orbital implants: a 21-year review. AB - AIMS: To analyse the long-term outcomes of different types of orbital implant and the results of dermis fat graft for the management of large-area implant exposure. METHODS: Retrospective case series. From 1994 to 2015, 256 patients who received primary implantation after enucleation or evisceration and were followed up for an average of 108.9 months were recruited. Detailed characteristics of patients, including previous surgery or trauma, surgical indications and methods, pegging procedure, and implant types were collected. The long-term outcomes were recorded. For patients with extensive implant exposure (diameter of tissue defect >2 cm), implant removal and dermis fat graft were performed. RESULTS: The risk factors for implant exposure included eviscerated globes and pegged implants. The exposure rates were higher (24.7% in hydroxyapatite (HA), 23.5% in bioceramic and 76.5% in Medpor) as compared with those in previous reports. The average times to exposure were 67.4 months in HA, 52.5 months in bioceramic and 73.4 months in Medpor implants. Among the cases with implant exposure, late exposure (>2 years after operation) accounted for 67% of cases. Thirty eyes with large-area exposure were managed with dermis fat grafts. Twenty-four cases were successfully treated with single surgery. The other six cases developed fornix loss and required additional reconstruction with full thickness skin graft. CONCLUSIONS: Late exposures of porous orbital implants were noted during long-term follow-up. The causes of implant exposure may be associated with pegging procedures and evisceration. The implantation of dermis fat can be an effective procedure for the management of large-area implant exposure. PMID- 27474156 TI - Relationship between corneal hysteresis and lamina cribrosa displacement after medical reduction of intraocular pressure. AB - PURPOSE: To evaluate the relationship between the displacement of the lamina cribrosa (LC) and prelaminar tissue with corneal hysteresis (CH) using spectral domain coherence tomography (SD-OCT) after reducing intraocular pressure (IOP) with medical treatment. METHODS: Sixty-one eyes of 61 patients with ocular hypertension or primary open-angle glaucoma who were going to start with treatment were imaged by means of 12 cross-sectional scans of the optic nerve using enhanced depth imaging SD-OCT before and after 1 week of treatment. We used the 'follow-up' mode to make sure that all the measurements were performed in the same location. We also measured the CH using an Ocular Response Analyzer, and we related it to the magnitude of displacement of LC and prelaminar tissue and the thickness of both structures. RESULTS: There was a significant variation of LC thickness from 132.66+/-37.40 to 160.09+/-41.13 um (p<0001). LC distance was significantly reduced from 258.53+/-145 um before treatment to 239.86+/-135 um after it. No significant changes were found in the thickness and movement of prelaminar tissue before and after treatment. The only factors related with LC displacement were CH (R2=0.48) and age (R2=0.42). CONCLUSIONS: A significant increase in LC thickness and a reduction in the posterior displacement of LC but not in the prelaminar tissue were demonstrated after IOP reduction with medical treatment. The factors most related with LC displacement were age and CH. PMID- 27474157 TI - Th2 and Th9 responses in patients with chronic mucocutaneous candidiasis and hyper-IgE syndrome. AB - BACKGROUND: STAT1 mutations cause chronic mucocutaneous candidiasis (CMC), while STAT3 mutations cause hyper-IgE syndrome (HIES). CMC and HIES patients have T helper (Th) 17 defects suffering from mucosal Candida infections, but only patients with HIES show an allergic phenotype with eczema, eosinophilia and high IgE levels. OBJECTIVE: We investigated whether differential Th2 and Th9 responses may explain the clinical differences. METHODS: Peripheral blood mononuclear cells of patients with CMC (n = 4), patients with HIES (n = 4), patients with atopic dermatitis (n = 4) and healthy volunteers (n = 13) were stimulated with Candida and Staphylococcus aureus, with and without IL-4. The cytokines IL-5, IL-13, IL 9, IL-17 and TGFbeta and regulatory T cells were measured in cell culture supernatants by ELISA or flow cytometry, respectively. RESULTS: Peripheral blood mononuclear cells of patients with CMC showed a significantly impaired production of the Th2 cytokines IL-5 and IL-13, especially in the presence of IL-4. Moreover, IL-9 production was significantly lower in patients with CMC compared to healthy controls. In contrast, patients with HIES and patients with AD showed normal IL-5 and IL-13 production, while IL-9 production was significantly lower in patients with HIES compared to healthy controls. Although TGFbeta was involved in the IL-4-induced IL-9 production, TGFbeta levels and the frequency of regulatory T cells did not differ between patients with HIES and controls. Flow cytometry analysis demonstrated an IL-9+ IL-17+ CD4+ subset in healthy controls after stimulation with Candida which was less present in patients with HIES. CONCLUSION: Patients with CMC have a general Th defect including Th2 and Th9, while patients with HIES have normal Th2 cytokines. These differences are in line with their clinical presentation. Surprisingly, the allergic cytokine IL-9 was deficient in both HIES and CMC, suggesting a Th-17-derived origin. PMID- 27474158 TI - Effect of repetition time on metabolite quantification in the human brain in 1 H MR spectroscopy at 3 tesla. AB - PURPOSE: To examine the effects of repetition time (TR) on metabolite concentration measurements in the human brain in 1 H magnetic resonance spectroscopy at 3 Tesla (T). MATERIALS AND METHODS: Spectra were acquired from the posterior cingulate of five healthy adults at repetition times of 1.5 s, 3.0 s, 4.0 s, 6.0 s, and 8.0 s on a 3T MRI system. Relaxation data were also acquired for the water signal in the voxel of interest to separate tissue water and cerebrospinal fluid signal contributions. All data were quantified relative to total creatine and relative to the tissue water signal. RESULTS: On average, the variance for absolute metabolite concentrations was smaller than that of ratio concentrations (P = 0.003). Metabolite ratio concentrations calculated from a short TR of 1.5 s significantly differed (P < 0.05) from their "true" ratios, i.e., ratios corrected for T1 -weighting. In comparison, absolute metabolite concentrations exhibited significant differences (P < 0.05) up to a 4-s TR. CONCLUSION: To minimize potential TR-dependent concentration differences at 3T, a minimum TR of 2.5 s is suggested for ratio concentration measurements, and a 5-s TR for absolute concentrations. When possible, preference should be to perform absolute concentration measurements. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:710-721. PMID- 27474159 TI - Non-Linear Pharmacokinetics of Atomoxetine in Adult Japanese Patients With ADHD. AB - OBJECTIVE: The objective was to reveal the relationship between dose and concentration of atomoxetine. METHOD: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. RESULTS: The plasma concentrations were 53.2 +/- 67.0, 298.0 +/- 390.5, and 639.3 +/- 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 +/- 1.67, 3.73 +/- 4.88, and 5.33 +/- 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine (p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups (p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 +/- 1.67 and 4.22 +/- 5.53 ng/mL/mg, the latter was significantly higher than the former (p = .006), which suggested non-linear pharmacokinetics. CONCLUSION: Clinicians should carefully titrate in high dose atomoxetine treatment. PMID- 27474160 TI - Association Between Parenting Style and Socio-Emotional and Academic Functioning in Children With and Without ADHD: A Community-Based Study. AB - OBJECTIVE: In a community-based study, we examined parenting style and its relationship to functioning in 6- to 8-year-old children (n = 391; 66.2% male) with ADHD (n = 179), compared with non-ADHD controls (n = 212). METHOD: Parenting style was assessed using parent-reported (93.5% female) measures of warmth, consistency, and anger. Child socio-emotional and academic functioning was measured via parent- and teacher-reported scales, and direct academic assessment. RESULTS: Parents reported less consistency and more anger in the ADHD group compared with non-ADHD controls, with no differences in warmth. Parenting warmth, consistency, and anger were associated with parent-reported aspects of socio emotional functioning for children with ADHD and non-ADHD controls, after adjusting for socio-demographic variables, externalizing comorbidities, and ADHD symptom severity. Parenting style was no longer related to academic functioning and most teacher-reported outcomes after adjustment. CONCLUSION: Generic parenting interventions that promote warm, consistent, and calm parenting may help alleviate socio-emotional impairments in children with ADHD. PMID- 27474161 TI - Incidence and Cost of Ankle Sprains in United States Emergency Departments. AB - BACKGROUND: Ankle sprains represent a common injury in emergency departments, but little is known about common complications, procedures, and charges associated with ankle sprains in emergency departments. HYPOTHESIS: There will be a higher incidence of ankle sprains among younger populations (<=25 years old) and in female patients. Complications and procedures will differ between ankle sprain types. Lateral ankle sprains will have lower health care charges relative to medial and high ankle sprains. STUDY DESIGN: Descriptive epidemiological study. LEVEL OF EVIDENCE: Level 3. METHODS: A cross-sectional study of the 2010 Nationwide Emergency Department Sample was conducted. Outcomes such as charges, complications, and procedures were compared using propensity score matching between lateral and medial as well as lateral and high ankle sprains. RESULTS: The sample contained 225,114 ankle sprains. Female patients sustained more lateral ankle sprains (57%). After propensity score adjustment, lateral sprains incurred greater charges than medial ankle sprains (median [interquartile range], $1008 [$702-$1408] vs $914 [$741-$1108]; P < 0.01). Among complications, pain in the limb (1.92% vs 0.52%, P = 0.03), sprain of the foot (2.96% vs 0.70%, P < 0.01), and abrasion of the hip/leg (1.57% vs 0.35%, P = 0.03) were more common in lateral than medial ankle sprain events. Among procedures, medial ankle sprains were more likely to include diagnostic radiology (97.91% vs 83.62%, P < 0.01) and less likely to include medications than lateral ankle sprains (0.87% vs 2.79%, P < 0.01). Hospitalizations were more common following high ankle sprains than lateral ankle sprains (24 [6.06%] vs 1 [0.25%], P < 0.01). CONCLUSION: Ankle sprain emergency department visits account for significant health care charges in the United States. Age- and sex-related differences persist among the types of ankle sprains. CLINICAL RELEVANCE: The health care charges associated with ankle sprains indicate the need for additional preventive measures. There are age- and sex-related differences in the prevalence of ankle sprains that suggest these demographics may be risk factors for ankle sprains. PMID- 27474162 TI - Differential Inhibition of Water and Ion Channel Activities of Mammalian Aquaporin-1 by Two Structurally Related Bacopaside Compounds Derived from the Medicinal Plant Bacopa monnieri. AB - Aquaporin-1 (AQP1) is a major intrinsic protein that facilitates flux of water and other small solutes across cell membranes. In addition to its function as a water channel in maintaining fluid homeostasis, AQP1 also acts as a nonselective cation channel gated by cGMP, a property shown previously to facilitate rapid cell migration in a AQP1-expressing colon cancer cell line. Here we report two new modulators of AQP1 channels, bacopaside I and bacopaside II, isolated from the medicinal plant Bacopa monnieri Screening was conducted in the Xenopus oocyte expression system, using quantitative swelling and two-electrode voltage clamp techniques. Results showed bacopaside I blocked both the water (IC50 117 MUM) and ion channel activities of AQP1 but did not alter AQP4 activity, whereas bacopaside II selectively blocked the AQP1 water channel (IC50 18 MUM) without impairing the ionic conductance. These results fit with predictions from in silico molecular modeling. Both bacopasides were tested in migration assays using HT29 and SW480 colon cancer cell lines, with high and low levels of AQP1 expression, respectively. Bacopaside I (IC50 48 MUM) and bacopaside II (IC50 14 MUM) impaired migration of HT29 cells but had minimal effect on SW480 cell migration. Our results are the first to identify differential AQP1 modulators isolated from a medicinal plant. Bacopasides could serve as novel lead compounds for pharmaceutic development of selective aquaporin modulators. PMID- 27474163 TI - Live-cell imaging of budding yeast telomerase RNA and TERRA. AB - In most eukaryotes, the ribonucleoprotein complex telomerase is responsible for maintaining telomere length. In recent years, single-cell microscopy techniques such as fluorescent in situ hybridization and live-cell imaging have been developed to image the RNA subunit of the telomerase holoenzyme. These techniques are now becoming important tools for the study of telomerase biogenesis, its association with telomeres and its regulation. Here, we present detailed protocols for live-cell imaging of the Saccharomyces cerevisiae telomerase RNA subunit, called TLC1, and also of the non-coding telomeric repeat-containing RNA TERRA. We describe the approach used for genomic integration of MS2 stem-loops in these transcripts, and provide information for optimal live-cell imaging of these non-coding RNAs. PMID- 27474164 TI - Improving hot region prediction by parameter optimization of density clustering in PPI. AB - This paper proposed an optimized algorithm which combines density clustering of parameter selection with feature-based classification for hot region prediction. First, all the residues are classified by SVM to remove non-hot spot residues, then density clustering of parameter selection is used to find hot regions. In the density clustering, this paper studies how to select input parameters. There are two parameters radius and density in density-based incremental clustering. We firstly fix density and enumerate radius to find a pair of parameters which leads to maximum number of clusters, and then we fix radius and enumerate density to find another pair of parameters which leads to maximum number of clusters. Experiment results show that the proposed method using both two pairs of parameters provides better prediction performance than the other method, and compare these two predictive results, the result by fixing radius and enumerating density have slightly higher prediction accuracy than that by fixing density and enumerating radius. PMID- 27474165 TI - Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury. AB - Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1(+) macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP(+) fibrogenic cells. Stabilin-1(-/-) macrophages demonstrated a proinflammatory phenotype during liver injury and the normal induction of Ly6C(lo) monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1(+) monocytes efficiently internalized MDA-LDL and this suppressed their ability to secrete CCL3, suggesting that loss of stabilin-1 removes a brake to CCL3 secretion. Experiments with cell-lineage-specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a previously unidentified regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus, stabilin-1(+) macrophages shape the tissue microenvironment during liver injury and healing. PMID- 27474166 TI - Antigen-presenting cell-derived IL-6 restricts the expression of GATA3 and IL-4 by follicular helper T cells. AB - Follicular helper T cells (Tfh) support high-affinity Ab production by germinal center B cells through both membrane interactions and secretion of IL-4 and -21, two major cytokines implicated in B-cell survival and Ab class switch. Tfh-2 cells recently emerged in humans as a strong IL-4 producer Tfh cell subset implicated in both autoimmune and allergic diseases. Although the molecular mechanisms governing Tfh cell differentiation from naive T cells have been widely described, much less is known about the regulation of cytokine secretion by mouse Tfh-2 cells. The purpose of our study was to evaluate the role of dendritic cell derived IL-6 in fine-tuning cytokine secretion by Tfh cells. Our results demonstrate that priming of Th cells by IL-6-deficient antigen-presenting dendritic cells preferentially leads to accumulation of a subset of Tfh cells characterized by high expression of GATA3 and IL-4, associated with reduced production of IL-21. STAT3-deficient Tfh cells also overexpress GATA3, suggesting that early IL-6/STAT3 signaling during Tfh cell development inhibits the expression of a set of genes associated with the Th2 differentiation program. Overall, our data indicate that IL-6/STAT3 signaling restrains the expression of Th2-like genes in Tfh cells, thus contributing to the control of IgE secretion in vivo. PMID- 27474167 TI - Negative to positive lymph node ratio is a superior predictor than traditional lymph node status in stage III colorectal cancer. AB - Negative lymph node counts has recently attracted attention as a prognostic indicator in colorectal cancer (CRC). But little is known about prognostic significance of negative to positive lymph node ratio (NPR) in CRC. Our aim was to determine impact of NPR on oncological outcomes in patients with stage III CRC. This retrospective study included 2,256 patients with stage III CRC under curative resection at Fudan university Shanghai cancer center. Kaplan-Meier methods and multivariable Cox regression models were built for the analysis of survival outcomes and risk factors. Accuracy of the NPR was assessed with the Harrell's concordance-index(C-index).X-tile program identified 2.38 or 0.55/2.38 as the optimal cutoff value for NPR to divide the cohort into high/low risk or high/middle/low risk subsets in terms of CRC cause specific survival (CCSS). In a multivariate analysis, NPR was significant independent prognostic factors for CCSS (P<0.05), notably, N classification was not an independently prognostic factor (P>0.05).Further analysis found NPR could give detailed prognostic classification for both N1 and N2 stage (P<0.05). Interestingly, patients in N2+ NPR >2.38 stage have similar survival outcome with N1+ NPR >2.38 stage (chi2=0.030, P=0.863), and better than those at N1+ NPR <=2.38 and N2+ NPR <=2.38 stage (P<0.001). The TNNPRM stage was more accurate for predicting CCSS (C-index = 0.659) than current TNM stage system(C-index = 0.628) (P<0.001). Collectively, NPR was an independent prognostic factor for stage III CRC patients, it could provide more accurate prognostic information than the current node stage system. PMID- 27474168 TI - Dihydromyricetin promotes autophagy and apoptosis through ROS-STAT3 signaling in head and neck squamous cell carcinoma. AB - Chemotherapy is an effective weapon in the battle against cancer, but numerous cancer patients are either not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, an effective chemotherapy mechanism that enhances tumor sensitivity to chemotherapeutics is urgently needed. The aim of the present study was to determine the antitumor activity of dihydromyricetin (DHM) on head and neck squamous cell carcinoma (HNSCC) and its underlying mechanisms. We demonstrated that DHM can markedly induce apoptotic cell death and autophagy in HNSCC cells. Meanwhile, increased autophagy inhibited apoptosis. Pharmacological or genetic inhibition of autophagy further sensitized the HNSCC cells to DHM-induced apoptosis. Mechanistic analysis showed that the antitumor of DHM may be due to the activation phosphorylation of signal transducer and activator of transcription 3 (p-STAT3), which contributed to autophagy. Importantly, DHM triggered reactive oxygen species (ROS) generation in the HNSCC cells and the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger. Moreover, NAC abrogated the effects of DHM on STAT3-dependent autophagy. Overall, the following critical issues were observed: first, DHM increased the p-STAT3-dependent autophagy by generating ROS-signaling pathways in head and neck squamous cell carcinoma. Second, inhibiting autophagy could enhance DHM-induced apoptosis in head and neck squamous cell carcinoma. PMID- 27474169 TI - MiRSEA: Discovering the pathways regulated by dysfunctional MicroRNAs. AB - Recent studies have shown that dysfunctional microRNAs (miRNAs) are involved in the progression of various cancers. Dysfunctional miRNAs may jointly regulate their target genes and further alter the activities of canonical biological pathways. Identification of the pathways regulated by a group of dysfunctional miRNAs could help uncover the pathogenic mechanisms of cancer and facilitate development of new drug targets. Current miRNA-pathway analyses mainly use differentially-expressed miRNAs to predict the shared pathways on which they act. However, these methods fail to consider the level of differential expression level, which could improve our understanding of miRNA function. We propose a novel computational method, MicroRNA Set Enrichment Analysis (MiRSEA), to identify the pathways regulated by dysfunctional miRNAs. MiRSEA integrates the differential expression levels of miRNAs with the strength of miRNA pathway associations to perform direct enrichment analysis using miRNA expression data. We describe the MiRSEA methodology and illustrate its effectiveness through analysis of data from hepatocellular cancer, gastric cancer and lung cancer. With these analyses, we show that MiRSEA can successfully detect latent biological pathways regulated by dysfunctional miRNAs. We have implemented MiRSEA as a freely available R-based package on CRAN (https://cran.r project.org/web/packages/MiRSEA/). PMID- 27474170 TI - Metformin increases PDH and suppresses HIF-1alpha under hypoxic conditions and induces cell death in oral squamous cell carcinoma. AB - BACKGROUND: Metformin is a biguanide, belonging to the oral hypoglycemic agents and is a widely used in the treatment of type 2 diabetes. Evidence indicate that Metformin inhibits cell proliferation in several human cancers and inhibits the Warburg phenomenon in tumor cells. RESULTS: Low PDH levels were observed in OSCC, and Metformin promotes an increase in PDH levels in hypoxic conditions. Metformin also reduced HIF-1alpha mRNA and protein levels. Metformin demonstrated antiproliferative effects, inhibited migration, increased the number of apoptotic cells and increased the transcription of caspase 3. OBJECTIVE: The present study aims to explore the effects of Metformin in hypoxic conditions. Specifically, we focused on pyruvate dehydrogenase (PDH), (hypoxia-inducible factor 1alpha) HIF 1alpha levels and the oral squamous cell carcinoma (OSCC) cell phenotype. Additionally, we also investigated a theoretical consequence of Metformin treatment. METHODS: PDH levels in patients with OSCC and oral dysplasia were evaluated. Metformin was administered in vitro to test the effect of Metformin under hypoxic conditions. The results were complemented by Bioinformatics analyses. CONCLUSIONS: In conclusion, our current findings show that Metformin reduces HIF-1alpha gene expression and increases PDH expression. Metformin inhibits cell proliferation and migration in the OSCC cell line model. Additionally, Metformin enhances the number of apoptotic cells and caspase 3 levels. Interestingly enough, Metformin did not increase the mutant p53 levels under hypoxic conditions. PMID- 27474172 TI - Clonal evolution of acute myeloid leukemia highlighted by latest genome sequencing studies. AB - Decades of years might be required for an initiated cell to become a fully pledged, metastasized tumor. DNA mutations are accumulated during this process including background mutations that emerge scholastically, as well as driver mutations that selectively occur in a handful of cancer genes and confer the cell a growth advantage over its neighbors. A clone of tumor cells could be superseded by another clone that acquires new mutations and grows more aggressively. Tumor evolutional patterns have been studied for years using conventional approaches that focus on the investigation of a single or a couple of genes. Latest deep sequencing technology enables a global view of tumor evolution by deciphering almost all genome aberrations in a tumor. Tumor clones and the fate of each clone during tumor evolution can be depicted with the help of the concept of variant allele frequency. Here, we summarize the new insights of cancer evolutional progression in acute myeloid leukemia. Cancer evolution is currently thought to start from a clone that has accumulated the requisite somatically-acquired genetic aberrations through a series of increasingly disordered clinical and pathological phases, eventually leading to malignant transformation [1-3]. The observations in invasive colorectal cancer that usually emerges from an antecedent benign adenomatous polyp and in cervical cancer that proceeds through intraepithelial neoplasia support the idea of stepwise or linear cancerous progression [3-5]. Genetically, such progression is achieved by successive waves of clonal expansion during which cells acquire novel genomic alterations including single nucleotide variants (SNVs), small insertions and deletions (indels), and/or copy number variations (CNVs) [6]. The latest improvement in sequencing technology has allowed the deciphering of the whole exome or genome in different types of tumor and normal tissue pairs, providing detailed catalogue about genome aberrations during tumor initiation and progression, which have been reviewed in several papers [7-10]. Here, we focus on demonstrating the cancer clonal evolution pattern revealed by recent deep sequencing studies of samples from acute myeloid leukemia (AML) patients. PMID- 27474171 TI - Microenvironment drug resistance in multiple myeloma: emerging new players. AB - Multiple myeloma (MM) drug resistance (DR) is a multistep transformation process based on a powerful interplay between bone marrow stromal cells and MM cells that allows the latter to escape anti-myeloma therapies. Here we present an overview of the role of the bone marrow microenvironment in both soluble factors-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR), focusing on the role of new players, namely miRNAs, exosomes and cancer associated fibroblasts. PMID- 27474174 TI - Current status of parasitic ciliates Chilodonella spp. (Phyllopharyngea: Chilodonellidae) in freshwater fish aquaculture. AB - Freshwater fish farming contributes to more than two-thirds of global aquaculture production. Parasitic ciliates are one of the largest causes of production loss in freshwater farmed fishes, with species from the genus Chilodonella being particularly problematic. While Chilodonella spp. include 'free-living' fauna, some species are involved in mortality events of fish, particularly in high density aquaculture. Indeed, chilodonellosis causes major productivity losses in over 16 species of farmed freshwater fishes in more than 14 countries. Traditionally, Chilodonella species are identified based on morphological features; however, the genus comprises yet uncharacterized cryptic species, which indicates the necessity for molecular diagnostic methods. This review synthesizes current knowledge on the biology, ecology and geographic distribution of harmful Chilodonella spp. and examines pathological signs, diagnostic methods and treatments. Recent advances in molecular diagnostics and the ability to culture Chilodonella spp. in vitro will enable the development of preventative management practices and sustained freshwater fish aquaculture production. PMID- 27474173 TI - Triple negative breast cancer: shedding light onto the role of pi3k/akt/mtor pathway. AB - Breast cancer is one of the most widespread carcinoma and one of the main causes of cancer-related death worldwide, especially in women aged between 35 and 75 years. Among the different subtypes, triple negative breast cancer (TNBC) is characterized by the total absence of the estrogen-receptor (ER) and progesteron receptor (PR) expression as well as the lack of human epidermal growth factor receptor 2 (HER2) overexpression or gene amplification. These biological characteristics confer to TNBC a higher aggressiveness and relapse risk along with poorer prognosis compared to other subtypes. Indeed, 5-years survival rate is still low and almost all patients die, despite any adjuvant treatment which at moment represents the heading pharmacological approach. To date, several clinical trials have been designed to investigate the potential role of some molecular markers, such as VEGF, EGFR, Src and mTOR, for targeted treatments in TNBC. In fact, many inhibitors of the PI3K/AKT/mTOR pathway, frequently de-regulated in TNBC, are acquiring a growing interest and several inhibitors are in preclinical development or already in early phase clinical trials. In this Review, we investigated the role of the PI3K/AKT/mTOR pathway in TNBC patients, by summarizing the molecular features that led to the distinction of different histotypes of TNBC. Furthermore, we provided an overview of the inhibition mechanisms of the mTOR and PI3K/AKT signaling pathways, highlighting the importance of integrating biological and clinical data for the development of mTOR inhibitors in order to implement targeted therapies for TNBC patients. PMID- 27474175 TI - Featured Article: Nanoenhanced matrix metalloproteinase-responsive delivery vehicles for disease resolution and imaging. AB - The wide array of proteases, including matrix metalloproteinases, produced in response to many pathogenic insults, confers a unique proteolytic signature which is often disease specific and provides a potential therapeutic target for drug delivery. Here we propose the use of collagen-based nanoenhanced matrix metalloproteinase-responsive delivery vehicles that display matrix metalloproteinase-specific degradation in diverse in vitro models of proteolysis. We demonstrate that collagen particles comprised of protease substrates (primarily collagen) can be made of uniform size and loaded efficiently with assorted cargo including fluorescently labeled mesoporous silica, magnetic nanoparticles, proteins and antioxidants. We also demonstrate that pathologic concentrations of proteases produced in situ or in vitro display protease specific cargo release. Additionally, we show that the collagen-based particles display bright fluorescence when loaded with a fluorophore, and have the potential to be used as vehicles for targeted delivery of drugs or imaging agents to regions of high proteolytic activity. PMID- 27474176 TI - A posterior mediastinal mass is not always what it seems. PMID- 27474177 TI - In pregnancy, aortic tissue is the issue. PMID- 27474179 TI - The butterfly effect: From Seldinger technique to endovascular arch repair. PMID- 27474178 TI - Hypertrophic cardiomyopathy: New approaches and a time to reappraise older approaches. PMID- 27474181 TI - A choice-semantical approach to theoretical truth. AB - A central topic in the logic of science concerns the proper semantic analysis of theoretical sentences, that is sentences containing theoretical terms. In this paper, we present a novel choice-semantical account of theoretical truth based on the epsilon-term definition of theoretical terms. Specifically, we develop two ways of specifying the truth conditions of theoretical statements in a choice functional semantics, each giving rise to a corresponding logic of such statements. In order to investigate the inferential strength of these logical systems, we provide a translation of each truth definition into a modal definition of theoretical truth. Based on this, we show that the stronger notion of choice-semantical truth captures more adequately our informal semantic understanding of scientific statements. PMID- 27474180 TI - Clinical feasibility of interstitial brachytherapy using a "hybrid" applicator combining uterine tandem and interstitial metal needles based on CT for locally advanced cervical cancer. AB - PURPOSE: To explore the dosimetric advantage of target volume and surrounding normal tissue by using interstitial (IS) brachytherapy (BT) based on three dimensional CT in locally advanced cervical cancer, as a simple and effective clinical treatment approach. METHODS AND MATERIALS: Fifty-two patients with poor tumor response to external beam radiotherapy and a residual tumor >5 cm at the time of the first BT were included. IS BT was performed using a "hybrid" applicator combining uterine tandem and free metal needles based on three dimensional CT. The high-risk clinical target volume (HR-CTV), intermediate-risk clinical target volume, and organs at risk were contoured. The total dose, including external beam radiotherapy (45 Gy in 25 fractions) and high-dose-rate BT (30 Gy in 5 fractions), was biologically normalized to conventional 2-Gy fractions. D90 and D100 for HR-CTV and intermediate-risk clinical target volume and D2cc for the bladder, rectum, and sigmoid were analyzed. RESULTS: The mean D90 value for HR-CTV was 88.4 +/- 3.5 Gy. Totally, 88.5% of the patients received D90 for HR-CTV >=87 Gy. The D2cc for the bladder, rectum, and sigmoid were 81.1 +/- 5.6, 65.7 +/- 5.1, and 63.1 +/- 5.4 Gy, respectively. The mean number of needles was 6.9 +/- 1.3 for each application. IS BT was associated with minor complications. CONCLUSION: IS BT using the "hybrid" applicator provides a dosimetric advantage for target volume and organs at risk in large-volume (>5 cm) tumors and is, thereby, clinically feasible. However, the long-term curative effect and possible toxicity need further clinical observation. PMID- 27474182 TI - Hermann Cohen's Das Princip der Infinitesimal-Methode: The history of an unsuccessful book. AB - This paper offers an introduction to Hermann Cohen's Das Princip der Infinitesimal-Methode (1883), and recounts the history of its controversial reception by Cohen's early sympathizers, who would become the so-called 'Marburg school' of Neo-Kantianism, as well as the reactions it provoked outside this group. By dissecting the ambiguous attitudes of the best-known representatives of the school (Paul Natorp and Ernst Cassirer), as well as those of several minor figures (August Stadler, Kurd Lasswitz, Dimitry Gawronsky, etc.), this paper shows that Das Princip der Infinitesimal-Methode is a unicum in the history of philosophy: it represents a strange case of an unsuccessful book's enduring influence. The "puzzle of Cohen's Infinitesimalmethode," as we will call it, can be solved by looking beyond the scholarly results of the book, and instead focusing on the style of philosophy it exemplified. Moreover, the paper shows that Cohen never supported, but instead explicitly opposed, the doctrine of the centrality of the 'concept of function', with which Marburg Neo-Kantianism is usually associated. PMID- 27474183 TI - Taming theory with thought experiments: Understanding and scientific progress. AB - I claim that one way thought experiments contribute to scientific progress is by increasing scientific understanding. Understanding does not have a currently accepted characterization in the philosophical literature, but I argue that we already have ways to test for it. For instance, current pedagogical practice often requires that students demonstrate being in either or both of the following two states: 1) Having grasped the meaning of some relevant theory, concept, law or model, 2) Being able to apply that theory, concept, law or model fruitfully to new instances. Three thought experiments are presented which have been important historically in helping us pass these tests, and two others that cause us to fail. Then I use this operationalization of understanding to clarify the relationships between scientific thought experiments, the understanding they produce, and the progress they enable. I conclude that while no specific instance of understanding (thus conceived) is necessary for scientific progress, understanding in general is. PMID- 27474184 TI - The experimenters' regress reconsidered: Replication, tacit knowledge, and the dynamics of knowledge generation. AB - This paper revisits the debate between Harry Collins and Allan Franklin, concerning the experimenters' regress. Focusing my attention on a case study from recent psychology (regarding experimental evidence for the existence of a Mozart Effect), I argue that Franklin is right to highlight the role of epistemological strategies in scientific practice, but that his account does not sufficiently appreciate Collins's point about the importance of tacit knowledge in experimental practice. In turn, Collins rightly highlights the epistemic uncertainty (and skepticism) surrounding much experimental research. However, I will argue that his analysis of tacit knowledge fails to elucidate the reasons why scientists often are (and should be) skeptical of other researchers' experimental results. I will present an analysis of tacit knowledge in experimental research that not only answers to this desideratum, but also shows how such skepticism can in fact be a vital enabling factor for the dynamic processes of experimental knowledge generation. PMID- 27474185 TI - Introduction: Kant and the empirical sciences. PMID- 27474186 TI - Analogical reflection as a source for the science of life: Kant and the possibility of the biological sciences. AB - In contrast to the previously widespread view that Kant's work was largely in dialogue with the physical sciences, recent scholarship has highlighted Kant's interest in and contributions to the life sciences. Scholars are now investigating the extent to which Kant appealed to and incorporated insights from the life sciences and considering the ways he may have contributed to a new conception of living beings. The scholarship remains, however, divided in its interest: historians of science are concerned with the content of Kant's claims, and the ways in which they may or may not have contributed to the emerging science of life, while historians of philosophy focus on the systematic justifications for Kant's claims, e.g., the methodological and theoretical underpinnings of Kant's statement that living beings are mechanically inexplicable. My aim in this paper is to bring together these two strands of scholarship into dialogue by showing how Kant's methodological concerns (specifically, his notion of reflective judgment) contributed to his conception of living beings and to the ontological concern with life as a distinctive object of study. I argue that although Kant's explicit statement was that biology could not be a science, his implicit and more fundamental claim was that the study of living beings necessitates a distinctive mode of thought, a mode that is essentially analogical. I consider the implications of this view, and argue that it is by developing a new methodology for grasping organized beings that Kant makes his most important contribution to the new science of life. PMID- 27474188 TI - Kant on anatomy and the status of the life sciences. AB - This paper contributes to recent interest in Kant's engagement with the life sciences by focusing on one corner of those sciences that has received comparatively little attention: physical and comparative anatomy. By attending to remarks spread across Kant's writings, we gain some insight into Kant's understanding of the disciplinary limitations but also the methodological sophistication of the study of anatomy and physiology. Insofar as Kant highlights anatomy as a paradigmatic science guided by the principle of teleology in the Critique of the Power of Judgment, a more careful study of Kant's discussions of anatomy promises to illuminate some of the obscurities of that text and of his understanding of the life sciences more generally. In the end, it is argued, Kant's ambivalence with regard to anatomy gives way to a pessimistic conclusion about the possibility that anatomy, natural history, and, by extension, the life sciences more generally might one day become true natural sciences. PMID- 27474187 TI - Natural history and the formation of the human being: Kant on active forces. AB - In his 1785-review of the Ideen zur Philosophie der Geschichte der Menschheit, Kant objects to Herder's conception of nature as being imbued with active forces. This attack is usually evaluated against the background of Kant's critical project and his epistemological concern to caution against the "metaphysical excess" of attributing immanent properties to matter. In this paper I explore a slightly different reading by investigating Kant's pre-critical account of creation and generation. The aim of this is to show that Kant's struggle with the forces of matter has a long history and revolves around one central problem: that of how to distinguish between the non-purposive forces of nature and the intentional powers of the mind. Given this history, the epistemic stricture that Kant's critical project imposes on him no longer appears to be the primary reason for his attack on Herder. It merely aggravates a problem that Kant has been battling with since his earliest writings. PMID- 27474189 TI - Epigenesis in Kant: Recent reconsiderations. AB - Epigenesis has become a far more exciting issue in Kant studies recently, especially with the publication of Jennifer Mensch's Kant' Organicism. In my commentary, I propose to clarify my own position on epigenesis relative to that of Mensch and others by once again considering the discourse of epigenesis in the wider eighteenth century. Historically, I maintain that Kant was never fully an epigenesist because he feared its materialist implications. This makes it highly unlikely that he drew heavily, as other interpreters like Dupont and Huneman have suggested, on Caspar Friedrich Wolff for his ultimate theory of "generic preformation." In order to situate more precisely what Kant made of epigenesis, I distinguish his metaphysical use, as elaborated by Mensch, from his view of it as a theory for life science. In that light, I raise questions about the scope and authority of philosophy vis a vis natural science. PMID- 27474190 TI - The metaphor of epigenesis: Kant, Blumenbach and Herder. AB - Over the last few decades, the meaning of the scientific theory of epigenesis and its significance for Kant's critical philosophy have become increasingly central questions. Most recently, scholars have argued that epigenesis is a key factor in the development of Kant's understanding of reason as self-grounding and self generating. Building on this work, our claim is that Kant appealed to not just any epigenetic theory, but specifically Johann Friedrich Blumenbach's account of generation, and that this appeal must be understood not only in terms of self organization, but also in terms of the demarcation of a specific domain of inquiry: for Blumenbach, the study of life; for Kant, the study of reason. We argue that Kant adopted this specific epigenetic model as a result of his dispute with Herder regarding the independence of reason from nature. Blumenbach's conception of epigenesis and his separation of a domain of the living from the non-living lent Kant the tools to demarcate metaphysics, and to guard reason against Herder's attempts to naturalize it. PMID- 27474191 TI - Kant and the nature of matter: Mechanics, chemistry, and the life sciences. AB - Kant believed that the ultimate processes that regulate the behavior of material bodies can be characterized exclusively in terms of mechanics. In 1790, turning his attention to the life sciences, he raised a potential problem for his mechanically-based account, namely that many of the operations described in the life sciences seemed to operate teleologically. He argued that the life sciences do indeed require us to think in teleological terms, but that this is a fact about us, not about the processes themselves. Nevertheless, even were we to concede his account of the life sciences, this would not secure the credentials of mechanics as a general theory of matter. Hardly any material properties studied in the second half of the eighteenth century were, or could have been, conceived in mechanical terms. Kant's concern with teleology is tangential to the problems facing a general matter theory grounded in mechanics, for the most pressing issues have nothing to do with teleology. They derive rather from a lack of any connection between mechanical forces and material properties. This is evident in chemistry, which Kant dismisses as being unscientific on the grounds that it cannot be formulated in mechanical terms. PMID- 27474192 TI - Daytime Exposure to Short- and Medium-Wavelength Light Did Not Improve Alertness and Neurobehavioral Performance. AB - While previous studies have demonstrated short-wavelength sensitivity to the acute alerting effects of light during the biological night, fewer studies have assessed the alerting effect of light during the daytime. This study assessed the wavelength-dependent sensitivity of the acute alerting effects of daytime light exposure following chronic sleep restriction in 60 young adults (29 men, 31 women; 22.5 +/- 3.1 mean +/- SD years). Participants were restricted to 5 h time in bed the night before laboratory admission and 3 h time in bed in the laboratory, aligned by wake time. Participants were randomized for exposure to 3 h total of either narrowband blue (lambdamax 458-480 nm, n = 23) or green light (lambdamax 551-555 nm, n = 25) of equal photon densities (2.8-8.4 * 10(13) photons/cm(2)/sec), beginning 3.25 h after waking, and compared with a darkness control (0 lux, n = 12). Subjective sleepiness (Karolinska Sleepiness Scale), sustained attention (auditory Psychomotor Vigilance Task), mood (Profile of Mood States Bi-Polar form), working memory (2-back task), selective attention (Stroop task), and polysomnographic and ocular sleepiness measures (Optalert) were assessed prior to, during, and after light exposure. We found no significant effect of light wavelength on these measures, with the exception of a single mood subscale. Further research is needed to optimize the characteristics of lighting systems to induce alerting effects during the daytime, taking into account potential interactions between homeostatic sleep pressure, circadian phase, and light responsiveness. PMID- 27474193 TI - Bilateral presumed macular retinitis secondary to Rickettsial infection in south India. PMID- 27474194 TI - Can a virtual supermarket bring realism into the lab? Comparing shopping behavior using virtual and pictorial store representations to behavior in a physical store. AB - Immersive virtual reality techniques present new opportunities for research into consumer behavior. The current study examines whether the increased realism of a virtual store compared to pictorial (2D) stimuli elicits consumer behavior that is more in line with behavior in a physical store. We examine the number, variety, and type of products selected, amount of money spent, and responses to price promotions and shelf display, in three product categories (fruit & vegetables, milk, and biscuits). We find that virtual reality elicits behavior that is more similar to behavior in the physical store compared to the picture condition for the number of products selected (Milk: Mstore = 1.19, Mvirtual = 1.53, Mpictures = 2.58) and amount of money spent (Milk: Mstore = 1.27, Mvirtual = 1.53, Mpictures = 2.60 Euro), and for the selection of products from different areas of the shelf, both vertically (purchases from top shelves, milk and biscuits: Pstore = 21.6%, Pvirtual = 33.4%, Ppictures = 50.0%) and horizontally (purchase from left shelf, biscuits: Pstore = 35.5%, Pvirtual = 53.3%, Ppictures = 66.7%). This indicates that virtual reality can improve realism in responses to shelf allocation. Virtual reality was not able to diminish other differences between lab and physical store: participants bought more products and spent more money (for biscuits and fruit & vegetables), bought more national brands, and responded more strongly to price promotions in both virtual reality and pictorial representations than in the physical store. Implications for the use of virtual reality in studies of consumer food choice behavior as well as for future improvement of virtual reality techniques are discussed. PMID- 27474196 TI - Hypoglycaemia revealing heterozygous insulin receptor mutations. PMID- 27474195 TI - Hemoglobin A1c Testing and Amputation Rates in Black, Hispanic, and White Medicare Patients. AB - BACKGROUND: Major (above-knee or below-knee) amputation is a complication of diabetes and is seen more common among black and Hispanic patients. While amputation rates have declined for patients with diabetes in the last decade, it remains unknown if these improvements have equitably extended across racial groups and if measures of diabetic care, such as hemoglobin A1c testing, are associated with these improvements. We set out to characterize secular changes in amputation rates among black, Hispanic, and white patients, and to determine associations between hemoglobin A1c testing and amputation risk. METHODS: We identified 11,942,840 Medicare patients (55% female) with diabetes over the age of 65 years between 2002 and 2012 and followed them for a mean of 6.6 years. Of these, 86% were white, 11.5% were black, and 2.5% were Hispanic. We recorded the occurrence of major amputation and hemoglobin A1c testing during this time period and studied secular changes in amputation rate by race (black, Hispanic, and white). Finally, we examined associations between amputation risk and hemoglobin A1c testing. We measured both the presence of any testing and testing consistency using 3 categories: poor consistency (hemoglobin A1c testing in 0-50% of years), medium consistency (testing in 50-90% of years), and high consistency (testing in >90% of the years in the cohort). RESULTS: Between 2002 and 2012, the average major lower-extremity amputation rate in diabetic Medicare patients was 1.78 per 1,000 per year for black patients, 1.15 per 1,000 per year for Hispanic patients, and 0.56 per 1,000 per year for white patients (P < 0.001). Over the study period, the incidence of major amputation in Medicare patients with diabetes declined by 54%, from 1.15 per 1,000 in 2002 to 0.53 per 1,000 in 2012 (rate ratio = 0.53, 95% CI = 0.51-0.54). The reduction in amputation rate was similar across racial groups: 52% for black patients, 61% for Hispanic patients, and 55% for white patients. In multivariable analysis adjusting for patient characteristics, including race, any use of hemoglobin A1c testing was associated with a 15% decline in amputation risk (hazard ratio, 0.85; 95% CI, 0.83-0.87; P < 0.001). High consistency hemoglobin A1c testing was associated with a 39% decline in amputation (hazard ratio, 0.61; 95% CI, 0.59-0.62; P < 0.0001). CONCLUSIONS: Although more frequent among racial minorities, major lower-extremity amputation rates have declined similarly across black, Hispanic, and white patients over the last decade. Hemoglobin A1c testing, particularly the consistency of testing over time, may be an effective component metric of longitudinal quality measures toward limiting amputation in all races. PMID- 27474197 TI - Collagenous colitis and Crohn's disease: Guilty or innocent bystander? PMID- 27474198 TI - Patient satisfaction in the management of mild-to-moderate ulcerative colitis: Results of a Delphi study among patients and physicians. AB - GOALS: To determine factors contributing to satisfaction with treatment in mild to-moderate ulcerative colitis (UC) from both the patients and the physicians perspectives. BACKGROUND: Despite the impact of UC on different aspects of daily life, patient's and physician's satisfaction with clinical management has been poorly evaluated. STUDY: A Delphi study involving 22 patients and 20 clinicians was conducted. The patient's questionnaire included 285 items regarding diagnosis, treatment, and follow-up, whereas the physician's questionnaire added 32 specific items for clinicians. Relevance of items was scored from 1 (not at all important) to 9 (very important). Recommendations were based on very highly rated items. RESULTS: Most items were rated consistently by patients and physicians with some exceptions. Patients emphasized the choice of moderate flare ups to be followed at the hospital setting rather than in primary care as well as to be informed on aspects, such as diet and impact of UC on their health and lifestyle. Treatment-related efficacy, safety, and improved quality of life were relevant for both patients and physicians. Physicians believed that to reduce pill burden was a crucial aspect to improve patient's satisfaction. Patients preferred oral administration treatment over rectal treatment. CONCLUSIONS: The study identified specific aspects related to the management of mild-to-moderate UC that both patients and physicians considered to be highly relevant for patient satisfaction. Recommendation based on these factors would be important at the time of designing and implementing strategies targeting satisfaction in UC patients. PMID- 27474199 TI - HCV novel therapeutic regimens in Wonderland: A budget impact analysis in the Lombardy Region. AB - BACKGROUND: The advent of new HCV drugs has generated widespread economic concerns, particularly within the Italian setting, characterized by continuous linear cuts and spending review actions. The overall trade-off between investments and savings needs an in depth analysis. AIMS: The study aimed to estimate the budget impact of the introduction of the novel drugs approved during the year 2015, compared with the historical situation based on the different treatment options available prior to 2015. METHODS: A three-year budget impact model was developed, taking into consideration the Lombardy Region (Northern Italy) Health Service perspective. The degree of liver fibrosis, genotypes, presence of only HCV or HIV/HCV co-infections, presence or absence of sustained virological response, and direct healthcare total costs were the variables of the model. RESULTS: With the introduction of the novel regimens, a higher number of HCV patients achieved a sustained virological response (+20%). Further analysis showed that an investment in innovative technologies would have given the Regional System significant economic savings within the 36-month period (-6.64%/ 7.15%). CONCLUSIONS: Treating HCV-infected persons in the Lombardy Region with the new drugs would reduce healthcare expenditure on this specific disease, in each forecast implemented, thus reducing the economic burden of the pathology. PMID- 27474200 TI - Effectiveness of Endoscopic Ultrasonography during Double Balloon Enteroscopy for characterization and management of small bowel submucosal tumours. AB - BACKGROUND: Characterization of small bowel submucosal tumours is challenging, requiring additional investigations. Endoscopic Ultrasonography performed during Double Balloon Enteroscopy, appeared a promising technique although it has not been fully evaluated. The aim was to determine the effectiveness of this technique for characterization and management of sub mucosal tumours in a large cohort of patients. METHODS: Patients with suspected small bowel tumours, who underwent Endoscopic Ultrasonography performed during Double Balloon Enteroscopy in our Institution between 2005 and 2013, were reviewed. Demographic data, clinical, endoscopic and radiological findings, therapeutic management, final diagnosis and follow-up were analyzed. RESULTS: 30 patients (19 male; median age 61.5) affected by submucosal tumours were included in the study. Endoscopic Ultrasonography performed during Double Balloon Enteroscopy was successfully performed in all cases providing a correct characterization of 19 submucosal tumours (63%). Based on the ultrasonographic characteristics 8 patients were treated endoscopically, 16 were referred to surgery, and 6 were managed conservatively. CONCLUSION: Our results suggest that Endoscopic Ultrasonography performed during Double Balloon Enteroscopy is a safe and useful technique for submucosal tumours characterization. This procedure may be applied in clinical practice when small bowel tumours are encountered, to confirm the diagnosis and provide the most appropriate management. PMID- 27474201 TI - An increase in serum tumour necrosis factor-alpha during anti-tumour necrosis factor-alpha therapy for Crohn's disease - A paradox or a predictive index? AB - BACKGROUND: Soluble tumour necrosis factor-alpha (sTNF-alpha) has been reported to increase in the course of anti-TNF-alpha therapy for rheumatoid and skin diseases. AIMS: To assess changes in sTNF-alpha and clinical efficacy of anti-TNF alpha agents in Crohn's disease (CD). METHODS: Sixty-four patients on infliximab or adalimumab were analyzed. Clinical outcomes were assessed by using CD Activity Index after the induction therapy and at week 52. sTNF-alpha was measured before and after the induction therapy with high-sensitivity immunoassay. RESULTS: In the majority of patients, sTNF-alpha increased significantly. Those with the greatest increase were more likely to experience long-term response, were more often treated with infliximab, had less frequently isolated small bowel CD, and tended to have sTNF-alpha levels at baseline that correlated with C-reactive protein. CONCLUSIONS: Neutralization of sTNF-alpha does not seem to be critical for the efficacy of anti-TNF-alpha therapy in CD. Paradoxically - an increase in sTNF-alpha may reflect an ongoing process that is beneficial for the clinical outcome. PMID- 27474202 TI - Understanding the role of dynamics in the iron sulfur cluster molecular machine. AB - BACKGROUND: The bacterial proteins IscS, IscU and CyaY, the bacterial orthologue of frataxin, play an essential role in the biological machine that assembles the prosthetic FeS cluster groups on proteins. They form functionally binary and ternary complexes both in vivo and in vitro. Yet, the mechanism by which they work remains unclear. METHODS: We carried out extensive molecular dynamics simulations to understand the nature of their interactions and the role of dynamics starting from the crystal structure of a IscS-IscU complex and the experimentally-based model of a ternary IscS-IscU-CyaY complex and used nuclear magnetic resonance to experimentally test the interface. RESULTS: We show that, while being firmly anchored to IscS, IscU has a pivotal motion around the interface. Our results also describe how the catalytic loop of IscS can flip conformation to allow FeS cluster assembly. This motion is hampered in the ternary complex explaining its inhibitory properties in cluster formation. CONCLUSIONS: We conclude that the observed 'fluid' IscS-IscU interface provides the binary complex with a functional adaptability exploited in partner recognition and unravels the molecular determinants of the reported inhibitory action of CyaY in the IscS-IscU-CyaY complex explained in terms of the hampering effect on specific IscU-IscS movements. GENERAL SIGNIFICANCE: Our study provides the first mechanistic basis to explain how the IscS-IscU complex selects its binding partners and supports the inhibitory role of CyaY in the ternary complex. PMID- 27474203 TI - JAK-mediated autophagy regulates stemness and cell survival in cisplatin resistant bladder cancer cells. AB - BACKGROUND: Autophagy is a critical process in acquiring drug resistance in solid tumors. However, the mechanisms by which autophagy modulate resistance to chemotherapy in bladder cancer remains poorly understood. MATERIAL AND METHODS: We have established cisplatin resistant patient derived primary cultured cells as well as T24 bladder cancer cells. The autophagy flux as well as the effect of chemotherapeutic agents, gemcitabine (GC) and mitomycin (MM) were evaluated in these cells. Side population analysis, tumorisphere assay and expression of stemness genes were also studied to evaluate the role of autophagy during chemoresistance. The role of cytokines in autophagy induced chemoresistance was demonstrated. RESULTS: Our results show that resistant cells have higher basal autophagic flux. GC and MM led to increase in autophagy and combination of autophagy inhibitors synergistically inhibited bladder cancer cell growth. When autophagy was inhibited, only IFN-gamma level was decreased in cytokine array. Blocking IFN-gamma decreased JAK2 expression and reduced the autophagy. Inhibition of JAK2 decreased the proportion of cancer stem cell enriched side population, tumor sphere forming ability and led to decrease in expression of stemness genes. Combined treatment with inhibitors of JAK2 and autophagy led to inhibition in cell growth, reduced the levels of inflammatory cytokines and decreased the resistance gene expression. CONCLUSION: GC and MM treatment increased autophagy process via IFN-gamma mediated JAK2 and STAT3 pathway. GENERAL SIGNIFICANCE: These findings support a key role of the autophagy in drug resistance. Thus, autophagy-based, "customized" combinatorial approaches may effectively manage resistance and relapse in bladder cancer. PMID- 27474204 TI - Hsp60, amateur chaperone in amyloid-beta fibrillogenesis. AB - BACKGROUND: Molecular chaperones are a very special class of proteins that play essential roles in many cellular processes like folding, targeting and transport of proteins. Moreover, recent evidence indicates that chaperones can act as potentially strong suppressor agents in Alzheimer's disease (AD). Indeed, in vitro experiments demonstrate that several chaperones are able to significantly slow down or suppress aggregation of Abeta peptide and in vivo studies reveal that treatment with specific chaperones or their overexpression can ameliorate some distinct pathological signs characterizing AD. METHODS: Here we investigate using a biophysical approach (fluorescence, circular dichroism (CD), transmission electron (TEM) and atomic force (AFM) microscopy, size exclusion chromatography (SEC)) the effect of the human chaperonin Hsp60 on Abeta fibrillogenesis. RESULTS: We found that Hsp60 powerfully inhibits Abeta amyloid aggregation, by closing molecular pathways leading to peptide fibrillogenesis. CONCLUSIONS: We observe that Hsp60 inhibits Abeta aggregation through a more complex mechanism than a simple folding chaperone action. The action is specifically directed toward the early oligomeric species behaving as aggregation seeds for on-pathway amyloid fibrillogenesis. GENERAL SIGNIFICANCE: Understanding the specificity of the molecular interactions of Hsp60 with amyloid Abeta peptide allowed us to emphasize the important aspects to be taken into consideration when considering the recent promising therapeutic strategies for neurodegeneration. PMID- 27474205 TI - Impact of early treatment programs on HIV epidemics: An immunity-based mathematical model. AB - While studies on pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) have demonstrated substantial advantages in controlling HIV transmission, the overall benefits of the programs with early initiation of antiretroviral therapy (ART) have not been fully understood and are still on debate. Here, we develop an immunity-based (CD4+ T cell count based) mathematical model to study the impacts of early treatment programs on HIV epidemics and the overall community-level immunity. The model is parametrized using the HIV prevalence data from South Africa and fully analyzed for stability of equilibria and infection persistence criteria. Using our model, we evaluate the effects of early treatment on the new infection transmission, disease death, basic reproduction number, HIV prevalence, and the community-level immunity. Our model predicts that the programs with early treatments significantly reduce the new infection transmission and increase the community-level immunity, but the treatments alone may not be enough to eliminate HIV epidemics. These findings, including the community-level immunity, might provide helpful information for proper implementation of HIV treatment programs. PMID- 27474207 TI - Pressure and wall shear stress in blood hammer - Analytical theory. AB - We describe an analytical theory of blood hammer in a long and stiffened artery due to sudden blockage. Based on the model of a viscous fluid in laminar flow, we derive explicit expressions of oscillatory pressure and wall shear stress. To examine the effects on local plaque formation we also allow the blood vessel radius to be slightly nonuniform. Without resorting to discrete computation, the asymptotic method of multiple scales is utilized to deal with the sharp contrast of time scales. The effects of plaque and blocking time on blood pressure and wall shear stress are studied. The theory is validated by comparison with existing water hammer experiments. PMID- 27474206 TI - Competition in the chemostat: A stochastic multi-species model and its asymptotic behavior. AB - In this paper, a stochastic chemostat model in which n-species compete for a single growth-limiting substrate is considered. We first prove that the stochastic model has an unique global positive solution by using the comparison theorem for stochastic differential equations. Then we show that when the noise intensities are small, the competition outcome in the chemostat is completely determined by the species' stochastic break-even concentrations: the species with the lowest stochastic break-even concentration survives and all other species will go to extinction in the chemostat. In other words, the competitive exclusion principle holds for stochastic competition chemostat model when the noise intensities are small. Moreover, we find that noise may change the destiny of the species. Numerical simulations illustrate the obtained results. PMID- 27474208 TI - On the dynamics of a generalized predator-prey system with Z-type control. AB - We apply the Z-control approach to a generalized predator-prey system and consider the specific case of indirect control of the prey population. We derive the associated Z-controlled model and investigate its properties from the point of view of the dynamical systems theory. The key role of the design parameter lambda for the successful application of the method is stressed and related to specific dynamical properties of the Z-controlled model. Critical values of the design parameter are also found, delimiting the lambda-range for the effectiveness of the Z-method. Analytical results are then numerically validated by the means of two ecological models: the classical Lotka-Volterra model and a model related to a case study of the wolf-wild boar dynamics in the Alta Murgia National Park. Investigations on these models also highlight how the Z-control method acts in respect to different dynamical regimes of the uncontrolled model. PMID- 27474209 TI - Viable control of an epidemiological model. AB - In mathematical epidemiology, epidemic control often aims at driving the number of infected humans to zero, asymptotically. However, during the transitory phase, the number of infected individuals can peak at high values. Can we limit the number of infected humans at the peak? This is the question we address. More precisely, we consider a controlled version of the Ross-Macdonald epidemiological dynamical model: proportions of infected individuals and proportions of infected mosquitoes (vector) are state variables, and vector mortality is the control variable. We say that a state is viable if there exists at least one admissible control trajectory - time-dependent mosquito mortality rates bounded by control capacity - such that, starting from this state, the resulting proportion of infected individuals remains below a given infection cap for all times. The so called viability kernel is the set of viable states. We obtain three different expressions of the viability kernel, depending on the couple control capacity infection cap. In the comfortable case, the infection cap is high, the viability kernel is maximal and all admissible control trajectories are viable. In the desperate case, both control capacity and infection cap are too low and the viability kernel is the zero equilibrium without infection. In the remaining viable case, the viability kernel is neither zero nor maximal and not all admissible control trajectories are viable. We provide a numerical application in the case of the dengue outbreak in 2013 in Cali, Colombia. PMID- 27474210 TI - Acoustic Cluster Therapy for better treatment of solid tumors. PMID- 27474211 TI - Epidemiological investigation of the first human brucellosis case in Spain due to Brucella suis biovar 1 strain 1330. AB - INTRODUCTION: No cases of human brucellosis caused by Brucella suis has been reported in Spain. METHODS: This study involved interviews with the case and his co-workers, inspection of their workplace, checking infection control measures, and typing the Brucella strain isolated in the blood culture. RESULTS: Brucella suis biovar 1 strain 1330 was isolated from a patient who worked in a waste treatment plant. Food borne transmission, contact with animals, and risk jobs were ruled out. An accidental inoculation with a contaminated needle from a research laboratory waste container was identified as the most probable mode of transmission. CONCLUSION: There should be controls to ensure that waste containers are sealed. PMID- 27474212 TI - Analysis of extrapulmonary tuberculosis in Spain: 2007-2012 National Study. AB - INTRODUCTION: This study sought to study the epidemiological characteristics of the extrapulmonary tuberculosis (EPTB) in relation to pulmonary tuberculosis (PTB) from 2007 to 2012 in Spain, and plot its trend across the same period. METHODS: We conducted an analytical cross-sectional study in which the following variables were analysed: age; sex; disease site; history of antituberculosis treatment; country of birth; presence of HIV infection; and culture results. Age related differences were ascertained using the test of comparison of proportions, and crude and adjusted ORs were calculated using linear regression models. RESULTS: Of the total of 44,050 cases of tuberculosis reported in the period 2007 2012 and included in the study, 31,508 (71.53%) were pulmonary tuberculosis and 12,542 (28.47%) were EPTB. EPTB rates decreased across all age groups. The main EPTB risk factor was presence of HIV infection (OR 1.39). Persons aged under 65 years had a lower risk of EPTB. CONCLUSIONS: Although persons aged over 65 years displayed the highest incidence, there was nevertheless a downward trend across all age groups. Whereas children showed a significant decrease in tuberculous meningitis, this was not so for all extrapulmonary forms. EPTB rates among persons born outside Spain were much higher than those among the Spanish population. PMID- 27474213 TI - The POWeR of looking into the black box. PMID- 27474214 TI - An internet-based intervention with brief nurse support to manage obesity in primary care (POWeR+): a pragmatic, parallel-group, randomised controlled trial. AB - BACKGROUND: The obesity epidemic has major public health consequences. Expert dietetic and behavioural counselling with intensive follow-up is effective, but resource requirements severely restrict widespread implementation in primary care, where most patients are managed. We aimed to estimate the effectiveness and cost-effectiveness of an internet-based behavioural intervention (POWeR+) combined with brief practice nurse support in primary care. METHODS: We did this pragmatic, parallel-group, randomised controlled trial at 56 primary care practices in central and south England. Eligible adults aged 18 years or older with a BMI of 30 kg/m(2) or more (or >=28 kg/m(2) with hypertension, hypercholesterolaemia, or diabetes) registered online with POWeR+-a 24 session, web-based, weight management intervention lasting 6 months. After registration, the website automatically randomly assigned patients (1:1:1), via computer generated random numbers, to receive evidence-based dietetic advice to swap foods for similar, but healthier, choices and increase fruit and vegetable intake, in addition to 6 monthly nurse follow-up (control group); web-based intervention and face-to-face nurse support (POWeR+Face-to-face [POWeR+F]; up to seven nurse contacts over 6 months); or web-based intervention and remote nurse support (POWeR+Remote [POWeR+R]; up to five emails or brief phone calls over 6 months). Participants and investigators were masked to group allocation at the point of randomisation; masking of participants was not possible after randomisation. The primary outcome was weight loss averaged over 12 months. We did a secondary analysis of weight to measure maintenance of 5% weight loss at months 6 and 12. We modelled the cost-effectiveness of each intervention. We did analysis by intention to treat, with multiple imputation for missing data. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN21244703. FINDINGS: Between Jan 30, 2013, and March 20, 2014, 818 participants were randomly assigned to the control group (n=279), the POWeR+F group (n=269), or the POWeR+R group (n=270). Weight loss averaged over 12 months was recorded in 666 (81%) participants. The control group lost almost 3 kg over 12 months (crude mean weight: baseline 104.38 kg [SD 21.11; n=279], 6 months 101.91 kg [19.35; n=136], 12 months 101.74 kg [19.57; n=227]). The primary imputed analysis showed that compared with the control group, patients in the POWeR+F group achieved an additional weight reduction of 1.5 kg (95% CI 0.6-2.4; p=0.001) averaged over 12 months, and patients in the POWeR+R group achieved an additional 1.3 kg (0.34-2.2; p=0.007). 21% of patients in the control group had maintained a clinically important 5% weight reduction at month 12, compared with 29% of patients in the POWeR+F group (risk ratio 1.56, 0.96-2.51; p=0.070) and 32% of patients in the POWeR+R group (1.82, 1.31-2.74; p=0.004). The incremental overall cost to the health service per kg weight lost with the POWeR+ interventions versus the control strategy was L18 (95% CI -129 to 195) for POWeR+F and -L25 (-268 to 157) for POWeR+R; the probability of being cost effective at a threshold of L100 per kg lost was 88% and 98%, respectively. No adverse events were reported. INTERPRETATION: Weight loss can be maintained in some individuals by use of novel written material with occasional brief nurse follow-up. However, more people can maintain clinically important weight reductions with a web-based behavioural program and brief remote follow-up, with no increase in health service costs. Future research should assess the extent to which clinically important weight loss can be maintained beyond 1 year. FUNDING: Health Technology Assessment Programme of the National Institute for Health Research. PMID- 27474215 TI - Splitting atoms: the Endocrine Society guideline for the management of primary aldosteronism. PMID- 27474216 TI - Monogenic autoimmune diseases of the endocrine system. AB - The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. PMID- 27474217 TI - Reply: ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability. PMID- 27474219 TI - Widespread changes in network activity allow non-invasive detection of mesial temporal lobe seizures. AB - Decades of experience with intracranial recordings in patients with epilepsy have demonstrated that seizures can occur in deep cortical regions such as the mesial temporal lobes without showing any obvious signs of seizure activity on scalp electroencephalogram. Predicated on the idea that these seizures are purely focal, currently, the only way to detect these 'scalp-negative seizures' is with intracranial recordings. However, intracranial recordings are only rarely performed in patients with epilepsy, and are almost never performed outside of the context of epilepsy. As such, little is known about scalp-negative seizures and their role in the natural history of epilepsy, their effect on cognitive function, and their association with other neurological diseases. Here, we developed a novel approach to non-invasively identify scalp-negative seizures arising from the mesial temporal lobe based on scalp electroencephalogram network connectivity measures. We identified 25 scalp-negative mesial temporal lobe seizures in 10 patients and obtained control records from an additional 13 patients, all of whom underwent recordings with foramen ovale electrodes and scalp electroencephalogram. Scalp data from these records were used to train a scalp-negative seizure detector, which consisted of a pair of logistic regression classifiers that used scalp electroencephalogram coherence properties as input features. On cross-validation performance, this detector correctly identified scalp-negative seizures in 40% of patients, and correctly identified the side of seizure onset for each seizure detected. In comparison, routine clinical interpretation of these scalp electroencephalograms failed to identify any of the scalp-negative seizures. Among the patients in whom the detector raised seizure alarms, 80% had scalp-negative mesial temporal lobe seizures. The detector had a false alarm rate of only 0.31 per day and a positive predictive value of 75%. Of the 13 control patients, false seizure alarms were raised in only one patient. The fact that our detector specifically recognizes focal mesial temporal lobe seizures based on scalp electroencephalogram coherence features, lends weight to the hypothesis that even focal seizures are a network phenomenon that involve widespread neural connectivity. Our scalp-negative seizure detector has clear clinical utility in patients with temporal lobe epilepsy, and its potential easily translates to other neurological disorders, such as Alzheimer's disease, in which occult mesial temporal lobe seizures are suspected to play a significant role. Importantly, our work establishes a novel approach of using computational approaches to non-invasively detect deep seizure activity, without the need for invasive intracranial recordings. PMID- 27474218 TI - ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability. PMID- 27474220 TI - Auto-antibodies to contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathy. AB - Auto-antibodies against the paranodal proteins neurofascin-155 and contactin-1 have recently been described in patients with chronic inflammatory demyelinating polyradiculoneuropathy and are associated with a distinct clinical phenotype and response to treatment. Contactin-associated protein 1 (Caspr, encoded by CNTNAP1) is a paranodal protein that is attached to neurofascin-155 and contactin-1 (CNTN1) but has not yet been identified as a sole antigen in patients with inflammatory neuropathies. In the present study, we screened a cohort of 35 patients with chronic inflammatory demyelinating polyradiculoneuropathy (age range 20-80, 10 female, 25 male) and 22 patients with Guillain-Barre syndrome (age range 17-86, eight female, 14 male) for autoantibodies against paranodal antigens. We identified two patients, one with chronic inflammatory demyelinating polyradiculoneuropathy and one with Guillain-Barre syndrome, with autoantibodies against Caspr by binding assays using Caspr transfected human embryonic kidney cells and murine teased fibres. IgG3 was the predominant autoantibody subclass in the patient with Guillain-Barre syndrome, IgG4 was predominant in the patient with chronic inflammatory demyelinating polyradiculoneuropathy. Accordingly, complement deposition after binding to HEK293 cells was detectable in the patient with IgG3 autoantibodies only, not in the patient with IgG4. Severe disruption of the paranodal and nodal architecture was detectable in teased fibres of the sural nerve biopsy and in dermal myelinated fibres, supporting the notion of the paranodes being the site of pathology. Deposition of IgG at the paranodes was detected in teased fibre preparations of the sural nerve, further supporting the pathogenicity of anti-Caspr autoantibodies. Pain was one of the predominant findings in both patients, possibly reflected by binding of patients' IgG to TRPV1 immunoreactive dorsal root ganglia neurons. Our results demonstrate that the paranodal protein Caspr constitutes a new antigen that leads to autoantibody generation as part of the novel entity of neuropathies associated with autoantibodies against paranodal proteins. PMID- 27474221 TI - Preparation of High-quality Hematoxylin and Eosin-stained Sections from Rodent Mammary Gland Whole Mounts for Histopathologic Review. AB - Identifying environmental exposures that cause adverse mammary gland outcomes in rodents is a first step in disease prevention in humans and domestic pets. "Whole mounts" are an easy and inexpensive tissue preparation method that can elucidate typical or abnormal mammary gland morphology in rodent studies. Here, we propose procedures to facilitate the use of whole mounts for histological identification of grossly noted tissue alterations. We noted lesions in mammary whole mounts from 14-month-old CD-1 mice that were not found in the contralateral gland hematoxylin and eosin (H&E)-stained section. Whole mounts were removed from the slide and carefully processed to produce high-quality histological sections that mirrored the quality of the original H&E-stained section in order to properly diagnose the unidentified gross abnormalities. Incorporation of this method into testing protocols that focus on human relevant chemical and endocrine disruptors exposure will increase the chances of identifying lesions in the gland and reduce the risk of false negative findings. This method can be especially invaluable when lesions are not always palpable during the course of the study or visible at necropsy, or when a single cross section of the mammary gland is otherwise used for detecting lesions. PMID- 27474222 TI - Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs administered new generation lipid emulsions. AB - We aimed to characterize the lipidomic, metabolomic, and transcriptomic profiles in preterm piglets administered enteral (ENT) formula or three parenteral lipid emulsions [parenteral nutrition (PN)], Intralipid (IL), Omegaven (OV), or SMOFlipid (SL), for 14 days. Piglets in all parenteral lipid groups showed differential organ growth versus ENT piglets; whole body growth rate was lowest in IL piglets, yet there were no differences in either energy expenditure or (13)C-palmitate oxidation. Plasma homeostatic model assessment of insulin resistance demonstrated insulin resistance in IL, but not OV or SL, compared with ENT. The fatty acid and acyl-CoA content of the liver, muscle, brain, and plasma fatty acids reflected the composition of the dietary lipids administered. Free carnitine and acylcarnitine (ACT) levels were markedly reduced in the PN groups compared with ENT piglets. Genes associated with oxidative stress and inflammation were increased, whereas those associated with alternative pathways of fatty acid oxidation were decreased in all PN groups. Our results show that new generation lipid emulsions directly enrich tissue fatty acids, especially in the brain, and lead to improved growth and insulin sensitivity compared with a soybean lipid emulsion. In all total PN groups, carnitine levels are limiting to the formation of ACTs and gene expression reflects the stress of excess lipid on liver function. PMID- 27474224 TI - Interaction between Bms1 and Rcl1, two ribosome biogenesis factors, is evolutionally conserved in zebrafish and human. PMID- 27474223 TI - The early years of lipoprotein research: from discovery to clinical application. AB - This review outlines major milestones in the first four decades of lipoprotein research beginning with their discovery nearly 90 years ago. It focuses on the contributions of some of the key investigators during this era, and findings that set the stage for widespread clinical implementation of lipoprotein testing for evaluation and management of CVD risk. PMID- 27474225 TI - Enriched endogenous n-3 polyunsaturated fatty acids alleviate cognitive and behavioral deficits in a mice model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accompanied by memory deficits and neuropsychiatric dysfunction. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have seemly therapeutic potential in AD, but the benefit of n-3 PUFAs is still in debates. Here, we employed a transgenic mice carry fat-1 gene to encode n-3 desaturase from Caenorhabditis elegans, which increase endogenous n-3 PUFAs by converting n-6 PUFAs to n-3 PUFAs crossed with amyloid precursor protein (APP) Tg mice to evaluate the protective effects of endogenous n-3 PUFAs on cognitive and behavioral deficits of APP Tg mice. We fed APP, APP/fat-1 and fat-1 mice with n-6 PUFAs rich diet. Brain tissues were collected at 3, 9 and 12 months for fatty acid and gene expression analysis, histology and protein assays. Morris Water Maze Test, open field test and elevated plus maze test were performed to measure the behavior capability. From the results, the expression of fat-1 transgene increased cortical n-3: n-6 PUFAs ratio and n-3 PUFAs concentrations, and sensorimotor dysfunction and cognitive deficits in AD were significantly less severe in APP/fat-1 mice with endogenous n 3 PUFAs than in APP mice controls. The protection against disturbance of spontaneous motor activity and cognitive deficits in AD was strongly correlated with increased n-3: n-6 PUFAs ratio and endogenous n-3 PUFAs, reduced APP generation, inhibited amyloid beta peptide aggregation, suppressed nuclear factor kappa B and astroglia activation, and reduced death of neurons in the cortex of APP/fat-1 mice compared with APP mice controls. In conclusion, our study demonstrates that an available medication with the maintenance of enriched n-3 PUFAs in the brain could slow down cognitive decline and prevent neuropsychological disorder in AD. PMID- 27474227 TI - A novel nuclear factor erythroid 2-related factor 2 (Nrf2) activator RS9 attenuates brain injury after ischemia reperfusion in mice. AB - Recanalization of occluded vessels leads to ischemia-reperfusion injury (IRI), with oxidative stress as one of the main causes of injury, despite the fact that recanalization therapy is the most effective treatment for ischemic stroke. The nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the transcription factors which has an essential role in protection against oxidative stress. RS9 is a novel Nrf2 activator obtained from bardoxolone methyl (BARD), an Nrf2 activator that has already been tested in a clinical trial, using a biotransformation technique. RS9 has been reported to lead to higher Nrf2 activation and less cytotoxicity than BARD. In this study, we investigated the effects of RS9 on IRI. Mice were intraperitoneally treated immediately after 2h of transient middle cerebral artery occlusion (MCAO) with a vehicle solution or 0.2mg/kg of RS9. Post-onset treatment of RS9 attenuated the infarct volume and improved neurological deficits 22h after reperfusion. RS9 activated Nrf2 2 and 6h after reperfusion and activated heme oxygenase-1 at 6 and 22h after reperfusion. RS9 also attenuated the phosphorylation of NF-kappaB p65 2 and 6h after reperfusion. Finally, RS9 improved the survival rate and neurological deficits 7days after MCAO. Our results suggest that the activation of Nrf2 by RS9 has a neuroprotective effect, mediated by attenuating both oxidative stress and neuroinflammation, and that RS9 is an effective therapeutic candidate for the treatment of IRI. PMID- 27474228 TI - The long-term effect of bundle care for catheter-related blood stream infection: 5-year follow-up. AB - OBJECTIVE: To address the importance of bundle care for catheter-related infection (CRBSI) on the basis of long-term observation in a catheter-abundant cardiovascular intensive care unit (CVICU). DESIGN: Prospective longitudinal cohort study. SETTING: CVICU of a tertiary referring medical centre in northern Taiwan. PARTICIPANTS: Around 1400 critically ill patients annually for 5 years in the CVICU (from January 2010 to June 2015). CRBSI bundle care has been applied ever since by a multidisciplinary team. MAIN OUTCOME MEASURES: CRBSI per 1000 catheter days, bloodstream infection (BSI) per 1000 inpatient days, and catheter utilisation rates. RESULTS: From January 2010 to June 2015 (22 quarters), there were in total 45 140 inpatient days and 24 163 catheter days, with an overall central venous catheter utilisation rate of 53.5%. The duration of the indwelled catheter was 6.3+/-1.2 days. The beginning CRBSI rate was 7.0 per 1000 catheter days and was significantly decreased to 0.7 per 1000 catheter days (p<0.001). Regarding the time series, cubic polynomial function depicted the CRBSI decrement most vividly (R2=0.501, p=0.005). In addition, the improvement in overall BSIs (2010 Q1, 4.4 per 1000 inpatient days to 2015 Q2, 0.5 per 1000 inpatient days, p<0.001) significantly correlated with the decrease in CRBSI (r=0.86, p<0.001). CONCLUSIONS: Through the bundle care, we successfully reduced CRBSIs. After 5 years of follow-up, we observed that the effect of bundle care was stepwise and persistent, as long as we kept working on this integrated project. PMID- 27474226 TI - Expression of p21-activated kinases 1 and 3 is altered in the brain of subjects with depression. AB - The p21-activated kinases (PAKs) of group I are the main effectors for the small Rho GTPases, critically involved in neurodevelopment, plasticity and maturation of the nervous system. Moreover, the neuronal complexity controlled by PAK1/PAK3 signaling determines the postnatal brain size and synaptic properties. Stress induces alterations at the level of structural and functional synaptic plasticity accompanied by reductions in size and activity of the hippocampus and the prefrontal cortex (PFC). These abnormalities are likely to contribute to the pathology of depression and, in part, reflect impaired cytoskeleton remodeling pointing to the role of Rho GTPase signaling. Thus, the present study assessed the expression of the group I PAKs and their activators in the brain of depressed subjects. Using quantitative polymerase chain reaction (qPCR), mRNA levels and coexpression of the group I PAKs: PAK1, PAK2, and PAK3 as well as of their activators: RAC1, CDC42 and ARHGEF7 were examined in postmortem samples from the PFC (n=25) and the hippocampus (n=23) of subjects with depression and compared to control subjects (PFC n=24; hippocampus n=21). Results demonstrated that mRNA levels of PAK1 and PAK3, are significantly reduced in the brain of depressed subjects, with PAK1 being reduced in the PFC and PAK3 in the hippocampus. No differences were observed for the ubiquitously expressed PAK2. Following analysis of gene coexpression demonstrated disruption of coordinated gene expression in the brain of subjects with depression. Abnormalities in mRNA expression of PAK1 and PAK3 as well as their altered coexpression patterns were detected in the brain of subjects with depression. PMID- 27474229 TI - Early childhood adversity potentiates the adverse association between prenatal organophosphate pesticide exposure and child IQ: The CHAMACOS cohort. AB - BACKGROUND: Previous studies have observed an adverse association between prenatal exposure to organophosphate pesticide (OPs) and child cognition, but few studies consider the potential role of social stressors in modifying this relationship. OBJECTIVE: We seek to explore the potential role of early social adversities in modifying the relationship between OPs and child IQ in an agricultural Mexican American population. METHODS: Participants from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a prospective longitudinal pre-birth cohort study, include 329 singleton infants and their mothers followed from pregnancy through age 7. Dialkyl phosphate metabolite concentrations (DAPs), a biomarker of organophosphate pesticide exposure, were measured in maternal urine collected twice during pregnancy and averaged. Child cognitive ability was assessed at 7 years using the Wechsler Intelligence Scale for Children - Fourth Edition. Demographic characteristics and adversity information were collected during interviews and home visits at numerous time points from pregnancy until age 7. RESULTS: Among low-income Latina mothers and their children in the Salinas Valley, total adversity and specific domains of adversity including poor learning environment and adverse parent-child relationships were negatively associated with child cognition. Adverse associations between DAP concentrations and IQ were stronger in children experiencing greater adversity; these associations varied by child sex. For example, the association between prenatal OP exposure and Full-Scale IQ is potentiated among boys who experienced high adversity in the learning environment (beta=-13.3; p-value <0.01). CONCLUSIONS: Greater total and domain-specific adversity modifies negative relationships between prenatal OP exposure and child IQ differently among male and female children. These findings emphasize the need to consider plausible interactive pathways between social adversities and environmental exposures. PMID- 27474230 TI - Eating patterns and food choice as determinant of weight loss and improvement of metabolic profile after RYGB. AB - OBJECTIVE: Significant changes in the preference for different dietary components have been observed after Roux-en-Y gastric bypass (RYGB). The aim of this study was to evaluate the early post-RYGB changes in quality of eating patterns and their relationship to weight loss and metabolic parameters. METHODS: The sample was composed of 41 extremely obese individuals undergoing RYGB. Dietary data were collected using a validated food frequency questionnaire in Brazil. A food intake evaluation was conducted with a focus on the frequency of consumption (>=4 times/wk) of markers for healthy eating and markers for unhealthy eating. Furthermore, anthropometric and metabolic markers were collected before surgery and 6 mo post-RYGB. RESULTS: Compared with baseline, the postsurgery body mass index was reduced by 12.9 kg/m2, corresponding to an excess weight loss of 63.5%. Blood glucose, insulin, ferritin, cholesterol, low-density lipoprotein cholesterol, triacylglycerol (TG), and hemoglobin were reduced 6 mo after RYGB (P < 0.05). The consumption frequency of many foods defined as unhealthy decreased after surgery (e.g., from 15.4% to 5.1% for pizza and 18% to 0% for hamburger), and some healthy food increased (e.g., from 0% to 5.1% for fish and from 0% to 25.6% for plain yogurt). There was a decrease in the frequency of individuals who reported consuming fruit and vegetables. Conversely, insulin, glucose, and TG levels were positively associated with intake of chocolates/truffles and ice cream/sundaes. CONCLUSION: Participants in the present study appeared to develop a healthier dietary pattern by 6 mo after RYGB. These results show that a healthier dietary pattern is associated with a significant improvement of metabolic profile and weight loss. PMID- 27474231 TI - [Infections and epigenetic changes in cancer]. AB - The role of epigenetics and infectious diseases at early stages of life influence pre-malignant lesions of cancer, in particular, gastric cancer, one of the most frequent tumours in Chile, Latin America, and worldwide. This article examines the role of H.pylori and epigenetic alterations (i.e. DNA methylation) at early stages of gastric cancer and proposes, from the paediatric point of view, strategies for prevention and early detection. PMID- 27474232 TI - Early discharge as a mediator of greater ICU-level care requirements in patients not enrolled on the AAML0531 clinical trial: a Children's Oncology Group report. AB - Previous data suggest that patients enrolled on clinical trials for treatment of cancer have better overall survival than patients who do not enroll; however, short-term outcomes relative to trial enrollment and corresponding mediators have not been assessed. A cohort of pediatric patients with newly-diagnosed acute myeloid leukemia was assembled from the Pediatric Health Information System. We evaluated whether patients not enrolled onto Children's Oncology Group trial AAML0531 had greater intensive care unit (ICU)-level requirements than enrolled patients and whether early discharge after chemotherapy administration mediated this association. Patients not enrolled on AAML0531 were more likely to be discharged early (aOR = 1.40, 95% confidence interval [CI]: 1.02, 1.90) and to require ICU-level care (aOR = 2.00, 95% CI: 1.06, 3.78) than enrolled patients, but early discharge explained only a small proportion (12.3%) of the absolute difference in ICU-level care risk. The direct effect of nonenrollment on the need for ICU-level care was significant (aOR = 1.89, 95% CI: 1.00, 3.94), whereas the indirect effect mediated through early discharge was not (aOR = 1.07, 95% CI: 0.95, 1.19). Factors other than postchemotherapy discharge strategy drive the difference in ICU utilization by trial enrollment status. PMID- 27474233 TI - Triggering Intracellular Receptors for Vaccine Adjuvantation. AB - Immune adjuvants are components that stimulate, potentiate, or modulate the immune response to an antigen. They are key elements of vaccines in both the prophylactic and therapeutic domains. In the past decade substantial progress in our understanding of innate immunity has paved the way for the design of next generation adjuvants that stimulate a wide range of receptors. Within the framework of vaccine adjuvant design, this review outlines the interest of targeting endosomal and intracellular receptors to enhance and guide the immune response. We present and compare the molecules as well as potential combinations which are currently in the spotlight. We emphasize how targeting the appropriate receptor can direct immunity towards the appropriate response, such as a cytotoxic or mucosal response. PMID- 27474234 TI - Past, present and forecast of transfusion medicine: What has changed and what is expected to change? AB - Blood transfusion is the second most used medical procedures in health care systems worldwide. Over the last few decades, significant changes have been evolved in transfusion medicine practices. These changes were mainly needed to increase safety, efficacy, and availability of blood products as well as reduce recipients' unnecessary exposure to allogeneic blood. Blood products collection, processing, and storage as well as transfusion practices throughout all patient populations were the main stream of these changes. Health care systems across the world have adopted some or most of these changes to reduce transfusion risks, to improve overall patients' outcome, and to reduce health care costs. In this article, we are going to present and discuss some of these recent modifications and their impact on patients' safety. PMID- 27474235 TI - Improving the cytoplasmic maturation of bovine oocytes matured in vitro with intracellular and/or extracellular antioxidants is not associated with increased rates of embryo development. AB - The production of reactive oxygen species (ROS) is a normal process that occurs in the cellular mitochondrial respiratory chain. However, an increase in ROS levels during in vitro production of bovine embryos induces oxidative stress, leading to failed embryonic development. Therefore, we investigated whether supplementation of IVM medium with intracellular (cysteine and cysteamine; C + C) and/or extracellular (catalase; CAT) antioxidants improves the culture system, affects the mitochondrial membrane potential, affects the intracellular levels of ROS and glutathione (GSH) in the bovine oocytes at the end of maturation, and thereby affects the subsequent embryonic development. At the end of IVM, the metaphase II rates were unaffected by the treatments (76.7 +/- 1.7% to 80.6 +/- 5.2%; P > 0.05). The intracellular ROS levels, expressed in arbitrary fluorescence units, found in the oocytes treated with intracellular antioxidants (C + C and C + C + CAT groups; 1.06, averaged) were as low as those observed in immature oocytes (0 hour: 1.00 +/- 0.12). Among mature oocytes, higher (P < 0.05) ROS levels were found in the control group (1.91 +/- 0.10) when compared to the ROS levels found in oocytes treated with antioxidants. Intracellular GSH levels in all groups were lower (0.17 +/- 0.09 to 0.51 +/- 0.05; P < 0.05) than those in immature oocytes (1.00 +/- 0.08), although GSH levels in the C + C group (0.51 +/ 0.05) were greater (P < 0.05) than in the control, CAT, and C + C + CAT groups (0.23; averaged). The mitochondrial membrane potential in all groups was improved (1.6; averaged; P < 0.05) compared to the membrane potential observed in the immature oocytes (1.00 +/- 0.05), with the exception of the C + C group (0.94 +/- 0.03). There was no effect (P > 0.05) of antioxidant supplementation on embryonic development to the blastocyst stage (36.1%; averaged); however, there was an increased tendency (P = 0.0689) to obtain a higher blastocyst rate for the C + C + CAT group (47.5 +/- 5.6%) compared to the control group (29.9 +/- 4.8%). In conclusion, despite improvements in specific parameters of cytoplasmic maturation, the addition of intracellular and/or extracellular antioxidants during IVM did not affect embryo development. PMID- 27474236 TI - Total antioxidant capacity, catalase activity, and lipid peroxidation changes in seminal plasma of sex-reversed female and male rainbow trout (Oncorhynchus mykiss) during spawning season. AB - The advantages of gender-related characteristics are used in aquaculture practice to improve production. For instance, all-female stock is preferable than mixed or all-male stock in salmonid culture. The most effective way to obtain all-female populations is the using of sex-reversed (SR) female trouts, genotypically female but phenotypically male, by masculinizing androgen hormones as breeders in artificial insemination. This study was conducted to evaluate changes in the total antioxidant capacity (TAC), protein concentration, catalase (CAT) activity, lipid peroxidation level (LPO; malondialdehyde), and Fourier transform infrared spectra of seminal plasma of SR female and normal (N) male trouts during the spawning season. Seminal plasma TAC values of N male and SR female trouts were determined as 0.015 +/- 0.004 and 0.116 +/- 0.033 mM of Trolox equivalents, respectively, in the middle of the spawning season. Some regions related to aromatic rings in seminal plasma Fourier transform infrared spectra of SR female trouts differed from N male trouts were indicated to the higher TAC values. At the middle of the spawning season, protein concentrations were determined as 569.5 +/- 139.4 mg/dL in SR female trouts and 66.3 +/- 22.7 mg/dL in N male trouts. LPO levels in seminal plasma of N male trouts varied from 46.33 +/- 12.05 * 10(-3) to 270.02 +/- 70.64 * 10(-3) nmol/mg protein, whereas from 13.87 +/- 4.98 * 10(-3) to 48.49 +/- 17.31 * 10(-3) nmol/mg protein in SR female trouts throughout the spawning. CAT activities of seminal plasma in N male trouts ranged from 0.38 +/- 0.26 to 0.47 +/- 0.32 kU/mg protein, whereas those values in SR female trouts varied between 0.21 +/- 0.10 and 0.43 +/- 0.15 kU/mg protein. Moreover, there were the pairwise significant correlations among all variables except between CAT and TAC (P > 0.05). Remarkable correlations were found between LPO-protein (r = -0.922, P < 0.05, n = 190), LPO-TAC (r = -0.859, P < 0.05, n = 98), and TAC protein (r = +0.879, P < 0.05, n = 98). Similar to seminal plasma of N male trouts, TAC values, protein concentrations, and CAT activities in seminal plasma of SR female trouts have shown decline, whereas LPO levels increased toward the end of the spawning seasons. Seminal plasmas of SR female trouts were characterized by higher protein concentrations and TAC values and lower LPO levels than that from N male trouts. PMID- 27474237 TI - Comparison of two timed artificial insemination system schemes to synchronize estrus and ovulation in Nellore cattle. AB - The aim of this study was to evaluate the reproductive performance of 411 Nellore cows (198 nulliparous, 80 primiparous, and 133 multiparous) submitted to the 5dCO Synch + P4 or 7dEB + P4 systems. The 5dCO-Synch + P4 system consisted of insertion of an intravaginal progesterone (P4) insert and 100 MUg of GnRH (intramuscularly [i.m.]) on Day 0. On Day 5, the P4 insert was removed, and two doses of 25 mg of PGF2alpha (i.m.) were administered 6 hours apart. Cows not detected in estrus until 55 hours after insert removal received 100 MUg of GnRH i.m. 17 hours later (i.e., 72 hours after P4 removal). The 7dEB + P4 system consisted of insertion of a P4 insert and 2 mg of estradiol benzoate (i.m.) on Day 0. On Day 7, the P4 insert was removed and 25 mg of PGF2alpha, 0.6 mg of estradiol cypionate, and 300 IU of eCG were administered i.m. In both systems, artificial insemination (AI) was performed according to estrus detection (i.e., cows detected in estrus until 55 hours after insert removal were inseminated at 55 hours and cows detected in estrus later or those not detected in estrus were inseminated at 72 hours). Estrus-detection risk was greater (P < 0.05) in 7dEB + P4 (80.4%) than 5dCO-Synch + P4 system (36.4%). Progesterone concentration 10 days after AI was greater (P < 0.05) in 7dEB + P4 than 5dCO-Synch + P4 system in primiparous and multiparous but did not differ between systems in nulliparous cows. Pregnancy per AI was greater (P < 0.05) in 7dEB + P4 (49.7%) than 5dCO Synch + P4 (35.4%) system. Primiparous had lower estrus-detection risk (25.0%), ovulation risk (76.6%), and pregnancy per AI (28.7%) than multiparous or nulliparous cows. In conclusion, reproductive performance was reduced with the 5dCO-Synch + P4 in comparison with the 7dEB + P4 system in Nellore cows. Moreover, the reproductive traits observed for primiparous cows indicate that more attention is required when timed AI programs are started early after calving. PMID- 27474238 TI - High-yield fermentation and a novel heat-precipitation purification method for hydrophobin HGFI from Grifola frondosa in Pichia pastoris. AB - Hydrophobins are proteins produced by filamentous fungi with high natural surfactant activities and that can self-assemble in interfaces of air-water or solid-water to form amphiphilic membranes. Here, we reported a high-yield fermentation method for hydrophobin HGFI from Grifola frondosa in Pichia pastoris, attaining production of 300 mg/L by keeping the dissolved oxygen level at 15%-25% by turning the methanol-feeding speed. We also developed a novel HGFI purification method enabling large-scare purification of HGFI, with >90% recovery. Additionally, we observed that hydrophobin HGFI in fermentation broth precipitated at pH < 7.0 and temperatures >90 degrees C. We also identified the structure and properties of proteins purified by this method through atomic force microscopy, circular dichroism, X-ray photoelectron spectroscopy, and water contact angle measurement, which is similar to protein purification by ultrafiltration without heating treatment that enables our method to maintain native HGFI structure and properties. Furthermore, the purification method presented here can be applied to large-scale purification of other type I hydrophobins. PMID- 27474239 TI - Incidental cervical metastases from thyroid carcinoma during neck dissection. AB - OBJECTIVES: To quantify and discuss the prevalence of unsuspected thyroid lymph node metastases discovered in specimens from neck dissection for head and neck squamous cell carcinoma (HNSCC) and discuss the impact on patient management. STUDY DESIGN: Retrospective study between May 2004 and January 2007. SETTING: University hospital. METHODS: Pathological analysis of cervical lymph node dissection performed during surgery for HNSCC in a total of 349 neck dissections in 266 consecutive patients. RESULTS: Twenty-one patients showed metastatic lymph nodes from thyroid cancer (prevalence 7.9%): 13 cases were metastatic from a papillary thyroid carcinoma and 8 cases from a follicular carcinoma. In 5 of the 21 patients, classical dissection was associated to recurrent nerve dissection and unilateral lobectomy; no thyroid carcinoma was found. Thirteen patients received radiotherapy for HNSCC. Follow-up comprised annual ultrasonographic examination of the neck and thyroid in these 21 patients. Total thyroidectomy was decided on in 5, with discovery of 3 micro-papillary thyroid carcinomas, in a single patient (complementary 131I treatment). No thyroid carcinomas were found for the other 4 patients. No patients died from thyroid carcinoma during follow up (mean: 41 months). CONCLUSION: The prevalence of lymph node metastasis from thyroid carcinoma in cervical lymph node dissection during treatment of HNSCC seems higher (7.9%) than rates reported in the literature (0.3 to 1.6%). This may be due to the histopathological methods employed. Management of patients should be discussed in the light of thyroid ultrasonography and prognosis of HNSCC. PMID- 27474240 TI - [Analysis of the results of the SEIMC External Quality Control Program. Year 2014]. AB - The External Quality Control Program of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) include controls for bacteriology, serology, mycology, parasitology, mycobacteria, virology and molecular microbiology. This article presents the most relevant conclusions and lessons from the 2014 controls. As a whole, the results obtained in 2014 confirm the excellent skill and good technical standards found in previous editions. However, erroneous results can be obtained in any laboratory and in clinically relevant determinations. Once again, the results of the SEIMC program highlighted the need to implement both internal and external controls in order to assure the maximal quality of the microbiological tests. PMID- 27474241 TI - [Analysis of the results of the HIV-1, HCV and HBV viral load of SEIMC External Quality Control Program. Year 2014]. AB - Human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV) and hepatitis C virus (HCV) viral load determinations are among the most relevant markers for the follow up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of results obtained by microbiology laboratories. This article summarizes the results obtained from the 2014 SEIMC (Spanish Society of Infectious Diseases and Clinical Microbiology) External Quality Control Programme for HIV-1, HCV, and HBV viral loads. In the HIV-1 program, a total of 5 standards were sent. One standard consisted in seronegative human plasma, while the remaining 4 contained plasma from 3 different viremic patients, in the range of 2-5 log10 copies/mL; 2 of these standards were identical aiming to determine repeatability. A significant proportion of the laboratories (30.8% on average) obtained values out of the accepted range (mean +/- 0.25 log10 copies/mL), depending on the standard and on the method used for quantification. Repeatability was excellent, with up to 95.8% of laboratories reporting results within the limits (Delta < 0.5 log10 copies/mL). The HBV and HCV program consisted of 2 standards with different viral load contents. Most of the participants, 83.7% in the case of HCV and 87.9% in the HBV, obtained all the results within the accepted range (mean +/- 1.96 standard deviations log10 IU/mL). Data from this analysis reinforce the utility of proficiency programmes to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase on the overall quality. Due to the remarkable interlaboratory variability, it is advisable to use the same method and the same laboratory for patient follow up. PMID- 27474242 TI - [Bacterial vaginosis]. AB - Bacterial vaginosis (BV) is the main cause of vaginal dysbacteriosis in the women during the reproductive age. It is an entity in which many studies have focused for years and which is still open for discussion topics. This is due to the diversity of microorganisms that cause it and therefore, its difficult treatment. Bacterial vaginosis is probably the result of vaginal colonization by complex bacterial communities, many of them non-cultivable and with interdependent metabolism where anaerobic populations most likely play an important role in its pathogenesis. The main symptoms are an increase of vaginal discharge and the unpleasant smell of it. It can lead to serious consequences for women, such as an increased risk of contracting sexually transmitted infections including human immunodeficiency virus and upper genital tract and pregnancy complications. Gram stain is the gold standard for microbiological diagnosis of BV, but can also be diagnosed using the Amsel clinical criteria. It should not be considered a sexually transmitted disease but it is highly related to sex. Recurrence is the main problem of medical treatment. Apart from BV, there are other dysbacteriosis less characterized like aerobic vaginitis of which further studies are coming slowly but are achieving more attention and consensus among specialists. PMID- 27474243 TI - [Environmental microbiological control]. AB - The environmental microbiological control is necessary to prevent infections associated with certain procedures that are performed at the hospital. In this review the procedures for control of water and dialysis fluids, and air in operating rooms and immunocompromised units are addressed. The dialysis quality management guidelines define the highest levels of chemical, microbiological and endotoxin in purified water and dialysis fluids based on the recommendations of scientific societies. The microbiological control of water and dialysis fluids should include detection of microorganisms and endotoxin levels. Regarding the microbiological air sampling of operating rooms and immunocompromised units the types of clean rooms in which is recommended to perform microbiological air monitoring; the sample collection methods; culture media; incubation conditions; the most common microorganisms, and permissible levels depending on the type of surgery are described. PMID- 27474244 TI - [Screening of parasitic diseases in the asymptomatic immigrant population]. AB - Parasitic diseases suppose an important health problem in people from high endemic areas, so these must be discarded properly. Usually, these infections develop asymptomatically but, in propitious situations, are likely to reactivate themselves and can cause clinical symptoms and/or complications in the receiving country. Moreover, in some cases it is possible local transmission. Early diagnosis of these parasitic diseases made by appropriate parasitological techniques and its specific treatment will benefit both, the individual and the community. These techniques must be selected according to geoepidemiological criteria, patient's origin, migration route or time spent outside the endemic area; but other factors must also be considered as its sensitivity and specificity, implementation experience and availability. Given the high prevalence of intestinal parasites on asymptomatic immigrants, it is recommended to conduct a study by coproparasitological techniques. Because of its potential severity, the screening of asymptomatic malaria with sensitive techniques such as PCR (polymerase chain reaction) is also advisable. Serological screening for Chagas disease should be performed on all Latin American immigrants, except for people from the Caribbean islands. Other important parasites, which should be excluded, are filariasis and urinary schistosomiasis, by using microscopic examination. The aim of this paper is to review the different techniques for the screening of parasitic diseases and its advices within the care protocols for asymptomatic immigrants. PMID- 27474245 TI - [Next generation sequencing for the diagnostics and epidemiology of tuberculosis]. AB - Tuberculosis (TB) has overtaken HIV (human immunodeficiency virus) and malaria as the leading cause of death by an infectious disease worldwide. The reduction in the TB incidence is a modest 2% of cases per year, thus we will need 200 years to eradicate the disease. Part of the problem is that TB control tools are decades old and cannot anymore contribute to accelerate eradication of TB. New diagnostics, treatments and vaccines are urgently needed. Next generation sequencing has the potential to become one of these new tools. Genomic characterization of TB isolates is already showing its potential for epidemiology and diagnostics, particularly to identify drug resistance mutations. However, the experimental and bioinformatics skills needed are still far from being standardized and are not easy to incorporate as a routine in clinical laboratories. In this review we will describe current next generation sequencing approaches applied to the Mycobacterium tuberculosis complex, their contribution to the diagnostics and epidemiology of the disease and the efforts that are being undertaken to make the technology accessible to public health and clinical microbiology laboratories. PMID- 27474246 TI - [Molecular diagnostic methods of respiratory infections. Has the scheme diagnosis changed?]. AB - Lower respiratory tract infections remain one of the most common causes of mortality worldwide, which is why early diagnosis is crucial. Traditionally the microbiological diagnosis of these infections has been based on conventional methods including culture on artificial media for isolation of bacteria and fungi and cell cultures for virus and antibody or antigen detection using antigen antibody reactions. The main drawback of the above mentioned methods is the time needed for an etiological diagnosis of the infection. The techniques based on molecular biology have drawn much attention in recent decades as tools for rapid diagnosis of infections. Some techniques are very expensive, especially those that can detect various microorganisms in the same reaction, therefore the question that arises is whether the cost of such testing is justified by the information obtained and by the clinical impact that its implementation will determine. In this article we make a review of the various techniques of molecular biology applied to the diagnosis of pneumonia and focus primarily on analysing the impact they may have on the management of patients with acute respiratory tract infections. PMID- 27474247 TI - [Management and treatment of patients with hepatitis B]. AB - Chronic hepatitis B is a major cause of morbidity and mortality worldwide. Approximately one third of the world's population has serological evidence of past or present infection by hepatitis B virus (HBV) and 350-400 million people are chronic HBV surface antigen carriers. The aim of therapy is to prevent the onset of liver fibrosis and development of cirrhosis or hepatocarcinoma by sustained suppression of viral replication. Currently there are 2 strategies for the treatment of chronic hepatitis B: the pegylated interferon and long-term treatment with nucleoside/nucleotide analogues. Pegylated interferon has the advantage of being a treatment of limited duration, and is particularly suitable for patients with chronic hepatitis with positive HBeAg (hepatitis B e antigen), but the unfavorable adverse event profile and route of parenteral administration makes it less used than nucleoside/nucleotide analogues. Tenofovir and entecavir have shown to be potent inhibitors of HBV with a high genetic barrier to resistance and few adverse effects, so are considered as the first line therapy. PMID- 27474248 TI - [Epidemiological surveillance of syphilis in the city of Valencia. Impact and evolution of the period 2003-2014]. AB - In Spain syphilis shows an increasing trend from last decade and multiple papers reported an increasing of exposed population. Our aim was to describe the evolution of the incident of the syphilis in the geographical frame of the city of Valencia, to identify the characteristics and practices of risk of the affected ones. A classic design of vigilance of public health was applied, longitudinal retrospective study. Geographical area: the city of Valencia. PERIOD: January 2003-December 2014. VARIABLES: age and sex, national origin, dates of access to the sanitary system, date of diagnosis, clinical forms of presentation, conducts of risk, and practices of risk. The annual impact of the disease evolved from 2.4 * 10(5) in 2004 up to 14.5 * 10(5) in 2014. Males (82.96%) masculinity rate: 4.8. Major specific incidence took places on age groups 35-39 years with 16.49 * 10(5) and 40-44 years with 16.98 * 10(5). The difference between women stands out according to origin: middle ages in autochthonous (39.72 years) opposite to foreigners (32.91 years); P = .004. The primary forms were 5 times more probable in males. The major factor of risk was to have multiple couples (54.89%), man-to-man homo or bisexuals reaches 90.0% of it. The HIV (human immunodeficiency virus) infection was 29.07% in males and 4.35% in women. Precedent of multiple couple relations would not be a minor of 42 times more likely among the homosexual population with syphilis. Major determinant of risk were the relations with multiple pairs and the prevention will have to be focused to the group of men who practice sex with men. PMID- 27474250 TI - Removing transgender identity from the classification of mental disorders: a Mexican field study for ICD-11. AB - BACKGROUND: The conceptualisation of transgender identity as a mental disorder has contributed to precarious legal status, human rights violations, and barriers to appropriate health care among transgender people. The proposed reconceptualisation of categories related to transgender identity in WHO's forthcoming International Classification of Diseases (ICD)-11 removes categories related to transgender identity from the classification of mental disorders, in part based on the idea that these conditions do not satisfy the definitional requirements of mental disorders. We aimed to determine whether distress and impairment, considered essential characteristics of mental disorders, could be explained by experiences of social rejection and violence rather than being inherent features of transgender identity, and to examine the applicability of other elements of the proposed ICD-11 diagnostic guidelines. METHODS: This field study used a retrospective interview design in a purposive sample of transgender adults (aged >18 years or older) receiving health-care services at the Condesa Specialised Clinic in Mexico City, Mexico. Participants completed a detailed structured interview focusing on sociodemographic characteristics, medical history related to gender identity, and, during a specific period of adolescence, key concepts related to gender identity diagnoses as proposed for ICD-11 and from DSM-5 and ICD-10, psychological distress, functional impairment, social rejection, and violence. Data were analysed with descriptive statistics and univariate comparisons and multivariate logistic regression models predicting distress and dysfunction. FINDINGS: Between April 1, 2014, and Aug 17, 2014, 260 transgender adults were approached and 250 were enrolled in the study and completed the interview. Most (n=202 [81%]) had been assigned a male sex at birth. Participants reported first awareness of transgender identity at a mean age of 5.6 years (SD 2.5, range 2-17), and 184 (74%) had used health interventions for body transformation, most commonly hormones (182 [73%)], with the first such intervention at a mean age of 25.0 years (SD 9.1, range 10-54). 84 (46%) of those who had used hormones did so initially without medical supervision. During adolescence, distress related to gender identity was very common, but not universal (n=208 [83%]), and average level of distress was quite high among those who reported it (79.9 on a scale of 0 [none at all] to 100 [extreme], SD 20.7, range 20-100). Most participants (n=226 [90%] reported experiencing family, social, or work or scholastic dysfunction related to their gender identity, but this was typically moderate (on a scale of 0 [not at all disrupted] to 10 [extremely disrupted], family dysfunction mean 5.3 [SD 3.9, range 0-10]; social dysfunction mean 5.0 [SD 3.8, range 0-10]; work or scholastic dysfunction mean 4.8 [SD 3.6, range 0-10]). Multivariate logistic regression models indicated that distress and all types of dysfunction were strongly predicted by experiences of social rejection (odds ratios [ORs] 2.29-8.15) and violence (1.99-3.99). A current male gender identity also predicted distress (OR 3.90). Of the indicators of gender incongruence, only asking to be treated as a different gender was a significant predictor, and only of work or scholastic dysfunction (OR 1.82). INTERPRETATION: This study provides additional support for classifying health-related categories related to transgender identity outside the classification of mental disorders in the ICD-11. The reconceptualisation and related reclassification of transgender-related health conditions in the ICD-11 could serve as a useful instrument in the discussion of public health policies aimed at increasing access to appropriate services and reducing the victimisation of transgender people. FUNDING: National Institute of Psychiatry Ramon de la Fuente Muniz, Mexico. PMID- 27474251 TI - A gender incongruence diagnosis: where to go? PMID- 27474249 TI - Study on the molecular mechanism of antinociception induced by ghrelin in acute pain in mice. AB - Ghrelin has been identified as the endogenous ligand for the GHS-R1alpha (growth hormone secretagogue receptor 1 alpha). Our previous experiments have indicated that ghrelin (i.c.v.) induces antinociceptive effects in acute pain in mice, and the effects were mediated through the central opioid receptors and GHS-R1alpha. However, which opioid receptor (OR) mediates the antinociceptive effects and the molecular mechanisms are also needed to be further explored. In the present study, the antinociceptive effects of ghrelin (i.c.v.) could be fully antagonized by delta-opioid receptor antagonist NTI. Furthermore, the mRNA and protein levels of delta-opioid peptide PENK and delta-opioid receptor OPRD were increased after i.c.v injection of ghrelin. Thus, it showed that the antinociception of ghrelin was correlated with the GHS-R1alpha and delta-opioid receptors. To explore which receptor was firstly activated by ghrelin, GHS-R1alpha antagonist [D-Lys(3)]-GHRP 6 was co-injection (i.c.v.) with deltorphin II (selective delta-opioid receptor agonist). Finally, the antinociception induced by deltorphin II wasn't blocked by the co-injection (i.c.v.) of [D-Lys(3)]-GHRP-6, indicating that the GHS-R1alpha isn't on the backward position of delta-opioid receptor. The results suggested that i.c.v. injection of ghrelin initially activated the GHS-R1alpha, which in turn increased the release of endogenous PENK to activation of OPRD to produce antinociception. PMID- 27474252 TI - Reassessment of the cosyntropin stimulation test in the confirmatory diagnosis and subtype classification of primary aldosteronism. AB - OBJECTIVE: Although corticotropin is a representative secretagogue of aldosterone, the utility of the cosyntropin stimulation test (C-ST) in diagnosing primary aldosteronism (PA) has not been elucidated. Aim of the study was to evaluate the clinical utility of C-ST for confirmatory testing and subtype classification of PA. DESIGN, SETTING AND PATIENTS: In this retrospective study, we identified patients with hypertension and positive case-detection results for PA who underwent C-ST and saline infusion testing (SIT) between 2006 and 2013 at eight referral centres in Japan. PA and essential hypertension (EH) were distinguished based on SIT results. PA subtype classification was determined by adrenal venous sampling (AVS). Plasma aldosterone concentration (PAC) was measured before and 30 and 60 min after intravenous cosyntropin administration. The ability of C-ST to distinguish PA from EH and to distinguish unilateral from bilateral disease was assessed by the area under the receiver operating characteristic curve. RESULTS: Of 205 patients with hypertension and positive case-detection results, 139 (68%) had PA based on SIT results. Eighteen patients in whom AVS was unsuccessful were excluded from analysis. The baseline PAC before C-ST was significantly higher (P < 0.01) in patients with PA than in those with EH. However, the degree of difference in PAC between patients with PA and EH was not enhanced by the administration of cosyntropin. In addition, the administration of cosyntropin did not improve the distinction between bilateral and unilateral PA subtypes. CONCLUSIONS: C-ST has no utility as a confirmatory and subtype testing of PA when the diagnosis of PA is based on the positive results in SIT. PMID- 27474253 TI - Autism spectrum disorder and prenatal exposure to selective serotonin reuptake inhibitors: A systematic review and meta-analysis. AB - To obtain the risk estimates of autism spectrum disorder (ASD) in the offspring exposed to serotonin reuptake inhibitors (SSRI) in utero, we performed systematic review and meta-analysis of relevant studies. Five case-control and three cohort studies were eligible for the analysis. The SSRI group had significantly higher risk of ASD than the SSRI non-exposed group (pooled OR 1.45, 95% CI 1.15-1.82). In the subgroup analyses, however, the risk of ASD was similar between the SSRI group and other antidepressants group (pooled OR 1.14, 95% CI 0.67-1.96). Furthermore, when the analysis was confined to those born to the women with psychiatric disorders, the SSRI group did not show an increased ASD risk (pooled OR 0.96, 95% CI 0.57-1.63) compared to non-exposed groups. In conclusion, SSRI use in pregnancy is associated with an increased risk of ASD in the offspring, but maternal psychiatric condition is a major confounding factor. PMID- 27474255 TI - Toxicity of beauvericin on porcine oocyte maturation and preimplantation embryo development. AB - Beauvericin (BEA) is one of many toxins produced by Fusarium species that contaminate feed materials. The aim of this study was to assess its effects on porcine oocyte maturation and preimplantation embryo development. Cumulus-oocyte complexes and developing embryos were exposed to BEA and cultured until the blastocyst stage. Cumulus cells, oocytes and embryos were examined for viability, progesterone synthesis, multidrug resistance protein (MDR1), ATP content and gene expression related to MDR1 function, oxidative phosphorylation, steroidogenesis and apoptosis. BEA was toxic in embryos, oocytes and cumulus cells at concentrations exceeding 0.5MUM, and embryos were most vulnerable after the four cell stage. Since BEA exerted different effects in embryos, oocytes and cumulus cells, the toxic mechanism is suggested to involve different pathways. Currently there are no consistent data on adverse effects of BEA in pig farms. PMID- 27474254 TI - Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse. AB - Millions of children have been born worldwide though assisted reproductive technologies (ART). Consistent with the Developmental Origins of Health and Disease hypothesis, there is concern that ART can induce adverse effects, especially because procedures coincide with epigenetic reprogramming events. Although the majority of studies investigating the effects of ART have focused on perinatal outcomes, more recent studies demonstrate that ART-conceived children may be at increased risk for postnatal effects. Here, we present the current epidemiological evidence that ART-conceived children have detectable differences in blood pressure, body composition, and glucose homeostasis. Similar effects are observed in the ART mouse model, which have no underlying infertility, suggesting that cardiometabolic effects are likely caused by ART procedures and not due to reasons related to infertility. We propose that the mouse system can, consequently, be used to adequately study, modify, and improve outcomes for ART children. PMID- 27474256 TI - Induction of Biological Apatite Orientation as a Bone Quality Parameter in Bone Regeneration Using Hydroxyapatite/Poly E-Caprolactone Composite Scaffolds. AB - Changes in the biological apatite (BAp) c-axis orientation were investigated as a bone quality parameter in bone regeneration using hydroxyapatite/poly E caprolactone (HA/PCL) composite scaffolds. Three-dimensional (3D) HA/PCL composite scaffolds were fabricated using a layer manufacturing process in three grid sizes (200-, 600-, and 1000 MUm) and grafted into the forearm ulna of New Zealand white rabbits. The cross-sectional areas of the bones regenerated from the scaffolds with 600- and 1000-MUm grid sizes were significantly larger than those from the scaffold with 200-MUm grid sizes, whereas bone mineral density in the regenerated regions did not differ between the three grid sizes. Moreover, the BAp c-axis orientation in the bones regenerated from the scaffolds with grid sizes of 600- and 1000 MUm was not significantly different; however, both scaffolds showed enhanced BAp orientation, although the degree of BAp orientation was lower than that in intact bones. In conclusion, HA/PCL composite 3D scaffolds with 600- and 1000-MUm grid sizes induced BAp c-axis orientation and showed good bone regeneration behavior in vivo. PMID- 27474257 TI - Evaluation of a Proton Pump Inhibitor for Sleep Bruxism: A Randomized Clinical Trial. AB - Bruxism is a repetitive jaw-muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible. Recent advances have clarified the relationship between gastroesophageal reflux and sleep bruxism (SB). However, the influence of pharmacological elimination of gastric acid secretion on SB has not been confirmed. The authors aimed to assess the efficacy of a proton pump inhibitor (PPI) on SB and to examine the gastrointestinal (GI) symptoms and endoscopic findings of the upper GI tract in SB patients. The authors performed a randomized double-blind placebo-controlled crossover study at Kagoshima University Hospital. Twelve patients with polysomnography (PSG)-diagnosed SB underwent an assessment of GI symptoms using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) and esophagogastroduodenoscopy. At baseline (i.e., before interventions), the mean frequencies of electromyography (EMG) bursts and rhythmic masticatory muscle activity (RMMA) episodes were 65.4 +/- 49.0 bursts/h and 7.0 +/- 4.8 episodes/h, respectively, and at least 1 RMMA episode with grinding noise was confirmed in all participants. The mean FSSG score was 8.4 +/- 5.6, and 41.7% of patients were diagnosed with gastroesophageal reflux disease. Mild reflux esophagitis was confirmed in 6 patients. PSG, including EMG of the left masseter muscle and audio video recording, was performed on days 4 and 5 of administration of 10 mg of the PPI (rabeprazole) or placebo. PPI administration yielded a significant reduction in the frequency of EMG bursts, RMMA episodes, and grinding noise. No significant differences were observed regarding the swallowing events and sleep variables. Since the clinical application of PPI for SB treatment should remain on hold at present, the results of this trial highlight the potential application of pharmacological gastroesophageal reflux disease treatment for SB patients. Larger scale studies are warranted to corroborate these findings. (UMIN Clinical Trials Registry: UMIN000004577). PMID- 27474258 TI - Maternal Separation Induces Orofacial Mechanical Allodynia in Adulthood. AB - It is well known that exposure to maternal separation (MS) in early life causes plastic changes in the nervous system in adulthood, occasionally resulting in ubiquitous chronic pain. However, the pathogenic mechanisms of pain hypersensitivity remain unclear. Here, the authors examined the involvement of corticosterone in orofacial mechanical hypersensitivity induced by MS. To establish a rat model of MS, pups were placed in isolated cages 180 min/d and kept in a temperature-controlled environment at 22 +/- 2 degrees C for 14 d. Mechanical allodynia in the whisker pad skin in adulthood was induced by MS and was significantly suppressed by successive postnatal subcutaneous administration of the glucocorticoid receptor antagonist mifepristone. Corticosterone levels were increased in the serum of MS rats, and successive postnatal administration of subcutaneous corticosterone to naive rats induced mechanical allodynia in the whisker pad skin. The number of P2X3 receptor-immunoreactive (P2X3R-IR) trigeminal ganglion (TG) neurons innervating the whisker pad skin was significantly increased in MS rats and decreased following subcutaneous administration of mifepristone. The number of P2X3R-IR TG neurons innervating the whisker pad skin was also significantly increased following successive postnatal administration of subcutaneous corticosterone in naive rats. Moreover, the mechanical allodynia was suppressed 30 min after administration of the P2X3R antagonist A317491 to the whisker pad skin in MS rats. These findings suggest that the increase in P2X3R-IR TG neurons innervating the whisker pad skin via enhanced neonatal corticosterone signaling by MS plays an important role in orofacial mechanical allodynia in adulthood. PMID- 27474259 TI - Circulating galanin and galanin like peptide concentrations are correlated with increased triglyceride concentration in obese patients. AB - BACKGROUND: Obesity is strongly linked to metabolic complications, including type 2 diabetes mellitus and hyperlipidemia. Experimental evidences indicate that galanin (GAL) and galanin-like peptide (GALP) are involved in the regulation of feeding behavior and energy metabolism. We evaluated the possible relationships between both peptide concentrations and blood fat indexes in obese and normal subjects. METHODS: The study groups consisted of 41 obese subjects (age 35.17+/ 12.29year, BMI 30.97+/-2.75kg/m(2)) and 38 healthy controls (age 38.47+/ 11.63year, BMI 22.83+/-3.00kg/m(2)). Plasma GAL and GALP concentration was determined using ELISA. RESULTS: Plasma GAL and GALP concentration was significantly higher in obese subjects than healthy controls (P<0.001). In addition, the positive correlations were found between: GAL and triglyceride (TG) concentrations (r=0.636; P<0.001), GALP and TG concentrations (r=0.362; P=0.020) in obese subjects. CONCLUSIONS: Our results indicated that obese individuals have higher plasma GAL and GALP concentrations and both peptide concentrations were positively correlative to TG concentrations in obese human. GAL and GALP concentrations may be taken as potential biomarkers to predict development of obesity. PMID- 27474261 TI - Respiratory gases and the regulation of transcription. AB - What is the topic of this review? This review highlights the transcriptional consequences for decreased cellular O2 levels (hypoxia) and increased cellular CO2 levels (hypercapnia). What advances does it highlight? We discuss recent advances in our understanding of the cellular response to hypoxia and consider the potential cross-talk between O2 - and CO2 -dependent transcriptional regulation. Oxygen and carbon dioxide are the substrate and product of aerobic metabolism, respectively. Thus, the levels of these physiological gases are inextricably linked in physiological and pathophysiological conditions. Increased mitochondrial consumption of O2 (to produce ATP) will produce more CO2 . Furthermore, in lung pathologies such as chronic obstructive pulmonary disease, sleep apnoea and central hypoventilation syndrome, hypoxia and hypercapnia are co incident. Acute responses to hypoxia involve carotid body-mediated changes in the rate and depth of breathing. Chronic adaptation to hypoxia involves a multitude of changes on a transcriptional level, which simultaneously increases oxygen utilization (via hypoxia-inducible factor and others), while suppressing superfluous energy-demanding processes. Acute responses to CO2 affect breathing primarily via central chemoreceptors. The nature of hypercapnia-dependent transcriptional regulation is an emerging area of research, but at present the mechanisms underpinning this response are not fully characterized and understood. Thus, given the juxtaposition of hypoxia and hypercapnia in health and disease, this manuscript reviews the current evidence for transcriptional responses to hypoxia and hypercapnia. Finally, we discuss the potential cross-talk between hypoxia and hypercapnia on a transcriptional level. PMID- 27474260 TI - Carotid body chemoreflex: a driver of autonomic abnormalities in sleep apnoea. AB - What is the topic of this review? This article presents emerging evidence for heightened carotid body chemoreflex activity as a major driver of sympathetic activation and hypertension in sleep apnoea patients. What advances does it heighlight? This article discusses the recent advances on cellular, molecular and epigenetic mechanisms underlying the exaggerated chemoreflex in experimental models of sleep apnoea. The carotid bodies are the principal peripheral chemoreceptors for detecting changes in arterial blood oxygen concentration, and the resulting chemoreflex is a potent regulator of the sympathetic tone, blood pressure and breathing. Sleep apnoea is a disease of the respiratory system that affects several million adult humans. Apnoeas occur during sleep, often as a result of obstruction of the upper airway (obstructive sleep apnoea) or because of defective respiratory rhythm generation by the CNS (central sleep apnoea). Patients with sleep apnoea exhibit several co-morbidities, with the most notable among them being heightened sympathetic nerve activity and hypertension. Emerging evidence suggests that intermittent hypoxia resulting from periodic apnoea stimulates the carotid body, and the ensuing chemoreflex mediates the increased sympathetic tone and hypertension in sleep apnoea patients. Rodent models of intermittent hypoxia that simulate the O2 saturation profiles encountered during sleep apnoea have provided important insights into the cellular and molecular mechanisms underlying the heightened carotid body chemoreflex. This article describes how intermittent hypoxia affects the carotid body function and discusses the cellular, molecular and epigenetic mechanisms underlying the exaggerated chemoreflex. PMID- 27474262 TI - Microglia in health and pain: impact of noxious early life events. AB - NEW FINDINGS: What is the topic of this review? This review discusses the origins and development of microglia, and how stress, pain or inflammation in early life disturbs microglial function during critical developmental periods, leading to altered pain sensitivity and/or increased risk of chronic pain in later life. What advances does it highlight? We highlight recent advances in understanding how disrupted microglial function impacts the developing nervous system and the consequences for pain processing and susceptibility for development of chronic pain in later life. The discovery of microglia is accredited to Pio del Rio Hortega, who recognized this 'third element' of CNS cells as being morphologically distinct from neurons and astrocytes. For decades after this finding, microglia were altogether ignored or relegated as simply being support cells. Emerging from virtual obscurity, microglia have now gained notoriety as immune cells that assume a leading role in the development, maintenance and protection of a healthy CNS. Pioneering studies have recently shed light on the origins of microglia, their role in the developing nervous system and the complex roles they play beyond the immune response. These studies reveal that altered microglial function can have a profoundly negative impact on the developing brain and may be a determinant in a range of neurodevelopmental disorders and neurodegenerative diseases. The realization that aberrant microglial function also critically underlies chronic pain, a debilitating disorder that afflicts over 1.5 billion people worldwide, was a major conceptual leap forward in the pain field. Adding to this advance is emerging evidence that early life noxious experiences can have a long-lasting impact on central pain processing and adult pain sensitivity. With microglia now coming of age, in this review we examine the association between adverse early life events, such as stress, injury or inflammation, and the influence of sex differences, on the role of microglia in pain physiology in adulthood. PMID- 27474263 TI - Circadian regulation of cardiovascular and kidney function. AB - Video slideshow introduction to the symposium by symposium organiser David Pollock can be found here. PMID- 27474264 TI - Molecular basis of circadian rhythmicity in renal physiology and pathophysiology. AB - NEW FINDINGS: What is the topic of this review? This brief symposium report is focused on the molecular and physiological evidence that supports a key role for the circadian clock in the regulation of kidney function. What advances does it highlight? Progress in understanding the molecular mechanism of the kidney clock is reviewed here, including new results from global 'omics' studies and candidate gene approaches. The molecular kidney clock is a master regulator of gene expression that affects renal electrolyte and drug handling as well as blood pressure. In this brief review, an overview of the molecular and physiological evidence for the kidney clock and the implications for the regulation of renal physiology and pathophysiology are presented. Accumulating evidence suggests that the molecular circadian clock acts as a master regulator of gene expression in the kidney. Global transcriptomic approaches have revealed the important finding that there are thousands of genes in the kidney subject to regulation by the molecular clock. Candidate gene approaches have also yielded information regarding regulation of renal sodium transport genes by the molecular clock. To date, the evidence linking the molecular kidney clock to rhythmic renal function provides strong support for the concept that circadian control of gene expression underlies rhythms in physiological function. PMID- 27474265 TI - Time-of-day variation in vascular function. AB - What is the topic of this review? This report looks at the role of endothelial nitric oxide signalling in the time-of-day variation in vasoconstriction of resistance vessels. What advances does it highlight? It highlights a time-of-day variation in contraction of mesenteric arteries, characterized by a reduced contractile response to either phenylephrine or high K(+) and increased relaxation in response to acetylcholine during the active period. This time-of day variation in contraction results from a difference in endothelial nitric oxide synthase (eNOS) signalling that correlates with levels of eNOS expression, which peak during the active period and may have far reaching physiological consequences beyond regulation of blood pressure. There is a strong time-of-day variation in the vasoconstriction in response to sympathetic stimulation that may contribute to the time-of-day variation in blood pressure, which is characterized by a dip in blood pressure during the individual's rest period when sympathetic activity is low. Vasoconstriction is known to be regulated tightly by nitric oxide signalling from the endothelial cells, so we have looked at the effect of time-of-day on levels of endothelial nitric oxide synthase (eNOS) and vascular contractility. Mesenteric arteries isolated from the nocturnal rat exhibit a time of-day variation in their contractile response to alpha1 -adrenoreceptor and muscarinic activation, which is characterized by a reduced vasoconstriction in response to phenylephrine and enhanced vasodilatation in response to acetylcholine during the rat's active period at night. An increase in eNOS signalling during the active period is responsible for this time-of-day difference in response to phenylephrine and acetylcholine and correlates with the large increase in eNOS expression (mRNA and protein) during the active period, possibly driven by the presence of a functioning peripheral circadian clock. This increase in eNOS signalling may function to limit the increase in peripheral resistance and therefore blood pressure during the increased sympathetic activity. PMID- 27474266 TI - Temporal partitioning of cardiac metabolism by the cardiomyocyte circadian clock. AB - NEW FINDINGS: What is the topic of this review? This review highlights temporal partitioning of cardiac metabolism by the cardiomyocyte circadian clock. What advances does it highlight? Advances include: 1) cardiac glucose utilization peaks during the active period to meet increased energetic demands at this time; 2) synthesis of glycogen and triglyceride peak in the heart during the latter half of the active period, likely in anticipation of the upcoming sleep/fasting period; and 3) protein turnover increases in the heart at the beginning of the sleep phase, probably to promote growth and repair at this time. Cell-autonomous circadian clocks have emerged as crucial mediators of 24 h rhythms in cellular processes. In doing so, these molecular timekeepers confer the selective advantage of anticipation, allowing cells and organs to prepare for stimuli and stresses before their onset. The heart is subjected to dramatic fluctuations in energetic demand and nutrient supply in association with sleep-wake and fasting feeding cycles. Recent studies suggest that the cardiomyocyte circadian clock orchestrates daily rhythms in both oxidative and non-oxidative glucose and fatty acid metabolism, as well as protein turnover. Here, I review this evidence and discuss whether disruption of these rhythms can contribute to cardiovascular disease. PMID- 27474267 TI - Corrigendum to "Magnesium alloys as body implants: Fracture mechanism under dynamic and static loadings in a physiological environment" [Acta Biomater. 8 (2012) 916-923]. PMID- 27474268 TI - Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation. AB - T-cell receptor (TCR) signaling is essential for the function of T cells and negatively regulated by the E3 ubiquitin-protein ligases CBL and CBLB Here, we combined mouse genetics and affinity purification coupled to quantitative mass spectrometry to monitor the dynamics of the CBL and CBLB signaling complexes that assemble in normal T cells over 600 seconds of TCR stimulation. We identify most previously known CBL and CBLB interacting partners, as well as a majority of proteins that have not yet been implicated in those signaling complexes. We exploit correlations in protein association with CBL and CBLB as a function of time of TCR stimulation for predicting the occurrence of direct physical association between them. By combining co-recruitment analysis with biochemical analysis, we demonstrated that the CD5 transmembrane receptor constitutes a key scaffold for CBL- and CBLB-mediated ubiquitylation following TCR engagement. Our results offer an integrated view of the CBL and CBLB signaling complexes induced by TCR stimulation and provide a molecular basis for their negative regulatory function in normal T cells. PMID- 27474269 TI - Deep learning for computational biology. AB - Technological advances in genomics and imaging have led to an explosion of molecular and cellular profiling data from large numbers of samples. This rapid increase in biological data dimension and acquisition rate is challenging conventional analysis strategies. Modern machine learning methods, such as deep learning, promise to leverage very large data sets for finding hidden structure within them, and for making accurate predictions. In this review, we discuss applications of this new breed of analysis approaches in regulatory genomics and cellular imaging. We provide background of what deep learning is, and the settings in which it can be successfully applied to derive biological insights. In addition to presenting specific applications and providing tips for practical use, we also highlight possible pitfalls and limitations to guide computational biologists when and how to make the most use of this new technology. PMID- 27474270 TI - Post-Irradiation Bladder Syndrome After Radiotherapy of Malignant Neoplasm of Small Pelvis Organs: An Observational, Non-Interventional Clinical Study Assessing VESIcare(r)/Solifenacin Treatment Results. AB - BACKGROUND Radiotherapy is explicitly indicated as one of the excluding factors in diagnosing overactive bladder syndrome (OAB). Nevertheless, symptoms of OAB such as urgent episodes, incontinence, pollakiuria, and nocturia, which are consequences of irradiation, led us to test the effectiveness of VESIcare(r)/Solifenacin in patients demonstrating these symptoms after radiation therapy of small pelvis organs due to malignant neoplasm. MATERIAL AND METHODS We conducted an observatory clinical study including 300 consecutive patients with symptoms of post-irradiation bladder; 271 of those patients completed the study. The observation time was 6 months and consisted of 3 consecutive visits taking place at 12-week intervals. We used VESIcare(r) at a dose of 5 mg a day. Every sixth patient was examined urodynamically at the beginning and at the end of the observation period, with an inflow speed of 50 ml/s. RESULTS We noticed improvement and decline in the average number of episodes a day in the following parameters: number of micturitions a day (-36%, P<0.01), nocturia (-50%, P<0.01), urgent episodes (-41%, P<0.03), and episodes of incontinence (-43%, P<0.01). The patients' quality of life improved. The average maximal cystometric volume increased by 34 ml (21%, p<0.01), average bladder volume of "first desire" increased by 42 ml (49%, P<0.01), and average detrusor muscle pressure at maximal cystometric volume diminished by 9 cmH2O (-36%, P<0.03). CONCLUSIONS The substance is well-tolerated. Solifenacin administered long-term to patients with symptoms of OAB after radiotherapy of a malignant neoplasm of the small pelvis organs has a daily impact in decreasing number of urgent episodes, incontinence, pollakiuria, and nocturia. PMID- 27474271 TI - Highly efficient enrichment of phosphopeptides by a magnetic lanthanide metal organic framework. AB - Highly efficient enrichment of phosphopeptides from complex biological samples is crucial prior to mass spectrometry analysis due to the low abundance and ion suppression effects. In this study, a facile route was designed for preparation of a magnetic erbium(Er)-based metal-organic framework (denoted as Fe3O4@PDA@Er(btc)), which was synthesized with 1,3,5-benzenetricarboxylic acid(H3btc) as ligand and grafted on the polydopamine (PDA) - coated Fe3O4. The as-prepared material exhibited ultra-high sensitivity (detection limit of 20amol/MUL) and selectivity at a low mass ratio of beta-Casein/BSA (1:500). Moreover, it was also investigated for enrichment of phosphopeptides from human serum, which provided a promising technique for highly efficient enrichment of low-abundance phosphorylated peptides in the practical application. PMID- 27474272 TI - Design and characterization of novel all-solid-state potentiometric sensor array dedicated to physiological measurements. AB - A novel construction of all-solid-state potentiometric sensor array designed for physiological measurements has been presented. The planar construction and elimination of liquid phase creates broad opportunities for the modifications in the sensing part of the sensor. The designed construction is based on all-solid state ion-selective electrodes integrated with the ionic-liquid based reference electrode. Work parameters of the sensor arrays were characterized. It has been shown that presented sensor design indicates high sensitivity (55.2+/-1mV/dec, 56.3+/-2mV/dec, 58.4+/-1mV/dec and 53.5+/-1mV/pH for sodium-, potassium-, chloride- and pH-selective electrodes, respectively in 10(-5)-10(-1.5)M range of primary ions), low response time (t95 did not exceed 10s), high potential stability (potential drift in 28-h measurement was ca. +/-2mV) and potential repeatability ca. +/-1mV. The system was successfully applied to the simultaneous determination of K(+), Cl(-), Na(+) and pH in the model physiological solution and for the ion flux studies in human colon epithelium Caco-2 cell line as well. PMID- 27474273 TI - An improved matrix separation method for characterization of ultrapure germanium (8N). AB - An improved matrix separation method has been described to characterize ultrapure germanium of 8N (99.999999%) purity. In this method, temperature of the reaction vessel in which in-situ generated chlorine gas reacts with germanium solid material directly is optimized to quantitatively remove Ge matrix from all its impurities. Optimized reaction temperature has been found to be 230+/-5 degrees C. Recovery studies on more than 60 elements have been carried out at the optimized temperature. Recoveries of all the analytes except As, Se, Sn, Hg, Tl are found to be quantitative. The method has been examined for various amounts of Ge material and found to be suitable even for 10g of Ge sample and provides low parts per billion and trillion levels of process blanks. Determination of concentrations of impurities has been done by inductively coupled plasma quadrupole mass spectrometer (ICP-QMS) and high resolution continuum source graphite furnace atomic absorption spectrometer (HR-CS-GFAAS). In the absence of certified reference materials for ultrapure germanium, accuracy of the proposed method is established by spike recovery tests. Precision of this method is found to vary from 7% to 50% for concentrations between 4 and 0.004ngg(-1). Limits of detection (LOD) for the target analytes are found to be between 6 and 0.011ngmL( 1) or 1.8-0.003ngg(-1) for the proposed procedure. The method has been successfully applied for that characterization of ultrapure germanium material of 8N purity. PMID- 27474274 TI - Selective adsorption of hemoglobin with polyoxometalate-derived hybrid by solidification of super-lacunary phosphotungstate polyoxoanions. AB - A novel polyoxometalate (POM)-based hybrid P8W48-APTS is prepared by the solidification of super-lacunary P8W48O184(40-) polyoxoanions with APTS in an acidic medium. The oxygen (O(-)) atoms in P8W48O184(40-) are bound to silicon atoms in APTS by the formation of Si-O linkage through dehydration condensation. The solidification is confirmed by characterizations with XRD, FT-IR, TGA, SEM and EDXS. Selective isolation of proteins of interest, hemoglobin (Hb) in this case, from complex sample matrices is achieved by using P8W48-APTS hybrid as adsorbent under controlled conditions. 5.0mg of P8W48-APTS hybrid results in an adsorption efficiency of 93% for 100mgL(-1) hemoglobin in 1.0mL sample solution at pH 7. The adsorption behavior of Hb onto P8W48-APTS hybrid fits Langmuir adsorption model, corresponding to an adsorption capacity of 355.0mgg(-1). The retained Hb could be readily recovered with either a SDS solution (0.1molL(-1)) or a Na3PO4 (0.1molL(-1)) solution as stripping reagent, providing recoveries of 94.6% or 83.9%, respectively. The biological activity of Hb remains 96.7% after an adsorption/desorption process (with elution by SDS), which illustrates virtually no change on the conformation of hemoglobin. The P8W48-APTS hybrid has been applied for the selective adsorption of Hb from human whole blood, and the results are demonstrated by SDS-PAGE assay. PMID- 27474275 TI - Understanding microwave vessel contamination by chloride species. AB - Microwaves are widely used to assist digestion, general sample treatment and synthesis. The use of aqua regia is extensively adopted for the closed vessel mineralization of samples prior to trace element detection, leading to the contamination of microwave vessels by chlorine containing species. The latter are entrapped in the polymeric matrix of the vessels, leading to memory effects that are difficult to remove, among which the risk of silver incomplete recoveries by removal of the sparingly soluble chloride is the predominant one. In the present paper, we determined by mass spectrometry that hydrogen chloride is the species entrapped in the polymeric matrix and responsible for vessel contamination. Moreover, several decontamination treatments were considered to assess their efficiency, demonstrating that several cleaning cycles with water, nitric acid or silver nitrate in nitric acid were inefficient in removing chloride contamination (contamination reduction around 90%). Better results (~95% decrease) were achieved by a single decontamination step in alkaline environment (sodium hydroxide or ammonia). Finally, a thermal treatment in a common laboratory oven (i.e. without vacuum and ventilation) was tested: a one hour heating at 150 degrees C leads to a 98.5% decontamination, a figure higher than the ones obtained by wet treatments which requires comparable time. The latter treatment is a major advancement with respect to existing treatments as it avoids the need of a vacuum oven for at least 17h as presently proposed in the literature. PMID- 27474276 TI - The use of graphene nanoribbons as efficient electrochemical sensing material for nitrite determination. AB - In this work new designed, highly sensitive electrochemical method is developed for the determination of nitrites in tap water using glassy carbon electrode modified with graphene nanoribbons (GNs/GCE). Graphene nanoribbons (GNs) have been newly synthetized and aligned to the surface of glassy carbon electrode (GCE) and exhibited excellent electrocatalytic activity for nitrite oxidation with a very high peak currents. Studies about electrochemical behavior and optimization of the most important experimental conditions were done using cyclic voltammetry (CV), while quantitative studies were done with amperometric detection. Nitrite provides a well-defined, oxidation peak at +0.9V (vs. Ag/AgCl, 3.0M KCl) in Britton-Robinson buffer solution (BRBS) at pH 3. The influence of most possible interferent ions has been examined and was found to be negligible. Under optimized experimental conditions in BRBS at pH 3 linear calibration curves were obtained in the range from 0.5 to 105uM with the detection limit of 0.22uM. Reproducibility of ten replicate measurements of 1uM of nitrite was estimated to be 1.9%. Proposed method and constructed sensor is successfully applied for the determination of nitrite present in tap water samples without any pretreatment. This developed method represents inexpensive analytical alternative approach compared to other analytical methods. PMID- 27474277 TI - New evidences on efficacy of boronic acid-based derivatization method to identify sugars in plant material by gas chromatography-mass spectrometry. AB - This work presents an analytical procedure based on gas chromatography-mass spectrometry which allows the determination of aldoses (glucose, mannose, galactose, arabinose, xylose, fucose, rhamnose) and chetoses (fructose) in plant material. One peak for each target carbohydrate was obtained by using an efficient derivatization employing methylboronic acid and acetic anhydride sequentially, whereas the baseline separation of the analytes was accomplished using an ionic liquid capillary column. First, the proposed method was optimized and validated. Successively, it was applied to identify the carbohydrates present in plant material. Finally, the procedure was successfully applied to samples from a XVII century painting, thus highlighting the occurrence of starch glue and fruit tree gum as polysaccharide materials. PMID- 27474278 TI - Aptamer and PNIPAAm co-conjugated nanoparticles regulate activity of enzyme with different temperature. AB - In this paper, we described a temperature responsive nano-system that can regulate activity of enzyme with different temperature. Temperature responsive polymer poly(N-isopropylacrylamide) (PNIPAAm), with low critical solution temperature of 32 degrees C, was synthesized with thiol modification. PNIPAAm and thrombin aptamer were co-functionalized on the surface of gold nanoparticles for effective regulation of thrombin activity with different temperature. On the one hand, we studied the thermal responsive properties of this inhibitor via UV visible spectroscopy. On the other hand, we investigated the regulation of thrombin activity by this platform with different temperature. The PNIPAAm chains could extend and shrink with different temperature, which suggested that PNIPAAm on the surface of gold nanoparticles could regulate interaction between thrombin and aptamer according to temperature changing. At 25 degrees C, PNIPAAm was hydrophilic extended state, which blocked the interaction between thrombin and aptamer on the surface of gold nanoparticles, therefore thrombin activity had no change. On the contrary, at 37 degrees C, PNIPAAm transformed from hydrophilic extended state to hydrophobic shrank state, allowing the aptamer to capture thrombin, inhibiting the activity of thrombin. More interestingly, this regulation was reverse to normal condition, where 37 degrees C was always the optimum reaction temperature for most of human enzymes. This system we prepared was opposite, which was capable of inhibiting the thrombin activity at 37 degrees C. Furthermore, this was the first report of regulation of thrombin activity using this temperature responsive platform. PMID- 27474279 TI - Simultaneous determination of radiocesium ((135)Cs, (137)Cs) and plutonium ((239)Pu, (240)Pu) isotopes in river suspended particles by ICP-MS/MS and SF-ICP MS. AB - Due to radioisotope releases in the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident, long-term monitoring of radiocesium ((135)Cs and (137)Cs) and Pu isotopes ((239)Pu and (240)Pu) in river suspended particles is necessary to study the transport and fate of these long-lived radioisotopes in the land-ocean system. However, it is expensive and technically difficult to collect samples of suspended particles from river and ocean. Thus, simultaneous determination of multi-radionuclides remains as a challenging topic. In this study, for the first time, we report an analytical method for simultaneous determination of radiocesium and Pu isotopes in suspended particles with small sample size (1-2g). Radiocesium and Pu were sequentially pre-concentrated using ammonium molybdophosphate and ferric hydroxide co-precipitation, respectively. After the two-stage ion-exchange chromatography separation from the matrix elements, radiocesium and Pu isotopes were finally determined by ICP-MS/MS and SF-ICP-MS, respectively. The interfering elements of U ((238)U(1)H(+) and (238)U(2)H(+) for (239)Pu and (240)Pu, respectively) and Ba ((135)Ba(+) and (137)Ba(+) for (135)Cs and (137)Cs, respectively) were sufficiently removed with the decontamination factors of 1-8*10(6) and 1*10(4), respectively, with the developed method. Soil reference materials were utilized for method validation, and the obtained (135)Cs/(137)Cs and (240)Pu/(239)Pu atom ratios, and (239+240)Pu activities showed a good agreement with the certified/information values. In addition, the developed method was applied to analyze radiocesium and Pu in the suspended particles of land water samples collected from Fukushima Prefecture after the FDNPP accident. The (135)Cs/(137)Cs atom ratios (0.329-0.391) and (137)Cs activities (23.4-152Bq/g) suggested radiocesium contamination of the suspended particles mainly originated from the accident-released radioactive contaminates, while similar Pu contamination of suspended particles caused by the accident could be neglected as the (240)Pu/(239)Pu atom ratios (0.182-0.208) were within the range of global fallout. PMID- 27474280 TI - Purification of quantum dot-based bioprobes via high-performance size exclusion chromatography. AB - Due to excellent optical properties, quantum dots (QDs) have been widely applied to sensing, labeling, and imaging. For the fabrication of QD-based bioprobes, purification is usually the crucial step. Hydrophilic octylamine grafted polyacrylic acid modified QDs (OPA-QDs) were prepared, and purified by high performance size exclusion chromatography (HPSEC) to remove excess OPA and aggregated QDs. The percentage of suspended agglomerates of OPA-QDs in the unpurified OPA-QDs increases from 4% to 31% through a year, but the purified OPA QDs of the same batch possess excellent colloidal stability for at least one year. Subsequently, QD-based bioprobes were fabricated by the conjugation between QDs and streptavidin (SA) or antibody (IgG), generating QD-SA and QD-IgG, respectively, which were purified via HPSEC. Finally, the resulting QD-SA and QD IgG were adopted to detect tumour markers on slices and showed specific positive signals without nonspecific adsorption, which was contrary to the unpurified QD IgG. Thus, the HPSEC-coupled system proposed in the current work is potent and universal for the generation of purified and monodisperse QD-based bioprobes, which is promising in the nanobiodetection field. PMID- 27474281 TI - Fluorescent labelling of ciprofloxacin and norfloxacin and its application for residues analysis in surface water. AB - Sensitivity enhancement for residue analysis of ciprofloxacin and norfloxacin in surface water was performed by liquid chromatography with fluorescent detection (LC-FD). Labelling of both drugs were studied with fluorescent probes (e.g. Nile blue perchlorate (NBP) and 4- (N,N-Dimethylaminosulfonyl)-7-(N-chloroformylmethyl N-methylamino)-2,1,3-benzoxadiazole (DBD-COCl). Factors affecting the derivatization (e.g. stoichiometric ratios, reaction time and base catalysts) were optimized. The derivatization was achieved in 15min using a stoichiometric ratio between the substrate and DBD-COCl of 1:3, whereas NBP gave unsatisfactory results. Separation of the derivatives by LC was achieved (resolution (RS) > 1.8) on a C8 column using a mobile phase consisting of 50mM formic acid and acetonitrile (ACN) (68:32% v/v) in 20min. The method was linear (r(2) > 0.99) in a range of 200-2,000ug/L, precise (%RSD < 9.17) and accurate (%recovery of 102.5 122.2%) for the determination of the derivatives. The uses of fluoroquinolone molecularly imprinted polymer in conjunction with hydrophilic-lipophilic balance sorbents demonstrated an efficient procedure for sample pre-concentration and clean-up for water sample resulting in the improved percent recovery. Applications of the proposed method was shown in surface water samples in Thailand. PMID- 27474282 TI - Monitoring dissolved orthophosphate in a struvite precipitation reactor with a voltammetric electronic tongue. AB - This study demonstrates the feasibility of using a voltammetric electronic tongue to monitor effluent dissolved orthophosphate concentration in a struvite precipitation reactor. The electrochemical response of the electronic tongue to the presence of orthophosphate in samples collected from the effluent of the precipitation reactor is used to predict orthophosphate concentration via a statistical model based on Partial Least Squares (PLS) Regression. PLS predictions were suitable for this monitoring application in which precipitation efficiencies higher than 80% (i.e., effluent dissolved orthophosphate concentrations lower than 40mg P-PO4(3-) L(-1)) could be considered as indicator of good process performance. The electronic tongue consisted of a set of metallic (noble and non-noble) electrodes housed inside a stainless steel cylinder which was used as the body of the electronic tongue system. Fouling problems were prevented via a simple mechanical polishing of the electrodes. The measurement of each sample with the electronic tongue was done in less than 3s. Conductivity of the samples only affected the electronic tongue marginally, being the main electrochemical response due to the orthophosphate concentration in the samples. Copper, silver, iridium and rhodium were the electrodes that exhibited noticeable response correlated with the dissolved orthophosphate concentration variations, while gold, platinum and especially cobalt and nickel were the less useful electrodes for this application. PMID- 27474284 TI - A nontargeted screening method for covalent DNA adducts and DNA modification selectivity using liquid chromatography-tandem mass spectrometry. AB - A method for nontargeted screening for covalent DNA adducts was developed using combination of neutral loss scan and product ion scan in a hybrid linear-ion-trap - triple quadrupole mass spectrometer system. DNA 2'-deoxynucleosides and adducts eluted from liquid chromatography were first analyzed in neutral loss mode to screen for the neutral loss of the deoxyribose moiety ([M+H-116](+)) from the protonated molecular ion ([M+H](+)). The product ion scan was subsequently used to elucidate the structures for the molecular ions observed from the peaks in the neutral loss scan chromatogram. The synthesized DNA adducts were used to evaluate the developed method by reaction of 20-mer DNA oligonucleotide with two direct agents respectively, specifically phenyl glycidyl ether and styrene-7,8-oxide. The modification selectivity of two compounds to the four nitrogenous bases on DNA sequence was also investigated in this study. The results showed that the two compounds had different modification selectivity to the four bases. Both compounds could modify all four nitrogenous bases (i.e. adenine, guanine, thymine, and cytosine) on DNA sequences to form various covalent DNA adducts. While phenyl glycidyl ether modified almost all of thymidine on DNA sequence, styrene-7,8-oxide, on the other hand, modified only a small portion of thymidine. The developed method proved possibly a potential tool for screening of unknown DNA adducts as exposure biomarkers of contaminants to human in the environment. PMID- 27474283 TI - Modification-free and N-acetyl-L-cysteine-induced colorimetric response of AuNPs: A mechanistic study and sensitive Hg(2+) detection. AB - A facile yet sensitive and selective method was proposed for Hg(2+) detection based on N-acetyl-L-cysteine(NAC)-induced colorimetric response of AuNPs. The proposed method can be easily performed by introducing the premixing of NAC and Hg(2+) into as-prepared citrate-capped AuNPs solution. A combination of experimental and theoretical studies was applied to illustrate the mechanism of this AuNPs colorimetric system. The strong interaction of NAC and AuNPs through Au-S bond could lead to the aggregation of AuNPs, but the formation of NAC-Hg-NAC complex decreased the affinity between NAC and AuNPs and resulted in an anti aggregation effect. Therefore, the color of the AuNPs solution would progress from purple to red with the increase of Hg(2+) concentration. The proposed method had a high sensitivity with a limit of detection of 9.9nM. Coexistent metal ions, including Cd(2+), Mn(2+), Al(3+), Ag(+), K(+), Mg(2+), Ca(2+), Cr(3+), Cu(2+), Fe(3+), Pb(2+), Ni(2+) and Zn(2+), did not interfere with the detection of Hg(2+). This method can be used to monitor Hg(2+) in tap water. PMID- 27474285 TI - Separation and preconcentration of platinum-group metals from spent autocatalysts solutions using a hetero-polymeric S, N-containing sorbent and determination by high-resolution continuum source graphite furnace atomic absorption spectrometry. AB - This paper describes the potential of high-resolution continuum source graphite furnace atomic absorption spectrometry for determination of Pt, Pd and Rh after separation and concentration by original in-house developed heterochain polymer S, N-containing sorbent. The methods of sample preparation of spent ceramic-based autocatalysts were considered, two of which were used: autoclave decomposition in mixture of acids HCl:HNO3 (3:1) and high-temperature melting with K2S2O7. Both methods anyway limit the direct determination of analytes by HR CS GFAAS. Using the first method it is an incomplete digestion of spent autocatalysts samples, since the precipitate is Si, and the rhodium metal dissolves with difficulty and partially passes into solution. In contrast to the first method, the second method allow to completely transfer analytes into solution, however, the background signal produced by the chemical composition of the flux, overlaps the analytical zone. It was found, that Pt, Pd and Rh contained in the spent ceramic automotive catalysts could be effectively separated and concentrated by heterochain polymer S, N-containing sorbent, which has high sorption capacity, selectivity and resistant to dilute acids. The chosen HR CS GFAAS analysis conditions enable us to determine Pt, Pd and Rh with good metrological characteristics. The concentrations of Pt, Pd and Rh in two samples of automobile exhaust catalysts were found in range of 0.00015-0.00050; 0.170-0.189; 0.0180 0.0210wt%, respectively. The relative standard deviation obtained by HR CS GFAAS was not more than 5%. Limits of detection by HR CS GFAAS achieved were 6.2.10( 6)wt% for Pt, 1.8.10(-6)wt% for Pd, and 3.4.10(-6)wt% for Rh. Limits of determination achieved by HR CS GFAAS were 1.1.10(-5)wt% for Pt, 6.9.10(-5)wt% for Pd, and 8.3.10(-5)wt% for Rh. To control the accuracy of PGM in sorption concentrates by HR CS GFAAS method, it was appropriate to conduct an inter-method comparative experiment. The researches on the application of atomic-emission spectroscopy method with inductively coupled plasma as a comparative method were conducted. In addition, the trueness control of the obtained results is confirmed by added-found method. PMID- 27474286 TI - Fluorous modified magnetic mesoporous silica composites-incorporated fluorous solid-phase extraction for the specific enrichment of N-linked glycans with simultaneous exclusion of proteins. AB - Taking advantage of fluorine-fluorine interactions, fluorous solid-phase extraction (FSPE) is emerging as a novel approach in proteomics research. Notably, silica gel bound with perfluoroalkyl groups was applied to the FSPE of N linked glycans. Based on previous studies, mesoporous silica coated magnetic nanoparticles bound with perfluoroalkyl groups were synthesized for the specific enrichment of N-linked glycans in this study. The magnetic nanoparticles incorporated FSPE strategy successfully identified 22 N-linked glycans from the OVA digest with a concentration of 0.5MUg/MUL, and achieved a detection limit of 5ng/MUL (with 16 N-linked glycans identified). It also showed good day-to-day reproducibility. Its selectivity towards BSA protein is 1:200 (molar ratio), showing excellent size-exclusion effect. In addition, the present method proved to be effective for the analysis of the human serum digest, opening up new prospect for the identification of glycans and proteins with other post translational modifications in biological environment. PMID- 27474287 TI - Solvent bar micro-extraction with graphite atomic absorption spectrometry for the determination of silver in ocean water. AB - Main drawbacks for silver determination in seawater are the effects of samples matrix and that Ag appears in the sub ng L(-1). Available methods for sample preparation in Ag analysis are based on solid and liquid extraction using tedious process that increase the cost of analysis and the risk of sample contamination, producing important waste amounts. Solvent bar micro-extraction (SBME) allows the pre-concentration of Ag in a micro-volume of the ionic liquid Aliquat 336(r) in kerosene solution. For this reason, it is considered as a green alternative to standard methods. The method has been optimized using synthetic seawater samples, offering the highest response for samples at pH=2, using 5% Aliquat 336(r) dissolved in kerosene containing 5% dodecan-1-ol as acceptor solution and after 1h stirring at 800rpm. The method exhibited linearity up to 50ngL(-1), with a limit of detection of 0.09ngL(-1), covering the concentration range of interest for environmental studies. Finally, it was applied for determination of Ag in real seawater samples, and the results were compared with the reference method of liquid-liquid extraction with 1-pyrrolidine-dithiocarbamate and diethylammonium diethyldithiocarbamate, showing the applicability of ionic liquid based SBME using Aliquat 336((r)) for the simple monitoring of silver ultra-traces in seawater analysis. PMID- 27474288 TI - Detection of glucose based on the peroxidase-like activity of reduced state carbon dots. AB - It was found that reduced state carbon dots (r-CDs) possessed intrinsic peroxidase-like activity, and could catalytically oxidize 3,3',5,5' tetramethylbenzidine (TMB) by H2O2 to produce a color reaction. The effects of temperature, pH, incubating time and the concentration of H2O2 and TMB on catalytic activity of r-CDs were investigated. Finally we calculated the kinetic constant was ca. 0.00729min(-1) and applied r-CDs to glucose sensing by coupling glucose oxidase. As low as 2uM H2O2 could be detected with a linear range from 0.010 to 0.40mM via this method. This study offered a simple, sensitive, and high selectivity method for glucose determination even in serum. PMID- 27474289 TI - Selective determination of four arsenic species in rice and water samples by modified graphite electrode-based electrolytic hydride generation coupled with atomic fluorescence spectrometry. AB - This work describes a novel non-chromatographic approach for the accurate and selective determining As species by modified graphite electrode-based electrolytic hydride generation (EHG) for sample introduction coupled with atomic fluorescence spectrometry (AFS) detection. Two kinds of sulfydryl-containing modifiers, l-cysteine (Cys) and glutathione (GSH), are used to modify cathode. The EHG performance of As has been changed greatly at the modified cathode, which has never been reported. Arsenite [As(III)] on the GSH modified graphite electrode (GSH/GE)-based EHG can be selectively and quantitatively converted to AsH3 at applied current of 0.4A. As(III) and arsenate [As(V)] on the Cys modified graphite electrode (Cys/GE) EHG can be selectively and efficiently converted to arsine at applied current of 0.6A, whereas monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) do not form any or only less volatile hydrides under this condition. By changing the analytical conditions, we also have achieved the analysis of total As (tAs) and DMA. Under the optimal condition, the detection limits (3s) of As(III), iAs and tAs in aqueous solutions are 0.25MUgL(-1), 0.22MUgL(-1) and 0.10MUgL(-1), respectively. The accuracy of the method is verified through the analysis of standard reference materials (SRM 1568a). PMID- 27474290 TI - Headspace sorptive solid phase microextraction (HS-SPME) combined with a spectrophotometry system: A simple glass devise for extraction and simultaneous determination of cyanide and thiocyanate in environmental and biological samples. AB - A simple, low cost and efficient headspace sorptive solid phase microextraction (HS-SPME) method for determination of cyanide has been developed. The system comprises of a glass tube with two valves and a moveable glass slide fixed at its centre. It includes an acceptor phase polyurethane foam treated mercury (II) dithizonate [Hg(HDz)2-PUF] complex fixed inside by a septum cap in a cylindrical configuration (5.0cm length and 1.0cm diameter). The extraction is based upon the contact of the acceptor phase to the headspace and subsequently measuring the absorbance of the recovered mercury (II) dithizonate from PUFs sorbent. Unlike other HSSE, extraction and back - extractions was carried out in a closed system, thereby improving the analytical performance by preventing the analyte loss. Under the optimized conditions, a linear calibration plot in the range of 1.0 50.0umolL(-1) was achieved with limits of detection (LOD) and quantification (LOQ) of 0.34, 1.2umolL(-1) CN(-), respectively. Simultaneous analysis of cyanide and thiocyanate in saliva was also performed with satisfactory recoveries. PMID- 27474291 TI - Fabrication and evaluation of an electrodialytic carbonate eluent generator for ion chromatography. AB - An electrodialytic potassium carbonate eluent generator and its associated potassium bicarbonate eluent generator have been fabricated for ion chromatography (IC). The device can withstand high backpressure up to ~32MPa and no observable leakage under such pressure is found during 2h. In the range of 0 13.7mM, potassium carbonate concentration can be generated linearly with the applied current with a slope that is essentially Faradaic. At least 10mM potassium carbonate can be online changed into 10mM potassium bicarbonate via a potassium bicarbonate eluent generator, which offers an easy way to manipulate the separation selectivity. When coupled with IC system, the device demonstrated good reproducibility indicated by less than 0.52% of the relative standard deviation of the retention times. PMID- 27474292 TI - Determination of oleuropein using multiwalled carbon nanotube modified glassy carbon electrode by adsorptive stripping square wave voltammetry. AB - A multi-walled carbon nanotube modified glassy carbon electrode was used to prepare an electrochemical sensing platform for the determination of oleuropein. Results showed that, the accumulation of oleuropein on the prepared electrode takes place with the adsorption process. Electrochemical behavior of oleuropein was studied by using cyclic voltammetry. Compared to the bare GCE, the oxidation peak current of oleuropein increased about 340 times at MWCNT/GCE. Voltammetric determination of oleuropein on the surface of prepared electrode was studied using square wave voltammetry where the oxidation peak current of oleuropein was measured as an analytical signal. A calibration curve of oleuropein was performed between 0.01 and 0.70uM and a good linearity was obtained with a correlation coefficient of 0.9984. Detection and quantification limits of the method were obtained as 2.73 and 9.09nM, respectively. In addition, intra-day and inter-day precision studies indicated that the voltammetric method was sufficiently repeatable. Finally, the proposed electrochemical sensor was successfully applied to the determination of oleuropein in an olive leaf extract. Microwave-assisted extraction of oleuropein had good recovery values between 92% and 98%. The results obtained with the proposed electrochemical sensor were compared with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. PMID- 27474293 TI - Microwave-assisted enzymatic hydrolysis followed by extraction with restricted access nanocomposites for rapid analysis of glucocorticoids residues in liver tissue. AB - We developed a novel, simple and fast method for the determination of glucocorticoids residues in liver tissue by combining microwave-assisted enzymatic hydrolysis and restricted access matrix dispersive solid phase extraction (RAM-dSPE) followed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Firstly, microwave-assisted enzymatic hydrolysis was introduced in order to obtain a maximum amount of unconjugated parent drug in a short time (8s), while the traditional method commonly needs 4 12h. Secondly, further cleanup was carried out by RAM-dSPE based on the graphene@mSiO2-C8 nanomaterials which were synthesized by coating mesoporous silica onto hydrophilic graphene nano-sheets through a surfactant-mediated co condensation sol-gel process. The enzymatic hydrolysis influencing factors (pH of the buffer, microwave radiation power, incubation time) and the experimental conditions of RAM-dSPE (sorbents amount, type and volume of the elution solvent, adsorption and desorption time) were optimized. Three glucocorticoids (prednisolone (PREL), betamethasone (BE) and dexamethasone (DE)) were selected as models to evaluate the feasibility of the method. According to the results, the developed method provided low detection limit (S/N=3) of 0.01-0.05MUgkg(-1) and good linearity range of 0.25-800MUgkg(-1) (R(2)>0.996) for glucocorticoids. The limit of quantification (S/N=10) range from 0.03 to 0.19MUgkg(-1). Compared with other traditional methods, the developed method could provide similar or even better results in a greatly reduced analysis time. PMID- 27474294 TI - Simultaneous analysis of multiple classes of antimicrobials in environmental water samples using SPE coupled with UHPLC-ESI-MS/MS and isotope dilution. AB - A robust and sensitive analytical method was developed for the simultaneous analysis of 21 target antimicrobials in different environmental water samples. Both single SPE and tandem SPE cartridge systems were investigated to simultaneously extract multiple classes of antimicrobials. Experimental results showed that good extraction efficiencies (84.5-105.6%) were observed for the vast majority of the target analytes when extraction was performed using the tandem SPE cartridge (SB+HR-X) system under an extraction pH of 3.0. HPLC-MS/MS parameters were optimized for simultaneous analysis of all the target analytes in a single injection. Quantification of target antimicrobials in water samples was accomplished using 15 isotopically labeled internal standards (ILISs), which allowed the efficient compensation of the losses of target analytes during sample preparation and correction of matrix effects during UHPLC-MS/MS as well as instrument fluctuations in MS/MS signal intensity. Method quantification limit (MQL) for most target analytes based on SPE was below 5ng/L for surface waters, 10ng/L for treated wastewater effluents, and 15ng/L for raw wastewater. The method was successfully applied to detect and quantify the occurrence of the target analytes in raw influent, treated effluent and surface water samples. PMID- 27474295 TI - Speciation of inorganic selenium in environmental samples after suspended dispersive solid phase microextraction combined with inductively coupled plasma spectrometric determination. AB - A rapid and effective suspended dispersive solid phase microextraction (SDSPME) was developed for the speciation of inorganic selenium using alumina nanoparticles functionalized with Aliquat-336. The target analytes were preconcentrated and determined by inductively coupled plasma optical emission spectrometry. Alumina nanoparticles were characterized using XRD, BET, SEM and EDX while the functionalized nano-Al2O3 was characterized by FTIR. The effect of pH of the solution on speciation Se in water samples was optimized separately. It was observed that when the pH values of sample solution ranged from 2.0 to 7.0, successful separation of inorganic Se species was achieved. The percentage recoveries for Se (IV) and Se (VI) were >90% and 5%, respectively. The two-level fractional factorial design was used to optimize experimental parameters affecting the preconcentration system. Under optimal conditions, the enrichment factor (EF), limit of detection (LOD) and limit of quantification for Se (IV) were found to be 850, 1.4ngL(-1,) and 4.6ngL(-1), respectively. Furthermore, intra-day and inter-day precisions expressed in terms of relative standard deviation (RSD) were found to be 1.9% and 3.3%, respectively. The effect of coexisting ions on the recovery of Se (IV) was investigated. The accuracy of the developed method was checked by analysis of standard reference material (NIST SRM 1643e). The optimized method was applied for the determination of targets in surface water samples. PMID- 27474296 TI - Development and validation of a RP-UHPLC-ESI-MS/MS method for the chiral separation and determination of flavanone, naringenin and hesperetin enantiomers. AB - A quick and sensitive RP-UHPLC-ESI-MS/MS method for the separation of flavanone, naringenin and hesperetin enantiomers was developed. The separation of analytes was performed using a Chiralpak AD-3R column, and methanol was used as the mobile phase. Detection was carried out using a triple quadrupole tandem mass spectrometer with an electrospray ionisation source. Positive ionisation and multiple reaction monitoring (MRM) were used. The developed method showed satisfactory linearity with determination coefficients greater than 0.996 in the concentration ranges of 2.5-100.0ngmL(-1) for naringenin and flavanone enantiomers and 0.5-100.0ngmL(-1) for hesperetin enantiomers. The limits of quantification varied from 0.1 to 2.0ngmL(-1). The intra-day and inter-day precisions were below 15%, and the accuracy varied from -13.6% to 13.5%. The described method was successfully applied for the chiral separation and determination of flavonoid enantiomers in real samples of spices and herbal root. Due to the occurrence of the natural compounds in the forms of free aglycones and their glycosides, these samples were subjected to hydrolysis in order to obtain free aglycones from the glycosylated forms. Acid and enzymatic hydrolysis techniques were also compared. In the course of this study, the enzymatic hydrolysis technique was selected. PMID- 27474297 TI - Application of dried blood spot cards to determine olive oil phenols (hydroxytyrosol metabolites) in human blood. AB - In this study, a fast and simple blood sampling and sample pre-treatment method based on the use of the dried blood spot (DBS) cards and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for the quantification of olive oil phenolic metabolites in human blood was developed and validated. After validation, the method was applied to determine hydroxytyrosol metabolites in human blood samples after the acute intake of an olive oil phenolic extract. Using the FTA DMPK-A DBS card under optimum conditions, with 20uL as the blood solution volume, 100uL of methanol/Milli-Q water (50/50, v/v) as the extraction solvent and 7 disks punched out from the card, the main hydroxytyrosol metabolites (hydroxytyrosol-3-O-sulphate and hydroxytyrosol acetate sulphate) were identified and quantified. The developed methodology allowed detecting and quantifying the generated metabolites at low MUM levels. The proposed method is a significant improvement over existing methods to determine phenolic metabolites circulating in blood and plasma samples, thus making blood sampling possible with the volunteer pricking their own finger, and the subsequent storage of the blood in the DBS cards prior to chromatographic analysis. PMID- 27474298 TI - Highly sensitive nonenzymatic glucose sensor based on nickel nanoparticle attapulgite-reduced graphene oxide-modified glassy carbon electrode. AB - In this article, a fast and sensitive nonenzymatic glucose sensor is reported utilizing a glassy carbon electrode modified by synthesizing nanocomposites of nickel nanoparticle-attapulgite-reduced graphene oxide (Ni NPs/ATP/RGO). A facile one-step electrochemical co-deposition approach is adopted to synthesize Ni NPs ATP-RGO nanocomposites via electrochemical reduction of mixed precursor solution containing graphene oxide (GO), attapulgite (ATP) and nickel cations (Ni(2+)) at the cathode potentials. This strategy results in simultaneous depositions of ATP, cathodic reduction of Ni(2+) into nickel nanoparticles under acidic conditions, and in situ reduction of GO. The as-prepared NiNPs/ATP/RGO-based glucose sensor exhibits outstanding performance for enzymeless glucose sensing with sensitivity (1414.4 MUAmM(-1)cm(-2)), linear range (1-710MUM) and detection limit (0.37MUM). What is more, the sensor has excellent stability and selectivity against common interferences in real sample. PMID- 27474299 TI - Nuclear forensic analysis of a non-traditional actinide sample. AB - Nuclear forensic publications, performance tests, and research and development efforts typically target the bulk global inventory of intentionally safeguarded materials, such as plutonium (Pu) and uranium (U). Other materials, such as neptunium (Np), pose a nuclear security risk as well. Trafficking leading to recovery of an interdicted Np sample is a realistic concern especially for materials originating in countries that reprocesses fuel. Using complementary forensic methods, potential signatures for an unknown Np oxide sample were investigated. Measurement results were assessed against published Np processes to present hypotheses as to the original intended use, method of production, and origin for this Np oxide. PMID- 27474301 TI - Simultaneous determination of environmental estrogens: Diethylstilbestrol and estradiol using Cu-BTC frameworks-sensitized electrode. AB - It is quite important to monitor environmental estrogens in a rapid, sensitive, simple and cost-effective manner due to their wide existence and high toxicity. Using 1,3,5-Benzenetricarboxylic acid (H3BTC) as the ligand and copper ions as the center, Cu-BTC frameworks with surface area of 654.6m(2)/g were prepared, and then used to construct a novel electrochemical sensing platform for diethylstilbestrol (DES) and estradiol (E2). On the surface of Cu-BTC frameworks, two oxidation waves at 0.26V and 0.45V are observed for DES and E2, and the oxidation signals are improved greatly. The prepared Cu-BTC frameworks not only enhance the accumulation efficiency of DES and E2, but also improve their electron transfer ability. The influences of pH value, modification amount of Cu BTC and accumulation time were examined. As a result, a highly-sensitive, rapid and convenient electrochemical method was developed for the simultaneous determination of DES and E2, with detection limit of 2.7nM and 1.1nM. The practical applications manifest this new sensing system is accurate and feasible. PMID- 27474300 TI - A rapid and ultrasensitive SERRS assay for histidine and tyrosine based on azo coupling. AB - A simple and highly sensitive surface-enhanced resonance Raman scattering (SERRS) based approach coupled with azo coupling reaction has been put forward for quantitative analysis of histidine and tyrosine. The SERRS-based assay is simple and rapid by mixing the azo reaction products with silver nanoparticles (AgNPs) for measurements within 2min. The limits of detection (LODs) of the method are as low as 4.33*10(-11) and 8.80*10(-11)M for histidine and tyrosine, respectively. Moreover, the SERRS fingerprint information specific to corresponding amino acids guarantees the selective detection for the target histidine and tyrosine. The results from serum indicated the potential application of the proposed approach into biological samples. Compared with the methods ever reported, the main advantages of this methodology are simpleness, rapidity without time-consuming separation or pretreatment steps, high sensitivity, selectivity and the potential for determination of other molecules containing imidazole or phenol groups. PMID- 27474302 TI - Ionic liquid coated carbon nanospheres as a new adsorbent for fast solid phase extraction of trace copper and lead from sea water, wastewater, street dust and spice samples. AB - In this study a new adsorbent, ionic liquid (1,8-naphthalene monoimide bearing imidazolium salt) coated carbon nanospheres, was synthesized for the first time and it was used for the solid phase extraction of copper and lead from various samples prior to determination by flame atomic absorption spectrometry. The ionic liquid, carbon nanospheres and ionic liquid coated carbon nanospheres were characterized by using Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, (1)H NMR and (13)C NMR, Brunauer, Emmett and Teller surface area and zeta potential measurements. Various parameters for method optimization such as pH, adsorption and elution contact times, eluent volume, type and concentration, centrifuge time, sample volume, adsorption capacity and possible interfering ion effects were tested. The optimum pH was 6. The preconcentration factor, detection limits, adsorption capacity and precision (as RSD%) of the method were found to be 300-fold, 0.30ugL(-1), 60mgg( 1) and 1.1% for copper and 300-fold, 1.76ugL(-1); 50.3mgg(-1) and 2.2%, for lead, respectively. The effect of contact time results showed that copper and lead were adsorbed and desorbed from the adsorbent without vortexing. The equilibrium between analyte and adsorbent is reached very quickly. The method was rather selective for matrix ions in high concentrations. The accuracy of the developed method was confirmed by analyzing certified reference materials (LGC6016 Estuarine Water, Reference Material 8704 Buffalo River Sediment, and BCR-482 Lichen) and by spiking sea water, wastewater, street dust and spice samples. PMID- 27474303 TI - Synthesis of single-crystal alpha-MnO2 nanotubes-loaded Ag@C core-shell matrix and their application for electrochemical sensing of nonenzymatic hydrogen peroxide. AB - A nonenzymatic hydrogen peroxide sensor was fabricated by combing the crystal alpha-MnO2 nanotubes and Ag@C core-shell matrix with their own superior characteristics. The morphology, size and electrochemical of the sensing interface materials and the relationship between the electrical catalytic properties and sensor response performance were also studied, established a new method for the detection of hydrogen peroxide (H2O2). The structure and morphology of hollow tubular-like MnO2 and MnO2-Ag@C film were characterized by scanning electron micrograph (SEM), transmission electron microscopy (TEM) and X ray diffraction. The electrochemical properties of the sensor were explored by cyclic voltammetry and amperometry. The investigation showed that the MnO2-Ag@C at the sensor exhibited a high electrocatalytic activity towards electroreduction of hydrogen peroxide; and under the optimal conditions, the linear ranges of hydrogen peroxide were 0.5MUM to 5.7mM with a low detection limit of 0.17MUM (S/N=3) and high sensitivity of 127.2MUAmM(-1)cm(-2). Compared with other nonenzymatic hydrogen peroxide sensor, the fabricated sensor own lower detection limit, demonstrating that MnO2-Ag@C nanocomposite film will be a new promising platform for the construction of hydrogen peroxide sensors. PMID- 27474304 TI - Pre-analytical and analytical validations and clinical applications of a miniaturized, simple and cost-effective solid phase extraction combined with LC MS/MS for the simultaneous determination of catecholamines and metanephrines in spot urine samples. AB - It remains a challenge to simultaneously quantify catecholamines and metanephrines in a simple, sensitive and cost-effective manner due to pre analytical and analytical constraints. Herein, we describe such a method consisting of a miniaturized sample preparation and selective LC-MS/MS detection by the use of second morning spot urine samples. Ten microliters of second morning urine sample were subjected to solid phase extraction on an Oasis HLB microplate upon complexation with phenylboronic acid. The analytes were well resolved on a Luna PFP column followed by tandem mass spectrometric detection. Full validation and suitability of spot urine sampling and biological variation were investigated. The extraction recovery and matrix effect are 74.1-97.3% and 84.1-119.0%, respectively. The linearity range is 2.5-500, 0.5-500, 2.5-1250, 2.5 1250 and 0.5-1250ng/mL for norepinephrine, epinephrine, dopamine, normetanephrine and metanephrine, respectively. The intra- and inter-assay imprecisions are <=9.4% for spiked quality control samples, and the respective recoveries are 97.2 112.5% and 95.9-104.0%. The Deming regression slope is 0.90-1.08, and the mean Bland-Altman percentage difference is from -3.29 to 11.85 between a published and proposed method (n=50). A correlation observed for the spot and 24h urine collections is significant (n=20, p<0.0001, r: 0.84-0.95, slope: 0.61-0.98). No statistical differences are found in day-to-day biological variability (n=20). Reference intervals are established for an apparently healthy population (n=88). The developed method, being practical, sensitive, reliable and cost-effective, is expected to set a new stage for routine testing, basic research and clinical applications. PMID- 27474305 TI - Copolymeric hexyl acrylate-methacrylic acid microspheres - surface vs. bulk reactive carboxyl groups. Coulometric and colorimetric determination and analytical applications for heterogeneous microtitration. AB - Copolymeric acrylate microspheres were prepared from hexyl acrylate using different amounts of methacrylic acid, resulting in a series of microspheres of gradually changing properties. The distribution of carboxyl groups - between surface and bulk of microspheres was evaluated. Bulk reactive carboxyl groups were determined using reverse coulometric titration with H(+) ions, following hydroxide ions have been generated and allowed to react with microspheres in the first step. It was found that the number of reactive carboxyl groups available in copolymeric microspheres is lower compared to number of methacrylic acid units used for polymerization process. Moreover, there is correlation between the number of groups introduced and found to be reactive in microspheres. On the other hand, the number of surface reactive groups was proportional to the number of groups introduced in course of polymerization. Thus, the surface reactive groups can be used as reagent, in novel heterogeneous microtitration procedure, in which a constant number of microspheres of different carboxyl groups contents is introduced to the sample to react with the analyte. The applicability of novel proposed method was tested on the example of Ni(2+) determination. PMID- 27474307 TI - Analysis of the elemental composition of marine litter by field-portable-XRF. AB - Marine litter represents a pervasive environmental problem that poses direct threats to wildlife and habitats. Indirectly, litter can also act as a vehicle for the exposure and bioaccumulation of chemicals that are associated with manufactured or processed solids. In this study, we describe the use of a Niton field-portable-x-ray fluorescence (FP-XRF) spectrometer to determine the content of 17 elements in beached plastics, foams, ropes and painted items. The instrument was used in a 'plastics' mode configured for complex, low density materials, and employed a thickness correction algorithm to account for varying sample depth. Accuracy was evaluated by analysing two reference polyethylene discs and was better than 15% for all elements that had been artificially impregnated into the polymer. Regarding the litter samples, limits of detection for a 120s counting time varied between the different material categories and among the elements but were generally lowest for plastics and painted items with median concentrations of less than 10MUgg(-1) for As, Bi, Br, Cr, Hg, Ni, Pb, Se and Zn. Concentrations returned by the XRF were highly sensitive to the thickness correction applied for certain elements (Ba, Cl, Cr, Cu, Fe, Sb, Ti, Zn) in all matrices tested, indicating that accurate measurement and application of the correct thickness is critical for acquiring reliable results. An independent measure of the elemental content of selected samples by ICP spectrometry following acid digestion returned concentrations that were significantly correlated with those returned by the XRF, and with an overall slope of [XRF]/[ICP]=0.85. Within the FP-XRF operating conditions, Cl, Cr, Fe, Ti and Zn were detected in more than 50% and Hg and Se in less than 1% of the 376 litter samples analysed. Significant from an environmental perspective were concentrations of the hazardous elements, Cd, Br and Pb, that exceeded several thousand MUgg(-1) in many cases. PMID- 27474306 TI - Bright and photostable fluorescent probe with aggregation-induced emission characteristics for specific lysosome imaging and tracking. AB - We develop a new lysosome-targeting AIE fluorescent probe tetraphenylethene morpholine (TPE-MPL), by incorporating a typical lysosome-targeting moiety of morpholine into a stable tetraphenylethene skeleton. Due to both the AIE and antenna effects, TPE-MPL possesses superior photostability, appreciable tolerance to microenvironment change and high lysosome targeting ability. Our findings confirm that TPE-MPL is a well-suited imaging agent for targeting lysosome and tracking dynamic movement of lysosome. Moreover, due to its synthetic accessibility, TPE-MPL could be further modified as a dual-functional probe for lysosome, thereby gain further insight into the role of lysosome in biomedical applications. PMID- 27474308 TI - High-capacity anion exchangers based on poly (glycidylmethacrylate divinylbenzene) microspheres for ion chromatography. AB - Poly (glycidylmethacrylate-divinylbenzene) microspheres were prepared by the two staged swelling and polymerization method and applied to prepare anion exchange stationary phases. Methylamine, dimethylamine, trimethylamine, diethylamine and triethylamine were selected to prepare the quaternary ammonium groups of anion exchangers, respectively. The diameters and surface characteristics of microspheres were measured by scanning electron microscope and nitrogen adsorption-desorption measurements. The anion exchangers were characterized by Fourier transform infrared spectrum, elemental analysis and breakthrough curve methods. The chromatographic performances of anion exchangers were illustrated by separating conventional anions, organic weak acids and carbohydrates. The results indicated that the anion exchange capacities were controllable by changing either the content of glycidylmethacrylate in microspheres or the number of bonded quaternary ammonium layer. Meanwhile, the substituents of quaternary ammonium groups greatly influenced the separation properties of anion exchangers. Finally, the three-layer methylamine-quaternized anion exchanger was successfully applied for the determination of fluoride in tea sample. The content of fluoride was detected to be 0.13mgg(-1) without the interference of acetate and formate. PMID- 27474309 TI - Facile fabrication of Pt-Ag bimetallic nanoparticles decorated reduced graphene oxide for highly sensitive non-enzymatic hydrogen peroxide sensing. AB - A new electrocatalyst, Pt-Ag bimetallic nanoparticles decorated reduced graphene oxide nanocomposite, was successfully synthesized by a facile, eco-friendly and controllable route. The morphological characterization of RGO/Pt-Ag NPs nanocomposite was examined by transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDX) analyzer, X-ray diffraction (XRD) spectrum, and Fourier transform infrared spectrum (FT-IR), respectively. And then, the RGO/Pt-Ag NPs nanocomposite was immobilized on the surface of glassy carbon (GC) electrode to fabricate a novel and highly sensitive non-enzymatic hydrogen peroxide sensor. The electrochemical behaviors of the prepared sensor were investigated by cyclic voltammetry and chronoamperometry. The sensor showed excellent performance toward H2O2 with sensitivity as high as 699.6 MUA mM(-1)cm( 2) and 402.7 MUA mM(-1)cm(-2), wide linear range of 0.005-1.5mM and 1.5-7mM, and low detection limit of 0.04MUM (S/N=3). Moreover, the prepared hydrogen peroxide sensor was applied to in real samples with satisfactory results. These excellent results indicate that the prepared RGO/Pt-Ag NPs nanocomposite has broad application prospect in the field of sensors. PMID- 27474310 TI - Multi-block analysis coupled to laser-induced breakdown spectroscopy for sorting geological materials from caves. AB - In this study, multi-block analysis was applied for the first time to LIBS spectra provided by a portable LIBS system (IVEA Solution, France) equipped with three compact Czerny-Turner spectrometers covering the spectral ranges 200-397nm, 398-571nm and 572-1000nm. 41 geological samples taken from a laboratory-cave situated in the "Vezere valley", an area rich with prehistoric sites and decorated caves listed as a UNESCO world heritage in the south west of France, were analyzed. They were composed of limestone and clay considered as underlying supports and of two types of alterations referred as moonmilk and coralloid. Common Components and Specific Weights Analysis (CCSWA) allowed sorting moonmilk and coralloid samples. The loadings revealed higher amounts of magnesium, silicon, aluminum and strontium in coralloids and the saliences emphasized that among the three spectrometers installed in the LIBS instrument used in this work; that covering the range 572-1000nm was less contributive. This new approach for processing LIBS data not only provides good results for sorting geological materials but also clearly reveals which spectral range contains most of the information. This specific advantage of multi-block analysis could lead for some applications to simplify the design and to reduce the size of LIBS instruments. PMID- 27474311 TI - Synthesis and studies of selective chemosensor for naked-eye detection of anions and cations based on a new Schiff-base derivative. AB - A new chromogenic receptor, 4-((2,4-dichlorophenyl)diazenyl)-2-(3 hydroxypropylimino) methyl)phenol, has been designed and synthesized for quantitative and low-cost detection of various biological anions and cations. The dye was characterized by elemental analyses, infrared, UV-visible spectroscopy, and NMR spectroscopy. Upon the addition of F(-) and H2PO4(-) to the solution of chemosensor in DMSO, the dramatic naked eye detectable color changes were observed from yellow to red and orange with a limit of detection (LOD) of 1.66*10(-6)mol. L(-1) and 1.24*10(-6)mol. L(-1) at room temperature, respectively. The chemosensor showed visual changes towards cations, such as Al(3+), Cu(2+), Fe(3+), and Cr(3+), in DMSO/water (9:1). The detection limit of receptor L for the analysis of Al(3+) ion was calculated to be 3.02*10(-6)mol. L( 1). The anion recognition property of the receptor via proton transfer was monitored by UV-visible titration and (1)HNMR spectroscopy. The binding constant (Ka) and stoichiometry of the host-guest complexes formed were determined by the Benesi-Hildebrand (B-H) plot and Job's method, respectively. PMID- 27474312 TI - Determination of curcumin in biologically active supplements and food spices using a mesofluidic platform with fluorescence detection. AB - A mesofluidic platform (MP) with fluorescence detection based on a stepwise injection analysis (SWIA) was used for the determination of curcumin in biologically active supplements and food spices. The main units of the MP are a mixing chamber (MC) and an optical channel with a quartz capillary inside. The MC provides rapid and complete mixing solutions by gas bubbling. The proposed method is based on the new rapid and sensitive reaction of curcumin with a fluorescence reagent - 4-(2,3,3-trimethyl-3H-indolium-1-yl)butane-1-sulfonate (TIBS). The fluorescence intensity of TIBS is greatly quenched in the presence of curcumin in an alkaline medium. The linear range was from 1 to 10uM of curcumin, and the limit of detection, calculated as 3sigma of a blank test (n=5), was found to be 0.3uM. The sample throughput was 24h(-1). The proposed method was successfully applied for the determination of curcumin in biologically active supplements and samples of food spices. The obtained data were in good agreement with those measured by a HPLC-UV method. PMID- 27474313 TI - An electrochemical dopamine aptasensor incorporating silver nanoparticle, functionalized carbon nanotubes and graphene oxide for signal amplification. AB - In this work, immobilization of a dopamine (DA) aptamer was performed at the surface of an amino functionalized silver nanoparticle-carbon nanotube graphene oxide (AgNPs/CNTs/GO) nanocomposite. A 58-mer DA-aptamer was immobilized through the formation of phosphoramidate bonds between the amino group of chitosan and the phosphate group of the aptamer at the 5' end. An AgNPs/CNTs/GO nanocomposite was employed as a highly catalytic label for electrochemical detection of DA based on electrocatalytic activity of the nanocomposite toward hydrogen peroxide (H2O2). Interaction of DA with the aptamer caused conformational changes of the aptamer which, in turn, decreased H2O2 oxidation and reduction peak currents. On the other hand, the presumed folding of the DA-aptamer complexes on the sensing interface inhibited the electrocatalytic activity of AgNPs/CNTs/GO toward H2O2. Sensitive quantitative detection of DA was carried out by monitoring the decrease of differential pulse voltammetric (DPV) responses of AgNPs/CNTs/GO nanocomposite toward H2O2 oxidation. The DPV signal linearly decreased with increased concentration of DA from 3 to 110nmolL(-1) with a detection limit of 700+/ 19.23pmolL(-1). Simple preparation, low operation cost, speed and validity are the decisive factors of this method motivating its application to biosensing investigation. PMID- 27474314 TI - Evidential significance of automotive paint trace evidence using a pattern recognition based infrared library search engine for the Paint Data Query Forensic Database. AB - A prototype library search engine has been further developed to search the infrared spectral libraries of the paint data query database to identify the line and model of a vehicle from the clear coat, surfacer-primer, and e-coat layers of an intact paint chip. For this study, search prefilters were developed from 1181 automotive paint systems spanning 3 manufacturers: General Motors, Chrysler, and Ford. The best match between each unknown and the spectra in the hit list generated by the search prefilters was identified using a cross-correlation library search algorithm that performed both a forward and backward search. In the forward search, spectra were divided into intervals and further subdivided into windows (which corresponds to the time lag for the comparison) within those intervals. The top five hits identified in each search window were compiled; a histogram was computed that summarized the frequency of occurrence for each library sample, with the IR spectra most similar to the unknown flagged. The backward search computed the frequency and occurrence of each line and model without regard to the identity of the individual spectra. Only those lines and models with a frequency of occurrence greater than or equal to 20% were included in the final hit list. If there was agreement between the forward and backward search results, the specific line and model common to both hit lists was always the correct assignment. Samples assigned to the same line and model by both searches are always well represented in the library and correlate well on an individual basis to specific library samples. For these samples, one can have confidence in the accuracy of the match. This was not the case for the results obtained using commercial library search algorithms, as the hit quality index scores for the top twenty hits were always greater than 99%. PMID- 27474315 TI - Miniaturizing and automation of free acidity measurements for uranium (VI)-HNO3 solutions: Development of a new sequential injection analysis for a sustainable radio-analytical chemistry. AB - A miniaturized and automated approach for the determination of free acidity in solutions containing uranium (VI) is presented. The measurement technique is based on the concept of sequential injection analysis with on-line spectroscopic detection. The proposed methodology relies on the complexation and alkalimetric titration of nitric acid using a pH 5.6 sodium oxalate solution. The titration process is followed by UV/VIS detection at 650nm thanks to addition of Congo red as universal pH indicator. Mixing sequence as well as method validity was investigated by numerical simulation. This new analytical design allows fast (2.3min), reliable and accurate free acidity determination of low volume samples (10uL) containing uranium/[H(+)] moles ratio of 1:3 with relative standard deviation of <7.0% (n=11). The linearity range of the free nitric acid measurement is excellent up to 2.77molL(-1) with a correlation coefficient (R(2)) of 0.995. The method is specific, presence of actinide ions up to 0.54molL(-1) does not interfere on the determination of free nitric acid. In addition to automation, the developed sequential injection analysis method greatly improves the standard off-line oxalate complexation and alkalimetric titration method by reducing thousand fold the required sample volume, forty times the nuclear waste per analysis as well as the analysis time by eight fold. These analytical parameters are important especially in nuclear-related applications to improve laboratory safety, personnel exposure to radioactive samples and to drastically reduce environmental impacts or analytical radioactive waste. PMID- 27474316 TI - A green method for the quantification of plastics-derived endocrine disruptors in beverages by chemometrics-assisted liquid chromatography with simultaneous diode array and fluorescent detection. AB - The aim of this study was to develop a novel analytical method for the determination of bisphenol A, nonylphenol, octylphenol, diethyl phthalate, dibutyl phthalate and diethylhexyl phthalate, compounds known for their endocrine disruptor properties, based on liquid chromatography with simultaneous diode array and fluorescent detection. Following the principles of green analytical chemistry, solvent consumption and chromatographic run time were minimized. To deal with the resulting incomplete resolution in the chromatograms, a second order calibration was proposed. Second-order data (elution time-absorbance wavelength and elution time-fluorescence emission wavelength matrices) were obtained and processed by multivariate curve resolution-alternating least-squares (MCR-ALS). Applying MCR-ALS allowed quantification of the analytes even in the presence of partially overlapped chromatographic and spectral bands among these compounds and the potential interferents. The obtained results from the analysis of beer, wine, soda, juice, water and distilled beverage samples were compared with gas chromatography-mass spectrometry (GC-MS). Limits of detection (LODs) in the range 0.04-0.38ngmL(-1) were estimated in real samples after a very simple solid-phase extraction. All the samples were found to contain at least three EDs, in concentrations as high as 334ngmL(-1). PMID- 27474317 TI - Separation/preconcentration of ultra-trace levels of inorganic Sb and Se from different sample matrices by charge transfer sensitized ion-pairing using ultrasonic-assisted cloud point extraction prior to their speciation and determination by hydride generation AAS. AB - In the existing study, a new, simple and low cost process for separation/preconcentration of ultra-trace level of inorganic Sb and Se from natural waters, beverages and foods using ultrasonic-assisted cloud point extraction (UA-CPE) prior to their speciation and determination by hydride generation AAS, is proposed. The process is based on charge transfer sensitized complex formations of Sb(III) and Se(IV) with 3-amino-7-dimethylamino-2 methylphenazine hydrochloride (Neutral red, NRH(+)) in presence of pyrogallol and cetyltrimethylammonium bromide (CTAB) as both sensitivity enhancement and counter ion at pH 6.0. Under the optimized reagent conditions, the calibration curves were highly linear in the ranges of 8-300ngL(-1) and 12-250ngL(-1) (r(2)>=0.993) for Se(IV) and Sb(III), respectively. The limits of detection were 2.45 and 3.60ngL(-1) with sensitivity enhancement factors of 155 and 120, respectively. The recovery rate was higher than 96% with a relative standard deviation lower than 5.3% for five replicate measurements of 25, 75 and 150ngL(-1) Se(IV) and Sb(III), respectively. The method was validated by analysis of two certified reference materials (CRMs), and was successfully applied to the accurate and reliable speciation and determination of the contents of total Sb/Sb(III), and total Se/Se(IV) after UA-CPE of the pretreated sample matrices with and without pre-reduction with a mixture of l-cysteine and tartaric acid. Their Sb(V) and Se(VI) contents were calculated from the differences between total Sb and Sb(III) and/or total Se and Se(IV) levels. PMID- 27474318 TI - Au nanoparticles/poly(caffeic acid) composite modified glassy carbon electrode for voltammetric determination of acetaminophen. AB - An Au nanoparticles/poly(caffeic acid) (AuNPs/PCA) composite modified glassy carbon (GC) electrode was prepared by successively potentiostatic technique in pH 7.4 phosphate buffer solution containing 0.02mM caffeic acid and 1.0mM HAuCl4. Electrochemical characterization of the AuNPs/PCA-GC electrode was investigated by electrochemical impedance spectroscopy and cyclic voltammetry. The electrochemical behavior of acetaminophen (AP) at the AuNPs/PCA-GC electrode was also studied by cyclic voltammetry. Compared with bare GC and poly(caffeic acid) modified GC electrode, the AuNPs/PCA-GC electrode was exhibited excellent electrocatalytic activity toward the oxidation of AP. The plot of catalytic current versus AP concentration showed two linear segments in the concentration ranges 0.2-20uM and 50-1000uM. The detection limit of 14 nM was obtained by using the first range of the calibration plot. The AuNPs/PCA-GC electrode has been successfully applied and validated by analyzing AP in blood, urine and pharmaceutical samples. PMID- 27474319 TI - A novel sensor for dopamine based on the turn-on fluorescence of Fe-MIL-88 metal organic frameworks-hydrogen peroxide-o-phenylenediamine system. AB - In this work, a novel sensor based on fluorescence enhancement of Fe-MIL-88- H2O2 o-phenylenediamine (OPD) system for the determination of dopamine (DA) was developed. Fe-MIL-88 with intrinsic peroxidase-like catalytic activity tended to oxidize the nonfluorescent OPD into the fluorescent 2,3-diaminophenazine (DAP) with the presence of H2O2. When DA was introduced, the autoxidation of DA to yield hydroxyl radical (.OH) was further enhanced by Fe(3+) site in Fe3-MU3-oxo clusters exiting in Fe-MIL-88 MOFs, meanwhile the generated Fe(2+) appeared to involve a Fenton type reaction in the presence of H2O2 to cause a continuous production of .OH radicals which greatly enhanced the conversion efficiency of the OPD to fluorescent DAP. Thus, the turn-on fluorescence method for the DA detection was established. The linear range was from 50nm to 30MUM with detection limit 46nm (3sigma/s). Furthermore, the proposed method has been reliably applied to determine dopamine content in dopamine hydrochloride injection and human urine with satisfactory results, which suggests its great potential for assay DA in chemical and biological analytical applications. PMID- 27474320 TI - Fast, ultra-trace detection of juvenile hormone III from mosquitoes using mass spectrometry. AB - In the present work, a new protocol for fast separation and quantification of JH III from biological samples using liquid chromatography coupled to electrospray tandem mass spectrometry is described. In particular, the proposed protocol improves existing methodologies by combining a limited number of sample preparation steps with fast LC-MS/MS detection, providing lower limits of detection and demonstrated matrix effect control, together with high inter and intraday reproducibility. A limit of detection of 8pg/mL (0.32pg on column) was achieved, representing a 15-fold gain in sensitivity with respect to previous LC MS based protocols. The performance of the LC-MS/MS protocol is comparable to previously described JH III quantitation protocol based on fluorescence detection, with the added advantage that quantification is independent of the availability of fluorescent tags that are often unavailable or show quite diverse responses on a batch-to-batch basis. Additionally, a detailed description of the JH III fragmentation pathway is provided for the first time, based on isolation of the molecular ion and their intermediate fragments using in-source MS/MS, MS/MS(n) and FT-ICR MS/MS measurements. The JH III workflow was evaluated as a function of developmental changes, sugar feeding and farnesoic acid stimulation in mosquitoes and can be applied to the detection of other juvenile hormones. PMID- 27474321 TI - Electrochemical sensor for dopamine based on imprinted silica matrix-poly(aniline boronic acid) hybrid as recognition element. AB - A novel imprinted silica matrix-poly(aniline boronic acid) hybrid for electrochemical detection of dopamine (DA) was developed. Boronic acid functionalized conducting polymer was electrochemically prepared on Au electrode. The number of covalent binding sites toward DA templates was controlled by potential cycles. A precursory sol solution of ammonium fluorosilicate (as cross linking monomer) containing DA was spin-coated on the polymer modified electrode. Under NH3 atmosphere, the hydroxyl ions were generated in the solution and catalyzed the hydrolysis of fluorosilicate to form silica matrix. After this aqueous sol-gel process, an inorganic framework around the DA template was formed and the imprinted hybrid for DA was also produced. As revealed by scanning electron microscopy, UV-vis spectroscopy and cyclic voltammetry characterization, DA was embedded in the imprinted hybrid successfully. The affinity and selectivity of the imprinted hybrid were also characterized by cyclic voltammetry. The imprinted hybrid showed higher affinity for DA than that for epinephrine, and little or no affinity for ascorbic acid and uric acid due to the combined effects of covalent interaction, cavities matching and electrostatic repulsion. The imprinted hybrid sensor exhibited a quick response (within 5min) to DA in the concentration range from 0.05 to 500MUmolL(-1) with a detection limit of 0.018MUmolL(-1). The prepared sensor was also applied to detect DA in real samples with a satisfactory result. PMID- 27474322 TI - Acid retardation method in analysis of strongly acidic solutions by inductively coupled plasma mass-spectrometry. AB - Acid retardation on the sorbents as a technique for reduction of the acidity of the solutions prior to their analysis by inductively coupled plasma mass spectrometry was proposed and investigated. The proposed scheme provides substantial separation of the analytes and nitric acid, which allows direct introduction of the eluates in plasma without dilution. Two sorbents were examined - AV-17 anion-exchange resin and the Stirosorb 584 sorbent. Sorption and desorption of 38 elements on these sorbents were investigated. The efficiencies of the REEs' sorption on the anion-exchange and neutral sorbents were compared. The higher efficiency of the REEs and HNO3 separation was revealed for the neutral Stirosorb 584 sorbent. It was also found that most elements come out quantitatively of the column filled with the AV-17 resin after pumping 2-4mL of the solution. Wherein, the concentration of nitric acid decreased by 20 times. The anomalous behaviour of Ag, Pb, Th and U on the AV-17 resin was found. These analytes were eluted only after pumping 4 column volumes of deionized water. Na, K, Fe, Al and Li in concentrations within (50-1000mgL(-1)) range did not affect the recovery of REEs. The potential of ARM technique was demonstrate by the analysis of puriss. HNO3 and silverware. ARM enables to avoid dilution of highly acidic solutions prior to their introduction in ICP-MS. PMID- 27474323 TI - Portable and low cost fluorescence set-up for in-situ screening of Ochratoxin A. AB - The present article describes a portable and low cost fluorescence set-up designed and characterized for in-situ screening of Ochratoxin A (OTA) in cocoa samples at field settings. The sensing module (the set up) consists of a LED with the wavelength of 370-380nm and a color complementary metal oxide semiconductor (CMOS) micro-camera inbuilt at upright position of a black box to obtain an image of the sensing molecule. It allows the user to get an image of the sensing analytes under excitation conditions and process the image in order to predict the toxicity of the samples. The image capturing and processing of the system was based on the OTA concentration in the sample and analyzed data can be presented as RGB values. For each concentration of the OTA, the R, G, B co-ordinates were obtained and plotted to quantify actual OTA presents in the sample. Moreover, the system was tested for real sample analysis using cocoa contaminated with OTA. The system could detect OTA as low as 1.25ng/ml with the maximum recovery of 87.5% in cocoa samples. The OTA was extracted in 1% NaHCO3 and cleaned up using molecular imprinted polymer column (MIP). The method demonstrated a good linear range between 1.25 and 10ng/ml. The obtained results were cross validated using chromatographic method HPLC and also compared with commercially available fluorescence instrument. The developed fluorescence setup is simple, economical, and portable with added advantages of digital image processing. The system could be deployable to cocoa fields for monitoring of OTA in quick successions. It is noteworthy to mention that this is the first report of such portable fluorescence setup where, OTA sensing was explored. PMID- 27474324 TI - Rapid and alternative fabrication method for microfluidic paper based analytical devices. AB - A major application of microfluidic paper-based analytical devices (uPADs) includes the field of point-of-care (POC) diagnostics. It is important for POC diagnostics to possess properties such as ease-of-use and low cost. However, uPADs need multiple instruments and fabrication steps. In this study, two different chemicals (Hexamethyldisilazane and Tetra-ethylorthosilicate) were used, and three different methods (heating, plasma treatment, and microwave irradiation) were compared to develop uPADs. Additionally, an inkjet-printing technique was used for generating a hydrophilic channel and printing certain chemical agents on different regions of a modified filter paper. A rapid and effective fabrication method to develop uPADs within 10min was introduced using an inkjet-printing technique in conjunction with a microwave irradiation method. Environmental scanning electron microscope (ESEM) and x-ray photoelectron spectroscopy (XPS) were used for morphology characterization and determining the surface chemical compositions of the modified filter paper, respectively. Contact angle measurements were used to fulfill the hydrophobicity of the treated filter paper. The highest contact angle value (141 degrees +/-1) was obtained using the microwave irradiation method over a period of 7min, when the filter paper was modified by TEOS. Furthermore, by using this method, the XPS results of TEOS modified filter paper revealed Si2p (23%) and Si-O bounds (81.55%) indicating the presence of Si-O-Si bridges and Si(OEt) groups, respectively. The ESEM results revealed changes in the porous structures of the papers and decreases in the pore sizes. Washburn assay measurements tested the efficiency of the generated hydrophilic channels in which similar water penetration rates were observed in the TEOS-modified filter paper and unmodified (plain) filter paper. The validation of the developed uPADs was performed by utilizing the rapid urease test as a model test system. The detection limit of the developed uPADs was measured as 1unitml(-1) urease enzyme in detection zones within a period of 3min. The study findings suggested that a combination of microwave irradiation with inkjet-printing technique could improve the fabrication method of uPADs, enabling faster production of uPADs that are easy to use and cost-effective with long shelf lives. PMID- 27474325 TI - Functionalized photonic crystal for the sensing of Sarin agents. AB - The indiscriminate use of nerve agents by terrorist groups has attracted attention of the scientific communities toward the development of novel sensor technique for these deadly chemicals. A photonic crystal (PhC) hydrogel immobilized with butyrylcholinesterase (BuChE) was firstly prepared for the sensing of Sarin agents. Periodic polystyrene colloidal (240nm) array was embedded inside an acrylamide hydrogel, and then BuChE was immobilized inside the hydrogel matrix via condensation with 3-(diethoxyphosphoryloxy)-1,2,3 benzotriazin-4(3h)-one (DEPBT). It indicated that a total of 3.7 units of BuChE were immobilized onto the PhC hydrogel. The functionalized hydrogel recognized the Sarin agent and then shrunk, thus the diffraction of PhC hydrogel blue shifted significantly, and a limit of detection (LOD) of 10(-15)molL(-1) was achieved. PMID- 27474326 TI - Optical isopropanol biosensor using NADH-dependent secondary alcohol dehydrogenase (S-ADH). AB - Isopropanol (IPA) is an important solvent used in industrial activity often found in hospitals as antiseptic alcohol rub. Also, IPA may have the potential to be a biomarker of diabetic ketoacidosis. In this study, an optical biosensor using NADH-dependent secondary alcohol dehydrogenase (S-ADH) for IPA measurement was constructed and evaluated. An ultraviolet light emitting diode (UV-LED, lambda=340nm) was employed as the excitation light to excite nicotinamide adenine dinucleotide (NADH). A photomultiplier tube (PMT) was connected to a two-way branch optical fiber for measuring the fluorescence emitted from the NADH. S-ADH was immobilized on the membrane to catalyze IPA to acetone and reduce NAD(+) to be NADH. This IPA biosensor shows highly sensitivity and selectivity, the calibration range is from 500 nmol L(-1) to 1mmolL(-1). The optimization of buffer pH, temperature, and the enzyme-immobilized method were also evaluated. The detection of IPA in nail related cosmetic using our IPA biosensor was also carried out. The results showed that large amounts of IPA were used in these kinds of cosmetics. This IPA biosensor comes with the advantages of rapid reaction, good reproducibility, and wide dynamic range, and is also expected to use for clinical IPA detections in serum or other medical and health related applications. PMID- 27474327 TI - Thermogravimetric analysis coupled with chemometrics as a powerful predictive tool for beta-thalassemia screening. AB - beta-Thalassemia is a hemoglobin genetic disorder characterized by the absence or reduced beta-globin chain synthesis, one of the constituents of the adult hemoglobin tetramer. In this study the possibility of using thermogravimetric analysis (TGA) followed by chemometrics as a new approach for beta-thalassemia detection is proposed. Blood samples from patients with beta-thalassemia were analyzed by the TG7 thermobalance and the resulting curves were compared to those typical of healthy individuals. Principal Component Analysis (PCA) was used to evaluate the correlation between the hematological parameters and the thermogravimetric results. The thermogravimetric profiles of blood samples from beta-thalassemia patients were clearly distinct from those of healthy individuals as result of the different quantities of water content and corpuscular fraction. The hematological overview showed significant decreases in the values of red blood cell indices and an increase in red cell distribution width value in thalassemia subjects when compared with those of healthy subjects. The implementation of a predictive model based on Partial Least Square Discriminant Analysis (PLS-DA) for beta-thalassemia diagnosis, was performed and validated. This model permitted the discrimination of anemic patients and healthy individuals and was able to detect thalassemia in clinically heterogeneous patients as in the presence of deltabeta-thalassemia and beta-thalassemia combined with Hb Lepore. TGA and Chemometrics are capable of predicting beta thalassemia syndromes using only a few microliters of blood without any pretreatment and with an hour of analysis time. A fast, rapid and cost-effective diagnostic tool for the beta-thalassemia screening is proposed. PMID- 27474328 TI - Liver imaging reporting and data system v2014 categorization of hepatocellular carcinoma on gadoxetic acid-enhanced MRI: Comparison with multiphasic multidetector computed tomography. AB - PURPOSE: To investigate the Liver Imaging Reporting and Data System (LI-RADS) v2014 categorization of hepatocellular carcinomas (HCCs) on gadoxetic acid enhanced magnetic resonance imaging (Gd-EOB-MRI) in comparison with multiphasic multidetector computed tomography (MDCT). MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study and waived the requirement for informed consent. We included 182 high-risk patients with 216 pathologically confirmed HCCs who underwent both Gd-EOB-MRI at 1.5 or 3T and multiphasic MDCT. Two independent radiologists assessed the presence or absence of major HCC features and assigned LI-RADS categories before and after considering ancillary features on both MRI and MDCT. Finally, sensitivities of LR 5/5v and frequencies of major HCC features were compared between MRI and MDCT using the McNemar test. RESULTS: Sensitivities of LR-5/5v were not significantly different between MRI and MDCT (63.4% [137/216] vs. 64.4% [139/216], P = 0.831; 60.6% [131/216] vs. 60.6% [131/216], P = 0.868, for reviewers 1 and 2, respectively). Among major HCC features seen on consensus review, washout and capsule appearance were less frequently observed on MRI than on MDCT (69.0% [149/216] vs. 87.0% [188/216], P < 0.001 and 17.1% [37/216] vs. 31.5% [68/216], P < 0.001), while no significant differences were found for arterial hyperenhancement (88.9% [192/216] vs. 84.7% [183/216], P = 0.081). Ancillary features led to category changes in 18.1% (39/216) of nodules on MRI (all, LR-3 to LR-4), while no changes were seen on MDCT. CONCLUSION: Using LI-RADS, Gd-EOB MRI showed comparable sensitivity to multiphasic MDCT for the diagnosis of HCCs, and ancillary features of MRI frequently led to the upgrade of nodules from LR-3 to LR-4. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:731-740. PMID- 27474330 TI - Comparison of Two Different Red Blood Cell Transfusion Thresholds on Short-Term Clinical Outcomes of Patients Undergoing Aortic Surgery With Deep Hypothermic Circulatory Arrest. AB - OBJECTIVE: Patients undergoing aortic surgery with deep hypothermic circulatory arrest (DHCA) usually are associated with a high rate of allogeneic blood transfusion, and their red blood cell (RBC) transfusion threshold is unclear and controversial. The purpose of this study was to explore whether a restrictive transfusion threshold was as effective as a liberal transfusion threshold for patients undergoing aortic surgery with DHCA. DESIGN: Retrospective, controlled study. SETTING: National Center for Cardiovascular Diseases and a university hospital, Beijing, China. PARTICIPANTS: The study comprised 74 patients undergoing aortic surgery with DHCA from January 1 to December 31, 2014. INTERVENTIONS: Patients were divided retrospectively into the following 2 groups according to the RBC transfusion thresholds-the restrictive group received allogeneic RBC transfusion if the hemoglobin (Hb) level of the patient fell below 8 g/dL during the surgery, and in the liberal group the hemoglobin threshold for allogeneic transfusion was 10 g/dL. MEASUREMENTS AND MAIN RESULTS: Data on patient demographics, procedure characteristics, allogeneic blood use, and postoperational morbidity and mortality were collected and analyzed. In total, the restrictive group required fewer perioperative transfusions of RBCs (3.9+/ 4.8 v 8.5+/-6.9 units, p = 0.001) and platelets (1.9+/-0.8 v 2.6+/-1.0 units, p = 0.003) compared with the liberal group. Postoperative mortality and complications, including 30-day mortality and bleeding requiring re-exploration, did not differ significantly between the 2 groups. CONCLUSIONS: For patients undergoing aortic surgery with DHCA, a restrictive RBC transfusion threshold (Hb<8 g per deciliter) may be as effective as a liberal RBC transfusion threshold (Hb<10 g per deciliter) during the surgery, with similar short-term clinical outcomes and less allogeneic transfusion. PMID- 27474329 TI - Attenuation of Isoflurane Preconditioning-Induced Acute Cardioprotection in Hypertensive Hypertrophied Hearts. AB - OBJECTIVES: To evaluate the efficiency of isoflurane-induced anesthetic preconditioning and the role of mitochondrial manganese superoxide dismutase (MnSOD) in hypertensive hypertrophied hearts. DESIGN: A prospective animal investigation. SETTING: Medical center hospital research laboratory. PARTICIPANTS: Male spontaneously hypertensive rats (SHRs) and normotensive control Wistar-Kyoto (WKY) rats. INTERVENTIONS: All pentobarbital-anesthetized open-chest rats were subjected to a 45-minute left coronary artery occlusion followed by a 120-minute reperfusion. Before ischemia, both SHR and WKY rats were assigned randomly to receive a 30-minute exposure to 0.9% saline or 1.0 minimum alveolar concentration isoflurane. MEASUREMENTS AND MAIN RESULTS: The myocardial infarct size, assessed as a percentage of the area at risk, was significantly greater in the hypertrophied SHRs than in the WKY rats (65.3%+/-8.7% v 51.8%+/ 7.2%, p<0.05). Isoflurane preconditioning appreciably reduced the infarct size in the WKY hearts (30.9%+/-10.5%, p<0.05) but not in the SHR hearts. MnSOD protein expression and enzymatic activity were increased drastically in response to isoflurane exposure in the hearts of the WKY rats (p<0.05) but not in the SHRs. CONCLUSIONS: Isoflurane-induced anesthetic preconditioning is attenuated in hypertensive hypertrophied hearts. This impairment may be associated with the loss of MnSOD augmentation during ischemia and reperfusion. PMID- 27474331 TI - Evaluation of pH in Double-Lumen Tubes Removed After General Anesthesia: A Prospective Observational Study. PMID- 27474332 TI - Right Atrial Transverse Band Prevents a "Passing-by" Thrombus From Migrating Into Pulmonary Circulation. PMID- 27474333 TI - Moderate Aortic Valvular Insufficiency Invalidates Vortex Formation Time as an Index of Left Ventricular Filling Efficiency in Patients With Severe Degenerative Calcific Aortic Stenosis Undergoing Aortic Valve Replacement. AB - OBJECTIVE: Transmitral blood flow produces a vortex ring (quantified using vortex formation time [VFT]) that enhances the efficiency of left ventricular (LV) filling. VFT is attenuated in LV hypertrophy resulting from aortic valve stenosis (AS) versus normal LV geometry. Many patients with AS also have aortic insufficiency (AI). The authors tested the hypothesis that moderate AI falsely elevates VFT by partially inhibiting mitral leaflet opening in patients with AS. DESIGN: Observational study. SETTING: Veterans Affairs medical center. PARTICIPANTS: Patients with AS in the presence or absence of moderate AI (n = 8 per group) undergoing aortic valve replacement (AVR) were studied after institutional review board approval. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Under general anesthesia, peak early LV filling (E) and atrial systole (A) blood flow velocities and their corresponding velocity-time integrals were obtained using pulse-wave Doppler transesophageal echocardiography (TEE) to determine E/A and atrial filling fraction (beta). Mitral valve diameter (D) was calculated as the average of major and minor axis lengths obtained in the midesophageal bicommissural (transcommissural anterior-lateral-posterior medial) and LV long-axis (anterior-posterior) TEE imaging planes, respectively. VFT was calculated as 4.(1-beta).SV/piD(3), where SV = stroke volume measured using thermodilution. Hemodynamics, diastolic function, and VFT were determined during steady-state conditions before cardiopulmonary bypass. The severity of AS (mean and peak pressure gradients, peak transvalvular jet velocity, aortic valve area) and diastolic function (E/A, beta) were similar between groups. Moderate centrally directed AI was present in 8 patients with AS (ratio of regurgitant jet width to LV outflow tract diameter of 36+/-6%). Pulse pressure and mean pulmonary artery pressure were elevated in patients with versus without AI, but no other differences in hemodynamics were observed. Mitral valve minor and major axis lengths, diameter, and area were reduced in the presence versus the absence of AI. VFT was increased significantly (5.7+/-1.7 v 3.2+/-0.6; p = 0.00108) in patients with AS and AI compared with AS alone. CONCLUSION: Moderate AI falsely elevates VFT in patients with severe AS undergoing AVR by partially inhibiting mitral valve opening. VFT may be an unreliable index of LV filling efficiency with competitive diastolic flow into the LV. PMID- 27474334 TI - Should We Use Perioperative Transesophageal Echocardiography More in Non-Cardiac Surgery? PMID- 27474335 TI - A Score for Predicting Acute Kidney Injury After Coronary Artery Bypass Graft Surgery in an Asian Population. AB - OBJECTIVE: To develop a scoring system to predict acute kidney injury in Asian patients after coronary artery bypass grafting. DESIGN: A retrospective analysis of data collected in an institutional cardiac database. SETTING: A tertiary academic hospital in a large metropolitan city. PARTICIPANTS: The study comprised 954 patients with coronary artery disease. INTERVENTIONS: All patients underwent coronary artery bypass surgery with cardiopulmonary bypass but did not undergo any other concomitant procedures. MEASUREMENTS AND MAIN RESULTS: The main outcome measured was acute kidney injury as defined by the Acute Kidney Injury Network criteria. The following 6 clinical variables were independent predictors of kidney injury: age>60 years, diabetes requiring insulin, estimated glomerular filtration rate<60 mL/min/1.73 m(2), ejection fraction<40%, cardiopulmonary bypass time>140 minutes, and aortic cross-clamp time>100 minutes. These variables were used to develop the Singapore Acute Kidney Injury score. CONCLUSION: The Singapore Acute Kidney Injury score is a simple way to predict, at the time of admission to the intensive care unit, an Asian patient's risk of developing acute kidney injury after coronary artery bypass surgery. PMID- 27474336 TI - What Is the Role of Long-Acting Neuromuscular Blocking Agents in Modern Adult Cardiac Surgery? PMID- 27474337 TI - Predictive Value of Intraoperative Thromboelastometry for the Risk of Perioperative Excessive Blood Loss in Infants and Children Undergoing Congenital Cardiac Surgery: A Retrospective Analysis. AB - OBJECTIVE: Laboratory hemostatic variables and parameters of rotational thromboelastometry (ROTEM) were evaluated for their ability to predict perioperative excessive blood loss (PEBL) after congenital cardiac surgery. DESIGN: Retrospective and observational. SETTING: Single, large university hospital. PARTICIPANTS: The study comprised 119 children younger than 10 years old undergoing congenital cardiac surgery with cardiopulmonary bypass (CPB). MEASUREMENTS AND MAIN RESULTS: Intraoperative excessive blood loss was defined as estimated blood loss>=50% of estimated blood volume (EBV). Postoperative excessive blood loss was defined as measured postoperative chest tube and Jackson Pratt drainage>=30% of EBV over 12 hours or>=50% of EBV over 24 hours in the intensive care unit. PEBL was defined as either intraoperative or postoperative excessive blood loss. External temogram (EXTEM) and fibrinogen temogram (FIBTEM) were analyzed before and after CPB with ROTEM and laboratory hemostatic variables. Multivariate logistic regression was performed. Incidence of PEBL was 19.3% (n = 23). Independent risk factors for PEBL were CPB time>120 minutes, post CPB FIBTEM alpha-angle, clot firmness after 10 minutes<5 mm, post-CPB EXTEM alpha angle, clot firmness after 10 minutes<30 mm, and post-CPB EXTEM maximal lysis>20%. Laboratory hemostatic variables were not significant in multivariate analysis. The risk prediction model was developed from the results of multivariate analysis. The area under the receiver operating characteristic curve was 0.94 (95% confidence interval: 0.90-0.99). CONCLUSIONS: Post-CPB ROTEM may be useful for predicting both intraoperative and postoperative excessive blood loss in congenital cardiac surgery. This study provided an accurate prediction model for PEBL and supported intraoperative transfusion guidance using post-CPB FIBTEM A10 and EXTEM-A10. PMID- 27474338 TI - Usefulness of the Sum of Pulmonary Capillary Wedge Pressure and Right Atrial Pressure as a Congestion Index that Prognosticates Heart Failure Survival (from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness Trial). AB - In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, use of a pulmonary artery catheter did not significantly affect advanced heart failure outcomes. However, the success of achieving the targeted hemodynamic goals of pulmonary capillary wedge pressure (PCWP) of 15 mm Hg and right atrial pressure (RAP) of 8 mm Hg and the association of these goals with clinical outcomes were not addressed. Furthermore, goals with 2 independent variables, PCWP and RAP, left room for uncertainties. We assessed the ability of a single hemodynamic target to achieve a threshold sum of PCWP and RAP as a predictor of all-cause mortality, death-or transplantation (DT), or death-or-rehospitalization (DR) at 6 months in the pulmonary artery catheter-guided treatment arm of ESCAPE (n = 206). Patients with a posttreatment PCWP + RAP of <30 mm Hg had characteristics similar to those of the population who achieved the ESCAPE hemodynamic goals. This group had 8.7% mortality, 13.0% DT, and 58.7% DR at 6 months. The contrasting cohort with PCWP + RAP of >=30 mm Hg had 45.3% mortality, 54.7% DT, and 84.9% DR at 6 months, with greater relative risk (RR) of death (RR 5.76), DT (RR 4.92), and DR (RR 1.80) and higher prevalence of jugular venous pulsation, edema, hepatomegaly, and ascites at admission and discharge. In conclusion, PCWP + RAP of 30 mm Hg posttreatment, obtained early in the index hospitalization, may represent as a simple congestion index that has prognostic value for heart failure survival and readmission rates at 6 months and as a warning signal for more aggressive intervention, thus warranting further validation. PMID- 27474340 TI - Coupling of gel-based 2-DE and 1-DE shotgun proteomics approaches to dig deep into the leaf senescence proteome of Glycine max. AB - Leaf senescence is the last stage of leaf development that re-mobilizes nutrients from the source to sink. Here, we have utilized the soybean as a model system to unravel senescence-associated proteins (SAPs). A comparative proteomics approach was used at two contrasting stages of leaf development, namely mature (R3) and senescent (R7). Selection criteria for these two stages were the contrasting differences in their biochemical parameters - chlorophyll, carotenoids and malondialdehyde contents. Proteome analysis involved subjecting the total leaf proteins to 15% poly-ethylene glycol (PEG) pre-fractional method to enrich the low-abundance proteins (LAPs) and their analyses by gel-based 2-DE and 1-DE shotgun proteomics approaches. 2-DE profiling of PEG-supernatant and -pellet fractions detected 153 differential spots between R3 and R7 stages, of which 102 proteins were identified. In parallel, 1-DE shotgun proteomics approach identified 598 and 534 proteins in supernatant and pellet fractions of R3 and R7 stages, respectively. MapMan and Gene Ontology analyses showed increased abundance and/or specific accumulation of proteins related to jasmonic acid biosynthesis and defense, while proteins associated with photosynthesis and ROS detoxification were decreased during leaf senescence. These findings and the generated datasets further our understanding on leaf senescence at protein level, providing a resource for the scientific community. BIOLOGICAL SIGNIFICANCE: Leaf senescence is a major biological event in the life cycle of plants that leads to the recycling of nutrients. However, the molecular mechanisms underlying leaf senescence still remain poorly understood. Here, we used a combination of gel based 2-DE and 1-DE shotgun proteomics approaches to dig deeper into the leaf senescence proteome using soybean leaf as a model experimental material. For the identification of low-abundance proteins, polyethylene glycol (PEG) fractionation was employed and both PEG-supernatant and -pellet fractions were utilized for 2 DE and shotgun proteomic analysis. A total of 1234 (102 from 2-DE and 1132 from 1 DE shotgun proteome analysis) proteins were identified which were functionally annotated using GO and MapMan bioinformatics tools. Our results also emphasize the role of jasmonic acid in soybean leaf senescence. PMID- 27474341 TI - Enhanced biomass production and lipid accumulation of Picochlorum atomus using light-emitting diodes (LEDs). AB - The effects of light-emitting diode (LED) wavelength, light intensity, nitrate concentration, and time of exposure to different LED wavelength stresses in a two phase culture on lipid production were evaluated in the microalga, Picochlorum atomus. The biomass produced by red LED light was higher than that produced by purple, blue, green, or yellow LED and fluorescent lights from first phase of two phase culture. The highest lipid production of P. atomus was 50.3% (w/w) with green LED light at 2days of second phase as light stress. Fatty acid analysis of the microalgae showed that palmitic acid (C16:0) and linolenic acid (C18:3) accounted for 84-88% (w/w) of total fatty acids from P. atomus. The two-phase culture of P. atomus is suitable for biofuel production due to higher lipid productivity and favorable fatty acid composition. PMID- 27474339 TI - Usefulness of Palliative Care to Complement the Management of Patients on Left Ventricular Assist Devices. AB - Within the last decade, advancements in left ventricular assist device therapy have allowed patients with end-stage heart failure (HF) to live longer and with better quality of life. Like other life-saving interventions, however, there remains the risk of complications including infections, bleeding episodes, and stroke. The candidate for left ventricular assist device therapy faces complex challenges going forward, both physical and psychological, many of which may benefit from the application of palliative care principles by trained specialists. Despite these advantages, palliative care remains underused in many advanced HF programs. Here, we describe the benefits of palliative care, barriers to use within HF, and specific applications to the integrated care of patients on mechanical circulatory support. PMID- 27474342 TI - Determination of ciprofloxacin in Jiaozhou Bay using molecularly imprinted solid phase extraction followed by high-performance liquid chromatography with fluorescence detection. AB - A high selective pre-treatment method for the cleanup and preconcentration of ciprofloxacin in natural seawater samples was developed based on molecularly imprinted solid-phase extraction (MISPE). The ciprofloxacin imprinted polymers were synthesized and the characteristics of obtained polymers were evaluated by scanning electron microscopy, Fourier transform infrared spectroscopy and binding experiments. The imprinted materials showed high adsorption ability for ciprofloxacin and were applied as special solid-phase extraction sorbents for selective separation of ciprofloxacin. An off-line MISPE procedure was optimized and the developed MISPE method allowed direct purification and enrichment of the ciprofloxacin from the aqueous samples prior to high-performance liquid chromatography analysis. The recoveries of spiked seawater on the MISPE cartridges ranged from 75.2 to 112.4% and the relative standard deviations were less than 4.46%. Five seawater samples from Jiaozhou Bay were analyzed and ciprofloxacin was detected in two samples with the concentrations of 0.24 and 0.38MUgL(-1), respectively. PMID- 27474343 TI - Prioritization maps: The integration of environmental risks to manage water quality in harbor areas. AB - A method to integrate the environmental risk of the multiple effects from uses and activities developed in harbor areas is presented. Consequences are considered as the effects derived from all identified hazards. Vulnerability is expressed in terms of functional relations between environmental susceptibility against a disturbance and the state of protection of the receptors at risk. Consequences and vulnerability are integrated obtaining a spatial variation of risk: prioritization maps. The maps are developed by 4 main stages: (1) environmental hazard identification; (2) estimation of the consequences; (3) estimation of vulnerability and, (4) integration of environmental risks. To adapt prioritization maps to the peculiarities of the study area, three different methods for the integration of the effects are proposed: average-value, worst case and weighted methods. The implementation to a real case (Tarragona harbor, NE Spain) confirms its usefulness as a risk analysis tool to communicate and support water quality management in harbors. PMID- 27474344 TI - [Not Available]. PMID- 27474345 TI - [Fixed-dose combination fluticasone propionate/formoterol for the treatment of asthma: a review of its pharmacology, efficacy and tolerability]. AB - The fixed-dose combination fluticasone propionate/formoterol (FPF) is a novel combination of a widely known and used inhaled glucocorticoid (IGC) and a long acting beta2-adrenergic agonist (LABA), available for the first time in a single device. This fixed-dose combination of FPF has a demonstrated efficacy and safety profile in clinical trials compared with its individual components and other fixed-dose combinations of IGC/LABA and is indicated for the treatment of persistent asthma in adults and adolescents. FPF is available in a wide range of doses that can adequately cover the therapeutic steps recommended by treatment guidelines, constituting a fixed-dose combination of GCI/LABA that is effective, rapid, well tolerated and with a reasonable acquisition cost. Various assessment agencies of the Spanish Autonomous Communities consider this combination to be an appropriate alternative therapy for asthma in the primary care setting. PMID- 27474346 TI - Myoepithelioma of the parotid gland with extensive adipocytic metaplasia: Report of a case with intriguing aspects on fine needle aspiration and p63 immunohistochemical expression. AB - Myoepithelioma is a rare and usually benign salivary gland tumor derived from myoepithelial cells. Variability in cellular morphology and stromal composition leads to diagnostic pitfalls on fine-needle aspiration cytology; therefore, histology and immunohistochemistry are often required for definitive diagnosis. We describe a case of parotid gland myoepithelioma in a 76-year-old woman, which was discovered incidentally on cerebral magnetic resonance imaging. Fine-needle aspiration sampled cohesive aggregates of spindle-shaped cells embedded in a fibrillary matrix as well as abundant mature adipocytes, initially considered as part of normal salivary gland parenchyma. Histology of the resected specimen showed bundles of spindle-shaped cells embedded in loose connective tissue, admixed with numerous intralesional adipocytes. Immunohistochemical studies revealed a diffuse expression of p63 by this adipocytic population, an observation clearly indicating that myoepithelial cells can trans-differentiate and acquire the morphology of mature adipocytes. Knowledge of this phenomenon can be helpful in the work-up of salivary gland lesions. Diagn. Cytopathol. 2016;44:1090-1093. (c) 2016 Wiley Periodicals, Inc. PMID- 27474347 TI - A scalable method for automatically measuring pharyngeal pumping in C. elegans. AB - BACKGROUND: The nematode Caenorhabditis elegans is widely used for studying small neural circuits underlying behavior. In particular, the rhythmic feeding motions collectively termed pharyngeal pumping are regulated by a nearly autonomous network of 20 neurons of 14 types. Despite much progress achieved through laser ablation, genetics, electrophysiology, and optogenetics, key questions regarding the regulation of pumping remain open. NEW METHOD: We describe the implementation and application of a scalable automated method for measuring pumping in controlled environments. Our implementation is affordable and flexible: key hardware and software elements can be modified to accommodate different requirements. RESULTS: We demonstrate prolonged measurements under controlled conditions and the resulting high quality data. We show the scalability of our method, enabling high throughput, and its suitability for maintaining static and dynamic conditions. When food availability was oscillated, pumping rates were low as compared to steady conditions and pumping activity was not reliably modulated in response to changes in food concentration. COMPARISON WITH EXISTING METHOD: The prevailing method for measuring rates of pumping relies on scoring by visual inspection of short recordings. Our automated method compares well with manual scoring. It enables detailed statistical characterization under experimental conditions not previously accessible and minimizes unintentional bias. CONCLUSIONS: Our approach adds a powerful tool for studying pharyngeal pumping. It enhances the experimental versatility of assaying genetic and pharmacological manipulations and the ability to characterize the resulting behavior. Both the experimental setup and the analysis can be readily adapted to additional challenging motion detection problems. PMID- 27474348 TI - A study of type-1 diabetes associated autoantibodies in schizophrenia. AB - Epidemiological studies revealed an association between type-1 diabetes (T1D) and schizophrenia but the findings reported to date have been controversial. To clarify the inconsistency across studies, T1D-associated autoantibodies were examined in plasma samples collected from 272 patients with schizophrenia and 276 control subjects. An in-house enzyme-linked immunosorbent assay (ELISA) was developed using three linear peptide antigens, one of which was derived from glutamic acid decarboxylase (GAD) and two were derived from insulinoma-associated antigen 2 (IA2). Mann-Whitney U test showed a significant decrease in the levels of plasma IgG against the IA2b antigen in schizophrenia patients as compared to control subjects (Z=-3.54, p=0.0007), while no significant difference was found between these two groups either in anti-IA2a IgG levels (Z=-1.62, p=0.105) or in anti-GAD IgG levels (Z=-1.63, p=0.104). Linear regression analysis indicated no association of antipsychotic medication with the levels of plasma IgG against IA2a, IA2b or GAD, while the levels of plasma IgG for these 3 peptide antigens were significantly correlated with each other. Binary logistic regression showed that neither the DQ2.5 variant nor the DQ8 variant was associated with circulating levels of 3 T1D-associated autoantibodies in both the patient group and the control group. The coefficient of variation was 10.7% for anti-IA2a IgG assay, 10.1% for anti-IA2b IgG assay and 10.7% for anti-GAD IgG assay. The present work suggests that T1D-associated antibodies are unlikely to confer risk of schizophrenia and that the in-house ELISA developed with linear peptide antigens is highly reproducible. PMID- 27474349 TI - Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice. AB - Prostaglandin (PG)D2 is an endogenous sleep substance, and a series of animal studies reported that PGD2 or PGD2 receptor (DP1) agonists promote sleep, while DP1 antagonists promote wakefulness. This suggests the possibility of use of PG DP1 antagonists as wake-promoting compounds. We therefore evaluated the wake promoting effects of ONO-4127Na, a DP1 antagonist, in a mouse model of narcolepsy (i.e., orexin/ataxin-3 transgenic mice) and compared those to effects of modafinil. ONO-4127Na perfused in the basal forebrain (BF) area potently promoted wakefulness in both wild type and narcoleptic mice, and the wake-promoting effects of ONO-4127Na at 2.93 * 10(-4) M roughly corresponded to those of modafinil at 100 mg/kg (p.o.). The wake promoting effects of ONO-4127Na was observed both during light and dark periods, and much larger effects were seen during the light period when mice slept most of the time. ONO-4127Na, when perfused in the hypothalamic area, had no effects on sleep. We further demonstrated that wake-promoting effects of ONO-4127Na were abolished in DP1 KO mice, confirming that the wake-promoting effect of ONO-4127Na is mediated by blockade of the PG DP1 receptors located in the BF area. ONO-4127Na reduced DREM, an EEG/EMG assessment of behavioral cataplexy in narcoleptic mice, suggesting that ONO-4127Na is likely to have anticataplectic effects. DP1 antagonists may be a new class of compounds for the treatment of narcolepsy-cataplexy, and further studies are warranted. PMID- 27474351 TI - Improvement of the intracellular environment for enhancing l-arginine production of Corynebacterium glutamicum by inactivation of H2O2-forming flavin reductases and optimization of ATP supply. AB - l-arginine, a semi essential amino acid, is an important amino acid in food flavoring and pharmaceutical industries. Its production by microbial fermentation is gaining more and more attention. In previous work, we obtained a new l arginine producing Corynebacterium crenatum (subspecies of Corynebacterium glutamicum) through mutation breeding. In this work, we enhanced l-arginine production through improvement of the intracellular environment. First, two NAD(P)H-dependent H2O2-forming flavin reductases Frd181 (encoded by frd1 gene) and Frd188 (encoded by frd2) in C. glutamicum were identified for the first time. Next, the roles of Frd181 and Frd188 in C. glutamicum were studied by overexpression and deletion of the encoding genes, and the results showed that the inactivation of Frd181 and Frd188 was beneficial for cell growth and l arginine production, owing to the decreased H2O2 synthesis and intracellular reactive oxygen species (ROS) level, and increased intracellular NADH and ATP levels. Then, the ATP level was further increased by deletion of noxA (encoding NADH oxidase) and amn (encoding AMP nucleosidase), and overexpression of pgk (encoding 3-phosphoglycerate kinase) and pyk (encoding pyruvate kinase), and the l-arginine production and yield from glucose were significantly increased. In fed batch fermentation, the l-arginine production and yield from glucose of the final strain reached 57.3g/L and 0.326g/g, respectively, which were 49.2% and 34.2% higher than those of the parent strain, respectively. ROS and ATP are important elements of the intracellular environment, and l-arginine biosynthesis requires a large amount of ATP. For the first time, we enhanced l-arginine production and yield from glucose through reducing the H2O2 synthesis and increasing the ATP supply. PMID- 27474350 TI - The Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry: Rationale, Design, and Preliminary Recruitment. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex and clinically heterogeneous arrhythmic condition. Incomplete penetrance and variable expressivity are particularly evident in ARVC, making clinical decision making challenging. METHODS: Pediatric and adult cardiologists, geneticists, genetic counsellors, ethicists, nurses, and qualitative researchers are collaborating to create the Canadian ARVC registry using a web-based clinical database. Biological samples will be banked and systematic analysis will be performed to examine potentially causative mutations, variants, and biomarkers. Outcomes will include syncope, ventricular arrhythmias, defibrillator therapies, heart failure, and mortality. RESULTS: Preliminary recruitment has enrolled 365 participants (aged 42.7 +/- 17.1 years; 50% women), including 129 probands and 236 family members. Previous cardiac arrest occurred in 28 (8%) participants, syncope occurred in 43 (12%) participants, and 46% of probands had a family history of sudden death. Overall yield of genetic testing was 36% for a disease causing mutation and 20% for a variant of unknown significance. Target enrollment is 1000 affected patients and 500 unaffected family member controls over 7 years. The cross-sectional and longitudinal data collected in this manner will allow a robust assessment of the natural history and clinical course of genetic subtypes. CONCLUSIONS: The Canadian ARVC Registry will create a population-based cohort of patients and their families to inform clinical decisions regarding patients with ARVC. PMID- 27474352 TI - Dynamic control of the mevalonate pathway expression for improved zeaxanthin production in Escherichia coli and comparative proteome analysis. AB - Engineered heterologous multi-gene metabolic pathways often suffer from flux imbalance and toxic metabolites, as the production host typically lacks the regulatory mechanisms for the heterologous pathway. Here, we first coordinated the expression of all genes of the mevalonate (MEV) pathway from Saccharomyces cerevisiae using the tunable intergenic regions (TIGRs), and then dynamically regulated the TIGR-mediated MEV pathway to prevent the accumulation of toxic metabolites by using IPP/FPP-responsive promoter. After introduction of the dynamically controlled TIGR-mediated MEV pathway into Escherichia coli, the content and concentration of zeaxanthin in shaker flask cultures were 2.0- and 2.1-fold higher, respectively, than those of the strain harboring the statically controlled non-TIGR-mediated MEV pathway. The content and concentration of zeaxanthin in E. coli ZEAX (pZSPgadE-MevTTIGR-MevBTIGRIS-2) reached 722.46mg/L and 23.16mg/g dry cell weight (DCW), respectively, in 5.0L fed-batch fermentation. We also comparatively analyzed the proteomes between E. coli ZEAX and E. coli ZEAX (pZSPgadE-MevTTIGR-MevBTIGRIS-2) to understand the mechanism of zeaxanthin biosynthesis. The results of the comparative proteomes demonstrate that zeaxanthin overproduction may be associated with increased precursor availability, increased NADPH availability, increased ATP availability, oxidative stress response, and increased membrane storage capacity for zeaxanthin due to changes in both cellular shape and membrane composition. PMID- 27474353 TI - Efficient phototrophic production of a high-value sesquiterpenoid from the eukaryotic microalga Chlamydomonas reinhardtii. AB - The heterologous expression of terpene synthases in microbial hosts has opened numerous possibilities for bioproduction of desirable metabolites. Photosynthetic microbial hosts present a sustainable alternative to traditional fermentative systems, using freely available (sun)light and carbon dioxide as inputs for bio production. Here, we report the expression of a patchoulol synthase from Pogostemon cablin Benth in the model green microalga Chlamydomonas reinhardtii. The sesquiterpenoid patchoulol was produced from the alga and was used as a marker of sesquiterpenoid production capacity. A novel strategy for gene loading was employed and patchoulol was produced up to 922+/-242ugg-1 CDW in six days. We additionally investigated the effect of carbon source on sesquiterpenoid productivity from C. reinhardtii in scale-up batch cultivations. It was determined that up to 1.03mgL-1 sesquiterpenoid products could be produced in completely photoautotrophic conditions and that the alga exhibited altered sesquiterpenoid production metabolism related to carbon source. PMID- 27474354 TI - Corrigendum to "Comparison of Quantifiler(r) Trio and InnoQuantTM human DNA quantification kits for detection of DNA degradation in developed and aged fingerprints" [Forensic Sci. Int. 263C (2016) 132-138]. PMID- 27474355 TI - Identification and characterization of human UDP-glucuronosyltransferases responsible for the in vitro glucuronidation of ursolic acid. AB - This study aims to characterize the glucuronidation kinetics of ursolic acid (UA) in human liver microsomes (HLMs) and intestinal microsomes (HIMs) and identify the main UDP-glucuronosyltransferases (UGTs) involved. In our present study, only one type of UA glucuronide was observed after incubation with HLMs and HIMs respectively and was identified as a UA hydroxyl O-glucuronide. The glucuronidation of UA can be shown in HLMs and HIMs with Km values of 3.29 +/- 0.16 and 3.74 +/- 0.22 MUM and Vmax values of 0.33 +/- 0.03 and 0.42 +/- 0.03 nmol/min/(mg protein). Among the 12 recombinant UGT enzymes investigated, UGT1A3 and UGT1A4 were identified as the major enzymes catalyzing the glucuronidation of UA [Km values of 2.58 +/- 0.12 and 4.66 +/- 0.60 MUM, Vmax values of 0.72 +/- 0.01 and 1.00 +/- 0.06 nmol/min/(mg protein)]. The chemical inhibition study showed that the IC50 for hecogenin inhibition of UA glucuronidation was 51.79 +/- 4.32 MUM in HLMs. And chenodeoxycholic acid inhibited UA glucuronidation in HLMs with an IC50 of 28.26 +/- 2.91 MUM. In addition, UA glucuronidation in a panel of eight HLM was significantly correlated with telmisartan glucuronidation (r(2) = 0.7660, p < 0.01) and trifluoperazine glucuronidation (r(2) = 0.5866, p < 0.01) respectively. These findings collectively indicate that UGT1A3 and UGT1A4 were the main enzymes responsible for the glucuronidation of UA in human. PMID- 27474356 TI - Pharmacokinetics and pharmacodynamics of prasugrel in healthy Japanese subjects. AB - This randomized double-blind and placebo-controlled study assessed the pharmacodynamics and pharmacokinetics of prasugrel in healthy adult Japanese male subjects after single (n = 50) and multiple (n = 40) oral administration. With a single administration of prasugrel (2-30 mg), the plasma concentration of the active metabolite increased rapidly, reached a maximum at 30 min after administration, and then decreased rapidly within 4 h. The 5 mg and higher doses prevented ADP-induced platelet aggregation in a dose-dependent manner. Further analyses showed that 30 mg prasugrel exhibited the peak inhibition, and 20 mg prasugrel showed a nearly equivalent effect. With multiple doses (2.5-10 mg), the pharmacokinetic parameters on Day 1 and Day 7 were similar, and no accumulation attributable to multiple dosing was observed. The inhibitory effect on ADP induced platelet aggregation increased with doses from 2.5 to 7.5 mg, and reached the peak level at 7.5 mg. Regarding safety, all of the drug-related adverse events observed were mild, and there were no clinically significant bleeding related adverse events. This study indicates that a single oral administration of prasugrel at a dose of up to 30 mg and a maintenance dose of up to 10 mg are tolerated in Japanese healthy subjects. PMID- 27474357 TI - A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients. AB - OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-infinity (area under the plasma concentration-time curve from time 0 to infinity), and t1/2 (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-infinity , and t1/2 values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (+/-6.43) ng/mL in adolescents vs 21.89 (+/-6.15) ng/mL in adults; mean AUC0-infinity 98.1 (+/-28.1) ng.h/mL in adolescents vs 109.7 (+/ 26.1) ng.h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated. PMID- 27474358 TI - Quantification of Synthetic Cathinones in Rat Brain Using HILIC-ESI-MS/MS. AB - The abuse of synthetic cathinones, formerly marketed as "bath salts", has emerged over the last decade. Three common drugs in this class include 3,4 methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4 methylenedioxymethcathinone (methylone). An LC-MS/MS method has been developed and validated for the simultaneous quantification of MDPV, mephedrone, and methylone in brain tissue. Briefly, MDPV, mephedrone, methylone, and their deuterium-labeled analogs were subjected to solid phase extraction (SPE) and separated using an HILIC Silica Column. The HPLC was coupled to a Shimadzu IT-TOF (ion trap-time of flight) system with the electrospray source running in positive mode (+ESI). The method was validated for precision, accuracy, and extraction efficiency. All inter-day and intra-day % RSD (percent relative standard deviation) and % error values were less than 15% and extraction efficiency exceeded 80%. These conditions allowed for limits of detection of 1ng/mL for MDPV, and 5 ng/mL for both mephedrone and methylone. The limits of quantification were determined to be 5ng/mL for MDPV and 10 ng/mL for mephedrone and methylone. The method was utilized to evaluate the pharmacokinetics of these drugs in adult male rats following administration of a drug cocktail including MDPV, mephedrone, and methylone. All three compounds reached peak concentrations in the brain within 15 min. Although methylone and mephedrone were administered at the same dose, the peak concentration (Cmax) of mephedrone in the brain was significantly higher than that for methylone, as was the area under the curve (AUC). In summary, this quick and sensitive method for measuring synthetic cathinones may be used for future pharmacokinetic investigations of these drugs in target tissue. PMID- 27474359 TI - An Efficient, Robust Method for the Determination of Cannabinoids in Whole Blood by LC-MS-MS. AB - Due to the high prevalence of cannabinoids in forensic toxicology casework, it is desirable to have an efficient method that uses a small volume of blood and requires a minimal sample preparation. Although many methods have been reported, they are often labor intensive, require special sample preparation materials, use 1 mL or more of specimen or are difficult to replicate. The liquid chromatography with tandem mass spectrometry (LC-MS-MS) method presented herein employs a rapid and simple liquid-liquid extraction, has been successfully applied in two different laboratories, uses 0.5 mL of specimen and was extensively validated. The validated limit of detection and limit of quantitation were 1 ng/mL for delta 9-tetrahydrocannabinol (THC) and 11-hydroxy-delta-9-tetrahydrocannabinol (OH-THC) and 5 ng/mL for 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THCA). Each analyte demonstrated a zero-order linear range (r2 > 0.990) with 1/x weighting of 1-40 ng/mL for THC and OH-THC and 5-200 ng/mL for THCA. The coefficient of variation of replicate analyses was within 14%. Bias was within +/-13% of the prepared concentration. The validated method provides a sensitive, efficient and robust procedure for the quantitation of cannabinoids in blood using LC-MS-MS and a sample volume of 0.5 mL. PMID- 27474360 TI - Acute Methiopropamine Intoxication After "Synthacaine" Consumption. AB - Use of methiopropamine (MPA), a synthetic metamfetamine analog, has been detected since 2011 in Europe, but there is limited information on its acute toxicity. A 30-year-old man was admitted to the emergency department in a confused state, with paranoid delusion, auditory and visual hallucinatory experiences, and incoherent speech following the use of "synthacaine" (a slang term derived from "synthetic" and "cocaine"). Toxicological screening for pharmaceuticals and drugs of abuse by liquid chromatography-diode-array detector, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS-MS) detected MPA, which was subsequently quantified by a specific LC-MS-MS method. Of note, 13 h after presentation to the emergency department, the plasma concentration of MPA was 14 ng/mL. This case report confirms the toxicity of MPA and the need for toxicological analysis to confirm the substance actually ingested by users of new psychoactive substances. PMID- 27474361 TI - Loperamide-Related Deaths in North Carolina. AB - Loperamide (Imodium(r)) has been accepted as a safe, effective, over-the-counter anti-diarrheal drug with low potential for abuse. It is a synthetic opioid that lacks central nervous system activity at prescribed doses, rendering it ineffective for abuse. Since 2012, however, the North Carolina Office of the Chief Medical Examiner has seen cases involving loperamide at supratherapeutic levels that indicate abuse. The recommended dose associated with loperamide should not exceed 16 mg per day, although users seeking an opioid-like high reportedly take it in excess of 100 mg per dose. When taken as directed, the laboratory organic base extraction screening method with gas chromatography-mass spectrometry/nitrogen phosphorus detector lacks the sensitivity to detect loperamide. When taken in excess, the screening method identifies loperamide followed by a separate technique to confirm and quantify the drug by liquid chromatography-tandem mass spectrometry. Of the 21 cases involving loperamide, the pathologist implicated the drug as either additive or primary to the cause of death in 19 cases. The mean and median peripheral blood concentrations for the drug overdose cases were 0.27 and 0.23 mg/L, respectively. Furthermore, an extensive review of the pharmacology associated with loperamide and its interaction with P-glycoprotein will be examined as it relates to the mechanism of toxicity. PMID- 27474363 TI - Residues of Ractopamine and Identification of its Glucuronide Metabolites in Plasma, Urine, and Tissues of Cattle. AB - Ractopamine was approved by the US Food and Drug Administration for use as a growth promoter on cattle a decade ago is still banned by the European Union and most Asian countries. While, ractopamine residues in living samples and some organs (besides liver, muscle and kidney) of cattle under the recommended feed condition (10-30 mg/kg in dry matter, 28-42 days) remains unclear. In this study, nine cattle (246.22 +/- 18.17 kg) were fed 0.67 mg/kg body weight (equivalent to 30 mg/kg in dry matter) of ractopamine for 28 days to investigate the residues of ractopamine in plasma, urine and organs. Plasma and urine were sampled during treatment and withdrawal period. Three cattle were slaughtered on withdrawal days 0 and 3 for organs collection. Ractopamine was determined by LC-MS/MS and its glucuronide metabolites were identified by Q-TOF/MS. Ractopamine concentrations in plasma and urine reached highest on treatment day 14 (2.88 ng/mL) and day 7 (4713.25 ng/mL), respectively. On withdrawal day 28, ractopamine concentrations in plasma and urine and were undetectable (limit of quantitation, 0.2 ng/mL) and 4.21 ng/mL, respectively. On withdrawal day 0, ractopamine residue in tissues were as follows: liver > eye > lung > spleen > aqueous fluid > heart > bile > kidney > gluteus > rib eye muscle. Compared with those on withdrawal day 0, ractopamine contents in most tissues that sampled on withdrawal day 3 were lower (P < 0.05), while that in the eye tissues, aqueous fluid, and kidney were stable or higher. These results provide extensive data for risk management in ractopamine approved countries and monitoring of the illegal usage in countries that ban ractopamine. PMID- 27474362 TI - Identification of Drugs in Parenteral Pharmaceutical Preparations from a Quality Assurance and a Diversion Program by Direct Analysis in Real-Time AccuTOFTM-Mass Spectrometry (DART-MS). AB - In healthcare settings drug diversion and impairment of physicians are major concerns requiring a rapid and efficient method for surveillance and detection. A Direct Analysis in Real Time ion source coupled to a JEOL AccuTOFTM time-of flight mass spectrometer (DART-MS) method was developed to screen parenteral pharmaceutical formulations for potential drug diversion. Parenteral pharmaceutical formulations are also known as injectable formulations and are used with intravenous, subcutaneous, intramuscular and intra-articular administration. A library was created using the mass spectra data collected by a DART-MS operated in switching mode at 20, 60 and 90 V settings. This library contained 17 commonly encountered drugs in parenteral pharmaceutical formulations that included the surgical analgesic: fentanyl, hydromorphone and morphine; anesthetic: baclofen, bupivacaine, ketamine, midazolam, ropivacaine and succinylcholine; and a mixture of other drug classes: caffeine, clonidine, dexamethasone, ephedrine, heparin, methadone, oxytocin and phenylephrine. Randomly selected 200 de-identified parenteral pharmaceutical formulations containing one or more drugs were submitted for analysis to the FIRM Toxicology Laboratory at Virginia Commonwealth University Health and were screened using the DART-MS. The drug contents of the de-identified formulations were previously confirmed by a published high performance liquid chromatography (HPLC) method. The drugs in the formulations were rapidly and successfully identified using the generated library. The DART-MS and HPLC results were in complete agreement for all 200 parenteral pharmaceutical formulations. PMID- 27474364 TI - A double blind randomized clinical trial comparing lingualized and fully bilateral balanced posterior occlusion for conventional complete dentures. AB - PURPOSE: A lingualized occlusion (LO) for complete dentures reduces lateral inferences and occlusal force contacts and direction; thus, LO is theorized to be more suitable for patients with compromised ridges than fully bilateral balanced articulation (FBBA). However, no studies have yet provided evidence to support LO in edentate patients with compromised alveolar ridges. The purpose of this study was to compare LO and FBBA in edentulous individuals with compromised ridges. METHODS: Sixty edentulous individuals were randomly allocated into groups and received dentures with either LO or FBBA. Following delivery, several denture related satisfaction variables were measured using 100mm visual analogue scales; oral health-related quality of life (OHRQoL) was also assessed using the Oral Health Impact Profile (OHIP). Sub-group analyses of the effect of moderate and severe mandibular bone loss were also carried out. RESULTS: No significant differences were detected between LO and FBBA with the primary outcome. At 6 months, participants with severely atrophied mandibles and FBBA rated their satisfaction with retention of mandibular dentures significantly lower than those with LO (median LO: 86, FBBA: 58.5, p=0.03). They also had significantly lower OHRQoL for the domain of Pain (median LO: 4, FBBA: 5, p=0.02). General satisfaction and total OHIP scores significantly improved between baseline and 6 months only for the LO subjects with severely atrophied mandibles (satisfaction: p=0.003, OHIP total score: p=0.0007). CONCLUSIONS: The results indicate that the LO occlusal scheme with hard resin artificial teeth is more efficient for patients with severely resorbed mandibular ridges. PMID- 27474365 TI - Use of e-mail for Parkinson's disease consultations: Are answers just a clic away? AB - INTRODUCTION: The clinical problems of patients with movement disorders (MD) are complex, and the duration and frequency of face-to-face consultations may be insufficient to meet their needs. We analysed the implementation of an e-mail based query service for our MD unit's patients and their primary care physicians (PCPs). METHODS: We retrospectively reviewed all consecutive emails sent and received over a period of 4 months, one year after implementation of the e-mail inquiry system. All patients received the during consultations, and PCPs, during scheduled informative meetings. We recorded and later analysed the profile of the questioner, patients' demographic and clinical data, number of queries, reason for consultation, and actions taken. RESULTS: From 1 January 2015 to 30 April 2015, the service received 137 emails from 63 patients (43% male, mean age 71+/ 10.5) diagnosed with Parkinson's disease (76%), atypical parkinsonism (10%), and others (14%); 116 responses were sent. Twenty (32%) emails were written by patients, 38 (60%) by their caregivers, and 5 (8%) by their PCPs. The reasons for consultation were clinical in 50 cases (80%): 16 (32%) described clinical deterioration, 14 (28%) onset of new symptoms, and 20 (40%) side effects or concerns about medications. In 13 cases (20%), the query was bureaucratic: 11 were related to appointments (85%) and 2 were requests for clinical reports (15%). In response, new appointments were scheduled in 9 cases (14%), while the rest of the questions were answered by email. Patients were satisfied overall and the additional care burden on specialists was not excessive. CONCLUSIONS: Implementing an e-mail-based consultation system is feasible in MD units. It facilitates both communication between neurologists and patients and continued care in the primary care setting. PMID- 27474366 TI - Transcutaneous electrical nerve stimulation for spasticity: A systematic review. AB - INTRODUCTION: Although transcutaneous electrical nerve stimulation (TENS) has traditionally been used to treat pain, some studies have observed decreased spasticity after use of this technique. However, its use in clinical practice is still limited. Our purpose was twofold: to determine whether TENS is effective for treating spasticity or associated symptoms in patients with neurological involvement, and to determine which stimulation parameters exert the greatest effect on variables associated with spasticity. DEVELOPMENT: Two independent reviewers used PubMed, PEDro, and Cochrane databases to search for randomised clinical trials addressing TENS and spasticity published before 12 May 2015, and selected the articles that met the inclusion criteria. Of the initial 96 articles, 86 were excluded. The remaining 10 articles present results from 207 patients with a cerebrovascular accident, 84 with multiple sclerosis, and 39 with spinal cord lesions. CONCLUSIONS: In light of our results, we recommend TENS as a treatment for spasticity due to its low cost, ease of use, and absence of adverse reactions. However, the great variability in the types of stimulation used in the studies, and the differences in parameters and variables, make it difficult to assess and compare any results that might objectively determine the effectiveness of this technique and show how to optimise parameters. PMID- 27474367 TI - Insulin neuritis or treatment-induced diabetic neuropathy of diabetes. PMID- 27474368 TI - Biochemical diagnosis of nonketotic hyperglycinemia in Cuba. PMID- 27474369 TI - Improving the non-technical skills of hospital medical emergency teams: The Team Emergency Assessment Measure (TEAMTM). AB - OBJECTIVES: This prospective descriptive study aimed to test the validity and feasibility of the Team Emergency Assessment Measure (TEAMTM) for assessing real world medical emergency teams' non-technical skills. Second, the present study aimed to explore the instrument's contribution to practice regarding teamwork and learning outcomes. METHODS: Registered nurses (RNs) and medical staff (n = 104) in two hospital EDs in rural Victoria, Australia, participated. Over a 10 month period, the (TEAMTM) instrument was completed by multiple clinicians at medical emergency episodes. RESULTS: In 80 real-world medical emergency team resuscitation episodes (283 clinician assessments), non-technical skills ratings averaged 89% per episode (39 of a possible 44 points). Twenty-one episodes were rated in the lowest quartile (i.e. <=37 points out of 44). Ratings differed by discipline, with significantly higher scores given by medical raters (mean: 41.1 +/- 4.4) than RNs (38.7 +/- 5.4) (P = 0.001). This difference occurred in the Leadership domain. The tool was reliable with Cronbach's alpha 0.78, high uni dimensional validity and mean inter-item correlation of 0.45. Concurrent validity was confirmed by strong correlation between TEAMTM score and the awarded Global Rating (P < 0.001), with 38.4% of shared variance. RNs praised the instrument as it initiated staff reflection and debriefing discussions around performance improvement. CONCLUSION: Non-technical skills of medical emergency teams are known to often be suboptimal; however, average ratings of 89% were achieved in this real-world study. TEAMTM is a valid, reliable and easy to use tool, for both training and clinical settings, with benefits for team performance when used as an assessment and/or debriefing tool. PMID- 27474371 TI - Through experience to boldness? Deactivation of neophobia towards novel and aposematic prey in three European species of tits (Paridae). AB - European tits (Paridae) exhibit species-specific levels of initial wariness towards aposematic prey. This wariness may be caused by neophobia, dietary conservatism or innate bias against particular prey traits. We assessed the contribution of these three mechanisms to the behaviour of juvenile tits towards novel palatable prey and novel aposematic prey. We compared levels of initial wariness in great tits (Parus major), blue tits (Cyanistes caeruleus) and coal tits (Periparus ater), and tested how the wariness can be deactivated by experience with a palatable prey. One group of birds was pre-trained to attack familiar naturally coloured mealworms the other one, novel red-painted mealworms. Then all the birds were offered a novel palatable prey of different colour and shape: cricket (Acheta domestica) with blue sticker, and then a novel aposematic firebug (Pyrrhocoris apterus). The three species of tits differed in how the experience with a novel palatable prey affected their behaviour towards another novel prey. Great tits and coal tits from experienced groups significantly decreased their neophobia towards both palatable prey and aposematic prey while blue tits did not change their strongly neophobic reactions. The interspecific differences may be explained by differences in body size, geographic range, and habitat specialisation. PMID- 27474370 TI - CD40 in Retinal Muller Cells Induces P2X7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy. AB - Muller cells and macrophages/microglia are likely important for the development of diabetic retinopathy; however, the interplay between these cells in this disease is not well understood. An inflammatory process is linked to the onset of experimental diabetic retinopathy. CD40 deficiency impairs this process and prevents diabetic retinopathy. Using mice with CD40 expression restricted to Muller cells, we identified a mechanism by which Muller cells trigger proinflammatory cytokine expression in myeloid cells. During diabetes, mice with CD40 expressed in Muller cells upregulated retinal tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), intracellular adhesion molecule 1 (ICAM-1), and nitric oxide synthase (NOS2), developed leukostasis and capillary degeneration. However, CD40 did not cause TNF-alpha or IL-1beta secretion in Muller cells. TNF-alpha was not detected in Muller cells from diabetic mice with CD40+ Muller cells. Rather, TNF-alpha was upregulated in macrophages/microglia. CD40 ligation in Muller cells triggered phospholipase C-dependent ATP release that caused P2X7-dependent production of TNF-alpha and IL-1beta by macrophages. P2X7-/- mice and mice treated with a P2X7 inhibitor were protected from diabetes induced TNF-alpha, IL-1beta, ICAM-1, and NOS2 upregulation. Our studies indicate that CD40 in Muller cells is sufficient to upregulate retinal inflammatory markers and appears to promote experimental diabetic retinopathy and that Muller cells orchestrate inflammatory responses in myeloid cells through a CD40-ATP-P2X7 pathway. PMID- 27474372 TI - CD4+/CD25(high)/FoxP3+/CD127- regulatory T cells in bronchoalveolar lavage fluid of lung cancer patients. AB - The aim of the study was to compare the presence of regulatory T cells (Tregs) in the local lung cancer environment versus systemic immune response based on the examination of bronchoalveolar lavage fluid (BALf) and peripheral blood (PB) from the same patient. 35 patients with lung cancer were investigated. Flow cytometry method with panel of antibodies: anti CD4/CD25/FoxP3/CD127 for Tregs identification was used. We observed significantly higher proportion of Tregs in the BALF than in PB (median 9.4 vs. 5.4%, p<0.05). The increased proportion of Tregs in patients with advanced disease and in adenocarcinoma was found. This study confirmed the usefulness of BALF analysis in evaluation of immune response in lung cancer. Detection of Tregs in the local tumour environment may have therapeutic relevance in individual indication for anti-cancer immune-therapies. PMID- 27474373 TI - Growth of elaborate microbial pinnacles in Lake Vanda, Antarctica. AB - Microbial pinnacles in ice-covered Lake Vanda, McMurdo Dry Valleys, Antarctica, extend from the base of the ice to more than 50 m water depth. The distribution of microbial communities, their photosynthetic potential, and pinnacle morphology affects the local accumulation of biomass, which in turn shapes pinnacle morphology. This feedback, plus environmental stability, promotes the growth of elaborate microbial structures. In Lake Vanda, all mats sampled from greater than 10 m water depth contained pinnacles with a gradation in size from <1-mm-tall tufts to pinnacles that were centimeters tall. Small pinnacles were cuspate, whereas larger ones had variable morphology. The largest pinnacles were up to ~30 cm tall and had cylindrical bases and cuspate tops. Pinnacle biomass was dominated by cyanobacteria from the morphological and genomic groups Leptolyngbya, Phormidium, and Tychonema. The photosynthetic potential of these cyanobacterial communities was high to depths of several millimeters into the mat based on PAM fluorometry, and sufficient light for photosynthesis penetrated ~5 mm into pinnacles. The distribution of photosynthetic potential and its correlation to pinnacle morphology suggests a working model for pinnacle growth. First, small tufts initiate from random irregularities in prostrate mat. Some tufts grow into pinnacles over the course of ~3 years. As pinnacles increase in size and age, their interiors become colonized by a more diverse community of cyanobacteria with high photosynthetic potential. Biomass accumulation within this subsurface community causes pinnacles to swell, expanding laminae thickness and creating distinctive cylindrical bases and cuspate tops. This change in shape suggests that pinnacle morphology emerges from a specific distribution of biomass accumulation that depends on multiple microbial communities fixing carbon in different parts of pinnacles. Similarly, complex patterns of biomass accumulation may be reflected in the morphology of elaborate ancient stromatolites. PMID- 27474374 TI - Small-angle X-ray scattering of calpain-5 reveals a highly open conformation among calpains. AB - Calpain-5 is a calcium-activated protease expressed in the retina. Mutations in calpain-5 cause autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM#193235). The structure of calpain-5 has not been determined, thus hindering the investigation of its proteolytic targets and pathological role in ADNIV. Herein, we report models of the proteolytic core of calpain-5 (mini calpain-5) containing two globular domains (termed DIIa-IIb) connected by a short, flexible linker, consistent with small-angle X-ray scattering (SAXS) data. Structural modeling in the absence of calcium suggests that mini-calpain-5 adopts a more open conformation when compared to previously determined structures of other calpain cores. This open conformation, achieved by a rotation of DIIa and DIIb with respect to each other, prevents formation of the active site and constrains the enzyme in an inactivated form. The relative domain rotation of 60 100 degrees we found for mini-calpain-5 (a non-classical calpain) is significantly greater than the largest rotation previously observed for a classical calpain (i.e., 55.0 degrees for mini-calpain-9). Together with our prediction that, in the full-length form, a long loop in DIIb (loop C1), a few residues downstream of the inter-domain linker, likely interacts with the shorter, acidic, inactivating loop on domain-III (DIII), these structural insights illuminate the complexity of calpain regulation. Moreover, our studies argue that pursuing higher resolution structural studies are necessary to understand the complex activity regulation prevalent in the calpain family and for the design of specific calpain inhibitors. PMID- 27474375 TI - Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. AB - BACKGROUND: The absence of trial data comparing robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy is a crucial knowledge gap in uro-oncology. We aimed to compare these two approaches in terms of functional and oncological outcomes and report the early postoperative outcomes at 12 weeks. METHOD: In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, were able to read and speak English, had no previous history of head injury, dementia, or psychiatric illness or no other concurrent cancer, had an estimated life expectancy of 10 years or more, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women's Hospital (Brisbane, QLD). Participants were randomly assigned (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient's condition. Further, a masked central pathologist reviewed the biopsy and radical prostatectomy specimens. Primary outcomes were urinary function (urinary domain of EPIC) and sexual function (sexual domain of EPIC and IIEF) at 6 weeks, 12 weeks, and 24 months and oncological outcome (positive surgical margin status and biochemical and imaging evidence of progression at 24 months). The trial was powered to assess health related and domain-specific quality of life outcomes over 24 months. We report here the early outcomes at 6 weeks and 12 weeks. The per-protocol populations were included in the primary and safety analyses. This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12611000661976. FINDINGS: Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to radical retropubic prostatectomy and 163 to robot-assisted laparoscopic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group proceeded to surgery and 157 in the robot-assisted laparoscopic prostatectomy group. 121 assigned to radical retropubic prostatectomy completed the 12 week questionnaire versus 131 assigned to robot assisted laparoscopic prostatectomy. Urinary function scores did not differ significantly between the radical retropubic prostatectomy group and robot assisted laparoscopic prostatectomy group at 6 weeks post-surgery (74.50 vs 71.10; p=0.09) or 12 weeks post-surgery (83.80 vs 82.50; p=0.48). Sexual function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (30.70 vs 32.70; p=0.45) or 12 weeks post-surgery (35.00 vs 38.90; p=0.18). Equivalence testing on the difference between the proportion of positive surgical margins between the two groups (15 [10%] in the radical retropubic prostatectomy group vs 23 [15%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a Delta of 10%. However, a superiority test showed that the two proportions were not significantly different (p=0.21). 14 patients (9%) in the radical retropubic prostatectomy group versus six (4%) in the robot-assisted laparoscopic prostatectomy group had postoperative complications (p=0.052). 12 (8%) men receiving radical retropubic prostatectomy and three (2%) men receiving robot-assisted laparoscopic prostatectomy experienced intraoperative adverse events. INTERPRETATION: These two techniques yield similar functional outcomes at 12 weeks. Longer term follow-up is needed. In the interim, we encourage patients to choose an experienced surgeon they trust and with whom they have rapport, rather than a specific surgical approach. FUNDING: Cancer Council Queensland. PMID- 27474377 TI - Innovation and surgical clinical trials. PMID- 27474376 TI - Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. AB - BACKGROUND: Cardiovascular risk factors are associated with an increased risk of dementia. We assessed whether a multidomain intervention targeting these factors can prevent dementia in a population of community-dwelling older people. METHODS: In this open-label, cluster-randomised controlled trial, we recruited individuals aged 70-78 years through participating general practices in the Netherlands. General practices within each health-care centre were randomly assigned (1:1), via a computer-generated randomisation sequence, to either a 6-year nurse-led, multidomain cardiovascular intervention or control (usual care). The primary outcomes were cumulative incidence of dementia and disability score (Academic Medical Center Linear Disability Score [ALDS]) at 6 years of follow-up. The main secondary outcomes were incident cardiovascular disease and mortality. Outcome assessors were masked to group assignment. Analyses included all participants with available outcome data. This trial is registered with ISRCTN, number ISRCTN29711771. FINDINGS: Between June 7, 2006, and March 12, 2009, 116 general practices (3526 participants) within 26 health-care centres were recruited and randomly assigned: 63 (1890 participants) were assigned to the intervention group and 53 (1636 participants) to the control group. Primary outcome data were obtained for 3454 (98%) participants; median follow-up was 6.7 years (21 341 person-years). Dementia developed in 121 (7%) of 1853 participants in the intervention group and in 112 (7%) of 1601 participants in the control group (hazard ratio [HR] 0.92, 95% CI 0.71-1.19; p=0.54). Mean ALDS scores measured during follow-up did not differ between groups (85.7 [SD 6.8] in the intervention group and 85.7 [7.1] in the control group; adjusted mean difference -0.02, 95% CI -0.38 to 0.42; p=0.93). 309 (16%) of 1885 participants died in the intervention group, compared with 269 (16%) of 1634 participants in the control group (HR 0.98, 95% CI 0.80-1.18; p=0.81). Incident cardiovascular disease did not differ between groups (273 [19%] of 1469 participants in the intervention group and 228 [17%] of 1307 participants in the control group; HR 1.06, 95% CI 0.86-1.31; p=0.57). INTERPRETATION: A nurse-led, multidomain intervention did not result in a reduced incidence of all-cause dementia in an unselected population of older people. This absence of effect might have been caused by modest baseline cardiovascular risks and high standards of usual care. Future studies should assess the efficacy of such interventions in selected populations. FUNDING: Dutch Ministry of Health, Welfare and Sport; Dutch Innovation Fund of Collaborative Health Insurances; and Netherlands Organisation for Health Research and Development. PMID- 27474378 TI - Biochemical and histological studies on adverse effects of mobile phone radiation on rat's brain. AB - With the rapid development of electronic technologies, the public concern about the potential health hazards induced by radiofrequency (RF) radiation has been grown. To investigate the effect of 1800MHz RF radiation emitted from mobile phone on the rat's brain, the present study was performed. Forty male rats were randomly divided into two equal groups; control and exposed group. The later one exposed to 1800MHz emitted from mobile phone with an SAR value of 0.6W/kg for two hours/day for three months. The brain tissues were collected at the end of the experimental period and separated into hippocampus and cerebellum for subsequent biochemical, histological, immunohistochemical and electron microscopic investigations. The rats that were exposed to RF- radiation had a significant elevation in MDA content and a significant reduction in antioxidant parameters (glutathione, super oxide dismutase and glutathione peroxidase) in both regions. Degenerative changes were observed in the hippocampus pyramidal cells, dark cells and cerebellar Purkinje cells with vascular congestion. In addition a significant DNA fragmentation and over expression of cyclooxygenase-2 apoptotic gene was detected. Those results suggested that, direct chronic exposure to mobile phone caused severe biochemical and histopathological changes in the brain. PMID- 27474379 TI - Analysis of the Phenotype and Function of the Subpopulations of Mucosal Associated Invariant T Cells. AB - Mucosal-associated invariant T (MAIT) cells contain two main subpopulations, CD8(+) and double-negative (DN) cells. The first reports suggested that subpopulations of MAIT cells have similar phenotype and function. Recent works, however, demonstrate that the subpopulations have different ontogenesis and are differentially affected by xenobiotic treatment. In this work, we re-examined the possible differences between subpopulations of MAIT cells. We demonstrate that the main subpopulations of MAIT cells (CD8 and DN) are relatively uniform in terms of both phenotype and function. Both populations are memory/activated, tissue-homing and pro-inflammatory. CD8(+) MAIT cells are better equipped for pro inflammatory functions as they express higher levels of CD16 and NKG2D, produce more pro-inflammatory cytokines (TNF-alpha and IFN-gamma) and have higher cytotoxic potential (contain more granzyme B and express higher levels of CD107A upon stimulation). Our study contributes to the understanding of the heterogeneity of MAIT cell population. PMID- 27474380 TI - What Is the Association of Elite Sporting Activities With the Development of Hip Osteoarthritis? AB - BACKGROUND: Male athletes participating in certain elite sporting activities may be at an increased risk for development of hip osteoarthritis (OA) later in life. However, the strength of the association of participation in sporting activities with the increased risk of hip OA has not been well summarized. PURPOSE: To investigate the association of certain high-impact sporting activities with the risk of development of hip OA in elite athletes by conducting a systematic review of the available literature. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: PubMed, Cochrane, and EMBASE databases were searched to identify all potential studies. Eleven studies met the inclusion criteria, which included participation in elite-level sporting activities, greater than 50% male athletes in the study population, diagnosis of hip OA by radiograph, hospital admission or total hip arthroplasty (THA), and greater than 80% follow-up. Exclusion criteria were recreational sporting activities, primarily female cohorts as there was a dearth of available literature on the topic, and self-reported symptoms without radiographic confirmation of diagnosis. Most studies were with European athletes, where elite-level was defined as involvement in national- or professional-level competition. RESULTS: Participation across elite-level impact sports was associated with increased risk of development of hip OA when compared with matched controls (odds ratio, 1.8-8.7). Twelve of 15 studies reviewed demonstrated an odds ratio of 1.8 or greater of developing hip OA in elite-level athletes. Handball was associated with the highest rate of OA of any sport, nearly 5 times that of matched controls. Soccer players demonstrated between 2 and 9 times increased risk of hip OA as defined by radiography or THA. Hockey players demonstrated 2 to 3 times increased risk of hip OA (THA or hospital admission). Five studies investigating the association of competitive long distance running with hip OA demonstrated inconsistent results. CONCLUSION: Currently available literature suggests that male athletes participating in elite impact sports (soccer, handball, track and field, or hockey) are at an increased risk of developing hip OA, while those participating in high-level long-distance running do not have a clearly elevated risk. Further research is warranted to elucidate the pathomechanics of development of hip OA in these patients. PMID- 27474381 TI - Drop-Jump Landing Varies With Baseline Neurocognition: Implications for Anterior Cruciate Ligament Injury Risk and Prevention. AB - BACKGROUND: Neurocognitive status may be a risk factor for anterior cruciate ligament (ACL) injury. Neurocognitive domains such as visual attention, processing speed/reaction time, and dual-tasking may influence ACL injury risk via alterations to neuromuscular performance during athletic tasks. However, the relationship between neurocognition and performance during athletic tasks is not yet established. HYPOTHESIS: Athletes with low baseline neurocognitive scores will demonstrate poorer jump landing performance compared with athletes with high baseline neurocognitive score. STUDY DESIGN: Controlled laboratory study. METHODS: Neurocognitive performance was measured using the Concussion Resolution Index (CRI). Three-dimensional kinematic and kinetic data of the dominant limb were collected for 37 recreational athletes while performing an unanticipated jump-landing task. Healthy, nonconcussed subjects were screened using a computer based neurocognitive test into a high performers (HP; n = 20; average CRI percentile, 78th) and a low performers (LP; n = 17; average CRI percentile, 41st) group. The task consisted of a forward jump onto a force plate with an immediate rebound to a second target that was assigned 250 milliseconds before landing on the force plate. Kinematic and kinetic data were obtained during the first jump landing. RESULTS: The LP group demonstrated significantly altered neuromuscular performance during the landing phase while completing the jump-landing task, including significantly increased peak vertical ground-reaction force (mean +/- SD of LP vs HP: 1.81 +/- 0.53 vs 1.38 +/- 0.37 body weight [BW]; P < .01), peak anterior tibial shear force (0.91 +/- 0.17 vs 0.72 +/- 0.22 BW; P < .01), knee abduction moment (0.47 +/- 0.56 vs 0.03 +/- 0.64 BW * body height; P = .03), and knee abduction angle (6.1 degrees +/- 4.7 degrees vs 1.3 degrees +/- 5.6 degrees ; P = .03), as well as decreased trunk flexion angle (9.6 degrees +/- 9.6 degrees vs 16.4 degrees +/- 11.2 degrees ; P < .01). CONCLUSION: Healthy athletes with lower baseline neurocognitive performance generate knee kinematic and kinetic patterns that are linked to ACL injury. CLINICAL RELEVANCE: Neurocognitive testing using the CRI may be useful for identification of athletes at elevated risk for future ACL injury. PMID- 27474383 TI - Defining Thresholds for the Patient Acceptable Symptom State for the IKDC Subjective Knee Form and KOOS for Patients Who Underwent ACL Reconstruction. AB - BACKGROUND: A clinically meaningful change in patient-reported outcome (PRO) may not be associated with an acceptable state that corresponds to "feeling well," also known as the patient acceptable symptom state (PASS). The PASS thresholds for the International Knee Documentation Committee Subjective Knee Form (IKDC SKF) and the Knee injury and Osteoarthritis Outcome Score (KOOS) have not been determined for individuals after anterior cruciate ligament (ACL) reconstruction. PURPOSE: To determine the PASS thresholds for the IKDC-SKF and KOOS in individuals at 1 to 5 years after ACL reconstruction. STUDY DESIGN: Cohort study (diagnosis): Level of evidence, 2. METHODS: Individuals 1 to 5 years after primary ACL reconstruction completed a survey that included the IKDC-SKF and KOOS. All subjects assessed satisfaction with their current state by answering the question, "Taking into account all the activity you have during your daily life, your level of pain, and also your activity limitations and participation restrictions, do you consider the current state of your knee satisfactory?" RESULTS: A total of 251 participants (mean age +/- SD, 26.1 +/- 9.9 years) completed the survey at an average of 3.4 +/- 1.3 years after ACL reconstruction. Of these, 223 (89.2%) individuals indicated that they were in an acceptable symptom state (PASS-Y). Analysis of the receiver operating characteristic curve revealed that the IKDC-SKF and each of the KOOS subscales (pain, symptoms, activities of daily living [ADL], sport and recreation [sport/rec], and quality of life [QoL]) were significantly better identifiers of PASS than chance as indicated by the significance of the area under the curves. The PASS threshold (sensitivity, specificity) was 75.9 (0.83, 0.96) for the IKDC-SKF, 88.9 (0.82, 0.81) for the KOOS pain, 57.1 (0.78, 0.67) for the KOOS symptoms, 100.0 (0.70, 0.89) for the KOOS ADL, 75.0 (0.87, 0.88) for the KOOS sport/rec, and 62.5 (0.82, 0.85) for the KOOS QoL. In addition, the difference between PASS-Y and PASS-N was statistically significant (P < .001) for all PROs. CONCLUSION: To our knowledge, this is the first study to identify the PASS thresholds for the IKDC-SKF and the KOOS subscales for individuals 1 to 5 years after ACL reconstruction. By identifying threshold values for the PASS, this study provides additional information to facilitate interpretation of the IKDC-SKF and KOOS in daily practice and clinical research related to ACL reconstruction. PMID- 27474382 TI - Multiple Past Concussions in High School Football Players: Are There Differences in Cognitive Functioning and Symptom Reporting? AB - BACKGROUND: There is increasing concern about the possible long-term effects of multiple concussions, particularly on the developing adolescent brain. Whether the effect of multiple concussions is detectable in high school football players has not been well studied, although the public health implications are great in this population. PURPOSE: To determine if there are measureable differences in cognitive functioning or symptom reporting in high school football players with a history of multiple concussions. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Participants included 5232 male adolescent football players (mean [+/-SD] age, 15.5 +/- 1.2 years) who completed baseline testing between 2009 and 2014. On the basis of injury history, athletes were grouped into 0 (n = 4183), 1 (n = 733), 2 (n = 216), 3 (n = 67), or >=4 (n = 33) prior concussions. Cognitive functioning was measured by the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery, and symptom ratings were obtained from the Post-Concussion Symptom Scale. RESULTS: There were no statistically significant differences between groups (based on the number of reported concussions) regarding cognitive functioning. Athletes with >=3 prior concussions reported more symptoms than did athletes with 0 or 1 prior injury. In multivariate analyses, concussion history was independently related to symptom reporting but less so than developmental problems (eg, attention or learning problems) or other health problems (eg, past treatment for psychiatric problems, headaches, or migraines). CONCLUSION: In the largest study to date, high school football players with multiple past concussions performed the same on cognitive testing as those with no prior concussions. Concussion history was one of several factors that were independently related to symptom reporting. PMID- 27474384 TI - The Relationship of the Femoral Physis and the Medial Patellofemoral Ligament in Children: A Cadaveric Study. AB - BACKGROUND: Young athletes sustain patellar dislocations in a variety of sports. The medial patellofemoral ligament (MPFL) is a critical structure that functions as an anatomic checkrein to help prevent lateral patellar dislocation. Reconstruction of this ligament is challenging in patients with open physes because of concerns about iatrogenic damage to the femoral physis. PURPOSE: To evaluate the relationship of the distal femoral physis and the MPFL. STUDY DESIGN: Descriptive laboratory study. METHODS: In 15 cadaveric, pediatric knees (age, 7-11 years), markers were placed at the proximal/distal limits of the MPFL femoral attachment and were evaluated with computed tomography. The distance from the MPFL attachment midpoint to the most medial aspect of the distal femoral physis was measured. RESULTS: The mean femoral width of the MPFL was 8.1 mm (range, 4.3-13.8 mm). The femoral MPFL midpoint was distal to the femoral physis in 11 specimens and proximal to the physis in 4 specimens. The most proximal portion of the MPFL femoral attachment extended above the medial physis in 7, was at the physis in 5, and was below the physis in 3 specimens. One specimen had the entire MPFL femoral attachment above the physis. For knees with the MPFL midpoint above the medial physis, the distance between the center of the MPFL and physis was 3.3 mm (range, 0.3-7.1 mm). For knees with the MPFL below the medial physis, the distance between the center of the MPFL and physis was -6.8 mm (range, -0.7 to -22.0 mm). CONCLUSION: The relationship of the femoral attachment of the MPFL and the medial femoral physis shows some anatomic variation. In all cases, the MPFL is close to the medial femoral physis, but the midpoint of the MPFL is at, slightly above, or slightly below the physis. CLINICAL RELEVANCE: The relationship of the MPFL femoral attachment footprint to the femoral physis in the skeletally immature patient is not well understood, and access to pediatric cadaveric tissue is very limited. This small series demonstrates that there is considerable variation in the relationship between the MPFL and distal femoral physis. This anatomic information may guide MPFL reconstruction technique in young patients and reduce the risk of iatrogenic physeal arrest on the femur. PMID- 27474385 TI - Utilization of ACL Injury Biomechanical and Neuromuscular Risk Profile Analysis to Determine the Effectiveness of Neuromuscular Training. AB - BACKGROUND: The widespread use of anterior cruciate ligament (ACL) injury prevention interventions has not been effective in reducing the injury incidence among female athletes who participate in high-risk sports. PURPOSE/HYPOTHESIS: The purpose of this study was to determine if biomechanical and neuromuscular factors that contribute to the knee abduction moment (KAM), a predictor of future ACL injuries, could be used to characterize athletes by a distinct factor. Specifically, we hypothesized that a priori selected biomechanical and neuromuscular factors would characterize participants into distinct at-risk profiles. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 624 female athletes who participated in jumping, cutting, and pivoting sports underwent testing before their competitive season. During testing, athletes performed drop-jump tasks from which biomechanical measures were captured. Using data from these tasks, latent profile analysis (LPA) was conducted to identify distinct profiles based on preintervention biomechanical and neuromuscular measures. As a validation, we examined whether the profile membership was a significant predictor of the KAM. RESULTS: LPA using 6 preintervention biomechanical measures selected a priori resulted in 3 distinct profiles, including a low (profile 1), moderate (profile 2), and high (profile 3) risk for ACL injuries. Athletes with profiles 2 and 3 had a significantly higher KAM compared with those with profile 1 (P < .05). CONCLUSION: This is the first study to use LPA of biomechanical landing data to create ACL injury risk profiles. Three distinct risk groups were identified based on differences in the peak KAM. CLINICAL RELEVANCE: These findings demonstrate the existence of discernable groups of athletes that may benefit from injury prevention interventions. STUDY REGISTRATION: ClinicalTrials.gov NCT identifier: NCT01034527. PMID- 27474386 TI - One-Stage Cartilage Repair Using a Hyaluronic Acid-Based Scaffold With Activated Bone Marrow-Derived Mesenchymal Stem Cells Compared With Microfracture: Five-Year Follow-up. AB - BACKGROUND: Articular cartilage injury is frequently encountered, yet treatment options capable of providing durable cartilage repair are limited. PURPOSE: To investigate the medium-term clinical outcomes of cartilage repair using a 1-stage technique of a hyaluronic acid-based scaffold with activated bone marrow aspirate concentrate (HA-BMAC) and compare results with those of microfracture. A secondary aim of this study was to identify specific patient demographic factors and cartilage lesion characteristics that are associated with superior outcomes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Fifty physically active patients (mean age, 45 years) with grade IV cartilage injury of the knee (lesion size, 1.5-24 cm2) were treated with HA-BMAC or microfracture and were observed prospectively for 5 years. Patients were placed into the HA-BMAC group if the health insurance policy of the treating institution supported this option; otherwise, they were placed into the microfracture group. Objective and subjective clinical assessment tools were used preoperatively and at 2 and 5 years postoperatively to compare treatment outcomes. RESULTS: Significant improvements in outcome scores were achieved in both treatment groups at 2 years (P < .001). In the microfracture group, 64% were classified as normal or nearly normal according to the International Knee Documentation Committee (IKDC) objective score at 2 years, compared with 100% of those treated with HA-BMAC (P < .001). Normal or nearly normal objective assessments in the microfracture group declined significantly after 5 years to 28% of patients (P = .004). All patients treated with HA-BMAC maintained improvement at 5 years according to Lysholm, Tegner, IKDC objective, and IKDC subjective scores. Tegner, IKDC objective, and Knee injury and Osteoarthritis Outcome Score (KOOS) assessments demonstrated higher scores in the HA-BMAC treatment group compared with microfracture at 5 years. Lysholm and IKDC subjective scores were similar between treatment groups at 5 years. Poorer outcomes in the microfracture group were demonstrated in cases of lesions larger than 4 cm2 and nonsolitary lesions. Age greater than 45 years, large size of lesion, and treatment of multiple lesions were not associated with poorer outcome in patients treated with HA-BMAC. CONCLUSION: Repair of chondral injury using a hyaluronic acid-based scaffold with activated bone marrow aspirate concentrate provides better clinical outcomes and more durable cartilage repair at medium-term follow-up compared with microfracture. Positive short-term clinical outcomes can be achieved with either microfracture or HA-BMAC. Cartilage repair using HA-BMAC leads to successful medium-term outcomes independent of age or lesion size. PMID- 27474387 TI - Incorporation of Hamstring Grafts Within the Tibial Tunnel After Anterior Cruciate Ligament Reconstruction: Magnetic Resonance Imaging of Suspensory Fixation Versus Interference Screws. AB - BACKGROUND: The success of anterior cruciate ligament (ACL) reconstruction requires solid graft incorporation within the tunnels to enable graft remodeling. Resorbable interference screws (RIS) provide limited tendon-bone contact because much of the tunnel circumference is occupied by the screw itself, while adjustable suspensory fixation (ASF) systems provide larger contact zones, which favor ligamentization. PURPOSE: To evaluate ligamentization of a 4-strand semitendinosus (4ST) graft fixed with ASF compared with RIS within the tibial bone tunnel at 6 months postoperatively using magnetic resonance imaging (MRI). STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: We prospectively enrolled 121 consecutive patients undergoing primary ACL reconstruction using a single-bundle 4ST graft. The femoral end of the graft was fixed using suspensory fixation in all knees. The tibial end of the graft was fixed using ASF in 67 knees and RIS in 54 knees. Six months postoperatively, knee laxity measurements were taken, and MRI was performed to assess graft incorporation within the tibial tunnel. RESULTS: At 6-month follow-up, MRI scans of 109 knees were available for analysis. The mean tibial tunnel enlargement in the ASF group was 2.3 +/- 1.1 mm (range, 0.5-6.0 mm), while in the RIS group, it was 4.7 +/- 2.8 mm (range, 0.5 19.0 mm) (P < .001). The Howell graft signal assessment findings were excellent in 97% of knees in the ASF group and in 25% of knees in the RIS group (P < .001). The mean signal-to-noise quotient (SNQ) was 0.078 +/- 0.62 in the ASF group and 0.671 +/- 0.83 in the RIS group (P < .001). CONCLUSION: ASF provides more favorable conditions than RIS for the incorporation and ligamentization of 4ST grafts within the tibial tunnel. The ASF system used showed very little tunnel widening, which suggests that it grants stabilization. The SNQ was also considerably better in the ASF group. PMID- 27474388 TI - Glucocorticoids at the Olympic Games: state-of-the-art review. AB - In this state-of-the-art review, the author discusses the history of prohibiting glucocorticoids (GCs) and how this has occurred over nearly three decades at the Olympic Games. He relates how prohibiting systemic GCs in sport was a major factor in the development of therapeutic use exemptions and the fluctuating status of non-systemic GCs (banned, not banned). Concern is expressed that for 2017, the World Anti-Doping Agency (WADA) is proposing to prohibit injecting GCs shortly prior to competition. The author notes that in 1986, when GCs were first prohibited, analytical chemistry techniques could not distinguish the route of GC administration from its urinary concentration. Thirty years later, this remains the case. Importantly, this article discusses how the desired pharmacological effects of injecting GCs locally and intra-articularly can be achieved and why exercising vigorously immediately or shortly after a GC injection is therapeutically unsound. The review concludes by agreeing that injecting GCs shortly prior to strenuous training or competition is medically unwise but stresses that this is a clinical matter that sport-not WADA-needs to address. Cycling and rowing have managed this successfully for the past 5 years. PMID- 27474389 TI - Should Markus Rehm be permitted to compete in the long jump at the Olympic Games? PMID- 27474390 TI - Return to play in elite sport: a shared decision-making process. PMID- 27474391 TI - Infographic: Make physical activity a part of daily life at all stages in life: an infographic. PMID- 27474392 TI - Optimization of solid content, carbon/nitrogen ratio and food/inoculum ratio for biogas production from food waste. AB - Biogas production from food waste has been used as an efficient waste treatment option for years. The methane yields from decomposition of waste are, however, highly variable under different operating conditions. In this study, a statistical experimental design method (Taguchi OA9) was implemented to investigate the effects of simultaneous variations of three parameters on methane production. The parameters investigated were solid content (SC), carbon/nitrogen ratio (C/N) and food/inoculum ratio (F/I). Two sets of experiments were conducted with nine anaerobic reactors operating under different conditions. Optimum conditions were determined using statistical analysis, such as analysis of variance (ANOVA). A confirmation experiment was carried out at optimum conditions to investigate the validity of the results. Statistical analysis showed that SC was the most important parameter for methane production with a 45% contribution, followed by F/I ratio with a 35% contribution. The optimum methane yield of 151 l kg-1 volatile solids (VS) was achieved after 24 days of digestion when SC was 4%, C/N was 28 and F/I were 0.3. The confirmation experiment provided a methane yield of 167 l kg-1 VS after 24 days. The analysis showed biogas production from food waste may be increased by optimization of operating conditions. PMID- 27474393 TI - Determining the amount of waste plastics in the feed of Austrian waste-to-energy facilities. AB - Although thermal recovery of waste plastics is widely practiced in many European countries, reliable information on the amount of waste plastics in the feed of waste-to-energy plants is rare. In most cases the amount of plastics present in commingled waste, such as municipal solid waste, commercial, or industrial waste, is estimated based on a few waste sorting campaigns, which are of limited significance with regard to the characterisation of plastic flows. In the present study, an alternative approach, the so-called Balance Method, is used to determine the total amount of plastics thermally recovered in Austria's waste incineration facilities in 2014. The results indicate that the plastics content in the waste feed may vary considerably among different plants but also over time. Monthly averages determined range between 8 and 26 wt% of waste plastics. The study reveals an average waste plastics content in the feed of Austria's waste-to-energy plants of 16.5 wt%, which is considerably above findings from sorting campaigns conducted in Austria. In total, about 385 kt of waste plastics were thermally recovered in all Austrian waste-to-energy plants in 2014, which equals to 45 kg plastics cap-1. In addition, the amount of plastics co-combusted in industrial plants yields a total thermal utilisation rate of 70 kg cap-1 a-1 for Austria. This is significantly above published rates, for example, in Germany reported rates for 2013 are in the range of only 40 kg of waste plastics combusted per capita. PMID- 27474394 TI - Shipping Drug Resistance: Extracellular Vesicles in Ovarian Cancer. AB - Ovarian cancer is a deadly disease, largely because of relapse and chemotherapy resistance. Common genetic mechanisms causing drug resistance have not been identified. A recent study unravels a novel and unexpected pathway involving the transfer of microvesicle-encapsulated miRNA from omental adipocytes and fibroblasts, to cancer cells. PMID- 27474395 TI - Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment. AB - Anti-VEGF antibody bevacizumab has prolonged progression-free survival in several cancer types, however acquired resistance is common. Adaption has been observed pre-clinically, but no human study has shown timing and genes involved, enabling formulation of new clinical paradigms. In a window-of-opportunity study in 35 ductal breast cancer patients for 2weeks prior to neoadjuvant chemotherapy, we monitored bevacizumab response by Dynamic Contrast-Enhanced Magnetic Resonance [DCE-MRI], transcriptomic and pathology. Initial treatment response showed significant overall decrease in DCE-MRI median K(trans), angiogenic factors such ESM1 and FLT1, and proliferation. However, it also revealed great heterogeneity, spanning from downregulation of blood vessel density and central necrosis to continued growth with new vasculature. Crucially, significantly upregulated pathways leading to resistance included glycolysis and pH adaptation, PI3K-Akt and immune checkpoint signaling, for which inhibitors exist, making a strong case to investigate such combinations. These findings support that anti-angiogenesis trials should incorporate initial enrichment of patients with high K(trans), and a range of targeted therapeutic options to meet potential early resistance pathways. Multi-arm adaptive trials are ongoing using molecular markers for targeted agents, but our results suggest this needs to be further modified by much earlier adaptation when using drugs affecting the tumor microenvironment. PMID- 27474397 TI - Electroporation of Cas9 protein/sgRNA into early pronuclear zygotes generates non mosaic mutants in the mouse. AB - The CRISPR/Cas9 system is a powerful tool for elucidating the roles of genes in a wide variety of organisms including mice. To obtain genetically modified embryos or mice by this method, Cas9 mRNA and sgRNA are usually introduced into zygotes by microinjection or electroporation. However, most mutants generated with this method are genetically mosaic, composed of several types of cells carrying different mutations, which complicates phenotype analysis in founder embryos or mice. To simplify the analysis and to elucidate the roles of genes involved in developmental processes, a method for producing non-mosaic mutants is needed. Here, we established a method for generating non-mosaic mouse mutant embryos. We introduced Cas9 protein and sgRNA into in vitro fertilized (IVF) zygotes by electroporation, which enabled the genome editing to occur before the first replication of the mouse genome. As a result, all of the cells in the mutant carried the same set of mutations. This method solves the problem of mosaicism/allele complexity in founder mutant embryos or mice generated by the CRIPSR/Cas9 system. PMID- 27474396 TI - Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development. AB - The stepwise progression of common endoderm progenitors into differentiated liver and pancreas organs is regulated by a dynamic array of signals that are not well understood. The nuclear receptor subfamily 5, group A, member 2 gene nr5a2, also known as Liver receptor homolog-1 (Lrh-1) is expressed in several tissues including the developing liver and pancreas. Here, we interrogate the role of Nr5a2 at multiple developmental stages using genetic and chemical approaches and uncover novel pleiotropic requirements during zebrafish liver and pancreas development. Zygotic loss of nr5a2 in a targeted genetic null mutant disrupted the development of the exocrine pancreas and liver, while leaving the endocrine pancreas intact. Loss of nr5a2 abrogated exocrine pancreas markers such as trypsin, while pancreas progenitors marked by ptf1a or pdx1 remained unaffected, suggesting a role for Nr5a2 in regulating pancreatic acinar cell differentiation. In the developing liver, Nr5a2 regulates hepatic progenitor outgrowth and differentiation, as nr5a2 mutants exhibited reduced hepatoblast markers hnf4alpha and prox1 as well as differentiated hepatocyte marker fabp10a. Through the first in vivo use of Nr5a2 chemical antagonist Cpd3, the iterative requirement for Nr5a2 for exocrine pancreas and liver differentiation was temporally elucidated: chemical inhibition of Nr5a2 function during hepatopancreas progenitor specification was sufficient to disrupt exocrine pancreas formation and enhance the size of the embryonic liver, suggesting that Nr5a2 regulates hepatic vs. pancreatic progenitor fate choice. Chemical inhibition of Nr5a2 at a later time during pancreas and liver differentiation was sufficient to block the formation of mature acinar cells and hepatocytes. These findings define critical iterative and pleiotropic roles for Nr5a2 at distinct stages of pancreas and liver organogenesis, and provide novel perspectives for interpreting the role of Nr5a2 in disease. PMID- 27474398 TI - Avoiding false discovery in biomarker research. AB - BACKGROUND: Human tyrosine-protein phosphatase non-receptor type substrate 1alpha (SIRPA) is a surface marker identified in cardiomyocytes differentiated from human embryonic stem cells. Our objective was to determine if circulating SIRPA levels can serve as a biomarker of cardiac injury in children undergoing open heart surgery. RESULTS: Paired pre- and post-operative serum samples from 48 pediatric patients undergoing open heart surgery and from 6 pediatric patients undergoing non-cardiac surgery (controls) were tested for SIRPA protein levels using commercially available SIRPA ELISA kits from two manufacturers. Post operative SIRPA concentrations were significantly higher in patients after cardiac surgery compared to non-cardiac surgery when tested using SIRPA ELISA kits from both manufacturers. To verify the identity of the protein detected, recombinant human SIRPA protein (rhSIRPA) was tested on both ELISA kits. The calibrator from both ELISA kits was analyzed by Western blot as well as by Mass Spectrometry (MS). Western blot analysis of calibrators from both kits did not identity SIRPA. MS analysis of calibrators from both ELISA kits identified several inflammatory markers and albumin but no SIRPA was detected. CONCLUSIONS: We conclude that commercially available ELISA kits for SIRPA give false-positive results. Verifying protein identity using robust protein characterization is critical to avoid false biomarker discovery when using commercial ELISA kits. PMID- 27474399 TI - Plant diversity accurately predicts insect diversity in two tropical landscapes. AB - Plant diversity surely determines arthropod diversity, but only moderate correlations between arthropod and plant species richness had been observed until Basset et al. (Science, 338, 2012 and 1481) finally undertook an unprecedentedly comprehensive sampling of a tropical forest and demonstrated that plant species richness could indeed accurately predict arthropod species richness. We now require a high-throughput pipeline to operationalize this result so that we can (i) test competing explanations for tropical arthropod megadiversity, (ii) improve estimates of global eukaryotic species diversity, and (iii) use plant and arthropod communities as efficient proxies for each other, thus improving the efficiency of conservation planning and of detecting forest degradation and recovery. We therefore applied metabarcoding to Malaise-trap samples across two tropical landscapes in China. We demonstrate that plant species richness can accurately predict arthropod (mostly insect) species richness and that plant and insect community compositions are highly correlated, even in landscapes that are large, heterogeneous and anthropogenically modified. Finally, we review how metabarcoding makes feasible highly replicated tests of the major competing explanations for tropical megadiversity. PMID- 27474400 TI - Towards understanding the role of sialylation in melanoma progression. AB - Aberrant expression of sialic acids or altered linkage types is closely associated with malignant phenotype and metastatic potential, and can have prognostic significance in human cancer. The present study was undertaken to evaluate whether expression of sialylated derivatives on melanoma cell surface is associated with tumour progression. Four cell lines (WM1552C, WM115, IGR-39 and WM266-4) were used in the study. Cell surface expression of sialic acids was evaluated by flow cytometry with the use of Maackia amurensis and Sambucus nigra lectins. Moreover, adhesion and migration potential of melanoma cells and involvement of sialic acids in these processes were analysed. We have demonstrated that WM266-4 cells have a significantly higher level of alpha2,3 linked sialic acid residues than other cells, whereas IGR-39 cells had lower expression of alpha2,6-linked sialic acids. The adhesion efficiencies of WM1552C and WM115 cells were significantly lower than that of IGR-39 and WM266-4 cells. In contrast, WM266-4 cells repaired scratch wounds at least twice as fast as other cells. Melanoma cell adhesion to fibronectin in the presence of Sambucus nigra agglutinin (SNA) was reduced only in IGR-39 and WM266-4 cells, whereas the impact of Maackia amurensis agglutinin (MAA) on this process was much more important. Migration efficiency of melanoma cells was reduced more strongly in the presence of MAA than SNA. In conclusion, our results show that melanoma progression is associated with the increased expression of alpha2,3-linked sialic acids on the cell surface and these residues could promote melanoma cell interaction with fibronectin. PMID- 27474402 TI - Virus-like particles as drug delivery vectors. AB - Virus-like particles (VLPs) assemble spontaneously during the viral cycle or in heterologous systems during expression of viral structural protein. Depending on the complexity of the VLPs, they can be obtained by expression in prokaryotic or eukaryotic expression system from the suitable recombinant vectors, or formed in cell-free conditions. Moreover, they can be built from proteins of a single virus, or can present the proteins or peptides derived from a virus or cell on a platform derived from any other single virus, thus forming chimeric VLPs. VLPs are best known for their immunogenic properties, but the versatility of VLPs allows a wide variety of applications. They are lately in the centre of investigations in vaccinology, drug delivery and gene therapy. This review focuses on utilization of VLPs for drug delivery. PMID- 27474401 TI - Gastrodin ameliorates spinal cord injury via antioxidant and anti-inflammatory effects. AB - Spinal cord injury (SCI) is one of the most severe traumatic injuries that results in dysfunction of limbs and trunk below the damaged section. Recent studies have shown that gastrodin (GAS) could improve the recovery of SCI. In the current study, we aimed to examine the possible mechanism underlying the effect of GAS on recovery of SCI in rats. In rats with SCI, GAS improved locomotor functions and decreased permeability of blood-spinal cord barrier, as illustrated by increase of Basso-Beattie-Bresnahan scores and decrease of Evans blue leakage. In addition, GAS inhibited inflammation, as evidenced by decrease of proinflammatory cytokines, including tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) in rats following SCI. Moreover, increase of TBARS content and decrease of glutathione (GSH) content and superoxide dismutase (SOD) activities in SCI rats were inhibited by GAS. Furthermore, GAS enhanced mRNA expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), catalytic subunit of gamma-glutamylcysteine ligase (GCLc) and modified subunit of gamma glutamylcysteine ligase (GCLm). The data suggested that GAS may promote the recovery of SCI through the enhancement of Nrf2-GCLc/GCLm signaling pathway, and subsequent improvement of oxidative stress and inflammation, resulting in decrease of permeability of BSCB and improved recovery of locomotor function in rats with SCI. The results have provided novel insights into GAS-related therapy of SCI and associated neurodegenerative diseases. PMID- 27474403 TI - Endothelial progenitor cells participation in cardiovascular and kidney diseases: a systematic review. AB - Endothelial progenitor cells (EPCs) represent a small population of blood cells (5-40 cells/mm(3)), with an ability to differentiate into endothelial cells that form the lining of the blood vessels and contribute to postnatal angiogenesis. Abundant evidence shows that recruitment of EPCs from the bone marrow, the monocyte/macrophage lineage and the organs facilitate the endothelial regeneration and repair. Changes in the number of EPCs were observed in both, chronic kidney and cardiovascular diseases. Thus, these cells were tested for usage in diagnosis and therapy. In this paper, we review the current knowledge on the EPC biology and contribution of these cells to the kidney and cardiovascular diseases. PMID- 27474404 TI - Interaction of human fibronectin with Candida glabrata epithelial adhesin 6 (Epa6). AB - Adherence of pathogens to extracellular matrix proteins and host cells is one of the essential steps in the microbial colonization of the human organism. The adhesion of C. glabrata, i.e. the second major causative agent of human disseminated candidiases after C. albicans, to the host epithelium mainly engages specific fungal cell wall proteins - epithelial adhesins (Epa) - in particular, Epa1, Epa6 and Epa7. The aim of the present study was to identify the major Epa protein involved in the interactions with the human extracellular matrix protein fibronectin - and to present the kinetic and thermodynamic characteristics of these interactions. A relatively novel gel-free approach, i.e. the "cell surface shaving" that consists in short treatment of fungal cells with trypsin was employed to identify the C. glabrata surfaceome. Epa6 was purified, and the isolated protein was characterized in terms of its affinity to human fibronectin using a microplate ligand-binding assay and surface plasmon resonance measurements. The dissociation constants for the binding of Epa6 to fibronectin were determined to range between 9.03 * 10(-9) M and 7.22 * 10(-8) M, depending on the method used (surface plasmon resonance measurements versus the microplate ligand-binding assay, respectively). The identified fungal pathogen-human host protein-protein interactions might become a potential target for novel anticandidal therapeutic approaches. PMID- 27474405 TI - Characterization of the interactions between human high-molecular-mass kininogen and cell wall proteins of pathogenic yeasts Candida tropicalis. AB - Candida tropicalis is one of the most frequent causes of serious disseminated candidiasis in human patients infected by non-albicans Candida species, but still relatively little is known about its virulence mechanisms. In our current study, the interactions between the cell surface of this species and a multifunctional human protein - high-molecular-mass kininogen (HK), an important component of the plasma contact system involved in the development of the inflammatory state - were characterized at the molecular level. The quick release of biologically active kinins from candidal cell wall-adsorbed HK was presented and the HK binding ability was assigned to several cell wall-associated proteins. The predicted hyphally regulated cell wall protein (Hyr) and some housekeeping enzymes exposed at the cell surface (known as "moonlighting proteins") were found to be the major HK binders. Accordingly, after purification of selected proteins, the dissociation constants of the complexes of HK with Hyr, enolase, and phosphoglycerate mutase were determined using surface plasmon resonance measurements, yielding the values of 2.20 * 10(-7) M, 1.42 * 10(-7) M, and 5.81 * 10(-7) M, respectively. Therefore, in this work, for the first time, the interactions between C. tropicalis cell wall proteins and HK were characterized in molecular terms. Our findings may be useful for designing more effective prevention and treatment approaches against infections caused by this dangerous fungal pathogen. PMID- 27474406 TI - Pentoxifylline and its active metabolite lisofylline attenuate transforming growth factor beta1-induced asthmatic bronchial fibroblast-to-myofibroblast transition. AB - Bronchial asthma is characterized by persistent airway inflammation and airway wall remodeling. Among many different cells and growth factors triggering changes in bronchi structure, transforming growth factor beta1-induced fibroblast to myofibroblast transition is believed to be very important. The aim of this study was to evaluate whether theophylline (used in asthma therapy) and two other methylxanthines (pentoxifylline and its active metabolite lisofylline), may affect transforming growth factor beta1-induced fibroblast to myofibroblast transition in bronchial fibroblasts derived from asthmatic patients. We show here for the first time that selected methylxanthines effectively reduce transforming growth factor beta1-induced myofibroblast formation in asthmatic bronchial fibroblast populations. PTX was found to be the most effective methylxanthine. The number of differentiated myofibroblasts after PTX, LSF and THEO administration was reduced at least twofold. Studies on the use of methylxanthines opens a new perspective in the development of novel strategies in asthma therapy through their two-pronged, anti-inflammatory and anti-fibrotic action. In the future they can be considered as promising anti-fibrotic drugs. PMID- 27474407 TI - The Short Form of the Breastfeeding Self-Efficacy Scale as a Prognostic Factor of Exclusive Breastfeeding among Mandarin-Speaking Chinese Mothers. AB - BACKGROUND: Little is known about the effect of maternal perceived breastfeeding self-efficacy on the exclusive breastfeeding rate at 6 months postpartum in mainland China. OBJECTIVE: The aim of this study was to examine the relative effect of maternal breastfeeding self-efficacy and selected relevant factors on the exclusive breastfeeding rate at 6 months postpartum. The internal consistency and construct validity of the Chinese (Mandarin) version of the Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF) were also examined. METHODS: This was a prospective cohort study conducted at a regional teaching hospital in Guangzhou, China. A total of 562 in-hospital mothers who were within 72 hours postpartum were recruited to the study and followed up by telephone for 6 months. RESULTS: Although all of the mothers breastfed their babies within 72 hours postpartum, only 25% of the mothers breastfed exclusively. The mean survival time of continuation of exclusive breastfeeding was 16.7 days. The proportion of mothers who breastfed exclusively after discharge was 14.8%, 2.0%, and 0.2% at 1, 4, and 6 months, respectively. Cox regression analysis revealed that the mothers who had a higher BSES-SF score at baseline, underwent cesarean section, and practiced exclusive breastfeeding within 72 hours after delivery were significantly associated with a lower hazard of discontinuation of exclusive breastfeeding before 6 months postpartum. CONCLUSION: The exclusive breastfeeding rate among Chinese women is far from satisfactory. The Chinese (Mandarin) version of the BSES-SF can help in identifying mothers who need more support for exclusive breastfeeding before 6 months postpartum. PMID- 27474408 TI - Formula Feeding Is Independently Associated With Acute Kidney Injury in Very Low Birth Weight Infants. AB - BACKGROUND: Successful strategies to prevent neonatal acute kidney injury are lacking. Nevertheless, it is well known that in breastfed babies the excretory needs of the kidney are low because the intake of most nutrients is just above the nutritional requirement. OBJECTIVES: This study aimed to determine whether feeding type predicts acute kidney injury in the very low birth weight infant. METHODS: One hundred and eighty-six infants were enrolled in this pre-post cohort study (114 infants were included in the only human milk-fed group and 72 in the formula-fed group). Routine biological markers of acute kidney injury were collected in both groups from birth to discharge. RESULTS: Compared with formula feeding, human milk feeding was associated with almost 80% lower odds of acute kidney injury (odds ratio [OR] = 0.2; 95% confidence interval [CI], 0.05-0.77). After confounding variables had been controlled for, formula feeding was independently associated with acute kidney injury in very low birth weight infants. CONCLUSION: The study showed that, at our institution, acute kidney injury in the neonatal period is frequently associated with the avoidable procedure of formula feeding. Further prospective multicenter studies are needed to determine the generality of this association. PMID- 27474409 TI - Inositol hexakisphosphate kinase 1 (IP6K1) activity is required for cytoplasmic dynein-driven transport. AB - Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP7), are conserved eukaryotic signaling molecules that possess pyrophosphate and monophosphate moieties. Generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine pyrophosphorylation. Here, we report inositol pyrophosphates as novel regulators of cytoplasmic dynein-driven vesicle transport. Mammalian cells lacking IP6K1 display defects in dynein-dependent trafficking pathways, including endosomal sorting, vesicle movement, and Golgi maintenance. Expression of catalytically active but not inactive IP6K1 reverses these defects, suggesting a role for inositol pyrophosphates in these processes. Endosomes derived from slime mold lacking inositol pyrophosphates also display reduced dynein-directed microtubule transport. We demonstrate that Ser51 in the dynein intermediate chain (IC) is a target for pyrophosphorylation by IP7, and this modification promotes the interaction of the IC N-terminus with the p150(Glued) subunit of dynactin. IC-p150(Glued) interaction is decreased, and IC recruitment to membranes is reduced in cells lacking IP6K1. Our study provides the first evidence for the involvement of IP6Ks in dynein function and proposes that inositol pyrophosphate-mediated pyrophosphorylation may act as a regulatory signal to enhance dynein-driven transport. PMID- 27474410 TI - Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. AB - Autosomal dominant mutations that activate the leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson's disease. Recent work has revealed that LRRK2 directly phosphorylates a conserved threonine/serine residue in the effector binding switch-II motif of a number of Rab GTPase proteins, including Rab10. Here we describe a facile and robust method to assess phosphorylation of endogenous Rab10 in mouse embryonic fibroblasts (MEFs), lung and spleen-derived B-cells, based on the ability of the Phos-tag reagent to retard the electrophoretic mobility of LRRK2-phosphorylated Rab10. We exploit this assay to show that phosphorylation of Rab10 is ablated in kinase-inactive LRRK2[D2017A] knockin MEFs and mouse lung, demonstrating that LRRK2 is the major Rab10 kinase in these cells/tissue. We also establish that the Phos-tag assay can be deployed to monitor the impact that activating LRRK2 pathogenic (G2019S and R1441G) knockin mutations have on stimulating Rab10 phosphorylation. We show that upon addition of LRRK2 inhibitors, Rab10 is dephosphorylated within 1-2 min, markedly more rapidly than the Ser(935) and Ser(1292) biomarker sites that require 40-80 min. Furthermore, we find that phosphorylation of Rab10 is suppressed in LRRK2[S910A+S935A] knockin MEFs indicating that phosphorylation of Ser(910) and Ser(935) and potentially 14-3-3 binding play a role in facilitating the phosphorylation of Rab10 by LRRK2 in vivo The Rab Phos-tag assay has the potential to significantly aid with evaluating the effect that inhibitors, mutations and other factors have on the LRRK2 signalling pathway. PMID- 27474411 TI - Loss of cargo binding in the human myosin VI deafness mutant (R1166X) leads to increased actin filament binding. AB - Mutations in myosin VI have been associated with autosomal-recessive (DFNB37) and autosomal-dominant (DFNA22) deafness in humans. Here, we characterise an myosin VI nonsense mutation (R1166X) that was identified in a family with hereditary hearing loss in Pakistan. This mutation leads to the deletion of the C-terminal 120 amino acids of the myosin VI cargo-binding domain, which includes the WWY binding motif for the adaptor proteins LMTK2, Tom1 as well as Dab2. Interestingly, compromising myosin VI vesicle-binding ability by expressing myosin VI with the R1166X mutation or with single point mutations in the adaptor binding sites leads to increased F-actin binding of this myosin in vitro and in vivo As our results highlight the importance of cargo attachment for regulating actin binding to the motor domain, we perform a detailed characterisation of adaptor protein binding and identify single amino acids within myosin VI required for binding to cargo adaptors. We not only show that the adaptor proteins can directly interact with the cargo-binding tail of myosin VI, but our in vitro studies also suggest that multiple adaptor proteins can bind simultaneously to non-overlapping sites in the myosin VI tail. In conclusion, our characterisation of the human myosin VI deafness mutant (R1166X) suggests that defects in cargo binding may leave myosin VI in a primed/activated state with an increased actin binding ability. PMID- 27474412 TI - Heterogeneity in cervical spine assessment in paediatric trauma: A survey of physicians' knowledge and application at a paediatric major trauma centre. AB - OBJECTIVE: Evidence-based decision-making tools are widely used to guide cervical spine assessment in adult trauma patients. Similar tools validated for use in injured children are lacking. A paediatric-specific approach is appropriate given important differences in cervical spine anatomy, mechanism of spinal injury and concerns over ionising radiation in children. The present study aims to survey physicians' knowledge and application of cervical spine assessment in injured children. METHODS: A cross-sectional survey of physicians actively engaged in trauma care within a paediatric trauma centre was undertaken. Participation was voluntary and responses de-idenitified. The survey comprised 20 questions regarding initial assessment, imaging, immobilisation and perioperative management. Physicians' responses were compared with available current evidence. RESULTS: Sixty-seven physicians (28% registrars, 17% fellows and 55.2% consultants) participated. Physicians rated altered mental state, intoxication and distracting injury as the most important contraindications to cervical spine clearance in children. Fifty-four per cent considered adequate plain imaging to be 3-view cervical spine radiographs (anterior-posterior, lateral and odontoid), whereas 30% considered CT the most sensitive modality for detecting unstable cervical spine injuries. Physicians' responses reflected marked heterogeneity regarding semi-rigid cervical collars and what constitutes cervical spine 'clearance'. Greater consensus existed for perioperative precautions in this setting. CONCLUSIONS: Physicians actively engaged in paediatric trauma care demonstrate marked heterogeneity in their knowledge and application of cervical spine assessment. This is compounded by a lack of paediatric-specific evidence and definitions, involvement of multiple specialties and staff turnover within busy departments. A validated decision-making tool for cervical spine assessment will represent an important advance in paediatric trauma. PMID- 27474413 TI - The risk of cancer in patients with connective tissue diseases but without dermatomyositis or polymyositis: A multicenter cohort study conducted over 15 years in China. AB - OBJECTIVES: To investigate the relative risk of cancer in Chinese patients with connective tissue diseases (CTD) associated with and without dermatomyositis or polymyositis. METHODS: A retrospective, multicenter cohort study investigated 32,380 CTD patients (2334 diagnosed with dermatomyositis or polymyositis) without a history of malignancies treated from January 1, 1997, to December 31, 2011. Standardized incidence ratios (SIR) of cancers determined the incidence of malignancies during follow-up. The data was compared with the cancer morbidity of the general population from the Chinese Cancer Registry Annual Report of National Central Cancer Registry. RESULT: A total of 113 patients (348.98 per 100,000) developed cancer during follow-up, 75 (249.62 per 100,000) were patients with CTD without dermatomyositis or polymyositis. The risk of cancer among patients with CTD was increased (SIR=1.45, 95% confidence interval [CI] 1.22-1.71), and this risk increased with age (<40 years: SIR=1.00 [95%CI 0.45-2.21]; 41-60 years: SIR=1.53 [95%CI 1.17-2.00]; and >60 years SIR=2.34 (95%CI 0.93-2.77]) and the time of follow-up (<1year: SIR=1.22 [95%CI 0.88-1.70]; 1-5 years: SIR=1.14 [95%CI 0.79-1.65]; and 6-10 years SIR=1.70 [95%CI 1.34-2.85]), but was similar between genders (male SIR=1.60 [95%CI 1.10-2.31] and female SIR=1.25 [95%CI 1.01-1.55]). The cancer risk among CTD patients without dermatomyositis or polymyositis was not affected (SIR=0.93, 95%CI 0.75-1.16), regardless of gender, age, or follow up. CONCLUSION: The cancer risk for patients with CTD without dermatomyositis or polymyositis was not increased or decreased, but it was increased when patients with dermatomyositis or polymyositis were included. PMID- 27474414 TI - Association of interleukin-10 polymorphisms with risk factors of Alzheimer's disease and other dementias (SADEM study). AB - Some studies have reported a genetic association between single nucleotide polymorphisms (SNPs) in the promoter region of Interleukin (IL) 10 and Alzheimer's disease (AD), with conflicting results. To further investigate the proposed association and to clarify the role of cytokines as a potential cause for AD susceptibility, we analyzed genotypes, allele distributions and haplotypes of IL-10 promoter polymorphisms -1082 (rs1800896) and -819 (rs1800871) in a Mexican population: 986 normal controls and 221 cases divided as follows: 122 with Alzheimer disease (AD), 67 with (VaD) and 32 with mixed dementia (AD/VaD). Patients with dementia showed increased frequency of "ATA, CTG, and CTA" haplotypes when compared to controls. We identified two risk haplotypes: ATA (OR=3.56, 95%CI=2.84-4.45, p<0.0001), and CTA (OR=1.90, 95%CI=1.38-2.62, p<0.0001), and four protection haplotypes: ATG (OR=0.60, 95%CI=0.45-0.82, p=0.0012), CTG (OR=0.38, 95%CI=0.23-0.62, p<0.0001), ACG (OR=0.01, 95%CI=0.002 1.13, p<0.0001), and CCG (OR=0.02, 95%CI=0.004-0.203, p<0.0001). In summary, this is the first study in Mexican population that considers the analysis of IL-10 in patients with AD, VaD and AD/VaD. Our results showed the relevance of the role that IL-10 plays in the pathological mechanisms that result in the development of dementia. In addition, in our study, it was possible to distinguish two protective and two risk haplotypes for the development of dementia. PMID- 27474415 TI - Body fat percentage is more associated with low physical fitness than with sedentarism and diet in male and female adolescents. AB - BACKGROUND: Obesity is a multifactorial disease and our understanding of this disease is still incomplete. PURPOSE: The aim of this investigation was to examine the associations between body fat percentage and physical fitness, diet and active/sedentary behaviors in female and male adolescents. METHODS: A cross sectional study was carried out on a sample of 1389 Spanish adolescents (706 boys and 683 girls) aged between 14 and 17years. Individual body fat percentage was measured by means of bioelectrical impedance analysis and participants' physical fitness was determined by measuring cardiorespiratory fitness (20-m shuttle run test), muscular strength (handgrip dynamometry), muscular endurance (curl-up and 90 degrees push up repetition tests) and muscular flexibility (sit-and-reach test). Daily physical activity, sedentary time and diet were estimated using validated and self-reported questionnaires. The participants were divided into quartiles based on their body fat percentage. RESULTS: Boys and girls included in Q3 and Q4 presented lower values for cardiorespiratory fitness than Q1 (P<0.05). Boys and girls included in Q4 also presented lower values for muscular endurance than Q1 (P<0.05). Only boys in Q4 presented lower levels of physical activity than Q1 (P<0.05). Physical activity, physical fitness and diet can explain 30% of the variance for body fat percentage in boys and 17% in girls. CONCLUSIONS: Female and male adolescents with a higher body fat percentage presented lower cardiorespiratory and muscular endurance fitness than leaner counterparts. PMID- 27474416 TI - Reduced NPY Y1 receptor hippocampal expression and signs of decreased vagal modulation of heart rate in mice. AB - Central neuropeptide Y (NPY) signaling participates in the regulation of cardiac autonomic outflow, particularly via activation of NPY-Y1 receptors (Y1Rs). However, the specific brain areas and neural pathways involved have not been completely identified yet. Here, we evaluate the role of hippocampal Y1Rs in the modulation of the autonomic control of cardiac function using a conditional knockout mouse model. Radiotelemetric transmitters were implanted in 4-month-old male mice exhibiting reduced forebrain expression (rfb) of the Y1R (Npy1rrfb, n=10) and their corresponding controls (Npy1r2lox, n=8). ECG signals were recorded (i) during resting conditions, (ii) under selective pharmacological manipulation of cardiac vagal activity, and (iii) during acute and chronic psychosocial stress challenges, and analyzed via time- and frequency-domain analysis of heart rate variability. Npy1rrfb mice showed a lower Npy1r mRNA density in the dentate gyrus and in the CA1 region of the hippocampus. Under resting undisturbed conditions, Npy1rrfb mice exhibited (i) a higher heart rate, (ii) a reduced overall heart rate variability, and (iii) lower values of the indices of vagal modulation compared to Npy1r2lox counterparts. Following pharmacological vagal inhibition, heart rate was higher in control but not in Npy1rrfb mice compared to their respective baseline values, suggesting that tonic vagal influences on heart rate were reduced in Npy1rrfb mice. The magnitude of the heart rate response to acute stressors was smaller in Npy1rrfb mice compared to Npy1r2lox counterparts, likely due to a concurrent lower vagal withdrawal. These findings suggest that reduced Y1R expression leads to a decrease in resting vagal modulation and heart rate variability, which, in turn, may determine a reduced cardiac autonomic responsiveness to acute stress challenges. PMID- 27474417 TI - Ambient atomic resolution atomic force microscopy with qPlus sensors: Part 1. AB - Atomic force microscopy (AFM) is an enormous tool to observe nature in highest resolution and understand fundamental processes like friction and tribology on the nanoscale. Atomic resolution in highest quality was possible only in well controlled environments like ultrahigh vacuum (UHV) or controlled buffer environments (liquid conditions) and more specified for long-term high-resolution analysis at low temperatures (~4 K) in UHV where drift is nearly completely absent. Atomic resolution in these environments is possible and is widely used. However, in uncontrolled environments like air, with all its pollutants and aerosols, unspecified thin liquid films as thin as a single molecular water-layer of 200 pm or thicker condensation films with thicknesses up to hundred nanometer, have been a problem for highest resolution since the invention of the AFM. The goal of true atomic resolution on hydrophilic as well as hydrophobic samples was reached recently. In this manuscript we want to review the concept of ambient AFM with atomic resolution. The reader will be introduced to the phenomenology in ambient conditions and the problems will be explained and analyzed while a method for scan parameter optimization will be explained. Recently developed concepts and techniques how to reach atomic resolution in air and ultra-thin liquid films will be shown and explained in detail, using several examples. Microsc. Res. Tech. 80:50-65, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27474418 TI - Mitigating Misdiagnosis in Radiology: Educational CT CME Case Conference for Peer Review and Interpretative Improvement. PMID- 27474419 TI - Learning About Leadership by Making Mistakes. PMID- 27474420 TI - Multidisciplinary Oncology Education: Going Beyond Tumor Board. PMID- 27474421 TI - A Transactional/Ecological Perspective on Ethnic-Racial Identity, Socialization, and Discrimination. AB - We first review current literature on three ethnic-racial dynamics that are considered to be resources and stressors in the lives of ethnic-minority youth: ethnic-racial identity, socialization, and discrimination. Next, we propose that a more contextualized view of these ethnic-racial dynamics reveals that they are interdependent, inseparable, and mutually defining and that an ecological/transactional perspective on these ethnic-racial dynamics shifts researchers' gaze from studying them as individual-level processes to studying the features of settings that produce them. We describe what is known about how identity, socialization, and discrimination occur in four microsystems-families, peers, schools, and neighborhoods-and argue that focusing on specific characteristics of these microsystems in which particular types of identity, socialization, and discrimination processes cooccur would be informative. PMID- 27474422 TI - Racism, Racial Resilience, and African American Youth Development: Person Centered Analysis as a Tool to Promote Equity and Justice. AB - Racism constitutes a significant risk to the healthy development of African American youth. Fortunately, however, not all youth who experience racism evidence negative developmental outcomes. In this chapter, we examine person centered analysis (PCA)-a quantitative technique that investigates how variables combine across individuals-as a useful tool for elucidating racial and ethnic protective processes that mitigate the negative impact of racism. We review recent studies employing PCA in examinations of racial identity, racial socialization, and other race-related experiences, as well as how these constructs correlate with and impact African American youth development. We also consider challenges and limitations of PCA and conclude with a discussion of future research and how PCA might be used to promote equity and justice for African American and other racial and ethnic minority youth who experience racism. PMID- 27474424 TI - Social Exclusion Based on Group Membership is a Form of Prejudice. AB - Children around the world are affected by bias, prejudice, and discrimination. In this chapter, we argue that intergroup social exclusion-exclusion of peers on the basis of group membership-is a form of prejudice. As such, research efforts should be directed at uncovering the negative intergroup attitudes that sustain these behaviors, and encouraging the development of children's capacity to resist biases in favor of inclusion and just treatment of others. In order to interpret what is known about intergroup social exclusion in childhood, as well as identify compelling issues for current investigation, we introduce our integrative social reasoning developmental model, which emphasizes how children weigh moral and social concerns in everyday peer contexts. This chapter emphasizes three areas of research that have contributed to understanding social inclusion and exclusion decisions in childhood which include the roles of: (1) intergroup contact and friendship, (2) peer group norms, and (3) messages from parents and teachers. While providing a background on the state of research to date, this chapter also pinpoints recent work, shedding new light on the complex interplay of moral reasoning and intergroup attitudes in children's inclusion and exclusion decisions. PMID- 27474423 TI - Helping Children Navigate a Diverse World: Parents' Contributions. AB - We review the existing literature on how parents prepare their children to navigate an increasingly diverse world. In particular, we focus much of our attention on the ethnic-racial socialization practices and beliefs of ethnic minority and majority groups, as this area of the field is currently the most expounded. We begin by exploring the current and future demographic characteristics of the United States to better contextualize research on social justice by developmental scientists. We then review the theoretical frameworks typically used to guide this body of research. Next we examine ethnic minority parents' ethnic-racial socialization practices and discuss their implications. We then consider ethnic majority parents' ethnic-racial socialization practices. Finally we address gaps in the current literature and offer directions for future research. Taken together, this small body of literature is critical to understanding how children are socialized about diversity. PMID- 27474425 TI - Children's Intergroup Relations and Attitudes. AB - The existence of warm, intimate, supportive, and egalitarian relationships between members of differing social outgroups is likely, at the societal level, to facilitate cooperation and cohesion, and at the individual level, to promote positive social, educational, and occupational outcomes. The developmental pathway from intergroup contact to intergroup attitudes as it operates among children is not, however, well understood. In our chapter, we review and integrate selected social and developmental science related to intergroup relations and attitudes with the goal of proposing a conceptual model of the pathway from intergroup contact to positive intergroup attitudes among youth. PMID- 27474426 TI - Power, Process, and Protection: Juveniles as Defendants in the Justice System. AB - The juvenile court was created in 1899 in part to remedy the unfairness of trying youth in the adult criminal justice system, but its success at rectifying those problems is unclear. One concern is that the vast majority of youth who are adjudicated delinquent are adjudicated after waiving their right to trial and entering a guilty plea. Fairness and equity in the plea bargaining process are premised on the assumption that youth have the capacity to understand and elect between available options and will be given a meaningful opportunity to choose without coercion and deception. In legal terms, the Constitution will only sanction a plea when the defendant makes a knowing, voluntary, and intelligent waiver of her right to trial. In this chapter, we briefly describe the juvenile court process and explain the circumstances of a plea bargain, which constitutes both a waiver of Constitutional rights and an agreement to certain conditions. Then we evaluate the research and practice knowledge regarding the legal components of a valid waiver-that it must be knowing and voluntary. We consider how information, capacity, and circumstance contribute to a knowing waiver. Then we examine how procedural justice, paternalism, and coercion may affect a voluntary waiver. Throughout, we consider whether the people, policies, and practices meant to assess and safeguard that waiver decision fulfill their intended purpose. PMID- 27474427 TI - Social Justice and the Environmental Commons. AB - In this chapter, we build on the scholarship on youth civic engagement by turning attention to the environmental commons as a space for political action. We begin with a definition of the term and arguments about ways that social justice is implied in it. Following that, we raise several psychological challenges to motivating action on behalf of the environmental commons and discuss the critical experiences and actions that can defy those challenges. Finally, drawing from Ostrom's empirical evidence opposing a tragedy of the commons, we discuss practices consistent with a social justice approach that nurture in younger generations an identification with and commitment to the environmental commons and discuss how this orientation would benefit human beings, democracies, and the earth. PMID- 27474428 TI - Mixed-Status Immigrant Families in the United States: The Role of Social Justice in Intervention Research. AB - More than 4 million unauthorized parents of legal status children currently reside in the United States (Capps, Fix, & Zong, 2016). Developmental scientists and intervention researchers hoping to work with these mixed-status families face a myriad of challenges, largely generated from the population's policy-driven social exclusion. Despite the challenges, there is a moral imperative to work with and support parents and children currently living in mixed-status households. This chapter applies a social justice perspective, largely stemming from Prilleltensky's critical community psychological framework, to improve the relevance and usefulness of research on mixed-status families (Prilleltensky & Nelson, 1997). We discuss the utility of this social justice perspective in theory building, study design and implementation, and dissemination of findings regarding mixed-status families, with exemplars from recent research. PMID- 27474429 TI - And I Shot Her: On War, and the Creation of Inequities in the Development of Youths' Moral Capacities. AB - War creates a multifaceted web of inequities that encompass most levels of the ecology of youth development. These include psychosocial inequities bearing on war-exposed youth's limited access to medical and educational services and job training and employment opportunities, as well as some of the unique psychological sequelae of trauma exposure. In this chapter we put forth a twofold argument. First, we argue that the protracted hardships of war also create enduring psychological inequities that go beyond the well-documented psychosocial needs and psychological trauma, and encompass other aspects of youths' healthy development; these are inequities inasmuch as they represent profound alterations of the developmental pathways available to war-affected youth. Second, we maintain that the psychological sciences must strive to understand such longstanding developmental inequities even if we do not, at this time, have the tools to fully address them. PMID- 27474430 TI - Global Equity and Justice Issues for Young People During the First Three Decades of Life. AB - This chapter takes a global perspective on equity and justice during development from childhood into adulthood. Globally, the population of young people is booming with the most rapid growth among young people in the poorest countries. While already faced with significant issues related to development and thriving, this population boom also exacerbates equity and justice for these children. Given this urgent situation, this chapter builds from the large body of minority world research, as well as the emergent majority world research, to argue that in order to turn the youth bulge into a demographic dividend, researchers must utilize a positive development framing rather than the more dominant problem focused framing in studying these issues. The structural challenges confronting young people growing up in contexts marked by poverty; weak systems and institutions, especially those serving education, health, and justice; weak political and governance systems; and continual conflict must also be addressed by global and national governmental bodies. This chapter will emphasize the strengths and opportunities of the majority world, highlighting some of the strong, emergent examples of programs that support and develop the strengths of young people. We conclude with a discussion of appropriate support required from the minority and majority worlds that would further strengthen young people globally and enable them to become leaders of a more just, equitable world. PMID- 27474433 TI - Human cytomegalovirus infection contributes to glioma disease progression via upregulating endocan expression. AB - The etiology of malignant glioma remains unclear. To examine the association between glioma and human cytomegalovirus (HCMV) infection and the possible mechanism through which HCMV contributes to malignant glioma, we investigated the expression of HCMV components and an angiogenesis marker, endocan, in 79 glioma specimens and 8 control brain samples. HCMV pp65 protein and DNA were detected in 65.8% (52 of 79) and 54.4% (43 of 79) of glioma specimens, respectively. The positive rate and expression levels of pp65 were significantly correlated with the glioma grades. The endocan expression was detected in 78.5% (62 of 79) of glioma specimens, and elevated endocan immunoreactivity was also significantly associated with high-grade glioma. The pp65 was predominantly detected and colocalized with endocan in the cytoplasm of tumor cells. Importantly, there was a significant positive correlation in detection rates between those 2 proteins. In control samples, neither HCMV pp65 nor endocan expression was detected. Moreover, the serum endocan levels in glioma patients were markedly higher than that in healthy subjects. In in vitro study, HCMV infection induced the expression of interleukin 6 and tumor necrosis factor-alpha in human glioblastoma U87 MG (U87) cells and human umbilical vein endothelial cells (HUVECs). Furthermore, elevated endocan levels were also observed in HCMV-infected U87 cells and HUVECs and antiviral treatment with ganciclovir reduced the endocan expression. These results suggest HCMV infection leads to glioma progression through an upregulation of endocan and the secretion of inflammatory cytokines. Thus, anti-HCMV treatment may represent a potentially novel therapeutic strategy for glioma. PMID- 27474434 TI - Atmospheric CH4 oxidation by Arctic permafrost and mineral cryosols as a function of water saturation and temperature. AB - The response of methanotrophic bacteria capable of oxidizing atmospheric CH4 to climate warming is poorly understood, especially for those present in Arctic mineral cryosols. The atmospheric CH4 oxidation rates were measured in microcosms incubated at 4 degrees C and 10 degrees C along a 1-m depth profile and over a range of water saturation conditions for mineral cryosols containing type I and type II methanotrophs from Axel Heiberg Island (AHI), Nunavut, Canada. The cryosols exhibited net consumption of ~2 ppmv CH4 under all conditions, including during anaerobic incubations. Methane oxidation rates increased with temperature and decreased with increasing water saturation and depth, exhibiting the highest rates at 10 degrees C and 33% saturation at 5 cm depth (260 +/- 60 pmol CH4 gdw 1 d-1 ). Extrapolation of the CH4 oxidation rates to the field yields net CH4 uptake fluxes ranging from 11 to 73 MUmol CH4 m-2 d-1 , which are comparable to field measurements. Stable isotope mass balance indicates ~50% of the oxidized CH4 is incorporated into the biomass regardless of temperature or saturation. Future atmospheric CH4 uptake rates at AHI with increasing temperatures will be determined by the interplay of increasing CH4 oxidation rates vs. water saturation and the depth to the water table during summer thaw. PMID- 27474435 TI - Epigallocatechin-3-gallate attenuates cadmium-induced chronic renal injury and fibrosis. AB - Cadmium (Cd) pollution is a serious environmental problem. Kidney is a main target organ of Cd toxicity. This study was undertaken to investigate the potential protective effects of epigallocatechin-3-gallate (EGCG) against chronic renal injury and fibrosis induced by CdCl2. Rat model was induced by exposing to 250 mg/L CdCl2 through drinking water. The renal function was evaluated by detecting the levels of blood urea nitrogen (BUN) and serum creatinine (SCR). The oxidative stress was measured by detecting the levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione/oxidized glutathione (GSH/GSSG) and renal enzymatic antioxidant status. Additionally, the renal levels of transforming growth factor-beta1 (TGF-beta1), Smad3, phosphorylation-Smad3 (pp-Smad3), alpha smooth muscle actin (alpha-SMA), vimentin and E-cadherin were measured by western blot assay. Renal levels of microRNA-21 (miR-21), miR-29a/b/c and miR-192 were measured by quantitative RT-PCR. It was found that EGCG ameliorated the CdCl2 induced renal injury, inhibited the level of oxidative stress, normalized renal enzymatic antioxidant status and E-cadherin level, as well as attenuated the over generation of TGF-beta1, pp-Smad3, vimentin and alpha-SMA. EGCG also decreased the production of miR-21 and miR-192, and enhanced the levels of miR-29a/b/c. These results showed that EGCG could attenuate Cd induced chronic renal injury. PMID- 27474436 TI - Reframing Autism: Young Adults With Autism Share Their Strengths Through Photo Stories. AB - : A dearth of research describes the lives of young adults with autism spectrum disorder (ASD) from the perspectives of young adults themselves. We explored young adults' strengths using Photovoice, a method in which participants use images and discussions to express themselves. Images were purposefully chosen to help young people participate in the research process. DESIGN AND METHODS: Eleven young adults captured their experiences growing up with ASD via images, and participated in three group photo discussions, an individual photo interview, and a photo exhibit. Qualitative data for analysis included session transcripts and photographs. We used strategies of theme analysis to understand participants' experiences. RESULTS: The mean age of the sample was 20years, and 7 participants were male. Three sub-themes describe youth's strengths: 1) special interests that cultivated positive emotions and coping strategies; 2) skills and activities that evoked pride; and 3) reframing ASD as special versus a disadvantage. CONCLUSIONS: The Photovoice method is well-suited to help young adults identify and express their strengths. Self-generated images and stories may offer a creative and effective form of communication for young adults with ASD. PRACTICE IMPLICATIONS: Health care practitioners can capitalize on how Photovoice helps young adults express themselves by using images to understand their health priorities and involve young adults in their care plans. With images of strength, for example, nurses can build young adults' confidence and help these individuals to identify areas of their mental and physical lives in which they can thrive and experience improved quality of life. PMID- 27474437 TI - Metabolites: messengers between the microbiota and the immune system. AB - The mammalian intestine harbors one of the largest microbial densities on Earth, necessitating the implementation of control mechanisms by which the host evaluates the state of microbial colonization and reacts to deviations from homeostasis. While microbial recognition by the innate immune system has been firmly established as an efficient means by which the host evaluates microbial presence, recent work has uncovered a central role for bacterial metabolites in the orchestration of the host immune response. In this review, we highlight examples of how microbiota-modulated metabolites control the development, differentiation, and activity of the immune system and classify them into functional categories that illustrate the spectrum of ways by which microbial metabolites influence host physiology. A comprehensive understanding of how microbiota-derived metabolites shape the human immune system is critical for the rational design of therapies for microbiota-driven diseases. PMID- 27474438 TI - Nucleolar organizer regions: genomic 'dark matter' requiring illumination. AB - Nucleoli form around tandem arrays of a ribosomal gene repeat, termed nucleolar organizer regions (NORs). During metaphase, active NORs adopt a characteristic undercondensed morphology. Recent evidence indicates that the HMG-box-containing DNA-binding protein UBF (upstream binding factor) is directly responsible for this morphology and provides a mitotic bookmark to ensure rapid nucleolar formation beginning in telophase in human cells. This is likely to be a widely employed strategy, as UBF is present throughout metazoans. In higher eukaryotes, NORs are typically located within regions of chromosomes that form perinucleolar heterochromatin during interphase. Typically, the genomic architecture of NORs and the chromosomal regions within which they lie is very poorly described, yet recent evidence points to a role for context in their function. In Arabidopsis, NOR silencing appears to be controlled by sequences outside the rDNA (ribosomal DNA) array. Translocations reveal a role for context in the expression of the NOR on the X chromosome in Drosophila Recent work has begun on characterizing the genomic architecture of human NORs. A role for distal sequences located in perinucleolar heterochromatin has been inferred, as they exhibit a complex transcriptionally active chromatin structure. Links between rDNA genomic stability and aging in Saccharomyces cerevisiae are now well established, and indications are emerging that this is important in aging and replicative senescence in higher eukaryotes. This, combined with the fact that rDNA arrays are recombinational hot spots in cancer cells, has focused attention on DNA damage responses in NORs. The introduction of DNA double-strand breaks into rDNA arrays leads to a dramatic reorganization of nucleolar structure. Damaged rDNA repeats move from the nucleolar interior to form caps at the nucleolar periphery, presumably to facilitate repair, suggesting that the chromosomal context of human NORs contributes to their genomic stability. The inclusion of NORs and their surrounding chromosomal environments in future genome drafts now becomes a priority. PMID- 27474439 TI - Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase. AB - High-frequency point mutations of genes encoding histones have been identified recently as novel drivers in a number of tumors. Specifically, the H3K36M/I mutations were shown to be oncogenic in chondroblastomas and undifferentiated sarcomas by inhibiting H3K36 methyltransferases, including SETD2. Here we report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH (S-adenosylhomocysteine). In the complex structure, the catalytic domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel. Our structural and biochemical data reveal the molecular basis underying oncohistone recognition by and inhibition of SETD2. PMID- 27474440 TI - Loss of l(3)mbt leads to acquisition of the ping-pong cycle in Drosophila ovarian somatic cells. AB - In Drosophila germ cells, PIWI-interacting RNAs (piRNAs) are amplified through a PIWI slicer-dependent feed-forward loop termed the ping-pong cycle, yielding secondary piRNAs. However, the detailed mechanism remains poorly understood, largely because an ex vivo model system amenable to biochemical analyses has not been available. Here, we show that CRISPR-mediated loss of function of lethal (3) malignant brain tumor [l(3)mbt] leads to ectopic activation of the germ-specific ping-pong cycle in ovarian somatic cells. Perinuclear foci resembling nuage, the ping-pong center, appeared following l(3)mbt mutation. This activation of the ping-pong machinery in cultured cells will greatly facilitate elucidation of the mechanism underlying secondary piRNA biogenesis in Drosophila. PMID- 27474441 TI - Oncogenic transformation of Drosophila somatic cells induces a functional piRNA pathway. AB - Germline genes often become re-expressed in soma-derived human cancers as "cancer/testis antigens" (CTAs), and piRNA (PIWI-interacting RNA) pathway proteins are found among CTAs. However, whether and how the piRNA pathway contributes to oncogenesis in human neoplasms remain poorly understood. We found that oncogenic Ras combined with loss of the Hippo tumor suppressor pathway reactivates a primary piRNA pathway in Drosophila somatic cells coincident with oncogenic transformation. In these cells, Piwi becomes loaded with piRNAs derived from annotated generative loci, which are normally restricted to either the germline or the somatic follicle cells. Negating the pathway leads to increases in the expression of a wide variety of transposons and also altered expression of some protein-coding genes. This correlates with a reduction in the proliferation of the transformed cells in culture, suggesting that, at least in this context, the piRNA pathway may play a functional role in cancer. PMID- 27474442 TI - A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin. AB - Repair of DNA double-strand breaks (DSBs) must be properly orchestrated in diverse chromatin regions to maintain genome stability. The choice between two main DSB repair pathways, nonhomologous end-joining (NHEJ) and homologous recombination (HR), is regulated by the cell cycle as well as chromatin context.Pericentromeric heterochromatin forms a distinct nuclear domain that is enriched for repetitive DNA sequences that pose significant challenges for genome stability. Heterochromatic DSBs display specialized temporal and spatial dynamics that differ from euchromatic DSBs. Although HR is thought to be the main pathway used to repair heterochromatic DSBs, direct tests of this hypothesis are lacking. Here, we developed an in vivo single DSB system for both heterochromatic and euchromatic loci in Drosophila melanogaster Live imaging of single DSBs in larval imaginal discs recapitulates the spatio-temporal dynamics observed for irradiation (IR)-induced breaks in cell culture. Importantly, live imaging and sequence analysis of repair products reveal that DSBs in euchromatin and heterochromatin are repaired with similar kinetics, employ both NHEJ and HR, and can use homologous chromosomes as an HR template. This direct analysis reveals important insights into heterochromatin DSB repair in animal tissues and provides a foundation for further explorations of repair mechanisms in different chromatin domains. PMID- 27474444 TI - Corrigendum to "Preventive effect of a novel diosgenin derivative on arterial and venous thrombosis in vivo" [Bioorg. Med. Chem. Lett. 26 (2016) 3364-3369]. PMID- 27474443 TI - A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. AB - RNA degradation is tightly regulated to selectively target aberrant RNAs, including viral RNA, but this regulation is incompletely understood. Through RNAi screening in Drosophila cells, we identified the 3'-to-5' RNA exosome and two components of the exosome cofactor TRAMP (Trf4/5-Air1/2-Mtr4 polyadenylation) complex, dMtr4 and dZcchc7, as antiviral against a panel of RNA viruses. We extended our studies to human orthologs and found that the exosome as well as TRAMP components hMTR4 and hZCCHC7 are antiviral. While hMTR4 and hZCCHC7 are normally nuclear, infection by cytoplasmic RNA viruses induces their export, forming a cytoplasmic complex that specifically recognizes and induces degradation of viral mRNAs. Furthermore, the 3' untranslated region (UTR) of bunyaviral mRNA is sufficient to confer virus-induced exosomal degradation. Altogether, our results reveal that signals from viral infection repurpose TRAMP components to a cytoplasmic surveillance role where they selectively engage viral RNAs for degradation to restrict a broad range of viruses. PMID- 27474447 TI - Reply. PMID- 27474445 TI - SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a review. AB - Neurodegeneration is an important determinant of disability in multiple sclerosis (MS) but while currently approved treatments reduce inflammation, they have not been shown to reduce neurodegeneration. SIRT1, a NAD dependent protein deacetylase, has been implicated in the pathogenesis of neurodegeneration in neurological diseases including MS. We have studied the role of SIRT1 in experimental autoimmune encephalomyelitis (EAE) and found evidence for a neuroprotective role. In this review we summarize the most recent findings from the use of SIRT1 activators and SIRT1 overexpression in transgenic mice. These data support provide a rational for the use of SIRT1 activators in MS. PMID- 27474446 TI - Cloning of a big defensin gene and its response to Vibrio parahaemolyticus challenge in the noble scallop Chlamys nobilis (Bivalve: Pectinidae). AB - The noble scallop Chlamys nobilis has been an important marine cultured bivalve in the Southern Sea of China for decades. However, large-scale mortality events often occurred during the scallop' cultivation. As one of AMPs (antimicrobial peptides), big defensin is an important component of the innate immunity against pathogenic microorganisms in invertebrates. In order to investigate whether the big defensin can play a role in the immune defense against pathogenic microorganisms in noble scallop, a big defensin gene from the hemocytes of Chlamys nobilis (CnBD) was cloned, and the mRNA level was measured after an acute Vibrio parahaemolyticus challenge of 36 h. The CnBD cDNA contains an open reading frame (ORF) of 381 bp encoding a peptide of 126 amino acids residues. The deduce amino acid sequence of CnBD shows a high similarity with that from Argopecten irradians and displays common features of big defensin, indicating that CnBD is a new member of the big defensin family. Compared with the control group, the relative mRNA level of CnBD was significantly up-regulated at 3, 24 and 36 h. The present result indicated that CnBD played an immune role against bacterial infection in noble scallop. PMID- 27474448 TI - ROS and Ca(2+)-Partners in sickness and in health. PMID- 27474449 TI - Manganese ions enhance mitochondrial H2O2 emission from Krebs cycle oxidoreductases by inducing permeability transition. AB - Manganese-induced toxicity has been linked to mitochondrial dysfunction and an increased generation of reactive oxygen species (ROS). We could recently show in mechanistic studies that Mn2+ ions induce hydrogen peroxide (H2O2) production from the ubiquinone binding site of mitochondrial complex II (IIQ) and generally enhance H2O2 formation by accelerating the rate of superoxide dismutation. The present study with intact mitochondria reveals that manganese additionally enhances H2O2 emission by inducing mitochondrial permeability transition (mPT). In mitochondria fed by NADH-generating substrates, the combination of Mn2+ and different respiratory chain inhibitors led to a dynamically increasing H2O2emission which was sensitive to the mPT inhibitor cyclosporine A (CsA) as well as Ru-360, an inhibitor of the mitochondrial calcium uniporter (MCU). Under these conditions, flavin-containing enzymes of the mitochondrial matrix, e.g. the mitochondrial 2-oxoglutaratedehydrogenase (OGDH), were major sources of ROS. With succinate as substrate, Mn2+ stimulated ROS production mainly at complex II, whereby the applied succinate concentration had a marked effect on the tendency for mPT. Also Ca2+ increased the rate of H2O2 emission by mPT, while no direct effect on ROS-production of complex II was observed. The present study reveals a complex scenario through which manganese affects mitochondrial H2O2 emission: stimulating its production from distinct sites (e.g. site IIQ), accelerating superoxide dismutation and enhancing the emission via mPT which also leads to the loss of soluble components of the mitochondrial antioxidant systems and favors the ROS production from flavin-containing oxidoreductases of the Krebs cycle. PMID- 27474450 TI - Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation. AB - Advanced age is associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed central event is diminished amounts of nitric oxide (NO) due to reduced generation by endothelial NO synthase (eNOS) and increased oxidative stress. In addition, it is widely accepted that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling. Dietary nitrate supplementation for two weeks reduced blood pressure (10-15mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased insulin responses, reduced plasma creatinine as well as improved endothelial relaxation to acetylcholine and attenuated contractility to ANG II in resistance arteries. Mechanistically, nitrate reduced NADPH oxidase-mediated oxidative stress in the cardiovascular system and increased cGMP signaling. Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT1A, AT2, AT1A/AT2 ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II. Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate for age-related disturbances in endogenous NO generation via inhibition of NADPH oxidase and modulation of ANG II receptor expression. These novel findings may have implications for nutrition-based preventive and therapeutic strategies against cardiovascular and metabolic diseases. PMID- 27474451 TI - PRDM1 overexpression induce G0/G1 arrest in DF-1 cell line. AB - PRDM1 (PR domain containing 1) is a transcriptional repressor that affects the expression of numerous genes involved in cell proliferation, differentiation and metabolism. However, the molecular mechanisms underlying PRDM1-regulated gene expression in the DF-1 cell line remain to be elucidated. In this study, we explored the role of PRDM1 in cell proliferation and cell cycle by forced expression of PRDM1 in DF-1 cells. Our results showed an absence of endogenous PRDM1 in this cell line, while exogenous PRDM1 was specifically localized to the nucleus. Ectopic expression of PRDM1 inhibited DF-1 cell proliferation and altered clonal morphology. Furthermore, PRDM1 overexpression caused an increase in the G0/G1 phase population. The levels of p53 mRNA and the p53-regulated p21(WAF1) and MDM2 genes were significantly increased in DF-1 cells transfected with the PRDM1 expression vector. Examination of the Rb pathway further revealed that Rb, E2F-1 and p15(INK4b) alternate reading frame (ARF) mRNA were also significantly increased after transient transfection. Interestingly, the mRNA expression levels of multiple chicken cyclin genes were also increased. These results show that PRDM1 overexpression induced G0/G1 arrest in DF-1 cells through multiple parallel mechanisms, including the p53 and Rb pathways. PMID- 27474452 TI - Direct inhibition of matrix metalloproteinase-2 (MMP-2) by (-)-epigallocatechin-3 gallate: A possible role for the fibronectin type II repeats. AB - Matrix metalloproteinases (MMPs) -2 and -9, also called gelatinases, constitute a distinct subgroup within the MMP family of extracellular matrix remodeling proteases. Gelatinases are implicated in tumor cell invasion and metastasis, and are attractive therapeutic targets. Several synthetic small molecule inhibitors of MMPs developed till date have failed in clinical trials. This has prompted explorations into the gamut of dietary compounds and nutraceuticals for specific inhibitors of MMPs with desirable properties. (-)-epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, is popular as a potential chemotherapeutic agent with demonstrable anti-metastatic and MMP inhibitory activities. Here, we have addressed the mechanism of EGCG-mediated inhibition of MMP-2 using in silico molecular docking approach. We show for the first time that EGCG targets the fibronectin type II repeat regions 1 and 3 of MMP-2, binds amino acids that constitute the exosite of this enzyme and hinders proper positioning of the substrate. This study offers a novel insight into the inhibition of MMP-2 by EGCG and presents a starting point for development of novel therapeutic molecules that can specifically target the gelatinases. PMID- 27474453 TI - Occurrence and molecular characteristics of antimicrobial resistance of Escherichia coli from broilers, pigs and meat products in Thailand and Cambodia provinces. AB - Nine hundred and forty-one samples were collected in Sa Keao, Thailand (n = 554) and Banteay Meanchey, Cambodia (n = 387) from July 2014 to January 2015. A total of 667 Escherichia coli isolates (381 isolates from Sa Keao and 286 isolates from Banteay Meanchey) were obtained and examined for antimicrobial susceptibility, class 1 integrons, ESBL genes and horizontal transfer of resistance determinants. Prevalence of E. coli in pig and broiler carcass samples from slaughterhouses and fresh markets was 36-85% in Sa Keao and 11-69% in Banteay Meanchey. The majority of these isolates were multidrug resistant (75.3%). Class 1 integrons were common in both Thai (47%) and Cambodian (62%) isolates, of which four resistance gene cassette arrays including aadA1, dfrA1-aadA1, dfrA12-aadA2 and aadA2-linF were identified. Class 1 integrons in two broiler isolates from Sa Keao (dfrA12-aadA2) and one broiler isolate from Banteay Meanchey (dfrA1-aadA1) were horizontally transferable. Sixteen isolates were confirmed to be ESBL-producing strains with ESBL gene blaCTX-M-15 , broad spectrum beta-lactamase gene blaTEM-1 and the AmpC gene blaCMY-2 being detected. The blaTEM-1 gene was most prevalent and located on a conjugative plasmid. PMID- 27474454 TI - Magnetic Resonance Imaging Technique for Visualization of Irregular Cerebrospinal Fluid Motion in the Ventricular System and Subarachnoid Space. AB - BACKGROUND: Many studies have shown that cerebrospinal fluid (CSF) behaves irregularly, rather than with laminar flow, in the various CSF spaces. We adapted a modified previously known magnetic resonance imaging technique to visualize irregular CSF motion. Subsequently, we assessed the usefulness and clinical significance of the present method. MATERIALS AND METHODS: Normal CSF motion in 10 healthy volunteers was visualized with the dynamic improved, motion sensitized, driven-equilibrium steady-state free precession technique. Subsequently, CSF motion visualization with a modified sequence was applied to 3 patients. RESULTS: In healthy volunteers, we achieved visualization of the irregularity of CSF flow in the ventricles and spinal canal, whereas CSF motion was diminished in the peripheral part of the intracranial subarachnoid space. In one case, we confirmed the patency of the patient's third ventriculostomy fenestration site. In the other, we verified the usefulness of the proposed sequence for determining the communication between the ventricle or subarachnoid space and the cyst. CONCLUSIONS: Using the present sequence, we obtained images that accentuated CSF motion, which is largely composed of irregular motion. This method does not require pulse triggering or complex post-processing of images and allows visualization of CSF motion in a short period of time in selected whole imaging planes. It can therefore be applied clinically to diagnose various diseases that cause abnormalities in the CSF space. PMID- 27474455 TI - Hybrid Corpectomy and Disc Arthroplasty for Cervical Spondylotic Myelopathy Caused by Ossification of Posterior Longitudinal Ligament and Disc Herniation. AB - OBJECTIVE: The combination of anterior cervical discectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) has been demonstrated to be effective for multilevel cervical spondylotic myelopathy (CSM); however, the combination of ACCF and cervical disc arthroplasty (CDA) for 3-level CSM has never been addressed. METHODS: Consecutive patients (>18 years of age) with CSM caused by segmental ossification of posterior longitudinal ligament (OPLL) and degenerative disc disease (DDD) were reviewed. Inclusion criteria were patients who underwent hybrid ACCF and CDA surgery for symptomatic 3-level CSM with OPLL and DDD. Medical and radiologic records were reviewed retrospectively. RESULTS: A total of 15 patients were analyzed with a mean follow-up of 18.1 +/- 7.42 months. Every patient had hybrid surgery composed of 1-level ACCF (for segmental-type OPLL causing spinal stenosis) and 1-level CDA at the adjacent level (for DDD causing stenosis). All clinical outcomes, including visual analogue scale of neck and arm pain, Neck Disability Index, Japanese Orthopedic Association scores, and Nurick scores of myelopathy, demonstrated significant improvement at 12 months after surgery. All patients (100%) achieved arthrodesis for the ACCF (instrumented) and preserved mobility for CDA (preoperation 6.2 +/- 3.81 degrees vs. postoperation 7.0 +/- 4.18 degrees ; P = 0.579). CONCLUSIONS: For patients with multilevel CSM caused by segmental OPLL and DDD, the hybrid surgery of ACCF and CDA demonstrated satisfactory clinical and radiologic outcomes. Moreover, although located next to each other, the instrumented ACCF construct and CDA still achieved solid arthrodesis and preserved mobility, respectively. Therefore, hybrid surgery may be a reasonable option for the management of CSM with OPLL. PMID- 27474456 TI - The Adjunctive Use of Vancomycin Powder Appears Safe and May Reduce the Incidence of Surgical-Site Infections After Deep Brain Stimulation Surgery. AB - BACKGROUND: Postoperative surgical-site infections (SSIs) are a common complication after deep brain stimulation (DBS) surgery, occurring at a quoted rate of approximately 1%-9%. Intraoperative vancomycin powder has demonstrated efficacy in reducing SSIs after cranial and spinal surgery; however, its use during DBS surgery has yet to be established. In this study, we describe the senior author's experience with the use of intraoperative vancomycin powder to prevent SSIs after DBS surgery. METHODS: We retrospectively examined the incidence of SSI in 297 patients who underwent DBS surgery at the Mount Sinai Health System from September 2012 to December 2015. All patients underwent a uniform perioperative antiseptic protocol, including thorough skin cleansing, intravenous anticephalosporin antibiotics, copious irrigation, and the application of topical vancomycin powder (1 g) before skin closure. Patient information was obtained through a review of electronic medical records. Primary outcome was the incidence of SSI, which was defined per the standards of the Centers for Disease Control and Prevention and confirmed with wound cultures. RESULTS: Four patients developed clinical signs and symptoms of SSI (1.3%); all were men with Parkinson disease. The primary organism responsible was Staphylococcus aureus (75%). Two patients presented with neurostimulator infections, and 2 presented with parietal connector-site infections between 2 months and 1 year after initial surgery. No patients in our series developed topical or systemic reactions attributable to the use of vancomycin powder. CONCLUSIONS: In our experience, vancomycin powder has demonstrated safety and efficacy as an adjunct medication for infection prophylaxis after DBS surgery. Further prospective studies with larger patient cohorts are warranted. PMID- 27474457 TI - Posttraumatic Charcot (Neuropathic) Spinal Arthropathy at the Cervicothoracic Junction. AB - BACKGROUND: Charcot spine arthropathy (posttraumatic neuroarthropathy of the spine) has been reported to be a very late and rare complication of spinal cord injury. Charcot of the cervicothoracic and upper thoracic region rarely is reported in the literature. Charcot spinal arthropathy is a cause of progressive deformity and may present as late as 30 years after the original spinal cord injury. This is more common in paraplegic patients who are actively ambulating. CASE DESCRIPTION: A 56-year-old patient with complete paraplegia for approximately 20 years after spinal cord injury presented with severe kyphous deformity and instability of thoracolumbar spine. His sensory level to deep pain was at thoracic (D4). He kept developing new neuroarthropathies at different segments within a span of 5-6 months after every decompression and fusion with anterior cage and posterior instrumentation done. A total of 3 surgeries had been done in span of 2 years, initially thoracic, then lumbar and finally cervicothoracic junction. CONCLUSIONS: We present this case because of the challenges in surgery for instrumentation of new Charcot spinal arthropathy. Reports of neuroarthropathy developing above the level of spinal cord injury and at the cervicothoracic junction are rare. The treating surgeon should be cognizant of the possibility of developing secondary levels of neuroarthropathy above and below a previously successful fusion. PMID- 27474458 TI - Drivers of 30-Day Readmission in Elderly Patients (>65 Years Old) After Spine Surgery: An Analysis of 500 Consecutive Spine Surgery Patients. AB - BACKGROUND: Early readmission after spine surgery is being used as a proxy for quality of care. One-fifth of patients are rehospitalized within 30 days after spine surgery, and more than one-third within 90 days; however, there is a paucity of data about the cause of early readmissions in elderly patients after elective spine surgery. METHODS: A total of 500 elderly patients (>65 years old) undergoing elective spine surgery at a major academic hospital were included in the study. We identified all unplanned readmissions within 30 days of discharge. Unplanned readmissions were defined to have occurred as a result of either a surgical or a nonsurgical complication. Patient records were reviewed to determine the cause of readmission and the length of hospital stay. RESULTS: A total of 50 (10%) unplanned early readmissions were identified. The mean +/- SD age was 72.54 +/- 5.84 years. The mean +/- SD number of days from discharge to readmission was 11.02 +/- 7.25 days, and the average length of hospital stay for the readmissions was 7.7 days. The majority of patients that were readmitted presented to the emergency department from home (46%), whereas 38% were readmitted from a skilled nursing facility. The most common causes for readmission were infection or a concern for infection (42%) and pain (14%), with 32% of readmissions requiring a return to the operating room. CONCLUSION: Our study suggests that in elderly patients undergoing elective spine surgery, infection or a concern for infection, pain, and altered mental status were the most common primary reasons for unplanned readmission. PMID- 27474459 TI - Neuromonitoring for Intramedullary Spinal Cord Tumor Surgery. AB - BACKGROUND: Intramedullary spinal cord tumors (IMSCT) account for about 2%-4% of tumors of the central nervous system. Surgical resection continues to be the most effective treatment modality for most intramedullary tumors, with gross total resection leading to preserved neurologic function and improved survival. However, surgical treatment is often difficult and carries significant risk of postoperative neurologic complications. Intraoperative neuromonitoring has been shown to be of clinical importance in the surgical resection of IMSCT. The main monitoring modalities include somatosensory evoked potentials, transcranial motor evoked potentials via limb muscles or spinal epidural space (D-waves), and dorsal column mapping. These monitoring modalities have been shown to inform surgeons intraoperatively and in many cases, have led to alterations in operative decision. METHODS: We reviewed the literature on the usefulness of intraoperative neuromonitoring for intramedullary spinal tumor resection and its role in predicting postoperative neurologic deficits. A MEDLINE search was performed (2000-2015) and 13 studies were reviewed. Detailed information and data from the selected articles were assessed and compiled. Data were extracted showing the role of monitoring in outcomes of surgery. CONCLUSIONS: By using intraoperative somatosensory evoked potentials, transcranial motor evoked potentials, D-waves, and dorsal column mapping, spinal injury could be prevented in most cases, thereby improving postoperative neurologic functioning and outcome in patients undergoing surgery for IMSCT. PMID- 27474460 TI - Quantifying the Effect of Temporomandibular Joint Intra-Articular Steroid Injection on Synovial Enhancement in Juvenile Idiopathic Arthritis. AB - PURPOSE: To quantify the effect of intra-articular steroid injections (IASIs) on temporomandibular joint (TMJ) synovitis in children with juvenile idiopathic arthritis (JIA) using gadolinium-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: The present study was a retrospective study of children with JIA who had undergone TMJ IASIs at Boston Children's Hospital. The patients were included if they had undergone contrast-enhanced MRI both before and after IASI and if the pre-IASI MRI had demonstrated synovitis (enhancement ratio [ER] >1.55). Patients with TMJ pathology or pain unrelated to JIA or a history of facial trauma were excluded. The predictor variables were age, gender, JIA subtype, exposure to medications for arthritis, and a family history of autoimmune disease. The primary outcome variable was the ER. Additional outcome variables included patient-reported pain and the maximal incisal opening (MIO). RESULTS: Twenty-nine subjects (83% female) with a total of 50 injected TMJs were included. The average age at JIA diagnosis and at IASI was 6.8 +/- 1.7 years and 12.1 +/- 1.9 years, respectively. The mean follow-up period was 22.9 +/- 4.3 months (range 5 to 48). The ER decreased in all injected joints, with a mean reduction of 1.05 +/- 1.01 (P < .001). The post-IASI ER was less than the normal threshold (1.55) in 18% of the injected TMJs. IASI was associated with an elimination of pain in 89% of the subjects (P < .001) and in augmentation of the MIO by 5.8 +/- 2.6 mm (P < .001). CONCLUSIONS: In children with JIA and TMJ synovitis, TMJ IASI was associated with a reduction in synovial enhancement, decreased pain, and an increased MIO. Only 18% of injected joints, however, experienced complete resolution of synovitis. These results support the use of IASI in the management of the pain and dysfunction associated with TMJ synovitis. Further study is required to determine the efficacy of IASI in limiting inflammation and future joint destruction. PMID- 27474461 TI - Prognostic Factors Associated With Decreased Survival in Patients With Acinic Cell Carcinoma of the Parotid Gland. AB - PURPOSE: Acinic cell carcinoma (ACC) of the parotid gland is relatively rare. This study aimed to estimate 5-year survival and to identify prognostic factors associated with survival of ACC of the parotid gland. MATERIALS AND METHODS: Thirty-seven patients with ACC of the parotid gland were included in this retrospective cohort study. They were treated in Beijing Stomatological Hospital from January 2000 to December 2011. Predictor variables, including age, gender, tumor stage, nodal stage, perineural invasion, and margin status, were analyzed. The Cox regression model was used to determine prognostic factors for overall survival (OS) and disease-free survival (DFS). RESULTS: Of the 37 patients, 20 were men (54.1%). Mean age was 42 years (range, 13 to 73 yr). Six patients (16.2%) had T3 or T4 tumors and 5 (13.5%) had positive neck nodes. The 5-year OS and DFS were 86.5 and 78.3%, respectively. Positive margin status was associated with worse OS. Patients older than 60 years with a fixed mass, high-grade tumor and nodal stage, perineural invasion, and angiolymphatic invasion had adverse OS and DFS (P < .05). CONCLUSIONS: The present study identified several important prognostic factors associated with OS and DFS in patients with ACC. These prognostic variables include symptoms at presentation, clinical tumor stage and pathologic nodal status, and histopathology-related factors. All these factors were important in patient therapy and could prolong survival rate. PMID- 27474462 TI - Is Alveolar Ridge Split a Risk Factor for Implant Survival? AB - PURPOSE: There is a paucity of studies that have assessed the long-term outcomes of the alveolar ridge split (ARS). This study evaluated the intraoperative and postoperative complications and assessed the placed dental implant and prosthesis. MATERIALS AND METHODS: A retrospective study of the ARS was conducted in a single private dental clinic. The predictor variable was the ARS technique (1 stage vs 2 stages). The primary outcome was the dental implant survival rate. Secondary outcomes were intraoperative complications, marginal bone loss, prosthetic complications, and prosthesis success rate. Descriptive analysis was performed for patients' demographic data, implant details, and prosthetic complications. The Kaplan-Meier method was used to assess implant survival rate and prosthesis success rate. RESULTS: Twenty patients (mean age, 55 +/- 6 yr) had a mean follow-up time of 5 years. Delayed implant placement was performed when the residual alveolar bone width was narrower than 3 mm. No intraoperative or postoperative complications were reported. The survival rate of the 31 implants was 100% and the prosthesis success rate was 96.8%. CONCLUSIONS: The ARS is an effective technique for horizontal bone augmentation in the mandible. Delayed dental implant placement when the alveolar bone width is narrower than 3 mm could minimize the risk of buccal wall fracture. PMID- 27474463 TI - The Use of Solid-Phase Concentrated Growth Factors for Surgical Defects in the Treatment of Dysplastic Lesions of the Oral Mucosa. AB - PURPOSE: Use of the skin graft and artificial dermis to reconstruct a defect after the excision of dysplastic lesions of the oral mucosa has been practiced for years. The purpose of this case series was to introduce a novel resolution that is, an operating procedure using solid-phase concentrated growth factors (SPCGFs) to reconstruct oral mucosa defects-and observe the postoperative results and evaluate its clinical effects. MATERIALS AND METHODS: In this consecutive serial case study of patients with oral dysplastic lesions who underwent operations from April 2015 through July 2015, the primary endpoint of the study was to observe the clinical wound-healing profile at 1 week, 3 weeks, 3 months, and 6 months postoperatively. The secondary endpoint was to observe maximal interincisal opening (MIO) and wound pain preoperatively and at 1 and 3 days, 1 and 3 weeks, and 3 and 6 months postoperatively. The minimum follow-up was 8 months, and the longest was 1 year. RESULTS: All sites had healed with complete epithelialization after 3 weeks postoperatively. All patients had a wound-healing score no higher than 3 at 3 weeks postoperatively. The preoperative MIO was 52 +/ 4.64 mm and the 6-month postoperative MIO was 49.2 +/- 3.03 mm. No patient reported further pain from 3 weeks postoperatively. No recurrence of the lesion was found at or after the 6-month follow-up period. CONCLUSION: The results of this study show that the use of SPCGFs to reconstruct oral mucosa defects is feasible and practical. The efficacy of SPCGFs needs to be verified by additional studies with higher-level evidence bases in the future. PMID- 27474464 TI - Orbital and Periorbital Emphysema Following Maxillary Sinus Floor Elevation: A Case Report and Literature Review. AB - During the past 150 years, subcutaneous emphysema has been described as a rare complication in dentistry, the etiology of which might be maneuvers performed by the patient (eg, sneezing while the mouth is closed, blowing the nose) or the dental professional through the use of specific dental instruments (eg, dental drill, air syringe, etc). Irrespective of etiology, air is forced through the soft tissues, thus producing rapid swelling of the area. According to the most recent literature reviews, the iatrogenic etiology is the most frequent. This report describes the first case of emphysema related to the orbital and periorbital region after a maxillary sinus floor elevation procedure. PMID- 27474465 TI - Subtarsal Versus Transconjunctival Approach-Esthetic and Functional Long-Term Experience. AB - PURPOSE: In addition to the transconjunctival approach, the subtarsal incision is one of the most commonly used procedures for surgical exploration of the orbital floor and infraorbital rim. However, available data are limited regarding validity and long-term esthetic and functional outcomes. The aim of this study was to verify the favorable clinical results of the subtarsal approach and compare these results with the transconjunctival procedure. MATERIALS AND METHODS: Forty-five patients (subtarsal group, n = 30; transconjunctival group, n = 15) were examined 6 to 30 months after surgical intervention using a standardized follow-up. Clinically noted complications, such as paresthesia, epiphora, or ocular foreign body sensation, were scored. Postoperative scar formation was investigated using the modified Vancouver Scar Scale (mVSS) and recorded according to standardized photographic documentation procedures. Photographic images were evaluated in a blinded manner by experts and nonexperts according to fixed criteria. Concomitant photographic evaluation was performed by age- and gender-matched healthy controls. Recorded data analyzed by chi2 test and unrelated samples analyzed by the Wilcoxon-Mann-Whitney test were statistically significant (P = .05). RESULTS: Comparable complication rates were found for the 2 approaches without any significant differences (P = .29). Using the subtarsal approach, discrete scar formation was discerned in 7 of 30 cases. Moreover, categorization by the mVSS showed that, in 93.3% of cases, the scar was measured as unremarkable hyper- or hypotrophy (mean, 1.7 of 10 possible points). No statistically significant differences in conspicuous scars and asymmetries were observed between the 2 approaches in the nonexpert and expert groups (P > .05). CONCLUSION: The results of the present study confirm that the subtarsal approach is a safe and esthetically favorable method. PMID- 27474466 TI - A case of desmoid tumor co-existing with recurrent squamous cell carcinoma in the larynx. AB - Extra-abdominal desmoid tumor, also known as aggressive fibromatosis, has aggressive behavior with local infiltration and tendency for recurrence. Though head and neck is reported to be one of the most common sites, a desmoid tumor in the larynx is extremely rare. A 67-year-old male visited our hospital with prolonged hoarseness and received laryngo-microsurgery with the diagnosis of laryngeal polyp. After the operation, he eventually developed a laryngeal squamous cell carcinoma with papilloma, confirmed by second laryngo-microsurgery and received radiation therapy. After the third laryngo-microsurgery to remove residual papilloma, white irregular mass appeared on the right vocal cord and grew rapidly beneath the glottis, causing dyspnea. After 2 additional laryngo microsurgeries, he was diagnosed having the dermoid tumor co-existing with recurrent squamous cell carcinoma. He underwent near-total laryngectomy and is currently alive without disease, speaking using a vocal shunt. Only five cases of the desmoid tumors arising in the adult larynx have been reported in the English literature. In this case, repeated surgery and radiation were suspected as the causes. Also, the present report is the first to describe desmoid tumor co existing with recurrent squamous cell carcinoma in the larynx. PMID- 27474467 TI - Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus. AB - Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus. PMID- 27474468 TI - Challenge for higher colistin dosage in critically ill patients receiving continuous venovenous haemodiafiltration. AB - Traditionally, reduced daily doses of colistin methanesulphonate (CMS) in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF) have resulted in suboptimal colistin concentrations. The necessity of a loading dose (LD) at treatment initiation has been proposed. A LD of 9 million IU (MU) [ca. 270 mg of colistin base activity (CBA)] was administrated with a maintenance dose of 4.5 MU (ca. 140 mg CBA) every 12 h (q12h) to eight critically ill patients receiving renal replacement therapy. Blood samples were collected immediately before and at different time intervals after the LD and the fourth dose, whilst pre-filter and post-filter blood samples were also collected. CMS and colistin concentrations were determined using an LC-MS/MS assay. Median maximum observed concentrations after the LD were 22.1 mg/L for CMS and 1.55 mg/L for colistin, whereas during maintenance dosing the corresponding values were 12.6 mg/L and 1.72 mg/L, respectively. CVVHDF clearance was determined as 2.98 L/h for colistin, equivalent to 62% of total apparent colistin clearance in CVVHDF patients. Both CMS and colistin were cleared by CVVHDF. Application of a LD of 9 MU CMS resulted in more rapid achievement of the target colistin concentration. Following implementation of a predicted pharmacokinetic model on plasma CMS/colistin concentrations, a LD of 12 MU CMS appears more appropriate, whilst a CMS maintenance dosage of at least 6.5-7.5 MU q12h is suggested in patients undergoing CVVHDF. However, further clinical studies are warranted to assess the safety of a LD of 12 MU CMS in patients receiving CVVHDF. PMID- 27474470 TI - Cytoskeletal interference - A new mode of action for the anticancer drugs camptothecin and topotecan. AB - The anticancer drugs camptothecin (CPT) and topotecan (TPT) are known DNA topoisomerase I inhibitors which cause DNA damage and lead to cell death. In this study we provide evidence that CPT and TPT also interfere with the elements of cytoskeleton - microtubules and actin filaments which could be partly responsible for their cytotoxic properties. CPT and TPT apparently affected microtubule structures in living cells (Hela and U2OS) and inhibited tubulin polymerization in vitro with IC50 values of 74.57+/-9.96uM and 121.55+/-58.68uM, respectively. TPT significantly affected the nucleation and growth phase during the microtubule assembly in vitro, whereas the mode of action of CPT was different in that it specifically affected the 'tread milling' of polymerized microtubules. Cell cycle effects of CPT and TPT varied with their concentrations. CPT and TPT induced G2/M arrest and promoted the population to 76.94+/-11.20% and 83.91+/-2.43% at a concentration of 9.4nM and 46.9nM, respectively. As the concentration increased, cells were blocked in S phase with a dose-dependent reduction in G2/M population. In addition, CPT and TPT exhibited a certain effect on actin filaments by reducing the mass of actin filaments. The interactions of CPT and TPT with microtubules and actin filaments present new insights into their modes of action. PMID- 27474469 TI - Pharmacokinetic/pharmacodynamic evaluation of linezolid for the treatment of staphylococcal infections in critically ill patients. AB - Several studies have demonstrated that the ideal therapeutic effect of linezolid cannot be achieved in critically ill patients with the recommended standard dosing regimen of 600 mg every 12 h (q12h). Moreover, the optimal strategy for successful treatment is still lacking. This study analysed factors influencing the efficacy of linezolid treatment and determined the target for successful treatment by logistic regression in 27 critically ill patients with staphylococcal infection who received linezolid 600 mg q12h. The results showed that only the 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) ratio was significantly associated with staphylococcal eradication. Reaching 80% bacterial eradication required an AUC24/MIC of 120.5, defining the therapeutic target. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>99.9%) for the standard dosing regimen at MIC <= 1 mg/L, the PTA was almost 0 at MIC = 2 mg/L, thus the dosing regimen required adjustment. In addition, if the dosing regimen was adjusted to 600 mg every 8 h or 600 mg every 6 h, the major staphylococci (except for MRSA and MSSA) exhibited a cumulative fraction of response of >80%, showing a higher treatment success. These findings indicate that a strategy of high linezolid dosage may be needed to increase the probability of successful treatment at MIC > 1 mg/L. The role of therapeutic drug monitoring should be encouraged for optimising linezolid exposure in critically ill patients. PMID- 27474471 TI - Editorial. PMID- 27474479 TI - Hybrid Culotte for Bifurcations With Side Branch Lesion. PMID- 27474472 TI - Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4 dihydroxyphenylacetic acid in parkinsonian synucleinopathies. AB - INTRODUCTION: There is intense interest in identifying cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD), both for early diagnosis and to track effects of putative treatments. Nigrostriatal dopamine depletion characterizes PD. Predictably, CSF levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, are decreased in PD, even in patients with recent onset of the movement disorder. Whether low CSF DOPAC is associated specifically with parkinsonism has been unclear. In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DA). Theoretically, oxidative stress or decreased activity of aldehyde dehydrogenase (ALDH) in the residual nigrostriatal dopaminergic neurons would increase CSF Cys-DA levels with respect to DOPAC levels. PD, parkinsonian multiple system atrophy (MSA-P), and pure autonomic failure (PAF) are synucleinopathies; however, PAF does not entail parkinsonism. We examined whether an elevated Cys-DA/DOPAC ratio provides a specific biomarker of parkinsonism in synucleinopathy patients. METHODS: CSF catechols were assayed in PD (n = 24), MSA-P (n = 32), PAF (n = 18), and control subjects (n = 32). RESULTS: Compared to controls, CSF DOPAC was decreased in PD and MSA-P (p < 0.0001 each). In both diseases Cys-DA/DOPAC ratios averaged more than twice control (0.14 +/- 0.02 and 0.13 +/- 0.02 vs. 0.05 +/- 0.01, p < 0.0001 each), whereas in PAF the mean Cys-DA/DOPAC ratio was normal (0.05 +/- 0.01). CONCLUSIONS: CSF Cys-DA/DOPAC ratios are substantially increased in PD and MSA-P and are normal in PAF. Thus, in synucleinopathies an elevated CSF Cys-DA/DOPAC ratio seems to provide a specific biomarker of parkinsonism. PMID- 27474480 TI - Assessment of the New SCORE OP Cardiovascular Risk Charts in Patients Older Than 65 Years. PMID- 27474473 TI - Biomarkers in acute kidney injury - pathophysiological basis and clinical performance. AB - Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2) and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies. PMID- 27474481 TI - Usefulness of a Cardiovascular Polypill in the Treatment of Secondary Prevention Patients in Spain: A Cost-effectiveness Study. AB - INTRODUCTION AND OBJECTIVES: To estimate the health benefits and cost effectiveness of a polypill intervention (aspirin 100 mg, atorvastatin 20 mg, ramipril 10 mg) compared with multiple monotherapy for secondary prevention of cardiovascular events in adults with a history of myocardial infarction from the perspective of the Spanish National Health System. METHODS: An adapted version of a recently published Markov model developed and validated in Microsoft Excel was used to compare the cost-effectiveness of the polypill with that of its combined monocomponents over a 10-year time horizon. The population included in the model had a mean age of 64.7 years; most were male and had a history of myocardial infarction. The input parameters were obtained from a systematic literature review examining efficacy, adherence, utilities, and costs. The results of the model are expressed in events avoided, incremental costs, incremental life years, incremental quality-adjusted life years, and the incremental cost-effectiveness ratio. RESULTS: Over a 10-year period, use of the cardiovascular polypill instead of its monocomponents simultaneously would avoid 46 nonfatal and 11 fatal cardiovascular events per 1000 patients treated. The polypill would also be a more effective and cheaper strategy. Probabilistic analysis of the base case found a 90.9% probability that the polypill would be a cost-effective strategy compared with multiple monotherapy at a willingness-to-pay of 30 000 euros per quality-adjusted life year. CONCLUSIONS: The polypill would be a cost-effective strategy for the Spanish National Health System with potential clinical benefits. PMID- 27474482 TI - Dual Energy Coronary Computed Tomography Angiography for Detection and Quantification of Atherosclerotic Burden: Diagnostic and Prognostic Significance. PMID- 27474483 TI - Sex- and disease-specific inflammasome signatures in circulating blood leukocytes of patients with abdominal aortic aneurysm. AB - Male sex is a risk factor for abdominal aortic aneurysm (AAA). Within the AAA adventitia, infiltrating leukocytes express high levels of inflammasome components. To further elucidate the role of inflammatory cells in the pathogenesis of AAA, we here addressed expression and functionality of inflammasome components in peripheral blood mononuclear cells (PBMC) of AAA patients in association with sex. PBMC and plasma were isolated from 100 vascular patients, including 34 pairs of AAA patients and age/sex-matched non-AAA patients. Male PBMC were found to express significantly higher mRNA levels of AIM2, NLRP3, ASC (PYCARD), CASP1, CASP5, and IL1B (all P < 0.0001) than female PBMC. Within the male patients, PBMC of AAA patients displayed increased mRNA levels of NLRP3 (P = 0.044), CASP1 (P = 0.032) and IL1B (P = 0.0004) compared to matched non-AAA PBMC, whereas there was no difference between female AAA and non AAA patients. The relative protein level of NLRP3 was significantly lower in PBMC lysates from all AAA patients than in matched controls (P = 0.038), whereas AIM2 and active Caspase-1 (p10) protein levels were significantly increased (P = 0.014 and P = 0.049). ELISA revealed significantly increased IL-1alpha (mean = 6.34 vs 0.01 pg/ml) and IL-1beta plasma levels (mean = 12.07 vs. 0.04 pg/ml) in AAA patients. The data indicate that male PBMC display a systemic proinflammatory state with primed inflammasomes that may contribute to AAA-pathogenesis. The AAA specific inflammasome activation pattern suggests differential regulation of the sensors AIM2 and NLRP3 in inflammatory cells of AAA patients. PMID- 27474485 TI - [Responsibility for the loss of opportunity in malignant cancer care in the Spanish public healthcare system]. AB - OBJECTIVE: The loss of chance in healthcare has been forcibly introduced in the adjudications pronounced in recent years. Our objective was to analyse the verdicts of guilt resulting from the loss of chance ordered by the Contentious Administrative Court (i.e., in the public healthcare system), in which both the origin of the disease to be treated and the sequelae were oncological processes. METHOD: We analysed 137 cancer-related court judgments from the Contentious Administrative Court, which referred to the concept of loss of chance, issued in Spain up to May 2014. RESULTS: Of the 137 sentences, 119 (86.9%), were pronounced due to diagnostic error and 14 (10.2%) due to inadequate treatment. Since 2010, 100 sentences have been passed (73.0%), representing an increase of more than 170% with respect to the 37 (27.0%) ordered in the first six years of the study (from 2004 to 2009). Most of the patients (68.6%) died, predominantly from breast cancer and gynaecological cancer (24.1%), and gastrointestinal cancers (21.1%). These malignancies were the ones most often involved in the sentences. CONCLUSIONS: The litigant activity due to loss of chance in oncological processes in the public health care has significantly increased in the last years. The judgments were mainly given because of diagnostic error or inadequate treatment. PMID- 27474484 TI - Differential gene expression according to race and host plant in the pea aphid. AB - Host-race formation in phytophagous insects is thought to provide the opportunity for local adaptation and subsequent ecological speciation. Studying gene expression differences amongst host races may help to identify phenotypes under (or resulting from) divergent selection and their genetic, molecular and physiological bases. The pea aphid (Acyrthosiphon pisum) comprises host races specializing on numerous plants in the Fabaceae and provides a unique system for examining the early stages of diversification along a gradient of genetic and associated adaptive divergence. In this study, we examine transcriptome-wide gene expression both in response to environment and across pea aphid races selected to cover the range of genetic divergence reported in this species complex. We identify changes in expression in response to host plant, indicating the importance of gene expression in aphid-plant interactions. Races can be distinguished on the basis of gene expression, and higher numbers of differentially expressed genes are apparent between more divergent races; these expression differences between host races may result from genetic drift and reproductive isolation and possibly divergent selection. Expression differences related to plant adaptation include a subset of chemosensory and salivary genes. Genes showing expression changes in response to host plant do not make up a large portion of between-race expression differences, providing confirmation of previous studies' findings that genes involved in expression differences between diverging populations or species are not necessarily those showing initial plasticity in the face of environmental change. PMID- 27474486 TI - [Study protocol on the effect of the economic crisis on mortality and reproductive health and health inequalities in Spain]. AB - The aim is to present the protocol of the two sub-studies on the effect of the economic crisis on mortality and reproductive health and health inequalities in Spain. Substudy 1: describe the evolution of mortality and reproductive health between 1990 and 2013 through a longitudinal ecological study in the Autonomous Communities. This study will identify changes caused by the economic crisis in trends or reproductive health and mortality indicators using panel data (17 Autonomous Communities per study year) and adjusting Poisson models with random effects variance. Substudy 2: analyse inequalities by socioeconomic deprivation in mortality and reproductive health in several areas of Spain. An ecological study analysing trends in the pre-crisis (1999-2003 and 2004-2008) and crisis (2009-2013) periods will be performed. Random effects models Besag York and Mollie will be adjusted to estimate mortality indicators softened in reproductive health and census tracts. PMID- 27474487 TI - Age and gender effects on the prevalence of poor sleep quality in the adult population. AB - OBJECTIVE: Sleep quality has a significant impact on health and quality of life and is affected, among other factors, by age and sex. However, the prevalence of problems in this area in the general population is not well known. Therefore, our objective was to study the prevalence and main characteristics of sleep quality in an adult population sample. METHODS: 2,144 subjects aged between 43 and 71 years belonging to the Murcia (Spain) Twin Registry. Sleep quality was measured by self-report through the Pittsburgh Sleep Quality Index (PSQI). Logistic regression models were used to analyse the results. RESULTS: The prevalence of poor sleep quality stands at 38.2%. Univariate logistic regression analyses showed that women were almost twice as likely as men (OR: 1.88; 95% confidence interval [95%CI]: 1.54 to 2.28) to have poor quality of sleep. Age was directly and significantly associated with a low quality of sleep (OR: 1.05; 95%CI: 1.03 to 1.06). CONCLUSIONS: The prevalence of poor sleep quality is high among adults, especially women. There is a direct relationship between age and deterioration in the quality of sleep. This relationship also appears to be more consistent in women. PMID- 27474488 TI - [Zika virus infection: a new public health emergency with great media impact]. AB - Infection with Zika virus (ZV) has become a new epidemic, with great impact on the media, and is having a strong effect in Latin American countries. Its possible association with microcephaly and Guillain-Barre syndrome prompted the World Health Organization (WHO) to declare on 1 February 2016 that this epidemic is a public health emergency of international concern. Epidemiological data show an increasing incidence in countries like Brazil and Colombia, and that the epidemic is still expanding in many other countries. Between January 2007 and 27 April 2016, the WHO detected transmission in 55 countries (in 42 of these, this was the first outbreak of Zika) and 1,198 microcephalies and other neurological disorders in Brazil. Also, during 2015-2016, 13 countries detected an increase in Guillain-Barre syndrome and/or confirmation of ZV associated with Guillain-Barre syndrome. Research has already demonstrated a causal relationship between microcephaly and other serious brain disorders in newborns and ZV infection in the mother. Clinically, many cases are asymptomatic and it can be difficult to distinguish this diagnosis from that of other arboviruses. Vector control in Spain is a priority because of the presence of the Aedes albopictus (tiger mosquito). Early diagnosis is recommended, as is avoiding travel to endemic areas and unprotected sex, and ensuring that the high political profile, which can prevent this epidemic from becoming a high prevalence endemic disease, does not cause us to forget about other health problems. PMID- 27474489 TI - Maternal physical and sedentary activities in relation to reproductive outcomes following IVF. AB - Physical activity could benefit reproductive function through its ability to regulate energy balance and improve insulin sensitivity, but its association with IVF outcomes remains unclear. The aim of this study was to evaluate whether pre treatment physical and sedentary activity is associated with outcomes of IVF. The Environment and Reproductive Health Study is an ongoing prospective cohort study that enrols subfertile couples at Massachusetts General Hospital Fertility Center. Time spent in physical and sedentary activities in the year before IVF treatment is self-reported using a validated questionnaire. This analysis included 273 women who underwent 427 IVF cycles. Women engaged in a median of 2.8 h per week of moderate-to-vigorous activities. Time spent in moderate-to-vigorous physical activities and total metabolic equivalent task hours before IVF were not associated with probability of implantation, clinical pregnancy or live birth. Of the specific physical activities, only greater time spent in aerobics, rowing, and on the ski or stair machine was associated with higher probability of live birth. Time spent in total and specific sedentary activities were not associated with clinical outcomes of IVF. Physical activity is unlikely to have a deleterious effect on IVF success and certain forms of vigorous activity may be beneficial. PMID- 27474490 TI - Obtusifoliol related steroids from Euphorbia sogdiana with cell growth inhibitory activity and apoptotic effects on breast cancer cells (MCF-7 and MDA-MB231). AB - From the aerial parts of Euphorbia sogdiana Popov, obtusifoliol (1) and two related steroids (2-3) have been isolated and characterized along with a known cycloartane derivative (4). The chemical structure of the obtusifoliol-related compounds, obtained by 1D and 2D NMR, and MS measurements, have been determined as: 3beta,7alpha-dihydroxy-4alpha,14alpha-dimethyl-5alpha-ergosta-8,24(28)-diene 11-one (2) and 3beta-hydroxy-4alpha,14alpha-dimethyl-5alpha-ergosta-8,24(28) diene-1-one (3). Compound 2 has been previously isolated from Euphorbia chamaesyce while compound 3 was never reported before. The isolated compounds 1-4 were subjected to cytotoxic tests on the breast cancer cells, MCF-7 and MDA MB231. Further pharmacological tests on the more active compounds 2 and 3 indicated their action to be related to cell growth inhibitory activity and apoptotic effects on the tested cells. PMID- 27474492 TI - Brain metastasis in lung cancer: Building a molecular and systems-level understanding to improve outcomes. AB - Lung cancer is a clinically difficult disease with rising disease burden around the world. Unfortunately, most lung cancers present at a clinically advanced stage. Of these cancers, many also present with brain metastasis which complicates the clinical picture. This review summarizes current knowledge on the molecular basis of lung cancer brain metastases. We start from the clinical perspective, aiming to provide a clinical context for a significant problem that requires much deeper scientific investigation. We review new research governing the metastatic process, including tumor cell signaling, establishment of a receptive tumor niches in the brain and evaluate potential new therapeutic options that take advantage of these new scientific advances. Lung cancer remains the largest single cause of cancer mortality in the United States (Siegel et al., 2015). This continues to be the clinical picture despite significant advances in therapy, including the advent of targeted molecular therapies and newly adopted immunotherapies for certain subtypes of lung cancer. In the vast majority of cases, lung cancer presents as advanced disease; in many instances, this advanced disease state is intimately associated with micro and macrometastatic disease (Goldberg et al., 2015). For both non-small cell lung cancer and small cell lung cancer patients, the predominant metastatic site is the brain, with up to 68% of patients with mediastinal lymph node metastasis eventually demonstrating brain metastasis (Wang et al., 2009).The frequency (incidence) of brain metastasis is highest in lung cancers, relative to other common epithelial malignancies (Schouten et al., 2002). Other studies have attempted to predict the risk of brain metastasis in the setting of previously non-metastatic disease. One of the largest studies to do this, analyzing historical data from 1973 to 2011 using the SEER database revealed a 9% risk of patients with previously non-metastatic NSCLC developing brain metastasis over the course of their disease, while 18% of small cell lung cancer patients without previous metastasis went on to develop brain metastasis as their disease progressed (Goncalves et al., 2016).The reasons underlying this predilection for the central nervous system, as well as the recent increase in the frequency of brain metastasis identified in patients remain important questions for both clinicians and basic scientists. More than ever, the question of how brain metastasis develop and how they can be treated and managed requires the involvement of interdisciplinary teams-and more importantly-scientists who are capable of thinking like clinicians and clinicians who are capable of thinking like scientists. This review aims to present a translational perspective on brain metastasis. We will investigate the scope of the problem of brain metastasis and the current management of the metastatic disease process in lung cancer. From this clinical starting point, we will investigate the literature surrounding the molecular underpinnings of lung tumor metastasis and seek to understand the process from a biological perspective to generate new hypotheses. PMID- 27474493 TI - Plant-produced Crimean-Congo haemorrhagic fever virus nucleoprotein for use in indirect ELISA. AB - Crimean-Congo haemorrhagic fever (CCHF) is a disease of serious public concern caused by the CCHF virus (CCHFV). Anti-CCHFV IgG in humans can be detected using ELISA with native antigen prepared from cell cultures which have been infected with virus or from brain tissue of suckling mice which have been inoculated with virus. However, the preparation of these reagents requires high biosafety levels and is expensive. A safer, more cost-effective recombinantly-produced NP reagent is desirable. Recently, plants have been shown to be a cost-effective and safe system for expression of recombinant proteins. This work describes cloning of the CCHFV NP gene into three different plant expression systems and comparison of expression in Nicotiana benthamiana. The highest expressing construct was selected. Expressed NP was purified by ammonium sulphate fractionation prior to histidine affinity chromatography. Purified NP was tested in an indirect ELISA to determine if the recombinant antigen was able to detect anti-CCHFV IgG in sera from convalescent patients. Plant-produced NP detected IgG antibodies against CCHFV in 13/13 serum samples from convalescent patients and 0/13 samples collected from volunteers with no history of CCHFV infection. Results were compared with commercially available immunofluorescent assays and 100% concordance was obtained between the two assays. This suggests that a full evaluation of the plant produced NP for application as a safe recombinant is warranted. PMID- 27474494 TI - Development and validation of a cell-based assay system to assess human immunodeficiency virus type 1 integrase multimerization. AB - Multimerization of HIV-1 integrase (IN) subunits is required for the concerted integration of HIV-1 proviral DNA into the host genome. Thus, the disruption of IN multimerization represents a new avenue for intervening HIV-1 infection. Here, we generated a cell-based assay system to assess IN multimerization using a newly constructed bimolecular fluorescence complementation (BiFC-IN) system. BiFC-IN proteins were efficient in emitting fluorescence, and amino acid (AA) substitutions associated with IN multimerization attenuated fluorescence, suggesting that the BiFC-IN system may be useful for evaluating the profile of IN multimerization. A recently reported non-catalytic site IN inhibitor (NCINI), which allosterically induces IN over-multimerization/aggregation, significantly increased fluorescence in the BiFC-IN system. An IN's substitution, A128T, associated with viral resistance to NCINIs, decreased the NCINI-induced increase of fluorescence, suggesting that A128T reduces the potential for IN over multimerization. Moreover, E11K and F181T substitutions known to inhibit IN tetramerization also reduced the NCINI-induced fluorescence increase, suggesting that NCINI-induced IN over-multimerization was more likely to occur from tetramer subunits than from dimer subunits. The present study demonstrates that our cell based BiFC-IN system may be useful in elucidating the profile of IN multimerization, and also help evaluate and identify novel compounds that disrupt IN multimerization in living cells. PMID- 27474491 TI - Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD. AB - Myriad forms of endogenous and environmental stress disrupt mitochondrial function by impacting critical processes in mitochondrial homeostasis, such as mitochondrial redox system, oxidative phosphorylation, biogenesis, and mitophagy. External stressors that interfere with the steady state activity of mitochondrial functions are generally associated with an increase in reactive oxygen species, inflammatory response, and induction of cellular senescence (inflammaging) potentially via mitochondrial damage associated molecular patterns (DAMPS). Many of these are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations. In this review, we highlight the primary mitochondrial quality control mechanisms that are influenced by oxidative stress/redox system, including role of mitochondria during inflammation and cellular senescence, and how mitochondrial dysfunction contributes to the pathogenesis of COPD and its exacerbations via pathogenic stimuli. PMID- 27474495 TI - Time influence on the interaction between Cyt2Aa2 and lipid/cholesterol bilayers. AB - Protein-membrane interactions are still an important topic of investigation. One of the suitable experimental techniques used by the scientific community to address such question is atomic force microscopy. In a previous work, we have reported that the binding mechanism between the cytolytic and antimicrobial protein (Cyt2Aa2) and lipid/cholesterol bilayers was concentration-dependent, leading to either the formation of holes in the bilayer or aggregates. Here we study such binding mechanism as a function of time at low protein concentrations (10 ug/mL). We demonstrate that although holes are formed during the first stages of the protein-lipid interaction, a reparation process due to molecular mobility in the bilayer leads to a homogenous and isotropic protein-lipid/cholesterol layer within 3 hr. The combination of imaging, force spectroscopy, and phase contrast delivered information about topography dynamics (molecular mobility), layer thickness, and mechanical properties of the protein-lipid/cholesterol system. These results highlight the importance of the observation time in (such type of) protein-lipid interactions (at low protein concentrations). PMID- 27474496 TI - Learning by (video) example: a randomized study of communication skills training for end-of-life and error disclosure family care conferences. AB - BACKGROUND: Teaching residents to lead end of life (EOL) and error disclosure (ED) conferences is important. METHODS: We developed and tested an intervention using videotapes of EOL and error disclosure encounters from previous Objective Structured Clinical Exams. Residents (n = 72) from general and orthopedic surgery programs at 2 sites were enrolled. Using a prospective, pre-post, block group design with stratified randomization, we hypothesized the treatment group would outperform the control on EOL and ED cases. We also hypothesized that online course usage would correlate positively with post-test scores. RESULTS: All residents improved (pre-post). At the group level, treatment effects were insignificant, and post-test performance was unrelated to course usage. At the subgroup level for EOL, low performers assigned to treatment scored higher than controls at post-test; and within the treatment group, post graduate year 3 residents outperformed post graduate year 1 residents. CONCLUSIONS: To be effective, online curricula illustrating communication behaviors need face-to face interaction, individual role play with feedback and discussion. PMID- 27474497 TI - Sutureless closure of colonic defects with tissue adhesives: an in vivo study in the rat. AB - BACKGROUND: Tissue adhesives (TAs) in gastrointestinal surgery are gradually gaining acceptance. Before implementation as colonic sealants, an evaluation of the sealing capability of a TA when in contact with fecal matter, as in a leaking anastomosis, is needed. In this study, we used clinically available TAs for the sutureless closure of colonic defects evaluating mechanical strength and tissue healing. METHODS: A total of 160 rats were divided into 8 groups. Two .5-cm incisions were created, one in the proximal and another in the distal colon. Incisions were sealed with a TA: Histoacryl Flex, Bioglue, Dermabond, Tissucol, Duraseal Xact, gelatin-resorcinol-formaldehyde or Glubran 2. A control group was included in which the colonic defects were not sealed. Follow-up time was 3 or 10 days. Clinical complication rate, bursting pressure, and histopathologic analysis was included. RESULTS: Leakage rates in the TA groups were highest for Duraseal Xact, Bioglue, and gelatin-resorcinol-formaldehyde at 3 and 10 days. The cyanoacrylates Glubran 2, Histoacryl Flex, and Omnex, and the fibrin glue Tissucol showed the lowest overall clinical complication rates while maintaining the highest bursting pressure at day 10. Histoacryl Flex exhibited significantly higher collagen formation at day 10 than the other TAs. CONCLUSIONS: This experimental model evaluates the protective effect of a TA seal on a leaking colonic defect. We found large differences in leakage rates and inertness of the tested TAs. The cyanoacrylates Histoacryl Flex, Omnex, and Glubran 2 as well as the fibrin glue Tissucol demonstrated the lowest leakage rates and the most inert histopathologic profile while maintaining high mechanical strength. PMID- 27474498 TI - Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats. AB - Given that high mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, promotes nociception, we asked if inactivation of HMGB1 prevents or reverses chemotherapy-induced painful neuropathy in rats and also examined possible involvement of Toll-like receptor 4 (TLR4) and the receptor for advanced glycation endproduct (RAGE), known as targets for HMGB1. Painful neuropathy was produced by repeated i.p. administration of paclitaxel or vincristine in rats. Nociceptive threshold was determined by the paw pressure method and/or von Frey test in the hindpaw. Tissue protein levels were determined by immunoblotting. Repeated i.p. administration of the anti-HMGB1-neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, prevented the development of hyperalgesia and/or allodynia induced by paclitaxel or vincristine in rats. A single i.p. or intraplantar (i.pl.) administration of the antibody or rhsTM reversed the chemotherapy-induced neuropathy. A single i.pl. administration of a TLR4 antagonist or low molecular weight heparin, known to inhibit RAGE, attenuated the hyperalgesia caused by i.pl. HMGB1 and also the chemotherapy-induced painful neuropathy. Paclitaxel or vincristine treatment significantly decreased protein levels of HMGB1 in the dorsal root ganglia, but not sciatic nerves. HMGB1 thus participates in both development and maintenance of chemotherapy-induced painful neuropathy, in part through RAGE and TLR4. HMGB1 inactivation is considered useful to prevent and treat the chemotherapy-induced painful neuropathy. PMID- 27474499 TI - Inhibitory effect of NBL1 on PDGF-BB-induced human PASMC proliferation through blockade of PDGFbeta-p38MAPK pathway. AB - Pulmonary artery remodelling is a key feature in the pathological progress of pulmonary arterial hypertension (PAH). Moreover, excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a critical role in the pathogenesis of pulmonary artery remodelling. Neuroblastoma suppressor of tumorigenicity 1 (NBL1) has been previously shown to induce growth inhibition in tumour cells. However, the effect of NBL1 in the regulation of human PASMC proliferation remains unclear. In cultured human PASMCs, we observed a dose dependent inhibitory effect of NBL1 on platelet derived growth factor (PDGF)-BB induced cell growth, DNA synthesis and proliferating cell nuclear antigen (PCNA) expression, as measured by MTS assay, 5-ethynil-2-deoxyuridine (EdU) analysis and western blots respectively. We also detected the expression and activities of cell-cycle positive regulators (cyclin D1, cyclin E, CDK2, CDK4 and CDK6) and negative regulators (p21 and p27) in human PASMCs by western blots and co immuoprecipitation (IP). Our results show that NBL1-induced growth suppression is associated with the decreased activity of cyclin D1-CDK4 and the decreased phosphorylation of p27 in PDGF-BB-treated human PASMCs. By western blots using the phosphor-specific antibodies, we further demonstrated that NBL1 induced growth suppression is mediated by blockade of the up-stream PDGF-receptor beta (PDGFRbeta)-p38 mitogen-activated protein kinase (MAPK). In conclusion, our results suggest that NBL1 could inhibit PDGF-BB-induced human PASMC proliferation, and the underlying mechanism is associated with the decreased cyclin D1-CDK4 activity and up-regulated p27 by decreasing the phosphorylation of p27 via blockade of PDGFRbeta-p38MAPK signal cascade. Our findings may provide a potential therapeutic target for PAH. PMID- 27474501 TI - Functional outcome and complications following surgery for Dupuytren's disease: a multi-centre cross-sectional study. AB - : Variables associated with recurrent Dupuytren's disease, or a 'diathesis', have been investigated, but those associated with functional outcome and complications are less well studied. Outcomes 1 or 5 years after an aponeurotomy, fasciectomy or dermofasciectomy were assessed by patient interview and examination at five UK centres. A total of 432 procedures were studied. The reoperation rate did not differ at 1 year ( p = 0.396, Chi-square test with Monte Carlo simulation), but was higher after aponeurotomy in the 5-year group (30%, versus 6% after fasciectomy and 0% after dermofasciectomy, p = 0.003, Chi square test with Monte Carlo simulation). Loss of function (DASH>15) did not differ between procedures at 5 years, even when reoperation and other variables were controlled. Diabetes, female gender and previous ipsilateral surgery were associated with poorer function in logistic regression analysis. The variables associated with poor function after treatments differ from diathesis variables. Aponeurotomy had lower complication rates than fasciectomy and dermofasciectomy. This may counterbalance the former's higher recurrence rate and explain why aponeurotomy demonstrated similar long-term functional outcome compared with excisional surgery in this study. LEVEL OF EVIDENCE: III. PMID- 27474500 TI - The regulation roles of miR-125b, miR-221 and miR-27b in porcine Salmonella infection signalling pathway. AB - miRNAs are non-coding RNA molecules typically 18-22 nucleotides long that can suppress the expression of their target genes. Several laboratories have attempted to identify miRNAs from the pig that are involved in Salmonella infection. These bioinformatics strategies using the newly available genomic sequence are generally successful. Here, we report an in silico identification of miRNAs in pig focusing on the Salmonella infection pathway, and further investigated the differential expression of those miRNAs by quantitative real time PCR during pre- and post-natal stage of Salmonella inoculation from the peripheral blood of commercially breed pigs. We identified 29 miRNAs that have predicted targets in the Salmonella infection pathway and nine of them were not yet described in pig. In addition, the expression of nine selected miRNAs was validated in the peripheral blood by northern blotting. Through expression analyses, differences were found between pre- and post-natal stages of Salmonella inoculation for miR-221, miR-125b and miR-27b-all of them were suppressed 2 days after Salmonella inoculation. The predicted targets of those three miRNAs were validated by luciferase reporter assays. We show that FOS is a direct target of miR-221, miR-125b can suppress MAPK14, and miR-27b can target IFNG. These findings will be helpful in understanding the function and processing of these miRNAs in Salmonella infection. The miRNA differentially expressed in the peripheral blood of commercial breed pigs suggest that it can be used as genetic markers for salmonella infection resistance in pigs. PMID- 27474502 TI - Establishing a reproducible protocol for measuring index active extension strength. AB - : The goal of this study was to establish a reproducible protocol to measure active extension strength in the index finger. The secondary objectives consisted in correlating the independent or associated index extension strength to the other fingers force of contraction of the extensor indicis propius with hand dominance. The population studied consisted of 24 healthy volunteers, including 19 women and 20 right-handed individuals. The independent and dependent index extension strength in each hand was measured three times with a dynamometer by three examiners at Day 0 and again at Day 7. Intra and inter-examiner reproducibility were, respectively, >0.90 and >0.75 in all cases. The independent extension strength was lower than the dependent one. There was no difference between the independent index extension strength on the dominant and non-dominant sides. The same was true for the dependent strength. Our results show that our protocol is reproducible in measuring independent and dependent index extension strength. Dominance did not come into account. LEVEL OF EVIDENCE: II. PMID- 27474503 TI - Nonablative radiofrequency treatment for the skin in the eye area - clinical and cutometrical analysis. AB - OBJECTIVE: The purpose of the research was to evaluate skin elasticity and reduction in the aging eye area after using a nonablative radiofrequency treatment. MATERIAL AND METHODS: This study included 23 patients, aged 34-58 years with Fitzpatrick skin type II and III. They received five treatment sessions with a nonablative radiofrequency in 1-week intervals. Biomechanical properties of the skin were measured using Cutometer. A photodocumentation was used to compare changes before and after the series of treatment sessions. Additionally, the patients filled in a questionnaire in which they were asked to make a self-evaluation of the procedure. RESULTS: Cutometrical analysis showed improvement of skin elasticity. Changes in the measurements of R2 and R6 parameters indicate that the statistical significance level is mostly P < 0.0001 for the differences in the measurements. The comparison of clinical changes in the therapy, based on photodocumentation, showed a 33.26% improvement. CONCLUSIONS: This treatment was used to improve skin tightness and decrease the amount and depth of wrinkles. It is a noninvasive treatment, with low risk of complications. The cutometrical measurements seem to be useful to assess improvement of elasticity of the skin after cosmetology or esthetic dermatology treatments. PMID- 27474504 TI - 10-Year follow-up of 621 patients treated using high-dose rate brachytherapy as ambulatory boost technique in conservative breast cancer treatment. AB - PURPOSE: Breast conserving treatment, consisting of lumpectomy followed by whole breast irradiation, is considered the standard of care in early-stage breast cancer. Randomized studies have reported that delivering boost doses to tumor bed improves local control rates, particularly in young women. This study sought to evaluate local control and cosmetic results of delivering boost doses using a high-dose-rate (HDR) brachytherapy (HDRBT) in breast cancer conservative treatment. METHODS: We included 621 T1-T2, N0-N1 breast cancer patients who underwent lumpectomy, external irradiation (44Gy over 5weeks), and a boost dose of two fractions of 5Gy to the tumor bed by means of HDR iridium brachytherapy. Implantation was performed during the lumpectomy or 2-3weeks after external irradiation. Population characteristics were as follows: pTis=11.6%; pT1=63.4%; pT2=25.0%; median tumor size=1.5cm; histology: ductal carcinoma in situ (DCIS): 72 (11.6%); infiltrative ductal carcinoma (IDC): 471 (75.8%); other: 78 (12.6%). For IDCs, the surgical margins were positive in 38cases (6.2%) and an extensive intraductal component was present in 254 cases. RESULTS: With a median follow-up of 10.3years, 47 local relapses were observed (10-year local relapse rate: 7.4%). Small-volume implantation (V100<45cc) and ductal carcinoma in situ histology both significantly correlated with local relapse. The 10-year overall survival was 91%. Cosmetic results were evaluated in 264patients, proving excellent in 58 (22%), good in 153 (58%), fair in 40 (15%), and poor in 13 (5%). CONCLUSIONS: Small implant volume and ductal carcinoma in situ histology significantly correlated with local relapse following HDR brachytherapy dose boost in breast cancer conservative treatment. Modern image-guided breast brachytherapy techniques using surgical clips as a guide may decrease potential treatment targeting errors, consequently improving local control without increasing toxicity. PMID- 27474506 TI - Phytoglobin expression influences soil flooding response of corn plants. AB - BACKGROUND AND AIMS: Excess water is a limiting factor for crop productivity. Under conditions of full submergence or flooding, plants can experience prolonged oxygen depletion which compromises basic physiological and biochemical processes. Severe perturbations of the photosynthetic machinery with a concomitant decline in photosynthetic potential as a result of elevated levels of reactive oxygen species (ROS) are the major consequences of water excess. Phytoglobins (Pgbs) are ubiquitous proteins induced by several types of stress which affect plant response by modulating nitric oxide. METHODS: Maize plants overexpressing or downregulating two Pgb genes were subjected to soil flooding for 10 d and their performance was estimated by measuring several gas exchange parameters including photosynthetic rate. Above-ground tissue was utilized to localize ROS and to measure the expression and activities of major antioxidant enzymes. KEY RESULTS: Relative to the wild type, flooded plants overexpressing Pgb genes retained a greater photosynthetic rate and enhanced activity of several antioxidant enzymes. These plants also exhibited high levels of ascorbic acid and reduced ROS staining. This was in contrast to flooded plants downregulating Pgb genes and characterized by the lowest photosynthetic rates and reduced expression and activities of many antioxidant enzymes. CONCLUSIONS: Induction of Pgb genes alleviates flooding stress by limiting ROS-induced damage and ensuring a sustained photosynthetic rate. This is achieved through improvements of the ascorbate antioxidant status including an enrichment of the ascorbate pool via de novo and recycling mechanisms, and increased activities of several ROS-scavenging enzymes. PMID- 27474507 TI - Impact of axial root growth angles on nitrogen acquisition in maize depends on environmental conditions. AB - BACKGROUNDS AND AIMS: Crops with reduced requirement for nitrogen (N) fertilizer would have substantial benefits in developed nations, while improving food security in developing nations. This study employs the functional structural plant model SimRoot to test the hypothesis that variation in the growth angles of axial roots of maize (Zea mays L.) is an important determinant of N capture. METHODS: Six phenotypes contrasting in axial root growth angles were modelled for 42 d at seven soil nitrate levels from 10 to 250 kg ha(-1) in a sand and a silt loam, and five precipitation regimes ranging from 0.5* to 1.5* of an ambient rainfall pattern. Model results were compared with soil N measurements of field sites with silt loam and loamy sand textures. KEY RESULTS: For optimal nitrate uptake, root foraging must coincide with nitrate availability in the soil profile, which depends on soil type and precipitation regime. The benefit of specific root architectures for efficient N uptake increases with decreasing soil N content, while the effect of soil type increases with increasing soil N level. Extreme root architectures are beneficial under extreme environmental conditions. Extremely shallow root systems perform well under reduced precipitation, but perform poorly with ambient and greater precipitation. Dimorphic phenotypes with normal or shallow seminal and very steep nodal roots performed well in all scenarios, and consistently outperformed the steep phenotypes. Nitrate uptake increased under reduced leaching conditions in the silt loam and with low precipitation. CONCLUSIONS: Results support the hypothesis that root growth angles are primary determinants of N acquisition in maize. With decreasing soil N status, optimal angles resulted in 15-50 % greater N acquisition over 42 d. Optimal root phenotypes for N capture varied with soil and precipitation regimes, suggesting that genetic selection for root phenotypes could be tailored to specific environments. PMID- 27474508 TI - The MADS-box XAANTAL1 increases proliferation at the Arabidopsis root stem-cell niche and participates in transition to differentiation by regulating cell-cycle components. AB - BACKGROUND: Morphogenesis depends on the concerted modulation of cell proliferation and differentiation. Such modulation is dynamically adjusted in response to various external and internal signals via complex transcriptional regulatory networks that mediate between such signals and regulation of cell cycle and cellular responses (proliferation, growth, differentiation). In plants, which are sessile, the proliferation/differentiation balance is plastically adjusted during their life cycle and transcriptional networks are important in this process. MADS-box genes are key developmental regulators in eukaryotes, but their role in cell proliferation and differentiation modulation in plants remains poorly studied. METHODS: We characterize the XAL1 loss-of-function xal1-2 allele and overexpression lines using quantitative cellular and cytometry analyses to explore its role in cell cycle, proliferation, stem-cell patterning and transition to differentiation. We used quantitative PCR and cellular markers to explore if XAL1 regulates cell-cycle components and PLETHORA1 (PLT1) gene expression, as well as confocal microscopy to analyse stem-cell niche organization. KEY RESULTS: We previously showed that XAANTAL1 (XAL1/AGL12) is necessary for Arabidopsis root development as a promoter of cell proliferation in the root apical meristem. Here, we demonstrate that XAL1 positively regulates the expression of PLT1 and important components of the cell cycle: CYCD3;1, CYCA2;3, CYCB1;1, CDKB1;1 and CDT1a In addition, we show that xal1-2 mutant plants have a premature transition to differentiation with root hairs appearing closer to the root tip, while endoreplication in these plants is partially compromised. Coincidently, the final size of cortex cells in the mutant is shorter than wild type cells. Finally, XAL1 overexpression-lines corroborate that this transcription factor is able to promote cell proliferation at the stem-cell niche. CONCLUSION: XAL1 seems to be an important component of the networks that modulate cell proliferation/differentiation transition and stem-cell proliferation during Arabidopsis root development; it also regulates several cell cycle components. PMID- 27474510 TI - Transcriptome-Wide High-Density Microarray Analysis Reveals Differential Gene Transcription in Periprosthetic Tissue From Hips With Chronic Periprosthetic Joint Infection vs Aseptic Loosening. AB - BACKGROUND: Differentiating between periprosthetic hip infection and aseptic hip prosthesis loosening can be challenging, especially in patients with chronic infections. This study used whole-genome microarray analysis to investigate the transcriptomes of periprosthetic hip tissues to identify genes that are differentially transcripted between chronic periprosthetic hip infection and aseptic hip prosthesis loosening. METHODS: In this pilot study, a total of 24 patients with either chronic periprosthetic hip infection (n = 12) or aseptic hip prosthesis loosening (n = 12) were analyzed. Periprosthetic hip infection was diagnosed based on modified criteria of the Musculoskeletal Infection Society. To evaluate differences in gene transcription, whole-genome microarray analysis was performed on the mRNA of periprosthetic tissue. RESULTS: Microarray analysis revealed differential gene transcription in periprosthetic hip tissue affected by chronic hip infection vs aseptic hip prosthesis loosening. A total of 39 genes had area under the curve values greater than 0.9 for diagnosing chronic periprosthetic hip infection; 5 genes had annotations relevant to infection and metabolism. The 39 genes also included 7 genes that were differentially transcribed but that have no apparent connection to immune response processes plus 27 genes with unknown function. CONCLUSION: Differences in gene transcription profiles might represent novel diagnostic targets that can be used to differentiate between chronic periprosthetic hip infections and aseptic hip prosthesis loosening. Secondary metabolites of differentially transcripted genes might serve as easily accessible markers for detecting chronic periprosthetic joint infection in future. PMID- 27474509 TI - Auxin enhances aluminium-induced citrate exudation through upregulation of GmMATE and activation of the plasma membrane H+-ATPase in soybean roots. AB - BACKGROUND AND AIMS: Aluminium (Al) toxicity is a limiting factor for plant growth and crop production in acidic soils. Citrate exudation and activation of the plasma membrane H+-ATPase are involved in soybean responses to Al stress. Auxin has crucial functions in plant growth and stress responses. However, little is known about possible interactions between auxin and citrate exudation under Al stress. In this study, we elucidated the regulatory roles of IAA in Al-induced citrate exudation in soybean roots. METHODS: We measured IAA content, Al concentration, citrate exudation, plasma membrane H+-ATPase activity, expression of the relevant genes and phosphorylation of the plasma membrane H+-ATPase by integrating physiological characterization and molecular analysis using hydroponically grown soybean. KEY RESULT: s The concentration of IAA was increased by 25 and 50 MUm Al, but decreased to the control level at 200 MUm Al. External addition of 50 MUm IAA to the root medium containing 25, 50 or 200 MUm Al decreased root Al concentration and stimulated Al-induced citrate exudation and the plasma membrane H+-ATPase activity. Reverse transcription-PCR analysis showed that exogenous IAA enhanced the expression of citrate exudation transporter (GmMATE) but not the plasma membrane H+-ATPase gene. The western blot results suggested that IAA enhanced phosphorylation of the plasma membrane H+ ATPase under Al stress. CONCLUSIONS: Auxin enhanced Al-induced citrate exudation through upregulation of GmMATE and an increase in phosphorylation of the plasma membrane H+-ATPase in soybean roots. PMID- 27474511 TI - A Current Procedural Terminology Code for "Knee Conversion" Is Needed to Account for the Additional Surgical Time Required Compared to Total Knee Arthroplasty. AB - BACKGROUND: Previous knee injury requiring surgical intervention increases the rate of future arthroplasty. Coding modifiers for removal of previous hardware or increased complexity offer inconsistent results. A Current Procedural Terminology code for knee conversion does not currently exist as it does for conversion hip arthroplasty. We investigate the extra time associated with conversion knee arthroplasty. METHODS: Sixty-three total knee arthroplasty (TKA) cases in the setting of previous knee hardware were identified from our institution between 2008 and 2015. Knee conversions were matched to primary TKA by age, gender, body mass index, Charlson Comorbidity Index, and surgeon, in a 3:1 ratio. Patients who underwent knee conversions were compared to matched TKA with regard to operative time, length of stay, discharge destination, readmission, and repeat procedures within 90 days from index procedure. RESULTS: The mean operating room time for primary TKA was 71.7 minutes (range 36-138). The mean operating room time for knee conversion was significantly greater by an additional 31 minutes; mean 102.1 minutes (range 56-256 minutes, P < .0001). Rates of readmission, 0.5% vs 3.2%, and repeat procedures, 5.3% vs 12.7%, within 90 days were greater for knee conversions. There was no difference in length of stay or discharge destination. CONCLUSION: Total knee conversion results in a 43% increase in operative time and more than twice the rate of readmission and repeat procedures within 90 days compared to TKA. This suggests the need for an additional Current Procedural Terminology code for knee conversion arthroplasty to compensate surgeons for the extra time required for conversions. PMID- 27474513 TI - Psychopathology in adolescents with TLE and FLE. AB - BACKGROUND: To describe the rates and types of psychiatric disorders among adolescents with chronic symptomatic epilepsies and to evaluate syndrome-specific differences between temporal lobe (TLE) and frontal lobe (FLE) epilepsies. METHODS: A cross-sectional single-center study design applying the Youth Self Report (YSR) to investigate psychopathological symptoms and the Weinberger Adjustment Inventory (WAI) to investigate personality dimensions was used. Consecutive adolescents between 14 and 18 years of age with drug-resistant symptomatic TLE and FLE were investigated during pre-surgical evaluation prior to epilepsy surgery. Data from twenty-eight patients (19 with TLE and 9 with FLE) were analyzed for this report. RESULTS: Compared with the test norm, higher prevalence rates and a wider range of psychopathological symptoms were seen in patients with TLE. This result was not seen in patients with FLE. Concerning personality dimensions, significantly higher values of repressive defensiveness and significantly lower values of positive emotion and confidence were found in patients with TLE. In contrast, significantly lower levels of distress and significantly higher levels of repressive defensiveness and denial of distress were seen in patients with FLE. Comparing TLE with FLE, a significantly higher mean score for distress, and a significantly lower mean score for positive emotion and denial of distress were found in patients with TLE. CONCLUSION: In summary, psychiatric comorbidity was frequently found in this sample of youths with chronic drug-resistant localization-related epilepsies. Although results have to be interpreted with caution because of the small sample size, psychiatric symptomatology was significantly different between TLE and FLE. Our results show that continuous and syndrome-specific psychiatric monitoring is essential in young patients with epilepsy. PMID- 27474514 TI - Operating on Patients Who Smoke: A Survey of Thoracic Surgeons in the United States. AB - BACKGROUND: Although preoperative smoking is associated with increased postoperative complications in patients who undergo major thoracic surgical procedures, there are no national guidelines that address the patient's preoperative tobacco use. This study examined the typical preoperative management of thoracic surgical patients who are smokers. METHODS: The link to an anonymous survey was emailed to cardiothoracic surgeons in the United States. The survey included questions regarding the likelihood of a surgeon to offer surgery and strategies used to assist patients in quitting smoking before surgery. RESULTS: The majority of the 158 surgeons who responded to the survey were general thoracic surgeons (68%, 107 of 158), in an academic practice (57%, 90 of 158), with more than 15 years of experience (51%, 81 of 158). An overwhelming majority of respondents (98.1%, 155 of 158) considered smoking preoperatively a risk factor for postoperative complications. The most common cessation strategy offered to smokers was pharmacologic intervention (77%, 122 of 158). Nearly half of the surgeons (47%, 74 of 156) would not perform certain operations in a patient who was a current smoker, but only 14% (10 of 74) tested patients preoperatively for smoking. Thoracic surgeons (odds ratio 2.1, p = 0.0379) and surgeons in academic practice (odds ratio 1.9, p = 0.057) were more likely to deny certain surgeries to current smokers. Two thirds of the surgeons (66%, 48 of 74) thought that the ideal wait time from smoking cessation to surgery was 2 to 4 weeks. CONCLUSIONS: There is significant disagreement in the cardiothoracic surgical community regarding how to treat patients who smoke, especially when deciding to deny or postpone surgery. Prospective studies and guidelines are needed. PMID- 27474512 TI - Reduced respiratory neural activity elicits a long-lasting decrease in the CO2 threshold for apnea in anesthetized rats. AB - Two critical parameters that influence breathing stability are the levels of arterial pCO2 at which breathing ceases and subsequently resumes - termed the apneic and recruitment thresholds (AT and RT, respectively). Reduced respiratory neural activity elicits a chemoreflex-independent, long-lasting increase in phrenic burst amplitude, a form of plasticity known as inactivity-induced phrenic motor facilitation (iPMF). The physiological significance of iPMF is unknown. To determine if iPMF and neural apnea have long-lasting physiological effects on breathing, we tested the hypothesis that patterns of neural apnea that induce iPMF also elicit changes in the AT and RT. Phrenic nerve activity and end-tidal CO2 were recorded in urethane-anesthetized, ventilated rats to quantify phrenic nerve burst amplitude and the AT and RT before and after three patterns of neural apnea that differed in their duration and ability to elicit iPMF: brief intermittent neural apneas, a single brief "massed" neural apnea, or a prolonged neural apnea. Consistent with our hypothesis, we found that patterns of neural apnea that elicited iPMF also resulted in changes in the AT and RT. Specifically, intermittent neural apneas progressively decreased the AT with each subsequent neural apnea, which persisted for at least 60min. Similarly, a prolonged neural apnea elicited a long-lasting decrease in the AT. In both cases, the magnitude of the AT decrease was proportional to iPMF. In contrast, the RT was transiently decreased following prolonged neural apnea, and was not proportional to iPMF. No changes in the AT or RT were observed following a single brief neural apnea. Our results indicate that the AT and RT are differentially altered by neural apnea and suggest that specific patterns of neural apnea that elicit plasticity may stabilize breathing via a decrease in the AT. PMID- 27474515 TI - Neomensularia duplicata gen. et sp. nov. (Hymenochaetales, Basidiomycota) and two new combinations. AB - Neomensularia (Hymenochaetaceae) is a new genus introduced for N. duplicata sp. nov. (generic type), N. crocitincta and N. kanehirae combs. nov., based on a combination of distinct morphological characters and phylogenetic analyses inferred from nuc rDNA partial 28S and ITS datasets. The new genus is characterized by annual, pileate, brown to fuscous basidiocarps, duplex context, dimitic hyphal structure, ventricose, and hooked hymenial setae, golden yellow, thick-walled, smooth basidiospores that are negative in both Melzer's reagent and Cotton Blue and a growth habit in tropical forests. Neomensularia duplicata closely resembles Mensularia radiata by hooked hymenial setae, but M. radiata has a homogenous context, larger pores (5-7 per mm), monomitic hyphal structure, hyphoid setae, larger cyanophilic basidiospores and occurs in temperate forests. Central American specimens labeled as Inonotus crocitinctus and Asian specimens identified as Fulvifomes kanehirae were re-examined. The duplex context, hooked hymenial setae and colored basidiospores are similar to N. duplicata Phylogenetic inferences based on 28S and ITS sequence data confirm their affinities with N. duplicata and result in the proposal of new combinations, Neomensularia crocitincta and N. kanehirae. PMID- 27474516 TI - Lethal Amanita species in China. AB - Lethal amanitas (Amanita sect. Phalloideae) cause many casualties worldwide. Recent molecular phylogenetic studies revealed diverse lethal Amanita spp. in China. Here a 5-gene phylogeny (nuc rDNA region encompassing the internal transcribed spacers 1 and 2 with the 5.8S rDNA, the D1-D3 domains of nuc 28S rDNA, and partial RNA polymerase II second largest subunit, translation elongation factor 1-alpha and beta-tubulin genes) is used to investigate the phylogenetic lineages and species delimitation in this section. Thirteen species are recognized, including four new species, namely A. griseorosea, A. molliuscula, A. parviexitialis, and A. subfuliginea They are documented with morphological, multigene phylogenetic, and ecological evidence, line drawings, and photographs and compared with similar species. A key to the Chinese lethal Amanita species is provided. PMID- 27474517 TI - Two new species of Fomitiporia (Hymenochaetales, Basidiomycota) from Tibet, southwest China. AB - Two new species of Fomitiporia growing on Hippophae trees, F. norbulingka and F. subhippophaeicola, are described from southwest China based on morphological characters and phylogenetic analysis. Fomitiporia norbulingka is characterized by pileate basidiomata, mostly angular pores (6-9 per mm), slightly thick-walled generative hyphae, subglobose to globose basidiospores (6.5-7 * 5.5-7 MUm), and absence of cystidioles. Fomitiporia subhippophaeicola is diagnostic by effused reflexed to pileate basidiomata, angular pores (8-10 per mm), thick-walled generative hyphae, subglobose to obovoid basidiospores (6-8 * 5.5-7 MUm), and presence of ventricose to fusoid cystidioles. Phylogenetic analysis inferred from combined sequences including the nuc rDNA ITS1-5.8-ITS2 region, 28S rDNA D1-D2 domains, partial sequences of translation elongation factor 1-alpha, and RNA polymerase II second largest subunits genes indicated that F. norbulingka and F. subhippophaeicola represent two new lineages which group together with F. hippophaeicola. PMID- 27474518 TI - Morphological and molecular characterization, sexual reproduction, and pathogenicity of Setosphaeria rostrata isolates from rice leaf spot. AB - Setosphaeria rostrata, a common plant pathogen causing leaf spot disease, affects a wide range of plant species, mainly grasses. Fungi were isolated from brown spots on rice leaves throughout Peninsular Malaysia, and 45 isolates were identified as Setosphaeria rostrata The isolates were then characterized using morphological and molecular approaches. The mating type was determined using PCR amplification of the mating type alleles, and isolates of opposite mating types were crossed to examine sexual reproduction. Based on nuclear ribosomal DNA ITS1 5.8S-ITS2 region (ITS) and beta-tubulin (BT2) sequences, two phylogenetic trees were constructed using the maximum likelihood method; S. rostrata was clustered in one well-supported clade. Pathogenicity tests showed that S. rostrata isolates are pathogenic, suggesting that it is the cause of the symptoms. Mating-type analyses indicated that three isolates carried the MAT1-1 allele, and the other 42 isolates carried MAT1-2 After isolates with opposite mating types were crossed on Sach's medium and incubated for 3 wk, six crosses produced pseudothecia that contained eight mature ascospores, and 12 other crosses produced numerous pseudothecia with no ascospores. To our knowledge, this is the first report on S. rostrata isolated from leaf spots on rice. PMID- 27474519 TI - Multilocus, DNA-based phylogenetic analyses reveal three new species lineages in the Phellinus gabonensis-P. caribaeo-quercicola species complex, including P. amazonicus sp. nov. AB - Species complexes in the poroid Hymenochaetaceae are well documented in the temperate areas. Potential species complexes are less known in tropical areas, however. In the last ten years, four phylogenetically and morphologically closely related species of Phellinus (Hymenochaetaceae) were described from various tropical/subtropical areas viz. P. caribaeo-quercicola, P. gabonensis, P. ellipsoideus, and P. castanopsidis They are characterized by cushion-shaped basidiomata, ventricose, commonly hamate hymenial setae, and broadly ellipsoid, thick-walled, pale yellowish basidiospores. Pursuing the studies of this complex, a phylogenetic approach based on DNA sequence data from the nuc rDNA regions ITS1 5.8S-ITS2 (ITS) and partial 28S (including the domains D1, D2, D3) and on part of the translation elongation factor 1-alpha (tef1, region between exons 4 and 8) revealed three new lineages or phylogenetic species. Two of these phylogenetic species are composed of exclusively on Neotropical specimens. One of them, described below as Phellinus amazonicus sp. nov., is represented by multiple collections originating from Neotropical, lowland, dense, moist forest at the western edge of the Amazon Basin in Ecuador, the Guiana Shield in French Guiana and (more likely) Trinidad. The second Neotropical phylogenetic species is represented in our phylogenetic analyses by a single collection from northeastern Argentina. It is also potentially known from two herbarium specimens originating from southern Brazil, for which no sequence data is available. It is left for now as Phellinus sp. 1, waiting to gather more specimens and DNA sequences data. The third new phylogenetic species is known by a single collection (pure culture) of uncertain origin. It is thought to represent Phellinus setulosus, a Southeast Asian taxa. From an evolutionary perspective, tree species occurring in the Neotropics (P. amazonicus, P. caribaeo-quercicola, and Phellinus sp. 1) have a closely related genetic background and form a well supported Neotropical lineage. PMID- 27474520 TI - Fusarium agapanthi sp. nov., a novel bikaverin and fusarubin-producing leaf and stem spot pathogen of Agapanthus praecox (African lily) from Australia and Italy. AB - This study was conducted to characterize a novel Fusarium species that caused leaf and stem spot on Agapanthus praecox (Agapanthus, African lily) in northern Italy and leaf rot and spot on the same host in Melbourne, Australia. Formally described as Fusarium agapanthi, this pathogen was analyzed using phenotypic, phytopathogenic, secondary metabolite, molecular phylogenetic and genomic data. Five strains were characterized, including one isolated in 1999 from symptomatic A. praecox in Saluzzo, Italy, and four in 2010 from diseased leaf tissue from the same host exhibiting leaf rot and spot symptoms in the Melbourne Gardens, Royal Botanic Gardens Victoria, Australia. Maximum parsimony and maximum likelihood molecular phylogenetic analyses of portions of six individual genes and the combined dataset all strongly supported F. agapanthi either as the earliest diverging genealogically exclusive lineage in the American Clade of the F. fujikuroi species complex, or alternatively a novel monotypic lineage sister to the American Clade. Koch's postulates were completed on dwarf blue- and large white-flowering varieties of A. praecox, where two isolates of F. agapanthi produced slowly spreading necrotic lesions when inoculated onto leaves and flower stems. Fusarium agapanthi is distinguished from other fusaria by the production of densely branched aerial conidiophores with polyphialides throughout the aerial mycelium on synthetic nutrient-poor agar. BLASTn searches of the F. agapanthi NRRL 31653 and NRRL 54464 (= VPRI 41787) genome sequences were conducted to predict sexual reproductive mode and mycotoxin potential. Results indicated that they possessed MAT1-2 and MAT1-1 idiomorphs, respectively, indicating that this species might be heterothallic. Furthermore, based on the presence of homologs of the bikaverin and fusarubin biosynthetic gene clusters in the F. agapanthi genomes, liquid chromatography-mass spectrometry analysis was conducted and confirmed production of these secondary metabolites in rice and corn kernel cultures of the fungus. PMID- 27474521 TI - Striatal activation as a neural link between cognitive and perceptual flexibility. AB - Our brain continuously evaluates different perceptual interpretations of the available sensory data in order to enable flexible updates of conscious experience. Individuals' perceptual flexibility can be assessed using ambiguous stimuli that cause our perception to continuously switch between two mutually exclusive interpretations. Neural processes underlying perceptual switching are thought to involve the visual cortex, but also non-sensory brain circuits that have been implicated in cognitive processes, such as frontal and parietal regions. Perceptual flexibility varies strongly between individuals and has been related to dopaminergic neurotransmission. Likewise, there is also considerable individual variability in tasks that require flexibility in cognition, and dopamine-dependent striato-frontal signals have been associated with processes promoting cognitive flexibility. Given the anatomical and neurochemical similarities with regard to perceptual and cognitive flexibility, we here probed whether individual differences in perceptual flexibility during bistable perception are related to individual cognitive flexibility associated neural correlates. 126 healthy individuals performed rule-based task switching during functional magnetic resonance imaging (fMRI) and reported perceptual switching during the viewing of a modified version of the Necker cube. Mean phase duration as measure of perceptual flexibility correlated with task-switching associated activity in the right putamen as part of the basal ganglia. In addition, we found a tentative correlation between perceptual and cognitive flexibility. These results indicate that individual differences in cognitive flexibility and associated fronto-striatal processing contribute to differences in perceptual flexibility. Our findings thus provide empirical support for the general notion of shared mechanisms between perception and cognition. PMID- 27474522 TI - A depression network of functionally connected regions discovered via multi attribute canonical correlation graphs. AB - To establish brain network properties associated with major depressive disorder (MDD) using resting-state functional magnetic resonance imaging (Rs-fMRI) data, we develop a multi-attribute graph model to construct a region-level functional connectivity network that uses all voxel level information. For each region pair, we define the strength of the connectivity as the kernel canonical correlation coefficient between voxels in the two regions; and we develop a permutation test to assess the statistical significance. We also construct a network based classifier for making predictions on the risk of MDD. We apply our method to Rs fMRI data from 20 MDD patients and 20 healthy control subjects in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Using this method, MDD patients can be distinguished from healthy control subjects based on significant differences in the strength of regional connectivity. We also demonstrate the performance of the proposed method using simulationstudies. PMID- 27474523 TI - Neural representations of magnitude for natural and rational numbers. AB - Humans have developed multiple symbolic representations for numbers, including natural numbers (positive integers) as well as rational numbers (both fractions and decimals). Despite a considerable body of behavioral and neuroimaging research, it is currently unknown whether different notations map onto a single, fully abstract, magnitude code, or whether separate representations exist for specific number types (e.g., natural versus rational) or number representations (e.g., base-10 versus fractions). We address this question by comparing brain metabolic response during a magnitude comparison task involving (on different trials) integers, decimals, and fractions. Univariate and multivariate analyses revealed that the strength and pattern of activation for fractions differed systematically, within the intraparietal sulcus, from that of both decimals and integers, while the latter two number representations appeared virtually indistinguishable. These results demonstrate that the two major notations formats for rational numbers, fractions and decimals, evoke distinct neural representations of magnitude, with decimals representations being more closely linked to those of integers than to those of magnitude-equivalent fractions. Our findings thus suggest that number representation (base-10 versus fractions) is an important organizational principle for the neural substrate underlying mathematical cognition. PMID- 27474524 TI - Corrigendum to "Infrared imaging of calcified tissue in bone biopsies from adults with osteomalacia" [Bone 36(1) (Jan 2005): 6-12]. PMID- 27474525 TI - Genomic approaches to diagnose rare bone disorders. AB - Skeletal dysplasias are Mendelian disorders with a prevalence of approximatively 1 in every 5000 individuals and can usually be diagnosed based on clinical and radiological findings. However, given that some diseases can be caused by several different genes, and that some genes can cause a variety of different phenotypes, achieving a molecular diagnosis can be challenging. We review here different approaches, from single gene sequencing to genomic approaches using next generation sequencing, to reach a molecular diagnosis for skeletal dysplasias. We will further describe the overall advantages and limitations of first, second and third-generation sequencing, including single gene sequencing, whole-exome and genome sequencing (WES and WGS), multiple gene panel sequencing and single molecule sequencing. We also provide a brief overview of potential future applications of emerging technologies. PMID- 27474526 TI - The Role of Community Health Workers in Preventing Adolescent Repeat Pregnancies and Births. AB - Intervention by community health workers (CHWs) is believed to prevent repeated childbearing among teenagers. This review investigated the effectiveness of CHWs in reducing repeated pregnancies and births among adolescents aged <20 years, 2 years after the delivery of their first child. Through electronic database and hand searching, experimental and/or observational studies were screened with their results undergoing systematic review and meta-analyses. Subgroup analyses were performed to further assess how study characteristics affected the pooled estimates and heterogeneity. A total of 11 eligible articles, from January 1980 to May 2015, were included. Seven studies evaluated repeated births and eight measured repeated pregnancies. Studies showed relevant disparities in terms of selected methodological aspects and program characteristics. Although most studies (n = 9) were either of "strong" or of "moderate" quality, only two of five finding a significant reduction exhibited a high level of quality as the other three failed to adjust results for confounders. Random effects modeling revealed an overall 30% decrease in repeated adolescent births (odds ratio = .70, confidence interval = .49-.99) among CHW-visited areas relative to nonvisited sites. On the other hand, no significant association was detected in terms of repeated pregnancies (odds ratio = .96, confidence interval = .70-1.28). PMID- 27474527 TI - [Ambulatory blood pressure monitoring is a useful tool for all patients]. AB - Clinical blood pressure measurement (BP) is an occasional and imperfect way of estimating this biological variable. Ambulatory blood pressure monitoring (ABPM) is by far the best clinical tool for measuring an individual's blood pressure. Mean values over 24h, through the daytime and at night all make it more possible to predict organic damage and the future development of the disorder. ABPM enables the detection of white-coat hypertension and masked hypertension in both the diagnosis and follow-up of treated patients. Although some of the advantages of ABPM can be reproduced by more automated measurement without the presence of an observer in the clinic or self-measurement at home, there are some other elements of great interest that are unique to ABPM, such as seeing what happens to a patient's BP at night, the night time dipping pattern and short-term variability, all of which relate equally to the patient's prognosis. There is no scientific or clinical justification for denying these advantages, and ABPM should form part of the evaluation and follow-up of practically all hypertensive patients. Rather than continuing unhelpful discussions as to its availability and acceptability, we should concentrate our efforts on ensuring its universal availability and clearly explaining its advantages to both doctors and patients. PMID- 27474529 TI - Host-Bacterial Crosstalk Determines Staphylococcus aureus Nasal Colonization. AB - Staphylococcus aureus persistently colonizes the anterior nares of approximately one fifth of the population and nasal carriage is a significant risk factor for infection. Recent advances have significantly refined our understanding of S. aureus-host communication during nasal colonization. Novel bacterial adherence mechanisms in the nasal epithelium have been identified, and novel roles for both the innate and the adaptive immune response in controlling S. aureus nasal colonization have been defined, through the use of both human and rodent models. It is clear that S. aureus maintains a unique, complex relationship with the host immune system and that S. aureus nasal colonization is overall a multifactorial process which is as yet incompletely understood. PMID- 27474530 TI - [From new genetic and histological classifications to direct treatment]. AB - The most important criterion for optimal cancer treatment is a correct classification of the tumour. During the last three years, several very important progresses have been made with a better definition of urothelial carcinoma (UC), especially from a molecular point of view. We start having a global understanding of UC, although many details are still not completely understood. PMID- 27474531 TI - [Solitary fibrous tumors and hemangiopericytomas of the meninges: Immunophenotype and histoprognosis in a series of 17 cases]. AB - INTRODUCTION: The 2007 World Health Organization (WHO) classification of tumors of the central nervous system distinguishes meningeal hemangiopericytomas (HPC) from solitary fibrous tumors (TFS). In the WHO classification of tumors of soft tissue and bone, those neoplasms are no longer separate entities since the discovery in 2013 of a common oncogenic event, i.e. the NAB2-STAT6 gene fusion. A shared histopronostic grading system, called "Marseille grading system", was recently proposed, based on hypercellularity, mitotic count and necrosis. We evaluated the immunophenotype and histoprognosis in a retrospective cohort of intracranial HPC and TFS. METHODS: Fifteen initial tumors and 2 recurrences were evaluated by immunohistochemistry for STAT6, CD34, EMA, progesterone receptors and Ki67. The pronostic value of the WHO and the Marseille grading systems was tested on 12 patients with clinical follow-up. RESULTS: Initial tumors were 11 HPC and 4 SFT. STAT6 and CD34 were expressed in 16/17 tumors, EMA and progesterone receptors in 2 and 5 cases, respectively. The Ki67 labelling index was 6.25% in HPC and 3% in SFT. Half of the tumors recurred between 2 years and 9 years after initial diagnosis (mean time 5 years). No statistical difference in the risk of recurrence was associated with either grade (WHO or Marseille), in this small cohort. CONCLUSION: The diagnosis of HPC and TFS is facilitated by the almost constant immuno-expression of STAT6, and this justifies their common classification. The high rate of recurrence implies a very long-term follow-up because the current grading systems do not accurately predict the individual risk. PMID- 27474532 TI - [Authorization of pathologists for the estimation of the tumor cell percentage on tissue sample for molecular analysis purpose]. AB - Before molecular analysis is performed, morphological control with an estimation of the tumour cell percentage (%TC) could have a major impact on mutation detection. Accreditation according to NF EN ISO 15189 commands an authorization through evaluation of skills. The objective of this work was to validate the empowerment of pathologists to estimate %TC in tissue sample prior to molecular analysis. The accreditation technical guidance methods in Medical biology and histopathology were taken as references. %TC was the ratio of tumour cell nuclei on all nuclei within the area selected for the DNA extraction. External evaluations quality scores were used for accuracy. In order to assess the intermediate precision, 35 %TC estimation were performed 15 days apart in 4 samples (biopsies, transparietal biopsies or surgical specimen, either fixed or frozen) by 7 pathologists. Three other cases with interference (inflammation, mucus, necrosis) were evaluated. A result was satisfactory if %TC were within +/ 20 % of expected percentage obtained by the average of 35 estimates. The performances were satisfactory since no estimate was made more than 20 % of the expected percentage. Low interpathologists reproducibility has been reported in the literature and can have a consequence on molecular analysis in samples with low %TC, where the value reach the analytical sensitivity thresholds of molecular techniques. The current report is an example of a step of the accreditation process, which is a challenge for pathologists' activity in the future. PMID- 27474533 TI - [Multicystic lesion of the peritoneum in a child]. PMID- 27474534 TI - [An unusual cause of primary hyperparathyroidism]. PMID- 27474535 TI - [Fusiform cells renal tumor in a nineteen-year-old man]. PMID- 27474536 TI - Side effects from intense pulsed light: Importance of skin pigmentation, fluence level and ultraviolet radiation-A randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: Intense pulsed light (IPL) is a mainstream treatment for hair removal. Side effects after IPL are known, but risk factors remain to be investigated. The objective of this study was to assess the contribution of skin pigmentation, fluence level, and ultraviolet radiation (UVR) on IPL-induced side effects. METHODS: The study was a blinded, randomized intra-individual controlled trial including 16 healthy subjects with Fitzpatrick Skin Types (FST) II-V. Three test areas were each divided into four sites, randomized to a single IPL exposure of 22, 34, 46 J/cm2 or triple stacking of 46 J/cm2 . Areas were subsequently randomized to no UVR or single solar-simulated UVR exposure of 3 Standard Erythema Dose at 30 minutes or 24 hours after IPL. Each area had a corresponding control, resulting in 15 treatment sites. Follow-up visits were scheduled up to 4 weeks after IPL. Outcome measures were: (i) blinded clinical skin reactions; (ii) objectively measured erythema and pigmentation; (iii) pain measured by visual analog scale (VAS); (iv) histology (H&E, Fontana-Masson); and (v) mRNA-expression of p53. RESULTS: Fifteen subjects with FST II-IV completed the protocol. IPL induced a wide range of skin reactions, including erythema (87% of subjects), purpura (27%), blisters (20%), edema (13%), crusting (13%), hyper- (60%), and hypopigmentation (20%). Darker skin pigmentation and increasing IPL fluence were determinants for IPL-induced side effects (P <= 0.002), while a single exposure of UVR did not exacerbate side effects (P >= 0.180). Clinical findings were confirmed objectively by reflectance spectrometry and qualitatively by histological changes in skin architecture, inflammatory infiltration, and pigmentation. Marker of cellular DNA damage, that is, p53, did not increase after IPL (P >= 0.24). CONCLUSIONS: Skin pigmentation and IPL fluence are major determinants of side effects after IPL exposure, while a single exposure to three SED of UVR at 30 minutes or 24 hours after IPL, does not amplify such side effects. Lasers Surg. Med. 49:88-96, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27474537 TI - Preparation of cellulose nanocrystals from asparagus (Asparagus officinalis L.) and their applications to palm oil/water Pickering emulsion. AB - Nano cellulosic materials as promising emulsion stabilizers have attracted great interest in food industry. In this paper, five different sized cellulose nanocrystals (CNC) samples were prepared from stem of Asparagus officinalis L. using the same sulfuric acid hydrolysis conditions but different times (1.5, 2, 2.5, 3.0, and 3.5h). The sizes of these CNC ranged from 178.2 to 261.8nm, with their crystallinity of 72.4-77.2%. The CNC aqueous dispersions showed a typical shear thinning behavior. In a palm oil/water (30/70, v/v) model solution, stable Pickering emulsions were formed with the addition of CNC, and their sizes are in the range of 1-10MUm based on the optical and confocal laser scanning microscopy (CLSM) observation. The CNC sample prepared at 3h hydrolysis time, showed a relative efficient emulsion capacity for palm oil droplets, among these CNCs. Other parameters including the CNC, salt, and casein concentrations on the emulsion stability were studied. PMID- 27474538 TI - Enhancement of Egyptian soft white cheese shelf life using a novel chitosan/carboxymethyl cellulose/zinc oxide bionanocomposite film. AB - A novel bionanocomposites packaging material prepared using chitosan (CH), carboxymethyl cellulose (CMC), and zinc oxide nanoparticles (ZnO-NPs), namely CH/CMC/ZnO bionanocomposites, was prepared by casting method. The CH/CMC/ZnO bionanocomposites were investigated using FT-IR, TEM, SEM, XRD, and TGA. The acquired bionanocomposites exhibited improved mechanical and thermal properties compare with the biocomposites (CH/CMC) blend. The soft white cheese were manufactured, packaged within the prepared bionanocomposites films and stored at 7 degrees C for 30days. The influence of packaging material on packaged cheese (rheological properties, colour measurements, moisture, pH and titratable acidity) were assessed. Furthermore, the effect of packaging material on the total bacterial counts, mold & yeast and coliform in cheese was evaluated. The prepared bionanocomposites displayed good antibacterial activity against gram positive (Staphylococcus aureus), gram negative (Pseudomonas aeruginosa, Escherichia coli) bacteria and fungi (Candidia albicans). Moreover, the packaging films assisted in increasing the shelf life of white soft cheese. Therefore, it can be used in food packaging applications. PMID- 27474539 TI - Comparison of Co(2+) adsorption by chitosan and its triethylene-tetramine derivative: Performance and mechanism. AB - A cross-linked chitosan derivative (CCTS) was synthesized via cross-linking of epichlorohydrin and grafting of triethylene-tetramine. The adsorption performance and capacity of the raw chitosan (CTS) and its derivative were also investigated for removal of Co(2+) from aqueous solution. A maximum adsorbed amount of 30.45 and 59.51mg/g was obtained for CTS and CCTS, respectively under the optimized conditions. In addition, the adsorption kinetics for the adsorption of Co(2+) by CTS and CCTS were better described by the pseudo second-order equation. The adsorption isotherm of CCTS was well fitted by the Langmuir equation, but the data of the adsorption of Co(2+) onto CTS followed Freundlich and Sips isotherms better. Furthermore, the adsorbent still exhibited good adsorption performance after five regeneration cycles. Finally, Co(2+) removal mechanisms, including physical, chemical, and electrostatic adsorption, were discussed based on microstructure analysis and adsorption kinetics and isotherms. Chemical adsorption was the main adsorption method among these mechanisms. PMID- 27474540 TI - Structural basis for the roles of starch and sucrose in homo-exopolysaccharide formation by Lactobacillus reuteri 35-5. AB - Lactic acid bacteria (LAB) produce exopolysaccharides (EPS) that are important for biofilm formation in the mammalian oral cavity and gastrointestinal tract. Sucrose is a well-known substrate for homo-EPS formation by Lactobacillus reuteri glucansucrases (GS). Starch is the main fermentable carbohydrate in the human diet, and often consumed simultaneously with sucrose. Recently we have characterized L. reuteri strains that also possess 4,6-alpha-glucanotransferases (4,6-alpha-GTases) that act on starch yielding isomalto-/malto-polysaccharides. In this study we have characterized the EPS formed by L. reuteri 35-5 cells and enzymes from sucrose plus starch. The data show that both in vivo and in vitro the L. reuteri 35-5 GS and 4,6-alpha-GTase enzymes, incubated with sucrose plus starch, cross-react and contribute to synthesis of the final hybrid EPS products. This may have strong effects on the EPS functional properties, influence biofilm formation, and affect the relationship between dietary intake of sucrose and starch, and dental caries formation. PMID- 27474541 TI - Enhancing bio-availability of beta-naphthoflavone by supramolecular complexation with 6,6'-thiobis(methylene)-beta-cyclodextrin dimer. AB - The aryl hydrocarbon receptor (AhR) is a ligand activated transcriptional regulator, which governs key biological processes including detoxification of carcinogens. beta-Naphthoflavone (beta-NF) is a non-toxic flavonoid, and a potent AhR agonist. Thus, beta-NF can induce the representative detoxifying enzyme cytochrome P4501A1, thereby enhancing the detoxification potential. However, its low water solubility hampers the use. We found that supramolecular complexation of beta-NF with the synthetic 6,6'-thiobis(methylene)-beta-cyclodextrin (beta-CD S) dimer significantly enhanced beta-NF's role as an AhR agonist. The water solubility of beta-NF was increased to 469 fold by effective supramolecular complexation with the beta-CD-S dimer, and caused significant induction of cytochrome P4501A1. Stable formation of the supramolecular complex of beta-NF with beta-CD-S-dimer was verified by various analyses. In summary, supramolecular complexation of beta-NF with beta-CD-S dimer greatly enhanced bio-availability of beta-NF as an AhR agonist. Our findings provide an easy, non-destructive, and alternative approach to enhance the bio-availability of therapeutics. PMID- 27474542 TI - Low anticoagulant heparin oligosaccharides as inhibitors of BACE-1, the Alzheimer's beta-secretase. AB - Heparin (HP) is a promising agent for anti-Alzheimer's disease (AD), but its anticoagulant activity limits its applications. So a low anticoagulant heparin (LAH) with anti-AD effect is needed. A novel LAH and heparan sulfate (HS) were purified from crude porcine intestinal heparin. Their structures were characterized by nuclear magnetic resonance and liquid chromatography-mass spectrometry. LAH had a relatively high degree of sulfation, but lower than that of HP. 3-O-Sulfated-containing glucosamine residues further confirmed the low anticoagulant activity of LAH. Sixteen oligosaccharides of LAH and HS were prepared and assigned. Evaluation of anti-BACE-1 activities suggested that their potencies were positively correlated with degree of sulfation and polymerization of oligosaccharides. Besides, LAH-derived hexa- to dodecasaccharides was promised to be administrated in vitro as BACE-1 inhibitors. This study presented ideal BACE-1 inhibitors, LAH-derived oligosaccharides, with virtually no anticoagulant activities, which were promised to be excellent leads for treatment of AD. PMID- 27474543 TI - Crosslinking of agarose bioplastic using citric acid. AB - We report chemical crosslinking of agarose bioplastic using citric acid. Crosslinking was confirmed using Fourier transform infrared (FTIR) spectroscopy. The effects of crosslinking on the tensile strength, swelling, thermal stability, and degradability of the bioplastic were studied in detail. The tensile strength of the bioplastic films increased from 25.1MPa for control films up to a maximum of 52.7MPa for citric acid crosslinked films. At 37 degrees C, the amount of water absorbed by crosslinked agarose bioplastic was only 11.5% of the amount absorbed by non-crosslinked controls. Thermogravimetric results showed that the crosslinked samples retain greater mass at high temperature (>450 degrees C) than control samples. Moreover, while the crosslinked films were completely degradable, the rate of degradation was lower compared to non-crosslinked controls. PMID- 27474544 TI - Polyethylene glycol-conjugated chondroitin sulfate A derivative nanoparticles for tumor-targeted delivery of anticancer drugs. AB - Polyethylene glycol (PEG)-decorated chondroitin sulfate A-deoxycholic acid (CSD) nanoparticles (NPs) were fabricated for the selective delivery of doxorubicin (DOX) to ovarian cancer. CSD-PEG was synthesized via amide bond formation between the NH2 group of methoxypolyethylene glycol amine and the COOH group of CSD. CSD PEG/DOX NPs with a 247nm mean diameter, negative zeta potential, and >90% drug encapsulation efficiency were prepared. Sustained and pH-dependent DOX release profiles from CSD-PEG NPs were observed in dissolution tests. Endocytosis of NPs by SKOV-3 cells (CD44 receptor-positive human ovarian cancer cells), based on the CSA-CD44 receptor interaction, was determined by flow cytometry and confocal laser scanning microscopy (CLSM) studies. PEGylation of NPs also resulted in reduced drug clearance (CL) in vivo and improved relative bioavailability, compared to non-PEGylated NPs, as determined by the pharmacokinetic study performed after intravenous administration in rats. Developed CSD-PEG NPs can be a promising delivery vehicle for the therapy of CD44 receptor-expressing ovarian cancers. PMID- 27474545 TI - Enzymatic cross-linking of carboxymethylpullulan grafted with ferulic acid. AB - Carboxymethylpullulan (CMP) has been modified in a two-step grafting reaction of ferulic acid (FA). Acid adipic dihydrazyde (ADH) was first reacted with FA activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). Then the product of this first reaction was reacted with CMP (activated with EDC). Grafted polysaccharides structure was confirmed by FTIR and (1)H NMR spectroscopy. Analyses by size-exclusion chromatography (SEC) coupling on-line with a multi-angle light scattering detector (MALS), a viscometer and a differential refractive index detector (DRI) (SEC/MALS/DRI/Visco) showed that associations between FA moieties occurred due to hydrophobic interactions. The grafting rates of FA were determined by the Folin-Ciocalteu method and were found between 1.0% and 11.2% (mol/mol anhydroglucose unit). The CMP-FA were then enzymatically cross-linked with laccase from Pleurotus ostreatus. The crosslinking reactions were followed by rheological measurements, demonstrating the influence of laccase concentration on kinetics. Elastic modulus and swelling rates of hydrogels depends on FA content only for low values. PMID- 27474546 TI - A versatile pathway to end-functionalized cellulose ethers for click chemistry applications. AB - This paper describes a versatile pathway to heterobifunctional/telechelic cellulose ethers, such as tri-O-methyl cellulosyl azide and propargyl tri-O methyl celluloside, having one free C-4 hydroxyl group attached to the glucosyl residue at the non-reducing end for the use in Huisgen 1,3-dipolar cycloaddition and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The one-step end functionalization of cellulose ethers for molecular rod synthesis involves the introduction of two reactive groups at both ends of the cellulose molecule, and can afford linear triblock copolymers via CuAAC and further reactions. We were able to tailor the degree of polymerization of end-functionalized cellulose ethers with controlled amounts of a Lewis acid, namely SnCl4. Chemical structures of the above cellulose ethers and the reaction conditions for controlling molecular length are discussed. PMID- 27474547 TI - Advancement in conductive cotton fabrics through in situ polymerization of polypyrrole-nanocellulose composites. AB - Current research was undertaking with a view to innovate a new approach for development of conductive - coated textile materials through coating cotton fabrics with nanocellulose/polypyrrole composites. The study was designed in order to have a clear understanding of the role of nanocellulose as well as modified composite thereof under investigation. It is anticipated that incorporation of nanocellulose in the pyrrole/cotton fabrics/FeCl3/H2O system would form an integral part of the composites with mechanical, electrical or both properties. Three different nanocellulosic substrates are involved in the oxidation polymerization reaction of polypyrrole (Ppy) in presence of cotton fabrics. Polymerization was subsequently carried out by admixing at various ratios of FeCl3 and pyrrole viz. Ppy1, Ppy2 and pp3. The conductive, mechanical and thermal properties of cotton fabrics coated independently with different nanocellulose/polypyrrole were investigated. FTIR, TGA, XRD, SEM and EDX were also used for further characterization. Results signify that, the conductivity of cotton fabrics increases exponentially with increasing the dose of pyrrole and oxidant irrespective of nanocellulose substrate used. While, the mechanical properties of cotton fabrics are not significantly affected by the oxidant treatment. PMID- 27474548 TI - Mechanical and barrier properties of starch-based films plasticized with two- or three component deep eutectic solvents. AB - The aim of this work was to prepare two- and three-components deep eutectic solvents (DES) and investigate their potential as starch plasticizers. Starch/DES films were prepared via casting method. Mechanical properties, water vapor- and oxygen transmission rates were measured; additionally contact angle and moisture sorption were determined and FTIR analysis was applied on the films. Native potato starch and hydroxypropylated and oxidized starch (HOPS) with common plasticizers (e.g. polyols, urea) and DES were studied. Moreover, influence of three methods of DES introduction and concentration of plasticizer on the films properties were compared. HOPS films were prepared by two methods: as non-cured and cured samples. Some of DESs containing citrate anion exhibited crosslinking ability of polysaccharide matrix. Non-cured HOPS/DES films exhibited more favourable mechanical and barrier properties than cured analogue films. Samples prepared with unmodified potato starch had higher mechanical and barrier properties than films made with HOPS. Starch-based films plasticized with novel DESs with parallel crosslinking activity exhibited satisfactory mechanical and barrier properties. PMID- 27474549 TI - Freeze-thaw stability of rice starch modified by Improved Extrusion Cooking Technology. AB - This study aimed to explore freeze-thaw (FT) stability of rice starch modified by Improved Extrusion Cooking Technology (IECT). FT stability of IECT-modified rice starch was investigated and compared with native one. Syneresis and SEM analysis showed that IECT-modified rice starch had better FT stability than native starch. Furthermore, IECT-modified rice starch had less significant changes in the rheological parameters during the FT cycles than the native starch. XRD and iodine binding analysis demonstrated that IECT treatment inhibited the association of rice starch, especially amylose retrogradation. Additionally, the peak at around 20 degrees was detected in XRD patterns of IECT-modified rice starch, which confirmed the formation of amylose-lipid complex during the IECT treatment. These results suggested that the IECT treatment could improve FT stability of rice starch, which was ascribed to inhibition of starch retrogradation by IECT. PMID- 27474550 TI - Viscoelastic characteristics of all cellulose suspension and nanocomposite. AB - We prepared cellulose nanocrystal (CNC)/carboxymethyl cellulose (CMC) suspensions and nanocomposites and carried out rheological analysis of the all-cellulose samples. Morphological observation of the prepared CNCs was conducted using transmission electron microscopy (TEM) and atomic force microscopy (AFM). The electrokinetic characteristic of the CNCs was evaluated from zeta potential measurement. A simple shear test, an oscillatory shear test, and dynamic mechanical analysis (DMA) were carried out, and their results were compared. The findings revealed that the greater shear-thinning behavior and more solid-like rheological behavior were observed with an increase in the content of CNCs embedded in both the suspensions and nanocomposites. In addition, the viscoelastic properties acquired in different experimental modes (i.e., shear and extension) were compared from a rheological perspective. PMID- 27474551 TI - Preparation of copper-chelate quaternized carboxymethyl chitosan/organic rectorite nanocomposites for algae inhibition. AB - Quaternized carboxymethyl chitosan/organic rectorite (QCMC/OREC) nanocomposites were rapidly prepared by intercalating QCMC into the layer of OREC under microwave irradiation. And then copper-chelate QCMC/OREC (QCMC/OREC-Cu) nanocomposites were obtained by mixing QCMC/OREC with CuSO4 solution. XRD and TEM results indicated that QCMC/OREC nanocomposites were obtained and QCMC was dispersed in the interlayer of OREC. Besides, FT-IR results revealed that the hydrogen bonds and electrostatic interaction in QCMC/OREC-Cu were both stronger than those in QCMC/OREC because of introducing the Cu(2+). The thermogravimetric analysis showed that the thermal stability of QCMC/OREC-Cu nanocomposites was higher than QCMC and QCMC/OREC. Algae inhibition assay revealed that QCMC/OREC-Cu nanocomposites had stronger antifouling activity than original QCMC and QCMC/OREC. This work provides important basis for developing novel antifouling materials. PMID- 27474552 TI - Chitosan based polymer matrix with silver nanoparticles decorated multiwalled carbon nanotubes for catalytic reduction of 4-nitrophenol. AB - A novel catalyst for the reduction of 4-nitrophenol (4-NP) was prepared using carboxyl group-functionalized multiwalled carbon nanotubes (MWCNTs), polymer matrix, and silver nanoparticles (AgNPs). The AgNPs were prepared by the reduction of silver nitrate by trisodium citrate in the MWCNTs-polymer nanocomposite; the size of the synthesized AgNPs was found to be 3nm (average diameter). The synthesized nanocomposites were characterized using several analytical techniques. Ag@MWCNTs-polymer composite in the presence of sodium borohydride (NaBH4) in aqueous solution is an effective catalyst for the reduction of 4-NP. The apparent kinetics of reduction has a pseudo-first-order kinetics, and the rate constant and catalytic activity parameter were found to be respectively 7.88*10(-3)s(-1)and 11.64s(-1)g(-1). The MWCNTs-polymer nanocomposite renders stability to AgNPs against the environment and the reaction medium, which means that the Ag@MWCNTs-polymer composite can be re-used for many catalytic cycles. PMID- 27474553 TI - Rheological investigation of specific interactions in Na Alginate and Na MMT suspension. AB - Here we report on a study of a rheological behavior of sodium alginate and montmorillonite suspension. We find that viscoelastic behavior of this suspension is dramatically affected with increasing volume fraction of montmorillonite platelets. Addition of montmorillonite generally leads to gel formation, which is attributed to interactions of montmorillonite and alginate via H-bonding and attraction between the positive edges of the platelets and the anionic backbone of the biopolymer. A critical concentration for the measured system was observed at 20wt.% montmorillonite, where a crossover to a gel-like structure was detected. The observed gel has a rubber plateau, which develops further with higher montmorillonite concentration. In this physical gel the relaxation maximum was detected, which is associated with the breaking and reformation of the bonds between the platelets and the biopolymer. For this transient behavior, we find that a Maxwell type viscoelasticity quite well describes the relaxation time and the observed G'-G" crossover. We believe that this gel-like behavior plays an important role in formation of highly ordered nanostructures that develop during the drying of these bio-nanocomposite suspensions. PMID- 27474554 TI - Biodegradability and plasticizing effect of yerba mate extract on cassava starch edible films. AB - Biodegradable and edible cassava starch-glycerol based films with different concentrations of yerba mate extract (0, 5 and 20wt.%) were prepared by casting. The plasticizing effect of yerba mate extract when it was incorporated into the matrix as an antioxidant was investigated. Thermal degradation and biodegradability of the obtained biofilms were also studied. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflectance Fourier transform infrared spectroscopy (ATR/FTIR), X-ray diffraction analysis (XRD), water absorbance, stability in different solutions and biodegradability studies were performed. The clear correlation among the results obtained from the different analysis confirmed the plasticizing effect of yerba mate extract on the starch-glycerol matrix. Also, the extract led to a decrease in the degradation time of the films in soil ensuring their complete biodegradability before two weeks and to films stability in acidic and alkaline media. The plasticizing effect of yerba mate extract makes it an attractive additive for starch films which will be used as packaging or coating; and its contribution to an earlier biodegradability will contribute to waste reduction. PMID- 27474555 TI - Porphyrin dye into biopolymeric chitosan films for localized photodynamic therapy of cancer. AB - Porphyrins and some of its derivatives are well known and widely used as photosensitizers (PSs) for Photodynamic Therapy of Cancer (PDT). The present study regards the characterization and evaluation of a synthesized asymmetric porphyrin dye in solution to be used as PS for PDT. This molecule was also incorporated into biopolymeric films composed by chitosan, polyethylene glycol (PEG) and gelatin in order to overtake some of the disadvantages inherent to the PS, but more important, to evaluate the potential of a system composed by the porphyrin/biopolymer to be applied as localized therapeutic agents. FTIR spectroscopy showed a strong interaction between the polymers involved in the preparation of the films under study: film 1: chitosan, film 2: chitosan/PEG and film 3: chitosan/gelatin. Photochemical studies were performed for the dye in solution and into the three different biopolymeric films. Ground state absorption showed the characteristic bands of these kinds of dyes in solution and also incorporated into the films. The films composed by porphyrin/chitosan and porphyrin into chitosan/gelatin, revealed the presence of non-emissive aggregates exhibiting a strong quenching effect in the fluorescence intensity, quantum yields and lifetimes. In this way, the system composed by the porphyrin incorporated into the chitosan/PEG film presents the best fluorescence quantum yield and lifetime. The transient absorption spectra were obtained for all the systems indicating the formation of an excited triplet state of the porphyrins following excitation, which takes special importance in the generation of phototoxic species namely singlet oxygen. Singlet oxygen quantum yields were also determined and the results obtained were very promising for the dye in solution but also for the dye into the different substrates. The release of the dye from the three different films onto a buffer solution was evaluated and we conclude that after a few days the dye was completely released by the substrates in acidic conditions. Confocal microscopy was used for the determination of the intracellular localization of the compound under study onto HeLa cells (human cervical cancer cells line). The evaluation of the PSs anticancer activity assumes special importance for PDT studies. The system should be less toxic in the dark and more active when irradiated, therefore, toxicity in the dark and phototoxicity studies onto HeLa cells were performed. PMID- 27474556 TI - A review of chitosan and its derivatives in bone tissue engineering. AB - Critical-sized bone defects treated with biomaterials offer an efficient alternative to traditional methods involving surgical reconstruction, allografts, and metal implants. Chitosan, a natural biopolymer is widely studied for bone regeneration applications owing to its tunable chemical and biological properties. However, the potential of chitosan to repair bone defects is limited due to its water insolubility, faster in vivo depolymerization, hemo incompatibility, and weak antimicrobial property. Functionalization of chitosan structure through various chemical modifications provides a solution to these limitations. In this review, current trends of using chitosan as a composite with other polymers and ceramics, and its modifications such as quaternization, carboxyalkylation, hydroxylation, phosphorylation, sulfation and copolymerization in bone tissue engineering are elaborated. PMID- 27474557 TI - Xylan-based temperature/pH sensitive hydrogels for drug controlled release. AB - Xylan-based temperature/pH sensitive hydrogels were prepared by the crosslinking copolymerization of xylan with N-isopropylacrylamide (NIPAm) and acrylic acid (AA) using N,N-methylenebis-acrylamide (MBA) as a cross-linker and 2,2-dimethoxy 2-phenylacetophenone as a photoinitiator via ultraviolet irradiation. The influence of the NIPAm, AA and MBA amount on properties of xylan-based hydrogels was discussed. The morphology and interactions of hydrogels were characterized by SEM and FTIR. The lower critical solution temperature (LCST) of hydrogels was investigated by DSC. The results indicated that the LCST of hydrogels emerged at around 34 degrees C and increased with increasing the AA content. The drug encapsulation efficiency of as-prepared hydrogels reached to 97.60% and the cumulative release rate of acetylsalicylic acid was 90.12% and 26.35% in the intestinal and gastric fluid, respectively. Xylan-based hydrogels were proved to be biocompatible with NIH3T3 cell by MTT assay and showed the promising application as drug carriers for the intestinal-targeted oral drug delivery. PMID- 27474558 TI - Characterization and development mechanism of Apios americana tuber starch. AB - Apios americana is a wild legume-bearing plant with edible tubers. Domestication of Apios is in progress because of the superior nutritional value and health benefits of the tuber. Objectives of this study were to: (1) characterize physicochemical properties of the Apios tuber starch; and (2) understand differences in starch structures and properties between the mother (seed) and child (progeny) tubers and the mechanism of starch development. Granules of the Apios tuber starch displayed ellipsoidal, rod, or kidney shape with diameter ranges of 1-30MUm. The mother tuber starches displayed greater percentage crystallinity, larger gelatinization enthalpy-changes, longer branch-chain lengths of amylopectin, and lower pasting viscosity than their counterpart child tuber starches. The mother tuber starch of Apios 2127 displayed distinct two peaks of gelatinization, which were attributed to starch granules located at different regions of the tuber having different structures and properties. The mother tuber displayed more active starch biosynthesis in the periphery than in the center of the tuber. PMID- 27474559 TI - Gelatinization and retrogradation phenomena in starch/montmorillonite nanocomposites plasticized with different glycerol/water ratios. AB - This study aims to gain insights into the intermolecular interactions present in thermoplastic starch (TPS)/montmorillonite (MMT) nanocomposites prepared using water and/or glycerol as plasticizers. Specifically, the impact of using different glycerol/water proportions on the nature of gelatinization and retrogradation processes is studied. Nanocomposites were characterized by rheometry, scanning electron microscopy (SEM) and X-rays diffraction (XRD). It is shown that clay tactoids preferentially interact with glycerol molecules rather than starch macromolecules. Consequently, the effects of MMT incorporation strongly depend on the glycerol/water ratio; when a ratio of 0.5 is used minor variations were observed on the starch gelatinization process-although stronger clays-starch interactions were evident-whereas at higher ratios the addition of clays significantly increased the gelatinization temperature, up to values over 100 degrees C. In the gelatinization process of starch in TPS samples having only glycerol as a plasticizer, the leaching of amylose and the melting of amylopectin crystalline domains seem to occur simultaneously. This different gelatinization mechanism produces a TPS having a substantially different morphology, which exhibited reduced retrogradation characteristics. PMID- 27474560 TI - Electrically responsive materials based on polycarbazole/sodium alginate hydrogel blend for soft and flexible actuator application. AB - The electromechanical properties, namely the storage modulus sensitivity and bending, of sodium alginate (SA) hydrogels and polycarbazole/sodium alginate (PCB/SA) hydrogel blends under applied electric field was investigated. The electromechanical properties of the pristine SA were studied under effects of crosslinking types and SA molecular weights, whereas the PCB/SA hydrogel blends were studied under the effect of PCB concentrations. The storage modulus sensitivity and bending of the pristine SA as crosslinked by the ionic crosslinking agent were found to be higher than those of the covalent crosslinking. The storage modulus sensitivity and deflection of the SA increased monotonically with increasing molecular weight. The highest electromechanical response of the PCB/SA hydrogel blends was obtained from the blend with 0.10% v/v PCB as it provided surprisingly the highest ever storage modulus sensitivity, (G' G'0)/G'0 where G'0 and G' are the storage modulus without and with applied electric field, respectively, at 18.5 under applied electric field strength of 800V/mm. PMID- 27474561 TI - Cellulose-based films prepared directly from waste newspapers via an ionic liquid. AB - Waste newspapers, composed of cellulose (>60wt%), lignin (~15wt%), hemicellulose (~10wt%) and other additives, are one kind of low-cost, easily collected and abundant resources. In order to get value-added products from this waste, in this work an attempt was made to directly convert waste newspapers into cellulose based films by employing an ionic liquid 1-allyl-3-methylimidazolium chloride (AmimCl) as a solvent. Most of the organic substances in this waste were dissolved quickly in AmimCl under mild conditions, and then coagulated and dried. Although containing lignin, hemicellulose and inorganic additives, the regenerated cellulose-based films were smooth, compact and semi-transparent, and exhibited good mechanical properties. If the newspaper/AmimCl solution was filtered to remove undissolved inorganic substances, the regenerated films became transparent and had a tensile strength of 80MPa. Thus, this work provides a new, simple and highly efficient way to achieve a high-valued utilization of waste newspapers for packaging and wrapping. PMID- 27474562 TI - Efficient and selective adsorption of multi-metal ions using sulfonated cellulose as adsorbent. AB - Contamination of heavy metal in wastewater has caused great concerns on human life and health. Developing an efficient material to eliminate the heavy metal ions has been a popular topic in recent years. In this work, sulfonated cellulose (SC) was explored as efficient adsorbent for metal ions in solution. Thermo gravimetric analyzer (TGA), X-ray diffraction (XRD) and Fourier-transform infrared spectrometer (FTIR) first analyzed the characterizations of SC. Subsequently, effects of solution pH, adsorbent loading, temperature and initial metal ion concentration on adsorption performance were investigated. The results showed that sulfonated modification of cellulose could decrease the crystallinity and thermostability of cellulose. Due to its excellent performance of adsorption to metal ions, SC could reach adsorption equilibrium status within as short as 2min. In multi-component solution, SC can orderly removes Fe(3+), Pb(2+) and Cu(2+) with excellent selectivity and high efficiency. In addition, SC is a kind of green and renewable adsorbent because it can be easily regenerated by treatment with acid or chelating liquors. The mechanism study shows that the sulfonic group play a major role in the adsorption process. PMID- 27474563 TI - Preparation, characterization and protein sorption of photo-crosslinked cell membrane-mimicking chitosan-based hydrogels. AB - Photocrosslinkable biomimetic chitosan derivative, glycidyl methacrylate phosphorylcholine-chitosan (PCCs-GMA) was synthesized through the combination of Atherton-Todd reaction for coupling phosphorylcholine and ring opening reaction of epoxides for attaching GMA, and confirmed by (1)H and (31)P NMR and Fourier transform infrared (FTIR) spectroscopy. The photo-crosslinking reaction of PCCs GMA with different degree of substitution (DS) of GMA allowed the formation of biomimetic hydrogels with tunable mechanical and swelling properties. Cold crystallization behaviors ascribed to their restrained freezing bound water were investigated using differential scanning calorimetry (DSC). The rheological and swelling behaviors, hemolysis as well as protein sorption of PCCs-GMA hydrogels were investigated in terms of the DS of GMA, using fibrinogen, bovine serum albumin and lysozyme as model proteins. Low irreversible protein sorption and non hemolytic results indicated that photo-crosslinked PCCs-GMA hydrogels may offer a promising candidate material with resistance to protein fouling in biomedical applications. PMID- 27474564 TI - Transparent sunlight conversion film based on carboxymethyl cellulose and carbon dots. AB - Transparent sunlight conversion film based on carboxymethyl cellulose (CMC) and carbon dots (CDs) has been developed for the first time through dispersion of CDs in CMC aqueous solution. Due to the hydrogen bonds interaction, CMC can effectively absorb the CDs, whose surfaces are functionalized by lots of polar groups. The results from atomic force microscopy (AFM), scanning electron microscopy (SEM) confirm that the composite film possesses a homogeneous and compact structure. Besides, the CMC matrix neither competes for absorbing excitation light nor absorbs the emissions of CDs, which reserves the inherent optical properties of the individual CDs. The composite films can efficiently convert ultraviolet light to blue light. What's more, the film is transparent and possesses excellent mechanical properties, expected to apply in the field of agricultural planting for sunlight conversion. PMID- 27474565 TI - Multi-responsive magnetic microsphere of poly(N isopropylacrylamide)/carboxymethylchitosan hydrogel for drug controlled release. AB - Multi-responsive composite microspheres were synthesized via an in situ free radical polymerization of thermo-responsive poly(N-isopropylacrylamide) (poly(NIPAAm)) in the presence of carboxymethylchitosan (CMC) and magnetite nanoparticles (MNPs) followed by glutaraldehyde crosslinking. Formulation conditions of the composite microspheres were tuned such that spherical microspheres with narrow size distributions were obtained (30.0+/-1.0MUm in diameter). They responded well to an applied magnetic field and showed water swelling responses to the change in solution pH and temperature. The release of an entrapped indomethacin model drug was accelerated when the solution temperature was above its lower critical solution temperature (LCST) (50 degrees C) or when the solution pH was in basic conditions (pH 11). These responsive properties can be used as triggering mechanisms for releases of the entrapped drugs from the microspheres, indicating their great potentials for use in controlled release applications. PMID- 27474566 TI - Chitosan based substrates for wound infection detection based on increased lysozyme activity. AB - There is a strong need of point-of-care diagnostics for early detection of wound infection. In this study, substrates based on functionalized chitosan were developed for visual detection of elevated lysozyme activity, an infection biomarker in wound fluids. For efficient hydrolysis by lysozyme, N-acetyl chitosan with a final degree of acetylation of around 50% was synthesized. N acetylated chitosan and a chitosan-starch composite were labeled with structurally different dyes resulting in lysozyme-responsive biomaterials. Incubation with lysozyme in buffer and artificial wound fluid lead to a release of colored hydrolysis products already after 2h incubation. Tests in human wound fluid from infected wounds indicated a clear visual color change after 2.5h compared to control samples. A higher degree of swelling of the chitosan/starch containing substrate led to faster hydrolysis by lysozyme. This study demonstrates the potential of the lysozyme-responsive materials for diagnosis of wound infection and provides different diagnostic substrates for potential incorporation in point-of-care devices. PMID- 27474567 TI - Effects of abalone (Haliotis discus hannai Ino) gonad polysaccharides on cholecystokinin release in STC-1 cells and its signaling mechanism. AB - Abalone gonad polysaccharide (AGP) -31, -32 and -33 prepared in this study had the molecular weight (MW) of 37.8, 32.2 and 27.5kDa, respectively. They all contained mannose, rhamnose, glucuronic acid, glucose, galactose, xylose, arabinose, and fucose, with very similar monosaccharide profile. All the three polysaccharides could significantly increase the secretion of cholecystokinin (CCK) in STC-1 cells. Among them, AGP-32 showed the strongest effect. However, the low-MW fragments of AGP-32 showed significantly lower activity than AGP-32 itself. It was also found that the inhibitors on calcium-sensing receptor (CaSR), protein kinase A (PKA), Ca(2+)/calmodulin-dependent protein kinase (CaMK) II, p38 mitogen-activated protein kinases (MAPK), and an intracellular calcium chelator all inhibited AGP-induced CCK secretion. To conclude, Ca(2+)/calmodulin (CaM)/CaMK, cyclic adenosine monophosphate (cAMP)/PKA and MAPK pathways are all involved in AGP-induced CCK secretion. PMID- 27474568 TI - Production of starch nanoparticles using normal maize starch via heat-moisture treatment under mildly acidic conditions and homogenization. AB - Normal maize starch was subjected to heat-moisture treatment (HMT) under mildly acidic conditions (0.000, 0.050, or 0.075M H2SO4) for various treatment times (3, 5, or 8h) followed by homogenization up to 60min to prepare nanoparticles. The combination of HMT (0.075M, for 8h) and homogenization (60min) produced nanoparticles with diameters of less than 50nm at a yield higher than 80%. X-ray diffractometry and size-exclusion chromatography revealed that HMT under mildly acidic conditions selectively hydrolyzed the starch chains (especially amylose and/or long chains of amylopectin) in the amorphous region of the granules without significant damage to the crystalline structure, however, modification of the molecular structure in the amorphous region increased fragility of the granules during homogenization. Homogenization for 60min caused obvious damage in the long-range crystalline structure of the HMT starch (0.15N, for 8h), while the short-range chain associations (FT-IR) remained intact. PMID- 27474569 TI - Adsorption properties of crosslinking carboxymethyl cellulose grafting dimethyldiallylammonium chloride for cationic and anionic dyes. AB - Novel and efficient microspheres adsorbent (MCA-E0.7/CMC-g- PDMDAAC), based on monochloroacetic acid (MCA) modified epichlorohydrin (ECH) cross-linked carboxymethyl cellulose (CMC), then grafting by dimethyldiallylammonium chloride (DMDAAC), was synthesized and its adsorption properties on cationic and anionic dyes were investigated. The results demonstrated that such MCA-E0.7/CMC-g-PDMDAAC microspheres showed pH-sensitive and could effectively adsorb cationic dye methylene blue (MB) or anionic dye orange II (OR II), at near neutral (pH>4) or acidic (pH<3) condition, respectively. Moreover, it could selectively adsorb the cationic dye MB from the cationic/anionic dye mixture at neutral pH condition. The desorption experiments were mainly performed under acidic (pH 3) or basic (pH 11) condition, over 98.54% of MB and 83.07% of OR II can be desorbed within 20min, respectively. The pseudo-second-order kinetic model and Langmuir isotherm provide better correlation with the experimental data for the adsorption of dyes onto MCA-E0.7/CMC-g-PDMDAAC microspheres. PMID- 27474570 TI - Isolation and prebiotic activity of water-soluble polysaccharides fractions from the bamboo shoots (Phyllostachys praecox). AB - The water-soluble polysaccharides from bamboo shoots (Phyllostachys praecox) (WBP) were isolated, and the characterizations as well as prebiotic activities were investigated. The yield of WBP was 7.58+/-0.31% under optimal hot-water extraction conditions. Two fractions, i.e., WBP-1 and WBP-2 with molecular weight of 83.50kDa and 80.08kDa, respectively, were purified by chromatography. Both the polysaccharides fractions were identified as heteropolysaccharides-protein complexes composed of 15 kinds of common amino acids in protein part and rhamnose, arabinose, xylose, mannose, glucose and galactose in different molar ratios in polysaccharide part. The existence of alpha- and beta-glycosidic linkages between the sugar units was confirmed by FTIR and NMR spectra. Compared with the blank control and the reference of FOS, WBP-1 and WBP-2 significantly increased the numbers of Bifidobacterium adolescentis and Bifidobacterium bifidum (P<0.05), which contributed to the production of organic acids, suggesting that the polysaccharides have potential prebiotic properties. PMID- 27474571 TI - Effect of ultrasonic treatment on the physicochemical properties and antioxidant activities of polysaccharide from Cyclocarya paliurus. AB - The effects of ultrasonic treatment on the physicochemical properties and antioxidant activities of the polysaccharide from Cyclocarya paliurus leaves were investigated. The physicochemical properties were detected by high-performance gel permeation chromatography (HPGPC), high-performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD) and fourier transform infrared spectrometer (FT-IR) as well. The antioxidant activities were evaluated by the assay of DPPH, hydroxyl free radical, beta-carotene-linoleic acid, respectfully. Results showed that no considerable change was observed on the structure between the polysaccharide of Cyclocarya paliurus (CP) and the ultrasonic polysaccharide of Cyclocarya paliurus (UCP) by FT-IR, and no apparent differences were found on the content of sugar, uronic acid and protein after the ultrasonic treatment, but difference appeared in the ratio of monosaccharide composition of CP (1.0:4.6:3.5:4.5) and UCP (1.0:5.9:3.9:4.4), and the antioxidant activities of CP were promoted after ultrasonic treatment. PMID- 27474572 TI - Boron nitride nanotubes enhance properties of chitosan-based scaffolds. AB - With their low toxicity, high mechanical strength and chemical stability, boron nitride nanotubes (BNNTs) are good candidates to enhance the properties of polymers, composites and scaffolds. Chitosan-based scaffolds are exhaustively investigated in tissue engineering because of their biocompatibility and antimicrobial activity. However, their spontaneous degradation prevents their use in a range of tissue engineering applications. In this study, hydroxylated BNNTs (BNNT-OH) were included into a chitosan scaffold and tested for their mechanical strength, swelling behavior and biodegradability. The results show that inclusion of BNNTs-OH into the chitosan scaffold increases the mechanical strength and pore size at values optimal for high cellular proliferation and adhesion. The chitosan/BNNT-OH scaffold was also found to be non-toxic to Human Dermal Fibroblast (HDF) cells due to its slow degradation rate. HDF cell proliferation and adhesion were increased as compared to the chitosan-only scaffold as observed by scanning electron microscopy (SEM) and fluorescent microscopy images. PMID- 27474573 TI - Biological preparation of chitosan nanoparticles and its in vitro antifungal efficacy against some phytopathogenic fungi. AB - The aim of the present study was to prepare Chitosan nanoparticles through biological method with high antifungal activities. Chitosan nanoparticles were prepared by the addition of anionic proteins isolated from Penicillium oxalicum culture to chitosan solutions. The formation of chitosan nanoparticles was preliminary confirmed by UV-vis spectrophotometric analysis. The physico-chemical properties of the chitosan nanoparticles were determined by size and zeta potential analysis, FTIR analysis, HRTEM and XRD pattern. The chitosan nanoparticles were evaluated for its potential to inhibit the growth of phytopathogens viz., Pyricularia grisea, Alternaria solani, Fusarium oxysporum. It is evident from our results that chitosan nanoparticles inhibit the growth of phytopathogens tested. Chitosan nanoparticle treated chickpea seeds showed positive morphological effects such as enhanced germination%, seed vigor index and vegetative biomass of seedlings. All these results indicate that chitosan nanoparticle can be used further under field condition to protect various crops from the devastating fungal pathogens as well as growth promoters. PMID- 27474574 TI - TEMPO-oxidized cellulose nanofibers (TOCNs) as a green reinforcement for waterborne polyurethane coating (WPU) on wood. AB - In this work, TEMPO-oxidized cellulose nanofibers (TOCNs) were investigated as a green additive to the waterborne polyurethane (WPU) based coating, for improving its mechanical properties. The structure, morphology, mechanical properties and performances of the WPU/TOCNs coating were determined. Results showed that TOCNs had good compatibility to the WPU coating, and significantly enhanced the mechanical properties of the coating. The Halpin-Tsai and Ouali models were used to fit for the Young's modulus of the resulting coating, and good agreements were found between the Ouali model and experimental results when the TOCNs content exceeded the critical percolation threshold (0.7vol% or 1.0wt%). It was also found that the pencil hardness of the coating was improved with the addition of TOCNs. However, AFM and pull-off test revealed the negative effects of the TOCNs addition on the surface roughness and adhesion strength of the coating to the wood surface. PMID- 27474575 TI - Carboxymethyl cellulose enables silk fibroin nanofibrous scaffold with enhanced biomimetic potential for bone tissue engineering application. AB - Novel silk fibroin (SF) and carboxymethyl cellulose (CMC) composite nanofibrous scaffold (SFC) were developed to investigate their ability to nucleate bioactive nanosized calcium phosphate (Ca/P) by biomineralization for bone tissue engineering application. The composite nanofibrous scaffold was prepared by free liquid surface electrospinning method. The developed composite nanofibrous scaffold was observed to control the size of Ca/P particle (<=100nm) as well as uniform nucleation of Ca/P over the surface. The obtained nanofibrous scaffolds were fully characterized for their functional, structural and mechanical property. The XRD and EDX analysis depicted the development of apatite like crystals over SFC scaffolds of nanospherical in morphology and distributed uniformly throughout the surface of scaffold. Additionally, hydrophilicity as a measure of contact angle and water uptake capacity is higher than pure SF scaffold representing the superior cell supporting property of the SF/CMC scaffold. The effect of biomimetic Ca/P on osteogenic differentiation of umbilical cord blood derived human mesenchymal stem cells (hMSCs) studied in early and late stage of differentiation shows the improved osteoblastic differentiation capability as compared to pure silk fibroin. The obtained result confirms the positive correlation of alkaline phosphatase activity, alizarin staining and expression of runt-related transcription factor 2, osteocalcin and type1 collagen representing the biomimetic property of the scaffolds. Thus, the developed composite has been demonstrated to be a potential scaffold for bone tissue engineering application. PMID- 27474576 TI - Extraction optimization, preliminary characterization and immunological activities in vitro of polysaccharides from Elaeagnus angustifolia L. pulp. AB - In this research, extraction optimization, preliminary characterization and immunological activities in vitro of polysaccharides from Elaeagnus angustifolia L. pulp were investigated. A response surface methodology (RSM) with a Box Behnken design (BBD) was used to optimize the extraction process. The maximum EAP yield was 9.82+/-0.38%, which is in good agreement with the predicted value (9.93+/-0.24%). Two homogeneous polysaccharides, EAP-1a and EAP-1b with molecular weights of 8.70kDa and 4.39kDa respectively, were prepared by DEAE-52 cellulose and Sephadex G-100 columns and characterized by HPLC, HPGPC, and FT-IR. Three polysaccharides (EAP, EAP-1a and EAP-1b) could stimulate macrophages to release NO and enhance phagocytic activities of RAW 264.7 cells in dose-dependent manner. Moreover, there was no significant difference between crude EAP group (400MUg/mL) and positive control group (LPS) in effects on macrophages. The results implied that EAP had the potential to be developed as natural medicines or health foods. PMID- 27474577 TI - Prediction of the antiglycation activity of polysaccharides from Benincasa hispida using a response surface methodology. AB - Benincasa hispida is a popular vegetable in China. Our previous experiments suggested that polysaccharides isolated from B. hispida fruits (PBH) have antiglycation effect and DPPH free radical scavenging activity. Ultrasonic treatments can be used to extract polysaccharides from Benincasa hispida (PBH). The aim of this study was to investigate the correlation between the ultrasonic treatment conditions and the antiglycation activity of PBH. A mathematical model was generated with an artificial neural network (ANN) toolbox from MATLAB to analyze the effects of ultrasonic treatment conditions on antiglycation activity. The response surface plots showed relationships between ultrasonic extraction conditions and bioactivity. The R(2) value of the model was 0.9919, which suggested good fitness of the neural network. The application of genetic algorithms showed that the optimal ultrasonic extraction conditions resulted in the highest antiglycation activity for PBH. These were 150W, 46 degrees C, and 35min. These conditions produced a predicted antiglycation activity of 41.2%; the actual activity was 40.9% under optimal conditions. This is very close to the predicted value. The experimental data indicated that the PBH possessed both antiglycation and antioxidant activities. The maximum actual value of antiglycation was 101.7% that of the positive control, and the PBH inhibited the DPPH free radicals with an EC50 value of 0.98mg/mL. This is 66.2% that of ascorbic acid. These results explained the observations that B. hispida can decrease glucose levels in diabetic patients. The experimental results also showed that the ANN could be used for optimization and prediction. PMID- 27474578 TI - Optimization, characterization, sulfation and antitumor activity of neutral polysaccharides from the fruit of Borojoa sorbilis cuter. AB - Extraction optimization, purification, characterization, sulfation and antitumor activity of polysaccharides from the fruit body of Borojoa sorbilis cuter were investigated in present study. The optimal Ultrahigh Pressure extraction condition was determined as: extraction once with the solid-liquid ratio of 1:10 in 30 degrees C and 1500Mpa for crude polysaccharide (BP) and experimental yield was 8.28%. Four water-soluble polysaccharides named as BP1-1, BP1-2, BP1-3 and BP1-4, with molecular weight of 35.8, 32.4, 30.1 and 27.7kDa, were purified by DEAE Sepharose and Superdex 200 chromatography. On the basis of chemical and spectroscopic analyses, BP1-1-BP1-4 were found to be neutral beta-d-galactan containing a (1->4)-linked backbone. S-BP1s with the DSS of 1.18, was sulfated by chloro-sulfonic acid-pyridine method. Furthermore, S-BP1s exhibited significant in vitro antitumor activity against liver cancer HepG2 and lung cancer A549 cells in a dose-dependent manner. The results indicated that S-BP1s could be potentially developed as functional antitumor drug. PMID- 27474579 TI - AFM PeakForce QNM mode: Evidencing nanometre-scale mechanical properties of chitin-silica hybrid nanocomposites. AB - PeakForce Quantitative Nanomechanical Mapping (QNM) AFM mode was used to explore the mechanical properties of textured chitin-silica hybrid films at the nanoscale. The influence of the force applied by the tip on the sample surface was studied for standard homogeneous samples, for chitin nanorods and for chitin silica hybrid nanocomposites. Thick films of superimposed chitin nanorods showed a monotonous increase of DMT modulus (based on the Derjaguin-Muller-Toporov model) owing to an increase in modulus at the interface between nanorods due to geometrical constraints of the AFM acquisition. A similar variation of DMT modulus was obtained for chitin-silica hybrid thick films related to mechanical strengthening induced by the presence of silica. This work revealed the role of the organic-inorganic interface, at the nanoscale, in the mechanical behaviour of textured materials using PeakForce QNM mode, with optimized analysis conditions. PMID- 27474580 TI - Extraction optimization by response surface methodology of mucilage polysaccharide from the peel of Opuntia dillenii haw. fruits and their physicochemical properties. AB - In this study, response surface methodology (RSM) was employed to optimize microwave-assisted extraction (MAE) technology of mucilage polysaccharide from the peel of Opuntia dillenii haw. fruits (OFPP), and the physicochemical characteristics of OFPP were also investigated. The three parameters were the ratio of water to raw material (30-40ml/g), microwave power (300-400W) and extraction time (120-180s). The results indicated that the yield of OFPP was 15.62+/-0.37% under the optimum extraction conditions. Compared with MAE, the OFPP yield by hot water extraction (HWE) was 13.36+/-0.71%. In addition, the rheological properties of OFPP were also explored. The OFPP obtained by HWE exhibited a lower viscosity compared with that by MAE. The FT-IR spectra analysis, scanning electron microscopy (SEM) observation and thermogravimetric analysis (TGA) revealed that there were strong interactions between Ca(2+) and OFPP, which resulted in the high viscosity, different microstructure and thermal stability of OFPP. PMID- 27474581 TI - Physically and chemically cross-linked cellulose cryogels: Structure, properties and application for controlled release. AB - Porous cellulose matrices were prepared via cellulose dissolution in 8wt% NaOH water, physical gelation and chemical cross-linking with epichlorohydrin (ECH), coagulation in water and lyophilisation. Cellulose and cross-linker concentration were varied. The behaviour of gels upon coagulation and the swelling of cryogels in water were analysed. An anomalous high swelling at cross-linker concentration around stoichiometric molar ratio with cellulose was observed. Cellulose cryogel morphology, crystallinity and density were studied. The influence of chemical cross-linking on cellulose swelling was explained by suggesting that ECH acts as a spacer preventing cellulose chains tight packing during coagulation. Cellulose was loaded with a model drug, procaine hydrochloride, and the kinetics of its release was investigated. PMID- 27474582 TI - Preparation of chitosan grafted graphite composite for sensitive detection of dopamine in biological samples. AB - The accurate detection of dopamine (DA) levels in biological samples such as human serum and urine are essential indicators in medical diagnostics. In this work, we describe the preparation of chitosan (CS) biopolymer grafted graphite (GR) composite for the sensitive and lower potential detection of DA in its sub micromolar levels. The composite modified electrode has been used for the detection of DA in biological samples such as human serum and urine. The GR-CS composite modified electrode shows an enhanced oxidation peak current response and low oxidation potential for the detection of DA than that of electrodes modified with bare, GR and CS discretely. Under optimum conditions, the fabricated GR-CS composite modified electrode shows the DPV response of DA in the linear response ranging from 0.03 to 20.06MUM. The detection limit and sensitivity of the sensor were estimated as 0.0045MUM and 6.06MUA MUM(-1)cm(-2), respectively. PMID- 27474583 TI - Characterization of agar/soy protein biocomposite films: Effect of agar on the extruded pellets and compression moulded films. AB - Agar/soy protein biocomposite films were successfully processed by extrusion and compression moulding, obtaining transparent and homogeneous films. The conformational changes occurred during the extrusion process and the effect of agar on the final properties were analyzed. As shown by differential scanning calorimetry (DSC) and specific mechanical energy (SME) values, during the extrusion process protein denatured and unfolded protein chains could interact with agar. These interactions were analyzed by Fourier transform infrared spectroscopy (FTIR) and the secondary structure was determined from the amide I band. Those interactions were supported by the decrease of film solubility. Furthermore, the good compatibility between agar and soy protein was confirmed by the images from scanning electron microscopy (SEM). PMID- 27474584 TI - Proton play in the formation of low molecular weight chitosan (LWCS) by hydrolyzing chitosan with a carbon based solid acid. AB - Low molecular weight chitosan (LWCS) constitute a special class of value added chemicals that are primarily obtained from crustacean shells, which are the main water pollutants from crabs and shrimp processing centers. Unlike chitin and chitosan, LWCS possess improved solubility in water and aqueous solutions, making them widely applicable in numerous fields ranging from drug delivery to waste water treatment. Among the methods employed for their production, chemical breakdown by strong liquid acids has yielded good success. However, this method is met with severe concerns arising from the harsh nature of liquid acids, which may corrode the reactors for commercial synthesis, and their limited reusability. The physical methods like ultrasound and microwave are energy intensive in nature, while the enzymatic methods are expensive and offers limited scope for reuse. We have attempted to overcome these problems by employing carbon based solid acid (CSA) for hydrolyzing chitosan to LWCS. CSA can be easily produced using activated carbon, a cost-effective and easily available raw material. Reactions were carried out between chitosan and CSA in a hydrothermal glass reactor and the products, separated by cold centrifugation, were purified and dried. The dried products were characterized for their molecular weight and solubility. Results indicated more than ten-fold decrease in the molecular weight of chitosan and the product exhibited water solubility. The CSA could be used upto four times, without regeneration, to give a consistent quality product. The aqueous solution of resulting LWCS exhibited a pH of 6.03+/-0.11, as against the acidic pH range of solutions of commercially available LWCS, indicating its suitability for biomedical applications. Our investigation facilitates a 'green approach' that may be employed for commercial production of value added chemicals from waste products of marine industry. PMID- 27474585 TI - Chemical structures in pyrodextrin determined by nuclear magnetic resonance spectroscopy. AB - Glycosidic linkages in a pyrodextrin were identified by NMR spectroscopy for the first time. Pyrodextrin was prepared by slurrying waxy maize starch at pH 3, filtering and drying at 40 degrees C to 10-15% moisture content, then heating at 170 degrees C for 4h. (1)H and (13)C NMR resonances of the pyrodextrin were assigned with the assistance of 2D techniques including COSY, TOCSY, HSQC, and HMBC, all measured on a 500MHz instrument. During dextrinization, native waxy maize starch was hydrolyzed and extensively branched with new glycosidic linkages. The resulting pyrodextrin became 100% soluble in water and produced lower viscosity solutions at 30% solids. There were only 1.2% reducing ends (alpha-form) detected in the pyrodextrin, but 1,6-anhydro-beta-d-glucopyranosyl units accounted for 5.2% of repeating units and they were thought to be at the potential reducing end. New glycosyl linkages including alpha-1,6, beta-1,6, alpha-1,2, and beta-1,2 were identified. The total non-alpha-1,4 linkages in the pyrodextrin were about 17.8% compared to 5.8% in a maltodextrin prepared by alpha amylase digestion. Transglycosidation and depolymerization occurred during dextrinization, and the resulting pyrodextrin was highly branched. PMID- 27474586 TI - Flame retardation of cellulose-rich fabrics via a simplified layer-by-layer assembly. AB - Due to the high cellulose content of cotton (88.0-96.5%), the flame retardation of cotton fabrics can be achieved via an approach for the flame retardation of cellulose. In this work, a facile water-based flame retardant coating was deposited on cotton fabrics by a 'simplified' layer-by-layer (LbL) assembly. The novel coating solution was based on a mild reaction between ammonium polyphosphate (APP) and branched polyethyleneimine (BPEI), and the reaction mechanism was studied. TGA results showed that the char residues of coated fabrics were remarkably increased. The fabric with only 5wt% coating showed self extinguishing in the horizontal flame test, and the peak heat release rate (pHRR) in cone calorimeter test decreased by 51%. Furthermore, this coating overcame a general drawback of flame-retardant LbL assembly which was easily washed away. Therefore, the simplified LbL method provides a fast, low-cost, eco-friendly and wash-durable flame-retardant finishing for the cellulose-rich cotton fabrics. PMID- 27474587 TI - Development of a new antibacterial biomaterial by tetracycline immobilization on calcium-alginate beads. AB - In recent years, increasing risk of infection, caused by resistant microorganism to antibiotics, has become the limelight discovery of new and natural antibacterial materials. Heavy metals, such as silver, copper, mercury and titanium, have antibacterial activity. Products, which improved these metals, do not have stable antibacterial property. Therefore, use of these products is restricted. The aim of this study was to immobilize tetracycline to alginate and improve an antibacterial biomaterial. For this purpose, calcium-alginate beads were formed by dropping to calcium-chloride solution and tetracycline was immobilized to beads using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide at optimum conditions. After immobilization, actualization of immobilization was investigated by analyzing ATR-FTIR spectrum and SEM images. Also, antibacterial property of obtained product was tested. Improved product demonstrated antibacterial property. It has potential for open wound, surgical drapes, bed and pillow sheath in hospitals and it may also be used for increasing human comfort in daily life. PMID- 27474588 TI - Formation and properties of hyaluronan/nano Ag and hyaluronan-lecithin/nano Ag films. AB - A facile and environmentally friendly method of the preparation of silver nanoparticles embedded in hyaluronan (Hyal/Ag) and hyaluronan-lecithin (Hyal L/Ag) matrix was developed. Thin, elastic foils were prepared from gels by an in situ synthesis of Ag in an aqueous solution of sodium hyaluronate (Hyal), using aq. d-(+)-xylose solution as a reducing agent. The gels were applied to a clean, smooth, defatted Teflon surface and left for drying in the air. The dry foils were stored in a closed container. UV-vis spectroscopy, transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectra confirmed formation of about 10nm ball-shaped Ag nanoparticles situated within the polysaccharide template. Thermal properties of the composites were characterized involving differential scanning calorimetry (DSC) and thermogravimetric (TGA) analyses, whereas molecular weights of polysaccharide chains of the matrix were estimated with the size exclusion chromatography coupled with multiangle laser light scattering and refractometric detectors (HPSEC-MALLS-RI). An increase in the molecular weight of the hyaluronate after generation of Ag nanoparticles was observed. The foils showed specific properties. The study confirmed that silver nanoparticles can be successfully prepared with environmentally friendly method, using hyaluronan as a stabilizing template. Hyaluronan and hyaluronan-lecithin matrices provide nanocrystals uniform in size and shape. The composites demonstrated a bacteriostatic activity. PMID- 27474589 TI - Probing inclusion complexes of cyclodextrins with amino acids by physicochemical approach. AB - Formations of host-guest inclusion complexes of two natural amino acids, viz., l Leucine and l-Isoleucine as guests with alpha and beta-cyclodextrins have been investigated which include diverse applications in modern science such as controlled delivery in the field of pharmaceuticals, food processing etc. Surface tension and conductivity studies establish the formation of inclusion complexes with 1:1 stoichiometry. The interactions of cyclodextrins with amino acids have been supported by density, viscosity, refractive index, hydration and solvation number measurements indicating higher degree of inclusion in case of alpha cyclodextrin. l-Leucine interacts more with the hydrophobic cavity of cyclodextrin than its isomer. With the help of stability constant by NMR titration, hydrophobic effect, H-bonds and structural effects the formations of inclusion complexes have been explained. PMID- 27474590 TI - Magnetic field-responsive release of transforming growth factor beta 1 from heparin-modified alginate ferrogels. AB - Stimuli-responsive polymeric systems have been widely used for various drug delivery and tissue engineering applications. Magnetic stimulation can be also exploited to regulate the release of pharmaceutical drugs, growth factors, and cells from hydrogels in a controlled manner, on-demand. In the present study, alginate ferrogels containing iron oxide nanoparticles were fabricated via ionic cross-linking, and their various characteristics were investigated. The deformation of the ferrogels was dependent on the polymer concentration, calcium concentration, iron oxide concentration, and strength of magnetic field. To modulate the release of transforming growth factor beta 1 (TGF-beta1) under magnetic stimulation, alginate was chemically modified with heparin, as TGF-beta1 has a heparin-binding domain. Alginate was first modified with ethylenediamine, and heparin was then conjugated to the ethylenediamine-modified alginate via carbodiimide chemistry. Conjugation of heparin to alginate was confirmed by infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Sustained release of TGF-beta1 from alginate-g-heparin ferrogels was achieved, and application of a magnetic field to the ferrogels regulated TGF-beta1 release, resultantly enhancing chondrogenic differentiation of ATDC5 cells, which were used as a model chondrogenic cell line. Alginate-based ferrogels that release drugs in a controlled manner may therefore be useful in many biomedical applications. PMID- 27474591 TI - Chitosan and oligochitosan enhance ginger (Zingiber officinale Roscoe) resistance to rhizome rot caused by Fusarium oxysporum in storage. AB - The ability of chitosan and oligochitosan to enhance ginger (Zingiber officinale) resistance to rhizome rot caused by Fusarium oxysporum in storage was investigated. Both chitosan and oligochitosan at 1 and 5g/L significantly inhibited rhizome rot, with the best control at 5g/L. Chitosan and oligochitosan applied at 5g/L also reduced weight loss, measured as a decrease in fresh weight, but did not affect soluble solids content or titratable acidity of rhizomes. The two compounds applied at 5g/L induced beta-1,3-glucanase and phenylalanine ammonia-lyase enzyme activity and the transcript levels of their coding genes, as well as the total phenolic compounds in rhizome tissues. Therefore, the ability of chitosan and oligochitosan to reduce rot in stored rhizomes may be associated with their ability to induce defense responses in ginger. These results have practical implications for the application of chitosan and oligochitosan to harvested ginger rhizomes to reduce postharvest losses. PMID- 27474592 TI - (13)C NMR assignments of regenerated cellulose from solid-state 2D NMR spectroscopy. AB - From the assignment of the solid-state (13)C NMR signals in the C4 region, distinct types of crystalline cellulose, cellulose at crystalline surfaces, and disordered cellulose can be identified and quantified. For regenerated cellulose, complete (13)C assignments of the other carbon regions have not previously been attainable, due to signal overlap. In this study, two-dimensional (2D) NMR correlation methods were used to resolve and assign (13)C signals for all carbon atoms in regenerated cellulose. (13)C-enriched bacterial nanocellulose was biosynthesized, dissolved, and coagulated as highly crystalline cellulose II. Specifically, four distinct (13)C signals were observed corresponding to conformationally different anhydroglucose units: two signals assigned to crystalline moieties and two signals assigned to non-crystalline species. The C1, C4 and C6 regions for cellulose II were fully examined by global spectral deconvolution, which yielded qualitative trends of the relative populations of the different cellulose moieties, as a function of wetting and drying treatments. PMID- 27474593 TI - Preparation of chitosan-TPP sub-micron particles: Critical evaluation and derived recommendations. AB - The controlled preparation of chitosan particles is far from being trivial due to a considerable number of experimental parameters. For chitosan-tripolyphosphate (TPP) particles we evaluate the impact of chemical (type of chitosan, concentration, chitosan to TPP ratio, pH, ionic strength) and process factors (dialysis, stirring rate, rate of TPP addition, temperature, needle diameter) on the size and colloidal stability. The particles were prepared at pH=6.0 at which chitosan adopts the coiled conformation that is discussed as the dominant factor in controlling the stoichiometry of crosslinking reaction shifted towards TPP. These conditions result in identical particle size around 400nm and zeta potential around 22mV. The colloidal stability evaluated 24 hours after preparation depends on the amount of TPP during crosslinking. Under the same conditions, the colloidal stability up to 1 month is demonstrated. Several recommendations are provided to increase the control over formation of chitosan TPP particles. PMID- 27474594 TI - Starch, inulin and maltodextrin as encapsulating agents affect the quality and stability of jussara pulp microparticles. AB - The influence of encapsulating carbohydrates (EC) with varying properties on the technological and functional properties of jussara pulp microparticles produced by spray drying were evaluated using experimental design. Microparticles produced with sodium octenyl succinate (OSA) starch at 0.5 core to EC ratio and with mixtures of inulin and maltodextrin at 1.0 and 2.0 core to EC ratio showed darker color, and higher anthocyanins contents and antioxidant activity. Seven microparticles showing high water solubility and desirable surface morphology. Hygroscopicity (10.7% and 11.5%) and wettability (41s and 43s) were improved when OSA starch and mixtures of inulin and maltodextrin were used. The anthocyanins contents and color of the microparticles did not change when exposed to light at 50 degrees C for 38days. Finally, microparticles produced at 1.0 core to EC ratio with 2/3 OSA starch, 1/6 inulin and 1/6 maltodextrin were selected. These microparticles may be applied as colorant in numerous foods, whilst adding prebiotic fiber and anthocyanins. PMID- 27474595 TI - Structural characterization and functional properties of antihypertensive Cymodocea nodosa sulfated polysaccharide. AB - A sulfated polysaccharide was successfully isolated from Cymodocea nodosa (CNSP). This is the first report that indicates the chemical composition, structural characterization, functional and antihypertensive properties of this polysaccharide. The CNSP consisted mainly of sulfate (23.17%), total sugars (54.90%), galactose (44.89%), mannose (17.30%), arabinose (12.05%), xylose (9.18%), maltose (1.07%) and uronic acid (11.03%) with low water activity (0.49). CNSP had an XRD pattern that was typical for a semi-crystalline polymer with homogeneous structure. It also displayed an important anti-hypertensive activity (IC50=0.43mgml) with a dose-dependent manner using a synthetic substrate, N hippuryl-His-Leu hydrate salt (HHL). Overall, the results indicate that CNSP have attractive chemical, functional and biological properties, with a preliminary structural may have a backbone of branched 6-O-sulfated (1->4) galactosidic linkages, which can be considered in the future as alternative additive in various foods, cosmetic and pharmaceutical preparations. PMID- 27474596 TI - Structural analysis and cytokine-induced activity of gelling sulfated polysaccharide from the cystocarpic plants of Ahnfeltiopsis flabelliformis. AB - Gelling sulfated polysaccharide from the cystocarpic plants of Ahnfeltiopsis flabelliformis was studied. According to FT-IR and NMR spectroscopy data, the polysaccharide was found to be iota/kappa-carrageenan with iota- and kappa-type units in a 2:1 ratio containing beta-carrageenan units and minor amounts of nu- and mu-carrageenans. The HPLC and ESI MS/MS data of enzymatic hydrolysis products revealed that the main components of the polymer chain are iota-carrabiose, iota carratetraose and hybrid tetra- and hexasaccharides consisting of kappa- and iota units. Xylose was a substituent of a hydroxyl group at C-6 of 1,3-linked beta-d galactose in the total polysaccharides. It was shown that the ability of carrageenans to increase the synthesis of cytokines depended on their molecular weight. The polysaccharide induced the synthesis of the anti-inflammatory cytokine IL-10, whereas oligosaccharides increased the synthesis of both pro- and anti-inflammatory cytokines at high concentrations. PMID- 27474597 TI - Comments on "thermal degradation behavior of hypochlorite-oxidized starch nanocrystals under different oxidized levels". AB - This paper intends to discuss the employment of the Coats-Redfern equation to compute the kinetic parameters of the thermal degradation of hypochlorite oxidized starch nancrystals by Wei et al. [Carbohydrate Polymers 124 (2015) 124 130]. The original paper has shown some fundamental errors when presenting the Coats-Redfern (CR) integral kinetic model. This CR equation is commonly used to calculate the activation energy of the thermal degradation from a single non isothermal thermogravimetric curve. However, the use of a set of experiments recorded under different heating rates is often required to obtain accurate results, as recommended by the International Confederation for Thermal Analysis and Calorimetry (ICTAC) Kinetics Committee. The present comments are focused on these statements giving some arguments and elucidations concerning the Coats Redfern equation. PMID- 27474598 TI - Xyloglucans from flaxseed kernel cell wall: Structural and conformational characterisation. AB - The structure of ethanol precipitated fraction from 1M KOH extracted flaxseed kernel polysaccharides (KPI-EPF) was studied for better understanding the molecular structures of flaxseed kernel cell wall polysaccharides. Based on methylation/GC-MS, NMR spectroscopy, and MALDI-TOF-MS analysis, the dominate sugar residues of KPI-EPF fraction comprised of (1,4,6)-linked-beta-d glucopyranose (24.1mol%), terminal alpha-d-xylopyranose (16.2mol%), (1,2)-alpha-d linked-xylopyranose (10.7mol%), (1,4)-beta-d-linked-glucopyranose (10.7mol%), and terminal beta-d-galactopyranose (8.5mol%). KPI-EPF was proposed as xyloglucans: The substitution rate of the backbone is 69.3%; R1 could be T-alpha-d-Xylp-(1->, or none; R2 could be T-alpha-d-Xylp-(1->, T-beta-d-Galp-(1->2)-alpha-d-Xylp-(1->, or T-alpha-l-Araf-(1->2)-alpha-d-Xylp-(1->; R3 could be T-alpha-d-Xylp-(1->, T beta-d-Galp-(1->2)-alpha-d-Xylp-(1->, T-alpha-l-Fucp-(1->2)-beta-d-Galp-(1->2) alpha-d-Xylp-(1->, or none. The Mw of KPI-EPF was calculated to be 1506kDa by static light scattering (SLS). The structure-sensitive parameter (rho) of KPI-EPF was calculated as 1.44, which confirmed the highly branched structure of extracted xyloglucans. This new findings on flaxseed kernel xyloglucans will be helpful for understanding its fermentation properties and potential applications. PMID- 27474600 TI - Ternary cyclodextrin polyurethanes containing phosphate groups: Synthesis and complexation of ciprofloxacin. AB - Synthesis of ternary polyurethanes (PUs) from hexamethylenediisocyanate, beta cyclodextrin and beta-glycerophosphate (acid and calcium salt) was studies varying synthesis parameters such as monomer proportion, heating method (reflux and microwave), and catalyst amount. Favorable conditions were provided by microwave irradiation and use of beta-glycerophosphoric acid although the results suggest that it is possible to obtain ternary PUs with the calcium salt. FTIR data indicated the existence of secondary urea linkages. After characterization of ternary PUs by FTIR spectroscopy, XRD and thermal analysis, as well as evidences that the cyclodextrin cavities remained active toward inclusion of guest molecules, the possibility of inclusion of the antibiotic ciprofloxacin was evaluated. Absence of ciprofloxacin melting peak in DSC curves indicated that it is molecularly dispersed within the polymer, possibly included in the cyclodextrin. In vitro release experiments suggested additional non-inclusion interactions, showing also that the use of dialysis membranes may mask the actual release profile. PMID- 27474599 TI - Chondroitin sulfate-capped super-paramagnetic iron oxide nanoparticles as potential carriers of doxorubicin hydrochloride. AB - Chondroitin-4-sulfate (CS), a glycosaminoglycan, was used to prepare CS-capped super-paramagnetic iron oxide nanoparticles, which were further employed for loading a water-soluble chemotherapeutic agent (doxorubicin hydrochloride, DOX). CS-capped SPIONs have potential biomedical application in cancer targeting. The optimized formulation had a hydrodynamic size of 91.2+/-0.8nm (PDI; 0.228+/ 0.004) and zeta potential of -49.1+/-1.66mV. DOX was loaded onto the formulation up to 2% (w/w) by physical interaction with CS. TEM showed nano-sized particles having a core-shell structure. XRD confirmed crystal phase of iron oxide. FT-IR conceived the interaction of iron oxide with CS as bidentate chelation and also confirmed DOX loading. Vibration sample magnetometry confirmed super-paramagnetic nature of nanoparticles, with saturation magnetization of 0.238emug(-1). In vitro release profile at pH 7.4 showed that 96.67% of DOX was released within 24h (first order kinetics). MTT assay in MCF7 cells showed significantly higher (p<0.0001) cytotoxicity for DOX in SPIONs than DOX solution (IC50 values 6.294+/ 0.4169 and 11.316+/-0.1102MUgmL(-1), respectively). PMID- 27474601 TI - Ultraviolet-assisted synthesis of polyacrylamide-grafted chitosan nanoparticles and flocculation performance. AB - In the present work, a new flocculant, polyacrylamide-grafted chitosan nanoparticles (NCS-g-PAM), was synthesized by the copolymerization of acrylamide (AM) and chitosan nanoparticle (NCS) under ultraviolet irradiation using 2 hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone as photo-initiator. The NCS was prepared by the ionic gelation between chitosan and sodium tripolyphosphate. The structure and morphology of NCS-g-PAM were characterized by Fourier Transform Infraredspectroscopy (FT-IR), X-ray diffraction, (1)H-nuclear magnetic resonance spectrometry, scanning electron microscopy, and thermogravimetric analysis. The factors affecting the intrinsic viscosity and the yield of copolymer were studied, which showed that the optimum conditions for the synthesis of NCS-g-PAM were mAM:mNCS=8:1, 0.15g of initiator dosage, mCS:mTPP=4.5:1, 1min of ultrasonication time, 4h of illumination time, and 30min of stirring time. The NCS-g-PAM was found to be more effective than NC-g-PAM in the flocculation of both kaolin suspension and Cu(2+) simulated wastewater. With 5mg/L of polyaluminium chloride (PAC) coordinated and 1mg/L of NCS-g-PAM it was confirmed to be appropriate for flocculating kaolin suspension. PMID- 27474602 TI - Enhancing hyaluronan pseudoplasticity via 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium chloride-mediated conjugation with short alkyl moieties. AB - Hyaluronan (HA) is widely used in the clinical practice and in biomedical research. Through chemical modification, HA shear-thinning properties, essential for injectability and additive manufacturing, can be optimized. In this study, we employed 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) for grafting propylamine and butylamine to HA. A parametric study was performed to identify the optimal reaction conditions. Results showed that DMTMM amidation gives reproducible and accurate control over a range of degrees of substitution (DS) from 1% to 50% and proved reliable to tune viscoelasticity. At DS=3.0% for HA-propylamine and 3.7% for HA-butylamine a maximum for storage modulus and pseudoplasticity was found, whereas above or below this DS, rheological features go back to baseline values of pristine HA. Due to their singular rheological profiles, these derivatives are valuable biomaterials candidates for preparing bioinks and hydrogels for drug delivery and regenerative medicine. PMID- 27474603 TI - HPLC profiling of antimicrobial and antioxidant phyco sugars isolated from the South West coast of India. AB - Phyco sugars isolated from the South West coast of India are commercially and therapeutically interesting due to their various biological activities. These sugars were isolated from six (three red and three green) seaweed species using water at 100 degrees C followed by precipitation using ethanol. The physical, chemical and biological characteristics were explored with specific highlights onto the specific rotation, HPLC-RI sugar speciation, antioxidant and antimicrobial activities. The biological properties were evaluated based on multiple methods and standards, such that the actual nature of the sugar is understood. G. corticata var. cylindrica (31.66%) had the highest sugar content. All the sugars had levo rotatory specific rotation and interesting chemical characteristics. Sugars isolated had competitive biological activities and had the presence of seven monosaccharides and one disaccharide. The results highlighted the socio-economic importance of seaweeds which could be developed as a potential source of bioactive compounds in the upcoming future. PMID- 27474604 TI - Quantitative structure property relationship modeling of excipient properties for prediction of formulation characteristics. AB - Quantitative structure property relationship (QSPR) is used to relate the excipient descriptors with the formulation properties. A QSPR model is developed by regression analysis of selected descriptors contributing towards the targeted formulation properties. Developed QSPR model is validated by the true external method where it showed good accuracy and precision in predicting the formulation composition as experimental t90% (61.35min) is observed very close to predicted t90% (67.37min). Hence, QSPR approach saves resources by predicting drug release from an unformulated formulation; avoiding repetitive trials in the development of a new formulation and/or optimization of existing one. PMID- 27474605 TI - Synthesis of superparamagnetic carboxymethyl chitosan/sodium alginate nanosphere and its application for immobilizing alpha-amylase. AB - In order to improve catalytic activity, increase recycling times, reduce use cost for enzyme, superparamagnetic carboxymethyl chitosan/sodium alginate nanosphere (SM/CMC/SA) has been synthesized via an improved hydrothermal method, molecular self-assembly technology, electrostatic interaction and amide linkage. Its mean diameter was 65nm, zeta potential was -36.9mV and BET was 53.8m(2)/g. alpha Amylase was selected as a simulation object to manufacture an immobilized enzyme (SM/CMC/CA/alpha-Amy), and its catalytic activity, release behavior, reusability and stability were researched. Immobilization increased 4.67 times to catalytic activity, slowed down release rate and improved reusable performance. SM/CMC/CA/alpha-Amy showed higher activity over a wider pH range, especially in strong acidic and alkaline environments. The thermal stability and storage stability were improved remarkably too. All these results indicated that SM/CMC/SA was an ideal carrier for immobilizing enzyme. PMID- 27474606 TI - Effect of short-chain fatty acids on the formation of amylose microparticles by amylosucrase. AB - Amylose microparticles can be produced by self-assembly of amylose molecules through an amylosucrase-mediated synthesis. Here we investigated the role of short-chain fatty acids in the formation of amylose microparticles and the fate of these fatty acids at the end of the reaction. The rate of self-assembly and production yields of amylose microparticles were significantly enhanced in the presence of fatty acids. The effect was dependent on the length of the fatty acid carbon tail; butanoic acid (C4) was the most effective, followed by hexanoic acid (C6) and octanoic acid (C8). The amylose microparticles were investigated by carrying out SEM, XRD, Raman, NMR, FT-IR and DSC analysis. The size, morphology and crystal structure of the resulting amylose microparticles were comparable with those of amylose microparticles produced without fatty acids. The results indicated the carboxyl group of the fatty acid to be responsible for promoting the self-assembly of amylose chains to form microparticles. The fatty acids were eventually removed from the microstructure through the tight association of amylose double helices to form the amylose microparticles. PMID- 27474607 TI - Effect of thermal processing on the physicochemical properties of chestnut starch and textural profile of chestnut kernel. AB - The present study focused on the effect of thermal processing on the physicochemical properties of chestnut starch and textural profile of chestnut kernel. After thermal processing, the total starch content in both boiled and roasted chestnuts decreased significantly (P<0.05), while the amylose content of boiled chestnut increased and that of roasted chestnut remained stable. The granular microstructure of the starch in cooked chestnut was gradually destroyed during the thermal processing. The starch in cooked chestnut still exhibited C type X-ray diffraction patterns, but the intensity of diffraction peaks and the crystallinity were obviously declined compared with those of fresh chestnut. Textural profile analysis of chestnut starch gel and chestnut kernel showed that the main textural characterizations of roasted chestnut were higher than those of boiled chestnuts. These results are helpful for better understanding the texture change in fresh, boiled and roasted chestnuts, which indicated that roasting is an alternative industrial thermal processing method for chestnut kernel. PMID- 27474608 TI - Polyphenol-chitosan conjugates: Synthesis, characterization, and applications. AB - Chitosan, the only positively charged polysaccharide in the world, is very attractive for food, medicinal and pharmaceutical applications because of its promising properties, including non-toxicity, superb biodegradability, high biocompatibility, abundant availability and low cost. In order to overcome the poor water solubility and widen the applications of chitosan, various polyphenol chitosan conjugates have been synthesized in recent years. The present review focuses on the chitosan-based conjugates formed using different polyphenols, including gallic acid, caffeic acid, ferulic acid, salicylic acid, catechin, and EGGE, etc. Three major synthesis techniques, namely, activated ester-mediated modification, enzyme-mediated strategy, and free radical induced grafting approach are introduced in detail. In addition, the new physicochemical and biological properties of polyphenol-chitosan conjugates are introduced, including water solubility, thermo stability, in vitro and in vivo antioxidant activity, antimicrobial and anticancer activity. Furthermore, the novel applications of each conjugate are discussed in detail. Lastly, the challenges and prospective areas of study related to polyphenol-chitosan are summarized. PMID- 27474609 TI - Adsorptive removal of Lead from water by the effective and reusable magnetic cellulose nanocomposite beads entrapping activated bentonite. AB - Many efforts have been driven to decontaminate the drinking water, and the development of efficient adsorbents with the advantages of cost-effectiveness and operating convenience for the removal of Pb(2+) from water is a major challenge. This work was aimed to explore the possibility of using cellulose-based adsorbents for efficient adsorption of Pb(2+). The millimeter-scale magnetic cellulose-based nanocomposite beads were fabricated via an optimal extrusion dropping technology by blending cellulose with the carboxyl-functionalized magnetite nanoparticles and acid-activated bentonite in NaOH/urea aqueous solution, and then they had been tested to evaluate the effectiveness in the removal of Pb(2+) from water. The effects of contact time, initial heavy metal ion concentrations, adsorption isotherms and solution pH on the sorption behavior were studied. The thermodynamic parameters (DeltaG, DeltaH and DeltaS) indicated that the adsorption processes were feasible, spontaneous, endothermic and mainly controlled by chemical mechanisms. The reusability of the adsorbent was also studied. PMID- 27474610 TI - One-pot green synthesis of luminescent gold nanoparticles using imidazole derivative of chitosan. AB - Water soluble luminescent gold nanoparticles with average size 2.3nm were for the first time synthesized by completely green method of Au(III) reduction using chitosan derivative-biocompatible nontoxic N-(4-imidazolyl)methylchitosan (IMC) as both reducing and stabilizing agent. Reduction of Au(III) to gold nanoparticles in IMC solution is a slow process, in which coordination power of biopolymer controls both reducing species concentration and gold crystal growth rate. Gold nanoparticles formed in IMC solution do not manifest surface plasmon resonance, but exhibit luminescence at 375nm under UV light excitation at 230nm. Due to biological activity of imidazolyl-containing polymers and their ability to bind proteins and drugs, the obtained ultra-small gold nanoparticles can find an application for biomolecules detection, bio-imaging, drug delivery, and catalysis. Very high catalytic activity (as compared to gold nanoparticles obtained by other green methods) was found for Au/IMC nanoparticles in the model reaction of p-nitrophenol reduction providing complete conversion of p nitrophenol to p-aminophenol within 180-190s under mild conditions. PMID- 27474611 TI - Synthesis and characterization of retrograded starch nanoparticles through homogenization and miniemulsion cross-linking. AB - A new and convenient route to synthesizing retrograded starch nanoparticles (RS3NPs) through homogenization combined with a water-in-oil miniemulsion cross linking technique was developed. The RS3NPs were optimized using Box-Behnken experimental design. Homogenization pressure (X1), oil/water ratio (X2), and surfactant (X3) were selected as independent variables, whereas particle size was considered as a dependent variable. Results indicated that homogenization pressure was the main contributing variable for particle size. The optimum values for homogenization pressure, oil/water ratio, and surfactant were 30MPa, 9.34:1, and 2.54g, respectively, whereas the particle size was predicted to be 288.2 nm. Morphological, physical, chemical, and functional properties of the RS3NPs were the assessed. Scanning electron microscopy and dynamic light scattering images showed that RS3NP granules were broken down to size of about 222.2nm. X-ray diffraction results revealed a disruption in crystallinity. The RS3NPs exhibited a slight decrease in To, but Tp and Tc increased and narrowest Tc-To. The solubility and swelling power were also increased. New peaks at 1594.84 and 1403.65cm(-1) were observed in the FTIR graph. However, homogenization minimally influenced the antidigestibility of RS3NPs. The absorption properties improved, and the adsorption kinetic described the contact time on the adsorption of captopril onto RS3NPs. In vitro release experiment indicated that the drug was released as follows: 21% after 2h in SGF, 42.78% at the end of 8h (2h in SGF and 6h in SIF), and 92.55% after 12h in SCF. These findings may help better utilize RS3NP in biomedical applications as a drug delivery material. PMID- 27474612 TI - Understanding shape and morphology of unusual tubular starch nanocrystals. AB - Starch nanocrystals (SNC) are aptly described as the insoluble degradation byproducts of starch granules that purportedly display morphologies that are platelet-like, round, square, and oval-like. In this work, we reported the preparation of SNC with unprecedented tubular structures through sulfuric acid hydrolysis of normal maize starch, subsequent exposure to ammonia and relaxation at 4 degrees C. High-resolution transmission electron microscopy observation clearly proved that the SNCs possess tubular nanostructures with polygonal cross section. After further reviewing the transformations of SNC by acid hydrolysis, ammonia treatment, and curing time at 4 degrees C, a mechanism for T-SNC formation is suggested. It is conjectured that T-SNC gradually self-assembles by combination of smaller platelet-like/square nanocrystals likely loosely aggregated by starch molecular chains from residual amorphous regions. This work paves the way for the pursuit of new approaches for the preparation of starch based nanomaterials possessing unique morphologies. PMID- 27474613 TI - Evaluation of xylitol production using corncob hemicellulosic hydrolysate by combining tetrabutylammonium hydroxide extraction with dilute acid hydrolysis. AB - In this paper, we produced hemicellulosic hydrolysate from corncob by tetrabutylammonium hydroxide (TBAH) extraction and dilute acid hydrolysis combined, further evaluating the feasibility of the resultant corncob hemicellulosic hydrolysate used in xylitol production by Candida tropicalis. Optimized conditions for corncob hemicellulose extraction by TBAH was obtained via response surface methodology: time of 90min, temperature of 60 degrees C, liquid/solid ratio of 12 (v/w), and TBAH concentration of 55%, resulting in a hemicellulose extraction of 80.07% under these conditions. The FT-IR spectrum of the extracted corncob hemicellulose is consistent with that of birchwood hemicellulose and exhibits specific absorbance of hemicelluloses at 1380, 1168, 1050, and 900cm(-1). In addition, we found that C. tropicalis can ferment the resulting corncob hemicellulosic hydrolysate with pH adjustment and activated charcoal treatment leading to a high xylitol yield and productivity of 0.77g/g and 2.45g/(Lh), respectively. PMID- 27474614 TI - Biosynthesis of xanthan gum by Xanthomonas campestris LRELP-1 using kitchen waste as the sole substrate. AB - Herein, we report the production of xanthan gum by fermentation using kitchen waste as the sole substrate. The kitchen waste was firstly pretreated by a simple hydrolysis method, after which the obtained kitchen waste hydrolysate was diluted with an optimal ratio 1:2. In a 5-L fermentor, the maximum xanthan production, reducing sugar conversion and utilization rates reached 11.73g/L, 67.07% and 94.82%, respectively. The kinetics of batch fermentation was also investigated. FT-IR and XRD characterizations confirmed the fermentation product as xanthan gum. TGA analyses showed that the thermal stability of the xanthan gum obtained in this study was similar to commercial sample. The molecular weights of xanthan gum were measured to be 0.69-1.37*10(6)g/mol. The maximum pyruvate and acetyl contents in xanthan gum were 6.11% and 2.49%, respectively. This study provides a cost-effective solution for the reusing of kitchen waste and a possible low-cost approach for xanthan production. PMID- 27474615 TI - Novel aqueous chitosan-based dispersions as efficient drug delivery systems for topical use. Rheological, textural and release studies. AB - The use of a novel cross-linked thiolated chitosan (CTS) was investigated as the main component of aqueous dispersions (at 1% and 3% w/v) for topical drug delivery systems. The nonionic theophiline (Th) and the cationic diltiazem(.)HCl (Dt) (at 0.5% w/v concentration) were used as model drugs. All aqueous dispersions behaved as viscoelastic fluids. The CTS 1% dispersions showed predominance of viscous component and low viscosity. However, in the CTS 3% dispersions, both the elastic component and high viscosities prevailed. So, texture parameters improved from CTS 1% to 3% dispersions and CTS 3%-Dt showed greater cohesion and adhesion than CTS 3%-Th, but always below CTS alone. All dispersions showed a Fickian diffusion mechanism. Despite release profiles of both drugs almost fully overlapped at 1% CTS, diffusion coefficients confirmed Dt released faster than Th at 3% CTS. The rheological behavior and the chemical nature of the drugs explained these results. PMID- 27474616 TI - Effect of oxidization and chitosan on the surface activity of soy protein isolate. AB - The objective of this research was to study the effect of oxidization of performic acid and chitosan on the structure and surface properties of soy protein isolate. As the degree of oxidization increased, the emulsifying capacity and stability of all the oxidized soy protein isolate and chitosan (SPI/CHI) systems increased substantially, which were 29.7%, 31.7%, 34.1%, 31.9% and 31.9% respectively compared. Fluorescent spectrum showed that the fluorescence intensity of SPI/CHI conjugates decreased and the higher the oxidized degree was, the lower the fluorescence intensity. Results of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that the location of acidic bands of SPI/CHI conjugates moved upwards and broadened. Meanwhile, the basic bands lightened or even disappeared gradually as the oxidization increased. Scanning electron microscope (SEM) showed that the particles became lager as the degree of oxidization increased. Better thermostability of the oxidized SPI/CHI systems was shown in the differential scanning calorimetry (DSC). PMID- 27474617 TI - Dissolution state of cellulose in aqueous systems. 2. Acidic solvents. AB - Cellulose is insoluble in water but can be dissolved in strong acidic or alkaline conditions. How well dissolved cellulose is in solution and how it organizes are key questions often neglected in literature. The typical low pH required for dissolving cellulose in acidic solvents limits the use of typical characterization techniques. In this respect, Polarization Transfer Solid State NMR (PT ssNMR) emerges as a reliable alternative. In this work, combining PT ssNMR, microscopic techniques and X-ray diffraction, a set of different acidic systems (phosphoric acid/water, sulfuric acid/glycerol and zinc chloride/water) is investigated. The studied solvent systems are capable to efficiently dissolve cellulose, although degradation occurs to some extent. PT ssNMR is capable to identify the liquid and solid fractions of cellulose, the degradation products and it is also sensitive to gelation. The materials regenerated from the acidic dopes were found to be highly sensitive to the solvent system and to the presence of amphiphilic additives in solution. PMID- 27474618 TI - Properties of nanocellulose isolated from corncob residue using sulfuric acid, formic acid, oxidative and mechanical methods. AB - In this work, nanocellulose was extracted from bleached corncob residue (CCR), an underutilized lignocellulose waste from furfural industry, using four different methods (i.e. sulfuric acid hydrolysis, formic acid (FA) hydrolysis, 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation, and pulp refining, respectively). The self-assembled structure, morphology, dimension, crystallinity, chemical structure and thermal stability of prepared nanocellulose were investigated. FA hydrolysis produced longer cellulose nanocrystals (CNCs) than the one obtained by sulfuric acid hydrolysis, and resulted in high crystallinity and thermal stability due to its preferential degradation of amorphous cellulose and lignin. The cellulose nanofibrils (CNFs) with fine and individualized structure could be isolated by TEMPO-mediated oxidation. In comparison with other nanocellulose products, the intensive pulp refining led to the CNFs with the longest length and the thickest diameter. This comparative study can help to provide an insight into the utilization of CCR as a potential source for nanocellulose production. PMID- 27474619 TI - Isolation and characterization of cellulose nanofibers from bamboo using microwave liquefaction combined with chemical treatment and ultrasonication. AB - Cellulose nanofibers were successfully isolated from bamboo using microwave liquefaction combined with chemical treatment and ultrasonic nanofibrillation processes. The microwave liquefaction could eliminate almost all the lignin in bamboo, resulting in high cellulose content residues within 7min, and the cellulose enriched residues could be readily purified by subsequent chemical treatments with lower chemical charging and quickly. The results of wet chemistry analyses, SEM images, and FTIR and X-ray spectra indicated the combination of microwave liquefaction and chemical treatment was significantly efficient in removing non-cellulosic compounds. Ultrasonication was used to separate the nanofibrils from the purified residues to extract nanofibers. The TEM images confirmed the presence of elementary fibrils, nano-sized fibril bundles, and aggregated fibril bundles. As evidenced by the TGA analysis, cellulose nanofibers isolated by this novel technique had high thermal stability indicating that the isolated nanofibers could possibly be applied as reinforcing elements in biomaterials. PMID- 27474620 TI - Agarose functionalization: Synthesis of PEG-agarose amino acid nano-conjugate - its structural ramifications and interactions with BSA in a varying pH regime. AB - In a rapid one-step method protein-mimicking large agarose amino acid framework (AAE; GPC 156.7kDa) was conjugated with polyethylene glycol (PEG 9kDa) affording nano-sized PEGylated amphoteric agarose (PEG-AAE; <10nm; DLS) containing amino, carboxyl and ester groups [overall degree of substitution (DS) 0.91]. The PEG groups were at the residual free carboxylic acid groups of succinate half-ester moiety at C-6 positions of the 1, 3 beta-d-galactopyranose moieties of AAE. This new nano-sized PEG-AAE performed like a giant protein conjugate (GPC 331.2kDa) and exhibited pH-responsive interconversion between the triple helix and single stranded random structures (optical rotatory dispersion) presenting a mixed solubility pattern like random coil (soluble), helical (soluble) and aggregate (precipitation) formations. Circular dichroism studies showed its pH-dependent complexation and decomplexation with bovine serum albumin (BSA). Such pH responsive PEG-conjugate may be of pronounced therapeutic potential in the area of pharmacology as well as in sensing applications. PMID- 27474621 TI - Preactivated thiolated pullulan as a versatile excipient for mucosal drug targeting. AB - AIM: The purpose of the present study was to generate a novel mucoadhesive thiolated pullulan with protected thiol moieties and to evaluate its suitability as mucosal drug delivery system. METHODS: Two different synthetic pathways: bromination-nucleophilic substitution and reductive amination including periodate cleavage were utilized to synthesize such thiolated pullulans. The thiomer (pullulan-cysteamine) with the highest amount of free thiol groups was further enrolled in a reaction with 6-mercaptonicotinamide and its presence in pullulan structure was confirmed via NMR analysis. Furthermore, unmodified, thiolated and preactivated thiolated pullulan were investigated in terms of mucoadhesion via rotating cylinder studies and rheological synergism method as well as their toxicity potential over Caco-2 cells. RESULTS: Comparing both methods the reductive amination seems to be the method of choice resulting in comparatively higher coupling rates. Using this procedure pullulan-cysteamine conjugate displayed 1522+/-158MUmol immobilized thiol groups and 280+/-70MUmol free thiol groups per gram polymer. Furthermore, 82% of free thiol groups on this conjugate were linked with 6-mercaptonicotinamide (6-MNA). The adhesion time on the rotating cylinder was up to 46-fold prolonged in case of the thiolated polymer and up to 75-fold in case of the preactivated polymer. Rheological measurements of modified pullulan samples showed 98-fold and 160-fold increase in dynamic viscosity upon the addition of mucus within 60min, whereas unmodified pullulan did not show an increase in viscosity at all. Both conjugates had a minor effect on Caco-2 cell viability. CONCLUSION: Because of these features preactivated thiolated pullulan seems to represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems. PMID- 27474622 TI - Chitosan/titanium dioxide nanocomposite coatings: Rheological behavior and surface application to cellulosic paper. AB - Incorporation of nanofillers into a polymeric matrix has received much attention as a route to reinforced polymer nanocomposites. In the present work, an environmentally friendly chitosan (CTS)/titanium dioxide (TiO2) nanocomposite coating was designed/prepared and subsequently employed for imparting antibacterium and improved mechanical properties to cellulosic paper via surface coating. Effect of TiO2 nanoparticle loadings on the rheological behavior of nanocomposite coatings was investigated. Surface application of CTS/TiO2 nanocomposite coatings to cellulosic paper was performed, and the antibacterial activity and mechanical properties of surface-coated cellulosic paper were examined. Results showed that the increased TiO2 nanoparticle loadings decreased the viscosity and dynamic viscoelasticity of the as-prepared coatings, and improved the antibacterial activity and mechanical properties of surface-coated cellulosic paper. The optimum loading of TiO2 nanoparticles was identified at 10%. This work suggested that CTS/TiO2 nanocomposite coatings may have the potential to be used as a promising antibacterial protective coating for paper packaging. PMID- 27474623 TI - Fast ultrasound assisted synthesis of chitosan-based magnetite nanocomposites as a modified electrode sensor. AB - Chitosan-based magnetite nanocomposites were synthesized using a versatile ultrasound assisted in situ method involving one quick step. This synthetic route approach results in the formation of spheroidal nanoparticles (Fe3O4) with average diameter between 10 and 24nm, which were found to be superparamagnetic with saturation magnetization (Ms) ranges from 32-57emug(-1), depending on the concentration. The incorporation of Fe3O4 into chitosan matrix was also confirmed by FTIR and TG techniques. This hybrid nanocomposite has the potential application as electrochemical sensors, since the electrochemical signal was excepitionally stable. In addition, the in situ strategy proposed in this work allowed us to synthesize the nanocomposite system in a short time, around 2min of time-consuming, showing great potential to replace convencional methods. Herein, the procedure will permit a further diversity of applications into nanocomposite materials engineering. PMID- 27474624 TI - Dielectric and electric properties of new chitosan-hydroxyapatite materials for biomedical application: Dielectric spectroscopy and corona treatment. AB - Chitosan-hydroxyapatite composite materials were synthesized and the possibility to make their surface charged by corona discharge treatment has been evaluated. Dielectric and electric properties of the materials were studied by dielectric spectroscopy, including application of equivalent circuits method and computer simulations. Dielectric spectroscopy shows behavior of the materials quite different from that of both chitosan and HA alone. The obtained dielectric permittivity data are of particular interest in predicting the materials' behavior in electrostimulation after implantation. The epsilon values observed at physiological temperature in the frequency ranges applied are similar to epsilon data available for bone tissues. PMID- 27474625 TI - Transparent bionanocomposite films based on chitosan and TEMPO-oxidized cellulose nanofibers with enhanced mechanical and barrier properties. AB - The development of biobased active films for use in food packaging is increasing due to low cost, environmental appeal, renewability and availability. The objective of this research was to develop an effective and complete green approach for the production of bionanocomposite films with enhanced mechanical and barrier properties. This was accomplished by incorporating TEMPO-oxidized cellulose nanofibers (2,2,6,6-tetramethylpiperidine-1-oxyl radical) into a chitosan matrix. An aqueous suspension of chitosan (100-75wt%), sorbitol (25wt%) and TEMPO-oxidized cellulose nanofibers (TEMPO-CNFs, 0-25wt%) were cast in an oven at 40 degrees C for 2-4days. Films were preconditioned at 25 degrees C and 50% RH for characterization. The surface morphology of the films was revealed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The thermal properties and crystal structure of the films were evaluated by thermogravimetric analysis (TGA-DTG) and X-ray diffraction (XRD). Incorporation of TEMPO-CNFs enhanced the mechanical strength of the films due to the high aspect ratio (3 20nm width, and 10-100nm length) of TEMPO-CNFs and strong interactions with the chitosan matrix. Oxygen and water vapor transmission rates for films that are prepared with chitosan and TEMPO-CNFs (15-25wt%) were significantly reduced. Furthermore, these bionanocomposite films had good thermal stability. Use of TEMPO-CNFs in this method makes it possible to produce bionanocomposite films that are flexible, transparent, and thus have potential in food packaging applications. PMID- 27474626 TI - A functional chitosan membrane with grafted epigallocatechin-3-gallate and lovastatin enhances periodontal tissue regeneration in dogs. AB - Currently used guided tissue regeneration (GTR) membranes are mainly used as a barrier to prevent epithelial cells growth into defects before new bone formation. The aim of this study was to develop a tri-layer functional chitosan (CS) membrane with epigallocatechin-3-gallate (EGCG) grafted on the outer layer for bactericidal activity, and lovastatin was included in the middle layer for controlled release. Successful EGCG grafting was demonstrated using Fourier transform infrared spectroscopy and EGCG grafting significantly enhanced adhesion and proliferation of human gingival fibroblasts. The release duration of lovastatin reached 21days. CS-Lovastatin1 produced the highest alkaline phosphatase activity and EGCG14-CS exhibited the best bactericidal activity against periodontopathic bacteria. Finally, the EGCG14-CS-Lovastatin1 membrane showed a higher percentage of bone regeneration than BioMend((r)) and control groups in one-walled defects of beagle dogs. These results suggest that the EGCG14-CS-Lovastatin1 membrane has the potential to be used as a novel GTR membrane. PMID- 27474627 TI - Isolation and structure elucidation of pectic polysaccharide from rose hip fruits (Rosa canina L.). AB - A pectic polysaccharide from rose hip (RH) fruits has been obtained by extraction with 1% aqueous citric acid. It was found that the polysaccharide fraction mainly consisted of galacturonic acid (45.5%) next to galactose (5.5%) and arabinose (4.7%). RH pectin is having a relatively high degree of methylesterification (62%) and acetylation (10%) and consists of different molecular weight populations in the range of 10-100kDa. Enzymatic fingerprinting was performed using a combination of pectin lyase (PL) and endo-polygalacturonase. Detailed information about the structure and level of galacturonic acid oligomers released was obtained using LC-HILIC-MS/ELSD and HPAEC. Predominantly, unsaturated and methyl-esterified oligomers (DP 3-5) were released indicating that high proportions of methylesterified 'PL degradable' areas were present within the pectin. The data revealed that homogalacturonan is the main building block of the extracted pectin and consists of long methylesterified/acetylated GalA sequences interspersed with small blocks of non-methyl-esterified GalA units. PMID- 27474629 TI - Lignin profiling in extracted xylans by size-exclusion chromatography. AB - Utilization of the polymeric parts of lignocellulose is expected to gain increasing importance in future biorefinery scenarios. In that respect, a particular focus is placed on hemicelluloses from different wood species gained from an industrially feasible upgrading step in the production of dissolving pulps from paper pulps. During alkaline post-extractions for hemicellulose removal, residual lignins are extracted as well. They are either covalently linked to the extracted hardwood xylans or simply co-dissolved in the alkaline lye. In order to better describe the lignin in xylan containing lyes, a method for lignin profiling was set up by hyphenating size-exclusion chromatography of xylans with UV detection which facilitates visualization of the residual lignin distribution. Simultaneous lignin quantification was achieved with lignin standards prepared from Kraft cooking liquors. The setup presented may serve as advanced characterization for novel xylan products. PMID- 27474628 TI - Lactobionic acid and carboxymethyl chitosan functionalized graphene oxide nanocomposites as targeted anticancer drug delivery systems. AB - In this work, we report a targeted drug delivery system built by functionalizing graphene oxide (GO) with carboxymethyl chitosan (CMC), fluorescein isothiocyanate and lactobionic acid (LA). Analogous systems without LA were prepared as controls. Doxorubicin (DOX) was loaded onto the composites through adsorption. The release behavior from both the LA-functionalized and the LA-free material is markedly pH sensitive. The modified GOs have high biocompatibility with the liver cancer cell line SMMC-7721, but can induce cell death after 24h incubation if loaded with DOX. Tests with shorter (2h) incubation times were undertaken to investigate the selectivity of the GO composites: under these conditions, neither DOX-loaded system was found to be toxic to the non-cancerous L929 cell line, but the LA-containing composite showed the ability to selectively induce cell death in cancerous (SMMC-7721) cells while the LA-free analogue was inactive here also. These findings show that the modified GO materials are strong potential candidates for targeted anticancer drug delivery systems. PMID- 27474630 TI - Isolation and identification of cellulose-producing strain Komagataeibacter intermedius from fermented fruit juice. AB - A bacterial cellulose (BC) producing strain isolated from fermented fruit juice was identified as Komagataeibacter intermedius (K. intermedius) FST213-1 by 16s rDNA sequencing analysis and biochemical characteristics test. K. intermedius FST213-1 can produce BC within pH 4-9 and exhibit maximum BC production (1.2g/L) at pH 8 in short-term (4-day) cultivation. Results of Fourier transform infrared spectroscopy, X-ray diffraction, water content, thermogravimetric analysis and mechanical property indicated that BC produced from K. intermedius FST213-1 exhibits higher water content ability (99.5%), lower thermostability (315 degrees C), lower crystallinity (79.3%) and similar mechanical properties in comparison with the specimen from model BC producer, Gluconacetobacter xylinus 23769. Based on these analyses, the novel based-resistant strain K. intermedius FST213-1 can efficiently produce BC, which can be applied for industrial manufacturing with potential features. PMID- 27474631 TI - Preparation of silver nano-particles immobilized onto chitin nano-crystals and their application to cellulose paper for imparting antimicrobial activity. AB - Immobilized silver nano-particles (Ag NPs) possess excellent antimicrobial properties due to their unique surface characteristics. In this paper, immobilized silver nano-particles were synthesized in the presence of chitin nano crystals (CNC) based on the Tollens mechanism (reduction of silver ion by aldehydes in the chitosan oligosaccharides (COS)) under microwave-assisted conditions. The prepared Ag NPs-loaded CNC nano-composites were then applied onto the paper surface via coating for the preparation of antibacterial paper. Fourier transform infrared (FT-IR) and X-ray diffraction (XRD) results confirmed that the Ag NPs were immobilized onto the CNC. The transmission electron microscope (TEM) and scanning electron microscopy (SEM) results further revealed that the spherical Ag NPs (5-12nm) were well dispersed on the surface of CNC. The coated paper made from the Ag NPs-loaded CNC nano-composites exhibited a high effectiveness of the antibacterial activity against E. coli or S. aureus. PMID- 27474632 TI - Characterization and antimicrobial properties of cotton fabric loaded with green synthesized silver nanoparticles. AB - In the present study, antimicrobial formulations, based on silver nanoparticles (AgNPs) and butyl acrylate binder, were prepared and applied to a cotton fabric, followed by gamma-radiation or thermal curing, to protect it against the undesirable microbial effects. AgNPs were prepared by a biological method, using the biomass filtrate of fungus Alternaria alternata. Nanoparticles were characterized by UV-vis spectroscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, and dynamic light scattering. Besides, the thermal stability, surface morphology, color strength, and mechanical properties of treated fabric were investigated. Treated cotton fabric showed good quantitative and qualitative antimicrobial activity; the bacterial reduction efficiency reached ~100% for Escherichia coli and Staphylococcus aureus. They revealed excellent resistance to biodegradation caused by soil microflora. Moreover, they exhibited high durability of the attained antimicrobial activities, even after 20 washing cycles; where they achieved 99.1% and 98.7% reduction of E. coli and S. aureus bacterial counts, respectively. PMID- 27474633 TI - Impact of reagent infiltration time on reaction patterns and pasting properties of modified maize and wheat starches. AB - The impact of granular and molecular reaction patterns on modified starch properties was investigated as a function of the length of time allowed for reagent to infiltrate starch granules. A fluorescent reagent [5-(4,6 dichlorotriazinyl)aminofluorescein] was dispersed in aqueous normal maize or wheat starch slurries (35%, w/v) for 0, 5, 10, 30, or 60min, after which reaction was initiated by increasing the pH to 11.5 and allowing reaction to proceed for 3h. With increasing lengths of infiltration, the reaction became increasingly homogeneous within the granule interior (matrix) and the AM:AP reactivity ratio increased (wheat starch), as assessed by confocal laser scanning microscopy (CLSM) and size-exclusion chromatography (refractive index and fluorescence detection), respectively. A longer reagent infiltration time also led to a more inhibited (i.e., cross-linked) pasting viscosity, suggesting that both granular and/or molecular reaction patterns were altered by varied reagent infiltration times to ultimately impact modified starch properties. PMID- 27474634 TI - Microstructure and mechanical properties of arabinoxylan and (1,3;1,4)-beta glucan gels produced by cryo-gelation. AB - The interactions between heteroxylans and mixed linkage glucans determine the architecture and mechanical properties of cereal endosperm cell walls. In this work hydrogels made of cross-linked arabinoxylan with addition of beta-glucan were synthesised by cryogelation as a biomimetic tool to investigate endosperm walls. Molecular and microstructural properties were characterised by nuclear magnetic resonance ((13)C NMR), scanning electron microscopy (SEM) and immunolabelling/confocal laser scanning microscopy (CLSM). The response to mechanical stress was studied by compression-relaxation experiments. The hydrogels consisted of a scaffold characterised by dense walls interconnected by macropores with both hemicelluloses co-localised and homogeneously distributed. The gels showed a high degree of elasticity reflected in their ability to resist compression without developing cracks and recover 60-80% of their original height. Our results highlight the compatibility of these hemicelluloses to coexist in confined environments such as cell walls and their potential role in determining mechanical properties in the absence of cellulose. PMID- 27474635 TI - Oleic acid-grafted chitosan/graphene oxide composite coating for corrosion protection of carbon steel. AB - An anticorrosion coating film based on the formation of nanocomposite coating is reported in this study. The composite consisted of chitosan (green matrix), oleic acid, and graphene oxide (nano filler). The nanocomposite coating was arranged on the surface of carbon steel, and the corrosion resistance was monitored using electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PP). Compared to the pure chitosan (CS) coating, the corrosion resistance of oleic acid-modified chitosan/graphene oxide film (CS/GO-OA) is increased by 100 folds. Since the well-dispersed smart grafted nanolayers delayed the penetration rate of corrosive species and thus maintained long term anticorrosive stability which is correlated with hydrophobicity and permeability. PMID- 27474636 TI - Multifunctional zirconium oxide doped chitosan based hybrid nanocomposites as bone tissue engineering materials. AB - This paper reports the development of multifunctional zirconium oxide (ZrO2) doped nancomposites having chitosan (CTS), organically modified montmorillonite (OMMT) and nano-hydroxyapatite (HAP). Formation of these nanocomposites was confirmed by various characterization techniques such as Fourier transform infrared spectroscopy and powder X-ray diffraction. Scanning electron microscopy images revealed uniform distribution of OMMT and nano-HAP-ZrO2 into CTS matrix. Powder XRD study and TEM study revealed that OMMT has partially exfoliated into the polymer matrix. Enhanced mechanical properties in comparison to the reported literature were obtained after the addition of ZrO2 nanoparticle into the nanocomposites. In rheological measurements, CMZH I-III exhibited greater storage modulus (G') than loss modulus (G"). TGA results showed that these nanocomposites are thermally more stable compare to pure CTS film. Strong antibacterial zone of inhibition and the lowest minimum inhibition concentration (MIC) value of these nanocomposites against bacterial strains proved that these materials have the ability to prevent bacterial infection in orthopedic implants. Compatibility of these nanocomposites with pH and blood of human body was established. It was observed from the swelling study that the swelling percentage was increased with decreasing the hydrophobic OMMT content. Human osteoblastic MG-63 cell proliferations were observed on the nanocomposites and cytocompatibility of these nanocomposites was also established. Moreover, addition of 5wt% OMMT and 5wt% nano-HAP-ZrO2 into 90wt% CTS matrix provides maximum tensile strength, storage modulus, aqueous swelling and cytocompatibility along with strong antibacterial effect, pH and erythrocyte compatibility. PMID- 27474637 TI - Physicochemical and in vitro biocompatibility of films combining reconstituted bacterial cellulose with arabinogalactan and xyloglucan. AB - Reconstituted cellulose films were generated using residual bacterial cellulose membranes mechanically defibrillated (RBC fibrils) recycled following wound dressing production via a dry-cast process. Arabinogalactan (AG) extracted from Pereskia aculeata leaves and/or a xyloglucan (GHXG) from Guibourtia hymenifolia seeds were incorporating into the RBC at various compositions, and new films were created using the same process. Biocomposite properties were evaluated by scanning electron microscopy, contact angle (CA), and X-ray diffraction measurements. The attachment and proliferation of murine L929 fibroblasts on RBC and RBC/Hydrocolloids (HD) were also evaluated. RBC films with 20-30% GHXG replacement improved film stability and the inclusion of HD increased microfiber aggregation and reduced porous regions. Changes in the hydrophilic characteristics were also observed and owing to the adhesion effect the inclusion of HD on RBC led to a statistically significant effect of the mechanical properties of films. The RBC/AG films supported L929 adhesion similar to that observed for commercial bacterial cellulose, indicating their potential use for biomedical applications. PMID- 27474638 TI - Microcrystalline cellulose as reinforcing agent in silicone elastomers. AB - Cellulose is commonly used as filler for the reinforcement of polymer materials but data in the case of silicones remain rare. In this work we report the modification of microcrystalline cellulose (MCC) fibers from cotton linters by propargyl bromide, in aqueous medium without alteration of the crystalline domains. The analysis evidenced the efficient grafting of alkyne functions at the surface of the fibers, the DS being 0.5. The resulting MCC-Alkyne fibers were introduced within a bi-component reactive silicone formulation (up to 20wt%), allowing the formation of network through hydrosilylation reaction in which MCC Alkyne played the role of a reactive fillers. Comparison between the properties of composites prepared with unmodified MCC and MCC-Alkyne highlighted a densification of the network and an enhancement of mechanical and thermal properties when coupling reactions occurred. Mechanical properties of silicone elastomers were better if the load of MCC-Alkyne remains low. PMID- 27474639 TI - Surfactant-free emulsions stabilized by tempo-oxidized bacterial cellulose. AB - In order to seek a safe, biodegradable, and sustainable solid stabilizer for food, topical and pharmaceutical emulsions, individualized cellulose nanofibers were prepared by oxidizing bacterial cellulose (BC) in a Tempo-mediated system; their ability to stabilize oil/water interface was investigated. Significant amounts of C6 carboxylate groups were selectively formed on each cellulose microfibril surface, so that the hydrophilicity was strengthened, leading to lower contact angles. Meanwhile, both the length and width of fibrils were decreased significantly, by partial cleavage of numerous numbers of inter- and intra-fibrillar hydrogen bonds. Tempo-oxidized BC (TOBC) was more effective than BC in stabilizing oil-water interface, attributing to the much smaller size. Fibril dosage and oxidation degree exerted a great influence on the stability and particle size distribution of emulsion samples. When the fibril dosage was 0.7wt.%, the sample was so stable that it did not experience creaming and coalescence over 8 months. The 2-TOBC coated droplets showed the greatest stability, although both the zeta potential and the electric repulsion were the largest for the 10-TOBC analogue, which was manipulated by the wettability of fibrils. In addition, the stability of samples was analyzed from the viewpoint of particle size distribution. Consequently, fibril size and wettability are two counterbalanced factors influencing the stability of TOBC-stabilized emulsions; a combination of suitable wettability and size imparts TOBC-stabilized emulsion high stability. As a kind of biomass-based particle stabilizer, TOBC showed great potential applications in food, topical and pharmaceutical formulations. PMID- 27474640 TI - Elucidating the influence of polymorph-dependent interfacial solvent structuring at chitin surfaces. AB - Interfacial solvent structuring is thought to be influential in mediating the adsorption of biomolecules at aqueous materials interfaces. However, despite the enormous potential for exploitation of aqueous chitin interfaces in industrial, medical and drug-delivery applications, little is known at the molecular-level about such interfacial solvent structuring for chitin. Here we use molecular simulation to predict the structure of the [100] and [010] interfaces of alpha chitin and beta-chitin dihydrate in contact with liquid water and saline solution. We find the alpha-chitin [100] interface supports lateral high-density regions in the first water layer at the interface, which are also present, but not as pronounced, for beta-chitin. The lateral structuring of interfacial ions at the saline/chitin interface is also more pronounced for alpha-chitin compared with beta-chitin. Our findings provide a foundation for the systematic design of biomolecules with selective binding affinity for different chitin polymorphs. PMID- 27474641 TI - Effect of cross linking of PVA/starch and reinforcement of modified barley husk on the properties of composite films. AB - Barley husk (BH) was graft copolymerized by palmitic acid. The crystalline behavior of BH decreased after grafting. Poly vinyl alcohol (PVA)/starch (St) blend film, urea formaldehyde cross linked PVA/St films and composite films containing natural BH, grafted BH were prepared separately. The effect of urea/starch ratio, content of BH and grafted BH on the mechanical properties, water uptake (%), and biodegradability of the composite films was observed. With increase in urea: starch ratio from 0 to 0.5 in the blend, tensile strength of cross linked film increased by 40.23% compared to the PVA/St film. However, in grafted BH composite film, the tensile strength increased by 72.4% than PVA/St film. The degradation rate of natural BH composite film was faster than PVA/St film. Various films were characterized by SEM, FT-IR and thermal analysis. PMID- 27474642 TI - Characterization of cellulose membranes modified with luminescent silicon quantum dots nanoparticles. AB - A highly hydrophilic planar membrane fabricated with regenerated cellulose (RC-4 membrane), a biocompatible polymer, was modified by inclusion of water-soluble silicon quantum dot nanoparticles (SiQDs). Both bare SiQDs and SiQDs coated with a PAMAM-OH dendrimer were employed in order to obtain luminescent and thermally stable membrane systems (RC-4/SiQDs and RC-4/SiQDs-PAMAM-OH membranes). Original and SiQDs-modified membranes were characterized by fluorescence spectroscopy (steady and confocal), derivative thermogravimetric analysis and impedance spectroscopy measurements. According to these results, both SiQDs-regenerated cellulose composite membranes present luminescent character as well as higher thermal resistance and conductivity than the original sample, although the dendrimer coverage of the SiQDs might partially shield such effects. Moreover, the permanence of SiQDs nanoparticles in the structure of the cellulosic support in aqueous environments and their effect on diffusive transport were determined by water uptake as well as by membrane potential measurements at different concentrations of a model electrolyte (KCl). These results demonstrate the possible use of these stable nano-engineered membranes, which are based on SiQDs nanoparticles, in electrochemical devices under flow conditions. PMID- 27474643 TI - Complex coacervation for the development of composite edible films based on LM pectin and sodium caseinate. AB - Coacervation between sodium caseinate (CAS) and low methoxyl pectin (LMP) at pH 3 was investigated as a function of protein/polysaccharide ratio. The highest amount of complex coacervates was formed at a CAS/LMP ratio of 2 at which the zeta-potential value was zero and the turbidity reached its highest value. Then, the properties of films based on these complex coacervates were studied. Coacervation resulted in decreasing water content and water sorption of films as the protein concentration increased. The mechanical properties of films were highly influenced by the formation of electrostatic complexes. The highest values of Young's modulus (182.97+/- 6.48MPa) and tensile strength (15.64+/-1.74MPa) with a slight increase of elongation at break (9.35+/-0.10%) were obtained for films prepared at a CAS/LMP ratio equal to 0.05. These findings show that interactions between LMP and CAS can be used to develop innovative packaging containing active molecules. PMID- 27474644 TI - Sulfated polysaccharide from the marine algae Hypnea musciformis inhibits TNBS induced intestinal damage in rats. AB - Sulfated polysaccharides extracted from seaweed have important pharmacological properties. Thus, the aim of this study was to characterize the sulfated polysaccharide (PLS) from the algae Hypnea musciformis and evaluate its protective effect in colitis induced by trinitrobenzene sulfonic acid in rats. The sulfated polysaccharide possess a high molecular mass (1.24*10(5)gmol(-1)) and is composed of a kappa-carrageenan, as depicted by FT-IR and NMR spectroscopic data. PLS was administered orally (10, 30, and 60mg/kg, p.o.) for three days, starting before TNBS (trinitrobenzene sulfonic acid) instillation (day 1). The rats were killed on day three, the portion of distal colon (5cm) was excised and evaluated macroscopic scores and wet weight. Then, samples of the intestinal were used for histological evaluation and quantification of glutathione, malonyldialdehyde acid, myeloperoxidase, nitrate/nitrite and cytokines. Our results demonstrate that PLS reduced the colitis and all analyzed biochemical parameters. Thus, we concluded that the PLS extracted from the marine algae H. musciformis reduced the colitis in animal model and may have an important promising application in the inflammatory bowel diseases. PMID- 27474645 TI - Inclusion of terpenes in cyclodextrins: Preparation, characterization and pharmacological approaches. AB - Terpenes constitute the largest class of natural products and are important resources for the pharmaceutical, food and cosmetics industries. However, due to their low water solubility and poor bioavailability there has been a search for compounds that could improve their physicochemical properties. Cyclodextrins (natural and derived) have been proposed for this role and have been complexed with different types of terpenes. This complexation has been demonstrated by using analytical techniques for characterizing complexes such as DSC, NMR, XRD, FTIR, and TGA. The formation of inclusion complexes has been able to improve drug characteristics such as bioavailability, solubility and stability; and to enhance biological activity and efficacy. This review shows strong experimental evidence that cyclodextrins improve the pharmacological properties of terpenes, and therefore need to be recognized as being possible targets for clinical use. PMID- 27474646 TI - The effect of cellulose molar mass on the properties of palmitate esters. AB - Nowadays one of the growing trends is to replace oil-based products with cellulose-based materials. Currently most cellulose esters require a huge excess of chemicals and have therefore, not been broadly used in the industry. Here, we show that decreasing the molar mass of cellulose by ozone hydrolysis provides cellulose functionalization with less chemical consumption. To reveal the differences in reactivity and chemical consumption, we showed esterification of both native cellulose and ozone treated hydrolyzed cellulose. Based on the results, the molar mass of the starting cellulose has a significant effect on the end product's degree of substitution and properties. Furthermore, molar mass controlled palmitate esters form mechanically strong, flexible and optically transparent films with excellent water barrier properties. We anticipate that molar mass controlled cellulose will provide a starting point for the greater use of cellulose based materials, in various application, such as films and composites. PMID- 27474647 TI - Chitosan attenuates dibutyltin-induced apoptosis in PC12 cells through inhibition of the mitochondria-dependent pathway. AB - Dibutyltin (DBT) which was widely used as biocide and plastic stabilizer has been described as a potent neurotoxicant. Chitosan (CS), a natural nontoxic biopolymer, possesses a variety of biological activities including antibacterial, antifungal, free radical scavenging and neuroprotective activities. The present study was undertaken to investigate the protective effects of CS against DBT induced apoptosis in rat pheochromocytoma (PC12) cells and the underlying mechanisms in vitro. Our results demonstrated that pretreatment with CS significantly increased the cell viability and decreased lactate dehydrogenase (LDH) release induced by DBT in a dose-dependent manner. Meanwhile, DBT-induced cell apoptosis, mitochondrial membrane potential (MMP) disruption, and generation of intracellular reactive oxygen species (ROS) were attenuated by CS. Real-time PCR assay showed that DBT markedly enhanced the mRNA levels of Bax, Bad, cytochrome-c and Apaf-1, reduced the Bcl-2 and Bcl-xL mRNA levels, while these genes expression alteration could be partially reversed by CS treatment. Furthermore, CS also inhibited the DBT-inducted activation of caspase-9, and -3 at mRNA and protein expression levels. Taken together, these results suggested that CS could protect the PC12 cells from apoptosis induced by DBT through inhibition of the mitochondria-dependent pathway. PMID- 27474648 TI - Synthesis of surfactant-free hydroxypropyl methylcellulose nanogels for controlled release of insulin. AB - A facile controlled-release nanogels delivery system has been developed by using hydroxypropyl methylcellulose (HPMC) hybrid nanogels as encapsulation shell materials, which were synthesized by surfactant-free polymerization in aqueous solution. The effects of reaction time and cross-linker concentration on the size of the nanogels have been studied. The results showed that in a certain range, the particle size decreased with increasing reaction time and increasing concentration of cross-linker. Meanwhile, at the feeding ratio 0.05/1 of HPMC/methacrylic acid (MAA), the LCST of prepared nanogels at pH=6 was close to the body temperature, which can be used as sustained insulin delivery system. Besides, the HPMC nanogels loaded with insulin had a high drug loading of 21.3% and a high entrapment efficiency of 95.7%. The release behavior of the insulin nanogels can be adjusted by pH and temperature which will have potential applications in controlled release delivery system. PMID- 27474649 TI - Antibacterial cotton fibers treated with silver nanoparticles and quaternary ammonium salts. AB - Cotton fibers were treated chemically with glycidyltrimethylammonium chloride (GTAC), a quaternary ammonium salt, and coated with silver nanoparticles/3 mercaptopropyltrimethoxysilane (3-MPTMS) to increase the antibacterial efficacy. The coating process was accomplished by soaking the cotton fibers into a GTAC solution followed by a dry-cure method, and silver colloid/3-MPTMS solution was then applied at 43 degrees C for 90min. The properties of the cotton fibers were analyzed by scanning electron microscopy, X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis. SEM showed a rough surface when the cotton fibers were treated with GTAC/3-MPTMS/silver nanoparticles due to the increasing surface attachment. The existence of silver and 3-MPTMS on the cotton fibers was confirmed by XPS. The cotton fibers treated with both GTAC and silver nanoparticles showed synergistic antibacterial properties against P. aeruginosa. PMID- 27474650 TI - Fabrication of a novel bone ash-reinforced gelatin/alginate/hyaluronic acid composite film for controlled drug delivery. AB - In this study, a novel pH-sensitive composite film with enhanced thermal and mechanical properties was prepared by the incorporation of bone ash at varying concentrations from 0 to 10v.% into gelatin/sodium alginate/hyaluronic acid (Gel/SA/HyA) polymeric structure for colon-specific drug delivery system. Films were characterized by FT-IR, SEM, and XRD analyses. Thermal and mechanical performances of films were determined by DSC, TGA and universal mechanical tester, respectively. Results proved that thermal stability and mechanical properties of bone ash-reinforced composite films improved significantly with respect to that of neat Gel/SA/HyA film. Cytotoxicity assay for composite films was carried out by using L929 cells. Water uptake capacity of films was determined by swelling test. Herein, release experiments of 5-Fluorouracil (5-FU) were performed in two different solutions (pH 2.1 and 7.4). The results assured that Gel/SA/HyA film containing BA could be considered as a potential biomaterial for controlled drug delivery systems. PMID- 27474652 TI - Synthesis of alpha(1->4)-linked non-natural mannoglucans by alpha-glucan phosphorylase-catalyzed enzymatic copolymerization. AB - alpha-Glucan phosphorylase catalyzes enzymatic polymerization of alpha-d-glucose 1-phosphate (Glc-1-P) as a monomer from a maltooligosaccharide primer to produce alpha(1->4)-glucan, i.e., amylose, with liberating inorganic phosphate (Pi). Because of quite weak specificity for the recognition of substrates by thermostable alpha-glucan phosphorylase (from Aquifex aeolicus VF5), in this study, we investigated the enzymatic copolymerization of Glc-1-P with its analogue monomer, alpha-d-mannose 1-phosphate (Man-1-P) under the conditions for removal of Pi as the precipitate with ammonium and magnesium in ammonia buffer containing Mg(2+) ion to produce alpha(1->4)-linked non-natural mannoglucans composed of Glc/Man units. The reaction was conducted in different feed ratios using the maltotriose primer at 40 degrees C for 7days. The MALDI-TOF mass and (1)H NMR spectra of the products fully supported the mannoglucan structures. PMID- 27474651 TI - A polysaccharide from Huaier induced apoptosis in MCF-7 breast cancer cells via down-regulation of MTDH protein. AB - In this study, one homogeneous polysaccharide (SP1), with a molecular weight of 56kDa, was isolated from the Huaier fruiting bodies. It had a backbone consisting of 1,4-linked-beta-d-Galp and 1,3,6-linked-beta-d-Galp residues, which was terminated with 1-linked-alpha-d-Glcp and 1-linked-alpha-l-Araf terminal at O-3 position of 1,3,6-linked-beta-d-Galp unit along the main chain in the ratio of 1.1:2.0:1.1:1.1. MTT assay showed that shMTDH or SP1 (100, 200 and 400MUg/ml) was able to suppress the proliferation of MCF-7 cells, due to a significant increase in the number of apoptotic cells as determined by flow cytometric analysis. Furthermore, Western blot analysis revealed that SP1 or shMTDH treatment led to a rise of ratio between proapoptotic Bax and antiapoptotic Bcl-2 protein in MCF-7 cells. In addition, carcinogene MTDH protein expression in MCF-7 cells received SP1 (100, 200 and 400MUg/mL) or shMTDH treatment was also repressed after 48h incubation. Taken together, these findings indicated that SP1 has anticancer potential in the treatment of human breast cancer. PMID- 27474653 TI - Supramolecular aggregates of oligosaccharides with co-solvents in ternary systems for the solubilizing approach of triamcinolone. AB - A second compound is generally associated with oligosaccharides as a strategy to maximize the solubilizing effect for nonpolar compounds. This study elucidated the role and the mechanism whereby liquid compounds interact in these supramolecular aggregates in the solubilization of triamcinolone. Three different oligosaccharides (beta-cyclodextrin, 2-hydroxipropil-beta-cyclodextrin, and randomly methylated beta-cyclodextrin) and two potent co-solvents (triethanolamine and N-methyl pyrrolidone) were carefully evaluated by using three distinct experimental approaches. Incredibly stable complexes were formed with cyclodextrins (CDs). The structure of the complexes was elucidated by magnetic resonance spectra 2D-ROESY. The interactions of the protons of ring "A" of the drug with H(3) and H(5) protons of the CD cavity observed in the binary complexes remained in both ternary complexes. Unlike the observed ternary associations with triethanolamine, N-methyl pyrrolidone competed with the triamcinolone CD cavity and considerably decreased the stability of the complex and the solubility of the drug. The molecular dynamics (MD) and quantum mechanics:molecular mechanics (QM:MM) calculations supported that triethanolamine stabilized the drug-CD interactions for the conformer identified in the 2D-ROESY experiments, improving the quality and uniformity of the formed complex. The role played by the co-solvent in the ternary complexes depends on its specific ability to interact with the CD cavity in the presence of the drug, which can be predicted in theoretical studies to select the best candidate. PMID- 27474654 TI - Dynamic measurement of starch granule swelling during microwave heating. AB - The size of starch granules in dilute aqueous suspension was measured in-line during gelatinization in a microwave-heated, well-mixed system. The results were compared with those of a previous study conducted with conventional heating. For the starches used (common corn, waxy maize, and cross-linked waxy maize), no significant difference was found between microwave and conventional heating in terms of maximum diameter, temperature of maximum rate of diameter increase, or diameter vs. temperature behavior. These results suggest that there are no differences in the swelling behavior of common and modified maize starches between microwave and conventional heating. PMID- 27474655 TI - Testing zinc chloride as a new catalyst for direct synthesis of cellulose di- and tri-acetate in a solvent free system under microwave irradiation. AB - This research demonstrates the effect of ZnCl2 as a catalyst on the esterification of commercial cotton cellulose using acetic anhydride in order to obtain di- and tri-cellulose acetates under microwave irradiation. It was discovered that microwave irradiation significantly increased the yield and reduced the reaction time. It was found that the maximum yield for cellulose triacetates was 95.83% under the reaction conditions that were as follows: 3min reaction time, 200mg of ZnCl2 catalyst and 20ml of Ac2O for 5g cellulose. However, the cellulose acetate obtained in this manner had the highest DS (2.87). The cellulose di-acetate was produced with the maximum yield of 89.97% and with the highest DS (2.69) using 25ml Ac2O, 200mg of ZnCl2 for 5g cellulose and in 3min reaction time. The effect of some factors such as the amount of used catalyst, the quantity of acetic acid anhydride and the reaction time of the esterification process have been investigated. The production of di- and tri cellulose acetate and the degree of substitution were confirmed using Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR). The thermal stability was investigated using thermo gravimetric analysis (TGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC). The molecular weight and the degree of polymerization were obtained using Gel Permeation Chromatography (GPC). The analysis confirmed the successful synthesis of di- and tri-cellulose acetate without degradation during the reaction; these results were found to be in contrast to some recent studies. The present study reveals that ZnCl2 is a new catalyst; it is effective as well as inexpensive and is a low toxicity catalyst for usage in cellulose esterification. PMID- 27474656 TI - Production of nano bacterial cellulose from beverage industrial waste of citrus peel and pomace using Komagataeibacter xylinus. AB - Bacterial cellulose (BC) is a high-purity and robust cellulose that is utilised in medicine, consumer goods, and industrial practices. The present study aimed to investigate the suitability of beverage industrial waste for the production of BC by Komagataeibacter xylinus CICC No. 10529 and to study the structural properties of BC films in both citrus peel and pomace enzymolysis (CPPE) and Hestrin-Schramm (HS, Hestrin & Schramm, 1954) media. Under similar experimental conditions, the yield of BC from CPPE medium was 5.7+/-0.7g/L, which was higher than from HS medium (3.9+/-0.6g/L). To evaluate the structure of BC, fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and colour evaluation using a chroma meter were utilised. The average diameters of BC, obtained from CPPE and HS mediums, were 50nm and 60nm, respectively. The crystallinity index of BC from the CPPE medium was approximately 63%, which was lower than BC produced from the HS medium (65%). The two varieties of BC showed no significant differences in relation to their colour parameters. Therefore, BC production from CPPE medium had similar properties to BC from HS medium, but it is more environmentally friendly and cheaper to produce. PMID- 27474657 TI - Influence of natural and synthetic crosslinking reagents on the structural and mechanical properties of chitosan-based hybrid hydrogels. AB - The objective of this work was to correlate the physical and chemical properties of chitosan/poly(vinyl alcohol)/genipin (CS/PVA/GEN) and chitosan/poly(vinyl alcohol)/glutaraldehyde (CS/PVA/GA) hydrogels with their structural and mechanical responses. In addition, their molecular structures were determined and confirmed using FTIR spectroscopy. The results indicated that the hybrid hydrogels crosslinked with genipin showed similar crystallinity, thermal properties, elongation ratio and structural parameters as those crosslinked with glutaraldehyde. However, it was found that the elastic moduli of the two hybrid hydrogels were slightly different: 2.82+/-0.33MPa and 2.08+/-0.11MPa for GA and GEN, respectively. Although the hybrid hydrogels crosslinked with GEN presented a lower elastic modulus, the main advantage is that GEN is five to ten thousand times less cytotoxic than GA. This means that the structural and mechanical properties of hybrid hydrogels crosslinked with GEN can easily be tuned and could have potential applications in the tissue engineering, regenerative medicine, food, agriculture and environmental industries. PMID- 27474658 TI - The rheological injectability of N-succinyl-chitosan solutions. AB - The viscosity of a set of N-succinyl-chitosan (NSC) solutions was characterized near the 0.2Pas rheological injectability limit. This is believed to be the first such report in the open literature. Viscosity was characterized at physiological pH and ionic strength as a function of NSC degree of substitution, NSC concentration, temperature, and shear rate. NSC was synthesized via Yamaguci's method and characterized using H-NMR, membrane osmometry, TGA and isothermal vacuum drying. NSC synthesis results were shown to fit a reproducible log-linear correlation and both optimum drying temperature and thermal decomposition temperature were found to be a function of NSC degree of substitution. Viscosity results were explained using Katchalsky's full model for polyampholyte ionization combined with a charge induced excluded volume model proposed by Higgs. The model predicted a polyelectrolyte/polyampholyte transition which agreed well with experimental data. For minimally injectable formulations a maximum in primary amine concentration is expected at 32sub% amine NSC. PMID- 27474659 TI - Preparation of methacrylamide-functionalized crosslinked chitosan by free radical polymerization for the removal of lead ions. AB - A new poly(methacrylamide) grafted crosslinked chitosan was prepared for removal of lead, Pb(II) ion from aqueous solution. Crosslinked chitosan, in beads form, was grafted with methacrylamide (MAm) using ammonium persulfate (APS) as free radical initiator. Evidence of grafting was determined by comparing FTIR, TGA, SEM and (13)C NMR analyses of chitosan and graft copolymer. The optimal conditions for grafting reaction were as follow: crosslinked chitosan beads (1g), MAm (17.62*10(-1)M), APS (2.63*10(-1)M), reaction time (3h) and temperature (60 degrees C). The modified chitosan bead was then used in laboratory batch experiments to evaluate the removal of Pb(II) ion from water samples. The Langmuir and Freundlich adsorption models were also applied to describe the equilibrium isotherms. The results revealed that the adsorption of Pb(II) ions onto the beads fitted very well with the Langmuir model with the maximum capacity (qmax) of 250mgg(-1). PMID- 27474660 TI - Synthesis of assorted metal ions anchored alginate bentonite biocomposites for Cr(VI) sorption. AB - Biocomposites were synthesized by dispersing bentonite (Bent) clay in a biopolymer namely alginate (Alg) and cross-linked with bi (Ca(2+)), tri (Ce(3+)) and tetravalent (Zr(4+)) metal ions viz., Ca@AlgBent, Ce@AlgBent and Zr@AlgBent composites respectively. The synthesized biocomposites were characterized by various instrumental techniques like FTIR, SEM and EDAX. Cr(VI) sorption capacities (SCs) of the biocomposites Ca@AlgBent, Ce@AlgBent and Zr@AlgBent were examined by batch process. Various adsorption influencing factors viz., contact time, dosage of the sorbent, pH of the medium, temperature, presence of common co ions and initial Cr(VI) concentration were studied. Freundlich, Langmuir and Dubinin-Radushkevich (D-R) isotherm models were adopted to examine the adsorption equilibrium. Kinetics of the sorption process was carried out by pseudo-first order and pseudo-second-order models. The nature of the sorption process was explained using thermodynamic parameters like DeltaS degrees , DeltaG degrees and DeltaH degrees and a possible mechanism for the sorption of Cr(VI) onto the biocomposites was given. The application of the biocomposites at field conditions was also examined by testing it with industrial water. The regeneration studies were carried to know about the reusability of the biocomposites. PMID- 27474661 TI - The effect of hydration on the micromechanics of regenerated cellulose fibres from ionic liquid solutions of varying draw ratios. AB - Regenerated cellulose fibres - Ioncell-F, have been prepared with different draw ratios from cellulose solution in 1,5-diazabicyclo[4.3.0]non-5-ene-1-ium acetate ([DBNH]OAc) ionic liquid. Properties of the fibres were investigated in dry and wet conditions. The stiffness of fibres decreased on average 5 times upon the hydration while the tensile strength remained at around 70% of the initial value. The effect of hydration on the deformation mechanisms and mechanical properties was addressed using Raman spectroscopy. Bands located at 1095cm(-1) and 1414cm( 1) corresponding to the glucosidic linkage C-O-C and side groups C-O-H were followed upon straining. Raman band shifts were observed indicating molecular deformations. Moreover, the hydration of fibres altered the shifting rates implying changes in the molecular micromechanics. It is suggested that hydration affects inter-chain hydrogen bonds thus resulting in the slippage of the chains and lower stiffness of fibres. Some discrepancies from the series aggregate model have been observed which is indicative of changes in the deformation mechanisms upon hydration of the fibres. PMID- 27474662 TI - Evaluation of ethylenediamine-modified nanofibrillated cellulose/chitosan composites on adsorption of cationic and anionic dyes from aqueous solution. AB - A multi-functional adsorbent was prepared by modifying nanofibrillated cellulose/chitosan composites with ethylenediamine (E-NFC/CS). The E-NFC/CS was characterized by FTIR and used for adsorption of cationic dye methylene blue (MB) and anionic dye new coccine (NC) from aqueous solution. The FTIR results showed that the E-NFC/CS contained more amino groups than the NFC/CS due to the modification for the NFC/CS with ethylenediamine. The results indicated that the maximum adsorption capacities occurred at pH 4.0 for MB and pH 2.0 for NC, respectively. The adsorption equilibrium time for MB and NC was 30 and 50min, respectively. In addition, the regenerated E-NFC/CS exhibited excellent adsorption performance for NC. It can keep almost 98% of the adsorption capacity after reused three times. Therefore, the E-NFC/CS can be potentially used as an effective adsorbent of cationic and anionic dyes in industrial effluents. PMID- 27474663 TI - Preparation of aminated chitosan/alginate scaffold containing halloysite nanotubes with improved cell attachment. AB - The chemical nature of biomaterials play important role in cell attachment, proliferation and migration in tissue engineering. Chitosan and alginate are biodegradable and biocompatible polymers used as scaffolds for various medical and clinical applications. Amine groups of chitosan scaffolds play an important role in cell attachment and water adsorption but also associate with alginate carboxyl groups via electrostatic interactions and hydrogen bonding, consequently the activity of amine groups in the scaffold decreases. In this study, chitosan/alginate/halloysite nanotube (HNTs) composite scaffolds were prepared using a freeze-drying method. Amine treatment on the scaffold occurred through chemical methods, which in turn caused the hydroxyl groups to be replaced with carboxyl groups in chitosan and alginate, after which a reaction between ethylenediamine, 1-ethyl-3,(3-dimethylaminopropyl) carbodiimide (EDC) and scaffold triggered the amine groups to connect to the carboxyl groups of chitosan and alginate. The chemical structure, morphology and mechanical properties of the composite scaffolds were investigated by FTIR, CHNS, SEM/EDS and compression tests. The electrostatic attraction and hydrogen bonding between chitosan, alginate and halloysite was confirmed by FTIR spectroscopy. Chitosan/alginate/halloysite scaffolds exhibit significant enhancement in compressive strength compared with chitosan/alginate scaffolds. CHNS and EDS perfectly illustrate that amine groups were effectively introduced in the aminated scaffold. The growth and cell attachment of L929 cells as well as the cytotoxicity of the scaffolds were investigated by SEM and Alamar Blue (AB). The results indicated that the aminated chitosan/alginate/halloysite scaffold has better cell growth and cell adherence in comparison to that of chitosan/alginate/halloysite samples. Aminated chitosan/alginate/halloysite composite scaffolds exhibit great potential for applications in tissue engineering, ideally in cell culture. PMID- 27474664 TI - Edible films based on cassava starch and fructooligosaccharides produced by Bacillus subtilis natto CCT 7712. AB - The objectives of this work were to produce fructooligosaccharides (FOSs) by using the microorganism Bacillus subtilis natto CCT 7712 and to employ these FOSs as a functional ingredient in cassava starch edible films, which were characterized according to their microstructure, mechanical and barrier properties. The produced FOSs could be easily dissolved, resulting in homogeneous filmogenic solutions, which were easily manipulated to obtain films by casting. FOSs were added in different concentrations (0, 1, 5 and 10g/100g solids), and glycerol was used as a plasticizer (20g/100g solids). All formulations resulted in films that had a good appearance and were easily removable from the plates without bubbles or cracks. The FOSs exerted a plasticizing effect on the starch films and decreased their glass transition temperature. The addition of FOSs resulted in higher solubility and elongation and a decreased water vapor permeability of the films. FOSs were shown to be a promising ingredient for use in edible starch films. PMID- 27474665 TI - Enhancement of antioxidant activity of green tea epicatechins in beta cyclodextrin cavity: Single-crystal X-ray analysis, DFT calculation and DPPH assay. AB - Green tea catechins are potent antioxidant for prevention of various free radical related diseases. Their antioxidant properties can be improved by encapsulation in cyclodextrins (CDs). Four inclusion complexes of beta-CD with (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG) and (-) epigallocatechin gallate (EGCG) have been investigated using single-crystal X-ray diffraction analysis combined with full geometry optimization by DFT/B3LYP calculation and the DPPH assay, aiming to deepen the understanding on their structure-antioxidant activity relationship. Scrutinizing the inclusion structures and conformational changes of the four encapsulated epicatechins reveals the common host-guest stabilization scheme and the epicatechin conformational flexibility facilitating the enhancement of activity. Thermodynamic stability order derived from DFT calculation in vacuum fairly agrees with the order of improved antioxidant capacity deduced from the DPPH assay, beta-CD-EGCG>beta-CD-ECG>beta-CD-EGC~beta-CD-EC. PMID- 27474666 TI - Formation of kappa-carrageenan-gelatin polyelectrolyte complexes studied by (1)H NMR, UV spectroscopy and kinematic viscosity measurements. AB - The intermolecular interactions between an anionic polysaccharide from the red algae kappa-carrageenan and a gelatin polypeptide, forming stoichiometric polysaccharide-polypeptide (bio)polyelectrolyte complexes in the aqueous phase, were examined. The major method of investigation was high-resolution (1)H NMR spectroscopy. Additional data were obtained by UV absorption spectroscopy, light scattering dispersion and capillary viscometry. Experimental data were interpreted in terms of the changing roles of electrostatic interactions, hydrophobic interactions and hydrogen bonds when kappa-carrageenan-gelatin complexes are formed. At high temperatures, when biopolymer macromolecules in solution are in the state of random coil, hydrophobic interactions make a major contribution to complex stabilization. At the temperature of gelatin's coil >helix conformational transition and at lower temperatures, electrostatic interactions and hydrogen bonds play a defining role in complex formation. A proposed model of the kappa-carrageenan-gelatin complex is discussed. PMID- 27474667 TI - Polymeric micelles of amphiphilic graft copolymer of alpha-tocopherol succinate-g carboxymethyl chitosan for tamoxifen delivery: Synthesis, characterization and in vivo pharmacokinetic study. AB - Novel amphiphilic graft copolymers were prepared from low molecular weight carboxymethyl chitosan (LMW Cmc) and alpha-tocopherol succinate (TS) via an amidation reaction and confirmed by (1)H NMR and IR spectroscopy. These graft copolymers are self-assembled to nanosized core-shell-structural micelles in an aqueous milieu. The critical micelle concentration (CMC) decreased with an increasing substitution of TS on LMW Cmc, which ranged from 7.94*10(-8) to 1.58*10(-6)g/mL. Cmc-TS4.5 (Cmc-TS with a charged molar ratio of TS to glucosamine units of Cmc~4.5) was shown maximum TMX loading up to 8.08+/-0.98%. Both blank and TMX-loaded PM's of Cmc-TS4.5 exhibit spherical shape with particle size below 200nm. An in vitro release study in simulated gastric and intestinal fluid demonstrated that TMX release from TMX-PM4.5 (TMX-PMs prepared with amphiphilic polymer Cmc-TS4.5, and the weight ratio of Cmc-TS4.5 to TMX was 8:1) was slow and pH dependent. In vivo oral absorption study revealed Cmc-TS4.5 based PM's permeated the epithelial barrier via the paracellular route without causing any intestinal damage. In vivo toxicity study demonstrated the safety of PM's after oral administration. Compared to tamoxifen control, TMX-PM4.5 dosed to fasted female Sprague Dawley rats showed a 1.9 fold increase in AUC0-72h. Thus, the results suggested that Cmc-TS micelles are a promising carrier for TMX delivery. PMID- 27474668 TI - Synthesis of novel amphiphilic hyaluronan containing-aromatic fatty acids for fabrication of polymeric micelles. AB - Novel hydrophobized hyaluronan (HA) derivatives, containing omega-phenylalkanoic acids (omega-PAA, 4-phenylbutyric acid, 6-phenylhexanoic, 8-phenyloctanoic or 11 tolylundecanoic acids) were prepared by esterification. Mixed anhydrides obtained after reaction of the carboxyl acid moiety and benzoyl chloride were found to be active acylating agents, affording hydrophobized HA in good yield and under mild conditions. The reactivity of the aromatic fatty acids towards esterification has decreased with the increasing length of the aliphatic spacer between the aromatic substituent and carboxylic acid moiety. The novel HA derivatives self-assembled from very low concentrations and were found to be non-cytotoxic. The potential use of omega-phenylalkanoic acids grafted-HA towards drug delivery applications was demonstrated by hydrophobic drugs (resveratrol and retinyl palmitate) encapsulation. The drug loading capacity of the novel HA derivatives was significantly improved most likely because of pi?pi interactions between the micelle core and loaded hydrophobic aromatic compound. PMID- 27474669 TI - Synthesis and screening of N-acyl thiolated chitosans for antibacterial applications. AB - Low-molecular weight chitosan-thioglycolic acid has shown significant antibacterial properties against different microorganisms. In order to explore the potential and structure-activity relationships of newly synthesized alkyl thiomers, chitosan has been functionalized with a series of thio-acids with increasing alkyl chain length. All thiomers were characterized with special emphasis on the determination of their degree of deacetylation and substitution, as well as on their molecular weight and amount of thiol groups. The pre-screened chitosan-thiomers were further investigated with plate counting on Pseudomonas aeruginosa, Streptococcus sobrinus and Streptococcus mutans. Furthermore, LIVE/DEAD assays supported the efficiency of chitosan-thiomers against the above microorganisms. All fully characterized chitosan-thiomers showed comparable or enhanced antimicrobial activity compared to pristine chitosan. Our comprehensive approach paves the way to detailed explorations of much sought-after structure activity relationships in the complex chitosan parameter room, starting from correlations between alkyl chain length and antimicrobial activity. PMID- 27474670 TI - Effect of hydroxypropyl-beta-cyclodextrin and coadjuvants on the sorption capacity of hydrophilic polymer films for monoterpene alcohols. AB - Chitosan films filled with hydroxypropyl-beta-cyclodextrin at a 1:1 weight ratio and plasticized with 35 or 50% glycerol or 35% propylene glycol were prepared by casting and conditioned at different relative humidities to achieve a similar water content. Sorption properties of the films for various monoterpene compounds with phenolic, or with linear or cyclohexyl alcohol structures were studied after their immersion in the volatile liquids. In general, the films presented a considerable capacity to retain monophenolic compounds, with sorption values ranging from 455% for meta-cumenol to 193% for guaiacol, for chitosan films with the same formulation. These values were two orders of magnitude higher than those of compounds without the phenol group. The affinity for monophenolic compounds decreased in films plasticized with hydrophilic propylene glycol, whereas no changes were observed in the retention of non-phenolic monoterpenes. Replacement of chitosan with polyvinyl alcohol polymer considerably decreased the retention of monophenolic compounds, with the exception of isoeugenol. Finally, the antimicrobial activity of monoterpenes and films loaded with them was evaluated in vitro by the microatmosphere test against Escherichia coli and Staphylococcus aureus. The present study shows that hydroxypropyl-beta-cyclodextrin and the plasticization level achieved by hydrophilic films can be used to regulate loading capacity and sorption selectivity of naturally occurring antimicrobial compounds. PMID- 27474671 TI - Cellulose nanocrystals reinforced environmentally-friendly waterborne polyurethane nanocomposites. AB - Focusing on eco-friendly materials, cellulose nanocrystals (CNC) have gained attention as nanoreinforcement due to their exceptional properties conferred by the elevated length/diameter aspect ratio and high specific mechanical properties. Furthermore, their water dispersibility makes them suitable nanoreinforcements for their incorporation in waterborne polyurethanes (WBPU). The possibility of tailoring the properties by varying the composition and nature of the reagents, opens the opportunity for a wide range of applications. Therefore, in this work a WBPU was synthesized for the preparation of nanocomposite films with different CNC content and the properties of the films were analyzed. The effective incorporation of CNC resulted in an increase in moduli and stress at yield besides in an increased thermomechanical stability, reaching the percolation threshold at a 3wt% CNC as determined theoretically. Nevertheless, above the percolation threshold, the presence of agglomerates reduced slightly these values. The prepared nanocomposites showed increased hydrophilicity after CNC addition. PMID- 27474672 TI - Production of new cellulose nanomaterial from red algae marine biomass Gelidium elegans. AB - Nanocellulose was successfully isolated from Gelidium elegans red algae marine biomass. The red algae fiber was treated in three stages namely alkalization, bleaching treatment and acid hydrolysis treatment. Morphological analysis was performed by field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). TEM results revealed that the isolated nanocellulose had the average diameter and length of 21.8+/-11.1nm and of 547.3+/-23.7nm, respectively. Fourier transform infrared (FTIR) spectroscopy proved that the non cellulosic polysaccharides components were progressively removed during the chemically treatment, and the final derived materials composed of cellulose parent molecular structure. X-ray diffraction (XRD) study showed that the crystallinity of yielded product had been improved after each successive treatments subjected to the treated fiber. The prepared nano-dimensional cellulose demonstrated a network-like structure with higher crystallinity (73%) than that of untreated fiber (33%), and possessed of good thermal stability which is suitable for nanocomposite material. PMID- 27474673 TI - A one-step bioprocess for production of high-content fructo-oligosaccharides from inulin by yeast. AB - Commercial fructo-oligosaccharides (FOS) are predominantly produced from sucrose by transfructosylation process that presents a maximum theoretical yield below 0.60gFOSgSucrose(-1). To obtain high-content FOS, costly purification is generally employed. Additionally, high-content FOS can be produced from inulin by using endo-inulinases. However, commercial endo-inulinases have not been extensively used in scale-up production of FOS. In the present study, a one-step bioprocess that integrated endo-inulinase production, FOS fermentation, and non FOS sugars removal into one reactor was proposed to produce high-content FOS from inulin. The bioprocess was implemented by a recombinant yeast strain JZHDeltaS TSC, in which a heterologous endo-inulinase gene was expressed and the inherent invertase gene SUC2 was disrupted. FOS fermentation at 40 degrees C from 200g/L chicory inulin presented the maximun titer, yield, and productivity of 180.2+/ 0.8g/L, 0.9gFOSgInulin(-1), and 7.51+/-0.03g/L/h, respectively. This study demonstrated that the one-step bioprocess was simple and highly efficient. PMID- 27474674 TI - The antihyperlipidemic activities of enzymatic and acidic intracellular polysaccharides by Termitomyces albuminosus. AB - Two polysaccharides, EIPS and AIPS were obtained by the hydrolysis of IPS from Termitomyces albuminosus, and their pharmacological effects on blood lipid profiles metabolism and oxidative stress were investigated. The results demonstrated that EIPS was superior to IPS and AIPS on reducing hepatic lipid levels and preventing oxidative stress by improving serum enzyme activities (ALT, AST, and ALP), serum lipid levels (TC, TG, HDL-C, LDL-C and VLDL-C), hepatic lipid levels (TC and TG), and antioxidant status (SOD, GSH-Px, CAT, T-AOC, MDA, and LPO). These conclusions indicated that EIPS, AIPS and IPS might be suitable for functional foods and natural drugs on preventing the high-fat emulsion induced hyperlipidemia. In addition, the monosaccharide compositions of IPS and its hydrolyzate were also processed. PMID- 27474675 TI - Chitosan-bound pyridinedicarboxylate Ni(II) and Fe(III) complex biopolymer films as waste water decyanidation agents. AB - Chitosan is a biopolymer with immense structural advantage for chemical and mechanical modifications to generate novel properties, functions and applications. This work depicts new pyridinedicarboxylicacid (PDC) crosslinked chitosan-metal ion films as veritable material for cyanide ion removal from aqueous solution. The PDC-crosslinked chitosan-metal films (PDC-Chit-Ni(II) and PDC-Chit-Fe(III)) were formed by complexing PDC-crosslinked chitosan film with anhydrous nickel(II) and iron(III) chloride salts respectively. The PDC-Chit and its metal films were characterized employing various analytical and spectroscopic techniques. The FT-IR, UV-vis and the XRD results confirm the presence of the metal ions in the metal coordinated PDC-crosslinked chitosan film. The surface morphological difference of PDC-Chit-Ni(II) film before and after decyanidation was explored with scanning electron microscopy. Furthermore, the quantitative amount of nickel(II) and iron(III) present in the complex were determined using Atomic Absorption Spectrophotometer as 32.3 and 37.2MUg/g respectively which portends the biopolymer film as a good complexing agent. Removal of cyanide from aqueous solution with PDC-Chit, PDC-Chit-Ni(II) and PDC-Chit-Fe(III) films was studied with batch equilibrium experiments. At equilibrium, decyanidation capacity (DC) followed the order PDC-Chit-Ni (II)~PDC-Chit-Fe(III)>PDC-Chit. PDC Chit-Ni(II) film gave 100% CN(-) removal within 40min decyanidation owing to favorable coordination geometry. PMID- 27474676 TI - pH responsive polyurethane (core) and cellulose acetate phthalate (shell) electrospun fibers for intravaginal drug delivery. AB - In this study we present the use of co-axial electrospinning to produce core shell composite micro-/nano- fibers of polyurethane (PU) and cellulose acetate phthalate (CAP). The designed fibers possess enhanced mechanical properties with a tensile strength of 13.27+/-2.32MPa, which is a clear improvement over the existing CAP fibers that suffer from a poor mechanical strength (0.2+/-0.03MPa). The CAP imparts pH responsiveness to the core-shell structure giving the fibers potential for "semen sensitive" (intravaginal) drug delivery. PMID- 27474677 TI - Release studies of trans-anethole from beta-cyclodextrin solid inclusion complexes by Multiple Headspace Extraction. AB - This study aimed to evaluate the effect of the preparation method, temperature and humidity on the release of aroma from beta-cyclodextrin (beta-CD) solid inclusion complexes (IC). Therefore beta-CD/trans-anethole (beta-CD/AN) IC were prepared by freeze-drying (FD) and co-precipitation coupled to FD (Cop-FD). Release experiments were performed at various temperatures and relative humidities (RH). Multiple headspace extraction-gas chromatography (MHE) was used to determine the loading capacity (LC) and encapsulation efficiency (EE%) and perform release studies. Results underlined that the quantification of encapsulated AN by MHE requires the IC dissolution. The release of AN was accelerated by increases in RH and temperature. However, it was quite negligible below 75% RH. The release behavior of AN was well simulated by Avrami's equation. Cop-FD IC retained more efficiently AN and the release depended on the preparation method and treatment conditions. Thus, the preparation method could be chosen based on the application. PMID- 27474678 TI - A rapid, non-invasive and non-destructive method for studying swelling behavior and microstructure variations of hydrogels. AB - A new method for studying swelling behavior of hydrogels was developed based on low field NMR (LF-NMR). This method is established on these facts: firstly, internal water (water trapped in hydrogel) and external water (water outside of hydrogel) correspond to different components of transverse relaxation time (T2); secondly, T2 component amplitude is proportional to relative water content; and finally, T2 value is closely related to mesh size of hydrogel network, the main effect being due to the overall concentration (degree of swelling). This method was successfully applied to swelling ratio determination of chitosan/glutaraldehyde (CS/GA) hydrogels in situ, and the results had better accuracy and repeatability compared with that of weighing method. Furthermore, swelling kinetics at different pH and microstructure of CS/GA hydrogels was well elucidated based on T2. It is clearly showed that LF-NMR provides a powerful tool for probing processes related to water transport and microstructure variation of hydrogels. PMID- 27474679 TI - Attenuation of inflammation by marine algae Turbinaria ornata in cotton pellet induced granuloma mediated by fucoidan like sulphated polysaccharide. AB - Turbinaria ornata, a commonly found marine brown algae along the Gulf of Mannar, Southeast coast of India was evaluated for its anti-inflammatory potential and the bioactive compound present in it was characterized. Cotton pellet induced granuloma model in rats was used to assess the anti-inflammatory potential of the aqueous extract of Turbinaria ornata (ATO) (30, 100 and 300mg/kg, p.o) which was compared with dexamethasone (0.1mg/kg, p.o) a standard anti-inflammatory agent. Granuloma weight, haematological parameters and plasma markers (LDH, GPT, and CRP) were estimated. Further, the levels of oxidative stress markers (SOD, GPx, GSH, LPO, and Nitrite) and inflammatory markers (Cathepsin D and MPO) in the hepatic tissue were measured. ATO decreased the granuloma weight dose dependently. ATO significantly reversed the levels of biochemical and inflammatory markers in comparison to the vehicle treated rats. The active constituent, fucoidan (sulphated polysaccharide) from the aqueous extract was fractionated and characterized using GCMS. The sulphated polysaccharide (TSP) from ATO confirms the presence of sulphates and sugars. The present findings suggest ATO to be a potent inhibitor of both proliferative and exudative phases of inflammation possibly mediated by the sulphated polysaccharides which might inhibit the action of COX-2 enzyme analogous to dexamethasone. PMID- 27474680 TI - Synthesis, structure and antimicrobial property of green composites from cellulose, wool, hair and chicken feather. AB - Novel composites between cellulose (CEL) and keratin (KER) from three different sources (wool, hair and chicken feather) were successfully synthesized in a simple one-step process in which butylmethylimidazolium chloride (BMIm(+)Cl(-)), an ionic liquid, was used as the sole solvent. The method is green and recyclable because [BMIm(+)Cl(-)] used was recovered for reuse. Spectroscopy (FTIR, XRD) and imaging (SEM) results confirm that CEL and KER remain chemically intact and homogeneously distributed in the composites. KER retains some of its secondary structure in the composites. Interestingly, the minor differences in the structure of KER in wool, hair and feather produced pronounced differences in the conformation of their corresponding composites with wool has the highest alpha helix content and feather has the lowest content. These results correlate well with mechanical and antimicrobial properties of the composites. Specifically, adding CEL into KER substantially improves mechanical strength of [CEL+KER] composites made from all three different sources, wool, hair and chicken feathers i.e., [CEL+wool], [CEL+hair] and [CEL+feather]. Since mechanical strength is due to CEL, and CEL has only random structure, [CEL+feather] has, expectedly, the strongest mechanical property because feather has the lowest content of alpha helix. Conversely, [CEL+wool] composite has the weakest mechanical strength because wool has the highest alpha-helix content. All three composites exhibit antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA). The antibacterial property is due not to CEL but to the protein and strongly depends on the type of the keratin, namely, the bactericidal effect is strongest for feather and weakest for wool. These results together with our previous finding that [CEL+KER] composites can control release of drug such as ciprofloxacin clearly indicate that these composites can potentially be used as wound dressing. PMID- 27474681 TI - Retraction notice to "Carrageenan: A natural seaweed polysaccharide and its applications" [CARP 105 (2014) 97-112]. PMID- 27474682 TI - Corrigendum to "Preparation of bulk sodium carboxymethyl cellulose aerogels with tunable morphology" [Carbohydr. Polym. 118 (2015)126-122]. PMID- 27474683 TI - Corrigendum to "Preparation of functionalized cotton fabrics by means of melatonin loaded beta-cyclodextrin nanosponges" [Carbohydrate Polymers (2016) 24 30]. PMID- 27474684 TI - A simulation model to estimate the risk of transfusion-transmitted arboviral infection. AB - BACKGROUND: The arboviruses West Nile virus (WNV), dengue virus (DENV) and Ross River virus (RRV) have been demonstrated to be blood transfusion-transmissible. A model to estimate the risk of WNV to the blood supply using a Monte Carlo approach has been developed and also applied to Chikungunya virus. Also, a probabilistic model was developed to assess the risk of DENV to blood safety, which was later adapted to RRV. To address efficacy and limitations within each model we present a hybrid model that promises improved accuracy, and is broadly applicable to assess the risk of arboviral transmission by blood transfusion. MATERIAL AND METHODS: Data were drawn from the Cairns Public Health Unit (Australia) and published literature. Based on the published models and using R code, a novel 'combined' model was developed and validated against the BP model using sensitivity testing. RESULTS: The mean risk per 10,000 of the combined model is 0.98 with a range from 0.79 to 1.25, while the maximum risk was 4.45 ranging from 2.62 to 7.67 respectively. These parameters for the BP model were 1.20 ranging from 0.84 to 1.55, and 2.86 ranging from 1.33 to 5.23 respectively. CONCLUSION: The combined simulation model is simple and robust. We propose it can be applied as a 'generic' arbovirus model to assess the risk from known or novel arboviral threats to the blood supply. PMID- 27474685 TI - Normal, Regular, and Standard: Scaling the Body through Fecal Microbial Transplants. AB - In 2013, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) held a workshop to determine the risks and benefits associated with the experimental use of fecal microbial transplants to treat Clostridium difficile and other gastroenterological disorders. By focusing on the proceedings of the NIH-FDA workshop on the treatment of the human microbiome, the question of how medicine colonizes human bodies through microbial transplants raises questions about what an individual body is, how determinative of human health the microbiome is, and what the limits of molecular biomedicine are when the microbiome is taken into consideration. In the workshop presentations and discussion of this emerging treatment, experts used ideas about the normal, regular, and standard to move between scales of bodily analysis, from the microbial to the body politic, demonstrating how the individual and society are deeply influenced by the unruly community of microbial symbiotes that humans host. PMID- 27474686 TI - Increased mRNA expression of peripheral glial cell markers in bipolar disorder: The effect of long-term lithium treatment. AB - Neuroinflammation, with microglial activation as an important element, plays a role in the pathogenesis of bipolar disorder (BD). Also, in mood disorders, pathological changes have been demonstrated in macroglial cells, such as astrocyctes and oligodendrocytes. Postmortem brain studies of BD patients to assess glial cells, such as astrocytes and oligodendrocytes and their markers such as glial fibrillary acidic protein (GFAP), Olig1 and Olig2, produced controversial results. On the other hand, investigation of these markers in the peripheral blood of such patients has not been performed so far. In this study, we examined the mRNA levels of GFAP, Olig1 and Olig2, in the peripheral blood of three groups: 15 BD subjects with a duration of illness at least 10 years (mean 20+/-9 years) but never treated with lithium, 15 subjects with BD treated continuously with lithium for 8-40 years (mean 16+/-8 years), and 15 control subjects. The groups were age-and sex-matched. Expression of mRNA markers was measured by real-time quantitative reverse transcription PCR (RQ-PCR). We observed increased mRNA levels of the Olig1 and Olig 2 glial markers studied in the BD patients not taking lithium, compared with the control subjects and increased mRNA level of GFAP, compared with lithium-treated patients. In the lithium-treated BD patients GFAP and Olig1 expression was at similar levels to that in the control group. However, Olig 2 expression was even higher than in the BD patients not taking lithium. The possible mechanisms concerning the higher expression of peripheral mRNA markers in BD patients may involve ongoing inflammatory process, compensatory mechanisms and regenerative responses. The beneficial effect of lithium may be related to its anti-inflammatory properties. PMID- 27474687 TI - Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study. AB - Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the alpha7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the alpha7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective alpha7 agonist (PNU282987) and a alpha7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the alpha7 nAChRs, perhaps especially alpha7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that alpha7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression. PMID- 27474688 TI - Assessment of the efficacy and safety of single platelet-rich plasma injection on different types and grades of facial wrinkles. AB - BACKGROUND: Platelet-rich plasma (PRP) is considered as a growing modality for tissue regeneration and a developing research area for clinicians and researchers. PRP injection treatment provides supraphysiological concentrations of growth factors that may help in accelerated tissue remodeling and regeneration. AIM OF THE STUDY: To evaluate the efficacy and safety of single autologous PRP intradermal injection for treatment of facial wrinkles and for facial rejuvenation. PATIENTS AND METHODS: A total of 20 subjects with different types of facial wrinkles were included in this study. All subjects received single PRP intradermal injection and were clinically assessed before and after treatment for a period of 8 weeks using Wrinkle Severity Rating Scale (WSRS), Skin Homogeneity and Texture (SHnT) Scale, Physician Assessment Scale, and Subject Satisfaction Scale. RESULTS: The mean value of WSRS reduced from 2.90 +/- 0.91 before treatment to 2.10 +/- 0.79 after 8 weeks of treatment. The most significant results were with younger subjects that have mild and moderate wrinkles of the nasolabial folds (NLFs). Fourteen of seventeen subjects with NLFs showed more than 25% improvement in their appearance. Side effects of PRP treatment were minimal to mild and with excellent tolerability. CONCLUSION: Single PRP intradermal injection is well tolerated and capable of rejuvenating the face and producing a significant correction of wrinkles especially the NLFs. PMID- 27474689 TI - Opisthorchis felineus infection and cholangiocarcinoma in the Russian Federation: A review of medical statistics. AB - Opisthorchis felineus (O. felineus) occurs in Western Siberia and many other parts of the Russian Federation (RF). The true extent of its distribution is not known. Chronic infection may lead to severe hepatobiliary morbidity. According to surgical and experimental reports, long-term infestation might significantly increase the risk for cholangiocarcinoma (CCA). To date, no association between O. felineus infection and CCA has been demonstrated. The objective of this study was to review existing health data on the incidence of O. felineus infection and on the incidence of CCA in the RF. We reviewed the official medical statistics on reported O. felineus infection and CCA in 83 political/geographical units of the RF, covering the period January 2011-December 2013. Annual incidence data were obtained from Rospotrebnadzor and from official medical statistics. We calculated the average annual incidence of infection and cancer. The average annual incidence of O. felineus was 24.7+/-9.0 cases per 100,000 population. The highest incidence was observed in Khanty-Mansiysk district (599.7 cases per 100,000 population per year). In 27 geographical units, no O. felineus cases were reported. The incidence of liver and intrahepatic bile duct cancers was 4.8+/-0.2 cases per 100,000 population; the highest rate was reported in Sakha Republic and Tomsk Oblast (14.5 and 9.3 cases per 100,000 population), and the lowest in Yamalo-Nenets Autonomous Okrug (0.9 cases per 100,000 population). O. felineus incidence was not associated with the mean annual incidence of liver and intrahepatic bile duct cancers (r=0.20, p=0.07). This study documents the importance of opisthorchiasis in certain endemic areas and presents the best available data on associations between O. felineus infection and liver/intrahepatic bile duct cancers in RF. The findings support the need to implement a public health control programme against liver fluke infections and to increase the availability of anthelmintic treatment. Further studies are warranted to assess the contribution of opisthorchiasis to the CCA in RF. PMID- 27474690 TI - Endocrine effects of duodenal-jejunal exclusion in obese patients with type 2 diabetes mellitus. AB - Duodenal-jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10months after the implantation, and 3months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of fibroblast growth factor 19 (FGF19) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF19 and bile acids levels could be at least partially responsible for these effects. PMID- 27474691 TI - [Capacity impairments and participation restrictions : Assessment and qualifying in the sociomedical evaluation of mental disorders]. AB - Participation is defined, according to the International Classification of Functioning, Disability and Health (ICF), as inclusion in life. Participation restrictions are the result of a mismatch between capacities and context requirements. Mental disorders are more impairing than many somatic disorders.There are instruments to assess and operationalize capacity and participation restrictions like the ADL-scales, the GAF, the ICF-AT-50, the ICFPsych A&P, the IMET, the ICF-Coresets, the WHODAS, or the Mini-ICF-APP, which differ in respect to indications, differentiation between function, capacity or context and context-adjusted qualifying.In addition to the type of participation restrictions, their chronicity must also be assessed. This is done in reference to the present mental disorder, the course, and the earlier treatment in respect to functions, capacities, and context.The assessment and qualifying of participation restrictions needs an adjustment to the environment or context. This is not only a problem for the individual but also for societal developments. PMID- 27474692 TI - Response to proposed research to reverse brain death: more than regulatory failure. AB - In early May 2016, reports of a bizarre study to attempt a reversal of brain death made the headlines, but there was not even a squeak from the authorities. The "Reanima Project" is a collaboration between an Indian surgeon, Himanshu Bansal, and a US-based biotech company, Bioquark Inc. The research will be conducted by Bansal's own biotech company, Revita Life Sciences, at his Anupam hospital in Rudrapur, a city in Uttarakhand state. PMID- 27474693 TI - What rural doctors want: a qualitative study in Chhattisgarh state. AB - The importance of addressing concerns of rural health worker welfare in order to improve their performance and retention is widely acknowledged; yet there is little empirical research on the needs of rural health professionals. We report findings from a qualitative research study in rural Chhattisgarh, involving indepth interviews with 37 practitioners and data analysis using the "framework" approach. Participants' expressions of their needs encompassed a range of reforms and improvements, including better salaries and job security, more rational posting and promotion procedures, and facility improvements. Opportunities for need-based skills training and better housing also emerged as key needs, as did better schools, assurance of personal security, and recognition and appreciation of their services by the administration. Increased investment in rural infrastructure and training, graded packages of benefits for rural doctors, and governance reforms to improve the internal accountability of government health services emerge as recommendations from the study. PMID- 27474694 TI - Personal experience narratives by students: a teaching-learning tool in bioethics. AB - The principles of bioethics have been identified as important requirements for training basic medical doctors. Till now, various modalities have been used for teaching bioethics, such as lectures, followed by a small case-based discussion, case vignettes or debates among students. For effective teaching-learning of bioethics, it is necessary to integrate theory and practice rather than merely teach theoretical constructs without helping the students translate those constructs into practice. Classroom teaching can focus on the theoretical knowledge of professional relationships, patient-doctor relationships, issues at the beginning and end of life, reproductive technologies, etc. However, a better learning environment can be created through an experiencebased approach to complement lectures and facilitate successful teaching. Engaging students in reflective dialogue with their peers would allow them to refine their ideas with respect to learning ethics. It can help in the development both of the cognitive and affective domains of the teaching of bioethics. Real-life narratives by the interns, when used as case or situation analysis models for a particular ethical issue, can enhance other students' insight and give them a moral boost. Doing this can change the classroom atmosphere, enhance motivation, improve the students' aptitude and improve their attitude towards learning bioethics. Involving the students in this manner can prove to be a sustainable way of achieving the goal of deep reflective learning of bioethics and can serve as a new technique for maintaining the interest of students as well as teachers. PMID- 27474695 TI - A critical ethnography of doctor-patient interaction in southern Iran. AB - Doctor-patient interaction is a subject with ethical ramifications, besides being an important issue in medical sociology. The main goal of this critical study is to explore the interactional experience of hospital admitted patients. For this reason, the study, carried out in an educational hospital in southern Iran, entailed 156 recorded clinical consultations, 920 hours of participant observation, and six focus groups consisting of patients and their families. The research method used is Critical Ethnography, which was introduced by PF Carspecken. The results showed that negative interactional experience was common among the participants. Six related themes were: doctors' inattentiveness; weak interaction; violation of patients' privacy; unjustified pain; long waiting period and ambiguity; and faceless physicians. According to the participants' observations, poor interaction with doctors has led to these negative experiences. The findings showed that doctors were inconsiderate about patients' concerns and due to this, patients were dissatisfied. Theoretically, this form of fragmented collaboration has deep roots in the framework of modern medicine, but in the context of this study, the intensity of the fragmentation between doctors and patients was observed to be intolerable. To solve this problem, models of patient-centredness and narrative medicine are recommended. In addition, the health system should monitor and evaluate the observance of ethics by physicians. PMID- 27474696 TI - The Epidemic Diseases Act of 1897: public health relevance in the current scenario. AB - Recently, many states in India have invoked various provisions of the Epidemic Diseases Act of 1897 to control communicable diseases. In this context, the Act was reviewed with reference to its relevance in the current context of surveillance and other relevant Acts and legislations at the national and international levels. It is felt that the Act has major limitations in the current scenario as it is outdated, merely regulatory and not rights-based, and lacks a focus on the people. There is a need for an integrated, comprehensive, actionable and relevant legal provision for the control of outbreaks in India. PMID- 27474697 TI - Reintroducing differences linguistically! AB - Different models have defined the term disability and grouped persons with disabilities accordingly. Time and again, various terms and phrases have been used in different languages to identity persons according to the differences in their bodies and the level of functioning of those bodies. Analogies and metaphors create stereotypes and can affect the formation of an individual's self concept. Cliches like "divyang", ie one who has some divine powers to compensate for the deficiency in the body, based on the supercrip theory of disability, can distort the self-concept and hamper identity formation. Society and the state cannot and must not shrug off their responsibility by using such sugar-coated terms to label individuals. The real requirement is the creation of a nondisabling environment and the provision of equal opportunities to those with disabilities rather than coining of new terms. PMID- 27474698 TI - Ethics of dental health screening. AB - Screening is the detection of disease at a point in its natural history when it is not yet symptomatic. In the natural history of dental caries, for example, the incipient lesions are at a reversible stage, which is a pre-symptomatic or an unrecognised symptomatic disease. Ideally, this is the stage during which screening should identify the risk of dental caries; however, presently, the so called dental screening employed identifies the clinical cavitation of the tooth, which is very obvious to the individual. The individual already knows that he/she has dental caries and needs treatment, which the screening personnel (dental doctor) explains again during the screening procedure. Is it ethical to call such an event screening? The mushrooming of dental teaching hospitals has promoted regular screening of dental diseases among the communities and schoolchildren through their community dentistry-related activities. More often, it is a dental "check-up" that is carried out on the pretext of screening for dental diseases. Though the basic intention of this activity is to promote awareness of dental diseases and promote good health, there is also a hidden agenda to it. An artificial demand for dental care is created that is easily capitalised on by the dental teaching institutions to enhance its clinical activity. Dental screening is doing more harm than good as patients are made aware of the diseases for which they may not be able to afford treatment. This narrative review gives an account of the scientific evidence on screening for oral diseases, the current practices in screening and the ethical dilemmas of dental screening programmes. PMID- 27474699 TI - Who decides the "best interests" of the child? AB - B was a frail 15-year-old girl who was brought to the hospital by the police. She had met a 22-year-old boy on a social networking site a few months earlier. They had fallen in love and she had started living with him. On finding his daughter missing, B's father reported the matter to the police station. The police caught the couple and brought them to the police station. The boy was arrested. The father sent B to a shelter home lest she run away from home again. The police registered a complaint of rape. PMID- 27474700 TI - Prescribing generic drugs using a generic name: Are we teaching it right? AB - The Indian Medical Council (Professional conduct, Etiquette and Ethics) Regulations, 2002, state that "Every physician should, as far as possible, prescribe drugs with generic names and he/she shall ensure that there is a rational prescription and use of drugs.". Undergraduate medical students are introduced to drug nomenclature early on during their pharmacology course. They are told that generic name or, more appropriately, non-proprietary name (usually international non-proprietary name INN), is to be used while writing prescriptions. PMID- 27474701 TI - Conversion therapy for homosexuality: serious violation of ethics. AB - Across the world, homosexuality is gaining legitimacy; stigma and discrimination are gradually giving way to equality and inclusion. The situation in India is in stark contrast to these trends. In this country, homosexuality is an offence as per Section 377 of the IPC. The homosexual community is fighting for its rights and continues to suffer from intense stigma and discrimination. Their healthcare needs are not at all attended to; their sexual orientation is conceptualised as a socially deviant mental disease that needs psychiatric treatment. PMID- 27474702 TI - The choices we make as teachers. AB - "She wasn't like you...wasn't like any politician I've ever known." Ethan Kanin, Secretary of State about US president Allison Taylor in the US serial, 24. When an ethical dilemma arises, the choices we make decide our ethical concerns and moral position in a given situation. In the TV serial, 24, the US president faces such an ethical dilemma when she has to either cover up for her daughter's crime or get her arrested. She is torn between the role of a mother and that of a President. She chooses her sworn duty to protect the country and has her daughter arrested. She gives precedence to her duty as the President of a country over her mother's role. PMID- 27474703 TI - Dealing with requests for pharmacological cognitive enhancement from healthy students. AB - The use of drugs to enhance cognitive function and academic performance is clearly a global phenomenon, with the reported prevalence of stimulant use among medical students ranging from 15-20%. A multi-institution study from the USA reported a 6.9% lifetime prevalence of non-prescription use of cognitive enhancers among college students. A comprehensive systematic review indicates a 16-29% use of non-prescribed stimulants among all students for reasons that include increasing concentration and alertness. While mental health professionals and guidance counsellors anecdotally recall requests for pharmacological cognitive enhancement from otherwise healthy students, the exact magnitude of this problem in the Indian context is not clear. PMID- 27474705 TI - Food insecurity and low self-efficacy are associated with increased healthcare utilization among adults with type II diabetes mellitus. AB - OBJECTIVE: Food insecurity has been shown to negatively impact health outcomes, disease management and hospitalizations. Despite the increasing burden of type II diabetes mellitus (T2DM) in the United States, little research exists on the role of food insecurity and its association to T2DM-related healthcare utilization. The purpose of our study was to address such a gap in the literature by evaluating the role of food insecurity and T2DM-related past 12-month hospitalization or emergency department (ED) admission among adults with healthcare professional diagnosed T2DM. METHODS: We utilized the California Health Interview Survey (CHIS), 2009, 2011/2012 data to select CHIS participants who were aged 18 or older and reported doctor diagnosis of T2DM; resulting in a total of 8252 participants. Food insecurity was defined as: living at or above 200% federal poverty level (FPL), living below 200% FPL but food secure, living below 200% FPL and food insecure. A secondary exposure variable of interest was self-efficacy, based on the CHIS-provided variable of confidence to manage T2DM. All analyses were survey weighted with alpha less than .05 noting significance. RESULTS: Those with low food security (12.96%) and low-self efficacy (15.14%), reported significantly higher prevalence of T2DM-related healthcare utilization, as compared to their counterparts. Both living with low food security and having low self-efficacy were also associated with over two-fold increase in healthcare utilization. CONCLUSION: Our results demonstrate the cumulative need for community-based resources to improve the continuum of care and ensure that such at-risk populations have adequate resources for disease management. PMID- 27474704 TI - A rapid decline in corneal small fibers and occurrence of foot ulceration and Charcot foot. AB - We present clinical, neuropathy and corneal nerve morphology data in a participant with type 2 diabetes who developed diabetic foot ulceration, partial amputation and Charcot during a longitudinal observational study. While conventional measures of neuropathy did not deteriorate significantly, corneal nerve parameters showed a rapid reduction prior to the development of foot complications. PMID- 27474706 TI - Adaptive management of ecosystem services across different land use regimes. AB - Using adaptive management to manage desired flows of ecosystem services may seem on the surface to be a good fit, but many social, economic, environmental, legal, and political factors influence how good a fit. One strongly influential factor is the land use regime within which the profile of ecosystem services is being managed. Shaped largely by legal mandates, market forces, and social and cultural practices, different land use regimes present different opportunities for and constraints on goals for ecosystem services and pose different decision making environments. Even where all other conditions appear amenable to using adaptive management, therefore, it is essential to consider the constraining (or liberating) effects of different land use regimes when deciding whether to adopt adaptive management to achieve those goals and, if so, how to implement it. PMID- 27474707 TI - Case studies on the physical-chemical parameters' variation during three different purification approaches destined to treat wastewaters from food industry. AB - The paper presents a set of three interconnected case studies on the depuration of food processing wastewaters by using aeration & ozonation and two types of hollow-fiber membrane bioreactor (MBR) approaches. A secondary and more extensive objective derived from the first one is to draw a clearer, broader frame on the variation of physical-chemical parameters during the purification of wastewaters from food industry through different operating modes with the aim of improving the management of water purification process. Chemical oxygen demand (COD), pH, mixed liquor suspended solids (MLSS), total nitrogen, specific nitrogen (NH4+, NO2-, NO3-) total phosphorous, and total surfactants were the measured parameters, and their influence was discussed in order to establish the best operating mode to achieve the purification performances. The integrated air-ozone aeration process applied in the second operating mode lead to a COD decrease by up to 90%, compared to only 75% obtained in a conventional biological activated sludge process. The combined purification process of MBR and ozonation produced an additional COD decrease of 10-15%, and made the Total Surfactants values to comply to the specific legislation. PMID- 27474708 TI - Use of a Bacterial Luciferase Monitoring System To Estimate Real-Time Dynamics of Intracellular Metabolism in Escherichia coli. AB - Regulation of central carbon metabolism has long been an important research subject in every organism. While the dynamics of metabolic flows during changes in available carbon sources have been estimated based on changes in metabolism related gene expression, as well as on changes in the metabolome, the flux change itself has scarcely been measured because of technical difficulty, which has made conclusions elusive in many cases. Here, we used a monitoring system employing Vibrio fischeri luciferase to probe the intracellular metabolic condition in Escherichia coli Using a batch culture provided with a limited amount of glucose, we performed a time course analysis, where the predominant carbon source shifts from glucose to acetate, and identified a series of sequential peaks in the luciferase activity (peaks 1 to 4). Two major peaks, peaks 1 and 3, were considered to correspond to the glucose and acetate consuming phases, respectively, based on the glucose, acetate, and dissolved oxygen concentrations in the medium. The pattern of these peaks was changed by the addition of a different carbon source or by an increasing concentration of glucose, which was consistent with the present model. Genetically, mutations involved in glycolysis or the tricarboxylic acid (TCA) cycle/gluconeogenesis specifically affected peak 1 or peak 3, respectively, as expected from the corresponding metabolic phase. Intriguingly, mutants for the acetate excretion pathway showed a phenotype of extended peak 2 and delayed transition to the TCA cycle/gluconeogenesis phase, which suggests that peak 2 represents the metabolic transition phase. These results indicate that the bacterial luciferase monitoring system is useful to understand the real-time dynamics of metabolism in living bacterial cells. IMPORTANCE: Intracellular metabolic flows dynamically change during shifts in available carbon sources. However, because of technical difficulty, the flux change has scarcely been measured in living cells. Here, we used a Vibrio fischeri luciferase monitoring system to probe the intracellular metabolic condition in Escherichia coli Using a limited amount of glucose batch culture, a series of sequential peaks (peaks 1 to 4) in the luciferase activity was observed. Changes in the pattern of these peaks by the addition of extra carbon sources and in mutant strains involved in glycolysis or the TCA cycle/gluconeogenesis gene assigned the metabolic phase corresponding to peak 1 as the glycolysis phase and peak 3 as the TCA cycle/gluconeogenesis phase. Intriguingly, the acetate excretion pathway engaged in peak 2 represents the metabolic transition phase. These results indicate that the bacterial luciferase monitoring system is useful to understand the real-time dynamics of metabolism in living bacterial cells. PMID- 27474709 TI - Ultrastructure Variability of the Exosporium Layer of Clostridium difficile Spores from Sporulating Cultures and Biofilms. AB - The anaerobic sporeformer Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea in developed and developing countries. The metabolically dormant spore form is considered the morphotype responsible for transmission, infection, and persistence, and the outermost exosporium layer is likely to play a major role in spore-host interactions during recurrent infections, contributing to the persistence of the spore in the host. A recent study (M. Pizarro-Guajardo, P. Calderon-Romero, P. Castro-Cordova, P. Mora-Uribe, and D. Paredes-Sabja, Appl Environ Microbiol 82:2202-2209, 2016, http://dx.doi.org/10.1128/AEM.03410-15) demonstrated by transmission electron microscopy the presence of two ultrastructural morphotypes of the exosporium layer in spores formed from the same sporulating culture. However, whether these distinct morphotypes appeared due to purification techniques and whether they appeared during biofilm development remain unclear. In this communication, we demonstrate through transmission electron microscopy that these two exosporium morphotypes are formed under sporulation conditions and are also present in spores formed during biofilm development. In summary, this work provides definitive evidence that in a population of sporulating cells, spores with a thick outermost exosporium layer and spores with a thin outermost exosporium layer are formed. IMPORTANCE: Clostridium difficile spores are recognized as the morphotype of persistence and transmission of C. difficile infections. Spores of C. difficile are intrinsically resistant to all known antibiotic therapies. Development of spore-based removal strategies requires a detailed knowledge of the spore surface for proper antigen selection. In this context, in this work we provide definitive evidence that two types of spores, those with a thick outermost exosporium layer and those with a thin outermost exosporium layer, are formed in the same C. difficile sporulating culture or during biofilm development. PMID- 27474710 TI - Comparative Profiling and Discovery of Novel Glycosylated Mycosporine-Like Amino Acids in Two Strains of the Cyanobacterium Scytonema cf. crispum. AB - The mycosporine-like amino acids (MAAs) are a group of small molecules with a diverse ecological distribution among microorganisms. MAAs have a range of physiological functions, including protection against UV radiation, making them important from a biotechnological perspective. In the present study, we identified a putative MAA (mys) gene cluster in two New Zealand isolates of Scytonema cf. crispum (UCFS10 and UCFS15). Homology to "Anabaena-type" mys clusters suggested that this cluster was likely to be involved in shinorine biosynthesis. Surprisingly, high-performance liquid chromatography analysis of S cf. crispum cell extracts revealed a complex MAA profile, including shinorine, palythine-serine, and their hexose-bound variants. It was hypothesized that a short-chain dehydrogenase (UCFS15_00405) encoded by a gene adjacent to the S cf. crispum mys cluster was responsible for the conversion of shinorine to palythine serine. Heterologous expression of MysABCE and UCFS15_00405 in Escherichia coli resulted in the exclusive production of the parent compound shinorine. Taken together, these results suggest that shinorine biosynthesis in S cf. crispum proceeds via an Anabaena-type mechanism and that the genes responsible for the production of other MAA analogues, including palythine-serine and glycosylated analogues, may be located elsewhere in the genome. IMPORTANCE: Recently, New Zealand isolates of S cf. crispum were linked to the production of paralytic shellfish toxins for the first time, but no other natural products from this species have been reported. Thus, the species was screened for important natural product biosynthesis. The mycosporine-like amino acids (MAAs) are among the strongest absorbers of UV radiation produced in nature. The identification of novel MAAs is important from a biotechnology perspective, as these molecules are able to be utilized as sunscreens. This study has identified two novel MAAs that have provided several new avenues of future research related to MAA genetics and biosynthesis. Further, we have revealed that the genetic basis of MAA biosynthesis may not be clustered on the genome. The identification of the genes responsible for MAA biosynthesis is vital for future genetic engineering. PMID- 27474711 TI - Role of Wax Ester Synthase/Acyl Coenzyme A:Diacylglycerol Acyltransferase in Oleaginous Streptomyces sp. Strain G25. AB - Recently, we isolated a novel Streptomyces strain which can accumulate extraordinarily large amounts of triacylglycerol (TAG) and consists of 64% fatty acids (dry weight) when cultivated with glucose and 50% fatty acids (dry weight) when cultivated with cellobiose. To identify putative gene products responsible for lipid storage and cellobiose utilization, we analyzed its draft genome sequence. A single gene encoding a wax ester synthase/acyl coenzyme A (CoA):diacylglycerol acyltransferase (WS/DGAT) was identified and heterologously expressed in Escherichia coli The purified enzyme AtfG25 showed acyltransferase activity with C12- or C16-acyl-CoA, C12 to C18 alcohols, or dipalmitoyl glycerol. This acyltransferase exhibits 24% amino acid identity to the model enzyme AtfA from Acinetobacter baylyi but has high sequence similarities to WS/DGATs from other Streptomyces species. To investigate the impact of AtfG25 on lipid accumulation, the respective gene, atfG25, was inactivated in Streptomyces sp. strain G25. However, cells of the insertion mutant still exhibited DGAT activity and were able to store TAG, albeit in lower quantities and at lower rates than the wild-type strain. These findings clearly indicate that AtfG25 has an important, but not exclusive, role in TAG biosynthesis in the novel Streptomyces isolate and suggest the presence of alternative metabolic pathways for lipid accumulation which are discussed in the present study. IMPORTANCE: A novel Streptomyces strain was isolated from desert soil, which represents an extreme environment with high temperatures, frequent drought, and nutrient scarcity. We believe that these harsh conditions promoted the development of the capacity for this strain to accumulate extraordinarily large amounts of lipids. In this study, we present the analysis of its draft genome sequence with a special focus on enzymes potentially involved in its lipid storage. Furthermore, the activity and importance of the detected acyltransferase were studied. As discussed in this paper, and in contrast to many other bacteria, streptomycetes seem to possess a complex metabolic network to synthesize lipids, whereof crucial steps are still largely unknown. This paper therefore provides insights into a range of topics, including extremophile bacteria, the physiology of lipid accumulation, and the biotechnological production of bacterial lipids. PMID- 27474713 TI - Physiological and Proteomic Responses of Continuous Cultures of Microcystis aeruginosa PCC 7806 to Changes in Iron Bioavailability and Growth Rate. AB - The hepatotoxin microcystin (MCYST) is produced by a variety of freshwater cyanobacterial species, including Microcystis aeruginosa Interestingly, MCYST producing M. aeruginosa strains have been shown to outcompete their nontoxic counterparts under iron-limiting conditions. However, the reasons for this are unclear. Here we examined the proteomic response of M. aeruginosa PCC 7806 continuous cultures under different iron and growth regimes. Iron limitation was correlated with a global reduction in levels of proteins associated with energy metabolism and photosynthesis. These proteomic changes were consistent with physiological observations, including reduced chlorophyll a content and reduced cell size. While levels of MCYST biosynthesis proteins did not fluctuate during the study period, both intra- and extracellular toxin quotas were significantly higher under iron-limiting conditions. Our results support the hypothesis that intracellular MCYST plays a role in protecting the cell against oxidative stress. Further, we propose that extracellular MCYST may act as a signaling molecule, stimulating MCYST production under conditions of iron limitation and enhancing the fitness of bloom populations. IMPORTANCE: Microcystin production in water supply reservoirs is a global public health problem. Understanding the ecophysiology of hepatotoxic cyanobacteria, including their responses to the presence of key micronutrient metals such as iron, is central to managing harmful blooms. To our knowledge, this was the first study to examine proteomic and physiological changes occurring in M. aeruginosa continuous cultures under conditions of iron limitation at different growth rates. PMID- 27474712 TI - Transmission of Staphylococcus aureus from Humans to Green Monkeys in The Gambia as Revealed by Whole-Genome Sequencing. AB - Staphylococcus aureus is an important pathogen of humans and animals. We genome sequenced 90 S. aureus isolates from The Gambia: 46 isolates from invasive disease in humans, 13 human carriage isolates, and 31 monkey carriage isolates. We inferred multiple anthroponotic transmissions of S. aureus from humans to green monkeys (Chlorocebus sabaeus) in The Gambia over different time scales. We report a novel monkey-associated clade of S. aureus that emerged from a human-to monkey switch estimated to have occurred 2,700 years ago. Adaptation of this lineage to the monkey host is accompanied by the loss of phage-carrying genes that are known to play an important role in human colonization. We also report recent anthroponotic transmission of the well-characterized human lineages sequence type 6 (ST6) and ST15 to monkeys, probably because of steadily increasing encroachment of humans into the monkeys' habitat. Although we have found no evidence of transmission of S. aureus from monkeys to humans, as the two species come into ever-closer contact, there might be an increased risk of additional interspecies exchanges of potential pathogens. IMPORTANCE: The population structures of Staphylococcus aureus in humans and monkeys in sub Saharan Africa have been previously described using multilocus sequence typing (MLST). However, these data lack the power to accurately infer details regarding the origin and maintenance of new adaptive lineages. Here, we describe the use of whole-genome sequencing to detect transmission of S. aureus between humans and nonhuman primates and to document the genetic changes accompanying host adaptation. We note that human-to-monkey switches tend to be more common than the reverse and that a novel monkey-associated clade is likely to have emerged from such a switch approximately 2,700 years ago. Moreover, analysis of the accessory genome provides important clues as to the genetic changes underpinning host adaptation and, in particular, shows that human-to-monkey switches tend to be associated with the loss of genes known to confer adaptation to the human host. PMID- 27474714 TI - Effects of Glucose and Starch on Lactate Production by Newly Isolated Streptococcus bovis S1 from Saanen Goats. AB - When ruminants are fed high-concentrate diets, Streptococcus bovis proliferates rapidly and produces lactate, potentially causing rumen acidosis. Understanding the regulatory mechanisms of the metabolism of this species might help in developing dietary strategies to alleviate rumen acidosis. S. bovis strain S1 was newly isolated from the ruminal fluid of Saanen dairy goats and then used to examine the effects of glucose and starch on bacterial metabolism and gene regulation of the organic acid-producing pathway in cultures at a pH of 6.5. Glucose or starch was added to the culture medium at 1 g/liter, 3 g/liter (close to a normal range in the rumen fluid), or 9 g/liter (excessive level). Lactate was the dominant acid produced during the fermentation, and levels increased with the amount of glucose or starch in a dose-dependent manner (P < 0.001). The production of formate and acetate in the fermentation media fluctuated slightly with the dose but accounted for small fractions of the total acids. The activities of lactate dehydrogenase (LDH) and alpha-amylase (alpha-AMY) increased with the starch dose (P < 0.05), but the alpha-AMY activity did not change with the glucose dose. The relative expression levels of the genes ldh, pfl (encoding pyruvate formate lyase), ccpA (encoding catabolite control protein A), and alpha amy were higher at a dose of 9 g/liter than at 1 g/liter (P < 0.05). Expression levels of pfl and alpha-amy genes were higher at 3 g/liter than at 1 g/liter (P < 0.05). The fructose 1,6-diphosphate (FDP) concentration tended to increase with the glucose and starch concentrations. In addition, the S. bovis S1 isolate fermented glucose much faster than starch. We conclude that the quantities of glucose and soluble starch had a major effect on lactate production due to the transcriptional regulation of metabolic genes. IMPORTANCE: This work used a newly isolated S. bovis strain S1 from the rumen fluid of Saanen goats and examined the effects of glucose and soluble starch on organic acid patterns, enzyme activity, and expression of genes for in vitro fermentation. It was found that lactate was the dominant product from S. bovis strain S1, and the quantities of both glucose and starch in the medium were highly correlated with lactate production and with the corresponding changes in associated enzymes and genes. Therefore, manipulating the metabolic pathway of S. bovis to alter the dietary level of readily fermentable sugar and carbohydrates may be a strategy to alleviate rumen acidosis. PMID- 27474715 TI - Escherichia coli O157:H7 Strain EDL933 Harbors Multiple Functional Prophage Associated Genes Necessary for the Utilization of 5-N-Acetyl-9-O-Acetyl Neuraminic Acid as a Growth Substrate. AB - Enterohemorrhagic Escherichia coli (EHEC) O157:H7 strain EDL933 harbors multiple prophage-associated open reading frames (ORFs) in its genome which are highly homologous to the chromosomal nanS gene. The latter is part of the nanCMS operon, which is present in most E. coli strains and encodes an esterase which is responsible for the monodeacetylation of 5-N-acetyl-9-O-acetyl neuraminic acid (Neu5,9Ac2). Whereas one prophage-borne ORF (z1466) has been characterized in previous studies, the functions of the other nanS-homologous ORFs are unknown. In the current study, the nanS-homologous ORFs of EDL933 were initially studied in silico Due to their homology to the chromosomal nanS gene and their location in prophage genomes, we designated them nanS-p and numbered the different nanS-p alleles consecutively from 1 to 10. The two alleles nanS-p2 and nanS-p4 were selected for production of recombinant proteins, their enzymatic activities were investigated, and differences in their temperature optima were found. Furthermore, a function of these enzymes in substrate utilization could be demonstrated using an E. coli C600DeltananS mutant in a growth medium with Neu5,9Ac2 as the carbon source and supplementation with the different recombinant NanS-p proteins. Moreover, generation of sequential deletions of all nanS-p alleles in strain EDL933 and subsequent growth experiments demonstrated a gene dose effect on the utilization of Neu5,9Ac2 Since Neu5,9Ac2 is an important component of human and animal gut mucus and since the nutrient availability in the large intestine is limited, we hypothesize that the presence of multiple Neu5,9Ac2 esterases provides them a nutrient supply under certain conditions in the large intestine, even if particular prophages are lost. IMPORTANCE: In this study, a group of homologous prophage-borne nanS-p alleles and two of the corresponding enzymes of enterohemorrhagic E. coli (EHEC) O157:H7 strain EDL933 that may be important to provide alternative genes for substrate utilization were characterized. PMID- 27474716 TI - Two-Component Systems Involved in Susceptibility to Nisin A in Streptococcus pyogenes. AB - Two-component systems (TCSs) are regulatory systems in bacteria that play important roles in sensing and adapting to the environment. In this study, we systematically evaluated the roles of TCSs in the susceptibility of the group A Streptococcus (GAS; Streptococcus pyogenes) SF370 strain to several types of lantibiotics. Using individual TCS deletion mutants, we found that the deletion of srtRK (spy_1081-spy_1082) in SF370 increased the susceptibility to nisin A, which is produced by Lactococcus lactis ATCC 11454, but susceptibility to other types of lantibiotics (nukacin ISK-1, produced by Staphylococcus warneri, and staphylococcin C55, produced by Staphylococcus aureus) was not altered in the TCS mutants tested. The expression of srtFEG (spy_1085 to spy_1087), which is located downstream of srtRK and is homologous to ABC transporters, was increased in response to nisin A. However, srtEFG expression was not induced by nisin A in the srtRK mutant. The inactivation of srtFEG increased the susceptibility to nisin A. These results suggest that SrtRK controls SrtFEG expression to alter the susceptibility to nisin A. Further experiments showed that SrtRK is required for coexistence with L. lactis ATCC 11454, which produces nisin A. Our results elucidate the important roles of S. pyogenes TCSs in the interactions between different bacterial species, including bacteriocin-producing bacteria. IMPORTANCE: In this study, we focused on the association of TCSs with susceptibility to bacteriocins in S. pyogenes SF370, which has no ability to produce bacteriocins, and reported two major new findings. We demonstrated that the SrtRK TCS is related to susceptibility to nisin A by controlling the ABC transporter SrtFEG. We also showed that S. pyogenes SrtRK is important for survival when the bacteria are cocultured with nisin A-producing Lactococcus lactis This report highlights the roles of TCSs in the colocalization of bacteriocin-producing bacteria and non-bacteriocin-producing bacteria. Our findings provide new insights into the function of TCSs in S. pyogenes. PMID- 27474717 TI - Niche-Specific Impact of a Symbiotic Function on the Persistence of Microbial Symbionts within a Natural Host. AB - How the function of microbial symbionts is affected by their population/consortium structure within a host remains poorly understood. The symbiosis established between Euprymna scolopes and Vibrio fischeri is a well characterized host-microbe association in which the function and structure of V. fischeri populations within the host are known: V. fischeri populations produce bioluminescence from distinct crypt spaces within a dedicated host structure called the light organ. Previous studies have revealed that luminescence is required for V. fischeri populations to persist within the light organ and that deletion of the lux gene locus, which is responsible for luminescence in V. fischeri, leads to a persistence defect. In this study, we investigated the impact of bioluminescence on V. fischeri population structure within the light organ. We report that the persistence defect is specific to crypt I, which is the most developmentally mature crypt space within the nascent light organ. This result provides insight into the structure/function relationship that will be useful for future mechanistic studies of squid-Vibrio symbiosis. In addition, our report highlights the potential impact of the host developmental program on the spatiotemporal dynamics of host-microbe interactions. IMPORTANCE: Metazoan development and physiology depend on microbes. The relationship between the symbiotic function of microbes and their spatial structure within the host environment remains poorly understood. Here we demonstrate, using a binary symbiosis, that the host requirement for the symbiotic function of the microbial symbiont is restricted to a specific host environment. Our results also suggest a link between microbial function and host development that may be a fundamental aspect of the more complex host-microbe interactions. PMID- 27474718 TI - Transcriptional Control in Marine Copiotrophic and Oligotrophic Bacteria with Streamlined Genomes. AB - Bacteria often respond to environmental stimuli using transcriptional control, but this may not be the case for marine bacteria such as "Candidatus Pelagibacter ubique," a cultivated representative of the SAR11 clade, the most abundant organism in the ocean. This bacterium has a small, streamlined genome and an unusually low number of transcriptional regulators, suggesting that transcriptional control is low in Pelagibacter and limits its response to environmental conditions. Transcriptome sequencing during batch culture growth revealed that only 0.1% of protein-encoding genes appear to be under transcriptional control in Pelagibacter and in another oligotroph (SAR92) whereas >10% of genes were under transcriptional control in the copiotrophs Polaribacter sp. strain MED152 and Ruegeria pomeroyi When growth levels changed, transcript levels remained steady in Pelagibacter and SAR92 but shifted in MED152 and R. pomeroyi Transcript abundances per cell, determined using an internal RNA sequencing standard, were low (<1 transcript per cell) for all but a few of the most highly transcribed genes in all four taxa, and there was no correlation between transcript abundances per cell and shifts in the levels of transcription. These results suggest that low transcriptional control contributes to the success of Pelagibacter and possibly other oligotrophic microbes that dominate microbial communities in the oceans. IMPORTANCE: Diverse heterotrophic bacteria drive biogeochemical cycling in the ocean. The most abundant types of marine bacteria are oligotrophs with small, streamlined genomes. The metabolic controls that regulate the response of oligotrophic bacteria to environmental conditions remain unclear. Our results reveal that transcriptional control is lower in marine oligotrophic bacteria than in marine copiotrophic bacteria. Although responses of bacteria to environmental conditions are commonly regulated at the level of transcription, metabolism in the most abundant bacteria in the ocean appears to be regulated by other mechanisms. PMID- 27474719 TI - High-Level Culturability of Epiphytic Bacteria and Frequency of Biosurfactant Producers on Leaves. AB - To better characterize the bacterial community members capable of biosurfactant production on leaves, we distinguished culturable biosurfactant-producing bacteria from nonproducers and used community sequencing to compare the composition of these distinct cultured populations with that from DNA directly recovered from leaves. Communities on spinach, romaine, and head lettuce leaves were compared with communities from adjacent samples of soil and irrigation source water. Soil communities were poorly described by culturing, with recovery of cultured representatives from only 21% of the prevalent operational taxonomic units (OTUs) (>0.2% reads) identified. The dominant biosurfactant producers cultured from soil included bacilli and pseudomonads. In contrast, the cultured communities from leaves are highly representative of the culture-independent communities, with over 85% of the prevalent OTUs recovered. The dominant taxa of surfactant producers from leaves were pseudomonads as well as members of the infrequently studied genus Chryseobacterium The proportions of bacteria cultured from head lettuce and romaine leaves that produce biosurfactants were directly correlated with the culture-independent proportion of pseudomonads in a given sample, whereas spinach harbored a wider diversity of biosurfactant producers. A subset of the culturable bacteria in irrigation water also became enriched on romaine leaves that were irrigated overhead. Although our study was designed to identify surfactant producers on plants, we also provide evidence that most bacteria in some habitats, such as agronomic plant surfaces, are culturable, and these communities can be readily investigated and described by more classical culturing methods. IMPORTANCE: The importance of biosurfactant production to the bacteria that live on waxy leaf surfaces as well as their ability to be accurately assessed using culture-based methodologies was determined by interrogating epiphytic populations by both culture-dependent and culture independent methods. Biosurfactant production was much more frequently observed in cultured communities on leaves than in other nearby habitats, such as soil and water, suggesting that this trait is important to life on a leaf by altering either the leaf itself or the interaction of bacteria with water. While pseudomonads were the most common biosurfactant producers isolated, this habitat also selects for taxa, such as Chryseobacterium, for which this trait was previously unrecognized. The finding that most epiphytic bacterial taxa were culturable validates strategies using more classical culturing methodologies for their study in this habitat. PMID- 27474720 TI - An Ecotype of Neorickettsia risticii Causing Potomac Horse Fever in Canada. AB - Neorickettsia (formerly Ehrlichia) risticii is an obligatory intracellular bacterium of digenetic trematodes. When a horse accidentally ingests aquatic insects containing encysted trematodes infected with N. risticii, the bacterium is transmitted from trematodes to horse cells and causes an acute and often fatal disease called Potomac horse fever (PHF). Since the discovery of N. risticii in the United States in 1984, using immunofluorescence and PCR assays, PHF has been increasingly recognized throughout North America and South America. However, so far, there exist only a few stable N. risticii culture isolates, all of which are from horses within the United States, and the strain diversity and environmental spreading and distribution of pathogenic N. risticii strains remain poorly understood. This paper reports the isolation of N. risticii from the blood of a horse with acute PHF in Ontario, Canada. Intracellular N. risticii colonies were detected in P388D1 cells after 47 days of culturing and 8 days after the addition of rapamycin. Molecular phylogenetic analysis based on amino acid sequences of major surface proteins P51 and Ssa1 showed that this isolate is distinct from any previously sequenced strains but closely related to midwestern U.S. strains. This is the first Canadian strain cultured, and a new method was developed to reactivate dormant N. risticii to improve culture isolation. IMPORTANCE: Neorickettsia risticii is an environmental bacterium that lives inside flukes that are parasitic to aquatic snails, insects, and bats. When a horse accidentally ingests insects harboring flukes infected with N. risticii, the bacterium is transmitted to the horse and causes an acute and often fatal disease called Potomac horse fever. Although the disease has been increasingly recognized throughout North and South America, N. risticii has not been cultured outside the United States. This paper reports the first Canadian strain cultured and a new method to effectively culture isolate N. risticii from the horse blood sample. Molecular analysis showed that the genotype of this Canadian strain is distinct from previously sequenced strains but closely related to midwestern U.S. strains. Culture isolation of N. risticii strains would confirm the geographic presence of pathogenic N. risticii, help elucidate N. risticii strain diversity and environmental spreading and distribution, and improve diagnosis and development of vaccines for this dreadful disease. PMID- 27474721 TI - Systematic Assessment of Nonproteolytic Clostridium botulinum Spores for Heat Resistance. AB - Heat treatment is an important controlling factor that, in combination with other hurdles (e.g., pH, aw), is used to reduce numbers and prevent the growth of and associated neurotoxin formation by nonproteolytic C. botulinum in chilled foods. It is generally agreed that a heating process that reduces the spore concentration by a factor of 10(6) is an acceptable barrier in relation to this hazard. The purposes of the present study were to review the available data relating to heat resistance properties of nonproteolytic C. botulinum spores and to obtain an appropriate representation of parameter values suitable for use in quantitative microbial risk assessment. In total, 753 D values and 436 z values were extracted from the literature and reveal significant differences in spore heat resistance properties, particularly those corresponding to recovery in the presence or absence of lysozyme. A total of 503 D and 338 z values collected for heating temperatures at or below 83 degrees C were used to obtain a probability distribution representing variability in spore heat resistance for strains recovered in media that did not contain lysozyme. IMPORTANCE: In total, 753 D values and 436 z values extracted from literature sources reveal significant differences in spore heat resistance properties. On the basis of collected data, two z values have been identified, z = 7 degrees C and z = 9 degrees C, for spores recovered without and with lysozyme, respectively. The findings support the use of heat treatment at 90 degrees C for 10 min to reduce the spore concentration by a factor of 10(6), providing that lysozyme is not present during recovery. This study indicates that greater heat treatment is required for food products containing lysozyme, and this might require consideration of alternative recommendation/guidance. In addition, the data set has been used to test hypotheses regarding the dependence of spore heat resistance on the toxin type and strain, on the heating technique used, and on the method of D value determination used. PMID- 27474722 TI - Inclusion of Konjac Flour in the Gestation Diet Changes the Gut Microbiota, Alleviates Oxidative Stress, and Improves Insulin Sensitivity in Sows. AB - Although dietary fibers contribute to health and physiology primarily via the fermentative actions of the gut microbiota of the hosts, few studies have focused on how these interactions influence the metabolic status of sows. Here, the effects of inclusion of konjac flour (KF) in a gestation diet on oxidative stress status, insulin sensitivity, and gut microbiota were investigated to elucidate the correlation between the microbiota and metabolic changes in sows. Sows were assigned to either control or 2.2% KF dietary treatment during gestation. The gut microbiota population in sows during gestation and lactation was assessed by 16S rRNA gene sequencing. The oxidative stress parameters, homeostasis model assessment (HOMA) values, and fatty acids in the blood of sows were also assessed. Compared to the control diet group, KF significantly reduced the serum levels of reactive oxygen species (ROS) and 8-hydroxy-deoxyguanosine (8-OHdG) but increased the serum concentrations of glutathione peroxidase (GSH-Px) in sows on day 1 in lactation. Additionally, sows in the KF group had a lower HOMA insulin resistance value but a higher HOMA insulin sensitivity (HOMA-IS) value. KF induced changes in the gut microbial composition at the phylum and genus levels. The increased relative abundances of Akkermansia and Roseburia in the KF group were positively correlated with the HOMA-IS. Overall, dietary KF alleviated oxidative stress and improved insulin sensitivity of sows, and the changes in the gut microbiota in response to KF may have been correlated with the host metabolism response. IMPORTANCE: To date, the effect of dietary fiber on metabolism responses and gut microbiota in sows has not been investigated. Here, KF supplementation of a gestation diet in sows was found to alleviate oxidative stress and to improve insulin sensitivity. Pyrosequencing analysis revealed that KF treatment induces changes in the gut microbiota composition at the phylum and genus levels. Moreover, the changes of gut microbiota in response to KF may be correlated with the host metabolism response. PMID- 27474723 TI - Novel Metal Cation Resistance Systems from Mutant Fitness Analysis of Denitrifying Pseudomonas stutzeri. AB - Metal ion transport systems have been studied extensively, but the specificity of a given transporter is often unclear from amino acid sequence data alone. In this study, predicted Cu(2+) and Zn(2+) resistance systems in Pseudomonas stutzeri strain RCH2 are compared with those experimentally implicated in Cu(2+) and Zn(2+) resistance, as determined by using a DNA-barcoded transposon mutant library. Mutant fitness data obtained under denitrifying conditions are combined with regulon predictions to yield a much more comprehensive picture of Cu(2+) and Zn(2+) resistance in strain RCH2. The results not only considerably expand what is known about well-established metal ion exporters (CzcCBA, CzcD, and CusCBA) and their accessory proteins (CzcI and CusF), they also reveal that isolates with mutations in some predicted Cu(2+) resistance systems do not show decreased fitness relative to the wild type when exposed to Cu(2+) In addition, new genes are identified that have no known connection to Zn(2+) (corB, corC, Psest_3226, Psest_3322, and Psest_0618) or Cu(2+) resistance (Mrp antiporter subunit gene, Psest_2850, and Psest_0584) but are crucial for resistance to these metal cations. Growth of individual deletion mutants lacking corB, corC, Psest_3226, or Psest_3322 confirmed the observed Zn-dependent phenotypes. Notably, to our knowledge, this is the first time a bacterial homolog of TMEM165, a human gene responsible for a congenital glycosylation disorder, has been deleted and the resulting strain characterized. Finally, the fitness values indicate Cu(2+)- and Zn(2+)-based inhibition of nitrite reductase and interference with molybdenum cofactor biosynthesis for nitrate reductase. These results extend the current understanding of Cu(2+) and Zn(2+) efflux and resistance and their effects on denitrifying metabolism. IMPORTANCE: In this study, genome-wide mutant fitness data in P. stutzeri RCH2 combined with regulon predictions identify several proteins of unknown function that are involved in resisting zinc and copper toxicity. For zinc, these include a member of the UPF0016 protein family that was previously implicated in Ca(2+)/H(+) antiport and a human congenital glycosylation disorder, CorB and CorC, which were previously linked to Mg(2+) transport, and Psest_3322 and Psest_0618, two proteins with no characterized homologs. Experiments using mutants lacking Psest_3226, Psest_3322, corB, corC, or czcI verified their proposed functions, which will enable future studies of these little-characterized zinc resistance determinants. Likewise, Psest_2850, annotated as an ion antiporter subunit, and the conserved hypothetical protein Psest_0584 are implicated in copper resistance. Physiological connections between previous studies and phenotypes presented here are discussed. Functional and mechanistic understanding of transport proteins improves the understanding of systems in which members of the same protein family, including those in humans, can have different functions. PMID- 27474724 TI - Variable High-Pressure-Processing Sensitivities for Genogroup II Human Noroviruses. AB - Human norovirus (HuNoV) is a leading cause of foodborne diseases worldwide. High pressure processing (HPP) is one of the most promising nonthermal technologies for the decontamination of viral pathogens in foods. However, the survival of HuNoVs after HPP is poorly understood because these viruses cannot be propagated in vitro In this study, we estimated the survival of different HuNoV strains within genogroup II (GII) after HPP treatment using viral receptor-binding ability as an indicator. Four HuNoV strains (one GII genotype 1 [GII.1] strain, two GII.4 strains, and one GII.6 strain) were treated at high pressures ranging from 200 to 600 MPa. After treatment, the intact viral particles were captured by porcine gastric mucin-conjugated magnetic beads (PGM-MBs) that contained histo blood group antigens, the functional receptors for HuNoVs. The genomic RNA copies of the captured HuNoVs were quantified by real-time reverse transcriptase PCR (RT PCR). Two GII.4 HuNoVs had similar sensitivities to HPP. The resistance of HuNoV strains against HPP ranked as follows: GII.1 > GII.6 > GII.4, with GII.4 being the most sensitive. Evaluation of temperature and matrix effects on HPP-mediated inactivation of HuNoV GII.4, GII.1, and GII.6 strains showed that HuNoV was more easily inactivated at lower temperatures and at a neutral pH. In addition, phosphate-buffered saline (PBS) and minimal essential medium (MEM) can provide protective effects against HuNoV inactivation compared to H2O. Collectively, this study demonstrated that (i) different HuNoV strains within GII exhibited different sensitivities to high pressure, and (ii) HPP is capable of inactivating HuNoV GII strains by optimizing pressure parameters. IMPORTANCE: Human norovirus (HuNoV) is a leading cause of foodborne disease worldwide. Noroviruses are highly diverse, both antigenically and genetically. Genogroup II (GII) contains the majority of HuNoVs, with GII genotype 4 (GII.4) being the most prevalent. Recently, GII.1 and GII.6 have emerged and caused many outbreaks worldwide. However, the survival of these GII HuNoVs is poorly understood because they are uncultivable in vitro Using a novel receptor-binding assay conjugated with real time RT-PCR, we found that GII HuNoVs had variable susceptibilities to high pressure processing (HPP), which is one of the most promising food-processing technologies. The resistance of HuNoV strains to HPP ranked as follows: GII.1 > GII.6 > GII.4. This study highlights the ability of HPP to inactivate HuNoV and the need to optimize processing conditions based on HuNoV strain variability and sample matrix. PMID- 27474725 TI - FocalScan: Scanning for altered genes in cancer based on coordinated DNA and RNA change. AB - Somatic genomic copy-number alterations can lead to transcriptional activation or inactivation of tumor driver or suppressor genes, contributing to the malignant properties of cancer cells. Selection for such events may manifest as recurrent amplifications or deletions of size-limited (focal) regions. While methods have been developed to identify such focal regions, finding the exact targeted genes remains a challenge. Algorithms are also available that integrate copy number and RNA expression data, to aid in identifying individual targeted genes, but specificity is lacking. Here, we describe FocalScan, a tool designed to simultaneously uncover patterns of focal copy number alteration and coordinated expression change, thus combining both principles. The method outputs a ranking of tentative cancer drivers or suppressors. FocalScan works with RNA-seq data, and unlike other tools it can scan the genome unaided by a gene annotation, enabling identification of novel putatively functional elements including lncRNAs. Application on a breast cancer data set suggests considerably better performance than other DNA/RNA integration tools. PMID- 27474726 TI - Divergent Transactivation of Maize Storage Protein Zein Genes by the Transcription Factors Opaque2 and OHPs. AB - Maize transcription factors (TFs) opaque2 (O2) and the O2 heterodimerizing proteins (OHP1 and OHP2) originated from an ancient segmental duplication. The 22 kDa (z1C) and 19-kDa (z1A, z1B, and z1D) alpha-zeins are the most abundant storage proteins in maize endosperm. O2 is known to regulate alpha-zein gene expression, but its target motifs in the 19-kDa alpha-zein gene promoters have not been identified. The mechanisms underlying the regulation of alpha-zein genes by these TFs are also not well understood. In this study, we found that the O2 binding motifs in the alpha-zein gene promoters are quite flexible, with ACGT being present in the z1C and z1A promoters and a variant, ACAT, being present in the z1B and z1D promoters. OHPs recognized and transactivated all of the alpha zein promoters, although to much lower levels than did O2. In the presence of O2, the suppression of OHPs did not cause a significant reduction in the transcription of alpha-zein genes, but in the absence of O2, OHPs were critical for the expression of residual levels of alpha-zeins. These findings demonstrated that O2 is the primary TF and that OHPs function as minor TFs in this process. This relationship is the converse of that involved in 27-kDa gamma-zein gene regulation, indicating that the specificities of O2 and the OHPs for regulating zein genes diverged after gene duplication. The prolamine-box binding factor by itself has limited transactivation activity, but it promotes the binding of O2 to O2 motifs, resulting in the synergistic transactivation of alpha-zein genes. PMID- 27474727 TI - Fine-Scale Human Population Structure in Southern Africa Reflects Ecogeographic Boundaries. AB - Recent genetic studies have established that the KhoeSan populations of southern Africa are distinct from all other African populations and have remained largely isolated during human prehistory until ~2000 years ago. Dozens of different KhoeSan groups exist, belonging to three different language families, but very little is known about their population history. We examine new genome-wide polymorphism data and whole mitochondrial genomes for >100 South Africans from the ?Khomani San and Nama populations of the Northern Cape, analyzed in conjunction with 19 additional southern African populations. Our analyses reveal fine-scale population structure in and around the Kalahari Desert. Surprisingly, this structure does not always correspond to linguistic or subsistence categories as previously suggested, but rather reflects the role of geographic barriers and the ecology of the greater Kalahari Basin. Regardless of subsistence strategy, the indigenous Khoe-speaking Nama pastoralists and the N|u-speaking ?Khomani (formerly hunter-gatherers) share ancestry with other Khoe-speaking forager populations that form a rim around the Kalahari Desert. We reconstruct earlier migration patterns and estimate that the southern Kalahari populations were among the last to experience gene flow from Bantu speakers, ~14 generations ago. We conclude that local adoption of pastoralism, at least by the Nama, appears to have been primarily a cultural process with limited genetic impact from eastern Africa. PMID- 27474728 TI - Comparing the Statistical Fate of Paralogous and Orthologous Sequences. AB - For several decades, sequence alignment has been a widely used tool in bioinformatics. For instance, finding homologous sequences with a known function in large databases is used to get insight into the function of nonannotated genomic regions. Very efficient tools like BLAST have been developed to identify and rank possible homologous sequences. To estimate the significance of the homology, the ranking of alignment scores takes a background model for random sequences into account. Using this model we can estimate the probability to find two exactly matching subsequences by chance in two unrelated sequences. For two homologous sequences, the corresponding probability is much higher, which allows us to identify them. Here we focus on the distribution of lengths of exact sequence matches between protein-coding regions of pairs of evolutionarily distant genomes. We show that this distribution exhibits a power-law tail with an exponent [Formula: see text] Developing a simple model of sequence evolution by substitutions and segmental duplications, we show analytically and computationally that paralogous and orthologous gene pairs contribute differently to this distribution. Our model explains the differences observed in the comparison of coding and noncoding parts of genomes, thus providing a better understanding of statistical properties of genomic sequences and their evolution. PMID- 27474730 TI - Effective vitamin B12 treatment can reduce serum antigastric parietal cell antibody titer in patients with oral mucosal disease. AB - BACKGROUND/PURPOSE: Patients with serum antigastric parietal cell antibody (GPCA) positivity may have vitamin B12 deficiency and some oral symptoms. This study assessed the changes of serum GPCA titer in GPCA-positive patients after effective vitamin B12 treatment. METHODS: Two hundred and ten GPCA-positive oral mucosal disease patients became oral symptom free (complete response) after 1.0 67.1 months of treatment with regular and continuous intramuscular injection of vitamin B12 once per week. The changes of serum GPCA titers after treatment were evaluated in these 210 patients. RESULTS: We found a significant drop of the GPCA positive rate from 100% to 42.9% in our 210 complete response patients after effective vitamin B12 treatment (p < 0.001). When 210 patients were further divided into seven subgroups according to the low to high serum GPCA titers, we noted that the higher serum GPCA titers decreased to significantly lower levels after treatment in all seven subgroups (all p < 0.001). However, serum GPCA titers increased to significantly higher levels in 46 GPCA-positive control patients receiving only oral administration of two vitamin BC capsules (containing 10 MUg of vitamin B12) plus deficient hematinic supplements per day after a follow-up period of 2.7-27 months. A maintenance vitamin B12 treatment once a month could retain the GPCA-negative status in 87% of treated-to GPCA negative patients compared with those (10%) without further maintenance vitamin B12 treatment. CONCLUSION: Regular and continuous effective vitamin B12 treatment can reduce the relatively higher serum GPCA titers to significantly lower or undetectable levels in GPCA-positive patients. PMID- 27474731 TI - [Terbinafine : Relevant drug interactions and their management]. AB - The allylamine terbinafine is the probably most frequently prescribed systemic antifungal agent in Germany for the treatment of dermatomycoses and onychomycoses. According to the German drug law, terbinafine is approved for patients who are 18 years and older; however, this antifungal agent is increasingly used off-label for treatment of onychomycoses and tinea capitis in children. Terbinafine is associated with only a few interactions with other drugs, which is why terbinafine can generally be used without problems in older and multimorbid patients. Nevertheless, some potential interactions of terbinafine with certain drug substances are known, including substances of the group of antidepressants/antipsychotics and some cardiovascular drugs. Decisive for the relevance of interactions is-along with the therapeutic index of the substrate and the possible alternative degradation pathways-the genetically determined type of metabolism. When combining terbinafine with tricyclic antidepressants or selective serotonin reuptake inhibitors and serotonin/noradrenalin reuptake inhibitors, the clinical response and potential side effects must be monitored. Problematic is the use of terbinafine with simultaneous treatment with tamoxifen. The administration of potent CYP2D6 inhibitors leads to a diminished efficacy of tamoxifen because one of its most important active metabolites-endoxifen-is not sufficiently available. Therefore, combination of tamoxifen and terbinafine should be avoided. In conclusion, the number of substances which are able to cause clinically relevant interactions in case of simultaneously administration with terbinafine is clear and should be manageable in the dermatological office with adequate monitoring. PMID- 27474729 TI - Identification of the Target of the Retrograde Response that Mediates Replicative Lifespan Extension in Saccharomyces cerevisiae. AB - The retrograde response signals mitochondrial status to the nucleus, compensating for accumulating mitochondrial dysfunction during Saccharomyces cerevisiae aging and extending replicative lifespan. The histone acetylase Gcn5 is required for activation of nuclear genes and lifespan extension in the retrograde response. It is part of the transcriptional coactivators SAGA and SLIK, but it is not known which of these complexes is involved. Genetic manipulation showed that these complexes perform interchangeably in the retrograde response. These results, along with the finding that the histone deacetylase Sir2 was required for a robust retrograde response informed a bioinformatics screen that reduced to four the candidate genes causal for longevity of the 410 retrograde response target genes. Of the four, only deletion of PHO84 suppressed lifespan extension. Retrograde-response activation of PHO84 displayed some preference for SAGA. Increased PHO84 messenger RNA levels from a second copy of the gene in cells in which the retrograde response is not activated achieved >80% of the lifespan extension observed in the retrograde response. Our studies resolve questions involving the roles of SLIK and SAGA in the retrograde response, pointing to the cooperation of these complexes in gene activation. They also finally pinpoint the gene that is both necessary and sufficient to extend replicative lifespan in the retrograde response. The finding that this gene is PHO84 opens up a new set of questions about the mechanisms involved, as this gene is known to have pleiotropic effects. PMID- 27474732 TI - Empirically Derived Patterns of Pain, Stooling, and Incontinence and Their Relations to Health-Related Quality of Life Among Youth With Chronic Constipation. AB - Objective: Chronic constipation is associated with pain, stress, and fecal incontinence, which negatively impact health-related quality of life (HRQoL); however, it is unclear if patterns of pain, stool frequency, and incontinence are differentially associated with HRQoL in youth with chronic constipation. Methods: 410 caregivers completed a demographics and symptoms form, the Parental Opinions of Pediatric Constipation, Pediatric Symptom Checklist, and the Functional Disability Inventory. Results: Stooling patterns were derived using Latent Variable Mixture Modeling. A three-class model emerged: withholding/avoiding ( WA ), pain , and fecal incontinence ( FI ). The pain class reported the greatest amount of disease burden/distress, greatest impairments in illness-related activity limitations, more psychosocial problems, and, along with the FI class, elevated levels of family conflict. The FI class reported the greatest amount of parental worry of social impact. Conclusions: Youth with chronic constipation who experience pain or fecal incontinence may be at a greater risk for specific HRQoL problems such as illness-related activity limitations, psychosocial issues, disease burden and worry, and family conflict. PMID- 27474733 TI - [Immune-mediated neuropathies]. AB - The Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are the most common immune-mediated polyneuropathies, which can show variable clinical and electrophysiological manifestations. Rarer immune mediated neuropathies encompass paraproteinemic neuropathies (PPN), multifocal motor neuropathy (MMN) and vasculitic neuropathies. The diagnosis usually relies on the history of symptom evolution, distribution of nerve dysfunction and particularly on characteristic features in nerve conduction studies, aided by cerebrospinal fluid (CSF) examination and nerve biopsy findings. The therapeutic toolbox encompasses corticosteroids, immunoglobulins and plasmapheresis often accompanied by long-term immunosuppression. It is important to note that immune mediated neuropathies selectively respond to treatment and contraindications need to be considered. Despite treatment a considerable number of patients suffer from permanent neurological deficits. PMID- 27474734 TI - Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome. AB - The equilibrium linking the intestinal microbiota, the intestinal epithelium, and the host immune system establishes host health and homeostasis, with perturbations of this balance resulting in chronic inflammatory and autoimmune immunopathologies. The mutualistic symbiosis between gut microbiota and host immunity raises the possibility that dysbiosis of the intestinal content also influences the outcome of cancer immunotherapy. Here, we present our recent findings that specific gut-resident bacteria determine the immunotherapeutic responses associated with CTLA-4 checkpoint blockade. This new evidence hints that interindividual differences in the microbiome may account for the significant heterogeneity in therapeutic and immunopathologic responses to immune checkpoint therapies. We discuss how this new understanding could improve the therapeutic coverage of immune checkpoint inhibitors, and potentially limit their immune-mediated toxicity, through the use of adjunctive "oncomicrobiotics" that indirectly promote beneficial immune responses through optimizing the gut microbiome. Cancer Res; 76(16); 4602-7. (c)2016 AACR. PMID- 27474735 TI - Corrigendum. PMID- 27474736 TI - The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria. AB - The forward reaction of nicotinamide nucleotide transhydrogenase (NNT) reduces NADP(+) at the expense of NADH oxidation and H(+) movement down the electrochemical potential across the inner mitochondrial membrane, establishing an NADPH/NADP(+) ratio severalfold higher than the NADH/NAD(+) ratio in the matrix. In turn, NADPH drives processes, such as peroxide detoxification and reductive biosynthesis. In this study, we generated a congenic mouse model carrying a mutated Nnt(C57BL/6J) allele from the C57BL/6J substrain. Suspensions of isolated mitochondria from Nnt(+/+), Nnt(+/-), and Nnt(-/-) mouse liver were biochemically evaluated and challenged with exogenous peroxide under different respiratory states. The respiratory substrates were also varied, and the participation of concurrent NADPH sources (i.e. isocitrate dehydrogenase-2, malic enzymes, and glutamate dehydrogenase) was assessed. The principal findings include the following: Nnt(+/-) and Nnt(-/-) exhibit ~50% and absent NNT activity, respectively, but the activities of concurrent NADPH sources are unchanged. The lack of NNT activity in Nnt(-/-) mice impairs peroxide metabolism in intact mitochondria. The contribution of NNT to peroxide metabolism is decreased during ADP phosphorylation compared with the non-phosphorylating state; however, it is accompanied by increased contributions of concurrent NADPH sources, especially glutamate dehydrogenase. NNT makes a major contribution to peroxide metabolism during the blockage of mitochondrial electron transport. Interestingly, peroxide metabolism in the Nnt(+/-) mitochondria matched that in the Nnt(+/+) mitochondria. Overall, this study demonstrates that the respiratory state and/or substrates that sustain energy metabolism markedly influence the relative contribution of NNT (i.e. varies between nearly 0 and 100%) to NADPH dependent mitochondrial peroxide metabolism. PMID- 27474738 TI - Structural Insights into Substrate Recognition and Catalysis in Outer Membrane Protein B (OmpB) by Protein-lysine Methyltransferases from Rickettsia. AB - Rickettsia belong to a family of Gram-negative obligate intracellular infectious bacteria that are the causative agents of typhus and spotted fever. Outer membrane protein B (OmpB) occurs in all rickettsial species, serves as a protective envelope, mediates host cell adhesion and invasion, and is a major immunodominant antigen. OmpBs from virulent strains contain multiple trimethylated lysine residues, whereas the avirulent strain contains mainly monomethyllysine. Two protein-lysine methyltransferases (PKMTs) that catalyze methylation of recombinant OmpB at multiple sites with varying sequences have been identified and overexpressed. PKMT1 catalyzes predominantly monomethylation, whereas PKMT2 catalyzes mainly trimethylation. Rickettsial PKMT1 and PKMT2 are unusual in that their primary substrate appears to be limited to OmpB, and both are capable of methylating multiple lysyl residues with broad sequence specificity. Here we report the crystal structures of PKMT1 from Rickettsia prowazekii and PKMT2 from Rickettsia typhi, both the apo form and in complex with its cofactor S-adenosylmethionine or S-adenosylhomocysteine. The structure of PKMT1 in complex with S-adenosylhomocysteine is solved to a resolution of 1.9 A. Both enzymes are dimeric with each monomer containing an S-adenosylmethionine binding domain with a core Rossmann fold, a dimerization domain, a middle domain, a C-terminal domain, and a centrally located open cavity. Based on the crystal structures, residues involved in catalysis, cofactor binding, and substrate interactions were examined using site-directed mutagenesis followed by steady state kinetic analysis to ascertain their catalytic functions in solution. Together, our data reveal new structural and mechanistic insights into how rickettsial methyltransferases catalyze OmpB methylation. PMID- 27474737 TI - Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na+ and K+ Ions and the Protonation State of Glu290. AB - Ions play key mechanistic roles in the gating dynamics of neurotransmitter:sodium symporters (NSSs). In recent microsecond scale molecular dynamics simulations of a complete model of the dopamine transporter, a NSS protein, we observed a partitioning of K(+) ions from the intracellular side toward the unoccupied Na2 site of dopamine transporter following the release of the Na2-bound Na(+) Here we evaluate with computational simulations and experimental measurements of ion affinities under corresponding conditions, the consequences of K(+) binding in the Na2 site of LeuT, a bacterial homolog of NSS, when both Na(+) ions and substrate have left, and the transporter prepares for a new cycle. We compare the results with the consequences of binding Na(+) in the same apo system. Analysis of >50-MUs atomistic molecular dynamics and enhanced sampling trajectories of constructs with Glu(290), either charged or neutral, point to the Glu(290) protonation state as a main determinant in the structural reconfiguration of the extracellular vestibule of LeuT in which a "water gate" opens through coordinated motions of residues Leu(25), Tyr(108), and Phe(253) The resulting water channel enables the binding/dissociation of the Na(+) and K(+) ions that are prevalent, respectively, in the extracellular and intracellular environments. PMID- 27474739 TI - Non-canonical Interactions between Heat Shock Cognate Protein 70 (Hsc70) and Bcl2 associated Anthanogene (BAG) Co-Chaperones Are Important for Client Release. AB - Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. The release of nucleotide is known to be mediated by interactions between the conserved BAG domain and the Hsc70 NBD. However, less is known about the regions required for client release, and it is often assumed that this activity also requires the BAG domain. It is important to better understand this step because it determines how long clients remain in the inactive, bound state. Here, we report the surprising observation that truncated versions of either human Bag1 or Bag3, comprised only the BAG domain, promoted rapid release of nucleotide, but not client, in vitro Rather, we found that a non-canonical interaction between Bag1/3 and the Hsc70 SBD is sufficient for accelerating this step. Moreover, client release did not seem to require the BAG domain or Hsc70 NBD. These results suggest that Bag1 and Bag3 control the stability of the Hsc70 client complex using at least two distinct protein-protein contacts, providing a previously under-appreciated layer of molecular regulation in the human Hsc70 system. PMID- 27474740 TI - The Effectors and Sensory Sites of Formaldehyde-responsive Regulator FrmR and Metal-sensing Variant. AB - The DUF156 family of DNA-binding transcriptional regulators includes metal sensors that respond to cobalt and/or nickel (RcnR, InrS) or copper (CsoR) plus CstR, which responds to persulfide, and formaldehyde-responsive FrmR. Unexpectedly, the allosteric mechanism of FrmR from Salmonella enterica serovar Typhimurium is triggered by metals in vitro, and variant FrmR(E64H) gains responsiveness to Zn(II) and cobalt in vivo Here we establish that the allosteric mechanism of FrmR is triggered directly by formaldehyde in vitro Sensitivity to formaldehyde requires a cysteine (Cys(35) in FrmR) conserved in all DUF156 proteins. A crystal structure of metal- and formaldehyde-sensing FrmR(E64H) reveals that an FrmR-specific amino-terminal Pro(2) is proximal to Cys(35), and these residues form the deduced formaldehyde-sensing site. Evidence is presented that implies that residues spatially close to the conserved cysteine tune the sensitivities of DUF156 proteins above or below critical thresholds for different effectors, generating the semblance of specificity within cells. Relative to FrmR, RcnR is less responsive to formaldehyde in vitro, and RcnR does not sense formaldehyde in vivo, but reciprocal mutations FrmR(P2S) and RcnR(S2P), respectively, impair and enhance formaldehyde reactivity in vitro Formaldehyde detoxification by FrmA requires S-(hydroxymethyl)glutathione, yet glutathione inhibits formaldehyde detection by FrmR in vivo and in vitro Quantifying the number of FrmR molecules per cell and modeling formaldehyde modification as a function of [formaldehyde] demonstrates that FrmR reactivity is optimized such that FrmR is modified and frmRA is derepressed at lower [formaldehyde] than required to generate S-(hydroxymethyl)glutathione. Expression of FrmA is thereby coordinated with the accumulation of its substrate. PMID- 27474741 TI - Mechanistic and Evolutionary Insights from the Reciprocal Promiscuity of Two Pyridoxal Phosphate-dependent Enzymes. AB - Enzymes that utilize the cofactor pyridoxal 5'-phosphate play essential roles in amino acid metabolism in all organisms. The cofactor is used by proteins that adopt at least five different folds, which raises questions about the evolutionary processes that might explain the observed distribution of functions among folds. In this study, we show that a representative of fold type III, the Escherichia coli alanine racemase (ALR), is a promiscuous cystathionine beta lyase (CBL). Furthermore, E. coli CBL (fold type I) is a promiscuous alanine racemase. A single round of error-prone PCR and selection yielded variant ALR(Y274F), which catalyzes cystathionine beta-elimination with a near-native Michaelis constant (Km = 3.3 mm) but a poor turnover number (kcat ~10 h(-1)). In contrast, directed evolution also yielded CBL(P113S), which catalyzes l-alanine racemization with a poor Km (58 mm) but a high kcat (22 s(-1)). The structures of both variants were solved in the presence and absence of the l-alanine analogue, (R)-1-aminoethylphosphonic acid. As expected, the ALR active site was enlarged by the Y274F substitution, allowing better access for cystathionine. More surprisingly, the favorable kinetic parameters of CBL(P113S) appear to result from optimizing the pKa of Tyr-111, which acts as the catalytic acid during l alanine racemization. Our data emphasize the short mutational routes between the functions of pyridoxal 5'-phosphate-dependent enzymes, regardless of whether or not they share the same fold. Thus, they confound the prevailing model of enzyme evolution, which predicts that overlapping patterns of promiscuity result from sharing a common multifunctional ancestor. PMID- 27474743 TI - Type IV Pilus Alignment Subcomplex Proteins PilN and PilO Form Homo- and Heterodimers in Vivo. AB - Pseudomonas aeruginosa is a leading cause of hospital-acquired infections and is resistant to many antibiotics. Type IV pili (T4P) are among the key virulence factors used by P. aeruginosa for host cell attachment, biofilm formation, and twitching motility, making this system a promising target for novel therapeutics. Point mutations in the conserved PilMNOP alignment subcomplex were previously shown to have distinct effects on assembly and disassembly of T4P, suggesting that it may function in a dynamic manner. We introduced mutations encoding Cys substitutions into pilN and/or pilO on the chromosome to maintain normal stoichiometry and expression levels and captured covalent PilNO heterodimers, as well as PilN and PilO homodimers, in vivo Most covalent PilN or PilO homodimers had minimal functional impact in P. aeruginosa, suggesting that homodimers are a physiologically relevant state. However, certain covalent homo- or heterodimers eliminated twitching motility, suggesting that specific PilNO configurations are essential for T4P function. These data were verified using soluble N-terminal truncated fragments of PilN and PilO Cys mutants, which purified as a mixture of homo- and heterodimers at volumes consistent with a tetramer. Deletion of genes encoding alignment subcomplex components, PilM or PilP, but not other T4P components, including the motor ATPases PilB or PilT, blocked in vivo formation of disulfide-bonded PilNO heterodimers, suggesting that both PilM and PilP influence the heterodimer interface. Combined, our data suggest that T4P function depends on rearrangements at PilN and PilO interfaces. PMID- 27474742 TI - A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis. AB - Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-beta. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical alpha-, beta-, and gamma-secretases is simplistic, with the discovery of a number of novel APP secretases (including delta- and eta secretases, alternative beta-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis. PMID- 27474744 TI - Accumulation of Peptidoglycan O-Acetylation Leads to Altered Cell Wall Biochemistry and Negatively Impacts Pathogenesis Factors of Campylobacter jejuni. AB - Campylobacter jejuni is a leading cause of bacterial gastroenteritis in the developed world. Despite its prevalence, its mechanisms of pathogenesis are poorly understood. Peptidoglycan (PG) is important for helical shape, colonization, and host-pathogen interactions in C. jejuni Therefore, changes in PG greatly impact the physiology of this organism. O-acetylation of peptidoglycan (OAP) is a bacterial phenomenon proposed to be important for proper cell growth, characterized by acetylation of the C6 hydroxyl group of N-acetylmuramic acid in the PG glycan backbone. The OAP gene cluster consists of a PG O-acetyltransferase A (patA) for translocation of acetate into the periplasm, a PG O acetyltransferase B (patB) for O-acetylation, and an O-acetylpeptidoglycan esterase (ape1) for de-O-acetylation. In this study, reduced OAP in DeltapatA and DeltapatB had minimal impact on C. jejuni growth and fitness under the conditions tested. However, accumulation of OAP in Deltaape1 resulted in marked differences in PG biochemistry, including O-acetylation, anhydromuropeptide levels, and changes not expected to result directly from Ape1 activity. This suggests that OAP may be a form of substrate level regulation in PG biosynthesis. Ape1 acetylesterase activity was confirmed in vitro using p-nitrophenyl acetate and O acetylated PG as substrates. In addition, Deltaape1 exhibited defects in pathogenesis-associated phenotypes, including cell shape, motility, biofilm formation, cell surface hydrophobicity, and sodium deoxycholate sensitivity. Deltaape1 was also impaired for chick colonization and adhesion, invasion, intracellular survival, and induction of IL-8 production in INT407 cells in vitro The importance of Ape1 in C. jejuni biology makes it a good candidate as an antimicrobial target. PMID- 27474747 TI - Arterial stiffness and its relationship to clinic and ambulatory blood pressure: a longitudinal study in non-dialysis chronic kidney disease. AB - Background: Both arterial stiffness and systolic blood pressure (BP) are established cardiovascular risk factors, yet little is known about their interrelationship in chronic kidney disease (CKD). The goal of this prospective study was to describe the trajectory of aortic pulse wave velocity (PWV) and BP and to compare the longitudinal interrelationship of BP (clinic and 24 h ambulatory recording) with the PWV. Methods: Clinic BP was taken in two ways: at the time of the measurement of the PWV (Clinic-S) and as an average of triplicate measurements on three separate occasions within 1 week (Clinic-M). 24 h ambulatory BP was measured using a validated monitor and PWV was measured in the aorta using an echo-Doppler technique. Results: Among 255 veterans with CKD followed for over up to 4 years, the rate of change of log PWV was inversely related to the baseline PWV; the trajectories were variable among individuals and the net population change was no different from zero. In contrast, systolic BP significantly increased, but linearly, and a strong relationship was seen between cross-sectional and longitudinal changes in Clinic-M systolic BP and log PWV. In contrast, a longitudinal relationship between Clinic-S and log PWV was absent. In the case of 24-h ambulatory BP, a strong cross-sectional change was seen between awake and 24 h systolic BP but not between sleep BP and log PWV. Conclusion: In conclusion, among people with CKD, the PWV changes over time and is inversely related to the baseline PWV. An average of clinic BP measurements taken over three visits, but not single measurements, are useful to assess the PWV and its change over time. Differences exist between ambulatory BP monitoring recording during the sleep and awake states in their ability to predict the PWV. Taken together, these data support the view that among those with CKD not on dialysis, targeting clinic BP taken on multiple occasions using a standardized methodology or daytime ambulatory systolic BP may slow the progression of arterial damage. PMID- 27474746 TI - iniBAC induction Is Vitamin B12- and MutAB-dependent in Mycobacterium marinum. AB - Tuberculosis can be treated with a 6-month regimen of antibiotics. Although the targets of most of the first-line antibiotics have been identified, less research has focused on the intrabacterial stress responses that follow upon treatment with antibiotics. Studying the roles of these stress genes may lead to the identification of crucial stress-coping mechanisms that can provide additional drug targets to increase treatment efficacy. A three-gene operon with unknown function that is strongly up-regulated upon treatment with isoniazid and ethambutol is the iniBAC operon. We have reproduced these findings and show that iniBAC genes are also induced in infected host cells, although with higher variability. Next, we set out to elucidate the genetic network that results in iniBAC induction in Mycobacterium marinum By transposon mutagenesis, we identified that the operon is highly induced by mutations in genes encoding enzymes of the vitamin B12 biosynthesis pathway and the vitamin B12-dependent methylmalonyl-CoA-mutase MutAB. Lipid analysis showed that a mutA::tn mutant has decreased phthiocerol dimycocerosates levels, suggesting a link between iniBAC induction and the production of methyl-branched lipids. Moreover, a similar screen in Mycobacterium bovis BCG identified that phthiocerol dimycocerosate biosynthesis mutants cause the up-regulation of iniBAC genes. Based on these data, we propose that iniBAC is induced in response to mutations that cause defects in the biosynthesis of methyl-branched lipids. The resulting metabolic stress caused by these mutations or caused by ethambutol or isoniazid treatment may be relieved by iniBAC to increase the chance of bacterial survival. PMID- 27474745 TI - Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism. AB - Cerebral malaria is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain barrier, and a strong inflammation in the brain. We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM). Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2(-/-)) inoculated with Plasmodium berghei ANKA erythrocytes exhibited enhanced survival and a diminished blood-brain barrier disruption. Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice. Hematopoietic derived immune cells were responsible for the enhanced protection in bone marrow (BM) chimeric Cnr2(-/-) mice. Mixed BM chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b(+) cell population, containing macrophages and neutrophils, expanded in the Cnr2(-/-) spleen after infection and expressed macrophage mannose receptors, arginase-1 activity, and IL-10. Also in the Cnr2(-/-) brain, CD11b(+) cells that expressed selected anti-inflammatory markers accumulated, and expression of inflammatory mediators IFN-gamma and TNF-alpha was reduced. Finally, the M2 macrophage chemokine CCL17 was identified as an essential factor for enhanced survival in the absence of CB2, because CCL17 * Cnr2 double-deficient mice were fully susceptible to ECM. Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM. PMID- 27474748 TI - Four seasons for reflecting: autumn, hearing. PMID- 27474749 TI - Atherosclerotic renal artery stenosis is associated with elevated cell cycle arrest markers related to reduced renal blood flow and postcontrast hypoxia. AB - BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow (RBF), ultimately leading to kidney hypoxia and inflammation. Insulin-like growth factor binding protein-7 (IGFBP-7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) are biomarkers of cell cycle arrest, often increased in ischemic conditions and predictive of acute kidney injury (AKI). This study sought to examine the relationships between renal vein levels of IGFBP-7, TIMP-2, reductions in RBF and postcontrast hypoxia as measured by blood oxygen level dependent (BOLD) magnetic resonance imaging. METHODS: Renal vein levels of IGFBP 7 and TIMP-2 were obtained in an ARAS cohort (n= 29) scheduled for renal artery stenting and essential hypertensive (EH) healthy controls (n = 32). Cortical and medullary RBFs were measured by multidetector computed tomography (CT) immediately before renal artery stenting and 3 months later. BOLD imaging was performed before and 3 months after stenting in all patients, and a subgroup (N = 12) underwent repeat BOLD imaging 24 h after CT/stenting to examine postcontrast/procedure levels of hypoxia. RESULTS: Preintervention IGFBP-7 and TIMP-2 levels were elevated in ARAS compared with EH (18.5 +/- 2.0 versus 15.7 +/ 1.5 and 97.4 +/- 23.1 versus 62.7 +/- 9.2 ng/mL, respectively; P< 0.0001); baseline IGFBP-7 correlated inversely with hypoxia developing 24 h after contrast injection (r = -0.73, P< 0.0001) and with prestent cortical blood flow (r = 0.59, P= 0.004). CONCLUSION: These data demonstrate elevated IGFBP-7 and TIMP-2 levels in ARAS as a function of the degree of reduced RBF. Elevated baseline IGFBP-7 levels were associated with protection against postimaging hypoxia, consistent with 'ischemic preconditioning'. Despite contrast injection and stenting, AKI in these high-risk ARAS subjects with elevated IGFBP-7/TIMP-2 was rare and did not affect long-term kidney function. PMID- 27474750 TI - Positive and Negative Cross-Talk between Lysophosphatidic Acid Receptor 1, Free Fatty Acid Receptor 4, and Epidermal Growth Factor Receptor in Human Prostate Cancer Cells. AB - Lysophosphatidic acid (LPA) is a lipid mediator that mediates cellular effects via G protein-coupled receptors (GPCRs). Epidermal growth factor (EGF) is a peptide that acts via a receptor tyrosine kinase. LPA and EGF both induce proliferation of prostate cancer cells and can transactivate each other's receptors. The LPA receptor LPA1 is particularly important for LPA response in human prostate cancer cells. Previous work in our laboratory has demonstrated that free fatty acid 4 (FFA4), a GPCR activated by omega-3 fatty acids, inhibits responses to both LPA and EGF in these cells. One potential mechanism for the inhibition involves negative interactions between FFA4 and LPA1, thereby suppressing responses to EGF that require LPA1 In the current study, we examined the role of LPA1 in mediating EGF and FFA4 agonist responses in two human prostate cancer cell lines, DU145 and PC-3. The results show that an LPA1 selective antagonist inhibits proliferation and migration to both LPA and EGF. Knockdown of LPA1 expression, using silencing RNA, blocks responses to LPA and significantly inhibits responses to EGF. The partial response to EGF that is observed after LPA1 knockdown is not inhibited by FFA4 agonists. Finally, the role of arrestin-3, a GPCR-binding protein that mediates many actions of activated GPCRs, was tested. Knockdown of arrestin-3 completely inhibits responses to both LPA and EGF in prostate cancer cells. Taken together, these results suggest that LPA1 plays a critical role in EGF responses and that FFA4 agonists inhibit proliferation by suppressing positive cross-talk between LPA1 and the EGF receptor. PMID- 27474751 TI - Regulation of UGT2B Expression and Activity by miR-216b-5p in Liver Cancer Cell Lines. AB - The UDP-glucuronosyltransferase (UGT) 2B enzymes are important in the detoxification of a variety of endogenous and exogenous compounds, including many hormones, drugs, and carcinogens. Identifying novel mechanisms governing their expression is important in understanding patient-specific response to drugs and cancer risk factors. In silico prediction algorithm programs were used to screen for microRNAs (miRNAs) as potential regulators of UGT2B enzymes, with miR-216b-5p identified as a potential candidate. Luciferase data suggested the presence of a functional miR-216b-5p binding motif within the 3' untranslated regions of UGTs 2B7, 2B4, and 2B10. Overexpression of miR-216b-5p mimics significantly repressed UGT2B7 (P < 0.001) and UGT2B10 (P = 0.0018) mRNA levels in HuH-7 cells and UGT2B4 (P < 0.001) and UGT2B10 (P = 0.018) mRNA in Hep3B cells. UGT2B7 protein levels were repressed in both HuH-7 and Hep3B cells in the presence of increasing miR 216b-5p concentrations, corresponding with significant (P < 0.001 and P = 0.011, respectively) decreases in glucuronidation activity against the UGT2B7-specific substrate epirubicin. Inhibition of endogenous miR-216b-5p levels significantly increased UGT2B7 mRNA levels in HuH-7 (P = 0.021) and Hep3B (P = 0.0068) cells, and increased epirubicin glucuronidation by 85% (P = 0.057) and 50% (P = 0.012) for HuH-7 and Hep3B cells, respectively. UGT2B4 activity against codeine and UGT2B10 activity against nicotine were significantly decreased in both HuH-7 and Hep3B cells (P < 0.001 and P = 0.0048, and P = 0.017 and P = 0.043, respectively) after overexpression of miR-216b-5p mimic. This is the first evidence that miRNAs regulate UGT 2B7, 2B4, and 2B10 expression, and that miR-216b-5p regulation of UGT2B proteins may be important in regulating the metabolism of UGT2B substrates. PMID- 27474752 TI - A Design-Based Approach to Improve External Validity in Welfare Policy Evaluations. AB - BACKGROUND: Large-scale randomized experiments are important for determining how policy interventions change average outcomes. Researchers have begun developing methods to improve the external validity of these experiments. One new approach is a balanced sampling method for site selection, which does not require random sampling and takes into account the practicalities of site recruitment including high nonresponse. METHOD: The goal of balanced sampling is to develop a strategic sample selection plan that results in a sample that is compositionally similar to a well-defined inference population. To do so, a population frame is created and then divided into strata, which "focuses" recruiters on specific subpopulations. Units within these strata are then ranked, thus identifying "replacements" similar to sites that can be recruited when the ideal site refuses to participate in the experiment. RESULT: In this article, we consider how a balanced sample strategic site selection method might be implemented in a welfare policy evaluation. CONCLUSION: We find that simply developing a population frame can be challenging, with three possible and reasonable options arising in the welfare policy arena. Using relevant study-specific contextual variables, we craft a recruitment plan that considers nonresponse. PMID- 27474753 TI - Verapamil eluting stents as a possible treatment for vasospasm after subarachnoid hemorrhage. AB - OBJECTIVE: The only pharmacologic prophylaxis for cerebral vasospasm after subarachnoid hemorrhage is oral nimodipine. A novel way to mitigate this risk may be to design a drug eluting stent that elutes verapamil over the time period typically associated with vasospasm. In this study, we explore different methods of coating nitinol stents with a bioabsorbable polymer and determine the release profile of various verapamil coated stents for the potential treatment of vasospasm. METHODS: Nitinol stents were coated with different concentrations of poly(lactic acid-co-glycolic acid) (PLGA) in chloroform solution and using three coating techniques: dip coating, spin coating, and electrospinning. Morphology of the coatings were studied with scanning electron microscopy. 12 verapamil eluting stents were then prepared using different verapamil concentrations and coatings with different numbers of layers. Drug release behaviors were studied using UV spectroscopy for 21 days. RESULTS: Electrospinning at 20% w/v resulted in a smooth uniform coating without significant surface irregularities, and may be the most effective technique to coat stents. Stents with a single layer of PLGA/verapamil coating showed a two phase release profile (initial burst release followed by a slow rate of release) whereas stents with a bilayer coating showed a lower level of initial release followed by a slower sustained release phase. CONCLUSIONS: Development of verapamil eluting stents that elute drug over the time course typical of cerebral vasospasm, and for either immediate or prophylactic treatment, is technically feasible. Further in vitro and in vivo studies are required to determine whether this can improve the outcome of patients after subarachnoid hemorrhage. PMID- 27474754 TI - Hope and doubt in the promise of neuroimaging: The case of autism spectrum disorder. AB - Although neuroimaging is currently not a component of the diagnostic process for autism spectrum disorders, some scientists hail these technologies for their promise to one day replace behaviorally based psychiatric diagnostic techniques. This article examines how psychiatrists understand the potential use of neuroimaging technologies within the context of clinical practice. Drawing on 10 semi-structured interviews with child and adolescent psychiatrists, I describe the hope and doubt that comprise their discourse of ambivalence. This analysis demonstrates that the uses and meanings of neuroimaging technologies are rearticulated in ongoing debates in the field of psychiatry regarding the role of the biopsychiatric model in the diagnosis and treatment of mental illness. This study highlights issues surrounding the perceived biopsychiatric focus of neuroimaging technologies within clinical practice, concerns regarding misdirected research attention, and the ways in which understandings of future utility mediate perceptions of technological utility. PMID- 27474755 TI - Postthrombotic syndrome and other outcomes of lower extremity deep vein thrombosis in children. AB - Pediatric lower extremity deep vein thrombosis (LE-DVT) can lead to postthrombotic syndrome (PTS) and other adverse events. We investigated the outcomes of LE-DVT in children. Three groups were compared: non-line-related (Non LR) DVT, LR DVT in neonates (LRneonates), and LR DVT in non-neonates (LRnon neonates). A total of 339 children were included (Non-LR, n = 56; LRneonates, n = 95; and LRnon-neonates, n = 188). We found a statistically significant difference in the frequency of PTS (P = .04; 62.5%, 40.0%, and 46.3% in Non-LR, LRneonates, and LRnon-neonates, respectively), of recurrent LE-DVT (P = .001; 10.7% and 2.0% in Non-LR and LRnon-neonates, respectively), and pulmonary embolism (PE) (P < .001; 19.6% and 3.2% in Non-LR and LRnon-neonates, respectively) among groups. There was no difference in DVT resolution (P = .41). Multivariable analysis showed that DVT resolution, triggering event, and sex predicted Modified Villalta Scale (MVS; for pediatric PTS) scores >1; there was an interaction between DVT triggering event and sex. The time to reach an MVS >1 was significantly different when comparing groups (log-rank test, P < .001). Moreover, we found a significant difference in baseline MVS scores among groups, but the difference did not appear to change over time. In conclusion, LR LE-DVT had more benign outcomes than Non LR DVT. Sex, DVT triggering event, and DVT resolution predicted LE-PTS in our cohort. PMID- 27474756 TI - Is being resolute better than being pragmatic when it comes to breastfeeding? Longitudinal qualitative study investigating experiences of women intending to breastfeed using the Theoretical Domains Framework. AB - Background: In the UK, initiating then discontinuing breastfeeding before two weeks post-partum is common. The aim of this longitudinal qualitative study was to explore which psychosocial factors may influence discontinuation. Methods: A sample of 10 pregnant women intending to breastfeed were recruited. A longitudinal qualitative design was used to capture views prior to and two weeks following birth. Semi-structured interviews were conducted underpinned by the Theoretical Domains Framework to explore a comprehensive list of psychosocial factors. Results: Four women discontinued breastfeeding at the time of the second interview. Pre-partum differences were identified between maintainers and discontinuers; discontinuers appeared to have stronger intentions to breastfeed based on their self-determination, self-confidence and perception of fewer barriers to breastfeeding. Post-partum, discontinuers highlighted how they felt physically unable to carry on; their feeding experiences elicited negative emotions and pain. Negative emotions appeared to be exacerbated by original breastfeeding beliefs and advice given by healthcare professionals. Conclusions: The women in this study who discontinued breastfeeding showed less cognitive flexibility, which appeared to exacerbate post-partum emotional distress, when they encountered difficulties. Women with strong intentions and self determination might benefit from support in anticipating potential barriers and identifying ways of overcoming them. PMID- 27474757 TI - Demographic and regional characteristics of road traffic injury deaths in Jiangsu Province, China. AB - Background: The study investigates the magnitude and distribution of fatal road traffic injuries (RTIs) in the Chinese province of Jiangsu by road user. Method: The 13 694 RTI deaths and years of potential life lost (YPLL) that occurred in 2012 were analysed; vulnerable and non-vulnerable road users were considered separately. Age-adjusted mortality and YPLL were compiled and the association between demographic characteristics and RTI mortality rate was analysed using negative binomial regression. Results: The age-adjusted RTI mortality and YPLL in Jiangsu in 2012 were 18.14 (95% CI: 17.84-18.45) and 494.3 (95% CI: 492.7-496.0) per 100 000 population. Half of the deaths were among pedestrians and for vulnerable road users as a whole, male fatalities were over three times that of female (adjusted incidence rate ratio = 3.26, 95% CI: 1.89-3.77). Fatalities in the oldest age group (80+ years) were over 14 times that of the youngest one (0-9 years) (adjusted incidence rate ratio = 14.13, 95% CI: 9.49-21.01). Fatality rates in the central and northern regions surpassed that of the south. Conclusion: As in the rest of the country, RTIs are a considerable public health problem in Jiangsu where fatality and YPLL rates fall heavily on pedestrians, men, and older persons and are more pronounced in the less developed regions. PMID- 27474758 TI - The association of air pollution with birthweight and gestational age: evidence from Hong Kong's 'Children of 1997' birth cohort. AB - Background: Previous studies from Western settings have found inconsistent associations of air pollutants with birth outcomes, which are open to residual confounding by socioeconomic position (SEP). We assessed this association in the economically developed non-Western setting of Hong Kong, with high levels of air pollution but little social patterning of these outcomes. Methods: We obtained PM10, SO2, NO and NO2 from monitoring stations, and assessed their associations with birthweight and gestational age in a large population-representative birth cohort 'Children of 1997', using partial least-square regression to account for the colinearity between pollutants. Results: PM10 (per 5.7 ug/m3 higher) and NO2 (per 10.9 ug/m3 higher) were associated with birthweight lower by 47.0 g (95% confidence interval (CI) 36.2-56.3) and 16.9 g (95% CI 10.8-22.6), respectively; and were associated with gestational age shorter by 2.1 days (95% CI 1.7-2.4) and 0.7 days (95% CI 0.5-0.8), respectively. Conclusions: Given minimal confounding by SEP in our setting, these findings provide unequivocal evidence of adverse effects of PM10 and NO2 exposure during pregnancy on birthweight and gestational age. Physiological mechanisms need to be better understood to support effective public health action globally. PMID- 27474759 TI - Patient choice and private provision decreased public provision and increased inequalities in Scotland: a case study of elective hip arthroplasty. AB - Background: This is the first research to examine how the policy of patient choice and commercial contracting where NHS funds are given to private providers to tackle waiting times, impacted on direct NHS provision and treatment inequalities. Methods: An ecological study of NHS funded elective primary hip arthroplasties in Scotland using routinely collected inpatient data 1 April 1993 31 March 2013. Results: An increased use of private sector provision by NHS Boards was associated with a significant decrease in direct NHS provision in 2008/09 (P < 0.01) and with widening inequalities by age and socio-economic deprivation. National treatment rate fell from 143.8 (140.3, 147.3) per 100 000 in 2006/07 to 137.8 (134.4, 141.2) per 100 000 in 2007/08. By 2012/13, territorial NHS Boards had not recovered 2006/07 levels of provision; this was most marked for NHS Boards with the greatest use of private sector, namely Fife, Grampian and Lothian. Patients aged 85 years and over or living in the more deprived areas of Scotland appear to have been disadvantaged since the onset of patient choice in 2002. Conclusions: NHS funding of private sector provision for elective hip arthroplasty was associated with a decrease in public provision and may have contributed to an increase in age and socio-economic inequalities in treatment rates. PMID- 27474760 TI - Kalipso Chalkidou: Internationally NICE. PMID- 27474761 TI - NHS's financial woes undermine quality and safety drive. PMID- 27474762 TI - MAIT cells: not just another brick in the wall. PMID- 27474763 TI - Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome. AB - OBJECTIVE: To explore whether gene expression profiling can identify a molecular mechanism for the clinical benefit of canakinumab treatment in patents with tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Blood samples were collected from 20 patients with active TRAPS who received canakinumab 150 mg every 4 weeks for 4 months in an open-label proof-of-concept phase II study, and from 20 aged-matched healthy volunteers. Gene expression levels were evaluated in whole blood samples by microarray analysis for arrays passing quality control checks. RESULTS: Patients with TRAPS exhibited a gene expression signature in blood that differed from that in healthy volunteers. Upon treatment with canakinumab, many genes relevant to disease pathogenesis moved towards levels seen in the healthy volunteers. Canakinumab downregulated the TRAPS-causing gene (TNF super family receptor 1A (TNFRSF1A)), the drug-target gene (interleukin (IL)-1B) and other inflammation-related genes (eg, MAPK14). In addition, several inflammation-related pathways were evident among the differentially expressed genes. Canakinumab treatment reduced neutrophil counts, but the observed expression differences remained after correction for this. CONCLUSIONS: These gene expression data support a model in which canakinumab produces clinical benefit in TRAPS by increasing neutrophil apoptosis and reducing pro-inflammatory signals resulting from the inhibition of IL-1beta. Notably, treatment normalised the overexpression of TNFRSF1A, suggesting that canakinumab has a direct impact on the main pathogenic mechanism in TRAPS. TRIAL REGISTRATION NUMBER: NCT01242813. PMID- 27474765 TI - Locking doors in mental health hospitals does not reduce suicide or absconding, shows study. PMID- 27474764 TI - Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. AB - OBJECTIVES: To develop a Glucocorticoid Toxicity Index (GTI) to assess glucocorticoid (GC)-related morbidity and GC-sparing ability of other therapies. METHODS: Nineteen experts on GC use and outcome measures from 11 subspecialties participated. Ten experts were from the USA; nine from Canada, Europe or Australia. Group consensus methods and multicriteria decision analysis (MCDA) were used. A Composite GTI and Specific List comprise the overall GTI. The Composite GTI reflects toxicity likely to change during a clinical trial. The Composite GTI toxicities occur commonly, vary with GC exposure, and are weighted and scored. Relative weights for items in the Composite GTI were derived by group consensus and MCDA. The Specific List is designed to capture GC toxicity not included in the Composite GTI. The Composite GTI was evaluated by application to paper cases by the investigators and an external group of 17 subspecialists. RESULTS: Thirty-one toxicity items were included in the Composite GTI and 23 in the Specific List. Composite GTI evaluation showed high inter-rater agreement (investigators kappa 0.88, external raters kappa 0.90). To assess the degree to which the Composite GTI corresponds to expert clinical judgement, participants ranked 15 cases by clinical judgement in order of highest to lowest GC toxicity. Expert rankings were then compared with case ranking by the Composite GTI, yielding excellent agreement (investigators weighted kappa 0.87, external raters weighted kappa 0.77). CONCLUSIONS: We describe the development and initial evaluation of a comprehensive instrument for the assessment of GC toxicity. PMID- 27474766 TI - Kohler's disease: an unusual cause for a limping child. PMID- 27474767 TI - New Pakistani visa controls leave patients from Afghanistan without treatment. PMID- 27474768 TI - Commentary on: The Effects of Fat Harvesting and Preparation, Air Exposure, Obesity, and Stem Cell Enrichment on Adipocyte Viability Prior to Graft Transplantation. PMID- 27474769 TI - A Fractional Bipolar Radiofrequency Device Combined with a Bipolar Radiofrequency and Infrared Light Treatment for Improvement in Facial Wrinkles and Overall Skin Tone and Texture. AB - BACKGROUND: A variety of techniques and energy-based technologies are currently utilized for the treatment of facial wrinkles. Fractional bipolar radiofrequency treatment and treatment with bipolar radiofrequency combined with infrared light have both been reported to be safe and effective for the non-invasive treatment of wrinkles and overall facial rejuvenation. OBJECTIVES: A multicenter, prospective clinical trial evaluated a protocol of treatment with a device incorporating bipolar radiofrequency and infrared light followed by treatment with a fractional bipolar radiofrequency device for facial wrinkle reduction and improvement in the overall appearance of aged facial skin. METHODS: Fifty-six patients with mild to moderate facial wrinkles received three full-face treatments (forehead, nose, cheeks, periorbital, and perioral areas) at 4 to 6 week intervals and were evaluated at 12 and 24 weeks after the last treatment. Clinical photographs at baseline and follow-ups were assessed by both the investigators and patients using the Global Aesthetic Improvement scale. Treatment safety was evaluated. Study participants also completed a satisfaction and improvement questionnaire. RESULTS: Fitzpatrick Wrinkling and Elastosis Score was decreased significantly at three months (P < .01; paired t test) and at six months (P < .001; paired t test) after the final treatment. Investigators' assessments of overall improvement in facial appearance, demonstrated 88% improvement at 12 weeks and 82% at 24 weeks after the final treatment. Subject evaluations were similar, consistently reporting improvement in wrinkles and overall facial skin appearance throughout the study, and high a degree of satisfaction with their final results. Subjects tolerated the procedures well, with only transient mild to moderate erythema and edema occurring in most patients, and without complications. CONCLUSIONS: A combined protocol of bipolar radiofrequency and infrared light treatment followed by fractionated bipolar radiofrequency treatment results in safe, well tolerated, and effective improvement in overall skin tone and texture and reduction of facial wrinkles. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 27474770 TI - The Effects of Fat Harvesting and Preparation, Air Exposure, Obesity, and Stem Cell Enrichment on Adipocyte Viability Prior to Graft Transplantation. AB - BACKGROUND: Adipocyte viability is affected by fat preparation and processing methods, but rigorous and objective studies of these relationships are lacking. OBJECTIVES: The authors conducted a comprehensive evaluation of variables affecting adipocyte viability prior to injection of fat at the recipient site. METHODS: Lipoaspirates from 48 patients were processed by high or low vacuum pressure, decantation, electric or manual centrifugation, concentration with cotton gauze, washing, repeated syringe transfer, exposure to lidocaine, and exposure to air. The effects of these variables on adipocyte viability in vitro were ascertained with the MTT assay. The influences of patient obesity (ie, a body mass index [BMI] >30 kg/m2) and enrichment with stem cells on adipocyte viability also were determined. RESULTS: High vacuum pressure decreased adipocyte viability. Decantation yielded the highest cell viability, followed by washing, concentration with cotton gauze, and centrifugation. Exposure to concentrated lidocaine ambient air exposure, and transfer between syringes significantly decreased viability. Patient obesity was predictive of lower adipocyte viability regardless of processing method, whereas stem cell enrichment significantly improved viability (P < .0001). CONCLUSIONS: To maximize adipocyte viability, fat should be obtained with dilute local anesthetics and low vacuum pressure, and the lipoaspirate should be maintained in a closed system. To clear cellular debris and blood, the lipoaspirate should be prepared by washing, and the fat should be enriched with adipose stem cells. Decreased adipocyte viability should be expected when fat is harvested from patients with high BMIs. PMID- 27474772 TI - Erratum for Charoenbhakdi et al., Vacuolar H+-ATPase Protects Saccharomyces cerevisiae Cells against Ethanol-Induced Oxidative and Cell Wall Stresses. PMID- 27474775 TI - Rivaroxaban Therapy, False-Positive Lupus Anticoagulant Screening Results, and Confirmatory Assay Results. AB - OBJECTIVE: To examine the effects of patients taking the direct blood coagulation factor Xa inhibitor rivaroxaban on lupus anticoagulant testing results in a clinical setting. METHODS: We reviewed the results of lupus anticoagulant testing performed over a 2-year period. Of 59 patients who met criteria for a lupus anticoagulant, 18 were taking rivaroxaban. We reviewed and compared the parameters of lupus anticoagulant testing. RESULTS: The average dilute Russell viper venom time (DRVVT) and normal plasma-mix screening results to confirmation ratios in rivaroxaban-naive patients were 1.6 and 1.7, respectively. In the rivaroxaban group, the same parameters were 1.7 and 1.6, respectively (P = - 0.28 and 0.46, respectively). For 15 of 18 patients taking rivaroxaban, results were corrected on the confirmation steps of both tests. CONCLUSIONS: Rivaroxaban confounds lupus anticoagulant testing because the DRVVT is prolonged in these patients but it also corrects with excess phospholipid, mimicking a lupus anticoagulant. Patient medication review is critical to avoid false-positive findings and inappropriate diagnosis of antiphospholipid syndrome. PMID- 27474776 TI - Evaluation of 2 Batched Pretreatment Systems for the Measurement of Whole Blood Tacrolimus on the ARCHITECT Immunoassay Analyzer. AB - BACKGROUND: Measurement of tacrolimus using the ARCHITECT immunoassay analyzer requires a manual extraction step that puts clinical laboratory workers at risk for ergonomic injury. Therefore, we developed 2 batched extraction systems for tacrolimus measurement on the ARCHITECT analyzer and describe their features herein. METHODS: Two batched extraction methods were developed at 2 different laboratories. The batched extraction methods allow processing of at least 20 specimens at a time. We evaluated the analytical performance of those methods and compared them with the United States Food and Drug Administration (FDA)-cleared process for manually extracting individual specimens. RESULTS: Comparing the performance of batched- and individual-extraction methods revealed that both methods had comparable between-day imprecision, high patient-results correlation (R2 values >=0.9869), equivalent functional sensitivity (0.48 ng/mL), and good linearity between 1 ng per mL and 25 ng per mL. Further, we observed decreased delta check-identified errors using the batched method. CONCLUSION: The 2 developed batched extraction methods for tacrolimus measurement that we describe herein demonstrate excellent performance and can replace individual specimen extraction. PMID- 27474777 TI - Calcitonin and amylin receptor peptide interaction mechanisms. INSIGHTS INTO PEPTIDE-BINDING MODES AND ALLOSTERIC MODULATION OF THE CALCITONIN RECEPTOR BY RECEPTOR ACTIVITY-MODIFYING PROTEINS. PMID- 27474778 TI - Manipulation of interleukin-1beta and interleukin-18 production by Yersinia pestis effectors YopJ and YopM and redundant impact on virulence. PMID- 27474779 TI - Determination of free fatty acids in olive oils by UPHLC-MS. AB - A simple, fast, highly efficient and direct method using ultra-performance liquid chromatography coupled to mass spectrometry has been established for the simultaneous separation, identification and quantitation of a few saturated and unsaturated fatty acids in olive oils from various countries. No sample pretreatment techniques were employed such as extraction or derivatization for the analysis of target acids from oil samples, as the oil samples were just diluted, filtered and then directly injected to the instrument. The chromatographic separations of all target fatty acids were achieved on a Hypersil Gold C18 column of particle size 1.9MUm, 50*2.1mm I.D, while the gradient elution using a binary mobile phase mixture of acetonitrile and water at a flow rate of 1.5ml/min was adopted for achieving optimum separations. The identification and quantitation of target compounds was accomplished using selected ion reaction monitoring mode. The recoveries of the fatty acids were obtained higher than 89% with good validation parameters; linearity (r(2)>0.992), detection limit between 0.09 and 0.24MUg/ml, run to run and day to day precisions with percent relative standard deviation lower than 2.4% at both low (1MUg/ml) and medium (10MUg/ml) concentration levels. The total content of fatty acids in each individual oils was found in the range of 472.63-7751.20MUg/ml of olive oil, while oleic acid was found to be the major fatty acid among all analyzed oils with the amount 3785.94MUg/ml (maximum) in Syrian olive oil. The obtained validation parameters confirm that the proposed analytical method is rapid, sensitive, reproducible and simple and it could be applied for the successful evaluation of fatty acids in various oils and other matrices. All the fatty acids were efficiently eluted in a time of less than 8min with well resolved peaks by employing the proposed method. PMID- 27474780 TI - Analysis of nerve agent metabolites from nail clippings by liquid chromatography tandem mass spectrometry. AB - While several methods for the bioanalysis of nerve agents or their metabolites have been developed for the verification of nerve agent exposure, these methods are generally limited in the amount of time after an exposure that markers of exposure can be detected (due to rapid metabolism from biological matrices). In this study, a method for the analysis of nerve agent hydrolysis products from nail clippings was developed to allow evaluation of nails as a long-term repository of these markers. Pinacolyl methylphosphonic acid (PMPA) and isopropyl methylphosphonic acid (IMPA) were extracted from nail samples with N,N dimethylformamide and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Limits of detection for PMPA and IMPA were 0.3MUg/kg and 7.5MUg/kg and linear ranges were 0.75-300MUg/kg and 30-1500MUg/kg, respectively. Precision was within 10% and 8% for PMPA and IMPA, respectively, and accuracy was 100+/-12% for both analytes. The approach presented here is complementary to current methods for nerve agent exposure verification, and should allow for long-term determination of nerve agent poisoning. PMID- 27474781 TI - Appraisal of inflammation-based prognostic scores in patients with unresectable perihilar cholangiocarcinoma. AB - BACKGROUND: Inflammation-based prognostic scores are useful prognostic indicators for several types of cancer. The aim of this study was to evaluate whether the scores predict survival impact in unresectable perihilar cholangiocarcinoma. METHODS: The modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio, and Prognostic Nutritional Index, were retrospectively assessed in 219 patients with unresectable perihilar cholangiocarcinoma. RESULTS: Of the four scores evaluated, mGPS and NLR demonstrated prognostic value, whereas the remaining two systems did not. The median survival time (MST) of patients with a mGPS of 0 and NLR of 0 or 1 were significantly better than that of patients with a mGPS of 1 or 2 and NLR of 2 (12.3 vs. 4.8 months, P < 0.001, and 10.5 vs. 4.4 months, P = 0.001). Multivariate analysis revealed that both mGPS and NLR were independent prognostic factors. The combination of mGPS and NLR stratified survival well: the MST was 12.8 months in patients with a mGPS of 0 and NLR of 1 or 2, while only 3.0 months in patients with a mGPS of 1 or 2 and NLR of 2. CONCLUSIONS: Both mGPS and NLR are independent prognostic factors and pivotal in refining patient stratification in unresectable perihilar cholangiocarcinoma. PMID- 27474783 TI - Chiral HPLC Separation and Modeling of Four Stereomers of DL-Leucine-DL Tryptophan Dipeptide on Amylose Chiral Column. AB - Chiral high-performance liquid chromatography (HPLC) separation and modeling of four stereomers of DL-leucine-tryptophan DL-dipeptide on AmyCoat-RP column are described. The mobile phase applied was ammonium acetate (10 mM)-methanol acetonitrile (50:5:45, v/v). The flow rate of the mobile phases was 0.8 mL/min with UV detection at 230 nm. The values of retention factors for LL-, DD-, DL-, and LD- stereomers were 2.25, 3.60, 5.00, and 6.50, respectively. The values of separation and resolution factors were 1.60, 1.39, and 1.30 and 7.76, 8.05, and 7.19. The limits of detection and quantitation were ranging from 1.0-2.3 and 5.6 14.0 MUg/mL. The simulation studies established the elution orders and the mechanism of chiral recognition. It was seen that pi-pi connections and hydrogen bondings were the main forces for enantiomeric resolution. The reported chiral HPLC method may be applied for the enantiomeric separation of DL-leucine-DL tryptophan in unknown matrices. Chirality 28:642-648, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27474782 TI - A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug induced liver injury and postinjury inflammation in mice. AB - : Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP induced acute liver injury (APAP-ALI) and justifies development of anti inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N-acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP-ALI. The anti-HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti-HMGB1 polyclonal antibody treatment improves survival in a model of APAP-ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti-HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP-ALI. The mouse anti-HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody-Fc backbones. Effector function-deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP-ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP-induced serum elevations of alanine aminotransferase and microRNA-122 and completely abrogated markers of APAP induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C-X-C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. CONCLUSION: This is the first report describing the generation of a partly humanized HMGB1-neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1-specific therapy as a means to treat APAP-ALI and other inflammatory conditions. (Hepatology 2016;64:1699-1710). PMID- 27474784 TI - Structural and functional diversity among amyloid proteins: Agents of disease, building blocks of biology, and implications for molecular engineering. AB - Amyloids have long been associated with protein dysfunction and neurodegenerative diseases, but recent research has demonstrated that some organisms utilize the unique properties of the amyloid fold to create functional structures with important roles in biological processes. Additionally, new engineering approaches have taken advantage of amyloid structures for implementation in a wide variety of materials and devices. In this review, the role of amyloid in human disease is discussed and compared to the functional amyloids, which serve a largely structural purpose. We then consider the use of amyloid constructs in engineering applications, including their utility as building blocks for synthetic biology and molecular engineering. Biotechnol. Bioeng. 2017;114: 7-20. (c) 2016 Wiley Periodicals, Inc. PMID- 27474785 TI - The influence of light quality on the accumulation of flavonoids in tobacco (Nicotiana tabacum L.) leaves. AB - Flavonoids are important secondary metabolites in plants regulated by the environment. To analyze the effect of light quality on the accumulation of flavonoids, we performed a rapid analysis of flavonoids in extracts of tobacco leaves using UHPLC-QTOF. A total of 12 flavonoids were detected and identified in tobacco leaves, which were classified into flavonoid methyl derivatives and flavonoid glycoside derivatives according to the groups linked to the flavonoid core. Correlation analysis was further conducted to investigate the effect of different wavelengths of light on their accumulation. The content of flavonoid methyl derivatives was positively correlated with the proportions of far-red light (FR; 716-810nm) and near-infrared light (NIR; 810-2200nm) in the sunlight spectrum and negatively correlated with the proportion of ultraviolet (UV-A; 350 400nm) and the red/far-red ratio (R/FR). By contrast, the content of flavonoid glycoside derivatives was positively correlated with the proportion of UV-A and the R/FR, and negatively correlated with FR and NIR. The results indicated that light quality with higher proportions of FR and NIR increases the activity of flavonoid methyltransferases but suppresses the activity of flavonoid glycoside transferases. While a high proportion of UV-A and a high R/FR can increase flavonoid glycoside transferase activity but suppress flavonoid methyltransferase activity. PMID- 27474786 TI - RSM optimized Moringa oleifera peel extract for green synthesis of M. oleifera capped palladium nanoparticles with antibacterial and hemolytic property. AB - Palladium nanoparticles (Pd NPs) are the very good catalytic agents in many coupling reactions, also these are very well biological agents against bacteria and fungus. M. oleifera capped Pd NPs were synthesized from microwave assisted methanolic extract of M. oleifera peel. To optimize the extraction process RSM (Response Surface Methodology) was applied. To get a good extraction yield BBD (Box-Behnken Design) was employed. The better optimized conditions for the extraction was found as 400W, 25mL of CH3OH at 65 degrees C for 2min. We observed 61.66mg of extract yield from this method. Eco-friendly M. oleifera capped Pd NPs were synthesized using M. oleifera peel extract and confirmed using the different characterization techniques like UV- Vis spectroscopy, XRD, SEM and HR-TEM analysis. We found the size of the M. oleifera capped Pd NPs nanoparticles as 27+/-2nm and shape of the particles as spherical through the TEM analysis. M. oleifera capped Pd NPs exhibits good antibacterial activity against S. aureus (Staphylococcus aureus) and E. coli (Escherichia coli) bacterial strains and we found the zone inhibition as 0.6 and 0.7mm. The synthesized M. oleifera capped Pd NPs are screened for hemolytic activity and it proved the M. oleifera capped Pd NPs are non-toxic on RBCs cells. PMID- 27474787 TI - Assessment of the clinical cardiac drug-drug interaction associated with the combination of hepatitis C virus nucleotide inhibitors and amiodarone in guinea pigs and rhesus monkeys. AB - : In 2015, European and U.S. health agencies issued warning letters in response to 9 reported clinical cases of severe bradycardia/bradyarrhythmia in hepatitis C virus (HCV)-infected patients treated with sofosbuvir (SOF) in combination with other direct acting antivirals (DAAs) and the antiarrhythmic drug, amiodarone (AMIO). We utilized preclinical in vivo models to better understand this cardiac effect, the potential pharmacological mechanism(s), and to identify a clinically translatable model to assess the drug-drug interaction (DDI) cardiac risk of current and future HCV inhibitors. An anesthetized guinea pig model was used to elicit a SOF+AMIO-dependent bradycardia. Detailed cardiac electrophysiological studies in this species revealed SOF+AMIO-dependent selective nodal dysfunction, with initial, larger effects on the sinoatrial node. Further studies in conscious, rhesus monkeys revealed an emergent bradycardia and bradyarrhythmia in 3 of 4 monkeys administered SOF+AMIO, effects not observed with either agent alone. Morever, bradycardia and bradyarrhythmia were not observed in rhesus monkeys when intravenous infusion of MK-3682 was completed after AMIO pretreatment. CONCLUSIONS: These are the first preclinical in vivo experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential in vivo mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective in vivo cardiac electrophysiological effect, these data enable targeted cellular/molecular mechanistic studies to more precisely identify cell types, receptors, and/or ion channels responsible for the clinical DDI. (Hepatology 2016;64:1430-1441). PMID- 27474788 TI - Paleogenetic records of Daphnia pulicaria in two North American lakes reveal the impact of cultural eutrophication. AB - Understanding the evolutionary consequences of the green revolution, particularly in wild populations, is an important frontier in contemporary biology. Because human impacts have occurred at varying magnitudes or time periods depending on the study ecosystem, evolutionary histories may vary considerably among populations. Paleogenetics in conjunction with paleolimnology enable us to associate microevolutionary dynamics with detailed information on environmental change. We used this approach to reconstruct changes in the temporal population genetic structure of the keystone zooplankton grazer, Daphnia pulicaria, using dormant eggs extracted from sediments in two Minnesota lakes (South Center, Hill). The extent of agriculture and human population density in the catchment of these lakes has differed markedly since European settlement in the late 19th century and is reflected in their environmental histories reconstructed here. The reconstructed environments of these two lakes differed strongly in terms of environmental stability and their associated patterns of Daphnia population structure. We detected long periods of stability in population structure and environmental conditions in South Center Lake that were followed by a dramatic temporal shift in population genetic structure after the onset of European settlement and industrialized agriculture in its watershed. In particular, we noted a 24.3-fold increase in phosphorus (P) flux between pre-European and modern sediment P accumulation rates (AR) in this lake. In contrast, no such shifts were detected in Hill Lake, where the watershed was not as impacted by European settlement and rates of change were less directional with a much smaller increase in sediment P AR (2.3-fold). We identify direct and indirect effects of eutrophication proxies on genetic structure in these lake populations and demonstrate the power of using this approach in understanding the consequences of anthropogenic environmental change on natural populations throughout historic time periods. PMID- 27474789 TI - Development of novel fortified beef patties with added functional protein ingredients for the elderly. AB - The effects of clean label functional protein ingredients; pea protein isolate (PPI), rice protein (RP) and lentil flour (LF), at 3% and 7% inclusion levels on technological and shelf life parameters of beef patties were evaluated over 12days. Protein content in the RP7 treatment was higher (P<0.05) than controls, but did not differ significantly from PPI7 and RP3. No effects on moisture, fat or ash content were detected. LF addition reduced product hardness, cohesiveness, gumminess and chewiness compared with controls. RP-enriched and control patties were associated with lower lipid oxidation over storage than PPI- and LF-enriched patties. RP had a differential effect on (L*), (a*) and (b*) when compared with controls. Microbiological characteristics for all treatments were acceptable after 12days. Protein fortified beef patties with a softer texture and acceptable technological properties targeted for ease of consumption by older adults were produced in an attempt to reach dietary targeted protein requirements for this segment. PMID- 27474790 TI - Evolution of robot-assisted orthotopic ileal neobladder formation: a step-by-step update to the University of Southern California (USC) technique. AB - OBJECTIVE: To describe our, step-by-step, technique for robotic intracorporeal neobladder formation. PATIENTS AND METHODS: The main surgical steps to forming the intracorporeal orthotopic ileal neobladder are: isolation of 65 cm of small bowel; small bowel anastomosis; bowel detubularisation; suture of the posterior wall of the neobladder; neobladder-urethral anastomosis and cross folding of the pouch; and uretero-enteral anastomosis. Improvements have been made to these steps to enhance time efficiency without compromising neobladder configuration. RESULTS: Our technical improvements have resulted in an improvement in operative time from 450 to 360 min. CONCLUSION: We describe an updated step-by-step technique of robot-assisted intracorporeal orthotopic ileal neobladder formation. PMID- 27474791 TI - Does residual microscopic disease after chemoradiotherapy for locally advanced rectal cancer translate into a good clinical outcome? AB - AIM: This study aimed to assess the progression-free and overall survival of patients with residual microscopic disease following neoadjuvant chemoradiotherapy and rectal resection for locally advanced rectal cancer. METHOD: Two-hundred and thirty-four consecutive rectal cancer patients who had neoadjuvant chemoradiotherapy followed by radical resection (from May 2000 to April 2012) were divided according to pathological tumour response: residual microscopic disease (MIC), complete response (pCR) and partial/no response (non CR). Data on the neoadjuvant regime, treatment-to-surgery interval, final pathology, type of operation, operative time, postoperative complications, length of hospital stay, disease recurrence and mortality were compared between the groups. RESULTS: There were 13 (5.5%) MIC patients, 48 (20.5%) with pCR and 173 (73.9%) with non-CR group. The groups were demographically comparable. MIC patients had more retrieved lymph nodes compared with the non-CR and pCR patients (median 13 compared with 8 and 10, respectively, P = 0.0086). The 5-year overall survival rates were 93.4% for the pCR and MIC patients vs 82.1% for the non-CR patients (P = 0.0324). The 5-year progression-free survival was 85.2% for the pCR and MIC patients vs 73.8% for the non-CR patients (P = 0.086). CONCLUSION: We have identified and assessed a new pathological subgroup of rectal cancer patients who had residual microscopic disease after neoadjuvant therapy. The survival analysis aligned them closely with pCR patients. PMID- 27474792 TI - One session treatment for specific phobias in children: Comorbid anxiety disorders and treatment outcome. AB - BACKGROUND AND OBJECTIVES: One-Session Treatment (OST) for specific phobias has been shown to be effective in reducing phobia severity; however, the effect of different types of co-occurring anxiety disorders on OST outcomes is unknown. The present study examined (1) the effects of co-occurring generalized anxiety disorder (GAD), social anxiety disorder (SAD), or another non-targeted specific phobia (OSP) on the efficacy of OST for specific phobias, and (2) the effects of OST on these co-occurring disorders following treatment. METHODS: Three groups of 18 youth (7-15 years) with a specific phobia and comorbid GAD, SAD, or OSP were matched on age, gender, and phobia type. Outcome measures included diagnostic status and severity, and clinician rated improvement. RESULTS: All groups demonstrated an improvement in their specific phobia following treatment. Treatment was equally effective regardless of co-occurring anxiety disorder. In addition, comorbid anxiety disorders improved following OST; however, this effect was not equal across groups. The SAD group showed poorer improvement in their comorbid disorder than the GAD group post-treatment. However, the SAD group continued to improve and this differential effect was not evident six-months following treatment. LIMITATIONS: The current study sample was small, with insufficient power to detect small and medium effect sizes. Further, the sample only included a portion of individuals with primary GAD or SAD, which may have attenuated the findings. CONCLUSIONS: The current study demonstrated that co occurring anxiety disorders did not interfere with phobia treatment. OST, despite targeting a single specific phobia type, significantly reduced comorbid symptomatology across multiple anxiety disorders. PMID- 27474793 TI - Weak network efficiency in young children with Autism Spectrum Disorder: Evidence from a functional near-infrared spectroscopy study. AB - Functional near infrared spectroscopy (fNIRS) is particularly suited for the young population and ecological measurement. However, thus far, not enough effort has been given to the clinical diagnosis of young children with Autism Spectrum Disorder (ASD) by using fNIRS. The current study provided some insights into the quantitative analysis of functional networks in young children (ages 4.8-8.0years old) with and without ASD and, in particular, investigated the network efficiency and lobe-level connectivity of their functional networks while watching a cartoon. The main results included that: (i) Weak network efficiency was observed in young children with ASD, even for a wide range of threshold for the binarization of functional networks; (ii) A maximum classification accuracy rate of 83.3% was obtained for all participants by using the k-means clustering method with network efficiencies as the feature parameters; and (iii) Weak lobe-level inter-region connections were uncovered in the right prefrontal cortex, including its linkages with the left prefrontal cortex and the bilateral temporal cortex. Such results indicate that the right prefrontal cortex might make a major contribution to the psychopathology of young children with ASD at the functional network architecture level, and at the functional lobe-connectivity level, respectively. PMID- 27474795 TI - A rapid MCM-41 dispersive micro-solid phase extraction coupled with LC/MS/MS for quantification of ketoconazole and voriconazole in biological fluids. AB - A rapid dispersive micro-solid phase extraction (D-MU-SPE) combined with LC/MS/MS method was developed and validated for the determination of ketoconazole and voriconazole in human urine and plasma samples. Synthesized mesoporous silica MCM 41 was used as sorbent in d-MU-SPE of the azole compounds from biological fluids. Important D-MU-SPE parameters, namely type desorption solvent, extraction time, sample pH, salt addition, desorption time, amount of sorbent and sample volume were optimized. Liquid chromatographic separations were carried out on a Zorbax SB-C18 column (2.1 * 100 mm, 3.5 MUm), using a mobile phase of acetonitrile-0.05% formic acid in 5 mm ammonium acetate buffer (70:30, v/v). A triple quadrupole mass spectrometer with positive ionization mode was used for the determination of target analytes. Under the optimized conditions, the calibration curves showed good linearity in the range of 0.1-10,000 MUg/L with satisfactory limit of detection (<=0.06 MUg/L) and limit of quantitation (<=0.3 MUg/L). The proposed method also showed acceptable intra- and inter-day precisions for ketoconazole and voriconazole from urine and human plasma with RSD <=16.5% and good relative recoveries in the range 84.3-114.8%. The MCM-41-D-MU-SPE method proved to be rapid and simple and requires a small volume of organic solvent (200 MUL); thus it is advantageous for routine drug analysis. PMID- 27474794 TI - Transcranial direct current stimulation over the parietal cortex alters bias in item and source memory tasks. AB - Neuroimaging data have shown that activity in the lateral posterior parietal cortex (PPC) correlates with item recognition and source recollection, but there is considerable debate about its specific contributions. Performance on both item and source memory tasks were compared between participants who were given bilateral transcranial direct current stimulation (tDCS) over the parietal cortex to those given prefrontal or sham tDCS. The parietal tDCS group, but not the prefrontal group, showed decreased false recognition, and less bias in item and source discrimination tasks compared to sham stimulation. These results are consistent with a causal role of the PPC in item and source memory retrieval, likely based on attentional and decision-making biases. PMID- 27474796 TI - Eph and Ephrin function in dispersal and epithelial insertion of pigmented immunocytes in sea urchin embryos. AB - The mechanisms that underlie directional cell migration are incompletely understood. Eph receptors usually guide migrations of cells by exclusion from regions expressing Ephrin. In sea urchin embryos, pigmented immunocytes are specified in vegetal epithelium, transition to mesenchyme, migrate, and re-enter ectoderm, distributing in dorsal ectoderm and ciliary band, but not ventral ectoderm. Immunocytes express Sp-Eph and Sp-Efn is expressed throughout dorsal and ciliary band ectoderm. Interfering with expression or function of Sp-Eph results in rounded immunocytes entering ectoderm but not adopting a dendritic form. Expressing Sp-Efn throughout embryos permits immunocyte insertion in ventral ectoderm. In mosaic embryos, immunocytes insert preferentially in ectoderm expressing Sp-Efn. We conclude that Sp-Eph signaling is necessary and sufficient for epithelial insertion. As well, we propose that immunocytes disperse when Sp-Eph enhances adhesion, causing haptotactic movement to regions of higher ligand abundance. This is a distinctive example of Eph/Ephrin signaling acting positively to pattern migrating cells. PMID- 27474799 TI - TauG-guidance of dynamic balance control during gait initiation in patients with chronic fatigue syndrome and fibromyalgia. AB - BACKGROUND: Impaired postural control has been reported in static conditions in chronic fatigue syndrome and fibromyalgia, but postural control in dynamic tasks have not yet been investigated. Thus, we investigated measurements from a force plate to evaluate dynamic balance control during gait initiation in patients with chronic fatigue syndrome and fibromyalgia compared to matched healthy controls. METHODS: Thirty female participants (10 per group) performed five trials of gait initiation. Center of pressure (CoP) trajectory of the initial weight shift onto the supporting foot in the mediolateral direction (CoPX) was analyzed using General Tau Theory. We investigated the hypothesis that tau of the CoPX motion gap (tauCoPx) is coupled onto an intrinsic tauG-guide (tauG) by keeping the relation tauCoPx=KtauG, where K is a scaling factor that determines the relevant kinematics of a movement. FINDINGS: Mean K values were 0.57, 0.55, and 0.50 in fibromyalgia, chronic fatigue syndrome, and healthy controls, respectively. Both patient groups showed K values significantly higher than 0.50 (P<0.05), indicating that patients showed poorer dynamic balance control, CoPX colliding with the boundaries of the base of support (K>0.5). INTERPRETATION: The findings revealed a lower level of dynamic postural control in both fibromyalgia and chronic fatigue syndrome compared to controls. PMID- 27474797 TI - Spatial control of translation repression and polarized growth by conserved NDR kinase Orb6 and RNA-binding protein Sts5. AB - RNA-binding proteins contribute to the formation of ribonucleoprotein (RNP) granules by phase transition, but regulatory mechanisms are not fully understood. Conserved fission yeast NDR (Nuclear Dbf2-Related) kinase Orb6 governs cell morphogenesis in part by spatially controlling Cdc42 GTPase. Here we describe a novel, independent function for Orb6 kinase in negatively regulating the recruitment of RNA-binding protein Sts5 into RNPs to promote polarized cell growth. We find that Orb6 kinase inhibits Sts5 recruitment into granules, its association with processing (P) bodies, and degradation of Sts5-bound mRNAs by promoting Sts5 interaction with 14-3-3 protein Rad24. Many Sts5-bound mRNAs encode essential factors for polarized cell growth, and Orb6 kinase spatially and temporally controls the extent of Sts5 granule formation. Disruption of this control system affects cell morphology and alters the pattern of polarized cell growth, revealing a role for Orb6 kinase in the spatial control of translational repression that enables normal cell morphogenesis. PMID- 27474800 TI - Predictors of crystal methamphetamine use in a community-based sample of UK men who have sex with men. PMID- 27474798 TI - mRNA poly(A)-tail changes specified by deadenylation broadly reshape translation in Drosophila oocytes and early embryos. AB - Because maturing oocytes and early embryos lack appreciable transcription, posttranscriptional regulatory processes control their development. To better understand this control, we profiled translational efficiencies and poly(A)-tail lengths throughout Drosophila oocyte maturation and early embryonic development. The correspondence between translational-efficiency changes and tail-length changes indicated that tail-length changes broadly regulate translation until gastrulation, when this coupling disappears. During egg activation, relative changes in poly(A)-tail length, and thus translational efficiency, were largely retained in the absence of cytoplasmic polyadenylation, which indicated that selective poly(A)-tail shortening primarily specifies these changes. Many translational changes depended on PAN GU and Smaug, and these changes were largely attributable to tail-length changes. Our results also revealed the presence of tail-length-independent mechanisms that maintained translation despite tail-length shortening during oocyte maturation, and prevented essentially all translation of bicoid and several other mRNAs before egg activation. In addition to these fundamental insights, our results provide valuable resources for future studies. PMID- 27474801 TI - Reproductive aspects of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an auto-immune systemic disease showing a strong predilection for women of reproductive age. Higher prevalance of SLE among young women are in part accounted for by the effects of estrogen hormone on immune system. The key pathophysiological features of this disease are the generation of autoantibodies and the deposition of antibody-antigen complexes in the basal membranes of the organs where they evoke inflammatory responses and injury. Young females diagnosed with SLE are more prone to developing a multitude of adverse reproductive and obstetric outcomes, especially in the presence of active disease. Our motivation in writing this review article is to outline the recent interesting findings of molecular and clinical studies showing multi faceted roles of estrogen hormone in both normal immune function and auto immunity and to provide an update on the ovarian function and other poor reproductive outcomes in young females with SLE. PMID- 27474802 TI - Assessment of clinical improvement in patients undergoing endovascular coiling in traumatic carotid cavernous fistulas. AB - OBJECTIVES: We attempt to find key points in endovascular coiling which can help us predict degree of clinical recovery, in an attempt to make the treatment of CCF safe and effective. PATIENTS AND METHODS: We analyzed a series of 15 patients with traumatic CCFs undergoing coiling by performing clinical, angiographical and radiological assessment before and at regular time periods after the procedure till 6 months. The findings were analyzed to find critical points predicting clinical outcome in each of the patients. RESULTS: 80% patients had complete occlusion of fistula (n=12) with a 100% ICA patency rate. Angiographic occlusion of fistula, visualization of ophthalmic artery and disappearance of bruit predicted a good clinical outcome. Cranial nerve palsies and fixed neurological deficits do not always reverse suggesting an alternate etiopathology. CONCLUSION: The degree of occlusion had direct correlation with improvement in clinical symptoms, which was remarkable when the extent of occlusion was more than 90%. To our knowledge this is one of the largest series in published literature on clinical outcomes of patients with traumatic CCFs using detachable coils as the embolizing agent and can serve as standard for comparison for future treatment alternatives. PMID- 27474803 TI - In silico binding analysis and SAR elucidations of newly designed benzopyrazine analogs as potent inhibitors of thymidine phosphorylase. AB - Thymidine phosphorylase (TP) is up regulated in wide variety of solid tumors and therefore presents a remarkable target for drug discovery in cancer. A novel class of extremely potent TPase inhibitors based on benzopyrazine (1-28) has been developed and evaluated against thymidine phosphorylase enzyme. Out of these twenty-eight analogs eleven (11) compounds 1, 4, 14, 15, 16, 17, 18, 19, 20, 24 and 28 showed potent thymidine phosphorylase inhibitory potentials with IC50 values ranged between 3.20+/-0.30 and 37.60+/-1.15MUM when compared with the standard 7-Deazaxanthine (IC50=38.68+/-4.42MUM). Structure-activity relationship was established and molecular docking studies were performed to determine the binding interactions of these newly synthesized compounds. Current studies have revealed that these compounds established stronger hydrogen bonding networks with active site residues as compare to the standard compound 7DX. PMID- 27474804 TI - Synthesis of novel bisindolylmethanes: New carbonic anhydrase II inhibitors, docking, and 3D pharmacophore studies. AB - In this study, 45 bisindolylmethanes having sulfonamide moiety had been synthesized through 3 steps. In vitro assay for inhibition of carbonic anhydrase showed that some of the compounds having sulfonamide moiety are capable of inhibiting carbonic anhydrase II. Bisindoles having halogens at fifth position showed better inhibitory activity as compared to unsubstituted bisindoles. The results obtained from in vitro inhibitory activity were subjected through 3D QSAR and docking studies to identify important features contributing to the activity and further improve the structure. Pharmacophore studies suggest that bisindolylmethane moiety is contributing significantly towards the inhibition activity. Docking studies showed that compounds having nitro substituent (5g and 5i) were found to be able interact with Zn(2+) ion, Thr199, His94, His96, and His119, which interferes with the ZnOHThr199Glu106 hydrogen bond network. Bulky nitro substituent at ortho position for compound 5g prevents the compound from interacting with other residues like Thr199 and Thr200. Methyl substituent at ortho position for Compound 5i induces less steric hindrance effect, thus allowing second oxygen atom of sulfonamide to interact with Thr199 (2.51A). Hydrogen bonding between NH on indole ring with Glu69 might have increased stability of ligand-receptor complex. PMID- 27474805 TI - Modeling human disease using organotypic cultures. AB - Reliable disease models are needed in order to improve quality of healthcare. This includes gaining better understanding of disease mechanisms, developing new therapeutic interventions and personalizing treatment. Up-to-date, the majority of our knowledge about disease states comes from in vivo animal models and in vitro cell culture systems. However, it has been exceedingly difficult to model disease at the tissue level. Since recently, the gap between cell line studies and in vivo modeling has been narrowing thanks to progress in biomaterials and stem cell research. Development of reliable 3D culture systems has enabled a rapid expansion of sophisticated in vitro models. Here we focus on some of the latest advances and future perspectives in 3D organoids for human disease modeling. PMID- 27474806 TI - Live imaging of stem cells: answering old questions and raising new ones. AB - Stem cells are essential for both tissue maintenance and injury repair, but many aspects of stem cell biology remain incompletely understood. Recent advances in live imaging technology have allowed the direct visualization and tracking of a wide variety of tissue-resident stem cells in their native environments over time. Results from these studies have helped to resolve long-standing debates about stem cell regulation and function while also revealing previously unanticipated phenomena that raise new questions for future work. Here we review recent discoveries of both types, with a particular emphasis on how stem cells behave and interact with their niches during homeostasis, as well as how these behaviours change in response to wounding. PMID- 27474807 TI - Tracing cellular dynamics in tissue development, maintenance and disease. AB - The coordination of cell proliferation and differentiation is central to the development and maintenance of tissues, while its dysregulation underlies the transition to diseased states. By combining lineage tracing with transcriptional profiling and marker-based assays, statistical methods are delivering insights into the dynamics of stem cells and their developmental precursors. These studies have provided evidence for molecular heterogeneity and fate priming, and have revealed a role for stochasticity in stem cell fate, refocusing the search for regulatory mechanisms. At the same time, they present a quantitative platform to study the initiation and progression of disease. Here, we review how quantitative lineage tracing strategies are shaping our understanding of the cellular mechanisms of tissue development, maintenance and disease. PMID- 27474809 TI - Self-expanding metal stent should be considered in patients with cirrhosis and uncontrolled variceal bleeding. PMID- 27474808 TI - Peripheral blood blast clearance is an independent prognostic factor for survival and response to acute myeloid leukemia induction chemotherapy. AB - In patients with acute myeloid leukemia (AML), rapid reduction of circulating blasts with induction chemotherapy may serve as an in vivo marker of chemosensitivity. We performed a retrospective analysis of 363 patients with untreated AML who received induction chemotherapy in order to determine the relationship between day of blast disappearance (DOBD) and complete remission (CR) rates, event-free survival (EFS), and overall survival (OS). DOBD <= 5 vs. >5 was identified as the most discriminating cutoff for OS. DOBD > 5 was observed in 35 patients (9.6%). The CR rate for patients with DOBD <= 5 vs. >5 was 74.0 and 28.6%, median EFS was 9.4 and 1.8 months, and median OS was 17.1 and 5.8 months, respectively (P < 0.001 for all). DOBD > 5 was independently associated with a lower CR rate and shorter EFS and OS (P < 0.001 for all). DOBD > 5 retained prognostic significance for EFS and OS when patients were stratified by cytogenetic risk group, de novo vs. secondary or therapy-related AML, European LeukemiaNet-based risk groups, and whether CR was achieved. We propose DOBD > 5 as a simple and early marker of disease resistance that identifies patients with poor prognosis who otherwise may not be identified with existing risk stratification systems. Am. J. Hematol. 91:1221-1226, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27474810 TI - A multichannel time-frequency and multi-wavelet toolbox for uterine electromyography processing and visualisation. AB - The uterine electromyogram, also called electrohysterogram (EHG), is an electrical signal generated by the uterine contractile activity. The EHG has been considered a promising biomarker for labour and preterm labour prediction, for which there is a demand for accurate estimation methods. Preterm labour is a significant public health concern and one of the major causes of neonatal mortality and morbidity [1]. Given the non-stationary properties of the EHG signal, time-frequency domain analysis can be used. For real life signals it is not generally possible to determine a priori the suitable quadratic time frequency kernel or the appropriate wavelet family and relative parameters, regarding, for instance, the adequate detection of the signal frequency variation in time. There has been a lack of a comprehensive software tool for the selection of the appropriate time frequency representation of a multichannel EHG signal and extraction of relevant spectral and temporal information. The presented toolbox (Uterine Explorer) has been specifically designed for the EHG analysis and exploration in view of the characterisation of its components. The starting point is the multichannel scalogram or spectrogram representation from which frequency and time marginals, instantaneous frequency and bandwidth are obtained as EHG features. From this point the detected components undergo parametric and non parametric spectral estimation and wavelet packet analysis. Intrauterine pressure estimation (IUP) is obtained using the Teager, RMS, wavelet marginal and Hilbert operators over the EHG. This toolbox has been tested to build up a dictionary of 288 EHG components [2], useful for research in preterm labour prediction. PMID- 27474811 TI - Effects of the herbicide surfactant MON 0818 on oviposition and viability of eggs of the ramshorn snail (Planorbella pilsbryi). AB - The surfactant mixture MON 0818 is an adjuvant in various commercial formulations of the herbicide glyphosate. Initial studies have shown that MON 0818 is more toxic to aquatic animals than the active ingredient. However, few studies have examined the effect of exposure to MON 0818 on species of mollusks, and no studies have examined the effect on gastropods. The present study investigated the effect of acute exposure (96 h) of MON 0818 to the eggs, juveniles, and adults of the file ramshorn snail (Planorbella pilsbryi). Concentrations of MON 0818 up to 9.9 mg/L did not have a significant effect on the viability of eggs (p > 0.05). Juvenile snails (50% lethal concentration [LC50] = 4.0 mg/L) were more sensitive than adult snails (LC50 = 4.9-9.1 mg/L). Oviposition was inhibited by exposure to MON 0818 (median effective concentration [EC50] = 0.4-2.0 mg/L). However, oviposition resumed when snails were removed to clean water, even after 96-h exposure to up to 4.9 mg/L of MON 0818. Exposure to a concentration >=2.7 mg/L caused visible damage to the tentacles of adult snails, which could potentially impact chemoreception. A deterministic hazard assessment indicated that environmentally relevant concentrations of MON 0818 could pose a hazard to the deposition of eggs. However, because of the relatively short half-life of MON 0818 in aquatic systems and the ability of snails to resume oviposition following the dissipation of MON 0818, environmentally relevant concentrations of MON 0818 likely pose a de minimis risk to populations of ramshorn snails. Environ Toxicol Chem 2017;36:522-531. (c) 2016 SETAC. PMID- 27474813 TI - Composite films of poly(allylamine)-capped polydopamine nanoparticles and P8W48 polyoxometalates with electroactive properties. AB - Polyoxometalates (POMs) are often used to functionalize surfaces with photochromic or electroactive compounds. Among the common deposition methods, besides the Langmuir-Blodgett deposition, the layer-by-layer (LBL) deposition method has become more and more popular due to its facility and versatility combined with the polyanionic character of POMs. The LBL deposition of POMs and oppositely charged nanoparticles is however poorly described in the literature. Using polydopamine nanoparticles (PDA) produced in the presence of poly(allylamine) and displaying a hydrodynamic diameter of 25nm, we show that LBL films containing the large, cyclic P8W48 polyanion and the PDA@PAH nanoparticles display reduction currents which are proportional to the number of deposition steps and hence to the film thickness. In addition the obtained films display not only the electrochemical properties of the POM but also that of PDA nanoparticles. Hence we demonstrate the feasibility to build up films based on particles only with the electrochemical behavior of each kind of particles being conserved. PMID- 27474812 TI - Characterization of a Clostridium beijerinckii spo0A mutant and its application for butyl butyrate production. AB - Spo0A is a master regulator that governs the metabolic shift of solventogenic Clostridium species such as Clostridium beijerinckii. Its disruption can thus potentially cause a significant alteration of cellular physiology as well as metabolic patterns. To investigate the specific effect of spo0A disruption in C. beijerinckii, a spo0A mutant of C. beijerinckii was characterized in this study. In a batch fermentation with pH control at 6.5, the spo0A mutant accumulated butyrate and butanol up to 8.96 g/L and 3.32 g/L, respectively from 60 g/L glucose. Noticing the unique phenotype of the spo0A mutant accumulating both butyrate and butanol at significant concentrations, we decided to use the spo0A mutant for the production of butyl butyrate that can be formed by the condensation of butyrate and butanol during the ABE fermentation in the presence of the enzyme lipase. Butyl butyrate is a value-added chemical that has numerous uses in the food and fragrance industry. Moreover, butyl butyrate as a biofuel is compatible with Jet A-1 aviation kerosene and used for biodiesel enrichment. In an initial trial of small-scale extractive batch fermentation using hexadecane as the extractant with supplementation of lipase CalB, the spo0A mutant was subjected to acid crash due to the butyrate accumulation, and thus produced only 98 mg/L butyl butyrate. To alleviate the butyrate toxicity, the biphasic medium was supplemented with 10 g/L CaCO3 and 5 g/L butanol. The butyl butyrate production was then increased up to 2.73 g/L in the hexadecane layer. When continuous agitation was performed to enhance the esterification and extraction of butyl butyrate, 3.32 g/L butyl butyrate was obtained in the hexadecane layer. In this study, we successfully demonstrated the use of the C. beijerinckii spo0A mutant for the butyl butyrate production through the simultaneous ABE fermentation, condensation, and extraction. Biotechnol. Bioeng. 2017;114: 106 112. (c) 2016 Wiley Periodicals, Inc. PMID- 27474814 TI - Tactile perception of skin and skin cream by friction induced vibrations. AB - Skin cream smooths, softens, and moistens skin by altering surface roughness and tribological properties of skin. Sliding generates vibrations that activate mechanoreceptors located in skin. The brain interprets tactile information to identify skin feel. Understanding the tactile sensing mechanisms of skin with and without cream treatment is important to numerous applications including cosmetics, textiles, and robotics sensors. In this study, frequency spectra of friction force and friction induced vibration signals were carried out to investigate tactile perception by an artificial finger sliding on skin. The influence of normal load, velocity, and cream treatment time were studied. Coherence between friction force and vibration signals were found. The amplitude of vibration decreased after cream treatment, leading to smoother perception. Increasing normal load or velocity between contacting surfaces generated a smoother perception with cream treatment, but rougher perception without treatment. As cream treatment time increases, skin becomes smoother. The related mechanisms are discussed. PMID- 27474815 TI - Enhanced photocatalytic activity of Ce-doped Zn-Al multi-metal oxide composites derived from layered double hydroxide precursors. AB - In this work, a series of novel Zn-Al-Ce multi-metal oxide (Zn-Al-Ce-MMO) photocatalysts with different Ce doping contents were prepared by calcination of Ce-doped Zn-Al layered double hydroxide (Zn-Al-Ce-LDH) precursors at various temperatures in air atmosphere. The synthesized Zn-Al-Ce-MMO materials were characterized by XRD, FTIR, TGA, BET, SEM, TEM, XPS and UV-vis DRS. The photocatalytic activities of the Zn-Al-Ce-MMO materials were evaluated by the photodegradation of rhodamine B (RhB) dye and paracetamol in aqueous solution under simulated solar light irradiation. The result of photodegradation of RhB showed that the Zn-Al-Ce-MMO samples exhibit much higher photocatalytic activity than that of Zn-Al-MMO, and the optimal Ce doping content is 5% of mole ratio (nCe/n(Zn+Al+Ce)). The enhanced photocatalytic activity of the Zn-Al-Ce-MMO was mainly attributed to the increasing in the separation efficiency of electrons and holes. The effect of calcination temperature was also studied. The photocatalytic activity of Zn-Al-Ce-MMO increased with increasing calcination temperature up to 750 degrees C, which can be ascribed to the formation of well-crystallized metal oxides during calcination. Under experimental conditions, 97.8% degradation efficiency of RhB and 98.9% degradation efficiency of paracetamol were achieved after 240min. Active species trapping and EPR experiments suggested that hole (h(+)), superoxide radical (O2(-)) and hydroxyl radical (OH) played important roles during the RhB photocatalytic process. Moreover, the results indicated that the synthesized Zn-Al-Ce-MMO materials had good stability and reusability. PMID- 27474816 TI - Effect of polyelectrolyte morphology and adsorption on the mechanism of nanocellulose flocculation. AB - The effect of polyelectrolyte morphology, charge density, molecular weight and concentration on the adsorption and flocculation of Microfibrillated Cellulose (MFC) were investigated. Linear Cationic Polyacrylamide (CPAM) and Branched Polyethylenimine (PEI) of varying charge density and molecular weight were added at different dosages to MFC suspensions. The flocculation mechanisms were quantified by measuring gel point by sedimentation, and floc size, strength and reflocculation ability through Focussed Beam Reflectance Measurements. Polymer adsorption was quantified through zeta potential and adsorption measurements using polyelectrolyte titration. The flocculation mechanism of MFC is shown to be dependent on polyelectrolyte morphology. The high molecular weight branched polymer, HPEI formed rigid bridges between the MFC fibres. HPEI had low coverage and negative zeta potential at the optimum flocculation dosage, forming flocs of high strength. After breaking of flocs, total reflocculation was achieved because the high rigidity of polymer did not allow reconformation or flattening of the polyelectrolyte adsorbed on MFC surface. The lower molecular weight branched polymer, LPEI (2kDa) showed rapid total deflocculation, complete reflocculation and had maximum flocculation occurring at the point of zero charge. These characteristics correspond to a charge neutralisation mechanism. However, if the flocculation mechanism was purely charge neutralisation mechanism, the minimum gel point would be at the point of zero charge. Since this is not the case, this difference was attributed to the high polydispersity of the commercial LPEI used, allowing some bridges to be formed by the largest molecules, changing the minimum gel point. With the linear 80% charged 4MDa CPAM, bridging mechanism dominates since maximum flocculation occurred at the minimum gel point, negative zeta potential and low coverage required for maximum flocculation. Reflocculation was not possible as the long linear polymer reconformed on the MFC surface under a flat conformation. Flocculation with the linear 50% charged 13MDa CPAM happened by bridging with the minimum gel point and maximum flocculation corresponding to roughly half polyelectrolyte surface coverage on cellulose. PMID- 27474817 TI - Mechanism of highly efficient adsorption of 2-chlorophenol onto ultrasonic graphene materials: Comparison and equilibrium. AB - The deficiencies of the recently reported improved Hummers method for the synthesis of graphene oxide (GO), such as high reaction temperature (60 degrees C) and long reaction time (10h), were successfully solved using a low-intensity ultrasonic bath for 30min at 40 degrees C. Furthermore, compared to its conventional synthesis counterpart, a facile and fast, one-step ultrasonic method that excluded hydrazine hydrate was developed to synthesize reduced GO (rGO) from graphite (10min, 50 degrees C) in the presence of hydrazine hydrate (rGO-C, 12h, 90 degrees C). The adsorption characteristics of 2-chlorophenol (2-CP) from an aqueous solution were investigated using rGOs and GOs prepared by ultrasonic (rGO Us/GO-Us) and conventional (rGO-C/GO-C) methods. Whereas 2-CP was completely removed with rGO-Us after 50min, only 40% of 2-CP was eliminated with rGO-C. The maximum adsorption capacity of 2-CP calculated by the Langmuir model onto rGO-Us (208.67mg/g) was much higher than that onto GO-Us (134.49mg/g). In addition, the ultrasonic graphene adsorption capacities were much higher than the corresponding values of rGO-C (49.9mg/g) and GO-C (32.06mg/g). The enhanced adsorption for rGO Us and GO-Us is attributed to their greater surface areas, excellent oxygenated groups for GO-Us and superior pi-electron-rich matrix for rGO-Us, compared to other adsorbents. The adsorption of 2-CP on the rGO materials increased with increasing solution pH to a maximum around its pKa (pKa=8.85), while the adsorption for the GO materials increased with decreasing solution pH. The adsorption mechanism proceeded via hydrogen bonding in neutral and acidic media, but via pi-pi electron donor-accepter (EDA) interactions between 2-CP and graphene materials in basic medium. The FTIR spectrum of GO-Us after adsorption indicates that the position and intensity of many peaks of GO-Us were affected due to the adsorption of different 2-CP groups at different pHs. PMID- 27474818 TI - Beyond the bull's eye: Recognizing Lyme disease. AB - A rash occurs in 80% of Lyme disease cases, but only about a third of the rashes develop into a classic bull's-eye lesion. Here's what to look for and how best to treat. PMID- 27474819 TI - E-cigarettes: How "safe" are they? AB - Without tobacco, tar, ash, or carbon monoxide, e-cigarettes are marketed as "healthier" alternatives to cigarettes. But they are not without risk. PMID- 27474820 TI - E-cigarettes: Who's using them and why? AB - Background: Electronic cigarettes (e-cigarettes) are often marketed as safe and effective aids for quitting cigarette smoking, but concerns remain that use of e cigarettes might actually reduce the number of quit attempts. To address these issues, we characterized the utilization and demographic correlates of dual use of e-cigarettes and traditional cigarettes (referred to here as simply "cigarettes") among smokers in a rural population of Illinois. Methods: The majority of survey participants were recruited from the 2014 Illinois State Fair and from another event-the Springfield Mile (a motorcycle racing event)-in Springfield, Ill. Survey questions explored participant demographics and cigarette and e-cigarette use history. Results: Of 201 total cigarette smokers, 79 smoked only tobacco cigarettes (smokers), while 122 also used e-cigarettes (dual users). Dual users did not differ significantly from smokers in gender, age, income, or education. Compared to smokers, dual users were more likely to smoke within 30 minutes of awakening (odds ratio [OR]=3.3; 95% confidence interval [CI], 1.8-6.3), but did not smoke more cigarettes per day or perceive a greater likelihood of quit success. Non-white dual users smoked fewer cigarettes per day than smokers . In addition, 79.5% of all dual users reported that they were using e-cigarettes to quit smoking or reduce the number of cigarettes smoked, and white respondents were 6 times more likely than non-whites to use e cigarettes for 'trying to quit smoking' (OR=6.0; 95% CI, 1.1-32.9). Males and respondents with lower income were less likely to say they were using e cigarettes to reduce the number of cigarettes smoked than females or participants with higher income (OR=0.2; 95% CI, 0.1-0.8 and OR=0.1; 95% CI, 0.0-0.5, respectively). Conclusions: E-cigarettes may significantly alter the landscape of nicotine physical dependence, and local influences likely are associated with use patterns. Future research should continue to examine whether dual use of traditional and electronic cigarettes impacts smoking cessation, and clinicians should be aware that local norms may create differences from national level data. PMID- 27474821 TI - Sore throat . vaginal discharge . labial ulcer . Dx? AB - The patient complained of worsening vaginal pain and increased vaginal discharge, but reported resolution of her back and chest pain. She also said that a week earlier, she'd had a fever that reached 104 degrees F and a sore throat. She denied urinary frequency/urgency, sexual activity, or sexual abuse. PMID- 27474822 TI - PURLs: More isn't better with acute low back pain treatment. AB - Adding cyclobenzaprine or oxycodone/acetaminophen to naproxen for the treatment of acute low back pain does nothing more than increase adverse effects. PMID- 27474823 TI - Large plaques on a baby boy. AB - This newborn's prenatal lab work and delivery were normal. So, too, were his Apgar scores and neurologic exam. So why was he covered in brown and black plaques? PMID- 27474824 TI - Help Desk Answers: Do novel oral anticoagulants safely prevent stroke in patients with nonvalvular A-fib? AB - Yes. Dabigatran, rivaroxaban, and apixaban are safe and effective compared with warfarin for preventing stroke in patients with nonvalvular atrial fibrillation. These novel oral anticoagulants (NOACs) are noninferior in reducing the number of strokes and systemic emboli and in lowering all-cause mortality while not increasing major bleeding complications and hemorrhagic events. PMID- 27474825 TI - Help Desk Answers: What's the most effective topical Tx for scalp psoriasis? AB - Single-agent therapy with a very potent or potent topical corticosteroid appears more effective than other topical agents, including vitamin D3 analogues, for treating scalp psoriasis. PMID- 27474826 TI - What do we really know about e-cigarettes? AB - Are e-cigarettes a "gateway" to the use of tobacco and other substances of abuse? Or do they represent an effective way to quit smoking? PMID- 27474827 TI - Darkened skin, vomiting, and salt cravings in a teenager . Dx? AB - Acute adrenal insufficiency crisis usually occurs after a prolonged period of nonspecific complaints due to a loss of both glucocorticoids and mineralocorticoids; by the time overt symptoms occur, 90% of the adrenal gland may be destroyed. Patients (such as ours) may present with symptoms such as abdominal pain, weakness, vomiting, fever, and decreased responsiveness. PMID- 27474828 TI - Uric Acid Amplifies Abeta Amyloid Effects Involved in the Cognitive Dysfunction/Dementia: Evidences From an Experimental Model In Vitro. AB - There is still a considerable debate concerning whether uric acid is neuroprotective or neurotoxic agent. To clarify this topic, we tested the effects of uric acid on neuronal cells biology by using differentiated SHSY5Y neuroblastoma cells incubated with amyloid beta to reproduce an in vitro model of Alzheimer's disease. The incubation of cells with uric acid at the dose of 40 uM or higher significantly reduced cell viability and potentiated the proapoptotic effect of amyloid beta. Finally, uric acid enhanced the generation of 4 hydroxynonenal and the expression of PPARbeta/delta promoted by amyloid beta, indicating a prooxidant effects. In conclusion, uric acid could exert a detrimental influence on neuronal biology being this influence further potentiated by the concomitant exposure to neurotoxic stimuli. This effect is evident for uric acid concentrations close to those achievable in cerebrospinal fluid in presence of mild hyperuricemia thus suggesting a potential role of uric acid in pathophysiology of cognitive dysfunction. These effects are influenced by the concentrations of uric acid and by the presence of favoring conditions that commonly occur in neurodegenerative disorders and well as in the aging brain, including increased oxidative stress and exposure to amyloid beta. J. Cell. Physiol. 232: 1069-1078, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27474829 TI - Combination of diagnostic laparoscopy and intraoperative indocyanine green fluorescence angiography for the early detection of intestinal ischemia not detectable at CT scan. AB - INTRODUCTION: Acute mesenteric ischemia is the most severe gastrointestinal complication of acute aortic dissection. The timing of diagnosis is of major importance, in fact the recognition of acute mesenteric ischemia often occurs too late due to the presence of unspecific symptoms and lack of reliable exams. Recently, indocyanine green fluorescence angiography has been adopted in order to measure blood perfusion and microcirculation. PRESENTATION OF CASE: We decided to perform a diagnostic laparoscopy with the support of intra-operative near infrared indocyanine green fluorescence angiography, in order to detect an initial intestinal ischemia in a 68-year-old patient previously treated with a TEVAR procedure for a type-B aortic dissection. The fluorescence system demonstrated an hypoperfused area in the ascending colon, therefore an ileocholic resection was thus performed. Opening the operatory specimen, the mucosa of the colon appeared totally ischemic, whilst the serosa was normal. DISCUSSION: When ischemia occurs, the oxygen supply is interrupted, hence the necrosis of the enteral mucosa occurs within 3h, whilst the necrosis of the full thickness of the bowel wall occurs within 6h. A diagnosis during these "golden hours" is of major importance for a successful treatment. CONCLUSION: The combination of laparoscopy and UV light and fluorescein dye should be considered as an invaluable diagnostic procedure for the diagnosis of early stage acute bowel ischemia which is not visible at instrumental examinations nor with diagnostic laparoscopy. PMID- 27474830 TI - Post-coital vaginal cuff dehiscence with small bowel evisceration after laparoscopic type II radical hysterectomy: A case report. AB - INTRODUCTION: Vaginal cuff dehiscence after hysterectomy can be life-threating condition. Vaginal evisceration of bowel may lead to intestinal ischemia and intraabdominal infection. Immediate recognition and surgical repair are crucial for succesful management. CASE REPORT: Herein, we report a case of vaginal cuff dehiscence with small bowel evisceration in a 32-year old woman who underwent laparoscopic type II hysterectomy for stage IA2 cervical cancer. CONCLUSION: Patients who have undergone hysterectomy should be advised about when to restart coitus. Vaginal repair of vaginal cuff dehiscence is recommended if intestinal ischemia is excluded. PMID- 27474831 TI - Myositis ossificans: A rare location in the foot. Report of a case and review of literature. AB - BACKGROUND: Myositis ossificans is a benign, tumor-like lesion characterized by heterotopic ossification of soft tissue that usually affects the elbow and thigh. At different stages of maturity, it show similar histologic appearances with sarcomatous lesions or maturing bone. Misdiagnosis can result in unnecessary radical treatment. CASE REPORT: A 50-year-old woman with dorsal forefoot soft tissue mass was diagnosed as myositis ossificans after surgical excision and confirmed by a histopathological examination. DISCUSSION: To our knowledge, myositis ossificans occurrence in the foot is rare and only a few cases have been reported in the literature. SUMMARY: Increasing awareness on the unusual sites for myositis ossificans occurrence is necessary for differentiating this lesion from a malignant soft- tissue tumors and avoiding diagnostic pitfalls and unnecessary investigations, which can have major consequences and complications for patients. PMID- 27474832 TI - Effects of maternal stress during pregnancy on learning and memory via hippocampal BDNF, Arc (Arg3.1) expression in offspring. AB - The intrauterine environment has a significant long-term impact on individual's life, this study was designed to investigate the effect of stress during pregnancy on offspring's learning and memory abilities and analyze its mechanisms from the expression of BDNF and Arc in the hippocampus of the offspring. A rat model of maternal chronic stress during pregnancy was mating from 3rd day during been subjecting to chronic unpredictable mild stress (CUMS). The body weights and behavioral changes were recorded, and plasma corticosterone levels were determined by radioimmunoassay. The learning and memory abilities of the offspring were measured by Morris water maze testing from PND 42. The expression of hippocampal BDNF and Arc mRNA and protein were respectively measured using RT PCR and Western blotting. Results indicated that an elevation was observed in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy, a reduction in the crossing and rearing movement times and the preference for sucrose. The body weight of maternal stress's offspring was lower than the control group, and the plasma corticosterone level was increased. Chronic stress during pregnancy had a significant impact on the spatial learning and memory of the offspring. The expression of BDNF mRNA and protein, Arc protein in offspring of maternal stress during pregnancy was attenuated and some relationships existed between these parameters. Collectively, these findings disclose that long-time maternal stress during pregnancy could destroy spatial learning and memory abilities of the offspring, the mechanism of which is related to been improving maternal plasma corticosterone and reduced hippocampal BDNF, Arc of offspring rats. PMID- 27474833 TI - Multiple sources driving the organic matter dynamics in two contrasting tropical mangroves. AB - In this study, we have selected two different mangroves based on their geological, hydrological and climatological variations to investigate the origin (terrestrial, phytobenthos derived, and phytoplankton derived) of dissolved organic carbon (DOC), particulate organic carbon (POC) in the water column and the sedimentary OC using elemental ratios and stable isotopes. Qeshm Island, representing the Iranian mangroves received no attention before this study in terms of DOC, POC biogeochemistry and their sources unlike the Sundarbans (Indian side), the world's largest mangrove system. Slightly higher DOC concentrations in the Iranian mangroves were recorded in our field campaigns between 2011 and 2014, compared to the Sundarbans (315+/-25MUM vs. 278+/-42MUM), owing to the longer water residence times, while 9-10 times greater POC concentration (303+/-37MUM, n=82) was linked to both suspended load (345+/-104mgL(-1)) and high algal production. Yearlong phytoplankton bloom in the mangrove-lined Persian Gulf was reported to be the perennial source of both POC and DOC contributing 80-86% to the DOC and 90-98% to the POC pool. Whereas in the Sundarbans, riverine input contributed 50-58% to the DOC pool and POC composition was regulated by the seasonal litter fall, river discharge and phytoplankton production. Algal derived organic matter (microphytobenthos) represented the maximum contribution (70-76%) to the sedimentary OC at Qeshm Island, while mangrove leaf litters dominated the OC pool in the Indian Sundarbans. Finally, hydrographical settings (i.e. riverine transport) appeared to be the determinant factor in differentiating OM sources in the water column between the dry and wet mangroves. PMID- 27474834 TI - Impact of harbour emissions on ambient PM10 and PM2.5 in Barcelona (Spain): Evidences of secondary aerosol formation within the urban area. AB - With the objective of estimating the impact of harbour activities on ambient PM10 and PM2.5 levels at the urban area of Barcelona, a one year long monitoring campaign was carried out in the context of the European APICE project (MED-FEDER EC). This campaign was simultaneously conducted at the port and a central urban background site. A detailed PM10 and PM2.5 chemical speciation analysis was carried out with samples from both sites. Subsequently, a source apportionment analysis by means of the PMF receptor model was performed. Six common factors were identified, explaining local to regional emission sources (fuel oil combustion, industrial emissions, mineral-road dust resuspension, and road traffic emissions) and aerosol formation/transformation processes (secondary aerosols including ammonium sulphate and organic aerosols, and a mixed source accounting for aged sea spray and secondary nitrate). Around 50-55% PM10 and PM2.5 measured at the port was attributed to harbour activities: mineral matter from road dust and construction works of a new port area, vehicle traffic and fuel oil combustion. The estimated contribution of harbour emissions to the urban background reached 9-12% for PM10 and 11-15% for PM2.5 and is linked to primary emissions from fuel oil combustion but also to the formation of secondary aerosols. It becomes relevant to highlight the significantly higher contribution of secondary aerosols at the urban background when compared with the harbour site. Our hypothesis points to the fast formation of secondary ammonium sulphate within the city, after the reaction of SO2/H2SO4 transported by sea breezes with NH3, which is emitted in large amounts in Barcelona; and also to the enhanced formation of secondary organic aerosols within the city. This study broadens our knowledge on atmospheric phenomenology in urban Mediterranean cities and claims for effective abatement strategies focused on maritime practises, in agreement with the driving axis of the APICE project. PMID- 27474835 TI - Exploring the potential for using 210Pbex measurements within a re-sampling approach to document recent changes in soil redistribution rates within a small catchment in southern Italy. AB - In recent years, the fallout radionuclides caesium-137 (137Cs) and unsupported lead-210 (210Pbex) have been successfully used to document rates of soil erosion in many areas of the world, as an alternative to conventional measurements. By virtue of their different half-lives, these two radionuclides are capable of providing information related to different time windows. 137Cs measurements are commonly used to generate information on mean annual erosion rates over the past ca. 50-60 years, whereas 210Pbex measurements are able to provide information relating to a longer period of up to ca. 100 years. However, the time-integrated nature of the estimates of soil redistribution provided by 137Cs and 210Pbex measurements can be seen as a limitation, particularly when viewed in the context of global change and interest in the response of soil redistribution rates to contemporary climate change and land use change. Re-sampling techniques used with these two fallout radionuclides potentially provide a basis for providing information on recent changes in soil redistribution rates. By virtue of the effectively continuous fallout input, of 210Pb, the response of the 210Pbex inventory of a soil profile to changing soil redistribution rates and thus its potential for use with the re-sampling approach differs from that of 137Cs. Its greater sensitivity to recent changes in soil redistribution rates suggests that 210Pbex may have advantages over 137Cs for use in the re-sampling approach. The potential for using 210Pbex measurements in re-sampling studies is explored further in this contribution. Attention focuses on a small (1.38 ha) forested catchment in southern Italy. The catchment was originally sampled for 210Pbex measurements in 2001 and equivalent samples were collected from points very close to the original sampling points again in 2013. This made it possible to compare the estimates of mean annual erosion related to two different time windows. This comparison suggests that mean annual rates of net soil loss had increased during the period between the two sampling campaigns and that this increase was associated with a shift to an increased sediment delivery ratio. This change was consistent with independent information on likely changes in the sediment response of the study catchment provided by the available records of annual sediment yield and changes in the annual rainfall documented for the local area. PMID- 27474836 TI - Hyperemesis gravidarum is associated with increased maternal serum ischemia modified albumin. AB - AIM: Our objective was to measure the circulating levels of ischemia-modified albumin (IMA) among pregnant with hyperemesis gravidarum (HEG) and to compare their levels with age- and body mass index (BMI)-matched control pregnant women. METHOD: The pregnant subjects were classified into the HEG group diagnosed with HEG (n=45) and age- and BMI-matched control group without a diagnosis of HEG (n=45) during their pregnancies. Serum IMA, hemoglobin, hematocrit, white blood cells, platelet, fasting blood glucose, creatinine, lipid profile, aspartate aminotransferase (AST) urea, alanine aminotransferase (ALT), sodium, potassium and thyroid-stimulating hormone (TSH) levels of the groups were measured. RESULT: Serum hemoglobin, hematocrit, white blood cells, platelet, fasting blood glucose, creatinine, lipid profile, AST, urea, ALT, sodium, potassium and TSH levels of the groups were statistically similar. Serum IMA values were significantly higher in subjects with HEG compared to the subjects without HEG. CONCLUSIONS: We found that HEG was related to increased maternal serum IMA levels. HEG might be due to an ischemic intrauterine environment leading to elevated serum IMA concentrations. PMID- 27474837 TI - Longitudinal changes of cardiotocographic parameters throughout pregnancy: a prospective cohort study comparing small-for-gestational-age and normal fetuses from 24 to 40 weeks. AB - OBJECTIVE: To compare longitudinal trends of cardiotocographic (CTG) parameters between small-for-gestational-age (SGA) and normal fetuses, from 24 to 41 weeks of pregnancy. METHODS: A prospective cohort study was carried out in singleton pregnancies without fetal malformations. At least one CTG was performed in each of the following intervals: 24-26 weeks+6 days, 27-29 weeks+6 days, 30-32 weeks+6 days, 33-35 weeks+6 days, 36-38 weeks+6 days and >=39 weeks. Tracings were analyzed using the Omniview-SisPorto(r) 3.6 system. Cases with a normal pregnancy outcome, including a birthweight >=10th percentile for gestational age, were compared with two groups of SGA fetuses: with birthweight <10th percentile (SGA= 3 (P < 0.001), smoking (P = 0.001), diabetes (P = 0.035), a preoperative serum albumin level of < 4 g/dl (P = 0.030), elective rectal cancer surgery (P = 0.024), emergency colectomy for bleeding (P = 0.013) and splenic flexure mobilization (P = 0.043) were associated with an increased risk of AL. Preoperative oral antibiotics (P < 0.001), right hemicolectomy (open or laparoscopic) and laparoscopic partial colectomy were associated with a reduced risk of AL compared with the entire group. Body mass index, preoperative chemotherapy, emergency surgery and mechanical bowel preparation were not related to AL. CONCLUSION: In contrast to most studies, younger age was found to be an independent risk factor for AL. The risk for AL was lower with laparoscopic partial colectomy and open or laparoscopic right hemicolectomy. Preoperative oral antibiotic preparation significantly reduces the risk of AL and should be incorporated as a standard protocol. PMID- 27474845 TI - Stop-related subthalamic beta activity indexes global motor suppression in Parkinson's disease. AB - BACKGROUND: Rapid action stopping leads to global motor suppression. This is shown by studies using transcranial magnetic stimulation to measure corticospinal excitability of task-unrelated effectors (e.g., from the hand during speech stopping). We hypothesize that this global suppression relates to the STN of the basal ganglia. Several STN local field potential studies in PD patients have shown increased beta-band power during successful stopping. OBJECTIVES: Here, we aimed to test whether this STN beta-band activity indexes global motor suppression measured by transcranial magnetic stimulation. METHODS: We studied 9 medicated PD patients (age, 47-67 years; mean, 55.8; 3 female) who were implanted with STN-DBS electrodes. Participants performed a vocal stop-signal task (i.e., they had to occasionally stop a vocal response) while we simultaneously recorded local field potentials from right STN and delivered transcranial magnetic stimulation to primary motor cortex to measure corticospinal excitability from a task-unrelated hand muscle (first dorsal interosseous). RESULTS: Replicating previous results, STN beta-band power was increased (P < 0.005) and corticospinal excitability was reduced (P = 0.024; global motor suppression) during successful stopping. As hypothesized, global motor suppression was greater for successful stop trials with higher STN beta-power (median split: P = 0.043), which was further evident in a negative correlation between single-trial STN beta-power and corticospinal excitability (mean, r = -0.176; P = 0.011). CONCLUSION: These findings link stopping-related global motor suppression to STN beta-band activity through simultaneous recordings of STN and corticospinal excitability. The results support models of basal ganglia function that propose the STN has broad motor suppressive effects. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27474846 TI - Sequenced application of ascorbate-proline-glutathione improves salt tolerance in maize seedlings. AB - The role of antioxidants exogenously-applied individually or in sequences in the improvement of salt tolerance in maize seedlings, and their effects on changes in the activities of endogenous enzymatic and non-enzymatic antioxidants, and the concentrations of phytohormones in seedlings grown under 100mM NaCl stress were assessed. The efficiency of maize seedlings to tolerate salt stress in terms of growth was noticed to varying degrees with antioxidants applied singly or in sequences. The healthy growth of salt-stressed seedlings was correlated with the improvements in the activities of enzymatic and non-enzymatic antioxidants, the concentrations of osmoprotectants and phytohormones, and tissue health in terms of relative water content and membrane stability index. Results show that, seed soaking in AsA, GSH and proline applied in sequences (i.e., AsA0.50-Pro0.50 GSH0.50 or GSH0.50-Pro0.50-AsA0.50) was better than their applications individually. In addition, the sequenced application of AsA0.50-Pro0.50-GSH0.50 as integrated treatment was better, generating maize seedlings more tolerant to salinity than those generated from the sequenced application of GSH0.50-Pro0.50 AsA0.50. Therefore, we recommend using the sequenced application of AsA0.50 Pro0.50-GSH0.50 as integrated soaking treatment for maize to grow under salt stress. PMID- 27474847 TI - Body mass index and brain white matter structure in young adults at risk for psychosis - The Oulu Brain and Mind Study. AB - Antipsychotic medications and psychotic illness related factors may affect both weight and brain structure in people with psychosis. Genetically high-risk individuals offer an opportunity to study the relationship between body mass index (BMI) and brain structure free from these potential confounds. We examined the effect of BMI on white matter (WM) microstructure in subjects with familial risk for psychosis (FR). We used diffusion tensor imaging and tract-based spatial statistics to explore the effect of BMI on whole brain FA in 42 (13 males) participants with FR and 46 (16 males) control participants aged 20-25 years drawn from general population-based Northern Finland Birth Cohort 1986. We also measured axial, radial and mean diffusivities. Most of the participants were normal weight rather than obese. In the FR group, decrease in fractional anisotropy and increase in radial diffusivity were associated with an increase in BMI in several brain areas. In controls the opposite pattern was seen in participants with higher BMI. There was a statistically significant interaction between group and BMI on FA and radial and mean diffusivities. Our results suggest that the effect of BMI on WM differs between individuals with FR for psychosis and controls. PMID- 27474848 TI - Comprehensive review on phytotechnology: Heavy metals removal by diverse aquatic plants species from wastewater. AB - Environmental pollution specifically water pollution is alarming both in the developed and developing countries. Heavy metal contamination of water resources is a critical issue which adversely affects humans, plants and animals. Phytoremediation is a cost-effective remediation technology which able to treat heavy metal polluted sites. This environmental friendly method has been successfully implemented in constructed wetland (CWs) which is able to restore the aquatic biosystem naturally. Nowadays, many aquatic plant species are being investigated to determine their potential and effectiveness for phytoremediation application, especially high growth rate plants i.e. macrophytes. Based on the findings, phytofiltration (rhizofiltration) is the sole method which defined as heavy metals removal from water by aquatic plants. Due to specific morphology and higher growth rate, free-floating plants were more efficient to uptake heavy metals in comparison with submerged and emergent plants. In this review, the potential of wide range of aquatic plant species with main focus on four well known species (hyper-accumulators): Pistia stratiotes, Eicchornia spp., Lemna spp. and Salvinia spp. was investigated. Moreover, we discussed about the history, methods and future prospects in phytoremediation of heavy metals by aquatic plants comprehensively. PMID- 27474849 TI - Evaluation of gemfibrozil effects on a marine fish (Sparus aurata) combining gene expression with conventional endocrine and biochemical endpoints. AB - The information on the potential hazardous effects of gemfibrozil (GEM) on marine fish is extremely scarce. In the current study, molecular, endocrine and biochemical parameters were assessed in Sparus aurata after 96h waterborne exposure to a GEM concentration range. Hepatic mRNA levels of target genes known to be regulated via peroxisome proliferator-activated receptor alpha (pparalpha) in mammals, such as apolipoprotein AI (apoa1) and lipoprotein (lpl) were significantly increased, without a concomitant activation of the ppar pathways. GEM (15MUgL(-1)) induced an upregulation in mRNA levels of interleukin 1beta (il1beta), tumour necrosis factor-alpha (tnfalpha) and caspase 3 (casp3), suggesting an activation of proinflammatory processes in S. aurata liver. However, mRNA levels of genes related with the antioxidant defence system and cell-tissue repair were unaltered under the tested experimental conditions. Higher levels of GEM induced a cortisol rise, an indication that it is recognized as a stressor by S. aurata. Cortisol levels and the mRNA levels of il1beta, tnfalpha and casp3 may be suggested as potential biomarkers of GEM effects in marine fish. PMID- 27474850 TI - Effects of Ag nanomaterials (NM300K) and Ag salt (AgNO3) can be discriminated in a full life cycle long term test with Enchytraeus crypticus. AB - Information on effects of silver nanoparticles on soil invertebrates, especially using long-term exposures, is scarce. In this study we investigated the effects of the reference Ag (NM300K) (compared to AgNO3) using the full life cycle test (FLCt) of the soil invertebrate Enchytraeus crypticus. Results showed that effects were higher compared to the standard reproduction test, which is shorter and does not cover the FLC. Both Ag forms caused a reduction on hatching success, juvenile and adult survival and reproduction with similar ECx. Differences between AgNO3 and Ag NM300K could be discriminated using the FLCt: AgNO3 decreased hatching success was shown to be a delay in the process, whereas Ag NM300K caused irreversible effects during the same time frame. These effects may have occurred during the embryo development, hatching (inhibition) or survival of hatched juveniles. Ag NM300K caused non-monotonic concentration-response effect as observed by the high effect of the lowest concentration (20mgkg-1). It is known that dispersion is higher at lower concentrations - this could explain the increased effect at low concentration. Non monotonic responses are well described in the literature, where effects of high cannot predict for low concentrations, hence special attention should be given for NMs low concentration effects. PMID- 27474851 TI - Identification of the arsenic resistance on MoO3 doped CeO2/TiO2 catalyst for selective catalytic reduction of NOx with ammonia. AB - Arsenic resistance on MoO3 doped CeO2/TiO2 catalysts for selective catalytic reduction of NOx with NH3 (NH3-SCR) is investigated. It is found that the activity loss of CeO2-MoO3/TiO2 caused by As oxide is obvious less than that of CeO2/TiO2 catalysts. The fresh and poisoned catalysts are compared and analyzed using XRD, Raman, XPS, H2-TPR and in situ DRIFTS. The results manifest that the introduction of arsenic oxide to CeO2/TiO2 catalyst not only weakens BET surface area, surface acid sites and adsorbed NOx species, but also destroy the redox circle of Ce(4+) to Ce(3+) because of interaction between Ce and As. When MoO3 is added into CeO2/TiO2 system, the main SCR reaction path are found to be changed from the reaction between coordinated NH3 and ad-NOx species to that between an amide and gaseous NO. Additionally, for CeO2-MoO3/TiO2 catalyst, As toxic effect on active sites CeO2 can be released because of stronger As-Mo interaction. Moreover, not only are the reactable Bronsted and Lewis acid sites partly restored, but the cycle of Ce(4+) to Ce(3+) can also be free to some extent. PMID- 27474852 TI - Consumption of alcoholic beverages in adolescence and adulthood and risk of testicular germ cell tumor. AB - The etiology of testicular germ cell tumor (TGCT) remains obscure and accumulating evidence suggests that postnatal environmental or lifestyle factors may play a role. To investigate whether consumption of alcoholic beverages during adolescence or adulthood is associated with TGCT risk, we analyzed data from a USA population-based case-control study of 540 18-44 year-old TGCT cases and 1,280 age-matched controls. Participants were queried separately about consumption of beer, wine and liquor during grades 7-8, grades 9-12 and the 5 years before reference date (date of diagnosis for cases and corresponding date for controls). We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of TGCT risk with alcoholic beverage consumption during the different periods, both total and by specific beverage types and separately for seminomas and nonseminomas. Compared with nondrinkers in the 5 years before reference date, the OR (95% CI) for 1-6, 7-13 and >=14 drinks per week were 1.20 (0.85, 1.69), 1.23 (0.81, 1.85) and 1.56 (1.03, 2.37), respectively (p-trend = 0.04). The corresponding results for alcohol consumption in grades 9-12 were 1.39 (1.06, 1.82), 1.07 (0.72, 1.60), 1.53 (1.01, 2.31) (p-trend = 0.05). Alcohol consumption in grades 7-8 was uncommon and no statistically significant associations with TGCT were observed. Associations with alcohol consumption in the 5 years before reference date appeared stronger for nonseminomas than for seminomas, but the differences were not statistically significant (p>=0.10). Associations were similar across different alcoholic beverage types. Consumption of alcoholic beverages may be associated with an increased TGCT risk. PMID- 27474853 TI - Visual dorsal stream is associated with Chinese reading skills: A resting-state fMRI study. AB - The present study explored the relationship between visual dorsal stream and Chinese reading by resting-state fMRI technique. We collected the resting-state brain activities and reading skills of Chinese-speaking adult readers. The results showed that the values of amplitude of low frequency fluctuation (ALFF) in right posterior parietal cortex (PPC) and left visual middle temporal area (MT) (two regions of dorsal stream) were significantly correlated with rapid naming (RAN) speed, and the ALFF values of right PPC were correlated with orthographic awareness (OA). Further resting-state functional connectivity (RSFC) analysis revealed that RAN speed was related to RSFCs between dorsal stream areas and reading areas (e.g., left fusiform gyrus, bilateral middle occipital gyrus). OA was correlated with RSFCs between right PPC and left middle occipital gyrus. It suggested that spontaneous activities of visual dorsal stream, as well as connection between it and reading-related areas, were highly associated with Chinese reading skills. PMID- 27474854 TI - Enrichment and acclimation of an anaerobic mesophilic microorganism's inoculum for standardization of BMP assays. AB - Appropriate enrichment of anaerobic microorganism's consortium is crucial for accurate biochemical methane potential (BMP) assays. An alternative method to produce and maintain a mesophilic methanogenic inoculum was demonstrated. Three sources of inoculum were mixed and acclimated for 857days in order to reach steady conditions (pH=7.90+/-0.46; VS/TS>50%; VFA/alkalinity=0.16+/-0.04gAcetic Acid/ [Formula: see text] ). Biogas yield >80% was obtained after 70days of inoculum acclimation in comparison to standard cellulose (>600mLN/gVS). Methanogen community analysis based on 16S rDNA of the inoculum revealed Archaea concentration of 3*10(12) gene copies/g (Methanobacteriales 8*10(10); Methanomicrobiales 8*10(10); and Methanosarcinales 4*10(11) gene copies/g). The proposed method for development and maintenance of microorganism enrichment inoculum demonstrates consistent BMP data which is a requirement for dependable prediction of biogas production at field scale operations. PMID- 27474855 TI - Effect of biochar addition on hydrogen and methane production in two-phase anaerobic digestion of aqueous carbohydrates food waste. AB - Effect of biochar addition on hydrogen and methane production in two-phase anaerobic digestion of aqueous carbohydrates was studied using bench-scale bioreactors. The cultures with biochar additions were placed in 100ml reactors and incubated at 35 degrees C and pH 5 for hydrogen production. The residual cultures were then used for methane production, incubated at 35 degrees C and pH 7. Daily yields of hydrogen and methane and weekly yield of volatile fatty acids (VFA) were measured. The hydrogen and methane production potentials, rate and lag phases of the two phases were analysed using the Gompertz model. The results showed that biochar addition increased the maximum production rates of hydrogen by 32.5% and methane 41.6%, improved hydrogen yield by 31.0% and methane 10.0%, and shortened the lag phases in the two phases by 36.0% and 41.0%, respectively. Biochar addition also enhanced VFA generation during hydrogen production and VFA degradation in methane production. PMID- 27474856 TI - Gestational length affects neurocognition in early-onset schizophrenia. AB - Obstetric complications (OC) have been linked to an increased risk for schizophrenia in offspring, especially in early-onset schizophrenia (EOS). Extensive cognitive deficits occur in EOS, although no study has yet to investigate the relationship between OC and cognition in EOS. This study aims to examine the frequency of OC in EOS compared to controls, and also investigates the relationship between OC and neurocognitive dysfunction in the two groups. Nineteen EOS patients and 53 healthy controls were tested with the MATRICS Consensus Cognitive Battery (MCCB), and the cognitive measures were combined with OC data from the Norwegian Birth Registry. The results indicated no group differences in OC in EOS and healthy controls, but a shorter gestational length in the EOS group led to significant decreases in the overall neurocognitive composite score, and in processing speed. This suggests that the poorer neuropsychological performances commonly found in EOS may be partly attributable to the length of gestation. The worsened neurocognitive functioning did not appear among controls, so gestational length had a different impact on the two groups. Our findings indicated that a shorter gestational length did not increase the risk for developing EOS, but did significantly affect the cognitive difficulties in this group. PMID- 27474857 TI - The effect and mechanisms of implementation intention in improving prospective memory performance in schizophrenia patients. AB - People with schizophrenia (SCZ) have been shown to have prospective memory (PM) deficits. PM refers to the ability to remember to perform delayed intentions in the future and plays an important role in everyday independent functioning in SCZ. To date, few studies have investigated methods to improve PM in SCZ. This study aimed to examine whether implementation intention can improve PM performance and to explore its underlying mechanisms. Fifty people with SCZ and 50 demographically matched healthy controls (HC) participated in this study. Participants were randomly assigned to an implementation intention condition or a control instruction condition. Participants were required to make PM responses when PM cue words appeared while they were undertaking an ongoing task with two levels of cognitive load (1-back or 2-back). Results showed that people with SCZ were impaired in PM, and implementation intention improved PM performances for both SCZ and HC. Implementation intention improved PM performance in SCZ in both the low and the high cognitive load conditions without ongoing task cost, suggesting that implementation intention improved PM remembering in an automatic way. These results indicate that implementation intention may be a beneficial technique for improving PM performances in people with SCZ. PMID- 27474858 TI - Osteogenic response of human MSCs and osteoblasts to hydrophilic and hydrophobic nanostructured titanium implant surfaces. AB - Microstructured implant surfaces created by grit blasting and acid etching titanium (Ti) support osseointegration. This effect is further enhanced by storing in aqueous solution to retain hydrophilicity, but this also leads to surface nanostructure formation. The purpose of this study was to assess the contributions of nanostructures on the improved osteogenic response of osteoblast lineage cells to hydrophilic microstructured Ti. Human mesenchymal stem cells (MSCs) and normal human osteoblasts (NHOsts) were cultured separately on non nanostructured/hydrophobic (SLA), nanostructured/hydrophilic (modSLA), or nanostructured/hydrophobic (SLAnano) Ti surfaces. XPS showed elevated carbon levels on SLA and SLAnano compared to modSLA. Contact angle measurements indicated only modSLA was hydrophilic. Confocal laser microscopy revealed minor differences in mean surface roughness. SEM showed the presence of nanostructures on modSLA and SLAnano. MSCs and NHOst cells exhibited similar morphology on the substrates and osteoblastic differentiation and maturation were greatest on modSLA. These results suggest that when the appropriate microstructure is present, hydrophilicity may play a greater role in stimulating MSC and NHOst osteoblastic differentiation and maturation than the presence of nanostructures generated during storage in an aqueous environment. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3137-3148, 2016. PMID- 27474859 TI - The genetic architecture of body mass index from infancy to adulthood modified by parental education. AB - OBJECTIVE: A higher prevalence of obesity in lower socioeconomic classes is common in Western societies. This study examined the role of gene-environment interactions in the association between parental education and body mass index (BMI) from infancy to the onset of adulthood. METHODS: Parentally reported BMI from 1 to 13 and self-reported BMI from 14 to 20 years of age were collected in 16,646 complete Dutch twin pairs and analyzed by genetic twin modeling. RESULTS: At 7 to 8 years of age, children whose parents had middle or low educational levels had more excess weight than the children of more highly educated parents, and the difference increased until 18 to 20 years of age. The major part of the BMI variation was explained by additive genetic factors (a(2) = 0.55-0.85), but environmental factors common for co-twins also played a significant role, especially from 3 to 7-8 years of age (c(2) = 0.15-0.29). The genetic variation in BMI was higher in children whose parents had middle or low educational levels compared with children whose parents had a high educational level. CONCLUSIONS: The interaction between genetic factors and the childhood social environment may contribute to the formation of socioeconomic differences in obesity. PMID- 27474860 TI - Application of ecosystem services in natural resource management decision making. AB - An ecosystem services (ES) approach to natural resource management (NRM) can provide the framework for balancing economic, ecological, and societal drivers in decision making. The efficacy of such an approach depends on the successful execution of several key activities, from early and continuous engagement with relevant stakeholders, to development and application of ecological production functions (EPFs), to explicit recognition of uncertainty in the process. Although there are obstacles to the implementation of an ES approach in NRM, including unclear regulatory and policy frameworks and the paucity of useful EPFs, many of the tools are currently available or sufficiently developed. An ES approach can and, in some cases, should involve qualitative rather than quantitative assessment when the stakes are not very high or when quantitative approaches would not be cost effective because of highly uncertain results. Integr Environ Assess Manag 2017;13:74-84. (c) 2016 SETAC. PMID- 27474861 TI - GNPAT polymorphism rs11558492 is not associated with increased severity in a large cohort of HFE p.Cys282Tyr homozygous patients. PMID- 27474862 TI - Exposure to PBB-153 and Digit Ratio. AB - The ratio between the second and fourth digits is a sexually dimorphic measure, established in utero and linked to prenatal sex steroid levels. An association was found between prenatal levels of Polybrominated Biphenyls, a synthetic chemical suspected to disrupt the endocrine system function, and the digit ratio in adult women. PMID- 27474863 TI - Percutaneous transhepatic cholangioscopy for biliary complications after liver transplantation: a single center experience. AB - BACKGROUND: Some biliary complications after liver transplantation (LT) are difficult to manage by endoscopic or radiologic intervention alone. In these cases, percutaneous transhepatic cholangioscopy (PTCS) can be used as an adjuvant option. METHODS: Patients who underwent PTCS for post-LT biliary complications between August 1992 and January 2016 were retrospectively reviewed. RESULTS: Fifteen patients underwent PTCS for post-LT biliary complications. The median age at LT was 47 years and 11 patients were male. Indications for LT were as follows: decompensated liver cirrhosis (n = 9), hepatocellular carcinoma (n = 5), and acute fulminant liver failure (n = 1). Single living donor was common (n = 11) and duct-to-duct anastomosis was performed in 11 patients. The median age at PTCS was 52 years and indications for PTCS were as follows: intrahepatic duct stone (n = 10), common bile duct stone (n = 1), biliary cast (n = 1), and biliary stricture (n = 3). There were no significant PTCS-related morbidity and mortality. However, four patients (26.7%) needed additional radiologic intervention (n = 2) or surgery (n = 2) after PTCS. CONCLUSIONS: Percutaneous transhepatic cholangioscopy in conjunction with endoscopic and radiologic interventions can aid in managing post-LT biliary complications and avoiding reoperation. PMID- 27474864 TI - Long-term outcomes in patients with gallstones detected by mass screening. AB - BACKGROUND: Gallstones are detected in about 5% of healthy Japanese. We followed up individuals showing gallstones upon screening, investigating features of those requiring surgery. METHODS: In 2002 we performed health evaluations for 21,550 persons (13,986 men and 7,564 women), detecting gallstones ultrasonographically in 837 or 3.9% (561 men, or 4.0%; 276 women, or 3.6%). Up until 2012, we followed up 720 of the 837 persons with gallstones (86.0%) and compared individuals requiring or not requiring cholecystectomy as to age, gender, body mass index, diabetes, liver function, lifestyle, abdominal symptoms, and ultrasonographic findings. We also compared laboratory data obtained before and after surgery. The study was reviewed and approved by our institutional review board, and registered on UMIN-CTR (ID: UMIN000021995). RESULTS: Among 720 persons with gallstones, 55 (7.6%) were treated by surgery. Men tended to undergo surgery more frequently than women (P = 0.086, 43 of 488, or 8%, vs. 12 of 232, or 5.2%). Need for cholecystectomy was significantly more likely among ethanol drinkers (P = 0.008). Gallstone diameters between 6 to 15 mm were more frequent in the surgical group (51.5%) than in subjects requiring only observation (29.5%; P = 0.002). Adenomyomatosis or gallbladder wall thickening was more frequent in the surgical group (P = 0.002), as was presence of abdominal symptoms (P = 0.0002). Hemoglobin A1c was significantly higher after surgery (5.4 +/- 0.6) than before (5.3 +/- 0.5; P = 0.001). CONCLUSIONS: Among persons with gallstones detected by screening, men who drank, had abdominal symptoms, and showed gallbladder wall thickening or adenomyomatosis were more likely to require surgery within 4 years. PMID- 27474865 TI - Modeling the protonation states of beta-secretase binding pocket by molecular dynamics simulations and docking studies. AB - beta-secretase (BACE1) is an aspartyl protease that processes the beta-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is -1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors. PMID- 27474866 TI - Peptides design based on transmembrane Escherichia coli's OmpA protein through molecular dynamics simulations in water-dodecane interfaces. AB - Recent research efforts have focused on the production of environmentally nonthreatening products, including identifying biosurfactants that can replace conventional surfactants. In order to utilize biosurfactants in different industries such as cosmetic, food or petroleum, it is necessary to understand the underpinnings behind the interactions that could take place for biosurfactants which display potential for interface activity. This work aimed to use molecular dynamics simulations to understand the interactions of rationally obtained peptide sequences from the original sequence of the OmpA gene in Escherichia coli, based on the free energy change (DeltaG) during peptide insertion at the water-dodecane interface. Seventeen OmpA-based peptide sequences were selected and analyzed based on their hydropathy index profiles. We found that free energy change due to Columbic interactions and SASA (DeltaGCoul/SASA), total free energy change and MW (DeltaG/MW), and free energy change due to Coulombic and van der Waals interactions (DeltaGCoul/DeltaGvdW) ratios could provide a better understating in the contribution of the free energy decrease at the interface. The results indicated that the peptide sequences GKNHDTGVSPVFA and THENQLGAGAFG display biosurfactant potential based on low DeltaG per square nanometer, high DeltaGCoul/DeltaGvdW ratio, clearly defined moieties along its hydrophobic surface and sequence, and the presence of charged residues in the polar head. Clearly defined moieties and SASA were determinant for electrostatic interactions between oil-water interfaces. Experimental validations exhibited that the emulsions prepared remained stable between 3 and 27h, respectively. Even though the peptide GKNHDTGVSPVFA displays strong interactions at the interface, stabilization times showed that the peptide THENQLGAGAFG exhibited the best performance suggesting that the stability can be better described by kinetic rather than thermodynamic criteria once the emulsion is formed. PMID- 27474867 TI - Toluene promotes lid 2 interfacial activation of cold active solvent tolerant lipase from Pseudomonas fluorescens strain AMS8. AB - The utilization of cold active lipases in organic solvents proves an excellent approach for chiral synthesis and modification of fats and oil due to the inherent flexibility of lipases under low water conditions. In order to verify whether this lipase can function as a valuable synthetic catalyst, the mechanism concerning activation of the lid and interacting solvent residues in the presence of organic solvent must be well understood. A new alkaline cold-adapted lipase, AMS8, from Pseudomonas fluorescens was studied for its structural adaptation and flexibility prior to its exposure to non-polar, polar aprotic and protic solvents. Solvents such as ethanol, toluene, DMSO and 2-propanol showed to have good interactions with active sites. Asparagine (Asn) and tyrosine (Tyr) were key residues attracted to solvents because they could form hydrogen bonds. Unlike in other solvents, Phe-18, Tyr-236 and Tyr-318 were predicted to have aromatic aromatic side-chain interactions with toluene. Non-polar solvent also was found to possess highest energy binding compared to polar solvents. Due to this circumstance, the interaction of toluene and AMS8 lipase was primarily based on hydrophobicity and molecular recognition. The molecular dynamic simulation showed that lid 2 (residues 148-167) was very flexible in toluene and Ca(2+). As a result, lid 2 moves away from the catalytic areas, leaving an opening for better substrate accessibility which promotes protein activation. Only a single lid (lid 2) showed the movement following interactions with toluene, although AMS8 lipase displayed double lids. The secondary conformation of AMS8 lipase that was affected by toluene observed a reduction of helical strands and increased coil structure. Overall, this work shows that cold active lipase, AMS8 exhibits distinguish interfacial activation and stability in the presence of polar and non polar solvents. PMID- 27474868 TI - Multi-scale molecular dynamics study of cholera pentamer binding to a GM1 phospholipid membrane. AB - The AB5 type toxin produced by the Vibrio cholerae bacterium is the causative agent of the cholera disease. The cholera toxin (CT) has been shown to bind specifically to GM1 glycolipids on the membrane surface. This binding of CT to the membrane is the initial step in its endocytosis and has been postulated to cause significant disruption to the membrane structure. In this work, we have carried out a combination of coarse-grain and atomistic simulations to study the binding of CT to a membrane modelled as an asymmetrical GM1-DPPC bilayer. Simulation results indicate that the toxin binds to the membrane through only three of its five B subunits, in effect resulting in a tilted bound configuration. Additionally, the binding of the CT can increase the area per lipid of GM1 leaflet, which in turn can cause the membrane regions interacting with the bound subunits to experience significant bilayer thinning and lipid tail disorder across both the leaflets. PMID- 27474869 TI - Unwanted reminders: The effects of emotional memory suppression on subsequent neuro-cognitive processing. AB - The neural basis of voluntarily suppressing conscious access to one's own memories (retrieval suppression [RS]) has recently received considerable attention. However, to date there has been limited research examining the effects of RS on subsequent processing of associated retrieval cues. In this study 47 healthy participants completed a Think/No Think task for memories of emotionally unpleasant visual scenes. While undergoing functional magnetic resonance imaging (fMRI), participants were then presented with cues associated with both suppressed ("no-think-cues") and non-suppressed ("think-cues") memories, and then asked to perform simple arithmetic problems. We observed that, compared to think cues, no-think-cues were associated with greater left mid/anterior insula activation and with greater insula-anterior cingulate functional connectivity; left insula activation also predicted worse arithmetic performance. These results suggest that cues associated with suppressed negative memories may lead to greater activation of the brain's "salience" network, and reduced available cognitive resources for completion of an ongoing goal-directed task. PMID- 27474870 TI - Does socioeconomic status impact physical activity and sleep among children with cancer? AB - BACKGROUND: Compared with healthy children, pediatric oncology patients have impaired sleep and engage in less physical activity (PA). Socioeconomic status (SES) may be one determinant of PA and sleep among pediatric oncology patients. PROCEDURE: Between November 12, 2009 and March 27, 2013, 50 pediatric oncology patients between the ages of 8 and 18 years were recruited from an urban children's hospital. PA and sleep were assessed by actigraphy and diaries over 7 days. Fatigue was assessed using the Fatigue Scale. SES was defined by primary payer status of insurance (state or private) and by Median Household Income (MHI) obtained from 2010 U.S. Census block data for residences. MHI was compared to Connecticut state median income ($67,000). Multivariate regression models examined the relationship between SES and PA, sleep and fatigue. RESULTS: PA and sleep efficiency were strongly correlated (r = 0.31, P = 0.03). Children with state insurance had higher average PA (P = 0.004) than children on private insurance. There were no significant differences in PA or sleep efficiency by block MHI. The 7-day fatigue score was lower among the participants aged 8-12 years in the group with MHI less than $67,000 (P = 0.03), although there was no significant difference among participants aged 13-18 years in the group. There was no difference in mean fatigue scores by insurance status. CONCLUSIONS: Participants on state insurance had higher PA than those with private insurance. Although block MHI did not influence PA or sleep efficiency among children with cancer, participants aged 8-12 years in a lower MHI block had less fatigue. Future research is needed to further understand how SES influences PA. PMID- 27474872 TI - Decreased melanocortin-4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene. AB - OBJECTIVE: The melanocortin receptor accessory protein 2 (MRAP2) is relevant for weight regulation in mice and humans. This function is likely mediated by regulation of the melanocortin-4 receptor (MC4R). Functional implications of human MRAP2 mutations have not been described yet. METHODS: A mutation screen was conducted in MRAP2 in 184 children and adolescents with (extreme) obesity and in 184 lean controls. Detected nonsynonymous variants were genotyped in larger independent study groups (300 people with obesity and 436 individuals with normal weight). The influence of mutant MRAP2 on MC4R signaling was analyzed in vitro. RESULTS: (1) Three (two novel) nonsynonymous MRAP2 variants were detected: p.Ala137Thr, p.Gln174Arg, p.Arg125His (rs115655382), two synonymous variants, and three intronic variants. (2) The impact of MRAP2 on MC4R function was dependent on the ratio between the two co-expressed proteins. Increased MC4R signaling was detected at MRAP2/MC4R ratios of 2 + 1 and above. (3) The function of MC4R was reduced with the infrequent allele at the MRAP2 p.Gln174Arg variant. (4) The three nonsynonymous mutations were each only detected once among the 484 people with obesity and not among 620 individuals with normal weight. CONCLUSIONS: This was the first study describing an effect of a MRAP2 mutation on MC4R function. PMID- 27474871 TI - Membrane potentials regulating GPCRs: insights from experiments and molecular dynamics simulations. AB - G-protein coupled receptors (GPCRs) form the largest class of membrane proteins in humans and the targets of most present drugs. Membrane potential is one of the defining characteristics of living cells. Recent work has shown that the membrane voltage, and changes thereof, modulates signal transduction and ligand binding in GPCRs. As it may allow differential signalling patterns depending on tissue, cell type, and the excitation status of excitable cells, GPCR voltage sensitivity could have important implications for their pharmacology. This review summarises recent experimental insights on GPCR voltage regulation and the role of molecular dynamics simulations in identifying the structural basis of GPCR voltage-sensing. We discuss the potential significance for drug design on GPCR targets from excitable and non-excitable cells. PMID- 27474873 TI - Investigating risk factors of traffic casualties at private highway-railroad grade crossings in the United States. AB - Private highway-railroad grade crossings (HRGCs) are intersections of highways and railroads on roadways that are not maintained by a public authority. Since no public authority maintains private HRGCs, fatal and injury crashes at these locations are of concern. However, no study has been conducted at private HRGCs to identify the safety issues that might exist and how to alleviate them. This study identifies the significant predictors of traffic casualties (including both injuries and fatalities) at private HRGCs in the U.S. using six years of nationwide crashes from 2009 to 2014. Two levels of injury severity were considered, injury (including fatalities and injuries) and no injury. The study investigates multiple predictors, e.g., temporal crash characteristics, geometry, railroad, traffic, vehicle, and environment. The study applies both the mixed logit and binary logit models. The mixed logit model was found to outperform the binary logit model. The mixed logit model revealed that drivers who did not stop, railroad equipment that struck highway users, higher train speeds, non-presence of advance warning signs, concrete road surface type, and cloudy weather were associated with an increase in injuries and fatalities. For example, a one-mile per-hour higher train speed increases the probability of fatality by 22%. On the contrary, male drivers, PM peak periods, and presence of warning devices at both approaches were associated with a fatality reduction. Potential strategies are recommended to alleviate injuries and fatalities at private HRGCs. PMID- 27474874 TI - Road crossing behavior under traffic light conflict: Modulating effects of green light duration and signal congruency. AB - A large number of pedestrians and cyclists regularly ignore the traffic lights to cross the road illegally. In a recent analysis, illegal road crossing behavior has been shown to be enhanced in the presence of incongruent stimulus configurations. Pedestrians and cyclists are more likely to cross against a red light when exposed to an irrelevant conflicting green light. Here, we present experimental and observational data on the factors moderating the risk associated with incongruent traffic lights. In an observational study, we demonstrated that the conflict-related increase in illegal crossing rates is reduced when pedestrian and cyclist green light periods are long. In a laboratory experiment, we manipulated the color of the irrelevant signals to expose participants to different degrees of incongruency. Results revealed that individuals' performance gradually varied as a function of incongruency, suggesting that the negative impact of a conflicting green light can be reduced by slightly adjusting its color. Our findings highlight that the observation of real-world behavior at intersections and the experimental analysis of psychological processes under controlled laboratory conditions can complement each other in identifying risk factors of risky road crossing behavior. Based on this combination, our study elaborates on promising measures to improve safety at signalized intersections. PMID- 27474875 TI - Professional experience and traffic accidents/near-miss accidents among truck drivers. AB - AIM: To investigate the relationship between the time working as a truck driver and the report of involvement in traffic accidents or near-miss accidents. METHODS: A cross-sectional study was performed with truck drivers transporting products from the Brazilian grain harvest to the Port of Paranagua, Parana, Brazil. The drivers were interviewed regarding sociodemographic characteristics, working conditions, behavior in traffic and involvement in accidents or near-miss accidents in the previous 12 months. Subsequently, the participants answered a self-applied questionnaire on substance use. The time of professional experience as drivers was categorized in tertiles. Statistical analyses were performed through the construction of models adjusted by multinomial regression to assess the relationship between the length of experience as a truck driver and the involvement in accidents or near-miss accidents. RESULTS: This study included 665 male drivers with an average age of 42.2 (+/-11.1) years. Among them, 7.2% and 41.7% of the drivers reported involvement in accidents and near-miss accidents, respectively. In fully adjusted analysis, the 3rd tertile of professional experience (>22years) was shown to be inversely associated with involvement in accidents (odds ratio [OR] 0.29; 95% confidence interval [CI] 0.16-0.52) and near miss accidents (OR 0.17; 95% CI 0.05-0.53). The 2nd tertile of professional experience (11-22 years) was inversely associated with involvement in accidents (OR 0.63; 95% CI 0.40-0.98). CONCLUSIONS: An evident relationship was observed between longer professional experience and a reduction in reporting involvement in accidents and near-miss accidents, regardless of age, substance use, working conditions and behavior in traffic. PMID- 27474876 TI - The results of local excision with or without postoperative adjuvant chemoradiotherapy for early rectal cancer among patients choosing to avoid radical surgery. AB - AIM: The study aimed to establish the oncological outcome of patients who opted for close surveillance with or without adjuvant chemoradiotherapy rather than radical surgery after local excision (LE) of early rectal cancer. METHOD: The Royal Marsden Hospital Rectal Cancer database was used to identify rectal cancer patients treated by primary LE from 2006 to 2015. All patients were entered in an intensive surveillance programme. RESULTS: Twenty-eight of 34 analysed patients had a high or very high risk of residual disease predicted by adverse histopathological features for which the recommendation had been radical surgery. Eighteen (52%) of the 34 had received radiotherapy following LE. Three-year disease-free survival for the 34 patients was 85% (95% CI 78.8%-91.2%) and overall survival was 100%. Twenty-two of 24 patients with a low tumour which would have required total rectal excision have so far avoided radical surgery and remain disease free at a median follow-up of 3.2 years. CONCLUSION: The findings suggest that with modern MRI and clinical surveillance radical surgery can be avoided in patients following initial LE of a histopathologically defined high risk early rectal cancer. These findings are comparable with those obtained after major radical resection and warrant further prospective investigation as a treatment arm in larger prospective trials. PMID- 27474877 TI - Identifying and assessing the application of ecosystem services approaches in environmental policies and decision making. AB - The presumption is that ecosystem services (ES) approaches provide a better basis for environmental decision making than do other approaches because they make explicit the connection between human well-being and ecosystem structures and processes. However, the existing literature does not provide a precise description of ES approaches for environmental policy and decision making, nor does it assess whether these applications will make a difference in terms of changing decisions and improving outcomes. We describe 3 criteria that can be used to identify whether and to what extent ES approaches are being applied: 1) connect impacts all the way from ecosystem changes to human well-being, 2) consider all relevant ES affected by the decision, and 3) consider and compare the changes in well-being of different stakeholders. As a demonstration, we then analyze retrospectively whether and how the criteria were met in different decision-making contexts. For this assessment, we have developed an analysis format that describes the type of policy, the relevant scales, the decisions or questions, the decision maker, and the underlying documents. This format includes a general judgment of how far the 3 ES criteria have been applied. It shows that the criteria can be applied to many different decision-making processes, ranging from the supranational to the local scale and to different parts of decision making processes. In conclusion we suggest these criteria could be used for assessments of the extent to which ES approaches have been and should be applied, what benefits and challenges arise, and whether using ES approaches made a difference in the decision-making process, decisions made, or outcomes of those decisions. Results from such studies could inform future use and development of ES approaches, draw attention to where the greatest benefits and challenges are, and help to target integration of ES approaches into policies, where they can be most effective. Integr Environ Assess Manag 2017;13:41-51. (c) 2016 SETAC. PMID- 27474879 TI - Single port laparoscopic staging for peritoneal malignancy - a video vignette. PMID- 27474878 TI - Synthesis and Pharmacological Evaluation of Indole Derivatives as Deaza Analogues of Potent Human Neutrophil Elastase Inhibitors. AB - Preclinical Research A number of N-benzoylindoles were designed and synthesized as deaza analogs of previously reported potent and selective HNE inhibitors with an indazole scaffold. The new compounds containing substituents and functions that were most active in the previous series were active in the micromolar range (the most potent had IC50 = 3.8 MUM) or inactive. These results demonstrated the importance of N-2 in the indazole nucleus. Docking studies performed on several compounds containing the same substituents but with an indole or an indazole scaffold, respectively, highlight interesting aspects concerning the molecule orientation and H-bonding interactions, which could help to explain the lower activity of this new series. Drug Dev Res, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27474880 TI - Incidence and risk factors for anastomotic stenosis of continuous hepaticojejunostomy after pancreaticoduodenectomy. AB - BACKGROUND: There have been no reports showing the incidence of anastomotic stenosis of continuous hepaticojejunostomy (HJ) and identifying its risk factors for patients who underwent pancreaticoduodenectomy (PD). METHOD: We retrospectively investigated 200 patients whose HJ was established by unified method, single layered continuous suture. HJ stenosis was diagnosed with endoscopic or radiologic examinations. Uni and multivariable unconditional logistic modeling were performed to explore the predictive factors and to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: Sixteen patients (8.0%) were diagnosed as HJ stenosis. Multivariable analysis showed that body mass index (BMI) (OR: 1.24; 95% CI: 1.03-1.51), absence of preoperative biliary stenting (OR: 11.10; 95% CI: 1.22-101.12), operative time (OR: 1.74 per one hour increase; 95% CI: 1.01-2.98), age (OR: 1.58 per 10 years increase; 95% CI: 0.88-2.85), and absence of nodal metastasis (OR: 3.43; 95% CI: 0.90-13.12) correlated with HJ stenosis. Among these, BMI and preoperative biliary stenting were associated with stenosis with a lower P-value than the others (P = 0.026 and 0.033, respectively). CONCLUSIONS: The incidence of HJ stenosis was 8.0%. Close attention would be needed especially for patients at high risk of HJ stenosis, such as high BMI or absence of preoperative biliary stenting. PMID- 27474882 TI - Preoperative diagnosis of portal vein invasion in pancreatic head cancer: appropriate indications for concomitant portal vein resection. AB - BACKGROUND: The surgical indications for patients with pancreatic head cancer (PHC) with clinical portal vein (PV) invasion (cPV) remain controversial. The present study aimed to determine the ability of computed tomography (CT) to diagnose pathological PV involvement (pPV) in PHC. METHODS: We evaluated the morphological features (length and circumference) and two sets of diagnostic criteria for cPV determined from preoperative CT findings of 112 consecutive patients who underwent pancreatoduodenectomy for PHC. This study is listed in the UMIN Clinical Trials Registry (UMIN-CTR; No: UMIN000016827). RESULTS: Five patients were excluded because enhanced CT data were missing. Morphological features have low diagnostic ability for pPV. We diagnosed 67 patients with cPV based on our diagnostic criteria and those of Klauss, and 42 of them had pPV. The negative predictive values of these diagnostic criteria for pPV were satisfactory (>95%) and the positive predictive value was relatively low (61.2%). Postoperative survival could be predicted based on the cPV type. CONCLUSION: An accurate diagnosis of pPV based on morphological features determined by preoperative CT is difficult. However, preoperative CT appears useful for selecting patients with PHC who could be candidates for pancreaticoduodenectomy with or without PV resection. PMID- 27474881 TI - Extracellular vesicles carry microRNA-195 to intrahepatic cholangiocarcinoma and improve survival in a rat model. AB - : The cancer microenvironment plays a central role in cancer development, growth, and homeostasis. This paradigm suggests that cancer fibroblasts support cancers, probably in response to stimuli received from the cancer cells. We aimed at investigating whether extracellular vesicles (EVs) can shuttle microRNA (miR) species between cancer-associated fibroblasts (CAFs) and cancer cells. To this end, we extracted EVs according to published protocols. EVs were studied for their miR content by quantitative reverse-transcription polymerase chain reaction. EVs were transfected with select miR species and utilized in vitro as well as in vivo in a rat model of cholangiocarcinoma (CCA). We found that miR-195 is down-regulated in CCA cells, as well as in adjoining fibroblasts. Furthermore, we report that EVs shuttle miR-195 from fibroblasts to cancer cells. Last, we show that fibroblast-derived EVs, loaded with miR-195, can be administered in a rat model of CCA, concentrate within the tumor, decrease the size of cancers, and improve survival of treated rats. CONCLUSION: EVs play a salient role in trafficking miR species between cancer cells and CAFs in human CCA. Understanding of these mechanisms may allow devising of novel therapeutics. (Hepatology 2017;65:501-514). PMID- 27474883 TI - Gene cloning of an efficiency oleate hydratase from Stenotrophomonas nitritireducens for polyunsaturated fatty acids and its application in the conversion of plant oils to 10-hydroxy fatty acids. AB - Hydroxy fatty acids are used as precursors of lactones and dicarboxylic acids, as starting materials of polymers, and as additives in coatings and paintings. Stenotrophomonas nitritireducens efficiently converts cis-9 polyunsaturated fatty acids (PUFAs) to 10-hydroxy fatty acids. However, gene encoding enzyme involved in this conversion has not been identified to date. We purified a putative fatty acid double-bond hydratase from S. nitritireducens by ultrafiltration and HiPrep DEAE FF and Resource Q ion exchange chromatographies. Peptide sequences of the purified enzyme were obtained by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analysis. Sequence of the partial gene encoding this putative fatty acid double-bond hydratase was determined by degenerate polymerase chain reaction (PCR) based on the peptide sequences. The remaining gene sequence was identified by rapid amplification of cDNA ends using cDNA of S. nitritireducens as a template, and the full-length gene was cloned subsequently. The expressed enzyme was identified as an oleate hydratase by determining its kinetic parameters toward unsaturated fatty acids. S. nitritireducens oleate hydratase showed higher activity toward PUFAs compared with other available oleate hydratases. This suggested that the enzyme could be used effectively to convert plant oils to 10-hydroxy fatty acids because these oils contained unsaturated fatty acids such as oleic acid (OA) and linoleic acid (LA) and PUFAs such as alpha-linolenic acid and/or gamma-linolenic acid. The enzyme converted soybean oil and perilla seed oil hydrolyzates containing 10 mM total unsaturated fatty acids, including OA, LA, and ALA, to 8.87 and 8.70 mM total 10-hydroxy fatty acids, respectively, in 240 min. To our knowledge, this is the first study on the biotechnological conversion of PUFA-containing oils to hydroxy fatty acids. Biotechnol. Bioeng. 2017;114: 74-82. (c) 2016 Wiley Periodicals, Inc. PMID- 27474885 TI - High Protein Pasta is Not More Satiating than High Fiber Pasta at a Lunch Meal, Nor Does it Decrease Mid-Afternoon Snacking in Healthy Men and Women. AB - This study compared satiety after high protein pasta (16 g protein, 6 g fiber), high fiber pasta (11 g protein, 8 g fiber) or control pasta (11 g protein, 6 g fiber) in a randomized, placebo-controlled, double-blind crossover trial. Participants were 36 healthy and men and women from the University of Minnesota campus. Fasted men and women ate calorie controlled, but macronutrient different pastas at 12:00 pm along with 500 mL of water. The primary outcome was satiety assessed by Visual Analogue Scales at 0, 15, 30, 45, 60, 90, 120, and 180 min daily after consuming the pastas. Secondary outcomes were calories consumed at an ad libitum snack at 3:00 pm, calories from food intake, gastrointestinal tolerance, and palatability. No differences were found among the pasta treatments for satiety, snacking, or gastrointestinal tolerance. Men ate significantly more calories for the rest of the (P = 0.007) after the high protein pasta versus the high fiber pasta (1701 +/- 154 compared with 1083 +/- 154) with control pasta being intermediate to the other treatments. No significant differences were found for gastrointestinal tolerance, but the palatability ratings showed the high protein pasta was less tasty (P = 0.03) and less pleasant (P = 0.01) than the other 2 pastas. Satisfaction was positively associated with pleasantness and negatively associated with aftertaste. Our results do not support the idea that high protein or high fiber pasta produces a greater satiety response compared to pasta with lower amounts of either nutrient. It is likely that since pasta is already a very satiating food, the subjects were unable to differentiate between the 3 conditions. PMID- 27474884 TI - The myeloid heat shock transcription factor 1/beta-catenin axis regulates NLR family, pyrin domain-containing 3 inflammasome activation in mouse liver ischemia/reperfusion injury. AB - : Heat shock transcription factor 1 (HSF1) has been implicated in the differential regulation of cell stress and disease states. beta-catenin activation is essential for immune homeostasis. However, little is known about the role of macrophage HSF1-beta-catenin signaling in the regulation of NLRP3 inflammasome activation during ischemia/reperfusion (I/R) injury (IRI) in the liver. This study investigated the functions and molecular mechanisms by which HSF1-beta-catenin signaling influenced NLRP3-mediated innate immune response in vivo and in vitro. Using a mouse model of IR-induced liver inflammatory injury, we found that mice with a myeloid-specific HSF1 knockout (HSF1M-KO ) displayed exacerbated liver damage based on their increased serum alanine aminotransferase levels, intrahepatic macrophage/neutrophil trafficking, and proinflammatory interleukin (IL)-1beta levels compared to the HSF1-proficient (HSF1FL/FL ) controls. Disruption of myeloid HSF1 markedly increased transcription factor X box-binding protein (XBP1), NLR family, pyrin domain-containing 3 (NLRP3), and cleaved caspase-1 expression, which was accompanied by reduced beta-catenin activity. Knockdown of XBP1 in HSF1-deficient livers using a XBP1 small interfering RNA ameliorated hepatocellular functions and reduced NLRP3/cleaved caspase-1 and IL-1beta protein levels. In parallel in vitro studies, HSF1 overexpression increased beta-catenin (Ser552) phosphorylation and decreased reactive oxygen species (ROS) production in bone-marrow-derived macrophages. However, myeloid HSF1 ablation inhibited beta-catenin, but promoted XBP1. Furthermore, myeloid beta-catenin deletion increased XBP1 messenger RNA splicing, whereas a CRISPR/CRISPR-associated protein 9-mediated XBP1 knockout diminished NLRP3/caspase-1. CONCLUSION: The myeloid HSF1-beta-catenin axis controlled NLRP3 activation by modulating the XBP1 signaling pathway. HSF1 activation promoted beta-catenin, which, in turn, inhibited XBP1, leading to NLRP3 inactivation and reduced I/R-induced liver injury. These findings demonstrated that HSF1/beta catenin signaling is a novel regulator of innate immunity in liver inflammatory injury and implied the therapeutic potential for management of sterile liver inflammation in transplant recipients. (Hepatology 2016;64:1683-1698). PMID- 27474886 TI - Qualitative analysis of foot intersegment coordination in the sagittal plane following surgery for end-stage ankle osteoarthrosis. AB - Today, ankle joint kinematic assessment gives important information regarding the intersegment range of motion. It does not, however, provide information regarding coordination between the segments. This study aimed to determine whether or not intersegment coordination can provide valuable, otherwise missed information in relation to kinematic alterations of the ankle joint. The study consisted of 40 participants, including 12 total ankle replacement (TAR) patients, 12 ankle arthrodesis (AA) patients, and 16 controls. Gait assessment was carried out wearing 3-D inertial sensors. Intersegment coordination was determined by calculation of the continuous relative phase (CRP) between foot intersegments. CRP analysis found useful information regarding the magnitude and directionality of segment motion throughout the gait cycle, with AA patients reporting an altered coordination pattern for all three intersegments, forefoot-hindfoot, hindfoot-shank, and forefoot-shank, and TAR patients showing alterations in the hindfoot-shank intersegment. Results show that assessment of intersegment coordination can provide further information, otherwise overlooked by the general kinematic assessment, which could be used to optimize patient rehabilitation. Furthermore, the study showed that such information could be used to compare surgical outcomes. As a result, the study concludes that the inclusion of intersegment coordination assessment could be beneficial in clinical practice. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1304-1310, 2017. PMID- 27474887 TI - Funding Research in Emergency Department Shared Decision Making: A Summary of the 2016 Academic Emergency Medicine Consensus Conference Panel Discussion. AB - As part of the 2016 Academic Emergency Medicine Consensus Conference, "Shared Decision Making in the Emergency Department: Development of a Policy-relevant Patient-centered Research Agenda," a panel of representatives from the Office of Emergency Care Research, the Patient-Centered Outcomes Research Institute, the American Heart Association, the John A. Hartford Foundation, and the Emergency Care Coordination Center were assembled to discuss funding opportunities for future research in this field. This article summarizes their discussion of funding priorities and examples of successfully funded projects related to shared decision making in emergency medicine. PMID- 27474888 TI - Minimally clinically important decline in the parkinsonian variant of multiple system atrophy. AB - INTRODUCTION: We provide the first characterization of the minimally clinically important difference on the Unified Multiple System Atrophy Rating Scale in patients with the parkinsonian variant of early MSA. METHODS: Data from a randomized controlled trial of rasagiline were analyzed using clinical global impression as an anchor. Because too few patients improved with treatment, analyses were limited to defining scale cutoffs that discriminated between minimal worsening and no change. RESULTS: Based on receiver operating characteristic curves, minimally clinically important differences were 1.5 points on the activities of daily living scale, 1.5 points on the motor scale, and 3.5 points on the total scale. CONCLUSIONS: Appreciation of the minimally clinically important difference is important when deciding if statistically significant effects should influence practice. For the Unified Multiple System Atrophy Rating Scale, further work is required to establish cutoffs for improvement, extend relevance to cerebellar-predominant disease, and characterize progression rates at different disease stages. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27474889 TI - Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. AB - Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis with ascites. We used data from three 1-year trials of satavaptan for ascites control. We used Cox regression to compare HE and SBP rates between users and nonusers of PPIs. At inclusion, 39% of the 865 patients with cirrhosis with ascites used PPIs, 52% used them at some point during the follow-up, and the proportion of current users was always in the 30%-39% range. There were 189 first time HE episodes during the follow-up, and the cumulative 1-year risk was 31% for those who used PPIs at baseline versus 25% for those who did not. The confounder adjusted hazard ratio (HR) of HE for current PPI use versus current nonuse was 1.36 (95% confidence interval [CI], 1.01-1.84). The HR for overt HE was higher (adjusted HR = 1.88; 95% CI, 1.21-1.91). During the follow-up, 86 patients developed SBP. The adjusted HR of SBP for current PPI users versus nonusers was 1.72 (95% CI, 1.10-2.69). CONCLUSION: PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272). PMID- 27474890 TI - Adapting viral safety assurance strategies to continuous processing of biological products. AB - There has been a recent drive in commercial large-scale production of biotechnology products to convert current batch mode processing to continuous processing manufacturing. There have been reports of model systems capable of adapting and linking upstream and downstream technologies into a continuous manufacturing pipeline. However, in many of these proposed continuous processing model systems, viral safety has not been comprehensively addressed. Viral safety and detection is a highly important and often expensive regulatory requirement for any new biological product. To ensure success in the adaption of continuous processing to large-scale production, there is a need to consider the development of approaches that allow for seamless incorporation of viral testing and clearance/inactivation methods. In this review, we outline potential strategies to apply current viral testing and clearance/inactivation technologies to continuous processing, as well as modifications of existing unit operations to ensure the successful integration of viral clearance into the continuous processing of biological products. Biotechnol. Bioeng. 2017;114: 21-32. (c) 2016 Wiley Periodicals, Inc. PMID- 27474891 TI - Anticoagulation with intravenous unfractionated heparin and major bleeding in cirrhosis. PMID- 27474892 TI - Multichannel silk protein/laminin grafts for spinal cord injury repair. AB - The physical, chemical, and bioactive cues provided by biomaterials are critical for spinal cord regeneration following injury. In this study, we investigated the bioactivity of a silk-based scaffold for nerve tissue remodeling that featured morphological guidance in the form of ridges as well as bioactive molecules. Multichannel/laminin (LN) silk scaffolds stimulated growth, development, and the extension of primary hippocampal neurons after 7 days of culture in vitro. And then, the multichannel/LN silk scaffolds were implanted into 2-mm-long hemisection defects in Sprague-Dawley rat spinal cords for 70 days to evaluate their bioactivities of spinal cord remolding. Our results demonstrated that animal behavior was significantly improved in the multichannel/LN group, as evaluated by Basso-Beattie-Bresnahan score, whereas the implantation of multichannels and random pores groups resulted in recurring limps. Moreover, histology and immunohistochemical staining revealed an increase in blood vessels and expression of growth associated protein-43 and neurofilament-200 as well as reduced expression of glial fibrillary acidic protein in the multichannel/LN group, which contributed to the rebuilding of spinal cord defects. Thus, multichannel/LN silk scaffolds mediated cell migration, stimulated blood capillary formation, and promoted axonal extension, suggesting the utility of these scaffolds for spinal cord reconstruction. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3045-3057, 2016. PMID- 27474893 TI - Toxicant mixtures in sediment alter gene expression in the cysteine metabolism of Chironomus tepperi. AB - Sediment contamination can pose risks to the environment, and sediment toxicity tests have been developed to isolate the impact of sediment from other factors. Mixtures of contaminants often occur in sediments, and traditional endpoints used in toxicity testing, such as growth, reproduction, and survival, cannot discern the cause of toxicity from chemical mixtures because of complex interactions. In urban waterways, the synthetic pyrethroid bifenthrin and the metal copper are commonly found in mixtures, so the present study was designed to investigate how these contaminants cause toxicity in mixtures. To investigate this, Chironomus tepperi was exposed to environmentally relevant concentrations of copper and bifenthrin-spiked sediments in a 2-way factorial mixture for 5 d. Growth and expression profiles of cysteine metabolism genes were measured after exposure. Growth increased at low copper concentrations, decreased at high copper concentrations, and was unaffected by bifenthrin exposures. Copper exposures induced possible cellular repair by upregulating S-adenosylmethionine synthetase expression and downregulating expression of S-adenosylhomocysteine hydrolase and cystathionine-beta-synthase. Metallothionein upregulation was also observed. Bifenthrin exposure altered cysteine metabolism to a lesser extent, downregulating cystathionine-beta-synthase and gamma-glutamylcysteine synthase. Synergistic, antagonistic, and dose-dependent interactions were observed, and there was evidence of conflicting modes of action and limited substrate production. These findings demonstrate how contextual gene expression changes can be sensitive and specific identifiers of toxicant exposure in mixtures. Environ Toxicol Chem 2017;36:691-698. (c) 2016 SETAC. PMID- 27474894 TI - Investigation of adult stainless steel crown longevity as an interim restoration in pediatric patients. AB - BACKGROUND: Preformed metal crowns, also known as stainless steel crowns (SSC), are utilized for providing full coverage to young permanent teeth and have been used extensively as restorations of primary teeth for approximately 65 years. AIM: Evaluate permanent tooth SSC longevity as an interim restoration for teeth requiring full coverage restoration in pediatric patients. DESIGN: Retrospective chart review from 2006 through 2014 in a hospital-based dental clinic for permanent tooth pre-fabricated crown longevity. One hundred and fifty-five SSCs were evaluated with regard to: age of patient at restoration placement, diagnoses, and duration of crown service. Duration service was further categorized as successful or failed. RESULTS: Of 155 SSCs, 137 were considered successfully functioning. Total failures were 18. The overall combined success rate for the study group was observed to be 88% with an average service period of 45.18 months. Significant success was noted in patients less than 9 years of age, and significant failure was observed in patients 12 years and older. CONCLUSIONS: Stainless steel crowns are a viable option for interim restoration needs, with an 88% overall success rate during an average service period of 45.18 months. PMID- 27474895 TI - Assessing medical student cultural competence: what really matters. AB - OBJECTIVES: The study aimed to explore medical students' attitudes and beliefs toward Latino patients, specifically: to assess students' levels of knowledge, cultural competence, and comfort with Latinos; to determine students' exposure to and previous experience with Latinos; and to evaluate whether factors such as study abroad, living abroad, previous clinical experience with Latinos, and language proficiency predict Latino knowledge, cultural competence, and comfort with Latinos. METHODS: This study utilized a cross-sectional survey design. Participants were third and fourth year medical students at three medical schools in the Southeastern United States. Three composite measures: Latino knowledge, Cultural competence, and Comfort with Latino patients, were predicted in a multivariate regression model including individual sociodemographic characteristics and past clinical or social experience with Latinos. RESULTS: A total of 170 medical students completed the survey (43% response rate). Spanish language proficiency was a statistically significant predictor (t(131)=2.72, p<0.05) of Latino knowledge. Social interaction with Latinos in the past year (t(126)=3.09, p<0.01), ever having lived in a Spanish-speaking country (t(126)=2.86, p<0.01), and Spanish language proficiency (t(126)=3.28, p<0.01) independently predicted cultural competence. Previous clinical experience with Latinos was not significantly associated with the three composite dependent variables, and comfort with Latino patients was not significantly predicted by any of the six Latino-related explanatory variables. CONCLUSIONS: Factors prior to medical school matriculation and during medical education may contribute to increased cultural competence and comfort with multicultural patients. Cultural patient-partner programs may be an effective way to increase cultural competence within the confines of medical school curricula. PMID- 27474896 TI - Assessing uncertainties in land cover projections. AB - Understanding uncertainties in land cover projections is critical to investigating land-based climate mitigation policies, assessing the potential of climate adaptation strategies and quantifying the impacts of land cover change on the climate system. Here, we identify and quantify uncertainties in global and European land cover projections over a diverse range of model types and scenarios, extending the analysis beyond the agro-economic models included in previous comparisons. The results from 75 simulations over 18 models are analysed and show a large range in land cover area projections, with the highest variability occurring in future cropland areas. We demonstrate systematic differences in land cover areas associated with the characteristics of the modelling approach, which is at least as great as the differences attributed to the scenario variations. The results lead us to conclude that a higher degree of uncertainty exists in land use projections than currently included in climate or earth system projections. To account for land use uncertainty, it is recommended to use a diverse set of models and approaches when assessing the potential impacts of land cover change on future climate. Additionally, further work is needed to better understand the assumptions driving land use model results and reveal the causes of uncertainty in more depth, to help reduce model uncertainty and improve the projections of land cover. PMID- 27474897 TI - Behavior and clinical impact of ascites after living donor liver transplantation: risk factors associated with massive ascites. AB - BACKGROUND: Massive ascites after living donor liver transplantation (LDLT), defined as small-for-size graft syndrome, is a risk factor for a poor prognosis. Few studies have reported factors associated with ascites and the relevant outcome after LDLT. METHODS: Data from 413 adult patients that underwent LDLT were retrospectively analyzed. RESULTS: Recipient age, preoperative albumin level, Child-Pugh score, preoperative ascites, graft volume, intraoperative blood loss, and duration of warm ischemic time and the anhepatic phase were significantly associated with the total amount of ascites between postoperative day (POD) 1 and POD14. Multivariate analysis identified preoperative ascites, intraoperative blood loss, and duration of anhepatic phase as factors. Massive ascites (ascitic fluid discharge >1,000 ml/day on POD14 after LDLT) occurred in 200 (48.4%) patients, and mild ascites occurred in the remaining 213 patients. Daily changes in the ascites volume differed between the two groups. Nevertheless, massive ascites itself did not have a critical impact on the patient short- and long-term outcomes when properly managed with rigorous diuretics and albumin administration. CONCLUSION: Massive ascites is frequent after LDLT; however, the impact of it could be minimized with an appropriate management. PMID- 27474899 TI - Different waves of effector genes with contrasted genomic location are expressed by Leptosphaeria maculans during cotyledon and stem colonization of oilseed rape. AB - Leptosphaeria maculans, the causal agent of stem canker disease, colonizes oilseed rape (Brassica napus) in two stages: a short and early colonization stage corresponding to cotyledon or leaf colonization, and a late colonization stage during which the fungus colonizes systemically and symptomlessly the plant during several months before stem canker appears. To date, the determinants of the late colonization stage are poorly understood; L. maculans may either successfully escape plant defences, leading to stem canker development, or the plant may develop an 'adult-stage' resistance reducing canker incidence. To obtain an insight into these determinants, we performed an RNA-sequencing (RNA-seq) pilot project comparing fungal gene expression in infected cotyledons and in symptomless or necrotic stems. Despite the low fraction of fungal material in infected stems, sufficient fungal transcripts were detected and a large number of fungal genes were expressed, thus validating the feasibility of the approach. Our analysis showed that all avirulence genes previously identified are under expressed during stem colonization compared with cotyledon colonization. A validation RNA-seq experiment was then performed to investigate the expression of candidate effector genes during systemic colonization. Three hundred and seven 'late' effector candidates, under-expressed in the early colonization stage and over-expressed in the infected stems, were identified. Finally, our analysis revealed a link between the regulation of expression of effectors and their genomic location: the 'late' effector candidates, putatively involved in systemic colonization, are located in gene-rich genomic regions, whereas the 'early' effector genes, over-expressed in the early colonization stage, are located in gene-poor regions of the genome. PMID- 27474900 TI - Metabolically healthy obesity is associated with an increased risk of diabetes independently of nonalcoholic fatty liver disease. AB - OBJECTIVE: This study examined whether the metabolically healthy obesity (MHO) phenotype was associated with an increased risk of diabetes in a large cohort of metabolically healthy individuals and whether that association differed by presence of nonalcoholic fatty liver disease (NAFLD). METHODS: The cohort consisted of 74,509 Korean adults who were metabolically healthy at baseline, defined as not having any metabolic syndrome component except large waist circumference and having homeostasis model assessment of insulin resistance <2.5. NAFLD was defined as hepatic steatosis on ultrasonography in the absence of excessive alcohol use or any other identifiable cause. RESULTS: Over 304,852.6 person-years of follow-up, 472 participants developed diabetes (incidence density, 1.5 per 1,000 person-years). The multivariable-adjusted hazard ratios (95% confidence intervals) for incident diabetes in subjects with overweight and obesity compared with subjects with normal weight were 1.29 (1.00-2.16) and 1.57 (1.14-2.16), respectively, for subjects without NAFLD and 1.90 (0.95-3.80) and 2.57 (1.32-5.02), respectively, for those with NAFLD (P for interaction =0.57). CONCLUSIONS: In this metabolically healthy population, individuals with overweight and obesity exhibited an increased incidence of diabetes, regardless of the presence of NAFLD. This finding suggests that the obese phenotype per se, independent of the presence of NAFLD, can increase the development of diabetes. PMID- 27474898 TI - Functional Effects of Cigarette Smoke-Induced Changes in Airway Smooth Muscle Mitochondrial Morphology. AB - Long-term exposure to cigarette smoke (CS) triggers airway hyperreactivity and remodeling, effects that involve airway smooth muscle (ASM). We previously showed that CS destabilizes the networked morphology of mitochondria in human ASM by regulating the expression of mitochondrial fission and fusion proteins via multiple signaling mechanisms. Emerging data link regulation of mitochondrial morphology to cellular structure and function. We hypothesized that CS-induced changes in ASM mitochondrial morphology detrimentally affect mitochondrial function, leading to CS effects on contractility and remodeling. Here, ASM cells were exposed to 1% cigarette smoke extract (CSE) for 48 h to alter mitochondrial fission/fusion, or by inhibiting the fission protein Drp1 or the fusion protein Mfn2. Mitochondrial function was assessed via changes in bioenergetics or altered rates of proliferation and apoptosis. Our results indicate that both exposure to CS and inhibition of mitochondrial fission/fusion proteins affect mitochondrial function (i.e., energy metabolism, proliferation, and apoptosis) in ASM cells. In vivo, the airways in mice chronically exposed to CS are thickened and fibrotic, and the expression of proteins involved in mitochondrial function is dramatically altered in the ASM of these mice. We conclude that CS-induced changes in mitochondrial morphology (fission/fusion balance) correlate with mitochondrial function, and thus may control ASM proliferation, which plays a central role in airway health. J. Cell. Physiol. 232: 1053-1068, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27474901 TI - Adsorptive removal of dye using biochar derived from residual algae after in-situ transesterification: Alternate use of waste of biodiesel industry. AB - The primary aim of this present study was to utilize the residual biomass (DB) of Spirulina platensis algae, left after in-situ transesterification, for biochar preparation. This is a solid waste residue of biodiesel industry. The biochar (BC) prepared was examined for its capacity to adsorb congo red dye from the aqueous solution. The results were compared with other adsorbents used in the study such as commercial activated carbon (AC), original algae biomass (AB) and DB. The results of proximate analysis of BC showed the decrease in the percentage of volatile matter and an increase in fixed carbon content compared to DB. The physico-chemical properties of BC were studied using elemental analysis, SEM, FTIR and XRD techniques. The AC and BC adsorbents showed better performance in removing 85.4% and 82.6% of dye respectively from solution compared to AB (76.6%) and DB (78.1%). The effect of initial dye concentration, adsorbent dosage and pH of solution on the adsorption phenomena was studied by conducting the batch adsorption experiments. The highest specific uptake for biochar was observed at acidic pH of 2 with 0.2 g/100 ml of adsorbent dosage and 90 mg/l of initial concentration. The equilibrium adsorption data were fitted to three isotherms, namely Langmuir, Freundlich and Temkin. Freundlich model proved to show the best suited results with value of correlation coefficient of 99.12%. Thus, the application of DB for production of biochar as potential adsorbent supports sustainability of algae biodiesel. PMID- 27474902 TI - A fuzzy 'boater' model to detect fouling and spreading risk of non-indigenous species by recreational boats. AB - Recreational boating is an unregulated and underestimated vector of spread of non indigenous species (NIS) in marine environments. The risk of a single boat to spread NIS depends not only on the local environmental context, but also on the type of boat and on the boat owner's behaviour (hull cleaning and painting frequency, travel history). In this paper we present a model to assess the risk of fouling and spreading of NIS and its application to data derived from a questionnaire given to Italian boat owners. The model uses a two-levels fuzzy logic approach: (1) the first level assesses the risk of hull fouling and risk of spreading separately; (2) the second level combines the two separate risks in an overall index ranging from 0 (null risk) to 100 (highest risk) and measures the global risk of NIS introduction and spread through recreational boating. The questionnaire and the fuzzy model allow for a simple and rapid assessment of boats most likely to be infested. The proposed fuzzy model can be easily edited and adapted to context-specific ecological and social conditions. The results of this Italian study showed that 53.9% of the respondents were in the very-low and low risk categories, and 46.1% in the medium, high and very-high risk categories. Possible associations between some boaters habits and the fouling and spreading risk were explored using logistic regression analyses. The results indicate a high-risk profile of boat owner as an experienced sailor who visits many marinas during the summer season. Biosecurity guidelines, containment measures and awareness raising programmes should be implemented to prevent and avoid further spread of NIS in marine environments, and such management actions would benefit from the early detection of high-risk boats, and from the identification of profiles of boaters upon which these initiatives should be prioritized. PMID- 27474903 TI - Radioactivity and metal concentrations in marine sediments associated with mining activities in Ierissos Gulf, North Aegean Sea, Greece. AB - Marine sediment samples were collected from Ierissos Gulf, N Aegean Sea, close to the coastal mining facilities. Measurements of radionuclide and metal concentrations, mineral composition and grain size distribution were performed. The concentrations of (226)Ra, (235)U and trace metals showed enhanced values in the port of Stratoni compared with those obtained near to Ierissos port. The dose rates received by marine biota were also calculated by the ERICA Assessment Tool and the results indicated no significant radiological risk. PMID- 27474904 TI - Optimization of data analysis for the in vivo neutron activation analysis of aluminum in bone. AB - An existing system at McMaster University has been used for the in vivo measurement of aluminum in human bone. Precise and detailed analysis approaches are necessary to determine the aluminum concentration because of the low levels of aluminum found in the bone and the challenges associated with its detection. Phantoms resembling the composition of the human hand with varying concentrations of aluminum were made for testing the system prior to the application to human studies. A spectral decomposition model and a photopeak fitting model involving the inverse-variance weighted mean and a time-dependent analysis were explored to analyze the results and determine the model with the best performance and lowest minimum detection limit. The results showed that the spectral decomposition and the photopeak fitting model with the inverse-variance weighted mean both provided better results compared to the other methods tested. The spectral decomposition method resulted in a marginally lower detection limit (5MUg Al/g Ca) compared to the inverse-variance weighted mean (5.2MUg Al/g Ca), rendering both equally applicable to human measurements. PMID- 27474905 TI - Radiotracer investigation in a glass production unit. AB - A radiotracer investigation was carried out in a glass production unit in a glass industry. Lanthanum-140 as lanthanium oxide mixed with silica was used as a radiotracer to trace the molten glass in various sections of the unit. Residence time distributions of molten glass were measured and analyzed to identify the flow abnormities. The flow parameters such as breakthrough time, mean residence time, homogenization time, dead volume and flow patterns in different sections of the unit were obtained from the measured RTD data. The results of the investigation were used to improve and optimize the operation of the glass production unit. PMID- 27474906 TI - A precise method to determine the activity of a weak neutron source using a germanium detector. AB - A standard high purity germanium (HPGe) detector was used to determine the previously unknown neutron activity of a weak americium-beryllium (AmBe) neutron source. gamma rays were created through (27)Al(n,n'), (27)Al(n,gamma) and (1)H(n,gamma) reactions induced by the neutrons on aluminum and acrylic disks, respectively. These gamma rays were measured using the HPGe detector. Given the unorthodox experimental arrangement, a Monte Carlo simulation was developed to model the efficiency of the detector system to determine the neutron activity from the measured gamma rays. The activity of our neutron source was determined to be 307.4+/-5.0n/s and is consistent for the different neutron-induced gamma rays. PMID- 27474907 TI - Clinical factors predict surgical outcomes in pediatric MRI-negative drug resistant epilepsy. AB - PURPOSE: Lack of a potentially epileptogenic lesion on brain magnetic resonance imaging (MRI) is a poor prognostic marker for epilepsy surgery. We present a single-center series of childhood-onset MRI-negative drug-resistant epilepsy (DRE) and analyze surgical outcomes and predictors. METHODS: Children with MRI negative DRE who had resective surgery from January 2007 to December 2013 were identified using an institutional database. Relevant clinical, neurophysiological, imaging, and surgical data was extracted. The primary outcome measure was seizure freedom. Predictors of seizure freedom were obtained using multivariate logistic regression. RESULTS: Out of 47 children with MRI-negative DRE, 12 (25.5%) were seizure free (International League Against Epilepsy [ILAE] outcome class I), after mean follow-up of 2.75 (+/-1.72) years. Seizure-free proportion was significantly higher in patients with single seizure semiology and concordant ictal EEG (50.0% vs. 15.2%, p=0.025). Multivariate analysis using only non-invasive pre-surgical data showed that children with daily seizures (OR 0.02, 95% CI<0.001-0.55), and earlier onset of seizures (OR 0.72, 95% CI 0.52-0.99) were less likely to be seizure-free. Also, each additional anti-epileptic drug (AED) tried before surgery decreased the probability of seizure-free outcome (OR 0.16, 95% CI 0.04-0.63). Repeat multivariate analysis after including surgical variables found no additional significant predictors of seizure-freedom. Cortical dysplasia (ILAE type IB) was the commonest histopathology. CONCLUSION: Surgical outcomes in children with MRI-negative DRE are determined by clinical factors including seizure frequency, age of onset of seizures, and number of failed AEDs. PMID- 27474908 TI - Acute cortisol reactivity attenuates engagement of fronto-parietal and striatal regions during emotion processing in negative mood disorders. AB - OBJECTIVE: Depression and bipolar disorder (negative mood disorders, NMD) are associated with dysregulated hypothalamic-pituitary-adrenal (HPA)-axis function and disrupted emotion processing. The neural networks involved in attenuation of HPA-axis reactivity overlap with the circuitry involved in perception and modulation of emotion; however, direct links between these systems are understudied. This study investigated whether cortisol activity prior to undergoing fMRI was related to neural processing of emotional information in participants with NMD. METHODS: Forty-one adults (Mage=40.33, SD=15.57) with major depression (n=29) or bipolar disorder (n=12) and 23 healthy control comparisons (Mage=36.43, SD=17.33) provided salivary cortisol samples prior to completing a facial emotion perception test during 3-Tesla fMRI. RESULTS: Overall, pre-scan cortisol level was positively associated with greater engagement of the dorsal anterior cingulate (dACC), inferior parietal lobule, insula, putamen, precuneus, middle and medial frontal and postcentral gyri, posterior cingulate, and inferior temporal gyrus during emotion processing of all faces. NMD status moderated this effect; in NMD participants' pre-scan cortisol was associated with attenuated activation of the insula, postcentral gyrus, precuneus, and putamen for fearful faces and the medial frontal gyrus for angry faces relative to HCs. Cortisol-related attenuation of activation among NMD participants was also observed for facial identification in the dACC, putamen, middle temporal gyrus, precuneus, and caudate. CONCLUSIONS: Across all participants, cortisol was associated with greater activation in several regions involved in the perception and control of emotion. However, cortisol responsivity was associated with hypoactivation of several of these regions in the NMD group, suggesting that HPA-axis activity may selectively interfere with the potentially adaptive recruitment of circuits supporting emotion perception, processing and/or regulation in mood disorders. PMID- 27474910 TI - Effects of bioaugmentation on sorption and desorption of benzene, 1,3,5 trimethylbenzene and naphthalene in freshly-spiked and historically-contaminated sediments. AB - This work investigated the frequently observed "rebounds" of contaminants of concern in groundwater systems. Specifically, influences of bioaugmented microorganisms on the sorption and desorption of representative petroleum constituents [benzene, 1,3,5-trimethylbenzene and naphthalene (BTN)] were studied in freshly-spiked and historically-contaminated sediments. Capable microorganisms were enriched and supplemented to contaminated sediments to enhance biodegradation of petroleum hydrocarbons. In freshly-spiked sediments, when petroleum-degrading microorganisms were added, concentrations of dissolved petroleum constituents appeared to increase initially, and 12.4, 14.0 and 20.0 mg/kg of benzene, 1,3,5-trimethylbenzene and naphthalene, respectively desorbed from the sediments into the water phase. In the historically-contaminated sediments, the augmentation of petroleum-degrading microorganisms led to the desorption of 0.023-0.059, 0009-0.016, and 1.731-2.763 mg/L of previously sequestrated BTN into the water phase, and also triggered the desorption of 0.051 0.223, -0.133-2.630, and 2.324-1.200 mg/kg of previously sequestrated BTN as the methanol extraction quantity. The mechanisms of the enhanced desorption at the presence of microbes remain to be determined; however, we presumed that microbially produced constituents such as biosurfactants and cell mass could have attributed to the partition of petroleum compounds from the sediments. Findings from this study may partially explain "rebounds" of certain petroleum constituents into the groundwater during in situ bioremediation practice, although such immediate rebounds sometimes are weak, and the desorbed constituents can be eventually biodegraded under proper biogeochemical conditions. PMID- 27474909 TI - Diurnal coupling between testosterone and cortisol from adolescence to older adulthood. AB - The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes are typically conceptualized as mutually inhibitory systems; however, previous studies have found evidence for positive within-person associations (i.e., coupling) between cortisol and testosterone. One developmental hypothesis is that positive testosterone-cortisol coupling is unique to the adolescent period and that coupling becomes attenuated, or even switches direction, in adulthood. This study used a lifespan sample (N=292, ages 11-88) to test for age related differences in coupling between cortisol and testosterone in daily life. Participants provided salivary hormone samples at waking, 30min after waking, and during the evening for two days. Hierarchical linear modeling was used to test the within-person and between-person associations between testosterone and cortisol. Within-person associations were further decomposed into associations due to coupled diurnal change versus coupled variability around diurnal change. Results indicated positive associations between cortisol and testosterone at all levels of analysis. Additionally, positive coupling was evident across the lifespan, even in older adults who are no longer expected to reproduce, but further investigation of developmental differences with a larger sample is necessary. Potential mechanisms and functions for positive coupling are discussed. PMID- 27474911 TI - Analytical and mineralogical study of a Ghana manganese ore: Quantification of Mn speciation and effect of mechanical activation. AB - In-depth understanding of the manganese ore would be beneficial to make the best use more environmental-friendly. A Ghana manganese ore before/after mechanical activation (MA) was therefore extensively characterized in our investigation. Surface Mn(4+)(35.5%), Mn(3+)(35.9%), Mn(2+)(28.6%) were detected by XPS, though XRD only revealed the presence of Mn(2+)-containing minerals. Thermal decomposition curve of manganese ore obtained by TG-DSC was divided into four stages from 373.15 K to 1273.15 K, which were quite consistent with the pattern of generated gases obtained by TG-FTIR and the theoretical thermodynamics analysis of the incorporated components involving DeltaGT(theta) and Kp(theta). Mn species distribution showed no difference for manganese ores before/after MA, but quantitative analysis showed the decrease of residual Mn content (cannot be extracted effectively by acid, from about 12% to 1%), and thereby the increased contents of other four Mn species (exchangeables, carbonates, oxides, organics), which was suggested to be correlated with the dissociation of Mn-containing flocs and SiO2 particles witnessed by SEM-EDS. It was also found that MA could obviously promote the Mn dissolution kinetics in acid condition, though the dissolution of manganese ore before/after MA were both diffusion controlled. This investigation gives benignant inspiration for the resource utilization of manganese ore, taking the increasingly severer situation of Mn resource supply into consideration. PMID- 27474912 TI - Bioavailability of CeO2 and SnO2 nanoparticles evaluated by dietary uptake in the earthworm Eisenia fetida and sequential extraction of soil and feed. AB - The growing number of nanotechnology products on the market will inevitably lead to the release of engineered nanomaterials with potential risk to humans and environment. This study set out to investigate the exposure of soil biota to engineered nanoparticles (NPs). Cerium dioxide (CeO2 NPs) and tin dioxide nanoparticles (SnO2 NPs) were radiolabelled using neutron activation, and employed to assess the uptake and excretion kinetics in the earthworm Eisenia fetida. Through sequential extraction, NPs bioavailability in two contrasting soils and in earthworm feed was also investigated. Neither CeO2 NPs nor SnO2 NPs bioaccumulated in earthworms, and both were rapidly excreted when worms were transferred to clean soil. Low bioavailability was also indicated by low amounts of NPs recovered during extraction with non-stringent extractants. CeO2 NPs showed increasing mobility in organic soil over time (28 days), indicating that organic matter has a strong influence on the fate of CeO2 NPs in soil. PMID- 27474913 TI - Hepatocellular carcinoma recurrence pattern following liver transplantation and a suggested surveillance algorithm. AB - PURPOSE: This study aims to evaluate the recurrence pattern of hepatocellular carcinoma (HCC) following liver transplantation. MATERIALS AND METHODS: A total of 54 patients underwent liver transplantation for HCC; 9 patients developed biopsy-proven recurrent HCC (16.6%). The site of HCC recurrence along with other factors was analyzed. RESULTS: Seven patients were diagnosed with HCC prior to liver transplantation and 2 patients had incidental HCC in the explanted liver. Two patients had locoregional recurrence, 4 patients had distant metastasis, and 3 patients had synchronous locoregional recurrence and distant metastasis. CONCLUSION: A significant proportion of HCC recurrence following liver transplantation is extrahepatic. PMID- 27474915 TI - Non-reward neural mechanisms in the orbitofrontal cortex. AB - Single neurons in the primate orbitofrontal cortex respond when an expected reward is not obtained, and behaviour must change. The human lateral orbitofrontal cortex is activated when non-reward, or loss occurs. The neuronal computation of this negative reward prediction error is fundamental for the emotional changes associated with non-reward, and with changing behaviour. Little is known about the neuronal mechanism. Here we propose a mechanism, which we formalize into a neuronal network model, which is simulated to enable the operation of the mechanism to be investigated. A single attractor network has a reward population (or pool) of neurons that is activated by expected reward, and maintain their firing until, after a time, synaptic depression reduces the firing rate in this neuronal population. If a reward outcome is not received, the decreasing firing in the reward neurons releases the inhibition implemented by inhibitory neurons, and this results in a second population of non-reward neurons to start and continue firing encouraged by the spiking-related noise in the network. If a reward outcome is received, this keeps the reward attractor active, and this through the inhibitory neurons prevents the non-reward attractor neurons from being activated. If an expected reward has been signalled, and the reward attractor neurons are active, their firing can be directly inhibited by a non reward outcome, and the non-reward neurons become activated because the inhibition on them is released. The neuronal mechanisms in the orbitofrontal cortex for computing negative reward prediction error are important, for this system may be over-reactive in depression, under-reactive in impulsive behaviour, and may influence the dopaminergic 'prediction error' neurons. PMID- 27474914 TI - The occipital place area represents first-person perspective motion information through scenes. AB - Neuroimaging studies have identified multiple scene-selective regions in human cortex, but the precise role each region plays in scene processing is not yet clear. It was recently hypothesized that two regions, the occipital place area (OPA) and the retrosplenial complex (RSC), play a direct role in navigation, while a third region, the parahippocampal place area (PPA), does not. Some evidence suggests a further division of labor even among regions involved in navigation: While RSC is thought to support navigation through the broader environment, OPA may be involved in navigation through the immediately visible environment, although this role for OPA has never been tested. Here we predict that OPA represents first-person perspective motion information through scenes, a critical cue for such "visually-guided navigation", consistent with the hypothesized role for OPA. Response magnitudes were measured in OPA (as well as RSC and PPA) to i) video clips of first-person perspective motion through scenes ("Dynamic Scenes"), and ii) static images taken from these same movies, rearranged such that first-person perspective motion could not be inferred ("Static Scenes"). As predicted, OPA responded significantly more to the Dynamic than Static Scenes, relative to both RSC and PPA. The selective response in OPA to Dynamic Scenes was not due to domain-general motion sensitivity or to low level information inherited from early visual regions. Taken together, these findings suggest the novel hypothesis that OPA may support visually-guided navigation, insofar as first-person perspective motion information is useful for such navigation, while RSC and PPA support other aspects of navigation and scene recognition. PMID- 27474916 TI - The neural correlates of auditory and visuospatial span in logopenic progressive aphasia and Alzheimer's disease. AB - INTRODUCTION: Logopenic progressive aphasia (lv-PPA) is a form of primary progressive aphasia and is predominantly associated with Alzheimer's disease (AD) pathology. The neuropsychological profiles of lv-PPA and typical clinical AD are, however, distinct. In particular, these two syndromes differ on attention span measures, where auditory attention span is more impaired in lv-PPA than in AD and visuospatial span appears more impaired in AD than in lv-PPA. The neural basis of these span profiles, however, remains unclear. METHOD: Sixteen lv-PPA and 21 AD matched patients, and 15 education-matched healthy controls were recruited. All participants were assessed by a neurologist and completed a neuropsychological assessment that included the Wechsler Memory Scale-III Digit and Spatial Span tasks, and underwent a high-resolution structural brain MRI to conduct cortical thickness analyses. RESULTS: Patient groups were impaired on all span tasks compared to Controls. In addition, performance on Digit Span Forward (DSF) was significantly lower in the lv-PPA than the AD group, while Spatial Span Forward (SSF) was significantly lower in the AD than the lv-PPA group. No differences were found between patient groups on the Digit or Spatial Span Backward tasks. Neuroimaging analyses revealed that reduced DSF performance correlated to thinning of the left superior temporal gyrus in the lv-PPA group, whereas reduced SSF performance was related to bilateral precentral sulcus and parieto-occipital thinning in the AD group. Analyses of the backward span tasks revealed that reduced Spatial Span Backward (SSB) performance in the lv-PPA group related to cortical thinning of the left superior parietal lobule. CONCLUSIONS: This study demonstrates that while lv-PPA and AD commonly share the same underlying neuropathology, their span profiles are distinct and are mediated by divergent patterns of cortical degeneration. PMID- 27474917 TI - Electricity generation from defective tomatoes. AB - The United States faces a significant burden in treating 0.61billionkg of defective tomatoes (culls) every year. We present a proof-of-concept for generating electricity from culled tomatoes in microbial-electrochemical systems (MESs). This study delineates impedance behavior of the culled tomatoes in MESs and compares its impedance spectra with that of soluble substrates (dextrose, acetate, and wastewater). A series of AC and DC diagnostic tests have revealed the superior performance of the culled tomatoes compared to the pure substrates. Cyclic voltammetry results have indicated the active role of indigenous, diffusible redox-active pigments in the culled tomatoes on overall electricity production. Electrochemical impedance spectroscopy results have elucidated the role of peel and seed on the oxidation behavior of the culled tomatoes. PMID- 27474918 TI - Novel pyrazolo[3,4-d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line. AB - Some novel 6-substituted pyrazolo[3,4-d]pyrimidines 4, 5, 6a-d, 7a-c, 8 and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines 9a-c, 10a-c, 11, 12a,b, 13a-c and 14 were synthesized and characterized by spectral and elemental analyses. They were screened for their biological activity in vitro against Abl and Src kinases. Compounds 7a and 7b revealed the highest activity against both wild and mutant Abl kinases as well as the Src kinase and the leukemia K-562 cell line. They can be considered as new hits for further structural optimization to obtain better activity. PMID- 27474919 TI - Bioevaluation of sixteen ADMDP stereoisomers toward alpha-galactosidase A: Development of a new pharmacological chaperone for the treatment of Fabry disease and potential enhancement of enzyme replacement therapy efficiency. AB - A unique molecular library consisting of all sixteen synthetic ADMDP (1 aminodeoxy-DMDP) stereoisomers has been prepared and evaluated for inhibitory activity against alpha-Gal A, and ability to impart thermal stabilization of this enzyme. The results of this testing led us to develop a novel pharmacological chaperone for the treatment of Fabry disease. 3-Epimer ADMDP was found to be an effective pharmacological chaperone, able to rescue alpha-Gal A activity in the lymphoblast of the N215S Fabry patient-derived cell line, without impairment of cellular beta-galactosidase activity. When 3-epimer ADMDP was administered with rh-alpha-Gal A (enzyme replacement therapy) for the treatment of Fabry patient derived cell lines, improvements in the efficacy of rh-alpha-Gal A was observed, which suggests this small molecule can also provide clinical benefit of enzyme replacement therapy in Fabry disease. PMID- 27474920 TI - Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives. AB - Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction. We assessed the ability of the prepared calix [n]arene polyhydroxyamine derivatives to induce cytotoxicity in six cancer cell lines by performing cancer cell growth inhibition assays. Results demonstrated that compounds 3a-3d achieved IC50 values ranging from 1.6 MUM to 11.3 MUM. Among the different compounds, 3a and 3b exerted the strongest cytotoxic effect in inhibiting the growth of SKOV3 cells. In relation to the underlying mechanisms of cytotoxic effects, cell cycle analysis revealed that the exposure of SKOV3 cells to 3a induced cell cycle arrest in the G0/G1 phase, suggesting a reduction in DNA synthesis. Immunofluorescent staining indicated that the protein expression levels of caspase-3 and p53 in cells significantly increased, whereas that of Bcl-2 was effectively suppressed. Meanwhile, no significant changes in Bax were observed in SKOV3 cells. These results highlight that calixarene 3a can be further studied as a potential anticancer agent. PMID- 27474921 TI - Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication. AB - A structure-based virtual screening technique was applied to the study of the HCV NS3 helicase, with the aim to find novel inhibitors of the HCV replication. A library of ~450000 commercially available compounds was analysed in silico and 21 structures were selected for biological evaluation in the HCV replicon assay. One hit characterized by a substituted thieno-pyrimidine scaffold was found to inhibit the viral replication with an EC50 value in the sub-micromolar range and a good selectivity index. Different series of novel thieno-pyrimidine derivatives were designed and synthesised; several new structures showed antiviral activity in the low or sub-micromolar range. PMID- 27474922 TI - Substituted conformationally restricted guanidine derivatives: Probing the alpha2 adrenoceptors' binding pocket. AB - In this paper we report the design, synthesis and pharmacological evaluation of new N-substituted 2-amino-1,4-dihydroquinazolines, 2-amino-1,4 dihydropyridopyrimidines and 2-amino-4,5-dihydro-1,3-benzodiazepines as alpha2 adrenoceptors ligands. Computational studies show that the proposed substitutions and guanidine-containing ring size will probe an extensive area of the active site. Preparation of these molecules involved novel routes than those previously utilised in our laboratory for the preparation of the acyclic aryl-guanidine counterparts. Compounds 8b and 18c showed the highest affinity and antagonistic activity, within their series, towards the alpha2-adrenoceptor in human brain tissue in vitro experiments. Structure-activity relationships have been established for the design and biological evaluation of novel alpha2-adrenoceptor ligands. PMID- 27474923 TI - Synthesis and biofilm formation reduction of pyrazole-4-carboxamide derivatives in some Staphylococcus aureus strains. AB - The ability of several N-phenyl-1H-pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl-N phenyl-1H-pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC50 ranging from 2.3 to 32 MUM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo by improving the survival of wax moth larva (Galleria mellonella) infected with S. aureus ATCC 29213. These findings indicate that 14d is a potential lead compound for the development of new anti-virulence agents against S. aureus infections. PMID- 27474924 TI - Synthesis, anticancer activity and photostability of novel 3-ethyl-2-mercapto thieno[2,3-d]pyrimidin-4(3H)-ones. AB - Some derivatives of 3-ethyl-2-mercapto-thieno[2,3-d]pyrimidin-4(3H)-ones were synthesized using ethyl 2-aminothiophene-3-carboxylates as precursors in order to estimate their cytotoxicity, respectively proliferative activity. Thienopyrimidinones containing thiosemicarbazide as well as 1,3,4-thiadiazole moieties were evaluated for their cytotoxical effect on four cancer cell lines: HT-29, breast cancer cells MDA-MB-231, HeLa, HepG2 as well as human diploid cell line Lep-3. Compounds 5b, 6a and 6b revealed cytotoxicity to the four studied cancer cell lines. The highst cytotoxicity against MDA-MB-31 exhibited the thiosemicarbazide 5b with IC50 2.31.10(-4) MUM, but most active towards HT-29 cell lines was thienopyrimidine 6c with IC50 0.001 MUM. Compound 6a showed the highest inhibitory activity with IC50 - 0.99 MUM to human liver carcinoma HepG2 cells and low cytotoxicity towards Lep3 (IC50 = 191 MUM). The thienopyrimidine derivative linked to thiadiazole 6b was toxic to the four studied cancer cell lines, especially to HeLa (IC50-0.83 MUM), and besides that the compound demonstrated toxicity to Lep 3 cells at very high concentration 89 * 10(3) MUM. The solid-state photostability of the derivatives 5a-c and 6a-c was tested by irradiation with UV light. All of the studied compounds show solid-state photostability in 240 min of irradiation. Using MOE software molecular docking of the three ligands 5b, 6b and 7 was accomplished into an internal pocket formed by the activation segment and the P-loop of (V599E)B-Raf. It was established that the binding of the ligands to (V599E)B-Raf promotes an inactive conformation of the enzyme. PMID- 27474925 TI - Design, synthesis and biological evaluation of novel 4-arylaminopyrimidine derivatives possessing a hydrazone moiety as dual inhibitors of L1196M ALK and ROS1. AB - A series of 4-arylaminopyrimidine derivatives possessing a hydrazone moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against ALK-addicted KARPAS299 and ROS1-addicted HCC78, while also showing much less potent activity against A549, H460 and HT-29, whose growth were not dependent on ALK and/or ROS1, as compared with crizotinib and ceritinib. The most promising compound, 7b, showed high antiproliferative effects on ALK-addicted KARPAS299 and ROS1-addicted HCC78 cell lines with IC50 of 20 nM and 28 nM, respectively, but showed no inhibitory activity against A549, H460 and HT-29. The enzymatic assay identified 7b as a potent and selective ALK and ROS1 dual inhibitor with IC50 of 2.5 nM and 2.7 nM, respectively. It also exhibited good inhibitory activity against the L1196M ALK with an IC50 value of 67 nM. PMID- 27474926 TI - Synthesis and immunopotentiating activity of novel isoxazoline functionalized coumarins. AB - A novel series (13) of isoxazoline functionalized coumarins was synthesized through 1,3-dipolar cyclization of nitrile oxides with Allylated coumarins. Synthesis of effective and target selective immunostimulators through conjugation of diversely substituted isoxazolines and 7-hydroxycoumarins is the focus of the present article. The proposed synthetic scheme was observed to be highly regiospecific yielding attempted conjugates in good yield (>90%). Kinetic resolution of the racemates was carried out by employing lipase B from Candida antarctica (CALB). The synthesized compounds were screened in vitro and in vivo for their biological activities viz. toxicity and impact on splenocyte proliferation (T- and B-cell proliferation), antibody production (HA titre), delayed-type hypersensitivity reaction (DTH), T-cell subtypes (CD4 and CD8), cytokine production (IL-2, IFN-gamma, and IL-4) and NO (macrophage) production. Our results establish that isoxazoline functionalized coumarins exhibit excellent immune potentiating activity especially compounds 2, 4 and 8 whose activity is more than that of Levimasole as standard. The structure activity relations are explained in light of the structural/functional aspects of tested compounds. To the best of our knowledge the presented work is first of its kind and is presaged to prove very useful for the design and synthesis of bis-heterocycle based novel, therapeutically selective and effective immunopotentiators. PMID- 27474927 TI - Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2 a]pyridines derivatives as protein kinase inhibitors. AB - We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2 bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC50 of 0.7 MUM) and DYRK1A (IC50 of 2.6 MUM). PMID- 27474928 TI - Design, synthesis and evaluation of novel potent angiotensin II receptor 1 antagonists. AB - A series of new angiotensin II (Ang II) receptor 1 antagonists were designed, synthesized and evaluated. All compounds showed nanomolar affinities for the angiotensin II type 1 receptor in radioligand binding assays and could reduce blood pressure significantly in spontaneously hypertensive rats(SHRs). From which, compound 2b displayed higher affinity binding to angiotensin II type 1 receptor at the same order of magnitude to irbesartan with an IC50 value of 1.26 +/- 0.08 nM in radioligand binding assays. 2b showed an efficient and long lasting effect in reducing blood pressure, the maximal reducing responses were 40.62 +/- 4.08 mmHg of MBP at 15 mg/kg and 28.39 +/- 2.09 mmHg at 10 mg/kg in SHRs, 39.56 +/- 4.83 mmHg at 15 mg/kg and 29.05 +/- 2.20 mmHg at 10 mg/kg in RHRs, the significant antihypertensive effect lasted beyond 12 h both in SHRs and in RHRs. In the single-dose pharmacokinetic experiments, compound 2b could be absorbed efficiently and metabolized smoothly in Wistar rats after oral administration. The values of Cmax, Tmax, AUC0-72 and MRT0-72 were 885.61 +/- 432.7 ng/mL, 5.67 +/- 1.51 h, 6110.28 +/- 7398.33 ng/mL h and 7.87 +/- 2.30 h at 10 mg/kg, 2945.55 +/- 1543.67 ng/mL, 4.33 +/- 0.82 h, 26473.62 +/- 12217.16 ng/mL h and 10.24 +/- 6.94 h at 15 mg/kg, 5759.03 +/- 1331.75 ng/mL, 5 +/- 1.10 h, 89488.44 +/- 18413.15 ng/mL.h and 12.89 +/- 2.0 h at 30 mg/kg respectively. The T1/2 values of the three groups were similar, about 9-10 h. Compound 2b was distributed into tissues rapidly and extensively after oral administration. The level of it was the highest in the liver, followed by in spleen, kidney, and the lowest in brain. The acute toxicity assays of 2b proved its low acute toxicity with an LD50 value of 1551.71 mg/kg, and no toxicity reaction appeared at dose of 1200.00 mg/kg. These encouraging results make compound 2b an effective, long lasting and safe anti-hypertensive drug candidate and worthy of further investigation. PMID- 27474929 TI - In vitro and in vivo studies of the antineoplastic activity of copper (II) compounds against human leukemia THP-1 and murine melanoma B16-F10 cell lines. AB - We investigated the antineoplastic activities of a previously reported copper (II) coordination compound, [Cu(BMPA)Cl2]CH3OH (1), and a new compound, [Cu(HBPA)Cl2]H2O (2), where BMPA is bis(pyridin-2-ylmethyl)amine and HBPA is (2 hydroxybenzyl)(2-pyridylmethyl)amine, using various cellular models of human leukemia (THP-1, U937, HL60, Molt-4, JURKAT) and human colon cancer (COLO 205), as well as a murine highly metastatic melanoma (B16-F10) cell line. Compound (2) was characterized using several physical and chemical techniques, including X-ray diffraction studies. The IC50 values of the copper coordination complexes in the human leukemia cell lines ranged from 87.63 +/- 1.02 to >=400 MUM at high cell concentrations and from 19.17 +/- 1.06 to 97.67 +/- 1.23 MUM at low cell concentrations. Both compounds induced cell death, which was determined by cell cycle analyses and phosphatidylserine exposure studies. THP-1 cells released cytochrome c to the cytoplasm 12 h after treatment with 400 MUM of compound (2). To evaluate the apoptosis pathway induced by compound (2), we measured the activities of initiator caspases 8 and 9 and executioner caspases 3 and 6. The results were suggestive of the activation of both intrinsic and extrinsic apoptosis pathways. To investigate the activities of the compounds in vivo, we selected two sensitive cell lines from leukemia (THP-1) and solid tumor (B16-F10) lineages. BALB/c nude bearing THP-1 tumors treated with 12 mg.kg(-1) of compound (2) showed a 92.4% inhibition of tumor growth compared with the control group. PMID- 27474930 TI - beta-Ionone and its analogs as promising anticancer agents. AB - beta-Ionone is an end-ring analog of beta-carotenoids which widely distributed in fruit and vegetables. Recent studies have demonstrated anti-proliferative, anti metastatic and apoptosis induction properties of beta-ionone in vitro and in vivo. Also, the studies have focused on investigating the beta-ionone action on different types of malignant cells and the possible mechanisms of action. Moreover, the quest of new synthetic beta-ionone-based compounds possessing anti proliferative, anti-metastatic and apoptosis induction activities may enable the discovery of compounds which can be used in combination regimes thus overcoming tumor resistance to conventional anticancer agents. These new agents will also be useful for targeting distinct signaling pathways, to activate selectively mechanisms for apoptosis in cancer cells but devoid of undesirable side effects. In this paper, we reviewed the potentialities of beta-ionone and related compounds in cancer prevention and chemotherapy. PMID- 27474931 TI - Selenoureido-iminosugars: A new family of multitarget drugs. AB - Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of beta glucosidase, Ki = 1.6-5.5 MUM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Ki up to 5.8 MUM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2 (Kcat/Kuncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders. PMID- 27474932 TI - Prevalence of low birth weight, macrosomia and stillbirth and their relationship to associated maternal risk factors in Hohoe Municipality, Ghana. AB - INTRODUCTION: birth weight is vital to the development potential of the newborn. Abnormal birth weight (such as low birth weight and macrosomia) is an important determinant of child survival, disabilities, stunting, and long-term adverse consequences for the onset of non-communicable diseases in the life course and therefore demands appropriate public health interventions. Stillbirths are also considered one of the most important, but most poorly understood and documented adverse outcomes of pregnancy. Therefore, this study aimed to assess the prevalence of abnormal birth weight and related maternal risk factors, as well as pregnancy outcomes, such as stillbirth. METHODS: a retrospective study design was used to analyze 4262 delivery records for singleton pregnancies from January 2013 to December 2014 seen at the Hohoe municipal hospital, Volta region in Ghana. The data on birth weight and related factors were derived from the delivery book. Data was analyzed using STATA. Multinomial logistic regression was used to assess the association between maternal factors such as parity, age and intermittent preventive treatment of malaria, sex of infant and abnormal birth weight. Association between stillbirth and related factors was assessed using logistic regression. RESULTS: prevalence of low birth weight (<2.5kg) was 9.69% and macrosomia (>=4.0kg) was 3.03%. There was an increased risk of a first born being of low birth weight than second or third born (RR; 2.04, CI; 1.59-2.64, p<0.0001). There were also an increased risks of mothers <20 years giving birth to low-birthweight infants (RR; 1.46, CI; 1.11-1.93, p=0.007) compared to mothers who were within the age ranges of 20-30 years and also among those who took only one (RR; 1.57, CI; 1.02-2.39, p=0.039) or no intermittent preventive treatment for malaria during pregnancy (RR; 1.57, CI; 1.24-1.98, p=<0.0001) compared to those who took three doses. Risk of macrosomic birth was particularly high among 5th born (RR; 2.66, CI; 1.43-4.95, p=0.002) compared to first or second born. Stillbirth rate was 27/1000 births. Thirty-two percent of the stillbirths (n=38) had low birth weight whereas 6.8% (n=8) were macrosomic. There was a greater than fivefold (AOR; 5.6, CI; 3.6-8.7) and greater than twofold (AOR; 2.4, CI; 1.1-5.3, p=0.025) increase in odds for stillbirth among low birth weight and macrosomic infants respectively. CONCLUSION: macrosomia and low birth weight co-existed among infants in Hohoe municipality, both of which are associated with adverse pregnancy outcome such as stillbirth. Given the apparent association between maternal age <20 years and increased risk, health promotion strategies aimed at preventing pregnancies among teenagers could be implemented to aid the reduction of stillbirth rates. PMID- 27474933 TI - Genome-wide analysis of the fructose 1,6-bisphosphate aldolase (FBA) gene family and functional characterization of FBA7 in tomato. AB - Fructose 1,6-bisphosphate aldolase (FBA) is a key enzyme in plants that is involved in glycolysis, gluconeogenesis, and the Calvin cycle. FBA genes play significant roles in biotic and abiotic stress responses and also regulate growth and development. Despite the importance of FBA genes, little is known about it in tomato. In this study, we identified 8 FBA genes in tomato and classified them into 2 subgroups based on a phylogenetic tree, gene structures, and conserved motifs. Five (SlFBA1, 2, 3, 4 and 5) and three (SlFBA6, 7, and 8) SlFBA proteins were predicted to be localized in chloroplasts and cytoplasm, respectively. The phylogenetic analysis of FBAs from tomato, Arabidopsis, rice, and other organisms suggested that SlFBA shared the highest protein homology with FBAs from other plants. Synteny analysis indicated that segmental duplication events contributed to the expansion of the tomato FBA family. The expression profiles revealed that all SlFBAs were involved in the response to low and high temperature stresses. SlFBA7 overexpression increased the expression and activities of other main enzymes in Calvin cycle, net photosynthetic rate (Pn), seed size and stem diameter. SlFBA7 overexpression enhanced tolerances in seed germination under suboptimal temperature stresses. Taken together, comprehensive analyses of SlFBAs would provide a basis for understanding of evolution and function of SlFBA family. PMID- 27474934 TI - Comparison of polyamine metabolism in tomato plants exposed to different concentrations of salicylic acid under light or dark conditions. AB - In this study the effect of exogenous 0.1 mM and 1 mM salicylic acid (SA) treatments were investigated on polyamine (PA) metabolism in tomato (Solanum lycopersicum L. cv. Ailsa Craig) leaves in illuminated or dark environments. The former proved to be sublethal and the latter lethal concentration for tomato leaf tissues. While PA biosynthetic genes, arginine- and ornitine decarboxylases or spermidine- and spermine synthases were highly up-regulated by 1 mM SA, the enzymes participating in PA catabolism, diamine- (DAOs, EC 1.4.3.6) and polyamine oxidases (PAOs, EC 1.5.3.3) displayed higher transcript abundance and enzyme activity at 0.1 mM SA. As a result, putrescine and spermine content but not that of spermidine increased after 1 mM SA application, which proved to be higher in the dark than in the light. H2O2 content produced on the effect of 1 mM SA was significantly higher than at 0.1 mM SA in the light. Since there was no coincidence between H2O2 accumulation and terminal PA catabolism, reactive oxygen species produced by photosynthesis and by other sources had more pronounced effect on H2O2 generation at tissue level than DAOs and PAOs. Accordingly, H2O2 in the absence of NO accumulation contributed to the initiation of defence reactions after 0.1 mM SA treatment, while high SA concentration generated simultaneous increase in H2O2 and NO production in the light, which induced cell death within 24 h in illuminated leaves. However, the appearance of necrotic lesions was delayed in the absence of NO if these plants were kept in darkness. PMID- 27474935 TI - RPN1a negatively regulates ABA signaling in Arabidopsis. AB - The 26S proteasome selectively regulates key abscisic acid (ABA) signaling proteins, but the physiological functions and mechanisms of RPN1a (a subunit of the 26S proteasome) in ABA signaling remain largely unknown. In this study, we found that the mRNA expression of RPN1a was suppressed by ABA treatment, and that RPN1a protein was expressed abundantly in guard cells. In the presence of ABA, rpn1a mutants showed rapid stomatal closure, low water loss, delayed germination, and inhibited root elongation. In addition, the transcripts of key ABA signaling genes, including ABI5, RD22, RD29A, and RD29B, were upregulated in rpn1a mutant plants in response to ABA. Furthermore, the ABI5 protein level was higher in rpn1a mutants subjected to ABA treatment. Yeast two-hybrid and bimolecular fluorescence complementation assays showed that RPN1a interacts with ABI1. Overall, these findings suggest that RPN1a negatively regulates ABA signaling in Arabidopsis. PMID- 27474936 TI - Identification and validation of reference genes for quantitative real-time PCR studies in Hedera helix L. AB - Reference gene evaluation and selection are necessary steps in gene expression analysis, especially in new plant varieties, through reverse transcription quantitative real-time PCR (RT-qPCR). Hedera helix L. is an important traditional medicinal plant recorded in European Pharmacopoeia. Research on gene expression in H. helix has not been widely explored, and no RT-qPCR studies have been reported. Thus, it is important and necessary to identify and validate suitable reference genes to for normalizing RT-qPCR results. In our study, 14 candidate protein-coding reference genes were selected. Their expression stability in five tissues (root, stem, leaf, petiole and shoot tip) and under seven abiotic stress conditions (cold, heat, drought, salinity, UV-C irradiation, abscisic acid and methyl jasmonate) were evaluated using geNorm and NormFinder. This study is the first to evaluate the stability of reference genes in H. helix. The results show that different reference genes should be chosen for normalization on the basis of various experimental conditions. F-box was more stable than the other selected genes under all analysis conditions except ABA treatment; 40S was the most stable reference gene under ABA treatment; in contrast, EXP and UBQ were the most unstable reference genes. The expressions of HhSE and Hhbeta-AS, which are two genes related to the biosynthetic pathway of triterpenoid saponins, were also examined for reference genes in different tissues and under various cold stress conditions. The validation results confirmed the applicability and accuracy of reference genes. Additionally, this study provides a basis for the accurate and widespread use of RT-qPCR in selecting genes from the genome of H. helix. PMID- 27474937 TI - APOE epsilon4 allele modifies the association of lead exposure with age-related cognitive decline in older individuals. AB - BACKGROUND: Continuing chronic and sporadic high-level of lead exposure in some regions in the U.S. has directed public attention to the effects of lead on human health. Long-term lead exposure has been associated with faster cognitive decline in older individuals; however, genetic susceptibility to lead-related cognitive decline during aging has been poorly studied. METHODS: We determined the interaction of APOE-epsilon variants and environmental lead exposure in relation to age-related cognitive decline. We measured tibia bone lead by K-shell-x-ray fluorescence, APOE-epsilon variants by multiplex PCR and global cognitive z scores in 489 men from the VA-Normative Aging Study. To determine global cognitive z-scores we incorporated multiple cognitive assessments, including word list memory task, digit span backwards, verbal fluency test, sum of drawings, and pattern comparison task, which were assessed at multiple visits. We used linear mixed-effect models with random intercepts for individual and for cognitive test. RESULTS: An interquartile range (IQR:14.23MUg/g) increase in tibia lead concentration was associated with a 0.06 (95% confidence interval [95%CI]: -0.11 to -0.01) lower global cognition z-score. In the presence of both epsilon4 alleles, one IQR increase in tibia lead was associated with 0.57 (95%CI: -0.97 to -0.16; p-value for interaction: 0.03) lower total cognition z-score. A borderline association was observed in presence of one epsilon4 allele (Estimate-effect per 1-IQR increase: -0.11, 95%CI: -0.22, 0.01) as well as lack of association in individuals without APOE epsilon4 allele. CONCLUSIONS: Our findings suggest that individuals carrying both epsilon4 alleles are more susceptible to lead impact on global cognitive decline during aging. PMID- 27474938 TI - Triclosan activates aryl hydrocarbon receptor (AhR)-dependent apoptosis and affects Cyp1a1 and Cyp1b1 expression in mouse neocortical neurons. AB - Triclosan (TCS) is an antimicrobial agent that is used extensively in personal care and in sanitizing products, such as soaps, toothpastes, and hair products. A number of studies have revealed the presence of TCS in human tissues, such as fat, liver and brain, in addition to blood and breast milk. The aim of the present study was to investigate the impact of TCS on AhR and Cyp1a1/Cyp1b1 signaling in mouse neocortical neurons in primary cultures. In addition to the use of selective ligands and siRNAs, expression levels of mRNA and proteins as well as caspase-3 activity, reactive oxygen species (ROS) formation, and lactate dehydrogenase (LDH) release have been measured. We also studied the involvement of the AhR in TCS-induced LDH release and caspase-3 activation as well as the effect of TCS on ROS generation. Cultures of neocortical neurons were prepared from Swiss mouse embryos on day 15/16 of gestation. The cells were cultured in phenol red-free Neurobasal medium with B27 and glutamine, and the neurons were exposed to 1 and 10uM TCS. Our experiments showed that the expression of AhR and Cyp1a1 mRNA decreased in cells exposed to 10uM TCS for 3 or 6h. In the case of Cyp1b1, mRNA expression remained unchanged compared with the control group following 3h of exposure to TCS, but after 6h, the mRNA expression of Cyp1b1 was decreased. Our results confirmed that the AhR is involved in the TCS mechanism of action, and our data demonstrated that after the cells were transfected with AhR siRNA, the cytotoxic and pro-apoptotic properties of TCS were decreased. The decrease in Cyp1a1 mRNA and protein expression levels accompanied by a decrease in its activity. The stimulation of Cyp1a1 activity produced by the application of an AhR agonist (betaNF) was attenuated by TCS, whereas the addition of AhR antagonist (alphaNF) reversed the inhibitory effects of TCS. In our experiments, TCS diminished Cyp1b1 mRNA and enhanced its protein expression. In case of Cyp1a1 we observed paradoxical effect of TCS action, which caused the decrease in activity and protein expression of Cyp1a1 and the increase in protein level of AhR. Therefore, we determined the effects of TCS on the production of ROS. Our results revealed that TCS increased the production of ROS and that this effect of TCS was reversed by 10uM N-acetyl-L-cysteine (NAC), the ROS scavenger. To confirm an involvement of ROS in TCS-induced neurotoxicity we measured AhR, Cyp1a1, and Cyp1b1 mRNA expression levels in cells co-treated with TCS and NAC. In the presence of NAC, TCS enhanced mRNA expression of the cytochromes and AhR at 3 and 6h, respectively. We postulate that TCS exhibits primary and secondary effects. The primary effects such as impairment of Cyp1a1 signaling are mediated by TCS induced ROS production, whereas secondary effects of TCS are due to transcriptional activity of AhR and estrogenic properties of TCS. PMID- 27474939 TI - Biofouling control: Bacterial quorum quenching versus chlorination in membrane bioreactors. AB - Biofilm formation (biofouling) induced via cell-to-cell communication (quorum sensing) causes problems in membrane filtration processes. Chorine is one of the most common chemicals used to interfere with biofouling; however, biofouling control is challenging because it is a natural process. This study demonstrates biofouling control for submerged hollow fiber membranes in membrane bioreactors by means of bacterial quorum quenching (QQ) using Rhodococcus sp. BH4 with chemically enhanced backwashing. This is the first trial to bring QQ alongside chlorine injection into practice. A high chlorine dose (100 mg/L as Cl2) to the system is insufficient for preventing biofouling, but addition of the QQ bacterium is effective for disrupting biofouling that cannot be achieved by chlorination alone. QQ reduces the biologically induced metal precipitate and extracellular biopolymer levels in the biofilm, and biofouling is significantly delayed when QQ is applied in addition to chlorine dosing. QQ with chlorine injection gives synergistic effects on reducing physically and chemically reversible fouling resistances while saving substantial filtration energy. Manipulating microbial community functions with chemical treatment is an attractive tool for biofilm dispersal in membrane bioreactors. PMID- 27474940 TI - Nutrient reduction magnifies the impact of extreme weather on cyanobacterial bloom formation in large shallow Lake Taihu (China). AB - Cyanobacterial bloom formation is dependent on nutrient levels and meteorological conditions. In this study, we elucidated the effects of extreme weather events (EWEs, heavy rainfall and strong winds) on the cyanobacterial blooms in Lake Taihu in recent years based on an analysis of the meteorological, nutrient, and bloom area data from 2007 to 2015. The levels of total phosphorus (TP) and total nitrogen (TN) decreased by 42.5% and 31.2%, respectively, in the water of Lake Taihu over the past nine years. However, the frequency and intensity of cyanobacterial blooms did not significantly decrease. A total of 50.5% of the extended blooms (>300 km(2)) were associated with EWEs from 2007 to 2015, 36.2% of which were due to heavy rainfall and 38.3% of which were due to strong winds (25.5% were due to both). Interestingly, the frequency of the EWE-induced extended blooms significantly increased after 2012. Principal component analysis (PCA) showed that this frequency correlated positively with EWE-induced nutrient increases in the water, indicating that the complement from nutrient increases induced by EWE allow cyanobacterial cells to reach high biomass under relatively low nutrient condition. Our results suggest that EWEs play a more important role in extended bloom formation after the nutrient levels in shallow lakes are reduced. PMID- 27474941 TI - Enhanced GSH synthesis by Bisphenol A exposure promoted DNA methylation process in the testes of adult rare minnow Gobiocypris rarus. AB - DNA methylation is a commonly studied epigenetic modification. The mechanism of BPA on DNA methylation is poorly understood. The present study aims to explore whether GSH synthesis affects DNA methylation in the testes of adult male rare minnow Gobiocypris rarus in response to Bisphenol A (BPA). Male G. rarus was exposed to 1, 15 and 225MUgL(-1) BPA for 7 days. The levels of global DNA methylation, hydrogen peroxide (H2O2) and glutathione (GSH) in the testes were analyzed. Meanwhile, the levels of enzymes involved in DNA methylation and de novo GSH synthesis, and the substrate contents for GSH production were measured. Furthermore, gene expression profiles of the corresponding genes of all studied enzymes were analyzed. Results indicated that BPA at 15 and 225MUgL(-1) caused hypermethylation of global DNA in the testes. The 15MUgL(-1) BPA resulted in significant decrease of ten-eleven translocation proteins (TETs) while 225MUgL( 1) BPA caused significant increase of DNA methyltransferase proteins (DNMTs). Moreover, 225MUgL(-1) BPA caused significant increase of H2O2 and GSH levels, and the de novo GSH synthesis was enhanced. These results indicated that the significant decrease of the level of TETs may be sufficient to cause the DNA hypermethylation by 15MUgL(-1) BPA. However, the significantly increased of DNMTs contributed to the significant increase of DNA methylation levels by 225MUgL(-1) BPA. Moreover, the elevated de novo GSH synthesis may promote the DNA methylation process. PMID- 27474942 TI - Alterations in the intestine of Patagonian silverside (Odontesthes hatcheri) exposed to microcystin-LR: Changes in the glycosylation pattern of the intestinal wall and inhibition of multidrug resistance proteins efflux activity. AB - Accumulation and toxicity of cyanobacterial toxins, particularly microcystin-LR (MCLR) have been extensively studied in fish and aquatic invertebrates. However, MCLR excretion mechanisms, which could reduce this toxin's effects, have received little attention. The Patagonian silverside, Odontesthes hatcheri, is an omnivorous-planktivorous edible fish, which has been shown to digest cyanobacterial cells absorbing MCLR and eliminating the toxin within 48h without suffering significant toxic effects. We studied the effects of MCLR on glycoconjugate composition and the possible role of multidrug resistance associated proteins (Abcc) in MCLR export from the cells in O. hatcheri intestine. We treated O. hatcheri with 5MUg MCLRg(-1) body mass administered with the food. Twenty four hours later, the intestines of treated and control fish were processed for lectin-histochemistry using concanavalin A (ConA), Triticum vulgaris agglutinin (WGA), and Dolichos biflorus agglutinin (DBA). MCLR affected the distribution of glycoconjugates by augmenting the proportion of ConA-positive at the expense of WGA-positive cells. We studied MCLR effects on the transport of the Abcc-like substrates 2,4-dinitrophenyl-S-glutathione (DNP-SG) and calcein in ex vivo intestine preparations (everted and no-everted sacs and strips). In treated preparations, CDNB together with MCLR (113MUg MCLRg(-1) intestine, equivalent to 1.14MUmolL(-1) when applied in the bath) or the Abcc inhibitor, MK571 was applied for one hour, during which DNP-SG was measured in the bath every 10min in order to calculate mass-specific DNP-SG transport rate. MCLR significantly inhibited DNP-SG transport (p<0.05), especially in middle intestine (47 and 24%, for luminal and serosal transport, respectively). In middle intestine strips, MCLR and MK571inhibited DNP-SG transport in a concentration dependent fashion (IC50 3.3 and 0.6MUmolL(-1), respectively). In middle intestine strips incubated with calcein-AM (0.25MUmolL(-1)), calcein efflux was inhibited by MCLR (2.3MUmolL(-1)) and MK571 (3MUmolL(-1)) by 38 and 27%, respectively (p<0.05). Finally, middle intestine segments were incubated with different concentrations of MCLR applied alone or together with 3MUM MK571. After one hour, protein phosphatase 1 (PP1) activity, the main target of MCLR, was measured. 2.5MUM MCLR did not produce any significant effect, while the same amount plus MK571 inhibited PP1 activity (p<0.05). This effect was similar to that of 5MUM MCLR. Our results suggest that in O. hatcheri enterocytes MCLR is conjugated with GSH via GST and then exported to the intestinal lumen through Abcc-like transporters. This mechanism would protect the cell from MCLR toxicity, limiting toxin transport into the blood, which is probably mediated by basolateral Abccs. From an ecotoxicological point of view, elimination of MCLR through this mechanism would reduce the amount of toxin available for trophic transference. PMID- 27474943 TI - The effect of using an abdominal binder on postoperative gastrointestinal function, mobilization, pulmonary function, and pain in patients undergoing major abdominal surgery: A randomized controlled trial. AB - BACKGROUND: Evidence on the effectiveness of using a binder following abdominal surgery and its effect on gastrointestinal function, mobilization, pulmonary function, and pain is currently unclear. OBJECTIVE: The purpose of this study is to determine the effect of abdominal binder usage on gastrointestinal function, mobilization, pulmonary function, and postoperative pain in patients undergoing major abdominal surgery. DESIGN: This research was conducted as a randomized controlled trial. SETTINGS: The study was conducted at the Department of General Surgery at a military education and research hospital in Ankara, Turkey, between September 2013 and April 2014. PARTICIPANTS: 104 patients were assessed for eligibility. The study was conducted on 84 eligible patients. METHODS: The study sample consisted of 84 patients who underwent effective major abdominal surgery. The patients were randomized into two groups, the intervention group, which used an abdominal binder and the control group, which did not. Gastrointestinal function, mobilization, pulmonary function, and the pain status of both groups were evaluated on the first, fourth, and seventh days before and after surgery, and the intergroup results were compared. RESULTS: No significant difference was found between the two groups in terms of gastrointestinal and pulmonary function on the first, fourth, and seventh days following surgery (p>0.05). A comparative assessment of mobility by walking distance showed that patients in the intervention group were able to walk further on the fourth [mean (SD); 221.19 (69.08) m] and seventh [227.85 (60.02) m] days after surgery (p=0.003, p<0.001). There were differences in the acute pain status between patients in both groups (p<0.05). On the first [mean (SD); 8.80 (5.03)], fourth [4.83 (2.78)], and seventh [3.09 (3.17)] days after surgery, the sensory sub-scale pain scores were higher in the control group (p<0.001). On the first [mean (SD); 10.16 (6.14)], fourth [5.28 (3.52)], and seventh [3.30 (3.51)] days after surgery the total pain scores were higher in the control group (p<0.001). The visual analogue scale scores were also higher in the control group on the first [mean (SD) 6.26 (1.86)], fourth [4.50 (2.10)], and seventh [3.04 (2.43)] days after surgery (p<0.001). CONCLUSION: The study's findings reveal that the use of an abdominal binder does not have any effect on postoperative gastrointestinal and pulmonary function. However, an abdominal binder increases patient mobility soon after surgery. There was also a measurable effect on pain, with lower scores reported by patients who used an abdominal binder after any exercise or activity. These results indicate that the use of a routine abdominal binder is helpful for patients undergoing major abdominal surgery. PMID- 27474944 TI - Efficacy and safety of repeated oral sucrose for repeated procedural pain in neonates: A systematic review. AB - BACKGROUND: Although sucrose is most extensively examined for its analgesia effect on a single procedural pain, neonates in neonatal intensive care units can be exposed to numerous painful procedures every day requiring multiple doses of sucrose. Some experiments have been performed to examine the efficacy and safety of repeated sucrose administration for repeated procedural pain; however, a systematic review of this topic has not yet been carried out. OBJECTIVE: To identify and assess the evidence demonstrating the efficacy and safety of repeated sucrose for repeated procedural pain in neonates. METHOD: A systematic review was conducted using the Cochrane methodology. Pubmed, Cochrane Library, Web of Science, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CBMdisc, CNKI, VIP, and Wanfang databases were searched through December 2015. All related abstracts were reviewed and the full texts of relevant articles were studied. Randomized controlled trials (RCTs) were included. Risk of bias was assessed for RCTs using quality critical appraisal criteria recommended by Cochrane Handbook. A standardised data form was used to extract information. RESULTS: Eight RCTs met our inclusion criteria. Different study designs were used in the included RCTs, which did not allow us to carry out a meta-analysis. The findings from this review indicated that repeated sucrose was effective in reducing both behavioral pain response and composite pain scores during repeated procedural pain. However, as for physiological pain response, one trial found less variability in physiological pain response for term neonates in the sucrose group than the sterile water group, while two trials demonstrated repeated sucrose was inefficacious for preterm neonates. Regarding the clinical outcomes, no study reported adverse effects related to the repeated sucrose administration. Regarding the neurobehavioral development, two trials reported repeated sucrose for repeated procedural pain would not lead to poor neurologic development, while one trial reported that preterm infants <31 weeks' gestational age who received >10 doses of sucrose per 24h in the first week of life had poorer neurologic development compared with infants who received fewer sucrose doses. What's more, no study reported the long-term neurobehavioral development outcome of neonates who repeatedly received sucrose across repeated procedural pain. CONCLUSION: Evidence regarding the efficacy and safety of repeated sucrose across repeated procedural pain for neonates is limited. More prospective, multi-centered, large randomized controlled clinical trials with a standardised study design are required before sucrose can be recommended widely as an analgesia for repeated procedural pain in neonates. PMID- 27474945 TI - Pharmacokinetics of homoplantaginin in rats following intravenous, peritoneal injection and oral administration. AB - The purpose of the present paper was to study the pharmacokinetic characteristics of homoplantaginin, a major active ingredient of Salvia plebeia R.Br. In this study, the effective partition coefficient, in situ absorption in rat intestinal segments and in vitro biotransformation of homoplantaginin by rat intestinal bacteria were determined. In addition, homoplantaginin was administered to rats by intravenous, peritoneal injection and oral administration. The concentrations of homoplantaginin and hispidulin, a metabolite of homoplantaginin, were determined by a validated highperformance liquid chromatographic (HPLC) assay. After intravenous, peritoneal injection, the concentration of hispidulin could not be determined. In contrast, after oral administration, hispidulin and homoplantaginin were simultaneous quantified, homoplantaginin was rapidly absorbed (Tmax=16.00+/-8.94min), reaching a mean Cmax between 0.77 and 1.27nmol/mL. The absolute oral bioavailability was calculated to be only 0.75%, and the area under curve (AUC) of hispidulin was about 5.4 times than that of homoplantaginin. The poor oral bioavailability may be attributed to the biotransformation of homoplantaginin by rat intestinal bacteria. PMID- 27474946 TI - Esterification of pseudoephedrine hydrochloride by citric acid in a solid dose pharmaceutical preparation. AB - Esterification of pseudoephedrine hydrochloride (PSE) by citric acid was observed in a solid dose pharmaceutical preparation at room temperature and accelerated stability condition (40 degrees C/75% relative humidity). The esterification of PSE with citric acid was confirmed by a solid-state binary reaction in the presence of minor level of water at elevated temperature to generate three isomeric esters. The structures of the pseudoephedrine citric acid esters were elucidated using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy (NMR). Occurrence of esterification in solid state, instead of amidation which is generally more favorable than esterification, is likely due to remaining HCl salt form of solid pseudoephedrine hydrochloride to protect its amino group from amidation with citric acid. In contrast, the esterification was not observed from solution reaction between PSE and citric acid. PMID- 27474947 TI - Recovery of ambulation activity across the first six months post-stroke. AB - Stroke survivors commonly adopt sedentary activity behaviours by the chronic phase of recovery. However, the change in activity behaviours from the subacute to chronic phase of stroke is variable. This study explored the recovery of ambulation activity (volume and bouts) at one, three and six months after hospital discharge post-stroke. A total of 42 stroke survivors were recruited at hospital discharge and followed up one, three and six months later. At follow-up, ambulation activity was measured over four days using the ActivPALTM accelerometer. Measures included volume of activity and frequency and intensity of ambulation activity bouts per day. Linear mixed effects modelling was used to determine changes over time. There was wide variation in activity. Total step counts across all time points were below required levels for health benefits (mean 4592 SD 3411). Most activity was spread across short bouts. While most number of bouts was of low intensity, most time was spent in moderate intensity ambulation across all time points. Daily step count and time spent walking and sitting/lying increased from one month to three and six months. The number of and time spent in short and medium duration bouts increased from one to six months. Time in long duration bouts increased at three months only. Time spent in moderate intensity ambulation increased over time. No change was observed for any other measures. In future, it would be valuable to identify strategies to increase engagement in activity behaviours to improve health outcomes after stroke. PMID- 27474948 TI - Exploring the feasibility and acceptability of sensor monitoring of gait and falls in the homes of persons with multiple sclerosis. AB - Gait parameters variability and falls are problems for persons with MS and have not been adequately captured in the home. Our goal was to explore the feasibility and acceptability of monitoring of gait and falls in the homes of persons with MS over a period of 30 days. To test the feasibility of measuring gait and falls for 30days in the home of persons with MS, spatiotemporal gait parameters stride length, stride time, and gait speed were compared. A 3D infrared depth imaging system has been developed to objectively measure gait and falls in the home environment. Participants also completed a 16-foot GaitRite electronic pathway walk to validate spatiotemporal parameters of gait (gait speed (cm/s), stride length (cm), and gait cycle time(s)) during the timed 25 foot walking test (T25FWT). We also documented barriers to feasibility of installing the in-home sensors for these participants. The results of the study suggest that the Kinect sensor may be used as an alternative device to measure gait for persons with MS, depending on the desired accuracy level. Ultimately, using in-home sensors to analyze gait parameters in real time is feasible and could lead to better analysis of gait in persons with MS. PMID- 27474949 TI - Motor-cognitive dual-task deficits in individuals with early-mid stage Huntington disease. AB - BACKGROUND: Huntington disease (HD) results in a range of cognitive and motor impairments that progress throughout the disease stages; however, little research has evaluated specific dual-task abilities in this population, and the degree to which they may be related to functional ability. OBJECTIVES: The purpose of this study was to a) examine simple and complex motor-cognitive dual-task performance in individuals with HD, b) determine relationships between dual-task walking ability and disease-specific measures of motor, cognitive and functional ability, and c) examine the relationship of dual-task measures to falls in individuals with HD. METHODS: Thirty-two individuals with HD were evaluated for simple and complex dual-task ability using the Walking While Talking Test. Demographics and disease-specific measures of motor, cognitive and functional ability were also obtained. RESULTS: Individuals with HD had impairments in simple and complex dual task ability. Simple dual-task walking was correlated to disease-specific motor scores as well as cognitive performance, but complex dual-task walking was correlated with total functional capacity, as well as a range of cognitive measures. Number of prospective falls was moderately-strongly correlated to dual task measures. CONCLUSIONS: Our results suggest that individuals with HD have impairments in cognitive-motor dual-task ability that are related to disease progression and specifically functional ability. Dual-task measures appear to evaluate a unique construct in individuals with early to mid-stage HD, and may have value in improving the prediction of falls risk in this population. PMID- 27474950 TI - Inhibition of influenza A virus matrix and nonstructural gene expression using RNA interference. AB - Influenza antiviral drugs that use protein inhibitors can lose their efficacy as resistant strains emerge. As an alternative strategy, we investigated the use of small interfering RNA molecules (siRNAs) by characterizing three siRNAs (M747, M776 and M832) targeting the influenza matrix 2 gene and three (NS570, NS595 and NS615) targeting the nonstructural protein 1 and 2 genes. We also re-examined two previously reported siRNAs, M331 and M950, which target the matrix 1 and 2 genes. Treatment with M331-, M776-, M832-, and M950-siRNAs attenuated influenza titer. M776-siRNA treated cells had 29.8% less infectious virus than cells treated with the previously characterized siRNA, M950. NS570-, NS595- and NS615-siRNAs reduced nonstructural protein 1 and 2 expression and enhanced type I interferon expression by 50%. Combination siRNA treatment attenuated 20.9% more infectious virus than single siRNA treatment. Our results suggest a potential use for these siRNAs as an effective anti-influenza virus therapy. PMID- 27474952 TI - Effects of sludge retention time on oxic-settling-anoxic process performance: Biosolids reduction and dewatering properties. AB - In this study, the effect of sludge retention time (SRT) on oxic-settling-anoxic (OSA) process was determined using a sequencing batch reactor (SBR) attached to external aerobic/anoxic reactors. The SRT of the external reactors was varied from 10 to 40d. Increasing SRT from 10 to 20d enhanced volatile solids destruction in the external anoxic reactor as evidenced by the release of nutrients, however, increasing the SRT to 40d did not enhance volatile solids destruction further. Relatively short SRT (10-20d) favoured the conversion of destroyed solids into inert products. The application of an intermediate SRT (20d) of the external reactor showed the highest sludge reduction performance (>35%). Moreover, at the optimum SRT, OSA improved sludge dewaterability as demonstrated by lower capillary suction time and higher dewatered cake solids content. PMID- 27474951 TI - Autophagic flux regulates microglial phenotype according to the time of oxygen glucose deprivation/reperfusion. AB - Microglial phenotype alternation is a potential novel pathogenic mechanism for cerebral ischemia. Cerebral ischemia induced autophagy aggravates inflammation and neural injury. However, the effect of autophagy in the modulation of microglial phenotype is still unknown. In this study, we investigated the role of autophagic flux in the alternation of microglial phenotype following oxygen glucose deprivation/reperfusion (OGD/R) in BV-2 cells. Inhibition of autophagic flux by NH4Cl exposure significantly increased the level of microtubule associated protein 1 light chain 3 (LC3)-II and p62 in control and OGD/R (12h, 24h and 48h) groups, but did not change their expression in OGD/R 72h group, indicating that autophagic flux was inhibited at OGD/R 72h. Once autophagic flux was inhibited at OGD/R 72h or at OGD/R 24h (with NH4Cl), BV-2 cells mainly showed M1 phenotype with increased tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and decreased M2 markers including interleukin-10 (IL-10), Arginase 1 (Arg-1), and brain derived neurotrophic factor (BDNF). Further study indicated that inhibition of autophagic flux activated NF-kappaB pathway and decreased the activity of cAMP-response element binding protein (CREB), which contributed to the alternation of microglial phenotype. Therefore, inhibition of autophagic flux regulated the alternation of microglial phenotype by modulating the balance between NF-kappaB and CREB. PMID- 27474953 TI - A hybrid cascade control scheme for the VFA and COD regulation in two-stage anaerobic digestion processes. AB - A hybrid (continuous-discrete) cascade control is proposed to regulate both, volatile fatty acids (VFA) and chemical oxygen demand (COD) concentrations in two stage (acidogenic-methanogenic) anaerobic digestion (TSAD) processes. The outer loop is a discrete controller that regulates the COD concentration of the methanogenic bioreactor by using a daily off-line measurement and that modifies the set-point tracked by inner loop, which manipulates the dilution rate to regulate the VFA concentration of the acidogenic bioreactor, estimated by continuous on-line conductivity measurements, avoiding acidification. The experimental validation was conducted in a TSAD process for the treatment of tequila vinasses during 110days. Results showed that the proposed cascade control scheme was able to achieve the VFA and COD regulation by using conventional measurements under different set-point values in spite of adverse common scenarios in full-scale anaerobic digestion processes. Microbial composition analysis showed that the controller also favors the abundance and diversity toward methane production. PMID- 27474954 TI - Pyrolysis process for the treatment of food waste. AB - Different waste materials were pyrolysed in the laboratory pyrolysis unit to the final temperature of 800 degrees C with a 10min delay at the final temperature. After the pyrolysis process a mass balance of the resulting products, off-line analysis of the pyrolysis gas and evaluation of solid and liquid products were carried out. The gas from the pyrolysis experiments was captured discontinuously into Tedlar gas sampling bags and the selected components were analyzed by gas chromatography (methane, ethene, ethane, propane, propene, hydrogen, carbon monoxide and carbon dioxide). The highest concentration of measured hydrogen (WaCe 61%vol.; WaPC 66%vol.) was analyzed at the temperature from 750 to 800 degrees C. The heating values of the solid and liquid residues indicate the possibility of its further use for energy recovery. PMID- 27474955 TI - Butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1 with high butyric acid yield and selectivity. AB - The aim of this work was to study the butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1. Results showed that Clostridium sp. S1 produced butyric acid by simultaneously utilizing glucose and mannose in softwood hydrolysate and, more remarkably, it consumed acetic acid in hydrolysate. Clostridium sp. S1 utilized each of glucose, mannose, and xylose as well as mixed sugars simultaneously with partially repressed xylose utilization. When softwood (Japanese larch) hydrolysate containing glucose and mannose as the main sugars was used, Clostridium sp. S1 produced 21.17g/L butyric acid with the yield of 0.47g/g sugar and the selectivity of 1 (g butyric acid/g total acids) owing to the consumption of acetic acid in hydrolysate. The results demonstrate potential of Clostridium sp. S1 to produce butyric acid selectively and effectively from hydrolysate not only by utilizing mixed sugars simultaneously but also by converting acetic acid to butyric acid. PMID- 27474956 TI - Biogas production from undiluted chicken manure and maize silage: A study of ammonia inhibition in high solids anaerobic digestion. AB - The feasibility of co-digestion of chicken manure (CM) and maize silage (MS) without water dilution was investigated in 5-L digesters. Specific methane production (SMP) of 0.309LCH4g(-1) volatile solids (VS) was achieved but only at lower %CM. Above a critical threshold for total ammonia nitrogen (TAN), estimated at 7gNL(-1), VFA accumulated with a characteristic increase in acetic acid followed by its reduction and an increase in propionic acid. During this transition the predominant methanogenic pathway was hydrogenotrophic. Methanogenesis was completely inhibited at TAN of 9gNL(-1). The low digestibility of the mixed feedstock led to a rise in digestate TS and a reduction in SMP over the 297-day experimental period. Methanogenesis appeared to be failing in one digester but was recovered by reducing the %CM. Co-digestion was feasible with CM ?20% of feedstock VS, and the main limiting factor was ammonia inhibition. PMID- 27474957 TI - Biodiesel production from crude jatropha oil catalyzed by immobilized lipase/acyltransferase from Candida parapsilosis in aqueous medium. AB - The lipase/acyltransferase from Candida parapsilosis (CpLIP2) immobilized on two synthetic resins (Accurel MP 1000 and Lewatit VP OC 1600) was used as catalyst for the production of biodiesel (fatty acid methyl esters, FAME) by transesterification of jatropha oil with methanol, in a lipid/aqueous system. The oil was dispersed in a buffer solution (pH 6.5) containing methanol in excess (2M in the biphasic system; molar ratio methanol/acyl chains 2:1). Transesterification was carried out at 30 degrees C, under magnetic stirring, using 10% (w/w) of immobilized enzyme in relation to oil. The maximum FAME yields were attained after 8h reaction time: 80.5% and 93.8%, when CpLIP2 immobilized on Accurel MP 1000 or on Lewatit VP OC 1600 were used, respectively. CpLIP2 on both Accurel MP 1000 and Lewatit VP OC 1600 showed high operational stability along 5 consecutive 8h batches. PMID- 27474958 TI - High conversion of sugarcane bagasse into monosaccharides based on sodium hydroxide pretreatment at low water consumption and wastewater generation. AB - The generation of a great quantity of black liquor (BL) and waste wash water (WWW) has been key problems of the alkaline pretreatment. This work tried to build a sustainable way to recycle the BL for pretreating sugarcane bagasse (SCB) and the WWW for washing the residual solid (RS) of alkali-treated SCB which would be subsequently hydrolysed and fermented. The enzymatic hydrolysis efficiency of the washed RS decreased with the recycling times of BL and WWW increasing. Tween80 at the loading of 0.25% (V/V) could notably improve the enzymatic hydrolysis and had no negative impact on the downstream fermentation. Compared with the non-recycling and BL recycling ways based on alkaline pretreatment, the BL-WWW recycling way could not only maintain high conversion of carbohydrate into monosaccharides and save alkali amount of 45.5%, but also save more than 80% water and generate less than 15% waste water. PMID- 27474959 TI - Association of childhood trauma and panic symptom severity in panic disorder: Exploring the mediating role of alexithymia. AB - BACKGROUND: The aim of the present study was to examine the association between childhood trauma (CT), alexithymia, and panic symptom severity in patients with panic disorder (PD). Moreover, the effect of specific subtypes of CT on alexithymia and panic symptom severity was also investigated. METHODS: 142 patients with PD and 146 healthy age-matched and sex-matched controls were enrolled in the study. The Structured Clinical Interview for DSM-IV axis I (SCID I), Childhood Trauma Questionnaire-28 item Short Form (CTQ-28), Toronto Alexithymia Scale (TAS-20), and Panic Disorder Severity Scale (PDSS) were administered to all subjects. The relationships among CT subtypes, alexithymia, and panic symptom severity were investigated using Pearson's correlation analysis. The types of CT that predict alexithymia and panic symptom severity were also investigated using Regression analyses. RESULTS: PD patients showed higher scores on reporting all kinds of CT except sexual abuse. In addition, the TAS-20, DIF (difficulty identifying feelings) and DDF (difficulty describing feelings) scores were significantly higher in patients with PD than in controls. Significant positive correlations were noted among CT, alexithymia and panic symptoms severity. Results of regression analyses showed alexithymia as a mediator between the different types of CT and panic disorder severity, except sexual abuse. LIMITATIONS: Although self-report questionnaires are reliable and widely used, the phenomenon of patients who underreport or overreport their symptoms cannot be ignored. CONCLUSION: The present study showed that CT and alexithymia are more common in patients with PD and impact the severity of panic symptoms. Results suggest that alexithymia may be an important mediator between CT and panic disorder severity. PMID- 27474960 TI - A meta-analysis of the efficacy of vortioxetine in patients with major depressive disorder (MDD) and high levels of anxiety symptoms. AB - BACKGROUND: Coexisting anxiety is common in major depressive disorder (MDD) and more difficult to treat than depression without anxiety. This analysis assessed the efficacy, safety, and tolerability of vortioxetine in MDD patients with high levels of anxiety (baseline Hamilton Anxiety Rating Scale [HAM-A] total score >=20). METHODS: Efficacy was assessed using an aggregated, study-level meta analysis of 10 randomized, placebo-controlled, 6/8-week trials of vortioxetine 5 20mg/day in adults (18-75 years), with a study in elderly patients (>=65 years) analyzed separately. Outcome measures included mean differences from placebo in change from baseline to endpoint (Delta) in the Montgomery-Asberg Depression Rating Scale (MADRS), HAM-A total, and HAM-A subscales. Safety and tolerability were assessed by treatment-emergent adverse events (TEAEs). RESULTS: A total of 1497 (48.6%) vortioxetine-treated and 860 (49.1%) placebo-treated patients had baseline HAM-A>=20. There were significant differences from placebo in MADRS (vortioxetine 5mg/day, n=415, Delta-2.68, P=0.005; 10mg/day, n=373, Delta-3.59, P<0.001; 20mg/day, n=207, Delta-4.30, P=0.005) and HAM-A total (5mg/day, n=419, Delta-1.64, P=0.022; 10mg/day, n=373, Delta-2.04, P=0.003; 20mg/day, n=207, Delta 2.19, P=0.027). There were significantly greater improvements versus placebo on the HAM-A psychic subscale for all doses. The most common TEAEs (>=5.0%) were nausea, headache, dizziness, dry mouth, diarrhea, nasopharyngitis, constipation, and vomiting. Incidence of serious TEAEs was 1.3% (placebo) and <=1.3% (vortioxetine, across doses). LIMITATIONS: Study heterogeneity limits this analysis. Patients with baseline HAM-A>=20 were not directly compared to baseline HAM-A<20 or total MDD population. CONCLUSIONS: Vortioxetine was efficacious in reducing depressive and anxiety symptoms in patients with MDD and high levels of anxiety. PMID- 27474961 TI - Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies. AB - BACKGROUND: The efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy in adults with major depressive disorder (MDD) from two phase 3 studies are reported. METHODS: Across study 1 (placebo, n=201; LDX, n=201) and study 2 (placebo, n=213; LDX, n=211), most participants (placebo and LDX) in the safety analysis set were female (study 1: 66.2% and 64.2%; study 2: 67.1% and 66.8%); mean+/-SD ages were 41.8+/-12.04 with placebo and 42.2+/-12.32 with LDX in study 1 and 42.6+/-11.41 with placebo and 42.0+/-11.63 with LDX in study 2. Participants (18-65 y) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Asberg Depression Rating Scale (MADRS) total scores >=24. Eight-week antidepressant lead-in phases prospectively assessed antidepressant response. Then, 8 weeks of randomized (1:1), double-blind treatment with dose-optimized LDX (20-70mg) or placebo in participants exhibiting inadequate antidepressant monotherapy responses (augmentation baseline MADRS total scores >=18 and <50% MADRS total score reductions from lead-in baseline to augmentation baseline) was initiated. The primary endpoint was MADRS total score change from augmentation baseline to week 16. Safety and tolerability measures included the occurrence of treatment-emergent adverse events (TEAEs). RESULTS: Least squares mean (95% CI) treatment differences (LDX-placebo) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 (0.1 [-1.7, 2.0], P=0.883) or study 2 (-0.5 [-2.3, 1.3], P=0.583). The only TEAE reported by >5% of LDX participants at twice the placebo rate in both studies was dry mouth. LIMITATIONS: Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders, the inability to assess specific MDD symptom domains (eg, anhedonia, cognition) or subtypes, the use of telephone-based depression assessments, and the potential influence of placebo response. CONCLUSION: Contrary to expectations, LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy. PMID- 27474962 TI - (68)Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: Selection, radiolabelling and preliminary biological evaluation. AB - INTRODUCTION: Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and (68)Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. METHODS: Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N',N",N''' tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine-serine-glycine spacer (GSG). The (68)Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA. Stability of (68)Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of (68)Ga-A9 K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. RESULTS: The (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA remained stable in product formulation, whereas (68)Ga-A8-K-DOTA was unstable. The S. aureus binding of (68)Ga-A11-GSGK-DOTA and (68)Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The (68)Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the (68)Ga-A9-K-DOTA. CONCLUSION: The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected (68)Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo. PMID- 27474963 TI - Short-term neurocognitive outcomes following anterior temporal lobectomy. AB - Changes in cognitive function are a well established risk of anterior temporal lobectomy (ATL). Deficits in verbal memory are a common postoperative finding, though a small proportion of patients may improve. Postoperative evaluation typically occurs after six to 12months. Patients may benefit from earlier evaluation to identify potential needs; however, the results of a formal neuropsychological assessment at an early postoperative stage are not described in the literature. We compared pre- and postoperative cognitive function for 28 right ATL and 23 left ATL patients using repeated measures ANOVA. Changes in cognitive function were compared to ILAE seizure outcome. The mean time to postoperative neuropsychological testing was 11.1weeks (SD=6.7weeks). There was a side*surgery interaction for the verbal tasks: immediate memory recall (F(1,33)=20.68, p<0.001), short delay recall (F(1,29)=4.99, p=0.03), long delay recall (F(1,33)=10.36, p=0.003), recognition (F(1,33)=5.69, p=0.02), and naming (F(1,37)=15.86, p<0.001). This indicated that the left ATL group had a significant decrement in verbal memory following surgery, while the right ATL group experienced a small but significant improvement. For the right ATL group, there was a positive correlation between ILAE outcome and improvement in immediate recall (r=-0.62, p=0.02) and long delay recall (r=-0.57, p=0.03). There was no similar finding for the left ATL group. This study demonstrates that short interval follow-up is effective in elucidating postoperative cognitive changes. Right ATL was associated with improvement in verbal memory, while left ATL resulted in a decrement in performance. Improvement in the right ATL group was related to improved seizure outcome. Short-interval follow-up may lend itself to the identification of patients who could benefit from early intervention. PMID- 27474964 TI - The synergistic induction of bone formation by the osteogenic proteins of the TGF beta supergene family. AB - The momentum to compose this Leading Opinion on the synergistic induction of bone formation suddenly arose when a simple question was formulated during a discussion session on how to boost the often limited induction of bone formation seen in clinical contexts. Re-examination of morphological and molecular data available on the rapid induction of bone formation by the recombinant human transforming growth factor-beta3 (hTGF-beta3) shows that hTGF-beta3 replicates the synergistic induction of bone formation as invocated by binary applications of hOP-1:hTGF-beta1 at 20:1 by weight when implanted in heterotopic sites of the rectus abdominis muscle of the Chacma baboon, Papio ursinus. The rapid induction of bone formation in primates by hTGF-beta3 may stem from bursts of cladistic evolution, now redundant in lower animal species but still activated in primates by relatively high doses of hTGF-beta3. Contrary to rodents, lagomorphs and canines, the three mammalian TGF-beta isoforms induce rapid and substantial bone formation when implanted in heterotopic rectus abdominis muscle sites of P. ursinus, with unprecedented regeneration of full thickness mandibular defects with rapid mineralization and corticalization. Provocatively, thus providing potential molecular and biological rationales for the apparent redundancy of osteogenic molecular signals in primates, binary applications of recombinant human osteogenic protein-1 (hOP-1) with low doses of hTGF-beta1 and -beta3, synergize to induce massive ossicles in heterotopic rectus abdominis, orthotopic calvarial and mandibular sites of P. ursinus. The synergistic binary application of homologous but molecularly different soluble molecular signals has indicated that per force several secreted molecular signals are required singly, synchronously and synergistically to induce optimal osteogenesis. The morphological hallmark of the synergistic induction of bone formation is the rapid differentiation of large osteoid seams enveloping haematopoietic bone marrow that forms by day 15 in heterotopic rectus abdominis sites. Synergistic binary applications also induce the morphogenesis of rudimentary embryonic growth plates indicating that the "memory" of developmental events in embryo can be redeployed postnatally by the application of morphogen combinations. Synergistic binary applications or single relatively high doses of hTGF-beta3 have shown that hTGF-beta3 induces bone by expressing a variety of inductive morphogenetic proteins that result in the rapid induction of bone formation. Tissue induction thus invocated singly by hTGF-beta3 recapitulates the synergistic induction of bone formation by binary applications of hTGF-beta1 and -beta3 isoforms with hOP 1. Both synergistic strategies result in the rapid induction and expansion of the transformed mesenchymal tissue into large corticalized heterotopic ossicles with osteoblast-like cell differentiation at the periphery of the implanted reconstituted specimens with "tissue transfiguration" in vivo. Molecularly, the rapid induction of bone formation by binary applications of hOP-1 and hTGF-beta3 or by hTGF-beta3 applied singly resides in the up-regulation of selected genes involved in tissue induction and morphogenesis, Osteocalcin, RUNX-2, OP-1, TGF beta1 and -beta3 with however the noted lack of TGF-beta2 up-regulation. PMID- 27474965 TI - Closed-loop adaptation of neurofeedback based on mental effort facilitates reinforcement learning of brain self-regulation. AB - OBJECTIVE: Considering self-rated mental effort during neurofeedback may improve training of brain self-regulation. METHODS: Twenty-one healthy, right-handed subjects performed kinesthetic motor imagery of opening their left hand, while threshold-based classification of beta-band desynchronization resulted in proprioceptive robotic feedback. The experiment consisted of two blocks in a cross-over design. The participants rated their perceived mental effort nine times per block. In the adaptive block, the threshold was adjusted on the basis of these ratings whereas adjustments were carried out at random in the other block. Electroencephalography was used to examine the cortical activation patterns during the training sessions. RESULTS: The perceived mental effort was correlated with the difficulty threshold of neurofeedback training. Adaptive threshold-setting reduced mental effort and increased the classification accuracy and positive predictive value. This was paralleled by an inter-hemispheric cortical activation pattern in low frequency bands connecting the right frontal and left parietal areas. Optimal balance of mental effort was achieved at thresholds significantly higher than maximum classification accuracy. CONCLUSION: Rating of mental effort is a feasible approach for effective threshold-adaptation during neurofeedback training. SIGNIFICANCE: Closed-loop adaptation of the neurofeedback difficulty level facilitates reinforcement learning of brain self regulation. PMID- 27474966 TI - Interaction of vectors and parental viruses with the host genome. AB - Viral replication by acquisition of the host cell biology represents a central part of a virus life cycle. Thereby, integration into the host genome constitutes a successful strategy to ensure viral persistence and viruses have developed different mechanisms to integrate and benefit from cell's transcriptional and translational machinery. While lentiviral (e.g. HIV) integration is influenced by the chromatin landscape encountered upon nuclear entry, certain parvoviruses (e.g. AAV) integrate specifically within genomic regions bearing increasingly known sequence motifs. Gene therapy exploits these viral persistence strategies to achieve efficient and safe long-term transgene expression. Here we focus on two widely used vectors and their parental viruses, HIV and AAV, to discuss recent insights into lentiviral vector oncogenicity by alteration of endogenous transcripts as well as the unresolved AAV vectors genotoxic potential. PMID- 27474967 TI - In situ, dual-mode monitoring of organ-on-a-chip with smartphone-based fluorescence microscope. AB - The use of organ-on-a-chip (OOC) platforms enables improved simulation of the human kidney's response to nephrotoxic drugs. The standard method of analyzing nephrotoxicity from existing OOC has majorly consisted of invasively collecting samples (cells, lysates, media, etc.) from an OOC. Such disruptive analyses potentiate contamination, disrupt the replicated in vivo environment, and require expertize to execute. Moreover, traditional analyses, including immunofluorescence microscopy, immunoblot, and microplate immunoassay are essentially not in situ and require substantial time, resources, and costs. In the present work, the incorporation of fluorescence nanoparticle immunocapture/immunoagglutination assay into an OOC enabled dual-mode monitoring of drug-induced nephrotoxicity in situ. A smartphone-based fluorescence microscope was fabricated as a handheld in situ monitoring device attached to an OOC. Both the presence of gamma-glutamyl transpeptidase (GGT) on the apical brush border membrane of 786-O proximal tubule cells within the OOC surface, and the release of GGT to the outflow of the OOC were evaluated with the fluorescence scatter detection of captured and immunoagglutinated anti-GGT conjugated nanoparticles. This dual-mode assay method provides a novel groundbreaking tool to enable the internal and external in situ monitoring of the OOC, which may be integrated into any existing OOCs to facilitate their subsequent analyses. PMID- 27474968 TI - Synthesis of molecularly imprinted carbon dot grafted YVO4:Eu(3+) for the ratiometric fluorescent determination of paranitrophenol. AB - A facilely prepared ratiometric fluorescent molecularly imprinted sensor has been constructed for highly sensitive and selective detection of 4-nitrophenol (4-NP) using carbon dots (CDs) as the target sensitive fluorophore and YVO4: Eu(3+) nanoparticles (NPs) as the reference fluorophore. Through the hydrolysis and condensation reactions of the silica precursor, CDs and YVO4 Eu(3+) NPs can be incorporated into silica networks through silylation reaction by one pot synthesis procedure. The as-prepared fluorescent molecularly imprinted sensor shows characteristic fluorescence emissions of CDs (blue) and YVO4:Eu(3+) (red) under a single excitation wavelength. With the addition of 4-NP, the fluorescence of CDs is selectively quenched, resulting in the ratiometric fluorescence response. Under optimum conditions, the proposed sensor exhibits a high sensitivity with a linear range from 0 to 12.0MUM and shows the limit of detection as low as 0.15MUM in the determination of 4-NP, which is probably benefits from the tailor-made imprinted cavities for binding 4-NP. Furthermore, the proposed method was successfully applied for the determination of 4-NP in real water samples and human urine samples with great potentials for monitoring of 4-NP in environmental application. PMID- 27474969 TI - An ultrasensitive electrochemiluminescence sensor based on reduced graphene oxide copper sulfide composite coupled with capillary electrophoresis for determination of amlodipine besylate in mice plasma. AB - A new electrochemiluminescence (ECL) sensor based on reduced graphene oxide copper sulfide (rGO-CuS) composite coupled with capillary electrophoresis (CE) was constructed for the ultrasensitive detection of amlodipine besylate (AML) for the first time. In this work, rGO-CuS composite was synthesized by one-pot hydrothermal method and used for electrode modification. The electrochemical and ECL behaviors of the sensor were investigated. More than 5-fold enhance in ECL intensity was observed after modified with rGO-CuS composite. The results can be ascribed to the presence of rGO-CuS composite on the electrode surface that facilitates the electron transfer rate between the electroactive center of Ru(bpy)3(2+) and the electrode. The ECL sensor was coupled with CE to improve the selectivity and the CE-ECL parameters that affect separation and detection were optimized. Under the optimum conditions, the linear ranges for AML was 0.008 5.0MUg/mL with a detection limit of 2.8ng/mL (S/N=3). The method displayed the advantages of high sensitivity, good selectivity, wide linear range, low detection limit and fine reproducibility, and was used to analyze AML in mice plasma with a satisfactory result, which holds a great potential in the field of pharmaceutical analysis. PMID- 27474970 TI - Novel electrochemiluminescence of perylene derivative and its application to mercury ion detection based on a dual amplification strategy. AB - In this paper, a novel covalently crosslinked perylene derivative (PTC-PEI) composed of polyethylenimine (PEI) and perylenetetracarboxylic acid (PTCA) has been first investigated for cathodic electrochemiluminescence (ECL) in an aqueous system with dissolved O2 as coreactant. The promising novel ECL materials of PTC PEI exhibited admirable physical and chemical stability and high ECL intensity, which held an alternative way to construct ECL sensor with improved sensitivity. Thus, it was applied to construct a dual amplified "signal-on" mercury ion (Hg(2+)) sensor by the employment of nicking endonuclease (NEase)-assisted target recycling and rolling circle amplification (RCA) for signal amplification. Herein, a long G-rich sequence was generated by RCA process to capture abundant hemin on the electrode surface, and then a significantly amplified ECL signal of PTC-PEI was obtained. Based on dual signal amplification strategy, the devised sensor showed a linear range from 0.1pM to 0.1MUMU with a detection limit down to 33fM (S/N=3), and was successfully used in the direct detection of real water sample with high sensitivity and selectivity. PMID- 27474971 TI - Human salivary proteins with affinity to lipoteichoic acid of Enterococcus faecalis. AB - Enterococcus faecalis is associated with refractory apical periodontitis and its lipoteichoic acid (Ef.LTA) is considered as a major virulence factor. Although the binding proteins of Ef.LTA may play an important role for mediating infection and immunity in the oral cavity, little is known about Ef.LTA-binding proteins (Ef.LTA-BPs) in saliva. In this study, we identified salivary Ef.LTA-BPs with biotinylated Ef.LTA (Ef.LTA-biotin) through mass spectrometry. The biotinylation of Ef.LTA was confirmed by binding capacity with streptavidin-FITC on CHO/CD14/TLR2 cells. The biological activity of Ef.LTA-biotin was determined based on the induction of nitric oxide and macrophage inflammatory protein-1alpha in a macrophage cell-line, RAW 264.7. To identify salivary Ef.LTA-BPs, the Ef.LTA biotin was mixed with a pool of human saliva obtained from nine healthy subjects followed by precipitation with a streptavidin-coated bead. Ef.LTA-BPs were then separated with 12% SDS-PAGE and subjected to the mass spectrometry. Six human salivary Ef.LTA-BPs including short palate lung and nasal epithelium carcinoma associated protein 2, zymogen granule protein 16 homolog B, hemoglobin subunit alpha and beta, apolipoprotein A-I, and lipocalin-1 were identified with statistical significance (P<0.05). Ef.LTA-BPs were validated with lipocalin-1 using pull-down assay. Hemoglobin inhibited the biofilm formation of E. faecalis whereas lipocalin-1 did not show such effect. Collectively, the identified Ef.LTA BPs could provide clues for our understanding of the pathogenesis of E. faecalis and host immunity in oral cavity. PMID- 27474972 TI - Echocardiographic assessment of the right ventricle: Impact of the distinctly load dependency of its size, geometry and performance. AB - Right ventricular (RV) size, shape and function are distinctly load-dependent and pulmonary load is an important determinant of RV function in patients with congestive heart failure (CHF) due to primary impaired left ventricular function and in those with pre-capillary pulmonary hypertension (PH). In a pressure overloaded RV, not only dilation and aggravation of tricuspid regurgitation, but also systolic dysfunction leading to RV failure (RVF) can occur already before the development of irreversible alterations in RV myocardial contractility. This explains RV ability for reverse remodeling and functional improvement in patients with post-capillary and pre-capillary PH of a different etiology, after normalization of loading conditions. There is increasing evidence that RV evaluation by echocardiography in relation with its loading conditions can improve the decision-making process and prognosis assessments in clinical praxis. Recent approaches to evaluate the RV in relation with its actual loading conditions by echo-derived composite variables which either incorporate a certain functional parameter (i.e. tricuspid annulus peak systolic excursion, stroke volume, RV end-systolic volume index, velocity of myocardial shortening) and load, or incorporate measures which reflect the relationship between RV load and RV dilation, also taking the right atrial pressure into account (i.e. "load adaptation index"), appeared particularly suited and therefore also potentially useful for evaluation of RV contractile function. Special attention is focused on the usefulness of RV echo-evaluation in relation to load for proper decision making before ventricular assist-device implantation in patients with CHF and for optimal timing of listing procedures to transplantation in patients with end stage pre-capillary PH. PMID- 27474973 TI - alphavbeta3 Integrin and tumour blood vessels-learning from the past to shape the future. AB - Angiogenesis, the formation of new blood vessels from pre-existing ones, is thought to enhance tumour growth and these blood vessels can act as conduits of tumour cell metastasis. Integrins, the family of cell surface extracellular matrix receptors, can promote endothelial cell migration and survival, both essential features of angiogenesis, and were thus considered good targets for anti-angiogenic therapy. This sparked the development of agents to block integrin function as new cancer therapies. Here, we review the current status of alphavbeta3-integrin in tumour angiogenesis. Learning from what we now know about integrin conformational changes and endocytosis, we discuss the possible future of targeting blood vessel alphavbeta3-integrin in the control of cancer. PMID- 27474974 TI - Spatial modelling of landscape aesthetic potential in urban-rural fringes. AB - The aesthetic potential of landscape has to be modelled to provide tools for land use planning. This involves identifying landscape attributes and revealing individuals' landscape preferences. Landscape aesthetic judgments of individuals (n = 1420) were studied by means of a photo-based survey. A set of landscape visibility metrics was created to measure landscape composition and configuration in each photograph using spatial data. These metrics were used as explanatory variables in multiple linear regressions to explain aesthetic judgments. We demonstrate that landscape aesthetic judgments may be synthesized in three consensus groups. The statistical results obtained show that landscape visibility metrics have good explanatory power. Ultimately, we propose a spatial modelling of landscape aesthetic potential based on these results combined with systematic computation of visibility metrics. PMID- 27474975 TI - [Is follow-up of premature babies well organized in France? The place of regional monitoring networks for vulnerable children]. PMID- 27474976 TI - Assessment of dietary ratios of red clover and corn silages on milk production and milk quality in dairy cows. AB - Twenty-four multiparous Holstein-Friesian dairy cows were used in a replicated 3*3 Latin square changeover design experiment to test the effects of changing from corn (Zea mays) silage to red clover (Trifolium pratense) silage in graded proportions on feed intakes, milk production, and whole-body N and P partitioning. Three dietary treatments with ad libitum access to 1 of 3 forage mixtures plus a standard allowance of 4kg/d dairy concentrates were offered. The 3 treatment forage mixtures were, on a dry matter (DM) basis: (1) R10: 90% corn silage and 10% red clover silage, (2) R50: 50% corn silage and 50% red clover silage, and (3) R90: 10% corn silage and 90% red clover silage. In each of 3 experimental periods, there were 21d for adaptation to diets, and 7d for measurements. Diet crude protein intakes increased, and starch intakes decreased, as the silage mixture changed from 90% corn to 90% red clover, although the highest forage DM intakes and milk yields were achieved on diet R50. Although milk fat yields were unaffected by diet, milk protein yields were highest with the R 0250 diet. Whole-body partitioning of N was measured in a subset of cows (n=9), and both the daily amount and proportion of N consumed that was excreted in feces and urine increased as the proportion of red clover silage in the diet increased. However, the apparent efficiency of utilization of feed N for milk protein production decreased from 0.33g/g for diet R10 to 0.25g/g for diet R90. The urinary excretion of purine derivatives (sum of allantoin and uric acid) tended to increase, suggesting greater flow of microbial protein from the rumen, as the proportion of red clover silage in the diet increased, and urinary creatinine excretion was affected by diet. Fecal shedding of E. coli was not affected by dietary treatment. In conclusion, even though microbial protein flow may have been greatest from the R 0450 diet, optimum feed intakes and milk yields were achieved on a diet that contained a 1:1 DM mixture of corn and red clover silages. PMID- 27474977 TI - The effect of increasing concentrations of dl-methionine and 2-hydroxy-4 (methylthio) butanoic acid on hepatic genes controlling methionine regeneration and gluconeogenesis. AB - Metabolizable methionine (Met) concentrations can be increased by feeding rumen protected dl-Met or the isopropyl ester of 2-hydroxy-4-(methylthio) butanoic acid (HMBi). Hepatic responses to increasing concentrations of metabolizable Met as a result of supplementation of different Met sources have not been comparatively examined. The objective of this experiment was to examine the regulation of key genes for Met metabolism, gluconeogenesis, and fatty acid oxidation in response to increasing concentrations of dl-Met or 2-hydroxy-4-(methylthio) butanoic acid (HMB) in bovine primary hepatocytes. Hepatocytes isolated from 4 Holstein calves less than 7d old were maintained as monolayer cultures for 24h before addition of treatments. Cells were then exposed to treatments of dl-Met or HMB (0, 10, 20, 40, or 60 uM) in Met-free medium for 24h and collected for RNA isolation and quantification of gene expression by quantitative PCR. Expression of betaine homocysteine methyltransferase (BHMT), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5,10 methylenetetrahydrofolate reductase (MTHFR) genes, which catalyze regeneration of Met from betaine and homocysteine, decreased linearly with increasing dl-Met concentration. We observed similar effects with increasing HMB concentration, except expression of MTHFR, which was not altered. Expression of Met adenosyltransferase 1A (MAT1A), which catalyzes the first step of Met metabolism to generate S-adenosylmethionine (SAM), a primary methyl donor, was decreased with increasing dl-Met or HMB concentration. Expression of S-adenosylhomocysteine hydrolase (SAHH) was decreased linearly with increasing HMB concentration, but not altered by dl-Met. Increasing concentrations of dl-Met and HMB decreased cytosolic phosphoenolpyruvate carboxykinase (PCK1) expression, but did not alter the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2) or pyruvate carboxylase (PC). Expression of glucose-6-phosphatase(G6PC) decreased linearly with increasing HMB concentration, but not altered by dl-Met. Neither dl-Met nor HMB altered the expression of carnitine palmitoyltransferase 1A(CPT1a). These findings demonstrate reduced necessity for Met regeneration with increased Met concentrations in the medium, regardless of the Met source. The lack of upregulation of gluconeogenesis indicates that increased dl-Met or HMB is not prioritized for glucose synthesis in primary bovine hepatocytes. PMID- 27474978 TI - Short communication: Pre- and postmilking anatomical characteristics of teats and their associations with risk of clinical mastitis in dairy cows. AB - The primary objective of this study was to describe and compare anatomical characteristics of teats before and after machine milking adjusted for parity and teat location (front versus rear). The second objective was to determine if selected milking and anatomical characteristics of teats were associated with occurrence of clinical mastitis. To address objective 1, a cross-sectional study was done to describe and compare teat dimensions before and after milking (n=1,751 teats from 445 cows). To fulfill objective 2, a case-control study was performed. Quarters having their first case of clinical mastitis in the current lactation from 2 mo before to 2 mo after the day the teats were measured were selected as cases (n=47), provided no other quarters from that cow were affected by clinical mastitis at that time. Three controls (n=141) were matched with each case; these were selected from quarters that did not experience any case of clinical mastitis during their current lactation. A conditional logistic regression model was used to determine associations between teat dimensions and occurrence of clinical mastitis. Primiparous and multiparous Holstein cows were enrolled in both studies. As compared with premilking dimensions, postmilking teats were longer and narrower at the barrel and the apex. Significant interactions between teat position and parity were identified for premilking teat length and diameter of the teat barrel. Premilking, teats were longer and wider with increasing parity. Front teats were longer and wider than rear teats premilking. Also during premilking, differences between the front and rear teat were less at increasing parity. Teat apex diameter was greater for premilking teats of cows in parity >=3 and the apexes of front teats were wider than those of rear teats. Teats enrolled in the case-control study had twice as many clinical mastitis cases in front quarters compared with rear quarters. Premilking diameter of the teat apex was positively associated with risk of clinical mastitis (odds ratio=1.20 per 1-mm increase in the diameter of the apex of the teat, 95% confidence interval=1.05-1.37). Milking machine-related changes in teat dimensions had no association with occurrence of clinical mastitis. PMID- 27474979 TI - Whole-genome scan to detect quantitative trait loci associated with milk protein composition in 3 French dairy cattle breeds. AB - In the context of the PhenoFinLait project, a genome-wide analysis was performed to detect quantitative trait loci (QTL) that affect milk protein composition estimated using mid-infrared spectrometry in the Montbeliarde (MO), Normande (NO), and Holstein (HO) French dairy cattle breeds. The 6 main milk proteins (alpha-lactalbumin, beta-lactoglobulin, and alphaS1-, alphaS2-, beta-, and kappa caseins) expressed as grams per 100g of milk (% of milk) or as grams per 100g of protein (% of protein) were estimated in 848,068 test-day milk samples from 156,660 cows. Genotyping was performed for 2,773 MO, 2,673 NO, and 2,208 HO cows using the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA). Individual test-day records were adjusted for environmental effects and then averaged per cow to define the phenotypes analyzed. Quantitative trait loci detection was performed within each breed using a linkage disequilibrium and linkage analysis approach. A total of 39 genomic regions distributed on 20 of the 29 Bos taurus autosomes (BTA) were significantly associated with milk protein composition at a genome-wide level of significance in at least 1 of the 3 breeds. The 9 most significant QTL were located on BTA2 (133 Mbp), BTA6 (38, 47, and 87 Mbp), BTA11 (103 Mbp), BTA14 (1.8 Mbp), BTA20 (32 and 58 Mbp), and BTA29 (8 Mbp). The BTA6 (87 Mbp), BTA11, and BTA20 (58 Mbp) QTL were found in all 3 breeds, and they had highly significant effects on kappa-casein, beta-lactoglobulin, and alpha-lactalbumin, expressed as a percentage of protein, respectively. Each of these QTL explained between 13% (BTA14) and 51% (BTA11) of the genetic variance of the trait. Many other QTL regions were also identified in at least one breed. They were located on 14 additional chromosomes (1, 3, 4, 5, 7, 15, 17, 19, 21, 22, 24, 25, 26, and 27), and they explained 2 to 8% of the genetic variance of 1 or more protein composition traits. Concordance analyses, performed between QTL status and sequence-derived polymorphisms from 13 bulls, revealed previously known causal polymorphisms in LGB (BTA11) and GHR (BTA20 at 32 Mbp) and excluded some other previously described mutations. These results constitute a first step in identifying causal mutations and using routinely collected mid-infrared predictions in future genomic selection programs to improve bovine milk protein composition. PMID- 27474980 TI - Failure and preventive costs of mastitis on Dutch dairy farms. AB - Mastitis is an important disease from an economic perspective, but most cost assessments of mastitis include only the direct costs associated with the disease (e.g., production losses, culling, and treatment), which we call failure costs (FC). However, farmers also invest time and money in controlling mastitis, and these preventive costs (PC) also need to be taken into account. To estimate the total costs of mastitis, we estimated both FC and PC. We combined multiple test day milk records from 108 Dutch dairy farms with information on applied mastitis prevention measures and farmers' registration of clinical mastitis for individual dairy cows. The aim was to estimate the total costs of mastitis and to give insight into variations between farms. We estimated the average total costs of mastitis to be ?240/lactating cow per year, in which FC contributed ?120/lactating cow per year and PC contributed another ?120/lactating cow per year. Milk production losses, discarded milk, and culling were the main contributors to FC, at ?32, ?20, and ?20/lactating cow per year, respectively. Labor costs were the main contributor to PC, next to consumables and investments, at ?82, ?34, and ?4/lactating cow per year, respectively. The variation between farmers was substantial, and some farmers faced both high FC and PC. This variation may have been due to structural differences between farms, different mastitis-causing pathogens, the time at which preventive action is initiated, stockmanship, or missing measures in PC estimates. We estimated the minimum FC to be ?34 per lactating cow per yr. All farmers initiated some preventive action to control or reduce mastitis, indicating that farmers will always have mastitis related costs, because mastitis will never be fully eradicated from a farm. Insights into both the PC and FC of a specific farm will allow veterinary advisors and farmers to assess whether current udder health strategies are appropriate or whether there is room for improvement from an economic perspective. PMID- 27474981 TI - Using protein-fatty acid complexes to improve vitamin D stability. AB - Liprotides are complexes between lipids and partially denatured proteins in which the protein forms a stabilizing shell around a fatty acid micelle core. We have previously shown that liprotides stabilize small aliphatic molecules such as retinal and tocopherol by sequestering these molecules in the fatty acid core. This opens up the use of liprotides to formulate food additives. Here, we expand our investigations to the large and bulky molecule vitamin D3 (vitD), motivated by the population-wide occurrence of vitD deficiency. We prepared liprotides using different proteins and fatty acids and evaluated their ability to protect vitD upon exposure to heating or intense UV light. Additionally, we determined the stability of liprotides toward pH, Ca(2+), and BSA. The best results were obtained with liprotides made from alpha-lactalbumin and oleate. These liprotides were able to completely solubilize vitD, increase the stability toward UV light 9 fold, and increase the long-term stability at 37 degrees C up to 1,000-fold. Native alpha-lactalbumin binds Ca(2+), making Ca(2+) potentially disruptive toward liprotides. However, liprotides prepared by incubation at 80 degrees C were stable toward Ca(2+), in contrast to those made at 20 degrees C. Nevertheless, the fatty acid binding protein BSA reduced the ability of both liprotides to protect vitD; the amount of vitD remianing after 20d at 20 degrees C decreased from 79+/-3% in the absence of BSA to 49+/-4 and 23+/-3% in the presence of BSA for liprotides made at 80 and 20 degrees C, respectively. Both classes of liprotides were able to release their vitD content, as demonstrated by the transfer of vitD encapsulated in liprotides to phospholipid vesicles. Importantly, liprotides were not stable at pH 6 and below, limiting the useful pH range of the liprotides to >pH 6. Our results indicate that vitD may be encapsulated and stabilized for enrichment of clear beverages at neutral pH to improve the intake and bioavailability of vitD. PMID- 27474982 TI - Rapid, sensitive, and reproducible screening of liquid milk for adulterants using a portable Raman spectrometer and a simple, optimized sample well. AB - We have developed a powerful general spectroscopic method for rapidly screening liquid milk for adulterants by combining reflective focusing wells simply fabricated in aluminum with a small, portable Raman spectrometer with a focusing fiber optic probe. Hemispherical aluminum sample wells were specially designed to optimize internal reflection and sampling volume by matching the focal length of the mirror to the depth of focus of the laser probe. The technique was tested on milk adulterated with 4 different nitrogen-rich compounds (melamine, urea, dicyandiamide, and ammonium sulfate) and sucrose. No sample preparation of the milk was needed, and the total analysis time was 4min. Reliable sample presentation enabled average reproducibility of 8% residual standard deviation. The limit of detection interval measured from partial least squares calibrations ranged between 140 and 520mg/L for the 4 N-rich compounds and between 7,000 and 36,000mg/L (0.7-3.6%) for sucrose. The portability of the system and the reliability and reproducibility of this technique open opportunities for general, reagentless screening of milk for adulterants at the point of collection. PMID- 27474983 TI - Fish oil-induced milk fat depression and associated downregulation of mammary lipogenic genes in dairy ewes. AB - Several studies in dairy cows have shown a relationship between milk fat depression (MFD) and alterations caused in lipogenic gene expression by dietary nutrients. However, information on small ruminants is not only scarce but also inconsistent. Therefore, this experiment was conducted in dairy ewes to study the effect of a diet known to induce MFD on milk fatty acid (FA) composition and mRNA abundance of key candidate genes involved in mammary lipogenesis. Twelve lactating Assaf ewes (on average 63d in milk) were randomly assigned to 2 treatments consisting of a total mixed ration based on alfalfa hay and concentrates (50:50), supplemented with 0 (control) or 17g of fish oil/kg of diet dry matter (FO). Profiles of milk FA and mRNA abundance of candidate genes in biopsied mammary tissue were examined before starting the treatments and after 1 and 4.5wk on the diets. As expected, FO induced MFD and modified milk FA composition. Compared with the control, reductions in milk fat concentration and yield were not detected on d 7, but reached up to 25 and 22%, respectively, on d 30. However, increases in confirmed or putative antilipogenic FA (trans-10,cis-12 and trans-9,cis-11 18:2, cis-9 16:1, cis-11 18:1, and oxo-FA) were already established on the early stage of the treatment and lasted until the end of the feeding period. These changes were accompanied by decreases in the mRNA abundance of genes encoding lipogenic enzymes. The coordinated nature of the downregulation, which tended to affect most studied metabolic pathways, including FA activation (ACSS1), de novo synthesis (ACACA and FASN), uptake and transport (LPL and FABP3), desaturation (SCD1), and esterification (AGAPT6), supports the involvement of a central regulator of milk fat synthesis. In this regard, without ruling out the potential contribution of PPARG, our results suggest that SREBF1 would have a relevant role in the MFD syndrome in sheep fed FO. Among the other studied transcription factors, the tendency to a downregulation of INSIG1 was associated with that of SREBF1, whereas no variation was detected for SCAP or THRSP. Fish oil had no significant effects on the transcript abundance of CD36, GPAM, DGAT1, LPIN1, and XDH. Overall, changes in potential antilipogenic FA and mRNA abundance of candidate lipogenic genes support a relationship between them and suggest that FO-induced MFD in dairy ewes would be mediated by transcriptional mechanisms. PMID- 27474984 TI - The effects of increasing amounts of milk replacer powder added to whole milk on feed intake and performance in dairy heifers. AB - The aim of this study was to evaluate the effects on feed intake, heifer performance, and health of increasing the total solids (TS) content of liquid feed (whole milk) by adding increasing amounts of milk replacer powder during the pre- and postweaning periods. Crossbred Holstein-Gyr heifers (n=60) were assigned to 1 of 4 treatments (n=15 per group), which consisted of different TS concentrations: 12.5, 15.0, 17.5, and 20.0% of liquid feed. Heifers received 6 L of liquid feed per day, divided into 2 equal meals (0800 and 1600h) and provided in buckets, from 5 to 55d of age. From 56 to 59d of age, the total amount of liquid feed was reduced by half, maintaining only morning feedings. Heifers were weaned at 60d and monitored until 90d of age. Water and starter were provided ad libitum during the entire experiment. Corn silage was included in the diet during the postweaning period (70d of age). Feed intake and health scores were evaluated daily. Body weight and body frame development were recorded weekly. Starting at 14d, ruminal pH was measured every other week. Laboratory analysis determined that the actual TS contents of the liquid feed were 13.5, 16.1, 18.2, and 20.4%, for the proposed 12.5, 15.0, 17.5, and 20.0% TS treatments, respectively. The osmolality of liquid feed treatments was 265 to 533mOsm/L. Intake of liquid feed was similar among treatments from 4wk of age. During the preweaning period, starter intake, fecal score, and days with diarrhea were similar among treatments. Ruminal pH at weaning averaged 6.2 and was similar among treatments. Increasing concentrations of TS in the liquid feed were associated with linear increases in average daily gain, final body weight, and growth performance, but linear decreases in feed efficiency. During the postweaning period, intake of starter, corn silage, and water were similar among treatments, as well as average daily gain and feed efficiency. Final body weight and growth performance during the postweaning period also increased linearly with concentration of TS in liquid feed. Increasing the concentration of TS in liquid feed up to 20.4% increased performance and body frame development in dairy heifers during the pre- and postweaning periods and had no effects on solid feed intake or health. PMID- 27474985 TI - Technical note: Comparison of instantaneous sampling and continuous observation of dairy cattle behavior in freestall housing. AB - Recording behavior at fixed intervals (instantaneous sampling) can reduce labor relative to observing continuously. However, instantaneous sampling may inaccurately estimate potentially important responses, such as how frequently cows perform a behavior (i.e., the number of bouts). Our objective was to validate the use of instantaneous sampling for capturing how long and how frequently cows in freestall housing lie down or visit the feed bunk and water trough. We predicted that more frequent sampling would be needed to accurately reflect the behaviors that cows spent less time performing. In addition, we predicted that instantaneous sampling would underestimate how often cows engaged in behaviors that they frequently performed in short bouts or with short intervals between bouts, as some of these events may occur between sample intervals. Continuous video observations of 18 lactating Holstein-Friesian dairy cows were conducted for 48-h periods. Instantaneous samples (1 and 30 s, and 1, 3, 5, 10, 15, and 30 min) were generated from continuous data, with the samples recorded at 1-s intervals representing true values. Estimates from each sample interval >=30 s were compared pairwise to true values with regression analysis. Sample intervals were considered accurate if they met 3 criteria: coefficient of determination >=0.9 (i.e., strongly related to true values), slope=1, and intercept=0 (i.e., did not over- or underestimate true values). The amount of time cows spent lying (12.1+/-1.8h/24h, mean +/- standard deviation) or visiting the water trough (1.1+/-0.8h/24h) and feed bunk (5.6+/-0.8h/24h) were accurately captured using sample intervals <=30, 10, and 5 min, respectively. In addition, sample intervals <=3 min accurately estimated the number of lying bouts (10.3+/ 2.4 per 24h), likely because cows were recumbent for long periods (74.0+/-17.4 min, on average, with <6% of bouts lasting <5 min) and rarely resumed lying soon after standing up (0.4% of intervals between lying bouts were <30 s). However, shorter sample intervals may be needed in situations where cows more frequently transition between lying and standing. In contrast to lying in this study, cows visited the water trough and feed bunk for shorter periods (3.5+/-1.7 and 25.6+/ 5.8 min, respectively) and frequently returned to these resources soon after leaving (17 and 7% of intervals between visits were <30 s long). As some of these events likely occurred between sample intervals, all sample intervals >=30 s underestimated the number of times cows visited the water trough and feed bunk (18.5+/-6.2 and 14.1+/-4.4 per 24h, respectively). Therefore, continuous observation is needed to determine how often cows visit these resources. PMID- 27474986 TI - Dutch dairy farms after milk quota abolition: Economic and environmental consequences of a new manure policy. AB - The abolition of the Dutch milk quota system has been accompanied by the introduction of a new manure policy to limit phosphate production (i.e., excretion via manure) on expanding dairy farms. The objective of this study was to evaluate the effect of these recent policy changes on the farm structure, management, labor income, nitrogen and phosphate surpluses, and greenhouse gas emissions of an average Dutch dairy farm. The new manure policy requires that any increase in phosphate production be partly processed and partly applied to additional farmland. In addition, phosphate quotas have been introduced. Herein, we used a whole-farm optimization model to simulate an average farm before and after quota abolition and introduction of the new manure policy. The objective function of the model maximized labor income. We combined the model with a farm nutrient balance and life-cycle assessment to determine environmental impact. Based on current prices, increasing the number of cows after quota abolition was profitable until manure processing or additional land was required to comply with the new manure policy. Manure processing involved treatment so that phosphate was removed from the national manure market. Farm intensity in terms of milk per hectare increased by about 4%, from 13,578kg before quota abolition to 14,130kg after quota abolition. Labor income increased by ?505/yr. When costs of manure processing decreased from ?13 to ?8/t of manure or land costs decreased from ?1,187 to ?573/ha, farm intensity could increase up to 20% until the phosphate quota became limiting. Farms that had already increased their barn capacity to prepare for expansion after milk quota abolition could benefit from purchasing extra phosphate quota to use their full barn capacity. If milk prices increased from ?355 to ?420/t, farms could grow unlimited, provided that the availability of external inputs such as labor, land, barn capacity, feed, and phosphate quota at current prices were also unlimited. The milk quota abolition, accompanied by a new manure policy, will slightly increase nutrient losses per hectare, due to an increase in farm intensity. Greenhouse gas emissions per unit of milk will hardly change, so at a given milk production per cow, total greenhouse gas emissions will increase linearly with an increase in the number of cows. PMID- 27474987 TI - Determinants of consumer intention to purchase animal-friendly milk. AB - Concern about the welfare of production animals is growing among various stakeholders, including the general public. Citizens can influence the market for premium welfare products by expressing public concerns, and consumers-the actors who actually purchase products-can do so through their purchasing behavior. However, current market shares for premium welfare products are small in Europe. To better align purchase behavior with public and individuals' concerns, insight is needed into determinants that influence the intention to purchase premium welfare products. A cross-sectional online survey of 787 Flemish milk consumers was conducted to investigate attitudes toward and intention to purchase animal friendly milk. More than half of the sample (52.5%) expressed the intention to purchase animal-friendly milk. Linear regression modeling indicated that intention was positively influenced by (1) higher perceived product benefits from animal-friendly milk (milk with more health benefits and higher quality); (2) higher personal importance of extrinsic product attributes such as local production and country of origin; (3) higher personal importance of animal welfare; (4) a more natural living oriented attitude toward cows; and (5) a more positive general attitude toward milk. Intention was negatively influenced by (1) a stronger business-oriented attitude toward cows; and (2) by a higher personal importance attached to price. These insights in key components of purchase intention can assist producers, the dairy industry, and retailers to position and market animal-friendly milk. PMID- 27474988 TI - Bacterial microbiota compositions of naturally fermented milk are shaped by both geographic origin and sample type. AB - Naturally fermented dairy products contain a rich microbial biodiversity. This study aimed to provide an overview on the bacterial microbiota biodiversity of 85 samples, previously collected across a wide region of China, Mongolia, and Russia. Data from these 85 samples, including 55 yogurts, 18 naturally fermented yak milks, 6 koumisses, and 6 cheeses, were retrieved and collectively analyzed. The most prevalent phyla shared across samples were Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria, which together accounted for 99% of bacterial sequences. The predominant genera were Lactobacillus, Lactococcus, Streptococcus, Acetobacter, Acinetobacter, Leuconostoc, and Macrococcus, which together corresponded to 96.63% of bacterial sequences. Further multivariate statistical analyses revealed significant differences in the microbiota structure across sample geographic origin and type. First, on the principal coordinate score plot, samples representing the 3 main sample collection regions (Russia, Xinjiang, and Tibet) were mostly located respectively in the upper left, lower right, and lower left quadrants, although slight overlapping occurred. In contrast, samples from the minor sampling areas (Inner Mongolia, Mongolia, Gansu, and Sichuan) were predominantly distributed in the lower left quadrant. These results suggest a possible association between sample geographical origin and microbiota composition. Second, bacterial microbiota structure was stratified by sample type. In particular, the microbiota of cheese was largely distinct from the other sample types due to its high abundances of Lactococcus and Streptococcus. The fermented yak milk microbiota was most like that of the yogurts. Koumiss samples had the lowest microbial diversity and richness. In conclusion, both geographic origin and sample type shape the microbial diversity of naturally fermented milk. PMID- 27474989 TI - Temporal variability in domestic point source discharges and their associated impact on receiving waters. AB - Discharges from the widely distributed small point sources of pollutants such as septic tanks contribute to microbial and nutrient loading of streams and can pose risks to human health and stream ecology, especially during periods of ecological sensitivity. Here we present the first comprehensive data on the compositional variability of septic tank effluents (STE) as a potential source of water pollution during different seasons and the associated links to their influence on stream waters. To determine STE parameters and nutrient variations, the biological and physicochemical properties of effluents sampled quarterly from 12 septic tank systems were investigated with concurrent analyses of upstream and downstream receiving waters. The study revealed that during the warmer dryer months of spring and summer, effluents were similar in composition, as were the colder wetter months of autumn and winter. However, spring/summer effluents differed significantly (P<0.05) from autumn/winter for concentrations of biological oxygen demand (BOD), arsenic, barium (Ba), cobalt, chromium, manganese, strontium (Sr), titanium, tungsten (W) and zinc (Zn). With the exception of BOD, Ba and Sr which were greater in summer and spring, the concentrations of these parameters were greater in winter. Receiving stream waters also showed significant seasonal variation (P<=0.05) in alkalinity, BOD, dissolved organic carbon, sulphate, sulphur, lithium, W, Zn and Escherichiacoli abundance. There was a clear significant influence of STE on downstream waters relative to upstream from the source (P<0.05) for total suspended solids, total particulate P and N, ammonium-N, coliforms and E. coli. The findings of this study found seasonal variation in STE and place effluent discharges as a factor affecting adjacent stream quality and call for appropriate measures to reduce or redirect STE discharges away from water courses. PMID- 27474990 TI - Surface ozone levels in the forest and vegetation areas of the Biga Peninsula, Turkey. AB - Spatial and temporal variability of surface ozone in the rural, mountainous and suburban sites of Biga Peninsula, at the northwest of Turkey which is about 300km southwest of Istanbul was investigated using passive samplers and continuous analyzers. A total 10 passive samplers and two continuous analyzers were used between 1.1.2013 and 31.12.2014. OX levels in the study region were examined to understand NOx dependent or independent contribution to ozone. The influences of the meteorological parameters on ozone levels were also examined by wind speed and ambient temperature. The results clearly show that mountainous areas have higher cumulative exposure to ozone than suburban locations. In order to understand the long range transport sources contributing to the high ozone levels in the region backward trajectories were computed using HYSPLIT model and then clustering of trajectories are performed. The results clearly show the characteristics of pollutant transport from north to Biga Peninsula. Additionally, AOT40 (Accumulated hourly O3 concentrations Over a Threshold of 40ppb) cumulative index was calculated using daytime hourly measurements. The results indicate that the ozone values in the study area are much higher than the critical levels for forest and vegetation based on EU Directive 2008/50/EC. PMID- 27474991 TI - Geogenic and anthropogenic impacts on indoor radon in the Techa River region. AB - Indoor radon concentration was studied in the 14 settlements located near the Techa River, which was contaminated by radioactive wastes in 1950-s. Results of the radon survey were used for analysis of the relationship between the indoor radon and main geologic factors (Pre-Jurassic formations, Quaternary sediments and faults), local geogenic radon potential and anthropogenic factors. Main influencing factors explain 58% of the standard deviation of indoor radon concentration. Association of the air exchange influence over radon concentration with underlying geological media was related to different contributions of geogenic advective and diffusive radon entries. The properties of geological formation to transfer radon gas in interaction with the house can be considered within the radon geogenic potential concept. The study of the radon exposure of the Techa River population can be used to estimate the contribution of natural radon to the overall radiation exposure of the local population during the period of radioactive waste discharges. PMID- 27474992 TI - Environmental metabarcoding reveals contrasting microbial communities at two poplar phytomanagement sites. AB - The aim of the present study is to deepen the current understanding of the microbial communities at two poplar phytomanagement sites to reveal the environmental factors that drive the abundance, diversity and composition of microbial communities. A soil analysis revealed that the two soils displayed contrasting physico-chemical characteristics, with significant lower pH and higher Cd, Zn and Mn CaCl2-extractable fractions at Leforest site, compared with Pierrelaye site. The fungal and bacterial community profiles in the poplar roots and soils were assessed through Illumina MiSeq sequencing. Diversity indices and beta-diversity measures illustrated that the root microbial communities were well separated from the soil microbial communities at both sites. A detailed study of the fungal composition showed that Ascomycota dominated the overall fungal communities on poplar soil, the root samples at Pierrelaye, and the unplanted soil at the experimental sites. Conversely, Basidiomycota accounted for a much higher percentage of the fungal community in poplar root samples from the Leforest site. The root bacterial communities were dominated by Alphaproteobacteria and Actinobacteria, and the soil samples were dominated by Alphaproteobacteria and Acidobacteria. The occurrence and dominance of the ectomycorrhizal community at Leforest but not at Pierrelaye is the major feature of our data set. Overall, ectomycorrhizal root symbionts appeared to be highly constrained by soil characteristics at the phytomanagement sites. Our data support the view that mycorrhizal inoculation is needed in highly stressed and nutrient-poor environments. PMID- 27474993 TI - Captivating New Roles of F-Actin Cortex in Exocytosis and Bulk Endocytosis in Neurosecretory Cells. AB - The cortical actin network is a tight array of filaments located beneath the plasma membrane. In neurosecretory cells, secretory vesicles are recruited on this network via a small insert isoform of myosin VI in a Ca(2+)-dependent manner. Upon secretagogue stimulation, myosin II mediates a relaxation of the actin network leading to synchronous translocation of bound or caged vesicles to the plasma membrane where they undergo exocytosis. F-actin is also recruited to secretory sites, where structural changes are detected immediately preceding and following exocytic events. Here we examine the mechanism underpinning the astonishing multifunctionality of this network in the various stages of vesicular exocytosis and compensatory bulk endocytosis. We propose a theoretical framework incorporating critical roles of the actin network in coupling these processes. PMID- 27474994 TI - Malaria protection in Sierra Leone during the Ebola outbreak 2014/15; The UK military experience with malaria chemoprophylaxis Sep 14-Feb 15. AB - BACKGROUND: The UK deployed a task force to Sierra Leone to assist in ending the 2014/15 Ebola outbreak. Malaria protection was based on existing Defence Policy which saw a wide range of bite prevention measures deployed. Atovaquone/Proguanil ("A/P"), Doxycycline ("D") and Mefloquine ("M") were the chemoprophylactic medications that were prescribed. A survey was undertaken to audit the Adverse Effect (AE) burden experienced by the population. METHOD: A questionnaire based survey was administered that sought information on individuals' experiences with malaria chemoprophylaxis. RESULTS: 337 personnel were eligible to take part and 151 (46.3%) individuals returned questionnaires. The reported AE rates for the three drugs were "A/P" 28% of the respondents, "D" 25% and "M" 23.1%. 24 individuals (15.9%) reported 1 AE while 34 (22.5%) reported multiple AEs. Eight (5.3%) individuals changed medication (Five "A/P", two "M" and one "D") because of unacceptable AE but no significant neuro/psychological conditions were reported. The malaria attack rate for the deployed population was 0.4 cases per thousand person weeks which is very low when compared to other military deployments to the West African Area. CONCLUSION: UK Defence policy is effective in the way it balances the risk of malaria with that of AE due to chemoprophylaxis. "M" remains an acceptable chemoprophylactic agent for a section of the population. PMID- 27474996 TI - The Effectiveness of Pitch-raising Surgery in Male-to-Female Transsexuals: A Systematic Review. AB - OBJECTIVES: This study aimed to review the evidence of the effectiveness of pitch raising surgery performed in male-to-female transsexuals. METHODS: A search for studies was performed in PubMed, Web of Science, Science Direct, EBSCOhost, Google Scholar, and the references in retrieved manuscripts, using as keywords "transsexual" or "transgender" combined with terms related to voice surgery. We included eight studies using cricothyroid approximation, six studies using anterior glottal web formation, and six studies using other surgery types or a combination of surgical techniques, leading to 20 studies in total. RESULTS: Objectively, a substantial rise in postoperative fundamental frequency was identified. Perceptually, mainly laryngeal web formation seems risky for decreasing voice quality. The majority of patients seemed satisfied with the outcome. However, none of the studies used a control group and randomization process. Further investigation regarding long-term results is necessary. CONCLUSION: Future research needs to investigate long-term effects of pitch raising surgery using a stronger study design. PMID- 27474997 TI - Opposite Regulation of Ghrelin and Glucagon-like Peptide-1 by Metabolite G Protein-Coupled Receptors. AB - Gut hormones send information about incoming nutrients to the rest of the body and thereby control many aspects of metabolism. The secretion of ghrelin and glucagon-like protein (GLP)-1, two hormones with opposite secretory patterns and opposite actions on multiple targets, is controlled by a limited number of G protein coupled receptors (GPCRs); half of which recognize and bind dietary nutrient metabolites, metabolites generated by gut microbiota, and metabolites of the host's intermediary metabolism. Most metabolite GPCRs controlling ghrelin secretion are inhibitory, whereas all metabolite receptors controlling GLP-1 secretion are stimulatory. This dichotomy in metabolite sensor function, which is obtained through a combination of differential expression and cell-dependent signaling bias, offers pharmacological targets to stimulate GLP-1 and inhibit ghrelin through the same mechanism. PMID- 27474995 TI - Testosterone Therapy Among Prostate Cancer Survivors. AB - INTRODUCTION: The use of testosterone in men with a history of prostate cancer remains controversial in light of established findings linking androgens to prostate cancer growth. However, hypogonadism significantly affects quality of life and has negative sequelae, and the risks and benefits of testosterone therapy might be worthwhile to consider in all men, even those with a history of high-risk prostate cancer. AIM: To discuss the effects of testosterone on the prostate and the use of testosterone therapy in hypogonadal men with a history of prostate cancer. METHODS: Review of the literature examining the effects of testosterone on the prostate and the efficacy and safety of exogenous testosterone in men with a history of prostate cancer. MAIN OUTCOME MEASURES: Summary of effects of exogenous and endogenous testosterone on prostate tissue in vitro and in vivo, with a focus on effects in men with a history of prostate cancer. RESULTS: Testosterone therapy ameliorates the symptoms of hypogonadism, decreases the risk for its negative sequelae, and can significantly improve quality of life. Recent studies do not support an increased risk for de novo prostate cancer, progression of the disease, or biochemical recurrence in hypogonadal men with a history of non-high-risk prostate cancer treated with testosterone therapy. Evidence supporting the use of testosterone in the setting of high-risk prostate cancer is less clear. CONCLUSION: Despite the historical reluctance toward the use of testosterone therapy in men with a history of prostate cancer, modern evidence suggests that testosterone replacement is a safe and effective treatment option for hypogonadal men with non-high-risk prostate cancer. Additional work to definitively demonstrate the efficacy and safety of testosterone therapy in men with prostate cancer is needed, and persistent vigilance and surveillance of treated men remains necessary. PMID- 27474998 TI - Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding. AB - BACKGROUND: Semi-synthetic oleanane triterpenoid antioxidant inflammation modulators (tpAIMs) are small molecules that interact with KEAP1 cysteine residue 151 (C151) and activate NRF2. Exploration of the structure-activity relationship between the tpAIMs and KEAP1 is limited by the predominantly hydrocarbon nature of the oleanane triterpenoid pentacyclic ring structure. Therefore, we used novel, chemically-tractable, synthetic antioxidant inflammation modulators (sAIMs) to probe the stereoselectivity of the ligand-protein interaction. METHODS: We measured several parameters of NRF2 activation to assess the potency of sAIM enantiomers with natural (tpAIM-like) 4(S),5(S),10(R) or unnatural 4(R),5(R),10(S) configurations. Additionally, we determined the crystal structure of the KEAP1 BTB domain in complex with two different sAIMs. RESULTS: We found that the potencies of sAIM enantiomers in the natural configuration were similar to those of the tpAIM, RTA 405. Strikingly, sAIM enantiomers in the unnatural configuration were 10- to 40-fold less potent than their natural counterparts. Crystallographic studies of sAIMs in complex with the KEAP1 BTB domain demonstrated that these ligands form a covalent bond with C151 and revealed the presence of additional hydrogen bonds, Van der Waals interactions, and pi stacking interactions. CONCLUSIONS: Although KEAP1 C151 is required for NRF2 activation by tpAIMs and sAIMs, interactions with other KEAP1 residues are critical for the stereospecific recognition and potency of these ligands. GENERAL SIGNIFICANCE: This work demonstrates that reversible cyanoenone Michael acceptors, such as the tpAIMs and sAIMs, can be specifically tuned to regulate redox sensitive cysteine residues on key signaling molecules, an approach with significant promise for innovative drug development. PMID- 27474999 TI - Isolation and characterization of a structurally unique beta-hairpin venom peptide from the predatory ant Anochetus emarginatus. AB - BACKGROUND: Most ant venoms consist predominantly of small linear peptides, although some contain disulfide-linked peptides as minor components. However, in striking contrast to other ant species, some Anochetus venoms are composed primarily of disulfide-rich peptides. In this study, we investigated the venom of the ant Anochetus emarginatus with the aim of exploring these novel disulfide rich peptides. METHODS: The venom peptidome was initially investigated using a combination of reversed-phase HPLC and mass spectrometry, then the amino acid sequences of the major peptides were determined using a combination of Edman degradation and de novo MS/MS sequencing. We focused on one of these peptides, U1 PONTX-Ae1a (Ae1a), because of its novel sequence, which we predicted would form a novel 3D fold. Ae1a was chemically synthesized using Fmoc chemistry and its 3D structure was elucidated using NMR spectroscopy. The peptide was then tested for insecticidal activity and its effect on a range of human ion channels. RESULTS: Seven peptides named poneritoxins (PONTXs) were isolated and sequenced. The three dimensional structure of synthetic Ae1a revealed a novel, compact scaffold in which a C-terminal beta-hairpin is connected to the N-terminal region via two disulfide bonds. Synthetic Ae1a reversibly paralyzed blowflies and inhibited human L-type voltage-gated calcium channels (CaV1). CONCLUSIONS: Poneritoxins from Anochetus emarginatus venom are a novel class of toxins that are structurally unique among animal venoms. GENERAL SIGNIFICANCE: This study demonstrates that Anochetus ant venoms are a rich source of novel ion channel modulating peptides, some of which might be useful leads for the development of biopesticides. PMID- 27475000 TI - Neuroprotective hypothermia - Why keep your head cool during ischemia and reperfusion. AB - BACKGROUND: Targeted temperature management (TTM) is the induced cooling of the entire body or specific organs to help prevent ischemia and reperfusion (I/R) injury, as may occur during major surgery, cardiac resuscitation, traumatic brain injury and stroke. Ischemia and reperfusion induce neuronal damage by mitochondrial dysfunction and oxidative injury, ER stress, neuronal excitotoxicity, and a neuroinflammatory response, which may lead to activation of apoptosis pathways. SCOPE OF REVIEW: The aim of the current review is to discuss TTM targets that convey neuroprotection and to identify potential novel pharmacological intervention strategies for the prevention of cerebral ischemia and reperfusion injury. MAJOR CONCLUSIONS: TTM precludes I/R injury by reducing glutamate release and oxidative stress and inhibiting release of pro-inflammatory factors and thereby counteracts mitochondrial induced apoptosis, neuronal excitotoxicity, and neuroinflammation. Moreover, TTM promotes regulation of the unfolded protein response and induces SUMOylation and the production of cold shock proteins. These advantageous effects of TTM seem to depend on the clinical setting, as well as type and extent of the injury. Therefore, future aims should be to refine hypothermia management in order to optimize TTM utilization and to search for pharmacological agents mimicking the cellular effects of TTM. GENERAL SIGNIFICANCE: Bundling knowledge about TTM in the experimental, translational and clinical setting may result in better approaches for diminishing I/R damage. While application of TTM in the clinical setting has some disadvantages, targeting its putative protective pathways may be useful to prevent I/R injury and reduce neurological complications. PMID- 27475001 TI - Nuclear hormone receptor BmFTZ-F1 is involved in regulating the fibroin heavy chain gene in the silkworm, Bombyx mori. AB - BACKGROUND: The synthesis of silk protein is controlled by hormones. The expression of the nuclear hormone Bmftz-f1 in the posterior silk gland (PSG) is induced by 20-hydroxyecdysone in vivo and in vitro. However, whether Bmftz-f1 regulates silk protein expression is unknown. METHODS: In our study, western blotting and quantitative polymerase chain reactions were conducted to detect the expression of FTZ-F1 in the PSG. Electrophoretic mobility shift, chromatin immunoprecipitation, far-western blotting, bimolecular fluorescence complementation, and dual luciferase reporter assays were performed to investigate the effect of FTZ-F1 on the fibH promoter. RESULTS: (1) The expression of the hormone receptor BmFTZ-F1 was opposite to that of fibH. It was highly expressed in the PSG during the fourth molting stage and the beginning of the fifth instar, and then its expression decreased gradually until it disappeared at the end of the fifth instar and the wandering stage. (2) We identified a FTZ-F1 response element 390bp upstream of the transcription initiation site of the fibH promoter. (3) BmFTZ-F1 interacted with the basic helix-loop-helix transcription factor Bmdimm. (4) BmFTZ-F1 down-regulated fibH promoter activity and counteracted the effect of Bmdimm on fibH expression. CONCLUSIONS: Integrating these results, we conclude that BmFTZ-F1 regulates the transcription of fibH by binding to the FTZ-F1 response element in the fibH promoter and counteracts the effect of Bmdimm on fibH expression. GENERAL SIGNIFICANCE: These findings provide new insights into the mechanism of regulation of the silk protein gene. PMID- 27475002 TI - Calcium signaling mechanisms disrupt the cytoskeleton of primary astrocytes and neurons exposed to diphenylditelluride. AB - BACKGROUND: Diphenylditelluride (PhTe)2 is a potent neurotoxin disrupting the homeostasis of the cytoskeleton. METHODS: Cultured astrocytes and neurons were incubated with (PhTe)2, receptor antagonists and enzyme inhibitors followed by measurement of the incorporation of [32P]orthophosphate into intermediate filaments (IFs). RESULTS: (PhTe)2 caused hyperphosphorylation of glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits (NFL, NFM and NFH) from primary astrocytes and neurons, respectively. These mechanisms were mediated by N-methyl-d-aspartate (NMDA) receptors, L-type voltage-dependent calcium channels (L-VDCCs) as well as metabotropic glutamate receptors upstream of phospholipase C (PLC). Upregulated Ca(2+) influx activated protein kinase A (PKA) and protein kinase C (PKC) in astrocytes causing hyperphosphorylation of GFAP and vimentin. Hyperphosphorylated (IF) together with RhoA-activated stress fiber formation, disrupted the cytoskeleton leading to altered cell morphology. In neurons, the high intracellular Ca(2+) levels activated the MAPKs, Erk and p38MAPK, beyond PKA and PKC, provoking hyperphosphorylation of NFM, NFH and NFL. CONCLUSIONS: Our findings support that intracellular Ca(2+) is one of the crucial signals that modulate the action of (PhTe)2 in isolated cortical astrocytes and neurons modulating the response of the cytoskeleton against the insult. GENERAL SIGNIFICANCE: Cytoskeletal misregulation is associated with neurodegeneration. This compound could be a valuable tool to induce molecular changes similar to those found in different pathologies of the brain. PMID- 27475003 TI - [Innovations in medical undergraduate pathology education: The Paris Descartes medicine faculty experience]. AB - At the Paris Descartes medicine faculty, we tested some newly developed tools to enhance the pedagogic value of the pathology teaching. In our faculty, this teaching is largely multidisciplinary and integrated in various teaching units; a large part is dedicated to practice works with thirteen 90min sessions. Virtual slides have been used for years in numerous medicine faculties; we successfully implemented this tool by adding contextual annotations, which facilitate students revising. We showed that rewarding students' assiduity enhanced their exam success. To do so, we now propose a short continuous assessment exam at the beginning of each practice session in the form of electronic multi-choice questions. Finally, we now propose a completely computerized final exam, on touchpads, that enhanced its docimologic value. PMID- 27475004 TI - [Neu-Laxova syndrome: Three case reports and a review of the literature]. AB - INTRODUCTION: The Neu-Laxova syndrome (NLS) is a rare autosomal recessive and early lethal disorder. It is characterized by severe intra-uterine growth retardation, abnormal facial features, ichthyotic skin lesions and severe central nervous system malformations, especially microlissencephaly. Others characteristic features associated with fetal hypokinesia sequence, including arthrogryposis, subcutaneous edema and pulmonary hypoplasia, are frequently reported in NLS. PATIENTS AND METHODS: The clinicopathological characteristics of NLS are described in three cases with striking prenatal diagnostic findings and detailed post-mortem examinations. A review of the literature is undertaken with a focus on molecular basis. RESULTS: We present three new patients with NLS: one stillbirth male and two female newborns, delivered at 29, 35 and 40 weeks of gestational age, respectively. Characteristic ultrasound findings included hydramnios, severe intra-uterine growth restriction, craniofacial and cental nervous system anomalies. The cytogenetic study, performed in one case, was normal. The post-mortem examination revealed characteristic abnormalities in all three cases, that allowed to make a prompt diagnosis of the NLS. Data from these patients suggest that the NLS represents a heterogeneous phenotype. This feature has been highlighted in the literature. CONCLUSION: The SNL is a lethal developmental disorder characterized by phenotypic heterogeneity with striking neurological defects. It is underpinned by genetic heterogeneity. It can be caused by mutations in all three genes involved in de novo L-serine biosynthesis: PHGDH, PSAT1 and PSPH. Hence, the NLS constitutes the most severe end of already known human disease, i.e. serine-deficiency disorder. PMID- 27475005 TI - [Endobronchial aspergilloma revealing a bronchial carcinoma]. AB - Endobronchial aspergillosis is a rare presentation of pulmonary aspergillosis in immunocompetent patients; this raises questions about structural changes inducing airflow stasis in order to colonize the bronchial lumen. We present the case of a patient diagnosed with endobronchial aspergilloma covering a bronchial adenocarcinoma. PMID- 27475006 TI - [Vaginal adenosis: A case report and literature review]. AB - We report a case of vaginal adenosis in a woman of 42years. This is a rare congenital disorder since cessation of use of diethylstilbestrol (DES), usually of benign course, not to ignore in its tubo-endometrial histological form which may progress to atypical adenosis precursor of vaginal clear cell adenocarcinoma in patients exposed in utero to DES. PMID- 27475008 TI - Current Trends in Geriatric Emergency Medicine. AB - The number of geriatric visits to United States emergency departments continues to rise. This article reviews demographics, statistics, and future projections in geriatric emergency medicine. Included are discussions of US health care spending, geriatric emergency departments, prehospital care, frailty of geriatric patients, delirium, geriatric trauma, geriatric screening and prediction tools, medication safety, long-term care, and palliative care. PMID- 27475007 TI - [Sinonasal fungal infections are not exclusively due to mucorales and Aspergillus!]. AB - Rhino-sinusal infections are serious diseases and possibly lethal. When they are invasive, we easily discuss apergilloses and mucormycoses. The confirmation of the diagnosis of mucormycosis need an extensive surgery for precise histopathological and mycological evaluation. The pathologist may be faced to other rare mycoses such as phaeohyphomycoses, which present different morphological features than mucormycoses and Aspergillus. Once the diagnosis is established, an appropriate antifungal treatment is quickly started. The aim of our work is to report two observations of phaeohyphomycoses, to describe their histopathological features, to discuss complementary diagnostic methods and to present the main differential diagnoses. PMID- 27475009 TI - Geriatric Resuscitation. AB - The geriatric population makes up a large portion of the emergency patient population. Geriatric patients have less reserve and more comorbid diseases. They are frequently on multiple medications and are more likely to require aggressive treatment during acute illness. Although it may not be obvious, it is important to recognize the signs of shock as early as possible. Special care and monitoring should be used when resuscitating the elderly. The use of bedside ultrasound and monitoring for coagulopathies are discussed. Clinicians should be constantly vigilant and reassess throughout diagnosis and treatment. Ethical considerations in this population need to be considered on an individual basis. PMID- 27475010 TI - Pharmacology in the Geriatric Patient. AB - The aging population of the United States creates pharmaceutical challenges for the practicing emergency physician. Polypharmacy, drug-drug and drug-disease interactions, and other pharmaceutical complications from the pathophysiologic changes associated with aging need to be recognized in order to optimize outcomes in the elderly. Effective strategies that improve patients outcomes include a better understanding of the physiologic and pharmacologic changes that occur with aging, integrated use of clinical emergency department pharmacists, and choosing nonpharmacologic treatment options when possible. PMID- 27475011 TI - Geriatric Trauma. AB - Within the next 15 years, 1 in 5 Americans will be over age 65. $34 billion will be spent yearly on trauma care of this age group. This section covers situations in trauma unique to the geriatric population, who are often under-triaged and have significant injuries underestimated. Topics covered include age-related pathophysiological changes, underlying existing medical conditions and certain daily medications that increase the risk of serious injury in elderly trauma patients. Diagnostic evaluation of this group requires liberal testing, imaging, and a multidisciplinary team approach. Topics germane to geriatric trauma including hypothermia, elder abuse, and depression and suicide are also covered. PMID- 27475013 TI - Evaluation and Management of Chest Pain in the Elderly. AB - Geriatric patients are at increased risk for serious morbidity and mortality from life-threatening causes of chest pain. This article covers 5 life-threatening causes of chest pain in the elderly: acute coronary syndrome, aortic dissection, pulmonary embolism, pneumothorax, and esophageal rupture. Atypical presentations, frailty, and significant comorbidities that characterize the elderly make the diagnosis and treatment of these already complicated conditions even more complicated. The emergency provider must be vigilant and maintain a low threshold to test. When a diagnosis is made, treatment must be aggressive. The elderly benefit from optimal care. PMID- 27475014 TI - Dyspnea in the Elderly. AB - This article discusses the evaluation and management of stable and unstable elderly patients with dyspnea. Several of the changes in the elderly that alter cardiopulmonary physiology are discussed. A review of common presenting illnesses and their evaluation and management are highlighted. The reader should be left with a better understanding of this unique population and the overall evaluation and treatment. PMID- 27475012 TI - Sepsis and Other Infectious Disease Emergencies in the Elderly. AB - Waning immunity and declining anatomic and physiologic defenses render the elder vulnerable to a wide range of infectious diseases. Clinical presentations are often atypical and muted, favoring global changes in mental status and function over febrile responses or localizing symptoms. This review encompasses early recognition, evaluation, and appropriate management of these common infections specifically in the context of elders presenting to the emergency department. With enhanced understanding and appreciation of the unique aspects of infections in the elderly, emergency physicians can play an integral part in reducing the morbidity and mortality associated with these often debilitating and life threatening diseases. PMID- 27475015 TI - Abdominal Pain in the Geriatric Patient. AB - With an aging population, emergency department clinicians can expect an increase in geriatric patients presenting with abdominal pain. Compared with younger patients, this patient population is less likely to present with classic symptoms, physical examination findings, and laboratory values of abdominal disease. However, the morbidity and mortality associated with elderly patients presenting with abdominal pathologic conditions are significant. For this reason, the clinician must be familiar with some subtle and not so subtle differences when caring for the geriatric patient with abdominal pain to ensure timely diagnosis and appropriate treatment. PMID- 27475016 TI - Neurologic Emergencies in the Elderly. AB - Neurologic diseases are a major cause of death and disability in elderly patients. Due to the physiologic changes and increased comorbidities that occur as people age, neurologic diseases are more common in geriatric patients and a major cause of death and disability in this population. This article discusses the elderly patient presenting to the emergency department with acute ischemic stroke, transient ischemic attack, intracerebral hemorrhage, subarachnoid hemorrhage, chronic subdural hematoma, traumatic brain injury, seizures, and central nervous system infections. This article reviews the subtle presentations, difficult workups, and complicated treatment decisions as they pertain to our older patients." PMID- 27475017 TI - Evaluation of Syncope in Older Adults. AB - The older adult patient with syncope is one of the most challenging evaluations for the emergency physician. It requires clinical skill, patience, and knowledge of specific older adult issues. It demands care in the identification of necessary resources, such as medication review, and potential linkage with several multidisciplinary follow-up services. Excellent syncope care likely requires reaching out to ensure institutional resources are aligned with emergency department patient needs, thus asking emergency physicians to stretch their administrative talents. This is likely best done as preset protocols prior to individual patient encounters. Emergency physicians evaluate elders with syncope every day and should rise to the challenge to do it well. PMID- 27475018 TI - The Geriatric Emergency Department. AB - This article presents an overview of the complex needs of older patients presenting to the emergency department for care. Discussion points for hospital communities considering emergency services to accommodate the aging population are highlighted. The essential components of a geriatric emergency department, including transition of care strategies, are reviewed. PMID- 27475019 TI - Altered Mental Status and Delirium. AB - Older patients who present to the emergency department frequently have acute or chronic alterations of their mental status, including their level of consciousness and cognition. Recognizing both acute and chronic changes in cognition are important for emergency physicians. Delirium is an acute change in attention, awareness, and cognition. Numerous life-threatening conditions can cause delirium; therefore, prompt recognition and treatment are critical. The authors discuss an organized approach that can lead to a prompt diagnosis within the time constraints of the emergency department. PMID- 27475020 TI - Palliative Care in the Emergency Department. AB - As the geriatric population increases in the United States, there is an increase in number of visits to emergency departments for end-of-life and palliative care. This provides the emergency physician with a unique opportunity to alleviate and prevent further suffering in this vulnerable population. Competency in communication strategies that support shared decision making and familiarity with medicolegal terminology increase physician confidence about addressing complaints at the end of life. Familiarity with evidence-based recommendations for symptom management of pain at the end of life aids the emergency physician in creating a positive experience for the patient and their loved ones. PMID- 27475022 TI - Geriatric Emergency Medicine. PMID- 27475021 TI - Zika Virus: Critical Information for Emergency Providers. AB - Zika virus is an arbovirus of the Flaviviridae family. It is primarily a minimally symptomatic mosquito-borne infection. However, with Zika's 2015 to 2016 introduction into the Western Hemisphere and its dramatic and rapid spread, it has become a public health concern, in large part due to congenital abnormalities associated with infection in pregnant women. In early 2016, the World Health Organization declared the microcephaly and other neurologic conditions associated with Zika virus infection a public health emergency of international concern. This article discusses the current epidemiologic and clinical understanding of Zika virus, focusing on critical information needed by emergency providers. PMID- 27475023 TI - Geriatric Emergencies. PMID- 27475024 TI - Comparison of 1,3-beta-d-glucan with galactomannan in serum and bronchoalveolar fluid for the detection of Aspergillus species in immunosuppressed mechanical ventilated critically ill patients. AB - PURPOSE: Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity/mortality in immunocompromised critically ill patients. New diagnostic strategies for early detection of IPA include the noninvasive biomarkers 1,3-beta d-glucan (BDG), serum, and bronchoalveolar (BAL) fluid galactomannan (GM). The aim of this study was to compare these markers for early detection of IPA in immunosuppressed critically ill patients. METHODS: Between December 2014 and December 2015, 49 immunosuppressed patients with respiratory failure were treated at our intensive care unit (ICU). We compared the BDG Fungitell assay with GM Platelia assay in serum and BAL for early detection of IPA. All tests were performed initially after admission at the ICU. RESULTS: In our study with 49 patients, 13 (26%) had probable IPA. These patients had a higher Acute Physiology And Chronic Health Evaluation II score (28 vs 23, P<.001), Sequential Organ Failure Assessment score (16 vs 14, P<.001), more neutropenia (77% vs 30%, P<.001), worse Horowitz Index (99 vs 73 P<.020), a longer ICU stay (26 vs 17 days, P<.044), and a higher mortality rate (77% vs 58%, P<.001) as compared with patients without probable IPA. The used biomarker BDG presented in patients with probable IPA showed significantly higher levels as compared with patients without probable IPA (375 [103-1000 pg/mL; P<.001] vs 64 [30-105 pg/mL; P < .001]). Comparison of BDG with GM showed that positive serum GM could be detected in only 4 (30%), whereas positive BAL GM could be detected in 12 (92%; mean optical density index, 3.7) of 13 probable IPA cases. These results can be expressed as an overall sensitivity of 88% and a specificity of 82% for probable IPA using the BDG Fungitell assay, a sensitivity of 35% and a specificity of 70% using the serum GM Platelia assay, and a sensitivity of 70% and a specificity of 94% using the BAL GM Platelia assay. The negative predictive values of the used tests were 94% for the BDG Fungitell assay, 94% for the serum GM Platelia assay, and 90% for the BAL GM Platelia assay. CONCLUSION: 1,3-beta-d-Glucan may be a useful marker for patients under surveillance at risk for IPA. In critically ill patients with immunosuppression, early diagnosis of IPA may be improved by BDG as compared with serum GM. However, diagnostic performance and accuracy increase when BDG is run in parallel with GM from BAL; moreover, the association of the 2 parameters has also the advantage of detecting early and reliable IPA. PMID- 27475025 TI - Cimetidine disrupts the renewal of testicular cells and the steroidogenesis in a hermaphrodite fish. AB - The importance of histamine in the physiology of the testis in mammals and reptiles has been recently shown. Histamine receptors (Hrs) are well conserved in fish and are functional in several fish species. We report here for the first time that histamine and the mRNA of Hrh1, Hrh2 and Hrh3 are all present in the gonad of the hermaphrodite teleost fish gilthead seabream. Moreover, cimetidine, which acts in vitro as an agonist of Hrh1 and Hrh2 on this species, was intraperitoneally injected in one and two years old gilthead seabream males. After three and five days of cimetidine injection, we found that this compound differently modified the gonadal hrs transcript levels and affects the testicular cell renewal and the gene expression of steroidogenesis-related molecules as well as the serum steroid levels. Our data point to cimetidine as a reproductive disruptor and elucidate a role for histamine in the gonad of this hermaphrodite fish species through Hr signalling. PMID- 27475027 TI - Controversies in Veterinary Nephrology: Differing Viewpoints: Role of Dietary Protein in the Management of Feline Chronic Kidney Disease. AB - The role of diet in management of chronic kidney disease (CKD) is important. There are different interpretations of the current knowledge on this topic. Neither clinical trials involving product testing, nor prospective research investigating dietary influences on cats with induced kidney disease provide guidance on the utility of specific nutritional strategies. Likewise, data derived from other species also has limitations. More research is needed to further our understanding of this topic. However, practical guidance from current knowledge for the management of individual patients can be utilized with success. PMID- 27475026 TI - Sodium fluoride induces hypercalcemia resulting from the upregulation of both osteoblastic and osteoclastic activities in goldfish, Carassius auratus. AB - The influence of sodium fluoride (NaF) on calcium metabolism was examined in goldfish (fresh water teleost). At 2days after administration of NaF (500ng/g body weight; 5MUg/g body weight) (around 10(-5) to 10(-4)M in goldfish), we indicated that plasma calcium levels upregulated in both doses of NaF-treated goldfish. To examine the mechanism of hypercalcemia by NaF treatments, therefore, direct effects of NaF on osteoblasts and osteoclasts in goldfish were investigated by an original assay system using teleost scale which has osteoblasts, osteoclasts and bone matrix. Alkaline phosphatase activity in the scales increased with the treatment of NaF (10(-6) and 10(-5)M) during 6h of incubation. Also, tartrate-resistant acid phosphatase activity increased after exposure to NaF (10(-5)M) at the 6h of incubation. To investigate the osteoclastic activation, the mRNA expression of osteoclastogenesis related factors were examined. The receptor activator of the nuclear factor-kappaB ligand (RANKL) which is known as a factor for osteoclastogenesis, increased in the NaF treated scales after 6h of incubation. The ratio of RANKL/osteoprotegerin (osteoclastogenesis inhibitory factor) significantly increased after 6h of incubation. Resulting from the increase of RANKL mRNA level, the expression of transcription-regulating factors was significantly increased. Furthermore, the expression of functional genes, cathepsin K and matrix metalloproteinase-9 mRNA, was significantly increased. In our knowledge, this is the first report concerning the effects of NaF on osteoblasts and osteoclasts in teleosts. We concluded that NaF influences calcium metabolism via osteoclastic activation in goldfish. PMID- 27475028 TI - [Tap water vs. sterile saline for cleaning acute and chronic wounds]. PMID- 27475029 TI - [Differentiation between moisture lesions and pressure ulcers using photographs in a critical area]. AB - OBJECTIVES: To identify difficulties for nurses in differentiating between moisture lesions and pressure ulcers, proper classification of pressure ulcers to assess the adequate classification of the Grupo Nacional para el Estudio y Asesoramiento de Ulceras por Presion y Heridas Cronicas (GNEAUPP) and the degree of agreement in the correct assessment by type and category of injury. METHOD: Cross-sectional study in a critical area during 2014. All nurses who agreed to participate were included. They performed a questionnaire with 14 photographs validated by experts of moisture lesions or pressure ulcers in the sacral area and buttocks, with 6 possible answers: Pressure ulcer category I, II, III, IV, moisture lesions and unknown. Demographics and knowledge of the classification system of the pressure ulcers were collected according to GNEAUPP. RESULTS: It involved 98% of the population (n=56); 98.2% knew the classification system of the GNEAUPP; 35.2% of moisture lesions were considered as pressure ulcers, most of them as a category II (18.9%). The 14.8% of the pressure ulcers photographs were identified as moisture lesions and 16.1% were classified in another category. The agreement between nurses earned a global Kappa index of .38 (95% CI: .29-.57). CONCLUSION: There are difficulties differentiating between pressure ulcers and moisture lesions, especially within initial categories. Nurses have the perception they know the pressure ulcers classification, but they do not classify them correctly. The degree of concordance in the diagnosis of skin lesions was low. PMID- 27475030 TI - [Microsurgery in children]. AB - While we celebrated the fortieth anniversary of the first free flap in children, new techniques emerged in reconstructive surgery (NPT, artificial dermis...) and reduced microsurgery procedures. However, microsurgery in children as in adults still have clinical applications in reconstructive surgery. Free flaps remain essential in clinical situations where they are the only ones to provide capacity for growth and stability scarring, two elements essential to the future quality of life of the children. PMID- 27475031 TI - [Addition to the dorsal decubitus position for scapular based flap harvest: The Spider(r) limb positioning system]. AB - Subscapular vascular system based flaps provide excellent solutions for the coverage of a large variety of soft tissue defects. Dorsal decubitus position allows two teams of surgeons to work simultaneously and to harvest the flap in both an effective and safer way. Previously described for orthopaedic surgery, the Spider(r) limb positioning system offers a precious addition to the technique, giving a simple mean to keep the arm in the desired position while harvesting the flap. The need for an assistant to hold the upper limb is no longer required, enabling him to help in a more effective and time sparing way during surgery. PMID- 27475032 TI - The Detroit Young Adult Asthma Project: Pilot of a Technology-Based Medication Adherence Intervention for African-American Emerging Adults. AB - PURPOSE: To conduct a randomized controlled pilot of a multicomponent, technology based intervention promoting adherence to controller medication in African American emerging adults with asthma. The intervention consisted of two computer delivered sessions based on motivational interviewing combined with text messaged reminders between sessions. METHODS: Participants (N = 49) were 18-29 years old, African-American, with persistent asthma requiring controller medication. Participants had to report poor medication adherence and asthma control. Youth were randomized to receive the intervention or an attention control. Data were collected through computer-delivered self-report questionnaires at baseline, 1, and 3 months. Ecological Momentary Assessment via two-way text messaging was also used to collect "real-time" data on medication use and asthma control. RESULTS: The intervention was feasible and acceptable to the target population, as evidenced by high retention rates and satisfaction scores. Changes in study outcomes from pre- to postintervention favored the intervention, particularly for decrease in asthma symptoms, t (42) = 2.22, p < .05 (Cohen's d = .071). CONCLUSIONS: Results suggest that the intervention is feasible and effective. However, findings are preliminary and should be replicated with a larger sample and more sophisticated data analyses. PMID- 27475033 TI - Horses seropositive for Toxoplasma gondii, Sarcocystis spp. and Neospora spp.: Possible risk factors for infection in Brazil. AB - Many parasitic diseases are considered asymptomatic, even though some studies have shown that they may cause pathological changes in the host. Therefore, the aim of this study was to evaluate the occurrence of antibodies against Toxoplasma gondii, Neospora spp. and Sarcocystis spp. in horses, and to identify the risk factors for disease. For this, 174 horses were studied, 90 males and 84 females aged between two and 20 years old. Blood samples were collected and stored in tubes without anticoagulant to obtain serum, which was subjected to serological tests for T. gondii, Sarcocystis spp., and Neospora spp. using indirect immunofluorescence assay (IFA). IFA results were as follows: Sarcocystis spp. 41.37% (72/174) (CI95%-34.05-49.09); T. gondii 32.18% (56/174) (CI95%-25.42 39.74) and Neospora spp. 48.27% (84/174) (CI95%-40.68.50-55.93). Out of 174 horses, 81 had simple infection, 61 had mixed infections with two or three of these pathogens, and therefore, only 32 horses showed no antibodies to any of these pathogens. No risk factors for Sarcocystis spp. and T. gondii infection were identified. However, there was a significant (1.22-CI95%-1.02-1.52) relationship between animal age and Neospora spp. infection, since older animals showed higher prevalence. Therefore, it was possible to conclude that T. gondii and Neospora spp. affect horses in Southern Brazil, however all the animals studied were asymptomatic without reproductive, neurological or locomotor problems. PMID- 27475034 TI - Perspectives on variability in pharmacokinetics of an oral contraceptive product. AB - The early literature and reviews have described the pharmacokinetics (PK) of oral contraceptive (OC) compounds such as ethinyl estradiol (EE) and levonorgestrel (LNG) in women as subject to large intersubject variability. This was partly due to the use of diverse radioimmunoassays, limited sampling periods and an incomplete understanding of single- vs. multiple-dose kinetics and the role of EE in causing both inhibition of hepatic metabolism along with induction of sex hormone binding globulin. Over the past two decades, LNG and EE have been used as target drugs for the assessment of possible drug interactions upon introduction of many new therapeutic agents. This has resulted in at least 17 publications that describe the PK of LNG and EE in women using various 150 mcg/30 mcg products under fairly standard multiple-dose conditions. A review of these studies indicates only moderate variability in the Cmax and area under the curve both within and across these studies. There is impressive similarity in these drug exposure indices found in studies carried out with several products by investigators at numerous sites and countries. PMID- 27475036 TI - Alzheimer Mythology: A Time to Think Out of the Box. PMID- 27475035 TI - Levonorgestrel butanoate intramuscular injection does not reliably suppress ovulation for 90 days in obese and normal-BMI women: a pilot study. AB - BACKGROUND: We performed a pilot evaluation of a new formulation of levonorgestrel butanoate (LB) designed to be a long-acting injectable (6 months) contraceptive to determine pharmacodynamic end points in normal-body mass index (BMI) and obese women. STUDY DESIGN: Obese (BMI >=30 kg/m2) and normal-BMI, otherwise healthy, women received a single intramuscular injection of LB after ovulation was confirmed in a baseline cycle. The primary outcome was return of ovulation in days. RESULTS: A total of 14 women enrolled and completed the study [normal BMI n=9, median BMI 22.7kg/m2 (range 19.4-25.8); obese n=5, median BMI 35.7kg/m2 (30.1-39.2)]. The first 6 subjects (normal BMI=4/9, obese BMI=2/5) received 40 mg of LB, and the remaining 8 received 20 mg. All women except one returned to ovulation prior to 6 months. Return to ovulation occurred earlier in the obese group; 3/5 obese and 0/9 normal BMI subjects returned to ovulation within 90 days (p=.03). No serious adverse events were reported during the study. CONCLUSION: Return to ovulation was earlier than 6 months in both BMI groups but more so in the obese BMI group. IMPLICATIONS: Since return of ovulation was earlier than expected for this LB injectable formulation, additional steps are needed to develop a preparation suitable as a longer-lasting product. PMID- 27475037 TI - Separating and characterizing functional alkane degraders from crude-oil contaminated sites via magnetic nanoparticle-mediated isolation. AB - Uncultivable microorganisms account for over 99% of all species on the planet, but their functions are yet not well characterized. Though many cultivable degraders for n-alkanes have been intensively investigated, the roles of functional n-alkane degraders remain hidden in the natural environment. This study introduces the novel magnetic nanoparticle-mediated isolation (MMI) technology in Nigerian soils and successfully separates functional microbes belonging to the families Oxalobacteraceae and Moraxellaceae, which are dominant and responsible for alkane metabolism in situ. The alkR-type n-alkane monooxygenase genes, instead of alkA- or alkP-type, were the key functional genes involved in the n-alkane degradation process. Further physiological investigation via a BIOLOG PM plate revealed some carbon (Tween 20, Tween 40 and Tween 80) and nitrogen (tyramine, l-glutamine and d-aspartic acid) sources promoting microbial respiration and n-alkane degradation. With further addition of promoter carbon or nitrogen sources, the separated functional alkane degraders significantly improved n-alkane biodegradation rates. This suggests that MMI is a promising technology for separating functional microbes from complex microbiota, with deeper insight into their ecological functions and influencing factors. The technique also broadens the application of the BIOLOG PM plate for physiological research on functional yet uncultivable microorganisms. PMID- 27475038 TI - Activation of Tag1 transposable elements in Arabidopsis dedifferentiating cells and their regulation by CHROMOMETHYLASE 3-mediated CHG methylation. AB - Dedifferentiation, that is, the acquisition of stem cell-like state, commonly induced by stress (e.g., protoplasting), is characterized by open chromatin conformation, a chromatin state that could lead to activation of transposable elements (TEs). Here, we studied the activation of the Arabidopsis class II TE Tag1, in which two copies, situated close to each other (near genes) on chromosome 1 are found in Landsberg erecta (Ler) but not in Columbia (Col). We first transformed protoplasts with a construct in which a truncated Tag1 (DeltaTag1 non-autonomous) blocks the expression of a reporter gene AtMBD5-GFP and found a relatively high ectopic excision of DeltaTag1 accompanied by expression of AtMBD5-GFP in protoplasts derived from Ler compared to Col; further increase was observed in ddm1 (decrease in DNA methylation1) protoplasts (Ler background). Ectopic excision was associated with transcription of the endogenous Tag1 and changes in histone H3 methylation at the promoter region. Focusing on the endogenous Tag1 elements we found low level of excision in Ler protoplasts, which was slightly and strongly enhanced in ddm1 and cmt3 (chromomethylase3) protoplasts, respectively, concomitantly with reduction in Tag1 gene body (GB) CHG methylation and increased Tag1 transcription; strong activation of Tag1 was also observed in cmt3 leaves. Notably, in cmt3, but not in ddm1, Tag1 elements were excised out from their original sites and transposed elsewhere in the genome. Our results suggest that dedifferentiation is associated with Tag1 activation and that CMT3 rather than DDM1 plays a central role in restraining Tag1 activation via inducing GB CHG methylation. PMID- 27475039 TI - Urinary levels of phthalate metabolites and cardiovascular disease mortality (NHANES, 1999-2008). AB - BACKGROUND: Mechanistic data and results from a limited number of cross-sectional epidemiologic studies have suggested a possible link between phthalates and adverse cardiovascular outcomes. OBJECTIVE: To evaluate the association between urinary levels of eight phthalate metabolites and subsequent risk of cardiovascular death in a prospective cohort analysis. METHODS: We identified 5080 individuals 40 years or older who participated in the continuous National Health and Nutrition Examination Survey (NHANES) from 1999 to 2008 and who had measured phthalate levels available. We a priori excluded individuals in later cycles of NHANES with measured phthalates so as to have the potential of at least three years of follow-up time on all members of the cohort. Questionnaire, exam and laboratory data were merged with a public access NHANES mortality file updated through December 31, 2011. The associations between cardiovascular death and quartile levels of the phthalate metabolites were investigated using Cox proportional hazard models. RESULTS: There were 175 deaths due to cardiovascular disease deaths over a mean of 7.0 years of follow-up. No association between cardiovascular disease mortality and individual urinary phthalate metabolites was observed. After adjustments, hazard ratios comparing the highest to lowest quartile ranged from 0.73 (95%CI: 0.5-1.2) for mono-ethyl phthalate [MEP] to 1.4 (95%CI:0.8-2.5) for mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP]. CONCLUSIONS: Urinary levels of phthalate metabolites were not associated with increased cardiovascular disease mortality. Additional larger cohort studies with longer follow-up focused on cardiovascular disease incidence are needed. PMID- 27475040 TI - Prognostic significance of C5a2 on polymorphonuclear neutrophil and C5a2intra/C5a2 ratio level for early sepsis in an ED. AB - INTRODUCTION: The current study was designed to evaluate the expression of the second C5a receptor (C5a2) on polymorphonuclear neutrophil and in the cytoplasm of polymorphonuclear neutrophils (C5a2intra) in patients with sepsis in the emergency department (ED) for risk stratification and mortality. METHODS: Consecutive patients fulfilling the criteria for systemic inflammatory response syndrome (n = 357) were admitted to Beijing Chao-Yang Hospital ED between January 2015 and July 2015. They were enrolled to identify the expression of C5a2 and C5a2intra and categorized into the following 4 groups: systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock. RESULTS: We report that the surface C5a2 decreased and the C5a2intra/C5a2 ratio level increased with sepsis severity. As independent predictors of 28-day mortality, the areas under the receiver operating characteristic curves of combination of C5a2 or C5a2intra/C5a2 ratio level and the Mortality in ED Sepsis score were significantly higher than that of procalcitonin alone in predicting 28-day mortality in septic patients. CONCLUSION: The C5a2 and the C5a2intra/C5a2 ratio levels are probably valuable for the risk stratification of sepsis and are associated with the mortality of early sepsis in the ED. PMID- 27475041 TI - Diseases associated with electrolyte imbalance in the ED: age-related differences. AB - OBJECTIVE: The objective of the study is to investigate the prevalence of electrolyte imbalance (EI) in the emergency department (ED) with systemic diseases in different decades of life. METHODS: We enrolled patients admitted to the ED. The population study included 7941 patients, subdivided in 3 groups: young group (Y), middle-aged group (MA), and elderly group (E). RESULTS: We observed EI in 13.7% of the whole population. Hyponatremia (hNa+) is the most frequent EI (44%) followed by hypokalemia (hK+) (39%), hyperkalemia (HK+) (13%), and hypernatremia (HNa+) (4.4%). In the Y group, the EI occurred in 7.1% of all patients (P< .05 vs MA and E), whereas in the MA group, they were shown in 11.5% of patients and in the E group in 22% of all patients group (P< .05 vs MA and Y). In the Y group, gastrointestinal diseases are the most frequently associated disease (24.6%; P< .05 vs MA and E). In the MA group, the most frequently associated disease was a current cardiovascular disease (29.7%; P< .05 vs Y and E). In the E group, the frequently associated diseases are cardiovascular (22.8%; P< .05 vs Y) and lung diseases (16.7%; P< .05 vs MA and Y). CONCLUSIONS: In our study, 13.7% of all patients showed an EI, and only 2% of cases were alone without any associated systemic disease. Most EIs are associated to other systemic diseases. The present data also depict different age-related and disease associated prevalence patterns of EI, thus highlighting a complex clinical scenario. PMID- 27475042 TI - Acupuncture vs intravenous morphine in the management of acute pain in the ED. AB - BACKGROUND: Acupuncture is one of the oldest techniques to treat pain and is commonly used for a large number of indications. However, there is no sufficient evidence to support its application in acute medical settings. METHODS: This was a prospective, randomized trial of acupuncture vs morphine to treat ED patients with acute onset moderate to severe pain. Primary outcome consists of the degree of pain relief with significant pain reduction defined as a pain score reduction >=50% of its initial value. We also analyzed the pain reduction time and the occurrence of short-term adverse effects. We included in the protocol 300 patients with acute pain: 150 in each group. RESULTS: Success rate was significantly different between the 2 groups (92% in the acupuncture group vs 78% in the morphine group P<.001). Resolution time was 16+/-8 minutes in the acupuncture group vs 28+/-14 minutes in the morphine group (P<.005). Overall, 89 patients (29.6%) experienced minor adverse effects: 85 (56.6%) in morphine group and 4 (2.6%) in acupuncture group (P<.001). No major adverse effects were recorded during the study protocol. In patients with acute pain presenting to the ED, acupuncture was associated with more effective and faster analgesia with better tolerance. CONCLUSION: This article provides an update on one of the oldest pain relief techniques (acupuncture) that could find a central place in the management of acute care settings. This should be considered especially in today's increasingly complicated and polymedicated patients to avoid adverse drug reactions. PMID- 27475043 TI - RIFM fragrance ingredient safety assessment, linalyl cinnamate, CAS Registry Number 78-37-5. AB - The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03 and 1.4 mg/day, respectively). The developmental toxicity endpoint was completed using linalool (CAS # 78-70-6), dehydrolinalool (CAS # 29171-20-8) and cinnamic acid (CAS # 621-82-9) as suitable read across analogs, which provided a MOE > 100. The repeated dose toxicity endpoint was completed using data on the target material which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework. PMID- 27475044 TI - RIFM fragrance ingredient safety assessment, 2-methylundecanol, CAS Registry Number 10522-26-6. AB - This material was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the suitable read across analogs 2-butyloctan-1-ol (CAS # 3913 02-8) and 2-ethyl-1-hexanol (CAS # 104-76-7) show that this material is not genotoxic nor does it have skin sensitization potential. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03 and 1.4 mg/day, respectively). The repeated dose toxicity endpoint was completed using 2-ethyl-1 hexanol (CAS # 104-76-7) and 1-heptanol, 2-propyl (CAS # 10042-59-8) as suitable read across analogs, which provided a MOE > 100. The developmental toxicity endpoint was completed using 2-ethyl-1-hexanol (CAS # 104-76-7) as a suitable read across analog, which provided a MOE > 100 The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework. PMID- 27475045 TI - RIFM fragrance ingredient safety assessment, 1-(1,2,3,4-tetrahydro-4,4-dimethyl-1 naphthyl)propan-1-one, CAS Registry Number 74499-60-8. AB - The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the target material and the suitable read across analog 6 acetyl-1,1,2,4,4,7-hexamethyltetraline (CAS # 21145-77-7) show that this material is not genotoxic. Data from the suitable read across analog 6-acetyl-1,1,2,4,4,7 hexamethyltetraline (CAS # 21145-77-7) provided a MOE > 100 for the repeat dose and developmental toxicity endpoints. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class II material (0.009 mg/kg/day and 0.47 mg/day, respectively). Data on the target material showed that this material is below the non-reactive DST for skin sensitization and did not have the potential for phototoxicity or photoallergenicity. The environmental endpoint was completed as described in the RIFM Framework. PMID- 27475047 TI - Integrating structural and mutagenesis data to elucidate GPCR ligand binding. AB - G protein-coupled receptors (GPCRs) represent the largest family of human membrane proteins, as well as drug targets. A recent boom in GPCR structural biology has provided detailed images of receptor ligand binding sites and interactions on the molecular level. An ever-increasing number of ligands is reported that exhibit activity through multiple receptors, binding in allosteric sites, and bias towards different intracellular signalling pathways. Furthermore, a wealth of single point mutants has accumulated in literature and public databases. Integrating these structural and mutagenesis data will help elucidate new GPCR ligand binding sites, and ultimately design drugs with tailored pharmacological activity. PMID- 27475046 TI - Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. AB - Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease. PMID- 27475048 TI - The effect of fluorescent labeling on alpha-synuclein fibril morphology. AB - The misfolding and aggregation of a small, natively unfolded protein alpha synuclein (alpha-syn) is presumably an important factor in the development of Parkinson's disease. However, the mechanism of alpha-syn aggregation into amyloid fibrils and their morphology are not well understood. To elucidate the aggregation kinetics and the morphology of aggregates by the use of fluorescent techniques the protein needs to be suitably labeled. In this study, using atomic force microscopy, we demonstrate a significant effect of fluorescent labels on the alpha-syn fibrillization process. We studied in detail the morphology of alpha-syn aggregates as a function of the composition of mixtures of labeled and wild type (WT) alpha-syn in solution using different types of fluorescent dyes. Although the overall charge of the fluorophores we used and their chemical structure varied significantly, the morphology of alpha-syn fibrils changed in a similar way in all cases. The increase in the fraction of labeled alpha-syn in solution led to shortening of the fibrils as compared to those from WT-only alpha syn, whereas the height of the fibrils remained mainly unaffected. The twisted fibril morphology observed in the WT and A140C alpha-syn mutant completely disappeared when the A140C alpha-syn mutant was 100% fluorescently labeled. PMID- 27475049 TI - Effectiveness and safety of natalizumab in real-world clinical practice: Review of observational studies. AB - Clinical trials have shown that natalizumab is highly effective for treating relapsing forms of multiple sclerosis (MS). The purpose of this analysis was to conduct a targeted review of data from country-specific observational studies and registries of natalizumab-treated patients with relapsing MS in order to more fully investigate the longer-term effectiveness and safety of this disease modifying therapy in real-world clinical practice settings. A PubMed search was conducted on March 13, 2014, using the terms (natalizumab AND multiple sclerosis) AND (observational OR registry OR post-marketing OR clinical practice). Only English-language papers that reported effectiveness (in terms of effects on relapses, disability progression, and magnetic resonance imaging findings) and/or safety results from studies were included. Data from 22 studies/registries were included. Annualized relapse rates decreased by 73%-94% from baseline across the studies, with improvement maintained for up to 5 years during natalizumab treatment. Natalizumab effectiveness was also demonstrated via assessment of disability progression (Expanded Disability Status Scale), radiological measures, and no-evidence-of-disease-activity measures (clinical, radiological, and overall). Results were similar among patient groups stratified by level of disease activity. Safety outcomes were consistent with natalizumab's known safety profile. Data from country-specific observational studies and registries varying in size and scope support the effectiveness and safety of natalizumab in a broad range of patients in clinical practice. PMID- 27475050 TI - Is Susac syndrome associated with bipolar disorder? PMID- 27475051 TI - Dengue in a changing climate. AB - Dengue is the world's most important arboviral disease in terms of number of people affected. Over the past 50 years, incidence increased 30-fold: there were approximately 390 million infections in 2010. Globalization, trade, travel, demographic trends, and warming temperatures are associated with the recent spread of the primary vectors Aedes aegypti and Aedes albopictus and of dengue. Overall, models project that new geographic areas along the fringe of current geographic ranges for Aedes will become environmentally suitable for the mosquito's lifecycle, and for dengue transmission. Many endemic countries where dengue is likely to spread further have underdeveloped health systems, increasing the substantial challenges of disease prevention and control. Control focuses on management of Aedes, although these efforts have typically had limited effectiveness in preventing outbreaks. New prevention and control efforts are needed to counter the potential consequences of climate change on the geographic range and incidence of dengue, including novel methods of vector control and dengue vaccines. PMID- 27475052 TI - Increasing ambient temperature reduces emotional well-being. AB - This study examines the impact of ambient temperature on emotional well-being in the U.S. population aged 18+. The U.S. is an interesting test case because of its resources, technology and variation in climate across different areas, which also allows us to examine whether adaptation to different climates could weaken or even eliminate the impact of heat on well-being. Using survey responses from 1.9 million Americans over the period from 2008 to 2013, we estimate the effect of temperature on well-being from exogenous day-to-day temperature variation within respondents' area of residence and test whether this effect varies across areas with different climates. We find that increasing temperatures significantly reduce well-being. Compared to average daily temperatures in the 50-60 degrees F (10-16 degrees C) range, temperatures above 70 degrees F (21 degrees C) reduce positive emotions (e.g. joy, happiness), increase negative emotions (e.g. stress, anger), and increase fatigue (feeling tired, low energy). These effects are particularly strong among less educated and older Americans. However, there is no consistent evidence that heat effects on well-being differ across areas with mild and hot summers, suggesting limited variation in heat adaptation. PMID- 27475054 TI - Does fiscal decentralization improve health outcomes? Evidence from infant mortality in Italy. AB - Despite financial and decision-making responsibilities having been increasingly devolved to lower levels of government worldwide, the potential impact of these reforms remains largely controversial. This paper investigates the hypothesis that a shift towards a higher degree of fiscal autonomy of sub-national governments could improve health outcomes, as measured by infant mortality rates. Italy is used as a case study since responsibilities for healthcare have been decentralized to regions, though the central government still retains a key role in ensuring all citizens uniform access to health services throughout the country. A linear fixed-effects regression model with robust standard errors is employed for a panel of 20 regions over the period 1996-2012 (340 observations in the full sample). Decentralization is proxied by two different indicators, capturing the degree of decision-making autonomy in the allocation of tax revenues and the extent to which regions rely on fiscal transfers from the central government. The results show that a higher proportion of tax revenues raised and/or controlled locally as well as a lower transfer dependency from the central government are consistently associated with lower infant mortality rates, ceteris paribus. The marginal benefit from fiscal decentralization, however, is not constant but depends on the level of regional wealth, favouring poorest regions. In terms of policy implications, this study outlines how the effectiveness of decentralization in improving health outcomes is contingent on the characteristics of the context in which the process takes place. PMID- 27475053 TI - Challenges and priorities for modelling livestock health and pathogens in the context of climate change. AB - Climate change has the potential to impair livestock health, with consequences for animal welfare, productivity, greenhouse gas emissions, and human livelihoods and health. Modelling has an important role in assessing the impacts of climate change on livestock systems and the efficacy of potential adaptation strategies, to support decision making for more efficient, resilient and sustainable production. However, a coherent set of challenges and research priorities for modelling livestock health and pathogens under climate change has not previously been available. To identify such challenges and priorities, researchers from across Europe were engaged in a horizon-scanning study, involving workshop and questionnaire based exercises and focussed literature reviews. Eighteen key challenges were identified and grouped into six categories based on subject specific and capacity building requirements. Across a number of challenges, the need for inventories relating model types to different applications (e.g. the pathogen species, region, scale of focus and purpose to which they can be applied) was identified, in order to identify gaps in capability in relation to the impacts of climate change on animal health. The need for collaboration and learning across disciplines was highlighted in several challenges, e.g. to better understand and model complex ecological interactions between pathogens, vectors, wildlife hosts and livestock in the context of climate change. Collaboration between socio-economic and biophysical disciplines was seen as important for better engagement with stakeholders and for improved modelling of the costs and benefits of poor livestock health. The need for more comprehensive validation of empirical relationships, for harmonising terminology and measurements, and for building capacity for under-researched nations, systems and health problems indicated the importance of joined up approaches across nations. The challenges and priorities identified can help focus the development of modelling capacity and future research structures in this vital field. Well-funded networks capable of managing the long-term development of shared resources are required in order to create a cohesive modelling community equipped to tackle the complex challenges of climate change. PMID- 27475055 TI - Agroecology and sustainable food systems: Participatory research to improve food security among HIV-affected households in northern Malawi. AB - This article shares results from a long-term participatory agroecological research project in northern Malawi. Drawing upon a political ecology of health conceptual framework, the paper explores whether and how participatory agroecological farming can improve food security and nutrition among HIV-affected households. In-depth interviews were conducted with 27 farmers in HIV-affected households in the area near Ekwendeni Trading Centre in northern Malawi. The results show that participatory agroecological farming has a strong potential to meet the food, dietary, labour and income needs of HIV-affected households, whilst helping them to manage natural resources sustainably. As well, the findings reveal that place-based politics, especially gendered power imbalances, are imperative for understanding the human impacts of the HIV/AIDS epidemic. Overall, the study adds valuable insights into the literature on the human environment dimensions of health. It demonstrates that the onset of disease can radically transform the social relations governing access to and control over resources (e.g., land, labour, and capital), and that these altered social relations in turn affect sustainable disease management. The conclusion highlights how the promotion of sustainable agroecology could help to partly address the socio-ecological challenges associated with HIV/AIDS. PMID- 27475056 TI - Rhetoric and the law, or the law of rhetoric: How countries oppose novel tobacco control measures at the World Trade Organization. AB - The tobacco industry has developed an extensive array of strategies and arguments to prevent or weaken government regulation. These strategies and arguments are well documented at the domestic level. However, there remains a need to examine how these arguments are reflected in the challenges waged by governments within the World Trade Organization (WTO). Decisions made at the WTO have the potential to shape how countries govern. Our analysis was conducted on two novel tobacco control measures: tobacco additives bans (Canada, United States and Brazil) and plain, standardized packaging of tobacco products (Australia, New Zealand, Ireland, EU and UK). We analyzed WTO documents (i.e. meeting minutes and submissions) (n = 62) in order to identify patterns of argumentation and compare these patterns with well-documented industry arguments. The pattern of these arguments reveal that despite the unique institutional structure of the WTO, country representatives opposing novel tobacco control measures use the same non technical arguments as those that the tobacco industry continues to use to oppose these measures at the domestic level. PMID- 27475057 TI - The impact of primary care reform on health system performance in Canada: a systematic review. AB - BACKGROUND: We aimed to synthesize the evidence of a causal effect and draw inferences about whether Canadian primary care reforms improved health system performance based on measures of health service utilization, processes of care, and physician productivity. METHODS: We searched the Embase, PubMed and Web of Science databases for records from 2000 to September 2015. We based our risk of bias assessment on the Grading of Recommendations Assessment, Development and Evaluation guidelines. Full-text studies were synthesized and organized according to the three outcome categories: health service utilization, processes of care, and physician costs and productivity. RESULTS: We found moderate quality evidence that team-based models of care led to reductions in emergency department use, but the evidence was mixed for hospital admissions. We also found low quality evidence that team-based models, blended capitation models and pay-for performance incentives led to small and sometimes non-significant improvements in processes of care. Studies examining new payment models on physician costs and productivity were of high methodological quality and provided a coherent body of evidence assessing enhanced fee-for-service and blended capitation payment models. CONCLUSION: A small number of studies suggested that team-based models contributed to reductions in emergency department use in Quebec and Alberta. Regarding processes of diabetes care, studies found higher rates of testing for blood glucose levels, retinopathy and cholesterol in Alberta's team-based primary care model and in practices eligible for pay-for-performance incentives in Ontario. However pay-for-performance in Ontario was found to have null to moderate effects on other prevention and screening activities. Although blended capitation payment in Ontario contributed to decreases in the number of services delivered and patients seen per day, the number of enrolled patients and number of days worked in a year was similar to that of enhanced fee-for-service practices. PMID- 27475058 TI - Case report of Lewy body disease mimicking Creutzfeldt-Jakob disease in a 44-year old man. AB - BACKGROUND: Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. CASE PRESENTATION: We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14-3-3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on (18)F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. CONCLUSIONS: This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed. PMID- 27475061 TI - Global robust dissipativity of interval recurrent neural networks with time varying delay and discontinuous activations. AB - In this paper, the problems of robust dissipativity and robust exponential dissipativity are discussed for a class of recurrent neural networks with time varying delay and discontinuous activations. We extend an invariance principle for the study of the dissipativity problem of delay systems to the discontinuous case. Based on the developed theory, some novel criteria for checking the global robust dissipativity and global robust exponential dissipativity of the addressed neural network model are established by constructing appropriate Lyapunov functionals and employing the theory of Filippov systems and matrix inequality techniques. The effectiveness of the theoretical results is shown by two examples with numerical simulations. PMID- 27475060 TI - Analysis of symptoms and their potential associations with e-liquids' components: a social media study. AB - BACKGROUND: The electronic cigarette (e-cigarette) market has grown rapidly in recent years. However, causes of e-cigarette related symptoms among users and their impact on health remain uncertain. This research aims to mine the potential relationships between symptoms and e-liquid components, such as propylene glycol (PG), vegetable glycerine (VG), flavor extracts, and nicotine, using user generated data collected from Reddit. METHODS: A total of 3605 e-liquid related posts from January 1st, 2011 to June 30th, 2015 were collected from Reddit. Then the patterns of VG/PG distribution among different flavors were analyzed. Next, the relationship between throat hit, which was a typical symptom of e-cigarette use, and e-liquid components was studied. Finally, other symptoms were examined based on e-liquid components and user sentiment. RESULTS: We discovered 3 main sets of findings: 1) We identified three groups of flavors in terms of VG/PG ratios. Fruits, cream, and nuts flavors were similar. Sweet, menthol, and seasonings flavors were classified into one group. Tobacco and beverages flavors were the third group. 2) Throat hit was analyzed and we found that menthol and tobacco flavors, as well as high ratios of PG and nicotine level, could produce more throat hit. 3) A total of 9 systems of 25 symptoms were identified and analyzed. Components including VG/PG ratio, flavor, and nicotine could be possible reasons for these symptoms. CONCLUSIONS: E-liquid components shown to be associated with e-cigarette use symptomology were VG/PG ratios, flavors, and nicotine levels. Future analysis could be conducted based on the structure of e liquid components categories built in this study. Information revealed in this study could be utilized by e-cigarette users to understand the relationship between e-liquid type and symptoms experienced, by vendors to choose appropriate recipes of e-liquid, and by policy makers to develop new regulations. PMID- 27475059 TI - Safety of the primary percutaneous coronary intervention strategy combining pre hospital prasugrel, enoxaparin and in-hospital bivalirudin in acute ST-segment elevation myocardial infarction. AB - BACKROUND: The optimal antithrombotic treatment during a primary percutaneous coronary intervention (pPCI) is not known. This single center registry study aims to assess the safety of a novel antithrombotic regimen combining enoxaparine and prasugrel at presentation, followed by bivalirudin at the catheterisation laboratory. METHODS: All consecutive patients who underwent a pPCI were collected prospectively. The primary endpoint was major bleeding within 30 days. The secondary endpoints were a composite of major adverse cardiovascular events (MACE) consisting of cardiovascular death, non-fatal myocardial infarction, non fatal stroke, a new target vessel revascularisation and all-cause mortality at 30 days. RESULTS: Ninety-nine out of the total of 390 patients were treated according to the new regimen (protocol-treated group). The rest received other antithrombotic treatment (non-protocol-treated group). The protocol-treated group had a lower risk than the non-protocol-treated group according to the GRACE ischaemic (112 vs. 124, p = 0.002) and CRUSADE bleeding scores (21 vs. 28, p < 0.0001). The incidences of bleeding were similar: severe GUSTO or TIMI bleeding occurred in 0 % of the protocol-treated group and in 1.0 and 0.3 %, respectively, of the other group (p = 0.311 for GUSTO and p = 0.559 for TIMI). The incidence of MACE in the groups was 6.1 and 10.7 %, respectively (p = 0.178). The respective incidences of all-cause mortality were 5.1 and 9.6 % (p = 0.158). CONCLUSIONS: Administration of the novel antithrombotic regimen seems to be safe. PMID- 27475062 TI - Consecutive transitions from localized to delocalized transport states in the anharmonic chain of three coupled oscillators. AB - In the present paper, we study the mechanism of formation and bifurcations of highly nonstationary regimes manifested by different energy transport intensities, emerging in an anharmonic trimer model. The basic model under investigation comprises a chain of three coupled anharmonic oscillators subject to localized excitation, where the initial energy is imparted to the first oscillator only. We report the formation of three basic nonstationary transport states traversed by locally excited regimes. These states differ by spatial energy distribution, as well as by the intensity of energy transport along the chain. In the current study, we focus on numerical and analytical investigation of the intricate resonant mechanism governing the inter-state transitions of locally excited regimes. Results of the analytical study are in good agreement with the numerical simulations of the trimer model. PMID- 27475063 TI - Critical phenomena at a first-order phase transition in a lattice of glow lamps: Experimental findings and analogy to neural activity. AB - Networks of non-linear electronic oscillators have shown potential as physical models of neural dynamics. However, two properties of brain activity, namely, criticality and metastability, remain under-investigated with this approach. Here, we present a simple circuit that exhibits both phenomena. The apparatus consists of a two-dimensional square lattice of capacitively coupled glow (neon) lamps. The dynamics of lamp breakdown (flash) events are controlled by a DC voltage globally connected to all nodes via fixed resistors. Depending on this parameter, two phases having distinct event rate and degree of spatiotemporal order are observed. The transition between them is hysteretic, thus a first-order one, and it is possible to enter a metastability region, wherein, approaching a spinodal point, critical phenomena emerge. Avalanches of events occur according to power-law distributions having exponents ~3/2 for size and ~2 for duration, and fractal structure is evident as power-law scaling of the Fano factor. These critical exponents overlap observations in biological neural networks; hence, this circuit may have value as building block to realize corresponding physical models. PMID- 27475064 TI - Attractors of relaxation discrete-time systems with chaotic dynamics on a fast time scale. AB - In this work, a new type of relaxation systems is considered. Their prominent feature is that they comprise two distinct epochs, one is slow regular motion and another is fast chaotic motion. Unlike traditionally studied slow-fast systems that have smooth manifolds of slow motions in the phase space and fast trajectories between them, in this new type one observes, apart the same geometric objects, areas of transient chaos. Alternating periods of slow regular motions and fast chaotic ones as well as transitions between them result in a specific chaotic attractor with chaos on a fast time scale. We formulate basic properties of such attractors in the framework of discrete-time systems and consider several examples. Finally, we provide an important application of such systems, the neuronal electrical activity in the form of chaotic spike-burst oscillations. PMID- 27475065 TI - Unfolding homoclinic connections formed by corner intersections in piecewise smooth maps. AB - The stable and unstable manifolds of an invariant set of a piecewise-smooth map are themselves piecewise-smooth. Consequently, as parameters of a piecewise smooth map are varied, an invariant set can develop a homoclinic connection when its stable manifold intersects a non-differentiable point of its unstable manifold (or vice-versa). This is a codimension-one bifurcation analogous to a homoclinic tangency of a smooth map, referred to here as a homoclinic corner. This paper presents an unfolding of generic homoclinic corners for saddle fixed points of planar piecewise-smooth continuous maps. It is shown that a sequence of border-collision bifurcations limits to a homoclinic corner and that all nearby periodic solutions are unstable. PMID- 27475066 TI - Experimental study on dynamics of coherent structures formed by inertial solid particles in three-dimensional periodic flows. AB - We present experimental results obtained under normal gravity on the dynamics of solid particles in periodic oscillatory thermocapillary-driven flows in a non isothermal liquid bridge made of decane. Inertial particles of different densities and in the size range approximately 0.75-75 MUm are able to form stable coherent structures (particle accumulation structures, or PASs). Two image processing techniques were developed and successfully applied to compute time required for an ensemble of particles to form a structure. It is shown that the formation time grows with the decrease of the Stokes number. The observations indicate the probable irrelevance of the memory term for these experiments. Two types of PAS were observed-single (SL-I) and double-loop (SL-II)-which sometimes co-existed. Only large or very dense particles may form an SL-II type structure. A number of novel features of the system were perceived. In some cases, intermittently stable structures emerged (their dynamics is characterized by alternating time intervals during which a structure exists and is destroyed). Whereas in most experiments we observed a conventional symmetric and centered PAS, there were cases when a long-term stable asymmetric structure appeared. Experiments wherein two different types of PAS-forming particles were used simultaneously revealed the destructive role of collisions between the particles on formation of structures. PMID- 27475067 TI - Extreme multistability in a memristor-based multi-scroll hyper-chaotic system. AB - In this paper, a new memristor-based multi-scroll hyper-chaotic system is designed. The proposed memristor-based system possesses multiple complex dynamic behaviors compared with other chaotic systems. Various coexisting attractors and hidden coexisting attractors are observed in this system, which means extreme multistability arises. Besides, by adjusting parameters of the system, this chaotic system can perform single-scroll attractors, double-scroll attractors, and four-scroll attractors. Basic dynamic characteristics of the system are investigated, including equilibrium points and stability, bifurcation diagrams, Lyapunov exponents, and so on. In addition, the presented system is also realized by an analog circuit to confirm the correction of the numerical simulations. PMID- 27475068 TI - A digital matched filter for reverse time chaos. AB - The use of reverse time chaos allows the realization of hardware chaotic systems that can operate at speeds equivalent to existing state of the art while requiring significantly less complex circuitry. Matched filter decoding is possible for the reverse time system since it exhibits a closed form solution formed partially by a linear basis pulse. Coefficients have been calculated and are used to realize the matched filter digitally as a finite impulse response filter. Numerical simulations confirm that this correctly implements a matched filter that can be used for detection of the chaotic signal. In addition, the direct form of the filter has been implemented in hardware description language and demonstrates performance in agreement with numerical results. PMID- 27475069 TI - Pyramidal fractal dimension for high resolution images. AB - Fractal analysis (FA) should be able to yield reliable and fast results for high resolution digital images to be applicable in fields that require immediate outcomes. Triggered by an efficient implementation of FA for binary images, we present three new approaches for fractal dimension (D) estimation of images that utilize image pyramids, namely, the pyramid triangular prism, the pyramid gradient, and the pyramid differences method (PTPM, PGM, PDM). We evaluated the performance of the three new and five standard techniques when applied to images with sizes up to 8192 * 8192 pixels. By using artificial fractal images created by three different generator models as ground truth, we determined the scale ranges with minimum deviations between estimation and theory. All pyramidal methods (PM) resulted in reasonable D values for images of all generator models. Especially, for images with sizes >=1024*1024 pixels, the PMs are superior to the investigated standard approaches in terms of accuracy and computation time. A measure for the possibility to differentiate images with different intrinsic D values did show not only that the PMs are well suited for all investigated image sizes, and preferable to standard methods especially for larger images, but also that results of standard D estimation techniques are strongly influenced by the image size. Fastest results were obtained with the PDM and PGM, followed by the PTPM. In terms of absolute D values best performing standard methods were magnitudes slower than the PMs. Concluding, the new PMs yield high quality results in short computation times and are therefore eligible methods for fast FA of high-resolution images. PMID- 27475070 TI - Stable dipole solitons and soliton complexes in the nonlinear Schrodinger equation with periodically modulated nonlinearity. AB - We develop a general classification of the infinite number of families of solitons and soliton complexes in the one-dimensional Gross-Pitaevskii/nonlinear Schrodinger equation with a nonlinear lattice pseudopotential, i.e., periodically modulated coefficient in front of the cubic term, which takes both positive and negative local values. This model finds direct implementations in atomic Bose Einstein condensates and nonlinear optics. The most essential finding is the existence of two branches of dipole solitons (DSs), which feature an antisymmetric shape, being essentially squeezed into a single cell of the nonlinear lattice. This soliton species was not previously considered in nonlinear lattices. We demonstrate that one branch of the DS family (namely, which obeys the Vakhitov-Kolokolov criterion) is stable, while unstable DSs spontaneously transform into stable fundamental solitons (FSs). The results are obtained in numerical and approximate analytical forms, the latter based on the variational approximation. Some stable bound states of FSs are found too. PMID- 27475071 TI - Canards in a minimal piecewise-linear square-wave burster. AB - We construct a piecewise-linear (PWL) approximation of the Hindmarsh-Rose (HR) neuron model that is minimal, in the sense that the vector field has the least number of linearity zones, in order to reproduce all the dynamics present in the original HR model with classical parameter values. This includes square-wave bursting and also special trajectories called canards, which possess long repelling segments and organise the transitions between stable bursting patterns with n and n + 1 spikes, also referred to as spike-adding canard explosions. We propose a first approximation of the smooth HR model, using a continuous PWL system, and show that its fast subsystem cannot possess a homoclinic bifurcation, which is necessary to obtain proper square-wave bursting. We then relax the assumption of continuity of the vector field across all zones, and we show that we can obtain a homoclinic bifurcation in the fast subsystem. We use the recently developed canard theory for PWL systems in order to reproduce the spike-adding canard explosion feature of the HR model as studied, e.g., in Desroches et al., Chaos 23(4), 046106 (2013). PMID- 27475072 TI - Realization of consensus of multi-agent systems with stochastically mixed interactions. AB - In this paper, we propose a new consensus model in which the interactions among agents stochastically switch between attraction and repulsion. Such a positive and-negative mechanism is described by the white-noise-based coupling. Analytic criteria for the consensus and non-consensus in terms of the eigenvalues of the noise intensity matrix are derived, which provide a better understanding of the constructive roles of random interactions. Specifically, we discover a positive role of noise coupling that noise can accelerate the emergence of consensus. We find that the converging speed of the multi-agent network depends on the square of the second smallest eigenvalue of its graph Laplacian. The influence of network topologies on the consensus time is also investigated. PMID- 27475073 TI - Probing infinity in bounded two-dimensional electrostatic systems. AB - The total electrostatic energy of systems of identical particles of equal charge is studied in configurations bounded in space, but divergent in the number of charges. This approach shall guide us to unveil a non-linear, functional form specifying the divergent nature of system energy. We consider fractals to be physical entities, with charges located in their vertices or nodes. This description is interesting since features, such as the corresponding fractal dimension, can characterize the total energy EN. Finally, at local length scales, we describe how energy diverges at charge accumulation points in the fractal, that is, almost everywhere by definition. PMID- 27475074 TI - Using ordinal partition transition networks to analyze ECG data. AB - Electrocardiogram (ECG) data from patients with a variety of heart conditions are studied using ordinal pattern partition networks. The ordinal pattern partition networks are formed from the ECG time series by symbolizing the data into ordinal patterns. The ordinal patterns form the nodes of the network and edges are defined through the time ordering of the ordinal patterns in the symbolized time series. A network measure, called the mean degree, is computed from each time series-generated network. In addition, the entropy and number of non-occurring ordinal patterns (NFP) is computed for each series. The distribution of mean degrees, entropies, and NFPs for each heart condition studied is compared. A statistically significant difference between healthy patients and several groups of unhealthy patients with varying heart conditions is found for the distributions of the mean degrees, unlike for any of the distributions of the entropies or NFPs. PMID- 27475075 TI - Mixing with piecewise isometries on a hemispherical shell. AB - We introduce mixing with piecewise isometries (PWIs) on a hemispherical shell, which mimics features of mixing by cutting and shuffling in spherical shells half filled with granular media. For each PWI, there is an inherent structure on the hemispherical shell known as the exceptional set E, and a particular subset of E, E+, provides insight into how the structure affects mixing. Computer simulations of PWIs are used to visualize mixing and approximations of E+ to demonstrate their connection. While initial conditions of unmixed materials add a layer of complexity, the inherent structure of E+ defines fundamental aspects of mixing by cutting and shuffling. PMID- 27475076 TI - An analysis of spatiotemporal localized solutions in the variable coefficients (3 + 1)-dimensional nonlinear Schrodinger equation with six different forms of dispersion parameters. AB - We construct spatiotemporal localized envelope solutions of a (3 + 1)-dimensional nonlinear Schrodinger equation with varying coefficients such as dispersion, nonlinearity and gain parameters through similarity transformation technique. The obtained localized rational solutions can serve as prototypes of rogue waves in different branches of science. We investigate the characteristics of constructed localized solutions in detail when it propagates through six different dispersion profiles, namely, constant, linear, Gaussian, hyperbolic, logarithm, and exponential. We also obtain expressions for the hump and valleys of rogue wave intensity profiles for these six dispersion profiles and study the trajectory of it in each case. Further, we analyze how the intensity of another localized solution, namely, breather, changes when it propagates through the aforementioned six dispersion profiles. Our studies reveal that these localized solutions co exist with the collapsing solutions which are already found in the (3 + 1) dimensional nonlinear Schrodinger equation. The obtained results will help to understand the corresponding localized wave phenomena in related fields. PMID- 27475077 TI - Stochastic basins of attraction for metastable states. AB - Basin of attraction of a stable equilibrium point is an effective concept for stability analysis in deterministic systems; however, it does not contain information on the external perturbations that may affect it. Here we introduce the concept of stochastic basin of attraction (SBA) by incorporating a suitable probabilistic notion of basin. We define criteria for the size of the SBA based on the escape probability, which is one of the deterministic quantities that carry dynamical information and can be used to quantify dynamical behavior of the corresponding stochastic basin of attraction. SBA is an efficient tool to describe the metastable phenomena complementing the known exit time, escape probability, or relaxation time. Moreover, the geometric structure of SBA gives additional insight into the system's dynamical behavior, which is important for theoretical and practical reasons. This concept can be used not only in models with small noise intensity but also with noise whose amplitude is proportional or in general is a function of an order parameter. As an application of our main results, we analyze a three potential well system perturbed by two types of noise: Brownian motion and non-Gaussian alpha-stable Levy motion. Our main conclusions are that the thermal fluctuations stabilize the metastable system with an asymmetric three-well potential but have the opposite effect for a symmetric one. For Levy noise with larger jumps and lower jump frequencies ( alpha=0.5) metastability is enhanced for both symmetric and asymmetric potentials. PMID- 27475078 TI - Particle swarm optimization algorithm based parameters estimation and control of epileptiform spikes in a neural mass model. AB - This paper proposes an epilepsy detection and closed-loop control strategy based on Particle Swarm Optimization (PSO) algorithm. The proposed strategy can effectively suppress the epileptic spikes in neural mass models, where the epileptiform spikes are recognized as the biomarkers of transitions from the normal (interictal) activity to the seizure (ictal) activity. In addition, the PSO algorithm shows capabilities of accurate estimation for the time evolution of key model parameters and practical detection for all the epileptic spikes. The estimation effects of unmeasurable parameters are improved significantly compared with unscented Kalman filter. When the estimated excitatory-inhibitory ratio exceeds a threshold value, the epileptiform spikes can be inhibited immediately by adopting the proportion-integration controller. Besides, numerical simulations are carried out to illustrate the effectiveness of the proposed method as well as the potential value for the model-based early seizure detection and closed-loop control treatment design. PMID- 27475079 TI - Nonlinear dynamics of C-terminal tails in cellular microtubules. AB - The mechanical and electrical properties, and information processing capabilities of microtubules are the permanent subject of interest for carrying out experiments in vitro and in silico, as well as for theoretical attempts to elucidate the underlying processes. In this paper, we developed a new model of the mechano-electrical waves elicited in the rows of very flexible C-terminal tails which decorate the outer surface of each microtubule. The fact that C terminal tails play very diverse roles in many cellular functions, such as recruitment of motor proteins and microtubule-associated proteins, motivated us to consider their collective dynamics as the source of localized waves aimed for communication between microtubule and associated proteins. Our approach is based on the ferroelectric liquid crystal model and it leads to the effective asymmetric double-well potential which brings about the conditions for the appearance of kink-waves conducted by intrinsic electric fields embedded in microtubules. These kinks can serve as the signals for control and regulation of intracellular traffic along microtubules performed by processive motions of motor proteins, primarly from kinesin and dynein families. On the other hand, they can be precursors for initiation of dynamical instability of microtubules by recruiting the proper proteins responsible for the depolymerization process. PMID- 27475080 TI - Non-insect crustacean models in developmental genetics including an encomium to Parhyale hawaiensis. AB - The impressive diversity of body plans, lifestyles and segmental specializations exhibited by crustaceans (barnacles, copepods, shrimps, crabs, lobsters and their kin) provides great material to address longstanding questions in evolutionary developmental biology. Recent advances in forward and reverse genetics and in imaging approaches applied in the amphipod Parhyale hawaiensis and other emerging crustacean model species have made it possible to probe the molecular and cellular basis of crustacean diversity. A number of biological and technical qualities like the slow tempo and holoblastic cleavage mode, the stereotypy of many cellular processes, the functional and morphological diversity of limbs along the body axis, and the availability of various experimental manipulations, have made Parhyale a powerful system to study normal development and regeneration. PMID- 27475081 TI - Predicting runoff induced mass loads in urban watersheds: Linking land use and pyrethroid contamination. AB - Pyrethroid pesticide mass loadings in the Ballona Creek Watershed were calculated using the volume-concentration method with a Geographic Information Systems (GIS) to explore potential relationships between urban land use, impervious surfaces, and pyrethroid runoff flowing into an urban stream. A calibration of the GIS volume-concentration model was performed using 2013 and 2014 wet-weather sampling data. Permethrin and lambda-cyhalothrin were detected as the highest concentrations; deltamethrin, lambda-cyhalothrin, permethrin and cyfluthrin were the most frequently detected synthetic pyrethroids. Eight neighborhoods within the watershed were highlighted as target areas based on a Weighted Overlay Analysis (WOA) in GIS. Water phase concentration of synthetic pyrethroids (SPs) were calculated from the reported usage. The need for stricter BMP and consumer product controls was identified as a possible way of reducing the detections of pyrethroids in Ballona Creek. This model has significant implications for determining mass loadings due to land use influence, and offers a flexible method to extrapolate data for a limited amount of samplings for a larger watershed, particularly for chemicals that are not subject to environmental monitoring. Offered as a simple approach to watershed management, the GIS-volume concentration model has the potential to be applied to other target pesticides and is useful for simulating different watershed scenarios. Further research is needed to compare results against other similar urban watersheds situated in mediterranean climates. PMID- 27475084 TI - EVICR.net Activities - Update. PMID- 27475082 TI - Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area. AB - Enhanced dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to the ventral striatum is thought to drive drug self-administration and mediate positive reinforcement. We examined neuronal firing rates in slices of mouse midbrain following adolescent binge-like alcohol drinking and find that prior alcohol experience greatly enhanced the sensitivity to excitation by ethanol itself (10-50 mM) in a subset of ventral midbrain DA neurons located in the medial VTA. This enhanced response after drinking was not associated with alterations of firing rate or other measures of intrinsic excitability. In addition, the phenomenon appears to be specific to adolescent drinking, as mice that established a drinking preference only after the onset of adulthood showed no change in alcohol sensitivity. Here we demonstrate not only that drinking during adolescence induces enhanced alcohol sensitivity, but also that this DA neuronal response occurs over a range of alcohol concentrations associated with social drinking in humans. PMID- 27475083 TI - Genetic correlation estimates between beef fatty acid profile with meat and carcass traits in Nellore cattle finished in feedlot. AB - The objective of this study was to estimate the genetic-quantitative relationships between the beef fatty acid profile with the carcass and meat traits of Nellore cattle. A total of 1826 bulls finished in feedlot conditions and slaughtered at 24 months of age on average were used. The following carcass and meat traits were analysed: subcutaneous fat thickness (BF), shear force (SF) and total intramuscular fat (IMF). The fatty acid (FA) profile of the Longissimus thoracis samples was determined. Twenty-five FAs (18 individuals and seven groups of FAs) were selected due to their importance for human health. The animals were genotyped with the BovineHD BeadChip and, after quality control for single nucleotide polymorphisms (SNPs), only 470,007 SNPs from 1556 samples remained. The model included the random genetic additive direct effect, the fixed effect of the contemporary group and the animal's slaughter age as a covariable. The (co)variances and genetic parameters were estimated using the REML method, considering an animal model (single-step GBLUP). A total of 25 multi-trait analyses, with four traits, were performed considering SF, BF and IMF plus each individual FA. The heritability estimates for individual saturated fatty acids (SFA) varied from 0.06 to 0.65, for monounsaturated fatty acids (MUFA) it varied from 0.02 to 0.14 and for polyunsaturated fatty acids (PUFA) it ranged from 0.05 to 0.68. The heritability estimates for Omega 3, Omega 6, SFA, MUFA and PUFA sum were low to moderate, varying from 0.09 to 0.20. The carcass and meat traits, SF (0.06) and IMF (0.07), had low heritability estimates, while BF (0.17) was moderate. The genetic correlation estimates between SFA sum, MUFA sum and PUFA sum with BF were 0.04, 0.64 and -0.41, respectively. The genetic correlation estimates between SFA sum, MUFA sum and PUFA sum with SF were 0.29, -0.06 and 0.04, respectively. The genetic correlation estimates between SFA sum, MUFA sum and PUFA sum with IMF were 0.24, 0.90 and -0.67, respectively. The selection to improve meat tenderness in Nellore cattle should not change the fatty acid composition in beef, so it is possible to improve this attribute without affecting the nutritional beef quality in zebu breeds. However, selection for increased deposition of subcutaneous fat thickness and especially the percentage of intramuscular fat should lead to changes in the fat composition, highlighting a genetic antagonism between meat nutritional value and acceptability by the consumer. PMID- 27475085 TI - Efficacy of Ozurdex implant in recalcitrant diabetic macular edema: a single center experience. PMID- 27475086 TI - Intraocular pressure during lamellar cuts with two different microkeratomes. AB - BACKGROUND: The rapid integration of new technology into ophthalmologic practice, e. g. LASIK (laser in situ keratomileusis), is associated with new complications. The limitations of the new technology cannot be precisely determined. During lamellar cuts with microkeratomes intraocular pressure (IOP) elevations occur. The IOP elevation during the lamellar cut cannot be determined by conventional tonometry. MATERIALS AND METHOD: We examined the IOP rise during the complete microkeratome treatment. Fresh enucleated porcine eyes were cannulated and direct IOP measurement with a Statham manometer was carried out. Thus we evaluated the IOP during the complete treatment for two differently constructed microkeratome systems. RESULTS: IOP elevations (mean values) between 77 mm Hg for the Corneal Shaper and 229 mm Hg for the Keratek during the vacuum phase and 140 mm Hg for the Corneal Shaper and 360 mm Hg for the Keratek during the lamellar cut were monitored. A sudden IOP decrease to -5 mm Hg was registered for the post-vacuum phase. CONCLUSIONS: In our opinion unphysiologic high IOP values could be dangerous for risk eyes. PMID- 27475088 TI - Bilateral mastectomy and the retreat from breast-conserving surgery. AB - The purpose of this study is to assess the consequences for breast cancer patients of the trend away from breast conservation in favor of bilateral and contralateral mastectomy. The methods are followed from the review of the literature from 1991 to 2015. Breast-conserving surgery and sentinel lymph node biopsy, introduced into mainstream practice in the 1980s and 1990s, respectively, are now the standard of care for early-stage breast cancer. Disruptive change has unexpectedly supervened in the guise of bilateral mastectomy for cancer or prophylaxis and contralateral prophylactic mastectomy. These operations are now being resorted to at a rate which cannot be explained by any of the biological imperatives related to breast cancer and related diseases. This phenomenon extends across the Western world and beyond, driven by patients' cancer concern, a misunderstanding of what surgery can and cannot achieve and preserve, and the current popular media/cultural environment. These developments and their consequences for patients are reviewed. Surgical complications, especially those related to reconstruction, are unusually common. Of equal or greater concern are the physical, esthetic, psychosocial, psychosexual morbidities, and other adverse sequelae of these operations. PMID- 27475087 TI - Phase II studies of two different schedules of dasatinib in bone metastasis predominant metastatic breast cancer: SWOG S0622. AB - Bone metastases from breast cancer are common, causing significant morbidity. Preclinical data of dasatinib, an oral small molecule inhibitor of multiple oncogenic tyrosine kinases, suggested efficacy in tumor control and palliation of bone metastases in metastatic breast cancer (MBC). This clinical trial aimed to determine whether treatment with either of 2 dose schedules of dasatinib results in a progression-free survival (PFS) >50 % at 24 weeks in bone metastasis predominant MBC, to evaluate the toxicity of the 2 dosing regimens, and explore whether treatment results in decreased serum bone turnover markers and patient reported "worst pain." Subjects with bone metastasis predominant MBC were randomly assigned to either 100 mg of dasatinib once daily, or 70 mg twice daily, with treatment continued until time of disease progression or intolerable toxicity. Planned accrual was 40 patients in each arm. The primary trial endpoint was PFS, defined as time from registration to progression or death due to any cause. Median PFS for all eligible patients (79) was 12.6 weeks (95 % CI 9.1 16.7). Neither cohort met the threshold for further clinical interest. There were no significant differences in PFS by randomized treatment arm (p = 0.85). Toxicity was similar in both cohorts, with no clear trend in serum biomarkers of bone turnover or patient-reported pain. Dasatinib was ineffective in controlling bone-predominant MBC in a patient population, unselected by molecular markers. Further study of dasatinib in breast cancer should not be pursued unless performed in molecularly determined patient subsets, or rational combinations. PMID- 27475089 TI - Patterns of change over time and history of the inflammatory potential of diet and risk of breast cancer among postmenopausal women. AB - We utilized the dietary inflammatory index (DII) to investigate associations between patterns of change in, and history of the inflammatory potential of diet and risk of breast cancer in the Women's Health Initiative (WHI). We included 70,998 postmenopausal women aged 50-79 years recruited from 1993 to 1998 into the WHI Observational Study and Dietary Modification trial control group and followed through August 29, 2014. We utilized data from food frequency questionnaires administered at baseline and Year 3, to calculate average DII scores, patterns of change in DII, and used these measures in multivariable-adjusted Cox regression models to estimate hazards ratios (HR) and 95 % confidence intervals (CI) for incident invasive breast cancer and its subtypes. After 1,093,947 person-years of follow-up, 3471 cases of invasive breast cancer were identified. There was no substantial association between average DII scores or patterns of change in DII and risk of overall invasive breast cancer (HR, 1.03; 95 % CI, 0.90, 1.17; P trend = 0.79; comparing extreme average DII quintiles). However, there was a significant nonlinear association between average DII scores and the ER-, PR-, HER2+, subtype (HR, 2.37; 95 % CI, 1.08, 5.20; P-trend = 0.18; comparing extreme quintiles). For patterns of change in DII, the age-adjusted association with ER-, PR-, HER2+ subtype comparing women in the proinflammatory stable to those in the anti-inflammatory stable categories (HR, 1.82; 95 % CI, 1.06, 3.13) persisted in the multivariable-adjusted model but was less precise (HR, 1.85; 95 % CI, 0.96, 3.55; P = 0.06). Dietary inflammatory potential may differentially influence the development of specific breast cancer phenotypes. PMID- 27475090 TI - Comparable outcomes of the consistent use versus switched use of anti- tumor necrosis factor agents in postoperative recurrent Crohn's disease following ileocolonic resection. AB - PURPOSE: There are no published data or guidelines on whether the same anti-tumor necrosis factor (TNF) agents used preoperatively or different anti-TNF agents are preferable to treat postoperative recurrence. Our aim was to compare the efficacy of the consistent vs. switched anti-TNF approaches in patients with recurrent Crohn's disease (CD) after their inception ileocolonic resection (ICR). METHODS: Patients with CD receiving anti-TNF agents before the inception ICR who were treated for clinical recurrence with the same or different anti-TNF agents after surgical resection were included in the study. The outcome of the study was the need for the subsequent resection of ileocolonic anastomosis (ICA) as calculated with survival curves. RESULTS: Eighty-five patients were included in the study. The mean age of the whole cohort at the inception ICR was 35.1 +/- 13.5 years. The whole cohort consisted 42 (49.4 %) in the consistent group and 43 (50.6 %) in the switched group. No significant differences were observed in demographic and clinical variables between the two groups. During the median follow-up of 1.5 (interquartile range, 0.8-3.1) years, seven (16.7 %) patients in the consistent group and eight (18.6 %) in the switched group required the repeat resection of ICA. Similar results were found in terms of the subsequent resection of ICA-free survival (hazard ratio = 1.36, 95 % confidence interval 0.49-3.76, P = 0.54) between the consistent and switched groups. CONCLUSIONS: The adherence to the same anti-TNF agent appeared to be as effective as the switching approach to different anti-TNF agent in treating postoperative recurrent CD after the inception ICR. PMID- 27475091 TI - Robot-assisted versus laparoscopic rectal resection for cancer in a single surgeon's experience: a cost analysis covering the initial 50 robotic cases with the da Vinci Si. AB - PURPOSE: The aim of this study is to compare surgical parameters and the costs of robotic surgery with those of laparoscopic approach in rectal cancer based on a single surgeon's early robotic experience. METHODS: Data from 25 laparoscopic (LapTME) and the first 50 robotic (RobTME) rectal resections performed at our institution by an experienced laparoscopic surgeon (>100 procedures) between 2009 and 2014 were retrospectively analyzed and compared. Patient demographic, procedure, and outcome data were gathered. Costs of the two procedures were collected, differentiated into fixed and variable costs, and analyzed against the robotic learning curve according to the cumulative sum (CUSUM) method. RESULTS: Based on CUSUM analysis, RobTME group was divided into three phases (Rob1: 1-19; Rob2: 20-40; Rob3: 41-50). Overall median operative time (OT) was significantly lower in LapTME than in RobTME (270 vs 312.5 min, p = 0.006). A statistically significant change in OT by phase of robotic experience was detected in the RobTME group (p = 0.010). Overall mean costs associated with LapTME procedures were significantly lower than with RobTME (p < 0.001). Statistically significant reductions in variable and overall costs were found between robotic phases (p < 0.009 for both). With fixed costs excluded, the difference between laparoscopic and Rob3 was no longer statistically significant. CONCLUSIONS: Our results suggest a significant optimization of robotic rectal surgery's costs with experience. Efforts to reduce the dominant fixed cost are recommended to maintain the sustainability of the system and benefit from the technical advantages offered by the robot. PMID- 27475092 TI - Polysomnographic indicators of mortality in stroke patients. AB - PURPOSE: The purpose of the study was to assess polysomnographic indicators of increased mortality risk in patients with stroke or a transient ischemic attack (TIA). METHODS: We performed polysomnographies in 63 acute stroke/TIA patients. Mortality data were collected from a national database after a 19-37-month follow up period. RESULTS: Of the 57 stroke and 6 TIA patients, 9 stroke patients died during follow-up. All nine had moderate or severe sleep-related breathing disorders (SRBDs). Binarily divided, the group with the highest apnea hypopnea index (AHI) had an almost 10-fold higher mortality risk (hazard ratio (HR) 9.71; 95 % confidence interval (CI) 1.20-78.29; p = 0.033) compared to the patients with the lowest AHI. The patients with the longest versus shortest nocturnal wake time had a higher mortality (HR 8.78; 95 % CI 1.1-71.8; p = 0.0428). Lung disease increased mortality (HR 9.92; 95 % CI 2.00-49.23; p = 0.005), and there was a trend toward a higher mortality risk with atrial fibrillation/flutter (HR 3.63; 95 % CI 0.97-13.51; p = 0.055). CONCLUSIONS: In stroke patients, the AHI and nocturnal wake time are indicators of increased mortality risk. SRBDs in stroke patients should receive increased attention. PMID- 27475093 TI - Physical Activity in Youth With Type 1 Diabetes: a Review. AB - Youth with type 1 diabetes are at risk for developing cardiovascular disease, and regular physical activity is strongly recommended as one strategy for prevention, as well as for good glycemic control. Despite recommendations, families in this pediatric population face unique barriers to physical activity, including fear of hypoglycemia. Moreover, families are not routinely counseled in the specific health and psychosocial benefits of following physical activity recommendations for youth with type 1 diabetes. To bridge this gap, the recent literature regarding physical activity in children with type 1 diabetes is reviewed with particular focus on young children. A discussion of the limitations of the current body of research, and recommendations for objectively measured physical activity are provided. Specific recommendations for clinical practice are given, including provider endorsements for regular physical activity for longer than 60 minutes, at least three times a week. PMID- 27475094 TI - When Is an Endophenotype Useful to Detect Association to a Disease? Exploring the Relationships between Disease Status, Endophenotype and Genetic Polymorphisms. AB - OBJECTIVES: To investigate the conditions and analysis strategies required so that endophenotypes related to a disease help discover genetic variants involved in the disease. METHODS: The association with disease susceptibility variants is examined as a function of the relationships between disease status, endophenotype values and the genotype at another disease or endophenotype susceptibility locus assumed to be previously known, using approximate linear models of allele frequencies as a function of these variables and simulations in the context of family studies when the endophenotype is dichotomous. RESULTS: Under genetic mechanisms where the risk allele of the tested locus has an effect exclusively in subjects with the endophenotype, the risk allele frequency differences between affected and unaffected subjects are much greater in the subset of subjects with an endophenotype impairment than in those without such an impairment, and power gains are obtained when testing the association under a joint disease endophenotype model, both with two-locus or single-locus tests. However, with moderate main effect on the risk of disease or endophenotype impairment, testing directly the association between risk allele and disease or endophenotype is more powerful than testing under a joint disease-endophenotype model. CONCLUSIONS: Joint modeling of disease and endophenotype should be used only in parallel with standard disease association testing. PMID- 27475095 TI - Diagnostic accuracy of two tests for determination of anti-m2 in the diagnosis of primary biliary cirrhosis: Is it possible to predict the course of the disease? AB - To evaluate the analytical agreement between results obtained from the indirect immunofluorescence methods and from the multiplexed line-blot assay and EliA-M2, to analyze the diagnostic accuracy in a cohort of primary biliary cirrhosis (PBC) patients and in control patients of two different types of tests for anti-M2 and assess whether, with the advent of a quantitative test, the possibility exists to correlate disease activity with the value of AMA. Serum analysis of 67 patients with fluorescence patterns detected on Hep-2 cells suggestive of PBC-related antibodies and three groups of patients (15 PBC, 16 PBC suspect and 48 disease controls) was carried out. All samples were tested by both a qualitative test multiplexed line-blot Autoimmune Liver Disease Profile Euroline and by a quantitative test EliA-M2 IgG. In order to evaluate a possible correlation between the quantitative M2 and disease activity, we divided patients mixed in a further three groups based on the value EliA-M2. For each of these groups were calculated the average values of the main indices of cholestasis. A perfect agreement was shown between the EliA-M2 and the multiplexed line-blot method for AMA detection. All sera of patients with PBC were positive with both tests, with a 100 % sensitivity. Forty-seven of the 48 sera of the control group were negative for both tests with a 100 % next specificity, and only 70 % for the AMA IIF. We had also observed in the other three groups of patients that the average of the values of gamma-glutamyl transpeptidase and alkaline phosphatase increases with the increase of the value EliA-M2. The difference between the mean values of the most significant parameter which the alkaline phosphatase of the three groups is significant, with a statistically significant difference between the first and the third group (p value 0.023). Both the qualitative method Profile Euroline and the quantitative EliA-M2 have a high diagnostic accuracy for PBC, with a specificity higher than the immunofluorescence method. These preliminary data might suggest the possibility of using the dosage EliA-M2 not only in the diagnosis phase but also in the monitoring of disease activity. PMID- 27475098 TI - Adrenomedullin Promotes the Proliferation and Inhibits Apoptosis of Dental Pulp Stem Cells Involved in Divergence Pathways. AB - INTRODUCTION: Adrenomedullin (ADM) is highly expressed in dental tissues at the critical developmental time points during tooth development. However, its role in pulp repair and pulp injury is still unknown. The study aimed to investigate the mechanisms by which ADM affects the proliferation and apoptosis of human dental pulp stem cells (DPSCs). METHODS: Fifty-four freshly extracted wisdom teeth were obtained from 27 patients with caries and 27 without. Enzyme-linked immunosorbent assay and immunohistochemistry were used to examine the expression levels of ADM in caries and normal pulp tissues. Human primary DPSCs from the third passage were incubated with ADM (10(-8) mol/L) for 24 hours; the cell cycle and apoptosis were investigated by flow cytomery, and protein expression was investigated using Western blot analysis. RESULTS: The levels of ADM in caries pulp tissues were significantly higher than those in normal pulp tissues. Incubation with ADM enhanced the percentage of G2/S/M phase DPSCs (P < .01) by the addition of a JNK/c-Jun inhibitor. Incubation with ADM reduced DPSC apoptosis by the addition of the Src/glycogen synthase kinase-3 inhibitor. ADM also ameliorated CoCl2 induced apoptosis and caspase-3 expression. CONCLUSIONS: ADM enhances the proliferation of DPSCs through activation of the JNK/c-Jun signaling pathway and inhibits apoptosis of DPSCs through activation of the Src/glycogen synthase kinase-3 signaling pathway. PMID- 27475096 TI - Glaucoma: recent advances in the involvement of autoimmunity. AB - Glaucomatous optic neuropathy is the most commonly acquired optic neuropathy encountered in clinical practice. It is the second leading cause of blindness globally, after cataracts, but it presents a greater public health challenge than cataracts, because the blindness it causes is irreversible. It has pathogenesis still largely unknown and no established cure. Alterations in serum antibody profiles, upregulation, and downregulation have been described, but it still remains elusive if the autoantibodies seen in glaucoma are an epiphenomenon or causative. Hypertension, diabetes, and hearing disorders also are associated. This review is a glaucoma update with focus about the recent advances in the last 15 years. PMID- 27475099 TI - Comparison of the Anesthetic Efficacy of Mepivacaine and Lidocaine in Patients with Irreversible Pulpitis: A Double-blind Randomized Clinical Trial. AB - INTRODUCTION: The objective of this study was to compare the anesthetic efficacy of 2% mepivacaine combined with 1:100,000 epinephrine with 2% lidocaine combined with 1:100,000 epinephrine during pulpectomy of mandibular posterior teeth in patients with irreversible pulpitis. METHODS: Forty-two patients with irreversible pulpitis who were admitted to the Emergency Center at the University of Sao Paulo School of Dentistry volunteered to take part in the study and were randomized to receive conventional inferior alveolar nerve block containing 1.8 or 3.6 mL of either 2% mepivacaine with 1:100,000 epinephrine or 2% lidocaine with 1:100,000 epinephrine. We recorded patients' subjective assessments of lip anesthesia, absence/presence of pulpal anesthesia tested by using electric pulp stimulation, and absence/presence of pain during the subsequent pulpectomy by using a verbal analogue scale. RESULTS: All patients tested reported lip anesthesia after application of either type of inferior alveolar nerve block. Pulpal anesthesia success rates measured by using the pulp tester were satisfactory for both solutions (86% for mepivacaine and 67% for lidocaine). Success rates according to patient report of no pain or mild pain during pulpectomy were higher for mepivacaine solution (55%) than for lidocaine solution (14%). The differences between mepivacaine and lidocaine were statistically significant. CONCLUSIONS: Mepivacaine resulted in effective pain control during irreversible pulpitis treatments. The success rates with either solution were not high enough to ensure complete pulpal anesthesia. PMID- 27475100 TI - Long-term outcomes of occipital nerve stimulation for chronic migraine: a cohort of 53 patients. AB - BACKGROUND: Chronic migraine affects up to 2 % of the general population and has a substantial impact on sufferers. Occipital nerve stimulation has been investigated as a potentially effective treatment for refractory chronic migraine. Results from randomised controlled trials and open label studies have been inconclusive with little long-term data available. METHODS: The long-term efficacy, functional outcome and safety of occipital nerve stimulation was evaluated in an uncontrolled, open-label, prospective study of 53 intractable chronic migraine patients. RESULTS: Fifty-three patients were implanted in a single centre between 2007 and 2013. Patients had a mean age of 47.75 years (range 26-70), had suffered chronic migraine for around 12 years and had failed a mean of 9 (range 4-19) preventative treatments prior to implant. Eighteen patients had other chronic headache phenotypes in addition to chronic migraine. After a median follow-up of 42.00 months (range 6-97) monthly moderate-to-severe headache days (i.e. days on which pain was more than 4 on the verbal rating score and lasted at least 4 h) reduced by 8.51 days (p < 0.001) in the whole cohort, 5.80 days (p < 0.01) in those with chronic migraine alone and 12.16 days (p < 0.001) in those with multiple phenotypes including chronic migraine. Response rate of the whole group (defined as a >30 % reduction in monthly moderate-to severe headache days) was observed in 45.3 % of the whole cohort, 34.3 % of those with chronic migraine alone and 66.7 % in those with multiple headache types. Mean subjective patient estimate of improvement was 31.7 %. Significant reductions were also seen in outcome measures such as pain intensity (1.34 points, p < 0.001), all monthly headache days (5.66 days, p < 0.001) and pain duration (4.54 h, p < 0.001). Responders showed substantial reductions in headache-related disability, affect scores and quality of life measures. Adverse event rates were favourable with no episodes of lead migration and only one minor infection reported. CONCLUSIONS: Occipital nerve stimulation may be a safe and efficacious treatment for highly intractable chronic migraine patients even after relatively prolonged follow up of a median of over 3 years. PMID- 27475102 TI - Bovine leukemia virus becomes established in dairy herds before the first lactation. AB - In this work, we studied seven groups of pregnant heifers from a consortium of dairy farms heavily infected with bovine leukemia virus (BLV). ELISA testing showed that the seroprevalence ranges of BLV in heifers between 36.1 and 66.5 %. No significant differences in proviral load were found when comparing heifers with adult cattle. Before their first delivery, more than 9.8 % of heifers show a high proviral load. Because BLV infection can occur during the first two years of life, the rationale of any strategy should be to take action as early as possible after birth. PMID- 27475103 TI - Development of a highly sensitive real-time nested RT-PCR assay in a single closed tube for detection of enterovirus 71 in hand, foot, and mouth disease. AB - Enterovirus 71 (EV71) is one of the major causative agents of outbreaks of hand, foot, and mouth disease (HFMD). A commercial TaqMan probe-based real-time PCR assay has been widely used for the differential detection of EV71 despite its relatively high cost and failure to detect samples with a low viral load (Ct value > 35). In this study, a highly sensitive real-time nested RT-PCR (RTN RT PCR) assay in a single closed tube for detection of EV71 in HFMD was developed. The sensitivity and specificity of this assay were evaluated using a reference EV71 stock and a panel of controls consisting of coxsackievirus A16 (CVA16) and common respiratory viruses, respectively. The clinical performance of this assay was evaluated and compared with those of a commercial TaqMan probe-based real time PCR (qRT-PCR) assay and a traditional two-step nested RT-PCR assay. The limit of detection for the RTN RT-PCR assay was 0.01 TCID50/ml, with a Ct value of 38.3, which was the same as that of the traditional two-step nested RT-PCR assay and approximately tenfold lower than that of the qRT-PCR assay. When testing the reference strain EV71, this assay showed favorable detection reproducibility and no obvious cross-reactivity. The testing results of 100 clinical throat swabs from HFMD-suspected patients revealed that 41 samples were positive for EV71 by both RTN RT-PCR and traditional two-step nested RT-PCR assays, whereas only 29 were EV71 positive by qRT-PCR assay. PMID- 27475101 TI - Release of PACAP-38 in episodic cluster headache patients - an exploratory study. AB - BACKGROUND: Activation of the trigeminal-autonomic reflex, involving the trigeminal ganglion, the superior salivatory nucleus and the sphenopalatine ganglion (SPG) is crucial in the pathophysiology of cluster headache (CH). Since pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) is present both in the SPG and the trigeminal ganglion (TG) and its role in migraine has been described, our aim was to determine the plasma PACAP-38 levels in different phases of episodic CH (ECH). Peripheral cubital fossa blood samples were taken during the ictal and inter-bout periods of male ECH patients and from age-matched healthy controls (n = 9). Plasma PACAP-38-like immunoreactivity (LI) was measured with specific and sensitive radioimmunoassay. FINDINGS: Significantly lower plasma PACAP-38-LI was detected in the inter-bout period of ECH patients than in healthy controls. However, PACAP-38 was significantly elevated in the plasma during CH attacks as compared to the inter-bout phase in the same subjects (n = 5). CONCLUSIONS: This exploratory study suggests that PACAP-38 may be released during the attacks of ECH. Further patients and long-term follow-up are necessary to reveal its function. PMID- 27475104 TI - Evaluation of differentially expressed immune-related genes in intestine of Pelodiscus sinensis after intragastric challenge with lipopolysaccharide based on transcriptome analysis. AB - Pelodiscus sinensis is the most common turtle species that has been raised in East and Southeast Asia. However, there are still limited studies about the immune defense mechanisms in its small intestine until now. In the present research, histological analysis and transcriptome analysis was performed on the small intestine of P. sinensis after intragastric challenge with LPS to explore its mechanisms of immune responses to pathogens. The result showed the number of intraepithelial lymphocytes (IELs) and goblet cells (GCs) in its intestine increased significantly at 48 h post-challenge with LPS by intragastrical route, indicating clearly the intestinal immune response was induced. Compared with the control, a total of 748 differentially expressed genes (DEGs) were identified, including 361 up-regulated genes and 387 down-regulated genes. Based on the Gene Ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG), 48 immune-related DEGs were identified, which were classified into 82 GO terms and 14 pathways. Finally, 18 DEGs, which were randomly selected, were confirmed by quantitative real-time PCR (qRT-PCR). Our results provide valuable information for further analysis of the immune defense mechanisms against pathogens in the small intestine of P. sinensis. PMID- 27475105 TI - Providers' advice concerning smoking cessation: Evidence from the Medical Expenditures Panel Survey. AB - IMPORTANCE AND OBJECTIVE: We estimate how often adult smokers are advised to quit using a nationally representative sample of adults in the United States. DESIGN AND PARTICIPANTS: Data are from the 2012-2013 household component of the United States (US) Medical Expenditures Panel Survey (MEPS). MAIN OUTCOME MEASURE: Current smoking and advice to quit offered by providers. RESULTS: Smoking was reported by 18.26% (CI 17.13%-19.38%) of 2012 MEPS respondents. Less than half of adult smokers (47.24%, CI 44.30%-50.19%) were advised to quit by their physicians although 17.57% (CI 15.37%-19.76%) had not seen a doctor in the last 12months. Advice to quit was given significantly less often to respondents classified as: aged 18-44 (40.29%), men (40.20%), less educated (42.26%), lower family income (43.51%), Hispanic (33.82%), never married (39.55%), and living outside the northeast. Smoking status at year 2 for patients who had received advice to quit was similar (85.13%: SE 1.62%) to those who had seen a physician but were not advised to quit (81.95%: SE 2.05%). Advice to quit smoking was less common than the use of common medical screening tests. CONCLUSIONS AND RELEVANCE: Smoking cessation advice is given to less than half of current cigarette smokers and it is least likely to be given to the most vulnerable populations. Efforts to reduce smoking are deployed less often than other preventive practices. The rate of advice to quit has not changed over the last decade. Health care providers are missing an important opportunity to affect health behaviors and outcomes. PMID- 27475107 TI - Arylthiosemicarbazones as antileishmanial agents. AB - Based on a screening process, we targeted substituted thiosemicarbazone as potential antileishmanial agents. Our objective was to identify the key structural elements contributing to the anti-parasite activity that might be used for development of effective drugs. A series of 32 compounds was synthesized and their efficacy was evaluated against the clinically relevant intracellular amastigotes of Leishmania donovani. From these, 22 compounds showed EC50 values below 10 MUM with the most active derivative (compound 14) showing an EC50 of 0.8 MUM with very low toxicity on two different mammalian cell lines. The most relevant structural elements required for higher activity indicate that the presence of a fused bicyclic aromatic ring such as a naphthalene bearing an alkyl or an alkoxy group substituent are prerequisites. Owing to the easy synthesis, high activity and low toxicity, the most active compounds could be considered as a lead for further development. PMID- 27475106 TI - Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse. AB - RATIONALE: The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms. OBJECTIVES: In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway. METHODS: An inhibitor of kynurenine-3-monooxygenase (KMO) Ro61-8048 (4 and 40 mg/kg) and its prodrug JM6 (100 and 200 mg/kg) were tested in two behavioural rat models for drug seeking and relapse-the alcohol deprivation effect (ADE) model in long-term alcohol-drinking rats and the model of cue induced reinstatement of alcohol- and cocaine-seeking behaviour. RESULTS: Our results show that relapse-like alcohol drinking during the ADE was abolished by repeated intraperitoneal administration of Ro61-8048 and significantly reduced by its oral prodrug JM6. Cue-induced reinstatement of both alcohol- and cocaine seeking behaviour was also abolished by administration of Ro61-8048. CONCLUSIONS: Pharmacological enhancement of endogenous kynurenic acid levels provides a novel treatment strategy to interfere with glutamatergic/NMDAR activity as well as with craving and relapse in alcohol-dependent patients and drug addicts. PMID- 27475108 TI - Establishment of a human indoleamine 2, 3-dioxygenase 2 (hIDO2) bioassay system and discovery of tryptanthrin derivatives as potent hIDO2 inhibitors. AB - As an analogue of IDO1 (indoleamine 2, 3-dioxygenase 1), the well-known new therapeutic target, IDO2 is receiving increased attention. Herein, the expression and purification of recombinant human IDO2 (hIDO2) and the establishment of a hIDO2 bioassay system on both enzymatic and cellular levels are described. Nine tryptanthrin derivatives were screened for potential hIDO2 inhibitory activities, and their Ki values, enzymatic and cellular IC50 values, as well as the types of inhibition were measured. The typtanthrin derivatives 5i, 5c and 5d (especially 5i) were found to be potent hIDO2 inhibitors with superior efficiency far better than that of the most frequently-used inhibitor L-1-MT. Two ultimate purposes of the present study have been achieved: establishing an IDO2 bioassay system and screening novel IDO2 inhibitors that can be used (directly or with some modifications) for potential therapeutic applications. PMID- 27475109 TI - 5-HT7 receptor modulators: Amino groups attached to biphenyl scaffold determine functional activity. AB - 5-HT7 receptor (5-HT7R) agonists and antagonists have been reported to be used for treatment of neuropathic pain and depression, respectively. In this study, as a novel scaffold for 5-HT7R modulators, we designed and prepared a series of biphenyl-3-yl-methanamine derivatives with various amino groups. Evaluation of functional activities as well as binding affinities of the title compounds identified partial agonists (EC50 = 0.55-3.2 MUM) and full antagonists (IC50 = 5.57-23.1 MUM) depending on the amino substituents. Molecular docking study suggested that the ligand-based switch in functional activity from agonist to antagonist results from the size of the amino groups and thereby different binding modes to 5-HT7R. In particular, interaction of the ligand with Arg367 of 5-HT7R is shown to differentiate agonists and antagonists. In the pharmacophore model study, two distinct pharmacophore models can tell whether a ligand is an agonist or an antagonist. Taken together, this study provides valuable information for designing novel compounds with selective agonistic or antagonistic properties against 5-HT7R. PMID- 27475110 TI - Coprinopsis cinerea intracellular lactonases hydrolyze quorum sensing molecules of Gram-negative bacteria. AB - Biofilm formation on fungal hyphae and production of antifungal molecules are strategies of bacteria in their competition with fungi for nutrients. Since these strategies are often coordinated and under control of quorum sensing by the bacteria, interference with this bacterial communication system can be used as a counter-strategy by the fungi in this competition. Hydrolysis of N-acyl homoserine lactones (HSL), a quorum sensing molecule used by Gram-negative bacteria, by fungal cultures has been demonstrated. However, the enzymes that are responsible for this activity, have not been identified. In this study, we identified and characterized two paralogous HSL hydrolyzing enzymes from the coprophilous fungus Coprinopsis cinerea. The C. cinerea HSL lactonases belong to the metallo-beta-lactamase family and show sequence homology to and a similar biochemical activity as the well characterized lactonase AiiA from Bacillus thuringiensis. We show that the fungal lactonases, similar to the bacterial enzymes, are kept intracellularly and act as a sink for the bacterial quorum sensing signals both in C. cinerea and in Saccharomyces cerevisiae expressing C. cinerea lactonases, due to the ability of these signal molecules to diffuse over the fungal cell wall and plasma membrane. The two isogenes coding for the C. cinerea HSL lactonases are arranged in the genome as a tandem repeat and expressed preferentially in vegetative mycelium. The occurrence of orthologous genes in genomes of other basidiomycetes appears to correlate with a saprotrophic lifestyle. PMID- 27475111 TI - Serum cytokine profile contributes to discriminating M. pneumoniae pneumonia in children. AB - BACKGROUND: To evaluate the role of serum cytokines in discriminating M. pneumoniae infection in children with community-acquired pneumonia (CAP). METHODS: A prospective observational study was conducted. 385 hospitalized patients with CAP had only M. pneumoniae (MP group) infection; 321 hospitalized patients with CAP had no M. pneumoniae and other specific pathogen (control group) infections. Serum interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were detected by flow cytometry. RESULTS: In children younger than 5years, serum IL-6, TNF-alpha, and IFN-gamma levels from MP group were significantly higher than those from control group. However in children 5-15years, serum IL-6, IL-10, and IFN-gamma levels from MP group were significantly higher than those from control group. In the final multivariate logistic regression model for serum cytokine, moderately elevated IL-6, IL-10, and IFN-gamma shows a higher prediction of development of M. pneumoniae pneumonia among CAP patients. CONCLUSIONS: A specific cytokine pattern showed a higher prediction of M. pneumoniae pneumonia among CAP patients, further suggesting that serum cytokine pattern might be useful in differentiating infectious causative agents in children. PMID- 27475112 TI - The incremental validity of the dark triad in predicting driving aggression. AB - This research tested the association between the Dark Triad and driving aggression as well as the incremental validity of the Dark Triad in predicting aggressive driving and the mediation role of the Dark Triad in the relationship between Big Five personality factors and aggressive driving. 274 undergraduate students in Study 1 and 95 amateur drivers in Study 2 completed measures of the Dark Triad (Machiavellianism, Narcissism and Psychopathy), the Big Five personality factors and the aggressive driving expression. Results showed that all the Dark Triad traits were related to aggressive driving behavior in both Study 1 and Study 2 and that the Dark Triad predicted driving aggression after the effect of the Big five personality factors was controlled, with Psychopathy being the strongest predictor of driving aggression in both Study 1 and Study 2. Machiavellianism and Psychopathy mediated the relationship between Emotional Stability, Agreeableness, Conscientiousness on one hand and aggressive driving on the other hand. PMID- 27475113 TI - Macro-level safety analysis of pedestrian crashes in Shanghai, China. AB - Pedestrian safety has become one of the most important issues in the field of traffic safety. This study aims at investigating the association between pedestrian crash frequency and various predictor variables including roadway, socio-economic, and land-use features. The relationships were modeled using the data from 263 Traffic Analysis Zones (TAZs) within the urban area of Shanghai - the largest city in China. Since spatial correlation exists among the zonal-level data, Bayesian Conditional Autoregressive (CAR) models with seven different spatial weight features (i.e. (a) 0-1 first order, adjacency-based, (b) common boundary-length-based, (c) geometric centroid-distance-based, (d) crash-weighted centroid-distance-based, (e) land use type, adjacency-based, (f) land use intensity, adjacency-based, and (g) geometric centroid-distance-order) were developed to characterize the spatial correlations among TAZs. Model results indicated that the geometric centroid-distance-order spatial weight feature, which was introduced in macro-level safety analysis for the first time, outperformed all the other spatial weight features. Population was used as the surrogate for pedestrian exposure, and had a positive effect on pedestrian crashes. Other significant factors included length of major arterials, length of minor arterials, road density, average intersection spacing, percentage of 3 legged intersections, and area of TAZ. Pedestrian crashes were higher in TAZs with medium land use intensity than in TAZs with low and high land use intensity. Thus, higher priority should be given to TAZs with medium land use intensity to improve pedestrian safety. Overall, these findings can help transportation planners and managers understand the characteristics of pedestrian crashes and improve pedestrian safety. PMID- 27475114 TI - Adult colo-colonic intussusception caused by congenital bands: A case report and literature review. AB - INTRODUCTION: Intussusception refers to the telescoping of a segment of bowel into the lumen of an adjacent segment. While pediatric intussusception is common and generally idiopathic, adult intussusception is exceedingly rare and is usually attributable to a pathologic lead point. PRESENTATION OF CASE: 37-year old man who presented with abdominal pain, and was preoperatively diagnosed with a colo-colonic intussusception. Intraoperatively, the lead point was found to be congenital bands, and there was no evidence of underlying malignancy. He underwent a laparoscopic-assisted extended right hemicolectomy with side-to-side ileo-colic anastomosis. DISCUSSION: Colo-colonic intussusception is a rare cause of intestinal obstruction in adults. Patients generally present with subacute abdominal pain and obstructive symptoms, rendering the clinical diagnosis challenging. Computed tomography has been shown to be the most accurate diagnostic imaging modality. Due to the high incidence of underlying malignancy in adult colo-colonic intussusception, en-bloc resection of the involved bowel segment remains the standard of care. CONCLUSION: Congenital bands can serve as a lead point in colo-colonic intussusception, particularly in younger adults. Prompt surgical intervention remains paramount to limit morbidity. PMID- 27475115 TI - Management of facial asymmetry due to overgrowing costochondral graft: A case report. AB - Costochondral grafts are used to replace the mandibular condyle in cases of TMJ ankylosis, and are generally viewed as a gold standard for autogenous reconstruction of the mandibular condyle (Guven, 2000; Posnick and Goldstein, 1993 [1,2]). We report a case where overgrowth of costochondral grafts is seen, resulting in asymmetric mandibular growth and dentofacial asymmetry (Posnick and Goldstein, 1993 [2]). A 17 year old male patient presented with an existing costochondral graft performed due to TMJ ankylosis during childhood. He fell from a height at the age of 4, and was lost to follow up through non-attendance until the age of 9, when he presented with a progressive reduction in maximal incisal opening (MIO). At this stage his maximal incisal opening was noted to be 11mm, and the CT showed a grossly deformed ankylosed left TMJ. This post traumatic ankyloses was managed with gap arthroplasty and costochondral graft reconstruction. This immediately improved his MIO to 22mm and at 1 year follow up was noted to be 30mm. At age 12 he was noted to have a clinically obvious overgrowth of the left ramus of the mandible, and deviation of the chin point to the right. MIO remained at 38mm. He declined orthognathic surgery and represented 2 years later requesting treatment without orthodontic intervention for his facial asymmetry. He subsequently underwent a Le Fort 1 impaction osteotomy, right BSSO and left condylar ostectomy, coronoidectomy and left lower border mandibulectomy. Regrowth of the CCG occurred during the 6 months of follow up. This case illustrates the problems that can occur after condylar trauma. It also highlights issues with costochondral grafts which can continue to grow. PMID- 27475116 TI - The largest and neglected giant phyllodes tumor of the breast-A case report and literature review. AB - INTRODUCTION: Phyllodes tumours are rare fibro-epithelial lesions. The role of the pathologist in the preoperative diagnosis of phyllodes tumours of the breast is critical to appropriate surgical planning. Wide local excision or mastectomy with adequate margin remains the treatment of choice. Local recurrence occurs in approximately 10- 16.1% of patients (Wei et al., 2014) [1] and distant metastases occurs in 6.3-31% of patients with malignant phyllodes tumours (Wei et al. (2014), Chaney et al., 1998) [1,2] but only in 4% of all phyllodes tumours (Salvador et al., 1989) [3]. Emphasis should be given in early diagnosis and intervention to decrease morbidity and mortality. PMID- 27475117 TI - The choice of locking plate in the treatment of peri-implant femoral fracture eight years after trans-trochanteric rotational osteotomy: A case report. AB - INTRODUCTION: Transtrochanteric anterior rotational osteotomy of the femoral head (TRO) was developed as a joint preserving surgery for osteonecrosis of the femoral head. To the best of our knowledge, peri-implant fractures after femoral osteotomy have rarely been reported. PRESENTATION OF CASE: We report a 58-year old female who suffered a peri-implant femoral shaft fracture following a fall from a stepladder eight years after TRO. Fracture union was achieved six months after a preferred proximal femoral locking plate. DISCUSSION: The entry point of the ante-grade femoral nail would have been very close to the new position of the nutrient artery of the femoral head occasioned by the TRO and to avoid injury, we chose proximal femoral locking plate. CONCLUSION: It is important to consider the new position of the nutrient artery of the femoral head in the surgical planning of peri-implant fracture after TRO. PMID- 27475118 TI - The nuclear envelope and gene organization in parasitic protozoa: Specializations associated with disease. AB - The parasitic protozoa Trypanosoma brucei and Plasmodium falciparum are lethal human parasites that have developed elegant strategies of immune evasion by antigenic variation. Despite the vast evolutionary distance between the two taxa, both parasites employ strict monoallelic expression of their membrane proteins, variant surface glycoproteins in Trypanosomes and the var, rif and stevor genes in Plasmodium, in order to evade their host's immune system. Additionally, both telomeric location and epigenetic controls are prominent features of these membrane proteins. As such, telomeres, chromatin structure and nuclear organization all contribute to control of gene expression and immune evasion. Here, we discuss the importance of epigenetics and sub-nuclear context for the survival of these disease-causing parasites. PMID- 27475119 TI - Patient and Family Member Factors Influencing Outcomes of Poststroke Inpatient Rehabilitation. AB - OBJECTIVE: To investigate how family members' attitudes toward functional regain, and patients' knowledge and intention of independence influence poststroke rehabilitation. DESIGN: Cross-sectional study. SETTING: Three rehabilitation inpatient settings. PARTICIPANTS: Younger (n=79) and older (n=84) poststroke patients, along with their family members (spouses, n=104; children, n=59). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Custom-designed questionnaires were used to tap into the patients' knowledge about rehabilitation (Patient's Rehabilitation Questionnaire-Knowledge About Rehabilitation) and intention of independence (Patient's Rehabilitation Questionnaire-Intention of Independence), and family members' attitudes toward patients in performing basic activities of daily living (BADL) (Family Member Attitudes Questionnaire-BADL) and instrumental activities of daily living (Family Member Attitudes Questionnaire-instrumental activities of daily living). The rehabilitation outcomes included gains in motor, cognitive, and emotional functions, and self care independence, measured with common clinical instruments. RESULTS: The Family Member Attitudes Questionnaire-BADL predicted cognitive outcome and the Patient's Rehabilitation Questionnaire-Intention of Independence predicted motor outcome for both groups. Differential age-related effects were revealed for the Patient's Rehabilitation Questionnaire-Intention of Independence in predicting emotional outcome only for the younger group, and self-care independence only for the older group. CONCLUSIONS: Patients' intention of independence positively affected motor recovery, while family members' positive attitudes promoted cognitive regain. The findings suggested plausible age-related differences in how patients' intentions affect emotion versus self-care independence outcomes. Future studies should explore strategies for promoting positive attitudes toward independence among patients and family members during poststroke rehabilitation. PMID- 27475120 TI - Ultra-wetting graphene-based PES ultrafiltration membrane - A novel approach for successful oil-water separation. AB - Oil pollution in water and separation of oil from water are receiving much attention in recent years due to the growing environmental concerns. Membrane technology is one of the emerging solutions for oil-water separation. However, there is a limitation in using polymeric membrane for oil water separation due to its surface properties (wetting behaviour), thermal and mechanical properties. Here, we have shown a simple method to increase the hydrophilicity of the polyethersulfone (PES) hollow fibre ultrafiltration (UF) membrane by using carboxyl, hydroxyl and amine modified graphene attached poly acrylonitrile-co maleimide (G-PANCMI). The prepared membranes were characterized for its morphology, water and oil contact angle, liquid entry pressure of oil (LEPoil), water permeability and finally subjected to a continuous 8 h filtration test of oil emulsion in water. The experimental data indicates that the G-PANCMI play an important role in enhancing the hydrophilicity, permeability and selectivity of the PES membrane. The water contact angle (CAw) of the PES membrane is reduced from 63.7 +/- 3.8 degrees to 22.6 +/- 2.5 degrees which is 64.5% reduction while, the oil contact angle was increased from 43.6 +/- 3.5 degrees to 112.5 +/ 3.2 degrees which is 158% higher compared to that of the PES membrane. Similarly, the LEPoil increased 350% from 50 +/- 10 kPa of the control PES membrane to 175 +/- 25 kPa of PES-G-PANCMI membrane. More importantly, the water permeability increased by 43% with >99% selectivity. Based on our findings we believe that the development of PES-G-PANCMI membrane will open up a solution for successful oil-water separation. PMID- 27475121 TI - Removal of strontium from drinking water by conventional treatment and lime softening in bench-scale studies. AB - The United States Environmental Protection Agency Contaminant Candidate List 3 lists strontium as a contaminant for potential regulatory consideration in drinking water. Very limited data is available on strontium removal from drinking water and as a result, there is an immediate need for treatment information. The objective of this work is to evaluate the effectiveness of coagulation/filtration and lime-soda ash softening treatment methods to remove strontium from surface and ground waters. Coagulation/filtration jar test results on natural waters showed that conventional treatment with aluminum and iron coagulants were able to achieve only 12% and 5.9% strontium removal, while lime softening removed as high as 78% from natural strontium-containing ground water. Controlled batch experiments on synthetic water showed that strontium removal during the lime-soda ash softening was affected by pH, calcium concentration and dissolved inorganic carbon concentration. In all softening jar tests, the final strontium concentration was directly related to the initial strontium concentration and the removal of strontium was directly associated with calcium removal. Precipitated solids showed well-formed crystals or agglomerates of mixed solids, two polymorphs of calcium carbonate (vaterite and calcite), and strontianite, depending on initial water quality conditions. X-ray diffraction analysis suggested that strontium was likely incorporated in the calcium carbonate crystal lattice and was likely responsible for removal during lime softening. PMID- 27475122 TI - Infracentimetric cervical lymph node metastasis in head and neck squamous cell carcinoma: Incidence and prognostic value. AB - OBJECTIVES: Supracentimetric cervical lymph node metastasis is classically a poor prognostic factor for locoregional recurrence and survival in head and neck cancer. Causality, however, is more controversial for infracentimetric cervical lymph node metastases. The objective of this study was to evaluate the incidence and prognostic value of infracentimetric lymph node metastasis. MATERIALS AND METHODS: Two hundred and forty-three neck dissections from 150 head and neck cancer patients were analyzed. A single pathologist exhaustively inventoried the number and size of all adenopathies in the surgical specimen. RESULTS: Cervical lymph node metastases were infracentimetric in 38% of cases, with 72% extracapsular spread (versus 91% for supracentimetric adenopathies; P<0.01). Infracentimetric metastases were more often associated with other cervical lymph node metastases (mean 5.3 versus 3.9; P=0.14). Fifty three percent of specimens showed only supracentimetric metastases (versus 13% infracentimetric metastases; P<0.01). Disease-specific and failure-free survival were lower in case of infracentimetric metastasis, associated with supracentimetric metastasis or not, than in case of macrometastasis only. CONCLUSION: Infracentimetric cervical lymph node metastasis is a factor of poor prognosis, and may represent a different, more aggressive lymphatic process. We suggest complete neck dissection by the surgeon and meticulous analysis by the pathologist, the results of which guide complementary therapy. Close surveillance of recurrence is also recommended. PMID- 27475123 TI - Impact of a stand-alone course in gerontological nursing on undergraduate nursing students' perceptions of working with older adults: A Quasi-experimental study. AB - BACKGROUND: With an aging population, it is critical that nurses are educated and prepared to offer quality healthcare to this client group. Incorporating gerontology content into nursing curricula and addressing students' perceptions and career choices in relation to working with older adults are important faculty concerns. OBJECTIVES: To examine the impact of a stand-alone course in gerontological nursing on undergraduate nursing students' perceptions of working with older adults and career intentions. DESIGN: Quasi-experimental, pre- and post-test design. SETTING: Medium-sized state university in the Mid Western United States PARTICIPANTS: Data were collected from three student cohorts during the spring semesters of 2012 (n=98), 2013 (n=80) and 2014 (n=88) for a total of N=266 with an average response rate of 85%. METHODS: A survey instrument was administered via Qualtrics and completed by students prior to, and following completion of the course. RESULTS: There was an overall significant increase (p=0.000) in positive perceptions of working with older adults among nursing students following completion of the course. The majority of participants (83.5%) reported having previous experience with older adults. Those with previous experience had higher perception scores at pre-test than those without (p=0.000). Post-test scores showed no significant difference between these two groups, with both groups having increased perception scores (p=0.120). Student preferences for working with different age groups suggested an overall increase in preference for working with older adults following the course. CONCLUSIONS: A course in gerontological nursing, incorporating learning partnerships with community dwelling older adults, promotes positive perceptions of working with older adults, independently of the quality of prior experience. There was some evidence that students changed their preferences of working with different age groups in favor of working with older adults. Further research should be conducted to determine the mechanisms through which this takes place. PMID- 27475124 TI - Controversial aspects of the life cycle of Fasciola hepatica. AB - Fasciola hepatica is a well-known helminth parasite, with significant economic and public health importance all over the world. It has been known since more than 630 years ago and a considerable research work has been carried out on the life cycle of this important parasite. In the hepatic phase of the life cycle of F. hepatica, it is assumed that the young flukes, after about 6-7 weeks of migration in the liver parenchyma, enter into the bile ducts of the definitive hosts and become sexually mature. Even though the secretion of cysteine peptidases including cathepsin L and B proteases by F. hepatica may justify this opinion, because of several scientific reasons and based on the experimental studies conducted in different animals (reviewed in this article), the entry of parasites into the bile ducts, after their migration in the liver parenchyma seems to be doubtful. However, considering all the facts relating to the hepatic and biliary phases of the life cycle of F. hepatica, two alternative ideas are suggested: 1) some of the migrating juvenile flukes may enter into the bile ducts immediately after reaching the liver parenchyma while they are still very small, or 2) when newly excysted juvenile flukes are penetrating into the intestinal wall to reach the liver through the abdominal cavity, a number of these flukes may enter into the choleduct and reach the hepatic bile ducts, where they mature. According to the previously performed natural and experimental studies in different animals and human beings, the supporting and opposing evidences for the current opinion as well as the evidences that might justify the two new ideas are reviewed and discussed briefly. In conclusion, our present knowledge about the time and quality of the entry of F. hepaticas into the bile ducts, seems to be insufficient, therefore, there are still some dark corners and unknown aspects in this field that should be clarified. PMID- 27475125 TI - Pediatric computed tomography practice in Japanese university hospitals from 2008 2010: did it differ from German practice? AB - Computed tomography (CT) is an essential tool in modern medicine and is frequently used to diagnose a wide range of conditions, particularly in industrial countries, such as Japan and Germany. However, markedly higher doses of ionizing radiation are delivered during CT imaging than during conventional X ray examinations. To assess pediatric CT practice patterns, data from three university hospital databases (two in Japan and one in Germany) were analyzed. Anonymized data for patients aged 0 to 14 years who had undergone CT examinations between 2008 and 2010 were extracted. To assess CT practice, an interdisciplinary classification scheme for CT indications, which incorporated the most common examination types and radiosensitive tissues, was developed. The frequency of CT examinations was determined according to sex, age at examination, and indications. A total of 5182 CT examinations were performed in 2955 children. Overall, the frequency of CT examinations at the Japanese university hospitals did not differ significantly from that at the German hospital. However, differences were detected in the age distribution of the patients who underwent CT examinations (the proportion of patients <5 years of age was significantly higher in Japan than in Germany) and in the indications for CT. Substantial practice differences regarding the use of CT in pediatric health care were detected between the three hospitals. The results of this study point towards a need for approaches such as clinical guidelines to reduce unwarranted medical radiation exposures, particularly abdominal and head CT, in the Japanese health system. PMID- 27475126 TI - Long-term complications of definitive chemoradiotherapy for esophageal cancer using the classical method. AB - Chemoradiation therapy is widely used to treat both inoperable and operable patients, and is less invasive than surgery. Although the number of long-term survivors who have received chemoradiation therapy is increasing, the long-term toxicity pattern and cumulative incidence of toxicity regarding this modality are poorly understood. Classically, chemoradiation therapy for esophageal cancer consists of an anterior-posterior field and a subsequent oblique boost field. We retrospectively analyzed patients who were treated with definitive chemoradiation therapy for esophageal cancer using this classical method from 1999 to 2008. For the assessment of toxicity, the National Cancer Institute Common Toxicity Criteria Version 3.0 was adopted. A total of 101 patients were analyzed. The median follow-up time was 16 months for all patients and 62 months for the surviving patients. Eleven patients experienced late toxicities of >=Grade 3. Two patients died of late toxicities. The 3- and 5-year cumulative incidences for the first late cardiopulmonary toxicities of >=Grade 3 were 17.4% and 20.8%, respectively. Cardiopulmonary effusions were observed within the first 3 years of completion of the initial treatment in seven out of eight patients. Sudden death and cardiac ischemia were observed over a 10-year period. Older age was found to be a risk factor for late toxicity after definitive chemoradiation therapy for esophageal cancer. Substantial toxicities were observed in patients who had received chemoradiation therapy for esophageal cancer using the classical method. To minimize the incidence of late toxicity, more sophisticated radiation techniques may be useful. PMID- 27475127 TI - Finite difference time domain model of ultrasound propagation in agarose scaffold containing collagen or chondrocytes. AB - Measurement of ultrasound backscattering is a promising diagnostic technique for arthroscopic evaluation of articular cartilage. However, contribution of collagen and chondrocytes on ultrasound backscattering and speed of sound in cartilage is not fully understood and is experimentally difficult to study. Agarose hydrogels have been used in tissue engineering applications of cartilage. Therefore, the aim of this study was to simulate the propagation of high frequency ultrasound (40 MHz) in agarose scaffolds with varying concentrations of chondrocytes (1 to 32 * 10(6) cells/ml) and collagen (1.56-200 mg/ml) using transversely isotropic two-dimensional finite difference time domain method (FDTD). Backscatter and speed of sound were evaluated from the simulated pulse-echo and through transmission measurements, respectively. Ultrasound backscatter increased with increasing collagen and chondrocyte concentrations. Furthermore, speed of sound increased with increasing collagen concentration. However, this was not observed with increasing chondrocyte concentrations. The present study suggests that the FDTD method may have some applicability in simulations of ultrasound scattering and propagation in constructs containing collagen and chondrocytes. Findings of this study indicate the significant role of collagen and chondrocytes as ultrasound scatterers and can aid in development of modeling approaches for understanding how cartilage architecture affects to the propagation of high frequency ultrasound. PMID- 27475128 TI - Distinct neural systems recruited when speech production is modulated by different masking sounds. AB - When talkers speak in masking sounds, their speech undergoes a variety of acoustic and phonetic changes. These changes are known collectively as the Lombard effect. Most behavioural research and neuroimaging research in this area has concentrated on the effect of energetic maskers such as white noise on Lombard speech. Previous fMRI studies have argued that neural responses to speaking in noise are driven by the quality of auditory feedback-that is, the audibility of the speaker's voice over the masker. However, we also frequently produce speech in the presence of informational maskers such as another talker. Here, speakers read sentences over a range of maskers varying in their informational and energetic content: speech, rotated speech, speech modulated noise, and white noise. Subjects also spoke in quiet and listened to the maskers without speaking. When subjects spoke in masking sounds, their vocal intensity increased in line with the energetic content of the masker. However, the opposite pattern was found neurally. In the superior temporal gyrus, activation was most strongly associated with increases in informational, rather than energetic, masking. This suggests that the neural activations associated with speaking in noise are more complex than a simple feedback response. PMID- 27475129 TI - Bowhead whale localization using asynchronous hydrophones in the Chukchi Sea. AB - This paper estimates bowhead whale locations and uncertainties using non-linear Bayesian inversion of their modally-dispersed calls recorded on asynchronous recorders in the Chukchi Sea, Alaska. Bowhead calls were recorded on a cluster of 7 asynchronous ocean-bottom hydrophones that were separated by 0.5-9.2 km. A warping time-frequency analysis is used to extract relative mode arrival times as a function of frequency for nine frequency-modulated whale calls that dispersed in the shallow water environment. Each call was recorded on multiple hydrophones and the mode arrival times are inverted for: the whale location in the horizontal plane, source instantaneous frequency (IF), water sound-speed profile, seabed geoacoustic parameters, relative recorder clock drifts, and residual error standard deviations, all with estimated uncertainties. A simulation study shows that accurate prior environmental knowledge is not required for accurate localization as long as the inversion treats the environment as unknown. Joint inversion of multiple recorded calls is shown to substantially reduce uncertainties in location, source IF, and relative clock drift. Whale location uncertainties are estimated to be 30-160 m and relative clock drift uncertainties are 3-26 ms. PMID- 27475130 TI - Feasibility of coded vibration in a vibro-ultrasound system for tissue elasticity measurement. AB - The ability of various methods for elasticity measurement and imaging is hampered by the vibration amplitude on biological tissues. Based on the inference that coded excitation will improve the performance of the cross-correlation function of the tissue displacement waves, the idea of exerting encoded external vibration on tested samples for measuring its elasticity is proposed. It was implemented by integrating a programmable vibration generation function into a customized vibro ultrasound system to generate Barker coded vibration for elasticity measurement. Experiments were conducted on silicone phantoms and porcine muscles. The results showed that coded excitation of the vibration enhanced the accuracy and robustness of the elasticity measurement especially in low signal-to-noise ratio scenarios. In the phantom study, the measured shear modulus values with coded vibration had an R(2 )= 0.993 linear correlation to that of referenced indentation, while for single-cycle pulse the R(2) decreased to 0.987. In porcine muscle study, the coded vibration also obtained a shear modulus value which is more accurate than the single-cycle pulse by 0.16 kPa and 0.33 kPa at two different depths. These results demonstrated the feasibility and potentiality of the coded vibration for enhancing the quality of elasticity measurement and imaging. PMID- 27475131 TI - Acoustic characteristics of clearly spoken English tense and lax vowels. AB - Clearly produced vowels exhibit longer duration and more extreme spectral properties than plain, conversational vowels. These features also characterize tense relative to lax vowels. This study explored the interaction of clear-speech and tensity effects by comparing clear and plain productions of three English tense-lax vowel pairs (/i-i/, /alpha-v/, /u-upsilon/ in /kVd/ words). Both temporal and spectral acoustic features were examined, including vowel duration, vowel-to-word duration ratio, formant frequency, and dynamic spectral characteristics. Results revealed that the tense-lax vowel difference was generally enhanced in clear relative to plain speech, but clear-speech modifications for tense and lax vowels showed a trade-off in the use of temporal and spectral cues. While plain-to-clear vowel lengthening was greater for tense than lax vowels, clear-speech modifications in spectral change were larger for lax than tense vowels. Moreover, peripheral tense vowels showed more consistent clear-speech modifications in the temporal than spectral domain. Presumably, articulatory constraints limit the spectral variation of these extreme vowels, so clear-speech modifications resort to temporal features and reserve the primary spectral features for tensity contrasts. These findings suggest that clear-speech and tensity interactions involve compensatory modifications in different acoustic domains. PMID- 27475133 TI - Speech intelligibility in rooms: Effect of prior listening exposure interacts with room acoustics. AB - There is now converging evidence that a brief period of prior listening exposure to a reverberant room can influence speech understanding in that environment. Although the effect appears to depend critically on the amplitude modulation characteristic of the speech signal reaching the ear, the extent to which the effect may be influenced by room acoustics has not been thoroughly evaluated. This study seeks to fill this gap in knowledge by testing the effect of prior listening exposure or listening context on speech understanding in five different simulated sound fields, ranging from anechoic space to a room with broadband reverberation time (T60) of approximately 3 s. Although substantial individual variability in the effect was observed and quantified, the context effect was, on average, strongly room dependent. At threshold, the effect was minimal in anechoic space, increased to a maximum of 3 dB on average in moderate reverberation (T60 = 1 s), and returned to minimal levels again in high reverberation. This interaction suggests that the functional effects of prior listening exposure may be limited to sound fields with moderate reverberation (0.4 <= T60 <= 1 s). PMID- 27475132 TI - Binaural release from masking with single- and multi-electrode stimulation in children with cochlear implants. AB - Cochlear implants (CIs) provide children with access to speech information from a young age. Despite bilateral cochlear implantation becoming common, use of spatial cues in free field is smaller than in normal-hearing children. Clinically fit CIs are not synchronized across the ears; thus binaural experiments must utilize research processors that can control binaural cues with precision. Research to date has used single pairs of electrodes, which is insufficient for representing speech. Little is known about how children with bilateral CIs process binaural information with multi-electrode stimulation. Toward the goal of improving binaural unmasking of speech, this study evaluated binaural unmasking with multi- and single-electrode stimulation. Results showed that performance with multi-electrode stimulation was similar to the best performance with single electrode stimulation. This was similar to the pattern of performance shown by normal-hearing adults when presented an acoustic CI simulation. Diotic and dichotic signal detection thresholds of the children with CIs were similar to those of normal-hearing children listening to a CI simulation. The magnitude of binaural unmasking was not related to whether the children with CIs had good interaural time difference sensitivity. Results support the potential for benefits from binaural hearing and speech unmasking in children with bilateral CIs. PMID- 27475135 TI - A broadband polygonal cloak for acoustic wave designed with linear coordinate transformation. AB - Previous acoustic cloaks designed with transformation acoustics always involve inhomogeneous material. In this paper, a design of acoustic polygonal cloak is proposed using linear polygonal transformation method. The designed acoustic polygonal cloak has homogeneous and anisotropic parameters, which is much easier to realize in practice. Furthermore, a possible acoustic metamaterial structure to realize the cloak is proposed. Simulation results on the real structure show that the metamaterial acoustic cloak is effective to reduce the scattering of the object. PMID- 27475136 TI - Level variations in speech: Effect on masking release in hearing-impaired listeners. AB - Acoustic speech is marked by time-varying changes in the amplitude envelope that may pose difficulties for hearing-impaired listeners. Removal of these variations (e.g., by the Hilbert transform) could improve speech reception for such listeners, particularly in fluctuating interference. Leger, Reed, Desloge, Swaminathan, and Braida [(2015b). J. Acoust. Soc. Am. 138, 389-403] observed that a normalized measure of masking release obtained for hearing-impaired listeners using speech processed to preserve temporal fine-structure (TFS) cues was larger than that for unprocessed or envelope-based speech. This study measured masking release for two other speech signals in which level variations were minimal: peak clipping and TFS processing of an envelope signal. Consonant identification was measured for hearing-impaired listeners in backgrounds of continuous and fluctuating speech-shaped noise. The normalized masking release obtained using speech with normal variations in overall level was substantially less than that observed using speech processed to achieve highly restricted level variations. These results suggest that the performance of hearing-impaired listeners in fluctuating noise may be improved by signal processing that leads to a decrease in stimulus level variations. PMID- 27475137 TI - Enhanced nearfield acoustic holography for larger distances of reconstructions using fixed parameter Tikhonov regularization. AB - This paper evaluates the performance of various regularization parameter choice methods applied to different approaches of nearfield acoustic holography when a very nearfield measurement is not possible. For a fixed grid resolution, the larger the hologram distance, the larger the error in the naive nearfield acoustic holography reconstructions. These errors can be smoothed out by using an appropriate order of regularization. This study shows that by using a fixed/manual choice of regularization parameter, instead of automated parameter choice methods, reasonably accurate reconstructions can be obtained even when the hologram distance is 16 times larger than the grid resolution. PMID- 27475138 TI - Interactions between amplitude modulation and frequency modulation processing: Effects of age and hearing loss. AB - Frequency modulation (FM) and amplitude modulation (AM) detection thresholds were measured for a 500-Hz carrier frequency and a 5-Hz modulation rate. For AM detection, FM at the same rate as the AM was superimposed with varying FM depth. For FM detection, AM at the same rate was superimposed with varying AM depth. The target stimuli always contained both amplitude and frequency modulations, while the standard stimuli only contained the interfering modulation. Young and older normal-hearing listeners, as well as older listeners with mild-to-moderate sensorineural hearing loss were tested. For all groups, AM and FM detection thresholds were degraded in the presence of the interfering modulation. AM detection with and without interfering FM was hardly affected by either age or hearing loss. While aging had an overall detrimental effect on FM detection with and without interfering AM, there was a trend that hearing loss further impaired FM detection in the presence of AM. Several models using optimal combination of temporal-envelope cues at the outputs of off-frequency filters were tested. The interfering effects could only be predicted for hearing-impaired listeners. This indirectly supports the idea that, in addition to envelope cues resulting from FM to-AM conversion, normal-hearing listeners use temporal fine-structure cues for FM detection. PMID- 27475140 TI - Acoustic source identification of an axial fan in a duct considering the rotation effect. AB - For developing the quiet axial fans, the spatial distribution of acoustic source parameters over the source plane provides essential information. In this study, the previously suggested source identification technique by authors is newly applied to an axial fan. To obtain the acoustic source parameters in a duct, one should overcome many technical difficulties related with: the turbulent flow, high order modes, rotating sources, inverse estimation. Measurements are conducted with several arrays of flush mounted microphones deployed on the periphery of the duct wall. A reference trigger signal obtained from the rotating blade is used to suppress the effect of turbulent flow in the measured pressure spectra with a reduction of about 25 dB in the present work. The maximum error between measurement and estimation is generally <-20 dB in the measurement plane in the very vicinity to the source. The visualized source images clearly indicate the locations and the strengths of main contributors to the radiated sound, e.g., for the inlet of the axial fan, the tip clearance between fan blades and shroud wall. PMID- 27475139 TI - Determining the energetic and informational components of speech-on-speech masking. AB - Identification of target speech was studied under masked conditions consisting of two or four independent speech maskers. In the reference conditions, the maskers were colocated with the target, the masker talkers were the same sex as the target, and the masker speech was intelligible. The comparison conditions, intended to provide release from masking, included different-sex target and masker talkers, time-reversal of the masker speech, and spatial separation of the maskers from the target. Significant release from masking was found for all comparison conditions. To determine whether these reductions in masking could be attributed to differences in energetic masking, ideal time-frequency segregation (ITFS) processing was applied so that the time-frequency units where the masker energy dominated the target energy were removed. The remaining target-dominated "glimpses" were reassembled as the stimulus. Speech reception thresholds measured using these resynthesized ITFS-processed stimuli were the same for the reference and comparison conditions supporting the conclusion that the amount of energetic masking across conditions was the same. These results indicated that the large release from masking found under all comparison conditions was due primarily to a reduction in informational masking. Furthermore, the large individual differences observed generally were correlated across the three masking release conditions. PMID- 27475141 TI - Reverberation of flexural waves scattered by a local heterogeneity in a plate. AB - A statistical model is proposed to relate the scattering properties of a local heterogeneity in a plate to the statistical properties of scattered and reverberated flexural waves. The contribution of the heterogeneity is isolated through the computation of differential signals consisting of a subtraction of the signals recorded after and before introduction of the heterogeneity. The theoretical expression of the average reverberation envelope of these differential signals is obtained as a function of the scattering cross-section of the heterogeneity. Successful numerical and experimental validations in various cases of canonical heterogeneities with known scattering cross-sections are shown. These satisfying results offer a way to estimate the scattering cross section of an unknown scatterer from the reverberated differential signals. PMID- 27475142 TI - A perfectly matched layer for fluid-solid problems: Application to ocean acoustics simulations with solid ocean bottoms. AB - A time-domain Legendre spectral-element method is described for full-wave simulation of ocean acoustics models, i.e., coupled fluid-solid problems in unbounded or semi-infinite domains, taking into account shear wave propagation in the ocean bottom. The technique can accommodate range-dependent and depth dependent wave speed and density, as well as steep ocean floor topography. For truncation of the infinite domain, to efficiently absorb outgoing waves, a fluid solid complex-frequency-shifted unsplit perfectly matched layer is introduced based on the complex coordinate stretching technique. The complex stretching is rigorously taken into account in the derivation of the fluid-solid matching condition inside the absorbing layer, which has never been done before in the time domain. Two implementations are designed: a convolutional formulation and an auxiliary differential equation formulation because the latter allows for implementation of high-order time schemes, leading to reduced numerical dispersion and dissipation, a topic of importance, in particular, in long-range ocean acoustics simulations. The method is validated for a two dimensional fluid solid Pekeris waveguide and for a three dimensional seamount model, which shows that the technique is accurate and numerically long-time stable. Compared with widely used paraxial absorbing boundary conditions, the perfectly matched layer is significantly more efficient at absorbing both body waves and interface waves. PMID- 27475143 TI - Gulf of Mexico low-frequency ocean soundscape impacted by airguns. AB - The ocean soundscape of the Gulf of Mexico (GOM) has not been well-studied, although it is an important habitat for marine mammals, including sperm and beaked whales, many dolphin species, and a potentially endangered baleen whale species. The GOM is also home to high levels of hydrocarbon exploration and extraction, heavily used commercial shipping ports, and significant fishery industry activity, all of which are known contributors to oceanic noise. From 2010-2013, the soundscape of three deep and two shallow water sites in the GOM were monitored over 10 - 1000 Hz. Average sound pressure spectrum levels were high, >90 dB re 1 MUPa(2)/Hz at <40 Hz for the deep water sites and were associated with noise from seismic exploration airguns. More moderate sound pressure levels, <55 dB re 1 MUPa(2)/Hz at >700 Hz, were present at a shallow water site in the northeastern Gulf, removed from the zone of industrial development and bathymetrically shielded from deep water anthropogenic sound sources. During passage of a high wind event (Hurricane Isaac, 2012), sound pressure levels above 200 Hz increased with wind speed, but at low frequencies (<100 Hz) sound pressure levels decreased owing to absence of noise from airguns. PMID- 27475144 TI - Exploring different attributes of source information for speaker verification with limited test data. AB - This work explores mel power difference of spectrum in subband, residual mel frequency cepstral coefficient, and discrete cosine transform of the integrated linear prediction residual for speaker verification under limited test data conditions. These three source features are found to capture different attributes of source information, namely, periodicity, smoothed spectrum information, and shape of the glottal signal, respectively. On the NIST SRE 2003 database, the proposed combination of the three source features performs better [equal error rate (EER): 20.19%, decision cost function (DCF): 0.3759] than the mel frequency cepstral coefficient feature (EER: 22.31%, DCF: 0.4128) for 2 s duration of test segments. PMID- 27475145 TI - Erratum: An experimental application of aeroacoustic time-reversal to the Aeolian tone [J. Acoust. Soc. Am. 139(2), 740-763 (2016)]. PMID- 27475146 TI - Predicting binaural speech intelligibility using the signal-to-noise ratio in the envelope power spectrum domain. AB - This study proposes a binaural extension to the multi-resolution speech-based envelope power spectrum model (mr-sEPSM) [Jorgensen, Ewert, and Dau (2013). J. Acoust. Soc. Am. 134, 436-446]. It consists of a combination of better-ear (BE) and binaural unmasking processes, implemented as two monaural realizations of the mr-sEPSM combined with a short-term equalization-cancellation process, and uses the signal-to-noise ratio in the envelope domain (SNRenv) as the decision metric. The model requires only two parameters to be fitted per speech material and does not require an explicit frequency weighting. The model was validated against three data sets from the literature, which covered the following effects: the number of maskers, the masker types [speech-shaped noise (SSN), speech-modulated SSN, babble, and reversed speech], the masker(s) azimuths, reverberation on the target and masker, and the interaural time difference of the target and masker. The Pearson correlation coefficient between the simulated speech reception thresholds and the data across all experiments was 0.91. A model version that considered only BE processing performed similarly (correlation coefficient of 0.86) to the complete model, suggesting that BE processing could be considered sufficient to predict intelligibility in most realistic conditions. PMID- 27475147 TI - Passive acoustic monitoring of coastally associated Hawaiian spinner dolphins, Stenella longirostris, ground-truthed through visual surveys. AB - Effective decision making to protect coastally associated dolphins relies on monitoring the presence of animals in areas that are critical to their survival. Hawaiian spinner dolphins forage at night and rest during the day in shallow bays. Due to their predictable presence, they are targeted by dolphin-tourism. In this study, comparisons of presence were made between passive acoustic monitoring (PAM) and vessel-based visual surveys in Hawaiian spinner dolphin resting bays. DSG-Ocean passive acoustic recording devices were deployed in four bays along the Kona Coast of Hawai'i Island between January 8, 2011 and August 30, 2012. The devices sampled at 80 kHz, making 30-s recordings every four minutes. Overall, dolphins were acoustically detected on 37.1% to 89.6% of recording days depending on the bay. Vessel-based visual surveys overlapped with the PAM surveys on 202 days across the four bays. No significant differences were found between visual and acoustic detections suggesting acoustic surveys can be used as a proxy for visual surveys. Given the need to monitor dolphin presence across sites, PAM is the most suitable and efficient tool for monitoring long-term presence/absence. Concomitant photo-identification surveys are necessary to address changes in abundance over time. PMID- 27475148 TI - Low-frequency pulse propagation over 510 km in the Philippine Sea: A comparison of observed and theoretical pulse spreading. AB - Observations of the spread of wander-corrected averaged pulses propagated over 510 km for 54 h in the Philippine Sea are compared to Monte Carlo predictions using a parabolic equation and path-integral predictions. Two simultaneous m sequence signals are used, one centered at 200 Hz, the other at 300 Hz; both have a bandwidth of 50 Hz. The internal wave field is estimated at slightly less than unity Garrett-Munk strength. The observed spreads in all the early ray-like arrivals are very small, <1 ms (for pulse widths of 17 and 14 ms), which are on the order of the sampling period. Monte Carlo predictions show similar very small spreads. Pulse spread is one consequence of scattering, which is assumed to occur primarily at upper ocean depths where scattering processes are strongest and upward propagating rays refract downward. If scattering effects in early ray-like arrivals accumulate with increasing upper turning points, spread might show a similar dependence. Real and simulation results show no such dependence. Path integral theory prediction of spread is accurate for the earliest ray-like arrivals, but appears to be increasingly biased high for later ray-like arrivals, which have more upper turning points. PMID- 27475149 TI - Robustness against distortion of fundamental frequency cues in simulated electro acoustic hearing. AB - Speech recognition by cochlear implant users can be improved by adding an audible low frequency acoustic signal to electrical hearing; the resulting improvement is deemed "electro-acoustic stimulation (EAS) benefit." However, a crucial low frequency cue, fundamental frequency (F0), can be distorted via the impaired auditory system. In order to understand how F0 distortions may affect EAS benefit, normal-hearing listeners were presented monaurally with vocoded speech (frequencies >250 Hz) and an acoustical signal (frequencies <250 Hz) with differing manipulations of the F0 signal, specifically: a pure tone with the correct mean F0 but with smaller variations around this mean, or a narrowband of white noise centered around F0, at varying bandwidths; a pure tone down-shifted in frequency by 50 Hz but keeping overall frequency modulations. Speech recognition thresholds improved when tones with reduced frequency modulation were presented, and improved significantly for noise bands maintaining F0 information. A down-shifted tone, or only a tone to indicate voicing, showed no EAS benefit. These results confirm that the presence of the target's F0 is beneficial for EAS hearing in a noisy environment, and they indicate that the benefit is robust to F0 distortion, as long as the mean F0 and frequency modulations of F0 are preserved. PMID- 27475150 TI - Detection of regional infrasound signals using array data: Testing, tuning, and physical interpretation. AB - This work quantifies the physical characteristics of infrasound signal and noise, assesses their temporal variations, and determines the degree to which these effects can be predicted by time-varying atmospheric models to estimate array and network performance. An automated detector that accounts for both correlated and uncorrelated noise is applied to infrasound data from three seismo-acoustic arrays in South Korea (BRDAR, CHNAR, and KSGAR), cooperatively operated by Korea Institute of Geoscience and Mineral Resources (KIGAM) and Southern Methodist University (SMU). Arrays located on an island and near the coast have higher noise power, consistent with both higher wind speeds and seasonably variable ocean wave contributions. On the basis of the adaptive F-detector quantification of time variable environmental effects, the time-dependent scaling variable is shown to be dependent on both weather conditions and local site effects. Significant seasonal variations in infrasound detections including daily time of occurrence, detection numbers, and phase velocity/azimuth estimates are documented. These time-dependent effects are strongly correlated with atmospheric winds and temperatures and are predicted by available atmospheric specifications. This suggests that commonly available atmospheric specifications can be used to predict both station and network detection performance, and an appropriate forward model improves location capabilities as a function of time. PMID- 27475151 TI - Homogenization models for thin rigid structured surfaces and films. AB - A homogenization method for thin microstructured surfaces and films is presented. In both cases, sound hard materials are considered, associated with Neumann boundary conditions and the wave equation in the time domain is examined. For a structured surface, a boundary condition is obtained on an equivalent flat wall, which links the acoustic velocity to its normal and tangential derivatives (of the Myers type). For a structured film, jump conditions are obtained for the acoustic pressure and the normal velocity across an equivalent interface (of the Ventcels type). This interface homogenization is based on a matched asymptotic expansion technique, and differs slightly from the classical homogenization, which is known to fail for small structuration thicknesses. In order to get insight into what causes this failure, a two-step homogenization is proposed, mixing classical homogenization and matched asymptotic expansion. Results of the two homogenizations are analyzed in light of the associated elementary problems, which correspond to problems of fluid mechanics, namely, potential flows around rigid obstacles. PMID- 27475152 TI - Modelling acoustic scattering, sound speed, and attenuation in gassy soft marine sediments. AB - A model for nonlinear gas bubble pulsation in marine sediments is presented. This model is then linearized to determine the resonance frequency and the damping terms for linear radial oscillations. The linear model is then used to predict the effects that such bubble pulsations will have on the sound speed and attenuation of acoustic waves propagating in gassy marine sediment. The results are compared for monodisperse populations against the predictions of a model of Anderson and Hampton and, furthermore, the additional abilities of the model introduced in this paper are discussed. These features include the removal of the sign ambiguities in the expressions, the straightforward implementation for acoustic propagation through polydisperse bubble populations, the capability to estimate bubble size distributions through a full acoustic inversion, and the capability to predict nonlinear effects. PMID- 27475153 TI - Diffraction of acoustic-gravity waves in the presence of a turning point. AB - Acoustic-gravity waves (AGWs) in an inhomogeneous atmosphere often have caustics, where the ray theory predicts unphysical, divergent values of the wave amplitude and needs to be modified. Unlike acoustic waves and gravity waves in incompressible fluids, AGW fields in the vicinity of a caustic have never been systematically studied. Here, asymptotic expansions of acoustic gravity waves are derived in the presence of a turning point in a horizontally stratified, moving fluid such as the atmosphere. Sound speed and the background flow (wind) velocity are assumed to vary gradually with height, and slowness of these variations determines the large parameter of the problem. It is found that uniform asymptotic expansions of the wave field in the presence of a turning point can be expressed in terms of the Airy function and its derivative. The geometrical, or Berry, phase, which arises in the consistent Wentzel-Kramers-Brillouin approximation for AGWs, plays an important role in the caustic asymptotics. In the dominant term of the uniform asymptotic solution, the terms with the Airy function and its derivative are weighted by the cosine and sine of the Berry phase, respectively. The physical meaning and corollaries of the asymptotic solutions are discussed. PMID- 27475154 TI - Short-term enhancement and suppression of dolphin auditory evoked responses following echolocation click emission. AB - Biosonar gain control mechanisms in a bottlenose dolphin were investigated by measuring the auditory steady-state response (ASSR) to an external tone while the animal echolocated. The dolphin performed an echo change-detection task that utilized electronically synthesized echoes with echo delays corresponding to 25- and 50-m target range. During the task, amplitude modulated tones with carrier frequencies from 25 to 125 kHz were continuously presented and the instantaneous electroencephalogram stored for later analysis. ASSRs were extracted from the electroencephalogram by synchronously averaging time epochs temporally aligned with the onset of the external tone modulation cycle nearest to each of the dolphin's echolocation clicks. Results showed an overall suppression of the ASSR amplitude for tones with frequencies near the click center frequencies. A larger, temporary suppression of the ASSR amplitude was also measured at frequencies above 40-50 kHz, while a temporary enhancement was observed at lower frequencies. Temporal patterns for ASSR enhancement or suppression were frequency-, level-, and range-dependent, with recovery to pre-click values occurring within the two way travel time. Suppressive effects fit the patterns expected from forward masking by the emitted biosonar pulse, while the specific mechanisms responsible for the frequency-dependent enhancement are unknown. PMID- 27475155 TI - Deriving disyllabic word variants from a Chinese conversational speech corpus. AB - Motivated by the quasi-categorical reduced forms of disyllabic words produced in Chinese conversational speech, a frequency-based selection procedure of typical pronunciation by disyllabic word type and reduction degree is proposed in this paper. This variant-selection algorithm utilizes techniques of free phone recognition and phonetic similarity score calculation to account for Chinese syllable structure. Four reduction types are suggested by considering the presence of a within-word syllable boundary: Citation form-like reduction, marginal segment deletion, nuclei merger, and syllable merger. The results show that the most frequent reduction types for disyllabic words in Chinese conversation are citation form-like reduction and syllable merger. In particular, high-frequency disyllabic words preferentially take the extreme syllable-merger form. As shown in the analysis, segmental reduction in Chinese disyllabic words is morphology-dependent. It is also related to the prosodic position at which a disyllabic word is produced as well as the temporal quality of the word. Finally, in the automatic speech recognition experiments, the performance was improved by adding a small number of variants selected by the algorithm to the pronunciation dictionary of the system. PMID- 27475156 TI - Quantitative analysis of the acoustic repertoire of southern right whales in New Zealand. AB - Quantitatively describing the acoustic repertoire of a species is important for establishing effective passive acoustic monitoring programs and developing automated call detectors. This process is particularly important when the study site is remote and visual surveys are not cost effective. Little is known about the vocal behavior of southern right whales (Eubalaena australis) in New Zealand. The aim of this study was to describe and quantify their entire vocal repertoire on calving grounds in the sub-Antarctic Auckland Islands. Over three austral winters (2010-2012), 4349 calls were recorded, measured, and classified into 10 call types. The most frequently observed types were pulsive, upcall, and tonal low vocalizations. A long tonal low call (<=15.5 s duration) and a very high call (peak frequency ~750 Hz) were described for the first time. Random Forest multivariate analysis of 28 measured variables was used to classify calls with a high degree of accuracy (82%). The most important variables for classification were maximum ceiling frequency, number of inflection points, duration, and the difference between the start and end frequency. This classification system proved to be a repeatable, fast, and objective method for categorising right whale calls and shows promise for other vocal taxa. PMID- 27475157 TI - Longitudinal guided waves confined in radius filler regions of composite joints. AB - This paper studies the feasibility of using ultrasonic guided waves for fast inspection of conformal deltoid radius filler or "Noodle" regions of joints in stringer composite structures. Semi-analytical finite element simulations, supported by experiments and three-dimensional finite element models, are used to demonstrate the existence of a longitudinal guided ultrasonic mode confined or trapped in the Noodle regions. Studies reveal that this mode has attractive properties for rapid screening of Noodle joints, including strong energy concentration, low dispersion, and attenuation. Discussing the physics of mode confinement in light of material differences and geometry, the phenomenon is shown to be related to feature-guiding effects noted in literature recently. PMID- 27475158 TI - Investigations on sound energy decays and flows in a monumental mosque. AB - This work investigates the sound energy decays and flows in the Suleymaniye Mosque in Istanbul. This is a single-space superstructure having multiple domes. The study searches for the non-exponential sound energy decay characteristics. The effect of different material surfaces and volumetric contributions are investigated using acoustic simulations and in situ acoustical measurements. Sound energy decay rates are estimated by Bayesian decay analysis. The measured data reveal double- or triple-slope energy decay profiles within the superstructure. To shed light on the mechanism of energy exchanges resulting in multi-slope decay, spatial sound energy distributions and energy flow vectors are studied by diffusion equation model (DEM) simulations. The resulting sound energy flow vector maps highlight the contribution of a sound-reflective central dome contrasted with an absorptive carpeted floor in providing delayed energy feedback. In contrast, no multi-slope energy decay pattern is observed in DEM simulations with a bare marble floor, which generates a much more diffuse sound field than in the real situation with a carpeted floor. The results demonstrate that energy fragmentation, in support of the non-exponential energy decay profile, is due to both the sound absorption characteristics of materials and to their distributions, as well as to relations between the subvolumes of the mosque's interior. PMID- 27475159 TI - "Fake" gemination in suffixed words and compounds in English and German. AB - In languages with an underlying consonantal length contrast, the most salient acoustic cue differentiating singletons and geminates is duration of closure. When concatenation of identical phonemes through affixation or compounding produces "fake" geminates, these may or may not be realized phonetically as true geminates. English and German no longer have a productive length contrast in consonants, but do allow sequences of identical consonants in certain morphological contexts, e.g., suffixation (green-ness; zahl-los "countless") or compounding (pine nut; Schul-leiter "headmaster"). The question is whether such concatenated sequences are produced as geminates and realized acoustically with longer closure duration, and whether this holds in both languages. This issue is investigated here by analyzing the acoustics of native speakers reading suffixed and compound words containing both fake geminate and non-geminate consonants in similar phonological environments. Results indicate that the closure duration is consistently nearly twice as long for fake geminates across conditions. In addition, voice onset time is proportionally longer for fake geminates in English while vowel duration shows few significant differences (in German sonorants only). These results suggest that English and German speakers articulate fake geminates with acoustic characteristics similar to those found in languages with an underlying length contrast, despite no longer displaying the contrast morpheme internally. PMID- 27475161 TI - Vowel reduction across tasks for male speakers of American English. AB - This study examined acoustic variation of vowels within speakers across speech tasks. The overarching goal of the study was to understand within-speaker variation as one index of the range of normal speech motor behavior for American English vowels. Ten male speakers of American English performed four speech tasks including citation form sentence reading with a clear-speech style (clear speech), citation form sentence reading (citation), passage reading (reading), and conversational speech (conversation). Eight monophthong vowels in a variety of consonant contexts were studied. Clear-speech was operationally defined as the reference point for describing variation. Acoustic measures associated with the conventions of vowel targets were obtained and examined. These included temporal midpoint formant frequencies for the first three formants (F1, F2, and F3) and the derived Euclidean distances in the F1-F2 and F2-F3 planes. Results indicated that reduction toward the center of the F1-F2 and F2-F3 planes increased in magnitude across the tasks in the order of clear-speech, citation, reading, and conversation. The cross-task variation was comparable for all speakers despite fine-grained individual differences. The characteristics of systematic within speaker acoustic variation across tasks have potential implications for the understanding of the mechanisms of speech motor control and motor speech disorders. PMID- 27475162 TI - Low frequency sound spatial encoding within an enclosure using spherical microphone arrays. AB - In a spherical coordinate system, interior sound field can be expressed in terms of a series of Fourier-Bessel expansions. The process that obtains the expansion coefficients by use of a microphone array (e.g., a spherical microphone array) is called spatial encoding. Until now spatial encoding has mainly been examined in a free field or a diffuse field which can be modeled as a sum of plane waves. For spatial encoding within an enclosure at low frequencies, special challenges would be encountered in two aspects. First, the expansions are influenced by array configurations. Second, an acoustic mode based model instead of a plane wave based one should be considered. This study focuses on these challenges. Different kinds of array configurations were compared specifically at low frequencies, and the spatial encoding for the cylindrical cavity modes was investigated. It was found that the spherical array with cardioid microphones was optimal when kr<1, the cavity modes can be effectively represented by only a sparse subset of expansion coefficients and a good reproduction can be achieved even outside the spherical valid region, which demonstrates an effective alternative way to describe the cylindrical cavity modes and can be implemented efficiently in practice. PMID- 27475163 TI - Benefit of contralateral routing of signals for unilateral cochlear implant users. AB - One way to improve speech understanding in noise for HI with a unilateral hearing loss is by contralateral routing of signals (CROS). Such a CROS-system captures sounds with an additional microphone at the worst hearing ear and transmits these to the better one. The better ear is then provided with a mix of signals originating from both ears. The goal of this study is to quantify the effect of a CROS-system on speech reception thresholds (SRTs) with unilaterally implanted CI users in diffuse and directional noise as a function of speaker location. Listening tests are performed and an accurate directional intelligibly model is proposed used for further analysis. In diffuse noise it is concluded that the use of a CROS system results in a maximum gain in SRT of 7.9 dB when speech comes from the CROS side compared to a maximum loss in SRT of 2.1 dB when speech comes from the implanted side. In the case of directional noise, the effect of the CROS is symmetric and the maximum loss or gain in SRT was around 9 dB. The study therefore shows a clear potential of using the CROS system in diffuse noise. PMID- 27475164 TI - Effectiveness of a loudness model for time-varying sounds in equating the loudness of sentences subjected to different forms of signal processing. AB - A model for the loudness of time-varying sounds [Glasberg and Moore (2012). J. Audio. Eng. Soc. 50, 331-342] was assessed for its ability to predict the loudness of sentences that were processed to either decrease or increase their dynamic fluctuations. In a paired-comparison task, subjects compared the loudness of unprocessed and processed sentences that had been equalized in (1) root-mean square (RMS) level; (2) the peak long-term loudness predicted by the model; (3) the mean long-term loudness predicted by the model. Method 2 was most effective in equating the loudness of the original and processed sentences. PMID- 27475165 TI - Spectral and temporal cues for perception of material and action categories in impacted sound sources. AB - In two experiments, similarity ratings and categorization performance with recorded impact sounds representing three material categories (wood, metal, glass) being manipulated by three different categories of action (drop, strike, rattle) were examined. Previous research focusing on single impact sounds suggests that temporal cues related to damping are essential for material discrimination, but spectral cues are potentially more efficient for discriminating materials manipulated by different actions that include multiple impacts (e.g., dropping, rattling). Perceived similarity between material categories across different actions was correlated with the distribution of long term spectral energy (spectral centroid). Similarity between action categories was described by the temporal distribution of envelope energy (temporal centroid) or by the density of impacts. Moreover, perceptual similarity correlated with the pattern of confusion in categorization judgments. Listeners tended to confuse materials with similar spectral centroids, and actions with similar temporal centroids and onset densities. To confirm the influence of these different features, spectral cues were removed by applying the envelopes of the original sounds to a broadband noise carrier. Without spectral cues, listeners retained sensitivity to action categories but not to material categories. Conversely, listeners recognized material but not action categories after envelope scrambling that preserved long-term spectral content. PMID- 27475166 TI - Whistle characteristics and daytime dive behavior in pantropical spotted dolphins (Stenella attenuata) in Hawai'i measured using digital acoustic recording tags (DTAGs). AB - This study characterizes daytime acoustic and dive behavior of pantropical spotted dolphins (Stenella attenuata) in Hawai'i using 14.58 h of data collected from five deployments of digital acoustic recording tags (DTAG3) in 2013. For each tagged animal, the number of whistles, foraging buzzes, dive profiles, and dive statistics were calculated. Start, end, minimum, and maximum frequencies, number of inflection points and duration were measured from 746 whistles. Whistles ranged in frequency from 9.7 +/- 2.8 to 19.8 +/- 4.2 kHz, had a mean duration of 0.7 +/- 0.5 s and a mean of 1.2 +/- 1.2 inflection points. Thirteen foraging buzzes were recorded across all tags. Mean dive depth and duration were 16 +/- 9 m and 1.9 +/- 1.0 min, respectively. Tagged animals spent the majority of time in the upper 10 m (76.9% +/- 16.1%) of the water column. Both whistle frequency characteristics and dive statistics measured here were similar to previously reported values for spotted dolphins in Hawai'i. Shallow, short dive profiles combined with few foraging buzzes provide evidence that little spotted dolphin feeding behavior occurs during daytime hours. This work represents one of the first successful DTAG3 studies of small pelagic delphinids, providing rare insights into baseline bioacoustics and dive behavior. PMID- 27475167 TI - Sound speed in downhole flow measurement. AB - This paper describes the use of sound speed in flow measurement applications in the high-pressure/high-temperature downhole environment. The propagation speed of a sound wave is a powerful tool to extract useful information from a flowing fluid medium in pipe whether the medium consists of a single-phase or multiphase flow. Considering the complex nature of the flow patterns and changing phase fractions from reservoir to surface, utilizing the propagation speed of sound of a fluid mixture is not a trivial task, especially if the interest is real-time flow measurement. The demanding applications span a wide spectrum from noisy medium originating from fast-moving gas/liquid flows to quiet medium originating from slow-moving liquid/liquid flows. In the current work, multiple flow loop tests are conducted in different facilities to evaluate the direct use of sound speed in flow rate measurement and the results are associated with real-life field examples. A tool analysis map is developed that addresses the use of sound speed for flow measurement under different scenarios. Although most examples are based on strain-based local sensing of the flow, the use of sound speed is independent of the methodology and can be implemented by other methods such as acoustic-based distributed sensing. PMID- 27475168 TI - Assessing auditory evoked potentials of wild harbor porpoises (Phocoena phocoena). AB - Testing the hearing abilities of marine mammals under water is a challenging task. Sample sizes are usually low, thus limiting the ability to generalize findings of susceptibility towards noise influences. A method to measure harbor porpoise hearing thresholds in situ in outdoor conditions using auditory steady state responses of the brainstem was developed and tested. The method was used on 15 live-stranded animals from the North Sea during rehabilitation, shortly before release into the wild, and on 12 wild animals incidentally caught in pound nets in Denmark (inner Danish waters). Results indicated that although the variability between individuals is wide, the shape of the hearing curve is generally similar to previously published results from behavioral trials. Using 10-kHz frequency intervals between 10 and 160 kHz, best hearing was found between 120 and 130 kHz. Additional testing using one-third octave frequency intervals (from 16 to 160 kHz) allowed for a much faster hearing assessment, but eliminated the fine scale threshold characteristics. For further investigations, the method will be used to better understand the factors influencing sensitivity differences across individuals and to establish population-level parameters describing hearing abilities of harbor porpoises. PMID- 27475169 TI - Relationship between sound radiation from sound-induced and force-excited vibration: Analysis using an infinite elastic plate model. AB - Although sound radiation from sound-induced vibration and from force-excited vibration of solid structures are similar phenomena in terms of radiating from vibrating structures, the general relationship between them has not been explicitly studied to date. In particular, airborne sound transmission through walls and sound radiation from structurally vibrating surfaces in buildings are treated as different issues in architectural acoustics. In this paper, a fundamental relationship is elucidated through the use of a simple model. The transmission coefficient for random-incidence sound and the radiated sound power under point force excitation of an infinite elastic plate are both analyzed. Exact and approximate solutions are derived for the two problems, and the relationship between them is theoretically discussed. A conversion function that relates the transmission coefficient and radiated sound power is obtained in a simple closed form through the approximate solutions. The exact solutions are also related by the same conversion function. It is composed of the specific impedance and the wavenumber, and is independent of any elastic plate parameters. The sound radiation due to random-incidence sound and point force excitation are similar phenomena, and the only difference is the gradient of those characteristics with respect to the frequency. PMID- 27475170 TI - Effect of several acoustic cues on perceiving Mandarin retroflex affricates and fricatives in continuous speech. AB - Relatively little attention has been paid to the perception of the three-way contrast between unaspirated affricates, aspirated affricates and fricatives in Mandarin Chinese. This study reports two experiments that explore the acoustic cues relevant to the contrast between the Mandarin retroflex series /ts/, /ts(h)/ and /s/ in continuous speech. Twenty participants performed two three-alternative forced-choice tasks, in which acoustic cues including closure, frication duration (FD), aspiration, and vocalic contexts (VCs) were systematically manipulated and presented in a carrier phrase. A subsequent classification tree analysis shows that FD distinguishes /ts/ from /ts(h)/ and /s/, and that closure cues the affricate manner. Interactions between VC and individual cues are also found. The FD threshold for separating /s/ and /ts/ is susceptible to the influence of the following vocalic segments, shifting to lower values if frication is followed by the low vowel /a/. On the other hand, while aspiration cues /ts(h)/ before /a/ and //, this acoustic cue is obscured by gesture continuation when /ts(h)/ precedes its homorganic approximant /r/ in natural speech, which might cause potential confusion between /ts(h)/ and /s/. PMID- 27475171 TI - Visual capture of a stereo sound: Interactions between cue reliability, sound localization variability, and cross-modal bias. AB - Multisensory interactions involve coordination and sometimes competition between multiple senses. Vision usually dominates audition in spatial judgments when light and sound stimuli are presented from two different physical locations. This study investigated the influence of vision on the perceived location of a phantom sound source placed in a stereo sound field using a pair of loudspeakers emitting identical signals that were delayed or attenuated relative to each other. Results show that although a similar horizontal range (+/-45 degrees ) was reported for timing-modulated and level-modulated signals, listeners' localization performance showed greater variability for the timing signals. When visual stimuli were presented simultaneously with the auditory stimuli, listeners showed stronger visual bias for timing-modulated signals than level-modulated and single-speaker control signals. Trial-to-trial errors remained relatively stable over time, suggesting that sound localization uncertainty has an immediate and long-lasting effect on the across-modal bias. Binaural signal analyses further reveal that interaural differences of time and intensity-the two primary cues for sound localization in the azimuthal plane-are inherently more ambiguous for signals placed using timing. These results suggest that binaural ambiguity is intrinsically linked with localization variability and the strength of cross modal bias in sound localization. PMID- 27475172 TI - Surface/interface effects on the effective propagation constants of coherent waves in composites with random parallel nanofibers. AB - The effective propagation constants of elastic waves in an inhomogeneous medium with randomly distributed parallel cylindrical nanofibers are studied. First, the surface energy theory proposed by Huang and Wang (Handbook of Micromechanics and Nanomechanics, 2013) is used to derive the nontraditional boundary conditions on the surfaces of the nanoholes and the interfaces between the nanofibers and the host. Then, the scattering matrix of individual scatterer (cylindrical hole or nanofiber) is derived from the nontraditional boundary condition. The total wave field is obtained by considering the multiple scattering processes among the dispersive scatterers. The configuration average of the total wave field results in the coherent waves or the averaged waves. By using the corrected Linton-Martin formula, the effective propagation constants (effective speed and effective attenuation) of the coherent waves are estimated. The in-plane waves (P and SV waves) and the anti-plane waves (SH wave) are considered, respectively, and the numerical results are shown graphically. Apart from the effects of surface elasticity, the effects of inertia of surface/interface and the effects of residual surface tension (which are often ignored in the previous literature) are also considered. Moreover, the influences of the nonsymmetric parts of in-plane surface stress and the out-of-plane parts of the surface stress are both discussed first based on the numerical examples. These investigations show the underestimation and overestimation of effective propagation constants caused by various simplifications. PMID- 27475173 TI - Investigation of the interwire energy transfer of elastic guided waves inside prestressed cables. AB - Elastic guided waves are of interest for the non-destructive evaluation of cables. Cables are most often multi-wire structures, and understanding wave propagation requires numerical models accounting for the helical geometry of individual wires, the interwire contact mechanisms and the effects of prestress. In this paper, a modal approach based on a so-called semi-analytical finite element method and taking advantage of a biorthogonality relation is proposed in order to calculate the forced response under excitation of a cable, multi-wired, twisted, and prestressed. The main goal of this paper is to investigate how the energy transfers from a given wire, directly excited, to the other wires in order to identify some localization of energy inside the active wire as the waves propagate along the waveguide. The power flow of the excited field is theoretically derived and an energy transfer parameter is proposed to evaluate the level of energy localization inside a given wire. Numerical results obtained for different polarizations of excitation, central and peripheral, highlight how the energy may localize, spread, or strongly change in the cross-section as waves travel along the axis. In particular, a compressional mode localized inside the central wire is found, with little dispersion and significant excitability. PMID- 27475174 TI - Analyzing excitation forces acting on a plate based on measured acoustic pressure. AB - This paper presents a theoretical study on "seeing" through an elastic structure to uncover the root cause of sound and vibration by using nearfield acoustical holography (NAH) and normal modes expansion. This approach is of generality because vibro-acoustic responses on the surface of a vibrating structure can always be reconstructed, exactly or approximately. With these vibro-acoustic responses, excitation forces acting on the structure can always be determined, analytically or numerically, given any set of boundary conditions. As an example, the explicit formulations for reconstructing time-harmonic excitation forces, including point, line and surface forces, and their arbitrary combinations acting on a rectangular thin plate in vacuum mounted on an infinite baffle are presented. The reason for choosing this example is that the analytic solutions to vibro-acoustic responses are available, and in-depth analyses of results are possible. Results demonstrate that this approach allows one to identify excitation forces based on measured acoustic pressures and reveal their characteristics such as locations, types and amplitudes, as if one could "see" excitation forces acting behind the plate based on acoustic pressure measured on the opposite side. This approach is extendable to general elastic structures, except that in such circumstance numerical results must be sought. PMID- 27475175 TI - Monaural speech intelligibility and detection in maskers with varying amounts of spectro-temporal speech features. AB - Speech intelligibility is strongly affected by the presence of maskers. Depending on the spectro-temporal structure of the masker and its similarity to the target speech, different masking aspects can occur which are typically referred to as energetic, amplitude modulation, and informational masking. In this study speech intelligibility and speech detection was measured in maskers that vary systematically in the time-frequency domain from steady-state noise to a single interfering talker. Male and female target speech was used in combination with maskers based on speech for the same or different gender. Observed data were compared to predictions of the speech intelligibility index, extended speech intelligibility index, multi-resolution speech-based envelope-power-spectrum model, and the short-time objective intelligibility measure. The different models served as analysis tool to help distinguish between the different masking aspects. Comparison shows that overall masking can to a large extent be explained by short-term energetic masking. However, the other masking aspects (amplitude modulation an informational masking) influence speech intelligibility as well. Additionally, it was obvious that all models showed considerable deviations from the data. Therefore, the current study provides a benchmark for further evaluation of speech prediction models. PMID- 27475176 TI - Ultrasonic imaging of defects in coarse-grained steels with the decomposition of the time reversal operator. AB - In the present work, the Synthetic Transmit Aperture (STA) imaging is combined with the Decomposition of the Time Reversal Operator (DORT) method to image a coarse grained austenitic-ferritic steel using a contact transducer array. The highly heterogeneous structure of this material produces a strong scattering noise in ultrasound images. Furthermore, the surface waves guided along the array interfere with the bulk waves backscattered by defects. In order to overcome these problems, the DORT method is applied before calculating images with the STA algorithm. The method consists in analyzing in the frequency domain the singular values and singular vectors of the full array transfer matrix. This paper first presents an analysis of the singular values of different waves contained in the data acquisition, which facilitates the identification of the subspace associated with the surface guided waves for filtering operations. Then, a filtered matrix is defined where the contribution of structural noise and guided waves are reduced. Finally, in the time domain, the STA algorithm is applied to this matrix in order to calculate an image with reduced structural noise. Experiments demonstrate that this filtering improves the signal-to-noise ratio by more than 12 dB in comparison with the STA image before filtering. PMID- 27475177 TI - Concert hall acoustics: Repertoire, listening position, and individual taste of the listeners influence the qualitative attributes and preferences. AB - Some studies of concert hall acoustics consider the acoustics in a hall as a single entity. Here, it is shown that the acoustics vary between different seats, and the choice of music also influences the perceived acoustics. The presented study compared the acoustics of six unoccupied concert halls with extensive listening tests, applying two different music excerpts on three different seats. Twenty eight assessors rated the halls according to the subjective preference of the assesors and individual attributes with a paired comparison method. Results show that assessors can be classified into two preference groups, which prioritize different perceptual factors. In addition, the individual attributes elicited by assessors were clustered into three latent classes. PMID- 27475180 TI - Nonlinear dynamics induced in a structure by seismic and environmental loading. AB - In this study, it is shown that under very weak dynamic and quasi-static deformation that is orders of magnitude below the yield deformation of the equivalent stress-strain curve (around 10(-3)), the elastic parameters of a civil engineering structure (resonance frequency and damping) exhibit nonlinear softening and recovery. These observations bridge the gap between laboratory and seismic scales where elastic nonlinear behavior has been previously observed. Under weak seismic or atmospheric loading, modal frequencies are modified by around 1% and damping by more than 100% for strain levels between 10(-7) and 10( 4). These observations support the concept of universal behavior of nonlinear elastic behavior in diverse systems, including granular materials and damaged solids that scale from millimeter dimensions to the scale of structures to fault dimensions in the Earth. PMID- 27475179 TI - Dynamic acoustic properties of monophthongs and diphthongs in Western Sydney Australian English. AB - This study provides a thorough acoustic analysis of the 18 Australian English monophthongs and diphthongs produced in a variety of phonetic contexts by young adult speakers from Western Sydney. The 18 vowels are well separated by duration and dynamic formant trajectory information. Vowel durations and formant trajectories were affected by the consonantal context in which the vowels were produced, particularly those produced in the /hVd/ context. Finally, the results indicate that capturing aspects of vowel inherent spectral change may be useful in future cross-dialectal and cross-linguistic studies. PMID- 27475181 TI - Negative reflection of Lamb waves at a free edge: Tunable focusing and mimicking phase conjugation. AB - The paper studies the interaction of Lamb waves with the free edge of a plate. The reflection coefficients of a Lamb mode at a plate free edge are calculated using a semi-analytical method, as a function of frequency and angle of incidence. The conversion between forward and backward Lamb modes is thoroughly investigated. It is shown that at the zero-group velocity (ZGV) frequency, the forward S1 Lamb mode fully converts into the backward S2b Lamb mode at normal incidence. Besides, this conversion is very efficient over most of the angular spectrum and remains dominant at frequencies just above the ZGV-point. This effect is observed experimentally on a Duralumin plate. First, the S1 Lamb mode is selectively generated using a transducer array, second the S2b mode is excited using a single circular transducer. The normal displacement field is probed with an interferometer. The free edge is shown to retro-focus the incident wave at different depths depending on the wave number mismatch between the forward and backward propagating modes. In the vicinity of the ZGV-point, wave numbers coincide and the wave is retro-reflected on the source. In this frequency range, the free edge acts as a perfect phase conjugating mirror. PMID- 27475182 TI - The stability of multichannel sound systems with time-varying mixing matrices. AB - Various time-varying algorithms have been applied in multichannel sound systems to improve the system's stability and, among these, frequency shifting has been demonstrated to reach the maximum stability improvement achievable by time variation in general. However, the modulation artifacts have been found to diminish the gain improvement unusable for a higher number of channels and high quality applications such as music reproduction. This paper proposes alternatively time-varying mixing matrices, which is an efficient algorithm corresponding to symmetric up and down frequency shifting. It is shown with a statistical approach that time-varying mixing matrices can as well achieve maximum stability improvement for a higher number of channels. A listening test demonstrates the improved quality of time-varying mixing matrices over frequency shifting. PMID- 27475178 TI - Pitch perception and production in congenital amusia: Evidence from Cantonese speakers. AB - This study investigated pitch perception and production in speech and music in individuals with congenital amusia (a disorder of musical pitch processing) who are native speakers of Cantonese, a tone language with a highly complex tonal system. Sixteen Cantonese-speaking congenital amusics and 16 controls performed a set of lexical tone perception, production, singing, and psychophysical pitch threshold tasks. Their tone production accuracy and singing proficiency were subsequently judged by independent listeners, and subjected to acoustic analyses. Relative to controls, amusics showed impaired discrimination of lexical tones in both speech and non-speech conditions. They also received lower ratings for singing proficiency, producing larger pitch interval deviations and making more pitch interval errors compared to controls. Demonstrating higher pitch direction identification thresholds than controls for both speech syllables and piano tones, amusics nevertheless produced native lexical tones with comparable pitch trajectories and intelligibility as controls. Significant correlations were found between pitch threshold and lexical tone perception, music perception and production, but not between lexical tone perception and production for amusics. These findings provide further evidence that congenital amusia is a domain general language-independent pitch-processing deficit that is associated with severely impaired music perception and production, mildly impaired speech perception, and largely intact speech production. PMID- 27475183 TI - Physiological and acoustic characteristics of the male music theatre voice. AB - Six male music theatre singers were recorded in three different voice qualities: legit and two types of belt ("chesty" and "twangy"), on two vowels ([e] and [o]), at four increasing pitches in the upper limit of each singer's belt range (~250 440 Hz). The audio signal, the electroglottographic (EGG) signal, and the vocal tract impedance were all measured simultaneously. Voice samples were analyzed and then evaluated perceptually by 16 expert listeners. The three qualities were produced with significant differences at the physiological, acoustical, and perceptual levels: Singers produced belt qualities with a higher EGG contact quotient (CQEGG) and greater contacting speed quotient (Qcs), greater sound pressure level (SPL), and energy above 1 kHz (alpha ratio), and with higher frequencies of the first two vocal tract resonances (fR1, fR2), especially in the upper pitch range when compared to legit. Singers produced the chesty belt quality with higher CQEGG, Qcs, and SPL values and lower alpha ratios over the whole belt range, and with higher fR1 at the higher pitch range when compared to twangy belt. Consistent tuning of fR1 to the second voice harmonic (2f0) was observed in all three qualities and for both vowels. Expert listeners tended to identify all qualities based on the same acoustical and physiological variations as those observed in the singers' intended qualities. PMID- 27475184 TI - Sound speed as a proxy variable to temperature in Fram Strait. AB - The application of ocean acoustic tomography in Fram Strait requires a careful assessment of the accuracy to which estimates of sound speed from tomography can be converted to estimates of temperature. The Fram Strait environment is turbulent, with warm, salty, northward-flowing North Atlantic water interacting with cold, fresh, southward-flowing Arctic water. The nature of this environment suggests that salinity could play an important role with respect to sound speed. The properties of sound speed with respect to temperature and salinity in this environment were examined using climatological and in situ glider data. In cold water, a factor of about 4.5 m s(-1) degrees C(-1) can be used to scale between sound speed and temperature. In situ data obtained by gliders were used to determine the ambiguities between temperature, salinity, and sound speed. Tomography provides a depth-averaging measurement. While errors in the sound speed-temperature conversion at particular depths may be 0.2 degrees C or larger, particularly within 50 m of the surface, such errors are suppressed when the depth is averaged. Using a simple scale factor to compute temperature from sound speed introduced an error of about 20 m degrees C for depth-averaged temperature, a value less than formal uncertainties estimated from acoustic tomography. PMID- 27475186 TI - A numerical study of nonlinear infrasound propagation in a windy atmosphere. AB - Direct numerical simulations of the two-dimensional unsteady compressible Navier Stokes equations are performed to study the acoustic field generated by an infrasonic source in a realistic atmosphere. Some of the main phenomena affecting the propagation of infrasonic waves at large distances from the source are investigated. The effects of thermal and wind-related refraction on the signals recorded at ground level are highlighted, with particular emphasis on the phase shift induced by the presence of caustics in the acoustic field. Nonlinear waveform steepening associated with harmonic generation, and period lengthening, both of which are typical of large source amplitudes, are illustrated, and the importance of thermoviscous absorption in the upper atmosphere is clearly demonstrated. The role of diffraction in the shadow zone, around caustics and at stratospheric altitudes is also pointed out. The Navier-Stokes equations are solved using high-order finite-differences and a Runge-Kutta time integration method both originally developed for aeroacoustic applications, along with an adaptive shock-capturing algorithm which allows high-intensity acoustic fields to be examined. An improvement to the shock detection procedure is also proposed in order to meet the specificities of nonlinear propagation at long range. The modeling as well as the numerical results are reported in detail and discussed. PMID- 27475187 TI - A full-field perturbation approach to scattering and reverberation in range dependent environments with rough interfaces. AB - A perturbation approach to roughness scattering and reverberation in range dependent environments is developed treating each interface as a superposition of a smooth reference interface, which may include large-scale deterministic features (such as bathymetry changes), and small compared to the acoustic wavelength vertical deviations from this interface that are considered as random roughness perturbations. The reference interface is assumed to be smooth enough to allow analytic or numerical solution for the field in the vicinity of this interface that can then be used in perturbation theory. Expressions for both the reverberation field and average reverberation intensity in a general case of an arbitrary number of rough interfaces are obtained in a form convenient for numerical simulations. In the case of long-range ocean reverberation, several approximations for these expressions are developed, relevant to various environmental scenarios and different types of interfaces: sea-surface, water sediment interface, buried sediment interfaces, and bottom basement. The results are presented in a simple form and provide a direct relationship of the reverberation intensity with three critical characteristics defined at each interface: (1) local spectrum of roughness, (2) local contrast of acoustic parameters, and (3) two-way full-field transmission intensity calculated taking into account only large-scale changes of the environment. PMID- 27475188 TI - Determination of glottal open regions by exploiting changes in the vocal tract system characteristics. AB - This paper presents an approach to determine the open phase region of a glottal cycle based on changes in the characteristics of the vocal tract system. The glottal closing phase contributes to major excitation of the vocal tract system. The opening phase affects the vocal tract system characteristics by effectively increasing the length of the tract, due to coupling of the subglottal region. To determine the glottal open region, it is necessary to estimate the vocal tract characteristics from the segment with subglottal coupling. The proposed method derives the dominant resonance frequency (DRF) of the vocal tract system at every sampling instant, using a heavily decaying window (HDW) for analysis. The DRF contour transits to lower frequencies during glottal open region, when compared to the glottal closed region. The open region, within the glottal cycles from voiced speech segment, is extracted using the HDW method. The results are compared with the open region derived from the electroglottograph (EGG) signals and speech signals. The results show that the proposed method based on DRF contour, derived from the speech signals, seems to perform better than the methods based on EGG signals. PMID- 27475189 TI - Cross-frequency coherence and pulse propagation in a turbulent atmosphere. AB - Cross-frequency coherence of acoustic signals in a turbulent atmosphere is an important consideration for source localization with acoustic sensor arrays and for remote sensing of the atmosphere with sodars and tomography techniques. This paper takes as a starting point recently derived, closed-form equations for the spatial-temporal correlation function of a broadband acoustic signal propagating in a turbulent atmosphere with coupled spatial-temporal fluctuations in temperature and wind velocity. This theory is employed to calculate, based on the Rytov approximation, the two-point, two-time, two-frequency mutual coherence function of plane and spherical waves in the weak scattering regime. The cross frequency coherence for these waveforms is then obtained and compared with that in the geometrical acoustics approximation. The coherence bandwidth is calculated and analyzed for typical meteorological regimes of the atmospheric surface layer and parameters of sound propagation. The results obtained are compared with available experimental data. The cross-frequency coherence is also used to study the effect of atmospheric turbulence on the mean intensity of an acoustic pulse propagating in a turbulent atmosphere. PMID- 27475190 TI - How to measure community tolerance levels for noise. AB - Relationships between noise exposure and transportation noise induced annoyance have been studied extensively for several decades. The annoyance due to aircraft noise exposure is in the present paper assumed to be influenced by the day-night yearly average sound level (DNL). It has long been recognized that the annoyance also depends on non-DNL factors, but this is complicated-resulting in a variety of different modeling strategies. Motivated by this, the community tolerance level (CTL) was introduced in 2011 for a loudness-based psychometric function. It is a single parameter that accounts for the aggregate influence of other factors. This paper suggests and investigates different methods for the measurement of the CTL. The methods are illustrated on data found in the literature, on recent surveys around two Norwegian airports, and on simulated data. The results from the presented methods differ significantly. An elementary method is shown to give a measurement of the CTL with smaller uncertainty, and is recommended as a replacement for the originally suggested least-squares method. Methods for evaluating the measurement uncertainty are also presented. PMID- 27475191 TI - Fluctuations in the cross-correlation for fields lacking full diffusivity: The statistics of spurious features. AB - Inasmuch as ambient noise fields are often not fully diffuse the question arises as to how, or whether, noise cross-correlations converge to Green's function in practice. Well-known theoretical estimates suggest that the quality of convergence scales with the square root of the product of integration time and bandwidth. However, correlations from natural environments often show random features too large to be consistent with fluctuations from insufficient integration time. Here it is argued that empirical seismic correlations suffer in practice from spurious arrivals due to scatterers, and not from insufficient integration time. Estimates are sought for differences by considering a related problem consisting of waves from a finite density of point sources. The resulting cross-correlations are analyzed for their mean and variance. The mean is, as expected, Green's function with amplitude dependent on noise strength. The variance is found to have support for all times up to its maximum at the main arrival. The signal-to-noise ratio there scales with the square root of source density. Numerical simulations support the theoretical estimates. The result permits estimates of spurious arrivals' impact on identification of cross correlations with Green's function and indicates that spurious arrivals may affect estimates of amplitudes, complicating efforts to infer attenuation. PMID- 27475192 TI - Temporal artifact minimization in sonoelastography through optimal selection of imaging parameters. AB - Sonoelastography is an ultrasonic technique that uses Kasai's autocorrelation algorithms to generate qualitative images of tissue elasticity using external mechanical vibrations. In the absence of synchronization between the mechanical vibration device and the ultrasound system, the random initial phase and finite ensemble length of the data packets result in temporal artifacts in the sonoelastography frames and, consequently, in degraded image quality. In this work, the analytic derivation of an optimal selection of acquisition parameters (i.e., pulse repetition frequency, vibration frequency, and ensemble length) is developed in order to minimize these artifacts, thereby eliminating the need for complex device synchronization. The proposed rule was verified through experiments with heterogeneous phantoms, where the use of optimally selected parameters increased the average contrast-to-noise ratio (CNR) by more than 200% and reduced the CNR standard deviation by 400% when compared to the use of arbitrarily selected imaging parameters. Therefore, the results suggest that the rule for specific selection of acquisition parameters becomes an important tool for producing high quality sonoelastography images. PMID- 27475193 TI - Wavenumber transform analysis for acoustic black hole design. AB - Acoustic black holes (ABHs) are effective, passive, lightweight vibration absorbers that have been developed and shown to effectively reduce the structural vibration and radiated sound of beam and plate structures. ABHs employ a local thickness change that reduces the speed of bending waves and increases the transverse vibration amplitude. The vibrational energy can then be effectively focused and dissipated by material losses or through conventional viscoelastic damping treatments. In this work, the measured vibratory response of embedded ABH plates was transformed into the wavenumber domain in order to investigate the use of wavenumber analysis for characterizing, designing, and optimizing practical ABH systems. The results showed that wavenumber transform analysis can be used to simultaneously visualize multiple aspects of ABH performance including changes in bending wave speed, transverse vibration amplitude, and energy dissipation. The analysis was also used to investigate the structural acoustic coupling of the ABH system and determine the radiation efficiency of the embedded ABH plates compared to a uniform plate. The results demonstrated that the ABH effect results in acoustic decoupling as well as vibration reduction. The wavenumber transform based methods and results will be useful for implementing ABHs into real world structures. PMID- 27475194 TI - Passive time-domain numerical models of viscothermal wave propagation in acoustic tubes of variable cross section. AB - Numerical modeling of wave propagation in acoustic tubes is a subject of longstanding interest, particularly for enclosures of varying cross section, and especially when viscothermal losses due to boundary layer effects are taken into consideration. Though steady-state, or frequency domain methods, are a common avenue of approach, recursive time domain methods are an alternative, allowing for the generation of wideband responses, and offer a point of departure for more general modeling of nonlinear wave propagation. The design of time-domain methods is complicated by numerical stability considerations, and to this end, a passive representation is a useful design principle leading to simple stable and explicit numerical schemes, particularly in the case of viscothermal loss modeling. Such schemes and the accompanying energy and stability analysis are presented here. Numerical examples are presented for a variety of duct profiles, illustrating strict energy dissipation, and for comparison of computed input impedances against frequency-domain results. PMID- 27475195 TI - Sum-of-harmonics method for improved narrowband and broadband signal quantification during passive monitoring of ultrasound therapies. AB - Passive Acoustic Mapping (PAM) enables real-time monitoring of ultrasound therapies by beamforming acoustic emissions emanating from the ultrasound focus. Reconstruction of the narrowband or broadband acoustic emissions component enables mapping of different physical phenomena, with narrowband emissions arising from non-linear propagation and scattering, non-inertial cavitation or tissue boiling, and broadband (generally, of significantly lower amplitude) indicating inertial cavitation. Currently, accurate classification of the received signals based on pre-defined frequency-domain comb filters cannot be guaranteed because varying levels of leakage occur as a function of signal amplitude and the choice of windowing function. This work presents a time-domain parametric model aimed at enabling accurate estimation of the amplitude of time varying narrowband components in the presence of broadband signals. Conversely, the method makes it possible to recover a weak broadband signal in the presence of a dominant harmonic or other narrowband component. Compared to conventional comb filtering, the proposed sum-of-harmonics method enables PAM of cavitation sources that better reflect their physical location and extent. PMID- 27475196 TI - The role of prosodic boundaries in word discovery: Evidence from a computational model. AB - This study aims to quantify the role of prosodic boundaries in early language acquisition using a computational modeling approach. A spoken term discovery system that models early word learning was used with and without a prosodic component on speech corpora of English, Spanish, and Japanese. The results showed that prosodic information induces a consistent improvement both in the alignment of the terms to actual word boundaries and in the phonemic homogeneity of the discovered clusters of terms. This benefit was found also when automatically discovered prosodic boundaries were used, boundaries which did not perfectly match the linguistically defined ones. PMID- 27475197 TI - Subjective audio quality evaluation of embedded-optimization-based distortion precompensation algorithms. AB - Subjective audio quality evaluation experiments have been conducted to assess the performance of embedded-optimization-based precompensation algorithms for mitigating perceptible linear and nonlinear distortion in audio signals. It is concluded with statistical significance that the perceived audio quality is improved by applying an embedded-optimization-based precompensation algorithm, both in case (i) nonlinear distortion and (ii) a combination of linear and nonlinear distortion is present. Moreover, a significant positive correlation is reported between the collected subjective and objective PEAQ audio quality scores, supporting the validity of using PEAQ to predict the impact of linear and nonlinear distortion on the perceived audio quality. PMID- 27475198 TI - Internal and contextual cues to tone perception in Medumba. AB - This study presents results of an identification experiment with speakers of Medumba, a Grassfields Bantu language, aimed at evaluating the relative effects of f0 and duration in cuing tonal contrasts, as well as the role of lexical vs non-speech pitch contexts in biasing tone perception. Results show that duration is a cue for tone perception, with the influence of duration strongest where target f0 values were lower. Lexical tone perception is also sensitive to the identity of a preceding lexical tone, but not to the presence of a preceding non speech pure tone. PMID- 27475199 TI - Tonal noise of a controlled-diffusion airfoil at low angle of attack and Reynolds number. AB - The acoustic signature of a controlled-diffusion airfoil immersed in a flow is experimentally characterized. Acoustic measurements have been carried out in an anechoic open-jet-wind-tunnel for low Reynolds numbers (from 5 * 10(4) to 4.3 * 10(5)) and several angles of attack. As with the NACA0012, the acoustic spectrum is dominated by discrete tones. These tonal behaviors are divided into three different regimes. The first one is characterized by a dominant primary tone which is steady over time, surrounded by secondary peaks. The second consists of two unsteady primary tones associated with secondary peaks and the third consists of a hump dominated by several small peaks. A wavelet study allows one to identify an amplitude modulation of the acoustic signal mainly for the unsteady tonal regime. This amplitude modulation is equal to the frequency interval between two successive tones. Finally, a bispectral analysis explains the presence of tones at higher frequencies. PMID- 27475200 TI - Memory cost of absorbing conditions for the finite-difference time-domain method. AB - Three absorbing layers are investigated using standard rectilinear finite difference schemes. The perfectly matched layer (PML) is compared with basic lossy layers terminated by two types of absorbing boundary conditions, all simulated using equivalent memory consumption. Lossy layers present the advantage of being scalar schemes, whereas the PML relies on a staggered scheme where both velocity and pressure are split. Although the PML gives the lowest reflection magnitudes over all frequencies and incidence angles, the most efficient lossy layer gives reflection magnitudes of the same order as the PML from mid- to high frequency and for restricted incidence angles. PMID- 27475201 TI - Passive fathometer reflector identification with phase shift modeling. AB - In passive fathometer processing, the presence of wavelets in the estimate of the medium's Green's function corresponds to the location of reflectors in the seabed; amplitudes are related to seabed properties. Bayesian methods have been successful in identifying reflectors that define layer interfaces. Further work, however, revealed that phase shifts are occasionally present in the wavelets and hinder accurate layer identification for some reflectors. With a Gibbs sampler that computes probability densities of reflector depths, strengths of the reflections, and wavelet phase shifts, the significance of phase shift modeling in successful estimation of reflectors and their strengths is demonstrated. PMID- 27475202 TI - Sediment sound speed inversion with time-frequency analysis and modal arrival time probability density functions. AB - The dispersion pattern of a received signal is critical for understanding physical properties of the propagation medium. The objective of this work is to estimate accurately sediment sound speed using modal arrival times obtained from dispersion curves extracted via time-frequency analysis of acoustic signals. A particle filter is used that estimates probability density functions of modal frequencies arriving at specific times. Employing this information, probability density functions of arrival times for modal frequencies are constructed. Samples of arrival time differences are then obtained and are propagated backwards through an inverse acoustic model. As a result, probability density functions of sediment sound speed are estimated. Maximum a posteriori estimates indicate that inversion is successful. It is also demonstrated that multiple frequency processing offers an advantage over inversion at a single frequency, producing results with reduced variance. PMID- 27475203 TI - Estimating temperature and current using a pair of transceivers in a harbor environment. AB - Obtaining the horizontal variation of temperature and current fields of a water column usually requires travel-time measurements of acoustic signals traveling along different paths between several horizontally distributed transceivers. This study explores the possibility of using a pair of transceivers deployed in a highly-reverberant harbor environment to extract spatial information of the water. Multipath acoustic propagation of two main arrival groups, i.e., direct arrivals and arrivals reflecting off the harbor side, was observed in the pulse responses measured in the harbor environment during the flood tide. Compared with the direct point measurements of temperature and current, the path-averaged measurements show a similar temporal variation during the experiment, demonstrating the possibility of estimating the spatial variation of the currents and temperatures using the multipath acoustic propagation. PMID- 27475204 TI - Sound source localization identification accuracy: Level and duration dependencies. AB - Sound source localization accuracy for noises was measured for sources in the front azimuthal open field mainly as a function of overall noise level and duration. An identification procedure was used in which listeners identify which loudspeakers presented a sound. Noises were filtered and differed in bandwidth and center frequency. Sound source localization accuracy depended on the bandwidth of the stimuli, and for the narrow bandwidths, accuracy depended on the filter's center frequency. Sound source localization accuracy did not depend on overall level or duration. PMID- 27475205 TI - Sound localization in the presence of multiple reflections using a binaurally integrated cross-correlation/auto-correlation mechanism. AB - A precedence effect model is described that can use a binaural signal to robustly localize a sound source in the presence of multiple reflections for the frontal horizontal plane. The model also estimates a room impulse response from a running binaural signal and determines the spatial locations and delays of early reflections, without any prior or additional knowledge of the source. A dual layer cross-correlation/auto-correlation algorithm is used to determine the interaural time difference of the direct sound source component and to estimate a binaural activity pattern. PMID- 27475206 TI - Approximate formulas and physical interpretations for horizontal acoustic modes in a shelf-slope front model. AB - The structure and behavior of horizontal acoustic modes for a three-dimensional idealized model of a shelf-slope front are examined analytically. The Wentzel Kramers-Brillouin-Jeffreys (WKBJ) method is used to obtain convenient simple expressions and to provide physical insight into the structure and behavior of horizontal modes as trapped, leaky, or transition types. Validity regions for WKBJ expressions in terms of slope and frontal parameters are found, and outside the regions the asymptotic formulas for large order and large argument Hankel functions are used. These combined approximations have very good accuracy as shown by comparisons with numerical solutions for modal shapes and horizontal wavenumbers. PMID- 27475207 TI - Classification and automatic transcription of primate calls. AB - This paper reports on an automated and openly available tool for automatic acoustic analysis and transcription of primate calls, which takes raw field recordings and outputs call labels time-aligned with the audio. The system's output predicts a majority of the start times of calls accurately within 200 milliseconds. The tools do not require any manual acoustic analysis or selection of spectral features by the researcher. PMID- 27475208 TI - Effects of duty-cycled passive acoustic recordings on detecting the presence of beaked whales in the northwest Atlantic. AB - This study investigated the effects of using duty-cycled passive acoustic recordings to monitor the daily presence of beaked whale species at three locations in the northwest Atlantic. Continuous acoustic records were subsampled to simulate duty cycles of 50%, 25%, and 10% and cycle period durations from 10 to 60 min. Short, frequent listening periods were most effective for assessing the daily presence of beaked whales. Furthermore, subsampling at low duty cycles led to consistently greater underestimation of Mesoplodon species than either Cuvier's beaked whales or northern bottlenose whales, leading to a potential bias in estimation of relative species occurrence. PMID- 27475209 TI - Correction method for averaging slowly time-variant room impulse response measurements. AB - Various methods exist for room acoustic measurements. To increase the signal-to noise-ratio (SNR), averaging of repeated room impulse responses (RIR) can be performed under the assumption of time-invariant systems. Associated with a study of the Paris Notre Dame cathedral, time-variances due to minute temperature changes were observed which confounded results of averaged RIRs, producing significantly shorter reverberation times. A correction method for such time variance of the acoustic system is proposed, based on time-stretching. Following correction, reverberation times of averaged RIRs were comparable to expected tolerance ranges for measurements, well within one just noticeable difference, while also exhibiting a mid-frequency SNR gain of 8 dB. PMID- 27475210 TI - Joint inversion for transponder localization and sound-speed profile temporal variation in high-precision acoustic surveys. AB - This letter develops a Bayesian inversion for localizing underwater acoustic transponders using a surface ship which compensates for sound-speed profile (SSP) temporal variation during the survey. The method is based on dividing observed acoustic travel-time data into time segments and including depth-independent SSP variations for each segment as additional unknown parameters to approximate the SSP temporal variation. SSP variations are estimated jointly with transponder locations, rather than calculated separately as in existing two-step inversions. Simulation and sea-trial results show this localization/SSP joint inversion performs better than two-step inversion in terms of localization accuracy, agreement with measured SSP variations, and computational efficiency. PMID- 27475211 TI - Rapid auditory learning of temporal gap detection. AB - The rapid initial phase of training-induced improvement has been shown to reflect a genuine sensory change in perception. Several features of early and rapid learning, such as generalization and stability, remain to be characterized. The present study demonstrated that learning effects from brief training on a temporal gap detection task using spectrally similar narrowband noise markers defining the gap (within-channel task), transfer across ears, however, not across spectrally dissimilar markers (between-channel task). The learning effects associated with brief training on a gap detection task were found to be stable for at least a day. These initial findings have significant implications for characterizing early and rapid learning effects. PMID- 27475212 TI - On the use of geometric and harmonic means with the generalized cross-correlation in the time domain to improve noise source maps. AB - Microphone array techniques are an efficient tool to detect acoustic source positions. The delay and sum beamforming is the standard method. In the time domain, the generalized cross-correlation can be used to compute the noise source map. This technique is based on the arithmetic mean of the spatial likelihood functions. In this study, the classical arithmetic mean is replaced by the more standard generalized mean. The noise source maps provide by the arithmetic, geometric and harmonic means are compared in the case of numerical and experimental data obtained in a reverberant room. The geometric and harmonic means provide the best noise source maps with no side lobes and a better source level estimation. PMID- 27475213 TI - Head wave correlations in ambient noise. AB - Ambient ocean noise is processed with a vertical line array to reveal coherent time-separated arrivals suggesting the presence of head wave multipath propagation. Head waves, which are critically propagating water waves created by seabed waves traveling parallel to the water-sediment interface, can propagate faster than water-only waves. Such eigenrays are much weaker than water-only eigenrays, and are often completely overshadowed by them. Surface-generated noise is different whereby it amplifies the coherence between head waves and critically propagating water-only waves, which is measured by cross-correlating critically steered beams. This phenomenon is demonstrated both experimentally and with a full wave simulation. PMID- 27475214 TI - Beam diffraction effects in sound transmission of a fluid-embedded viscoelastic plate at normal incidence. AB - The characteristics of a sound beam transmitted through a fluid-embedded viscoelastic plate at normal incidence can deviate significantly from those of a plane-wave. Phenomena such as frequency shift, signal amplification or reduction, and changed beam properties, are observed for resonance peaks associated with specific leaky Lamb modes. When interpreting measurements using plane-wave theory, such deviations will influence the measurement of material parameters and plate thickness. The finite-element-based models used in this study describe the signal chain from the electrical voltage excitation at the piezoelectric transducer terminals to the sound pressure propagated through the plate and fluid to the position at which it is measured by a hydrophone. The measured phenomena are described at a quantitative level. PMID- 27475215 TI - Acoustic performance of boundaries having constant phase gradient. AB - In this paper, inhomogeneous boundaries having constant phase gradient are investigated. In principle, such a theoretically proposed boundary is dispersionless. In practice, however, when the boundary is realized by a subwavelength-structured tubes array, the impedance discretization brings about sub-reflections at high frequencies. Moreover, determined by the longest duct in the array, a realized boundary is impractically thick. Therefore, a finite thickness boundary is further proposed by truncating and periodizing the tubes in the array. In this paper, the theoretical analysis agrees well with the numerical simulations. By appropriately choosing its phase gradient and target frequency, the finite-thickness boundaries have potential applications in noise control. PMID- 27475216 TI - Release from masking for small spatial separations: Effects of age and hearing loss. AB - Spatially separating target and masking speech can result in substantial spatial release from masking (SRM) for normal-hearing listeners. In this study, SRM was examined at eight spatial configurations of azimuth angle: maskers co-located with the target (0 degrees ) or symmetrically separated by 2 degrees , 4 degrees , 6 degrees , 8 degrees , 10 degrees , 15 degrees , or 30 degrees . Results revealed that different listening groups (young normal-hearing, older normal hearing, and older hearing-impaired) required different minimum amounts of spatial separation between target and maskers to achieve SRM. The results also indicated that aging was the contributing factor predicting SRM at smaller separations, whereas hearing loss was the contributing factor at larger separations. PMID- 27475217 TI - The effect of microphone wind noise on the amplitude modulation of wind turbine noise and its mitigation. AB - Microphone wind noise can corrupt outdoor recordings even when wind shields are used. When monitoring wind turbine noise, microphone wind noise is almost inevitable because measurements cannot be made in still conditions. The effect of microphone wind noise on two amplitude modulation (AM) metrics is quantified in a simulation, showing that even at low wind speeds of 2.5 m/s errors of over 4 dBA can result. As microphone wind noise is intermittent, a wind noise detection algorithm is used to automatically find uncorrupted sections of the recording, and so recover the true AM metrics to within +/-2/+/-0.5 dBA. PMID- 27475218 TI - The effect of sound speed profile on shallow water shipping sound maps. AB - Sound mapping over large areas can be computationally expensive because of the large number of sources and large source-receiver separations involved. In order to facilitate computation, a simplifying assumption sometimes made is to neglect the sound speed gradient in shallow water. The accuracy of this assumption is investigated for ship generated sound in the Dutch North Sea, for realistic ship and wind distributions. Sound maps are generated for zero, negative and positive gradients for selected frequency bands (56 Hz to 3.6 kHz). The effect of sound speed profile for the decidecade centred at 125 Hz is less than 1.7 dB. PMID- 27475219 TI - Whistle source levels of free-ranging beluga whales in Saguenay-St. Lawrence marine park. AB - Wild beluga whistle source levels (SLs) are estimated from 52 three-dimensional (3D) localized calls using a 4-hydrophone array. The probability distribution functions of the root-mean-square (rms) SL in the time domain, and the peak, the strongest 3-dB, and 10-dB SLs from the spectrogram, were non-Gaussian. The average rms SL was 143.8 +/- 6.7 dB re 1 MUPa at 1 m. SL spectral metrics were, respectively, 145.8 +/- 8 dB, 143.2 +/- 7.1 dB, and 138.5 +/- 6.9 dB re 1 MUPa(2).Hz(-1) at 1 m. PMID- 27475220 TI - Coherent perfect absorption induced by the nonlinearity of a Helmholtz resonator. AB - In this work, coherent perfect absorption of sound waves induced by the nonlinear response of a Helmholtz Resonator side loaded to a waveguide, is reported. It is shown that this two-port system can perfectly absorb two high amplitude symmetric incident waves under a certain condition. For the one-sided incidence configuration, this condition leads to an absorption equal to 0.5. Experiments verify these results and are in agreement with an analytical nonlinear impedance model for the resonator. The nonlinear control of perfect absorption opens new possibilities in the design of high amplitude sound attenuators for aero-engine applications. PMID- 27475221 TI - Does socioeconomic status predict outcomes after cholecystectomy? AB - BACKGROUND: This study was performed to evaluate the effect of socioeconomic status (SES) on outcomes after cholecystectomy. METHODS: The National Inpatient Sample (NIS) database (2005 to 2011) was queried for patients undergoing cholecystectomy. Clinically relevant variables were used to examine clinical characteristics, postoperative complications, and mortality. SES was investigated by examining income quartile. RESULTS: More than 2 million patients underwent cholecystectomy during this period. They were divided into quartiles by SES. The lowest cohort was younger (50 years, P < .001) and had the lowest Charlson Comorbidity Index (2.08, P < .001). This cohort was more likely African American (15.8%, P < .001) and more likely to have Medicaid (19.2%, P < .001). Using split sample validation and multivariate analysis, lower SES, Charlson comorbidity Index, and Medicaid recipients were associated with increased mortality. CONCLUSIONS: Patients with Medicaid and lower SES had poorer outcomes after cholecystectomy. PMID- 27475222 TI - Optimal timing for a repeat fine-needle aspiration biopsy of thyroid nodule following an initial nondiagnostic fine-needle aspiration. AB - BACKGROUND: In the case of a nondiagnostic thyroid fine-needle aspiration (FNA) biopsy result, recent guidelines from the Bethesda system recommend repeat thyroid FNA after 3 months to prevent false-positive results. We aimed to examine our institutional data to determine whether the 3-month period affects the diagnostic yield of repeat biopsies. METHODS: A retrospective review of patient records over a 5-year period at our institution was performed. Patients who required repeat FNA due to nondiagnostic results were included. The time between the FNA biopsies, adequacy of the FNA specimens, as well as the surgical pathology diagnosis were analyzed. RESULTS: We identified 317 patients who required a repeat FNA. Of these, 96 (30.3%) patients had repeat FNAs less than 3 months after initial biopsy, while 221 (69.7%) patients had repeat FNAs in greater than 3 months. One hundred five patients were referred to our clinic with an initial nondiagnostic biopsy from an outside institution. Repeat FNA was nondiagnostic in 35 patients (11.04%) in the total study population. There was no difference in satisfactory diagnostic yield between repeat FNAs performed greater than 3 months (201 patients, 90.95%) or less than 3 months (81 patients, 84.38%) after the initial biopsy (P = .117). Of the 35 patients with repeat nondiagnostic biopsy, 17 patients underwent diagnostic lobectomy and 3 (17.6%) patients were found to have malignant disease. CONCLUSIONS: Early (<3 months) repeat FNA does not affect diagnostic yield of the subsequent sample. Patients with suspicious thyroid nodules could therefore receive a repeat FNA as soon as needed, rather than waiting 3 months. The shortened biopsy interval would alleviate stress on patients with benign nodules and expedite surgical intervention in patients with malignancy. PMID- 27475223 TI - Open repair of incisional ventral abdominal hernias with mesh leads to long-term improvement in pain interference as measured by patient-reported outcomes. AB - BACKGROUND: The Patient-Reported Outcomes Measurement Information System was used to evaluate the effects of open incisional ventral hernia repair on hernia related pain. METHODS: All patients who underwent elective repair of a primary or recurrent midline incisional hernia over a 3-year period completed Patient Reported Outcomes Measurement Information System pain surveys and rated their pain intensity on a visual analogue scale. A retrospective review of these patients was performed. RESULTS: Seventy-seven patients underwent midline incisional ventral hernia repair and completed preoperative and postoperative surveys. Thirty-eight patients completed surveys at least 6 months after surgery. These patients demonstrated significant improvement in pain interference postoperatively (P < .05) but not in pain behavior. Patients with higher pain intensity scores preoperatively had greater improvements in pain behavior and pain interference postoperatively. CONCLUSIONS: Patients with incisional ventral hernias have improvement in pain interference 6 months after open surgical repair. Changes are most pronounced in patients who experience higher magnitudes of pain preoperatively. PMID- 27475224 TI - Social role conflict predicts stimulated cytokine production among men, not women. AB - OBJECTIVE: To assess whether perceived role conflict is associated with stimulated pro-inflammatory cytokine production and glucocorticoid sensitivity, and whether these associations are moderated by sex. METHODS: 153 healthy adults (aged 45.8+/-5.5years, 78% female) listed their 3 main social roles and indicated the amount of role conflict they perceived between each pair of social roles. Subsequently, participants underwent blood draws and leukocyte response to microbial challenge and glucocorticoid sensitivity were assessed by incubating whole blood with lipopolysaccharide (LPS) in the presence or absence of hydrocortisone. Stimulated levels of Interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor alpha (TNFalpha) were measured. RESULTS: Multiple regression analyses controlling for sociodemographics revealed significant sex*role conflict interactions for LPS-stimulated production of IL-1beta, IL-6, and TNFalpha (all interaction ps<0.05), and a marginal interaction on LPS stimulated IL-8 production (interaction p<0.10). Greater perceived role conflict was associated with greater pro-inflammatory cytokine production in response to microbial stimulation only among men, not women. There also were significant sex*role conflict interactions with respect to glucocorticoid sensitivity for IL 1beta, IL-6, and TNFalpha production (all interaction ps<0.05) and a marginal interaction for IL-8 (interaction p<0.10). Greater perceived role conflict was unrelated to glucocorticoid sensitivity among women, but associated with less sensitivity to glucocorticoid signaling among men. CONCLUSIONS: Perceived social role conflict, indicating greater perceived demand across multiple social roles, may take a greater toll on the regulation of inflammatory processes among men compared to women. PMID- 27475225 TI - Ana Maria Cuervo: Breaking Down Autophagy. PMID- 27475226 TI - Exon Junction Complexes Show a Distributional Bias toward Alternatively Spliced mRNAs and against mRNAs Coding for Ribosomal Proteins. AB - The exon junction complex (EJC) connects spliced mRNAs to posttranscriptional processes including RNA localization, transport, and regulated degradation. Here, we provide a comprehensive analysis of bona fide EJC binding sites across the transcriptome including all four RNA binding EJC components eIF4A3, BTZ, UPF3B, and RNPS1. Integration of these data sets permits definition of high-confidence EJC deposition sites as well as assessment of whether EJC heterogeneity drives alternative nonsense-mediated mRNA decay pathways. Notably, BTZ (MLN51 or CASC3) emerges as the EJC subunit that is almost exclusively bound to sites 20-24 nucleotides upstream of exon-exon junctions, hence defining EJC positions. By contrast, eIF4A3, UPF3B, and RNPS1 display additional RNA binding sites suggesting accompanying non-EJC functions. Finally, our data show that EJCs are largely distributed across spliced RNAs in an orthodox fashion, with two notable exceptions: an EJC deposition bias in favor of alternatively spliced transcripts and against the mRNAs that encode ribosomal proteins. PMID- 27475227 TI - Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement. AB - The spread of tau pathology correlates with cognitive decline in Alzheimer's disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron microglia co-cultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau. PMID- 27475228 TI - The proteasome - victim or culprit in autoimmunity. AB - The ubiquitin proteasome system is closely connected to apoptosis, autophagy, signaling of inflammatory cytokines and generation of ligands for MHC class I antigen presentation. Proteasome function in the innate immune response becomes particularly evident in patients with proteasome-associated autoinflammatory syndromes (PRAAS), where disease causing mutations result in reduced proteasome activity. PRAAS can be classified as a novel type of interferonopathy, however the molecular mechanism and signaling pathways leading from impaired proteasome capacity, the accumulation of damaged proteins, and the induction of type I IFN genes remain to be determined. In contrast, several studies have confirmed an up regulation of inducible subunits of the proteasome in systemic autoimmune diseases. Since proteasome inhibition was shown to be efficacious in several in vitro studies and animal models of autoimmune diseases, it is justified to investigate the application of proteasome inhibitors in human disease. In this context, a number of available proteasome inhibitors has been characterized as potent immune-suppressants. The mode of action of proteasome inhibition interferes with the quality control of the huge amounts of synthetized antibodies causing an unfolded protein response. Further effects of proteasome inhibition includes inhibition of NFkappaB activation as well as direct activation of intrinsic and extrinsic pathways of apoptosis. The preliminary clinical work on proteasome inhibition in autoimmune diseases comprises only few studies in small cohorts with promising effects, which needs to be confirmed in controlled clinical trials. PMID- 27475229 TI - Stromal cell-derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy. AB - The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic prone mice, but not in kidneys from diabetic-resistant mice. The DPP-4 inhibitor linagliptin, but not the GLP-1R agonist liraglutide, further augmented renal SDF 1 expression in both Glp1r(+/+) and Glp1r(-/-) diabetic-prone mice. Along with upregulation of renal SDF-1 expression, the progression of albuminuria, glomerulosclerosis, periglomerular fibrosis, podocyte loss, and renal oxidative stress was suppressed in linagliptin-treated Glp1r(+/+) diabetic-prone mice. Linagliptin treatment increased urinary sodium excretion and attenuated the increase in glomerular filtration rate which reflects glomerular hypertension and hyperfiltration. In contrast, selective SDF-1 receptor blockade with AMD3100 reduced urinary sodium excretion and aggravated glomerular hypertension in the Glp1r(+/+) diabetic-prone mice. Thus, DPP-4 inhibition, independent of GLP-1R signaling, contributes to protection of the diabetic kidney through SDF-1 dependent antioxidative and antifibrotic effects and amelioration of adverse renal hemodynamics. PMID- 27475231 TI - Calcium and vitamin D have a synergistic role in a rat model of kidney stone disease. AB - Vitamin D supplementation in humans should be accompanied by calcium administration to avoid bone demineralization through vitamin D receptor signaling. Here we analyzed whether long-term exposure of rats to vitamin D supplementation, with or without a calcium-rich diet, would promote kidney stone formation. Four groups of rats received vitamin D alone (100,000 UI/kg/3 weeks), a calcium-enriched diet alone, both vitamin D supplementation and calcium enriched diet, or a standard diet (controls) for 6 months. Serum and urine parameters and crystalluria were monitored. Kidney stones were assessed by 3 dimensional micro-computed tomography, infrared spectroscopy, von Kossa/Yasue staining, and field emission scanning electron microscopy. Although serum calcium levels were similar in the 4 groups, rats receiving vitamin D had a progressive increase in urinary calcium excretion over time, especially those receiving both calcium and vitamin D. However, oral calcium supplementation alone did not increase urinary calcium excretion. At 6 months, rats exposed to both calcium and vitamin D, but not rats exposed to calcium or vitamin D alone, developed significant apatite kidney calcifications (mean volume, 0.121 mm(3)). Thus, coadministration of vitamin D and increased calcium intake had a synergistic role in tubular calcifications or kidney stone formation in this rat model. Hence, one should be cautious about the cumulative risk of kidney stone formation in humans when exposed to both vitamin D supplementation and high calcium intake. PMID- 27475230 TI - Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout. AB - Alterations in myocardial wall texture stand out among ADPKD cardiovascular manifestations in hypertensive and normotensive patients. To elucidate their pathogenesis, we analyzed the cardiac phenotype in Pkd1(cond/cond)Nestin(cre) (CYG+) cystic mice exposed to increased blood pressure, at 5 to 6 and 20 to 24 weeks of age, and Pkd1(+/-) (HTG+) noncystic mice at 5-6 and 10-13 weeks. Echocardiographic analyses revealed decreased myocardial deformation and systolic function in CYG+ and HTG+ mice, as well as diastolic dysfunction in older CYG+ mice, compared to their Pkd1(cond/cond) and Pkd1(+/+) controls. Hearts from CYG+ and HTG+ mice presented reduced polycystin-1 expression, increased apoptosis, and mild fibrosis. Since galectin-3 has been associated with heart dysfunction, we studied it as a potential modifier of the ADPKD cardiac phenotype. Double-mutant Pkd1(cond/cond):Nestin(cre);Lgals3(-/-) (CYG-) and Pkd1(+/-);Lgals3(-/-) (HTG-) mice displayed improved cardiac deformability and systolic parameters compared to single-mutants, not differing from the controls. CYG- and HTG- showed decreased apoptosis and fibrosis. Analysis of a severe cystic model (Pkd1(V/V); VVG+) showed that Pkd1(V/V);Lgals3(-/-) (VVG-) mice have longer survival, decreased cardiac apoptosis and improved heart function compared to VVG+. CYG- and VVG- animals showed no difference in renal cystic burden compared to CYG+ and VVG+ mice. Thus, myocardial dysfunction occurs in different Pkd1-deficient models and suppression of galectin-3 expression rescues this phenotype. PMID- 27475232 TI - Identification of a novel DFA I-producing inulin fructotransferase from Streptomyces davawensis. AB - In this work, a novel gene encoding DFA I-forming inulin fructotransferase (IFTase) from Streptomyces davawensis SK39.001 was cloned and expressed in Escherichia coli. The enzyme was purified, identified, and characterized. The results showed that this IFTase (DFA I-forming) is a trimer (molecular weight of 125KDa) consisting of three identical subunits (the molecular weight as assayed by SDS-PAGE was approximately 40KDa). At pH 5.5 and 40 degrees C, the maximum specific activity (approximately 100Umg-1) was achieved. Moreover, the enzyme was stable up to 70 degrees C. Km and Vmax were 2.89+/-0.2mM and 1.94+/-0.9mMmin-1, respectively. For exploring putative active sites and probable catalytic mechanisms, homology modelling and molecular docking methods after site-directed mutagenesis were applied to IFTase (DFA I-forming). The results revealed that D183 and E194 were potential catalytic residues of the purified enzyme. PMID- 27475234 TI - Formation of redispersible polyelectrolyte complex nanoparticles from gallic acid chitosan conjugate and gum arabic. AB - Polyelectrolyte complex (PEC) nanoparticles between chitosan (CS) and biomacromolecules offer better physicochemical properties as delivery vehicles for nutrients than other CS-based nanoparticles. Our major objective was to fabricate PEC nanoparticles between water soluble gallic acid-chitosan conjugate (GA-CS) and gum arabic. The optimal fabrication method, physicochemical characteristics and stability were investigated. Furthermore, we also evaluated the effects of nano spray drying technology on the morphology and redispersibility of nanoparticle powders using Buchi B-90 Nano Spray Dryer. Results showed that the mass ratio between GA-CS and gum arabic and the preparation pH had significant contributions in determining the particle size and count rate of the nanoparticles, with the ratio of 3:1 and pH 5.0 being the optimal conditions that resulted in 112.2nm and 122.9kcps. The polyethylene glycol (PEG) played a vital role in forming the well-separated spray dried nanoparticles. The most homogeneous nanoparticles with the smoothest surface were obtained when the mass ratio of GA-CS and PEG was 1:0.5. In addition, the GA CS/gum arabic spray dried nanoparticles exhibited excellent water-redispersibiliy compared to native CS/gum arabic nanoparticles. Our results demonstrated GA CS/gum arabic nanoparticles were successfully fabricated with promising physicochemical properties and great potential for their applications in food and pharmaceutical industries. PMID- 27475233 TI - RG-I regions from elderflower pectins substituted on GalA are strong immunomodulators. AB - Sambuci flos, also known as elderflower, has traditionally been used and is still in use for treatment of various types of illnesses related to the immune system such as cold, flu, fever and inflammation. Pectic polysaccharides from 50% EtOH, 50 degrees C water and 100 degrees C water extracts from elderflowers were treated with endo-alpha-d-(1-4)-polygalacturonase after previous de esterification with the intention of isolating hairy regions and relate variation in structure to immunomodulating activity. High molecular weight sub-fractions (25-29kDa) and medium molecular weight sub-fractions (6-17kDa) were isolated after enzymatic treatment in addition to oligogalacturonides. Structural elucidation indicated that RG-I regions with AG-I and AG-II sidechains were the predominant structures in the high molecular weight sub-fractions, and two of three 1,4-linked GalA units in the rhamnogalacturonan backbone were branched in either position 2 or 3. The medium molecular weight sub-fractions had monomers and linkages typical for both RG-I and RG-II. The results showed that the high molecular RG-I containing polymers exhibit the highest dose-dependent complement fixing and macrophage stimulating activities. PMID- 27475235 TI - Assembly of ligands interaction models for glutathione-S-transferases from Plasmodium falciparum, human and mouse using enzyme kinetics and molecular docking. AB - BACKGROUND: Glutathione-s-transferases (GSTs) are enzymes that principally catalyze the conjugation of electrophilic compounds to the endogenous nucleophilic glutathione substrate, besides, they have other non-catalytic functions. The Plasmodium falciparum genome encodes a single isoform of GST (PfGST) which is involved in buffering the toxic heme, thus considered a potential anti-malarial target. In mammals several classes of GSTs are available, each of various isoforms. The human (human GST Pi-1 or hGSTP1) and mouse (murine GST Mu-1 or mGSTM1) GST isoforms control cellular apoptosis by interaction with signaling proteins, thus considered as potential anti-cancer targets. In the course of GSTs inhibitors development, the models of ligands interactions with GSTs are used to guide rational molecular modification. In the absence of X-ray crystallographic data, enzyme kinetics and molecular docking experiments can aid in addressing ligands binding modes to the enzymes. METHODS: Kinetic studies were used to investigate the interactions between the three GSTs and each of glutathione, 1-chloro-2,4-dinitrobenzene, cibacron blue, ethacrynic acid, S-hexyl glutathione, hemin and protoporphyrin IX. Since hemin displacement is intended for PfGST inhibitors, the interactions between hemin and other ligands at PfGST binding sites were studied kinetically. Computationally determined binding modes and energies were interlinked with the kinetic results to resolve enzymes-ligands interaction models at atomic level. RESULTS: The results showed that hemin and cibacron blue have different binding modes in the three GSTs. Hemin has two binding sites (A and B) with two binding modes at site-A depending on presence of GSH. None of the ligands were able to compete hemin binding to PfGST except ethacrynic acid. Besides bind differently in GSTs, the isolated anthraquinone moiety of cibacron blue is not maintaining sufficient interactions with GSTs to be used as a lead. Similarly, the ethacrynic acid uses water bridges to mediate interactions with GSTs and at least the conjugated form of EA is the true hemin inhibitor, thus EA may not be a suitable lead. CONCLUSIONS: Glutathione analogues with bulky substitution at thiol of cysteine moiety or at gamma-amino group of gamma-glutamine moiety may be the most suitable to provide GST inhibitors with hemin competition. PMID- 27475236 TI - An integrative approach predicted co-expression sub-networks regulating properties of stem cells and differentiation. AB - The differentiation of human Embryonic Stem Cells (hESCs) is accompanied by the formation of different intermediary cells, gradually losing its stemness and acquiring differentiation. The precise mechanisms underlying hESCs integrity and its differentiation into fibroblast (Fib) are still elusive. Here, we aimed to assess important genes and co-expression sub-networks responsible for stemness, early differentiation of hESCs into embryoid bodies (EBs) and its lineage specification into Fibs. To achieve this, we compared transcriptional profiles of hESCs-EBs and EBs-Fibs and obtained differentially expressed genes (DEGs) exclusive to hESCs-EBs (early differentiation), EBs-Fibs (late differentiation) and common DEGs in hESCs-EBs and EBs-Fibs. Then, we performed gene set enrichment analysis (GSEA) followed by overrepresentation study and identified key genes for each gene category. The regulations of these genes were studied by integrating ChIP-Seq data of core transcription factors (TFs) and histone methylation marks in hESCs. Finally, we identified co-expression sub-networks from key genes of each gene category using k-clique sub-network extraction method. Our study predicted seven genes edicting core stemness properties forming a co-expression network. From the pathway analysis of sub-networks of hESCs-EBs, we hypothesize that FGF2 is contributing to pluripotent transcription network of hESCs in association with DNMT3B and JARID2 thereby facilitating cell proliferation. On the contrary, FGF2 is found to promote cell migration in Fibs along with DDR2, CAV1, DAB2, and PARVA. Moreover, our study identified three k-clique sub-networks regulating TGF-beta signaling pathway thereby promoting EBs to Fibs differentiation by: (i) modulating extracellular matrix involving ITGB1, TGFB1I1 and GBP1, (ii) regulating cell cycle remodeling involving CDKN1A, JUNB and DUSP1 and (iii) helping in epithelial to mesenchymal transition (EMT) involving THBS1, INHBA and LOX. This study put forward the unexplored genes and co-expression sub networks regulating stemness and different stages of differentiation of hESCs which will undoubtedly add to the comprehensive understanding of hESCs biology. PMID- 27475237 TI - Perceptron ensemble of graph-based positive-unlabeled learning for disease gene identification. AB - Identification of disease genes, using computational methods, is an important issue in biomedical and bioinformatics research. According to observations that diseases with the same or similar phenotype have the same biological characteristics, researchers have tried to identify genes by using machine learning tools. In recent attempts, some semi-supervised learning methods, called positive-unlabeled learning, is used for disease gene identification. In this paper, we present a Perceptron ensemble of graph-based positive-unlabeled learning (PEGPUL) on three types of biological attributes: gene ontologies, protein domains and protein-protein interaction networks. In our method, a reliable set of positive and negative genes are extracted using co-training schema. Then, the similarity graph of genes is built using metric learning by concentrating on multi-rank-walk method to perform inference from labeled genes. At last, a Perceptron ensemble is learned from three weighted classifiers: multilevel support vector machine, k-nearest neighbor and decision tree. The main contributions of this paper are: (i) incorporating the statistical properties of gene data through choosing proper metrics, (ii) statistical evaluation of biological features, and (iii) noise robustness characteristic of PEGPUL via using multilevel schema. In order to assess PEGPUL, we have applied it on 12950 disease genes with 949 positive genes from six class of diseases and 12001 unlabeled genes. Compared with some popular disease gene identification methods, the experimental results show that PEGPUL has reasonable performance. PMID- 27475238 TI - Recent structural insights into the enzymology of the ubiquitous plant cell wall glycan xyloglucan. AB - The xyloglucans (XyGs) constitute a family of highly decorated beta(1->4)-glucans whose members are widespread and abundant across the plant kingdom. As such, XyGs constitute a significant reserve of metabolically accessible monosaccharides for diverse phytopathogenic, saprophytic, and gut symbiotic micro-organisms. To overcome the intrinsic stability of the diverse glycosidic bonds in XyGs, bacteria and fungi have evolved extensive repertoires of xyloglucan-active enzymes from manifold families, whose exquisitely adapted tertiary structures are recently coming to light. PMID- 27475239 TI - Ectopic Penile Prosthesis Reservoir Placement: An Anatomic Cadaver Model of the High Submuscular Technique. AB - INTRODUCTION: High submuscular ectopic placement of inflatable penile prosthesis (IPP) reservoirs via the inguinal canal has been popularized as an alternative to the retropubic (orthotopic) location, particularly among men with prior pelvic surgery. Published results suggest minimal complications and high patient satisfaction. However, in our practice, we identified several patients presenting for IPP revision after high submuscular placement who were found to have reservoirs within the peritoneal cavity. AIM: Given the potential for complications, we performed a cadaveric study to define the anatomic location of reservoirs placed using this technique. METHODS: We utilized 10 fresh male cadavers without embalming. Bilateral ectopic reservoir placement (10 AMS Conceal [Boston Scientific, Marlborough, MA] and 10 Coloplast Cloverleaf [Coloplast Corp, Humlebaek, Denmark]) was performed using the high submuscular technique via a penoscrotal incision. Strict adherence to published reports detailing the technique was emphasized to assure reliability of findings. MAIN OUTCOME MEASURES: Anatomic dissection was performed to identify reservoir location within the abdominal wall layers. RESULTS: Twenty IPP reservoirs were placed without difficulty or concern for inadvertent malpositioning. Sixteen reservoirs (80%) were found anterior to the transversalis fascia, including 7 (35%) deep to the rectus muscle and 9 (45%) deep to the external oblique fascia and lateral to the rectus muscle belly. Two reservoirs (10%) were identified in the retroperitoneal space, while 1 (5%) was preperitoneal (deep to transversalis fascia) and 1 (5%) was intraperitoneal. CONCLUSION: Placement of IPP reservoirs using the high submuscular technique results in variable anatomic locations, including within or immediately superficial to the peritoneal cavity. Given the lack of immediate recognition and risk of delayed complications with suboptimal reservoir placement, further studies are mandated to assess the long-term safety of the technique. PMID- 27475240 TI - Patient-Reported Esthetic and Functional Outcomes of Primary Total Laparoscopic Intestinal Vaginoplasty in Transgender Women With Penoscrotal Hypoplasia. AB - INTRODUCTION: Puberty-suppressing hormonal treatment may result in penoscrotal hypoplasia in transgender women, making standard penile inversion vaginoplasty not feasible. For these patients, intestinal vaginoplasty is a surgical alternative, but knowledge on patient-reported postoperative outcomes and quality of life is lacking. AIMS: To assess patient-reported functional and esthetic outcomes, quality of life, satisfaction, and sexual well-being after primary total laparoscopic intestinal vaginoplasty in transgender women. METHODS: A survey study was performed on transgender women who underwent primary total laparoscopic intestinal vaginoplasty with at least 1 year of clinical follow-up. Thirty-one transgender women completed the questionnaires (median age at time of surgery = 19.1 years, range = 18.3-45.0) after a median clinical follow-up of 2.2 years (range = 0.8-7.5). Consenting women were asked to complete a combined questionnaire of the Subjective Happiness Scale, the Satisfaction With Life Scale, Cantril's Ladder of Life Scale, the Female Sexual Function Index, the Female Genital Self-Imaging Scale, the Amsterdam Hyperactive Pelvic Floor Scale Women, and a questionnaire addressing postoperative satisfaction. MAIN OUTCOME MEASURES: Patient-reported functional and esthetic outcomes and postoperative quality of life. RESULTS: Patients graded their life satisfaction a median of 8.0 (range = 4.0-10.0) on Cantril's Ladder of Life Scale. Patients scored a mean total score of 27.7 +/- 5.8 on the Satisfaction With Life Scale, which indicated high satisfaction with life, and a mean total score of 5.6 +/- 1.4 on the Subjective Happiness Scale. Functionality was graded a median score of 8.0 of 10 (range = 1.0-10.0) and esthetics a score of 8.0 out of 10 (range = 3.0-10.0). The mean Female Sexual Function Index total score of sexually active transgender women was 26.0 +/- 6.8. CONCLUSION: This group of relatively young transgender women reported satisfactory functional and esthetic results of the neovagina and a good quality of life, despite low Female Sexual Function Index scores. PMID- 27475241 TI - Effect of 5alpha-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials. AB - INTRODUCTION: 5alpha-Reductase inhibitors (5ARIs) are widely used for the treatment of benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA). AIM: To review all the available data on the effect of 5ARIs on sexual function and assess whether 5ARIs increase the risk of sexual dysfunction. METHODS: A systematic search of the literature was conducted using the Medline, Embase, and Cochrane databases. The search was limited to articles published in English and up to October 2015. Article selection proceeded according to the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Data were analyzed using Stata 12.0. A fixed- or a random-effects model was used to calculate the overall combined risk estimates. Publication bias was assessed using Begg and Egger tests. MAIN OUTCOME MEASURES: Sexual dysfunction, erectile dysfunction, and decreased libido. RESULTS: After screening 493 articles, 17 randomized controlled trials with 17,494 patients were included. Nine studies evaluated the efficacy of 5ARIs in men with BPH. The other eight reported using 5ARIs in the treatment of men with AGA. The mean age of participants was 60.10 years across all studies. We included 10 trials (6,779 patients) on the efficacy and safety of finasteride, 4 trials (6,222 patients) on the safety and tolerability of dutasteride, and 3 trials (4,493 patients) using finasteride and dutasteride for AGA. The pooled relative risks for sexual dysfunction were 2.56 (95% CI = 1.48-4.42) in men with BPH and 1.21 (95% CI = 0.85-1.72) in men with AGA; those for erectile dysfunction were 1.55 (95% CI = 1.14-2.12) in men with BPH and 0.66 (95% CI = 0.20-2.25) in men with AGA; and those for decreased libido were 1.69 (95% CI = 1.03-2.79) in men with BPH and 1.16 (95% CI = 0.50-2.72) in men with AGA. Estimates of the total effects were generally consistent with the sensitivity analysis. No evidence of publication bias was observed. CONCLUSION: Evidence from the randomized controlled trials suggested that 5ARIs were associated with increased adverse effects on sexual function in men with BPH compared with placebo. However, the association was not statistically significant in men with AGA. Well-designed randomized controlled trials are indicated to study further the mechanism and effects of 5ARIs on sexual function. PMID- 27475242 TI - Optimizing Irreversible Electroporation Ablation with a Bipolar Electrode. AB - PURPOSE: To optimize single-insertion bipolar irreversible electroporation (IRE) by characterizing effects of electric parameters and controlling tissue electric properties in a porcine model. MATERIALS AND METHODS: Single-insertion electrode bipolar IRE was performed in 28 in vivo pig livers (78 ablations). First, effects of voltage (2,700-3,000 V), number of pulses, repeated cycles (1-6 cycles), and pulse width (70-100 us) were studied. Next, electric conductivity was altered by instillation of hypertonic and hypotonic fluids. Finally, effects of thermal stabilization were assessed using internal electrode cooling. Treatment effect was evaluated 2-3 hours after IRE. Dimensions were compared and subjected to statistical analysis. RESULTS: Delivering 3,000 V at 70 us for a single 90-pulse cycle yielded 3.8 cm +/- 0.4 * 2.0 cm +/- 0.3 of ablation. Applying 6 cycles of energy increased ablation to 4.5 cm +/- 0.4 * 2.6 cm +/- 0.3 (P < .001). Further increasing pulse lengths to 100 us (6 cycles) increased ablation to 5.0 cm +/- 0.4 * 2.9 cm +/- 0.3 (P < .001) but resulted in electric spikes and system crashes in 40%-50% of cases. Increasing tissue electric conductivity via hypertonic solution instillation in surrounding tissues increased frequency of generator crashes, whereas continuous instillation of distilled water eliminated this arcing phenomenon but reduced ablation to 2.3 cm +/- 0.1. Controlled instillation of distilled water when electric arcing was suspected from audible popping produced ablations of 5.3 cm +/- 0.6 * 3.1 cm +/-0.3 without crashes. Finally, 3.1 cm +/- 0.1 short-axis ablation was achieved without system crashes with internal electrode perfusion at 37 degrees C versus 2.3 cm +/- 0.1 with 4 degrees C-10 degrees C perfusion (P < .001). CONCLUSIONS: Bipolar IRE ablation zones can be increased with repetitive high voltage and greater pulse widths accompanied by either judicious instillation of hypotonic fluids or internal electrode perfusion to minimize unwanted electric arcing. PMID- 27475243 TI - Iodination improves the phototoxicity of an amphiphilic porphyrin. PMID- 27475244 TI - Chylothorax due to Upper-Extremity Deep Vein Thrombosis. PMID- 27475245 TI - A New Concept in Maintaining the Emergence Profile in Immediate Posterior Implant Placement: The Anatomic Harmony Abutment. AB - As the knowledge base in the demanding realm of esthetic management of anterior implant sites continues to expand, there exists a void in the literature on solutions to accelerate posterior implant protocols. This article proposes a new protocol using the anatomic harmony abutment for immediate molar implant placement. This technique preserves the anatomic emergence form with sutureless implant site sealing and improves the predictability of final restoration fabrication and delivery. The purpose of this report is to describe this concept and its numerous benefits to patients, surgeons, laboratories, and restorative dentists. PMID- 27475246 TI - Morbidity and Mortality Rates After Maxillomandibular Advancement for Treatment of Obstructive Sleep Apnea. PMID- 27475247 TI - Patient-Centered Measures of Oral and Maxillofacial Surgery Quality. PMID- 27475248 TI - Urinary KIM-1, but not urinary cystatin C, should be corrected for urinary creatinine. AB - OBJECTIVES: The interest for tubular damage markers such as urinary cystatin C (U CystC) and kidney injury molecule-1 (U-KIM-1) grows, especially for the diagnosis of acute kidney injury. The trend to measure proteins in spot urine samples instead of 24-h urine collections calls for adjustment of urine dilution with urinary creatinine (UCr). However, it is not known whether UCr adjustment provides a more true value of basal U-CystC and U-KIM-1 levels than absolute values. DESIGN & METHODS: This study examines the rationale for UCr correction for U-CystC and U-KIM-1 by exploring the linear relations between U-CystC and U KIM-1 and UCr, respectively, and the biological day to day variation of absolute concentrations and UCr adjusted values of the two biomarkers. RESULTS: Both U CystC and U-KIM-1 concentrations correlated positively with UCr (R=0.37, P<0.001 and R=0.62, P<0.001, respectively) in 378 participants in a community cohort, which indicated a rationale for adjustment with UCr. However, U-CystC/Cr ratio associated negatively with UCr (R=- 0.31, P<0.001), which could indicate a certain amount of 'over-adjustment'. Morning urine collected for 10 consecutive days from 13 healthy volunteers showed a biological day to day variation of 82% for U-CystC, 75% for U-cystC/Cr ratio, 70% for U-KIM-1 and 46% for U-KIM-1/Cr ratio. CONCLUSIONS: This study supports the use of U-KIM-1/Cr ratio in clinical population studies. Data supporting the use of U-CysC/U-Cr ratio were less convincing and the possible confounding of UCr has to be acknowledged in clinical settings. PMID- 27475249 TI - Investigation into the interference of the monoclonal antibody daratumumab on the free light chain assay. AB - OBJECTIVES: Recently monoclonal antibody therapy has been introduced in the treatment of multiple Myeloma (MM). One such efficacious therapy is the anti-CD38 monoclonal antibody, daratumumab (Dara). Since it is an Ig-G-kappa it can interfere with both the serum protein electrophoresis and immunofixation electrophoresis (IFE). The free light chain (FLC) assay is also useful in the diagnosis and therapeutic monitoring of MM. Hence we tested the effect of Dara on the FLC assay. METHODS: 30 serum samples from patients with known IgG-kappa (n=20) and non-IgG-kappa M -proteins (n=10) were spiked with Dara at a final concentration of 1.0mg/mL and the FLC performed on samples. On a further 20 samples we performed IFE to determine the migration of Dara. RESULTS: On IFE, Dara migrated in the same area of the gamma zone. In the 30 samples in which we assayed FLC there was no significant differences in levels of kappa, lambda and the ratio of kappa to lambda between untreated and Dara-spiked samples. CONCLUSION: Whilst Dara can interfere with the IFE to determine clinical responses the FLC assay can be useful in patients who have abnormal FLC ratios prior to Dara therapy to determine responses especially in IgG-kappa Myeloma. PMID- 27475250 TI - Human t-DARPP is induced during striatal development. AB - Human Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32kDa (DARPP-32, also known as PPP1R1B) gene codes for different transcripts that are mainly translated into two DARPP-32 protein isoforms, full length (fl)-DARPP-32 and truncated (t)-DARPP. The t-DARPP lacks the first 36 residues at the N terminal, which alters its function. In the central nervous system, fl-DARPP-32 is highly expressed in GABAergic striatal medium spiny neurons (MSNs), where it integrates dopaminergic and glutamatergic input signaling. However, no information about human DARPP-32 isoform expression during MSNs maturation is available. In this study, our aim is to determine the expression of the two DARPP 32 isoforms in human fetal and adult striatal samples. We show that DARPP-32 isoform expression is differentially regulated during human striatal development, with the t-DARPP isoform being virtually absent from whole ganglionic eminence (WGE) and highly induced in the adult striatum (in both caudate and putamen). We next compared the four most common anti-DARPP-32 antibodies used in human specimens, to study their recognition of the two isoforms in fetal and adult human striatal samples by western blot and immunohistochemistry. The four antibodies specifically identify the fl-DARPP-32 in both fetal and adult samples, while t-DARPP form was only detected in adult striatal samples. In addition, the lack of t-DARPP recognition in human adult striatum by the antibody generated against the full-length domain produces in turn different efficacy by immunohistochemical analysis. In conclusion, our results show that expression of human DARPP-32 protein isoforms depends on the striatal neurodevelopmental stage with t-DARPP being specific for the human adult striatum. PMID- 27475251 TI - Short-term dietary restriction in old zebrafish changes cell senescence mechanisms. AB - Brain aging is marked by a decline in cognitive abilities and associated with neurodegenerative disorders. Recent studies have shown, neurogenesis continues into adulthood but is known to be decreasing during advancing age and these changes may contribute to cognitive alterations. Advances, which aim to promote better aging are of paramount importance. Dietary restriction (DR) is the only non-genetic intervention that reliably extends life- and health-span. Mechanisms of how and why DR and age affect neurogenesis are not well-understood, and have not been utilized much in the zebrafish, which has become a popular model to study brain aging and neurodegenerative disease due to widely available genetic tools. In this study we used young (8-8.5months) and old (26-32.5months) zebrafish as the model to investigate the effects of a short-term DR on actively proliferating cells. We successfully applied a 10-week DR to young and old fish, which resulted in a significant loss of body weight in both groups with no effect on normal age-related changes in body growth. We found that age decreased cell proliferation and increased senescence associated beta-galactosidase, as well as shortened telomere lengths. In contrast, DR shortened telomere lengths only in young animals. Neither age nor DR changed the differentiation patterns of glial cells. Our results suggest that the potential effects of DR could be mediated by telomere regulation and whether these are beneficial or negative remains to be determined. PMID- 27475252 TI - My Way: Noncanonical Biosynthesis Pathways for Plant Volatiles. AB - Plant volatiles are crucial for various interactions with other organisms and their surrounding environment. A large number of these volatiles belong to the terpenoid and benzenoid/phenylpropanoid classes, which have long been considered to be exclusively synthesized from a few canonical pathways. However, several alternative pathways producing these plant volatiles have been discovered recently. This review summarizes the current knowledge about new pathways for these two major groups of plant volatiles, which open new perspectives for applications in metabolic engineering. PMID- 27475253 TI - Trends and Challenges in Pesticide Resistance Detection. AB - Pesticide resistance is a crucial factor to be considered when developing strategies for the minimal use of pesticides while maintaining pesticide efficacy. This goal requires monitoring the emergence and development of resistance to pesticides in crop pests. To this end, various methods for resistance diagnosis have been developed for different groups of pests. This review provides an overview of biological, biochemical, and molecular methods that are currently used to detect and quantify pesticide resistance. The agronomic, technical, and economic advantages and drawbacks of each method are considered. Emerging technologies are also described, with their associated challenges and their potential for the detection of resistance mechanisms likely to be selected by current and future plant protection methods. PMID- 27475254 TI - Perceived distress tolerance accounts for the covariance between discrimination experiences and anxiety symptoms among sexual minority adults. AB - Sexual orientation-related discrimination experiences have been implicated in elevated rates of anxiety symptoms within sexual minority groups. Theory suggests that chronic discrimination experiences may dampen the ability to tolerate distress, increasing vulnerability for anxiety. This study examined the role of distress tolerance, or the capacity to withstand negative emotions, as a construct underlying associations between discriminatory experiences and anxiety among sexual minority adults. Participants (N=119;Mage=36.4+/-14.8; 50% cisgender male, 31% cisgender female, 19% transgender; 37% non-Latino white) were recruited from Houston, Texas. Measures administered included the Heterosexist Harassment, Rejection, and Discrimination Scale (discrimination experiences), Distress Tolerance Scale (distress tolerance), and the State-Trait Inventory for Cognitive and Somatic Anxiety (anxiety). The association of discrimination experiences and anxiety through distress tolerance was assessed using covariate-adjusted mediation modeling. Results indicated that sexual orientation-related discrimination experiences were significantly and positively associated with anxiety and that this association was mediated through lower distress tolerance. Significant indirect effects were specific to cognitive (versus somatic) anxiety symptoms. Results suggest that distress tolerance may be an explanatory mechanism in the association between discriminatory experiences and cognitive symptoms of anxiety and a potentially relevant target within clinical interventions to address anxiety-related health disparities among sexual minority adults. However, more sophisticated designs are needed to delineate causal associations. PMID- 27475255 TI - Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency related postmenopausal obesity and hepatic steatosis in mice. AB - : Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, have emerged as putative therapeutic targets for obesity and NAFLD. AIM OF THIS STUDY: to evaluate the efficacy of selective agonists INT747/obeticholic acid (FXR) and INT777 (TGR5) as novel treatments for the metabolic effects of oestrogen deficiency. Ovariectomized (OVX) or sham-operated (SHAM) mice were fed a high-fat diet (HFD) for 5weeks. During the last 4weeks two groups of OVX and SHAM mice received either INT747- or INT777-supplemented HFD. OVX mice had significantly higher bodyweight gain than SHAM mice, which was attenuated by INT747- or INT777-treatment. No significant changes in food intake or physical activity were found. OVX mice had significantly lower energy expenditure than SHAM mice; INT747- and INT777-treated OVX mice had intermediate energy expenditure. Liver triglyceride and cholesterol content was significantly increased in OVX compared to SHAM mice, which was normalized by INT747- or INT777-treatment. Significant changes in metabolic gene expression were found in liver (Cpt1, Acox1), muscle (Ucp3, Pdk4, Cpt1, Acox1, Fasn, Fgf21), brown adipocytes (Dio2) and white adipocytes (c/EBPalpha, Ppargamma, Adipoq). For the first time, expression of FXR and induction of its target gene Pltp1 was shown in skeletal muscle. BA receptor agonists are suitable therapeutics to correct postmenopausal metabolic changes in an OVX mouse model. Potential mechanisms include increased energy expenditure and changes in expression patterns of key metabolic genes in liver, muscle and adipose tissues. PMID- 27475256 TI - Novel miR-5582-5p functions as a tumor suppressor by inducing apoptosis and cell cycle arrest in cancer cells through direct targeting of GAB1, SHC1, and CDK2. AB - MicroRNAs (miRNAs) play pivotal roles in tumorigenesis as either tumor suppressors or oncogenes. In the present study, we discovered and demonstrated the tumor suppressive function of a novel miRNA miR-5582-5p. miR-5582-5p induced apoptosis and cell cycle arrest in cancer cells, but not in normal cells. GAB1, SHC1, and CDK2 were identified as direct targets of miR-5582-5p. Knockdown of GAB1/SHC1 or CDK2 phenocopied the apoptotic or cell cycle arrest-inducing function of miR-5582-5p, respectively. The expression of miR-5582-5p was lower in tumor tissues than in adjacent normal tissues of colorectal cancer patients, while the expression of the target proteins exhibited patterns opposite to that of miR-5582-5p. Intratumoral injection of a miR-5582-5p mimic or induced expression of miR-5582-5p in tumor cells suppressed tumor growth in HCT116 xenografts. Collectively, our results suggest a novel tumor suppressive function for miR-5582-5p and its potential applicability for tumor control. PMID- 27475257 TI - Staphylococcus aureus protein A enhances osteoclastogenesis via TNFR1 and EGFR signaling. PMID- 27475258 TI - Impact of Insurance Type on Initial Rejection Post Heart Transplant. AB - BACKGROUND: Heart transplantation allocation is often restricted from patients with low socioeconomic status (SES) due to concern for worse outcomes. We hypothesised that comorbidities would have a greater impact on risk of severe rejection post-orthotopic heart transplant than would Medicaid insurance and Median Household Income (MHI). METHODS: A retrospective study of 171 patients who underwent orthotopic heart transplant between 7/1999-11/2013 at our facility were followed until 9/2014 for rejection hospitalisations or death. Survival and multivariable analyses with adjustment for age, race, and gender were performed to estimate the risk of severe cellular rejection, >=2r (hazard ratio [HR], 95% confidence interval [CI]). RESULTS: Eighteen per cent of patients had Medicaid, and 72% of patients had low or medium MHI. Severe rejection occurred in 23% of patients. In the univariable analysis, Medicaid and diabetes were associated with increased risk of rejection while age >60 years, Caucasian race, and male sex were associated with reduced risk [Medicaid 2.32(1.20,4.51), diabetes 2.49(1.09,5.69), age 0.41(0.20,0.84), Caucasian 0.44(0.21,0.93), male 0.49(0.26,0.92)]. Median Household Income had no correlation [MHI 0.79(0.51,1.23)]. In the multivariable adjusted model, Medicaid was not associated with rejection [1.65(0.79,3.41)]; diabetes was strongly associated with risk of severe rejection [3.9(1.59,9.39)], and age >60 years was associated with risk reduction [0.42(0.20,0.82)]. CONCLUSIONS: Medicaid insurance and MHI were not associated with increased risk of severe cellular rejection requiring hospitalisation post-orthotopic heart transplant in the adjusted model. Rather the presence of diabetes and age <=60 years were associated with increased risk. PMID- 27475259 TI - Pulmonary Hypertension due to Radiofrequency Catheter Ablation (RFCA) for Atrial Fibrillation: The Lungs, the Atrium or the Ventricle? AB - Atrial fibrillation is the most common heart rhythm disorder in United States, characterised by rapid and irregular beating of both the atria resulting in the similar ventricular response. While rate and rhythm control using pharmacological regimens remain the primary management strategies in these patients, radiofrequency catheter ablation (RFCA) is rapidly rising as an alternative modality of treatment. Increase in the incidence of RFCA has shed light on complications associated with this procedure. Pulmonary hypertension (PH) is one of the long-term complications that has been observed postcatheter ablation. There have been multiple mechanisms which have been proposed to explain these elevated pulmonary pressures. These include the involvement of the lungs due to pulmonary vein stenosis, pulmonary vein occlusion and, rarely, pulmonary embolism. Radiofrequency catheter ablation can also lead to scarring of the atrium which can cause left atrial diastolic dysfunction leading to elevated pulmonary pressures. Recently, it was also proposed that elevated pulmonary pressure was related to the unmasking of left ventricular diastolic dysfunction occurring after this procedure. In this article, we review all the mechanisms that are associated with the development of pulmonary hypertension in patients undergoing RCFA for atrial fibrillation and the approach to diagnosis and management of such patients. PMID- 27475260 TI - Takotsubo Cardiomyopathy Due to Systemic Absorption of Intraocular Phenylephrine. AB - We present a case of Takotsubo cardiomyopathy (TTC) with regional variation in left ventricular function precipitated by intraocular injection of phenylephrine. To our knowledge, this is the first described case of TTC occurring in the setting of an intraocular medication. Contrary to the traditional model of the beta2-receptor underlying the pathophysiology behind Takotsubo cardiomyopathy, phenylephrine is a pure alpha1-agonist implicating alternative mechanisms of myocardial injury resulting in a similar clinical phenotype. One should be alert to the possibility of catecholamine induced TTC occurring in patients subject to medications administered via the intraocular route with the potential for significant systemic absorption. PMID- 27475261 TI - Pacemaker Use in New Zealand - Data From the New Zealand Implanted Cardiac Device Registry (ANZACS-QI 15). AB - BACKGROUND: The New Zealand Cardiac Implanted Device Registry (Device) has recently been developed under the auspices of the New Zealand Branch of the Cardiac Society of Australia and New Zealand. This study describes the initial Device registry cohort of patients receiving a new pacemaker, their indications for pacing and their perioperative complications. METHODS: The Device Registry was used to audit patients receiving a first pacemaker between 1st January 2014 and 1st June 2015. RESULTS: We examined 1611 patients undergoing first pacemaker implantation. Patients were predominantly male (59%), and had a median age of 70 years. The most common symptom for pacemaker implantation was syncope (39%), followed by dizziness (30%) and dyspnoea (12%). The most common aetiology for a pacemaker was a conduction tissue disorder (35%), followed by sinus node dysfunction (22%). Atrioventricular (AV) block was the most common ECG abnormality, present in 44%. Dual chamber pacemakers were most common (62%), followed by single chamber ventricular pacemakers (34%), and cardiac resynchronisation therapy - pacemakers (CRT-P) (2%). Complications within 24hours of the implant procedure were reported in 64 patients (3.9%), none of which were fatal. The most common complication was the need for reoperation to manipulate a lead, occurring in 23 patients (1.4%). CONCLUSION: This is the first description of data entered into the Device registry. Patients receiving a pacemaker were younger than in European registries, and there was a low use of CRT-P devices compared to international rates. Complications rates were low and compare favourably to available international data. PMID- 27475262 TI - Renin angiotensin system blockade reduces urinary levels of soluble urokinase plasminogen activator receptor (suPAR) in patients with type 2 diabetes. AB - Soluble urokinase plasminogen activator receptor (suPAR) is associated with faster decline in kidney function and the pathogenesis of diabetic nephropathy. However, little is known about the impact of treatment on plasma and urinary levels of suPAR. We aimed to investigate the impact of renin angiotensin system (RAS) single and dual blockade on suPAR levels in patients with type 2 diabetes and albuminuria. We conducted a post-hoc analysis of a randomized controlled crossover trial. Urine and plasma samples were analyzed for suPAR levels. The placebo period was considered reference and all treatment periods were compared to placebo. Patients (n = 22) were treated for 2-month periods with either placebo, irbesartan 300 mg once daily, aliskiren 300 mg once daily or irbesartan/aliskiren combination in random order. Placebo geometric mean plasma (SEM) levels of suPAR were 3.3 ng/mL (1.1) and urine levels were 4.0 ng/mL (1.1). None of the treatments had significant effects on plasma levels of suPAR compared to placebo. Compared to placebo, irbesartan and combination treatment decreased urinary levels of suPAR significantly (-1.3 ng/mL), while aliskiren did not. In patients with type 2 diabetes urinary levels of suPAR were reduced during RAS blockade treatment, which may contribute to renoprotection. PMID- 27475263 TI - Urinary exosomal microRNA panel unravels novel biomarkers for diagnosis of type 2 diabetic kidney disease. AB - BACKGROUND: A potential approach adopted in the current study is to design a panel based on in silico retrieval of novel miRNAs related to diabetic kidney disease and to evaluate its usefulness in disease diagnosis. PATIENT AND METHODS: In the current study, we measured the differential expression of a 6 miRNA panel in urine pellet and exosome in an initial screening group using syber green-based PCR array. Also, we performed pathway enrichment analysis of the key target genes of these miRNAs. Finally, we selected the most significantly up-regulated miRNAs in DKD, exosomal miR-15b, miR-34a and miR-636, that were measured by real-time PCR in a larger independent set of 180 participants to evaluate their usefulness as novel urine biomarkers for diagnosis diabetic kidney disease. RESULTS: PCR array analysis showed that miR-15b, miR-34a, and miR-636 were upregulated in both urine pellet and exosome of type 2DKD patients. qRT-PCR validation in the larger independent set of participants confirmed the significant up-regulation of these urinary exosomal miRs (P<0.001). Notably, a positive correlation was found between these miRs, serum creatinine and urinary protein creatinine ratio. The sensitivity of this miRs based panel in urine exosomes reached 100% in diagnosis of DKD. CONCLUSION: We identified urinary exosomal miR-15b, miR-34a, and miR-636 as a novel diagnostic panel and a major contributor in the pathogenesis of diabetic kidney disease. PMID- 27475264 TI - The Iowa Gambling Task in Parkinson's disease: A meta-analysis on effects of disease and medication. AB - BACKGROUND: Decision-making under uncertainty as measured by the Iowa Gambling Task has frequently been studied in Parkinson's disease. The dopamine overdose hypothesis assumes that dopaminergic effects follow an inverted U-shaped function, restoring some cognitive functions while overdosing others. The present work quantitatively summarizes disease and medication effects on task performance and evaluates evidence for the dopamine overdose hypothesis of impaired decision making in Parkinson's disease. METHODS: A systematic literature search was performed to identify studies examining the Iowa Gambling Task in patients with Parkinson's disease. Outcomes were quantitatively combined, with separate estimates for the clinical (patients ON medication vs. healthy controls), disease (patients OFF medication vs. healthy controls), and medication effects (patients ON vs. OFF medication). Furthermore, using meta-regression analysis it was explored whether the study characteristics drug level, disease duration, and motor symptoms explained heterogeneous performance between studies. RESULTS: Patients with Parkinson's disease ON dopaminergic medication showed significantly impaired Iowa Gambling Task performance compared to healthy controls. This impairment was not normalized by short-term withdrawal of medication. Heterogeneity across studies was not explained by dopaminergic drug levels, disease durations or motor symptoms. DISCUSSION: While this meta-analysis showed significantly impaired decision-making performance in Parkinson's disease, there was no evidence that this impairment was related to dopamine overdosing. However, only very few studies assessed patients OFF medication and future studies are needed to concentrate on the modulation of dopaminergic drug levels and pay particular attention to problems related to repeated testing. Furthermore, short- vs. long-term medication effects demand further in-depth investigation. PMID- 27475265 TI - Improving low health literacy and patient engagement: A social ecological approach. AB - OBJECTIVE: This article posits four principal objectives related to the overarching goal of broadening the conceptualization of health literacy. We propose a social ecological approach to health literacy and patient engagement by illustrating how this multilevel approach offers an array of strategic options for interventions. DISCUSSION: A social ecological approach supports a broader understanding of health literacy that aligns with increased patient engagement. The ecological model highlights the importance of context, demonstrates how health literacy and patient engagement are inextricably connected, and gives rise to strategies to enhance them both. We illustrate the five multilevel intervention strategies for addressing low health literacy and promoting patient engagement: accumulation, amplification, facilitation, cascade, and convergence strategies. In addition, we provide a theoretical foundation to facilitate the development of interventions to enhance health literacy and ultimately increase patient engagement. CONCLUSIONS: The practice implications of adopting a broader social ecological perspective to address low health literacy shifts the field from thinking about individual educational interventions to how individual interventions may be augmented or supported by interventions at additional levels of influence. The potential benefit of adopting a multilevel intervention approach is that combining interventions could produce synergies that are greater than interventions that only utilize one level of influence. PMID- 27475266 TI - The economic burden of physical inactivity: a global analysis of major non communicable diseases. AB - BACKGROUND: The pandemic of physical inactivity is associated with a range of chronic diseases and early deaths. Despite the well documented disease burden, the economic burden of physical inactivity remains unquantified at the global level. A better understanding of the economic burden could help to inform resource prioritisation and motivate efforts to increase levels of physical activity worldwide. METHODS: Direct health-care costs, productivity losses, and disability-adjusted life-years (DALYs) attributable to physical inactivity were estimated with standardised methods and the best data available for 142 countries, representing 93.2% of the world's population. Direct health-care costs and DALYs were estimated for coronary heart disease, stroke, type 2 diabetes, breast cancer, and colon cancer attributable to physical inactivity. Productivity losses were estimated with a friction cost approach for physical inactivity related mortality. Analyses were based on national physical inactivity prevalence from available countries, and adjusted population attributable fractions (PAFs) associated with physical inactivity for each disease outcome and all-cause mortality. FINDINGS: Conservatively estimated, physical inactivity cost health care systems international $ (INT$) 53.8 billion worldwide in 2013, of which $31.2 billion was paid by the public sector, $12.9 billion by the private sector, and $9.7 billion by households. In addition, physical inactivity related deaths contribute to $13.7 billion in productivity losses, and physical inactivity was responsible for 13.4 million DALYs worldwide. High-income countries bear a larger proportion of economic burden (80.8% of health-care costs and 60.4% of indirect costs), whereas low-income and middle-income countries have a larger proportion of the disease burden (75.0% of DALYs). Sensitivity analyses based on less conservative assumptions led to much higher estimates. INTERPRETATION: In addition to morbidity and premature mortality, physical inactivity is responsible for a substantial economic burden. This paper provides further justification to prioritise promotion of regular physical activity worldwide as part of a comprehensive strategy to reduce non-communicable diseases. FUNDING: None. PMID- 27475267 TI - Pedro Hallal: putting physical activity at the heart of better health. PMID- 27475268 TI - Gender equality in sport for improved public health. PMID- 27475269 TI - Physical activity-time to take it seriously and regularly. PMID- 27475270 TI - Progress in physical activity over the Olympic quadrennium. AB - On the eve of the 2012 summer Olympic Games, the first Lancet Series on physical activity established that physical inactivity was a global pandemic, and global public health action was urgently needed. The present paper summarises progress on the topics covered in the first Series. In the past 4 years, more countries have been monitoring the prevalence of physical inactivity, although evidence of any improvements in prevalence is still scarce. According to emerging evidence on brain health, physical inactivity accounts for about 3.8% of cases of dementia worldwide. An increase in research on the correlates of physical activity in low income and middle-income countries (LMICs) is providing a better evidence base for development of context-relevant interventions. A finding specific to LMICs was that physical inactivity was higher in urban (vs rural) residents, which is a cause for concern because of the global trends toward urbanisation. A small but increasing number of intervention studies from LMICs provide initial evidence that community-based interventions can be effective. Although about 80% of countries reported having national physical activity policies or plans, such policies were operational in only about 56% of countries. There are important barriers to policy implementation that must be overcome before progress in increasing physical activity can be expected. Despite signs of progress, efforts to improve physical activity surveillance, research, capacity for intervention, and policy implementation are needed, especially among LMICs. PMID- 27475271 TI - Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women. AB - BACKGROUND: High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality. METHODS: We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV viewing time instead of daily sitting time. FINDINGS: Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1 005 791 individuals who were followed up for 2-18.1 years, during which 84 609 (8.4%) died. Compared with the referent group (ie, those sitting <4 h/day and in the most active quartile [>35.5 MET-h per week]), mortality rates during follow-up were 12-59% higher in the two lowest quartiles of physical activity (from HR=1.12, 95% CI 1.08-1.16, for the second lowest quartile of physical activity [<16 MET-h per week] and sitting <4 h/day; to HR=1.59, 1.52-1.66, for the lowest quartile of physical activity [<2.5 MET-h per week] and sitting >8 h/day). Daily sitting time was not associated with increased all-cause mortality in those in the most active quartile of physical activity. Compared with the referent (<4 h of sitting per day and highest quartile of physical activity [>35.5 MET-h per week]), there was no increased risk of mortality during follow-up in those who sat for more than 8 h/day but who also reported >35.5 MET-h per week of activity (HR=1.04; 95% CI 0.99-1.10). By contrast, those who sat the least (<4 h/day) and were in the lowest activity quartile (<2.5 MET-h per week) had a significantly increased risk of dying during follow-up (HR=1.27, 95% CI 1.22-1.31). Six studies had data on TV-viewing time (N=465 450; 43 740 deaths). Watching TV for 3 h or more per day was associated with increased mortality regardless of physical activity, except in the most active quartile, where mortality was significantly increased only in people who watched TV for 5 h/day or more (HR=1.16, 1.05-1.28). INTERPRETATION: High levels of moderate intensity physical activity (ie, about 60-75 min per day) seem to eliminate the increased risk of death associated with high sitting time. However, this high activity level attenuates, but does not eliminate the increased risk associated with high TV-viewing time. These results provide further evidence on the benefits of physical activity, particularly in societies where increasing numbers of people have to sit for long hours for work and may also inform future public health recommendations. FUNDING: None. PMID- 27475272 TI - Renewing commitments to physical activity targets in Thailand. PMID- 27475274 TI - Reduce vascular risk to prevent dementia? PMID- 27475273 TI - Scaling up physical activity interventions worldwide: stepping up to larger and smarter approaches to get people moving. AB - The global pandemic of physical inactivity requires a multisectoral, multidisciplinary public-health response. Scaling up interventions that are capable of increasing levels of physical activity in populations across the varying cultural, geographic, social, and economic contexts worldwide is challenging, but feasible. In this paper, we review the factors that could help to achieve this. We use a mixed-methods approach to comprehensively examine these factors, drawing on the best available evidence from both evidence-to-practice and practice-to-evidence methods. Policies to support active living across society are needed, particularly outside the health-care sector, as demonstrated by some of the successful examples of scale up identified in this paper. Researchers, research funders, and practitioners and policymakers in culture, education, health, leisure, planning, and transport, and civil society as a whole, all have a role. We should embrace the challenge of taking action to a higher level, aligning physical activity and health objectives with broader social, environmental, and sustainable development goals. PMID- 27475275 TI - Update on the global pandemic of physical inactivity. PMID- 27475276 TI - Diffusion-weighted magnetic resonance imaging for evaluation of salivary gland function in head and neck cancer patients treated with intensity-modulated radiotherapy. AB - BACKGROUND AND PURPOSES: Permanent xerostomia as a result of radiation-induced salivary gland damage remains a common side effect of radiotherapy (RT) of the head and neck. The purpose of this study was to evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing the post-RT salivary gland function in patients with head and neck cancer (HNC). MATERIALS AND METHODS: In this prospective study, 20 HNC patients scheduled for bilateral neck chemoradiotherapy (CRT) with weekly cisplatin went through diffusion weighted magnetic resonance imaging (DW-MRI) and salivary gland scintigraphy (SGS) prior to and at a mean of six months after completing the treatment. The changes in apparent diffusion coefficient (ADC) before and after treatment were compared with ejection fraction (EF) measured with SGS and the radiation dose absorbed by the salivary glands. RESULTS: As a result of gustatory stimulation with ascorbic acid, the ADC showed a biphasic response with an initial increase and subsequent decrease. This pattern was seen both before and after RT. Post-RT ADC increased as a function of RT dose absorbed by the salivary glands. A moderate statistical correlation between pre- and post-RT ADCs at rest and EF measured with SGS was found. CONCLUSIONS: DW-MRI seems a promising tool for detection of physiological and functional changes in major salivary glands after RT. PMID- 27475277 TI - Skin cancer of the head and neck with gross or microscopic perineural involvement: Patterns of failure. AB - OBJECTIVES: Analyze patterns of failure of patients with head-and-neck cutaneous squamous cell carcinoma with perineural involvement: gross cranial nerve involvement (GCNI), microscopic focal perineural invasion (MFPNI), and microscopic extensive perineural invasion (MEPNI), managed with or without radiotherapy (RT). MATERIALS AND METHODS: Retrospective review: 102 patients with GCNI, MFPNI and MEPNI, observed or treated with RT from 2000 through 2013. The pathology specimens were reviewed for the purpose of the study. RESULTS: 35 patients had GCNI, all irradiated definitely; 37% failed in-field, and two year disease free survival (DFS) rate was 56%. 19/30 patients (63%) with MEPNI without evidence of GCNI received adjuvant RT to the course of the nerves supplying the involved skin. Recurrence-free survival (RFS) in nerves (94% vs. 25%, P=0.01) and DFS (73% vs. 40%, P=0.05) were significantly higher in the irradiated MEPNI patients compared with the observed. 10/37 (27%) patients with MFPNI were irradiated adjuvantly. MFPNI had low rate of neural and overall failure, without significant benefit to irradiation over observation. CONCLUSIONS: In patients with GCNI radiotherapy achieves a substantial chance of disease control. Radiotherapy to nerves at risk in MFPNI did not affect outcome, but in MEPNI it achieved less gross perineural recurrences and better DFS, compared with observation. PMID- 27475278 TI - Clinical implementation of 3D printing in the construction of patient specific bolus for electron beam radiotherapy for non-melanoma skin cancer. AB - BACKGROUND AND PURPOSE: Creating an individualized tissue equivalent material build-up (i.e. bolus) for electron beam radiation therapy is complex and highly labour-intensive. We implemented a new clinical workflow in which 3D printing technology is used to create the bolus. MATERIAL AND METHODS: A patient-specific bolus is designed in the treatment planning system (TPS) and a shell around it is created in the TPS. The shell is printed and subsequently filled with silicone rubber to make the bolus. Before clinical implementation we performed a planning study with 11 patients to evaluate the difference in tumour coverage between the designed 3D-print bolus and the clinically delivered plan with manually created bolus. For the first 15 clinical patients a second CT scan with the 3D-print bolus was performed to verify the geometrical accuracy. RESULTS: The planning study showed that the V85% of the CTV was on average 97% (3D-print) vs 88% (conventional). Geometric comparison of the 3D-print bolus to the originally contoured bolus showed a high similarity (DSC=0.89). The dose distributions on the second CT scan with the 3D print bolus in position showed only small differences in comparison to the original planning CT scan. CONCLUSIONS: The implemented workflow is feasible, patient friendly, safe, and results in high quality dose distributions. This new technique increases time efficiency. PMID- 27475279 TI - Enhancing deep convolutional neural network scheme for breast cancer diagnosis with unlabeled data. AB - In this study we developed a graph based semi-supervised learning (SSL) scheme using deep convolutional neural network (CNN) for breast cancer diagnosis. CNN usually needs a large amount of labeled data for training and fine tuning the parameters, and our proposed scheme only requires a small portion of labeled data in training set. Four modules were included in the diagnosis system: data weighing, feature selection, dividing co-training data labeling, and CNN. 3158 region of interests (ROIs) with each containing a mass extracted from 1874 pairs of mammogram images were used for this study. Among them 100 ROIs were treated as labeled data while the rest were treated as unlabeled. The area under the curve (AUC) observed in our study was 0.8818, and the accuracy of CNN is 0.8243 using the mixed labeled and unlabeled data. PMID- 27475280 TI - Ketogenic diet treatment for pediatric super-refractory status epilepticus. AB - PURPOSE: We aimed to study whether ketogenic diet (KD) therapy leads to resolution of super-refractory status epilepticus in pediatric patients without significant harm. METHOD: A retrospective review was performed at Phoenix Children's Hospital on patients with super-refractory status epilepticus undergoing ketogenic diet therapy from 2011 to 2015. RESULTS: Ten children with super-refractory status epilepticus, ages 2-16 years, were identified. 4/10 patients had immune mediated encephalitis, including Rasmussen encephalitis, anti N-methyl-d-aspartate receptor encephalitis, and post-infectious mycoplasma encephalitis. Other etiologies included Lennox Gastaut Syndrome, non-ketotic hyperglycinemia, PCDH19 and GABRG2 genetic epilepsy, New Onset Refractory Status Epilepticus, and Febrile Infection-Related Epilepsy Syndrome. 4/10 patients' EEG features suggested focal with status epilepticus, and 6/10 suggested generalized with status epilepticus. Median hospital length was 61days and median ICU length was 27days. The median number of antiepileptic medications prior to diet initiation was 3.0 drugs, and the median after ketogenic diet treatment was 3.5 drugs. Median duration of status epilepticus prior to KD was 18days. 9/10 patients had resolution of super-refractory status epilepticus in a median of 7days after diet initiation. 8/9 patients were weaned off anesthesia within 15days of diet initiation, and within 1day of achieving ketonuria. 1/10 patients experienced side effects on the diet requiring supplementation. CONCLUSION: Most patients achieved resolution of status epilepticus on KD therapy, suggesting it could be an effective therapy that can be utilized early in the treatment of children with super refractory status epilepticus. PMID- 27475282 TI - Assessment of Activities of Daily Living, Self-Care, and Independence. AB - Activities of daily living (ADL) comprise the basic actions that involve caring for one's self and body, including personal care, mobility, and eating. In this review article, we (1) review useful clinical tools including a discussion on ways to approach ADL assessment across settings, (2) highlight relevant literature evaluating the relationship between cognitive functioning and ADLs, (3) discuss other biopsychosocial factors affecting ADL performance, (4) provide clinical recommendations for enhancing ADL capacity with an emphasis on self-care tasks (eating, grooming, dressing, bathing and toileting), and (5) identify interventions that treatment providers can implement to reduce the burden of ADL care. PMID- 27475281 TI - Sulfotyrosine dipeptide: Synthesis and evaluation as HIV-entry inhibitor. AB - Human immunodeficiency virus type 1 (HIV-1) is responsible for the worldwide AIDS pandemic. Due to the lack of prophylactic HIV-1 vaccine, drug treatment of the infected patients becomes essential to reduce the viral load and to slow down progression of the disease. Because of drug resistance, finding new antiviral agents is necessary for AIDS drug therapies. The interaction of gp120 and co receptor (CCR5/CXCR4) mediates the entry of HIV-1 into host cells, which has been increasingly exploited in recent years as the target for new antiviral agents. A conserved co-receptor binding site on gp120 that recognizes sulfotyrosine (sTyr) residues represents a structural target to design novel HIV entry inhibitors. In this work, we developed an efficient synthesis of sulfotyrosine dipeptide and evaluated it as an HIV-1 entry inhibitor. PMID- 27475283 TI - Glucose homeostasis, insulin resistance and inflammatory biomarkers in patients with non-alcoholic fatty liver disease: Beneficial effects of supplementation with microalgae Chlorella vulgaris: A double-blind placebo-controlled randomized clinical trial. AB - BACKGROUND: Chlorella vulgaris (C. vulgaris) is reported to improve dyslipidemia and hypertension; however, its effect on inflammatory biomarkers and insulin resistance has not been noticed thus far. Non-alcoholic fatty liver disease (NAFLD) as a hepatic symptom of metabolic syndrome is strongly associated with insulin resistance and inflammation. AIM OF THE STUDY: In the current interventional trial, we aimed to study the effects of C. vulgaris supplementation on glucose homeostasis, insulin resistance and inflammatory biomarkers in patients with NAFLD. METHODS: Seventy NAFLD patients confirmed by ultra-sonographic findings were randomly assigned into intervention group (four 300 mg tablets of C. vulgaris) or placebo group (four 300 mg tablets of placebos) for 8 weeks. Anthropometric measurements, liver enzymes, fasting serum glucose (FSG), insulin, high sensitive C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-alpha) were assessed and homeostatic model assessment (HOMA) score for insulin resistance was estimated before and after the intervention. RESULTS: Anthropometric measurements decreased significantly in both group (p < 0.001). However, mean reduction in weight was significantly higher in C. vulgaris - treated group compared to placebo group. Serum concentrations of liver enzymes, FSG and hs-CRP also significantly decreased and serum insulin concentration and HOMA score increased significantly only in C. vulgaris-treated group (P < 0.001, P < 0.006 and P < 0.025, respectively). Mean change in serum glucose and TNF alpha levels were significant between the groups even after adjusting for the serum insulin and baseline values of variables (P = 0.014, P = 0.005, P = 0.014, respectively); between-group differences were not significant for the other variables by the end of study. CONCLUSION: To our finding, C. vulgaris supplementation could be considered as an adjunctive therapy to decrease weight and improve glycemic status and reducing hs-CRP as well as improving liver function in patients with NAFLD. IRCT NUMBER: 201202233320N7. PMID- 27475284 TI - Rates of past-year alcohol treatment across two time metrics and differences by alcohol use disorder severity and mental health comorbidities. AB - INTRODUCTION: Little is known about how alcohol treatment rates vary across age or years since onset of an alcohol use disorder (AUD). We examined past-year treatment prevalence and associations across these important time metrics. METHOD: Data on 22,278 adults ages 18-50 were from the National Epidemiologic Survey on Alcohol and Related Conditions-III (2012-2013). We examined the age varying prevalence of alcohol treatment and associations of past-year AUD severity, MDD status, and DUD status with treatment. Additionally, for individuals with a lifetime AUD (N=7089), we examined associations of severity, MDD, and DUD across years since AUD onset. RESULTS: Individuals with Moderate/Severe past-year AUD had significantly higher treatment rates at nearly all ages, compared to those with Mild or no AUD. For those with Moderate/Severe AUD, treatment rates were highest during late adolescence and middle adulthood and lowest during early adulthood. Mental health comorbidities were positively associated with treatment at certain age ranges in mid-adulthood. Among individuals with a lifetime AUD, those with Moderate/Severe past-year AUD had significantly higher past-year treatment rates across all years since onset. MDD and DUD were both positively associated with treatment at nearly all years since AUD onset. CONCLUSIONS: Alcohol treatment rates varied notably by age and, to a lesser extent, by years since AUD onset. Greater AUD severity was consistently associated with higher rates of treatment, whereas Mild AUD had a much weaker relationship. MDD and DUD showed similar patterns of positive association with treatment. Our results highlight important subgroups where unmet treatment needs are highest. PMID- 27475285 TI - Inhibition of PAR-4 and P2Y12 receptor-mediated platelet activation produces distinct hepatic pathologies in experimental xenobiotic-induced cholestatic liver disease. AB - Emerging evidence supports a protective effect of platelets in experimental cholestatic liver injury and cholangiofibrosis. Coagulation-mediated platelet activation has been shown to inhibit experimental chronic cholestatic liver necrosis and biliary fibrosis. This occurs through thrombin-mediated activation of protease activated receptor-4 (PAR-4) in mice. However, it is not known whether other pathways of platelet activation, such as adenosine diphosphate (ADP)-mediated receptor P2Y12 activation is also protective. We tested the hypothesis that inhibition of P2Y12-mediated platelet activation exacerbates hepatic injury and cholangiofibrosis, and examined the impact of P2Y12 inhibition in both the presence and absence of PAR-4. Treatment of wild-type mice with the P2Y12 receptor antagonist clopidogrel increased biliary hyperplasia and cholangiofibrosis in wild-type mice exposed to the xenobiotic alpha naphthylisothiocyanate (ANIT) for 4 weeks compared to vehicle-treated mice exposed to ANIT. Interestingly, this effect of clopidogrel occurred without a corresponding increase in hepatocellular necrosis. Whereas biliary hyperplasia and cholangiofibrosis were increased in PAR-4(-/-) mice, clopidogrel treatment failed to further increase these pathologies in PAR-4(-/-) mice. The results indicate that inhibition of receptor P2Y12-mediated platelet activation exacerbates bile duct fibrosis in ANIT-exposed mice, independent of hepatocellular necrosis. Moreover, the lack of an added effect of clopidogrel administration on the exaggerated pathology in ANIT-exposed PAR-4(-/-) mice reinforces the prevailing importance of coagulation-mediated platelet activation in limiting this unique liver pathology. PMID- 27475286 TI - Biological effects of double-walled carbon nanotubes on the innate immune system: An in vitro study on THP-1 human monocytes. AB - DWCNTs have numerous industrial and biomedical applications and several studies reported that they could act as immunomodulator systems. The immune system is the first line of defence of the human body when exposed to particulate matter. In order to investigate DWCNTs' role on innate immunity, we used THP-1 monocytic cells for the purpose of this study. We showed that DWCNTs were not cytotoxic until 6h, 24h, 48h and 72h of incubation with THP-1 monocytic cells (concentrations tested from 10 to 50MUg/mL). From 6h to 72h of incubation of THP 1 cells with DWCNTs, we measured a significant increase of the baseline cell index using xCELLigence((r)) technology showing cell adhesion. After 24h of exposure, DWCNTs agglomerates were localized in THP-1 monocyte cytoplasm and cell adhesion was observed simultaneously with a significant increase in the expression of CD11b and CD14 cell surface proteins. Pro-inflammatory cytokine secretion (IL-1beta, IL-6, IL-8, TNF-alpha and IL-10) was also measured in supernatants after 6h or 24h of exposure to DWCNTs. This pro-inflammatory response was increased in THP-1 monocytic cells pre-treated with LPS. Altogether, our data indicate that DWCNTs induce an increased pro-inflammatory response of THP-1 monocytes and seem to modulate cell surface protein expression confirming that DWCNTs could act as stimulators of innate immunity. PMID- 27475287 TI - Do Patient-reported Outcome Measures Agree with Clinical and Photographic Assessments of Normal Tissue Effects after Breast Radiotherapy? PMID- 27475288 TI - Combining Ipilimumab and Bevacizumab in Glioblastoma: Is it Really Safe and Effective? Author Response. PMID- 27475289 TI - The role of symmetry in neural networks and their Laplacian spectra. AB - Human and animal nervous systems constitute complexly wired networks that form the infrastructure for neural processing and integration of information. The organization of these neural networks can be analyzed using the so-called Laplacian spectrum, providing a mathematical tool to produce systems-level network fingerprints. In this article, we examine a characteristic central peak in the spectrum of neural networks, including anatomical brain network maps of the mouse, cat and macaque, as well as anatomical and functional network maps of human brain connectivity. We link the occurrence of this central peak to the level of symmetry in neural networks, an intriguing aspect of network organization resulting from network elements that exhibit similar wiring patterns. Specifically, we propose a measure to capture the global level of symmetry of a network and show that, for both empirical networks and network models, the height of the main peak in the Laplacian spectrum is strongly related to node symmetry in the underlying network. Moreover, examination of spectra of duplication-based model networks shows that neural spectra are best approximated using a trade-off between duplication and diversification. Taken together, our results facilitate a better understanding of neural network spectra and the importance of symmetry in neural networks. PMID- 27475291 TI - Midfrontal theta tracks action monitoring over multiple interactive time scales. AB - Quickly detecting and correcting mistakes is a crucial brain function. EEG studies have identified an idiosyncratic electrophysiological signature of online error correction, termed midfrontal theta. Midfrontal theta has so far been investigated over the fast time-scale of a few hundred milliseconds. But several aspects of behavior and brain activity unfold over multiple time scales, displaying "scale-free" dynamics that have been linked to criticality and optimal flexibility when responding to changing environmental demands. Here we used a novel line-tracking task to demonstrate that midfrontal theta is a transient yet non-phase-locked response that is modulated by task performance over at least three time scales: a few hundred milliseconds at the onset of a mistake, task performance over a fixed window of the previous 5s, and scale-free-like fluctuations over many tens of seconds. These findings provide novel evidence for a role of midfrontal theta in online behavioral adaptation, and suggest new approaches for linking EEG signatures of human executive functioning to its neurobiological underpinnings. PMID- 27475290 TI - Evaluation of multi-echo ICA denoising for task based fMRI studies: Block designs, rapid event-related designs, and cardiac-gated fMRI. AB - Multi-echo fMRI, particularly the multi-echo independent component analysis (ME ICA) algorithm, has previously proven useful for increasing the sensitivity and reducing false positives for functional MRI (fMRI) based resting state connectivity studies. Less is known about its efficacy for task-based fMRI, especially at the single subject level. This work, which focuses exclusively on individual subject results, compares ME-ICA to single-echo fMRI and a voxel-wise T2(*) weighted combination of multi-echo data for task-based fMRI under the following scenarios: cardiac-gated block designs, constant repetition time (TR) block designs, and constant TR rapid event-related designs. Performance is evaluated primarily in terms of sensitivity (i.e., activation extent, activation magnitude, percent detected trials and effect size estimates) using five different tasks expected to evoke neuronal activity in a distributed set of regions. The ME-ICA algorithm significantly outperformed all other evaluated processing alternatives in all scenarios. Largest improvements were observed for the cardiac-gated dataset, where ME-ICA was able to reliably detect and remove non-neural T1 signal fluctuations caused by non-constant repetition times. Although ME-ICA also outperformed the other options in terms of percent detection of individual trials for rapid event-related experiments, only 46% of all events were detected after ME-ICA; suggesting additional improvements in sensitivity are required to reliably detect individual short event occurrences. We conclude the manuscript with a detailed evaluation of ME-ICA outcomes and a discussion of how the ME-ICA algorithm could be further improved. Overall, our results suggest that ME-ICA constitutes a versatile, powerful approach for advanced denoising of task based fMRI, not just resting-state data. PMID- 27475292 TI - The preservation of vital functions in cat ovarian tissues during vitrification depends more on the temperature of the cryoprotectant exposure than on the sucrose supplementation. AB - The objective of this study was to better characterize the impact of cryoprotectant exposure (temperature and sucrose supplementation) on the health and function of preantral follicles in ovarian tissues during vitrification using the domestic cat model. Ovarian cortical pieces from peri-pubertal individuals were exposed to cryoprotectants at 4 degrees C or room temperature and supplemented with 0 or 0.5 M of sucrose, followed by vitrification. After rapid warming, cortical pieces were cultured in vitro and assessed for normal follicular morphology, viability and resumption of transcriptional activities for up to 7 days. Throughout the culture period, follicular morphology (up to 67.5% normal follicles) and global RNA transcription (up to 50.9% follicles with transcriptional activity) in warmed tissues were improved by cryoprotectant exposure at 4 degrees C compared to room temperature, but viability (up to 84.6% viable follicles) did not seem to be affected by exposure temperature. Sucrose supplementation did not have a consistent effect as it increased RNA transcription but decreased normal follicular morphology. For the first time, the study demonstrated that the preservation of critical tissue functions, such as the transcriptional activities, highly depends on the temperature of the cryoprotectant exposure and not necessarily on the presence of sucrose. PMID- 27475293 TI - Cystic Fibrosis Papers of the Year 2015. AB - Studies published in the last year have expanded our knowledge of potential disease modifying agents in the treatment of class II, III and IV CFTR mutations, and included the first report of an efficacious gene therapy for CF. There is also an important message on increasing use of conventional chronic therapies even in milder disease, and the pernicious effect of chronic infection on pulmonary function. PMID- 27475294 TI - Smart magnetic markers use in hydraulic fracturing. AB - One of the main challenges and unknowns during shale gas exploration is to assess the range and efficiency of hydraulic fracturing. It is also essential to assess the distribution of proppant, which keeps the fracture pathways open. Solving these problems may considerably increase the efficiency of the shale gas extraction. Because of that, the idea of smart magnetic marker, which can be detected when added to fracturing fluid, has been considered for a long time. This study provides overview of the possibilities of magnetic marker application for shale gas extraction. The imaging methods using electromagnetic markers, are considered or developed in two directions. The first possibility is the markers' electromagnetic activity throughout the whole volume of the fracturing fluid. Thus, it can be assumed that the whole fracturing fluid is the marker. Among these type of hydraulic fracturing solutions, ferrofluid could be considered. The second possibility is marker, which is just one of many components of the fracturing fluid. In this case feedstock magnetic materials, ferrites and nanomaterials could be considered. Magnetic properties of magnetite could be too low and ferrofluids' or nanomaterials' price is unacceptably high. Because of that, ferrites, especially ZnMn ferrites seems to be the best material for magnetic marker. Because of the numerous applications in electronics, it is cheap and easily available, although the price is higher, then that of magnetite. The disadvantage of using ferrite, could be too small mechanical strength. It creates an essential need for combining magnetic marker with proppant into magnetic ceramic composite. PMID- 27475295 TI - Polyaromatic hydrocarbon (PAH) degradation potential of a new acid tolerant, diazotrophic P-solubilizing and heavy metal resistant bacterium Cupriavidus sp. MTS-7 isolated from long-term mixed contaminated soil. AB - An isolate of Cupriavidus (strain MTS-7) was identified from a long-term PAHs and heavy metals mixed contaminated soil with the potential to biodegrade both LMW and HMW PAHs with added unique traits of acid and alkali tolerance, heavy metal tolerance, self-nutrient assimilation by N fixation and P solubilization. This strain completely degraded the model 3 (150 mg L(-1) Phe), 4 (150 mg L(-1) Pyr) and 5 (50 mg L(-1) BaP) ring PAHs in 4, 20 and 30 days, respectively. It could mineralize 90-100% of PAHs (200 mg L(-1) of Phe and Pyr) within 15 days across pH ranging from 5 to 8 and even in the presence of toxic metal contaminations. During biodegradation, the minimum inhibitory concentrations were 5 (Cu(2+)) and 3 (Cd(2+), Pb(2+), Zn(2+)) mg L(-1) of the potentially bioavailable metal ions and over 17 mg L(-1) metal levels was lethal for the microbe. Further, it could fix 217-274 MUg mL(-1) of N and solubilize 79-135 MUg mL(-1) of P while PAHs degradation. MTS-7 as a superior candidate could be thus used in the enhanced bioaugmentation and/or phytoremediation of long-term mixed contaminated sites. PMID- 27475296 TI - Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study. AB - Fluorescence spectroscopy and microscopy have been utilized as tools in membrane biophysics for decades now. Because phospholipids are non-fluorescent, the use of extrinsic membrane probes in this context is commonplace. Among the latter, 1,6 diphenylhexatriene (DPH) and its trimethylammonium derivative (TMA-DPH) have been extensively used. It is widely believed that, owing to its additional charged group, TMA-DPH is anchored at the lipid/water interface and reports on a bilayer region that is distinct from that of the hydrophobic DPH. In this study, we employ atomistic MD simulations to characterize the behavior of DPH and TMA-DPH in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and POPC/cholesterol (4:1) bilayers. We show that although the dynamics of TMA-DPH in these membranes is noticeably more hindered than that of DPH, the location of the average fluorophore of TMA-DPH is only ~3-4A more shallow than that of DPH. The hindrance observed in the translational and rotational motions of TMA-DPH compared to DPH is mainly not due to significant differences in depth, but to the favorable electrostatic interactions of the former with electronegative lipid atoms instead. By revealing detailed insights on the behavior of these two probes, our results are useful both in the interpretation of past work and in the planning of future experiments using them as membrane reporters. PMID- 27475297 TI - Membrane re-arrangements and rippled phase stabilisation by the cell penetrating peptide penetratin. AB - Cell penetrating peptides are promising vectors for molecular drug delivery in eukaryotic cells. Despite of their discovery 20years ago, the mechanisms of peptide membrane crossing are still controversial. The different suggested penetration mechanisms reflect the high sequence and structural diversity of cell penetrating peptides. The fundamental step for peptide penetration into the cytosol is the crossing of the membrane lipid barrier at the level of the plasma membrane or the endosomes. Therefore, the study of the peptide-lipid interaction is the key for peptide penetration mechanisms understanding. In order to study the changes in lipid organisation induced by the cell penetrating peptide penetratin, several experiments by three different physicochemical approaches were performed. X-ray diffraction data shows that penetratin is able to induce membrane phase separation and lipid rearrangements observed by inter-lipid distances. These changes are accompanied by a temperature stable behaviour of some of the induced membrane domains. The membrane environment fluorescent probe laurdan showed that, in DMPC and DMPC/DMPG membranes, the peptide induces de packing of lipids. Calorimetric analyses show that penetratin favours the gel phase to gel-like rippled phase transition. Overall, the data suggest both, that the rippled phase is a heterogeneous structure formed by gel-like and fluid-like coexisting components, and that the penetratin-induced membrane heterogeneity could be important for membrane destabilisation during cell penetration. PMID- 27475299 TI - Molecular cloning of kisspeptin receptor genes (gpr54-1 and gpr54-2) and their expression profiles in the brain of a tropical damselfish during different gonadal stages. AB - The kisspeptin receptor (GPR54) mediates neuroendocrine control of kisspeptin in the brain and acts as a gateway for a pulsatile release of hypothalamic gonadotropin-releasing hormone. This study aimed to clone two GPR54 genes (gpr54 1 and gpr54-2) from the brain of the sapphire devil Chrysiptera cyanea, a tropical damselfish, and to study their involvement in reproduction. The partial sequences of the sapphire devil gpr54-1 cDNA (1059bp) and gpr54-2 cDNA (1098bp) each had an open reading frame encoding a protein of 353 and 366 amino acids, respectively, both of which had structural features of a G-protein-coupled receptor. The expression of gpr54-1 mRNA was observed in the diencephalon and telencephalon, and gpr54-2 mRNA was found in the optic tectum of sapphire devil. When gpr54-1 and gpr54-2 mRNA levels were examined in the brain of sapphire devil by real-time quantitative polymerase chain reaction (qPCR), they were found to increase during late vitellogenesis and post-spawning. Treatment of fish with estradiol-17beta (Epsilon2) resulted in an increase in gpr54-1 and gpr54-2 expression in the brain of sapphire devil. Thus, kisspeptin receptors likely mediate the activity of kisspeptin in the brain and are involved in controlling reproductive events in a tropical damselfish. PMID- 27475298 TI - Mesenchymal stem cell and derived exosome as small RNA carrier and Immunomodulator to improve islet transplantation. AB - Human bone marrow mesenchymal stem cells (hBMSCs) and their exosomes can suppress immune reaction and deliver small RNAs. Thus, they may improve islet transplantation by delivering small RNAs for promoting islet function and inhibiting immune rejection. Here, we proposed an hBMSC and its exosome-based therapy to overcome immune rejection and poor islet function, both of which hinder the success of islet transplantation. We found overexpressed siFas and anti-miR-375 in plasmid encoding shFas and anti-miR-375 transfected hBMSC-derived exosomes, which silenced Fas and miR-375 of human islets and improved their viability and function against inflammatory cytokines. This plasmid transfected hBMSCs downregulated Fas and miR-375 of human islets in a humanized NOD scid gamma (NSG) mouse model, whose immune reaction was inhibited by injecting hBMSC and peripheral blood mononuclear cell (PBMC) co-cultured exosomes. These exosomes suppressed immune reaction by inhibiting PBMC proliferation and enhancing regulatory T cell (Treg) function. Collectively, our studies elucidated the mechanisms of RNA delivery from hBMSCs to human islets and the immunosuppressive effect of hBMSC and peripheral blood mononuclear cell co-cultured exosomes for improving islet transplantation. PMID- 27475300 TI - Dietary antioxidants enhance immunocompetence in larval amphibians. AB - Dietary antioxidants have been shown to confer a variety of benefits through their ability to counter oxidative stress, including increased immunocompetence and reduced susceptibility to both infectious and non-infectious diseases. However, little is known about the effects of dietary antioxidants on immune function in larval amphibians, a group experiencing worldwide declines driven by factors that likely involve altered immunocompetence. We investigated the effects of dietary antioxidants (quercetin, vitamin E, and beta-carotene) on two components of the immune system, as well as development and growth. Lithobates pipiens tadpoles fed diets with supplemental beta-carotene or vitamin E exhibited an enhanced swelling response as measured with a phytohemagglutinin assay (PHA), but there was no induced antibody response. Effects were often dose-dependent, with higher antioxidant levels generally conferring stronger swelling that possibly corresponds to the innate immune response. Our results indicate that the antioxidant content of the larval amphibian diets not only had a detectable effect on their immune response capability, but also promoted tadpole growth (mass gain), although developmental stage was not affected. Given that many environmental perturbations may cause oxidative stress or reduce immunocompetence, it is critical to understand how nutrition may counter these effects. PMID- 27475301 TI - Dietary glucose stimulus at larval stage modifies the carbohydrate metabolic pathway in gilthead seabream (Sparus aurata) juveniles: An in vivo approach using (14)C-starch. AB - The concept of nutritional programming was investigated in order to enhance the use of dietary carbohydrates in gilthead seabream juveniles. We assessed the long term effects of high-glucose stimuli, exerted at the larval stage, on the growth performance, nutrient digestibility and metabolic utilization and gene expression of seabream juveniles, challenged with a high-carbohydrate intake. During early development, a group of larvae (control, CTRL) were kept under a rich-protein lipid feeding regime whereas another group (GLU) was subjected to high-glucose stimuli, delivered intermittently over time. At juvenile stage, triplicate groups (IBW: 2.5g) from each fish nutritional background were fed a high-protein (59.4%) low-carbohydrate (2.0%) diet before being subjected to a low-protein (43.0%) high carbohydrate (33.0%) dietary challenge for 36-days. Fish from both treatments increased by 8-fold their initial body weight, but neither growth rate, feed intake, feed and protein efficiency, nutrient retention (except lipids) nor whole body composition were affected (P?0.05) by fish early nutritional history. Nutrient digestibility was also similar among both groups. The metabolic fate of (14)C-starch and (14)C-amino acids tracers was estimated; GLU juveniles showed higher absorption of starch-derived glucose in the gut, suggesting an enhanced digestion of carbohydrates, while amino acid use was not affected. Moreover, glucose was less used for de novo synthesis of hepatic proteins and muscle glycogen from GLU fish (P<0.05). Our metabolic data suggests that the early glucose stimuli may alter carbohydrate utilization in seabream juveniles. PMID- 27475302 TI - Regression model analysis of the decreasing trend of cesium-137 concentration in the atmosphere since the Fukushima accident. AB - The decreasing trend of the atmospheric 137Cs concentration in two cities in Fukushima prefecture was analyzed by a regression model to clarify the relation between the parameter of the decrease in the model and the trend and to compare the trend with that after the Chernobyl accident. The 137Cs particle concentration measurements were conducted in urban Fukushima and rural Date sites from September 2012 to June 2015. The 137Cs particle concentrations were separated in two groups: particles of more than 1.1 MUm aerodynamic diameters (coarse particles) and particles with aerodynamic diameter lower than 1.1 MUm (fine particles). The averages of the measured concentrations were 0.1 mBq m-3 in Fukushima and Date sites. The measured concentrations were applied in the regression model which decomposed them into two components: trend and seasonal variation. The trend concentration included the parameters for the constant and the exponential decrease. The parameter for the constant was slightly different between the Fukushima and Date sites. The parameter for the exponential decrease was similar for all the cases, and much higher than the value of the physical radioactive decay except for the concentration in the fine particles at the Date site. The annual decreasing rates of the 137Cs concentration evaluated by the trend concentration ranged from 44 to 53% y-1 with average and standard deviation of 49 +/- 8% y-1 for all the cases in 2013. In the other years, the decreasing rates also varied slightly for all cases. These indicated that the decreasing trend of the 137Cs concentration was nearly unchanged for the location and ground contamination level in the three years after the accident. The 137Cs activity per aerosol particle mass also decreased with the same trend as the 137Cs concentration in the atmosphere. The results indicated that the decreasing trend of the atmospheric 137Cs concentration was related with the reduction of the 137Cs concentration in resuspended particles. PMID- 27475303 TI - Development and evaluation of a simple and effective real time PCR assay for mitochondrial quantification in racing camels. AB - Camel racing is a popular sport in the Middle East region, where the demand is high for racing camels with higher stamina and endurance. Devising a technique to measure oxidative capacity and endurance in camels should be useful. Mitochondria are highly specialized organelles involved in metabolism in all higher organisms for sustaining life and providing energy for physical functions. The ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) is often used as an estimate for the metabolic status of the tissue. A greater quantity of mitochondria per unit of tissue translates into greater oxidative capacity and endurance. In this report, we describe a simple, sensitive and efficient real-time PCR assay for the quantification of blood mitochondria in racing camels. The primer sequences selected for the SYBR green-based PCR assay included mitochondrial D-loop region, mitochondrial ATP6ase gene and the nuclear beta-actin gene. The assay was validated using two groups of camels comprising racing and dairy camels. The racing camels demonstrated a higher mtDNA/nDNA ratio compared with dairy camels based on the DeltaDeltaCt values, with a higher variability among racing camels. The mean DeltaDeltaCt values of adult and young racing camels did not vary considerably. The findings show that the present assay can be used as an evaluative tool for racing camels. PMID- 27475304 TI - Dermatophagoides pteronyssinus group 2 allergen bound to 8-OH modified adenine reduces the Th2-mediated airway inflammation without inducing a Th17 response and autoimmunity. AB - 8-OH modified adenine bound to Dermatophagoides pteronyssinus group 2 (nDer p2 Conj), a novel allergen-TLR7 agonist conjugate, improves murine airway inflammation in priming and therapeutic settings, however no data are known on the activity of this construct on Th17 cells. The aim of the study was to evaluate if nDer p2-Conj elicited in vivo Th17 cells and Th17-driven autoimmune responses, by using both short- and long-term priming and therapeutic protocols in a nDer p2-driven model of murine airway inflammation. The conjugate induced the in vitro production of cytokines favouring the Th17 polarization by bone marrow-derived dendritic cells. In short-term protocols, the priming or treatment with the conjugate ameliorated the airway inflammation by shifting Th2 allergen specific cells into T cells producing IFN-gamma, IL-10, but not IL-17A. Similar results were found in long-term protocol where the conjugate down-regulated airway inflammation without any evidence of autoimmune response and B cell compartment expansion. nDer p2-Conj also failed to shorten the spontaneous onset of diabetes on conjugates-primed NOD/LtJ mice. We found that neutrophils in BALF, ROR-gammat and IL-17A expression in lungs were increased in conjugate-treated IL 10KO mice. These data emphasize the role of conjugate-driven IL-10 production, which can regulate the activity of memory Th17 cells and prevent the onset of autoimmune response. PMID- 27475307 TI - Early development and function of the Xenopus tadpole retinotectal circuit. AB - The retinotectal circuit is the major component of the amphibian visual system. It is comprised of the retinal ganglion cells (RGCs) in the eye, which project their axons to the optic tectum and form synapses onto postsynaptic tectal neurons. The retinotectal circuit is relatively simple, and develops quickly: Xenopus tadpoles begin displaying retinotectal-dependent visual avoidance behaviors by approximately 7-8 days post-fertilization, early larval stage. In this review we first provide a summary of the dynamic development of the retinotectal circuit, including the microcircuitry formed by local tectal-tectal connections within the tectum. Second, we discuss the basic visual avoidance behavior generated specifically by this circuit, and how this behavior is being used as an assay to test visual system function. PMID- 27475306 TI - Increased Activation of the TRESK K+ Mediates Vago-Vagal Reflex Malfunction in Diabetic Rats. AB - BACKGROUND & AIMS: Patients with diabetes have defects in the vagal afferent pathway that result in abnormal gastrointestinal function. We investigated whether selective increased activation of the 2-pore domain potassium channel TRESK (2-pore-domain weak inward-rectifying potassium channel-related spinal cord potassium channel) contributes to nodose ganglia (NG) malfunction, disrupting gastrointestinal function in diabetic rats. METHODS: We conducted whole-cell current-clamp and single-unit recordings in NG neurons from diabetes-prone BioBreeding/Worcester rats and streptozotocin-induced diabetic (STZ-D) rats and compared them with control rats. NG neurons in rats or cultured NG neurons were exposed to pharmacologic antagonists and/or transfected with short hairpin or small interfering RNAs that reduced expression of TRESK. We then made electrophysiologic recordings and studied gastrointestinal functions. RESULTS: We observed reduced input resistance, hyperpolarized membrane potential, and increased current threshold to elicit action potentiation in NG neurons of STZ-D rats compared with controls. NG neuron excitability was similarly altered in diabetes-prone rats. In vivo single-unit NG neuronal discharges in response to 30 and 60 pmol cholecystokinin octapeptide were significantly lower in STZ-D rats compared with controls. Reducing expression of the TRESK K+ channel restored NG excitability in vitro and in vivo, as well as cholecystokinin 8-stimulated secretion of pancreatic enzymes and secretin-induced gastrointestinal motility, which are mediated by vago-vagal reflexes. These abnormalities resulted from increased intracellular Ca2+ in the NG, activating calcineurin, which, in turn, bound to an nuclear factor of activated T cell-like docking site on the TRESK protein, resulting in neuronal membrane hyperpolarization. CONCLUSIONS: In 2 rate models of diabetes, we found that activation of the TRESK K+ channel reduced NG excitability and disrupted gastrointestinal functions. PMID- 27475305 TI - Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes. AB - BACKGROUND & AIMS: Aspirin use reduces colorectal cancer risk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell mediated adaptive immunity. We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates. METHODS: We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study. Participants were asked whether they took aspirin in most weeks, the number of tablets taken per week, and years of aspirin use. We collected available tumor specimens (n = 1458) from pathology laboratories in the United States. A pathologist confirmed the diagnosis of colorectal adenocarcinoma (excluding anal squamous cell carcinoma), and evaluated histopathology features, including patterns and degrees of lymphocytic infiltrates within and around tumor areas. Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis, death, or the end of follow-up evaluation (June 2010). Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral reaction, or Crohn's-like reaction. RESULTS: We documented 1458 rectal and colon cancers. The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs (Pheterogeneity = .007). Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63-0.81), and strength of the association depended on aspirin dose and duration (both Ptrend < .001). In contrast, aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs. This differential association was consistent regardless of the status of tumor microsatellite instability, mutations in BRAF, or expression of PTGS2. Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3+ T cells, CD8+ T cells, or CD45RO (PTPRC)+ T cells (measured by immunohistochemistry and computer-assisted image analysis). CONCLUSIONS: Based on data from the prospective cohort studies, regular use of aspirin is associated with a lower risk of colorectal carcinomas with low concentrations of TILs. These findings indicate that the immune response in the tumor microenvironment could be involved in the chemopreventive effects of aspirin. PMID- 27475308 TI - Functional characterization of rainbow trout (Oncorhynchus mykiss) Abcg2a (Bcrp) transporter. AB - ABCG2 (BCRP - breast cancer resistance protein) belongs to the ATP-binding cassette (ABC) superfamily. It plays an important role in the disposition and elimination of xeno- and endobiotics and/or their metabolites in mammals. Likewise, the protective role of ABC transporters, including Abcg2, has been reported for aquatic organisms. In our previous study we have cloned the full gene sequence of rainbow trout (Oncorhynchus mykiss) Abcg2a and showed its high expression in liver and primary hepatocytes. Based on those insights, the main goal of this study was to perform a detailed functional characterization of trout Abcg2a using insect ovary cells (Spodoptera frugiperda, Sf9) as a heterologous expression system. Membrane vesicles preparations from Sf9 cells were used for the ATPase assay determinations and basic biochemical properties of fish Abcg2a versus human ABCG2 have been compared. A series of 39 physiologically and/or environmentally relevant substances was then tested on interaction with trout Abcg2a and human ABCG2. Correlation analysis reveals highly similar pattern of activation and inhibition. Significant activation of trout Abcg2a ATPase was observed for prazosin, doxorubicine, sildenafil, furosemid, propranolol, fenofibrate and pheophorbide. Pesticides showed either a weak activation (malathione) or strong (endosulfan) to weak (chlorpyrifos, fenoxycarb, DDE) inhibition of trout Abcg2a ATPase while the highest activation was obtained for benzo(a)pyrene, curcumine and testosterone. In conclusion, data from this study offer the first characterization of fish Abcg2a, reveal potent interactors among physiologically or environmentally relevant substances and point to similarities regarding strengths and interactor preferences between human ABCG2 and fish Abcg2a. PMID- 27475309 TI - A novel stability-indicating UPLC method development and validation for the determination of seven impurities in various diclofenac pharmaceutical dosage forms. AB - An innovative simple, fast, precise and accurate ultra-high performance liquid chromatography (UPLC) method was developed for the determination of diclofenac (Dic) along with its impurities including the new dimer impurity in various pharmaceutical dosage forms. An Acquity HSS T3 (C18, 100*2.1mm, 1.8MUm) column in gradient mode was used with mobile phase comprising of phosphoric acid, which has a pH value of 2.3 and methanol. The flow rate and the injection volume were set at 0.35ml.min(-1) and 1MUl, respectively, and the UV detection was carried out at 254nm by using photodiode array detector. Dic was subjected to stress conditions from acid, base, hydrolytic, thermal, oxidative and photolytic degradation. The new developed method was successfully validated in accordance to the International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantitation, precision, linearity, accuracy and robustness. The degradation products were well resolved from main peak and its seven impurities, proving the specificity power of the method. The method showed good linearity with consistent recoveries for Dic content and its impurities. The relative percentage of standard deviation obtained for the repeatability and intermediate precision experiments was less than 3% and LOQ was less than 0.5MUg.ml(-1) for all compounds. The new proposed method was found to be accurate, precise, specific, linear and robust. In addition, the method was successfully applied for the assay determination of Dic and its impurities in the several pharmaceutical dosage forms. PMID- 27475310 TI - [Enzymes for disrupting bacterial communication, an alternative to antibiotics?] AB - Quorum sensing (QS) is used by bacteria to communicate and synchronize their actions according to the cell density. In this way, they produce and secrete in the surrounding environment small molecules dubbed autoinducers (AIs) that regulate the expression of certain genes. The phenotypic traits regulated by QS are diverse and include pathogenicity, biofilm formation or resistance to anti microbial treatments. The strategy, aiming at disrupting QS, known as quorum quenching (QQ), has emerged to counteract bacterial virulence and involves QS inhibitors (QSI) or QQ-enzymes degrading AIs. Differently from antibiotics, QQ aims at blocking cell signaling and does not alter bacterial survival. This considerably decreases the selection pressure as compared to bactericide treatments and may reduce the occurrence of resistance mechanisms. QQ-enzymes are particularly appealing as they may disrupt molecular QS-signal without entering the cell and in a catalytic way. This review covers several aspects of QQ-based medical applications and the potential subsequent emergence of resistance is discussed. PMID- 27475311 TI - Publications presenting negative impacts of pharmacists. AB - OBJECTIVES: The main objective was to evaluate the rate of publications with at least one indicator of the negative impact of clinical pharmaceutics activity. METHODS: This is a descriptive and retrospective literature review. A literature search was conducted using Pubmed. Articles published between 2009-2014 that described the role and impacts of pharmacists were included. We calculated the rate of publication containing at least one negative indicator. We collected the indicators with negative results. RESULTS: A total of 203 articles were included. Nine articles (4%) that had at least one indicator of negative impact were identified. A total of 66% (6/9) were conducted in the United States. The study designs of the articles included were a meta-analysis (n=1), a systematic review (n=1), randomized studies (n=2), pre-post studies (n=3), a cohort study (n=1) and a survey (n=1). Nine indicators of negative impact were identified. CONCLUSION: There were nine publications with at least one negative indicator of the impact of clinical pharmacy activity. While there are a large number of studies about the positive impact of clinical pharmacy activities; the publication of negative results should be encouraged. PMID- 27475312 TI - Acute chest pain with elevated troponin due to rupture of previously stented saphenous vein graft aneurysm. PMID- 27475313 TI - Preclinical study on an animal model of a new non-adhesive cyanoacrylate (Purefill(r)) for arterial embolization. AB - PURPOSE: The goal of this study was to assess the distal dispersion, the adhesion strength to catheter, the vascular toxicity and the ability in excluding embolized vessels using Purefill(r) (alpha-hexil-cyanoacrylate) as embolic material, which is a new high purity cyanoacrylate and compare these results with those obtained with N-butyl-2-cyanoacrylate (Histoacryl(r)) and a mixture of N butyl-2-cyanoacrylate and methacryloxysulfolane. MATERIAL AND METHODS: In six pigs, the right rete mirabile (RM) and right renal arteries were embolized with alpha-hexil-cyanoacrylate, and the left rete mirabile and left renal artery were embolized with N-butyl-2-cyanoacrylate and N-butyl-2 cyanoacrylate+Methacryloxysulfolane for comparison. One minute after glue injection through the microcatheter, displacements of the kidney and the pharyngeal artery were measured on angiographic images, before exercising any traction and during catheter pulling, when the forces were maximal. Displacement was measured in terms of distance (mm) with respect to renal pedicles and in terms of angle ( degrees ) with respect to the rete. After acute embolization (4 pigs) or three-month follow-up (2 pigs), the kidneys and the RM were removed and further analysed using computed tomography and histopathological examination. RESULTS: Similar short and long-term embolic efficacies were observed with the three glues. The mean displacement distances of renal pedicles were 2.6mm for alpha-hexil-cyanoacrylate, 22.6mm for N-butyl-2-cyanoacrylate and 19.8mm for N butyl-2-cyanoacrylate+Methacryloxysulfolane (P=0.021). The mean angles of displacement of the ascending pharyngeal arteries were for 12.2 degrees for alpha-hexil-cyanoacrylate, 23.5 degrees for N-butyl-2-cyanoacrylate and 30 degrees for N-butyl-2-cyanoacrylate+Methacryloxysulfolane (P=0.070). Histopathologically, findings were similar for the three glues, immediately and 90 days after embolization. CONCLUSION: alpha-hexil-cyanoacrylate has occlusive efficacy in the short and long term similar to those of N-butyl-2-cyanoacrylate and N-butyl-2-cyanoacrylate+Methacryloxysulfolane. In addition, histopathological changes are similar with the three glues immediately or 90 days after embolization. Conversely, alpha-hexil-cyanoacrylate results in a reduced angle and distance of displacement compared to the other two glues, assumably reflecting a limited adhesive strength. PMID- 27475315 TI - Percutaneous endoscopic lumbar discectomy for lumbar disc herniation. AB - This study aims to compare the advantages and disadvantage of percutaneous endoscopic lumbar discectomy (PELD) and standard discectomy (SD) for the treatment of lumbar intervertebral disc herniation (LDH). We searched in MEDLINE, EMBASE, PubMed, Web of Science and Cochrane databases for relevant trials that compare PELD and SD for the treatment of LDH. The Cochrane Collaboration's Revman 5.3 software was used for data analyses. This meta-analysis compiled 1301 cases from four random controlled trials and three retrospective studies. Compared with SD, PELD showed a shorter operative time (mean difference (MD)=-18.68, 95% confidence interval (CI): -24.92 to -12.43; p<0.00001), less blood loss (MD= 64.88, 95% CI: -114.51 to -15.25, p<0.0001), shorter hospital stay (MD=-3.51, 95% CI: -4.93 to -2.08, p<0.00001), and shorter mean disability period (MD=-34.34, 95% CI: -53.90 to -14.77, p<0.006). However, there were no significant differences in the visual analogue scale (VAS) scores at the final follow up (MD= 0.23, 95% CI: -0.53 to 0.07, p=0.14), Macnab criteria at the final follow up (MD=1.04, 95% CI: 0.72 to 1.50, p=0.82), complications (RR=0.76, 95% CI: 0.40 to 1.43, p=0.39), recurrence rate (risk ratio (RR)=1.00, 95% CI: 0.61 to 1.64, p=1) and reoperation rate (RR=1.40, 95% CI: 0.90 to 2.16, p=0.13). In conclusion, despite PELD showing significant benefit in short term outcomes such as hospital course and mean disability period, similar clinical efficacy and long term outcomes were observed when compared to SD. Therefore, we suggest that PELD can be a feasible alternative to the conventional posterior approach for the LDH depending on surgeon preference and indication. High-quality randomized controlled trials with sufficient large sample sizes necessary further confirm these results. PMID- 27475316 TI - A case of encephalomyeloradiculopathy in a non-carcinomatous patient associated with P/Q type voltage gated calcium channel antibodies. AB - The presence of P/Q type voltage gated calcium channel (VGCC) antibodies has been strongly correlated with Lambert Eaton Syndrome (LES), present in 90% of non immunocompromised patients with LES. However, there have been case reports which have shown its association between paraneoplastic syndrome affecting both central nervous system and the peripheral nervous system causing encephalomyelitis and sensory neuronopathy/neuropathy. We present a case of a young man, who presented with encephalomyelitis, and was further noted to have superimposed cervical polyradiculopathy associated with P/Q type VGCC antibodies. PMID- 27475314 TI - Bifocal germinomas in the pineal region and hypothalamo-neurohypophyseal axis: Primary or metastasis? AB - Whether bifocal germinomas (BFGs) synchronously presenting within the pineal region and the hypothalamo-neurohypophyseal axis (HNA) are primary germinomas of dual-origin remains to be elucidated. We analyzed MRI images and clinical features of 95 neurohypophyseal germinomas and 21 BFG patients and developed a tentative definition of the BFGs. We found dual-primary BFGs (true BFGs) do exist. The fundamental difference between primary and metastatic HNA germinomas was the direction of tumor growth. For a true BFG, the primary HNA tumor grew from the neurohypophysis toward the hypothalamus and almost invaded the whole pituitary stalk. For a false BFG (primary pineal germinoma with HNA metastasis), the metastatic HNA tumor first appeared at the third ventricular floor (TVF), grew toward the neurohypophysis, but commonly did not invade the inferior pituitary stalk. Compared to false BFGs, true BFGs commonly had diabetes insipidus as the first symptom, dysfunction of the anterior pituitary, no high intensity MRI signal at the posterior pituitary, a larger extension of the HNA tumor, and fewer numbers of remote lesions from cerebrospinal fluid seeding. Accordingly, 12.8% (12/96) of our germinoma patients had true BFGs, and of these, 58.3% (7/12) were free of remote metastases and warranted treatment with limited radiotherapy. True BFGs with remote metastases and all false BFGs should be treated with craniospinal irradiation. We provided evidence for the diagnosis of true BFGs that is useful for radiotherapy strategy, suggesting that the existence of metastasis to other locations is not a diagnostic criterion for a true BFG. PMID- 27475317 TI - The association of renin-angiotensin system blockade use with the risks of cognitive impairment of aging and Alzheimer's disease: A meta-analysis. AB - A quantitative meta-analysis was performed to evaluate the association of renin angiotensin system blockade (RASB) use with the incidence of cognitive impairment of aging and Alzheimer's disease (AD). Pubmed, Embase, and Cochrane Library databases were searched up to October 2015. Ten studies that assessed the relationship between RASB use and the incidence of cognitive impairment of aging or AD were included. When randomized trials and observational studies were combined, the use of RASB was significantly associated with a reduced risk of AD (risk ratio [RR], 0.80; 95% confidence interval [CI] 0.68-0.92) and cognitive impairment of aging (RR, 0.65; 95% CI 0.35-0.94) compared no use of RASB. Meanwhile, in an analysis of subgroups, both subjects with angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use were lower incidence of AD (RR, 0.87; 95% CI 0.74-1.00; RR, 0.69; 95% CI 0.44-0.93, respectively) than those without, whereas, indirect comparison between ACEI and ARB revealed no significance in the risk of AD (RR, 1.27, 95% CI 0.85-1.89, p=0.245). In an analysis of cognitive impairment of aging, ARB use (RR, 0.40; 95% CI 0.02-0.78), rather than ACEI use (RR, 0.72; 95% CI 0.36-1.09), was shown to decrease the risk of cognitive impairment of aging. In conclusion, RASB treatments, regardless of the drug class, have benefits on prevention of AD, and the effects of ACEI may analogous to ARB. However, the benefit differs according to drug classes for cognitive impairment of aging, with ARB use, rather than ACEI use, being a potential treatment for reducing the incidence of cognitive impairment of aging. PMID- 27475318 TI - The survival significance of a measurable enhancing lesion after completing standard treatment for newly diagnosed glioblastoma. AB - The goal of this study was to analyze the survival outcome according to the treatment response after completing standard treatment protocol for newly diagnosed glioblastoma (GBM) and to suggest a patient who should be considered for further treatment. After approving by our Institutional Review Board, 57 patients (38 male, 19 female; median age, 52years; age range, 16-81years) with newly diagnosed GBM who completed standard treatment protocol were examined retrospectively. According to the treatment response using the RANO criteria, there were 20 patients with complete response (CR), five patients with partial response (PR), 13 patients with stable disease (SD) and 19 patients with progressive disease (PD) after the completion of standard treatment. Patients (PR+SD+PD) with a measurable enhancing lesion were categorized the MEL group (n=37). We analyzed the difference of survival outcome between CR group and MEL group. The median progression-free survival (PFS) in the CR group was significantly better than that of the MEL group (18.0months vs. 3.0months, p=0.004). The median overall survival (OS) was also significantly longer in the CR group (25.0months vs. 15.0months, p=0.005). However, there was no significant difference in the survival outcome of the CR group compared with that of the subset of MEL group patients who showed PR or SD. Poor survival outcome was found only in MEL group patients who exhibited progression. Patients with a measurable enhancing lesion showing progression after completion of standard treatment protocol are appropriate candidates for further treatment. PMID- 27475319 TI - Zolpidem-triggered seizures, depression, and reduced locomotion. PMID- 27475320 TI - Total intracranial and lateral ventricle volumes measurement in Alzheimer's disease: A methodological study. AB - Measuring of brain and its compartments' sizes from magnetic resonance (MR) images is an effective way to assess disease progression in neurodegenerative disorders, particularly Alzheimer's disease (AD). The objective of this study was to compare total intracranial volume (TIV) and lateral ventricle volume (LVV) in patients with Alzheimer's disease with those in elderly control subjects, and to compare an automated method (automatic lateral ventricle delineation [ALVIN]) and a manual method (ImageJ). MRI of the brain was performed on 20 patients with Alzheimer's disease and 18 control subjects. The TIV was calculated by a manual method and the LVV was calculated by using two methods: an automated and manual method. We found a significant increase in LVVs in Alzheimer's disease patients compared to control subjects, but no difference in TIV between the two groups. A perfect agreement, with 0.989 (0.973-0.996) intraclass correlation coefficient (ICC) and 0.978 (0.946-0.991) concordance correlation coefficient (CCC), was observed between the manual and automatic lateral ventricle measurements in Alzheimer patients. The results revealed that LVV measure has predictive performance in AD. We demonstrated that ALVIN and ImageJ are both effective in determining lateral ventricular volume, providing an objective tool for quantitative assessment of AD. PMID- 27475321 TI - Divided visual attention: A comparison of patients with multiple sclerosis and controls, assessed with an optokinetic nystagmus suppression task. AB - Multiple sclerosis (MS) frequently causes impairment of cognitive function. We compared patients with MS with controls on divided visual attention tasks. The MS patients' and controls' stare optokinetic nystagmus (OKN) was recorded in response to a 24 degrees /s full field stimulus. Suppression of the OKN response, judged by the gain, was measured during tasks dividing visual attention between the fixation target and a second stimulus, central or peripheral, static or dynamic. All participants completed the Audio Recorded Cognitive Screen. MS patients had lower gain on the baseline stare OKN. OKN suppression in divided attention tasks was the same in MS patients as in controls but in both groups was better maintained in static than in dynamic tasks. In only dynamic tasks, older age was associated with less effective OKN suppression. MS patients had lower scores on a timed attention task and on memory. There was no significant correlation between attention or memory and eye movement parameters. Attention, a complex multifaceted construct, has different neural combinations for each task. Despite impairments on some measures of attention, MS patients completed the divided visual attention tasks normally. PMID- 27475322 TI - A systematic review and meta-analysis of outcomes in hybrid constructs for multi level lumbar degenerative disc disease. AB - A systematic review and meta-analysis was performed to assess the effect of hybrid constructs which involve a total disc arthroplasty (TDA) with stand-alone anterior lumbar interbody fusion (ALIF) versus non-hybrid constructs including multi-level TDA, multi-level transforaminal lumbar interbody fusion (TLIF) with posterior transpedicular fixation or multi-level stand-alone ALIF as a surgical intervention for degenerative disc disease (DDD) in the lumbar spine. Primary outcomes analysed included the Oswestry Disability Index (ODI) and the Visual Analogue Scale (VAS) for back pain. A systematic search of Medline, Embase, Pubmed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Google Scholar was undertaken by two separate reviewers and a meta-analysis of the outcomes was performed. Three studies met our search criteria. When comparing hybrid constructs to multi-level TDA or lumbar fusion (LF) improvements in back pain were found with a VAS back pain score reduction of 1.38 (P<0.00001) postoperatively and a VAS back pain score reduction of 0.99 points (P=0.0006) at 2-years follow-up. Results so far slightly favour clinically significant improved VAS back pain score outcomes postoperatively and at 2-years follow-up for hybrid constructs in multi-level lumbar DDD of the spine when compared with non-hybrid multi-level LF or TDA. It cannot however be concluded that a hybrid construct is superior to multi-level LF or TDA based on this meta analysis. The results highlight the need for further prospective studies to delineate best practice in the management of degenerative disc disease of the lumbar spine. PMID- 27475323 TI - Outpatient anterior cervical discectomy and fusion: A meta-analysis. AB - Anterior cervical discectomy and fusion (ACDF) performed as an outpatient has become increasingly common for treating cervical spine pathology, largely due to its cost savings compared with inpatient ACDF. Nearly all outpatient ACDF patient reports have originated from single-center studies, with the procedure yet to be addressed via a meta-analysis of the peer-reviewed literature. The Entrez gateway of the PubMed database was used to conduct a comprehensive literature search for articles published in English up to 3/9/16. Data from studies meeting inclusion criteria (minimum of 25 patients, control group of inpatient ACDF patients, non duplicative data source) was then categorized and assimilated for analysis. Seven studies met inclusion criteria, encompassing a 21-year timespan. Each provided Oxford Center for Evidence-Based Medicine Level 3 evidence. The studies yielded a total of 2448 outpatient ACDF patients; only 125 (5.1%) originated from studies published prior to 2011. Single-level surgery occurred in 63.8% of patients, with 0.5% extending beyond two-level fusions. The overall complication rate was 1.8% (mean follow-up of 141.2days); only 2% of patients required readmission. In conclusion, outpatient ACDF has become increasingly popular, with more than 95% of patients represented by studies published since 2011. Nearly two-thirds of outpatient ACDFs underwent single-level fusion, with virtually none undergoing 3+ level ACDF. Outpatient ACDF is safe, with a low readmission rate and complication rates comparable to those (2-5%) associated with inpatient ACDF. These findings support an argument for increasing ACDFs performed on an outpatient basis in appropriately selected patients. PMID- 27475324 TI - Insight into the messenger role of reactive oxygen intermediates in immunostimulated hemocytes from the scallop Argopecten purpuratus. AB - Reactive oxygen intermediates (ROI) are metabolites produced by aerobic cells which have been linked to oxidative stress. Evidence reported in vertebrates indicates that ROI can also act as messengers in a variety of cellular signaling pathways, including those involved in innate immunity. In a recent study, an inhibitor of NF-kB transcription factors was identified in the scallop Argopecten purpuratus, and its functional characterization suggested that it may regulate the expression of the big defensin antimicrobial peptide ApBD1. In order to give new insights into the messenger role of ROI in the immune response of bivalve mollusks, the effect of ROI production on gene transcription of ApBD1 was assessed in A. purpuratus. The results showed that 48 h-cultured hemocytes were able to display phagocytic activity and ROI production in response to the beta glucan zymosan. The immune stimulation also induced the transcription of ApBD1, which was upregulated in cultured hemocytes. After neutralizing the ROI produced by the stimulated hemocytes with the antioxidant trolox, the transcription of ApBD1 was reduced near to base levels. The results suggest a potential messenger role of intracellular ROI on the regulation of ApBD1 transcription during the immune response of scallops. PMID- 27475325 TI - The role of microRNAs in metabolic interactions between viruses and their hosts. AB - Productive viral infection requires changes to the cellular metabolic landscape in order to obtain the building blocks and create the microenvironments necessary for the viral life cycle. In mammals, these alterations of metabolic pathways have been shown to be mediated in part by host and virus-encoded microRNAs. To counteract virally-induced changes in the cellular metabolic profile, the interferon-regulated antiviral response restricts viral access to key metabolites by altering cellular metabolism, mediated through induction of specific microRNAs regulating key lipid biosynthetic processes. In this review, we examine recent studies demonstrating the important role of microRNAs in the regulation of metabolic flux during viral infection. PMID- 27475326 TI - Collapsin response mediator protein 4 isoforms (CRMP4a and CRMP4b) have opposite effects on cell proliferation, migration, and invasion in gastric cancer. AB - BACKGROUND: Collapsin response mediator proteins (CRMPs) were originally identified in the nervous system and are involved in neuronal development. Similar to CRMP1, CRMP4 has a shorter transcript encoding a short isoform known as CRMP4a, and a longer transcript encoding a long isoform known as CRMP4b. Previous studies have shown that CRMP4a and CRMP4b exhibit opposing functions in neurite outgrowth. In the present study, we aimed to determine whether CRMP4a and CRMP4b have divergent effects in gastric cancer. METHODS: We first analyzed the mRNA and protein expression levels of CRMP4a and CRMP4b in surgical resected specimens, gastric cancer cell lines and normal gastric epithelial cell line GES 1 by quantitative real-time PCR. Open reading frame and CRMP4b shRNA were generated by lentivirus package and stable cells stably expressing CRMP4a open reading frame and CRMP4b shRNA were constructed. Then the roles of CRMP4a and CRMP4b in cell proliferation, cell cycle progression, apoptosis, migration, invasion, and adhesion were determined by cell proliferation assays, flow cytometry analysis, transwell migration and invasion assays, cell Adhesion Assay, and tumorigenicity assays in nude mice, respectively. RESULTS: CRMP4a expression was lower and CRMP4b expression was higher in tumor tissue samples as compared to paired non-tumor tissue samples. Additionally, CRMP4a expression was lower and CRMP4b expression was higher in gastric cancer cell lines than in the normal gastric epithelial cell line GES-1. CRMP4a overexpression and CRMP4b silencing suppressed cell proliferation in vitro and in vivo. Additionally, CRMP4a overexpression and CRMP4b silencing induced a significant G1-phase arrest and a decrease of the percentage of cells in S-phase. Furthermore, CRMP4a overexpression and CRMP4b silencing inhibited cell migration, invasion, and adhesion. However, neither CRMP4a overexpression nor CRMP4b silencing affected apoptosis. CONCLUSION: These results indicate that CRMP4a and CRMP4b have opposite effects on cell proliferation, migration, and invasion in gastric cancer. PMID- 27475327 TI - A network based approach to drug repositioning identifies plausible candidates for breast cancer and prostate cancer. AB - BACKGROUND: The high cost and the long time required to bring drugs into commerce is driving efforts to repurpose FDA approved drugs-to find new uses for which they weren't intended, and to thereby reduce the overall cost of commercialization, and shorten the lag between drug discovery and availability. We report on the development, testing and application of a promising new approach to repositioning. METHODS: Our approach is based on mining a human functional linkage network for inversely correlated modules of drug and disease gene targets. The method takes account of multiple information sources, including gene mutation, gene expression, and functional connectivity and proximity of within module genes. RESULTS: The method was used to identify candidates for treating breast and prostate cancer. We found that (i) the recall rate for FDA approved drugs for breast (prostate) cancer is 20/20 (10/11), while the rates for drugs in clinical trials were 131/154 and 82/106; (ii) the ROC/AUC performance substantially exceeds that of comparable methods; (iii) preliminary in vitro studies indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. We briefly discuss the biological plausibility of the candidates at a molecular level in the context of the biological processes that they mediate. CONCLUSIONS: Our method appears to offer promise for the identification of multi-targeted drug candidates that can correct aberrant cellular functions. In particular the computational performance exceeded that of other CMap-based methods, and in vitro experiments indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. The approach has the potential to provide a more efficient drug discovery pipeline. PMID- 27475328 TI - Multiple somatic symptoms in primary care patients: a cross-sectional study of consultation content, clinical management strategy and burden of encounter. AB - BACKGROUND: Consultations involving patients with multiple somatic symptoms may be considered as challenging and time-consuming by general practitioners (GPs). Yet, little is known about the possible links between consultation characteristics and GP-experienced burden of encounter. We aimed to explore consultation content, clinical management strategies, time consumption and GP experienced burden of encounters with patients suffering from multiple somatic symptoms as defined by the concept of bodily distress syndrome (BDS). METHODS: Cross-sectional study of patient encounters in primary care from December 2008 to December 2009; 387 GPs participated (response rate: 44.4 %). Data were based on a one-page registration form completed by the GP and a patient questionnaire including the 25-item BDS checklist for somatic symptoms. Using logistic regression analyses, we compared patients who met the BDS criteria with patients who did not. RESULTS: A total of 1505 patients were included (response rate: 55.6 %). Health problems were less frequently reported as 'new' in patients with BDS (odds ratio (OR) = 0.73, 95 % confidence interval (CI): 0.54; 0.97). Medical prescriptions and referral rates were comparable in the two patient groups. Consultations focusing on mainly biomedical aspects were less frequent among patients with BDS (OR = 0.31, 95 % CI: 0.22; 0.43), whereas additional biomedical and psychosocial problems were more often discussed. GPs were more likely to ensure continuity of care in BDS patients by watchful waiting strategies (OR = 2.32, 95 % CI: 1.53; 3.52) or scheduled follow-up visits (OR = 1.61, 95 % CI: 1.09; 2.37). Patients with BDS were found to be more time-consuming (OR = 1.77, 95 % CI: 1.26; 2.48) and burdensome (OR = 2.54, 95 % CI: 1.81; 3.55) than patients without BDS. However, after adjustments for biomedical and psychosocial content of the consultation, the identified differences for time consumption and burden were no longer statistically significant. CONCLUSIONS: Patients with BDS represent higher care complexity in terms of biomedical and psychosocial needs. GPs seem to allow space and time for discussing these issues and to aim at ensuring continuity in care through watchful waiting or scheduled follow-up consultations. However, the reported GP-experienced burden call for professional development. PMID- 27475329 TI - Long term testing of Microbial Fuel Cells: Comparison of different anode materials. AB - This paper focuses on the long term operation and testing of three Microbial Fuel Cells (MFC) having three different anode materials: commercial carbon felt (C FELT), polyaniline-deposited carbon felt (C-PANI) and carbon-coated Berl saddles (C-SADDLES). A mixed consortium from seawater was used as inoculum and acetate was used as substrate. Tests were conducted for four months under 1000Omega external load. The maximum power generation was obtained by C-SADDLES (102mWm( 2)) followed by C-FELT and C-PANI, respectively. A similar trend was obtained with the evaluation of electrical energy produced: C-SADDLES (2222J), C-PANI (2183J) and C-FELT (2114J). However, the performance of C-PANI decreased over time, most evidently due to degradation or deactivation of deposited polyaniline by the microorganisms' activity. These results provide evidence that the three dimensional structure, C-SADDLES, offers excellent biocompatibility, high specific surface area, high conductivity and most importantly these properties are maintained for a long period of time. PMID- 27475330 TI - Techno-economic and Monte Carlo probabilistic analysis of microalgae biofuel production system. AB - This study focuses on the characterization of the technical and economic feasibility of an enclosed photobioreactor microalgae system with annual production of 37.85 million liters (10 million gallons) of biofuel. The analysis characterizes and breaks down the capital investment and operating costs and the production cost of unit of algal diesel. The economic modelling shows total cost of production of algal raw oil and diesel of $3.46 and $3.69 per liter, respectively. Additionally, the effects of co-products' credit and their impact in the economic performance of algal-to-biofuel system are discussed. The Monte Carlo methodology is used to address price and cost projections and to simulate scenarios with probabilities of financial performance and profits of the analyzed model. Different markets for allocation of co-products have shown significant shifts for economic viability of algal biofuel system. PMID- 27475331 TI - Effects of hydraulic retention time and carbon to nitrogen ratio on micro pollutant biodegradation in membrane bioreactor for leachate treatment. AB - This research investigated the biodegradation of the micro-pollutants in leachate by the membrane bioreactor (MBR) system under six treatment conditions, comprising two C/N ratios (6, 10) and three hydraulic retention time (HRT) durations (6, 12, 24h). The experimental results indicated that the C/N 6 environment was more advantageous to the bacterial growth. The bacterial communities residing in the sludge were those of heterotrophic bacteria (HB), heterotrophic nitrifying bacteria (HNB) and ammonia oxidizing bacteria (AOB). It was found that HB and HNB produced phenol hydroxylase (PH), esterase (EST), phthalate dioxygenase (PDO) and laccase (LAC) and also enhanced the biodegradation rate constants (k) in the system. At the same time, AOB promoted the production of HB and HNB. The findings also revealed that the 12h HRT was the optimal condition with regard to the highest growth of the bacteria responsible for the biodegradation of phenols and phthalates. Meanwhile, the longer HRT duration (i.e. 24h) was required to effectively bio-degrade carbamazepine (CBZ), N,N-diethyl-m-toluamide (DEET) and diclofenac (DCF). PMID- 27475332 TI - Valorization of the aqueous phase obtained from hydrothermally treated Dunaliella salina remnant biomass. AB - Up to 90% of Dunaliella salina biomass remains unused after extraction of the main product beta-carotene. The potential of mild hydrothermal liquefaction (HTL) to exploit this biomass as a source of valuable by-products was assessed. The results indicate that 80% of the remnant was converted into glucose by mild HTL (100 degrees C, 0min). The recovered glucose was successfully used as a carbon source to cultivate biotechnologically relevant microorganisms, namely Chlorella vulgaris, Escherichia coli and Saccharomyces cerevisiae. Furthermore, the analysis of energy demand and operating costs confirms the beneficial effect of mild liquefaction on the overall process economics of algal beta-carotene production. PMID- 27475333 TI - The economic burden of methicillin-resistant Staphylococcus aureus in community onset pneumonia inpatients. AB - BACKGROUND: The quantitative effect of multidrug-resistant bacterial infections on real-world health care resources is not clear. This study aimed to estimate the burden of methicillin-resistant Staphylococcus aureus (MRSA) infections in pneumonia inpatients in Japan. METHODS: Using a nationwide administrative claims database, we analyzed pneumonia patients who had been hospitalized in 1,063 acute care hospitals. Patients who received anti-MRSA drugs were categorized into an anti-MRSA drug group, and the remaining patients comprised the control group. We estimated the burden of length of stay, in-hospital mortality, total antibiotic agent costs, and total hospitalization costs. Risk adjustments were conducted using propensity score matching. RESULTS: The study sample comprised 634 patients administered anti-MRSA drugs and 87,427 control patients. In propensity score matching analysis (1 to 1), the median length of stay, antibiotic costs, and hospitalization costs of the anti-MRSA drug group were significantly higher than those of the control group (21 days vs 14 days [P < .001], $756 vs $172 [P < .001] and $8,741 vs $5,063 [P < .001], respectively); the attributable excess of these indicators were 9.0 +/- 1.6 days, $1,044 +/- $101, and $5,548 +/- $580, respectively. CONCLUSIONS: These findings may serve as a reference to support further research on multidrug-resistant bacterial infections and eventually inform policy formulation. PMID- 27475334 TI - Treatment of Kienbock's disease using a fourth extensor compartmental artery as a vascularized pedicle bone graft. AB - BACKGROUND: Vascularized bone grafts for the treatment of Kienbock's disease may facilitate revascularization and remodeling of the avascular lunate. The aim of this study was to evaluate the radiological and clinical results obtained when a fourth extensor compartmental artery (ECA) bone graft was used to treat Kienbock's disease. METHODS: Between May 2009 and June 2012, 13 patients (6 men, 7 women) with Kienbock's disease were treated with placement of fourth ECA vascularized bone grafts. The mean patient age was 39.2 (20-58) years, and the mean follow-up period was 32.5 (12-72) months. At the time of surgery, One patient had Lichtman's stage II Kienbock's disease, 11 stage IIIA disease, and one stage IIIB disease. We measured the pre- and post-operative ranges of motion, pain, grip strength, and radiological parameters, including the carpal height ratio and the radioscaphoid angle. RESULTS: At the last follow-up, pain was significantly reduced, and grip strength had improved from 60.5% to 87.8% relative to that of the contralateral side. The mean range of motion for flexion had improved from 39 degrees to 53 degrees while that of wrist joint extension improved from 41 degrees to 56 degrees . There were little or no changes in either the carpal height ratio or the radioscaphoid angle (both p values > 0.05). CONCLUSIONS: Placing of a fourth ECA vascularized bone graft is a reliable alternative to other revascularization procedures for treatment of Kienbock's disease. Such grafting is effective, minimally invasive, and associated with a low risk of pedicle kinking. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic/IV. PMID- 27475335 TI - Improved healthcare economic outcomes after liposomal bupivacaine administration in first-stage breast reconstruction. PMID- 27475336 TI - Predictors of internal mammary vessel diameter: A computed tomographic angiography-assisted anatomic analysis. AB - The internal mammary vessels are the most common recipient vessels in free flap breast reconstruction. The literature on internal mammary vascular anatomy is limited by small sample sizes, cadaveric studies, or intraoperative changes. The purpose of this study is to analyze internal mammary anatomy using computed tomographic angiography. A retrospective review of 110 consecutive computed tomographic angiography studies of female patients was performed. Measurements of vessel caliber, distance of internal mammary vessels to sternum, location of internal mammary vein bifurcation, intercostal space height, and chest width were analyzed. Patient demographics and comorbidities were reviewed. The right internal mammary artery and vein were larger than the left in all intercostal spaces (p = 0.02 and p < 0.001, respectively). A significant correlation was found between both skeletal chest width and body mass index with internal mammary vessel caliber at the third intercostal space (p <= 0.02). The internal mammary vein bifurcated at the third intercostal space bilaterally, 4.3 and 1.2 mm caudal to the third rib on the right and left sides, respectively. The third intercostal space was <1.5 cm in 25% of patients. Understanding the anatomy, bifurcation, and caliber of internal mammary vessels can aid preoperative planning of autologous, free flap breast reconstruction. On average, the internal mammary vein bifurcates at the third intercostal space; patients with larger chest widths and body mass index had larger caliber internal mammary vessels, and 25% of patients had third intercostal space <1.5 cm and, thus, may not be suitable candidates for rib sparing techniques. PMID- 27475337 TI - General practice trainee's perceptions of the scope and practice of plastic surgery. PMID- 27475338 TI - Intravenous Vitamin B6 Increases Resistance to Erythropoiesis-Stimulating Agents in Hemodialysis Patients: A Randomized Controlled Trial. AB - OBJECTIVE: Vitamin B6 deficiency is common in hemodialysis patients and may contribute to anemia and abnormal bone metabolism in this population. DESIGN: 6 month, open-label, randomized controlled parallel-group study in hemodialysis centers. SUBJECTS: Fifty-six maintenance hemodialysis patients with relatively high resistance to erythropoiesis-stimulating agents (ESA). INTERVENTION: Intravenous vitamin B6 (60 mg of intravenous pyridoxal 5'-phosphate after each thrice-weekly hemodialysis session). MAIN OUTCOME MEASURE: The primary and secondary outcomes were changes over time in ESA resistance index and bone turnover markers, respectively. RESULTS: The prevalence of vitamin B6 deficiency was 40% overall. Compared with the control group, the B6 group showed an upward change in ESA resistance index over time (Pinteraction = .038). At week 13 (a priori-defined time point), pyridoxal 5'-phosphate administration was associated with higher ESA resistance index by 0.97 (95% confidence interval, 0.02-1.92) *10 2 MUg ?darbepoetin-alpha/kg per g/dL?hemoglobin after baseline adjustment, which was not modified by baseline vitamin B6 status. There was a trend toward increase in serum erythropoietin concentrations in the B6 group after adjustment for baseline values, hemoglobin, and weekly ESA dose (Pinteraction = .06). The downward changes of bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b in the B6 group relative to the control group were pronounced in patients without vitamin B6 deficiency (Pinteraction < .001 and .017, respectively), despite nonsignificant between-group difference in 1-84 parathyroid hormone. CONCLUSIONS: Thrice-weekly intravenous vitamin B6 (60 mg pyridoxal 5'-phosphate hydrate) worsens the response to ESA and may blunt the response of bone to parathyroid hormone in hemodialysis patients. PMID- 27475341 TI - Communication: The origin of many-particle signals in nonlinear optical spectroscopy of non-interacting particles. AB - Nonlinear spectroscopy signals detected by fluorescence from dilute samples of N non-interacting molecules are usually adequately described by simply multiplying the single molecule response by N. We show that signals that scale with higher powers of N are generated by the joint detection of several particles. This can be accomplished by phase sensitive detection such as phase cycling, photo acoustic modulation, or by Hanbury-Brown Twiss photon coincidence. Such measurements can dissect the ensemble according to the number of excited particles. PMID- 27475340 TI - Communication: Contrasting effects of glycerol and DMSO on lipid membrane surface hydration dynamics and forces. AB - Glycerol and dimethyl sulfoxide (DMSO) are commonly used cryoprotectants in cellular systems, but due to the challenges of measuring the properties of surface-bound solvent, fundamental questions remain regarding the concentration, interactions, and conformation of these solutes at lipid membrane surfaces. We measured the surface water diffusivity at gel-phase dipalmitoylphosphatidylcholine (DPPC) bilayer surfaces in aqueous solutions containing <=7.5 mol. % of DMSO or glycerol using Overhauser dynamic nuclear polarization. We found that glycerol similarly affects the diffusivity of water near the bilayer surface and that in the bulk solution (within 20%), while DMSO substantially increases the diffusivity of surface water relative to bulk water. We compare these measurements of water dynamics with those of equilibrium forces between DPPC bilayers in the same solvent mixtures. DMSO greatly decreases the range and magnitude of the repulsive forces between the bilayers, whereas glycerol increases it. We propose that the differences in hydrogen bonding capability of the two solutes leads DMSO to dehydrate the lipid head groups, while glycerol affects surface hydration only as much as it affects the bulk water properties. The results suggest that the mechanism of the two most common cryoprotectants must be fundamentally different: in the case of DMSO by decoupling the solvent from the lipid surface, and in the case of glycerol by altering the hydrogen bond structure and intermolecular cohesion of the global solvent, as manifested by increased solvent viscosity. PMID- 27475342 TI - Studies of spuriously shifting resonances in time-dependent density functional theory. AB - Adiabatic approximations in time-dependent density functional theory (TDDFT) will in general yield unphysical time-dependent shifts in the resonance positions of a system driven far from its ground-state. This spurious time-dependence is explained in Fuks et al. [Phys. Rev. Lett. 114, 183002 (2015)] in terms of the violation of an exact condition by the non-equilibrium exchange-correlation kernel of TDDFT. Here we give details on the derivation and discuss reformulations of the exact condition that apply in special cases. In its most general form, the condition states that when a system is left in an arbitrary state, the TDDFT resonance position for a given transition in the absence of time dependent external fields and ionic motion is independent of the state. Special cases include the invariance of TDDFT resonances computed with respect to any reference interacting stationary state of a fixed potential, and with respect to any choice of appropriate stationary Kohn-Sham reference state. We then present several case studies, including one that utilizes the adiabatically exact approximation, that illustrate the conditions and the impact of their violation on the accuracy of the ensuing dynamics. In particular, charge-transfer across a long-range molecule is hampered, and we show how adjusting the frequency of a driving field to match the time-dependent shift in the charge-transfer resonance frequency results in a larger charge transfer over time. PMID- 27475339 TI - Effectiveness evaluation of a health promotion programme in primary schools: a cluster randomised controlled trial. AB - BACKGROUND: Programmes based on the World Health Organization's Health Promoting Schools framework (HPS) have been implemented in several countries but for evidence-based policy-making more research is required to determine the effectiveness of the HPS approach. METHODS: We conducted a cluster randomised controlled trial. The units of randomisation were primary school classes recruited in May 2010. Eligible participants were Year 3 primary school classes in Lower Austria that had not participated in a similar programme during the last two years. After baseline assessment in September 2010, 53 classes from 45 primary schools in Lower Austria were randomly assigned to an intervention (n = 26 classes, 432 children) or waiting control arm (n = 27 classes, 493 children aged 8.7 years +/- 4 months). Over the course of 1.5 academic years, participating teachers received on-the-job training (20 h) and two workshops (8 h) to promote health related behaviour in students such as physical activity during the school day and to improve the quality of regular physical education classes. We assessed 15 outcomes grouped into five categories: Emotional and Social Experience in School, Physical Activity, Well-being, and Attention Performance measured by validated and standardised questionnaire and Motor Skills measured by validated and standardised motoric and coordination tests in the school gym. The primary outcome was Classroom Climate and part of the outcomecategory Emotional and Social Experience in School. The final assessment took place in April 2012. All assessors were blinded to the allocation of classes. Multilevel growth modelling was used to investigate programme effectiveness. RESULTS: We could not detect any statistically significant differences between groups for the outcomecategories Emotional and Social Experience in school (p = 0.22 to 0.78), Physical Activity, Well-being, and Attention Performance. Significant differences between groups were limited to the outcomecategory Motor Skills (Complex Reaction Ability, Spatial Orientation Skills, Coordination with Precision) which were higher in the intervention group (P < .05). CONCLUSIONS: Despite small statistically significant differences in Motor Skills, our study could not detect any clinically relevant improvements in the Emotional and Social Experience at School (including the primary outcome ClassroomClimate), Physical Activity, Well-being, Motor Skills and Attention Performance of students. TRIAL REGISTRATION: German register of clinical studies: DRKS00000622 . Retrospectively registered: 03.12.2010. Approved by the Ethics Committee of Lower Austria (GS4-EK-4/107-2010). PMID- 27475343 TI - A comparative study of coarse-graining methods for polymeric fluids: Mori-Zwanzig vs. iterative Boltzmann inversion vs. stochastic parametric optimization. AB - We construct effective coarse-grained (CG) models for polymeric fluids by employing two coarse-graining strategies. The first one is a forward-coarse graining procedure by the Mori-Zwanzig (MZ) projection while the other one applies a reverse-coarse-graining procedure, such as the iterative Boltzmann inversion (IBI) and the stochastic parametric optimization (SPO). More specifically, we perform molecular dynamics (MD) simulations of star polymer melts to provide the atomistic fields to be coarse-grained. Each molecule of a star polymer with internal degrees of freedom is coarsened into a single CG particle and the effective interactions between CG particles can be either evaluated directly from microscopic dynamics based on the MZ formalism, or obtained by the reverse methods, i.e., IBI and SPO. The forward procedure has no free parameters to tune and recovers the MD system faithfully. For the reverse procedure, we find that the parameters in CG models cannot be selected arbitrarily. If the free parameters are properly defined, the reverse CG procedure also yields an accurate effective potential. Moreover, we explain how an aggressive coarse-graining procedure introduces the many-body effect, which makes the pairwise potential invalid for the same system at densities away from the training point. From this work, general guidelines for coarse-graining of polymeric fluids can be drawn. PMID- 27475344 TI - Asymptotic neutron scattering laws for anomalously diffusing quantum particles. AB - The paper deals with a model-free approach to the analysis of quasielastic neutron scattering intensities from anomalously diffusing quantum particles. All quantities are inferred from the asymptotic form of their time-dependent mean square displacements which grow ?t(alpha), with 0 <= alpha < 2. Confined diffusion (alpha = 0) is here explicitly included. We discuss in particular the intermediate scattering function for long times and the Fourier spectrum of the velocity autocorrelation function for small frequencies. Quantum effects enter in both cases through the general symmetry properties of quantum time correlation functions. It is shown that the fractional diffusion constant can be expressed by a Green-Kubo type relation involving the real part of the velocity autocorrelation function. The theory is exact in the diffusive regime and at moderate momentum transfers. PMID- 27475345 TI - The relative entropy is fundamental to adaptive resolution simulations. AB - Adaptive resolution techniques are powerful methods for the efficient simulation of soft matter systems in which they simultaneously employ atomistic and coarse grained (CG) force fields. In such simulations, two regions with different resolutions are coupled with each other via a hybrid transition region, and particles change their description on the fly when crossing this boundary. Here we show that the relative entropy, which provides a fundamental basis for many approaches in systematic coarse-graining, is also an effective instrument for the understanding of adaptive resolution simulation methodologies. We demonstrate that the use of coarse-grained potentials which minimize the relative entropy with respect to the atomistic system can help achieve a smoother transition between the different regions within the adaptive setup. Furthermore, we derive a quantitative relation between the width of the hybrid region and the seamlessness of the coupling. Our results do not only shed light on the what and how of adaptive resolution techniques but will also help setting up such simulations in an optimal manner. PMID- 27475346 TI - Theoretical modeling of electron mobility in superfluid (4)He. AB - The Orsay-Trento bosonic density functional theory model is extended to include dissipation due to the viscous response of superfluid (4)He present at finite temperatures. The viscous functional is derived from the Navier-Stokes equation by using the Madelung transformation and includes the contribution of interfacial viscous response present at the gas-liquid boundaries. This contribution was obtained by calibrating the model against the experimentally determined electron mobilities from 1.2 K to 2.1 K along the saturated vapor pressure line, where the viscous response is dominated by thermal rotons. The temperature dependence of ion mobility was calculated for several different solvation cavity sizes and the data are rationalized in the context of roton scattering and Stokes limited mobility models. Results are compared to the experimentally observed "exotic ion" data, which provides estimates for the corresponding bubble sizes in the liquid. Possible sources of such ions are briefly discussed. PMID- 27475347 TI - Multicomponent density functional theory embedding formulation. AB - Multicomponent density functional theory (DFT) methods have been developed to treat two types of particles, such as electrons and nuclei, quantum mechanically at the same level. In the nuclear-electronic orbital (NEO) approach, all electrons and select nuclei, typically key protons, are treated quantum mechanically. For multicomponent DFT methods developed within the NEO framework, electron-proton correlation functionals based on explicitly correlated wavefunctions have been designed and used in conjunction with well-established electronic exchange-correlation functionals. Herein a general theory for multicomponent embedded DFT is developed to enable the accurate treatment of larger systems. In the general theory, the total electronic density is separated into two subsystem densities, denoted as regular and special, and different electron-proton correlation functionals are used for these two electronic densities. In the specific implementation, the special electron density is defined in terms of spatially localized Kohn-Sham electronic orbitals, and electron-proton correlation is included only for the special electron density. The electron-proton correlation functional depends on only the special electron density and the proton density, whereas the electronic exchange-correlation functional depends on the total electronic density. This scheme includes the essential electron-proton correlation, which is a relatively local effect, as well as the electronic exchange-correlation for the entire system. This multicomponent DFT-in-DFT embedding theory is applied to the HCN and FHF(-) molecules in conjunction with two different electron-proton correlation functionals and three different electronic exchange-correlation functionals. The results illustrate that this approach provides qualitatively accurate nuclear densities in a computationally tractable manner. The general theory is also easily extended to other types of partitioning schemes for multicomponent systems. PMID- 27475348 TI - A variational approach to the liquid-vapor phase transition for hardcore ions in the bulk and in nanopores. AB - We employ a field-theoretical variational approach to study the behavior of ionic solutions in the grand canonical ensemble. To describe properly the hardcore interactions between ions, we use a cutoff in Fourier space for the electrostatic contribution of the grand potential and the Carnahan-Starling equation of state with a modified chemical potential for the pressure one. We first calibrate our method by comparing its predictions at room temperature with Monte Carlo results for excess chemical potential and energy. We then validate our approach in the bulk phase by describing the classical "ionic liquid-vapor" phase transition induced by ionic correlations at low temperature, before applying it to electrolytes at room temperature confined to nanopores embedded in a low dielectric medium and coupled to an external reservoir of ions. The ionic concentration in the nanopore is then correctly described from very low bulk concentrations, where dielectric exclusion shifts the transition up to room temperature for sufficiently tight nanopores, to high concentrations where hardcore interactions dominate which, as expected, modify only slightly this ionic "capillary evaporation." PMID- 27475349 TI - On the representability problem and the physical meaning of coarse-grained models. AB - In coarse-grained (CG) models where certain fine-grained (FG, i.e., atomistic resolution) observables are not directly represented, one can nonetheless identify indirect the CG observables that capture the FG observable's dependence on CG coordinates. Often, in these cases it appears that a CG observable can be defined by analogy to an all-atom or FG observable, but the similarity is misleading and significantly undermines the interpretation of both bottom-up and top-down CG models. Such problems emerge especially clearly in the framework of the systematic bottom-up CG modeling, where a direct and transparent correspondence between FG and CG variables establishes precise conditions for consistency between CG observables and underlying FG models. Here we present and investigate these representability challenges and illustrate them via the bottom up conceptual framework for several simple analytically tractable polymer models. The examples provide special focus on the observables of configurational internal energy, entropy, and pressure, which have been at the root of controversy in the CG literature, as well as discuss observables that would seem to be entirely missing in the CG representation but can nonetheless be correlated with CG behavior. Though we investigate these problems in the framework of systematic coarse-graining, the lessons apply to top-down CG modeling also, with crucial implications for simulation at constant pressure and surface tension and for the interpretations of structural and thermodynamic correlations for comparison to experiment. PMID- 27475350 TI - Approaching the basis set limit for DFT calculations using an environment-adapted minimal basis with perturbation theory: Formulation, proof of concept, and a pilot implementation. AB - Recently developed density functionals have good accuracy for both thermochemistry (TC) and non-covalent interactions (NC) if very large atomic orbital basis sets are used. To approach the basis set limit with potentially lower computational cost, a new self-consistent field (SCF) scheme is presented that employs minimal adaptive basis (MAB) functions. The MAB functions are optimized on each atomic site by minimizing a surrogate function. High accuracy is obtained by applying a perturbative correction (PC) to the MAB calculation, similar to dual basis approaches. Compared to exact SCF results, using this MAB SCF (PC) approach with the same large target basis set produces <0.15 kcal/mol root-mean-square deviations for most of the tested TC datasets, and <0.1 kcal/mol for most of the NC datasets. The performance of density functionals near the basis set limit can be even better reproduced. With further improvement to its implementation, MAB-SCF (PC) is a promising lower-cost substitute for conventional large-basis calculations as a method to approach the basis set limit of modern density functionals. PMID- 27475351 TI - Using a pruned, nondirect product basis in conjunction with the multi configuration time-dependent Hartree (MCTDH) method. AB - In this paper, we propose a pruned, nondirect product multi-configuration time dependent Hartree (MCTDH) method for solving the Schrodinger equation. MCTDH uses optimized 1D basis functions, called single particle functions, but the size of the standard direct product MCTDH basis scales exponentially with D, the number of coordinates. We compare the pruned approach to standard MCTDH calculations for basis sizes small enough that the latter are possible and demonstrate that pruning the basis reduces the CPU cost of computing vibrational energy levels of acetonitrile (D = 12) by more than two orders of magnitude. Using the pruned method, it is possible to do calculations with larger bases, for which the cost of standard MCTDH calculations is prohibitive. Pruning the basis complicates the evaluation of matrix-vector products. In this paper, they are done term by term for a sum-of-products Hamiltonian. When no attempt is made to exploit the fact that matrices representing some of the factors of a term are identity matrices, one needs only to carefully constrain indices. In this paper, we develop new ideas that make it possible to further reduce the CPU time by exploiting identity matrices. PMID- 27475352 TI - The multilevel CC3 coupled cluster model. AB - We present an efficient implementation of the closed shell multilevel coupled cluster method where coupled cluster singles and doubles (CCSD) is used for the inactive orbital space and CCSD with perturbative triples (CC3) is employed for the smaller active orbital space. Using Cholesky orbitals, the active space can be spatially localized and the computational cost is greatly reduced compared to full CC3 while retaining the accuracy of CC3 excitation energies. For the small organic molecules considered we achieve up to two orders of magnitude reduction in the computational requirements. PMID- 27475353 TI - A deterministic alternative to the full configuration interaction quantum Monte Carlo method. AB - Development of exponentially scaling methods has seen great progress in tackling larger systems than previously thought possible. One such technique, full configuration interaction quantum Monte Carlo, is a useful algorithm that allows exact diagonalization through stochastically sampling determinants. The method derives its utility from the information in the matrix elements of the Hamiltonian, along with a stochastic projected wave function, to find the important parts of Hilbert space. However, the stochastic representation of the wave function is not required to search Hilbert space efficiently, and here we describe a highly efficient deterministic method that can achieve chemical accuracy for a wide range of systems, including the difficult Cr2 molecule. We demonstrate for systems like Cr2 that such calculations can be performed in just a few cpu hours which makes it one of the most efficient and accurate methods that can attain chemical accuracy for strongly correlated systems. In addition our method also allows efficient calculation of excited state energies, which we illustrate with benchmark results for the excited states of C2. PMID- 27475354 TI - Analytic second derivative of the energy for density-functional tight-binding combined with the fragment molecular orbital method. AB - The analytic second derivative of the energy is developed for the fragment molecular orbital (FMO) method combined with density-functional tight-binding (DFTB), enabling simulations of infrared and Raman spectra of large molecular systems. The accuracy of the method is established in comparison to full DFTB without fragmentation for a set of representative systems. The performance of the FMO-DFTB Hessian is discussed for molecular systems containing up to 10 041 atoms. The method is applied to the study of the binding of alpha-cyclodextrin to polyethylene glycol, and the calculated IR spectrum of an epoxy amine oligomer reproduces experiment reasonably well. PMID- 27475355 TI - The magnetism and spin-dependent electronic transport properties of boron nitride atomic chains. AB - Very recently, boron nitride atomic chains were successively prepared and observed in experiments [O. Cretu et al., ACS Nano 8, 11950 (2015)]. Herein, using a first-principles technique, we study the magnetism and spin-dependent electronic transport properties of three types of BN atomic chains whose magnetic moment is 1 MUB for BnNn-1, 2 MUB for BnNn, and 3 MUB for BnNn+1 type atomic chains, respectively. The spin-dependent electronic transport results demonstrate that the short BnNn+1 chain presents an obvious spin-filtering effect with high spin polarization ratio (>90%) under low bias voltages. Yet, this spin-filtering effect does not occur for long BnNn+1 chains under high bias voltages and other types of BN atomic chains (BnNn-1 and BnNn). The proposed short BnNn+1 chain is predicted to be an effective low-bias spin filters. Moreover, the length conductance relationships of these BN atomic chains were also studied. PMID- 27475356 TI - Origin of double-line structure in nonsequential double ionization by few-cycle laser pulses. AB - We investigate nonsequential double ionization (NSDI) of molecules by few-cycle laser pulses at the laser intensity of 1.2-1.5 * 10(14) W/cm(2) using the classical ensemble model. The same double-line structure as the lower intensity (1.0 * 10(14) W/cm(2)) is also observed in the correlated electron momentum spectra for 1.2-1.4 * 10(14) W/cm(2). However, in contrast to the lower intensity where NSDI proceeds only through the recollision-induced double excitation with subsequent ionization (RDESI) mechanism, here, the recollision-induced excitation with subsequent ionization (RESI) mechanism has a more significant contribution to NSDI. This indicates that RDESI is not necessary for the formation of the double-line structure and RESI can give rise to the same type of structure independently. Furthermore, we explore the ultrafast dynamics underlying the formation of the double-line structure in RESI. PMID- 27475357 TI - Postcollision multifragmentation in fullerene-surface impact: Microscopic insights via molecular dynamics simulations. AB - Postcollision multifragmentation which we have recently observed experimentally in C60 (-)-surface impact is the phenomenon of a delayed multiparticle breakup of a highly collisionally vibrationally excited large molecule/cluster (the precursor species) into several polyatomic fragments, after leaving the surface. In this paper, we show that the molecular dynamics simulations of near-grazing C60 collisions with a gold surface at 300 eV impact energy (very similar to the experimental conditions) successfully reproduce the experimentally observed characteristics of the postcollision multifragmentation process. The calculated mass resolved kinetic energy distributions and the time dependent yield curves of the Cn fragments revealed a precursor mediated, velocity correlated, delayed fragmentation event along the outgoing trajectory, far away from the surface. Most of the large fragments (n >= 5) are formed within a time window of 2-20 ps after leaving the surface, corresponding to the vertical distances of 3-30 nm from the surface. Analysis of delay times and actual time duration for multifragmentation reveal that a large part can be described as simultaneous postcollision (delayed) multifragmentation events. The delayed nature of the event seems to be due to an early sequence of structural transformations of the precursor. PMID- 27475358 TI - High resolution spectroscopy of jet cooled phenyl radical: The nu1 and nu2 a1 symmetry C-H stretching modes. AB - A series of CH stretch modes in phenyl radical (C6H5) has been investigated via high resolution infrared spectroscopy at sub-Doppler resolution (~60 MHz) in a supersonic discharge slit jet expansion. Two fundamental vibrations of a1 symmetry, nu1 and nu2, are observed and rotationally analyzed for the first time, corresponding to in-phase and out-of-phase symmetric CH stretch excitation at the ortho/meta/para and ortho/para C atoms with respect to the radical center. The nu1 and nu2 band origins are determined to be 3073.968 50(8) cm(-1) and 3062.264 80(7) cm(-1), respectively, which both agree within 5 cm(-1) with theoretical anharmonic scaling predictions based on density functional B3LYP/6 311g++(3df,3dp) calculations. Integrated band strengths for each of the CH stretch bands are analyzed, with the relative intensities agreeing remarkably well with theoretical predictions. Frequency comparison with previous low resolution Ar-matrix spectroscopy [A. V. Friderichsen et al., J. Am. Chem. Soc. 123, 1977 (2001)] reveals a nearly uniform Deltanu ~ + 10-12 cm(-1) blue shift between gas phase and Ar matrix values for nu1 and nu2. This differs substantially from the much smaller red shift (Deltanu ~ - 1 cm(-1)) reported for the nu19 mode, and suggests a simple physical model in terms of vibrational mode symmetry and crowding due to the matrix environment. Finally, the infrared phenyl spectra are well described by a simple asymmetric rigid rotor Hamiltonian and show no evidence for spectral congestion due to intramolecular vibrational coupling, which bodes well for high resolution studies of other ring radicals and polycyclic aromatic hydrocarbons. In summary, the combination of slit jet discharge methods with high resolution infrared lasers enables spectroscopic investigation of even highly reactive combustion and interstellar radical intermediates under gas phase, jet-cooled (Trot ~ 11 K) conditions. PMID- 27475359 TI - Infrared absorption spectrum of the simplest deuterated Criegee intermediate CD2OO. AB - We report a transient infrared (IR) absorption spectrum of the simplest deuterated Criegee intermediate CD2OO recorded using a step-scan Fourier transform spectrometer coupled with a multipass absorption cell. CD2OO was produced from photolysis of flowing mixtures of CD2I2, N2, and O2 (13 or 87 Torr) with laser light at 308 nm. The recorded spectrum shows close structural similarity with the spectrum of CH2OO reported previously [Y.-T. Su et al., Science 340, 174 (2013)]. The four bands observed at 852, 1017, 1054, and 1318 cm(-1) are assigned to the OO stretching mode, two distinct in-plane OCD bending modes, and the CO stretching mode of CD2OO, respectively, according to vibrational wavenumbers, IR intensities, rotational contours, and deuterium isotopic shifts predicted with extensive quantum-chemical calculations. The CO stretching mode of CD2OO at 1318 cm(-1) is blue shifted from the corresponding band of CH2OO at 1286 cm(-1); this can be explained by a mechanism based on mode mixing and isotope substitution. A band near 936 cm(-1), observed only at higher pressure (87 Torr), is tentatively assigned to the CD2 wagging mode of CD2IOO. PMID- 27475360 TI - Full observation of ultrafast cascaded radiationless transitions from S2(pipi(*)) state of pyrazine using vacuum ultraviolet photoelectron imaging. AB - A photoexcited molecule undergoes multiple deactivation and reaction processes simultaneously or sequentially, which have been observed by combinations of various experimental methods. However, a single experimental method that enables complete observation of the photo-induced dynamics would be of great assistance for such studies. Here we report a full observation of cascaded electronic dephasing from S2(pipi(*)) in pyrazine (C4N2H4) by time-resolved photoelectron imaging (TRPEI) using 9.3-eV vacuum ultraviolet pulses with a sub-20 fs time duration. While we previously demonstrated a real-time observation of the ultrafast S2(pipi(*)) -> S1(npi(*)) internal conversion in pyrazine using TRPEI with UV pulses, this study presents a complete observation of the dynamics including radiationless transitions from S1 to S0 (internal conversion) and T1(npi(*)) (intersystem crossing). Also discussed are the role of (1)Au(npi(*)) in the internal conversion and the configuration interaction of the S2(pipi(*)) electronic wave function. PMID- 27475361 TI - Ultrafast photodynamics of pyrazine in the vacuum ultraviolet region studied by time-resolved photoelectron imaging using 7.8-eV pulses. AB - The ultrafast electronic dynamics of pyrazine (C4N2H4) were studied by time resolved photoelectron imaging (TRPEI) using the third (3omega, 4.7 eV) and fifth harmonics (5omega, 7.8 eV) of a femtosecond Ti:sapphire laser (omega). Although the photoionization signals due to the 5omega - 3omega and 3omega - 5omega pulse sequences overlapped near the time origin, we have successfully extracted their individual TRPEI signals using least squares fitting of the observed electron kinetic energy distributions. When the 5omega pulses preceded the 3omega pulses, the 5omega pulses predominantly excited the S4 (pipi(*), (1)B1 u+(1)B2u) state. The photoionization signal from the S4 state generated by the time-delayed 3omega pulses was dominated by the D3((2)B2g)<-S4 photoionization process and exhibited a broad electron kinetic energy distribution, which rapidly downshifted in energy within 100 fs. Also observed were the photoionization signals for the 3s, 3pz, and 3py members of the Rydberg series converging to D0((2)Ag). The Rydberg signals appeared immediately within our instrumental time resolution of 27 fs, indicating that these states are directly photoexcited from the ground state or populated from S4 within 27 fs. The 3s, 3pz, and 3py states exhibited single exponential decay with lifetimes of 94 +/- 2, 89 +/- 2, and 58 +/- 1 fs, respectively. With the reverse pulse sequence of 3omega - 5omega, the ultrafast internal conversion (IC) from S2(pipi(*)) to S1(npi(*)) was observed. The decay associated spectrum of S2 exhibited multiple bands ascribed to D0, D1, and D3, in agreement with the 3omega-pump and 6omega-probe experiment described in our preceding paper [T. Horio et al., J. Chem. Phys. 145, 044306 (2016)]. The electron kinetic energy and angular distributions from S1 populated by IC from S2 are also discussed. PMID- 27475362 TI - [Sb4Au4Sb4](2-): A designer all-metal aromatic sandwich. AB - We report on the computational design of an all-metal aromatic sandwich, [Sb4Au4Sb4](2-). The triple-layered, square-prismatic sandwich complex is the global minimum of the system from Coalescence Kick and Minima Hopping structural searches. Following a standard, qualitative chemical bonding analysis via canonical molecular orbitals, the sandwich complex can be formally described as [Sb4](+)[Au4](4-)[Sb4](+), showing ionic bonding characters with electron transfers in between the Sb4/Au4/Sb4 layers. For an in-depth understanding of the system, one needs to go beyond the above picture. Significant Sb -> Au donation and Sb <- Au back-donation occur, redistributing electrons from the Sb4/Au4/Sb4 layers to the interlayer Sb-Au-Sb edges, which effectively lead to four Sb-Au-Sb three-center two-electron bonds. The complex is a system with 30 valence electrons, excluding the Sb 5s and Au 5d lone-pairs. The two [Sb4](+) ligands constitute an unusual three-fold (pi and sigma) aromatic system with all 22 electrons being delocalized. An energy gap of ~1.6 eV is predicted for this all metal sandwich. The complex is a rare example for rational design of cluster compounds and invites forth-coming synthetic efforts. PMID- 27475363 TI - Integral cross section measurements and product recoil velocity distributions of Xe(2+) + N2 hyperthermal charge-transfer collisions. AB - Charge exchange from doubly charged rare gas cations to simple diatomics proceeds with a large cross section and results in populations of many vibrational and electronic product states. The charge exchange between Xe(2+) and N2, in particular, is known to create N2 (+) in both the A and B electronic states. In this work, we present integral charge exchange cross section measurements of the Xe(2+) + N2 reaction as well as axial recoil velocity distributions of the Xe(+) and N2 (+) product ions for collision energies between 0.3 and 100 eV in the center-of-mass (COM) frame. Total charge-exchange cross sections decrease from 70 A(2) to about 40 A(2) with increasing collision energy through this range. Analysis of the axial velocity distributions indicates that a Xe(2+) - N2 complex exists at low collision energies but is absent by 17.6 eV COM. Analysis of the axial velocity distributions reveals evidence for complexes with lifetimes comparable to the rotational period at low collision energies. The velocity distributions are consistent with quasi-resonant single charge transfer at high collision energies. PMID- 27475364 TI - Precursor anion states in dissociative electron attachment to chlorophenol isomers. AB - We report a theoretical study on low-energy (<10 eV) elastic electron scattering from chlorophenol isomers, namely, para-chlorophenol (pCP), meta-chlorophenol (mCP), and ortho-chlorophenol (oCP). The calculations were performed with the Schwinger multichannel method with pseudopotentials, and analysis of the computed integral cross sections and virtual orbitals revealed one sigmaCCl (*), one sigmaOH (*), and three pi(*) shape resonances. We show that electron capture into the two lower lying pi(*) orbitals initiates dissociative processes that lead to the elimination of the chloride ion, accounting for the two overlapping peaks where this fragment was observed. Despite the relatively small differences on the energetics of the pi(*) resonances, a major isomeric effect was found on their corresponding autodetachment lifetimes, which accounts for the observed increasing cross sections in the progression pCP < mCP < oCP. In particular, dissociation from the pi1 (*) anion of pCP is largely suppressed because of the unfavorable mixing with the sigmaCCl (*) state. We found the intramolecular hydrogen bond present in oCP to have the opposite effects of stabilizing the sigmaCCl (*) resonance and destabilizing the sigmaOH (*) resonance. We also suggest that the hydrogen abstraction observed in chlorophenols and phenol actually takes place by a mechanism in which the incoming electron is directly attached to the dissociative sigmaOH (*) orbital. PMID- 27475365 TI - Coupled cluster evaluation of the frequency dispersion of the first and second hyperpolarizabilities of water, methanol, and dimethyl ether. AB - The static and dynamic first (beta||) and second (gamma||) hyperpolarizabilities of water, methanol, and dimethyl ether have been evaluated within the response function approach using a hierarchy of coupled cluster levels of approximation and doubly augmented correlation consistent atomic basis sets. For the three compounds, the electronic beta|| and gamma|| values calculated at the CCSD and CC3 levels are in good agreement with gas phase electric field-induced second harmonic generation (EFISHG) measurements. In addition, for dimethyl ether, the frequency dispersion of both properties follows closely recent experimental values [V. W. Couling and D. P. Shelton, J. Chem. Phys. 143, 224307 (2015)] demonstrating the reliability of these methods and levels of approximation. This also suggests that the vibrational contributions to the EFISHG responses of these molecules are small. PMID- 27475366 TI - Direct observation of unimolecular decay of CH3CH2CHOO Criegee intermediates to OH radical products. AB - The unimolecular decay of carbonyl oxide intermediates, known as Criegee intermediates, produced in alkene ozonolysis is a significant source of OH radicals in the troposphere. Here, the rate of appearance of OH radical products is examined directly in the time-domain for a prototypical alkyl-substituted Criegee intermediate, CH3CH2CHOO, following vibrational activation under collision-free conditions. Complementary statistical Rice-Ramsperger-Kassel Marcus calculations of the microcanonical unimolecular decay rate for CH3CH2CHOO are also carried out at energies in the vicinity of the barrier for 1,4 hydrogen atom transfer that leads to OH products. Tunneling through the barrier, derived from high level electronic structure calculations, contributes significantly to the decay rate. Infrared transitions of CH3CH2CHOO are identified in the CH stretch overtone region, which are detected by ultraviolet laser-induced fluorescence of the resultant OH products. The features observed are attributed to CH vibrational excitations and conformational forms utilizing insights from theory. Both experiment and theory yield unimolecular decay rates for CH3CH2CHOO of ca. 10(7) s(-1), which are slower than those obtained for syn-CH3CHOO or (CH3)2COO reported previously [Fang et al., J. Chem. Phys. 144, 061102 (2016)] at similar energies. Master equation modeling is also utilized to predict the thermal decay rate of CH3CH2CHOO under atmospheric conditions, giving a rate of 279 s(-1) at 298 K. PMID- 27475367 TI - Selective detection of singlet gerade metastable states of N2. AB - Metastable N2 molecules produced by electron impact on N2 are detected using a unique solid nitrogen matrix detector. The time-of-flight system is shown to be selectively sensitive to a(1)Pig and (1)Sigmag (+) or (1)Gammag metastable species. The latter species had been identified theoretically previously but was detected experimentally for the first time in the present investigation. Their identification and excitation as a function of electron energy from threshold to 300 eV are presented. Comparison is made with the data obtained by other techniques. PMID- 27475368 TI - Fine- and hyperfine-structure effects in molecular photoionization. I. General theory and direct photoionization. AB - We develop a model for predicting fine- and hyperfine intensities in the direct photoionization of molecules based on the separability of electron and nuclear spin states from vibrational-electronic states. Using spherical tensor algebra, we derive highly symmetrized forms of the squared photoionization dipole matrix elements from which we derive the salient selection and propensity rules for fine and hyperfine resolved photoionizing transitions. Our theoretical results are validated by the analysis of the fine-structure resolved photoelectron spectrum of O2 reported by Palm and Merkt [Phys. Rev. Lett. 81, 1385 (1998)] and are used for predicting hyperfine populations of molecular ions produced by photoionization. PMID- 27475369 TI - Fine- and hyperfine-structure effects in molecular photoionization. II. Resonance enhanced multiphoton ionization and hyperfine-selective generation of molecular cations. AB - Resonance-enhanced multiphoton ionization (REMPI) is a widely used technique for studying molecular photoionization and producing molecular cations for spectroscopy and dynamics studies. Here, we present a model for describing hyperfine-structure effects in the REMPI process and for predicting hyperfine populations in molecular ions produced by this method. This model is a generalization of our model for fine- and hyperfine-structure effects in one photon ionization of molecules presented in Paper I [M. Germann and S. Willitsch, J. Chem. Phys. 145, 044314 (2016)]. This generalization is achieved by covering two main aspects: (1) treatment of the neutral bound-bound transition including the hyperfine structure that makes up the first step of the REMPI process and (2) modification of our ionization model to account for anisotropic populations resulting from this first excitation step. Our findings may be used for analyzing results from experiments with molecular ions produced by REMPI and may serve as a theoretical background for hyperfine-selective ionization experiments. PMID- 27475370 TI - Non-adiabatic dynamics investigation of the radiationless decay mechanism of trans-urocanic acid in the S2 state. AB - The trans-urocanic acid, a UV chromophore in the epidermis of human skin, was found to exhibit a wavelength dependent isomerization property. The isomerization quantum yield to cis-urocanic is greatest when being excited to the S1 state, whereas exciting the molecule to the S2 state causes almost no isomerization. The comparative photochemical behavior of the trans-urocanic on the S1 and S2 states continues to be the subject of intense research effort. This study is concerned with the unique photo-behavior of this interesting molecule on the S2 state. Combining the on-the-fly surface hopping dynamics simulations and static electronic structure calculations, three decay channels were observed following excitation to the S2 state. An overwhelming majority of the molecules decay to the S1 state through a planar or pucker characterized minimum energy conical intersection (MECI), and then decay to the ground state along a relaxation coordinate driven by a pucker deformation of the ring. A very small fraction of molecules decay to the S1 state by a MECI characterized by a twisting motion around the CC double bond, which continues to drive the molecule to deactivate to the ground state. The latter channel is related with the photoisomerization process, whereas the former one will only generate the original trans-form products. The present work provides a novel S2 state decay mechanism of this molecule, which offers useful information to explain the wavelength dependent isomerization behavior. PMID- 27475371 TI - Mixed cerium-platinum oxides: Electronic structure of [CeO]Ptn (n = 1, 2) and [CeO2]Pt complex anions and neutrals. AB - The electronic structures of several small Ce-Pt oxide complexes were explored using a combination of anion photoelectron (PE) spectroscopy and density functional theory calculations. Pt and Pt2 both accept electron density from CeO diatomic molecules, in which the cerium atom is in a lower-than-bulk oxidation state (+2 versus bulk +4). Neutral [CeO]Pt and [CeO]Pt2 complexes are therefore ionic, with electronic structures described qualitatively as [CeO(+2)]Pt(-2) and [CeO(+)]Pt2 (-), respectively. The associated anions are described qualitatively as [CeO(+)]Pt(-2) and [CeO(+)]Pt2 (-2), respectively. In both neutrals and anions, the most stable molecular structures determined by calculations feature a distinct CeO moiety, with the positively charged Ce center pointing toward the electron rich Pt or Pt2 moiety. Spectral simulations based on calculated spectroscopic parameters are in fair agreement with the spectra, validating the computationally determined structures. In contrast, when Pt is coupled with CeO2, which has no Ce-localized electrons that can readily be donated to Pt, the anion is described as [CeO2]Pt(-). The molecular structure predicted computationally suggests that it is governed by charge-dipole interactions. The neutral [CeO2]Pt complex lacks charge-dipole stabilizing interactions, and is predicted to be structurally very different from the anion, featuring a single Pt-O-Ce bridge bond. The PE spectra of several of the complexes exhibit evidence of photodissociation with Pt(-) daughter ion formation. The electronic structures of these complexes are related to local interactions in Pt-ceria catalyst-support systems. PMID- 27475373 TI - Photodissociation dynamics of the iodide-uracil (I(-)U) complex. AB - Photofragment action spectroscopy and femtosecond time-resolved photoelectron imaging are utilized to probe the dissociation channels in iodide-uracil (I(-) ? U) binary clusters upon photoexcitation. The photofragment action spectra show strong I(-) and weak [U-H](-) ion signal upon photoexcitation. The action spectra show two bands for I(-) and [U-H](-) production peaking around 4.0 and 4.8 eV. Time-resolved experiments measured the rate of I(-) production resulting from excitation of the two bands. At 4.03 eV and 4.72 eV, the photoelectron signal from I(-) exhibits rise times of 86 +/- 7 ps and 36 +/- 3 ps, respectively. Electronic structure calculations indicate that the lower energy band, which encompasses the vertical detachment energy (4.11 eV) of I(-)U, corresponds to excitation of a dipole-bound state of the complex, while the higher energy band is primarily a pi-pi(*) excitation on the uracil moiety. Although the nature of the two excited states is very different, the long lifetimes for I(-) production suggest that this channel results from internal conversion to the I(-) ? U ground state followed by evaporation of I(-). This hypothesis was tested by comparing the dissociation rates to Rice-Ramsperger-Kassel-Marcus calculations. PMID- 27475372 TI - Solvation structure of the halides from x-ray absorption spectroscopy. AB - Three-dimensional models for the aqueous solvation structures of chloride, bromide, and iodide are reported. K-edge extended X-ray absorption fine structure (EXAFS) and Minuit X-ray absorption near edge (MXAN) analyses found well-defined single shell solvation spheres for bromide and iodide. However, dissolved chloride proved structurally distinct, with two solvation shells needed to explain its strikingly different X-ray absorption near edge structure (XANES) spectrum. Final solvation models were as follows: iodide, 8 water molecules at 3.60 +/- 0.13 A and bromide, 8 water molecules at 3.40 +/- 0.14 A, while chloride solvation included 7 water molecules at 3.15 +/- 0.10 A, and a second shell of 7 water molecules at 4.14 +/- 0.30 A. Each of the three derived solvation shells is approximately uniformly disposed about the halides, with no global asymmetry. Time-dependent density functional theory calculations simulating the chloride XANES spectra following from alternative solvation spheres revealed surprising sensitivity of the electronic state to 6-, 7-, or 8-coordination, implying a strongly bounded phase space for the correct structure during an MXAN fit. MXAN analysis further showed that the asymmetric solvation predicted from molecular dynamics simulations using halide polarization can play no significant part in bulk solvation. Classical molecular dynamics used to explore chloride solvation found a 7-water solvation shell at 3.12 (-0.04/+0.3) A, supporting the experimental result. These experiments provide the first fully three-dimensional structures presenting to atomic resolution the aqueous solvation spheres of the larger halide ions. PMID- 27475374 TI - First spectroscopic observation of gold(i) butadiynylide: Photodetachment velocity map imaging of the AuC4H anion. AB - The velocity map imaging technique was used in the investigation of gold(i) butadiynylide, AuC4H(-), with images recorded at two excitation wavelengths. The resultant photodetachment spectra show a well defined vibrational progression in the neutral with an energy spacing of 343 +/- 3 cm(-1). The adiabatic electron affinity was determined to be 1.775 +/- 0.005 eV and assigned to the X(1)Sigma(+)<-X(2)Sigma(+) transition between the anionic and neutral ground states. Franck-Condon simulations performed on density functional theory optimized geometries assisted the assignment of linear geometries to the neutral and anion and the observed vibrational progression to that of the Au-C4H stretch. PMID- 27475375 TI - The effects of replacing the water model while decoupling water-water and water solute interactions on computed properties of simple salts. AB - The effects of decoupling the water-water and water-solute interactions are studied with selected mono-valent ions as the solute. Using the ion-water cross terms developed for the BLYPSP-4F water model, we replaced the water potential with WAIL, TIP4P, and TIP3P without changing the ion-water parameters. When the adaptive force matching (AFM) derived BLYPSP-4F model is replaced by the other AFM derived WAIL model, the difference in ion properties, such as hydration free energies, radial distribution functions, relative diffusion constants, is negligible, demonstrating the feasibility for combining AFM parameters from different sources. Interestingly, when the AFM-derived ion-water cross-terms are used with a non-AFM based water model, only small changes in the ion properties are observed. The final combined models with TIP3P or TIP4P water reproduce the salt hydration free energies within 6% of experiments. The feasibility of combining AFM models with other non-AFM models is of significance since such combinations allow more complex systems to be studied without specific parameterization. In addition, the study suggests an interesting prospect of reusing the cross-terms when a part of a general force field is replaced with a different model. The prevailing practice, which is to re-derive all cross-terms with combining rules, may not have been optimal. PMID- 27475376 TI - Excitation-energy dependence of solvation dynamics in room-temperature ionic liquids. AB - Influence of the excitation energy of a probe solute molecule on its solvation dynamics and emission spectrum in 1-ethyl-3-methylimidazolium hexafluorophosphate (EMI(+)PF6 (-)) is studied via molecular dynamics simulations using a coarse grained model description. By exciting the probe at different energies, each with an extremely narrow distribution, ensuing solvent relaxation and its dynamic variance are monitored using the isoconfigurational ensemble method. Resulting Stokes shift function, S(t), indicates that long-time solvent relaxation becomes slower with the decreasing excitation energy and approaches the equilibrium correlation function, C(t), of solvent fluctuations. This suggests that the system excited at the red-edge of the spectrum observes linear response better than that at the blue-edge. A detailed analysis of nonequilibrium trajectories shows that the effect of initial configurations on variance of relaxation dynamics is mainly confined to short times; it reaches a maximum around 0.1 ? t ? 1 ps and diminishes as time further increases. The influence of the initial velocity distribution, on the other hand, tends to grow with time and dominates the long-time variations of dynamics. The emission spectrum shows the red-edge effect in accord with previous studies. PMID- 27475377 TI - Two structural relaxations in protein hydration water and their dynamic crossovers. AB - We study the translational single particle dynamics of hydration water of lysozyme upon cooling by means of molecular dynamics simulations. We find that water close to the protein exhibits two distinct relaxations. By characterizing their behavior upon cooling, we are able to assign the first relaxation to the structural alpha-relaxation also present in bulk water and in other glass-forming liquids. The second, slower, relaxation can be ascribed to a dynamic coupling of hydration water motions to the fluctuations of the protein structure. Both relaxation times exhibit crossovers in the behavior upon cooling. For the alpha process, we find upon cooling a crossover from a fragile behavior to a strong behavior at a temperature which is about five degrees higher than that of bulk water. The long-relaxation time appears strictly connected to the protein motion as it shows upon cooling a temperature crossover from a strong behavior with a lower activation energy to a strong behavior with a higher activation energy. The crossover temperature coincides with the temperature of the protein dynamical transition. These findings can help experimentalists to disentangle the different information coming from total correlators and to better characterize hydration water relaxations in different biomolecules. PMID- 27475378 TI - The impacts of surface polarity on the solubility of nanoparticle. AB - In order to study the dependence of water solubility and hydration behavior of nanoparticles on their surface polarity, we designed polar nanoparticles with varying surface polarity by assigning atomic partial charge to the surface of C60. The water solubility of the nanoparticle is enhanced by several orders of magnitude after the introduction of surface polarity. Nevertheless, when the atomic partial charge grows beyond a certain value (qM), the solubility continuously decreases to the level of nonpolar nanoparticle. It should be noted that such qM is comparable with atomic partial charge of a variety of functional groups. The hydration behaviors of nanoparticles were then studied to investigate the non-monotonic dependence of solubility on the surface polarity. The interaction between the polar nanoparticle and the hydration water is stronger than the nonpolar counterpart, which should facilitate the dissolution of the nanoparticles. On the other hand, the surface polarity also reduces the interaction of hydration water with the other water molecules and enhances the interaction between the nanoparticles which may hinder their dispersion. Besides, the introduction of surface polarity disturbs and even rearranges the hydration structure of nonpolar nanoparticle. Interestingly, the polar nanoparticle with less ordered hydration structure tends to have higher water solubility. PMID- 27475379 TI - Nanoindentation of the pristine and irradiated forms of a sodium borosilicate glass: Insights from molecular dynamics simulations. AB - We have carried out classical molecular dynamics simulations in order to get insight into the atomistic mechanisms of the deformation during nanoindentation of the pristine and irradiated forms of a sodium borosilicate glass. In terms of the glass hardness, we have found that the primary factor affecting the decrease of hardness after irradiation is depolymerization rather than free volume, and we argue that this is a general trend applicable to other borosilicate glasses with similar compositions. We have analyzed the changes of the short- and medium-range structures under deformation and found that the creation of oxygen triclusters is an important mechanism in order to describe the deformation of highly polymerized borosilicate glasses and is essential in the understanding of the folding of large rings under stress. We have equally found that the less polymerized glasses present a higher amount of relative densification, while the analysis of bond breaking during the nanoindentation has showed that shear flow is more likely to appear around sodium atoms. The results provided in this study can be proven to be useful in the interpretation of experimental results. PMID- 27475380 TI - Effects of the molecule-electrode interface on the low-bias conductance of Cu-H2 Cu single-molecule junctions. AB - The atomic structure and electronic transport properties of a single hydrogen molecule connected to both symmetric and asymmetric Cu electrodes are investigated by using the non-equilibrium Green's function formalism combined with the density functional theory. Our calculations show that in symmetric Cu-H2 Cu junctions, the low-bias conductance drops rapidly upon stretching, while asymmetric ones present a low-bias conductance spanning the 0.2-0.3 G0 interval for a wide range of electrode separations. This is in good agreement with experiments on Cu atomic contacts in a hydrogen environment. Furthermore, the distribution of the calculated vibrational energies of the two hydrogen atoms in the asymmetric Cu-H2-Cu junction is also consistent with experiments. These findings provide clear evidence for the formation of asymmetric Cu-H2-Cu molecular junctions in breaking Cu atomic contacts in the presence of hydrogen and are also helpful for the design of molecular devices with Cu electrodes. PMID- 27475381 TI - A DFT study of water adsorption on rutile TiO2 (110) surface: The effects of surface steps. AB - The associative and dissociative adsorption of water molecules at low-coverage situations on rutile TiO2 (110) surface with step defects was investigated by the density functional theory calculations. Structural optimization of the hydroxylated/hydrated configurations at step edges along the 111 crystal directions and the dynamic process of water dissociation were discussed to get a better description of the water/TiO2 interface. Our results indicate that steps on the TiO2 (110) surface could be an active site for water dissociation. The results of geometry optimization suggest that the stability of hydroxylated configuration is largely dependent on the locations of the H species and the recombination of water molecules from hydroxyls is observed in the fully hydroxylated condition. However, these hydroxyls can be stabilized by the associatively absorbed water nearby by forming competitive intermolecular hydrogen bonds. The dynamics of water dissociation and hydrogen diffusion were studied by the first principles molecular dynamics simulation and our results suggest that the hydrogen released by water dissociation can be transferred among the adsorbates, such as the unsaturated oxygen atoms-H2O-hydroxyl (TiO-H2O-OH) complex at step edges, or gradually diffuses to the bulk water system in the form of hydronium (H3O(+)) at higher water coverage. PMID- 27475382 TI - Vibrational effects on surface energies and band gaps in hexagonal and cubic ice. AB - Surface energies of hexagonal and cubic water ice are calculated using first principles quantum mechanical methods, including an accurate description of anharmonic nuclear vibrations. We consider two proton-orderings of the hexagonal and cubic ice basal surfaces and three proton-orderings of hexagonal ice prism surfaces, finding that vibrations reduce the surface energies by more than 10%. We compare our vibrational densities of states to recent sum frequency generation absorption measurements and identify surface proton-orderings of experimental ice samples and the origins of characteristic absorption peaks. We also calculate zero point quantum vibrational corrections to the surface electronic band gaps, which range from -1.2 eV for the cubic ice basal surface up to -1.4 eV for the hexagonal ice prism surface. The vibrational corrections to the surface band gaps are up to 12% smaller than for bulk ice. PMID- 27475383 TI - Electron-hole pair effects in methane dissociative chemisorption on Ni(111). AB - The dissociative chemisorption of methane on metal surfaces has attracted much attention in recent years as a prototype of gas-surface reactions in understanding the mode specific and bond selective chemistry. In this work, we systematically investigate the influence of electron-hole pair excitations on the dissociative chemisorption of CH4/CH3D/CHD3 on Ni(111). The energy dissipation induced by surface electron-hole pair excitations is modeled as a friction force introduced in the generalized Langevin equation, in which the independent atomic friction coefficients are determined within the local-density friction approximation. Quasi-classical trajectory calculations for CH4/CH3D/CHD3 have been carried out on a recently developed twelve-dimensional potential energy surface. Comparing the dissociation probabilities obtained with and without friction, our results clearly indicate that the electron-hole pair effects are generally small, both on absolute reactivity of each vibrational state and on the mode specificity and bond selectivity. Given similar observations in both water and methane dissociation processes, we conclude that electron-hole pair excitations would not play an important role as long as the reaction is direct and the interaction time between the molecule and metal electrons is relatively short. PMID- 27475384 TI - What interactions can distort the orientational distribution of interfacial water molecules as probed by second harmonic and sum frequency generation? AB - Aqueous interfaces are omnipresent in nature. Nonlinear optical methods such as second harmonic and sum frequency generation (SHG/SFG) are valuable techniques to access molecular level information from these interfaces. In the interpretation of SHG and SFG data for both scattering and reflection mode experiments, the relation between the second-order hyperpolarizability tensor beta(2), a molecular property, and the surface second-order susceptibility chi(2), a surface averaged property, plays a central role. To correctly describe the molecular details of the interface, it needs to be determined how molecules are oriented, and what the influence is of interfacial electrostatic fields and H-bonding on the orientational distribution. Here, we revisit the relations between beta(2) and chi(2) and show, by means of a Boltzmann average, that significant energy differences are needed to generate measurable changes in the molecular orientational distribution at the interface. In practice, H-bonding and surface pressure such as applied in a Langmuir trough can be strong enough to alter the shape of the orientational distribution function of water. In contrast, electrostatic fields, such as those present in the Stern layer, will not have a significant impact on the shape of the orientational distribution function of water molecules. PMID- 27475385 TI - Freezing effects of oil-in-water emulsions studied by sum-frequency scattering spectroscopy. AB - Temperature-dependent sum-frequency scattering spectroscopy is used to study the properties of hexadecane and dodecane oil droplets in water. The sum-frequency scattering spectra contain vibrational bands that correspond to the symmetric and antisymmetric CH stretching vibrations of the methylene (CH2) and methyl (CH3) groups of the alkane molecules. The relative amplitudes of the vibrational bands provide information on the surface structure and the shape of the oil droplets. We study the sum-frequency scattering spectra over a temperature range of -48 to 24 degrees C, including the freezing transitions of the water matrix and the oil droplets. Hexadecane oil droplets freeze at a higher temperature than the surrounding water, whereas dodecane oil droplets freeze at a lower temperature than the surrounding water. This allows us to independently study the freezing effect of oil and water on the surface structure of the oil droplets. In both cases, freezing leads to a change in the polarization dependencies that are valid in the case of the spherical-symmetric shapes that the oil droplets assume when both water and oil are liquid. We find that the freezing of water leads to a strong distortion of the liquid dodecane surface but has little effect on the surface of already solidified hexadecane. For completely frozen emulsions a further decrease in temperature is observed to lead to a further distortion of the surface of the solid oil particles, which might be caused by increasing hardness of the ice matrix encapsulating the particles. PMID- 27475386 TI - van der Waals torque and force between dielectrically anisotropic layered media. AB - We analyse van der Waals interactions between a pair of dielectrically anisotropic plane-layered media interacting across a dielectrically isotropic solvent medium. We develop a general formalism based on transfer matrices to investigate the van der Waals torque and force in the limit of weak birefringence and dielectric matching between the ordinary axes of the anisotropic layers and the solvent. We apply this formalism to study the following systems: (i) a pair of single anisotropic layers, (ii) a single anisotropic layer interacting with a multilayered slab consisting of alternating anisotropic and isotropic layers, and (iii) a pair of multilayered slabs each consisting of alternating anisotropic and isotropic layers, looking at the cases where the optic axes lie parallel and/or perpendicular to the plane of the layers. For the first case, the optic axes of the oppositely facing anisotropic layers of the two interacting slabs generally possess an angular mismatch, and within each multilayered slab the optic axes may either be the same or undergo constant angular increments across the anisotropic layers. In particular, we examine how the behaviors of the van der Waals torque and force can be "tuned" by adjusting the layer thicknesses, the relative angular increment within each slab, and the angular mismatch between the slabs. PMID- 27475387 TI - In a search for a shape maximizing packing fraction for two-dimensional random sequential adsorption. AB - Random sequential adsorption of various two dimensional objects is studied in order to find a shape which maximizes the saturated packing fraction. This investigation was begun in our previous paper [Ciesla et al., Phys. Chem. Chem. Phys. 17, 24376 (2015)], where the densest packing was studied for smoothed dimers. Here this shape is compared with the smoothed n-mers, spherocylinders, and ellipses. It is found that the highest packing fraction out of the studied shapes is 0.584 05 +/- 0.0001 and is obtained for ellipses having long-to-short axis ratio of 1.85 +/- 0.07. PMID- 27475388 TI - A density functional theory study of the adsorption behaviour of CO2 on Cu2O surfaces. AB - Copper has many applications, particularly in electro-catalysis, where the oxidation state of the copper electrode plays a significant role in the selectivity towards products. Although copper-based materials have clear potential as catalysts in the reduction of CO2 and conversion to products, fundamental understanding of CO2 adsorption and activation on different copper oxide surfaces is still limited. We have used DFT+U methodology to study the surface reconstruction of the three most exposed (111), (110), and (001) surfaces of Cu2O with different possible terminations. Considering several adsorbate geometries, we have investigated CO2 adsorption on five different possible terminations and proposed eight different configurations in which CO2 binds with the surface. Similar to earlier findings, CO2 binds weakly with the most stable Cu2O(111):O surface showing no molecular activation, whereas a number of other surfaces, which can appear in the Cu2O particles morphology, show stronger binding as well as activation of the CO2 molecule. Different CO2 coverages were studied and a detailed structural and electronic charge analysis is presented. The activation of the CO2 molecule is characterized by structural transformations and charge transfer between the surface and the CO2 molecule, which is further confirmed by considerable red shifts in the vibrational frequencies. PMID- 27475389 TI - Influence of surface vacancy defects on the carburisation of Fe 110 surface by carbon monoxide. AB - Adsorption and dissociation of gaseous carbon monoxide (CO) on metal surfaces is one of the most frequently occurring processes of carburisation, known as primary initiator of metal dusting corrosion. Among the various factors that can significantly influence the carburisation process are the intrinsic surface defects such as single surface vacancies occurring at high concentrations due to their low formation energy. Intuitively, adsorption and dissociation barriers of CO are expected to be lowered in the vicinity of a surface vacancy, due to the strong attractive interaction between the vacancy and the C atom. Here the adsorption energies and dissociation pathways of CO on clean and defective Fe 110 surface are explored by means of density functional theory. Interestingly, we find that the O adatom, resulting from the CO dissociation, is unstable in the electron-deficit neighbourhood of the vacancy due to its large electron affinity, and raises the barrier of the carburisation pathway. Still, a full comparative study between the clean surface and the vacancy-defected surface reveals that the complete process of carburisation, starting from adsorption to subsurface diffusion of C, is more favourable in the vicinity of a vacancy defect. PMID- 27475390 TI - Calculations of oxide formation on low-index Cu surfaces. AB - Density-functional theory is used to evaluate the mechanism of copper surface oxidation. Reaction pathways of O2 dissociation on the surface and oxidation of the sub-surface are found on the Cu(100), Cu(110), and Cu(111) facets. At low oxygen coverage, all three surfaces dissociate O2 spontaneously. As oxygen accumulates on the surfaces, O2 dissociation becomes more difficult. A bottleneck to further oxidation occurs when the surfaces are saturated with oxygen. The barriers for O2 dissociation on the O-saturated Cu(100)-c(2*2)-0.5 monolayer (ML) and Cu(100) missing-row structures are 0.97 eV and 0.75 eV, respectively; significantly lower than those have been reported previously. Oxidation of Cu(110)-c(6*2), the most stable (110) surface oxide, has a barrier of 0.72 eV. As the reconstructions grow from step edges, clean Cu(110) surfaces can dissociatively adsorb oxygen until the surface Cu atoms are saturated. After slight rearrangements, these surface areas form a "1 ML" oxide structure which has not been reported in the literature. The barrier for further oxidation of this "1 ML" phase is only 0.31 eV. Finally the oxidized Cu(111) surface has a relatively low reaction energy barrier for O2 dissociation, even at high oxygen coverage, and allows for facile oxidation of the subsurface by fast O diffusion through the surface oxide. The kinetic mechanisms found provide a qualitative explanation of the observed oxidation of the low-index Cu surfaces. PMID- 27475391 TI - Reducing spurious flow in simulations of electrokinetic phenomena. AB - Electrokinetic transport phenomena can strongly influence the behaviour of macromolecules and colloidal particles in solution, with applications in, e.g., DNA translocation through nanopores, electro-osmotic flow in nanocapillaries, and electrophoresis of charged macromolecules. Numerical simulations are an important tool to investigate these electrokinetic phenomena, but are often plagued by spurious fluxes and spurious flows that can easily exceed physical fluxes and flows. Here, we present a method that reduces one of these spurious currents, spurious flow, by several orders of magnitude. We demonstrate the effectiveness and generality of our method for both the electrokinetic lattice-Boltzmann and finite-element-method based algorithms by simulating a charged sphere in an electrolyte solution and flow through a nanopore. We also show that previous attempts to suppress these spurious currents introduce other sources of error. PMID- 27475392 TI - Nonequilibrium simulations of model ionomers in an oscillating electric field. AB - We perform molecular dynamics simulations of a coarse-grained model of ionomer melts in an applied oscillating electric field. The frequency-dependent conductivity and susceptibility are calculated directly from the current density and polarization density, respectively. At high frequencies, we find a peak in the real part of the conductivity due to plasma oscillations of the ions. At lower frequencies, the dynamic response of the ionomers depends on the ionic aggregate morphology in the system, which consists of either percolated or isolated aggregates. We show that the dynamic response of the model ionomers to the applied oscillating field can be understood by comparison with relevant time scales in the systems, obtained from independent calculations. PMID- 27475393 TI - A canonical replica exchange molecular dynamics implementation with normal pressure in each replica. AB - In this paper, we present a new canonical replica exchange molecular dynamics (REMD) simulation method with normal pressure for all replicas (REMD-NV(p) T). This method is suitable for systems for which conventional constant NPT-setups are difficult to implement. In this implementation, each replica has an individual volume, with normal pressure maintained for each replica in the simulation. We derive a novel exchange term and validate this method on the structural properties of SPC/E water and dialanine (Ala2) in the bulk and in the presence of a graphene layer. Compared to conventional constant NPT-REMD and NVT REMD simulations, we find that the structural properties of our new method are in good agreement with simulations in the NPT-ensemble at all temperatures. The structural properties of the systems considered are affected by high pressures at elevated temperatures in the constant NVT-ensemble, an effect that our method corrects for. Unprojected distributions reveal that essential motions of the peptide are affected by the presence of the barostat in the NPT implementation but that the dynamical eigenmodes of the NV(p)T method are in close quantitative agreement with the NVT-ensemble. PMID- 27475394 TI - Induced liquid-crystalline ordering in solutions of stiff and flexible amphiphilic macromolecules: Effect of mixture composition. AB - Impact of mixture composition on self-organization in concentrated solutions of stiff helical and flexible macromolecules was studied by means of molecular dynamics simulation. The macromolecules were composed of identical amphiphilic monomer units but a fraction f of macromolecules had stiff helical backbones and the remaining chains were flexible. In poor solvents the compacted flexible macromolecules coexist with bundles or filament clusters from few intertwined stiff helical macromolecules. The increase of relative content f of helical macromolecules leads to increase of the length of helical clusters, to alignment of clusters with each other, and then to liquid-crystalline-like ordering along a single direction. The formation of filament clusters causes segregation of helical and flexible macromolecules and the alignment of the filaments induces effective liquid-like ordering of flexible macromolecules. A visual analysis and calculation of order parameter relaying the anisotropy of diffraction allow concluding that transition from disordered to liquid-crystalline state proceeds sharply at relatively low content of stiff components. PMID- 27475395 TI - Colloids exposed to random potential energy landscapes: From particle number density to particle-potential and particle-particle interactions. AB - Colloidal particles were exposed to a random potential energy landscape that has been created optically via a speckle pattern. The mean particle density as well as the potential roughness, i.e., the disorder strength, were varied. The local probability density of the particles as well as its main characteristics were determined. For the first time, the disorder-averaged pair density correlation function g((1))(r) and an analogue of the Edwards-Anderson order parameter g((2))(r), which quantifies the correlation of the mean local density among disorder realisations, were measured experimentally and shown to be consistent with replica liquid state theory results. PMID- 27475396 TI - A first principle particle mesh method for solution SAXS of large bio-molecular systems. AB - This paper will show that the solution small angle X-ray scattering (SAXS) intensity of globular and membrane proteins can be efficiently and accurately computed from molecular dynamics trajectories using 3D fast Fourier transforms (FFTs). A suitable particle meshing interpolation, similar to the one used in smooth particle mesh Ewald for electrostatic energies and forces, was combined with a uniform solvent density FFT padding scheme to obtain a convenient SAXS spectral resolution. The CPU time scaling of the method, as a function of system size, is highly favorable and its application to large systems such as solutions of solvated membrane proteins is computationally undemanding. Differently from other approaches, all contributions from the simulation cell are included. This means that the subtraction of the buffer from the solution scattering intensity is straightforward and devoid of artifact due to ad hoc definitions of proximal and distal solvent intensity contributions. PMID- 27475397 TI - Noise-induced multistability in the regulation of cancer by genes and pseudogenes. AB - We extend a previously introduced model of stochastic gene regulation of cancer to a nonlinear case having both gene and pseudogene messenger RNAs (mRNAs) self regulated. The model consists of stochastic Boolean genetic elements and possesses noise-induced multistability (multimodality). We obtain analytical expressions for probabilities for the case of constant but finite number of microRNA molecules which act as a noise source for the competing gene and pseudogene mRNAs. The probability distribution functions display both the global bistability regime as well as even-odd number oscillations for a certain range of model parameters. Statistical characteristics of the mRNA's level fluctuations are evaluated. The obtained results of the extended model advance our understanding of the process of stochastic gene and pseudogene expressions that is crucial in regulation of cancer. PMID- 27475398 TI - Conformational landscape of an amyloid intra-cellular domain and Landau-Ginzburg Wilson paradigm in protein dynamics. AB - The Landau-Ginzburg-Wilson paradigm is proposed as a framework, to investigate the conformational landscape of intrinsically unstructured proteins. A universal Calpha-trace Landau free energy is deduced from general symmetry considerations, with the ensuing all-atom structure modeled using publicly available reconstruction programs Pulchra and Scwrl. As an example, the conformational stability of an amyloid precursor protein intra-cellular domain (AICD) is inspected; the reference conformation is the crystallographic structure with code 3DXC in Protein Data Bank (PDB) that describes a heterodimer of AICD and a nuclear multi-domain adaptor protein Fe65. Those conformations of AICD that correspond to local or near-local minima of the Landau free energy are identified. For this, the response of the original 3DXC conformation to variations in the ambient temperature is investigated, using the Glauber algorithm. The conclusion is that in isolation the AICD conformation in 3DXC must be unstable. A family of degenerate conformations that minimise the Landau free energy is identified, and it is proposed that the native state of an isolated AICD is a superposition of these conformations. The results are fully in line with the presumed intrinsically unstructured character of isolated AICD and should provide a basis for a systematic analysis of AICD structure in future NMR experiments. PMID- 27475399 TI - Note: Activity coefficients and solubilities for the NaCl/epsilon force field. PMID- 27475400 TI - Erratum: "Temperature dependence of contact and dipolar NMR chemical shifts in paramagnetic molecules" [J. Chem. Phys. 142, 054108 (2015)]. PMID- 27475401 TI - Erratum: "The electrostatic response of water to neutral polar solutes: Implications for continuum solvent modeling" [J. Chem. Phys. 138, 224504 (2013)]. PMID- 27475402 TI - Erratum: "Assessment of approximate computational methods for conical intersections and branching plane vectors in organic molecules" [J. Chem. Phys. 141, 124122 (2014)]. PMID- 27475403 TI - Absent MicroRNAs in Different Tissues of Patients with Acquired Cardiomyopathy. AB - MicroRNAs (miRNAs) can be found in a wide range of tissues and body fluids, and their specific signatures can be used to determine diseases or predict clinical courses. The miRNA profiles in biological samples (tissue, serum, peripheral blood mononuclear cells or other body fluids) differ significantly even in the same patient and therefore have their own specificity for the presented condition. Complex profiles of deregulated miRNAs are of high interest, whereas the importance of non-expressed miRNAs was ignored. Since miRNAs regulate gene expression rather negatively, absent miRNAs could indicate genes with unaltered expression that therefore are normally expressed in specific compartments or under specific disease situations. For the first time, non-detectable miRNAs in different tissues and body fluids from patients with different diseases (cardiomyopathies, Alzheimer's disease, bladder cancer, and ocular cancer) were analyzed and compared in this study. miRNA expression data were generated by microarray or TaqMan PCR-based platforms. Lists of absent miRNAs of primarily cardiac patients (myocardium, blood cells, and serum) were clustered and analyzed for potentially involved pathways using two prediction platforms, i.e., miRNA enrichment analysis and annotation tool (miEAA) and DIANA miRPath. Extensive search in biomedical publication databases for the relevance of non-expressed miRNAs in predicted pathways revealed no evidence for their involvement in heart related pathways as indicated by software tools, confirming proposed approach. PMID- 27475404 TI - The Role of Quality Control in Targeted Next-generation Sequencing Library Preparation. AB - Next-generation sequencing (NGS) is getting routinely used in the diagnosis of hereditary diseases, such as human cardiomyopathies. Hence, it is of utter importance to secure high quality sequencing data, enabling the identification of disease-relevant mutations or the conclusion of negative test results. During the process of sample preparation, each protocol for target enrichment library preparation has its own requirements for quality control (QC); however, there is little evidence on the actual impact of these guidelines on resulting data quality. In this study, we analyzed the impact of QC during the diverse library preparation steps of Agilent SureSelect XT target enrichment and Illumina sequencing. We quantified the parameters for a cohort of around 600 samples, which include starting amount of DNA, amount of sheared DNA, smallest and largest fragment size of the starting DNA; amount of DNA after the pre-PCR, and smallest and largest fragment size of the resulting DNA; as well as the amount of the final library, the corresponding smallest and largest fragment size, and the number of detected variants. Intriguingly, there is a high tolerance for variations in all QC steps, meaning that within the boundaries proposed in the current study, a considerable variance at each step of QC can be well tolerated without compromising NGS quality. PMID- 27475405 TI - Quantitative determination of multi markers in five varieties of Withania somnifera using ultra-high performance liquid chromatography with hybrid triple quadrupole linear ion trap mass spectrometer combined with multivariate analysis: Application to pharmaceutical dosage forms. AB - An ultra-high performance liquid chromatography electrospray ionization tandem mass spectrometry method has been developed and validated for simultaneous quantification of six major bioactive compounds in five varieties of Withania somnifera in various plant parts (leaf, stem and root). The analysis was accomplished on Waters ACQUITY UPLC BEH C18 column with linear gradient elution of water/formic acid (0.1%) and acetonitrile at a flow rate of 0.3mLmin(-1). The proposed method was validated with acceptable linearity (r(2), 0.9989-0.9998), precision (RSD, 0.16-2.01%), stability (RSD, 1.04-1.62%) and recovery (RSD <=2.45%), under optimum conditions. The method was also successfully applied for the simultaneous determination of six marker compounds in twenty-six marketed formulations. Hierarchical cluster analysis and principal component analysis were applied to discriminate these twenty-six batches based on characteristics of the bioactive compounds. The results indicated that this method is advance, rapid, sensitive and suitable to reveal the quality of Withania somnifera and also capable of performing quality evaluation of polyherbal formulations having similar markers/raw herbs. PMID- 27475406 TI - Determination of the main impurities formed after acid hydrolysis of soybean extracts and the in vitro mutagenicity and genotoxicity studies of 5-ethoxymethyl 2-furfural. AB - Soybean acid hydrolyzed extracts are raw-materials widely used for manufacturing of pharmaceuticals and cosmetics products due to their high content of isoflavone aglycones. In the present study, the main sugar degradation products 5 hydroxymethyl-2-furfural (HMF) and 5-ethoxymethyl-2-furfural (EMF) were quantitatively determined after acid hydrolysis of extracts from different soybean cultivars by a validated liquid chromatography method. The furanic compounds determined in samples cover the range of 0.16-0.21mg/mL and 0.22 0.33mg/mL for HMF and EMF, respectively. Complementarily, due to the scarce literature regarding the EMF toxicology, this study also assessed the EMF mutagenicity by the Salmonella/microsome test and genotoxicity by the comet assay. The results revealed that EMF did not show mutagenicity at the range of 50 5000MUg/plate in S. typhimurium strains TA98, TA97a, TA100, TA102 and TA1535, but induced DNA damage in HepG2 cells at non-cytotoxic doses of 0.1-1.3mg/mL, mainly by oxidative stress mechanisms. Based on literature of HMF genotoxicity, and considering the EMF genotoxicity results herein shown, purification procedures to remove these impurities from extracts are recommended during healthcare products development to ensure the security of the products. PMID- 27475407 TI - Corrigendum to "Simultaneous determination of itraconazole, hydroxy itraconazole, keto itraconazole and N-desalkyl itraconazole concentration in human plasma using liquid chromatography with tandem mass spectrometry" [J. Chromatogr. B 1020 (2016) 111-119]. PMID- 27475408 TI - Factors associated with having a medical marijuana card among Veterans with recent substance use in VA outpatient treatment. AB - Psychiatric symptoms, somatic problems, and co-occurring substance use have been associated with medical marijuana consumption among civilian patients with substance use disorders. It is possible that these factors may impact Veterans' ability to engage in or adhere to mental health and substance use disorder treatment. Therefore, we examined whether psychiatric functioning, substance use, and somatic problems were associated with medical marijuana use among Veterans receiving substance use disorder and/or mental health treatment. Participants (n=841) completed screening measures for a randomized controlled trial and 67 (8%) reported that they had a current medical marijuana card. Most of these participants (78%) reported using marijuana to treat severe/chronic pain. Significant bivariate differences revealed that, compared to participants without a medical marijuana card, those with a card were more likely to be in a middle income bracket, unemployed, and they had a significantly higher number of recent days of marijuana use, synthetic marijuana use, and using sedatives prescribed to them. Additionally, a significantly higher proportion of participants with a medical marijuana card scored above the clinical cutoff for posttraumatic stress disorder (PTSD) symptoms, had significantly higher severity of sleep-related problems, and reported a higher level of pain. These findings highlight the co occurrence of substance use, PTSD symptoms, sleep-related problems, and chronic pain among Veterans who use medical marijuana. Future research should investigate the inter-relationships among medical marijuana use and other clinical issues (e.g., PTSD symptoms, sleep, pain) over time, and potential implications of medical marijuana use on treatment engagement and response. PMID- 27475410 TI - [Stimulation of spermatogenesis: For whom? Why? How?]. AB - The stimulation of spermatogenesis is the best treatment of infertility for male hypogonadotropic-hypogonadism. The results are very pleasing because a real improvement of semen is sometimes obtained with spontaneous pregnants describing in the literature but after a long duration of treatment, often many months. Sometimes, the treatment improves the technical conditions of ICSI for the embryologists. Stimulation of spermatogenesis by gonadotrophins rFSH and/or hCG is the most used but others treatments, like pulsatile GnRH therapy or clomifene citrate can be used. The purpose of this review is to described the different protocols of stimulation of spermatogenesis and explain their results and finally to see if others indications of stimulation of spermatogenesis are existing. PMID- 27475409 TI - Diphenyl diselenide attenuates oxidative stress and inflammatory parameters in ulcerative colitis: A comparison with ebselen. AB - OBJETIVE: The aim of this study was to evaluate the effects of diphenyl diselenide (PhSe)2 and ebselen (EB) in ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in rats. METHODS: The effects of (PhSe)2 and EB in rats submitted to DSS-induced colitis were determined by measurement of oxidative stress parameters, inflammatory response and bowel histopathological alterations. RESULTS: Animals developed moderate to severe neutrophil infiltration in histopathology assay in DSS rats and (PhSe)2 improved this response. Moreover, the treatment with (PhSe)2 decreased the oxidative damage in lipids and proteins, as well as reversed the superoxide dismutase (SOD) and catalase (CAT) levels in rats treated with DSS. EB was able only to reverse damage in lipids and the low levels of SOD in this animal model. CONCLUSIONS: The organoselenium compounds tested demonstrated an anti-inflammatory and antioxidant activity reducing the colon damage, being (PhSe)2 more effective than EB. PMID- 27475411 TI - Antimullerian hormone among women with and without type 1 diabetes: the Epidemiology of Diabetes Interventions and Complications Study and the Michigan Bone Health and Metabolism Study. AB - OBJECTIVE: To compare concentrations of antimullerian hormone (AMH) in women with and without type 1 diabetes. DESIGN: Cross-sectional analysis of longitudinal studies, adjusting for repeated measures. SETTING: Not applicable. PATIENT(S): Women aged 30-45 years who had not undergone oophorectomy, hysterectomy, or natural menopause at the time of AMH measurement were included (n = 376 in the Michigan Bone Health and Metabolism Study and n = 321 in the Epidemiology of Interventions and Complications Study). Linear mixed regression was used to evaluate whether AMH concentrations differed by diabetes status, adjusting for repeated measurements of AMH within individual women, body mass index, smoking status, and oral contraceptive use. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH. RESULT(S): In unadjusted comparisons, women with and without diabetes had similar median AMH values before 35 years of age, although women with type 1 diabetes had a lower proportion of women with elevated AMH concentrations (>=5.0 ng/dL). After adjustment for covariates and multiple observations per woman, log AMH concentrations were significantly lower among women with type 1 diabetes compared with women without diabetes (beta-coefficient -1.27, 95% confidence interval [-2.18, -0.36] in fully adjusted models) before 35 years of age. CONCLUSION(S): Before 35 years of age, women with type 1 diabetes have lower AMH levels than women without diabetes. Further investigation is needed to determine the etiologies of this difference and how it may contribute to reproductive disorders among women with type 1 diabetes. PMID- 27475413 TI - Is gonadotropin ovarian stimulation for unexplained infertility any longer warranted? PMID- 27475412 TI - Immune-inflammation gene signatures in endometriosis patients. AB - OBJECTIVE: To determine if the molecular profiles of endometriotic lesions contain informative measures of inflammation and immune dysfunction that may contribute to better understanding of the interplay between immune dysfunction and inflammation and their contribution to endometriosis pathogenesis. DESIGN: Immune and inflammation transcriptomic analysis with the use of the Nanostring nCounter GX Human Immunology V2 platform (579 human immune and inflammation related genes and 15 housekeeping genes). SETTING: Academic university and teaching hospital. INTERVENTION(S): None. PATIENT(S): Stage III-IV endometriosis patients with infertility (n = 8) and fertile disease-free control women undergoing tubal ligation (n = 8). Menstrual stage was matched to secretory phase in all participants. MAIN OUTCOME MEASURE(S): Immune and inflammation transcriptomics quantification from ectopic endometriotic lesions and matched eutopic endometrium from patients. Endometria of fertile women served as control subjects. RESULT(S): Our results displayed endometriotic lesions as molecularly distinct entities compared with eutopic endometrium and endometrium of control samples; 396 out of 579 screened immune and inflammation-related genes were significantly different in ectopic tissues compared with control endometrium. Most importantly, eutopic endometrium of the patients displayed a unique molecular profile compared with the control endometrium (91/579 genes were significantly different), particularly of genes involved in regulation of cell apoptosis and decidualization. CONCLUSION(S): We characterize differential expression of immune-inflammation genes in endometriosis patients, and show molecular distinction of eutopic endometrium of patients compared with control fertile women. PMID- 27475414 TI - Loss of object ownership feeling following a left hemisphere infarct. PMID- 27475416 TI - Alterations in neurofilaments and the transformation of the cytoskeleton in axons may provide insight into the aberrant neuronal changes of Alzheimer's disease. AB - Neurofilaments are major protein constituents of the brain, but are particularly abundant in specific subpopulations of neurons and likely have a key role in the regulation of axonal calibre. Neurofilament proteins may also be involved in the transformation of the neuronal cytoskeleton leading to substantial tau pathology in axons damaged by Abeta, subsequently leading to neurofibrillary pathology in their cell bodies of origin. An understanding of neurofilamentous changes in axons and subsequent tau pathology may provide insight into how Abeta pathology may stimulate an aberrant plasticity-related response of damaged neurons, leading to the progressive and degenerative changes in the neuronal cytoskeleton that result in synapse loss and neuronal degeneration. PMID- 27475415 TI - Abnormal cortical synaptic plasticity in minimal hepatic encephalopathy. AB - Minimal hepatic encephalopathy (MHE) represents the earliest stage of hepatic encephalopathy (HE). MHE is characterized by cognitive function impairment in the domains of attention, vigilance and integrative function, while obvious clinical manifestations are lacking. In the present study, we aimed at assessing whether subjects with MHE showed alterations in synaptic plasticity within the motor cortex. Previous findings suggest that learning in human motor cortex occurs through long-term potentiation (LTP)-like mechanisms. We employed therefore the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP-like effects in the motor cortex of normal subjects. Fifteen patients with MHE and 15 age- and sex-matched cirrhotic patients without MHE were recruited. PAS consisted of 180 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right abductor pollicis brevis (APB) at an ISI of 25ms (PAS25). We measured motor evoked potentials (MEPs) before and after each intervention for up to 30min. In healthy subjects the PAS25 protocol was followed by a significant increase of the MEP amplitude. On the contrary, in patients with MHE the MEP amplitude was slightly reduced after PAS. These findings demonstrated that associative sensorimotor plasticity, an indirect probe for motor learning, is impaired in MHE patients. PMID- 27475417 TI - Personalized, relevance-based Multimodal Robotic Imaging and augmented reality for Computer Assisted Interventions. AB - In the last decade, many researchers in medical image computing and computer assisted interventions across the world focused on the development of the Virtual Physiological Human (VPH), aiming at changing the practice of medicine from classification and treatment of diseases to that of modeling and treating patients. These projects resulted in major advancements in segmentation, registration, morphological, physiological and biomechanical modeling based on state of art medical imaging as well as other sensory data. However, a major issue which has not yet come into the focus is personalizing intra-operative imaging, allowing for optimal treatment. In this paper, we discuss the personalization of imaging and visualization process with particular focus on satisfying the challenging requirements of computer assisted interventions. We discuss such requirements and review a series of scientific contributions made by our research team to tackle some of these major challenges. PMID- 27475418 TI - Brief Report: DSM-5 Sensory Behaviours in Children With and Without an Autism Spectrum Disorder. AB - Atypical responses to sensory stimuli are a new criterion in DSM-5 for the diagnosis of an autism spectrum disorder (ASD) but are also reported in other developmental disorders. Using the Short Sensory profile (SSP) and Autism Diagnostic Interview-Revised we compared atypical sensory behaviour (hyper- or hypo-reactivity to sensory input or unusual sensory interests) in children aged 10-14 years with (N = 116) or without an ASD but with special educational needs (SEN; N = 72). Atypical sensory behaviour was reported in 92 % of ASD and 67 % of SEN children. Greater sensory dysfunction was associated with increased autism severity (specifically restricted and repetitive behaviours) and behaviour problems (specifically emotional subscore) on teacher and parent Strengths and Difficulties Questionnaires but not with IQ. PMID- 27475420 TI - Factors affecting functional outcome in patients with intramedullary spinal cord tumors: results from a literature analysis. AB - Recently, great advances have been made in the surgical treatment of intramedullary spinal cord tumors (IMSCTs). Many articles have been published; but looking at the literature of the last 5 years, there are only descriptive reviews and no works in which a literature statistical analysis was performed. Here, we analyzed the literature to identify potential prognosticators of good functional outcome in IMSCT patients. To level out the selected studies, we stratified patients' neurological status as independent (ambulation possible without caregiver assistance) or disabled (cannot ambulate or can only ambulate with caregiver assistance). 18 out of 125 articles were included in the analysis (691 patients). A significant higher percentage of gross total resection (GTR) in ependymomas, hemangioblastomas and cavernomas compared to the astrocytomas (particularly high-grade gliomas) was observed. We found a strong correlation between a good pre-operative neurological function and a good post-operative and at follow-up (FU) neurological status and between GTR and a good post-operative and at FU neurological status. A significant better outcome was found in ependymomas, hemangioblastomas and cavernomas compared to astrocytomas. Our analysis suggests that an early surgery could be reasonable in IMSCTs, because a good pre-operative neurological function is a strong predictor of good neurological outcome. In patients with high-grade gliomas, there is no indication to attempt a GTR due to the infiltrative growth pattern of this tumor that leads to a higher surgical morbidity. Although not innovative, the evidences of our literature statistical analysis strengthen the results from previous surgical series and descriptive reviews. PMID- 27475419 TI - Brief Report: Early VEPs to Pattern-Reversal in Adolescents and Adults with Autism. AB - Autism spectrum disorder (ASD) is characterized by atypical visual perception both in the social and nonsocial domain. In order to measure a reliable visual response, visual evoked potentials were recorded during a passive pattern reversal stimulation in adolescents and adults with and without ASD. While the present results show the same age-related changes in both autistic and non autistic groups, they reveal a smaller P100 amplitude in the ASD group compared to controls. These results confirm that early visual responses are affected in ASD even with a simple, non social and passive stimulation and suggest that they should be considered in order to better understand higher-level processes. PMID- 27475422 TI - Detection of diastereomer peptides as the intermediates generating D-amino acids during acid hydrolysis of peptides. AB - In this study, we investigated whether the amino acid residues within peptides were isomerized (and the peptides converted to diastereomers) during the early stages of acid hydrolysis. We demonstrate that the model dipeptides L-Ala-L-Phe and L-Phe-L-Ala are epimerized to produce the corresponding diastereomers at a very early stage, prior to their acid hydrolytic cleavage to amino acids. Furthermore, the sequence-inverted dipeptides were generated via formation of a diketopiperazine during hydrolytic incubation, and these dipeptides were also epimerized. The proportion of diastereomers increased rapidly during incubation for 0.5-2 h. During acid hydrolysis, C-terminal residues of the model dipeptides were isomerized faster than N-terminal residues, consistent with the observation that the D-amino acid values of the C-terminal residues determined by the 0 h extrapolating method were larger than those of the N-terminal residues. Thus, the artificial D-amino acid contents determined by the 0 h-extrapolating method appear to be products of the isomerization of amino acid residues during acid hydrolysis. PMID- 27475426 TI - Colonoscopy tutorial software made with a cadaver's sectioned images. AB - Novice doctors may watch tutorial videos in training for actual or computed tomographic (CT) colonoscopy. The conventional learning videos can be complemented by virtual colonoscopy software made with a cadaver's sectioned images (SIs). The objective of this study was to assist colonoscopy trainees with the new interactive software. Submucosal segmentation on the SIs was carried out through the whole length of the large intestine. With the SIs and segmented images, a three dimensional model was reconstructed. Six-hundred seventy-one proximal colonoscopic views (conventional views) and corresponding distal colonoscopic views (simulating the retroflexion of a colonoscope) were produced. Not only navigation views showing the current location of the colonoscope tip and its course, but also, supplementary description views were elaborated. The four corresponding views were put into convenient browsing software to be downloaded free from the homepage (anatomy.co.kr). The SI colonoscopy software with the realistic images and supportive tools was available to anybody. Users could readily notice the position and direction of the virtual colonoscope tip and recognize meaningful structures in colonoscopic views. The software is expected to be an auxiliary learning tool to improve technique and related knowledge in actual and CT colonoscopies. Hopefully, the software will be updated using raw images from the Visible Korean project. PMID- 27475427 TI - Photochemical internalisation for solid malignancies. PMID- 27475428 TI - Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial. AB - BACKGROUND: Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies. METHODS: In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged >=18 to <85 years) with local recurrent, advanced, or metastatic cutaneous or subcutaneous malignancies who were clinically assessed as eligible for bleomycin chemotherapy from a single centre in the UK. Patients were given TPCS2a on day 0 by slow intravenous injection, followed by a fixed dose of 15 000 IU/m(2) bleomycin by intravenous infusion on day 4. After 3 h, the surface of the target tumour was illuminated with 652 nm laser light (fixed at 60 J/cm(2)). The TPCS2a starting dose was 0.25 mg/kg and was then escalated in successive dose cohorts of three patients (0.5, 1.0, and 1.5 mg/kg). The primary endpoints were safety and tolerability of TPCS2a; other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00993512, and has been completed. FINDINGS: Between Oct 3, 2009, and Jan 14, 2014, we recruited 22 patients into the trial. 12 patients completed the 3-month follow-up period. Adverse events related to photochemical internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1.0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1.5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1.0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred. INTERPRETATION: TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0.25 mg/kg as the recommended treatment dose for future trials. FUNDING: PCI Biotech. PMID- 27475430 TI - What Is the Optimal Induction Therapy for Younger Fit Patients With AML? AB - Acute myeloid leukemia (AML) is a complex clonal disorder. The disease is characterized by chromosomal and molecular abnormalities that propagate and expand the abnormal clone(s). The main goal of therapy is to achieve and ultimately maintain a complete remission. In the younger AML patient (less than 60 years of age), there has been a standardization of the initial therapy with the 3 + 7 regimen, consisting of an anthracycline and cytarabine combination. Recent intensification of the anthracycline has led to improved remission and survival outcomes in these patients. Prognosis and therapy in this disease is driven by cytogenetic studies and the additional molecular information that is gathered at the time of diagnosis. With the finding of potential targetable lesions within these molecular aberrancies, new treatments are emerging to deepen remissions and ultimately improve survival. PMID- 27475429 TI - Chimeric Antigen Receptor T cells for B Cell Neoplasms: Choose the Right CAR for You. AB - Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors against cancer. Chimeric antigen receptor (CAR) T cells are the best-in-class example that genetic engineering of T cells can lead to deep and durable responses, as has been shown in several clinical trials for CD19+ B cell malignancies. As a consequence, in the last few years, several academic institutions and commercial partners have started developing anti-CD19 CAR T cell products. Although most of these T cell products are highly effective in vivo, basic differences among them can generate different performance characteristics and thereby impact their long-term clinical outcome. Several strategies are being implemented in order to solve the current open issues of CART19 therapy: (i) increasing efficacy against indolent B cell leukemias and lymphomas, (ii) avoiding or preventing antigen-loss relapses, (iii) reducing and managing toxicity, and (iv) bringing this CART therapy to routine clinical practice. The field of CART therapies is thriving, and exciting new avenues are opening for both scientists and patients. PMID- 27475431 TI - Zinc status, dietary zinc intake and metabolic risk in Australian children and adolescents; Nepean Longitudinal Study. AB - PURPOSE: Zinc is essential for normal growth and metabolism. We aimed to characterise the total and bioavailable dietary zinc intake and plasma zinc concentrations in healthy children, longitudinally, and to examine the association between plasma zinc concentrations, dietary zinc intake and cardiometabolic markers in the same cohort. METHODS: A secondary data analysis of a prospective cohort study, the Nepean Longitudinal Study, which followed an Australian birth cohort at ages 8 (n = 436) and 15 years (n = 290) collecting dietary, anthropometry and biochemistry data (plasma zinc, fasting glucose, insulin and lipid profile). Diet was assessed by a 3-day food record and a food frequency questionnaire at 8 and 15 years, respectively. Zinc bioavailability was determined by the phytate/zinc molar ratio. RESULTS: At 8 years, the median zinc intake was 7.84 mg (interquartile range 6.57-9.35) for boys and 7.06 mg (5.98 8.30) for girls. Three of 345 children reported inadequate absorbable zinc intake, and none reported inadequate total zinc intake. At 15 years, median zinc intake was 11.8 mg (9.41-14.8) for boys and 8.54 mg (6.76-10.7) for girls. The prevalence of inadequate intakes of absorbable zinc and total zinc was 19 and 29 %, respectively. Plasma zinc concentration was not correlated with dietary zinc intake, adiposity nor lipids at either time point, but it was inversely correlated with fasting glucose at 8 year and with insulin at 15 years. CONCLUSIONS: Australian children had an overall adequate zinc status. However, adolescents who reported suboptimal dietary zinc intakes were more likely to have raised insulin concentrations. PMID- 27475432 TI - Water-soluble ions and carbon content of size-segregated aerosols in New Delhi, India: direct and indirect influences of firework displays. AB - The particle size distribution and water-soluble inorganic ion (WSII) and carbonaceous species in size-segregated aerosols, Dp < 0.95, 0.95 < Dp < 1.5, 1.5 < Dp < 3.0, 3.0 < Dp < 7.2, and 7.2 < Dp < 10 MUm, were investigated during Diwali firework displays in New Delhi, India. The firework activity had the maximum contribution to the mass loading of PM0.95 (786 MUg/m3) followed by PM0.95-1.5 (216 MUg/m3) with all other three fractions accounting to a total of 214 MUg/m3. The percentage contributions of WSII to the total mass of aerosols were highest in first two size fractions (39 and 40 %, respectively), compared to other fractions. The firework marker ion (Mg2+, Cl-, and K+) mass concentration shows higher values in PM0.95 during Diwali compared to before Diwali period. The mass size distribution of particles, NH4+, K+, Cl-, SO42-, Mg2+, and NO3-, also showed changes on the Diwali night compared to previous and after days. The high Cl-/Na+ (5.6) and OC/EC (3.4) ratio of PM0.95 can be used as the indicators of firework displays. The lowering of mixing height on Diwali night to 50 m compared to before (277 mts) and after (269 mts) Diwali period further concentrated the aerosols in ambient atmosphere. Therefore, the firework display not only released the gaseous or elemental constituent but also influenced the temperature profile and both put together result in high aerosol concentrations, WSII, OC, and BC contents in ambient atmosphere. The alveolar, respirable, and inhalable fractions accounted for 64.6, 90.8, and 97.8 %, respectively, of the total PM10 mass. People stay exposed to such high pollution level in short span of 6-8 h and experience adverse health impacts due to high mass concentrations and the chemical components of fine aerosols. PMID- 27475433 TI - Performance of ZnO synthesized by sol-gel as photocatalyst in the photooxidation reaction of NO. AB - ZnO samples were prepared by sol-gel method applying a factorial design in order to improve the photocatalytic properties of the semiconductor oxide in the NO photooxidation reaction. The concentrations of zinc acetate and ammonium hydroxide were selected as critical variables in the synthesis of ZnO. Nine samples of ZnO were obtained as product of the factorial design and were characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, diffuse reflectance spectroscopy, and N2 adsorption-desorption isotherms. The photocatalytic activity of ZnO samples was associated with the physical properties developed by each sample according to its respective conditions of synthesis. Some photocatalytic reaction parameters, such as mass of photocatalyst, irradiance, and relative humidity, were modified in order to evaluate its effect in the photocatalytic conversion of NO. As a relevant point, the relative humidity played an important role in the increase of the selectivity of the NO photooxidation reaction to innocuous nitrate ions when ZnO was used as photocatalyst. PMID- 27475434 TI - Variations of polycyclic aromatic hydrocarbons in ambient air during haze and non haze episodes in warm seasons in Hangzhou, China. AB - To investigate the characteristics of polycyclic aromatic hydrocarbons (PAHs) during haze episodes in warm seasons, daily PM2.5 and gaseous samples were collected from March to September 2015 in Hangzhou, China. Daily samples were further divided into four groups by the definition of haze according to visibility and relative humidity (RH), including non-haze (visibility, >10 km), light haze (visibility, 8-10 km, RH <90 %), medium haze (visibility, 5-8 km, RH <90 %), and heavy haze (visibility, <5 km, RH <90 %). Significantly higher concentrations of PM2.5-bound PAHs were found in haze days, but the mean PM2.5 bound PAH concentrations obviously decreased with the aggravation of haze pollution from light to heavy. The gas/particle partitioning coefficients of PAHs decreased from light-haze to heavy-haze episodes, which indicated that PM2.5 bound PAHs were restricted to adhere to the particulate phase with the aggravation of haze pollution. Absorption was considered the main mechanism of gas/particle partitioning of PAHs from gaseous to particulate phase. Analysis of air mass transport indicated that the PM2.5-bound PAH pollution in haze days was largely from regional sources but also significantly affected by long-range air mass transport. The inhalation cancer risk associated with PAHs exceeded the acceptable risk level markedly in both haze and non-haze days. PMID- 27475435 TI - Human exposure and risk assessment associated with mercury pollution in the Caqueta River, Colombian Amazon. AB - Mercury (Hg) is a global contaminant posing severe risks to human health worldwide. The aim of this study was to assess the levels of total Hg (T-Hg) in human hair and fish in the Caqueta River, at the Colombian Amazon, as well as to determine fish consumption-based risks for T-Hg ingestion. T-Hg levels were measured using a direct mercury analyzer. The overall mean T-Hg level in hair for humans in the Caqueta River sample (n = 200) was 17.29 +/- 0.61 MUg/g (1.2 to 47.0 MUg/g). Ninety-four percent of the individuals had hair T-Hg concentrations greater than the WHO threshold level (5 MUg/g), and 79 % displayed levels higher than 10 MUg/g. Average Hg concentrations in fish varied between 0.10-0.15 MUg/g and 0.10-1.60 MUg/g, for noncarnivorous and carnivorous species, respectively. Based on the maximum allowable fish consumption rate for adults, most carnivorous species should be avoided in the diet, as their target hazard quotient ranged from 2.96 up to 31.05, representing a risk for Hg-related health problems. In the light of existing evidence for elevated Hg levels in the indigenous population of the Colombian Amazon, carnivorous fish should be restricted as part of the diet, and breastfeeding should be reduced to protect children health. Most importantly, gold mining activities directly on rivers demand immediate attention from the national government to avoid extensive damage on the environment and human health. PMID- 27475436 TI - Comprehensive assessment of seldom monitored trace elements pollution in the riparian soils of the Miyun Reservoir, China. AB - The South-to-North Water Diversion Project has aroused widespread concerns about the potential ecological risks posed by the project, especially for the Miyun Reservoir (MYR). The potential release risk of metals from the flooded riparian soils into MYR after water impoundment is one of key scientific problems. In this study, riparian soil samples were collected considering three vertical heights (130, 140, and 145 m) and four types of land uses in the MYR areas, namely, forestland, grassland, wasteland, and recreational land. We analyzed soils texture, the content and chemical fractionations of seldom monitored trace elements (SMTEs): Li, Be, B, V, Co, Ni, Ga, Sn, Sb, Tl, and Bi). Results showed that the four types of soils in MYR had the similar textures, while recreational land showed significantly higher contents of Ni and V. Additionally, there were no significant differences found for most SMTEs (except for V) at different vertical heights in each soil type, while the concentrations of V at 140 and 145 m in forestland and recreational land were significantly higher than those at 130 m. However, a comprehensive evaluation of potential ecological risk (contamination factor (CF), modified degree of contamination (mCd), and geoaccumulation factor (I geo)) consistently indicated the insignificant contaminations of all SMTEs in MYR soils before water impoundment. The Community Bureau of Reference (BCR) sequential extraction results showed that the chemical fractionations of SMTEs were independent of land use patterns and vertical heights. Co in reducible fractions and Ni were identified as the candidates which had potential to release into MYR when the lands were submerged. Principal component analysis (PCA) and cluster analysis (CA) results suggested that a portion of V, Co, and Ni may originate from anthropogenic activities, and the coal combustion was possibly the main anthropogenic source. The findings of this work would provide valuable information on the environment management of MYR and offer a reference for the investigation on the effect of water impoundment on potential release risk of SMTEs in MYR. PMID- 27475438 TI - Atmospheric monitoring of organochlorine pesticides across some West African countries. AB - Most African countries have ratified the Stockholm Convention on persistent organic pollutants (POPs) and are expected to reduce emissions of POPs such as organochlorine pesticides (OCPs) to the atmosphere. Emerging evidence, however, suggests that there are contemporary sources of OCPs in African countries despite the global ban on these products. This study investigated the atmospheric contamination from OCPs in four West African countries-Togo, Benin, Nigeria, and Cameroon-to ascertain the emission levels of OCPs and the characteristic signatures of contamination. Polyurethane foam (PUF) disk passive air samplers (PAS) were deployed in each country for ca. 55 days in 2012 and analyzed for 25 OCPs. Hexachlorocyclohexanes (HCHs) and DDTs constituted the highest burden of atmospheric OCPs in the target countries, at average concentrations of 441 pg m-3 (range 23-2718) and 403 pg m-3 (range 91-1880), respectively. Mirex had the lowest concentration, ranged between 0.1 and 3.3 pg m-3. The concentration of OCPs in rainy season was higher than in dry season in Cameroon, and presupposed inputs from agriculture during the rainy season. The concentrations of ?25 OCPs in each country were in the following order: Cameroon > Nigeria > Benin > Togo. There was significant evidence, based on chemical signatures of the contamination that DDT, aldrin, chlordane, and endosulfan were recently applied at certain sites in the respective countries. PMID- 27475437 TI - Genotoxicity assessment of the Danube River using tissues of freshwater bream (Abramis brama). AB - This study examines the use of freshwater bream (Abramis brama) as a sentinel organism for genotoxicity assessment of the Danube River using the comet assay. Sampling of bream was performed during February, April, August, and November in 2014 to assess seasonal variation of DNA damage level as a response to genotoxicity in annual cycle. Additionally, concentrations of fecal coliforms and enterococci were analyzed and they indicated a critical to strong level of fecal pollution on investigated locality during annual cycle. Comet assay was performed on blood, liver, and gill cells of bream. DNA damage level was expressed using tail intensity (TI %), Olive tail moment (OTM), and tail length (TL pix). According to TI and OTM, all three tissues had the highest level of DNA damage in August. The lowest level of DNA damage in liver was measured during February, in blood during November, and in gills during April. According to TL, gills had the highest level of DNA damage in February, and liver cells had the lowest level of damage during April. Multiple correspondence analysis (MCA) showed that DNA damage in blood cells is under the strong influence of variations in NO2, NO3-, NH4+ levels and also the variation in temperature and oxygen levels. DNA damage in liver cells is highly associated with the variations of Mn, Fe, Cu, Zn, and PO43- levels. DNA damage in gill cells is strongly affected by the variations of As, Cd, Pb, Cr, and COD (Mn) levels. Freshwater bream is shown to be a potentially good indicator organism in genotoxic potential field studies. PMID- 27475439 TI - Assessing persistent organic pollutants (POPs) in the Sicily Island atmosphere, Mediterranean, using PUF disk passive air samplers. AB - In this study, PUF disk passive air samplers were deployed at eight sites, during two sampling periods, on the Island of Sicily in the Mediterranean basin. Samples were screened for a number of persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs) (n = 28 congeners), organochlorine pesticides (OCPs) (n = 16 compounds), and polybrominated biphenyl ethers (PBDEs n = 28) using GC-MS. PCB concentrations in air ranged ~10-300 pg m-3. The PCB pattern was dominated by lower to middle molecular weight PCBs (Cl3-5) and PCB-28 and PCB-52 were the most abundant congeners. alpha- and gamma-Hexachlorocyclohexanes (HCHs) concentrations in air were relatively high ~420 +/- 320 (50-1000) and 460 +/- 340 (30-1000) pg m-3, respectively, with an average alpha/gamma ratio of 1 +/- 0.5, indicating a tendency of higher use of lindane than of technical HCH. Among DDTs, only p,p'-DDT 90 +/- 15 (~10-800) and p,p'-DDE 60 +/- 60 (20-400) were frequently detected. DDT/DDE = 0.4-3.0 (1.0 +/- 0.7 for both periods) suggesting past and fresh inputs of DDT at the sampling sites. alpha-Endosulfan, recently included in Annex A of the Stockholm Convention, fluctuated between 120 +/- 50 (50-1000) pg m 3. In contrast, PBDE levels were very low (0.2-2 pg m-3). Back trajectories of advection suggest that POP levels are mainly related to local sources (primary or secondary) from Sicily (50-70 % contribution of air masses), Southern Italy, and Sardinia (20 %). This study provides new information for POP levels in the atmosphere of the Mediterranean region. PMID- 27475440 TI - Sequestration of precious and pollutant metals in biomass of cultured water hyacinth (Eichhornia crassipes). AB - The aim of this study was to investigate the overall root/shoot allocation of metal contaminants, the amount of metal removal by absorption and adsorption within or on the external root surfaces, the dose-response of water hyacinth metal uptake, and phytotoxicity. This was examined in a single-metal tub trial, using arsenic (As), gold (Au), copper (Cu), iron (Fe), mercury (Hg), manganese (Mn), uranium (U), and zinc (Zn). Iron and Mn were also used in low-, medium-, and high-concentration treatments to test their dose effect on water hyacinth's metal uptake. Water hyacinth was generally tolerant to metallotoxicity, except for Cu and Hg. Over 80 % of the total amount of metals removed was accumulated in the roots, of which 30-52 % was adsorbed onto the root surfaces. Furthermore, 73 98 % of the total metal assimilation by water hyacinth was located in the roots. The bioconcentration factor (BCF) of Cu, Hg, Au, and Zn exceeded the recommended index of 1000, which is used in selection of phytoremediating plants, but those of U, As, and Mn did not. Nevertheless, the BCF for Mn increased with the increase of Mn concentration in water. This suggests that the use of BCF index alone, without the consideration of plant biomass and metal concentration in water, is inadequate to determine the potential of plants for phytoremediation accurately. Thus, this study confirms that water hyacinth holds potential for a broad spectrum of phytoremediation roles. However, knowing whether these metals are adsorbed on or assimilated within the plant tissues as well as knowing their allocation between roots and shoots will inform decisions how to re-treat biomass for metal recovery, or the mode of biomass reduction for safe disposal after phytoremediation. PMID- 27475441 TI - Global identification and expression analysis of stress-responsive genes of the Argonaute family in apple. AB - Argonaute (AGO) proteins, which are found in yeast, animals, and plants, are the core molecules of the RNA-induced silencing complex. These proteins play important roles in plant growth, development, and responses to biotic stresses. The complete analysis and classification of the AGO gene family have been recently reported in different plants. Nevertheless, systematic analysis and expression profiling of these genes have not been performed in apple (Malus domestica). Approximately 15 AGO genes were identified in the apple genome. The phylogenetic tree, chromosome location, conserved protein motifs, gene structure, and expression of the AGO gene family in apple were analyzed for gene prediction. All AGO genes were phylogenetically clustered into four groups (i.e., AGO1, AGO4, MEL1/AGO5, and ZIPPY/AGO7) with the AGO genes of Arabidopsis. These groups of the AGO gene family were statistically analyzed and compared among 31 plant species. The predicted apple AGO genes are distributed across nine chromosomes at different densities and include three segment duplications. Expression studies indicated that 15 AGO genes exhibit different expression patterns in at least one of the tissues tested. Additionally, analysis of gene expression levels indicated that the genes are mostly involved in responses to NaCl, PEG, heat, and low temperature stresses. Hence, several candidate AGO genes are involved in different aspects of physiological and developmental processes and may play an important role in abiotic stress responses in apple. To the best of our knowledge, this study is the first to report a comprehensive analysis of the apple AGO gene family. Our results provide useful information to understand the classification and putative functions of these proteins, especially for gene members that may play important roles in abiotic stress responses in M. hupehensis. PMID- 27475442 TI - Photosensitive diazotized poly(ethylene glycol) covalent capillary coatings for analysis of proteins by capillary electrophoresis. AB - A new method for the fabrication of covalently cross-linked capillary coatings of poly(ethylene glycol) (PEG) is described using diazotized PEG (diazo-PEG) as a new photosensitive coating agent. The film of diazo-PEG depends on ionic bonding and was first prepared on the inner surface of capillary by self-assembly, and ionic bonding was converted into covalent bonding after reaction of ultraviolet light with diazo groups through unique photochemical reaction. The covalently bonded coating impedance adsorption of protein on the central surface of capillary and hence the four proteins ribonuclease A, cytochrome c, bovine serum albumin, and lysosome can be baseline separated by using capillary electrophoresis (CE). The covalently cross-linked diazo-PEG capillary column coatings not only improved the CE separation performance for proteins compared to non-covalently cross-linked coatings or bare capillary but also showed a remarkable chemical solidity and repeatability. Because photosensitive diazo-PEG took the place of the highly noxious and silane moisture-sensitive coating reagents in the fabrication of covalent coating, this technique shows the advantage of being environment-friendly and having a high efficiency for CE to make the covalently bonded capillaries. PMID- 27475443 TI - Determination of type A trichothecenes in coix seed by magnetic solid-phase extraction based on magnetic multi-walled carbon nanotubes coupled with ultra high performance liquid chromatography-tandem mass spectrometry. AB - Magnetic solid-phase extraction (m-SPE) is a promising sample preparation approach due to its convenience, speed, and simplicity. For the first time, a rapid and reliable m-SPE approach using magnetic multi-walled carbon nanotubes (m MWCNTs) as the adsorbent was proposed for purification of type A trichothecenes including T-2 toxins (T2), HT-2 toxins (HT-2), diacetoxyscirpenol (DAS), and neosolaniol (NEO) in coix seed. The m-MWCNTs were synthesized by assembling the magnetic nanoparticles (Fe3O4) with MWCNTs by sonication through an aggregation wrap mechanism, and characterized by transmission electron microscope. Several key parameters affecting the performance of the procedure were extensively investigated including extraction solutions, desorption solvents, and m-MWCNT amounts. Under the optimal sample preparation conditions followed by analysis with ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS), high sensitivity (limit of quantification in the range of 0.3-1.5 MUg kg( 1)), good linearity (R (2) > 0.99), satisfactory recovery (73.6-90.6 %), and acceptable precision (<=2.5 %) were obtained. The analytical performance of the developed method has also been successfully evaluated in real coix seed samples. Graphical Abstract Flow chart of determination of type A trichothecenes in coix seed by magnetic solid-phase extraction coupled with ultra-high performance liquid chromatography-tandem mass spectrometry. PMID- 27475444 TI - Identification of Stachybotrys spp. by MALDI-TOF mass spectrometry. AB - Stachybotrys (S.) spp. are omnipresent cellulolytic molds. Some species are highly toxic owing to their ability to synthesize various secondary metabolites such as macrocyclic trichothecenes or hemolysins. The reliable identification of Stachybotrys at species level is currently limited to genome-based identification. This study aimed to establish a fast and reliable MALDI-TOF MS identification method by optimizing the pre-analytical steps for protein extraction for subsequent generation of high-quality fingerprint mass spectra. Eight reference strains of the American Type Culture Collection and the Technical University of Denmark were cultivated in triplicate (biological repetitions) for 2 days in malt extract broth. The mycelia (1.5 ml) were first washed with 75 % ethanol and an additional washing step with dimethyl sulfoxide (10 %) was added to remove unspecific low weight masses. Furthermore, mycelia were broken with roughened glass beads in formic acid (70 %) and acetonitrile. The method was successfully applied to a total of 45 isolates of Stachybotrys originating from three different habitats (indoor, feed, and food samples; n = 15 each): Twenty seven isolates of S. chartarum and 18 isolates of S. chlorohalonata could be identified by MALDI-TOF MS. The data obtained exactly matched those obtained by genome-based identification. The mean score values for S. chartarum ranged from 2.509 to 2.739 and from 2.148 to 2.622 for S. chlorohalonata with a very good reproducibility: the relative standard deviations were between 0.3 % and 6.8 %. Thus, MALDI-TOF MS proved to be a fast and reliable alternative to identification of Stachybotrys spp. by nucleotide amplification and sequencing. PMID- 27475445 TI - Process Evaluation of a Workers' Health Surveillance Program for Meat Processing Workers. AB - Objective To evaluate the implementation process of a workers' health surveillance (WHS) program in a Dutch meat processing company. Methods Workers from five plants were eligible to participate in the WHS program. The program consisted of four evaluative components and an intervention component. Qualitative and quantitative methods were used to evaluate seven process aspects. Data were gathered by interviews with stakeholders, participant questionnaires, and from registries of the company and occupational health service. Results Two recruitment strategies were used: open invitation or automatic participation. Of the 986 eligible workers, 305 participated in the program. Average reach was 53 %. Two out of five program components could not be assessed on dose delivered, dose received and fidelity. If components were assessable, 85-100 % of the components was delivered, 66-100 % of the components was received by participants, and fidelity was 100 %. Participants were satisfied with the WHS program (mean score 7.6). Contextual factors that facilitated implementation were among others societal developments and management support. Factors that formed barriers were program novelty and delayed follow-up. Conclusion The WHS program was well received by participants. Not all participants were offered the same number of program components, and not all components were performed according to protocol. Deviation from protocol is an indication of program failure and may affect program effectiveness. PMID- 27475446 TI - Employer Policies and Practices to Manage and Prevent Disability: Conclusion to the Special Issue. AB - Purpose Research of employer policies and practices to manage and prevent disability spans many disciplines and perspectives, and there are many challenges related to stakeholder collaboration, data access, and interventions. The purpose of this article is to synthesize the findings from a conference and year-long collaboration among a group of invited researchers intended to spur new research innovations in this field. Methods A multidisciplinary team of 26 international researchers with published research in employer-based disability management or related fields were invited to attend a 3-day conference in Hopkinton, Massachusetts, USA. The conference goals were to review the status of current research of workplace disability management and prevention, examine its relevance for employer decision-making, compare conceptual frameworks or theoretical perspectives, and recommend future research directions. In this paper, we summarize key points from the 6 resulting papers, compare them with an earlier 2005 conference on improving return-to-work research, and conclude with recommendations for further overarching research directions. Results/Conclusion In comparison with the 2005 conference, a greater emphasis was placed on organizational and social factors, employer roles and responsibilities, methods of implementation, non-clinical approaches, and facilitating stay-at-work as well as return-to-work. A special panel of employer consultants and representatives who were featured at the 2015 conference reinforced the importance of organizational culture, leadership style, and financial decision-making strategies at the employer level. Based on the conference proceedings, we recommend that future research in this area should strive for: (a) broader inclusion of workers and workplaces; (b) attention to multilevel influences in the workplace; PMID- 27475448 TI - Microfinance participation and contraceptive decision-making: results from a national sample of women in Bangladesh. AB - OBJECTIVES: Our objective was to assess whether microfinance participation affords greater contraceptive decision-making power to women. STUDY DESIGN: Population based secondary data analysis. METHODS: In this cross-sectional study using nationally representative data from the Bangladesh Demographic and Health Survey 2011 we conducted multinomial logistic regression to estimate the odds of contraceptive decision-making by respondents and their husbands based on microfinance participation. Microfinance participation was measured as a dichotomous variable and contraceptive decision-making was conceptualized based on who made decisions about contraceptive use: respondents only; their partners or husbands only; or both. RESULTS: The odds of decision-making by the respondent, with the reference case being joint decision-making, were higher for microfinance participants, but they were not significant. The odds of decision making by the husband, with the reference case again being joint decision-making, were significantly lower among men who were partnered with women who participated in microfinance (RRR = 0.70, P < 0.01). CONCLUSION: Microfinance participation by women allowed men to share decision-making power with their wives that resulted in higher odds of joint decision-making. PMID- 27475447 TI - The Role of Ivabradine in the Management of Angina Pectoris. AB - Stable angina pectoris affects 2-4 % of the population in Western countries and entails an annual risk of death and nonfatal myocardial infarction of 1-2 % and 3 %, respectively. Heart rate (HR) is linearly related to myocardial oxygen consumption and coronary blood flow, both at rest and during stress. HR reduction is a key target for the prevention of ischemia/angina and is an important mechanism of action of drugs which are recommended as first line therapy for the treatment of angina in clinical guidelines. However, many patients are often unable to tolerate the doses of beta blocker or non-dihydropyridine calcium antagonists required to achieve the desired symptom control. The selective pacemaker current inhibitor ivabradine was developed as a drug for the management of patients with angina pectoris, through its ability to reduce HR specifically. The available data suggest that ivabradine is a well-tolerated and effective anti anginal agent and it is recommended as a second-line agent for relief of angina in guidelines. However, recent clinical trials of ivabradine have failed to show prognostic benefit and have raised potential concerns about safety. This article will review the available evidence base for the current role of ivabradine in the management of patients with symptomatic angina pectoris in the context of stable coronary artery disease. PMID- 27475449 TI - Diffusion of an innovative online education intervention: experiences and lessons learned. PMID- 27475450 TI - Self-rated health as a predictor of outcomes of type 2 diabetes patient education programmes in Denmark. AB - OBJECTIVE: To explore if self-rated health (SRH) can predict differences in outcomes of patient education programmes among patients with type 2 diabetes over time. STUDY DESIGN: This is an observational cohort study conducted among 83 patients with type 2 diabetes participating in patient education programmes in the Capital Region of Denmark. METHODS: Questionnaire data were collected by telephone interview at baseline and 2 weeks (77 participants, 93%) and 12 months (66, 80%) after the patient education ended. The seven-scale Health Education Impact Questionnaire (HeiQ) was the primary outcome. The independent variable was SRH, which was dichotomized into optimal or poor SRH. Changes over time were assessed using mean values and standard deviation (SD) at each time point and Cohen effect sizes. Odds ratios and 95% confidence intervals were calculated for the likelihood of having poor SRH for each baseline sociodemographic and health related variable. RESULTS: Twelve months after patient education programmes, 60 (72%) patients with optimal SRH at baseline demonstrated increased self management skills, overall acceptance of chronic illness, positive social interaction with others, and improved emotional well-being. Participants with poor SRH (23, 28%) reported no improvements over time. Not being married (odds ratio [OR] 7.79, P < 0.001), living alone (OR 4.93, P = 0.003), having hypertension (OR 8.00, P = 0.031), and being severely obese (OR 4.07, P = 0.009) were significantly associated with having poor SRH. After adjusting for sex, age and vocational training, marital status (OR 9.35, P < 0.001), cohabitation status (OR = 4.96, P = 0.005) and hypertension (OR 10.9, P = 0.03) remained associated with poor SRH. CONCLUSIONS: We found a strong association between SRH and outcomes of patient education, as measured by the HeiQ, at 12 months. Only participants with optimal SRH appeared to benefit from patient education. Other patient characteristics may be responsible to explain the observed difference between patients with optimal and poor SRH. PMID- 27475451 TI - Improving public health competencies through required practice experience. PMID- 27475452 TI - Multi-residue determination of 171 pesticides in cowpea using modified QuEChERS method with multi-walled carbon nanotubes as reversed-dispersive solid-phase extraction materials. AB - A rapid and sensitive method for the determination of 171 pesticides in cowpea was developed using multi-walled carbon nanotubes (MWCNTs) as reversed-dispersive solid-phase (r-DSPE) extraction materials. The clean-up performance of MWCNTs was proved to be obviously superior to PSA and GCB. This method was validated on cowpea spiked at 0.01 and 0.1mgkg(-1) with five replicates. The mean recoveries for 169 pesticides ranged from 74% to 129% with relative standard deviations (RSDs) (n=5) lower than 16.4%, except diflufenican and quizalofop-ethyl. Good linearity for all pesticides was obtained with the calibration curve coefficients (R(2)) larger than 0.9970. The limit of detection (LODs) and limit of quantification (LOQs) for the 171 pesticides ranged from 0.001 to 0.003mgkg(-1) and from 0.002 to 0.009mgkg(-1), respectively. The method was demonstrated to be reliable and sensitive for the routine monitoring of the 171 pesticides in cowpea samples. PMID- 27475453 TI - Pharmacokinetics and bioavailability assessment of Miltefosine in rats using high performance liquid chromatography tandem mass spectrometry. AB - Miltefosine (MFS) is the first effective oral drug for treatment of visceral, mucosal and cutaneous leishmaniasis. In this study, liquid chromatography coupled mass spectrometry (LC-MS/MS) method of MFS was validated in rat plasma and its practical utilization to pharmacokinetic studies in rats for the first time. A rapid, selective and sensitive LC-MS/MS method for MFS in rat plasma was linear over the calibration range of 1-500ng/mL. MFS and Phenacetin (internal standard) were separated on Phenomenex Luna 3MU HILIC 200A (150*4.6mm) column under isocratic condition using methanol: 0.1% formic acid in triple distilled water, 90:10 (v/v) mobile phase at a flow rate of 0.8mL/min. The total chromatographic run time was 4.0min. The intra- and inter-day assay accuracy was observed between 99.45-102.88% and 99.92-101.58%, respectively. The intra- and inter-day assay precision was observed between 2.68-5.54% and 2.35-5.94%, respectively. The validated assay was practically applied to determine the plasma concentrations after oral and intravenous administration of MFS to rats. After oral administration, MFS showed Cmax (3200.00+/-95.39ng/mL) was observed at 12.00h (tmax) and t1/2 was 102.36+/-16.65h. The absolute bioavailability of MFS was 60.33+/-2.32%. PMID- 27475454 TI - Intra-aortic migration of a Kirschner pin: hybrid surgical repair. PMID- 27475455 TI - Effects of two stretching methods on shoulder range of motion and muscle stiffness in baseball players with posterior shoulder tightness: a randomized controlled trial. AB - BACKGROUND: The cross-body stretch and sleeper stretch are widely used for improving flexibility of the posterior shoulder. These stretching methods were modified by Wilk. However, few quantitative data are available on the new, modified stretching methods. A recent study reported the immediate effects of stretching and soft tissue mobilization on the shoulder range of motion (ROM) and muscle stiffness in subjects with posterior shoulder tightness. However, the long term effect of stretching for muscle stiffness is unknown. The objective of this study was to examine the effects of 2 stretching methods, the modified cross-body stretch (MCS) and the modified sleeper stretch (MSS), on shoulder ROM and muscle stiffness in baseball players with posterior shoulder tightness. METHODS: Twenty four college baseball players with ROM limitations in shoulder internal rotation were randomly assigned to the MCS or MSS group. We measured shoulder internal rotation and horizontal adduction ROM and assessed posterior shoulder muscle stiffness with ultrasonic shear wave elastography before and after a 4-week intervention. Subjects were asked to perform 3 repetitions of the stretching exercises every day, for 30 seconds, with their dominant shoulder. RESULTS: In both groups, shoulder internal rotation and horizontal adduction ROM were significantly increased after the 4-week intervention. Muscle stiffness of the teres minor decreased in the MCS group, and that of the infraspinatus decreased in the MSS group. CONCLUSIONS: The MCS and MSS are effective for increasing shoulder internal rotation and horizontal adduction ROM and decreasing muscle stiffness of the infraspinatus or teres minor. PMID- 27475456 TI - A high level of male sexual activity is necessary for the activation of the medial preoptic area and the arcuate nucleus during the 'male effect' in anestrous goats. AB - In small ungulates such as sheep or goats, the introduction of a male among a group of anovulatory females during the anestrus season leads to the reactivation of the gonadotrope axis and ovulation, a phenomenon known as the 'male effect'. In goats, our previous studies have demonstrated the importance of male sexual activity for an efficient reactivation of the gonadotrope axis assessed through ovulation and blood LH pulsatility. In the present experiment, we assessed whether the level of male sexual activity would also induce differential activation of two brain regions of key importance for the reactivation of GnRH activity, namely the medial preoptic area and the hypothalamic arcuate nucleus. In both structures, we observed a differential activation of Fos in females, depending on the level of buck sexual activity. Indeed, goats unexposed to males showed low levels of expression of Fos while those exposed to sexually inactive bucks showed an intermediate level of Fos expression. Finally, the highest level of Fos expression was found in females exposed to sexually active males. However, and contrary to our initial hypothesis, we were not able to find any specific activation of kisspeptin cells in the arcuate nucleus following the introduction of highly sexually active males. As a whole, these results demonstrate that the level of male sexual activity is a key factor to stimulate brain regions involved in the control of the gonadotrope axis in the context of the male effect in goats. PMID- 27475457 TI - Validity and Reliability of the Arabic Version of the Positive and Negative Syndrome Scale. AB - BACKGROUND: The Positive and Negative Syndrome Scale (PANSS) is widely used for patients with schizophrenia. This scale is reliable and valid. The PANSS was translated and validated in several languages. OBJECTIVE: The aim of this study was to translate and validate the PANSS in the Arab population. SUBJECTS AND METHODS: The PANSS was translated into formal Arabic language using the back translation method. 101 Arab patients with schizophrenia and 98 Arabs with no diagnosis of any mental disorder were recruited. The Arabic version of the Mini International Neuropsychiatric Interview (MINI-6) was used as a diagnostic tool to confirm the diagnosis of schizophrenia or rule out any diagnosis for the healthy control group. Reliability of the scale was assessed by calculating internal consistency, interrater reliability and test-retest reliability. Construct validity was assessed using the Arabic version of the MINI-6. PANSS total scores were correlated with the Clinical Global Impression-Severity scale. RESULTS: Our findings showed that the internal consistency was good (0.92). Scores on the PANSS of the patients were much higher than those of the healthy controls. The PANSS showed good interrater reliability and test-retest reliability (0.92 and 0.75, respectively). In comparison with the MINI-6, the PANSS showed good sensitivity and specificity, which implies good construct validity of this version. CONCLUSION: In conclusion, the Arabic version of the PANSS is a reliable and valid instrument for the assessment of patients with schizophrenia in the Arab population. PMID- 27475458 TI - BIOBRAD Study: The Search for Biomarkers of Bradykinin-Mediated Angio-Oedema Attacks. AB - BACKGROUND: The aetiology of angio-oedema (AE) is difficult to determine; however, it is essential in emergency situations when two major contexts may be present: mast cell-mediated AE and bradykinin-mediated AE. Different forms of AE are currently distinguished based on clinical criteria (spontaneous duration of the attack, presence of concomitant or late-appearing superficial urticaria, history of atopy, and others), but specific biomarkers could improve patient management. OBJECTIVE: In this prospective study, potential biomarkers have been identified, and their statistical characteristics were examined. METHODS: Samples were taken on day 0 (D0) and D7 for 3 patient groups (n = 11 each): bradykinin mediated AE [peripheral site of attack, ear, nose, throat (ENT), and abdominal involvement], mast cell-mediated AE, and non-bradykinin-mediated abdominal pain. RESULTS: Assay of the potential biomarkers revealed no significant differences in C1 inhibitor and C4 levels. In contrast, D-dimer levels peaked during bradykinin mediated AE attacks (median 2.2 mg/l at D0 vs. 0.52 mg/l at D7; p < 10-3) as well as during mast cell-mediated AE attacks (1.97 vs. 0.65 mg/l; p = 0.04) and were high in bradykinin-mediated AE compared to the control group (0.69 mg/l; p = 0.01). A threshold value of 0.62 mg/l was found to have a negative predictive value of 100% for bradykinin-mediated AE compared to other causes of abdominal pain (group 3). Circulating VE-cadherin levels were also increased during an attack (1,990 at D0 vs. 1,566 ng/ml at D7; p = 0.01), but could not distinguish between bradykinin-mediated and mast cell-mediated AE, like D-dimers. CONCLUSIONS: Exploration of changes in fibrinolysis-related markers (particularly D-dimers) is thus promising for the diagnosis of AE attacks in difficult-to diagnose abdominal forms, although it was not able to differentiate between bradykinin and mast cell-mediated AE. PMID- 27475459 TI - Brain transporters: From genes and genetic disorders to function and drug discovery. PMID- 27475460 TI - Theoretical study of nitrodibenzofurans: A possible relationship between molecular properties and mutagenic activity. AB - In this study we present a theoretical investigation of the molecular properties of nitrodibenzofurans (NDFs) and dinitrodibenzofurans (DNDFs) and their relation to mutagenic activity. Equilibrium geometries, relative energies, vertical ionization potentials (IP), vertical electron activities (EA), electronic dipole polarizabilities, and dipole moments of all NDFs and three DNDFs calculated by Density Functional Theory (DFT) methods are reported. The Ziegler/Rauk Energy Decomposition Analysis (EDA) is employed for a direct estimate of the variations of the orbital interaction and steric repulsion terms corresponding to the nitro group and the oxygen of the central ring of NDFs. The results indicate differences among NDF isomers for the cleavage of the related bonds and steric effects in the active site. The results show a good linear relationship between polarizability (), anisotropy of polarizability (Deltaalpha), the summation of IR intensities (SigmaIIR) and the summation of Raman activities (SigmaARaman) over all 3N-6 vibrational modes and experimental mutagenic activities of NDF isomers in Salmonella typhimurium TA98 strain. The polarizability changes with respect to the nusNO+CN vibrational mode are in correlation with the mutagenic activities of NDFs and suggest that intermolecular interactions are favoured along this coordinate. PMID- 27475461 TI - Novel porous fly-ash containing geopolymer monoliths for lead adsorption from wastewaters. AB - In this study novel porous biomass fly ash-containing geopolymer monoliths were produced using a simple and flexible procedure. Geopolymers exhibiting distinct total porosities (ranging from 41.0 to 78.4%) and low apparent density (between 1.21 and 0.44g/cm(3)) were fabricated. Afterwards, the possibility of using these innovative materials as lead adsorbents under distinct conditions was evaluated. Results demonstrate that the geopolymers' porosity and the pH of the ion solution strongly affect the lead adsorption capacity. Lead adsorption by the geopolymer monoliths ranged between 0.95 and 6.34mglead/ggeopolymer. More porous geopolymers presented better lead removal efficiency, while higher pH in the solution reduced their removal ability, since metal precipitation is enhanced. These novel geopolymeric monoliths can be used in packed beds that are easily collected when exhausted, which is a major advantage in comparison with the use of powdered adsorbents. Furthermore, their production encompasses the reuse of biomass fly ash, mitigating the environmental impact associated with this waste disposal, while decreasing the adsorbents production costs. PMID- 27475462 TI - Exploring the potential of anaerobic sulfate reduction process in treating sulfonated diazo dye: Microbial community analysis using bar-coded pyrosequencing. AB - Anaerobic decolorization and biotransformation of azo dye was investigated in a sulfate-reducing environment. Batch reactor studies were performed with mixed cultures of anaerobic sulfate-reducing bacteria (SRBs) enriched from anaerobic digester sludge. Complete sulfate and color removal were achieved in batch experiments with different initial dye concentrations (50-2500mg/L) and 1000mg/L of sulfate. Induction of various oxidoreductive enzyme activities such as phenol oxidase, veratryl alcohol oxidase, lignin peroxidase, and azo reductase was studied to understand their involvement in dye metabolism under anoxic environment. The degradation of Cotton Red B was confirmed using high-performance liquid chromatography and gas chromatography-mass spectroscopy. Sulfidogenic sludge demonstrated excellent dye degradation and mineralization ability, producing aniline and 1,4-diamino benzene as metabolites. A barcoded 16S rRNA gene-pyrosequencing approach was used to assess the bacterial diversity in the sludge culture and a phylogenetic tree was constructed for sulfate-reducing bacteria. PMID- 27475463 TI - Toxicological effects of multi-walled carbon nanotubes on Saccharomyces cerevisiae: The uptake kinetics and mechanisms and the toxic responses. AB - Using Saccharomyces cerevisiae as an experimental model, the potential toxicological effects of oxidized multi-walled carbon nanotubes (MWCNTs) were investigated following exposure to 0-600mg/L for 24h. Results indicated that MWCNTs (>100mg/L) had adverse effects on the cell proliferation. MWCNTs were clearly visible in lysosome, vacuole, endosome, mitochondria, multivesicular body and localization in the perinuclear region. The uptake kinetics data demonstrated that the maximum MWCNTs content (209.61mg/g) was reached at 3h, and a steady state was reached after 18h. Based on the combined results of transmission electron microscope, endocytosis inhibition experiments and endocytosis-related genes (END3, END6, Sla2 and Rsp5) expression analysis, we elucidated MWCNTs uptake mechanism: (i) via a direct penetration of single MWCNTs; (ii) via endocytosis of single MWCNTs; and (iii) via endocytosis of MWCNTs aggregates. The percentage of apoptosis was significant increased at 600mg/L. The decrease of mitochondrial transmembrane potential and the leakage of cytochrome c shown dose dependent manners. Interestingly, there was no significant increase of reactive oxygen species (ROS). The apoptosis-related genes (SOD1, SOD2, Yca1, Nma111 and Nuc1) were significant changed. These results obtained in our study demonstrated that oxidized MWCNTs induce Saccharomyces cerevisiae apoptosis via mitochondrial impairment pathway. PMID- 27475464 TI - Function of a landscape lake in the reduction of biotoxicity related to trace organic chemicals from reclaimed water. AB - The storage of water in a landscape lake can act as a buffer zone between reclaimed water production and reuse, but there is still uncertainty about the variation of water quality and toxic effects during the open-storage process. In this study, long-term sample collection, chemical analyses and biotoxicity assessments were conducted on reclaimed water before and after open storage in a landscape lake. The organic contents, in terms of chemical oxygen demand and total organic carbon, were found to be slightly higher in the lake water than that in the reclaimed water, but substantial reduction of the total concentration of 52 trace organic chemicals was obtained and microorganism toxicity, phytotoxicity, aquatic vertebrate toxicity and genotoxicity, were significantly weakened after open storage. Furthermore, the total risk quotient (RQTotal) decreased from 5.12 (potential ecological risk level) in the reclaimed water to 0.18 (negligible ecological risk level) in the lake water. The removal of chlorpyrifos, dichlorphos and tetracycline was identified as the main reason for biotoxicity reduction after open storage. The seminatural environment of the landscape lake would have provided a favorable condition for the decay of toxic trace organic chemicals so that the stored water turned to be safer for further reuse. PMID- 27475465 TI - Evaluation of three analysis methods for 99mTc MDP SPECT scintigraphy in the diagnosis of unilateral condylar hyperplasia. AB - The aims of the study were to evaluate the diagnostic accuracy and utility of the mean region of interest (ROI) and mean and maximum volume of interest (VOI) analysis methods for 99mTc MDP SPECT scintigraphy in the diagnosis of active unilateral condylar hyperplasia (UCH). Inactive UCH (n=43) and active UCH (n=8) patients, and patients without condylar hyperplasia (controls, n=41) were analyzed. Inter-observer agreement was good for all methods. Condylar uptake was not normally distributed, with a longer right tail in UCH patients compared to control patients. Receiver operating characteristic curve analysis indicated that the ROI method was slightly superior to both VOI methods for the diagnosis of active UCH (area under the curve=0.866, 0.811, and 0.817, and J=0.642, 0.596, and 0.573, respectively). The 'traditional' 55% cut-off value proved optimal for ROI and mean VOI methods, but a cut-off of 56.125% was optimal for maximum VOI. Sensitivity was 88% for all three methods using these cut-off values, while specificity was 77%, 65%, and 70% for mean ROI, mean VOI, and maximum VOI, respectively. These results indicate that corrective surgery for negative scan patients can be performed without delay, with an error rate of only 3%, but not in positive scan patients. PMID- 27475466 TI - Incidence of and risk factors for bowel ischemia after abdominal aortic aneurysm repair. AB - BACKGROUND: Bowel ischemia is a rare but devastating complication after abdominal aortic aneurysm (AAA) repair. Its rarity has prohibited extensive risk-factor analysis, particularly since the widespread adoption of endovascular AAA repair (EVAR); therefore, this study assessed the incidence of postoperative bowel ischemia after AAA repair in the endovascular era and identified risk factors for its occurrence. METHODS: All patients undergoing intact or ruptured AAA repair in the Vascular Study Group of New England (VSGNE) between January 2003 and November 2014 were included. Patients with and without postoperative bowel ischemia were compared and stratified by indication (intact and ruptured) and treatment approach (open repair and EVAR). Criteria for diagnosis were endoscopic or clinical evidence of ischemia, including bloody stools, in patients who died before diagnostic procedures were performed. Independent predictors of postoperative bowel ischemia were established using multivariable logistic regression analysis. RESULTS: Included were 7312 patients, with 6668 intact (67.0% EVAR) and 644 ruptured AAA repairs (31.5% EVAR). The incidence of bowel ischemia after intact repair was 1.6% (open repair, 3.6%; EVAR, 0.6%) and 15.2% after ruptured repair (open repair, 19.3%; EVAR, 6.4%). Ruptured AAA was the most important determinant of postoperative bowel ischemia (odds ratio [OR], 6.4, 95% confidence interval [CI], 4.5-9.0), followed by open repair (OR, 2.9; 95% CI, 1.8 4.7). Additional predictive patient factors were advanced age (OR, 1.4 per 10 years; 95% CI, 1.1-1.7), female gender (OR, 1.6; 95% CI, 1.1-2.2), hypertension (OR, 1.8; 95% CI, 1.1-3.0), heart failure (OR, 1.8; 95% CI, 1.2-2.8), and current smoking (OR, 1.5; 95% CI, 1.1-2.1). Other risk factors included unilateral interruption of the hypogastric artery (OR, 1.7; 95% CI, 1.0-2.8), prolonged operative time (OR, 1.2 per 60-minute increase; 95% CI, 1.1-1.3), blood loss >1 L (OR, 2.0; 95% CI, 1.3-3.0), and a distal anastomosis to the femoral artery (OR, 1.7; 95% CI, 1.1-2.7). Bowel ischemia patients had a significantly higher perioperative mortality after intact (open repair: 20.5% vs 1.9%; P < .001; EVAR: 34.6% vs 0.9%; P < .001) as well as after ruptured AAA repair (open repair: 48.2% vs 25.6%; P < .001; EVAR: 30.8% vs 21.1%; P < .001). CONCLUSIONS: This study underlines that although bowel ischemia after AAA repair is rare, the associated outcomes are very poor. The cause of postoperative bowel ischemia is multifactorial and can be attributed to patient factors and operative characteristics. These data should be considered during preoperative risk assessment and for optimization of both the patient and the procedure in an effort to reduce the risk of postoperative bowel ischemia. PMID- 27475467 TI - Carotid endarterectomy significantly improves postoperative laryngeal sensitivity. AB - OBJECTIVE: Iatrogenic injury of the vagus nerve or its branches during carotid endarterectomy (CEA) can result in globus sensation, dysphagia, and even vocal fold immobility. Knowledge of morphologic and functional laryngopharyngeal outcomes after CEA is poor. The present study was performed to determine potential iatrogenic damage to the laryngeal innervation after CEA. An area of particular interest was the supraglottic sensory threshold, which was examined by Fiberoptic Endoscopic Evaluation of Swallowing With Sensory Testing (FEESST; Pentax Medical Company, Montvale, NJ), a validated and safe method for the determination of the motor and sensory components of swallowing. METHODS: FEESST was used preoperatively in 32 patients scheduled to undergo CEA and twice postoperatively to examine the motor and sensory components of swallowing. In this endolaryngeal examination, laryngopharyngeal sensory thresholds (in mm Hg) were defined as normal at <4.0 mm Hg air pulse pressure (APP), moderate deficit at 4.0 to 6.0 mm Hg APP, or severe deficit at >6.0 mm Hg APP, with a value >10.0 mm Hg APP indicating abolished laryngeal adductor reflex. Acoustic voice parameters were also analyzed for further functional changes of the larynx. RESULTS: The mean +/- standard deviation preoperative FEESST measures showed no significant differences (P = .065) between the operated-on side (6.73 +/- 1.73 mm Hg) and the opposite side (5.83 +/- 1.68 mm Hg). At 2 days postoperatively, the threshold increased (P = .001) to 7.62 +/- 1.98 mm Hg on the operated-on side. A laryngopharyngeal mucosal hematoma on the operated side was endoscopically detectable in eight patients (30.8%); in these patients, we found a markedly elevated (P = .021) measure of 9.50 +/- 0.93 mm Hg. On the opposite (nonoperated on) side of the laryngopharynx, the thresholds remained at the same level as preoperatively over all assessments (P >.05), whereas the differences between the operated and nonoperated-on sides and the hematoma and nonhematoma groups were highly significant (P = .004 and P = .001, respectively). Surprisingly, the sensory threshold on the operated-on side (6.08 +/- 2.02 mm Hg) decreased significantly at the 6-week follow-up, even in relation to the preoperative measure (P = .022). With the exception of one patient with permanent unilateral vocal fold immobility, no signs of nerve injury were detected. CONCLUSIONS: In accordance with previous reports, injuries to the recurrent laryngeal nerve during CEA seem to be rare. In most patients, postoperative symptoms (globus, dysphagia, dysphonia) and signs fade within a few weeks without any specific therapeutic intervention. This study shows an improved long-term postoperative superior laryngeal nerve function with regard to laryngopharyngeal sensitivity. PMID- 27475469 TI - Adjective conjunction as a window into the LATL's contribution to conceptual combination. AB - Though a large literature implicates the left anterior temporal lobe (LATL) for combinatory operations, recent MEG studies have suggested that it is specifically involved in the composition of complex concepts, rather than syntactic or semantic composition in a more general sense. To further specify the computational contribution of the LATL, we tested whether LATL effects as observed in MEG require a situation in which features combine to form a single coherent entity representation or whether the relevant computation simply requires the attribution of features to a set but not necessarily to the same members of the set. Under the former hypothesis, the LATL would be sensitive to the number of features added to the representation of a single entity whereas under the latter account, LATL activity would reflect the total number of features integrated across different members of a set. To test this, we employed conjunctions of two adjectives whose lexical semantics were varied such that they either allowed or disallowed the attribution of their denoted properties to the same members of a set, i.e., the properties were either compatible or incompatible. The compatible properties resulted in so-called intersective and the incompatible in so-called collective readings. Our results show that the LATL tracks the number of features attributed to an individual as opposed to the number of features attributed to a set. Interestingly, the reverse pattern was found in the right ATL, demonstrating that although this region often shows parallel effects to the LATL, its functional contribution is clearly distinct. PMID- 27475468 TI - Medication adherence in Alzheimer's disease: The mediator role of mindfulness. AB - BACKGROUND: Medication adherence is often assessed based on compliance to the dosage and frequency of physician's prescription. Cognitive impairment is one of the biggest barriers in elderly patients with Alzheimer's disease (AD), who are usually polymedicated with different oral drugs. Transdermal drug delivery, also requires mobility abilities, reinforcing the role of patients' caregivers. OBJECTIVE: To evaluate the relationship between psychological variables such as social support, family satisfaction, psychological morbidity, awareness of the disease, coping, mindfulness and medication adherence, in patients with AD, taking in consideration the patient's perspective. DESIGN: Cross-sectional and quantitative study including 128 patients with mild AD. RESULTS: Medication adherence showed a positive relationship with social support, mindfulness, family satisfaction and awareness of the disease. Mindfulness was a mediator in the relationship between awareness of the disease and medication adherence. CONCLUSIONS: This study reinforces the importance of psychological assessment in medication adherence in mild AD patients, specially the role of mindfulness. Intervention programs to promote mindfulness may have a potential dual benefit, preserving cognitive skills and promoting medication adherence. PMID- 27475470 TI - [The opening of the French national health database: Opportunities and difficulties. The experience of the Gazel and Constances cohorts]. AB - BACKGROUND: In France, the national health database (SNIIRAM) is an administrative health database that collects data on hospitalizations and healthcare consumption for more than 60 million people. Although it does not record behavioral and environmental data, these data have a major interest for epidemiology, surveillance and public health. One of the most interesting uses of SNIIRAM is its linkage with surveys collecting data directly from persons. Access to the SNIIRAM data is currently relatively limited, but in the near future changes in regulations will largely facilitate open access. However, it is a huge and complex database and there are some important methodological and technical difficulties for using it due to its volume and architecture. METHODS: We are developing tools for facilitating the linkage of the Gazel and Constances cohorts to the SNIIRAM: interactive documentation on the SNIIRAM database, software for the verification of the completeness and validity of the data received from the SNIIRAM, methods for constructing indicators from the raw data in order to flag the presence of certain events (specific diagnosis, procedure, drug...), standard queries for producing a set of variables on a specific area (drugs, diagnoses during a hospital stay...). Moreover, the REDSIAM network recently set up aims to develop, evaluate and make available algorithms to identify pathologies in SNIIRAM. CONCLUSION: In order to fully benefit from the exceptional potential of the SNIIRAM database, it is essential to develop tools to facilitate its use. PMID- 27475471 TI - Impact of PCV7/PCV13 introduction on invasive pneumococcal disease (IPD) in young children: Comparison between meningitis and non-meningitis IPD. AB - BACKGROUND: The worldwide introduction of pneumococcal conjugate vaccines (PCV) into National Immunization Programs resulted in rapid and substantial reduction of invasive pneumococcal disease (IPD) rates in children. However, the reduction of meningitis vs. non-meningitis IPD (nm-IPD) was not yet fully elucidated. We compared 7-valent and 13-valent PCV (PCV7 and PCV13) impact on pneumococcal meningitis vs. nm-IPD in Israeli children <5years. METHODS: We conducted an ongoing nationwide, prospective, population-based, active surveillance. PCV7 and PCV13 were implemented in Israel in July 2009 and November 2010, respectively. All pneumococcal isolates (blood and/or CSF) from IPD episodes in children <5years from July 2000 through June 2015 were included. Extrapolation for missing serotypes (34.7% of all isolates) was conducted. RESULTS: 4163 IPD cases were identified; 3739nm-IPD (89.8%) and 424 meningitis (10.2%). During the pre-PCV period (2000-2008), children <12months constituted 52.1% and 33.7% of meningitis and nm-IPD, respectively (p<0.001). The respective proportions of non-PCV13 serotypes (non-VT) were 18.2% vs. 10.1%, (p<0.001). Comparing the last study year (2014-2015) to the mean of pre-PCV period, meningitis incidence in children <5years decreased non-significantly by 27%, while nm-IPD decreased significantly by 69%. Dynamic rates of meningitis and nm-IPD caused by PCV13 serotypes were similar, with 93% and 95% overall reductions, respectively. However, non-VT increased in meningitis relatively to nm-IPD, mainly in children <24months. Serotype 12F rose sharply and significantly since 2009-2010 through 2014-2015 (28.6% of all non-VT meningitis in children <24m). CONCLUSIONS: The overall impact of PCV7/PCV13 in children <5years in Israel was less prominent in meningitis than in nm-IPD. This could be attributed to the younger age of children with meningitis and differences in causative serotypes between the two groups, as the decline of the incidence of meningitis and nm-IPD caused by vaccine-serotypes is similar. Continuous monitoring of meningitis and nm-IPD is warranted. PMID- 27475472 TI - Complementary medicine and childhood immunisation: A critical review. AB - BACKGROUND: Vaccination is one of the most significant and successful public health measures of recent times. Whilst the use of complementary medicine (CM) continues to grow, it has been suggested that CM practitioners hold anti vaccination views. The objective of this critical review is to examine the evidence base in relation to CM practitioner attitudes to childhood vaccination alongside attitudes to vaccination among parents who visit CM practitioners and/or use CM products. METHODS: A database search was conducted in MEDLINE, PubMed, CINAHL, EMBASE and AMED for research articles published between January 2000 and September 2015 that evaluated either CM practitioner or CM user attitudes and intention towards childhood vaccination. RESULTS: A total of 23 articles were found that detailed the attitudes of CM practitioners to vaccination. A further 16 papers examined the association between the use of CM products and visits to CM practitioners, and immunisation. The interface between CM and vaccination is complex, multi-factorial and often highly individualised. The articles suggest that there is no default position on immunisation by CM practitioners or parents who use CM themselves, or for their children. Although CM use does seem positively associated with lower vaccination uptake, this may be confounded by other factors associated with CM use (such as higher income, higher education or distrust of the medical system), and may not necessarily indicate independent or predictive relationships. CONCLUSIONS: Although anti-vaccination sentiment is significant amongst some CM practitioners, this review uncovers a more nuanced picture, and one that may be more agreeable to public health values than formerly assumed. PMID- 27475473 TI - Contrasting female-male mortality ratios after routine vaccinations with pentavalent vaccine versus measles and yellow fever vaccine. A cohort study from urban Guinea-Bissau. AB - BACKGROUND: In addition to protection against the target diseases, vaccines may have non-specific effects (NSEs). Measles vaccine (MV) has beneficial NSEs, providing protection against non-measles deaths, most so for girls. By contrast, though protecting against diphtheria, tetanus and pertussis, DTP vaccine is associated with increased female mortality relative to male mortality. In 2008, Guinea-Bissau replaced DTP with the DTP-containing pentavalent vaccine (Penta; DTP-H. influenza type B-Hepatitis B) at 6, 10 and 14weeks and yellow fever vaccine (YF) was to be given with MV. We investigated possible sex-differential mortality rates following Penta and MV+YF vaccination. METHODS: Bandim Health Project (BHP) registers vaccines given by the three government health centres in the study area and vital status through demographic surveillance. We assessed the association between sex and mortality by vaccination status in Cox proportional hazards models with age as underlying timescale. Follow-up was censored at a subsequent vaccination contact or after 6months of follow-up. RESULTS: Between September 2008 and April 2011, we registered 23,448 vaccination contacts for children aged 42-365days; 17,313 were for Penta and 3028 for MV (2907 co administered with YF). During follow-up 112 children died. The female/male mortality rate ratio was 1.73 (1.11-2.70) following Penta and 0.38 (0.12-1.19) after MV (p=0.02 for same effect). Adjusting for maternal education or weight-for age at the time of vaccination did not change the estimates. CONCLUSION: Penta appears to have the same negative effects on mortality as those seen for DTP. Assessing post-vaccination mortality for boys and girls is necessary to improve the vaccination programme. PMID- 27475474 TI - Safety evaluation of adenovirus type 4 and type 7 vaccine live, oral in military recruits. AB - Before the widespread adoption of vaccination, adenovirus type 4 and type 7 were long associated with respiratory illnesses among military recruits. When supplies were depleted and vaccination was suspended in 1999 for approximately a decade, respiratory illnesses due to adenovirus infections resurged. In March 2011, a new live, oral adenovirus vaccine was licensed by the US Food and Drug Administration and was first universally administered to military recruits in October 2011, leading to rapid, dramatic elimination of the disease within a few months. As part of licensure, a postmarketing study (Sentinel Surveillance Plan) was performed to detect potential safety signals within 42days after immunization of military recruits. This study retrospectively evaluated possible adverse events related to vaccination using data from the Armed Forces Health Surveillance Branch Defense Medical Surveillance System (DMSS) database. Among 100,000 recruits who received the adenovirus vaccine, no statistically significant greater risk of prespecified medical events was observed within 42days after vaccination when compared with a historical cohort of 100,000 unvaccinated recruits. In an initial statistical analysis of International Classification of Disease, 9th Revision, Clinical Modification codes, a statistically significant higher risk for 19 other (not prespecified) medical events occurring in 5 or more recruits was observed among vaccinated compared with unvaccinated groups. After case record data abstraction for attribution and validation, two events (psoriasis [21 vs 7 cases] and serum reactions [12 vs 4 cases]) occurred more frequently in the vaccinated cohort. A causal relation of these rare events with adenovirus vaccination could not be established given confounding factors in the DMSS, such as coadministration of other vaccines and incomplete or inaccurate medical information, for some recruits. Prospective surveillance assessing these uncommon, but potentially relevant, immune-related symptoms may be beneficial in defining potential causal association with adenovirus vaccination. PMID- 27475475 TI - Changes in the anti-HBc profile of infants born to HBV infected mothers from Iran. AB - From 2007 to 2014, 328 infants born to hepatitis B surface antigen (HBsAg) positive mothers, who received passive-active immunization against hepatitis B at birth were tested for HBsAg, antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B surface antigen (anti-HBs) at 12-15months of age. Thirteen (4%) cases were HBsAg positive. Forty-four infants who were anti-HBs, anti-HBc positive (group 1) and twenty-one infants who were anti-HBc positive alone (group 2) were identified. Both groups were followed-up annually for testing anti-HBs and anti-HBc to verify if anti-HBc was of maternal origin. In group 1, anti-HBc disappeared in 41 cases at month 24, and it disappeared from the remaining 3 cases at month 36. In group 2, anti-HBc disappeared in 18 cases at month 24 and in the remaining 3 cases at month 36. The results show that maternal anti-HBc may persist up to 3years in some children. PMID- 27475476 TI - Self-relevant threat contexts enhance early processing of fear-conditioned faces. AB - Anxiety states are characterized by attentional biases to threat and increased early brain responses to potentially threat signaling stimuli. How such stimuli are processed further depends on prior learning experiences (e.g. conditioning and extinction) and the context in which a stimulus appears. Whether context information and prior learning experiences interact with early threat processing in humans is largely unknown. Here, EEG was recorded while healthy participants (N=20) viewed faces that were fear-conditioned and/or extinguished 24h before. Faces were either passively viewed or presented within different contexts, which were created by describing scenarios that could either involve participants directly (self-threatening), or made them observers (other-threatening) of a potentially dangerous situation. Early brain responses (i.e., P1 amplitudes) were specifically enhanced during the self-threatening condition in response to non extinguished versus extinguished fear-conditioned faces. This finding suggests that top-down contextual information is incorporated into early attention modulation of previously learned threat signals. PMID- 27475477 TI - The effects of safety behaviors during exposure therapy for anxiety: Critical analysis from an inhibitory learning perspective. AB - In the context of clinical anxiety, safety behaviors are actions performed to prevent, escape, or minimize feared catastrophes and/or associated distress. Research consistently implicates safety behaviors in the development and maintenance of anxiety disorders; accordingly, safety behaviors are traditionally eliminated during exposure treatments for pathological anxiety. The notion that safety behaviors are ubiquitously deleterious in the context of exposure has recently been challenged, yet findings regarding safety behaviors' effects on exposure outcomes are limited, mixed, and controversial. Furthermore, developments in explanatory models for exposure's effectiveness (e.g., inhibitory learning theory) highlight other possible consequences of safety behaviors performed during exposure. Unfortunately, these theoretical advances are neglected in experimental research. The present review critically examines the literature addressing the role of safety behaviors in exposure therapy from an inhibitory learning perspective. Limitations, future directions, and clinical recommendations are also discussed. PMID- 27475478 TI - Accelerated partial breast irradiation: An update on published Level I evidence. AB - Multiple adjuvant radiation therapy options currently exist for women following breast-conserving surgery including standard fractionated whole breast irradiation (WBI), accelerated whole breast irradiation (AWBI), and accelerated partial breast irradiation (APBI). The recent publication of several randomized trials comparing APBI to standard WBI provides Level I evidence supporting APBI. The purpose of this review is to summarize the Level I data supporting APBI in an effort to provide guidance when to offer this treatment approach vs. standard WBI, AWBI, or excision alone and to address questions related to its application. Four contemporary trials with over 2000 patients comparing APBI and WBI have been published and demonstrate no differences in the rates of local/regional recurrence or survival though long-term followup is limited to one study. In addition, reductions in the rates of acute and chronic toxicity and improvements in cosmetic outcome were noted in two of these trials (the University of Florence and the Hungarian Phase III trials, respectively). When contrasting other treatment approaches to APBI, patients treated in studies using AWBI have many comparable clinical and pathologic characteristics, whereas studies investigating endocrine therapy alone (surgery with no adjuvant radiation therapy) have much "lower risk" patients based on clinical, pathologic, and treatment-related criteria. Although significant Level I evidence now exists supporting the use of APBI as an alternative to WBI in selected patients undergoing breast-conserving therapy, additional data are needed to (1) help further refine patient selection criteria, (2) better clarify the optimal partial breast irradiation target and technique for each clinical setting, (3) determine when AWBI, standard WBI, or excision alone may be more appropriate, and (4) investigate if further reductions in fractionation schedules are possible. PMID- 27475479 TI - High-dose-rate interstitial brachytherapy for the treatment of high-volume locally recurrent endometrial carcinoma. AB - PURPOSE: Limited therapeutic options are available for the treatment of locally recurrent endometrial carcinoma. Our objective was to report an institutional experience using interstitial brachytherapy (IBT) to treat significant recurrent endometrial carcinoma, including previously irradiated disease. METHODS AND MATERIALS: Between December 2004 and September 2012, 40 patients with high-volume locally recurrent endometrial cancer were treated by high-dose-rate IBT (+/- external beam radiation therapy EBRT). Sixteen patients had prior radiotherapy: EBRT alone (n = 5), intracavitary brachytherapy alone (n = 3), or EBRT with intracavitary brachytherapy boost (n = 8). Actuarial outcome rates were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Median followup interval was 18 months. Median disease-free interval was 61 months. Actuarial local control, progression-free survival (PFS), and overall survival were 74% and 60%, 70% and 51%, and 83% and 72% at 12 and 24 months, respectively. p-Values for local control, progression-free survival, and overall survival between patient who had prior RT (n = 16) to no prior RT (n = 24) were p = 0.38, 0.32, and 0.90, respectively. Acute toxicities include Grade 1-2 pain (5%), genitourinary (7%), gastrointestinal (12%), soft tissue (5%), and dermatologic (12%). Four patients observed late Grade 3-4 toxicities, including rectal bleeding/fistula and soft tissue necrosis. CONCLUSIONS: High-dose-rate IBT is an effective treatment for locally recurrent endometrial carcinoma with an acceptable toxicity profile. Outcomes are similar between previously irradiated and nonirradiated patients. In women who have received prior radiotherapy and are often considered for palliative treatment, interstitial brachytherapy is a potentially curative option. PMID- 27475481 TI - Failure modes and effects analysis in image-guided high-dose-rate brachytherapy: Quality control optimization to reduce errors in treatment volume. AB - PURPOSE: Analyze the inputs which cause treatment to the wrong volume in high dose-rate brachytherapy (HDRB), with emphasis on imaging role during implant, planning, and treatment verification. The end purpose is to compare our current practice to the findings of the study and apply changes where necessary. METHODS AND MATERIALS: Failure mode and effects analysis was used to study the failure pathways for treating the wrong volume in HDRB. The role of imaging and personnel was emphasized, and subcategories were formed. A quality assurance procedure is proposed for each high-scoring failure mode (FM). RESULTS: Forty FMs were found that lead to treating the wrong volume. Of these, 73% were human failures, 20% were machine failures, and 7% were procedural/guideline failures. The use of imaging was found to resolve 85% of the FMs. We also noted that imaging processes were under used in current practice of HDRB especially in pretreatment verification. Twelve FMs (30%) scored the highest, and for each one of them, we propose clinical/practical solutions that could be applied to reduce the risk by increasing detectability. CONCLUSIONS: This work resulted in two conclusions: the role of imaging in improving failure detection and the emphasized role of human based failures. The majority of FMs are human failures, and imaging increased the ability to detect 85% of all FMs. We proposed quality assurance practices for each high-scoring FM and have implemented some of them in our own practice. PMID- 27475480 TI - Trends in the utilization of adjuvant vaginal brachytherapy in women with early stage endometrial carcinoma: Results of an updated period analysis of SEER data. AB - PURPOSE: Adjuvant vaginal brachytherapy (VB) is a well-established and effective radiation treatment modality in women with early-stage endometrial carcinoma. We sought to evaluate and update published trends in the utilization of VB vs. other radiation therapy modalities (pelvic external beam radiation therapy (EBRT) or the combination of VB and pelvic EBRT using the National Cancer Institute's Surveillance, Epidemiology, and End Results database. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I-II endometrial carcinoma diagnosed from 1995 to 2012 and treated definitively with hysterectomy and adjuvant radiation therapy. Chi-square tests were used to assess differences by radiation type (VB, EBRT, and VB + EBRT) and various demographic and clinical variables. RESULTS: We identified 15,201 patients that met inclusion criteria. There was a significant overall increase in the use of VB was observed from 17.1% in 1995-2000 compared to 57.1% in 2007-2012 (p < 0.0001). Similarly, there was a proportional decrease in the use of EBRT from 54.0% to 25.5% (p < 0.0001) as well as in the use of VB + EBRT from 28.9% to 17.4% during the same period (p < 0.0001). The observed increase in utilization of VB was not limited to any variables (age, race, histological type, International Federation of Gynecology and Obstetrics stage, and the status of lymph node dissection [yes or no]) or the number of dissected lymph nodes. CONCLUSIONS: In this large national database set, there continues to be an increasing trend for the use of VB in the adjuvant setting in women with early stage endometrial carcinoma. PMID- 27475482 TI - Dose-volume histogram analysis of composite EQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy. AB - PURPOSE: To analyze the dose-volume histogram of the central shielding technique for cervical cancer radiotherapy by computing the composite three-dimensional EQD2 dose distributions of external-beam radiotherapy plus intracavitary brachytherapy. METHODS AND MATERIALS: On a phantom, three patterns of high-risk clinical target volume (HR-CTV) with right-left diameters of 3, 4, and 5 cm were created using clinical data. Four patterns of combinations of whole-pelvis irradiation plus "pelvis irradiation using the central shielding technique" (CS) (shielding width, 3 or 4 cm) were created: 20 Gy/10 fractions + 30 Gy/15 fractions, 30 Gy/15 fractions + 20 Gy/10 fractions, 40 Gy/20 fractions + 10 Gy/5 fractions, and 50 Gy/25 fractions + 0 Gy. The intracavitary brachytherapy plan was set as 24 Gy/4 fractions prescribed to the Point A. The HR-CTV D90/D98 and modeled bladder/rectum D2cc were computed using the composite EQD2 dose distributions of all the treatment combinations. RESULTS: If appropriate combinations of the treatment plans were selected on the basis of the CS doses and the HR-CTV sizes, the D90/D98 of HR-CTV 3 cm, HR-CTV 4 cm, and HR-CTV 5 cm were 89.7 Gy/80.6 Gy, 77.3 Gy/72.0 Gy, and 73.0 Gy/69.2 Gy in the case of CS width 3 cm, respectively; and 86.2 Gy/76.0 Gy, 73.3 Gy/67.6 Gy, and 70.9 Gy/67.1 Gy in the case of CS width 4 cm, respectively. The contributions of CS to the HR CTV D90/bladder D2cc/rectum D2cc values were 24-56%/28-32%/9% of the CS plan doses for shielding width of 3 cm and were 13-35%/11-16%/5-6% for shielding width of 4 cm. CONCLUSION: The dose contributions of CS were variable but not negligible when analyzing the total doses delivered to the HR-CTV. PMID- 27475483 TI - The risk of second malignancies after 125I prostate brachytherapy as monotherapy in a single Australian institution. AB - PURPOSE: To report the incidence of second primary cancer (SPC) after 125I brachytherapy (BT) for early prostate cancer in an Australian institution. METHODS AND MATERIALS: All the patients in our cohort had a cystoscopy before the implant. Data were prospectively collected on all subsequent SPC diagnoses. Standardized incidence ratios (SIRs) were calculated to compare data with the Australian population. Kaplan-Meier analysis was used to determine the actuarial second malignancy and pelvic malignancy rates and the death from SPC and from any cause. RESULTS: A total of 889 patients were followed up for a median of 4.16 (0 13) years with 370 (42%) patients having >=5 years of followup. Sixty patients subsequently developed an SPC of which 11 were pelvic malignancies. The 5- and 10 year cumulative incidences were 1.3% (95% confidence interval [CI]: 0.6-3) and 3.3% (95% CI: 1-7) for any pelvic malignancy and 1% (95% CI: 0.4-2) and 2.6% (1 6) for bladder cancer, respectively. The SIR was significantly higher than expected for all bladder cancers at 2.9 (95% CI: 1-6) and close to significance (SIR, 3.0; 95% CI: 0.97-7) for bladder cancers within the first 5 years of followup in the subgroup analysis. On multivariate analysis, older age was associated with increased SPC risk and older age and positive smoking status were associated with increased overall mortality, mortality due to SPC, and mortality from second malignancy (p < 0.05). CONCLUSIONS: There may be a small increased risk of bladder SPC after prostate BT. A tendency toward a higher risk of bladder SPC after BT was found within the first 5 years of followup probably reflecting screening bias. PMID- 27475484 TI - Investigating the dosimetric impact of seed location uncertainties in Collaborative Ocular Melanoma Study-based eye plaques. AB - PURPOSE: To quantify the dosimetric effects of random and systematic seed position uncertainties in Collaborative Ocular Melanoma Study-based eye plaques. METHODS AND MATERIALS: An eye plaque dose calculation routine was created using Task Group 43 formalism. A variety of clinical configurations were simulated, including two seed models: (125)I and (103)Pd, three eye plaque sizes, and eight plaque/eye orientations. Dose was calculated at four ocular anatomic sites and three central axis plaque depths. Random seed positional uncertainty was modeled by adding Gaussian random displacements, in one of three seed-motion degrees of freedom, to each seed's nominal coordinate. Distributions of dosimetric outcomes were obtained and fitted after 10(6) randomizations. Similar analysis was performed for deterministic, systematic shifts of the plaque along the eye surface and radially from the globe center. RESULTS: Random seed placement uncertainties of 0.2-mm root mean square (RMS) (amplitude) produce dose changes that are typically <4% for each degree of freedom (95% confidence interval). Systematic seed placement uncertainties are generally greater than random uncertainty 95% confidence intervals (factor of 0.72-2.15), with the relative magnitudes depending on plaque size and location of interest. Eye plaque dosimetry is most sensitive to seed movement toward the center of the eye. Dosimetric uncertainty also increases with increasing dose gradients, which are typically greatest near the inner sclera, with smaller plaques, and with lower energy radionuclides (e.g., (103)Pd). CONCLUSIONS: Dosimetric uncertainties due to the random seed positional displacements anticipated in the clinic are expected to be <4% for each degree of freedom in most circumstances. PMID- 27475485 TI - New objective method in reporting the breast cosmesis after breast-conservative treatment based on nonstandardized photographs: The Objective Breast Cosmesis Scale. AB - PURPOSE: Subjective scoring is the most widely used approach in reporting the cosmetic outcome after breast-conservative therapy. This work introduces an objective system to document the breast cosmetic changes using nonstandardized photographs without scale calibration. METHODS AND MATERIALS: Two hundred twenty eight photographs of 114 breast cancer patients were analyzed. Baseline photographs were taken after breast-conservation surgery and before partial breast irradiation. Further photographs were taken during followup. The photographs were taken with a frontal view of the patient and without any skin marks for scaling. The baseline and the last followup photographs were analyzed by measuring certain anatomic distances (representing the nipple displacement and the asymmetry in breast dimensions and contour) to calculate the objective breast cosmesis score (OBCS). The measurements represent the nipple displacement and the asymmetry in breast dimensions and contour. Same photographs were scored subjectively by a multidisciplinary team (MDT) using the Harvard breast cosmesis scale. The patient-reported self-scoring was also recorded. RESULTS: The MDT results were favorable (excellent?good) in 72.3% of the photographs and adverse in 27.7%. Agreement among the MDT members was strong (intraclass correlation coefficient = 0.798, p < 0.001, 95% CI: 0.753-0.937, Cronbach's alpha = 0.809). The patient self-scoring was satisfactory in 82.5% of the cases and nonsatisfactory in 17.5%. The results of the OBCS ranged between 0.0 and 20.4 with a median value of 4.5. There was a strong significant correlation between the OBCS and both the MDT subjective scoring (p < 0.001) and the patient self scoring (p < 0.001). CONCLUSIONS: The OBCS seems to be eligible for the objective assessment of cosmesis after breast-conservative therapy using nonstandardized photographs without scale calibration. PMID- 27475486 TI - A comprehensive analysis of brachytherapy clinical trials over the past 15 years. AB - PURPOSE: Clinical trials (CTs) involving brachytherapy (BT) are crucial in establishing the role of BT in the evolving landscape of cancer treatment. An analysis of BT trials is warranted to understand the factors driving their success and the future direction of the field. METHODS AND MATERIALS: We queried the clinicaltrials.gov website using the search terms: Radiation Therapy, Brachytherapy, and associated terms. This yielded 10,417 CTs between 2000 and 2015. Trials not using BT were excluded; yielding 319 CTs. Characteristics of individual CTs were obtained. Least squared linear regression, chi2 analysis, and logistic regression were used to evaluate trial characteristics. RESULTS: The majority of the CTs were phase II (37%), involving interstitial BT (45%), and treating the prostate (36%). Nongovernmental institutions (NGIs) have funded the greatest number of CTs. New CTs involving radiotherapy of all types showed increase over time (p < 0.05), whereas no corresponding increase was seen in BT trials. New BT trials independently funded by industry have declined (p = 0.01). Collaboration between industry and NGIs was associated with greater likelihood of trial completion. Industry funding was associated with Phase IV trials, usage of surface BT, among others. NIH/government funding was associated with Phase I trials, intracavitary BT, trials focused on systemic therapy, among others. CONCLUSIONS: Trials examining radiotherapy have increased, whereas trials incorporating BT have remained unchanged. Collaboration between industry and NGIs was associated with a greater likelihood for successful trial completion. The role of BT can be better realized with greater incorporation into CTs. PMID- 27475488 TI - The C. elegans hox gene lin-39 controls cell cycle progression during vulval development. AB - Cell fate specification during organogenesis is usually followed by a phase of cell proliferation to produce the required number of differentiated cells. The Caenorhabditis elegans vulva is an excellent model to study how cell fate specification and cell proliferation are coordinated. The six vulval precursor cells (VPCs) are born at the first larval stage, but they arrest in the G1 phase of the cell cycle until the beginning of the third larval stage, when their fates are specified and the three proximal VPCs proliferate to generate 22 vulval cells. An epidermal growth factor (EGF) signal from the gonadal anchor cell combined with lateral DELTA/NOTCH signaling between the VPCs determine the primary (1 degrees ) and secondary (2 degrees ) fates, respectively. The hox gene lin-39 plays a key role in integrating these spatial patterning signals and in maintaining the VPCs as polarized epithelial cells. Using a fusion-defective eff 1(lf) mutation to keep the VPCs polarized, we find that VPCs lacking lin-39 can neither activate lateral NOTCH signaling nor proliferate. LIN-39 promotes cell cycle progression through two distinct mechanisms. First, LIN-39 maintains the VPCs competent to proliferate by inducing cdk-4 cdk and cye-1 cyclinE expression via a non-canonical HOX binding motif. Second, LIN-39 activates in the adjacent VPCs the NOTCH signaling pathway, which promotes VPC proliferation independently of LIN-39. The hox gene lin-39 is therefore a central node in a regulatory network coordinating VPC differentiation and proliferation. PMID- 27475487 TI - Polarity in plant asymmetric cell division: Division orientation and cell fate differentiation. AB - Asymmetric cell division (ACD) is universally required for the development of multicellular organisms. Unlike animal cells, plant cells have a rigid cellulosic extracellular matrix, the cell wall, which provides physical support and forms communication routes. This fundamental difference leads to some unique mechanisms in plants for generating asymmetries during cell division. However, plants also utilize intrinsically polarized proteins to regulate asymmetric signaling and cell division, a strategy similar to the differentiation mechanism found in animals. Current progress suggests that common regulatory modes, i.e. protein spontaneous clustering and cytoskeleton reorganization, underlie protein polarization in both animal and plant cells. Despite these commonalities, it is important to note that intrinsic mechanisms in plants are heavily influenced by extrinsic cues. To control physical asymmetry in cell division, although our understanding is fragmentary thus far, plants might have evolved novel polarization strategies to orientate cell division plane. Recent studies also suggest that the phytohormone auxin, one of the most pivotal small molecules in plant development, regulates ACD in plants. PMID- 27475490 TI - One-dimensional and 2-dimensional tumor size measurement for prediction of lymph node metastasis in differentiated early gastric cancer with minute submucosal invasion. AB - BACKGROUND AND AIMS: Differentiated minute submucosal cancers measuring <=3 cm that exhibit no lymphovascular invasion are considered eligible for endoscopic resection; however, the <=3-cm criterion remains debatable. The aim of this study was to verify the optimal tumor size cutoff for endoscopic resection eligibility, and to determine whether 2-dimensional tumor size measurement would be more accurate for this purpose. METHODS: The clinicopathologic data for 574 patients undergoing curative surgery for differentiated minute submucosal cancer were reviewed retrospectively. A receiver operating curve analysis and bootstrapped samples were used to identify the optimal cutoff values for predicting lymph node (LN) metastasis. RESULTS: Four hundred fourteen patients were eligible for the study. LN metastasis accompanied 2.5% of differentiated minute submucosal cancers that were <=3 cm in size and lacked lymphovascular invasion. There was no lymph node metastasis in the tumors with 1-dimensional sizes <=1.0 cm and 2-dimensional sizes <=1.0 cm2. When 10,000 bootstrapped data were used, optimal cutoff values were 2.9 cm (LN metastasis: 2.1%) and 8.3 cm2 (LN metastasis: 2.5% incidence) for 1- and 2-dimensional tumor size, respectively. Although the area under the curve was 0.611 (P = .046) for 2-dimensional size, specificity and accuracy were greater for the dichotomized 2-dimensional measure than for the dichotomized 1 dimensional measure (P < .001, McNemar test). In addition, 2-dimensional tumor size was the only significant risk factor for LN metastasis (odds ratio, 1.09; 95% confidence interval, 1.01-1.20). CONCLUSIONS: One- and 2-dimensional cutoff values of 2.9 cm and 8.3 cm2 might be suitable for patients at high risk of postoperative morbidity and mortality. Two-dimensional tumor size is an acceptable measurement method for estimating the risk of LN metastasis. PMID- 27475489 TI - Predictors of outcomes in patients undergoing covered and uncovered self expandable metal stent placement for malignant gastric outlet obstruction: a multicenter study. AB - BACKGROUND AND AIMS: Uncovered self-expandable metal stents (U-SEMSs) and covered self-expandable metal stents (C-SEMSs) are available for palliative therapy for malignant gastric outlet obstruction (GOO). However, clinical differences and indications between the 2 types of SEMSs have not been elucidated. METHODS: We retrospectively compared 126 patients with U-SEMS and 126 patients with C-SEMSs with regard to clinical outcome and factors predictive of clinical improvement after SEMSs placement. RESULTS: No significant difference was observed between the U-SEMS and C-SEMS groups with respect to technical success, clinical success, GOO score, or time to stent dysfunction. Stent migration was significantly more frequent in patients with C-SEMSs (U-SEMSs, .79%; C-SEMSs, 8.73%; P = .005). Karnofsky performance status, chemotherapy, peritoneal dissemination, and stent expansion <= 30% were associated significantly with poor GOO score improvement in multivariable analyses, but stent type was not (P = .213). In subgroup analyses, insufficient (<=30%) stent expansion was an independent factor in patients with U SEMSs (P = .041) but not C-SEMSs. In the insufficient stent expansion subgroup, C SEMSs was associated significantly with superior clinical improvement compared with U-SEMSs (P = .01). Insufficient stent expansion was observed more frequently in patients with GI obstruction because of anastomotic sites or metastatic cancer (44.8% [13/29], P = .001). CONCLUSIONS: No clinical difference, apart from stent migration, was observed between patients with U-SEMSs and C-SEMSs. GI obstruction because of an anastomotic site or metastatic cancer may be an indication for C SEMS use to improve oral intake after SEMSs placement. PMID- 27475491 TI - Endoscopic slip-knot clip suturing method: prospective pilot study (with video). AB - BACKGROUND AND AIMS: We developed a suturing method with a slip-knot string and clips for a single-channel endoscope. The feasibility of the slip-knot clip suturing method was evaluated in this clinical pilot study. METHODS: Ten patients underwent endoscopic submucosal dissection for colorectal and duodenal tumors 5 cm or less. A slip-knot loop can be tightened when tension is applied to the free end of the string. A clip and string can be passed through an instrument channel (3.2 mm) of a single-channel endoscope. The slip-knot loop is anchored onto the mucosal defect's proximal margin with the clip. Additional clips anchoring the slip-knot loop are placed at the opposite side of the margin. The slip-knot loop is tightened by pulling the string. Additional clips are placed to achieve complete closure. RESULTS: The mean size of resected specimen was 34.4 +/- 10.0 mm. The success rate of the slip-knot clip suturing method was 90% (9/10). In the first patient, the string was cut because of friction, and the patient dropped out of the study. After the failure of the first patient, we used wet string to reduce friction, and slip-knot string worked effectively. The mean procedure time was 18.2 +/- 3.3 minutes. CONCLUSION: The slip-knot clip suturing method could close large mucosal defects completely using a single-channel endoscope. (Clinical trial registration number: UMIN000017583.). PMID- 27475492 TI - Long-term outcomes after endoscopic submucosal dissection for superficial colorectal tumors. AB - BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is an effective procedure for en bloc resection of superficial colorectal tumors regardless of tumor size or location. However, there are few reports on long-term outcomes for patients with superficial colorectal tumors after ESD. We therefore aimed to evaluate the long-term outcomes after ESD for superficial colorectal tumors. METHODS: ESD was performed on 257 colorectal tumors in 255 consecutive patients at Hiroshima University Hospital between June 2003 and July 2010. We investigated the following variables: patient characteristics, the American Society of Anesthesiologists score, tumor location, tumor size, growth type, histology, en bloc resection rate, achievement of curative resection, procedure time, and adverse events. The 5-year overall survival (OS), 5-year disease-specific survival (DSS), local recurrence, and metachronous tumor occurrence were also analyzed. RESULTS: We identified 224 tumors in 222 patients who were confirmed dead or had follow-up data for more than 5 years. After a median follow-up of 79 months, 5-year OS and DSS rates were 94.6% and 100%, respectively. The local recurrence rate (1.5%) was significantly higher in patients undergoing piecemeal resection (9.1%) compared with en bloc resection (0.6%), in cases of histologic incomplete resection compared with complete resection, and in cases of non-R0 resection compared with R0 resection. The rates of total number of tumors (>=6 mm) and carcinoma metachronous tumors after ESD without additional surgical resection were 18.9% (38/201) and 4.0% (8/201), respectively. CONCLUSIONS: Long term outcomes after ESD for superficial colorectal tumors are favorable. Patients should be surveyed for both local recurrence and metachronous tumors after ESD. PMID- 27475493 TI - Preimplantation maternal stress impairs embryo development by inducing oviductal apoptosis with activation of the Fas system. AB - STUDY QUESTION: What are the mechanisms by which the preimplantation restraint stress (PIRS) impairs embryo development and pregnancy outcome? SUMMARY ANSWER: PIRS impairs embryo development by triggering apoptosis in mouse oviducts and embryos,and this involves activation of the Fas system. WHAT IS KNOWN ALREADY: Although it is known that the early stages of pregnancy are more vulnerable than later stages to prenatalstress, studies on the effect of preimplantation stress on embryo developmentare limited. Furthermore, the mechanisms by which psychological stress impairs embryo development are largely unknown. These issues are worth exploring using the mouse PIRS models because restraint of mice is an efficient experimental procedure developed for studies of psychogenic stress. STUDY DESIGN, SIZE AND DURATION: Mice of Kunming strain, the generalized lymphoproliferative disorder (gld) mice with a germline mutation F273L in FasL in a C57BL/6J genomic background and the wild-type C57BL/6J mice were used. Female and male mice were used 8-10 weeks and 10-12 weeks after birth, respectively. Female mice showing vaginal plugs were paired by weight and randomly assigned to restraint treatments or as controls. For restraint treatment, an individual mouse was put in a micro-cage with food and water available. Control mice remained in their cages with food and water during the time treated females were stressed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female mice were exposed to PIRS for 48 h starting from 16:00 on the day of vaginal plug detection. At the end of PIRS, levels of glucorticoids (GC), corticotropin-releasing hormone (CRH)and redox potential were measured in serum, while levels of GC, GC receptor (GR), CRH, CRH receptor (CRHR), Fas and Fas ligand (FasL) protein, mRNAs for brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), oxidative stress (OS) and apoptosis were examined in oviducts. Preimplantation development and levels of GR, Fas, redox potential and apoptosis were observed in embryos recovered at different times after the initiation of PIRS. The gld mice were used to confirm a role for the Fas system in triggering apoptosis of embryos and oviducts. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those in control mice, while the number of blastocysts/mouse (5.0 +/- 0.7 versus 11.1 +/- 0.5), cell number/blastocyst (49.1 +/- 1.3 versus 61.5 +/- 0.9), percentages of term pregnancy (37.5% versus 90.9%) and litter size (3.7 +/- 0.1versus 9.6 +/- 0.6) decreased, blood CRH (560 +/- 23 versus 455 +/- 37 pg/ml), cortisol (27.3 +/- 3.4 versus 5 +/- 0.5 ng/ml) and OS index (OSI: 2.8 versus 1.7) increased significantly (all P < 0.05) following PIRS. In the oviduct, while levels of CRH (1175 +/- 85 versus 881 +/- 33 pg/100 mg), cortisol (28.9 +/- 1.7 versus14 +/- 4 ng/g), CRHR (2.3 +/- 0.3 versus 1.0 +/- 0.0), FasL (1.31 +/- 0.06 versus 1.08 +/- 0.05 ng/g), Fas (1.42 +/- 0.13 versus 1.0 +/- 0.0) and apoptotic cells (19.1 +/- 0.5% versus 8.4 +/- 0.4%) increased, levels of GR proteins (0.67 +/- 0.14 versus 1.0 +/- 0.0) and Igf-1 (0.6 +/- 0.09 versus 1.0 +/- 0.0) and Bdnf (0.73 +/- 0.03 versus 1.0 +/- 0.0) mRNAs decreased significantly (all P < 0.05 versus control) after PIRS. Mouse embryos expressed GR and Fas at all stages of preimplantation development and embryo OS (GSH/GSSG ratio: 0.88 +/- 0.03 versus 1.19 +/- 0.13) and annexin-positive cells (blastocysts: 31.4 +/- 3.8% versus 10.96 +/- 3.4%) increased significantly (P < 0.05) following PIRS. Furthermore, the detrimental effects of PIRS on embryo development and oviductal apoptosis were much reduced in gld mice. Thus, PIRS triggered apoptosis in oviductal cells with activation of the Fas/FasL system. The apoptotic oviductal cells promoted embryo apoptosis with reduced production of IGF-1 and BDNF and increased production of FasL. LIMITATIONS, REASONS FOR CAUTION: Although important, the conclusions were drawn from limited results obtained using a single model in one species and thus they need further verification using other models and/or in other species. Furthermore, as differences in stressed samples were modest and sometimes not significant between gld and wild-type mice whereas differences between control and stressed samples were always present within gld mice, it is deduced that signaling pathways other than the Fas/FasL system might be involved as well in the PIRS-triggered apoptosis of oviducts and embryos. WIDER IMPLICATIONS OF THE FINDINGS: The data are important for studies on the mechanisms by which psychological stress affects female reproduction, as FasL expression has been observed in human oviduct epithelium. LARGE SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by grants from the National Basic Research Program of China (Nos. 2014CB138503 and 2012CB944403), the China National Natural Science Foundation (Nos. 31272444 and 30972096) and the Animal breeding improvement program of Shandong Province. All authors declare that their participation in the study did not involve factual or potential conflicts of interests. PMID- 27475494 TI - Effect of dietary choline levels on growth performance, lipid deposition and metabolism in juvenile yellow catfish Pelteobagrus fulvidraco. AB - The present experiment was conducted to determine the effect and mechanism of dietary choline levels on growth performance and lipid deposition of yellow catfish Pelteobagrus fulvidraco. Dietary choline was included at three levels of 239.2 (control (without extra choline addition), 1156.4 and 2273.6mg choline per kg diet, respectively) and fed to yellow catfish (mean initial weight: 3.45+/ 0.02g mean+/-standard errors of mean (SEM)) for 8weeks. Fish fed the diet containing 1156.4mgkg-1 choline showed the higher weight gain (WG), specific growth rate (SGR) and feed intake (FI), but the lower feed conversion rate (FCR), than those in control and highest choline group. Hepatosomatic index (HSI) and hepatic lipid content declined with increasing dietary choline levels. Muscle lipid content was the lowest for fish fed adequate choline diets and showed no significant difference between other two groups. Choline contents in liver and muscle increased with increasing dietary choline levels. Dietary choline levels significantly influenced mRNA levels of genes involved in lipid homeostasis in muscle and liver, such as CTP:phosphocholine cytidylyltransferase a (CCTa), phosphatidylethanolamine N-methyl-transferase (PEMT), microsomal triglyceride transfer protein (MTP), apolipoprotein b (APOBb), apolipoprotein E (ApoE) and lipoprotein lipase (LPL), and effects of dietary choline levels on lipid deposition and metabolism were tissue-specific. Different responses of these genes at the mRNA levels partially explained the profiles of lipid deposition in liver and muscle for fish fed different choline diets. To our knowledge, this is the first to explore the effect of dietary choline level on mRNA expression of these genes, which provides new insights into choline nutrition in fish. PMID- 27475495 TI - Do genes lie? Mitochondrial capture masks the Red Sea collector urchin's true identity (Echinodermata: Echinoidea: Tripneustes). AB - Novel COI and bindin sequences of the Red Sea collector echinoid Tripneustes gratilla elatensis are used to show that (1) discordance between mitochondrial and nuclear loci exists in this echinoid genus, (2) Tripneustes gratilla as currently defined possibly comprises a complex of cryptic species, and (3) Red Sea Tripneustes form a genetically distinct clade in the bindin tree, which diverged from other Tripneustes clades at least 2-4million years ago. Morphological reassessment of T. gratilla elatensis shows perfect congruence between identification based on skeletal features and genetic data based on a nuclear marker sequence. Hence the Red Sea Tripneustes subspecies established by Dafni in 1983 is a distinct biological unit. All T. g. elatensis samples analyzed are highly similar to or share mtDNA haplotypes with Philippine T. g. gratilla, as do representatives from other edge-of-range occurrences. This lack of genetic structure in Indo-Pacific Tripneustes is interpreted as a result of wide-spread mitochondrial introgression. New fossil specimens from the Red Sea area confirm the sympatric occurrence of T. g. elatensis and T. g. gratilla in the northern Red Sea during Late Pleistocene, identifying a possible timing for the introgression. In addition, present-day distribution shows a contact zone in the Southern Red Sea (in the Dahlak Archipelago). T. g. elatensis, is yet another example of a Red Sea taxon historically identified as conspecific with its Indo Pacific relatives, but which turned out to be a morphologically and genetically distinct endemic taxon, suggesting that the level of endemism in the Red Sea may still be underestimated. PMID- 27475496 TI - Depth as a driver of evolution in the deep sea: Insights from grenadiers (Gadiformes: Macrouridae) of the genus Coryphaenoides. AB - Here we consider the role of depth as a driver of evolution in a genus of deep sea fishes. We provide a phylogeny for the genus Coryphaenoides (Gadiformes: Macrouridae) that represents the breadth of habitat use and distributions for these species. In our consensus phylogeny species found at abyssal depths (>4000m) form a well-supported lineage, which interestingly also includes two non abyssal species, C. striaturus and C. murrayi, diverging from the basal node of that lineage. Biogeographic analyses suggest the genus may have originated in the Southern and Pacific Oceans where contemporary species diversity is highest. The abyssal lineage seems to have arisen secondarily and likely originated in the Southern/Pacific Oceans but diversification of this lineage occurred in the Northern Atlantic Ocean. All abyssal species are found in the North Atlantic with the exception of C. yaquinae in the North Pacific and C. filicauda in the Southern Ocean. Abyssal species tend to have broad depth ranges and wide distributions, indicating that the stability of the deep oceans and the ability to live across wide depths may promote population connectivity and facilitate large ranges. We also confirm that morphologically defined subgenera do not agree with our phylogeny and that the Giant grenadier (formerly Albatrossia pectoralis) belongs to Coryphaenoides, indicating that a taxonomic revision of the genus is needed. We discuss the implications of our findings for understanding the radiation and diversification of this genus, and the likely role of adaptation to the abyss. PMID- 27475497 TI - Pressure-volume Relationship in the Stress-echocardiography Laboratory: Does (Left Ventricular End-diastolic) Size Matter? AB - INTRODUCTION AND OBJECTIVES: The variation between rest and peak stress end systolic pressure-volume relation is an afterload-independent index of left ventricular contractility. Whether and to what extent it depends on end-diastolic volume remains unclear. The aim of this study was to assess the dependence of the delta rest-stress end-systolic pressure-volume relation on end-diastolic volume in patients with negative stress echo and all ranges of resting left ventricular function. METHODS: We analyzed interpretable data obtained in 891 patients (593 men, age 63 +/- 12 years) with ejection fraction 47% +/- 12%: 338 were normal or near-normal or hypertensive; 229 patients had coronary artery disease; and 324 patients had ischemic or nonischemic dilated cardiomyopathy. They were studied with exercise (n = 172), dipyridamole (n = 482) or dobutamine (n = 237) stress echocardiography. The end-systolic pressure-volume relation was evaluated at rest and peak stress from raw measurement of systolic arterial pressure by cuff sphygmomanometer and end-systolic volume by biplane Simpson rule 2-dimensional echocardiography. RESULTS: Absolute values of delta rest-stress end-systolic pressure-volume relation were higher for exercise and dobutamine than for dipyridamole. In the overall population, an inverse relationship between end systolic pressure-volume relation and end-diastolic volume was present at rest (r2 = 0.69, P < .001) and peak stress (r2 = 0.56, P < .001), but was absent if the delta rest-stress end-systolic pressure-volume relation was considered (r2 = 0.13). CONCLUSIONS: Left ventricular end-diastolic volume does not affect the rest-stress changes in end-systolic pressure-volume relation in either normal or abnormal left ventricles during physical or pharmacological stress. PMID- 27475498 TI - Structural insight into the inhibition of carbonic anhydrase by the COX-2 selective inhibitor polmacoxib (CG100649). AB - Polmacoxib is not only a selective COX-2 inhibitor but also a potent inhibitor of carbonic anhydrases (CAs). Both CA I and CA II are highly expressed in the GI tract and kidneys, organs that are also thought to be the sites at which selective COX-2 inhibitors show their side effects. By inhibition assays, we show that both CA I and CA II are strongly inhibited by polmacoxib, while CA II also demonstrates direct competition with COX-2. To understand, at the molecular level, how polmacoxib interacts with CA I and II, we solved the first crystal structures of CA I and CA II in complex with polmacoxib, at 2.0 A and 1.8 A, respectively. Interestingly, three polmacoxib molecules bind to the active site of CA I, whereas only one molecule binds CA II. In the active site, the three molecules of polmacoxib organize itself along hydrophobic interaction as "stack on-formation", and fully occupy a cone-shaped active pocket in CA I. The binding mode of polmacoxib to CA II was found different than its binding to celecoxib and valdecoxib. Our results provide structural insight into inhibition of CA I and CA II by polmacoxib, to assess its potential clinical efficacy. PMID- 27475499 TI - Effects of overexpressing FoxO1 on apoptosis in glomeruli of diabetic mice and in podocytes cultured in high glucose medium. AB - Podocyte apoptosis induced by high levels of glucose is a key event in the development and prognosis of diabetic nephropathy (DN). Forkhead transcription factor O1 (FoxO1) has been defined as a critical mediator of oxidative stress in animal models of diabetes and is involved in mitophagy. To test the role of FoxO1 in regulating podocyte apoptosis both in vivo and in vitro, we generated FoxO1 overexpression models. High-glucose (HG) induced podocyte apoptosis with decreased mitophagy. These changes were accompanied by mitochondrial dysfunction and more severe podocyte loss in mouse kidney. FoxO1 overexpression prevented the apoptosis induced by HG. Reduction of cell apoptosis and renal damage depended upon the expression of PTEN-induced putative kinase 1 (PINK1). These findings suggest that specific overexpression of renal FoxO1 decreases podocyte apoptosis, which may be explained in part by its regulation of PINK1, and that targeting FoxO1 may represent a novel therapeutic approach for DN. PMID- 27475500 TI - Quantification of fibronectin as a method to assess ex vivo extracellular matrix remodeling. AB - Altered architecture, composition and quality of the extracellular matrix (ECM) are pathological hallmarks of several inflammatory and fibro-proliferative pathological processes such as osteoarthritis (OA), rheumatoid arthritis (RA), fibrosis and cancer. One of the most important components of the ECM is fibronectin. Fibronectin serves as an adhesion molecule anchoring cells to the underlying basement membrane through direct interaction with integrin receptors. Fibronectin hereby modulates the properties of the ECM and affects cellular processes. Quantification of fibronectin remodeling could therefore be used to assess the changes in the ECM that occur during progression of fibro proliferative pathologies. Ex vivo models are becoming state-of-the-art tools to study ECM remodeling as the cellular composition and the organization of the ECM are preserved. Ex vivo models may therefore be a valuable tool to study the ECM remodeling that occurs during progression of fibro-proliferative pathologies. The aim of this study was to quantify fibronectin remodeling in ex vivo models of cartilage and cancer. A competitive The enzyme-linked immunosorbent assay (ELISA) against the C-terminus of fibronectin was developed (FBN-C). The assay was evaluated in relation to specificity, technical performance and as a marker for quantification of fibronectin in cartilage and cancer ex vivo models. The ELISA was specific and technically stable. Cleavage of tumor tissue with MMP-2 released significantly higher levels of FBN-C compared to tissue with buffer only and western blot analysis revealed that FBN-C recognizes both full length and degraded fibronectin. When ex vivo cartilage cultures were stimulated with the anabolic factor TGFbeta and catabolic factors TNF-alpha and OSM, significantly higher levels of FBN-C were found in the conditioned media. Lastly, FBN-C was released from a cancer ex vivo model. In conclusion, we were able to quantify fibronectin remodeling in ex vivo models of cartilage and cancer. Quantification of fibronectin remodeling could be a valuable tool to understand ECM remodeling in ex vivo models of fibro-proliferative pathologies. PMID- 27475501 TI - The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation. AB - Somatic mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is a decisive factor for the therapeutic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma. The stability of mutant EGFR is maintained by various regulators, including heat shock protein 90 (Hsp90). The C terminus of Hsc70-interacting protein (CHIP) is a Hsp70/Hsp90 co chaperone and exhibits E3 ubiquitin ligase activity. The high-affinity Hsp90-CHIP complex recognizes and selectively regulates their client proteins. CHIP also works with its own E3 ligase activity independently of Hsp70/Hsp90. Here, we investigated the role of CHIP in regulating EGFR in lung adenocarcinoma and also evaluated the specificity of CHIP's effects on mutant EGFR. In HEK 293T cells transfected with either WT EGFR or EGFR mutants, the overexpression of CHIP selectively decreased the expression of certain EGFR mutants (G719S, L747_E749del A750P and L858R) but not WT EGFR. In a pull-down assay, CHIP selectively interacted with EGFR mutants and simultaneously induced their ubiquitination and proteasomal degradation. The expressions of mutant EGFR in PC9 and H1975 were diminished by CHIP, while the expression of WT EGFR in A549 was nearly not affected. In addition, CHIP overexpression inhibited cell proliferation and xenograft's tumor growth of EGFR mutant cell lines, but not WT EGFR cell lines. EGFR mutant specific ubiquitination by CHIP may provide a crucial regulating mechanism for EGFR in lung adenocarcinoma. Our results suggest that CHIP can be novel therapeutic target for overcoming the EGFR TKI resistance. PMID- 27475502 TI - A robust adaptive load frequency control for micro-grids. AB - The goal of this study is to introduce a novel robust load frequency control (LFC) strategy for micro-grid(s) (MG(s)) in islanded mode operation. Admittedly, power generators in MG(s) cannot supply steady electric power output and sometimes cause unbalance between supply and demand. Battery energy storage system (BESS) is one of the effective solutions to these problems. Due to the high cost of the BESS, a new idea of Vehicle-to-Grid (V2G) is that a battery of Electric-Vehicle (EV) can be applied as a tantamount large-scale BESS in MG(s). As a result, a new robust control strategy for an islanded micro-grid (MG) is introduced that can consider electric vehicles' (EV(s)) effect. Moreover, in this paper, a new combination of the General Type II Fuzzy Logic Sets (GT2FLS) and the Modified Harmony Search Algorithm (MHSA) technique is applied for adaptive tuning of proportional-integral (PI) controller. Implementing General Type II Fuzzy Systems is computationally expensive. However, using a recently introduced alpha plane representation, GT2FLS can be seen as a composition of several Interval Type II Fuzzy Logic Systems (IT2FLS) with a corresponding level of alpha for each. Real-data from an offshore wind farm in Sweden and solar radiation data in Aberdeen (United Kingdom) was used in order to examine the performance of the proposed novel controller. A comparison is made between the achieved results of Optimal Fuzzy-PI (OFPI) controller and those of Optimal Interval Type II Fuzzy-PI (IT2FPI) controller, which are of most recent advances in the area at hand. The Simulation results prove the successfulness and effectiveness of the proposed controller. PMID- 27475503 TI - Orofacial manifestations of scleroderma. A literature review. AB - INTRODUCTION: Scleroderma is a rare disease of the connective tissue (50 to 200 patients/1 million people; 60,000 patients in France). We conducted a literature review about the orofacial manifestations of scleroderma that have been little studied. MATERIAL AND METHODS: The 45 articles found in 6 different databases by using the keywords "scleroderma", "systemic sclerosis", "oral medicine", "face" and published between 1944 and 2016 were selected, for a total of 328 patients. RESULTS: A total of 1187 orofacial manifestations of scleroderma were identified, occurring mainly in women (84.5%) with a mean age of 40.2 years, 10 years on average after the first manifestation of the disease. The main ones were limitation of mouth opening (69.8%), widening of the periodontal ligament (67.3%), xerostomia (63.4%), telangiectasia (36.2%) and bone lesions (34.5%). Dental root resorptions, pulp and nose calcifications were also reported but with no evident link with scleroderma. DISCUSSION: Orofacial manifestations of scleroderma are probably more common than reported. They mostly affect women with a mean age of 40. The most common oral manifestations are limitation of mouth opening, widening of the periodontal ligament and xerostomia. Because of the handicap they may be responsible for, these manifestations must be detected early in order to prevent from functional impairments and from dental and periodontal lesions. PMID- 27475504 TI - Classification and Differential Diagnosis of Oral and Maxillofacial Pain. AB - Pain in the orofacial region is a common presenting symptom. The majority of symptoms are related to dental disease and the cause can readily be established, the problem dealt with, and the pain eliminated. However, pain may persist and defy attempts at treatment. Intractable oral or facial pain can be diagnostically challenging. To make a definitive diagnosis and initiate proper treatment, a rigorous protocol for evaluation includes a thorough history and an appropriate comprehensive clinical examination and diagnostic testing, including chief complaint, history of present illness, medical history, physical examination, diagnostic studies, including imaging, and psychosocial evaluation. PMID- 27475505 TI - Chronic Orofacial Pain and Behavioral Medicine. AB - Patients with chronic orofacial pain disorders have significant psychological distress that plays an important role in modulating and maintaining their pain. For many patients, doing procedures or giving them medications does not relieve their pain. This article discusses the role of cognitive behavioral therapy and other related types of therapy, including mindfulness practices in modulating their pain disorders and helping patients to understand and participate in exercises and practices that will downregulate their pain and add to their toolbox of things they can do to gain relief. PMID- 27475506 TI - A Model for Opioid Risk Stratification: Assessing the Psychosocial Components of Orofacial Pain. AB - This article describes a model of opiate risk stratification with a special focus on dentistry and oral surgery. A brief overview covers the scope of the US opioid abuse and misuse epidemic, and the role of the dentist in mitigating the problems of diversion and misuse of controlled substances. The expanding role of dentistry is summarized. An assessment outlines gathering critical risk information, screening questionnaires, access to state prescription monitoring programs, and communication with cotreating providers. Special populations are discussed. Barriers and possible solutions for effective implementation of these strategies are summarized. PMID- 27475507 TI - Intraoral Pain Disorders. AB - Those experiencing intraoral pain associated with dental and oral diseases are likely to pursue treatment from medical and dental providers. The causes for intraoral pain include odontogenic, periodontal, oral mucosal, or contiguous hard and soft tissue structures to the oral cavity. Providers should be vigilant when diagnosing these, as they should be among the first in their differential diagnoses to be ruled out. This review provides brief overviews of frequently encountered oral/dental diseases that cause intraoral pain, originating from the teeth, the surrounding mucosa and gingivae, tongue, bone, and salivary glands and their causes, features, diagnosis, and management strategies. PMID- 27475508 TI - Myofascial Pain: Mechanisms to Management. AB - More than 100 million adults in the United States have chronic pain conditions, costing more than $500 billion annually in medical care and lost productivity. They are the most common reason for seeking health care, for disability and addiction, and the highest driver of health care costs. Myofascial pain is the most common condition causing chronic pain and can be diagnosed through identifying clinical characteristics and muscle palpation. Management is focused on integrating patient training in changing lifestyle risk factors with evidence based treatment. Understanding the cause, diagnosis, and management of myopain conditions will help prevent the impact of chronic pain. PMID- 27475509 TI - Internal Derangement of the Temporomandibular Joint: New Perspectives on an Old Problem. AB - Internal derangement is caused by loss of the structure and function of the intra articular tissues, leading to a failure in the biomechanics of the temporomandibular joint. This tissue failure is usually caused by joint overload, leading to an inflammatory/degenerative arthropathy of the temporomandibular joint. The intra-articular changes associated with internal derangement of the temporomandibular joint can also be caused by a systemic arthropathy or a localized atypical arthropathy involving the temporomandibular joint. Clinicians must be diligent in establishing the correct diagnosis and cause of the internal derangement, which ultimately leads to the appropriate management of patients with these disorders. PMID- 27475510 TI - Temporomandibular Disorders and Headache. AB - Temporomandibular disorders (TMD) and primary headaches can be perpetual and debilitating musculoskeletal and neurological disorders. The presence of both can affect up to one-sixth of the population at any one time. Initially, TMDs were thought to be predominantly musculoskeletal disorders, and migraine was thought to be solely a cerebrovascular disorder. The further understanding of their pathophysiology has helped to clarify their clinical presentation. This article focuses on the role of the trigeminal system in associating TMD and migraine. By discussing recent descriptions of prevalence, diagnosis, and treatment of headache and TMD, we will further elucidate this relationship. PMID- 27475511 TI - Cranial Neuralgias. AB - Advances in diagnostic modalities have improved the understanding of the pathophysiology of neuropathic pain involving head and face. Recent updates in nomenclature of cranial neuralgias and facial pain have rationalized accurate diagnosis. Clear diagnosis and localization of pain generators are paramount, leading to better use of medical and targeted surgical treatments. PMID- 27475512 TI - Painful Traumatic Trigeminal Neuropathy. AB - This article discusses neuropathic pain of traumatic origin affecting the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy by the International Headache Society and replaces atypical odontalgia, deafferentation pain, traumatic neuropathy, and phantom toothache. The discussion emphasizes the diagnosis and the early and late management of injuries to the trigeminal nerve and subsequent painful conditions. PMID- 27475513 TI - Burning Mouth Syndrome. AB - Burning mouth syndrome (BMS) is an enigmatic, misunderstood, and under-recognized painful condition. Symptoms associated with BMS can be varied, thereby providing a challenge for practitioners and having a negative impact on oral health-related quality of life for patients. Management also remains a challenge for practitioners because it is currently only targeted for symptom relief without a definitive cure. There is an urgent need for further investigations to determine the efficacy of different therapies because this is the only way viable therapeutic options can be established for patients with this chronic and painful syndrome. PMID- 27475514 TI - Orofacial Movement Disorders. AB - Orofacial movement disorders (OMDs) include dystonia, dyskinesia, drug-induced extrapyramidal reactions, and bruxism. The definition, epidemiology, pathophysiology, clinical features, and management are detailed. OMDs are often disabling and affect patients' overall quality of life with pain, difficulty chewing food, speech difficulty, drooling, and social embarrassment. Management involves medications, botulinum toxin injections, and peripheral or central surgery. Botulinum toxin injections are the most effective management, often used in conjunction with medications. Surgery is the last resort for patients who fail to respond to medications or develop resistance to botulinum toxin type A. PMID- 27475515 TI - Medication Treatment Efficacy and Chronic Orofacial Pain. AB - Chronic pain in the orofacial region has always been a vexing problem for dentists to diagnose and treat effectively. For trigeminal neuropathic pain, there are 3 medications (gabapentinoids, tricyclic antidepressants, and serotonin norepinephrine reuptake inhibitors) to use plus topical anesthetics that have therapeutic efficacy. For chronic daily headaches (often migraine in origin), 3 prophylactic medications have reasonable therapeutic efficacy (beta-blockers, tricyclic antidepressants, and antiepileptic drugs). The 3 Food and Drug Administration-approved drugs for fibromyalgia (pregabalin, duloxetine, and milnacipran) are not robust, with poor efficacy. For osteroarthritis, nonsteroidal anti-inflammatory drugs have therapeutic efficacy and when gastritis contraindicates them, corticosteriod injections are helpful. PMID- 27475516 TI - Injection Therapy for Headache and Facial Pain. AB - Peripheral nerve blocks are an increasingly viable treatment option for selected groups of headache patients, particularly those with intractable headache or facial pain. Greater occipital nerve block, the most widely used local anesthetic procedure in headache conditions, is particularly effective, safe, and easy to perform in the office. Adverse effects are few and infrequent. These procedures can result in rapid relief of pain and allodynia, and effects last for several weeks or months. Use of nerve block procedures and potentially onabotulinum toxin therapy should be expanded for patients with intractable headache disorders who may benefit, although more studies are needed for efficacy and clinical safety. PMID- 27475517 TI - Oral and Maxillofacial Pain. PMID- 27475518 TI - Effect of implementation of a preconception counselling resource for women with diabetes: A population based study. AB - AIM: To evaluate the effect of regional implementation of a preconception counselling resource into routine diabetes care on pregnancy planning indicators. METHODS: A preconception counselling DVD was distributed to women by diabetes care teams and general practices. Subsequently, in a prospective population-based study, pregnancy planning indicators were evaluated. The post-DVD cohort (n=135), including a viewed-DVD subgroup (n=58), were compared with an historical cohort (pre-DVD, n=114). Primary outcome was HbA1c at first diabetes-antenatal visit. Secondary outcomes included preconception folic acid consumption, planned pregnancy and HbA1c recorded in the 6 months preconception. RESULTS: Mean first visit HbA1c was lower post-DVD vs. pre-DVD: 7.5% vs. 7.8% [58.4 vs. 61.8mmol/mol]; p=0.12), although not statistically significant. 53% and 20% of women with type 1 and 2 diabetes, respectively, viewed the DVD. The viewed-DVD subgroup were significantly more likely to have lower first visit HbA1c: 6.9% vs. 7.8% [52.1 vs. 61.8mmol/mol], P<0.001; planned pregnancy (88% vs. 59%, P<0.001); taken folic acid preconception (81% vs. 43%, P=0.001); and had HbA1c recorded preconception (88% vs. 53%, P<0.001) than the pre-DVD cohort. CONCLUSIONS: Implementation of a preconception counselling resource was associated with improved pregnancy planning indicators. Women with type 2 diabetes are difficult to reach. Greater awareness within primary care of the importance of preconception counselling among this population is needed. PMID- 27475519 TI - Age and gender related prevalence of intracranial calcifications in CT imaging; data from 12,000 healthy subjects. AB - PURPOSE: Location and extent of intracranial calcifications have been detected accurately with the use of CT technology and since, many clinical or pathological entities have been linked to these calcifications. Our purpose is to provide data regarding the prevalence of calcifications in various locations in brain. MATERIAL AND METHODS: We retrospectively examined 11,941 subjects who underwent non-contrast enhanced brain CT examination. We determined the prevalence of choroid plexus, pineal gland, habenula, dura mater, basal ganglia and vascular calcifications. RESULTS: Of 11,941 subjects, 70.2% had choroid plexus calcifications. Calcifications were most frequently seen in pineal gland and 71.6% of the study population had pineal calcifications. Habeluna and dural calcifications were present in 19.2% and 12.5% of the population respectively. Basal ganglia calcifications and vascular calcifications only constituted 1.3% and 3.5% of the study population respectively. Male dominance was present in all calcification types except basal ganglia calcifications. CONCLUSIONS: Showing associations and dissociations from the literature, our study provides a baseline data regarding the prevalence of various types of intracranial calcifications. PMID- 27475520 TI - Proposal for a New Predictive Scale for Recurrent Risk of Fall in a Cohort of Community-Dwelling Patients with Stroke. AB - OBJECTIVES: This study aimed to determine risk factors related to the occurrence of falls in stroke patients and to propose a new predictive scale for falls. METHODS: Demographic and clinical data were collected and the following scales were applied: Barthel Index, Timed Up and Go Test (TUG), and National Institutes of Health Stroke Scale (NIHSS). Subjects were followed prospectively for 2 years for the occurrence of recurrent (>=2) falls. Kaplan-Meier curves were constructed and univariable associations were tested using log-rank test. Two separate multivariable models were then used: the first used Cox proportional hazards regression and the second used Poisson regression. In each model, significant associations were considered present with a P value less than .05. RESULTS: We evaluated 150 individuals and the final analysis included 131 patients; the average age of the patients was 55.8 +/- 13 years, 52% were women, and the median NIHSS score was 2 (interquartile range = 1-5). Falls occurred in 17% of patients, with a median of 23 months of follow-up (interquartile range = 16-26 months). In the multivariable Cox regression model, only TUG quartile, female gender, and posterior circulation territory involvement remained significant predictors of recurrent falls. We used the predictors from the Cox regression model to propose a new recurrent fall risk scale. The area under the receiver operating characteristic curve was 73%, 95% confidence interval = 62%-83%, P = .001, with 81.3% sensitivity and 41.8% specificity. CONCLUSIONS: The new predictive scale for recurrent risk (including TUG, posterior circulation territory involvement, and female gender) is presented as an instrument for monitoring the risk of recurrent falls. PMID- 27475521 TI - Practice Patterns of Percutaneous Endoscopic Gastrostomy Tube Placement in Acute Stroke: Are the Guidelines Achievable? AB - OBJECTIVES: Our objectives were to evaluate trends in percutaneous endoscopic gastrostomy (PEG) tube placement rate and timing in acute stroke patients. We hypothesized that noncompliance with clinical practice guidelines for timing of tube placement and an increase in placement occurred because of a decrease in length of hospital stay. METHODS: We conducted a retrospective observational study of archival hospital billing data from the Florida state inpatient healthcare cost and utilization project database from 2001 to 2012 for patients with a primary diagnosis of stroke. Outcome measures were timing of PEG tube placements by year (2006-2012), rate of placements by year (2001-2012), and length of hospital stay. Univariate analyses and simple and multivariable logistic regression analyses were conducted. RESULTS: The timing of gastrostomy tube placement remained stable with a median of 7 days post admission from 2006 through 2012. The proportion of tubes that were placed at or after 14 days and thereby met the guideline recommendations varied from 14.09% in 2006 to 13.41% in 2012. The rate of tube placement in stroke patients during the acute hospital stay decreased significantly by 25% from 6.94% in 2001 to 5.22% in 2012 (P < .0001). The length of hospital stay for all stroke patients decreased over the study period (P < .0001). CONCLUSIONS: The vast majority of PEG tube placements happen earlier than clinical practice guidelines recommend. Over the study period, the rate of tubes placed in stroke patients decreased during the acute hospital stay despite an overall reduced length of stay. PMID- 27475522 TI - Crassostrea gigas exposure to the dinoflagellate Prorocentrum lima: Histological and gene expression effects on the digestive gland. AB - Bivalve mollusks bioaccumulate toxins via ingestion of toxic dinoflagellates. In this study, Crassostrea gigas was used to investigate the effects related to Prorocentrum lima exposure. Oysters were fed with three diets Isochrysis galbana (2 * 10(6) cell mL(-1)) control treatment; algal mix of I. galbana (2 * 10(6)) and P. lima (3 * 10(3) cell mL(-1)); and P. lima alone (3 * 10(3) cell mL(-1)). Feeding behavior changes, histopathological alterations, and expression patterns changes of genes involved in cell cycle (p21, cafp55, p53), cytoskeleton (tub, act), and inflammatory process (casp1) were evaluated. Results indicated that the presence of diarrheic shellfish poisoning by P. lima cells decreased the clearance rate (p < 0.05), induced structural loss, significantly decreased tubule area of the digestive gland (p < 0.05), and up-regulated in expression all gene (p < 0.05), suggesting that toxic cells might trigger inflammatory tissue process, disturb cell cycle and cytoskeleton representing a risk to oysters integrity. PMID- 27475523 TI - Feasibility and safety of same-day discharge after minimally invasive hysterectomy in gynecologic oncology: A systematic review of the literature. AB - OBJECTIVE: To compare same-day discharge (SDD) versus traditional admission to the hospital following minimally invasive hysterectomy (conventional laparoscopy and robotic assisted laparoscopy) for the treatment of gynecologic malignancies. METHODS: A systematic review was conducted in which MEDLINE and Cochrane Center Register of Controlled Trials were searched using terms related to same-day discharge, outpatient, and hysterectomy. We reviewed published English language trials and studies that compared safety, feasibility, readmission rate, emergency department (ED) visits, complication rate, and associated risk factors for admission. Studies of any design that included at least 20 patients who underwent minimally invasive hysterectomy (conventional laparoscopy and robotic laparoscopy) for gynecologic oncology indications were included. RESULTS: The literature review yielded 421 citations, of which 27 full-text articles were reviewed. Six comparative studies met eligibility criteria. Study data were abstracted and inputted into structural electronic forms. CONCLUSION: Our results suggest that in comparison to admission post minimally invasive hysterectomy with or without full staging, SDD in gynecologic oncology procedures is safe, and feasible. It is associated with low complication and readmissions rates, few visits, and low rates of unscheduled visits within the follow up period of two to six weeks after surgery. PMID- 27475524 TI - Respiratory weakness after mechanical ventilation is associated with one-year mortality - a prospective study. AB - BACKGROUND: Diaphragm dysfunction in mechanically ventilated patients is associated with poor outcome. Maximal inspiratory pressure (MIP) can be used to evaluate inspiratory muscle function. However, it is unclear whether respiratory weakness is independently associated with long-term mortality. The aim of this study was to determine if low MIP is independently associated with one-year mortality. METHODS: We conducted a prospective observational cohort study in an 18-bed ICU. Adults requiring at least 24 hours of mechanical ventilation with scheduled extubation and no evidence of pre-existing muscle weakness underwent MIP evaluation just before extubation. Patients were divided into two groups: low MIP (MIP <=30 cmH2O) and high MIP (MIP >30 cmH2O). Mortality was recorded for one year after extubation. For the survival analysis, the effect of low MIP was assessed using the log-rank test. The independent effect of low MIP on post mechanical ventilation mortality was analyzed using a multivariable Cox regression model. RESULTS: One hundred and twenty-four patients underwent MIP evaluation (median age 66 years (25(th)-75(th) percentile 56-74), Simplified Acute Physiology Score (SAPS) 2 = 45 (33-57), duration of mechanical ventilation 7 days (4-10)). Fifty-four percent of patients had low MIP. One-year mortality was 31 % (95 % CI 0.21, 0.43) in the low MIP group and 7 % (95 % CI 0.02, 0.16) in the high MIP group. After adjustment for SAPS 2 score, body mass index and duration of mechanical ventilation, low MIP was independently associated with one year mortality (hazard ratio 4.41, 95 % CI 1.5, 12.9, p = 0.007). Extubation failure was also associated with low MIP (relative risk 3.0, 95 % CI 1, -9.6; p = 0.03) but tracheostomy and ICU length of stay were not. CONCLUSION: Low MIP is frequent in patients on mechanical ventilation and is an independent risk factor for long-term mortality in ICU patients requiring mechanical ventilation. MIP is easily evaluated at the patient's bedside. TRIAL REGISTRATION: This study was retrospectively registered in www.clinicaltrials.gov (NCT02363231) in February 2015. PMID- 27475526 TI - Effect of embryo morphology and morphometrics on implantation of vitrified day 3 embryos after warming: a retrospective cohort study. AB - BACKGROUND: Characteristics routinely used to evaluate embryo quality after thawing include number of blastomeres survived and presence of mitosis resumption after overnight culture. It is unknown to which extent symmetry and fragmentation affect implantation after warming and whether application of stricter criteria either before vitrification or after warming would improve implantation rate (IR) of vitrified/warmed embryos. This study aimed to find new parameters to improve selection criteria for vitrification and for transfer after warming. METHODS: Firstly, we evaluated standard morphological characteristics (intact survival, mitosis resumption, number of blastomeres, symmetry and fragmentation) of 986 warmed day 3 embryos and, from a subset of 654, we evaluated morphometric characteristics (fragmentation, symmetry and volume change). Secondly, we tested the hypothesis that IR of day 3 vitrified/warmed embryos is influenced by morphometric characteristics. IR per embryo transferred was calculated using embryos that were transferred in a single embryo transfer (SET) or a double embryo transfer (DET) with either 0 or 100 % implantation (830/986). We investigated the significant differences in IR between the different categories of a specific characteristic. These categories were based on our standard embryo evaluation system. The statistical tests Chi-square, Fisher's exact or Cochrane Armitage were used according to the type and/or categories of the variable. RESULTS: The 986 embryos were transferred in 671 FET cycles with 16.9 % (167/986) IR. After exclusion of DET with 1 embryo implanted, IR per embryo transferred was 12.4 % (103/830). Embryo symmetry, fragmentation and volume change in vitrified/warmed day 3 embryos were not associated with IR. However, when mitosis resumption was present after overnight culture, intact embryos reached significantly higher IR than non-intact embryos and only when the embryo compacted after overnight culture the number of cells damaged after warming had no effect on IR. Concretely, embryos with 8 cells after warming or >9 cells after overnight culture-including compacted embryos-reached the highest IR (>15 %) while embryos with <6 cells after warming or with <=6 cells after overnight culture had extremely low IR (<1 %). CONCLUSIONS: IR of vitrified embryos is determined by the number of cells lost, by the occurrence of mitosis resumption, and by the specific number of blastomeres present but not by fragmentation, blastomere symmetry or volume change. Unselecting embryos for cryopreservation because of fragmentation >10 % and/or symmetry < 75 % only leads to unwanted loss of embryos with acceptable implantation potential. TRIAL REGISTRATION: Retrospectively registered NCT02639715 . PMID- 27475525 TI - Mesenchymal stem cells enhance the metastasis of 3D-cultured hepatocellular carcinoma cells. AB - BACKGROUND: Accumulating evidences have demonstrated that mesenchymal stem cells (MSC) could be recruited to the tumor microenvironment. Umbilical cord mesenchymal stem cells (UCMSC) were attractive vehicles for delivering therapeutic agents against cancer. Nevertheless, the safety of UCMSC in the treatment of tumors including hepatocellular carcinoma (HCC) was still undetermined. METHODS: In this study, an in vitro co-culture system was established to evaluate the effect of UCMSC on the cell growth, cancer stem cell (CSC) characteristics, drug resistance, metastasis of 3D-cultured HCC cells, and the underlying mechanism was also investigated. RESULTS: It was found that after co-cultured with UCMSC, the metastatic ability of 3D-cultured HCC cells was significantly enhanced as indicated by up-regulation of matrix metalloproteinase (MMP), epithelial-mesenchymal transition (EMT)-related genes, and migration ability. However, cell growth, drug resistance and CSC-related gene expression of HCC cells were not affected by UCMSC. Moreover, EMT was reversed, MMP-2 expression was down-regulated, and migration ability of HCC cell was significantly inhibited when TGF-beta receptor inhibitor SB431542 was added into the co-culture system. CONCLUSIONS: Therefore, these data indicated that UCMSC could significantly enhance the tumor cell metastasis, which was due to the EMT of HCC cells induced by TGF-beta. PMID- 27475527 TI - A qualitative evaluation to explore the suitability, feasibility and acceptability of using a 'celebration card' intervention in primary care to improve the uptake of childhood vaccinations. AB - BACKGROUND: Childhood vaccination remains a primary mechanism for reducing the burden of infectious disease. In the United Kingdom, as in many countries, a sustained effort is required to ensure that vaccination targets are met to afford protection to the whole population from vaccine preventable disease. The Celebrate and Protect programme is a collaborative partnership developed to improve the uptake of childhood vaccination across a number of boroughs within London through the use of a celebration card to encourage attendance for vaccination and enhance relationships between general practices and the parents/carers of children. METHODS: This study was undertaken to assess the suitability, feasibility and acceptability of the Celebrate and Protect programme across nine boroughs in London. Data were collected either from telephone interviews (n = 24) or from focus groups (n = 31). A total of 55 key informants were included in the study, representing strategic, commissioning or policy leads, healthcare professionals and primary care teams delivering vaccinations and parents/carers of children under five. RESULTS: The analysis of data identified that whilst parents/carers saw the celebration card positively this raised the issue of 'vaccine hesitancy' and the lack of information that parents/carers have to make informed decisions about vaccination. Similarly, healthcare professionals viewed the programme positively and felt that it was deliverable within existing resources although they raised wider questions about on-going sustainability and about quantitative data collection. In relation to the collaboration between primary care and a pharmaceutical company in developing the Celebrate and Protect programme, it was generally felt that, provided appropriate governance is in place, it was a pragmatic approach in which the benefits outweighed any perceived disadvantages. DISCUSSION: The Celebrate and Protect programme was seen as an innovative collaborative programme to engage with parents and carers of children in order to improve relationships between service users and providers and subsequently increase vaccination uptake. The analysis demonstrates that that the celebration card is suitable for its purpose, acceptable to both healthcare professionals and to parents/carers of children and the Celebrate and Protect programme has been able to deliver its aims. CONCLUSION: Whilst the delivery of the 'celebration card' intervention in primary met its objectives there are some outstanding issues in terms of the sustainability of the initiative and the ability to demonstrate quantitative improvements in vaccination uptake rates. PMID- 27475529 TI - Towards the characterisation of carotid plaque tissue toughness: Linking mechanical properties to plaque composition. AB - The morphological manifestation of calcification within an atherosclerotic plaque is diverse and the response to cutting balloon angioplasty remains an elusive target to predict in the presence of extensive calcification. This study examines the resistance of plaque tissue to blade penetration by characterising the underlying toughness properties and stratifying the upper and lower scale toughness limits based on the strong mechanical influence of calcification. Mechanical toughness properties of the common, bifurcation and internal carotid artery (n=62) were determined using guillotine-cutting tests measuring the energy required to pass a surgical blade through a unit length of plaque tissue. The corresponding structural composition of the dissected plaque segments was characterised using Fourier transform infrared analysis, electron microscopy and energy dispersive x-ray spectroscopy. Mechanical results reveal a clear distinction in toughness properties within each region of the carotid vessel with significantly tougher properties localised in the bifurcation (p=0.004) and internal region (p=0.0003) compared to the common. The severity of the intra plaque variance is highest in plaques with high toughness localised in the bifurcation region (p<0.05). Structural examination reveals that the diverse mechanical influence of the level of calcification present is characteristic of specific regions within the carotid plaque. The energy required to overcome the calcific resistance and propagate a controlled cut in the calcified tissue at each region varies further with the degree of plaque progression. The identification of the localised calcification characteristics is a key determinant in achieving successful dissection of the severely toughened plaque segments during cutting balloon angioplasty. STATEMENT OF SIGNIFICANCE: Calcification plays a fundamental role in plaque tissue mechanics and demonstrates a diverse range of material moduli properties. This work addresses the characterisation of the toughness properties in human carotid plaque tissue using a fracture mechanics approach. Toughness determines the energy required to propagate a controlled cut in the plaque material. This parameter is crucial for predicting the cutting forces required during endovascular cutting balloon angioplasty intervention. Results demonstrate that a strong relationship exists between the structural calcification configurations, fracture mechanisms and associated toughness properties that are characteristic of specific regions within the carotid artery plaque. The identification of the morphological characteristics of localised calcification may serve as a valuable quantitative measure for cutting balloon angioplasty treatment. PMID- 27475528 TI - Combination scaffolds of salmon fibrin, hyaluronic acid, and laminin for human neural stem cell and vascular tissue engineering. AB - Human neural stem/progenitor cells (hNSPCs) are good candidates for treating central nervous system (CNS) trauma since they secrete beneficial trophic factors and differentiate into mature CNS cells; however, many cells die after transplantation. This cell death can be ameliorated by inclusion of a biomaterial scaffold, making identification of optimal scaffolds for hNSPCs a critical research focus. We investigated the properties of fibrin-based scaffolds and their effects on hNSPCs and found that fibrin generated from salmon fibrinogen and thrombin stimulates greater hNSPC proliferation than mammalian fibrin. Fibrin scaffolds degrade over the course of a few days in vivo, so we sought to develop a novel scaffold that would retain the beneficial properties of fibrin but degrade more slowly to provide longer support for hNSPCs. We found combination scaffolds of salmon fibrin with interpenetrating networks (IPNs) of hyaluronic acid (HA) with and without laminin polymerize more effectively than fibrin alone and generate compliant hydrogels matching the physical properties of brain tissue. Furthermore, combination scaffolds support hNSPC proliferation and differentiation while significantly attenuating the cell-mediated degradation seen with fibrin alone. HNSPCs express two fibrinogen-binding integrins, alphaVbeta1 and alpha5beta1, and several laminin binding integrins (alpha7beta1, alpha6beta1, alpha3beta1) that can mediate interaction with the scaffold. Lastly, to test the ability of scaffolds to support vascularization, we analyzed human cord blood-derived endothelial cells alone and in co-culture with hNSPCs and found enhanced vessel formation and complexity in co-cultures within combination scaffolds. Overall, combination scaffolds of fibrin, HA, and laminin are excellent biomaterials for hNSPCs. STATEMENT OF SIGNIFICANCE: Interest has increased recently in the development of biomaterials as neural stem cell transplantation scaffolds to treat central nervous system (CNS) injury since scaffolds improve survival and integration of transplanted cells. We report here on a novel combination scaffold composed of fibrin, hyaluronic acid, and laminin to support human neural stem/progenitor cell (hNSPC) function. This combined biomaterial scaffold has appropriate physical properties for hNSPCs and the CNS, supports hNSPC proliferation and differentiation, and attenuates rapid cell mediated scaffold degradation. The hNSPCs and scaffold components synergistically encourage new vessel formation from human endothelial cells. This work marks the first report of a combination scaffold supporting human neural and vascular cells to encourage vasculogenesis, and sets a benchmark for biomaterials to treat CNS injury. PMID- 27475530 TI - Effects of passage number and post-expansion aggregate culture on tissue engineered, self-assembled neocartilage. AB - Chondrocyte dedifferentiation presents a major barrier in engineering functional cartilage constructs. To mitigate the effects of dedifferentiation, this study employed a post-expansion aggregate culture step to enhance the chondrogenic phenotype of passaged articular chondrocytes (ACs) before their integration into self-assembled neocartilage constructs. The objective was twofold: (1) to explore how passage number (P2, P3, P4, P5, P6, and P7), with or without aggregate culture, affected construct properties; and (2) to determine the highest passage number that could form neocartilage with functional properties. Juvenile leporine ACs were passaged to P2-P7, with or without aggregate culture, and self-assembled into 5mm discs in non-adhesive agarose molds without using any exogenous scaffolds. Construct biochemical and biomechanical properties were assessed. With aggregate culture, neocartilage constructs had significantly higher collagen content, higher tensile properties, and flatter morphologies. These beneficial effects were most obvious at higher passage numbers. Specifically, collagen content, Young's modulus, and instantaneous compressive modulus in the P7, aggregate group were 53%, 116%, and 178% higher than those in the P7, non aggregate group. Most interestingly, these extensively passaged P7 ACs (expansion factor of 85,000), which are typically highly dedifferentiated, were able to form constructs with properties similar to or higher than those formed by lower passage number cells. This study not only demonstrated that post-expansion aggregate culture could significantly improve the properties of self-assembled neocartilage, but also that chondrocytes of exceedingly high passage numbers, expanded using the methods in this study, could be used in cartilage engineering applications. STATEMENT OF SIGNIFICANCE: This work demonstrated that extensively passaged chondrocytes (up to passage 7 (P7); expansion factor of 85,000) could potentially be used for cartilage tissue engineering applications. Specifically, an aggregate culture step, employed after cell expansion and before cell integration into a neocartilage construct, was shown to enhance the ability of the chondrocytes to form neocartilage with better biochemical and biomechanical properties. The beneficial effects of this aggregate culture step was especially noticeable at the high passage numbers. Most interestingly, P7 chondrocytes, which are typically highly dedifferentiated, were able to form neocartilage with properties similar to or higher than those formed by lower passage number cells. The ability to obtain high chondrocyte yields with an enhanced chondrogenic potential could have a broad, beneficial impact in improving current therapies (e.g., using higher cell seeding densities for repair) or developing new strategies that require high cell numbers, such as a scaffold-free approach in forming engineered cartilage. PMID- 27475531 TI - Brain stiffness increases with myelin content. AB - Brain stiffness plays an important role in neuronal development and disease, but reported stiffness values vary significantly for different species, for different brains, and even for different regions within the same brain. Despite extensive research throughout the past decade, the mechanistic origin of these stiffness variations remains elusive. Here we show that brain tissue stiffness is correlated to the underlying tissue microstructure and directly proportional to the local myelin content. In 116 indentation tests of six freshly harvested bovine brains, we found that the cerebral stiffnesses of 1.33+/-0.63kPa in white matter and 0.68+/-0.20kPa in gray matter were significantly different (p<0.01). Strikingly, while the inter-specimen variation was rather moderate, the minimum and maximum cerebral white matter stiffnesses of 0.59+/-0.19 kPa and 2.36+/ 0.64kPa in each brain varied by a factor of four on average. To provide a mechanistic interpretation for this variation, we performed a histological characterization of the tested brain regions. We stained the samples with hematoxylin and eosin and luxol fast blue and quantified the local myelin content using image analysis. Interestingly, we found that the cerebral white matter stiffness increased with increasing myelin content, from 0.72kPa at a myelin content of 64-2.45kPa at a myelin content of 89%, with a Pearson correlation coefficient of rho=0.91 (p<0.01). This direct correlation could have significant neurological implications. During development, our results could help explain why immature, incompletely myelinated brains are softer than mature, myelinated brains and more vulnerable to mechanical insult as evident, for example, in shaken baby syndrome. During demyelinating disease, our findings suggest to use stiffness alterations as clinical markers for demyelination to quantify the onset of disease progression, for example, in multiple sclerosis. Taken together, our study indicates that myelin might play a more important function than previously thought: It not only insulates signal propagation and improves electrical function of single axons, it also provides structural support and mechanical stiffness to the brain as a whole. STATEMENT OF SIGNIFICANCE: Increasing evidence suggests that the mechanical environment of the brain plays an important role in neuronal development and disease. Reported stiffness values vary significantly, but the origin of these variations remains unknown. Here we show that stiffness of our brain is correlated to the underlying tissue microstructure and directly proportional to the local myelin content. Myelin has been discovered in 1854 as an insulating layer around nerve cells to improve electric signal propagation. Our study now shows that it also plays an important mechanical role: Using a combined mechanical characterization and histological characterization, we found that the white matter stiffness increases linearly with increasing myelin content, from 0.5kPa at a myelin content of 63-2.5kPa at 92%. PMID- 27475532 TI - Is thoracic spine posture associated with shoulder pain, range of motion and function? A systematic review. AB - INTRODUCTION: Excessive thoracic kyphosis is considered a predisposing factor for shoulder pain, though there is uncertainty about the nature of the relationship between shoulder pain and thoracic spine posture. The aim of this systematic review was to investigate the relationship between thoracic kyphosis and shoulder pain, shoulder range of motion (ROM) and function. METHODS: Two reviewers independently searched eight electronic databases and identified relevant studies by applying eligibility criteria. Sources of bias were assessed independently by two reviewers using a previously validated tool (Ijaz et al., 2013). Data were synthesised using a level of evidence approach (van Tulder et al., 2003). RESULTS: Ten studies were included. Four studies were rated as low risk of bias, three at moderate risk of bias and three at high risk of bias. There is a moderate level of evidence of no significant difference in thoracic kyphosis between groups with and without shoulder pain. One study at high risk of bias demonstrated significantly greater thoracic kyphosis in people with shoulder pain (p < 0.05). There is a strong level of evidence that maximum shoulder ROM is greater in erect postures compared to slouched postures (p < 0.001), in people with and without shoulder pain. CONCLUSIONS: Thoracic kyphosis may not be an important contributor to the development of shoulder pain. While there is evidence that reducing thoracic kyphosis facilitates greater shoulder ROM, this is based on single-session studies whose long-term clinical relevance is unclear. Higher quality research is warranted to fully explore the role of thoracic posture in shoulder pain. PMID- 27475533 TI - Design, synthesis, molecular docking and biological evaluation of thiophen-2 iminothiazolidine derivatives for use against Trypanosoma cruzi. AB - In this study, we designed and synthesized a series of thiophen-2 iminothiazolidine derivatives from thiophen-2-thioureic with good anti Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03MUM. The 8c derivative showed the highest potency against cruzain (IC50=2.4MUM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal.mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease. PMID- 27475535 TI - Multiantigenic peptide-polymer conjugates as therapeutic vaccines against cervical cancer. AB - Immunotherapy is one of the most promising strategies for the treatment of cancer. Human papillomavirus (HPV) is responsible for virtually all cases of cervical cancer. The main purpose of a therapeutic HPV vaccine is to stimulate CD8(+) cytotoxic T lymphocytes (CTLs) that can eradicate HPV infected cells. HPV oncoproteins E6 and E7 are continuously expressed and are essential for maintaining the growth of HPV-associated tumor cells. We designed polymer-based multi-antigenic formulations/constructs that were comprised of the E6 and E7 peptide epitopes. We developed an N-terminus-based epitope conjugation to conjugate two unprotected peptides to poly tert-butyl acrylate. This method allowed for the incorporation of the two antigens into a polymeric dendrimer in a strictly equimolar ratio. The most effective formulations eliminated tumors in up to 50% of treated mice. Tumor recurrence was not observed up to 3months post initial challenge. PMID- 27475534 TI - Effects of stereochemistry, saturation, and hydrocarbon chain length on the ability of synthetic constrained azacyclic sphingolipids to trigger nutrient transporter down-regulation, vacuolation, and cell death. AB - Constrained analogs containing a 2-hydroxymethylpyrrolidine core of the natural sphingolipids sphingosine, sphinganine, N,N-dimethylsphingosine and N-acetyl variants of sphingosine and sphinganine (C2-ceramide and dihydro-C2-ceramide) were synthesized and evaluated for their ability to down-regulate nutrient transporter proteins and trigger cytoplasmic vacuolation in mammalian cells. In cancer cells, the disruptions in intracellular trafficking produced by these sphingolipids lead to cancer cell death by starvation. Structure activity studies were conducted by varying the length of the hydrocarbon chain, the degree of unsaturation and the presence or absence of an aryl moiety on the appended chains, and stereochemistry at two stereogenic centers. In general, cytotoxicity was positively correlated with nutrient transporter down-regulation and vacuolation. This study was intended to identify structural and functional features in lead compounds that best contribute to potency, and to develop chemical biology tools that could be used to isolate the different protein targets responsible for nutrient transporter loss and cytoplasmic vacuolation. A molecule that produces maximal vacuolation and transporter loss is expected to have the maximal anti-cancer activity and would be a lead compound. PMID- 27475536 TI - Zinc-mediated binding of a low-molecular-weight stabilizer of the host anti-viral factor apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G. AB - Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, A3G), is a human anti-virus restriction protein which works deaminase-dependently and -independently. A3G is known to be ubiquitinated by HIV-1 viral infectivity factor (Vif) protein, leading to proteasomal degradation. A3G contains two zinc ions at the N-terminal domain and the C-terminal domain. Four lysine residues, K(297), K(301), K(303), and K(334), are known to be required for Vif-mediated A3G ubiquitination and degradation. Previously, we reported compound SN-1, a zinc chelator that increases steady-state expression level of A3G in the presence of Vif. In this study, we prepared Biotin-SN-1, a biotinylated derivative of SN-1, to study the SN-1-A3G interaction. A pull-down assay revealed that Biotin-SN-1 bound A3G. A zinc-abstraction experiment indicated that SN-1 binds to the zinc site of A3G. We carried out a SN-1-A3G docking study using molecular operating environment. The calculations revealed that SN-1 binds to the C-terminal domain through Zn(2+), H(216), P(247), C(288), and Y(315). Notably, SN-1-binding covers the H(257), E(259), C(288), and C(291) residues that participate in zinc-mediated deamination, and the ubiquitination regions of A3G. The binding of SN-1 presumably perturbs the secondary structure between C(288) and Y(315), leading to less efficient ubiquitination. PMID- 27475537 TI - Bacterial versus human sphingosine-1-phosphate lyase (S1PL) in the design of potential S1PL inhibitors. AB - A series of potential active-site sphingosine-1-phosphate lyase (S1PL) inhibitors have been designed from scaffolds 1 and 2, arising from virtual screening using the X-ray structures of the bacterial (StS1PL) and the human (hS1PL) enzymes. Both enzymes are very similar at the active site, as confirmed by the similar experimental kinetic constants shown by the fluorogenic substrate RBM13 in both cases. However, the docking scoring functions used probably overestimated the weight of electrostatic interactions between the ligands and key active-site residues in the protein environment, which may account for the modest activity found for the designed inhibitors. In addition, the possibility that the inhibitors do not reach the enzyme active site should not be overlooked. Finally, since both enzymes show remarkable structural differences at the access channel and in the proximity to the active site cavity, caution should be taken when designing inhibitors acting around that area, as evidenced by the much lower activity found in StS1PL for the potent hS1PL inhibitor D. PMID- 27475539 TI - Invited Review Article: "Hands-on" laser-driven ion acceleration: A primer for laser-driven source development and potential applications. AB - An overview of progress and typical yields from intense laser-plasma acceleration of ions is presented. The evolution of laser-driven ion acceleration at relativistic intensities ushers prospects for improved functionality and diverse applications which can represent a varied assortment of ion beam requirements. This mandates the development of the integrated laser-driven ion accelerator system, the multiple components of which are described. Relevant high field laser plasma science and design of controlled optimum pulsed laser irradiation on target are dominant single shot (pulse) considerations with aspects that are appropriate to the emerging petawatt era. The pulse energy scaling of maximum ion energies and typical differential spectra obtained over the past two decades provide guidance for continued advancement of laser-driven energetic ion sources and their meaningful applications. PMID- 27475538 TI - Unwanted sexual attention at work and long-term sickness absence: a follow-up register-based study. AB - BACKGROUND: The current understanding of the relationship between unwanted sexual attention at work and long-term sickness absence (LTSA) is limited for three reasons: 1) the under-researched role of unwanted sexual attention perpetrated by individuals outside the work organization; 2) a widespread use of self-reported measures of sickness absence, with an unclear identification of sickness absence episodes of long duration; 3) the cross-sectional design of most existing studies. The aim of this study was therefore to investigate the relationship between self-reported unwanted sexual attention at work and subsequent LTSA (>=3 weeks), stratifying by gender and source of exposure (i.e., colleagues, managers and/or subordinates vs. clients/customers/patients). METHODS: This prospective study is based on a pooled sample of 14,605 employees from three Danish surveys conducted in 2000, 2004 and 2005, providing a total of 19,366 observations. A single questionnaire-based item was used to assess exposure to unwanted sexual attention. The pooled dataset was merged with Danish register data on LTSA. The risk of first-onset episode of LTSA (up to 18 months after baseline) in connection with unwanted sexual attention was examined using Cox proportional hazards models. We estimated Hazard ratios (HR) and 95 % confidence intervals (95 % CI) adjusted for age, influence at work, work pace, occupational group and mode of data collection. We also adjusted for repeated measures from individual respondents by stratifying the Cox models by wave of survey. RESULTS: Unwanted sexual attention from colleagues, managers and/or subordinates predicted LTSA among men (HR 2.66; 95 % CI 1.42-5.00). Among women, an elevated but non statistically significant risk of LTSA (HR 1.18; 95 % CI 0.65-2.14) was found. Unwanted sexual attention from clients/customers/patients did not predict LTSA, neither among men nor among women. CONCLUSIONS: The findings indicate a significantly elevated risk of LTSA, among men only, in relation to exposure to unwanted sexual attention from colleagues, managers and/or subordinates. This study therefore suggests both individual and organizational costs associated with unwanted sexual attention at work. Due to the low prevalence of unwanted sexual attention, larger studies with more statistical power are needed to confirm (or disconfirm) the present findings. PMID- 27475540 TI - Contributed Review: A new synchronized source solution for coherent Raman scattering microscopy. AB - Based on vibrational spectroscopy, coherent Raman Scattering (CRS) microscopy allows label-free imaging of biological and chemical samples with endogenous image contrast. Two-color, synchronized picosecond pulses are typically used for high spectral resolution imaging, which in turn constitutes a dramatic laser source challenge for CRS microscopy. Recently, synchronized time-lens source, inspired from ultrafast optical signal processing, has emerged as a promising laser source solution and has found application in various modalities of CRS microscopy. Time-lens is based on space-time analogy, which uses a "lens" in the time domain to compress long optical pulses or even continuous waves to ultrashort pulses, mimicking a lens in the space domain. Phase and intensity modulators driven with electrical signals are used in the time-lens source for picosecond pulse generation. As a result, the time-lens source is highly versatile and naturally compatible with modulation capabilities. More importantly, if the electrical signals used to drive the time-lens source are derived from other laser sources, such as mode-locked lasers, then synchronization between them can be realized, underlying the physics of a synchronized time-lens source. In this paper, we review recent progress on the basic principle, design of the synchronized time-lens source, and its applications to CRS microscopy of both biological and chemical samples. PMID- 27475541 TI - Contributed Review: Quartz force sensing probes for micro-applications. AB - As self-sensing and self-exciting probes, quartz sensors present many advantages over silicon cantilevers for microscopy, micro-robotics, and other micro applications. Their development and use is further bolstered by the fact that they can be manufactured from common quartz components. This paper therefore reviews applications of the increasingly popular quartz tuning fork probes as force sensors in the literature and examines the options for higher-frequency quartz probes using the other available types of flexional, thickness-shear or length-extensional resonators. PMID- 27475542 TI - Time-resolved single-photon detection module based on silicon photomultiplier: A novel building block for time-correlated measurement systems. AB - We present the design and preliminary characterization of the first detection module based on Silicon Photomultiplier (SiPM) tailored for single-photon timing applications. The aim of this work is to demonstrate, thanks to the design of a suitable module, the possibility to easily exploit SiPM in many applications as an interesting detector featuring large active area, similarly to photomultipliers tubes, but keeping the advantages of solid state detectors (high quantum efficiency, low cost, compactness, robustness, low bias voltage, and insensitiveness to magnetic field). The module integrates a cooled SiPM with a total photosensitive area of 1 mm(2) together with the suitable avalanche signal read-out circuit, the signal conditioning, the biasing electronics, and a Peltier cooler driver for thermal stabilization. It is able to extract the single-photon timing information with resolution better than 100 ps full-width at half maximum. We verified the effective stabilization in response to external thermal perturbations, thus proving the complete insensitivity of the module to environment temperature variations, which represents a fundamental parameter to profitably use the instrument for real-field applications. We also characterized the single-photon timing resolution, the background noise due to both primary dark count generation and afterpulsing, the single-photon detection efficiency, and the instrument response function shape. The proposed module can become a reliable and cost-effective building block for time-correlated single-photon counting instruments in applications requiring high collection capability of isotropic light and detection efficiency (e.g., fluorescence decay measurements or time-domain diffuse optics systems). PMID- 27475543 TI - A table-top monochromator for tunable femtosecond XUV pulses generated in a semi infinite gas cell: Experiment and simulations. AB - We present a new design of a time-preserving extreme-ultraviolet (XUV) monochromator using a semi-infinite gas cell as a source. The performance of this beamline in the photon-energy range of 20 eV-42 eV has been characterized. We have measured the order-dependent XUV pulse durations as well as the flux and the spectral contrast. XUV pulse durations of <=40 fs using 32 fs, 800 nm driving pulses were measured on the target. The spectral contrast was better than 100 over the entire energy range. A simple model based on the strong-field approximation is presented to estimate different contributions to the measured XUV pulse duration. On-axis phase-matching calculations are used to rationalize the variation of the photon flux with pressure and intensity. PMID- 27475544 TI - A novel lobster-eye imaging system based on Schmidt-type objective for X-ray backscattering inspection. AB - This paper presents a novel lobster-eye imaging system for X-ray-backscattering inspection. The system was designed by modifying the Schmidt geometry into a treble-lens structure in order to reduce the resolution difference between the vertical and horizontal directions, as indicated by ray-tracing simulations. The lobster-eye X-ray imaging system is capable of operating over a wide range of photon energies up to 100 keV. In addition, the optics of the lobster-eye X-ray imaging system was tested to verify that they meet the requirements. X-ray backscattering imaging experiments were performed in which T-shaped polymethyl methacrylate objects were imaged by the lobster-eye X-ray imaging system based on both the double-lens and treble-lens Schmidt objectives. The results show similar resolution of the treble-lens Schmidt objective in both the vertical and horizontal directions. Moreover, imaging experiments were performed using a second treble-lens Schmidt objective with higher resolution. The results show that for a field of view of over 200 mm and with a 500 mm object distance, this lobster-eye X-ray imaging system based on a treble-lens Schmidt objective offers a spatial resolution of approximately 3 mm. PMID- 27475545 TI - Frequency analysis of temperature-dependent interferometric signal for the measurement of the temperature coefficient of refractive index. AB - A method of frequency analysis for the measurement of the temperature coefficient of refractive index (dn/dT) using a Fabry-Perot interferometer was developed and tested against ethanol and water. The temperature-dependent interferometric signal described by Airy's formula was analyzed in both the temperature and frequency domains. By fast Fourier transform, a low-pass filter was designed and employed to eliminate the noise superimposed on the signal. dn/dT was determined accurately from the noise-removed signal by peak analysis. Furthermore, the signal frequency parameters may be utilized for the material thermophysical property characterization. This method lays the foundation for an online dn/dT instrument for monitoring chemical processes. PMID- 27475546 TI - A simple multipurpose double-beam optical image analyzer. AB - In the paper we present a low cost optical device which splits the light in the focal plane into two separate optical paths and collimates it back into a single image plane, and where a selective information processing can be carried out. The optical system is straightforward and easily implementable as it consists of only three lenses and two mirrors. The system is dedicated for imaging in low-light level conditions in which widely used optical devices, based on beam splitters or dichroic mirrors, suffer from light loss. We expose examples of applications of our device, using a prototype model. The proposed optical system may be employed for: monitoring the objects located at different distances from observer (1), creating regions of different magnification within a single image plane (2), high dynamic range photometry (3), or imaging in two wavelength bands simultaneously (4). PMID- 27475547 TI - A simple laser locking system based on a field-programmable gate array. AB - Frequency stabilization of laser light is crucial in both scientific and industrial applications. Technological developments now allow analog laser stabilization systems to be replaced with digital electronics such as field programmable gate arrays, which have recently been utilized to develop such locking systems. We have developed a frequency stabilization system based on a field-programmable gate array, with emphasis on hardware simplicity, which offers a user-friendly alternative to commercial and previous home-built solutions. Frequency modulation, lock-in detection, and a proportional-integral-derivative controller are programmed on the field-programmable gate array and only minimal additional components are required to frequency stabilize a laser. The locking system is administered from a host-computer which provides comprehensive, long distance control through a versatile interface. Various measurements were performed to characterize the system. The linewidth of the locked laser was measured to be 0.7 +/- 0.1 MHz with a settling time of 10 ms. The system can thus fully match laser systems currently in use for atom trapping and cooling applications. PMID- 27475548 TI - Long working distance objective lenses for single atom trapping and imaging. AB - We present a pair of optimized objective lenses with long working distances of 117 mm and 65 mm, respectively, that offer diffraction limited performance for both Cs and Rb wavelengths when imaging through standard vacuum windows. The designs utilise standard catalog lens elements to provide a simple and cost effective solution. Objective 1 provides NA = 0.175 offering 3 MUm resolution whilst objective 2 is optimized for high collection efficiency with NA = 0.29 and 1.8 MUm resolution. This flexible design can be further extended for use at shorter wavelengths by simply re-optimising the lens separations. PMID- 27475549 TI - Transmission and fluorescence X-ray absorption spectroscopy cell/flow reactor for powder samples under vacuum or in reactive atmospheres. AB - X-ray absorption spectroscopy is an element-specific technique for probing the local atomic-scale environment around an absorber atom. It is widely used to investigate the structures of liquids and solids, being especially valuable for characterization of solid-supported catalysts. Reported cell designs are limited in capabilities-to fluorescence or transmission and to static or flowing atmospheres, or to vacuum. Our goal was to design a robust and widely applicable cell for catalyst characterizations under all these conditions-to allow tracking of changes during genesis and during operation, both under vacuum and in reactive atmospheres. Herein, we report the design of such a cell and a demonstration of its operation both with a sample under dynamic vacuum and in the presence of gases flowing at temperatures up to 300 degrees C, showing data obtained with both fluorescence and transmission detection. The cell allows more flexibility in catalyst characterization than any reported. PMID- 27475550 TI - Absolute dosimetric characterization of Gafchromic EBT3 and HDv2 films using commercial flat-bed scanners and evaluation of the scanner response function variability. AB - Radiochromic films (RCF) are commonly used in dosimetry for a wide range of radiation sources (electrons, protons, and photons) for medical, industrial, and scientific applications. They are multi-layered, which includes plastic substrate layers and sensitive layers that incorporate a radiation-sensitive dye. Quantitative dose can be retrieved by digitizing the film, provided that a prior calibration exists. Here, to calibrate the newly developed EBT3 and HDv2 RCFs from GafchromicTM, we used the Stanford Medical LINAC to deposit in the films various doses of 10 MeV photons, and by scanning the films using three independent EPSON Precision 2450 scanners, three independent EPSON V750 scanners, and two independent EPSON 11000XL scanners. The films were scanned in separate RGB channels, as well as in black and white, and film orientation was varied. We found that the green channel of the RGB scan and the grayscale channel are in fact quite consistent over the different models of the scanner, although this comes at the cost of a reduction in sensitivity (by a factor ~2.5 compared to the red channel). To allow any user to extend the absolute calibration reported here to any other scanner, we furthermore provide a calibration curve of the EPSON 2450 scanner based on absolutely calibrated, commercially available, optical density filters. PMID- 27475551 TI - Development of an FPGA-based multipoint laser pyroshock measurement system for explosive bolts. AB - Pyroshock can cause failure to the objective of an aerospace structure by damaging its sensitive electronic equipment, which is responsible for performing decisive operations. A pyroshock is the high intensity shock wave that is generated when a pyrotechnic device is explosively triggered to separate, release, or activate structural subsystems of an aerospace architecture. Pyroshock measurement plays an important role in experimental simulations to understand the characteristics of pyroshock on the host structure. This paper presents a technology to measure a pyroshock wave at multiple points using laser Doppler vibrometers (LDVs). These LDVs detect the pyroshock wave generated due to an explosive-based pyrotechnical event. Field programmable gate array (FPGA) based data acquisition is used in the study to acquire pyroshock signals simultaneously from multiple channels. This paper describes the complete system design for multipoint pyroshock measurement. The firmware architecture for the implementation of multichannel data acquisition on an FPGA-based development board is also discussed. An experiment using explosive bolts was configured to test the reliability of the system. Pyroshock was generated using explosive excitation on a 22-mm-thick steel plate. Three LDVs were deployed to capture the pyroshock wave at different points. The pyroshocks captured were displayed as acceleration plots. The results showed that our system effectively captured the pyroshock wave with a peak-to-peak magnitude of 303 741 g. The contribution of this paper is a specialized architecture of firmware design programmed in FPGA for data acquisition of large amount of multichannel pyroshock data. The advantages of the developed system are the near-field, multipoint, non-contact, and remote measurement of a pyroshock wave, which is dangerous and expensive to produce in aerospace pyrotechnic tests. PMID- 27475552 TI - Three-dimensional particle-in-cell simulation on gain saturation effect of microchannel plate. AB - We present here the results of the simulation work, using the three-dimensional particle-in-cell method, on the performance of the lead glass microchannel plate under saturated state. We calculated the electron cascade process with different DC bias voltages under both self-consistent condition and non-self-consistent condition. The comparative results have demonstrated that the strong self consistent field can suppress the cascade process and make the microchannel plate saturated. The simulation results were also compared to the experimental data and good agreement was obtained. The simulation results also show that the electron multiplication process in the channel is accompanied by the buildup process of positive charges in the channel wall. Though the interactions among the secondary electron cloud in the channel, the positive charges in the channel wall, and the external acceleration field can make the electron-surface collision more frequent, the collision energy will be inevitably reduced, thus the electron gain will also be reduced. PMID- 27475553 TI - A 5 kA pulsed power supply for inductive and plasma loads in large volume plasma device. AB - This paper describes 5 kA, 12 ms pulsed power supply for inductive load of Electron Energy Filter (EEF) in large volume plasma device. The power supply is based upon the principle of rapid sourcing of energy from the capacitor bank (2.8 F/200 V) by using a static switch, comprising of ten Insulated Gate Bipolar Transistors (IGBTs). A suitable mechanism is developed to ensure equal sharing of current and uniform power distribution during the operation of these IGBTs. Safe commutation of power to the EEF is ensured by the proper optimization of its components and by the introduction of over voltage protection (>6 kV) using an indigenously designed snubber circuit. Various time sequences relevant to different actions of power supply, viz., pulse width control and repetition rate, are realized through optically isolated computer controlled interface. PMID- 27475554 TI - Experimental analysis of a novel and low-cost pin photodiode dosimetry system for diagnostic radiology. AB - Silicon PIN photodiode has recently found broad and exciting applications in the ionizing radiation dosimetry. In this study a compact and novel dosimetry system using a commercially available PIN photodiode (BPW34) has been experimentally tested for diagnostic radiology. The system was evaluated with clinical beams routinely used for diagnostic radiology and calibrated using a secondary reference standard. Measured dose with PIN photodiode (Air Kerma) varied from 10 to 430 MUGy for tube voltages from 40 to 100 kVp and tube current from 0.4 to 40 mAs. The minimum detectable organ dose was estimated to be 10 MUGy with 20% uncertainty. Results showed a linear correlation between the PIN photodiode readout and dose measured with standard dosimeters spanning doses received. The present dosimetry system having advantages of suitable sensitivity with immediate readout of dose values, low cost, and portability could be used as an alternative to passive dosimetry system such as thermoluminescent dosimeter for dose measurements in diagnostic radiology. PMID- 27475555 TI - Design of multichord Halpha detector arrays for the U-3M torsatron and identification of rotating plasma perturbations. AB - An Halpha camera has been designed and installed in the U-3M torsatron for spatially and temporally resolved measurements. This device provides fast measurements of the emission brightness profile in the noisy environment of the radio frequency (RF) heated plasma. Unusual topology of diagnostics and the data acquisition system are applied. All the system components, including digitizers, are assembled in a single unit. It allows the suppression of a low-frequency electromagnetic interference by eliminating the ground loops. And the suppression of RF noises is achieved by eliminating the signal interface cables and digital interface cables in the design. The Wi-Fi interface is used to prevent a ground loop in the data transfer stage. The achieved sensitivity of our diagnostics is high enough for measuring the Halpha emission from the low-density (ne ~ (1 2)?10(10) cm(-3)) plasma with a temporal resolution of about 20 MUs in the noisy environment. Different types of Halpha emission fluctuations within the frequency range of 1-5 kHz and poloidal mode numbers m = 0 and m = 5 have been observed in U-3M. A simple technique of the line-of-sight data analysis, based on the U-3M magnetic surface asymmetry, is proposed and used for the spatial localization of the rotating mode and for the determination of mode numbers and its poloidal rotation direction using a single Halpha array. PMID- 27475556 TI - A photoelastic-modulator-based motional Stark effect polarimeter for ITER that is insensitive to polarized broadband background reflections. AB - A motional Stark effect polarimeter insensitive to polarized broadband light is proposed. Partially polarized background light is anticipated to be a significant source of systematic error for the ITER polarimeter. The proposed polarimeter is based on the standard dual photoelastic modulator approach, but with the introduction of a birefringent delay plate, it generates a sinusoidal spectral filter instead of the usual narrowband filter. The period of the filter is chosen to match the spacing of the orthogonally polarized Stark effect components, thereby increasing the effective signal level, but resulting in the destructive interference of the broadband polarized light. The theoretical response of the system to an ITER like spectrum is calculated and the broadband polarization tolerance is verified experimentally. PMID- 27475557 TI - 3D printing of gas jet nozzles for laser-plasma accelerators. AB - Recent results on laser wakefield acceleration in tailored plasma channels have underlined the importance of controlling the density profile of the gas target. In particular, it was reported that the appropriate density tailoring can result in improved injection, acceleration, and collimation of laser-accelerated electron beams. To achieve such profiles, innovative target designs are required. For this purpose, we have reviewed the usage of additive layer manufacturing, commonly known as 3D printing, in order to produce gas jet nozzles. Notably we have compared the performance of two industry standard techniques, namely, selective laser sintering (SLS) and stereolithography (SLA). Furthermore we have used the common fused deposition modeling to reproduce basic gas jet designs and used SLA and SLS for more sophisticated nozzle designs. The nozzles are characterized interferometrically and used for electron acceleration experiments with the Salle Jaune terawatt laser at Laboratoire d'Optique Appliquee. PMID- 27475558 TI - A new dump system design for stray light reduction of Thomson scattering diagnostic system on EAST. AB - Thomson scattering (TS) diagnostic is an important diagnostic for measuring electron temperature and density during plasma discharge. However, the measurement of Thomson scattering signal is disturbed by the stray light easily. The stray light sources in the Experimental Advanced Superconducting Tokamak (EAST) TS diagnostic system were analyzed by a simulation model of the diagnostic system, and simulation results show that the dump system is the primary stray light source. Based on the optics theory and the simulation analysis, a novel dump system including an improved beam trap was proposed and installed. The measurement results indicate that the new dump system can reduce more than 60% of the stray light for the diagnostic system, and the influence of stray light on the error of measured density decreases. PMID- 27475559 TI - Time resolved quantitative imaging of charring in materials at temperatures above 1000 K. AB - A device is presented allowing for in situ investigation of chemically changing materials by means of X-ray imaging. A representative cork ablator sample, additionally instrumented with thermocouples, is encapsulated in an evacuated cell heating a sample surface with a heat flux of 230 kW/m(2). The images show the sample surface and the in-depth progression of the char front dividing the char layer from the virgin material. Correlating the images to thermocouple data allows for the deduction of a reaction temperature. For the representative cork ablator investigated at the present conditions, the progression rate of the pyrolysis layer is determined to 0.0285 mm/s and pyrolysis temperature is 770 or 737 K, depending on the pre-existing conditions. It is found that the novel device is ideally suited for volume process imaging. PMID- 27475560 TI - Set-up of a high-resolution 300 mK atomic force microscope in an ultra-high vacuum compatible (3)He/10 T cryostat. AB - The design of an atomic force microscope with an all-fiber interferometric detection scheme capable of atomic resolution at about 500 mK is presented. The microscope body is connected to a small pumped (3)He reservoir with a base temperature of about 300 mK. The bakeable insert with the cooling stage can be moved from its measurement position inside the bore of a superconducting 10 T magnet into an ultra-high vacuum chamber, where the tip and sample can be exchanged in situ. Moreover, single atoms or molecules can be evaporated onto a cold substrate located inside the microscope. Two side chambers are equipped with standard surface preparation and surface analysis tools. The performance of the microscope at low temperatures is demonstrated by resolving single Co atoms on Mn/W(110) and by showing atomic resolution on NaCl(001). PMID- 27475561 TI - Double micropipettes configuration method of scanning ion conductance microscopy. AB - In this paper, a new double micropipettes configuration mode of scanning ion conductance microscopy (SICM) is presented to better overcome ionic current drift and further improve the performance of SICM, which is based on a balance bridge circuit. The article verifies the feasibility of this new configuration mode from theoretical and experimental analyses, respectively, and compares the quality of scanning images in the conventional single micropipette configuration mode and the new double micropipettes configuration mode. The experimental results show that the double micropipettes configuration mode of SICM has better effect on restraining ionic current drift and better performance of imaging. Therefore, this article not only proposes a new direction of overcoming the ionic current drift but also develops a new method of SICM stable imaging. PMID- 27475562 TI - Development of birefringence imaging analysis method for observing cubic crystals in various phase transitions. AB - Optical birefringence imaging systems demonstrate a high potential for comprehensively investigating various phase transitions. To completely demonstrate such abilities, the temperature dependence of birefringence (Deltan) was measured in Deltan ? 0 materials (i.e., cubic crystals with imperfect crystallization) via a background subtraction method. As a result, highly accurate birefringence imaging at 384 * 288 pixels was obtained using phase transition processes as well as varying temperatures visually characterized by the spatial distribution of not only the retardance level but also the optical fast-axis azimuth. PMID- 27475563 TI - Calibration of higher eigenmodes of cantilevers. AB - A method is presented for calibrating the higher eigenmodes (resonant modes) of atomic force microscopy cantilevers that can be performed prior to any tip-sample interaction. The method leverages recent efforts in accurately calibrating the first eigenmode by providing the higher-mode stiffness as a ratio to the first mode stiffness. A one-time calibration routine must be performed for every cantilever type to determine a power-law relationship between stiffness and frequency, which is then stored for future use on similar cantilevers. Then, future calibrations only require a measurement of the ratio of resonant frequencies and the stiffness of the first mode. This method is verified through stiffness measurements using three independent approaches: interferometric measurement, AC approach-curve calibration, and finite element analysis simulation. Power-law values for calibrating higher-mode stiffnesses are reported for several cantilever models. Once the higher-mode stiffnesses are known, the amplitude of each mode can also be calibrated from the thermal spectrum by application of the equipartition theorem. PMID- 27475564 TI - A multi-wavelength, high-contrast contact radiography system for the study of low density aerogel foams. AB - A multi-wavelength, high contrast contact radiography system has been developed to characterize density variations in ultra-low density aerogel foams. These foams are used to generate a ramped pressure drive in materials strength experiments at the National Ignition Facility and require precision characterization in order to reduce errors in measurements. The system was used to characterize density variations in carbon and silicon based aerogels to ~10.3% accuracy with ~30 MUm spatial resolution. The system description, performance, and measurement results collected using a 17.8 mg/cc carbon based JX-6 (C20H30) aerogel are discussed in this manuscript. PMID- 27475565 TI - New design of the pulsed electro-acoustic upper electrode for space charge measurements during electronic irradiation. AB - The behaviour of space charges injected in irradiated dielectrics has been studied for many years for space industry applications. In our case, the pulsed electro-acoustic method is chosen in order to determine the spatial distribution of injected electrons. The feasibility of a ring-shaped electrode which will allow the measurements during irradiation is presented. In this paper, a computer simulation is made in order to determine the parameters to design the electrode and find its position above the sample. The obtained experimental results on polyethylene naphthalate samples realized during electronic irradiation and through relaxation under vacuum will be presented and discussed. PMID- 27475567 TI - A uniaxial stress capacitive dilatometer for high-resolution thermal expansion and magnetostriction under multiextreme conditions. AB - Thermal expansion and magnetostriction are directional dependent thermodynamic quantities. For the characterization of novel quantum phases of matter, it is required to study materials under multi-extreme conditions, in particular, down to very low temperatures, in very high magnetic fields or under high pressure. We developed a miniaturized capacitive dilatometer suitable for temperatures down to 20 mK and usage in high magnetic fields, which exerts a large spring force between 40 to 75 N on the sample. This corresponds to a uniaxial stress up to 3 kbar for a sample with cross section of (0.5 mm)(2). We describe design and performance test of the dilatometer which resolves length changes with high resolution of 0.02 A at low temperatures. The miniaturized device can be utilized in any standard cryostat, including dilution refrigerators or the commercial physical property measurement system. PMID- 27475566 TI - Aerodynamic levitator for in situ x-ray structure measurements on high temperature and molten nuclear fuel materials. AB - An aerodynamic levitator with carbon dioxide laser beam heating was integrated with a hermetically sealed controlled atmosphere chamber and sample handling mechanism. The system enabled containment of radioactive samples and control of the process atmosphere chemistry. The chamber was typically operated at a pressure of approximately 0.9 bars to ensure containment of the materials being processed. Samples 2.5-3 mm in diameter were levitated in flowing gas to achieve containerless conditions. Levitated samples were heated to temperatures of up to 3500 degrees C with a partially focused carbon dioxide laser beam. Sample temperature was measured using an optical pyrometer. The sample environment was integrated with a high energy (100 keV) x-ray synchrotron beamline to enable in situ structure measurements to be made on levitated samples as they were heated, melted, and supercooled. The system was controlled from outside the x-ray beamline hutch by using a LabVIEW program. Measurements have been made on hot solid and molten uranium dioxide and binary uranium dioxide-zirconium dioxide compositions. PMID- 27475568 TI - Multi-frequency force-detected electron spin resonance in the millimeter-wave region up to 150 GHz. AB - In this article, a novel technique is developed for multi-frequency force detected electron spin resonance (ESR) in the millimeter-wave region. We constructed a compact ESR probehead, in which the cantilever bending is sensitively detected by a fiber-optic Fabry-Perot interferometer. With this setup, ESR absorption of diphenyl-picrylhydrazyl radical (<1 MUg) was clearly observed at multiple frequencies of up to 150 GHz. We also observed the hyperfine splitting of low-concentration Mn(2+) impurities(~0.2%) in MgO. PMID- 27475569 TI - Vibration-induced electrical noise in a cryogen-free dilution refrigerator: Characterization, mitigation, and impact on qubit coherence. AB - Cryogen-free low-temperature setups are becoming more prominent in experimental science due to their convenience and reliability, and concern about the increasing scarcity of helium as a natural resource. Despite not having any moving parts at the cold end, pulse tube cryocoolers introduce vibrations that can be detrimental to the experiments. We characterize the coupling of these vibrations to the electrical signal observed on cables installed in a cryogen free dilution refrigerator. The dominant electrical noise is in the 5-10 kHz range and its magnitude is found to be strongly temperature dependent. We test the performance of different cables designed to diagnose and tackle the noise, and find triboelectrics to be the dominant mechanism coupling the vibrations to the electrical signal. Flattening a semi-rigid cable or jacketing a flexible cable in order to restrict movement within the cable, successfully reduces the noise level by over an order of magnitude. Furthermore, we characterize the effect of the pulse tube vibrations on an electron spin qubit device in this setup. Coherence measurements are used to map out the spectrum of the noise experienced by the qubit, revealing spectral components matching the spectral signature of the pulse tube. PMID- 27475570 TI - Apparatus for testing gas-surface reactions for epicatalysis. AB - Recently, a new mode of gas-surface heterogeneous catalysis (epicatalysis) has been identified, having potential applications ranging from industrial and green chemistry to novel forms of power generation. This article describes an inexpensive, easily constructed, vacuum-compatible apparatus by which multiple candidate gas-surface combinations can be rapidly screened for epicatalytic activity. In exploratory experiments, candidate surfaces (teflon, kapton, glass, and gold) and gases (helium, argon, cyclohexane, water, methanol, formic acid, and acetic acid) were tested for epicatalytic activity. Kapton and teflon displayed small but reproducible differences in formic acid and methanol dimer desorption, thereby demonstrating the first examples of room-temperature epicatalysis. Other gas-surface combinations showed smaller or inconclusive evidence for epicatalysis. PMID- 27475571 TI - Thermal dissociation cavity attenuated phase shift spectroscopy for continuous measurement of total peroxy and organic nitrates in the clean atmosphere. AB - A thermal dissociation cavity attenuated phase shift spectroscopy (TD-CAPS) instrument was developed for measuring total peroxy nitrates (PNs) and organic nitrates (ONs) concentrations in the clean atmosphere. This instrument is easy to operate and can be applied to continuous measurement of PNs and ONs. A continuously measurable system is convenient to perform observations, especially in remote areas. Three lines (NO2, PNs, and ONs lines) were used for thermal dissociation. The NO2 line contains a quartz tube that is not heated, while the PN and ON lines contain quartz tubes that are heated at 433 K and 633 K, respectively. The concentrations of NO2, NO2 + PNs, and NO2 + PNs + ONs can be obtained from the NO2, PN, and ON lines, respectively. The lower limit values of the detection limit (3sigma) for PNs and ONs were estimated to be 21 parts per trillion by volume with an integration time of 2 min. PNs were selectively thermally decomposed in the PNs line and formed NO2 quantitatively. In the ONs line, both PNs and ONs were thermally decomposed to produce NO2 quantitatively, but partial decomposition of HNO3 at 633 K interfered with the ONs measurement. Therefore, a HNO3 scrubber is required before the ONs line. Continuous observations were conducted with the TD-CAPS instrument in a remote area, and the instrument performed well for obtaining PNs and ONs concentrations. PMID- 27475572 TI - Relation between clinical mature and immature lymphocyte cells in human peripheral blood and their spatial label free scattering patterns. AB - A single living cell's light scattering pattern (LSP) in the horizontal plane, which has been denoted as the cell's "2D fingerprint," may provide a powerful label-free detection tool in clinical applications. We have recently studied the LSP in spatial scattering planes, denoted as the cell's "3D fingerprint," for mature and immature lymphocyte cells in human peripheral blood. The effects of membrane size, morphology, and the existence of the nucleus on the spatial LSP are discussed. In order to distinguish clinical label-free mature and immature lymphocytes, the special features of the spatial LSP are studied by statistical method in both the spatial and frequency domains. Spatial LSP provides rich information on the cell's morphology and contents, which can distinguish mature from immature lymphocyte cells and hence ultimately it may be a useful label-free technique for clinical leukemia diagnosis. PMID- 27475573 TI - Novel magnetic indenter for rheological analysis of thin biological sheet for regenerative medicine. AB - A novel method is proposed for analyzing the mechanical properties of a thin sheet of cells or extracellular matrix cultured for regenerative medicine. A steel sphere is mounted onto the center of the sheet sample, placed over a circular aperture, and a loading force is exerted via an electromagnet with well regulated current while the displacement of the sample center is optically detected. Details of the instrument and its performance are described. Loading and unloading experiment with stepwise magnetic force revealed that creep response of each of the cell sheet and matrix sheet can be expressed as a combination of a quasi-instantaneous deformation and two delayed elastic responses having different retardation times. The retardation time exhibited an increasing trend with the loading force. Close analysis of loading-force dependence and reversibility of the derived mechanical parameters revealed that these deformation modes are not independent but flexibly switches to each other depending on load magnitude and loading history. The cell sheet sample exhibited remarkable irreversibility between loading and unloading responses, which is attributed to response of the live cells to the sustained loading. PMID- 27475574 TI - Multispectral medical image fusion in Contourlet domain for computer based diagnosis of Alzheimer's disease. AB - Computer based diagnosis of Alzheimer's disease can be performed by dint of the analysis of the functional and structural changes in the brain. Multispectral image fusion deliberates upon fusion of the complementary information while discarding the surplus information to achieve a solitary image which encloses both spatial and spectral details. This paper presents a Non-Sub-sampled Contourlet Transform (NSCT) based multispectral image fusion model for computer aided diagnosis of Alzheimer's disease. The proposed fusion methodology involves color transformation of the input multispectral image. The multispectral image in YIQ color space is decomposed using NSCT followed by dimensionality reduction using modified Principal Component Analysis algorithm on the low frequency coefficients. Further, the high frequency coefficients are enhanced using non linear enhancement function. Two different fusion rules are then applied to the low-pass and high-pass sub-bands: Phase congruency is applied to low frequency coefficients and a combination of directive contrast and normalized Shannon entropy is applied to high frequency coefficients. The superiority of the fusion response is depicted by the comparisons made with the other state-of-the-art fusion approaches (in terms of various fusion metrics). PMID- 27475575 TI - 3D analysis of eddy current loss in the permanent magnet coupling. AB - This paper first presents a 3D analytical model for analyzing the radial air-gap magnetic field between the inner and outer magnetic rotors of the permanent magnet couplings by using the Amperian current model. Based on the air-gap field analysis, the eddy current loss in the isolation cover is predicted according to the Maxwell's equations. A 3D finite element analysis model is constructed to analyze the magnetic field spatial distributions and vector eddy currents, and then the simulation results obtained are analyzed and compared with the analytical method. Finally, the current losses of two types of practical magnet couplings are measured in the experiment to compare with the theoretical results. It is concluded that the 3D analytical method of eddy current loss in the magnet coupling is viable and could be used for the eddy current loss prediction of magnet couplings. PMID- 27475576 TI - Simultaneous depth-profiling of electrical and elemental properties of ion implanted arsenic in silicon by combining secondary-ion mass spectrometry with resistivity measurements. AB - A method is proposed to extract the electrical data for surface doping profiles of semiconductors in unison with the chemical profile acquired by secondary-ion mass spectrometry (SIMS)-a method we call SIMSAR (secondary-ion mass spectrometry and resistivity). The SIMSAR approach utilizes the inherent sputtering process of SIMS, combined with sequential four-point van der Pauw resistivity measurements, to surmise the active doping profile as a function of depth. The technique is demonstrated for the case of ion-implanted arsenic doping profiles in silicon. Complications of the method are identified, explained, and corrections for these are given. While several techniques already exist for chemical dopant profiling and numerous for electrical profiling, since there is no technique which can measure both electrical and chemical profiles in parallel, SIMSAR has significant promise as an extension of the conventional dynamic SIMS technique, particularly for applications in the semiconductor industry. PMID- 27475577 TI - Generation of constant-amplitude radio-frequency sweeps at a tunnel junction for spin resonance STM. AB - We describe the measurement and successful compensation of the radio-frequency transfer function of a scanning tunneling microscope over a wide frequency range (15.5-35.5 GHz) and with high dynamic range (>50 dB). The precise compensation of cabling resonances and attenuations is critical for the production of constant voltage frequency sweeps for electric-field driven electron spin resonance (ESR) experiments. We also demonstrate that a well-calibrated tunnel junction voltage is necessary to avoid spurious ESR peaks that can arise due to a non-flat transfer function. PMID- 27475578 TI - A versatile rotary-stage high frequency probe station for studying magnetic films and devices. AB - We present a rotary-stage microwave probe station suitable for magnetic films and spintronic devices. Two stages, one for field rotation from parallel to perpendicular to the sample plane (out-of-plane) and the other intended for field rotation within the sample plane (in-plane) have been designed. The sample probes and micro-positioners are rotated simultaneously with the stages, which allows the field orientation to cover theta from 0(?) to 90(?) and phi from 0(?) to 360(?). theta and phi being the angle between the direction of current flow and field in a out-of-plane and an in-plane rotation, respectively. The operation frequency is up to 40 GHz and the magnetic field up to 1 T. The sample holder vision system and probe assembly are compactly designed for the probes to land on a wafer with diameter up to 3 cm. Using homemade multi-pin probes and commercially available high frequency probes, several applications including 4 probe DC measurements, the determination of domain wall velocity, and spin transfer torque ferromagnetic resonance are demonstrated. PMID- 27475579 TI - Reduction of S-parameter errors using singular spectrum analysis. AB - A free space measurement method, which consists of two horn antennas, a network analyzer, two frequency extenders, and a sample holder, is used to measure transmission (S21) coefficients in 75-110 GHz (W-Band) frequency range. Singular spectrum analysis method is presented to eliminate the error and noise of raw S21 data after calibration and measurement processes. The proposed model can be applied easily to remove the repeated calibration process for each sample measurement. Hence, smooth, reliable, and accurate data are obtained to determine the dielectric properties of materials. In addition, the dielectric constant of materials (paper, polyvinylchloride-PVC, Ultralam(r) 3850HT, and glass) is calculated by thin sheet approximation and Newton-Raphson extracting techniques using a filtered S21 transmission parameter. PMID- 27475581 TI - Design and experiment study of compact circular-rectangular waveguide mode converter. AB - A compact mode converter that transforms TM01 circular waveguide mode to TE10 rectangular waveguide mode is investigated. It consists of a circular waveguide with a short circuit terminal and a rectangular waveguide which is perpendicular to the circular waveguide. Simulation results show that conversion efficiency of the mode converter is about 99.8% at central frequency of 1.75 GHz, and the total return loss is approximately -30 dB. The experimental results are well consistent with the computer simulation, which demonstrates the feasibility and high power handling capacity of the mode converter. PMID- 27475580 TI - Design of compact Marx module with square pulse output. AB - Compact pulsed power system based on compact Marx generator is widely used in terms of drive resistance and capacitive loads. This system usually adopts high performance components such as high energy density capacitors, compact switches, and integrated structure. Traditional compact Marx generator can only output double-exponential pulse profile. In this paper a compact, low-impedance Marx module which can output rectangular pulse profile is design and tested. This module has multiple circuits of different discharge frequencies in parallel to generate quasi-rectangular pulse. Discharge characteristic of an ideal module with infinite branches is calculated theoretically. A module with two branches has been designed and tested. Test results show that the impedance of the module is 1.2 Omega. When charging voltage is 100.6 kV and load resistance is 1 Omega, the peak output pulse is 45.2 kV voltage, the peak power is about 2 GW, the pulse width is about 130 ns, and the rise time is about 35 ns. The energy density and power density of the module are 15 kJ/m(3) and 140 GW/m(3), respectively. PMID- 27475582 TI - Wireless energizing system for an automated implantable sensor. AB - The wireless drive of an automated implantable electronic sensor has been explored for health monitoring applications. The proposed system comprises of an automated biomedical sensing system which is energized through resonant inductive coupling. The implantable sensor unit is able to monitor the body temperature parameter and sends back the corresponding telemetry data wirelessly to the data recoding unit. It has been observed that the wireless power delivery system is capable of energizing the automated biomedical implantable electronic sensor placed over a distance of 3 cm from the power transmitter with an energy transfer efficiency of 26% at the operating resonant frequency of 562 kHz. This proposed method ensures real-time monitoring of different human body temperatures around the clock. The monitored temperature data have been compared with a calibrated temperature measurement system to ascertain the accuracy of the proposed system. The investigated technique can also be useful for monitoring other body parameters such as blood pressure, bladder pressure, and physiological signals of the patient in vivo using various implantable sensors. PMID- 27475583 TI - Tunable microwave bandpass filter integrated power divider based on the high anisotropy electro-optic nematic liquid crystal. AB - A novel, compact microwave tunable bandpass filter integrated power divider, based on the high anisotropy electro-optic nematic liquid crystal, is proposed in this letter. Liquid crystal, as the electro-optic material, is placed between top inverted microstrip line and the metal plate. The proposed structure can realize continuous tunable bandpass response and miniaturization. The proposed design concept is validated by the good performance of simulation results and experimental results. The electro-optic material has shown great potential for microwave application. PMID- 27475584 TI - Thermal conductivity versus depth profiling of inhomogeneous materials using the hot disc technique. AB - Transient measurements of thermal conductivity are performed with hot disc sensors on samples having a thermal conductivity variation adjacent to the sample surface. A modified computational approach is introduced, which provides a method of connecting the time-variable to a corresponding depth-position. This allows highly approximate-yet reproducible-estimations of the thermal conductivity vs. depth. Tests are made on samples incorporating different degrees of sharp structural defects at a certain depth position inside a sample. The proposed methodology opens up new possibilities to perform non-destructive testing; for instance, verifying thermal conductivity homogeneity in a sample, or estimating the thickness of a deviating zone near the sample surface (such as a skin tumor), or testing for presence of other defects. PMID- 27475585 TI - Nanoscale thermometry by scanning thermal microscopy. AB - Measuring temperature is a central challenge in nanoscience and technology. Addressing this challenge, we report the development of a high-vacuum scanning thermal microscope and a method for non-equilibrium scanning probe thermometry. The microscope is built inside an electromagnetically shielded, temperature stabilized laboratory and features nanoscopic spatial resolution at sub-nanoWatt heat flux sensitivity. The method is a dual signal-sensing technique inferring temperature by probing a total steady-state heat flux simultaneously to a temporally modulated heat flux signal between a self-heated scanning probe sensor and a sample. Contact-related artifacts, which so far limit the reliability of nanoscopic temperature measurements by scanning thermal microscopy, are minimized. We characterize the microscope's performance and demonstrate the benefits of the new thermometry approach by studying hot spots near lithographically defined constrictions in a self-heated metal interconnect. PMID- 27475586 TI - Load-cell based characterization system for a "Violin-Mode" shadow-sensor in advanced LIGO suspensions. AB - The background to this work was a prototype shadow sensor, which was designed for retro-fitting to an advanced LIGO (Laser Interferometer Gravitational wave Observatory) test-mass/mirror suspension, in which 40 kg test-mass/mirrors are each suspended by four approximately 600 mm long by 0.4 mm diameter fused-silica suspension fibres. The shadow sensor comprised a LED source of Near InfraRed (NIR) radiation and a rectangular silicon photodiode detector, which, together, were to bracket the fibre under test. The aim was to detect transverse Violin Mode resonances in the suspension fibres. Part of the testing procedure involved tensioning a silica fibre sample and translating it transversely through the illuminating NIR beam, so as to measure the DC responsivity of the detection system to fibre displacement. However, an equally important part of the procedure, reported here, was to keep the fibre under test stationary within the beam, whilst trying to detect low-level AC Violin-Mode resonances excited on the fibre, in order to confirm the primary function of the sensor. Therefore, a tensioning system, incorporating a load-cell readout, was built into the test fibre's holder. The fibre then was excited by a signal generator, audio power amplifier, and distant loudspeaker, and clear resonances were detected. A theory for the expected fundamental resonant frequency as a function of fibre tension was developed and is reported here, and this theory was found to match closely with the detected resonant frequencies as they varied with tension. Consequently, the resonances seen were identified as being proper Violin-Mode fundamental resonances of the fibre, and the operation of the Violin-Mode detection system was validated. PMID- 27475587 TI - An AC modulated near infrared gain calibration system for a "Violin-Mode" transimpedance amplifier, intended for advanced LIGO suspensions. AB - The background to this work was a prototype shadow sensor, which was designed for retro-fitting to an advanced LIGO (Laser Interferometer Gravitational wave Observatory) test-mass/mirror suspension, in which a 40 kg test-mass/mirror is suspended by four approximately 600 mm long by 0.4 mm diameter fused-silica suspension fibres. The shadow sensor comprised a LED source of Near InfraRed (NIR) radiation, and a "tall-thin" rectangular silicon photodiode detector, which together were to bracket the fibre under test. The photodiode was positioned so as to be sensitive (primarily) to transverse "Violin-Mode" vibrations of such a fibre, via the oscillatory movement of the shadow cast by the fibre, as this moved across the face of the detector. In this prototype shadow sensing system the photodiode was interfaced to a purpose-built transimpedance amplifier, this having both AC and DC outputs. A quasi-static calibration was made of the sensor's DC responsivity, i.e., incremental rate of change of output voltage versus fibre position, by slowly scanning a fused-silica fibre sample transversely through the illuminating beam. The work reported here concerns the determination of the sensor's more important AC (Violin-Mode) responsivity. Recognition of the correspondence between direct AC modulation of the source, and actual Violin-Mode signals, and of the transformative role of the AC/DC gain ratio for the amplifier, at any modulation frequency, f, resulted in the construction of the AC/DC calibration source described here. A method for determining in practice the transimpedance AC/DC gain ratio of the photodiode and amplifier, using this source, is illustrated by a specific numerical example, and the gain ratio for the prototype sensing system is reported over the frequency range 1 Hz-300 kHz. In fact, a maximum DC responsivity of 1.26 kV.m(-1) was measured using the prototype photodiode sensor and amplifier discussed here. Therefore, the measured AC/DC transimpedance gain ratio of 922.5 for this sensor, at 500 Hz, translated into a maximum Violin-Mode (AC) responsivity of (1.16 +/- 0.05) MV m(-1), at that frequency. PMID- 27475588 TI - Micro digital sun sensor with linear detector. AB - In this paper, the design of a novel micro digital sun sensor is described. It relies on V-shaped slit and linear array CCD to measure sun-ray angle against two axes. A highly integrated microprogram control unit) is used to make a very simple and compact system. V-shaped slit can simplify algorithm and achieve a wider field of view. Error compensation and accurate calibration are employed to improve accuracy. Adaptive threshold and adjustable expose time further improve reliability. Experiments and flight validation show that the FOV (Field of View) of the sun sensor is +/-65 degrees * +/- 65 degrees and the accuracy is 0.1 degrees in the whole FOV. It can work reliably at an update rate of 25 Hz, while the consumption is only 200 mW. This sun sensor is proved to have a good prospect in micro/nanosatellites. PMID- 27475589 TI - Accurate measurements of cross-plane thermal conductivity of thin films by dual frequency time-domain thermoreflectance (TDTR). AB - Accurate measurements of the cross-plane thermal conductivity Lambdacross of a high-thermal-conductivity thin film on a low-thermal-conductivity (Lambdas) substrate (e.g., Lambdacross/Lambdas > 20) are challenging, due to the low thermal resistance of the thin film compared with that of the substrate. In principle, Lambdacross could be measured by time-domain thermoreflectance (TDTR), using a high modulation frequency fh and a large laser spot size. However, with one TDTR measurement at fh, the uncertainty of the TDTR measurement is usually high due to low sensitivity of TDTR signals to Lambdacross and high sensitivity to the thickness hAl of Al transducer deposited on the sample for TDTR measurements. We observe that in most TDTR measurements, the sensitivity to hAl only depends weakly on the modulation frequency f. Thus, we performed an additional TDTR measurement at a low modulation frequency f0, such that the sensitivity to hAl is comparable but the sensitivity to Lambdacross is near zero. We then analyze the ratio of the TDTR signals at fh to that at f0, and thus significantly improve the accuracy of our Lambdacross measurements. As a demonstration of the dual-frequency approach, we measured the cross-plane thermal conductivity of a 400-nm-thick nickel-iron alloy film and a 3-MUm-thick Cu film, both with an accuracy of ~10%. The dual-frequency TDTR approach is useful for future studies of thin films. PMID- 27475590 TI - A solid-state dedicated circularly polarized luminescence spectrophotometer: Development and application. AB - A new solid-state dedicated circularly polarized luminescence (CPL) instrument (CPL-200CD) was successfully developed for measuring true CPL spectra for optically anisotropic samples on the basis of the Stokes-Mueller matrix approach. Electric components newly installed in the CPL-200CD include a pulse motor-driven sample rotation holder and a 100 kHz lock-in amplifier to achieve the linearly polarized luminescence measurement, which is essential for obtaining the true CPL signal for optically anisotropic samples. An acquisition approach devised for solid-state CPL analysis reduces the measurement times for a data set by ca. 98% compared with the time required in our previous method. As a result, the developed approach is very effective for samples susceptible to light-induced degradation. The theory and implementation of the method are described, and examples of its application to a CPL sample with macroscopic anisotropies are provided. An important advantage of the developed instrument is its ability to obtain molecular information for both excited and ground states because circular dichroism measurements can be performed by switching the monochromatic light to white light without rearrangement of the sample. PMID- 27475591 TI - Wavelet analysis methods for radiography of multidimensional growth of planar mixing layers. AB - The counter-propagating shear campaign is examining instability growth and its transition to turbulence in the high-energy-density physics regime using a laser driven counter-propagating flow platform. In these experiments, we observe consistent complex break-up of and structure growth in a tracer layer placed at the shear flow interface during the instability growth phase. We present a wavelet-transform based analysis technique capable of characterizing the scale- and directionality-resolved average intensity perturbations in static radiographs of the experiment. This technique uses the complete spatial information available in each radiograph to describe the structure evolution. We designed this analysis technique to generate a two-dimensional power spectrum for each radiograph from which we can recover information about structure widths, amplitudes, and orientations. The evolution of the distribution of power in the spectra for an experimental series is a potential metric for quantifying the structure size evolution as well as a system's evolution towards isotropy. PMID- 27475592 TI - E/N effects on K0 values revealed by high precision measurements under low field conditions. AB - Ion mobility spectrometry (IMS) is used to detect chemical warfare agents, explosives, and narcotics. While IMS has a low rate of false positives, their occurrence causes the loss of time and money as the alarm is verified. Because numerous variables affect the reduced mobility (K0) of an ion, wide detection windows are required in order to ensure a low false negative response rate. Wide detection windows, however, reduce response selectivity, and interferents with similar K0 values may be mistaken for targeted compounds and trigger a false positive alarm. Detection windows could be narrowed if reference K0 values were accurately known for specific instrumental conditions. Unfortunately, there is a lack of confidence in the literature values due to discrepancies in the reported K0 values and their lack of reported error. This creates the need for the accurate control and measurement of each variable affecting ion mobility, as well as for a central accurate IMS database for reference and calibration. A new ion mobility spectrometer has been built that reduces the error of measurements affecting K0 by an order of magnitude less than +/-0.2%. Precise measurements of +/-0.002 cm(2) V(-1) s(-1) or better have been produced and, as a result, an unexpected relationship between K0 and the electric field to number density ratio (E/N) has been discovered in which the K0 values of ions decreased as a function of E/N along a second degree polynomial trend line towards an apparent asymptote at approximately 4 Td. PMID- 27475593 TI - High resolution kilometric range optical telemetry in air by radio frequency phase measurement. AB - We have developed an optical Absolute Distance Meter (ADM) based on the measurement of the phase accumulated by a Radio Frequency wave during its propagation in the air by a laser beam. In this article, the ADM principle will be described and the main results will be presented. In particular, we will emphasize how the choice of an appropriate photodetector can significantly improve the telemeter performances by minimizing the amplitude to phase conversion. Our prototype, tested in the field, has proven its efficiency with a resolution better than 15 MUm for a measurement time of 10 ms and distances up to 1.2 km. PMID- 27475594 TI - A visualization instrument to investigate the mechanical-electro properties of high temperature superconducting tapes under multi-fields. AB - We construct a visible instrument to study the mechanical-electro behaviors of high temperature superconducting tape as a function of magnetic field, strain, and temperature. This apparatus is directly cooled by a commercial Gifford McMahon cryocooler. The minimum temperature of sample can be 8.75 K. A proportion integration differentiation temperature control is used, which is capable of producing continuous variation of specimen temperature from 8.75 K to 300 K with an optional temperature sweep rate. We use an external loading device to stretch the superconducting tape quasi-statically with the maximum tension strain of 20%. A superconducting magnet manufactured by the NbTi strand is applied to provide magnetic field up to 5 T with a homogeneous range of 110 mm. The maximum fluctuation of the magnetic field is less than 1%. We design a kind of superconducting lead composed of YBa2Cu3O7-x coated conductor and beryllium copper alloy (BeCu) to transfer DC to the superconducting sample with the maximum value of 600 A. Most notably, this apparatus allows in situ observation of the electromagnetic property of superconducting tape using the classical magnetic optical imaging. PMID- 27475595 TI - Research on structural design and test technologies for a three-chamber launching device. AB - A three-chamber launching device with improved acceleration is proposed and developed. As indicated by the damage generated during the pill and engineering protection tests, the proposed device is applicable as a high-speed launching platform for pills of different shapes and quality levels. Specifically, it can be used to investigate kinetic energy weapons and their highly destructive effects due to the resulting large bomb fragments. In the horizontal direction of the barrel, two auxiliary chambers are set at a certain distance from the main chamber. When the pill reaches the mouth of the auxiliary chambers, the charges in the auxiliary chambers are ignited by the high-temperature, high-pressure combustible gas trailing the pill. The combustible gas in the auxiliary chambers can resist the rear pressure of the pill and thus maintain the high pressure of the pill base. In this way, the required secondary acceleration of the pill is met. The proposed device features the advantage of launching a pill with high initial velocity under low bore pressure. Key techniques are proposed in the design of the device to address the problems related to the angle between the main chamber axis and the ancillary chamber axis, the overall design of a three chamber barrel, the structural design of auxiliary propellant charge, the high pressure combustible gas sealing technology, and the sabot and belt design. Results from the launching test verify the reasonable design of this device and its reliable structural sealing. Additionally, the stiffness and the strength of the barrel meet design requirements. Compared with the single-chamber launching device with the same caliber, the proposed device increases the average launching velocity by approximately 15% and the amount of muzzle kinetic energy by approximately 35%. Therefore, this equipment is capable of carrying out small caliber, high-speed pill firing tests. PMID- 27475596 TI - A novel imaging technique for measuring kinematics of light-weight flexible structures. AB - A new imaging algorithm is proposed to capture the kinematics of flexible, thin, light structures including frequencies and motion amplitudes for real time analysis. The studied case is a thin flexible beam that is preset at different angles of attack in a wind tunnel. As the angle of attack is increased beyond a critical value, the beam was observed to undergo a static deflection that is ensued by limit cycle oscillations. Imaging analysis of the beam vibrations shows that the motion consists of a superposition of the bending and torsion modes. The proposed algorithm was able to capture the oscillation amplitudes as well as the frequencies of both bending and torsion modes. The analysis results are validated through comparison with measurements from a piezoelectric sensor that is attached to the beam at its root. PMID- 27475597 TI - Reconstruction of elongated bubbles fusing the information from multiple optical probes through a Bayesian inference technique. AB - In this communication, a novel optical technique has been proposed for the reconstruction of the shape of a Taylor bubble using measurements from multiple arrays of optical sensors. The deviation of an optical beam passing through the bubble depends on the contour of bubble surface. A theoretical model of the deviation of a beam during the traverse of a Taylor bubble through it has been developed. Using this model and the time history of the deviation captured by the sensor array, the bubble shape has been reconstructed. The reconstruction has been performed using an inverse algorithm based on Bayesian inference technique and Markov chain Monte Carlo sampling algorithm. The reconstructed nose shape has been compared with the true shape, extracted through image processing of high speed images. Finally, an error analysis has been performed to pinpoint the sources of the errors. PMID- 27475598 TI - Superconducting radio-frequency resonator in magnetic fields up to 6 T. AB - We have measured the characteristics of a superconducting radio-frequency resonator in an external magnetic field. The magnetic field strength has been varied with 10 mT resolution between zero and 6 T. The resonance frequency and the quality factor of the resonator have been found to change significantly as a function of the magnetic field strength. Both parameters show a hysteresis effect which is more pronounced for the resonance frequency. Quantitative knowledge of such behaviour is particularly important when experiments require specific values of resonance frequency and quality factor or when the magnetic field is changed while the resonator is in the superconducting state. PMID- 27475599 TI - Accurate Young's modulus measurement based on Rayleigh wave velocity and empirical Poisson's ratio. AB - This paper presents a method for Young's modulus measurement based on Rayleigh wave speed. The error in Poisson's ratio has weak influence on the measurement of Young's modulus based on Rayleigh wave speed, and Poisson's ratio minimally varies in a certain material; thus, we can accurately estimate Young's modulus with surface wave speed and a rough Poisson's ratio. We numerically analysed three methods using Rayleigh, longitudinal, and transversal wave speed, respectively, and the error in Poisson's ratio shows the least influence on the result in the method involving Rayleigh wave speed. An experiment was performed and has proved the feasibility of this method. Device for speed measuring could be small, and no sample pretreatment is needed. Hence, developing a portable instrument based on this method is possible. This method makes a good compromise between usability and precision. PMID- 27475600 TI - Development of a fluorescence based flux sensor for thin film growth and nanoparticle deposition. AB - An optical flux sensor, based on the fluorescence properties of materials and nanoparticles, has been developed to control the deposition rate in thin film deposition systems. Using a simple diode laser and a photomultiplier tube with a light filter, we report the detection of gallium atoms and CdSe-ZnS quantum dots. This setup has a high sensitivity and reproducibility. PMID- 27475601 TI - A curved edge diffraction-utilized displacement sensor for spindle metrology. AB - This paper presents a new dimensional metrological sensing principle for a curved surface based on curved edge diffraction. Spindle error measurement technology utilizes a cylindrical or spherical target artifact attached to the spindle with non-contact sensors, typically a capacitive sensor (CS) or an eddy current sensor, pointed at the artifact. However, these sensors are designed for flat surface measurement. Therefore, measuring a target with a curved surface causes error. This is due to electric fields behaving differently between a flat and curved surface than between two flat surfaces. In this study, a laser is positioned incident to the cylindrical surface of the spindle, and a photodetector collects the total field produced by the diffraction around the target surface. The proposed sensor was compared with a CS within a range of 500 MUm. The discrepancy between the proposed sensor and CS was 0.017% of the full range. Its sensing performance showed a resolution of 14 nm and a drift of less than 10 nm for 7 min of operation. This sensor was also used to measure dynamic characteristics of the spindle system (natural frequency 181.8 Hz, damping ratio 0.042) and spindle runout (22.0 MUm at 2000 rpm). The combined standard uncertainty was estimated as 85.9 nm under current experiment conditions. It is anticipated that this measurement technique allows for in situ health monitoring of a precision spindle system in an accurate, convenient, and low cost manner. PMID- 27475602 TI - Signal pulse emulation for scintillation detectors using Geant4 Monte Carlo with light tracking simulation. AB - The anode pulse of a photomultiplier tube (PMT) coupled with a scintillator is used for pulse shape discrimination (PSD) analysis. We have developed a novel emulation technique for the PMT anode pulse based on optical photon transport and a PMT response function. The photon transport was calculated using Geant4 Monte Carlo code and the response function with a BC408 organic scintillator. The obtained percentage RMS value of the difference between the measured and simulated pulse with suitable scintillation properties using GSO:Ce (0.4, 1.0, 1.5 mol%), LaBr3:Ce and BGO scintillators were 2.41%, 2.58%, 2.16%, 2.01%, and 3.32%, respectively. The proposed technique demonstrates high reproducibility of the measured pulse and can be applied to simulation studies of various radiation measurements. PMID- 27475603 TI - Novel high-pressure windows made of glass-like carbon for x-ray analysis. AB - Original high-pressure glass-like carbon windows developed for x-ray spectroscopy applications are presented. The scientific and technological background of this new technical development is exposed, in particular the limitations of our existing beryllium windows in the context of x-ray absorption spectroscopy (XAS) measurements of solutions with very low solute concentrations at hydrothermal conditions (0.1-200 MPa, 30-600 degrees C). The benefits of glass-like carbon are exposed, notably its non-crystalline character, the absence of impurities which has been verified by micro-fluorescence laboratory measurements, and its non-toxicity which makes its machining safer. Finite elements mechanical calculations and experimental pressure tests were conducted to determine the pressure limits of windows with two different geometries: cylindrical (thickness 0.5 mm) and inversed-dome shape (thickness 0.5 mm at the tip of the dome). The former break at 150 MPa and the latter show no sign of rupture at 400 MPa. Recent XAS measurements conducted with the new dome shaped windows are presented to show the advantages of the design that allow for the detection of very low concentrations in the transmission mode (down to 30 ppm) and the acquisition of fluorescence XAS spectra in diluted solutions at high pressure. Eventually the perspectives of this original development are discussed. PMID- 27475604 TI - A high-stability non-contact dilatometer for low-amplitude temperature-modulated measurements. AB - Temperature modulated thermophysical measurements can deliver valuable insights into the phase transformation behavior of many different materials. While especially for non-metallic systems at low temperatures numerous powerful methods exist, no high-temperature device suitable for modulated measurements of bulk metallic alloy samples is available for routine use. In this work a dilatometer for temperature modulated isothermal and non-isothermal measurements in the temperature range from room temperature to 1300 K is presented. The length measuring system is based on a two-beam Michelson laser interferometer with an incremental resolution of 20 pm. The non-contact measurement principle allows for resolving sinusoidal length change signals with amplitudes in the sub-500 nm range and physically decouples the length measuring system from the temperature modulation and heating control. To demonstrate the low-amplitude capabilities, results for the thermal expansion of nickel for two different modulation frequencies are presented. These results prove that the novel method can be used to routinely resolve length-change signals of metallic samples with temperature amplitudes well below 1 K. This high resolution in combination with the non contact measurement principle significantly extends the application range of modulated dilatometry towards high-stability phase transformation measurements on complex alloys. PMID- 27475605 TI - High temperature Hall measurement setup for thin film characterization. AB - Hall measurement using the van der Pauw technique is a common characterization approach that does not require patterning of contacts. Measurements of the Hall voltage and electrical resistivity lead to the product of carrier mobility and carrier concentration (Hall coefficient) which can be decoupled through transport models. Based on the van der Paw method, we have developed an automated setup for Hall measurements from room temperature to ~500 degrees C of semiconducting thin films of a wide resistivity range. The resistivity of the film and Hall coefficient is obtained from multiple current-voltage (I-V) measurements performed using a semiconductor parameter analyzer under applied constant "up," zero, and "down" magnetic field generated with two neodymium permanent magnets. The use of slopes obtained from multiple I-Vs for the three magnetic field conditions offer improved accuracy. Samples are preferred in square shape geometry and can range from 2 mm to 25 mm side length. Example measurements of single-crystal silicon with known doping concentration show the accuracy and reliability of the measurement. PMID- 27475606 TI - Fuzzy adaptive strong tracking scaled unscented Kalman filter for initial alignment of large misalignment angles. AB - In the initial alignment process of strapdown inertial navigation system (SINS), large misalignment angles always bring nonlinear problem, which can usually be processed using the scaled unscented Kalman filter (SUKF). In this paper, the problem of large misalignment angles in SINS alignment is further investigated, and the strong tracking scaled unscented Kalman filter (STSUKF) is proposed with fixed parameters to improve convergence speed, while these parameters are artificially constructed and uncertain in real application. To further improve the alignment stability and reduce the parameters selection, this paper proposes a fuzzy adaptive strategy combined with STSUKF (FUZZY-STSUKF). As a result, initial alignment scheme of large misalignment angles based on FUZZY-STSUKF is designed and verified by simulations and turntable experiment. The results show that the scheme improves the accuracy and convergence speed of SINS initial alignment compared with those based on SUKF and STSUKF. PMID- 27475607 TI - A novel high-density power energy harvesting methodology for transmission line online monitoring devices. AB - This paper presents a novel energy-harvesting model which takes the primary current, secondary turns, dimension, the magnitude of magnetic flux density B, and the core loss resistance into consideration systematically. The relationship among the potential maximum output power, the dimension of energy harvesting coil (EHC), the load type of EHC, and the secondary turns is predicted by theoretical analysis and further verified by experiments. A high power density harvester is also developed and tested. It is shown that the power density of this novel harvester is 0.7 mW/g at 10 A, which is more than 2 times powerful than the traditional ones. Hence, it could lighten the half weight of the harvester at the same conditions. PMID- 27475608 TI - Note: Application of a novel 2(3HUS+S) parallel manipulator for simulation of hip joint motion. AB - In the paper, a novel 2(3HUS+S) parallel manipulator, which has two moving platforms, is proposed. The parallel manipulator is adopted to simulate hip joint motion and can conduct an experiment for two hip joints simultaneously. Motion experiments are conducted in the paper, and the recommended hip joint motion curves from ISO14242 and actual hip joint motions during jogging and walking are selected as the simulated motions. The experimental results indicate that the 2(3HUS+S) parallel manipulator can realize the simulation of many kinds of hip joint motions without changing the structure size. PMID- 27475609 TI - Note: Fully integrated 3.2 Gbps quantum random number generator with real-time extraction. AB - We present a real-time and fully integrated quantum random number generator (QRNG) by measuring laser phase fluctuations. The QRNG scheme based on laser phase fluctuations is featured for its capability of generating ultra-high-speed random numbers. However, the speed bottleneck of a practical QRNG lies on the limited speed of randomness extraction. To close the gap between the fast randomness generation and the slow post-processing, we propose a pipeline extraction algorithm based on Toeplitz matrix hashing and implement it in a high speed field-programmable gate array. Further, all the QRNG components are integrated into a module, including a compact and actively stabilized interferometer, high-speed data acquisition, and real-time data post-processing and transmission. The final generation rate of the QRNG module with real-time extraction can reach 3.2 Gbps. PMID- 27475610 TI - Note: Novel diamond anvil cell for electrical measurements using boron-doped metallic diamond electrodes. AB - A novel diamond anvil cell suitable for electrical transport measurements under high pressure has been developed. A boron-doped metallic diamond film was deposited as an electrode on a nano-polycrystalline diamond anvil using a microwave plasma-assisted chemical vapor deposition technique combined with electron beam lithography. The maximum pressure that can be achieved by this assembly is above 30 GPa. We report electrical transport measurements of Pb up to 8 GPa. The boron-doped metallic diamond electrodes showed no signs of degradation after repeated compression. PMID- 27475611 TI - Note: Broadband low-noise photodetector for Pound-Drever-Hall laser stabilization. AB - The Pound-Drever-Hall laser stabilization technique requires a fast, low-noise photodetector. We present a simple photodetector design that uses a transformer as an intermediary between a photodiode and cascaded low-noise radio-frequency amplifiers. Our implementation using a silicon photodiode yields a detector with 50 MHz bandwidth, gain >10(5) V/A, and input current noise <4 pA/Hz, allowing us to obtain shot-noise-limited performance with low optical power. PMID- 27475613 TI - Publisher's Note: "Deployment shock attenuation of a solar array tape hinge by means of the Martensite detwinning of NiTi Shape Memory Alloy" [Rev. Sci. Instrum. 87, 035104 (2016)]. PMID- 27475614 TI - Erratum: "Multi-point, high-speed passive ion velocity distribution diagnostic on the Pegasus Toroidal Experiment" [Rev. Sci. Instrum. 83, 10D516 (2012)]. PMID- 27475615 TI - Erratum: "Printed circuit board metal powder filters for low electron temperatures" [Rev. Sci. Instrum. 84, 044706 (2013)]. PMID- 27475616 TI - Should hepatic resection be recommended to patients with hepatocellular carcinoma and portal vein invasion? PMID- 27475617 TI - Non-invasive assessment of portal hypertension using quantitative magnetic resonance imaging. AB - BACKGROUND & AIMS: Hepatic venous pressure gradient (HVPG) measurement is currently the only validated technique to accurately evaluate changes in portal pressure. In this study, we evaluate the use of non-contrast quantitative magnetic resonance imaging (MRI) as a surrogate measure of portal pressure. METHODS: Thirty patients undergoing HVPG measurement were prospectively recruited. MR parameters of longitudinal relaxation time (T1), perfusion of the liver and spleen (by arterial spin labelling), and blood flow in the portal, splanchnic and collateral circulation (by phase contrast MRI) were assessed. We estimated the liver stiffness measurement (LSM) and enhanced liver fibrosis (ELF) score. The correlation of all non-invasive parameters with HVPG was evaluated. RESULTS: The mean (range) HVPG of the patients was 9.8 (1-22) mmHg, and 14 patients (48%) had clinically significant portal hypertension (CSPH, HVPG ?10mmHg). Liver T1 relaxation time, splenic artery and superior mesenteric artery velocity correlated significantly with HVPG. Using multiple linear regression, liver T1 and splenic artery velocity remained as the two parameters in the multivariate model significantly associated with HVPG (R=0.90, p<0.001). This correlation was maintained in patients with CSPH (R=0.85, p<0.001). A validation cohort (n=10) showed this linear model provided a good prediction of HVPG. LSM and ELF score correlated significantly with HVPG in the whole population but the correlation was absent in CSPH. CONCLUSIONS: MR parameters related to both hepatic architecture and splanchnic haemodynamics correlate significantly with HVPG. This proposed model, confirmed in a validation cohort, could replace the invasive HVPG measurement. LAY SUMMARY: In patients with cirrhosis, the development and progression of portal hypertension is related to worse outcomes. However, the standard technique of assessing portal pressure is invasive and not widely used in clinical practice. Here, we have studied the use of non-invasive MRI in evaluating portal pressure. The MRI measures of liver architecture and blood flow in the splenic artery correlated well with portal pressure. Therefore, this non-invasive method can potentially be used to assess portal pressure in clinical trials and monitoring treatment in practice. PMID- 27475618 TI - Femoral derotation osteotomy in adults with cerebral palsy. AB - BACKGROUND: Internal rotation gait constitutes a complex gait disorder in bilateral spastic cerebral palsy (BSCP) including static torsional and dynamic components resulting in lever arm dysfunction. Although femoral derotation osteotomy (FDO) is a standard procedure to correct increased femoral anteversion in children, unpredictable outcome has been reported. The effect of FDO when it is done as part of single-event multilevel surgery (SEMLS) in adulthood has not been investigated. METHODS: In this study mid-term data of 63 adults with BSCP and internal rotation gait, undergoing SEMLS including FDO were analyzed pre- and 1.7 years postoperatively by clinical examination and 3D-instrumented gait analysis. All legs were categorized as the more or less involved side to consider asymmetry. The mean hip rotation in stance preoperatively and the intraoperative derotation was correlated with the difference pre- and postoperatively. RESULTS: The group as a whole experienced the following results postoperatively: improved mean hip rotation in stance (p=0.0001), mean foot progression angle (p=0.0001) and a significant improvement of the clinical parameter: passive internal and external hip rotation, midpoint and anteversion (p=0.0001) for both legs separately. With regard to the less and more involved side, clinical and kinematic parameters showed comparable significant changes (p=0.0001). The anteversion improved significantly in proximal compared to distal FDO (p=0.03). CONCLUSION: This study emphasizes an overall good correction of internal rotation gait in adults with bilateral involvement after FDO. However, the results are more predictable in adults compared to studies reporting outcome after FDO in children. PMID- 27475619 TI - Knee loading patterns of the non-paretic and paretic legs during post-stroke gait. AB - BACKGROUND: Post-stoke gait disorders could cause secondary musculoskeletal complications associated with excessive repetitive loading. The study objectives were to 1) determine the feasibility of measuring common proxies for dynamic medial knee joint loading during gait post-stroke with external knee adduction (KAM) and flexion moments (KFM) and 2) characterize knee loading and typical load reducing compensations post-stroke. METHODS: Participants with stroke (n=9) and healthy individuals (n=17) underwent 3D gait analysis. The stroke and healthy groups were compared with unpaired t-tests on peak KAM and peak KFM and on typical medial knee joint load-reducing compensations; toe out and trunk lean. The relationship between KAM and load-reducing compensations in the stroke group were investigated with Spearman correlations. RESULTS: Mean (SD) values for KAM and KFM in the healthy group[KAM=2.20 (0.88)%BW*ht; KFM=0.64 (0.60)%BW*ht] were not significantly different from the values for the paretic [KAM=2.64 (0.98)%BW*ht; KFM=1.26 (1.13)%BW*ht] or non-paretic leg of the stroke group[KAM=2.23(0.62)%BW*ht; KFM=1.10 (1.20)%BW*ht]. Post hoc one sample t-tests revealed greater loading in stroke participants on the paretic (n=3), non-paretic (n=1) and both legs (n=2) compared to the healthy group. The angle of trunk lean and the angle of toe out were not related to KAM in the stroke group. DISCUSSION: Measurement of limb loading during a gait post-stroke is feasible and revealed excessive loading in individuals with mild to moderate stroke compared to healthy adults. Further investigation of potential joint degeneration and pain due to repetitive excessive loading associated with post-stroke gait is warranted. PMID- 27475620 TI - Is passive metatarsophalangeal joint stiffness related to leg stiffness, vertical stiffness and running economy during sub-maximal running? AB - This study examined whether passive metatarsophalangeal joints (MPJ) stiffness was associated with leg stiffness (Kleg) vertical stiffness (Kvert) and running economy (RE) during sub-maximal running. Nine male experienced runners underwent passive MPJ stiffness measurements in standing and sitting positions followed by sub-maximal running on an instrumented treadmill. With the individual foot position properly aligned, the MPJ passive stiffness in both sitting (MPJsit) and standing positions (MPJstand) were measured with a computerized dynamometer. Data were collected at a running speed of 2.78m/s, representing a stabilized level of energy expenditure. Pedar pressure insole was used to determine the contact time (tc) and peak reaction force for the calculation of Kleg and Kvert. A respiratory gas analysis system was used to estimate the RE. Bivariate correlation test was performed to examine the correlation among MPJ stiffness, contact time, Kleg, Kvert, and RE. The results showed that MPJsit and MPJstand were inversely correlated with RE (p=0.04, r=-0.68 to -0.69), suggesting that stiffer MPJ improves RE. In addition, MPJsit was correlated positively with Kleg (p<0.01, r=0.87),Kvert (p=0.03, r=0.70) but inversely with tc (p=0.02, r=-0.76), while MPJstand was correlated positively with the Kvert (p=0.02, r=0.77). These findings suggested that strength of toe plantar flexors provides stability and agility in the stance phase for more effective and faster forward movement. PMID- 27475621 TI - A Schwannoma of the Distal Esophagus. PMID- 27475622 TI - A practical alpha particle irradiator for studying internal alpha particle exposure. AB - An alpha particle irradiator has been built in the Radiation Bioengineering Laboratory at Seoul National University (SNU) to investigate the cellular responses to alpha emissions from radon and the progeny. This irradiator is designed to have the energy of alpha particles entering target cells similar to that of alpha emissions from the radon progeny Po-218 and Po-214 residing in the human respiratory tract. For the SNU alpha particle irradiator, an irradiation system is equipped with cell dishes of 4um thick Mylar bottom and a special setup of cells on slide for gamma-H2AX assay. Dose calibration for the alpha particle irradiator was performed by dual approaches, detection and computer simulation, in consideration of the source-to-target distance (STD) and the size of a cell dish. The uniformity of dose among cells in a dish is achieved by keeping the STD and the size of cell dish in certain ranges. The performance of the SNU alpha particle irradiator has been proven to be reliable through the gamma-H2AX assay with the human lung epithelial cells irradiated. PMID- 27475623 TI - Epithelial-mesenchymal transition promotes reactivity of human lung adenocarcinoma A549 cells to CpG ODN. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is reported to promote airway remodeling in asthmatics, which is the main histological change that causes complex and severe symptoms in asthmatics. However, little is known about whether EMT also plays a role in acute exacerbations of asthma evoked by respiratory tract infections. METHODS: A human lung adenocarcinoma line, A549, was incubated with TGF-beta1 at 10 ng/ml to induce EMT. Then the cells were stimulated with CpG ODN. Expression of surface and intracellular molecules was analyzed by flow cytometry. IL-6, IL-8 and MCP-1 in the culture supernatant were measured by Cytometric Bead Assay, and the expression of mRNA was quantitated by real-time PCR. CpG ODN uptake was analyzed by flow cytometry. RESULTS: The culture supernatant levels of IL-6, IL-8 and MCP-1 and the expression of mRNA for these cytokines in CpG ODN-stimulated A549 cells that had undergone EMT was significantly higher compared to those that had not. Addition of ODN H154, a TLR9 inhibiting DNA, significantly suppressed the CpG ODN-induced production of those cytokines. However, flow cytometry found the level of TLR9 expression to be slightly lower in A549 cells that had undergone EMT compared to those that had not. On the other hand, CpG ODN uptake was increased in cells that had undergone EMT. CONCLUSIONS: EMT induction of A549 cells enhanced CpG ODN uptake and CpG ODN induced production of IL-6, IL-8 and MCP-1. These results suggest that EMT plays an important role in exacerbation in asthmatics with airway remodeling by enhancing sensitivity to extrinsic pathogens. PMID- 27475624 TI - The effect of calprotectin on TSLP and IL-25 production from airway epithelial cells. AB - BACKGROUND: Calprotectin is a heterodimer complex of the S100A8 and S100A9 proteins, and has various functions as an innate mediator at the sites of inflammation. The aim of this study was to elucidate the roles of calprotectin in the eosinophilic chronic rhinosinusitis (ECRS). METHODS: Allergen-induced production of calprotectin was evaluated in cultured normal human bronchial epithelial (NHBE) cells by ELISA and RT-PCR. We then examined the roles of calprotectin on Alternaria alternata (Alternaria)-induced production of thymic stromal lymphopoietin (TSLP) and IL-25 in NHBE cells. The extracellular concentration and allergen-induced secretion of calprotectin in cultured primary nasal epithelial (PNE) cells were examined and compared between patients with ECRS and non-eosinophilic chronic rhinosinusitis (NECRS). RESULTS: Alternaria, house dust mites, protease from Staphylococcus aureus, papain, trypsin, polyinosinic:polycytidylic acid and lipopolysaccharide stimulated calprotectin production in the cultured NHBE cells. The combination of calprotectin and ATP stimulated the production of TSLP and IL-25 in NHBE cells, and calprotectin stimulated Alternaria-induced production of TSLP and IL-25, which was suppressed by blocking P2 purinergic receptors and by treatment with siRNA for S100A8, S100A9 or calprotectin receptors (Toll-like receptor 4 or receptor for advanced glycation end products). Allergen-induced calprotectin production was significantly stimulated in PNE cells from patients with ECRS. CONCLUSIONS: These results indicate that calprotectin enhances the allergen-induced Th2-type inflammatory responses in airway epithelial cells via the secretion of TSLP and IL-25, and that calprotectin secreted by the epithelial cells may be involved in the pathogenesis of ECRS. PMID- 27475625 TI - Therapeutic effect of bilastine in Japanese cedar pollinosis using an artificial exposure chamber (OHIO Chamber). AB - BACKGROUND: Environmental exposure chambers have been used to expose subjects to aeroallergens to investigate the efficacy of prophylactic treatment with symptomatic agents in Japan. We first examined the therapeutic effect of bilastine (BIL), a novel non-sedative second-generation H1-antihistamine, in subjects with Japanese cedar pollinosis using an artificial exposure chamber (OHIO Chamber). METHODS: This was a randomized, double-blind, four-way crossover, placebo- and active-controlled phase II study (trial registration number JapicCTI 132213). Subjects were exposed to cedar pollen (8000 grains/m3) for 2 h on Day -1 and 4 h each on Day 1 and 2. BIL 10 or 20 mg, placebo, or fexofenadine hydrochloride (FEX) 60 mg was administered orally 1 h after the start of pollen exposure on Day 1. Placebo or FEX was administered 12 h after the first dosing. The primary efficacy endpoint was the sum of total nasal symptom score (TNSS) from 0 to 3 h after the Day 1 dosing. RESULTS: We enrolled 136 subjects and the sum of TNSS on Day 1 of the three active treatments was significantly lower than that of placebo and was maintained up to 26 h after the first dosing (Day 2). The sum of TNSS or sneezing score on Day 1 after BIL 20 mg was more significantly decreased than after FEX. Moreover, BIL showed a faster onset of action than FEX. CONCLUSIONS: We demonstrated the efficacy, rapid onset, and long duration of action of BIL in subjects with Japanese cedar pollinosis exposed to cedar pollen using the OHIO Chamber. PMID- 27475626 TI - Pediatric admissions due to travel-related asthmatic attacks in Japan: A retrospective case series and case-control study. PMID- 27475627 TI - A catalog of Xenopus tropicalis transcription factors and their regional expression in the early gastrula stage embryo. AB - Gene regulatory networks (GRNs) involve highly combinatorial interactions between transcription factors and short sequence motifs in cis-regulatory modules of target genes to control cellular phenotypes. The GRNs specifying most cell types are largely unknown and are the subject of wide interest. A catalog of transcription factors is a valuable tool toward obtaining a deeper understanding of the role of these critical effectors in any biological setting. Here we present a comprehensive catalog of the transcription factors for the diploid frog Xenopus tropicalis. We identify 1235 genes encoding DNA-binding transcription factors, comparable to the numbers found in typical mammalian species. In detail, the repertoire of X. tropicalis transcription factor genes is nearly identical to human and mouse, with the exception of zinc finger family members, and a small number of species/lineage-specific gene duplications and losses relative to the mammalian repertoires. We applied this resource to the identification of transcription factors differentially expressed in the early gastrula stage embryo. We find transcription factor enrichment in Spemann's organizer, the ventral mesoderm, ectoderm and endoderm, and report 218 TFs that show regionalized expression patterns at this stage. Many of these have not been previously reported as expressed in the early embryo, suggesting thus far unappreciated roles for many transcription factors in the GRNs regulating early development. We expect our transcription factor catalog will facilitate myriad studies using Xenopus as a model system to understand basic biology and human disease. PMID- 27475629 TI - Enough Epidemiology! We Know They are Common, We Need Proven Better Ways to Care for Children with Functional Gastrointestinal Disorders. PMID- 27475628 TI - Analysis of embryonic development in the unsequenced axolotl: Waves of transcriptomic upheaval and stability. AB - The axolotl (Ambystoma mexicanum) has long been the subject of biological research, primarily owing to its outstanding regenerative capabilities. However, the gene expression programs governing its embryonic development are particularly underexplored, especially when compared to other amphibian model species. Therefore, we performed whole transcriptome polyA+ RNA sequencing experiments on 17 stages of embryonic development. As the axolotl genome is unsequenced and its gene annotation is incomplete, we built de novo transcriptome assemblies for each stage and garnered functional annotation by comparing expressed contigs with known genes in other organisms. In evaluating the number of differentially expressed genes over time, we identify three waves of substantial transcriptome upheaval each followed by a period of relative transcriptome stability. The first wave of upheaval is between the one and two cell stage. We show that the number of differentially expressed genes per unit time is higher between the one and two cell stage than it is across the mid-blastula transition (MBT), the period of zygotic genome activation. We use total RNA sequencing to demonstrate that the vast majority of genes with increasing polyA+ signal between the one and two cell stage result from polyadenylation rather than de novo transcription. The first stable phase begins after the two cell stage and continues until the mid-blastula transition, corresponding with the pre-MBT phase of transcriptional quiescence in amphibian development. Following this is a peak of differential gene expression corresponding with the activation of the zygotic genome and a phase of transcriptomic stability from stages 9-11. We observe a third wave of transcriptomic change between stages 11 and 14, followed by a final stable period. The last two stable phases have not been documented in amphibians previously and correspond to times of major morphogenic change in the axolotl embryo: gastrulation and neurulation. These results yield new insights into global gene expression during early stages of amphibian embryogenesis and will help to further develop the axolotl as a model species for developmental and regenerative biology. PMID- 27475630 TI - Usefulness of Hepatobiliary Scintigraphy in the Evaluation of Hepatic Cystic Lesions in Children. PMID- 27475631 TI - Drip bloodstain appearance on inclined apparel fabrics: Effect of prior laundering, fibre content and fabric structure. AB - The interaction of blood and fabrics is currently a 'hot topic', since the understanding and interpretation of these stains is still in its infancy. A recent simplified perpendicular impact experimental programme considering bloodstains generated on fabrics laid the foundations for understanding more complex scenarios. Blood rarely impacts apparel fabrics perpendicular; therefore a systematic study was conducted to characterise the appearance of drip stains on inclined fabrics. The final drip stain appearance for 45 degrees and 15 degrees impact angles on torso apparel fabrics (100% cotton plain woven, 100% polyester plain woven, a blend of polyester and cotton plain woven and 100% cotton single jersey knit) that had been laundered for six, 26 and 52 cycles prior to testing was investigated. The relationship between drop parameters (height and volume), angle and the stain characteristics (parent stain area, axis 1 and 2 and number of satellite stains) for each fabric was examined using analysis of variance. The appearance of the drip stains on these fabrics was distorted, in comparison to drip stains on hard-smooth surface. Examining the parent stain allowed for classification of stains occurring at an angle, however the same could not be said for the satellite stains produced. All of the dried stains visible on the surface of the fabric were larger than just after the impacting event, indicating within fabric spreading of blood due to capillary force (wicking). The cotton containing fabrics spread the blood within the fabrics in all directions along the stain's circumference, while spreading within the polyester plain woven fabric occurred in only the weft (width of the fabric) and warp (length) directions. Laundering affected the formation of bloodstain on the blend plain woven fabric at both impact angles, although not all characteristics were significantly affected for the three impact conditions considered. The bloodstain characteristics varied due to the fibre content and fabric structure for both impact angles investigated. It is therefore necessary to consider the age of the fabric (which is fabric specific), the fibre type (including blends) and the fabric structure, before interpreting bloodstain patterns. An understanding of this simplified inclined drip stain interaction has been investigated to generate a basis for more complex interactions, such as spatter bloodstains. PMID- 27475632 TI - Language deficits in schizophrenia and autism as related oscillatory connectomopathies: An evolutionary account. AB - Schizophrenia (SZ) and autism spectrum disorders (ASD) are characterised by marked language deficits, but it is not clear how these arise from gene mutations associated with the disorders. Our goal is to narrow the gap between SZ and ASD and, ultimately, give support to the view that they represent abnormal (but related) ontogenetic itineraries for the human faculty of language. We will focus on the distinctive oscillatory profiles of the SZ and ASD brains, in turn using these insights to refine our understanding of how the brain implements linguistic computations by exploring a novel model of linguistic feature-set composition. We will argue that brain rhythms constitute the best route to interpreting language deficits in both conditions and mapping them to neural dysfunction and risk alleles of the genes. Importantly, candidate genes for SZ and ASD are overrepresented among the gene sets believed to be important for language evolution. This translational effort may help develop an understanding of the aetiology of SZ and ASD and their high prevalence among modern populations. PMID- 27475634 TI - A Systematic Review of Economic Evaluation Methodologies Between Resource-Limited and Resource-Rich Countries: A Case of Rotavirus Vaccines. AB - BACKGROUND: For more than three decades, the number and influence of economic evaluations of healthcare interventions have been increasing and gaining attention from a policy level. However, concerns about the credibility of these studies exist, particularly in studies from low- and middle- income countries (LMICs). This analysis was performed to explore economic evaluations conducted in LMICs in terms of methodological variations, quality of reporting and evidence used for the analyses. These results were compared with those studies conducted in high-income countries (HICs). METHODS: Rotavirus vaccine was selected as a case study, as it is one of the interventions that many studies in both settings have explored. The search to identify individual studies on rotavirus vaccines was performed in March 2014 using MEDLINE and the National Health Service Economic Evaluation Database. Only full economic evaluations, comparing cost and outcomes of at least two alternatives, were included for review. Selected criteria were applied to assess methodological variation, quality of reporting and quality of evidence used. RESULTS: Eighty-five studies were included, consisting of 45 studies in HICs and 40 studies in LMICs. Seventy-five percent of the studies in LMICs were published by researchers from HICs. Compared with studies in HICs, the LMIC studies showed less methodological variety. In terms of the quality of reporting, LMICs had a high adherence to technical criteria, but HICs ultimately proved to be better. The same trend applied for the quality of evidence used. CONCLUSION: Although the quality of economic evaluations in LMICs was not as high as those from HICs, it is of an acceptable level given several limitations that exist in these settings. However, the results of this study may not reflect the fact that LMICs have developed a better research capacity in the domain of health economics, given that most of the studies were in theory led by researchers from HICs. Putting more effort into fostering the development of both research infrastructure and capacity building as well as encouraging local engagement in LMICs is thus necessary. PMID- 27475633 TI - Increasing of blastocyst rate and gene expression in co-culture of bovine embryos with adult adipose tissue-derived mesenchymal stem cells. AB - PURPOSE: Despite advances in the composition of defined embryo culture media, co culture with somatic cells is still used for bovine in vitro embryo production (IVEP) in many laboratories worldwide. Granulosa cells are most often used for this purpose, although recent work suggests that co-culture with stem cells of adult or embryonic origin or their derived biomaterials may improve mouse, cattle, and pig embryo development. MATERIALS AND METHODS: In experiment 1, in vitro produced bovine embryos were co-cultured in the presence of two concentrations of bovine adipose tissue-derived mesenchymal cells (b-ATMSCs; 103 and 104 cells/mL), in b-ATMSC preconditioned medium (SOF-Cond), or SOF alone (control). In experiment 2, co-culture with 104 b-ATMSCs/mL was compared to the traditional granulosa cell co-culture system (Gran). RESULTS: In experiment 1, co culture with 104 b-ATMSCs/mL improved blastocyst rates in comparison to conditioned and control media (p < 0.05). Despite that it did not show difference with 103 b-ATMSCs/mL (p = 0.051), group 104 b-ATMSCs/mL yielded higher results of blastocyst production. In experiment 2, when compared to group Gran, co-culture with 104 b-ATMSCs/mL improved not only blastocyst rates but also quality as assessed by increased total cell numbers and mRNA expression levels for POU5F1 and G6PDH (p < 0.05). CONCLUSIONS: Co-culture of bovine embryos with b-ATMSCs was more beneficial than the traditional co-culture system with granulosa cells. We speculate that the microenvironmental modulatory potential of MSCs, by means of soluble substances and exosome secretions, could be responsible for the positive effects observed. Further experiments must be done to evaluate if this beneficial effect in vitro also translates to an increase in offspring following embryo transfer. Moreover, this study provides an interesting platform to study the basic requirements during preimplantation embryo development, which, in turn, may aid the improvement of embryo culture protocols in bovine and other species. PMID- 27475635 TI - Cost-Utility Analysis of Telemonitoring Interventions for Patients with Chronic Obstructive Pulmonary Disease (COPD) in Germany. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) poses major challenges for health care systems. Previous studies suggest that telemonitoring could be effective in preventing hospitalisations and hence reduce costs. OBJECTIVE: The aim was to evaluate whether telemonitoring interventions for COPD are cost effective from the perspective of German statutory sickness funds. METHODS: A cost-utility analysis was conducted using a combination of a Markov model and a decision tree. Telemonitoring as add-on to standard treatment was compared with standard treatment alone. The model consisted of four transition stages to account for COPD severity, and a terminal stage for death. Within each cycle, the frequency of exacerbations as well as outcomes for 2015 costs and quality adjusted life years (QALYs) for each stage were calculated. Values for input parameters were taken from the literature. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, telemonitoring led to an increase in incremental costs (?866 per patient) but also in incremental QALYs (0.05 per patient). The incremental cost-effectiveness ratio (ICER) was thus ?17,410 per QALY gained. A deterministic sensitivity analysis showed that hospitalisation rate and costs for telemonitoring equipment greatly affected results. The probabilistic ICER averaged ?34,432 per QALY (95 % confidence interval 12,161-56,703). CONCLUSION: We provide evidence that telemonitoring may be cost-effective in Germany from a payer's point of view. This holds even after deterministic and probabilistic sensitivity analyses. PMID- 27475637 TI - In memoriam Jan Gillquist 1934-2016. PMID- 27475636 TI - How light attenuation and filler content affect the microhardness and polymerization shrinkage and translucency of bulk-fill composites? AB - OBJECTIVES: The purpose of this study was to investigate the microhardness, polymerization shrinkage, and translucency of bulk-fill composites (BFCs) which have different light attenuation properties and filler contents. MATERIALS AND METHODS: Five BFCs [Filtek Bulk Fill (FB), SureFil SDR (SS), Venus Bulk Fill (VB), SonicFill (SF), and Tetric N-Ceram Bulk Fill (TB)] and two resin-based composites (RBCs) [Tetric N-Ceram (TN) and Filtek Z350XT Flowable (ZF)] were chosen. Numbers of transmitted photons, refractive index, microhardness at different thicknesses, polymerization shrinkage, and translucency parameter (TP) were evaluated. RESULTS: Attenuation coefficients (ACs) based on measured photons ranged from -0.88 to -1.90. BFCs, except SF, had lower AC values than TN or ZF, and BFCs, except TN, had smaller refractive index decreases between top and bottom surfaces. Regardless of an exponential decrease in photon counts, microhardness decreased linearly as specimen thickens. Moreover, microhardness of BFCs showed smaller top-to-bottom decreases (11.5-48.8 %) than TN or ZF (57.3 and 71.5 %, respectively). BFCs with low filler contents showed lower microhardness and higher polymerization shrinkage than those of high filler contents. Also, BFCs had significantly higher (p < 0.001) TP values than TN or ZF. CONCLUSION: BFCs attenuated light less than RBCs. However, some BFCs had much lower top surface microhardness and higher polymerization shrinkage than tested RBCs. CLINICAL RELEVANCE: Despite the convenience of bulk filling, careful selection of BFC is advised because some BFCs have worse microhardness and polymerization shrinkage than RBCs due to their lower filler contents. PMID- 27475640 TI - Evaluation of biomechanical properties: are porcine flexor tendons and bovine extensor tendons eligible surrogates for human tendons in in vitro studies? AB - INTRODUCTION: Porcine flexor tendons, bovine extensor tendons, and human (semitendinosus) tendons are frequently used as substitutes for human ACL grafts in biomechanical in vitro studies. This study compares the biomechanical properties and structural differences of these tendons. MATERIALS AND METHODS: In this biomechanical study, fresh-frozen porcine flexor tendons, bovine extensor tendons, and human semitendinosus tendons were used (n = 36). The tendons were mounted in a uniaxial testing machine (Zwick/Roell) with cryo-clamps, leaving a 60 mm tendon part free between the two clamps. Specimens have been loaded to failure to evaluate the biomechanical parameters stiffness, yield load, and maximum load. A Total Collagen Assay Kit was used to detect differences in the total collagen type I concentration (n = 30). A one-way ANOVA was performed to detect differences in the means. The significance level was set at p < 0.05. RESULTS: There were no significant differences in the stiffness between the groups (bovine 194 +/- 43 N/mm, porcine 211 +/- 63 N/mm, and human cadaveric 208 +/- 58 N/mm). The yield and maximum loads were high (>1000 N) in all groups, but they were significantly increased in both animal specimens (means of 1681-1795 N) compared with human cadaveric specimen (means of 1289-1406 N; p < 0.01). No difference in the collagen type I concentration was detected (N.S.). CONCLUSION: Porcine flexor and bovine extensor tendons are eligible substitutes with similar stiffness and high failure loads compared with human cadaveric semitendinosus tendons in in vitro studies. PMID- 27475641 TI - Short- and long-term outcomes following hallux-valgus correction: a modified Kramer osteotomy. AB - BACKGROUND: Short- and long-term assessments were performed of a modification to the Kramer osteotomy that developed to stabilize the metatarsal head using an angular implant, the LINK((r)) internal hallux fixator (Waldemar LINK GmbH & Co. KG, Hamburg, Germany). METHODS: For this retrospective study, radiological assessments were used to measure outcomes in 72 feet with hallux valgus treated from 2006 to 2011. The hallux-valgus angle, the intermetatarsal angle between the first and second intermetarsal shaft axes, and the distal metatarsal articular angle were measured at short- and long-term intervals. Long-term clinical assessments included results of the Foot Function Index and the American Orthopedic Foot and Ankle Society Forefoot Score. RESULTS: Of the 72 feet treated, 12 were done as bilateral operations. Fifty-five patients at a mean age of 52 years (+/-12; range 22-78) were included in short-term assessments. Significant improvements in angular measurements were made (p < 0.001) between baseline and 3 month assessments. Three postoperative complications occurred and 40 % (29/72) of the implants were eventually removed. Fifty-five of the 72 feet were available for long-term assessments at a median of 5 years postoperatively (IQR 5-7; range 3-9). No significant loss of correction was detected (p = 0.373). Clinical assessments indicated successful outcomes in 86 % (47/55) of the feet, with slightly better results in older patients (p = 0.033; OR 1.1, CI 95 % 1.01 1.15). CONCLUSION: This technique can achieve normal angular configuration, even with severe deformities, without significant long-term loss of correction. Patients should be informed of potential discomfort necessitating hardware removal, although the likelihood of complications is low. LEVEL OF EVIDENCE: Level III study. PMID- 27475642 TI - Predicting imminent risk for fracture in patients aged 50 or older with osteoporosis using US claims data. AB - Patient characteristics contributing to imminent risk for fracture, defined as risk of near-term fracture within the next 12 to 24 months, have not been well defined. In patients without recent fracture, we identified factors predicting imminent risk for vertebral/nonvertebral fracture, including falls, age, comorbidities, and other potential fall risk factors. PURPOSE: Several factors contribute to long-term fracture risk in patients with osteoporosis, including age, bone mineral density, and fracture history. Some patients may be at imminent risk for fracture, defined here as a risk of near-term fracture within 12-24 months. Many patient characteristics contributing to imminent risk for fracture have not been well defined. This case-control study used US commercial and Medicare supplemental insured data for women and men without recent fracture to identify factors associated with imminent risk for fracture. METHODS: Patients included were aged >=50 with osteoporosis, had a vertebral or nonvertebral fracture claim (index date; fracture group) or no fracture claim (control group) from January 1, 2006, to September 30, 2012, continuously enrolled and without fracture in the 24 months before index. Potential risk factors during the period before fracture were assessed. RESULTS: Using data from 12 months before fracture, factors significantly associated with imminent risk for fracture were previous falls, older age, poorer health status, specific comorbidities (psychosis, Alzheimer's disease, central nervous system disease), and other fall risk factors (wheelchair use, psychoactive medication use, mobility impairment). Similar findings were observed with data from 24 months before fracture. CONCLUSIONS: In patients with osteoporosis and no recent fracture, falls, older age, poorer health status, comorbidities, and other potential fall risk factors were predictive of imminent risk for fracture. Identification of factors associated with imminent risk for vertebral/nonvertebral fracture may help identify and risk stratify those patients most in need of immediate and appropriate treatment to decrease fracture risk. PMID- 27475644 TI - Actinidia chinensis Planch root extract (acRoots) inhibits hepatocellular carcinoma progression by inhibiting EP3 expression. AB - A wide range of studies has demonstrated the potent anticancer activity of Chinese herbs. Here, we evaluated the anticancer activity and molecular mechanisms of Actinidia chinensis root extract (acRoots) on hepatocellular carcinoma (HCC). HepG2 HCC cells were treated with various concentrations of acRoots for 72 h and examined by mRNA expression profiling, revealing alterations in cellular immunity, inflammation, proliferation, cell cycle, and metabolic signaling responses. Further analysis of the altered genes in cellular immunity and inflammation gene clusters identified prostaglandin E receptor 3 (EP3) as a key regulator of gene expression in response to acRoots. Further analysis revealed inhibition of cell growth, migration, and invasion in HCC in response to acRoots, along with increased apoptosis due to downregulation of EP3 expression. Treatment with acRoots and EP3 antagonist L-798106 led to decreases in VEGF, EGFR, MMP2, and MMP9 expression in HCC cells, along with significant effects on growth, migration, invasion, and apoptosis; the effects were reversed/blocked by the EP3 agonist sulprostone. Taken together, these data clearly demonstrated that acRoots inhibit HCC cell invasion and metastasis via inhibition of EP3 expression, resulting in decreased activation of VEGF, EGFR, MMP2, and MMP9. PMID- 27475645 TI - Concentrations of Metals, Metalloids, and Chlorinated Pollutants in Blood and Plasma of White Stork (Ciconia ciconia) Nestlings From Spain. AB - The aim of this study was to determine the levels of different inorganic elements (lead [Pb], mercury [Hg], and arsenic [As]) and persistent chlorinated pollutants (including polychlorinated biphenyls [PCBs] and organochlorine pesticides [OCPs]) in blood and plasma of White stork (Ciconia ciconia) nestlings from northwest (NW) Spain. The concentrations of PCBs were lower than the limit of detection in all samples. The OCPs gamma-HCH, 4,4'-DDE, HCB, and endosulfan were detected most frequently in plasma from White stork nestlings. These OCPs were detected in 98, 54, 39, and 37 % of all samples, respectively. However, the concentrations of organic pollutants were lower than the risk thresholds for birds. The mean levels of the inorganic elements Pb, Hg, and As were found to be 36.92 +/- 33.48, 16.48 +/- 12.87, and 9.813 +/- 13.84 ug/L, respectively. These levels were also lower than the risk thresholds for birds. This study not only provides a snapshot of the levels of both inorganic and organic contaminants in wild White storks in NW Spain, it also provides a useful baseline for biomonitoring levels of the measured contaminants in this area. PMID- 27475646 TI - Chronic Ingestion of Coal Fly-Ash Contaminated Prey and Its Effects on Health and Immune Parameters in Juvenile American Alligators (Alligator mississippiensis). AB - Coal-burning power plants supply approximately 37 % of the electricity in the United States. However, incomplete combustion produces ash wastes enriched with toxic trace elements that have historically been disposed of in aquatic basins. Organisms inhabiting such habitats may accumulate these trace elements; however, studies investigating the effects on biota have been primarily restricted to shorter-lived, lower-trophic organisms. The American alligator (Alligator mississippiensis), a long-lived, top-trophic carnivore, has been observed inhabiting these basins, yet the health or immune effects of chronic exposure and possible accumulation remains unknown. In this study, we investigated how chronic dietary ingestion of prey contaminated with coal combustion wastes (CCWs) for 25 months, and subsequent accumulation of trace elements present in CCWs, affected juvenile alligator immune function and health. Alligators were assigned to one of four dietary-treatment groups including controls and those fed prey contaminated with CCWs for one, two, or three times a week. However, no effect of Dietary Treatment (p > 0.05) was observed on any immune parameter or hematological or plasma analyte we tested. Our results suggest that neither exposure to nor accumulation of low doses of CCWs had a negative effect on certain aspects of the immune and hematological system. However, future studies are required to elucidate this further. PMID- 27475643 TI - Community-Based Interventions to Improve and Sustain Antiretroviral Therapy Adherence, Retention in HIV Care and Clinical Outcomes in Low- and Middle-Income Countries for Achieving the UNAIDS 90-90-90 Targets. AB - Little is known about the effect of community versus health facility-based interventions to improve and sustain antiretroviral therapy (ART) adherence, virologic suppression, and retention in care among HIV-infected individuals in low- and middle-income countries (LMICs). We systematically searched four electronic databases for all available randomized controlled trials (RCTs) and comparative cohort studies in LMICs comparing community versus health facility based interventions. Relative risks (RRs) for pre-defined adherence, treatment engagement (linkage and retention in care), and relevant clinical outcomes were pooled using random effect models. Eleven cohort studies and eleven RCTs (N = 97,657) were included. Meta-analysis of the included RCTs comparing community- versus health facility-based interventions found comparable outcomes in terms of ART adherence (RR = 1.02, 95 % CI 0.99 to 1.04), virologic suppression (RR = 1.00, 95 % CI 0.98 to 1.03), and all-cause mortality (RR = 0.93, 95 % CI 0.73 to 1.18). The result of pooled analysis from the RCTs (RR = 1.03, 95 % CI 1.01 to 1.06) and cohort studies (RR = 1.09, 95 % CI 1.03 to 1.15) found that participants assigned to community-based interventions had statistically significantly higher rates of treatment engagement. Two studies found community based ART delivery model either cost-saving or cost-effective. Community- versus facility-based models of ART delivery resulted in at least comparable outcomes for clinically stable HIV-infected patients on treatment in LMICs and are likely to be cost-effective. PMID- 27475647 TI - Quantification of Circulating Free DNA as a Diagnostic Marker in Gall Bladder Cancer. AB - Gall bladder Carcinoma (GBC) is the fifth most common cancer of the digestive tract and frequently diagnosed in late stage of disease. Estimation of circulating free DNA (cfDNA) in serum has been applied as a "liquid biopsy" in several deep seated malignancies. Its value in diagnosis of gall bladder carcinoma has not been studied. The present study was designed to assess the role of cfDNA in the diagnosis of GBC and correlate levels with the TNM stage. Serum was collected from 34 patients with GBC and 39 age and sex matched controls including 22 cholecystitis and 17 healthy individuals. Serum cfDNA levels were measured through quantitative polymerase chain reaction (qPCR) by amplification of beta-globin gene. Performance of the assay was calculated through the receiver operating characteristic (ROC) curve. The cfDNA level was significantly lower in healthy controls and cholecystitis (89.32 +/- 59.76 ng/ml, 174.21 +/- 99.93 ng/ml) compared to GBC (1245.91 +/- 892.46 ng/ml, p = <0.001). The cfDNA level was significantly associated with TNM stage, lymph node involvement and jaundice (0.002, 0.027, and 0.041, respectively). Area under curve of ROC analysis for cancer group versus healthy and cholecystitis group was 1.00 and 0.983 with sensitivity of 100 %, 88.24 % and specificity of 100 % respectively. Quantitative analysis of cfDNA may distinguish cholecystitis and gall bladder carcinoma and may serve as new diagnostic, noninvasive marker adjunct to imaging for the diagnosis of GBC. PMID- 27475648 TI - Vibrational Spectroscopic Techniques for Probing Bioelectrochemical Systems. AB - A more complete understanding of bioelectrochemical interfaces is of increasing importance in both fundamental studies and biotechnological applications of proteins. Bioelectrochemical methods provide detailed information about the activity or rate of a process, but in situ spectroscopic methods are needed to gain direct structural insight into functionally relevant states. A number of methods have been reported that allow electrochemical and spectroscopic data to be collected from the same electrode, providing direct spectroscopic 'snapshots' of protein function, and here we focus on the application of infrared and Raman spectroscopies to the study of electrode-immobilised species. The ability to probe coordination at metal centres, protonation changes in amino acid side chains, reaction-induced changes in organic cofactors or substrates, protein orientation and subtle changes in protein secondary structure simultaneously, rapidly and at room temperature means that vibrational spectroscopic approaches are almost uniquely applicable to answering a wide range of questions in bioelectrochemistry. PMID- 27475649 TI - Biophotoelectrochemistry of Photosynthetic Proteins. AB - This chapter presents biophotoelectrochemical systems where one of nature's photosynthetic proteins, such as photosystem 1 (PS1), photosystem 2 (PS2), or bacterial reaction centers, are employed to create devices for technological applications. We use recent advances in biophotoelectrodes for energy conversion and sensing to illustrate the fundamental approaches in half-cell design and characterization. The aim is to guide electrochemists and photosynthetic researchers in the development of hybrid systems interfacing photosynthetic proteins with electrodes ranging from biosensors to biophotovoltaic cells. The first part gives an overview of the photosynthetic electron transfer chain with details on photosynthetic proteins and on the properties relevant for technological applications. The second part describes and critically discusses the main applications of biophotoelectrochemical cells based on photosynthetic proteins and exposes the respective requirement in electrode design. The following and final parts present the standard methodologies for the characterization of the biophotoelectrochemical half-cells with the main objectives of enhancing our mechanistic understanding of electron transfer, charge recombination, overpotential in photocurrent generation and protein degradation processes in devices, and thus open the perspectives for novel biophotoelectrochemical concepts and their rational optimization toward practical efficiencies. PMID- 27475650 TI - The Relevance of Nasal Provocation Testing in Children with Nonallergic Rhinitis. AB - BACKGROUND: It is important to understand that allergic rhinitis, whether seasonal or perennial, may be difficult to distinguish clinically from the nonallergic forms of rhinitis. OBJECTIVE: This study aimed to investigate the presence of local allergic rhinitis (LAR) in children who have allergic rhinitis symptoms in the absence of skin test positivity and specific IgE by performing a nasal provocation test (NPT). METHODS: Our study followed a case-controlled, prospective design. Twenty-eight patients and 30 healthy children were included in the study in a pollen-free season. The NPTs with a grass mix, Dermatophagoides pteronyssinus (DP) and D. farinae (DF) allergens were performed with an interval of 1 week. The total symptom score and visual analog scale, nasal eosinophilia and pulmonary function tests were evaluated before and after each NPT. The change to nasal flow and resistance was recorded by anterior rhinomanometry. RESULTS: The symptom frequencies before the NPTs were as follows: nasal congestion 100%; itching 82.1%; rhinorrhea 75% and sneezing 71.4%. The NPT was positive in 7 (25%) patients. In the NPT-positive group there was a statistically significant decrease in nasal flow at the concentrations of 10 and 100 IR/ml for DF (p = 0.026, p = 0.031, respectively). In the NPT-positive group total nasal resistance for DP was increased at the concentrations of 0.1 and 10 IR/ml, and for DF at 10 and 100 IR/ml (p = 0.049, p = 0.041, p = 0.022, p = 0.035, respectively). CONCLUSIONS: We emphasize that the diagnosis of LAR should be taken into consideration by pediatricians and pediatric allergy specialists. PMID- 27475651 TI - Editorial: Wound healing and fibrosis-two sides of the same coin. AB - Graphical Abstract ?. PMID- 27475652 TI - Frequency of low serum LH is associated with increased early pregnancy loss in IVF/ICSI cycles. AB - The role of LH during ovarian stimulation remains uncertain. Previous studies defined the low LH group using a single LH measurement on a predefined day of stimulation possibly not reflecting the entire follicular phase. This study retrospectively collected data from 619 IVF/ICSI cycles with GnRH antagonist and recombinant FSH. The low LH group was defined as LH concentration <=0.8 mIU/ml at any time during the cycle. Pregnancy results were compared between patients with one episode of low LH or more than two episodes of low LH (study group) and those without low LH (control group). There was no difference in fertilization rates between the two groups (67.5 +/- 1.7% versus 68.8 +/- 1.0%, respectively). The implantation rates (20.4% versus 25.2%), clinical pregnancy rates (43.9% versus 45.2%) and live-birth rates (LBR) (23.7% versus 30.4%) appeared lower in the study group, but the differences were not significant. In the study group, there were significantly increased early pregnancy loss rates (31.1% versus 16.3%, P = 0.012). The odds of early pregnancy loss increases by 1.55 fold for increased episodes of low serum LH (P = 0.029). Whether the adverse outcome is due to impaired oocyte quality or an endometrial component deserves further investigation. PMID- 27475653 TI - Wastewater treatment plant effluent alters pituitary gland gonadotropin mRNA levels in juvenile coho salmon (Oncorhynchus kisutch). AB - It is well known that endocrine disrupting compounds (EDCs) present in wastewater treatment plant (WWTP) effluents interfere with reproduction in fish, including altered gonad development and induction of vitellogenin (Vtg), a female-specific egg yolk protein precursor produced in the liver. As a result, studies have focused on the effects of EDC exposure on the gonad and liver. However, impacts of environmental EDC exposure at higher levels of the hypothalamic-pituitary gonad axis are less well understood. The pituitary gonadotropins, follicle stimulating hormone (Fsh) and luteinizing hormone (Lh) are involved in all aspects of gonad development and are subject to feedback from gonadal steroids making them a likely target of endocrine disruption. In this study, the effects of WWTP effluent exposure on pituitary gonadotropin mRNA expression were investigated to assess the utility of Lh beta-subunit (lhb) as a biomarker of estrogen exposure in juvenile coho salmon (Oncorhynchus kisutch). First, a controlled 72-h exposure to 17alpha-ethynylestradiol (EE2) and 17beta-trenbolone (TREN) was performed to evaluate the response of juvenile coho salmon to EDC exposure. Second, juvenile coho salmon were exposed to 0, 20 or 100% effluent from eight WWTPs from the Puget Sound, WA region for 72h. Juvenile coho salmon exposed to 2 and 10ng EE2L(-1) had 17-fold and 215-fold higher lhb mRNA levels relative to control fish. Hepatic vtg mRNA levels were dramatically increased 6670-fold, but only in response to 10ng EE2L(-1) and Fsh beta-subunit (fshb) mRNA levels were not altered by any of the treatments. In the WWTP effluent exposures, lhb mRNA levels were significantly elevated in fish exposed to five of the WWTP effluents. In contrast, transcript levels of vtg were not affected by any of the WWTP effluent exposures. Mean levels of natural and synthetic estrogens in fish bile were consistent with pituitary lhb expression, suggesting that the observed lhb induction may be due to estrogenic activity of the WWTP effluents. These results suggest that lhb gene expression may be a sensitive index of acute exposure to estrogenic chemicals in juvenile coho salmon. Further work is needed to determine the kinetics and specificity of lhb induction to evaluate its utility as a potential indicator of estrogen exposure in immature fish. PMID- 27475654 TI - The radiologist and the technique: the essential symbiosis. PMID- 27475655 TI - Introduction: A Foreword to CKD. PMID- 27475656 TI - Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease. AB - Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD. PMID- 27475657 TI - Measuring and Assessing Kidney Function. AB - Assessment of kidney function is important for the detection and management of chronic kidney disease. The glomerular filtration rate (GFR) and level of albuminuria are two frequently used indices of kidney function assessment. Administration of an exogenous filtration marker to measure GFR and collection of urine for 24 hours to measure albumin excretion generally are considered the gold standard for GFR and albuminuria, respectively, but they are time consuming and onerous for the patient. Thus, in routine clinical practice, other methods are used more frequently to assess GFR and albuminuria. In this review, we discuss the role of GFR and albuminuria in staging of chronic kidney disease as well as the pros and cons and prognostic implications of various methods of assessment of GFR and albuminuria. PMID- 27475658 TI - The Patterns, Risk Factors, and Prediction of Progression in Chronic Kidney Disease: A Narrative Review. AB - Chronic kidney disease (CKD) is a global public health problem that is associated with excess morbidity, mortality, and health resource utilization. The progression of CKD is defined by a decrease in glomerular filtration rate and leads to a variety of metabolic abnormalities including acidosis, hypertension, anemia, and mineral bone disorder. Lower glomerular filtration rate also bears a strong relationship with an increased risk of cardiovascular events, end-stage renal disease, and death. Patterns of CKD progression include linear and nonlinear trajectories, but kidney function can remain stable for years in some individuals. Addressing modifiable risk factors for the progression of CKD is needed to attenuate its associated morbidity and mortality. Developing effective risk prediction models for CKD progression is critical to identify patients who are more likely to benefit from interventions and more intensive monitoring. Accurate risk-prediction algorithms permit systems to best align health care resources with risk to maximize their effects and efficiency while guiding overall decision making. PMID- 27475660 TI - Cardiovascular Disease Consequences of CKD. AB - Chronic kidney disease, defined as reduced glomerular filtration rate (estimated using serum creatinine- and/or serum cystatin C-based equations) or excess urinary protein excretion, affects approximately 13% of adult Americans and is linked to a variety of clinical complications. Although persons with end-stage renal disease requiring chronic dialysis therapy experience a substantially high cardiovascular burden, whether mild-to-moderate chronic kidney disease is an independent risk factor for fatal and nonfatal cardiovascular events has been more controversial. This review evaluates the current evidence about the clinical and subclinical cardiovascular consequences associated with chronic kidney disease of varying levels of severity. In addition, it discusses the predictors of adverse cardiovascular outcomes while also focusing on recent insights into the relationships between chronic kidney disease and cardiovascular disease from the Chronic Renal Insufficiency Cohort study, a large current prospective cohort study of adults from across the spectrum of chronic kidney disease. PMID- 27475659 TI - The Role of Acute Kidney Injury in Chronic Kidney Disease. AB - There is increasing recognition that acute kidney injury (AKI) and chronic kidney disease (CKD) are closely linked and likely promote one another. Underlying CKD now is recognized as a clear risk factor for AKI because both decreased glomerular filtration rate and increased proteinuria have been shown to be associated strongly with AKI. A growing body of literature also provides evidence that AKI accelerates the progression of CKD. Individuals who suffered dialysis requiring AKI are particularly vulnerable to worse long-term renal outcomes, including end-stage renal disease. The association between AKI and subsequent renal function decline is amplified by pre-existing severity of CKD, higher stage of AKI, and the cumulative number of AKI episodes. However, residual confounding and ascertainment bias may partly explain the epidemiologic association between AKI and CKD in observational studies. As the number of AKI survivors increases, we need to better understand other clinically important outcomes after AKI, identify those at highest risk for the most adverse sequelae, and develop strategies to optimize their care. PMID- 27475662 TI - The Economic Burden of Chronic Kidney Disease and End-Stage Renal Disease. AB - The growing prevalence and progression of chronic kidney disease (CKD) raises concerns about our capacity to manage its economic burden to patients, caregivers, and society. The societal direct and indirect costs of CKD and end stage renal disease are substantial and increase throughout disease progression. There is significant variability in the evidence about direct and indirect costs attributable to CKD and end-stage renal disease, with the most complete evidence concentrated on direct health care costs of patients with advanced to end-stage CKD. There are substantial gaps in evidence that need to be filled to inform clinical practice and policy. PMID- 27475663 TI - Established and Emerging Strategies in the Treatment of Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is a common condition that has become a significant public health concern. The mainstay therapeutic approach to CKD is based on renin angiotensin system blockade as well as blood pressure and glycemic control. Despite these interventions, the management of CKD remains suboptimal, with a large proportion of the CKD population progressing to end-stage renal disease. Newer strategies for the treatment of CKD have emerged over the past years focusing on decreasing inflammation and delaying the development of fibrosis. Despite promising results in experimental models and small randomized studies, adequately powered randomized trials are required to evaluate the benefits and risks of these therapies in the CKD population. In this review, we discuss the evidence behind, and gaps in our knowledge of, established therapies as well as newer potential strategies for managing CKD, concentrating on interventions that currently are being evaluated in randomized studies. PMID- 27475664 TI - Advanced oxidation protein products induce catabolic effect through oxidant dependent activation of NF-kappa B pathway in human chondrocyte. AB - Advanced oxidation protein products (AOPPs) have been shown to participate in the progression of rheumatoid arthritis (RA). However, the effect of AOPPs accumulation on catabolic effect in human chondrocyte and the underlying mechanism(s) remain unclear. The present study demonstrated that AOPPs inhibited cell viability and glycosaminoglycan (GAG) production in human chondrocyte. Exposure of chondrocyte to AOPPs significantly increased the production of catabolic factors, such as cyclooxygenase-2 (COX-2), matrix metalloproteinase 3 (MMPs)-3 and MMP-13. AOPPs stimulation induced ROS generation and NF-kappa B p65 phosphorylation, which could be inhibited by soluble receptor for advanced glycan end products (sRAGE), NADPH oxidase inhibitor (apocynin), ROS scavenger (N-acetyl cysteine, NAC). Furthermore, NF-kappa B inhibitor Bay11-7082 significantly reversed the AOPPs-induced expression of catabolic factors and phosphorylation of NF-kappa B p65. Targeting AOPPs-triggered catabolic effect might be as a promising option for patients with RA. PMID- 27475661 TI - Consequences of CKD on Functioning. AB - Chronic kidney disease (CKD) is highly prevalent in the United States and throughout the world,(1) with approximately 13% of adults affected.(2) In addition, according to recent estimates, almost half of patients with CKD stages 3 to 5 are 70 years of age and older.(2) In the United States, the number of prevalent end-stage renal disease cases continues to increase in patients older than age 65. In light of the demographic characteristics of patients with CKD and ESRD, there has been considerable focus on associations between CKD and cardiovascular outcomes.(3) Until recently, less attention had been paid to other consequences of CKD in general and among older individuals with CKD in particular, but there is now solid evidence linking CKD with impairments of physical function, cognitive function, and emotional function and quality of life. This review summarizes available literature on these topics, focusing specifically on physical functioning and frailty, cognitive function, emotional health, including depression and anxiety, and health-related quality of life. PMID- 27475665 TI - The latex sap of the 'Old World Plant' Lagenaria siceraria with potent lectin activity mitigates neoplastic malignancy targeting neovasculature and cell death. AB - Lifestyle and dietary modifications have contributed much to somatic genetic alteration which has concomitantly led to increase in malignant diseases. Henceforth, plant based and dietary interventions to mitigate and impede oncogenic transformation are in great demand. We investigated the latex sap (LSL) of the dietary Lagenaria siceraria vegetable, the first domesticated plant species with the potent lectin activity for its functional role against the tumor progression and its mechanism. LSL has markedly stimulated proliferation of lymphocytes and displayed strong cytotoxic activity against cancer both in-vitro and in-vivo. The tumor regression was paralleled with drastic reduction in tumoral neovasculature as evidenced from angiogenic parameters and abrogated related gene expressions. LSL has also triggered apoptotic signaling cascade in cancer cells through activation of caspase-3 mediated activation of endonuclease and inducing apoptotic cellular events. Collectively our study provides tangible evidences that latex sap from L. siceraria with immunopotentiating ability significantly regresses the tumor progression by targeting angiogenesis and inducing cell death. PMID- 27475666 TI - Perception of acceptable antibiotic stewardship strategies in outpatient settings. AB - INTRODUCTION: Antibiotics are still often inappropriately prescribed in France despite specific measures being taken for over 10years. The 25% decrease in antibiotic prescription advocated in the 2011-2016 National Antibiotic Plan seems difficult to achieve. One of the strategies currently considered in France is the use of a specific prescription form dedicated to antibiotics, with an educational message for patients. We aimed to evaluate the acceptability - by primary care prescribers - of this measure and to evaluate their perception of other antibiotic stewardship strategies. METHODS: Qualitative study conducted among family physicians, pediatricians, dermatologists, dentists, and ENT specialists using semi-structured interviews. A thematic and framework analysis was then performed. RESULTS: Thirty prescribing physicians practicing in a specific region of France were included in the study. The dedicated prescription form for antibiotics was deemed excessive and questionable. Other measures, not directly targeting prescribers, were rather well perceived: the unit sales of antibiotics, the restricted reporting of susceptibility tests, or the limitation of the number of molecules available in outpatient settings. CONCLUSION: The results of this exploratory study may guide the national antibiotic stewardship policy in France. PMID- 27475667 TI - Contribution of radioactive 137Cs discharge by suspended sediment, coarse organic matter, and dissolved fraction from a headwater catchment in Fukushima after the Fukushima Dai-ichi Nuclear Power Plant accident. AB - Radiocesium (137Cs) migration from headwaters in forested areas provides important information, as the output from forest streams subsequently enters various land-use areas and downstream rivers. Thus, it is important to determine the composition of 137Cs fluxes (dissolved fraction, suspended sediment, or coarse organic matter) that migrate through a headwater stream. In this study, the 137Cs discharge by suspended sediment and coarse organic matter from a forest headwater catchment was monitored. The 137Cs concentrations in suspended sediment and coarse organic matter, such as leaves and branches, and the amounts of suspended sediment and coarse organic matter were measured at stream sites in three headwater catchments in Yamakiya District, located ~35 km northwest of Fukushima Dai-ichi Nuclear Power Plant (FDNPP) from August 2012 to September 2013, following the earthquake and tsunami disaster. Suspended sediment and coarse organic matter were sampled at intervals of approximately 1-2 months. The 137Cs concentrations of suspended sediment and coarse organic matter were 2.4-49 kBq/kg and 0.85-14 kBq/kg, respectively. The 137Cs concentrations of the suspended sediment were closely correlated with the average deposition density of the catchment. The annual proportions of contribution of 137Cs discharge by suspended sediment, coarse organic matter, and dissolved fraction were 96-99%, 0.0092-0.069%, and 0.73-3.7%, respectively. The total annual 137Cs discharge from the catchment was 0.02-0.3% of the deposition. PMID- 27475668 TI - Genetic alterations in meningiomas of different textures. AB - Meningiomas are complex brain tumors and 20% of meningiomas are clinically aggressive and recur. Aside from descriptors such as "soft" or "hard", the precise molecular mechanisms underlying these two subtypes have been unclear. In our study, we applied Affymetrix GeneChip Human Transcriptome Array 2.0 against 3 "soft" texture meningioma patients and 3 "hard" textures meningiomas as well as 3 normal controls. The array data showed that 949 coding genes and 568 non-coding RNAs in soft texture meningioma groups and 796 coding genes and 479 non-coding RNAs in hard textures were differentially expressed compared with control group. We further discovered 283 overlapped up-regulated genes and 279 overlapped down regulated genes in soft and stiff groups. Osteomodulin and Alpha-2 Type I Collagen changed most in soft and hard texture meningiomas respectively. Gene ontology analysis against the differentially changed genes revealed that extracellular matrix assembly and disassembly dysfunction might lead to the differences between soft and hard textures. Meanwhile, pathway analysis demonstrated that extracellular matrix was the nature cause of the difference between the two subtypes. Our data firstly provide the molecular difference between soft and hard textures which are propitious to dissecting the pathological mechanism of meningiomas and targeted therapy. PMID- 27475669 TI - Reducing Anesthesia and Health Care Cost Through Utilization of Child Life Specialists in Pediatric Radiation Oncology. AB - PURPOSE: To analyze the effectiveness of a certified child life specialist (CCLS) in reducing the frequency of daily anesthesia at our institution, and to quantify the potential health care payer cost savings of CCLS utilization in the United States. METHODS AND MATERIALS: From 2006 to 2014, 738 children (aged <=21 years) were treated with radiation therapy at our institution. We retrospectively analyzed the frequency of daily anesthesia before and after hiring a CCLS in 2011 after excluding patients aged 0 to 2 and >12 years. In the analyzed cohort of 425 patients the median age was 7.6 years (range, 3-12.9 years). For the pre-CCLS period the overall median age was 7.5 years; for the post-CCLS period the median age was 7.7 years. An average 6-week course of pediatric anesthesia for radiation therapy costs $50,000 in charges to the payer. The average annual cost to employ one CCLS is approximately $50,000. RESULTS: Before employing a CCLS, 69 of 121 children (57%) aged 3 to 12 years required daily anesthesia, including 33 of 53 children (62.3%) aged 5 to 8 years. After employing a CCLS, 124 of 304 children (40.8%) aged 3 to 12 years required daily anesthesia, including only 34 of 118 children (28.8%) aged 5 to 8 years (P<.0001). With a >16% absolute reduction in anesthesia use after employment of a CCLS, the health care payer cost savings was approaching $50,000 per 6 children aged 3 to 12 years treated annually with radiation therapy in our institution. This reduction resulted in a total of only 6 children aged 3 to 12 years required anesthesia to be treated per year at our center to achieve nearly break-even cost savings to the health care payer if the payer were to subsidize the employment expense of a CCLS. Overall, the CCLS intervention can provide an average annualized health care payer cost savings of "$[(anesthesia cost to payer during radiation therapy course/6) - (CCLS expense to payer/N)]" per child (N) treated with radiation therapy, where N equals the number of children aged 3 to 12 years treated in 1 year. This formula assumes that the payer subsidizes the cost for the employment of a CCLS, although our institution absorbed this expense for this data cohort. The predicted annualized health care system cost savings from reducing the frequency of anesthesia with radiation therapy when treating 100 children aged 3 to 12 years per year could exceed $775,000. CONCLUSIONS: These data suggest that a CCLS significantly reduces the frequency of daily anesthesia for children treated with radiation therapy. Health care system payers may achieve significant cost savings by financially supporting the employment of a CCLS in high-volume pediatric radiation therapy centers. PMID- 27475670 TI - Macroscopic Hematuria After Conventional or Hypofractionated Radiation Therapy: Results From a Prospective Phase 3 Study. AB - PURPOSE: To assess the macroscopic hematuria rates within a single-institution randomized phase 3 trial comparing dose-escalated, conventionally fractionated radiation therapy (CFRT) and moderately hypofractionated radiation therapy (MHRT) for localized prostate cancer. METHODS AND MATERIALS: Patients with intermediate- to high-risk localized prostate cancer were treated with conformal RT and short course androgen deprivation. Both the prostate and the entire seminal vesicles were treated to 80 Gy in 40 fractions over 8 weeks (CFRT) or 62 Gy in 20 fractions over 5 weeks (MHRT). The endpoint of the present study was the development of any episode or grade of macroscopic hematuria. The median follow up period was 93 months (range 6-143). RESULTS: Macroscopic hematuria was reported by 25 of 168 patients (14.9%). The actuarial estimate of hematuria at 8 years was 17.0% (95% confidence interval [CI] 10.7%-23.3%). The number of patients with hematuria was 6 and 19 in the CFRT and MHRT arms, respectively, for an actuarial 8-year estimate of 9.7% and 24.3%, respectively (hazard ratio 3.468, 95% CI 1.385-8.684; P=.008). Overall, 8 of 25 patients were found to have biopsy proven urothelial carcinoma (3 in the CFRT arm and 5 in the MHRT arm; P=.27). Thus, the 8-year actuarial incidence of macroscopic hematuria (after censoring urothelial cancer-related episodes) was 4.1% and 18.2% after CFRT and MHRT, respectively (hazard ratio 4.961, 95% CI 1.426-17.263; P=.012). The results were confirmed by multivariate analysis after accounting for several patient-, treatment-, and tumor-related covariates. CONCLUSIONS: MHRT was associated with a statistically significant increased risk of macroscopic hematuria compared with CFRT. PMID- 27475671 TI - Simulation Model of Microsphere Distribution for Selective Internal Radiation Therapy Agrees With Observations. AB - PURPOSE: To perform a detailed analysis of microsphere distribution in biopsy material from a patient treated with (90)Y-labeled resin spheres and characterize microsphere distribution in the hepatic artery tree, and to construct a novel dichotomous bifurcation model for microsphere deposits and evaluate its accuracy in simulating the observed microsphere deposits. METHODS AND MATERIALS: Our virtual model consisted of arteries that successively branched into 2 new generations of arteries at 20 nodes. The artery diameter exponentially decreased from the lowest generation to the highest generation. Three variable parameters were optimized to obtain concordance between simulations and measure microsphere distributions: an artery coefficient of variation (ACV) for the diameter of all artery generations and the microsphere flow distribution at the nodes; a hepatic tree distribution volume (HDV) for the artery tree; and an artery diameter reduction (ADR) parameter. The model was tested against previously measured activity concentrations in 84 biopsies from the liver of 1 patient. In 16 of 84 biopsies, the microsphere distribution regarding cluster size and localization in the artery tree was determined via light microscopy of 30-MUm sections (mean concentration, 14 microspheres/mg; distributions divided into 3 groups with mean microsphere concentrations of 4.6, 14, and 28 microspheres/mg). RESULTS: Single spheres and small clusters were observed in terminal arterioles, whereas large clusters, up to 450 microspheres, were observed in larger arterioles. For 14 microspheres/mg, the optimized parameter values were ACV=0.35, HDV = 50 cm(3), and ADR=6 MUm. For 4.6 microspheres/mg, ACV and ADR decreased to 0.26 and 0 MUm, respectively, whereas HDV increased to 130 cm(3). The opposite trend was observed for 28 microspheres/mg: ACV = 0.49, HDV = 20 cm(3), and ADR = 8 MUm. CONCLUSION: Simulations and measurements reveal that microsphere clusters are larger and more common in volumes with high microsphere concentrations and indicate that the spatial distribution of the artery tree must be considered in estimates of microsphere distributions. PMID- 27475672 TI - Reirradiation of Prostate Cancer Local Failures After Previous Curative Radiation Therapy: Long-Term Outcome and Tolerance. AB - PURPOSE: To evaluate the safety, feasibility, side-effect profile, and proof of concept of external beam radiation therapy (EBRT) with or without a brachytherapy (BT) boost for salvage of exclusive local failure after primary EBRT for prostate cancer. METHODS AND MATERIALS: Fourteen patients with presumed exclusive local recurrence after primary EBRT with or without BT were considered eligible for reirradiation. The median normalized total dose in 2-Gy fractions (NTD2Gy, alpha/beta ratio = 1.5 Gy) was 74 Gy (range, 66-98.4 Gy) at first irradiation. Median time between the first irradiation and the reirradiation was 6.1 years (range, 4.7-10.2 years). RESULTS: Between 2003 and 2008 salvage treatment was delivered with a median NTD2Gy of 85.1 Gy (range, 70-93.4) to the prostate with EBRT with (n=10) or without (n=4) BT. Androgen deprivation was given to 12 patients (median time of 12 months). No grade >=3 toxicity was observed during and within 6 weeks after RT. After a median follow-up of 94 months (range, 48-172 months) after salvage RT, 5-year grade >=3 genitourinary and gastrointestinal toxicity-free survival figures were 77.9% +/- 11.3% and 57.1% +/- 13.2%, respectively. Four patients presented with combined grade 4 genitourinary/gastrointestinal toxicity. The 5-year biochemical relapse-free, local relapse-free, distant metastasis-free, and cancer-specific survival rates were 35.7% +/- 12.8%, 50.0% +/- 13.4%, 85.7% +/- 9.4%, and 100%, respectively. CONCLUSION: Salvage whole-gland reirradiation for patients with a suspicion of exclusive local recurrence after initial RT may be associated with a high rate of severe radiation-induced side effects and poor long-term biochemical and local control. PMID- 27475673 TI - Multi-institutional Validation Study of Commercially Available Deformable Image Registration Software for Thoracic Images. AB - PURPOSE: To assess the accuracy of the commercially available deformable image registration (DIR) software for thoracic images at multiple institutions. METHODS AND MATERIALS: Thoracic 4-dimensional (4D) CT images of 10 patients with esophageal or lung cancer were used. Datasets for these patients were provided by DIR-lab (dir-lab.com) and included a coordinate list of anatomic landmarks (300 bronchial bifurcations) that had been manually identified. Deformable image registration was performed between the peak-inhale and -exhale images. Deformable image registration error was determined by calculating the difference at each landmark point between the displacement calculated by DIR software and that calculated by the landmark. RESULTS: Eleven institutions participated in this study: 4 used RayStation (RaySearch Laboratories, Stockholm, Sweden), 5 used MIM Software (Cleveland, OH), and 3 used Velocity (Varian Medical Systems, Palo Alto, CA). The ranges of the average absolute registration errors over all cases were as follows: 0.48 to 1.51 mm (right-left), 0.53 to 2.86 mm (anterior-posterior), 0.85 to 4.46 mm (superior-inferior), and 1.26 to 6.20 mm (3-dimensional). For each DIR software package, the average 3-dimensional registration error (range) was as follows: RayStation, 3.28 mm (1.26-3.91 mm); MIM Software, 3.29 mm (2.17 3.61 mm); and Velocity, 5.01 mm (4.02-6.20 mm). These results demonstrate that there was moderate variation among institutions, although the DIR software was the same. CONCLUSIONS: We evaluated the commercially available DIR software using thoracic 4D-CT images from multiple centers. Our results demonstrated that DIR accuracy differed among institutions because it was dependent on both the DIR software and procedure. Our results could be helpful for establishing prospective clinical trials and for the widespread use of DIR software. In addition, for clinical care, we should try to find the optimal DIR procedure using thoracic 4D CT data. PMID- 27475674 TI - A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458). AB - PURPOSE: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. METHODS AND MATERIALS: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. RESULTS: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). CONCLUSION: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials. PMID- 27475675 TI - Pharmacological characterization of the mechanisms underlying the vascular effects of succinate. AB - We investigated the mechanisms underlying the vascular effects of succinate. Vascular reactivity experiments were performed in aortic rings isolated from male Wistar rats and C57BL/6 wild type (WT) or GPR91(-/-) mice. Nitrate/nitrite (NOx) was measured colorimetrically whereas 6-keto-prostaglandin F1alpha (stable product of prostacyclin) was measured by enzyme immunoassay (EIA). Phosphorylation of endothelial nitric oxide synthase (eNOS) was assessed by western immunoblotting. Functional assays revealed that the direct effect of succinate in the vasculature is biphasic. At lower concentrations succinate induced relaxation while at higher concentrations succinate induced vascular contraction. Succinate concentration dependently relaxed rat aortic rings with intact endothelium. Endothelial removal reduced, but not abolished succinate induced relaxation. Similarly, succinate relaxed endothelium-intact and endothelium-denuded aortas isolated from both C57BL/6 and GPR91(-/-) mice. Pre incubation of endothelium-intact, but not endothelium-denuded rat aortic rings with l-NAME, indomethacin and tetraethylammonium (TEA) reduced succinate-induced relaxation. In endothelium-intact rings, succinate-induced relaxation was attenuated by ODQ, haemoglobin, Rp-8-Br-Pet-cGMPS, thapsigargin, wortmannin and SC-560. Blockade of K(+) channels with 4-aminopyridine, apamin and charybdotoxin reduced succinate-induced relaxation. Succinate increased the concentration of NOx and 6-keto-prostaglandin F1alpha as well as eNOS phosphorylation at ser(1177) residue. CaCl2-induced contraction of endothelium-intact or endothelium-denuded aortas was not affected by succinate. The major finding of our study is that it first demonstrates a direct effect of succinate in the vasculature. Succinate displays a biphasic and concentration-dependent effect. The vascular relaxation induced by succinate is partially mediated by endothelial GPR91 receptors via the NO-cGMP pathway, a vasodilator cyclooxygenase (COX) product(s) and the opening of K(+) channels. PMID- 27475676 TI - Evaluation of neuroprotective, anticonvulsant, sedative and anxiolytic activity of citicoline in rats. AB - Citicoline (cytidine-5'-diphosphocholine) is a neuroprotective agent that is administered following ischemic and traumatic brain injuries. There is little information about the antiseizure and anxiolytic effects of citicoline, which are therefore addressed in the present study. For evaluating the anticonvulsant effect of citicoline in the pentylentetrazole seizure model, a single intraperitoneal dose of citicoline was administered at 50, 100 or 150mg/kg. Sedative and anxiolytic effects of citicoline were examined via elevated plus maze and pentobarbital induced sleep tests. Results show that citicoline at the doses of 100 and 150mg/kg significantly delayed the latent period compared with the control (P<0.05). Citicoline at the doses of 100 and 150mg/kg significantly decreased total locomotion compared with the control (P<0.05). Additionally, citicoline at the doses of 100 and 150mg/kg significantly increased both percentage of entry and time spent in the open arms in the elevated plus maze test (P<0.05). The pentobarbital induced sleep test showed that citicoline significantly reduced the latency to sleep (P<0.05). Our results suggest that acute administration of citicoline has anticonvulsant activity and sedative effect. PMID- 27475677 TI - Effects of andrographolide on intrahepatic cholestasis induced by alpha naphthylisothiocyanate in rats. AB - Cholestasis is a cardinal manifestation of liver diseases but effective therapeutic approaches are limited. Therefore, alternative therapy for treating and preventing cholestatic liver diseases is necessary. Andrographolide, a promising anticancer drug derived from the medicinal plant Andrographis paniculata, has diverse pharmacological properties and multi-spectrum therapeutic applications. However, it is unknown whether andrographolide has a hepatoprotective effect on intrahepatic cholestasis. The aims of this study were to investigate the protective effect and possible mechanisms of andrographolide in a rat model of acute intrahepatic cholestasis induced by alpha naphthylisothiocyanate (ANIT). Andrographolide was administered intragastrically for four consecutive days, with a single intraperitoneal injection of ANIT on the second day. Liver injury was evaluated biochemically and histologically together with hepatic gene and protein expression analysis. Rats pretreated with andrographolide prior to ANIT injection demonstrated lower levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyltransferase, as well as bilirubin and bile acids as compared to rats treated with ANIT alone. Andrographolide also decreased the incidence and extent of periductular fibrosis and bile duct proliferation. Analysis of protein expression in livers from andrographolide-treated cholestatic rats revealed markedly decreased expression of alpha-smooth muscle actin and nuclear factor kappa-B (NF-kappaB). In conclusion, andrographolide has a potent protective property against ANIT-induced cholestatic liver injury. The mechanisms that underlie this protective effect are mediated through down-regulation of NF-kappaB expression and inhibition of hepatic stellate cell activation. These findings suggest that andrographolide could be a promising therapeutic option in prevention and slowing down the progression of cholestatic liver diseases. PMID- 27475678 TI - Promising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence. AB - Pterostilbene (PS) is a well-recognized antioxidant that primarily exists in blueberries, grapevines and heartwood of red sandalwood. Interest in this compound has been renewed in recent years, and studies have found that PS possesses an array of pharmacological properties, including chemopreventive, antiinflammatory, antidiabetic, antidyslipidemic, antiatherosclerotic and neuroprotective effects. However, the greater in vivo bioavailability of PS, as compared to resveratrol, is an added advantage for its efficacy. This review provides a summary regarding the sources, pharmacokinetic aspects and pharmacodynamics of PS, with a focus on the molecular mechanisms underlying its protective effects against cancer, brain injuries and heart disease. Studies regarding the safety profile of PS have also been included. Based on the presently available evidence, we conclude that PS represents an active phytonutrient and a potential drug with pleiotropic health applications. PMID- 27475680 TI - Topographic characterisation of dental implants for commercial use. AB - BACKGROUND: To characterize the surface topography of several dental implants for commercial use. MATERIAL AND METHODS: Dental implants analyzed were Certain (Biomet 3i), Tissue Level (Straumann), Interna (BTI), MG-InHex (MozoGrau), SPI (Alphabio) and Hikelt (Bioner). Surface topography was ascertained using a confocal microscope with white light. Roughness parameters obtained were: Ra, Rq, Rv, Rp, Rt, Rsk and Rku. The results were analysed using single-factor ANOVA and Student-Neuman-Keuls (p<0.05) tests. RESULTS: Certain and Hikelt obtained the highest Ra and Rq scores, followed by Tissue Level. Interna and SPI obtained lower scores, and MG-InHex obtained the lowest score. Rv scores followed the same trend. Certain obtained the highest Rp score, followed by SPI and Hikelt, then Interna and Tissue Level. MG-InHex obtained the lowest scores. Certain obtained the highest Rt score, followed by Interna and Hikelt, then SPI and Tissue Level. The lowest scores were for MG-InHex. Rsk was negative (punctured surface) in the MG-InHex, SPI and Tissue Level systems, and positive (pointed surface) in the other systems. Rku was higher than 3 (Leptokurtic) in Tissue Level, Interna, MG InHex and SPI, and lower than 3 (Platykurtic) in Certain and Hikelt. CONCLUSIONS: The type of implant determines surface topography, and there are differences in the roughness parameters of the various makes of implants for clinical use. PMID- 27475679 TI - Vascular peroxidase 1 up regulation by angiotensin II attenuates nitric oxide production through increasing asymmetrical dimethylarginine in HUVECs. AB - Asymmetric dimethylarginine (ADMA), the endogenous inhibitor of nitric oxide synthase, contributes to endothelial dysfunction and subsequent cardiovascular events including hypertension. Vascular peroxidase 1 (VPO1) is a novel heme containing peroxidase that uses hydrogen peroxide (H2O2) generated from co expressed nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to catalyze peroxidative reactions. Our previous study revealed a clear connection between VPO1 gene expression and endothelial dysfunction in spontaneously hypertensive rats. In the present study, we explored whether VPO1 participates in endothelial dysfunction during hypertension by increasing ADMA production. Spontaneously hypertensive rats displayed impaired endothelium-dependent relaxation, decreased eNOS expression and nitric oxide production, significantly increased VPO1 expression in both plasma and aorta tissue, and an increased ADMA level in plasma. In cultured endothelial cells, angiotensin II increased the ADMA level by inhibiting dimethylarginine dimethylaminohydrolase activity, which was inhibited by knockdown of VPO1 using small hairpin RNA. Moreover, the NADPH oxidase inhibitor and the hydrogen peroxide scavenger attenuated angiotensin II-mediated up-regulation of VPO1 and generation of hypochlorous acid. Furthermore, VPO1 derived hypochlorous acid suppressed recombinant dimethylarginine dimethylaminohydrolase activity and increased ADMA production. VPO1 plays a critical role in ADMA production via H2O2-VPO1-hypochlorous acid pathways, which may contribute to endothelial dysfunction in hypertension. PMID- 27475681 TI - Bisphosphonate treatment and dental implants: A systematic review. AB - BACKGROUND: To analyze articles that studied patients submitted to diphosphonates therapy and who received dental implants before, during or after bisphosphonate (BP) treatment, compared to healthy patients, analyzing the increase of failure and loss of implants or bisphosphonate related osteonecrosis of the jaw (BRONJ) incidence. MATERIAL AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement was used in this study. The clinical question in "PICO" format was: In patients under bisphosphonate therapy, do dental implants placement, compared to healthy patients, increase the failure and loss of implants or bisphosphonate related osteonecrosis of the jaw incidence? PubMed/MEDLINE was searched for articles published up until April 15, 2015 using a combination of MeSH terms and their Entry terms. RESULTS: The search resulted in 375 articles. After selection according to the eligibility criteria, 15 studies fulfilled were included (eight retrospective, one prospective and six case series), with a total of 1339 patients analyzed, 3748 implants placed, 152 loss of implants and 78 cases of BRONJ. CONCLUSIONS: Due to the lack of randomized clinical trials looking at this theme, further studies with longer follow-up are needed to elucidate the remaining questions. Thus, it is wise to be careful when planning dental implant surgery in patients undergoing bisphosphonate therapy because of the risk of developing BRONJ as well as occurring failure of implant. Moreover, complete systemic condition of the patient must be also taking into considering when such procedures are performed. PMID- 27475682 TI - Impact of rare diseases in oral health. AB - BACKGROUND: Rare diseases (RD) are those that present a lower prevalence than 5 cases per 10.000 population. The main objective of this review was to study the effect on oral health in rare diseases, while the secondary objective of the study is theme upgrade. MATERIAL AND METHODS: Comparative observational case control studies were analysed and a systematic review was conducted in PubMed. Each rare disease listed on the statistical data record of the Health Portal of the Ministry of Equality, Health and Social Policies Board of Andalusia was associated with "oral health". The variables studied included dental, oral mucosa and occlusion alterations, oral pathologies (caries, periodontal disease) and other alterations (mouth breathing, parafunctional habits, etc). A bias analysis of the variable caries was conducted. RESULTS: Six RD were selected through our inclusion and exclusion criteria (hypogammaglobulinemia, Rett syndrome, Marfan syndrome, Prader-Willi syndrome, cystic fibrosis and Cri du chat syndrome) in a total of 8 publications, of which four trials were classified as high risk of bias and one of them as medium risk. There were not trials with low risk of bias. CONCLUSIONS: The main statistically significant differences found by Syndrome compared to a control group were in Hypogammaglobulinemia with a greater tendency to enamel hypoplasia and dry mouth. The Rett syndrome had, as well, a greater tendency to an anterior open bite, ogival palate, bruxism, mouth breathing and tongue thrusting. Prader-Willi syndrome had a tendency of dental erosion, and Cri du chat syndrome showed a higher association to Tannerella forsythia. PMID- 27475684 TI - Current methods of sedation in dental patients - a systematic review of the literature. AB - OBJECTIVE: The main objective of this systematic literature review is to identify the safest and most effective sedative drugs so as to ensure successful sedation with as few complications as possible. STUDY DESIGN: A systematic literature review of the PubMed MEDLINE database was carried out using the key words "conscious sedation," "drugs," and "dentistry." A total of 1,827 scientific articles were found, and these were narrowed down to 473 articles after applying inclusion and exclusion criteria. These 473 studies were then individually assessed for their suitability for inclusion in this literature review. RESULTS: A total of 21 studies were selected due to their rigorous study design and conduciveness to further, more exhaustive analysis. The selected studies included a total of 1,0003 patients classified as ASA I or II. Midazolam was the drug most frequently used for successful sedation in dental surgical procedures. Ketamine also proved very useful when administered intranasally, although some side effects were observed when delivered via other routes of administration. Both propofol and nitrous oxide (N2O) are also effective sedative drugs. CONCLUSIONS: Midazolam is the drug most commonly used to induce moderate sedation in dental surgical procedures, and it is also very safe. Other sedative drugs like ketamine, dexmedetomidine and propofol have also been proven safe and effective; however, further comparative clinical studies are needed to better demonstrate which of these are the safest and most effective. PMID- 27475683 TI - Treatment of osteonecrosis of the jaw related to bisphosphonates and other antiresorptive agents. AB - BACKGROUND: The clinical management of medication-related osteonecrosis of the jaw (MRONJ) in patients treated with bisphosphonates and other antiresorptive agents is subject to controversy. The American Association of Oral and Maxillofacial Surgeons (AAOMS) has developed guidelines for the correct management of the disorder which are revised and updated by a panel of experts. MATERIAL AND METHODS: The present systematic review analyzes the different treatments currently used to treat this clinical condition, based on the PRISMA(r) (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement published in 2009. An electronic Medline search was made of the PubMed database, covering the period 2006-2014. The last search date was 31 December 2014. RESULTS: A total of 29 articles were selected from the initial search according to the different drugs implicated in the appearance of osteonecrosis; the treatment modality used according to the stage of the disease; and the recorded success rate. CONCLUSIONS: It is currently still recommended that the management of MRONJ should be decided according to the stage of the disease - conservative treatment being preferred in early stages without symptoms, while surgical management is preferred in the case of bone exposure with symptoms. PMID- 27475685 TI - Alcohol abusive use increases facial trauma? AB - BACKGROUND: Trauma is among the main death causes and morbidity in the world and is often related to the use of alcohol and its abuse has reached massive proportions, no matter if the country is developed or not, being considered as public health problem. Since there are very few randomized and prospective studies in literature about the association of facial trauma and the use of alcohol, this study aims to investigate the impact of alcohol use in facial trauma. MATERIAL AND METHODS: This was a prospective and cross sectional study, involving facial trauma patients attended at Oral Maxillofacial Surgery Division of a State Hospital. Variables included patient's profile, trauma etiology, facial region involved, type of injury and treatment and days of hospitalization. AUDIT test was applied to identify risks and damages of alcohol use and chemical dependence. Absolute distribution, uni and mutilvaried percentages were made for data evaluation. Pearson's qui-squared and Fisher's Exact tests were also used. RESULTS: One hundred patients were evaluated. The patient's mean age was 33.50 years-old, 48% had between 17 and 29 years old, 28% had 30 to 39, and 24% 40 or more. Most of them were male (86%). The most frequent etiology was traffic accident (57%), the extraoral area was most committed (62%), the most frequent type of injury was fractures (78%) and the most affected bone was the mandible (36%). More than half of the patients (53%) had surgical treatment. 38% had their discharge from hospital right after the first attendance. The AUDIT most frequent answer was "moderate use" (46%) and use at risk (39%). There was significant difference between the use of alcohol (AUDIT) and hematoma (0.003) and number of days of hospitalization (p=0.005). CONCLUSIONS: In this study it was not observed association between alcohol consumption using the AUDIT and trauma etiology, but patient victims of traffic accidents were classified as with risk in the scale. Most of the trauma were caused by traffic accidents using motorcycles and occurred in young aged men. PMID- 27475686 TI - Positive effect of platelet rich fibrin on osseointegration. AB - BACKGROUND: Leukocyte-platelet rich fibrin (L-PRF) is a second generation platelet concentrate clinically used to accelerate tissue healing and bone regeneration. Achieving reduced implant osseointegration time could provide immediate or early loading of implants. The aim of this study was to evaluate the L-PRF-induced osseointegration and bone-implant contact (BIC) in an experimental animal model. MATERIAL AND METHODS: Twelve 4-month-old New Zealand white rabbits were used. Following general anesthesia, 3-5 mL of blood was obtained from the central artery in rabbit ear and L-PRF was prepared. Two implant cavities (5 mm long and 3 mm in diameter) were created in each tibia with a total of four cavities in each animal. Two of these cavities were selected and covered with PRF (test group). The remaining L-PRF was used to soak the implants placed into the L PRF covered sockets. Other cavities were left as controls. In total, 48 implants were placed. Animals were sacrificed after two, three, or four weeks. Histological samples were obtained and peri-implant tissues were histomorphometrically evaluated for bone-to-implant contact and new bone formation. RESULTS: Histomorphometric analyses of the defects revealed that the L PRF was detectable up to the second week. Application of L-PRF increased the rate and amount of new bone formation in the experimental group compared to the control group. Bone-to-implant contact was enhanced when the surface was pre wetted with L-PRF (p<0.01). CONCLUSIONS: The results of this study demonstrated that L-PRF application may increases amount and rate of new bone formation during the early healing period and provides a faster osseointegration around implants. PMID- 27475687 TI - Alternative method to treat oroantral communication and fistula with autogenous bone graft and platelet rich fibrin. AB - BACKGROUND: Removing a tooth from the jaw results in the occurrence of oroantral communication in beneficial anatomic conditions or in the case of a iatrogenic effect. Popularized treatments of the oroantral communication have numerous faults. Large bone defect eliminates the chance to introduce an implant. Purpose of this work was assessment of the usefulness of autogenous bone graft and PRF in normal bone regeneration in the site of oroantral communication. MATERIAL AND METHODS: Bone regeneration in the site of oroantral communication was assessed in 20 patients. Bone defects were supplemented autogenous bone graft from mental protuberance in 14 cases and from oblique line in 6 cases. The graft was covered with a PRF membrane. RESULTS: In the study group in all cases closure of the oroantral communication was observed. The average width of the alveolar was 13 mm and the average height was 12.5 mm. In 3 patients an average increase of alveolar height of 1.5 mm was observed. CONCLUSIONS: This method may be the best option to prepare alveolar for new implant and prosthetic solutions. PMID- 27475688 TI - Comparison of the analgesic efficacy of oral ketorolac versus intramuscular tramadol after third molar surgery: A parallel, double-blind, randomized, placebo controlled clinical trial. AB - BACKGROUND: Preemptive analgesia is considered an alternative for treating the postsurgical pain of third molar removal. The aim of this study was to evaluate the preemptive analgesic efficacy of oral ketorolac versus intramuscular tramadol after a mandibular third molar surgery. MATERIAL AND METHODS: A parallel, double blind, randomized, placebo-controlled clinical trial was carried out. Thirty patients were randomized into two treatment groups using a series of random numbers: Group A, oral ketorolac 10 mg plus intramuscular placebo (1 mL saline solution); or Group B, oral placebo (similar tablet to oral ketorolac) plus intramuscular tramadol 50 mg diluted in 1 mL saline solution. These treatments were given 30 min before the surgery. We evaluated the time of first analgesic rescue medication, pain intensity, total analgesic consumption and adverse effects. RESULTS: Patients taking oral ketorolac had longer time of analgesic covering and less postoperative pain when compared with patients receiving intramuscular tramadol. CONCLUSIONS: According to the VAS and UAC results, this study suggests that 10 mg of oral ketorolac had superior analgesic effect than 50 mg of tramadol when administered before a mandibular third molar surgery. PMID- 27475689 TI - Haemostatic agents in apical surgery. A systematic review. AB - BACKGROUND: Blood presence in apical surgery can prevent the correct vision of the surgical field, change the physical properties of filling materials and reduce their sealing ability. OBJECTIVES: To describe which are the most effective and safest haemostatic agents to control bleeding in patients undergoing apical surgery. MATERIAL AND METHODS: We carried out a systematic review, using Medline and Cochrane Library databases, of human clinical studies published in the last 10 years. RESULTS: The agents that proved more effective in bleeding control were calcium sulphate (100%) and collagen plus epinephrine (92.9%) followed by ferric sulphate (60%), gauze packing (30%) and collagen (16.7%). When using aluminium chloride (Expasyl(r)), over 90% of the apical lesions improved, but this agent seemed to increase swelling. Epinephrine with collagen did not significantly raise either blood pressure or heart rate. CONCLUSIONS: Despite the use of several haemostatic materials in apical surgery, there is little evidence on their effectiveness and safety. The most effective haemostatic agents were calcium sulphate and epinephrine plus collagen. Epinephrine plus collagen did not seem to significantly raise blood pressure or heart rate during surgery. Aluminium chloride did not increase postoperative pain but could slightly increase postoperative swelling. Randomized clinical trials are needed to assess the haemostatic effectiveness and adverse effects of haemostatic materials in apical surgery. PMID- 27475690 TI - Rehabilitation of the severely atrophied dentoalveolar ridge in the aesthetic region with corticocancellous grafts from the iliac crest and dental implants. AB - Backround: The aim of this study was to assess changes in bone volume after block bone augmentation and placement of dental implants and further evaluate the aesthetic outcome of the treatment. MATERIAL AND METHODS: 9 patients with atrophied anterior maxilla were included in this study. They received total of 21 implants. Dimensions of the alveolar ridge were measured from cone-beam computed tomography x-rays. The bone level at the implant sites was analysed from intraoral x-rays and the aesthetic outcome was assessed from clinical photographs using a pink aesthetic score (PES) scaling. RESULTS: The mean gained horizontal bone width at the marginal crest and 5 mm apically was accordingly 2.7mm and 5.0 mm. The mean PES rating was 9.8/14. The survival rate of. CONCLUSIONS: Reconstruction of the atrophied anterior maxilla with bone blocks and dental implants is a safe procedure with high survival rate and acceptable aesthetic outcome. PMID- 27475691 TI - Efficacy of fentanyl transdermal patch in pain control after lower third molar surgery: A preliminary study. AB - BACKGROUND: Surgical removal of impacted lower third molars is a common oral surgical procedure, generally followed by moderate to severe postoperative pain. Transdermal drug delivery as a concept offers interesting possibilities for postoperative pain control. The aim of this study was to evaluate the efficacy of transdermal system with fentanyl in relieving pain following impacted lower third molar surgery. MATERIAL AND METHODS: Seventeen patients with bilateral impacted lower third molars were included in this preliminary study. For postoperative pain control, patients randomly received a fentanyl patch plus placebo tablet after the first operation and regular (placebo) patch and an analgesic, after the second operation. Analgesia was evaluated during first 24 hours postoperatively according to patients' reports about time of first pain appearance and additional analgesic consumption. Pain severity was rated using a 10 cm long visual analogue scale (VAS). RESULTS: Intensity of postoperative pain and postoperative analgesic consumption were significantly lower after the Fentanyl Transdermal System (FTS) was applied (p<0.05). Duration of postoperative analgesia was significantly higher with FTS when compared to control treatment (p<0.05). CONCLUSIONS: Based on the results of this preliminary study, transdermal system with fentanyl significantly reduced postoperative pain after third molar surgery. PMID- 27475692 TI - Prevalence of the colonization of Helicobacter pylori among students of the school of dentistry, University of Granada, Spain. AB - BACKGROUND: The oral cavity is a reservoir for Helicobacter pylori, and occupations that involve close contact with it, like Dentistry, could entail a higher risk of colonization. The aim of this study was to evaluate if the length of stay at the School of Dentistry of the University of Granada could influence colonization by H. pylori, , and to furthermore correlate colonization by H. pylori, with the state of oral health and oral hygiene habits. MATERIAL AND METHODS: The study groups were: Group 1, 35 students of Odontology in their first year of studies; Group 2, the same 35 students when they were in their fifth academic year; Group 3, 35 students from University study programs unrelated with Health and of the same age as the group 2 students. All underwent H. pylori, colonization determinations by means of the urea breath test (UBT), stool antigen test and a serological test. Also studied were the variables plaque index, gingival index and the number of times teeth were brushed per day. The Student t test was used for comparisons among the three studied groups. The Chi-squared test and Pearson correlation coefficient were used to determine any connection between colonization by H. pylori, and the variables studied. RESULTS: Comparisons between groups 1 and 2 and between groups 2 and 3 showed significant differences regarding colonization by H. pylori, plaque index, gingival bleeding index and tooth brushing. A positive correlation was found between being colonized by H. pylori, and having a gingival index higher than 10% and tooth brushing once a day or less, in all the studied groups. CONCLUSIONS: Colonization by H. pylori, among Dentistry students at the University of Granada decreased over a four-year time period at the University. Factors related with better oral health, such as a lower gingival index and more frequent tooth brushings, would explain these results. PMID- 27475693 TI - Paranasal sinuses malignancies: A 12-year review of clinical characteristics. AB - BACKGROUND: Inadequate epidemiologic investigations of the paranasal sinuses malignancies prompted this retrospective study with special emphasis on a major group of 111 tumors. MATERIAL AND METHODS: Clinical records of 111 patients with histologically confirmed malignant tumors of the paranasal sinuses were investigated retrospectively from April 2000 to January 2012. Collection of data included demographic information, clinical manifestations, treatment plans, and histopathology of the tumor. RESULTS: There were 69 (62.16%) male and 42 (37.83%) female patients (male-to-female ratio of 1.6:1), with a median age of 49+/-12.2 years (range 21 to 88 years). A high level of occurrence was noticed in the fifth (26.3%) decade of life. The most frequent histological types were squamous cell carcinoma (43.5%) and adenoid cystic carcinoma (19%). Among clinical manifestations, nasal obstruction was the most frequent followed by diplopia, and facial swelling. Fifty three patients (47.74%) were treated with combined approach of surgery and radiation therapy. CONCLUSIONS: Paranasal sinuses malignancies are rare conditions with nonspecific symptoms which make early diagnosis of the lesions more challenging. The optimal therapeutic protocol for patients suffering from these tumors is still a somewhat controversial entity and requires further studies. PMID- 27475694 TI - Impact of functional mandibular advancement appliances on the temporomandibular joint - a systematic review. AB - BACKGROUND: Although many orthodontists have no doubts about the effectiveness of functional appliances for mandibular advancement, the impact on the temporomandibular joint (TMJ) is still in dispute. The objective of this systematic review is to examine the main effects on the TMJ of using functional appliances, both in healthy patients and in patients with a pre-existing disorder. MATERIAL AND METHODS: A systematic review of the literature was conducted in accordance with the PRISMA guidelines. Only systematic reviews, meta analyses, randomized clinical trials (RCTs), case-control studies and cohort studies were included. A detailed language-independent electronic search was conducted in the Pubmed, Scopus, Cochrane Library and Embase databases. All studies published between 2000 and 2015 were included. RESULTS: A total of 401 articles were identified. Of these, 159 were duplicates and were excluded. On reading the title and abstract, 213 articles were excluded because they did not answer the research question, leaving a total of 29 articles. These articles were read and assessed. Following critical reading of the full text, eight articles were excluded: seven because they were considered of low quality and one because it published redundant data. As a result, 21 articles were included. CONCLUSIONS: After treatment with functional appliances, the condyle was found to be in a more advanced position, with remodelling of the condyle and adaptation of the morphology of the glenoid fossa. No significant adverse effects on the TMJ were observed in healthy patients and the appliances could improve joints that initially presented forward dislocation of the disk. PMID- 27475695 TI - Keratocystic odontogenic tumor: A biopsy service's experience with 104 solitary, multiple and recurrent lesions. AB - BACKGROUND: Keratocystic odontogenic tumor (KCOT) is a clinically significant cystic lesion of odontogenic origin. This study aimed to retrospectively review and describe the clinicopathologic features of KCOT and to objectively compare the clinical and histological features of solitary, multiple and recurrent KCOT in a Saudi Arabian population. MATERIAL AND METHODS: Biopsy request forms, pathology records and archival materials (all histological slides) of 104 cases of KCOT from 75 patients were retrieved. Demographic and clinical details as well as histological evaluation were analyzed and compared between the 3 groups using chi-squared or Mann-Whitney tests of association as appropriate. RESULTS: Significant differences were noted in the age of presentation, location and association with impaction between multiple and solitary cases. Histologically, there was a difference in the mitotic count, presence of satellite cysts and proliferating odontogenic epithelium between solitary and multiple lesions. There was no difference between the KCOT that later recurred and solitary lesion which did not recur even when matched clinically for age, sex and location. There were differences when solitary KCOT that later recurred or recurrent KCOT were compared with multiple lesions. Multiple lesions still had more significant proliferative activity parameters than solitary recurrence-related KCOT. CONCLUSIONS: KCOTs in Saudi Arabians are not different from those reported from other parts of the world. Clinical and histological analyses showed multiple KCOT is different from its solitary recurrent or non-recurrent counterparts and has a higher proliferative activity than both. Clinicohistologic features alone cannot wholly explain the behavior of KCOT. PMID- 27475696 TI - Estrogen and Progesterone hormone receptor expression in oral cavity cancer. AB - BACKGROUND: Recent studies have shown an increase in the incidence of oral squamous cell carcinoma (OSCC) in younger patients. The hypothesis that tumors could be hormonally induced during pregnancy or in young female patients without the well-known risk factors alcohol or tobacco abuse seems to be plausible. MATERIAL AND METHODS: Estrogen Receptor alpha (ERalpha) and Progesterone Receptor (PR) expression were analyzed in normal oral mucosa (n=5), oral precursor lesions (simple hyperplasia, n=11; squamous intraepithelial neoplasia, SIN I-III, n=35), and OSCC specimen. OSCCs were stratified in a young female (n=7) study cohort and older patients (n=46). In the young female study cohort three patients (n=3/7) developed OSCC during or shortly after pregnancy. Breast cancer tissues were used as positive control for ERalpha and PR expression. RESULTS: ERalpha expression was found in four oral precursor lesions (squamous intraepithelial neoplasia, SIN I-III, n=4/35, 11%) and in five OSCC specimen (n=5/46, 11%). The five ERalpha positive OSCC samples were older male patients. All patients within the young female study cohort were negatively stained for both ERalpha and PR. CONCLUSIONS: ER expression could be regarded as a seldom risk factor for OSCC. PR expression seems to be not relevant for the development of OSCC. PMID- 27475697 TI - Evaluation of total alloplastic temporo-mandibular joint replacement with two different types of prostheses: A three-year prospective study. AB - BACKGROUND: Temporo-Mandibular Joint (TMJ) replacement has been used clinically for years. The objective of this study was to evaluate outcomes achieved in patients with two different categories of TMJ prostheses. MATERIAL AND METHODS: All patients who had a TMJ replacement (TMJR) implanted during the study period from 2006 through 2012 were included in this 3-year prospective study. All procedures were performed using the Biomet Microfixation TMJ Replacement System, and all involved replacing both the skull base component (glenoid fossa) and the mandibular condyle. RESULTS: Fifty-seven patients (38 females and 19 males), involving 75 TMJs with severe disease requiring reconstruction (39 unilateral, 18 bilateral) were operated on consecutively, and 68 stock prostheses and 7 custom made prostheses were implanted. The mean age at surgery was 52.6+/-11.5 years in the stock group and 51.8+/-11.7 years in the custom-made group. In the stock group, after three years of TMJR, results showed a reduction in pain intensity from 6.4+/-1.4 to 1.6+/-1.2 (p<0.001), and an improvement in jaw opening from 2.7+/-0.9 cm to 4.2+/-0.7 cm (p<0.001). In the custom-made group, after three years of TMJR, results showed a reduction in pain intensity from 6.0+/-1.6 to 2.2+/-0.4 (p<0.001), and an improvement in jaw opening from 1.5+/-0.5 cm to 4.3+/ 0.6 cm (p<0.001). No statistically significant differences between two groups were detected. CONCLUSIONS: The results of this three-year prospective study support the surgical placement of TMJ prostheses (stock prosthetic, and custom made systems), and show that the approach is efficacious and safe, reduces pain, and improves maximum mouth opening movement, with few complications. As such, TMJR represents a viable technique and a stable long-term solution for cranio mandibular reconstruction in patients with irreversible end-stage TMJ disease. Comparing stock and custom-made groups, no statistically significant differences were detected with respect to pain intensity reduction and maximum mouth opening improvement. PMID- 27475698 TI - Corticotomies as a surgical procedure to accelerate tooth movement during orthodontic treatment: A systematic review. AB - BACKGROUND: One of the main aims of orthodontists is to reduce the treatment time as much as possible, particularly in view of the rise in demand for orthodontic treatment among adult patients. The objective of this systematic review was to examine the effectiveness of corticotomy as a surgical procedure that accelerates orthodontic tooth movement, together with its possible adverse effects. MATERIAL AND METHODS: A systematic review of articles in 4 databases, Pubmed, Cochrane, Scopus and Embase, complemented by a manual search, identified 772 articles. The duplicates were eliminated and a critical reading of titles and abstracts led to the rejection of articles that did not meet the objectives of the review, leaving 69. After reading the full text of these articles, 49 were excluded because they did not meet the inclusion criteria. On applying the CONSORT criteria as a quality filter, a further 4 were eliminated due to low quality. Finally, 16 articles (4 systematic reviews and 12 controlled trials) were reviewed. RESULTS: All the studies agree that corticotomy prior to orthodontic treatment accelerates dental movement, reducing the treatment time. With regard to side-effects, no periodontal damage was found, although this was only studied in the short term. CONCLUSIONS: The evidence regarding the results of corticotomy is limited, given the small number of quality clinical studies available. Before this procedure is included as a routine practice in dental surgeries, studies of higher methodological quality are required, studying a greater number of individuals and examining the possible long-term adverse effects and the cost/benefit of the procedure. PMID- 27475700 TI - The effects of a topical gel containing chitosan, 0,2% chlorhexidine, allantoin and despanthenol on the wound healing process subsequent to impacted lower third molar extraction. AB - BACKGROUND: Despite efforts to prevent postoperative discomfort, there are still many immediate side effects associated with the surgical extraction of impacted lower third molars. Cicatrization is a physiological process through which the loss of integrity of oral mucosa is recovered and damaged tissues are repaired. Bexident Post (ISDIN, Spain) is a topical gel that contains chitosan, 0.2% chlorhexidine, allantoin and dexpanthenol. While this gel has many clinical indications, there are no published clinical trials evaluating its use in impacted mandibular third molar surgery. This study aims to clinically evaluate the efficacy of a gel containing chitosan, 0.2% chlorhexidine, allantoin and dexpanthenol on wound healing and reduction of postoperative side effects and complications after extraction of an impacted mandibular third molar. MATERIAL AND METHODS: A split-mouth design study was carried out on a total of 50 bilaterally and symmetrically impacted third molar extractions, which were randomly placed into either a control group (CG=25) or an experimental group (EG=25). Patients were all informed of the purpose of the study and provided written consent. All procedures were carried out by the same dental practitioner, in accordance with standard surgical protocol. A different dental practitioner, unaware of which treatment had been applied, provided follow-up care. The EG applied 10 ml of topical gel composed of chitosan, 0.2% chlorhexidine, allantoin and dexpanthenol to the surgical wound three times a day for 10 days, patients in the CG did not apply any gel. RESULTS: The groups were homogeneous insofar as potentially confounding variables. No significant findings were found regarding postoperative swelling and pain. Neither of the groups displayed poor healing or infectious complications of the wound during the postoperative period. In all the recorded follow-ups (Day 7 p=0.001, and Day 14 p=0.01), the wound's aesthetic appearance was better in the EG. Overall treatment tolerance was satisfactory and similar in both groups. CONCLUSIONS: The gel composed of chitosan, 0.2% chlorhexidine, allantoin and dexpanthenol did not aid in patients' postoperative comfort; however, improved wound healing was observed. PMID- 27475699 TI - Role of Carnoy's solution in the treatment of keratocystic odontogenic tumor: A systematic review. AB - INTRODUCTION AND OBJECTIVE: The keratocystic odontogenic tumor is a benign but aggressive neoplasm. As enucleation alone obtains high recurrence rates, some adjuvant treatments such as Carnoy's solution have been proposed. The aim of this study is to evaluate the reduction of recurrences with the use of Carnoy's solution as adjuvant in the treatment of keratocystic odontogenic tumors. MATERIAL AND METHODS: An electronic search in Pubmed (MEDLINE), ScienceDirect and Cochrane databases was conducted with the key words "odontogenic keratocyst", "keratocystic odontogenic tumor", "carnoy's solution", "treatment" and "enucleation". The inclusion criteria were clinical studies using Carnoy's solution as adjuvant for the treatment of keratocystic odontogenic tumors, published in English, including at least 10 patients. Articles with an unclear reporting of the treatment applied, nonhuman studies, case reports and lesions associated to Gorlin-Goltz syndrome were excluded. RESULTS: All the studies included were case series. The recurrence rate of enucleation ranged from 0% to 58.8%. With the only use of Carnoy's solution as adjuvant treatment to the enucleation, recurrences varied from 0% to 100%. The use of >= 2 adjuvant treatments reduced the range between 0% and 7.9%. CONCLUSIONS: The use of Carnoy's solution as adjuvant therapy for the treatment of keratocystic odontogenic tumor has a grade C recommendation. PMID- 27475702 TI - Differences in urbanization degree and consequences on the diversity of conventional vs. rapidly mutating Y-STRs in five municipalities from a small region of the Tyrolean Alps in Austria. AB - In this study we set out to test at a micro-geographic scale for the potential effects of differences in urbanization degree on Y-chromosomal diversity and the paternal lineage differentiation of "conventional" and rapidly-mutating (RM) Y STR markers. To avoid systematic underrepresentation of common lineages, 551 male samples were collected under a sampling regime allowing for the inclusion of paternal relatives. All participants came from a small, topographically highly structured, yet culturally homogeneous settlement area in the Tyrolean Alps of Austria, a region that is characterized by a longstanding coexistence of communities differing considerably in size and connection. The study participants reported provenance in one of the three rural villages Alpbach, Brandenberg, and Wildschonau - all being separated by topographical barriers from each other - or in one of the two more urban-like and better connected municipalities Kitzbuhel and St. Johann in Tirol. When compared with the sample pools from the two larger communities, the three small villages showed distinctly higher rates of self reported patrilocality since the paternal grandfather (85-95% vs. ~42%), and featured evidence for a considerably higher proportion of close and cryptic paternal relationships among the study participants. We observed marked differences in the Y-SNP haplogroup frequency spectra and statistically significant Y-STR-based FST distances among the municipality samples, suggesting population sub-structuring along municipality borders. While for the two larger settlements a widely used "core" set of 17 conventional Y-STRs (Yfiler) provided reasonably high lineage resolution (H: 0.99515+/-0.00256, 0.99739+/-0.00224), a markedly reduced haplotype diversity was seen in samples from the rural villages (H: 0.96126+/-0.00701-0.98515+/-0.00278). This difference largely diminished when instead using a set of 13 RM Y-STRs (H: 0.99180+/-0.00380-0.99922+/-0.00187, for all groups). Most notably, in the Alpbach sample the number of different haplotypes rose from 42 (Yfiler) to 99 (RM Y-STRs) and the proportion of matching haplotypes dropped from nearly 4% (Yfiler) to about 0.4% (RM Y-STRs) of the pairwise comparisons. Consistent results were obtained with a reduced version of the dataset, being devoid of inferred close male relatives up to the degree of first cousins. Finally, consequences potentially arising from a gain in lineage resolution for population reference-sample size requirements will be addressed briefly. PMID- 27475701 TI - The culture of gut explants: A model to study the mucosal response. AB - Various experimental model designs have been used to analyze the inflammatory pathways in human gastrointestinal illnesses. Traditionally, analytical techniques and animal models are popular experimental tools to study the inflammation process of intestinal diseases. However, the comparison of results between animal and human models is difficult for the inconsistency of outcomes. Although there are different animal models for studying the intestinal diseases, none of them fully represents the physiological and environmental conditions typical of the human species. Also, there is currently a concerted effort to decrease the experimental use of animals. On the converse, experimental protocols using the culture of gut mucosa had become popular with the advent of endoscopy which allows explanting multiple fragments from the intestine. The peculiar characteristic of this model is the ability to preserve in vitro the features that we found in vivo, thus also the response to various stimuli that differs from person to person. The aim of the present paper is to provide a review of some of the possible uses of the organ intestinal mucosa culture. PMID- 27475704 TI - Monitoring therapeutic apheresis utilization: Database versus registry. PMID- 27475703 TI - Human blood cell levels of 5-hydroxymethylcytosine (5hmC) decline with age, partly related to acquired mutations in TET2. AB - Epigenetic alteration may play a role in age-associated dysfunction of stem cells and predispose to the development of hematological cancers. We analyzed global levels of hematopoietic 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in a cross-sectional study comprising 198 unrelated individuals from four age categories (neonates, 25-30, 70-75, and >90 years old) by liquid chromatography electrospray ionization-tandem mass spectrometry with multiple reaction monitoring. X-chromosome inactivation (XCI) ratios and telomere length (TL) were measured in all individuals by polymerase chain reaction. Sequencing of epigenetic regulator genes (including TET2, DNMT3A, ASXL1, IDH1, IDH2, and WT1) was performed in the two older subcohorts. We found that global 5hmC levels declined with age in human blood cells (27.5% reduction from birth to old age, p < 0.0005). The levels of 5mC underwent a more modest reduction (2.4% drop) between newborns and the elderly (p < 0.0005). Low 5hmC was associated with increased skewing of XCI (age-adjusted p = 0.0304) and reduced TL (age-adjusted p = 0.0354), both surrogate markers of clonal dominance. Of the 100 individuals over the age of 70, 16 had somatic mutations in TET2, 14 in DNMT3A, and none in IDH1, IDH2, or WT1. Individuals with TET2 mutations had significantly lower 5hmC (relative to unmutated individuals), whereas DNMT3A-mutated subjects did not. However, mutations in TET2 cannot account solely for the decline in 5hmC levels observed with aging because unmutated older individuals also had lower 5hmC levels compared with younger individuals. This suggests that the age-associated decline in 5hmC is multifactorial. Larger prospective studies are needed to determine whether 5hmC reduction is a biomarker of hematological cancer development. PMID- 27475705 TI - Mechanisms of chain adsorption on porous substrates and critical conditions of polymer chromatography. AB - Polymer adsorption is a ubiquitous phenomenon with numerous technological and healthcare applications. The mechanisms of polymer adsorption on surfaces and in pores are complex owing to a competition between various entropic and enthalpic factors. Due to adsorption of monomers to the surface, the chain gains in enthalpy yet loses in entropy because of confining effects. This competition leads to the existence of critical conditions of adsorption when enthalpy gain and entropy loss are in balance. The critical conditions are controlled by the confining geometry and effective adsorption energy, which depends on the solvent composition and temperature. This phenomenon has important implications in polymer chromatography, since the retention at the critical point of adsorption (CPA) is chain length independent. However, the mechanisms of polymer adsorption in pores are poorly understood and there is an ongoing discussion in the theoretical literature about the very existence of CPA for polymer adsorption on porous substrates. In this work, we examine the mechanisms of chain adsorption on a model porous substrate using Monte Carlo (MC) simulations. We distinguish three adsorption mechanisms depending on the chain location: on external surface, completely confined in pores, and also partially confined in pores in so-called "flower" conformations. The free energies of different conformations of adsorbed chains are calculated by the incremental gauge cell MC method that allows one to determine the partition coefficient as a function of the adsorption potential, pore size, and chain length. We confirm the existence of the CPA for chain length independent separation on porous substrates, which is explained by the dominant contributions of the chain adsorption at the external surface, in particular in flower conformations. Moreover, we show that the critical conditions for porous and nonporous substrates are identical and depend only on the surface chemistry. The theoretical results are confirmed by comparison with experimental data on chromatographic separation of a series of linear polystyrenes. PMID- 27475706 TI - Fabrication of smart magnetite/reduced graphene oxide composite nanoparticles and their magnetic stimuli-response. AB - Novel Fe3O4/reduced graphene oxide (RGO) composite nanoparticles were synthesized and confirmed by FT-IR spectra as good candidates for magnetic stimuli-responsive magnetorheological (MR) materials. The morphology of Fe3O4/RGO was observed by both scanning and transmission electron microscopy and their sedimentation stability improved due to a decreased density of the synthesized composites. The MR performance of the Fe3O4/RGO-based fluid was investigated with a rotational rheometer, and the Cho-Choi-Jhon model of the rheological equation of state was adopted to explain their performances for the entire shear rate region. PMID- 27475707 TI - Interaction of a biosurfactant, Surfactin with a cationic Gemini surfactant in aqueous solution. AB - The interaction between biosurfactant Surfactin and cationic Gemini surfactant ethanediyl-1,3-bis(dodecyldimethylammonium bromide) (abbreviated as 12-3-12) was investigated using turbidity, surface tension, dynamic light scattering (DLS) and small angle neutron scattering (SANS). Analysis of critical micelle concentration (CMC) values in Surfactin/12-3-12 mixture indicates that there is synergism in formation of mixed Surfactin/12-3-12 micelles. Although Surfactin and 12-3-12 are oppositely charged in phosphate buffer solution (PBS, pH7.4), there are no precipitates observed at the concentrations below the CMC of Surfactin/12-3-12 system. However, at the concentration above CMC value, the Surfactin/12-3-12 mixture is severely turbid with high 12-3-12 content. DLS and SANS measurements follow the size and shape changes of mixed Surfactin/12-3-12 aggregates from small spherical micelles via elongated aggregates to large bulk complexes with increasing fraction of Gemini surfactant. PMID- 27475708 TI - Interfacial thermodynamics and kinetics of sorption of diclofenac on prepared high performance flower-like MoS2. AB - Flower-like MoS2 with numerous wrinkled nanosheets was prepared via a facile hydrothermal method. The surface morphology and microstructure of the obtained materials were characterized using X-ray diffraction data (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Additionally, the compositions of the flower-like MoS2 were further revealed by an energy dispersion spectrometer (EDX) and X-ray photoelectron spectrometry (XPS). The obtained MoS2 was used as an adsorbent to remove diclofenac (DCF, C14H10Cl2NO2Na) from aqueous solutions and presented excellent performance for removing DCF. The sorption kinetics, isotherms and effect of solution pH on the sorption were evaluated in batch sorption experiments. The sorption characteristics of the interactions between DCF and MoS2 in water were analyzed using a pseudo-second-order model, an intraparticle diffusion model and Boyd model to determine the sorption rate-determining steps. It was concluded that the sorption of DCF on MoS2 was fitted better by the pseudo-second-order model and that external diffusion governed the sorption process of DCF onto the MoS2. The interfacial interaction free energies between DCF and MoS2 in the sorption process can be calculated based on the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO). The flower-like MoS2 presenting excellent performance for removing DCF, could be a better choice of treating DCF-containing wastewaters. PMID- 27475709 TI - Single step synthesis of amine-functionalized mesoporous magnetite nanoparticles and their application for copper ions removal from aqueous solution. AB - Amine-functionalized mesoporous superparamagnetic Fe3O4 nanoparticles with an average size of 70nm have been synthesized using a single step solvothermal method by the introduction of triethylenetetramine (TETA), a chelating agent recommended for the removal of excess copper in patients with Wilson's disease. The synthesized nanoparticles were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, nitrogen adsorption/desorption isotherm, vibrating sample magnetometer (VSM), and Fourier transform infrared spectroscopy (FTIR). It is confirmed that the magnetic nanoparticles have been functionalized with TETA during the synthetic process, and the concentration of TETA is crucial for the formation of monodisperse mesoporous nanoparticles. The obtained single-crystal magnetic nanoparticles have a high magnetization, which enhances their response to external magnetic field and therefore should greatly facilitate the manipulation of the particles in practical uses. Reaction parameters affecting the formation of mesoporous structure were explored, and a possible formation mechanism involving templated aggregation and recrystallization processes was proposed. The capacity of the synthesized amine-functionalized Fe3O4 nanoparticles toward Cu(II) removal from aqueous solution was investigated. The adsorption rate of Cu(II) on amine functionalized Fe3O4 nanoparticles followed a pseudo-second order kinetic model. The results of this study demonstrated that the amine-functionalized mesoporous superparamagnetic Fe3O4 nanoparticles could be used as an efficient adsorbent in water treatment and would also find potential application for Cu(II) removal in vivo. PMID- 27475710 TI - Highly sensitive electrochemical determination of Sunset Yellow based on the ultrafine Au-Pd and reduced graphene oxide nanocomposites. AB - A sensitive and novel electrochemical sensor with Au-Pd and reduced graphene oxide (RGO) nanocomposites modified glassy carbon electrode (Au-Pd-RGO/GCE) was successfully fabricated by one-step synthesis method for the detection of Sunset Yellow. The as-prepared composites were uniformly dispersed on the surface of electrode with an average diameter of approximately 3.44nm, and the ultrafine nanoparticles effectively enhanced the electrochemical active surface area of GCE. The modified electrode had been characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction and electrochemical tests. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) results showed high stability and outstanding electrocatalytic activity of Au-Pd-RGO/GCE for the detection of SY with low detection limits (1.5 nM, S/N=3) and wide concentration ranges (0.686-331.686MUM). The Au-Pd-RGO/GCE was further applied to detect SY in real samples with good recovery. Herein, the fabricated Au-Pd-RGO/GCE showed excellent sensitivity, stability and repeatability for the detection of SY and will be a promising application in electrochemical sensor. PMID- 27475711 TI - Reoperation and Reamputation After Transmetatarsal Amputation: A Systematic Review and Meta-Analysis. AB - Transmetatarsal amputations have generally been accepted as a relatively more definitive amputation compared with other lesser ray resections. However, many investigators have reported a high occurrence of more proximal amputation after transmetatarsal amputation. A systematic review was performed to evaluate the occurrence of reamputation and reoperation after transmetatarsal amputations. A search of the Medline, CINAHL, and Cochrane Central databases yielded 159 abstracts. After review, 24 reports were included in the study. A total of 391 (26.9%) reoperations were identified after 1453 transmetatarsal amputations. Any level reamputation occurred in 152 (29.7%) of 365 transmetatarsal amputations and major amputation occurred in 380 (33.2%) of 1146 transmetatarsal amputations. Using a random effects model, the reoperation rate was estimated at 24.43% (95% confidence interval 11.64% to 37.21%), the reamputation rate was estimated at 28.37% (95% confidence interval 19.56% to 37.19%), and the major amputation rate was estimated at 30.16% (95% confidence interval 23.86% to 36.47%). These findings raise questions about the conventional wisdom of performing primary transmetatarsal amputation in lieu of other minor amputations, such as partial first ray amputation, and suggest that the choice between transmetatarsal amputation and other minor amputations might be a decision that depends on very patient-specific factors. PMID- 27475712 TI - Joint Preserving Procedure for Moderate Hallux Rigidus: Does the Metatarsal Index Really Matter? AB - Surgical treatment of moderate hallux rigidus remains controversial and the optimal surgical technique has yet to be defined. Decompressive metatarsal osteotomy is one of the procedures available; however, one of the potential drawbacks is the effect of the metatarsal shortening. We evaluated the global effect of the decompressive metatarsal osteotomy, accounting for the metatarsal index. We retrospectively evaluated 78 patients with stage II and III hallux rigidus who had undergone Youngswick osteotomy and analyzed their outcomes according to the metatarsal index. The candidates for inclusion underwent clinical and radiographic evaluation, including the visual analog scale foot and ankle score, first metatarsophalangeal joint range of motion, and first metatarsal protrusion distance to define the metatarsal index. Also, shortening of the first metatarsal was measured postoperatively, and the occurrence of metatarsalgia was considered a postoperative complication. The mean follow-up period was 53 +/- 17 months. The groups stratified according to the metatarsal index (index plus, index plus minus, and index minus) presented with similar results (p > .05). The average preoperative visual analog scale foot and ankle score of 56.4 +/- 13.8 points improved significantly to 84.1 +/- 5.5 points postoperatively (p < .0001). Also, the mean preoperative dorsiflexion of 20.4 degrees +/- 1.5 degrees improved to 37.3 degrees +/- 1.6 degrees postoperatively (p < .0001). Of the 78 patients, 97% would recommend the procedure to a family member or friend. Four patients (6%) experienced postoperative metatarsal pain. We found consistent results with this procedure. The reported functional score and dorsiflexion improvement provide evidence that good outcomes and high levels of patient satisfaction can be achieved, regardless of the metatarsal length. PMID- 27475713 TI - Cannabis clubs in Uruguay: The challenges of regulation. AB - BACKGROUND: The Uruguayan Cannabis Clubs (UCCs) constitute one of three ways to obtain cannabis under the new cannabis regulation laws. These organizations, formed by up to 45 adults and with a legal limit to grow up to 99 plants, appear to provide a safe method of procuring cannabis in a country that is trying to regulate aspects of cannabis production and distribution. This article describes the operations of the UCCs and the challenges these organizations face. METHODS: The paper draws on data from in-depth interviews conducted with representatives of UCCs and conversations with government officials conducted between March and August of 2015. We collected information about membership, facilities and forms of organization, methods of cannabis cultivation and distribution, and activities within the community. RESULTS: This article describes how UCCs are formed, their resources, rules for cannabis production and distribution; and their relationships with government institutions and the community. Data show that UCCs face four main challenges: compliance with the extant regulation, financial sustainability, tolerance from the community, and collective action dilemmas. CONCLUSIONS: Organizational challenges are as frequent in Uruguay as in other country where cannabis clubs exist, however this paper shows that in order to be sustainable, UCCs need to address issues of collective action, financial sustainability, and possible competition with cannabis distribution via pharmacies that could diminish membership. In the case of Uruguay, UCCs are part of a regulation effort, though they may not be preferred over other legal alternatives already in place. PMID- 27475714 TI - Exercises focusing on rotator cuff and scapular muscles do not improve shoulder joint position sense in healthy subjects. AB - Proprioception is essential for shoulder neuromuscular control and shoulder stability. Exercise of the rotator cuff and scapulothoracic muscles is an important part of shoulder rehabilitation. The purpose of this study was to investigate the effect of rotator cuff and scapulothoracic muscle exercises on shoulder joint position sense. Thirty-six healthy subjects were recruited and randomly assigned into either a control or training group. The subjects in the training group received closed-chain and open-chain exercises focusing on rotator cuff and scapulothoracic muscles for four weeks. Shoulder joint position sense errors in elevation, including the humerothoracic, glenohumeral and scapulothoracic joints, was measured. After four weeks of exercise training, strength increased overall in the training group, which demonstrated the effect of exercise on the muscular system. However, the changes in shoulder joint position sense errors in any individual joint of the subjects in the training group were not different from those of the control subjects. Therefore, exercises specifically targeting individual muscles with low intensity may not be sufficient to improve shoulder joint position sense in healthy subjects. Future work is needed to further investigate which types of exercise are more effective in improving joint position sense, and the mechanisms associated with those changes. PMID- 27475715 TI - Cardiac action of the first G protein biased small molecule apelin agonist. AB - Apelin peptide analogues displaying bias towards G protein signalling pathways have beneficial cardiovascular actions compared with the native peptide in humans in vivo. Our aim was to determine whether small molecule agonists could retain G protein bias. We have identified a biased small molecule, CMF-019, and characterised it in vitro and in vivo. In competition radioligand binding experiments in heart homogenates, CMF-019 bound to the human, rat and mouse apelin receptor with high affinity (pKi=8.58+/-0.04, 8.49+/-0.04 and 8.71+/-0.06 respectively). In cell-based functional assays, whereas, CMF-019 showed similar potency for the Galphai pathway to the endogenous agonist [Pyr(1)]apelin-13 (pD2=10.00+/-0.13 vs 9.34+/-0.15), in beta-arrestin and internalisation assays it was less potent (pD2=6.65+/-0.15 vs 8.65+/-0.10 and pD2=6.16+/-0.21 vs 9.28+/ 0.10 respectively). Analysis of these data demonstrated a bias of ~400 for the Galphai over the beta-arrestin pathway and ~6000 over receptor internalisation. CMF-019 was tested for in vivo activity using intravenous injections into anaesthetised male Sprague-Dawley rats fitted with a pressure-volume catheter in the left ventricle. CMF-019 caused a significant increase in cardiac contractility of 606+/-112mmHg/s (p<0.001) at 500nmol. CMF-019 is the first biased small molecule identified at the apelin receptor and increases cardiac contractility in vivo. We have demonstrated that Galphai over beta arrestin/internalisation bias can be retained in a non-peptide analogue and predict that such bias will have the therapeutic benefit following chronic use. CMF-019 is suitable as a tool compound and provides the basis for design of biased agonists with improved pharmacokinetics for treatment of cardiovascular conditions such as pulmonary arterial hypertension. PMID- 27475718 TI - Corrigendum to "Immunological responses of customised probiotics-fed marron, Cherax tenuimanus, (Smith 1912) when challenged with Vibrio mimicus" [Fish Shellfish Immunol. 35 (2) (2013) 262-270]. PMID- 27475717 TI - Andrographolide inhibits adipogenesis of 3T3-L1 cells by suppressing C/EBPbeta expression and activation. AB - Andrographolide, a diterpenoid, is the most abundant terpenoid in Andrographis paniculata, a popular Chinese herbal medicine. Andrographolide displays diverse biological activities including hypoglycemia, hypolipidemia, anti-inflammation, and anti-tumorigenesis. Recent evidence indicates that andrographolide displays anti-obesity property by inhibiting lipogenic gene expression, however, the underlying mechanisms remain to be elucidated. In this study, the effects of andrographolide on transcription factor cascade and mitotic clonal expansion in 3T3-L1 preadipocyte differentiation into adipocyte were determined. Andrographolide dose-dependently (0-15MUM) inhibited CCAAT/enhancer-binding protein alpha (C/EBPalpha) and C/EBPbeta mRNA and protein expression as well as peroxisome proliferator-activated receptor gamma (PPARgamma) protein level during the adipogenesis of 3T3-L1 cells. Concomitantly, fatty acid synthase and stearoyl CoA desaturase expression and lipid accumulation were attenuated by andrographolide. Oil-red O staining further showed that the first 48h after the initiation of differentiation was critical for andrographolide inhibition of adipocyte formation. Andrographolide inhibited the phosphorylation of PKA and the activation of cAMP response element-binding protein (CREB) in response to a differentiation cocktail, which led to attenuated C/EBPbeta expression. In addition, ERK and GSK3beta-dependent C/EBPbeta phosphorylation was attenuated by andrographolide. Moreover, andrographolide suppressed cyclin A, cyclin E, and CDK2 expression and impaired the progression of mitotic clonal expansion (MCE) by arresting the cell cycle at the Go/G1 phase. Taken together, these results indicate that andrographolide has a potent anti-obesity action by inhibiting PKA CREB-mediated C/EBPbeta expression as well as C/EBPbeta transcriptional activity, which halts MCE progression and attenuates C/EBPalpha and PPARgamma expression. PMID- 27475716 TI - A novel real time imaging platform to quantify macrophage phagocytosis. AB - Phagocytosis of pathogens, apoptotic cells and debris is a key feature of macrophage function in host defense and tissue homeostasis. Quantification of macrophage phagocytosis in vitro has traditionally been technically challenging. Here we report the optimization and validation of the IncuCyte ZOOM(r) real time imaging platform for macrophage phagocytosis based on pHrodo(r) pathogen bioparticles, which only fluoresce when localized in the acidic environment of the phagolysosome. Image analysis and fluorescence quantification were performed with the automated IncuCyteTM Basic Software. Titration of the bioparticle number showed that the system is more sensitive than a spectrofluorometer, as it can detect phagocytosis when using 20* less E. coli bioparticles. We exemplified the power of this real time imaging platform by studying phagocytosis of murine alveolar, bone marrow and peritoneal macrophages. We further demonstrate the ability of this platform to study modulation of the phagocytic process, as pharmacological inhibitors of phagocytosis suppressed bioparticle uptake in a concentration-dependent manner, whereas opsonins augmented phagocytosis. We also investigated the effects of macrophage polarization on E. coli phagocytosis. Bone marrow-derived macrophage (BMDM) priming with M2 stimuli, such as IL-4 and IL-10 resulted in higher engulfment of bioparticles in comparison with M1 polarization. Moreover, we demonstrated that tolerization of BMDMs with lipopolysaccharide (LPS) results in impaired E. coli bioparticle phagocytosis. This novel real time assay will enable researchers to quantify macrophage phagocytosis with a higher degree of accuracy and sensitivity and will allow investigation of limited populations of primary phagocytes in vitro. PMID- 27475720 TI - Cervical myelopathy involving os odontoideum and retro-odontoid cyst treated with Harms C1-C2 arthrodesis. AB - An episode of acute decompensation of cervical myelopathy occurred after an injury without fracture of an os odontoideum associated with a compressive retro odontoid cyst. The 51-year-old female patient presented Frankel C, Nurick grade 4 neurological status and pyramid syndrome. The initial MRI demonstrated an intramedullary T2 hyperintense signal in the context of spinal cord narrowing. The retro-odontoid cyst demonstrates atlantoaxial instability related to the os odontoideum. Harms C1-C2 arthrodesis without laminectomy was performed and the cyst disappeared completely. Spinal cord decompression was thus obtained on the MRI taken 3 months later. Neurological recovery was complete and continued at 1 year. PMID- 27475719 TI - Ivacaftor and symptoms of extra-oesophageal reflux in patients with cystic fibrosis and G551D mutation. AB - BACKGROUND: Extra-oesophageal reflux (EOR) may lead to microaspiration in patients with cystic fibrosis (CF), a probable cause of deteriorating lung function. Successful clinical trials of ivacaftor highlight opportunities to understand EOR in a real world study. METHODS: Data from 12 patients with CF and the G551D mutation prescribed ivacaftor (150mg bd) was collected at baseline, 6, 26 and 52weeks. The changes in symptoms of EOR were assessed by questionnaire (reflux symptom index (RSI) and Hull airway reflux questionnaire (HARQ)). RESULTS: Six patients presented EOR at baseline (RSI >13; median 13; range 2-29) and 5 presented airway reflux (HARQ >13; median 12; range 3 to 33). Treatment with ivacaftor was associated with a significant reduction of EOR symptoms (P<0?04 versus baseline) denoted by the reflux symptom index and Hull airway reflux questionnaire. CONCLUSION: Ivacaftor treatment was beneficial for patients with symptoms of EOR, thought to be a precursor to microaspiration. PMID- 27475721 TI - Correlation between slow-wave myoelectric signals and mechanical contractions in the gastrointestinal tract: Advanced electromyographic method in rats. AB - AIM: Gastrointestinal motility disorders are presumed to be associated with abnormalities of the generation of slow-wave electric impulses. A requirement for the development of non-invasive clinical methods for the diagnosis of motility disorders is the identification of these signals. We set out to separate and characterize the signals from the various sections of the gastrointestinal tract and to detect changes in the smooth muscle electromyography (SEMG) signals. METHODS: Partially resected (stomach-small intestine, stomach-large intestine or small and large intestine) or non-resected male SPRD rats were measured under deep anaesthesia. Bipolar thread and disk electrodes and strain gauge sensors were used for SEMG and the detection of mechanical contractions, respectively. The electric activity was characterized by cycle per minute (cpm) and power spectrum density maximum (PsDmax) W by fast Fourier transformation analysis. Contractions were evaluated by area under the curve analysis. RESULTS: The myoelectric signals of the stomach, ileum and caecum were at 3-5, 20-25 and 1 3cpm, respectively. Neostigmine increased (40-60%), while atropine decreased (30 50%) the PsDmax values. However, the cpm values remained unchanged. Linear regression revealed a good correlation between the PsDmax values and the smooth muscle contractions. CONCLUSIONS: Electric signals of the same character were recorded from the organ and from the abdominal surface. The change in PsDmax perfectly reflects the change in the contractions of the smooth muscle. These results may serve as the basis for non-invasive gastrointestinal measurements in experimental animals, which can be translated into clinical practice for motility studies. PMID- 27475722 TI - Biliary cirrhosis secondary to bile duct obstruction by hamartomatous polyps in a patient with Peutz-Jeghers syndrome. Case Report. PMID- 27475723 TI - Comparative in vitro investigation of the cariogenic potential of bifidobacteria. AB - OBJECTIVE: This study aimed to assess the in vitro cariogenic potential of some Bifidobacterium species in comparison with caries-associated bacteria. DESIGN: Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium animalis, Bifidobacterium dentium, Lactobacillus acidophilus, Lactobacillus casei, Actinomyces israelii, Streptococcus sobrinus and Streptococcus mutans were tested for acidogenicity and aciduricity by measuring the pH of the cultures after growth in glucose and bacterial growth after exposure to acid solutions. Biofilm biomass was determined for each species either alone or associated with S. mutans or S. mutans/S. sobrinus. Enamel hardness was analyzed before and after 7-days biofilm formation using bacterial combinations. RESULTS: B. animalis and B. longum were the most acidogenic and aciduric strains, comparable to caries associated bacteria, such as S. mutans and L. casei. All species had a significantly increased biofilm when combined either with S. mutans or with S. mutans/S. sobrinus. The greatest enamel surface loss was produced when B. longum or B. animalis were inoculated with S. mutans, similar to L. casei and S. sobrinus. All strains induced similar enamel demineralization when combined with S. mutans/S. sobrinus, except by B. lactis. CONCLUSION: The ability to produce acidic environments and to enhance biofilm formation leading to increased demineralization may mean that Bifidobacterium species, especially B. animalis and B. longum, are potentially cariogenic. PMID- 27475725 TI - Quercetin reduces manic-like behavior and brain oxidative stress induced by paradoxical sleep deprivation in mice. AB - Quercetin is a known antioxidant and protein kinase C (PKC) inhibitor. Previous studies have shown that mania involves oxidative stress and an increase in PKC activity. We hypothesized that quercetin affects manic symptoms. In the present study, manic-like behavior (hyperlocomotion) and oxidative stress were induced by 24h paradoxical sleep deprivation (PSD) in male Swiss mice. Both 10 and 40mg/kg quercetin prevented PSD-induced hyperlocomotion. Quercetin reversed the PSD induced decrease in glutathione (GSH) levels in the prefrontal cortex (PFC) and striatum. Quercetin also reversed the PSD-induced increase in lipid peroxidation (LPO) in the PFC, hippocampus, and striatum. Pearson's correlation analysis revealed a negative correlation between locomotor activity and GSH in the PFC in sleep-deprived mice and a positive correlation between locomotor activity and LPO in the PFC and striatum in sleep-deprived mice. These results suggest that quercetin exerts an antimanic-like effect at doses that do not impair spontaneous locomotor activity, and the antioxidant action of quercetin might contribute to its antimanic-like effects. PMID- 27475724 TI - The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex. AB - The human dopamine D4 receptor (hD4R) variants with long tandem repeats in the third intracellular loop have been strongly associated with attention deficit hyperactivity disorder (ADHD) and risk taking behaviors. To understand the potential molecular mechanism underlying the connection, we have investigated the synaptic function of human D4R polymorphism by virally expressing the ADHD-linked 7-repeat allele, hD4.7, or its normal counterpart, hD4.4, in the prefrontal cortex (PFC) of D4R knockout mice. We found that hD4R bound to the SH3 domain of PSD-95 in a state-dependent manner. Activation of hD4.7 caused more reduction of NR1/PSD-95 binding and NR1 surface expression than hD4.4 in PFC slices. Moreover, the NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSC) in PFC pyramidal neurons were suppressed to a larger extent by hD4.7 than hD4.4 activation. Direct stimulation of NMDARs with the partial agonist d-cycloserine prevented the NMDAR hypofunction induced by hD4.7 activation. Moreover, hD4.7-expressing mice exhibited the increased exploratory and novelty seeking behaviors, mimicking the phenotypic hallmark of human ADHD. d-cycloserine administration ameliorated the ADHD-like behaviors in hD4.7-expressing mice. Our results suggest that over suppression of NMDAR function may underlie the role of hD4.7 in ADHD, and enhancing NMDAR signaling may be a viable therapeutic strategy to ADHD humans carrying the D4.7 allele. PMID- 27475726 TI - A ratiometric theranostic probe for tumor targeting therapy and self-therapeutic monitoring. AB - Feedback imaging-guided precise photodynamic therapy (PDT) can facilitate the development of personalized medicine. In this work, a Forster resonance energy transfer (FRET) based theranostic probe was fabricated for simultaneous tumor targeting PDT and ratiometric imaging of the therapeutic effect. The theranostic probe (designated as P-PpIX) was comprised of a targeting moiety, a caspase-3 responsive linker, a FRET fluorophore pair and a photosensitizer. It was found that P-PpIX exhibited low intrinsic background fluorescence due to the high FRET quenching efficiency. The Arg-Gly-Asp (RGD) targeting moiety allowed P-PpIX to selectively accumulate in alphavbeta3 integrin overexpressed tumor cells. Upon photo irradiation, the PDT effect of P-PpIX could induce cell death with apoptosis related mechanism, and the activated caspase-3 would subsequently cleave the Asp-Glu-Val-Asp (DEVD) peptide sequence to terminate the intramolecular FRET process. The activated caspase-3 expression and the real time therapeutic efficacy could be precisely assessed in situ by the fluorescence intensity ratio of the released 5(6)-carboxylfluorescein (FAM, reporter fluorescence) and protoporphyrin IX (PpIX, internal reference fluorescence). This novel ratiometric theranostic probe could provide the real-time feedback for precise PDT. PMID- 27475727 TI - Dual stimulation of antigen presenting cells using carbon nanotube-based vaccine delivery system for cancer immunotherapy. AB - Although anti-cancer immuno-based combinatorial therapeutic approaches have shown promising results, efficient tumour eradication demands further intensification of anti-tumour immune response. With the emerging field of nanovaccinology, multi walled carbon nanotubes (MWNTs) have manifested prominent potentials as tumour antigen nanocarriers. Nevertheless, the utilization of MWNTs in co-delivering antigen along with different types of immunoadjuvants to antigen presenting cells (APCs) has not been investigated yet. We hypothesized that harnessing MWNT for concurrent delivery of cytosine-phosphate-guanine oligodeoxynucleotide (CpG) and anti-CD40 Ig (alphaCD40), as immunoadjuvants, along with the model antigen ovalbumin (OVA) could potentiate immune response induced against OVA-expressing tumour cells. We initially investigated the effective method to co-deliver OVA and CpG using MWNT to the APC. Covalent conjugation of OVA and CpG prior to loading onto MWNTs markedly augmented the CpG-mediated adjuvanticity, as demonstrated by the significantly increased OVA-specific T cell responses in vitro and in C57BL/6 mice. alphaCD40 was then included as a second immunoadjuvant to further intensify the immune response. Immune response elicited in vitro and in vivo by OVA, CpG and alphaCD40 was significantly potentiated by their co incorporation onto the MWNTs. Furthermore, MWNT remarkably improved the ability of co-loaded OVA, CpG and alphaCD40 in inhibiting the growth of OVA-expressing B16F10 melanoma cells in subcutaneous or lung pseudo-metastatic tumour models. Therefore, this study suggests that the utilization of MWNTs for the co-delivery of tumour-derived antigen, CpG and alphaCD40 could be a competent approach for efficient tumours eradication. PMID- 27475728 TI - Bio-inspired in situ crosslinking and mineralization of electrospun collagen scaffolds for bone tissue engineering. AB - Bone disorders are the most common cause of severe long term pain and physical disability, and affect millions of people around the world. In the present study, we report bio-inspired preparation of bone-like composite structures by electrospinning of collagen containing catecholamines and Ca(2+). The presence of divalent cation induces simultaneous partial oxidative polymerization of catecholamines and crosslinking of collagen nanofibers, thus producing mats that are mechanically robust and confer photoluminescence properties. Subsequent mineralization of the mats by ammonium carbonate leads to complete oxidative polymerization of catecholamines and precipitation of amorphous CaCO3. The collagen composite scaffolds display outstanding mechanical properties with Young's modulus approaching the limits of cancellous bone. Biological studies demonstrate that human fetal osteoblasts seeded on to the composite scaffolds display enhanced cell adhesion, penetration, proliferation, differentiation and osteogenic expression of osteocalcin, osteopontin and bone matrix protein when compared to pristine collagen or tissue culture plates. Among the two catecholamines, mats containing norepinephrine displayed superior mechanical, photoluminescence and biological properties than mats loaded with dopamine. These smart multifunctional scaffolds could potentially be utilized to repair and regenerate bone defects and injuries. PMID- 27475729 TI - Associations between maternal exposure to air pollution and traffic noise and newborn's size at birth: A cohort study. AB - BACKGROUND: Maternal exposure to air pollution and traffic noise has been suggested to impair fetal growth, but studies have reported inconsistent findings. Objective To investigate associations between residential air pollution and traffic noise during pregnancy and newborn's size at birth. METHODS: From a national birth cohort we identified 75,166 live-born singletons born at term with information on the children's size at birth. Residential address history from conception until birth was collected and air pollution (NO2 and NOx) and road traffic noise was modeled at all addresses. Associations between exposures and indicators of newborn's size at birth: birth weight, placental weight and head and abdominal circumference were analyzed by linear and logistic regression, and adjusted for potential confounders. RESULTS: In mutually adjusted models we found a 10MUg/m(3) higher time-weighted mean exposure to NO2 during pregnancy to be associated with a 0.35mm smaller head circumference (95% confidence interval (CI): 95% CI: -0.57; -0.12); a 0.50mm smaller abdominal circumference (95% CI: 0.80; -0.20) and a 5.02g higher placental weight (95% CI: 2.93; 7.11). No associations were found between air pollution and birth weight. Exposure to residential road traffic noise was weakly associated with reduced head circumference, whereas none of the other newborn's size indicators were associated with noise, neither before nor after adjustment for air pollution. CONCLUSIONS: This study indicates that air pollution may result in a small reduction in offspring's birth head and abdominal circumference, but not birth weight, whereas traffic noise seems not to affect newborn's size at birth. PMID- 27475730 TI - Risk perception and access to environmental information in four areas in Italy affected by natural or anthropogenic pollution. AB - A human biomonitoring (HBM) survey in four areas affected by natural or anthropogenic arsenic pollution was conducted in Italy within the framework of the SEpiAs project. A questionnaire, including the exploration of risk perception (RP) regarding environmental hazards and access to and trust in information, was administered to 282 subjects stratified by area, gender and age. The survey was designed to investigate how populations living in polluted areas could adopt prevention-oriented habits, fostered by the awareness of existing risks and, in addition, how increased knowledge of RP and information flows could support researchers in identifying recommendations, and presenting and disseminating HBM results. This study characterizes the four areas in terms of RP and access to and trust in environmental information, and provides insights into the influence of RP and environmental information on food consumption. For the data analysis, a combined random forest (RF) and logistic regression approach was carried out. RF was applied to the variables derived from the questionnaire in order to identify the most important in terms of the aims defined. Associations were then tested using Fisher's exact test and assessed with logistic regression in order to adjust for confounders. Results showed that the perception of and personal exposure to atmospheric and water pollution, hazardous industries and waste, hazardous material transportation and waste was higher in geographical areas characterized by anthropogenic pollution. Citizens living in industrial areas appeared to be aware of environmental risks and had more confidence in environmental non-governmental organizations (NGOs) than in public authorities. In addition, they reported an insufficient circulation of information. Concerning the influence of RP and environmental information on food consumption, a high perception of personal exposure to atmospheric pollution and hazardous industries was associated with a lower consumption of local fish. In conclusion, different RPs and information flow patterns were observed in areas with arsenic of natural origin or in industrial contexts. These findings may be useful for targeted risk communication plans in support of risk-management strategies. PMID- 27475731 TI - Intraoperative Echocardiographic Assessment of Mitral Valve Area After Degenerative Mitral Valve Repair: A Call for Guidelines or Recommendations. PMID- 27475732 TI - Outcome Predictors in Patients Presenting With Acute Aortic Dissection. AB - OBJECTIVE: To investigate the role of thyroid hormones and other factors in acute aortic dissection and an association with in-hospital adverse events. DESIGN: A retrospective analysis. SETTING: A university-affiliated cardiac center. PARTICIPANTS: A total of 151 patients with aortic dissection admitted to the authors' hospital between January 2011 and May 2015. INTERVENTION: None. MEASUREMENTS AND RESULTS: The total in-hospital mortality rate was 12.6%. Triiodothyronine (T3) level was lower in nonsurviving than surviving patients (0.8+/-0.3 v 1.0+/-0.4 nmol/L, p<0.05). T3 independently predicted in-hospital mortality (hazard ratio [HR] 0.07, 95% CI 0.01-0.43, p<0.01) and in-hospital acute renal failure (HR 0.22, 0.05-0.89, p<0.05) for all patients. Other independent predictors of in-hospital mortality were pericardial effusion (HR 8.18, 2.11-31.67, p<0.01), conservative treatment (HR 82.12, 12.49-540.09, p<0.01) and Stanford type-A aortic dissection (HR 3.86, 1.06-14.09, p<0.05). Inpatient conservative treatment, T3 (HR 0.01, 0.00-0.18, p<0.01) as well as pericardial effusion (HR 11.80, 2.46-56.59, p<0.01), Stanford type-A dissection (HR 22.35, 3.15-158.40, p<0.01), and in-hospital acute renal failure (HR 16.95, 2.04-140.86, p<0.01) were predictors for in-hospital mortality. In nonconservatively treated patients, T3 (HR 0.02, 0.00-0.88, p<0.05) as well as cardiac care unit stay (HR 0.74, 0.59-0.94, p<0.01) and postoperative acute renal failure (HR 21.32, 3.07-147.88, p<0.01) were predictors for in-hospital mortality. CONCLUSION: T3 was downregulated in acute aortic dissection. Low T3 level was a risk factor for in-hospital death and acute renal failure in patients with acute aortic dissection. PMID- 27475733 TI - An Adjusted Calculation Model of Reduced Heparin Doses in Cardiopulmonary Bypass Surgery in a Chinese Population. AB - OBJECTIVE: To investigate the safety and efficacy of an adjusted regimen of heparin infusion in cardiopulmonary bypass (CPB) surgery in a Chinese population. DESIGN: Prospective, single-center, observational study. SETTING: University teaching hospital. PARTICIPANTS: Patients having cardiac surgery with CPB were selected for this study using the following criteria: 18 to 75 years of age, undergoing first-time cardiac surgery with conventional median sternotomy, aortic clamping time between 40 and 120 minutes, and preoperative routine blood tests showing normal liver, renal, and coagulation functions. The exclusion criteria include salvage cases, a history of coagulopathy in the family, and long-term use of anticoagulation or antiplatelet drugs. INTERVENTIONS: Sixty patients were divided randomly into a control group (n = 30) receiving a traditional heparin regimen and an experimental group (n = 30) receiving an adjusted regimen. MEASUREMENTS AND MAIN RESULTS: Activated coagulation time (ACT) was monitored at different time points, ACT>480 seconds was set as the safety threshold of CPB. Heparin doses (initial dose, added dose, and total dose), protamine doses (initial dose, added dose, and total dose), CPB time, aortic clamping time, assisted circulation time, sternal closure time, blood transfusion volume, and drainage volume 24 hours after surgery were recorded. There was no significant difference in achieving target ACT after the initial dose of heparin between the 2 groups; CPB time, aortic clamping time, assisted circulation time, postoperative complication rate, and drainage volume between the 2 groups were not significantly different (p>0.05). However, initial and total dosage of heparin, initial and total dosage of protamine, sternal closure time, and intraoperative blood transfusion volume in the experimental group were significantly lower (p< 0.05). CONCLUSIONS: Adjusted regimen of heparin infusion could be used safely and effectively in Chinese CPB patients, which might reduce the initial and total dosage of heparin and protamine as well as sternal closure time and intraoperative blood transfusion volume. PMID- 27475734 TI - Noninvasively Measured Hemoglobin Concentration Reflects Arterial Hemoglobin Concentration Before but Not After Cardiopulmonary Bypass in Patients Undergoing Coronary Artery or Valve Surgery. AB - OBJECTIVE: This study compared noninvasively measured hemoglobin and arterial hemoglobin before and after cardiopulmonary bypass in patients undergoing coronary artery or valve surgery. DESIGN: Observational study with retrospective data analysis. SETTING: Veterans Affairs hospital. PARTICIPANTS: Thirty-five men. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hemoglobin values were measured noninvasively by co-oximetry to corresponding arterial hemoglobin concentrations taken at clinically relevant time points chosen at the discretion of the cardiac anesthesiologist. Thirty-five and 27 pooled pairs of data were obtained before and after cardiopulmonary bypass, respectively. Arterial hemoglobin concentration was analyzed using i-STAT CG8+test cartridges routinely used in the authors' operating rooms and those of other institutions. Linear regression and Bland-Altman analysis revealed a significant positive bias, wide limits of agreement, and low correlation coefficients between the noninvasive and arterial hemoglobin measurements. These findings were especially notable after compared with before cardiopulmonary bypass. CONCLUSIONS: The results suggested that noninvasive measurement of hemoglobin overestimates arterial hemoglobin by almost 1 g/dL when compared to iSTAT. A lack of precision also was observed with noninvasive measurement of hemoglobin, especially after cardiopulmonary bypass. These findings supported the contention that sole reliance on noninvasive measurement of hemoglobin for transfusion decisions in cardiac surgery patients may be inappropriate. PMID- 27475735 TI - Alternation of circadian clock modulates forkhead box protein-3 gene transcription in CD4+ T cells in the intestine. PMID- 27475736 TI - Risk factors for lymph node metastasis in papillary thyroid microcarcinoma: Older patients with fewer lymph node metastases. AB - BACKGROUND: Lymph node metastasis (LNM) is an important consideration in treatment strategy selection for papillary thyroid microcarcinoma (PTMC). The aim of this study was to investigate the risk factors for LNM and high-volume LNM (hvLNM, >5 metastatic lymph nodes). METHODS: A consecutive series of 1226 PTMC (947 female, 279 male) patients was reviewed. All patients underwent at least central neck dissection. Clinical-pathological features were assessed. All patients were allocated into Group A (<=39 yrs), Group B (40-59 yrs), or Group C (>=60 yrs) for risk factor analysis. RESULTS: Among all patients, 438 LNM and 73 hvLNM were detected. Older patients had significantly fewer LNM (A: 51.45% of 346, B: 30.15% of 786, and C: 24.47% of 94) and fewer hvLNM (A: 11.85%, B: 3.94%, and C: 1.06%). Male, multifocality, and tumor diameter >0.5 cm were also correlated with LNM and hvLNM. In multivariate analysis, older patients had lower risk of LNM (odds ratio [OR] 0.389 in B, 0.305 in C), and chronic thyroiditis was protective factor for LNM (OR 0.524). Male (OR 1.651), tumor diameter >0.5 cm (OR 1.850), and multifocality (OR 1.928) were risk factors for LNM. Similarly, older patients had lower risk of hvLNM (OR 0.313 in B, OR 0.085 in C). Male (OR 2.590), tumor diameter >0.5 cm (OR 2.180), and multifocality (OR 1.980) were also risk factors for hvLNM. CONCLUSION: Older PTMC patients may have fewer LNM and lower risk of hvLNM. For patients >=60 years old, dynamic observation may be an option for clinical management. PMID- 27475737 TI - Rapid molecular determination of methicillin resistance in staphylococcal bacteraemia improves early targeted antibiotic prescribing: a randomized clinical trial. AB - Empiric therapy of methicillin-susceptible Staphylococcus aureus (MSSA) infections with vancomycin is associated with poorer outcome than targeted therapy with beta-lactams. Our objective was to evaluate whether rapid determination of methicillin resistance shortens the time from Gram stain to targeted antimicrobial therapy in staphylococcal bacteraemia, thereby reducing vancomycin overuse. This was a single-centre open parallel RCT. Gram-positive cocci in clusters in positive blood culture underwent real-time PCR for rapid species and methicillin resistance determination parallel to conventional microbiology. Patients were randomized 1:1 so that clinicians would be informed of PCR results (intervention group) or not (control group). Eighty-nine patients (intervention 48, control 41) were analysed. MRSA was identified in seven patients, MSSA in 46, and CoNS in 36. PCR results were highly concordant (87/89) with standard microbiology. Median time (hours) from Gram stain to transmission of methicillin-susceptibility was 3.9 (2.8-4.3) vs. 25.4 (24.4-26-7) in intervention vs. control groups (p <0.001). Median time (hours) from Gram stain to targeted treatment was similar for 'all staphylococci' [6 (3.8-10) vs. 8 (1 36) p 0.13] but shorter in the intervention group when considering S. aureus only [5 (3-7) vs. 25.5 (3.8-54) p <0.001]. When standard susceptibility testing was complete, 41/48 (85.4%) patients in the intervention group were already receiving targeted therapy compared with 23/41 (56.1%) in the control group (p 0.004). There was no significant effect on clinical outcomes. Rapid determination of methicillin resistance in staphylococcal bacteraemia is accurate and reduces significantly the time to targeted antibiotic therapy in the subgroup of S. aureus, thereby avoiding unnecessary exposure to vancomycin. PMID- 27475738 TI - Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteraemia: implications of daptomycin dose. AB - Treatment options for vancomycin-resistant enterococci (VRE) bloodstream infection are limited. Studies comparing daptomycin or linezolid in treating VRE bloodstream infection have conflicting results and suggest daptomycin underdosing. The responses to different daptomycin doses have not been studied. We conducted a multicentre prospective cohort study to compare linezolid and daptomycin (>=6 mg/kg) for the treatment of VRE bloodstream infection. The primary outcome was 14-day mortality. We used multivariate logistic regression analysis for outcome analysis and a generalized additive model for dose-dependent response estimation. Two hundred twelve patients were included (daptomycin, n = 141; linezolid, n = 71). All-cause 14-day mortality was higher in the daptomycin group (36.9% vs. 21.1%; p 0.03). After adjusting for confounders in logistic regression, mortality was lower in the linezolid group (adjusted odds ratio (aOR), 0.45; 95% confidence interval (CI), 0.21-0.96; p 0.04). The generalized additive model showed that higher-dose daptomycin (>=9 mg/kg) was associated with better survival than lower-dose daptomycin (6-9 mg/kg). Logistic regression showed that linezolid (aOR, 0.36; 95% CI, 0.17-0.79; p 0.01) and higher-dose daptomycin (aOR, 0.26; 95% CI, 0.09-0.74; p 0.01) independently predicted lower mortality compared to lower-dose daptomycin. Linezolid was not superior to higher dose daptomycin in terms of mortality (aOR, 1.40; 95% CI, 0.45-4.37; p 0.57). Higher-dose daptomycin had lower mortality than lower-dose daptomycin. Despite higher mortality for lower-dose daptomycin than linezolid, linezolid conferred no survival benefit compared to higher-dose daptomycin. Our findings suggest that the recommended daptomycin dose is suboptimal for treating VRE bacteraemia. PMID- 27475740 TI - Emerging fungi causing human infection: new or better identified? PMID- 27475739 TI - Surveillance of the Middle East respiratory syndrome (MERS) coronavirus (CoV) infection in healthcare workers after contact with confirmed MERS patients: incidence and risk factors of MERS-CoV seropositivity. AB - Given the mode of transmission of Middle East respiratory syndrome (MERS), healthcare workers (HCWs) in contact with MERS patients are expected to be at risk of MERS infections. We evaluated the prevalence of MERS coronavirus (CoV) immunoglobulin (Ig) G in HCWs exposed to MERS patients and calculated the incidence of MERS-affected cases in HCWs. We enrolled HCWs from hospitals where confirmed MERS patients had visited. Serum was collected 4 to 6 weeks after the last contact with a confirmed MERS patient. We performed an enzyme-linked immunosorbent assay (ELISA) to screen for the presence of MERS-CoV IgG and an indirect immunofluorescence test (IIFT) to confirm MERS-CoV IgG. We used a questionnaire to collect information regarding the exposure. We calculated the incidence of MERS-affected cases by dividing the sum of PCR-confirmed and serology-confirmed cases by the number of exposed HCWs in participating hospitals. In total, 1169 HCWs in 31 hospitals had contact with 114 MERS patients, and among the HCWs, 15 were PCR-confirmed MERS cases in study hospitals. Serologic analysis was performed for 737 participants. ELISA was positive in five participants and borderline for seven. IIFT was positive for two (0.3%) of these 12 participants. Among the participants who did not use appropriate personal protective equipment (PPE), seropositivity was 0.7% (2/294) compared to 0% (0/443) in cases with appropriate PPE use. The incidence of MERS infection in HCWs was 1.5% (17/1169). The seroprevalence of MERS-CoV IgG among HCWs was higher among participants who did not use appropriate PPE. PMID- 27475741 TI - Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV negative recipients with an anti-HBc-positive donor. AB - The overall rate of hepatitis B virus (HBV) reactivation was evaluated in a population of 373 haematological stem cell transplant (HSCT) patients treated with lamivudine (LMV) if they were anti-HBc-positive/HBV-DNA-negative recipients or if they were HBV-negative recipients with an anti-HBc-positive donor. The incidence of HBV reactivation was calculated in two groups of autologous (auto) or allogeneic (allo) HSCT patients who were stratified according to their HBV serostatus. The former group included 57 cases: 10 auto-HSCT and 27 allo-HSCT anti-HBc-positive recipients, two auto-HSCT and three allo-HSCT inactive carriers, and 15 allo-HSCT recipients with an anti-HBc-positive donor. Forty seven (82.4%) patients in this group received LMV prophylaxis (the median (interquartile range, IQR) of LMV treatment was 30 (20-38) months). The second group consisted of 320 anti-HBc-negative auto-HSCT and allo-HSCT recipients with anti-HBc-negative donors. None of these patients received any prophylaxis. Two patients in the first group and two in the second group experienced reactivation of HBV infection, with an incidence of 3.5% (95% CI 0.4-12.1%) and 0.6% (95% CI 0.1-2.2%), respectively. Only one out of four reactivated patients was LMV treated. The cumulative probability of HBV reactivation at 6 years from HSCT was 15.8% (95% CI 15.2-16.4%). Three of four viral isolates obtained from the HBV reactivated patients harboured mutations in the immune-active HBsAg-region. In a HSCT population carefully evaluated for HBV prophylaxis, a risk of HBV reactivation persisted in the group of patients who were not LMV-treated. Only one LMV-treated patient experienced reactivation of HBV with a resistant HBV isolate. PMID- 27475742 TI - Enhanced surveillance of carbapenemase-producing Gram-negative bacteria to support national and international prevention and control efforts. PMID- 27475743 TI - Comparison of the post-operative outcomes and survival of laparoscopic versus open resections for gastric gastrointestinal stromal tumors: A multi-center prospective cohort study. AB - BACKGROUND AND OBJECTIVES: Laparoscopic resection (LR) is increasingly performed for gastrointestinal stromal tumor (GIST). The aim of this study is to investigate the short-term outcomes and therapeutic effects of LR compared to open resection (OR) of gastric GISTs. METHODS: During 2009-2014, a prospective cohort of 200 patients with gastric GISTs indicated for resection underwent LR and OR procedures in three centers in Shanghai. Patient demographics, peri operative complications, and clinical outcomes were compared between the two groups. RESULTS: After exclusions, 176 patients who underwent gastric GIST resections were compared, of which 91 were laparoscopic, 85 were open. Compared to open surgery, laparoscopic resection of GIST has shorter operative time (102 vs. 172 min, p < 0.001), lower blood loss (100 vs 144 ml, p < 0.001), and shorter length of stay (9.1 vs. 15.3 d, p < 0.001). No statistical significant difference is observed for time to bowel function or semi-liquid diet, complications, recurrence rates, and mortality. CONCLUSION: LR is a safe and efficacious treatment for gastric GISTs, providing the advantages of shorter operative time, reduced blood loss, and shorter length of stay, all without compromising post operative outcomes and survival. PMID- 27475744 TI - Long-term surgical and seizure outcomes of frontal low-grade gliomas. AB - INTRODUCTION: Low-grade gliomas are infrequent lesions requiring special emphasis because of their relatively long follow-up time, and therefore the need for patients' well-being. Surgery provides not only increased survival but also improved quality of life for these patients. The purpose of this study was to present surgical series of frontal low-grade gliomas that were operated in our clinic and to discuss their epileptic and functional outcomes. METHODS: A series of 40 patients with low-grade glioma (WHO Grade II) were retrospectively analysed for patient characteristics, tumour location, epileptic history, surgery type (awake craniotomy, general anaesthesia), extent of resection and complications. RESULTS: Tumour was localized to primary motor area in most of the cases (35%, n = 14), 25 patients were operated under general anaesthesia and 15 with awake craniotomy. New deficit rate in the early postoperative period was 32.5% (dysarthria in one patient and motor deficits in 12). Karnofsky scores were >=90 in 92.5% of the patients at the late follow-up. 31 patients were Engel I (77.5%), 5 were Engel II (12.5%) and 4 were Engel IV (10%) postoperatively. CONCLUSION: Frontal LGGs are eligible to resect vigorously without persistent functional deficits. Patients with immediate postoperative complications benefit from neuro rehabilitation. However, pre-existing speech dysfunctions are hard to recover with surgery. Surgical resection ends with favourable epileptic outcomes whereas tumour location may influence the results. PMID- 27475745 TI - Comparison of mortality rates and functional results after transtibial and transfemoral amputations due to diabetes in elderly patients-a retrospective study. AB - INTRODUCTION: This study aimed to compare mortality rates and functional results of transtibial and transfemoral amputations in elderly patients with diabetes. METHODS: 87 amputees [54 (62.1%) transtibial and 33 (37.9%) transfemoral] were included. Mean ages were 70.7 and 69.3 years in transfemoral and transtibial groups, respectively. Mean follow up time was 41.8 months. Amputee Mobility Predictor scores (with and without prosthesis) and Barthel Daily Living Index were used for functional evaluation of the survivors. RESULTS: First year mortality rates were 29.6% and 30.3% in transtibial and transfemoral groups, respectively. Overall mortality rate of both groups was 65.5% (66.7% in transtibial and 63.6% in transfemoral group). There was no difference between mortality rates of two groups. Duration between surgery and death was significantly shorter in transfemoral group. The mean Amputee Mobility Predictor scores (with prosthesis) of the transtibial and transfemoral groups were 32.3 and 26.9 points, respectively. The average Amputee Mobility Predictor scores (without prosthesis) of the transtibial and transfemoral groups were 29.5 and 22.7 points respectively. The differences between two groups' scores were significant. The mean Barthel Daily Living Index scores of the transtibial and transfemoral groups were 82.5 and 80.2 points respectively. The difference was not significant. CONCLUSIONS: High mortality rates and morbidities after major lower limb amputations emphasize the importance of preventive measures and foot care in patients with diabetes. PMID- 27475746 TI - Cytologic follow up of Low-grade Squamous Intraepithelial Lesions in Pap smears after integrated treatment with antimicrobials followed by oral turmeric oil extract. AB - Cervical cancer is preventable because the carcinogenesis is slow and there are opportunities to detect precancerous lesions by Papanicolaou (Pap) smears, colposcopy, or HPV DNA tests and to treat them by antimicrobials, surgery or cold CO2 vapourization. We have earlier reported on the chemopreventive potential of integrated treatment with antimicrobials therapy followed by a standardized oral Turmeric Oil (TO) extract upto 12 weeks in women who had persistent Low-grade Squamous Intra-epithelial Lesion (LSIL) in their Pap smears. In this communication we report their post-therapy follow up for 36 months (N = 18) with Pap smears. We were also able to follow up for 36 months control cases (N = 10) who had only standard therapy with antimicrobials. During 36 months of follow up none of the cases with integrated treatment, progressed to HSIL or cancer. Out of 15/18 cases which had a regression of Pap smear, all 15 remained free of LSIL from 6 to 36 months post-therapy showing persistent therapeutic effect of integrated therapy. In one case there was recurrence of LSIL in Pap smear, ten months post-therapy, which regressed to mild atypia after a second course of oral TO for 8 weeks. In the control group, persistence of LSIL after antimicrobials was observed in Pap smears in 5/10 cases when followed up by Pap smears up to 36 months. This preliminary report indicates some post-therapeutic benefit with integrative treatment as compared to the use of antimicrobials alone. A large scale controlled study is warranted. PMID- 27475748 TI - 'Mainstreaming of Ayurveda' essay competition at 24th Prof P K Devi memorial oration function. PMID- 27475747 TI - Effect of yoga based techniques on stress and health indices using electro photonic imaging technique in managers. AB - BACKGROUND: Meditation techniques are known to elicit relaxation response in which moving meditation which combines the practice of yoga postures and guided relaxation is known as Cyclic Meditation reported helpful in reducing the sympathetic arousal and improving health of practitioners. OBJECTIVES: The objective of this study was to investigate the effect of Cyclic Meditation on stress and health indices in managers as measured by Electro Photonic Imaging (EPI) technique. MATERIALS AND METHODS: EPI technique was used to assess participants before and after 35 min of Cyclic Meditation (CM) and equal duration of Supine Rest (SR) session. A total of sixty six male managers, age ranges from 35 to 60 years (mean +/- SD 53.97 +/- 5.96) were included in the study. EPI parameters, including Activation Coefficient, Integral Area left and right and Integral Entropy, left and right were taken for statistical analyses. RESULTS: Cyclic Meditation has produced a highly significant reduction in stress level, whereas this reduction was not found significant within SR group. There was a significant improvement in health index 'Integral Area' values in both left and right sides within the CM group while only IA right side showed a significant improvement within the CM group. The integral entropy value right side decreased significantly within the CM group, whereas IE left was found deteriorated within the SR group. Moreover, only IE left side has shown a significant difference between the groups. CONCLUSION: The investigations in this study suggest that Cyclic Meditation practice reduces stress and improves psychosomatic health indices more effectively than Supine Rest in managers. PMID- 27475750 TI - IDACstar: A MCNP Application to Perform Realistic Dose Estimations from Internal or External Contamination of Radiopharmaceuticals. AB - A Monte Carlo-based stand-alone program, IDACstar (Internal Dose Assessment by Computer), was developed, dedicated to perform radiation dose calculations using complex voxel simulations. To test the program, two irradiation situations were simulated, one hypothetical contamination case with 600 MBq of 99mTc and one extravasation case involving 370 MBq of 18F-FDG. The effective dose was estimated to be 0.042 mSv for the contamination case and 4.5 mSv for the extravasation case. IDACstar has demonstrated that dosimetry results from contamination or extravasation cases can be acquired with great ease. An effective tool for radiation protection applications is provided with IDACstar allowing physicists at nuclear medicine departments to easily quantify the radiation risk of stochastic effects when a radiation accident has occurred. PMID- 27475749 TI - Association between Staphylococcus aureus nasal carriage and disease phenotype in patients affected by systemic lupus erythematosus. AB - BACKGROUND: Staphylococcus aureus (SA) is a commensal bacterium representing one of the most important components of the skin microbiome, mostly isolated in the anterior nares. A higher rate of SA nasal colonization in patients affected by Wegener's granulomatosis and rheumatoid arthritis compared with healthy subjects (HS) has been described. No studies focusing on systemic lupus erythematosus (SLE) are available. We aimed at analyzing the prevalence of SA nasal carriers in an SLE cohort and evaluating correlation between nasal colonization and clinical, laboratory and therapeutic features. METHODS: We enrolled 84 patients with SLE (number of male/female patients 6/78; mean age 41.3 +/- 12.2 years, mean disease duration 142.1 +/- 103.8 months) and 154 HS blood donors. Patients with SLE underwent a physical examination and the clinical/laboratory data were collected. All the patients with SLE and the HS received a nasal swab for SA isolation and identification. RESULTS: SA nasal colonization prevalence was 21.4 % in patients with SLE and 28.6 % in HS (P not significant). We analyzed patients with SLE according to the presence (n = 18, SA-positive SLE) or the absence (n = 66, SA negative SLE) of nasal colonization. Renal involvement was significantly more frequent in SA-positive SLE (11.6 % vs 3.0 %; P = 0.0009). Moreover, the presence of anti-dsDNA, anti-Sm, anti-SSA, anti-SSB, anti-RNP antibodies was significantly higher in SA-positive SLE (P < 0.0001, P = 0.01, P = 0.008, P = 0.03, P = 0.03, respectively). CONCLUSION: SA colonization is a relatively frequent condition in patients with SLE, with a frequency similar to HS. The presence of SA seems associated with a peculiar SLE phenotype characterized by renal manifestations and autoantibody positivity, confirming the role of the microbiome in disease phenotype. PMID- 27475751 TI - Risk Analysis as Regulatory Science: Toward The Establishment of Standards. AB - Understanding how to establish standards is essential for risk communication and also provides perspectives for further study. In this paper, the concept of risk analysis as regulatory science for the establishment of standards is demonstrated through examples of standards for evacuation and provisional regulation values in foods and drinking water. Moreover, academic needs for further studies related to standards are extracted. The concepts of the traditional 'Standard I', which has a paternalistic orientation, and 'Standard II', established through stakeholder consensus, are then systemized by introducing the current status of the new standards-related movement that developed after the Fukushima nuclear power plant accident, and the perspectives of the standards are discussed. Preparation of standards on the basis of stakeholder consensus through intensive risk dialogue before a potential nuclear power plant accident is suggested to be a promising approach to ensure a safe society and enhance subjective well-being. PMID- 27475752 TI - The efficacy of nudge theory strategies in influencing adult dietary behaviour: a systematic review and meta-analysis. AB - BACKGROUND: Obesity has become a world-wide epidemic and is spreading to countries with emerging economies. Previously tested interventions are often too costly to maintain in the long term. This leaves a need for improved strategies for management of the epidemic. Nudge Theory presents a new collection of methods, deemed "nudges", which have the potential for low-cost and broad application to guide healthier lifestyle choices without the need for restrictive regulation. There has not yet been a large-scale examination of the effectiveness of nudges, despite several policy making bodies now considering their use. METHODS: To address this gap in knowledge, an adapted systematic review methodology was used to collect and consolidate results from current Nudge papers and to determine whether Nudge strategies are successful in changing adults' dietary choices for healthier ones. RESULTS: It was found that nudges resulted in an average 15.3 % increase in healthier dietary or nutritional choices, as measured by a change in frequency of healthy choices or a change in overall caloric consumption. All of the included studies were from wealthy nations, with a particular emphasis on the United States with 31 of 42 included experiments. CONCLUSIONS: This analysis demonstrates Nudge holds promise as a public health strategy to combat obesity. More research is needed in varied settings, however, and future studies should aim to replicate previous results in more geographically and socioeconomically diverse countries. PMID- 27475753 TI - Safety and efficacy of pregabalin in adolescents with fibromyalgia: a randomized, double-blind, placebo-controlled trial and a 6-month open-label extension study. AB - BACKGROUND: Fibromyalgia (FM) is a common pain condition characterized by widespread musculoskeletal pain and tenderness. Pregabalin is an approved treatment for adults in the United States, but there are no approved treatments for adolescents with FM. METHODS: This was a 15-week, randomized, double-blind, placebo-controlled study and 6-month open-label safety trial of flexible-dose pregabalin (75-450 mg/day) for the treatment of adolescents (12-17 years) with FM. Primary outcome was change in mean pain score at endpoint (scored from 0-10, with 24-h recall). Secondary outcomes included global assessments and measures of pain, sleep, and FM impact. RESULTS: A total of 107 subjects were randomized to treatment (54 pregabalin, 53 placebo) and 80 completed the study (44 pregabalin, 36 placebo). Improvement in mean pain score at endpoint with pregabalin versus placebo was not statistically significant, treatment difference (95 % CI), -0.66 (-1.51, 0.18), P = 0.121. There were significant improvements with pregabalin versus placebo in secondary outcomes of change in pain score by week (P < 0.05 for 10 of 15 weeks); change in pain score at week 15 (1-week recall), treatment difference (95 % CI), -0.87 (-1.68, -0.05), P = 0.037; and patient global impression of change, 53.1 % versus 29.5 % very much or much improved (P = 0.013). Trends toward improvement with pregabalin in other secondary outcomes measuring pain, sleep, and FM impact were not significant. Safety was consistent with the known profile of pregabalin in adults with FM. CONCLUSION: Pregabalin did not significantly improve the mean pain score in adolescents with FM. There were significant improvements in secondary outcomes measuring pain and impression of change. TRIAL REGISTRATIONS: NCT01020474 ; NCT01020526 . PMID- 27475754 TI - The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. AB - BACKGROUND: The human gut is the habitat for diverse and dynamic microbial ecosystem. The human microbiota plays a critical role in functions that sustain health and is a positive asset in host defenses. Establishment of the human intestinal microbiota during infancy may be influenced by multiple factors including delivery mode. Present review compiles existing evidences on the effect of delivery mode on the diversity and colonization pattern of infants gut microbiota. METHODS: Two investigators searched for relevant scientific publications from four databases (Pubmed, Medline, Embase, and Web of Science). The last search was performed on September 21, 2015, using key terms ((delivery mode OR caesarean delivery OR cesarean section OR vaginal delivery) AND (gut microbiota OR gut microbiome OR gut microflora OR intestinal microflora OR microbial diversity) AND (infants OR children)). All included studies described at least two types of gut microbiota in relation to delivery mode (caesarean section vs vaginal delivery) and used fecal samples to detect gut microbiota. RESULTS: Seven out of 652 retrieved studies met inclusion criteria, were included in systematic analysis. Caesarean Section (CS) was associated with both lower abundance and diversity of the phyala Actinobacteria and Bacteroidetes, and higher abundance and diversity of the phylum Firmicute from birth to 3 months of life. At the colonization level, Bifidobacterium, and Bacteroides genera seems to be significantly more frequent in vaginally delivered infants compared with CS delivered. These infants were more colonized by the Clostridium, and Lactobacillus genera. From the reports, it is tempting to say that delivery mode has less effect on colonization and diversity of Bifidobacteria, Bacteroides, Clostridium, and Lactobacillus genera from the age of 6 to 12 months of life. CONCLUSION: The diversity and colonization pattern of the gut microbiota were significantly associated to the mode of delivery during the first three months of life, however the observed significant differences disappears after 6 months of infants life. The healthy gut microbiota is considered to promote development and maturation of the immune system while abnormal gut is considered as the major cause of severe gastrointestinal infections during the infancy. Further studies should investigate the diversity and colonization levels of infant gut microbiota in relation to the mode of delivery and its broad impact on infants' health at each stage of life. PMID- 27475755 TI - A global assessment of the gender gap in self-reported health with survey data from 59 countries. AB - BACKGROUND: While surveys in high-income countries show that women generally have poorer self-reported health than men, much less is known about gender differences in other regions of the world. Such data can be used to examine the determinants of sex differences. METHODS: We analysed data on respondents 18 years and over from the World Health Surveys 2002-04 in 59 countries, which included multiple measures of self-reported health, eight domains of functioning and presumptive diagnoses of chronic conditions. The age-standardized female excess fraction was computed for all indicators and analysed for five regional groups of countries. Multivariate regression models were used to examine the association between country gaps in self-reported health between the sexes with societal and other background characteristics. RESULTS: Women reported significantly poorer health than men on all self-reported health indicators. The excess fraction was 15 % for the health score based on the eight domains, 28 % for "poor" or "very poor" self rated health on the single question, and 26 % for "severe" or "extreme" on a single question on limitations. The excess female reporting of poorer health occurred at all ages, but was smaller at ages 60 and over. The female excess was observed in all regions, and was smallest in the European high-income countries. Women more frequently reported problems in specific health domains, with the excess fraction ranging from 25 % for vision to 35 % for mobility, pain and sleep, and with considerable variation between regions. Angina, arthritis and depression had female excess fractions of 33, 32 and 42 % respectively. Higher female prevalence of the presumptive diagnoses was observed in all regional country groups. The main factors affecting the size of the gender gap in self reported health were the female-male gaps in the prevalence of chronic conditions, especially arthritis and depression and gender characteristics of the society. CONCLUSIONS: Large female-male differences in self-reported health and functioning, equivalent to a decade of growing older, consistently occurred in all regions of the world, irrespective of differences in mortality levels or societal factors. The multi-country study suggests that a mix of biological factors and societal gender inequalities are major contributing factors to gender gap in self-reported measures of health. PMID- 27475757 TI - Blood biomarkers in psychiatry. PMID- 27475756 TI - Association of TAS2R38 variants with sweet food intake in children aged 1-6 years. AB - We aimed at studying whether genetic variants of the TAS2R38 gene are associated with energy intake from sweet tasting foods, total energy and macronutrient intake and body weight in children. Children (n = 691) from five European countries were genotyped for the first variant site rs713598 of the TAS2R38 bitter receptor gene. Three-day dietary records were obtained yearly from one to six years of age. Foods were categorized in sweet and non-sweet-tasting. Mixed models were used to describe group differences in food and nutrient intake and BMI z-score over time. TAS2R38 genotype was related to energy intake from sweet tasting foods: Children with PP and PA genotype consumed an average 83 kJ/d (95% CI 21 to 146; p = 0.009) more sweet tasting foods than children with AA genotype and a mean 56 kJ/d (95% CI 15 to 98; p = 0.007) more energy from energy dense sweet products. Intake of sweet tasting foods was lower in girls than boys and differed between countries. TAS2R38 genotype was not associated with the intake of energy, macronutrients, sugar, single food groups and BMI z-score. Despite many other factors influencing food preference and intake in children, actual intake of sweet food items is associated with TAS2R38 genotype. Children with PP or PA genotype consume more (energy dense) sweet tasting foods. PMID- 27475758 TI - Bringing together pharmacological and psychological approaches to mental health research. PMID- 27475759 TI - Integrating mental health simulation into routine health-care education. PMID- 27475760 TI - Does folic acid interfere with lamotrigine? PMID- 27475761 TI - Does folic acid interfere with lamotrigine? - Authors' reply. PMID- 27475762 TI - Building bridges for integrative medicine. PMID- 27475763 TI - Top 10 research priorities for eating disorders. PMID- 27475764 TI - Investment in mental health services urgently needed in Nepal. PMID- 27475766 TI - Shubulade Smith: seeing the bigger picture. PMID- 27475767 TI - Ways of escape. PMID- 27475768 TI - Another soul to cling to. PMID- 27475770 TI - Suicide and poverty in low-income and middle-income countries: a systematic review. AB - Suicide is the 15th leading cause of death worldwide, with over 75% of suicides occurring in low-income and middle-income countries. Nonetheless, evidence on the association between suicide and poverty in low-income and middle-income countries is scarce. We did a systematic review to understand the association between suicidal ideations and behaviours and economic poverty in low-income and middle income countries. We included studies testing the association between suicidal ideations and behaviours and economic poverty in low-income and middle-income countries using bivariate or multivariate analysis and published in English between January, 2004, and April, 2014. We identified 37 studies meeting these inclusion criteria. In 18 studies reporting the association between completed suicide and poverty, 31 associations were explored. The majority reported a positive association. Of the 20 studies reporting on the relationship between non fatal suicidal ideations and behaviours and poverty, 36 associations were explored. Again, almost all studies reported a positive association. However, when considering each poverty dimension separately, we found substantial variations. These findings show a consistent trend at the individual level indicating that poverty, particularly in the form of worse economic status, diminished wealth, and unemployment is associated with suicidal ideations and behaviours. At the country level, there are insufficient data to draw clear conclusions. Available data show a potential benefit in addressing economic poverty within suicide prevention strategies, with particular attention to both chronic poverty and acute economic events. PMID- 27475771 TI - Prediction of FAD binding sites in electron transport proteins according to efficient radial basis function networks and significant amino acid pairs. AB - BACKGROUND: Cellular respiration is a catabolic pathway for producing adenosine triphosphate (ATP) and is the most efficient process through which cells harvest energy from consumed food. When cells undergo cellular respiration, they require a pathway to keep and transfer electrons (i.e., the electron transport chain). Due to oxidation-reduction reactions, the electron transport chain produces a transmembrane proton electrochemical gradient. In case protons flow back through this membrane, this mechanical energy is converted into chemical energy by ATP synthase. The convert process is involved in producing ATP which provides energy in a lot of cellular processes. In the electron transport chain process, flavin adenine dinucleotide (FAD) is one of the most vital molecules for carrying and transferring electrons. Therefore, predicting FAD binding sites in the electron transport chain is vital for helping biologists understand the electron transport chain process and energy production in cells. RESULTS: We used an independent data set to evaluate the performance of the proposed method, which had an accuracy of 69.84 %. We compared the performance of the proposed method in analyzing two newly discovered electron transport protein sequences with that of the general FAD binding predictor presented by Mishra and Raghava and determined that the accuracy of the proposed method improved by 9-45 % and its Matthew's correlation coefficient was 0.14-0.5. Furthermore, the proposed method enabled reducing the number of false positives significantly and can provide useful information for biologists. CONCLUSIONS: We developed a method that is based on PSSM profiles and SAAPs for identifying FAD binding sites in newly discovered electron transport protein sequences. This approach achieved a significant improvement after we added SAAPs to PSSM features to analyze FAD binding proteins in the electron transport chain. The proposed method can serve as an effective tool for predicting FAD binding sites in electron transport proteins and can help biologists understand the functions of the electron transport chain, particularly those of FAD binding sites. We also developed a web server which identifies FAD binding sites in electron transporters available for academics. PMID- 27475772 TI - Ecologically optimizing exercise maintenance in men and women post-cardiac rehabilitation: Protocol for a randomized controlled trial of efficacy with economics (ECO-PCR). AB - BACKGROUND: Exercise-based cardiac rehabilitation (CR) participation results in increased cardio-metabolic fitness, which is associated with reduced mortality. However, many graduates fail to maintain exercise post-program. ECO-PCR investigates the efficacy and cost-effectiveness of a social ecologically-based intervention to increase long-term exercise maintenance following the completion of CR. METHODS/DESIGN: A three-site, 2-group, parallel randomized controlled trial is underway. 412 male and 192 female (N=604) supervised CR participants are being recruited just before CR graduation. Participants are randomized (1:1 concealed allocation) to intervention or usual care. A 50-week exercise facilitator intervention has been designed to assist CR graduates in the transition from structured, supervised exercise to self-managed home- or community-based (e.g., Heart Wise Exercise programs) exercise. The intervention consists of 8 telephone contacts over the 50week period: 3 individual and 5 group. Assessments occur at CR graduation, and 26, 52 and 78weeks post randomization. The primary outcome is change in minutes of accelerometer-measured moderate to vigorous-intensity physical activity (MVPA) from CR graduation to 52weeks post-randomization. Secondary measures include exercise capacity, quality of life, and cardiovascular risk factors. Analyses will be undertaken based on intention-to-treat. For the primary outcome, an analysis of variance will be computed to test the change in minutes of MVPA in each group between CR graduation and 52week follow-up (2 [arm]*2 [time]). Secondary objectives will be assessed using mixed-model repeated measures analyses to compare differences between groups over time. Mean costs and quality-adjusted life years for each arm will be estimated. PMID- 27475769 TI - Neurobiology of addiction: a neurocircuitry analysis. AB - Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction. PMID- 27475773 TI - Serum vitamin D levels decrease in children with acute urticaria. AB - BACKGROUND: Acute urticaria is an immune-inflammatory disease, characterised by acute immune activation. There has been increasing evidence showing that vitamin D deficiency is associated with increased incidence and severity of immune inflammatory disorders. OBJECTIVE: The aim of this study was to evaluate serum vitamin D levels in acute urticaria. METHODS: We enrolled 30 children with acute urticaria and 30 control subjects. Concentrations of 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D status, were measured in serum of acute urticaria patients and compared with the control group. RESULTS: There were no significant differences in baseline variables (age, gender, weight) between the groups. Vitamin D deficiency (<20ng/ml) was significantly higher in patients with acute urticaria than in control patients. Serum 25(OH)D levels were significantly lower in the study group compared to those in the control group (13.1+/-4.3 vs 28.2+/-7.4ng/mL, p<0.05). Moreover, we found negative correlation between mean duration of acute urticaria and serum vitamin D levels (p<0.01). CONCLUSION: This study revealed a significant association of lower serum 25(OH)D concentrations with acute urticaria and an inverse relationship with disease duration. These findings may open up the possibility of the clinical use of vitamin D as a contributing factor in the pathogenesis of acute urticaria and a predictive marker for disease activity in acute urticaria. A potential role of vitamin D in pathogenesis and additive therapy in acute urticaria needs to be examined. PMID- 27475774 TI - Prevalence and factors associated to peanut allergy in Mexican school children. AB - BACKGROUND: In our country, the prevalence and the factors associated to peanut allergy are unknown, a health problem that has been emerging worldwide. OBJECTIVE: To establish the prevalence and the factors that are associated to peanut allergy amongst school children. METHODS: This is a population-based cross sectional study. We included 756 children aged 6-7 years. The children's parents were questioned about their peanut intake habits. A structured questionnaire was applied, it included questions regarding peanut intake; family and personal history of asthma; rhinitis; and atopic dermatitis. Allergic reactions to peanuts were registered as: probable, convincing and systematic. The statistical analyses included logistical regression models to look for associated factors. RESULTS: Males were 356/756 (47.1%). Peanut allergy prevalence: probable reaction: 14/756 (1.8%), convincing reaction: 8/756 (1.1%) and systemic reaction: 3/756 (0.4%). Through multivariate analysis, the presence of symptoms of allergic rhinitis (OR=4.2 95% CI 1.3-13.2) and atopic dermatitis (OR=5.2; 95% CI 1.4-19.5) during the previous year, showed significant association to probable peanut reaction. The former year, the presence of atopic dermatitis was the only variable that was substantially associated to a convincing reaction (OR=7.5; 95% CI 1.4-38.4) and to a systematic reaction (OR=45.1; 95% CI 4.0-510.0), respectively. CONCLUSIONS: The reported prevalence of peanut allergy was consistent with that found in previous studies; symptoms of allergic rhinitis and atopic dermatitis were identified as associated factors to peanut allergy. PMID- 27475775 TI - Non-steroidal anti-inflammatory drug hypersensitivity in children. AB - INTRODUCTION: There are rather few publications about hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAID) in the paediatric age. In this study, we aimed to assess the frequency of confirmed NSAID hypersensitivity in children with a previous reported reaction to NSAID in order to investigate the role of the drug provocation test (DPT) in the diagnostic workup and to explore the factors associated with confirmed NSAID hypersensitivity. METHODS: We conducted a retrospective analysis of the clinical files from every patient under 18 years old who attended two Portuguese paediatric allergy outpatient clinics, from January 2009 to August 2014, due to a suspected NSAID hypersensitivity. RESULTS: We included 119 patients, with a median age of nine years (P25-P75: 5 14). Ibuprofen was the commonest implicated NSAID in the patients' reports (n=94 79%). After DPT, NSAID hypersensitivity was confirmed in nine (7.6%) patients, excluded in 93 (78.2%) and was inconclusive in 17 (14.3%). In the majority (n=95 79.8%), the reaction occurred in the first 24h after intake. Eighty-four patients (70.6%) reported only cutaneous manifestations and 18 (15.1%) had systemic symptoms. Anaphylaxis represented a relative risk to NSAID hypersensitivity confirmation. No association was found for atopy and the number of previous reactions. CONCLUSION: In our study, NSAID hypersensitivity was confirmed in a small proportion of the patients with a previous reported reaction. Ibuprofen was the most implicated drug with urticaria/angio-oedema as the commonest manifestation. Anaphylaxis was associated with confirmed drug hypersensitivity. The drug provocation test was essential to establish the diagnosis. PMID- 27475776 TI - Parent-reported prevalence of food allergy in Mexican schoolchildren: A population-based study. AB - BACKGROUND: Food allergy (FA) prevalence is well documented in developed countries and appears to be increasing, but remains unknown in most Latin American countries. We aimed to evaluate on a population basis the parent reported prevalence of FA and its clinical characteristics in Mexican schoolchildren. METHODS: A validated Spanish version of a structured written questionnaire was administered to parents of schoolchildren aged 5-13 years old from Culiacan, Mexico. RESULTS: A total of 1049 parents responded to the survey (response rate, 84%). The estimated prevalence rates (95% CI) were: adverse food reactions 10.0% (8.3-11.9), "perceived FA, ever" 5.5% (4.3-7.0), "physician diagnosed FA, ever" 4.9% (3.7-6.3), "immediate-type FA, ever" 4.4% (3.3-5.8), "immediate-type FA, current" 3.5% (2.6-4.8), and anaphylaxis 1.2% (0.72-2.1). Immediate hypersensitivity reactions were mainly triggered by the consumption of shrimp (1.3%), other shellfish (0.7%), strawberry (0.6%), chocolate (0.5%), and egg (0.4%). Schoolchildren with "immediate-type FA, current" had more atopic dermatitis and allergic rhinitis (p<0.05), but not asthma or drug allergy (p>0.05) than children without FA. All cases of anaphylaxis sought medical attention, but only one child had physician-diagnosed anaphylaxis and was advised to acquire an epinephrine autoinjector. CONCLUSIONS: The prevalence of "immediate type FA, current" to any food is 3.5% in Mexican schoolchildren. The poor recognition of anaphylaxis and the low frequency of prescription of epinephrine autoinjectors suggest that acute food-induced allergic reactions are not optimally managed in Mexico. PMID- 27475777 TI - The school as a health promoter for children with asthma: The purpose of an education programme. AB - BACKGROUND: Not only is asthma one of the leading causes of hospitalisation in children under 15 years and one of the main reasons for primary care outpatient visits, it also accounts for 13 million lost days of school annually, which can affect children's learning, integration at school and overall academic achievements. MATERIAL AND METHODS: This review article highlights the important role of the school in helping children and adolescents to control and manage their asthma through integrated and coordinated actions of health professionals, school staff, family, and the community. RESULTS: We recommended key elements for a multidisciplinary team asthma school programme that can be replicated and implemented especially in developing countries where children and adolescents are in a more disadvantaged environment. CONCLUSION: This multidisciplinary asthma school intervention when demonstrated with efficacy can be applied in the context of the real world, where many children and families who need care the most currently do not receive it. PMID- 27475778 TI - DNA melting properties of the dityrosine cross-linked dimer of Ribonuclease A. AB - Several DNA binding proteins exist in dimeric form when bound with DNA to be able to exhibit various biological processes such as DNA repair, DNA replication and gene expression. Various dimeric forms of Ribonuclease A (RNase A) and other members of the ribonuclease A superfamily are endowed with a multitude of biological activities such as antitumor and antiviral activity. In the present study, we have compared the DNA binding properties between the RNase A monomer and the dityrosine (DT) cross-linked RNase A dimer, and checked the inhibitory effect of DNA on the ribonucleolytic activity of the dimeric protein. An agarose gel based assay shows that like the monomer, the dimer also binds with DNA. The number of nucleotides bound per monomer unit of the dimer is higher than the number of nucleotides that bind with the each monomer. From fluorescence measurements, the association constant (Ka) values for complexation of the monomer and the dimer with ct-DNA are (4.95+/-0.45)*10(4)M(-1) and (1.29+/ 0.05)*10(6)M(-1) respectively. Binding constant (Kb) values for the binding of the monomer and the dimer with ct-DNA were determined using UV-vis spectroscopy and were found to be (4.96+/-1.67)*10(4)M(-1) and (4.32+/-0.31)*10(5)M(-1) respectively. Circular dichroism studies shows that the dimer possesses significant effect on DNA conformation. The melting profile for the ct-DNA-dimer indicated that the melting temperature (Tm) for the ct-DNA-dimer complex is lower compared to the ct-DNA-monomer complex. The ribonucleolytic activity of the dimer, like the monomer, diminishes upon binding with DNA. PMID- 27475779 TI - Cobalt(III) complexes as potential anticancer agents: Physicochemical, structural, cytotoxic activity and DNA/protein interactions. AB - Cobalt(III) complexes (1-3) such as [Co(acac)(bpy)(N3)2.H2O] 1, [Co(acac)(en)(N3)2] 2, and [Co(acac)(2-pic)(N3)2] 3 (where, acac=acetylacetone, bpy=2.2'-bipyridine, en=ethylenediamine, 2-pic=2-picolylamine and NaN3=sodium azide) were synthesized and characterized. The structure of complexes (1-3) has been determined by single crystal X-ray diffraction studies and the configuration around cobalt(III) ion was distorted octahedral coordination geometry. Density functional theory calculations were performed to examine the molecular geometry and frontier molecular orbital properties of complexes (1-3). DNA binding properties of the cobalt(III) complexes with calf thymus DNA (CT-DNA) were investigated by UV-visible absorption, fluorescence, circular dichroism spectroscopy and viscosity measurements. The docking studies showed the preferred orientation of sterically acceptable Co(III) complexes (1, 2) inside the DNA through the mode of intercalation, whereas complex 3 exhibited minor groove binding modes. The intrinsic binding constants Kb of complexes (1-3) with CT-DNA were in the following order 1>3>2. Complexes (1-3) exhibit a good binding propensity to bovine serum albumin (BSA) and gel electrophoresis assay demonstrated that the complexes (1-3) promote the cleavage of the pBR322 DNA in the presence of 3-mercaptopropionic acid (MPA) and cleavage process was found to proceed by singlet oxygen cleavage mechanism. Further, the in vitro cytotoxicity studies of complexes (1-3) were tested on human breast cancer cell line (MCF-7). PMID- 27475780 TI - Quantitative parameters of complexes of tris(1-alkylindol-3-yl)methylium salts with serum albumin: Relevance for the design of drug candidates. AB - Triarylmethane derivatives are extensively investigated as antitumor and antibacterial drug candidates alone and as photoactivatable compounds. In the series of tris(1-alkylindol-3-yl)methylium salts (TIMs) these two activities differed depending on the length of N-alkyl chain, with C4-5 derivatives being the most potent compared to the shorter or longer chain analogs and to the natural compound turbomycin A (no N-substituent). Given that the human serum albumin (HSA) is a major transporter protein with which TIMs can form stable complexes, and that the formation of these complexes might be advantageous for phototoxicity of TIMs we determined the quantitative parameters of TIMs-HSA binding using spectroscopic methods and molecular docking. TIMs bound to HSA (1:1 stoichiometry) altered the protein's secondary structure by changing the alpha helix/beta-turn ratio. The IIa subdomain (Sudlow site I) is the preferred TIM binding site in HSA as determined in competition experiments with reference drugs ibuprofen and warfarin. The values of binding constants increased with the number of CH2 groups from 0 to 6 and then dropped down for C10 compound, a dependence similar to the one observed for cytocidal potency of TIMs. We tend to attribute this non-linear dependence to an interplay between hydrophobicity and steric hindrance, the two key characteristics of TIMs-HSA complexes calculated in the molecular docking procedure. These structure-activity relationships provide evidence for rational design of TIMs-based antitumor and antimicrobial drugs. PMID- 27475781 TI - Effect of low-level laser irradiation on proliferation of human dental mesenchymal stem cells; a systemic review. AB - CONTEXT: Identification of factors that enhance the proliferation of human dental mesenchymal stem cells (DMSCs) is vital to facilitate tissue regeneration. The role of low-level laser irradiation (LLLI) on proliferation of human DMSCs has not been well established. OBJECTIVE: To assess the effect of LLLI on proliferation of human DMSCs when applied in-vitro. DATA SOURCES: Electronic search of literature was conducted (2000-2016) on PubMed, Web of Science, and Scopus databases. Search terms included low-level light therapy, low-level laser irradiation, low-level light irradiation, LLLT, humans, adolescent, adult, cells, cultured, periodontal ligament, dental pulp, stem cells, dental pulp stem cells, mesenchymal stem cells, periodontal ligament stem cell, deciduous teeth, cell proliferation, adult stem cells, radiation, and proliferation. RESULTS: The literature search identified 165 studies with 6 being eligible for inclusion; all used diode lasers; 5 studies used InGaAIP diode lasers; 4 used 660nm, and the other two applied 810nm or 980nm wavelength LLLI. The distance between the DMSCs and the laser spot ranged between 0.5mm to 2mm. The time intervals of cell proliferation analysis ranged from 0h to 7days after LLLI. After 660nm LLLI, an increase in the DMSC's proliferation was reported [DMSCs extracted from dental pulp of deciduous teeth (two irradiations, 3J/cm(2), 20mW was more effective than 40mW), adult teeth (two irradiations, 0.5 and 1.0J/cm(2), 30mW), and from adult periodontal ligament (two irradiations, 1.0J/cm(2) was more effective than 0.5J/cm(2), 30mW)]. Similarly, an increase in the proliferation of DMSCs extracted from dental pulp of adult teeth was reported after 810nm LLLI (7 irradiations in 7days, 0.1 and 0.2J/cm(2), 60mW) or 980nm LLLI (single irradiation, 3J/cm(2), 100mW). However, 660nm LLLI in one study did not increase the proliferation of DMSCs (single irradiation, energy densities of 0.05, 0.30, 7, and 42J/cm(2), 28mW). CONCLUSION: There is limited evidence that in-vitro LLLI (660/810/980nm, with energy densities of 0.1-3J/cm(2)) increases the proliferation of DMSCs. Considering the limited evidence and their method heterogeneity it is difficult to reach a firm conclusion. Further research is necessary to identify the optimal characteristics of the LLLI setting (wave length, energy density, power output, frequency/duration of irradiations, distance between the cells and the laser spot/probe) to increase proliferation of DMSCs, and assess its impact on replicative senescence, as well as determine feasibility of the use in the clinical setting. PMID- 27475782 TI - Influence of fracture geometry on bone healing under locking plate fixations: A comparison between oblique and transverse tibial fractures. AB - Mechano-regulation plays a crucial role in bone healing and involves complex cellular events. In this study, we investigate the change of mechanical microenvironment of stem cells within early fracture callus as a result of the change of fracture obliquity, gap size and fixation configuration using mechanical testing in conjunction with computational modelling. The research outcomes show that angle of obliquity (theta) has significant effects on interfragmentary movement (IFM) which influences mechanical microenvironment of the callus cells. Axial IFM at near cortex of fracture decreases with theta, while shear IFM significantly increases with theta. While a large theta can increase shear IFM by four-fold compared to transverse fracture, it also result in the tension-stress effect at near cortex of fracture callus. In addition, mechanical stimuli for cell differentiation within the callus are found to be strongly negatively correlated to angle of obliquity and gap size. It is also shown that a relatively flexible fixation could enhance callus formation in presence of a large gap but could lead to excessive callus strain and interstitial fluid flow when a small transverse fracture gap is present. In conclusion, there appears to be an optimal fixation configuration for a given angle of obliquity and gap size. PMID- 27475783 TI - Measurement and modelling the sensitivity of tetrapolar transfer impedance measurements. AB - Finite element method (FEM) modelling of a small disk in a homogeneous saline medium showed that the sensitivity distribution for tetrapolar transfer impedance measurements was dependant on the ratio, sigmadisk/sigmasaline, and not absolute conductivity values. In addition, the amplitude of the negative sensitivity regions between the drive and receive electrodes decreased non-linearly with sigmadisk/sigmasaline for sigmadisk/sigmasaline < 1, eventually becoming zero. This non-linear behaviour determined the limit of the assumption of a small change in conductivity in Geselowitz's lead theorem with 0.5 =65 year-old. Most cases presented with meningitis only (n = 2057, 44.53%), septicaemia only (n = 1725, 37.35%) or both meningitis and septicaemia (n = 389, 8.42%). Over half the cases (2526/4619, 54.69%) were confirmed by PCR only, 22.91% (1058/4619) by culture only and 22.41% (1035/4619) by both. The case fatality rate was 4.46% (206/4619; 95% CI, 3.88-5.10%) and varied by age, clinical presentation and capsular group. Children under 15 years who died within 30 days of diagnosis were significantly more likely to have been diagnosed by culture than by PCR alone (OR, 1.56; 95% CI, 1.02-2.39; P = 0.040). CONCLUSIONS: We identified complex interactions between age, meningococcal capsular group, clinical presentation, diagnostic method and death. The recent introduction of two new meningococcal immunisation programmes in the UK should significantly reduce IMD cases and deaths in the coming years. PMID- 27475789 TI - Prevalence of ESBL-producing Enterobacteriaceae in paediatric urinary tract infections: A systematic review and meta-analysis. AB - OBJECTIVES: We aimed to evaluate the prevalence of paediatric urinary tract infections (UTIs) caused by extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE), identify predisposing factors and examine their effect on the length of hospital stay (LOS). METHODS: For this systematic review and meta-analysis, we searched the PubMed and EMBASE databases for studies that provide data on the rate of ESBL-PE among paediatric UTIs. RESULTS: Out of 1828 non-duplicate citations, 16 studies reporting a total of 7374 cases of UTI were included. The prevalence of ESBL-PE was 14% [(95%CI 8, 21)]. Vesicoureteral reflux (VUR) [OR = 2.79, (95%CI 1.39, 5.58)], history of UTI [OR = 2.89 (95%CI 1.78, 4.68)] and recent antibiotic use [OR = 3.92, (95%CI 1.76, 8.7)] were identified as risk factors. The LOS was significantly longer among children infected with ESBL-PE, compared to those infected with other uropathogens. [SMD = 0.88, (95%CI 0.40, 1.35)]. CONCLUSIONS: In the paediatric population, 1 out of 7 UTIs are caused by ESBL-PE. Patients with VUR, previous UTI or recent antibiotic use constitute a high risk group and these pathogens are associated with increased LOS. The significant incidence of ESBL-PE in this population should be taken into consideration in the development of empiric treatment protocols and antibiotic stewardship programmes, especially in high-prevalence areas. PMID- 27475790 TI - Participation in Social Activities and the Association with Socio-Demographic and Health-Related Factors among Community-Dwelling Older Adults in Jamaica. AB - Social participation is critical for maintaining independence and facilitating active ageing. The aim of this paper is to describe participation in social activities among older adults in Jamaica and to identify independently associated socio-demographic and health characteristics. We analysed data from a nationally representative, community-based survey of 2943 persons 60 years and older. Sixty three percent of older adults attended religious services and 60 % were visited by friends at least once per month in the 12 months preceding the survey. Age was not independently associated with social participation. Persons with post secondary level education were twice as likely as those with primary education or less, to be visited by friends and to attend meetings of formal organisations. Men, persons not in union, and those with less functional independence had reduced odds of attending meetings of formal organisations. These variables were however not independently associated with having visits with friends. Persons with a positive depression screen were between 42 % and 44 % less likely to be visited by friends. Persons who received an income through livestock/farming were more likely to visit or be visited by friends. The variables independently associated with social participation vary depending on the type of social activity considered. Where possible, health and social interventions should focus on prevention, delay and reversal of risk factors associated with reduced social participation. Social participation programmes should be prioritized and be informed by input from older adults. Future research should include other forms of social interactions and clarify older adults' perceptions of their quality. PMID- 27475791 TI - Immunosuppressive treatment for pure membranous lupus nephropathy in a Hispanic population. AB - Optimal treatment for pure membranous lupus nephritis (MLN) remains unknown. The aim of this study was to evaluate the response to immunosuppressive treatment of Hispanics with pure MLN. This was a retrospective cohort analysis from a tertiary care center. Pure MLN patients were segregated into three groups according to the received induction treatment. All patients received adjunctive steroids. Outcomes included complete remission (CR), partial remission (PR), flare incidence, adverse events, and renal and patient survival. All outcomes were analyzed by Cox regression analysis. A total of 60 patients diagnosed with pure MLN between 2004 and 2014 were segregated into mycophenolate mofetil (MMF) (n = 18), intravenous cyclophosphamide (IVC) (n = 16), or azathioprine (AZA) (n = 26) groups. Complete remission rates at 6, 12, and 24 months were 33.3, 52.9, and 76.4 %, respectively, for MMF; 26.9, 42.3, and 54.6 %, respectively, for AZA; and 6.2, 14.8, and 26.9 %, respectively, for IVC. Based on Cox-adjusted analysis, treatment with MMF was associated with higher CR rates (hazard ratio (HR) 4.43, 1.19-16.4, p = 0.026) compared to IVC. There were no differences in CR rates between MMF and AZA groups. Patients treated with adjunctive antimalarial drugs were more likely to achieve CR (HR 2.46, 1.08-5.64, p = 0.032) and had a non significant trend to lower incidence of thrombotic events (odds ratio (OR) 0.10, 0.010-1.14, p = 0.064). There were no differences in adverse events, renal flares, and renal or patient survival between groups. MMF might be superior to IVC as induction treatment for pure MLN in Hispanics, while AZA might remain as a valid alternative for treatment. Adjunctive treatment with an antimalarial drug may enhance renal response to therapy. PMID- 27475792 TI - Predictors of response to intra-articular steroid injections in patients with osteoarthritis of the knee joint. AB - This study aimed to determine the factors associated with response to intra articular steroid injection (IASI) in patients with knee joint osteoarthritis. One hundred seventy-four female patients, age ranging from 30 to 80 years, diagnosed to have osteoarthritis of the knee joint, were given IASI. Response to IASI was assessed by using WOMAC and VAS at 2 weeks, 4 weeks and 3 months. At 3 months, the subjects were categorized as responders, partial responders and non responders to treatment by IASI. Various factors were narrowed down to see their effect on response, namely age, BMI, smoking habits, comorbidities, presence of clinical effusion, radiographic score, local knee tenderness, range of movement and socioeconomic status. One hundred twenty-four patients completed the study. 16.1 % showed 50 % or more improvement in WOMAC score at 3 months post IASI therapy, whereas 38.7 % of OA patients had more than 50 % improvement in VAS score. Out of all factors, range of movement, local knee tenderness and radiographic score of the affected joint are the three parameters which can predict the improvement in WOMAC score after 3 months of IASI therapy (P = 0.013, P = 0.045 and P = 0.000, respectively). Age of the patient can predict improvement in VAS at 3 months post IASI (P = 0.027). We conclude that age, range of movement, local knee tenderness and radiographic score of the affected joint can predict response to IASI after 3 months of IASI therapy. PMID- 27475793 TI - Auditory involvement in Behcet's disease: relationship with demographic, clinical, and therapeutic characteristics. AB - The study objective was to evaluate the occurrence of sensorineural hearing loss (SNHL) in patients with Behcet's disease (BD), looking at potential correlations with specific demographic, clinical, and therapeutic features. Forty-four consecutive patients (15 males, 29 females) fulfilling the International Study Group (ISG) and/or the International Criteria for Behcet's Disease (ICBD) were enrolled. The endpoints of the study consisted in identifying a deflection of at least 25 dB on pure-tone audiometry and performing statistical analysis to evaluate demographic, clinical, or therapeutic differences between patients with and without SNHL. Our patients showed a mean age +/- SD of 45.43 +/- 14.05 years; a mean age at disease onset +/- SD of 31.54 +/- 15.53 years; a disease duration +/- SD of 13.89 +/- 9.15 years. SNHL was highlighted in 28 (63 %) patients representing the fourth most frequent clinical manifestation in our group of patients. Otologic involvement was significantly more frequent among subjects fulfilling ISG criteria than in patients fulfilling ICBD criteria (p = 0.04). Regarding correlations with BD manifestations, SNHL was significantly associated with cutaneous plus articular involvement (p = 0.013). Conversely, detached analysis of articular and skin manifestations led to no significant differences (p = 0.085 and p = 0.067). No further significant correlations were found between SNHL and BD clinical features or previous or concomitant treatments. Hearing loss was the fourth most common clinical feature in our patients and probably represents an underrated aspect of BD. Hearing impairment was significantly associated with cutaneous plus articular involvement, suggesting the importance of an otologic evaluation in such patients. PMID- 27475794 TI - Living with pelvic organ prolapse: voices of women from Amhara region, Ethiopia. AB - INTRODUCTION: The objective of the study was to explore how women with symptomatic pelvic organ prolapse in a low-income setting explain, experience, and handle the potential practical and social consequences of the condition. METHODS: An explorative qualitative design was employed using in-depth interviews in the data collection. A total of 24 women with different degrees of symptomatic pelvic organ prolapse were included; 18 were recruited at the hospital and 6 from the community. Fieldwork was carried out in the Amhara region of northwest Ethiopia in 2011 and 2015. RESULTS: The informants held that the pelvic organ prolapse was caused by physical strain on their body, such as childbirth, food scarcity or hard physical work, particularly during pregnancy and shortly after delivery. Severe difficulties and pain while carrying out daily chores were common among the women. The informants used a variety of strategies to manage their work while striving to avoid disclosure of their condition. Disclosure was related to embarrassment and fear of discrimination from people living close to them, including the fear of being expelled from the household. Most of the informants, however, experienced substantial support from relatives, friends, and at times also from their husband, after disclosing their condition. CONCLUSIONS: The study highlights how symptomatic pelvic organ prolapse may severely affect women's lives in a low-income setting. The condition is perceived to be both caused by and aggravated by the heavy physical burdens of daily work. PMID- 27475798 TI - Regarding Liver Function 1 Year After Omega Loop Gastric Bypass. PMID- 27475796 TI - Safety and effectiveness of the Bonebridge transcutaneous active direct-drive bone-conduction hearing implant at 1-year device use. AB - The objective of this study is to evaluate the safety and efficacy of a new transcutaneous bone-conduction implant (BCI BB) in patients with conductive and mixed hearing loss or with single-sided deafness (SSD), 1 year after surgical implantation. The study design is multicentric prospective, intra-subject measurements. Each subject is his/her own control. The setting is nine university hospitals: 7 French and 2 Belgian. Sixteen subjects with conductive or mixed hearing loss with bone-conduction hearing thresholds under the upper limit of 45 dB HL for each frequency from 500 to 4000 Hz, and 12 subjects with SSD (contralateral hearing within normal range) were enrolled in the study. All subjects were older than 18 years. The intervention is rehabilitative. The main outcome measure is the evaluation of skin safety, audiological measurements, benefit, and satisfaction questionnaires with a 1-year follow up. Skin safety was rated as good or very good. For the mixed or conductive hearing loss groups, the average functional gain (at 500 Hz, 1, 2, 4 kHz) was 26.1 dB HL (SD 13.7), and mean percentage of speech recognition in quiet at 65 dB was 95 % (vs 74 % unaided). In 5/6 SSD subjects, values of SRT in noise were lower with BB. Questionnaires revealed patient benefit and satisfaction. The transcutaneous BCI is very well tolerated at 1-year follow up, improves audiometric thresholds and intelligibility for speech in quiet and noise, and gives satisfaction to both patients with mixed and conductive hearing loss and patients with SSD. PMID- 27475799 TI - Levothyroxine Dosing Following Bariatric Surgery. AB - BACKGROUND: Based on the mechanisms of drug absorption, increased levothyroxine requirements are expected after bariatric surgery. However, there are conflicting data on this topic. This review evaluates the effects of bariatric surgery on levothyroxine dosing. METHODS: Data were obtained from PubMed, Scopus, and review of published bibliographies. RESULTS: Six of 10 studies demonstrated decreased postoperative requirements. Most demonstrated correlations between weight loss and dose. Only 3 case reports and 1 case series demonstrated increased levothyroxine requirements, attributed to malabsorption. CONCLUSIONS: The loss of both fat and lean body mass may counteract malabsorptive effects from surgery, resulting in decreased postoperative levothyroxine requirements. In addition, the reversal of impaired levothyroxine pharmacokinetics and an altered set point of thyroid hormone homeostasis may also contribute to postoperative levothyroxine reductions. PMID- 27475801 TI - Safety and efficacy of the leukocytapheresis procedure in eighty-five patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disease in which the predominant symptom is polyarthritis that follows a chronic and progressive clinical course characterized by destructive synovitis and various immune disorders. Striking progress in RA treatment was achieved with the emergence of monoclonal antibodies to target cytokines. However, drug choices are limited for many patients due to resistance to multidrug antirheumatic therapy, concomitant disease, and infection. We evaluated the efficacy of treatment in 85 patients with RA for whom leukocytapheresis (LCAP) was initiated at our hospital between 2006 and 2015. All patients continued drug therapy and were treated with LCAP once a week for up to 5 weeks. The clinical response was evaluated at the completion of LCAP series and 4 weeks later using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of European League Against Rheumatism (EULAR). The tender joint counts, swollen joint counts, and C-reactive protein (CRP) levels decreased remarkably. DAS28-CRP was significantly improved by LCAP. And furthermore, the efficacy lasted at least 4 weeks after the completion of LCAP. These results suggest that LCAP is a beneficial and are consistent with several trials' reported effect of LCAP. This treatment can contribute to improvements in activities of daily living (ADLs) and long-term outcome by improving swollen and tender joint counts and CRP levels even in refractory patients for whom the use of conventional disease-modifying antirheumatic drugs (DMARDs) and biopharmaceuticals is problematic. LCAP might be a promise therapy to refractory RA. PMID- 27475802 TI - Inflammatory cytokines in serum samples of healthy blood donors. PMID- 27475800 TI - The Contributing Role of Bile Acids to Metabolic Improvements After Obesity and Metabolic Surgery. AB - Obesity and metabolic surgery (OMS) leads to several metabolic improvements, which often occur prior to substantial weight loss. Therefore, other factors in addition to weight loss contribute to the metabolic benefits. This literature review offers an overview of studies investigating bile acids (BAs) and their metabolic effects after OMS. Rearrangement of enterohepatic circulation, changes in BA synthesis, BA conjugation, intestinal reabsorption, and alterations in the gut microbiota are potential mechanisms for altered BA profiles after surgery. Increased BA levels are associated with improved glucose homeostasis and lipid profiles, which are mediated by two major receptors: the Transmembrane G-protein Coupled Receptor and the Farnesoid X Receptor. Therefore, pharmacological manipulation of BAs and their receptors may be viable targets for less invasive obesity treatment. PMID- 27475803 TI - Measurement of extracellular vesicles as biomarkers of consequences or cause complications of pathological states, and prognosis of both evolution and therapeutic safety/efficacy. AB - Utility of EVs, as biomarkers of cause or consequence of various pathological complications, and prognosis of blood components' therapy in terms of safety/efficacy and their potential associated hazards, primed by EVs involvements in pro-inflammatory, immunomodulatory and activations of both pro/anti-coagulatory and others associated pathways, as well as various cellular cross talks, are highlighted as the fundamental. Today EVs are becoming the "buzz" words of the current diagnosis, development and research [DDR] strategies, with the aim of ensuring safer therapeutic approaches in the current clinical practices, also incorporating their potential in long term cost effectiveness in health care systems. The main focus of this manuscript is to review the current opinions in some fundamental areas of EVs involvements in health and diseases. Firstly, our goal is highlighting what are EVs/MVs/MPs and how are they generated in physiology, pathology or blood products; classification and significance of EVs generated in vivo; followed by consequences and physiological/pathological induced effects of EVs generation in vivo. Secondly, specific cell origin EVs and association with malignancy; focus on EVs carrying TF and annexin V as a protective protein for harmful effects of EVs, and associations with LA; and incidence of anti-annexin V antibodies are also discussed. Thirdly, utility of EVs is presented: as diagnostic tools of disease markers; prognosis and follow-up of clinical states; evaluation of therapy efficacy; quality and risk assessment of blood products; followed by the laboratory tools for exploring, characterizing and measuring EVs, and/or their associated activity, using our own experiences of capture based assays. Finally, in perspective, the upcoming low volume sampling, fast, reliable and reproducibility and friendly use laboratory tools and the standardization of measurement methods are highlighted with the beneficial effects that we are witnessing in both wound healing and tissue remodeling, with an expected blockbuster status EVs as future therapeutic directions. PMID- 27475804 TI - Immunotherapy as a Potential Treatment for Chordoma: a Review. AB - Chordoma is a locally aggressive primary malignancy of the axial skeleton. The gold standard for treatment is en bloc resection, with some centers now advocating for the use of radiation to help mitigate the risk of recurrence. Local recurrence is common, and salvaging local failures is quite difficult. Chemotherapy has been ineffective and small molecule targeted therapy has had only marginal benefits in small subsets of patients with rare tumor phenotypes or refractory disease. Recent successes utilizing immunotherapy in a variety of cancers has led to a resurgence of interest in modifying the host immune system to develop new ways to treat tumors. This review will discuss these studies and will highlight the early studies employing immune strategies for the treatment of chordoma. PMID- 27475805 TI - The Obesity Paradox in Cancer: a Review. AB - There is a common perception that excess adiposity, commonly approximated by body mass index (BMI), is associated with reduced cancer survival. A number of studies have emerged challenging this by demonstrating that overweight and early obese states are associated with improved survival. This finding is termed the "obesity paradox" and is well recognized in the cardio-metabolic literature but less so in oncology. Here, we summarize the epidemiological findings related to the obesity paradox in cancer. Our review highlights that many observations of the obesity paradox in cancer reflect methodological mechanisms including the crudeness of BMI as an obesity measure, confounding, detection bias, reverse causality, and a specific form of the selection bias, known as collider bias. It is imperative for the oncologist to interpret the observation of the obesity paradox against the above methodological framework and avoid the misinterpretation that being obese might be "good" or "protective" for cancer patients. PMID- 27475807 TI - Editorial Comment. PMID- 27475806 TI - Evolving Immunotherapy Approaches for Renal Cell Carcinoma. AB - Metastatic renal cell carcinoma (mRCC) continues to be associated with high rates of morbidity and mortality. Renal cell carcinoma (RCC) is typically resistant to cytotoxic chemotherapy, and while targeted therapies have activity and prolong progression-free and overall survival, responses are usually not durable. Modulating the immune system with cytokine therapy, vaccine therapy, cell therapy, and checkpoint inhibitors offers hope of prolonged survival. Standard and emerging immune therapy approaches and combinations of immune therapies and other modalities are reviewed. PMID- 27475808 TI - Application of biodegradation in mitigating and remediating pesticide contamination of freshwater resources: state of the art and challenges for optimization. AB - In recent years, the application of pesticide biodegradation in remediation of pesticide-contaminated matrices moved from remediating bulk soil to remediating and mitigating pesticide pollution of groundwater and surface water bodies. Specialized pesticide-degrading microbial populations are used, which can be endogenous to the ecosystem of interest or introduced by means of bioaugmentation. It involves (semi-)natural ecosystems like agricultural fields, vegetated filter strips, and riparian wetlands and man-made ecosystems like on farm biopurification systems, groundwater treatment systems, and dedicated modules in drinking water treatment. Those ecosystems and applications impose challenges which are often different from those associated with bulk soil remediation. These include high or extreme low pesticide concentrations, mixed contamination, the presence of alternative carbon sources, specific hydraulic conditions, and spatial and temporal variation. Moreover, for various indicated ecosystems, limited knowledge exists about the microbiota present and their physiology and about the in situ degradation kinetics. This review reports on the current knowledge on applications of biodegradation in mitigating and remediating freshwater pesticide contamination. Attention is paid to the challenges involved and current knowledge gaps for improving those applications. PMID- 27475809 TI - CD4+FOXP3+ T regulatory cells decrease and CD3+CD8+ T cells recruitment in TILs from melanoma metastases after electrochemotherapy. AB - Electrochemotherapy (ECT) represents an effective local treatment for skin unresectable melanoma metastases with high overall objective response rate. ECT is based on the combination of anti-neoplastic drugs administration and cancer cells electroporation. Whether ECT can also activate the immune system is a matter of debate, however a significant recruitment of dendritic cells in melanoma treated metastases has been described. Herein we investigated immediate and late effects of ECT treatment on T cell subsets in ECT-treated lesions by fluorescent immunohistochemistry. Biopsies from melanoma patients (n = 10) were taken before ECT (t0), at d1 and d14 from treatment. At t0, CD3+CD4+ T cells were the most represented T cells, well detected in the perilesional dermis, particularly at tumour margin, while CD3+CD8+ T cells were less represented. CD4+FOXP3+ T regulatory (Treg) cells were present in the perilesional dermis and within the lesion. ECT induced a significant decrease of CD4+FOXP3+ Treg cells percentage in the perilesional dermis, observed at d1 and at d14 (p < 0.001). CD3+CD8+ T cells frequency significantly increased at d14 from treatment in the perilesional dermis (p < 0.001). Furthermore calreticulin translocation to the plasma membrane, a hallmark of immunogenic cell death, was observed in metastatic cells after ECT. The data reported here confirm that ECT induces a local response, with a lymphoid infiltrate characterized by CD4+FOXP3+ Treg cells decrease and CD3+CD8+ T cells recruitment in the treated lesions. These results might contribute to design novel combinational therapeutic approaches with ECT and immunotherapy in order to generate a systemic long-lasting anti-melanoma immunity. PMID- 27475810 TI - Ants detect but do not discriminate diseased workers within their nest. AB - Social insects have evolved an array of individual and social behaviours that limit pathogen entrance and spread within the colony. The detection of ectoparasites or of fungal spores on a nestmate body triggers their removal by allogrooming and appears as a primary component of social prophylaxis. However, in the case of fungal infection, one may wonder whether ant workers are able to detect, discriminate and keep at bay diseased nestmates that have no spores over their cuticle but which constitute a latent sanitary risk due to post-mortem corpse sporulation. Here, we investigate the ability of Myrmica rubra workers to detect and discriminate a healthy from a diseased nestmate infected by the entomopathogen Metarhizium anisopliae. During dyadic encounters in a neutral location, workers were more aggressive towards isolated sick nestmates on the 3rd post-infection day. However, no such detection or discrimination of fungus infected nestmates occurred in a social context inside the nest or at the nest entrance. Gatekeepers never actively rejected incoming diseased nestmates that rather spontaneously isolated themselves outside the nest. Our study reveals that ant workers may detect health-dependent cues and that their 'acceptance level' of sick nestmates is tunable depending on the social context. This raises questions about possible trade-offs between a social closure to pathogens and risks of erroneous rejection of healthy nestmates. Social isolation of moribund ants also appears as a widespread prophylactic strategy of social insects allowing them to reduce exposure to pathogens and to spare costs associated with the management of infected individuals. PMID- 27475811 TI - Short-Term Cardioprotective Effects of the Original Perindopril/Amlodipine Fixed Dose Combination in Patients with Stable Coronary Artery Disease: Results of the PAPA-CAD Study. AB - INTRODUCTION: Long-term therapy with a combination of perindopril and amlodipine has shown a beneficial effect on the morbidity and mortality of patients with stable coronary artery disease (SCAD) and hypertension. On the basis of the antiproliferative, antithrombotic, and antiatherogenic effects of the active substances, we initiated data collection to examine the short-term cardioprotective effect of perindopril/amlodipine fixed-dose combination therapy in this patient group. The aim of this study was to evaluate the effect of perindopril/amlodipine fixed-dose combination on the Canadian Cardiovascular Society (CCS) class and exercise capacity of patients with SCAD in everyday medical practice. METHODS: This was a multicenter, prospective, observational, non-interventional, open-label, 6-month clinical study. Patients attended four visits (inclusion, and at months 1, 3, and 6), and clinical information was collected [risk factors, comorbidities, blood pressure (BP), and heart rate measured at the physician's office, drug treatment, CCS class, adverse events, optional laboratory blood tests, and exercise electrocardiography (ECG)]. RESULTS: This study included 3472 patients. The mean office systolic BP/diastolic BP decreased from 157.5 +/- 12.9/92.9 +/- 8.6 to 130.3 +/- 8.3/79.8 +/- 6.1 mmHg (P < 0.0001). During the 6-month study period, a favorable change in CCS grading was observed following treatment with fixed-dose combination perindopril/amlodipine: CCS I, from 42.6% to 71.4%; CCS II, from 46.4% to 26.5%; CCS III, from 10.2% to 2.0%; and CCS IV, from 0.8% to 0.1% (all P < 0.0001). In those patients who had exercise ECG at inclusion and the end of month 6 (n = 197) the mean performance, measured in watts, increased from 88.9 +/- 37.9 to 110.5 +/ 38.4 W (+24.4%; P < 0.001) and from 7.86 +/- 2.95 to 8.78 +/- 2.92 metabolic equivalent of task (MET) (+11.7%; P < 0.001). No serious adverse events were reported and the treatment was found to have a positive impact on patients' metabolic profiles. CONCLUSION: The fixed-dose combination of perindopril and amlodipine improved the CCS class and exercise capacity in patients with SCAD after 6 months of treatment. The fixed-dose combination of perindopril and amlodipine can have favorable effects on the cardiovascular system, not only by its BP-lowering effect and its effect on vascular resistance but also through its direct cardiovascular protective effects. FUNDING: Egis Pharmaceuticals. TRIAL REGISTRATION: 21938-1/2011-EKU (698/PI/11.). PMID- 27475812 TI - Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide. AB - BACKGROUND/AIMS: Major depressive disorder is one of the most common diseases in western countries. The disease is mainly defined by its psychiatric symptoms. However, the disease has also many symptoms outside the central nervous system, in particular cardiovascular symptoms. Recent studies demonstrated that the acid sphingomyelinase/ceramide system plays an important role in the development of major depressive disorder and functions as a target of antidepressants. METHODS: Here, we investigated (i) whether ceramide accumulates in endothelial cells in the neurogenetic zone of the hippocampus after glucocorticosterone-mediated stress, (ii) whether ceramide is released into the extracellular space of the hippocampus and (iii) whether extracellular ceramide inhibits neuronal proliferation. Ceramide was determined in endothelial cell culture supernatants or extracellular hippocampus extracts by a kinase assay. Endothelial ceramide in the hippocampus was analyzed by confocal microscopy of brain sections stained with Cy3-labelled anti-ceramide antibodies and FITC-Isolectin B4. Neuronal proliferation was measured by incubation of pheochromocytoma neuronal cells with culture supernatants and extracellular hippocampus extracts. RESULTS: Treatment of cultured endothelial cells with glucocorticosterone induces a release of ceramide into the supernatant. Likewise, treatment of mice with glucocorticosterone triggers a release of ceramide into the extracellular space of the hippocampus. The release of ceramide is inhibited by concomitant treatment with the antidepressant amitriptyline, which also inhibits the activity of the acid sphingomyelinase. Studies employing confocal microscopy revealed that ceramide is formed and accumulates exclusively in endothelial cells in the hippocampus of stressed mice, a process that was again prevented by co application of amitriptyline. Ceramide released in the culture supernatant or into the extracellular space of the hippocampus reduced proliferation of neurons in vitro. CONCLUSION: The data suggest a novel model for the pathogenesis of major depressive disorder, i.e. the release of ceramide-enriched microvesicles from endothelial cells that negatively affect neuronal proliferation in the hippocampus, but may also induce cardiovascular disease and other systemic symptoms of patients with major depressive disorder. PMID- 27475813 TI - Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II. AB - BACKGROUND/AIMS: Despite significant advancements in the diagnosis and treatment of osteosarcoma, the overall survival has remained relatively unchanged for over two decades. Hypoxic conditions have been demonstrated in solid tumors and are associated with increased cell proliferation and angiogenesis. L-arginine metabolism by arginase produces L-ornithine, the precursor for polyamine and proline synthesis required for cellular proliferation. We hypothesized that hypoxia would increase cellular proliferation via arginase induction in human osteosarcoma cell lines. METHODS: We utilized a variety of approaches to examine the role of arginase II in hypoxic (1% O2, 5% CO2) cellular proliferation. RESULTS: Arginase II mRNA and protein levels were significantly increased in osteosarcoma cells exposed to hypoxia for 48 hours. There were twice as many viable cells following 48 hours of hypoxia than following 48 hours of normoxia (21% O2, 5% CO2). The addition of difluoromethylornithine (DFMO), a putative arginase inhibitor, prevented hypoxia-induced proliferation. Transfection of small interfering RNAs (siRNA) targeting arginase II resulted in knockdown of arginase II protein levels and prevented hypoxia-induced cellular proliferation. CONCLUSIONS: These data support our hypothesis that hypoxia increases proliferation of osteosarcoma cells in an arginase II-dependent manner. We speculate that arginase II may represent a therapeutic target in osteosarcoma. PMID- 27475814 TI - Retraction Statement: Paper by Qian Y, Ma J, Guo X, Sun J, Yu Y, CaoB, Zhang L, Ding X, Huang J, Shao JF, entitled 'Curcumin Enhances the Radiosensitivity ofU87 Cells by Inducing DUSP-2 Up-Regulation' Cell Physiol Biochem 2015;35(4):1381 93.doi: 10.1159/000373959. PMID- 27475816 TI - Discussion. PMID- 27475815 TI - Achieving a 5-star rating: Analysis of Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores among patients undergoing elective colorectal operations. AB - BACKGROUND: Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) is a publicly reported survey of patients' hospital experience. METHODS: All inpatient, elective colorectal resections with completed HCAHPS surveys at a single institution between June 2012 and April 2015 were identified. HCAHPS measures were analyzed according to published methodologies. Univariate logistic regression evaluated associations of various HCAHPS measures with age, sex, ostomy, approach, diagnosis, and prolonged length of stay (PLOS; >=7 days). Key driver analysis demonstrated associations between the individual HCAHPS measures and the global hospital rating measure. RESULTS: We identified 755 patients. Younger age, inflammatory bowel disease, open approach, ostomy construction, and PLOS were associated with low quality of pain management. Patients with inflammatory bowel disease, open approach, and PLOS had a low overall star score (all P < .05). Care transitions and communication about medications received low scores but were associated highly with the global hospital rating measure. CONCLUSION: Efforts aimed at improving pain management among patients with colorectal resection should focus on patients with inflammatory bowel disease, open operations, ostomies, and PLOS. Improving care transitions and communication about medications are important targets for improvement to increase the overall hospital score. Considering the importance of improving patient-centered outcomes, we suggest that all institutions utilize their existing HCAHPS data in this manner. PMID- 27475817 TI - Operative correction of abdominal rectus diastasis (ARD) reduces pain and improves abdominal wall muscle strength: A randomized, prospective trial comparing retromuscular mesh repair to double-row, self-retaining sutures. AB - BACKGROUND: The primary aim of this prospective, randomized, clinical, 2-armed trial was to evaluate the risk for recurrence using 2 different operative techniques for repair of abdominal rectus diastasis. Secondary aims were comparison of pain, abdominal muscle strength, and quality of life and to compare those outcomes to a control group receiving physical training only. METHODS: Eighty-six patients were enrolled. Twenty-nine patients were allocated to retromuscular polypropylene mesh and 27 to double-row plication with Quill technology. Thirty-two patients participated in a 3-month training program. Diastasis was evaluated with computed tomography scan and clinically. Pain was assessed using the ventral hernia pain questionnaire, a quality-of-life survey, SF-36, and abdominal muscle strength using the Biodex System-4. RESULTS: One early recurrence occurred in the Quill group, 2 encapsulated seromas in the mesh group, and 3 in the suture group. Significant improvements in perceived pain, the ventral hernia pain questionnaire, and quality of life appeared at the 1-year follow-up with no difference between the 2 operative groups. Significant muscular improvement was obtained in all groups (Biodex System-4). Patient perceived gain in muscle strength assessed with a visual analog scale improved similarly in both operative groups. This improvement was significantly greater than that seen in the training group. Patients in the training group still experienced bodily pain at follow-up. CONCLUSION: There was no difference between the Quill technique and retromuscular mesh in the effect on abdominal wall stability, with a similar complication rate 1 year after operation. An operation improves functional ability and quality of life. Training strengthens the abdominal muscles, but patients still experience discomfort and pain. PMID- 27475818 TI - Bacterial diversity across a highly stratified ecosystem: A salt-wedge Mediterranean estuary. AB - Highly stratified Mediterranean estuaries are unique environments where the tidal range is low and the tidal currents are almost negligible. The main characteristics of these environments are strong salinity gradients and other environmental parameters. In this study, 454 pyrosequencing of the 16S rRNA gene in combination with catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH) was used to estimate the bacterial diversity across the Krka estuary in February and July 2013. The comparison of the data derived from these two techniques resulted in a significant but weak positive correlation (R=0.28) indicating a substantial difference in the bacterial community structure, depending on the applied method. The phytoplankton bloom observed in February was identified as one of the main factors shaping the bacterial community structure between the two environmentally contrasting sampling months. Roseobacter, Bacteroidetes and Gammaproteobacteria differed substantially between February and July. Typical freshwater bacterial classes (Actinobacteria and Betaproteobacteria) showed strong vertical distribution patterns depending on the salinity gradient. Cyanobacteria decreased in abundance in February due to competition with phytoplankton, while the SAR11 clade increased its abundance in July as a result of a better adaptation toward more oligotrophic conditions. The results provided the first detailed insight into the bacterial diversity in a highly stratified Mediterranean karstic estuary. PMID- 27475819 TI - New method to secure cyst decompression tube in tooth-bearing areas. PMID- 27475820 TI - Orbitocranial wooden foreign body retrieved by transcranial and superior orbitotomy. PMID- 27475821 TI - Postpartum Contraception and Interpregnancy Intervals Among Adolescent Mothers Accessing Public Services in California. AB - Objective To determine the association of age at index birth with postpartum contraceptive use and optimal interpregnancy interval (IPI, defined as delivery to next pregnancy >18 months), controlling for provider type and client demographics among adolescent mothers who have repeat pregnancies. Methods California's 2008 birth records were linked to California's Medi-Cal and Family PACT claims data to identify 26,393 women with repeat births between 2002 and 2008, whose index birth occurred as an adolescent, and who received publicly funded services within 18 months after the index birth. Multivariable regression analyses were conducted to examine the relationship between timing of contraception provision and interpregnancy intervals, adjusting for socio demographic factors. Results Seventy-eight percent of adolescent women did not receive contraception at their first postpartum visit, and twenty-eight percent of adolescent women never received contraception from a Family PACT or Medi-Cal provider. Adolescents who were older at their index birth had lower rates of optimal IPIs. Native American, Asian-Pacific Islander and Latina women had lower rates of optimal IPIs compared to white women. Compared to those using only barrier methods, adolescent women receiving highly effective contraceptive methods had a 4.25 times higher odds of having an optimal IPI than those receiving hormonal methods (OR 2.10), or using no method (OR 0.70). Conclusion Effective postpartum contraceptive use and being a Family PACT provider were associated with optimal birth spacing among adolescent mothers, yet racial and ethnic disparities persisted. A missed opportunity was the provision of contraception at the first postpartum visit. Providers should aim to remove barriers to initiation of contraception at this visit. PMID- 27475822 TI - Newborn Outcomes and Maternity Waiting Homes in Low and Middle-Income Countries: A Scoping Review. AB - Objectives Decreasing neonatal morbidity and mortality remains a challenge in low resource settings. Maternity waiting homes (MWHs) may offer a way to better provide perinatal obstetric care and improve newborn outcomes. The purpose of this scoping review is to examine the impact of MWHs on newborn outcomes and to inform the development of targeted interventions and services to decrease neonatal mortality. Methods A literature search of four databases in the fields of nursing, medicine and global health was conducted yielding a total of 11 articles included for the review. Results Results indicate studies with extremely limited qualitative or quantitative measures of the impact of MWHs on neonatal health. Conclusions An exceptionally wide gap in knowledge on the outcomes of neonates born at MWHs was identified through this scoping review of the scientific literature. The review illustrates the need for more research to understand the effectiveness of MWHs on newborn morbidity and mortality. An increased focus on the study of MWHs for improving newborn outcomes in low resource settings merits immediate attention. PMID- 27475823 TI - Postnatal Care Experiences and Barriers to Care Utilization for Home- and Facility-Delivered Newborns in Uganda and Zambia. AB - Objectives The objective of this study was to examine experiences with, and barriers to, accessing postnatal care services, in the context of a maternal health initiative. Methods As part of a larger evaluation of an initiative to promote facility deliveries in 8 rural districts in Uganda and Zambia, 48 focus groups were held with recently-delivered women with previous home and facility deliveries (6 per district). Data on postnatal care experiences were translated, coded and analyzed using thematic content analysis techniques. Results were categorized into: positive postnatal care experiences, barriers to postnatal care utilization, and negative postnatal care experiences. Results Women who accessed care largely reported positive experiences, with Zambian women generally reporting more positive interactions than Ugandan women. The main reasons given for low postnatal care utilization were low awareness about the need, fear of mistreatment by clinic staff, cost and distance. In half of the focus groups, women described personal experience or knowledge of denial or threatened denial of postnatal care due to the birth location. Although outright denial of care was not common, women frequently described various types of actual or presumed discrimination because of having a home birth. Conclusions for Practice While many women reported positive experiences with postnatal care utilization, cases of delay or denial of postnatal care exist. As programs incentivize facility deliveries, the lack of focus on postnatal support may place home-delivered newborns in "double jeopardy" due to poor quality intra-partum care and reduced access to postnatal care. PMID- 27475824 TI - What Factors Influence States' Capacity to Report Children's Health Care Quality Measures? A Multiple-Case Study. AB - Objectives The objective of this study was to describe factors that influence the ability of state Medicaid agencies to report the Centers for Medicare & Medicaid Services' (CMS) core set of children's health care quality measures (Child Core Set). Methods We conducted a multiple-case study of four high-performing states participating in the Children's Health Insurance Program Reauthorization Act (CHIPRA) Quality Demonstration Grant Program: Illinois, Maine, Pennsylvania, and Oregon. Cases were purposively selected for their diverse measurement approaches and used data from 2010 to 2015, including 154 interviews, semiannual grant progress reports, and annual public reports on Child Core Set measures. We followed Yin's multiple-case study methodology to describe how and why each state increased the number of measures reported to CMS. Results All four states increased the number of Child Core Set measures reported to CMS during the grant period. Each took a different approach to reporting, depending on the available technical, organizational, and behavioral inputs in the state. Reporting capacity was influenced by a state's Medicaid data availability, ability to link to other state data systems, past experience with quality measurement, staff time and technical expertise, and demand for the measures. These factors were enhanced by CHIPRA Quality Demonstration grant funding and other federal capacity building activities, as hypothesized in our conceptual framework. These and other states have made progress reporting the Child Core Set since 2010. Conclusion With financial support and investment in state data systems and organizational factors, states can overcome challenges to reporting most of the Child Core Set measures. PMID- 27475826 TI - The Potential of Behavioral Economics to Promote Safe Infant Sleep Practices. AB - Objectives The purpose of this commentary is to highlight the potential of six Behavioral Economics (BE) concepts for promoting infant safe sleep practices. The rate of sleep-related deaths has not decreased over the last decade. It may be time to consider a novel paradigm to address this public health concern. BE has not yet been specifically considered for encouraging safe infant sleep practices. Methods This commentary features an integration of behavioral economic concepts and findings from the infant safe sleep literature. Results Six BE concepts salience, choice overload, loss aversion, social norms, framing, and the identifiable victim effect- were identified for their potential in developing novel interventions for reducing sleep-related deaths during the first year of life. Conclusions BE strategies differ significantly from non-BE approaches for this public health concern. BE strategies appear feasible for widespread dissemination should they ultimately be efficacious. PMID- 27475825 TI - Examining the Psychometric Properties of Three Standardized Screening Tools in a Pregnant and Parenting Population. AB - Significance Although standardized tools such as the Speilberger State Anxiety scale (1970) and Cohen's Perceived Stress Index (1983) have often been used in pregnant and postpartum populations to evaluate psychosocial risk, there exists very little literature on the reliability of these scales in this population. Given the potentially grave consequences of undiagnosed pre and postpartum mental distress, it is of paramount importance that the tools that are commonly used are evaluated for their psychometric properties within the pregnant and parenting population. Methods The psychometric properties of three mental health scales were evaluated using the All Our Babies data. The All Our Babies cohort is a prospective longitudinal study based in Calgary, Alberta. A total of 3300 women were recruited from prenatal care sites from all four quadrants of the city. Participants were mailed questionnaires at 24-26 weeks gestation, 34-36 weeks and at 4 months postpartum. Reliability for the Speilberger State Anxiety Scale, the Perceived Stress Index and the Life Optimism Test-revised were evaluated by calculating Cronbach's alphas. Validity with related constructs were tested for the State Anxiety Scale and the Perceived Stress Index by calculating Pearson Correlation Coefficients with closely related constructs. Sample size varied from 2670 to 3376, according to the response rate and time point. Depression as a related construct was evaluated using the Edinburgh Postpartum Depression Scale. Results The Cronbach's Alphas for the Speilberger State Anxiety scale were 0.92, 0.92 and 0.93 for 24-26 weeks, 34-36 weeks and 4 months postpartum respectively. The Alpha's for the Perceived Stress index were 0.88, 0.88 and 0.89 respectively. The Life Optimism Test Revised was only measured in the third trimester and the Cronbach's alpha was 0.83. The Pearson Correlation Coefficient for Anxiety with depression were r = 0.73, r = 0.72 and r = 0.77 respectively. The coefficients for stress and depression were r = 0.75, r = 0.75 and r = 0.77 respectively. Discussion/Conclusion The psychometric properties for all three scales were strong, with alphas that were comparable or higher to literature values. These data provide evidence that the use of these scales, previously validated in other populations are appropriate for use in among pregnant and parenting women at risk for mental distress. PMID- 27475827 TI - Attachment to Conventional Institutions and Adolescent Rapid Repeat Pregnancy: A Longitudinal National Study Among Adolescents in the United States. AB - Introduction There is limited research on rapid repeat pregnancies (RRP) among adolescents, especially using nationally representative samples. We examine distal factors-school, family, peers, and public/private religious ties-and their associations with RRP among adolescent mothers. Methods Guided by social development theory, we conducted multivariate logistic regression analyses, adjusted for sociodemographic characteristics, to examine associations between RRP and attachment to school, family, peers, and religion among 1158 female respondents from the National Longitudinal Study of Adolescent to Adult Health (Add Health) who reported at least one live birth before age 20. Results Attachments to conventional institutions were associated with lower likelihood of RRP. Adolescent mothers who had a stronger relationship with their parents had reduced odds of RRP (adjusted odds ratio [aOR] 0.83, 95 % CI 0.71-0.99). Increased odds of RRP were associated with anticipating fewer negative social consequences of sex (aOR 1.18, 95 % CI 1.02-1.35), never praying (versus praying daily; aOR 1.47, 95 % CI 1.10-1.96), and never participating in church-related youth activities (versus participating once a week; 1.04, 95 % CI 1.01-1.07). Discussion After an adolescent birth, social support from family, peers, and the community can benefit young mothers. Private aspects of religiosity may be especially important. Understanding the processes by which these distal factors are linked to the likelihood of RRP is needed to create multifaceted intervention programs that provide diverse methods of support customized to specific circumstances of adolescent mothers. PMID- 27475828 TI - Racial Differences in the Influence of Interpregnancy Interval on Fetal Growth. AB - Objectives Assess the influence of maternal race on the association between interpregnancy interval (IPI) and risk of small for gestational age (SGA) and large for gestational age (LGA) births. Methods Statewide population-based cohort study of 380,520 singleton births. We calculated risk of SGA and LGA births following IPIs of 0 to <6, 6 to <12, 12 to <24 (referent), 24 to <60 months, and >=60 months, by maternal race after adjustment for confounding influences. Results The highest risk for SGA among white women followed short IPI of 0 to <6 months [adjRR 1.14 (95 % CI 1.08-1.21)], and long IPI >= 60 months [adjRR 1.37 (95 % CI 1.31-1.43)]. Only long IPI >= 60 months increased SGA risk in black women [adjRR 1.22 (95 % CI 1.13-1.32)]. LGA risk in white women was lowest with shortest and longest IPIs, 0 to <6 [adjRR 0.80 (95 % CI 0.76-0.84)] and >=60 months [adjRR 0.68 (95 % CI 0.66-0.70)]. The crude risk of LGA was directly proportional to longer IPIs in black women. However, after adjusting for confounding effects of age, obesity, excessive gestational weight gain, and gestational diabetes, the effect was reversed to reduced risk following long IPI >= 60 months [adjRR 0.82 (95 % CI 0.74-0.91)], similar to that of white women. Conclusions In black and white women, an interpregnancy interval of 1-2 years is associated with optimal fetal growth. In addition to birth spacing, addressing modifiable factors such as pre-pregnancy BMI, monitoring gestational weight gain, and control of gestational diabetes in black women may help optimize fetal growth. PMID- 27475829 TI - Perioperative medicine: From theorical guidelines to clinical practice. PMID- 27475830 TI - Accuracy of a cardiac output monitor: Is it a relevant issue without an adequate therapeutic algorithm? PMID- 27475831 TI - Neostigmine: Timing and dosing in 2016. PMID- 27475832 TI - The Multiple Faces of Nervous System Lymphoma. Atypical Magnetic Resonance Imaging Features and Contribution of the Advanced Imaging. AB - Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma, which involves the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease. In addition to a detailed history and physical examination, the evaluation of patients suspected of having a PCNSL should include a contrast-enhanced magnetic resonance imaging. Occassionaly, PCNSL shows peculiarities on magnetic resonance imaging, which delay the diagnosis and thus the start of treatment. It is essential that radiologists be aware of these less common presentations such as isolated spine or meningeal lymphoma, angiocentric lymphoma, ocular lymphoma, and Epstein-Barr virus-associated lymphoma. Advanced neuroimaging (diffusion and perfusion sequences, spectroscopy-magnetic resonance, and positron emission tomography metabolic imaging) are useful techniques for the differential diagnosis of PCNSL with processes such as brain glioblastoma, multiple sclerosis, and metastases and brain abscesses, especially in atypical presentations. In this article, a review of unusual radiological findings for PCNSL in immunocompetent patients is made, highlighting the usefulness of functional and metabolic imaging for establishing an early presumptive diagnosis, which reduces delays in treatment. PMID- 27475833 TI - Why Sexually Selected Weapons Are Not Ornaments. AB - The elaboration and diversification of sexually selected weapons remain poorly understood. We argue that progress in this topic has been hindered by a strong bias in sexual selection research, and a tendency for weapons to be conflated with ornaments used in mate choice. Here, we outline how male-male competition and female choice are distinct mechanisms of sexual selection, and why weapons and ornaments are fundamentally different types of traits. We call for research on the factors contributing to weapon divergence, the potential for male-male competition to drive speciation, and the specific use of weapons in the context of direct fights versus displays. Given that weapons are first and foremost fighting structures, biomechanical approaches are an especially promising direction for understanding weapon design. PMID- 27475834 TI - Development of Cetylpyridinium-Alginate Nanoparticles: A Binding and Formulation Study. AB - In this study the development of stable polyelectrolyte-surfactant complex nanoparticles composed of alginate and cetylpyridinium chloride (CPC), with and without ZnCl2, for therapeutic use, is investigated. The mechanism of CPC binding by alginate was analyzed using a cetylpyridinium cation (CP(+)) selective membrane electrode. The cooperative nature of the interaction between CP(+) and alginate was underlined by the sigmoidal shape of the binding isotherms. The presence of salts was shown to weaken interactions and, moreover, ZnCl2 reduced the cooperativity of binding. The CP(+) cations in the form of micellar associates acted as multivalent crosslinkers of the alginate chains where stable dispersions of CP-alginate nanoparticles were formed in water at CP(+)/alginate charge ratios from 0.2 to 0.8. Characterization of the nanoparticles showed hydrodynamic diameters from 140 to 200nm, a polydispersity index below 0.2, a negative zeta potential and spherical morphology. The entrapment efficiency of CPC was ~94%, the loading capacity more than 50% and prolonged release over 7days were shown. The formulations with noted charge ratios resulted in stable CP alginate nanoparticles with a potential of treating periodontal disease. PMID- 27475835 TI - Rural health systems' perceptions of referral to community pharmacists during transitions of care. AB - OBJECTIVES: To identify rural health systems' perceptions of value, benefits, barriers, and opportunities associated with community pharmacist involvement in patient transitions of care. SETTING: Rural health systems in northwest and central Missouri. PRACTICE DESCRIPTION AND INNOVATION: Qualitative descriptive study of key informant interviews with self-identified decision makers of rural health systems within a 50-mile radius of 15 independent community pharmacy chain locations. EVALUATION: Interviews were recorded, transcribed, and coded to evaluate themes in participant responses. RESULTS: Fifteen interviews were conducted at 8 rural health systems. Participants expressed significant value in community pharmacist involvement in transitions of care and highlighted several benefits, barriers, and opportunities related to potential collaboration. Benefits that were identified included medication monitoring, resource for patient information, and desire among health care providers to work with community pharmacists. Barriers included legal and regulatory issues with referral, communication, and prescriber utilization. Opportunities described included: patient education, monitoring, and follow-up; targeted interventions; medication access assistance; bedside medication delivery; and collaboration between community pharmacies and health care entities. CONCLUSION: Rural health system informants perceived community pharmacy involvement to be valuable and were receptive to collaboration during transitional care to improve patient outcomes. They highlighted barriers to overcome to truly incorporate community pharmacists into the transitional care arena. Understanding these rural health systems' perceptions can guide community pharmacies in developing collaborative relationships and patient care services to assist with care transitions. PMID- 27475836 TI - Banned and discouraged-use ingredients found in weight loss supplements. AB - OBJECTIVES: To identify banned and discouraged-use ingredients, such as ephedra, 1,3-dimethylamylamine, and beta-methyl-phenylethylamine, in readily available weight loss dietary supplements within a 10-mile radius of Regis University. METHODS: A list of banned and discouraged-use ingredients was compiled with the use of the Food and Drug Administration (FDA) dietary supplement website which provides information on supplement ingredients that are no longer legal or are advised against owing to adverse event reporting. Investigators visited all retail outlet stores within a 10-mile radius of Regis University in Denver, Colorado. Retail chains were not duplicated and only one of each chain was evaluated. RESULTS: A total of 51 weight loss supplement products from retail stores were found with banned or discouraged-use substances listed on their labels. At least one banned ingredient was found to be listed on the product labels in 17 of the 51 studied supplements (33%). At least one discouraged-use ingredient was found in 46 of the 51 products (90%). Retail outlet stores dedicated to supplements and sports nutrition alone were found to have the greatest number of weight loss supplements that included banned and discouraged use ingredients. CONCLUSION: The FDA has taken action to remove some weight loss supplements from the market that contain banned ingredients. Unfortunately, based on the findings of this study, it is evident that products containing these ingredients remain on the market today. PMID- 27475837 TI - An acetaminophen icon helps reduce medication decision errors in an experimental setting. AB - OBJECTIVES: To assess the effect of adding an acetaminophen ingredient icon to acetaminophen medication labels on consumer decision making about concomitant use of acetaminophen medications to avoid overdose, which is associated with liver injury. DESIGN: Parallel-group randomized study. SETTING: Consumer research facilities in Indianapolis, Baltimore, and Los Angeles. PARTICIPANTS: A total of 517 adults (30% with limited health literacy) recruited at 3 consumer research sites. INTERVENTION: Participants were randomized to a non-icon condition in which medications carried current labeling or an icon condition in which all acetaminophen medications were additionally marked with an icon. MAIN OUTCOME MEASURES: Participants were presented with a medicine cabinet containing 12 diverse prescription and non-prescription medications, one-half containing acetaminophen, and made decisions about which medications were appropriate to take after an acetaminophen medication had already been taken. Outcome measures were errors in medication decisions and response time. RESULTS: The icon reduced the odds of participants making medication-decision errors by 53% (CI 31%-68%), with effects evident across medication categories. The icon eliminated a trend for those with lower health literacy or less education to have a greater likelihood of making errors. The icon also reduced response times, indicating reduced cognitive load for decisions. CONCLUSION: An icon can improve decision making regarding acetaminophen-containing medications, particularly among individuals with limited health literacy or education. PMID- 27475838 TI - Comparison between fibroblast wound healing and cell random migration assays in vitro. AB - Cell migration plays a key role in many biological processes, including cancer growth and invasion, embryogenesis, angiogenesis, inflammatory response, and tissue repair. In this work, we compare two well-established experimental approaches for the investigation of cell motility in vitro: the cell random migration (CRM) and the wound healing (WH) assay. In the former, extensive tracking of individual live cells trajectories by time-lapse microscopy and elaborate data processing are used to calculate two intrinsic motility parameters of the cell population under investigation, i.e. the diffusion coefficient and the persistence time. In the WH assay, a scratch is made in a confluent cell monolayer and the closure time of the exposed area is taken as an easy-to measure, empirical estimate of cell migration. To compare WH and CRM we applied the two assays to investigate the motility of skin fibroblasts isolated from wild type and transgenic mice (TgPED) overexpressing the protein PED/PEA-15, which is highly expressed in patients with type 2 diabetes. Our main result is that the cell motility parameters derived from CRM can be also estimated from a time resolved analysis of the WH assay, thus showing that the latter is also amenable to a quantitative analysis for the characterization of cell migration. To our knowledge this is the first quantitative comparison of these two widely used techniques. PMID- 27475839 TI - DNA methylation and not H3K4 trimethylation dictates the expression status of miR 152 gene which inhibits migration of breast cancer cells via DNMT1/CDH1 loop. AB - MicroRNAs (miRNA) are small non-coding RNAs which targets most protein-coding transcripts (mRNA) and destroy them. Thus miRNA controls the abundance of those specific proteins and impact on developmental, physiological and pathological processes. Dysregulation of miRNA function thus may lead to various clinicopathological complications, including breast cancer. Silencing of miR-152 gene due to promoter DNA methylation alter the expression pattern of several other genes. E-cadherin (CDH1) forms the core of adherent junctions between surrounding epithelial cells, link with actin cytoskeleton and affects cell signaling. CDH1 gene is down regulated by promoter DNA methylation during cancer progression. In this investigation, we attempt to elucidate the correlation of miR-152 and CDH1 function, as it is well known that the loss of CDH1 function is one of the major reasons for cancer metastasis and aggressiveness of spreading. For the first time we have shown that loss of CDH1 expression is directly proportional to the loss of miR-152 function in breast cancer cells. mRNA and protein expression profile of DNMT1 implicate that miR-152 targets DNMT1 mRNA and inhibits its protein expression. Tracing the molecular marks on DNA and histone 3 for understanding the mechanism of gene regulation by ChIP analyses leads to a paradoxical result that shows DNA methylation adjacent to active histone marking (enrichment of H3K4me3) silence miR-152 gene. Further experiments revealed that DNMT1 plays crucial role for regulation of miR-152 gene. When DNMT1 protein function is blocked miR-152 expression prevails and destroys the mRNA of DNMT1; this molecular regulatory mechanism is creating a cyclic feedback loop, which is now focused as DNMT1/miR-152 switch for on/off of DNMT1 target genes. We discovered modulation of CDH1 gene expression by DNMT1/miR-152 switches. We have demonstrated further that DNMT1 down regulation mediated upregulation of CDH1 (hereafter, DNMT1/CDH1 loop) in presence of ectopic-excess of miR-152 prevents migration of cancer cells. Our data provides novel insights into the regulation mechanism of miRNA and mRNA/protein coding genes and enhances the amplitude of cancer epigenome. PMID- 27475840 TI - Simvastatin induces differentiation of rabbit articular chondrocytes via the ERK 1/2 and p38 kinase pathways. AB - Statins are competitive inhibitors of hydroxy-methyl-glutaryl Coenzyme A (HMG CoA) reductase, a key enzyme involved in the conversion of HMG-CoA to the cholesterol precursor mevalonate. Some statins, such as simvastatin (simvastatin), have been shown to have anti-cancer and anti-inflammatory effects, reducing cartilage degradation in osteoarthritic rabbits in vivo. However, the regulatory mechanisms undergirding simvastatin mediated chondrocyte differentiation have not been well elucidated. Thus, we investigated the action and mechanism of simvastatin on differentiation of rabbit articular chondrocytes through western blot analyses, RT-PCR, and immunohistochemical (IHC) and immunofluorescence (IF) staining. Simvastatin treatment was found to induce type II collagen expression and sulfated-proteoglycan synthesis in a dose- and time dependent manner. Indeed, RT-PCR revealed increased expression of type II collagen on treatment with simvastatin. Both IHC and IF staining indicated differentiation of chondrocytes. Simvastatin treatment reduced activation of ERK 1/2 and stimulated activation of p38 kinase. Inhibition of ERK-1/2 with PD98059 enhanced simvastatin induced differentiation, whereas inhibition of p38 kinase with SB203580 inhibited simvastatin induced differentiation. Simvastatin treatment also inhibits loss of type II collagen in serial monolayer culture. Collectively, our results indicate that ERK-1/2 and p38 kinase regulate simvastatin-induced differentiation of chondrocytes in opposing manners. Thus, these findings suggest that simvastatin may be a potential therapeutic drug for osteoarthritis. PMID- 27475841 TI - Is single-incision laparoscopic cholecystectomy ready for prime time? PMID- 27475842 TI - Lumping evolutionary game dynamics on networks. AB - We study evolutionary game dynamics on networks (EGN), where players reside in the vertices of a graph, and games are played between neighboring vertices. The model is described by a system of ordinary differential equations which depends on players payoff functions, as well as on the adjacency matrix of the underlying graph. Since the number of differential equations increases with the number of vertices in the graph, the analysis of EGN becomes hard for large graphs. Building on the notion of lumpability for Markov chains, we identify conditions on the network structure allowing to reduce the original graph. In particular, we identify a partition of the vertex set of the graph and show that players in the same block of a lumpable partition have equivalent dynamical behaviors, whenever their payoff functions and initial conditions are equivalent. Therefore, vertices belonging to the same partition block can be merged into a single vertex, giving rise to a reduced graph and consequently to a simplified system of equations. We also introduce a tighter condition, called strong lumpability, which can be used to identify dynamical symmetries in EGN which are related to the interchangeability of players in the system. PMID- 27475843 TI - A hybrid agent-based model of the developing mammary terminal end bud. AB - Mammary gland ductal elongation is spearheaded by terminal end buds (TEBs), where populations of highly proliferative cells are maintained throughout post-pubertal organogenesis in virgin mice until the mammary fat pad is filled by a mature ductal tree. We have developed a hybrid multiscale agent-based model to study how cellular differentiation pathways, cellular proliferation capacity, and endocrine and paracrine signaling play a role during development of the mammary gland. A simplified cellular phenotypic hierarchy that includes stem, progenitor, and fully differentiated cells within the TEB was implemented. Model analysis finds that mammary gland development was highly sensitive to proliferation events within the TEB, with progenitors likely undergoing 2-3 proliferation cycles before transitioning to a non-proliferative phenotype, and this result is in agreement with our previous experimental work. Endocrine and paracrine signaling were found to provide reliable ductal elongation rate regulation, while variations in the probability a new daughter cell will be of a proliferative phenotype were seen to have minimal effects on ductal elongation rates. Moreover, the distribution of cellular phenotypes within the TEB was highly heterogeneous, demonstrating significant allowable plasticity in possible phenotypic distributions while maintaining biologically relevant growth behavior. Finally, simulation results indicate ductal elongation rates due to cellular proliferation within the TEB may have a greater sensitivity to upstream endocrine signaling than endothelial to stromal paracrine signaling within the TEB. This model provides a useful tool to gain quantitative insights into cellular population dynamics and the effects of endocrine and paracrine signaling within the pubertal terminal end bud. PMID- 27475844 TI - Efficacy and Safety of Thrombectomy Combined with Intracoronary Administration of Tirofiban in ST-segment Elevation Myocardial Infarction (STEMI). AB - BACKGROUND No/slow reflow gives rise to serious complications in STEMI patients undergoing PCI, and can lead to worse outcomes. Several measures are used to prevent no/slow reflow, including thrombus removal processes and intensive use of anticoagulant agents. Our study was designed to evaluate the efficacy and safety of thrombectomy and intracoronary administration of GPIIb/IIIa inhibitors in STEMI patients undergoing PPCI. MATERIAL AND METHODS We randomly assigned 240 STEMI patients into 3 groups. Before PPCI, patients in group A received thrombectomy and intracoronary administration of tirofiban. Patients in group B received thrombectomy, and patients in group C neither of these 2 treatments. Their demographic data and coronary angiography results were recorded. TIMI grade flow was used to evaluate the effect. After the follow-up, major adverse cardiac events were regarded as study endpoints in evaluating the safety of the combined therapy. RESULTS We found no significant differences among the 3 groups in demographic and clinical characteristics (p>0.05). Patients in group A had better TIMI grade classifications and ST-segment elevation (p=0.005), and lower incidence of no/slow reflow (p=0.031) and MACE. During 6-month follow-up, the MACE rate was lower in group A than in groups B and C (p=0.038). CONCLUSIONS The use of thrombectomy combined with intracoronary administration of tirofiban is relatively effective and safe in STEMI patients undergoing PPCI. PMID- 27475845 TI - Joint dynamics and intra-subject variability during countermovement jumps in children and adults. AB - The present study investigated lower limb joint work, lower limb joint energy transport and intra-subject variation of the joint dynamics during countermovement jumps in children and adults. Twelve healthy men and eleven healthy boys performed ten maximal countermovement jumps. Three dimensional kinematics and kinetics were recorded in synchrony. Hip, knee and ankle joint eccentric and concentric work, joint energy transfer, intra-subject variation of joint moment, joint power and joint moment components were calculated. The children had lower eccentric and concentric hip work and lower eccentric knee work but no group difference was observed in the concentric knee joint work and ankle joint work. Eccentric hip and knee joint energy transfer and concentric hip joint energy transfer were higher in adults. The children had higher intra subject variation in the eccentric and concentric hip joint work, hip joint moment and hip and knee joint power. Higher intra-subject variation was observed in horizontal joint reaction force components for the children and higher intra subject variation in the segment angular inertia components was observed for the adults. The joint dynamics of children during countermovement jumps were less efficient in producing proximal joint work, transferring energy through joint centres and characterized by a higher intra-subject variation. PMID- 27475847 TI - Role of C1q complement fixing antibody assay in therapeutic plasma exchange management of pediatric cardiac antibody mediated rejection. AB - Pediatric cardiac transplant patients with antibody-mediated rejection (AMR) often undergo therapeutic plasma exchange (TPE) to remove pathologic donor specific antibodies (DSA). In cases where DSA persist, it is unclear how long TPE should be continued. We report a case of a 17-year-old cardiac transplant patient with AMR where use of a C1q complement fixing antibody assay helped guide TPE cessation. This report adds to the existing literature that highlights the potential clinical significance of C1q antibodies in AMR management. PMID- 27475846 TI - Pin1 enhances adipocyte differentiation by positively regulating the transcriptional activity of PPARgamma. AB - Pin1 is a peptidylprolyl cis/trans isomerase and it has a unique enzymatic activity of catalyzing isomerization of the peptide bond between phospho serine/threonine and proline. Through the conformational change of its substrates, Pin1 regulates diverse biological processes including adipogenesis. In mouse embryonic fibroblasts and 3T3-L1 preadipocytes, overexpression of Pin1 enhances adipocyte differentiation whereas inhibition of Pin1 activity suppresses it. However, the precise functions of Pin1 during adipogenesis are not clear. In the present study, we investigated the potential targets of Pin1 during adipogenesis. We found that Pin1 interacts directly with and regulates the transcriptional activity of PPARgamma, a key regulator of adipogenesis. In addition, ERK activity and Ser273 of PPARgamma, a potential ERK phosphorylation target site, are important for the regulation of PPARgamma function by Pin1 in 3T3-L1 cells. Taken together our results suggest a novel regulatory mechanism of Pin1 during adipogenesis, in which Pin1 enhances adipocyte differentiation by regulating the function of PPARgamma. PMID- 27475848 TI - Regulation of the Embryonic Cell Cycle During Mammalian Preimplantation Development. AB - The preimplantation development stage of mammalian embryogenesis consists of a series of highly conserved, regulated, and predictable cell divisions. This process is essential to allow the rapid expansion and differentiation of a single cell zygote into a multicellular blastocyst containing cells of multiple developmental lineages. This period of development, also known as the germinal stage, encompasses several important developmental transitions, which are accompanied by dramatic changes in cell cycle profiles and dynamics. These changes are driven primarily by differences in the establishment and enforcement of cell cycle checkpoints, which must be bypassed to facilitate the completion of essential cell cycle events. Much of the current knowledge in this area has been amassed through the study of knockout models in mice. These mouse models are powerful experimental tools, which have allowed us to dissect the relative dependence of the early embryonic cell cycles on various aspects of the cell cycle machinery and highlight the extent of functional redundancy between members of the same gene family. This chapter will explore the ways in which the cell cycle machinery, their accessory proteins, and their stimuli operate during mammalian preimplantation using mouse models as a reference and how this allows for the usually well-defined stages of the cell cycle to be shaped and transformed during this unique and critical stage of development. PMID- 27475849 TI - Genome Duplication at the Beginning of Mammalian Development. AB - Nothing is more fundamental to mammalian development than the ability to accurately reproduce its genome once-but only once-each time a cell divides. In fact, the basic mechanism for replicating DNA has been conserved throughout evolution, even though the magnitude of the problem became monumental. A human cell contains 670 times the DNA in an E. coli cell, and human development requires trillions of cell divisions that produce about 37 billion miles of DNA! But instead of increasing the speed of replication forks to compensate for increasing genome size and organism complexity, evolution simply increased the number of replication origins. This allowed mammalian development regulate initiation of DNA replication during cell proliferation without interfering with the ever-changing demands of gene expression during cell differentiation. Moreover, it allowed developing tissues to complete genome duplication before beginning mitosis and to restrict genome duplication to once per cell division. And yet, to overproduce gene products during development, some cells are allowed to differentiate into nonproliferating polyploid cells. This chapter summarizes the mechanisms that make these events possible. Ironically, aberrations in these mechanisms are linked to cancer. In fact, the pluripotent cells produced during preimplantation development not only share characteristics of cancer cells, but they can also initiate cancer. PMID- 27475850 TI - Zygotic Genome Activation Revisited: Looking Through the Expression and Function of Zscan4. AB - Zygotic genome activation (ZGA, a.k.a. zygotic gene activation) is a critical event in development, when the paternally derived genome and maternally derived genome begin to be activated and transcribed after fertilization. Major ZGA occurs at the two-cell stage in mice and the four- to eight-cell stage in human preimplantation embryos. It has been thought that ZGA exists to provide RNAs and proteins supporting embryonic development after supplies stored in oocytes are used up; however, this paradigm does not seem to explain recent findings. For example, many ZGA genes-once activated-are quickly turned off, and thus ZGA forms a transient wave of transcriptional activation. In addition, ZGA genes are not evolutionarily conserved. In this review, we address these issues by focusing on Zscan4 (zinc finger and SCAN domain-containing 4), which was identified for its specific expression in preimplantation embryos during ZGA. Detailed molecular analyses of Zscan4 expression and function have revealed common features of Zscan4-associated events (Z4 events) in mouse embryonic stem cells and ZGA in preimplantation embryos. One feature is a rapid derepression and rerepression of constitutive heterochromatin, which includes pericentromeric major satellites and telomeres, and facultative heterochromatin, which includes retrotransposons and Z4 event-associated genes. We propose that the Z4 event superimposed on ZGA plays a critical role in the maintenance of genome and chromosome integrity in preimplantation embryos by promoting correction of DNA damage and chromosome abnormalities. PMID- 27475851 TI - From Meiosis to Mitosis: The Astonishing Flexibility of Cell Division Mechanisms in Early Mammalian Development. AB - The execution of female meiosis and the establishment of the zygote is arguably the most critical stage of mammalian development. The egg can be arrested in the prophase of meiosis I for decades, and when it is activated, the spindle is assembled de novo. This spindle must function with the highest of fidelity and yet its assembly is unusually achieved in the absence of conventional centrosomes and with minimal influence of chromatin. Moreover, its dramatic asymmetric positioning is achieved through remarkable properties of the actin cytoskeleton to ensure elimination of the polar bodies. The second meiotic arrest marks a uniquely prolonged metaphase eventually interrupted by egg activation at fertilization to complete meiosis and mark a period of preparation of the male and female pronuclear genomes not only for their entry into the mitotic cleavage divisions but also for the imminent prospect of their zygotic expression. PMID- 27475852 TI - The Genetic Regulation of Cell Fate During Preimplantation Mouse Development. AB - The adult body is estimated to contain several hundred distinct cell types, each with a specialized physiological function. Failure to maintain cell fate can lead to devastating diseases and cancer, but understanding how cell fates are assigned and maintained during animal development provides new opportunities for human health intervention. The mouse is a premier model for evaluating the genetic regulation of cell fate during development because of the wide variety of tools for measuring and manipulating gene expression levels, the ability to access embryos at desired developmental stages, and the similarities between mouse and human development, particularly during the early stages of development. During the first 3 days of mouse development, the preimplantation embryo sets aside cells that will contribute to the extraembryonic tissues. The extraembryonic tissues are essential for establishing pregnancy and ensuring normal fetal development in both mice and humans. Genetic analyses of mouse preimplantation development have permitted identification of genes that are essential for specification of the extraembryonic lineages. In this chapter, we review the tools and concepts of mouse preimplantation development. We describe genes that are essential for cell fate specification during preimplantation stages, and we describe diverse models proposed to account for the mechanisms of cell fate specification during early development. PMID- 27475853 TI - Polarity in Cell-Fate Acquisition in the Early Mouse Embryo. AB - Establishing polarity is a fundamental part of embryogenesis and can be traced back to the earliest developmental stages. It can be achieved in one of two ways: through the preexisting polarization of germ cells before fertilization or via symmetry breaking after fertilization. In mammals, it seems to be the latter, and we will discuss the various cytological and molecular events that lead up to this event, its mechanisms and the consequences. In mammals, the first polarization event occurs in the preimplantation period, when the embryo is but a cluster of cells, free-floating in the oviduct. This provides a unique, autonomous system to study the de novo polarization that is essential to life. In this review, we will cover modern and past studies on the polarization of the early embryo, using the mouse as a model system, as well as hypothesizing the potential implications and functions of the biological events involved. PMID- 27475854 TI - Mouse Embryo Compaction. AB - Compaction is a critical first morphological event in the preimplantation development of the mammalian embryo. Characterized by the transformation of the embryo from a loose cluster of spherical cells into a tightly packed mass, compaction is a key step in the establishment of the first tissue-like structures of the embryo. Although early investigation of the mechanisms driving compaction implicated changes in cell-cell adhesion, recent work has identified essential roles for cortical tension and a compaction-specific class of filopodia. During the transition from 8 to 16 cells, as the embryo is compacting, it must also make fundamental decisions regarding cell position, polarity, and fate. Understanding how these and other processes are integrated with compaction requires further investigation. Emerging imaging-based techniques that enable quantitative analysis from the level of cell-cell interactions down to the level of individual regulatory molecules will provide a greater understanding of how compaction shapes the early mammalian embryo. PMID- 27475855 TI - Metabolism of Preimplantation Embryo Development: A Bystander or an Active Participant? AB - Unicellular organisms are exquisitely sensitive to nutrient availability in the environment and have evolved elaborate mechanisms to sense the levels and types of nutrients, altering gene expression patterns accordingly to adjust the metabolic activities required to survive. Thus, environmental cues induce adaptive metabolic differentiation through transcriptional and posttranscriptional changes. Similarly, preimplantation embryos are exposed to various environmental cues within the maternal reproductive tract prior to implantation. Because only "simple" culture conditions are required, it is assumed that these embryos are genetically preprogrammed to develop with little influence from the environment, with the exception of few "necessities" provided by the environment. However, a wealth of literature now suggests that the developing embryos are greatly influenced by the maternal environment. Even though the developing embryos have the capacity and plasticity to deal with nutritional imbalance posed by an altered maternal environment, there is often a trade-off to the overall fitness of those embryos later in life. Despite these studies that underline the general importance of the reproductive environment during development, it is thought that the primary driver of mammalian development is strictly genetic and that metabolic adaptation by the preimplantation embryo is secondary to genetic control. In this review, I propose that not only does the maternal environment of developing preimplantation embryos influence developmental potential, pregnancy outcomes, and postnatal disease states, but that it has an active role in induction and potentiation of the first differentiation event, the production of trophectoderm and inner cell mass lineages. PMID- 27475856 TI - Epigenetic Control of Early Mouse Development. AB - Although the genes sequentially transcribed in the mammalian embryo prior to implantation have been identified, understanding of the molecular processes ensuring this transcription is still in development. The genomes of the sperm and egg are hypermethylated, hence transcriptionally silent. Their union, in the prepared environment of the egg, initiates their epigenetic genomic reprogramming into a totipotent zygote, in which the genome gradually becomes transcriptionally activated. During gametogenesis, sex-specific processes result in sperm and eggs with disparate epigenomes, both of which require drastic reprogramming to establish the totipotent genome of the zygote and the pluripotent inner cell mass of the blastocyst. Herein, we describe the factors, DNA and histone modifications, activation and repression of retrotransposons, and cytoplasmic localizations, known to influence the activation of the mammalian genome at the initiation of new life. PMID- 27475857 TI - Capturing Identity and Fate Ex Vivo: Stem Cells from the Mouse Blastocyst. AB - During mouse preimplantation development, three molecularly, morphologically, and spatially distinct lineages are formed, the embryonic epiblast, the extraembryonic primitive endoderm, and the trophectoderm. Stem cell lines representing each of these lineages have now been derived and can be indefinitely maintained and expanded in culture, providing an unlimited source of material to study the interplay of tissue-specific transcription factors and signaling pathways involved in these fundamental cell fate decisions. Here we outline our current understanding of the derivation, maintenance, and properties of these in vitro stem cell models representing the preimplantation embryonic lineages. PMID- 27475858 TI - Species-Specific Variation Among Mammals. AB - Reproduction across mammalian species is conserved with a general pattern of fertilization followed by nascent embryo development in transcriptional silence for a variable length of time, a series of cleavage divisions that occur without growth in size of the embryo, compaction to form a morula, and production of a blastocyst. Following blastocyst formation, the embryo may implant immediately or after substantial differentiation of the epiblast and hypoblast layers. In this chapter, the shared and unique properties of several species, commonly used in studies of reproduction and embryology, are outlined. PMID- 27475859 TI - Genetic Analysis of Human Preimplantation Embryos. AB - Preimplantation development comprises the initial stages of mammalian development, before the embryo implants into the mother's uterus. In normal conditions, after fertilization the embryo grows until reaching blastocyst stage. The blastocyst grows as the cells divide and the cavity expands, until it arrives at the uterus, where it "hatches" from the zona pellucida to implant into the uterine wall. Nevertheless, embryo quality and viability can be affected by chromosomal abnormalities, most of which occur during gametogenesis and early embryo development; human embryos produced in vitro are especially vulnerable. Therefore, the selection of chromosomally normal embryos for transfer in assisted reproduction can improve outcomes in poor-prognosis patients. Additionally, in couples with an inherited disorder, early diagnosis could prevent pregnancy with an affected child and would, thereby, avoid the therapeutic interruption of pregnancy. These concerns have prompted advancements in the use of preimplantation genetic diagnosis (PGD). Genetic testing is applied in two different scenarios: in couples with an inherited genetic disorder or carriers of a structural chromosomal abnormality, it is termed PGD; in infertile couples with increased risk of generating embryos with de novo chromosome abnormalities, it is termed preimplantation genetic screening, or PGS. PMID- 27475860 TI - Preface. PMID- 27475861 TI - Gambierol and n-alkanols inhibit Shaker Kv channel via distinct binding sites outside the K(+) pore. AB - The marine polycyclic-ether toxin gambierol and 1-butanol (n-alkanol) inhibit Shaker-type Kv channels by interfering with the gating machinery. Competition experiments indicated that both compounds do not share an overlapping binding site but gambierol is able to affect 1-butanol affinity for Shaker through an allosteric effect. Furthermore, the Shaker-P475A mutant, which inverses 1-butanol effect, is inhibited by gambierol with nM affinity. Thus, gambierol and 1-butanol inhibit Shaker-type Kv channels via distinct parts of the gating machinery. PMID- 27475862 TI - Roles of NTE protein and encoding gene in development and neurodevelopmental toxicity. AB - Neuropathy Target Esterase (NTE) is a membrane protein codified by gene PNPLA6. NTE was initially discovered as a target of the so-called organophosphorus induced delayed polyneuropathy triggered by the inhibition of the NTE-associated esterase center by neuropathic organophosphorus compounds (OPs). The physiological role of NTE might be related to membrane lipid homeostasis and seems to be involved in adult organisms in maintaining nervous system integrity. However, NTE is also involved in cell differentiation and embryonic development. NTE is expressed in embryonic and adult stem cells, and the silencing of Pnpla6 by interference RNA in D3 mouse cells causes significant alterations in several genetic pathways related to respiratory tube and nervous system formation, and in vasculogenesis and angiogenesis. The silencing of gene PNPLA6 in human NT2 cells at the beginning of neurodifferentiation causes severe phenotypic alterations in neuron-like differentiated cells; e.g. reduced electrical activity and the virtual disappearance of markers of neural tissue, synapsis and glia. These phenotypic effects were not reproduced when NTE esterase activity was inhibited by neuropathic OP mipafox instead of being silenced at the genetic level. Neuropathic OP chlorpyrifos seems able to induce neurodevelopmental alterations in animals. However, the effects of chlorpyrifos in the expression of biomarker genes of differentiation in D3 cells differ considerably from the effects induced by Pnpla6 silencing. In conclusion, available information suggests that PNPLA6 and/or the NTE protein play a role in early neurodifferentiation stages, although this role is not dependent upon the esterase NTE center. Therefore, impairments caused by OPs, such as chlorpyrifos, on neurodevelopment are not due to inhibition of NTE esterase enzymatic activity. PMID- 27475864 TI - Popular naturally occurring antioxidants as potential anticoagulant drugs. AB - Blood coagulation is a physiological process whose main task is prevention of blood loss from injured vessels. This process consists of a series of zymogens proteolytic activation leading to the generation of the main coagulation enzyme - thrombin. Besides its important role in blood coagulation process, thrombin is involved in many cardiovascular diseases, which are responsible for almost half of fatalities in economically developed countries. The evidence for the increased generation and in vivo activity of thrombin was observed in the plasma of individuals at high risk for clinically significant venous and arterial thromboembolic complications. Antioxidants activity of plants extracts has been well known for many years and was confirmed by many publications. However, during the last decade many research centers presented results suggesting anticoagulant potential of various plant extracts. Many researchers have also provided evidence that polyphenol compounds are able to inhibit the activity of many enzymes, including serine proteases. All research described in this review clearly indicate that polyphenols and polyphenol-rich extracts possess not only antioxidative but also anticoagulant properties and may be useful in creation of new therapeutic agents or dietary supplements. Based on described properties polyphenols would be very helpful with both prevention and treatment of thromboembolic complications associated with multiple failures of haemostasis, because the available therapeutic agents do not offer such double-effects (antioxidant and anticoagulant). PMID- 27475863 TI - Piceatannol and resveratrol share inhibitory effects on hydrogen peroxide release, monoamine oxidase and lipogenic activities in adipose tissue, but differ in their antilipolytic properties. AB - Piceatannol is a hydroxylated derivative of resveratrol. While both dietary polyphenols coexist in edible plants and fruits, and share equivalent concentrations in several wines, the influence of piceatannol on adiposity has been less studied than that of resveratrol. Though resveratrol is now recognized to limit fat deposition in various obesity models, the benefit of its dietary supplementation remains under debate regarding human obesity treatment or prevention. The research for more potent resveratrol analogs is therefore still undergoing. This prompted us to compare various effects of piceatannol and resveratrol directly on human adipose tissue (hAT). Hydrogen peroxide release was measured by Amplex Red-based fluorescence in subcutaneous hAT samples from obese patients. Interactions of stilbenes with human amine oxidases and quinone reductase were assessed by radiometric methods, computational docking and electron paramagnetic resonance. Influences on lipogenic and lipolytic activities were compared in mouse adipocytes. Resveratrol and piceatannol inhibited monoamine oxidase (MAO) with respective IC50 of 18.5 and 133.7 MUM, but not semicarbazide-sensitive amine oxidase (SSAO) in hAT. For both stilbenes, the docking scores were better for MAO than for SSAO. Piceatannol and resveratrol similarly hampered hydrogen peroxide detection in assays with and without hAT, while they shared pro-oxidant activities when incubated with purified quinone reductase. They exhibited similar dose-dependent inhibition of adipocyte lipogenic activity. Only piceatannol inhibited basal and stimulated lipolysis when incubated at a dose >=100 MUM. Thus, piceatannol exerted on fat cells dose dependent effects similar to those of resveratrol, except for a stronger antilipolytic action. In this regard, piceatannol should be useful in limiting the lipotoxicity related to obesity when ingested or administered alone - or might hamper the fat mobilization induced by resveratrol when simultaneously administered with it. PMID- 27475865 TI - The causes of the municipal solid waste and the greenhouse gas emissions from the waste sector in the United States. AB - The United States generated approximately 730kg of waste per capita in 2013, which is the highest amount of waste among OECD countries. The waste has adverse effects to human health and the environment. One of the most serious adverse effects is greenhouse gas emissions, especially methane (CH4), which causes global warming. However, the United States' amount of waste generation is not decreasing, and the recycling rate is only 26%, which is lower than other OECD countries. In order to decrease waste generation and greenhouse gas emissions, identifying the causality of the waste generation and greenhouse gas emissions from waste sector should be made a priority. The research objective is to verify whether the Environmental Kuznets Curve relationship is supported for waste generation and GDP across the U.S. Moreover, it also confirmed that total waste generation and recycling of waste influences carbon dioxide emissions from the waste sector. Based on the results, critical insight and suggestions were offered to policymakers, which is the potential way to lower the solid waste and greenhouse gas emissions from the waste sector. This research used annually based U.S. data from 1990 to 2012, and these data were collected from various data sources. To verify the causal relationship, the Granger causality test was applied. The results showed that there is no causality between GDP and waste generation, but total waste and recycling generate significantly increasing and decreasing greenhouse gas emissions from the waste sector, respectively. This implies that waste generation will not decrease even if GDP increases. And, if waste generation decreases or the recycling rate increases, greenhouse gas emission will decrease. Based on these results, increasing the recycling rate is first suggested. The second suggestion is to break the causal relationship between MSW and greenhouse gas emission from the waste sector. The third is that the U.S. government should benchmark a successful case of waste management. Based on the research, it is expected that waste generation and carbon dioxide emission from the waste sector can be decreased more efficiently. PMID- 27475866 TI - Recirculation of reverse osmosis concentrate in lab-scale anaerobic and aerobic landfill simulation reactors. AB - Leachate treatment is a major issue in the context of landfill management, particularly in view of the consistent changes manifested over time in the quality and quantity of leachate produced, linked to both waste and landfill characteristics, which renders the procedure technically difficult and expensive. Leachate recirculation may afford a series of potential advantages, including improvement of leachate quality, enhancement of gas production, acceleration of biochemical processes, control of moisture content, as well as nutrients and microbe migration within the landfill. Recirculation of the products of leachate treatment, such as reverse osmosis (RO) concentrate, is a less common practice, with widespread controversy relating to its suitability, potential impacts on landfill management and future gaseous and leachable emissions. Scientific literature provides the results of only a few full-scale applications of concentrate recirculation. In some cases, an increase of COD and ammonium nitrogen in leachate was observed, coupled with an increase of salinity; which, additionally, might negatively affect performance of the RO plant itself. In other cases, not only did leachate production not increase significantly but the characteristics of leachate extracted from the well closest to the re-injection point also remained unchanged. This paper presents the results of lab-scale tests conducted in landfill simulation reactors, in which the effects of injection of municipal solid waste (MSW) landfill leachate RO concentrate were evaluated. Six reactors were managed with different weekly concentrate inputs, under both anaerobic and aerobic conditions, with the aim of investigating the short and long-term effects of this practice on landfill emissions. Lab-scale tests resulted in a more reliable identification of compound accumulation and kinetic changes than full-scale applications, further enhancing the development of a mass balance in which gaseous emissions and waste characteristics were also taken into consideration. Results showed that RO concentrate recirculation did not produce consistent changes in COD emissions and methane production. Simultaneously, ammonium ion showed a consistent increase in leachate (more than 25%) in anaerobic reactors, free ammonia gaseous emissions doubled with concentrate injection, while chloride resulted accumulated inside the reactor. PMID- 27475867 TI - Method development and qualification of capillary zone electrophoresis for investigation of therapeutic monoclonal antibody quality. AB - Capillary electrophoresis techniques are widely used in the analytical biotechnology. Different electrophoretic techniques are very adequate tools to monitor size-and charge heterogenities of protein drugs. Method descriptions and development studies of capillary zone electrophoresis (CZE) have been described in literature. Most of them are performed based on the classical one-factor-at time (OFAT) approach. In this study a very simple method development approach is described for capillary zone electrophoresis: a "two-phase-four-step" approach is introduced which allows a rapid, iterative method development process and can be a good platform for CZE method. In every step the current analytical target profile and an appropriate control strategy were established to monitor the current stage of development. A very good platform was established to investigate intact and digested protein samples. Commercially available monoclonal antibody was chosen as model protein for the method development study. The CZE method was qualificated after the development process and the results were presented. The analytical system stability was represented by the calculated RSD% value of area percentage and migration time of the selected peaks (<0.8% and <5%) during the intermediate precision investigation. PMID- 27475874 TI - Incidence and antibiotic treatment of erythema migrans in Norway 2005-2009. AB - The first stage of Lyme borreliosis (LB) is mainly the typical skin lesion, erythema migrans (EM), which is estimated to comprise 80-90% of all LB cases. However, the reporting of, and the actual incidence of LB varies throughout Europe. Studies from Sweden and Holland have found EM incidences varying from 53 to 464 EM/100,000 inhabitants/year. Under-reporting of LB is common and a coefficient of three to reach a realistic estimate is suggested. In Norway, it is mandatory to report only the second and third LB stages to the National Institute of Public Health. To find the Norwegian incidence of EM, we extracted data from the electronic medical records of regular general practitioners and out-of-hours services in the four counties with the highest rates of registered LB in the 5 years from 2005 to 2009. We found an EM incidence of 448 EM/100,000 inhabitants/year in these counties, which yields a national incidence of 148 EM/100,000 inhabitants/year. Our findings show that solitary EMs comprised almost 96% of the total LB incidence in Norway. Older females have the highest rates of EM. Phenoxymethylpenicillin is the most commonly used drug to treat EM in Norway, which complies with the national guidelines for antibiotic use. Antibody tests are performed in 15% of cases. Less than 1% of patients are referred to secondary care. The study also shows a high number of patients seeking care for tick bites without signs of infection and there is an overuse of antibiotics in these patients. PMID- 27475876 TI - Pain in context: Cues predicting a reward decrease fear of movement related pain and avoidance behavior. AB - Previous research shows that goal-directed behavior might be modulated by cues that predict (dis)similar outcomes. However, the literature investigating this modulation with pain outcomes is scarce. Therefore, this experiment investigated whether environmental cues predicting pain or reward modulate defensive pain responding. Forty-eight healthy participants completed a joystick movement task with two different movement orientations. Performing one movement was associated with a painful stimulus, whereas performance of another movement was associated with reward, i.e. lottery tickets. In a subsequent task, participants learned to associate three different cues withpain, reward, or neither of the two. Next, these cues were integrated in the movement task. This study demonstrates that in general, aversive cues enhance and appetitive cues reduce pain-related fear. Furthermore, we found that incongruence between the outcomes predicted by the movement and the cue results in more oscillatory behavior, i.e., participants were more willing to perform a painful movement when a cue predicting reward was simultaneously presented, and vice versa. Similarly, when given a choice, participants preferred to perform the reward movement, unless there was an incongruence between the outcomes predicted by the movements and cues. Taken together, these results provide experimental evidence that environmental cues are capable of modulating pain-related fear and avoidance behavior. PMID- 27475875 TI - Paired real-time PCR assays for detection of Borrelia miyamotoi in North American Ixodes scapularis and Ixodes pacificus (Acari: Ixodidae). AB - Borrelia miyamotoi is an emerging, tick-borne human pathogen. In North America, it is primarily associated with Ixodes scapularis and Ixodes pacificus, two species known to bite humans. Here we describe the development and evaluation of a pair of real-time TaqMan PCR assays designed to detect B. miyamotoi in North American ticks. We sought to achieve sensitivity to B. miyamotoi strains associated with ticks throughout North America, the full genetic diversity of which is unknown, by targeting sequences that are largely conserved between B. miyamotoi strains from the eastern United States and genetically distinct B. miyamotoi strains from Japan. The two assays target different loci on the B. miyamotoi chromosome and can be run side by side under identical cycling conditions. One of the assays also includes a tick DNA target that can be used to verify the integrity of tick-derived samples. Using both recombinant plasmid controls and genomic DNA from North American and Japanese strains, we determined that both assays reliably detect as few as 5 copies of the B. miyamotoi genome. We verified that neither detects B. burgdorferi, B. lonestari or B. turicatae. This sensitive and specific pair of assays successfully detected B. miyamotoi in naturally-infected, colony-reared nymphs and in field-collected I. scapularis and I. pacificus from the Northeast and the Pacific Northwest respectively. These assays will be useful in screening field-collected Ixodes spp. from varied regions of North America to assess the risk of human exposure to this emerging pathogen. PMID- 27475877 TI - Similar efficacy and safety of daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bloodstream infections: a meta-analysis. AB - Daptomycin and linezolid are the most commonly used antibiotics for bloodstream infection caused by vancomycin-resistant enterococci (VRE-BSI). However, the best therapeutic agent to treat VRE-BSI remains to be established. In order to provide evidence for an optimal treatment decision, a systematic review and meta-analysis was performed comparing the efficacy and safety of daptomycin and linezolid for the treatment of VRE-BSI. After thorough searching of relevant studies from MEDLINE, EMBASE, Clinicaltrials.gov and international meetings up to November 2015, 11 retrospective cohort studies were finally included with a sample size of 1339 patients. Among these 11 included studies, all patients in the daptomycin group received standard or high-dose daptomycin treatment (>=6 mg/kg/day). Data were extracted and pooled risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated using a random-effects model. The meta-analysis indicated similar crude overall mortality between patients receiving daptomycin and those treated with linezolid (RR = 1.07, 95% CI 0.83-1.37). Moreover, no difference regarding clinical cure (RR = 1.11, 95% CI 0.88-1.42), microbiological cure (RR = 0.99, 95% CI 0.90-1.09) or relapse rate of VRE-BSI (RR = 1.08, 95% CI 0.76-1.52) was found between daptomycin and linezolid. Adverse event rates were not significantly different between the two groups. Currently available evidence indicates similar efficacy and safety of daptomycin and linezolid for the treatment of VRE-BSI. However, the findings in the meta-analysis are limited by heterogeneity between relatively small-scale retrospective studies and should be interpreted cautiously. PMID- 27475878 TI - The Room Where It Happens: A Skeptic's Analysis of the New Heart Failure Guidelines. AB - New heart failure guidelines have been issued during the past several months, both in the United States and in Europe, in response to recent advances in and the approval of new drugs for the treatment of heart failure. Although guidelines documents are often viewed as authoritative and purely evidence-based, there are replete with meaningful (and inexplicable) inconsistencies, which derive from a review of the same body of scientific data by different groups. This satirical review highlights several examples of the entertaining foolishness of recent guideline documents in the good-natured hope that physicians will understand what the guidelines are, and more importantly, what they are not. Specifically, this paper describes the emergence of a new nonexistent disease; the strange battle between 2 bradycardic drugs (digoxin and ivabradine); the confusion that reigns over the positioning and dosing of inhibitors of the renin-angiotensin system; and the special recommendations that have been issued for certain special populations. As Otto von Bismarck remarked, guideline deliberations are like sausages; it is better not to see them being made. Yet, even after they are ready for public view, we should be cautious. Practitioners who rely on them for clinical decision-making engage in an unnecessary form of self-deception; those who read them literally and adhere to them strictly do not practice evidence based medicine; and those who delve into them in a search for the truth are destined to be disappointed. PMID- 27475879 TI - Quality of life assessments in nursing homes revealed a tendency of proxies to moderate patients' self-reports. AB - OBJECTIVE: Research into different patient populations suggests that, on average, proxies report poorer health-related quality of life (HRQoL) compared to self reports. We aimed to investigate whether the difference between proxy reports and self-reports (interrater gap) varies across the whole range of self-reports from low to high HRQoL scores. STUDY DESIGN AND SETTING: A cross-sectional study in 16 Dutch nursing home (NH) dementia special care (DSC) units (n = 256) and 17 somatic units (n = 326). Professional carers, blinded to self-reports, provided EuroQol-5D scores from two perspectives: their own perspective (proxy-proxy) of the patients' HRQoL and the estimation of the patient's view (proxy-patient). RESULTS: The interrater gap varied linearly in both DSC and somatic patients from proxy scores overestimating low self-reports to proxy scores underestimating high self-reports. This attenuation tendency existed for both proxy-proxy and proxy patient perspectives. The interrater gap tended to be smaller for the proxy patient perspective. CONCLUSIONS: Proxies (professional carers) tend to attenuate self-reports in NH patients with and without dementia toward moderate scores rather than report systematically poorer HRQoL. A proxy-patient perspective may be preferable to a proxy-proxy perspective for the purpose of estimating self reports. Further research into other populations is needed to understand whether the attenuation tendency is a general phenomenon. PMID- 27475880 TI - Neuropathic pain in cancer patients treated with bortezomib. AB - INTRODUCTION: The neuropathic pain is the most habitual problem in the neuropathy induced by chemotherapy (NIQ) and the one that more interferes in the quality of life of the patients. His precocious detection turns out to be fundamental to reduce or to eliminate the problems that from this one stem. The aims of this study were: 1) determine the incident and NIQ's characteristics and neuropathic pain in patients with mieloma multiple (MM) treated with bortezomib, and 2) to evaluate the impact of the neuropathic pain in the activities of the daily life (AVD). METHOD: All the patients diagnosed of MM candidates for treatment with bortezomib attended in the Hospital Joan XXIII during 2013, took part. The participants were interviewed individually and were reporting on the presence, the characteristics and the impact of the pain, as well as of the adverse effects of the bortezomib. RESULTS: There took part 22 persons, of which NIQ presented the half, being the degree 2 the predominant one. The most habitual location of the neuropathic pain was hands and feet; it was appearing in a spontaneous and progressive way deteriorating in rest and during the night, with predominance of positive symptoms. The impact of the pain was reflected in all the AVD. The principal limitation was the disability to enjoy the life. The peripheral neuropathy occupied the first place in order of subjective importance for the patient followed by the fatigue and the constipation. CONCLUSIONS: A proper assessment and early detection of neuropathic pain is critical to minimizing its impact on the quality of life of patients. PMID- 27475881 TI - Hydrogen sulfide-releasing anti-inflammatory drugs for chemoprevention and treatment of cancer. AB - For many years it has been recognized that inhibition of cyclooxygenase enzymes is effective in reducing the incidence of many types of cancer, but the adverse effects of these drug, particularly in the gastrointestinal and cardiovascular systems, limits their utility. Recently developed hydrogen sulfide-releasing anti inflammatory drugs may be a promising option for cancer chemoprevention. In this paper we review evidence suggesting that these novel compounds are effective in a range of animal models of various types of cancer, while exhibiting greatly reduced toxicity relative to currently marketed non-steroidal anti-inflammatory drugs. Some of the possible mechanisms of action of hydrogen sulfide-releasing anti-inflammatory drugs are also discussed. PMID- 27475882 TI - Histamine and astrocyte function. AB - Astrocytes support the brain through numerous functional interactions in health and disease. The recent advances in our knowledge of astrocyte involvement in various neurological disorders raised up several questions about their role and functioning in the central nervous system. From the evidence discussed in this review, we show that histamine importantly influences the main astrocytic activities such as ion homeostasis, energy metabolism, neurotransmitter clearance, neurotrophic activity and immune response. These processes are mediated through at least three histamine receptor subtypes, H1, H2 and H3, expressed on the astrocyte surface. Thus, we recognize histamine as an important player in the modulation of astrocytic functions that deserves further considerations in exploring involvement of astrocytes in neurological disorders. PMID- 27475883 TI - Targeting the transsulfuration-H2S pathway by FXR and GPBAR1 ligands in the treatment of portal hypertension. AB - Cirrhosis is a end-stage disease of the liver in which fibrogenesis, angiogenesis and distortion of intrahepatic microcirculation lead to increased intrahepatic resistance to portal blood flow, a condition known as portal hypertension. Portal hypertension is maintained by a variety of molecular mechanisms including sinusoidal endothelial cells (LSECs) hyporeactivity, activation of hepatic stellate cells (HSCs), reduction in hepatic endothelial nitric oxide synthase (eNOS) activity along with increased eNOS-derived NO generation in the splanchnic and systemic circulations. A reduction of the expression/function of the two major hydrogen sulfide (H2S)-producing enzymes, cystathionine gamma-lyase (CSE) and cystathionine beta-synthase (CBS), has also been demonstrated. A deficit in the transsulfuration pathway leading to the accumulation of homocysteine might contribute to defective generation of H2S and endothelial hyporeactivity. Bile acids are ligands for nuclear receptors, such as farnesoid X receptor (FXR), and G-protein-coupled receptors (GPCRs), such as the G-protein bile acid receptor 1 (GPBAR1). FXR and GPBAR1 ligands regulate the expression/activity of CSE by both genomic and non-genomic effects and have been proved effective in protecting against endothelial dysfunction observed in rodent models of cirrhosis. GPBAR1, a receptor for secondary bile acids, is selectively expressed by LSECs and its activation increases the expression of CSE and attenuates the production of endotelin-1, a potent vasoconstrictor agent. In vivo GPBAR1 ligand attenuates the imbalance between vasodilatory and vaso-constricting agents, making GPBAR1 a promising target in the treatment of portal hypertension. PMID- 27475884 TI - Role of histamine H4 receptor ligands in bleomycin-induced pulmonary fibrosis. AB - Fibrosis of lung tissue is a disease where a chronic inflammatory process determines a pathological remodelling of lung parenchyma. The animal model obtained by intra-tracheal administration of bleomycin in C57BL/6 mice is one of the most validated murine model. Bleomycin stimulates oxidative stress and the production of pro-inflammatory mediators. Histamine H4R have recently been implicated in inflammation and immune diseases. This study was focused to investigate the effects of H4R ligands in the modulation of inflammation and in the reduction of lung fibrosis in C57BL/6 mice treated with bleomycin. C57BL/6 mice were treated with vehicle, JNJ7777120 (JNJ, selective H4R antagonist) or ST 1006 (partial H4R agonist), ST-994 (H4R neutral antagonist) and ST-1012 (inverse H4R agonist) at equimolar doses, released by micro-osmotic pumps for 21days. Airway resistance to inflation was assayed and lung samples were processed to measure malondialdehyde (TBARS); 8-hydroxy-2'-deoxyguanosine (8OHdG); myeloperoxidase (MPO); COX-2 expression and activity as markers of oxidative stress and inflammation. Fibrosis and airway remodelling were evaluated throughout transforming growth factor-beta (TGF-beta), percentage of positive Goblet cells, smooth muscle layer thickness determination. Our results indicated that JNJ, ST-994 and ST-1012 decreased inflammation and oxidative stress markers, i.e. the number of infiltrating leukocytes evaluated as lung tissue MPO, COX-2 expression and activity, TBARS and 8OHdG production. They also reduced the level of TGF-beta, a pro-fibrotic cytokine, collagen deposition, thickness of smooth muscle layer, Goblet cells hyperplasia; resulting in a decrease of airway functional impairment. The results here reported clearly demonstrated that H4R ligands have a beneficial effect in a model of lung fibrosis in the mouse, thus indicating that H4R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases. PMID- 27475885 TI - Nanosystems based on siRNA silencing HuR expression counteract diabetic retinopathy in rat. AB - We evaluated whether specifically and directly targeting human antigen R (HuR), a member of embryonic lethal abnormal vision (ELAV) proteins family, may represent a new potential therapeutic strategy to manage diabetic retinopathy. Nanosystems loaded with siRNA silencing HuR expression (lipoplexes), consisting of solid lipid nanoparticles (SLN) and liposomes (SUV) were prepared. Photon correlation spectroscopy analysis, Zeta potential measurement and atomic force microscopy (AFM) studies were carried out to characterize the complexation of siRNA with the lipid nanocarriers. Nanosystems were evaluated by using AFM and scanning electron microscopy. The lipoplexes were injected into the eye of streptozotocin (STZ) induced diabetic rats. Retinal HuR and VEGF levels were detected by Western blot and ELISA, respectively. Retinal histology was also carried out. The results demonstrated that retinal HuR and VEGF are significantly increased in STZ-rats and are blunted by HuR siRNA treatment. Lipoplexes with a weak positive surface charge and with a 4:1 N/P (cationic lipid nitrogen to siRNA phosphate) ratio exert a better transfection efficiency, significantly dumping retinal HuR and VEGF levels. In conclusion, we demonstrated that siRNA can be efficiently delivered into the rat retina using lipid-based nanocarriers, and some of the lipoplexes loaded with siRNA silencing HuR expression are potential candidates to manage retinal diseases. PMID- 27475886 TI - Uncovering key patterns in self-harm in adolescents: Sequence analysis using the Card Sort Task for Self-harm (CaTS). AB - BACKGROUND: Self-harm is a significant clinical issue in adolescence. There is little research on the interplay of key factors in the months, weeks, days and hours leading to self-harm. We developed the Card Sort Task for Self-harm (CaTS) to investigate the pattern of thoughts, feelings, events and behaviours leading to self-harm. METHODS: Forty-five young people (aged 13-21 years) with recent repeated self-harm completed the CaTS to describe their first ever/most recent self-harm episode. Lag sequential analysis determined significant transitions in factors leading to self-harm (presented in state transition diagrams). RESULTS: A significant sequential structure to the card sequences produced was observed demonstrating similarities and important differences in antecedents to first and most recent self-harm. Life-events were distal in the self-harm pathway and more heterogeneous. Of significant clinical concern was that the wish to die and hopelessness emerged as important antecedents in the most recent episode. First ever self-harm was associated with feeling better afterward, but this disappeared for the most recent episode. LIMITATIONS: Larger sample sizes are necessary to examine longer chains of sequences and differences in genders, age and type of self-harm. The sample was self-selected with 53% having experience of living in care. CONCLUSIONS: The CaTs offers a systematic approach to understanding the dynamic interplay of factors that lead to self-harm in young people. It offers a method to target key points for intervention in the self-harm pathway. Crucially the factors most proximal to self-harm (negative emotions, impulsivity and access to means) are modifiable with existing clinical interventions. PMID- 27475887 TI - The role of hazardous drinking reductions in predicting depression and anxiety symptom improvement among psychiatry patients: A longitudinal study. AB - BACKGROUND: Co-occurrence of depression, anxiety, and hazardous drinking is high in clinical samples. Hazardous drinking can worsen depression and anxiety symptoms (and vice versa), yet less is known about whether reductions in hazardous drinking improve symptom outcomes. METHODS: Three hundred and seven psychiatry outpatients were interviewed (baseline, 3-, 6-months) for hazardous drinking (drinking over recommended daily limits), depression (PHQ-9), and anxiety (GAD-7) as part of a hazardous drinking intervention trial. Longitudinal growth models tested associations between hazardous drinking and symptoms (and reciprocal effects between symptoms and hazardous drinking), adjusting for treatment effects. RESULTS: At baseline, participants had moderate anxiety (M=10.81; SD=10.82) and depressive symptoms (M=13.91; SD=5.58); 60.0% consumed alcohol at hazardous drinking levels. Over 6-months, participants' anxiety (B= 3.03, p<.001) and depressive symptoms (B=-5.39, p<.001) improved. Continued hazardous drinking led to slower anxiety (B=0.09, p=.005) and depressive symptom (B=0.10, p=.004) improvement; reductions in hazardous drinking led to faster anxiety (B=-0.09, p=.010) and depressive (B=-0.10, p=.015) symptom improvement. Neither anxiety (B=0.07, p=.066) nor depressive (B=0.05, p=.071) symptoms were associated with hazardous drinking outcomes. LIMITATIONS: Participants were psychiatry outpatients, limiting generalizability. CONCLUSIONS: Reducing hazardous drinking can improve depression and anxiety symptoms but continued hazardous use slows recovery for psychiatry patients. Hazardous drinking-focused interventions may be helpful in promoting symptom improvement in clinical populations. PMID- 27475888 TI - Depression during the perimenopause: A meta-analysis. AB - BACKGROUND: Women are believed to be more vulnerable to develop a depression or depressive symptoms during the perimenopause. Estimates from individual studies are heterogeneous and hence true risk estimate is unknown. OBJECTIVE: This study investigated the risk on clinical depression and depressive symptoms during the perimenopause when compared to other female hormonal stages. METHODS: We performed a meta-analysis of 11 studies identified in Pubmed, Web of Science and the Cochrane library (up to July 2015). Studies were included when the perimenopause was defined according the criteria of Stages of Reproductive Aging Workshop (STRAW). The outcome measures were Odds Ratio's (OR) on depression diagnosis and depressive symptoms and standardized mean difference (Hedges's g) in depression scores during each menopausal stage. RESULTS: The odds to develop a depression were not significantly higher during the perimenopause than in the premenopause (OR=1.78 95% CI=0.99-3.2; p=0.054). A higher risk was found on depressive symptoms during the perimenopause as compared to the premenopause (OR=2.0, 95% CI=1.48-2.71; p<0.001) but not compared to the postmenopause (OR=1.07, 95% CI=0.737-1.571; p=0.70). There was a higher symptom severity of depression in the perimenopause when compared to the premenopause (Hedges's g=0.44, 95% CI=0.11-0.73, p=0.007). The odds on vasomotor symptoms and depression were 2.25 (95% CI=1.14-3.35; p<0.001) during the perimenopause. LIMITATIONS: Time interval in measuring the depressive symptoms was different in studies. Menopausal symptoms possibly may have confounded our results by increasing the scores on depression questionnaires. Publication bias needs to be considered. CONCLUSION: The perimenopause is a phase in which women are particular vulnerable to develop depressive symptoms and have higher symptom severity compared to the premenopause. There are indications that vasomotor symptoms are positively related to depressive symptoms during menopausal transition. PMID- 27475890 TI - Prevalence of paternal depression in pregnancy and the postpartum: An updated meta-analysis. AB - BACKGROUND: Research in paternal prenatal and postpartum depression has nearly doubled since prevalence rates were last meta-estimated in October 2009. An updated meta-analysis allows additional questions to be answered about moderators that influence risk. METHODS: Studies reporting paternal depression between the first trimester and one-year postpartum were obtained for the period from January 1980 to November 2015. In total 74 studies with 41,480 participants were included, and data was extracted independently by two authors. Moderator analyses included measurement method, timing of assessment, study location, publication year, age, education, parity, history of depression, and maternal depression. RESULTS: The meta-estimate for paternal depression was 8.4% (95% confidence interval [CI], 7.2-9.6%) with significant heterogeneity observed among prevalence rates. Prevalence significantly varied based on publication year, study location, measurement method, and maternal depression. Prevalence was not conditional on paternal age, education, parity, history of paternal depression, and timing of assessment. LIMITATIONS: Analyses were limited by variability in assessment measures, countries from which studies were available, extant data for the first trimester and 6- to 9-month postpartum, and method of reporting sociodemographic information. CONCLUSIONS: Paternal depression was present in 8% of men in the included studies. Future screening policies and interventions should consider moderating risk factors for depression throughout the transition to parenthood. PMID- 27475889 TI - Glucocorticoid receptor DNA methylation, childhood maltreatment and major depression. AB - INTRODUCTION: Altered DNA methylation (DNAm) levels of hypothalamic-pituitary adrenal (HPA) axis genes has been associated with exposure to childhood maltreatment (CM) and depression; however, it is unknown whether CM and depression have joint and potentially interacting effects on the glucocorticoid receptor (NR3C1) DNAm. We investigated the impact of CM and lifetime major depressive disorder (MDD) on NR3C1 DNAm and gene expression (GE) in 147 adult participants from the Detroit Neighborhood Health Study. METHODS: NR3C1 promoter region DNAm was assessed via pyrosequencing using whole blood-derived DNA. Quantitative RT-PCR assays measured GE from leukocyte-derived RNA. Linear regression models were used to examine the relationship among CM, MDD, and DNAm. RESULTS: Both CM and MDD were significant predictors of NR3C1 DNAm: CM was associated with an increase in DNAm in an EGR1 transcription factor binding site (TFBS), whereas MDD was associated with a decrease in DNAm downstream of the TFBS. No significant CM-MDD interactions were observed. CM alone was associated with significantly lower NR3C1 GE. LIMITATIONS: Our report of CM is a retrospective self-report of abuse, which may introduce recall bias. DNAm was measured in whole blood and may not reflect brain-derived DNAm levels. CONCLUSIONS: CM and MDD are both associated with altered DNAm levels in the NR3C1 promoter region, however the location and direction of effects differ between the two exposures, and the functional effects, as measured by GE, appear to be limited to CM exposure alone. CM exposure may be biologically embedded in this key HPA axis gene. PMID- 27475891 TI - Computerized Adaptive Test vs. decision trees: Development of a support decision system to identify suicidal behavior. AB - BACKGROUND: Several Computerized Adaptive Tests (CATs) have been proposed to facilitate assessments in mental health. These tests are built in a standard way, disregarding useful and usually available information not included in the assessment scales that could increase the precision and utility of CATs, such as the history of suicide attempts. METHODS: Using the items of a previously developed scale for suicidal risk, we compared the performance of a standard CAT and a decision tree in a support decision system to identify suicidal behavior. We included the history of past suicide attempts as a class for the separation of patients in the decision tree. RESULTS: The decision tree needed an average of four items to achieve a similar accuracy than a standard CAT with nine items. The accuracy of the decision tree, obtained after 25 cross-validations, was 81.4%. A shortened test adapted for the separation of suicidal and non-suicidal patients was developed. CONCLUSION: CATs can be very useful tools for the assessment of suicidal risk. However, standard CATs do not use all the information that is available. A decision tree can improve the precision of the assessment since they are constructed using a priori information. PMID- 27475892 TI - Serum S100B in manic bipolar disorder patients: Systematic review and meta analysis. AB - BACKGROUND: Bipolar disorder (BD) is a neuropsychiatric disorder characterized by recurrent episodes of mania/hypomania, affecting more than 1% of the world population. S100B is a calcium-binding protein, mostly produced and secreted by astrocytes in the CNS that participate in several cellular responses. Previous studies have shown that patients with bipolar disorder had higher peripheral S100B levels than healthy individuals, suggesting a potential role for S100B BD. METHODS: In this study, a systematic and quantitative meta-analysis of studies S100B serum was performed according to the guidelines PRISMA-statement to confirm the increase of serum S100B in patients with manic bipolar disorder. RESULTS: We included in the meta-analysis two studies that reported the mean and standard deviation of serum S100B 52 patients manic BP and 52 control studies. Our results showed higher levels of S100B peripheral TB patients compared with healthy controls. In this meta-analysis, we found evidence that serum S100B are increased in patients with bipolar disorder. CONCLUSION: In conclusion, several studies have observed morphological abnormalities in the brains of bipolar disorder patients, changes in the peripheral S100B levels in mood disorders were described, and this protein could be a putative marker for damage to the brain. Thus, in this meta-analysis we have found evidence, based on two studies of 52 patients and 52 healthy controls, that the serum concentrations of S100B are increased in bipolar disorder patients. PMID- 27475893 TI - Comprehensive analysis of TEM methods for LiFePO4/FePO4 phase mapping: spectroscopic techniques (EFTEM, STEM-EELS) and STEM diffraction techniques (ACOM TEM). AB - Transmission electron microscopy (TEM) has been used intensively in investigating battery materials, e.g. to obtain phase maps of partially (dis)charged (lithium) iron phosphate (LFP/FP), which is one of the most promising cathode material for next generation lithium ion (Li-ion) batteries. Due to the weak interaction between Li atoms and fast electrons, mapping of the Li distribution is not straightforward. In this work, we revisited the issue of TEM measurements of Li distribution maps for LFP/FP. Different TEM techniques, including spectroscopic techniques (energy filtered (EF)TEM in the energy range from low-loss to core loss) and a STEM diffraction technique (automated crystal orientation mapping (ACOM)), were applied to map the lithiation of the same location in the same sample. This enabled a direct comparison of the results. The maps obtained by all methods showed excellent agreement with each other. Because of the strong difference in the imaging mechanisms, it proves the reliability of both the spectroscopic and STEM diffraction phase mapping. A comprehensive comparison of all methods is given in terms of information content, dose level, acquisition time and signal quality. The latter three are crucial for the design of in-situ experiments with beam sensitive Li-ion battery materials. Furthermore, we demonstrated the power of STEM diffraction (ACOM-STEM) providing additional crystallographic information, which can be analyzed to gain a deeper understanding of the LFP/FP interface properties such as statistical information on phase boundary orientation and misorientation between domains. PMID- 27475894 TI - Right ventricular and pulmonary vascular reserve in asymptomatic BMPR2 mutation carriers. AB - BACKGROUND: Non-invasive estimates have suggested that asymptomatic BMPR2 mutation carriers may have an abnormal pulmonary vascular response to exercise and hypoxia. However, this has not been assessed with "gold standard" invasive measures. METHODS: Eight controls and 8 asymptomatic BMPR2 mutation carriers underwent cardiac magnetic resonance imaging with simultaneous invasive pressure recording during bicycle exercise in normoxia, hypoxia and after sildenafil administration. Abnormal pulmonary vascular reserve was defined as an increase in mean pulmonary artery pressure relative to cardiac output (P/Q slope) >3 mm Hg/liter/min. RESULTS: During normoxic exercise, BMPR2 mutation carriers had a similar P/Q slope when compared with healthy subjects. Only 1 of 8 BMPR2 mutation carriers had a P/Q slope >3 mm Hg/liter/min. During exercise in hypoxia, 3 of 8 BMPR2 mutation carriers had P/Q slopes >3 mm Hg/liter/min compared with none of the controls. Sildenafil decreased the P/Q slope both in controls and BMPR2 mutation carriers. The exercise-induced increase in right ventricular ejection fraction was similar between groups. None of the BMPR2 mutation carriers developed pulmonary arterial hypertension within 2 (range 1.3 to 2.8) years. CONCLUSIONS: The presence of a BMPR2 mutation, per se, is not associated with an abnormal pulmonary vascular and right ventricular functional response to exercise in asymptomatic individuals. Longer follow-up will be required to determine whether a P/Q slope of >3 mm Hg/liter/min during exercise in normoxia or hypoxia is a sign of pre-clinical disease expression. PMID- 27475896 TI - Finding Clues for Congenital Zika Syndrome: Zika Virus Selective Infection of Immature Neurons. PMID- 27475895 TI - Structural Basis of Zika Virus-Specific Antibody Protection. AB - Zika virus (ZIKV) infection during pregnancy has emerged as a global public health problem because of its ability to cause severe congenital disease. Here, we developed six mouse monoclonal antibodies (mAbs) against ZIKV including four (ZV-48, ZV-54, ZV-64, and ZV-67) that were ZIKV specific and neutralized infection of African, Asian, and American strains to varying degrees. X-ray crystallographic and competition binding analyses of Fab fragments and scFvs defined three spatially distinct epitopes in DIII of the envelope protein corresponding to the lateral ridge (ZV-54 and ZV-67), C-C' loop (ZV-48 and ZV 64), and ABDE sheet (ZV-2) regions. In vivo passive transfer studies revealed protective activity of DIII-lateral ridge specific neutralizing mAbs in a mouse model of ZIKV infection. Our results suggest that DIII is targeted by multiple type-specific antibodies with distinct neutralizing activity, which provides a path for developing prophylactic antibodies for use in pregnancy or designing epitope-specific vaccines against ZIKV. PMID- 27475897 TI - Laser Therapy Inhibits Tumor Growth in Mice by Promoting Immune Surveillance and Vessel Normalization. AB - Laser therapy, recently renamed as photobiomodulation, stands as a promising supportive treatment for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. Here we explored the anti-cancer effect of 3 laser protocols, set at the most commonly used wavelengths, in B16F10 melanoma and oral carcinogenesis mouse models. While laser light increased cell metabolism in cultured cells, the in vivo outcome was reduced tumor progression. This striking, unexpected result, was paralleled by the recruitment of immune cells, in particular T lymphocytes and dendritic cells, which secreted type I interferons. Laser light also reduced the number of highly angiogenic macrophages within the tumor mass and promoted vessel normalization, an emerging strategy to control tumor progression. Collectively, these results set photobiomodulation as a safety procedure in oncological patients and open the way to its innovative use for cancer therapy. PMID- 27475898 TI - Acetabular Labral Debridement/Segmental Resection Versus Reconstruction in the Comprehensive Treatment of Symptomatic Femoroacetabular Impingement: A Systematic Review. AB - PURPOSE: To perform a systematic review comparing outcomes of labral debridement/segmental resection with labral reconstruction as part of a comprehensive treatment strategy for femoroacetabular impingement. METHODS: A systematic review was conducted according to established PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines using defined inclusion and exclusion criteria. The study groups were divided into labral debridement/segmental resection (group 1) and labral reconstruction (group 2). Multiple search engines were queried (PubMed, Medline) for this analysis. RESULTS: After an exhaustive search of the available literature, 20 publications were included. Twelve studies explored outcomes after labral debridement/resection in a total of 400 hips, whereas 7 studies reported on outcomes after labral reconstruction in a total of 275 hips. One additional matched-pair control study compared labral resection (22 hips) with reconstruction (11 hips). The surgical intervention was a revision in 0% to 100% for group 1 versus 5% to 55% for group 2. A direct anterior approach was not performed in group 2, and cam-type impingement appeared to make up a larger percentage of group 1. The Tonnis grade ranged from 0 to 1 for group 1 versus 0.3 to 1.1 for group 2. Joint replacements were performed in 0% to 30% and 0% to 25%, respectively. The modified Harris Hip Score was the most widely used patient reported outcome measure and suggested that labral reconstruction was not inferior to labral debridement/segmental resection. CONCLUSIONS: Clinical outcomes after labral debridement/segmental resection versus labral reconstruction were found to be comparable. In the setting of unsalvageable labral pathology, labral reconstruction was used more frequently as a revision option whereas debridement may be more commonly used in the index setting. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, III, and IV studies. PMID- 27475899 TI - GM-CSF has disparate roles during intranasal and intradermal Francisella tularensis infection. AB - Our laboratory has employed in vitro and in vivo mouse models based on Francisella tularensis Live Vaccine Strain (LVS)-induced protection to elucidate immune correlates for intracellular bacteria. Among the effectors found was GM CSF, a pleiotropic cytokine that is integral to the development and proliferation of myeloid cells, including alveolar macrophages. GM-CSF has roles in resistance to primary murine infection with several intracellular pathogens, but its role during Francisella infection is unknown. Francisella is an intracellular pathogen that infects lungs after inhalation, primarily invading alveolar macrophages. Here we show that GM-CSF has route-dependent roles during primary infection of mice with LVS. GM-CSF deficient (GM-CSF KO) mice were slightly more susceptible than wild type to intradermal infection, but had increased resistance to intranasal infection. Similarly, these mice had increased resistance to pulmonary infection with virulent F. tularensis (SchuS4). LVS-vaccinated GM-CSF KO mice had normal adaptive immune responses, as measured by T cell activities after LVS intradermal or intranasal vaccination, and survived lethal secondary LVS challenge. GM-CSF KO mice also had robust humoral responses, producing elevated levels of serum antibodies following LVS vaccination compared to wild type mice. Taken together, our data demonstrates that the absence of GM-CSF improves resistance to pulmonary, but not intradermal, infection with Francisella. PMID- 27475900 TI - Toxoplasma gondii mitogen-activated protein kinases are associated with inflammasome activation in infected mice. AB - Toxoplasma gondii can activate the nucleotide-binding domain and leucine-rich repeat-containing proteins NLRP1/3 inflammasomes, which mediate host resistance to the infection. Here we showed that deletion of mitogen-activated protein kinases MAPK1 and MAPK2 of type I parasite decreases acute virulence in mice, characterized by low levels of interleukin (IL)-18, NLRP1/3, ASC, and caspase-1, and high levels of IL-10 and interferon (IFN)-beta transcripts. Additionally, the mutants increased phosphorylation of STAT1, and decreased phosphorylation of STAT3. These findings suggest that MAPKs are associated with inflammasome activation in T. gondii-infected mice, which may contribute to new insight into the pathogenesis of T. gondii infection. PMID- 27475901 TI - Linking hormonal profiles with variations in sugar and anthocyanin contents during the natural development and ripening of sweet cherries. AB - Sweet cherries are highly appreciated by consumers worldwide and are usually cold stored during postharvest to prevent over-ripening before distribution to the market. Sweet cherry is a non-climacteric fruit, for which ripening is known to be regulated by abscisic acid. Here we aimed to examine the hormone profiles, including measurements of abscisic acid, auxins, cytokinins and gibberellins by ultrahigh performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS), in relation to variations in sugar and anthocyanin contents, during growth and ripening of this fruit. Hormonal profiling revealed that indole 3-acetic acid, GA1 and trans-zeatin levels decreased at early stages of fruit development, while GA3 levels decreased at early stages but also later, once anthocyanin accumulation started. Conversely, abscisic acid levels rose significantly once the fruit started to synthetize anthocyanins, and isopentenyladenosine levels also increased during the ripening of sweet cherries. A strong negative correlation was found between GA4 levels and both fruit biomass and anthocyanin levels, and between the levels of trans-zeatin and both fruit biomass and total sugar contents. In contrast, abscisic acid and isopentenyladenosine levels correlated positively with fruit biomass, anthocyanin and total soluble sugar content. Results suggest that auxins, cytokinins and gibberellins may act coordinately with abscisic acid in the regulation of sweet cherry development and ripening. Furthermore, it is shown that hormonal profile measurements by UHPLC-MS/MS may be a helpful tool to elucidate the timing of action of each specific hormonal compound during ripening, which has important applications in the agri-food biotechnological sector. PMID- 27475902 TI - Arsenite suppresses angiogenesis of vascular endothelial cells mediated by Platelet Derived Growth Factor Receptor-beta. AB - The present study aimed to investigate the effects of sodium arsenite (NaAsO2) on the angiogenesis of human umbilical vein endothelial cells (HUVECs) and the mechanism involved. Firstly, a Matrigel-based in vitro angiogenesis assay demonstrated that arsenite suppressed the angiogenesis of HUVECs in a dose dependent manner. Then by using a global inhibitor for multiple growth factor receptors (E7080) and a specific inhibitor of PDGFR-beta (CP-673451), we found that E7080 completely prevented and CP-673451 significantly decreased the angiogenesis of HUVECs. This suggested that angiogenesis of HUVECs depends on the signal pathway mediated by tyrosine kinase receptors and that among them, PDGFR beta has an important regulatory function. Finally by using porcine aortic endothelial cells which stably express human PDGFR-beta, we found that arsenite suppressed the angiogenesis mediated by PDGFR-beta. Based on these results, we conclude that arsenite suppressed the angiogenesis of the vascular endothelial cells, that this effect is mediated by PDGFR-beta, and postulate that it might contribute to the injuries of blood vessel in arsenism. PMID- 27475903 TI - Practical review on the use of synchrotron based micro- and nano- X-ray fluorescence mapping and X-ray absorption spectroscopy to investigate the interactions between plants and engineered nanomaterials. AB - The increased use of engineered nanomaterials (ENMs) in commercial products and the continuous development of novel applications, is leading to increased intentional and unintentional release of ENMs into the environment with potential negative impacts. Particularly, the partition of nanoparticles (NPs) to waste water treatment plant (WWTP) sludge represents a potential threat to agricultural ecosystems where these biosolids are being applied as fertilizers. Moreover, several applications of ENMs in agriculture and soil remediation are suggested. Therefore, detailed risk assessment should be done to evaluate possible secondary negative impacts. The impact of ENMS on plants as central component of ecosystems and worldwide food supply is of primary relevance. Understanding the fate and physical and chemical modifications of NPs in plants and their possible transfer into food chains requires specialized analytical techniques. Due to the importance of both chemical and physical factors to consider for a better understanding of ENMs behavior in complex matrices, these materials can be considered a new type of analyte. An ideal technique should require minimal sample preparation, be non-destructive, and offer the best balance between sensitivity, chemical specificity, and spatial resolution. Synchrotron radiation (SR) techniques are particularly adapted to investigate localization and speciation of ENMs in plants. SR X-ray fluorescence mapping (SR-XFM) offers multi elemental detection with lateral resolution down to the tens of nm, in combination with spatially resolved X-ray absorption spectroscopy (XAS) speciation. This review will focus on important methodological aspects regarding sample preparation, data acquisition and data analysis of SR-XFM/XAS to investigate interactions between plants and ENMs. PMID- 27475904 TI - Feasibility and challenges of inpatient psychotherapy for psychosis: lessons learned from a veterans health administration pilot randomized controlled trial. AB - BACKGROUND: In large health care systems, decision regarding broad implementation of psychotherapies for inpatients with psychosis require substantial evidence regarding effectiveness and feasibility for implementation. It is important to recognize challenges in conducting research to inform such decisions, including difficulties in obtaining consent from and engaging inpatients with psychosis in research. We set out to conduct a feasibility and effectiveness Hybrid Type I pilot randomized controlled trial of acceptance and commitment therapy (ACT) and a semi-formative evaluation of barriers and facilitators to implementation. FINDINGS: We developed a training protocol and refined an ACT treatment manual for inpatient treatment of psychosis for use at the Veterans Health Administration. While our findings on feasibility were mixed, we obtained supportive evidence of the acceptability and safety of ACT. Identified strengths of ACT included a focus on achievement of valued goals rather than symptoms. Weaknesses included that symptoms may limit patient's understanding of ACT. Facilitators included building trust and multi-stage informed consent processes. Barriers included restrictive eligibility criteria, rigid use of a manualized protocol, and individual therapy format. Conclusions are limited by our randomization of only 18 patient participants (with nine completing all aspects of the study) out of 80 planned. CONCLUSIONS: Future studies should include (1) multi-stage informed consent processes to build trust and alleviate patient fears, (2) relaxation of restrictions associated with obtaining efficacy/effectiveness data, and (3) use of Hybrid Type II and III designs. PMID- 27475905 TI - Healthy Food Intake Index (HFII) - Validity and reproducibility in a gestational diabetes-risk population. AB - BACKGROUND: The aim was to develop and validate a food-based diet quality index for measuring adherence to the Nordic Nutrition Recommendations (NNR) in a pregnant population with high risk of gestational diabetes (GDM). METHODS: This study is a part of the Finnish Gestational Diabetes Prevention Study (RADIEL), a lifestyle intervention conducted between 2008 and 2014. The 443 pregnant participants (61 % of those invited), were either obese or had a history of GDM. Food frequency questionnaires collected at 1st trimester served for composing the HFII; a sum of 11 food groups (available score range 0-17) with higher scores reflecting higher adherence to the NNR. RESULTS: The average HFII of the participants was 10.2 (SD 2.8, range 2-17). Factor analysis for the HFII component matrix revealed three factors that explained most of the distribution (59 %) of the HFII. As an evidence of the component relevance 9 out of 11 of the HFII components independently contributed to the total score (item-rest correlation coefficients <0.31). Saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, sucrose, and fiber intakes (among other nutrients) showed linearity across the HFII categories (P <= 0.030 for all nutrients tested); the higher the HFII, the closer the nutrient intake to the recommended intake level. Educational attainment (P = 0.0045), BMI (P = 0.0098), smoking (P = 0.007), and leisure time physical exercise (P = 0.038) showed linearity across the HFII categories. Intra-class correlation coefficient for the HFII was 0.85 (CI 0.79, 0.90). CONCLUSIONS: The HFII components reflect the food guidelines of the NNR, intakes of relevant nutrients, and characteristics known to vary with diet quality. It largely ignores energy intake, its components have independent contribution to the HFII, and it exhibits reproducibility. The main shortcomings are absence of red and processed meat component, and the validation in a selected study population. It is suitable for ranking participants according to the adherence to the NNR in pregnant women at high risk of GDM. PMID- 27475907 TI - The effects of musculoskeletal loading regimes on numerical evaluations of acetabular component. AB - The importance of clinical studies notwithstanding, the failure assessment of implant-bone structure has alternatively been carried out using finite element analysis. However, the accuracy of the finite element predicted results is dependent on the applied loading and boundary conditions. Nevertheless, most finite element-based evaluations on acetabular component used a few selective load cases instead of the eight load cases representing the entire gait cycle. These in silico evaluations often suffer from limitations regarding the use of simplified musculoskeletal loading regimes. This study attempts to analyse the influence of three different loading regimes representing a gait cycle, on numerical evaluations of acetabular component. Patient-specific computer tomography scan-based models of intact and resurfaced pelvises were used. One such loading regime consisted of the second load case that corresponded to peak hip joint reaction force. Whereas the other loading regime consisted of the second and fifth load cases, which corresponded to peak hip joint reaction force and peak muscle forces, respectively. The third loading regime included all the eight load cases. Considerable deviations in peri-acetabular strains, standard error ranging between 115 and 400 uepsilon, were observed for different loading regimes. The predicted bone strains were lower when selective loading regimes were used. Despite minor quantitative variations in bone density changes (less than 0.15 g cm(-3)), the final bone density pattern after bone remodelling was found to be similar for all the loading regimes. Underestimations in implant-bone micromotions (40-50 um) were observed for selective loading regimes after bone remodelling. However, at immediate post-operative condition, such underestimations were found to be less (less than 5 um). The predicted results highlight the importance of inclusion of eight load cases representing the gait cycle for in silico evaluations of resurfaced pelvis. PMID- 27475906 TI - Leukotriene receptor expression in esophageal squamous cell cancer and non transformed esophageal epithelium: a matched case control study. AB - BACKGROUND: Leukotriene B4 (LTB4R and LTB4R2) and cysteinyl leukotriene receptors (CYSLTR1 and CYSLTR2) contribute to malignant cell transformation. We aimed to investigate the expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 in esophageal squamous cell carcinoma and adjacent non-transformed squamous epithelium of the esophagus, as well as in control biopsy samples from esophageal squamous epithelium of patients with functional dyspepsia. METHODS: Expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 was analyzed by immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in biopsy samples of 19 patients with esophageal squamous cell cancer and 9 sex- and age matched patients with functional dyspepsia. RESULTS: LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 were expressed in all biopsy samples. Major findings were: 1) protein levels of all leukotriene receptors were significantly increased in esophageal squamous cell cancer compared to control mucosa (p < 0.05); 2) CYSLTR1 and CYSLTR2 gene expression was decreased in cancer tissue compared to control at 0.26-fold and 0.23-fold respectively; 3) an up-regulation of LTB4R (mRNA and protein expression) and a down-regulation of CYSLTR2 (mRNA expression) in non transformed epithelium of cancer patients compared to control (p < 0.05) was observed. CONCLUSIONS: The expression of leukotriene receptors was deregulated in esophageal squamous cell cancer. Up-regulation of LTB4R and down-regulation of CYSLTR2 gene expression may occur already in normal squamous esophageal epithelium of patients with esophageal cancer suggesting a potential role of these receptors in early steps of esophageal carcinogenesis. Larger studies are warranted to confirm these observations. PMID- 27475909 TI - "It is challenging... oh, nobody likes it!": a qualitative study exploring Mozambican adolescents and young adults' experiences with contraception. AB - BACKGROUND: By focusing upon formal sex education programmes, the Mozambican government has significantly enhanced the general health of adolescents and young adults. However, when it comes to contraception, little is known about how adolescents and young adults actually behave. METHODS: Based upon a qualitative study in two settings in Maputo province - Ndlavela and Boane - this paper explores the knowledge and practices of contraception among adolescents and young adults. A total of four focus group discussions, 16 in-depth interviews, four informal conversations, and observations were equally divided between both study sites. RESULTS: Discrepancies between what adolescents and young adults know and what they do quickly became evident. Ambivalent and contradictory practices concerning contraceptive use was the result. As well, young people had numerous interpretations of risk-taking when not using contraceptives. These inconsistencies are influenced by social and medical barriers such as restricted dialogue on sexuality among adolescents and young adults and their parents and peers. Additionally, ideas about indigenous contraceptives, notions of masculinity and femininity, misconceptions and fear of the side effects of contraceptives, make people of all ages wary of modern birth control. Other barriers include imposed contraceptive choice - meaning no choice, overly technical medical language used at clinics and the absence of healthcare workers more attuned to the needs of adolescents and young adults. CONCLUSIONS: Adolescents and young adults have numerous - often erroneous - opinions about contraception, leading to inconsistent use as well as vague perceptions of risk taking. Moreover, social norms and cultural gender roles often contradict and hinder risk-avoiding behaviour. Therefore, in order to improve young people's health, policymakers must address the reasons behind this ambivalence and inconsistency. PMID- 27475908 TI - The bactericidal effect of an ionizer under low concentration of ozone. AB - BACKGROUND: Several mechanisms have been suggested for the bactericidal action of ionizers including electrical phenomena, effects of negative and positive ions and electrostatic repulsion. Negative and positive ions have indeed been shown to have bactericidal effects. In addition, since ozone is generated along with ions, these may contribute to the bacterial killing. In this study, we used a newly developed ionizer, which generates a relatively low concentration of ozone, to determine whether its effect on bacterial cells were due to ions or ozone, and, if ions, how the ions exerted their effects. RESULTS: The effect of ions on bacterial killing was compared with that of the ozone produced using an ion trap to remove the ions. The ionizer had the ability to kill the bacteria, and ion capture dramatically reduced its bactericidal effect, indicating that the ozone generated had little or no bactericidal effect under these conditions, and the ions produced were responsible for almost all the bacterial killing. Operation of the ionizer increased the level of 8-oxo-dG, a marker of oxidative DNA damage, and decreased aconitase activity, which is known to be sensitive to ROS. The ionizer further affected the adenylate energy charge of bacterial cells. Removal of the ions with the ion trap greatly reduced all these effects. CONCLUSION: These results indicate that negative and positive ions generated by the ionizer are responsible for inducing oxidative stress and so reducing bacterial survival. PMID- 27475910 TI - Personalized mitral valve closure computation and uncertainty analysis from 3D echocardiography. AB - Intervention planning is essential for successful Mitral Valve (MV) repair procedures. Finite-element models (FEM) of the MV could be used to achieve this goal, but the translation to the clinical domain is challenging. Many input parameters for the FEM models, such as tissue properties, are not known. In addition, only simplified MV geometry models can be extracted from non-invasive modalities such as echocardiography imaging, lacking major anatomical details such as the complex chordae topology. A traditional approach for FEM computation is to use a simplified model (also known as parachute model) of the chordae topology, which connects the papillary muscle tips to the free-edges and select basal points. Building on the existing parachute model a new and comprehensive MV model was developed that utilizes a novel chordae representation capable of approximating regional connectivity. In addition, a fully automated personalization approach was developed for the chordae rest length, removing the need for tedious manual parameter selection. Based on the MV model extracted during mid-diastole (open MV) the MV geometric configuration at peak systole (closed MV) was computed according to the FEM model. In this work the focus was placed on validating MV closure computation. The method is evaluated on ten in vitro ovine cases, where in addition to echocardiography imaging, high-resolution MUCT imaging is available for accurate validation. PMID- 27475913 TI - Prognosis role of clinical ultrasound in acute heart failure: Inferior cava vein only? PMID- 27475912 TI - Rubimetide, humanin, and MMK1 exert anxiolytic-like activities via the formyl peptide receptor 2 in mice followed by the successive activation of DP1, A2A, and GABAA receptors. AB - Rubimetide (Met-Arg-Trp), which had been isolated as an antihypertensive peptide from an enzymatic digest of spinach ribulose-bisphosphate carboxylase/oxygenase (Rubisco), showed anxiolytic-like activity prostaglandin (PG) D2-dependent manner in the elevated plus-maze test after administration at a dose of 0.1mg/kg (ip.) or 1mg/kg (p.o.) in male mice of ddY strain. In this study, we found that rubimetide has weak affinities for the FPR1 and FPR2, subtypes of formyl peptide receptor (FPR). The anxiolytic-like activity of rubimetide (0.1mg/kg, ip.) was blocked by WRW4, an antagonist of FPR2, but not by Boc-FLFLF, an antagonist of FPR1, suggesting that the anxiolytic-like activity was mediated by the FPR2. Humanin, an endogenous agonist peptide of the FPR2, exerted an anxiolytic-like activity after intracerebroventricular (icv) administration, which was also blocked by WRW4. MMK1, a synthetic agonist peptide of the FPR2, also exerted anxiolytic-like activity. Thus, FPR2 proved to mediate anxiolytic-like effect as the first example of central effect exerted by FPR agonists. As well as the anxiolytic-like activity of rubimetide, that of MMK1 was blocked by BW A868C, an antagonist of the DP1-receptor. Furthermore, anxiolytic-like activity of rubimetide was blocked by SCH58251 and bicuculline, antagonists for adenosine A2A and GABAA receptors, respectively. From these results, it is concluded that the anxiolytic-like activities of rubimetide and typical agonist peptides of the FPR2 were mediated successively by the PGD2-DP1 receptor, adenosine-A2A receptor, and GABA-GABAA receptor systems downstream of the FPR2. PMID- 27475914 TI - Reply to "Prognostic value of measuring the diameter and inspiratory collapse of the inferior vena cava in acute heart failure". PMID- 27475911 TI - ISLES 2015 - A public evaluation benchmark for ischemic stroke lesion segmentation from multispectral MRI. AB - Ischemic stroke is the most common cerebrovascular disease, and its diagnosis, treatment, and study relies on non-invasive imaging. Algorithms for stroke lesion segmentation from magnetic resonance imaging (MRI) volumes are intensely researched, but the reported results are largely incomparable due to different datasets and evaluation schemes. We approached this urgent problem of comparability with the Ischemic Stroke Lesion Segmentation (ISLES) challenge organized in conjunction with the MICCAI 2015 conference. In this paper we propose a common evaluation framework, describe the publicly available datasets, and present the results of the two sub-challenges: Sub-Acute Stroke Lesion Segmentation (SISS) and Stroke Perfusion Estimation (SPES). A total of 16 research groups participated with a wide range of state-of-the-art automatic segmentation algorithms. A thorough analysis of the obtained data enables a critical evaluation of the current state-of-the-art, recommendations for further developments, and the identification of remaining challenges. The segmentation of acute perfusion lesions addressed in SPES was found to be feasible. However, algorithms applied to sub-acute lesion segmentation in SISS still lack accuracy. Overall, no algorithmic characteristic of any method was found to perform superior to the others. Instead, the characteristics of stroke lesion appearances, their evolution, and the observed challenges should be studied in detail. The annotated ISLES image datasets continue to be publicly available through an online evaluation system to serve as an ongoing benchmarking resource (www.isles-challenge.org). PMID- 27475915 TI - Prevalence and importance of comorbidities in patients with heart failure: The importance of sleep apnea syndrome. PMID- 27475916 TI - Effects of whitening dentifrice on yttria-stabilized tetragonal zirconia polycrystal surfaces after simulating brushing. AB - STATEMENT OF PROBLEM: The changes that occur after brushing yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) are unknown. These changes may favor the retention of microorganisms and chemisorption of water, impairing its longevity. OBJECTIVE: The purpose of this in vitro study was to evaluate the effects of a whitening dentifrice on Y-TZP surfaces after simulating 10 years of brushing. MATERIAL AND METHODS: Seventy-two bar-shaped specimens (20*4*1.2 mm) were divided into 4 groups: storage in distilled water (SW, control), brushing with distilled water (BW), brushing with dentifrice (BD), and brushing with whitening dentifrice (BWD). Brushing was conducted using a linear brushing machine (878400 cycles, 0.98 N, soft toothbrush). The mean roughness (Ra) was analyzed with a profilometer and the superficial topography with scanning electron microscopy (SEM) at baseline and after treatment. Crystalline phases were characterized using x-ray diffraction. Baseline and posttreatment Ra were analyzed using the 1 way ANOVA and Tukey HSD multiple comparison test; the paired t test was used for intragroup comparison (all alpha=.05). RESULTS: The Ra (MUm) means (before/after treatment) were SW 0.28/0.28; BW 0.32/0.31; BD 0.28/0.36; BWD 0.30/0.20. No statistically significant difference was found for Ra at baseline (P=.108) than for posttreatment results (P<.001); the BD group had higher Ra values when compared with baseline (P=.019); the BWD group had the lowest values (P<.001). The BD surfaces showed pronounced scratches and detachment of the surface, while BWD showed smoother surfaces; similar crystallographic results among groups were observed. CONCLUSIONS: Brushing Y-TZP with conventional dentifrice increased roughness, while brushing with whitening dentifrice reduced roughness. Neither dentifrice changed the crystallographic phases after brushing. PMID- 27475917 TI - Torque resistance of impression copings after direct implant impression: An in vitro evaluation of impression materials with and without adhesive. AB - STATEMENT OF PROBLEM: No data are available on the ability of an impression coping to resist the manual placement of an abutment replica (implant analog) during prosthodontic laboratory procedures after a direct (pick-up) impression. PURPOSE: The purpose of this in vitro study was to evaluate the torque resistance of impression copings after a direct impression, that is, the amount of rotational torque sufficient to induce irreversible displacement of impression copings in the impression material bulk once the impression has been made. MATERIAL AND METHODS: A reference model with 5 abutment replicas was constructed. Five impression copings were screwed onto the abutment replicas, and standardized impressions were made. A controlled twisting force was applied to each impression coping. A torque tester recorded the torque variation. Three elastomeric impression materials were tested. ANOVA and the Tukey test (alpha=.05) were performed using an average of 30 measurements per impression material, with and without adhesive. RESULTS: ANOVA and the Tukey test results showed that the adhesive, cohesive, and mechanical bonds between the impression coping and the impression material depended greatly on the type of material and that the average rupture threshold of these bonds was statistically significantly different in pairwise comparisons (P<.05). The curve analysis showed that when the impression materials are used with adhesives, the deformation of the interface is irreversible beyond 5 Ncm of torque. CONCLUSIONS: The polyether impression material is the direct impression material that showed the highest breakdown threshold for adhesive bonding when used without an adhesive. The use of an adhesive on impression copings leads to irreversible deformation of the interface at torque stresses well below the adhesive bond threshold of the same materials used without an adhesive. PMID- 27475918 TI - Effect of different fiber post surface treatments on microtensile bond strength to composite resin. AB - STATEMENT OF PROBLEM: The interface of fiber post and composite resin is a site of potential failure of adhesion. Improving this interface adhesion through different pretreatments of the fiber post surface has been suggested, but the results are controversial. PURPOSE: The purpose of this in vitro study was to evaluate the effect on the bond strength to composite resin of pretreating glass fiber post surfaces with hydrogen peroxide, phosphoric acid, and a silane coupling agent. MATERIAL AND METHODS: Glass fiber posts were treated for 1 or 5 minutes with 30% hydrogen peroxide or 35% phosphoric acid. Treated posts were divided into silanization and no silanization groups. Control groups included no treatment or treatment with silanization alone (total of 10 groups; n=14). Composite resin was bonded to the fiber posts, and the specimens were cut into beams with the fiber post in the middle and the composite resin at both sides. The beams were attached to a mechanical testing device, and microtensile bond strength was evaluated. Fracture modes were assessed using stereomicroscopy. Statistical analysis was done with 3- and 2-way ANOVA (alpha=.05). Additional specimens were evaluated with a scanning electron microscope (SEM) to evaluate the effect of treatments on the characteristics of fiber post surfaces. RESULTS: The highest bond strength values were found in the group treated with phosphoric acid for 5 minutes with silanization, followed by the group treated with silanization alone. ANOVA showed a statistically significant effect for silanization (P<.05), but no statistically significant effect for surface treatment. SEM evaluation revealed cracked and dislodged superficial fibers in all groups, with no obvious difference in fiber exposure among the groups. CONCLUSIONS: The silane coupling agent had a significant effect on the bond strength of the tested glass fiber posts to composite resin, whereas 30% hydrogen peroxide or 35% phosphoric acid did not. PMID- 27475919 TI - Customized procedure to display T-Scan occlusal contacts. AB - The virtual technique described in this article integrates reverse engineering and mandibular dynamics into dental computer-aided design and computer-aided manufacturing (CAD-CAM) systems. This technique aims to provide more objective information to the dental technician for the diagnosis, planning, and treatment phases. In order to carry out this protocol, the following devices, currently available in many practices, are necessary: an intraoral scanner, a T-Scan system, and some specific open reverse engineering software. By means of a virtual procedure, the T-Scan system detects the occlusal contacts, and the occlusal surfaces are obtained using an intraoral scanner. Once the alignment between the 3-dimensional occlusal surface and the T-Scan registration is carried out, the resulting contacts are projected onto the patient's occlusal surfaces; in this way, occlusal forces are obtained over time. The results obtained with this procedure demonstrate the feasibility of integrating different tools and software and the full integration of this procedure into a dental digital workflow. PMID- 27475920 TI - A 2-part facebow for CAD-CAM dentistry. AB - Converting the patient's clinical information into the virtual world is a prerequisite for the computer-aided design and computer-aided manufacturing (CAD CAM) of dental restorations. This article describes a modified facebow which facilitates the radiation-free registration of the maxillary teeth to a 3 dimensional face image for transfer to a virtual articulator. This facebow can be easily fabricated with minimal materials and adjusted to fit different patients; its error in tooth registration was demonstrated to be less than 1 mm. PMID- 27475921 TI - Modified PEEK resin-bonded fixed dental prosthesis as an interim restoration after implant placement. AB - A polyetheretherketone (PEEK) (BioHPP) framework veneered with composite resin was used as an alternative material for the fabrication of an interim 3-pontic resin-bonded fixed dental prosthesis (RBFDP) after implant placement. The low modulus of elasticity (4 GPa) of PEEK combined with the use of indirect light polymerized resin as a veneering material used for a RBFDP provided an advantage over metal ceramics or ceramics in dampening the occlusal forces and reducing debonding rates. Further long-term clinical evidence is required before recommending the application as a substitute material. PMID- 27475922 TI - Neurophysiological profile of peripheral neuropathy associated with childhood mitochondrial disease. AB - INTRODUCTION: Peripheral nerve involvement is common in mitochondrial disease but often unrecognised due to the prominent central nervous system features. Identification of the underlying neuropathy may assist syndrome classification, targeted genetic testing and rehabilitative interventions. METHODS: Clinical data and the results of nerve conduction studies were obtained retrospectively from the records of four tertiary children's hospital metabolic disease, neuromuscular or neurophysiology services. Nerve conductions studies were also performed prospectively on children attending a tertiary metabolic disease service. Results were classified and analysed according to the underlying genetic cause. RESULTS: Nerve conduction studies from 27 children with mitochondrial disease were included in the study (mitochondrial DNA (mtDNA) - 7, POLG - 7, SURF1 - 10, PDHc deficiency - 3). Four children with mtDNA mutations had a normal study while three had mild abnormalities in the form of an axonal sensorimotor neuropathy when not acutely unwell. One child with MELAS had a severe acute axonal motor neuropathy during an acute stroke-like episode that resolved over 12months. Five children with POLG mutations and disease onset beyond infancy had a sensory ataxic neuropathy with an onset in the second decade of life, while the two infants with POLG mutations had a demyelinating neuropathy. Seven of the 10 children with SURF1 mutations had a demyelinating neuropathy. All three children with PDHc deficiency had an axonal sensorimotor neuropathy. Unlike CMT, the neuropathy associated with mitochondrial disease was not length-dependent. CONCLUSIONS: This is the largest study to date of peripheral neuropathy in genetically- classified childhood mitochondrial disease. Characterising the underlying neuropathy may assist with the diagnosis of the mitochondrial syndrome and should be an integral part of the assessment of children with suspected mitochondrial disease. PMID- 27475924 TI - Characterizations of the submerged fermentation of Aspergillus oryzae using a Fullzone impeller in a stirred tank bioreactor. AB - A Fullzone (FZ) impeller was used in the first study of the characteristics involved in the fermentation of Aspergillus oryzae. Both the experimental and simulation results of this study revealed novel findings into the positive relationship between the global-axial mixing patterns of a FZ impeller and fermentation efficiency. The mixing results when using the FZ impeller compared with a double Rushton turbine (DRT) impeller indicated that the culture mixed by the FZ resulted in a more homogeneous medium with higher values for oxygen mass transfer, cell growth rate, and alpha amylase activity. The simulation of fluid flow was done in a laminar regime using a two-fluid model. According to the simulation results, the maximum shear stress when using the DRT was higher than that with the FZ at the same power input (Pin). A high degree of local shear stress and the shear rate near the turbine blade of the DRT resulted in cell damage and a reduction in the enzyme activity, biomass, pellet diameter, and dissolved oxygen concentration. Calculations using the Brown equation showed that the maximum and average shear rates during mixing with the FZ impeller were lower than that when using the DRT. Therefore, the use of an FZ impeller, particularly at low Pin, enhanced the cultivation of A. oryzae. PMID- 27475923 TI - Isolation and characterization of sake yeast mutants with enhanced isoamyl acetate productivity. AB - Isoamyl acetate is an important flavor compound in sake. However, production of isoamyl acetate by Saccharomyces cerevisiae is significantly reduced during sake brewing with rice that has a high polishing ratio, because unsaturated fatty acids derived from the outer layer of rice repress the expression of ATF1, which encodes an alcohol acetyl transferase. Yeast mutants capable of relieving this repression would allow the brewing of rice with high polishing ratios, improving the diversity of taste and flavor of sake. Atf1p is also believed to contribute to biological membrane homeostasis. We isolated four yeast mutants (hia1, hia2, hia4, and hia6) that have high isoamyl acetate productivity and are resistant to aureobasidin A, an inhibitor of sphingolipid biosynthesis. The isoamyl acetate content of sake brewed with the hia1 mutant was 2.6 times higher than that of the parental strain. ATF1 was expressed constitutively in the hia1 mutant during brewing and remained derepressed upon the addition of unsaturated fatty acids. Whole-genome sequence analysis of the hia mutants revealed a homozygous nonsense mutation (Ser706*) in MGA2 in all four mutants. Mga2p, an endoplasmic reticulum (ER) membrane protein, regulates ATF1 transcription. The expression of ATF1 was elevated in BY4743 Deltamga2 cells complemented with MGA2 (Ser706*), and this was not completely inhibited by the addition of unsaturated fatty acids. These results indicate that a nonsense mutation in MGA2 induces high levels of isoamyl acetate production in S. cerevisiae. This finding has applications for brewing sake with high levels of isoamyl acetate. PMID- 27475925 TI - Synergistic effects of pain intensity and anxiety sensitivity in relation to anxiety and depressive symptoms and disorders among economically disadvantaged latinos in a community-based primary care setting. AB - The present investigation examined the interactive effects of anxiety sensitivity and pain intensity in relation to anxious arousal, social anxiety, and depressive symptoms and disorders among 203 Latino adults with an annual income of less than $30,000 (84.4% female; Mage=38.9, SD=11.3 and 98.6% used Spanish as their first language) who attended a community-based primary healthcare clinic. As expected, the interaction between anxiety sensitivity and pain intensity was significantly related to increased anxious arousal, social anxiety, and depressive symptoms as well as number of depressive/anxiety disorder diagnoses. The form of the significant interactions indicated that participants reporting co-occurring higher levels of anxiety sensitivity and pain intensity evinced the greatest levels of anxious arousal, social anxiety, and depressive symptoms as well as higher levels of depressive and anxiety disorders. These data provide novel empirical evidence suggesting that there is clinically-relevant interplay between anxiety sensitivity and pain intensity in regard to a relatively wide array of anxiety and depressive variables among Latinos in a primary care medical setting. PMID- 27475926 TI - Reproducibility of Acoustic Radiation Force Impulse Imaging in Thyroid and Salivary Glands with Experienced and Inexperienced Examiners. AB - Acoustic radiation force impulse (ARFI) imaging enables the sonographic measurement of tissue stiffness. The aim of this study was to evaluate if experience in ARFI imaging influences the reproducibility of ARFI imaging of the head and neck. Three experienced sonographers and three inexperienced sonographers performed ARFI imaging of thyroid, submandibular and parotid glands in 10 healthy volunteers. The examination was repeated after 2 wk. Ten single ARFI measurements were done in every gland. Inter-rater and intra-rater reliability was analyzed using the intra-class correlation coefficient (ICC). Moderate agreement was observed between experienced and inexperienced examiners (ICC = 0.46). In salivary glands, agreement was fair between the groups (ICC = 0.33), whereas in separate evaluations, inter-rater reliability in the submandibular glands was moderate (ICC = 0.52), and that in the parotid glands, only poor (ICC = 0.09). For ARFI imaging of the thyroid gland, there was moderate agreement between the groups (ICC = 0.50). The intra-rater reliability for the salivary and thyroid glands together and separately was strong in both groups. ARFI imaging of the thyroid and salivary glands did exhibit good reproducibility. ARFI imaging of the thyroid gland reached the highest levels of inter- and intra observer agreement in both groups. ARFI imaging in salivary glands is only reproducible with experienced examiners. PMID- 27475927 TI - Contrast-Enhanced Ultrasound Imaging in Detection of Changes in Cerebral Perfusion. AB - Contrast-enhanced ultrasonography (CEU) is a non-invasive imaging technique that provides real-time, bedside information on changes in global and segmental organ perfusion. Currently, there is a lack of data concerning changes in the distribution of segmental brain perfusion in acute ischemic stroke treated by decompressive craniectomy. The aim of our case series was to assess the role of CEU after decompressive craniectomy in patients with acute ischemic stroke. CEU was performed in 12 patients at baseline and after any one of the following interventions was performed as dictated by the patient's clinical condition: vasoactive drug administration (in order to achieve cerebral perfusion pressure >=70 mm Hg and mean arterial pressure <100 mm Hg for management of arterial blood pressure) and mild hyperventilation (carbon dioxide arterial pressure = 30-35 mm Hg). CEU was able to detect a significant variation in cerebral contrast distribution in both normal and pathologic hemispheres after induced hyperventilation (difference in time to peak [dTTP] = -38.4%), vasodilation (dTTP = -6.6%) and vasoconstriction (dTTP = +31.2%) (p < 0.05). CEU can be useful in assessing real-time cerebral perfusion changes in neurocritical care patients. PMID- 27475928 TI - Using Technology to Affect Influenza Vaccine Coverage Among Children With Chronic Respiratory Conditions. AB - INTRODUCTION: Influenza presents additional burdens for children with chronic respiratory conditions. Influenza vaccinations may reduce complications, yet approximately half of children remain unprotected. Evidence supports integration of text and e-mail into multicomponent strategies to increase influenza vaccination rates among children with chronic respiratory conditions. METHODS: A single text and e-mail message was sent to those with enabled preferences in the patient portal. A follow-up survey assessed aspects of message receipt. Surveys were completed without collection of demographics. RESULTS: A total of 3,206 messages were successfully delivered. Surveys were initiated by 107 recipients. Frequency analysis showed that text and e-mail messages were preferred forms of communication. A statistically significant relationship was found between receiving a message and receiving an influenza vaccination (p = .027). DISCUSSION: Text and e-mail messaging are cost effective and well received, and they can be easily integrated into existing systems. These methods are translatable across populations and can convey various types of messages. PMID- 27475929 TI - Muscle specific nucleus ambiguus neurons isolation and culturing. AB - BACKGROUND: Peripheral nerve injury leads to a regenerative state. However, the reinnervation process is highly non-selective. Growing axons are often misrouted and establish aberrant synapsis to abductor or adductor muscles. Determining the complex properties of abductor and adductor motoneurons in a neuron culture, may lay the groundwork for future studies on axon guidance, leading to a clinical treatment for a selective reinnervation. NEW METHOD: In the present study we develop a neuron culture protocol to isolate recurrent laryngeal nerve abductor and adductor motoneurons in order to study their unique properties. Comparison with existing methods the best period to perform the present protocol for postnatal rat cranial motoneurons isolation was determined. In addition, the method allows identification of specific motoneurons from other primary motoneurons and interneurons within brainstem. CONCLUSION: The present protocol will allow investigators to perform targeted and novel studies of the mechanisms of peripheral nerve regeneration. PMID- 27475930 TI - Subjects with osteoporosis to remain at high risk for fracture despite benefit of prior bisphosphonate treatment-a Danish case-control study. AB - : The benefits of pharmaceutical treatment for osteoporosis may be limited for a number of patients, as they continue to experience fractures. Alternative treatments may be considered for subjects whom remain at high risk for future fractures. INTRODUCTION: Previous studies have investigated the effects of good adherence to anti-osteoporosis medication. However, very few studies have described why some patients experience fractures and loss of BMD despite adherence to treatment. The aim of this study was to estimate the proportion of patients at high risk for fracture despite being compliant to bisphosphonate treatment and examine which factors influence why some osteoporotic patients remain at a high risk for fracture despite being compliant to bisphosphonate treatment. METHODS: This case-control study is based on Danish national health registry data. The subjects had to have either one BMD test or a fracture prior to inclusion. "High-risk" subjects (cases) were defined as BMD t-score < =-2.5 SD, any drop in BMD from baseline or a fracture 24-36 months following inclusion. RESULTS: A total of 2406 subjects (66.3 % women; 33.7 % men) fulfilled the inclusion criteria, and of these, 352 (14.6 %) were identified as high risk subjects. A multiple logistical regression analysis showed that high risk subjects were more likely to have lower plasma calcium and/or vitamin D levels (OR: 2.9) and were more frequently diagnosed with hyperparathyroidism (OR: 2.6). CONCLUSION: Based on Danish national health registry data, 14.6 % patients were identified as patients remaining at high risk for fracture despite being compliant to bisphosphonate treatment. Lower plasma calcium and/or vitamin D level is the greatest predictor of high risk for fracture despite persistent bisphosphonate treatment. Secondary causes of osteoporosis should be considered and alternative treatments may be advised for subjects whom remain at high risk. PMID- 27475931 TI - Operator variability in scan positioning is a major component of HR-pQCT precision error and is reduced by standardized training. AB - : In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection ("scout view image") and define the region to be scanned by positioning a "reference line" on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanner's software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p < 0.001). New trained operators achieved comparable intra-operator reproducibility to experienced operators and lower inter-operator reproducibility (p < 0.001). Precision errors were significantly greater for the radius than for the tibia. CONCLUSION: Operator reference line positioning contributes significantly to in vivo measurement precision and is significantly greater for multi-operator datasets. Inter-operator variability can be significantly reduced using a systematic training platform, now available online ( http://webapps.radiology.ucsf.edu/refline/ ). PMID- 27475932 TI - Irreversible inhibition of Delta16HER2 is necessary to suppress Delta16HER2 positive breast carcinomas resistant to Lapatinib. AB - HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Delta16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Delta16HER2 isoform (Delta16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Delta16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer. Of note, Dacomitinib, an irreversible small molecule pan-HER inhibitor, was able to completely suppress Delta16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Delta16HER2 activation. PMID- 27475934 TI - Restorative Materials in Orthodontics. PMID- 27475933 TI - Long-term results and recurrence rates after spironolactone treatment in non resolving central serous chorio-retinopathy (CSCR). AB - PURPOSE: To evaluate the long-term results of spironolactone in non-resolving central serous chorio-retinopathy (CSCR) and recurrence rates of CSCR. METHODS: Interventional uncontrolled open-label prospective clinical trial of patients with non-resolving CSCR who were treated with spironolactone 50 mg daily (Spironolacton AL(r) 50 mg, ALIUD PHARMA) for up to 16 weeks. Follow-up visits were performed at 3, 6, 9, and 12 months. Retreatment criteria for recurrence were: gain in sub-retinal fluid (SRF) of more than 25 % plus/or increase of central retinal thickness (CRT) of more than 50 MUm plus visual symptoms compared to last visit. MAIN OUTCOME MEASURES: 12-month efficacy of upload treatment with spironolactone. Secondary outcome measure was the recurrence rate at 6, 9, and 12 months. RESULTS: Of the 21 study eyes treated, 71 % (n = 15) showed significant improvement or complete regression on OCT examination over 12 months. Nineteen percent of the patients (n = 4) showed a stable course from visit 1 to visit 12. The overall reduction of sub-retinal fluid from visit 1 (156 MUm +/- 131 SD) to visit 12 (53 MUm +/- 93 SD) was statistically significant (p = 0.003). The change of mean visual acuity (log MAR) from 0.25 (+/- 0.17 SD) at baseline to 0.17 (+/- 0.18 SD) at visit 12 was statistically significant, with p = 0.044. CONCLUSION: Our results confirm a positive effect of spironolactone in non-resolving CSCR in 71 % of cases. Evaluation of recurrence rates and retreatments showed good results in patients who responded to spironolactone primarily. A prospective randomized trial may provide better data about this non-invasive treatment. PMID- 27475935 TI - Effectiveness of Composite Attachments in Controlling Upper-Molar Movement with Aligners. PMID- 27475936 TI - Esthetic Provisional Restoration after Space Closure in Patients with Missing Upper Lateral Incisors. PMID- 27475937 TI - Quad Helix Canine System for Forced Eruption of Impacted Upper Canines. PMID- 27475939 TI - Incisor Intrusion with a Miniscrew-Anchored Segmental Utility Arch. PMID- 27475938 TI - Mini-Implant-Supported Orthodontic Extrusion and Restorative Treatment of Fractured Teeth. PMID- 27475940 TI - Correction of Complete Upper Canine-Premolar Transposition with Palatal Miniscrew Anchorage. PMID- 27475941 TI - Contributions of Disease Severity, Psychosocial Factors, and Cognition to Behavioral Functioning in US Youth Perinatally Exposed to HIV. AB - Among perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth, we evaluated the contributions of home environment, psychosocial, and demographic factors and, among PHIV only, HIV disease severity and antiretroviral treatment (ART), to cognitive functioning (CF) and behavioral functioning (BF). A structural equation modeling (SEM) approach was utilized. Exploratory factor analysis was used to reduce predictor variables to major latent factors. SEMs were developed to measure associations between the latent factors and CF and BF outcomes. Participants included 231 PHIV and 151 PHEU youth (mean age = 10.9 years) enrolled in the PHACS adolescent master protocol. Youth and caregivers completed assessments of CF, BF, psychosocial factors and HIV health. Medical data were also collected. Clusters of predictors were identified, establishing four parsimonious SEMs: child-assessed and caregiver-assessed BF in PHIV and PHEU youth. Among both groups, higher caregiver-child stress predicted worse BF. Caregiver resources and two disease severity variables, late presenter and better past HIV health, were significant predictors of CF in PHIV youth. Higher youth CF was associated with better caregiver-reported BF in both groups. Caregiver resources predicted caregiver-reported BF in PHEU youth, which was mediated via youth CF. Among PHIV youth, better past HIV health and caregiver resources mediated the effects of CF on caregiver-assessed BF. Using SEMs, we found a deleterious impact of caregiver and child stress on BF in both groups and of HIV disease factors on the CF of PHIV youth, reinforcing the importance of early comprehensive intervention to reduce risks for impairment. PMID- 27475942 TI - Health Services Use and HIV Prevalence Among Migrant and National Female Sex Workers in Portugal: Are We Providing the Services Needed? AB - This cross-sectional bio-behavioral survey conducted with 853 female sex workers (FSW) aimed to examine differences in use of HIV health services, testing and prevalence among migrant and national FSW. A quarter of undocumented FSW had never used National Health Service (NHS) and 15 % never tested for HIV, significantly more than nationals (p < 0.001 and p = 0.024, respectively). HIV infection was self-reported by 11.9 % of nationals, 1.8 % of documented and 0.8 % of undocumented migrants (p < 0.001). The HIV rapid test was reactive in 13.6 % of undocumented, 8.0 % of nationals and 2.3 % of documented. A higher proportion of migrants were unaware of their positive serostatus compared to nationals. Ever had HIV testing was less likely among undocumented, who never used the NHS and who didn't know where to go if suspected being HIV-infected. Promoting early diagnosis with linkage to care among migrant FSW should be supported, while developing health services better tailored to their needs. PMID- 27475943 TI - Sexual Risk-Taking in HIV-Negative Gay and Bisexual Men Increases with Depression: Results from a U.S. National Study. AB - The link between depression and sexual risk-taking has received mixed findings in the literature. The current study analyzed the links between depression and recent condomless anal sex (CAS) with casual partners among 1033 HIV-negative, non-PrEP-using, gay and bisexual men. When CAS was dichotomized as either none or some, depression was not associated with the odds of CAS (with receptive and insertive combined) or insertive CAS only, but was positively associated with the odds of receptive CAS. When CAS was tallied as a count variable of events, depression was positively associated with total CAS, receptive CAS, and insertive CAS. With the addition of a quadratic term for depression, a positive quadratic effect was only found for total CAS and receptive CAS, but not for insertive CAS. These findings highlight the utility of using count data for CAS events and treating CAS separately with regard to receptive and insertive positioning when considering the role of depression among gay and bisexual men. PMID- 27475944 TI - The Importance of Sexual History Taking for PrEP Comprehension Among Young People of Color. AB - Despite demonstrated efficacy, uptake of pre-exposure prophylaxis (PrEP) remains low, especially among highest priority populations. This study examined four PrEP messaging factors hypothesized to impact comprehension of PrEP educational information: (1) modality (video versus in-person message delivery); (2) frame (risk versus health focus); (3) specificity (gist versus verbatim efficacy information); and (4) sexual history (administered either before or after PrEP education). We examined message comprehension among 157 young people of color (YPoC) eligible for PrEP, using a series of multiple choice questions. Overall, 65.6 % (n = 103) got all message comprehension questions correct. In multivariate analyses, engaging in a sexual history before receiving PrEP education was associated with increased odds of message comprehension (aOR 2.23; 95 % CI 1.06 4.72). This effect was even stronger among those who received PrEP education via video (aOR 3.53; 95 % CI 1.16-10.81) compared to via health educator. This research underscores the importance of sexual history-taking as part of PrEP education and clinical practice for YPoC, and suggests that engaging patients in a sexual history prior to providing them with PrEP education may be key to increasing comprehension. PMID- 27475945 TI - What are the Patterns Between Depression, Smoking, Unhealthy Alcohol Use, and Other Substance Use Among Individuals Receiving Medical Care? A Longitudinal Study of 5479 Participants. AB - To evaluate and characterize the structure of temporal patterns of depression, smoking, unhealthy alcohol use, and other substance use among individuals receiving medical care, and to inform discussion about whether integrated screening and treatment strategies for these conditions are warranted. Using the Veterans Aging Cohort Study (VACS) we measured depression, smoking, unhealthy alcohol use and other substance use (stimulants, marijuana, heroin, opioids) and evaluated which conditions tended to co-occur within individuals, and how this co occurrence was temporally structured (i.e. concurrently, sequentially, or discordantly). Current depression was associated with current use of every substance examined with the exception of unhealthy alcohol use. Current unhealthy alcohol use and marijuana use were also consistently associated. Current status was strongly predicted by prior status (p < 0.0001; OR = 2.99-22.34) however, there were few other sequential relationships. Associations in the HIV infected and uninfected subgroups were largely the same with the following exceptions. Smoking preceded unhealthy alcohol use and current smoking was associated with current depression in the HIV infected subgroup only (p < 0.001; OR = 1.33-1.41 and p < 0.001; OR = 1.25-1.43). Opioid use and current unhealthy alcohol use were negatively associated only in the HIV negative subgroup (p = 0.01; OR = 0.75). Patterns of depression, smoking, unhealthy alcohol use, and other substance use were temporally concordant, particularly with regard to depression and substance use. These patterns may inform future development of more integrated screening and treatment strategies. PMID- 27475946 TI - Robot-assisted bilateral simultaneous pyeloplasty: safe and feasible. AB - Traditionally, bilateral UPJO in adults was managed by the staged approach during the open surgery era, because of need for two separate incisions and change of patient positioning. In addition, there was a feared risk of post-operative bilateral renal obstruction. Even with advent minimal invasive laparoscopic surgery, simultaneous pyeloplasty did not pick up due to difficult suturing. However, robot-assisted surgery, with its distinct advantageous, had made it feasible. In this case series, we demonstrate safety and feasibility of bilateral simultaneous pyeloplasty over short term. PMID- 27475947 TI - Creep analysis of silicone for podiatry applications. AB - PURPOSE: This work shows an effective methodology to characterize the creep recovery behavior of silicones before their application in podiatry. The aim is to characterize, model and compare the creep-recovery properties of different types of silicone used in podiatry orthotics. METHODS: Creep-recovery phenomena of silicones used in podiatry orthotics is characterized by dynamic mechanical analysis (DMA). Silicones provided by Herbitas are compared by observing their viscoelastic properties by Functional Data Analysis (FDA) and nonlinear regression. The relationship between strain and time is modeled by fixed and mixed effects nonlinear regression to compare easily and intuitively podiatry silicones. RESULTS: Functional ANOVA and Kohlrausch-Willians-Watts (KWW) model with fixed and mixed effects allows us to compare different silicones observing the values of fitting parameters and their physical meaning. The differences between silicones are related to the variations of breadth of creep-recovery time distribution and instantaneous deformation-permanent strain. Nevertheless, the mean creep-relaxation time is the same for all the studied silicones. Silicones used in palliative orthoses have higher instantaneous deformation-permanent strain and narrower creep-recovery distribution. CONCLUSIONS: The proposed methodology based on DMA, FDA and nonlinear regression is an useful tool to characterize and choose the proper silicone for each podiatry application according to their viscoelastic properties. PMID- 27475948 TI - Neonatal Lupus: What We Have Learned and Current Approaches to Care. AB - Neonatal lupus results from the passive transfer of autoantibodies; however, this transfer is not sufficient to cause disease. This article reviews clinical presentation with a focus on autoimmune-mediated congenital heart disease. Recent data looking for additional disease mechanisms and biomarkers as well as latest information on interventions will be reviewed. Our understanding of this rare disease is often dependent on patient participation in disease registries and biorepositories. Future participation in registries including descriptive as well as biophysical data is critical to our knowledge. PMID- 27475949 TI - Pulmonary vein reconnection following catheter ablation of atrial fibrillation using the second-generation cryoballoon versus open-irrigated radiofrequency: results of a multicenter analysis. AB - PURPOSE: Catheter ablation of atrial fibrillation (CAAF) using the cryoballoon has emerged as an alternate strategy to point-by-point radiofrequency. However, there is little comparative data on long-term durability of pulmonary vein (PV) isolation comparing these two modalities. METHODS: In this multicenter, retrospective analysis, the incidences/patterns of late PV reconnection following an index CAAF using the second-generation cryoballoon versus open-irrigated, non force-sensing radiofrequency were examined. RESULTS: Of the 2002 patients who underwent a first-time CAAF, 186/1126 patients (16.5 %) ablated using cryoballoon and 174/876 patients (19.9 %) with non-contact force-guided radiofrequency required a repeat procedure at 11 +/- 5 months. During follow-up, the incidence of atrial flutters/tachycardias was lower (19.9 vs. 32.8 %; p = 0.005) and fewer patients exhibited PV reconnection (47.3 vs. 60.9 %; p = 0.007) with cryoballoon versus radiofrequency. Additionally, fewer PVs had reconnected with cryoballoon versus radiofrequency (18.8 vs. 34.6 %; p < 0.001). With cryoballoon, the right inferior (p < 0.001) and left common (p = 0.039) PVs were more likely to exhibit late reconnection, versus the left superior PV with radiofrequency (p = 0.012). However, when comparing the two strategies, the left common PV was more likely to exhibit reconnection with cryoballoon, whereas all other PVs with the exception of the right inferior PV demonstrated a lower reconnection rate with cryoballoon versus radiofrequency. Lastly, in a logistic regression multivariate analysis, cryoballoon ablation and PV ablation time emerged as significant predictors of durable PV isolation at repeat procedure. CONCLUSIONS: In this large multicenter, retrospective analysis, CAAF using the second-generation cryoballoon was associated with improved durability of PV isolation compared to open-irrigated, non-force-sensing radiofrequency. PMID- 27475950 TI - Near-critical SIR epidemic on a random graph with given degrees. AB - Emergence of new diseases and elimination of existing diseases is a key public health issue. In mathematical models of epidemics, such phenomena involve the process of infections and recoveries passing through a critical threshold where the basic reproductive ratio is 1. In this paper, we study near-critical behaviour in the context of a susceptible-infective-recovered epidemic on a random (multi)graph on n vertices with a given degree sequence. We concentrate on the regime just above the threshold for the emergence of a large epidemic, where the basic reproductive ratio is [Formula: see text], with [Formula: see text] tending to infinity slowly as the population size, n, tends to infinity. We determine the probability that a large epidemic occurs, and the size of a large epidemic. Our results require basic regularity conditions on the degree sequences, and the assumption that the third moment of the degree of a random susceptible vertex stays uniformly bounded as [Formula: see text]. As a corollary, we determine the probability and size of a large near-critical epidemic on a standard binomial random graph in the 'sparse' regime, where the average degree is constant. As a further consequence of our method, we obtain an improved result on the size of the giant component in a random graph with given degrees just above the critical window, proving a conjecture by Janson and Luczak. PMID- 27475951 TI - Acclimation capacity of the three-spined stickleback (Gasterosteus aculeatus, L.) to a sudden biological stress following a polymetallic exposure. AB - To get closer to the environmental reality, ecotoxicological studies should no longer consider the evaluation of a single pollutant, but rather combination of stress and their interaction. The aim of this study was to determine if responses of a fish to a sudden biological stress could be modified by a prior exposure to a chemical stress (a polymetallic contamination). For this purpose, in situ experiment was conducted in three ponds in the Haute-Vienne department (France). One pond was chosen for its high uranium concentration due to uranium mine tailings, and the two other ponds, which were not submitted to these tailings. Three-spined sticklebacks (Gasterosteus aculeatus) were caged in these ponds for 14 days. After this period, fish were submitted to a biological stress, exerted by lipopolysaccharides injection after anesthesia, and were sacrificed 4 days after these injections for multi-biomarkers analyses (leucocyte viability, phagocytic capacity and reactive oxygen species production, antioxidant peptide and enzymes, lipid peroxidation and DNA damage). The pond which received uranium mine tailings had higher metallic concentrations. Without biological stress, sticklebacks caged in this pond presented an oxidative stress, with increasing of reactive oxygen species levels, modification of some parts of the antioxidant system, and lipid peroxidation. Caging in the two most metal-contaminated ponds resulted in an increase of susceptibility of sticklebacks to the biological stress, preventing their phagocytic responses to lipopolysaccharides and modifying their glutathione contents and glutathione-S-transferase activity. PMID- 27475954 TI - Survival or death: a dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy. AB - AIMS/HYPOTHESIS: Intra-retinal extravasation and modification of LDL have been implicated in diabetic retinopathy: autophagy may mediate these effects. METHODS: Immunohistochemistry was used to detect autophagy marker LC3B in human and murine diabetic and non-diabetic retinas. Cultured human retinal capillary pericytes (HRCPs) were treated with in vitro-modified heavily-oxidised glycated LDL (HOG LDL) vs native LDL (N-LDL) with or without autophagy modulators: green fluorescent protein-LC3 transfection; small interfering RNAs against Beclin-1, c Jun NH(2)-terminal kinase (JNK) and C/EBP-homologous protein (CHOP); autophagy inhibitor 3-MA (5 mmol/l) and/or caspase inhibitor Z-VAD-fmk (100 MUmol/l). Autophagy, cell viability, oxidative stress, endoplasmic reticulum stress, JNK activation, apoptosis and CHOP expression were assessed by western blots, CCK-8 assay and TUNEL assay. Finally, HOG-LDL vs N-LDL were injected intravitreally to STZ-induced diabetic vs control rats (yielding 50 and 200 mg protein/l intravitreal concentration) and, after 7 days, retinas were analysed for ER stress, autophagy and apoptosis. RESULTS: Intra-retinal autophagy (LC3B staining) was increased in diabetic vs non-diabetic humans and mice. In HRCPs, 50 mg/l HOG LDL elicited autophagy without altering cell viability, and inhibition of autophagy decreased survival. At 100-200 mg/l, HOG-LDL caused significant cell death, and inhibition of either autophagy or apoptosis improved survival. Further, 25-200 mg/l HOG-LDL dose-dependently induced oxidative and ER stress. JNK activation was implicated in autophagy but not in apoptosis. In diabetic rat retina, 50 mg/l intravitreal HOG-LDL elicited autophagy and ER stress but not apoptosis; 200 mg/l elicited greater ER stress and apoptosis. CONCLUSIONS: Autophagy has a dual role in diabetic retinopathy: under mild stress (50 mg/l HOG LDL) it is protective; under more severe stress (200 mg/l HOG-LDL) it promotes cell death. PMID- 27475955 TI - Phenotypic differences based on staging of Alzheimer's neuropathology in autopsy confirmed dementia with Lewy bodies. AB - INTRODUCTION: The goal was to compare subgroups of dementia with Lewy Bodies (DLB) using neuropathological measures to differentiate 'pure' Lewy body (LB) dementia from 'mixed' DLB [co-occurring LB and Alzheimer's disease (AD) pathology] to facilitate diagnostic decision-making and future development of interventions based on predicted type(s) of neuropathology. Studies comparing these groups are rare relative to those differentiating 'pure' AD and all-cause DLB, and are limited by insufficient sample size, brief cognitive batteries, and/or absence of autopsy confirmation. To address these limitations, we assessed cognition and other features in a large, autopsy-confirmed DLB sample using an extensive neuropsychological battery. METHODS: Subjects from an AD research center autopsy series satisfying DLB pathology criteria were divided by an AD neuropathology index into DLB-LB (Braak stage 0-3) (n = 38) and DLB-AD (Braak stage 4-6) (n = 41) and compared on baseline variables from chart reviews and standardized measures. RESULTS: DLB-LB subjects were more impaired on visuospatial constructions, visual conceptual reasoning, and speed of processing, but less impaired on verbal memory and confrontation naming. All-type hallucinations occurred more frequently in DLB-LB, while delusions were common in both groups. Groups were similar in education and age at onset, and in baseline age, dementia severity, and functional capacity. CONCLUSION: Salient findings included greater impairment on visual tasks and speed of processing and more frequent reports of all-type hallucinations in DLB-LB compared to DLB-AD. Relatively intact confrontation naming in DLB-LB and no differences in reported delusions were of note. Identifying differences in phenotypic features can improve prediction of underlying neuropathology. PMID- 27475952 TI - The Impact of Hyperoxia on Human Performance and Recovery. AB - Hyperoxia results from the inhalation of mixtures of gas containing higher partial pressures of oxygen (O2) than normal air at sea level. Exercise in hyperoxia affects the cardiorespiratory, neural and hormonal systems, as well as energy metabolism in humans. In contrast to short-term exposure to hypoxia (i.e. a reduced partial pressure of oxygen), acute hyperoxia may enhance endurance and sprint interval performance by accelerating recovery processes. This narrative literature review, covering 89 studies published between 1975 and 2016, identifies the acute ergogenic effects and health concerns associated with hyperoxia during exercise; however, long-term adaptation to hyperoxia and exercise remain inconclusive. The complexity of the biological responses to hyperoxia, as well as the variations in (1) experimental designs (e.g. exercise intensity and modality, level of oxygen, number of participants), (2) muscles involved (arms and legs) and (3) training status of the participants may account for the discrepancies. PMID- 27475953 TI - Core Stability in Athletes: A Critical Analysis of Current Guidelines. AB - Over the last two decades, exercise of the core muscles has gained major interest in professional sports. Research has focused on injury prevention and increasing athletic performance. We analyzed the guidelines for so-called functional strength training for back pain prevention and found that programs were similar to those for back pain rehabilitation; even the arguments were identical. Surprisingly, most exercise specifications have neither been tested for their effectiveness nor compared with the load specifications normally used for strength training. Analysis of the scientific literature on core stability exercises shows that adaptations in the central nervous system (voluntary activation of trunk muscles) have been used to justify exercise guidelines. Adaptations of morphological structures, important for the stability of the trunk and therefore the athlete's health, have not been adequately addressed in experimental studies or in reviews. In this article, we explain why the guidelines created for back pain rehabilitation are insufficient for strength training in professional athletes. We critically analyze common concepts such as 'selective activation' and training on unstable surfaces. PMID- 27475957 TI - [Targeting high-risk drugs to optimize clinical pharmacists' intervention]. AB - OBJECTIVES: By the Order of 6 April 2011, the pharmacist must validate all the prescriptions containing "high-risk drugs" or those of "patients at risk". To optimize this clinical pharmacy activity, we identified high-risk drugs. METHOD: A list of high-risk drugs has been established using literature, pharmacists' interventions (PI) performed in our hospital and a survey sent to hospital pharmacists. In a prospective study (analysis of 100 prescriptions for each high risk drug selected), we have identified the most relevant to target. RESULTS: We obtained a statistically significant PI rate (P<0.05) for digoxin, oral anticoagulants direct, oral methotrexate and colchicine. CONCLUSION: This method of targeted pharmaceutical validation based on high-risk drugs is relevant to detect patients with high risk of medicine-related illness. PMID- 27475956 TI - Structure Prediction of a Novel Exo-beta-1,3-Glucanase: Insights into the Cold Adaptation of Psychrophilic Yeast Glaciozyma antarctica PI12. AB - We report a detailed structural analysis of the psychrophilic exo-beta-1,3 glucanase (GaExg55) from Glaciozyma antarctica PI12. This study elucidates the structural basis of exo-1,3-beta-1,3-glucanase from this psychrophilic yeast. The structural prediction of GaExg55 remains a challenge because of its low sequence identity (37 %). A 3D model was constructed for GaExg55. Threading approach was employed to determine a suitable template and generate optimal target-template alignment for establishing the model using MODELLER9v15. The primary sequence analysis of GaExg55 with other mesophilic exo-1,3-beta-glucanases indicated that an increased flexibility conferred to the enzyme by a set of amino acids substitutions in the surface and loop regions of GaExg55, thereby facilitating its structure to cold adaptation. A comparison of GaExg55 with other mesophilic exo-beta-1,3-glucanases proposed that the catalytic activity and structural flexibility at cold environment were attained through a reduced amount of hydrogen bonds and salt bridges, as well as an increased exposure of the hydrophobic side chains to the solvent. A molecular dynamics simulation was also performed using GROMACS software to evaluate the stability of the GaExg55 structure at varying low temperatures. The simulation result confirmed the above findings for cold adaptation of the psychrophilic GaExg55. Furthermore, the structural analysis of GaExg55 with large catalytic cleft and wide active site pocket confirmed the high activity of GaExg55 to hydrolyze polysaccharide substrates. PMID- 27475958 TI - Chronic oral mucositis after radiotherapy to the head and neck: a new insight. AB - PURPOSE: Oral mucositis is a major complication of anticancer therapy yet the literature focuses on immediate (acute) mucosal changes and hardly describes the chronic form. We aim to report the clinical manifestations of chronic mucositis. METHODS: A retrospective chart review of oral mucositis referrals was performed. Inclusion/exclusion criteria defined the patients that were considered to have chronic mucositis. RESULTS: Four female patients treated for tongue/lower lip squamous cell carcinoma were included. Extensive painful oral mucositis lesions developed in all patients during the course of radiotherapy, with ulcers remaining for 5-24 months after completion of therapy. We describe two presentations, namely the persistent form (long-lasting ulcers continuing from acute ulcers) and the recurrent form (new discrete ulcers appearing on atrophic mucosa following the completion of radiotherapy). CONCLUSIONS: The long-term oral complications of radiotherapy to the head and neck may include chronic atrophic, erythematous, and/or ulcerated lesions. A diagnosis of chronic oral mucositis should be considered when the lesions are observed at least 3 months after radiotherapy, and other possible etiologies have been excluded. The influence of age and comorbidities (primarily diabetes mellitus) on chronic mucositis, the significance to patient's quality of life, and the management of chronic mucositis are important subjects for future research. PMID- 27475959 TI - Whole genome sequencing identifies ANXA3 and MTHFR mutations in a large family with an unknown equinus deformity associated genetic disorder. AB - The aim of this study was to characterize a previously uncharacterized genetic disorder associated with equinus deformity in a large Chinese family at the genetic level. Blood samples were obtained and whole genome sequencing was performed. Differential gene variants were identified and potential impacts on protein structure were predicted. Based on the control sample, several diseases associated variants were identified and selected for further validation. One of the potential variants identified was a ANXA3 gene [chr4, c.C820T(p.R274*)] variant. Further bioinformatic analysis showed that the observed mutation could lead to a three-dimensional conformational change. Moreover, a MTHFR variant that is different from variants associated with clubfoot was also identified. Bioinformatic analysis showed that this mutation could alter the protein binding region. These findings imply that this uncharacterized genetic disorder is not clubfoot, despite sharing some similar symptoms. Furthermore, specific CNV profiles were identified in association with the diseased samples, thus further speaking to the complexity of this multigenerational disorder. This study examined a previously uncharacterized genetic disorder appearing similar to clubfoot and yet having distinct features. Following whole genome sequencing and comparative analysis, several differential gene variants were identified to enable a further distinction from clubfoot. It is hoped that these findings will provide further insight into this disorder and other similar disorders. PMID- 27475960 TI - In vitro antimicrobial synergy of colistin with rifampicin and carbapenems against colistin-resistant Acinetobacter baumannii clinical isolates. AB - Increased use of colistin in a clinical setting had resulted in the emergence of colistin-resistant (CoR) Acinetobacter baumannii. Combination therapy has been studied as a new approach to treat infections caused by A. baumannii. Here, we investigated the in vitro antimicrobial synergistic activities of several antimicrobial agent combinations against CoR A. baumannii. A total of 41 non duplicate clinical isolates of CoR A. baumannii from a tertiary care hospital in Korea were prospectively collected from April 2012 to December 2014. As a control group, 41 carbapenem-resistant but colistin-susceptible (CoS) A. baumannii strains were also evaluated. Minimum inhibitory concentrations (MICs) of antimicrobial agents were determined by Etest in triplicate, and in vitro synergy tests were performed by the Etest MIC:MIC ratio method. Synergistic activity was determined as the sum of each antimicrobial agent's fractional inhibitory concentration evaluated (SigmaFIC): synergy, <=0.5; indifference, >0.5-4; and antagonism, >4. Synergistic activities were more frequently observed in the CoR group than the CoS group for combinations of colistin-rifampicin (80.5% vs. 14.6%, P< 0.0001), colistin-meropenem (85.4% vs. 4.9%, P< 0.0001), and colistin imipenem (46.3% vs. 2.4%, P< 0.0001). Combination with rifampicin or meropenem lowered colistin MICs against CoR A. baumannii clinical isolates to the susceptible range (<= 2 MUg/mL) more frequently (61.0%, 25/41, both) than combination with imipenem (29.3%, 12/41). Clinical trials are needed to prove the in vivo efficacy of those antimicrobial combinations that exhibited significant in vitro antimicrobial synergistic effects against CoR A. baumannii. PMID- 27475961 TI - Postoperative Growth in Radial Polydactyly: A Clinical Study. AB - PURPOSE: This study was designed to evaluate thumb growth after surgical management of a duplicate thumb and investigate its developmental pattern. METHODS: We compared the thumbs and index fingers of 486 normal children (aged 1 18 y) (group A) with 15 children showing radial polydactyly (group B). All duplicate thumbs were treated with excision of the radial thumb and reconstruction of the ulnar thumb. Radiographs of groups A and B were used to compute the thumb-to-index finger length ratio and width ratio, and the thumb-to index finger phalanx length ratio and phalanx width ratio. RESULTS: In group A, the length ratio, width ratio, phalanx length ratio, and phalanx width ratio did not change with age, and remained constant in males and females. In group B, after an average follow-up period of 41.0 months, the original findings were also similar to the final ratios. In group B, only the phalanx width ratio was obviously smaller than normal. CONCLUSIONS: A permanent developmental stability exists between the thumb and the index finger, even in patients with radial polydactyly. The development of the retained digit is not influenced by the ablation of the extra digit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 27475962 TI - Hotspots of black carbon and PM2.5 in an urban area and relationships to traffic characteristics. AB - Three instrumented bicycles were used to measure black carbon (BC) and PM2.5 concentrations in a midsized city in southern Brazil. The objective of this study was to map the spatial distribution of BC and PM2.5, to identify air pollution hotspots and to assess factors that may affect the concentrations of these pollutants, e.g. traffic volume, number of heavy-duty diesel vehicles (HDDV), position of traffic signals and street incline. The cyclists collected data in the city centre along streets of different traffic density during nine sampling sessions in the weekday morning and afternoon rush hours, between March 13 and April 28, 2015. The sampling by bicycle covered an area of 2.70 km2, over variable elevation, and travelled a total distance of 215 km. BC and PM2.5 exhibited a large spatial variability on a scale of tens of metres and the concentrations were positively correlated with traffic counts, but exhibited a stronger relationship with the number of HDDV. These results imply that older buses and diesel-powered trucks may be the main driver behind the high pollution levels in the city's inner core. We observed a strong relationship between BC concentrations at junctions managed by traffic signals and the quantity of HDDV. The mean BC concentration was found to be 8.10 MUg m-3 near traffic signals located on an inclined street (HDDV > 100 vehicles h-1) compared to traffic signals on flat terrain (6.00 MUg m-3), which can be attributed to the higher acceleration required at the start of motion. This pattern was less evident for PM2.5 concentrations. PMID- 27475963 TI - PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential. AB - BACKGROUND: Neoplastic stroma is believed to influence tumour progression. Here, we examine phosphatase and tensin homolog deleted on chromosome ten (PTEN) status in the tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) focussing especially at the stromal cells. METHODS: We asses PTEN at protein, messenger RNA and DNA level using a well-characterised PDAC cohort (n = 117). miR 21, known to target PTEN, is assessed after RNA extraction from different laser capture-microdissected cell populations, including cancer cells and juxta tumoural and tumour-remote stroma. RESULTS: PTEN deletion was the most frequent cause of PTEN protein loss in PDAC cells (71%) and correlated with vascular invasion (p = 0.0176) and decreased overall survival (p = 0.0127). Concomitant PTEN protein loss in tumour and juxta-tumoural stroma, found in 21.4% of PDACs, correlated with increased distant metastasis (p = 0.0045). Stromal cells with PTEN protein loss frequently showed PTEN genetic aberrations, including hemizygous PTEN deletion (46.6%) or chromosome 10 monosomy (40%). No alterations were found in the tumour-remote stroma. miR-21 was overexpressed by cancer- and juxta-tumoural stromal cells, in some cases without simultaneous PTEN gene alterations. No PTEN mutations or promoter methylation were detected. CONCLUSIONS: We find various mechanisms of PTEN protein loss in the different tumour cell populations, including allelic PTEN deletions, gross chromosomal 10 aberrations and altered miR-21 expression. PTEN deletion is a major cause of PTEN protein loss in PDAC and correlates with aggressive characteristics and worse outcome. PTEN protein loss in juxta-tumoural stromal cells is mostly due to PTEN haplo-insufficiency and characterises a subgroup of PDACs with enhanced metastatic potential. In the tumour microenvironment of the invasive front, PTEN silencing by miR-21 in cancer and surrounding stromal cells acts not only cooperatively but also independently of the genetic aberrations to precipitate PTEN protein loss and promote further tumour growth. PMID- 27475966 TI - Brain Research: The Journal and the Field at 50! PMID- 27475965 TI - Altered spontaneous neural activity in the occipital face area reflects behavioral deficits in developmental prosopagnosia. AB - Individuals with developmental prosopagnosia (DP) exhibit severe difficulties in recognizing faces and to a lesser extent, also exhibit difficulties in recognizing non-face objects. We used fMRI to investigate whether these behavioral deficits could be accounted for by altered spontaneous neural activity. Two aspects of spontaneous neural activity were measured: the intensity of neural activity in a voxel indexed by the fractional amplitude of spontaneous low-frequency fluctuations (fALFF), and the connectivity of a voxel to neighboring voxels indexed by regional homogeneity (ReHo). Compared with normal adults, both the fALFF and ReHo values within the right occipital face area (rOFA) were significantly reduced in DP subjects. Follow-up studies on the normal adults revealed that these two measures indicated further functional division of labor within the rOFA. The fALFF in the rOFA was positively correlated with behavioral performance in recognition of non-face objects, whereas ReHo in the rOFA was positively correlated with processing of faces. When considered together, the altered fALFF and ReHo within the same region (rOFA) may account for the comorbid deficits in both face and object recognition in DPs, whereas the functional division of labor in these two measures helps to explain the relative independency of deficits in face recognition and object recognition in DP. PMID- 27475964 TI - Fractones: extracellular matrix niche controlling stem cell fate and growth factor activity in the brain in health and disease. AB - The stem cell niche refers to a specific microenvironment where stem cells proliferate and differentiate to produce new specialized cells throughout an organism's adulthood. Growth factors are crucial signaling molecules that diffuse through the extracellular space, reach the stem cell niche, and ultimately promote stem cell proliferation and differentiation. However, it is not well known how multiple growth factors, often with antagonistic activities, work together in the stem cell niche to select target stem cell populations and determine stem cell fate. There is accumulating evidence suggesting that extracellular matrix (ECM) molecules play an important role in promoting growth factor access and activity in the stem cell niche. In the adult brain neurogenic zone, where neural stem cells (NSCs) reside, there exist specialized ECM structures, which we have named fractones. The processes of NSC allow them to come into contact with fractones and interact with its individual components, which include heparan sulfate proteoglycans (HSPGs) and laminins. We have demonstrated that fractone-associated HSPGs bind growth factors and regulate NSC proliferation in the neurogenic zone. Moreover, emerging results show that fractones are structurally altered in animal models with autism and adult hydrocephalus, as demonstrated by changes in fractone size, quantity, or HSPG content. Interestingly, ECM structures similar to fractones have been found throughout beta-amyloid plaques in the brain of patients with Alzheimer's disease. Pathological fractones may cause imbalances in growth factor activity and impair neurogenesis, leading to inflammation and disorder. Generally speaking, these stem cell niche structures play a potentially vital role in controlling growth factor activity during both health and disease. PMID- 27475967 TI - Clinical Use of Expanded Prostate Cancer Index Composite for Clinical Practice to Assess Patient Reported Prostate Cancer Quality of Life Following Robot-Assisted Radical Prostatectomy. AB - PURPOSE: EPIC-CP (Expanded Prostate Cancer Index Composite for Clinical Practice) is a short questionnaire that comprehensively measures patient reported health related quality of life at the point of care. We evaluated the feasibility of using EPIC-CP in the routine clinical care of patients with prostate cancer without research infrastructure. We compared longitudinal patient and practitioner reported prostate cancer outcomes. MATERIALS AND METHODS: We reviewed health related quality of life outcomes in 482 patients who underwent radical prostatectomy at our institution from 2010 to 2014. EPIC-CP was administered and interpreted in routine clinical practice without research personnel. We compared practitioner documented rates of incontinence pad use and functional erections to patient reported rates using EPIC-CP. RESULTS: A total of 708 EPIC-CP questionnaires were completed. Mean urinary incontinence domain scores were significantly higher (worse) than baseline (mean +/- SD 0.6 +/- 0.2) 3 and 6 months after treatment (mean 3.1 +/- 2.3 and 2.2 +/- 2.1, respectively, each p <0.05) but they returned to baseline at 12 months (mean 1.6 +/- 1.7, p >0.05). Mean sexual domain scores were significantly worse than baseline (mean 2.4 +/- 2.8) at all posttreatment time points (each p <0.05). Practitioners significantly overestimated incontinence pad-free rates at 3 months (48% vs 39%) and functional erection rates at 3 months (18% vs 12%), 6 months (38% vs 23%) and 12 months (45% vs 23%, each p <0.05). CONCLUSIONS: EPIC-CP is feasible to use in the routine clinical care of patients with prostate cancer without requiring a research infrastructure. Using EPIC-CP in clinical practice may help practitioners objectively assess and appropriately manage posttreatment side effects in patients with prostate cancer. PMID- 27475968 TI - Optical Coherence Tomography as a Tool for In Vivo Staging and Grading of Upper Urinary Tract Urothelial Carcinoma: A Study of Diagnostic Accuracy. AB - PURPOSE: Biopsies and cytology are cornerstones in the diagnosis of upper urinary tract urothelial carcinoma. However, a high rate of nondiagnostic biopsies, tumor upgrading and tumor up staging after nephroureterectomy has been observed. In this prospective in vivo study we evaluated the diagnostic accuracy of optical coherence tomography for the grading and staging of upper tract urothelial carcinoma. MATERIALS AND METHODS: A total of 26 patients underwent diagnostic ureterorenoscopy including biopsies and optical coherence tomography, followed by nephroureterectomy or segmental ureter resection. The sensitivity, specificity, negative predictive value and positive predictive value of upper tract urothelial carcinoma grading and staging by optical coherence tomography were evaluated according to the STARD (Standards for Reporting of Diagnostic Accuracy) initiative and the second stage (2a and 2b) of the IDEAL model. For tumor staging a 2*2 table for sensitivity and specificity was calculated. For tumor grading the Wilcoxon rank sum test was used to test MUoct in low and high grade lesions followed by ROC analysis for sensitivity and specificity. RESULTS: In 83% the staging of lesions was in accordance with final histopathology. Sensitivity and specificity analysis for tumor invasion was 100% and 92%, respectively. Tumor size greater than 2 mm and inflammation were risks for false-positives. For low and high grade lesions median MUoct was 2.1 and 3.0 mm-1, respectively (p <0.01). ROC analysis showed a sensitivity of 87% and a specificity of 90% using a MUoct cutoff of 2.4 mm-1. CONCLUSIONS: This report describes optical coherence tomography as a real-time, intraoperatively diagnostic modality in the diagnostic evaluation of upper tract urothelial carcinoma. We confirmed the ability of optical coherence tomography to visualize, grade and stage urothelial carcinoma in the upper urinary tract. PMID- 27475970 TI - Providers' Access of Imaging Versus Only Reports: A System Log File Analysis. AB - BACKGROUND: An increasing number of technologies allow providers to access the results of imaging studies. This study examined differences in access of radiology images compared with text-only reports through a health information exchange system by health care professionals. METHODS: The study sample included 157,256 historical sessions from a health information exchange system that enabled 1,670 physicians and non-physicians to access text-based reports and imaging over the period 2013 to 2014. The primary outcome was an indicator of access of an imaging study instead of access of a text-only report. Multilevel mixed-effects regression models were used to estimate the association between provider and session characteristics and access of images compared with text-only reports. RESULTS: Compared with primary care physicians, specialists had an 18% higher probability of accessing actual images instead of text-only reports (beta = 0.18; P < .001). Compared with primary care practice settings, the probability of accessing images was 4% higher for specialty care practices (P < .05) and 8% lower for emergency departments (P < .05). Radiologists, orthopedists, and neurologists accounted for 79% of all the sessions with actual images accessed. Orthopedists, radiologists, surgeons, and pulmonary disease specialists accessed imaging more often than text-based reports only. CONCLUSIONS: Consideration for differences in the need to access images compared with text-only reports based on the type of provider and setting of care are needed to maximize the benefits of image sharing for patient care. PMID- 27475971 TI - Knowledge of the Costs of Diagnostic Imaging: A Survey of Physician Trainees at a Large Academic Medical Center. AB - PURPOSE: To study the awareness of postgraduate physician trainees across a variety of specialties regarding the costs of common imaging examinations. METHODS: During early 2016, we conducted an online survey of all 1,238 physicians enrolled in internships, residencies, and fellowships at a large academic medical center. Respondents were asked to estimate Medicare national average total allowable fees for five commonly performed examinations: two-view chest radiograph, contrast-enhanced CT abdomen and pelvis, unenhanced MRI lumbar spine, complete abdominal ultrasound, and unenhanced CT brain. Responses within +/-25% of published amounts were deemed correct. Respondents were also asked about specialty, postgraduate year of training, previous radiology education, and estimated number of imaging examinations ordered per week. RESULTS: A total of 381 of 1,238 trainees returned complete surveys (30.8%). Across all five examinations, only 5.7% (109/1,905) of responses were within the correct +/-25% range. A total of 76.4% (291/381) of all respondents incorrectly estimated every examination's cost. Estimation accuracy was not associated with number of imaging examinations ordered per week or year of training. There was no significant difference in cost estimation accuracy between those who participated in medical school radiology electives and those who did not (P = .14). Only 17.5% of trainees considered their imaging cost knowledge adequate. Overall, 75.3% desire integration of cost data into clinical decision support and/or computerized physician order entry systems. CONCLUSIONS: Postgraduate physician trainees across all disciplines demonstrate limited awareness of the costs of commonly ordered imaging examinations. Targeted medical school education and integration of imaging cost information into clinical decision support / computerized physician order entry systems seems indicated. PMID- 27475969 TI - Design and Methodological Considerations of the Centers for Disease Control and Prevention Urologic and Renal Protocol for the Newborn and Young Child with Spina Bifida. AB - PURPOSE: Care of children with spina bifida has significantly advanced in the last half century, resulting in gains in longevity and quality of life for affected children and caregivers. Bladder dysfunction is the norm in patients with spina bifida and may result in infection, renal scarring and chronic kidney disease. However, the optimal urological management for spina bifida related bladder dysfunction is unknown. MATERIALS AND METHODS: In 2012 the Centers for Disease Control and Prevention convened a working group composed of pediatric urologists, nephrologists, epidemiologists, methodologists, community advocates and Centers for Disease Control and Prevention personnel to develop a protocol to optimize urological care of children with spina bifida from the newborn period through age 5 years. RESULTS: An iterative quality improvement protocol was selected. In this model participating institutions agree to prospectively treat all newborns with spina bifida using a single consensus based protocol. During the 5-year study period outcomes will be routinely assessed and the protocol adjusted as needed to optimize patient and process outcomes. Primary study outcomes include urinary tract infections, renal scarring, renal function and bladder characteristics. The protocol specifies the timing and use of testing (eg ultrasonography, urodynamics) and interventions (eg intermittent catheterization, prophylactic antibiotics, antimuscarinic medications). Starting in 2014 the Centers for Disease Control and Prevention began funding 9 study sites to implement and evaluate the protocol. CONCLUSIONS: The Centers for Disease Control and Prevention Urologic and Renal Protocol for the Newborn and Young Child with Spina Bifida began accruing patients in 2015. Assessment in the first 5 years will focus on urinary tract infections, renal function, renal scarring and clinical process improvements. PMID- 27475972 TI - Practical considerations for optimizing cardiac computed tomography protocols for comprehensive acquisition prior to transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is performed frequently in patients with severe, symptomatic aortic stenosis who are at high risk or inoperable for open surgical aortic valve replacement. Computed tomography angiography (CTA) has become the gold standard imaging modality for pre-TAVR cardiac anatomic and vascular access assessment. Traditionally, cardiac CTA has been most frequently used for assessment of coronary artery stenosis, and scanning protocols have generally been tailored for this purpose. Pre-TAVR CTA has different goals than coronary CTA and the high prevalence of chronic kidney disease in the TAVR patient population creates a particular need to optimize protocols for a reduction in iodinated contrast volume. This document reviews details which allow the physician to tailor CTA examinations to maximize image quality and minimize harm, while factoring in multiple patient and scanner variables which must be considered in customizing a pre-TAVR protocol. PMID- 27475973 TI - Metabonomic profiles reveal dose-dependent effects of Bu-Shen-Gu-Chi-Wan on the serum in experimental periodontitis of rat model. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Bu-Shen-Gu-Chi-Wan is a Chinese patent medicine for the treatment of chronic periodontitis. It has an anti-inflammatory function in experimental periodontitis and can improve alveolar bone remodeling. AIM OF THE STUDY: This study aims to explore the effects of Bu-Shen-Gu-Chi-Wan on serum metabolism in a rat model of periodontitis using 1H nuclear magnetic resonance (1H NMR) based metabonomics. MATERIALS AND METHODS: The model of experimental periodontitis in a rat was established by steel wire ligation, plus a high glucose diet and Porphyromonas gingivalis inoculation. When the models had been established, 6-week-old Sprague-Dawley female rats (n=31) were divided into 5 groups: high dose group (Group H), medium dose group (Group M), low dose group (Group L), periodontitis group (Group P) and healthy control group (Group N). Rats in Group H, M and L were given the Bu-Shen-Gu-Chi-Wan solution (0.8, 2 and 4g/kg of body weight) daily for 60 days. Rats in Group P and N were administered normal saline (10ml/kg of body weight) in the same period. All rats were sacrificed at the end of the study and serum samples were collected. The metabolites in the serum were analyzed using 1H NMR in conjunction with principal component analysis (PCA) and partial least squares discriminant analysis (PLS DA). RESULTS: The metabonomic profiles of five groups showed the clustering of individual dataset in every group, and the 1st principal component and the 2nd principal component could significantly differentiate the datasets of medium dose or high dose group from other groups. The chemical shift regions at delta 1.22ppm, 1.86ppm, 2.26ppm, 2.34ppm and 2.42ppm showed the most obvious differences among the five groups. The correspondent metabolites were high density lipoprotein, pyruvate/oxaloacetate, arginine and glutamine. CONCLUSION: The effects of Bu-Shen-Gu-Chi-Wan on the rat serum metabolites were dose dependent. High density lipoprotein, pyruvate/oxaloacetate, arginine and glutamine may be the serum biomarkers of Bu-Shen-Gu-Chi-Wan. PMID- 27475974 TI - Evidence-based recommendations for analgesic efficacy to treat pain of endodontic origin: A systematic review of randomized controlled trials. AB - BACKGROUND: The purpose of this investigation was to identify evidence-based clinical trials to aid dental clinicians in establishing the efficacy for recommending or prescribing analgesics for pain of endodontic origin. TYPES OF STUDIES REVIEWED: The authors prepared and registered a protocol on PROSPERO and conducted electronic searches in MEDLINE, Scopus, the Cochrane Library, and ClinicalTrials.gov. In addition, the authors manually searched the bibliographies of all relevant articles, the gray literature, and textbooks for randomized controlled trials. Two authors selected the relevant articles independently. There were no disagreements between the authors. RESULTS: The authors analyzed 27 randomized, placebo-controlled trials. The authors divided the studies into 2 groups: preoperative and postoperative analgesic treatments. There was moderate evidence to support the use of steroids for patients with symptomatic irreversible pulpitis. Also, there was moderate evidence to support nonsteroidal anti-inflammatory drugs (NSAIDs) preoperatively or postoperatively to control pain of endodontic origin. When NSAIDs were not effective, a combination of NSAIDs with acetaminophen, tramadol, or an opioid appeared beneficial. CONCLUSIONS AND PRACTICAL IMPLICATIONS: NSAIDs should be considered as the drugs of choice to alleviate or minimize pain of endodontic origin if there are no contraindications for the patient to ingest an NSAID. In situations in which NSAIDs alone are not effective, the combination of an NSAID with acetaminophen or a centrally acting drug is recommended. Steroids appear effective in irreversible pulpitis. PMID- 27475976 TI - Management of plateau iris syndrome with cataract extraction and endoscopic cyclophotocoagulation. AB - Plateau iris configuration describes an anatomic abnormality in which large or anteriorly positioned pars plicata push the iris root forward, thereby narrowing the anterior chamber angle. Plateau iris syndrome (PIS) is diagnosed if the angle remains occludable, either spontaneously or pharmacologically, after iridotomy. PIS has traditionally been treated with chronic pilocarpine or laser peripheral iridoplasty. A series of 9 eyes of 6 patients with PIS, diagnosed by dark room provocative testing and ultrasound biomicroscopy (UBM) following iridotomy, underwent cataract extraction and endoscopic cyclophotocoagulation (ECP). The ciliary body was treated for a median of 180 degrees (range of 120-360 degrees ). Post-ECP, the angles in areas treated with ECP were open with corresponding flattened ciliary processes on UBM, while the angles remained occludable in quadrants untreated by ECP despite lens extraction. The mean follow-up time post ECP was 73.7 +/- 34 months (range 11-122 months). The mean IOP was reduced from a baseline of 25.2 +/- 10.9 mm Hg on 3.4 +/- 1.0 IOP lowering medications to a mean IOP of 17.1 +/- 5.3 mm Hg (p < 0.05) on 1.9 +/- 1.5, (p < 0.01) medications at last visit. There were no cases of chronic inflammation, eye pain, decreased vision, retinal detachment, or hypotony. Lens extraction and ECP offers an alternative treatment option for patients with PIS, which may directly address the underlying anatomic abnormality leading to angle closure in PIS. PMID- 27475975 TI - Future Perspective of Single-Molecule FRET Biosensors and Intravital FRET Microscopy. AB - Forster (or fluorescence) resonance energy transfer (FRET) is a nonradiative energy transfer process between two fluorophores located in close proximity to each other. To date, a variety of biosensors based on the principle of FRET have been developed to monitor the activity of kinases, proteases, GTPases or lipid concentration in living cells. In addition, generation of biosensors that can monitor physical stresses such as mechanical power, heat, or electric/magnetic fields is also expected based on recent discoveries on the effects of these stressors on cell behavior. These biosensors can now be stably expressed in cells and mice by transposon technologies. In addition, two-photon excitation microscopy can be used to detect the activities or concentrations of bioactive molecules in vivo. In the future, more sophisticated techniques for image acquisition and quantitative analysis will be needed to obtain more precise FRET signals in spatiotemporal dimensions. Improvement of tissue/organ position fixation methods for mouse imaging is the first step toward effective image acquisition. Progress in the development of fluorescent proteins that can be excited with longer wavelength should be applied to FRET biosensors to obtain deeper structures. The development of computational programs that can separately quantify signals from single cells embedded in complicated three-dimensional environments is also expected. Along with the progress in these methodologies, two-photon excitation intravital FRET microscopy will be a powerful and valuable tool for the comprehensive understanding of biomedical phenomena. PMID- 27475977 TI - Serum levels of cholesterol, pregnenolone, DHEA, and their sulfate conjugates based on sex and pubertal stage in adolescents. AB - BACKGROUND: The study aim was to evaluate the correlation of sexual dimorphism and pubertal stage with steroid metabolism in adolescents. METHODS: The serum levels of cholesterol, pregnenolone, and dehydroepiandrosterone (DHEA) and their sulfate conjugates were quantitatively profiled from serum samples of 199 adolescents (87 boys and 112 girls), aged 6 to 14years. RESULTS: In the prepubertal stage, DHEA levels in girls were higher than those in boys; however, significantly increased DHEA levels during pubertal development in boys. Pregnenolone levels were significantly higher in girls; however, the levels of its sulfate were higher in boys. The serum levels of both cholesterol and its sulfate were higher in boys, especially in the early to mid-pubertal stages. DHEA and DHEA sulfate levels in both sexes significantly increased with pubertal development (P for trend<0.05), while pregnenolone, cholesterol, and cholesterol sulfate in both sexes were stable. The metabolic ratios, indicating sulfotransferase activity, were significantly higher in boys, and increased with pubertal development in boys, but not in girls, while CYP11A1 activity levels increased significantly in both sexes with pubertal development. CONCLUSIONS: Sexual dimorphism in key enzymes of androgen biosynthesis during pubertal changes may help elucidate the normal physiology of steroidogenesis. PMID- 27475978 TI - The Warburg effect: A new story in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a rare yet fatal condition that is characterized by a continuous and notable elevation of pulmonary arterial pressure (PAP), resulting in right heart failure and death. Pulmonary arterial remodelling does not result from abnormal proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) but from pulmonary arterial endothelial cell (PAEC) dysfunction. However, the pathological mechanism of these two types of vascular cells in pulmonary artery remodelling is unclear. The Warburg effect describes aerobic glycolysis wherein cells commonly reprogram their energy metabolism to preferentially utilize glycolysis over oxidative phosphorylation for ATP production. Recent research has demonstrated that the Warburg effect plays a significant role in the development of PAH, which involves the abnormal proliferation of PASMCs and endothelial dysfunction. This review attempts to illustrate the functions of the Warburg effect in PAH, which may provide a new therapeutic target for PAH treatment. PMID- 27475979 TI - Differences in microbial metabolites in urine headspace of subjects with Immune Thrombocytopenia (ITP) detected by volatile organic compound (VOC) analysis and metabolomics. AB - ITP is an organ-specific autoimmune disorder characterised by a low platelet count whose cause is uncertain. A possible factor is food intolerance, although much of the information linking this with ITP is anecdotal. The role of food intolerance in ITP was studied by replacing a normal diet with an elemental diet (E028), but this did not increase platelet counts. Clear differences, however, were apparent between the volatile organic compounds (VOCs) in the urine headspace of patients with ITP and those present in healthy volunteers, which leads to speculation that abnormal metabolic activity of the intestinal microbiome may be a factor causing ITP. However, further work is needed to confirm this. There were also differences between the VOCs of patients on a normal diet and those on the elemental diet, and in this case, the VOCs involved are very likely to be of bacterial origin, as their production is affected by dietary manipulation. Many of these VOCs are known to be toxic. PMID- 27475980 TI - 2-Ethylhexanoic acid, found in common plasticizers, leads to an artificial increase in C8 acylcarnitine levels in two neonates treated with extracorporeal membrane oxygenation (ECMO). PMID- 27475981 TI - Serum phosphorus, cardiovascular and all-cause mortality in the general population: A meta-analysis. AB - BACKGROUND: The association between elevated serum phosphorus concentration and cardiovascular or all-cause mortality yielded conflicting results. OBJECTIVE: To assess the association between elevated serum phosphorus concentration and cardiovascular or all-cause mortality in the general population by conducting a meta-analysis. METHODS: We systematically searched the Pubmed and Embase databases until March 2016 for the prospective studies investigating serum phosphorus concentration and cardiovascular or all-cause mortality in the general population. We pooled risk ratio (RR) and corresponding 95% confidence intervals (CI) for the highest versus the reference category of serum concentration of phosphorus. RESULTS: Six prospective cohort studies involving 120,269 subjects were identified. When compared the highest with the reference concentration of serum phosphorus, the pooled RR of cardiovascular mortality and all-cause mortality were 1.36 (95% CI 1.07-1.72) and 1.35 for all-cause mortality (95% CI 1.15-1.58), respectively. Stratified analyses revealed that elevated serum phosphorus significantly increased all-cause mortality risk among men (RR 1.33; 95% CI 1.11-1.60), but not in women (RR 1.09; 95% CI 0.89-1.33). CONCLUSIONS: Elevated serum phosphorus concentration is independently associated with excessive risk of cardiovascular and all-cause mortality in the general population without chronic kidney disease. Serum phosphorus on all-cause mortality risk appears to be pronounced in men but exhibits no clear effect on women. However, gender difference of elevated serum phosphorus on mortality risk should be verified by more prospective studies. PMID- 27475982 TI - Predictors of CD4 count over time among HIV patients initiated ART in Felege Hiwot Referral Hospital, northwest Ethiopia: multilevel analysis. AB - BACKGROUND: The response of HIV patients to antiretroviral therapy could be measured by its strong predictor, the CD4+ T cell (CD4) count for the initiation of antiretroviral therapy and proper management of disease progress. However, in addition to HIV, there are other factors which can influence the CD4 cell count. Patient's socio-economic, demographic, and behavioral variables, accessibility, duration of treatment etc., can be used to predict CD4 count. METHODS: A retrospective cohort study was conducted to examine the predictors of CD4 count among ART users enrolled in the first 6 months of 2010 and followed upto mid 2014. The covariance components model was employed to determine the predictors of CD4 count over time. RESULTS: A total of 1196 ART attendants were used to analyze their data descriptively. Eight hundred sixty-one of the attendants had two or more CD4 count measurements and were used in modeling their data using the linear mixed method. Thus, the mean rates of incensement of CD4 counts for patients with ambulatory/bedridden and working baseline functional status were 17.4 and 30.6 cells/mm(3) per year, respectively. After adjusting for other variables, for each additional baseline CD4 count, the gain in CD4 count during treatment was 0.818 cells/mm(3) (p value <0.001). Patient's age and baseline functional status were also statistically significantly associated with CD4 count. CONCLUSION: In this study, higher baseline CD4 count, younger age, working functional status, and time in treatment contributed positively to the increment of the CD4 count. However, the observed increment at 4 year was unsatisfactory as the proportion of ART users who reached the normal range of CD4 count was very low. To see their long term treatment outcome, it requires further research with a sufficiently longer follow up data. In line with this, the local CD4 count for HIV negative persons should also be investigated for better comparison and proper disease management. PMID- 27475983 TI - Deubiquitinating enzymes in skeletal muscle atrophy-An essential role for USP19. AB - The ubiquitin proteasome system is well recognized to be involved in mediating muscle atrophy in response to diverse catabolic conditions. To date, almost all of the genes that have been implicated are ubiquitin ligases. Although ubiquitination is modulated also by deubiquitinating enzymes, the roles of these enzymes in muscle wasting remains largely unexplored. In this article, the potential roles of deubiquitinating enzymes in regulating muscle size are discussed. This is followed by a review of the roles described for USP19, the deubiquitinating enzyme that has been most studied in muscle wasting. This enzyme is upregulated in muscle in many catabolic conditions and its inactivation leads to protection from muscle loss induced by stimuli that are common in many illnesses causing cachexia. It can regulate both protein synthesis and protein degradation as well as myogenesis, thereby modulating the key processes that control muscle mass. Roles for other deubiquitinating enzymes remain possible and to be explored. PMID- 27475984 TI - Truck drivers' perceptions on wearable devices and health promotion: a qualitative study. AB - BACKGROUND: Professional truck drivers, as other shift workers, have been identified as a high-risk group for various health conditions including cardiovascular disease, obesity, diabetes, sleep apnoea and stress. Mobile health technologies can potentially improve the health and wellbeing of people with a sedentary lifestyle such as truck drivers. Yet, only a few studies on health promotion interventions related to mobile health technologies for truck drivers have been conducted. We aimed to explore professional truck drivers' views on health promotion delivered via mobile health technologies such as wearable devices. METHODS: We conducted a phenomenological qualitative study, consisting of four semi-structured focus groups with 34 full-time professional truck drivers in the UK. The focus groups were audio-taped, transcribed verbatim and analysed using thematic content analysis. We discussed drivers' perceptions of their health, lifestyle and work environment, and their past experience and expectations from mobile health technologies. RESULTS: The participants viewed their lifestyle as unhealthy and were aware of possible consequences. They expressed the need and wish to change their lifestyle, yet perceived it as an inherent, unavoidable outcome of their occupation. Current health improvement initiatives were not always aligned with their working conditions. The participants were generally willing to use mobile health technologies such as wearable devices, as a preventive measure to avoid prospect morbidity, particularly cardiovascular diseases. They were ambivalent about privacy and the risk of their employer's monitoring their clinical data. CONCLUSIONS: Wearable devices may offer new possibilities for improving the health and wellbeing of truck drivers. Drivers were aware of their unhealthy lifestyle. They were interested in changing their lifestyle and health. Drivers raised concerns regarding being continuously monitored by their employer. Health improvement initiatives should be aligned with the unique working conditions of truck drivers. Future research is needed to examine the impact of wearable devices on improving the health and wellbeing of professional drivers. PMID- 27475985 TI - Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred. AB - BACKGROUND: Leber congenital amaurosis (LCA) is a severe retinal degenerative disease that manifests as blindness or poor vision in infancy. The purpose of this study was to clinically characterize and identify the cause of disease in a large inbred Bedouin Israeli tribe with LCA. METHODS: Thirty individuals of a single kindred, including eight affected with LCA, were recruited for this study. Patients' clinical data and electroretinography (ERG) findings were collected. Molecular analysis included homozygosity mapping with polymorphic markers and Sanger sequencing of candidate genes. RESULTS: Of the eight affected individuals of the kindred, nystagmus was documented in five subjects and keratoconus in three. Cataract was found in 5 of 16 eyes. Photopic and scotopic ERG performed in 5 patients were extinguished. All affected subjects were nearly blind, their visual acuity ranged between finger counting and uncertain light perception. Assuming autosomal recessive heredity of a founder mutation, studies using polymorphic markers excluded homozygosity of affected individuals at the genomic loci of all previously known genes associated with LCA, except GUCY2D. Sequencing of GUCY2D identified a novel missense mutation (c.2129C>T; p.Ala710Val) resulting in substitution of alanine by valine at position 710 within the protein kinase domain of the retina-specific enzyme guanylate cyclase 1 (GC1) encoded by GUCY2D. Molecular modeling implied that the mutation changes the conformation of the regulatory segment within the kinase styk-domain of GC1 and causes loss of its helical structure, likely inhibiting phosphorylation of threonine residue within this segment, which is needed to activate the catalytic domain of the protein. CONCLUSIONS: This is the first documentation of the p.Ala710Val mutation in GC1 and the second ever described mutation in its protein kinase domain. Our findings enlarge the scope of genetic variability of LCA, highlight the phenotypic heterogeneity found amongst individuals harboring an identical LCA mutation, and possibly provide hope for gene therapy in patients with this congenital blinding disease. As the Bedouin kindred studied originates from Saudi Arabia, the mutation found might be an ancient founder mutation in that large community. PMID- 27475986 TI - Optimal timing of salvage radiotherapy for biochemical recurrence after radical prostatectomy: is ultra-early salvage radiotherapy beneficial? AB - BACKGROUND: The optimal timing of salvage radiotherapy for biochemical recurrence after radical prostatectomy is controversial. In particular, the prognostic significance of salvage radiotherapy delivered before a current definition of biochemical recurrence, i.e. ultra-early salvage radiotherapy, is unclear. METHODS: We reviewed 76 patients with pT2-3N0M0 prostate cancer who underwent salvage radiotherapy for post-prostatectomy biochemical recurrence at the following three timings: ultra-early salvage radiotherapy (n = 20) delivered before meeting a current definition of biochemical recurrence (two consecutive prostate-specific antigen [PSA] values >=0.2 ng/mL); early salvage radiotherapy (n = 40) delivered after meeting the definition but before PSA reached 0.5 ng/mL; and delayed salvage radiotherapy (n = 16) delivered after PSA reached 0.5 ng/mL. The primary endpoint was failure of salvage radiotherapy, defined as a PSA value >=0.2 ng/mL. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analyses, respectively. RESULTS: During the follow-up period (median: 70 months), four of 20 (20 %), nine of 40 (23 %) and seven of 16 (44 %) patients failed biochemically in the ultra-early, early and delayed salvage radiotherapy groups, respectively. On univariate analyses, the outcome of delayed salvage radiotherapy was worse than the others, while there was no significant difference between ultra-early and early groups. Multivariate analysis demonstrated the presence of Gleason pattern 5, perineural invasion and delayed salvage radiotherapy as independent predictors of poorer survival. CONCLUSIONS: No survival benefit of ultra-early salvage radiotherapy was demonstrated, whereas delayed salvage radiotherapy was associated with worse outcome as reported in previous studies. Our results may support the current recommendations that salvage radiotherapy should be undertaken after two consecutive PSA values >=0.2 ng/mL and before reaching 0.5 ng/mL. PMID- 27475987 TI - Antibiotic resistance is the quintessential One Health issue. PMID- 27475989 TI - Complement triggers relocation of Mortalin/GRP75 from mitochondria to the plasma membrane. AB - Mortalin/GRP75 is a ubiquitously expressed mitochondrial chaperon that is overexpressed in cancer. Mortalin protects cells from complement-dependent cytotoxicity (CDC) and facilitates elimination of the complement C5b-9 complexes from the cell surface. We performed a nanoscopical study aimed at imaging the distribution of the C5b-9 complexes in the plasma membrane and the postulated relocation of mortalin from the mitochondria to the plasma membrane. To gain a resolution of 35nm, the locations of the C5b-9 complex and mortalin were imaged with a STED (Stimulated Emission Depletion) microscope at sub-diffraction resolution. Early changes in the spatial distribution of the C5b-9 on the cell surface are described. Juxtaposition of the labeled mortalin and C5b-9 at the plasma membrane region within minutes after complement attack is evident. Microscopical analysis of the distribution of mortalin in the vicinity of the mitochondria of complement-treated cells shows a more diffused pattern relative to control cells, proposing exit of mortalin from the mitochondria in response to complement-induced stress. In support, analysis of cytoplasmic mortalin by immunoblotting shows enhanced level of mortalin in the cytoplasm in complement treated cells. Our data demonstrates that cells can sense complement activation at the plasma membrane and in response, swiftly send mortalin to this region in order to deactivate it. PMID- 27475990 TI - Hydroxytyrosol modulates Par j 1-induced IL-10 production by PBMCs in healthy subjects. AB - Several papers have demonstrated the importance of substances from natural sources which can exert powerful anti-inflammatory effects. In this respect, hydroxytyrosol, one of the major elements of the phenolic components of olive oil, has been extensively studied for its anti-inflammatory activities and safety profile. In this report, we demonstrate that the co-stimulation of human PBMCs from healthy subjects with the Par j 1 allergen and hydroxytyrosol induced a statistically significant increase in the amount of Par j 1-induced IL-10, demonstrating that hydroxytyrosol can modulate an allergen-specific immune response potentiating a suppressive immune response towards an allergen. Our work opens the way to further studies to elaborate the possibility of using hydroxytyrosol as a nutrient for allergy prevention. PMID- 27475991 TI - Complement analysis 2016: Clinical indications, laboratory diagnostics and quality control. AB - In recent years, complement analysis of body fluids and biopsies, going far beyond C3 and C4, has significantly enhanced our understanding of the disease process. Such expanded complement analysis allows for a more precise differential diagnosis and for critical monitoring of complement-targeted therapy. These changes are a result of the growing understanding of the involvement of complement in a diverse set of disorders. To appreciate the importance of proper complement analysis, it is important to understand the role it plays in disease. Historically, it was the absence of complement as manifested in severe infection that was noted. Since then complement has been connected to a variety of inflammatory disorders, such as autoimmune diseases and hereditary angioedema. While the role of complement in the rejection of renal grafts has been known longer, the significant impact of complement. In certain nephropathies has now led to the reclassification of some rare kidney diseases and an increased role for complement analysis in diagnosis. Even more unexpected is that complement has also been implicated in neural, ophtalmological and dermatological disorders. With this level of involvement in some varied and impactful health issues proper complement testing is clearly important; however, analysis of the complement system varies widely among laboratories. Except for a few proteins, such as C3 and C4, there are neither well-characterized standard preparations nor calibrated assays available. This is especially true for the inter-laboratory variation of tests which assess classical, alternative, or lectin pathway function. In addition, there is a need for the standardization of the measurement of complement activation products that are so critical in determining whether clinically relevant complement activation has occurred in vivo. Finally, autoantibodies to complement proteins (e.g. anti-C1q), C3 and C4 convertases (C3 and C4 nephritic factor) or to regulatory proteins (e.g. anti-C1inhibitor, anti factor H) are important in defining autoimmune processes and diseases based on complement dysregulation. To improve the quality of complement laboratory analysis a standardization commmittee of the International Complement Society (ICS) and the International Union of Immunological Societies (IUIS) was formed to provide guidelines for modern complement analysis and standards for the development of international testing programs. PMID- 27475988 TI - Insight into the AP2/ERF transcription factor superfamily in sesame and expression profiling of DREB subfamily under drought stress. AB - BACKGROUND: Sesame is an important oilseed crop mainly grown in inclement areas with high temperatures and frequent drought. Thus, drought constitutes one of the major constraints of its production. The AP2/ERF is a large family of transcription factors known to play significant roles in various plant processes including biotic and abiotic stress responses. Despite their importance, little is known about sesame AP2/ERF genes. This constitutes a limitation for drought tolerance candidate genes discovery and breeding for tolerance to water deficit. RESULTS: One hundred thirty-two AP2/ERF genes were identified in the sesame genome. Based on the number of domains, conserved motifs, genes structure and phylogenetic analysis including 5 relatives species, they were classified into 24 AP2, 41 DREB, 61 ERF, 4 RAV and 2 Soloist. The number of sesame AP2/ERF genes was relatively few compared to that of other relatives, probably due to gene loss in ERF and DREB subfamilies during evolutionary process. In general, the AP2/ERF genes were expressed differently in different tissues but exhibited the highest expression levels in the root. Mostly all DREB genes were responsive to drought stress. Regulation by drought is not specific to one DREB group but depends on the genes and the group A6 and A1 appeared to be more actively expressed to cope with drought. CONCLUSIONS: This study provides insights into the classification, evolution and basic functional analysis of AP2/ERF genes in sesame which revealed their putative involvement in multiple tissue-/developmental stages. Out of 20 genes which were significantly up- /down-regulated under drought stress, the gene AP2si16 may be considered as potential candidate gene for further functional validation as well for utilization in sesame improvement programs for drought stress tolerance. PMID- 27475992 TI - Deconvoluting the effects of buffer salt concentration in hydrophilic interaction chromatography on a zwitterionic stationary phase. AB - Quantitative structure-retention relationships (QSRRs) furnish a detailed and reliable description of the role and extent of different molecular interactions that can be established between the analytes and the chromatographic system. Among QSRRs, the solvation parameter model using Abraham descriptors has gained acceptance as a general tool to explore the factors affecting retention in chromatographic systems. We have previously shown how a modified version of the solvation parameter model, with two extra terms to take account of interactions occurring with ionic and ionizable species (with positive and/or negative charges), could be applied to the characterization of hydrophilic interaction chromatographic (HILIC) systems. In the present study, we will show how this methodology can be used to evaluate the effects of increasing buffer salt concentration on retention and separation in a HILIC system. A commercial stationary phase possessing a sulfobetaine zwitterionic bonded ligand (Nucleodur HILIC) was used with a mobile phase composed of 80% acetonitrile and 20% pwwH4 ammonium acetate buffer, with aqueous buffer concentrations varying from 10 to 100mM, resulting in overall concentrations ranging from 2 to 20mM in the mobile phase. Retention factors were measured for a selection of 76 probe analytes. The chosen compounds are small molecules presenting a wide diversity of molecular structures and are relevant to biomedical and pharmaceutical applications. The QSRR models obtained allow for a rationalization of the interactions contributing to retention and separation in the HILIC system considered and shed some light on the effect of varying buffer salt concentration, namely the progressive transition from ion-exchange and electrostatic-repulsion mechanisms to hydrophilic partitioning. PMID- 27475993 TI - An integrated strategy for the rapid extraction and screening of phosphatidylcholines and lysophosphatidylcholines using semi-automatic solid phase extraction and data processing technology. AB - This study attempts to establish a comprehensive strategy for the rapid extraction and screening of phosphatidylcholines (PCs) and lysophosphatidylcholines (LysoPCs) in biological samples using semi-automatic solid phase extraction (SPE) and data processing technology based on ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS). First, the Ostro sample preparation method (i.e., semi-automatic SPE) was compared with the Bligh-Dyer method in terms of substance coverage, reproducibility and sample preparation time. Meanwhile, the screening method for PCs and LysoPCs was built through mass range screening, mass defect filtering and diagnostic fragments filtering. Then, the Ostro sample preparation method and the aforementioned screening method were combined under optimal conditions to establish a rapid extraction and screening platform. Finally, this developed method was validated and applied to the preparation and data analysis of tissue samples. Through a systematic evaluation, this developed method was shown to provide reliable and high-throughput experimental results and was suitable for the preparation and analysis of tissue samples. Our method provides a novel strategy for the rapid extraction and analysis of functional phospholipids. In addition, this study will promote further study of phospholipids in disease research. PMID- 27475994 TI - Comparative risk of death in older adults treated with antipsychotics: A population-based cohort study. AB - Although the use of antipsychotics has been associated with an increased risk of death, data on the safety of individual substances is scarce. We thus aimed to compare the risk of death in new users of individual antipsychotics aged =>65 years and conducted a cohort study in the German Pharmacoepidemiological Research Database between 2005 and 2011. Patients were followed from initiation of treatment until death, 90 days after cohort entry, end of insurance or the end of the study period. Multivariable cox regression was used to estimate confounder adjusted hazard ratios (aHR) of death for 14 individual antipsychotics compared to risperidone. In sensitivity analyses, we also applied high-dimensional propensity score (HDPS) methods to explore possible unmeasured confounding. In a cohort of 137,713 new users of antipsychotics, a higher risk of death was found for haloperidol (aHR: 1.45; 95% confidence interval: 1.35-1.55), levomepromazine (aHR: 1.34; 1.16-1.54), zuclopenthixol (aHR: 1.32; 1.02-1.72) and to a lesser extent for melperone (aHR: 1.13; 1.07-1.19) compared to risperidone. Lower risks were observed for quetiapine, prothipendyl, olanzapine, tiapride, clozapine, perazine and flupentixol. In subgroup analyses, levomepromazine and chlorprothixene were only associated with a higher risk of death in patients aged =>80 years and with dementia. The application of HDPS methods did not substantially change the results. In conclusion, our study suggests that initiation of haloperidol, levomepromazine, zuclopenthixol and chlorprothixene treatment is associated with an increased risk of death compared to risperidone and should be avoided in older patients except in palliative care when treatment alternatives are available. PMID- 27475995 TI - Rodent models for studying empathy. AB - Empathy is the important capacity to recognize and share emotions with others. Recent evidence shows that rodents possess a remarkable affective sensitivity to the emotional state of others and that primitive forms of empathy exist in social lives of rodents. However, due to the ambiguous definitional boundaries between empathy, emotional contagion and other related terms, distinct components of empathic behaviors in rodents need to be clarified. Hence, we review recent experimental studies demonstrating that rodents are able to share emotions with others. Specifically, we highlight several behavioral models that examine different aspects of rodent empathic behaviors in response to the various distress of conspecifics. Experimental approaches using rodent behavioral models will help elucidate the neural circuitry of empathy and its neurochemical association. Integrating these findings with corresponding experiments in humans will ultimately provide novel insights into therapeutic interventions for mental disorders associated with empathy. PMID- 27475996 TI - The effects of diode laser on Staphylococcus aureus biofilm and Escherichia coli lipopolysaccharide adherent to titanium oxide surface of dental implants. An in vitro study. AB - Effective decontamination of biofilm and bacterial toxins from the surface of dental implants is a yet unresolved issue. This in vitro study aims at providing the experimental basis for possible use of diode laser (lambda 808 nm) in the treatment of peri-implantitis. Staphylococcus aureus biofilm was grown for 48 h on titanium discs with porous surface corresponding to the bone-implant interface and then irradiated with a diode laser (lambda 808 nm) in noncontact mode with airflow cooling for 1 min using a O 600-MUm fiber. Setting parameters were 2 W (400 J/cm2) for continuous wave mode; 22 MUJ, 20 kHz, 7 MUs (88 J/cm2) for pulsed wave mode. Bactericidal effect was evaluated using fluorescence microscopy and counting the residual colony-forming units. Biofilm and titanium surface morphology were analyzed by scanning electron microscopy (SEM). In parallel experiments, the titanium discs were coated with Escherichia coli lipopolysaccharide (LPS), laser-irradiated and seeded with RAW 264.7 macrophages to quantify LPS-driven inflammatory cell activation by measuring the enhanced generation of nitric oxide (NO). Diode laser irradiation in both continuous and pulsed modes induced a statistically significant reduction of viable bacteria and nitrite levels. These results indicate that in addition to its bactericidal effect laser irradiation can also inhibit LPS-induced macrophage activation and thus blunt the inflammatory response. The lambda 808-nm diode laser emerges as a valuable tool for decontamination/detoxification of the titanium implant surface and may be used in the treatment of peri-implantitis. PMID- 27475997 TI - High wavenumber Raman spectroscopy in the characterization of urinary metabolites of normal subjects, oral premalignant and malignant patients. AB - Urine has emerged as one of the diagnostically potential bio fluids, as it has many metabolites. As the concentration and the physiochemical properties of the urinary metabolites may vary under pathological transformation, Raman spectroscopic characterization of urine has been exploited as a significant tool in identifying several diseased conditions, including cancers. In the present study, an attempt was made to study the high wavenumber (HWVN) Raman spectroscopic characterization of urine samples of normal subjects, oral premalignant and malignant patients. It is concluded that the urinary metabolites flavoproteins, tryptophan and phenylalanine are responsible for the observed spectral variations between the normal and abnormal groups. Principal component analysis-based linear discriminant analysis was carried out to verify the diagnostic potentiality of the present technique. The discriminant analysis performed across normal and oral premalignant subjects classifies 95.6% of the original and 94.9% of the cross-validated grouped cases correctly. In the second analysis performed across normal and oral malignant groups, the accuracy of the original and cross-validated grouped cases was 96.4% and 92.1% respectively. Similarly, the third analysis performed across three groups, normal, oral premalignant and malignant groups, classifies 93.3% and 91.2% of the original and cross-validated grouped cases correctly. PMID- 27475999 TI - Prospective analysis of principles and frequency of self-adjustment of insulin dose in people with diabetes type 1 before and after participation in a diabetes treatment and teaching programme. AB - OBJECTIVE: Insulin dose self-adjustment is an essential part of intensified insulin therapy - nowadays the routine treatment of type 1 diabetes (DM1). The aim of this study was to evaluate principles and frequency of insulin dose self adjustments in people with DM1 before and one year after participating in a structured diabetes treatment and teaching programme (DTTP) and to determine to which extent the patients followed the way they had been trained. METHODS: 72 people with DM1 were interviewed before participation in our inpatient (32/72) or outpatient (40/72) DTTP. Sixty-six participants (91.7%) were followed up after one year. The number of adaptations of the insulin dose by the patients was recorded from 28days of the patients' diary. The ability to find the correct dose was tested using five different examples. RESULTS: Metabolic control improved significantly after one year (7.9+/-1.0 to 7.5+/-0.8%, p=0.004). The participants performed 86.0+/-37.1 insulin dosage adaptations per 28days before the DTTP. After one year the frequency increased significantly to 99.1+/-30.7 per 28days (p=0.011). Before the DTTP, 42 of 72 patients (58.3%) adjusted their insulin dose to correct high blood glucose levels by adjustment rules (factor for correction or correction scheme) and 20 of 72 people (27.8%) by personal experience/feeling. One year after the DTTP, 73% (48/66) used adjustment rules. CONCLUSIONS: After participating in an structured education programme, patients adjusted their insulin dosage more frequently. Metabolic control improved despite the fact that many patients did not strictly apply the rules they had been trained for. PMID- 27475998 TI - Self-administered multi-level pregnancy tests in simplified follow-up of medical abortion in Tunisia. AB - BACKGROUND: This study was conducted to assess the efficacy and acceptability of using a multi-level pregnancy test (MLPT) combined with telephone follow-up for medical abortion in Tunisia, where the majority of providers are midwives. METHODS: Four hundred and four women with gestational age <= 70 days' LMP seeking medical abortion at six study sites were enrolled in this open-label trial. Participants administered a baseline MLPT at the clinic prior to mifepristone administration and were asked to take a second MLPT at home and to call in its results before returning the day of their scheduled follow-up visit 10-14 days later. RESULTS: Almost all women with follow-up (97.1 %, n = 332/342) had successful abortions without the need for surgical intervention. The MLPT worked extremely well among women <=63 days' LMP in ruling out ongoing pregnancy (negative predictive value (NPV) =100 % (n = 298/298)) and also detecting women with ongoing pregnancies (sensitivity = 100 %; 2/2) as needing follow-up due to non-declining hCG. Among women 64-70 days' LMP, the test also worked well in ruling out ongoing pregnancy (NPV = 96.9 % (n = 31/32) but not as well in terms of sensitivity (50 %), with only one of two ongoing pregnancies detected by MLPT as needing follow-up. Most women (95.1 %) found the MLPT to be very easy or easy to use and would consider using the MLPT again (97.4 %) if needed. CONCLUSIONS: Self-administered pre and post MLPT are very easy for women to use and accurate in assessing medical abortion success up to 63 days' LMP. MLPT use for medical abortion follow-up has the potential to facilitate task sharing services and eliminate the burden of routine in-person follow-up visits for the large majority of women. Additional research is warranted to explore the accuracy of the MLPT in identifying ongoing pregnancy among women with gestational ages > 63 days. TRIAL REGISTRATION: This study was registered on May 13, 2010, on clinicaltrials.gov as NCT01150279 . PMID- 27476000 TI - Target and non-target toxicity of botanical insecticide derived from Couroupita guianensis L. flower against generalist herbivore, Spodoptera litura Fab. and an earthworm, Eisenia foetida Savigny. AB - Botanical insecticides may provide alternatives to synthetic insecticides for controlling Spodoptera litura (F.) and they are target specific, biodegradable, and harmless to mammals. Eight natural chemical compounds with larvicidal activity were identified from fraction F6 of C. guianensis flower extract. Probit analysis of 95% confidence level exposed an LC50 of 223ppm against S. litura third instar larvae. The growth and development of S. litura was affected in sub lethal concentrations of fraction F6 (50, 100, 150 and 200ppm) compared to controls. Similarly nutritional indices values decreased significantly compared to controls. Fraction F6 also damaged the gut epithelial layer and brush border membrane (BBM). This study also resolved the effects of toxicity to non-target earthworm treated with fraction F6 and chemical pesticides (monotrophos and cypermethrin) and the results showed that fraction F6 had no harmful effect on E. fetida. Further, fraction F6 was eluted and sub fractions F6c (50ppm) showed high mortality against S. litura third instar larvae. Octacosane from fraction F6c was established and confirmed using IR spectrum and HPLC. The time of retention of fraction F6c was confirmed with the octacosane standard. Fraction F6 of C. guianensis extract caused dose-dependent mortality towards S. litura. Octacosane in fraction F6c was establish to be the prominent chemical compound associated with causing mortality but other compounds present in the fraction F6 were shown to be associated with changes in development of S. litura at low dosages. S. litura at low dosage. Therefore, these findings suggest that octacosane may be one of the major insecticidal compounds affecting S. litura survival. PMID- 27476001 TI - DAB2IP regulates EMT and metastasis of prostate cancer through targeting PROX1 transcription and destabilizing HIF1alpha protein. AB - Prospero-related homeobox 1 (PROX1) is an essential regulator in lymphangiogenesis and has been implicated in both oncogenic and tumor-suppressive functions in many types of human cancers. However, the role of PROX1 in prostate cancer (PCa) remains poorly understood. In this study, based on different PCa cell lines and knockout mice, we showed that PROX1 could be suppressed by DAB2IP, a novel member of the Ras GTPase-activating protein family and a critical player in control of epithelial-mesenchymal transition (EMT) and PCa metastasis. Mechanistically, PROX1 overexpression in DAB2IP-deficient PCa cells could enhance the accumulation of HIF1alpha protein by inhibiting ubiquitin pathway and then consequently induce an EMT response, which is characterized by repression of E cadherin, up-regulation of vimentin and matrix metallopeptidases (MMPs) and enhancement of cell migration. Together, our data provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis, especially points out the potential roles of its downstream PROX1/HIF1alpha signaling in a unique non skeletal metastasis of PCa. PMID- 27476002 TI - [Insomnia in children and adolescents. A consensus document]. AB - Insomnia is very common during childhood (30% of children under 5), and causes a serious cognitive and emotional consequence in learning, as well as significant medical comorbidity. It also affects the quality of life, not only of the child, but also of the whole family. Paediatrician training in its diagnosis and treatment is usually poor. For this reason a consensus document is presented on the management of insomnia in children and adolescents. This has been developed by members of the Spanish Paediatrics Association, the Spanish Sleep Society, the Spanish Society of Paediatric Outpatient and Primary Care, the Spanish Adolescent Medicine Society, the Spanish Child and Adolescent Society, and the Spanish Paediatric Neurology Society. The group suggests that diagnosis must be clinical and complementary tests will only be required in doubtful cases or when a differential diagnosis is needed. Likewise, treatment should be mainly based on cognitive-behavioural therapy and the modification of sleeping habits. Using medicines and other substances to make the sleep easier is currently quite common, even although there are no clinical guidelines to support this. PMID- 27476003 TI - A two phase study to revise the Australian Practice Standards for Specialist Critical Care Nurses. AB - BACKGROUND: Observational work to develop the ACCCN Competency Standards was undertaken more than 20 years ago. Since then the landscape of critical care nursing as a specialty has changed and it is not known if the Competency Standards reflected contemporary practice. OBJECTIVES: To revise the ACCCN Competency Standards for Specialist Critical Care Nurses to ensure they continue to meet the needs of critical care nurses and reflect current practice. METHODS: A two-phased project was undertaken. In Phase I focus groups were held in all states. Thematic analysis was conducted using two techniques. The standards were revised based on the main themes. Phase II consisted of an eDelphi technique. A national panel of critical care nurses responded to three survey rounds using a 7 point likert-type scale to indicate their level of agreement with the revised standards. A 70% agreement level for each statement was determined a priori. RESULTS: Phase I: 12 focus groups (79 participants) were conducted. Phase II: A panel of specialist critical care nurses (research, management, clinical practice and education) responded to round 1 (n=64), round 2 (n=56), and round 3 (n=40). Fifteen practice standards with elements and performance criteria were grouped into four domains (professional practice, provision and coordination of care, critical thinking and analysis, collaboration and leadership). The revised Practice Standards for Specialist Critical Care Nurses build upon and are additional to the Nursing & Midwifery Board of Australia National Competency Standards for Registered Nurses. The standards reflect contemporary critical care nurse practices using an expanded range of technologies to care for complex critically ill patients across the lifespan in diverse settings. CONCLUSION: The national study has resulted in the 3rd edition of the Practice Standards for Specialist Critical Care Nurses. There was input from stakeholders and agreement that the revised standards capture contemporary Australian critical care nursing practice. PMID- 27476004 TI - On the inaccuracy of breath-by-breath metabolic gas exchange systems. AB - This technical note is presenting and discussing a severe limitation of the breath-by-breath (BBB) determination of pulmonary gas exchange routinely used as a surrogate for the metabolic gas exchange rate at rest and during exercise. We are presenting the view that continuous airway gas sampling at the mouth used for the determination of O2 and CO2 content is inaccurate in the range of a low-to medium expiratory flows, due to the discrepancy between the cross section surfaces of the sampling line and the expiratory tube (mask or mouth piece). This difference results in the sampling of a mixed exhaled gas at low expiratory flow, for which any temporal relationship between the instantaneous expired CO2 and O2 signals and instantaneous expiratory flow is lost. Further analysis of this mechanism points to the difference between the exhalation (ve) and sampling (vs) gas velocities, where the ratio of ve/vs must be equal or higher than 1 to enable proper analysis of the respiratory gas concentrations during exhalation. Moreover, the above requirement is particularly crucial in monitoring the tidal concentration of the respiratory gases in experiments with small animals. PMID- 27476005 TI - Rain-on-snow events, floods and climate change in the Alps: Events may increase with warming up to 4 degrees C and decrease thereafter. AB - This paper focuses on the influence of mountain rain-on-snow (ROS) events that can on occasion trigger major floods in alpine catchments. In order to assess the evolution of these events in a recent past, and the potential changes that could be experienced in a changing climate over coming decades, we have focused on a small catchment in north-eastern Switzerland, the Sitter, well-endowed with both climate and hydrological data. Observations show that there has been an increase in the number of rain-on-snow events since the early 1960s related to the rise in atmospheric temperatures. Results from a simple temperature-based snow model show that the number of ROS events could increase by close to 50% with temperatures 2 4 degrees C warmer than today, before declining when temperatures go beyond 4 degrees C. The likelihood of more ROS events suggests that the risks of flooding in a future climate may indeed get worse before they improve. PMID- 27476006 TI - Plastics and other anthropogenic debris in freshwater birds from Canada. AB - Plastics in marine environments are a global environmental issue. Plastic ingestion is associated with a variety of deleterious health effects in marine wildlife, and is a focus of much international research and monitoring. However, little research has focused on ramifications of plastic debris for freshwater organisms, despite marine and freshwater environments often having comparable plastic concentrations. We quantified plastic and other anthropogenic debris in 350 individuals of 17 freshwater and one marine bird species collected across Canada. We determined freshwater birds' anthropogenic debris ingestion rates to be 11.1% across all species studied. This work establishes that plastics and other anthropogenic debris are a genuine concern for management of the health of freshwater ecosystems, and provides a baseline for the prevalence of plastic and other anthropogenic debris ingestion in freshwater birds in Canada, with relevance for many other locations. PMID- 27476007 TI - GPs' implicit prioritization through clinical choices - evidence from three national health services. AB - We present results from an extensive discrete choice experiment, which was conducted in three countries (Norway, Scotland, and England) with the aim of disclosing stated prescription behaviour in different decision making contexts and across different cost containment cultures. We show that GPs in all countries respond to information about societal costs, benefits and effectiveness, and that they make trade-offs between them. The UK GPs have higher willingness to accept costs when they can prescribe medicines that are cheaper or more preferred by the patient, while Norwegian GPs tend to have higher willingness to accept costs for attributes regarding effectiveness or the doctors' experience. In general, there is a substantial amount of heterogeneity also within each country. We discuss the results from the DCE in the light of the GPs' two conflicting agency roles and what we know about the incentive structures and cultures in the different countries. PMID- 27476008 TI - Prediction of Protein-Protein Interaction via co-occurring Aligned Pattern Clusters. AB - Predicting Protein-Protein Interaction (PPI) is important for making new discoveries in the molecular mechanisms inside a cell. Traditionally, new PPIs are identified through biochemical experiments but such methods are labor intensive, expensive, time-consuming and technically ineffective due to high false positive rates. Sequence-based prediction is currently the most readily applicable and cost-effective method. It exploits known PPI Databases to construct classifiers for predicting unknown PPIs based only on sequence data without requiring any other prior knowledge. Among existing sequence-based methods, most feature-based methods use exact sequence patterns with fixed length as features - a constraint which is biologically unrealistic. SVM with Pairwise String Kernel renders better predicting performance. However it is difficult to be biologically interpretable since it is kernel-based where no concrete feature values are computed. Here we have developed a novel method WeMine-P2P to overcome these drawbacks. By assuming that the regions/sites that mediate PPI are more conserved, WeMine-P2P first discovers/locates the conserved sequence patterns in protein sequences in the form of Aligned Pattern Clusters (APCs), allowing pattern variations with variable length. It then pairs up all APCs into a set of Co-Occurring APC (cAPC) pairs, and computes a cAPC-PPI score for each cAPC pair on all PPI pairs. It further constructs a feature vector composed of all cAPC pairs with their cAPC-PPI scores for each PPI pair and uses them for constructing a PPI predictor. Through 40 independent experiments, we showed that (1) WeMine P2P outperforms the well-known algorithm, PIPE2, which also utilizes co-occurring amino acid sequence segments but does not allow variable lengths and pattern variations; (2) WeMine-P2P achieves satisfactory PPI prediction performance, comparable to the SVM-based methods particularly among unseen protein sequences with a potential reduction of feature dimension of 1280*; (3) Unlike SVM-based methods, WeMine-P2P renders interpretable biological features from which we observed that co-occurring sequence patterns from the compositional bias regions are more discriminative. WeMine-P2P is extendable to predict other biosequence interactions such as Protein-DNA interactions. PMID- 27476009 TI - Quantification of hydrogen peroxide in plant tissues using Amplex Red. AB - Reactive oxygen species (ROS) are by-products of photosynthesis and respiration in plant tissues. Abiotic and biotic stressors also induce the production and temporary accumulation of ROS in plants, including hydrogen peroxide (H2O2), whereby they can act as secondary messengers/chemical mediators in plant defense signaling and lead to programmed cell death. H2O2 acts as a hub for critical information flow in plants. Despite such key roles in fundamental cellular processes, reliable determination of H2O2 levels in plant tissues is hard to achieve. We optimized an Amplex Red-based quantitation method for H2O2 estimation from plant tissue lysate. The standard limit of detection and quantitation was determined as 6 and 18picomol respectively. In this study we also quantified constitutive and/or induced levels of H2O2 in three model plants, Pinus nigra (Austrian pine), Oryza sativa (rice), and Arabidopsis thaliana. Overall, assay sensitivity was in the nmolg-1 FW range. Commonly used additives for H2O2 extraction such as activated charcoal, ammonium sulfate, perchloric acid, polyvinylpolypyrrolidone, and trichloroacetic acid either degraded H2O2 directly or interfered with the Amplex Red assay. Finally, We measured stability of Amplex Red working solution over one month of storage at -80 degrees C and found it to be significantly stable over time. With appropriate modifications, this optimized method should be applicable to any plant tissue. PMID- 27476010 TI - Platelet concentrates: Balancing between efficacy and safety? AB - Platelet transfusions continue to be the mainstay to treat patients with quantitative and qualitative platelet disorders. Each year, about 10 millions of platelet transfusions are administered to patients worldwide with marked differences in usage between regions depending on socioeconomic development of the countries. Unfortunately, its use is associated to immune and non-immune side effects. Among the non-immune, bacterial contamination is still the major infectious risk. When bacterial culture methods are introduced for preventing bacterial septic reactions it has been found that this strategy reduce to one half the septic reactions, but do not eliminate completely that risk. To remove completely the risk, a new bacteria detection test at the time of issuance in the case of platelets stored for four or five days would be needed. Pathogen inactivation (PI) methods already in the market (based in the addition of amotosalen (A-L) or riboflavin (R-L) and the illumination with ultraviolet light) or under development (ultraviolet light C and agitation) have shown to be efficacious in the inactivation of bacteria and no cases of septic reactions associated to a pathogen-reduced product has been identified. However, it has been shown that PI technologies have measurable effects on platelet in vitro parameters and reduce the recovery and survival of treated platelets in vivo. Although these effects do not hamper the hemostatic capacity of treated platelets, an increased usage associated with PI technologies has been reported. This increase in utilization seems to be the toll to be paid if we want to completely eliminate the risk of bacterial sepsis in the recipients of platelet transfusion. PMID- 27476011 TI - Rethinking blood components and patients: Patient blood management. Possible ways for development in France. AB - As any therapeutic means, blood transfusion requires regular evaluation, particularly for its indications, effectiveness and risks. A better awareness of the risks of blood transfusion, the availability of randomized clinical trials, the evolution of the quality of blood components, and the economic constraints shared by all countries, all have led to rethink both transfusion therapy as a whole and the organization of the transfusion chain from donor to recipient. In this context, patient blood management (PBM) appears as an evidence-based, patient centred, multidisciplinary approach, aiming to optimise the care of patients who might need transfusion and consequently the use of blood products. This paper presents updated scientific bases of PBM and the three pillars founding it. As PBM is developing fast in other European countries, this review proposes ways to explore for its development in France. It finally proposes to integrate PBM in a wider and coordinated approach of the blood supply management, with tools to improve the effectiveness and efficiency of the transfusion chain, starting with the needs of the patients and ending with an optimum treatment of the patient, including the appropriate number of blood components of the required quality. A better understanding, implementation and assessment of this coordinated global approach, allowing to adapt donor collections to the patients' needs in compliance with safety requirements for patients and donors, in a coordinated way, will certainly be a major challenge for transfusion medicine in the near future, for the benefit of patients, donors and all other stakeholders involved in the transfusion chain. PMID- 27476012 TI - [Brown tumors of hyperparathyroidism revealed by bone pain]. PMID- 27476013 TI - Inflammatory pseudotumor of the liver. PMID- 27476014 TI - Ethics and blood donation: A marriage of convenience. AB - Quality, safety, risks and risk management are currently the leading words in transfusion medicine, and several approaches are necessary to correctly evaluate the fundamental basis of blood transfusion. Ethics is probably the most focused approach with which to examine the inconsistencies and conflicts of interest of the various stakeholders involved in the transfusion medicine field. In this short review, the authors will present some aspects of ethics related to blood transfusion, particularly those involving blood donation. PMID- 27476015 TI - [How could we remain deaf? Letter on the article "And, if deaf professionals could teach us about communication?"]. PMID- 27476016 TI - Red blood cell components: Meeting the quantitative and qualitative transfusion needs. AB - Red blood cell (RBC) transfusion is a very common therapeutic intervention. However, because of multiple recent studies improving our understanding of appropriate transfusion scenarios, the total number of RBC units transfused per year is actually decreasing in the developed world and there are no longer major shortages of RBC products for general use. Nonetheless, there are an increasing number of "special" uses, which can put strains on the blood supply for particular types of products; these may produce shortages of specific types of RBCs or require collections targeting certain types of donors. This review will focus on several broad topics, including providing some examples of "special" settings that require, or could require, special types of RBC products. PMID- 27476017 TI - The infectious risks in blood transfusion as of today - A no black and white situation. AB - Transfusion has been tainted with the risk of contracting an infection - often severe - and fears about this risk are still prevailing, in sharp contrast with the actual risk in Western countries. Those actual risks are rather immunological, technical (overload) or metabolic. Meanwhile, in developing countries and particularly in Africa, transfusion transmitted infections (TTIs) are still frequent, because of both the scarcity of volunteer blood donors and resources and the high incidence and prevalence of infections. Global safety of blood components has been declared as a goal to be attained everywhere by the World Heath Organization (WHO). However, this challenge is difficult to meet because of several intricate factors, of which the emergence of infectious agents, low income and breaches in sanitation and hygiene. This review aims at encompassing the situation of TTIs in different settings and means that can be deployed to improve the situation where this can possibly be. PMID- 27476018 TI - Revisiting transfusion safety and alternatives to transfusion. AB - Transfusion of blood products can be life saving when used appropriately. It carries however at the same time a potential for morbidity and mortality, depending on the patient, the product or the setting. Numerous strategies have been elaborated to minimize these risks, and in recent years, transfusion has no longer been regarded as essential for the management of a wide range of diseases. Uncomplicated surgeries in well-prepared patients can now be conducted without the use of transfusions. Questions about transfusion safety and shortage have led to extensive research on alternatives to blood transfusion, ranging from non pharmacological to pharmacological solutions. Restrictive transfusion therapies, preoperative autologous blood donations, perioperative red cell salvage, acute normovolaemic haemodilution techniques or patient blood management are potential solutions where prothrombin complex or fibrinogen concentrates, synthetic anti fibrinolytic agents, desmopressin, rFVIIa, or erythropoiesis stimulating agents may play a complementary pharmacologic role. PMID- 27476019 TI - [Zika virus maculopapular exanthema in traveller returning from Martinique to Mainland France]. PMID- 27476020 TI - Focus on fresh frozen plasma - facilitating optimal management of bleeding through collaboration between clinicians and transfusion specialists on component specifications. AB - BACKGROUND: A symposium on plasma for direct clinical use was held in September 2015 by the European directorate for the quality of medicines and healthcare (EDQM) in order to consider changes to the Council of Europe guide to the preparation, use and quality assurance of blood components monographs on plasma components. METHODS: The programme reviewed use of plasma in various settings, novel components, adverse reactions, manufacturing and quality monitoring issues. RESULTS: The main requirement identified was that plasma should be made available to support early transfusion in the trauma/massive haemorrhage setting. Further guidance on component manufacturing and reviewing of quality monitoring requirements will also be addressed. CONCLUSION: A working group has been established to review component monographs and other advice in the guide relating to plasma components, with the aim of providing optimal components to support clinical management of patients requiring plasma. PMID- 27476022 TI - [Undergraduate research funding in Peruvian medical schools]. PMID- 27476021 TI - ? PMID- 27476023 TI - Long-term physical workload in middle age and disability pension in men and women: a follow-up study of Swedish cohorts. AB - PURPOSE: The study investigates the association between level of long-term physical workload in middle age and disability pension (DP) before 61 years of age with adjustments made for early life factors, level of education, and psychosocial working conditions. Associations with DP overall, DP due to musculoskeletal disorders and DP due to psychiatric disorders were examined. METHODS: The study is based on cohorts of 21,809 Swedish men and women born in 1948 and 1953, with data on physical workload estimated with a job exposure matrix based on occupational titles in 1985 and 1990 and follow-up data on diagnosis-specific DP in the years 1991-2009. Data on paternal education and intelligence were collected in primary school. Data on level of education were taken from administrative records. Data on psychosocial working conditions were estimated with a job exposure matrix based on occupational titles in 1990. RESULTS: Long-term exposure to high physical workload measured 5 years apart at around age 40 was strongly associated with DP due to musculoskeletal disorders up to the age of 61 among both men (HR 5.44, 95 % CI 3.35-8.84) and women (HR 3.82, CI 95 % 2.88-5.08). For women, the association between high physical load and overall DP was also significantly increased (HR 2.33, CI 95 % 1.92-2.82). The increased risks remained but were clearly attenuated after adjustments for fathers' education, IQ in childhood, achieved education and level of control at work. CONCLUSIONS: Exposure to high physical workload is associated with long term risk of DP due to musculoskeletal disorders, even though adjustments for early life factors, level of education and psychosocial working conditions clearly attenuated the risks. PMID- 27476024 TI - Corrigendum to 'L-Ascorbic acid can abrogate SVCT-2-dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells': [Free Radic. Biol. Med. 95 (2016) 200-208]. PMID- 27476025 TI - Graph analysis of EEG resting state functional networks in dyslexic readers. AB - OBJECTIVE: Neuroimaging research suggested a mixed pattern of functional connectivity abnormalities in developmental dyslexia. We examined differences in the topological properties of functional networks between 29 dyslexics and 15 typically reading controls in 3rd grade using graph analysis. Graph metrics characterize brain networks in terms of integration and segregation. METHOD: We used EEG resting-state data and calculated weighted connectivity matrices for multiple frequency bands using the phase lag index (PLI). From the connectivity matrices we derived minimum spanning tree (MST) graphs representing the sub networks with maximum connectivity. Statistical analyses were performed on graph derived metrics as well as on the averaged PLI connectivity values. RESULTS: We found group differences in the theta band for two graph metrics suggesting reduced network integration and communication between network nodes in dyslexics compared to controls. CONCLUSION: Collectively, our findings point to a less efficient network configuration in dyslexics relative to the more proficient configuration in the control group. SIGNIFICANCE: Graph metrics relate to the intrinsic organization of functional brain networks. These metrics provide additional insights on the cognitive deficits underlying dyslexia and, thus, may advance our knowledge on reading development. Our findings add to the growing body literature suggesting compromised networks rather than specific dysfunctional brain regions in dyslexia. PMID- 27476026 TI - Skin-to-skin contact by fathers and the impact on infant and paternal outcomes: an integrative review. AB - OBJECTIVE: to summarise research evidence on the impact of father-infant skin-to skin contact on infant and paternal outcomes. DESIGN: an integrative literature review. DATA SOURCES: PubMed, ScienceDirect, PsycINFO, and Cumulative Index to Nursing & Allied Health. REVIEW METHODS: studies included were: (1) published in English between January 1995 to September 2015; (2) primary researches; and (3) focused on fathers providing skin-to-skin contact with their infants and its impact on infant and paternal outcomes. The Joanna Briggs Institute's Critical Appraisal Checklists were used to appraise the scientific rigour of the studies. FINDINGS: twelve studies (10 quantitative and two qualitative) were included in this review. Father-infant skin-to-skin contact had positive impacts on infants' outcomes, including temperature and pain, bio-physiological markers, behavioural response, as well as paternal outcomes, which include parental role attainment, paternal interaction behaviour, and paternal stress and anxiety. CONCLUSIONS: a father's involvement in providing skin-to-skin contact seems to be feasible and beneficial to both infants and fathers. However, there has been a scarcity of literature that exclusively examines fathers' involvement and perceptions related to skin-to-skin contact in the postpartum period. Future research should examine skin-to-skin contact by fathers and its associated benefits, as well as fathers' perceptions on father-infant SSC among varied populations. IMPLICATIONS FOR PRACTICE: a father's involvement in providing skin-to-skin contact should be promoted during the postnatal period. Father-infant skin-to-skin contact is a valuable alternative, especially during the unavailability of mothers due to special circumstances, including medical emergencies and caesarean section. PMID- 27476027 TI - Midwifery practice and maternity services: A multisite descriptive study in Latin America and the Caribbean. AB - OBJECTIVE: over the past three decades there has been a social movement in Latin American countries (LAC) to support humanised, physiologic birth. Rates of caesarean section overall in Latin America are approximately 35%, increasing up to 85% in some cases. There are many factors related to poor outcomes with regard to maternal and newborn/infant health in LAC countries. Maternal and perinatal outcome data within and between countries is scarce and inaccurate. The aims of this study were to: i) describe selected obstetric and neonatal outcomes of women who received midwifery care, ii) identify the level of maternal well-being after experiencing midwifery care in 6 Latin America countries. DESIGN: this was a cross sectional and descriptive study, conducted in selected maternity units in Argentina, Brazil, Chile, the Dominican Republic, Peru, and Uruguay. Quantitative methods were used to measure midwifery processes of care and maternal perceptions of well-being in labour and childbirth through a validated survey of maternal well-being and an adapted version of the American College of Nurse-Midwives (ACNM) standardized antepartum and intrapartum data set. SETTING: Maternity units from 6 Latin American countries. PARTICIPANTS: the final sample was a convenience sample, and the total participants for all sites in the six countries was 3009 low risk women. FINDINGS: for the countries reporting, overall, 82% of these low risk women had spontaneous vaginal deliveries. The rate of caesarean section was 16%; the Dominican Republic had the highest rate of Caesarean sections (30%) and Peru had the lowest rate (4%). The use of oxytocin in labour was widely variable, although overall there was a high proportion of women whose labour was augmented or induced. Ambulation was common, with the lowest proportion (48%) of women ambulating in labour in Chile, Uruguay (50%), Peru (65%), Brazil (85%). The presence of continuous support was highest in Uruguay (93%), Chile (75%) and Argentina (55%), and Peru had the lowest (22%). Episiotomies are still prevalent in all countries, the lowest rate was reported in the Dominican Republic (22%), and the highest rates were 52 and 53% (Chile and Peru, respectively). The Optimal Maternal well-being score had a prevalence of 43.5%, adequate score was 30.8%; 25% of the total sample of women rated their well-being during labour and childbirth as poor. KEY CONCLUSIONS: despite evidence-based guidelines and recommendations, birth is not managed accordingly in most cases. Women feel that care is adequate, although some women report mistreatment. IMPLICATIONS FOR PRACTICE: More research is needed to understand why such high levels of intervention exist and to test the implementation of evidence-based practices in local settings. PMID- 27476028 TI - Nonfunctional pacemaker leads: To remove or not to remove, that is the multifactorial question. PMID- 27476029 TI - Stimulus for change: Result of standardization of antimicrobial prophylaxis duration in pediatric cardiac surgery. PMID- 27476030 TI - The paravalvular regurgitation enigma. PMID- 27476031 TI - Can the Streamliner multilayer flow modulator really streamline the solution to complex arch and thoracoabdominal aortic pathology? PMID- 27476033 TI - How we treat thrombotic thrombocytopenic purpura: Results of a Canadian TTP practice survey. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare disease with 90% mortality if untreated. Since the Canadian Apheresis Group (CAG) trial showed greater survival with therapeutic plasma exchange (TPE) versus plasma infusion, there has been widespread adoption of TPE. Beyond TPE, there is significant practice variation. To characterize this, we developed a survey sent to physicians who might be directly involved in TTP management. METHODS: The survey was sent to CAG members as well as hematologists and nephrologists nationwide and addressed areas of controversy or recognized practice heterogeneity. Descriptive statistics were used to summarize responses, and the chi2 test was used to compare respondents who were and were not CAG physicians. We also compared responses by estimated frequency of TTP cases per year. RESULTS: The CAG response rate was 31% (13 of 42). The survey was sent to 665 non-CAG physicians, of whom 41 responded (6.1%). Though not statistically different, CAG and non-CAG respondents varied regarding use of corticosteroids, aspirin, and venous thromboembolism (VTE) prophylaxis. Significant differences were found between CAG and non-CAG groups regarding cryosupernatant as fluid choice (69.2% vs. 22.5%, P = .004) and the use of TPE tapering (84.6% vs. 51.3%, P = .034), respectively. CONCLUSION: TTP treatment is variable across centres in Canada. Areas of significant variation include the choice of replacement fluid for TPE and whether or not and how to taper TPE. Our survey highlights the practice heterogeneity that exists and identifies areas where more evidence is needed and perhaps where trials should be performed. PMID- 27476032 TI - Lymph node yield and tumor location in patients with upper tract urothelial carcinoma undergoing nephroureterectomy affects survival: A U.S. population-based analysis (2004-2012). AB - PURPOSE: The purpose of the study was to characterize the contemporary trends in lymphadenectomy for the treatment of upper tract urothelial carcinoma in a population-based cohort and to determine if number of lymph nodes removed and tumor location are predictors of cancer-specific survival in patients undergoing nephroureterectomy. MATERIALS AND METHODS: Individuals with upper tract urothelial carcinoma undergoing nephroureterectomy in the Surveillance, Epidemiology, and End Results program from 2004 to 2012 were identified. Linear regression was used to assess trends in lymphadenectomy. Patients were stratified based on nodal status, quartiles of nodes removed, and tumor location. Kaplan Meier analysis, log-rank tests, and Cox proportional hazards models were used to compare cancer-specific survival and overall survival among groups. RESULTS: In the cohort, 25% (721/2,862) of all patients and 27% (566/2,079) of grade 3/4 patients underwent lymphadenectomy. The percentage of patients undergoing lymphadenectomy increased from 20% (60/295) in 2004 to 33% (106/320) in 2012 (P = 0.02). Patients with the highest quartile of lymph nodes removed had improved the 5-year cancer-specific survival of 78% (95% CI: 69%-85%) compared to the second quartile (60%; 95% CI: 51%-67%; P = 0.003) and the third quartile (60%; 95% CI: 51%-68%; P = 0.002) of nodes removed. This trend held for node-negative and node positive patients. In multivariable modeling, a lower number of lymph nodes dissected (hazard ratio = 0.94, 95% CI: 0.91-0.98) and ureteral tumors (hazard ratio = 1.29, 95% CI: 1.07-1.56) were predictors of worse cancer-specific survival. CONCLUSIONS: In patients with upper tract urothelial carcinoma undergoing nephroureterectomy, rates of lymphadenectomy have increased from 2004 to 2012 in the United States. In this contemporary cohort, an increase in the number of nodes removed and renal pelvis tumors are associated with improved cancer-specific survival, which highlights the importance of intentional lymph node dissection with adequate lymph node yield in these patients. PMID- 27476034 TI - A combined proteomic and transcriptomic analysis of slime secreted by the southern bottletail squid, Sepiadarium austrinum (Cephalopoda). AB - Sepiadarium austrinum, the southern bottletail squid, is a small squid that inhabits soft sediments along Australia's south-east coast. When provoked, it rapidly secretes large volumes of slime, presumably as a form of chemical defense. We analyzed the proteomic composition of this slime using tandem mass spectrometry and transcriptomics and found that it was remarkably complex with 1735 identified protein groups (FDR:0.01). To investigate the chemical defense hypothesis we performed an Artemia toxicity assay and used sequence analysis to search for toxin-like molecules. Although the slime did not appear to be toxic to Artemia we found 13 proteins in slime with the hallmarks of toxins, namely cysteine richness, short length, a signal peptide and/or homology to known toxins. These included three short (80-130AA) cysteine rich secreted proteins with no homology to proteins on the NCBI or UniProt databases. Other protein families found included, CAP, phospholipase-B, ShKT-like peptides, peptidase S10, Kunitz BPTI and DNase II. Quantitative analysis using intensity based absolute quantification (iBAQ via MaxQuant) revealed 20 highly abundant proteins, accounting for 67% of iBAQ signal, and three of these were toxin-like. No mucin homologues were found suggesting that the structure of the slime gel may be formed by an unknown mechanism. BIOLOGICAL SIGNIFICANCE: This study is the first known instance of a slime secretion from a cephalopod to be analyzed by proteomics methods and is the first investigation of a member of the family Sepiadariidae using proteomic methods. 1735 proteins were identified with 13 of these fitting criteria established for the identification of putative toxins. The slime is dominated by 20 highly abundant proteins with secreted, cysteine rich proteins. The study highlights the importance of 'omics approaches in understanding novel organisms. PMID- 27476035 TI - Pineal region tumors: a simplified management scheme. PMID- 27476036 TI - George J. Garceau (1896-1977) and the first introduction of the "filum terminale syndrome". PMID- 27476037 TI - Johann Gaspar Spurzheim (1775-1832) and his contributions to our understanding of neuroanatomy. PMID- 27476038 TI - Intracranial germ cell tumors: a multi-institutional experience from three tertiary care centers in India. AB - OBJECTIVE: Central nervous system germ cell tumors (CNS GCTs) are relatively rare neoplasms. Incidence of CNS GCTs in Western literature is low (0.3-0.6 %) as compared to East Asia (3-4 %). No large study is available on CNS GCTs from India. METHODS: Intracranial GCT cases were retrieved from databases of three tertiary care institutes in India; clinicopathological data was reviewed. RESULTS: Ninety-five intracranial GCT cases were identified, accounting for 0.43 % of CNS tumors. Median age was 12 years (range, birth to 48 years); male preponderance was noted (66 %). Most patients (86.3 %) were aged <18 years. Pineal location was most common (45 %) and was associated with male gender and age >14 years. Germinoma was the commonest histopathological type (63.2 %), followed by teratoma (20 %). Suprasellar location was associated with germinoma histology. Follow-up was available for 71 patients (median, 15 months). Of these, 48 received adjuvant chemotherapy and/or radiotherapy. At the last follow-up, 44 patients showed no evidence of disease. Age >10 years, male gender, pineal location, and germinoma histology were associated with favorable outcome. CONCLUSION: This is the first multicentric study from India establishing that incidence of CNS GCT in India is similar to that in the West and differs from that in East Asian countries. However, similar to both, germinoma is the commonest histological type, and pineal location is most frequent. Studies on molecular alterations based on ethnicity and geographical location are necessary to provide clarity on differences in incidence. Attention needs to be focused on decreasing treatment heterogeneity and minimizing treatment-related morbidity and mortality, improving the cure rate of these highly treatable tumors. PMID- 27476039 TI - Spontaneous evacuation of hyperacute extradural hematoma: two illustrative case reports. AB - Spontaneous drainage of extradural hematoma (EDH) through a skull fracture is rare, with only 14 cases reported to date. Five of these belong to pediatric age group. The authors report two cases of spontaneous evacuation of acute EDH, in children, with two differing types of skull fractures, one being an elevated fracture. The context, in which the terminologies of "spontaneous evacuation" and "spontaneous resolution" to be used, is clarified. PMID- 27476040 TI - Loss of Hes1 expression is associated with poor prognosis in colorectal adenocarcinoma. AB - Alterations in the Notch signaling pathway play a role in colorectal cancer (CRC). Hes1, a Notch-induced transcription factor, has recently been reported to show decreased expression by immunohistochemistry in sessile serrated adenomas. Variable staining patterns have been reported in tubular adenomas, and existing data on Hes1 expression in CRC are limited and inconsistent. We therefore sought to investigate the expression of Hes1 by immunohistochemistry in a large and well characterized cohort of CRC patients to determine clinicopathological associations and prognostic significance. Immunohistochemistry for Hes1 was performed on 2775 consecutive CRCs in tissue microarray format. Hes1 expression was classified into 3 categories: absent, 1302 cases (46.9%); cytoplasmic staining only with loss of nuclear staining, 1002 cases (36.1%); and nuclear with or without cytoplasmic staining, 471 cases (17%). In univariate analysis, loss of nuclear expression of HES1 was significantly associated with older age, female sex, right-sided location, mucinous or medullary histology, higher histological grade, microsatellite instability, BRAFV600E mutation, and larger tumor size. Strong and statistically significant associations with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, and larger size remained in multivariate analysis. Patients with loss of nuclear expression of Hes1 had a significantly worse all-cause 5-year survival in both univariate (P = .002) and multivariate (P = .009) analysis. We conclude that loss of nuclear expression of Hes1 occurs in 83% of CRCs when studied in tissue microarray format and is associated with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, larger tumor size, and significantly worse survival. PMID- 27476041 TI - Prevalence and characterization of fibrosis in surveillance liver biopsies of patients with Fontan circulation. AB - The Fontan operation is a widely used palliative procedure in patients with single-ventricle anatomy that results in liver injury. As timely identification of liver fibrosis may result in management changes to Fontan patients, the aim of our study was to identify clinically meaningful semi quantitative/quantitative pathologic parameters for biopsy assessment. We performed a retrospective review of 74 liver needle biopsies from Fontan patients. Fibrosis was assessed using quantitative % collagen deposition by Sirius red image analysis, METAVIR, congestive hepatic fibrosis score, sinusoidal fibrosis score, and sinusoidal dilation score. Contemporaneous laboratory, hemodynamic, and ultrasound data were collected. Centrilobular and peri sinusoidal fibrosis was observed in all cases, with 39.2% high grade. Portal fibrosis was observed in 93.2%, with 36.2% high grade (METAVIR F3-F4). Cirrhosis was observed in 5.4%. % Collagen deposition was increased over control tissue (P < .001) and correlated with time from Fontan (r = 0.3, P = .009) and prothrombin time (r = 0.25, P = .034). Mildly elevated prothrombin time/international normalized ratio was the only measure of liver function consistently associated with multiple high-grade fibrosis scores (METAVIR P = .046, sinusoidal fibrosis P = .018). Abnormal liver echotexture on ultrasound was associated with high-grade congestive hepatic fibrosis score (P = .03). Pathologic gradings and %CD correlated with each other (r = 0.48-0.8, P < .001). Hepatic fibrosis in Fontan patients in our study is universally present, appears to be time dependent, and correlates with few laboratory measurements of liver function. Careful assessment of needle liver biopsies lends a more meaningful measure of liver fibrosis in the Fontan patient than clinical and laboratory data, allowing for appropriate changes to patient management. PMID- 27476042 TI - Neuroimaging genetic analyses of novel candidate genes associated with reading and language. AB - Neuroimaging measures provide useful endophenotypes for tracing genetic effects on reading and language. A recent Genome-Wide Association Scan Meta-Analysis (GWASMA) of reading and language skills (N=1862) identified strongest associations with the genes CCDC136/FLNC and RBFOX2. Here, we follow up the top findings from this GWASMA, through neuroimaging genetics in an independent sample of 1275 healthy adults. To minimize multiple-testing, we used a multivariate approach, focusing on cortical regions consistently implicated in prior literature on developmental dyslexia and language impairment. Specifically, we investigated grey matter surface area and thickness of five regions selected a priori: middle temporal gyrus (MTG); pars opercularis and pars triangularis in the inferior frontal gyrus (IFG-PO and IFG-PT); postcentral parietal gyrus (PPG) and superior temporal gyrus (STG). First, we analysed the top associated polymorphisms from the reading/language GWASMA: rs59197085 (CCDC136/FLNC) and rs5995177 (RBFOX2). There was significant multivariate association of rs5995177 with cortical thickness, driven by effects on left PPG, right MTG, right IFG (both PO and PT), and STG bilaterally. The minor allele, previously associated with reduced reading-language performance, showed negative effects on grey matter thickness. Next, we performed exploratory gene-wide analysis of CCDC136/FLNC and RBFOX2; no other associations surpassed significance thresholds. RBFOX2 encodes an important neuronal regulator of alternative splicing. Thus, the prior reported association of rs5995177 with reading/language performance could potentially be mediated by reduced thickness in associated cortical regions. In future, this hypothesis could be tested using sufficiently large samples containing both neuroimaging data and quantitative reading/language scores from the same individuals. PMID- 27476043 TI - Artificial ribonucleases inactivate a wide range of viruses using their ribonuclease, membranolytic, and chaotropic-like activities. AB - Artificial ribonucleases (aRNases) are small compounds catalysing RNA cleavage. Recently we demonstrated that aRNases readily inactivate various viruses in vitro. Here, for three series of aRNases (1,4-diazabicyclo [2.2.2]octane-based and peptide-like compounds) we show that apart from ribonuclease activity the aRNases display chaotropic-like and membranolytic activities. The levels of membranolytic and chaotropic-like activities correlate well with the efficiency of various viruses inactivation (enveloped, non-enveloped, RNA-, DNA-containing). We evaluated the impact of these activities on the efficiency of virus inactivation and found: i) the synergism between membranolytic and chaotropic like activities is sufficient for the inactivation of enveloped viruses (influenza A, encephalitis, vaccinia viruses) for 1,4-diazabicyclo [2.2.2]octane based aRNases, ii) the inactivation of non-enveloped viruses (encephalomyocarditis, acute bee paralysis viruses) is totally dependent on the synergism of chaotropic-like and ribonuclease activities, iii) ribonuclease activity plays a leading role in the inactivation of RNA viruses by aRNases Dp12F6, Dtr12 and K-D-1, iv) peptide-like aRNases (L2-3, K-2) being effective virus killers have a more specific mode of action. Obtained results clearly demonstrate that aRNases represent a new class of broad-spectrum virus inactivating agents. PMID- 27476044 TI - Lipopolysaccharide acts synergistically with the dengue virus to induce monocyte production of platelet activating factor and other inflammatory mediators. AB - BACKGROUND: Platelet Activating Factor (PAF) has been shown to be an important mediator of vascular leak in acute dengue. Antibody dependent enhancement (ADE) and microbial translocation has also shown to contribute to severe dengue. Since monocytes are one of the primary targets of the dengue virus (DENV) we sought to investigate if monocytes were a source of PAF, and the effect of ADE and microbial endotoxin (LPS) on DENV infected monocytes. METHODS: PAF and cytokine levels were evaluated in serial blood samples, in patients with acute dengue infection. The effect of ADE and LPS in production of PAF and cytokines from DENV infected primary human monocytes derived macrophages (MDMtheta) was assessed. Gene expression analysis was undertaken to investigate mechanisms by which LPS potentiates PAF and cytokine production by DENV infected MDMtheta. RESULTS: Serum PAF levels significantly correlated with both TNF-alpha (p < 0.0001) and IL-1beta (p < 0.0001) in patients with acute DENV infection. Although primary human MDMtheta produced inflammatory cytokines following infection with the DENV, they did not produce PAF following in vitro DENV infection alone, or in the presence of dengue immune serum. Levels of PAF produced by DENV infected MDMtheta co cultured with LPS was significantly higher than uninfected MDMthetas co-cultured with LPS. Although TLR-4 was upregulated in uninfected MDMthetas co-cultured with LPS, this upregulation was not significant in DENV infected MDMtheta. Only expression of RIG-I was significantly up regulated (p < 0.05) when DENV infected MDMtheta were co-cultured with LPS. CONCLUSION: LPS acts synergistically with the DENV to induce production of PAF and other inflammatory cytokines, which suggests that microbial translocation that has shown to occur in acute dengue, could contribute to dengue disease severity. PMID- 27476045 TI - 14-Deoxy-11,12-didehydroandrographolide attenuates excessive inflammatory responses and protects mice lethally challenged with highly pathogenic A(H5N1) influenza viruses. AB - Traditional Chinese medicine (TCM) has been an excellent treasury for centuries' accumulation of clinical experiences, which deserves to be tapped for potential drugs and improved using modern scientific methods. 14-Deoxy-11,12 didehydroandrographolide (DAP), a major component of an important TCM named Andrographis paniculata, with non-toxic concentration of 1000 mg/kg/day, effectively reduced the mortality and weight loss of mice lethally challenged with A/chicken/Hubei/327/2004 (H5N1) or A/PR/8/34 (H1N1) influenza A viruses (IAV) when initiated at 4 h before infection, or A/duck/Hubei/XN/2007 (H5N1) when initiated at 4 h or 48 h before infection, or 4 h post-infection (pi). DAP (1000 or 500 mg/kg/day) also significantly diminished lung virus titres of infected mice when initiated at 4 h or 48 h before infection, or 4 h pi. In the infection of A/duck/Hubei/XN/2007 (H5N1), DAP (1000 mg/kg/day) treatment initiated at 48 h before infection gained the best efficacy that virus titres in lungs of mice in log10TCID50/mL reduced from 2.61 +/- 0.14 on 3 days post-infection (dpi), 2.98 +/ 0.17 on 5 dpi, 3.54 +/- 0.19 on 7 dpi to 1.46 +/- 0.14 on 3 dpi, 1.86 +/- 0.18 on 5 dpi, 2.03 +/- 0.21 on 7 dpi. Moreover, DAP obviously alleviated lung histopathology and also strongly inhibited proinflammatory cytokines/chemokines expression. The mRNA levels of TNF-alpha, IL-1beta, IL-6, CCL-2/MCP-1, IFN-alpha, IFN-beta, IFN-gamma, MIP-1alpha, MIP-1beta in lungs of A/duck/Hubei/XN/2007 (H5N1)-infected mice and serum protein expression of TNF-alpha, IL-1beta, IL-6, CCL-2/MCP-1 and CXCL-10/IP-10 in mice infected with all the three strains of IAV were all significantly reduced by DAP. Results demonstrated that DAP could restrain both the host intense inflammatory responses and high viral load, which were considered to contribute to the pathogenesis of H5N1 virus and should be controlled together in a clinical setting. Considering the anti-inflammatory and anti-IAV activities of DAP, DAP may be a promising active component obtained from A. paniculata, which can be further investigated as a useful constitute of curative strategies in the future against IAV, the H5N1 strains in particular. PMID- 27476046 TI - Structure-activity relationships of nucleoside analogues for inhibition of tick borne encephalitis virus. AB - Tick-borne encephalitis (TBE) represents one of the most serious arboviral neuro infections in Europe and northern Asia. As no specific antiviral therapy is available at present, there is an urgent need for efficient drugs to treat patients with TBE virus (TBEV) infection. Using two standardised in vitro assay systems, we evaluated a series of 29 nucleoside derivatives for their ability to inhibit TBEV replication in cell lines of neuronal as well as extraneural origin. The series of tested compounds included 2'-C- or 2'-O-methyl substituted nucleosides, 2'-C-fluoro-2'-C-methyl substituted nucleosides, 3'-O-methyl substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C-azido substitution, heterobase modified nucleosides and neplanocins. Our data demonstrate a relatively stringent structure-activity relationship for modifications at the 2', 3', and 4' nucleoside positions. Whereas nucleoside derivatives with the methylation at the C2' position or azido modification at the C4'position exerted a strong TBEV inhibition activity (EC50 from 0.3 to 11.1 MUM) and low cytotoxicity in vitro, substitutions of the O2' and O3' positions led to a complete loss of anti-TBEV activity (EC50 > 50 MUM). Moreover, some structural modifications of the heterobase moiety resulted in a high increase of cytotoxicity in vitro. High antiviral activity and low cytotoxicity of C2' methylated or C4' azido substituted pharmacophores suggest that such compounds might represent promising candidates for further development of potential therapeutic agents in treating TBEV infection. PMID- 27476047 TI - Heterologous Pseudomonas aeruginosa O-antigen delivery using a Salmonella enterica serovar Typhimurium wecA mutant strain. AB - There is a broad interest in adapting live vaccine strains (LVS) for use as recombinant vaccines that can deliver heterologous antigens. The Salmonella enterica serovar Typhimurium SL1344 DeltawecA LVS contains a mutation in wecA that abrogates production of Enterobacterial common antigen. This DeltawecA strain is attenuated in vivo, persistently colonizes the host, and protects against both wild type and cross-Salmonella serovar lethal challenge in a murine model of salmonellosis. Given these characteristics, we hypothesized that the SL1344 DeltawecA strain could be used as a carrier for heterologous antigen expression. To test this hypothesis, SL1344 DeltawecA was engineered to express the Pseudomonas aeruginosa O11 O-antigen gene cluster. Intraperitoneal (IP) but not oral immunization of BALB/c mice with the heterologous expression strain protected against lethal P. aeruginosa intranasal (IN) challenge. Furthermore, IP immunization resulted in P. aeruginosa O11-specific Ig and IgG antibody production. Functional analysis of sera collected from the IP immunized mice showed antibody-mediated agglutination and opsonophagocytic activity against P. aeruginosa. En masse, these results indicate that the S. Typhimurium SL1344 DeltawecA strain expressing the P. aeruginosa O11 O-antigen gene cluster is able to induce a humoral immune response and to protect against lethal P. aeruginosa challenge. As such, the S. Typhimurium SL1344 DeltawecA LVS can likely serve as a vehicle for expression of a wide variety of heterologous antigens as a means to create recombinant vaccines. PMID- 27476049 TI - Human amnion epithelial cells expressing HLA-G as novel cell-based treatment for liver disease. AB - Despite routine liver transplantation and supporting medical therapies, thousands of patients currently wait for an organ and there is an unmet need for more refined and widely available regenerative strategies to treat liver diseases. Cell transplants attempt to maximize the potential for repair and/or regeneration in liver and other organs. Over 40years of laboratory pre-clinical research and 25years of clinical procedures have shown that certain liver diseases can be treated by the infusion of isolated cells (hepatocyte transplant). However, like organ transplants, hepatocyte transplant suffers from a paucity of tissues useful for cell production. Alternative sources have been investigated, yet with limited success. The tumorigenic potential of pluripotent stem cells together with their primitive level of hepatic differentiation, have limited the use of stem cell populations. Stem cell sources from human placenta, and the amnion tissue in particular are receiving renewed interest in the field of regenerative medicine. Unlike pluripotent stem cells, human amnion epithelial (AE) cells are easily available without ethical or religious concerns; they do not express telomerase and are not immortal or tumorigenic when transplanted. In addition, AE cells have been reported to express genes normally expressed in mature liver, when transplanted into the liver. Moreover, because of the possibility of an immune privileged status related to their expression of HLA-G, it might be possible to transplant human AE cells without immunosuppression of the recipient. PMID- 27476048 TI - Trends in the Incidence of Fatal Prostate Cancer in the United States by Race. AB - BACKGROUND: Prostate-specific antigen (PSA) testing has dramatically changed the composition of prostate cancer (PCa), making it difficult to interpret incidence trends. New methods are needed to examine temporal trends in the incidence of clinically significant PCa and whether trends vary by race. OBJECTIVE: To conduct an in-depth analysis of incidence trends in clinically significant PCa, defined as cases in which PCa was the underlying cause of death within 10 yr of diagnosis. DESIGN, SETTING, AND PARTICIPANTS: We extracted incident PCa cases during the period 1975-2002 and associated causes of death and survival through 2012 from nine cancer registries in the population-based Surveillance Epidemiology and End Results program database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We applied joinpoint regression analysis to identify when significant changes in trends occurred and age-period-cohort models to examine longitudinal and cross-sectional trends in the incidence of fatal PCa. RESULTS AND LIMITATIONS: Among 51 680 fatal PCa cases, incidence increased 1% per year prior to 1992, declined 15% per year from 1992 to 1995, and further declined by 5% per year through 2002. Age-specific incidence rates of fatal disease decreased >2% per year among men aged >=60 yr, yet rates remained relatively stable among men aged <=55 yr. Fatal disease rates were >2-fold higher in black men compared with white men, a racial disparity that increased to 4.2-fold among younger men. CONCLUSIONS: The incidence of fatal PCa substantially declined after widespread PSA screening and treatment advances. Nevertheless, rates of fatal disease among younger men have remained relatively stable, suggesting the need for additional attention to early onset PCa, especially among black men. The persistent black-to white racial disparity observed in fatal PCa underscores the need for greater understanding of the causes of this difference so that strategies can be implemented to eliminate racial disparities. PATIENT SUMMARY: We assessed how the incidence of ultimately fatal prostate cancer (PCa) changed over time. We found that the incidence of fatal PCa declined by >50% since the introduction of prostate-specific antigen testing and advances in treatment options; however, incidence rates among younger men remained relatively stable, and younger black men exhibited a 4.2-fold higher risk for fatal disease compared with white men. PMID- 27476050 TI - Early post-operative acute phase response in patients with early graft dysfunction is predictive of 6-month and 12-month mortality in liver transplant recipients. AB - Early allograft dysfunction (EAD) after liver transplantation is mostly a reversible event caused by factors related to ischemia/reperfusion (I/R) injury. EAD represents a hepatic injury associated with pre- and early post-transplant inflammatory cytokine responses. Aim of the present study was to evaluate the prognostic and diagnostic value of CRP in liver transplant recipients with EAD. MATERIALS AND METHODS: Forty-seven patients with EAD were compared with 115 non EAD patients. Pre- and post-transplant parameters were analyzed. EAD was defined based on postoperative liver function tests such as INR, bilirubin and liver enzymes. Statistical analysis was performed using SPSS version 18.0. RESULTS: Pre transplant liver enzyme were not significantly different in the two groups. At day 3, 5 and 10 post-transplant CRP was significantly higher in patients with EAD than in non-EAD patients (p?0.001 for all investigations) and remained consistently high in patients with EAD and low in non-EAD patients. EAD patients with high CRP at post-transplant days 3 and 5 showed lower survival at 6-month and 12-month post-transplant than patients with low CRP. CONCLUSION: Our results indicate a prognostic and diagnostic value of CRP in patients with early graft dysfunction and predict 6-month and 12-month mortality in liver transplant recipients. PMID- 27476051 TI - A Comprehensive Review of the Literature Supporting Recommendations From the Canadian Diabetes Association for the Use of a Plant-Based Diet for Management of Type 2 Diabetes. AB - Type 2 diabetes mellitus is considered one of the fastest growing diseases in Canada, representing a serious public health concern. Thus, clinicians have begun targeting modifiable risk factors to manage type 2 diabetes, including dietary patterns such as a plant-based diets (PBDs). The Canadian Diabetes Association has included PBDs among the recommended dietary patterns to be used in medical nutrition therapy for persons with type 2 diabetes. To support knowledge translation, this review summarizes the current literature relating to PBDs and the prevalence of type 2 diabetes, its clinical applications and its acceptability in the management of type 2 diabetes as well as its application in community settings. This comprehensive review seeks to close the literature gap by providing background and rationale to support the use of PBDs as medical nutrition therapy. Within this review is support from large observational studies, which have shown that PBDs were associated with lower prevalence of type 2 diabetes. As well, intervention studies have shown that PBDs were just as effective, if not more effective, than other diabetes diets in improving body weight, cardiovascular risk factors, insulin sensitivity, glycated hemoglobin levels, oxidative stress markers and renovascular markers. Furthermore, patient acceptability was comparable to other diabetes diets, and PBDs reduced the need for diabetes medications. Diabetes education centres in Canada could improve patients' perceptions of PBDs by developing PBD-focused education and support as well as providing individualized counselling sessions addressing barriers to change. The development of more standardized and user-friendly PBD practice guidelines could overcome the disparity in recommendations and, thereby, increase how frequently practitioners recommend PBDs. Based on current published research, PBDs lend support in the management of type 2 diabetes. PMID- 27476053 TI - A simple and efficient design to improve the detection of biotin-streptavidin interaction with plasmonic nanobiosensors. AB - In this manuscript we propose a simple and efficient strategy to improve the sensitivity of localized surface plasmon resonance (LSPR) shift-based biosensors using biotin-streptavidin recognition interaction as a proof-of-concept. Specifically, biotin molecules are immobilized on a low-cost plasmonic LSPR biosensor based on annealed self-assembled spherical gold nanoparticles (AuNSs) and successively incubated with increasing concentrations of streptavidin, achieving a limit of detection (LOD) of 5nM. Interestingly, when the detection is performed by the same biotin-functionalized plasmonic AuNSs substrate but against streptavidin previously conjugated to gold nanorods, the LSPR shift is 26-fold enhanced. Moreover, we confirm these results through numerical simulations and demonstrate that the proposed sensing architecture can operate as transducer not only to confirm the adsorption of bioanalyte but also to provide the chemical identity of the capture and targeted molecules from their vibrational Raman fingerprints. Therefore, we are confident that the development of such plasmonic biosensors that use metallic labels for improving the sensitivity of detection could become highly promising for future point-of-care diagnostic assays, pushing sensitivity towards single-molecule detection limit. PMID- 27476052 TI - High Incidence of Diabetes Mellitus Among a Middle-Aged Population in Iran: A Longitudinal Study. AB - OBJECTIVES: There are few data concerning the incidence rates of diabetes in Iran. This study aimed to determine the incidence of diabetes and its risk factors in a middle-aged population in Iran. METHODS: All of the people who participated in the first phase of the Shahroud eye cohort study were invited to the study in 2014; after signing informed consent forms, a total of 4737 people 45 to 69 years of age were enrolled in the second phase of the study (participation rate: 91.3%). The 5-year incidence rate of diabetes was determined by age and sex, and we used the binomial logistic regression model to calculate the risk ratio. RESULTS: The prevalence of diabetes in the second phase was 20.19% in men, 26.45% in women and 23.89% in the total group. The 5-year incidence of diabetes was 11.19% in men, 15.55% in women and 13.73% in both sexes. With increases in age, the incidence of diabetes rose in both sexes. Age (risk ratio [RR]: 1.02; CI 95%: 1.01 to 1.03) hypertension (RR: 1.41; CI 95%: 1.15 to 1.74), being overweight (RR: 2.17; CI 95%: 1.64 to 2.88) and obesity (RR: 3.4; CI 95%: 2.53 to 4.41) were associated with increased risks for the incidence of diabetes. CONCLUSIONS: This study is 1 of the few studies in Iran that has reported the incidence of diabetes. Because the incidence of diabetes was high in the studied population, it is necessary for the health system to design and implement emergency intervention to prevent further spread of diabetes and its complications. PMID- 27476054 TI - Gold nanoparticles labeling with hybridization chain reaction amplification strategy for the sensitive detection of HepG2 cells by inductively coupled plasma mass spectrometry. AB - Sensitive detection of circulating tumor cells (CTCs) is of great significance in the early detection of cancer and cancer metastasis. This work reported an efficient, specific, and sensitive immunoassay protocol for detection of tumor cells by using inductively coupled plasma mass spectrometry (ICP-MS) with gold nanoparticles (AuNPs) labeling and hybridization chain reaction (HCR) amplification. In the established approach, antibodies against epithelial cell adhesion molecule (anti-EpCAM) conjugated magnetic beads (MBs) were used for selective capture of tumor cells from peripheral blood, aptamer was applied for the recognition of captured tumor cells, and AuNPs labeled DNA concatamer was used as the signal probe for tumor cell labeling and ICP-MS detection. Due to the dual amplification effect of AuNPs and HCR, the limit of detection of this ICP-MS based method for HepG2 cells was as low as 15 cells, and the linear range was 40 8000 cells with the relative standard deviation for seven replicate detections of 200 HepG2 cells was 8.7%. Furthermore, the applicability of the method for the analysis of peripheral blood samples was demonstrated by the spiking tests. The established method was highly specific and sensitive for the detection of HepG2 cells, and has a good application potential in clinical diagnosis. PMID- 27476055 TI - "Sign-on/off" sensing interface design and fabrication for propyl gallate recognition and sensitive detection. AB - A new strategy based on sign-on and sign-off was proposed for propyl gallate (PG) determination by an electrochemical sensor. The successively modified poly(thionine) (PTH) and molecular imprinted polymer (MIP) showed an obvious electrocatalysis and a good recognition toward PG, respectively. Furthermore, the rebound PG molecules in imprinted cavities not only were oxidized but also blocked the electron transmission channels for PTH redox. Thus, a sign-on from PG current and a sign-off from PTH current were combined as a dual-sign for PG detection. Meanwhile, the modified MIP endowed the sensor with recognition capacity. The electrochemical experimental results demonstrated that the prepared sensor possessed good selectivity and high sensitivity. A linear ranging from 5.0*10(-8) to 1.0*10(-4)mol/L for PG detection was obtained with a limit of detection of 2.4*10(-8)mol/L. And the sensor has been applied to analyze PG in real samples with satisfactory results. The simple, low cost, and effective strategy reported here can be further used to prepare electrochemical sensors for other compounds selective recognition and sensitive detection. PMID- 27476056 TI - A dual-channel fluorescent chemosensor for discriminative detection of glutathione based on functionalized carbon quantum dots. AB - A convenient, fluorescent dual-channel chemosensor on the basis of bis(3 pyridylmethyl)amine-functionalized carbon quantum dots (BPMA-CQDs) nanoprobe was constructed, and it can discriminatively detect glutathione from its analogues cysteine and homocysteine based on two distinctive strategies. Two distinct fluorescence responses of BPMA-CQDs probe to Cu(II) and Ag(I) were identified and further employed to achieve selective detection of Cu(II) and Ag(I) respectively. Based on the BPMA-CQDs/Cu(II) conjugate, discriminative detection of GSH was achieved in terms of correlation between the amounts of GSH and fluorescence recovery. The addition of GSH into BPMA-CQDs/Cu(II) system induces the reduction of Cu(II) to Cu(I), which could efficiently block PET process resulting in the following fluorescence recovery. Based on the BPMA-CQDs/Ag(I) conjugate, GSH assay could also be established on the basis of fluorescence response to GSH. The introduction of GSH into the preceding system triggers the competitive coordination to Ag(I) between BPMA and GSH, and silver ions are finally taken away by GSH from the probe, where the fluorescence is restored to its original weak state. Both of the detection strategies can achieve discriminative detection of GSH from Cys and Hcy. The assays showed good stability and repeatability, and covered a broad linear range of up to 13.3MUM with a lowest detection limit of 42.0nM. Moreover, both of them were utilized to monitor GSH level in live cells. PMID- 27476057 TI - Paper analytical devices for dynamic evaluation of cell surface N-glycan expression via a bimodal biosensor based on multibranched hybridization chain reaction amplification. AB - A novel colorimetric/fluorescence bimodal lab-on-paper cyto-device was fabricated based on concanavalin A (Con A)-integrating multibranched hybridization chain reaction (mHCR). The product of mHCR was modified PtCu nanochains (colorimetric signal label) and graphene quantum dot (fluorescence signal label) for in situ and dynamically evaluating cell surface N-glycan expression. In this strategy, preliminary detection was carried out through colorimetric method, if needed, then the fluorescence method was applied for a precise determination. Au-Ag-paper devices increased the surface areas and active sites for immobilizing larger amount of aptamers, and then specifically and efficiently captured more cancer cells. Moreover, it could effectively reduce the paper background fluorescence. Due to the specific recognition of Con A with mannose and the effective signal amplification of mHCR, the proposed strategy exhibited excellent high sensitivity for the cytosensing of MCF-7 cells ranging from 100 to 1.0*10(7) and 80-5.0*10(7) cellsmL(-1) with the detection limit of 33 and 26 cellsmL(-1) for colorimetric and fluorescence, respectively. More importantly, this strategy was successfully applied to dynamically monitor cell-surface multi-glycans expression on living cells under external stimuli of inhibitors as well as for N-glycan expression inhibitor screening. These results implied that this biosensor has potential in studying complex native glycan-related biological processes and elucidating the N glycan-related diseases in biological and physiological processes. PMID- 27476058 TI - An electrochemical label-free and sensitive thrombin aptasensor based on graphene oxide modified pencil graphite electrode. AB - In this work, we tactfully constructed a novel label-free electrochemical aptasensor for rapid and facile detection of thrombin using graphene oxide (GO) and thrombin binding aptamer (TBA). The strategy relies on the preferential adsorption of single-stranded DNA (ssDNA) to GO over aptamer-target complexes. The TBA-thrombin complex formation was monitored by differential pulse voltammetry (DPV) using the guanine oxidation signal. In the absence of thrombin, the aptamers adsorbed onto the surface of GO leading to a strong background guanine oxidation signal. Conversely, in the presence of thrombin, the conformational transformation of TBA after incubating with the thrombin solution and formation of the aptamer-thrombin complexes which had weak binding ability to GO, leads to the desorption of TBA-thrombin complex from electrode surface and significant oxidation signal decrease. The selectivity of the biosensor was studied using other biological substances. The biosensor's signal was proportional to the thrombin concentration from 0.1 to 10nM with a detection limit of 0.07nM. Particularly, the proposed method could be widely applied to the aptamer-based determination of other target analytes. PMID- 27476059 TI - Fast and sensitive detection of foodborne pathogen using electrochemical impedance analysis, urease catalysis and microfluidics. AB - Early screening of pathogenic bacteria is a key to prevent and control of foodborne diseases. In this study, we developed a fast and sensitive bacteria detection method integrating electrochemical impedance analysis, urease catalysis with microfluidics and using Listeria as model. The Listeria cells, the anti Listeria monoclonal antibodies modified magnetic nanoparticles (MNPs), and the anti-Listeria polyclonal antibodies and urease modified gold nanoparticles (AuNPs) were incubated in a fluidic separation chip with active mixing to form the MNP-Listeria-AuNP-urease sandwich complexes. The complexes were captured in the separation chip by applying a high gradient magnetic field, and the urea was injected to resuspend the complexes and hydrolyzed under the catalysis of the urease on the complexes into ammonium ions and carbonate ions, which were transported into a microfluidic detection chip with an interdigitated microelectrode for impedance measurement to determine the amount of the Listeria cells. The capture efficiency of the Listeria cells in the separation chip was ~93% with a shorter time of 30min due to the faster immuno-reaction using the active magnetic mixing. The changes on both impedance magnitude and phase angle were demonstrated to be able to detect the Listeria cells as low as 1.6*10(2)CFU/mL. The detection time was reduced from original ~2h to current ~1h. The recoveries of the spiked lettuce samples ranged from 82.1% to 89.6%, indicating the applicability of this proposed biosensor. This microfluidic impedance biosensor has shown the potential for online, automatic and sensitive bacteria separation and detection. PMID- 27476060 TI - Determination of lactic acid with special emphasis on biosensing methods: A review. AB - Lactic acid (2-Hydroxypropanoic acid) is generated from pyruvic acid under anaerobic condition in skeletal muscles, brain, red blood cells, and kidney. Lactate in normal human subjects get cleared very quickly at a rate of 320mmol/L/hr, mostly by liver metabolism and re-conversion of lactate back to pyruvate. Measurement of lactate level in serum is required for the differential diagnosis and medical management of hyperlactatemia, cardiac arrest and resuscitation, sepsis, reduced renal excretion, hypoxia induced cancer, decreased extra hepatic metabolism, intestinal infarction and lactic acidosis. Determination of lactate is also important in dairy products and beverages to access their quality. Among the various methods available for detection of lactate, most are complicated, nonspecific, less sensitive and require time consuming sample pretreatment, expensive instrumental set-up and trained persons to operate, specifically for chromatographic methods. Biosensing methods overcome these drawbacks, as these are simple, fast, specific and highly sensitive. Lactate biosensors reported so far, work optimally within 3-180s, between pH, 5.5 8.5 and temperature 22 degrees C to 37 degrees C and lactate concentration ranging from 10 to 2000uM. These biosensors have been employed to measure lactate level in embryonic cell culture, beverages, urine, and serum samples and reused upto 200-times within a period of 7-216 days. This review presents the principles, merits and demerits of various analytical methods for lactate determination with special emphasis on lactate biosensors. The future perspective for improvement of analytic performance of lactate biosensors are discussed. PMID- 27476061 TI - Fluorescence resonance energy transfer biosensor between upconverting nanoparticles and palladium nanoparticles for ultrasensitive CEA detection. AB - An ultrasensitive biosensor for carcinoembryonic antigen (CEA) was constructed based on fluorescence resonance energy transfer (FRET) between upconverting nanoparticles (UCPs) and palladium nanoparticles (PdNPs). PdNPs was synthesized by the addition of a solution of Na2PdCl4 into a mixture of N2H4.H2O as the reducing agent and 11-mercaptoundecanoic acid (MUDA) as the stabilizer. The CEA aptamer (5'-NH2-ATACCAGCTTATTCAATT-3') was conjugated to hexanedioic acid (HDA) modified UCPs (HDA-UCPs) through an EDC-NHS coupling protocol. The coordination interaction between nitrogen functional groups of the CEA aptamer and PdNPs brought UCPs and PdNPs in close proximity, which resulted in the fluorescence quenching of UCPs to an extent of 85%. And the non-specific fluorescence quenching caused by PdNPs towards HDA-UCPs was negligible. After the introduction of CEA into the UCPs-CEA aptamer-PdNPs fluorescence quenching system, the CEA aptamer preferentially combined with CEA accompanied by the conformational change which weakened the coordination interaction between the CEA aptamer and PdNPs. So fluorescence recovery of UCPs was observed and a linear relationship between the fluorescence recovery of UCPs and the concentration of CEA was obtained in the range from 2pg/mL to 100pg/mL in the aqueous buffer with the detection limit of 0.8pg/mL. The ultrasensitive detection of CEA was also realized in diluted human serum with a linear range from 4pg/mL to 100pg/mL and a detection limit of 1.7pg/mL. This biosensor makes the most of the high quenching ability of PdNPs towards UCPs with negligible non-specific fluorescence quenching and has broad application prospects in biochemistry. PMID- 27476062 TI - Is Brown Adipose Tissue-Mediated Adaptive Thermogenesis the Missing Component of the Constrained Total Energy Expenditure Model? PMID- 27476063 TI - Is the IL-6 -174G/C Gene Polymorphism Related to the Disease Severity Score in Turkish Children with Familial Mediterranean Fever? AB - Familial Mediterranean fever (FMF) is an autosomal recessively inherited disease characterized by recurrent self-limited attacks of fever accompanied by aseptic inflammation of serosal spaces, joints and skin, peritonitis, pleuritis, and arthritis. Clinical features differ according to genetics variants. The aim of this study was to identify relationship between IL-6 -174G/C gene polymorphisms and clinical features, disease severity score (DSS) and proteinuria in children diagnosed with FMF. In this study, 99 children who were followed-up in Gaziosmanpasa University Medical Faculty Department of Pediatrics and diagnosed with Familial Mediterranean fever according to Tel-Hashomer criteria were included. One hundred and fifty seven children who admitted to the hospital with any complain and found healthy included in control group. Genotyping was done for polymorphism in a promoter region of IL-6 gene (G/C at -174). The IL-6 -174G/C gene polymorphism and the clinical features of FMF, proteinuria, the DSS, and the healthy control group were investigated. Data for the clinical features were obtained retrospectively from the electronic records of patients. All of the genotyping of blood samples were done in Medical Genetic laboratory of Gaziosmanpasa University School of Medicine. The results revealed that the distribution of the genotypes and allele frequencies of the IL-6 -174G/C polymorphism were not significantly different between the FMF patients and the healthy controls. The IL-6 -174G/C polymorphisms did not affect proteinuria, the DSS, and the clinical features of FMF patients. PMID- 27476064 TI - A study to investigate the factors that influence the prescribing habits of non consultant hospital doctors in Ireland. AB - BACKGROUND: The Health Service Executive estimates it spent just under ?2 billion on medicines in 2013 following a fivefold increase in the cost of medicines over the preceding decade. With this increasing cost, it is important to understand what factors affect doctors prescribing. AIMS: To investigate the influencing factors on prescribing of non-consultant hospital doctors (NCHDs) in Irish hospitals and to provide data regarding the sources of information NCHD's use for commonly prescribed drugs. METHODS: All medical manpower offices of adult public hospitals in the Republic of Ireland were emailed with our survey for distribution to NCHDs. It contained demographic information and questions regarding factors which most influence their prescribing of particular drug groups. Tests of significance were carried out using Chi-square. RESULTS: One hundred and seventy-nine surveys were returned out of a possible 8987 (0.02 %). Consultant preference was the biggest overall influencing factor on junior doctors prescribing (27 %). This was closely followed by local departmental policies (26 %). Evidence-based prescribing only influenced 14 % of the total prescribing of NCHDs with the pharmaceutical representative influence only a fraction behind (13 %). Knowledge obtained during medical school greater influenced postgraduate prescribing than undergraduate (34 vs 14 %, p = 0.046). Registrars were significantly more likely to prescribe using evidence-based medicine than intern and SHOs (p = 0.03). CONCLUSIONS: The prescription of medications in Ireland by NCHDs varies greatly depending not only on drug group, but it is also affected by the doctors' previous education and experience. This information is key in leading to sensible cost-effective prescribing. PMID- 27476065 TI - Streptomyces castaneus sp. nov., a novel actinomycete isolated from the rhizosphere of Peucedanum praeruptorum Dunn. AB - During an investigation of microbial diversity in medicinal herbs, a novel actinomycete, strain NEAU-QHHV11T was isolated from the rhizosphere of Peucedanum praeruptorum Dunn collected from Xianglu Mountain in Heilongjiang Province, northeast China and characterized using a polyphasic approach. The organism was found to have typical characteristics of the genus Streptomyces. Phylogenetic analysis based on 16S rRNA gene sequence also indicated that strain NEAU-QHHV11T belongs to the genus Streptomyces and was most closely related to Streptomyces graminilatus NBRC 108882T (98.7 % sequence similarity) and Streptomyces turgidiscabies NBRC 16080T (98.7 % sequence similarity). The results of DNA-DNA hybridization and some phenotypic characteristics indicated that strain NEAU QHHV11T could be distinguished from its close phylogenetic relatives. Thus, strain NEAU-QHHV11T represents a novel species of the genus Streptomyces, for which the name Streptomyces castaneus sp. nov. is proposed. The type strain is NEAU-QHHV11T (=CGMCC 4.7235T = DSM 100520T). PMID- 27476066 TI - Intrarater reliability of hand held dynamometry in measuring lower extremity isometric strength using a portable stabilization device. AB - Hand held dynamometry (HHD) is a more objective way to quantify muscle force production (MP) compared to traditional manual muscle testing. HHD reliability can be negatively impacted by both the strength of the tester and the subject particularly in the lower extremities due to larger muscle groups. The primary aim of this investigation was to assess intrarater reliability of HHD with use of a portable stabilization device for lower extremity MP in an athletic population. Isometric lower extremity strength was measured for bilateral lower extremities including hip abductors, external rotators, adductors, knee extensors, and ankle plantar flexors was measured in a sample of healthy recreational runners (8 male, 7 females, = 30 limbs) training for a marathon. These measurements were assessed using an intrasession intrarater reliability design. Intraclass correlation coefficients (ICC) were calculated using 3,1 model based on the single rater design. The standard error of measurement (SEM) for each muscle group was also calculated. ICC were excellent ranging from ICC (3,1) = 0.93-0.98 with standard error of measurements ranging from 0.58 to 17.2 N. This study establishes the use of a HHD with a portable stabilization device as demonstrating good reliability within testers for measuring lower extremity muscle performance in an active healthy population. PMID- 27476068 TI - Cu (II) Chemosensor Based on a Fluorogenic Bodipy-Salophen Combination: Sensitivity and Selectivity Studies. AB - A new fluorescent chemosensor (Bodipy-S) derived from Bodipy and Salophen was developed. After the characterization of all compounds, the behavior of the chemosensor Bodipy-S toward p, d and f block-metal ions was investigated by UV vis and fluorescence spectroscopy. This chemosensor can selectively detect to Cu (II) in methanol-aqueous solution based on chelation enhanced fluorescence (CHEF) and it almost exhibit to a fluorescence quenching effect with 20-fold. The binding constant of the fluorophore was interpreted by using of the Stern-Volmer method and the complex stoichiometry was defined by using Job's plot. Moreover, the effect of pH was performed by the fluorescence intensities of Bodipy-S in presence of Cu(II) ions. The chemosensor can be successfully used to the detection of Cu(II) in most areas. PMID- 27476067 TI - Treatment of Sleep Disorders in Dementia. AB - OPINION STATEMENT: Sleep and circadian disorders occur frequently in all types of dementia. Due to the multifactorial nature of sleep problems in dementia, we propose a structured approach to the evaluation and treatment of these patients. Primary sleep disorders such as obstructive sleep apnea should be treated first. Comorbid conditions and medications that impact sleep should be optimally managed to minimize negative effects on sleep. Patients and caregivers should maintain good sleep hygiene, and social and physical activity should be encouraged during the daytime. Given the generally benign nature of bright light therapy and melatonin, these treatments should be tried first. Pharmacological treatments should be added cautiously, due to the risk of cognitive side effects, sedation, and falls in the demented and older population. Regardless of treatment modality, it is essential to follow patients with dementia and sleep disorders closely, with serial monitoring of individual response to treatment. PMID- 27476069 TI - Photophysical Behavior and Computational Investigation of Novel 1,4-Bis(2-(2 Phenylpyrimido[1,2-a]Benzimidazol-4-Yl)Phenoxy)Butan (BPPB) Macromolecule. AB - A new macromolecule pyrimido[l,2-a]benzimidazole derivative named 1,4-bis(2-(2 phenylpyrimido[1,2-a]benzimidazol-4-yl)phenoxy)butan (BPPB) has been synthesized in accepted yield using microwave assistance. The new compound BPPB has been formed by the interaction of 3,3'-((butane-1,4-diylbis(oxy))bis(2,1 phenylene))bis(1-phenylprop-2-en-1-one) (3) with 2- aminobenzimidazole (4) in the presence of potassium hydroxide as a basic catalyst in dimethylformamide (DMF) under microwave radiation for 20 min. The chemical structure of this novel compound was elucidated by elemental and spectral techniques including: FT-IR, (1)H-NMR, (13)C-NMR and mass spectra. The electronic absorption and emission spectra of BPPB were measured in different solvents. BPPB displayed a solvatochromic effect of the emission spectrum that is reflected by red shifts of its fluorescence emission maxima on increasing the solvent polarity, indicating a change of electronic charge distribution upon excitation. BPPB crystalline solids gave excimer-like emission at 535 nm with a bandwidth of ca. 60 nm. Ground and excited states electronic geometry optimizations using density functional theory (DFT) and time-dependent density functional theory (TD-DFT), respectively, complemented these spectral findings. The intramolecular charge transfer was investigated by natural bond orbital (NBO) technique. PMID- 27476071 TI - Soil salinisation and irrigation management of date palms in a Saharan environment. AB - The continuance of agricultural production in regions of the world with chronic water shortages depends upon understanding how soil salinity is impacted by irrigation practises such as water salinity, irrigation frequency and amount of irrigation. A two-year field study was conducted in a Saharan oasis of Tunisia (Lazala Oasis) to determine how the soil electrical conductivity was affected by irrigation of date palms with high saline water. The study area lacked a saline shallow water table. Field results indicate that, under current irrigation practises, soil electrical conductivity can build up to levels which exceed the salt tolerance of date palm trees. The effects of irrigation practises on the soil electrical conductivity were also evaluated using model simulations (HYDRUS 1D) of various irrigation regimes with different frequencies, different amounts of added water and different water salinities. The comparison between the simulated and observed results demonstrated that the model gave an acceptable estimation of water and salt dynamics in the soil profile, as indicated by the small values of root mean square error (RMSE) and the high values of the Nash Sutcliffe model efficiency coefficient (NSE). The simulations demonstrated that, under field conditions without saline shallow groundwater, saline irrigation water can be used to maintain soil electrical conductivity and soil water content at safe levels (soil electrical conductivity <4 dS m(-1) and soil water content >0.04 cm(3) cm(-3)) if frequent irrigations with small amounts of water (90 % of the evapotranspiration requirements) were applied throughout the year. PMID- 27476070 TI - Omentin concentrations are independently associated with those of matrix metalloproteinase-3 in patients with mild but not severe rheumatoid arthritis. AB - Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, 3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [beta = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [beta (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [beta (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [beta (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [beta (SE) = -0.286 (0.202), p = 0.2], and in those with a small [beta (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [beta (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [ 0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA. PMID- 27476072 TI - The effect of glycaemic control in type 2 diabetic patients with subclinical hypothyroidism. AB - OBJECTIVE: The purpose of this study was to investigate the effect of glycaemic control on subclinical hypothyroidism (SCH) in Chinese type 2 diabetic patients. METHODS: The study included 476 diabetic patients with SCH admitted for treatment of type 2 diabetes. The controls were selected euthyroid patients with similar characteristics regarding [age, body mass index (BMI), gender, previous hypertension or duration of diabetes, and smoke]. Total cholesterol (TC), LDL cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), the homeostatic model assessment of insulin resistance ratio (HOMA-IR), fasting plasma glucose, hemoglobin A1c (HbA1c), as well as plasma levels of thyrotrophin, and free thyroxine (FT4) were assessed at baseline and after 6 months of glycaemic control treatment. RESULTS: The LDL-C level and HOMA-IR value were significantly higher in the SCH group. Glycaemic control reduced HOMA-IR, HbA1c, LDL-C, and TG level in patients with SCH. Furthermore, glycaemic control plays a negative effect on thyrotrophin in the SCH group, while this effect was not observed in euthyroid subjects. HbA1c plays a positive correlation with HOMA IR (r = 0.048, p < 0.001), fasting plasma glucose (r = 0.086, p < 0.001), LDL-C (r = 0.062, p < 0.001) and TG (r = 0.021, p = 0.009). CONCLUSION: Our study shows that glycaemic control may bring some benefits to type 2 diabetic patients with SCH. PMID- 27476074 TI - [Gastroschisis: A pandemic with increasing rates? ECLAMC experience in Chile 1982 2015]. AB - INTRODUCTION: Several communications have reported a significant increase in the prevalence of gastroschisis at birth in the last three decades. In many Countries it is referred to as "a pandemic strongly associated to low maternal age". OBJECTIVE: To verify if there has been a significant increase in the prevalence of gastroschisis at birth in Chile, and if this rate is associated with a low maternal age. PATIENTS AND METHODS: The study was performed using the ECLAMC data base from 26 Chilean Hospitals. Comparison between prevalence rates and maternal age categories were made using the X2 test or Fisher exact Test. The time series was studied comparing average tendencies using the Student t test and Wilcoxon test. RESULTS: There were 721,901 newborns in the period 1982-2014, among which 107 were diagnosed with gastroschisis (1.48/10,000). Around three-quarters (75.7%) of them were born from mothers younger than 25. The mean maternal age was 21.6 years in mothers of children with gastroschisis, while the mean maternal age of all mothers from Chile was almost 28 years old. The gastroschisis prevalence at birth rate was constant at around 1/10,000 until 1994. From 1995 this rate has a significant increasing tendency of 0.1591 by year (P=.00714). This increase is about a 300% on average for the 1995-2014 period, compared with the previous one (P<.00001). CONCLUSION: There has been a significant increase in the gastroschisis prevalence at birth in Chile from 1995, and this anomaly is associated with a low maternal age. PMID- 27476073 TI - Inequalities and Barriers to the Use of Supportive Care Among Young Breast Cancer Survivors: a Qualitative Understanding. AB - The development of supportive care for cancer patients has been shown to have a positive impact on both mortality rates and many aspects of life after cancer, particularly in young women. Meanwhile, there are still numerous inequalities in terms of cancer mortalities and quality of life among cancer survivors in France. The processes leading to unequal access to supportive care services, and the impact this has on the post-treatment period, have been poorly documented, however. The goal of this study was to understand the barriers to using supportive care services among young women breast cancer survivors under the age of 50 and to find out how this can contribute to inequalities. Thirty-six young breast cancer survivors, one third of which deemed socially deprived, were interviewed using a qualitative, inductive approach at two comprehensive care centres in France. Our findings primarily show that there are still a number of barriers to accessing supportive care for a large number of patients. The way information about supportive services is delivered is a major cause of inequalities in the use of these services. The guidance provided does not take into account either the patients' needs or their capacity to integrate the information and anticipate problems. Certain specific post-treatment issues have yet to be addressed. Some systemic barriers could be lifted by changing the way information on supportive care services is currently organised and thereby prevent the survivorship plans now being implemented in cancer care settings from reinforcing health inequalities. PMID- 27476075 TI - Spleen Tyrosine Kinase: A Crucial Player and Potential Therapeutic Target in Renal Disease. AB - Spleen tyrosine kinase (Syk), a 72 kDa cytoplasmic non-receptor protein-tyrosine kinase, plays an important role in signal transduction in a variety of cell types. Ever since its discovery in the early 1990s, there has been accumulating evidence to suggest a pathogenic role of Syk in various allergic disorders, autoimmune diseases and malignancies. Additionally, there is emerging data from both pre-clinical and clinical studies that Syk is implicated in the pathogenesis of proliferative glomerulonephritis (GN), including anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic antibody-associated GN, lupus nephritis and immunoglobulin A nephropathy (IgAN). Moreover, recent animal studies have shed light on the importance of Syk in mediating acute renal allograft rejection, Epstein Barr virus-associated post-transplant lymphoproliferative disease and kidney fibrosis. Fostamatinib, an oral Syk inhibitor, has undergone clinical testing in rheumatoid arthritis, refractory immune thrombocytopenic purpura, leukemia and lymphoma. The recent STOP-IgAN trial showed that the addition of non-selective immunosuppressive therapy to intensive supportive care did not improve clinical outcomes in high-risk IgAN patients. A Syk-targeted approach may be beneficial and is currently being evaluated in a phase II randomized controlled trial. In this review, we will discuss the pathogenic role of Syk and potential use of Syk inhibitor in a variety of renal diseases. PMID- 27476076 TI - Toxin-antitoxins and bacterial virulence. AB - Bacterial virulence relies on a delicate balance of signals interchanged between the invading microbe and the host. This communication has been extensively perceived as a battle involving harmful molecules produced by the pathogen and host defenses. In this review, we focus on a largely unexplored element of this dialogue, as are toxin-antitoxin (TA) systems of the pathogen. TA systems are reported to respond to stresses that are also found in the host and, as a consequence, could modulate the physiology of the intruder microbe. This view is consistent with recent studies that demonstrate a contribution of distinct TA systems to virulence since their absence alters the course of the infection. TA loci are stress response modules that, therefore, could readjust pathogen metabolism to favor the generation of slow-growing or quiescent cells 'before' host defenses irreversibly block essential pathogen activities. Some toxins of these TA modules have been proposed as potential weapons used by the pathogen to act on host targets. We discuss all these aspects based on studies that support some TA modules as important regulators in the pathogen-host interface. PMID- 27476077 TI - DNA methyltransferases and epigenetic regulation in bacteria. AB - Epigenetics is a change in gene expression that is heritable without a change in DNA sequence itself. This phenomenon is well studied in eukaryotes, particularly in humans for its role in cellular differentiation, X chromosome inactivation and diseases like cancer. However, comparatively little is known about epigenetic regulation in bacteria. Bacterial epigenetics is mainly present in the form of DNA methylation where DNA methyltransferases add methyl groups to nucleotides. This review focuses on two methyltransferases well characterized for their roles in gene regulation: Dam and CcrM. Dam methyltransferase in Escherichia coli is important for expression of certain genes such as the pap operon, as well as other cellular processes like DNA replication initiation and DNA repair. In Caulobacter crescentus and other Alphaproteobacteria, the methyltransferase CcrM is cell cycle regulated and is involved in the cell-cycle-dependent regulation of several genes. The diversity of regulatory targets as well as regulatory mechanisms suggests that gene regulation by methylation could be a widespread and potent method of regulation in bacteria. PMID- 27476081 TI - Formal analysis of the surgical pathway and development of a new software tool to assist surgeons in the decision making in primary breast surgery. AB - BACKGROUND: The increased complexity of the decisional process in breast cancer surgery is well documented. With this study we aimed to create a software tool able to assist patients and surgeons in taking proper decisions. METHODOLOGY: We hypothesized that the endpoints of breast cancer surgery could be addressed combining a set of decisional drivers. We created a decision support system software tool (DSS) and an interactive decision tree. A formal analysis estimated the information gain derived from each feature in the process. We tested the DSS on 52 patients and we analyzed the concordance of decisions obtained by different users and between the DSS suggestions and the actual surgery. We also tested the ability of the system to prevent post breast conservation deformities. RESULTS: The information gain revealed that patients preferences are the root of our decision tree. An observed concordance respectively of 0.98 and 0.88 was reported when the DSS was used twice by an expert operator or by a newly trained operator vs. an expert one. The observed concordance between the DSS suggestion and the actual decision was 0.69. A significantly higher incidence of post breast conservation defects was reported among patients who did not follow the DSS decision (Type III of Fitoussi, N = 4; 33.3%, p = 0.004). CONCLUSION: The DSS decisions can be reproduced by operators with different experience. The concordance between suggestions and actual decision is quite low, however the DSS is able to prevent post- breast conservation deformities. PMID- 27476080 TI - Predictive model for recovery of visual field after surgery of pituitary adenoma. AB - Visual field defect is a major indication for surgery of pituitary adenoma, but visual outcome after surgery is difficult to predict. We developed a nomogram that predicts postoperative restoration of visual field defects in patients with pituitary adenoma. This study was a retrospective cohort investigation of patients who were treated for pituitary adenoma between January 2009 and December 2013. We enrolled 111 eyes of 57 patients who completed one ophthalmological evaluation preoperatively and at least two evaluations within 6 months after surgery. Serial changes in visual fields and retinal nerve fiber layer (RNFL) thickness were evaluated. Multiple logistic regression analysis was performed to select prognostic variables, and a nomogram to predict restoration of visual field defects was constructed. Visual field defects continuously improved until 3 months after surgery. However, average, superior, and inferior RNFL thickness continuously decreased until 6 months after surgery. Multiple logistic regression analysis revealed that worse preoperative visual field defect (p = 0.018), high MRI compression grade (p = 0.009), and inferior RNFL thinning (p = 0.011) were significantly associated with worse visual outcome. The nomogram that predicts the visual restoration showed an area under the receiver operating characteristic curve of 0.84. In conclusion, we developed a nomogram that predicted the restoration of visual field defects after removal of pituitary adenoma. This would allow tailored counseling of individual patients by precisely predicting visual recovery after surgery. PMID- 27476082 TI - Treatment of the benign inverted nipple: A systematic review and recommendations for future therapy. AB - The inverted nipple is a frequently encountered problem which can cause difficulties with breastfeeding, sexuality, and aesthetic dissatisfaction. Up to now, no consensus exists on a preferred treatment method. We performed a systematic review to identify the best treatment method for correction of benign inverted nipples. Treatment techniques were subdivided in the categories lactiferous duct preserving and lactiferous duct damaging. A systematic review was performed using the PRISMA statement. Inclusion criteria were: female patients with congenital or acquired inverted nipples, a minimum sample size of 10 nipples, and studies reporting recurrence of inversion with a minimum follow up of six months. Exclusion criteria were nipple inversion caused by malignancy. Thirteen studies met the inclusion criteria which all had a level of evidence IV. No non-invasive treatment techniques were identified. In the duct preserving category eight studies were included with a recurrence rate of 0.6% (2/350) versus 9.9% (16/161) in the duct damaging category (n = 5). Other outcome parameters were not systematically reported in all studies. Because of a small number of low quality studies with heterogeneous interventions and outcomes a meta-analysis could not be performed and no preferred treatment method was identified. Based on the available data there is no statistical evidence that duct damaging treatment is superior to duct preserving treatment. We recommend that the first method of choice should be a duct preserving treatment method. In the future, more studies of better methodological quality are required and recommendations were made on how these could be conducted. PMID- 27476079 TI - Protein phosphorylation and its role in archaeal signal transduction. AB - Reversible protein phosphorylation is the main mechanism of signal transduction that enables cells to rapidly respond to environmental changes by controlling the functional properties of proteins in response to external stimuli. However, whereas signal transduction is well studied in Eukaryotes and Bacteria, the knowledge in Archaea is still rather scarce. Archaea are special with regard to protein phosphorylation, due to the fact that the two best studied phyla, the Euryarchaeota and Crenarchaeaota, seem to exhibit fundamental differences in regulatory systems. Euryarchaeota (e.g. halophiles, methanogens, thermophiles), like Bacteria and Eukaryotes, rely on bacterial-type two-component signal transduction systems (phosphorylation on His and Asp), as well as on the protein phosphorylation on Ser, Thr and Tyr by Hanks-type protein kinases. Instead, Crenarchaeota (e.g. acidophiles and (hyper)thermophiles) only depend on Hanks type protein phosphorylation. In this review, the current knowledge of reversible protein phosphorylation in Archaea is presented. It combines results from identified phosphoproteins, biochemical characterization of protein kinases and protein phosphatases as well as target enzymes and first insights into archaeal signal transduction by biochemical, genetic and polyomic studies. PMID- 27476083 TI - Factors influencing acute and late toxicity in the era of adjuvant hypofractionated breast radiotherapy. AB - PURPOSE: To evaluate toxicity in breast cancer patients treated with anthracycline and taxane based chemotherapy and whole breast hypofractionated radiotherapy, and to identify the risk factors for toxicity. METHODS AND MATERIALS: 537 early breast cancer patients receiving hypofractionated radiotherapy after conservative surgery were enrolled from April 2009 to December 2014, in an Italian cancer institute. The dose was 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction. The boost to the tumor bed was administered only in grade III breast cancer patients and in patients with close or positive margins. Acute and late toxicity were prospectively assessed during and after radiotherapy according to RTOG scale. The impact of patients clinical characteristics, performed treatments and dose inhomogeneities on the occurrence of an higher level of acute skin toxicity and late fibrosis has been evaluated by univariate and multivariate analysis. RESULTS: The mean age was 74 (range 46-91 yrs). 27% of patients received boost. 22% of cases (n = 119) received also chemotherapy. The median follow-up was 32 months. G1 and G2/G3 acute skin toxicity were 61.3% and 20.5% and G1 and G2/G3 late fibrosis 12.6% and 4.3% respectively. Chemotherapy (p = 0.04), diabetes (p = 0.04) and boost administration (p < 0.01) were found to be statistically significant on the occurrence of late fibrosis, but a multivariate analysis did not show any factors connected. The boost administration (p < 0.01), the breast volume (p = 0.05), dose inhomogeneities (p < 0.01) and boost volume (p = 0.04) were found to be statistically significant as concerns the occurrence of acute skin reaction at the univariate analysis, but only the boost administration (p = 0.02), at multivariate analysis. CONCLUSIONS: The results of our study, according to the large randomized trials, confirmed that hypofractionated whole breast irradiation is safe, and only the boost administration seems to be an important predictor for toxicity. Chemotherapy does not impact on acute and late skin toxicity. PMID- 27476085 TI - Clinical Characterization of Gastric Antral Vascular Ectasia: A Potential Manifestation of the Metabolic Syndrome. AB - BACKGROUND AND OBJECTIVES: Gastric antral vascular ectasia is a relatively common endoscopic finding. Past studies have shown an association of gastric antral vascular ectasia with cirrhosis and autoimmune disorders. We aimed to re-examine these associations and to investigate a possible association of gastric antral vascular ectasia with features of the metabolic syndrome. METHODS: There were 135 patients with a diagnosis of gastric antral vascular ectasia from years 1995-2013 seen at the University of Virginia who were identified from a clinical data repository and age and sex matched to a cohort of patients without gastric antral vascular ectasia undergoing endoscopy within the same time frame as the index cases. The groups were compared for comorbidities including autoimmune disease, cirrhosis, vascular disease, body mass index (BMI), diabetes mellitus, and cirrhosis due to nonalcoholic steatohepatitis. RESULTS: Sixty-four percent of gastric antral vascular ectasia patients were cirrhotic, compared with 14% of controls (P <.001). Vascular disease was more common in the gastric antral vascular ectasia cohort (57% vs 36%; P <.001). The mean BMI was also higher in the gastric antral vascular ectasia cohort (33.7 kg/m2 vs 28.8 kg/m2; P <.001). Diabetes mellitus and nonalcoholic steatohepatitis cirrhosis were more frequently observed in gastric antral vascular ectasia subjects (64% vs 29% in controls [P <.001] and 28% vs 2% [P <.001], respectively). There was not an increased prevalence of autoimmune disease in gastric antral vascular ectasia patients vs controls (15% vs 13%; P = .861). CONCLUSION: These results confirm the association of gastric antral vascular ectasia with underlying cirrhosis and revealed a significant correlation of gastric antral vascular ectasia with features of metabolic syndrome such as diabetes, BMI, vascular disease, and nonalcoholic steatohepatitis cirrhosis. The pathophysiology of gastric antral vascular ectasia remains uncertain, but we speculate that it may be a manifestation of the metabolic syndrome. PMID- 27476084 TI - Safety analysis, association with response and previous treatments of everolimus and exemestane in 181 metastatic breast cancer patients: A multicenter Italian experience. AB - PURPOSE: The everolimus and exemestane combination represents a treatment option for the endocrine sensitive metastatic breast cancer (MBC) patients. The toxicity profile reported in the Bolero 2 trial showed the feasibility in the selected patients. Few data are available for the unselected population. METHODS: In order to evaluate the safety in the unselected population of the clinical practice and to evaluate a possible association of toxicities with previous treatments, clinical data from 181 consecutive patients were retrospectively collected. RESULTS: Due to toxic events, everolimus dosage was reduced to 5 mg in 27% of patients. No association was found in the analysis between toxicity and number of prior therapies, neither between toxicity and response. In the multivariate analysis the previous exposure to anthracyclines for advanced disease represents the only predictive factor of developing grade >=2 toxicity (OR = 2.85 CI 95% 1.07-7.59, p = 0.036). CONCLUSIONS: The association of everolimus and exemestane has confirmed to be a safe and effective treatment for endocrine sensitive MBC patients even in routine clinical practice. The rate of treatment discontinuation due to toxicity is low and none association between previous number of treatments and response or between toxicity and response was found. PMID- 27476086 TI - Optimal Treatment Strategies in Patients with Chronic Kidney Disease and Coronary Artery Disease. AB - BACKGROUND: Chronic kidney disease is an independent risk factor for coronary artery disease and is associated with an increase in adverse outcomes. However, the optimal treatment strategies for patients with chronic kidney disease and coronary artery disease are yet to be defined. METHODS: MEDLINE, EMBASE, and CENTRAL were searched for studies including at least 100 patients with chronic kidney disease (defined as estimated glomerular filtration rate <=60 mL/min/1.73 m2 or on dialysis) and coronary artery disease treated with medical therapy, percutaneous coronary intervention, or coronary artery bypass surgery and followed for at least 1 month and reporting outcomes. The outcome evaluated was all-cause mortality. Meta-analysis was performed to evaluate the outcomes with revascularization (percutaneous coronary intervention or coronary artery bypass surgery) when compared with medical therapy alone. In addition, outcomes with percutaneous coronary intervention vs coronary artery bypass surgery were evaluated. RESULTS: The search yielded 38 nonrandomized studies that enrolled 85,731 patients. Revascularization (percutaneous coronary intervention or coronary artery bypass surgery) was associated with lower long-term mortality (mean 4.0 years) when compared with medical therapy alone (relative risk [RR] 0.73; 95% confidence interval [CI], 0.62-0.87), driven by lower mortality with percutaneous coronary intervention vs medical therapy and coronary artery bypass surgery vs medical therapy. Coronary artery bypass surgery was associated with a higher upfront risk of death (RR 1.81; 95% CI, 1.47-2.24) but a lower long-term risk of death (RR 0.94; 95% CI, 0.89-0.98) when compared with percutaneous coronary intervention. CONCLUSIONS: In chronic kidney disease patients with coronary artery disease, the current data from nonrandomized studies indicate lower mortality with revascularization, via either coronary artery bypass surgery or percutaneous coronary intervention, when compared with medical therapy. These associations should be tested in future randomized trials. PMID- 27476088 TI - CpG-ODN promotes phagocytosis and autophagy through JNK/P38 signal pathway in Staphylococcus aureus-stimulated macrophage. AB - AIMS: Phagocytic and autophagic responses are critical for effective host defense against bacterial infection. Bacterial DNA which contains unmethylated Cytosine phosphate-Guanine (CpG) motifs can trigger a variety of defense mechanisms via Toll-like receptor 9 (TLR9). Here, we aimed to investigate the underlying mechanism of TLR9-mediated phagocytosis and autophagy in Staphylococcus aureus (S.aureus)-stimulated macrophages. MAIN METHODS: The macrophage cell line RAW264.7 or primary peritoneal macrophage was pretreated with CpG-ODN and then stimulated by S. aureus, where some of them were pretreated with SP600125 or SB203580 simultaneously. The protein expressions of TLR9, MyD88, SR-A, CD36, LC3, Beclin-1, and phosphorylated level of c-Jun N-terminal kinase (JNK), P38 and extracellular-regulated protein kinase (ERK) were detected by western blotting. The phagocytosis and LC3 punctate-structures of macrophage were observed by confocal laser scanning microscope. KEY FINDINGS: CpG-ODN significantly amplified S. aureus-induced phagocytosis and autophagy of RAW264.7 and TLR9(+/+) primary peritoneal macrophage as compared to that of Non-CpG treated cells, while such effect was abolished in TLR9(-/-) primary peritoneal macrophages. Meanwhile, CpG ODN significantly enhanced S. aureus-induced phosphorylation of JNK and P38 but not ERK in RAW264.7. Specific inhibition of JNK or P38 by SP600125 or SB203580, dramatically down-regulated CpG-induced phagocytosis and autophagy in S. aureus stimulated RAW264.7 and TLR9(+/+) primary peritoneal macrophage, while they showed no further down-regulation of phagocytosis and autophagy in TLR9(-/-) primary peritoneal macrophages. SIGNIFICANCE: Our data indicated that CpG-ODN activates TLR9-JNK/P38 signaling to promote phagocytosis and autophagy in S. aureus-stimulated macrophages, these findings provide novel insights into how innate immune cells defend bacterial infection via TLR9. PMID- 27476087 TI - Causes of Death and Influencing Factors in Patients with Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation is associated with a higher mortality, but causes of death of atrial fibrillation patients and their specific predictors have been less well defined. We aimed to identify the causes of death among atrial fibrillation patients and secondly, clinical predictors for the different modes of deaths. METHODS: Patients diagnosed with atrial fibrillation in a four hospital institution between 2000 and 2010 were identified. During a follow-up of 929 +/- 1082 days (median 456, interquartile 10-1584), 1253 deaths were recorded (yearly rate 5.5%). RESULTS: Cardiovascular deaths accounted for 54% and noncardiovascular for 43%. The three main causes of death were heart failure (29%), infection (18%), and cancer (12%). Fatal stroke or fatal bleeding each accounted for 7% of all deaths. On multivariate analysis, the strongest predictors of death were permanent atrial fibrillation, heart failure (whether with decreased or with preserved ejection fraction), previous bleeding, and renal failure, which were independently associated with an increase in the risk of all cause mortality (35%, 78%, 42%, and 79%, respectively), cardiovascular mortality (43%, 129%, 46%, and 93%, respectively), and noncardiovascular mortality (21%, 45%, 40%, and 50%, respectively). Oral anticoagulant use was independently associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.62; 95% confidence interval [CI], 0.54-0.71; P <.0001), cardiovascular mortality (HR 0.60; 95% CI, 0.49-0.72; P <.0001), and noncardiovascular mortality (HR 0.60; 95% CI, 0.49-0.74; P <.0001). CONCLUSIONS: The majority of deaths were related to a cardiovascular origin, and heart failure was the most common cause of death in atrial fibrillation patients. Despite the high risk of stroke associated with atrial fibrillation, only 7% died from stroke. Optimization of management of any underlying heart disease and associated comorbidities should be a relevant therapeutic target to reduce total mortality in atrial fibrillation patients. PMID- 27476089 TI - Hyperacute Valve Thrombosis After Transapical Transcatheter Aortic Valve Replacement in a Patient With Polycythemia Vera. PMID- 27476090 TI - Spontaneous Giant Ascending Aortic Pseudoaneurysm in a Previously Healthy Man. PMID- 27476091 TI - Bioresorbable Vascular Scaffolds in Routine Clinical Practice: Should We Wait Longer? PMID- 27476092 TI - Orbital Atherectomy-Induced Coronary Fistula: Complication and Treatment. PMID- 27476093 TI - Transcatheter Aortic and Mitral Valve Replacement and Closure of Mitral Ring Perivalvular Leaks. PMID- 27476094 TI - Mid- to Long-Term Clinical Outcomes of Patients Treated With the Everolimus Eluting Bioresorbable Vascular Scaffold: The BVS Expand Registry. AB - OBJECTIVES: This study sought to report on clinical outcomes beyond 1 year of the BVS Expand registry. BACKGROUND: Multiple studies have proven feasibility and safety of the Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California). However, data on medium- to long-term outcomes are limited and available only for simpler lesions. METHODS: This is an investigator initiated, prospective, single-center, single-arm study evaluating performance of the BVS in a lesion subset representative of daily clinical practice, including calcified lesions, total occlusions, long lesions, and small vessels. Inclusion criteria were patients presenting with non-ST-segment elevation myocardial infarction, stable/unstable angina, or silent ischemia caused by a de novo stenotic lesion in a native previously untreated coronary artery. Procedural and medium- to long-term clinical outcomes were assessed. Primary endpoint was major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and target lesion revascularization. RESULTS: From September 2012 to January 2015, 249 patients with 335 lesions were enrolled. Mean number of scaffolds per patient was 1.79 +/- 1.15. Invasive imaging was used in 39%. In 38.1% there were American College of Cardiology/American Heart Association classification type B2/C lesions. Mean lesion length was 22.16 +/- 13.79 mm. Post procedural acute lumen gain was 1.39 +/- 0.59 mm. Median follow-up period was 622 (interquartile range: 376 to 734) days. Using Kaplan-Meier methods, the MACE rate at 18 months was 6.8%. Rates of cardiac mortality, myocardial infarction, and target lesion revascularization at 18 months were 1.8%, 5.2%, and 4.0%, respectively. Definite scaffold thrombosis rate was 1.9%. CONCLUSIONS: In our study, BVS implantation in a complex patient and lesion subset was associated with an acceptable rate of adverse events in the longer term, whereas no cases of early thrombosis were observed. PMID- 27476095 TI - Parallel Wire Technique With 40-g Tip-Load Guidewire for Severely Calcified Chronic Total Occlusion in the Infrainguinal Artery: Heaviness Makes the Difference. PMID- 27476096 TI - Reply to "Breast MRI background parenchymal enhancement (BPE) correlates with the risk of breast cancer". PMID- 27476097 TI - Assessment of cochlear nerve deficiency and its effect on normal maturation of auditory tract by diffusion kurtosis imaging and diffusion tensor imaging: A correlational approach. AB - OBJECTIVE: The use of diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) was evaluated in assessing cochlear nerve deficiency (CND) and its effect on normal maturation of auditory tract. METHODS: 25 CND patients and 25 controls (age matched: 2months to 17years, gender matched) were evaluated by mean kurtosis (MK), axial kurtosis, and radial kurtosis and compared against fractional anisotropy (FA), axial and radial diffusivities in internal auditory canal (IAC), lateral lemniscus (LL) and inferior colliculus (IC). The age related changes of auditory tract were studied through Pearson correlation between estimated indices and age of both CND and control populations. RESULTS: Significant loss of MK (IAC: 10.71%, IC: 10.87%, LL: 15.63%) was observed in CND cases as against moderate reduction in FA (IAC: 8.57%, IC: 10%, LL: 7.69%) in all three anatomical locations. Similarly, substantial decline is observed in radial kurtosis (IAC: 27.03%, IC: 33.33%, LL: 31.43%) in comparison to moderate increase in radial diffusivity (IAC: 13.46%, IC: 24.39%, LL: 24%) in CND cases. No statistically significant change was seen in both axial kurtosis and diffusivities. In control populations, MK (r=0.473, p=0.011) and radial kurtosis (r=0.418, p=0.016) correlate positively with age and had no correlation in case of CND cases. FA (r=0.356, p=0.019) minimally correlated with age in control population but showed no statistically significant correlation in CND cases (r=0.198, p=0.036). CONCLUSION: DKI metrics performed better than DTI in assessing microstructural changes of CND. In particular, MK and radial kurtosis are found to be more sensitive enough to differentiate the normal maturation of cochlear nerve from CND cases. PMID- 27476098 TI - Value of Genetic Testing for the Prediction of Long-Term Outcome in Patients With Hypertrophic Cardiomyopathy. AB - Pathogenic gene mutations are found in about 50% of patients with hypertrophic cardiomyopathy (HC). Previous studies have shown an association between sarcomere mutations and medium-term outcome. The association with long-term outcome has not been described. The aim of this cohort study was to assess the long-term outcomes of patients with genotype positive (G+) and genotype negative (G-) HC. The study population consisted of 626 patients with HC (512 probands and 114 relatives) who underwent phenotyping and genetic testing from 1985 to 2014. End points were all cause mortality, cardiovascular (CV) mortality, heart failure (HF)-related mortality, and sudden cardiac death/aborted sudden cardiac death (SCD/aborted SCD). Kaplan-Meier and multivariate Cox regression analyses were performed. A pathogenic mutation was detected in 327 patients (52%). G+ probands were younger than G- probands (46 +/- 15 vs 55 +/- 15 years, p <0.001), had more non sustained ventricular tachycardia (34% vs 13%; p <0.001), more often a history of syncope (14% vs 7%; p = 0.016), and more extreme hypertrophy (maximal wall thickness >=30 mm, 7% vs 1%; p <0.001). G- probands were more symptomatic (New York Heart Association >=II, 73% vs 53%, p <0.001) and had higher left ventricular outflow tract gradients (42 +/- 39 vs 29 +/- 33 mm Hg, p = 0.001). During 12 +/- 9 years of follow-up, G+ status was an independent risk factor for all-cause mortality (hazard ratio [HR] 1.90, 95% CI 1.14 to 3.15; p = 0.014), CV mortality (HR 2.82, 95% CI 1.49 to 5.36; p = 0.002), HF-related mortality (HR 6.33, 95% CI 1.79 to 22.41; p = 0.004), and SCD/aborted SCD (HR 2.88, 95% CI 1.23 to 6.71; p = 0.015). In conclusion, during long-term follow-up, patients with G+ HC are at increased risk of all-cause death, CV death, HF-related death, and SCD/aborted SCD. PMID- 27476099 TI - Health Care Costs for Adults With Congenital Heart Disease in the United States 2002 to 2012. AB - More adults than children with congenital heart disease (CHD) are alive today. Few studies have evaluated adult congenital heart disease (ACHD) health care utilization in the United States. Data from the National Inpatient Sample from 2002 to 2012, using International Classification of Diseases, Ninth Revision, codes for moderate and complex CHD were analyzed. Hospital discharges, total billed and reimbursed amounts, length of stay, and gender/age disparities were evaluated. There was an increase in CHD discharges (moderate CHD: 4,742 vs 6,545; severe CHD: 807 vs 1,115) and total billed and reimbursed dollar amounts across all CHD (billed: $2.7 vs $7.0 billion, 155% increase; reimbursed: $1.3 vs $2.3 billion, 99% increase) and in the ACHD subgroup (billed: $543 million vs $1.5 billion, 178% increase; reimbursed: $221 vs $433 million, 95% increase). Women comprised more discharges in 2002 but not in 2012 (men:women, 2002: 6,503 vs 7,805; 2012: 7,715 vs 7,200, p = 0.39). Gender-based billed amounts followed similar trends (2002: $263 vs $280 million; 2012: $845 vs $662 million, p = 0.006) as did reimbursements (2002: $108 vs $114 million; 2012: $243 vs $190 million, p = 0.008). All age subgroups demonstrated increased health care expenditures, including the >44 versus 18- to 44-year-old age subgroup (billed: $618 vs $347 million, p <0.001; reimbursed: $136 vs $75 million, p <0.001). Our results reveal increased ACHD billed and reimbursed amounts and hospital discharges with a shift in gender-based ACHD hospitalizations: men now account for more hospitalizations in the United States. In conclusion, increased health care expenditure in older patients with ACHD is likely to increase further as health care system use and costs continue to grow. PMID- 27476101 TI - Slow rhythms and sleep spindles in early infancy. AB - OBJECTIVE: To investigate the slow rhythm and its relationship to spindling in early infancy. METHODS: We analyzed sleep MEG recordings containing sleep spindles, taken from 7 normal, healthy subjects at conceptional age 46-63 weeks in 21 sessions. RESULTS: We show that the sleep MEG in early infancy contains a slow rhythm, centered at approximately 0.2Hz, which showed a striking association with spindling. The slow rhythm grouped sleep spindles, which were clock-like with a recurrence rate of approximately 0.1Hz. CONCLUSIONS: The association of the 0.2Hz oscillation and low delta rhythms with spindling was so strong as to suggest that they may play a critical role during brain development in the genesis of sleep spindles. SIGNIFICANCE: Infant brain rhythms exhibit relatively simple, regular behavior, allowing the relationships between them to be more easily discerned. PMID- 27476102 TI - ARAP2 promotes GLUT1-mediated basal glucose uptake through regulation of sphingolipid metabolism. AB - Lipid droplet formation, which is driven by triglyceride synthesis, requires several droplet-associated proteins. We identified ARAP2 (an ADP-ribosylation factor 6 GTPase-activating protein) in the lipid droplet proteome of NIH-3T3 cells and showed that knockdown of ARAP2 resulted in decreased lipid droplet formation and triglyceride synthesis. We also showed that ARAP2 knockdown did not affect fatty acid uptake but reduced basal glucose uptake, total levels of the glucose transporter GLUT1, and GLUT1 levels in the plasma membrane and the lipid micro-domain fraction (a specialized plasma membrane domain enriched in sphingolipids). Microarray analysis showed that ARAP2 knockdown altered expression of genes involved in sphingolipid metabolism. Because sphingolipids are known to play a key role in cell signaling, we performed lipidomics to further investigate the relationship between ARAP2 and sphingolipids and potentially identify a link with glucose uptake. We found that ARAP2 knockdown increased glucosylceramide and lactosylceramide levels without affecting ceramide levels, and thus speculated that the rate-limiting enzyme in glycosphingolipid synthesis, namely glucosylceramide synthase (GCS), could be modified by ARAP2. In agreement with our hypothesis, we showed that the activity of GCS was increased by ARAP2 knockdown and reduced by ARAP2 overexpression. Furthermore, pharmacological inhibition of GCS resulted in increases in basal glucose uptake, total GLUT1 levels, triglyceride biosynthesis from glucose, and lipid droplet formation, indicating that the effects of GCS inhibition are the opposite to those resulting from ARAP2 knockdown. Taken together, our data suggest that ARAP2 promotes lipid droplet formation by modifying sphingolipid metabolism through GCS. PMID- 27476100 TI - The impact of inflammation on respiratory plasticity. AB - Breathing is a vital homeostatic behavior and must be precisely regulated throughout life. Clinical conditions commonly associated with inflammation, undermine respiratory function may involve plasticity in respiratory control circuits to compensate and maintain adequate ventilation. Alternatively, other clinical conditions may evoke maladaptive plasticity. Yet, we have only recently begun to understand the effects of inflammation on respiratory plasticity. Here, we review some of common models used to investigate the effects of inflammation and discuss the impact of inflammation on nociception, chemosensory plasticity, medullary respiratory centers, motor plasticity in motor neurons and respiratory frequency, and adaptation to high altitude. We provide new data suggesting glial cells contribute to CNS inflammatory gene expression after 24h of sustained hypoxia and inflammation induced by 8h of intermittent hypoxia inhibits long-term facilitation of respiratory frequency. We also discuss how inflammation can have opposite effects on the capacity for plasticity, whereby it is necessary for increases in the hypoxic ventilatory response with sustained hypoxia, but inhibits phrenic long term facilitation after intermittent hypoxia. This review highlights gaps in our knowledge about the effects of inflammation on respiratory control (development, age, and sex differences). In summary, data to date suggest plasticity can be either adaptive or maladaptive and understanding how inflammation alters the respiratory system is crucial for development of better therapeutic interventions to promote breathing and for utilization of plasticity as a clinical treatment. PMID- 27476103 TI - Biochemical fingerprint and pharmacological applications of Barleria noctiflora L.f. leaves. AB - Background Antioxidant and antihistamine agents from Barleria noctiflora L.f. as natural source due to the existing modern medicine give various adverse effects to overcome these problems with natural products. MethodsB. noctiflora leaves extract was fractionated with column chromatography; the homogenized fractions were monitored with thin layer chromatography (TLC) and characterized by using UV visible, FT-IR, 1H NMR, 13C NMR and mass spectrometry spectral studies. The volatile phytoconstituents of B. noctiflora extract were analysed by gas chromatography-mass spectrometry. Phytoconstituents from B. noctiflora leaves extract were screened for their antioxidant and antihistamine potential in vitro (2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, 2,2'-azinobis-3 ethylbenzothiozoline-6-sulfonic acid radical decolouration assay, nitric oxide radical scavenging activity, superoxide radical scavenging activity and hydrogen peroxide radical scavenging activity) and in silico (molecular docking), respectively. Results Antioxidant and antihistamine barlerinoside has been isolated and characterized from the leaves of B. noctiflora L.f. Barlerinoside revealed their free-radical scavenging ability on OH-, OH*, NO-, O2- and H2O2 radicals and found high percentage inhibition against OH- radical at the IC50 value of 50.45+/-2.52 ug. The methanol (MeOH) extract of B. noctiflora leaves contains cyclotene; N,N-dimethylglycine; tetrahydrocyclopenta [1,3] dioxin-4-one; phenol, 2-methoxy-; benzofuran, 2-methyl-; 1,4:3,6-dianhydro-alpha-d glucopyranose; 2-methoxy-4-vinylphenol; 1,3;2,5-dimethylene-l-rhamnitol; levoglucosan and bicyclo[2.2.2]oct-7-ene-2,5-dione as being the major compounds. Among phytoconstituents present in the extract, the hexestrol; 1,2 benzenedicarboxylic acid, bis(2-methylpropyl) ester; 1-(3,6,6-trimethyl-1,6,7,7a tetrahydrocyclopenta[c]pyran-1-yl) ethanone; megastigmatrienone; furan interacted with histamine H1 receptor and bind at GLU-177 and ASP-178 with high binding energy score -13.95, -13.41, -12.56, -12.03, and -11.72 kcal/mol, respectively, and the expected hydrolysed products of compound-1a and compound-1b from barlerinoside showed -8.91 and -8.68 kcal/mol binding energy against the histamine H1 receptor. This showed that the active ligands exactly bind with active binding site of the protein. ConclusionsWe can conclude that isolated barlerinoside from B. noctflora L.f. has potent antioxidant activity against synthetic free radicals and antihistamine activity against histamine H1 receptor. PMID- 27476104 TI - Association of insulin-like growth factor (IGF)-1 gene polymorphisms with plasma levels of IGF-1 and acne severity. AB - BACKGROUND: Polymorphisms of the insulin-like growth factor (IGF)-1 gene consisting of variable cytosine adenosine repeats in the promoter region may directly influence the expression of IGF-1. OBJECTIVE: We sought to assess the role of IGF-1 gene polymorphisms in determination of plasma IGF-1 levels, acne, and its severity. METHODS: In this case-control study, 80 patients with acne vulgaris of 4 severity grades as per Global Acne Grading System and 80 age- and gender-matched control subjects without acne were studied. All the study subjects were without any disorder or a history of drug intake likely to affect IGF-1 level within a year before the study inclusion date. IGF-1 polymorphism was determined by polymerase chain reaction and plasma levels of IGF-1 by enzyme linked immunosorbent assay. Acne severity was assessed by Global Acne Grading System. RESULTS: Mean plasma IGF-1 level in acne cases was significantly higher than in non-acne controls (P = .04). Plasma IGF-1 level positively correlated with severity of acne (P = .01). Individuals homozygous for the 192-base pair (bp) allele had 4.29 times odds risk (95% confidence interval 1.38-13.33) of having acne and a significantly higher mean level of IGF-1 compared with non 192/non-192 participants. Individuals homozygous for the 192-bp allele had 3.08 times odds risk (95% confidence interval 1.15- 8.31) of having higher severity grade of acne compared with non-192/non-192 participants. LIMITATIONS: A relatively small number of participants were studied. CONCLUSIONS: Plasma IGF-1 levels positively correlate with severity of acne. The 192/192 homozygotes had higher risk of acne and higher severity grade of acne. Functional studies showing the relationship between IGF-1 promoter level polymorphism and actual gene expression in skin are warranted. PMID- 27476105 TI - A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients. AB - BACKGROUND: Transplant recipients are at increased risk of developing skin cancer as a result of chronic immunosuppression. Educating patients on sun protection has been routine posttransplantation, but to our knowledge, no systematic review has yet analyzed the efficacy of such education measures in this high-risk population. OBJECTIVE: We sought to examine the efficacy of educating transplant recipients on skin cancer and sun protection. METHODS: A literature search of interventional patient education studies published between January 1995 and March 2016 was performed in PubMed, CINAHL, Cochrane, and EMBASE databases. RESULTS: Data from 7 studies meeting inclusion criteria were analyzed. No study attempted to examine the direct effect of sun protection education on skin cancer incidence in transplant recipients. Two randomized controlled trials showed that educational intervention can improve sun-protective behavior and decrease skin pigmentation or skin damage in sun-exposed areas. Three other randomized controlled trials compared the efficacy of 2 different forms of patient education at changing sun-protective behavior, but did not examine patient-oriented outcomes. LIMITATIONS: A lack of high-quality randomized controlled trials with patient-oriented evidence and a dependence on self-reported data are limitations. CONCLUSION: Sun protection education can be effective at altering patient behavior in transplant recipients, but its effect on posttransplantation skin cancer incidence remains to be elucidated. PMID- 27476106 TI - Multilevel symmetric neuropathic pruritus (MSNP) presenting as recalcitrant "generalized" pruritus. AB - BACKGROUND: Chronic itch is a disruptive and disabling condition that can lead to psychological stress and depression. OBJECTIVE: We sought to describe an entity of generalized, symmetric, neuropathic pruritus, which we term "multilevel symmetric neuropathic pruritus," and offer possible explanations accounting for its pathogenesis. METHODS: A case series of 14 patients was evaluated at academic institutions from 2011 to 2015. RESULTS: All patients exhibited detectable degenerative vertebral changes, as seen by spinal x-ray or magnetic resonance imaging. In 12 of 14 (85.7%) subjects, the radiographic imaging abnormalities directly correlated with the distribution of their cutaneous findings. Twelve of 14 (85.7%) patients had cutaneous findings along the C5 to C6 and/or C6 to C7 dermatomal distributions. Eleven of 14 (78.5%) patients were overweight or obese, and 14 of 14 (100%) patients had at least 4 risk factors for the development of atherosclerosis. Twelve of 14 (85.7%) patients noted complete or near complete resolution after treatment with gabapentin (300-1200 mg daily). LIMITATIONS: No healthy age-matched control group without pruritus was investigated. CONCLUSION: A combination of multilevel degenerative disc disease of the spine, spinal nerve root impingement, and/or nerve root traction may play a pivotal role in the cause of multilevel symmetric neuropathic pruritus. PMID- 27476107 TI - Fungal Diseases: the Last Frontier? PMID- 27476108 TI - Cutaneous Ossifying Fibroma in a Neon Tetra (Paracheirodon innesi). AB - A cutaneous proliferative mass was identified arising from the caudal peduncle of a captive neon tetra fish (Paracheirodon innesi). The lesion was histologically consistent with an ossifying fibroma (OF), a fibro-osseous proliferative lesion typically identified in the jaws or tooth-associated supportive tissues of mammals. Although it has been previously reported, there is no recent report of this lesion occurring in a fish. This is the first report of a cutaneous ossifying fibroma in a characin fish. The authors speculate on the pathogenesis of this lesion, which may have arisen from the scale-associated mesenchymal tissues. PMID- 27476109 TI - Characterization of Immune System Cell Subsets in Fixed Tissues from Alpine Chamois (Rupicapra rupicapra). AB - Immune system cell subsets in lymph nodes and spleen from alpine chamois (Rupicapra rupicapra subspecies rupicapra) living in the Italian Alps were characterized immunohistochemically. Seven primary antibodies (against human CD3, CD79alphacy, CD68, or ovine CD4, CD8, CD21 and gammadelta T-cell receptor [TCR] epitopes) were tested on tissues fixed either in formalin or in zinc salts (ZS) and cross-reactivity with chamois immune cell epitopes was shown. ZS fixation allowed wider identification of immune cells, without the need for antigen retrieval. CD4(+) and CD21(+) cells were labelled only in ZS-fixed tissues. Reagents specific for human CD3, CD79 and CD68 antigens successfully detected chamois immune cells, both in ZS-fixed and formalin-fixed tissues. The reactivity and distribution of immune cells in lymph nodes and spleen were similar to those described in other domestic and wild ruminants. Results from this study may allow future investigation of the immune response and pathogenesis of diseases in the chamois. PMID- 27476110 TI - A community-engaged randomized controlled trial of an integrative intervention with HIV-positive, methamphetamine-using men who have sex with men. AB - BACKGROUND: Contingency management (CM) is an evidence-based intervention providing tangible rewards as positive reinforcement for abstinence from stimulants such as methamphetamine. Integrative approaches targeting affect regulation could boost the effectiveness of CM in community-based settings and optimize HIV/AIDS prevention efforts. METHODS/DESIGN: This randomized controlled trial with HIV-positive, methamphetamine-using men who have sex with men (MSM) is examining the efficacy of a 5-session, individually delivered positive affect regulation intervention - Affect Regulation Treatment to Enhance Methamphetamine Intervention Success (ARTEMIS). ARTEMIS is designed to sensitize individuals to non-drug-related sources of reward as well as assist with managing depression and other symptoms of stimulant withdrawal during CM. HIV-positive, methamphetamine using MSM who are enrolled in a community-based, 12-week CM program are randomized to receive ARTEMIS or an attention-matched control condition. Follow up assessments are conducted at 3, 6, 12, and 15 months after enrollment in CM. Four peripheral venous blood samples are collected over the 15-month follow-up with specimen banking for planned biomarker sub-studies. The primary outcome is mean HIV viral load. Secondary outcomes include: sustained HIV viral suppression, T-helper cell count, psychological adjustment, stimulant use, and potentially amplified transmission risk behavior. DISCUSSION: Implementation of this randomized controlled trial highlights the importance of delineating boundaries between research activities and community-based service provision. It also provides insights into best practices for integrating the distinct agendas of academic and community partners in clinical research. This trial is currently enrolling and data collection is anticipated to be completed in September of 2018. TRIAL REGISTRATION: This trial was registered on clinicaltrials.gov ( NCT01926184 ) on August 16, 2013. PMID- 27476111 TI - Everybody needs a cheerleader to get a kidney transplant: a qualitative study of the patient barriers and facilitators to kidney transplantation in the Southeastern United States. AB - BACKGROUND: Kidney transplantation (KTx) disparity is a significant problem in the United States, particularly in the Southeastern region. In response to this phenomenon, the Southeastern Kidney Transplant Coalition was created in 2011 to increase the KTx rate, and to reduce disparities in access to transplantation in the Southeast, by identifying and reducing barriers in the transplant process. METHODS: To determine perceived barriers and facilitators to KTx that dialysis patients in this region experience, we conducted three focus groups with 40 total patients in Georgia, North Carolina, and South Carolina. RESULTS: We identified two novel themes specific to Southeastern dialysis patients that describe the major barriers and facilitators to kidney transplantation: dialysis center approaches to patient education about KTx, and dialysis center advocacy and encouragement for KTx. In addition, themes related to barriers and facilitators of KTx were evident that were previously mentioned in the literature such as age, fear, knowing other patients with good or bad experiences with KTx, distrust of the KTx process equity, financial concerns and medical barriers. CONCLUSIONS: Dialysis providers are encouraged to enhance their delivery of information and active assistance to underserved patients related to KTx. PMID- 27476112 TI - Role and organization of the actin cytoskeleton during cell-cell fusion. AB - Cell-cell fusion is a ubiquitous process that underlies fertilization and development of eukaryotes. This process requires fusogenic machineries to promote plasma membrane merging, and also relies on the organization of dedicated sub cortical cytoskeletal assemblies. This review describes the role of actin structures, so called actin fusion foci, essential for the fusion of two distinct cell types: Drosophila myoblast cells, which fuse to form myotubes, and sexually differentiated cells of the fission yeast Schizosaccharomyces pombe, which fuse to form a zygote. I describe the respective composition and organization of the two structures, discuss their proposed role in promoting plasma membrane apposition, and consider the universality of similar structures for cell-cell fusion. PMID- 27476113 TI - SOX-mediated molecular crosstalk during the progression of tumorigenesis. AB - SOX family transcription factor has emerged as a double-edged sword relating to tumorigenesis and metastasis. Multiple studies have revealed different expression patterns and contradictory roles of SOX factors in the tumor initiation and progression. The aberrant expression of SOX factors is regulated by copy number alteration, methylation modulation, microRNAs, transcription factors and post translational modification. This review summarizes the role of SOX factors in molecular interactions and signaling pathways during different steps of carcinogenesis, such as CSCs stemness maintenance, EMT occurrence, cell invasion, cell proliferation and apoptosis. The Wnt signaling pathway is also shown to provide vital intermediate signaling transduction. We believe that SOX family proteins may be used as prognostic markers for human clinical therapy, and novel therapy strategies targeting SOX factors should be explored in future clinical applications. PMID- 27476114 TI - A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas. AB - BACKGROUND: Malignant gliomas are the most common primary brain tumors in adults and challenging cancers for diagnosis and treatment. They remain a disease for which non-invasive, diagnostic and/or prognostic novel biomarkers are highly desirable. Altered microRNA (miRNA) profiles have been observed in tumor tissues and biological fluids. To date only a small set of circulating/serum miRNA is found to be differentially expressed in brain tumors compared to normal controls. Here a restricted signature of circulating/serum miRNA including miR-15b*,-23a, 99a, -125b, -133a, -150*, -197, -340, -497, -548b-5p and let-7c were investigated as potential non-invasive biomarkers in the diagnosis of glioma patients. METHODS: Serum and tissues miRNAs expression in patients with brain cancers (n = 30) and healthy controls (n = 15) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Relative expression was calculated using the comparative Ct method. Statistical significance (p <= 0,05) was determined using the Mann-Whitney rank sum and Fisher's exact test. Diagnostic accuracy of miRNAs in distinguishing glioblastoma multiforme (GBM) from lower grade cancer was assessed by the Receiver Operating Characteristic (ROC) curve analysis. To validate the role of the identified miRNAs in cancer a comprehensive literature search was conducted using PubMed, Web of Science (Core Collection) and Scopus databases. RESULTS: We observed a decrease of miR-497 and miR-125b serum levels depending on tumor stages with reduced level in GBM than lower grade tumors. The ROC curve analysis distinguishing GBM from lower grade cases yielded an area under the curve (AUC) of 0.87 (95 % confidence interval (CI) = 0.712-1) and of 0.75 (95 % CI = 0.533-0.967) for miR-497 and -125b, respectively. GBM patients are more likely to show a miR-497 and -125b down-regulation than the lower grade group (p = 0.002 and p = 0.024, respectively). These results were subsequently compared with evidence from 19 studies included in the final systematic review. CONCLUSIONS: Although multiple biomarkers are currently leveraged in the clinic to detect specific cancer types, no such standard blood biomolecules are used as yet in gliomas. Our data suggest that serum miR-497 and -125b could be a novel diagnostic markers with good perspectives for future clinical applications in patients with glioma. PMID- 27476116 TI - Chemical analysis of Punica granatum fruit peel and its in vitro and in vivo biological properties. AB - BACKGROUND: The medical application of pomegranate fruits and its peel is attracted human beings. The aim of the present study was to evaluate the in vitro alpha-Glucosidase inhibition, antimicrobial, antioxidant property and in vivo anti-hyperglycemic activity of Punica granatum (pomegranate) fruit peel extract using Caenorhabditis elegans. METHODS: Various invitro antioxidant activity of fruit peel extracts was determined by standard protocol. Antibacterial and antifungal activities were determined using disc diffusion and microdilution method respectively. Anti-hyperglycemic activity of fruit peel was observed using fluorescence microscope for in vivo study. RESULTS: The ethyl acetate extract of P. granatum fruit peel (PGPEa) showed alpha-Glucosidase inhibition upto 50 % at the concentration of IC50 285.21 +/- 1.9 MUg/ml compared to hexane and methanol extracts. The total phenolic content was highest (218.152 +/- 1.73 mg of catechol equivalents/g) in ethyl acetate extract. PGPEa showed more scavenging activity on 2,2-diphenyl-picrylhydrazyl (DPPH) with IC50 value 302.43 +/- 1.9 MUg/ml and total antioxidant activity with IC50 294.35 +/- 1.68 MUg/ml. PGPEa also showed a significant effecton lipid peroxidation IC50 208.62 +/- 1.68 MUg/ml, as well as high reducing power. Among the solvents extracts tested, ethyl acetate extract of fruit peel showed broad spectrum of antimicrobial activity. Ethyl acetate extract supplemented C.elegans worms showed inhibition of lipid accumulation similar to acarbose indicating good hypoglycemic activity. The normal worms compared to test (ethyl acetate extract supplemented) showed the highest hypoglycaemic activity by increasing the lifespan of the worms. GC-MS analysis of PGPEa showed maximum amount of 5-hydroxymethylfurfural and 4-fluorobenzyl alcohol (48.59 %). CONCLUSION: In the present investigation we observed various biological properties of pomegranate fruit peel. The results clearly indicated that pomegranate peel extract could be used in preventing the incidence of long term complication of diabetics. PMID- 27476115 TI - Assessment of the cortical artery using computed tomography angiography for bypass surgery in moyamoya disease. AB - Computed tomography angiography (CTA) is often used to assess the vascular status in moyamoya disease. The purpose of the study is to identify the characteristics of cortical arteries (M4) of moyamoya disease on CTA; the clinical significance of which is also discussed. A total of 38 hemispheric sides of 27 patients with moyamoya disease were included in this study. The number of M4 was visualized on CTA using cortical surface imaging and compared between the moyamoya disease group and the non-moyamoya disease group or the control group. Then, the clinical and radiological factors associated with the number of M4, the distribution of M4, and collateral circulation were examined. The number of M4 was lower in the moyamoya disease group than in the non-moyamoya disease group and in the control group (p < 0.05). There are few predictive clinical factors of the number of M4 except male sex. The prefrontal artery, precentral artery, central artery, and angular artery had a significantly higher prevalence in moyamoya disease (p < 0.05). The durocortical and periventricular anastomosis had a significantly higher prevalence in moyamoya disease (p < 0.05). The prevalence and distribution pattern of cortical arteries in moyamoya disease differed from that of the non moyamoya disease group, and the distribution patterns of M4 might be influenced by collateral circulation. It is thus essential to recognize M4 to assess the recipient artery so as to ensure superficial temporal artery-middle cerebral artery bypass. PMID- 27476117 TI - Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents. AB - The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index. PMID- 27476118 TI - Crossing of acoustic envelope solitary waves in homogeneous elastic rods: Experiments. AB - In this letter we focused on the problem in which two shear envelope solitary waves traveling in 1-D homogeneous system (elastic PMMA rod of constant cross section) and incoming in opposite directions, meet one another and head-on collide. The properties of incident acoustic waves after collision are investigated. Two cases are experimentally examined: incoming waves with close amplitudes and quite large difference in magnitude. No phase shift and no variation of polarization are experimentally detected after the collision. PMID- 27476119 TI - High-frequency vibration effects on hole entrance chipping in rotary ultrasonic drilling of BK7 glass. AB - This present investigation exhibited some fundamental information about the influence of the high-frequency vibration on the hole entrance chipping formation involved in rotary ultrasonic drilling (RUD) of BK7 glass process. The entrance chipping morphologies, produced with and without ultrasonic, were observed and evaluated with respect to the fracture mechanics of brittle material. Giving consideration to the variation characteristics of the plastic deformation region in the interior material induced by the specific kinematics principles of the abrasive, the ultrasonic effects on the chipping formation mechanisms were investigated by assessing the groove morphologies obtained in the scratching experiment utilizing the formation mechanisms of the lateral cracking. Furthermore, the formal confirmatory tests with and without ultrasonic were performed to validate these chipping formation mechanisms. It was found that the plastic deformed region reached its maximum at the trajectory bottom. Moreover, the propagation of the lateral cracking initially nucleated at the bottom of the ductile deformation zone resulted in the formation of the entrance chipping in formal RUD process. The slight deformation of the material at the two terminals of each groove produced with ultrasonic would provide the inhibitory effects to the further extending of the lateral cracks, which would shrink with the increased spindle speed, and the inhibitory effect dominated in determining the improvement effects on the hole entrance quality. Additionally, a theoretical relationship between the nucleation depth and the propagation length of the lateral cracking was developed for the conventional drilling (CD) process. PMID- 27476122 TI - The Epidemiology of Benign Prostatic Hyperplasia Associated with Lower Urinary Tract Symptoms: Prevalence and Incident Rates. AB - This article assesses the reported prevalence and incidence rates for benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) by age, symptom severity, and race/ethnicity. BPH/LUTS prevalence and incidence rates increase with increasing age and vary by symptom severity. The BPH/LUTS relationship is complex due to several factors. This contributes to the range of reported estimates and difficulties in drawing epidemiologic comparisons. Cultural, psychosocial, economic, and/or disease awareness and diagnosis factors may influence medical care access, symptom reporting and help-seeking behaviors among men with BPH/LUTS. However, these factors and their epidemiologic association with BPH/LUTS have not been thoroughly investigated. PMID- 27476120 TI - Molecular cloning, expression, and functional analysis of the copper amine oxidase gene in the endophytic fungus Shiraia sp. Slf14 from Huperzia serrata. AB - Huperzine A (HupA) is a drug used for the treatment of Alzheimer's disease. However, the biosynthesis of this medicinally important compound is not well understood. The HupA biosynthetic pathway is thought to be initiated by the decarboxylation of lysine to form cadaverine, which is then converted to 5 aminopentanal by copper amine oxidase (CAO). In this study, we cloned and expressed an SsCAO gene from a HupA-producing endophytic fungus, Shiraia sp. Slf14. Analysis of the deduced protein amino acid sequence showed that it contained the Asp catalytic base, conserved motif Asn-Tyr-Asp/Glu, and three copper-binding histidines. The cDNA of SsCAO was amplified and expressed in Escherichia coli BL21(DE3), from which a 76 kDa protein was obtained. The activity of this enzyme was tested, which provided more information about the SsCAO gene in the endophytic fungus. Gas Chromatograph-Mass Spectrometry (GC-MS) revealed that this SsCAO could accept cadaverine as a substrate to produce 5 aminopentanal, the precursor of HupA. Phylogenetic tree analysis indicated that the SsCAO from Shiraia sp. Slf14 was closely related to Stemphylium lycopersici CAO. This is the first report on the cloning and expression of a CAO gene from HupA-producing endophytic fungi. Functional characterization of this enzyme provides new insights into the biosynthesis of the HupA an anti-Alzheimer's drug. PMID- 27476121 TI - Review of Prostate Anatomy and Embryology and the Etiology of Benign Prostatic Hyperplasia. AB - Prostate development follows a common pattern between species and depends on the actions of androgens to induce and support ductal branching morphogenesis of buds emerging from the urogenital sinus. The human prostate has a compact zonal anatomy immediately surrounding the urethra and below the urinary bladder. Rodents have a lobular prostate with lobes radiating away from the urethra. The human prostate is the site of benign hyperplasia, prostate cancer, and prostatitis. The rodent prostate has little naturally occurring disease. Rodents can be used to model aspects of human benign hyperplasia, but care should be taken in data interpretation and extrapolation to the human condition. PMID- 27476123 TI - Diagnostic Work-Up of Lower Urinary Tract Symptoms. AB - The goal of work-up of lower urinary tract symptoms is to establish the severity and cause of lower urinary tract symptoms and to predict with certainty which patients will respond to which treatments. Clinical guidelines exist to guide urologists in decision-making. All patients need a medical history with a validated symptom score, a physical examination, and a urinalysis. Prostate specific antigen, postvoid urine residual, and peak urine flow rate provide additional information at little cost. For more invasive testing high-level data are lacking and guidelines defer to the urologist. Even the most extensive work up is imperfect, and thus the attempt to balance costs with benefits of invasive testing. PMID- 27476124 TI - Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia. AB - Over the last 2 decades the evolution of alpha-blockers for lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) has been to preserve effectiveness, improve tolerability, and eliminate dose titration. Today, alpha blockers represent the first-line treatment of most men with BPH whereby the primary objective is relief from bothersome LUTS. PMID- 27476125 TI - 5-Alpha-Reductase Inhibitors and Combination Therapy. AB - By inhibiting the conversion from testosterone to dihydrotestosterone 5-Alpha reductase inhibitors (5ARIs) are able to hinder prostatic growth, shrink prostate volumes, and improve BPH-related LUTS. 5ARIs are particularly beneficial for patients with larger prostates (>30-40ml). Generally the side effects of 5ARI treatment are mild, and according to the FORTA classification 5ARIs are suitable for frail elderly. 5ARI / alpha-blocker (AB) combination therapy showed the best symptomatic outcome and risk reduction for clinical progression. Combining Phosphodieseterase type 5 inhbibitors (PDE5Is) with 5ARIs counteracts the negative androgenic sexual side effects of 5ARIs, and simultaneously combines their synergistic effects on LUTS. PMID- 27476126 TI - Antimuscarinics, beta-3 Agonists, and Phosphodiesterase Inhibitors in the Treatment of Male Lower Urinary Tract Symptoms: An Evolving Paradigm. AB - It is increasingly recognized that the bladder is the originator of storage lower urinary tract symptoms, including overactive bladder in men. As these symptoms are most bothersome for patients, there has been an increasing interest in the evaluation of drug treatment to better target the bladder. Consequently, several new drug classes have been introduced to the therapeutic armamentarium. Antimuscarinics, which were previously avoided due to the concern regarding urinary retention, are now used in routine practice; however, their use is still hampered by discontinuation due to side effects. PMID- 27476128 TI - Prostatic Urethral Lift: A Unique Minimally Invasive Surgical Treatment of Male Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. AB - The prostatic urethral lift (PUL) is a unique, nonthermal approach to treating lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). It can be conducted under local anesthesia in an outpatient setting. In published clinical studies, most voiding tested patients do not require a catheter. After PUL, patients experience rapid recovery with minimal adverse effects. Average symptom response is significant by 2 weeks, improves through 3 months, and remains stable through 4 years. Erectile and ejaculatory functions are preserved. This treatment represents a desirable solution for many patients who currently have male LUTS secondary to BPH. PMID- 27476127 TI - alpha-Blockers, 5-alpha-Reductase Inhibitors, Acetylcholine, beta3 Agonists, and Phosphodiesterase-5s in Medical Management of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: How Much Do the Different Formulations Actually Matter in the Classes? AB - Many monotherapies are currently available to clinically treat and alleviate symptoms of lower urinary tract symptoms secondary to benign prostatic hyperplasia: alpha-blockers, 5ARIs, PDE5Is, beta-3-andrenoceptor agonists, and anticholinergic agents. Current studies have evaluated the effective of these treatments in comparison to other groups or in combination therapies. The current review evaluates the effectiveness of class formulations. Based on the findings, alpha-blockers, specifically doxazosin and terazosin, were most effective in reducing IPSS scores and peak urinary flow rate, while being most cost-effective. However, further clinical investigations are required to evaluate the clinical implications of different formulations. PMID- 27476129 TI - Convective Water Vapor Energy for Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia. AB - Benign prostatic hyperplasia (BPH) refers to proliferation of smooth muscle and epithelial cells within the transition zone of the prostate. Half of men over 40 develop histologic BPH. About half of men with BPH develop an enlarged prostate gland, called benign prostatic enlargement; among these, about half develop some degree of bladder outlet obstruction. Bladder outlet obstruction and changes in smooth muscle tone and resistance may result in lower urinary tract symptoms, including storage disturbances (such as daytime urinary urgency, frequency, and nocturia) and voiding disturbances (such as urinary hesitancy, weak urinary stream, straining to void, and prolonged voiding). PMID- 27476130 TI - Bipolar, Monopolar, Photovaporization of the Prostate, or Holmium Laser Enucleation of the Prostate: How to Choose What's Best? AB - Endoscopic management of benign prostatic obstruction is based on resection, vaporization, or enucleation. Enucleation provides the best efficacy and long term outcome. Lasers have advantages in patients at high risk of bleeding. Holmium enucleation is the best evaluated technique, but has a steep learning curve. Greenlight photovaporization is a safe alternative to transurethral resection of the prostate (TURP) in prostates of less than 100 mL, especially in patients at high risk of bleeding. Bipolar devices can be used for resection, vaporization, and enucleation and provides efficacy results similar to TURP in the short term with better safety. PMID- 27476131 TI - Robotic-Assisted Simple Prostatectomy: An Overview. AB - Despite widespread use of medical therapy for benign prostatic hyperplasia, a need remains for robust surgical therapy in select patients. Robotic-assisted simple prostatectomy (RASP) is an efficacious and safe therapy for patients with bladder outlet obstruction owing to large volume prostates. Data from 13 published cohorts suggest functional outcomes equivalent to open simple prostatectomy with substantially decreased length of hospital stay and risk of transfusion. However, there are few longer term data. PMID- 27476132 TI - Sexual Side Effects of Medical and Surgical Benign Prostatic Hyperplasia Treatments. AB - Treatments for lower urinary tract symptoms due to benign prostatic hyperplasia can be evaluated by multiple metrics. A balance within the confines of patient expectations is key to determining the ideal treatment. A troubling adverse event for some patients is sexual dysfunction. Because the cohort of men who seek treatment of sexual dysfunction and lower urinary tract symptoms is essentially identical, these disease processes frequently overlap. This article considers potential pathophysiologic causes of dysfunction with treatment and attempts to critically review the available data to assess the true incidence of sexual adverse events with treatment. PMID- 27476133 TI - Testosterone and the Prostate: Artifacts and Truths. AB - Despite a lack of evidence, there have been stated concerns that testosterone replacement therapy (TRT) can pose a risk to men suffering with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). TRT may improve components of the metabolic syndrome, which is associated with worsening LUTS. Furthermore, the evidence suggests that TRT may decrease prostatic inflammation, which is also associated with worsening LUTS. The data on the relationship between TRT and LUTS have never shown worsening of LUTS, often show no change in LUTS, and occasionally show improvement. PMID- 27476134 TI - Treatment of Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. PMID- 27476135 TI - Preface. PMID- 27476136 TI - Freeze Dried Proximal Femoral Allografts in Revision of Femoral Stems. AB - BACKGROUND: Femoral bone deficiency is a challenging problem in revision femoral arthroplasty in younger patients. We evaluated outcomes of revision femoral arthroplasty using a freeze-dried allograft prosthetic composite (APC). METHODS: This was a retrospective review of 16 patients (12 men and 4 women) who had unilateral proximal femoral deficiencies (Paprosky type III B, 13 patients; type IV, 3 patients) revised with freeze-dried APC. Follow-up at mean 7 years included assessment with Merle D'Aubigne score and radiographs. RESULTS: At follow-up, the average hip score was improved for pain, function, and range of motion. The 5 year graft survival was 87%, and the estimated median survival was 8.8 years. There were 3 patients who walked without support, 10 patients who walked unlimited distance with a cane, 2 patients who walked with 2 crutches, and 1 patient who walked with a walker. Radiographs showed nonunion at the graft-host junction in 3 hips (19%), but only 1 patient was symptomatic. Asymptomatic trochanteric nonunion was observed in 4 hips (25%). There was moderate graft resorption in 2 patients at 9 years after surgery and mild graft resorption in 1 graft at 7 years. There was subsidence of <2 cm in 2 patients and 3.5 cm in 1 patient. CONCLUSION: The present study showed acceptable results in treatment of major femoral deficiencies using freeze-dried APC in younger patients. Freeze dried APC may be a useful for revision femoral arthroplasty. PMID- 27476137 TI - Prevalence of comorbid bipolar and substance use disorders in clinical settings, 1990-2015: Systematic review and meta-analysis. AB - BACKGROUND: Comorbidity between substance use disorders (SUDs) and bipolar disorder (BD) is highly prevalent to the extent it may almost be regarded the norm. This systematic review and meta-analysis aimed to estimate the prevalence rates of SUDs in treatment seeking patients diagnosed with BD in both inpatient and outpatient settings. METHODS: A comprehensive literature search of Medline, EMBASE, psychINFO and CINAHL databases was conducted from 1990 to 2015. Prevalence of co-morbid SUDs and BD were extracted and odds ratios (ORs) were calculated using random effects meta-analysis. RESULTS: There were 151 articles identified by electronic searches that yielded 22 large, multi-site studies and 56 individual studies describing comorbid rates of SUDs amongst community dwelling, BD inpatients or outpatients. The SUDs with the highest prevalence in BD were alcohol use (42%) followed by cannabis use (20%) and other illicit drug use (17%). Meta-analysis showed males had higher lifetime risks of SUDs compared to females. BD and comorbid SUDS were associated with earlier age of onset and slightly more hospitalisations than non-users. LIMITATIONS: The results do not take into account the possibility that individuals may have more than one comorbid disorder, such as having more than one SUD, anxiety disorder, or other combination. Some of the meta-analyses were based on relatively few studies with high rates of heterogeneity. Most included studies were cross-sectional and therefore causality cannot be inferred. CONCLUSIONS: This systematic review shows comorbidity between SUDs and bipolar illness is highly prevalent in hospital and community-based samples. The prevalence of SUDs was similar in patients with bipolar I and bipolar II disorders. This study adds to the literature demonstrating that SUDs are common in BD and reinforces the need to provide better interventions and properly conducted treatment trials to reduce the burden conferred by comorbid SUD and BD. PMID- 27476138 TI - An efficient chelator for complexation of thorium-227. AB - We present the synthesis and characterization of a highly efficient thorium chelator, derived from the octadentate hydroxypyridinone class of compounds. The chelator forms extremely stable complexes with fast formation rates in the presence of Th-227 (ambient temperature, 20min). In addition, mouse biodistribution data are provided which indicate rapid hepatobiliary excretion route of the chelator which, together with low bone uptake, supports the stability of the complex in vivo. The carboxylic acid group may be readily activated for conjugation through the E-amino groups of lysine residues in biomolecules such as antibodies. This chelator is a critical component of a new class of Targeted Thorium Conjugates (TTCs) currently under development in the field of oncology. PMID- 27476139 TI - A convenient synthesis and screening of benzosuberone bearing 1,2,3-triazoles against Mycobacterium tuberculosis. AB - A series of benzosuberone bearing 1,2,3-triazoles were rationally designed and alkyl/aryl groups appended on 1,2,3-triazole derivatives 5a-o were synthesized using click chemistry and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Compounds 5h (MIC: 3.125MUg/mL) and 5l, 5m, 5o (MIC: 6.25MUg/mL) exhibited promising hits. This is the first Letter on the synthesis and in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv of benzosuberone alkyl/aryl groups appended on 1,2,3-triazole derivatives. PMID- 27476140 TI - Colorectal anticancer activities of polymethoxylated 3-naphthyl-5 phenylpyrazoline-carbothioamides. AB - To develop potent chemotherapeutic agents for treating colorectal cancers, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamide derivatives were designed. Twenty-two novel derivatives were synthesized and their cytotoxicities were measured using a clonogenic long-term survival assay. Of these derivatives, 3-(1-hydroxynaphthalen-2-yl)-N-(3-methoxyphenyl)-5-(4-methoxyphenyl)-pyrazoline-1 carbothioamide (NPC 15) exhibited the best half-maximal cell growth inhibitory concentrations (196.35nM). To explain its cytotoxicity, further biological experiments were performed. Treatment with NPC 15 inhibited cell cycle progression and triggered apoptosis through the caspase-mediated pathway. Its inhibitory effects on several kinases participating in the cell cycle were investigated using an in vitro kinase assay. Its half-maximal inhibitory concentrations for aurora kinases A and B were 105.03MUM and 8.53MUM, respectively. Further analysis showed that NPC 15 decreased phosphorylation of aurora kinases A, B, and C and phosphorylation of histone H3, a substrate of aurora kinases A and B. Its molecular binding mode for aurora kinase B was elucidated using in silico docking. In summary, polymethoxylated 3-naphthyl-5 phenylpyrazoline-carbothioamides could be potent chemotherapeutic agents. PMID- 27476141 TI - Design and synthesis of fused bicyclic inhibitors targeting the L5 loop site of centromere-associated protein E. AB - Centromere-associated protein-E (CENP-E) is a mitotic kinesin which plays roles in cell division, and is regarded as a promising therapeutic target for the next generation of anti-mitotic agents. We designed novel fused bicyclic CENP-E inhibitors starting from previous reported dihydrobenzofuran derivative (S)-(+) 1. Our design concept was to adjust the electron density distribution on the benzene ring of the dihydrobenzofuran moiety to increase the positive charge for targeting the negatively charged L5 loop of CENP-E, using predictions from electrostatic potential map (EPM) analysis. For the efficient synthesis of our 2,3-dihydro-1-benzothiophene 1,1-dioxide derivatives, a new synthetic method was developed. As a result, we discovered 6-cyano-7-trifluoromethyl-2,3-dihydro-1 benzothiophene 1,1-dioxide derivative (+)-5d (Compound A) as a potent CENP-E inhibitor with promising potential for in vivo activity. In this Letter, we discuss the design and synthetic strategy used in the discovery of (+)-5d and structure-activity relationships for its analogs possessing various fused bicyclic L5 binding moieties. PMID- 27476143 TI - Synthesis and antileishmanial activity of the core structure of cristaxenicin A. AB - The core structure of cristaxenicin A having trans-fused dihydropyran and nine membered ring has been synthesized and evaluated the antileishmanial activity. The dihydropyran ring was synthesized by [4+2] cycloaddition reaction between an unsaturated aldehyde and a beta-alkoxy-alpha,beta-unsaturated ketone. The nine membered ring possessing alpha,beta-unsaturated aldehyde was constructed by the intramolecular NHK reaction followed by the Mitsunobu rearrangement. The racemic core structure of cristaxenicin A was evaluated the anti-leishmanial activity with an IC50 value of 2.4MUM. PMID- 27476142 TI - Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition. AB - This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity. PMID- 27476144 TI - Trypsin inhibitors for the treatment of pancreatitis. AB - Proline-based trypsin inhibitors occupying the S1-S2-S1' region were identified by an HTS screening campaign. It was discovered that truncation of the P1' moiety and appropriate extension into the S4 region led to highly potent trypsin inhibitors with excellent selectivity against related serine proteases and a favorable hERG profile. PMID- 27476145 TI - Gold catalyzed double condensation reaction: Synthesis, antimicrobial and cytotoxicity of spirooxindole derivatives. AB - Microwave assisted synthesis of spirooxindoles via tandem double condensation between isatins and 4-hydroxycoumarin under gold catalysis is reported. The reaction is practical to perform, since the products can be isolated by simple filtration without requiring tedious column chromatography. The scope of this chemistry is exemplified by preparing structurally diverse spirooxindoles (22 examples) in excellent yields. Antimicrobial evaluation of the synthesized compounds revealed that three compounds (3a, 3f and 3s) exhibited significant MIC values in comparison to the standard drugs. Molecular docking studies of these compounds with AmpC-beta-lactamase receptor revealed that 3a exhibited minimum binding energy (-117.819kcal/mol) indicating its strong affinity towards amino acid residues via strong hydrogen bond interaction. All compounds were also evaluated for their in vitro cytotoxicity against COLO320 cancer cells. Biological assay and molecular docking studies demonstrated that 3g is the most active compound in terms of its low IC50 value (50.0MUM) and least free energy of binding (-8.99kcal/mol) towards CHK1 receptor, respectively. PMID- 27476147 TI - Bodies in nature: Associations between exposure to nature, connectedness to nature, and body image in U.S. adults. AB - Here, we sought to replicate previous work showing a relationship between connectedness to nature and body appreciation, and extend it by examining associations between exposure to natural environments and other body image related variables. An online sample of 399 U.S. women and men (Mage=34.55 years) completed measures of body appreciation, connectedness to nature, nature exposure, appearance investment, sociocultural attitudes towards appearance, and self-esteem. Path analysis showed that nature exposure and connectedness to nature, respectively, were associated with body appreciation in women and men, both directly and indirectly via self-esteem. Connectedness to nature also mediated the link between nature exposure and body appreciation. In men, but not women, the link between connectedness to nature and body appreciation was also mediated by appearance investment and internalisation of a muscular ideal. These results may point to novel methods for promoting more positive body image in adults through engagement with nature. PMID- 27476146 TI - Locally advanced pancreatic duct adenocarcinoma: pancreatectomy with planned arterial resection based on axial arterial encasement. AB - : Pancreatectomy with arterial resection for locally advanced pancreatic duct adenocarcinoma (PDA) is associated with high morbidity and is thus considered as a contraindication. The aim of our study was to report our experience of pancreatectomy with planned arterial resection for locally advanced PDA based on specific selection criteria. MATERIAL AND METHODS: All patients receiving pancreatectomy for PDA between October 2008 and July 2014 were reviewed. The patients were classified into group 1, pancreatectomy without vascular resection (66 patients); group 2, pancreatectomy with isolated venous resection (31 patients), and group 3, pancreatectomy with arterial resection for locally advanced PDA (14 patients). The primary selection criteria for arterial resection was the possibility of achieving a complete resection based on the extent of axial encasement, the absence of tumor invasion at the origin of celiac trunk (CT) and superior mesenteric artery (SMA), and a free distal arterial segment allowing reconstruction. Patient outcomes and survival were analyzed. RESULTS: Six SMA, two CT, four common hepatic artery, and two replaced right hepatic artery resections were undertaken. The preferred arterial reconstruction was splenic artery transposition. Group 3 had a higher preoperative weight loss, a longer operative time, and a higher incidence of intraoperative blood transfusion. Ninety-day mortality occurred in three patients in groups 1 and 2. There were no statistically significant differences in the incidence, grade, and type of complications in the three groups. Postoperative pancreatic fistula and postpancreatectomy hemorrhage were also comparable. In group 3, none had arterial wall invasion and nine patients had recurrence (seven metastatic and two loco regional). Survival and disease-free survival were comparable between groups. CONCLUSION: Planned arterial resection for PDA can be performed safely with a good outcome in highly selected patients. Key elements for defining the resectability is based on the extent of the axial arterial encasement with two criteria: the origin of the CT and SMA are free from tumor invasion and the possibility of distal reconstruction. PMID- 27476148 TI - The design of symmetric protein nanomaterials comes of age in theory and practice. AB - In nature, protein molecules have evolved as building blocks for the assembly of diverse and complex structures, many of which exhibit a high degree of symmetry. This observation has motivated a number of recent engineering efforts in which the advantages of symmetry have been exploited to design novel self-assembling protein structures of great size. Materials ranging from cages to extended two and three-dimensional arrays have been demonstrated. Especially for extended arrays, a vast number of geometrically different design types are possible. A table of geometric rules is provided for designing a universe of novel materials by combining two component symmetries. PMID- 27476149 TI - Extracorporeal photopheresis as an immunomodulatory agent: Haematocrit-dependent effects on natural killer cells. AB - The GvHD is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) represents an alternative therapeutic strategy to immunosuppressive therapy. Although ECP is used since 1990s, the mechanism of action has not yet been completely clarified. We analyzed cells collected from 20 ECP procedures of 4 patients affected by chronic GvHD and, for comparison, Peripheral Blood Mononuclear Cells (PBMCs) of 10 healthy donors undergoing from same type of photochemiotherapy, evaluating by flow cytometry, the effects before and after photoactivation with 8-MOP. The analysis showed a significant increase in cell death after ECP in particular in CD4 T lymphocytes as described in literature correlated with haematocrit value. Most interesting data emerge from the analysis of cytotoxic activity of NK cells, using flow cytometry analysis of surface expression of CD107a in the presence of target cells (K562). In all analyzed samples it was possible to document a statistically significant reduction of the cytotoxic activity of NK cells after photoactivation. The decrease of the cytotoxic activity was related to hematocrit value of leukoapheresis: in fact, lower HCT values were associated with a more marked reduction of cytotoxic activity. The study confirms literature data about the increase of cellular mortality induce by ECP. Furthermore, for the first time it is demonstrated that the ECP exerts a marked and significant inhibitory effect on the cytotoxic activity of NK cells. Our study suggests that lower values of hematocrit are associated with better treatment outcome. PMID- 27476150 TI - Surgical intervention and perioperative risk factors of retroperitoneal teratomas in children: a single institution experience. AB - PURPOSE: Retroperitoneal teratomas (RTs) are rare among germ cell tumors and predominantly occur in infants. RTs are often difficult to manage by perioperative management. In this study, we retrospectively reviewed our series of RTs. METHODS: Seventy patients with germ cell tumors were treated from 1989 to 2015 in our institution. Fourteen patients had RTs (3 boys and 11 girls). The median age at diagnosis was 5.5 months (range 0-64), and three were antenatally diagnosed. RESULTS: All except one patient underwent total tumor excision. They exhibited dense adhesions with major vessels, and ligation of the splenic and gastroduodenal arteries was required in two patients. Injuries of PV and renal artery occurred in two patients. IVC injury in a neonate with a giant mass caused circulatory failure and brain death occurred postoperatively. Other major complications included injury of the diaphragm and bile duct. An infant whose tumor compressed the superior mesenteric artery developed enteritis while waiting for surgery and non-occlusive mesenteric ischemia, resulting in massive intestinal necrosis. The perioperative complication rate was 50 %. CONCLUSION: Surgery for RTs remains challenging, and a preoperative evaluation of the vascular anatomy is crucial due to the high complication rate. Moreover, pre- and intraoperative fluid management is important to avoid any unexpected fatalities. PMID- 27476151 TI - Prognostic values of serum bilirubin at 7th day post-Kasai for survival with native livers in patients with biliary atresia. AB - BACKGROUND: Biliary atresia (BA) is a serious liver disease with uncertain prognosis. The objective of this study was to investigate prognostic values of the >20 % decrease in serum total bilirubin (TB) at 7th day post-op regarding early outcome and 5-year survival with native liver in BA. METHODS: Biliary atresia patients undergoing Kasai operation between 2000 and 2014 were reviewed. The ratio of serum TB at 7th day post-op to pre-op TB levels (TB7/TB0) was calculated for every patient. TB7/TB0 ratio of <0.8 indicated the >20 % decrease in serum TB. At 6th month following Kasai operation, outcome of BA patients were categorized into good outcome (TB < 2 mg % or clinically jaundice free) and poor outcome (TB > 2 mg % or clinically jaundice). For outcome analysis, logistic regression was used. For survival analysis, Cox regression was applied. RESULTS: There were 133 BA patients (M:F = 68:65) undergoing Kasai operation. Median age at surgery was 79 days. BA patients with TB7/TB0 ratio of <0.8 were found in 38 %. Outcome at 6-month post-op could be evaluated in 126 patients (good: poor = 68:58). The 1-, 3- and 5-year survival rates with native livers were 85, 70 and 65 %, respectively. The median overall survival with native livers was 164 months. Median follow-up time was 87 months. Logistic regression showed that gender and age at operation were not significant factors impacting on early outcome (p > 0.05). However, TB7/TB0 ratio of <0.8 was an independent factor for good outcome (Odds ratio = 3.0, p = 0.006). Cox regression analysis demonstrated that 5-year survival rate was significantly correlated with TB7/TB0 ratio of <0.8 (HR = 0.46, 95 % CI 0.23-0.91, p = 0.025) and outcome at 6th month post-op (HR = 0.05, 95 % CI 0.01-0.15, p < 0.001). CONCLUSIONS: The >20 % decrease in serum TB at 7th day post-Kasai is a predictor for good outcome. BA patients with TB7/TB0 of <0.8 had 5-year survival with native livers significantly higher than those with the ratio of >0.8. PMID- 27476152 TI - Abdominal wall regenerative medicine for a large defect using tissue engineering: an experimental study. AB - PURPOSE: Treatment for a large abdominal wall defect remains challenging. The aim of this study was to optimize tissue engineering therapy of muscle constructs using a rat model. METHODS: Experimental abdominal wall defects were created in Wister rats. The animal model was divided into three groups: collagen sponge (CS), hybrid scaffold (HS) and hybrid scaffold containing bone marrow liquid (HSBM). Hybrid scaffolds comprised collagen sponge and poly L-lactide (PLLA) sheets. Abdominal wall defects were covered by three kinds of sheets. Thereafter, the bone marrow liquid was spread onto the sheets. Rats were killed at 4, 8, and 16 weeks. Pathological examinations were performed using hematoxylin-eosin and desmin antibody staining. RESULTS: The CS group showed abdominal hernia, whereas the HS and HSBM groups did not. Vascular formation was confirmed in all groups. Muscle tissue was recognized at the marginal area of the sheet only in the HSBM group. CONCLUSION: The HS and HSBM groups show a greater intensity than the CS group. Muscle tissue regeneration is solely recognized in the HSBM group. Our experimental data suggest that the triad of scaffold, cell, and growth factor is fundamental for ideal biomaterials. The HSBM may be useful for reconstruction of abdominal wall defects. PMID- 27476154 TI - Recalcitrant Venous Leg Ulcers May Heal by Outpatient Treatment of Venous Disease Even in the Presence of Concomitant Arterial Occlusive Disease. AB - OBJECTIVE/BACKGROUND: Peripheral arterial occlusive disease (PAOD) is reported in about 15-20% of patients with venous leg ulcers (VLU). In such cases arterial recanalization is often recommended, and compression therapy is considered a contraindication when the ankle brachial pressure index (ABPI) is < 0.8. The aim of this study was to compare the outcome of patients with recalcitrant VLU, both without any arterial impairment ("pure venous recalcitrant leg ulcer" [pvRLU]) and with associated PAOD ("mixed arterial and venous recalcitrant leg ulcer" [mavRLU]), by treating only the venous disease. METHODS: The records of 180 outpatients with recalcitrant ulcers treated between January 2011 and July 2014 were reviewed retrospectively. In total, 109 were affected by pvRLU and 71 by mavRLU, with moderate PAOD defined by an ABPI between 0.5 and 0.8. In addition to the same local wound dressing, the patients received ultrasound guided foam sclerotherapy of the refluxing superficial veins and a modified inelastic compression with a pressure <= 40 mmHg. No patient was referred for arterial revascularization. The patients were followed until ulcer healing. RESULTS: Patients with pvRLU and mavRLU showed comparable demographic characteristics. Twenty-five patients were lost to follow up and the outcomes were analyzed in 93 patients with pVLU (85.4%) and in 62 patients with mavRLU (87.4%). The maximum time to complete healing was 48 weeks in the pvRLU group and 52 weeks in the mavRLU group (p = .009), The median healing time was 23 (pvRLU) versus 25.5 weeks (mavRLU) (p = .030). Deep venous incompetence (p < .001), ulcer surface area (p < .001), arterial disease (p = .002), and ulcer duration (p < .010) were risk factors for prolonged healing. CONCLUSION: Treatment of recalcitrant leg ulcers by treating venous incompetence by foam sclerotherapy and modified compression is successful, even if underlying moderate PAOD is not actively treated. PMID- 27476153 TI - Use of the UPOINT Classification in Turkish Chronic Prostatitis or Chronic Pelvic Pain Syndrome Patients. AB - OBJECTIVE: To determine the positive subdomain numbers and distribution of the UPOINT classification in chronic prostatitis and to compare the erectile dysfunction (ED) pattern. MATERIALS AND METHODS: From 2008 to 2013, 839 patients with symptomatic chronic prostatitis or chronic pelvic pain syndrome were included in this study. The correlation between UPOINT domains and National Institutes of Health chronic prostatitis symptom index (NIH-CPSI) total score, subscores, and the 5-item International Index of Erectile Function scores were evaluated retrospectively. RESULTS: The mean patient age was calculated as 37.7 +/- 7.4 (range 21-65). The average total NIH-CPSI score was determined as 9.07 (range 1-40) and the average positive UPOINT subdomain number was determined as 2.87 +/- 0.32 (range 1-6). Subdomain patient numbers and rates were calculated as 529 urinary (63%), 462 psychosocial (55%), 382 organ specific (45%), 290 infection (34%), 288 neurological or systemic (34%), and 418 tenderness (skeletal muscle) (50%), respectively. It was determined that ED, determining the subdomain of sexual dysfunction in patients, was positive in a total of 326 (39.9%) patients, with 220 patients having mild (26.2%), 76 mild to moderate (9.1%), 19 moderate (2.3%), and 5 with severe (0.6%) ED. A statistically significant correlation was not determined between the 5-item International Index of Erectile Function score and UPOINT subdomain number and NIH-CPSI score. CONCLUSION: It has been determined that although there is a strong and significant correlation between UPOINT classification and NIH-CPSI score in Turkish patients with chronic prostatitis or chronic pelvic pain syndrome, the inclusion of ED as an independent subdomain to the UPOINT classification is not statistically significant. PMID- 27476155 TI - Ruptured Subclavian Aneurysm Revealed by Haemoptysis. PMID- 27476156 TI - Role of dopamine neurotransmission in the long-term effects of repeated social defeat on the conditioned rewarding effects of cocaine. AB - Numerous studies report that social defeat stress alters dopamine (DA) neurotransmission in several areas of the brain. Alterations of the mesolimbic dopaminergic pathway are believed to be responsible for the increased vulnerability to drug use observed as a result of social stress. In the present study, we evaluated the influence of DA receptors on the long-term effect of repeated social defeat (RSD) on the conditioned rewarding and reinstating effects of cocaine. For this purpose, the D1R antagonist SCH 23390 and the D1R antagonist raclopride were administered 30min before each social defeat and a cocaine induced CPP procedure was initiated three weeks later. The expression of the D1R and D2R was also measured in the cortex and hippocampus throughout the entire procedure. Mice exposed to RSD showed an increase in the conditioned rewarding effects of cocaine that was blocked by both DA receptors antagonists when a subthreshold dose of cocaine was employed. However, while the vulnerability to reinstatement of the preference induced by 25mg/kg cocaine-induced CPP was abolished by the D1R antagonist, it was practically unaffected by raclopride. Increases in D2R receptor levels were observed in the cortex of defeated animals after the first and fourth social defeats and in the hippocampus 3weeks later. Nevertheless, D1R receptor levels in the hippocampus decreased only after the last social defeat. Our results confirm that RSD enhances the conditioned rewarding effects of cocaine and that both DA receptors are involved in this enduring effect of social stress. PMID- 27476157 TI - Organogold(III) compounds as experimental anticancer agents: chemical and biological profiles. AB - In the last few years gold(III) complexes have attracted growing attention in the medicinal chemistry community as candidate anticancer agents. In particular some organogold(III) compounds manifested quite attractive pharmacological behaviors in preclinical studies. Here we compare the chemical and biological properties of the novel organogold(III) complex [Au(bipy(dmb)-H)(NH(CO)CH3)][PF6] (Aubipy(aa)) with those of its parent compounds [Au(bipy(dmb)-H)(OH)][PF6] (Aubipy(c)) and [Au2(bipy(dmb)-H)2)(MU-O)][PF6]2 (Au2bipy(c)), previously synthesized and characterized. The three study compounds were comparatively assessed for their antiproliferative actions against HCT-116 cancer cells, revealing moderate cytotoxic effects. Proapoptotic and cell cycle effects were also monitored. Afterward, to gain additional mechanistic insight, the three gold compounds were challenged against the model proteins HEWL, RNase A and cytochrome c and reactions investigated through UV-Vis and ESI-MS analysis. A peculiar and roughly invariant protein metalation profile emerges in the three cases consisting of protein binding of {Au(bipy(dmb)-H)} moieties. The implications of these results are discussed in the frame of current knowledge on anticancer gold compounds. PMID- 27476158 TI - Homeostasis of chosen bioelements in organs of rats receiving lithium and/or selenium. AB - Lithium is an essential trace element, widely used in medicine and its application is often long-term. Despite beneficial effects, its administration can lead to severe side effects including hyperparathyroidism, renal and thyroid disorders. The aim of the current study was to evaluate the influence of lithium and/or selenium treatment on magnesium, calcium and silicon levels in rats' organs as well as the possibility of using selenium as an adjuvant in lithium therapy. The study was performed on rats divided into four groups (six animals each): control-treated with saline; Li-treated with Li2CO3 (2.7 mg Li/kg b.w.); Se-treated with Na2SeO3.H2O (0.5 mg Se/kg b.w.); Se + Li-treated simultaneously with Li2CO3 and Na2SeO3.H2O (2.7 mg Li/kg b.w. and of 0.5 mg Se/kg b.w., respectively). The administration was performed in form of water solutions by stomach tube once a day for 3 weeks. In the organs (liver, kidney, brain, spleen, heart, lung and femoral muscle) the concentrations of magnesium, calcium and silicon were determined. Magnesium was increased in liver of Se and Se + Li given rats. Lithium decreased tissue Ca and co-administration of selenium reversed this effect. Silicon was not affected by any treatment. The beneficial effect of selenium on disturbances of calcium homeostasis let suggest that further research on selenium application as an adjuvant in lithium therapy is worth being performed. PMID- 27476159 TI - Long-Term Effect of Cranial Radiotherapy on Pituitary-Hypothalamus Area in Childhood Acute Lymphoblastic Leukemia Survivors. AB - OPINION STATEMENT: Survival rates of childhood cancer have improved markedly, and today more than 80 % of those diagnosed with a pediatric malignancy will become 5 year survivors. Nevertheless, survivors exposed to cranial radiotherapy (CRT) are at particularly high risk for long-term morbidity, such as endocrine insufficiencies, metabolic complications, and cardiovascular morbidity. Deficiencies of one or more anterior pituitary hormones have been described following therapeutic CRT for primary brain tumors, nasopharyngeal tumors, and following prophylactic CRT for childhood acute lymphoblastic leukemia (ALL). Studies have consistently shown a strong correlation between the total radiation dose and the development of pituitary deficits. Further, age at treatment and also time since treatment has strong implications on pituitary hormone deficiencies. There is evidence that the hypothalamus is more radiosensitive than the pituitary and is damaged by lower doses of CRT. With doses of CRT <50 Gy, the primary site of radiation damage is the hypothalamus and this usually causes isolated GH deficiency (GHD). Higher doses (>50 Gy) may produce direct anterior pituitary damage, which contributes to multiple pituitary deficiencies. The large group of ALL survivors treated with CRT in the 70-80-ties has now reached adulthood, and these survivors were treated mainly with 24 Gy, and the vast majority of these patients suffer from GHD. Further, after long-term follow-up, insufficiencies in prolactin (PRL) and thyroid stimulating hormone (TSH) have also been reported and a proportion of these patients were also adrenocoticotrophic hormone (ACTH) deficient. CRT to the hypothalamus causes neuroendocrine dysfunction, which means that the choice of GH test is crucial for the diagnosis of GHD. PMID- 27476160 TI - Behavioral and genotoxic evaluation of rosmarinic and caffeic acid in acute seizure models induced by pentylenetetrazole and pilocarpine in mice. AB - The goal of this study was to investigate the effects of rosmarinic acid (RA) and caffeic acid (CA) in the acute pentylenetetrazole (PTZ) and pilocarpine (PIL) seizure models. We also evaluated the effect of RA and CA on the diazepam (DZP) induced sleeping time test and its possible neuroprotective effect against the genotoxic damage induced by PTZ and PIL. Mice were treated intraperitoneally (i.p.) with saline, RA (2 or 4 mg/kg), or CA (4 or 8 mg/kg) alone or associated to low-dose DZP. After, mice received a single dose of PTZ (88 mg/kg) or PIL (250 mg/kg) and were monitored for the percentage of seizures and the latency to first seizure (LFS) >3 s. Vigabatrin and DZP were used as positive controls. In the DZP induced sleeping time test, mice were treated with RA and CA and 30 min after receiving DZP (25 mg/kg, i.p.). The alkaline comet assay was performed after acute seizure tests to evaluate the antigenotoxic profiles of RA and CA. The doses of RA and CA tested alone did not reduce the occurrence of seizures induced by PTZ or PIL. The association of 4 mg/kg RA + low-dose DZP was shown to increase LFS in the PTZ model, compared to the group that received only the DZP. In the DZP-induced sleeping time test, the latency to sleep was reduced by 4 mg/kg RA and 8 mg/kg CA. The PTZ-induced genotoxic damage was not prevented by RA or CA, but the PIL-induced genotoxic damage was decreased by pretreatment with 4 mg/kg RA (in cortex) and 4 mg/kg CA (in hippocampus). In conclusion, RA and CA presented neuroprotective effect against PIL-induced genotoxic damage and reduced the latency to DZP-induced sleep. Of the rosmarinic acid, 4 mg/kg enhanced the DZP effect in the increase of latency to clonic PTZ-induced seizures. PMID- 27476161 TI - Integrins AV and B8 Gene Polymorphisms and Risk for Intracerebral Hemorrhage in Greek and Polish Populations. AB - Alpha limited number of genetic variants have been linked to the development of intracerebral hemorrhage (ICH). Iotantegrin AV and/or B8-deficient mice were found to develop ICH. The present candidate gene association study was designed to investigate possible influence of integrin AV (ITGAV) and integrin B8 (ITGB8) gene region polymorphisms on the risk of ICH. 1015 participants (250 Greek and 193 Polish patients with primary ICH and 250 Greek and 322 Polish controls) were included in the study. Using logistic regression analyses, 11 tag single nucleotide polymorphisms (SNPs) for ITGAV and 11 for ITGB8 gene were tested for associations with ICH risk, lobar ICH risk and non-lobar ICH after adjustment for age, gender, history of hypertension and country of origin. Linear regression models were used to test the effect of tag SNPs on the ICH age of onset. Correction for multiple comparisons was carried out. The rs7565633 tag SNP of the ITGAV gene was independently associated with the risk of lobar ICH in the codominant model of inheritance [odds ratio (95 % confidence interval (CI)) 0.56 (0.36-0.86), p = 0.0013]. Furthermore, heterozygous individuals of the rs10251386 and the rs10239099 of the ITGB8 gene had significantly lower age of ICH onset compared to the wild-type genotypes [regression coefficient (b) -3.884 (95 % CI 6.519, -1.249), p = 0.0039 and b = -4.502 (95 % CI -7.159, -1.845), p = 0.0009, respectively]. The present study provides preliminary indication for an influence of ITGAV gene tag SNP in the development of lobar ICH and of ITGB8 gene variants in the age of ICH onset. PMID- 27476162 TI - Improving Human Papillomavirus (HPV) Vaccination in the Postpartum Setting. AB - Although the HPV vaccine has been shown to be highly effective in preventing cervical dysplasia, vaccination rates remain low. The objective of this study was to assess the effectiveness of an electronic medical record (EMR) prompt on HPV vaccination rates in the postpartum setting. We conducted a pre-post intervention study among postpartum women ages 18-26 seen at an outpatient clinic from 09/01/2012-08/31/2013 (pre-intervention) and from 10/01/2013-03/31/2014 (post intervention). The intervention was a drop-down menu that was inserted into the EMR postpartum note template inquiring about the patient's HPV vaccination status and whether or not the vaccine was administered at that visit. HPV vaccination uptake was compared pre and post-intervention. Of the 278 postpartum visits during the study period, 241 were eligible for analysis. There was a significant increase of the HPV vaccine uptake, from 1.2 % (2/173) among pre-intervention visits to 26.5 % (18/68) among post-intervention visits (p < 0.001). After adjusting for age, ethnicity, insurance, and religion, HPV vaccination was significantly higher at postpartum visits during the intervention period, with an adjusted OR = 93.49 [95 % CI 15.29-571.52]. Among visits in which the vaccine was not given, HPV vaccination was not discussed in 46 % and patients refused the vaccine in 40 % of visits. An EMR prompt in the postpartum note could be an effective way to promote HPV vaccination in the postpartum setting. It will likely take a combination of strategies to optimize vaccination uptake. PMID- 27476164 TI - Using observed sequence to orient causal networks. AB - In learning causal networks, typically cross-sectional data are used and the sequence among the network nodes is learned through conditional independence. Sequence is inherently a longitudinal concept. We propose to learn sequence of events in longitudinal data and use it to orient arc directions in a network learned from cross-sectional data. The network is learned from cross-sectional data using various established algorithms, with one modification. Arc directions that do not agree with the longitudinal sequence were prohibited. We established longitudinal sequence through two methods: Probabilistic Contrast, and Goodman and Kruskal error reduction methods. In simulated data, the error reduction method was used to learn the sequence in the data. The procedure reduced the number of arc direction errors and larger improvements were observed with increasing number of events in the network. In real data, different algorithms were used to learn the network from cross-sectional data, while prohibiting arc directions not supported by longitudinal information. The agreement among learned networks increased significantly. It is possible to combine sequence information learned from longitudinal data with algorithms organized for learning network models from cross-sectional data. Such models may have additional causal interpretation as they more explicitly take into account observed sequence of events. PMID- 27476163 TI - Redefining the implications of nasogastric tube placement following radical cystectomy in the alvimopan era. AB - PURPOSE: Alvimopan has decreased ileus and need for nasogastric tube (NGT) after radical cystectomy (RC). However, the natural history of ileus versus intestinal obstruction in patients receiving alvimopan is not well defined. We sought to examine the implications of NGT placement before and after the introduction of alvimopan for RC patients. METHODS: Retrospective review identified 278 and 293 consecutive patients who underwent RC before and after instituting alvimopan between June 2009 and May 2014. Baseline characteristics and postoperative outcomes were compared by alvimopan status. Multivariate logistic regression was performed to assess the impact of alvimopan on rates of NGT placement and reoperation for bowel complications. RESULTS: The cohorts had similar age, stage, approach, and BMI. Patients receiving alvimopan had decreased ileus (16 vs 32 %, p < 0.01) but similar rates of reoperation for bowel complications (2.8 vs 2.7 %). On multivariate analysis, alvimopan was associated with lower risk of NGT placement (OR 0.30, p < 0.01). For patients requiring NGT placement, there was an increased rate of reoperation among patients receiving alvimopan compared with those who did not (28 vs 11 %, p = 0.03). Patients receiving alvimopan who needed NGT had significantly increased median length of stay (22 vs 7 days), need for TPN (66 vs 5.3 %), and readmission for ileus (10.3 vs 2.3 %) compared with those who did not require NGT. CONCLUSIONS: Alvimopan significantly reduced the incidence of ileus and NGT placement following RC. NGT placement was associated with an increased need for reoperation for bowel complications in the setting of alvimopan. PMID- 27476166 TI - Pathogenesis of antimicrobial peptides LL-37 and CpG-ODN in ANCA associated vasculitis. AB - OBJECTIVES: Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) are a group of systemic autoimmune disorders characterized by necrotizing inflammation of small- to medium-sized blood vessels. The pathogenesis of patients with AAV are still in investigation. In this study, we explored the involvement of LL-37 and nucleic acids in AAV. METHODS: 15 patients with AAV diagnosed according to the Chapel Hill definition between October 2014 and July 2015 in the department of Nephrology of Huangdao, affiliated Hospital of Qingdao University were enrolled. 16 patients with chronic bronchitis (CB) were selected as disease control group. 15 cases of healthy people from Medical Healthy Center were as healthy control group. Peripheral blood mononuclear cells (PBMCs) were collected from these groups and stimulated by LL-37and (or) two types of CpG-ODN for 7 days. The IFN-alpha and ANCA in vitro were measured by ELISA. The serum IFN alpha, LL-37 and ANCA were measured also. RESULTS: The serum level of IFN-alpha in AAV group was much higher than that in CB group (692.13 +/- 407.28 vs 397.07 +/- 211.62 pg/ml, p = 0.019), and that in healthy control group (692.13 +/- 407.28 vs 251.54 +/- 190.46 pg/ml, p < 0.001). The serum level of LL-37 in AAV group was much higher than that in CB group (101.18 +/- 66.59 vs 40.23 +/- 13.51 ng/ml, p < 0.001, and that in healthy control group (101.18 +/- 66.59 vs 27.80 +/ 16.86 ng/ml, p < 0.001). Also the level of IFN-alpha showed a significant positive relationship with ANCA in AAV group both in serum and in supernatant of cultured PBMCs stimulated by LL-37 and (or) CpG-ODN (r = 0.783, p = 0.001; r = 0.575, p = 0.064; r = 0.649, p = 0.031; r = 0.806, p = 0.003). In patients with AAV, the supernatant levels of IFN-alpha in cultured PBMCs stimulated by LL-37 and (or) CpG-ODN were higher than that without stimulating factor (p < 0.05). The supernatant level of IFN-alpha in cultured PBMC stimulated by LL-37 alone was lower than that stimulated by CpGA alone (699.57 +/- 476.26 vs 2342.63 +/- 2025.11 pg/ml, p = 0.001). But the supernatant level of IFN-alpha in cultured PBMCs stimulated by LL-37 alone was higher than in that stimulated by CpGB alone (699.57 +/- 476.26 vs 153.35 +/- 78.08 pg/ml, p < 0.001). The supernatant level of IFN-alpha in cultured PBMCs stimulated by both LL-37 and CpG-ODN was higher than that stimulated by LL-37 or CpG-ODN alone (2550.57 +/- 2217.41 vs 699.57 +/- 476.26 pg/ml, p = 0.003; 2550.57 +/- 2217.41 vs 153.35 +/- 78.08 pg/ml, p = 0.001; 2660.95 +/- 391.31 vs 699.57 +/- 476.26 pg/ml, p < 0.001; 2660.95 +/- 391.31 vs 153.35 +/- 78.08 pg/ml, p < 0.001). Either it is stimulated by LL-37 or CpG-ODN or both, the supernatant level of IFN-alpha in cultured PBMCs in AAV patients was the highest, that in healthy controls was the lowest. Either stimulated by LL-37 or CPG-ODN, or both, the levels of ANCA production in vitro in AAV groups were statistically significantly higher than those in CB group and healthy control group. CONCLUSIONS: There were higher serum levels of LL-37 and IFN-alpha in patients with AAV. IFN-alpha could reach a higher level stimulated by LL-37 and nucleic acids both of which are related to infection. Patients with AAV have ANCA-producing B lymphocytes in the circulation even in remission stage. Infections could induce the relapse of AAV. PMID- 27476167 TI - Inhibition on Numb/Notch signal pathway enhances radiosensitivity of lung cancer cell line H358. AB - The objective of the study is to investigate the effects of the Numb/Notch signal pathway on the radiosensitivity of lung cancer cell line H358. MTT assay and colony forming assay were used to detect the effects of different doses of X-rays and MW167 on the in vitro proliferation of the lung cancer cell line H358. Flow cytometry was applied to evaluate the effects of X rays on the apoptosis of H358. Scratch assay and Transwell invasion assay were used to examine the effects of X rays on the migration and invasion abilities of H358. The mRNA and protein expressions in the signal pathway were detected by real-time PCR and western blot. Assays in vitro confirmed the effects of the Numb/Notch pathway inhibitor on the radiosensitivity to lung cancer. MW167 enhanced the inhibiting effects of X-ray on the proliferation of H358 cell line. After the addition of MW167, the apoptosis rates significantly increased, but the invasion and migration abilities decreased significantly. Meanwhile, MW167 could dose-dependently promote the increase of expression of Numb, which is the upstream gene of the Numb/Notch signaling pathway, but inhibit the expression of and HES1. In vivo experiments revealed that cell proliferation was suppressed in the radiation, pathway inhibitor, and pathway inhibitor + radiation groups, and the pathway inhibitor + radiation group exhibited more active anti-tumor ability when compared with the blank group (all P < 0.05); Numb expression was up-regulated, but Notch1 and HES1 expressions were down-regulated in those three groups, and also, the pathway inhibitor + radiation group exhibited more significant alternation when compared with the blank group (all P < 0.05); cell apoptosis was promoted in those three groups, and the pathway inhibitor + radiation group showed more active apoptosis when compared with the blank group (all P < 0.05). Repression of the Numb/Notch pathway enhances the effects of radiotherapy on the radiosensitivity of the lung cancer cell line H358, and thus the Numb/Notch pathway may be a new target of radiotherapy for lung cancer. PMID- 27476168 TI - Interactions between FGFR2 and RSK2-implications for breast cancer prognosis. AB - We have previously demonstrated that fibroblast growth factor receptor 2 (FGFR2) activates ribosomal s6 kinase 2 (RSK2) in mammary epithelial cells and that this pathway promotes in vitro cell growth and migration. Potential clinical significance of FGFR2 and RSK2 association has never been investigated. Herein, we have undertaken an evaluation of a possible relationship between FGFR2/RSK2 interdependence and disease outcome in breast cancer (BCa) patients. The clinical analysis was complemented by an in vitro investigation of an involvement of RSK2 in the regulation of FGFR2 function. Primary tumour samples from 152 stage I-III BCa patients were examined for FGFR2 and RSK2 gene and protein expression. FGFR2 showed a positive correlation with RSK2 at both protein (p = 0.003) and messenger RNA (mRNA) (p = 0.001) levels. Lack of both FGFR2 and activated RSK (RSK-P) significantly correlated with better disease-free survival (DFS) (p = 0.01). Patients with tumours displaying immunoreactivity for either or both FGFR2 and RSK-P had 4.89-fold higher risk of recurrence when compared to the FGFR2/RSK-P negative subgroup. FGFR2-RSK2 interactions were verified by co immunoprecipitation and internalization assays in HB2 mammary epithelial cell line (characterized by high endogenous FGFR2 and RSK2 expression). In vitro analyses revealed that FGFR2 and RSK2 formed an indirect complex and that activated RSK exerted a significant impact on fibroblast growth factor 2 (FGF2) triggered internalization of FGFR2. Our results suggest that the FGFR2-RSK2 signalling pathway is involved in pathophysiology of BCa and evaluation of FGFR2/RSK-P expression may be useful in disease prognostication. PMID- 27476170 TI - A guide for the analysis of long-term population growth in cancer. AB - Although cancer is a chronic disease, most of the in vitro experiments to assess the effectiveness of intervention are performed in hours or a few days. Moreover, none of the available methodologies to measure cell proliferation are adapted to provide information about the growth kinetic during and after treatment. Thus, the objective of this work is to provide a guide to assess long-term changes in cell population size to be used mainly in cancer research. Cumulative population doubling (CPD) graphs based on cell counting for in vitro or tumor volume for in vivo assays were used to calculate four parameters: relative end CPD (RendCPD), to quantify the end point analysis of proliferation; relative area under curve (rAUC), to describe the global chronic effect of a treatment; relative time to cross a threshold (RTCT), to indicate the delay in cell population recovery produced by a treatment; and relative proliferation rate (RPR), to describe the relative regrowth velocity of the cells that survived after treatment. These parameters describe not only the acute and chronic effects of a treatment but also the behavior of cells that are not eliminated by the treatment, providing crucial information about the growth kinetic of the surviving population. Moreover, the proposed analysis allowed the grouping of independent CPD experiments quantified at different time points and even the direct comparison of in vitro and in vivo experiments. Therefore, this new way to analyze long-term outcomes provides a global view of the effectiveness of an intervention, as an important tool for long-term studies. PMID- 27476169 TI - Knockdown of miR-182 promotes apoptosis via regulating RIP1 deubiquitination in TNF-alpha-treated triple-negative breast cancer cells. AB - Overexpression of microRNA-182 (miR-182) is found in multiple cancers, but the association of miR-182 expression with the sensitivity of triple-negative breast cancer (TNBC) cells to tumor necrosis factor-alpha (TNF-alpha) remains unknown. In this study, up-regulation of miR-182 was validated in TNBC patients and cell lines. Knockdown of miR-182 was observed to hinder the proliferation of BT-549 cells. More importantly, knockdown of miR-182 significantly promoted the apoptosis induced by TNF-alpha treatment in BT-549. JC-1 staining and western blot assays revealed that the K63-linked ubiquitin chains on receptor-interacting protein 1 (RIP1) were removed and the outer mitochondrial membrane potential (MMP) and permeability was altered upon combination of TNF-alpha with anti-miR 182. We then demonstrated that knockdown of miR-182 up-regulated the expression of cylindromatosis (CYLD) deubiquitinase, which promoted the formation of death inducing signaling complex (DISC) and subsequent caspase-8 activation in TNF alpha-treated BT-549 cells. Collectively, the results of the present study improve our understanding of the role of miR-182 in TNBC, knockdown of which facilitates the degradation of ubiquitin chains on RIP1, leading to the caspase-8 activation and apoptosis in TNF-alpha-treated TNBC cells. This may be valuable for the development of cancer therapy. PMID- 27476171 TI - miRNA-451 inhibits glioma cell proliferation and invasion by downregulating glucose transporter 1. AB - MicroRNAs play an important role in tumor development and progression. Tumor growth is closely associated with glucose metabolism. Specifically, tumor cells produce energy (ATP) under aerobic and anaerobic conditions through glycolysis and metabolites, such as lactic acid and ATP, as a result of the Warburg effect. However, the transport of glucose into cells depends on protein transporters in the cell membrane. Therefore, this area has recently become a topic of interest for research on targeted cancer therapy. We found that miRNA-451 inhibits the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway to modify the biological behavior of glioma cells. Inhibiting the PI3K/Akt pathway may prevent glucose-addicted cancer cells from performing glycolysis. Akt directly affects glycolysis by regulating the localization of the glucose transporter 1 (GLUT1). However, how miRNA-451 regulates glucose transporters on the cell membrane and affects the regulatory mechanisms of glucose metabolism in glioma cells remains unclear. Consequently, we predict and verify related gene protein interactions. By targeting CAB 39, miRNA-451 likely triggers the LKB1/AMPK/PI3K/AKT pathway, which regulates GLUT1, to inhibit the glucose metabolism of, reduce the energy supply to, and inhibit the proliferation and invasion of glioma cells. Our results suggest a new direction for the treatment of glioma. PMID- 27476172 TI - Different expression levels of glycans on leukemic cells-a novel screening method with molecularly imprinted polymers (MIP) targeting sialic acid. AB - Sialic acid (SA) is normally expressed on the cell membranes and is located at the terminal position of the sugar chains. SA plays an important role for regulation of the innate immunity, function as markers of the cells and can be recognized by a variety of receptors. Interestingly, the level of SA expression is increased on metastatic cancer cells. The availability of specific antibodies against SA is limited and, therefore, biomarker tools for detection of SA are lacking. We have recently presented a novel method for specific fluorescence labeling of SA molecular imprinted polymers (MIP). Here, we have performed an extended screening of SA expression by using SA-MIP and included four different chronic lymphocytic leukemia (CLL) cell lines, conveniently analyzed by flow cytometry and fluorescence microscopy. SA expression was detected in four cell lines at different levels, and the SA expression were verified with lectin-FITC. These results show that SA-MIP can be used as a plastic antibody for detection of SA using both flow cytometry and fluorescence microscopy. We suggest that SA-MIP can be used for screening of different tumor cells of various stages, including CLL cells. PMID- 27476173 TI - Renin-Angiotensin-Aldosterone System Antagonism and Polycystic Kidney Disease Progression. AB - Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease characterised by the formation of multiple renal cysts that adversely affect renal function. ADPKD shows significant progression with age when complications due to hypertension are most significant. The activation of the renin-angiotensin aldosterone system (RAAS) occurs in progressive kidney disease leading to hypertension. The RAAS system may also contribute to ADPKD progression by stimulating signalling pathways in the renal cyst cells to promote growth and deregulate epithelial transport. This mini review focuses on the contribution of the RAAS system to renal cyst enlargement and the potential for antagonists of the RAAS system to suppress cyst enlargement as well as control ADPKD-associated hypertension. PMID- 27476174 TI - Assessing in vivo platelet activation in patients with liver diseases. PMID- 27476176 TI - New double-door laminoplasty procedures to preserve the muscular attachments to the spinous processes including the axis. AB - Cervical malalignment occurring after conventional laminectomy or laminoplasty is caused by intraoperative injuries to the posterior extensor mechanism, including the deep extensor muscles. To minimize such injuries, we developed a technique for muscle-preserving double-door laminoplasty below C2 (TEMPL) and TEMPL for the axis (TEMPLA) in treating patients with multisegmental cervical myelopathy. In these procedures, the posterior arches, which were sagittally split in the midline, can be opened. This leaves untouched the semispinalis cervicis and multifidus muscle attachments to each split half of the spinous process below C2, and of all five muscles to each split half of the C2 spinous process. In review of short-term surgical outcomes from 41 patients who underwent the procedures, neurological improvement was demonstrated in each patient. Postoperative kyphosis development was identified in one patient only, in whom delayed fracture occurred at the bilateral C2 laminar hinge. TEMPL and TEMPLA, in which the deep extensor musculature is preserved as an important stabilizer of the cervical spine, are effective procedures to prevent postoperative cervical malalignment. PMID- 27476177 TI - Radial recession osteotomy for early Kienbock's disease. AB - Between 1995 and 1999, ten patients with Lichtman stage II and III Kienbock's disease with negative ulnar variance underwent a joint-levelling radial recession osteotomy in our unit. The procedure was performed by the senior author in all cases. Eight patients were available for follow-up (average 31 months). Based on the Mayo Clinic modification of the Green wrist score, there were three excellent, three good and two fair results. Radiologically, there was improvement in lunate density in five of eight patients and evidence of healing in two of five patients with lunate fractures. We found that simple radial recession osteotomy for Lichtman stage II and III Kienbock's disease offers excellent early results. PMID- 27476175 TI - Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia. AB - Heme is an essential molecule in many biological processes, such as transport and storage of oxygen and electron transfer as well as a structural component of hemoproteins. Defects of heme biosynthesis in developing erythroblasts have profound medical implications, as represented by sideroblastic anemia. The synthesis of heme requires the uptake of glycine into the mitochondrial matrix where glycine is condensed with succinyl coenzyme A to yield delta-aminolevulinic acid. Herein we describe the biochemical and molecular characterization of yeast Hem25p and human SLC25A38, providing evidence that they are mitochondrial carriers for glycine. In particular, the hem25Delta mutant manifests a defect in the biosynthesis of delta-aminolevulinic acid and displays reduced levels of downstream heme and mitochondrial cytochromes. The observed defects are rescued by complementation with yeast HEM25 or human SLC25A38 genes. Our results identify new proteins in the heme biosynthetic pathway and demonstrate that Hem25p and its human orthologue SLC25A38 are the main mitochondrial glycine transporters required for heme synthesis, providing definitive evidence of their previously proposed glycine transport function. Furthermore, our work may suggest new therapeutic approaches for the treatment of congenital sideroblastic anemia. PMID- 27476178 TI - Use of freeze-dried bone allografts in revision total hip arthroplasty. AB - Acetabular loosenings with severe bone loss require a large amount of graft material to fill the defect. Although all donors are systematically subjected to serologic screening, bone allografts that are chemically processed, freeze-dried, and radiosterilized ensure a higher level of microbiological safety than radiosterilised deep-frozen allografts. The bone allograft used in this study meets this requirement. Therefore, it was both interesting and important to evaluate its outcome in revision acetabuloplasty. This phase II multi-centre study involves 44 revision total hip replacements (35 evaluable) in patients with acetabular bone defects who received allografts obtained from femoral heads harvested from living donors. The results obtained at 40 months follow-up confirmed that reconstructions using a small amount of graft material have a satisfactory outcome. Where an allograft is used in association with an acetabular ring, good primary stability is provided by the ring and secondary stability is ensured by graft incorporation (which, in our study, has often shown to be enhanced by the use of bone cement). The advantages of this type of bone allograft are its greater ease of use and storage at room temperature. PMID- 27476179 TI - The uncemented Bicontact total hip arthroplasty in octogenarians. Medium-term results. AB - Uncemented total hip arthroplasty was developed on the principle of biological fixation to enhance longevity of the prosthesis. Though the role of uncemented total hip replacement as an alternative is well accepted in young patients, its role in elderly remains controversial. We reviewed a consecutive series of 60 uncemented Bicontact total hip arthroplasties in 51 octogenarian patients with a mean follow-up of 7 (range 5-9) years. Mean patient age was 87.8 (range 80-97) years. Mean preoperative Harris hip score of 48 (range 32-65) improved postoperatively to a mean of 88 (range 58-94). There were 26 hydroxyapatite (HA) and 34 non-HA plasma pore-coated acetabular cups; one cup was revised for recurrent dislocation. Radiological evaluation revealed no unstable cups; however, two were "probably unstable" (one non-HA and one infection in an HA coated cup) and two "possibly unstable" (one HA and one non-HA cup) ( P <0.05). None of these cups were clinically symptomatic. Two femoral stems were considered "possibly unstable" and one stem "fibrous stable", while the remaining stems were "osseo-integrated". There were no revisions of either femoral stem or cup for aseptic loosening. Using the recommendation of revision as the end point, cumulative prosthesis survival rate was 98.4% at a mean follow-up of 7 years (95%CI: 95.9-99.4%). However, cumulative survival with revision being the end point for aseptic loosening was 100% for the Bicontact prosthesis. Results of our series are encouraging and justify the continued use of this prosthesis in the elderly. PMID- 27476180 TI - Retrospective analysis of 110 ankle prostheses. AB - This study presents results of 110 third-generation ankle arthroplasties performed at four principle centers with a follow-up of 3 years. Prostheses used were the Star, the LCS, and the Ramses. Indications were represented by arthrosis (72 cases, almost all of which were post-traumatic) and rheumatoid arthritis (27 cases). There were 63 women and 47 men, with an average age of 56 years. Results were generally good, especially in relation to pain, which improved in 70% of cases. Function results were less favorable, particularly in relation to dorsal flexion, which did not improve after operation. Walking perimeter increased in more than 40% of cases. In the "Conclusion," we discuss indications for ankle arthroplasty instead of arthrodesis, as of the latter are not always good, and complications are frequent. PMID- 27476181 TI - Atlantoaxial instability after minor trauma with os odontoideum in children. AB - An os odontoideum is mostly diagnosed coincidentally on the basis of either painful movement of the cervical spine or neurological symptoms, or both. Diagnostic and therapeutic options are subjects of controversial discussion in the literature.Our report is about an 11-year-old boy who developed neurological symptoms with transitory tetraparesis after a fall of 1.5 m. Conventional X-ray examination resulted in the diagnosis of a dens fracture; MRI showed atlantoaxial instability and an os odontoideum with significant cord compression. After 4 months of nonoperative treatment, the patient had complete relief of symptoms but a significant atlantoaxial instability remained. A dorsal C1/C2 fusion in a modified Brooks technique was performed.In the event of neurological symptoms or instability, the authors advocate early surgical stabilisation, even in patients with little infirmity, particularly in view of the possible consequences. PMID- 27476182 TI - Neurological deterioration due to cord and cauda compression at the site of laminar hook insertion : Immediate complication of Texas Scottish Rite Hospital instrumentation for lumbar vertebral fracture. AB - We report an unusual case of a 71-year-old female patient with incomplete paraplegia who experienced neurological deterioration a few hours after the insertion of TSRH (Texas Scottish Hospital Rite) laminar hooks for correction and stabilisation of a fracture of the first lumbar vertebra. Combined CT-myelography revealed significant encroachment of the hooks on the spinal canal, associated with compression of the spinal cord and cauda. The hardware was removed a few hours after the first operation. Two weeks after the revision operation the neurological picture improved. Three months postoperatively the patient died from lung embolism while she was improving neurologically. This case demonstrates that caution should be exercised during the introduction of laminar hooks for thoracolumbar fractures in elderly patients with degeneration of the lumbar spine and stenosis. To avoid such problems careful attention should be paid to appropriate hook selection and safe hook anchorage during fixation and distraction-compression manoeuvres. PMID- 27476183 TI - Resection of chondrosarcoma of the pubic bone. AB - The incision often described in resection of the pubic bone is one that essentially traces the outline of this bone from the pubic tubercle along the superior pubic ramus, the pubic symphysis, and then the inferior pubic ramus all the way to the ischial tuberosity. This incision is satisfactory for sub periosteal resection of the pubic bone, but it is not suitable for malignant tumors of the pubic bone extending into the adjacent soft tissues and adductor muscles. The technique of the abdominoinguinal incision is described. This involves an extraperitoneal exposure of the superior aspect of the pubic bone and exposure of the iliofemoral vessels and the adductor muscles to the extent needed to completely resect the pubic bone en bloc with the adjacent adductor muscles and other soft tissues. Repair of the resulting defect is simple, usually achieved with mesh, providing muscle coverage of the external iliac and femoral vessels to avoid direct contact between the mesh and the vessels. PMID- 27476186 TI - Recent Literature. PMID- 27476184 TI - The "Clip U2", a new device in treating distal radial fractures. AB - Fracture of the distal radius is one of the most common lesions in the trauma practice. The relation between anatomic reconstruction, early motion and good or excellent clinical outcome, is well known. The "Clip U2", a new elastic pinning device used in the treatment of the distal radius fracture, promised to secure the reduction and to allow early functional treatment with a simple and minimally invasive technique. Convinced of the possible advantages of this technique, as presented to us by the inventor of the technique, we started a prospective trial in the setting of a university teaching hospital. Both the clinical and radiographic results were disappointing, so we were forced to abandon the trial after 14 patients. We present our clinical and radiographic data. PMID- 27476187 TI - Erratum to: Internal fixation of lateral clavicle fractures with Vicryl tape. PMID- 27476189 TI - Dengue vaccine: WHO position paper - July 2016. PMID- 27476188 TI - The Experiential Paradoxes of Pain. AB - Pain is far more than an aversive sensation. Chronic pain, in particular, involves the sufferer in a complex experience filled with ambiguity and paradox. The tensions thereby established, the unknowns, pressures, and oscillations, form a significant part of the painfulness of pain. This paper uses a phenomenological method to examine nine such paradoxes. For example, pain can be both immediate sensation and mediated by complex interpretations. It is a certainty for the experiencer, yet highly uncertain in character. It pulls one to the present but also projects one outward to a feared or desired future. Chronic pain can seem located in the body and/or mind; interior to the self, or an alien other; confined to a particular point and/or radiating everywhere. Such fundamental paradoxes, existential and epistemological, can challenge those living with long term pain. PMID- 27476190 TI - My child has lice. Which treatments are safe and effective? PMID- 27476192 TI - Supplements: a Complete Guide to Safety. PMID- 27476191 TI - Breathe Easier About Your Flooring. Worried about reports of formaldehyde? Read our test results and learn how to protect yourself. PMID- 27476193 TI - [Preface]. PMID- 27476194 TI - [Preface]. PMID- 27476195 TI - National School Lunch Program and School Breakfast Program: Nutrition Standards for All Foods Sold in School as Required by the Healthy, Hunger-Free Kids Act of 2010. Final rule and interim final rule. AB - This rule adopts as final, with some modifications, the National School Lunch Program and School Breakfast Program regulations set forth in the interim final rule published in the Federal Register on June 28, 2013. The requirements addressed in this rule conform to the provisions in the Healthy, Hunger-Free Kids Act of 2010 regarding nutrition standards for all foods sold in schools, other than food sold under the lunch and breakfast programs. Most provisions of this final rule were implemented on July 1, 2014, a full year subsequent to publication of the interim final rule. This was in compliance with section 208 of the Healthy, Hunger-Free Kids Act of 2010, which required that State and local educational agencies have at least one full school year from the date of publication of the interim final rule to implement the competitive food provisions. Based on comments received on the interim final rule and implementation experience, this final rule makes a few modifications to the nutrition standards for all foods sold in schools implemented on July 1, 2014. In addition, this final rule codifies specific policy guidance issued after publication of the interim rule. Finally, this rule retains the provision related to the standard for total fat as interim and requests further comment on this single standard. PMID- 27476196 TI - Local School Wellness Policy Implementation Under the Healthy, Hunger-Free Kids Act of 2010. Final rule. AB - This final rule requires all local educational agencies that participate in the National School Lunch and School Breakfast Programs to meet expanded local school wellness policy requirements consistent with the requirements set forth in section 204 of the Healthy, Hunger-Free Kids Act of 2010. The final rule requires each local educational agency to establish minimum content requirements for the local school wellness policies, ensure stakeholder participation in the development and updates of such policies, and periodically assess and disclose to the public schools' compliance with the local school wellness policies. These regulations are expected to result in local school wellness policies that strengthen the ability of a local educational agency to create a school nutrition environment that promotes students' health, well-being, and ability to learn. In addition, these regulations will increase transparency for the public with regard to school wellness policies and contribute to integrity in the school nutrition program. PMID- 27476197 TI - National School Lunch Program and School Breakfast Program: Eliminating Applications Through Community Eligibility as Required by the Healthy, Hunger Free Kids Act of 2010. Final rule. AB - This final rule establishes requirements for State agencies, local educational agencies, and schools operating the Community Eligibility Provision, a reimbursement option that allows the service of school meals to all children at no-cost in high poverty schools without collecting household applications. By eliminating the household application process and streamlining meal counting and claiming procedures through the Community Eligibility Provision, local educational agencies may substantially reduce administrative burden related to operating the National School Lunch and School Breakfast Programs. This rule codifies many requirements that were implemented through policy guidance following enactment of the Healthy, Hunger-Free Kids Act of 2010, as well as provisions of the proposed rule. These requirements will result in consistent, national implementation of the Community Eligibility Provision. PMID- 27476198 TI - Economics of NP primary care. PMID- 27476199 TI - Can NPs improve timely access to care in a cost-efficient way? PMID- 27476200 TI - [Evolution of Root Nodule Bacteria: Reconstruction of the Speciation Processes Resulting from Genomic Rearrangements in a Symbiotic System]. AB - The processes of speciation and macroevolution of root nodule bacteria (rhizobia), based on deep rearrangements of their genomes and occurring in the N2 fixing symbiotic system, are reconstructed. At the first stage of rhizobial evolution, transformation of free-living diazotrophs (related to Rhodopseudomonas) to symbiotic N2-fixers (Bradyrhizobium) occurred due to the acquisition of the fix gene system, which is responsible for providing nitrogenase with electrons and reducing equivalents, as well as for oxygen dependent regulation of nitrogenase synthesis in planta, and then of the nod genes responsible for the synthesis of the lipo- chito-oligosaccharide Nod factors, which induce root nodule development. The subsequent rearrangements of bacterial genomes included: (1) increased volume of hereditary information supported by species, genera (pan-genome), and individual strains; (2) transition from the unitary genome to a multicomponent one; and (3) enhanced levels of bacterial genetic plasticity and horizontal gene transfer, resulting in formation of new genera, of which Mesorhizobium, Rhizobium, and Sinorhizobium are the largest, and of over 100 species. Rhizobial evolution caused by development and diversification of the Nod factor synthesizing systems may result in both increased host specificity range (transition of Bradyrhizobium from autotrophic to symbiotrophic carbon metabolism in interaction with a broad spectrum of legumes) and to its contraction (transition of Rhizobium and Sinorhizobium to "altruistic" interaction with legumes of the galegoid clade). Reconstruction of the evolutionary pathway from symbiotic N2-fixers to their free-living ancestors makes it possible to initiate the studies based on up-to-date genome screening technologies and aimed at the issues of genetic integration of organisms into supracpecies complexes, ratios of the macro- and microevolutionary mechanisms, and developmetn of cooperative adaptations based on altruistic relationship between the symbiotic partners. PMID- 27476201 TI - [Role of Anammox Bacteria in Removal of Nitrogen Compounds from Wastewater]. AB - The review deals with the unique microbial group responsible for anaerobic ammonium oxidation with nitrite (anammox), and with the role of this process in development of the biotechnology for removal of nitrogen compounds from wastewater. The history of the study of this process is briefly related. Up-to date knowledge on the intracellular organization, energy metabolism, growth stoichiometry, and physiology of anammox bacteria is described, and the main methods for cultivation of these microorganisms are characterized. Special attention is paid to the problems associated with practical application of anammox bacteria, which result from their extremely slow growth, the absence of pure cultures, and the interaction with other microbial groups. PMID- 27476202 TI - [Exometabolites of the Fungal Isolates (Genus Penicillium, Section Chrysogena) from Low-Temperature Ecotopes]. AB - Exometabolites of 22 strains of the genus Penicillium, section Chrysogena isolated from low-temperature ecotopes of various geographical regions were analyzed. The ecotopes included permafrost deposits, frozen volcanic ash, a fossil horse, cryopeg, and water from an Antarctic lake. The studied strains were found to contain exometabolites belonging to the groups of penicillins (penicillin G), chrysogins (chrysogin, 3-acetylquinazolone-4, 2-pyruvoyl aminobenzamide, 2-hydroxypropionyl amunobenzamide, and questiomycin A), roquefortines (3,12-dihydroroquefortine, roquefortine, glandicolines A and B, and meleagrine), xanthocillins (xanthocillin X), and simple tryptophan derivatives (N acetyltriptamine and indoleacetic acid). In five P. chrysogenum strains and three P. nalgiovense strains a correlation was found between exometabolite spectra and morphological characteristics of the cultures isolated from modern ecotopes. For other strains species identification was based on morphological features, due to the absence of biosynthesis of penicillin G, on of the major chemotaxonomic markers for these species. PMID- 27476203 TI - [Role of the NO Synthase System in Response to Abiotic Stress Factors for Basidiomycetes Lentinula edodes and Grifola frondosa]. AB - Effect of stressors (unfavorable pH and temperature or carbon and nitrogen limitation) on the synthesis of the components of the NO synthase signaling system was studied in submerged cultures of xylotrophic basidiomycetes Lentinula edodes and Grifola frondosa. Marker compounds of the NO synthase signaling system were found in both cultures. A simultaneous increase of the concentrations of NO and citrulline in the culture liquid of the basidiomycetes grown at superoptimal pH and in nitrogen-limited medium indicates the activation of the NO synthase signaling system under such stress conditions. PMID- 27476204 TI - [Changes in Cell Surface Properties and Biofilm Formation Efficiency in Azospirillum brasilense Sp245 Mutants in the Putative Genes of Lipid Metabolism mmsB1 and fabG1]. AB - The previously obtained insertion mutants ofAzospirillum brasilense Sp245 in the genes mmsBl and fabG1 (strains SK039 and Sp245.1610, respectively) were characterized by impaired flagellation and motility. The putative products of expression of these genes are 3-hydroxyisobutyrate dehydrogenase and 3-oxoacyl [acyl-carrier protein] reductase, respectively. In the present work, A. brasilense- Sp245 strains SK039 and Sp245.1610 were found to have differences in the content of 3-hydroxyhexadecanoic, hexadecanoic, 3-hydroxytetradecanoic, hexadecenoic, octadecenoic, and nonadecanoic acids in their lipopolysaccharide prepa- rations, as well as in cell hydrophobicity and hemagglutination activity and dynamics of cell aggregation, in biomass amount, and in the relative content of lipopolysaccharide antigens in mature biofilms formed on hydrophilic or hydrophobic surfaces. PMID- 27476205 TI - [Morphological and Physiological Properties of the Micromycete Arthrobotrys longa, a Producer of Longolytin, a Proteolytic Complex with a Thrombolytic Effect]. AB - Production of proteinases with plasmin-like and plasminogen-activating activities by a micromycete Arthrobotrys longa 1 was studied. Polycyclic growth of the producer in submerged cultures was observed, with an endogenous rhythm of the periods of intense microconidia formation alternating with the phases of drastic increase in the content of producing mycelium. The highest plasminogen-like and plasminogen-activating activities (up to 1000 and 500 cond. U/mL, respectively) were found to correlate with the polycyclic growth of the producer, coinciding with the stage of microconidia germination. Enhanced secretion of proteinases with plasminogen-like and plasminogen-activating activity was found to be associated with increased specific growth rate of A. longa l. PMID- 27476206 TI - [Comparative Sensitivity of the Luminescent Photobacterium phosphoreum, Escherichia coli, and Bacillus subtilis Strains to Toxic Effects of Carbon-Based Nanomaterials and Metal Nanoparticles]. AB - A comparative analysis of the four commercially available and laboratory luminescent sensor strains to the toxic effect of 10 carbon-based nanomatherials (CBNs) and 10 metal nanoparticles (MNPs) was carried out in this study. The bioluminescence inhibition assays with marine Photobacterium phosphoreum and recombinant Escherichia coli strains were varied in minimal toxic concentrations and EC50 values but led to well correlated biotoxicity evaluation for the most active compounds were ranked as Cu > (MgO, CuO) > (fullerenol, graphene oxide). The novel sensor strain Bacillus subtilis EG 168-1 exhibited the highest sensitivity to CBNs and MNPs that increased significantly number of toxic compounds causing the bacterial bioluminescence inhibition effect. PMID- 27476207 TI - [Metagenomic Analysis of Microbial Communities of the Sediments of the Kara Sea Shelf and the Yenisei Bay]. AB - Microbial diversity in the sediments of the Kara Sea shelf and the southern Yenisei Bay, differing in pore water mineralization, was studied using massive parallel pyrosequencing according to the 454 (Roche) technology. Members of the same phyla (Cyanobacteria, Verrucomicrobia, Actinobacteria, Proteobacteria, and Bacteroidetes) predominated in bacterial communities of the sediments, while their ratio and taxonomic composition varied within the phyla and depended on pore water mineralization. Increasing salinity gradient was found to coincide with increased share of the gamma-Proteobacteria and decreased abundance of alpha and beta-Proteo- bacteria, as well as of the phyla Verrucomicrobia, Chloroflexi, Chlorobi, and Acidobacteria. Archaeal diversity was lower, with Thaumarchaeota predominant in the sediments with high and low mineralization, while Crenarchaeota predominated in moderately mineralized sediments. Microbial communities of the Kara Sea shelf and Yenisei Gulf sediments were found to contain the organisms capable of utilization of a broad spectrum of carbon sources, including gaseous and petroleum hydrocarbons. PMID- 27476208 TI - [Effect of Long-Term Application of Agrotechnical Techniques and Crops on Soil Microbial Communities]. AB - Effects of long-term application ofvarious fertilizers and crops on soil microbiomes an a long-term field experiment were investigated using the library of the 16S rRNA gene sequences obtained by high-throughput sequencing of the total DNA. The communities exhibited high diversity, with 655 microbial genera belonging to 34 phyla detected (31 bacterial and 3 archaeal ones). For analysis of the effect of the studied factors on community structure, a linear model was developed in order to simplify interpretation of the data of high-throughput sequencing and to obtain biologically important information. Liming was shown to modulate the effect of mineral fertilizers on the structure of microbial populations. The differences in the structure and alpha-diversity of microbial communities were shown to depend more on the crops and liming, rather than on the fertilizers applied. Interaction between the crop factor and liming expressed as an ambiguous effect of liming on the microbiome in the presence of different plants was reliably demonstrated. Thus, in the case of barley and clover, liming resulted in increased taxonomic diversity of the community, while in the case of potato and flax it had an opposite effect. PMID- 27476209 TI - [Relationships between the Biomass and Production of Bacterio- and Phytoplanktonic Communities]. AB - Quantitative ratios of the biomasses of bacterio- and phytoplankton, interrelation of their production characteristics, and association of the functional characteristics with environmental factors were studied for Lake Khanka, the Yenisei River and the Krasnoyarsk Reservoir. The ratio between the biomasses of bacterioplankton (Bb) and phytoplankton (Bp) in these water bodies was shown to vary within the range exceeding three orders of magnitude. Bacterioplankton biomass was relatively stable and varied from sample to sample by an order of magnitude. In more than 50% of the samples (total sample number, 495), bacterioplankton biomass exceeded that of the phytoplankton. The average Bb/Bp ratios for Lake Khanka, Yenisei River, and Krasnoyarsk Reservoir were 5.1, 2, and 1.4, respectively. Increased Bb/Bp ratios were found to correlate with elevated specific (per unit biomass) phytoplankton production. This finding indicated additional supply of biogenic elements to phytoplankton due to their recycling by bacterial communities. The ratio between bacterioplankton and phytoplankton production for Lake Khanka varied from year to year (0.07 to 0.76). For the Yenisei River and the Krasnoyarsk Reservoir these ratios were on average 0.19 and 0.27, respectively. According to the literature data for other water bodies, bacterial production may reach from 10 to over 100% of the primary production. The equilibrium density of bacterioplankton (maximal density of the population) in Lake Khanka was ~1.5 times higher than in the Yenisei River and the Krasnoyarsk Reservoir due to higher content of suspended mineral matter and associated organo-mineral detritus in the lake. The interaction between dissolved organic compounds sorbed of the surface of mineral particles results in chemical alteration of biochemically stable substrate into compounds which may be assimilated by aquatic micoorganisms. PMID- 27476210 TI - [Amylase- and Protease-Producing Staphylococcus Bacteria in a Geothermal Spring of Makhachkala Deposit (Dagestan)]. PMID- 27476212 TI - ANALYZING EIGHT MONTHS OF ICD-10. PMID- 27476211 TI - [Typing of the Closely Related Strains of Euryarchaeal Genus Acidiplasma (Thermoplasmatales) Using REP-PCR DNA Fingerprinting Technique]. PMID- 27476213 TI - Unlocking the Benefits of ICD-10 through Data Analytics. PMID- 27476214 TI - Coding Audits Evolve with ICD-10. INDUSTRY EXPERTS DEFINE NEW BENCHMARKS AND BEST PRACTICES. PMID- 27476215 TI - What to Expect When Phase 2 HIPAA Audits Begin. PMID- 27476216 TI - HIM's Role in Health Data Analysis. PMID- 27476217 TI - Semantic Content in EHR Systems. PMID- 27476218 TI - The Information Governance Road Map Mile Marker 2--Travel My Way, Take the Highway That's Best. PMID- 27476220 TI - Dissecting the Operative Report for Accurate ICD-10-PCS Code Assignment. PMID- 27476219 TI - Guidelines for Achieving a Compliant ICD-10 PCS Query. PMID- 27476221 TI - Quality Queries for Quality ICD-10-PCS Codes. PMID- 27476222 TI - THE NEED FOR INCREASED ACCESS TO GOOD QUALITY EVIDENCE TO IMPROVE PATIENT CARE. PMID- 27476223 TI - CARDIAC SURGERY FOR VALVULAR HEART DISEASE AT A REFERRAL HOSPITAL IN ETHIOPIA: A REVIEW OF CASES OPERATED IN THE LAST 30 YEARS. AB - BACKGROUND: Valvular heart disease has been a significant cause of heart disease worldwide. In Ethiopia, it particularly affects young individuals and constitutes the major cause of cardiovascular disease. Factors associated with choice of treatment for advanced valvular heart disease are variable. The objective of this study is to review surgery done for Ethiopian patients with valvular heart disease. METHODS: We analyzed data on patients who had valve surgery and follow up at the Tikur Anbessa Specialized Hospital cardiology unit. We collected data on sociodemographic characteristics, the pre-operative status of effected valves and co-morbidities, and assessed their associations with patient management options. RESULTS: A total of 157 valve surgeries were done from 1983 to 2013. Mean age at time of surgery was 26.7 years and females constituted 66% of the cases. Patients with rheumatic heart disease were younger, more likely to be female and have atrial fibrillation, but less likely to have impaired left ventricular systolic function when compared to patients with non-rheumatic heart disease. More than 75% of the surgical procedures done were mechanical valve replacement. Mechanical valves, compared with bioprosthetic valves, were more likely to be used in patients with rheumatic heart disease. The median age of those receiving mechanical valves, 24 (IQR 22-28) years, was lower than those receiving bioprosthetic valves, 31.5 (IQR 29.9-37.9) years. Mechanical valve replacement was significantly higher in those under the age of 20 years (Adjusted Odds Ratio 41.0, 95% CI: 3.0-557.2) and in those between 20 and 29 years of age (Adjusted Odds Ratio 14.3, 95% CI: 2.3-88.6). CONCLUSIONS: Valve surgery for valvular heart diseases has been more common performed for young and female patients. A great majority of the replacements done have been with mechanical valves. As many of the patients have been younger and female, the choice of valve surgery and the need for anticoagulation impacts subsequent management of rheumatic heart disease and associated morbidities, lifestyle plans and pregnancy. PMID- 27476225 TI - PATTERNS OF TRAUMA IN PATIENT SEEN AT THE EMERGENCY CLINICS OF PUBLIC HOSPITALS IN MEKELLE, NORTHERN ETHIOPIA. AB - BACKGROUND: Injuries are a neglected health problem in developing countries. Ethiopia has a high incidence of road traffic accidents and trauma constitutes about half of surgical emergencies among patient seen at health facilities. The objective of this study was to determine the pattern of trauma among patient seen at emergency outpatient departments of public hospitals in northern Ethiopia METHODS: Retrospective data on patient seen at the hospitals during a one-year period (January 1, 2013-December 31, 2013) was collected. The source population was all patients who visited the emergency OPD of two public hospitals in Mekelle, Tig ray. RESULTS: The 16-25 year old age group was the most commonly affected age group, accounting for 38.5% followed by the 26-35 year old group (21.4%) of the cases. Males were more frequently involved than females ((74.3%) vs 25.7%). Eighty-three per cent of the patients were from urban areas. Interpersonal violence (31%), accidental falls (19.2%) and Road Traffic Accidents (RTA) (14.1%) were the most common causes of injury. The Head (33.5%) was the most commonly involved part of the body. CONCLUSION: This study indicates a high burden of trauma in the study area and the need for interventions to control the problem. Given the morbidity and mortality associated with trauma, trauma registry system will be beneficial in Tigray and perhaps for the whole country. PMID- 27476224 TI - MANAGEMENT OF INFLAMMATORY APPENDICEAL MASS IN ZEWDITU MEMORIAL HOSPITAL, ADDIS ABABA, ETHIOPIA. AB - BACKGROUND: Appendiceal mass is one of the complications of acute appendicitis. The management of patients with appendiceal mass is controversial and different treatment options have been suggested. OBJECTIVE: The objective of this study was to assess the results of conservative management of patients with appendiceal mass followed by interval appendicecomy. METHODS: The study was a retrospective analysis of 73 medical records of patients with appendiceal mass who were managed conservatively between March 2007 and February 2014. RESULTS: Fifty patients were males and 23 patients were females making the male to female ratio of 2.2:1. The mean age was 29.6 +/- 6.3 years (range 12-68 years). The maximum incidence was in the 3rd decade. Forty one (55.8%) of the patients presented one week or more after the onset of their illness. Abdominal pain, right lower quadrant (RLQ) direct and rebound tenderness were observed in all patients. Mass was detected in the RLQ in 84.9% of the patients. Sixty five patients (89%) responded to conservative treatment and these patients were discharged after a mean hospital stay of 6.5 1.5 days (range 3-12 days). Interval appendicectomy was done for 58 patients 8-16 weeks after successful conservative management. The mean hospital stay after interval appendicectomy was 3.5 +/- 0.5 days with a range of 2-5 days. One patient (1.7%) had a wound infection. There were no deaths. CONCLUSION: Initial non-operative management of appendiceal mass was successful in most cases and the complication rate after interval appendicecomy seems lower than with early operative treatment. PMID- 27476226 TI - PATTERN AND OUTCOME OF TETANUS IN A TERTIARY HEALTH FACILITY IN NORTH WEST NIGERIA. AB - BACKGROUND: Tetanus, a disease that is largely preventable, is still a major public health problem in the developing world and is associated with high morbidity and mortality. There is a paucity of published literature on adult (non neonatal) tetanus in this study area in Nigeria. METHODS: This was a study describing the clinical characteristics of patients who were clinically diagnosed with tetanus in Ahmadu Bello University Teaching Hospital (ABUTH) Zaria, northwest of Nigeria between January 2001 and December 2014. RESULTS: A total of 91 cases were reviewed. The mean patient age was 20 years, and male to female ratio 2.9:1. The majority (88%) of patients were < 40 years old. The mean onset period was 19 days, nearly all patients (96.7%) had generalized tetanus, and the commonest presenting signs were spasm (93.4%) and trimus (78.0%). The most common site of injury was lower limbs (64.8% of cases). The complication rate was 71.4% and case fatality was 48.4%. CONCLUSION: Tetanus is still a major public health problem in our setting and affects the younger age group with a high case fatality rate. The incidence of tetanus can be reduced drastically by an effective and sustained immunization program. PMID- 27476227 TI - PATTERN OF ANTIHYPERTENSIVE THERAPY AMONG DIABETIC HYPERTEN- SIVE PATIENTS IN ZEWDITU MEMORIAL HOSPITAL, ADDIS ABABA. AB - INTRODUCTION: Diabetes mellitus is becoming a common chronic disease in both developed and developing nations and is associated with significant cardiovascular disease morbidity and mortality. The presence of hypertension in patients with diabetes mellitus doubles the risk of cardiovascular disease including coronary heart disease, congestive heart failure, ischemic and hemorrhagic stroke, renalfailure and peripheral arterial disease. OBJECTIVE: The aim of this study was to assess the pattern of antihypertensive drug therapy among diabetic hypertensive patients in Zewditu Memorial Hospital Diabetic Clinic in Addis Ababa. METHODS: This is a hospital based retrospective review of medical records of 382 diabetic-hypertensive patients who visited the Zewditu Memorial Hospital Diabetic Clinic in the period between August 2014 and January 2015. RESULTS: The most frequently prescribed antihypertensive drug classes were angiotensin converting enzyme inhibitor in 321 (84%) followed by calcium channel blocker in 229 (60%) and beta blocker in 145 (38%) patients. Enalapril, nifedipine, atenolol, losartan and hydrochlorthiazide were the only angiotensin converting enzyme inhibitor, calcium channel blocker, beta blocker, angiotensin receptor blocker and diuretic prescribed, respectively. Enalapril was used as a monotherapy in 73 (19%) and nifedipine in 26(7%), patients. The recommended target systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg was achieved in only 57 (15%) patients while the remaining 325 (85%) did not attain the target blood pressure. Renal function was assessed in 351(92%) patients, of whom 23 (6%) had renal impairment with an estimated glomerular filtrate rate < 60 ml/min. CONCLUSION: The pattern of antihypertensive drug therapy in our patients was consistent with the current treatment guidelines. However, the majority of diabetic-hypertensive patients did not reach target blood pressure. PMID- 27476228 TI - SNAKE BITE: CASE SERIES OF PATIENTS PRESENTED TO GONDAR UNIVERSITY HOSPITAL, NORTH WEST ETHIOPIA. AB - Snakebite is an important public health challenge. Venomous snake bites cause significant morbidity and mortality if treatment measures, especially antivenom therapy, are delayed. We did a case series of 27 adult patients admitted after snakebite to the medical wards of Gondar University Hospital (GUH) from September 2013 to August 2014. The age range was from 15 to 74 years. The male to female ratio was 8:1. The majority (25) of patients presented after 12 hours of being bitten. Most of the bites occurred on the legs. Hematologic complications, including prolonged bedside whole blood clotting test, bleeding complications and Disseminated Intravascular Coagulation, were the common complications detected. The case fatality rate was 4/27 (14.8%). Availability of affordable snake specific antivenom is recommended. A large population study is needed to address the burden in Ethiopia. PMID- 27476229 TI - SUBSEROSAL SIGMOID LIPOMA: A CASE REPORT AND REVIEW OF THE LITERATURE. AB - Colonic lipoma is a rare non-epithelial mesenchymal tumour which is the second most common benign tumour of the colon excluding hyper-plastic polyps. It is often small and asymptomatic but may become symptomatic and mimic malignant lesions as the size increases. This is a case report of a 68 year-old female patient who presented with lower abdominal pain, constipation and rectal bleeding of one year duration. Colonoscopy revealed a sessile tumour 40 cm from the anal verge with an inconclusive histology. After incising and removing the lipoma, the redundant mucosal fold was then resected. The patient recovered completely and was discharged on the fifth postoperative day. Keyword: Colonic lipoma , subserosal lipomas. PMID- 27476230 TI - KARTAGENER'S SYNDROME: A CASE REPORT. AB - Kartagener's syndrome is a rare autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract. Patients usually present with chronic recurrent rhinosinusitis, otitis media, pneumonia, and bronchiectasis caused by Pseudomonas infection. In this case report, we present a 12-year old female with Kartagener's syndrome from Tikur Anbessa Teaching Hospital which to our knowledge is the first of it's kind to be reported in Ethiopia. The clinical and imaging findings are discussed. PMID- 27476231 TI - EVOLUTION OF MYCOBACTERIUM TUBERCULOSIS AND IMPLICATIONS FOR VACCINE DEVELOPMENT. AB - Tuberculosis (TB) is a growing public health threat, particularly in the face of the global epidemics of multidrug resistance. Given the limited efficacy of the current TB vaccine and the recent clinical failure of the most advanced new TB vaccine candidate, novel concepts for vaccine design should be explored. Most T cell antigens in the human-adapted Mycobacterium tuberculosis complex (MTBC) are evolutionarily conserved and under strong purifying selection, indicating that host immune responses targeting these antigens might not be protective. By contrast, a few highly variable T cell epitopes have recently been discovered, which could serve as alternative vaccine antigens. Moreover, there is increasing evidence that the human-adapted MTBC has been co-evolving with the human host for a long time. Hence, studying the interaction between bacterial and human genetic diversity might help identify additional targets that could be exploited for TB vaccine development. PMID- 27476232 TI - President's Perspective. PMID- 27476233 TI - Case of the Month: Peripheral Ossifying Fibroma. PMID- 27476234 TI - Characteristics of Texas Dental Medicaid Providers and Their Locations. PMID- 27476235 TI - Practicing Clinical Dentistry Increases the Risk of Developing Musculoskeletal Disorders (UT CAT # 2839). PMID- 27476236 TI - THE INVISIBLE NUMBERS THAT IMPACT PRACTICE SUCCESS. PMID- 27476237 TI - The ADA Council on Access, Prevention, and Interprofessional Relations. PMID- 27476238 TI - Invest (A Verb!). PMID- 27476239 TI - Keeping Out of Harm's Way. PMID- 27476240 TI - Xerostomia and Depression. PMID- 27476241 TI - Making the List. PMID- 27476242 TI - Recruitment and Retention Conference: Sparks Ideas for Innovation. PMID- 27476243 TI - Editorial. PMID- 27476244 TI - Considering Tort Liability for Breaches to Privacy of Patient Data-- Managing Risks of Applicability of Privacy Torts, and Especially the Tort of "Intrusion on Seclusion" in the Health Context. AB - The mobile revolution is a watershed event across many fields, including health care. Now, electronic data storage, digital photography, smart phones and tablet devices present new opportunities for educators, researchers, and health care providers. Mobile technologies allow for new possibilities for physician collaboration as well as patient diagnosis, treatment and study. However, while it presents new opportunities, the mobile technological revolution in health care has brought about new risks to patient privacy. These risks to patients, in turn, translate into exposure to liability on the part of health care providers including physicians, allied health care professionals and institutions. This paper reviews recent developments in the legal landscape providing new forms of civil liability for breaches of privacy and discusses how risks of liability under those developing civil causes of action can be managed by health care providers, while they at the same time harness the potential of the mobile technological tide. PMID- 27476245 TI - The Ethical and Legal Dilemma in Terminating the Physician-Patient Relationship. AB - A physician-patient relationship is essential for the well-being of the patient, for without a strong and trusting relationship between both individuals, the patient may not receive the best care that they deserve. There are many legal policies and ethical principles a physician must follow when caring for a patient. It is both the legal and moral duty of the physician to act in the best interests of their patients, while making sure to respect them regardless of background and personal behaviours. The relationship is secured with both trust and respect, for without trust, the patient may hold back from stating their conditions which will result in the physician not providing them with all the care they require. Sometimes, lack of some of these key characteristics of the physician-patient relationship and other circumstances, may cause either the patient or the physician to terminate the relationship. Termination of a relationship creates a difficult situation for the patient, and therefore there are only specific situations where a physician may have permission to follow through and terminate their relationship. Both the law and ethical principles play a role in the decisions made by the physician in regards to their relationship with the patient, but regardless, the physician has the obligation to make sure their patient is receiving care by one means or another. PMID- 27476246 TI - Common Occupational Disability Tests and Case Law References: An Ontario MVA perspective on interpretation and best practice methodology supporting a holistic model, Part I of III (Pre-104 IRB). AB - This three-part paper presents practical holistic models of determining impairment and occupational disability with respect to common "own occupation" and "any occupation" definitions. The models consider physical, emotional and cognitive impairments in unison, and draw upon case law support for empirically based functional assessment of secondary cognitive symptoms arising from psychological conditions, including chronic pain disorders. Case law is presented, primarily in the context of Ontario motor vehicle accident legislation, to demonstrate how triers of fact have addressed occupational disability in the context of chronic pain; and interpreted the "own occupation" and "any occupation" definitions. In interpreting the definitions of "own occupation" and "any occupation", courts have considered various concepts, such as: work as an integrated whole, competitive productivity, demonstrated job performance vs. employment, work adaptation relative to impairment stability, suitable work, retraining considerations, self-employment, and remuneration/socio economic status. The first segment of the paper reviews the above concepts largely in the context of pre-104 Income Replacement Benefit (IRB) entitlement, while the second segment focuses on post-104 IRB entitlement. In the final segment, the paper presents a critical evaluation of computerized transferable skills analysis (TSAs) in the occupational disability context. By contrast, support is offered for the notion that (neuro) psychovocational assessments and situational work assessments should play a key role in "own occupation" disability determination, even where specific vocational rehabilitation/retraining recommendations are not requested by the referral source (e.g., insurer disability examination). PMID- 27476247 TI - [Low-risk pregnancy. Fact or deceit]. PMID- 27476248 TI - [Active management of postpartum hemorrhage and Bakri balloon placement in primiparous and multiparous]. AB - OBJECTIVE: To evaluate the usefulness of active management of the third stage of labor plus Bakri balloon in primiparous and multiparous. patients with postpartum hemorrhage. MATERIAL AND MET HOD: A retrospective, cross-sectional analytical study in the Hospital of Women, from 1st January 2013 to 31st December 2014. We use uterotonics and after persistence of postpartum hemorrhage also considered Bakri balloon placement, and further transfusion management were evaluated. Analysis descriptive and inferential statistics were performed (Mann-Whitney U and linear regression) and the relationship between inter- and intra-group variables analyzed, a significance level of p <0.05 was established. RESULTS: We choice 47 patients (26 primiparous and 21 multiparous). The 100% of cases avoids obstetric hysterectomy, average age was lower in primiparous than multiparous (p <0.05). Both groups required transfusion of blood products at similar. The relationship between days of hospitalization vs bleeding volume was directly proportional to primiparous, but inversely proportional to the multiparous (p <0.05), the analysis for combinations of uterotonics in the management of post partum hemorrhage, shown that misoprostol (800 mg, rectally) stressed this relationship in primiparous while effect disappears in multiparous. CONCLUSION: The Bakri balloon placement decreases the number of fatalities and hysterectomies in obstetric patients in both primiparous and multiparous with postpartum hemorrhage that does not response to the treatment with .uterotonic drugs. PMID- 27476249 TI - [Second stage of labor: Does accelerations matter?]. AB - BACKGROUND: Accelerations role during the second stage of labor has not been studied and current classification system NICHD downplays its presence. The objective of this study is to determine validity for acidemia detection of the loss of accelerations during the second stage of labor. MATERIAL AND METHOD: This is a one year retrospective case-control study of 102 neonates with acidemia defined as an umbilical cord gas pH<=7.10 compared to 100 non acidemic controls. The last thirty minutes of CTG were evaluated by two obstetricians blind to clinical and outcome data that classified tracings into categories according to NICHD definitions, determining the presence or absence of accelerations. Validity of NICHD categories and absence of accelerations were calculated. RESULTS: 85% of fetuses presented a category II tracing in the last 30 minutes of labor. Absence of accelerations was associated with neonatal acidemia (ORa 4.43). Category II tracings were not associated with acidemia after adjusting for confounding factors.Validity of the absence of accelerations during the second stage of labor was higher in terms of sensitivity (80.3%), specificity (54%) and global value (67%) to that of the presence of a category II tracing (96%, 24% and 60% respectively) in this period. CONCLUSIONS: The absence of accelerations during the second stage of labor shows a bigger validity for neonatal acidemia than the presence of a category II tracing. PMID- 27476250 TI - [Evaluation of visceral adipose tissue and lipid level in premenopausal and postmenopausal women's]. AB - BACKGROUND: Postmenopausal women present weight gain and intensification of obesity, especially visceral adipose tissue (VAT) increases in postmenopausal women. But it is still not clear whether abdominal fat increases during this stage independently of body weight. OBJECTIVE: compare the VAT and lipid profile between postmenopausal and premenopausal Mexican women. METHODS: A case control study in postmenopausal women matched for BMI with premenopausal women. Anthropometric and laboratory measurements as well as body composition analysis were performed. RESULTS: VAT was increased in postmenopausal women in contrast with premenopausal women (114.8 +/- 39.5 vs 97.3 +/- 29.0, p<0.05). Compared with premenopausal women, postmenopausal women showed higher total cholesterol (231 .6 +/- 56.1 vs 206.8 +/- 29.5 p <0.05), and LDL-cholesterol levels (145.9 +/- 48.3 vs 121.7 +/- 34.1, p < 0.05), whereas H DL-cholesterol remained unchanged. CONCLUSION: The results of the present study have demonstrated that Mexican postmenopausal women had a significant increment in visceral adipose tissue and in other metabolic risk factors, independent of the body mass index. PMID- 27476251 TI - [Frequency of menstrual disturbances in gynecology and obstetrics residents]. AB - OBJECTIVE: To determine the frequency of menstrual disorders in gynecology and obstetrics residents. MATERIAL AND MET HODS: All residents of the 2015-2016 academic cycle were studied. In all them the menstrual cycle characteristics such as: rhythm, duration and quantity were analyzed. For statistical analysis Mann Whitney U test and Spearman's correlation analysis were done. RESULTS: 61 residents, 18 of 2nd, 21 of 3rd and 22 of 4th year were studied. Body mass index was significantly greater in those of 4th grade when compared with those of 2nd. The waist hip ratio (WHR) was significantly smaller in those of 3rd when compared with those of 4th. The reported frequency of menstrual disturbances was 22.8%, 28.6% and 22.7% for the 2nd, 3rd and 4th years respectively. After comparing the groups, between them the total volume was greater in those of 2nd when compared with those of 3rd (p<0.009) and 4th (p<0.04) In the correlation analysis in those of 2nd grade the WHR negatively correlated with the duration of bled (p <0.483, p<0.049). In those of 3rd year the WHR positively correlated with the duration (p 0.544, p<0.024) and with the total volume (p 0.553, p<0.02 1). In those of 4th year any correlation was found. CONCLUSION: The 2nd year residents women's are more likely to suffer menstrual disorders compared with those of 3rd and 4th ear of residence. PMID- 27476252 TI - [Active management of the third stage of labor: Three schemes of oxytocin: randomised clinical trial]. AB - OBJECTIVE: To compare the effectiveness of intramuscular oxytocin against intravenous oxytocin against intravenous traditional oxytocin infusion, in the active management of the third period of the delayed impingement labor work and controlled cord traction. METHODS: Randomized controlled blinded clinical trial. In women age 14 to 40 with full term pregnancy, childbirth attended by ISSSTE's Regional Hospital "Gral. Ignacio Zaragoza", in the period from August to December 2015. RESULTS: 152 deliveries were attended, from which 66 fulfill with selection criteria. Group 1 = 22 patients, group 2 = 21 patients and Group 3 = 23 patients. The total age average was 26.92 + 5.8. For blood volume, statistical differences were significant among the three groups (p = 0.000). Adverse reactions were presented in 1 .5%, without difference between the groups. (P = 0.337). The differences in hemoglobin values and final and initial hematocrit presented differences with statistical significance (p = 0.000 for both). CONCLUSIONS: Nonetheless, the differences obtained in the analysis of the diverse variables among the three types of treatment, the three schemes are effective on the obstetrical hemorrhage prevention. PMID- 27476253 TI - [Genital tuberculosis: atypical manifestation in the pregnancy. Case report]. AB - BACKGROUND: In the last years has been an increase in cases of tu- berculosis, representing a global health problem that is also reflected in an increased of cases in pregnant population. Especially in developed countries has been observed a direct relation with VIH patients,and groups of immigrants from countries where the infection is endemic. Tuberculous disease during pregnancy presents good outcome if it is diagnosed and treated properly. CASE REPORT: We present the case of a romanian patient with uncon- trolled 23 weeks gestation that enters with the suspicion of chorioam- nionitis and after late septic miscarriage and clinical sepsis criteria, leaks out of the hospital reentering with signs of neurologic involvement and pelviperitonitis as a result of genital tuberculous. Diagnosed with tuber- culous meningitis and disseminated with a grim evolution until death. PMID- 27476254 TI - [Multidose treatment of methotrexate in cornual ectopic pregnancy]. AB - BACKROUND: Ectopic pregnancy represents a common entity when the differential diagnosis of first trimester pathologies is performed. Extratubal location, nonetheless, is an in unfrequent situation that delays and difficults the diagnoses. CASE REPORT: 41-year-old women who goes to clinic for a pregnancy test, which proved positive done. During normal ultrasonographic we observed attached with endometrial 8 mm thick, without gestational sac inside, no free liquid in the bottom of the pouch of Douglas. In the left cornual region had a suggestive image of ectopic pregnancy, of 2.8 cm, with embryo without cardiac activity, tested with Doppler color, according to 6 weeks of amenorrhea was observed. The level of beta-HCG was 17,656 mU/mL, which confirmed the diagnosis of corneal ectopic pregnancy. Multidose protocol of methotrexate and folinic acid was prescribed at a dose of 50 mg on days 1, 3, 5 and 7, and 5 mg in the days 2, 4, 6 and 8, respectively. After 14 days of treatment a new beta-HCG study control was made, which results was 2,519 mU/mL. From that time we take a weekly control studies of the beta-HCG until was negative (six months later). The multidose protocol of methotrexate and folinic acid is an effective treatment in patients with cornual ectopic pregnancy. PMID- 27476255 TI - [Placental site trophoblastic tumor with atypical choriocarcinoma. Case Report]. AB - BACKGROUND: The placental site trophoblastic tumor is the second rarest tumor of trophoblastic disease, with less than 300 cases reported. Clinical presentation it's a diagnostic challenge, it has an unpredictable malignant potential, and it can develop choriocarcinoma and even have simultaneous presentation. CASE REPORT: We present the case of a 34 year old woman with chronic transvaginal bleeding since her last cesarean (five months ago), with histologic diagnosis of placental site trophoblastic tumor and inmuno- histoquimic report of choriocarcinoma, this early diagnosis improves her survival prognostic. CONCLUSION: placental site trophoblastic tumor and their evolution to choriocarcinoma have a low rate but it's possible. That it's the reason why complete diagnosis with biopsy, histologic and inmunohistoquimic report is mandatory to improve therapeutic. PMID- 27476256 TI - [The Base of the Skull. Rudolf Virchow between Pathology and Anthropology]. AB - Throughout his scientific career, the pathologist and anthropologist Rudolf Virchow (1821-1902) examined countless skulls, gradually changing his perspective on this object of research. Initially, he was mainly concerned with pathologically deformed skulls. From the 1850s onwards, he gradually developed a more anthropological approach, and anthropology increasingly came to dominate his scientific interest. This article shows how different influences became central for the establishment of his specific and dynamic model of the human skull development and its successful application in anthropology. Crucial for this process were Virchow's collaboration with his teacher Robert Froriep (1804-1861) in the department of pathology of the Charite, his research on cretinism and rickets, as well as his description of the base of the skull as the center of skull development. His research work was attended by and showed a reciprocal interaction with the buildup of large skull collections. This article uses Virchow's original publications on skull pathology as well as his still preserved skull specimens from the collection of the Berlin Museum of Medical History at the Charite for an integrated text and object based analysis. PMID- 27476258 TI - Need to Revive Your Passion for Being a Nurse? ASNA Can Help. PMID- 27476257 TI - [The Appointment of Paediatric Professorships in the Soviet Occupation Zone and the early GDR. The Impact of the Political System Change after 1945]. AB - This paper examines the impact of the political system change after 1945 on the appointment of paediatric professorships in the Soviet Occupation Zone and the GDR up until the time the Wall was built in 1961. It can be demonstrated that the political purge in the post-war period had only minor impact on the appointment of professorships and the National Socialist past no longer mattered after the conclusion of denazification. In 1957, the proportion of former NSDAP members among East German university professors of paediatrics was 100 per cent. When it came to new appointments, both members of the "bourgeois" academic non professorial teaching staff from the GDR as well as paediatricians from West Germany, who had largely gained their scientifically qualifications under National Socialism, were in the running. A politically-controlled elite exchange did not take place until the construction of the Wall. State and party organs generally followed the personnel proposals of the universities since an insufficient number of qualified candidates was available for the systematic appointment of ,,progressive" paediatricians. Given the lack of staff, the SED personnel policy was aimed at the integration of previous elites, as long as they behaved loyally towards the new state. Since the East German faculties continued to make the questioning of the professionally competent professors in West Germany and East Germany the basis for their appointment lists, West German university paediatricians were able to exert considerable influence on the appointment of East German paediatric professorship until 1960s. PMID- 27476259 TI - You've Been Kidnapped! PMID- 27476260 TI - Alcohol Use Disorder--Medication Assisted Treatment. PMID- 27476261 TI - [Prototype analysis on beliefs about people with depression: Examining Japanese university students]. AB - The present studies examined what kinds of beliefs are typically held about people with depression based on data from samples of Japanese university students. Study 1a utilized text describing people with depression that was divided into categories, and examined which categories were most frequently described. In Study 1b, participants rated how much they agreed with the beliefs categorized in Study 1a. A similar approach was taken in Study 2a (qualitative) and 2b (quantitative), in order to examine prototypic negative beliefs. Results from Study 1a and 1b indicated that prototypic beliefs were the "serious and working too hard" belief in regard to characteristics of people with depression, and the "taking too much things on oneself" belief related to personal responsibility. Results from 2a and 2b indicated that prototypic negative beliefs were the "gloomy" belief in regard to characteristics of people with depression, and the "mental weakness" belief related to personal responsibility. Implications for research on stigma toward people with depression are discussed. PMID- 27476262 TI - [Action tendencies of respect-related emotions: Focus on emotion episodes in Japanese university students]. AB - This study examined the action tendencies of respect-related emotions in Japanese university students. Participants (n = 405) randomly received a questionnaire about one of six respect-related emotions: (a) keiai (respect mingled with mild love); (b) shinsui (idolatry worship, and adoration); (c) ifu (awe mingled with fear); (d) kanshin (admiration); (e) kyotan (wonder); and (f) sonkei (respect proper) and were asked to recall a situation they felt the emotion. Next, they rated how much they felt like doing the respect-related (intrapersonal or interpersonal) actions in the situation. Statistical analysis revealed several action tendencies of respect-related emotions, however, the degree of each differed between the prototypical episodes of the emotions (a)-(e). The action tendency pattern of sonkei was most similar to that of keiai, therefore keiai could be considered as the prototypical feeling of sonkei in university students. Furthermore, almost all the respect-related emotions tended to strongly motivate willingness for self-correction and improvement. These findings suggest that respect-related emotions play an important role in self-improvement and building good relationships with superiors, at least in late adolescence. PMID- 27476263 TI - [A sigh increases motivation for difficult and monotonous tasks: The effect of one-time voluntary brief exhalation on relief and achievement needs]. AB - We tested possible intrapersonal effects of a sigh as a psychological "resetter/rebooter." Fifty-eight undergraduates were randomly assigned to a sigh or a normal exhalation (control) group. We asked participants on each task to model the experimenter demonstrating how to exhale air into a small plastic bag for breathing manipulation under the pretext that we were interested in the exhaled gas in stressful situations. Results revealed that the sigh group did not experience more relief (as shown by prolonged reaction time) after exposure to threat stimuli, but showed more persistence on a highly-difficult puzzle task (p = .03, d = .62) and more willingness to continue working on a monotonous task (p < .10, d = .48), than the normal exhalation group. A sigh may have an adaptive function to motivate further work; although it may not induce relief--suggesting that a "sigh of refresh" is a voluntary but a "sigh of relief" is an involuntary response. PMID- 27476264 TI - [Reliability and validity of the Japanese translation of Brief Self-Control Scale (BSCS-J)]. AB - Self-control refers to the ability to execute goal-oriented behavior despite the presence of temptation(s) to do otherwise. Since self-control has a wide-range impact on our daily lives, it is of critical importance to assess individual differences of self-control with a highly reliable and valid, yet simple, measure. Toward this end, three studies were conducted to test reliability and validity of the Japanese-translated version of Brief Self-Control Scale (Tangney, Baumeister, & Boone, 2004). The scale showed good internal consistency (Study 1) and retest reliability (Study 2). The. total score of the scale was correlated with the self-reported indices of self-control (e.g., daily experience of ego depletion, study hours) and performance in the Stop Signal Task (Study 3), indicating its high converging validity. PMID- 27476265 TI - [Intention for self-change across the life span: Focusing on concern about self change]. AB - The purpose of the present study was to examine intention for self-change across the life span using measures of self-esteem, frequency of self-reflection, and concern about self-change. We hypothesized that: (a) Intention for self-change decreases with age because of increased self-esteem, decreased self-reflection and concern about self-change, and (b) Associations among self-esteem, frequency of self-reflection, and intention for self-change are mediated by concern about self-change. Participants (N = 997; age range, 15 to 69 yrs) completed an internet survey. ANOVA results suggested that intention for self-change, concern about self-change, and frequency of self-reflection decreased with age, and that self-esteem-scores increased with age. Simultaneous analysis of multiple age groups showed that for all groups of low self-esteem and frequent self-reflection promoted intention for self-change and that there were significant mediating effects for concern about self-change. Therefore, these findings supported out research hypotheses. PMID- 27476266 TI - [Effectiveness of an executive function task with a touch panel system for young children]. AB - The Dimensional Change Card Sort (DCCS) task is a widely used measure for the development of executive function during early childhood. In this task, children are asked to sort cards according to one rule (e.g., color) during preswitch phases, after which they are asked to sort cards according to another rule (e.g.; shape) during the postswitch phases. A computer version of the DCCS was needed to standardize the test material, but a previous study showed that children showed more difficulty in a computer version with a mouse device than the standard card version. In this study, we assessed the effectiveness of a computer version with a touch panel and compared performance with the standard card version. Three- and 4-year-old children were given the card version and computer version of the DCCS tasks. The results revealed that children showed similar performance during the preswitch and postswitch phases both in the computer version and in the card version. The results suggest that both versions of the task assessed the same underlying cognitive processes. PMID- 27476267 TI - [Reliability and validity of the Japanese version of the Thinking Style Inventory]. AB - This study examined the internal and external validity of the Japanese version of the Thinking Styles Inventory (TSI: Hiruma, 2000), which was originally developed by Sternberg and Wagner (1991) based on the framework of Sternberg's (1988) theory of mental self-government. The term "thinking style" refers to the concept that individuals differ in how they organize, direct, and manage their own thinking activities. We administered the Japanese version of the TSI to Japanese participants (N = 655: Age range 20-84 years). The results of item analysis, reliability analysis, and factor analysis, were consistent with the general ideas of the theory. In addition, there were significant relationships between certain thinking styles and 3 participant characteristics: age, gender, and working arrangement. Furthermore, some thinking styles were positively correlated with social skill. Implications of these results for the nature of Japanese thinking styles are discussed. PMID- 27476268 TI - [The relationship between Cognitive Emotion Regulation Questionnaire (CERQ) and depression, anxiety: Meta-analysis]. AB - This study aimed to investigate the relations between CERQ and depression, and anxiety and also aimed to reveal the characteristics of a Japanese sample through meta-analysis. The results showed that self-blame, acceptance, rumination, catastrophizing, and blaming others had significantly positive correlations with both depression and anxiety, whereas positive refocusing, refocus on planning, positive reappraisal, and putting into perspective had significantly negative correlations with both variables. Moreover, when comparing the correlation coefficients of the Japanese samples and the combined value, correlations between depression and positive reappraisal were significantly larger than the combined value. On the other hand, regarding the correlation coefficients of depression and putting into perspective, the combined value was larger than the value of Japanese samples. In addition, compared to the combined value, the Japanese sample's positive correlation between anxiety and rumination, and negative correlation between anxiety and positive reappraisal were larger. PMID- 27476269 TI - [Expansive personal space: Distance between personal belongings reflects the interpersonal distance of their owners]. AB - People feel uncomfortable when someone else comes spatially near and thus encroaches on their personal space (PS). Although many social psychologists have explored characteristics of PS of/between/among individuals so far, there is currently no empirical research on whether the PS of individuals expands into space surrounding their belongings (or objects) that are away from their body. This study measured the spatial distance between bags which participants and confederates left behind, and thus demonstrated that the distance between bags was modulated in response to the interpersonal relationship of their owners. The present study suggests new evidence for expansive PS, which is the concept that an individual's PS expands into space surrounding his/her belongings. PMID- 27476270 TI - [The effects of instruction about strategies for efficient calculation]. AB - Calculation problems such as "12x7/3" can be solved rapidly and easily by using certain techniques; we call these problems "efficient calculation problems." However, it has been pointed out that many students do not always solve them efficiently. In the present study, we examined the effects of an intervention on 35 seventh grade students (23 males, 12 females). The students were instructed to use an overview strategy that stated, "Think carefully about the whole expression", and were then taught three sub-strategies. The results showed that students solved similar problems efficiently after the intervention and the effects were preserved for five months. PMID- 27476271 TI - [Do envious people show better performance?: Focusing on the function of benign envy as personality trait]. AB - This study focused on the differences between two, subtypes of envy known as "benign envy" and "malicious envy" as personality traits, and examined the effects of these traits on academic achievement. Two hundred fifty-one university students participated in the study. Both benign envy and malicious envy were found to be independent as also found in a previous study by Lange & Crusius (2015), and a high criterion-related validity was revealed by an association with characteristic variables such as dispositional envy and self-esteem. The students with higher levels of benign envy were found to set goals higher, and as a result achieved higher levels of academic performance. In contrast, no such effect was found for malicious envy. The importance of focusing more attention on the positive aspects of the emotion of envy is discussed. PMID- 27476272 TI - RISK-FACTORS, PATHOGENESIS, AND PHARMACEUTICAL APPROACHES FOR TREATMENT OF STEROID-INDUCED BONE INFARCTION OF FEMORAL HEAD. AB - During first year of steroid usage, osteocyte necrosis and blood vessel blockage may occur, which subsequently may produce steroid-induced bone infarction (SIBI) resulting in painful movement of patient. For treatment of SIBI, pharmaceutical strategy is the basic approach. It involves the use of various pharmacologically active compounds including bisphosphonates, hyperbaric oxygen (HBO), coenzyme Q10, erythropoietin, antihyperlipidemics, anticoagulants, antioxidants, and tissue repair protein. Out of these, there is no pharmaceutical agent that may completely treat this disease because many factors are found to be responsible for SIBI development; therefore, there are multiple biomarkers of this disease. This situation argues for need of new therapeutic agents for SIEB1. PMID- 27476273 TI - PHARMACOLOGICAL ASSESSMENT OF HISPIDULIN - A NATURAL BIOACTIVE FLAVONE. AB - Hispidulin is well-known natural bioactive flavone on behalf of its pharmacological aspects. This review contains data on isolation, synthetic methodology, pharmacokinetics and bioactivities of hispidulin. The article provides a critical assessment of present knowledge about hispidulin with some clear conclusions, perspectives and directions for future research in potential applications. PMID- 27476274 TI - CORONARY EFFECT OF FIBRATES ON PROTEINS AND ENZYMES WHICH HYDROLYZE TRIACYLGLYCEROLS. AB - Clofibric acid derivatives called fibrates, are quite commonly used lipid lowering drugs, so it is necessary to know beneficial and adverse effects of these compounds on the body. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that benefits of four fibrates such as: bezafibrate, ciprofibrate, fenofibrate and gemfibrozil continue outweigh their risk in treatment of people with blood lipid disorders. According to recommendations of the CHMP fibrates should not be used as first-line drugs, except in patients with severe hypertriglyceridemia and patients who cannot use statins. In this paper, we focused on effect of clofibric acid derivatives on lipid metabolism, in particular on apoproteins and regulatory enzymes. PMID- 27476275 TI - CANTHARELLUS CIBARIUS - CULINARY-MEDICINAL MUSHROOM CONTENT AND BIOLOGICAL ACTIVITY. AB - One of the most frequently harvested mushrooms in Polish forests is Yellow chanterelle (chanterelle) - Cantharellus cibarius Fr. from the Cantharellaceae family. Chanterelle is an ectomycorrhizal mushroom occurring in Poland. Chanterelle lives in symbiosis with pine, spruce, oak and hombeam. In cookery, chanterelle is appreciated because of the aroma, taste, firmness and crunchiness of its fruiting bodies. Wild edible mushrooms are widely consumed in Asia, Western Europe and Central America. Chanterelle contains a great number of carbohydrates and proteins and a low amount of fat. Actual review presents the main groups of physiologically active primary and secondary metabolites in the fruiting bodies of chanterelle such as indole and phenolic compounds, carbohydrates, fatty acids, proteins, free amino acids, sterols, carotenoids, enzymes, vitamins and elements with biological activity. The presence of these compounds and elements conditions the nutrient and therapeutic activity of chanterelle, e.g., immunomodulatory, anti-inflammatory, antioxidant, antiviral, antimicrobial and antigenotoxic properties. PMID- 27476276 TI - ECONOMIC ISSUES IN THERAPEUTIC DRUG MONITORING. AB - The fact that resources for health care are limited has been found as a rationale for the development of pharmacoeconomics. Pharmacoeconomic analysis identifies, measures and compares the costs and the economic, clinical and humanistic outcomes of diseases, drug therapies and programmes directed to these diseases. As health care expenditures have escalated over the past decades, the number of its applications has increased. Taking into consideration outcome and economic issues and establishing their mutual relationship helps proper resource allocation. In the case of some effective and toxic drugs therapeutic drug monitoring has been proven to allow obtaining the desired clinical effects safely and thus to improve outcome. However, it requires the presence of clinical pharmacology or clinical pharmacy service within a hospital, which in turn is associated with some additional costs. This review sums up the results of pharmacoeconomic studies relevant to the use of therapeutic drug monitoring in case of the medicines for which it has been commonly performed so far. PMID- 27476277 TI - CHROMATOGRAPHIC TECHNIQUES IN PHARMACEUTICAL ANALYSIS IN POIAND: HISTORY AND THE PRESENCE ON THE BASIS OF PAPERS PUBLISHED IN SELECTED POLISH PHARMACEUTICAL JOURNALS IN XX CENTURY. AB - For a long time, chromatographic techniques and techniques related to them have stimulated the development of new procedures in the field of pharmaceutical analysis. The newly developed methods, characterized by improved metrological parameters, allow for more accurate testing of, among others, the composition of raw materials, intermediates and final products. The chromatographic techniques also enable studies on waste generated in research laboratories and factories producing pharmaceuticals and parapharmaceuticals. Based on the review of reports published in Polish pharmaceutical journals, we assessed the impact of chromatographic techniques on the development of pharmaceutical analysis. The first chromatographic technique used in pharmaceutical analysis was a so-called capillary analysis. It was applied in the 1930s to control the identity of pharmaceutical formulations. In the 1940s and 1950s, the chromatographic techniques were mostly a subject of review publications, while their use in experimental work was rare. Paper chromatography and thin layer chromatography were introduced in the 1960s and 1970s, respectively. These new analytical tools have contributed to the intensive development of research in the field of phytochemistry and the analysis of herbal medicines. The development of colunm chromatography-based techniques, i.e., gas chromatography and high performance liquid chromatography took place in the end of 20th century. Both aforementioned techniques were widely applied in pharmaceutical analysis, for example, to assess the stability of drugs, test for impurities and degradation products as well as in pharmacokinetics studies. The first decade of 21" century was the time of new detection methods in gas and liquid chromatography. The information sources used to write this article were Polish pharmaceutical journals, both professional and scientific, originating from the interwar and post-war period, i.e., "Kronika Farmaceutyczna", "Farmacja Wspolczesna", "Wiadomosci Farmaceutyczne", "Acta Poloniae Pharmaceutica", "Farmacja Polska", "Dissertationes Pharmaceuticae", "Annales UMCS sectio DDD Phamacia". The number of published works using various chromatography techniques was assessed based on the content description of individual issues of the journal "Acta Poloniae Pharmaceutica". PMID- 27476278 TI - INVESTIGATION OF A MIXTURE CONTAINING ALPRAZOLAM, CODEINE AND PARACETAMOL USING THIN-LAYER AND HIGH PERFORMANCE LIQUID CHROMATOGRAPHY METHODS. AB - The increasing drug consumption in Lithuania and all over the world makes us think about the negative consequences - the risk of toxicity. Fast and accurate identification of material that caused the poisoning reduces the probability in death cases and makes easier to determine the main cause of death. The results have shown that the most appropriate systems of solvents for qualitative analysis by TLC method of the mixture consisting of alprazolam, codeine and paracetanol are: system "D" (trichloromethane : acetone : conc. ammonia = 55 : 40 : 5 (v/v/v)) and system "F" (trichloromethane : diethyl ether: isobutanol : conc. ammonia = 50 : 30 : 15 : 5 (v/v/v/v)). For qualitative analysis of the mixture consisting of alprazolam, codeine and paracetamol by HPLC method the chromatographic column ACE C18 (25 cm x 4.6 mm x 5 um), gradient elution mode (mixture of 3% acetic acid and methanol and the flow rate 1 mL/min have been used. The injection volume was 10 pL. Photodiode array detector (210 - 240 nm range) has been used. UV absorption spectra of materials measured using photodiode array detector have been identical to those presented in the scientific literature. PMID- 27476279 TI - A SIMPLE AND-SENSITIVE STABILITY-INDICATING UHPLC-DAD METHOD FOR THE DETERMINATION OF CEFETAMET PIVOXIL HYDROCHLORIDE. AB - A fast and sensitive UHPLC-DAD method was developed and subsequently validated for determination of cefetamet pivoxil hydrochloride in the presence of its degradation products. The chromatographic separation was carried out on a Waters Acquity BEH C18, (2.1 x 100 mm, 1.7 um) column. The mobile phase was composed of 0.1% formic acid and acetonitrile (40 : 60, v/v) at the flow rate 0.7 mL/min. The detection wavelength was 265 nm and the temperature was 30 degrees C. Cefetamet pivoxil hydrochloride was susceptible to degradation under the influence of sodium hydroxide, hydrochloric acid and in the conditions of increased temperature and relative humidity. However, it was stable after irradiation, in increased temperature in dry air and in the presence of oxidizing agent. The developed UHPLC-DAD method was linear over the concentration range of 10-240 ug/mL (r2 = 0.9999; n = 12). The obtained RSD values were less than 2%, demonstrating that the described procedure is precise. The accuracy was also confirmed (mean recoveries were 97.79-102.08%). Under applied chromatographic conditions LOD and LOQ values were 2.08 mg/mL and 6.29 mg/mL, respectively. The proposed method was successfully applied in determination of cefetamet pivoxil hydrochloride in aqueous solutions as well as in the solid state. PMID- 27476280 TI - RAPID SPECTROPHOTOMETRIC DETERMINATION OF TRIFLUOPERAZINE DIHYDROCHLORIDE AS BASE FORM IN PHARMACEUTICAL FORMULATION THROUGH CHARGE-TRANSFER COMPLEXATION. AB - Two simple and selective spectrophotometric methods are described for the determination of trifluoperazine dihydrochloride (TFH) as base form (TFP) in bulk drug, and in tablets. The methods are based on the molecular charge-transfer complexation of trifluoperazine base (TFP) with either 2,4,6-trinitrophenol (picric acid; PA) or 2,4-dinitrophenol (DNP). The yellow colored radical anions formed are quantified at 410 run (PA method) or 415 nm (DNP method). The assay conditions were optimized for both the methods. Beer's law is obeyed over the concentration ranges of 1.5-24.0 pg/mL in PA method and 5.0-80.0 ug/mL in DNP method, with respective molar absorptivity values of 1.03 x 10(4) and 6.91 x 10(3) L mol-1 cm-1. The reaction stoichiometry in both methods was evaluated by Job's method of continuous variations and was found to be 1 : 2 (TFP : PA, TFP : DNP). The developed methods were successfully applied to the determination of TFP in pure form and commercial tablets with good accuracy and precision. Statistical comparison of the results was performed using Student's t-test and F-ratio at 95% confidence level and the results showed no significant difference between the reference and proposed methods with regard to accuracy and precision. Further, the accuracy and reliability of the methods were confirmed by recovery studies via standard addition technique. PMID- 27476281 TI - IN VITRO INfIBITION OF HHV-1 REPLICATION BY INOSINE PRANOBEX AND INTERFERON alpha. AB - Key issues in the development of novel antivirals are the emergence of resistant strains. The development of new drugs effective against herpes diseases has proven to be both difficult and time-consuming. Some alternative may be to optimize the efficacy and selectivity of existing antiviral drugs or combining them with other well known agents. Inosine pranobex exerts a direct antiviral effect as well as secondary effect to its immunomodulatory activity. We found that increasing concentrations of inosine pranobex (50-400 ug/mL) produced progressively growing inhibitory effect on HHV-1 replication, following infection of different cell lines. The combination of 1000 IU/mL IFN-alpha and inosine pranobex also resulted in enhanced anti-HHV activity. Immunotherapy may be beneficial for patients from whom strains resistant to currently known antiviral drugs have been isolated. PMID- 27476282 TI - INTRACELLULAR ANTIOXIDANT ACTIVITY OF A STREPTOMYCES SP. 8812 SECONDARY METABOLITE, 6,7-DIHYDROXY-3,4-DIHYDROISOQINO- LINE-3-CARBOXYLIC ACID, AND ITS SYNTHETIC DERIVATIVES. AB - The aim of this study was to determine the antioxidant properties of 6,7 dihydroxy-3,4-dihydroiso- quinoline-3-carboxylic acid (1) and its derivatives in living cells against reactive forms of oxygen and nitrogen, i.e., hydrogen peroxide and nitric oxide. Four of tested compounds scavenged the reactive form of nitrogen more efficiently or similarly to Trolox (EC50 = 55.80 uM). Two compounds exhibited antioxidant activity against reactive oxygen species better than Trolox (EC50 = 51.88 uM). The most active derivative of 1 was the compound containing an iodine atom at position 8 (6,7-dihydroxy-8-iodo-3,4 dihydroisoquinoline-3-carboxylic acid). Our studies showed that some of the derivatives had the ability to cross the cell membrane and scavenge free radicals inside living cells. Thus, they are able to protect DNA and other cellular structures from the dam- aging effects of reactive oxygen and nitrogen species. In addition, some molecular descriptors of the tested compounds were determined with the use of ICM Pro (Molsoft L.L.C.). PMID- 27476283 TI - EFFECT OF PARACETAMOL ON MELANIZATION PROCESS IN HUMAN EPIDERMAL MELANOCYTES. AB - Paracetamol (acetaminophen) is commonly used as a drug of choice for treatment of pain and fever. Unlike non-steroidal anti-inflammatory drugs (NSAIDs) it does not cause gastrointestinal damage or untoward cardiorenal effects, however cutaneous adverse effects have been reported. It is known that paracetamol binds to melanin biopolymers, but the relation between the affinity of this drug to melanin and its toxicity is not documented. The aim of this work was to examine the impact of paracetamol on melanogenesis in cultured human normal epidermal melanocytes (HEMn DP). The effect of paracetamol on cell viability was determined by WST-1 assay, melanin content and tyrosinase activity were measured spectrophotometrically. It has been demonstrated that paracetamol induced concentration-dependent loss in melanocytes viability. The value of EC50 was found to be - 20.0 mM. The analyzed drug inhibited melanin biosynthesis in a concentration-dependent manner by decreasing the melanin content as well as the tyrosinase activity. The demonstrated inhibitory effect of paracetamol on melanization process in normal epidermal melanocytes in vitro may explain the potential role of melanin biopolymer in the mechanisms of undesirable side effects of this drug in vivo, as a result of its accumulation in pigmented tissues. PMID- 27476284 TI - PROTECTIVE EFFECT OF LACTUCA SERRIOLA ON DOXORUBICIN-INDUCED TOXICITY IN H9C2 CELLS. AB - The use of doxorubicin (DOX) is limited by its dose-dependency because of its cardiotoxicity. Reactive oxygen species (ROS) play an important role in the pathological process. The aim of this study is to evaluate the protective effect of Lactuca seniola against DOX-induced apoptosis and death in H9C2 cells. The cells were incubated with different concentrations of extract for 4 h which continued in the presence or absence of 5 uM doxorubicin for 24 h. Cell viability, apoptotic induction and the level of apoptotic proteins were determined by using MTT, PI and immunoblotting assays, respectively. The level of lipid peroxidation was measured by fluorimetric method. DOX significantly decreased cell viability which was accompanied by an increase in ROS production and lipid peroxidation. Pretreatment with Lactuca seniola increased the viability of cardiomyocytes and could decrease lipid peroxidation. Also, Lactuca seriola inhibited the reduction of anti-apoptotic Bcl-2 protein and elevation of apoptotic Bax and caspase-3 proteins. In conclusion, Lactuca seniola exerts protective effect against oxidative stress-induced cardiomyocytes damage. Therefore, it has the potential to be used as cardioprotective agent by the patients with cardiovascular diseases. PMID- 27476285 TI - 5'-NUCLEOTIDASES OF NAJA NAJA KARACHIENSIS SNAKE VENOM: THEIR DETERMINATION, TOXICITIES AND REMEDIAL APPROACH BY NATURAL INHIBITORS (MEDICINAL PLANTS). AB - Present study was carried out regarding enzymatic assay for 5'-nucleotidase enzymes present in snake venom Naja naja karachiensis and to evaluate twenty eight medicinal plants as their antidotes. Elevated enzymatic activities i.e., 119, 183, 262 and 335 U/mL were observed in 10, 20, 30 and 40 ug of crude venom, respectively, in dose dependent manner. Among various plant extracts only two (Bauhinia vaiiegate L. and Citms linion (L.) Burm. f.) were found 94% effective at 160 ug to neutralize 112 U/mL activities (p 0.5) while reference standard was proved 93.2% useful at 80 pg to halt 111 U/mL activities. Cedrus deodara G. Don, Enicostemna hyssopifolium (Willd.) Verdoom, Terminalia arjuma Wight & Am. and Zingiber officinalis Rosc. (at 160 ug) were found >=90% effective (0.5 >= p >= 0.1) while Citrulus colocynthis, Fogonia cretica L., Rhazya stticta Dcne and Stenolobiun stans (L.) D. Don (at 320 ug) were proved 90% effective (0.05 >= p >= 0.02). The remaining plant extracts were observed abortive (p >= 0.001) in neutralization of 5'-nucleotidases enzymatic actions. This study emphasizes further characterization of active plant extracts to further explore the antivenom influences of these herbal remedies against deleterious effects produced by 5'-nucleotidase enzymes after snake bite envenomation. PMID- 27476286 TI - REPEATED EXPOSURE OF SODIUM TELLURITE ON THE RAT LIVER AND ON THE POTENTIAL MECHANISMS OF THE METALLOID-INDUCED HEPATOTOXICITY. AB - Tellurium (Te) is a semiconductor and is frequently doped with copper, tin, gold or silver. It is also used to color glass and ceramics and is one of the primary ingredients in blasting caps. Little is known about Te biological activity but it is well known for toxicity to human and animals. It has inhibited the lipids profiles and oxidative stress in the brain of mice. Sodium tellurite 4.15, 8.3 and 16.6 mg/kg (1/20, 1/10 and 1/5 of LD50, respectively) was given to male Wistar rats orally in saline for a period of 15 days. On day 16, the blood was collected and the livers were dissected out for biochemical assays. The hepatotoxicity biomarkers [bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)] were elevated significantly and dose dependently in the serum of Te treated groups as compared to control group. The content of thiobarbituric reactive substances in Te treated groups was increased significantly and dose-dependently as compared to control group. Conversely, the content of glutathione and activities of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase and catalase) were decreased significantly in Te treated groups as compared to control group. No data of inorganic Te compounds on the liver toxicity of rats are available. The aim of the present study was to evaluate the hepatotoxicity of inorganic Te compound. In conclusion, Te accelerated hepatotoxicity and oxidative stress in liver tissue of rats. PMID- 27476287 TI - SYNTHESIS AND CYTOTOXIC ACTIVITY OF NEW 5H-INDOLO[2,3-B]QUINOLINE O AMINOGLYCOSIDES. AB - Novel 5H-indolo[2,3-b]quinoline O-aminoglycosides were synthesized in order to check the hypothesis that the construction of hybrids composed of the active 5H indolo[2,3-b]quinoline chromophore and daunosaminyl or acosaminyl moiety may result in the cytotoxic activity of the obtained derivatives that is much higher than the one of the parent DIMIQ (5,11-dimethyl-5H-indolo[2,3-b]quinoline) and 6H indoloquinoline analogs. Actually, 5H-indolo[2,3-b]indoloquinoline O aminoglycosides showed the anti-proliferative activity in vitro against human lung adenocarcinoma A549, breast cancer MCF-7, melanoma Hs294T, promyelocytic leukemia HL-60, uterine sarcoma MES-SA and colon cancer LoVo cell lines, which was 10 times higher than that of the 6H-analogs and comparable to the one of the referential DIMIQ. Unexpectedly, it appeared that except for HL-60/MX2 (P-gp independent and topoisomerase II-dependent resistance), other MDR tumor cell lines (LoVo/DX. P-gp-dependent, MRP-, LRP-dependent multidrug resistance) and MES SA/DX5 (P-gp-dependent resistance to doxorubicin) are also resistant to the 5H indolo[2,3-b]indoloquinoline O-aminoglycosides tested. This is surprising because 6H-analogs, in general, 10 times less active against non-MDR tumor cell lines, as well as the DIMIQ itself, are able to overcome drug resistance in all MDR cell lines examined. The cytotoxicity of the tested compounds against tumor cell lines and against normal cells (mice fibroblasts BALB/3T3) was comparable. PMID- 27476288 TI - THIOUREA DERIVATIVES OF 4-AZATRICYCLO[5.2.2.0(2.6)]UNDEC-8-ENE-3,5 DIONE - SYNTHESIS AND BIOLOGICAL ACTIVITY. AB - A series of halogeno derivatives of thiourea bearing a polycyclic imide core has been efficiently synthesized and evaluated for antimicrobial activity. The structures of the compounds were established by 1H and 13C NMR and MS methods. The molecular structure of 4Clc was determined by an X-ray crystallography. Compounds containing 3-chloro-4-fluorophenyl substituent (3Cl4Fb, 3Cl4Fd) were found to be the most promising against Gram-positive bacteria (MIC values ranged from 8 to 32 pg/mL for standard and 32 - 64 ug/mL for hospital strains). The in vitro cytotoxicity against MT-4 cells of all compounds was evaluated. PMID- 27476289 TI - SYNTHESIS AND ANTIMICROBIAL PROPERTIES OF NEW MANDELATE IONIC LIQUIDS. AB - Novel mandelate ionic liquids with quartenary ammonium cations were synthesized and characterized. The compounds exhibit antimicrobial activity and the most potent one is of similar efficacy against Gram+ bacteria as its counterpart chloride. On the other hand, the mandelates are much less active against Gram bacteria and fungi. QSAR models suggest that, with respect to cation, their potency depends on lipophilicity. The synthesized ionic liquids are also quite cytotoxic against mammalian cells. PMID- 27476290 TI - PHARMACEUTICAL QUALITY OF GENERIC ATORVASTATIN PRODUCTS COMPARED WITH THE INNOVATOR PRODUCT: A NEED FOR REVISING PRICING POLICY IN PALESTINE. AB - Atorvastatin reduces morbidity and mortality due to cardiovascular events. This study was conducted to assess the prices and pharmaceutical quality of innovator atorvastatin 20 mg with its locally available generics in Palestine and to assess the suitability of their interchangeability. The prices of innovator and generic atorvastatin 20 mg were determined and compared. Innovator atorvastatin and four generic products were tested for their pharmaceutical quality. Tablets were tested for their drug contents, weight uniformity, hardness, disintegration and dissolution. Three out of four generics were less expensive than the innovator. Pharmaceutical quality assessments were satisfactory and within limits for all atorvastatin tested products. The average weight ranged from 206.6 +/- 8.40 to 330 +/- 3.92 mg and the %RSDs were within the permitted limits as per USP. Tablet hardness ranged from 102 +/- 1.41 to 197.4 +/- 6.88 kg and drug contents ranged from 92.2% to 105.3%. All products disintegrated within permitted time limits and showed very rapid dissolution. Products released more than 85% of their drug contents in less than 15 min. Our results showed that all tested innovator and generic atorvastatin products were of good pharmaceutical quality. Despite the lack of in vivo evaluation, our results indicate that these products are equivalent in vitro. Considering the in vitro release characteristics, these products might be used interchangeably. However, regulatory authorities permit the use of in vitro data in establishing similarity between immediate release oral dosage forms containing biopharmaceutical classification system class I and III drugs only. PMID- 27476291 TI - KINETICS STUDY ON KETOPROFEN RELEASE FROM MINI TABLETS AND MULTI-COMPARTMENT SYSTEMS. AB - Thanks to multi-compartment systems it is possible to modify drug release. Two types of mini tablets containing 12.5 mg of ketoprofen were made: mini tablets of immediate (IR) and sustained (SR) release. Some of the tablets of immediate release were coated with an enteric coating, thereby obtaining a delayed release effect (IRc). For each tablet type, release profiles were tested in three media: 0.1 M HCl, phosphate buffer pH 4.5 and phosphate buffer pH 6.8. Based on the obtained results, three appropriate multi-compartment models have been constructed and tested. The factor limiting the amount of available ketoprofen at the absorption place is pH of the environment. It was observed that the increase in pH caused the increase of ketoprofen solubility. Constructed multi-compartment systems allowed to change the composition and the dose of medicinal substances easily. Thanks to this it is possible to adjust the release profile of the active substance to the individual patient, which meets the expectations of personalized medicine. PMID- 27476292 TI - DISSOLUTION AND COMPATIBILITY STUDY OF BINARY AND TERNARY INTERACTIVE MIXTURES OF INDOMETHACIN: COMPARISON WITH COMMERCIALLY AVAILABLE CAPSULES. AB - The main objective of this work was to use Weibull distribution function and Baker-Lonsdale models to study the dissolution kinetics of prepared binary and ternary interactive mixtures containing indomethacin in comparison with three commercially available capsules of indomethacin, namely, Rothacin(r), Indomin(r) and Indylon(r). Differential scanning calorimetry (DSC) in conjunction with cloud point method was used to study the compatibility of indomethacin with polyvinylpyrrolidone (PVP) and lactose and to provide an explanation(s) for the insignificant increase in dissolution rate observed in the ternary interactive mixture as well as for the reduction in the dissolution rate observed from the binary system in our previous study. Results showed that the Weibull distribution function equation was the best fit to the dissolution data for all formulations used in this study. DSC curves showed that the decrease in dissolution rate from the binary and ternary interactive mixtures was due to incompatibility of indomethacin with PVP. Also DSC curves showed that lactose was compatible with indomethacin and that lactose was used as excipient in two commercial products (Rothacin(r) and Indylon(r)). Results from the cloud point method showed that the addition of indomethacin to 1% PVP solution containing ammonium sulfate (with cloud point at 76 degrees C) reduces the cloud point of PVP indicating that there is an interaction between indomethacin and PVP, while the cloud point of 1% PVP containing ammonium sulfate was not affected by the addition of lactose. PMID- 27476293 TI - DEVELOPMENT AND VERIFICATION OF NEW SOLID DENTAL FILLING TEMPORARY MATERIALS CONTAINING ZINC. FORMULA DEVELOPMENT STAGE. AB - Caries is the most popular problem affecting teeth and this is the reason why so many temporary dental filling materials are being developed. An example of such filling is zinc oxide paste mixed with eugenol, Thymodentin and Coltosol F(r). Zinc-oxide eugenol is used in dentistry because of its multiplied values: it improves heeling of the pulp by dentine bridge formation; has antiseptic properties; is hygroscopic. Because of these advantages compouds of zinc oxide are used as temporary fillings, especially in deep caries lesions when treatment is oriented on support of vital pulp. Temporary dental fillings based on zinc oxide are prepared ex tempone by simple mixing powder (Thymodentin) and eugenol liqiud together or a ready to use paste Coltosol F(r). Quantitative composition depends mainly on experience of person who is preparing it, therefore, exact qualitative composition of dental fillings is not replicable. The main goal of the study was to develop appropriate dental fillings in solid form containing set amount of zinc oxide. Within the study, the influence of preparation method on solid dental fillings properties like mechanical properties and zinc ions release were examined. PMID- 27476295 TI - ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITY OF 8-METHOXY-1,3-DIMETHYL-2,6-DIOXO PURIN-7-YL DERIVATIVES WITH TERMINAL CARBOXYLIC, ESTER OR AMIDE MOIETIES IN ANIMAL MODELS. AB - The previous studies in a series of 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives revealed their analgesic properties. We extended the study with these compounds in aim to assess their impact on inflammatory process. For this purpose we used: the zymosan-induced peritonitis and the carrageenan-induced edema model. Furthermore, the antioxidant activity of the investigated compounds by the FRAP assay was determined. For the most active derivatives from evaluated series their influence on plasma TNF-alpha level was also tested in vivo. All investigated purine-2,6-dione derivatives 1-11 decreased neutrophils count and inhibited intensity of early vascular permeability. Furthermore, all evaluated compounds reduced the volume of edema caused by subcutaneous injection of carrageenan. Derivatives 1 (with ester moiety), 3 and 4 (with carboxylic group) showed the highest activity in the zymosan-induced peritonitis. In addition, a significant inhibition of plasma TNF-alpha level in rats with endotoxemia was observed following intraperitoneal administration of these compounds. In turn, compounds 6 and 8-11 containing amide moiety showed the greatest anti-inflammatory (antiedematous) effect in the carrageenan-induced paw edema model. All compounds did not show significant antioxidant properties. The present studies revealed that the presented purine-2,6-dione derivatives exhibit a significant anti inflammatory activity and this effect may result from their ability to lower TNF alpha level. PMID- 27476294 TI - PREDICTIVE PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE FLOATING TABLETS. AB - The purpose of this study was to propose the effectiveness of convolution approach to predict pharmacokinetics of tramadol hydrochloride floating tablets, prepared by using various ratios of carbopol, HPMC K100M, and Hibiscus rosa Sinensis as excipient. The in vitro dissolution test was conducted using paddle method in 900 mL of HCl buffer with pH 1.2 to simulate the gastric condition. The stirring speed of paddles was set at 70 rpm. Temperature of dissolution medium was adjusted at 37 +/- 5 degrees C. At predetermined time points, 5 mL of dissolution samples were taken with a replacement of same volume using fresh medium. The obtained samples were analyzed at 271 nm using UV visible spectrophotometer. The values of predicted pharmacokinetic parameters like Cmax (maximum blood drug level), Tmax (time required to attain maximum blood drug level), and AUC (area under blood drug concentration curve) ranged between 80.8 +/- 3.2-119.6 +/- 4.7 ng/mL, 11.4 +/- 0.2-12.2 +/- 0.2 h, and 1430.5 +/- 209.5 1970.6 +/- 287.4 ng.h/mL, respectively. This certainly is a desired feature required at the formulation development step, where the formulator requires the development of a formulation using desired in vivo features on the basis of only accessible in vitro data. It can be concluded from the results that convolution method is a practical method for the prediction of drug concentration in blood and for quality control. PMID- 27476296 TI - PREVALENCE OF HEPATITIS C IN DIABETIC PATIENTS: A PROSPECTIVE STUDY. AB - There is a strong evidence of the relationship between diabetes and hepatitis C however, there are certain gaps in the literature. Therefore, this study was carried out to determine the prevalence of hepatitis C in diabetic patients and risk factors associated with it, to evaluate the presence of possible relationship between hepatitis C and diabetes. Serological testing for anti HCV antibody was carried out on a sample of 100 diabetic patients visiting the diabetic clinic Nishtar Medical College and Hospital Multan. An anti HCV antibody test was carried out on HCV ELISA 3.0 (third generation) kit, locally purchased. Data about demographic information and history of risk factors for HCV was collected from diabetic patients using a structured questionnaire as an experimental tool, after taking informed consent. Data of about 100 non diabetic subjects (volunteer blood donors) was taken from the blood bank of that hospital. Prevalence rate of HCV infection among diabetic patients was recorded 19% and in the control group (non-diabetics) was 3%. Prevalence of HCV infection is higher in type 2 diabetic patients as compared to type 1 diabetic patients (84% vs. 16%). Diabetic patients between age group 46-55 years of age has high prevalence rates (47%) as compared to healthy individuals. Female diabetic patients have higher seropositivity (74%) as compared to male diabetic patients (26%). High prevalence of HCV infection has been reported among diabetic patients with duration of disease = 11 years (47%). Most of the patients were married (95%) and from urban locality (89%) and almost all were poor (99%). HCV positive diabetic patients have also history of blood transfusion (16%), hospital admissions (84%), major surgical procedure (63%), family history of hepatitis C (16%), razor sharing among males (16%) and comb sharing (79%). There was not any I/V drug addict (or history of I/V drug addiction), and tattooing, nose/ear piercing from contaminated needle and toothbrush sharing have not been seen among the participants of research.The results showed that in the present study the prevalence of HCV infection is six times higher in diabetic patients as compared to non-diabetic subjects (control group). PMID- 27476298 TI - EVALUATION OF DRUG USE INDICATORS FOR NON-COMMUNICABLE DISEASES IN PAKISTAN. AB - Irrational drug use practices are a burden to healthcare facilities. Poor prescribing practices affect the overall management and cost of treatment of non communicable diseases that are the major cause of mortality and morbidity worldwide. In an effort to improve prescribing practices, this study was designed to assess prescribing, consultation and facility indicators in healthcare facilities of Punjab and Sindh provinces of Pakistan from December 2012 to December 2013. In this cross-sectional study, random and convenient sampling were used to collected data from both private and public healthcare facilities. Quantitative data were collected using structured questionnaire, observations and prescription analysis, whereas qualitative information on factors influencing prescribing practices was obtained by interviewing medical practitioners. A total of 13693 prescriptions were obtained from 500 patient-prescriber encounters. Results show that history taking, physical examination and diagnoses were adequate while generic prescribing was four-fold less than drugs prescribed by brands. Average number of drugs prescribed was 4.63 with more prescribing tendency in private facilities. 45.07% prescription costs were less than Rs. 150. Sulfonylureas, statins and ACE inhibitors were highly prescribed drugs for diabetes, hyperlipidemia and hypertension. Prescribing practices were dominantly influenced by severity of disease (73% Punjab; 81% Sindh), patient age (75% Punjab; 68% Sindh) and availability of drugs (62% Punjab; 56% Sindh) whereby 91% practitioners in Sindh and 52% in Punjab rely on medical representatives as the source of drug information. Moreover, the pharmacy and therapeutic committees in all facilities were non-functional along with non-availability of essential drug list in 87% health facilities. Thus, there are considerable opportunities to improve the rational use of medicines in Pakistan including low prices for generics, physician education, prescribing guidelines and formularies. PMID- 27476297 TI - THE INFLUENCE OF MONTELUKAST ON THE ACTIVITY OF THE AUTONOMIC NERVOUS SYSTEM ESTIMATED BY HEART RATE VARIABILITY IN EXPERIMENTAL PARTIAL BLADDER OUTLET OBSTRUCTION IN RATS. AB - Due to their paracrine action, leukotrienes released from the urothelium are involved in control of the bladder function. Anti-leukotriene agents appear to exert an ameliorating effect in bladder overactivity. It is unknown, whether their possible, modulatory impact on the autonomic nervous system (ANS) activity may also contribute to the potentially beneficial effect of those compounds. Therefore, our aim was to indirectly estimate the ANS function using the heart rate variability (HRV) study in rats with experimental partial bladder outlet obstruction (PBOO), reflecting human benign prostatic hyperplasia (BPH), treated with leukotriene receptor antagonist - montelukast (MLKT). Twenty rats with surgically induced PBOO lasting for 14 days, divided into two groups: group 1 (10 control subjects) and group 2 (10 MLKT-treated rats; 2 mg/rat/day) were subjected to HRV recordings, preceded by daily urine collection and a subsequent cystectomy with histopathological evaluation of collected bladders. Standard HRV time and spectral parameters were calculated. MLKT-treated animals demonstrated an increase in power of non-normalized LF (low frequency) and HF (high frequency) components with no change of the total HRV power. Moreover, an increase and decrease in normalized nLF and nHF, respectively, were assessed in those animals compared to the control. Additionally, a decrease in daily diuresis measurement was demonstrated in MLKT-treated animals. Montelukast treatment resulted in the functional ANS status re-arrangement, with sympathetic overdrive and parasympathetic withdrawal. Those changes may contribute to alleviation of bladder overactivity symptoms, independently on leukotriene receptors blockade. PMID- 27476299 TI - THE USE OF PANAX GINSENG AND ITS ANALOGUES AMONG PHARMACY CUSTOMERS IN ESTONIA: A CROSS-SECTIONAL STUDY. AB - The aim of the cross-sectional study was to evaluate the pattern of complementary self-treatment with P. ginseng and its analogues amongst pharmacy customers in Estonia. The study instrument consisted of multiple-choice items related to personal knowledge about and experience with the use of P. ginseng and its analogues. In total, 1233 customers participated in the study. Of study participants, 18.1% reported the use of P. ginseng and its analogues in their lives. P. ginseng preparations were used mostly according to the well- known indications (tiredness, weakness and decreased mental and physical capacity). Of P. ginseng users 44.3% reported positive treatment effects and 12.0% had experienced different side effects. With increase of age (p < 0.01) and at lower levels of education (p = 0.04), the use of ginseng or its analogues decreased. The better the users evaluated their health, the better they perceived the effect of P. ginseng preparations (p < 0.01). This study reported rather frequent use of P. ginseng and its analogues. P. ginseng could be seen in the treatment of conditions, where the use of local medicinal plants has not been established. Further research is needed to learn more about public knowledge and experiences about efficacy and safety of P. ginseng and its analogues. PMID- 27476300 TI - ASSESSMENT OF PRACTICE AT RETAIL PHARMACIES IN PAKISTAN: EXTENT OF COMPLIANCE WITH THE PREVAILING DRUG LAW OF PAKISTAN. AB - The main objective of this study was to assess the practice at retail pharmacies in Pakistan and to compare the same in rural and urban areas. The maintenance of pharmacy and drug inspectors' visit was also assessed. This cross sectional study was conducted in Abbottabad, Pakistan during October-November, 2012. A sample of 215 drug sellers or drug stores was selected by employing convenient sampling method. With a response rate of 91.6%, 197 drug sellers participated in this study. All the drug sellers were male. Overall, 35% (n = 197) of the drug sellers did not have any professional qualification. A majority of the drug sellers were involved in various malpractices like selling of medicines without prescription (80.7%), prescribing practice (60.9%), prescription intervention (62.4%) and selling of controlled substances (66%) without a license for selling it. These malpractices were significantly higher in rural area than that in urban area. PMID- 27476301 TI - [Not Available]. PMID- 27476302 TI - [L-dopa induced dyskinesia in Parkinson's disease]. AB - Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) is ultimately experienced by the vast majority of parkinsonian patients. Loss of dopamine in PD induces complex modifications in cellular signaling with numerous pathways showing altered responses to dopaminergic stimulation. Chronic L-dopa treatment further enhances the signaling alterations. The dopamine D1 receptor (D1R) signaling pathway has consistently been shown to be critically involved in LID genesis and manifestation in the striatum, the basal ganglia input structure. Interestingly, recent studies suggest an impact of structures outside of the basal ganglia in LID expression. The present attempts to provide an overview of our current understanding of LID pathophysiology. PMID- 27476303 TI - [Not Available]. PMID- 27476304 TI - [Quality of life during and after therapy]. AB - With a three-fold increase in life expectancy between 1770 and 1970 in western countries, but no significant improvement since then, quality of life (QoL) has progressively become more and more important for healthcare evaluation. Using the classical evidence-based methods, QoL remains, however, quite difficult to assess and to analyse. Colorectal cancer is a frequent and severe disease. Major therapeutic advances have, however, been made during the past two decades. Currently 75% of patients with a non metastatic disease may expect, after surgical removal of their primary tumor; a long lasting remission. This is also the case in 40% of patients with metastatic disease suitable for surgery. Finally, in non-surgical, advanced disease stage cases, median overall survival moved from 6 to 30 months. As treatment duration and percentage of remissions increased, QoL has been more and more studied in these patients. Follow-up of patients receiving adjuvant chemotherapy following complete surgical removal showed treatment-induced side effects impairing long term QoL. This has led to stopping rules. International consortiums have been developed in order to perform extremely large clinical trials so as to decrease the duration of adjuvant treatments, and thus limit the occurrence of the long lasting side effects impairing QoL. In patients with a more advanced disease, de-escalation of treatment intensity has been successfully evaluated, leading to the use of maintenance therapy, in order to preserve both patients' survival and QoL. These approaches have simplified treatment schedules, decreased the incidence of clinically relevant side effects and significantly improved patients QoL. They are currently part of our practice routine. If QoL seems today important in clinical trials and medico-economic assessment of new anti-cancer agents, it may be tomorrow integrated in daily practice through dedicated software in day hospital units in order to better choose each patients' tailored treatment. PMID- 27476305 TI - [Not Available]. PMID- 27476306 TI - [Empathy and Medicine]. AB - Empathy may be defined as the ability to share and/or understand others' emotional state. It is a multi-faceted construct that relies on discrete psychological processes with specific neural correlates. These psychological processes might be impaired in some mental disorders, such as schizophrenia, autism spectrum disorders, borderline personality disorder or mood disorders. Among these disorders, psychopathy is mainly characterized by a lack of empathy for others' distress associated with amygdala hypo-reactivity. In the context of doctor-patient relationships, clinical empathy also encompasses the physician's ability to communicate his or her understanding of the emotional state of the patient. However, sharing the emotional states may elicit compassion fatigue and burnout symptoms among physicians and medical students and reduce their empathic capacities. A decline of these capacities is indeed observed during medical training. Perspective-taking may protect physicians from such negative effects while allowing them to show sustained empathic concern. Interventions to promote empathy among medical students should target both communication skills and humanist values: communication skils may depend on humanist values to grow. PMID- 27476307 TI - [How our subjective coherence is built? The model of cognitive dissonance]. AB - Our conscious, subjective discourse, demonstrates a temporal coherence that distinguishes it from the many unconscious cognitive representations explored by cognitive neuroscience. This subjective coherence, --particularly its dynamics- can be modified in certain psychiatric syndromes including a " dissociative state " (e.g. schizophrenia), or in several neuropsychiatric disorders (e.g. frontal lobe syndrome). The medical and environmental consequences of these changes are significant. However, the psychological and neural mechanisms of this fundamental property remain largely unknown. We explored the dynamics of subjective coherence in an experimental paradigm (the "free choice "paradigm) originating for the field of cognitive dissonance. Using a series of behavioral experiments, conducted in healthy volunteers, we have discovered a key role for the episodic memory in the preference change process when simply making a choice. These results highlight the importance of conscious memory in the construction of subjective consistency, of which the subjects do not yet seem to be the conscious agents. PMID- 27476308 TI - [Pharmacoepidemiology: definition, methods and applications]. AB - Clinical evaluation of drugs before approval is based on the experimental design of clinical trial with randomization of drug exposure. Unfortunately, conclusions of clinical trials are necessarily limited to patients enrolled in the trial. It is therefore necessary to compare these experimental data from clinical trials with the real use of drugs in clinical practice. Pharmacoepidemiology is defined as the study in real conditions and on large populations, of use, effectiveness and risk of drugs. The methods and fields of application of pharmacoepidemiology are described. They allow to characterize conditions of use, misuse, clinical effectiveness, adverse drug reactions and risks of drugs. The development of pharmacoepidemiology should allow optimization of "rational use" of drugs. PMID- 27476309 TI - [Pharmacoepidemiology: an another kind of drug surveillance]. AB - Pharmacoepidemiology is a branch of medical pharmacology defined as "the study of use and beneficial and adverse drug effects in order to promote their proper use and allow to improve public health." This definition underlines the links between pharmacoepidemiology and public health and helps to show how pharmacoepidemiology extends the conclusion of pharmacovigilance, which is only the study of adverse drug reactions. Using several current examples, the author shows how pharmacoepidemiology allows drug risk assessment but also to investigate drug benefits during real drug use. PMID- 27476310 TI - [Pharmacoepidemiology: lights and shadows]. AB - Adverse drug reactions are a major cause of illness and death. They cause 5-10% of general practice consultations and 5 to 10% of hospital admissions and would be the third or fourth cause of death (after heart attack, stroke and cancer). It is a failure of contemporary medicine. The purpose of pharmacoepidemiology is the study of drug use in populations and its impact on public health. The author describes the four stages of the recent history of pharmacovigilance. The first, spontaneous reporting, has identified many adverse drug reactions but cannot provide with incidence or risk estimates. Observational epidemiological research has shaped second generation pharmacovigilance, providing incidence and relative and absolute risks which are essential for public health decision taking. The meta-analysis of clinical trials would be third-generation pharmacovigilance: it has contributed to the understanding of relatively common adverse drug reactions with great impact on public health. Research on big data will surely be the basis of the fourth generation of pharmacovigilance. PMID- 27476311 TI - [Critical care of Onco-hematology patients: new therapeutic targets, new complications and new admission policies]. AB - Overall prognosis of cancer or haematological has dramatically decreased over the last decades. Thus advances regarding cancer or haematological treatment, improved knowledge of usual complications and of their pathophysiology and changes in ICU admission policy and management are among factors which participated to the overall prognostic changes. Tyrosine-Kinase inhibitors in patients with chronic myeloid leukemia and anti-CD20 antibodies in patients with non-hodgkin's lymphoma were among the first success of targeted therapies. These success stories have been followed by others and no less than 13 targeted therapies were available for cancer patients in December 2013. Additionally, pathophysiology of complication is better understood and prognostic impact of organ failure better apprehended. Standardized diagnostic criteria of tumor lysis syndrome along with improved understanding of short-term and long term influence of acute kidney injury (AK) in this setting have led to specific management strategiesfocusing on prevention. In non-malignant haematological diseases, pathophysiological processes leading to thrombotic thrombocytopenic purpura or atypical haemolytic and uremic syndrome are now better understood leading to additional therapeutic options. Last, diversification of ICU admission policies may help in taking into account uncertainties, therapeutic advances and patients' autonomy. This review will give an overview of these recent advances. PMID- 27476312 TI - [Hypertension, catecholamine hypersecretion and potential for metastasis: recent progress in the pathophysiology and genetics of pheochromocytoma and paraganglioma]. AB - Pheochromocytomas and paragangliomas are catecholamine-secreting tumors usually associated with arterial hypertension. They can contribute to acute cardiovascular events. Ten to 15 percent of tumors are metastatic. Autosomal dominant gene alterations are present in more than a third of cases. The secretory phenotype and the risk of malignancy are driven by the presence of gene mutations, specifically in the subunits of succinate dehydrogenase. Recent advances in genomics have clinical implications for family screening, biological follow-up, prediction of the risk of recurrence, and therapeutic options in cases with malignant recurrence. PMID- 27476313 TI - [Review and perspective of a long-term follow-up of two cohorts of workers heavily exposed to asbestos]. AB - National screening programs for detection of breast, colon and cervical cancers have been set up in France. Occupational cancers are excluded from these programs. Surveillance is left to the initiative of former employees who can initiate post-professional medical monitoring. This study describes an experience of such monitoring organised by the health insurance in collaboration with "victims". The long term follow-up, every two years, of 324 workers directly and heavily exposed to asbestos confirms the high risk of developing lung cancer, mesothelioma or asbestosis, the latter at times rapidly evolving. The early discovery of 3 bronchopulmonary cancers points to the interest of an annual or biannual routine screening. While new imaging techniques reduce by a factor of 8 irradiation, without significantly affecting the diagnostic capacity, the health benefit provided by annual monitoring scanner in heavy smokers favors an early detection program for lung cancers. The population targeted for such a screening (active or former smoker with pleural plaques) should be defined in more detail. The increasingly frequent observation of lung or pleural changes besides the populations at risk should also be considered. Therefore the detecting procedures applied to those workers indirectly or discontinuously exposed should be reassessed (only 1 TDM at 60 y, or on retirement, for the relevant occupations). These data suggest that the recommendation HAS 2010 for post-professional screening of workers occupationally exposed to asbestos should be reconsidered, particularly in case of pleural plaques. An organized screening program needs to be overhauled. PMID- 27476314 TI - [Non-invasive imaging tests for detecting coronary artery disease in symptomatic stable patients. Is diagnostic performance sufficient for guiding strategy?]. AB - Several non-invasive imaging techniques are currently available for coronary artery disease detection in stable patients with chest pain: exercise electrocardiogram, myocardial scintigraphy, stress echocardiography, stress MRI, positron emission tomography and computed tomography coronary angiography. According to recent guidelines from the European Society of Cardiology, the diagnosis process shall be guided by the coronary risk of the patient. The first recommended step is to clinically assess the probability of coronary artery disease. Thereafter, the choice of technique will be driven by usual parameters such as availability, local expertise and the contraindications of each test. Although detection of coronary artery disease by non-invasive tests follows different pathophysiological pathways, diagnostic value appears comparable. Therefore, choice of a diagnostic test must also take into consideration other factors such as the risks and hazards of imaging techniques as well as cost efficiency parameters. PMID- 27476315 TI - [Estrogen, hormonal therapy and Aging]. AB - Recent data suggests that a "window of opportunity" to decrease the risk of mortality and coronary heart disease (CHD) exists, when initiation hormone replacement therapy (HRT) in menopausal women aged of 50 to 59 years, or within the 10 years following the onset of menopause. The risks of HRT are rare, especially in young postmenopausal women with symptoms who use HRT for long periods of time, and have lower rates of mortality and CHD than comparable postmenopausal women who do not use HRT Newer evidence suggests that there are distinct differences between synthetic molecules and estradiol ; the physiological hormone may be preferable especially from a non-oral delivery system as thrombosis risk is the lowest with such therapy. In addition, natural progesterone does not reverse the benefits of estrogen, particularly in the nervous system and the vessels, and seems to be neutral on breast cancer risk. HRT must be individualized and tailored according to symptoms and each woman's individual risk profile, her preferences and expectations. PMID- 27476316 TI - [Not Available]. PMID- 27476317 TI - [Asbestos: An up-to-date general review]. AB - Major risks associated with asbestos exposure (mesothelioma, lung cancer and asbestosis) have been knownfor a long time. Various clinical and epidemiological studies, which include assessment of risk of developing cancer after discovering atypical computer-tomography (CT) images or pleural plaques in persons who had been exposed to asbestos, are still ongoing, however. This short report updates the risk of occupational exposure in 2014, the consequences of the former occupational exposures, the scale of compensation and recent legal dispositions intended to reduce the risk of occupational and non-professional exposure in France. PMID- 27476318 TI - [What can be expected today of pharmacotherapy in the Alcohol Use Disorders?]. AB - During the last past years, numerous drug have been proposed to treat Alcohol Use Disorders. Besides classical drugs as acomprosate or naltrexone, new compounds are developed in this new indication. They are used in substitution therapies (baclofen), either when the aim of the treatment is total abstinence from alcohol or as an aid for craving reduction facilitating a "controlled drinking", or also for the maintaining of abstinence (nalmefene). Those drugs, availaible in diferent countries, are now marketed in France (nalmefene). As yet, baclofen may be prescribed in France by the mean of a Temporary Utilisation Recommandation, according to the settlement of the National Medicament Agency. Despite the emphasis of some spectacular effects of baclofen, highly publicised by the media and some enthousiastic practitioners, the drug dosage/frequency has to be assessed by two ongoing controlled studies. The pharmacotherapy remains, however, only one element in the treatment of alcoholism, a complex biopsychosocial disorder. Various forms of psychotherapy remain necessary, the pharmacotherapy being only one, sometimes useful, additionnal treatment. PMID- 27476319 TI - [Louis Desliens' contributions to modern cardiac exploration. Results of the cardiac catheterization in the horse]. AB - In 1916 Louis Desliens, veterinary practitioner; submitted to the Academy of Sciences a description of a new way of exploring the cardiovascular system: percutaneous catheteri- zation. In 1935 he published the results of thirty years of explorations in hemodynamics mainly in horses: physiology, pathophysiology and pharmacodynamics. The text considers the very pioneering nature of these studies. PMID- 27476320 TI - The presence of extreme feather peckers in groups of laying hens. AB - Feather pecking is a serious economic and welfare problem in laying hens. Feather damage occurs mainly through severe feather pecking (SFP). Selection experiments have proved that this behavior is heritable and lines have been divergently selected for high (HFP) and low feather pecking (LFP). The number of bouts of SFP per hen follows a Poisson distribution with a maximum nearby 0. A few studies indicate that the distribution within flocks is not homogenous but contains sub groups of birds showing extremely high levels of feather pecking (EFP). It was the aim of the current study to re-analyze data on SFP of lines selected for HFP/LFP and their F2 cross so as to uncover hidden sub-populations of EFP birds. Data of seven selection generations of HFP and LFP selection lines as well as their F2 cross have been used. We fitted a two-component mixture of Poisson distributions in order to separate the sub-group of EFP from the remaining birds. HFP and LFP lines differed mainly in mean bouts per bird. The proportion of EFP was only marginal in the LFP as compared with the HFP and the F2 population. Selection for LFP did not result in total elimination of EFP. The presence of even small proportions of EFP may play an important role in initiating outbreaks of feather pecking in large flocks. Further studies on feather pecking should pay special attention to the occurrence of EFP sub-groups. PMID- 27476321 TI - Investigations on the Reaction of C3 and C6 alpha-Dicarbonyl Compounds with Hydroxytyrosol and Related Compounds under Competitive Conditions. AB - alpha-Dicarbonyl compounds are intermediates in reactions that lead to the formation of potentially harmful advanced glycation end-products. Carbonyl trapping capacities of antiglycative substances have been traditionally limited to C2 and C3 alpha-dicarbonyl structures. Glyoxal (GO)-, methylglyoxal (MGO)-, 3 deoxyglucosone (3-DG)-, 3-deoxygalactosone (3-DGal)-, 3,4-dideoxyglucoson-3-ene-, and glucosone-trapping capacities of hydroxytyrosol (HT), hydroxytyrosol acetate (HTA), and 3,4-dihydroxyphenylacetic acid (DOPAC) in simple (phenolic/dicarbonyl) and competitive model systems (phenolic/dicarbonyl1/dicarbonyl2) were investigated. HT and HTA were more effective for MGO than 3-DG and 3-DGal. Furthermore, DOPAC exerted higher trapping capacity than HT and HTA for C3 and C6 alpha-dicarbonyl compounds. In the competitive systems, HT-related substances did not show preference for trapping 3-DG or 3-DGal and behaved as in the simple systems. In the presence of MGO, however, HT-related substances were more effective for trapping MGO than C6 structures. The results demonstrate the C6 alpha-dicarbonyl-trapping capacities of HT, HTA, and DOPAC, with DOPAC exerting the highest activity. PMID- 27476322 TI - Selection and Identification of Molecular Gold Clusters at the Nano(gram) Scale: Reversed Phase HPLC-ESI-MS of a Mixture of Au-Peth MPCs. AB - Recent advances in cluster synthesis make it possible to produce an enormous variety molecule-like MPCs of size, composition, shape, and surface-chemical combinations. In contrast to the significant growth in the synthetic capability to generate these materials, progress in establishing the physicochemical basis for their observed properties has remained limited. The main reason for this has been the lack of the analytical capability to generate and measure samples of suitably high (molecular) purity; such capability is also essential to support therapeutic and diagnostic MPC development. In order for MPC products to get to market, especially those products that are medical-field related, characterization is required to identify and quantify all components present in a material mixture. Here, we show results from analysis of several synthetic mixtures of gold MPCs by nonaqueous reversed-phase chromatography coupled with mass spectrometry detection. The additional or hidden components, revealed to be present in these mixtures, provide novel insights into their comparative stability and interactions. PMID- 27476323 TI - Protein-Based Multifunctional Nanocarriers for Imaging, Photothermal Therapy, and Anticancer Drug Delivery. AB - We report a simple approach for fabricating plasmonic and magneto-luminescent multifunctional nanocarriers (MFNCs) by assembling gold nanorods, iron oxide nanoparticles, and gold nanoclusters within BSA nanoparticles. The MFNCs showed self-tracking capability through single- and two-photon imaging, and the potential for magnetic targeting in vitro. Appreciable T2-relaxivity exhibited by the MFNCs indicated favorable conditions for magnetic resonance imaging. In addition to successful plasmonic-photothermal therapy of cancer cells (HeLa) in vitro, the MFNCs demonstrated efficient loading and delivery of doxorubicin to HeLa cells leading to significant cell death. The present MFNCs with their multimodal imaging and therapeutic capabilities could be eminent candidates for cancer theranostics. PMID- 27476324 TI - Re: Evaluating Ureteral Wall Injuries with Endoscopic Grading System and Analysis of the Predisposing Factors (From: Karakan T, Kilinc MF, Demirbas A, et al. J Endourol 2016;30:375-378). PMID- 27476326 TI - Effects of long-term training cessation in young top-level road cyclists. AB - In cycling, it is common practice to have a break in the off season longer than 4 weeks while adopting an almost sedentary lifestyle, and such a break is considered to be long-term detraining. No previous studies have assessed the effect of training cessation with highly trained young cyclists. The purpose of the present investigation was to examine effects of 5 weeks of training cessation in 10 young (20.1 +/- 1.4 years) male road cyclists for body composition, haematological and physiological parameters. After training cessation, body mass of cyclists increased (P = 0.014; ES = 0.9). [Formula: see text] (L . min-1 = 8.8 +/- 5.0%, mL . kg-1.min-1 = -10.8 +/- 4.2%,), Wmax (W = -6.5 +/- 3.1%, W . kg 1 = -8.5 +/- 3.3%,), WLT1 (W = -12.9 +/- 7.0%, W . kg-1 = -14.8 +/- 7.4%,), WLT2 (W = -11.5 +/- 7.0%, W . kg-1 = -13.4 +/- 7.6%,) and haematological (red blood cells count, -6.6 +/- 4.8%; haemoglobin, -5.4 +/- 4.3% and haematocrit, -2.9 +/- 3.0%) values decreased (P <= 0.028; ES >= 0.9). Five weeks of training cessation resulted in large decreases in physiological and haematological values in young top-level road cyclists suggesting the need for a shorter training stoppage. This long-term detraining is more pronounced when expressed relative to body mass emphasising the influence of such body mass on power output. A maintenance programme based on reduced training strategies should be implemented to avoid large declines in physiological values in young cyclists who aspire to become professionals. PMID- 27476327 TI - On cellulose dissolution and aggregation in aqueous tetrabutylammonium hydroxide. AB - Aqueous tetrabutylammonium hydroxide, TBAH(aq), has been found to dissolve cellulose and to be a potential solvent for chemical processing or fiber spinning. In this paper, we have investigated the dissolution state of cellulose in 40 wt % TBAH(aq) solvent, and present an extensive study of rheology, combined with static light and small-angle X-ray scattering, to correlate cellulose aggregation with changes in the rheological parameters. Two cellulose molecular weights are compared. Microcrystalline cellulose (MCC), with a degree of polymerization of ca. 260, and a dissolving pulp with an approximately ten times higher molecular weight. Scattering data demonstrate that cellulose is molecularly dissolved at lower cellulose concentrations, while aggregates are present when the concentration exceeds a certain value. The onset of the aggregate formation is marked by a pronounced increase in the scattering intensity at low q, shear thinning behavior and violation of the empirical Cox Merz rule. Additionally, the SAXS data suggest the presence of a solvation shell enriched in TBA(+) ions, compared to the bulk solvent. The results are consistent with the recent suggestion that while native cellulose I may still dissolve, solutions are, above a particular concentration, becoming supersaturated with respect to the more stable crystal form cellulose II. PMID- 27476328 TI - A renaissance of soaps? - How to make clear and stable solutions at neutral pH and room temperature. AB - Soaps are the oldest and perhaps most natural surfactants. However, they lost much of their importance since "technical surfactants", usually based on sulfates or sulfonates, have been developed over the last fifty years. Indeed, soaps are pH- and salt-sensitive and they are irritant, especially to the eyes. In food emulsions, although authorized, they have a bad taste, and long-chain saturated soaps have a high Krafft temperature. We believe that most or perhaps all of these problems can be solved with modern formulation approaches. We start this paper with a short overview of our present knowledge of soaps and soap formulations. Then we focus on the problem of the lacking soap solubility at neutral pH values. For example, it is well known that with the food emulsifier sodium oleate (NaOl), clear and stable aqueous solutions can only be obtained at pH values higher than 10. A decrease in the pH value leads to turbid and unstable solutions. This effect is not compatible with the formulation of aqueous stable and drinkable formulations with neutral or even acidic pH values. However, the pH value/phase behavior of aqueous soap solutions can be altered by the addition of other surfactants. Such a surfactant can be Rebaudioside A (RebA), a steviol glycoside from the plant Stevia rebaudiana which is used as a natural food sweetener. In a recent paper, we showed the influence of RebA on the apKa value of sodium oleate in a beverage microemulsion and on its clearing temperature. In the present paper, we report on the effect of the edible bio-surfactant RebA, on the macroscopic and microscopic phase behavior of simple aqueous sodium oleate solutions at varying pH values. The macroscopic phase behavior is investigated by visual observation and turbidity measurements. The microscopic phase behavior is analyzed by acid-base titration curves, phase-contrast and electron microscopy. It turned out that even at neutral pH, aqueous NaOl/RebA solutions can be completely clear and stable for more than 50days at room temperature. This is for the first time that a long chain soap could be really solubilized in water at neutral pH at room temperature. At last, these findings were applied to prepare stable, highly translucent and drinkable aqueous solutions of omega-3-fatty acids at a pH value of 7.5. PMID- 27476329 TI - Generalizing, deleting and distorting information about the experience and communication of chronic pain. PMID- 27476330 TI - Cytotoxic, mutagenicity, and genotoxicity effects of guanylhydrazone derivatives. AB - Several studies have reported that guanylhydrazones display a variety of desirable biological properties, such as antihypertensive, antibacterial, and antimalarial behaviour. They furthermore promote anti-pneumocystosis and anti trypanosomiasis, exhibit antitumor activity, and show significant cytotoxicity against cancer cell lines. In this work, we have evaluated the cytotoxicity, mutagenicity, and genotoxicity of two guanylhydrazones derivatives, (E)-2-[(2,3 dimethoxyphenyl) methylene] hydrazine carboxymidamide hydrochloride (2,3-DMeB) and (E)-2-[(3,4-dimethoxyphenyl) methylene] hydrazine carboxymidamide hydrochloride (3,4-DMeB), in different biological models. Both 2,3-DMeB and 3,4 DMeB induce weak cytotoxic and mutagenic effects in bacteria and yeast. The genotoxicity of these compounds was determined in a fibroblast cell line (V79) using alkaline comet assay, as well as a modified comet assay with bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (EndoIII). Both guanylhydrazone derivatives induced DNA damage. Treatment of V79 cells with EndoIII and FPG proteins demonstrated a significant effect of 2,3-DMeB and 3,4 DMeB with respect to oxidized bases. In addition, the derivatives induced a significant increase in the frequency of micronucleated cells at high doses. The antifungal and anti-trypanosomal properties of these guanylhydrazone derivatives were also evaluated, and the obtained results suggest that 2,3-DMeB is more effective than 3,4-DMeB. The biological activity of 2,3-DMeB and 3,4-DMeB may thus be related, at least in part, to their oxidative potential, as well as to their ability to interact with DNA. Considering the previously reported in vitro antitumor activity of guanylhydrazone derivatives in combination with the lack of acute toxicity and the fact that DNA damage is only observed at high doses should render both compounds good candidates for in vivo studies on antitumor activity. PMID- 27476331 TI - Polyvinyl polypyrrolidone attenuates genotoxicity of silver nanoparticles synthesized via green route, tested in Lathyrus sativus L. root bioassay. AB - The silver nanoparticles (AgNPs) were synthesized extracellularly from silver nitrate (AgNO3) using kernel extract from ripe mango Mengifera indica L. under four different reaction conditions of the synthesis media such as the (i) absence of the reducing agent, trisodium citrate (AgNPI), (ii) presence of the reducing agent (AgNPII), (iii) presence of the cleansing agent, polyvinyl polypyrrolidone, PVPP (AgNPIII), and (iv) presence of the capping agent, polyvinyl pyrrolidone, PVP (AgNPIV). The synthesis of the AgNPs was monitored by UV-vis spectrophotometry. The AgNPs were characterised by the energy-dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, and small angle X-ray scattering. Functional groups on the AgNPs were established by the Fourier transform infrared spectroscopy. The AgNPs (AgNPI, AgNPII, AgNPIII and AgNPIV) were spherical in shape with the diameters and size distribution-widths of 14.0+/-5.4, 19.2+/-6.6, 18.8+/-6.6 and 44.6+/-13.2nm, respectively. Genotoxicity of the AgNPs at concentrations ranging from 1 to 100mgL(-1) was determined by the Lathyrus sativus L. root bioassay and several endpoint assays including the generation of reactive oxygen species and cell death, lipid peroxidation, mitotic index, chromosome aberrations (CA), micronucleus formation (MN), and DNA damage as determined by the Comet assay. The dose-dependent induction of genotoxicity of the silver ion (Ag(+)) and AgNPs was in the order Ag(+)>AgNPII>AgNPI>AgNPIV>AgNPIII that corresponded with their relative potencies of induction of DNA damage and oxidative stress. Furthermore, the findings underscored the CA and MN endpoint-based genotoxicity assay which demonstrated the genotoxicity of AgNPs at concentrations (<=10mgL(-1)) lower than that (>=10mgL(-1)) tested in the Comet assay. This study demonstrated the protective action of PVPP against the genotoxicity of AgNPIII which was independent of the size of the AgNPs in the L. sativus L. root bioassay system. PMID- 27476332 TI - Cytochrome P450 expression system for high-throughput real-time detection of genotoxicity: Application to the study of human CYP1A2 variants. AB - Individual variations in cytochrome P450-mediated metabolism are believed to contribute to individual susceptibility to chemical carcinogenesis. CYP1A2 is one of the major forms of cytochrome P450 involved in drug metabolism and bioactivation of carcinogens. We have applied a recently developed high throughput Salmonella typhimurium TA1535 system for detection of DNA damaging agents to the study of CYP1A2 polymorphisms. Non-synonymous variants T83M [CYP1A2*9], S212C [CYP1A2*12], S298R [part of CYP1A2*21], G299S [CYP1A2*13], I314V [no allele designation], I386F [CYP1A2*4], C406Y [CYP1A2*5] and R456H [CYP1A2*8] were examined. The cDNAs for each of these variants and the wild-type were co-expressed with human NADPH cytochrome P450 oxidoreductase in the TA1535 based system. The bioactivation capacity of these CYP1A2 variants was investigated using three CYP1A2-dependent pro-mutagens, 1-aminopyrene (1AP), 2 aminoanthracene (2AA), and 2-amino-3-methylimidazo(4,5-f)quinoline (IQ). All CYP1A2 variants except R456H, T83M, and I386F gave positive responses with all three compounds. Variant R456H generated no detectable holoenzyme and no detectable response for any of the compounds; I386F did not bioactivate IQ; T83M did not bioactivate 1AP. Multivariate analysis indicated variant T83M to be substantially altered in catalytic properties when compared with wild-type CYP1A2; variants G299S and I386F are slightly but significantly different. These results corroborate our previous studies, indicating the effectiveness of this new high-throughput system, not only for examining the effect of CYP1A2 polymorphisms on pro-mutagen bioactivation, but also for obtaining insights on CYP1A2 function at the mechanistic level. PMID- 27476333 TI - The antileishmanial drug miltefosine (Impavido((r))) causes oxidation of DNA bases, apoptosis, and necrosis in mammalian cells. AB - Miltefosine was developed to treat skin cancer; further studies showed that the drug also has activity against Leishmania. Miltefosine is the first oral agent for treating leishmaniasis. However, its mechanism of action is not completely understood. We have evaluated the induction of DNA damage by miltefosine. Cytotoxicity and genotoxicity (comet assay) tests were performed on human leukocytes exposed to the drug in vitro. Apoptosis and necrosis were also evaluated. In vivo tests were conducted in Swiss male mice (Mus musculus) treated orally with miltefosine. Oxidation of DNA bases in peripheral blood cells was measured using the comet assay followed by digestion with formamidopyrimidine glycosylase (FPG), which removes oxidized guanine bases. The micronucleus test was performed on bone marrow erythrocytes. Miltefosine caused DNA damage, apoptosis, and necrosis in vitro. Mice treated with miltefosine showed an increase in the DNA damage score, which was further increased following FPG digestion. The micronucleus test was also positive. PMID- 27476335 TI - Long-term genotoxic effects of immunosuppressive drugs on lymphocytes of kidney transplant recipients. AB - Immunosuppressive therapy can prevent rejection after organ transplantation. However, increased cancer risk is a serious complication among patients undergoing such therapy. We have evaluated whether prolonged use of immunosuppressive drugs is genotoxic. DNA instability was assessed, using the comet and micronucleus assays, in blood lymphocytes of 76 kidney transplant patients. DNA damage detected by the comet assay increased with time after transplantation. The estimated glomerular filtration rate of the patients did not influence the incidence of DNA damage. No association between micronucleated mononucleated cells and time elapsed after transplantation was observed. Our results suggest that prolonged use of immunosuppressive drugs in kidney transplant patients can induce genetic instability. PMID- 27476334 TI - Resveratrol affects DNA damage induced by ionizing radiation in human lymphocytes in vitro. AB - Resveratrol (3,4',5-trihydroxystilbene; RSV) acts on cancer cells in several ways, inducing cell cycle delay and apoptotic death, and enhancing ionizing radiation (IR)-mediated responses. However, fewer studies have examined RSV effects on normal cells. We have treated human lymphocytes in vitro with RSV, either alone or combined with IR, to evaluate its potential use as a radioprotector. We measured the effects of RSV on induction of DNA damage, repair kinetics, and modulation of histone deacetylase activity. PMID- 27476336 TI - Head and neck sarcomas: clinical and histopathological presentation, treatment modalities, and outcomes. AB - BACKGROUND: Sarcoma of the head and neck is a rare condition that poses significant challenges in management and often requires radical multimodality treatment. OBJECTIVES: This study aimed to analyse current clinical presentation, evaluation, management dilemmas and oncological outcomes. METHODS: Computer records and case notes were analysed, and 39 patients were identified. Variables were compared using Pearson's chi-square test and the log-rank test, while survival outcomes were calculated using the Kaplan-Meier method. RESULTS: The histopathological diagnosis was Kaposi sarcoma in 20.5 per cent of cases, chondrosarcoma in 15.3 per cent and osteosarcoma in 10.2 per cent. A range of other sarcomas were diagnosed in the remaining patients. The site of disease was most commonly sinonasal, followed by the oral cavity and larynx. CONCLUSION: Wide local excision with clear resection margins is essential to achieve local control and long-term survival. There is a need for cross-specialty collaboration in order to accrue the evidence which will be necessary to improve long-term outcomes. PMID- 27476337 TI - Electrocardiographic Abnormalities Predict Adverse Clinical Outcomes in Patients with Subarachnoid Hemorrhage. AB - BACKGROUND: We conducted a retrospective cohort study of a large sample to assess whether electrocardiographic (ECG) abnormalities are independently associated with the occurrence of neurogenic pulmonary edema (NPE), delayed cerebral ischemia (DCI), and in-hospital death after nontraumatic subarachnoid hemorrhage (SAH). METHODS: In this retrospective observational study, patients who were admitted within 72 hours of SAH symptom onset between 2013 and 2015 were enrolled. Twelve-lead ECG findings obtained within 72 hours after SAH and the presence of NPE, DCI, and in-hospital death were collected based on the results reported in the medical records. RESULTS: We included 834 patients. NPE occurred in 192 patients (23%). The median delay from SAH onset to NPE was 3 days (interquartile range [IQR]: 5 days). DCI occurred in 223 patients (27%; median delay to DCI, 4 days; IQR: 5 days). In total, 141 patients (17%) died in the hospital (median time to death, 12 days; IQR: 18 days). The frequency of ECG abnormalities for all enrolled patients was 65%. Corrected QT prolongation had an adjusted risk ratio (RR) of 1.5 (1.1-2.2) for NPE and 1.8 (1.3-2.4) for DCI. ST depression had an adjusted RR of 3.0 (1.2-7.5) for in-hospital death. NSSTTCs (nonspecific ST- or T-wave changes) had an adjusted RR of 2.7 (1.8-4.2) for NPE, 2.8 (1.9-4.3) for DCI, and 2.2 (1.3-3.5) for in-hospital death. All RRs were adjusted for age and Hunt-Hess scores. CONCLUSIONS: ECG abnormalities assessed within 72 hours after SAH using a standard 12-lead ECG are independently associated with an increased risk of adverse clinical outcomes in patients with nontraumatic SAH. PMID- 27476338 TI - Effectiveness of the Combined Use of Distal Filter Protection Device and Mo.Ma Ultra: Technical Note. AB - BACKGROUND: Although Mo.Ma Ultra is an embolic protection device for interrupting the anterograde blood flow to the internal carotid artery, incomplete blood stagnation is often observed. We report the effectiveness of the combined use of a distal filter protection device and Mo.Ma Ultra (Medtronic, Minneapolis, MN). MATERIALS AND METHODS: Our case series comprises 10 consecutive patients (11 carotid arteries) who underwent carotid artery stenting (CAS) using Mo.Ma Ultra and FilterWire EZ (Boston Scientific, Natick, MA). RESULTS: The superior thyroid artery originated from the proximal side of the bifurcation of the common carotid artery, except for 1 artery. Although complete blood stagnation was observed in 6 arteries, filter debris was detected in 3 of these 6 arteries. Positive postoperative findings on diffusion-weighted magnetic resonance imaging were observed in 3 cases (3 arteries). Only 1 patient had transient neurological deficits. CONCLUSION: The combined use of a distal filter protection device and Mo.Ma Ultra could provide a more reliable embolic protection in CAS. PMID- 27476339 TI - The High Frequency of Guideline-Approved and Guideline-Disapproved Medication Use in Stroke and Transient Ischemic Attack. AB - BACKGROUND AND PURPOSE: Administration of evidence-based pharmacotherapy improves stroke outcome while the use of non-evidence-based medications may not be of benefit and leads to unnecessary patient care costs. The aim of our study was to determine the frequency of guideline-approved and guideline-disapproved pharmacotherapy use in acute stroke management in the Czech Republic (CR). METHODS: Using the ICD-10 codes, 500 stroke and transient ischemic attack (TIA) patients were randomly selected (random selection of 10 hospitals and then 50 patients from each hospital) from the National Registry of Hospitalized Patients for strokes occurring in 2011. Discharge summaries were reviewed for medications prescribed during hospitalization and at discharge. RESULTS: Of the 500 requested discharge summaries, 484 were available for review (response rate 97%). Up to 479 (96%) summaries were sufficient for evaluation and of these, 393 were confirmed to have a stroke or TIA diagnosis. Brain imaging (computed tomography or magnetic resonance imaging) was performed in 97% of the 393 cases. Intravenous thrombolysis was administered to 7% of patients with ischemic stroke (rate was 0% 25% in different hospitals). Up to 97% of patients with ischemic events (TIA or ischemic stroke) were treated with antiplatelets or anticoagulants. At least 1 non-evidence-based medication was administered to 28% of the 393 patients (rate was 5%-89% in different hospitals). CONCLUSIONS: Guideline-disapproved pharmacotherapy is common in stroke and TIA patients in the CR and processes should be put into place to lessen the frequency of their use. The use of guideline-approved medications is also high and should be further promoted. PMID- 27476340 TI - Intravenous Tissue Plasminogen Activator for Wake-Up Stroke: A Propensity Score Matched Analysis. AB - GOAL: To evaluate the safety and efficacy of intravenous (IV) tissue plasminogen activator (tPA) in the treatment of wake-up stroke (WUS) using propensity score (PS) analysis. MATERIALS AND METHODS: Consecutive acute ischemic stroke patients meeting inclusion criteria were retrospectively identified from our stroke registry between July 2008 and May 2014, and classified as stroke onset less than or equal to 4.5 hours treated with tPA (control; n = 369), tPA-treated WUS (n = 46), or nontreated WUS (n = 154). The primary outcome of interest for safety was symptomatic intracerebral hemorrhage (sICH), defined as parenchymal hemorrhage associated with a greater than or equal to 4-point increase in National Institutes of Health Stroke Scale (NIHSS) score. Multivariate logistic regression with adjustment for confounders and PS for receiving IV tPA assessed outcomes, along with PS-matched average treatment effect on the treated (ATT). FINDINGS: No significant difference was found in rates of sICH between tPA-treated WUS, nontreated WUS, and controls (2.2%, .7%, and 3%, respectively), or in the odds of sICH between tPA-treated WUS and controls (OR = .53, 95% CI = .06-4.60, P = .568). Among WUS patients, tPA treatment was significantly associated with higher odds of good functional outcome in fully adjusted analyses (OR = 7.22, 95% CI = 2.28-22.88, P = .001). The ATT of tPA for WUS patients demonstrated a significantly greater decrease in NIHSS score at discharge when compared to nontreated WUS patients (-4.32 versus -.34, P = .032). CONCLUSIONS: Comparable rates of sICH between treated WUS and stroke onset less than or equal to 4.5 hours treated with tPA suggest that tPA may be safely used to treat WUS. Superior outcomes for tPA-treated versus nontreated WUS subjects may suggest clinical efficacy of the treatment. PMID- 27476341 TI - Significant Association of the RNF213 p.R4810K Polymorphism with Quasi-Moyamoya Disease. AB - BACKGROUND: Quasi-moyamoya disease is an angiographical moyamoya disease equivalent accompanied by known underlying diseases. Mysterin/RNF213 is a major susceptibility gene for moyamoya disease, of which the p.R4810K variant is a founder polymorphism. The genetics of quasi-moyamoya disease is poorly understood, therefore, this study investigated a potential association between the p.R4810K polymorphism and quasi-moyamoya disease. METHODS: Genotyping of the p.R4810K variant was performed on 18 quasi-moyamoya disease cases and 91 controls, who visited Kyoto University Hospital or Kobe City Medical Center, Japan, between 2006 and 2015. RESULTS: The p.R4810K variant was found in 12 of 18 quasi-moyamoya disease patients. The frequency of p.R4810K carriers was significantly higher in quasi-moyamoya disease cases than in controls (66.7% versus 2.2%, odds ratio 89.0, 95% confidence interval: 19.2-669.4). CONCLUSIONS: Our data showed that the RNF213 p.R4810K polymorphism was significantly associated with quasi-moyamoya disease. PMID- 27476342 TI - Older Stroke Patients with High Stroke Scores Have Delayed Door-To-Needle Times. AB - INTRODUCTION: The timely administration of intravenous (IV) tissue plasminogen activator (t-PA) to acute ischemic stroke patients from the period of symptom presentation to treatment, door-to-needle (DTN) time, is an important focus for quality improvement and best clinical practice. METHODS: A retrospective review of our Get With The Guidelines database was performed for a 5-hospital telestroke network for the period between January 2010 and January 2015. All acute ischemic stroke patients who were triaged in the emergency departments connected to the telestroke network and received IV t-PA were included. Optimal DTN time was defined as less than 60 minutes. Logistic regression was performed with clinical variables associated with DTN time. Age and National Institutes of Health Stroke Scale (NIHSS) score were categorized based on clinically significant cutoffs. RESULTS: Six-hundred and fifty-two patients (51% women, 46% White, 45% Hispanic, and 8% Black) were included in this study. The mean age was 70 years (range 29 98). Of the variables analyzed, only arrival mode, initial NIHSS score, and the interaction between age and initial NIHSS score were significant. DTN time more than or equal to 60 minutes was most common in patients aged more than 80 years with NIHSS score higher than 10. CONCLUSIONS: The cause of DTN time delay for older patients with higher NIHSS score is unclear but was not related to presenting blood pressure or arrival mode. Further study of this subgroup is important to reduce overall DTN times. PMID- 27476343 TI - Two-year outcome after treatment of severely calcified lesions with newer generation drug-eluting stents in acute coronary syndromes: A patient-level pooled analysis from TWENTE and DUTCH PEERS. AB - BACKGROUND: Data on medium-term outcome of patients with acute coronary syndrome (ACS), treated with newer-generation durable polymer drug-eluting stents (DES) in severely calcified coronary lesions, are scarce. We aimed to assess the impact of severe coronary lesion calcification on clinical outcome of patients with ACS, treated with newer-generation DES. METHODS: The TWENTE and DUTCH PEERS randomized trials comprise 1779 ACS patients, who were categorized into patients with versus without severe target lesion calcification. We performed a patient-level pooled analysis to assess 2-year outcome, including target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction (MI), or target vessel revascularization (TVR). RESULTS: Patients with severe target lesion calcification (n=340, 19.1%) were older (66.8+/-10.6 years vs. 62.8+/-11.5 years, p<0.001) and had more often diabetes (22.1% vs. 16.8%, p=0.02) and hypercholesterolemia (51.5% vs. 42.9%, p=0.005) than other patients (n=1439, 79.9%). In addition they showed a higher TVF rate (12.4% vs.7.0%, p=0.001), mainly related to a difference in TVR (6.8% vs. 3.3%, p=0.003). There was a borderline significant between-group difference in cardiac death (3.6% vs. 1.8%, p=0.05), but not in target vessel MI (3.8% vs.2.6%, p=0.23) and definite stent thrombosis (0.9% vs. 0.6%, p=0.71). Multivariate analysis demonstrated that severe lesion calcification was an independent risk factor of TVF (adjusted HR; 1.58, 95% CI: 1.23-2.03; p<0.001). CONCLUSIONS: In patients with ACS, treatment of severely calcified lesions with newer-generation DES was associated with an overall higher clinical event risk - related in particular to a higher TVR rate, while the risk of MI was low. PMID- 27476344 TI - Do-it-yourself impressions and clear retainers: A fairy tale. PMID- 27476345 TI - Antibacterial properties of retainers with silver nanoparticles. PMID- 27476346 TI - Corticotomy and piezocision in rapid canine retraction. PMID- 27476347 TI - Authors' response. PMID- 27476348 TI - Authors' response. PMID- 27476349 TI - Reproducibility of the lip position at rest. PMID- 27476350 TI - Author's response. PMID- 27476352 TI - Just do as I say. PMID- 27476353 TI - Earl Wiley Renfroe: Man of fortitude and orthodontist extraordinaire. PMID- 27476354 TI - Comparative assessment of chewing gum and ibuprofen in the management of orthodontic pain with fixed appliances: A pragmatic multicenter randomized controlled trial. AB - INTRODUCTION: The aim of this randomized trial was to investigate the effect of the use of a sugar-free chewing gum vs ibuprofen on reported pain in orthodontic patients. METHODS: This was a 2-arm parallel design randomized controlled trial in 9 sites in the southwest of England. Patients about to undergo orthodontic treatment with maxillary and mandibular fixed appliances were recruited and randomly allocated to an experimental chewing gum group or a control ibuprofen group. Eligibility criteria included patients undergoing fixed maxillary and mandibular appliance therapy, aged 11 to 17 years, and able to use ibuprofen and chewing gum. The primary outcome measure was pain experienced after appliance placement using a mean of 3 recordings on a scale of 0 to 10. Secondary outcome measures were pain experienced in the subsequent 3 days, pain after the first archwire change, ibuprofen use, and appliance breakages. Pain scores were recorded with a questionnaire and posted to a collection center by each patient. Randomization was by means of a central telephone service and comprised computer generated random numbers used to generate a sequential allocation list, with permuted blocks of variable size (2 and 4) and stratified by center. Neither the clinicians nor the patients were blinded to the intervention. Patients in the control group were permitted to use ibuprofen only, and patients in the experimental group were allowed to use ibuprofen if they did not get sufficient analgesia from the chewing gum. Data were analyzed using the principle of intention to treat with multilevel modeling to reflect the structured nature of the data (scores within patient within site). RESULTS: One thousand patients were recruited and randomized in a ratio of 1:1 to the chewing gum and ibuprofen (control) groups. The male-to-female ratios were similar in the groups. The pain questionnaire response rates were good at approximately 84% and 83% after appliance placement (chewing gum group, 419; ibuprofen group, 407) and 70% and 71% after the first archwire change (chewing gum group, 343; ibuprofen group, 341). The primary outcomes were similar for the 2 groups: mean pain scores, 4.31 in the chewing gum group and 4.17 in the ibuprofen group; difference, 0.14 (95% CI, -0.13 to 0.41). There was a suggestion that the relative pain scores for the 2 groups changed over time, with the chewing gum group experiencing slightly more pain on the day of bond-up and less on the subsequent 3 days; however, the differences had no clinical importance. There were no significant differences for the period after archwire change. The reported use of ibuprofen was less in the chewing gum group than in the ibuprofen group; after appliance placement, the mean numbers of occasions that ibuprofen was used were 2.1 in the chewing gum group and 3.0 in the ibuprofen group (adjusted difference, -0.96 [95% CI, -0.75 to -1.17; P <0.001]); after archwire change, the figures were 0.8 and 1.5 occasions (difference, -0.65 [-0.44 to -0.86; P <0.001]). After appliance placement and the first archwire change, there was no clinically or statistically significant difference in appliance breakages between the chewing gum and ibuprofen groups after either bond-up (7% and 8.8%, respectively) or the first archwire change (4.2% and 5.5%, respectively). No adverse events were reported. CONCLUSIONS: The use of a sugar-free chewing gum may reduce the level of ibuprofen usage but has no clinically or statistically significant effect on bond failures. REGISTRATION: International Standard Randomised Controlled Trial Number (79884739) and National Institute of Health Research (6631) portfolios. FUNDING: This research was supported by an award by the British Orthodontic Society Foundation. PMID- 27476355 TI - Prosthetic replacement vs space closure for maxillary lateral incisor agenesis: A systematic review. AB - INTRODUCTION: Defining the best treatment for maxillary lateral incisor agenesis is a challenge. Our aim in this study was to determine, with the evidence available in the literature, the best treatment for maxillary lateral incisor agenesis in the permanent dentition, evaluating the esthetic, occlusal (functional), and periodontal results between prosthetic replacement and orthodontic space closure. METHODS: Electronic databases (CENTRAL, PubMed, Web of Science, Scopus, and LILACS) were searched in September 2014 and updated in January 2015, with no restriction on language or initial date. A manual search of the reference lists of the potential studies was performed. Risk of bias was assessed by the Newcastle Ottawa Scale. RESULTS: The search identified 2174 articles, of which 1196 were excluded because they were duplicates. Titles and abstracts of 978 articles were accessed, and 957 were excluded. In total, 21 articles were read in full, and 9 case-control studies were included after applying the inclusion and exclusion criteria. Data were extracted from the articles selected, and a table was compiled for comparison and analysis of the results. There were no randomization and blinding, and the risk of bias evaluation found gaps in compatibility and outcome domains in almost all selected studies. CONCLUSIONS: Tooth-supported dental prostheses of maxillary lateral incisor agenesis had worse scores in the periodontal indexes than did orthodontic space closure. Space closure is evaluated better esthetically than prosthetic replacements, and the presence or absence of a Class I relationship of the canines showed no relationship with occlusal function or with signs and symptoms of temporomandibular disorders. PMID- 27476357 TI - Statistical shape analysis-based determination of optimal midsagittal reference plane for evaluation of facial asymmetry. AB - INTRODUCTION: The purpose of this study was to determine, by statistical shape analysis of original and mirrored skeletal landmarks, the optimal landmark-based midsagittal reference plane for evaluation of facial asymmetry. METHODS: The study sample comprised 69 patients with facial asymmetry (36 men, 33 women; mean age, 23.0 +/- 4.1 years). All landmarks were obtained with cone-beam computed tomography using a 3-dimensional coordinate system. For identifying the landmark based midsagittal reference plane, the 3 landmarks nearest to the symmetric midsagittal reference plane were selected by ordinary and generalized Procrustes analyses. To verify the 3-landmark-based midsagittal reference plane's compatibility with the symmetric midsagittal reference plane, asymmetry measurements were calculated and tested for each. RESULTS: The 3 nearest landmarks (nasion, anterior nasal spine, and posterior nasal spine) were selected for the 3-landmark-based midsagittal reference plane. The averages of the sums of the squared Euclidean distance and the squared Procrustes distance differences between the 2 configurations and shapes fabricated by the symmetric and landmark based midsagittal reference planes, respectively, were calculated as 0.121 +/- 0.241 mm and 1.69 * 10(-6) +/- 3.25 * 10(-6). The testing results for the symmetric and landmark-based midsagittal reference planes were almost the same. CONCLUSION: The results indicated that a 3-dimensional midsagittal reference plane constructed of nasion, anterior nasal spine, and posterior nasal spine could be a valuable tool for the evaluation of patients with facial asymmetry. PMID- 27476358 TI - Treatment comfort, time perception, and preference for conventional and digital impression techniques: A comparative study in young patients. AB - INTRODUCTION: The aim of this crossover study was to assess perceptions and preferences for impression techniques in young orthodontic patients receiving alginate and 2 different digital impressions. METHODS: Thirty-eight subjects aged 10 to 17 years requiring impressions for orthodontic treatment were randomly allocated to 3 groups that differed in the order that an alginate impressions and 2 different intraoral scanning procedures were administered. After each procedure, the patients were asked to score their perceptions on a 5-point Likert scale for gag reflex, queasiness, difficulty to breathe, uncomfortable feeling, perception of the scanning time, state of anxiety, and use of a powder, and to select the preferred impression system. Chairside time and maximal mouth opening were also registered. RESULTS: More queasiness (P = 0.00) and discomfort (P = 0.02) during alginate impression taking of the maxilla were perceived compared with the scans with the CEREC Omnicam (Sirona Dental Systems, Bensheim, Germany). There were no significant differences in perceptions between the alginate impressions and the Lava C.O.S. (3M ESPE, St Paul, Minn) and between the 2 scanners. Chairside times for the alginate impressions (9.7 +/- 1.8 minutes) and the CEREC Omnicam (10.7 +/- 1.8 minutes) were significantly lower (P <0.001) than for the Lava C.O.S. (17.8 +/- 4.0 minutes). Digital impressions were favored by 51% of the subjects, whereas 29% chose alginate impressions, and 20% had no preference. Regardless of the significant differences in the registered times among the 3 impression-taking methods, the distributions of the Likert scores of time perception and maximal mouth opening were similar in all 3 groups. CONCLUSIONS: Young orthodontic patients preferred the digital impression techniques over the alginate method, although alginate impressions required the shortest chairside time. PMID- 27476356 TI - Congenital and acquired mandibular asymmetry: Mapping growth and remodeling in 3 dimensions. AB - INTRODUCTION: Disordered craniofacial development frequently results in definitive facial asymmetries that can significantly impact a person's social and functional well-being. The mandible plays a prominent role in defining facial symmetry and, as an active region of growth, commonly acquires asymmetric features. Additionally, syndromic mandibular asymmetry characterizes craniofacial microsomia (CFM), the second most prevalent congenital craniofacial anomaly (1:3000 to 1:5000 live births) after cleft lip and palate. We hypothesized that asymmetric rates of mandibular growth occur in the context of syndromic and acquired facial asymmetries. METHODS: To test this hypothesis, a spherical harmonic-based shape correspondence algorithm was applied to quantify and characterize asymmetries in mandibular growth and remodeling in 3 groups during adolescence. Longitudinal time points were automatically registered, and regions of the condyle and posterior ramus were selected for growth quantification. The first group (n = 9) had a diagnosis of CFM, limited to Pruzansky-Kaban type I or IIA mandibular deformities. The second group (n = 10) consisted of subjects with asymmetric, nonsyndromic dentofacial asymmetry requiring surgical intervention. A control group (n = 10) of symmetric patients was selected for comparison. A linear mixed model was used for the statistical comparison of growth asymmetry between the groups. RESULTS: Initial mandibular shape and symmetry displayed distinct signatures in the 3 groups (P <0.001), with the greatest asymmetries in the condyle and ramus. Similarly, mandibular growth had unique patterns in the groups. The dentofacial asymmetry group was characterized by significant asymmetry in condylar and posterior ramal remodeling with growth (P <0.001). The CFM group was characterized by asymmetric growth of the posterior ramus (P <0.001) but relatively symmetric growth of the condyles (P = 0.47). CONCLUSIONS: Forms of CFM are characterized by active and variable growth of the dysplastic side, which has a distinct pattern from other disorders of mandibular growth. PMID- 27476359 TI - Relationship between body mass and dental and skeletal development in children and adolescents. AB - INTRODUCTION: The purpose of this investigation was to determine whether a relationship exists between body mass and dental and skeletal development in children and adolescents. A sample of 197 orthodontic patients (82 boys, 115 girls) was selected. Ethnicity was recorded, and body mass index (BMI) was calculated according to the standard equation from the Centers for Disease Control and Prevention, and then a BMI percentile according to sex and age was obtained. The panoramic radiographs were used to calculate the dental ages with an index. The chronologic ages were subtracted from the calculated dental ages to determine a "dental age difference" for each subject. The lateral cephalogram radiographs were analyzed for skeletal development using the cervical vertebral maturation stage method. RESULTS: The white population (60%) had an average BMI percentile of 53.6 and was statistically different from the Hispanic/black population (40%), which had an average percentile of 64.3. There were no significant differences for boys and girls for the BMI percentile and dental age difference, or for the BMI percentile and cervical vertebral stages. The multiple regression model showed that BMI percentile and ethnicity were statistically significant explanatory variables for the dental age difference. CONCLUSIONS: A relationship exists between body mass and dental and skeletal development. BMI percentile, dental age difference, and cervical vertebral stage are weakly correlated. No significant differences existed between boys and girls in any variables. BMI percentile and ethnicity are weak predictors of the discrepancy between dental age and chronologic age. PMID- 27476360 TI - Quantitative and qualitative assessment of anchorage loss during en-masse retraction with indirectly loaded miniscrews in patients with bimaxillary protrusion. AB - INTRODUCTION: This study provides vital insight in assessing anchorage loss when miniscrews are indirectly loaded. METHODS: The study sample comprised 18 patients with bimaxillary protrusion (14 girls, 4 boys; mean age, 17.3 +/- 4.6 years) selected from a database of 89 patients treated with miniscrews. All subjects who were selected required extraction of all first premolars and maximum anchorage. After initial leveling and aligning, miniscrews were placed between the first molar and the second premolar in all 4 quadrants and loaded by the indirect method at 3 weeks after placement with 200-g nickel-titanium alloy closed-coil springs for en-masse retraction. Mean treatment duration was 29.7 +/- 6.8 months. Pretreatment and posttreatment lateral cephalograms were analyzed to measure the amount of anchorage loss, incisor retraction, and the incisors' angular change in reference to the pterygoid vertical reference line and were evaluated by the structural superimposition method. RESULTS: The ratio of incisor retraction to molar protraction was 4.2 in the maxilla and 4.7 in the mandible. The first molars showed mean extrusion of 0.20 mm in the maxilla and 0.57 mm in the mandible; these were statistically insignificant. The mean angular change of the first molars was -2.43 degrees in the maxilla and -0.03 degrees in the mandible. The mean anchorage loss in reference to the pterygoid vertical was 1.3 mm in the maxilla and 1.1 mm in the mandible; these were statistically significant. Structural superimpositions showed mean change in molar position of 0.83 mm in the maxilla and 0.87 mm in the mandible, and 5.77 mm in the maxillary incisor and 5.43 mm in the mandibular incisor. These results were compared with the direct anchorage method reported in the literature. CONCLUSIONS: Indirect miniscrew anchorage can be a viable alternative to direct anchorage. PMID- 27476361 TI - Genetic and clinical risk factors of root resorption associated with orthodontic treatment. AB - INTRODUCTION: External apical root resorption (EARR) is a common complication in orthodontic treatment. Despite many studies on EARR, great controversies remain with regard to its risk factors. The objective of this study was to explore the relationship among sex, root movement, IL-1RN single nucleotide polymorphism (SNP) rs419598, IL-6 SNP rs1800796, and EARR associated with orthodontic treatment. METHODS: Altogether 174 patients (with 174 maxillary left central incisors) were selected for this study. Cone-beam computed tomography was performed before the start of the treatment and at the end of the treatment. Cone beam computed tomography data were used to reconstruct a 3-dimensional image of each tooth; the volume and the root resorption volume of each tooth were calculated. Three-dimensional matching was used to measure the amount of movement of each root. Genomic DNA was extracted from buccal swabs, and genotypes of SNP rs419598 and SNP rs1800796 of each subject were determined using TaqMan polymerase chain reaction genotyping (Applied Biosystems, Foster City, Calif). The data were analyzed with multiple linear regression analysis. RESULTS: The statistical analysis indicated no relationship between sex, tooth movement amount, and IL-1RN SNP rs419598 with EARR. The IL-6 SNP rs1800796 GC was associated with EARR, and root resorption differed significantly between SNP rs1800796 GC and CC. CONCLUSIONS: IL-6 SNP rs1800796 GC is a risk factor for EARR. The amount of root movement, IL-1RN SNP rs419598, and sex as risk factors for EARR need further study. PMID- 27476362 TI - Comparing orthodontic bond failures of light-cured composite resin with chemical cured composite resin: A 12-month clinical trial. AB - INTRODUCTION: In this clinical trial, we evaluated and compared bond failure rates of light-cured composite resin vs chemical-cured composite resin for 12 months. METHODS: Twenty-two subjects (356 stainless steel brackets) were included in this study, and a split-mouth design was used to randomly allocate diagonally opposite quadrants to either chemical-cured (178 brackets) or light-cured (178 brackets) composite resin; the brackets came from the same manufacturer. The survival and failure rates of the brackets were evaluated by the mode of polymerization. The overall bracket survival rates were estimated using the Kaplan-Meier product limit estimate. RESULTS: There were no significant differences in the bond failure rates between the chemical-cured and the light cured composites (P = 0.52). Bond failures were greater in posterior teeth (6.7%) than in anterior teeth (1.2%). The highest failure rate was observed in the second premolars (7.7%). CONCLUSIONS: The overall failure rate of brackets with the 2 bonding systems was 2.8%, which is acceptable for clinical use. The polymerization mode did not influence the bracket survival rate significantly. PMID- 27476363 TI - Alteration of palatine ruga pattern in subjects with oligodontia: A pilot study. AB - INTRODUCTION: The aim of this study was to compare the palatal ruga patterns in subjects with oligodontia and normal tooth numbers. METHODS: An observational investigation was conducted by using maxillary dental study casts to compare ruga numbers, lengths, and shapes in subjects with diagnosed oligodontia or normal tooth numbers. RESULTS: A total of 32 subjects comprised both the oligodontia (mean age, 14.0 years; SD, 5.0 years) and the control (mean age, 14.5 years; SD, 5.1 years) groups. The mean number of missing teeth in the oligodontia group was 8.7. The mean number of rugae in the whole sample was 7.36 (SD, 1.16), with no significant difference between the groups (P = 0.264). For ruga pattern, no differences were found for right-sided rugae; however, on the left side, a significant difference existed in shape frequency associated with ruga 2. Specifically, a curved shape was seen more frequently in ruga 2 of the oligodontia group (P = 0.01). CONCLUSIONS: The identification of subtle differences in ruga patterns between subjects with oligodontia and normal tooth numbers suggests potentially shared pathways during the development of these oral structures. Further large-scale investigations are warranted. PMID- 27476364 TI - Miniscrew-assisted slow expansion of mature rabbit sutures. AB - INTRODUCTION: In this study, we experimentally evaluated whether complex, mature sutures can be separated using skeletal anchorage and light, continuous forces. METHODS: Twelve adult, 8- to 9-month-old female New Zealand white rabbits were randomly assigned to 1 control group and 2 experimental groups. Open-coil nickel titanium springs delivered constant forces of 100 g across the sagittal suture to miniscrew implants placed bilaterally in the frontal bone. Sutural separation was measured biweekly. Separation was also measured with microcomputed tomography. Bone formation (mineral apposition) was measured with fluorescent labels. Qualitative histologic analyses of the suture tissues were performed using hematoxylin and eosin staining; osteoclasts were evaluated with tartrate resistant acid phosphatase staining. RESULTS: All 24 miniscrew implants remained stable throughout the experiment. There was no statistically significant sutural separation in the control group. In the experimental groups, sutural separation was significant (P <0.05) at all time points after the initial records were taken. The rate of separation was linear during the first 42 days. There were moderate correlations (R = 0.59-0.89; P <0.05) between miniscrew implant separation and bone marker separation. Mineral apposition rate, which was not measureable in the control group, was significant in the experimental group. The mineral apposition rate was greater between 14 and 28 days than between 28 and 38 days, and it was greater on the ectocranial than on the endocranial surface. Based on the microcomputed tomography analysis, 3-dimensional sutural volume of the experimental group increased significantly (P = 0.02), but surface area did not (P = 0.26). CONCLUSIONS: It is possible to separate the sagittal suture of mature rabbits. Sutural separation is limited, indicating involvement of other articulations. PMID- 27476365 TI - Biomechanical effects of maxillary expansion on a patient with cleft palate: A finite element analysis. AB - INTRODUCTION: The aims of this study were to evaluate the effects of rapid palatal expansion on the craniofacial skeleton of a patient with unilateral cleft lip and palate (UCLP) and to predict the points of force application for optimal expansion using a 3-dimensional finite element model. METHODS: A 3-dimensional finite element model of the craniofacial complex with UCLP was generated from spiral computed tomographic scans with imaging software (Mimics, version 13.1; Materialise, Leuven, Belgium). This model was imported into the finite element solver (version 12.0; ANSYS, Canonsburg, Pa) to evaluate transverse expansion forces from rapid palatal expansion. Finite element analysis was performed with transverse expansion to achieve 5 mm of anterolateral expansion of the collapsed minor segment to simulate correction of the anterior crossbite in a patient with UCLP. RESULTS: High-stress concentrations were observed at the body of the sphenoid, medial to the orbit, and at the inferior area of the zygomatic process of the maxilla. The craniofacial stress distribution was asymmetric, with higher stress levels on the cleft side. When forces were applied more anteriorly on the collapsed minor segment and more posteriorly on the major segment, there was greater expansion of the anterior region of the minor segment with minimal expansion of the major segment. CONCLUSIONS: The transverse expansion forces from rapid palatal expansion are distributed to the 3 maxillary buttresses. Finite element analysis is an appropriate tool to study and predict the points of force application for better controlled expansion in patients with UCLP. PMID- 27476366 TI - Landmark errors on posteroanterior cephalograms. AB - INTRODUCTION: It is important to reduce the method errors when evaluating posteroanterior cephalograms to see either small deviations from normal or transverse changes caused by orthodontic treatment. The aim of this study was to determine horizontal and vertical intraexaminer and interexaminer agreement in localization of landmarks in posteroanterior cephalograms of adult patients. METHODS: The sample was gathered retrospectively from the archives of the Department of Orthodontics of Yeditepe University in Istanbul, Turkey. Radiographs of 39 patients diagnosed with skeletal asymmetries (20 women, 19 men) were drawn manually, and a coordinate system was established with software. The tracings were made by 2 operators, after a calibration session on 29 landmarks (22 bilateral, 7 midline). Intraclass correlation coefficients and the Bland Altman test were used for detecting interexaminer and intraexaminer agreement for each cephalometric variable. RESULTS: The interexaminer agreement test showed that the most problematic landmark was crista galli, which showed moderate consistency between 2 examiners in the y coordinates at 2 time points. Condylar and zygomatic landmarks showed good agreement. The greater wing inferior and superior orbit, maxillary point, menton, anterior nasal spine, antegonial notch, mandibular and maxillary molar point, maxillary and mandibular incisor point, and maxillary and mandibular incisor edge landmarks had excellent agreement between the 2 examiners at the 2 time points in both the x and y coordinates. CONCLUSIONS: There are fewer errors in intraexaminer than in interexaminer correlations in landmark identifications on posteroanterior radiographs. All landmarks investigated except crista galli showed good agreement between measurements. PMID- 27476367 TI - Impact of dentofacial development on early mandibular incisor crowding. AB - INTRODUCTION: In this retrospective longitudinal study, we evaluated the influence of dentofacial development on mandibular incisor crowding from the early mixed dentition (T1) to the early permanent dentition (T2). METHODS: The sample was selected from 1212 longitudinally followed untreated subjects. Cephalometric radiographs and dental casts of 42 subjects (mean age, 8.66 years) with mandibular incisor crowding were evaluated at T1 and T2. Dentoskeletal variables were compared, and their influence on crowding changes was estimated. The sample was divided regarding incisor crowding severity (<=2 mm and >2 mm) and behavior (improvement and worsening), and the variables with a significant influence on the crowding changes were compared between the groups (P <0.05). RESULTS: Incisor crowding decreased from T1 to T2. The crowding changes were influenced by the amount of initial crowding, leeway space, incisor protrusion, and maxillary width increase. Crowding of 2 mm or less was not a good predictor for self-correction, with similar chances for improvement or worsening. CONCLUSIONS: Incisor crowding reduction can be expected from the early mixed to the early permanent dentition. The potential for crowding reduction was associated with greater initial incisor crowding, leeway space, incisor protrusion, and maxillary width increase. A crowding threshold of 2 mm was not a valid borderline condition to define the self-correction prognosis. PMID- 27476369 TI - Rescue therapy with orthodontic traction to manage severely impacted mandibular second molars and to restore an alveolar bone defect. AB - This case report describes the successful treatment of severely impacted mandibular second molars with severe apical root resorption of the mandibular first molars. The vertically impacted second molars were orthodontically moved (using orthodontic mini-implants) without additional root resorption of the first molars. The orthodontic treatment provided a satisfactory and stable outcome by improving the periodontium surrounding the first and second molars. The treatment also eliminated the need for prosthetic treatment by preserving the first and second molars. PMID- 27476368 TI - Management of severely impacted mandibular canines and congenitally missing mandibular premolars with protraction of autotransplanted maxillary premolar. AB - Transmigrated mandibular canines increase the treatment complexity in terms of both anchorage and biomechanical planning. Additionally, a Class II malocclusion with a deep overbite and associated dental anomalies such as hypodontia can further increase the treatment complexity and the overall treatment time. This case report describes the successful interdisciplinary treatment of a patient, aged 12.5 years, with transmigrated and severely impacted mandibular canines and congenitally missing mandibular second premolars. The transmigrated mandibular right canine was extracted, and a maxillary second premolar was autotransplanted to the missing mandibular right second premolar site with the aid of a stereolithographic donor tooth replica fabricated with 3-dimensional cone-beam computed tomography and a rapid prototyping technique. Furthermore, the autotransplanted tooth was protracted by 4 to 5 mm to close the space caused by the extraction of the mandibular right canine. The impacted mandibular left canine was orthodontically guided into its normal position in the arch. Good esthetic outcome and functional occlusion were achieved. PMID- 27476370 TI - Distalization of the mandibular dentition with a ramal plate for skeletal Class III malocclusion correction. AB - The retromolar fossa is an anatomically suitable skeletal anchorage site. The aim of this report was to introduce a novel appliance for the correction of skeletal Class III malocclusions with mandibular dentition distalization. The placement site and the procedure of the ramal plate are described. The resulting force vectors are parallel to the functional occlusal plane leading to efficient molar distalization. This approach is demonstrated with 2 adult patients who refused a surgical treatment option. This ramal plate may be indicated for total arch distalization for nonextraction and nonsurgical cases. PMID- 27476371 TI - Relationships between soft tissues in a posed smile and vertical cephalometric skeletal measurements. AB - INTRODUCTION: The purposes of this study were to measure the 3-dimensional parameters of the posed smile and to see whether there are any correlations with vertical cephalometric skeletal measurements. METHODS: Pretreatment records from a sample of 110 white girls between the ages of 12 and 18 years were gathered. The measurements of SN-GoGn, anterior facial height, and lower and upper facial height percentages were obtained from tracing lateral cephalograms. Superimposing the repose and the posed smile facial scans allowed for measurements to be obtained showing the movements in the x, y, and z dimensions of the upper and lower lips, the commissures, and the Cupid's bows. Correlations and multiple linear regression analyses were run to check for associations and predictive relationships between the cephalometric skeletal measurements and soft tissue changes. RESULTS: We found significant moderate correlations and weak correlations. Significant multiple regression models were found for intercommissural width, smile index, and lower lip in the y and z dimensions. CONCLUSIONS: There were moderate correlations showing that as SN-GoGn and anterior facial height increased, the interlabial gap increased as the smile index decreased. Significant relationships were found between certain hard tissue cephalometric measurements and the width of the smile as well as the movements of the lower lip. PMID- 27476372 TI - Learned intermediary. PMID- 27476373 TI - Analysis of covariance, Part 2. PMID- 27476374 TI - Are ultrasonographic findings like periosteal and tendinous edema associated with medial tibial stress syndrome? A case-control study. AB - OBJECTIVES: Medial tibial stress syndrome (MTSS) is one of the most common sporting injuries. As of yet, the development of effective therapeutic interventions to treat MTSS is hindered by the fact that its pathology is unknown. Our aim was to explore the pathology of MTSS, by assessing whether the presence of MTSS is related to periosteal, bony or tendinous abnormalities in the lower leg. DESIGN: Case-control study. METHODS: Participants with MTSS and athletic control participants were recruited from the same (high-risk) base population. Musculoskeletal ultrasonography was performed on the posteromedial tibial border and deep plantar flexor muscles by an experienced radiological specialist who was blinded to group membership. Associations between MTSS and tissue abnormalities were expressed in odds ratios (OR). RESULTS: A total of 42 participants, 15 MTSS cases and 27 control athletes completed the study. Overall, periosteal and tendinous abnormalities were common in cases with and without MTSS. Periosteal edema was present in 8 (53.3%) MTSS cases and in 10 (37.0%) control athletes, in specific painful spots in the distal 2/3 of the posteromedial tibial border OR=1.9 (95% CI 0.54-6.99, p=0.35). Also, tendinous abnormalities in the tibialis posterior muscle were frequently seen in MTSS cases (N=7, 46.7%) and in control athletes (N=13, 48.1%) (OR=0.97, 95% CI 0.27-3.51, p=0.96). No bone abnormalities were observed in either group. CONCLUSIONS: Periosteal and tendinous findings seem to be common in both athletes with and without MTSS, and consequently are not associated with MTSS. PMID- 27476375 TI - The effect of exercise training on cutaneous microvascular reactivity: A systematic review and meta-analysis. AB - OBJECTIVES: This study aimed to review the efficacy of exercise training for improving cutaneous microvascular reactivity in response to local stimulus in human adults. DESIGN: Systematic review with meta-analysis. METHODS: A systematic search of Medline, Cinahl, AMED, Web of Science, Scopus, and Embase was conducted up to June 2015. Included studies were controlled trials assessing the effect of an exercise training intervention on cutaneous microvascular reactivity as instigated by local stimulus such as local heating, iontophoresis and post occlusive reactive hyperaemia. Studies where the control was only measured at baseline or which included participants with vasospastic disorders were excluded. Two authors independently reviewed and selected relevant controlled trials and extracted data. Quality was assessed using the Downs and Black checklist. RESULTS: Seven trials were included, with six showing a benefit of exercise training but only two reaching statistical significance with effect size ranging from -0.14 to 1.03. The meta-analysis revealed that aerobic exercise had a moderate statistically significant effect on improving cutaneous microvascular reactivity (effect size (ES)=0.43, 95% CI: 0.08-0.78, p=0.015). CONCLUSIONS: Individual studies employing an exercise training intervention have tended to have small sample sizes and hence lacked sufficient power to detect clinically meaningful benefits to cutaneous microvascular reactivity. Pooled analysis revealed a clear benefit of exercise training on improving cutaneous microvascular reactivity in older and previously inactive adult cohorts. Exercise training may provide a cost-effective option for improving cutaneous microvascular reactivity in adults and may be of benefit to those with cardiovascular disease and metabolic disorders such as diabetes. PMID- 27476376 TI - Serum CX3CL1/fractalkine concentrations are positively associated with disease severity in postmenopausal osteoporotic patients. AB - BACKGROUND: The chemokine (C-X3-C motif) ligand 1 (CX3CL1), also called fractalkine (FKN), has recently been reported to be involved in osteoclastogenic process and pathological bone destruction. OBJECTIVE: This study aimed to investigate the link between serum CX3CL1/FKN levels with disease progression of postmenopausal osteoporotic patients. METHODS: A total of 53 women with postmenopausal osteoporosis (PMOP group), 51 postmenopausal non-osteoporotic female patients (PMNOP group) and 50 premenopausal non-osteoporotic healthy women of childbearing age (control group) were enrolled in the study. The bone mineral density (BMD) for all subjects was determined via dual-energy X-ray absorptiometry of the lumbar spine, femoral neck, internal trochanter, total hip, greater trochanter and Ward's triangle. The levels of FKN in the serum were examined using the enzyme-linked immunosorbent assay method. The serum bone resorption markers TRACP-5b, NTX levels, inflammation markers IL-1beta and IL-6 as well as oestrogen-2(E2) were also detected in all participants. The visual analogue scores (VAS) and Oswestry Disability Index (ODI) for low back pain were recorded in PMOP females for evaluation of osteoporotic pain and function. RESULTS: FKN levels were significantly higher in postmenopausal osteoporotic patients compared with postmenopausal non-osteoporotic females (139.8 +/- 44.3 pg/mL VS 116.5 +/- 23.1 pg/mL, p < 0.05) and healthy controls (139.8 +/- 44.3 pg/mL VS 109.7 +/- 19.4 pg/mL, p < 0.05). Serum FKN concentrations were negatively associated with BMD at femoral neck (r = -0.394, p = 0.004), total hip(r = -0.374, p = 0.006), internal trochanter(r = -0.340, p = 0.013), greater trochanter(r = -0.376, p = 0.006), Ward's triangle(r = -0.343, p = 0.012), L1-L4 lumbar spine(r = -0.339, p = 0.013) and positively associated with VAS (r = 0.321, p = 0.019) and ODI (r = 0.377, p = 0.005) scores, bone turnover makers (TRACP-5b:r = 0.341, p = 0.012; NTX:r = 0.364, p = 0.007)as well as inflammation markers (IL-1beta: r = 0.396, p = 0.003; IL-6:r = 0.355, p = 0.009) in postmenopausal osteoporotic patients. CONCLUSIONS: Serum FKN may serve as a novel biomarker for assessing disease progression and a new potential therapeutic target for anti-resorptive treatment in osteoporosis patients. PMID- 27476377 TI - [Ecthyma gangrenosum of the eyelid after chickenpox]. AB - BACKGROUND: Ecthyma gangrenosum is an acute ulcer necrotic skin infection frequently caused by Pseudomonas aeruginosa. It is characterised by necrotic ulcerations circumscribed by an inflammatory halo. Lesions are normally found in the anal, genital and axillary regions. Ecthyma gangrenosum is most commonly seen in immunodepressed patients (cytotoxic chemotherapy, HIV infection, neutropenia or functional neutrophil deficiency, agammaglobulinemia). It is a rarely described complication in chicken pox. PATIENTS AND METHODS: Herein we report the case of a girl aged 2 1/2 years presenting in our dermatology department with ecthyma gangrenosum on the right upper eyelid secondary to varicella. The disease course was marked by fibrous scarring of the inner canthus with ptosis of the right upper eyelid. The retractile scarring caused disability. DISCUSSION: There have been previous reports of the contribution of non-steroidal anti- inflammatory drugs (NSAIDs) to the appearance of necrotic cutaneous super infections during the course of chickenpox. The occurrence of such complications on an eyelid may be harmful not only for the function of the eye but it can also cause extensive aesthetic impairment. Subsequent aesthetic and functional impairment may be improved by corrective surgery. PMID- 27476378 TI - [Efficacy of hyperbaric oxygen therapy in the treatment of ischemic toe ulcer in a patient presenting systemic sclerosis]. AB - BACKGROUND: The medical treatment of ischemic ulcers in patients with systemic sclerosis remains difficult. Despite the major help provided by vasodilator treatments, the risk of spontaneous or surgical amputation remains high. OBSERVATION: A 48-year-old female patient from Guadeloupe was treated in our department for diffuse systemic sclerosis present for 15 years complicated by lung, joint and digestive involvement, and associated with severe Raynaud's phenomenon. The clinical course was marked by the occurrence of multiple ischemic ulcers, which were resistant to conventional medical treatment and resulted in two surgical amputations (to the 2nd and 3rd interphalangeal joints of the toes of the left foot). Treatment with an endothelin-receptor antagonist and a calcium inhibitor was then introduced for secondary prevention. Two years later, the patient consulted for a further ischemic ulcer of the left 4th toe. She refused the proposed treatment with iloprost. Because of the unfavorable outcome and the absence of therapeutic alternative to amputation, hyperbaric oxygen therapy was initiated. Thirty 90-minutes sessions of pure oxygen at 2.5 ATA were conducted over a 10-week period. Complete healing was obtained after 8 months. DISCUSSION: We report herein a clinical case illustrating the efficacy of hyperbaric oxygen therapy for the treatment of ischemic ulcers of the toes in systemic sclerosis. It could offer an alternative therapeutic option, in particular for patients presenting resistant ischemic ulcers and a contraindication for or intolerance to the conventional medical treatment. PMID- 27476379 TI - The correlation of Acanthamoeba from the ventilation system with other environmental parameters in commercial buildings as possible indicator for indoor air quality. AB - The free-living protozoan Acanthamoeba is an opportunistic pathogen that is ubiquitous in our environment. However, its role in affecting indoor air quality and ill-health of indoor occupants is relatively unknown. The present study investigated the presence of Acanthamoeba from the ventilation system and its correlation with other indoor air quality parameters, used in the industry code of practice and its potential as an indicator for indoor air quality. Indoor air quality assessments were carried out in nine commercial buildings with approval from the building management, and the parameters assessed were as recommended by the Department of Occupational Safety and Health. The presence of Acanthamoeba was determined through dust swabs from the ventilation system and indoor furniture. Logistic regression was performed to study the correlation between assessed parameters and occupants' complaints. A total of 107 sampling points were assessed and 40.2% of the supplying air diffuser and blowing fan and 15% of the furniture were positive for cysts. There was a significant correlation between Acanthamoeba detected from the ventilation system with ambient total fungus count (r=0.327; p=0.01) and respirable particulates (r=0.276; p=0.01). Occupants' sick building syndrome experience also correlated with the presence of Acanthamoeba in the ventilation system (r=0.361; p=0.01) and those detected on the furniture (r=0.290; p=0.01). Logistic regression showed that there was a five fold probability of sick building syndrome among occupants when Acanthamoeba was detected in the ventilation system. PMID- 27476380 TI - Combination of parity and pre-pregnancy BMI and low birth weight infants among Japanese women of reproductive age. AB - This study aimed to examine the effects of parity and pre-pregnancy body mass index (BMI) on low birth weight (LBW) infants among Japanese women. Participants included 1,518 mothers (mean age 34.0 years) of singleton full-term infants in 2011. The incidence of LBW infants was 7.5% in primiparous women with BMI<18.5 (Group A; n=239), 4.0% in multiparous women with BMI<18.5 (Group B; n=124), 6.0% in primiparous women with 18.5<=BMI<25 (Group C; n=715), and 1.8% in multiparous women with 18.5<=BMI<25 (Group D; n=440). A multivariable logistic regression model revealed that mothers in Group A were more likely to deliver a LBW infant [odds ratio (OR) 6.41, 95% confidence interval (CI), 2.65-15.49] than were mothers in Group D. Being both underweight (OR 1.8, 95% CI: 1.05-3.11) and primiparous (OR 3.41, 95% CI: 1.82-6.44) were independently associated with LBW infants. This study demonstrated that the characteristics of primiparous and underweight in mothers are additively associated with LBW infants. PMID- 27476381 TI - Transient Method for Determining Indoor Chemical Concentrations Based on SPME: Model Development and Calibration. AB - Solid-phase microextraction (SPME) is regarded as a nonexhaustive sampling technique with a smaller extraction volume and a shorter extraction time than traditional sampling techniques and is hence widely used. The SPME sampling process is affected by the convection or diffusion effect along the coating surface, but this factor has seldom been studied. This paper derives an analytical model to characterize SPME sampling for semivolatile organic compounds (SVOCs) as well as for volatile organic compounds (VOCs) by considering the surface mass transfer process. Using this model, the chemical concentrations in a sample matrix can be conveniently calculated. In addition, the model can be used to determine the characteristic parameters (partition coefficient and diffusion coefficient) for typical SPME chemical samplings (SPME calibration). Experiments using SPME samplings of two typical SVOCs, dibutyl phthalate (DBP) in sealed chamber and di(2-ethylhexyl) phthalate (DEHP) in ventilated chamber, were performed to measure the two characteristic parameters. The experimental results demonstrated the effectiveness of the model and calibration method. Experimental data from the literature (VOCs sampled by SPME) were used to further validate the model. This study should prove useful for relatively rapid quantification of concentrations of different chemicals in various circumstances with SPME. PMID- 27476382 TI - Colorectal Cancer Trends in California and the Need for Greater Screening of Hispanic Men. AB - INTRODUCTION: Colorectal cancer (CRC) incidence and mortality rates have decreased dramatically since 1990, both nationally and in California, except among Hispanic men. This study examined trends in CRC incidence, mortality, and survival to determine likely contributing factors for the differential trends between Hispanic and non-Hispanic white men in California. METHODS: California Cancer Registry data were used to identify 23,157 Hispanic and 114,944 white men diagnosed with CRC between 1990 and 2012. Joinpoint trends in incidence, mortality, and 5-year relative survival were examined by age, stage at diagnosis, and tumor location. Data used in the study were extracted from the California Cancer Registry database and analyzed in 2015. RESULTS: Both incidence and mortality rates decreased substantially among white men between 1990 and 2012, but no corresponding decrease was observed among Hispanic men. Both groups experienced similar trends in survival and stage at diagnosis over time. White men had greater declines in CRC incidence and mortality in all age groups, particularly those aged >50 years. Hispanic men had a significantly higher proportion (65%) of tumors in the distal colon than white men (59%). CONCLUSIONS: CRC incidence and mortality rates have decreased among white men since 1990, but not among Hispanic men. Results from this study suggest lower screening rates may be an important reason why CRC rates in California did not decline in Hispanic men. Effective strategies aimed at both Hispanics and their healthcare providers are needed to increase CRC screening among Hispanic men and reduce their CRC burden. PMID- 27476383 TI - eReferral Between Hospitals and Quitlines: An Emerging Tobacco Control Strategy. PMID- 27476384 TI - Underage Drinking: A Review of Trends and Prevention Strategies. AB - Underage drinking and its associated problems have profound negative consequences for underage drinkers themselves, their families, their communities, and society as a whole, and contribute to a wide range of costly health and social problems. There is increased risk of negative consequences with heavy episodic or binge drinking. Alcohol is a factor related to approximately 4,300 deaths among underage youths in the U.S. every year. Since the mid-1980s, the nation has launched aggressive underage drinking prevention efforts at the federal, state, and local levels, and national epidemiologic data suggest that these efforts are having positive effects. For example, since 1982, alcohol-related traffic deaths among youth aged 16-20 years have declined by 79%. Evidence-based or promising strategies for reducing underage drinking include those that limit the physical, social, and economic availability of alcohol to youth, make it illegal for drivers aged <21 years to drive after drinking, and provide mechanisms for early identification of problem drinkers. Strategies may be implemented through a comprehensive prevention approach including policies and their enforcement, public awareness and education, action by community coalitions, and early brief alcohol intervention and referral programs. This paper focuses on underage drinking laws and their enforcement because these constitute perhaps the most fundamental component of efforts to limit youth access to and use of alcohol. PMID- 27476385 TI - Risk Factors for Low Back Pain and Spine Surgery: A Retrospective Cohort Study in Soldiers. AB - INTRODUCTION: Musculoskeletal low back pain (LBP) is commonly treated symptomatically, with practice guidelines advocating reserving surgery for cases that fail conservative care. This study examined medical comorbidities and demographic variables as risk factors for chronic/recurrent LBP, spinal surgery, and time to surgery. METHODS: A 2015 retrospective cohort study was conducted in U.S. Army soldiers (N=1,092,420) from 2002 to 2011. Soldiers with medical encounters for LBP were identified using ICD-9 codes. Surgical treatment for LBP was identified according to Current Procedural Terminology codes. Comorbid medical conditions (psychological disorders, sleep disorders, tobacco use, alcohol use, obesity) and demographic variables were examined as risk factors for chronic/recurrent LBP within 1 year of the incident encounter, surgery for LBP, and time to surgery. RESULTS: Of 383,586 patients with incident LBP, 104,169 (27%) were treated for chronic/recurrent LBP and 7,446 (1.9%) had surgery. Comorbid variables showed increased risk of chronic/recurrent LBP ranging from 26% to 52%. Tobacco use increased risk for surgery by 33% (risk ratio, 1.33; 95% CI=1.24, 1.44). Comorbid variables showed 10%-42% shorter time to surgery (psychological disorders, time ratio [TR]=0.90, 95% CI=0.83, 0.98; sleep disorders, TR=0.68, 95% CI=0.60, 0.78; obesity, TR=0.88, 95% CI=0.79, 0.98; tobacco use, TR=0.58, 95% CI=0.54, 0.63; alcohol use, TR=0.85, 95% CI=0.70, 1.05). Women showed 20% increased risk of chronic/recurrent LBP than men but 42% less risk of surgery. CONCLUSIONS: In the presence of comorbidities associated with mental health, sleep, obesity, tobacco use, and alcohol use, LBP shows increased risk of becoming chronic/recurrent and faster time to surgery. PMID- 27476412 TI - A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. AB - Currently there are no approved vaccines or specific therapies to prevent or treat Zika virus (ZIKV) infection. We interrogated a library of FDA-approved drugs for their ability to block infection of human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7). More than 20 out of 774 tested compounds decreased ZIKV infection in our in vitro screening assay. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental, and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types. This study identifies drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis. PMID- 27476414 TI - Expression of Hox paralog group 13 genes in adult and developing Megalobrama amblycephala. AB - Hox genes encode transcription factors that play a key role in specifying the body plan in most metazoans. HoxPG13 genes most probably played an important role in body length variation during the evolution of animals. This is the first report of the mRNA expression patterns of the entire Hox paralog group 13 (HoxA13a, HoxA13b, HoxB13a, HoxC13a, HoxC13b, HoxD13a) in fish. Expression was studied by qPCR in five tissues of adult Megalobrama amblycephala specimens (spleen, liver, kidney, intestine and gills) and during development (17 stages: fertilised egg to 90 days-old juveniles). Expression in tissues (for all six genes) was generally very low in gills (0.0006-0.05), spleen (0.006-0.09) and kidney (0.02-0.39); the highest in intestine (from 2.28 for HoxC13b to 244.29 for HoxC13a). During the development, a peak in expression around the hatching was observed for all six genes. Results suggest a high maternal expression of HoxA13a, and low for HoxA13ab. HoxD13a paralog exhibited the lowest expression: 0.0006-2.63 in tissues and 0.0005-1.7 during development, suggesting the possibility of a gradual loss of functionality. Expression of HoxC13 paralogs corroborates the findings in zebrafish: HoxC13b is maternally expressed and more important during the development. In adults, it was the opposite: expression was low for HoxC13b and very variable for HoxC13a (0.06-244.29). Differences in expression levels between both pairs of paralogs (Aa/Ab and Ca/Cb) indicate the possibility of the existence of some redundancy afforded by maintaining both paralogs. PMID- 27476413 TI - Gut Microbial Metabolites Fuel Host Antibody Responses. AB - Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis, and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance. PMID- 27476415 TI - Gilles de la Tourette syndrome - A treatable condition? AB - INTRODUCTION: Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Psychiatric comorbidity is frequent but does not enter into the official classification of the syndrome. In the present article, we will focus on treatment options for tics. METHODS: We have reviewed the relevant literature on treatment of tics and GTS, especially in the period from 2011-2016 since the publication of the European Society for the Study of Tourette Syndrome (ESSTS) treatment guidelines in 2011. RESULTS: We present current and up-to-date approaches in psychotherapy, pharmacotherapy and neurosurgery for GTS with an outlook for the upcoming years. CONCLUSIONS: Although many patients and health-care professionals seem to view tics and/or GTS as difficult to treat, or believe that treatment requires severe side effects with reduction in quality of life, we wish to convey that there is cause for optimism, both with regard to available treatment modalities and future therapeutic developments. PMID- 27476417 TI - Movement disorders and stroke. AB - Stroke may be associated with different types of movement disorders, such as hyperkinetic syndromes (hemichorea-hemiballism, unilateral asterixis, limb shaking, dystonia, tremor, myoclonus) and hypokinetic syndromes (especially vascular parkinsonism). However, movement disorders are rare and transient in acute stroke and, as a permanent consequence, are more often delayed. While ischemic and hemorrhagic strokes can happen at any level of the frontal subcortical motor system, they can be explained most of the time by a dysfunction in the basal ganglia motor circuit. However, only brain MRI allows the involved structure(s) to be precisely located, and each syndrome is specific to the type of lesion. Treatment is above all symptomatic. Only limb-shaking syndrome requires urgent surgical treatment because of the low-perfusion hemodynamic state. The functional prognosis depends on the type of movement disorder. PMID- 27476416 TI - Initial treatment of Parkinson's disease in 2016: The 2000 consensus conference revisited. AB - In 2000, a French consensus conference proposed guidelines for the treatment of Parkinson's disease (PD). Since then, new drugs have been concocted, new studies have been published and clinicians have become aware of some drug-induced adverse effects that were little known in the past. This has led us to reconsider the recommendations published 16 years ago. Thus, the aim of the present review is to present the recent data related to the different medications and non pharmacological approaches available for PD, with a special focus on early-stage PD. Levodopa (LD), dopamine agonists (DAs), catechol-O-methyltransferase inhibitors (COMT-Is), anticholinergics, monoamine oxidase inhibitors (MAOB-Is) and amantadine have been considered, and their efficacy and safety for both motor as well as non-motor aspects are reported here. This has led to our proposal for a revised therapeutic strategy for the initiation of treatment in newly diagnosed PD patients, based on the available literature and the relative benefits/side effects balance. PMID- 27476418 TI - Movement disorders in mitochondrial diseases. AB - Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns-Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function. Myoclonus is a key feature of MERFF, but may also be encountered in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), ARCA2, POLG1 mutations and Leigh syndrome. Dystonia is common in Leigh syndrome (which may be caused by 75 different genes) and in Leber hereditary ocular neuropathy (LHON) plus disease, due to mutations in mtDNA genes that encode subunits of NADH dehydrogenase, as well as in ARCA2, pantothenate kinase-associated neurodegeneration (PKAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and POLG1 mutations. Other movement disorders are rarer (such as parkinsonism, tremor, chorea). Although parkinsonism is more frequent in POLG1 mutations, and myoclonus in MERFF, most movement disorders are found either isolated or combined in numerous MIDs. The presence of associated neurological signs, whether central or peripheral, or of evocative magnetic resonance imaging (MRI) abnormalities (striatal necrosis) should prompt a search for MID. In cases of a particular clinical spectrum (LHON, MERFF, Kearns-Sayre, SANDO, SPG7, ARCA2, ARSACS), a search for the most frequently implicated mutation(s) is recommended. In other cases, muscle biopsies followed by metabolic and genetic studies may be useful for arriving at a diagnosis. PMID- 27476419 TI - C15-methoxyphenylated 18-deoxy-herbimycin A analogues, their in vitro anticancer activity and heat shock protein 90 binding affinity. AB - Benzoquinone ansamycins are important leads for the discovery of novel inhibitors of heat shock protein 90 (Hsp90), a promising target of cancer chemotherapeutics. Intrinsic hepatotoxicity caused by the benzoquinone moiety appeared to be a serious limitation to the development of these compounds. To solve this problem by rational structure optimization, a short series of C18-deoxy analogues of herbimycin A were designed based on putative interactions between the compound and the protein. Chemical synthesis of the target molecules were attempted by following the established synthetic route to the natural product, but resulted in the isolation of four serendipitous C15 phenylated final products. In vitro antiproliferative activity and Hsp90 binding affinity of the compounds were determined, suggesting the C18-oxygen of herbimycin A is removable and bulky lipophilic groups can be accommodated at C15 without loss of activity. PMID- 27476420 TI - Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors. AB - IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR. PMID- 27476421 TI - Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kdelta inhibitors. AB - Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kdelta signaling despite not binding to the specificity pocket of PI3Kdelta isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models. PMID- 27476422 TI - A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models. AB - Flavonoids are a large class of polyphenolic compounds ubiquitously distributed in dietary plants with an array of biological activities. Flavonols are a major sub-class of flavonoids featuring a hydroxyl group at C-3. Certain natural flavonols, such as quercetin and fisetin, have been shown by in vitro cell-based and in vivo animal experiments to be potential anti-prostate cancer agents. However, the Achilles' heel of flavonols as drug candidates is their moderate potency and poor pharmacokinetic profiles. This study aims to explore the substitution effect of 3-OH in flavonols on the in vitro anti-proliferative potency against both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Our first lead flavonol (3',4'-dimethoxyflavonol), eight 3-O alkyl-3',4'-dimethoxyflavonols, and six 3-O-aminoalkyl-3',4'-dimethoxyflavonols have been synthesized through aldol condensation and the Algar-Flynn-Oyamada (AFO) reaction. The WST-1 cell proliferation assay indicates (i) that all synthesized 3-O-alkyl-3',4'-dimethoxyflavonols and 3-O-aminoalkyl-3',4' dimethoxyflavonols are more potent than the parent 3',4'-dimethoxyflavonol and the natural flavonol quercetin in suppressing prostate cancer cell proliferation; and (ii) that incorporation of a dibutylamino group to the 3-OH group through a three- to five-carbon linker leads to the optimal derivatives with up to 292-fold enhanced potency as compared with the parent flavonol. Flow cytometry analysis showed that the most potent derivative 22 can activate PC-3 cell cycle arrest at the G2/M phase and induce PC-3 cell apoptosis. No inhibitory ability of 22 up to 50MUM concentration was observed against PWR-1E normal human epithelial prostate cells, suggesting its in vitro safety profile. The results indicate that chemical modulation at 3-OH is a vital strategy to optimize flavonols as anti-prostate cancer agents. PMID- 27476423 TI - Synthesis and immunostimulatory activity of substituted TLR7 agonists. AB - Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants. PMID- 27476424 TI - Identification of potent, selective KDM5 inhibitors. AB - This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization. PMID- 27476425 TI - Emission of poly and perfluoroalkyl substances, UV-filters and siloxanes to air from wastewater treatment plants. AB - The potential of wastewater treatment plants (WWTPs) to act as sources of poly and perfluoroalkyl substances (PFASs), volatile methyl siloxanes (VMSs) and organic UV-filters to the atmosphere was investigated. Target compounds included: PFASs (fluorotelomer alcohols (FTOHs), perfluorooctane sulfonamides/sulfonamidoethanols (FOSAs/FOSEs), perfluroalkyl sulfonic acids (PFSAs) and perfluroalkyl carboxylic acids (PFCAs)), cyclic VMSs (D3 to D6), linear VMSs (L3 to L5) and eight UV-filters. Emissions to air were assessed at eight WWTPs using paired sorbent-impregnated polyurethane foam passive air samplers, deployed during summer 2013 and winter 2014. Samplers were deployed on site above the active tank and off-site as a reference. Several types of WWTPs were investigated: secondary activated sludge in urban areas (UR-AS), secondary extended aeration in towns (TW-EA) and facultative lagoons in rural areas (RU LG). The concentrations of target compounds in air were ~1.7-35 times higher on site compared to the corresponding off-site location. Highest concentrations in air were observed at UR-AS sites while the lowest were at RU-LG. Higher air concentrations (~2-9 times) were observed on-site during summer compared to winter, possibly reflecting enhanced volatilization due to higher wastewater temperatures or differences in influent wastewater concentrations. A significant positive correlation was obtained between concentrations in air and WWTP characteristics (influent flow rate and population in the catchment of the WWTP); whereas a weak negative correlation was obtained with hydraulic retention time. Emissions to air were estimated using a simplified dispersion model. Highest emissions to air were seen at the UR-AS locations. Emissions to air (g/year/tank) were highest for VMSs (5000-112,000) followed by UV-filters (16-2000) then SigmaPFASs (10-110). PMID- 27476426 TI - Delayed effects of chlorpyrifos across metamorphosis on dispersal-related traits in a poleward moving damselfly. AB - How exposure to contaminants may interfere with the widespread poleward range expansions under global warming is largely unknown. Pesticide exposure may negatively affect traits shaping the speed of range expansion, including traits related to population growth rate and dispersal-related traits. Moreover, rapid evolution of growth rates during poleward range expansions may come at a cost of a reduced investment in detoxification and repair thereby increasing the vulnerability to contaminants at expanding range fronts. We tested effects of a sublethal concentration of the widespread pesticide chlorpyrifos on traits related to range expansion in replicated edge and core populations of the poleward moving damselfly Coenagrion scitulum reared at low and high food levels in a common garden experiment. Food limitation in the larval stage had strong negative effects both in the larval stage and across metamorphosis in the adult stage. Exposure to chlorpyrifos during the larval stage did not affect larval traits but caused delayed effects across metamorphosis by increasing the incidence of wing malformations during metamorphosis and by reducing a key component of the adult immune response. There was some support for an evolutionary trade-off scenario as the faster growing edge larvae suffered a higher mortality during metamorphosis. Instead, there was no clear support for the faster growing edge larvae being more vulnerable to chlorpyrifos. Our data indicate that sublethal delayed effects of pesticide exposure, partly in association with the rapid evolution of faster growth rates, may slow down range expansions. PMID- 27476427 TI - Effects of internal loading on phosphorus distribution in the Taihu Lake driven by wind waves and lake currents. AB - Wind-driven sediment resuspension exerts significant effects on the P behavior in shallow lake ecosystems. In this study, a comprehensive dynamic phosphorus (P) model that integrates hydrodynamic, wind wave and sediment transport is proposed to assess the importance of internal P cycling due to sediment resuspension on water column P levels. The primary contribution of the model is detailed modeling and rigorous coupling of sediment and P dynamics. The proposed model is applied to predict the P behavior in the shallow Taihu Lake, which is the third largest lake in China, and quantitatively estimate the effects of wind waves and lake currents on P release and distribution. Both the prevailing southeast winds in summer and northwest winds in winter are applied for the simulation, and different wind speeds of 5 m/s and 10 m/s are also considered. Results show that sediment resuspension and the resulting P release have a dominant effect on P levels in Taihu Lake, and likely similar shallow lakes. Wind-driven waves at higher wind speeds significantly enhance sediment resuspension and suspended sediment concentration (SSC). Total P concentration in the water column is also increased but not in proportion to the SSC. The different lake circulations resulting from the different prevailing wind directions also affect the distribution of suspended sediment and P around the lake ultimately influencing where eutrophication is likely to occur. The proposed model demonstrates that internal cycling in the lake is a dominant factor in the lake P and must be considered when trying to manage water quality in this and similar lakes. The model is used to demonstrate the potential effectiveness of remediation of an area where historical releases have led to P accumulation on overall lake quality. PMID- 27476428 TI - Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust. AB - There is limited information on the BDE-209 relative bioavailability (RBA) of indoor dust and the absorption of BDE-209 after in vitro digestion was seldom studied. In the present study, BDE-209 RBA in 6 household dust samples measured using an in vivo mouse model was compared to BDE-209 bioaccessibility determined using physiologically based extraction test (PBET) and solubility bioaccessibility research consortium method (SBRC) assays. BDE-209 RBA obtained ranged from 45.9 +/- 16.1 to 96.0 +/- 17.4% and exhibited a significant relationship with PBET gastric phase (r2 = 0.578, p = 0.080), small intestinal phase (r2 = 0.728, p = 0.031) and total BDE-209 bioaccessibility (r2 = 0.728, p = 0.031), which indicated PBET assay can serve as a surrogate to predict BDE-209 RBA to refine human health exposure. In addition, the absorption of BDE-209 by Caco-2 cell line was assessed. With the consideration of the corresponding bioaccessibility and absorption of BDE-209 by Caco-2 cell line, the human daily intake of BDE-209 via dust ingestion for adults and children was much lower than that estimated by total concentration. PMID- 27476429 TI - Revealing accumulation zones of plastic pellets in sandy beaches. AB - Microplastics such as pellets are reported worldwide on sandy beaches, and have possible direct and indirect impacts on the biota and physical characteristics of the habitats where they accumulate. Evaluations of their standing stock at different spatial scales generate data on levels of contamination. This information is needed to identify accumulation zones and the specific beach habitats and communities that are likely to be most affected. Standing stocks of plastic pellets were evaluated in 13 sandy beaches in Sao Paulo state, Brazil. The sampling strategy incorporated across-shore transects from coastal dunes and backshores, and vertical profiles of the accumulated pellets down to 1 m depth below the sediment surface. Accumulation zones were identified at regional (among beaches) and local (between compartments) scales. At the regional scale pellet density tended to increase at beaches on the central and southwestern coast, near ports and factories that produce and transport the largest amounts of pellets in the country. At the local scale coastal dunes showed larger accumulations of pellets than backshores. For both compartments pellets tended to occur deeper in areas where standing stocks were larger. Most of the pellets were concentrated from the surface down to 0.4 m depth, suggesting that organisms inhabiting this part of the sediment column are more exposed to the risks associated with the presence of pellets. Our findings shed light on the local and regional scales of spatial variability of microplastics and their consequences for assessment and monitoring schemes in coastal compartments. PMID- 27476431 TI - Reflections on Palliative Care in Beijing. PMID- 27476430 TI - Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells. AB - Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients. PMID- 27476432 TI - Development of a Targeted Smoking Relapse-Prevention Intervention for Cancer Patients. AB - We describe the series of iterative steps used to develop a smoking relapse prevention intervention customized to the needs of cancer patients. Informed by relevant literature and a series of preliminary studies, an educational tool (DVD) was developed to target the unique smoking relapse risk factors among cancer patients. Learner verification interviews were conducted with 10 cancer patients who recently quit smoking to elicit feedback and inform the development of the DVD. The DVD was then refined using iterative processes and feedback from the learner verification interviews. Major changes focused on visual appeal, and the inclusion of additional testimonials and graphics to increase comprehension of key points and further emphasize the message that the patient is in control of their ability to maintain their smoking abstinence. Together, these steps resulted in the creation of a DVD titled Surviving Smokefree(r), which represents the first smoking relapse-prevention intervention for cancer patients. If found effective, the Surviving Smokefree(r) DVD is an easily disseminable and low-cost portable intervention which can assist cancer patients in maintaining smoking abstinence. PMID- 27476433 TI - Social and physical environments as a source of individual variation in the rewarding effects of testosterone in male California mice (Peromyscus californicus). AB - Despite extensive research revealing the occurrence of testosterone (T) pulses following social encounters, it is unclear how they lead to varied behavioral responses. We investigated the influence of residency (home versus unfamiliar environment) and social/sexual experience (pair-bonded, isolated or housed with siblings) on the plasticity of T's rewarding effects by measuring the development of conditioned place preferences (CPPs), a classical paradigm used to measure the rewarding properties of drugs. For pair-bonded males, T-induced CPPs were only produced in the environment wherein the social/sexual experience was accrued and residency status had been achieved. For isolated males, the T-induced CPPs only occurred when the environment was unfamiliar. For males housed with a male sibling, the T-induced CPPs were prevented in both the home and unfamiliar chambers. Our results reveal the plasticity of T's rewarding effects, and suggest that the behavioral functions of T-pulses can vary based on social/sexual experience and the environment in which residency was established. The formation of CPPs or reward-like properties of drugs and natural compounds can therefore exhibit malleability based on past experience and the current environment. PMID- 27476434 TI - Effects of developmental exposure to bisphenol A and ethinyl estradiol on spatial navigational learning and memory in painted turtles (Chrysemys picta). AB - Developmental exposure of turtles and other reptiles to endocrine disrupting chemicals (EDCs), including bisphenol A (BPA) and ethinyl estradiol (EE2, estrogen present in birth control pills), can induce partial to full gonadal sex reversal in males. No prior studies have considered whether in ovo exposure to EDCs disrupts normal brain sexual differentiation. Yet, rodent model studies indicate early exposure to these chemicals disturbs sexually selected behavioral traits, including spatial navigational learning and memory. Thus, we sought to determine whether developmental exposure of painted turtles (Chrysemys picta) to BPA and EE2 results in sex-dependent behavioral changes. At developmental stage 17, turtles incubated at 260C (male-inducing temperature) were treated with 1) BPA High (100MUg /mL), 2) BPA Low (0.01MUg/mL), 3) EE2 (0.2MUg/mL), or 4) vehicle or no vehicle control groups. Five months after hatching, turtles were tested with a spatial navigational test that included four food containers, only one of which was baited with food. Each turtle was randomly assigned one container that did not change over the trial period. Each individual was tested for 14 consecutive days. Results show developmental exposure to BPA High and EE2 improved spatial navigational learning and memory, as evidenced by increased number of times spent in the correct target zone and greater likelihood of solving the maze compared to control turtles. This study is the first to show that in addition to overriding temperature sex determination (TSD) of the male gonad, these EDCs may induce sex-dependent behavioral changes in turtles. PMID- 27476435 TI - Steroid-independent male sexual behavior in B6D2F2 male mice. AB - It is well established that male sexual behavior (MSB) is regulated by gonadal steroids; however, individual differences in MSB, independent of gonadal steroids, are prevalent across a wide range of species, and further investigation is necessary to advance our understanding of steroid-independent MSB. Studies utilizing B6D2F1 hybrid male mice in which a significant proportion retain MSB after long-term orchidectomy, identified as steroid-independent-maters (SI maters), have begun to unravel the genetic underpinnings of steroid-independent MSB. A recent study demonstrated that steroid-independent MSB is a heritable behavioral phenotype that is mainly passed down from B6D2F1 hybrid SI-maters when crossed with C57BL6J female mice. To begin to uncover whether the strain of the dam plays a role in the inheritance of steroid-independent MSB, B6D2F1 hybrid females were crossed with B6D2F1 hybrid males. While the present study confirms the finding that steroid-independent MSB is a heritable behavioral phenotype and that SI-mater sires are more likely to pass down some components of MSB than SI non-maters to their offspring, it also reveals that the B6D2F2 male offspring that were identified as SI-maters that displayed the full repertoire of steroid independent MSB had the same probability of being sired from either a B6D2F1 SI mater or SI-non-mater. These results, in conjunction with previous findings, indicate that the specific chromosomal loci pattern that codes for steroid independent MSB in the B6D2F2 male offspring may result regardless of whether the father was a SI-mater or SI-non-mater, and that the maternal strain may be an important factor in the inheritance of steroid-independent MSB. PMID- 27476436 TI - Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions. AB - Dysfunction of N-Methyl-d-aspartate receptors (NMDARs) is believed to underlie some of the symptoms in schizophrenia, and non-competitive NMDAR antagonists (including phencyclidine (PCP)) are widely used as pharmacological schizophrenia models. Furthermore, mounting evidence suggests that impaired gamma-aminobutyric acid (GABA) neurotransmission contributes to the cognitive deficits in schizophrenia. Thus alterations in GABAergic interneurons have been observed in schizophrenia patients and animal models. Acute systemic administration of PCP increases levels of c-Fos in several cortical and subcortical areas, but whether such induction occurs in specific populations of GABAergic interneuron subtypes still remains to be established. We performed an immunohistochemical analysis of the PCP-induced c-Fos-immunoreactivity (IR) in parvalbumin (PV) and calbindin (CB) interneuron subtypes in the cortex and thalamus of rats. A single dose of PCP (10mg/kg, s.c.) significantly increased total number of c-Fos-IR in: (1) the prelimbic, infralimbic, anterior cingulate, ventrolateral orbital, motor, somatosensory and retrosplenial cortices as well as the nucleus accumbens (NAc), field CA1 of the hippocampus (CA1) field of hippocampus and mediodorsal thalamus (MD); (2) PV-IR cells in the ventrolateral orbitofrontal and retrosplenial cortices and CA1 field of hippocampus; and (3) CB-IR cells in the motor cortex. Overall, our data indicate that PCP activates a wide range of cortical and subcortical brain regions and that a substantial part of this activation is present in GABAergic interneurons in certain regions. This suggests that the psychotomimetic effect of PCP may be mediated via GABAergic interneurons. PMID- 27476437 TI - Electrical muscle stimulation elevates intramuscular BDNF and GDNF mRNA following peripheral nerve injury and repair in rats. AB - Despite advances in surgery, patients with nerve injuries frequently have functional deficits. We previously demonstrated in a rat model that daily electrical muscle stimulation (EMS) following peripheral nerve injury and repair enhances reinnervation, detectable as early as two weeks post-injury. In this study, we explain the enhanced early reinnervation observed with electrical stimulation. In two groups of rats, the tibial nerve was transected and immediately repaired. Gastrocnemius muscles were implanted with intramuscular electrodes for sham or muscle stimulation. Muscles were stimulated daily, eliciting 600 contractions for one hour/day, repeated five days per week. Sixteen days following nerve injury, muscles were assessed for functional reinnervation by motor unit number estimation methods using electromyographic recording. In a separate cohort of rats, surgical and electrical stimulation procedures were identical but muscles and distal nerve stumps were harvested for molecular analysis. We observed that stimulated muscles had significantly higher motor unit number counts. Intramuscular levels of brain-derived and glial cell line-derived neurotrophic factor (BDNF and GDNF) mRNA were significantly upregulated in muscles that underwent daily electrical stimulation compared to those without stimulation. The corresponding levels of trophic factor mRNA within the distal stump were not different from one another, indicating that the intramuscular electrical stimulus does not modulate Schwann cell-derived trophic factor transcription. Stimulation over a three-month period maintained elevated muscle derived GDNF but not BDNF mRNA. In conclusion, EMS elevates intramuscular trophic factor mRNA levels which may explain how EMS enhances neural regeneration following nerve injury. PMID- 27476438 TI - Development of excitatory synaptic transmission to the superior paraolivary and lateral superior olivary nuclei optimizes differential decoding strategies. AB - The superior paraolivary nucleus (SPON) is a prominent structure in the mammalian auditory brainstem with a proposed role in encoding transient broadband sounds such as vocalized utterances. Currently, the source of excitatory pathways that project to the SPON and how these inputs contribute to SPON function are poorly understood. To shed light on the nature of these inputs, we measured evoked excitatory postsynaptic currents (EPSCs) in the SPON originating from the intermediate acoustic stria and compared them with the properties of EPSCs in the lateral superior olive (LSO) originating from the ventral acoustic stria during auditory development from postnatal day 5 to 22 in mice. Before hearing onset, EPSCs in the SPON and LSO are very similar in size and kinetics. After the onset of hearing, SPON excitation is refined to extremely few (2:1) fibers, with each strengthened by an increase in release probability, yielding fast and strong EPSCs. LSO excitation is recruited from more fibers (5:1), resulting in strong EPSCs with a comparatively broader stimulus-response range after hearing onset. Evoked SPON excitation is comparatively weaker than evoked LSO excitation, likely due to a larger fraction of postsynaptic GluR2-containing Ca2+-impermeable AMPA receptors after hearing onset. Taken together, SPON excitation develops synaptic properties that are suited for transmitting single events with high temporal reliability and the strong, dynamic LSO excitation is compatible with high rate level sensitivity. Thus, the excitatory input pathways to the SPON and LSO mature to support different decoding strategies of respective coarse temporal and sound intensity information at the brainstem level. PMID- 27476439 TI - Nitrogen fixation in a non-heterocystous cyanobacterial mat from a mountain river. AB - In situ nitrogen fixation was investigated in a cyanobacterial mat growing on the bed of rocks of the Muga River, Spain. The filamentous non-heterocystous cyanobacterium Schizothrix dominated the mat, showing nitrogenase activity in the light at similar rates to those found in nearby heterocystous Rivularia colonies. N2 fixation in the light was significantly increased by an inhibitor of PSII and oxygen evolution, DCMU (3-[3,4-dichlorophenyl]-1,1-dimethylurea), and anaerobic conditions. However, no nitrogenase activity was found in the dark. Addition of fructose as a respiratory substrate induced nitrogenase activity in samples incubated under aerobic conditions in the dark but not in anaerobic conditions. Microelectrode oxygen profiles showed internal microaerobic microzones where nitrogen fixation might concentrate. Analyses of the 16S rRNA gene revealed only the presence of sequences belonging to filamentous non-heterocystous cyanobacteria. nifH gene diversity showed that the major phylotypes also belonged to this group. One of the three strains isolated from the Schizothrix mat was capable of fixing N2 and growing in the absence of combined N. This was consistent with the nifH gene analysis. These results suggest a relevant contribution of non-heterocystous cyanobacteria to nitrogen fixation in these mats. PMID- 27476440 TI - BMLA Abstracts 2016. PMID- 27476441 TI - Lower Plasma Ghrelin Levels are Found in Women with Diabetes-Complicated Pregnancies. AB - OBJECTIVE: To evaluate the associations of glycemic control and gestational age with ghrelin and proinsulin levels in cord blood and mothers' peripheral blood during pregnancy. METHODS: This is a cross-sectional comparative study of twenty four pregnant women with gestational diabetes (GD), 18 with type 2 diabetes mellitus (T2DM), and 36 without diabetes, as well as their neonates. Levels of proinsulin, ghrelin, and glycated hemoglobin A1c (HbA1c) were measured from maternal blood during the last week before caesarian delivery and in neonatal umbilical cord blood samples. RESULTS: Mothers with GD and T2DM had significantly lower ghrelin levels compared to the healthy mothers (p<0.001). Maternal proinsulin was lower in women with GD than in women without diabetes (p<0.001). Proinsulin was significantly elevated in the neonates of women with GD and in women with HbA1c >=6.5% (p<0.001). However, maternal ghrelin levels were higher (p=0.031) and neonate proinsulin levels lower in the pre-term offspring of mothers with GD (p=0.033). There was a negative correlation between HbA1c levels and birth weight (r=-0.407, p<0.001). CONCLUSION: Ghrelin levels were lower in pregnant women with diabetes, although pre-term birth appeared to reverse this trend in GD. Proinsulin levels were also low in pregnant women with diabetes and even lower in pre-term vs. at-term births. Both ghrelin and proinsulin levels were lower in pregnant women with diabetes and HbA1c of <6.5%. Thus, ghrelin participates in the adaptation to the caloric imbalance of diabetic pregnancy and may play a similar role in pregnancy-related complications, since high ghrelin concentrations may be necessary for normal fetal development. PMID- 27476443 TI - Oral, intestinal, and skin bacteria in ventral hernia mesh implants. AB - BACKGROUND: In ventral hernia surgery, mesh implants are used to reduce recurrence. Infection after mesh implantation can be a problem and rates around 6 10% have been reported. Bacterial colonization of mesh implants in patients without clinical signs of infection has not been thoroughly investigated. Molecular techniques have proven effective in demonstrating bacterial diversity in various environments and are able to identify bacteria on a gene-specific level. OBJECTIVE: The purpose of this study was to detect bacterial biofilm in mesh implants, analyze its bacterial diversity, and look for possible resemblance with bacterial biofilm from the periodontal pocket. METHODS: Thirty patients referred to our hospital for recurrence after former ventral hernia mesh repair, were examined for periodontitis in advance of new surgical hernia repair. Oral examination included periapical radiographs, periodontal probing, and subgingival plaque collection. A piece of mesh (1*1 cm) from the abdominal wall was harvested during the new surgical hernia repair and analyzed for bacteria by PCR and 16S rRNA gene sequencing. From patients with positive PCR mesh samples, subgingival plaque samples were analyzed with the same techniques. RESULTS: A great variety of taxa were detected in 20 (66.7%) mesh samples, including typical oral commensals and periodontopathogens, enterics, and skin bacteria. Mesh and periodontal bacteria were further analyzed for similarity in 16S rRNA gene sequences. In 17 sequences, the level of resemblance between mesh and subgingival bacterial colonization was 98-100% suggesting, but not proving, a transfer of oral bacteria to the mesh. CONCLUSION: The results show great bacterial diversity on mesh implants from the anterior abdominal wall including oral commensals and periodontopathogens. Mesh can be reached by bacteria in several ways including hematogenous spread from an oral site. However, other sites such as gut and skin may also serve as sources for the mesh biofilm. PMID- 27476444 TI - A novel compound to maintain a healthy oral plaque ecology in vitro. AB - OBJECTIVE: Dental caries is caused by prolonged episodes of low pH due to acid production by oral biofilms. Bacteria within such biofilms communicate via quorum sensing (QS). QS regulates several phenotypic biofilm parameters, such as biofilm formation and the production of virulence factors. In this study, we evaluated the effect of several QS modifiers on growth and the cariogenic potential of microcosm oral biofilms. METHODS: Biofilms were inoculated with pooled saliva and cultured in the presence of sucrose for 48 and 96 h. QS modifiers (or carrier controls) were continuously present. Lactic acid accumulation capacities were compared to evaluate the cariogenic potential of the biofilms. Subsequently, biofilm growth was quantified by determining colony forming unit counts (CFUs) and their ecology by 16S rDNA-based microbiome analyses. The minimal inhibitory concentration (MIC) for several Streptococcus spp. was determined using microbroth dilution. RESULTS: Of the tested QS modifiers only 3-oxo-N-(2 oxocyclohexyl)dodecanamide (3-Oxo-N) completely abolished lactic acid accumulation by the biofilms without affecting biofilm growth. This compound was selected for further investigation. The active range of 3-Oxo-N was 10-100 uM. The homologous QS molecule, acyl homoserine lactone C12, did not counteract the reduction in lactic acid accumulation, suggesting a mechanism other than QS inhibition. Microbial ecology analyses showed a reduction in the relative abundance of Streptococcus spp. in favor of the relative abundance of Veillonella spp. in the 3-Oxo-N exposed biofilms. The MIC of 3-Oxo-N for several streptococcal species varied between 8 and 32 uM. CONCLUSION: 3-Oxo-N changes the ecological homeostasis of in vitro dental plaque. It reduces its cariogenic potential by minimizing lactic acid accumulation. Based on our in vitro data, 3 Oxo-N represents a promising compound in maintaining a healthy, non-cariogenic, ecology in in vivo dental plaque. PMID- 27476442 TI - Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy. AB - INTRODUCTION: Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug. Areas covered: We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic therapy or drug/photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control. Expert opinion: Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery. PMID- 27476445 TI - Enhanced photocatalytic H2 production on CdS nanorods with simple molecular bidentate cobalt complexes as cocatalysts under visible light. AB - Photocatalytic hydrogen production via water splitting has attracted much attention for future clean energy application. Herein we report a noble-metal free photocatalytic hydrogen production system containing a simple bidentate cobalt Schiff base complex as the molecular cocatalyst, CdS nanorods as the photosensitizer, and ascorbic acid as the electron donor. The system shows highly enhanced photocatalytic activity compared to pure CdS NRs under visible light (lambda > 420 nm). Under optimal conditions, the turnover numbers (TONs) for hydrogen production reached ~15 200 after 12 hours of irradiation, and an apparent quantum yield of ~27% was achieved at 420 nm monochromatic light. Steady state photoluminescence (PL) spectra indicated efficient charge transfer between the excited CdS NRs and the cobalt cocatalyst for improved hydrogen production. Spectroscopic studies of the photocatalytic reaction revealed the reduction of the Co(ii) complex to Co(i) species, which are probably active intermediates for hydrogen evolution. On the basis of the spectroscopic studies, we propose a reaction mechanism for hydrogen production in the present photocatalytic system. PMID- 27476446 TI - Identification of a new psychoactive substance in seized material: the synthetic opioid N-phenyl-N-[1-(2-phenethyl)piperidin-4-yl]prop-2-enamide (Acrylfentanyl). AB - Among the new psychoactive substances (NPS) that have recently emerged on the market, many of the new synthetic opioids have shown to be particularly harmful. A new synthetic analogue of fentanyl, N-phenyl-N-[1-(2-phenethyl)piperidin-4 yl]prop-2-enamide (acrylfentanyl), was identified in powder from a seized capsule found at a forensic psychiatric ward in Denmark. Gas chromatography with mass spectrometry (GC-MS) identified a precursor to synthetic fentanyls, N-phenyl-1-(2 phenylethyl)piperidin-4-amine; however, the precursor 1-(2-phenethyl)piperidin-4 one, was not detected. Analysis of the electron impact mass spectrum of the main, unknown chromatographic peak (GC) tentatively identified an acryloyl analogue of fentanyl. Further analyses by quadrupole time-of-flight high resolution mass spectrometry (QTOF-MS), matrix-assisted laser ionization Orbitrap mass spectrometry (MALDI-Orbitrap-MS), nuclear magnetic resonance spectroscopy (NMR), and infra-red spectroscopy (IR) confirmed the presence of acrylfentanyl (also known as acryloylfentanyl). Quantitative analysis with liquid chromatography and triple quadrupole mass spectrometry (LC-MS/MS) determined the content of acrylfentanyl in the powder, equal to 88.3 mass-% acrylfentanyl hydrochloride. An impurity observed by NMR was identified as triethylamine hydrochloride. Acrylfentanyl is sold on the Internet as a 'research chemical'. Like other synthetic fentanyls, such as acetylfentanyl, it poses a serious risk of fatal intoxication. Copyright (c) 2016 The Authors. Drug Testing and Analysis Published by John Wiley & Sons Ltd. PMID- 27476447 TI - Poly ADP-ribose polymerase-1: Beyond transcription and towards differentiation. AB - Gene regulation mediates the processes of cellular development and differentiation leading to the origin of different cell types each having their own signature gene expression profile. However, the compact chromatin structure and the timely recruitment of molecules involved in various signaling pathways are of prime importance for temporal and spatial gene regulation that eventually contribute towards cell type and specificity. Poly (ADP-ribose) polymerase-1 (PARP-1), a 116-kDa nuclear multitasking protein is involved in modulation of chromatin condensation leading to altered gene expression. In response to activation signals, it adds ADP-ribose units to various target proteins including itself, thus regulating various key cellular processes like DNA repair, cell death, transcription, mRNA splicing etc. This review provides insights into the role of PARP-1 in gene regulation, cell differentiation and multicellular morphogenesis. In addition, the review also explores involvement of PARP-1 in immune cells development and therapeutic possibilities to treat various human diseases. PMID- 27476448 TI - Humoral innate immunity at the crossroad between microbe and matrix recognition: The role of PTX3 in tissue damage. AB - Innate immunity is involved in regulating inflammatory and tissue repair responses to injury. In particular, humoral innate immunity plays functions related to wound clearance from tissue debris, and regulation of macrophage and stromal cell activities. PTX3, a component of humoral innate immunity, orchestrates tissue repair by interacting with plasminogen and fibrin. Fluid phase molecules of innate immunity interact with elements of the extracellular matrix, and some of the latter display opsonic activity against certain bacterial species. Thus, recognition of extracellular matrix and microbial components is a recurrent theme in the humoral arm of the innate immune system. PMID- 27476450 TI - Infimal convolution of total generalized variation functionals for dynamic MRI. AB - PURPOSE: To accelerate dynamic MR applications using infimal convolution of total generalized variation functionals (ICTGV) as spatio-temporal regularization for image reconstruction. THEORY AND METHODS: ICTGV comprises a new image prior tailored to dynamic data that achieves regularization via optimal local balancing between spatial and temporal regularity. Here it is applied for the first time to the reconstruction of dynamic MRI data. CINE and perfusion scans were investigated to study the influence of time dependent morphology and temporal contrast changes. ICTGV regularized reconstruction from subsampled MR data is formulated as a convex optimization problem. Global solutions are obtained by employing a duality based non-smooth optimization algorithm. RESULTS: The reconstruction error remains on a low level with acceleration factors up to 16 for both CINE and dynamic contrast-enhanced MRI data. The GPU implementation of the algorithm suites clinical demands by reducing reconstruction times of one dataset to less than 4 min. CONCLUSION: ICTGV based dynamic magnetic resonance imaging reconstruction allows for vast undersampling and therefore enables for very high spatial and temporal resolutions, spatial coverage and reduced scan time. With the proposed distinction of model and regularization parameters it offers a new and robust method of flexible decomposition into components with different degrees of temporal regularity. Magn Reson Med 78:142-155, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27476451 TI - From Hansch-Fujita Analysis to AFMoC: A Road to Structure-Based QSAR. AB - Since the pioneering effort of Hansch and Fujita, quantitative structure-activity relationships (QSAR) have proved valuable in optimizing lead structures. Enriching classical 3D-QSAR analysis, which exploits the three-dimensional structure of ligands, with structural information of the target has helped to improve the interpretability of the derived models and to increase their predictive power. One such method is the Adaption of Fields for Molecular Comparison (AFMoC) approach where protein-specifically adapted knowledge-based pair-potentials are tailored to one particular protein by considering additional structural and energetic information about ligands. Here, we summarize applications of AFMoC, describe recent developments, and provide an outlook on how to improve the method. PMID- 27476452 TI - Chemical Descriptors Are More Important Than Learning Algorithms for Modelling. PMID- 27476453 TI - Lead Hopping for PfDHODH Inhibitors as Antimalarials Based on Pharmacophore Mapping, Molecular Docking and Comparative Binding Energy Analysis (COMBINE): A Three-Layered Virtual Screening Approach. PMID- 27476449 TI - Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors. AB - BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600) mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. PMID- 27476454 TI - An Investigation of the Relationship Between Molecular Topology and CYP3A4 Inhibition for Drug-like Compounds. AB - Earlier studies have shown that CYP3A4 inhibition is influenced by lipophilicity, size and fMF , where fMF is the size of the molecular framework divided by the total size of the molecule. Other previous studies have shown that there is an enrichment of compounds with only one ring system among drugs in comparison to clinical candidates and general bioactive compounds as well as enrichment among natural products and human metabolites compared to general bioactive compounds. Thus a logical extension of the earlier investigations would be to study how ring systems influence CYP3A4 inhibition. It is shown here that compounds with only one ring system have lower CYP3A4 inhibition compared to compounds with several ring systems. The reason therefore is that they are both smaller and have smaller fMF values compared to compounds with several ring systems. The investigation provides additional insights into how a molecule should be constituted to have low CYP3A4 inhibition and may influence library design and compound acquisitions. PMID- 27476455 TI - Construction and Consensus Performance of (Q)SAR Models for Predicting Phospholipidosis Using a Dataset of 743 Compounds. AB - Drug-induced phospholipidosis (PLD) continues to be a safety concern for pharmaceutical companies and regulatory agencies, prompting the FDA/CDER Phospholipidosis Working Group to develop a database of PLD findings that was recently expanded to contain a total of 743 compounds (385 positive and 358 negative). Three commercial (quantitative) structure-activity relationship [(Q)SAR)] software platforms [MC4PC, Leadscope Predictive Data Miner (LPDM), and Derek for Windows (DfW)] were used to build and/or test models with the database and evaluated individually and together for their ability to predict PLD induction. Models constructed with MC4PC showed improved sensitivity over previous models constructed with an earlier version of the database and software (61.2 % vs. 50.0 %), but lower specificity in cross-validation experiments (58.2 % vs. 91.9 %) due in part to the more balanced ratio of positives to negatives in the training set. A new model created with LPDM gave good cross-validation statistics (79.0 % sensitivity, 78.0 % specificity) and the single DfW structural alert for PLD was found to have high positive predictivity (83.3 %) but low sensitivity (10.4 %) when tested with the entire PLD database. Combining the predictions of MC4PC, LPDM and/or DfW resulted in increased sensitivity and coverage over using one software platform alone, although it did not enhance the overall prediction accuracy beyond that of the best performing individual software platform. The comparison across software platforms, however, facilitated the identification and analysis of chemicals that were consistently predicted incorrectly by all platforms. The prevalence of cationic amphiphilic drug (CAD) structural motifs in the database contributed heavily to many of the structural alerts and discriminating features in the models, but the subset of incorrectly predicted structures across all models underscores the need to account for mitigating features and/or additional filtering criteria to assess PLD, in particular for PLD-inducing non-CADs and non-PLD-inducing CADs. (Q)SAR tools may be used as part of an early screening battery or regulatory risk assessment approach to identify those compounds with the greatest chance of inducing PLD and potentially toxicity. PMID- 27476456 TI - A Kernel-Based Method for Assessing Uncertainty on Individual QSAR Predictions. AB - The assessment of uncertainty attached to individual predictions is now a priority for sound decision-making in risk assessment. QSAR predictive uncertainty is affected by a variety of factors related to the quality of the training set data, the adopted statistical models, and the distance between the query chemical and the training set. We developed a method to quantify uncertainty associated with individual linear QSAR predictions that integrates both model and experimental error uncertainty and that defines an applicability domain based on the density of training set data. Our method is based on chemical spaces defined by latent variables identified by Partial Least Squares (PLS) regressions. The method provides a kernel regression estimate of the activity of interest as well as a measure of predictive uncertainty based on a mathematical estimation of the domain of applicability and on local propagation of uncertainty associated with training set data. PMID- 27476458 TI - Real-based Polarity-preserving Asymmetric Fourier Imaging (RepAFI). AB - We proposed and assessed a modified asymmetric Fourier imaging (AFI) technique named real-based polarity-preserving AFI (RepAFI), in which the low-pass filter kernel for background phase estimation in AFI is optimized to preserve the magnetization polarity information for blood vessels and cerebrospinal fluid (CSF) even for data obtained using phase-sensitive inversion-recovery spin-echo based (PSIR-SE) sequences with asymmetrical sampling in the k-space. Our proposed RepAFI technique achieves a practical balance of image quality and simplicity to provide better performance than conventional AFI methods. PMID- 27476457 TI - Presentation for care and antenatal management of HIV in the UK, 2009-2014. AB - OBJECTIVES: Despite very low rates of vertical transmission of HIV in the UK overall, rates are higher among women starting antenatal antiretroviral therapy (ART) late. We investigated the timing of key elements of the care of HIV positive pregnant women [antenatal care booking, HIV laboratory assessment (CD4 count and HIV viral load) and antenatal ART initiation], to assess whether clinical practice is changing in line with recommendations, and to investigate factors associated with delayed care. METHODS: We used the UK's National Study of HIV in Pregnancy and Childhood for 2009-2014. Data were analysed by fitting logistic regression and Cox proportional hazards models. RESULTS: A total of 5693 births were reported; 79.5% were in women diagnosed with HIV prior to that pregnancy. Median gestation at antenatal booking was 12.1 weeks [interquartile range (IQR) 10.0-15.6 weeks] and booking was significantly earlier during 2012 2014 vs. 2009-2011 (P < 0.001), although only in previously diagnosed women. Overall, 42.2% of pregnancies were booked late (>= 13 gestational weeks). Among women not already on treatment, antenatal ART commenced at a median of 21.4 (IQR18.1-24.5) weeks and started significantly earlier in the most recent time period (P < 0.001). Compared with previously diagnosed women, those newly diagnosed during the current pregnancy booked later for antenatal care and started antenatal ART later (both P < 0.001). Multivariable analyses revealed demographic variations in access to or uptake of care, with groups including migrants and parous women initiating care later. CONCLUSIONS: Although women are accessing antenatal and HIV care earlier in pregnancy, some continue to face barriers to timely initiation of antenatal care and ART. PMID- 27476459 TI - Combining geodiversity with climate and topography to account for threatened species richness. AB - Understanding threatened species diversity is important for long-term conservation planning. Geodiversity-the diversity of Earth surface materials, forms, and processes-may be a useful biodiversity surrogate for conservation and have conservation value itself. Geodiversity and species richness relationships have been demonstrated; establishing whether geodiversity relates to threatened species' diversity and distribution pattern is a logical next step for conservation. We used 4 geodiversity variables (rock-type and soil-type richness, geomorphological diversity, and hydrological feature diversity) and 4 climatic and topographic variables to model threatened species diversity across 31 of Finland's national parks. We also analyzed rarity-weighted richness (a measure of site complementarity) of threatened vascular plants, fungi, bryophytes, and all species combined. Our 1-km2 resolution data set included 271 threatened species from 16 major taxa. We modeled threatened species richness (raw and rarity weighted) with boosted regression trees. Climatic variables, especially the annual temperature sum above 5 degrees C, dominated our models, which is consistent with the critical role of temperature in this boreal environment. Geodiversity added significant explanatory power. High geodiversity values were consistently associated with high threatened species richness across taxa. The combined effect of geodiversity variables was even more pronounced in the rarity weighted richness analyses (except for fungi) than in those for species richness. Geodiversity measures correlated most strongly with species richness (raw and rarity weighted) of threatened vascular plants and bryophytes and were weakest for molluscs, lichens, and mammals. Although simple measures of topography improve biodiversity modeling, our results suggest that geodiversity data relating to geology, landforms, and hydrology are also worth including. This reinforces recent arguments that conserving nature's stage is an important principle in conservation. PMID- 27476460 TI - Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein for patients with chronic hepatitis B and C: a comparative study. AB - We compared Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ M2BP) levels between patients with chronic hepatitis B (n=249) and chronic hepatitis C (n=386) based on the degree of liver fibrosis. We examined WFA+ -M2BP levels in patients with F4 (cirrhosis), F3 or more (advanced fibrosis) and F2 or more (significant fibrosis) in the two groups. We further examined the relationship between five fibrosis markers and the degree of fibrosis. The WFA+ M2BP values ranged from 0.25 cut-off index (COI) to 12.9 COI in patients with hepatitis B and 0.34-20.0 COI in patients with hepatitis C (P<.0001). The median WFA+ -M2BP values in F4 in the two groups were 2.83 COI in patients with hepatitis B and 5.03 COI in patients with hepatitis C (P=.0046). The median WFA+ M2BP values in F3 or more in the two groups were 1.79 COI in patients with hepatitis B and 3.79 COI in patients with hepatitis C (P<.0001). The median WFA+ M2BP values in F2 or more in the two groups were 1.49 COI in the hepatitis B cohort and 3.19 COI in the hepatitis C group (P<.0001). Among five liver fibrosis markers, WFA+ -M2BP had the highest correlation coefficient (rs =.629) in terms of correlation with the degree of fibrosis in the patients with hepatitis C and had the second highest rs value (.415) in the hepatitis B group. Although WFA+ M2BP could be a useful indicator of liver fibrosis, WFA+ -M2BP levels in the two groups significantly differed even in the same degree of fibrosis. Individual cut off values in each aetiology for the degree of fibrosis should be determined. PMID- 27476461 TI - Cyclopeptide toxins of lethal amanitas: Compositions, distribution and phylogenetic implication. AB - Lethal amanitas (Amanita sect. Phalloideae) are responsible for 90% of all fatal mushroom poisonings. Since 2000, more than ten new lethal Amanita species have been discovered and some of them had caused severe mushroom poisonings in China. However, the contents and distribution of cyclopeptides in these lethal mushrooms remain poorly known. In this study, the diversity of major cyclopeptide toxins in seven Amanita species from Eastern Asia and three species from Europe and North America were systematically analyzed, and a new approach to inferring phylogenetic relationships using cyclopeptide profile was evaluated for the first time. The results showed that there were diversities of the cyclopeptides among lethal Amanita species, and cyclopeptides from Amanita rimosa and Amanita fuligineoides were reported for the first time. The amounts of amatoxins in East Asian Amanita species were significantly higher than those in European and North American species. The analysis of distribution of amatoxins and phallotoxins in various Amanita species demonstrated that the content of phallotoxins was higher than that of amatoxins in Amanita phalloides and Amanita virosa. In contrast, the content of phallotoxins was significantly lower than that of amatoxins in all East Asian lethal Amanita species tested. However, the distribution of amatoxins and phallotoxins in different tissues showed the same tendency. Eight cyclopeptides and three unknown compounds were identified using cyclopeptide standards and high-resolution MS. Based on the cyclopeptide profiles, phylogenetic relationships of lethal amanitas were inferred through a dendrogram generated by UPGMA method. The results showed high similarity to the phylogeny established previously based on the multi-locus DNA sequences. PMID- 27476462 TI - Vip3Aa induces apoptosis in cultured Spodoptera frugiperda (Sf9) cells. AB - The vegetative insecticidal proteins (Vip) secreted by many Bacillus thuringiensis strains during their vegetative growth stage are regarded as second generation insecticidal proteins, as they share no sequence or structural homology with known crystal insecticidal proteins (Cry) and have a broad insecticidal spectrum. Compared with insecticidal crystal proteins (ICPs), the insecticidal mechanisms of Vips have been little studied. Here we investigated the mechanism responsible for Vip3Aa toxicity in cultured insect cells. Using, flow cytometry analyzes, TUNEL staining and DNA fragmentation assays, we show that Vip3Aa can induce apoptosis in Spodoptera frugiperda (Sf9) cells and cause cells to arrest at the G2/M phase. We also show that Vip3Aa can disrupt mitochondrial membrane potential (DeltaPsim), leading to the activation of Sf caspase-1, suggesting that a mitochondrial mediated and caspase dependent pathway may be involved in Vip3Aa-induced apoptosis in Sf9 cells. PMID- 27476463 TI - Hepatitis E in a region of Italy: An emerging autochthonous infection? AB - BACKGROUND: Recent data showed an increasing number of "autochthonous" cases of hepatitis E in Italy. AIMS: Analysing cases of acute hepatitis E to define frequency, clinical features, prognosis and risk factors. METHODS: We considered all the patients admitted to our Regional Hospital between August 2011 and September 2014, with a diagnosis of acute hepatitis; serological screening for hepatitis B, C and A viruses was performed; in the event of negative results, sera were tested for cytomegalovirus, Epstein-Barr and hepatitis E viruses. RESULTS: Among 200 patients, 66 were affected by viral infection. IgM anti-HEV was detected in 14 patients with a predominance of males (79%) with a mean age of 55. Genotype 3 of HEV was found in 8 patients. Only one patient died of acute on chronic liver failure; all others evolved favourably towards clinical remission within two months from clinical onset. Thirteen patients had had local exposure to infection and 9 reported the consumption of raw or undercooked locally produced pork. CONCLUSION: The incidence of HEV in our cohort of patients with acute viral hepatitis is high (about 20% per year). In over 85% an autochthonous exposure to infection could be recognised, with a clear link with food habits. PMID- 27476464 TI - Type 3 gastric neuroendocrine tumor with unique endoscopic features. PMID- 27476465 TI - Underuse of brachytherapy for the treatment of dysphagia owing to esophageal cancer. An Italian survey. AB - BACKGROUND: International guidelines strongly recommend brachytherapy as valid alternative or in addition to stenting in patients with dysphagia owing to esophageal cancer. However, for not well understood reasons, brachytherapy is definitively underused for the palliative treatment of malignant dysphagia. Aim of the current survey was to investigate the use of brachytherapy for the treatment of malignant dysphagia in Italy. METHODS: A structured questionnaire was submitted to the 1510 members of the Italian Association of Radiation Oncologists (AIRO). These members refer to 177 centres of radiotherapy across Italy and in 68 (38.4%) of them brachytherapy is routinely performed. RESULTS: Of the 1510 invited members, 178 completed the survey (11.7%). The answers provided by the 178 participants allowed to get information on 40 out of 68 brachytherapy centres (58.8%). Seven out of 40 (17.5%) centres perform brachytherapy of the oesophagus, in 3 out of 40 (7.5%) centres brachytherapy represents the first line of treatment. The main reason why brachytherapy is not routinely performed is the lack of experience. CONCLUSION: Despite the strong recommendations of the international guidelines and the wide diffusion of brachytherapy centres across Italy, only very few of them routinely considered brachytherapy for the treatment of dysphagia due to esophageal cancer. PMID- 27476466 TI - Capecitabine in advanced hepatocellular carcinoma. PMID- 27476467 TI - von Willebrand factor antigen (vWF-Ag): A non-invasive predictor of treatment response and serious adverse events in HCV patients with interferon triple therapy. AB - BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection was revolutionized within the last years. Interferon free antiviral regimens are not accessible without limitations. Combination of peginterferon/ribavirin with first generation direct acting antivirals is less effective and associated with serious adverse events. AIM: We have shown that vWF-Ag is associated with portal hypertension and treatment response to PEG/RBV and we evaluated if vWF-Ag is a predictive marker for treatment response and safety in patients with triple therapy. METHODS: 222 HCV-GT 1 patients and DAA based triple therapy were included in this retrospective, multicenter study. RESULTS: Median vWF-Ag levels were 167.0% [IQR: 124.0-210.0%]. Significantly higher levels were seen in patients without SVR; median 190% [IQR: 146.0-259.5%] versus SVR: 142.5% [IQR: 114.3-196.8%], p<0.001. Furthermore levels of vWF-Ag were identified as independent predictor of non SVR; (OR: 1.009; 95%CI: 1.016-1.3, p=0.005). In patients with cirrhosis elevated vWF-Ag levels were associated with increased incidence of SAEs (OR: 1.016; 95%CI: 1.004-1.028; p=0.007). Best cut off for prediction of SAEs was vWF-Ag>281.5% with a sensitivity of 78% and a specificity of 90%. CONCLUSION: Baseline vWF-Ag levels predict outcome of DAA based treatment in HCV-1 patients and identify patients with a risk of SAEs. Therefore vWF-Ag may be an additional marker for selecting patients for interferon free therapeutic regimens. PMID- 27476468 TI - Diagnostic value of microRNAs as biomarkers for cholangiocarcinoma. AB - BACKGROUND: It has been reported that microRNAs might serve as biomarkers for cholangiocarcinoma (CCA) detection, but their diagnostic accuracy are unclear and controversial. AIM: To evaluate the diagnostic accuracy of microRNAs for CCA. MATERIALS AND METHODS: PubMed, Embase, Web of Science and Cochrane Library were systematically searched to identify relevant articles by using the key words "cholangiocarcinoma" and "microRNA". The methodological quality of each study was assessed by QUADAS-2. According to the inclusive and exclusive criteria, 11 articles were identified and analyzed by Meta-disc software v.1.4 and STATA 12.0 software package. RESULTS: 11 articles with 430 CCA patients and 406 controls were identified. The results showed that the pooled sensitivity was 0.756 (95% CI: 0.693-0.810), specificity was 0.914 (95% CI: 0.861-0.947), positive likelihood ratio was 8.747 (95% CI: 5.320-14.381), negative likelihood ratio was 0.267 (95% CI: 0.208-0.341) and diagnostic odds ratio was 32.791 (95% CI: 17.327, 62.060). In addition, the area under the summary ROC cure (AUC) was 0.90 (95% CI: 0.87-0.93). CONCLUSION: MicroRNAs have great potential as biomarkers for the diagnosis of CCA patients. However, the clinical application of microRNA assays for CCA diagnosis still needs further validation by more prospective studies. PMID- 27476469 TI - CB2-63 polymorphism and immune-mediated diseases associated with HCV chronic infection. AB - AIMS: To evaluate whether CB2 variants are associated with the presence of immune mediated disorders (IMDs) in patients with chronic HCV infection. METHODS: One hundred and sixty-eight anti-HCV/HCV-RNA-positive patients were enrolled, 81 with signs of IMDs and 87 without. In the IMDs group, 22 (27.2%) showed ANA positivity (titers >=1:160), 3 (3.7%) SMA positivity (titers >=1:160), 24 (29.6%) had cryoglobulinemia, 25 (30.9%) autoimmune thyroiditis, 4 (4.9%) psoriasis, 2 (2.5%) B-cell non-Hodgkin lymphoma and 1 (1.2%) autoimmune hemolytic anemia. All patients were screened for the CNR2 rs35761398 single nucleotide polymorphism using a TaqMan Assay. RESULTS: Compared with the 87 patients without IMDs, the 81 with IMDs were more frequently females (65% vs. 45%, p=0.01), but no significant difference was found in the initial demographic, epidemiological, serological, biochemical or virological data. Instead, the prevalence of patients with the CB2 63 RR variant was significantly higher in the IMD than in the non-IMD group (49.4% vs. 24.1%, p=0.001). A logistic regression analysis including the CB2-63 receptor (RR vs. QR or QQ), age and sex identified the CB2-63 RR as the only independent predictor of IMDs (p=0.005). CONCLUSIONS: The data suggest a significant, previously unknown, independent association between the CB2-63 RR variant and IMDs in anti-HCV-positive patients. The study was approved by the Ethics Committee of the Azienda Ospedaliera Universitaria of the Second University of Naples (n degrees 214/2012). PMID- 27476470 TI - A Comparative Analysis of Community Detection Algorithms on Artificial Networks. AB - Many community detection algorithms have been developed to uncover the mesoscopic properties of complex networks. However how good an algorithm is, in terms of accuracy and computing time, remains still open. Testing algorithms on real-world network has certain restrictions which made their insights potentially biased: the networks are usually small, and the underlying communities are not defined objectively. In this study, we employ the Lancichinetti-Fortunato-Radicchi benchmark graph to test eight state-of-the-art algorithms. We quantify the accuracy using complementary measures and algorithms' computing time. Based on simple network properties and the aforementioned results, we provide guidelines that help to choose the most adequate community detection algorithm for a given network. Moreover, these rules allow uncovering limitations in the use of specific algorithms given macroscopic network properties. Our contribution is threefold: firstly, we provide actual techniques to determine which is the most suited algorithm in most circumstances based on observable properties of the network under consideration. Secondly, we use the mixing parameter as an easily measurable indicator of finding the ranges of reliability of the different algorithms. Finally, we study the dependency with network size focusing on both the algorithm's predicting power and the effective computing time. PMID- 27476471 TI - Evaluation of parameters of a plankton community's biological rhythms under the natural environment of the Black Sea using the Fourier transform method. AB - Night-time changes in bioluminescence intensity in the coastal area of the Black Sea were recorded. It was noted that the biomass of luminous organisms is closely correlated with the biomass of plankton and other pelagic organisms, including commercial pelagic fish. The parameters of plankton communities' basic biological rhythms were determined using the discrete Fourier transform method. These rhythms were manifest as spatial and temporal changes in the bioluminescence intensity. It was shown that changes in the bioluminescence intensity over a 14.0 h period were due to the duration of the light/dark cycles. By contrast, changes in bioluminescence intensity with periods of 4.7 and 2.8 h were due to the endogenous rhythms of the plankton community (feeding and cell division). An original method for evaluating of errors in the calculated periods of the biological rhythms was proposed. A strong correlation (r = 0.906) was observed between the measured and calculated values for the bioluminescence intensity, which provided support for the assumptions made. PMID- 27476472 TI - Inverse 4D conformal planning for lung SBRT using particle swarm optimization. AB - A critical aspect of highly potent regimens such as lung stereotactic body radiation therapy (SBRT) is to avoid collateral toxicity while achieving planning target volume (PTV) coverage. In this work, we describe four dimensional conformal radiotherapy using a highly parallelizable swarm intelligence-based stochastic optimization technique. Conventional lung CRT-SBRT uses a 4DCT to create an internal target volume and then, using forward-planning, generates a 3D conformal plan. In contrast, we investigate an inverse-planning strategy that uses 4DCT data to create a 4D conformal plan, which is optimized across the three spatial dimensions (3D) as well as time, as represented by the respiratory phase. The key idea is to use respiratory motion as an additional degree of freedom. We iteratively adjust fluence weights for all beam apertures across all respiratory phases considering OAR sparing, PTV coverage and delivery efficiency. To demonstrate proof-of-concept, five non-small-cell lung cancer SBRT patients were retrospectively studied. The 4D optimized plans achieved PTV coverage comparable to the corresponding clinically delivered plans while showing significantly superior OAR sparing ranging from 26% to 83% for D max heart, 10%-41% for D max esophagus, 31%-68% for D max spinal cord and 7%-32% for V 13 lung. PMID- 27476473 TI - The versatility of the medial thigh lift for defect coverage in the genito perineal region. AB - Soft tissue defects in the genito-perineal region are predominantly because of trauma, infections, neoplasms or iatrogenic causes. As a result of the region's urological, reproductive and gastrointestinal function, defects in this area may cause devastating physical and psychological consequences as well as diminished sexual functioning. The purpose of this study was to examine the efficacy of implementing a medial thigh lift for defect coverage in the perineal region. A retrospective analysis of all medial thigh lift procedures for defect coverage in the genito-perineal region between November 2010 and March 2015 was conducted at three institutions. Ten consecutive patients underwent a medial thigh lift for defect coverage in the genito-perineal region. Nine patients were male, and one was female. The causative factors were Fournier's gangrene in eight patients, one patient had a straddle injury, and one suffered from extramammary Paget's disease. The mean follow-up time was 19.8 months. The average total defect size was 11.1 * 11 cm (length * width). The medial thigh lift procedure is a safe, technically easy and reliable technique with discrete scars. Outstanding aesthetic and functional outcomes result in a high rate of patient satisfaction. Through immediate wound closure, a reduction of recovery time can be achieved. PMID- 27476474 TI - Management of glioblastoma after recurrence: A changing paradigm. AB - Glioblastoma remains the most common primary brain tumor after the age of 40years. Maximal safe surgery followed by adjuvant chemoradiotherapy has remained the standard treatment for glioblastoma (GBM). But recurrence is an inevitable event in the natural history of GBM with most patients experiencing it after 6 9months of primary treatment. Recurrent GBM poses great challenge to manage with no well-defined management protocols. The challenge starts from differentiating radiation necrosis from true local progression. A fine balance needs to be maintained on improving survival and assuring a better quality of life. Treatment options are limited and ranges from re-excision, re-irradiation, systemic chemotherapy or a combination of these. Re-excision and re-irradiation must be attempted in selected patients and has been shown to improve survival outcomes. To facilitate the management of GBM recurrences, a treatment algorithm is proposed. PMID- 27476475 TI - Giant Electroresistance in Edge Metal-Insulator-Metal Tunnel Junctions Induced by Ferroelectric Fringe Fields. AB - An enormous amount of research activities has been devoted to developing new types of non-volatile memory devices as the potential replacements of current flash memory devices. Theoretical device modeling was performed to demonstrate that a huge change of tunnel resistance in an Edge Metal-Insulator-Metal (EMIM) junction of metal crossbar structure can be induced by the modulation of electric fringe field, associated with the polarization reversal of an underlying ferroelectric layer. It is demonstrated that single three-terminal EMIM/Ferroelectric structure could form an active memory cell without any additional selection devices. This new structure can open up a way of fabricating all-thin-film-based, high-density, high-speed, and low-power non-volatile memory devices that are stackable to realize 3D memory architecture. PMID- 27476476 TI - Origin of tunable photoluminescence from graphene quantum dots synthesized via pulsed laser ablation. AB - A one-step synthesis of graphene quantum dots (GQDs) has been implemented using pulsed laser ablation (PLA) with carboxyl-functionalized multiwalled carbon nanotubes (MWCNTs). The synthesized GQDs with an average size smaller than 3 nm were obtained by the fragmentation of MWCNTs via oxidative cutting. The GQDs can generate tunable photoluminescence (PL) ranging from green to blue by controlling the PLA time. The PL spectrum (decay time) of the green GQDs remains unchanged under different excitation energies (emission energies), while that of the blue GQDs correlates with the excitation energy (emission energy). On the basis of the pH and temperature dependence of PL, we suggest that the localized intrinsic states associated with the sp(2) nanodomains and delocalized extrinsic states embedded on the GQD surface are responsible for blue and green emission in GQDs, respectively. PMID- 27476478 TI - MALDI-TOF mass spectrometry analysis of proteins and lipids in Escherichia coli exposed to copper ions and nanoparticles. AB - Escherichia coli (E. coli) is one of the most important foodborne pathogens to the food industry responsible for diseases as bloody diarrhea, hemorrhagic colitis and life-threatening hemolytic-uremic syndrome. For controlling and eliminating E. coli, metal nano-antimicrobials (NAMs) are frequently used as bioactive systems for applications in food treatments. Most NAMs provide controlled release of metal ions, eventually slowing down or completely inhibiting the growth of undesired microorganisms. Nonetheless, their antimicrobial action is not totally unraveled and is strongly dependent on metal properties and environmental conditions. In this work, we propose the use of matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry as a powerful tool for direct, time efficient, plausible identification of the cell membrane damage in bacterial strains exposed to copper based antimicrobial agents, such as soluble salts (chosen as simplified AM material) and copper nanoparticles. E. coli ATCC 25922 strain was selected as 'training bacterium' to set up some critical experimental parameters (i.e. cell concentration, selection of the MALDI matrix, optimal solvent composition, sample preparation method) for the MS analyses. The resulting procedure was then used to attain both protein and lipid fingerprints from E. coli after exposure to different loadings of Cu salts and NPs. Interestingly, bacteria exposed to copper showed over-expression of copper binding proteins and degradation of lipids when treated with soluble salt. These findings were completed with other investigations, such as microbiological experiments. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476479 TI - Influence of selective serotonin reuptake inhibitors on ocular surface. AB - BACKGROUND: Antidepressant drugs may have an effect on tear film stability. This study aimed to determine the influence of selective serotonin reuptake inhibitors, which are mostly prescribed antidepressants, on ocular surface and tear film stability. METHODS: Thirty-six patients (Group 1) and 36 healthy volunteers (Group 2) were enrolled. Group 1 comprised of depression and/or anxiety disorder patients using selective serotonin reuptake inhibitors, who were in clinical remission according to psychiatric history and questionnaires (Hamilton depression rating scale and Hamilton anxiety rating scale). All subjects underwent a detailed ophthalmological examination and the following tests were performed: corneal and conjunctival fluorescein staining and Oxford scoring, tear break-up time, Schirmer 1 test, ocular surface disease index score assessment. RESULTS: The mean age was 36.64 (18 to 61) years in Group 1 and 31.84 (18 to 48) years in Group 2 (p > 0.05). Male to female ratio was 0.38 in Group 1 and 0.89 in Group 2 (p > 0.05). In Group 1, 19 patients (52.8 per cent) had depression, 16 patients (44.4 per cent) had anxiety disorder and one patient (2.8 per cent) had a combination of depression and anxiety disorder. The mean tear break-up times in Groups 1 and 2 were 7.05 +/- 4.86 and 12.53 +/- 4.75 seconds, respectively (p < 0.001). The mean Schirmer 1 test results in Groups 1 and 2 were 14.44 +/- 10.81 and 17.69 +/- 10.46 mm, respectively (p > 0.05). The mean superficial punctate staining according to Oxford scale in Groups 1 and 2 were grade 0.78 +/- 0.76 and grade 0.11 +/- 0.32, respectively (p < 0.001). The mean ocular surface disease index scores in Groups 1 and 2 were 32.07 (zero to 75.00) and 16.31 (zero to 58.33), respectively (p < 0.001). CONCLUSION: Selective serotonin reuptake inhibitor usage might affect ocular surface by affecting tear film stability and such an association should be kept in mind by both psychiatrists and ophthalmologists in clinical practice. PMID- 27476480 TI - Accelerated degradation of MOFs under flue gas conditions. AB - The zero length column (ZLC) technique is used to investigate the stability of Mg and Ni-CPO-27 metal-organic framework (MOF) crystals in the presence of water and humid flue gas. The design of the ZLC enables the stability test to be conducted over a considerably shorter time period and with lower gas consumption than other conventional techniques. A key advantage over other experimental methods for testing the stability of adsorbents is the fact that the ZLC allows us to quantify the amount adsorbed of every component present in the gas mixture. The developed protocol is based on a two-stage stability test. The samples were first exposed to a humid carbon dioxide and helium mixture in order to study the effect of water on the carbon dioxide adsorption capacity of the samples. In the second stage the samples were exposed to a flue gas mixture containing water. From the preliminary water stability test, the Ni-sample exhibited the highest tolerance to the presence of water, retaining approximately 85% of its pristine CO2 capacity. The Mg-MOFs deactivated rapidly in the presence of water. The Ni CPO-27 was then selected for the second stage of the protocol in which the material was exposed to the wet flue gas. The sample showed an initial drop in CO2 capacity after the first exposure to the wet flue gas, followed by a stabilisation of the performance over several cycles. PMID- 27476477 TI - Modulation of Irisin and Physical Activity on Executive Functions in Obesity and Morbid obesity. AB - Whether the executive profile is different between obesity (OB) and morbid obesity (MO) remains unclear. Recent evidence suggests that physical activity (PA) can act as a cognitive enhancer. Irisin is a recently discovered hormone associated with some of the positive effects of PA. The objective of the study was to investigate the executive profile in OB and MO, and to explore the role of PA and irisin. 114 participants were included (21 OB, 44 MO and 49 healthy controls-HC) in the study and assessed with the Wisconsin Card Sorting Test, Stroop Color and Word Test, and Iowa Gambling Task. All participants were female, aged between 18 and 60 years. Results showed a similar dysfunctional profile on decision making in OB and MO compared with HC. Thus, no specific neuropsychological profiles between OB and MO can be clearly observed in our sample. However, a negative correlation was found between irisin and executive functioning. These results demonstrate a specific executive profile in OB and a relevant and negative modulation of irisin on executive functioning. Although irisin might be a promising target for the treatment of obesity, its effects on cognition might be considered when thinking about its therapeutic use. PMID- 27476481 TI - Probing effective slippage on superhydrophobic stripes by atomic force microscopy. AB - While the effective slippage of water past superhydrophobic surfaces has been studied over a decade, theoretical predictions have never been properly confirmed by experiments. Here we measure a drag force on a sphere approaching a plane decorated by superhydrophobic grooves and compare the results with the predictions of semi-analytical theory developed here, which employs the gas cushion model to calculate the local slip length at the gas sectors. We demonstrate that at intermediate and large (compared to a texture period) separations the half-sum of longitudinal and transverse effective slip lengths can be deduced from the force-distance curve by using the known analytical theory of hydrodynamic interaction of a sphere with a homogeneous slipping plane. This half-sum is shown to depend on the fraction of gas sectors and its value is in excellent agreement with theoretical predictions. At small distances the half-sum of effective longitudinal and transverse slip lengths becomes separation dependent, and is in quantitative agreement with the predictions of our semi analytical theory. PMID- 27476482 TI - Biomolecular proteomics discloses ATP synthase as the main target of the natural glycoside deglucoruscin. AB - Extracts of Ruscus aculeatus are a rich source of bioactive steroidal glycosides, such as ruscogenins which are reported to act against chronic venous disorders. Nowadays, several preparations of its roots, commonly used in traditional medicine, are on the market as food supplements for health care and maintenance. Although spirostanol deglucoruscin is one of the main metabolites in these extracts, literature reports about its pharmacological profile are scarce. In this paper, a multi-disciplinary approach, based on chemical proteomics, molecular modelling and bio-organic assays, has been used to disclose the whole interactome of deglucoruscin and the F0-F1 ATP synthase complex has been found as its main target. PMID- 27476483 TI - Visualization of the structural changes in plywood and gypsum board during the growth of Chaetomium globosum and Stachybotrys chartarum. AB - Fungal growth in indoor environments is associated with many negative health effects. Many studies focus on brown- and white-rot fungi and their effect on wood, but there is none that reveals the influence of soft-rot fungi, such as Stachybotrys spp. and Chaetomium spp., on the structure of building materials such as plywood and gypsum wallboard. This study focuses on using micro-computed tomography (microCT) to investigate changes of the structure of plywood and gypsum wallboard during fungal degradation by S. chartarum and C. globosum. Changes in the materials as a result of dampness and fungal growth were determined by measuring porosity and pore shape via microCT. The results show that the composition of the building material influenced the level of penetration by fungi as shown by scanning electron microscopy (SEM). Plywood appeared to be the most affected, with the penetration of moisture and fungi throughout the whole thickness of the sample. Conversely, fungi grew only on the top cardboard in the gypsum wallboard and they did not have significant influence on the gypsum wallboard structure. The majority of the observed changes in gypsum wallboard occurred due to moisture. This paper suggests that the mycelium distribution within building materials and the structural changes, caused by dampness and fungal growth, depend on the type of the material. PMID- 27476484 TI - Technical note: Discard the specimen collection swab directly at point of care to improve extensive automated processing in clinical microbiology laboratories. AB - We compared, in terms of microorganisms recovery, the discard of specimen collection swab, after swirling into its medium, directly at point of care, with its placing into the medium and vortexing on arrival in the laboratory. Our results show that these two procedures are overlapped in terms of bacterial recovery. PMID- 27476485 TI - Evaluating methods for purifying cyanobacterial cultures by qPCR and high throughput Illumina sequencing. AB - Cyanobacteria are commonly found in association with other microorganisms, which constitutes a great challenge during the isolation of cyanobacterial strains. Although several methods have been published for obtaining axenic cyanobacterial cultures, their efficiency is usually evaluated by observing the growth of non cyanobacteria in culture media. In order to verify whether uncultured bacteria should be a concern during cyanobacterial isolation, this work aimed to detect by molecular methods sequences from cyanobacteria and other bacteria present before and after a technique for obtaining axenic cultures from plating and exposure of Fischerella sp. CENA161 akinetes to the Extran detergent and sodium hypochlorite. Solutions containing 0.5, 1, and 2% sodium hypochlorite were able to remove contaminant bacterial CFUs from the culture. However, qPCR pointed that the quantity of sequences amplified with universal bacteria primers was higher than the number of cyanobacteria-specific sequences before and after treatments. The presence of uncultured bacteria in post-hypochlorite cultures was confirmed by high-throughput Illumina sequencing. These results suggest that culturing may overlook the presence of uncultured bacteria associated to cyanobacterial strains and is not sufficient for monitoring the success of cyanobacterial isolation by itself. Molecular methods such as qPCR could be employed as an additional measure for evaluating axenity in cyanobacterial strains. PMID- 27476487 TI - A macrocyclic 1,4-bis(4-pyridylethynyl)benzene showing unique aggregation-induced emission properties. AB - A box-like macrocycle based on 1,4-bis(4-pyridylethynyl)benzene was derived in high yield. The macrocyclic fluorogen shows unique aggregation-induced emission properties. PMID- 27476486 TI - Human Prostate Cancer Hallmarks Map. AB - Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID- 27476488 TI - Synergistic Effect of SH003 and Doxorubicin in Triple-negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is highly aggressive, resulting in poor prognosis. Chemotherapy of TNBC relies on anti-cancer agents with strong cytotoxicity, but it causes several side effects with recurrence. While combinational approaches of chemotherapeutics have been highlighted as a new treatment strategy for TNBC to reduce side effects, combinations of anti-cancer agents with herbal medicines have not been reported. We recently reported that newly modified traditional Chinese medicine named SH003 inhibited TNBC growth. Considering a combinational strategy for TNBC treatment, we further studied synergistic effects of SH003 with various anti-cancer drugs in TNBC treatment. Here, we demonstrate that SH003 shows a synergistic effect with doxorubicin on TNBC treatment. Our in vitro cell viability assays revealed that SH003 and doxorubicin showed a synergistic effect in the well-defined TNBC cell line, MDA MB-231. Moreover, we found that the combinational treatment caused Caspase dependent apoptotic cell death. Our in vivo mouse xenograft tumor growth assays confirmed that combinational treatment of SH003 with doxorubicin repressed MDA-MB 231 tumor growth with no weight loss. Therefore, we conclude that the combinational treatment of SH003 with doxorubicin shows the synergism in TNBC treatment, and suggest that SH003 can be used together with conventional anti cancer drugs in chemotherapeutic approaches. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476489 TI - Inflammatory and oxidative stress markers associated with decreased cervical length in pregnancy. AB - PROBLEM: We assess whether inflammatory and oxidative stress markers early in pregnancy are associated with decreasing cervical length in the second trimester. METHOD OF STUDY: This is a secondary analysis of a nested case-control study of preterm birth conducted at a tertiary care center from 2006 to 2008. Plasma inflammatory markers included the following: interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP); and urine oxidative stress markers included the following: 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane, measured at two study visits (median 10 and 18 weeks of gestation). The primary outcome was cervical length<10th percentile measured between 16 and 24 weeks of gestation. Logistic regression models were used, adjusting for body mass index, age, race, parity, tobacco use, education, and gestational age at cervical length measurement. RESULTS: Among 384 observed women, the 10th percentile cervical length was 3.0 cm. IL-10 levels were significantly higher among women with a cervical length<10th percentile compared to women with a longer cervix (mean IL 10: 95.5 vs 25.8 pg/mL, P<.01). Similarly, IL-6 levels were significantly higher among women with a cervical length<10th percentile (mean IL-6: 25.2 vs 4.3 pg/mL, P<.01). After controlling for potential confounders, an increase in IL-10 was significantly associated with a cervical length<10th percentile at both 10 and 18 weeks (adjusted odd ratio [AOR]: 1.74; 95% CI: 1.18-2.58; P=.005). At 18 weeks, only IL-6 was also significantly associated with a cervical length<10th percentile (AOR: 1.54; 95% CI: 1.11-2.13; P=.009). Other inflammatory biomarkers, including CRP, IL-1beta, TNF-alpha, and oxidative stress biomarkers, 8-OHdG and 8 isoprostane, were not associated with cervical length. CONCLUSION: There was a significant association between the cytokines IL-6 and IL-10 early in pregnancy and decreased cervical length, suggesting an imbalance of immune regulation could impact cervical length. PMID- 27476491 TI - Indispensable role for mouse ELP3 in embryonic stem cell maintenance and early development. AB - ELP3, a core component of Elongator, has been implicated in translational regulation via modification of tRNA at the wobble position. However, the precise biological function of ELP3 in early mouse development has not yet been defined. We here provide evidence that ELP3 plays crucial roles in mouse embryonic stem cell (ESC) maintenance and early development. ELP3 was detected ubiquitously in blastocysts and E10.5 embryos and shown to be increased during ESC differentiation. Depletion of ELP3 in ESC led to aberrant cell cycle progression, along with reduced expression of genes for pluripotency. Interestingly, our analyses revealed that, although the mRNA levels of the genes related to cell cycle were increased, protein levels were diminished in knockdown (KD) ESCs. The data, therefore, suggest that ELP3 function is critical for translational efficiency of the genes. Consistent with a proliferation defect in KD cells, Elp3 knockout (KO) embryos suffered from severe growth retardation and failed to develop beyond E12.5. In conclusion, we have demonstrated that ELP3 plays an indispensable role in ESC survival, differentiation and embryonic development in mouse. PMID- 27476490 TI - Clinical Impact of Not Achieving Recommended Dose on Duration of Atomoxetine Treatment in Adults with Attention-Deficit/Hyperactivity Disorder. AB - AIM: To compare atomoxetine (ATX) length of therapy (LoT) among adults with ADHD who reached the recommended dose of 80 mg/day (ATX >= 80) versus those who did not (ATX < 80) analyzed separately in patients prescribed ATX as monotherapy (mono) and in combination with other ADHD medications (combo). METHODS: This was a retrospective observational cohort study of the Truven Health Marketscan Commercial Claims Database from January 1, 2006-September 30, 2013, with a 6 month preindex period free of ATX (1st ATX claim as index event) and a 1-year follow-up. LoT during follow-up was calculated using prescription claim fill dates and included all days with medication on hand regardless of treatment gaps. RESULTS: Only 45.0% of the 36,076 mono and 77.9% of the 1548 combo patients reached an ATX dose of >=80 mg/day in 1-year follow-up. When patients filled at least one 80 mg prescription, their total days of therapy over the course of a year were significantly greater than if they did not (mono: 159.3 vs. 65.6 days; combo: 237.4 vs. 172.0; P < 0.0001). Across all timepoints examined (Day 14, 30, 60, 90, 210) for mono and combo, ATX >= 80 versus ATX < 80 patients had greater mean doses (P < 0.0001). Combo patients had longer ATX LoT than mono patients regardless if they reached 80 mg or not (P < 0.0001), but mono patients LoT was 93.8 days longer for ATX >= 80 versus ATX < 80 patients compared to 65.5 days for combo patients. Of patients reaching 80 mg/day, 71.7% of mono and 62.8% of combo patients did so by Day 30. For mono ATX >= 80 and ATX < 80 patients, LoT was significantly (P < 0.0001) less in previously treated patients compared to naive patients. CONCLUSION: Ensuring adult ADHD patients are treated with ATX at a target dose of 80 mg/day is an important clinical consideration for maximizing patient days on therapy, which can be important for treatment optimization. PMID- 27476492 TI - The effect of blood transfusion on central venous oxygen saturation in critically ill patients admitted to a neurointensive care unit. AB - BACKGROUND: Literature suggests poorer outcomes during anaemia as well as following red blood cell transfusion (BT) in brain injured patients. Recently, central venous oxygen saturation (ScvO2 ) has been proposed as a physiological trigger to guide red BT. In this study, we looked at ScvO2 changes following BT in patients admitted to a neurointensive care unit (NICU). STUDY DESIGN: In this prospective, observational study, adult, acutely ill neurological patients of >18 years were recruited. The following parameters were measured before and immediately after transfusion and then at 6, 12, 18 and 24 h after transfusion: haemoglobin (Hb), ScvO2 and central venous oxygen partial pressure (PcvO2 ) (blood sampled from central venous catheter). Simultaneously, hemodynamic parameters [central venous pressure (CVP), heart rate (HR), mean arterial pressure (MAP) and systolic blood pressure (SBP)] were also noted. RESULTS: Data from 70 adult patients were analysed. Following BT, significant improvement was noted in Hb, ScvO2 and all hemodynamic parameters. The ScvO2 changes correlated significantly with the number of units of BT (P = 0.039), pre-transfusion Hb (P = 0.010), ScvO2 (P = 0.001) and PcvO2 (P = 0.001). When receiver operating characteristic (ROC) curves were drawn, optimum cut-off values of baseline ScvO2 and Hb to predict the need for transfusion in terms of oxygen delivery were 70% and 8.6 gm dL-1 respectively. DISCUSSION: Baseline ScvO2 <70% appears to be a useful physiological trigger for deciding the need for BT in brain injured patients. Whether improvement in ScvO2 leads to improvement in regional brain oxygenation needs to be studied. PMID- 27476493 TI - Comparative performance of airyscan and structured illumination superresolution microscopy in the study of the surface texture and 3D shape of pollen. AB - The visualization of taxonomically diagnostic features of individual pollen grains can be a challenge for many ecologically and phylogenetically important pollen types. The resolution of traditional optical microscopy is limited by the diffraction of light (250 nm), while high resolution tools such as electron microscopy are limited by laborious preparation and imaging workflows. Airyscan confocal superresolution and structured illumination superresolution (SR-SIM) microscopy are powerful new tools for the study of nanoscale pollen morphology and three-dimensional structure that can overcome these basic limitations. This study demonstrates their utility in capturing morphological details below the diffraction limit of light. Using three distinct pollen morphotypes (Croton hirtus, Dactylis glomerata, and Helianthus sp.) and contrast-enhancing fluorescent staining, we were able to assess the effectiveness of the Airyscan and SR-SIM. We further demonstrate that these new superresolution methods can be easily applied to the study of fossil pollen material. PMID- 27476494 TI - Nurse-led hepatocellular carcinoma surveillance clinic provides an effective method of monitoring patients with cirrhosis. AB - The aim of this study is to examine the acceptability and effectiveness of a nurse-led hepatocellular carcinoma (HCC) surveillance clinic in high-risk patients with cirrhosis/advanced fibrosis. Early detection of HCC is associated with better treatment outcomes and improved survival. International guidelines recommend 6-monthly surveillance of patients at risk of developing HCC. A nurse led HCC surveillance protocol was established to support patients in adherence to surveillance protocols. The design used was retrospective document analysis. Retrospective analysis of healthcare records of patients referred to the clinic between August 2009 and December 2015. Extracted data included attendance of clinic visits, blood testing, ultrasound or other imaging, and outcomes. Ultrasound was attended within 6 months in 30.3% of cases and within 7 months in 71.2% of cases. The median time between Nurse-Led Clinic appointments, ultrasound scans and blood testing did not exceed 9 months. First year FibroScans were attended by 82.9% (63/76) patients; endoscopy was indicated for 42 and attended by 35 (83.3%) patients. Lesions were identified in 16 patients (21.5%) and HCC diagnosed in two patients. One patient died because of HCC and one to sub-dural haematoma. Nurse-led HCC surveillance was an effective method of monitoring patients with cirrhosis at high risk of developing HCC. Well-defined protocols enable timely identification of patients with HCC or hepatic decompensation so that management strategies can be implemented without delay. The potential benefits identified by this study warrant further, rigorous evaluation. PMID- 27476495 TI - Pharmacokinetics and distribution in interstitial and pulmonary epithelial lining fluid of danofloxacin in ruminant and preruminant calves. AB - The objective of this study was to compare active drug concentrations in the plasma vs. different effector compartments including interstitial fluid (ISF) and pulmonary epithelial lining fluid (PELF) of healthy preruminating (3-week-old) and ruminating (6-month-old) calves. Eight calves in each age group were given a single subcutaneous (s.c.) dose (8 mg/kg) of danofloxacin. Plasma, ISF, and bronchoalveolar lavage (BAL) fluid were collected over 96 h and analyzed by high pressure liquid chromatography. PELF concentrations were calculated by a urea dilution assay of the BAL fluids. Plasma protein binding was measured using a microcentrifugation system. For most preruminant and ruminant calves, the concentration-time profile of the central compartment was best described by a two compartment open body model. For some calves, a third compartment was also observed. The time to maximum concentration in the plasma was longer in preruminating calves (3.1 h) vs. ruminating calves (1.4 h). Clearance (CL/F) was 385.15 and 535.11 mL/h/kg in preruminant and ruminant calves, respectively. Ruminant calves maintained higher ISF/plasma concentration ratios throughout the study period compared to that observed in preruminant calves. Potential reasons for age-related differences in plasma concentration-time profiles and partitioning of the drug to lungs and ISF as a function of age are explored. PMID- 27476496 TI - Does Length of Developmental Behavioral Pediatrics Training Matter? AB - OBJECTIVE: Since 1997 pediatric residencies have been required to provide a 4 week block rotation in developmental and behavioral pediatrics (DBP), but it is not known whether this has altered the care and management of children by practicing pediatricians. The objective of this study was to compare the self reported practice patterns of pediatricians who were trained with 4 or more weeks of DBP with the practice patterns of those who were trained for <4 weeks. METHODS: We used self-reported practices from the American Academy of Pediatrics Periodic Survey 85. Pediatricians were asked whether they never, sometimes, or usually inquired about and screened for, and whether they treated/managed/comanaged attention deficit hyperactivity disorder, depression, anxiety, behavior problems and learning problems. They were also asked about a series of barriers to care. Analyses were weighted to account for low response rates. RESULTS: Those with more DBP training were significantly more likely to treat/manage/co-manage depression, anxiety, behavior problems and learning problems, but were still doing so less than one third of the time. There were no differences in the care of patients with attention deficit hyperactivity disorder or in screening or inquiring about mental health conditions. Those with more training were more likely to perceive somewhat fewer barriers and to report more specific familiarity with some Diagnostic and Statistical Manual of Mental Disorders criteria and some treatment modalities. CONCLUSIONS: Longer length of training is associated with more treatment, but significant deficits in self reported practice remain, leaving much room for additional improvement in the training of clinicians in DBP. PMID- 27476497 TI - The value of sentinel lymph node biopsy in Merkel cell carcinoma: reply from the authors. PMID- 27476498 TI - Microwave thawing and green tea extract efficiency for the formation of acrylamide throughout the production process of chicken burgers and chicken nuggets. AB - BACKGROUND: Initially, we measured the acrylamide (AA) levels of chicken burgers (CBs) and chicken nuggets (CNs) purchased from fast food restaurants. After the determination of AA in these products, we aimed to investigate whether the use of green tea extract in the covering material, and microwave thawing before frying, mitigated the formation of AA in CBs and CNs during the production process. RESULTS: According to our study, AA concentrations of CBs and CNs purchased from fast food restaurants were in the range of 13.43-118.97 and 32.92-134.90 ng g-1 coating, respectively. In our experiment, AA levels varied between 19.61 and 40.08 ng g-1 coating for CBs and 7.92-49.60 ng g-1 coating for CNs. Green tea extract reduced the AA formation in CBs and CNs at the pan frying and steam oven cooking heat treatment steps (P < 0.05). However, microwave thawing did not affect AA level of CBs and CNs. CONCLUSION: When the AA levels of commercial CBs and CNs are compared with those produced in our experiment, the use of green tea extract could be a novel, easy and practical application for fast food producers to minimise AA levels in the first two steps of the production without changes to the sensory properties of the final products. (c) 2016 Society of Chemical Industry. PMID- 27476499 TI - Economic costs to caregivers of diarrhoea treatment among children below 5 in rural Gujarat India: findings from an external evaluation of the DAZT programme. AB - INTRODUCTION: Diarrhoea is a leading cause of mortality among young children in India although few receive the recommended treatment. The diarrhoea alleviation through zinc and oral rehydration salts (ORS) therapy (DAZT) team initiated a programme in Gujarat from 2011 to 2013 to increase coverage of these interventions through public and private providers at scale. This study evaluates the economic impact of diarrhoea to caregivers before and after the introduction of zinc and ORS at scale through the DAZT programme. METHODS: The DAZT programme evaluation took a before-and-after study design using a two-stage clustered cross sectional survey. Factors associated with the odds of caregivers incurring economic costs and their amounts were evaluated in a two-part modelling approach. RESULTS: The DAZT programme lowered unadjusted economic costs to caregivers of treating a diarrhoeal episode from $4.04 to $2.49 in 2 years. Controlling for covariates, analysis showed no association between the programme and a change in odds of incurring an economic cost but did show an association with a reduction in economic cost of $2.15 (95% confidence interval (CI) $1.20-$3.11) per diarrhoea episode. A more than 4-fold increase in care-seeking from public community health workers, reduction in care-seeking from higher levels of the health system and reduced spending on drugs besides ORS and zinc may explain these results. DISCUSSION: This study found an association between zinc introduction and a reduction in economic burden of diarrhoea treatment to caregivers in underserved rural areas of Gujarat through more efficient patterns of care-seeking and content of care. PMID- 27476500 TI - Renewing membership in three community-based health insurance schemes in rural India. AB - Low renewal rate is a key challenge facing the sustainability of community-based health insurance (CBHI) schemes. While there is a large literature on initial enrolment into such schemes, there is limited evidence on the factors that impede renewal. This article uses longitudinal data to analyse what determines renewal, both 1 year and 2 years after the introduction of three CBHI schemes, which have been operating in rural Bihar and Uttar Pradesh since 2011. We find that initial scheme uptake is ~23-24% and that 2 years after scheme operation, only ~20% of the initial enrolees maintain their membership. A household's socio-economic status does not seem to play a large role in impeding renewal. In some instances, a greater understanding of the scheme boosts renewal. The link between health status and use of health care in maintaining renewal is mixed. The clearest effect is that individuals living in households that have received benefits from the scheme are substantially more likely to renew their contracts. We conclude that the low retention rates may be attributed to limited benefit packages, slow claims processing times and the gap between the amounts claimed and amounts paid out by insurance. PMID- 27476501 TI - Who bears the cost of 'informal mhealth'? Health-workers' mobile phone practices and associated political-moral economies of care in Ghana and Malawi. AB - Africa's recent communications 'revolution' has generated optimism that using mobile phones for health (mhealth) can help bridge healthcare gaps, particularly for rural, hard-to-reach populations. However, while scale-up of mhealth pilots remains limited, health-workers across the continent possess mobile phones. This article draws on interviews from Ghana and Malawi to ask whether/how health workers are using their phones informally and with what consequences. Health workers were found to use personal mobile phones for a wide range of purposes: obtaining help in emergencies; communicating with patients/colleagues; facilitating community-based care, patient monitoring and medication adherence; obtaining clinical advice/information and managing logistics. However, the costs were being borne by the health-workers themselves, particularly by those at the lower echelons, in rural communities, often on minimal stipends/salaries, who are required to 'care' even at substantial personal cost. Although there is significant potential for 'informal mhealth' to improve (rural) healthcare, there is a risk that the associated moral and political economies of care will reinforce existing socioeconomic and geographic inequalities. PMID- 27476502 TI - The effectiveness of social marketing in global health: a systematic review. AB - Social marketing is a commonly used strategy in global health. Social marketing programmes may sell subsidized products through commercial sector outlets, distribute appropriately priced products, deliver health services through social franchises and promote behaviours not dependent upon a product or service. We aimed to review evidence of the effectiveness of social marketing in low- and middle-income countries, focusing on major areas of investment in global health: HIV, reproductive health, child survival, malaria and tuberculosis. We searched PubMed, PsycInfo and ProQuest, using search terms linking social marketing and health outcomes for studies published from 1995 to 2013. Eligible studies used experimental or quasi-experimental designs to measure outcomes of behavioural factors, health behaviours and/or health outcomes in each health area. Studies were analysed by effect estimates and for application of social marketing benchmark criteria. After reviewing 18 974 records, 125 studies met inclusion criteria. Across health areas, 81 studies reported on changes in behavioural factors, 97 studies reported on changes in behaviour and 42 studies reported on health outcomes. The greatest number of studies focused on HIV outcomes (n = 45) and took place in sub-Saharan Africa (n = 67). Most studies used quasi experimental designs and reported mixed results. Child survival had proportionately the greatest number of studies using experimental designs, reporting health outcomes, and reporting positive, statistically significant results. Most programmes used a range of methods to promote behaviour change. Programmes with positive, statistically significant findings were more likely to apply audience insights and cost-benefit analyses to motivate behaviour change. Key evidence gaps were found in voluntary medical male circumcision and childhood pneumonia. Social marketing can influence health behaviours and health outcomes in global health; however evaluations assessing health outcomes remain comparatively limited. Global health investments are needed to (i) fill evidence gaps, (ii) strengthen evaluation rigour and (iii) expand effective social marketing approaches. PMID- 27476504 TI - High-density SNP-based genetic map for Odontobutis potamophila. PMID- 27476503 TI - Dynamic expression of the mouse orthologue of the human amyotropic lateral sclerosis associated gene C9orf72 during central nervous system development and neuronal differentiation. AB - The hexanucleotide repeat in the first intron of the C9orf72 gene is the most significant cause of amyotropic lateral sclerosis as well as some forms of fronto temporal dementia. The C9orf72 protein has been previously reported to be expressed in post-mortem human brain as well as in late embryonic and some postnatal stages in mice. Herein, we present a detailed study of the distribution of C9orf72 protein in the embryonic, postnatal and adult mouse brain, spinal cord as well as during the differentiation of P19 embryonal carcinoma cells to neurons including motor neurons. We show that the expression levels of the C9orf72 transcripts in the developing and adult mouse brain as well as in differentiating neurons, are dynamic. Besides the strong expression in the cerebellum and motor cortex reported previously, we show for the first time that C9orf72 is expressed strongly in the olfactory bulb and also in the hippocampus. Our immunostaining data also reveal a hitherto unreported switch in the cellular distribution of C9orf72 from a predominantly cytoplasmic to a nucleo-cytoplasmic distribution during corticogenesis. This switch in distribution was also observed during differentiation of the pluripotent embryonal carcinoma P19 cell line to mature neurons. Our findings have implications for interpreting the pathophysiology caused by the repeat expansions in C9orf72 in mouse models. PMID- 27476505 TI - The influence of tutor training for peer tutors in the dissection course on the learning behavior of students. AB - INTRODUCTION: Student tutors in the dissection course are expected to meet high demands in their job, to fulfill these expectations they receive training. Combined tutor training is well accepted by tutors and tutees, however, it is not known how tutor training influences student learning. Deduced from the learning goals of the tutor training, a randomized, controlled, single-blinded study was set up with a quantitative cross-sectional analysis to compare student learning behavior. METHODS: A total of 197 medical students, coached either by ten trained or ten untrained tutors, were enlisted in the study. To assess the students' learning behavior we employed the LIST questionnaire. A common factor analysis was calculated to extract dimensions. Factor scores of the extracted dimensions were calculated for both groups to estimate differences in learning behavior. RESULTS: Factor analysis of the LIST questionnaire revealed eight factors explaining 47.57% of the overall variance. The eight factors comprise: deep learning, attention, learning organization, cooperative learning, time management, learning effort, superficial learning and learning environment. Comparing the factor scores of the extracted dimensions, students coached by trained tutors learned significantly more with their fellow students (factor score in cooperative learning 0.194 vs. -0.205, p<0.05), than students trained by untrained tutors. Students coached by trained tutors also tend to be better organized in their learning (factor score in learning organization 0.115 vs. 0.122, p=0.16). CONCLUSION: The learning behavior of students coached by trained tutors differs from the learning behavior of students coached by untrained tutors. Students coached by trained tutors learn significantly more often in teams than their colleagues and are better organized. PMID- 27476506 TI - Comparison between autologous blood transfusion drainage and closed-suction drainage/no drainage in total knee arthroplasty: a meta-analysis. AB - BACKGROUND: Autologous blood transfusion (ABT) drainage system is a new unwashed salvaged blood retransfusion system for total knee replacement (TKA). However, whether to use ABT drainage, closed-suction (CS) drainage or no drainage in TKA surgery remains controversial. This is the first meta-analysis to assess the clinical efficiency, safety and potential advantages regarding the use of ABT drains compared with closed-suction/no drainage. METHODS: PubMed, Embase, and the Cochrane Library were comprehensively searched in March 2015. Fifteen randomized controlled trials (RCTs) were identified and pooled for statistical analysis. The primary outcome evaluated was homologous blood transfusion rate. The secondary outcomes were post-operative haemoglobin on days 3-5, length of hospital stay and wound infections after TKA surgery. RESULTS: The pooled data included 1,721 patients and showed that patients in the ABT drainage group might benefit from lower blood transfusion rates (16.59 % and 37.47 %, OR: 0.28 [0.14, 0.55]; 13.05 % and 16.91 %, OR: 0.73 [0.47,1.13], respectively). Autologous blood transfusion drainage and closed-suction drainage/no drainage have similar clinical efficacy and safety with regard to post-operative haemoglobin on days 3-5, length of hospital stay and wound infections. CONCLUSIONS: Autologous blood transfusion drainage offers a safe and efficient alternative to CS/no drainage with a lower blood transfusion rate. Future large-volume high-quality RCTs with extensive follow-up will affirm and update this system review. PMID- 27476509 TI - Inclusion body hepatitis associated with an outbreak of fowl adenovirus type 2 and type 8b in broiler flocks in South Africa. AB - Inclusion body hepatitis is an acute disease of chickens ascribed to viruses of the genus Aviadenovirus and referred to as fowl adenovirus (FAdV). There are 12 FAdV types (FAdV1to FAdV8a and FAdV8b to FAdV11), classified into five species based on their genotype (designated FAdVA to FAdVE). A total of 218 000 chickens, 2-29 days of age, were affected over a 1-year period, all testing positive by microscopy, virus isolation and confirmation with polymerase chain reaction (PCR). Affected birds were depressed, lost body weight,were weak and had watery droppings. Pathological changes observed during necropsy indicated consistent changes in the liver, characterised by hepatomegaly, cholestasis and hepatitis. Lesions were also discernible in the spleen, kidney and gizzard wall and were characterised by splenomegaly, pinpoint haemorrhages, nephritis with haemorrhage,visceral gout and serosal ecchymosis of the gizzard wall. Histopathological lesions were most consistently observed in the liver but could also be seen in renal and splenic tissue. Virus isolation was achieved in embryonated eggs and most embryos revealed multifocalto diffuse hepatic necrosis, with a mixed cellular infiltrate of macrophages and heterophils(necro granulomas), even in the absence of macroscopic pathology. Virus isolation results were verified by histopathology and PCR on embryonic material and further characterised by nucleotide sequence analysis. Two infectious bursal disease virus isolates were also made from the Klerksdorp flock. Nucleotide sequence analysis of the L1 hexon loop of all the FAdV isolates indicated homology (99%) with prototype strains P7-A for FAdV-2, as well as for FAdV-8b. PMID- 27476512 TI - Effect of Phytosterols on the Crystallization Behavior of Oil-in-Water Milk Fat Emulsions. AB - Milk has been used commercially as a carrier for phytosterols, but there is limited knowledge on the effect of added plant sterols on the properties of the system. In this study, phytosterols dispersed in milk fat at a level of 0.3 or 0.6% were homogenized with an aqueous dispersion of whey protein isolate (WPI). The particle size, morphology, zeta-potential, and stability of the emulsions were investigated. Emulsion crystallization properties were examined through the use of differential scanning calorimetry (DSC) and Synchrotron X-ray scattering at both small and wide angles. Phytosterol enrichment influenced the particle size and physical appearance of the emulsion droplets, but did not affect the stability or charge of the dispersed particles. DSC data demonstrated that, at the higher level of phytosterol addition, crystallization of milk fat was delayed, whereas, at the lower level, phytosterol enrichment induced nucleation and emulsion crystallization. These differences were attributed to the formation of separate phytosterol crystals within the emulsions at the high phytosterol concentration, as characterized by Synchrotron X-ray measurements. X-ray scattering patterns demonstrated the ability of the phytosterol to integrate within the milk fat triacylglycerol matrix, with a concomitant increase in longitudinal packing and system disorder. Understanding the consequences of adding phytosterols, on the physical and crystalline behavior of emulsions may enable the functional food industry to design more physically and chemically stable products. PMID- 27476513 TI - The impact of prescription opioids on all-cause mortality in Canada. AB - An influential study from the United States generated considerable discussion and debate. This study documented rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century, with clear linkages of all cause mortality to increasing rates of poisonings, suicides and chronic liver disease deaths. All of these causes of deaths are strongly related to the use of legal and illegal substances, but the study stressed the importance of prescription opioids. Given the similarities between the United States and Canada in prescription opioid use, the assessment of similar all-cause mortality trends is relevant for Canada. As this commentary highlights, the all-cause mortality shifts seen in the United States cannot be seen in Canada for either sex or age groups. The exact reasons for the differences between the two countries are not clear, but it is important for public health to further explore this question. PMID- 27476514 TI - Continuous and Discontinuous Dynamic Crossover in Supercooled Water in Computer Simulations. AB - The dynamic crossover behavior of supercooled water as described by the first principle based WAIL potential was investigated. Below the second liquid-liquid critical point, the viscosity shows a discontinuous jump consistent with a first order phase transition between the high density liquid and the low density liquid. Above the critical point, a continuous transition occurs with only the first derivative of viscosity being discontinuous, and the dynamic crossover temperature is about 8 K below the thermodynamic switchover temperature. The 8 K shift can be explained by a delay in dynamic crossover, which does not occur until the more viscous liquid starts to dominate the population and jams the flow. On the basis of finite-size effects observed in our simulations, we believe that dynamic discontinuity may be observable above the critical point in confined water when the confinement is on a length scale shorter than the spatial correlation. PMID- 27476515 TI - Interactions of alpha-Factor-1, a Yeast Pheromone, and Its Analogue with Copper(II) Ions and Low-Molecular-Weight Ligands Yield Very Stable Complexes. AB - alpha-Factor-1 (WHWLQLKPGQPMY), a peptidic pheromone of Saccharomyces cerevisiae yeast, contains a XHX type copper(II) binding N-terminal site. Using a soluble analogue, WHWSKNR-amide, we demonstrated that the W(1)H(2)W(3) site alone binds copper(II) with a Kd value of 0.18 pM at pH 7.4 and also binds imidazole (Im) in a ternary complex (Kd of 1 mM at pH 7.4). This interaction boosts the ability of the peptide to sequester copper(II) depending on the Im concentration up to a subfemtomolar range, not available for any oligopeptidic system studied before. Therefore, alpha-factor-1 and other XHX-type peptides are likely copper(II) carriers in biological systems. PMID- 27476516 TI - Recent advances in spinal cord stimulation for pain treatment. AB - Traditional (40-50 Hz) spinal column stimulation is an efficacious and widely accepted treatment for chronic neuropathic pain conditions. However, there are major challenges including its ineffectiveness for axial back pain, the burden of paresthesia-related discomfort and difficulties producing indisputable research. Recently, there have been the major technological innovations of high-frequency and burst stimulation. Studies have shown these to provide improved analgesia even for axial pain without the problems associated with paresthesia. Dorsal root ganglion stimulation may be useful in certain subsets of patients with dermatomal distribution of pain. Other scientific data and technological improvements such as recent research on cost-effectiveness, MRI compatibility and very recent advances in spinal column stimulation are appraised. PMID- 27476517 TI - [Up to date lipid lowering treatment]. AB - Considerable evidence suggests that "the lower the better" is a reasonable approach for reducing cardiovascular risk by lowering LDL cholesterol levels. Despite the reduction in cardiovascular events and mortality achieved by statin therapy, significant residual risk remains, especially in severe hereditary hypercholesterolemia, such as familial hypercholesterolemia. Some new strategies to achieve even lower LDL levels are now available, including the addition of cholesterol absorption inhibitor ezetimibe, and the recently available Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies. In addition, new LDL drugs may be effectively administrated in those individuals who are unable to tolerate statins. The authors summarize the efficacy and clinical indications of these new agents and review the currently available guidelines. Orv. Hetil., 2016, 157(31), 1219-1223. PMID- 27476518 TI - [Physiotherapy of cancer patients]. AB - Physiotherapy of cancer patients is one of the most controversial issues in our country. Malignant diseases are firstly mentioned as a contraindication of physiotherapy. Until now, physiotherapy was not suggested (or only in limited accessibility) for those patients who had malignant disease in medical history. International medical practice was less restrictive in managing this topic. The development of imaging techniques put this question in a new light. On the basis of evidence, the majority of articles have reported beneficial effects of physiotherapy in cancer patients, and only few articles mentioned it as harmful. Of course, each patient requires an individual assessment, however, if we exclude the possibility of tumor recurrence and metastasis, most of physiotherapy procedures can be used safely. One of the aims of this review is to support the physicians' decisions when to prescribe treatments, in such a way, that more patients could receive physiotherapy. Orv. Hetil., 2016, 157(31), 1224-1231. PMID- 27476519 TI - [Recent advances in the understanding and treatment of diffuse large B-cell lymphoma]. AB - Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. Using the conventional cyclophosphamide adriablastin vincristin prednisolon polychemotherapy about 50% of the patients were cured. The addition of rituximab to the regimen increased the cure rate to 60%. This is a major improvement, however, further advance is still needed to increase the cure rate. The extensive genetic testing performed recently revealed several important pathognomic mutations as potential targets in this disease. Routine diagnosis of patients now includes the use of (18)Fluor-deoxy-glucose positron emission computer tomography, according to the recent Lugano classification system. With all these data we can better predict the prognosis of patients, and we can select candidates for novel targeted therapies as well. Answering these questions, and utilizing novel therapies possibly will further increase the cure rate in the near future. This paper summarizes current diagnostic and therapeutic approaches and describes recent understanding in the mutations and pathognomic changes resulting in the disease. The authors also summarize the data available on experimental therapies possibly entering clinical pratice in the forthcoming years. Orv. Hetil., 2016, 157(31), 1232-1241. PMID- 27476520 TI - [Vitamin D and calcium in the mirror of clinical evidence]. AB - The biological mechanisms, ecological and observational studies indicate increased morbidity and mortality in vitamin D deficiency, while the controlled, randomized supplementation trials - carried out mostly in vitamin D deficient patients - have shown no or some marginal benefits, mostly in preventing institutionalized elderly individuals' falls and fractures. Clarity is also disturbed by that the primary end points of intervention studies were generally not extraskeletal. The ideal serum 25-hydroxyvitamin D levels also considerably controversial: there is clearly a J-curve, but the optimal range is uncertain. All of these uncertainties appear also in the vitamin D guidelines which are, however, concordant in that they do not recommend (i) a population-wide screening and (ii) vitamin D supplementation with extraskeletal aim - beyond the prevention of falls. Certain studies suggest that calcium supplementation increases the incidence of cardiovascular events, while others show a neutral effect in this respect. There are several ongoing vitamin D studies directly designed for extraskeletal events. Orv. Hetil., 2016, 157(31), 1242-1247. PMID- 27476522 TI - [Miscellaneous]. PMID- 27476521 TI - [Obese Hungary. Trend and prevalence of overweight and obesity in Hungary, 2015]. AB - INTRODUCTION: The prevalence of obesity is growing continuously worldwide, even in Hungary. Since 1988, when the first professional wide-range evaluation was performed, only limited data are available. AIM: Authors present the results of the ever largest Hungarian obesity-prevalence surveys, performed by family and occupational physicians. METHOD: Data from 0.55% of the population above 18 year were registered in all geographical regions of Hungary (43,287 persons; 17,901 males and 25,386 females), close to the proper national representativeness. Age, body mass index, waist circumference, educational level, presence of hypertension and/or diabetes were analyzed statistically and compared with previous data. RESULTS: The overall prevalence rate of overweight and obesity among men was 40% and 32%, respectively, while overweight and obesity occurred in 32% of women. In the different age groups of men, the prevalence of overweight and obesity was: 32.7% and 18.2% in 18-34 years; 40.1% and 34.4% in 35-59 years; 43.5% and 38.8% in over 60 years, respectively. In the same age groups of women, overweight and obesity occurred in 19.6% and 15.7%, 36.8% and 38.7%, and 36.5% and 39.7%, respectively. Body mass index and waist-circumference were presented according to age, by decades and by type of residency as well. The highest ratio of overweight was registered among men with the highest educational level, while highest ratio of obesity among women having the lowest education. Obesity according to Body mass index and abdominal obesity was the highest in the villages, especially among females. Registered metabolic morbidities were strongly correlated with body mass index and both were inversely related to the level of urbanization. CONCLUSIONS: Over the previous decades, the ratio of the overweight and even the number of obese persons increased significantly, and it was most prominent among males, mainly in younger generation. Obesity means a serious medical, public health and economic problem, and it requires higher public awareness and political support. Orv. Hetil., 2016, 157(31), 1248-1255. PMID- 27476523 TI - Serum prealbumin is a predictive biomarker for stroke-associated infection after an ischemic stroke. AB - BACKGROUND: Several prior studies have linked serum prealbumin (PA) as a predictor for perioperative infection. However, whether peripheral blood PA levels can be used as an indicator of stroke-associated infection (SAI) is still unclear. In this study, we attempt to find whether serum PA is a meaningful predictor in SAI after an ischemic stroke, so as to provide theoretical basis for clinical treatment. METHODS: Consecutive patients with acute ischemic stroke who were admitted to our hospital were enrolled and serum PA was collected. A prospective study was conducted to observe the predictive value of PA in the SAI incident in ischemic stroke patients. RESULTS: Of 104 patients, 29 (27.9%) developed an SAI after 7 d of follow-up. The stroke with SAI group had significantly lower PA levels than the stroke without SAI group ( p < 0.05). The optimal cutoff value for predicting SAI was PA <= 191 mg/L, with sensitivity and specificity of 58.62% and 81.33%, respectively. Kaplan-Meier survival analysis showed that stroke patients with low serum PA level (PA <= 191 mg/L) had a higher SAI rates (log-rank test, chi2 = 16.870, p < 0.001). Cox regression analysis showed that PA <= 191 mg/L (hazard ratio = 3.207; 95% CI, 1.430-7.190, p = 0.005) was an independent risk factor for SAI. CONCLUSIONS: Early detection of serum PA during the acute phase of ischemic stroke may help us to identify at-risk SAI patients, and hence rapidly guide the intervention to prevent SAI. PMID- 27476524 TI - The men with broken faces. Gueules cassees of the first world war. PMID- 27476525 TI - Short-term performance peaking in an elite cross-country mountain biker. AB - Endurance athletes usually achieve performance peaks with 2-4 weeks of overload training followed by 1-3weeks of tapering. With a tight competition schedule, this may not be appropriate. This case investigates the effect of a 7-day overload period including daily high-intensity aerobic training followed by a 5 day step taper between two competitions in an elite cross-country mountain biker. Pre-test peak oxygen consumption was 89 ml.kg-1.min-1, peak aerobic power 6.8 W.kg-1, power output at 2 mmol.L-1 blood lactate concentration 3.9 W.kg-1, maximal isometric force 180 Nm and squat jump 21 cm. During overload, perceived leg well-being went from normal to very heavy. On day 1 after overload, vastus lateralis and vastus medialis EMGmean activity was reduced by 3% and 7%, respectively. Other baseline measurements were reduced by 3-7%. On day 4 of the taper, he felt that his legs were good and all measurements were 3-7% higher than before overload. On day 6 after the taper, his legs felt very good. This case shows that an elite mountain biker (11th in UCI World Cup one week prior to the pre-test) could achieve a rather large supercompensation by using a 12-day performance peaking protocol. PMID- 27476526 TI - Reconstruction with latissimus dorsi, external abdominal oblique and cranial sartorius muscle flaps for a large defect of abdominal wall in a dog after surgical removal of infiltrative lipoma. AB - This animal was presented with a large-sized infiltrative lipoma in the abdominal wall that had been noted for 4 years. This lipoma was confirmed by histological examination from a previous biopsy, and the infiltrative features were identified by a computerized tomography scan. The surgical removal created a large-sized abdominal defect that was closed by a combination of latissimus dorsi and external abdominal oblique muscle flaps in a pedicle pattern. A small dehiscence at the most distal end of the muscle flap resulted in a small-sized abdominal hernia and was repaired with cranial sartorius muscle flap 14 days after surgery. The dog was in good general health with no signs of tumor recurrence after 18 months of follow-up. PMID- 27476527 TI - Effects of Bu-Shen-Ning-Xin Decoction on immune cells of the spleen and bone marrow in ovariectomized mice. AB - Osteoimmunology is a new discipline that focuses on the interaction between the bones and the immune system. Immune cells play an important role in bone metabolism. The aim of this study was to illustrate the effect of Bu-Shen-Ning Xin Decoction (BSNXD) on lymphocytes in the spleen and bone marrow to explore the potential role on the bone. C57BL/6 mice were divided into four groups: sham, ovariectomized (OVX), OVX+BSNXD, and OVX+ estrogen. The sham and OVX groups were treated with saline, the OVX+BSNXD group was treated with BSNXD, and the OVX+ estrogen group was treated with estrogen. After mice were sacrificed, the spleens and bones were collected, and the lymphocytes in the spleen and bone marrow were analyzed. We found that BSNXD lessened the extent of the increase of CD4+ and bone marrow. In contrast, these numbers were both increased in the OVX group. BSNXD had no influence on the percentage of gammadelta T cells. However, it increased the proportion of NK cells in the spleen and bone marrow. BSNXD lessened the extent of the increase of monocytes by ovariectomy. In vitro experiment, we found Tregs can decrease osteoclastogenesis when co-cultured with osteoclast precursor cells. This study suggests that BSNXD changes the immune environment and immune cells have a role in bone metabolism in OVX mice. PMID- 27476528 TI - Prevalence of Vitamin D Deficiency and Calcium Homeostasis in Saudi Children. AB - OBJECTIVE: Vitamin D deficiency (VDD) and vitamin D insufficiency (VDI) are significant health problems all over the world. The aim of this study was to determine the prevalence of VDD and VDI in children and adolescents residing in 8 provinces in the Kingdom of Saudi Arabia and to also investigate calcium homeostasis in these subjects. METHODS: A cross-sectional study was conducted in 2110 participants aged between 6 and 15 years. Information on socio-demographic status, anthropometric measurements, knowledge about vitamin D, color of the skin, dietary intake, sun exposure experience, smoking, and physical activity were collected through a questionnaire given to the parents of all subjects. The subjects were divided into three groups as vitamin D deficient, vitamin D insufficient, and vitamin sufficient according to their blood level of vitamin D [VDD <=25 nmol/L (25 hydroxy vitamin D), VDI >25-50 nmol/L, and VDS >50 nmol/L]. RESULTS: VDD was highly prevalent in this group of children. 95.3 of the subjects had either VDD (45.5%) or VDI (49.9%). The prevalence rate of VDD combined with VDI was higher in females (97.8%) compared to males (92.8%) (p<0.001). Only 1.6% had significant hypocalcaemia. Children with dark skin had lower concentrations of vitamin D and higher concentrations of parathormone. A positive correlation was observed between 25 hydroxy vitamin D level and serum calcium, inorganic phosphate, and alkaline phosphatase concentrations. onclusion: The results showed a high prevalence of VDD and VDI in Saudi children with significantly higher prevalence in girls. These findings necessitate the set-up of a national program for vitamin D supplementation and health education for this vulnerable group. PMID- 27476529 TI - Learning from other people's fear: amygdala-based social reference learning in social anxiety disorder. AB - BACKGROUND: Social anxiety disorder involves fear of social objects or situations. Social referencing may play an important role in the acquisition of this fear and could be a key determinant in future biomarkers and treatment pathways. However, the neural underpinnings mediating such learning in social anxiety are unknown. Using event-related functional magnetic resonance imaging, we examined social reference learning in social anxiety disorder. Specifically, would patients with the disorder show increased amygdala activity during social reference learning, and further, following social reference learning, show particularly increased response to objects associated with other people's negative reactions? METHOD: A total of 32 unmedicated patients with social anxiety disorder and 22 age-, intelligence quotient- and gender-matched healthy individuals responded to objects that had become associated with others' fearful, angry, happy or neutral reactions. RESULTS: During the social reference learning phase, a significant group * social context interaction revealed that, relative to the comparison group, the social anxiety group showed a significantly greater response in the amygdala, as well as rostral, dorsomedial and lateral frontal and parietal cortices during the social, relative to non-social, referencing trials. In addition, during the object test phase, relative to the comparison group, the social anxiety group showed increased bilateral amygdala activation to objects associated with others' fearful reactions, and a trend towards decreased amygdala activation to objects associated with others' happy and neutral reactions. CONCLUSIONS: These results suggest perturbed observational learning in social anxiety disorder. In addition, they further implicate the amygdala and dorsomedial prefrontal cortex in the disorder, and underscore their importance in future biomarker developments. PMID- 27476531 TI - Controlling film topography to form highly hydrophobic waterborne coatings. AB - Coatings have a tremendous impact on economy as they reduce corrosion that has an estimated cost of 3% of the world's GDP. Hydrophobic coatings are particularly efficient for this purpose and the challenge is to produce cost effective and environmentally friendly, highly hydrophobic, cohesive and non-porous coatings applicable to large and irregular surfaces. This work shows that this goal can be achieved by forming wrinkles on the surface of waterborne coatings through fine tuning of the film forming conditions. The proof of concept was demonstrated by using waterborne dispersions of copolymers of 1H,1H,2H,2H-perfluorodecyl acrylate and 2-ethylhexyl acrylate, and using the temperature and hardness of the copolymer as control variables during film formation. This allowed the formation of transparent films with a wrinkled surface that had a contact angle of 133 degrees , which represents an increase of 20 degrees with respect to the film cast under standard conditions. PMID- 27476532 TI - Breathing mode vibrations and elastic properties of single-crystal and penta twinned gold nanorods. AB - The acoustic vibrations of individual single-crystal and penta-twinned gold nanorods with widths from ~7 to ~26 nm are studied using atomic-level simulations and finite element calculations. It is demonstrated that the continuum model in the limit of an infinite rod length could be used to describe the breathing periods of nanorods with an aspect ratio as small as ~2.5, in combination with bulk material elastic constants. The elastic moduli of gold nanorods are determined via their atomistically simulated extensional periods and the dispersion relation based on long-wavelength approximation. The twinned nanorods become stiffer as the width is reduced, which is in contrast to the size dependence of the modulus in single-crystal nanorods. Further finite element calculations for the breathing periods of nanorods are performed using isotropic elastic constants of bulk gold. We find that the breathing vibrations of the penta-twinned nanorods are more affected by the crystal structure effect than those of single-crystal nanorods, because a smaller range of crystal directions perpendicular to the long axis is involved in the breathing vibrations of twinned nanorods. PMID- 27476530 TI - Common disease signatures from gene expression analysis in Huntington's disease human blood and brain. AB - BACKGROUND: Huntington's disease (HD) is a devastating brain disorder with no effective treatment or cure available. The scarcity of brain tissue makes it hard to study changes in the brain and impossible to perform longitudinal studies. However, peripheral pathology in HD suggests that it is possible to study the disease using peripheral tissue as a monitoring tool for disease progression and/or efficacy of novel therapies. In this study, we investigated if blood can be used to monitor disease severity and progression in brain. Since previous attempts using only gene expression proved unsuccessful, we compared blood and brain Huntington's disease signatures in a functional context. METHODS: Microarray HD gene expression profiles from three brain regions were compared to the transcriptome of HD blood generated by next generation sequencing. The comparison was performed with a combination of weighted gene co-expression network analysis and literature based functional analysis (Concept Profile Analysis). Uniquely, our comparison of blood and brain datasets was not based on (the very limited) gene overlap but on the similarity between the gene annotations in four different semantic categories: "biological process", "cellular component", "molecular function" and "disease or syndrome". RESULTS: We identified signatures in HD blood reflecting a broad pathophysiological spectrum, including alterations in the immune response, sphingolipid biosynthetic processes, lipid transport, cell signaling, protein modification, spliceosome, RNA splicing, vesicle transport, cell signaling and synaptic transmission. Part of this spectrum was reminiscent of the brain pathology. The HD signatures in caudate nucleus and BA4 exhibited the highest similarity with blood, irrespective of the category of semantic annotations used. BA9 exhibited an intermediate similarity, while cerebellum had the least similarity. We present two signatures that were shared between blood and brain: immune response and spinocerebellar ataxias. CONCLUSIONS: Our results demonstrate that HD blood exhibits dysregulation that is similar to brain at a functional level, but not necessarily at the level of individual genes. We report two common signatures that can be used to monitor the pathology in brain of HD patients in a non-invasive manner. Our results are an exemplar of how signals in blood data can be used to represent brain disorders. Our methodology can be used to study disease specific signatures in diseases where heterogeneous tissues are involved in the pathology. PMID- 27476533 TI - Endocrine-specific NIR fluorophores for adrenal gland targeting. AB - The adrenal glands (AGs) are relatively small yet require definitive identification during their resection, or more commonly their avoidance. To enable image-guided surgery involving the AGs, we have developed novel near infrared (NIR) fluorophores that target the AGs after a single intravenous injection, which provided dual-NIR image-guided resection or avoidance of the AGs during both open and minimally-invasive surgery. PMID- 27476534 TI - Distinct roles of a tyrosine-associated hydrogen-bond network in fine-tuning the structure and function of heme proteins: two cases designed for myoglobin. AB - A hydrogen-bond (H-bond) network, specifically a Tyr-associated H-bond network, plays key roles in regulating the structure and function of proteins, as exemplified by abundant heme proteins in nature. To explore an approach for fine tuning the structure and function of artificial heme proteins, we herein used myoglobin (Mb) as a model protein and introduced a Tyr residue in the secondary sphere of the heme active site at two different positions (107 and 138). We performed X-ray crystallography, UV-Vis spectroscopy, stopped-flow kinetics, and electron paramagnetic resonance (EPR) studies for the two single mutants, I107Y Mb and F138Y Mb, and compared to that of wild-type Mb under the same conditions. The results showed that both Tyr107 and Tyr138 form a distinct H-bond network involving water molecules and neighboring residues, which fine-tunes ligand binding to the heme iron and enhances the protein stability, respectively. Moreover, the Tyr107-associated H-bond network was shown to fine-tune both H2O2 binding and activation. With two cases demonstrated for Mb, this study suggests that the Tyr-associated H-bond network has distinct roles in regulating the protein structure, properties and functions, depending on its location in the protein scaffold. Therefore, it is possible to design a Tyr-associated H-bond network in general to create other artificial heme proteins with improved properties and functions. PMID- 27476535 TI - Post-combustion carbon dioxide capture cost reduction to 2030 and beyond. AB - Post-combustion CO2 capture (PCC) can be achieved using a variety of technologies. Importantly it is applicable to a wide range of processes and may also be retrofitted in certain cases. This paper covers the use of PCC for low carbon power generation from new natural gas combined cycle (NGCC) plants that are expected to be built in the UK in the 2020s and 2030s and that will run into the 2050s. Costs appear potentially comparable with other low carbon and controllable generation sources such as nuclear or renewables plus storage, especially with the lower gas prices that can be expected in a carbon-constrained world. Non-fuel cost reduction is still, however, desirable and, since CO2 capture is a new application, significant potential is likely to exist. For the NGCC+PCC examples shown in this paper, moving from 'first of a kind' (FOAK) to 'nth of a kind' (NOAK) gives significant improvements through both reduced financing costs and capital cost reductions. To achieve this the main emphasis needs to be on 'commercial readiness', rather than on system-level 'technical readiness', and on improvements through innovation activities, supported by underpinning research, that develop novel sub-processes; this will also maintain NOAK status for cost-effective financing. Feasible reductions in the energy penalty for PCC capture have much less impact, reflecting the inherently high levels of efficiency for modern NGCC+PCC plants. PMID- 27476536 TI - The doubly-bonded ditungsten anion [W2Cp2(MU-PPh2)(NO)2](-): an entry to the chemistry of unsaturated nitrosyl complexes. AB - Complex [W2Cp2(MU-I)(MU-PPh2)(NO)2] was prepared by reacting [W2Cp2(MU-I)(MU PPh2)(CO)2] with NO at 233 K followed by decarbonylation in refluxing toluene. It was reduced by Na(Hg) in acetonitrile to give Na[W2Cp2(MU-PPh2)(NO)2], the first anionic nitrosyl complex featuring a metal-metal double bond (computed W-W = 2.580 A). Reactions of the latter anion with (NH4)PF6 and [AuCl{P(p-tol)3}] gave the hydride [W2Cp2(MU-H)(MU-PPh2)(NO)2] and the cluster [AuW2Cp2(MU PPh2)(NO)2{P(p-tol)3}] respectively, also featuring multiple W-W bonding (experimental W-W ca. 2.75 A), and its reaction with S8 yielded the electron precise derivative Na[W2Cp2(MU-PPh2)(MU-S)(NO)2], which was methylated by Me2SO4 to give the thiolate complex [W2Cp2(MU-PPh2)(MU-SMe)(NO)2]. PMID- 27476537 TI - EQClinic: a platform for learning communication skills in clinical consultations. AB - BACKGROUND: Doctors' verbal and non-verbal communication skills have an impact on patients' health outcomes, so it is important for medical students to develop these skills. Traditional, non-verbal communication skills training can involve a tutor manually annotating a student's non-verbal behaviour during patient-doctor consultations, but this is very time-consuming. Tele-conference systems have been used in verbal communication skills training. METHODS: We describe EQClinic, a system that enables verbal and non-verbal communication skills training during tele-consultations with simulated patients (SPs), with evaluation exercises promoting reflection. Students and SPs can have tele-consultations through the tele-consultation component. In this component, SPs can provide feedback to students through a thumbs-up/ thumbs-down tool and a comments box. EQClinic automatically analyses communication features in the recorded consultations, such as facial expressions, and provides graphical representations. Our 2015 pilot study investigated whether EQClinic helped students be aware of their non-verbal behaviour and improve their communication skills, and evaluated the usability of the platform. Students received automated feedback, and SP and tutor evaluations, and then completed self-assessment and reflection questionnaires. RESULTS: Eight medical students and three SPs conducted 13 tele-consultations using EQClinic. More students paid attention to their non-verbal communication and students who were engaged in two consultations felt more confident in their second consultation. Students rated the system positively, felt comfortable using it (5.9/7), and reported that the structure (5.4/7) and information (5.8/7) were clear. This pilot provides evidence that EQClinic helps, and positively influences, medical students practise their communication skills with SPs using a tele-conference platform. DISCUSSION: It is not easy to improve non-verbal communication skills in a short time period. Further evaluation of EQClinic with larger numbers will ascertain learning gains and application in health professional training. Developing a standard model for the assessment of non verbal behaviour in tele-consultations and providing students with more valuable evaluation and suggestions are part of our future work. PMID- 27476538 TI - A meaningful MESS (Medical Education Scholarship Support). AB - BACKGROUND: Graduate medical education faculty bear the responsibility of demonstrating active research and scholarship; however, faculty who choose education-focused careers may face unique obstacles related to the lack of promotion tracks, funding, career options, and research opportunities. Our objective was to address education research and scholarship barriers by providing a collaborative peer-mentoring environment and improve the production of research and scholarly outputs. METHODS: We describe a Medical Education Scholarship Support (MESS) group created in 2013. MESS is an interprofessional, multidisciplinary peer-mentoring education research community that now spans multiple institutions. This group meets monthly to address education research and scholarship challenges. Through this process, we develop new knowledge, research, and scholarly products, in addition to meaningful collaborations. RESULTS: MESS originated with eight founding members, all of whom still actively participate. MESS has proven to be a sustainable unfunded local community of practice, encouraging faculty to pursue health professions education (HPE) careers and fostering scholarship. We have met our original objectives that involved maintaining 100% participant retention; developing increased knowledge in at least seven content areas; and contributing to the development of 13 peer reviewed publications, eight professional presentations, one Masters of Education project, and one educational curriculum. DISCUSSION: The number of individuals engaged in HPE research continues to rise. The MESS model could be adapted for use at other institutions, thereby reducing barriers HPE researchers face, providing an effective framework for trainees interested in education-focused careers, and having a broader impact on the education research landscape. PMID- 27476539 TI - Laxative utilization over time in chronic pain patients with opioid-induced constipation. AB - AIM: To determine laxative utilization over time among chronic noncancer pain patients with opioid-induced constipation (OIC). SETTING: A prospective longitudinal study conducted in the USA, Canada, Germany and UK. METHODS: Patients on daily opioid therapy for treatment of chronic noncancer pain with OIC were recruited from clinics to complete a survey at Baseline and weeks 2, 4, 6, 8, 12, 16, 20 and 24. RESULTS: 489 patients completed baseline with 452 completing one or more follow-up visits. 128 (28%) were nonlaxative users, 112 (25%) were insufficient laxative users and 212 (47%) were sufficient laxative users. The consistent sufficient laxative users reported the most bowel movements per week. CONCLUSION: The majority of OIC patients do not take or only intermittently take laxatives. PMID- 27476540 TI - Severe neurological manifestations in an Egyptian patient with a novel frameshift mutation in the Glutaryl-CoA dehydrogenase gene. AB - To characterize an Egyptian patient with glutaric acidemia type I (GA I) and to identify the causative mutation(s) that may be responsible for the disease phenotype. MRI was performed on the patient using the 1.5 T magnet, biochemical analysis was carried out using gas chromatography/mass spectrometry on the patient's dried blood spot, and the patient's organic acids were measured in dried blood and a urine sample using MS/MS and GC/MS, respectively. Total RNA was isolated from the patient's peripheral blood, and the synthesized cDNA was bi directionally sequenced. The patient exhibited clinical features and MRI findings compatible with a diagnosis of GA I. The abnormal elevation of organic acids in the urine supported the presence of glutaryl-CoA dehydrogenase deficiency. Gene sequencing revealed a novel homozygous frameshift mutation, c.644_645insCTCG; p.(Pro217Leufs*14), in exon 8 of the GCDH gene. The present study revealed a novel frameshift mutation responsible for a severe GA I phenotype in an Egyptian patient. This novel mutation will ultimately contribute to a better understanding of the molecular pathology of the disease and shed light on the intricacies of the genotype-phenotype correlation of GA I disease. PMID- 27476541 TI - Studying neuroprotective effect of Atorvastatin as a small molecule drug on high glucose-induced neurotoxicity in undifferentiated PC12 cells: role of NADPH oxidase. AB - Overproduction of reactive oxygen species (ROS) by NADPH oxidase (NOX) activation has been considered the essential mechanism induced by hyperglycemia in various tissues. However, there is no comprehensive study on the role of NOXs in high glucose (HG)-induced toxic effect in neural tissues. Recently, a therapeutic strategy in oxidative related pathologies has been introduced by blocking the undesirable actions of NOX enzymes by small molecules. The protective roles of Statins in ameliorating oxidative stress by NOX inhibition have been shown in some tissues except neural. We hypothesized then, that different NOXs may have role in HG-induced neural cell injury. Furthermore, we postulate that Atorvastatin as a small molecule may modulate this NOXs activity to protect neural cells. Undifferentiated PC12 cells were treated with HG (140 mM/24 h) in the presence and absence of Atorvastatin (1 MUM/96 h). The cell viability was measured by MTT assay and the gene and protein expressions profile of NOX (1-4) were determined by RT-PCR and western blotting, respectively. Levels of ROS and malondialdehyde (MDA) were also evaluated. Gene and protein expression levels of NOX (1-4) and consequently ROS and MDA levels were elevated in HG-treated PC12 cells. Atorvastatin could significantly decrease HG-induced NOXs, ROS and MDA elevation and improve impaired cell viability. It can be concluded that HG could elevate NOXs activity, ROS and MDA levels in neural tissues and Atorvastatin as a small molecule NOX inhibitor drug may prevent and delay diabetic complications, particularly neuropathy. PMID- 27476543 TI - Mucoadhesive niosomal in situ gel for ocular tissue targeting: in vitro and in vivo evaluation of lomefloxacin hydrochloride. AB - Eradication of ophthalmic infections depends on increasing transcorneal permeation and localizing antibiotics at ocular surface. This study aimed at formulating lomefloxacin HCl (LF) in the form of niosomes and evaluating the in vivo performance of best formula in rabbits' eyes. Vesicles were developed by mixing three surfactants at three molar ratios of 1:1, 1:2 and 1:3 of surfactant to cholesterol. Size, zeta potential, release percentage, transcorneal permeation parameters, stability studies, cytotoxicity and antibacterial activity of niosomes were determined. Niosomes showed encapsulation efficiency of more than 78%, particle size below 500 nm and zeta potential below -43.6. The produced vesicles showed significantly higher amounts of drug permeated across cornea (166%) compared to LF solution. The in vivo study showed 2-5 folds increase in drug concentration in ocular fluids and tissues following administration of niosomes compared to marketed formula (from 3.75 to 10.31 mcg/mL in the cornea). Microbiological studies showed 35 folds increase in the antibacterial activity of LF niosomes compared to free drug; where MBC decreased from 31.25 mcg/mL in case of LF solution to 0.97 mcg/mL for niosomal gel. The formulated niosomes enhanced the ocular bioavailability of LF through increasing transcorneal permeation and localizing drug at site of action. PMID- 27476544 TI - High-Capacity Drug Carriers from Common Polymer Amphiphiles. AB - We report herein a dual-purpose role for polyacidic domains in an aqueous-phase polymer amphiphile assembly. In addition to their typical role as ionized water solubilizing and self-repulsive motifs, we find that polycarboxylic acid domains uniquely enable high levels of hydrophobic drug encapsulation. By attenuated total reflectance infrared spectroscopy, we find significant differences in the carbonyl stretching region of the nanoparticles formed by polyacidic amphiphiles relative to those in soluble, single-domain poly(acrylic acid), suggesting that stabilization may be derived from limited ionization of the carboxylate groups upon assembly. Acidic-hydrophobic diblock polyacrylates were prepared and coassembled with up to 60 wt % camptothecin (CPT) into nanoparticles, the highest loading reported to date. Controlled release of bioactive CPT from polymer nanoparticles is observed, as well as protection from human serum albumin-induced hydrolysis. Surface protection with PEG limits uptake of the CPT-loaded nanoparticles by MCF-7 breast cancer cells, as expected. Acidic-hydrophobic polymer amphiphiles thus have the hallmarks of a useful and general drug delivery platform and are readily accessible from living radical polymerization of cheap, commercially available monomers. We highlight here the potential utility of this common polymer design in high-capacity, controlled-release polymer nanoparticle systems. PMID- 27476545 TI - Climate change velocity underestimates climate change exposure in mountainous regions. AB - Climate change velocity is a vector depiction of the rate of climate displacement used for assessing climate change impacts. Interpreting velocity requires an assumption that climate trajectory length is proportional to climate change exposure; longer paths suggest greater exposure. However, distance is an imperfect measure of exposure because it does not quantify the extent to which trajectories traverse areas of dissimilar climate. Here we calculate velocity and minimum cumulative exposure (MCE) in degrees Celsius along climate trajectories for North America. We find that velocity is weakly related to MCE; each metric identifies contrasting areas of vulnerability to climate change. Notably, velocity underestimates exposure in mountainous regions where climate trajectories traverse dissimilar climates, resulting in high MCE. In contrast, in flat regions velocity is high where MCE is low, as these areas have negligible climatic resistance to movement. Our results suggest that mountainous regions are more climatically isolated than previously reported. PMID- 27476546 TI - MicroRNA-16 is putatively involved in the NF-kappaB pathway regulation in ulcerative colitis through adenosine A2a receptor (A2aAR) mRNA targeting. AB - MicroRNAs (miRNAs) act as important post-transcriptional regulators of gene expression by targeting the 3'-untranslated region of their target genes. Altered expression of miR-16 is reported in human ulcerative colitis (UC), but its role in the development of the disease remains unclear. Adenosine through adenosine A2a receptor (A2aAR) could inhibit nuclear factor-kappaB (NF-kappaB) signaling pathway in inflammation. Here we identified overexpression of miR-16 and down regulation of A2aAR in the colonic mucosa of active UC patients. We demonstrated that miR-16 negatively regulated the expression of the A2aAR at the post transcriptional level. Furthermore, transfection of miR-16 mimics promoted nuclear translocation of NF-kappaB p65 protein and expression of pro-inflammatory cytokines, IFN-gamma and IL-8 in colonic epithelial cells. Treatment with miR-16 inhibitor could reverse these effects in cells. The A2aAR-mediated effects of miR 16 on the activation of the NF-kappaB signaling pathway were confirmed by the A2aAR knockdown assay. Our results suggest that miR-16 regulated the immune and inflammatory responses, at least in part, by suppressing the expression of the A2aAR to control the activation of the NF-kappaB signaling pathway. PMID- 27476548 TI - First in situ TOF-PET study using digital photon counters for proton range verification. AB - Positron emission tomography (PET) is the imaging modality most extensively tested for treatment monitoring in particle therapy. Optimal use of PET in proton therapy requires in situ acquisition of the relatively strong (15)O signal due to its relatively short half-life (~2 min) and high oxygen content in biological tissues, enabling shorter scans that are less sensitive to biological washout. This paper presents the first performance tests of a scaled-down in situ time-of flight (TOF) PET system based on digital photon counters (DPCs) coupled to Cerium doped Lutetium Yttrium Silicate (LYSO:Ce) crystals, providing quantitative results representative of a dual-head tomograph that complies with spatial constraints typically encountered in clinical practice (2 * 50 degrees , of 360 degrees , transaxial angular acceptance). The proton-induced activity inside polymethylmethacrylate (PMMA) and polyethylene (PE) phantoms was acquired within beam pauses (in-beam) and immediately after irradiation by an actively-delivered synchrotron pencil-beam, with clinically relevant 125.67 MeV/u, 4.6 * 10(8) protons s(-1), and 10(10) total protons. 3D activity maps reconstructed with and without TOF information are compared to FLUKA simulations, demonstrating the benefit of TOF-PET to reduce limited-angle artefacts using a 382 ps full width at half maximum coincidence resolving time. The time-dependent contributions from different radionuclides to the total count-rate are investigated. We furthermore study the impact of the acquisition time window on the laterally integrated activity depth-profiles, with emphasis on 2 min acquisitions starting at different time points. The results depend on phantom composition and reflect the differences in relative contributions from the radionuclides originating from carbon and oxygen. We observe very good agreement between the shapes of the simulated and measured activity depth-profiles for post-beam protocols. However, our results also suggest that available experimental cross sections underestimate the production of (10)C for in-beam acquisitions, which in PE results in an overestimation of the predicted activity range by 1.4 mm. The uncertainty in the activity range measured in PMMA using the DPC-based TOF-PET prototype setup equals 0.2 mm-0.3 mm. PMID- 27476547 TI - Ideal Cardiovascular Health and Carotid Atherosclerosis in a Mixed Cohort of HIV Infected and Uninfected Ugandans. AB - Preventable cardiovascular disease (CVD) risk factors are responsible for the majority of CVD-related deaths, and are increasingly recognized as a cause of morbidity and mortality for HIV-infected persons taking antiretroviral therapy (ART). Simplified tools such as the American Heart Association's ideal cardiovascular health (iCVH) construct may identify and prognosticate CVD risk in resource-limited settings. No studies have evaluated iCVH metrics in sub-Saharan Africa or among HIV-infected adults. Thus, the central aim of this study was to compare levels of iCVH metrics and their correlations with carotid atherosclerosis for HIV-infected adults versus uninfected controls in a well phenotyped Ugandan cohort. We analyzed the prevalence of iCVH metrics in a mixed cohort of HIV-infected persons on stable ART and uninfected, population-based comparators in Mbarara, Uganda. We also assessed the validity of iCVH by correlating iCVH values with common carotid intima media thickness (CCIMT). HIV infected persons had a mean of 4.9 (SD 1.1) iCVH metrics at ideal levels versus 4.3 (SD 1.2) for uninfected controls (p = .002). This difference was largely driven by differences in blood pressure, blood glucose, and diet. In multivariable-adjusted linear regression models, each additional iCVH metric at an ideal level was associated with a significant 0.024 mm decrease in CCIMT (p < .001).HIV-infected persons on ART in rural Uganda had more iCVH metrics at ideal levels than uninfected persons. The difference appeared driven by factors that are putatively influenced by access to routine medical care. Composite scores of iCVH metrics were associated with subclinical atherosclerosis and more predictive of atherosclerosis for uninfected persons. PMID- 27476549 TI - Effectiveness of pedalling retraining in reducing bilateral pedal force asymmetries. AB - Previous studies have been limited to describe asymmetries during pedalling and suggest possible repercussion on performance and/or injury risks. However, few studies have presented strategies to mitigate asymmetries. The purpose of this study was to assess the effectiveness of a pedalling retraining intervention to reduce bilateral pedal force asymmetries. Twenty cyclists were assessed and 10 enrolled in a pedalling retraining method receiving visual and verbal feedback of pedal forces. The asymmetry index was computed for comparison of bilateral peak pedal forces and used during retraining (12 trials at 70% of peak power). Significantly larger asymmetry was observed for asymmetrical cyclists at the first three trials (P < 0.01 and ES = 1.39), which was reduced when post retraining was compared to measures from symmetrical cyclists (P = 0.69 and ES = 0.18). Cyclists with larger asymmetry (>20%) in bilateral pedal forces reduce their asymmetries using sessions of pedalling retraining and achieve asymmetry indices similar to symmetrical cyclists. PMID- 27476550 TI - Combined effect of divergent selection for breast muscle ultimate pH and dietary amino acids on chicken performance, physical activity and meat quality. AB - Responses to changes in dietary Lys and other essential amino acid (AA) concentrations were evaluated in 480 male and female broilers originating from two lines divergently selected for high (pHu+) or low (pHu-) ultimate pH (pHu) of breast muscle. The two genetic lines were fed with two grower isoenergetic diets differing in both true digestible Lys (control=10.2 g/kg and experimental=7.0 g/kg) and amounts of other essential AA calculated in relation to Lys, which were sufficient for the control diet or in excess for the experimental diet. There were six repetitions per treatment. Birds were weighed individually at days 0, 21, 28 and 43. Feed consumption was recorded per pen and feed conversion was calculated over the growing period. The physical activity and walking ability of broilers were recorded during the whole rearing period. Breast and leg yield, and abdominal fat percentage were measured at 43 days of age, as were pHu, color, drip and cooking loss, Warner-Bratzler shear force, and curing-cooking yield of the breast Pectoralis major and pHu of the thigh Sartorius muscle. Divergent selection greatly affected most breast meat quality traits without significantly changing growth rate or feed efficiency. When subjected to a variation in dietary intake of AA, birds from the two genotypes responded in a similar way in terms of animal's growth, feed efficiency, body composition and meat quality traits. Although line and diet did not affect physical or feeding activities of the broilers, a significant effect of line-by-diet interaction was observed on gait score. Contrary to the pHu- birds, the walking ability of pHu+ birds was impaired when fed the control diet that favored growth and breast muscle development and limited storage of carbohydrate in muscle. PMID- 27476551 TI - Pharmacokinetics, pharmacodynamics and clinical efficacy of ospemifene for the treatment of dyspareunia and genitourinary syndrome of menopause. AB - INTRODUCTION: Ospemifene is a selective estrogen receptor modulator recently approved by the FDA for the treatment postmenopausal women experiencing moderate to-severe dyspareunia and by the EMA for the treatment of moderate-to-severe symptomatic genitourinary syndrome of menopause (GSM) in women who are not suitable candidates for local vaginal estrogen therapy. AREAS COVERED: This review offers an explanation of the pharmacodynamics and of the pharmacokinetics of ospemifene, and gives readers a complete overview of Phase II and III studies on the clinical efficacy, tolerability and safety of this agent in the setting of GSM. EXPERT OPINION: Ospemifene is efficacious for improving vaginal dryness or dyspareunia as the patient-identified most bothersome symptom, and Phase III clinical trials (4648 patients) have shown good efficacy in terms of improvement of objective and subjective signs and measures of GSM in postmenopausal women. Future studies with a long-term follow-up are required to better elucidate its safety profile. In particular, on the basis of preclinical and early clinical findings of antagonistic to neutral effect on breast tissue, more research is needed to assess the treatment with ospemifene in breast cancer survivors. PMID- 27476554 TI - Rotation is visualisation, 3D is 2D: using a novel measure to investigate the genetics of spatial ability. AB - Spatial abilities-defined broadly as the capacity to manipulate mental representations of objects and the relations between them-have been studied widely, but with little agreement reached concerning their nature or structure. Two major putative spatial abilities are "mental rotation" (rotating mental models) and "visualisation" (complex manipulations, such as identifying objects from incomplete information), but inconsistent findings have been presented regarding their relationship to one another. Similarly inconsistent findings have been reported for the relationship between two- and three-dimensional stimuli. Behavioural genetic methods offer a largely untapped means to investigate such relationships. 1,265 twin pairs from the Twins Early Development Study completed the novel "Bricks" test battery, designed to tap these abilities in isolation. The results suggest substantial genetic influence unique to spatial ability as a whole, but indicate that dissociations between the more specific constructs (rotation and visualisation, in 2D and 3D) disappear when tested under identical conditions: they are highly correlated phenotypically, perfectly correlated genetically (indicating that the same genetic influences underpin performance), and are related similarly to other abilities. This has important implications for the structure of spatial ability, suggesting that the proliferation of apparent sub-domains may sometimes reflect idiosyncratic tasks rather than meaningful dissociations. PMID- 27476555 TI - Facile Synthesis of Enhanced Fluorescent Gold-Silver Bimetallic Nanocluster and Its Application for Highly Sensitive Detection of Inorganic Pyrophosphatase Activity. AB - Herein, gold-silver bimetallic nanoclusters (Au-Ag NCs) with the high fluorescent intensity were first synthesized successfully and utilized for the fabrication of sensitive and specific sensing probes toward inorganic pyrophosphatase (PPase) activity with the help of copper ion (Cu(2+)) and inorganic pyrophosphate ion (PPi). Cu(2+) was used as the quencher of fluorescent Au-Ag NC, while PPi was employed as the hydrolytic substrate of PPase. The system consisted of PPi, Cu(2+) ion, and bovine serum albumin (BSA)-stabilized Au-Ag NC. The detection was carried out by enzyme-induced hydrolysis of PPi to liberate copper ion from the Cu(2+)-PPi complex. In the absence of target PPase, free copper ions were initially chelated with inorganic pyrophosphate ions to form the Cu(2+)-PPi complexes via the coordination chemistry, thus preserving the natural fluorescent intensity of the Au-Ag NCs. Upon addition of target PPase into the detection system, the analyte hydrolyzed PPi into phosphate ions and released Cu(2+) ion from the Cu(2+)-PPi complex. The dissociated copper ions readily quenched the fluorescent signal of Au-Ag NCs, thereby resulting in the decrease of fluorescent intensity. Under optimal conditions, the detectable fluorescent intensity of the as-prepared Au-Ag NCs was linearly dependent on the activity of PPase within a dynamic linear range of 0.1-30 mU/mL and allowed the detection at a concentration as low as 0.03 mU/mL at the 3sblank criterion. Good reproducibility (CV < 8.5% for the intra-assay and interassay), high specificity, and long-term stability (90.1% of the initial signal after a storage period of 48 days) were also received by using our system toward target PPase activity. In addition, good results with the inhibition efficiency of sodium fluoride were obtained in the inhibitor screening research of pyrophosphatase. Importantly, this system based on highly enhanced fluorescent Au-Ag NCs offer promise for simple and cost effective screening of target PPase activity without the needs of sample separation and multiple washing steps. PMID- 27476556 TI - Absence of obvious link between supra-therapeutic serum levels of beta lactams and clinical toxicity in ICU patients with acute renal failure treated with intermittent hemodialysis. PMID- 27476558 TI - The secure and the dispossessed: how the military and corporations are shaping a climate-changed world. PMID- 27476557 TI - HCV derived from sera of HCV-infected patients induces pro-fibrotic effects in human primary fibroblasts by activating GLI2. AB - Hepatitis C virus (HCV) infection is a leading cause of liver fibrosis, especially in developing countries. The process is characterized by the excess accumulation of ECM that may lead, over time, to hepatic cirrhosis, liver failure and also to hepatocarcinoma. The direct role of HCV in promoting fibroblasts trans-differentiation into myofibroblasts, the major fibrogenic cells, has not been fully clarified. In this study, we found that HCV derived from HCV-infected patients infected and directly induced the trans-differentiation of human primary fibroblasts into myofibroblasts, promoting fibrogenesis. This effect correlated with the activation of GLI2, one of the targets of Hedgehog signaling pathway previously reported to be involved in myofibroblast generation. Moreover, GLI2 activation by HCV correlated with a reduction of autophagy in fibroblasts, that may further promoted fibrosis. GLI2 inhibition by Gant 61 counteracted the pro fibrotic effects and autophagy inhibition mediated by HCV, suggesting that targeting HH/GLI2 pathway might represent a promising strategy to reduce the HCV induced fibrosis. PMID- 27476559 TI - Sudden death of a Siamese crocodile (Crocodylus siamensis) due to systemic aspergillosis. AB - A 4-year-old female Siamese crocodile (Crocodylus siamensis) housed at a zoo died without any prior clinical signs. During necropsy, numerous scattered, well demarcated, yellowish-white, firm nodules were observed throughout the liver and lungs. Microscopic examination with periodic acid-Schiff staining revealed granulomatous inflammation in the liver and lungs. Liver granulomas were characterized by the presence of a connective tissue barrier and hyphae, and the centers of the granulomas showed signs of necrosis. Lung samples showed characteristics similar to those observed in the liver samples. The fungus was identified as Aspergillus fumigatus based on its appearance on Sabouraud dextrose agar, microscopic examination with lactophenol cotton blue staining and genetic sequencing. Therefore, zoo veterinarians should pay close attention to fungal infections in captive animals. PMID- 27476560 TI - [Risk Factor Analysis of Pneumonia after Cardiovascular Surgery]. AB - Pneumonia is a major and life-threatening complication after cardiovascular surgery. The objective of our study was to describe epidemiology, clinical characteristics, and risk factors of pneumonia after cardiovascular surgery. From January 2007 to December 2011, 511 consecutive patients (age 67.3+/-11.9;336 men, 175 women) were enrolled in this study. Pneumonia was diagnosed according to Centers of Disease Control and Prevention surveillance criteria for healthcare associated infection. Data collection included preoperative, intraoperative, and post-operative variables. The overall incidence of pneumonia was 72 cases(14.0%). The mortality in pneumonia group was significantly higher than that in non pneumonia group (16.6% vs 4.3%, Odds ratio 4.4 p<0.001). Multi-logistic analysis revealed that elderly patient, preoperative congestive heart failure, preoperative hemodialysis, and operation of the thoracic aorta were independent risk factors for pneumonia after cardiovascular surgery. PMID- 27476561 TI - [Propensity-score-matched Comparison of Postoperative Pain Between Young and Elderly Patients Who Underwent Video-assisted Thoracoscopic Surgery for Spontaneous Pneumothorax]. AB - Video-assisted thoracoscopic surgery (VATS) is the standard treatment for spontaneous pneumothorax(SP). Although VATS has decreased the postoperative pain in comparison with conventional thoracotomy, the procedure still often requires sufficient postoperative pain management especially for young patients, and the present study on the postoperative pain management focused on the age difference was designed. Using the numerical rating scale, we compared postoperative pain between the young group(36 patients) and the elderly group (36 patients) selected by propensity score matching in order to adjust for the patients' backgrounds. Although the young group had significantly stronger pain than the elderly group immediately after surgery(4.9+/-2.5 vs.3.2+/-2.4, p=0.002), it improved promptly. Moreover, the young group required significantly more frequent continuous infusions of opioids after surgery( p=0.001). In conclusion, it is considered that the postoperative pain management in the pneumothorax surgery should be customized according to the age. PMID- 27476562 TI - [Migration of a Temporary Epicardial Pacing Lead into the Vascular Graft]. AB - A 48-year-old man was refered to our hospital for the treatment of bicusp aortic valve and severe aortic regurgitation. He underwent Bentall procedure (SJM 25mm+HemashieldO 28 mm composite graft). Temporary epicardial pacing lead( TPL) was placed on the right ventricle at the opetation, and was cut on his skin surface prior to discharge because of difficulty in traction removal. After 15 years from operation, follow up computered tomography and echocardiography showed migration of 2 retaining TPLs extending from vascular graft of ascending aorta to the right innominate artery. We performed Redo-median sternotomy and removed the TPLs. This is the 1st reported case of a migrated temporary pacing lead into the vascular graft of ascending aorta under noninfectious conditions. PMID- 27476563 TI - [Two Surgical Cases of Loeys-Dietz Syndrome in Childhood]. AB - Loeys-Dietz syndrome( LDS) is a recently recognized autosomal dominant connective tissue disorder. Mutations in the genes encoding transforming growth factor-beta( TGF-beta) receptor 1 and (2 TGFBR1, TGFBR2)have been associated with LDS. We report here 2 cases of LDS in childhood. Case 1 was a 10-year-old man, who had aneurysm of both the pulmonary trunk and the ascending aorta, associated with pulmonary and aortic valve insufficiency. Surgical repair was performed successfully at the age of 17. The aortic valve was replaced with a mechanical valve. The aneurysmal ascending aorta was replaced with a Dacron graft. Pulmonary valvuloplasty and pulmonary arterioplasty was performed. Case 2 was a 3-month-old female infant, who had a patent ductus arteriosus( PDA) and aortic root dilation. A detailed physical examination revealed hypertelorism, bifid uvula, retrognathia, talipes equinovarus, and camptodactyly. Computed tomography and echocardiography demonstrated PDA, Valsalva sinus dilation, and arterial tortuosity. These findings were consistent with the clinical manifestations of LDS. Surgical ligation and clipping of the PDA was performed with good results. A molecular genetic analysis subsequently demonstrated a heterozygous missense mutation of the TGFBR2. Since aortic dissection occurs at smaller aortic diameters, early diagnosis and close monitoring are important for patients with LDS. PMID- 27476564 TI - [Lung Cancer Incidentally Detected by a Subcutaneous Nodule at the Drainage Site for Pneumothorax]. AB - A 43-year-old male patient underwent thoracic drainage for the treatment of right pneumothorax. After 6 months, the patient visited our department because of a subcutaneous nodule found at the drainage site. Chest computed tomography revealed a mass lesion associated with a cavity in the right upper lobe of the lung and a subcutaneous nodule. Surgical resection was performed and both the pulmonary lesion and subcutaneous nodule were found to be adenocarcinoma. Although immunohistochemical analysis suggested that the pulmonary lesion was primary lung cancer, there were neither intrathoracic exposure of the tumor nor tumor cells in the pleural lavage cytology. The expression pattern of subcutaneous tumor in the right chest was slightly different from that of the lung lesion by immunohistochemistry. Therefore, it was difficult to determine whether this subcutaneous nodule was a tumor implantation through the drainage procedure or subcutaneous metastasis from the primary tumor. PMID- 27476565 TI - [Transmanubrial Osteomuscular-sparing Approach for Resection of Superior Mediastinal Schwannoma]. AB - Various approaches can be applied to resect superior mediastinal tumor. It is important to choose the procedure according to the location, size, and characteristics of the tumor in order to perform safe procedure surgery because of distinctive anatomy of this site. We hereby report on a case of Schwannoma of the superior mediastinum resected by the transmanubrial approach. A 67-year-old woman was referred to our department to examine an abnormal chest shadow found at a regular health checkup. Computed tomography revealed a tumor 58*52 mm in size extending from the left supraclavicular fossa to the upper border of the aortic arch. The surgery was performed under the diagnosis of neurogenic tumor using the transmanubrial approach. The tumor was resected safely and the pathological diagnosis was a Schwannoma. Transmanubrial approach was found to be quite useful in securing an adequate visual field and enabling the safe separation of blood vessels and nerves from the tumor. PMID- 27476566 TI - [Dedifferentiated Chondrosarcoma of the Chest Wall]. AB - A 79-year-old man complaining of an anterior chest mass with pain had an abnormal shadow on chest X-ray. A mass, 7 cm in size, with destruction of the right 4th rib was found on chest computed tomography. A F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) corresponding to the lesion showed an abnormal accumulation of FDG with the standardized uptake value(SUV) max=16.19. A malignant tumor of the chest wall origin was suspected and the tumor was resected with the 3th, 4th, and 5th ribs. Histologically, the tumor was diagnosed as dedifferentiated chondrosarcoma. He died of local recurrence about 5 months after the operation. PMID- 27476567 TI - [Annuloaortic Ectasia Associated with Single Coronary Artery and Ventricular Septal Defect;Report of a Case]. AB - Single coronary artery is rear. Various combination anomalies have been reported in patients with this anomaly undergoing heart surgery. We report a case of annuloaortic ectasia combined with single coronary artery and ventricular septal defect. The patient was a 67-year-old man with exertional dyspnea. Coronary angiography and computed tomography revealed a single coronary artery. Aortography showed severe aortic regurgitation and dilatation of Valsalva sinus. Ultrasonic cardiography showed small ventricular septal defect at the membranous septum. He underwent Modified Bentall's operation. He recovered without any complications. An annuloaortic ectasia associated with single coronary and ventricular septal defect is a very rare combination. PMID- 27476568 TI - [Intra-operative Acute Aortic Dissection during Aortic Root Reimplantation and Mitral Valve Reconstruction Surgery in a Patient with Marfan Syndrome;Report of a Case]. AB - In patients with Marfan syndrome, cardiovascular complication due to aortic dissection represents the primary cause of death. Iatrogenic acute aortic dissection during cardiac surgery is a rare, but serious adverse event. A 51-year old woman with Marfan syndrome underwent elective aortic surgery and mitral valve reconstruction surgery for the enlarged aortic root and severe mitral regurgitation. We replaced the aortic root and ascending aorta based on reimplantation technique. During subsequent mitral valve reconstruction, we found the heart pushed up from behind. Trans-esophageal echocardiography revealed a dissecting flap in the thoracic descending aorta. There was just weak signal of blood flow in the pseudolumen. We did not add any additional procedures such as an arch replacement. Cardio-pulmonary bypass was successfully discontinued. After protamine sulfate administration and blood transfusion, blood flow in the pseudolumen disappeared. The patient was successfully discharged from the hospital on 33th postoperative day without significant morbidities. PMID- 27476569 TI - [Thoracic Endovascular Aortic Aneurysm Repair in a Young Patient with Descending Aortic Injury;Report of a Case]. AB - A 15-year-old boy was referred to our emergency room due to a penetrating injury of the back. Computed tomography( CT) demonstrated a descending aortic injury at the Th9/10 level, bilateral hemothorax, and spinal cord injury. Although surgical treatment was indicated, multiple organ injury complicated open surgical repair, which required cardiopulmonary bypass with full heparinization. Therefore, the patient was scheduled to undergo thoracic endovascular aortic repair (TEVAR). A 23*33-mm Excluder aortic extension cuff was chosen for the small, 15-mm diameter aorta. The aortic extension was delivered and deployed in the descending aorta. Postoperative CT demonstrated neither endoleak nor collapse of the stent-graft. TEVAR for traumatic aortic aneurysm appears to be safe and effective, and an aortic extension for an abdominal aortic aneurysm may be utilized as an alternative device if the patient is young and the aorta is small. PMID- 27476570 TI - [Aortic Valve Replacement Concomitant with Right and Left Ventricular Outflow Tract Repair Eight Years after Arterial Switch Operation for Double Outlet Right Ventricle;Report of a Case]. AB - We report a case of successful aortic valve replacement and relief of right and left ventricular outflow tract obstruction 8 years after an arterial switch operation for double outlet right ventricle. Since the surgical access to the ascending aorta was limited because of the anatomical feature and the adhesion after the arterial switch operation, arterial infusion site for cardiopulmonary bypass was secured at the right common carotid artery ahead of the sternal re entry. After cardiopulmonary bypass was established, the right pulmonary artery was divided and then dissection of the ascending aorta was completed to secure the space for aortic valve replacement. A discrete membrane of the left ventricular outflow and muscle bands of the right ventricular outflow were completely resected. The right pulmonary artery was reconstructed by interpose of a prosthetic graft. Our experience would provide a technical option how to handle complex late complications after the arterial switch operation. PMID- 27476571 TI - [Acquired Left Ventricular-right Atrial Communication due to Infective Endocarditis;Report of a Case]. AB - A 77-year-old woman presented with a 3-week history of low grade fever, appetite loss and dizziness. An electrocardiogram showed complete heart block. Echocardiography demonstrated severe aortic valve stenosis and a mass of probable vegetation 2 cm in diameter on the atrioventricular septum in the right atrium (RA), but no obvious intra-cardiac fistula. There was no growth of organism in blood cul tures. In the 4th week after admission, a harsh and continuous cardiac murmur was detected for the 1st time. Portable echocardiography revealed disappearance of the mass in the RA, and showed an intra-cardiac shunt from the left ventricle( LV) to RA. The shunt was closed by autologous pericardial patch form LV side and directly with mattress suture form RA side during the emergency operation. The aortic valve was replaced with bio-prosthetic valve (SJM Trifecta 19 mm). No organism was detected in the excised tissue, but antibiotics were continued for 2 months until a permanent pacemaker was inserted. PMID- 27476572 TI - [Congenital Defect of the Left Pericardium with Spontaneous Pneumothorax;Report of a Case]. AB - Congenital cardiac membrane deficiency is a relatively rare condition. Here, we report a case of congenital cardiac membrane deficiency that manifested as left spontaneous pneumothorax. A 72-year-old man was hospitalized for recurrence of the spontaneous pneumothorax. Computed tomography findings led us to suspect pericardial deficits, and the perioperative findings during thoracoscopic surgery for the pneumothorax confirmed complete absence of the left pericardium. We resected a lung cyst but did not treat the pericardial deficit. The patient's postoperative course was uneventful. PMID- 27476573 TI - [Pulmonary Sequestration Associated with Increased Serum Tumor Markers;Report of a Case]. AB - A 51-year-old woman visited our hospital with chief complaints of cough and fever. A chest X-ray detected an abnormal shadow in the right lung field. A chest computed tomography scan showed solid consolidation at S10 of the right lung. A blood test revealed elevated levels of the tumor markers, CEA(12.1 ng/ml), SLX (134 U/ml) and CA19-9 (76.2 U/ml). Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed abnormally increased 18F-FDG uptake with an SUV max of 11.29. Lung cancer was strongly suspected, and the surgery was performed. Abnormal blood vessels were found within the pulmonary ligament. Intraoperative rapid pathology indicated no malignancy, and the final diagnosis was pulmonary sequestration. PMID- 27476574 TI - [Metastatic Lung Tumor Diagnosed as Primary Lung Cancer due to its Accompanying Lesion Mimicking Atypical Adenomatous Hyperplasia by Intraoperative Needle Biopsy Findings;Report of a Case]. AB - We reported a case of metastatic lung tumor, which was suspected as being a primary lung cancer because of its accompanying lesion mimicking atypical adenomatous hyperplasia(AAH) based on intraoperative needle biopsy findings. AAH is a preinvasive lesion or marginal lesion of primary lung cancer that is not accompanied by metastatic tumor. However, it needs to be distinguished pathologically from secondary changes of inflammation or fibrosis. In our case, the needle biopsy revealed AAH-like pathological findings, which indicates a primary lung cancer, and the standard lobectomy with lymph node dissection was performed, however, the final diagnosis turned out to be metastatic tumor. The rapidly enlarging tumor led to surrounding obstructive pneumonitis, which may have caused pathological changes mimicking AAH findings. In the case of obstructive pneumonitis, we must be careful to diagnose AAH, in addition to decisions about the surgical procedure especially when based on frozen section diagnosis. PMID- 27476575 TI - Health (care) and human rights: a fundamental conditions approach. AB - Many international declarations state that human beings have a human right to health care. However, is there a human right to health care? What grounds this right, and who has the corresponding duties to promote this right? Elsewhere, I have argued that human beings have human rights to the fundamental conditions for pursuing a good life. Drawing on this fundamental conditions approach of human rights, I offer a novel way of grounding a human right to health care. PMID- 27476576 TI - Impact of Stress Cardiac Magnetic Resonance Imaging on Clinical Care. AB - Given the rising costs of imaging, there is increasing pressure to provide evidence for direct additive impact on clinical care. Appropriate use criteria (AUC) were developed to optimize test-patient selection and are increasingly used by payers to assess reimbursement. However, these criteria were created by expert consensus with limited systematic validation. The aims of this study were therefore to determine (1) rates of active clinical change resulting from stress cardiovascular magnetic resonance (CMR) imaging and (2) whether the AUC can predict these changes. We prospectively enrolled 350 consecutive outpatients referred for stress CMR. Categories of "active changes in clinical care" due to stress CMR were predefined. Appropriateness was classified according to the 2013 AUC. Multivariate logistic regression analysis was used to identify factors independently associated with active change. Overall, stress CMR led to an active change in clinical care in about 70% of patients. Rates of change in clinical care did not vary significantly across AUC categories (p = 0.767). In a multivariate model adjusting for clinical variables and AUC, only ischemia (odds ratio [OR] 6.896, 95% CI 2.637 to 18.032, p <0.001), known coronary artery disease (OR 0.300, 95% CI 0.161 to 0.559, p <0.001), and age (OR 0.977, 95% CI 0.954 to 1.000, p = 0.050) independently predicted significant clinical change. In conclusion, stress CMR made a significant impact on clinical management, resulting in active change in clinical care in about 70% of patients. AUC categories were not an independent predictor of clinical change. Clinical change was independently associated with the presence of ischemia, absence of known coronary artery disease, and younger age. PMID- 27476577 TI - Preparation and Catalytic Activity for Aerobic Glucose Oxidation of Crown Jewel Structured Pt/Au Bimetallic Nanoclusters. AB - Understanding of the "structure-activity" relations for catalysts at an atomic level has been regarded as one of the most important objectives in catalysis studies. Bimetallic nanoclusters (NCs) in its many types, such as core/shell, random alloy, cluster-in-cluster, bi-hemisphere, and crown jewel (one kind of atom locating at the top position of another kind of NC), attract significant attention owing to their excellent optical, electronic, and catalytic properties. PVP-protected crown jewel-structured Pt/Au (CJ-Pt/Au) bimetallic nanoclusters (BNCs) with Au atoms located at active top sites were synthesized via a replacement reaction using 1.4-nm Pt NCs as mother clusters even considering the fact that the replacement reaction between Pt and Au(3+) ions is difficult to be occurred. The prepared CJ-Pt/Au colloidal catalysts characterized by UV-Vis, TEM, HR-TEM and HAADF-STEM-EELS showed a high catalytic activity for aerobic glucose oxidation, and the top Au atoms decorating the Pt NCs were about 15 times more active than the Au atoms of Au NCs with similar particle size. PMID- 27476578 TI - Tuning cation-binding selectivity and capacity via side chain-dependent molecular packing in the solid state. AB - Cavity-containing cation-binding pentameric macrocycles readily assemble, via side chain-dependent molecular packing, into either 1D nanotube bundles with the smallest being 10 nm in diameter or nanoplates of different sizes. The resultant nanostructures are able to selectively remove metal salts from aqueous solutions with varying selectivities and capacities. PMID- 27476579 TI - Tuning the electronic structures and magnetism of two-dimensional porous C2N via transition metal embedding. AB - Based on first-principles calculations, the electronic structures and magnetism are investigated in 3d transition metal (TM)-embedded porous two-dimensional (2D) C2N monolayers. Numerical results indicate that except Mn and Co atoms, other TM atoms can be embedded stably in the 2D C2N monolayer. Moreover, the magnetic moments of the TM-embedded C2N monolayer depend highly on the atomic number of the TM atoms. The Sc, Ti, V, Cr, Mn, Fe, Co and Ni atom-embedded C2N monolayers possess a ferromagnetic ground state, while embedding Cu can induce paramagnetic characteristics in the 2D C2N monolayer. Meanwhile, the Zn-embedded C2N monolayer exhibits a nonmagnetic ground state. These results indicate that the magnetism of 2D C2N monolayers can be tuned via embedding TM atoms. PMID- 27476580 TI - National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Management of Acute Coronary Syndromes 2016. PMID- 27476581 TI - The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial. AB - BACKGROUND: The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients. METHODS: A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume >=200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3 O-methyl glucose concentrations respectively. RESULTS: Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment. CONCLUSIONS: When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients. TRIAL REGISTRATION: The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ). PMID- 27476582 TI - Tomato yellow leaf curl virus: No evidence for replication in the insect vector Bemisia tabaci. AB - Begomovirus ssDNA plant virus (family Geminiviridae) replication within the Bemisia tabaci vector is controversial. Transovarial transmission, alteration to whitefly biology, or detection of viral transcripts in the vector are proposed as indirect evidence of replication of tomato yellow leaf curl virus (TYLCV). Recently, contrasting direct evidence has been reported regarding the capacity of TYLCV to replicate within individuals of B. tabaci based on quantitave PCR approaches. Time-course experiments to quantify complementary and virion sense viral nucleic acid accumulation within B. tabaci using a recently implemented two step qPCR procedure revealed that viral DNA quantities did not increase for time points up to 96 hours after acquisition of the virus. Our findings do not support a recent report claiming TYLCV replication in individuals of B. tabaci. PMID- 27476583 TI - Development of a Pipeline for Exploratory Metabolic Profiling of Infant Urine. AB - Numerous metabolic profiling pipelines have been developed to characterize the composition of human biofluids and tissues, the vast majority of these being for studies in adults. To accommodate limited sample volume and to take into account the compositional differences between adult and infant biofluids, we developed and optimized sample handling and analytical procedures for studying urine from newborns. A robust pipeline for metabolic profiling using NMR spectroscopy was established, encompassing sample collection, preparation, spectroscopic measurement, and computational analysis. Longitudinal samples were collected from five infants from birth until 14 months of age. Methods of extraction and effects of freezing and sample dilution were assessed, and urinary contaminants from breakdown of polymers in a range of diapers and cotton wool balls were identified and compared, including propylene glycol, acrylic acid, and tert-butanol. Finally, assessment of urinary profiles obtained over the first few weeks of life revealed a dramatic change in composition, with concentrations of phenols, amino acids, and betaine altering systematically over the first few months of life. Therefore, neonatal samples require more stringent standardization of experimental design, sample handling, and analysis compared to that of adult samples to accommodate the variability and limited sample volume. PMID- 27476584 TI - Three-dimensional Reconstruction of the Microstructure of Human Acellular Nerve Allograft. AB - The exact inner 3D microstructure of the human peripheral nerve has been a mystery for decades. Therefore, it has been difficult to solve several problems regarding peripheral nerve injury and repair. We used high-resolution X-ray computed microtomography (microCT) to scan a freeze-dried human acellular nerve allograft (hANA). The microCT images were then used to reconstruct a 3D digital model, which was used to print a 3D resin model of the nerve graft. The 3D digital model of the hANA allowed visualization of all planes. The magnified 3D resin model clearly showed the nerve bundles and basement membrane tubes of the hANA. Scanning electron microscopy (SEM) was used to analyse the microstructure of the hANA. Compared to the SEM images, the microCT image clearly demonstrated the microstructure of the hANA cross section at a resolution of up to 1.2 MUm. The 3D digital model of the hANA facilitates a clear and easy understanding of peripheral nerve microstructure. Furthermore, the enlarged 3D resin model duplicates the unique inner structure of each individual hANA. This is a crucial step towards achieving 3D printing of a hANA or nerve that can be used as a nerve graft. PMID- 27476585 TI - Teratoma replacing the gallbladder in an adult. PMID- 27476587 TI - Discussion. PMID- 27476586 TI - Patients with poor baseline walking capacity are most likely to improve their functional status with multimodal prehabilitation. AB - BACKGROUND: Evidence suggests that multimodal prehabilitation programs comprising interventions directed at physical activity, nutrition, and anxiety coping can improve functional recovery after colorectal cancer operations; however, such programs may be more clinically meaningful and cost-effective if targeted to specific subgroups. This study aimed to estimate the extent to which patients with poor baseline functional capacity improve their functional capacity. METHODS: Data for 106 participants enrolled in a multimodal, prehabilitation program before colorectal operations were analyzed. Low baseline functional capacity was defined as a 6-minute walking test distance (6MWD) of less than 400 m. Participants were categorized as higher fitness (6MWD >= 400 m, n = 70) or lower fitness (6MWD <400 m, n = 36). Changes in 6MWD over the preoperative period, and 4 weeks and 8 weeks after the operation were compared between groups. Secondary outcomes included patient-reported physical activity and health status, postoperative complications, duration of hospital stay, and readmissions. Less fit patients were then compared with subjects in the rehabilitation arm of the original studies who had a baseline 6MWD <400 m. RESULTS: Participants with lower baseline fitness had greater improvements in functional walking capacity with prehabilitation compared to patients with higher fitness (+46.5 [standard deviation 53.8] m vs +22.6 [standard deviation 41.8] m, P = .012). At 4 weeks postoperatively, patients with lower baseline fitness were more likely to be recovered to their baseline 6MWD than those with higher fitness. (74% vs 50%, P = .029). There were no differences in secondary outcome. Less-fit patients had a greater improvement through all the preoperative period compared to the control group. CONCLUSION: Patients with lower baseline walking capacity are more likely to experience meaningful improvement in physical function from prehabilitation before and after a colorectal cancer operation. PMID- 27476588 TI - Using Ecological Momentary Assessment to Identify Common Smoking Situations Among Korean American Emerging Adults. AB - The present study provides detailed contextual information about smoking habits among young Korean American smokers with the goal of characterizing situations where they are most at risk for smoking. Relevant situational factors included location, social context, concurrent activities, time of day, affective states, and food and beverage consumption. Using ecological momentary assessment (EMA) over 7 days, participants (N = 78) were instructed to respond to smoking prompts (n = 2614) and non-smoking prompts (n = 2136) randomly scheduled throughout the day. At each prompt, participants completed a short survey about immediate contextual factors. We used multilevel models to evaluate the association between contextual factors and smoking and further explored the distribution of smoking locations and concurrent activities across each social context and reason for smoking. Compared to non-smoking events, smoking events were associated with being outside, the presence of Korean friends, socializing, consuming alcohol, and experiencing more stress relative to one's average stress level (all ps < .01). Further analyses involving only smoking events showed that when participants smoked alone, they were most commonly at home (50 %) and most often studying/working (28 %). When smoking with Korean friends, participants were most often outside (38 %) and socializing (54 %). When smoking to reduce craving, participants were most often at home (39 %) and studying/working (25 %). To our knowledge, this is the first study to provide detailed descriptions of real-time smoking contexts among young Korean American smokers. Information with this level of granularity is needed to develop effective just-in-time adaptive interventions (JITAIs) for smoking cessation. PMID- 27476589 TI - [Antibiotic therapy of hospital-acquired pneumonia and its pharmacoeconomics]. AB - BACKGROUND: Important hospital-acquired infections include pneumonia, mainly because of the increasing resistance of bacterial pathogens to antimicrobials and the associated potential failure of antibiotic therapy. The present study aimed at determining the most frequent etiological agents of hospital-acquired pneumonia (HAP) and assessing the relationship between 30-day mortality and adequacy of antibiotic therapy. Based on the obtained information, optimal patterns of antibiotic therapy were to be defined, including a pharmacoeconomic perspective. METHODS: In patients with clinically confirmed HAP, bacterial etiological agents were identified, their susceptibility to antimicrobials was determined and statistical methods were used to assess the relationship between adequacy of antibiotic therapy and 30-day mortality. RESULTS: The study comprised 68 patients with clinically confirmed HAP. The most common etiological agents were strains of Pseudomonas aeruginosa (30.8 %), Klebsiella pneumoniae (23.1 %) and Burkholderia cepacia complex (15.4 %). Gram-negative bacteria accounted for 86.5 % of all bacterial pathogens. The overall mortality reached 42.5 %. In the subgroup of patients with inadequate antibiotic therapy, 30-day mortality was significantly higher (83.3 %) than in the subgroup with adequate therapy (30.0 %; p = 0.002). The risk for 30-day mortality was 2.78 times higher in case of inadequate antibiotic therapy (95%CI: 1.52-5.07). The proportion of Pseudomonas aeruginosa strains was significantly higher in the subgroup of patients with inadequate antibiotic therapy than in those with adequate therapy (67 % vs. 27 %; p = 0.032). CONCLUSION: Results of the present study suggest a significant relationship between mortality of patients with HAP and ineffective antibiotic therapy due to resistance of the bacterial pathogen. Thus, it is clear that initial antibiotic therapy must be based on qualified assumption of sufficient activity against the most common bacterial pathogens and results of surveillance of bacterial resistance in the relevant epidemiological unit. At the same time, however, it must be stressed that it is impossible to cover all potential variants of the etiological agents and their resistance phenotypes. PMID- 27476590 TI - [Bacterial pathogens causing acute otitis media]. AB - INTRODUCTION: The objectives were to assess the prevalence of etiological agents of acute otitis media (AOM) in children, age distribution of patients, frequency of the disease throughout the year, prescribed antibiotics, risk factors and complications. METHODS: Included in the study were 100 children and adolescents aged 0 to 18 years who had been diagnosed with AOM. From these patients, swabs for culture were obtained from the middle ear after paracentesis or perforation of the ear drum. RESULTS: Over the study period, a total of 111 isolates were obtained from 100 patients. The most prevalent etiological agents were Streptococcus pneumoniae (29 %), Streptococcus pyogenes (19 %) and Haemophilus influenzae (14 %). The frequency of other bacterial species was below 5 %; twenty one isolates were negative (19 %). Staphylococcus aureus was identified in 15 cases (14 %); of those, 9 cases had another pathogen. The rates of agents were different in patients with spontaneous perforation. The most frequent etiological agents were Streptococcus pyogenes (24 %), Haemophilus influenzae (20 %), Staphylococcus aureus (17 %) and Streptococcus pneumoniae (15 %). Negative findings were noted in 20 %. The most prescribed antibiotic was amoxicillin clavulanate (27 %), followed by phenoxymethylpenicillin (21 %) and cefuroxime (15 %). No antibiotics were administered in 20 % of cases and 3 % of patients received only local antibiotics. Complications (mastoiditis) developed in two children (2 %). CONCLUSION: The study showed that Streptococcus pneumoniae was the most prevalent etiological agent in children with OMA. After spontaneous perforation, however, these were replaced by Streptococcus pyogenes and Haemophilus influenzae. For empirical therapy, the most frequent drugs were amoxicillin-clavulanate, phenoxymethylpenicillin and cefuroxime. The initial empirical therapy had to be changed in only 2 % of the cases. PMID- 27476591 TI - [Guidelines for caring for HIV-infected adults and post-exposure prophylaxis of HIV infection]. AB - Presented are general principles of care for HIV-infected persons following their admission to an AIDS care center, initiation of antiretroviral therapy and follow up. Scientific research, drug development and new clinical data in recent years have led to a change in certain therapeutic perspectives and preferences for the treatment of HIV infection. Certain conditions are better specified, which affect the choice of antiretroviral regimens. Procedures and criteria for monitoring the effect of treatment and indication of post-exposure prophylaxis are specified. The development of this document was based on the latest updates of the most prominent international and European recommendations. It also reflects some of the new scientific information published in recent months. However, general recommendations cannot fully cover all the possible alternatives. They only state basic principles based on current clinical studies, clinical observation and practice. The present document should be the basic source of information for physicians involved in the treatment of patients with HIV infection and should provide a quick reference when selecting treatment regimens in terms of modern pharmacotherapy as well as information on the pitfalls of this treatment. Finally, it should be a support for negotiations between the professional society, state authorities and health care payers.This updated version of the guidelines follows the 2012 edition; once again, they are supplemented by a modified tabular overview. PMID- 27476592 TI - [Prolonged culture in a humid chamber increases the yields of pathogenic bacteria from the respiratory tract samples of patients suffering from cystic fibrosis]. AB - Current standards of care for cystic fibrosis (CF) patients lack unequivocal recommendations concerning the duration of primary culture of bacteriological samples. With the exception of Burkholderia cepacia (5 days), the minimum recommended duration of primary culture varies between 48 and 72 hours. Our aim was to evaluate the effect of an extended 10-day period of primary culture in a humid chamber in samples acquired from the respiratory tract of patients suffering from CF. Compared to standard culture, prolonged culture in a humid chamber yielded 1.85 times more isolates of pathogenic species in pharyngeal swabs (76 versus 41 isolates) and 1.4 times more isolates in sputum samples (116 versus 82), but only 1.14 times more isolates in nasal swabs (25 versus 22). Prolonged culture was most beneficial for Achromobacter spp. (6 versus 0), Stenotrophomonas maltophilia (16 versus 5) and Pseudomonas aeruginosa (69 versus 49), whereas there was little or no benefit at all for Staphylococcus aureus (87 versus 73) and Moraxella catarrhalis (10 versus 10). Therefore, prolonged culture in a humid chamber may definitely be recommended for pharyngeal swabs and sputum samples obtained from patients suffering from CF to achieve the maximum recovery rate of pathogenic bacteria, in particular non-fermenting Gram-negative rods. PMID- 27476593 TI - The Environmental Legacy of Modern Tropical Deforestation. AB - Tropical deforestation has caused a significant share of carbon emissions and species losses, but historical patterns have rarely been explicitly considered when estimating these impacts [1]. A deforestation event today leads to a time delayed future release of carbon, from the eventual decay either of forest products or of slash left at the site [2]. Similarly, deforestation often does not result in the immediate loss of species, and communities may exhibit a process of "relaxation" to their new equilibrium over time [3]. We used a spatially explicit land cover change model [4] to reconstruct the annual rates and spatial patterns of tropical deforestation that occurred between 1950 and 2009 in the Amazon, in the Congo Basin, and across Southeast Asia. Using these patterns, we estimated the resulting gross vegetation carbon emissions [2, 5] and species losses over time [6]. Importantly, we accounted for the time lags inherent in both the release of carbon and the extinction of species. We show that even if deforestation had completely halted in 2010, time lags ensured there would still be a carbon emissions debt of at least 8.6 petagrams, equivalent to 5 10 years of global deforestation, and an extinction debt of more than 140 bird, mammal, and amphibian forest-specific species, which if paid, would increase the number of 20(th)-century extinctions in these groups by 120%. Given the magnitude of these debts, commitments to reduce emissions and biodiversity loss are unlikely to be realized without specific actions that directly address this damaging environmental legacy. PMID- 27476594 TI - An Ectopic Network of Transcription Factors Regulated by Hippo Signaling Drives Growth and Invasion of a Malignant Tumor Model. AB - Cancer cells have abnormal gene expression profiles; however, to what degree these are chaotic or driven by structured gene regulatory networks is often not known. Here we studied a model of Ras-driven invasive tumorigenesis in Drosophila epithelial tissues and combined in vivo genetics with next-generation sequencing and computational modeling to decipher the regulatory logic of tumor cells. Surprisingly, we discovered that the bulk of the tumor-specific gene expression is controlled by an ectopic network of a few transcription factors that are overexpressed and/or hyperactivated in tumor cells. These factors are Stat, AP-1, the bHLH proteins Myc and AP-4, the nuclear hormone receptor Ftz-f1, the nuclear receptor coactivator Taiman/SRC3, and Mef2. Notably, many of these transcription factors also are hyperactivated in human tumors. Bioinformatic analysis predicted that these factors directly regulate the majority of the tumor-specific gene expression, that they are interconnected by extensive cross-regulation, and that they show a high degree of co-regulation of target genes. Indeed, the factors of this network were required in multiple epithelia for tumor growth and invasiveness, and knockdown of several factors caused a reversion of the tumor specific expression profile but had no observable effect on normal tissues. We further found that the Hippo pathway effector Yorkie was strongly activated in tumor cells and initiated cellular reprogramming by activating several transcription factors of this network. Thus, modeling regulatory networks identified an ectopic and ordered network of master regulators that control a large part of tumor cell-specific gene expression. PMID- 27476595 TI - Tyrosine Detoxification Is an Essential Trait in the Life History of Blood Feeding Arthropods. AB - Blood-feeding arthropods are vectors of infectious diseases such as dengue, Zika, Chagas disease, and malaria [1], and vector control is essential to limiting disease spread. Because these arthropods ingest very large amounts of blood, a protein-rich meal, huge amounts of amino acids are produced during digestion. Previous work on Rhodnius prolixus, a vector of Chagas disease, showed that, among all amino acids, only tyrosine degradation enzymes were overexpressed in the midgut compared to other tissues [2]. Here we demonstrate that tyrosine detoxification is an essential trait in the life history of blood-sucking arthropods. We found that silencing Rhodnius tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD), the first two enzymes of the phenylalanine/tyrosine degradation pathway, caused the death of insects after a blood meal. This was confirmed by using the HPPD inhibitor mesotrione, which selectively killed hematophagous arthropods but did not affect non-hematophagous insects. In addition, mosquitoes and kissing bugs died after feeding on mice that had previously received a therapeutic effective oral dose (1 mg/kg) of nitisinone, another HPPD inhibitor used in humans for the treatment of tyrosinemia type I [3]. These findings indicate that HPPD (and TAT) can be a target for the selective control of blood-sucking disease vector populations. Because HPPD inhibitors are extensively used as herbicides and in medicine, these compounds may provide an alternative less toxic to humans and more environmentally friendly than the conventional neurotoxic insecticides that are currently used, with the ability to affect only hematophagous arthropods. PMID- 27476597 TI - Auditory Efferent System Modulates Mosquito Hearing. AB - The performance of vertebrate ears is controlled by auditory efferents that originate in the brain and innervate the ear, synapsing onto hair cell somata and auditory afferent fibers [1-3]. Efferent activity can provide protection from noise and facilitate the detection and discrimination of sound by modulating mechanical amplification by hair cells and transmitter release as well as auditory afferent action potential firing [1-3]. Insect auditory organs are thought to lack efferent control [4-7], but when we inspected mosquito ears, we obtained evidence for its existence. Antibodies against synaptic proteins recognized rows of bouton-like puncta running along the dendrites and axons of mosquito auditory sensory neurons. Electron microscopy identified synaptic and non-synaptic sites of vesicle release, and some of the innervating fibers co labeled with somata in the CNS. Octopamine, GABA, and serotonin were identified as efferent neurotransmitters or neuromodulators that affect auditory frequency tuning, mechanical amplification, and sound-evoked potentials. Mosquito brains thus modulate mosquito ears, extending the use of auditory efferent systems from vertebrates to invertebrates and adding new levels of complexity to mosquito sound detection and communication. PMID- 27476596 TI - Parallel Actin-Independent Recycling Pathways Polarize Cdc42 in Budding Yeast. AB - The highly conserved Rho-family GTPase Cdc42 is an essential regulator of polarity in many different cell types. During polarity establishment, Cdc42 becomes concentrated at a cortical site, where it interacts with downstream effectors to orient the cytoskeleton along the front-back axis. To concentrate Cdc42, loss of Cdc42 by diffusion must be balanced by recycling to the front. In Saccharomyces cerevisiae, the guanine nucleotide dissociation inhibitor (GDI) Rdi1 recycles Cdc42 through the cytoplasm. Loss of Rdi1 slowed but did not eliminate Cdc42 accumulation at the front, suggesting the existence of other recycling pathways. One proposed pathway involves actin-directed trafficking of vesicles carrying Cdc42 to the front. However, we found no role for F-actin in Cdc42 concentration, even in rdi1Delta cells. Instead, Cdc42 was still able to exchange between the membrane and cytoplasm in rdi1Delta cells, albeit at a reduced rate. Membrane-cytoplasm exchange of GDP-Cdc42 was faster than that of GTP-Cdc42, and computational modeling indicated that such exchange would suffice to promote polarization. We also uncovered a novel role for the Cdc42-directed GTPase-activating protein (GAP) Bem2 in Cdc42 polarization. Bem2 was known to act in series with Rdi1 to promote recycling of Cdc42, but we found that rdi1Delta bem2Delta mutants were synthetically lethal, suggesting that they also act in parallel. We suggest that GAP activity cooperates with the GDI to counteract the dissipative effect of a previously unappreciated pathway whereby GTP-Cdc42 escapes from the polarity site through the cytoplasm. PMID- 27476598 TI - Extreme Inverted Trophic Pyramid of Reef Sharks Supported by Spawning Groupers. AB - The extent of the global human footprint [1] limits our understanding of what is natural in the marine environment. Remote, near-pristine areas provide some baseline expectations for biomass [2, 3] and suggest that predators dominate, producing an inverted biomass pyramid. The southern pass of Fakarava atoll-a biosphere reserve in French Polynesia-hosts an average of 600 reef sharks, two to three times the biomass per hectare documented for any other reef shark aggregations [4]. This huge biomass of predators makes the trophic pyramid inverted. Bioenergetics models indicate that the sharks require ~90 tons of fish per year, whereas the total fish production in the pass is ~17 tons per year. Energetic theory shows that such trophic structure is maintained through subsidies [5-9], and empirical evidence suggests that sharks must engage in wide ranging foraging excursions to meet energy needs [9, 10]. We used underwater surveys and acoustic telemetry to assess shark residency in the pass and feeding behavior and used bioenergetics models to understand energy flow. Contrary to previous findings, our results highlight that sharks may overcome low local energy availability by feeding on fish spawning aggregations, which concentrate energy from other local trophic pyramids. Fish spawning aggregations are known to be targeted by sharks, but they were previously believed to play a minor role representing occasional opportunistic supplements. This research demonstrates that fish spawning aggregations can play a significant role in the maintenance of local inverted pyramids in pristine marine areas. Conservation of fish spawning aggregations can help conserve shark populations, especially if combined with shark fishing bans. PMID- 27476599 TI - The Genetics of Seasonal Migration and Plumage Color. AB - Details on the genetics of behavioral and quantitative phenotypes remain limited to a few organisms. Such information is central to understanding both adaptation and speciation, as many of these phenotypes reduce gene flow between taxa [1-3]. Hybrid zones provide an ideal arena for studying this topic, as they consist of recombinant genotypes that allow genetic mapping of traits distinguishing natural populations [4]. We examined the genetic basis of migratory orientation and plumage color, both of which may contribute to speciation, in a hybrid zone between two groups of Swainson's thrushes that differ in these traits. We identified a cluster of SNPs on chromosome 4 strongly associated with migratory orientation. Genes involved with the circadian clock, nervous system, and cell signaling were located here and included candidates implicated in smaller-scale studies of migration in different animal groups, supporting previous suggestions that there is a common gene package for migration [5]. Plumage color was more polygenic than migratory orientation but showed strong associations on the Z chromosome that included SNPs linked to TYRP1, a gene involved in the production of eumelanin. We integrated these results with genomic data from pure populations and found that regions associated with both phenotypes co-localized with regions of elevated relative differentiation between the groups. This finding relates to the literature on islands of differentiation [6-8] by implicating divergent selection in generating these peaks. Together, our results identify specific genomic regions involved in both the regulation of complex phenotypes across animal groups and speciation [9]. PMID- 27476600 TI - Biophysical and Population Genetic Models Predict the Presence of "Phantom" Stepping Stones Connecting Mid-Atlantic Ridge Vent Ecosystems. AB - Deep-sea hydrothermal vents are patchily distributed ecosystems inhabited by specialized animal populations that are textbook meta-populations. Many vent associated species have free-swimming, dispersive larvae that can establish connections between remote populations. However, connectivity patterns among hydrothermal vents are still poorly understood because the deep sea is undersampled, the molecular tools used to date are of limited resolution, and larval dispersal is difficult to measure directly. A better knowledge of connectivity is urgently needed to develop sound environmental management plans for deep-sea mining. Here, we investigated larval dispersal and contemporary connectivity of ecologically important vent mussels (Bathymodiolus spp.) from the Mid-Atlantic Ridge by using high-resolution ocean modeling and population genetic methods. Even when assuming a long pelagic larval duration, our physical model of larval drift suggested that arrival at localities more than 150 km from the source site is unlikely and that dispersal between populations requires intermediate habitats ("phantom" stepping stones). Dispersal patterns showed strong spatiotemporal variability, making predictions of population connectivity challenging. The assumption that mussel populations are only connected via additional stepping stones was supported by contemporary migration rates based on neutral genetic markers. Analyses of population structure confirmed the presence of two southern and two hybridizing northern mussel lineages that exhibited a substantial, though incomplete, genetic differentiation. Our study provides insights into how vent animals can disperse between widely separated vent habitats and shows that recolonization of perturbed vent sites will be subject to chance events, unless connectivity is explicitly considered in the selection of conservation areas. PMID- 27476601 TI - On the Encoding of Panoramic Visual Scenes in Navigating Wood Ants. AB - A natural visual panorama is a complex stimulus formed of many component shapes. It gives an animal a sense of place and supplies guiding signals for controlling the animal's direction of travel [1]. Insects with their economical neural processing [2] are good subjects for analyzing the encoding and memory of such scenes [3-5]. Honeybees [6] and ants [7, 8] foraging from their nest can follow habitual routes guided only by visual cues within a natural panorama. Here, we analyze the headings that ants adopt when a familiar panorama composed of two or three shapes is manipulated by removing a shape or by replacing training shapes with unfamiliar ones. We show that (1) ants recognize a component shape not only through its particular visual features, but also by its spatial relation to other shapes in the scene, and that (2) each segmented shape [9] contributes its own directional signal to generating the ant's chosen heading. We found earlier that ants trained to a feeder placed to one side of a single shape [10] and tested with shapes of different widths learn the retinal position of the training shape's center of mass (CoM) [11, 12] when heading toward the feeder. They then guide themselves by placing the shape's CoM in the remembered retinal position [10]. This use of CoM in a one-shape panorama combined with the results here suggests that the ants' memory of a multi-shape panorama comprises the retinal positions of the horizontal CoMs of each major component shape within the scene, bolstered by local descriptors of that shape. PMID- 27476602 TI - Feedback-Controlled Transcranial Alternating Current Stimulation Reveals a Functional Role of Sleep Spindles in Motor Memory Consolidation. AB - Transient episodes of brain oscillations are a common feature of both the waking and the sleeping brain. Sleep spindles represent a prominent example of a poorly understood transient brain oscillation that is impaired in disorders such as Alzheimer's disease and schizophrenia. However, the causal role of these bouts of thalamo-cortical oscillations remains unknown. Demonstrating a functional role of sleep spindles in cognitive processes has, so far, been hindered by the lack of a tool to target transient brain oscillations in real time. Here, we show, for the first time, selective enhancement of sleep spindles with non-invasive brain stimulation in humans. We developed a system that detects sleep spindles in real time and applies oscillatory stimulation. Our stimulation selectively enhanced spindle activity as determined by increased sigma activity after transcranial alternating current stimulation (tACS) application. This targeted modulation caused significant enhancement of motor memory consolidation that correlated with the stimulation-induced change in fast spindle activity. Strikingly, we found a similar correlation between motor memory and spindle characteristics during the sham night for the same spindle frequencies and electrode locations. Therefore, our results directly demonstrate a functional relationship between oscillatory spindle activity and cognition. PMID- 27476603 TI - Mechanisms of CO2 capture in ionic liquids: a computational perspective. AB - We present computational studies of CO2 sorption in two different classes of ionic liquid. The addition of carbon dioxide to four superbase ionic liquids, [P3333][Benzim], [P3333][124Triz], [P3333][123Triz] and [P3333][Bentriz], was studied using the DFT approach and considering anions alone and individual ion pairs. The addition of CO2 to the anion alone clearly resulted in the formation of a covalently-bound carbamate function with the strength of binding correlated to experimental capacity. In the ion pair however the cation significantly alters the nature of the bonding such that the overall cohesive energy is reduced. Formation of a strong carbamate function occurs at the expense of weakening the interaction between anion and cation. In [N1111][l-ALA], a representative amino acid ionic liquid, evidence was found for a low-energy monomolecular mechanism for carbamate formation, explaining the 1 : 1 molar uptake ratio observed in some amino acid ionic liquids. The mechanism involves proton transfer to the carboxylate group of the aminate anion. PMID- 27476605 TI - Membrane species mobility under in-lipid-membrane forced convection. AB - Processing and managing cell membrane proteins for characterization while maintaining their intact structure is challenging. Hydrodynamic flow has been used to transport membrane species in supported lipid bilayers (SLBs) where the hydrophobic cores of the membrane species can be protected during processing. However, the forced convection mechanism of species embedded in lipid bilayers is still unclear. Developing a controlled SLB platform with a practical model to predict the membrane species mobility in the platform under in-lipid-membrane forced convection is imperative to ensure the practical applicability of SLBs in processing and managing membrane species with various geometrical properties. The mobility of membrane species is affected by the driving force from the aqueous environment in addition to the frictions from the lipid bilayer, in which both lipid leaflets may exhibit different speeds relative to that of the moving species. In this study, we developed a model, based on the applied driving force and the possible frictional resistances that the membrane species encounter, to predict how the mobility under in-lipid-membrane forced convection is influenced by the sizes of the species' hydrophilic portion in the aqueous environment and the hydrophobic portion embedded in the membrane. In addition, we used a microfluidic device for controlling the flow to arrange the lipid membrane and the tested membrane species in the desirable locations in order to obtain a SLB platform which can provide clear mobility responses of the species without disturbance from the species dispersion effect. The model predictions were consistent with the experimental observations, with the sliding friction coefficient between the upper leaflet and the hydrophilic portion of the species as the only regressed parameter. The result suggests that not only the lateral drag frictions from the lipid layers but also the sliding frictions between the species and the lipid layer planes could significantly influence the species mobility. The consistency between the experimental results and the model predictions suggests that our model based on lateral drag and sliding frictions between the species and the lipid leaflets can be used to describe the mobility of half-transmembrane species. We also demonstrated the possibility of how the scope of this model can be broadened to describe the mobility of transmembrane proteins extending through both lipid leaflets. PMID- 27476604 TI - Co-action provides rational basis for the evolutionary success of Pavlovian strategies. AB - Strategies incorporating direct reciprocity, e.g., Tit-for-Tat and Pavlov, have been shown to be successful for playing the Iterated Prisoners Dilemma (IPD), a paradigmatic problem for studying the evolution of cooperation among non-kin individuals. However it is an open question whether such reciprocal strategies can emerge as the rational outcome of repeated interactions between selfish agents. Here we show that adopting a co-action perspective, which takes into account the symmetry between agents - a relevant consideration in biological and social contexts - naturally leads to such a strategy. For a 2-player IPD, we show that the co-action solution corresponds to the Pavlov strategy, thereby providing a rational basis for it. For an IPD involving many players, an instance of the Public Goods game where cooperation is generally considered to be harder to achieve, we show that the cooperators always outnumber defectors in the co-action equilibrium. This can be seen as a generalization of Pavlov to contests involving many players. In general, repeated interactions allow rational agents to become aware of the inherent symmetry of their situation, enabling them to achieve robust cooperation through co-action strategies - which, in the case of IPD, is a reciprocal Pavlovian one. PMID- 27476606 TI - Comparison of the genetic variability of Blastocystis subtypes between human carriers from two contrasting climatic regions of Mexico. AB - Blastocystis sp. is an anaerobic intestinal microorganism commonly identified in the feces of several animals, including humans. Blastocystis exhibits high genetic polymorphism and at least 17 subtypes (ST) have been identified; ST1-ST3 are frequently found in the Americas. Furthermore, in vitro assays have shown that temperature and humidity can affect the viability of Blastocystis cysts. In this study, we describe the genetic variability and genetic differentiation among and within Blastocystis STs in adults and children from the cities of Hermosillo and Morelia cities, which represent arid and humid subtropical climatic regions of Mexico, respectively. Phylogenetic and genetic diversity was assessed by analyzing a region of the small subunit ribosomal DNA (SSU rDNA) gene as a marker. Blastocystis ST3 and ST1 were associated with children from Hermosillo and Morelia, respectively. An analysis of the nucleotide diversity (pi) and haplotype polymorphism (theta) indexes showed that they were similar within each ST, but different between ST1 and ST3. Interestingly, the group of symptomatic carriers from Hermosillo showed scarce mean nucleotide diversity compared to the asymptomatic carriers (0.0039+/-0.0030 and 0.0329+/-0.0286, respectively). Furthermore, the gene flow and genetic differentiation indexes between the children and adults suggested that the Blastocystis haplotypes in the adult carriers were "highly mobile" among humans, while the haplotypes found in the children were more isolated and genetically differentiated between them. PMID- 27476607 TI - Characterization of novel intragenotype recombination events among norovirus pandemic GII.4 variants. AB - Recently, there has been an increase in the number of children hospitalized due to norovirus infection in Brazil. This is due both to the occurrence of more severe norovirus-related gastroenteritis cases after the introduction of the rotavirus vaccine and an increase in the tools for the detection of the disease. This pathogen is transmitted by the fecal-oral route, and the illness is characterized by diarrhea, vomiting, nausea and abdominal cramps. The genome of the virus is organized into three open reading frames showing strong mutation rates. Additionally, homologous recombination events, which can increase the virulence of the virus and lead to genotyping mistakes in molecular epidemiological studies, frequently occur. The purpose of this study was to describe two recombination events among different GII.4 variants that infected children who were hospitalized for severe acute gastroenteritis during distinct periods of time in Belem, Brazil. The recombination among the variants US95_96/Kaiso_2003 and Den Haag_2006b/Yerseke_2006a were observed in May 2003 and February 2009, respectively. In both cases, the association between the dominant variant at that point in time and another that was circulating at a low frequency in the population of Belem was demonstrated. Interestingly, the position of the breakpoint of the recombination event in the genome was the polymerase gene and was located at the nucleotide positions 4.834 and 5.002, which is an unusual location for the occurrence of recombination as other studies have previously reported the junction region as a breakpoint. In this study, both recombinant variant strains were related to severe cases of diarrhea that lead to hospitalization, demonstrating the viral evolution of GII.4 in response to selective pressures, which ultimately lead to the emergence of novel viral types in the pediatric population. The cases discussed here reinforce the need for continuous norovirus surveillance. To our knowledge, these two GII.4 variant recombinations have not yet been previously described. PMID- 27476608 TI - Docetaxel-loaded polyglutamic acid-PEG nanocapsules for the treatment of metastatic cancer. AB - The design of nanomedicines with suitable physicochemical characteristics for the lymphatic targeting of drugs is critical in order to reach the lymph nodes, where metastatic cells often accumulate. Based on the known effect of particle size and surface hydrophilicity on the capacity of nanocarriers to reach the lymph nodes, here we report the formation and characterization of 100nm polyglutamic acid polyethylene glycol (PGA-PEG) nanocapsules together with the assessment of their potential for the treatment of cancer with lymphatic metastatic spread. To this purpose, we first studied the biodistribution of fluorescently labeled PGA-PEG nanocapsules (100nm), following, either intravenous or subcutaneous administration. The results confirmed the accumulation of nanocapsules in the lymphatic system, especially upon subcutaneous administration. Next, we evaluated the efficacy and toxicity of the docetaxel-loaded nanocapsules in an orthotopic lung cancer model that metastasizes to the lymph nodes. As expected from the rational design, DCX-loaded PGA-PEG nanocapsules exhibited a greatly enhanced antitumoral efficacy and a reduced toxicity when compared with the commercial formulation Taxotere(r). Furthermore, the administration of DCX-loaded PGA-PEG nanocapsules resulted in the practical elimination of the metastatic load in the mediastinal lymph nodes, whereas the treatment with the commercial formulation had a minor effect. Overall, these findings underscore the potential of PGA-PEG nanocapsules for the delivery of anticancer drugs to both, the tumor tissue and the metastatic lymph nodes. Therefore, they represent a promising therapy for the treatment of lung metastatic cancer. PMID- 27476609 TI - Increase of intracellular cisplatin levels and radiosensitization by ultrasound in combination with microbubbles. AB - The possibility to enhance drug delivery by using ultrasound in combination with microbubbles (USMB) is extensively studied. So far, these studies have focused on the delivery and efficacy of a single drug, e.g. in chemotherapy. In this study, we investigated the intracellular delivery of cisplatin by USMB and the subsequent increased efficacy in combination with radiotherapy in a head and neck cancer cell line in vitro. After USMB-mediated intracellular delivery was verified using the model-drug SYTOX(r) Green, we investigated the efficacy of cisplatin when combined with USMB and radiotherapy and measured whether intracellular cisplatin concentration was enhanced after applying USMB. In addition, the effect of USMB on cisplatin and radiotherapy-induced DNA damage was studied. Flow cytometry showed that USMB treatment increased the average percentage SYTOX(r) Green positive cells from 2.2% to 34.5%. Clonogenic assays demonstrated that exposure to USMB significantly increased the efficacy of cisplatin combined with radiotherapy. The enhanced efficacy was associated with increased intracellular cisplatin levels, which were 2.7-fold higher when cisplatin was combined with USMB. As a result, an 82% increase in levels of DNA double strand breaks was found when cisplatin was combined with USMB, compared to cisplatin only (p<0.05). In conclusion, cisplatin uptake was significantly increased by USMB, which resulted in enhanced levels of DNA damage and increased efficacy of cisplatin in combination with radiotherapy in vitro. PMID- 27476610 TI - Main-chain degradable single-chain cyclized polymers as gene delivery vectors. AB - Single-chain technology (SCT) allows the manipulation of polymeric architectures at an individual polymer chain level, providing a new platform for the fabrication of nanoscale polymeric objects. However, it remains problematic to apply this newborn technology to the biological and medical fields, since synthesis of single-chain polymeric nanoparticles relies heavily on controlled/living radical polymerization of vinyl based monomers, yielding a persistent non-degradable carbon-carbon based backbone. Moreover, the ultrahigh dilution conditions often required for single-chain polymer nanoparticle synthesis limits large-scale applicability. A versatile approach to achieve backbone degradability in single-chain cyclized polymers was developed by combining ring-opening addition polymerization and intramolecular cyclization into a one-pot RAFT copolymerization of cyclic and mono/multi-vinyl monomers system under concentrated conditions. The in situ intramolecular cyclization of individual propagating chains was achieved by kinetic control and statistical manipulation of mono- and multi-vinyl monomer copolymerization. The cyclic allylsulfide monomer 3-methylidene-1,9-dioxa-5,12,13-trithiacyclopentadecane-2,8 dione (MDTD) was copolymerized via the ring-opening pathway to introduce disulfide groups into the vinyl-based backbone without compromising the single chain propagation nature. Backbone degradable single chain polymeric nanoparticles were obtained with molecular weights of 10kDa and MDTD incorporation ratios of 4.7%. Chemical degradation of the nanoparticles confirmed both their single chain nature, as well as backbone degradability. The single chain cyclized polymeric nanoparticles were evaluated for their gene transfection capabilities. The backbone degradable nanoparticles displayed high transfection efficiencies and low cytotoxicities in both 3T3 and HeLa cells. PMID- 27476611 TI - Innovative encapsulation platform based on pancreatic extracellular matrix achieve substantial insulin delivery. AB - Cell-based therapies for the treatment of diabetes, generally aim to provide long term glucose regulated-insulin delivery using insulin producing cells. The delivery platform is crucial for the therapeutic outcome as well as for immunoisolation of the entrapped cells. We have developed a novel artificial pancreas encapsulation platform for the treatment of diabetes that is based on solubilized whole porcine pancreatic extracellular matrix (ECM). These unique capsules were used to entrap human liver cells and mesenchymal stem cells that were induced to differentiate into glucose-regulated insulin-producing cells. We demonstrate that the ECM-microcapsule platform provides a natural fibrous 3D niche, supporting cell viability and differentiation, while significantly improving insulin delivery. In vivo, ECM-encapsulated cells were shown to be non immunogenic, and most importantly, to significantly improve the glycemic control in diabetic mouse preclinical model, thus establishing a proof-of-concept for this new cell-based insulin delivery platform. PMID- 27476612 TI - Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP 3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue. AB - Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a key regulator of extracellular matrix turnover for its ability to inhibit matrix metalloproteinases (MMPs), adamalysin-like metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs). TIMP-3 is a secreted protein whose extracellular levels are regulated by endocytosis via the low-density-lipoprotein receptor-related protein-1 (LRP-1). In this study we developed a molecule able to "trap" TIMP-3 extracellularly, thereby increasing its tissue bioavailability. LRP 1 contains four ligand-binding clusters. In order to investigate the TIMP-3 binding site on LRP-1, we generated soluble minireceptors (sLRPs) containing the four distinct binding clusters or part of each cluster. We used an array of biochemical methods to investigate the binding of TIMP-3 to different sLRPs. We found that TIMP-3 binds to the ligand-binding cluster II of the receptor with the highest affinity and a soluble minireceptor containing the N-terminal half of cluster II specifically blocked TIMP-3 internalization, without affecting the turnover of metalloproteinases. Mass spectrometry-based secretome analysis showed that this minireceptor, named T3TRAP, selectively increased TIMP-3 levels in the extracellular space and inhibited constitutive shedding of a number of cell surface proteins. In conclusion, T3TRAP represents a biological tool that can be used to modulate TIMP-3 levels in the tissue and could be potentially developed as a therapy for diseases characterized by a deficit of TIMP-3, including arthritis. PMID- 27476613 TI - Testicular Adrenal Rest Tumor in Two Brothers with a Novel Mutation in the 3-Beta Hydroxysteroid Dehydrogenase-2 Gene. AB - Testicular adrenal rest tumors (TART) occur frequently in adolescents and adults with 21-hydroxylase deficiency. There have been no reports of TART in children with 3beta-hydroxysteroid dehydrogenase deficiency (HSD3beta). Biopsy proven TART was diagnosed in a 31/12-year-old male patient and also in his 22-month-old sibling. Hormonal and anthropometric measurements were performed during glucocorticoid and fludrocortisone treatment. The mutational analysis was performed by direct DNA sequencing of the complete coding region of the HSD3beta2 gene. Initially, both siblings were treated with high doses of hydrocortisone and fludrocortisone. TART regressed with dexamethasone treatment in both patients. However, growth velocity decreased and weight gain increased in both patients. Dexamethasone was changed to high-dose hydrocortisone (>20 mg/m2/d). Sequencing analyses revealed a novel homozygous p.W355R (c.763 T>C) mutation at exon 4 of the HSD3beta2 gene in both siblings. These two patients are, to our knowledge, the first known cases of TARTs with a novel mutation in the HSD3beta2 gene detected during childhood. High-dose hydrocortisone treatment is more reliable for TART in children. PMID- 27476614 TI - [Subacute anti-N-methyl-D-aspartate receptor encephalitis. A serie of 13 paediatric cases]. AB - INTRODUCTION: Subacute anti-NMDA receptor encephalitis was recognised in 2007 as a clinical entity, and was first described in young women with ovarian teratoma. The first paediatric series unrelated with tumours was reported in 2009. OBJECTIVE: To present the clinical features, treatment, and prognosis of 13 patients with anti-NMDA receptor encephalitis in Chile. PATIENTS AND METHOD: A description is presented of 13 children, 9 males, aged between 1 and 16 years, diagnosed between 2009 and 2016 in 7 hospitals. All patients were evaluated with cerebral magnetic resonance and electroencephalogram. Cytochemical, oligoclonal bands and virus studies (PCR and antibodies) were performed in cerebrospinal fluid. All patients were evaluated in search of anti NMDA receptor in serum and cerebrospinal fluid. Tumor imaging studies were performed in all children. RESULTS: All children began the disease with psychiatric symptoms, and 11/13 had seizures. All of them subsequently presented with psychomotor agitation, dystonia, and bucolingual dyskinesias, with 11/13 loss of language and 6/13 autonomic disorders. All of them (13/13) had positive anti-NMDA receptor antibodies. CSF was normal in 12/13 children, positive oligoclonal bands in 6/10 patients, normal brain resonance in 13/13 children, EEG changes in 11/13 children, and abnormal SPECT in 6/6 children. A methylprednisolone bolus of 30mg/kg was given for 3-5 days to 12/13 children, and 6 received immunoglobulin 2g/kg. The large majority (12/13) of children recovered 1-4 months after disease onset. One child had a recurrence one year later, and recovered quickly. CONCLUSIONS: Subacute encephalitis due to NMDA anti-receptor antibodies should be suspected in children with psychiatric disorders and abnormal movements. Functional studies, such as EEG and SPECT are valuable diagnostic support. Early detection of this encephalitis leads to a faster recovery of patients. PMID- 27476615 TI - Adsorption of Xyloglucan onto Cellulose Surfaces of Different Morphologies: An Entropy-Driven Process. AB - The temperature-dependence of xyloglucan (XG) adsorption onto smooth cellulose model films regenerated from N-methylmorpholine N-oxide (NMMO) was investigated using surface plasmon resonance spectroscopy, and it was found that the adsorbed amount increased with increasing temperature. This implies that the adsorption of XG to NMMO-regenerated cellulose is endothermic and supports the hypothesis that the adsorption of XG onto cellulose is an entropy-driven process. We suggest that XG adsorption is mainly driven by the release of water molecules from the highly hydrated cellulose surfaces and from the XG molecules, rather than through hydrogen bonding and van der Waals forces as previously suggested. To test this hypothesis, the adsorption of XG onto cellulose was studied using cellulose films with different morphologies prepared from cellulose nanocrystals (CNC), semicrystalline NMMO-regenerated cellulose, and amorphous cellulose regenerated from lithium chloride/dimethylacetamide. The total amount of high molecular weight xyloglucan (XGHMW) adsorbed was studied by quartz crystal microbalance and reflectometry measurements, and it was found that the adsorption was greatest on the amorphous cellulose followed by the CNC and NMMO-regenerated cellulose films. There was a significant correlation between the cellulose dry film thickness and the adsorbed XG amount, indicating that XG penetrated into the films. There was also a correlation between the swelling of the films and the adsorbed amounts and conformation of XG, which further strengthened the conclusion that the water content and the subsequent release of the water upon adsorption are important components of the adsorption process. PMID- 27476616 TI - Differences in availability of cancer drugs across Europe. PMID- 27476617 TI - Chemical constituents of Narcissus tazetta var. chinensis and their antioxidant activities. AB - Two new flavan derivatives tazettones C-D (1-2), one new beta-coumaranone (tazettone E, 3), one new flavan (tazettone F, 4), and one new phenylpropanoid (tazettone G, 5), together with six known flavonoids (6-11), were isolated from the bulbs of Narcissus tazetta var. chinensis Roem. Their structures were elucidated by spectroscopic analysis. In addition, the structures of 1-3 were confirmed by single crystal X-ray diffraction. All isolated compounds were tested for antioxidant activity by Cell Counting Kit-8 (CCK-8) assay. Compounds 6-8 and 10-11 exhibited potent antioxidant activity against H2O2-induced impairment in human SH-SY5Y neuroblastoma cells at tested concentrations. PMID- 27476618 TI - Modulation of plasminogen activator inhibitor-1 (PAI-1) by the naphthoquinone shikonin. AB - Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. Elevated levels of PAI-1 are associated with thrombosis and cardiovascular and metabolic diseases. Inhibition of PAI-1 activity represents a new strategy for antithrombotic and antifibrinolysis therapies. In this study, we systematically investigated the inhibitory effect of shikonin on PAI-1 activity. In the chromogenic substrate-based urokinase (uPA)/PAI-1 assay, we found that shikonin inhibited human PAI-1 activity with IC50 values of 30.68+/-2.32MUM. This result was further confirmed by urokinase-type plasminogen activator (uPA) mediated clot lysis assay. Mechanistic studies indicated that shikonin directly could bind to PAI-1 and prevent the binding of PAI-1 to uPA in a dose-dependent manner. Shikonin also blocked the formation of PAI-1/uPA complex, as shown by SDS/PAGE analysis. In the mouse arterial thrombosis model, intraperitoneal injection of shikonin at 1mgkg(-1) dose significantly prolonged tail bleeding time from 12.956+/-4.457min to 26.576+/-2.443min. It also reduced arterial thrombus weight from 0.01+/-0.001g to 0.006+/-0.001g (p<0.05). In a liver fibrosis treatment model, when shikonin was continuously injected intraperitoneally at a dose of 1mgkg(-1) over a two-week period, the hydroxyproline content in the mice plasma was significantly reduced and the degree of liver fibrosis was decreased significantly. Thus, shikonin may represent a novel small molecule inhibitor of PAI-1 that could have become a lead drug the treatment of thrombus and fibrosis. PMID- 27476620 TI - The search for new biomarkers in systemic sclerosis. PMID- 27476619 TI - Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study. AB - BACKGROUND: There are no existing longitudinal studies of inflammatory markers and atopic disorders in childhood and risk of hypomanic symptoms in adulthood. This study examined if childhood: (1) serum interleukin-6 (IL-6) and C-reactive protein (CRP); and (2) asthma and/or eczema are associated with features of hypomania in young adulthood. METHOD: Participants in the Avon Longitudinal Study of Parents and Children, a prospective general population UK birth cohort, had non-fasting blood samples for IL-6 and CRP measurement at the age of 9 years (n = 4645), and parents answered a question about doctor-diagnosed atopic illness before the age of 10 years (n = 7809). These participants completed the Hypomania Checklist at age 22 years (n = 3361). RESULTS: After adjusting for age, sex, ethnicity, socio-economic status, past psychological and behavioural problems, body mass index and maternal postnatal depression, participants in the top third of IL-6 values at 9 years, compared with the bottom third, had an increased risk of hypomanic symptoms by age 22 years [adjusted odds ratio 1.77, 95% confidence interval (CI) 1.10-2.85, p < 0.001]. Higher IL-6 levels in childhood were associated with adult hypomania features in a dose-response fashion. After further adjustment for depression at the age of 18 years this association remained (adjusted odds ratio 1.70, 95% CI 1.03-2.81, p = 0.038). There was no evidence of an association of hypomanic symptoms with CRP levels, asthma or eczema in childhood. CONCLUSIONS: Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania. Inflammatory pathways may be suitable targets for the prevention and intervention for bipolar disorder. PMID- 27476621 TI - Overlap between systemic sclerosis and rheumatoid arthritis: a distinct clinical entity? AB - INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disease of the connective tissue characterized by the triad of vascular injury, autoimmunity (cellular and humoral) and tissue fibrosis. It is estimated that musculoskeletal pain is a common complaint of patients with SSc, ranging from 40 to 80%, and mainly in patients with early diffuse disease. Arthritis, clinically observed, may be a feature seen in the presentation of SSc, often leading to early diagnostic errors with rheumatoid arthritis (RA). In the course of the disease, arthritis is observed in 24-97% of patients with SSc. OBJECTIVES: To correlate the occurrence or nonoccurrence of arthritis in patients with SSc of the Midwest region of Brazil with possible distinct clinical and laboratory manifestations observed in three groups of patients. To report the frequency of true association between systemic sclerosis and rheumatoid arthritis in patients with clinically and radiologically observed synovitis. METHODS: Sixty-one SSc patients were subsequently assessed every 3 months within 1 year, in order to clinically observe the occurrence of synovitis and its patterns of progression. Patients were divided into 3 groups: 41 patients with SSc without arthritis, 16 SSc patients with arthritis and 4 patients with overlap of SSc and RA. All patients underwent a radiological examination of the hands at the end of the study. RESULTS: Among all patients evaluated, we found a female predominance (98.7%), mean age of 50.94 years, white color (49.2%), limited form of the disease (47.6%), time of diagnosis between 5 and 10 years (47.6%) and duration of the disease of 8.30 years. Among all patients, 14 (22.9%) had positive rheumatoid factor (RF), while among those with positive RF, only 10 patients had arthritis during one-year follow-up. The antibody anticitrulline (anti-CCP) test was performed in 24 patients, being positive in 4 of them (16.7%), with positivity being observed only in patients with SSc/RA overlap. Comparing the clinical manifestations among the groups of patients, there was a higher incidence of gastritis and cardiac valvulopathy in patients with SSc and arthritis, but not in the others. In the group of patients with SSc/RA overlap and in patients with SSc and arthritis a significant reduction in quality of life was observed, measured by HAQ index, especially in patients with arthritis present during clinical evaluation. We found radiographic changes in 42.6% of patients with SSc. However, in patients with synovitis, radiological changes consistent with rheumatoid arthritis were found in 50% of patients. CONCLUSIONS: While the frequency of clinical arthritis observed in patients with systemic sclerosis was 32.8%, the true overlap between of SSc and RA was 6.6% in this study. We also observed the frequency of positive anti-CCP in 20% of patients with arthritis versus no patients with SSc without arthritis. PMID- 27476623 TI - Serum Clara cell 16-kDa protein levels and lung impairment in systemic sclerosis patients. AB - OBJECTIVE: To assess clinical utility of serum Clara cell 16-kDa protein measurements in relation with staging system for systemic sclerosis associated interstitial lung disease. MATERIALS AND METHODS: Serum levels of Clara cell 16 kDa protein were determined by ELISA in 28 systemic sclerosis patients and 30 healthy controls, and correlated with staging system for systemic sclerosis associated interstitial lung disease in systemic sclerosis patients. Lung involvement was assessed functionally (body plethysmography, diffusing capacity of the lung for carbon monoxide) and radiologically (an average disease extent on high resolution computed tomography of the lungs) in SSc patients. RESULTS: We observed statistically significant differences in serum Clara cell 16-kDa protein levels between systemic sclerosis patients and healthy controls only in non smokers. However, serum Clara cell 16-kDa protein concentrations were significantly elevated in patients with high resolution computed tomography extent >20% in comparison to patients with high resolution computed tomography extent <20% (p=0.01). They correlated positively with average disease extent on high resolution computed tomography (p=0.04), an extent of a reticular pattern on high resolution computed tomography (p<0.01), and negatively with a total lung capacity (p=0.03) and the results of the 6-min walk test (p<0.01). CONCLUSIONS: Clara cell 16-kDa protein levels can be considered as a supplemental serum biomarker for systemic sclerosis associated interstitial lung disease. PMID- 27476622 TI - (18)F-Fluorodeoxyglucose positron emission tomography and serum cytokines and matrix metalloproteinases in the assessment of disease activity in Takayasu's arteritis. AB - OBJECTIVE: To evaluate (18)F-fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography-computed tomography (PET-CT) and serum levels of different cytokines and matrix metalloproteinases (MMPs) in patients with Takayasu arteritis (TA) and associations with disease activity. METHODS: Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-2, IL-6, IL-8, IL-12, IL-18, MMP-3 and MMP-9 were measured in 36 TA patients and 36 controls. Maximum standard uptake value (SUVmax) of (18)F-FDG in arterial walls was determined by PET-CT scans. TA patients were classified as active disease, inactive disease and possible active disease. RESULTS: Serum IL-6 and MMP-3 levels were higher in TA patients than in controls (p<0.001). Serum IL-6 was higher in patients with active disease and in patients with possible active disease than in inactive disease (p<0.0001). Patients with active disease had higher serum TNFalpha levels than patients with inactive disease (p=0.049) while patients with possible active disease presented higher IL-18 levels than patients with inactive disease (p=0.046). Patients with active disease had higher SUVmax values than those with inactive disease (p=0.042). By receiver operating characteristic (ROC) curve SUVmax was predictive of active disease in TA and values >=1.3 were associated with disease activity (p=0.039). Serum TNF-alpha levels were higher in patients with SUVmax>=1.3 than <1.3 (p=0.045) and controls (p=0.012). Serum IL-6 levels were higher in patients with SUVmax>=1.3 than in controls (p<0.001). No differences regarding other biomarkers were found between TA patients and controls. CONCLUSIONS: Higher serum IL-6 and TNFalpha levels as well as higher (18)F-FDG uptake in arterial wall are associated with active TA. PMID- 27476624 TI - Familial autoimmunity and polyautoimmunity in 60 Brazilian Midwest patients with systemic sclerosis. AB - INTRODUCTION: Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, characterized by a triad of vascular injury, autoimmunity and tissue fibrosis. It is known that a positive family history is the greatest risk factor already identified for the development of SSc in a given individual. Preliminary observation of a high prevalence of polyautoimmunity and of familial autoimmunity in SSc patients support the idea that different autoimmune phenotypes may share common susceptibility variants. OBJECTIVES: To describe the frequency of familial autoimmunity and polyautoimmunity in 60 SSc patients in the Midwest region of Brazil, as well as to report the main autoimmune diseases observed in this association of comorbidities. METHODS: A cross-sectional study with recruitment of 60 consecutive patients selected at the Rheumatology Department, University Hospital, Medicine School, Federal University of Mato Grosso do Sul (FMUFMS), as well as interviews of their relatives during the period from February 2013 to March 2014. RESULTS: A frequency of 43.3% of polyautoimmunity and of 51.7% of familial autoimmunity in SSc patients was found. Patients with the presence of polyautoimmunity and familial autoimmunity presented primarily the diffuse form of SSc, but this indicator did not reach statistical significance. The autoimmune diseases most frequently observed in polyautoimmunity patients were: Hashimoto's thyroiditis (53.8%), Sjogren's syndrome (38.5%), and inflammatory myopathy (11.5%). The main autoimmune diseases observed in SSc patients' relatives were: Hashimoto's thyroiditis (32.3%), rheumatoid arthritis (22.6%), and SLE (22.6%). The presence of more than one autoimmune disease in SSc patients did not correlate with disease severity or activity. CONCLUSIONS: From the high prevalence of coexisting autoimmune diseases found in SSc patients, we stress the importance of the concept of shared autoimmunity, in order to promote a continued vigilance and promptly diagnose other possible autoimmune disease in patients, or in their kin. PMID- 27476625 TI - Substance use and sexual function in juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate alcohol/tobacco/illicit drug use and sexual function in adolescent juvenile idiopathic arthritis (JIA) and healthy controls. METHODS: 174 adolescents with pediatric rheumatic diseases were selected. A cross-sectional study with 54 JIA patients and 35 controls included demographic/anthropometric data and puberty markers assessments, physician-conducted CRAFFT (car/relax/alone/forget/friends/trouble) screen tool for substance abuse/dependence high risk and a questionnaire that evaluated sexual function, bullying and alcohol/tobacco/illicit drug use. Clinical/laboratorial data and treatment were also assessed in JIA. RESULTS: The median current age was similar between JIA patients and controls [15(10-19) vs. 15(12-18) years, p=0.506]. Frequencies of alcohol/tobacco/illicit drug use were high and similar in both JIA and controls (43% vs. 46%, p=0.829). However, age at alcohol onset was significantly higher in those with JIA [15(11-18) vs. 14(7-18) years, p=0.032], particularly in polyarticular onset (p=0.040). High risk for substance abuse/dependence (CRAFFT score>=2) was found in both groups (13% vs. 15%, p=1.000), likewise bullying (p=0.088). Further analysis of JIA patients regarding alcohol/tobacco/illicit drug use showed that the median current age [17(14-19) vs. 13(10-19)years, p<0.001] and education years [11(6-13) vs. 7(3-12)years, p<0.001] were significant higher in those that used substances. Sexual activity was significantly higher in the former group (48% vs. 7%, p<0.001). A positive correlation was evidenced between CRAFFT score and current age in JIA patients (p=0.032, r=+0.296). CONCLUSION: A high risk for substance abuse/dependence was observed in both JIA and controls. JIA substance users were more likely to have sexual intercourse. Therefore, routine screening is suggested in all visits of JIA adolescents. PMID- 27476626 TI - Prevalence of anxiety, depression and kinesiophobia in patients with low back pain and their association with the symptoms of low back spinal pain. AB - OBJECTIVE: To evaluate the prevalence of anxiety, depression and kinesiophobia and their association with the symptoms of low back pain. METHODS: A total of 65 patients were divided into three groups: Organic, Amplified Organic and Non Organic. They answered the Beck Anxiety Inventory, Beck Depression Inventory and Tampa Scale of Kinesiophobia and were evaluated according to their pain level using the Visual Analogic Scale. RESULTS: The average kinesiophobia scores of the patients in the Organic, Amplified Organic and Non-Organic groups were 36.26, 36.21 and 23.06 points, respectively. Patients who were classified into the Organic group experienced the most kinesiophobia out of all three groups (p=0.007). The average anxiety scores of the patients in the Organic, Amplified Organic and Non-Organic groups were 33.17, 32.79 and 32.81 points, respectively, with no significant difference among the groups (p=0.99). The average depression scores of the patients in the Organic, Amplified Organic and Non-Organic groups were 32.54, 28.79 and 37.69 points, respectively, with no significant difference among the groups (p=0.29). CONCLUSION: There was no association between the groups and anxiety and depression. However, there was a positive correlation between kinesiophobia and the Organic group. Studies of other patient samples are needed to confirm the reproducibility and validity of these data in other populations. PMID- 27476627 TI - Low vitamin D serum levels in diffuse systemic sclerosis: a correlation with worst quality of life and severe capillaroscopic findings. AB - OBJECTIVE: The aim of this study was to analyze the correlation of vitamin D levels with clinical parameters, bone mineral density (BMD), quality of life (QoL) and nailfold capillaroscopy (NC) in patients with diffuse systemic sclerosis (SSc). METHODS: Thirty-eight female patients with diffuse SSc were analyzed regarding 25-hydroxyvitamin D (25OHD) serum levels. At inclusion, organ involvement, autoantibodies, modified Rodnan skin score (mRSS), Medsger Disease Severity Index (MDSI), body mass index (BMI), BMD, NC, Short-Form-36 Questionnaire (SF-36), and Health Assessment Questionnaire (HAQ), were performed through a standardized interview, physical examination and electronic chart review. RESULTS: Mean 25OHD serum level was 20.66+/-8.20ng/mL. Eleven percent of the patients had 25OHD levels <=10ng/mL, 50% <=20ng/mL and 87% <=30ng/mL. Vitamin D serum levels were positively correlated with BMI (r=0.338, p=0.038), BMD-total femur (r=0.340, p=0.037), BMD-femoral neck (r=0.384, p=0.017), SF-36-Vitality (r=0.385, p=0.017), SF-36-Social Function (r=0.320, p=0.050), SF-36-Emotional Role (r=0.321, p=0.049) and SF-36-Mental Health (r=0.531, p=0.0006) and were negatively correlated with HAQ-Reach (r=-0.328, p=0.044) and HAQ-Grip Strength (r=-0.331, p=0.042). A negative correlation with NC-diffuse devascularization (p=0.029) and NC-avascular area (p=0.033) was also observed. CONCLUSION: The present study provides novel evidence demonstrating that low levels of 25OHD have a negative impact in diffuse SSc QoL and further studies are needed to define whether vitamin D supplementation can improve health related QoL in these patients. The additional observation of a correlation with severe NC alterations suggests a possible role of 25OHD in the underlying SSc vascular involvement. PMID- 27476629 TI - The effects of the Pilates method in the elderly: a systematic review. AB - Several studies show the benefits of including muscle strength and aerobic physical activity in the routine of elderly people. Among the various possibilities of physical activity, the Pilates method has become a popular modality in recent years, through a system of exercises enabling to work the whole body and that corrects posture and realigns the muscles, developing the body stability needed for a healthier life. The aim of this study was to review the current evidence on the effects of the practice of the Pilates method in the elderly. A systematic literature review was conducted in the following electronic databases: Pubmed, Scielo, Lilacs/Bireme, Scopus, Pedro and Isi of Knowledge, from descriptors pilates, elderly, old adults, aging. In the selection of studies the following inclusion criteria were used: original articles in English, Portuguese and Spanish languages. All selection and evaluation processes of the articles were performed by peers and the quality was verified by the Downs and Black scale. Twenty-one studies were included. The year of publication ranged from 2003 to 2014 and the size of the sample varied from 8 to 311 elderly subjects, aged at least 60 years old. The intervention period was from 4 weeks to 12 months of Pilates exercise practice. It was concluded that despite the studies pointing to physical and motor benefits of the Pilates method in the elderly, we cannot state whether or not the method is effective, in view of the poor methodological quality of the studies included in this review. PMID- 27476628 TI - Swimming and cycling do not cause positive effects on bone mineral density: a systematic review. AB - Osteoporosis is considered a common metabolic bone disease and its prevalence is increasing worldwide. In this context, physical activity has been used as a non pharmacological tool for prevention and auxiliary treatment of this disease. The aim of this systematic review was to evaluate the effects of cycling and swimming practice on bone mineral density (BMD). This research was conducted in accordance with the recommendations outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The studies were consulted in the period from 2004 to 2014, through major electronic databases: PubMed((r)), SciELO((r)) and LILACS((r)). Ten studies evaluated the effects of cycling on BMD, and the results showed that nine studies have linked the practice of professional cycling with low levels of BMD. Another 18 studies have reported that swimming has no positive effects on bone mass. We conclude that cycling and swimming do not cause positive effects on BMD; thus, these are not the most suitable exercises for prevention and treatment of osteoporosis. PMID- 27476630 TI - Intracerebral hemorrhage with a favorable outcome in a patient with childhood primary angiitis of the central nervous system. AB - Childhood primary angiitis of the central nervous system (cPACNS) is a rare inflammatory brain disease of unknown etiology. Of note, brain hemorrhage has been rarely reported in cPACNS patients, generally associated with a delayed clinical diagnosis, or with a diagnosis only at necropsy. We present the case of a boy with cPACNS that previously suffered an ischemic stroke. At the age of 7 years and 10 months, he presented a sudden and severe headache, vomiting and reduction in consciousness level (Glasgow coma scale 7), requiring prompt tracheal intubation. Brain computed tomography demonstrated intraparenchymal hematoma in the right parieto-occipital lobe and a small focus of bleeding in the right frontal lobe, vasogenic edema, herniation of the uncus and a 10mm deviation to the left from the midline. C-reactive protein (9.2mg/dL) and von Willebrand factor (vWF) antigen (202%) were elevated. Decompressive craniotomy was performed and methylprednisolone and cyclophosphamide were administered. One week later, the patient had left hemiparesis without other sequelae. Importantly, motor deficits have been improving progressively. Our case reinforces the inclusion of this vasculitis as a differential diagnosis in children and adolescents with CNS hemorrhage. PMID- 27476631 TI - Leflunomide in Takayasu arteritis - A long term observational study. AB - OBJECTIVE: To evaluate the extended follow-up data on efficacy and toxicity of leflunomide therapy in Takayasu arteritis (TA) patients previously enrolled in the original open-label study of short-term effects of leflunomide in TA. METHODS: An open-label long-term longitudinal study was performed in TA patients who fulfilled the 1990 American College of Rheumatology criteria for TA and had participated in a previous study that evaluated short-term efficacy of leflunomide in TA. Complete follow-up information could be retrieved from 12 out of 15 patients enrolled in the original study. Disease activity was evaluated by Kerr's criteria and by the Indian Takayasu Activity Score 2010 (ITAS2010). RESULTS: The mean follow up time was 43.0+/-7.6 months and 5 (41.6%) TA patients remained on leflunomide therapy while 7 (58.3%) TA patients had to change to another therapy due to failure to prevent relapses in 6 patients and toxicity in one patient. No significant differences were found between patients who remained on leflunomide therapy and those who changed to another agent regarding age at study entry, time since diagnosis, prednisone daily dose at study entry, baseline ITAS2010, mean or maximum ESR and CRP, and cumulative prednisone dose at study end. Among TA patients who had changed leflunomide to another agent, two had an additional clinical relapse and needed to change therapy. CONCLUSION: Leflunomide led to sustained remission in approximately half of patients at a mean time of 12 months and was well tolerated by TA patients. PMID- 27476632 TI - Erratum to "Recommendations from the Brazilian Society of Rheumatology on the diagnosis and treatment of intestinal parasitic infections in patients with autoimmune rheumatic disorders" [Rev Bras Reumatol. 2015;55(4):368-380]. PMID- 27476633 TI - Monitoring single coffee bean roasting by direct volatile compound analysis with proton transfer reaction time-of-flight mass spectrometry. AB - This study applies proton transfer reaction time-of-flight mass spectrometry for the rapid analysis of volatile compounds released from single coffee beans. The headspace volatile profiles of single coffee beans (Coffeea arabica) from different geographical origins (Brazil, Guatemala and Ethiopia) were analyzed via offline profiling at different stages of roasting. The effect of coffee geographical origin was reflected on volatile compound formation that was supported by one-way ANOVA. Clear origin signatures were observed in the formation of different coffee odorants. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476634 TI - A Decision Tree to Identify Children Affected by Prenatal Alcohol Exposure. AB - OBJECTIVE: To develop and validate a hierarchical decision tree model that combines neurobehavioral and physical measures to identify children affected by prenatal alcohol exposure even when facial dysmorphology is not present. STUDY DESIGN: Data were collected as part of a multisite study across the US. The model was developed after we evaluated more than 1000 neurobehavioral and dysmorphology variables collected from 434 children (8-16 years of age) with prenatal alcohol exposure, with and without fetal alcohol syndrome, and nonexposed control subjects, with and without other clinically-relevant behavioral or cognitive concerns. The model subsequently was validated in an independent sample of 454 children in 2 age ranges (5-7 years or 10-16 years). In all analyses, the discriminatory ability of each model step was tested with logistic regression. Classification accuracies and positive and negative predictive values were calculated. RESULTS: The model consisted of variables from 4 measures (2 parent questionnaires, an IQ score, and a physical examination). Overall accuracy rates for both the development and validation samples met or exceeded our goal of 80% overall accuracy. CONCLUSIONS: The decision tree model distinguished children affected by prenatal alcohol exposure from nonexposed control subjects, including those with other behavioral concerns or conditions. Improving identification of this population will streamline access to clinical services, including multidisciplinary evaluation and treatment. PMID- 27476635 TI - Para-Dichlorobenzene Exposure Is Associated with Thyroid Dysfunction in US Adolescents. AB - OBJECTIVE: To examine the association between exposure to para-dichlorobenzene, measured as urinary concentrations of 2,5-dichlorophenol (2,5-DCP), and thyroid function in US adolescents. STUDY DESIGN: A nationally representative subsample of 618 adolescents aged 12-19 years in the 2007-2008 and 2011-2012 National Health and Nutrition Examination Survey was analyzed for the association of urinary 2,5-DCP with serum thyroid function measures using multivariate logistic and general linear regression models. RESULTS: After adjusting for potential confounders, we found a significantly positive association between urinary concentrations of 2,5-DCP and serum levels of thyroid-stimulating hormone and thyroglobulin in adolescents. Furthermore, urinary 2,5-DCP was associated with an increased prevalence of hypothyroidism in the study population. CONCLUSIONS: This study demonstrates a potential relationship between para-dichlorobenzene exposure, measured as urinary 2,5-DCP, and thyroid dysfunction in adolescents; however, further studies are needed to confirm our findings and to elucidate mechanisms of action. PMID- 27476636 TI - Social Determinants of Health Are Associated with Modifiable Risk Factors for Cardiovascular Disease and Vascular Function in Pediatric Type 1 Diabetes. AB - OBJECTIVE: To evaluate the relationship between social determinants of health (SDH) and cardiovascular disease (CVD) risk factors as well as a measure of arterial stiffness in adolescents with type 1 diabetes (T1D). STUDY DESIGN: SDH were measured with the validated Ontario Marginalization Index, derived from deidentified postal code data and stratified by quintile (first = least deprived; fifth = most deprived). SDH dimensions included material deprivation; ethnic concentration; and measures of dependency and residential instability. Metabolic control (hemoglobin A1c), cardiovascular risk metrics, and pulse wave velocity, as a measure of arterial stiffness, were related to SDH. Data were evaluated from a cohort of Canadian adolescents within the Adolescent Diabetes Cardiorenal Intervention Trial, a T1D clinical trial RESULTS: A total of 704 participants were evaluated, and significant differences in hemoglobin A1c were evident at the extremes of material deprivation (8.4% vs 9.1% for least vs most deprived, P < .01). CVD risk factors were analyzed in 199 participants, with the most deprived reporting significantly less exercise (P = .004) and increased rates of smoking (P = .008). Increased material deprivation was associated with fewer metrics of "ideal" cardiovascular health attained. Arterial stiffness, as measured by pulse wave velocity, was associated positively with age, body mass index z score, and material deprivation. CONCLUSION: Increased material deprivation was associated with poorer glycemic control. Modifiable, lifestyle related risk factors for CVD and early arterial wall change are associated with SDH and represent a target for clinical intervention to reduce future CVD burden in adolescents with T1D. PMID- 27476637 TI - The copper rush of the nineties. AB - The nineties witnessed the discovery of the copper ATPases, enzymes which transport copper across the cytoplasmic membranes of bacteria and eukaryotes. In the same decade, several other key components of copper homeostasis have also been discovered, like copper chaperones and plasma membrane copper transporters. This has finally led to a molecular understanding of two inherited human diseases related to copper: Menkes disease, manifested by systemic copper deficiency, and Wilson disease, caused by defective secretion of excess copper. A historic perspective and untold stories of the events leading up to these discoveries are presented here. PMID- 27476639 TI - Serial optic nerve sheath diameter ultrasonography during pediatric diabetic ketoacidosis management: A pilot study. AB - OBJECTIVE: Intracranial hypertension is an infrequent but serious acute complication of pediatric diabetic ketoacidosis (DKA). Subclinical elevations of intracranial pressures however, may be more common, and can be indirectly evaluated with ultrasonography of the optic nerve sheath diameter (ONSD). In this pilot study, we report serial data on ONSD trajectories from five pediatric patients with DKA to generate hypotheses for future studies. METHODS: Five pediatric patients with type 1 diabetes presented to our emergency department with DKA and enrolled in our study <3h after initiation of treatment. Ultrasonographic evaluation of the ONSD was conducted at presentation, every three hours until resolution of acidosis, and finally 24h post presentation. Following each interval evaluation, a clinical bedside neurologic tool developed for detecting cerebral edema in DKA was utilized. RESULTS: Four of the five patients exhibited a similar "bell" shaped trajectory - an increase of ONSD after initiation of treatment followed by a return to admission baseline. Patients demonstrated peak ONSDs nine and twelve hours after DKA therapy was initiated, at resolution of acidosis, and at admission. No children exhibited clinical signs suggestive of cerebral edema. CONCLUSIONS: Peak ONSDs cannot be reliability determined in children with DKA unless serial investigations are conducted. Practices to mitigate risks for intracranial hypertension may require constant surveillance during DKA management. PMID- 27476638 TI - Inhibition of T-cell activation attenuates hypertension, TNFalpha, IL-17, and blood-brain barrier permeability in pregnant rats with angiogenic imbalance. AB - PROBLEM: Angiogenic imbalance during pregnancy is associated with immune activation, hypertension, increased T cell infiltration, and neurological insults. METHOD OF STUDY: On gestational day (GD) 12, timed-pregnant rats were infused with anti-angiogenic factors sFlt-1 and sEndoglin (4.7 and 7 MUg/kg) to create HELLP syndrome via mini-osmotic pumps for 8 days, with a subset of these rats having Orencia (2 mg/kg) infused on GD13. On GD19, blood-brain barrier (BBB) permeability was evaluated via Evan's Blue infusion, blood was collected for T cell measurements, inflammatory cytokine secretion. Brain tissues were also collected to examine inflammatory cytokine infiltration. RESULTS: T-cell attenuation with Orencia decreased circulating CD4(+) and CD8(+) T cells, circulating tumor necrosis factor alpha (TNFalpha) and IL-17, BBB permeability and significantly decreased biochemical evidence of HELLP compared to untreated HELLP rats. CONCLUSIONS: These data support the hypothesis that T cells have a critical role in contributing to the pathophysiology that is seen in angiogenic imbalance during pregnancy. PMID- 27476640 TI - Suture Anchor Fixation in Osteoporotic Bone: A Biomechanical Study in an Ovine Model. AB - PURPOSE: To evaluate the load to failure strength of anchor techniques suitable for osteoporotic bone. METHODS: Using an osteoporotic ovine model in 72 humeri, 6 fixation techniques were tested. Group 1: two interlocking 5-mm anchors with fewer, wider threads; group 2: one 5-mm anchor; group 3: one 5-mm anchor reinforced laterally by a 6.5-mm cancellous screw; group 4: one 5-mm anchor in an area reinforced with a cancellous plug; group 5: two interlocking 5-mm anchors with smaller threads; group 6: one 5-mm smaller threaded anchor. After a 10-N preload, the specimens were cyclically loaded between 10 N and 30 N for 50 cycles and then destructively tested. Peak-to-peak displacement, cyclic elongation, ultimate load, stiffness, and failure mode were recorded. RESULTS: Group 1 had lower peak-to-peak displacement than group 3 (P = .001), group 5 (P = .001), and group 6 (P = .033). In addition, group 1 showed lower cyclic elongation than group 3 (P = .001), group 5 (P = .035), and group 6 (P = .001). Group 1 had a higher ultimate load than group 2 (P = .002), group 3 (P = .019), and group 6 (P = .006). Group 1 also showed higher stiffness than group 2 (P = .007) and group 3 (P = .022). Mode of failure was predominantly caused by anchor pullout for all of the groups except group 3, which mainly failed by suture rupture. CONCLUSIONS: Two interlocking suture anchors are stronger than a single anchor in osteoporotic bone. The anchor with fewer, wider threads and a smaller core diameter showed greater strength and less elongation than the other constructs. Reinforcement by cancellous autografting increased suture anchor strength. CLINICAL RELEVANCE: Considering concerns about suture anchor pullout from osteoporotic bone, interlocking a second suture anchor with the first increases load to failure resistance. Anchors with small core diameters and fewer but wider threads are more efficient in osteoporotic bone. PMID- 27476641 TI - Comparison of effect between group discussion and educational booklet on Iranian nursing students' attitude and practice toward patient privacy. AB - PURPOSE: This study aimed to compare the effects between group discussion and educational booklet on nursing students' attitude and practice toward patient privacy in Iran. METHODS: A two-group, pre-test and post-test design study was conducted in 2015. The study was conducted on 60 nursing students in Kashan, Iran who were randomly allocated into two groups to be trained on patient privacy either through group discussion or by an educational booklet. The students' attitude and practice was assessed before and after the education using a questionnaire and a checklist. Data analysis was performed through paired t-test, Wilcoxon signed ranks test, and independent samples t-tests. RESULTS: Before the intervention, no significant difference was found between the group designated to group discussion and that designated to the educational booklet in the mean overall score of attitude (P=0.303) and practice (P=0.493) toward patient privacy. After the intervention, the mean attitude score significantly increased in the two groups (P=0.001). Moreover, the students' practice score increased in the discussion group while it did not significantly change in the booklet group (P=0.001). CONCLUSION: Both methods were effective on the students' attitude; however, the educational booklet did not affect their practice toward patient privacy. Group discussion can effectively improve the students' attitude and practice toward patient privacy. PMID- 27476642 TI - Corrigendum to . PMID- 27476643 TI - A survey of parabens in commercial pharmaceuticals from China and its implications for human exposure. AB - Parabens are widely used as antimicrobial preservatives during pharmaceutical production. However, little information is available regarding the occurrence of parabens in commercial pharmaceuticals and their implications for human exposure. In this study, six commonly used parabens were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry with 100 commercial pharmaceuticals collected from China. Almost all of the pharmaceutical samples contained at least one kind of parabens with the detection frequency of 97%. The concentrations of Sigma6parabens (sum of the six parabens) ranged from below MDL to 1256ng/g, with mean and median values of 94.8 and 119ng/g, respectively. Methyl paraben (MeP), ethyl paraben (EtP) and propyl paraben (PrP) were the predominant compounds. Significant positive correlation was observed between concentrations of MeP and PrP, indicating their co-applications in pharmaceuticals. Levels of Sigma6parabens varied in different categories of pharmaceuticals and increased with their shelf lives. Based on the measured concentrations and daily ingestion rates of pharmaceuticals, the estimated daily intake (EDI) of parabens was calculated. The median values of EDIpharmaceutical for male adults, female adults and children were 4.05, 4.75 and 9.73ng/kg-bw/day, respectively, which were three orders of magnitude lower than those from foodstuffs and personal care products (PCPs). It was firstly reported that the total exposure dose was 0.326mg/kg-bw/day via foodstuffs, PCPs, and pharmaceuticals for Chinese female adults. PMID- 27476644 TI - Pharmacokinetics of butafosfan after intravenous and intramuscular administration in piglets. AB - The pharmacokinetics and bioavailability of butafosfan in piglets were investigated following intravenous and intramuscular administration at a single dose of 10 mg/kg body weight. Plasma concentration-time data and relevant parameters were best described by noncompartmental analysis after intravenous and intramuscular injection. The data were analyzed through WinNolin 6.3 software. After intravenous administration, the mean pharmacokinetic parameters were determined as T1/2lambdaz of 3.30 h, Cl of 0.16 L kg/h, AUC of 64.49 +/- 15.07 MUg h/mL, Vss of 0.81 +/- 0.44/kg, and MRT of 1.51 +/- 0.27 h. Following intramuscular administration, the Cmax (28.11 MUg/mL) was achieved at Tmax (0.31 h) with an absolute availability of 74.69%. Other major parameters including AUC and MRT were 48.29 +/- 21.67 MUg h/mL and 1.74 +/- 0.29 h, respectively. PMID- 27476645 TI - Spectral sensitivity of guppy visual pigments reconstituted in vitro to resolve association of opsins with cone cell types. AB - The guppy (Poecilia reticulata) shows remarkable variation of photoreceptor cells in the retina, especially those sensitive to middle-to-long wavelengths of light. Microspectrophotometry (MSP) has revealed varying "green", "green-yellow" and "yellow" cone cells among guppies in Trinidad and Venezuela (Cumana). In the guppy genome, there are four "long-wave" opsin loci (LWS-1, -2, -3 and -4). Two LWS-1 alleles have potentially differing spectral sensitivity (LWS-1/180Ser and LWS-1/180Ala). In addition, two "middle-wave" loci (RH2-1 and -2), two "short wave" loci (SWS2-A and -B), and a single "ultraviolet" locus (SWS1) as well as a single "rhodopsin" locus (RH1) are present. However, the absorption spectra of these photopigments have not been measured directly and the association of cell types with these opsins remains speculative. In the present study, we reconstituted these opsin photopigments in vitro. The wavelengths of maximal absorbance (lambdamax) were 571nm (LWS-1/180Ser), 562nm (LWS-1/180Ala), 519nm (LWS-3), 516nm (LWS-2), 516nm (RH2-1), 476nm (RH2-2), 438nm (SWS2-A), 408nm (SWS2 B), 353nm (SWS1) and 503nm (RH1). The lambdamax of LWS-3 is much shorter than the value expected (560nm) from the "five-sites" rule. The two LWS-1 alleles could explain difference of the reported MSP lambdamax values for the yellow cone class between Trinidad and Cumana guppies. Absence of the short-wave-shifted LWS-3 and the green-yellow cone in the green swordtail supports the hypothesis that this cell class of the guppy co-expresses the LWS-1 and LWS-3. These results reveal the basis of variability in the guppy visual system and provide insight into the behavior and ecology of these tropical fishes. PMID- 27476646 TI - Workflow efficiency for the treatment planning process in CT-guided high-dose rate brachytherapy for cervical cancer. AB - PURPOSE: To investigate process efficiency, we present a prospective investigation of the treatment planning phase of image-guided brachytherapy (BT) for cervical cancer using a specific checklist. METHODS AND MATERIALS: From October 2012 to January 2014, 76 BT procedures were consecutively performed. Prospective data on the CT-based treatment planning process was collected using a specific checklist which details the following steps: (1) dosimetry planning, (2) physician review start, (3) physician review time, (4) dosimetry processing, (5) physics review start, (6) physics review, and (7) procedural pause. Variables examined included the use of a pre-BT MRI, clinic duty conflicts, resident teaching, and the use of specific BT planners. Analysis was performed using descriptive statistics, t-test, and analysis of variance. RESULTS: Seventy-five prospectively gathered checklists comprised this analysis. The mean time for treatment planning was 95 minutes (med 94, std 18). The mean intervals in the above steps were (1) = 42, (2) = 5, (3) = 19, (4) = 10, (5) = 6, (6) = 13, and (7) = 26 minutes. There was no statistical difference in patients who had a pre BT MRI. Resident teaching did not influence time, p = 0.17. Treatment planning time was decreased with a specific planner, p = 0.0015. CONCLUSIONS: A skillful team approach is required for treatment planning efficiency in image-guided BT. We have found that the specific BT planners can have a significant effect on the overall planning efficiency. We continue to examine clinical and workflow-related factors that will enhance our safety and workflow process with BT. PMID- 27476647 TI - Ultra-wide field imaging in the diagnosis and management of adult-onset Coats' disease. AB - BACKGROUND: The conventional fundus imaging covers up to 60 degrees of retina only. Although various montaging techniques can significantly increase the area that can be imaged, it is still difficult to image and document the peripheral retina. The purpose of this study is to describe the use of ultra-wide field imaging in the diagnosis and management of adult-onset Coats' disease. METHODS: This is a retrospective case series of three patients diagnosed with adult-onset Coats' disease that were treated at the retina clinic of our institute. The case records, conventional and ultra-wide field fluorescein angiograms and optical coherence tomography scans were reviewed. RESULTS: The ultra-wide field pseudo colour photographs and fluorescein angiograms were able to provide clinically useful information over and above that provided by conventional imaging. In all three patients, ultra-wide field angiography showed the temporal avascular periphery. In addition, it revealed retinal neovascularisation, peripheral vascular leakage and documented peripheral telangiectasia in selected patients. CONCLUSION: Ultra-wide field imaging provides information that can help in the diagnosis and management of adult-onset Coat's disease. This may lead to better visual outcomes in Coats' disease. PMID- 27476648 TI - The Emergency Medicine Events Register: An analysis of the first 150 incidents entered into a novel, online incident reporting registry. AB - OBJECTIVE: Incident reporting systems are critical to understanding adverse events, in order to create preventative and corrective strategies. There are very few systems dedicated to Emergency Medicine with published results. All EDs in Australia and New Zealand were contacted to encourage the use of an Emergency Medicine - specific online reporting system called the Emergency Medicine Events Register (EMER). METHODS: We conducted an analysis of the first 150 incidents entered into EMER. EMER captures Emergency-medicine-specific details including triage score, clinical presentation, outcome, contributing factors, mitigating factors, other specialities involved and patient journey stage. These details were analysed by an expert panel. RESULTS: Over the first 26 months, 150 incidents were reported into EMER. The most common categories reported, in order, were diagnostic error, procedural complication and investigation errors. Most incidents contained more than one category of error. The most common stage of the patient's journey in which an incident was detected was after discharge from the ED. CONCLUSION: A focus on correct diagnosis, procedure performance and investigation interpretation may reduce errors in the ED. The ability to learn from incidents and make system changes to enhance patient safety in healthcare organisations is an inherent part of providing a proactive, quality culture. PMID- 27476649 TI - Innervation of taste buds revealed with Brainbow-labeling in mouse. AB - Nerve fibers that surround and innervate the taste bud were visualized with inherent fluorescence using Brainbow transgenic mice that were generated by mating the founder line L with nestin-cre mice. Multicolor fluorescence revealed perigemmal fibers as branched within the non-taste epithelium and ending in clusters of multiple rounded swellings surrounding the taste pore. Brainbow labeling also revealed the morphology and branching pattern of single intragemmal fibers. These taste bud fibers frequently innervated both the peripheral bud, where immature gemmal cells are located, and the central bud, where mature, differentiated cells are located. The fibers typically bore preterminal and terminal swellings, growth cones with filopodia, swellings, and rounded retraction bulbs. These results establish an anatomical substrate for taste nerve fibers to contact and remodel among receptor cells at all stages of their differentiation, an interpretation that was supported by staining with GAP-43, a marker for growing fibers and growth cones. PMID- 27476650 TI - Corrigendum to "Long-term hospitalizations for schizophrenia in the Czech Republic 1998-2012" (Schizophr. Res. vol. 175, issues 1-3, August 2016, pages 180 185). PMID- 27476651 TI - Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions. AB - SERPINS comprise a large and functionally diverse family of serine protease inhibitors. Here, we report three unrelated families with loss-of-function mutations in SERPINB8 in association with an autosomal-recessive form of exfoliative ichthyosis. Whole-exome sequencing of affected individuals from a consanguineous Tunisian family and a large Israeli family revealed a homozygous frameshift mutation, c.947delA (p.Lys316Serfs(*)90), and a nonsense mutation, c.850C>T (p.Arg284(*)), respectively. These two mutations are located in the last exon of SERPINB8 and, hence, would not be expected to lead to nonsense-mediated decay of the mRNA; nonetheless, both mutations are predicted to lead to loss of the reactive site loop of SERPINB8, which is crucial for forming the SERPINB8 protease complex. Using Sanger sequencing, a homozygous missense mutation, c.2T>C (p.Met1?), predicted to result in an N-terminal truncated protein, was identified in an additional family from UAE. Histological analysis of a skin biopsy from an individual homozygous for the variant p.Arg284(*) showed disadhesion of keratinocytes in the lower epidermal layers plus decreased SERPINB8 levels compared to control. In vitro studies utilizing siRNA-mediated knockdown of SERPINB8 in keratinocytes demonstrated that in the absence of the protein, there is a cell-cell adhesion defect, particularly when cells are subjected to mechanical stress. In addition, immunoblotting and immunostaining revealed an upregulation of desmosomal proteins. In conclusion, we report mutations in SERPINB8 that are associated with exfoliative ichthyosis and provide evidence that SERPINB8 contributes to the mechanical stability of intercellular adhesions in the epidermis. PMID- 27476652 TI - GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation. AB - Vascular tumors are among the most common neoplasms in infants and children; 5% 10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention. PMID- 27476653 TI - Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. AB - In ~30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis. PMID- 27476655 TI - ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects. AB - Cellular homeostasis is maintained by the highly organized cooperation of intracellular trafficking systems, including COPI, COPII, and clathrin complexes. COPI is a coatomer protein complex responsible for intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus. The importance of such intracellular transport mechanisms is underscored by the various disorders, including skeletal disorders such as cranio-lenticulo-sutural dysplasia and osteogenesis imperfect, caused by mutations in the COPII coatomer complex. In this article, we report a clinically recognizable craniofacial disorder characterized by facial dysmorphisms, severe micrognathia, rhizomelic shortening, microcephalic dwarfism, and mild developmental delay due to loss-of function heterozygous mutations in ARCN1, which encodes the coatomer subunit delta of COPI. ARCN1 mutant cell lines were revealed to have endoplasmic reticulum stress, suggesting the involvement of ER stress response in the pathogenesis of this disorder. Given that ARCN1 deficiency causes defective type I collagen transport, reduction of collagen secretion represents the likely mechanism underlying the skeletal phenotype that characterizes this condition. Our findings demonstrate the importance of COPI-mediated transport in human development, including skeletogenesis and brain growth. PMID- 27476654 TI - De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. AB - Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%-6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders. PMID- 27476656 TI - Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens. AB - In 80% of infertile men with obstructive azoospermia caused by a congenital bilateral absence of the vas deferens (CBAVD), mutations are identified in the cystic fibrosis transmembrane conductance regulator gene (CFTR). For the remaining 20%, the origin of the CBAVD is unknown. A large cohort of azoospermic men with CBAVD was retrospectively reassessed with more stringent selection criteria based on consistent clinical data, complete description of semen and reproductive excurrent ducts, extensive CFTR testing, and kidney ultrasound examination. To maximize the phenotypic prioritization, men with CBAVD and with unilateral renal agenesis were considered ineligible for the present study. We performed whole-exome sequencing on 12 CFTR-negative men with CBAVD and targeted sequencing on 14 additional individuals. We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related individuals with X-linked transmission of their infertility. Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility. Our study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis. In men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect. PMID- 27476658 TI - Diisopropylethylamine/hexafluoroisopropanol-mediated ion-pairing ultra-high performance liquid chromatography/mass spectrometry for phosphate and carboxylate metabolite analysis: utility for studying cellular metabolism. AB - RATIONALE: Mass spectrometric (MS) analysis of low molecular weight polar metabolites can be challenging because of poor chromatographic resolution of isomers and insufficient ionization efficiency. These metabolites include intermediates in key metabolic pathways, such as glycolysis, the pentose phosphate pathway, and the Krebs cycle. Therefore, sensitive, specific, and comprehensive quantitative analysis of these metabolites in biological fluids or cell culture models can provide insight into multiple disease states where perturbed metabolism plays a role. METHODS: An ion-pairing reversed-phase ultra high-performance liquid chromatography (IP-RP-UHPLC)/MS approach to separate and analyze biochemically relevant phosphate- and carboxylic acid-containing metabolites was developed. Diisopropylethylamine (DIPEA) was used as an IP reagent in combination with reversed-phase liquid chromatography (RP-LC) and a triple quadrupole mass spectrometer using selected reaction monitoring (SRM) and negative electrospray ionization (NESI). An additional reagent, hexafluoroisopropanol (HFIP), which has been previously used to improve sensitivity of nucleotide analysis by UHPLC/MS, was used to enhance sensitivity. RESULTS: HFIP versus acetic acid, when added with the IP base, increased the sensitivity of IP-RP-UHPLC/NESI-MS up to 10-fold for certain analytes including fructose-1,6-bisphosphate, phosphoenolpyruvate, and 6-phosphogluconate. It also improved the retention of the metabolites on a C18 reversed-phase column, and allowed the chromatographic separation of important isomeric metabolites. This methodology was amenable to quantification of key metabolites in cell culture experiments. The applicability of the method was demonstrated by monitoring the metabolic adaptations resulting from rapamycin treatment of DB-1 human melanoma cells. CONCLUSIONS: A rapid, sensitive, and specific IP-RP-UHPLC/NESI-MS method was used to quantify metabolites from several biochemical pathways. IP with DIPEA and HFIP increased the sensitivity and improved chromatographic separation when used with reversed-phase UHPLC. PMID- 27476660 TI - Hydrogen isotopic analysis with a chromium-packed reactor of organic compounds of relevance to ecological, archaeological, and forensic applications. AB - RATIONALE: The delta(2) H values of some nitrogen-containing organic compounds measured by High-Temperature Conversion (HTC) with a glassy carbon reactor have been shown to be inaccurate. A probable explanation for these analytical inaccuracies is the formation of HCN, allowing some hydrogen atoms to escape isotope ratio measurement. We assess this isotopic effect in sample types commonly used for (paleo)ecological, environmental, archaeological, and forensic investigations. METHODS: The delta(2) HVSMOW-SLAP values and mass fraction H using a factory-recommended glassy carbon HTC reactor packing were compared with those obtained from using two Cr-containing reactor packings for a variety of N containing substances, including amino acids, collagen, hair, and silk. RESULTS: delta(2) HVSMOW-SLAP values and mass fraction H differed by reactor packing for most, but not all, N-containing samples. The delta(2) HVSMOW-SLAP difference was 10-11 0/00 for modern collagen and 12-14 0/00 for hair, demonstrating that reactor configuration is important for these proteins, and that the use of a chromium-packed reactor may be desirable. In contrast, Bombyx mori cocoon (silk) delta(2) HVSMOW-SLAP values did not differ with reactor type. In general, delta(2) HVSMOW-SLAP and mass fraction H differences by reactor packing increased with mass fraction nitrogen in the sample. With the Cr-packed reactor hydrogen mass fractions were at theoretically expected values, while the glassy carbon reactor produced lower yields of hydrogen. CONCLUSIONS: The protein and amino acid delta(2) HVSMOW-SLAP values measured by factory-recommended online HTC methods differ from those from Cr-containing reactor packing. The magnitude of the differences is variable with sample type; the molecular structure and diagenetic history of each sample may be important. Careful attention to this effect is therefore recommended for the delta(2) H measurement for all nitrogen containing analytes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476657 TI - Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling. AB - Vascular malformations are non-neoplastic expansions of blood vessels that arise due to errors during angiogenesis. They are a heterogeneous group of sporadic or inherited vascular disorders characterized by localized lesions of arteriovenous, capillary, or lymphatic origin. Vascular malformations that occur inside bone tissue are rare. Herein, we report loss-of-function mutations in ELMO2 (which translates extracellular signals into cellular movements) that are causative for autosomal-recessive intraosseous vascular malformation (VMOS) in five different families. Individuals with VMOS suffer from life-threatening progressive expansion of the jaw, craniofacial, and other intramembranous bones caused by malformed blood vessels that lack a mature vascular smooth muscle layer. Analysis of primary fibroblasts from an affected individual showed that absence of ELMO2 correlated with a significant downregulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration. Unexpectedly, elmo2-knockout zebrafish appeared phenotypically normal, suggesting that there might be human specific ELMO2 requirements in bone vasculature homeostasis or genetic compensation by related genes. Comparative phylogenetic analysis indicated that elmo2 originated upon the appearance of intramembranous bones and the jaw in ancestral vertebrates, implying that elmo2 might have been involved in the evolution of these novel traits. The present findings highlight the necessity of ELMO2 for maintaining vascular integrity, specifically in intramembranous bones. PMID- 27476659 TI - Compound-specific amino acid (15) N stable isotope probing of nitrogen assimilation by the soil microbial biomass using gas chromatography/combustion/isotope ratio mass spectrometry. PMID- 27476661 TI - Blood-specific isotopic discrimination factors in the Magellanic penguin (Spheniscus magellanicus). AB - RATIONALE: The use of stable isotopes for ecological studies has increased exponentially in recent years. Isotopic trophic studies are based on the assumption that animals are what they eat plus a discrimination factor. The discrimination factor is affected by many variables and can be determined empirically. The Magellanic penguin is a highly abundant marine bird that plays a key role in the southern oceans. This study provides the first estimation of the Magellanic penguin blood discrimination factor for (13) C and (15) N. METHODS: A two and a half month feeding experiment was performed, in which ten captive penguins were fed their main natural prey (anchovy Engraulis anchoita). The discrimination factors were estimated by comparing anchovy delta(13) C and delta(15) N values (obtained with isotope ratio mass spectrometry using lipid extracted and bulk anchovy muscle) with penguin blood delta(13) C and delta(15) N values. RESULTS: Penguin blood was shown to be enriched, compared with anchovies, for (13) C and (15) N. No changes were observed in the stable isotope ratios of anchovies and discrimination factors during the experiment. The overall discrimination factors were 0.93 +/- 0.12 (bulk) and 0.41 +/- 0.12 (lipid-free) for (13) C; and 2.81 +/- 0.17 (bulk) and 2.31 +/- 0.17 (lipid-free) for (15) N. CONCLUSIONS: Having an accurate discrimination factor for the studied species is key in any trophic or food web isotopic study. Comparisons of estimated diet-to blood discrimination factors with published values of aquatic piscivore birds showed that the (13) C discrimination factor is particularly variable, and therefore ecologists should be cautious when using a surrogate value from other species. In this study, the Magellanic penguin discrimination factor of a tissue that does not require euthanasia was obtained, a fundamental input for trophic isotopic modeling of the species. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476662 TI - Discontinuous atmospheric pressure interface for mass spectrometry using a solenoid pulse valve. AB - RATIONALE: For the development of on-site mass spectrometry for security and safety, point-of-care analysis, etc., the gas volume introduced into the vacuum should be reduced to a minimum. To cope with this demand, a discontinuous atmospheric pressure interface using a solenoid pulse valve was developed. METHODS: The sample gas was introduced discontinuously into the ionization cell with a volume of 0.17 cm(3) . The sampled gas in the cell was ionized by an alternating current (ac) corona discharge. The generated ions were sampled through a 0.25 mm i.d. and 12 mm long nickel capillary into the vacuum of a time of-flight mass spectrometer. RESULTS: A gas flow rate of ~25 mL/min was achieved with the 1 Hz pulse valve operation and 20 ms valve opening time. Sub-ng limits of detection for less volatile compounds such as explosives and drugs were obtained. CONCLUSIONS: Due to its compact size and low gas load to the vacuum, this new interface may be useful for applications in miniaturized mass spectrometry. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476663 TI - Accelerated hydrazone formation in charged microdroplets. AB - RATIONALE: Electrospray ionization-mass spectrometry (ESI-MS) is an emerging tool for reaction monitoring. It can be accompanied by reaction acceleration in charged droplets. METHODS: The time course of the bulk reaction of indoline-2,3 dione with phenylhydrazine in methanol to produce 3-(2- phenylhydrazono)indolin-2 one was monitored by ESI. Both nanoESI and electrosonic spray ionization (ESSI) were used for this study as representing two common forms of ionization for reaction monitoring. The effect on product yield of the distance the droplets travel between the source and the MS inlet was varied and product/starting material ratios were examined. RESULTS: Product yield is dramatically increased by increasing the distance. At short distances reaction monitoring can be performed without acceleration and at greater distances reaction acceleration occurs. This distance effect over the course of the reaction roughly parallels the time dependence of the bulk-phase reaction. CONCLUSIONS: Reaction acceleration in droplets is attributed to solvent evaporation leading to increased surface to volume ratios. An acceleration factor of 10(4) , measured relative to the bulk reaction at short times, is readily achieved by simply increasing the droplet distance of flight showing that the same ionization source can be used to monitor reactions with or without acceleration. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476664 TI - High pressure effects in high-field asymmetric waveform ion mobility spectrometry. AB - RATIONALE: High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) is an analytical technique based on the principle of non-linear electric field dependence of coefficient of mobility of ions for separation that was originally conceived in the Soviet Union in the early 1980s. Being well developed over the past decades, FAIMS has become an efficient method for the separation and characterization of gas-phase ions at ambient pressure, often in air, to detect trace amounts of chemical species including explosives, toxic chemicals, chemical warfare agents and other compounds. However the resolution of FAIMS and ion separation capability need to be improved for more applications of the technique. METHODS: The effects of above-ambient pressure varying from 1 to 3 atm on peak position, resolving power, peak width, and peak intensity are investigated theoretically and experimentally using micro-fabricated planar FAIMS in purified air. RESULTS: Peak positions, varying with pressure in a way as a function of dispersion voltage, could be simplified by expressing both compensation and dispersion fields in Townsend units for E/N, the ratio of electric field intensity (E) to the gas number density (N). CONCLUSIONS: It is demonstrated that ion Townsend-scale peak positions remain unchanged for a range of pressures investigated, implying that the higher the pressure is, stronger compensation and separation fields are needed within limits of air breakdown field. Increase in pressure is found to separate ions that could not be distinguished in ambient pressure, which could be interpreted as the differentials of ions' peak compensation voltage expanded wider than the dilation of peak widths leading to resolving power enhancement with pressure. Increase in pressure can also result in an increase in peak intensity. PMID- 27476666 TI - CETP Activity: A Link between Lipid Metabolism and Coagulation System. PMID- 27476667 TI - Antiplatelet Drugs and Endothelial Function. PMID- 27476665 TI - Functional Heterogeneity of Nadph Oxidases in Atherosclerotic and Aneurysmal Diseases. AB - NADPH oxidases (NOX) are enzymes that catalyze the production of reactive oxygen species (ROS). Four species of NOX catalytic homologs (NOX1, NOX2, NOX4, and NOX5) are reportedly expressed in vascular tissues. The pro-atherogenic roles of NOX1, NOX2, and their organizer protein p47ph degrees x were manifested, and it was noted that the hydrogen peroxide-generating enzyme NOX4 possesses atheroprotective effects. Loss of NOX1 or p47ph degrees x appears to ameliorate murine aortic dissection and subsequent aneurysmal diseases; in contrast, the ablation of NOX2 exacerbates the aneurysmal diseases. It is possible that the loss of NOX2 activates inflammatory cascades in macrophages in the lesions. Roles of NOX5 in vascular functions are currently undetermined, owing to the absence of this enzyme in rodents and the limitation of the experimental procedure. Thus, it is possible that the NOX family of enzymes exhibits heterogeneity in the atherosclerotic diseases. In this aspect, subtype-selective NOX inhibitor may be promising when NOX systems serve as a molecular target for atherosclerotic and aneurysmal diseases. PMID- 27476668 TI - Subsequent Response of VWF and ADAMTS13 to Aortic Valve Replacement. PMID- 27476669 TI - A Novel Link between Plasma MicroRNA-33b Levels and Lipid Disorders in Diabetes Mellitus. PMID- 27476671 TI - Haemophagocytosis and encephalitis in chronic lymphocytic leukaemia. PMID- 27476670 TI - NLRP3 protects alveolar barrier integrity by an inflammasome-independent increase of epithelial cell adherence. AB - Bacterial pneumonia is a major cause of acute lung injury and acute respiratory distress syndrome, characterized by alveolar barrier disruption. NLRP3 is best known for its ability to form inflammasomes and to regulate IL-1beta and IL-18 production in myeloid cells. Here we show that NLRP3 protects the integrity of the alveolar barrier in a mouse model of Streptococcus pneumoniae-induced pneumonia, and ex vivo upon treatment of isolated perfused and ventilated lungs with the purified bacterial toxin, pneumolysin. We reveal that the preserving effect of NLRP3 on the lung barrier is independent of inflammasomes, IL-1beta and IL-18. NLRP3 improves the integrity of alveolar epithelial cell monolayers by enhancing cellular adherence. Collectively, our study uncovers a novel function of NLRP3 by demonstrating that it protects epithelial barrier function independently of inflammasomes. PMID- 27476672 TI - Defect visualization of Cu(InGa)(SeS)2 thin films using DLTS measurement. AB - Defect depth profiles of Cu (In1-x,Gax)(Se1-ySy)2 (CIGSS) were measured as functions of pulse width and voltage via deep-level transient spectroscopy (DLTS). Four defects were observed, i.e., electron traps of ~0.2 eV at 140 K (E1 trap) and 0.47 eV at 300 K (E2 trap) and hole traps of ~0.1 eV at 100 K (H1 trap) and ~0.4 eV at 250 K (H2 trap). The open circuit voltage (VOC) deteriorated when the trap densities of E2 were increased. The energy band diagrams of CIGSS were also obtained using Auger electron spectroscopy (AES), X-ray photoelectron spectroscopy (XPS), and DLTS data. These results showed that the valence band was lowered at higher S content. In addition, it was found that the E2 defect influenced the VOC and could be interpreted as an extended defect. Defect depth profile images provided clear insight into the identification of defect state and density as a function of depth around the space charge region. PMID- 27476673 TI - Synthesis, characterization and in vitro evaluation of substituted N-(2 phenylcyclopropyl)carbamates as acetyl- and butyrylcholinesterase inhibitors. AB - A serie of O-substituted N-2-phenylcyclopropylcarbamates was prepared and characterized. These carbamates were tested as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was found, that these compounds exhibit moderate inhibition activity with values of IC50 in the range of 54.8 94.4 MUM (for AChE) and up to 5.8 MUM (for BChE). The AChE/BChE selectivity for each carbamate was calculated. These values varied from 0.50 to 9.46, two carbamate derivatives inhibited only AChE selectively. The most promising derivative was prepared in all optically pure forms (four isomers). It was found that individual stereoisomers differed only slightly in the inhibition ability. The cytotoxicity of all carbamates was evaluated using the standard in vitro test with Jurkat cells. With regard to their inhibition activity and cytotoxicity as well as easy preparation, O-substituted N-2-phenylcyclopropylcarbamates can be considered as promising compounds for potential medicinal applications. PMID- 27476674 TI - Influence of feed type and its effect on repressing wool-biting behavior in housed sheep. AB - Sheep sometimes develop an abnormal behavior termed as wool-biting when kept in an indoor system; however, little is known about this behavior. As the provided feed type may affect the foraging behavior and repress abnormal behavior in animals, we tested the effect of feed type on repressing wool-biting behavior in this study. We used hay prepared in three forms, that is hay bales, rolls and cubes. The wool-biting frequency associated with hay bales was significantly higher than that associated with rolls (P < 0.05) and cubes (P < 0.05); however, there was no significant difference between rolls and cubes. For hay rolls, wool biting significantly decreased after feeding (P < 0.05), suggesting that rolls may provide sheep with appropriate oral stimulation; thus, decreasing the post feeding oral abnormal behavior. An individual difference of wool-biting behavior between sheep was also detected, and an unexpected bed-eating behavior was found in the hay cube treatment. We suggest that sheep performing movements that are similar to their natural foraging behavior while grazing would repress wool biting behavior, which happened in hay roll and hay cube treatments. Considering sanitation and animal welfare, providing sheep with hay rolls may provide an easier method to control wool-biting behavior in housed sheep. PMID- 27476675 TI - Multi-color magnetic particle imaging for cardiovascular interventions. AB - Magnetic particle imaging (MPI) uses magnetic fields to visualize the spatial distribution of superparamagnetic iron oxide nanoparticles (SPIOs). Guidance of cardiovascular interventions is seen as one possible application of MPI. To safely guide interventions, the vessel lumen as well as all required interventional devices have to be visualized and be discernible from each other. Until now, different tracer concentrations were used for discerning devices from blood in MPI, because only one type of SPIO could be imaged at a time. Recently, it was shown for 3D MPI that it is possible to separate different signal sources in one volume of interest, i.e. to visualize and discern different SPIOs or different binding states of the same SPIO. The approach was termed multi-color MPI. In this work, the use of multi-color MPI for differentiation of a SPIO coated guide wire (Terumo Radifocus 0.035") from the lumen of a vessel phantom filled with diluted Resovist is demonstrated. This is achieved by recording dedicated system functions of the coating material containing solid Resovist and of liquid Resovist, which allows separation of their respective signal in the image reconstruction process. Assigning a color to the different signal sources results in a differentiation of guide wire and vessel phantom lumen into colored images. PMID- 27476676 TI - The response of two species of unionid mussels to extended exposure to elevated carbon dioxide. AB - Changes in environmental conditions can act as stressors, with potential consequences for the health and fitness of organisms. Rising levels of carbon dioxide (CO2) is one potential environmental stressor that is occurring more frequently in the environment and can be a stressor for aquatic organisms. In this study, the physiological responses of two species of unionid mussel, Lampsilis siliquoidea and Amblema plicata, were assessed in response to exposure to two levels of elevated partial pressure of CO2 (pCO2) (~20,000 and ~55,000MUatm) over a 28d period, followed by a subsequent 14d recovery period. Observations were consistent with responses associated with respiratory acidosis, as demonstrated by changes in hemolymph HCO3(-), Ca(2+), Cl(-), and Na(2+). Both species exposed to elevated pCO2 had elevated hemolymph HCO3(-) during the pCO2 treatment period compared to control mussels, but recovered once pCO2 was removed. Similarly, both species had elevated hemolymph Na(+) during exposure to elevated pCO2, and this returned to control levels for A. plicata but remained elevated for L. siliquoidea once the pCO2 stimuli was removed. Changes in hemolymph Ca(2+) and Cl(-) in response to elevated pCO2 were also observed, but these changes were species-specific. Additional physiological responses to elevated pCO2 (e.g., changes in hemolymph glucose and Mg(2+)) were consistent with a stress response in both species. This study demonstrates the importance of considering inter-specific differences in the response of organisms to stress, and also that responses to elevated pCO2 may be transient and can recover once the stress is removed. PMID- 27476678 TI - Flowing Liquid Anode Atmospheric Pressure Glow Discharge as an Excitation Source for Optical Emission Spectrometry with the Improved Detectability of Ag, Cd, Hg, Pb, Tl, and Zn. AB - A novel atmospheric pressure glow discharge generated in contact with a flowing liquid anode (FLA-APGD) was developed as the efficient excitation source for the optical emission spectrometry (OES) detection. Differences in the appearance and the electrical characteristic of the FLA-APGD and a conventional system operated with a flowing liquid cathode (FLC-APGD) were studied in detail and discussed. Under the optimal operating conditions for the FLA-APGD, the emission from the analytes (Ag, Cd, Hg, Pb, Tl, and Zn) was from 20 to 120 times higher as compared to the FLC-APGD. Limits of detections (LODs) established with a novel FLA-APGD system were on average 20 times better than those obtained for the FLC-APGD. A further improvement of the LODs was achieved by reducing the background shift interferences and, as a result, the LODs for Ag, Cd, Hg, Pb, Tl, and Zn were 0.004, 0.040, 0.70, 1.7, 0.035, and 0.45 MUg L(-1), respectively. The precision of the FLA-APGD-OES method was evaluated to be within 2-5% (as the relative standard deviation of the repeated measurements). The method found its application in the determination of the content of Ag, Cd, Hg, Pb, Tl, and Zn in a certified reference material (CRM) of Lobster hepatopancreas (TORT-2), four brass samples as well as mineral water and tea leaves samples spiked with the analytes. In the case of brass samples, a reference method, i.e., inductively coupled plasma optical emission spectrometry (ICP-OES) was used. A good agreement between the results obtained with FLA-APGD-OES and the certified values for the CRM TORT-2 as well as the reference values obtained with ICP-OES for the brass samples was revealed, indicating the good accuracy of the proposed method. The recoveries obtained for the spiked samples of mineral water and tea leaves were within the range of 97.5-102%. PMID- 27476679 TI - MiRNA-183-5p promotes cell proliferation and inhibits apoptosis in human breast cancer by targeting the PDCD4. AB - MicroRNAs are often aberrantly expressed in breast cancer and postulated to play a causal role in the onset and maintenance of breast cancer by binding to its target mRNA. Here, we evaluated the effects of miRNA-183-5p on cell proliferation and apoptosis which attempted to elucidate the potential role of miR-183-5p/PDCD4 axis in human breast cancer. We found that the miR-183-5p expression level was extremely promoted in breast cancer in comparison with the adjacent normal tissues. Overexpression of miR-183-5p significantly enhanced the cell proliferation and inhibited cell apoptosis in MCF-7 and MDA-MB-231 cells. Moreover, PDCD4 was predicted as a putative target of miR-183-5p by bioinformatic approaches, and miR-183-5p negatively regulated the expression of PDCD4. Furthermore, knockdown of PDCD4 suppressed expression of p21 and p27, which was consistent with the result of the attachment of miR-183-5p. These data collectively demonstrate that miR-183-5p exerts oncomiRs effects in breast cancer, and may have broad impacts on the field of using antimiRs as anti-cancer drugs for breast cancer. PMID- 27476677 TI - Lateral Ridge Augmentation Using Autogenous Block Grafts and Guided Bone Regeneration: A 10-Year Prospective Case Series Study. AB - BACKGROUND: The use of autogenous block grafts harvested from intraoral donor sites has proven to be effective for the reconstruction of horizontal bone defects. PURPOSE: The objective of this study was to analyze implant success and the rate of block graft resorption 10 years after ridge augmentation to elucidate contributing factors influencing graft maintenance. MATERIALS AND METHODS: A staged horizontal block graft augmentation was performed in 52 implant sites exhibiting severe horizontal bone atrophy using autogenous block grafts protected by DBBM and collagen membranes. The crest width was assessed intraoperatively at surgery and at re-entry after 6 months. At the 10 year reexamination clinical and radiographic parameters were assessed using cone beam computed tomography. RESULTS: The 10-year implant success rate amounted to 98.1%, with minimal peri implant bone loss (-0.17 mm for the maxilla, -0.09 mm for the mandible). The surface resorption rate after 10 years was 7.7% (0.38 mm). Grafts originating from the chin demonstrated significantly better graft maintenance at 10 years compared to retromolar grafts. Recipient site and age had no significant impact on graft resorption, whereas females showed more bone loss at the 10-year examination. CONCLUSIONS: Lateral ridge augmentation using autogenous block grafts and guided bone regeneration demonstrated a favorable success rate of 98.1% with minimal block graft resorption of 7.7% after 10 years. Modulating factors were origin of the graft and gender. PMID- 27476680 TI - Urban ponds as an aquatic biodiversity resource in modified landscapes. AB - Urbanization is a global process contributing to the loss and fragmentation of natural habitats. Many studies have focused on the biological response of terrestrial taxa and habitats to urbanization. However, little is known regarding the consequences of urbanization on freshwater habitats, especially small lentic systems. In this study, we examined aquatic macro-invertebrate diversity (family and species level) and variation in community composition between 240 urban and 782 nonurban ponds distributed across the United Kingdom. Contrary to predictions, urban ponds supported similar numbers of invertebrate species and families compared to nonurban ponds. Similar gamma diversity was found between the two groups at both family and species taxonomic levels. The biological communities of urban ponds were markedly different to those of nonurban ponds, and the variability in urban pond community composition was greater than that in nonurban ponds, contrary to previous work showing homogenization of communities in urban areas. Positive spatial autocorrelation was recorded for urban and nonurban ponds at 0-50 km (distance between pond study sites) and negative spatial autocorrelation was observed at 100-150 km and was stronger in urban ponds in both cases. Ponds do not follow the same ecological patterns as terrestrial and lotic habitats (reduced taxonomic richness) in urban environments; in contrast, they support high taxonomic richness and contribute significantly to regional faunal diversity. Individual cities are complex structural mosaics which evolve over long periods of time and are managed in diverse ways. This facilitates the development of a wide range of environmental conditions and habitat niches in urban ponds which can promote greater heterogeneity between pond communities at larger scales. Ponds provide an opportunity for managers and environmental regulators to conserve and enhance freshwater biodiversity in urbanized landscapes whilst also facilitating key ecosystem services including storm water storage and water treatment. PMID- 27476682 TI - Automated nuclei segmentation of malignant using level sets. AB - Segmentation of objects from a noisy and complex image is still a challenging task that needs to be addressed. This article proposed a new method to detect and segment nuclei to determine whether they are malignant or not (determination of the region of interest, noise removal, enhance the image, candidate detection is employed on the centroid transform to evaluate the centroid of each object, the level set [LS] is applied to segment the nuclei). The proposed method consists of three main stages: preprocessing, seed detection, and segmentation. Preprocessing stage involves the preparation of the image conditions to ensure that they meet the segmentation requirements. Seed detection detects the seed point to be used in the segmentation stage, which refers to the process of segmenting the nuclei using the LS method. In this research work, 58 H&E breast cancer images from the UCSB Bio-Segmentation Benchmark dataset are evaluated. The proposed method reveals the high performance and accuracy in comparison to the techniques reported in literature. The experimental results are also harmonized with the ground truth images. PMID- 27476681 TI - Epidemiological Profile of Newly Diagnosed HIV-Infected Patients in Northern Paris: A Retrospective Study. AB - In attempt to identify the factors associated with delayed diagnosis during HIV infection, we studied retrospectively the epidemiological profile of HIV-infected patients diagnosed between January 1, 2012 and December 31, 2013 and followed in our clinical center in Paris. Data were compared to those obtained at the same site during the year 2003. One hundred eighty-six patients fulfilled the inclusion criteria: 49 (26%) had a CD4 count <200/mm3 at diagnosis. Compared to subjects with CD4 count >=200/mm3, advanced patients were older, had a higher plasma viral load, had more often an AIDS-defining event at the time of HIV diagnosis (45% vs. 3%), had been infected more often through heterosexual contact (69% vs. 44%), had less frequently past HIV testing (23% vs. 63%), and tended to live in less favorable conditions. A higher proportion of these patients initiated antiretroviral therapy in the 3 months following diagnosis (93.9% vs. 48.1%). Compared to data obtained in 161 patients in 2003, the proportions of advanced patients were similar between the two periods (26% vs. 22%). There was a significant increase from year 2003 to the 2012-2013 period in the proportion of men who have sex with men (MSM) (50% vs. 27%) and in the percentage of patients infected with HIV-1 subtype B (48% vs. 27%) and with positive syphilis serology (22% vs. 8%). Our data show that (1) HIV screening should be extended to populations with the following characteristics: older age, heterosexuality, and low socioeconomic level, and (2) HIV transmission continues to progress in MSM, arguing for the value of preexposure prophylaxis. PMID- 27476683 TI - Upgrading plant amino acids through cattle to improve the nutritional value for humans: effects of different production systems. AB - Efficiency in animal protein production can be defined in different ways, for example the amount of human-digestible essential amino acids (HDEAA) in the feed ration relative to the amount of HDEAA in the animal products. Cattle production systems are characterised by great diversity and a wide variety of feeds and feed ration compositions, due to ruminants' ability to digest fibrous materials inedible to humans such as roughage and by-products from the food and biofuel industries. This study examined the upgrading of protein quality through cattle by determining the quantity of HDEAA in feeds and animal products and comparing different milk and beef production systems. Four different systems for milk and beef production were designed, a reference production system for milk and beef representing typical Swedish production systems today and three alternative improved systems: (i) intensive cattle production based on maize silage, (ii) intensive systems based on food industry by-products for dairy cows and high quality forage for beef cattle, and (iii) extensive systems based on forage with only small amounts of concentrate. In all four production systems, the quantity of HDEAA in the products (milk and meat) generally exceeded the quantity of HDEAA in the feeds. The intensive production models for beef calves generally resulted in output of the same magnitude as input for most HDEAA. However, in beef production based on calves from dairy cows, the intensive rearing systems resulted in lower output than input of HDEAA. For the extensive models, the amounts of HDEAA in meat were of the same magnitude as the amounts in the feeds. The extensive models with beef calves from suckler cows resulted in higher output in meat than input in feeds for all HDEAA. It was concluded that feeding cattle plants for production of milk and meat, instead of using the plants directly as human food, generally results in an upgrading of both the quantity and quality of protein, especially when extensive, forage-based production models are used. The results imply that the key to efficiency is the utilisation of human-inedible protein by cattle and justifies their contribution to food production, especially in regions where grasslands and/or forage production has comparative benefits over plant food production. By fine-tuning estimation of the efficiency of conversion from human-edible protein to HDEAA, comparisons of different sources of protein production may be more complete and the magnitude of amino acid upgrading in plants through cattle more obvious. PMID- 27476685 TI - A nonanuclear triangular macrocycle and a linear heptanuclear heterometallic complex based on a 2-substituted imidazole-4,5-dicarboxylate ligand. AB - A Cp*Rh-based nonanuclear triangular macrocycle complex [(Cp*Rh)9L3(NO3)4.5(MeOH)](OTf)4.5 (1), a Cp*Ir-based trinuclear complex [(Cp*Ir)3L(MeCN)4](OTf)3 (2) and a linear heptanuclear heterometallic complex [(Cp*Ir)6ZnL2(MeCN)8(MeOH)2](OTf)8 (3) (Cp* = eta(5)-pentamethylcyclopentadienyl) have been synthesized from a 2-(4-(pyridin-4-yl)phenyl)-1H-imidazole-4,5 dicarboxylic acid proligand. These complexes were further characterized by X-ray crystallography, (1)H NMR, DOSY NMR, IR spectroscopy, and elemental analyses. PMID- 27476684 TI - Diffusion-weighted DESS protocol optimization for simultaneous mapping of the mean diffusivity, proton density and relaxation times at 3 Tesla. AB - PURPOSE: To design a general framework for the optimization of an MRI protocol based on the the diffusion-weighted dual-echo steady-state (DW-DESS) sequence, enabling quantitative and simultaneous mapping of proton density (PD), relaxation times T1 and T2 and diffusion coefficient D. METHODS: A parameterization of the DW-DESS sequence minimizing the Cramer-Rao lower bound of each parameter estimate was proposed and tested in a phantom experiment. An extension of the protocol was implemented for brain imaging to return the rotationally invariant mean diffusivity (MD). RESULTS: In an NiCl2 -doped agar gel phantom wherein T1/T2=920/65 ms, the parameter estimation errors were below 3% for PD and T1 and below 7% for T2 and D while the measured signal-to-noise ratio always exceeded 20. In the human brain, the in vivo parametric maps obtained were overall in reasonable agreement with gold standard measurements, despite a broadening of the distributions due to physiological motion. CONCLUSION: Within the optimization framework presented here, DW-DESS images can be quantitatively interpreted to yield four intrinsic parameters of the tissue. Currently, the method is limited by the sensitivity of the DW-DESS sequence in terms of physiological motion. Magn Reson Med 78:130-141, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27476686 TI - October 2016 Editor-in-Chief Letter. PMID- 27476687 TI - To Retain or Remove the Bone Flap During Evacuation of Acute Subdural Hematoma: Factors Associated with Perioperative Brain Edema. AB - BACKGROUND: The fate of the bone flap is a significant decision during surgical treatment of acute subdural hematoma (SDH). A general guideline revolves around the surgeon's concern for brain edema. Limited studies, however, have focused on the factors that contribute to perioperative brain edema. METHODS: From 2012 to 2015, 38 patients who underwent decompressive craniectomy for acute SDH were reviewed. Clinical data were extracted (age, sex, initial Glasgow Coma Scale (GCS) score, sodium level, hematocrit, and intraoperative blood loss). From the preoperative scan, SDH volume, midline shift (MLS), and volume within the skull (to estimate baseline brain volume) were measured. From the postoperative scan, brain volume (including any herniating regions) was measured. Delta% was defined as the percentage change in postoperative brain volume compared with preoperative volume. Evident contralateral injury, contusions, and intraventricular hemorrhage (IVH) were noted. RESULTS: Fifteen patients demonstrated negative Delta%. Univariate analysis found significant correlations between Delta% and preoperative MLS, initial GCS, presence of IVH, and presence of contralateral injury (P < 0.05). A multiple regression for Delta% elicited a significant model (F [3, 34] = 17.387, P < 0.01) with R2 0.605, where Delta% = 16.197 - 1.246*GCS - 0.986 * MLS + 3.292 * IVH (with 0 = no IVH, 1 = presence of IVH). CONCLUSIONS: A high proportion of patients can exhibit negative Delta%, or relative brain compression after decompression of SDH. For these patients, replacement of the bone flap may be reasonable to avoid obligatory interval cranioplasty. Preoperative MLS, initial GCS, and presence of IVH can help predict whether overall brain volume will swell or compress within the normal confines of the skull. This can guide the decision to retain or remove the bone flap. PMID- 27476688 TI - 2016 World Health Organization Classification of Central Nervous System Tumors: An Era of Molecular Biology. PMID- 27476689 TI - The Bone Flap Dilemma in Acute Subdural Hematoma Surgery. PMID- 27476690 TI - Microsurgical and Tractographic Anatomy of the Supplementary Motor Area Complex in Humans. AB - OBJECTIVE: To evaluate the microsurgical anatomy of the fiber tract connections of the supplementary motor area (SMA) and pre-SMA, and examine its potential functional role with reference to clinical trials in the literature. METHODS: Ten postmortem formalin-fixed human brains (20 sides) and 1 cadaveric head were prepared following Klingler's method. The fiber dissection was performed in a stepwise fashion, from lateral to medial and also from medial to lateral, under an operating microscope, with 3D images captured at each stage. Our findings were supported by in vivo magnetic resonance imaging tractography in 2 healthy subjects. RESULTS: The connections of the SMA complex, composed of the pre-SMA and the SMA proper, are composed of short "U" association fibers and the superior longitudinal fasciculus I, cingulum, claustrocortical fibers, callosal fibers, corticospinal tract, frontal aslant tract, and frontostriatal tract. The claustrocortical fibers may play an important role in the integration of motor, language, and limbic functions of the SMA complex. The frontostriatal tract connects the pre-SMA to the putamen and caudate nucleus, and also forms parts of both the internal capsule and the dorsal external capsule. CONCLUSIONS: The SMA complex has numerous connections throughout the cerebrum. An understanding of these connections is important for presurgical planning for lesions in the frontal lobe and helps explain symptoms related to SMA injury. PMID- 27476692 TI - To Fuse or Not to Fuse: That is (Still) the Question. PMID- 27476691 TI - Clinical Interrogation for Unveiling an Isolated Hypophysitis Mimicking Pituitary Adenoma. AB - BACKGROUND: Hypophysitis is a rare disease entity mimicking a pituitary adenoma. Despite crucial disease involving a pituitary gland which is a main component of the hormonal axis, there have been minimal researches regarding the hypophysitis. In this study, we described the constellation of the preoperative findings including clinical, radiologic, and endocrinologic features, as well as postoperative outcomes of the hypophysitis. METHODS: The authors reviewed the data retrospectively of a total of 2814 patients who underwent microsurgery at our institution to treat a pituitary mass lesion. Among them, the patients proven as hypophysitis in histologic examination were enrolled, followed by stratification into tumor-associated hypophysitis and isolated hypophysitis depending on the existence of associated tumor lesion. As a result, a total 21 cases were enrolled consisting of the 13 cases of tumor-associated and the 8 cases of isolated hypophysitis. In this study, the isolated hypophysitis was focused on the analysis. All patients with isolated hypophysitis were evaluated the clinical, radiologic, and endocrinologic tests preoperatively. After microsurgery, all patients had a minimum follow up of 6 months (6~72 months). The clinical symptoms, endocrinologic tests, and brain MRI were checked at every 6 months during first 2 year, since then, at every 12 months. RESULTS: Among 2814 cases of pituitary mass lesion underwent microsurgery, the hypophysitis were found 21 cases (0.74 %). The 13 cases were the tumor-associated hypophysitis, consisting of rathke's cleft cyst (7 cases), craniopharyngioma (3 cases), pituitary adenoma (2 cases), and germinoma (1 case). The 8 cases were the isolated hypophysitis including lymphocytic (4 cases), granulomatous (3 cases), and IgG4-related (1 case) hypophysitis. The patients presented a wide range of clinical symptoms from general weakness to panhypopituitarism. In addition, the most remarkable radiologic features of the isolated hypophysitis were infundibular thickening and the low signal intensity in T1WI and T2WI. All 8 patients with isolated hypophysitis presented endocrinologic deficiency with various extent in a preoperative biochemistry. After surgery, the hormonal status were not changed in 4 patients (50%), however, aggravated in 4 patients (50%). The 3 patients (37.5%) complained visual field defects in preoperative ophthalmologic test, but improved all after surgery. CONCLUSION: In this study, the preoperative clinical manifestations, radiologic and endocrinologic features of hypophysitis were described comprehensively. In addition, we also revealed the long-term outcomes of hypophysitis in the aspect of visual function and endocrinologic outcomes. Preexisting visual field defects were improved in all patients (3 cases). However, all patients presented endocrinologic deficiency in preoperative biochemistry, among them, the 4 patients (50 %) were unchanged and the 4 patients (50 %) were exacerbated after surgery. In conclusion, the visual outcomes were satisfactory, however, the endocrinologic outcomes were vice versa, because the preoperative endocrinologic deterioration was unchanged or even aggravated after surgery in some cases. PMID- 27476693 TI - Improving Neurosurgical Outcomes in the Intensive Care Unit: Could Dexmedetomidine Make a Difference in Ventilator Free Days, Neurological Monitoring, and Outcomes? PMID- 27476694 TI - Pleomorphic Xanthoastrocytoma with Anaplastic Features: Retrospective Case Series. AB - OBJECTIVE: Pleomorphic xanthoastrocytoma (PXA) is a unique meningocerebral glioma with a relatively favorable prognosis. PXA also possesses a variant with anaplastic features (aPXA), which is associated with poor outcomes. To date, few studies have examined the clinicopathologic importance of these anaplastic features. METHODS: From 1999-2012, 8 patients with aPXA were treated at the University of California, San Francisco, California, United States. Cases were reconfirmed by neuropathology, and clinical information regarding patient demographics, tumor characteristics, and treatment outcomes was assembled. Tumors were classified as aPXA according to the World Health Organization diagnostic criteria established in 2007. RESULTS: There were 5 female and 3 male patients in our cohort, ranging in age from 4-74 years at initial diagnosis. Seizure was the most common presenting symptom (50%), and the majority of tumors arose in the frontal or temporal lobes (88%). Six patients received subtotal resection (STR), and all suffered from progression despite adjuvant radiotherapy and chemotherapy. Median time to progression was 20 months, with a 1-year progression-free survival rate of 57%. Three aPXA patients expired with a median survival of 87 months. Four patients developed disseminated disease. Three of 8 (38%) showed BRAFv600 mutation. CONCLUSION: aPXA is associated with poorer clinical outcomes compared with PXA. Gross total resection should be the goal of initial treatment. It remains unclear whether adjuvant radiation and chemotherapy are able to prevent progression or dissemination. Long-term monitoring of all patients is a critical step in management due to the potential for tumors to transform into higher-grade lesions. PMID- 27476695 TI - International Defensive Medicine in Neurosurgery: Comparison of Canada, South Africa, and the United States. AB - OBJECTIVE: Perception of medicolegal risk has been shown to influence defensive medicine behaviors. Canada, South Africa, and the United States have 3 vastly different health care and medicolegal systems. There has been no previous study comparing defensive medicine practices internationally. METHODS: An online survey was sent to 3672 neurosurgeons across Canada, South Africa, and the United States. The survey included questions on the following domains: surgeon demographics, patient characteristics, physician practice type, surgeon liability profile, defensive behavior-including questions on the frequency of ordering additional imaging, laboratory tests, and consults-and perception of the liability environment. Responses were analyzed, and multivariate logistic regression was used to examine the correlation of medicolegal risk environment and defensive behavior. RESULTS: The response rate was 30.3% in the United States (n = 1014), 36.5% in Canada (n = 62), and 41.8% in South Africa (n = 66). Canadian neurosurgeons reported an average annual malpractice premium of $19,110 (standard deviation [SD] = $11,516), compared with $16,262 (SD = $7078) for South African respondents, $75,857 (SD = $50,775) for neurosurgeons from low-risk U.S. states, and $128,181 (SD = $79,355) for those from high-risk U.S. states. Neurosurgeons from South Africa were 2.8 times more likely to engage in defensive behaviors compared with Canadian neurosurgeons, while neurosurgeons from low-risk U.S. states were 2.6 times more likely. Neurosurgeons from high-risk U.S. states were 4.5 times more likely to practice defensively compared with Canadian neurosurgeons. CONCLUSIONS: Neurosurgeons from the United States and South Africa are more likely to practice defensively than neurosurgeons from Canada. Perception of medicolegal risk is correlated with reported neurosurgical defensive medicine within these countries. PMID- 27476696 TI - [Alcohol and driving: attitudes and habits of students after an intervention]. AB - OBJECTIVE: Knowing and contrasting attitudes and habits toward alcohol when it comes to driving among nursing students and to analyze the effectiveness of an educational intervention with testimonies in order to modify them. METHOD: Analytical and quasiexperimental design with pre-test and post-test. The study population consists of students of nursing degree of the Red Cross from Sevilla. The intervention is based on attending an educational activity from people directly and personally experienced on car accidents, narrating their own lived facts. A specific questionnaire was used to measure attitudes and trends of behaviors towards alcohol drinking and driving. RESULTS: The mean of the responses related to the false beliefs of students in first course is 2.73 (standard deviation [SD]=0.14) versus 2.29 (SD=0.27) in fourth. For questions regarding the intentions of risky behavior, first course have a mean of 2.01 (SD=0.51) versus 1.76 (SD=1.76) in fourth. These differences were not found to be significant. No differences were found before and after the intervention on the two global dimensions studied. The disaggregated results per item show that the intervention significantly reduced the belief that alcohol does not affect safety (p=.001) and intention not to drink to accompany friends with your car (p=.026), among others. CONCLUSIONS: The analyzed intervention has a positive but limited influence. It is recommended to repeat it several times to improve a healthy lifestyle and also to improve the health habits of the general population in the future. PMID- 27476697 TI - Apple (Malus domestica) MdERF2 negatively affects ethylene biosynthesis during fruit ripening by suppressing MdACS1 transcription. AB - Ripening in climacteric fruit requires the gaseous phytohormone ethylene. Although ethylene signaling has been well studied, knowledge of the transcriptional regulation of ethylene biosynthesis is still limited. Here we show that an apple (Malus domestica) ethylene response factor, MdERF2, negatively affects ethylene biosynthesis and fruit ripening by suppressing the transcription of MdACS1, a gene that is critical for biosynthesis of ripening-related ethylene. Expression of MdERF2 was suppressed by ethylene during ripening of apple fruit, and we observed that MdERF2 bound to the promoter of MdACS1 and directly suppressed its transcription. Moreover, MdERF2 suppressed the activity of the promoter of MdERF3, a transcription factor that we found to bind to the MdACS1 promoter, thereby increasing MdACS1 transcription. We determined that the MdERF2 and MdERF3 proteins directly interact, and this interaction suppresses the binding of MdERF3 to the MdACS1 promoter. Moreover, apple fruit with transiently downregulated MdERF2 expression showed higher ethylene production and faster ripening. Our results indicate that MdERF2 negatively affects ethylene biosynthesis and fruit ripening in apple by suppressing the transcription of MdACS1 via multiple mechanisms, thereby acting as an antagonist of positive ripening regulators. Our findings offer a deep understanding of the transcriptional regulation of ethylene biosynthesis during climacteric fruit ripening. PMID- 27476699 TI - Consumption of pomegranate juice decreases blood lipid peroxidation and levels of arachidonic acid in women with metabolic syndrome. AB - BACKGROUND: Pomegranate juice is a rich source of polyphenols and is thus a promising dietary antioxidant with numerous health-promoting effects. These include a beneficial impact on cardiovascular health that could be partly attributed to the effects of polyphenols on lipid metabolism. The aim of this study was to investigate whether consumption of pomegranate juice for 6 weeks could modify lipid peroxidation and phospholipid fatty acid composition of plasma and erythrocytes in subjects with metabolic syndrome. Twenty-three women, aged 40 60 years, were enrolled and randomly assigned into two groups: the intervention group, in which each participant consumed 300 mL of juice per day for 6 weeks; and a control group. RESULTS: A statistically significant decrease in the relative amount of arachidonic acid (P < 0.05) and an increase in the relative amount of saturated fatty acids (P < 0.05) were observed in the intervention group at the end of the consumption period. In addition, pomegranate juice significantly increased the relative amount of total mono-unsaturated fatty acids (P < 0.05), and significantly decreased the levels of thiobarbituric acid reactive substances in erythrocytes (P < 0.05). The status of blood lipids and the values for blood pressure were not changed during the study. CONCLUSION: The results obtained indicate a positive impact of the consumption of pomegranate juice on lipid peroxidation and fatty acid status in subjects with metabolic syndrome and suggest potential anti-inflammatory and cardio-protective effects. (c) 2016 Society of Chemical Industry. PMID- 27476698 TI - Selective Gas-Phase Oxidation and Localization of Alkylated Cysteine Residues in Polypeptide Ions via Ion/Ion Chemistry. AB - The thiol group in cysteine residues is susceptible to several post-translational modifications (PTMs), including prenylation, nitrosylation, palmitoylation, and the formation of disulfide bonds. Additionally, cysteine residues involved in disulfide bonds are commonly reduced and alkylated prior to mass spectrometric analysis. Several of these cysteine modifications, specifically S-alkyl modifications, are susceptible to gas-phase oxidation via selective ion/ion reactions with periodate anions. Multiply protonated peptides containing modified cysteine residues undergo complex formation upon ion/ion reaction with periodate anions. Activation of the ion/ion complexes results in oxygen transfer from the reagent to the modified sulfur residue to create a sulfoxide functionality. Further activation of the sulfoxide derivative yields abundant losses of the modification with the oxidized sulfur as a sulfenic acid (namely, XSOH) to generate a dehydroalanine residue. This loss immediately indicates the presence of an S-alkyl cysteine residue, and the mass of the loss can be used to easily deduce the type of modification. An additional step of activation can be used to localize the modification to a specific residue within the peptide. Selective cleavage to create c- and z-ions N-terminal to the dehydroalanine residue is often noted. As these types of ions are not typically observed upon collision induced dissociation (CID), they can be used to immediately indicate where in the peptide the PTM was originally located. PMID- 27476700 TI - The Association of Combat Exposure With Postdeployment Behavioral Health Problems Among U.S. Army Enlisted Women Returning From Afghanistan or Iraq. AB - An association between combat exposure and postdeployment behavioral health problems has been demonstrated among U.S. military service members returning from Afghanistan or Iraq in predominantly male samples, yet few studies have focused on the experiences of women. Using data from the longitudinal, observational Substance Use and Psychological Injury Combat (SUPIC) Study, we explored the self report of 4 combat exposure items and postdeployment behavioral health screening results for 42,397 Army enlisted women who had returned from Afghanistan or Iraq from fiscal years 2008 through 2011. We ran multivariate logistic regression models to examine how a constructed composite combat exposure score (0, 1, 2, 3+) was associated with screening positive postdeployment for posttraumatic stress disorder (PTSD), depression, and at-risk drinking among active duty (AD) and National Guard/Reserve (NG/R) women. AD and NG/R women commonly reported being wounded, injured, assaulted, or hurt (17.3% and 29.0%, respectively). In all 6 multivariate models, Army women with any report of combat exposure had increased odds of the behavioral health problem (i.e., PTSD, depression, or at-risk drinking). The magnitude of the association between combat exposure and PTSD was most striking, indicating increased odds of PTSD as combat exposure score increased. AD and NG/R women with a combat exposure score of 3+ had increased odds of PTSD, 20.7, 95% confidence interval (CI) [17.0, 25.1] and 27.8, 95% CI [21.0, 36.9], respectively. Women who report combat exposure may benefit from early prevention and confidential intervention to promote postdeployment health and reduce long-term behavioral health problems. PMID- 27476702 TI - Evolving from academic to academic entrepreneur: overcoming barriers to scientific progress and finance. AB - The overall goal of my career as an academic chemist has always been the design and creation of advanced therapeutics and diagnostics that address unmet medical need in the management of chronic diseases. Realising this goal has been an immensely difficult process involving multidisciplinary problem-driven research at the chemistry-biology-medicine interfaces. With success in the laboratory, I started seriously to question the value of remaining an academic whose career is spent in the pursuit of knowledge and understanding alone without making any significant effort to translate knowledge and understanding gained into products of genuine utility for public benefit. Therefore, I elected by choice to become an academic entrepreneur, seeking opportunities wherever possible for the translation of the best of my personal and collaborative academic research work into potentially valuable and useful products. This choice has brought with it many unexpected difficulties and challenges. Nevertheless, progress bas been made and sufficient learnt to suggest that this would be an appropriate moment to take stock and provide some personal reflections on what it takes to design and create advanced therapeutics and diagnostics in the laboratory then seek to develop, innovate and translate the best towards market. PMID- 27476703 TI - Precision active pharmaceutical ingredients are the goal. AB - Understanding and exploiting molecular mechanisms in biology is central to chemical biology. Chemical biology studies of biological macromolecules are now in a perfect continuum with molecular level and nanomolecular level mechanistic studies involving whole organisms. The potential opportunity presented by such studies is the design and creation of genuine precision active pharmaceutical ingredients (APIs; including DNA, siRNA, smaller-molecule bioactives) that demonstrate exceptional levels of disease target specificity and selectivity. This article covers the best of my personal and collaborative academic research work using an organic chemistry and chemical biology approach towards understanding biological molecular recognition processes, work that appears to be leading to the generation of novel precision APIs with genuine potential for the treatments of major chronic diseases that afflict globally. PMID- 27476701 TI - The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific. AB - The apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than apoE2 and apoE3 isoforms and carboxyl-terminal truncated apoE4 forms have been found in AD patients' brain. We have previously shown that a specific apoE4 fragment, apoE4 165, promotes amyloid-peptide beta 42 (Abeta42) accumulation in human neuroblastoma SK-N-SH cells and increased intracellular reactive oxygen species formation, two events considered to occur early in AD pathogenesis. Here, we show that these effects are allele-dependent and absolutely require the apoE4 background. Furthermore, the exact length of the fragment is critical since longer or shorter length carboxyl-terminal truncated apoE4 forms do not elicit the same effects. Structural and thermodynamic analyses showed that apoE4-165 has a compact structure, in contrast to other carboxyl-terminal truncated apoE4 forms that are instead destabilized. Compared however to other allelic backgrounds, apoE4-165 is structurally distinct and less thermodynamically stable suggesting that the combination of a well-folded structure with structural plasticity is a unique characteristic of this fragment. Overall, our findings suggest that the ability of apoE fragments to promote Abeta42 intraneuronal accumulation is specific for both the apoE4 isoform and the particular structural and thermodynamic properties of the fragment. PMID- 27476704 TI - Indole molecules as inhibitors of tubulin polymerization: potential new anticancer agents, an update (2013-2015). AB - Discovery of new indole-based tubulin polymerization inhibitors will continue to dominate the synthetic efforts of many medicinal chemists working in the field. The indole ring system is an essential part of several tubulin inhibitors identified in the recent years. The present review article will update the synthesis, anticancer and tubulin inhibition activities of several important new indole classes such as 2-phenylindoles (28, 29 & 30), oxindoles (35 & 38), indole 3-acrylamides (44), indolines (46), aroylindoles (49), carbozoles (75, 76 & 82), azacarbolines (87) and annulated indoles (100-105). PMID- 27476705 TI - Obstructive Sleep Apnea-a Perioperative Risk Factor. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common disorder of breathing but is probably underappreciated as a perioperative risk factor. METHODS: This review is based on pertinent articles, published up to 15 August 2015, that were retrieved by a selective search in PubMed based on the terms "sleep apnea AND anesthesia" OR "sleep apnea AND pathophysiology." The guidelines of multiple specialty societies were considered as well. RESULTS: OSA is characterized by phases of upper airway obstruction accompanied by apnea/hypoventilation, with hypoxemia, hypercapnia, and recurrent overactivation of the sympathetic nervous system. It has been reported that 22% to 82% of all adults who are about to undergo surgery have OSA. The causes of OSA are multifactorial and include, among others, an anatomical predisposition and /or a reduced inspiratory activation of the bronchodilator muscles, particularly when the patient is sleeping or has taken a sedative drug, anesthetic agent, or muscle relaxant. OSA is associated with arterial hypertension, coronary heart disease, and congestive heart failure. It can be assessed before the planned intervention with polysomnography and structured questionnaires (STOP/STOP-BANG), with sensitivities of 62% and 88%. The utility of miniaturized screening devices is debated. Patients with OSA are at risk for perioperative problems including difficult or ineffective mask ventilation and/or intubation, postoperative airway obstruction, and complications arising from other comorbid conditions. They should be appropriately monitored postoperatively depending on the type of intervention they have undergone, and depending on individually varying, patient-related factors; postoperative management in an intensive care unit may be indicated, although no validated data on this topic are yet available. CONCLUSION: OSA patients need care by specialists from multiple disciplines, including anesthesiologists with experience in recognizing OSA, securing the airway of OSA patients, and managing them postoperatively. No randomized trials have yet compared the modalities of general anesthesia for OSA patients with respect to postoperative complications or phases of apnea or hypopnea. PMID- 27476706 TI - The Diagnosis and Treatment of Multiple Myeloma. AB - BACKGROUND: Multiple myeloma is a malignant disease of plasma cells with a worldwide incidence of 6-7 cases per 100 000 persons per year. It is among the 20 most common types of cancer in Germany. METHODS: This review is based on pertinent publications up to December 2015 that were retrieved by a selective search of PubMed employing the terms "multiple myeloma" AND "therapy" OR "diagnostic." Systematic reviews, meta-analyses, randomized controlled trials, and treatment recommendations from Germany and abroad were considered. RESULTS: The diagnostic evaluation of multiple myeloma comprises thorough history-taking and physical examination, various laboratory tests including analysis of a 24 hour urine sample, a bone-marrow biopsy, and skeletal radiography. Systemic treatment should be administered only when organ damage has been diagnosed. The type of treatment to be given is chosen individually on the basis of the patient's age, comorbidities, and risk profile. High-dose therapy with autologous stem-cell transplantation remains the treatment of choice for patients under age 70 who are otherwise in good health. For patients who are not candidates for high dose therapy or who have had a recurrence of multiple myeloma after prior high dose therapy, there are a number of further conventional treatment options. Patients need not only systemic antineoplastic treatment, but also supportive treatment for the prevention of treatment-induced toxicity and myeloma-associated organ damage. CONCLUSION: Recent therapeutic advances have made the treatment of multiple myeloma both more complex and more costly. In particular, the median survival of patients with multiple myeloma has been markedly prolonged through the use of targeted drugs such as proteasome inhibitors and immune modulators. PMID- 27476708 TI - Reasons for Refusal Were not Given. PMID- 27476709 TI - Further Long-term Studies Are Required. PMID- 27476707 TI - The Indications, Applications, and Risks of Proton Pump Inhibitors. AB - BACKGROUND: Proton pump inhibitors (PPI) are the most effective drugs for inhibiting gastric acid secretion. They have been in clinical use for more than 25 years, In 2014, 3.475 billion daily defined doses (DDD) of PPI were prescribed in Germany. This high number alone calls for a critical analysis of the spectrum of indications for PPI and their potential adverse effects. METHODS: This review is based on pertinent publications retrieved by a selective search in the PubMed and Cochrane Library databases, with particular emphasis on randomized, prospective multicenter trials, cohort studies, case-control studies, and meta analyses. RESULTS: The inhibition of gastric acid secretion with PPI is successfully used for the treatment of gastroesophageal reflux disease and of gastric and duodenal ulcers, for the secondary prevention of gastroduodenal lesions that have arisen under treatment with nonsteroidal anti-inflammatory drugs and acetylsalicylic acid, and for the prevention of recurrent hemorrhage from ulcers after successful endoscopic hemostasis. PPI are given along with practically all antibiotic regimens for the eradication of Helicobacter pylori infection. The number of prescriptions for PPI has risen linearly over the past 25 years. As there has been no broadening of indications, one may well ask whether the current, extensive use of PPI is justified. There is evidence that patients taking PPI are at greater risk for fractures. Moreover, the vitamin B12 level should be checked occasionally in all patients taking PPI. CONCLUSION: PPI are among the more effective drugs for the treatment of diseases associated with gastric acid. In view of their cost and potential adverse effects, they should only be prescribed for scientifically validated indications. PMID- 27476710 TI - In Reply. PMID- 27476711 TI - No Medical Indication. PMID- 27476712 TI - Minimum Age Concept: Full of Pitfalls. PMID- 27476713 TI - One-sided Overview of the Problem. PMID- 27476714 TI - Exceedingly Rare. PMID- 27476715 TI - In Reply. PMID- 27476717 TI - Putative extremely high rate of proteome innovation in lancelets might be explained by high rate of gene prediction errors. AB - A recent analysis of the genomes of Chinese and Florida lancelets has concluded that the rate of creation of novel protein domain combinations is orders of magnitude greater in lancelets than in other metazoa and it was suggested that continuous activity of transposable elements in lancelets is responsible for this increased rate of protein innovation. Since morphologically Chinese and Florida lancelets are highly conserved, this finding would contradict the observation that high rates of protein innovation are usually associated with major evolutionary innovations. Here we show that the conclusion that the rate of proteome innovation is exceptionally high in lancelets may be unjustified: the differences observed in domain architectures of orthologous proteins of different amphioxus species probably reflect high rates of gene prediction errors rather than true innovation. PMID- 27476718 TI - Intact attentional orienting towards inverted faces revealed by both manual responses and eye-movement measurement in individuals with Williams syndrome. AB - BACKGROUND: Individuals with Williams syndrome (WS) exhibit atypical attentional characteristics when viewing faces. Although atypical configural processing of faces has been reported in WS, the relative strengths of configural and local feature information to capture visual attention in WS remains unclear. We previously demonstrated that attentional capture by target-unrelated upright faces differs depending on what response is measured. Whereas eye movements reflected subtle atypical attentional properties at the late stage of visual search, manual responses could not capture the atypical attentional profiles towards target-unrelated upright faces in individuals with WS. Here we used the same experimental paradigm to assess whether sensitivity to configural facial information is necessary for capturing attention in WS. METHODS: We measured both eye movements and manual responses from 17 individuals with WS and 34 typically developing children and adults while they were actively involved in a visual search task with an inverted face distractor. Task measures (reaction time and performance accuracy) and gaze behaviour (initial direction of attention and fixation duration) were analysed for each stimulus. RESULTS: When the target and the inverted face were displayed in the same search array, reaction times and accuracies in individuals with WS showed similar tendencies as typical controls. Analysis of task and gaze measures revealed that attentional orienting towards inverted faces was not atypical. CONCLUSION: Although individuals with WS exhibited atypical gaze behaviour towards upright faces in our previous study, this unusual behaviour disappears if the faces are upside down. These findings suggest that local feature information alone (e.g. eyes) does not contribute to the heightened attention to faces, but configural information appears necessary for drawing attention to faces in individuals with WS, at least in the current experimental paradigm. PMID- 27476719 TI - Hetero-dinuclear complexes of 3d metals with a bridging dinitrogen ligand: theoretical prediction of the characteristic features of geometry and spin multiplicity. AB - Spin multiplicities and coordination structures of dinitrogen-bridged hetero dinuclear complexes of 3d metals, (MU-N2)[M(1)(AIP)][M(2)(AIP)] (AIPH = (Z)-1 amino-3-imino-prop-1-ene; M(1), M(2) = V(i) to Co(i)), were investigated using the CASPT2 method. (MU-N2)[V(AIP)][Cr(AIP)] has a low spin doublet ((2)B2) ground state with an eta(2)-side-on dinitrogen coordination structure but (MU N2)[Mn(AIP)][Fe(AIP)] has a high spin octet ((8)A2) ground state with an eta(1) end-on coordination structure. These results are similar to those of the homo dinuclear Cr and Fe analogues, respectively. In (MU-N2)[Cr(AIP)][M(AIP)] (M = Mn(i), Fe(i), or Co(i)) consisting of an early 3d metal (Cr) and a late one (Mn to Co), on the other hand, we found characteristic features in the geometry and the ground state electronic structure which are different from those of homo dinuclear analogues. The Cr-Mn complex has a high spin decet ((10)B1) ground state with an eta(2)-side-on structure. This decet state has the highest spin multiplicity in the dinuclear transition metal complexes, to our knowledge. The A2 state with a doublet spin multiplicity is moderately less stable than the (10)B1 state. The optimized structures and the molecular orbitals indicate that the Cr atom strongly interacts with the N2 moiety in the (10)B1 state but the Mn atom strongly interacts with the N2 moiety in the (2)A2 state. The Cr-Fe complex has a high spin nonet ((9)B1) ground state with an eta(2)-side-on structure like the Cr-Mn complex, but only the Cr-Co complex has a medium spin quartet (4)A2 ground state with an eta(2)-side-on structure. The different ground electronic state of the Cr-Co complex arises from the presence of 3d orbitals at low energy. Based on these results, it is concluded that the geometry is determined by the Cr center but the electronic structure and the spin multiplicity are determined by the combination of early and late 3d metals in the dinitrogen-bridged hetero dinuclear chelates of 3d metals. PMID- 27476720 TI - Association between population structure and allele frequencies of the glycogen synthase 1 mutation in the Austrian Noriker draft horse. AB - The aim of this study was to determine the allele frequency of the glycogen synthase 1 (GYS1) mutation associated with polysaccharide storage myopathy type 1 in the Austrian Noriker horse. Furthermore, we examined the influence of population substructures on the allele distribution. The study was based upon a comprehensive population sample (208 breeding stallions and 309 mares) and a complete cohort of unselected offspring from the year 2014 (1553 foals). The mean proportion of GYS1 carrier animals in the foal cohort was 33%, ranging from 15% to 50% according to population substructures based on coat colours. In 517 mature breeding horses the mutation carrier frequency reached 34%, ranging on a wider scale from 4% to 62% within genetic substructures. We could show that the occurrence of the mutated GYS1 allele is influenced by coat colour; genetic bottlenecks; and assortative, rotating and random mating strategies. Highest GYS1 carrier frequencies were observed in the chestnut sample comprising 50% in foals, 54% in mares and 62% in breeding stallions. The mean inbreeding of homozygous carrier animals reached 4.10%, whereas non-carrier horses were characterized by an inbreeding coefficient of 3.48%. Lowest GYS1 carrier frequencies were observed in the leopard spotted Noriker subpopulation. Here the mean carrier frequency reached 15% in foals, 17% in mares and 4% in stallions and inbreeding decreased from 3.28% in homozygous non-carrier horses to 2.70% in heterozygous horses and 0.94% in homozygous carriers. This study illustrates that lineage breeding and specified mating strategies result in genetic substructures, which affect the frequencies of the GYS1 gene mutation. PMID- 27476721 TI - Notch1-MAPK Signaling Axis Regulates CD133+ Cancer Stem Cell-Mediated Melanoma Growth and Angiogenesis. AB - Functional characterization and understanding of the intricate signaling mechanisms in stem-like cells is crucial for the development of effective therapies in melanoma. We have studied whether melanoma cells are phenotypically distinct and hierarchically organized according to their tumorigenic nature. We report that melanoma-specific CD133+ cancer stem cells exhibit increased tumor initiating potential, tumor-endothelial cell interaction, and lung metastasis. These cells are able to transdifferentiate into an endothelial-like phenotype when cultured under endothelial differentiation-promoting conditions. Mechanistically, Notch1 upregulates mitogen-activated protein kinase activation through CD133, which ultimately controls vascular endothelial growth factor and matrix metalloproteinase expression in CD133+ stem cells leading to melanoma growth, angiogenesis, and lung metastasis. Blockade or genetic ablation of Notch1 and mitogen-activated protein kinase pathways abolishes melanoma cell migration and angiogenesis. Chromatin immunoprecipitation and reporter assays revealed that Notch1 intracellular domain regulates CD133 expression at the transcriptional level. Andrographolide inhibits Notch1 intracellular domain expression, Notch1 intracellular domain-dependent CD133-mediated mitogen-activated protein kinase and activator protein-1 activation, and epithelial to mesenchymal-specific gene expression, ultimately attenuating melanoma growth and lung metastasis. Human malignant melanoma specimen analyses revealed a strong correlation between Notch1 intracellular domain, CD133, and p-p38 mitogen-activated protein kinase expression and malignant melanoma progression. Thus, targeting Notch1 and its regulated signaling network may have potential therapeutic implications for the management of cancer stem cell-mediated melanoma progression. PMID- 27476722 TI - HLA-C*06:02 Allele and Response to IL-12/23 Inhibition: Results from the Ustekinumab Phase 3 Psoriasis Program. AB - Several small studies suggest that the presence of the human leukocyte antigen (HLA)-Cw6 (C*06:02) allele may be a predictor of improved response to ustekinumab. This study was designed to assess the association of the HLA-C*06:02 allele with response to ustekinumab in large cohorts of patients from the phase 3 studies of ustekinumab in moderate-to-severe psoriasis. In this retrospective study, both HLA-C*06:02-positive and -negative patients demonstrated good responses to ustekinumab (86% vs. 76%, respectively, achieved at least a 75% improvement from baseline in Psoriasis Area and Severity Index [PASI 75] at week 24). A modestly higher proportion of HLA-C*06:02-positive than HLA-C*06:02 negative patients achieved PASI 75/90 responses at weeks 12 and 24. The largest response difference between the positive and negative patients (17.9%) was observed for PASI 75 (week 12), with smaller differences noted at later time points for PASI 90 (11.8% at week 24) and PASI 100 (10.2% at week 28). A differential response to ustekinumab has been confirmed in HLA-C*06:02-positive versus HLA-C*06:02-negative patients; however, this difference is modest, particularly at the higher response rate thresholds (PASI 90/100) and later time points (weeks 24/28). PMID- 27476723 TI - Diverse Human Skin Fungal Communities in Children Converge in Adulthood. AB - Understanding the skin mycobiome (fungal communities) is important because both commensal and pathogenic fungi can drive cutaneous disease depending on host status and body sites, including the scalp, feet, and groin. Interestingly, age may also affect skin fungal infections as certain dermatophytoses (i.e., tinea capitis) are more frequent in children than adults. We previously described the skin mycobiomes in healthy adults, showing lipophilic fungi Malassezia predominate in most skin sites. Because children have less sebaceous skin before puberty, we compared the fungal communities of primary clinical samples from healthy children and adults, based on sequencing of a fungal phylogenetic marker. Although Malassezia predominated on the trunk, head, and arm skin of adults (age 18-39), children (age < 14) had more diverse fungal communities, for example, Eurotiomycetes, which includes common dermatophytes. Species-level classification showed that Malassezia globosa predominated in children. Collectively, our findings indicate that prepubertal skin is colonized by diverse fungi, whereas adult skin is predominantly obligatory lipophilic Malassezia, suggesting that fungal communities on skin profoundly shift during puberty. Mycobiome shifts during puberty are likely due to alterations in sebaceous gland activation and sebum composition. This study provides a foundational framework for studies investigating interactions between fungi, skin, and pediatric dermatophytosis. PMID- 27476725 TI - Comparative liver accumulation of dioxin-like compounds in sheep and cattle: Possible role of AhR-mediated xenobiotic metabolizing enzymes. AB - PCDDs, PCDFs, and PCBs are persistent organic pollutants (POPs) that accumulate in animal products and may pose serious health problems. Those able to bind the aryl hydrocarbon receptor (AhR), eliciting a plethora of toxic responses, are defined dioxin-like (DL) compounds, while the remainders are called non-DL (NDL). An EFSA opinion has highlighted the tendency of ovine liver to specifically accumulate DL-compounds to a greater extent than any other farmed ruminant species. To examine the possible role in such an accumulation of xenobiotic metabolizing enzymes (XME) involved in DL-compound biotransformation, liver samples were collected from ewes and cows reared in an area known for low dioxin contamination. A related paper reported that sheep livers had about 5-fold higher DL-compound concentrations than cattle livers, while the content of the six marker NDL-PCBs did not differ between species. Specimens from the same animals were subjected to gene expression analysis for AhR, AhR nuclear translocator (ARNT) and AhR-dependent oxidative and conjugative pathways; XME protein expression and activities were also investigated. Both AhR and ARNT mRNA levels were about 2-fold lower in ovine samples and the same occurred for CYP1A1 and CYP1A2, being approximately 3- and 9-fold less expressed in sheep compared to cattle, while CYP1B1 could be detectable in cattle only. The results of the immunoblotting and catalytic activity (most notably EROD) measurements of the CYP1A family enzymes were in line with the gene expression data. By contrast, phase II enzyme expression and activities in sheep were higher (UGT1A) or similar (GSTA1, NQO1) to those recorded in cattle. The overall low expression of CYP1 family enzymes in the sheep is in line with the observed liver accumulation of DL compounds and is expected to affect the kinetics and the dynamics of other POPs such as many polycyclic aromatic hydrocarbons, as well as of toxins (e.g. aflatoxins) or drugs (e.g. benzimidazole anthelmintics) known to be metabolized by those enzymes. PMID- 27476726 TI - Footprint of roman and modern mining activities in a sediment core from the southwestern Iberian Atlantic shelf. AB - A 5-m long sediment core (VC2B), retrieved in the Southwestern Iberian Atlantic shelf, at 96m water depth, was used to assess major changes in climate and human activities during the last 9.7kyrs. Analytical measurements included sedimentological (mean grain size, and the contents of sand, silt and clay), geochemical (major, minor, trace and rare earth elements; REEs) and chronological ((210)Pb and (14)C) parameters. Two episodes of increment of fine-grained particles, occurring at 3050BCE and 1350CE, suggest the retreat of the coast line to the present level and the beginning of a wetter phase associated with the "Little Ice Age". The North American Shale Composite (NASC)-normalized REE pattern detected in the shelf is similar to that found in the Guadiana estuarine sediments. The possibility of this estuary as a contributor to the sediment load deposited in the adjacent coastal zone was indicated. Trace elements were significantly correlated with Al until 1850CE, pointing that grain-size rules its distribution in sediments. The depth variation of As, Cu and Pb enrichment factors relative to background values shows two periods of intense human activity that can be mainly linked to mining: (i) across the Roman Period, marked by low enrichments; and (ii) starting on the second half of the 19th century until nowadays with significantly increased enrichments, especially of Pb and Cu. In addition to As, Cu and Pb, this period is also marked by high enrichments of Hg and Zn. Despite the decrease/closure of sulphide massive deposits mining exploitation (e.g., Sao Domingos, Las Herrerias) during the second half of the 20th century, results showed ongoing input of Pb, Cu, As, Hg and Zn to coastal sediments. Thus, the legacy of contamination by these elements, mainly from leaching of slags and tailings, and remobilization/reworking of contaminated estuarine sediments, is still recorded in marine sediments. PMID- 27476724 TI - Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma. AB - Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma. PMID- 27476727 TI - Rhamnolipid-enhanced aerobic biodegradation of triclosan (TCS) by indigenous microorganisms in water-sediment systems. AB - Bioremediation of triclosan (TCS) is a challenge because of its low bioavailability, persistence in the environment and recalcitrance to remediation efforts. Rhamnolipid (RL) was used to enhance TCS biodegradation by indigenous microbes in an aerobic water-sediment system. However, knowledge of the effects of TCS on the bacterial community and environmental factors in an RL-enhanced, TCS-degrading system are lacking. Therefore, in this study, the influence of environmental factors on RL-enhanced biodegradation of TCS was investigated by single factor experiments, and shifts in aerobic TCS-degrading bacterial populations, with and without RL, were analyzed by high-throughput sequencing technology. The results showed that aerobic biodegradation of TCS was significantly promoted by the addition of RL. Environmental conditions, which included RL addition (0.125-0.5g/L), medium concentrations of TCS (<90MUg/g), water disturbance, elevated temperature, ionic strength (0.001-0.1mol/L NaCl) and weak alkaline environments (pH8-9), were monitored. High concentrations of TCS had a remarkable influence on the bacterial community structure, and this influence on the distribution proportion of the main microorganisms was strengthened by RL addition. Alpha-proteobacteria (e.g., Sphingomonadaceae and Caulobacteraceae) might be resistant to TCS or even capable of TCS biodegradation, while Sphingobacteria, Beta- and Delta-proteobacteria were sensitive to TCS toxicity. This research provides ecological information on the degradation efficiency and bacterial community stability in RL-enhanced bioremediation of TCS-polluted aquatic environments. PMID- 27476728 TI - Low cost drip irrigation: Impact on sugarcane yield, water and energy saving in semiarid tropical agro ecosystem in India. AB - Low cost drip irrigation (LCDI) has been a recent introduction to India and it may be an inexpensive means of expanding irrigation into uncultivated areas, thereby increasing land productivity. This paper is structured into two phases. The first phase, presents an assessment of different irrigation methods (LCDI, conventional drip irrigation (CDI) with single row and paired row, siphon and flood irrigation) on sugarcane production. The results showed that cane yield and water productivity was significantly increased in both plant and ratoon crop of sugarcane owing to the methods of irrigation. Among the methods, LCDI recorded 118.6tha-1 of cane yield and it was on par with the single row CDI, which recorded the highest mean yield of 120.4tha-1 and both are found to be significantly superior to the rest of the treatments. The lowest yield was recorded in the treatment of flood irrigation (94.40tha-1). Benefit Cost Ratio analysis confirmed that LCDI performed better compared to other irrigation methods. The second phase deals with the farmer participatory research demonstrations at multi location on evaluation of LCDI with flood irrigation. LCDI out performed flood irrigation under all the locations in terms of sugarcane yield, soil moisture content, postharvest soil fertility, reduction in nutrient transport to surface and ground water, water and energy saving. These results suggest that LCDI is a feasible option to increase the sugarcane production in water scarcity areas of semiarid agro ecosystems, and have long-term sustained economic benefits than flood irrigation in terms of water productivity, energy saving and environmental sustainability. PMID- 27476729 TI - Susceptibility to acidification of groundwater-dependent wetlands affected by water level declines, and potential risk to an early-breeding amphibian species. AB - Eggs of the Western spadefoot toad (Pelobates cultripes) reached a 100% mortality in all 29 clutches deposited at a pH below 5.0 in a temporary pond of the Donana National Park (SW Spain) throughout the wet season of 2006-2007. A similar trend was detected in a neighbouring pond. The proximity of these two ponds to a groundwater pumping area (<1.5km), prompted us to elucidate the possible links between the reduction in pond hydroperiod over past decades (1989-2008) and the decrease of groundwater pH-buffering capacity. The average hydroperiod had decreased by 4months since 1998-99 in the pond where the extensive egg mortality had occurred. The total alkalinity, and the Mg(2+)concentration had also significantly declined in the shallow water-table since 1998-99, from an average of 8.56 to 0.32meql(-1), and of 3.57 to 1.15meql(-1), respectively. This decline of the shallow groundwater buffering capacity could turn this pond more susceptible to the inorganic acidity associated with pyrite oxidation as the sediment S content was often above 0.03%. The initial ratio of S/Ca+Mg in the summer dry sediment was a good predictor of pore-water pH on re-wetting after desiccation (r(2)=0.802, p<0.01). Therefore, this ratio can give some anticipation to mitigate the impact of acidity on toad hatching before these temporary ponds are reflooded on the next wet season. Our results suggest that the long-term damage to pond water levels can trigger a potential risk of soil acidification in the presence of iron-sulphide minerals. PMID- 27476730 TI - Prevalence of virulence and resistance to antibiotics in pathogenic enterococci isolated from mastitic cows. AB - The prevalence of enterococci was examined in 280 milk samples collected from dairy cattle diagnosed with mastitis in three provinces of western China. Sixty strains of enterococci were isolated, and the species were determined based on their biochemical characters and 16S rRNA sequences. Resistance to seven antibiotic agents, frequency of seven virulence genes and pathogenicity in Kunming mice were tested to evaluate biological risks. The correlation between the number of virulence genes and pathogenicity in Kunming mice was also evaluated. The 60 isolates were allocated to Enterococcus hirae (68.3%), E. faecium (25.0%), E. mundtii (3.3%) and E. durans (3.3%). A total of 83.3% of the isolates were resistant to penicillin, whereas 15.0% were resistant to ampicillin, 15.0% to vancomycin, 6.7% to tetracycline and 25.0% to ciprofloxacin. Moreover, isolates exhibited 50.0% and 21.7% resistance to high levels of gentamycin and streptomycin, respectively. The gene asa1 was detected in all enterococcal isolates, whereas 66.7% of strains harbored three or more virulence factors and 56.7% were asa1-ccf-gelE-positive. In pathogenicity tests, isolates harboring numerous virulence factors did not show greater invasiveness than isolates harboring fewer virulence traits against Kunming mice. In conclusion, the number of virulence factors does not appear to predict the risk of enterococcal infection. Isolates were commonly resistant to penicillin and sporadically to ampicillin and vancomycin. These results suggest that the use of gentamycin, streptomycin and ciprofloxacin against enterococci should be avoided in mastitic cows. Additionally, the results demonstrate that the majority of isolates are sensitive to tetracycline. PMID- 27476731 TI - Rotator Cuff Repair: Is there any role for acromioplasty? AB - OBJECTIVES: Acromioplasty has been one of the most common techniques amongst orthopedic surgeries in the past decade. However, its efficacy in arthroscopic surgeries of rotator cuff repair is still debatable. The purpose of this study is to compare the arthroscopic rotator cuff repair with or without acromioplasty in patients with complete rotator cuff tear. METHODS: In this prospective cohort study, patients with complete rotator cuff tear (acromion type II or III Bigliani) and a history of failure to the conservative treatment for at least 6 months were evaluated for eligibility. Patients, based on the time interval, were placed in one of two groups: arthroscopic rotator cuff repair with (RCR-A group) and without acromioplasty (RCR group). Patients were assessed for two years in term of pain intensity by VAS criteria and shoulder functional status by Quick DASH, Constant score and simple shoulder test criteria. RESULTS: In the baseline assessment, RCR-A group (34 patients) and RCR group (33 patients) were similar. Comparing patients in two groups in relation to SST, Quick-DASH and VAS scores preoperatively showed there is no significant difference between the two groups. The SST, Quick-DASH and VAS scores improved significantly in both groups at both the 6-month and 2-year follow-ups (all P < 0.001). The extent of progress in the functional scores was similar in both groups (P > 0.05). CONCLUSION: Arthroscopic rotator cuff repair without acromioplasty may be as reliable and useful as conventional rotator cuff repair with acromioplasty. Thus, acromioplasty cannot be recommended as a routine technique in every rotator cuff repair. PMID- 27476732 TI - Evolution of PLS for Modeling SAR and omics Data. AB - In quantitative structure-activity relationship (QSAR), multivariate statistical methods are commonly used for data analysis. Partial least squares (PLS) is of particular interest because it can analyze data with strongly collinear, noisy and numerous X variables, and also simultaneously models several activity variables Y. PLS provides several prediction regions and diagnostic plots as statistical measures. PLS has evolved for coping with the severe demands imposed by complex data structures. In this review article, we outline the algorithms of five advanced PLS techniques and provide some representative examples of each. The selected models are Nonlinear PLS, Multiway PLS, Hierarchical PLS, Orthogonal PLS, and Bi-modal PLS. Studies of particular aspects of living cells (such as the set of genes or proteins in the cell and their interactions) are collectively known as the -omics fields. Omics integrate heterogeneous scientific disciplines and include chemogenomics, proteomics, and metabolomics. The datasets produced within the omics fields are numerous, megavariate and extremely complex. The data structures are frequently incomplete, noisy, nonlinear and collinear demanding modern and powerful multivariate data analysis methods. In particular, the omics technologies have steered biology towards the adoption of orthogonal PLS. We also describe future prospects for the use of PLS algorithms in the omics fields. PMID- 27476733 TI - Staying Grounded in Reality - an Opinion on Why Informatics Students Should Have Laboratory Experience. PMID- 27476734 TI - Theoretical Analysis of Fas Ligand-Induced Apoptosis with an Ordinary Differential Equation Model. AB - Upon the treatment of Fas ligand, different types of cells exhibit different apoptotic mechanisms, which are determined by a complex network of biological pathways. In order to derive a quantitative interpretation of the cell sensitivity and apoptosis pathways, we have developed an ordinary differential equation model. Our model is intended to include all of the known major components in apoptosis pathways mediated by Fas receptor. It is composed of 29 equations using a total of 49 rate constants and 13 protein concentrations. All parameters used in our model were derived through nonlinear fitting to experimentally measured concentrations of four selected proteins in Jurkat T cells, including caspase-3, caspase-8, caspase-9, and Bid. Our model is able to correctly interpret the role of kinetic parameters and protein concentrations in cell sensitivity to FasL. It reveals the possible reasons for the transition between type-I and type-II pathways and also provides some interesting predictions, such as the more decisive role of Fas over Bax in apoptosis pathway and a possible feedback mechanism between type-I and type-II pathways. But our model failed in predicting FasL-induced apoptotic mechanism of NCI-60 cells from their gene-expression levels. Limitations in our model are also discussed. PMID- 27476735 TI - Using Molecular Docking to Compare Toxicity of Reactive Chemicals to Freshwater and Marine Luminous Bacteria. AB - Vibrio fischeri is a marine luminous bacterium that has been widely used in toxicity bioassays, while Vibrio qinghaiensis sp.-Q67 is a newly found freshwater species which is more suitable for the tests on freshwater samples. However, there is a sensitive difference between these two species due to the media, chemical modes of action and the tested species. It remains unclear how these factors induce toxicity changes in luminous bioassays. Therefore, by using molecular docking between reactive chemicals and the target proteins of Vibrio fischeri and Vibrio qinghaiensis sp.-Q67 respectively, the sensitive difference was explored from the angle of amino acid residues that involved in the interactions. Mutation of amino acid residues was performed to investigate the role of these amino acids in the interactions and the most important amino acid residues in toxicity effect were found. The results suggested tat the most important amino acid residues in toxicity effect would affect the binding affinity between chemicals and target proteins of Vibrio fischeri and Vibrio qinghaiensis sp.-Q67, and then induce distinct toxic effect on them. As there are fewer toxicity data for freshwater Vibrio qinghaiensis sp.-Q67 than for Vibrio fischeri, this study helps to take advantage of the plentiful toxicity data of Vibrio fischeri to predict toxicities of freshwater samples. PMID- 27476737 TI - Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps. AB - Structure-activity relationships (SAR) of compound databases play a key role in hit identification and lead optimization. In particular, activity cliffs, defined as a pair of structurally similar molecules that present large changes in potency, provide valuable SAR information. Herein, we introduce the concept of activity cliff generator, defined as a molecular structure that has a high probability to form activity cliffs with molecules tested in the same biological assay. To illustrate this concept, we discuss a case study where Structure Activity Similarity maps were used to systematically identify and analyze activity cliff generators present in a dataset of 168 compounds tested against three peroxisome-proliferator-activated receptor (PPAR) subtypes. Single-target and dual-target activity cliff generators for PPARalpha and delta were identified. In addition, docking calculations of compounds that were classified as cliff generators helped to suggest a hot spot in the target protein responsible of activity cliffs and to analyze its implication in ligand-enzyme interaction. PMID- 27476736 TI - QSAR Modeling is not "Push a Button and Find a Correlation": A Case Study of Toxicity of (Benzo-)triazoles on Algae. AB - A case study of toxicity of (benzo)triazoles ((B)TAZs) to the algae Pseudokirchneriella subcapitata is used to discuss some problems and solutions in QSAR modeling, particularly in the environmental context. The relevance of data curation (not only of experimental data, but also of chemical structures and input formats for the calculation of molecular descriptors), the crucial points of QSAR model validation and the potential application for new chemicals (internal robustness, exclusion of chance correlation, external predictivity, applicability domain) are described, while developing MLR-OLS models based on molecular descriptors, calculated by various QSAR software tools (commercial DRAGON, free PaDEL-Descriptor and QSPR-THESAURUS). Additionally, the utility of consensus models is highlighted. This work summarizes a methodology for a rigorous statistical approach to obtain reliable QSAR predictions, also for a large number of (B)TAZs in the ECHA preregistration list of REACH (even if starting from limited experimental data availability), and has evidenced some ambiguities and discrepancies related to SMILES notations from different databases; furthermore it highlighted some general problems related to QSAR model generation and was useful in the implementation of the PaDEL-Descriptor software. PMID- 27476738 TI - Wine Compounds as a Source for HTS Screening Collections. A Feasibility Study. AB - High throughput screening (HTS) is extensively used to identify hit and lead compounds in drug discovery programmes. Designing quality screening libraries is a challenge in terms of water solubility, stability and potential oral bioavailability of the compounds. Wines are widely consumed and wine compounds are inherently water soluble, stable and relatively non-toxic. Furthermore, many wine compounds have been proved health-beneficial. To evaluate the feasibility to use wine compounds 3317 were collected from the literature. Their physiochemical properties were evaluated with main stream molecular descriptors. According to the results ~25 % of the compounds are lead-like; nearly 80 % lie within drug like chemical space and finally 90 % conform to known drug space (KDS). The rotatable bonds descriptor was the most effective defining lead-like space. The results suggest that many of the wine compounds are interesting and suitable candidates for screening libraries after suitable filtering. PMID- 27476739 TI - Pharmacophore Identification, Molecular Docking, Virtual Screening, and In Silico ADME Studies of Non-Nucleoside Reverse Transcriptase Inhibitors. AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity and low toxicity in antiretroviral combination therapies used to treat HIV. In this study, chemical feature based pharmacophore models of different classes of NNRT inhibitors of HIV 1 have been developed. The best HypoRefine pharmacophore model, Hypo 1, which has the best correlation coefficient (0.95) and the lowest RMS (0.97), contains two hydrogen bond acceptors, one hydrophobic and one ring aromatic feature, as well as four excluded volumes. Hypo 1 was further validated by test set and Fischer validation method. The best pharmacophore model was then utilized as a 3D search query to perform a virtual screening to retrieve potential inhibitors. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking studies by Libdock and Gold methods to refine the retrieved hits. Finally, 7 top ranked compounds based on Gold score fitness function were subjected to in silico ADME studies to investigate for compliance with the standard ranges. PMID- 27476740 TI - Prediction of Bovine Serum Albumin-Water Partition Coefficients of a Wide Variety of Neutral Organic Compounds by Means of Support Vector Machine. AB - Support vector machine (SVM) was used to develop a quantitative structure property relationship (QSPR) model that correlates molecular structures to their bovine serum albumin water partition coefficients (KBSA/W ). The performance and predictive aptitude of SVM are considered and compared with other methods such as multiple linear regression (MLR) and artificial neural network (ANN) methods. A set of 83 natural organic compounds and drugs were selected and suitable sets of molecular descriptors were calculated. Genetic algorithm (GA) was used to select important molecular descriptors, and linear and nonlinear models were applied to correlate the selected descriptors with the experimental values of log KBSA/W . The correlation coefficients, R, between experimental and predicted log KBSA/W for the validation set by MLR, ANN and SVM are 0.951, 0.986 and 0.991, respectively. Results obtained document the reliability and good predictability of the nonlinear QSPR model to predict partition coefficients of organic compounds. Comparison between the values of statistical parameters demonstrates that the predictive ability of the SVM model is comparable or superior to those obtained by MLR and ANN. PMID- 27476741 TI - Prediction of hERG Potassium Channel Blocking Actions Using Combination of Classification and Regression Based Models: A Mixed Descriptors Approach. AB - A set of 242 compounds with diverse molecular structures and having different mechanisms of therapeutic actions was used to develop classification and regression based QSAR models for the identification of potential hERG channel blockers. The developed in silico models made it possible to obtain a quantitative interpretation of the structural information and physicochemical properties of the molecules for their hERG binding affinity along with exploration of the discriminant functions differentiating between lower and higher hERG blocking potency compounds by the classification approach. The developed models were rigorously validated internally as well as externally with the application of the principles of Organization for Economic Cooperation and Development (OECD) for the validation purpose. The test for domain of applicability was also carried out for checking reliability of the predictions. Pharmacological distribution diagrams (PDDs) were employed as a visualizing technique for the classification approach. Important fragments relevant to hERG binding affinity were identified through critical analysis and interpretation of the developed models. Finally, the developed models were implemented to screen hERG channel blocking properties for a huge number compounds of the DrugBank database. In silico prediction for hERG channel blocking potential for each of the DrugBank compounds is possible from the developed models. PMID- 27476743 TI - Superior short-term learning effect of visual and sensory organisation ability when sensory information is unreliable in adolescent rhythmic gymnasts. AB - Rhythmic gymnasts specialise in dynamic balance under sensory conditions of numerous somatosensory, visual, and vestibular stimulations. This study investigated whether adolescent rhythmic gymnasts are superior to peers in Sensory Organisation test (SOT) performance, which quantifies the ability to maintain standing balance in six sensory conditions, and explored whether they plateaued faster during familiarisation with the SOT. Three and six sessions of SOTs were administered to 15 female rhythmic gymnasts (15.0 +/- 1.8 years) and matched peers (15.1 +/- 2.1 years), respectively. The gymnasts were superior to their peers in terms of fitness measures, and their performance was better in the SOT equilibrium score when visual information was unreliable. The SOT learning effects were shown in more challenging sensory conditions between Sessions 1 and 2 and were equivalent in both groups; however, over time, the gymnasts gained marginally significant better visual ability and relied less on visual sense when unreliable. In conclusion, adolescent rhythmic gymnasts have generally the same sensory organisation ability and learning rates as their peers. However, when visual information is unreliable, they have superior sensory organisation ability and learn faster to rely less on visual sense. PMID- 27476742 TI - Very low level viraemia and risk of virological failure in treated HIV-1-infected patients. AB - OBJECTIVES: The aim of the study was to investigate whether very low level viraemia (VLLV) (20-50 HIV-1 RNA copies/mL) was associated with increased risk of virological failure (VF) as compared with persistent full suppression (< 20 copies/mL). METHODS: From the VACH Cohort database, we selected those patients who started antiretroviral therapy (ART) after January 1997 and who achieved effective viral suppression [two consecutive viral loads (VLs) < 50 copies/mL] followed by full suppression (at least one VL <20 copies/mL). We carried out survival analyses to investigate whether the occurrence of VLLV rather than maintaining full suppression at < 20 copies/mL was associated with virological failure (two consecutive VLs > 200 copies/mL or one VL > 200 copies/mL followed by a change of ART regimen, administrative censoring or loss to follow-up), adjusted for nadir CD4 cell count, sex, age, ethnicity, transmission group, type of ART and time on effective suppression at < 50 copies/mL. RESULTS: Of 21 480 patients who started ART, 13 674 (63.7%) achieved effective suppression at < 50 copies/mL, of whom 4289 (31.4%) further achieved full suppression at < 20 copies/mL after May 2009. A total of 2623 patients (61.1%) remained fully suppressed thereafter, while 1666 had one or more episodes of VL detection > 20 copies/mL (excluding virological failure). A total of 824 patients had VLLV after suppression at < 20 copies/mL. VLLV was not associated with virological failure as compared with persistent full suppression [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.44-1.00], independently of the number of blips recorded (from one to 18). CONCLUSIONS: In our population of HIV-infected patients on ART who achieved viral suppression at < 20 copies/mL, the risk of virological failure was no different for patients who remained fully suppressed compared with those who experienced subsequent episodes of VLLV. PMID- 27476744 TI - Exchange coupled ferrite nanocomposites through chemical synthesis. AB - Exchange coupling between magnetically hard and soft phases has the potential to yield a large gain in the energy product. In this work, we present a scalable chemical synthetic route to produce magnetic iron oxide based nanocomposites, consisting of cobalt ferrite (CoFe2O4) and strontium ferrite (SrFe12O19) components. PMID- 27476745 TI - Phase transitions in two tunnel-coupled HgTe quantum wells: Bilayer graphene analogy and beyond. AB - HgTe quantum wells possess remarkable physical properties as for instance the quantum spin Hall state and the "single-valley" analog of graphene, depending on their layer thicknesses and barrier composition. However, double HgTe quantum wells yet contain more fascinating and still unrevealed features. Here we report on the study of the quantum phase transitions in tunnel-coupled HgTe layers separated by CdTe barrier. We demonstrate that this system has a 3/2 pseudo spin degree of freedom, which features a number of particular properties associated with the spin-dependent coupling between HgTe layers. We discover a specific metal phase arising in a wide range of HgTe and CdTe layer thicknesses, in which a gapless bulk and a pair of helical edge states coexist. This phase holds some properties of bilayer graphene such as an unconventional quantum Hall effect and an electrically-tunable band gap. In this "bilayer graphene" phase, electric field opens the band gap and drives the system into the quantum spin Hall state. Furthermore, we discover a new type of quantum phase transition arising from a mutual inversion between second electron- and hole-like subbands. This work paves the way towards novel materials based on multi-layered topological insulators. PMID- 27476747 TI - Investigating the mechanical properties of zona pellucida of whole human oocytes by atomic force spectroscopy. AB - The role of mechanics in numerous biological processes is nowadays recognized, while in others, such as the fertilization process, it is still neglected. In the case of oocytes the description of their mechanical properties could improve the comprehension of the oocyte-spermatozoon interaction and be helpful for application in in vitro fertilization (IVF) clinics. Herein the mechanical properties of whole human oocytes (HOs) immediately after retrieval are investigated by indentation measurements with atomic force spectroscopy under physiological conditions. Measurements are performed on immature (metaphase I - MI) and mature (metaphase II - MII) HOs. According to their morphological characteristics MII-HOs are classified as "suitable" and "rejected"; these latter would be usually rejected for intracytoplasmic sperm injection (ICSI). For all maturation stages we observe that the elastic response of the zona pellucida (ZP) outer layer was different and distinguishable from the rest of the ZP-HO. The elasticity of this ZP outer layer varies with maturation and quality: stiffness decreases from immature MI to good quality MII, up to poor-quality rejected MII. An indirect analysis with IVF outcome indicates that the ZP outer layer of analysed HOs donated by women who achieved pregnancy is stiffer than that of HOs from women with negative outcome. Our findings suggest that mechanical properties can represent important oocyte quality indicators that may be exploited for the design of innovative ICSI dedicated cell sorters. PMID- 27476748 TI - Marine Non-Cyanobacterial Diazotrophs: Moving beyond Molecular Detection. AB - The nitrogen input through biological N2 fixation is essential for life in vast areas of the global ocean. The belief is that cyanobacteria are the only relevant N2-fixing (diazotrophic) organisms. It has, however, now become evident that non cyanobacterial diazotrophs, bacteria and archaea with ecologies fundamentally distinct from those of cyanobacteria, are widespread and occasionally fix N2 at significant rates. The documentation of a globally relevant nitrogen input from these diazotrophs would constitute a new paradigm for research on oceanic nitrogen cycling. Here we highlight the need for combining rate measurements and molecular analyses of field samples with cultivation studies in order to clarify the ecology of non-cyanobacteria and their contribution to marine N2 fixation on local and global scales. PMID- 27476749 TI - Polysomnographic findings in persistent allergic rhinitis. AB - PURPOSE: Persistent allergic rhinitis (PAR) is characterized by a chronic, eosinophilic inflammation with nasal congestion and rhinorrhea. Nasal congestion can constitute to sleep-disordered breathing problems that range from simple snoring to obstructive sleep apnea syndrome (OSAS). The purpose of this study was to investigate the effect of PAR on sleep quality and severity of OSAS. METHODS: The study included 150 patients presenting with typical symptoms of sleep apnea. Fifty-five patients were diagnosed as PAR (group-1) and were compared with age and body mass index matched 95 individuals (group-2) without any nasal disease. Skin prick tests and polysomnography were performed in all patients. RESULTS: There were no differences between groups for polysomnographic findings including sleep architecture, arousal and respiratory index, and mean and minimal oxygen saturations. Simple snoring was determined in 41.8 % allergic and 32.6 % non allergic patients. Mild OSAS was determined in 32.7 % allergic and 29.4 % non allergic patients. Moderate OSAS was determined in 9 % allergic and 17.8 % non allergic patients. Severe OSAS was determined in 16.3 % allergic and 20 % non allergic patients. Their entire Epworth sleepiness scale index was also found similar. CONCLUSIONS: Our data pointed out that in patients with sleep-related breathing disorders symptoms, presence of PAR does not affect polysomnographic parameters compared with other patients without any nasal inflammation. Besides, prevalence of OSAS was similar between groups. PMID- 27476750 TI - The role of vision for navigation in the crown-of-thorns seastar, Acanthaster planci. AB - Coral reefs all over the Indo-Pacific suffer from substantial damage caused by the crown-of-thorns seastar Acanthaster planci, a voracious predator that moves on and between reefs to seek out its coral prey. Chemoreception is thought to guide A. planci. As vision was recently introduced as another sense involved in seastar navigation, we investigated the potential role of vision for navigation in A. planci. We estimated the spatial resolution and visual field of the compound eye using histological sections and morphometric measurements. Field experiments in a semi-controlled environment revealed that vision in A. planci aids in finding reef structures at a distance of at least 5 m, whereas chemoreception seems to be effective only at very short distances. Hence, vision outweighs chemoreception at intermediate distances. A. planci might use vision to navigate between reef structures and to locate coral prey, therefore improving foraging efficiency, especially when multidirectional currents and omnipresent chemical cues on the reef hamper chemoreception. PMID- 27476746 TI - Major parasitic diseases of poverty in mainland China: perspectives for better control. AB - Significant progress has been made in the prevention, control, and elimination of human parasitic diseases in China in the past 60 years. However, parasitic diseases of poverty remain major causes of morbidity and mortality, and inflict enormous economic costs on societies.In this article, we review the prevalence rates, geographical distributions, epidemic characteristics, risk factors, and clinical manifestations of parasitic diseases of poverty listed in the first issue of the journal Infectious Diseases of Poverty on 25 October 2012. We also address the challenges facing control of parasitic diseases of poverty and provide suggestions for better control. PMID- 27476751 TI - A review of the additive health risk of cannabis and tobacco co-use. AB - INTRODUCTION: Cannabis and tobacco are the most widely used substances, and are often used together. The present review examines the toxicant exposure associated with co-use (e.g., carbon monoxide, carcinogens), co-use via electronic nicotine delivery systems (ENDS), and problematic methodological issues present across co use studies. METHOD: An extensive literature search through PubMed was conducted and studies utilizing human subjects and in vitro methods were included. Keywords included tobacco, cigarette, e-cigarette, ENDS, smoking, or nicotine AND marijuana OR cannabis OR THC. RESULTS: Co-use may pose additive risk for toxicant exposure as certain co-users (e.g., blunt users) tend to have higher breath carbon monoxide levels and cannabis smoke can have higher levels of some carcinogens than tobacco smoke. Cannabis use via ENDS is low and occurs primarily among established tobacco or cannabis users, but its incidence may be increasing and expanding to tobacco/cannabis naive individuals. There are several methodological issues across co-use research including varying definitions of co use, sample sizes, lack of control for important covariates (e.g., time since last cigarette), and inconsistent measurement of outcome variables. CONCLUSIONS: There are some known additive risks for toxicant exposure as a result of co-use. Research utilizing consistent methodologies is needed to further establish the additive risk of co-use. Future research should also be aware of novel technologies (e.g., ENDS) as they likely alter some toxicant exposure when used alone and with cannabis. PMID- 27476752 TI - Aluminum chloride induced splenic lymphocytes apoptosis through NF-kappaB inhibition. AB - This research investigated the relationship between lymphocytes apoptosis, hypothalamic-pituitary-adrenal (HPA) axis and NF-kappaB in AlCl3-treated rats. Eighty Wistar rats were orally exposed to 0 (control group, CG), 0.4 mg/mL (low dose group, LG), 0.8 mg/mL (mid-dose group, MG) and 1.6 mg/mL (high-dose group, HG) AlCl3 for 90 days, respectively. A variety of measurements were taken including lymphocyte apoptosis index, serum corticotropin-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH) and glucocorticoids (GCs) contents, GC receptors (GCR) and NF-kappaB mRNA and nuclear protein expressions, caspase 3 and 9 mRNA expressions and activities. The results showed that in the AlCl3-treated rats serum CRH, ACTH and GCs contents, lymphocyte GC receptors (GCR) mRNA and nuclear protein expressions, caspase 3 and 9 mRNA expressions and activities increased, while Bcl-2/Bax ratio and NF-kappaB mRNA and nuclear protein expressions decreased compared with the CG. Furthermore GCR and NF-kappaB nuclear protein expressions were negatively correlated. And NF-kappaB mRNA expression was positively correlated with that of Bcl-2, but negatively correlated with that of Bax in AlCl3-treated rats. These findings indicated that AlCl3 activated HPA axis, then induced splenic lymphocytes apoptosis through NF-kappaB inhibition. PMID- 27476753 TI - Editorial overview: Cancer. PMID- 27476754 TI - Reply to Commentary Letter by Dr. Melvin Khee Shing Leow. PMID- 27476755 TI - Amorphous Silk Nanofiber Solutions for Fabricating Silk-Based Functional Materials. AB - As a functional material, silk has been widely used in tissue engineering, drug release, and tissue regeneration. Increasing subtle control of silk hierarchical structures and thus specific functional performance is required for these applications but remains a challenge. Here, we report a novel silk nanofiber solution achieved through tuning solvent systems used to generate the material. Unlike the beta-sheet rich silk nanofibers reported previously, these new silk nanofibers are mainly composed of amorphous structures and maintain a solution state in aqueous environments. The amorphous silk nanofibers are stable enough for storage and also metastable, making them easy to use in the further fabrication of materials through various processes. Silk scaffolds, hydrogels, and films were prepared from these silk nanofiber solutions. These silk materials from amorphous nanofiber solutions show different properties and tunable performance features. Therefore, these amorphous silk nanofibers are suitable units or building blocks for designing silk-based materials. PMID- 27476756 TI - Targeting mitochondrial function to treat optic neuropathy. AB - Many reports have illustrated a tight connection between vision and mitochondrial function. Not only are most mitochondrial diseases associated with some form of vision impairment, many ophthalmological disorders such as glaucoma, age-related macular degeneration and diabetic retinopathy also show signs of mitochondrial dysfunction. Despite a vast amount of evidence, vision loss is still only treated symptomatically, which is only partially a consequence of resistance to acknowledge that mitochondria could be the common denominator and hence a promising therapeutic target. More importantly, clinical support of this concept is only emerging. Moreover, only a few drug candidates and treatment strategies are in development or approved that selectively aim to restore mitochondrial function. This review rationalizes the currently developed therapeutic approaches that target mitochondrial function by discussing their proposed mode(s) of action and provides an overview on their development status with regards to optic neuropathies. PMID- 27476757 TI - Lysine acetylation in mitochondria: From inventory to function. AB - Cellular signaling pathways are regulated in a highly dynamic fashion in order to quickly adapt to distinct environmental conditions. Acetylation of lysine residues represents a central process that orchestrates cellular metabolism and signaling. In mitochondria, acetylation seems to be the most prevalent post translational modification, presumably linked to the compartmentation and high turnover of acetyl-CoA in this organelle. Similarly, the elevated pH and the higher concentration of metabolites in mitochondria seem to favor non-enzymatic lysine modifications, as well as other acylations. Hence, elucidating the mechanisms for metabolic control of protein acetylation is crucial for our understanding of cellular processes. Recent advances in mass spectrometry-based proteomics have considerably increased our knowledge of the regulatory scope of acetylation. Here, we review the current knowledge and functional impact of mitochondrial protein acetylation across species. We first cover the experimental approaches to identify and analyze lysine acetylation on a global scale, we then explore both commonalities and specific differences of plant and animal acetylomes and the evolutionary conservation of protein acetylation, as well as its particular impact on metabolism and diseases. Important future directions and technical challenges are discussed, and it is pointed out that the transfer of knowledge between species and diseases, both in technology and biology, is of particular importance for further advancements in this field. PMID- 27476758 TI - Using intra-microgel crosslinking to control the mechanical properties of doubly crosslinked microgels. AB - Microgels (MGs) are crosslinked polymer particles that swell when the pH approaches the pKa of the constituent polymer. Our earlier work showed that concentrated MG dispersions can be covalently interlinked to form macroscopic hydrogels, which are termed doubly crosslinked microgels (DX MGs). Here, we study for the first time the effects of intra-MG crosslinking on the swelling of the MGs and the mechanical properties of the DX MGs. The MGs were synthesised by emulsion copolymerisation of ethyl acrylate (EA) or methacrylic acid (MAA) and divinylbenzene (DVB). The latter was a crosslinking monomer. For comparison, MGs were prepared where DVB was replaced by either 1,4-butanediol diacrylate (BDDA) or a 1 : 1 mixture of both DVB and BDDA. The MG swelling behaviours were studied by dynamic light scattering; whereas, the DX MG mechanical properties were studied by dynamic rheology and uniaxial compression measurements. Inclusion of DVB within the MGs resulted in both highly swelling MGs and highly ductile DX MGs. The average strain-at-break value for the DVB-containing DX MGs was 76% which represents the highest value yet reported for a DX MG prepared using commercially available monomers. It was also shown that good tuneability of the DX MG properties could be obtained simply by controlling the DVB and BDDA contents within the MG particles. Analysis of the swelling and compression data enabled relationships between the volume-swelling ratio of the MGs and either the modulus or strain-at-break values for the DX MGs. These relationships also applied to a DVB-free system prepared with a low BDDA content. An interesting conclusion from this study is that the DX MGs can be thought of mechanically as macroscopic MG particles. The results of this study provide design tools for improving DX MG ductility and hence increasing the range of potential applications for this new class of hydrogel. PMID- 27476759 TI - Annular Erythematous Patches as the Presenting Sign of Extranodal Natural Killer/T-Cell Lymphoma. PMID- 27476760 TI - Five-Year Incidence of Amyotrophic Lateral Sclerosis in British Columbia (2010 2015). AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative neurological disease with significant effects on quality of life. International studies continue to provide consistent incidence values, though complete case ascertainment remains a challenge. The Canadian population has been understudied, and there are currently no quantitative data on the incidence of ALS in British Columbia (BC). The objectives of this study were to determine the five-year incidence rates of ALS in BC and to characterize the demographic patterns of the disease. METHODS: The capture-recapture method was employed to estimate ALS incidence over a five-year period (2010-2015). Two sources were used to identify ALS cases: one database from an ALS medical centre and another from a not-for profit ALS organization. RESULTS: During this time period, there were 690 incident cases within the two sources. The capture-recapture method estimated 57 unobserved cases, corresponding to a crude five-year incidence rate of 3.29 cases per 100,000 (CI 95%=3.05-3.53). The mean age of diagnosis was 64.6 (CI 95%=59.7 69.4), with 63.5 (CI 95%=56.9-70.1) for men and 65.7 (CI 95%=58.6-72.7) for women. There was a slight male preponderance in incidence, with a 1.05:1 ratio to females. Peak numbers in incidence occurred between the ages of 70 and 79. CONCLUSIONS: The incidence of ALS in BC was found to be consistent with international findings though nominally higher than that in other Canadian provinces to date. PMID- 27476761 TI - Effects of bilateral vasectomy on the interleukin 1 system in mouse epididymis. AB - PROBLEM: Regional difference in the inflammatory response in vasectomized (VAX) epididymis remains unraveled. METHOD OF STUDY: Epididymal expression of interleukin 1alpha (IL1alpha), IL1beta, IL1 receptor antagonist (IL1ra), IL1 receptor 1 (IL1R1), IL6, IL10, tumor necrosis factor alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) was examined in bilateral VAX mice by real-time RT-PCR and immunohistochemistry. RESULTS: IL1alpha, IL1beta, IL1ra, and IL1R1 were expressed in the epididymal epithelia of normal mice. Following VAX, IL1R1 mRNA was not changed, but TNF-alpha, IL10, IL1alpha, IL1beta, and IL1ra mRNA were significantly upregulated in whole epididymis, whereas IL6 and TGF-beta1 mRNA were significantly increased in corpus and cauda but not in caput epididymis. Consistently, IL1alpha, IL1beta, and IL1ra immunoreactivities were visibly increased in epididymis following VAX. CONCLUSION: Following VAX, IL1alpha, IL1beta, IL1ra, IL10, and TNF-alpha may mediate immune reaction in whole epididymis, whereas IL6 and TGF-beta1 may mediate regionally different immune response primarily in the lower part of epididymis. PMID- 27476762 TI - Relationship Between Respiratory Dynamics and Body Mass Index in Patients Undergoing General Anesthesia with Laryngeal Mask Airway (LMA) and Comparison Between Lithotomy and Supine Positions. AB - BACKGROUND This study aimed to compare respiratory dynamics in patients undergoing general anesthesia with a laryngeal mask airway (LMA) in lithotomy and supine positions and to validate the impact of operational position on effectiveness of LMA ventilation. MATERIAL AND METHODS A total of 90 patients (age range, 18-65 years) who underwent general anesthesia were selected and divided into supine position (SP group) and lithotomy position groups (LP group). Vital signs and respiratory dynamic parameters of the 2 groups were measured at different time points and after implantation of an LMA. The arterial blood gas was monitored at 15 min after induction. The intraoperative changes of hemodynamic indexes and postoperative adverse reactions of LMA were recorded. The possible correlation between body mass index (BMI) and respiratory dynamic indexes was analyzed. RESULTS With prolonged duration of the operation, the inspiratory plateau pressure (Pplat), inspiratory resistance (RI), and work of breathing (WOB) gradually increased, while chest-lung compliance (Compl) and partial pressure of carbon dioxide in end-expiratory gas (PetCO2) gradually decreased (all P value <0.05). The mean airway pressure (Pmean), Pplat, and expiratory resistance (Re) in the LP group were significantly higher than in the SP group (P<0.05), while the peak inspiratory flow (FImax), peak expiratory flow (FEmax), WOB, and Compl in the LP group were significantly lower than in the SP group (P<0.05). BMI was positively correlated with peak airway pressure (PIP/Ppeak), Pplat, and airway resistance (Raw) and was negatively correlated with Compl; the differences among patients in lithotomy position were more remarkable (P<0.05). CONCLUSIONS The inspiratory plateau pressure and airway resistance increased with prolonged duration of the operation, accompanied by decreased chest-lung compliance. Peak airway pressure and airway resistance were positively correlated with BMI, and chest-lung compliance was negatively correlated with BMI. Changes among patients in lithotomy position were more remarkable than those in supine position. PMID- 27476763 TI - Unexpected high incidence of hepatocellular carcinoma in patients with hepatitis C in the era of DAAs: Too alarming? PMID- 27476764 TI - Reply to "Revising metrics for aggressiveness assessment in liver transplantation centers". PMID- 27476765 TI - Effectiveness of surveillance for hepatocellular carcinoma in clinical practice: A United States cohort. AB - BACKGROUND & AIMS: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in reducing cancer related mortality among patients with cirrhosis is largely unknown. The objective of this study was to study the effectiveness of HCC surveillance in the national Veterans Administration (VA) clinical practice. METHODS: We conducted a retrospective cohort study of patients with HCC during 2005-2010 by reviewing patients' medical records to determine receipt of HCC surveillance in the 2years prior to HCC diagnosis. We determined association of HCC surveillance with overall mortality adjusting for age, risk factors, model for end-stage liver disease (MELD) score, comorbidity index, alpha-fetoprotein levels, healthcare utilization, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment. We accounted for lead and length time biases. RESULTS: Of 887 patients with HCC, only 412 (46.5%) received any surveillance prior to HCC diagnosis. Patients who received surveillance were significantly more likely to have early stage disease HCC (BCLC stage 0/A 27.2% vs. 11.6%) and receive potentially curative (20.9% vs. 11.6%) or palliative (59.2% vs. 45.5%) treatments compared to those without HCC surveillance. Receipt of HCC surveillance was associated with 38% reduction in mortality risk (unadjusted hazard ratios (HR) 0.62, 95% confidence intervals (CI) 0.54-0.71) that declined to 20% (HR 0.80, 95% CI 0.69 0.94) after adjusting for HCC stage and treatment, compared to those without HCC surveillance. CONCLUSIONS: Among patients with HCC, pre-diagnosis HCC surveillance is associated with a significant 38% reduction in overall mortality. The reduction in mortality risk with surveillance is mediated via stage migration and receipt of HCC specific treatment. LAY SUMMARY: Surveillance for liver cancer leads to earlier detection of cancer and increases chances of getting curative treatment. This ultimately leads to increased longevity in patients with liver cancer. PMID- 27476766 TI - Revising metrics for aggressiveness assessment in liver transplantation centers. PMID- 27476767 TI - Pre-treatment estimation of future remnant liver function using gadoxetic acid MRI in patients with HCC. AB - BACKGROUND & AIMS: This study aimed to determine whether the predicted remnant liver function on dynamic hepatocyte-specific contrast media-enhanced magnetic resonance (DHCE-MR) imaging correlates with the results of the indocyanin green retention test (ICG R15) after hepatic resection or radiofrequency ablation (RFA). METHODS: This prospective multicenter study was approved by the Institutional Review Boards of each hospital. Informed consents were obtained from all. DHCE-MRI and ICG R15 were performed in 57 patients scheduled to undergo hepatectomy or RFA for hepatocellular carcinoma, once before treatment and repeated on post-treatment day 3. In nine donors and three recipients, DHCE-MRI and ICG R15 were performed only preoperatively. The predicted remnant liver function (HEFml) was estimated using the hepatic extraction fraction (HEF) multiplied by the remnant liver volume, and compared with post-treatment ICG R15. Intra-individual heterogeneity of HEF was assessed using pooled coefficients of variation (CV) among hepatic segments. Finally, development of post-treatment hepatic failure was assessed according to the 50-50 criteria on post-treatment day 5. RESULTS: Predicted remnant HEFml showed a negative correlation with post treatment ICG R15 (r=-0.45, p=0.001), whereas liver volume did not (p>0.05). There were significant correlations between pre-treatment HEFml and pre-treatment ICG R15 (r=-0.33, p=0.006) and between post-treatment HEFml and post-treatment ICG R15 (r=-0.54, p<0.001). Pooled CV among segmental HEFs was 12.6%. No patients showed post-treatment liver failure on post-treatment day 5. CONCLUSIONS: DHCE MRI using Gd-EOB-DTPA was able to provide both global and segmental liver function information, and post-treatment remnant liver function predicted on pre treatment DHCE-MRI showed a significant negative correlation with post-treatment ICG R15. LAY SUMMARY: Post-treatment liver function could be predicted at pre treatment DHCE-MRI. Liver function was heterogeneous among the liver segments. Liver anatomy, disease extent, and underlying liver function can be assessed in one DHCE-MRI examination. CLINICAL TRIAL NUMBER: ClinicalTrials.gov number, NCT01490203. PMID- 27476768 TI - High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis. PMID- 27476769 TI - Last male wins the egg fertilization fight: A case study in ladybird, Menochilus sexmaculatus. AB - Sexual selection and the mechanisms involved in sperm competition have not been greatly explored in ladybird beetles. The present study was conducted to investigate the processes of sperm competition and the role of mate guarding behaviour in its regulation in ladybird beetles. We investigated these questions in polyandrous females of the ladybird, Menochilus sexmaculatus (Coleoptera: Coccinellidae) using a phenotypic marker (typical and intermediate morph) to assess paternity of offspring; to determine sperm competition. We conducted two double mating experiments: (i) complete first and second matings, and (ii) disrupted first and complete second matings each using homomorphic and heteromorphic pairing in alternation. Males which mated last were found to sire up to 72% of the offspring produced, indicating last male sperm precedence. Morph itself, independent of mating order, did not have a significant effect on proportion of offspring sired. Paternity share of the last male was negatively associated with mating duration of the first male; mating duration of the first male being indicative of mate guarding. This therefore indicates that prolonged matings by first males are essentially examples of post-copulatory mate guarding to prevent last male sperm precedence. PMID- 27476771 TI - Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib. AB - The effectiveness of different polymers, alone or in combination, in inhibiting the crystallization of celecoxib (CEX) from amorphous solid dispersions (ASDs) exposed to different temperatures and relative humidities was evaluated. It was found that polyvinylpyrrolidone (PVP) and PVP-vinyl acetate formed stronger or more extensive hydrogen bonding with CEX than cellulose-based polymers. This, combined with their better effectiveness in raising the glass transition temperature (Tg) of the dispersions, provided better physical stabilization of amorphous CEX against crystallization in the absence of moisture when compared with dispersions formed with cellulose derivatives. In ternary dispersions containing 2 polymers, the physical stability was minimally impaired by the presence of a cellulose-based polymer when the major polymer present was PVP. On exposure to moisture, stability of the CEX ASDs was strongly affected by both the dispersion hygroscopicity and the strength of the intermolecular interactions. Binary and ternary ASDs containing PVP appeared to undergo partial amorphous amorphous phase separation when exposed 94% relative humidity, followed by crystallization, whereas other binary ASDs crystallized directly without amorphous-amorphous phase separation. PMID- 27476770 TI - The road less traveled - defining molecular commensalism with Streptococcus sanguinis. AB - The commensal oral microbial flora has evolved with the human host to support colonization of the various intraoral sites without triggering a significant immune response. In exchange, the commensal microbes provide critical protection against invading pathogens. The intrinsic ability of the oral flora to create a symbiotic microbial community with the host can be disturbed, selecting for the overgrowth of a dysbiotic community that can result in dental diseases, such as caries and periodontitis. Although the mechanisms of molecular pathogenesis in oral diseases are well characterized, much less is known about the molecular mechanisms used by the commensal flora to maintain oral health. Here we focus on the commensal species Streptococcus sanguinis, which is found in abundance in the early oral biofilm and is strongly correlated with oral health. Streptococcus sanguinis exhibits a variety of features that make it ideally suited as a model organism to explore the molecular basis for commensalism. As such, this review will describe our current mechanistic understanding of S. sanguinis commensalism and speculate upon its molecular traits that may be exploitable to maintain or restore oral health under conditions that would otherwise lead to disease. PMID- 27476773 TI - Peer Profile: Felipe Medeiros, MD. PMID- 27476772 TI - Adjuvant Dendritic Cell Vaccination in High-Risk Uveal Melanoma. PMID- 27476774 TI - A New Automated Method to Grade Pterygium Severity Using Scheimpflug Imaging. PMID- 27476775 TI - Metastatic ocular melanoma to the liver exhibits infiltrative and nodular growth patterns. AB - We examined liver specimens from 15 patients with uveal melanoma (UM) who had died of their disseminated disease. We found 2 distinct growth patterns of UM metastasis: infiltrative (n = 12) and nodular (n = 3). In the infiltrative pattern, individual UM cells with a CD133+ cancer stem cell-like phenotype were present and formed aggregates of stage I <50-MUm-diameter micrometastases in the sinusoidal spaces. These micrometastases appeared to expand, destroy adjacent hepatocytes, and form stage II 51- to 500-MUm-diameter and then stage III >500MUm diameter metastases, which were encapsulated by collagenized fibrous septae. In the nodular growth pattern, CD133+ melanoma cells aggregated adjacent to portal venules and subsequently appeared to grow and efface the adjacent hepatocytes to form stage II 51- to 500-MUm-diameter nodules that surrounded the portal venule. These avascular nodules appeared to further expand to form stage III >500-MUm diameter nodules that exhibited vascularization with minimal fibrosis. The tumor stem cell-like phenotype seen in individual UM cells was lost as the tumors progressed. There were CD56+ natural killer cells in sinusoidal spaces and CD3+ lymphocytes in periportal areas. The nodular growth pattern showed UM cells expressing MMP9 and VEGF. UM cells in both above-described growth patterns exhibited variable BAP1 expression. We propose that changes in the liver microenvironment are related to metastatic UM growth. We hypothesize that these changes include immune regulation within the sinusoidal space for the infiltrative pattern and changes in the VEGF/PEDF ratio for the nodular pattern. PMID- 27476777 TI - Human epidermal growth factor receptor 2 expression in micropapillary urothelial carcinoma of the bladder: an analysis of 27 cases. AB - The significance of human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is well established. However, only a few large studies have analyzed HER2 expression in invasive high-grade urothelial carcinoma (UCA). In this study, we sought to analyze the expression of HER2 in a large cohort of micropapillary UCA. A search was performed through our Urologic Pathology files and expert consult files of the senior author for cases of micropapillary UCA of the bladder. Twenty-seven cases were identified. The mean patient age was 68 years (range: 39-87 years). There were 26 male patients and 1 female patient. Twenty of 27 (74%) cases were positive for HER2. Eleven of 15 (73%) cases with angiolymphatic invasion were positive for HER2. Seven of 10 (70%) cases that developed metastasis were positive for HER2. Six of 11 (54%) cases with pT3 disease were positive for HER2, 8/10 (80%) cases with pT2 disease were positive for HER2, 5/5 (100%) cases with pT1 disease were positive for HER2, and the only case with pTa disease was positive for HER2. In our cohort, a significant number of patients with angiolymphatic invasion also had HER2 overexpression. Interestingly, although the majority of cases with advanced disease also demonstrated positive HER2 expression, it was more predominant in cases with less advanced disease. It is therefore highly conceivable that both patients with early or advanced micropapillary UCA of the bladder, including those with angiolymphatic invasion, may benefit from trastuzumab and other related therapeutic agents. PMID- 27476778 TI - [Hypertension during pregnancy: Epidemiology, definition]. AB - Hypertension in pregnancy has several forms that differ by their mechanisms and their consequences for mothers and fetus. Chronic hypertension is defined by SBP>=140mm Hg or DBP>=90mm Hg before pregnancy or before the 20th week of amenorrhea. Gestational hypertension is defined by SBP>=140mm Hg or DBP>=90mm Hg during or after the 20th week of amenorrhea. Preeclampsia is the occurrence of hypertension and proteinuria after 20weeks of amenorrhea. Severe preeclampsia is accompanied by clinical signs and symptoms indicating visceral pain. The HELLP syndrome is a severe preeclampsia accompanied by intravascular hemolysis and hepatic cytolysis. Eclampsia is characterized by seizures of the tonic-clonic type. A chronic hypertension is observed in 1-5% of pregnancies. Gestational hypertension without proteinuria appears in 5-6% of pregnancies. A preeclampsia develops in 1-2% of pregnancies, but much more frequently (up 34%) in the presence of risk factors. High blood pressure during pregnancy remains, by its complications, the leading cause of maternal morbidity and mortality. PMID- 27476776 TI - MCM4 and MCM7, potential novel proliferation markers, significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma, and precancerous lesions. AB - Minichromosomal maintenance (MCM) proteins are participants of DNA replication and may represent more accurate markers in determining the proliferative fraction within a tumor than proliferative marker Ki-67. Our study investigated the correlation between MCM4 and MCM7 expression and Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma, and precancerous lesions. MCM4 and MCM7 expression had similar distribution as Ki-67 and Bmi1 expression in esophageal carcinoma and precancerous lesions. The mean percentage of MCM4, MCM7, and Ki-67 expression increased from squamous epithelium (5.5%, 7.3%, and 5.9%, respectively), to columnar cell metaplasia (11.2, 13.5%, and 3.4%), Barrett's esophagus (27.7%, 35.3%, and 8.3%), low-grade dysplasia (42.6%, 52.2%, and 12.9%), high-grade dysplasia (63.2%, 77.7%, and 29.6%), adenocarcinoma (61.3%, 75.5%, and 24.5%), and squamous cell carcinoma (74.1, 85.4%, and 36.3%). The percentages of MCM4 and MCM7 expression were significantly higher than Ki-67 expression. Using univariate analysis we found a high percentage of MCM4 expression (>70%) to be significantly associated with lymph node metastasis and shorter survival in the adenocarcinoma group. We also demonstrated the percentage of MCM4 and MCM7 expression to be significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal carcinoma and precancerous lesions. MCM4 and MCM7 may serve as more sensitive proliferative markers for the evaluation of esophageal lesions. PMID- 27476779 TI - The outsider adverse event in transfusion: Inflammation. AB - In order to maintain adequate inventories of red blood cells (RBCs) for transfusion, RBC units are refrigerator-stored for variable amounts of time prior to transfusion. A subset of RBCs is damaged during prolonged storage. Clearance of these damaged RBCs is hypothesized to induce an inflammatory response in the transfusion recipient. However, there is controversy over whether RBC transfusions are in fact associated with inflammation, and more generally, whether current standards for maximal RBC storage times are safe. We will explore the evidence for and against this outsider adverse event in transfusion: whether certain RBC transfusions do or do not cause inflammation. PMID- 27476780 TI - Blood transfusion in 2016-Towards a "Nouvelle Vague" therapy? PMID- 27476781 TI - Doping and athlete health. PMID- 27476782 TI - Costs of haematological disease high and rising. PMID- 27476783 TI - Health-care use drives the economic burden of blood disorders in Europe. PMID- 27476784 TI - Direct oral anticoagulants and cancer: no swansong yet for the low-molecular weight heparins. PMID- 27476785 TI - High-dose therapy for primary CNS lymphoma. PMID- 27476786 TI - Correction to Lancet Haematol 2016; 3: e323. PMID- 27476787 TI - Economic burden of malignant blood disorders across Europe: a population-based cost analysis. AB - BACKGROUND: Malignant blood disorders are a leading contributor to cancer incidence and mortality across Europe. Despite their burden, no study has assessed the economic effect of blood cancers in Europe. We aimed to assess the economic burden of malignant blood disorders across the 28 countries in the European Union (EU), Iceland, Norway, and Switzerland. METHODS: Malignant blood disorder-related costs were estimated for 28 EU countries, Iceland, Norway, and Switzerland for 2012. Country-specific costs were estimated with aggregate data on morbidity, mortality, and health-care resource use obtained from international and national sources. Health-care costs were estimated from expenditure on primary, outpatient, emergency, inpatient care, and drugs. Costs of informal care and productivity losses due to morbidity and early death were also included. For countries in the EU, malignant blood disorders were compared with the economic burden of overall cancer. FINDINGS: Malignant blood disorders cost the 31 European countries ?12 billion in 2012. Health-care cost ?7.3 billion (62% of total costs), productivity losses cost ?3.6 billion (30%), and informal care cost ?1 billion (8%). For the EU countries, malignant blood disorders cost ?6.8 billion (12%) of the total health-care expenditure on cancer (?57 billion), with this proportion being second only to breast cancer. In terms of total cancer costs in the EU (?143 billion), malignant blood disorders cost ?12 billion (8%). INTERPRETATION: Malignant blood disorders represent a leading cause of death, health-care service use, and costs, not only to European health-care systems, but to society overall. Our results add to essential public health knowledge needed for effective national cancer-control planning and priorities for public research funding. FUNDING: European Hematology Association. PMID- 27476788 TI - Economic burden of non-malignant blood disorders across Europe: a population based cost study. AB - BACKGROUND: Blood disorders comprise a wide range of diseases including anaemia, malignant blood disorders, and haemorrhagic disorders. Although they are a common cause of disease, no systematic cost-of-illness studies have been done to assess the economic effect of non-malignant blood disorders in Europe. We aimed to assess the economic burden of non-malignant blood disorders across the 28 countries of the European Union (EU), Iceland, Norway, and Switzerland. METHODS: Non-malignant blood disorder-related costs (WHO International Classification of Diseases, 10th revision [ICD] D50-89) were estimated for 28 EU countries, Iceland, Norway, and Switzerland for 2012. Country-specific costs were estimated with aggregate data on morbidity, mortality, and health-care resource use obtained from international and national sources. Health-care costs were estimated from expenditure on primary care, outpatient care, emergency care, hospital inpatient care, and drugs. Costs of informal care and productivity losses due to morbidity and early death were also included. To these costs we added those due to malignant blood disorders (ICD-10 C81-96 and D47) as estimated in a Burns and colleagues' companion Article to obtain the total costs of blood disorders. FINDINGS: Non-malignant disorders of the blood cost the 31 European countries ?11 billion in 2012. Health-care costs accounted for ?8 billion (75% of total costs), productivity losses for ?2 billion (19%), and informal care for less than ?1 billion (6%). Averaged across the European population studied, non malignant disorders of the blood represented an annual health-care cost of ?159 per ten citizens. Combining malignant and non-malignant blood disorders, the total cost of blood disorders was ?23 billion in 2012. INTERPRETATION: Our study highlights the economic burden that non-malignant blood disorders place on European health-care systems and societies. Our study also shows that blood disorder costs were evenly distributed between malignant and non-malignant blood disorders. Our results should be of use to decision makers and research-funding authorities charged with allocating health-care resources and research funds. FUNDING: European Hematology Association. PMID- 27476789 TI - Edoxaban for venous thromboembolism in patients with cancer: results from a non inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double dummy trial. AB - BACKGROUND: Venous thromboembolism occurs commonly in patients with cancer. Direct oral anticoagulants are non-inferior to conventional anticoagulants for the treatment of venous thromboembolism. We hypothesised that edoxaban, a direct oral inhibitor of activated clotting factor Xa, might be more suitable than conventional anticoagulants in the management of cancer-associated venous thromboembolism. The aim of this study was to assess the efficacy and safety of edoxaban compared with warfarin in a subgroup of patients with cancer enrolled in the Hokusai-VTE trial. METHODS: We did a prespecified subgroup analysis in August, 2013, and a post-hoc analysis of non-inferiority and safety in March, 2016, of the patients with cancer enrolled in the randomised, double-blind, double-dummy, multicentre, Hokusai-VTE trial done between Jan 28, 2010, and Oct 31, 2012. In this study, patients aged at least 18 years with acute symptomatic deep-vein thrombosis or acute symptomatic pulmonary embolism (with or without deep-vein thrombosis) were assigned to receive edoxaban 60 mg once per day (or 30 mg once per day for patients with a creatinine clearance of 30-50 mL/min, bodyweight <60 kg, or who were receiving concomitant treatment with the P glycoprotein inhibitors quinidine or verapamil) or warfarin (dose adjusted to maintain the international normalised ratio between 2.0 and 3.0) or placebos for either group for at least 3 months up to 12 months. All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days. Edoxoban (or placebo) was started after discontinuation of initial heparin; warfarin (or placebo) started concurrently with the study regimen of heparin. In our analysis we examined data for a subgroup of these patients who had a history of cancer or who had been categorised as having active cancer by the study physician at the time of enrolment. Additionally, all patients with a history of cancer were reviewed post hoc and categorised according to the presence or absence of active cancer. The primary efficacy outcome was the proportion of these patients with symptomatic recurrent venous thromboembolism during the 12 month study period, analysed in the modified intention-to-treat population, with an upper limit of the CI for the hazard ratio (HR) of 1.5. The principal safety outcome was the proportion of patients who had clinically relevant bleeding in the population of patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT00986154. FINDINGS: Of 771 patients with cancer enrolled in the trial, 378 were assigned to edoxaban and 393 to warfarin. Recurrent venous thromboembolism occurred in 14 (4%) of 378 patients given edoxaban and in 28 (7%) of 393 patients given warfarin (hazard ratio [HR] 0.53, 95% CI 0.28-1.00; p=0.0007). The upper limit of this 95% CI did not exceed the non-inferiority margin of 1.5 that was prespecified for the trial. Clinically relevant bleeding (major or non-major) occurred in 47 (12%) of 378 patients who received edoxaban and in 74 (19%) of 393 patients who received warfarin; HR for clinically relevant bleeding 0.64, 95% CI 0.45-0.92; p=0.017. Major bleeding occurred in ten (3%) of 378 patients with a history of cancer who received edoxaban and in 13 (3%) of 393 who received warfarin (HR 0.80, 95% CI 0.35-1.83). INTERPRETATION: Edoxaban might be as effective as warfarin for the treatment of patients with cancer with venous thromboembolism, and with less clinically relevant bleeding. Additional clinical trials of edoxaban versus low-molecular weight heparin for the treatment of venous thromboembolism in patients with cancer are warranted. FUNDING: Daiichi Sankyo. PMID- 27476790 TI - High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. AB - BACKGROUND: High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma. METHODS: In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) [day 1], carmustine 400 mg/m(2) [day 2], thiotepa 2 * 5 mg/kg [days 3 and 4], and infusion of stem cells [day 7]), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049. FINDINGS: Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77.2% [95% CI 66.1-86.6]) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 [47%]) and the most common grade 4 toxicity was thrombocytopenia (50 [63%]). During HCT-ASCT, the most common grade 3 toxicity was fever (50 [68%] of 73) and the most common grade 4 toxicity was leucopenia (68 [93%] of 73). We recorded four (5%) treatment-related deaths (three [4%] during induction and one [1%] 4 weeks after HCT-ASCT). INTERPRETATION: HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed. FUNDING: University Hospital Freiburg and Amgen. PMID- 27476794 TI - Inhibitors of the bone morphogenetic protein (BMP) signaling pathway: a patent review (2008-2015). AB - INTRODUCTION: The bone morphogenetic protein (BMP) is a critical signaling pathway and plays a diverse role in embryonic pattern formation and is implicated in a variety of disease processes, including anemia, bone formation, atherosclerosis, skin diseases, and cancers, among others. AREAS COVERED: This review covers small molecule inhibitors/antagonists of BMP in patent applications between 2008 - 2015, along with brief synopses of the disclosed inhibitors in the primary literature. EXPERT OPINION: The development of potent and selective BMP inhibitors is ongoing with most of the work centered around improving the selectivity and pharmacokinetic profile. Early work was for the treatment of the rare and neglected disease, fibrodysplasia ossificans progressiva (FOP). Recently, however, there has been increased interest in their use in a number of other diseases such as cancer, atherosclerosis, and anemia of chronic disease, to name a few. Although the primary participants in the early work were from academic laboratories, recently a significant surge from the pharmaceutical industry has elevated the interest in the development of BMP inhibitors for a wide-range of therapeutic indications. Due to this, expect a number of new approaches such as repurposing of other kinase inhibitors to be brought into clinical trials in the near future. PMID- 27476793 TI - Optimizing the Selection of General Surgery Residents: A National Consensus. AB - BACKGROUND: Surgical programs strive to recruit trainees who will graduate as competent surgeons; however, selection processes vary between institutions. The purpose of the present study was to (1) solicit program directors' (PDs) opinions on the proportion of trainees who have difficulty achieving competence and (2) establish consensus on the desired attributes of general surgery (GS) candidates and the technical skills that would be most indicative of future performance. METHODS: Delphi consensus methodology was used. An open-ended questionnaire, followed by a closed-ended questionnaire, formulated as a 5-point Likert scale, was administered. A Cronbach alpha >= 0.8 with 80% of responses in agreement (4 agree and 5-strongly agree) determined the threshold for consensus. RESULTS: The first and second rounds were completed by 14 and 11, of a potential 17, GS PDs, respectively. PDs felt that 5% or less of trainees have difficulty reaching competence in clinical knowledge, 5% to 10% in decision-making, and 5% to 15% in technical skill by the time of completion of training. Consensus was excellent (alpha = 0.92). The top attributes for success in GS included work ethic and passion for surgery. Technical skills that felt to be most appropriate were open tasks (one-handed tie and subcuticular suture) and laparoscopic tasks (coordination, grasping, and cutting). CONCLUSION: PDs indicate that of the 3 domains, the largest proportion of trainees had difficulty reaching competence in technical skill. Consensus among PDs suggests that top personal attributes include work ethic and passion for surgery. Consensus of technical tasks for inclusion into selection was basic open and laparoscopic skills. PMID- 27476792 TI - Objective Assessment of General Surgery Residents Followed by Remediation. AB - OBJECTIVE: Surgical training programs often lack objective assessment strategies. Complicated scheduling characteristics frequently make it difficult for surgical residents to undergo formal assessment; actually having the time and opportunity to remediate poor performance is an even greater problem. We developed a novel methodology of assessment for residents and created an efficient remediation system using a combination of simulation, online learning, and self-assessment options. DESIGN: Postgraduate year (PGY) 2 to 5 general surgery (GS) residents were tested in a 5 station, objective structured clinical examination style event called the Surgical X-Games. Stations were 15 minutes in length and tested both surgical knowledge and technical skills. Stations were scored on a scale of 1 to 5 (1 = Fail, 2 = Mediocre, 3 = Pass, 4 = Good, and 5 = Stellar). Station scores <= 2 were considered subpar and required remediation to a score >= 4. Five remediation sessions allowed residents the opportunity to practice the stations with staff surgeons. Videos of each skill or test of knowledge with clear instructions on how to perform at a stellar level were offered. Trainees also had the opportunity to checkout take-home task trainers to practice specific skills. Residents requiring remediation were then tested again in-person or sent in self made videos of their performance. SETTING: Academic medical center. PARTICIPANTS: PGY2, 3, 4, and 5 GS residents at Mayo Clinic in Rochester, MN. RESULTS: A total of, 35 residents participated in the Surgical X-Games in the spring of 2015. Among all, 31 (89%) had scores that were deemed subpar on at least 1 station. Overall, 18 (58%) residents attempted remediation. All 18 (100%) achieved a score >= 4 on the respective stations during a makeup attempt. Overall X-Games scores and those of PGY2s, 3s, and 4s were higher after remediation (p < 0.05). No PGY5s attempted remediation. CONCLUSIONS: Despite difficulties with training logistics and busy resident schedules, it is feasible to objectively assess most GS trainees and offer opportunities to remediate if performance is poor. Our multifaceted remediation methodology allowed 18 residents to achieve good or stellar performance on each station after deliberate practice. Enticing chief residents to participate in remediation efforts in the spring of their final year of training remains a work in progress. PMID- 27476791 TI - Innate and adaptive immunologic functions of complement in the host response to Listeria monocytogenes infection. AB - Listeria monocytogenes is a leading cause of foodborne-illness associated mortality that has attracted considerable attention in recent years due to several significant outbreaks. It has also served as a model organism for the study of intracellular pathogens. For these reasons the host response to L. monocytogenes has long been the subject of investigation. A potent innate and adaptive immune response is required for containment and clearance of L. monocytogenes. However, some elements of this response, such as type 1 interferons, can be detrimental to the host. Recent studies have revealed novel functions for the complement system, an ancient arm of innate immunity, in this process. Here we review the role of complement in the host response to L. monocytogenes. PMID- 27476796 TI - Biodegradable resistive switching memory based on magnesium difluoride. AB - This study presents a new type of resistive switching memory device that can be used in biodegradable electronic applications. The biodegradable device features magnesium difluoride as the active layer and iron and magnesium as the corresponding electrodes. This is the first report on magnesium difluoride as a resistive switching layer. With on-off ratios larger than one hundred, the device on silicon switches at voltages less than one volt and requires only sub-mA programming current. AC endurance of 10(3) cycles is demonstrated with +/-1 V voltage pulses. The switching mechanism is attributed to the formation and rupture of conductive filaments comprising fluoride vacancies in magnesium difluoride. Devices fabricated on a flexible polyethylene terephthalate substrate are tested for functionality, and degradation is subsequently demonstrated in de ionized water. An additional layer of magnesium difluoride is used to hinder the degradation and extend the lifetime of the device. PMID- 27476795 TI - Protein dynamics as seen by (quasi) elastic neutron scattering. AB - BACKGROUND: Elastic and quasielastic neutron scattering studies proved to be efficient probes of the atomic mean square displacement (MSD), a fundamental parameter for the characterization of the motion of individual atoms in proteins and its evolution with temperature and compositional environment. SCOPE OF REVIEW: We present a technical overview of the different types of experimental situations and the information quasi-elastic neutron scattering approaches can make available. In particular, MSD can crucially depend on the time scale over which the averaging (building of the "mean") takes place, being defined by the instrumental resolution. Due to their high neutron scattering cross section, hydrogen atoms can be particularly sensitively observed with little interference by the other atoms in the sample. A few examples, including new data, are presented for illustration. MAJOR CONCLUSIONS: The incoherent character of neutron scattering on hydrogen atoms restricts the information obtained to the self-correlations in the motion of individual atoms, simplifying at the same time the data analysis. On the other hand, the (often overlooked) exploration of the averaging time dependent character of MSD is crucial for unambiguous interpretation and can provide a wealth of information on micro- and nanoscale atomic motion in proteins. GENERAL SIGNIFICANCE: By properly exploiting the broad range capabilities of (quasi)elastic neutron scattering techniques to deliver time dependent characterization of atomic displacements, they offer a sensitive, direct and simple to interpret approach to exploration of the functional activity of hydrogen atoms in proteins. Partial deuteration can add most valuable selectivity by groups of hydrogen atoms. "This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazu and Dr. Federica Migliardo". PMID- 27476797 TI - Functionalization of silicon nanowire arrays by silver nanoparticles for the laser desorption ionization mass spectrometry analysis of vegetable oils. AB - In this work, novel hybrid nanostructured surfaces, consisting of dense arrays of silicon nanowires (SiNWs) functionalized by Ag nanoparticles (AgNP/SiNWs), were used for the laser desorption/ionization time-of-flight mass spectrometry (LDI TOF MS) analysis of some typical unsaturated food components (e.g. squalene, oleic acid) to assess their MS performance. The synthesis of the novel platforms is an easy, cost-effective process based on the maskless wet-etching preparation at room temperature of SiNWs followed by their decoration with AgNPs, produced by pulsed laser deposition. No particular surface pretreatment or addition of organic matrixes/ionizers was necessary. Moreover, oil extracts (e.g. extra virgin olive oil, peanut oil) could be investigated on AgNP/SiNWs surfaces, revealing their different MS profiles. It was shown that such substrates operate at reduced laser energy, typically generating intense silver cluster ions and analyte adducts. A comparison with bare SiNWs was also performed, indicating the importance of AgNP density on NW surface. In this case, desorption/ionization on silicon was invoked as probable LDI mechanism. Finally, the influence of SiNW length and surface composition on MS results was assessed. The combination of typical properties of SiNWs (hydrophobicity, antireflectivity) with ionization ability of metal NPs can be a valid methodology for the further development of nanostructured surfaces in LDI-TOF MS applications. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476798 TI - Lower urgency paediatric injuries: Parent preferences for emergency department or general practitioner care. AB - OBJECTIVES: Injuries are a significant proportion of lower urgency (triage category 4 or 5) child presentations to the EDs in metropolitan Melbourne. The purpose of the present study was to assess parental preferences and experiences regarding the treatment of lower urgency child injuries and the role of general practitioners (GPs) in such care. METHODS: A self-administered survey study of 1150 parents of children <=9 years of age attending the ED at one of four Victorian hospitals triaged with a lower urgency condition (triage category 4 or 5) looked at whether children with lower urgency injuries are frequently referred by their GP to the ED and parent preferences for the care of lower urgency child injuries. Parents were recruited by time of day and weekday/weekend. Descriptive and bivariate analyses were performed. RESULTS: Fewer parents of injured children, compared with illness, attempted to make a GP appointment prior to attending ED (35% vs 46%; P < 0.001). A greater proportion of injured children were referred to the ED by their GP than ill children (84% vs 59%; P = <0.001). More parents (53%) preferred ED for the care of child injuries than primary care. Parents who presented to the ED with an ill child were more likely to indicate that they have greater trust in ED doctors for the treatment of injuries than primary care doctors (56% vs 46%; P = 0.003). CONCLUSIONS: Treatment provided in the ED for child injuries is valued highly by most parents, with a higher proportion of children with an injury being referred to the ED by their GP. Improving GP treatment skills and training opportunities may reduce GP referrals of lower urgency child injuries to the ED. PMID- 27476800 TI - Geographic variation and trade-offs in parasitoid virulence. AB - Host-parasitoid systems are characterized by a continuous development of new defence strategies in hosts and counter-defence mechanisms in parasitoids. This co-evolutionary arms race makes host-parasitoid systems excellent for understanding trade-offs in host use caused by evolutionary changes in host immune responses and parasitoid virulence. However, knowledge obtained from natural host-parasitoid systems on such trade-offs is still limited. In this study, the aim was to examine trade-offs in parasitoid virulence in Asecodes parviclava (Hymenoptera: Eulophidae) when attacking three closely related beetles: Galerucella pusilla, Galerucella calmariensis and Galerucella tenella (Coleoptera: Chrysomelidae). A second aim was to examine whether geographic variation in parasitoid infectivity or host immune response could explain differences in parasitism rate between northern and southern sites. More specifically, we wanted to examine whether the capacity to infect host larvae differed depending on the previous host species of the parasitoids and if such differences were connected to differences in the induction of host immune systems. This was achieved by combining controlled parasitism experiments with cytological studies of infected larvae. Our results reveal that parasitism success in A. parviclava differs both depending on previous and current host species, with a higher virulence when attacking larvae of the same species as the previous host. Virulence was in general high for parasitoids from G. pusilla and low for parasitoids from G. calmariensis. At the same time, G. pusilla larvae had the strongest immune response and G. calmariensis the weakest. These observations were linked to changes in the larval hemocyte composition, showing changes in cell types important for the encapsulation process in individuals infected by more or less virulent parasitoids. These findings suggest ongoing evolution in parasitoid virulence and host immune response, making the system a strong candidate for further studies on host race formation and speciation. PMID- 27476801 TI - Control of discrete time systems based on recurrent Super-Twisting-like algorithm. AB - Most of the research in sliding mode theory has been carried out to in continuous time to solve the estimation and control problems. However, in discrete time, the results in high order sliding modes have been less developed. In this paper, a discrete time super-twisting-like algorithm (DSTA) was proposed to solve the problems of control and state estimation. The stability proof was developed in terms of the discrete time Lyapunov approach and the linear matrix inequalities theory. The system trajectories were ultimately bounded inside a small region dependent on the sampling period. Simulation results tested the DSTA. The DSTA was applied as a controller for a Furuta pendulum and for a DC motor supplied by a DSTA signal differentiator. PMID- 27476802 TI - Non-linear backstepping control of five-phase IM drive at low speed conditions experimental implementation. AB - In this paper non-linear backstepping control (BSC) is employed for high performance five-phase induction motor drive for low speed operation. The traditional control approaches such as direct torque control and indirect rotor field oriented control introduces stability problem at low speed. The proposed BSC is shown to offer stable operation in the sense of Lyapunov and high dynamics at low speed. Experimental results are provided to present the proprieties of the proposed approach at low speed in terms of stability, torque ripple, desired control performance, achievable dynamics and complexity of implementation etc. PMID- 27476803 TI - Association of Supported Employment With Cognitive Functioning and Employment Outcomes. AB - OBJECTIVE: Cognitive functioning affects employment outcomes in supported employment. This study examined which cognitive parameters are associated with employment outcomes for persons with mental illnesses and discusses possible mechanisms involved. METHODS: Data stem from a randomized controlled trial conducted as part of the Zurich Impulse Program for the Sustainable Development of Mental Health Services (ZInEP). A sample of 116 patients in supported employment was recruited, coached, and followed up. Factor analysis and logistic regression were used to determine cognitive parameters associated with employment outcomes. RESULTS: Results showed that verbal learning was positively associated with better employment outcomes (any job and employment for at least three months). CONCLUSIONS: Results of this study imply that training in verbal learning should be included in supported employment programs. More generally, elaborated models are needed to explain interactions between cognitive functioning, supported employment, and employment outcomes and to enhance understanding of the interrelationships between cognitive functioning, employment outcomes, and any mediating and moderating variables. PMID- 27476799 TI - Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2. AB - Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (beta = 0.22, p = 1.9 * 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (beta = 0.09, p = 1.2 * 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 * 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (beta = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (beta = 0.12, FDR p = 1.7 * 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. (c) 2016 American Society for Bone and Mineral Research. PMID- 27476804 TI - Prevalence of Alcohol Misuse and Follow-Up Care in a National Sample of OEF/OIF VA Patients With and Without TBI. AB - OBJECTIVE: Information on prevalence and management of alcohol misuse among Afghanistan and Iraq veterans with traumatic brain injury (TBI) is limited. This study compared rates of alcohol misuse and follow-up care-brief intervention (BI) and addiction treatment-among Afghanistan and Iraq veterans with and without TBI receiving care from the Department of Veterans Affairs (VA). METHODS: The sample included veterans ages 18 and older screened with the Alcohol Use Disorders Identification Test alcohol consumption questions (AUDIT-C) in 2012 who received VA health care in the prior year (N=358,417). Overall and age-specific estimates of alcohol misuse (AUDIT-C score >=5) were compared for men and women with and without TBI by logistic regression. BI and addiction treatment after screening were compared between groups by using multivariable logistic regression. RESULTS: Alcohol misuse was higher among men with TBI than among men without TBI (20.3%, 95% confidence interval [CI]=19.9-20.8, versus 16.4%, CI=16.3-16.6) and among women with TBI than among women without TBI (6.8%, CI=5.8-8.1, versus 5.6%, CI=5.4-5.8); younger (age <30) patients with TBI had the highest rates. BI rates did not differ by TBI status (76.4%-80.2%). Addiction treatment rates for those with severe misuse were higher among those with TBI (men, 20.0%, CI=18.4-21.6, versus 15.4%, CI=14.9-15.9; women, 36.6%, CI=21.8-51.3, versus 21.1%, CI=18.2 24.0). CONCLUSIONS: Alcohol misuse is common among Iraq and Afghanistan veterans with TBI, particularly young men. BI rates were high and did not vary by TBI status, although addiction treatment rates were higher among patients with TBI than among those without TBI. PMID- 27476805 TI - Trends in Racial-Ethnic Disparities in Access to Mental Health Care, 2004-2012. AB - OBJECTIVE: This study compared trends in racial-ethnic disparities in mental health care access among whites, blacks, Hispanics, and Asians by using the Institute of Medicine definition of disparities as all differences except those due to clinical appropriateness, clinical need, and patient preferences. METHODS: Racial-ethnic disparities in mental health care access were examined by using data from a nationally representative sample of 214,597 adults from the 2004-2012 Medical Expenditure Panel Surveys. The main outcome measures included three mental health care access measures (use of any mental health care, any outpatient care, and any psychotropic medication in the past year). RESULTS: Significant disparities were found in 2004-2005 and in 2011-2012 for all three racial-ethnic minority groups compared with whites in all three measures of access. Between 2004 and 2012, black-white disparities in any mental health care and any psychotropic medication use increased, respectively, from 8.2% to 10.8% and from 7.6% to 10.0%. Similarly, Hispanic-white disparities in any mental health care and any psychotropic medication use increased, respectively, from 8.4% to 10.9% and 7.3% to 10.3%. CONCLUSIONS: No reductions in racial-ethnic disparities in access to mental health care were identified between 2004 and 2012. For blacks and Hispanics, disparities were exacerbated over this period. Clinical interventions that improve identification of symptoms of mental illness, expansion of health insurance, and other policy interventions that remove financial barriers to access may help to reduce these disparities. PMID- 27476806 TI - Comparison of Injectable and Oral Antipsychotics in Relapse Rates in a Pragmatic 30-Month Schizophrenia Relapse Prevention Study. AB - OBJECTIVE: In a pragmatic clinical trial, this study sought to compare relapses among patients receiving either long-acting injectable or oral second-generation antipsychotics. METHODS: PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy), a prior 30-month relapse prevention study, compared use of a long-acting injectable second-generation antipsychotic with use of an oral second-generation antipsychotic by 305 patients with schizophrenia or schizoaffective disorder and found similar rates of first relapse between groups (42% with injectable medication, 32% with oral medication). This study examined subsequent relapses among patients who had relapsed in PROACTIVE and who continued in treatment, follow-up, or both. RESULTS: Thirty-two patients (11%) experienced two relapses, and 13 patients (4%) had three relapses. Neither rate of relapse nor time to successive relapses differed between treatment groups. CONCLUSIONS: There was an impressively low rate of subsequent relapses in this pragmatic clinical trial. Because all patients had a clinic visit according to the biweekly long-acting injectable medication administration schedule, frequent contact may have contributed to low relapse rates. Maintaining frequent clinical contact may be a valid psychosocial relapse prevention treatment. PMID- 27476807 TI - Association Between Restriction of Involuntary Medication and Frequency of Coercive Measures and Violent Incidents. AB - OBJECTIVE: In the German federal state of Baden-Wuerttemberg, involuntary medication of psychiatric inpatients was illegal during eight months from July 2012 until February 2013. The authors examined whether the number and duration of mechanical coercive measures (seclusion and restraint) and the number and severity of violent incidents changed in this period. METHODS: A cross-sectional analysis was conducted of admission-related routine data collected in seven psychiatric hospitals in three time periods (period 1, July 2011-February 2012; period 2, July 2012-February 2013; and period 3, July 2013-February 2014). All patients with psychotic disorders and at least one admission during at least one of the three time periods were included (N=2,071), for a total of 3,482 admissions. RESULTS: The mean number of mechanical coercive measures and violent incidents per admission increased significantly during period 2, when involuntary medication was not possible, and decreased significantly during period 3. They also differed significantly between periods 1 and 3. The percentage of admissions involving seclusion increased during period 2 significantly and was significantly different during period 1 compared with period 3. The severity of illness and the length of hospitalization did not change over the three periods. CONCLUSIONS: Restriction of involuntary medication was associated with a significant increase in use of mechanical coercive measures and violent incidents. PMID- 27476808 TI - Psychiatric Hospitalizations: A Comparison by Gender, Sociodemographics, Clinical Profile, and Postdischarge Outcomes. AB - OBJECTIVE: The objective of this study was to identify differences between men and women hospitalized for psychiatric conditions. METHODS: Men and women with an inpatient psychiatric hospitalization in Ontario, Canada, between 2008 and 2013 (N=95,055) were compared on sociodemographic characteristics, health history, and clinical profiles and on 30-day and 90-day postdischarge readmission, emergency department (ED) visits, self-harm, and death. RESULTS: Compared with men, women were older and more likely to be educated, to live with a partner, and to report trauma history. Mood disorders were more common among women; psychotic and substance use disorders were more common among men. Postdischarge, there was no difference in either readmission or ED revisits. Compared with men, women had greater risk of self-harm at 30 days (adjusted odds ratio [AOR]=1.17, 95% confidence interval [CI]=1.04-1.32) and at 90 days (AOR=1.28, CI=1.17-1.39). Death was rare (<1%), with women at lower risk at both 30 days (AOR=.49, CI=.38 .63) and 90 days (AOR=.53, CI=.45-.63). CONCLUSIONS: These data can inform inpatient psychiatric service delivery for both men and women. PMID- 27476809 TI - Timeliness of Autism Spectrum Disorder Diagnosis and Use of Services Among U.S. Elementary School-Aged Children. AB - OBJECTIVE: This study assessed the relationship of timeliness of autism spectrum disorder (ASD) diagnosis with current use of ASD-related services in a nationally representative sample of U.S. children. METHODS: The Centers for Disease Control's (CDC's) Survey of Pathways to Diagnosis and Services was used to assess experiences of 722 children ages six to 11 with ASD. Bivariate and multivariate analyses were used to explore associations between age at ASD diagnosis and delay in ASD diagnosis and use of health services. Health services included current use of behavioral intervention (BI) therapy, school-based therapy, complementary and alternative medicine (CAM), and psychotropic medications. RESULTS: Mean age at ASD diagnosis was 4.4 years, and mean diagnostic delay was 2.2 years. In adjusted analysis, older age at diagnosis (>=4 versus <4) was associated with lower likelihood of current BI or school-based therapy use and higher likelihood of current psychotropic medication use. Analyses that treated age at diagnosis as a continuous variable found that likelihood of current psychotropic medication use increased with older age at diagnosis. A delay of two or more years between parents' first discussion of concerns with a provider and ASD diagnosis was associated with higher likelihood of current CAM use. Likelihood of current CAM use increased as delay in diagnosis became longer. CONCLUSIONS: Both older age at diagnosis and longer delay in diagnosis were associated with different health services utilization patterns among younger children with ASD. Prompt and early diagnosis may be associated with increased use of evidence-based therapies for ASD. PMID- 27476811 TI - Follow-up comment on the use of alternative mass reference standards for Direct Analysis in Real Time mass spectrometry. PMID- 27476810 TI - Variability of piperacillin concentrations in relation to tazobactam concentrations in critically ill patients. AB - Therapeutic drug monitoring for critically ill patients receiving piperacillin/tazobactam is described as a useful tool. However, the minimum inhibitory concentration of piperacillin depends on a sufficiently high concentration of tazobactam in case of beta-lactamase-producing strains. Therefore, the relationship between piperacillin and tazobactam concentrations was assessed in a heterogeneous group of critically ill patients. Sixty patients with severe infections receiving 4.5 g of piperacillin/tazobactam 2-3 times daily by intermittent infusion were included in this prospective observational study (NCT01793012). Over 4 days, multiple serum samples were obtained to determine the total piperacillin and tazobactam concentrations. The target ranges were defined as trough levels >16 mg/L (>22.5 mg/L) and >4 mg/L (>5.7 mg/L) for the calculated unbound concentrations (measured total concentrations) of piperacillin and tazobactam, respectively. Despite a high correlation coefficient (r = 0.93) comparing piperacillin and tazobactam trough levels, the piperacillin/tazobactam quotients varied between ca. 1 and 10. From linear regression analysis of piperacillin versus tazobactam values, it follows that a piperacillin trough level of 22.5 mg/L might be associated with tazobactam trough levels ranging from 1.5 mg/L to 10.1 mg/L. A 70 mg/L threshold for total piperacillin trough levels would be necessary to ensure that tazobactam concentrations are >5.7 mg/L. Because of the observed variability of piperacillin/tazobactam quotients, defining the total piperacillin target range >=70 mg/L might be useful to ensure that tazobactam concentrations do not fall below 5.7 mg/L. Further studies are necessary to confirm that the used therapeutic ranges are associated with optimal outcomes in critically ill patients. PMID- 27476812 TI - Observing Electrochemical Dealloying by Single-Nanoparticle Collision. AB - We report direct observation of electrochemical and thermal dealloying processes of individual metal alloy nanoparticles (NPs). Electrochemical dealloying of single Ag-Hg alloy NPs was achieved in a basic solution (e.g., pH 13) by oxidizing Hg under controlled potentials. Ag can also be oxidized during single particle collision. However, it requires elevated potentials. The strong basic environment promoted the formation of metal oxides during collision leading to a unique core-shell type nanostructure which was further confirmed by transmission electron microscopy (TEM). In thermal dealloying, Hg was evaporated due to the use of a high-energy electron beam and the process was imaged in situ inside a TEM. Both electrochemical and thermal dealloying processes resulted in the transformation of an amorphous NP to a more stable Ag-Hg alloy nanocrystal. This work demonstrates that NP collision can be a useful tool to study dealloying processes of various nanomaterials at a single-particle level. PMID- 27476813 TI - Occupational Exposure Limits of lead, dimethylamine, n-butyl-2,3-epoxypropyl ether, and 2-ethyl-1-hexanol and carcinogenicity and occupational sensitizer classification. PMID- 27476814 TI - Discovery of a new function of curcumin which enhances its anticancer therapeutic potency. AB - Curcumin has received immense attention over the past decades because of its diverse biological activities and recognized as a promising drug candidate in a large number of diseases. However, its clinical application has been hindered due to extremely low aqueous solubility, chemical stability, and cellular uptake. In this study, we discovered quite a new function of curcumin, i.e. pH-responsive endosomal disrupting activity, derived from curcumin's self-assembly. We selected anticancer activity as an example of biological activities of curcumin, and investigated the contribution of pH-responsive property to its anticancer activity. As a result, we demonstrated that the pH-responsive property significantly enhances the anticancer activity of curcumin. Furthermore, we demonstrated a utility of the pH-responsive property of curcumin as delivery nanocarriers for doxorubicin toward combination cancer therapy. These results clearly indicate that the smart curcumin assemblies act as promising nanoplatform for development of curcumin-based therapeutics. PMID- 27476815 TI - In vitro safety assessments and antimicrobial activities of Lactobacillus rhamnosus strains isolated from a fermented mare's milk. AB - Safety and probiotic characteristics such as antimicrobial activities of three Lactobacillus rhamnosus strains, FSMM15, FSMM22 and FSMM26, previously isolated as potential probiotics from fermented mare's milk were investigated. The three FSMM strains were susceptible to ampicillin, gentamycin, kanamycin, streptomycin, tetracycline and chloramphenicol, whereas they were resistant to erythromycin (minimal inhibitory concentration (MIC) = 4-8 ug/mL) and clindamycin (MIC = 4 ug/mL); bioconversion of bile salts, hemolytic activity and mucin degradation activity were negative; enzymatic activities of alpha-chymotrypsin and beta glucosidase were detected, but those of alpha-galactosidase, beta-glucuronidase and N-acetyl-beta-glucosaminidase, were undetectable. Among the strains, strain FSMM15 was chosen as a safer probiotic candidate due mainly to the lack of plasminogen binding ability. Despite lower acid production of strain FSMM15 than others, its cell-free culture supernatant inhibited growths of Salmonella Typhimurium LT-2, Shigella sonnei, Listeria monocytogenes, and Escherichia coli O157 with comparable levels of ampicillin, suggesting a favorable aspect of strain FSMM15 as a probiotic strain. PMID- 27476816 TI - Microbial Nanoculture as an Artificial Microniche. AB - Microbes self-organize in microcolonies while transitioning to a sessile form within a protective biofilm matrix. To enable the detailed study of microbial dynamics within these microcolonies, new sessile culture systems are needed that sequester cells and mimic their complex growth conditions and interactions. We present a new nanoliter-scale sessile culture system that is easily implemented via microfluidics-enabled fabrication. Hundreds of thousands of these nanocultures can be easily generated and imaged using conventional or confocal microscopy. Each nanoculture begins as a several nanoliter droplet of suspended cells, encapsulated by a polydimethylsiloxane (PDMS) membrane. The PDMS shell provides long-lasting mechanical support, enabling long term study, and is selectively permeable to small molecules including antibiotics, signaling molecules and functional fluorescent probes. Thus, as microcolonies mature within the nanocultures, they can be stressed or interrogated using selected probes to characterize cell physiological properties, antibiotic susceptibilities, and antagonistic interactions. We demonstrate this platform by investigating broad ranges of microcolony dynamics, including direct and indirect bacterial-fungal interactions. This versatile new tool has broad potential for addressing biological questions associated with drug resistance, chronic infections, microbiome dynamics, and antibiotic discovery. PMID- 27476817 TI - Prevalence of halitosis in elderly living in nursing homes. AB - OBJECTIVES: Halitosis is a concern for many people, but has sparsely been studied in elderly living in nursing homes. The aim of this investigation was to study the prevalence of halitosis in this particular group and factors that could be associated with this condition. METHOD AND MATERIALS: One hundred and twenty-four residents at three different nursing homes were included in the study. The level of halitosis was assessed using an organoleptic method based on a 6-graded scale. Oral status, including registrations of plaque, gingivitis and assessment of hyposalivation, was performed by two investigators who both examined all patients. Medical history, that is medication, neurological conditions, diabetes, cardiovascular disease, chronic obstructive pulmonary disease (COPD)/asthma, dementia and mental illness, was obtained from the patient files. Registrations of the use of oral hygiene aids, ADL (Activity of Daily Life) and the frequency of contact with dental services were included in the clinical examination. RESULTS: Halitosis occurred in over 50% of residents living in nursing homes and was found to be associated with the presence of hyposalivation, periodontal disease, calculus, fixed prosthodontics and dementia. CONCLUSION: Halitosis was a common finding in the elderly living in Swedish nursing homes. PMID- 27476818 TI - The Role of Systemic Steroids in Postintubation Tracheal Stenosis: A Randomized Clinical Trial. AB - BACKGROUND: Most patients with postintubation tracheal stenosis are not ideal candidates for airway resection at presentation and their airways must be temporarily kept open by repeated bronchoscopic dilation (RBD). Meanwhile, some sufficiently recover by RBD without further airway resection requirement. We hypothesized whether systemic corticosteroids could lengthen RBD intervals, decrease the number of patients who eventually need airway resection, and shorten the required length of airway resection. METHODS: Between February 2009 and November 2012, a randomized double-blind clinical trial with a 1:1 ratio (corticosteroids group [group C], prednisolone 15 mg/day; placebo group [group P]) was conducted on 120 patients without tracheostomy or T tube and in no ideal situation for airway resection at presentation, whose precipitating injury had occurred recently. All underwent RBD until they became asymptomatic or prepared for airway resection. Asymptomatic patients received the capsules (prednisolone or placebo) for 6 months; others discontinued them before surgery. Those requiring RBD at short intervals underwent tracheostomy or T tube placement and were then excluded. Follow-up terminated 6 months after airway resection or capsule discontinuation. RESULTS: There were 105 patients (72 male; 50 in group C), aged 15 to 64 years, who completed their follow-up. There was no significant difference between the two groups in age, sex, history of tracheostomy, intubation cause and duration, time interval between intubation and initial bronchoscopy, length of stenosis, and subglottic involvement. Our study showed a trend for RBD with longer intervals (22 days), and fewer operations, 17% (28 of 50 versus 40 of 55) in group C, although statistically insignificant. Furthermore, the required airway resection length became significantly shorter (5.3 mm) in group C. CONCLUSIONS: Early low-dose systemic corticosteroids can be beneficial in postintubation tracheal stenosis management. PMID- 27476819 TI - Induction Chemotherapy is Not Superior to a Surgery-First Strategy for Clinical N1 Non-Small Cell Lung Cancer. AB - BACKGROUND: Guidelines recommend primary surgical resection for non-small cell lung cancer (NSCLC) patients with clinical N1 disease and adjuvant chemotherapy if nodal disease is confirmed after resection. We tested the hypothesis that induction chemotherapy for clinical N1 (cN1) disease improves survival. METHODS: Patients treated with lobectomy or pneumonectomy for cT1-3 N1 M0 NSCLC from 2006 to 2011 in the National Cancer Data Base were stratified by treatment strategy: surgery first vs induction chemotherapy. Propensity scores were developed and matched with a 2:1 nearest neighbor algorithm. Survival analyses using Kaplan Meier methods were performed on the unadjusted and propensity-matched cohorts. RESULTS: A total of 5,364 cN1 patients were identified for inclusion, of which 565 (10.5%) were treated with induction chemotherapy. Clinical nodal staging was accurate in 68.6% (n = 3,292) of patients treated with surgical resection first, whereas 16.3% (n = 780) were pN0 and 10.7% (n = 514) were pN2-3. Adjuvant chemotherapy was given to 60.9% of the surgery-first patients who were pN1-3 after resection. Before adjustment, patients treated with induction chemotherapy were younger, with lower comorbidity burden, were more likely to be treated at an academic center and to have private insurance (all p < 0.001), but were significantly more likely to have T3 tumors (28.7% vs 9.9%, p < 0.001) and to require pneumonectomy (23.5% vs 18.5%, p = 0.005). The unadjusted and propensity matched analyses found no differences in short-term outcomes or survival between groups. CONCLUSIONS: Induction chemotherapy for cN1 NSCLC is not associated with improved survival. This finding supports the currently recommended treatment paradigm of surgery first for cN1 NSCLC. PMID- 27476820 TI - Operative Risk for Major Lung Resection Increases at Extremes of Body Mass Index. AB - BACKGROUND: Although body mass index (BMI) has been used in risk stratification for lung resection, many models only take obesity into account. Recent studies have demonstrated that underweight patients also experience increased postoperative complications. We explored the relationship of extremes of BMI to outcomes after lung resection for non-small cell cancer. METHODS: Patients in the Society of Thoracic Surgeons General Thoracic Surgery Database (2009 to 2014) undergoing elective lung resection for cancer were evaluated. Multivariable logistic regression was used to adjust for potential confounders including functional status and spirometry. RESULTS: We evaluated 41,446 patients (median 68 years of age; 53% female) grouped by BMI: underweight (<18.5 kg/m2; 3.0%), normal (18.5 to 24.9 kg/m2; 33.5%), overweight (25 to 29.9 kg/m2; 35.4%), obese I (30 to 34.9 kg/m2; 18.1%), obese II (35 to 39.9 kg/m2; 6.4%), and obese III (>=40 kg/m2; 3.6%). Pulmonary complication rates were higher in underweight and obese III patients compared to normal BMI patients (p < 0.001). On multivariable analysis, compared to patients with normal BMI, being underweight was associated with an increased risk of pulmonary complications (adjusted odds ratio [OR]: 1.41, 95% confidence interval [CI]: 1.16 to 1.70) and any postoperative event (adjusted OR: 1.44, 95% CI: 1.26 to 1.64). Obese III patients had an increased risk of any major postoperative complication (adjusted OR: 1.18, 95% CI: 1.02 to 1.36). Overweight and obese class I to II patients had a lower risk of pulmonary complications and any postoperative event. CONCLUSIONS: BMI is associated with postoperative complications after lung resection for cancer. Being underweight or severely overweight is associated with an increased risk of complications, whereas being overweight or moderately obese appears to have a protective effect. PMID- 27476821 TI - Socioeconomic Factors Are Associated With Readmission After Lobectomy for Early Stage Lung Cancer. AB - BACKGROUND: Data regarding risk factors for readmissions after surgical resection for lung cancer are limited and largely focus on postoperative outcomes, including complications and hospital length of stay. The current study aims to identify preoperative risk factors for postoperative readmission in early stage lung cancer patients. METHODS: The National Cancer Data Base was queried for all early stage lung cancer patients with clinical stage T2N0M0 or less who underwent lobectomy in 2010 and 2011. Patients with unplanned readmission within 30 days of hospital discharge were identified. Univariate analysis was utilized to identify preoperative differences between readmitted and not readmitted cohorts; multivariable logistic regression was used to identify risk factors resulting in readmission. RESULTS: In all, 840 of 19,711 patients (4.3%) were readmitted postoperatively. Male patients were more likely to be readmitted than female patients (4.9% versus 3.8%, p < 0.001), as were patients who received surgery at a nonacademic rather than an academic facility (4.6% versus 3.6%; p = 0.001) and had underlying medical comorbidities (Charlson/Deyo score 1+ versus 0; 4.8% versus 3.7%; p < 0.001). Readmitted patients had a longer median hospital length of stay (6 days versus 5; p < 0.001) and were more likely to have undergone a minimally invasive approach (5.1% video-assisted thoracic surgery versus 3.9% open; p < 0.001). In addition to those variables, multivariable logistic regression analysis identified that median household income level, insurance status (government versus private), and geographic residence (metropolitan versus urban versus rural) had significant influence on readmission. CONCLUSIONS: The socioeconomic factors identified significantly influence hospital readmission and should be considered during preoperative and postoperative discharge planning for patients with early stage lung cancer. PMID- 27476822 TI - Use of a Dacron Annular Sparing Versus Limited Transannular Patch With Nominal Pulmonary Annular Expansion in Infants With Tetralogy of Fallot. AB - BACKGROUND: Repair of tetralogy of Fallot (ToF) using a transannular patch can result in severe pulmonary insufficiency (PI) and subsequent right ventricular (RV) dilation. Use of a Dacron (Maquet Cardiovascular LLC, Wayne, NJ) limited transannular patch with nominal pulmonary annular expansion (LTAP) attempts to limit PI. We sought to evaluate the degree of PI and RV dilation resulting from a LTAP or annular sparing (AS) approach. METHODS: Infants less than 1 year of age undergoing ToF repair between 2000 and 2010 were divided into 2 groups: LTAP and AS RV outflow tract patch. Echocardiograms were used to determine RV dimensions and corresponding Z-values. RESULTS: From 94 infants, 48 required a LTAP and 46 required an AS patch. The preoperative pulmonary valve annulus Z-value was significantly smaller in the LTAP versus AS group (-2.7 +/- 1.4 versus -0.9 +/- 1.5; p < 0.001). Mean follow-up was obtained at 7.9 +/- 3.4 years. Ten-year freedom from severe pulmonary insufficiency was 78.5% versus 93.2% (p = 0.3) in the LTAP and AS groups, respectively. There was no significant difference in the diameter of the RV base Z-value between groups (LTAP: 0.9 +/- 0.8 versus AS: 0.0 +/- 2.3; p = 0.1). Further, the freedom from reoperation at 10 years was also not significantly different between the LTAP and AS groups (95.6% versus 91.8%; p = 0.5). CONCLUSIONS: When required, a LTAP results in a similar change in RV chamber size and rate of reoperation at an intermediate-term follow-up. PMID- 27476823 TI - Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. AB - Hepatitis C virus (HCV) is a major leading cause of hepatocellular carcinoma (HCC). HCV-induced hepatocarcinogenesis is a multistep process resulting from a combination of pathway alterations that are either caused directly by viral factors or immune mediated as a consequence of a chronic state of inflammation. Host genetic variation is now emerging as an additional element that contribute to increase the risk of developing HCC. The advent of direct-acting antiviral agents foresees a rapid decline of HCC rate in HCV patients. However, a full understanding of the HCV-mediated tumourigenic process is required to elucidate if pro-oncogenic signatures may persist after virus clearance, and to identify novel tools for HCC prevention and therapy. In this review, we summarize the current knowledge of the molecular mechanisms responsible for HCV-induced hepatocarcinogenesis. PMID- 27476824 TI - LFQProfiler and RNP(xl): Open-Source Tools for Label-Free Quantification and Protein-RNA Cross-Linking Integrated into Proteome Discoverer. AB - Modern mass spectrometry setups used in today's proteomics studies generate vast amounts of raw data, calling for highly efficient data processing and analysis tools. Software for analyzing these data is either monolithic (easy to use, but sometimes too rigid) or workflow-driven (easy to customize, but sometimes complex). Thermo Proteome Discoverer (PD) is a powerful software for workflow driven data analysis in proteomics which, in our eyes, achieves a good trade-off between flexibility and usability. Here, we present two open-source plugins for PD providing additional functionality: LFQProfiler for label-free quantification of peptides and proteins, and RNP(xl) for UV-induced peptide-RNA cross-linking data analysis. LFQProfiler interacts with existing PD nodes for peptide identification and validation and takes care of the entire quantitative part of the workflow. We show that it performs at least on par with other state-of-the art software solutions for label-free quantification in a recently published benchmark ( Ramus, C.; J. Proteomics 2016 , 132 , 51 - 62 ). The second workflow, RNP(xl), represents the first software solution to date for identification of peptide-RNA cross-links including automatic localization of the cross-links at amino acid resolution and localization scoring. It comes with a customized integrated cross-link fragment spectrum viewer for convenient manual inspection and validation of the results. PMID- 27476825 TI - Development of the beta-lactam type molecular scaffold for selective estrogen receptor alpha modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells. AB - The estrogen receptors (ERalpha and ERbeta) which are ligand inducible nuclear receptors are recognized as pharmaceutical targets for diseases such as osteoporosis and breast cancer. There is an increasing interest in the discovery of subtype Selective Estrogen Receptor Modulators (SERMs). A series of novel beta lactam compounds with estrogen receptor modulator properties have been synthesized. The antiproliferative effects of these compounds on human MCF-7 breast tumor cells are reported, together with binding affinity for the ERalpha and ERbeta receptors. The most potent compound 15g demonstrated antiproliferative effects on MCF-7 breast tumor cells (IC50 = 186 nM) and ERalpha binding (IC50 = 4.3 nM) with 75-fold ERalpha/beta receptor binding selectivity. The effect of positioning of the characteristic amine containing substituted aryl ring (on C-4 or N-1 of the beta-lactam scaffold) on the antiproliferative activity and ER binding properties of the beta-lactam compounds is rationalized in a molecular modeling study. PMID- 27476826 TI - Body weight changes after adjuvant chemotherapy of patients with breast cancer: results of a Mexican cohort study. AB - Weight gain is observed in breast cancer patients receiving chemotherapy and is a well-known complication. Several factors that contributing to weight gain have been identified. However, there is a lack of information about factors associated with weight changes following adjuvant chemotherapy. A retrospective cohort of 200 pre- and post-menopausal Mexican patients treated for breast cancer was made. Anthropometric variables were measured before/after treatment. Biomarkers, cellular differentiation and chemotherapy were similar between groups. Weight gain occurred in 85.6% of pre-menopausal and 72.6% of post-menopausal women (p = .03). At the end of chemotherapy, weight and body mass index (BMI) did not differ significantly between pre-menopausal (69.3 +/- 12.6 kg; 26.6 +/- 4.8 kg/m2 ) and post-menopausal women (69.5 +/- 10.9 kg; 27.3 +/- 4.4 kg/m2 ) (p = .91 and 0.34). Dexamethasone doses were higher in pre-menopausal (85.7 +/- 39.1 g) than post menopausal patients (79.2 +/- 22.5 g; p = .13). Weight loss was observed in 9.2% of pre-menopausal and 20.2% of post-menopausal patients (p = .04). A multivariate analysis revealed that age (OR = 2.7; 95% CI = 1.26-5.79; p = .01), menopausal status (OR = 2.29; 95% CI = 1.09-4.80; p = .03), dexamethasone dosage (OR = 2.1; 95% CI = 1.04-4.23; p = .03) and daily caloric intake (OR = 2.3; 95% CI = 1.12 5.10; p = .02) were independent variables that inducted weight gain. Pre- and post-menopausal women gained weight, but more pre-menopausal patients showed gain. An effort should be made to administer lower steroid doses to reduce weight gain. PMID- 27476827 TI - Chloride toxicity in critically ill patients: What's the evidence? AB - Crystalloids have become the fluid of choice in critically ill patients and in the operating room both for fluid resuscitation and fluid maintenance. Among crystalloids, NaCl 0.9% has been the most widely used fluid. However, emerging evidence suggests that administration of 0.9% saline could be harmful mainly through high chloride content and that the use of fluid with low chloride content may be preferable in major surgery and intensive care patients. Administration of NaCl 0.9% is the leading cause of metabolic hyperchloraemic acidosis in critically ill patients and side effects might target coagulation, renal function, and ultimately increase mortality. More balanced solutions therefore may be used especially when large amount of fluids are administered in high-risk patients. In this review, we discuss physiological background favouring the use of balanced solutions as well as the most recent clinical data regarding the use of crystalloid solutions in critically ill patients and patients undergoing major surgery. PMID- 27476828 TI - Ultrasound-guided intermediate cervical block versus superficial cervical block for carotid artery endarterectomy: The randomized-controlled CERVECHO trial. AB - INTRODUCTION: The value of ultrasound guidance for intermediate cervical blocks in patients undergoing carotid artery endarterectomy is poorly described. This study aimed at comparing the efficacy of ultrasound-guided intermediate cervical block to superficial cervical block for carotid artery endarterectomies. PATIENTS AND METHODS: We conducted a single-centre randomized-controlled study in a French University Hospital, from April 2011 to March 2012. The anaesthesia technique was randomly allocated to patients scheduled for carotid artery endarterectomy under regional anaesthesia (ropivacaine 4.75mg/mL): superficial cervical block in the Control group, and ultrasound-guided intermediate cervical block in the Echo group. The main outcome measure was the percentage of surgery performed without supplemental topical anaesthesia. The secondary outcomes were: rate of conversion to general anaesthesia, amount of supplemental topical lidocaine and block related complications. P<0.05 was considered significant. RESULTS: Demographic data for the 86 patients included [mean (SD) age 73 (11) years] did not differ between groups. Surgery was performed without supplemental topical lidocaine in 23% and 7% of the patients in the Echo and Control groups, respectively (P=0.068). Conversion to general anaesthesia for inadequate analgesia was needed in 0 and 2 patients in the Echo and Control groups, respectively. The mean dose of topical lidocaine was not different between groups. No complication directly related to a cervical block was observed. CONCLUSIONS: Ultrasound-guided intermediate cervical plexus block and superficial cervical blocks performed for carotid artery surgery seems to provide similar results, but this study was probably underpowered to detect any difference. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials (Eudra-CT) registration number: 2010-A 01490-39. PMID- 27476830 TI - The defect structure and chemical lattice strain of the double perovskites Sr2BMoO6-delta (B = Mg, Fe). AB - The defect structure of B-site ordered double perovskites Sr2BMoO6-delta was analyzed. The defect structure model was proposed and successfully verified using data on oxygen nonstoichiometry of Sr2MgMoO6-delta and Sr2FeMoO6-delta. As a result, equilibrium constants of the defect reactions involved were estimated. Fe and Mo in Sr2FeMoO6-delta were found to be in the mixed oxidation state close to +2.5 and +5.5, respectively. Chemical strain of the Sr2FeMoO6-delta double perovskite lattice was studied by in situ high temperature XRD at 1100 degrees C depending on pO2. Parameter a of the Sr2FeMoO6-delta cubic cell was found to increase with decreasing pO2 because of lattice chemical expansion. The tetragonal polymorph of Sr2FeMoO6-delta was shown to exhibit transversal isotropy with respect to chemical expansion. It was also found that its crystal lattice expands in the ab-plane and simultaneously contracts along the c-axis when the oxygen content in the double perovskite decreases. In order to describe the degree of anisotropy of chemical strain a new phenomenological coefficient was introduced. This coefficient was shown to affect both the magnitude and change direction of an oxide cell volume caused by its reduction/oxidation. Excellent agreement between the chemical expansion along the a-axis calculated for both polymorphs of Sr2FeMoO6-delta according to the model recently developed and that measured experimentally was shown. Chemical contraction observed along the c-axis with a decreasing oxygen content in the tetragonal polymorph was also found to coincide completely with that calculated using the approach developed in the present study. PMID- 27476829 TI - Stock Versus CAD/CAM Customized Zirconia Implant Abutments - Clinical and Patient Based Outcomes in a Randomized Controlled Clinical Trial. AB - BACKGROUND: Single-tooth replacement often requires a prefabricated dental implant and a customized crown. The benefits of individualization of the abutment remain unclear. PURPOSE: This randomized controlled clinical trial aims to study potential benefits of individualization of zirconia implant abutments with respect to preservation of marginal bone level and several clinical and patient based outcome measures. MATERIAL AND METHODS: Fifty participants with a missing premolar were included and randomly assigned to standard (ZirDesign, DentsplySirona Implants, Molndal, Sweden) or computer aided design/computer aided manufacturing (CAD/CAM) customized (Atlantis, DentsplySirona Implants, Molndal, Sweden) zirconia abutment therapy. Peri-implant bone level (primary outcome), Plaque-index, calculus formation, bleeding on probing, gingiva index, probing pocket depth, recession, appearance of soft tissues and patients' contentment were assessed shortly after placement and one year later. RESULTS: No implants were lost and no complications related to the abutments were observed. Statistically significant differences between stock and CAD/CAM customized zirconia abutments could not be demonstrated for any of the operationalized variables. CONCLUSION: The use of a CAD/CAM customized zirconia abutment in single tooth replacement of a premolar is not associated with an improvement in clinical performance or patients' contentment when compared to the use of a stock zirconia abutment. PMID- 27476831 TI - The effectiveness of taping on children with cerebral palsy: a systematic review. AB - AIM: Taping is popular in a variety of paediatric clinical settings. The purpose of this study was to investigate the effectiveness of taping on the rehabilitation of children with cerebral palsy (CP). METHOD: We used MEDLINE, Embase, PubMed, CINAHL, and the Cochrane Central Register of Controlled Trials as the electronic databases for the review. We reviewed all relevant studies published up to May 2015. We also analysed pertinent secondary references. We used Sackett's Levels of Evidence and the guidelines for critical review of McMaster University to criticize the reviewed articles. RESULTS: Nine papers met the inclusion criteria. Five of these were randomized controlled trials, three were case series, and one was a single case study. Four papers were high quality according to the methodological critical forms of this review, and two of these found that taping was effective in increasing activity in children with CP. INTERPRETATION: Although benefits of taping were found in the population, and functional gains according to the International Classification of Functioning, Disability and Health were obtained, the evidence was not conclusive. Randomized controlled trials with larger sample sizes and with more specific taping procedures are required to strengthen the evidence for the effectiveness of taping on children with CP. PMID- 27476832 TI - Simultaneous determination of six mycotoxins in peanut by high-performance liquid chromatography with a fluorescence detector. AB - BACKGROUND: Mycotoxins, which may contaminate peanut and peanut products, are responsible for many diseases to humans. Aflatoxin B1 (AFB1), aflatoxin G1 (AFG1), aflatoxin B2 (AFB2), aflatoxin G2 (AFG2), ochratoxin A (OTA) and zearalenone (ZEN) are considered the most relevant groups of mycotoxins found in food. This work aimed to develop a high-performance liquid chromatography method with a fluorescence detector (HPLC-FLD) combined with dispersive liquid-liquid microextraction (DLLME) method for the simultaneous determination of the six mycotoxins in peanuts. The six mycotoxins were simultaneously determined under their best wavelength by means of changing wavelength. RESULTS: Under the optimum conditions, the linear ranges were 1-100 ng mL-1 for AFB1, AFG1 and OTA, 0.3-30 ng mL-1 for AFB2 and AFG2, 5-1000 ng mL-1 for ZEN, with the correlation coefficient (R2 ) of 0.9969-0.9997. Limits of detection (LODs) were 0.10, 0.10, 0.30, 0.03, 0.03 and 1.0 ug kg-1 , respectively, and the mean recoveries were in the range of 83.1% to 99.3% with RSD < 10% (n = 6, independent analysis). Thirteen (46%) of these tested samples were contaminated with at least one mycotoxin. CONCLUSION: The proposed method was demonstrated to be simple, highly selective, accurate, reliable, and was successfully applied to simultaneously analyse the six mycotoxins in real peanut samples from China. (c) 2016 Society of Chemical Industry. PMID- 27476833 TI - Introduction: Tumors of the spinal column. PMID- 27476834 TI - The 100 most cited articles in metastatic spine disease. AB - OBJECTIVE Despite the growing neurosurgical literature, a subset of pioneering studies have significantly impacted the field of metastatic spine disease. The purpose of this study was to identify and analyze the 100 most frequently cited articles in the field. METHODS A keyword search using the Thomson Reuters Web of Science was conducted to identify articles relevant to the field of metastatic spine disease. The results were filtered based on title and abstract analysis to identify the 100 most cited articles. Statistical analysis was used to characterize journal frequency, past and current citations, citation distribution over time, and author frequency. RESULTS The total number of citations for the final 100 articles ranged from 74 to 1169. Articles selected for the final list were published between 1940 and 2009. The years in which the greatest numbers of top-100 studies were published were 1990 and 2005, and the greatest number of citations occurred in 2012. The majority of articles were published in the journals Spine (15), Cancer (11), and the Journal of Neurosurgery (9). Forty-four individuals were listed as authors on 2 articles, 9 were listed as authors on 3 articles, and 2 were listed as authors on 4 articles in the top 100 list. The most cited article was the work by Batson (1169 citations) that was published in 1940 and described the role of the vertebral veins in the spread of metastases. The second most cited article was Patchell's 2005 study (594 citations) discussing decompressive resection of spinal cord metastases. The third most cited article was the 1978 study by Gilbert that evaluated treatment of epidural spinal cord compression due to metastatic tumor (560 citations). CONCLUSIONS The field of metastatic spine disease has witnessed numerous milestones and so it is increasingly important to recognize studies that have influenced the field. In this bibliographic study the authors identified and analyzed the most influential articles in the field of metastatic spine disease. PMID- 27476835 TI - Posterior approaches for symptomatic metastatic spinal cord compression. AB - Surgical interventions for spinal metastasis are commonly performed for mechanical stabilization, pain relief, preservation of neurological function, and local tumor reduction. Although multiple surgical approaches can be used for the treatment of metastatic spinal lesions, posterior approaches are commonly performed. In this study, the role of posterior surgical procedures in the treatment of spinal metastases was reviewed, including posterior laminectomy with and without instrumentation for stabilization, transpedicular corpectomy, and costotransversectomy. A review of the literature from 1980 to 2015 was performed using Medline, as was a review of the bibliographies of articles meeting preset inclusion criteria, to identify studies on the role of these posterior approaches among adults with spinal metastasis. Thirty-four articles were ultimately analyzed, including 1 randomized controlled trial, 6 prospective cohort studies, and 27 retrospective case reports and/or series. Some of the reviewed articles had Level II evidence indicating that laminectomy with stabilization can be recommended for improvement in neurological outcome and reduction of pain in selected patients. However, the use of laminectomy alone should be carefully considered. Additionally, transpedicular corpectomy and costotransversectomy can be recommended with the expectation of improving neurological outcomes and reducing pain in properly selected patients with spinal metastases. With improvements in the treatment paradigms for patients with spinal metastasis, as well as survival, surgical therapy will continue to play an important role in the management of spinal metastasis. While this review presents a window into determining the utility of posterior approaches, future prospective studies will provide essential data to better define the roles of the various options now available to surgeons in treating spinal metastases. PMID- 27476837 TI - Factors associated with improved survival following surgery for renal cell carcinoma spinal metastases. AB - OBJECTIVE Renal cell carcinoma (RCC) frequently metastasizes to the spine, causing pain or neurological dysfunction, and is often resistant to standard therapies. Spinal surgery is frequently required, but may result in high morbidity rates. The authors sought to identify prognostic factors and determine clinical outcomes in patients undergoing surgery for RCC spinal metastases. METHODS The authors searched the records of patients who had undergone spinal surgery for metastatic disease at a single institution during a 12-year period and retrieved data for 30 patients with metastatic RCC. The records were retrospectively reviewed for data on preoperative conditions, treatment, and survival. Statistical analyses (i.e., Kaplan-Meier survival analysis and log-rank test in univariate analysis) were performed with R version 2.15.2. RESULTS The 30 patients (23 men and 7 women with a mean age of 57.6 years [range 29-79 years]) had in total 40 spinal surgeries for metastatic RCC. The indications for surgery included pain (70%) and weakness (30%). Fourteen patients (47%) had a Spinal Instability Neoplastic Score (SINS) indicating indeterminate or impending instability, and 6 patients (20%) had a SINS denoting instability. The median length of postoperative survival estimated with Kaplan-Meier analysis was 11.4 months. Younger age (p = 0.001) and disease control at the primary site (p = 0.005), were both significantly associated with improved survival. In contrast, visceral (p = 0.002) and osseous (p = 0.009) metastases, nonambulatory status (p = 0.001), and major comorbidities (p = 0.015) were all significantly associated with decreased survival. Postoperative Frankel grades were the same or had improved in 78% of patients. Major complications occurred in 9 patients, and there were 3 deaths (10%) during the 30-day in-hospital period. Three en bloc resections were performed. CONCLUSIONS Resection and fixation may provide pain relief and neurological stabilization in patients with spinal metastases arising from RCC, but surgical morbidity rates remain high. Younger patients with solitary spinal metastases, good neurological function, and limited major comorbidities may have longer survival and may benefit from aggressive intervention. PMID- 27476836 TI - Application of morphometric analysis to patients with lung cancer metastasis to the spine: a clinical study. AB - OBJECTIVE Predicting the survival rate for patients with cancer is currently performed using the TNM Classification of Malignant Tumors (TNM). Identifying accurate prognostic markers of survival would allow better treatment stratification between more aggressive treatment strategies or palliation. This is especially relevant for patients with spinal metastases, who all have identical TNM staging and whose surgical decision-making is potentially complex. Analytical morphometrics quantifies patient frailty by measuring lean muscle mass and can predict risk for postoperative morbidity after lumbar spine surgery. This study evaluates whether morphometrics can be predictive of survival in patients with spinal metastases. METHODS Utilizing a retrospective registry of patients with spinal metastases who had undergone stereotactic body radiation therapy, the authors identified patients with primary lung cancer. Morphometric measurements were taken of the psoas muscle using CT of the lumbar spine. Additional morphometrics were taken of the L-4 vertebral body. Patients were stratified into tertiles based on psoas muscle area. The primary outcome measure was overall survival, which was measured from the date of the patient's CT scan to date of death. RESULTS A total of 168 patients were identified, with 54% male and 54% having multiple-level metastases. The median survival for all patients was 185.5 days (95% confidence interval [CI] 146-228 days). Survival was not associated with age, sex, or the number of levels of metastasis. Patients in the smallest tertile for the left psoas area had significantly shorter survival compared with a combination of the other two tertiles: 139 days versus 222 days, respectively, hazard ratio (HR) 1.47, 95% CI 1.06-2.04, p = 0.007. Total psoas tertiles were not predictive of mortality, but patients whose total psoas size was below the median size had significantly shorter survival compared with those greater than the median size: 146 days versus 253.5 days, respectively, HR 1.43, 95% CI 1.05 1.94, p = 0.025. To try to differentiate small body habitus from frailty, the ratio of psoas muscle area to vertebral body area was calculated. Total psoas size became predictive of mortality when normalized to vertebral body ratio, with patients in the lowest tertile having significantly shorter survival (p = 0.017). Left psoas to vertebral body ratio was also predictive of mortality in patients within the lowest tertile (p = 0.021). Right psoas size was not predictive of mortality in any calculations. CONCLUSIONS In patients with lung cancer metastases to the spine, morphometric analysis of psoas muscle and vertebral body size can be used to identify patients who are at risk for shorter survival. This information should be used to select patients who are appropriate candidates for surgery and for the tailoring of oncological treatment regimens. PMID- 27476838 TI - Histopathological examination of spine tumors after treatment with radiosurgery. AB - OBJECTIVE Increased survival time after diagnosis of neoplastic disease has resulted in a gradual increase in spine tumor incidence. Radiosurgery is frequently a viable alternative to operative management in a population with severe medical comorbidities. The authors sought to assess the histopathological consequences of radiosurgery in the subset of patients progressing to operative intervention. METHODS Eighteen patients who underwent radiosurgery for spine tumors between 2008 and 2014 subsequently progressed to surgical treatment. A histopathological examination of these cases was performed. Indications for surgery included symptomatic compression fractures, radiographic instability, and symptoms of cord or cauda equina compression. Biopsy samples were obtained from the tumor within the radiosurgical zone in all cases and were permanently fixated. Viable tumor samples were stained for Ki 67. RESULTS Fifteen patients had metastatic lesions and 3 patients had neurofibromas. The mean patient age was 57 years. The operative indication was symptomatic compression in 10 cases (67%). The most frequent metastatic lesions were breast cancer (4 cases), renal cell carcinoma (3), prostate cancer (2), and endometrial cancer (2). In 9 (60%) of the 15 metastatic cases, histological examination of the lesions showed minimal evidence of inflammation. Viable tumor at the margins of the radiosurgery was seen in 9 (60%) of the metastatic cases. Necrosis in the tumor bed was frequent, as was fibrotic bone marrow. Vascular ectasia was seen in 2 of 15 metastatic cases, but sclerosis with ectasia was frequent. No evidence of malignant conversion was seen in the periphery of the lesions in the 3 neurofibroma cases. In 1 case of neurofibroma, the lesion demonstrated some small areas of remnant tumor in the radiosurgical target zone. CONCLUSIONS This case series demonstrates important histopathological characteristics of spinal lesions treated by SRS. Regions with the highest exposure to radiation appear to be densely necrotic and show little evidence of tumor growth, whereas peripheral regions distant from the radiation dosage are more likely to demonstrate viable tumor in malignant and benign neoplasms. Physiological tissue appears to be similarly affected. With additional investigation, a more homogenized field of hypofractionated radiation exposure may allow for tumor obliteration with relative preservation of critical anatomical structures. PMID- 27476839 TI - Resection of spinal column tumors utilizing image-guided navigation: a multicenter analysis. AB - OBJECTIVE The use of intraoperative stereotactic navigation has become more available in spine surgery. The authors undertook this study to assess the utility of intraoperative CT navigation in the localization of spinal lesions and as an intraoperative tool to guide resection in patients with spinal lesions. METHODS This was a retrospective multicenter study including 50 patients from 2 different institutions who underwent biopsy and/or resection of spinal column tumors using image-guided navigation. Of the 50 cases reviewed, 4 illustrative cases are presented. In addition, the authors provide a description of surgical technique with image guidance. RESULTS The patient group included 27 male patients and 23 female patients. Their average age was 61 +/- 17 years (range 14 87 years). The average operative time (incision to closure) was 311 +/- 188 minutes (range 62-865 minutes). The average intraoperative blood loss was 882 +/- 1194 ml (range 5-7000 ml). The average length of hospitalization was 10 +/- 8.9 days (range 1-36 days). The postoperative complications included 2 deaths (4.0%) and 4 radiculopathies (8%) secondary to tumor burden. CONCLUSIONS O-arm 3D imaging with stereotactic navigation may be used to localize lesions intraoperatively with real-time dynamic feedback of tumor resection. Stereotactic guidance may augment resection or biopsy of primary and metastatic spinal tumors. It offers reduced radiation exposure to operating room personnel and the ability to use minimally invasive approaches that limit tissue injury. In addition, acquisition of intraoperative CT scans with real-time tracking allows for precise targeting of spinal lesions with minimal dissection. PMID- 27476840 TI - The role of the mini-open thoracoscopic-assisted approach in the management of metastatic spine disease at the thoracolumbar junction. AB - OBJECTIVE Treatment advances have resulted in improved survival for many cancer types, and this, in turn, has led to an increased incidence of metastatic disease, specifically to the vertebral column. Surgical decompression and stabilization prior to radiation therapy have been shown to improve functional outcomes, but anterior access to the thoracolumbar junction may involve open thoracotomy, which can cause significant morbidity. The authors describe the treatment of 12 patients in whom a mini-open thoracoscopic-assisted approach (mini-open TAA) to the thoracolumbar junction was used to treat metastatic disease, with an analysis of outcomes. METHODS The authors reviewed a retrospective cohort of patients treated for thoracolumbar junction metastatic disease with mini-open TAA between 2004 and 2016. Data collection included operative time, estimated blood loss, length of stay, follow-up duration, and pre and postoperative visual analog scale scores and Frankel grades. RESULTS Twelve patients underwent a mini-open TAA procedure for metastatic disease at the thoracolumbar junction. The mean age of patients was 59 years (range 53-77 years), mean estimated blood loss was 613 ml, and the mean duration of the mini open TAA procedure was 234 minutes (3.8 hours). The median length of stay in the hospital was 7.5 days (range 5-21 days). All 12 patients had significant improvement in their postoperative pain scores in comparison with their preoperative pain scores (p < 0.001). No patients suffered from worsening neurological function after surgery, and of 7 patients who presented with neurological dysfunction, 6 (86%) had an improvement in their Frankel grade after surgery. No patients experienced delayed hardware failure requiring reoperation over a mean follow-up of 10 months (range 1-45 months). CONCLUSIONS The mini-open TAA to the thoracolumbar junction for metastatic disease is a durable procedure that has a reduced morbidity rate compared with traditional open thoracotomy for ventral decompression and fusion. It compares well with traditional and novel posterior approaches to the thoracolumbar junction. The authors found a significant improvement in preoperative pain and neurological symptoms that supports greater use of the mini-open TAA for the treatment of complex metastatic disease at the thoracolumbar junction. PMID- 27476841 TI - Computed tomography-guided percutaneous biopsy for vertebral neoplasms: a department's experience and hybrid biopsy technique to improve yield. AB - OBJECTIVE Recent articles have identified the poor diagnostic yield of percutaneous needle biopsy for vertebral osteomyelitis. The current study aimed to confirm the higher accuracy of CT-guided spinal biopsy for vertebral neoplasms and to identify which biopsy technique provides the highest yield. METHODS Over a 9-year period, the radiology department at University Hospitals Case Medical Center performed 222 CT-guided biopsies of vertebral lesions, of which clinicians indicated a concern for vertebral neoplasms in 122 patients. A retrospective chart review was performed to confirm the higher sensitivity of the percutaneous intervention for vertebral neoplasms. RESULTS A core sample was obtained for all 122 biopsies of concern (100.0%). Only 6 cases (4.9%) were reported as nondiagnostic per histological sampling, and 12 cases (9.8%) were negative for disease. The question of vertebral neoplastic involvement warrants follow-up, and the current study was able to determine the subsequent diagnosis of each lesion. Of the 122 total, 94 (77.0%) core samples provided true-positive results, and the sensitivity of core biopsy measured 87.9%. The technical approach did not demonstrate any significant difference in diagnostic yield. However, when the vertebral cortex was initially pierced with a coaxial bone biopsy system and subsequently a 14-gauge spring-loaded cutting biopsy needle was coaxially advanced into lytic lesions, 14 true positives were obtained with a corresponding sensitivity of 100.0%. CONCLUSIONS This study confirms the higher sensitivity of image-guided percutaneous needle biopsy for vertebral neoplasms. In addition, it demonstrates how the use of a novel cutting needle biopsy approach, performed coaxially through a core biopsy track, provides the highest yield. PMID- 27476842 TI - Intraoperative neurophysiological mapping and monitoring in spinal tumor surgery: sirens or indispensable tools? AB - Spinal tumor (ST) surgery carries the risk of new neurological deficits in the postoperative period. Intraoperative neurophysiological monitoring and mapping (IONM) represents an effective method of identifying and monitoring in real time the functional integrity of both the spinal cord (SC) and the nerve roots (NRs). Despite consensus favoring the use of IONM in ST surgery, in this era of evidence based medicine, there is still a need to demonstrate the effective role of IONM in ST surgery in achieving an oncological cure, optimizing patient safety, and considering medicolegal aspects. Thus, neurosurgeons are asked to establish which techniques are considered indispensable. In the present study, the authors focused on the rationale for and the accuracy (sensitivity, specificity, and positive and negative predictive values) of IONM in ST surgery in light of more recent evidence in the literature, with specific emphasis on the role of IONM in reducing the incidence of postoperative neurological deficits. This review confirms the role of IONM as a useful tool in the workup for ST surgery. Individual monitoring and mapping techniques are clearly not sufficient to account for the complex function of the SC and NRs. Conversely, multimodal IONM is highly sensitive and specific for anticipating neurological injury during ST surgery and represents an important tool for preserving neuronal structures and achieving an optimal postoperative functional outcome. PMID- 27476843 TI - Electrophysiological monitoring during preoperative angiography to guide decisions regarding permanent occlusion of major radicular arteries in patients undergoing total en bloc spondylectomy. AB - OBJECTIVE Preoperative embolization is performed before spine tumor surgery when significant intraoperative hemorrhage is anticipated. Occlusion of radicular and segmental arteries may result in spinal ischemia. The goal of this study was to check whether neurophysiological monitoring during preoperative angiography in patients scheduled for total en bloc spondylectomy (TES) of spine tumors improves the safety of vessel occlusion. METHODS This was a case series study of patients who underwent tumor embolization under somatosensory evoked potential (SSEP) and motor evoked potential (MEP) monitoring in preparation for TES in treating spine tumors. The angiography findings, the embolized vessels, and the results are presented. RESULTS Five patients whose ages ranged from 33 to 75 years and who had thoracic spine tumors are reported. Four patients suffered from primary tumor and 1 patient had a metastatic tumor. Radicular arteries at the tumor level, 1 level above, and 1 level below were permanently occluded when SSEPs and MEPs were preserved during temporary occlusion. No complications were encountered during or after the angiography procedure and embolization. CONCLUSIONS Temporary occlusion with electrophysiological monitoring during preoperative angiography may improve the safety of permanent radicular artery occlusion, including the artery of Adamkiewicz in patients undergoing TES for the treatment of spine tumors. PMID- 27476844 TI - Decompression surgery for spinal metastases: a systematic review. AB - OBJECTIVE The aim of this study was to systematically review the literature on reported outcomes following decompression surgery for spinal metastases. METHODS The authors conducted MEDLINE, Scopus, and Web of Science database searches for studies reporting clinical outcomes and complications associated with decompression surgery for metastatic spinal tumors. Both retrospective and prospective studies were included. After meeting inclusion criteria, articles were categorized based on the following reported outcomes: survival, ambulation, surgical technique, neurological function, primary tumor histology, and miscellaneous outcomes. RESULTS Of the 4148 articles retrieved from databases, 36 met inclusion criteria. Of those included, 8 were prospective studies and 28 were retrospective studies. The year of publication ranged from 1992 to 2015. Study size ranged from 21 to 711 patients. Three studies found that good preoperative Karnofsky Performance Status (KPS >= 80%) was a significant predictor of survival. No study reported a significant effect of time-to-surgery following the onset of spinal cord compression symptoms on survival. Three studies reported improvement in neurological function following surgery. The most commonly cited complication was wound infection or dehiscence (22 studies). Eight studies reported that preoperative ambulatory or preoperative motor status was a significant predictor of postoperative ambulatory status. A wide variety of surgical techniques were reported: posterior decompression and stabilization, posterior decompression without stabilization, and posterior decompression with total or subtotal tumor resection. Although a wide range of functional scales were used to assess neurological outcomes, four studies used the American Spinal Injury Association (ASIA) Impairment Scale to assess neurological function. Four studies reported the effects of radiation therapy and local disease control for spinal metastases. Two studies reported that the type of treatment was not significantly associated with the rate of local control. The most commonly reported primary tumor types included lung cancer, prostate cancer, breast cancer, renal cancer, and gastrointestinal cancer. CONCLUSIONS This study reports a systematic review of the literature on decompression surgery for spinal metastases. The results of this study can help educate surgeons on the previously published predictors of outcomes following decompression surgery for metastatic spinal disease. However, the authors also identify significant gaps in the literature and the need for future studies investigating the optimal practice with regard to decompression surgery for spinal metastases. PMID- 27476845 TI - Primary osseous tumors of the pediatric spinal column: review of pathology and surgical decision making. AB - Spinal column tumors are rare in children and young adults, accounting for only 1% of all spine and spinal cord tumors combined. They often present diagnostic and therapeutic challenges. In this article, the authors review the current management of primary osseous tumors of the pediatric spinal column and highlight diagnosis, management, and surgical decision making. PMID- 27476846 TI - Osteoblastomas of the spine: a comprehensive review. AB - Osteoblastomas are primary bone tumors with an affinity for the spine. They typically involve the posterior elements, although extension through the pedicles into the vertebral body is not uncommon. Histologically, they are usually indistinguishable from osteoid osteomas. However, there are different variants of osteoblastomas, with the more aggressive type causing more pronounced bone destruction, soft-tissue infiltration, and epidural extension. A bone scan is the most sensitive radiographic examination used to evaluate osteoblastomas. These osseous neoplasms usually present in the 2nd decade of life with dull aching pain, which is difficult to localize. At times, they can present with a painful scoliosis, which usually resolves if the osteoblastoma is resected in a timely fashion. Neurological manifestations such as radiculopathy or myelopathy do occur as well, most commonly when there is mass effect on nerve roots or the spinal cord itself. The mainstay of treatment involves surgical intervention. Curettage has been a surgical option, although marginal excision or wide en bloc resection are preferred options. Adjuvant radiotherapy and chemotherapy are generally not undertaken, although some have advocated their use after less aggressive surgical maneuvers or with residual tumor. In this manuscript, the authors have aimed to systematically review the literature and to put forth an extensive, comprehensive overview of this rare osseous tumor. PMID- 27476847 TI - Thirty-day readmission and reoperation after surgery for spinal tumors: a National Surgical Quality Improvement Program analysis. AB - OBJECTIVE The goal of this study was to use a large national registry to evaluate the 30-day cumulative incidence and predictors of adverse events, readmissions, and reoperations after surgery for primary and secondary spinal tumors. METHODS Data from adult patients who underwent surgery for spinal tumors (2011-2014) were extracted from the prospective National Surgical Quality Improvement Program (NSQIP) registry. Multivariable logistic regression was used to evaluate predictors of reoperation, readmission, and major complications (death, neurological, cardiopulmonary, venous thromboembolism [VTE], surgical site infection [SSI], and sepsis). Variables screened included patient age, sex, tumor location, American Society of Anesthesiologists (ASA) physical classification, preoperative functional status, comorbidities, preoperative laboratory values, case urgency, and operative time. Additional variables that were evaluated when analyzing readmission included complications during the surgical hospitalization, hospital length of stay (LOS), and discharge disposition. RESULTS Among the 2207 patients evaluated, 51.4% had extradural tumors, 36.4% had intradural extramedullary tumors, and 12.3% had intramedullary tumors. By spinal level, 20.7% were cervical lesions, 47.4% were thoracic lesions, 29.1% were lumbar lesions, and 2.8% were sacral lesions. Readmission occurred in 10.2% of patients at a median of 18 days (interquartile range [IQR] 12-23 days); the most common reasons for readmission were SSIs (23.7%), systemic infections (17.8%), VTE (12.7%), and CNS complications (11.9%). Predictors of readmission were comorbidities (dyspnea, hypertension, and anemia), disseminated cancer, preoperative steroid use, and an extended hospitalization. Reoperation occurred in 5.3% of patients at a median of 13 days (IQR 8-20 days) postoperatively and was associated with preoperative steroid use and ASA Class 4-5 designation. Major complications occurred in 14.4% of patients: the most common complications and their median time to occurrence were VTE (4.5%) at 9 days (IQR 4-19 days) postoperatively, SSIs (3.6%) at 18 days (IQR 14-25 days), and sepsis (2.9%) at 13 days (IQR 7-21 days). Predictors of major complications included dependent functional status, emergency case status, male sex, comorbidities (dyspnea, bleeding disorders, preoperative systemic inflammatory response syndrome, preoperative leukocytosis), and ASA Class 3-5 designation (p < 0.05). The median hospital LOS was 5 days (IQR 3-9 days), the 30-day mortality rate was 3.3%, and the median time to death was 20 days (IQR 12.5-26 days). CONCLUSIONS In this NSQIP analysis, 10.2% of patients undergoing surgery for spinal tumors were readmitted within 30 days, 5.3% underwent a reoperation, and 14.4% experienced a major complication. The most common complications were SSIs, systemic infections, and VTE, which often occurred late (after discharge from the surgical hospitalization). Patients were primarily readmitted for new complications that developed following discharge rather than exacerbation of complications from the surgical hospital stay. The strongest predictors of adverse events were comorbidities, preoperative steroid use, and higher ASA classification. These models can be used by surgeons to risk-stratify patients preoperatively and identify those who may benefit from increased surveillance following hospital discharge. PMID- 27476848 TI - Spinal meningiomas: clinicoradiological factors predicting recurrence and functional outcome. AB - OBJECTIVE Spinal meningiomas are benign tumors with a wide spectrum of clinical and radiological features at presentation. The authors analyzed multiple clinicoradiological factors to predict recurrence and functional outcome in a cohort with a mean follow-up of more than 4 years. The authors also discuss the results of clinical studies regarding spinal meningiomas in the last 15 years. METHODS The authors retrospectively reviewed the clinical and radiological details of patients who underwent surgery for spinal tumors between 2001 and 2015 that were histopathologically confirmed as meningiomas. Demographic parameters, such as age, sex, race, and association with neurofibromatosis Type 2, were considered. Radiological parameters, such as tumor size, signal changes of spinal cord, spinal level, number of levels, location of tumor attachment, shape of tumor, and presence of dural tail/calcification, were noted. These factors were analyzed to predict recurrence and functional outcome. Furthermore, a pooled analysis was performed from 13 reports of spinal meningiomas in the last 15 years. RESULTS A total of 38 patients were included in this study. Male sex and tumors with radiological evidence of a dural tail were associated with an increased risk of recurrence at a mean follow-up of 51.2 months. Ventral or ventrolateral location, large tumors, T2 cord signal changes, and poor preoperative functional status were associated with poor functional outcome at 1 year follow-up. CONCLUSIONS Spine surgeons must be aware of the natural history and risk factors of spinal meningiomas to establish a prognosis for their patients. PMID- 27476849 TI - Surgical treatment of aggressive vertebral hemangiomas. AB - OBJECTIVE Vertebral hemangiomas are common tumors that are benign and generally asymptomatic. Occasionally these lesions can exhibit aggressive features such as bony expansion and erosion into the epidural space resulting in neurological symptoms. Surgery is often recommended in these cases, especially if symptoms are severe or rapidly progressive. Some surgeons perform decompression alone, others perform gross-total resection, while others perform en bloc resection. Radiation, embolization, vertebroplasty, and ethanol injection have also been used in combination with surgery. Despite the variety of available treatment options, the optimal management strategy is unclear because aggressive vertebral hemangiomas are uncommon lesions, making it difficult to perform large trials. For this reason, the authors chose instead to report their institutional experience along with a comprehensive review of the literature. METHODS A departmental database was searched for patients with a pathological diagnosis of "hemangioma" between 2008 and 2015. Medical records were reviewed to identify patients with aggressive vertebral hemangiomas, and these cases were reviewed in detail. RESULTS Five patients were identified who underwent surgery for treatment of aggressive vertebral hemangiomas during the specified time period. There were 2 lumbar and 3 thoracic lesions. One patient underwent en bloc spondylectomy, 2 patients had piecemeal gross-total resection, and the remaining 2 had subtotal tumor resection. Intraoperative vertebroplasty was used in 3 cases to augment the anterior column or to obliterate residual tumor. Adjuvant radiation was used in 1 case where there was residual tumor as well. The patient who underwent en bloc spondylectomy experienced several postoperative complications requiring additional medical care and reoperation. At an average follow-up of 31 months (range 3-65 months), no patient had any recurrence of disease and all were clinically asymptomatic, except the patient who underwent en bloc resection who continued to have back pain. CONCLUSIONS Gross-total resection or subtotal resection in combination with vertebroplasty or adjuvant radiation therapy to treat residual tumor seems sufficient in the treatment of aggressive vertebral hemangiomas. En bloc resection appears to provide a similar oncological benefit, but it carries higher morbidity to the patient. PMID- 27476850 TI - Clinical and pathological outcomes after resection of intramedullary spinal cord tumors: a single-institution case series. AB - OBJECTIVE The objective of this study was to identify clinically relevant predictors of progression-free survival and functional outcomes in patients who underwent surgery for intramedullary spinal cord tumors (ISCTs). METHODS An institutional spinal tumor registry and billing records were reviewed to identify adult patients who underwent resection of ISCTs between 1993 and 2014. Extensive data were collected from patient charts and operative notes, including demographic information, extent of resection, tumor pathology, and functional and oncological outcomes. Survival analysis was used to determine important predictors of progression-free survival. Logistic regression analysis was used to evaluate the association between an "optimal" functional outcome on the Frankel or McCormick scale at 1-year follow-up and various clinical and surgical characteristics. RESULTS The consecutive case series consisted of 63 patients (50.79% female) who underwent resection of ISCTs. The mean age of patients was 41.92 +/- 14.36 years (range 17.60-75.40 years). Complete microsurgical resection, defined as no evidence of tumor on initial postoperative imaging, was achieved in 34 cases (54.84%) of the 62 patients for whom this information was available. On univariate analysis, the most significant predictor of progression free survival was tumor histology (p = 0.0027). Patients with Grade I/II astrocytomas were more likely to have tumor progression than patients with WHO Grade II ependymomas (HR 8.03, 95% CI 2.07-31.11, p = 0.0026) and myxopapillary ependymomas (HR 8.01, 95% CI 1.44-44.34, p = 0.017). Furthermore, patients who underwent radical or subtotal resection were more likely to have tumor progression than those who underwent complete resection (HR 3.46, 95% CI 1.23 9.73, p = 0.018). Multivariate analysis revealed that tumor pathology was the only significant predictor of tumor progression. On univariate analysis, the most significant predictors of an "optimal" outcome on the Frankel scale were age (OR 0.94, 95% CI 0.89-0.98, p = 0.0062), preoperative Frankel grade (OR 4.84, 95% CI 1.33-17.63, p = 0.017), McCormick score (OR 0.22, 95% CI 0.084-0.57, p = 0.0018), and region of spinal cord (cervical vs conus: OR 0.067, 95% CI 0.012-0.38, p = 0.0023; and thoracic vs conus: OR 0.015: 95% CI 0.001-0.20, p = 0.0013). Age, tumor pathology, and region were also important predictors of 1-year McCormick scores. CONCLUSIONS Extent of tumor resection and histopathology are significant predictors of progression-free survival following resection of ISCTs. Important predictors of functional outcomes include tumor histology, region of spinal cord in which the tumor is present, age, and preoperative functional status. PMID- 27476851 TI - Clinical, surgical, and molecular prognostic factors for survival after spinal sarcoma resection. AB - OBJECTIVE The goal of this study was to investigate the local recurrence rate and long-term survival after resection of spinal sarcomas. METHODS A retrospective review of patients who underwent resection of primary or metastatic spinal sarcomas between 1997 and 2015 was performed. Tumors were classified according to the Enneking classification, and resection was categorized as Enneking appropriate (EA) if the specimen margins matched the Enneking recommendation, and as Enneking inappropriate (EI) if they did not match the recommendation. The primary outcome measure for all tumors was overall survival; local recurrence was also an outcome measure for primary sarcomas. The association between clinical, surgical, and molecular (tumor biomarker) factors and outcomes was also investigated. RESULTS A total of 60 patients with spinal sarcoma were included in this study (28 men and 32 women; median age 38 years). There were 52 primary (86.7%) and 8 metastatic sarcomas (13.3%). Thirty-nine tumors (65.0%) were classified as high-grade, and resection was considered EA in 61.7% of all cases (n = 37). The local recurrence rate was 10 of 52 (19.2%) for primary sarcomas; 36.8% for EI resection and 9.1% for EA resection (p = 0.010). Twenty-eight patients (46.7%) died during the follow-up period, and median survival was 26 months. Overall median survival was longer for patients with EA resection (undefined) compared with EI resection (13 months, p < 0.001). After multivariate analysis, EA resection significantly decreased the hazard of local recurrence (HR 0.24, 95% CI 0.06-0.93; p = 0.039). Age 40 years or older (HR 4.23, 95% CI 1.73 10.31; p = 0.002), previous radiation (HR 3.44, 95% CI 1.37-8.63; p = 0.008), and high-grade sarcomas (HR 3.17, 95% CI 1.09-9.23; p = 0.034) were associated with a significantly increased hazard of death, whereas EA resection was associated with a significantly decreased hazard of death (HR 0.22, 95% CI 0.09-0.52; p = 0.001). CONCLUSIONS The findings in the present study suggest that EA resection may be the strongest independent prognostic factor for improved survival in patients with spinal sarcoma. Additionally, patients who underwent EA resection had lower local recurrence rates. Patients 40 years or older, those with a history of previous radiation, and those with high-grade tumors had an increased hazard of mortality in this study. PMID- 27476852 TI - Analysis of Variability in HIV-1 Subtype A Strains in Russia Suggests a Combination of Deep Sequencing and Multitarget RNA Interference for Silencing of the Virus. AB - Any method for silencing the activity of the HIV-1 retrovirus should tackle the extremely high variability of HIV-1 sequences and mutational escape. We studied sequence variability in the vicinity of selected RNA interference (RNAi) targets from isolates of HIV-1 subtype A in Russia, and we propose that using artificial RNAi is a potential alternative to traditional antiretroviral therapy. We prove that using multiple RNAi targets overcomes the variability in HIV-1 isolates. The optimal number of targets critically depends on the conservation of the target sequences. The total number of targets that are conserved with a probability of 0.7-0.8 should exceed at least 2. Combining deep sequencing and multitarget RNAi may provide an efficient approach to cure HIV/AIDS. PMID- 27476853 TI - Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. AB - Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor of metalloproteinase 3) accumulation in the vascular extracellular matrix in CADASIL is a key contributor to cerebrovascular dysfunction. However, the linkage between elevated TIMP3 and compromised cerebral blood flow (CBF) remains unknown. Here, we show that TIMP3 acts through inhibition of the metalloprotease ADAM17 and HB-EGF to regulate cerebral arterial tone and blood flow responses. In a clinically relevant CADASIL mouse model, we show that exogenous ADAM17 or HB-EGF restores cerebral arterial tone and blood flow responses, and identify upregulated voltage-dependent potassium channel (KV) number in cerebral arterial myocytes as a heretofore unrecognized downstream effector of TIMP3-induced deficits. These results support the concept that the balance of TIMP3 and ADAM17 activity modulates CBF through regulation of myocyte KV channel number. PMID- 27476854 TI - Reorganisation of Hoxd regulatory landscapes during the evolution of a snake-like body plan. AB - Within land vertebrate species, snakes display extreme variations in their body plan, characterized by the absence of limbs and an elongated morphology. Such a particular interpretation of the basic vertebrate body architecture has often been associated with changes in the function or regulation of Hox genes. Here, we use an interspecies comparative approach to investigate different regulatory aspects at the snake HoxD locus. We report that, unlike in other vertebrates, snake mesoderm-specific enhancers are mostly located within the HoxD cluster itself rather than outside. In addition, despite both the absence of limbs and an altered Hoxd gene regulation in external genitalia, the limb-associated bimodal HoxD chromatin structure is maintained at the snake locus. Finally, we show that snake and mouse orthologous enhancer sequences can display distinct expression specificities. These results show that vertebrate morphological evolution likely involved extensive reorganisation at Hox loci, yet within a generally conserved regulatory framework. PMID- 27476856 TI - Aquaculture: a rapidly growing and significant source of sustainable food? Status, transitions and potential. AB - The status and potential of aquaculture is considered as part of a broader food landscape of wild aquatic and terrestrial food sources. The rationale and resource base required for the development of aquaculture are considered in the context of broader societal development, cultural preferences and human needs. Attention is drawn to the uneven development and current importance of aquaculture globally as well as its considerable heterogeneity of form and function compared with established terrestrial livestock production. The recent drivers of growth in demand and production are examined and the persistent linkages between exploitation of wild stocks, full life cycle culture and the various intermediate forms explored. An emergent trend for sourcing aquaculture feeds from alternatives to marine ingredients is described and the implications for the sector with rapidly growing feed needs discussed. The rise of non conventional and innovative feed ingredients, often shared with terrestrial livestock, are considered, including aquaculture itself becoming a major source of marine ingredients. The implications for the continued expected growth of aquaculture are set in the context of sustainable intensification, with the challenges that conventional intensification and emergent integration within, and between, value chains explored. The review concludes with a consideration of the implications for dependent livelihoods and projections for various futures based on limited resources but growing demand. PMID- 27476855 TI - Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia. AB - Somatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of ?3% during CR on outcome in 56 adult AML patients. Mutational remission, defined as clearance of pre-treatment DNMT3A R882 and all other AML-associated mutations to a variant allele frequency ?3%, occurred in 14 patients whereas persistent DNMT3A R882 mutations were observed in 42 patients. There were no significant differences in disease-free or overall survival between patients with and without DNMT3A R882 mutation clearance. Patients with persistent DNMT3A R882 who cleared all other AML mutations and did not acquire new mutations (n = 30), trended towards longer disease-free survival (1.6 vs. 0.6 years, P = 0.06) than patients with persistence of DNMT3A R882, in addition to other mutations or acquisition of new AML-associated mutations, such as those in TET2, JAK2, ASXL1 and TP53 (n = 12). These data demonstrate that DNMT3A R882 mutations, as assessed by traditional NGS methods, persist in the majority of AML patients in CR. PMID- 27476858 TI - Learning Curve Assessment for Percutaneous Left Atrial Appendage Closure With the WATCHMAN Occluder. AB - OBJECTIVES: We sought to evaluate the effect of increasing experience with left atrial appendage (LAA) closure on short-term outcome. BACKGROUND: Data regarding the impact of the learning curve of LAA closure-particularly regarding technical aspects of the procedure-are lacking. METHODS: The present analysis represents first data from a single-center all-comer registry. The population was divided into 3 groups according to treatment time (group 1: patients 1-30; group 2: patients 31-60; group 3: patients 61-90). RESULTS: The mean age of the population was 77 years. Median CHA2 DS2 VASC Score and HAS-BLED were 5 (IQR 3-5) and 3 (IQR 3-4), respectively. Implantation success was 90% with a slight but not statistically significant increase during the course of the registry. Procedure time (75 [62-108] vs. 50 [43-66] vs. 47 [41-61] minutes; P < 0.0001), fluoroscopy time (20 [15-30] vs. 11 [8-19] vs. 11 [9-18] minutes; P = 0.002), and contrast volume (105 [70-170] vs. 60 [50-75] vs. 50 [50-73] ml; P < 0.0001) were reduced across the 3 groups. In-hospital complications decreased significantly (20 vs. 7% vs. 0%; P = 0.021). The compression grade of the occluder was chosen higher with increasing learning curve (15 [11-25] vs. 25 [17-29] vs. 21 [14-26] %; P = 0.05). CONCLUSIONS: With increasing operator experience the performance and safety of percutaneous LAA closure improved continuously. PMID- 27476857 TI - The application of lichens as ecological surrogates of air pollution in the subtropics: a case study in South Brazil. AB - The use of lichens as ecological surrogates has been an important tool to evaluate the impact of air pollution in both ecosystem and human health but remains underused in the subtropics due to lack of knowledge. Aiming to support the application of lichen as ecological surrogates of the effects of air pollution in the subtropics, we hypothesized that urbanization was an important driver of changes on lichen diversity, composition, and vitality. For that, we quantified several lichen diversity metrics (richness, cover, and community composition) and photobiont vitality in relation to atmospheric pollution or its surrogates (modeled pollutant gases, pollutants in lichen thallus, and land cover). We confirmed that air pollution was a key driver for lichen diversity. Changes in lichen community composition and vitality were very significantly related to air pollution and integrated the effect of multiple stressors (particulate matter, NOx, and Cu), thus being powerful ecological indicators of air pollution in the subtropics. PMID- 27476859 TI - Letter to the Editor and Response: Percutaneous Closure of Atrial Septal Defects Under Transthoracic Echocardiography Without Fluoroscopy. PMID- 27476860 TI - Erratum. PMID- 27476861 TI - Automated eye blink detection and correction method for clinical MR eye imaging. AB - PURPOSE: To implement an on-line monitoring system to detect eye blinks during ocular MRI using field probes, and to reacquire corrupted k-space lines by means of an automatic feedback system integrated with the MR scanner. METHODS: Six healthy subjects were scanned on a 7 Tesla MRI whole-body system using a custom built receive coil. Subjects were asked to blink multiple times during the MR scan. The local magnetic field changes were detected with an external fluorine based field probe which was positioned close to the eye. The eye blink produces a field shift greater than a threshold level, this was communicated in real-time to the MR system which immediately reacquired the motion-corrupted k-space lines. RESULTS: The uncorrected images, using the original motion-corrupted data, showed severe artifacts, whereas the corrected images, using the reacquired data, provided an image quality similar to images acquired without blinks. CONCLUSION: Field probes can successfully detect eye blinks during MRI scans. By automatically reacquiring the eye blink-corrupted data, high quality MR-images of the eye can be acquired. Magn Reson Med 78:165-171, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27476862 TI - Natalizumab: a new therapy for acute ischemic stroke? AB - INTRODUCTION: Natalizumab, a well-characterized treatment for multiple sclerosis, is a humanized antibody against alpha-4 integrin (CD49d) that mitigates the transmigration of leukocytes across the endothelium. Although numerous experimental studies have evaluated the efficacy of anti-CD49d antibody treatment for ischemic stroke, discrepancies in their results have raised concerns about the benefits of this approach. AREAS COVERED: This article reviews the main experimental studies on the blockage of CD49d and identifies the potential underlying causes for their inconclusive results. Despite these divergences and the difficulties in translation of experimental studies, a phase II clinical trial has recently been conducted to evaluate the efficacy of natalizumab in stroke patients (ACTION trial). Preliminary results of the trial are also discussed here, together with a general overview of the emerged importance of the neuroprotective strategies based on the mitigation of post-stroke neuroinflammation. Expert commentary: Despite natalizumab showing positive effects on functional outcome similar to what was found in experimental models, a better understanding of how this happens without reducing the infarct volume requires further research. Therefore, new clinical trials are needed to confirm its neuroprotectant role in ischemic stroke. PMID- 27476865 TI - The role of surveillance in assuring mutual protection for vaccine-preventable diseases. AB - Herd immunity is crucial for the success of vaccination programmes. Immunity levels needed for assuring mutual protection strongly depend on vaccine coverage, and thus on acceptance of vaccination by the public. Surveillance activities are essential for monitoring vaccine coverage as well as the impact of vaccination programme on disease spread. Vaccine programme managers may use data and information provided by surveillance activities for monitoring the programme and implementing actions aimed at establishing herd immunity. During the last decades, effective communication has become more and more important due to a progressive lack of confidence of the public towards vaccination. Evidence-based communication supported by reliable information on vaccine effectiveness and safety may be central for improving vaccine confidence and assuring mutual protection. PMID- 27476866 TI - A process evaluation of a Training of Trainers (TOT) model of men's health training. AB - This study set out to identify the mediators of diffusion of a Training of Trainers (ToT) programme; focusing on ENGAGE, Ireland's national men's health training programme, we explored the process (planning, implementation and maintenance) of using a ToT model of training to affect change in gender sensitive health and social service provision for men. Our findings indicate that an experiential learning approach in combination with mechanisms for feedback and fostering peer-based support during training and beyond are key strategies that foster individual (Trainer), community (of Trainers) and organizational (Trainer workplaces) level ownership. Moreover, by adapting in response to feedback, ENGAGE was able to remain relevant over a number years and to different cohorts of Trainers. As such, core strategies used by ENGAGE could be used to inform new models of health training elsewhere. PMID- 27476867 TI - Exploring the mental health benefits of participation in an Australian anti racism intervention. AB - There is a vast body of research demonstrating the deleterious effects of racism on health. Despite this, there is limited research that considers the health benefits of anti-racism interventions. We assess the mental health effects for young people participating in an anti-racism intervention that was based on the principles of intergroup contact theory and delivered through five projects addressing specific issues and contexts. An evaluation of the intervention used a before-and-after design. The analyses reported here focus on data collected from participants who completed both pre- and post-intervention surveys (n = 246). Analyses examine the characteristics of participants, the environment for intergroup contact (equal status between ethnic groups, shared goals, co operation and institutional support for intergroup relationships) and basic psychological needs (competence, relatedness and autonomy) as defined by Self Determination Theory. The results suggest that the projects met the criteria for promoting positive intergroup contact. There was also evidence that participants' involvement in these projects had positive effects on their autonomy, with particular improvements among people with ethnicities other than 'Australian'. The findings suggest that anti-racism interventions can have positive mental health effects for participants. These benefits redress some of the individual level effects of racism experiences by supporting young people to develop confidence and self-esteem. PMID- 27476868 TI - Infectious disease-specific health literacy in Tibet, China. AB - This study was aimed to develop an instrument to assess infectious disease specific health literacy (IDSHL) in the general population of Tibet, China and identify the association between IDSHL and reported infectious disease-related symptoms. A survey using a standardized questionnaire, which included 25 questions on knowledge, behaviors and skills regarding infectious diseases, was conducted in the general population of Tibet, China between September 2011 and November 2011. The 25 questions formed the index system of the instrument assessing IDSHL (total scores: 25 scores). Factors associated with index scores of IDSHL were identified by general linear model. The association between the index score of IDSHL and the occurrence of the five selected infectious disease symptoms (fever, diarrhea, rash, jaundice or conjunctivitis) were investigated using multivariate unconditional logistic regression. Among 5717 eligible participants in the survey, 4631 participants completed all of the 25 questions in the instrument. The instrument was reliable and valid as measured by the Cronbach's alpha coefficient and split-half coefficient, and the confirmatory factor analysis. Only 1.0% (48/4631) answered >=80% of the 25 questions correctly (score >= 20). Significant factors associated with lower health literacy score included female gender, older age, Tibetan group, lower education level, underlying diseases and more undeveloped area. For each increasing score of IDSHL, reports of fever, diarrhea or jaundice in the prior year were significantly decreased by 3% (p = 0.015), 4% (p = 0.004) and 16% (p < 0.001), respectively. Accurately measuring IDSHL could help identify those individuals with poor IDSHL, who could be targeted with specific interventions to improve health. PMID- 27476869 TI - Dietary intervention for people with mental illness in South Australia. AB - Background: People with serious mental illness (SMI) have a 25-30 year lower life expectancy than the general population due largely to cardiovascular disease (CVD). Mediterranean diet can reduce CVD risk and repeat events by 30-70%. We conducted a pilot feasibility study (HELFIMED) with people who have SMI residing within a Community Rehabilitation Centre in South Australia, aimed at improving participants' diets according to Mediterranean diet principles. Methods: During a 3-month intervention, participants were provided with nutrition education, food hampers, and twice-weekly cooking workshops and guided shopping trips. This report presents the results of a mixed method evaluation of the programme using thorough in-depth interviews with participants and support staff (n = 20), contextualized by changes in dietary biomarkers and CVD risk factors. Results: The framework thematic analysis revealed evidence of improvements in participants' knowledge of and intake of the key elements of a Mediterranean style diet (fruit and vegetables, olive oil, fish, legumes), reduction in poor nutrition habits (soft drinks, energy drinks, take away meals) and development of independent living skills-culinary skills such as food preparation and cooking based on simple recipes, food shopping and budgeting, healthy meal planning and social interaction. These changes were supported by dietary biomarkers, and were associated with reduced CVD risk factors. Conclusions: A Mediterranean diet-based pilot study achieved positive change in dietary behaviours associated with CVD risk for participants with SMI. This supports a need to include dietary education and cooking skills into rehabilitation programmes for people with SMI. PMID- 27476870 TI - Implementing health promotion tools in Australian Indigenous primary health care. AB - Background: In Australia, significant resources have been invested in producing health promotion best practice guidelines, frameworks and tools (herein referred to as health promotion tools) as a strategy to improve Indigenous health promotion programmes. Yet, there has been very little rigorous implementation research about whether or how health promotion tools are implemented. This paper theorizes the complex processes of health promotion tool implementation in Indigenous comprehensive primary healthcare services. Methods: Data were derived from published and grey literature about the development and the implementation of four Indigenous health promotion tools. Tools were theoretically sampled to account for the key implementation types described in the literature. Data were analysed using the grounded-theory methods of coding and constant comparison with construct a theoretical implementation model. Results: An Indigenous Health Promotion Tool Implementation Model was developed. Implementation is a social process, whereby researchers, practitioners and community members collectively interacted in creating culturally responsive health promotion to the common purpose of facilitating empowerment. The implementation of health promotion tools was influenced by the presence of change agents; a commitment to reciprocity and organizational governance and resourcing. Conclusion: The Indigenous Health Promotion Tool Implementation Model assists in explaining how health promotion tools are implemented and the conditions that influence these actions. Rather than simply developing more health promotion tools, our study suggests that continuous investment in developing conditions that support empowering implementation processes are required to maximize the beneficial impacts and effectiveness of health promotion tools. PMID- 27476871 TI - Writing peer-reviewed articles with diverse teams: considerations for novice scholars conducting community-engaged research. AB - Given the growth of interdisciplinary and community-engaged health promotion research, it has become increasingly common to conduct studies in diverse teams. While there is literature to guide collaborative research proposal development, data collection and analysis, little has been written about writing peer-reviewed publications collaboratively in teams. This gap is particularly important for junior researchers who lead articles involving diverse and community-engaged co authors. The purpose of this article is to present a series of considerations to guide novice researchers in writing for peer-reviewed publication with diverse teams. The following considerations are addressed: justifying the value of peer reviewed publication with non-academic partners; establishing co-author roles that respect expertise and interest; clarifying the message and audience; using the article outline as a form of engagement; knowledge translation within and beyond the academy; and multiple strategies for generating and reviewing drafts. Community-engaged research often involves collaboration with communities that have long suffered a history of colonial and extractive research practices. Authentic engagement of these partners can be supported through research practices, including manuscript development, that are transparent and that honour the voices of all team members. Ensuring meaningful participation and diverse perspectives is key to transforming research relationships and sharing new insights into seemingly intractable health problems. PMID- 27476872 TI - Coordination of signaling and tissue mechanics during morphogenesis of murine intestinal villi: a role for mitotic cell rounding. AB - Efficient digestion and absorption of nutrients by the intestine requires a very large apical surface area, a feature that is enhanced by the presence of villi, fingerlike epithelial projections that extend into the lumen. Prior to villus formation, the epithelium is a thick pseudostratified layer. In mice, villus formation begins at embryonic day (E)14.5, when clusters of mesenchymal cells form just beneath the thick epithelium. At this time, analysis of the flat lumenal surface reveals a regular pattern of short apical membrane invaginations that form in regions of the epithelium that lie in between the mesenchymal clusters. Apical invaginations begin in the proximal intestine and spread distally, deepening with time. Interestingly, mitotically rounded cells are frequently associated with these invaginations. These mitotic cells are located at the tips of the invaginating membrane (internalized within the epithelium), rather than adjacent to the apical surface. Further investigation of epithelial changes during membrane invagination reveals that epithelial cells located between mesenchymal clusters experience a circumferential compression, as epithelial cells above each cluster shorten and widen. Using a computational model, we examined whether such forces are sufficient to cause apical invaginations. Simulations and in vivo data reveal that proper apical membrane invagination involves intraepithelial compressive forces, mitotic cell rounding in the compressed regions and apico-basal contraction of the dividing cell. Together, these data establish a new model that explains how signaling events intersect with tissue forces to pattern apical membrane invaginations that define the villus boundaries. PMID- 27476873 TI - Influence of Block Copolymerization on the Antifreeze Protein Mimetic Ice Recrystallization Inhibition Activity of Poly(vinyl alcohol). AB - Antifreeze (glyco) proteins are produced by many cold-acclimatized species to enable them to survive subzero temperatures. These proteins have multiple macroscopic effects on ice crystal growth which makes them appealing for low temperature applications-from cellular cryopreservation to food storage. Poly(vinyl alcohol) has remarkable ice recrystallization inhibition activity, but its mode of action is uncertain as is the extent at which it can be incorporated into other high-order structures. Here the synthesis and characterization of well defined block copolymers containing poly(vinyl alcohol) and poly(vinylpyrrolidone) by RAFT/MADIX polymerization is reported, as new antifreeze protein mimetics. The effect of adding a large second hydrophilic block is studied across a range of compositions, and it is found to be a passive component in ice recrystallization inhibition assays, enabling retention of all activity. In the extreme case, a block copolymer with only 10% poly(vinyl alcohol) was found to retain all activity, where statistical copolymers of PVA lose all activity with very minor changes to composition. These findings present a new method to increase the complexity of antifreeze protein mimetic materials, while retaining activity, and also to help understand the underlying mechanisms of action. PMID- 27476874 TI - Elevated in vivo [18F]-AV-1451 uptake in a patient with progressive supranuclear palsy. PMID- 27476875 TI - A genome-wide association study of heat stress-associated SNPs in catfish. AB - Heat tolerance is a complex and economically important trait for catfish genetic breeding programs. With global climate change, it is becoming an increasingly important trait. To better understand the molecular basis of heat stress, a genome-wide association study (GWAS) was carried out using the 250 K catfish SNP array with interspecific backcross progenies, which derived from crossing female channel catfish with male F1 hybrid catfish (female channel catfish * male blue catfish). Three significant associated SNPs were detected by performing an EMMAX approach for GWAS. The SNP located on linkage group 14 explained 12.1% of phenotypical variation. The other two SNPs, located on linkage group 16, explained 11.3 and 11.5% of phenotypical variation respectively. A total of 14 genes with heat stress related functions were detected within the significant associated regions. Among them, five genes-TRAF2, FBXW5, ANAPC2, UBR1 and KLHL29- have known functions in the protein degradation process through the ubiquitination pathway. Other genes related to heat stress include genes involved in protein biosynthesis (PRPF4 and SYNCRIP), protein folding (DNAJC25), molecule and iron transport (SLC25A46 and CLIC5), cytoskeletal reorganization (COL12A1) and energy metabolism (COX7A2, PLCB1 and PLCB4) processes. The results provide fundamental information about genes and pathways that is useful for further investigation into the molecular mechanisms of heat stress. The associated SNPs could be promising candidates for selecting heat-tolerant catfish lines after validating their effects on larger and various catfish populations. PMID- 27476877 TI - Characterization of circular RNAs in human, mouse and rat hearts. AB - Deep sequencing techniques and advanced data analysis methods recently enabled the characterization of thousands of circular RNA isoforms (circRNAs) from a number of tissues and organisms. There is emerging evidence that some circRNAs may have important biological functions or serve as diagnostic biomarkers in disease conditions. In order to analyze circRNA expression in the heart and its changes in different conditions we performed RNA-Seq analysis of ribosome depleted libraries from rats (neonatal and adult), mice (sham or after transverse aortic constriction, TAC) and humans (failing, non-failing). All samples were sequenced after treatment with exonuclease RNase R or a mock treatment and >9000 candidate circRNAs were detected for each species. Additionally, we performed separate isolation of nuclear and cytoplasmic RNA and co-immunoprecipitated RNA interacting with endogenous argonaute 2 (Ago2) in primary cardiac myocytes. We found circRNAs to be significantly enriched in the cytoplasm compared to linear transcripts and to have a similar level of association with Ago2. Notably in all three species we observed dozens of circRNAs arising from the titin (Ttn) gene, which is known to undergo highly complex alternative splicing during heart maturation. Correspondingly we observed extensive differential regulation of Ttn circRNAs between neonatal and adult rat hearts, suggesting that circRNA formation could be involved in the regulation of titin splicing. We expect that our inventory of cardiac circRNAs, as well as the information on their conservation and differential expression will provide an important basis for further studies addressing their function and suitability as biomarkers. PMID- 27476879 TI - Myocardial bridge and proximal stenosis in hypertensive patients. PMID- 27476878 TI - Light-controlled active release of photocaged ciprofloxacin for lipopolysaccharide-targeted drug delivery using dendrimer conjugates. AB - We report an active delivery mechanism targeted specifically to Gram(-) bacteria based on the photochemical release of photocaged ciprofloxacin carried by a cell wall-targeted dendrimer nanoconjugate. PMID- 27476876 TI - Disentangling the Role of Astrocytes in Alcohol Use Disorder. AB - Several laboratories recently identified that astrocytes are critical regulators of addiction machinery. It is now known that astrocyte pathology is a common feature of ethanol (EtOH) exposure in both humans and animal models, as even brief EtOH exposure is sufficient to elicit long-lasting perturbations in astrocyte gene expression, activity, and proliferation. Astrocytes were also recently shown to modulate the motivational properties of EtOH and other strongly reinforcing stimuli. Given the role of astrocytes in regulating glutamate homeostasis, a crucial component of alcohol use disorder (AUD), astrocytes might be an important target for the development of next-generation alcoholism treatments. This review will outline some of the more prominent features displayed by astrocytes, how these properties are influenced by acute and long term EtOH exposure, and future directions that may help to disentangle astrocytic from neuronal functions in the etiology of AUD. PMID- 27476880 TI - Silibinin and colorectal cancer chemoprevention: a comprehensive review on mechanisms and efficacy. AB - Globally, the risk of colorectal cancer (CRC) as well as the incidence of mortality associated with CRC is increasing. Thus, it is imperative that we look at alternative approaches involving intake of non-toxic natural dietary/non dietary agents, for the prevention of CRC. The ultimate goal of this approach is to reduce the incidence of pre-neoplastic adenomatous polyps and prevent their progression to more advanced forms of CRC, and use these natural agents as a safe intervention strategy during the clinical course of this deadly malignancy. Over the years, pre-clinical studies have shown that silibinin (a flavonolignan isolated from the seeds of milk thistle, Silybum marianum) has strong preventive and therapeutic efficacy against various epithelial cancers, including CRC. The focus of the present review is to provide a comprehensive tabular summary, categorically for an easy accessibility and referencing, pertaining to the efficacy and associated mechanisms of silibinin against CRC growth and progression. PMID- 27476881 TI - Autoantibodies in Alzheimer's disease: potential biomarkers, pathogenic roles, and therapeutic implications. AB - Alzheimer's disease (AD) is a prevalent and debilitating neurodegenerative disorder in the elderly. The etiology of AD has not been fully defined and currently there is no cure for this devastating disease. Compelling evidence suggests that the immune system plays a critical role in the pathophysiology of AD. Autoantibodies against a variety of molecules have been associated with AD. The roles of these autoantibodies in AD, however, are not well understood. This review attempts to summarize recent findings on these autoantibodies and explore their potential as diagnostic/prognostic biomarkers for AD, their roles in the pathogenesis of AD, and their implications in the development of effective immunotherapies for AD. PMID- 27476882 TI - Functional morphology of pituitary -thyroid and -adrenocortical axes in middle aged male rats treated with Vitex agnus castus essential oil. AB - We previously reported that Vitex agnus-castus L. essential oil (VACEO), when administered to middle-aged males, exerts a bone-protective effect, induces silencing of locomotor activities and decreases pituitary prolactin immunopositivity. To further assess the putative endocrine effects of VACEO, we examined the pituitary-thyroid and -adrenocortical axes in our model. Sixteen month-old Wistar rats were subcutaneously administered 60mg/kg of VACEO dissolved in sterile olive oil, while the control group received the same amount of vehicle alone for three weeks. Pituitaries, thyroids and adrenals were analyzed by qualitative and quantitative histological approaches. Concentration of thyroid stimulating hormone (TSH), total thyroxine and triiodothyronine (TH), adrenocorticotrophic hormone (ACTH), corticosterone in serum and in adrenal tissue were measured. In VACEO-treated rats, the relative volume density of pituitary thyrotrophs increased (p<0.001), while intensity of cytoplasmic TSHbeta immunostaining decreased (p<0.001), consistent with elevated TSH in serum (p<0.01). The thyroid tissue was characterized by a micro-follicular structure, increased relative volume of follicular epithelium (p<0.05), decreased volume of luminal colloid (p<0.001) and increased basolateral expression of sodium-iodide symporter-immunopositivity (p<0.05). Serum TH also increased (p<0.01). The relative volume density of pituitary corticotrophs decreased (p<0.05), compatible with decline in circulating ACTH (p<0.05). Neither tissue nor serum corticosterone levels were affected by VACEO treatment. In conclusion, the observed changes in TSH and ACTH strongly indicate central endocrine effects of prolonged VACEO treatment. In this respect, production of ACTH decreased without impact on corticosterone production. Increase in serum concentration of both TH and TSH are not compatible with a negative feedback loop and suggest a major change in set-point regulation of the hypothalamic-pituitary-thyroid axis. PMID- 27476883 TI - Tweaking Mesenchymal Stem/Progenitor Cell Immunomodulatory Properties with Viral Vectors Delivering Cytokines. AB - Mesenchymal Stem Cells (MSCs) can be found in various body sites. Their main role is to differentiate into cartilage, bone, muscle, and fat cells to allow tissue maintenance and repair. During inflammation, MSCs exhibit important immunomodulatory properties that are not constitutive, but require activation, upon which they may exert immunosuppressive functions. MSCs are defined as "sensors of inflammation" since they modulate their ability of interfering with the immune system both in vitro and in vivo upon interaction with different factors. MSCs may influence immune responses through different mechanisms, such as direct cell-to-cell contact, release of soluble factors, and through the induction of anergy and apoptosis. Human MSCs are defined as plastic-adherent cells expressing specific surface molecules. Lack of MHC class II antigens makes them appealing as allogeneic tools for the therapy of both autoimmune diseases and cancer. MSC therapeutic potential could be highly enhanced by the expression of exogenous cytokines provided by transduction with viral vectors. In this review, we attempt to summarize the results of a great number of in vitro and in vivo studies aimed at improving the ability of MSCs as immunomodulators in the therapy of autoimmune, degenerative diseases and cancer. We will also compare results obtained with different vectors to deliver heterologous genes to these cells. PMID- 27476884 TI - Is softcast (3M) strong enough for potentially unstable paediatric forearm fractures? AB - INTRODUCTION: The majority of paediatric forearm fractures are treated using a circumferential splint, with prior manipulation as necessary. Plaster of Paris is often chosen for its ease of application, cost and proven reliability. Softcast is an alternative, providing a comfortable and water-resistant splint that can be removed without a plaster saw, and is in widespread use for immobilising buckle fractures. Softcast has not been recommended for acute unstable fractures. We established whether a Softcast splint could provide sufficient mechanical stability to control an unstable paediatric forearm fracture. METHODS: A laboratory study was undertaken to compare the 3 point (kinking) and 4 point bending, and torsion loads to defined clinical failure points withstood by standardised 4-wrap POP compared to Softcast splints with 6-wrap, 4 wrap and reinforced 4-wrap configurations. RESULTS: The load at clinically relevant failure of a 6-wrap Softcast forearm splint was 504N in 4 point bending, 202N in 3 point bending (kinking), and 11Nm in torsion (equalling 30.4%, 26% and 42.2% of the equivalent values for a circumferential 4-wrap POP). The 6-wrap Softcast was however stronger in all modes than a fibreglass-reinforced Softcast splint (previously recommended for acute fractures). Furthermore, the load to failure in all modes exceeds that which can be exerted by body weight in many paediatric patients. Softcast demonstrated complete recovery of its original shape on unloading, whereas POP was permanently deformed. 6-wrap Softcast splints were 4% lighter than POP. CONCLUSION: A 6-wrap Softcast splint provides adequate mechanical stability and protection for paediatric patients up to approximately 20kg, avoiding high-risk activities. The primary risk is not of fracture angulation and loss of position, but temporary indentation of the splint, causing discomfort or pain. Considering its ease of removal, Softcast may be preferable for younger paediatric patients. Its cost may be offset by reducing the number and duration of hospital visits. PMID- 27476885 TI - Female patients display poorer burn-specific quality of life 12 months after a burn injury. AB - INTRODUCTION: Although gender differences in morbidity and mortality have been measured in patients with moderate to severe burn injury, little attention has been directed at gender effects on health-related quality of life (HRQoL) following burn injury. The current study was therefore conducted to prospectively measure changes in HRQoL for males and females in a sample of burn patients. METHODS: A total of 114 adults who received treatment at a statewide burns service for a sustained burns injury participated in this study. Instruments measuring generic health status (Short Form 36 Medical Outcomes Survey version 2), burn-specific HRQoL (Burns Specific Health Scale-Brief), psychological distress (Kessler Psychological Distress Scale) and alcohol use (Alcohol Use Disorders Identification Tool) were prospectively measured at 3, 6 and 12 months post-burn. RESULTS: In the 12 months post-injury, female patients showed overall poorer physical (p=0.01) and mental health status (p<0.001), greater psychological distress (p<0.001), and greater difficulty with aspects of burn specific HRQoL: body image (p<0.001), affect (p<0.001), interpersonal functioning (p=0.005), heat sensitivity (p=0.01) and treatment regime (p=0.01). While significant interaction effects suggested that female patients had more improvement in difficulties with treatment regime (p=0.007), female patients continued to report greater difficulty with multiple aspects of physical and psychosocial health status 12 months post-injury. CONCLUSION: Even though demographic variables, injury characteristics and burn care interventions were similar across genders, following burn injury female patients reported greater impairments in generic and burn-specific HRQoL along with psychological morbidity, when compared to male patients. Urgent clinical and research attention utilising an evidence-based research framework, which incorporates the use of larger sample sizes, the use of validated instruments to measure appropriate outcomes, and a commitment to monitoring long-term care, can only improve burn care. PMID- 27476886 TI - Assessing protocol adherence in a clinical trial with ordered treatment regimens: Quantifying the pragmatic, randomized optimal platelet and plasma ratios (PROPPR) trial experience. AB - BACKGROUND: Medication dispensing errors are common in clinical trials, and have a significant impact on the quality and validity of a trial. Therefore, the definition, calculation and evaluation of such errors are important for supporting a trial's conclusions. A variety of medication dispensing errors can occur. In this paper, we focus on errors in trials where the intervention includes multiple therapies that must be given in a pre-specified order that varies across treatment arms and varies in duration. METHODS: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was a Phase III multi-site, randomized trial to compare the effectiveness and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with a 1:1:2 ratio. In this trial, these three types of blood products were to be transfused in a pre defined order that differed by treatment arm. In this paper, we present approaches from the PROPPR trial that we used to define and calculate the occurrence of out of order blood transfusion errors. We applied the proposed method to calculate protocol adherence to the specified order of transfusion in each treatment arm. RESULTS: Using our proposed method, protocol adherence was greater in the 1:1:1 group than in the 1:1:2 group (96% vs 93%) (p<0.0001), although out of order transfusion errors in both groups were low. Final transfusion ratios of plasma to platelets to red blood cells for the 1:1:1 ratio group was 0.93:1.32:1, while the transfusion ratio for the 1:1:2 ratio group was 0.48:0.48:1. CONCLUSIONS: Overall, PROPPR adherence to blood transfusion order pre-specified in the protocol was high, and the required order of transfusions for the 1:1:2 group was more difficult to achieve. The approaches proposed in this manuscript were useful in evaluating the PROPPR adherence and are potentially useful for other trials where a specific treatment orders with varying durations must be maintained. PMID- 27476887 TI - Test-meal palatability is associated with overconsumption but better represents preceding changes in appetite in non-obese males. AB - Single-course, ad libitum meals are recommended for the assessment of energy intake within appetite research. This study represents the first investigation of the comparative sensitivity of two single-course, ad libitum meals designed to differ in palatability. We conducted two experiments using a preload study design. All protocols were identical except for the energy content of the preloads (Expt 1: 579 and 1776 kJ; Expt 2: 828 and 4188 kJ). During each experiment, ten healthy men completed four experimental trials constituting a low or high-energy preload beverage, a 60-min intermeal interval and consumption of a pasta-based or a porridge-based, ad libitum meal. Appetite ratings were measured throughout each trial, and palatability was assessed after food consumption. Preload manipulation did not influence appetite (P=0.791) or energy intake (P=0.561) in Expt 1. Palatability and energy intake were higher for the pasta meal than for the porridge meal in both experiments (palatability P<=0.002; energy intake P<=0.001). In Expt 2, consumption of the high-energy preload decreased appetite (P=0.051) and energy intake (P=0.002). Energy compensation was not significantly different between pasta and porridge meals (P=0.172), but was more strongly correlated with preceding changes in appetite at the pasta meal (r 0.758; P=0.011) than the porridge meal (r -0.498; P=0.143). The provision of a highly palatable, pasta-based meal produced energy intakes that were more representative of preceding appetite ratings, but the moderately palatable, porridge-based meal produced more ecologically valid energy intakes. Ad libitum meal selection and design may require a compromise between sensitivity and ecological validity. PMID- 27476888 TI - Defective natural killer cell activity in a mouse model of eczema herpeticum. AB - BACKGROUND: Patients with atopic dermatitis (AD) are susceptible to several viruses, including herpes simplex virus (HSV). Some patients experience 1 or more episodes of a severe skin infection caused by HSV termed eczema herpeticum (EH). There are numerous mouse models of AD, but no established model exists for EH. OBJECTIVE: We sought to establish and characterize a mouse model of EH. METHODS: We infected AD-like skin lesions with HSV1 to induce severe skin lesions in a dermatitis-prone mouse strain of NC/Nga. Gene expression was investigated by using a microarray and quantitative PCR; antibody titers were measured by means of ELISA; and natural killer (NK) cell, cytotoxic T-cell, regulatory T-cell, and follicular helper T-cell populations were evaluated by using flow cytometry. The role of NK cells in HSV1-induced development of severe skin lesions was examined by means of depletion and adoptive transfer. RESULTS: Inoculation of HSV1 induced severe erosive skin lesions in eczematous mice, which had an impaired skin barrier, but milder lesions in small numbers of normal mice. Eczematous mice exhibited lower NK cell activity but similar cytotoxic T-cell activity and humoral immune responses compared with normal mice. The role of NK cells in controlling HSV1-induced skin lesions was demonstrated by experiments depleting or transferring NK cells. CONCLUSION: A murine model of EH with an impaired skin barrier was established in this study. We demonstrated a critical role of defective NK activities in the development of HSV1-induced severe skin lesions in eczematous mice. PMID- 27476890 TI - Effectiveness of Visual Methods in Information Procedures for Stem Cell Recipients and Donors. AB - OBJECTIVE: Obtaining informed consent from hematopoietic stem cell recipients and donors is a critical step in the transplantation process. Anxiety may affect their understanding of the provided information. However, use of audiovisual methods may facilitate understanding. In this prospective randomized study, we investigated the effectiveness of using an audiovisual method of providing information to patients and donors in combination with the standard model. MATERIALS AND METHODS: A 10-min informational animation was prepared for this purpose. In total, 82 participants were randomly assigned to two groups: group 1 received the additional audiovisual information and group 2 received standard information. A 20-item questionnaire was administered to participants at the end of the informational session. RESULTS: A reliability test and factor analysis showed that the questionnaire was reliable and valid. For all participants, the mean overall satisfaction score was 184.8+/-19.8 (maximum possible score of 200). However, for satisfaction with information about written informed consent, group 1 scored significantly higher than group 2 (p=0.039). Satisfaction level was not affected by age, education level, or differences between the physicians conducting the informative session. CONCLUSION: This study shows that using audiovisual tools may contribute to a better understanding of the informed consent procedure and potential risks of stem cell transplantation. PMID- 27476891 TI - Ulnar nerve tuberculoma: A case report and literature review. AB - Ulnar nerve tuberculoma is a rare case of tuberculous involvement of the peripheral nerve, which has attracted the attention of physicians. Here, we report the case of a patient with ulnar nerve tuberculoma. A 25-year-old patient presented progressive numbness on his left hand and forearm, and typical symptoms were not evident. The patient had no history of trauma or contact with any individuals with active tuberculosis. Exploratory surgery was performed and a granuloma-like lesion was found on the left ulnar nerve of the patient. The lesion was completely removed. We prepared hand-painted renderings for this rare disease for the first time, to the best of our knowledge. Histopathological examination of the specimen confirmed the presence of tuberculoma. After 1year of adequate antitubercular treatment, the patient recovered fully. Doctors need the most detailed radiographic information and histological results to confirm the diagnosis of this rare disease. At present, surgery is an effective way to resolve symptoms of ulnar nerve tuberculoma. PMID- 27476889 TI - Regulation of the host immune system by helminth parasites. AB - Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research. PMID- 27476892 TI - A small animal model for early cerebral aneurysm pathology. AB - Prior studies, using systemic hypertension and elastase infusion, have induced cerebral aneurysm (CA) formation in mice. However, the CAs induced were rapidly formed, relatively large, and often ruptured. These features are not completely representative of human CAs. We set out to develop a mouse model representative of the early pathological features of human CA. Twenty male C57/BL6 mice were placed in a stereotactic frame. Low dose elastase solution (2MUl/min) was manually injected into the right basal cistern. Human angiotensin II (0.11MUl/h) was infused subcutaneously. Mice were observed for 2-3weeks prior to euthanasia. Early CA histopathological features including endothelial change (EC) and internal elastic lamina degeneration (IELD) were systematically sought at major cerebral arterial bifurcations. Brains were harvested from 11 of 15 mice, yielding 27 bifurcations. Sub-arachnoid haemorrhage (SAH) without CA formation was observed in one brain. Macroscopic CA without SAH was observed in another brain. Early CA features were observed in 8/11 (73%) brains. All bifurcations with IELD demonstrated EC: where EC was absent, IELD was also absent. EC severity appeared to correlate with IELD severity. EC and IELD were both severe within the CA. Using lower dose elastase solution than previously employed, we developed a model of early CA pathology. Our model demonstrated that the spectrum of known early CA pathology can be created at multiple bifurcations in mice, with EC severity appearing to correlate with IELD severity. This model permits the study of factors which potentially advance or retard the progression of CA formation. PMID- 27476893 TI - Mental Health Services and Public Safety: Unanswered Questions. PMID- 27476895 TI - A Sane Struggle. PMID- 27476896 TI - Technology-Supported Peer-to-Peer Intervention for People With Serious Mental Illness. PMID- 27476897 TI - The Hamilton Mobile Crisis Rapid Response Team: A First-Responder Mental Health Service. PMID- 27476898 TI - Public Psychiatry's Accomplishments. PMID- 27476899 TI - An Update on the Quality of Medication Treatment for Mental Disorders in the VA. PMID- 27476900 TI - Backward to Nowhere. PMID- 27476901 TI - Bored in Board-and-Care and Other Settings: Perspectives of Latinos With Schizophrenia. PMID- 27476903 TI - News & Notes. PMID- 27476902 TI - Can E-Mail Reminders Sustain Training Gains From Continuing Education? PMID- 27476909 TI - Sorting centimetre-long single-walled carbon nanotubes. AB - While several approaches have been developed for sorting metallic (m) or semiconducting (s) single-walled carbon nanotubes (SWCNTs), the length of SWCNTs is limited within a micrometer, which restricts excellent electrical performances of SWCNTs for macro-scale applications. Here, we demonstrate a simple sorting method of centimetre-long aligned m- and s-SWCNTs. Ni particles were selectively and uniformly coated along the 1-cm-long m-SWCNTs by applying positive gate bias during electrochemical deposition with continuous electrolyte injection. To sort s-SWCNTs, the Ni coating was oxidized to form insulator outer for blocking of current flow through inner m-SWCNTs. Sorting of m-SWCNTs were demonstrated by selective etching of s-SWCNTs via oxygen plasma, while the protected m-SWCNTs by Ni coating remained intact. The series of source-drain pairs were patterned along the 1-cm-long sorted SWCNTs, which confirmed high on/off ratio of 10(4)-10(8) for s-SWCNTs and nearly 1 for m-SWCNTs. PMID- 27476910 TI - Ultrafast Airy beam optical parametric oscillator. AB - We report on the first realization of an ultrafast Airy beam optical parametric oscillator (OPO). By introducing intracavity cubic phase modulation to the resonant Gaussian signal in a synchronously-pumped singly-resonant OPO cavity and its subsequent Fourier transformation, we have generated 2-dimensional Airy beam in the output signal across a 250 nm tuning range in the near-infrared. The generated Airy beam can be tuned continuously from 1477 to 1727 nm, providing an average power of as much as 306 mW at 1632 nm in pulses of ~23 ps duration with a spectral bandwidth of 1.7 nm. PMID- 27476911 TI - Detailed faecal fat analysis using Fourier transform infrared spectroscopy: Exploring the possibilities. AB - OBJECTIVES: Fourier transform infrared (FTIR) spectroscopic determination of faecal fat is a simple and elegant alternative for the classical Van De Kamer approach. Besides quantification of the total amount of fat, analysis of the lipase hydrolysis efficiency (fatty acid/triglyceride ratio), fatty acid chain length and trans-unsaturated fatty acids could provide a better monitoring of dietary treatment. DESIGN AND METHODS: Stool samples (26 routine samples and 36 cystic fibrosis patients) were analysed with the Perkin Elmer Spectrum Two(r) spectrometer (3500-450cm-1). Fatty acid/triglyceride ratio was calculated using the absorbance ratio at 2855:1746cm-1. To estimate lipase hydrolysis efficiency, sample ratios were compared with the ratio of butter and pure free fatty acids. Mean fatty acid chain length was calculated using the absorbance ratio at 2855:1709cm-1. The absorbance at 966cm-1 was used to trace the presence of trans type unsaturated fatty acids. RESULTS: Butter showed a low fatty acid/triglyceride ratio (1.21) and pure free fatty acids a high fatty acid/triglyceride ratio (6.76). Mean fatty acid/triglyceride ratio of routine stool samples was 4.16+/-1.01. The applicability of fatty acid/triglyceride ratios was also tested in cystic fibrosis patients under treatment with a mean of 4.92+/-0.98. Relative absorbance contribution per carbon atom was 0.06 (ratio 1.06 for C18 standard, 0.91 for C16 standard). The mean ratio of the stool samples was 1.12 (mean acyl chain length of C19), with values ranging from 0.73 (C12) to 1.68 (C28). The presence of traceable amounts of trans-unsaturated fatty acids was also demonstrated. CONCLUSIONS: For the analysis of faecal material, FTIR provides unique information, difficult to obtain using other techniques. These findings offer perspectives for diet monitoring in patients with (non )pancreatic malabsorption. PMID- 27476912 TI - Binding Characteristics of Sphingosine-1-Phosphate to ApoM hints to Assisted Release Mechanism via the ApoM Calyx-Opening. AB - Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator carried by the HDL associated apoM protein in blood, regulating many physiological processes by activating the G protein-coupled S1P receptor in mammals. Despite the solved crystal structure of the apoM-S1P complex, the mechanism of S1P release from apoM as a part of the S1P pathway is unknown. Here, the dynamics of the wild type apoM S1P complex as well as of mutants were investigated by means of atomistic molecular dynamics simulations. The potential of mean force for S1P unbinding from apoM reflected a large binding strength of more than 60 kJ/mol. This high unbinding free energy for S1P underlines the observed specificity of the physiological effects of S1P as it suggests that the spontaneous release of S1P from apoM is unlikely. Instead, S1P release and thus the control of this bioactive lipid probably requires the tight interaction with other molecules, e.g. with the S1P receptor. Mutations of specific S1P anchoring residues of apoM decreased the energetic barrier by up to 20 kJ/mol. Moreover, the ligand-free apoM protein is shown to adopt a more open upper hydrophilic binding pocket and to result in complete closure of the lower hydrophobic cavity, suggesting a mechanism for adjusting the gate for ligand access. PMID- 27476913 TI - Temperament and Character Profile in Failed Back Surgery Syndrome: A Cross Sectional Clinical Study. AB - AIM: Some psychometric properties may predict the development of failed back surgery syndrome (FBSS). The aim of this study was to determine the pain, disability, and depression severity in patients diagnosed with FBSS, and to determine the temperament and character subgroups in comparison with control group. MATERIAL AND METHODS: Thirty-eight patients diagnosed with FBSS, and 35 patients with favourable outcome after lumbar spinal surgery were included to the study. Pain intensity, disability, depression scores, temperament and character profile were determined by the visual analogue scale (VAS), Roland Morris Disability Index, Beck Depression Inventory, and Temperament and Character Inventory. RESULTS: Pain intensity, disability, and depression scores were higher in the FBSS group (p < 0.001). There were no significant differences between temperament and character subgroups between study groups except one of the temperament subgroup, reward dependence (p=0.05). There was a negative correlation between self-directedness and leg pain severity in the FBSS group (p=0.01, r=-0.400). CONCLUSION: No significant differences were found between the FBSS and control groups with respect to temperament and character profile but FBSS was the cause of severe pain, disability, and higher depression scores. This group of patients must therefore be evaluated psychiatrically and should also be subjected to a clinical examination, and they should be managed using a multidisciplinary approach. PMID- 27476914 TI - Glasgow Coma Scale Versus Full Outline of UnResponsiveness Scale for Prediction of Outcomes in Patients with Traumatic Brain Injury in the Intensive Care Unit. AB - AIM: Glasgow Coma Scale (GCS) is the most applied tool for classifying intensity of coma and predicting patient outcomes with traumatic brain injuries. The present study was conducted with the aim of comparing two criteria of Full Outline of UnResponsiveness (FOUR) scale and GCS in predicting prognosis in patients with traumatic brain injuries. MATERIAL AND METHODS: In this prospective study, 198 patients with traumatic brain injuries were investigated. FOUR and GCS criteria for each patient were determined by four well-educated nurses. The area under receiver operating characteristic (ROC) curve was determined for in hospital mortality outcomes. RESULTS: Of all patients, 65.2% survived and 34.8% died, and FOUR had correctly predicted 82% of them. FOUR had 0.76 sensitivity and GCS had a sensitivity 0.85. Mean scores for mortality and survival rates were 4.59+/-2.36 and 10.71+/-2.24 in GCS, and 3.15+/-3.52 and 12.77+/-2.43 in FOUR, respectively. The area under ROC curve was 0.961 for FOUR and 0.928 for GCS. The area under the curve was high for FOUR in scores 6 and 7, and for GCS in scores 5 and 6. CONCLUSION: FOUR score is a valuable, sensitive and specific diagnostic criterion for predicting outcomes in patients with traumatic brain injuries. PMID- 27476915 TI - Surgical Management of Sacrococcygeal Region Giant Tumors by Use of Balloon Occlusion Abdominal Aorta. AB - AIM: Sacrococcygeal region giant tumors are a challenge for neurosurgeons. The purpose of this paper was to retrospectively analyze the clinical records of sacrococcygeal region giant tumors treated surgically by balloon occlusion of the abdominal aorta. MATERIAL AND METHODS: A total of 130 patients of sacral region tumors underwent surgery in our department from February 2009 to February 2013. Among these patients, 35 giant tumors were treated by balloon catheter occlusion of the abdominal aorta and electrophysiological monitoring. Thirty patients returned for follow-up evaluations and their clinical and imaging records were analyzed. RESULTS: Thirty patients underwent surgery via a posterior approach; these cases included 21 chordomas, 5 schwannomas, and 4 giant cell tumors of bone. Wide resections were performed in 26 patients (86.7%) and margin resections were performed in 4 (13.3%) patients. Most patients' symptoms were relieved through surgery and only nine patients (30%) experienced recurrence of the tumors during follow-up. CONCLUSION: Sacrococcygeal region giant tumors are still difficult to treat, especially for malignant tumors. Balloon catheter occlusions of the lower abdominal aorta can notably decreased intraoperative hemorrhage, shorten operation time, and decrease postoperative complications. This method is a good choice for neurosurgeons to manage these giant tumors in the sacral region. PMID- 27476916 TI - Histomorphometric and Ultrastructural Evaluation of Long-Term Alpha Lipoic Acid and Vitamin B12 Use After Experimental Sciatic Nerve Injury in Rats. AB - AIM: To analyze the therapeutic effects of long-term alpha lipoic acid (A-LA) and vitamin B12 use via histomorphometric methods and electron microscopy in the transected sciatic nerves of rats. MATERIAL AND METHODS: Forty rats were randomized into five groups (n=8/group). In group I, 1 cm segment of sciatic nerve was resected without any other intervention. In group II (sham), following right sciatic nerve transection, primary epineurial anastomosis was performed by placing the edges of the nerve end-to-end. In group III (saline), after right sciatic nerve transection, the ends of the nerves were brought together and closed after application of intraperitoneal physiologic saline. In group IV, 2 mg/kg of alpha lipoic acid and in group V, 2 mg/kg of vitamin B12 was administered intraperitoneally before surgical intervention. RESULTS: Histomorphometric and electron microscopic analyses revealed that vitamin B12 did not prevent structural changes, abnormal myelination and g-ratio deviations regarding the functional aspects of the sciatic nerve. Alpha lipoic acid was more effective in restructuring the histomorphometric and structural aspects of the nerve with more myelinated fibers with optimal values (0.55-0.68) than vitamin B12 groups, in which the number of myelinated nerve fibers significantly decreased at optimal intervals (0.55-0.68). CONCLUSION: A-LA administration following peripheral nerve transection injury is more effective in promoting nerve healing regarding the structural aspects of the sciatic nerve compared to vitamin B12 and also myelination of nerve fibers by increasing g-values. PMID- 27476917 TI - Preoperative Visualization of Cranial Nerves in Skull Base Tumor Surgery Using Diffusion Tensor Imaging Technology. AB - AIM: To visualize cranial nerves (CNs) using diffusion tensor imaging (DTI) with special parameters. This study also involved the evaluation of preoperative estimates and intraoperative confirmation of the relationship between nerves and tumor by verifying the accuracy of visualization. MATERIAL AND METHODS: 3T magnetic resonance imaging scans including 3D-FSPGR, FIESTA, and DTI were used to collect information from 18 patients with skull base tumor. DTI data were integrated into the 3D slicer for fiber tracking and overlapped anatomic images to determine course of nerves. 3D reconstruction of tumors was achieved to perform neighboring, encasing, and invading relationship between lesion and nerves. RESULTS: Optic pathway including the optic chiasm could be traced in cases of tuberculum sellae meningioma and hypophysoma (pituitary tumor). The oculomotor nerve, from the interpeduncular fossa out of the brain stem to supraorbital fissure, was clearly visible in parasellar meningioma cases. Meanwhile, cisternal parts of trigeminal nerve and abducens nerve, facial nerve were also imaged well in vestibular schwannomas and petroclival meningioma cases. The 3D-spatial relationship between CNs and skull base tumor estimated preoperatively by tumor modeling and tractography corresponded to the results determined during surgery. CONCLUSION: Supported by DTI and 3D slicer, preoperative 3D reconstruction of most CNs related to skull base tumor is feasible in pathological circumstances. We consider DTI Technology to be a useful tool for predicting the course and location of most CNs, and syntopy between them and skull base tumor. PMID- 27476918 TI - Prognostic Factors in Patients who Underwent Aneurysmal Clipping due to Spontaneous Subarachnoid Hemorrhage. AB - AIM: Despite technical and medical advances, aneurysmal subarachnoid hemorrhages (SAH) continue to be a challenging pathology, associated with high rates of morbidity and mortality. In this regard, a definition is required of the various prognostic indicators of an SAH. The aim of the present retrospective study is to examine the various prognostic factors of the clinical outcomes of the patients who underwent a neurosurgical clipping of aneurysms due to aneurysmal SAH. MATERIAL AND METHODS: The data of 104 patients that had suffered an aneurysmal SAH were analyzed. The baseline demographic, clinical and radiological data were all analyzed. The prognostic study was derived from an analysis of these variables. Relationship between prognostic factors and outcome was evaluated by univariate and logistic multivariate regression analysis. RESULTS: This study has identified unfavorable outcomes on the Glasgow Outcome Scale at discharge after the surgical treatment of aneurysmal SAH associated with increased age, poor World Federation of Neurosurgical Societies (WFNS) grade on admission, higher Fisher's grade on admission computed tomography scan, larger aneurysm, and clinical vasospasm. In a multivariate logistic regression analysis, age, high WFNS grade, positive clinical vasospasm and size of aneurysm were found to be independent risk factors for mortality. The presence of hydrocephalus, number of aneurysms, positive risk factors, and the presence of Doppler vasospasm did not reach statistical significance. CONCLUSION: The most important prognostic factors in patients undergoing surgery due to aneurysmal subarachnoid hemorrhage were WFNS grade, age, size of aneurysm and clinical vasospasm. PMID- 27476919 TI - Intrathecal Administration of Flavopiridol Promotes Regeneration in Experimental Model of Spinal Cord Injury. AB - AIM: Spinal cord injury (SCI) is a serious condition of the central nervous system and it affects the quality of life and even hampers the day-to-day activity of the patient. In the current study, we investigated the efficacy of intrathecal administration of flavopiridol in an experimental animal model of SCI. The study also aimed at exploring the physiological effects of flavopiridol on neurons, astrocytes and cell cycle regulatory proteins. MATERIAL AND METHODS: In vitro scratch wound experiments were performed on female Sprague-Dawley rats (n=23). A complete hemisection to the right of T10 was made, and flavopiridol solution (200 mM, 0.8 nmol flavopiridol/animal) was delivered topically to the lesion site. Cell viability assay, in vitro scratch injury assay, cell cycle analysis using flow cytometry and behavioural assessments were performed. RESULTS: The local delivery of flavopiridol reduced cavity formation and improved regeneration of neurons with improvement in physiological performance. Flavopiridol also inhibited the migration and proliferation of astrocytes, and at the same time, promoted the survival of neurons. CONCLUSION: Intrathecal administration of flavopiridol can be a promising treatment strategy in patients with SCI and it needs to be validated in patient setting. PMID- 27476920 TI - Intratumoral Ethyl Alcohol Injection for Devascularization of Hypervascular Intracranial Tumors. AB - AIM: Hypervascular intracranial tumors may cause serious bleeding in surgery. Though pre-operative endovascular embolization of tumor is a widely accepted method, sometimes despite embolization, an effective and safer intraoperative hemostatic technique is needed to prevent or at least decrease the massive bleeding from the tumors. The aim of this study was to investigate the effect of the ethyl alcohol (EA) injection in hypervascular tumors and find out whether it is likely to be an alternative method to prevent massive bleeding from tumor. MATERIAL AND METHODS: Fifty-five cases that had hypervascular intracranial tumor and underwent EA injections into their tumors were included in the study. A small amount (0.1-0.2 ml) of EA was used in every injection. Total EA amount differed from 1.2 to 18 ml for each patient. RESULTS: Most of the tumors were removed with less bleeding, because bleedings stopped or decreased during resection after EA injections. No serious complication that might be related to EA was observed. CONCLUSION: EA injection into the tumor is an easy, cheap and less invasive method to obtain effective and safe tumor devascularization. It may be an alternative method for tumor devascularization when preoperative embolization cannot be performed due to any reason or severe bleeding despite embolization. PMID- 27476921 TI - 14-3-3zeta Positive Cells Show More Tumorigenic Characters in Human Glioblastoma. AB - AIM: Expression of 14-3-3zeta is upregulated in many cancer types and plays an important role in tumorigenesis. Our previous studies have shown that 14-3-3zeta has a positive expression and is associated with a poor prognosis in patients with glioblastoma. In this study, we investigated whether 14-3-3zeta positive cells show more tumorigenic character and stronger chemotherapy resistance. MATERIAL AND METHODS: Six human glioblastoma cells lines were derived from the 6 patients with tumor, and the cells were sorted by 14-3-3zeta expression. The cell viability, invasion, tumorigenic ability and chemotherapy resistance were compared between the 14-3-3 positive and negative expression groups. RESULTS: 14 3-3zeta positive cells displayed oncogenic properties, more tumorigenic character, high invasiveness, tumorsphere formation ability and resistance to temozolomide chemotherapy treatment. CONCLUSION: Cells with 14-3-3zeta positive expression show more tumorigenic character and should be administered other treatments in the future. PMID- 27476922 TI - Children with Metopic Ridge. AB - AIM: The premature closure of the metopic suture results in metopic synostosis, also known as trigonocephaly. However, there is a group of children who have only a frontal metopic ridge, obvious with inspection and fingertip palpation, without the clinical features of trigonocephaly. This study aims to report a group of children with metopic ridge with a special emphasis on the definition and the diagnostic features. MATERIAL AND METHODS: Thirty-eight children with a diagnosis of metopic ridge were followed up with clinical examinations and photographs in the pediatric neurosurgery outpatient clinic between January 2010 and November 2015. RESULTS: Children were between 3 and 30 (mean=14) months of age at diagnosis. Twenty-five (65.8%) of the children were boys and 13 (34.2%) were girls. A midline metopic ridge without fronto-orbital trigonocephalic deformity was the only diagnostic criterion. The parents" concern about the metopic deformity at initial diagnosis was a common feature in every case. Seven (18.4%) of the children had a sibling with either metopic ridge (n=4) or trigonocephaly (n=3). None of the children had worsened or had received surgery in the follow-up period. CONCLUSION: The metopic ridge is a pathology of the metopic suture and is a concern for parents in the context of craniosynostosis. Radiological investigation and craniosynostosis surgery are unnecessary in children with a metopic ridge.This clinical entity may be considered the mildest form of metopic synostosis. PMID- 27476923 TI - Impact of Magnetic Field on Pressures of Programmable Cerebrospinal Fluid Shunts: An Experimental Study. AB - AIM: To investigate whether programmable cerebrospinal fluid (CSF) shunts are influenced by exposure to the magnetic field and to compare the effects of magnetic field in 4 different brands of programmable CSF shunts. MATERIAL AND METHODS: This experimental study was performed in the laboratory using a novel design of magnetic field. Four types of programmable CSF shunts (Miethke(r), Medtronic(r), Sophysa(r) and Codman(r)Hakim(r)) were exposed to the magnetic field generated by an apparatus consisting of Helmholtz coil for 5 minutes. In every CSF shunt, initial pressures were adjusted to 110 mm H2O and pressures after exposure to magnetic field were noted. These measurements were implemented at frequencies of 5 Hz, 20 Hz, 30 Hz, 40 Hz, 60 Hz and 80 Hz. In each type, three shunts were utilized and evaluations were made twice for every shunt. RESULTS: At 5, 30, 40 and 60 Hz, Groups 1, 2 and 3 had significantly higher average pressures than Group 4. At 20 and 80 Hz, Groups 1 and 2 had notably different pressure values than Groups 3 and 4. Group 3 displayed the highest pressure, while Group 4 demonstrated the lowest pressure. CONCLUSION: Exposure to magnetic fields may affect the pressures of programmable CSF shunts. However, further controlled, clinical trials are warranted to elucidate the in-vivo effects of magnetic field exposure. PMID- 27476924 TI - The Effect of Quetiapine on Treatment of Experimental Acute Spinal Cord Injury. AB - AIM: It is well known that treatment modalities against secondary damage due to spinal cord injury (SCI) are very important. This phase has been researched in many experimental studies. Apoptosis is one of the major mechanisms of secondary damage on spinal cord. The present study was undertaken to determine if quetiapine, a 5-HT2 receptor blocker atypical antipsychotic agent can rescue neuronal cells from apoptosis in a SCI model. MATERIAL AND METHODS: Thirty-two female Wistar rats were separated to 4 equal groups. Total laminectomy was performed at T5-7 level and spinal cord injury was produced by using the clip compression technique. Each rat from groups "1 day" (D-I) and "7 days" (D-II) was daily injected intraperitoneally with Quetiapine (10 mg/kg/day). No treatment was administered to the control groups "1 day" (K-I) and "7 days" (K-II). At the end of follow-up periods, all animals were sacrificed and spinal cords were removed. Apoptotic cells were evaluated by using immunohistochemical technique (TUNEL) in injured spinal cord specimens. RESULTS: There was a statistically significant difference while counting ApopTag positive cells, both at 1 day groups of K-I and D-I (p=0.00000008) and at 7 day groups of K-II and D-II (p=0.000005). Unlike the 1-day period, a statistically significant difference was found between grey and white matter ApopTag positive cells at the 7 < sup > th < /sup > day (p=0.0001). CONCLUSION: Quetiapine has a protective effect on secondary damage caused by SCI, while also can be used in post-traumatic stress disorder, depression and agitation as a versatile agent. PMID- 27476925 TI - Distal Anterior Cerebral Artery (Pericallosal Artery) Aneurysms: Report of 19 Cases and Literature Review. AB - AIM: To evaluate the follow-up results of patients who underwent surgical treatment for distal anterior cerebral artery (pericallosal artery) aneurysms and compare our results with the literature. MATERIAL AND METHODS: Nineteen patients were operated between 2000 and 2013 with preoperative angiography and computed tomography (CT) studies. Fisher"s classification and World Federation of Neurosurgical Societies (WFNS) subarachnoid hemorrhage (SAH) scale were used to classify the CT findings of the patients. In addition to the clinical and radiological analyses, bibliographical review in indexed databases was also performed. RESULTS: The female/male ratio was 4:1 and the average age was 34 years. The right side was affected in 53% of cases and 42% of the aneurysm was ruptured. Distribution of the ruptured aneurysms based on Fisher"s classification was as follows: Fisher IV in 25% of the cases, Fisher III in 37.5%, Fisher II in 12.5%, and Fisher I in 25% of the cases. The ruptured aneurysms were Grade I in 50% of cases, Grade III in 12.5%, and Grade IV in 37.5% of the cases according to the WFNS grading scale. The average size of the aneurysms was 3.5 mm, and ranged from 3 to 8 mm. One was fusiform and the others were saccular type of aneurysms. The aneurysm was located in fronto-polar artery in 53% of the cases, while in the callosomarginal artery in 47% of the cases. Multiple aneurysms were detected in 6 patients. There was no mortality due to surgery. CONCLUSION: Pericallosal artery aneurysms should have a better prognosis than the aneurysms located in the other parts of the circle of Willis. Complications are related to the patients" age. If possible, these aneurysms should always be clipped due to potential risk of bleeding and difficulty of embolization. PMID- 27476926 TI - Topical Application of Cyclosporine Reduces Epineurial Fibrosis: Gross Postsurgical, Histopathological and Ultrastructural Analysis in a Rat Sciatic Nerve Model. AB - AIM: To investigate the antiscarring potential of topical cyclosporine on rat sciatic nerves. MATERIAL AND METHODS: Both sciatic nerves were exposed in 24 adult male albino Wistar rats, and an abrasion injury was made on the biceps femoris close to the sciatic nerve. Cotton pads soaked with cyclosporine (5 mg/mL) and saline (0.9% NaCl) were placed around the nerves for 10 minutes in the experimental group and control group, respectively. All rats were sacrificed 8 weeks later and the sciatic nerves were examined. Epineural adhesions were assessed using light and electron microcopy. Quantitative histologic parameters, epineurial thickness, and scar density were evaluated in the histologic investigation. RESULTS: Significantly fewer epineurial adhesions were observed in the cyclosporine group in the postsurgical assessment, and the histopathologic and ultrastructural examination of the nerve segments than in the controls. The cyclosporine-treated animanls had a statistically significant reduction in the density and quantity of epineurial scarring compared with the controls. CONCLUSION: Topical cyclosporine effectively reduced epineurial scar formation on rat sciatic nerves. PMID- 27476927 TI - Neuroprotective Effects of Pregabalin Against Spinal Cord Ischemia-Reperfusion Injury in Rats. AB - AIM: To evaluate the effect of pregabalin pre-treatment on spinal cord ischemia reperfusion (I/R) injury and compare with methylprednisolone (MP). MATERIAL AND METHODS: Thirty-two rats were randomly divided into four groups as follow: Group 1 (sham)(n=8), group 2 (ischemia only)(n=8), group 3 (30 mg/kg pregabalin)(n=8), and group 4 (30 mg/kg methylprednisolone)(n=8). Laparotomy was performed without aortic clamp in the sham group. All animals were sacrificed 24 hours after surgery. The spinal cord tissue samples were harvested and caspase-3 activity, tumor necrosis factor-alpha (TNF-alpha) and Interleukin-1 Beta (IL-1beta) levels, catalase (CAT) activity, glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) levels malondialdehyde (MDA) levels and nitric oxide (NO) levels were analyzed to investigate the effects of different excitatory and inflammatory pathways in mechanism of I/R injury. Ultrastructural and histopathological examinations were carried out. Neurological recovery was measured by Basso, Beattie, Bresnahan (BBB) test and Inclined Plane Test. RESULTS: Decresead caspase 3 activity and decreased inflammatory markers like TNF-alpha, IL-1beta, and decresaed excitotatory pathways like CAT, GPx, MDA, NO and SOD were observed in both pregabalin pre-treatment and MP treatment groups. Pregabalin pre-treatment produced better ultrastructural results compared to MP treatment, as with histopathological examination. Pregabalin group showed better recovery compared to MP treament group according to BBB scoring system. CONCLUSION: Pregabalin pre treatmet and MP treatment both has neuroprotective effect on I/R injury by decreasing caspase dependant apoptosis, and inflammatory and oxidative stress markers. In addition, pregabalin pre-treatment had better clinical effects compared to MP treatment. PMID- 27476928 TI - Size-dependent concentrations of thermal vacancies in solid films. AB - Solid films are considered as typical model systems to study size effects on thermal vacancy concentration in nanomaterials. By combining the generalized Young-Laplace equation with the chemical potential of vacancies, a strict size dependent thermodynamic model of vacancies, which includes the surface intrinsic elastic parameters of the eigenstress, Young's modulus and the geometric size of the solid films, was established. The vacancy concentration changes in the film with respect to the bulk value, depending on the geometric size and surface stress sign of the solid films. Atomistic simulations of Au and Pt films verified the developed thermodynamic model. These results provide physical insights into the size-dependent thermal vacancy concentration in nanomaterials. PMID- 27476929 TI - Recent trends and patterns in HIV-1 transmitted drug resistance in the United Kingdom. AB - OBJECTIVES: Transmission of drug-resistant HIV-1 has decreased in the UK since the early 2000s. This analysis reports recent trends and characteristics of transmitted drug resistance (TDR) in the UK from 2010 to 2013. METHODS: Resistance tests conducted in antiretroviral treatment (ART)-naive individuals between 2010 and 2013 were analysed for the presence of transmitted drug resistance mutations (TDRMs), defined as any mutations from a modified 2009 World Health Organization surveillance list, or a modified 2013 International Antiviral Society-USA list for integrase tests. Logistic regression was used to examine associations between demographics and the prevalence of TDRMs. RESULTS: TDRMs were observed in 1223 (7.5%) of 16 425 individuals; prevalence declined from 8.1% in 2010 to 6.6% in 2013 (P = 0.02). The prevalence of TDRMs was higher among men who have sex with men (MSM) compared with heterosexual men and women (8.7% versus 6.4%, respectively) with a trend for decreasing TDRMs among MSM (P = 0.008) driven by a reduction in nucleoside reverse transcriptase inhibitor (NRTI) related mutations. The most frequently detected TDRMs were K103N (2.2%), T215 revertants (1.6%), M41L (0.9%) and L90M (0.7%). Predicted phenotypic resistance to first-line ART was highest to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) rilpivirine and efavirenz (6.2% and 3.4%, respectively) but minimal to NRTIs, including tenofovir, and protease inhibitors (PIs). No major integrase TDRMs were detected among 101 individuals tested while ART-naive. CONCLUSIONS: We observed a decrease in TDRMs in recent years. However, this was confined to the MSM population and rates remained stable in those with heterosexually acquired HIV infection. Resistance to currently recommended first line ART, including integrase inhibitors, remained reassuringly low. PMID- 27476931 TI - Where there's smoke, there's fire: Chimney stent grafts for hybrid repair of the aortic arch. PMID- 27476930 TI - Artificial miRNA-mediated silencing of ecdysone receptor (EcR) affects larval development and oogenesis in Helicoverpa armigera. AB - The insect pests are real threat to farmers as they affect the crop yield to a great extent. The use of chemical pesticides for insect pest control has always been a matter of concern as they pollute the environment and are also harmful for human health. Bt (Bacillus thuringensis) technology helped the farmers to get rid of the insect pests, but experienced a major drawback due to the evolution of insects gaining resistance towards these toxins. Hence, alternative strategies are high on demand to control insect pests. RNA-based gene silencing is emerging as a potential tool to tackle with this problem. In this study, we have shown the use of artificial microRNA (amiRNA) to specifically target the ecdysone receptor (EcR) gene of Helicoverpa armigera (cotton bollworm), which attacks several important crops like cotton, tomato chickpea, pigeon pea, etc and causes huge yield losses. Insect let-7a precursor miRNA (pre-miRNA) backbone was used to replace the native miRNA with that of amiRNA. The precursor backbone carrying the 21 nucleotide amiRNA sequence targeting HaEcR was cloned in bacterial L4440 vector for in vitro insect feeding experiments. Larvae fed with Escherichia coli expressing amiRNA-HaEcR showed a reduction in the expression of target gene as well as genes involved in the ecdysone signaling pathway downstream to EcR and exhibited mortality and developmental defects. Stem-loop RT-PCR revealed the presence of amiRNA in the insect larvae after feeding bacteria expressing amiRNA HaEcR, which was otherwise absent in controls. We also found a significant drop in the reproduction potential (oogenesis) of moths which emerged from treated larvae as compared to control. These results demonstrate the successful use of an insect pre-miRNA backbone to express amiRNA for gene silencing studies in insects. The method is cost effective and can be exploited as an efficient and alternative tool for insect pest management. PMID- 27476932 TI - Multi-layer ventilation inhomogeneity in cystic fibrosis. AB - Differences in regional lung function between the 3rd and 5th intercostal space (ICS) were explored in 10 cystic fibrosis (CF) patients and compared to 10 lung healthy controls by electrical impedance tomography (EIT). Regional ratios of impedance changes corresponding to the maximal volume of air exhaled within the first second of a forced expiration (DeltaIFEV1) and the forced vital capacity (DeltaIFVC) were determined. Regional airway obstruction and ventilation inhomogeneity were assessed by the frequency distribution of these ratios (DeltaIFEV1/DeltaIFVC) and an inhomogeneity index (GITI). The mean of the frequency distribution of DeltaIFEV1/DeltaIFVC and the GITI in both thorax planes were significantly different between CF patients and controls (p<0.001). CF patients exhibited a significantly lower mean of DeltaIFEV1/DeltaIFVC frequency distribution (p<0.05) and a significantly higher degree of ventilation inhomogeneity (p<0.01) in the 3rd ICS compared to the 5th ICS. Results indicated that EIT measurements at more cranial thorax planes may benefit the early diagnosis in CF. PMID- 27476933 TI - Analysis of the structure and surfactant activity of novel formulations containing exogenous pulmonary surfactant and glucocorticoids. AB - Exogenous pulmonary surfactant (EPS) could be used as carrier of glucocorticoids (GCs) in therapy for respiratory diseases. We formulated novel combination drug products containing bovine EPS and one GC (10wt%): beclomethasone (Be), budesonide (Bu) or fluticasone (Flu), and studied the GCs action on the surface activity and biophysical properties of EPS. Subtype ratio was evaluated by phospholipid determination; surface tension (ST) with a pulsating bubble surfactometer and conformational changes by Electron Spin Resonance (ESR). GCs were incorporated into EPS in more than 80%. None of them generated disaggregation of surfactant, only Bu was found in the light subtype. Bu and Be caused minimal changes in fluidity on polar region of bilayers, but these changes were not enough to inactivate the surfactant. Flu did not significantly alter any biophysical properties or surface activity. These novel combination EPS-GC products might be a promising strategy in the therapy of pulmonary diseases as the incorporation of the GCs tested did not cause detrimental effects on EPS functionality. PMID- 27476934 TI - Minocycline Attenuates Kidney Injury in a Rat Model of Streptozotocin-Induced Diabetic Nephropathy. AB - The effects of minocycline on the development of diabetic nephropathy (DN) in streptozotocin (STZ) induced diabetic rats were evaluated in this study. The diabetes rats with DN were induced by STZ (55 mg/kg) injection. The experiment included 5 groups 1) normal, 2) normal plus minocycline for 16 weeks, 3) DN plus vehicle, 4) DN plus minocycline 16 weeks and 5) DN plus minocycline for 8 weeks. The pathological changes were analyzed by hematoxylin and eosin (H&E) staining and the apoptotic cells were stained by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining. The mRNA expression of caspase-3, Bax and Bcl-2 in the kidney tissues was detected by quantitative RT-PCR. The biochemical parameters of blood and urine were determined by biochemical analyzer. Treatment with minocycline reduced the urine volume, 24-h urine protein, serum creatinine (Scr), blood urea nitrogen (BUN) but not blood alanine aminotransferase (ALT) in the DN rats. Furthermore, treatment with minocycline improved the pathological score of STZ-injured kidney and reduced the numbers of apoptotic cells in the kidney of DN rats. Moreover, minocycline mitigated the expression of caspase-3 and Bax mRNA, but increased Bcl 2 expression in the kidney of DN rats. These data indicated that minocycline improved the STZ-induced kidney damages, at least partially by protection form long-term hyperglycemia-induced kidney cell apoptosis. PMID- 27476935 TI - Novel Antitumor Invasive Actions of p-Cymene by Decreasing MMP-9/TIMP-1 Expression Ratio in Human Fibrosarcoma HT-1080 Cells. AB - p-Cymene (4-isopropyltoluene) has been reported to have beneficial actions such as anti-inflammatory and antinociceptive activities. To evaluate whether p-cymene exhibits antitumor invasive actions, we examined the effects of p-cymene on the production of matrix metalloproteinase 9 (MMP-9)/gelatinase B and tissue inhibitor of metalloproteinases-1 (TIMP-1) in human fibrosarcoma HT-1080 cells. p Cymene was found to dose-dependently inhibit the 12-O-tetradecanoylphorbol 13 acetate (TPA)-augmented production and gene expression of MMP-9 in HT-1080 cells. In contrast, p-cymene enhanced the TPA-augmented production and gene expression of TIMP-1 in HT-1080 cells. However, there was no change in the constitutive level of MMP-9 and TIMP-1 mRNAs and TIMP-1 protein in p-cymene-treated cells. In addition, we found that the in-vitro TPA-augmented invasiveness of HT-1080 cells was inhibited by p-cymene in a dose-dependent manner. Furthermore, p-cymene was found to suppress the constitutive and/or TPA-augmented phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) in HT-1080 cells. Thus, these results provide novel evidence that p cymene is an effective candidate for the prevention of tumor invasion and metastasis through mechanisms that include the inhibition of MMP-9 expression and the augmentation of TIMP-1 production along with the suppression of ERK1/2 and p38 MAPK signal pathways in tumor cells. PMID- 27476936 TI - Skin Transport of Hydrophilic Compound-Loaded PEGylated Lipid Nanocarriers: Comparative Study of Liposomes, Niosomes, and Solid Lipid Nanoparticles. AB - The effect of surface grafting with N-(carbonyl-methoxypolyethylene glycol-2000) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG2000-DSPE) onto three types of lipid nanocarriers, liposomes, niosomes and solid lipid nanoparticles (SLNs) on the skin penetration of sodium fluorescein (NaFI) was investigated. Confocal laser scanning microscopy (CLSM) was used to visualize the penetration pathways. Fourier transform infrared spectroscopy (FT-IR) was used to determine the skin hydration. The results showed that the physicochemical properties of each nanocarrier were modified after PEG grafting. In the skin penetration study, PEG grafting increased the flux of NaFI-loaded PEGylated liposomes and significantly decreased the flux of NaFI-loaded PEGylated niosomes and NaFI-loaded PEGylated SLNs. The skin deposition study and CLSM images showed that the intact liposome vesicles permeated into the skin. The niosomes and SLNs had little or no vesicles in the skin, suggesting that NaFI may have been released from these nanocarriers before permeation. Additionally, the fluorescent CLSM images of the SLNs showed that NaFI deposited along the length of hair follicles inside the skin, indicating that the skin penetration route may be through the transfollicular pathway. For the PEGylated nanocarriers, the PEGylated liposomes had higher fluorescence intensities than the non-PEGylated liposomes, indicating higher NaFI concentrations. The PEGylated niosomes and PEGylated SLNs had lower fluorescence intensities than those of the non-PEG modified niosomes and SLNs. For FT-IR results, PEGylated liposomes increased the skin hydration, while the grafting PEG onto niosomes and SLN surfaces decreased the skin hydration. This study showed that the surface grafting of PEG onto various nanocarriers affected the skin transport of NaFI. PMID- 27476937 TI - Promotion Effect of Apo-9'-fucoxanthinone from Sargassum muticum on Hair Growth via the Activation of Wnt/beta-Catenin and VEGF-R2. AB - This study was conducted to evaluate the effects of Sargassum muticum extract and apo-9'-fucoxanthinone, a principal component of S. muticum, on hair growth. When rat vibrissa follicles were treated with S. muticum extract for 21 d, the hair fiber lengths for the vibrissa follicles increased significantly. Treatment with the S. muticum extract and the EtOAc fraction of the S. muticum extract markedly increased the proliferation of dermal papilla cells (DPCs) and decreased the 5alpha-reductase activity. In addition, the EtOAc fraction of the S. muticum extract significantly promoted anagen initiation in C57BL/6 mice. Especially, apo 9'-fucoxanthinone, an active constituent from the S. muticum extract, caused an increase in DPC proliferation and a decrease in 5alpha-reductase activity. To elucidate the molecular mechanisms of apo-9'-fucoxanthinone on the proliferation of DPCs, we examined the level of various signaling proteins. Apo-9' fucoxanthinone increased the level of vascular endothelial growth factor receptor 2 (VEGF-R2), Wnt/beta-catenin signaling proteins such as phospho(ser9)-glycogen synthase kinase-3beta (GSK-3beta) and phospho(ser552)-beta-catenin, whereas apo 9'-fucoxanthinone did not affect the transforming growth factor-beta (TGF-beta) signaling proteins such as Smad2/3. These results suggest that apo-9' fucoxanthinone from S. muticum could have the potential for hair growth with DPC proliferation via the activation of Wnt/beta-catenin signaling and the VEGF-R2 pathway. PMID- 27476938 TI - Protective Effect of Ginsenoside Rg1 on Bleomycin-Induced Pulmonary Fibrosis in Rats: Involvement of Caveolin-1 and TGF-beta1 Signal Pathway. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and high mortality rate. Panax Notoginseng Saponins (PNS), extracted from Panax Notoginseng as a traditional Asian medicine, displayed a significant anti fibrosis effect in liver and lung. However, whether Ginsenoside Rg1 (Rg1), an important and active ingredient of PNS, exerts anti-fibrotic activity on IPF still remain unclear. In this study, we investigated the effect of Rg1 on bleomycin-induced pulmonary fibrosis in rats. Bleomycin (5 mg/kg body weight) was intratracheally administrated to male rats. Rg1 (18, 36 and 72 mg/kg) was orally administered on the next day after bleomycin. Lungs were harvested at day 7 and 28 for the further experiments. Histological analysis revealed that bleomycin successfully induced pulmonary fibrosis, and that Rg1 restored the histological alteration of bleomycin-induced pulmonary fibrosis (PF), significantly decreased lung coefficient, scores of alveolitis, scores of PF as well as contents of alpha smooth muscle actin (alpha-SMA) and hydroxyproline (Hyp) in a dose-dependent manner in PF rats. Moreover, Rg1 increased the expression levels of Caveolin-1 (Cav-1) mRNA and protein, lowered the expression of transforming growth factor beta1 (TGF-beta1) mRNA and protein in the lung tissues of PF rats. These data suggest that Rg1 exhibits protective effect against bleomycin-induced PF in rats, which is potentially associated with the down-regulation of TGF-beta1 and up regulation of Cav-1. PMID- 27476939 TI - Effect of Mechanical Agitation on Cationic Liposome Transport across an Unstirred Water Layer in Caco-2 Cells. AB - To develop an effective oral delivery system for plasmid DNA (pDNA) using cationic liposomes, it is necessary to clarify the characteristics of uptake and transport of cationic liposome/pDNA complexes into the intestinal epithelium. In particular, evaluation of the involvement of an unstirred water layer (UWL), which is a considerable permeability barrier, in cationic liposome transport is very important. Here, we investigated the effects of a UWL on the transfection efficiency of cationic liposome/pDNA complexes into a Caco-2 cell monolayer. When Caco-2 cells were transfected with cationic liposome/pDNA complexes in shaking cultures to reduce the thickness of the UWL, gene expression was significantly higher in Caco-2 cells compared with static cultures. We also found that this enhancement of gene expression by shaking was not attributable to activation of transcription factors such as activator protein-1 and nuclear factor-kappaB (NF kappaB). In addition, the increase in gene expression by mechanical agitation was observed at all charge ratios (1.5, 2.3, 3.1, 4.5) of cationic liposome/pDNA complexes. Transport experiments using Transwells demonstrated that mechanical agitation increased the uptake of cationic liposome/pDNA complexes by Caco-2 cells, whereas transport of the complexes across a Caco-2 cell monolayer did not occurr. Moreover, the augmentation of the gene expression of cationic liposome/pDNA complexes by shaking was observed in Madin-Darby canine kidney cells. These results indicate that a UWL greatly affects the uptake and transfection efficiency of cationic liposome/pDNA complexes into an epithelial monolayer in vitro. PMID- 27476940 TI - Lysosomal Trapping Is Present in Retinal Capillary Endothelial Cells: Insight into Its Influence on Cationic Drug Transport at the Inner Blood-Retinal Barrier. AB - Lysosomal trapping was investigated in the retinal capillary endothelial cells that are responsible for the inner blood-retinal barrier (BRB) using LysoTracker((r)) Red (LTR). Using confocal microscopy on TR-iBRB2 cells, an in vitro model of the inner BRB, the presence of lysosomal trapping in retinal capillary endothelial cells was suggested since TR-iBRB2 cells exhibited punctuate intracellular localization of LTR that was attenuated by NH4Cl treatment. The study confirmed that LTR uptake by retinal capillary endothelial cells took place in a time- and temperature-dependent manner, and exhibited the 1.58-fold greater uptake at pH 8.4 than that at pH 7.4 while there was no change in uptake between pH 6.4 and pH 7.4, suggesting that passive diffusion is not enough to explain LTR uptake. The inhibition study showed the possible influence of lysosomal trapping on cationic drug transport by retinal capillary endothelial cells since LTR uptake was significantly inhibited by cationic amphiphilic drugs. Inhibition profiling and the estimation of IC50 suggested the influence of lysosomal trapping on propranolol and low-affinity pyrilamine transport while lysosomal trapping had only a partial effect on verapamil, clonidine, nicotine and high-affinity pyrilamine transport in retinal capillary endothelial cells. PMID- 27476941 TI - Cargo-Free Nanoparticles Containing Cationic Lipids Induce Reactive Oxygen Species and Cell Death in HepG2 Cells. AB - Nanoparticles (NPs) containing cationic monovalent lipids such as 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP) and N-(1-[2,3-dioleyloxy]propyl)-N,N,N trimethylammonium chloride (DOTMA), have been widely used for the delivery of nucleic acid such as small-interfering RNA and polypeptide to cells as cancer therapies and vaccine development. Several previous reports have suggested that cationic liposomes induce reactive oxygen species (ROS) and ROS-mediated toxicity in cells. Here, we systematically investigated the effects of DOTAP- or DOTMA containing NPs without any cargo on the human carcinoma cells, HepG2. Treatment with NPs containing DOTAP or DOTMA increased the production of cellular ROS, such as H2O2 and lipid peroxidation, in HepG2 cells and concomitantly decreased cell viability. These effects were dependent on the lipid concentration, surface density of cationic lipids, and particle size of NPs. However, neutral NPs consisting of 1,2-dioleoyl-3-phosphocholine did not elicit the effective ROS generation or cell death regardless of the lipid concentration and particle size. The present study suggests that DOTAP- and DOTMA-NPs are able to induce cancer cell death through production of ROS in the absence of any therapeutic cancer reagents. These results also provide a rational background for the design of delivery systems using cationic lipid-based NP formulations. PMID- 27476942 TI - Immunotoxic Effect of Low-Dose Methylmercury Is Negligible in Mouse Models of Ovalbumin or Mite-Induced Th2 Allergy. AB - Methylmercury (MeHg) is one of the most toxic environmental pollutants and presents a serious hazard to health worldwide. Although the adverse effects of MeHg, including neurotoxicity, have been studied, its effects on immune function, in particular the immune response, remain unclear. This study examined the effects of low-dose MeHg on immune responses in mice. Mice were orally immunized with ovalbumin (OVA) or subcutaneously injected with mite extract to induce a T helper 2 (Th2) allergic response. They were then exposed to MeHg (0, 0.02, 1.0, or 5.0 mg.kg(-1).d(-1)). Immunization with oral OVA or subcutaneous mite extract increased serum levels of OVA-specific immunoglobulin (Ig) E (OVA-IgE), OVA-IgG1, interleukin (IL)-4, and IL-13, and total IgE, total IgG, and IL-13 when compared with levels in non-immunized mice. However, no interferon (IFN)-gamma was detected. By contrast, serum levels of OVA-IgE, OVA-IgG1, IL-4, and IL-13, or total IgE, total IgG, and IL-13 in Th2 allergy model mice subsequently treated with MeHg were no higher than those in MeHg-untreated mice. These results suggest that MeHg exposure has no adverse effects on Th2 immune responses in antigen immunized mice. PMID- 27476943 TI - In Vitro Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin. AB - Carvedilol is mainly metabolized in the liver to O-glucuronide (O-Glu). We previously found that the glucuronidation activity of racemic carvedilol in pooled human liver microsomes (HLM) was increased, R-selectively, in the presence of amiodarone. The aim of this study was to clarify the mechanisms for the enhancing effect of amiodarone on R- and S-carvedilol glucuronidation. We evaluated O-Glu formation of R- and S-carvedilol enantiomers in a reaction mixture of HLM including 0.2% bovine serum albumin (BSA). In the absence of amiodarone, glucuronidation activity of R- and S-carvedilol for 25 min was 0.026, and 0.51 pmol/min/mg protein, and that was increased by 6.15 and 1.60-fold in the presence of 50 uM amiodarone, respectively. On the other hand, in the absence of BSA, or when BSA was replaced with human serum albumin, no enhancing effect of amiodarone on glucuronidation activity was observed, suggesting that BSA played a role in the mechanisms for the enhancement of glucuronidation activity. Unbound fraction of S-carvedilol in the reaction mixture was greater than that of R carvedilol in the absence of amiodarone. Also, the addition of amiodarone caused a greater increase of unbound fraction of R-carvedilol than that of S-carvedilol. These results suggest that the altered protein binding by amiodarone is a key mechanism for R-selective stimulation of carvedilol glucuronidation. PMID- 27476944 TI - Differences in Esterase Activity to Aspirin and p-Nitrophenyl Acetate among Human Serum Albumin Preparations. AB - Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and also hydrolyzes some compounds at both sites. In the present study, we investigated differences in esterase activity among HSA preparations, and also the effects of warfarin, indomethacin, and naproxen on the hydrolytic activities of HSA to aspirin and p-nitrophenyl acetate. The esterase activities of HSA to aspirin or p-nitrophenyl acetate were measured from the pseudo-first-order formation rate constant (kobs) of salicylic acid or p-nitrophenol by HSA. Inter lot variations were observed in the esterase activities of HSA to aspirin and p nitrophenyl acetate; however, the esterase activity of HSA to aspirin did not correlate with that to p-nitrophenyl acetate. The inhibitory effects of warfarin and indomethacin on the esterase activity of HSA to aspirin were stronger than that of naproxen. In contrast, the inhibitory effect of naproxen on the esterase activity of HSA to p-nitrophenyl acetate was stronger than those of warfarin and indomethacin. These results suggest that the administration of different commercial HSA preparations and the co-administration with site I or II high affinity binding drugs may change the pharmacokinetic profiles of drugs that are hydrolyzed by HSA. PMID- 27476945 TI - Assessment of the Anti-anginal Effect of Tetramethylpyrazine Using Vasopressin Induced Angina Model Rats. AB - Intravenous tetramethylpyrazine has been widely used in China as a complementary and/or alternative medicine to treat patients with ischemic heart disease. We assessed the anti-anginal effect of tetramethylpyrazine (10 mg/kg, intravenously (i.v.), n=6) in comparison with that of its vehicle, saline (1 mL/kg, i.v., n=6), using vasopressin-induced angina model rats. First, Donryu rats were anesthetized with pentobarbital sodium (60 mg/kg, intraperitoneally (i.p.)), and the surface lead I electrocardiogram was continuously monitored. Administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram, indicating the onset of subendocardial ischemia. However, pretreatment with tetramethylpyrazine suppressed the vasopressin-induced depression of the S-wave level, which was not observed following pretreatment with its vehicle alone (saline), suggesting that tetramethylpyrazine ameliorated the vasopressin-induced subendocardial ischemia in vivo. These results may provide experimental evidence for the empirically known clinical efficacy of tetramethylpyrazine against ischemic heart disease, and could provide clues to better understanding its in vivo mechanism of action. PMID- 27476946 TI - A Comparative Study of Vasorelaxant Effects of ATP, ADP, and Adenosine on the Superior Mesenteric Artery of SHR. AB - We investigated superior mesenteric arteries from spontaneously hypertensive rats (SHR) to determine the relaxation responses induced by ATP, ADP, and adenosine and the relationship between the relaxant effects of these compounds and nitric oxide (NO) or cyclooxygenase (COX)-derived prostanoids. In rat superior mesenteric artery, relaxation induced by ATP and ADP but not by adenosine was completely eliminated by endothelial denudation. In the superior mesenteric arteries isolated from SHR [vs. age-matched control Wistar Kyoto rats (WKY)], a) ATP- and ADP-induced relaxations were weaker, whereas adenosine-induced relaxation was similar in both groups, b) ATP- and ADP-induced relaxations were substantially and partly reduced by N(G)-nitro-L-arginine [a NO synthase (NOS) inhibitor], respectively, c) indomethacin, an inhibitor of COX, increased ATP- and ADP-induced relaxations, d) ADP-induced relaxation was weaker under combined inhibition by NOS and COX, and e) adenosine-induced relaxation was not altered by treatment with these inhibitors. These data indicate that levels of responsiveness to these nucleotides/adenosine vary in the superior mesenteric arteries from SHR and WKY and are differentially modulated by NO and COX-derived prostanoids. PMID- 27476947 TI - Synthesis of 24,24-Difluoro-1,3-cis-25-dihydroxy-19-norvitamin D3 Derivatives and Evaluation of Their Vitamin D Receptor-Binding Affinity. AB - Two vitamin D3 derivatives, namely 24,24-difluoro-1beta,3beta,25-dihydroxy-19 norvitamin D3 (6a) and 24,24-difluoro-1alpha,3alpha,25-dihydroxy-19-norvitamin D3 (6b), were synthesized via a convergent route employing Julia-Kocienski olefination as a key step. Compounds 6a and b bound to vitamin D receptor (VDR) with IC50 values of 64.8 and 57.6 nM, respectively, exhibiting about 400- and 30 fold greater binding affinity than the corresponding non-fluorinated derivatives 5a and b. PMID- 27476948 TI - Cleavage of Target DNA Promotes Sequence Conversion with a Tailed Duplex. AB - Base sequence conversion in target DNA is achieved when a 5'-tailed duplex (TD) is introduced into cells. In this study, the effects of target DNA cleavage on sequence conversion with a TD were examined. Plasmid DNAs with and without cleavage near the target position were each introduced into HeLa cells, together with the TD. The cleavage promoted the sequence alteration efficiency by ca. 7 fold. These results suggested that the sequence conversion efficiency with the TD fragment is increased when an artificial nuclease introduces cleavage near the target site. PMID- 27476949 TI - Bioactive Compounds of Cold-pressed Thyme (Thymus vulgaris) Oil with Antioxidant and Antimicrobial Properties. AB - Herbs rich in bioactive phytochemicals were recognized to have biological activities and possess many health-promoting effects. In this work, cold-pressed thyme (Thymus vulgaris L.) oil (TO) was studied for its lipid classes, fatty acid profile, tocols and phenolics contents. Antioxidant activity and radical scavenging potential of TO against free radicals (DPPH(?) and galvinoxyl) was determined. Antimicrobial activity (AA) of TO against food borne bacteria, food spoilage fungi and dermatophyte fungi were also evaluated. Neutral lipids accounted for the main lipid fraction in TO, followed by glycolipids and phospholipids. The major fatty acids in TO were linoleic, oleic, stearic, and palmitic. gamma-Tocopherol (60.2% of total tocols) followed by alpha-tocotrienol (26.9%) and alpha-tocopherol (9.01% of total tocols) were the main tocols. TO contained high amounts of phenolic compounds (7.3 mg/g as GAE). TO had strong antiradical action wherein 65% of DPPH(?) radicals and 55% of galvinoxyl radical were quenched after 60 min of incubation. Rancimat assay showed that induction time (IT) for TO: sunflower oil blend (1:9, w/w) was 6.5 h, while TO: sunflower oil blend (2:8, w/w) recorded higher IT (9 h). TO inhibited the growth of all tested microorganisms. TO exhibited various degrees of AA against different food borne bacteria, food spoilage fungi and dermatophyte fungi, wherein the highest AA was recorded against dermatophyte fungi and yeasts including T. mentagrophytes (62 mm), T. rubrum (40 mm), and C. albicans (20 mm) followed by food spoilage fungi including A. flavus (32 mm) with minimal lethal concentrations (MLC) ranging between 80 to 320 MUg/mL. Furthermore, TO exhibited broad-spectra activity against food borne bacteria including S. aureus (30 mm), E. coli (25 mm) and L. Monocytogenes (20 mm) with MLC ranging between 160 to 320 MUg/mL. The results suggest that TO could be used economically as a valuable natural product with novel functional properties in food, cosmetics and pharmaceutical industries. PMID- 27476951 TI - Erratum to Palareti et al. "The SAME-TT2R2 score predicts the quality of anticoagulation control in patients with acute VTE. A real-life inception cohort study" (Thromb Haemost 2016; 115: 1101-1108). AB - [This corrects the article DOI: 10.1160/TH15-10-0830.]. PMID- 27476950 TI - Effects of neratinib and combination with irradiation and chemotherapy in head and neck cancer cells. AB - OBJECTIVE: Prognosis of patients with head and neck squamous cell carcinoma (HNSCC) is still poor. Novel therapeutic approaches are of great interest to improve the effects of radiochemotherapy. We evaluated the effects of tyrosine kinase inhibitor neratinib on HNSCC cell lines CAL27, SCC25 and FaDu as a single agent and in combination with irradiation and chemotherapy. METHODS: Effects of neratinib were evaluated in HNSCC cell lines CAL27, SCC25 and FaDu. Effect on cell viability of neratinib and combination with cisplatin and irradiation was measured using CCK-8 assays and clonogenic assays. Western blot analysis was performed to distinguish the effect on epithelial growth factor receptor and HER2 expression. Apoptosis was evaluated by flow cytometry analysis. RESULTS: Growth inhibition was achieved in all cell lines, whereas combination of cisplatin and neratinib showed greater inhibition than each agent alone. Apoptosis was induced in all cell lines. Combination of neratinib with irradiation or cisplatin showed significantly increased apoptosis. In clonogenic assays, significant growth inhibition was observed in all investigated cell lines. CONCLUSION: Neratinib, as a single agent or in combination with chemo-irradiation, may be a promising treatment option for patients with head and neck cancer. PMID- 27476953 TI - The effect of physicochemical factors on the self-association of HMGB1: A surface plasmon resonance study. AB - HMGB1 triggers proinflammatory reactions by interacting extracellularly with various receptors. HMGB1 also acts in the nucleus by interacting with DNA and controlling DNA transcription, a process which involves its self-association. The self-association of HMGB1 was characterized using surface plasmon resonance (SPR). A dimer/tetramer binding model was developed that provided a good fit to the SPR sensorgrams and enabled the kinetics of self-association of different HMGB1 oligomers to be evaluated under a variety of physicochemical conditions. The formation of HMGB1 tetramers, and not dimers, was strongly influenced by ionic strength. HMGB1 self-association increased as the pH was decreased from 7.4 to 4.8 but was abolished at pH4.0, suggesting the involvement of acidic amino acids of HMGB1 in its self-association. HMGB1 dimers were found to predominate in the absence of zinc, but addition of zinc promoted the formation of HMGB1 tetramers. More reducing conditions favored dimerization but diminished tetramer formation. In contrast, oxidizing conditions favored tetramer formation. Physicochemical factors modulate the extent of self-association of HMGB1. We speculate that HMGB1 dimers may preferentially bind DNA, whereas HMGB1 tetramers may promote inflammatory responses by binding to RAGE and TLRs. The self association of HMGB1, regulated by variations of physicochemical factors, may influence its roles in DNA rearrangement and regulation of pathophysiological diseases. PMID- 27476954 TI - Cobalt-Catalyzed C(sp(2))-H Borylation: Mechanistic Insights Inspire Catalyst Design. AB - A comprehensive study into the mechanism of bis(phosphino)pyridine (PNP) cobalt catalyzed C-H borylation of 2,6-lutidine using B2Pin2 (Pin = pinacolate) has been conducted. The experimentally observed rate law, deuterium kinetic isotope effects, and identification of the catalyst resting state support turnover limiting C-H activation from a fully characterized cobalt(I) boryl intermediate. Monitoring the catalytic reaction as a function of time revealed that borylation of the 4-position of the pincer in the cobalt catalyst was faster than arene borylation. Cyclic voltammetry established the electron withdrawing influence of 4-BPin, which slows the rate of C-H oxidative addition and hence overall catalytic turnover. This mechanistic insight inspired the next generation of 4 substituted PNP cobalt catalysts with electron donating and sterically blocking methyl and pyrrolidinyl substituents that exhibited increased activity for the C H borylation of unactivated arenes. The rationally designed catalysts promote effective turnover with stoichiometric quantities of arene substrate and B2Pin2. Kinetic studies on the improved catalyst, 4-(H)2BPin, established a change in turnover limiting step from C-H oxidative addition to C-B reductive elimination. The iridium congener of the optimized cobalt catalyst, 6-(H)2BPin, was prepared and crystallographically characterized and proved inactive for C-H borylation, a result of the high kinetic barrier for reductive elimination from octahedral Ir(III) complexes. PMID- 27476955 TI - Regulation of plasma agouti-related protein and its relationship with hunger in lean and obese men. AB - Agouti-related protein (AgRP) is an orexigenic (appetite stimulating) neuropeptide suggested to exert tonic control over long-term energy balance. While some have speculated AgRP is not involved in the episodic (i.e. meal to meal energy intake) control, acute decreases in plasma agouti-related protein (AgRP) following a meal have been observed in humans in a role consistent with episodic control for AgRP. Whether changes in plasma AgRP are associated with episodic, and/or tonic changes in appetite has yet to be directly examined. The present study examined the relationship between agouti-related protein (AgRP), leptin and the regulation of appetite following a 48-h fast and an acute meal challenge. Blood samples were obtained from young lean and obese men before and after a 48 h fast (lean n = 10; obese n = 7). Fasting resulted in an increase in AgRP and a decrease in leptin with these changes being greater in lean than obese. In addition, blood samples were obtained from lean men before and 1, 2, 3 and 4 h after a meal (n = 8). Following a meal, AgRP was reduced from 2 to 4 h, a change that was dissociated from both leptin and subjective measures of hunger and satiety. These results demonstrate that AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin. PMID- 27476956 TI - Free Energy Calculations by the Molecular Mechanics Poisson-Boltzmann Surface Area Method. AB - Detailed knowledge of how molecules recognize interaction partners and of the conformational preferences of biomacromolecules is pivotal for understanding biochemical processes. Such knowledge also provides the foundation for the design of novel molecules, as undertaken in pharmaceutical research. Computer-based free energy calculations enable a detailed investigation of the energetic factors that are responsible for molecular stability or binding affinity. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach is an efficient method for the calculation of free energies of diverse molecular systems. Here we describe the concepts of this approach and outline the practical proceeding. Furthermore we give an overview of the wide spectrum of problems that have been addressed with this method and of successful analyses carried out, thereby focussing on ambitious and recent studies. Limits of the approach in terms of accuracy and applicability are discussed. Despite these limitations MM-PBSA is a method with great potential that allows comparative free energy analyses for various molecular systems at low computational cost. PMID- 27476957 TI - From Molecular Docking to 3D-Quantitative Structure-Activity Relationships (3D QSAR): Insights into the Binding Mode of 5-Lipoxygenase Inhibitors. AB - Pharmacological intervention with 5-Lipoxygenase (5-LO) is a promising strategy for treatment of inflammatory and allergic ailments, including asthma. With the aim of developing predictive models of 5-LO affinity and gaining insights into the molecular basis of ligand-target interaction, we herein describe QSAR studies of 59 diverse nonredox-competitive 5-LO inhibitors based on the use of molecular shape descriptors and docking experiments. These studies have successfully yielded a predictive model able to explain much of the variance in the activity of the training set compounds while predicting satisfactorily the 5-LO inhibitory activity of an external test set of compounds. The inspection of the selected variables in the QSAR equation unveils the importance of specific interactions which are observed from docking experiments. Collectively, these results may be used to design novel potent and selective nonredox 5-LO inhibitors. PMID- 27476958 TI - Automatic Perception of Chemical Similarities Between Metabolic Pathways. AB - Metabolic pathways are at the crossroad between the chemical world of small molecules and the biological world of enzymes, genes and regulation. Methods for their processing are therefore required for a great variety of applications. The work presented here reports a new method to encode metabolic pathways and reactomes of organisms based on the MOLMAP approach. Pathways are represented from features of the metabolites involved in their reactions enabling to automatically perceive chemical similarities, and making no use of EC numbers. MOLMAP descriptors are based on atomic topological and physicochemical features of the bonds involved in reactions. The results show that self-organizing maps (SOM) can be trained with MOLMAPs of pathways to automatically recognize similarities between pathways of the same type of metabolism. The study also illustrates the possibility of applying the MOLMAP methodology at progressively higher levels of complexity, bridging chemical and biological information, and going all the way from atomic properties to the classification of organisms. PMID- 27476959 TI - Comparing Measures of Promiscuity and Exploring Their Relationship to Toxicity. AB - Recent research has focused on algorithms to derive numerical measures of selectivity based on panels of in vitro pharmacology assays so that one molecule's activity profile may be compared easily with that of another. However, the questions concerning which method or algorithm is best to use, the optimal number of assays required to give an accurate measure of selectivity and the correlation of these measures to in vivo toxicity have remained largely unexplored. In this manuscript we describe a systematic approach to compare and contrast different calculation methods for promiscuity and determine the optimal number and constitution of a panel of assays to measure the selectivity/promiscuity of compounds across all targets. We then go on to examine their relationship to toxicity using a Pfizer proprietary compound set that has both selectivity profiles and exploratory toxicology study results. From this study we conclude that all five methods studied are useful in estimating compound selectivity; that a small panel of between 15 to 30 binding assays can be used as a surrogate for a broader panel enabling higher throughput with lower costs and this panel will most likely have the highest prediction power when correlating this measure to in vivo effects. PMID- 27476960 TI - A New Method for Mapping the Molecular Surface of a Protein Structure Using a Spherical Self-Organizing Map. AB - A spherical self-organizing map (SSOM) was applied for mapping the molecular surface of a protein structure on a spherical structure. The active site of the X ray crystal structure of beta2 receptor protein was used for this purpose. After mapping the molecular surface points and assigning the associated molecular electrostatic potential (MEP) values, the original 3D structure of the active site was well reproduced by the SSOM. In order to validate the geometrical transformation and the resulting MEP distribution, the molecular surfaces of twenty beta2 ligands were mapped on the established SSOM sphere. The MEP values of two spheres derived from the ligand and the beta2 receptor protein were compared. In almost all cases of strong ligands, the two spheres had a moderate negative correlation. PMID- 27476961 TI - Identification of Novel Nitrosative Stress Inhibitors through Virtual Screening and Experimental Evaluation. AB - Nitrosative and oxidative stress, associated with the generation of excessive reactive nitrogen and oxygen radical species respectively, are thought to contribute to protein misfolding diseases which represent a group of neurodegenerative disorders that are characterized by protein aggregation and plaque formation. Curcumin, a polyphenolic compound, possesses diverse anti inflammatory, antitumor, and antioxidant properties. Several studies have revealed that curcumin can reduce the oxidative/nitrosative stress and thereby decrease the neuronal attrition. However, curcumin has poor bioavailability and has raised several concerns focused on its limited clinical impact. The aim of this study was to find other compounds which can assist in decreasing nitrosative stress and possess enhanced bioavailability. Here, use of beta-lactoglobulin was examined as a vehicle to transport molecules to the gut. The Zinc database was searched using curcumin as reference and 6457 compounds were selected for the study. These compounds were docked to beta-lactoglobulin using Glide to find the best fit ligands. Our studies identified four compounds that bind to beta lactoglobulin and scavenge NOx (free radicals) efficiently. PMID- 27476962 TI - Benchmarking Variable Selection in QSAR. AB - Variable selection is important in QSAR modeling since it can improve model performance and transparency, as well as reduce the computational cost of model fitting and predictions. Which variable selection methods that perform well in QSAR settings is largely unknown. To address this question we, in a total of 1728 benchmarking experiments, rigorously investigated how eight variable selection methods affect the predictive performance and transparency of random forest models fitted to seven QSAR datasets covering different endpoints, descriptors sets, types of response variables, and number of chemical compounds. The results show that univariate variable selection methods are suboptimal and that the number of variables in the benchmarked datasets can be reduced with about 60 % without significant loss in model performance when using multivariate adaptive regression splines MARS and forward selection. PMID- 27476963 TI - QSPR Study of Valproic Acid and Its Functionalized Derivatives. AB - This work establishes a Quantitative Structure-Property Relationships (QSPR) based analysis with the aim of interpreting both the structural and electronic properties of the polar region of valproic acid and its derivatives, in terms of stabilizing intramolecular interactions related to the involved substituents. We consider ten different calculated properties as dependent variables for the QSPR models: the bond lengths C8 ?O9 , C8 ?X10 , and the percentage of s-character of the natural hybrids forming the bonding sigma orbitals of the O9 ?C8 ?X10 region. The representative descriptors are the charges transferred during donor/acceptor interactions around this function calculated at the B3LYP/6-311++G**(6d,10f) level of theory, and/or hybrid descriptors derived therefrom. The models so established result simple, predictive, and have a quite direct physical meaning. PMID- 27476964 TI - Older Driver Safety: A Survey of Psychologists' Attitudes, Knowledge, and Practices. AB - Using an online survey, we examined the knowledge, attitudes, and practices with respect to older driver safety concerns of clinical psychologists from across Canada who self-identified as working with at least some drivers over 60 years of age. Eighty-four psychologists completed the survey, and many were aware of the issues relevant to older driver safety, although only about half reported that assessing fitness to drive was an important issue in their practice. The majority (75%) reported that they would benefit from education concerning evaluation of fitness to drive. The primary recommendation emerging from this investigation is to increase efforts to inform and educate psychologists about driving-related assessment and regulatory issues in general, and specifically with respect to older adults. As the population ages, it is of growing importance for all health care providers to understand the influence of mental health conditions-including cognitive impairment and dementia-on driving skills. PMID- 27476965 TI - Epigenetic Variation between Human Induced Pluripotent Stem Cell Lines Is an Indicator of Differentiation Capacity. AB - Variation in the differentiation capacity of induced pluripotent stem cells (iPSCs) to specific lineages is a significant concern for their use in clinical applications and disease modeling. To identify factors that affect differentiation capacity, we performed integration analyses between hematopoietic differentiation performance and molecular signatures such as gene expression, DNA methylation, and chromatin status, using 35 human iPSC lines and four ESC lines. Our analyses revealed that hematopoietic commitment of PSCs to hematopoietic precursors correlates with IGF2 expression level, which in turn depends on signaling-dependent chromatin accessibility at mesendodermal genes. Maturation capacity for conversion of PSC-derived hematopoietic precursors to mature blood associates with the amount and pattern of DNA methylation acquired during reprogramming. Our study therefore provides insight into the molecular features that determine the differential capacities seen among human iPSC lines and, through the predictive potential of this information, highlights a way to select optimal iPSCs for clinical applications. PMID- 27476966 TI - Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. AB - Recent advances in 3D culture systems have led to the generation of brain organoids that resemble different human brain regions; however, a 3D organoid model of the midbrain containing functional midbrain dopaminergic (mDA) neurons has not been reported. We developed a method to differentiate human pluripotent stem cells into a large multicellular organoid-like structure that contains distinct layers of neuronal cells expressing characteristic markers of human midbrain. Importantly, we detected electrically active and functionally mature mDA neurons and dopamine production in our 3D midbrain-like organoids (MLOs). In contrast to human mDA neurons generated using 2D methods or MLOs generated from mouse embryonic stem cells, our human MLOs produced neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues. Thus our MLOs bearing features of the human midbrain may provide a tractable in vitro system to study the human midbrain and its related diseases. PMID- 27476968 TI - miRNA-29a targets COL3A1 to regulate the level of type III collagen in pig. AB - COL3A1 encodes the protein, collagen type III alpha 1, which is an important component of collagen. Collagen can have a considerable effect on the processing quality of meat, and is nutritious. Bioinformatic analysis using Targetscan showed that COL3A1 could be a target gene of miRNA-29a. Moreover, we found that Laiwu pigs have higher levels of type III collagen and lower levels of miRNA-29a than Landrace pigs. Therefore, we hypothesized that miRNA-29a suppresses the expression of COL3A1 by targeting its 3'-UTR. miRNA-29a appears to play an inhibitory role in the regulation of COL3A1 in PK15 cells because of the following: (1) overexpression of miRNA-29a resulted in a significant down regulation of COL3A1 protein levels (2) overexpression of miRNA-29a significantly decreased the level of COL3A1 mRNA. (3) The activity of a COL3A1 luciferase reporter was significant reduced by miRNA-29a. Furthermore, the levels of miRNA 29a and collagen type III in four tissues in Laiwu and Landrace pigs were consistent with the above observations. In this study, we identified COL3A1 as a direct target for miRNA-29a, which will inform further studies of meat quality. PMID- 27476967 TI - Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis. AB - The genome-wide localization and function of endogenous Dnmt3a and Dnmt3b in adult stem cells are unknown. Here, we show that in human epidermal stem cells, the two proteins bind in a histone H3K36me3-dependent manner to the most active enhancers and are required to produce their associated enhancer RNAs. Both proteins prefer super-enhancers associated to genes that either define the ectodermal lineage or establish the stem cell and differentiated states. However, Dnmt3a and Dnmt3b differ in their mechanisms of enhancer regulation: Dnmt3a associates with p63 to maintain high levels of DNA hydroxymethylation at the center of enhancers in a Tet2-dependent manner, whereas Dnmt3b promotes DNA methylation along the body of the enhancer. Depletion of either protein inactivates their target enhancers and profoundly affects epidermal stem cell function. Altogether, we reveal novel functions for Dnmt3a and Dnmt3b at enhancers that could contribute to their roles in disease and tumorigenesis. PMID- 27476969 TI - Therapeutic effect of spermatogonial stem cell on testicular damage caused by lead in rats. AB - OBJECTIVE: To investigate the possible therapeutic effect of spermatogonial stem cells (SSCs) on lead-induced apoptosis and consequently infertility in adult male rats. MATERIALS AND METHODS: Sixty-six Sprague Dawley adult male rats were divided into three groups: control group, lead (Pb) acetate exposed group received (20mg Pb/kg) for 3weeks, and SSCs treated group. Each group included twenty-two rats. Serum testosterone level, 3 beta-hydroxysteroid dehydrogenase (3beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17beta-HSD), proliferating cell nuclear antigen (PCNA) genes expression by RT-PCR, caspase 3 expression by immunohistochemistry and testicular histological findings were tested. RESULTS: Pb acetate exposed rats showed a significant decrease in the epididymal sperm count, motility, viability, serum testosterone level and testicular expression of 3beta-HSD, 17beta-HSD and PCNA compared to the control group, while treatment with SSCs attenuated Pb acetate induced decrease for these variables. Moreover, the increasing apoptosis of germinal cells as well as the high expression of caspase-3 induced by Pb acetate was reduced by SSCs treatment. CONCLUSION: SSCs exhibited therapeutic effect on reproductive system by inhibiting Pb-induced excessive cell apoptosis. PMID- 27476970 TI - Increased betaTrCP are associated with imiquimod-induced psoriasis-like skin inflammation in mice via NF-kappaB signaling pathway. AB - Psoriasis is a common inflammatory skin disease characterized by T cell-mediated hyperproliferation of keratinocytes, increased angiogenesis and inflammation. Accumulating evidence suggests that some keratinocyte differentiation events are controlled by the ubiquitin/proteasome system. beta-transducin repeat-containing protein (betaTrCP) serve as substrate recognition component of E3 ubiquitin ligases that control stability of important regulators of signal transduction including the nuclear factor (NF)-kappaB signaling, a key regulatory element in inflammatory pathways related to psoriasis, suggesting a potential role of betaTrCP in psoriasis pathogenesis. However, no published study has investigated the role of betaTrCP in the etiology of psoriasis. Here, we combined an in vitro cell model of tumor necrosis factor (TNF)-alpha-induced keratinocyte inflammation and an animal model of imiquimod (IMQ)-induced psoriasis-like inflammation to investigate the pathogenic mechanisms in psoriasis-like dermatitis and assess its betaTrCP/NF-kappaB dependency. Daily application of IMQ on mouse back skin induced inflamed scaly skin lesions resembling plaque type psoriasis. These lesions were associated with elevated betaTrCP levels, reduced inhibitor kappaB (IkappaB), and enhanced NF-kappaB activation in epidermal tissues. Furthermore, betaTrCP knockdown via siRNA in in TNF-alpha-stimulated HaCaT and normal human epidermal keratinocytes (NHEK) cells significantly inhibited the over-activation of NF-kappaB and expression of intercellular adhesion molecule 1 (ICAM-1), demonstrating a pivotal role of betaTrCP in regulation the TNF-alpha-activated NF kappaB inflammatory pathways. Moreover, downregulation of betaTrCP through lentiviral shRNA ameliorates IMQ-induced psoriasis-like skin lesions in vivo. In conclusion, betaTrCP is involved in the NF-kappaB signaling mediated-, psoriasis related inflammation and represent a novel target for developing agents to treat psoriasis. PMID- 27476971 TI - Identification and expression analysis of cellular and viral microRNAs in CyHV3 infected KCF-1 cells. AB - MicroRNAs (miRNAs) are small non-coding RNAs with approximately 22 nucleotides (nt) that are encoded by a diverse range of metazoan eukaryotes, plants and viruses. CyHV-3 (cyprinid herpesvirus-3) is a member of the Alloherpesviridae virus family and has caused severe economic losses for the common carp and koi carp fishery industries. In this study, a total of 15,987,652 clean reads were generated from a cDNA library of CyHV-3-infected KCF-1 (koi caudal fin) cells using high-throughput sequencing technology. Following annotation and secondary structure prediction, 28 miRNAs were identified as novel candidate miRNAs encoded by common carp (Cyprinus carpio), and seven miRNAs were shown to be encoded by CyHV-3. Next, 19 host miRNAs and seven viral miRNAs were validated by stem-loop real-time PCR. Northern blot analysis confirmed the presence of 14 host miRNAs and five CyHV-3-encoded novel miRNAs. The results of this study expand the knowledge of common carp and CyHV-3 microRNAs and provide a useful theoretical foundation for further study of CyHV-3. PMID- 27476972 TI - Msh2 deficiency leads to dysmyelination of the corpus callosum, impaired locomotion, and altered sensory function in mice. AB - A feature in patients with constitutional DNA-mismatch repair deficiency is agenesis of the corpus callosum, the cause of which has not been established. Here we report a previously unrecognized consequence of deficiency in MSH2, a protein known primarily for its function in correcting nucleotide mismatches or insertions and deletions in duplex DNA caused by errors in DNA replication or recombination. We documented that Msh2 deficiency causes dysmyelination of the axonal projections in the corpus callosum. Evoked action potentials in the myelinated corpus callosum projections of Msh2-null mice were smaller than wild type mice, whereas unmyelinated axons showed no difference. Msh2-null mice were also impaired in locomotive activity and had an abnormal response to heat. These findings reveal a novel pathogenic consequence of MSH2 deficiency, providing a new mechanistic hint to previously recognized neurological disorders in patients with inherited DNA-mismatch repair deficiency. PMID- 27476974 TI - Racial disparities in melanoma survival. AB - BACKGROUND: Melanoma is a cutaneous malignancy common in the white population but can also occur in other racial groups. OBJECTIVE: We sought to evaluate survival across racial groups in patients given a diagnosis of malignant melanoma. METHODS: The Surveillance, Epidemiology, and End Results database was used to populate a cohort of 96,953 patients given a diagnosis of cutaneous melanoma as their primary cancer, from 1992 to 2009. RESULTS: White patients had the longest survival time (P < .05), followed by Hispanic (P < .05), Asian American/Native American/Pacific Islander (P < .05), and black (P < .05) patients, respectively. Survival stratified by race and stage showed that for stages I and III, blacks had a significantly lower survival (P < .05), and increased hazard ratios (stage I hazard ratio, 3.037 [95% confidence interval, 2.335-3.951]; stage III hazard ratio, 1.864 [95% confidence interval, 1.211-2.87]). The proportion of later stage cutaneous melanoma (stages II-IV) was greater in blacks compared with whites. CONCLUSION: Despite higher incidence of cutaneous melanoma in whites, overall survival for cutaneous melanoma in non-whites was significantly lower. Our results suggest that more emphasis is needed for melanoma screening and awareness in non-white populations to improve survival outcomes. PMID- 27476973 TI - Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naive patients with psoriasis. AB - BACKGROUND: To our knowledge, no clinical trials directly compare apremilast with methotrexate (the standard of care for initial systemic treatment of psoriasis). OBJECTIVE: We sought to compare apremilast's relative efficacy with that of methotrexate for moderate to severe psoriasis. METHODS: An anchor-based indirect comparison was conducted for 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) rates for systemic-naive patients from Efficacy and Safety Trial Evaluating the Effects of apreMilast in psoriasis (ESTEEM) 1 and 2 (apremilast vs placebo) and Comparative study of HumirA vs. Methotrexate vs Placebo In psOriasis patieNts (CHAMPION) (adalimumab vs methotrexate vs placebo) trials. The difference-in-difference in PASI 75 response rates was calculated as the difference between the ESTEEM apremilast and placebo rates and the CHAMPION methotrexate versus placebo rates. Number needed to treat and incremental drug cost per responder were also estimated. RESULTS: No statistically significant difference was found between apremilast and methotrexate in PASI 75 (risk difference 13.1%; 95% confidence interval -1.8% to 28.0%; P = .09). Number needed to treat with apremilast versus methotrexate to gain 1 additional PASI 75 responder was 7.6. Annual incremental drug cost of this responder was estimated at $187,888.33. LIMITATIONS: Few trials compare systemic naive patients. Only direct medication costs were considered. CONCLUSIONS: There was no statistical evidence of greater efficacy for apremilast versus methotrexate. The $187,888 incremental cost per PASI 75 may exceed what payers are willing to pay. PMID- 27476975 TI - Circadian Rhythm Disruption Promotes Lung Tumorigenesis. AB - Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. PMID- 27476976 TI - alpha-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells. AB - Pluripotent stem cells (PSCs) can self-renew or differentiate from naive or more differentiated, primed, pluripotent states established by specific culture conditions. Increased intracellular alpha-ketoglutarate (alphaKG) was shown to favor self-renewal in naive mouse embryonic stem cells (mESCs). The effect of alphaKG or alphaKG/succinate levels on differentiation from primed human PSCs (hPSCs) or mouse epiblast stem cells (EpiSCs) remains unknown. We examined primed hPSCs and EpiSCs and show that increased alphaKG or alphaKG-to-succinate ratios accelerate, and elevated succinate levels delay, primed PSC differentiation. alphaKG has been shown to inhibit the mitochondrial ATP synthase and to regulate epigenome-modifying dioxygenase enzymes. Mitochondrial uncoupling did not impede alphaKG-accelerated primed PSC differentiation. Instead, alphaKG induced, and succinate impaired, global histone and DNA demethylation in primed PSCs. The data support alphaKG promotion of self-renewal or differentiation depending on the pluripotent state. PMID- 27476977 TI - Psat1-Dependent Fluctuations in alpha-Ketoglutarate Affect the Timing of ESC Differentiation. AB - Embryonic stem cells (ESCs) undergo coordinated epigenetic and metabolic changes to differentiate properly. However, the precise mechanisms by which these alterations are fine-tuned in the early stages of differentiation have not been identified. In this study, we demonstrate that phosphoserine aminotransferase 1 (Psat1), an Oct4/Sox2/Nanog (OSN) target protein, regulates changes in alpha ketoglutarate (alpha-KG), determining the fate of mouse ESCs (mESCs). Maintaining Psat1 levels was essential for mESC self-renewal and pluripotency. Moderate knockdown (KD) of Psat1 in mESCs lowered DNA 5'-hydroxymethylcytosine (5'-hmC) and increased histone methylation levels by downregulating permissive amounts of alpha-KG, ultimately accelerating differentiation. We found that intracellular alpha-KG declined transiently during differentiation and that its dysregulation by treatment with dimethyl-alpha-KG impeded differentiation. Further, by in vivo teratoma formation assay, pluripotency of Psat1 KD mESCs was impaired, especially into the ectodermal lineage. Thus, we have established how Psat1 is regulated in maintaining intracellular alpha-KG levels and determining the fate of mESCs. PMID- 27476978 TI - Nucleases from Prevotella intermedia can degrade neutrophil extracellular traps. AB - Periodontitis is an inflammatory disease caused by periodontal bacteria in subgingival plaque. These bacteria are able to colonize the periodontal region by evading the host immune response. Neutrophils, the host's first line of defense against infection, use various strategies to kill invading pathogens, including neutrophil extracellular traps (NETs). These are extracellular net-like fibers comprising DNA and antimicrobial components such as histones, LL-37, defensins, myeloperoxidase, and neutrophil elastase from neutrophils that disarm and kill bacteria extracellularly. Bacterial nuclease degrades the NETs to escape NET killing. It has now been shown that extracellular nucleases enable bacteria to evade this host antimicrobial mechanism, leading to increased pathogenicity. Here, we compared the DNA degradation activity of major Gram-negative periodontopathogenic bacteria, Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. We found that Pr. intermedia showed the highest DNA degradation activity. A genome search of Pr. intermedia revealed the presence of two genes, nucA and nucD, putatively encoding secreted nucleases, although their enzymatic and biological activities are unknown. We cloned nucA- and nucD-encoding nucleases from Pr. intermedia ATCC 25611 and characterized their gene products. Recombinant NucA and NucD digested DNA and RNA, which required both Mg2+ and Ca2+ for optimal activity. In addition, NucA and NucD were able to degrade the DNA matrix comprising NETs. PMID- 27476979 TI - Patient population with multiple myeloma and transitions across different lines of therapy in the USA: an epidemiologic model. AB - PURPOSE: Multiple myeloma (MM) is a progressive, malignant neoplasia with a worldwide, age-standardized annual incidence of 1.5 per 100 000 individuals and 5 year prevalence around 230 000 patients. Main favorable prognostic factors are younger age, low/standard cytogenetic risk, and undergoing stem cell transplantation. Our aim was to estimate the size of the patient population with MM eligible to receive a new MM therapy at different lines of therapy in the USA. METHODS: We constructed a compartmental, differential equation model representing the flow of MM patients from diagnosis to death, via two possible treatment pathways and distinguished in four groups based on prognostic factors. Parameters were obtained from published references, available statistics, and assumptions. The model was used to estimate number of diagnosed MM patients and number of patient transitions from one line of therapy to the next over 1 year. Model output included 95% credible intervals from probabilistic sensitivity analyses. RESULTS: The base-case estimates were 80 219 patients living with MM, including 70 375 on treatment, 780 symptomatic untreated patients, and 9064 asymptomatic untreated patients. Over a 1-year period, the number of MM patients on treatment line 1 was estimated at 23 629 (credible intervals 22 236-25 029), and the number of transitions from treatment line 1 to treatment line 2 was estimated at 14 423. CONCLUSIONS: The size of the patient population with MM on different lines of therapy and in patient subgroups of interest estimated from this epidemiologic model can be used to assess the number of patients who could benefit from new MM therapies and their corresponding budgetary impact. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476980 TI - Psychotropic drugs and risk of burn injury in individuals with mental illness: a 10-year population-based case-control study. AB - PURPOSE: We aimed to investigate the association between psychotropic treatment and risk of burn injury in individuals with mental illness. METHODS: A nested case-control study was conducted by using the National Health Insurance Research Database in Taiwan. A total of 3187 cases with burn injury under International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 940-949 and 19 122 matched controls were identified from 2003 to 2012. Four kinds of psychotropic agents (antipsychotics (APs), antidepressants (ADs), benzodiazepines, and z-drugs) were examined. Psychotropic exposure status was measured, and a set of potential confounding factors was adjusted in the analyses. Conditional logistic regressions were applied to determine the effect of psychotropic use on burn injury. RESULTS: A significant increased risk of burn injury was observed among psychotropic users compared with non-users (adjusted odds ratio (AOR) = 1.45, 95%CI = 1.31-1.61). When classifying psychotropic users into current, new, continuous, and past users, a significant elevated risk of burn injury was found across all groups (AOR = 1.76, 95%CI = 1.54-2.00 in current users; AOR = 2.02, 95%CI = 1.55-2.65 in new users; AOR = 1.72, 95%CI = 1.50-1.96 in continuous users; and AOR = 1.35, 95%CI = 1.21-1.51 in past users). When assessing each individual kind of examined psychotropic agents, a significant elevated risk of burn injury was found among users of APs, ADs, benzodiazepines, and z-drugs except for current and continuous users of z-drugs. CONCLUSIONS: The results demonstrate an elevated risk of burn injury among individuals with current psychotropic use. The findings underscore the need for greater attention to be given to the cognitive performance and psychomotor abilities of individuals taking psychotropic medications in order to prevent the occurrence of burn injury. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476981 TI - Complete sequence of a plasmid from a bovine methicillin-resistant Staphylococcus aureus harbouring a novel ica-like gene cluster in addition to antimicrobial and heavy metal resistance genes. AB - The multiresistance plasmid pAFS11, obtained from a bovine methicillin-resistant Staphylococcus aureus (MRSA) isolate, was completely sequenced and analysed for its structure and organisation. Moreover, the susceptibility to the heavy metals cadmium and copper was determined by broth macrodilution. The 49,189-bp plasmid harboured the apramycin resistance gene apmA, two copies of the macrolide/lincosamide/streptogramin B resistance gene erm(B) (both located on remnants of a truncated transposon Tn917), the kanamycin/neomycin resistance gene aadD, the tetracycline resistance gene tet(L) and the trimethoprim resistance gene dfrK. The latter three genes were part of a 7,284-bp segment which was bracketed by two copies of IS431. In addition, the cadmium resistance operon cadDX as well as the copper resistance genes copA and mco were located on the plasmid and mediated a reduced susceptibility to cadmium and copper. Moreover, a complete novel ica-like gene cluster of so far unknown genetic origin was detected on this plasmid. The ica-like gene cluster comprised four different genes whose products showed 64.4-76.9% homology to the Ica proteins known to be involved in biofilm formation of the S. aureus strains Mu50, Mu3 and N315. However, 96.2-99.4% homology was seen to proteins from S. sciuri NS1 indicating an S. sciuri origin. The finding of five different antibiotic resistance genes co located on a plasmid with heavy metal resistance genes and an ica-like gene cluster is alarming. With the acquisition of this plasmid, antimicrobial multiresistance, heavy metal resistances and potential virulence properties may be co-selected and spread via a single horizontal gene transfer event. PMID- 27476983 TI - Assessment and Utility of Frailty Measures in Critical Illness, Cardiology, and Cardiac Surgery. AB - Frailty is a clearly emerging theme in acute care medicine, with obvious prognostic and health resource implications. "Frailty" is a term used to describe a multidimensional syndrome of loss of homeostatic reserves that gives rise to a vulnerability to adverse outcomes after relatively minor stressor events. This is conceptually simple, yet there has been little consensus on the operational definition. The gold standard method to diagnose frailty remains a comprehensive geriatric assessment; however, a variety of validated physical performance measures, judgement-based tools, and multidimensional scales are being applied in critical care, cardiology, and cardiac surgery settings, including open cardiac surgery and transcatheter aortic value replacement. Frailty is common among patients admitted to the intensive care unit and correlates with an increased risk for adverse events, increased resource use, and less favourable patient centred outcomes. Analogous findings have been described across selected acute cardiology and cardiac surgical settings, in particular those that commonly intersect with critical care services. The optimal methods for screening and diagnosing frailty across these settings remains an active area of investigation. Routine assessment for frailty conceivably has numerous purported benefits for patients, families, health care providers, and health administrators through better informed decision-making regarding treatments or goals of care, prognosis for survival, expectations for recovery, risk of complications, and expected resource use. In this review, we discuss the measurement of frailty and its utility in patients with critical illness and in cardiology and cardiac surgery settings. PMID- 27476982 TI - Heart Failure in Older Adults. AB - Heart failure (HF) is a leading cause of morbidity, hospitalization, and mortality in older adults and a growing public health problem placing a huge financial burden on the health care system. Many challenges exist in the assessment and management of HF in geriatric patients, who often have coexisting multimorbidity, polypharmacy, cognitive impairment, and frailty. These complex "geriatric domains" greatly affect physical and functional status as well as long term clinical outcomes. Geriatric patients have been under-represented in major HF clinical trials. Nonetheless, available data suggest that guideline-based medical and device therapies improve morbidity and mortality. Nonpharmacologic strategies, such as exercise training and dietary interventions, are an active area of research. Targeted geriatric evaluation, including functional and cognitive assessment, can improve risk stratification and guide management in older patients with HF. Clinical trials that enroll older patients with multiple morbidities and HF and evaluate functional status and quality of life in addition to mortality and cardiovascular morbidity should be encouraged to guide management of this age group. PMID- 27476984 TI - Contemporary Outcomes and Factors Associated With Mortality After a Fetal or Neonatal Diagnosis of Ebstein Anomaly and Tricuspid Valve Disease. AB - BACKGROUND: Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare anomalies and data on outcomes after a fetal or neonatal EA/TVD diagnosis are conflicting. METHODS: To examine the outcome and identify markers predictive of mortality, we reviewed our single-centre experience from 2000-2014. Variables were analyzed separately for cases diagnosed in utero without pregnancy termination and for all live-born patients. RESULTS: Of 47 fetal cases, 8 (17%) died in utero and 10 (21%) as neonates. Independent predictors associated with fetal demise included severe tricuspid regurgitation with a Doppler gradient < 40 mm Hg (odds ratio, 1.22 per mm Hg deduction; P = 0.003) and pulmonary regurgitation (odds ratio, 11.4; P = 0.03) at the baseline examination. A novel prognostic score (range, 0-10) combining the severity of 5 echocardiographic findings was independently associated with overall mortality (hazard ratio [HR], 1.39 per point increase; P = 0.01). Survival rates of 66 live births at 1 month, 1 year, and 5 years were 86%, 82%, and 80% respectively, and 75%, 60%, and 55% remained free from surgery at the same points in time. Factors associated with postnatal death in multivariate analysis included a younger gestational age at birth (HR per week, 1.59; P < 0.001), tricuspid annulus diameter (HR per z-score increase, 1.76; P = 0.004), and no pulmonary forward flow (HR, 4.63; P = 0.03). CONCLUSIONS: Our experience with fetal and neonatal EA/TVD shows better survival rates than previously reported. Mortality after a fetal diagnosis was significantly associated with hemodynamic changes indicative of a circular shunt, including pulmonary and tricuspid regurgitation severe enough to cause diastolic umbilical arterial flow reversal. PMID- 27476985 TI - Chronic Osteomyelitis Is Associated With Increased Risk of New-Onset Atrial Fibrillation: Evidence From a Nationwide Cohort of 23 Million People. AB - BACKGROUND: The objective of the study was to determine whether chronic osteomyelitis (COM) is associated with increased risk of new-onset atrial fibrillation (AF). METHODS: A national insurance claim data set of 23 million enrollees was used to identify 19,002 patients with newly-diagnosed COM and 76,008 randomly selected age- and sex-matched control subjects between January 1, 2000 and December 31, 2009 for comparing the risk and incidence of AF. The study end point was defined as the first diagnosis of AF, death, withdrawal from the insurance program, or the end of 2010. RESULTS: During a follow-up period of 91,927 person-years, the incidence of new-onset AF in COM cohort was 1.42-fold higher than for the non-COM cohort (4.54 vs 3.19 per 1000 person-years). After adjusting for age, sex, and classical AF risk factors such as hypertension, diabetes, heart failure, coronary artery disease, and valvular heart disease, the risk of new-onset AF remained significantly higher in the COM cohort (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.18-1.49; P < 0.0001). In age stratified analysis, the younger population carried a higher risk for incident AF than the elderly population (from HR 2.05; 95% CI, 1.12-3.74 in age younger than 50 years to HR 1.19; 95% CI, 0.95-1.49 in age 80 years and older). The adjusted Kaplan-Meier analysis showed a lower AF-free survival rate in the COM group compared with the control group (log-rank P < 0.0001) during the follow-up period. CONCLUSIONS: This study showed that patients with COM carry an increased risk for developing new-onset AF, particularly in the younger population. Further studies are required to explore the underlying mechanisms that link COM and AF. PMID- 27476987 TI - Frailty: A Vital Sign for Older Adults With Cardiovascular Disease. AB - Mechanisms of aging predispose to cardiovascular disease (CVD), as well as to aggregate health challenges. For older adults, CVD is likely to exist in combination with comorbid conditions, disability, polypharmacy, falling risks, and body composition changes. These other dimensions of health result in cumulative weakening with greater clinical complexity that confound basic precepts of CVD presentation, prognosis, and treatments. A convenient operational tool is needed to gauge this age-related vulnerability such that it can be integrated in the evaluation and treatment of CVD. Frailty is a concept that is neither disease- nor age-specific, but is used to characterize the reserve that a person has available to tolerate stresses associated with aging, disease, and even therapy. Frailty arises from specific biological mechanisms in association with cumulative physiological decrements, psychosocial stresses, and physical impairments. Performance-based and survey tools have been developed and tested to measure frailty. Although different frailty tools vary in practicality, measured domains, and precise applications, all are useful in identifying risks that commonly accrue with age. Although comparisons between frailty tools are ongoing and sometimes even controversial, the rationale to integrate routine use of frailty screening as part of routine care is relatively straightforward and easy to envision. Frailty assessment applied as a vital sign (for standard maintenance and evaluation of new symptoms) enhances perspectives of risk, decision-making, and opportunities for tailored CVD management. PMID- 27476986 TI - Effect of Lesion Age on Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary US Multicenter Registry. AB - BACKGROUND: We sought to determine the effect of lesion age on procedural techniques and outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: We examined the characteristics and outcomes of 394 CTO PCIs with data on lesion age, performed between 2012 and 2016 at 11 experienced US centres. RESULTS: Mean patient age was 66 +/- 10 years and 85.6% of the patients were men. Overall technical and procedural success rates were 90.1% and 87.5%, respectively. A major adverse cardiovascular event (MACE) occurred in 16 patients (4.1%). Mean and median lesion ages were 43 +/- 62 months and 12 months (interquartile range, 3-64 months), respectively. Patients were stratified into tertiles according to lesion age (3-5, 5-36.3, and > 36.3 months). Older lesion age was associated with older patient age (68 +/- 8 vs 65 +/- 10 vs 64 +/- 11 years; P = 0.009), previous coronary artery bypass grafting (62% vs 42% vs 30%; P < 0.001), and moderate/severe calcification (75% vs 53% vs 59%; P = 0.001). Older lesions more often required use of the retrograde approach and antegrade dissection/re-entry for successful lesion crossing. There was no difference in technical (87.8% vs 89.6% vs 93.0%; P = 0.37) or procedural (86.3% vs 87.4% vs 89.0%; P = 0.80) success, or the incidence of MACE (3.1% vs 3.0% vs 6.3%; P = 0.31) for older vs younger occlusions. CONCLUSIONS: Older CTO lesions exhibit angiographic complexity and more frequently necessitate the retrograde approach or antegrade dissection/re-entry. Older CTOs can be recanalized with high technical and procedural success and acceptable MACE rates. Lesion age appears unlikely to be a significant determinant of CTO PCI success. PMID- 27476989 TI - Cell-Free Mixing of Escherichia coli Crude Extracts to Prototype and Rationally Engineer High-Titer Mevalonate Synthesis. AB - Cell-free metabolic engineering (CFME) is advancing a powerful paradigm for accelerating the design and synthesis of biosynthetic pathways. However, as most cell-free biomolecule synthesis systems to date use purified enzymes, energy and cofactor balance can be limiting. To address this challenge, we report a new CFME framework for building biosynthetic pathways by mixing multiple crude lysates, or extracts. In our modular approach, cell-free lysates, each selectively enriched with an overexpressed enzyme, are generated in parallel and then combinatorically mixed to construct a full biosynthetic pathway. Endogenous enzymes in the cell free extract fuel high-level energy and cofactor regeneration. As a model, we apply our framework to synthesize mevalonate, an intermediate in isoprenoid synthesis. We use our approach to rapidly screen enzyme variants, optimize enzyme ratios, and explore cofactor landscapes for improving pathway performance. Further, we show that genomic deletions in the source strain redirect metabolic flux in resultant lysates. In an optimized system, mevalonate was synthesized at 17.6 g.L-1 (119 mM) over 20 h, resulting in a volumetric productivity of 0.88 g.L 1.hr-1. We also demonstrate that this system can be lyophilized and retain biosynthesis capability. Our system catalyzes ~1250 turnover events for the cofactor NAD+ and demonstrates the ability to rapidly prototype and debug enzymatic pathways in vitro for compelling metabolic engineering and synthetic biology applications. PMID- 27476988 TI - Geriatric Cardiology: An Emerging Discipline. AB - Given changing demographics, patients with cardiovascular (CV) disease in developed countries are now older and more complex than even a decade ago. This trend is expected to continue into the foreseeable future; accordingly, cardiologists are encountering patients with a greater number of comorbid illnesses as well as "geriatric conditions," such as cognitive impairment and frailty, which complicate management and influence outcomes. Simultaneously, technological advances have widened the therapeutic options available for patients, including those with the most advanced CV disease. In the setting of these changes, geriatric cardiology has recently emerged as a discipline that aims to adapt principles from geriatric medicine to everyday cardiology practice. Accordingly, the tasks of a "geriatric cardiologist" may include both traditional evidence-based CV management plus comprehensive geriatric assessment, medication reduction, team-based coordination of care, and explicit incorporation of patient goals into management. Given that the field is still in its relative infancy, the training pathways and structure of clinical programs in geriatric cardiology are still being delineated. In this review, we highlight the rationale behind geriatric cardiology as a discipline, several current approaches by geriatric cardiology programs, and future directions for the field. PMID- 27476990 TI - Novel pharmacological modulators of autophagy: an updated patent review (2012 2015). AB - INTRODUCTION: Autophagy is a lysosome-dependent degradation pathway that maintains cellular homeostasis in response to a variety of cellular stresses. Accumulating reports based on animal models have indicated the importance of this catabolic program in many human pathophysiological conditions, including diabetes, neurodegenerative diseases, aging, and cancers. Therefore, autophagy has been highlighted as a novel therapeutic target with a wide range of beneficial effects on human diseases. Here, we review the recent advances of our knowledge toward autophagy, as well as the efforts for developing autophagy modulators. Areas covered: The relevant patents (published at 2012-2015) and the research literature claiming the pharmacological modulation of autophagy are reviewed. Also, their molecular mechanisms and potential therapeutic utilities are discussed. Expert opinion: Considering the molecular machinery involved in autophagy induction, the targeting of autophagy-specific protein is very important to design the therapeutic interventions for specifically treating a variety of autophagy-associated disorders. Many patents and the research literature described in this review have shown promising applications of the relevant autophagy modulators for cancer or neurodegeneration treatments, a few of which are already being considered for clinical evaluation. However, most patents have claimed the modulators of autophagy with little information regarding their mechanisms of action. To design highly potent therapeutics, further work, such as developing compounds that specifically target the autophagy specific machinery, are required. PMID- 27476991 TI - Scaled down glass transition temperature in confined polymer nanofibers. AB - Arrays of polymer nanostructures have been widely used in many novel devices and nanofabrication methods. The glass transition temperature, which is a key parameter influencing the long-term stability of polymer nanostructures, has not yet been systematically studied and well understood. Here we study this technological and fundamental issue with polymers of different values of molar mass M confined in nanocylinders of a varying diameter D. The glass transition temperature Tg loses its dependence on the molar mass for D ? 100 nm, a range in which the relative depression of Tg varies as D(-0.44). For higher cylinder diameters, Tg progressively recovers its dependence on the molar mass. This is quantitatively reproduced by a model based on an equilibrium interfacial excess of free volume, which needs to be created unless provided by the chain ends. Our findings suggest that the structural perturbations during nanofabrication may strongly affect the long-term stability of arrays of polymer nanostructures. PMID- 27476993 TI - Competing fragmentation processes of beta-substituted propanoate ions upon collision-induced dissociation. AB - RATIONALE: When subjected to collisional activation, gas-phase carboxylate ions typically undergo decarboxylation. However, alternative fragmentation processes dominate when the carboxylate group is located within certain structural motifs. In this work, the fragmentation processes of beta-substituted carboxylate ions are characterized to improve correlations between reactivity and structure. METHODS: Mass spectra were collected using both ion trap and triple quadrupole mass spectrometers operating in the negative ion mode; collision-induced dissociation (CID) of ions was used to study the relationship between product ions and the structures of their precursor ions. Quantum mechanical computations were performed on a full range of reaction geometries at the MP2/6 311++G(2d,p)//B3LYP/6-31++G(2d,p) level of theory. RESULTS: For a series of beta substituted carboxylate ions, a product ion corresponding to the anion of the beta-substituent was obtained upon CID. Detailed computations indicated that decarboxylative elimination and at least one other fragmentation mechanism had feasible energetics for the formation of substituent anions differing in their gas-phase basicities. Predicted energetics for anti- and synperiplanar alignments in the transition structures for decarboxylative elimination correlated with the positions of crossover points in breakdown curves acquired for conformationally constrained ions. CONCLUSIONS: The feasibility of more than one mechanism was established for the fragmentation of beta-substituted propanoates. The contribution of each mechanistic pathway to the formation of the substituent anion was influenced by structural variations and conformational constraints, but mostly depended on the nature of the substituent. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476992 TI - A one-step matrix application method for MALDI mass spectrometry imaging of bacterial colony biofilms. AB - Matrix-assisted laser desorption/ionization imaging of biofilms cultured on agar plates is challenging because of problems related to matrix deposition onto agar. We describe a one-step, spray-based application of a 2,5-dihydroxybenzoic acid solution for direct matrix-assisted laser desorption/ionization imaging of hydrated Bacillus subtilis biofilms on agar. Using both an optimized airbrush and a home-built automatic sprayer, region-specific distributions of signaling metabolites and cannibalistic factors were visualized from B. subtilis cells cultivated on biofilm-promoting medium. The approach provides a homogeneous, relatively dry coating on hydrated samples, improving spot to spot signal repeatability compared with sieved matrix application, and is easily adapted for imaging a range of agar-based biofilms. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27476994 TI - Limit of viability: The Swiss experience. AB - Progress made in the field of perinatology over the past four decades has led to unprecedented low mortality rates for extremely low birth weight infants. However, because rates of important short-term complications and neurodevelopmental impairment among survivors have remained high, the best approach to borderline viable infants continues to be debated. Not surprisingly, guidelines from various national medical societies for the care of infants born at the limit of viability vary considerably. In 2002, the first Swiss recommendations for the care of borderline viable infants were published. They had been developed by a multidisciplinary team of experts from the fields of obstetrics, pediatrics, and neonatology. Despite the availability of national guidelines, center-to-center outcome variability has since persisted, suggesting that care for the most immature infants is not only evidence-based and guideline driven but also strongly influenced by local neonatal intensive care unit (NICU) culture. In 2011, revised national recommendations for perinatal care at the limit of viability between 22 and 26 completed weeks of gestation were published. It remains to be seen whether this has led to more uniform outcomes across the Swiss centers in the years that followed. PMID- 27476995 TI - Erratum: Steady State Ocean Response to Wind Forcing in Extratropical Frontal Regions. PMID- 27476996 TI - Effect of heat stress on age at first calving of Japanese Black cows in Okinawa. AB - Calving records from birth certificates of cows were analyzed to investigate the effect of heat stress on age at first calving (AFC) of Japanese Black cows. The data set covered 20 years (1990-2009) of calving records. Total number of records was 9279. Daily weather information from weather stations in the vicinity of the farms was used. Temperature-humidity index (THI) fitted to a linear model covered 30 days pre-insemination to 61 days post-insemination. Statistical analysis was conducted with procedures of SAS/STAT. Preliminary analysis showed that THI of the lowest temperature and humidity was most conducive to AFC. Covariance analysis, including main effect of sire, farm and year of insemination and covariates of THI on days showed that regression coefficients of THI on day -7, day -2 and day +31 were statistically significant. The estimated piecewise regression line showed different responses of AFC to THI on days: roof-shasped downward trend on day -7, hockey-stick shaped upward trend on day -2 and day +31. The difference among the estimated regression lines may be caused by direct and indirect factors on reproduction: indirect effect of reduced feed intake, failure of conception at previous insemination, direct effect of heat stress on oocyte and embryo development. PMID- 27476997 TI - Synthesis and crystal structures of cobalt(II), cadmium(II), and zinc(II) complexes of 4-nitro phenylcyanamide: enhancing the biological properties through bound to human serum albumin. AB - Metal complexes of the type [Co(phen)2(4-NO2pcyd)2].CH3OH, 1, [Zn(phen)2(4 NO2pcyd)2].CH3OH, 2, [Cd(phen)2(4-NO2pcyd)2], and 3, (phen = 1,10-phenanthroline, 4-NO2pcyd = 4-nitro phenylcyanamide) have been studied. The synthesis, characterization, and the biological activities of complexes 1-3 have been investigated. The geometries of complexes 1-3 were confirmed by single-crystal X ray crystallography. The interactions of complexes 1-3 with human serum albumin (HSA) were studied using fluorescence and circular dichroism spectroscopy. The thermodynamic studies have showed the reaction for the binding of complexes 1-3 with HSA is hydrophobic (DeltaH0 ? 0 and DeltaS0 > 0). The in vitro cytotoxic potential of complexes 1-3 and their complexes with HSA were examined. The complexes 1-3 with HSA enhance about 3-fold cytotoxicity in cancer cells lines. PMID- 27476998 TI - Understanding the Percolation Characteristics of Nonlinear Composite Dielectrics. AB - Nonlinear composite dielectrics can function as smart materials for stress control and field grading in all fields of electrical insulations. The percolation process is a significant issue of composite dielectrics. However, the classic percolation theory mainly deals with traditional composites in which the electrical parameters of both insulation matrix and conducting fillers are independent of the applied electric field. This paper measured the nonlinear V-I characteristics of ZnO microvaristors/silicone rubber composites with several filler concentrations around an estimated percolation threshold. For the comparison with the experiment, a new microstructural model is proposed to simulate the nonlinear conducting behavior of the composite dielectrics modified by metal oxide fillers, which is based on the Voronoi network and considers the breakdown feature of the insulation matrix for near percolated composites. Through both experiment and simulation, the interior conducting mechanism and percolation process of the nonlinear composites were presented and a specific percolation threshold was determined as 33%. This work has provided a solution to better understand the characteristics of nonlinear composite dielectrics. PMID- 27476999 TI - Hexane Extract of Echinops spinosissimus Turra subsp. spinosus from Tunisia: A Potential Source of Acetylated Sterols - Investigation of its Biological Activities. AB - The hexane extract of Echinops spinosissimus Turra subsp. spinosus flower heads was analyzed for its fatty acid and sterol composition. Its physicochemical characteristics were also studied. The saponification, iodine and peroxide values were determined as 255 mg KOH/g, 42.57 g I2 /100 g and 110 m equiv. O2 /kg of oil, respectively. The oleic (C18:1; 61.14%), palmitic (C16:0; 21.36%) and linoleic (C18:2; 10.45%) acids were the dominant fatty acids. This extract was also found to contain high levels of beta-sitosterol and stigmasterol (44.97% and 34.95% of total sterols, respectively). On the other hand, the identification of terpenoid compounds was investigated by using GC/MS, which revealed fourteen major terpenoids mainly taraxasterol, lupeol, pseudotaraxasterol, lup-22(29)-en-3 yl acetate, taraxasteryl acetate, alpha-amyrin, beta-amyrin, pseudotaraxasteryl acetate, hop-20(29)-en3-beta-ol, alpha-amirenone, along with beta-sitosterol and stigmasterol. Moreover, we have evaluated the in vitro antibacterial and antifungal activities of the unsaponifiable matter and a fraction isolated from this extract. These activities were conducted using the diffusion disc methods and broth microdilution assay. The resulted fraction from this extract showed the highest antibacterial activity with significant minimum inhibitory concentrations (MIC) values 125.0 MUg/ml against Staphylococcus aureus, Micrococcus luteus and Bacillus cereus. However, it did exhibit no substantial antifungal activity. PMID- 27477000 TI - Phenotypic characterization of the Francisella tularensis DeltapdpC and DeltaiglG mutants. AB - Several bacterial pathogens interact with their host through protein secretion effectuated by a type VI secretion system (T6SS). Francisella tularensis is a highly pathogenic intracellular bacterium that causes the disease tularemia. Proteins encoded by the Francisella pathogenicity island (FPI), which constitute a type VI secretion system, are essential for the virulence of the bacterium and a key mechanism behind this is the escape from the phagosome followed by productive cytosolic replication. It has been shown that T6SS in Francisella is distinct since all putative substrates of F. tularensis T6SS, except for VgrG, are unique to the species. Many of the FPI proteins are secreted into the macrophage cytosol and this is dependent on the functional components of DotU, VgrG, IglC and IglG. In addition, PdpC seems to have a regulatory role for the expression of iglABCD. Since previous results showed peculiar phenotypes of the DeltapdpC and DeltaiglG mutants in mouse macrophages, their unique behavior was characterized in human monocyte-derived macrophages (HMDM) in this study. Our results show that both DeltapdpC and DeltaiglG mutants of the live vaccine strain (LVS) of F. tularensis did not replicate within HMDMs. The DeltapdpC mutant did not escape from the Francisella containing phagosome (FCP), neither caused cytopathogenicity in primary macrophages and was attenuated in a mouse model. Interestingly, the DeltaiglG mutant escaped from the HMDMs FCP and also caused pathological changes in the spleen and liver tissues of intradermally infected C57BL/6 mice. The DeltaiglG mutant, with its unique phenotype, is a potential vaccine candidate. PMID- 27477001 TI - The system neurophysiological basis of non-adaptive cognitive control: Inhibition of implicit learning mediated by right prefrontal regions. AB - Cognitive control is adaptive in the sense that it inhibits automatic processes to optimize goal-directed behavior, but high levels of control may also have detrimental effects in case they suppress beneficial automatisms. Until now, the system neurophysiological mechanisms and functional neuroanatomy underlying these adverse effects of cognitive control have remained elusive. This question was examined by analyzing the automatic exploitation of a beneficial implicit predictive feature under conditions of high versus low cognitive control demands, combining event-related potentials (ERPs) and source localization. It was found that cognitive control prohibits the beneficial automatic exploitation of additional implicit information when task demands are high. Bottom-up perceptual and attentional selection processes (P1 and N1 ERPs) are not modulated by this, but the automatic exploitation of beneficial predictive information in case of low cognitive control demands was associated with larger response-locked P3 amplitudes and stronger activation of the right inferior frontal gyrus (rIFG, BA47). This suggests that the rIFG plays a key role in the detection of relevant task cues, the exploitation of alternative task sets, and the automatic (bottom up) implementation and reprogramming of action plans. Moreover, N450 amplitudes were larger under high cognitive control demands, which was associated with activity differences in the right medial frontal gyrus (BA9). This most likely reflects a stronger exploitation of explicit task sets which hinders the exploration of the implicit beneficial information in case of high cognitive control demands. Hum Brain Mapp 37:4511-4522, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27477002 TI - Pharmacotherapy for the management of cancer regimen-related oral mucositis. AB - INTRODUCTION: Oral mucositis is a frequent and devastating toxicity secondary to cancer treatment, which may affect 20-40% of patients receiving conventional chemotherapy and 60-85% of patients undergoing hematopoietic stem cell transplantation. The pathobiology of mucositis includes a complex cascade of biologic events in which pro-inflammatory cytokines, ROS, second messengers, and the oral microbiome contribute to tissue damage of the oral mucosa. Management strategies to oral mucositis secondary to chemotherapy include preventative measures and therapeutic approaches. AREA COVERED: A literature search of published animal and clinical studies was perform to review the epidemiology, pathophysiology and treatment options for cancer regimen-induced mucositis. We also discuss new data coming from recent pertinent clinical trials. EXPERT OPINION: Mucositis is one of the most common debilitating toxicities secondary to cancer treatment and can adversely affect patients' quality of life. Epidemiological data for mucositis are often under-reported. Research efforts have shown that genetics plays a major role in the development of this toxicity. Although few therapeutic agents are available, several promising drugs are under investigations. PMID- 27477003 TI - Atypical femur fracture in an adolescent boy treated with bisphosphonates for X linked osteoporosis based on PLS3 mutation. AB - Long-term use of bisphosphonates has raised concerns about the association with Atypical Femur Fractures (AFFs) that have been reported mainly in postmenopausal women. We report a case of an 18-year-old patient with juvenile osteoporosis based on X-linked osteoporosis due to a PLS3 mutation who developed a low trauma femoral fracture after seven years of intravenous and two years of oral bisphosphonate use, fulfilling the revised ASBMR diagnostic criteria of an AFF. The occurrence of AFFs has not been described previously in children or adolescents. The underlying monogenetic bone disease in our case strengthens the possibility of a genetic predisposition at least in some cases of AFF. We cannot exclude that a transverse fracture of the tibia that also occurred after a minor trauma at age 16 might be part of the same spectrum of atypical fractures related to the use of bisphosphonates. In retrospect our patient experienced prodromal pain prior to both the tibia and the femur fracture. Case reports of atypical fractures in children with a monogenetic bone disease such as Osteogenesis Imperfecta (OI) or juvenile osteoporosis are important to consider in the discussion about optimal duration of bisphosphonate therapy in growing children. In conclusion, this case report 1) highlights that AFFs also occur in adolescents treated with bisphosphonates during childhood and pain in weight-bearing bones can point towards this diagnosis 2) supports other reports suggesting that low trauma fractures of other long bones besides the femur may be related to long term use of bisphosphonates 3) strengthens the concept of an underlying genetic predisposition in some cases of AFF, now for the first time reported in X-linked osteoporosis due to a mutation in PLS3 and 4) should be considered in decisions about the duration of bisphosphonate therapy in children with congenital bone disorders. PMID- 27477005 TI - Negatively charged Ir(iii) cyclometalated complexes containing a chelating bis tetrazolato ligand: synthesis, photophysics and the study of reactivity with electrophiles. AB - The bis-tetrazolate dianion [1,2 BTB](2-), which is the deprotonated form of 1,2 bis-(1H-tetrazol-5-yl)benzene [1,2-H2BTB], is for the first time exploited as an ancillary N^N ligand for negatively charged [Ir(C^N)2(N^N)](-)-type complexes, where C^N is represented by cyclometalated 2-phenylpyridine (ppy) or 2-(2,4 difluorophenyl)pyridine (F2ppy). The new Ir(iii) complexes [Ir(ppy)2(1,2 BTB)]- and [Ir(F2ppy)2(1,2 BTB)]- have been fully characterised and the analysis of the X-ray structure of [Ir(ppy)2(1,2 BTB)]- confirmed the coordination of the [1,2 BTB](2-) dianion in a bis chelated fashion through the N-atoms adjacent to each of the tetrazolic carbons. Both of the new anionic Ir(iii) complexes displayed phosphorescence in the visible region, with intense sky-blue (lambdamax = 460-490 nm) or aqua (lambdamax = 490-520 nm) emissions originating from [Ir(F2ppy)2(1,2 BTB)]- and [Ir(ppy)2(1,2 BTB)]-, respectively. In comparison with our very recent examples of anionic Ir(iii)tetrazolate cyclometalates, the new Ir(iii) tris chelate complexes [Ir(F2ppy)2(1,2 BTB)]- and [Ir(ppy)2(1,2 BTB)]-, display an improved robustness, allowing the study of their reactivity toward the addition of electrophiles such as H(+) and CH3(+). In all cases, the electrophilic attacks occurred at the coordinated tetrazolate rings, involving the reversible - by a protonation deprotonation mechanism - or permanent - upon addition of a methyl moiety - switching of their global net charge from negative to positive and, in particular, the concomitant variation of their photoluminescence output. The combination of the anionic complexes [Ir(F2ppy)2(1,2 BTB)]- or [Ir(ppy)2(1,2 BTB)]- with a deep red emitting (lambdamax = 686 nm) cationic Ir(iii) tetrazole complex such as [IrTPYZ-Me]+, where TPYZ-Me is 2-(2-methyl-2H-tetrazol-5 yl)pyrazine, gave rise to two fully Ir(iii)-based soft salts capable of displaying additive and O2-sensitive emission colours, with an almost pure white light obtained by the appropriate choice of the ionic components. PMID- 27477004 TI - Exercise loading history and femoral neck strength in a sideways fall: A three dimensional finite element modeling study. AB - Over 90% of hip fractures are caused by falls. Due to a fall-induced impact on the greater trochanter, the posterior part of the thin superolateral cortex of the femoral neck is known to experience the highest stress, making it a fracture prone region. Cortical geometry of the proximal femur, in turn, reflects a mechanically appropriate form with respect to habitual exercise loading. In this finite element (FE) modeling study, we investigated whether specific exercise loading history is associated with femoral neck structural strength and estimated fall-induced stresses along the femoral neck. One hundred and eleven three dimensional (3D) proximal femur FE models for a sideways falling situation were constructed from magnetic resonance (MR) images of 91 female athletes (aged 24.7+/-6.1years, >8years competitive career) and 20 non-competitive habitually active women (aged 23.7+/-3.8years) that served as a control group. The athletes were divided into five distinct groups based on the typical loading pattern of their sports: high-impact (H-I: triple-jumpers and high-jumpers), odd-impact (O I: soccer and squash players), high-magnitude (H-M: power-lifters), repetitive impact (R-I: endurance runners), and repetitive non-impact (R-NI: swimmers). The von Mises stresses obtained from the FE models were used to estimate mean fall induced stresses in eight anatomical octants of the cortical bone cross-sections at the proximal, middle, and distal sites along the femoral neck axis. Significantly (p<0.05) lower stresses compared to the control group were observed: the H-I group - in the superoposterior (10%) and posterior (19%) octants at the middle site, and in the superoposterior (13%) and posterior (22%) octants at the distal site; the O-I group - in the superior (16%), superoposterior (16%), and posterior (12%) octants at the middle site, and in the superoposterior (14%) octant at the distal site; the H-M group - in the superior (13%) and superoposterior (15%) octants at the middle site, and a trend (p=0.07, 9%) in the superoposterior octant at the distal site; the R-I group - in the superior (14%), superoposterior (23%) and posterior (22%) octants at the middle site, and in the superoposterior (19%) and posterior (20%) octants at the distal site. The R-NI group did not differ significantly from the control group. These results suggest that exercise loading history comprising various impacts in particular is associated with a stronger femoral neck in a falling situation and may have potential to reduce hip fragility. PMID- 27477006 TI - Microbiomes: Symbionts - in it for the long run. PMID- 27477007 TI - Gene regulation: May the force be with you. PMID- 27477008 TI - Transcriptome response of Lolium arundinaceum to its fungal endophyte Epichloe coenophiala. AB - Tall fescue (Lolium arundinaceum) is one of the primary forage and turf grasses in temperate regions of the world. A number of favourable characteristics of tall fescue are enhanced by its seed-transmissible fungal symbiont (endophyte) Epichloe coenophiala. Our approach was to assemble the tall fescue transcriptome, then identify differentially expressed genes (DEGs) for endophyte-symbiotic (E+) vs endophyte-free (E-) clones in leaf blades, pseudostems, crowns and roots. RNA seq reads were used to construct a tall fescue reference transcriptome and compare gene expression profiles. Over all tissues examined, 478 DEGs were identified between the E+ and E- clones for at least one tissue (more than two fold; P < 0.0001, 238 E+ > E- and 240 E- > E+), although no genes were differentially expressed in all four tissues. Gene ontology (GO) terms, GO:0010200 (response to chitin), GO:0002679 (respiratory burst during defence response) and GO:0035556 (intracellular signal transduction) were significantly overrepresented among 25 E- > E+ DEGs in leaf blade, and a number of other DEGs were associated with defence and abiotic response. In particular, endophyte effects on various WRKY transcription factors may have implications for symbiotic stability, endophyte distribution in the plant, or defence against pathogens. PMID- 27477009 TI - A comparative study on bioactive constituents in different parts of Lonicera japonica determined by HPLC-ESI-MS(n). AB - Lonicera japonica Thunb. is a well-known traditional herbal medicine in most East Asian countries. In China, the flower bud and stem of this plant are used for various clinical therapies, while the leaf is not officially recognized as an active part. Due to the similarities in their chemical constituents but great differences in their commercial values, the flower bud has been found to be adulterated with leaf and/or stem during the production of formulations by some drug manufactures. In order to identify adulteration in products and enable quality control, it is necessary to chemically discriminate these three parts of L. japonica. In the current study, an HPLC-ESI-MS(n) method was developed and validated for the quantitative analysis of 18 bioactive compounds: 7 organic acids, 6 iridoids, and 5 flavonoids, in batches of flower bud, stem, and leaf samples. Subsequently, chemometric analyses, such as one-way analysis of variance, principal component analysis, and hierarchical clustering analysis, were performed based on the quantitative data. The results indicated that there were remarkable differences in the distribution of the investigated compounds among the three parts of L. japonica, and that they could be straightforwardly and reliably distinguished according to their chemical profiles. Twelve compounds were selected as potential differential metabolites, which would be useful for quality control of L. japonica. As the content of caffeic acid was low in the flower bud but much higher in the stem and leaf, it could be used as a chemical marker to identify adulteration. PMID- 27477010 TI - Filling the (SR)GAP in Excitatory/Inhibitory Balance. AB - In this issue of Neuron, Fossati et al. (2016) report that through its domain structure, SRGAP2A, a Rho-GTPase-activating protein, can co-regulate excitatory and inhibitory synapse development, offering a putative evolutionary genetic mechanism for preserving excitatory/inhibitory balance during speciation. PMID- 27477011 TI - Should I Stay or Should I Go? AB - In this issue of Neuron, Lee et al. (2016) assessed the brain-wide effects of stimulating the direct and indirect pathway by optogenetic activation of D1 and D2 striatal neurons. This work demonstrates the exquisite power of combining cell type-specific perturbation methods with focal and whole-brain measurements of brain activity. PMID- 27477012 TI - Stressing out the Social Network. AB - In this issue of Neuron, Hultman et al. (2016) find that stress-induced abnormal social behavior reflects aberrant prefrontal regulation of downstream limbic networks. This illustrates how linking aberrant network dynamics to neuropsychiatric disorders may lead to new circuit-based therapeutic interventions. PMID- 27477013 TI - A Powerful DREADD: Revealing Structural Drivers of Functional Dynamics. AB - In this issue of Neuron, Grayson et al. (2016) report how inhibition of amygdala impacts amygdalocortical and corticocortical functional connectivity. Their study predicts changes in functional brain topology, induced by pharmacologic modulation of neuroanatomical circuits using designer receptors exclusively activated by designer drugs (DREADDs), through virtual lesioning of amygdala in structural brain networks. PMID- 27477014 TI - Gyorgy Buzsaki. AB - In an interview with Neuron, Gyorgy Buzsaki shares his thoughts on the balance of big-data gathering collaborations and discoveries driven by individual labs, the highlight of his career, and his strategy for understanding the brain from "within," by studying how internally generated patterns convert into action and eventually experience. PMID- 27477015 TI - Kerry Ressler. AB - In an interview with Neuron, Kerry Ressler discusses key questions in translational psychiatry, enthusiastically recounts a "eureka" moment he had as a student, and shares what he wishes the public understood about psychiatry and science. PMID- 27477016 TI - Analysis of Neuronal Spike Trains, Deconstructed. AB - As information flows through the brain, neuronal firing progresses from encoding the world as sensed by the animal to driving the motor output of subsequent behavior. One of the more tractable goals of quantitative neuroscience is to develop predictive models that relate the sensory or motor streams with neuronal firing. Here we review and contrast analytical tools used to accomplish this task. We focus on classes of models in which the external variable is compared with one or more feature vectors to extract a low-dimensional representation, the history of spiking and other variables are potentially incorporated, and these factors are nonlinearly transformed to predict the occurrences of spikes. We illustrate these techniques in application to datasets of different degrees of complexity. In particular, we address the fitting of models in the presence of strong correlations in the external variable, as occurs in natural sensory stimuli and in movement. Spectral correlation between predicted and measured spike trains is introduced to contrast the relative success of different methods. PMID- 27477018 TI - TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. AB - Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Trem2 knockout microglia showed reduced internalization of LDL and CLU. beta-amyloid (Abeta) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Abeta-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. These data link three genetic risk factors for AD and reveal a possible mechanism by which mutant TREM2 increases risk of AD. VIDEO ABSTRACT. PMID- 27477019 TI - The Rhesus Monkey Connectome Predicts Disrupted Functional Networks Resulting from Pharmacogenetic Inactivation of the Amygdala. AB - Contemporary research suggests that the mammalian brain is a complex system, implying that damage to even a single functional area could have widespread consequences across the system. To test this hypothesis, we pharmacogenetically inactivated the rhesus monkey amygdala, a subcortical region with distributed and well-defined cortical connectivity. We then examined the impact of that perturbation on global network organization using resting-state functional connectivity MRI. Amygdala inactivation disrupted amygdalocortical communication and distributed corticocortical coupling across multiple functional brain systems. Altered coupling was explained using a graph-based analysis of experimentally established structural connectivity to simulate disconnection of the amygdala. Communication capacity via monosynaptic and polysynaptic pathways, in aggregate, largely accounted for the correlational structure of endogenous brain activity and many of the non-local changes that resulted from amygdala inactivation. These results highlight the structural basis of distributed neural activity and suggest a strategy for linking focal neuropathology to remote neurophysiological changes. PMID- 27477020 TI - Self-Other Mergence in the Frontal Cortex during Cooperation and Competition. AB - To survive, humans must estimate their own ability and the abilities of others. We found that, although people estimated their abilities on the basis of their own performance in a rational manner, their estimates of themselves were partly merged with the performance of others. Reciprocally, their ability estimates for others also reflected their own, as well as the others', performance. Self-other mergence operated in a context-dependent manner: interacting with high or low performers, respectively, enhanced and diminished own ability estimates in cooperative contexts, but the opposite occurred in competitive contexts. Self other mergence not only influenced subjective evaluations, it also affected how people subsequently objectively adjusted their performance. Perigenual anterior cingulate cortex tracked one's own performance. Dorsomedial frontal area 9 tracked others' performances, but also integrated contextual and self-related information. Self-other mergence increased with the strength of self and other representations in area 9, suggesting it carries interdependent representations of self and other. PMID- 27477021 TI - Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases. PMID- 27477017 TI - GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits. AB - Cortical networks are composed of glutamatergic excitatory projection neurons and local GABAergic inhibitory interneurons that gate signal flow and sculpt network dynamics. Although they represent a minority of the total neocortical neuronal population, GABAergic interneurons are highly heterogeneous, forming functional classes based on their morphological, electrophysiological, and molecular features, as well as connectivity and in vivo patterns of activity. Here we review our current understanding of neocortical interneuron diversity and the properties that distinguish cell types. We then discuss how the involvement of multiple cell types, each with a specific set of cellular properties, plays a crucial role in diversifying and increasing the computational power of a relatively small number of simple circuit motifs forming cortical networks. We illustrate how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations. PMID- 27477022 TI - Bleeding related to disturbed fibrinolysis. AB - The components and reactions of the fibrinolysis system are well understood. The pathway has fewer reactants and interactions than coagulation, but the generation of a complete quantitative model is complicated by the need to work at the solid liquid interface of fibrin. Diagnostic tools to detect disease states due to malfunctions in the fibrinolysis pathway are also not so well developed as is the case with coagulation. However, there are clearly a number of inherited or acquired pathologies where hyperfibrinolysis is a serious, potentially life threatening problem and a number of antifibrinolytc drugs are available to treat hyperfibrinolysis. These topics will be covered in the following review. PMID- 27477023 TI - Orthotic management of instability of the knee related to neuromuscular and central nervous system disorders: systematic review, qualitative study, survey and costing analysis. AB - BACKGROUND: Patients who have knee instability that is associated with neuromuscular disease (NMD) and central nervous system (CNS) conditions can be treated using orthoses, such as knee-ankle-foot orthoses (KAFOs). OBJECTIVES: To assess existing evidence on the effectiveness of orthoses; patient perspectives; types of orthotic devices prescribed in the UK NHS; and associated costs. METHODS: Qualitative study of views of orthoses users - a qualitative in-depth interview study was undertaken. Data were analysed for thematic content. A coding scheme was developed and an inductive approach was used to identify themes. Systematic review - 18 databases were searched up to November 2014: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Cumulative Index to Nursing and Allied Health, EMBASE, PASCAL, Scopus, Science Citation Index, BIOSIS Previews, Physiotherapy Evidence Database, Recal Legacy, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, Cochrane Central Register of Controlled Trials, Conference Proceedings Citation Index: Science, Health Management Consortium, ClinicalTrials.gov, International Clinical Trials Registry Platform and National Technical Information Service. Studies of adults using an orthosis for instability of the knee related to NMD or a CNS disorder were included. Data were extracted and quality was assessed by two researchers. Narrative synthesis was undertaken. Survey and costing analysis - a web survey of orthotists, physiotherapists and rehabilitation medicine physicians was undertaken. Telephone interviews with orthotists informed a costing analysis. RESULTS: Qualitative study - a total of 24 people participated. Potential for engagement in daily activities was of vital importance to patients; the extent to which their device enabled this was the yardstick by which it was measured. Patients' prime desired outcome was a reduction in pain, falls or trips, with improved balance and stability. Effectiveness, reliability, comfort and durability were the most valued features of orthoses. Many expressed frustration with perceived deficiencies in service provision relating to appointment and administrative systems and referral pathways. Systematic review - a total of 21 studies (478 participants) were included of people who had post-polio syndrome, inclusion body myositis, were post stroke or had spinal cord injury. The studies evaluated KAFOs (mainly carbon fibre), stance control KAFO and hip KAFOs. All of the studies were at risk of bias and, in general, were poorly reported. Survey and costing analysis - in total, 238 health-care professionals responded. A range of orthoses is prescribed for knee instability that is related to NMD or CNS conditions, approximately half being custom-made. At least 50% of respondents thought that comfort and confidence in mobility were extremely important treatment outcomes. The cost of individual KAFOs was highly variable, ranging from L73 to L3553. CONCLUSIONS: Various types of orthoses are used in the NHS to manage patients with NMD/CNS conditions and knee instability, both custom-made and prefabricated, of variable cost. Evidence on the effectiveness of the orthoses is limited, especially in relation to the outcomes that are important to orthoses users. LIMITATIONS: The population included was broad, limiting any in-depth consideration of specific conditions. The response rate to the survey was low, and the costing analysis was based on some assumptions that may not reflect the true costs of providing KAFOs. FUTURE WORK: Future work should include high quality research on the effectiveness and cost-effectiveness of orthoses; development of a core set of outcome measures; further exploration of the views and experiences of patients; and the best models of service delivery. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014010180. The qualitative study is registered as Current Controlled Trials ISRCTN65240228. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27477024 TI - Drug Coated Balloon Is Less Effective for Treatment of DES In-Stent Restenosis Both in Native Coronary Arteries and Saphenous Vein Grafts: Results From a Bicenter Registry. AB - BACKGROUND: The paclitaxel drug coated balloon (DCB) is an established treatment for bare metal stent (BMS) in-stent restenosis (ISR) in native coronary arteries. The evidence of DCB-application for drug eluting stent (DES) ISR both in native coronaries and saphenous vein grafts (SVG) is limited. Aim of our study was to compare the differential efficacy of DCB for treatment of BMS- and DES-ISR in native coronary vessels and SVGs. METHODS AND RESULTS: N = 135 DCB-treated patients with available follow up (FU) angiography were included in this retrospective study. Patients received treatment between April 2009 and March 2013 at 2 tertiary care hospitals in Germany. DCB was applied in BMS-ISR (n = 65; 48%) and DES-ISR (n = 70; 52%). DCB-treated lesions were located in native coronary arteries (n = 110; 81%; BMS-ISR: n = 58; 53%; DES-ISR: n = 52; 47%) and SVGs (n = 25; 19%; BMS-ISR: n = 7, 28%; DES-ISR: n = 18, 72%). Median FU was 12 months. Endpoints were binary restenosis and target lesion revascularization (TLR). Binary restenosis (29% vs. 57%; P < 0.01) and TLR (18% vs. 46%; P < 0.01) were significantly more frequent in DES-ISR versus BMS-ISR. In SVGs, TLR was required in 72% (DES-ISR) versus 14% (BMS-ISR); P = 0.02. In the Kaplan-Meier analysis freedom from both endpoints was significantly decreased in the DES lesions both in the total population (binary restenosis P < 0.01; TLR P < 0.01) and native coronaries (binary restenosis P = 0.02; TLR P = 0.04). CONCLUSIONS: DCB treatment is less effective in DES-ISR than in BMS-ISR. The diminished efficacy of DCB treatment is even more pronounced in DES-ISR located within degenerated SVGs. PMID- 27477025 TI - Retarded Embryo Development 1 (RED1) regulates embryo development, seed maturation and plant growth in Arabidopsis. AB - Plant seeds accumulate large amounts of protein and carbohydrate as storage reserves during maturation. Thus, understanding the genetic control of embryo and seed development may provide bioengineering tools for yield improvement. In this study, we report the identification of Retarded Embryo Development 1 (RED1) gene in Arabidopsis, whose two independent T-DNA insertion mutant lines, SALK_085642 (red1-1) and SALK_022583 (red1-2), show a retarded embryo development phenotype. The embryogenesis process ceases at the late heart stage in red1-1 and at the bent-cotyledon stage in red1-2, respectively, resulting in seed abortion in both lines. The retarded embryo development and seed abortion phenotypes reverted to normal when RED1 complementation constructs were introduced into mutant plants. Small red1-2 homozygous plants can be successfully rescued by culturing immature seeds, indicating that seed abortion likely results from compromised tolerance to the desiccation process associated with seed maturation. Consistent with this observation, red1-2 seeds accumulate less protein, and the expression of two late embryo development reporter transgenes, LEA::GUS and beta-conglycinin::GUS, was significantly weak and started relatively late in the red1-2 mutant lines compared to the wild type. The RED1 gene encodes a plant specific novel protein that is localized in the nucleus. These results indicate that RED1 plays important roles in embryo development, seed maturation and plant growth. PMID- 27477026 TI - Molecular dynamics of de novo telomere heterochromatin formation in budding yeast. AB - In the budding yeast Saccharomyces cerevisiae, heterochromatin structure is found at three chromosome regions, which are homothallic mating-type loci, rDNA regions and telomeres. To address how telomere heterochromatin is assembled under physiological conditions, we employed a de novo telomere addition system, and analyzed the dynamic chromatin changes of the TRP1 reporter gene during telomere elongation. We found that integrating a 255-bp, but not an 81-bp telomeric sequence near the TRP1 promoter could trigger Sir2 recruitment, active chromatin mark(s)' removal, chromatin compaction and TRP1 gene silencing, indicating that the length of the telomeric sequence inserted in the internal region of a chromosome is critical for determining the chromatin state at the proximal region. Interestingly, Rif1 but not Rif2 or yKu is indispensable for the formation of intra-chromosomal silent chromatin initiated by telomeric sequence. When an internal short telomeric sequence (e.g., 81 bp) gets exposed to become a de novo telomere, the herterochromatin features, such as Sir recruitment, active chromatin mark(s)' removal and chromatin compaction, are detected within a few hours before the de novo telomere reaches a stable length. Our results recapitulate the molecular dynamics and reveal a coherent picture of telomere heterochromatin formation. PMID- 27477027 TI - The coiled-coil domain containing protein Ccdc136b antagonizes maternal Wnt/beta catenin activity during zebrafish dorsoventral axial patterning. AB - The coiled-coil domain containing protein CCDC136 is a putative tumor suppressor and significantly down-regulated in gastric and colorectal cancer tissues. However, little is known about its biological functions during vertebrate embryo development. Zebrafish has two CCDC136 orthologs, ccdc136a and ccdc136b, but only ccdc136b is highly expressed during early embryonic development. In this study, we demonstrate that ccdc136b is required for dorsal-ventral axial patterning in zebrafish embryos. ccdc136b morphants display strongly dorsalized phenotypes. Loss- and gain-of-function experiments in zebrafish embryos and mammalian cells show that Ccdc136b is a crucial negative regulator of the Wnt/beta-catenin signaling pathway, and plays a critical role in the establishment of the dorsal ventral axis. We further find that Ccdc136b interacts with APC, promotes the binding affinity of APC with beta-catenin and then facilitates the turnover of beta-catenin. These results provide the first evidence that CCDC136 regulates zebrafish dorsal-ventral patterning by antagonizing Wnt/beta-catenin signal transduction and suggest a potential mechanism underlying its suppressive activity in carcinogenesis. PMID- 27477028 TI - The effect of L-dopa in Parkinson's disease as revealed by neurophysiological studies of motor and sensory functions. AB - INTRODUCTION: This review will first discuss evidence of motor and sensory abnormalities as yielded by neurophysiological techniques in patients with PD. It will then go on to describe the effects of L-dopa replacement on motor and sensory abnormalities in PD as assessed by neurophysiological studies. Areas covered: We analyzed papers in English using Pubmed with the following keywords: L-dopa, dopamine, bradykinesia, basal ganglia, kinematic analysis, TMS, motor cortex plasticity, motor cortex excitability, somatosensory discrimination threshold, pain Expert commentary: L-dopa improves the amplitude and speed of upper limb voluntary movements, but it does not restore abnormalities in the sequence effect or voluntary facial movements. L-dopa only partially normalizes changes in motor cortex excitability and plasticity and has also contrasting effects on the sensory system and on sensory-motor integration. The neurophysiological studies reviewed here show that PD is more than a hypo dopaminergic disease, and non-dopaminergic mechanisms should also be considered. PMID- 27477029 TI - Adiposity induced by interleukin-17A blockade. PMID- 27477030 TI - Usefulness of overnight pulse oximeter as the sleep assessment tool to assess the 6-year risk of road traffic collision: evidence from the Taiwan Bus Driver Cohort Study. AB - Background: In order to support health service organizations in arranging a system for prevention of road traffic collisions (RTC), it is important to study the usefulness of sleep assessment tools. A cohort study was used to evaluate the effectiveness of subjective and objective sleep assessment tools to assess for the 6-year risk of both first RTC event only and recurrent RTC events. Methods: The Taiwan Bus Driver Cohort Study (TBDCS) recruited 1650 professional drivers from a large bus company in Taiwan in 2005. The subjects were interviewed in person, completed the sleep assessment questionnaires and had an overnight pulse oximeter survey. Moreover, this cohort of drivers was linked to the National Traffic Accident Database (NTAD) and researchers found 139 new RTC events from 2005 to 2010. Primary outcomes were traffic collisions from NTAD, nocturnal oxygen desaturation index (ODI) from pulse oximeter, Pittsburg sleeping quality score, Epworth daytime sleepiness score, Snore Outcomes Survey score and working patterns from questionnaires. A Cox proportional hazards model and an extended Cox regression model for repeated events were performed to estimate the hazard ratio for RTC. Results: The RTC drivers had increased ODI4 levels (5.77 +/- 4.72 vs 4.99 +/- 6.68 events/h; P = 0.008) and ODI3 levels (8.68 +/- 6.79 vs 7.42 +/- 7.94 events/h; P = 0.007) in comparison with non-RTC drivers. These results were consistent regardless of whether ODI was evaluated as a continuous or a categorical variable. ODI4 and ODI3 levels increased the 6-year RTC risks among professional drivers even after adjusting for age, education, history of cardiovascular disease, caffeine intake, sleeping pills used, bus driving experience and shift modes. Moreover, there was an increased trend for ODI between the stratification of the number of RTCs in comparison with the non-RTC group. In the extended Cox regression models for repeated RTC events with the Anderson and Gill intensity model and Prentice-Williams-Petersen model, measurement of ODI increased hazards of the subsequent RTC events. Conclusion: This study showed that an increase in the 6-year risk of RTC was associated with objective measurement of ODI for a sign of sleep-disordered breathing (SDB), but was not associated with self-reported sleeping quality or daytime sleepiness. Therefore, the overnight pulse oximeter is an effective sleep assessment tool for assessing the risk of RTC. Further research should be conducted regarding measures to prevent against SDB among professional drivers. PMID- 27477031 TI - Exercise interventions and prevention of fall-related fractures in older people: a meta-analysis of randomized controlled trials. AB - Background: This meta-analysis aimed to determine whether exercise interventions were effective in preventing fall-related fractures in older people. The treatment effects on rate of falls, leg strength and balance were also examined. Methods: An electronic database search was conducted in PubMed, EMBASE, the Cochrane library and PEDro up to 1 September 2015. Randomized controlled trials (RCTs) that conducted exercise interventions and reported fall-related fracture data in older people were included. The primary outcome was the treatment effects on fall-related fractures determined by relative risk (RR) and 95% confidence interval (CI). The treatment effects on falls, leg strength and balance were also reported using rate ratio (RaR) with 95% CI and standardized mean difference (SMD) with 95% CI, respectively. Random effects models were used for meta analysis. Results: Fifteen studies including 3136 participants met the inclusion criteria. Exercise had a beneficial effect on reduction of fall-related fractures, with pooled estimates of RR 0.604 (95% CI 0.453 - 0.840, P = 0.003, I 2 = 0%). The rate of falls (RaR 0.856, 95% CI 0.778 - 0.941, P = 0.001, I 2 = 45%) and leg strength (SMD 0.613, 95% CI 0.119 - 1.107, P = 0.015, I 2 = 76.7%) were also potentially affected by exercise interventions. These only had a marginally beneficial effect on balance (SMD 0.468, 95% CI -0.011 - 0.947, P = 0.055, I 2 = 93.6%). Conclusions: Our findings implied that exercise interventions were effective in preventing fall-related fractures and reducing risk factors of fall-related fractures in older people. PMID- 27477033 TI - The predictive factors for remission of chronic spontaneous urticaria in childhood: Outcome from a prospective study. AB - BACKGROUND: There are few studies in children on the natural course of chronic spontaneous urticaria (CSU) because of its relative infrequency in childhood. OBJECTIVE: To estimate the rate of remission and evaluate the prognostic factors in children with CSU. METHOD: A total of 52 children with CSU were prospectively followed over a period of three years. RESULTS: The remission rates at 12 months and 36 months were 32.7% and 48.1%. The mean duration of disease at the first visit in the non-remission group was higher than in the remission group at the end of the study (P=0.016). The remission rate of the patients who had been treated by standard dose antihistamine was higher than that of the patients who had been treated with the high-dose antihistamine and combination medications (P=0.004, P<0.001). The treatment steps were independent prognostic factors for remission by logistic regression analysis. CONCLUSION: Our study indicates that urticaria controlled by a standard dose of antihistamine can predict a good prognosis independently from disease duration at first visit. PMID- 27477032 TI - Comparison of two diagnostic techniques, skin-prick test and component resolved diagnosis in the follow-up of a cohort of paediatric patients with pollinosis. Multicentre pilot study in a highly exposed allergenic area. AB - BACKGROUND: Over the last years, different works have been published about the importance of incorporating new diagnosis techniques in allergic patients such as component-resolved diagnosis (CRD). The objective of this study is to compare the evolution of allergic sensitisation profiles by means of CRD and cutaneous tests (SPT) on pollen-allergic patients. METHODS: A total of 123 patients aged between 2 and 14 years were included in an open, prospective, multicentre study. All the children had symptoms suggestive of seasonal respiratory allergic disease, with the diagnosis confirmed by cutaneous tests. Specific-IgE to major pollen allergens (CRD) and SPT were performed at basal and after three years of follow up. RESULTS: Out of 123 patients included, a total of 85 were analysed. The mean age was 8+/-3 years. Significant changes in the allergic sensitisation profiles were observed for the most prevalent allergens (Olea and grass) but it is in grass, the most relevant allergen in terms of allergen pressure, where changes in both absolute and relative frequencies between SPT and CRD were more evident. CONCLUSION: CRD seems to be an essential tool to carry out an appropriate follow up of patients with allergic respiratory disease, as well as to decide on the immunotherapy composition that best matches the allergic sensitisation profile of patients. PMID- 27477034 TI - The relationship between serum levels of vitamin D with asthma and its symptom severity: A case-control study. AB - BACKGROUND: Asthma is a heterogeneous disease characterised by chronic inflammatory airways, and is affected by several immunological factors. One of the most discussed and researched hypotheses is the relationship between vitamin D serum levels with asthma. This study aimed to investigate the relationship between vitamin D serum levels with asthma and pulmonary functions in children in Kurdistan province, Iran. MATERIALS AND METHODS: In this case-control study, 120 children ranging from 6 to 18 years were referred in summer for investigation. Participants were divided into two groups: asthma group, N=60; and control group, N=60. After serum separation, samples were analysed using vitamin D ELISA kit. Additionally, pulmonary function test and serum IgE levels were measured in both groups. Data were analysed using Chi-square test and multiple regression analysis in SPSS15. RESULTS: No difference was shown between the groups in terms of gender composition (male: 57.5; female: 42.5) (P>0.05). Average Vitamin D serum level in the case group (17.98+/-8.68) was less than in control group (22.35+/-6.26) (P<0.01). In addition, the difference of vitamin D deficiency in level of suboptimal between the asthma (17.77+/-6.41) and the control group (24.9+/-3.18) was statistically significant (P<0.0001). Positive correlation existed between vitamin D levels with FEV1, FVC, and FEV1/FVC. Multiple regression analysis showed a reverse relationship between vitamin D levels with IgE serum levels; this remained after adjustment for potential confounders (e.g. age, sex, BMI, FEV1, and FVC). CONCLUSION: The results showed that serum levels of vitamin D in asthma patients were less than in healthy people, and also reduced lung function in these patients. So, the serum levels of vitamin D in asthma patients must be checked continuously. PMID- 27477035 TI - Effects of low-dose combined drospirenone-ethinylestradiol on perimenstrual symptoms experienced by women with endometriosis. AB - OBJECTIVE: To determine the effectiveness of a 24/4-day regimen of a low-dose combination drospirenone-ethinylestradiol oral contraceptive in alleviating perimenstrual symptoms among Japanese women with endometriosis. METHODS: The present prospective, non-randomized study enrolled women diagnosed with endometriosis radiographically or surgically at the Kyoto Prefectural University of Medicine hospital, Japan, between December 1, 2010 and August 31, 2013. Patients received treatment with oral drospirenone-ethinylestradiol for six treatment cycles. Dysmenorrhea, chronic pelvic pain, and dyspareunia severity were assessed using visual analog scale scores after three and six treatment cycles, and changes in perimenstrual symptoms were assessed using the menstrual distress questionnaire (MDQ) scores. RESULTS: In total, 46 patients were recruited for the study. Dysmenorrhea, chronic pelvic pain, and dyspareunia were all significantly reduced after both three and six treatment cycles in comparison with baseline (P<0.001 for all comparisons). After six treatment cycles, significant reductions were observed for all menstrual MDQ measures and for the premenstrual water retention and negative-effect MDQ measures (all P<0.05). CONCLUSIONS: Combination drospirenone-ethinylestradiol was effective in the treatment of dysmenorrhea, chronic pelvic pain, dyspareunia, and somatic/psychological symptoms in Japanese women with endometriosis. PMID- 27477036 TI - Galactose-decorated light-responsive hydrogelator precursors for selectively killing cancer cells. AB - A multi-functional gelator precursor with high photosensitivity is rationally designed, which can not only selectively target hepatocellular carcinoma (HCC) cells, but also form intracellular self-assembly triggered by light and subsequently inducing cell death. The study develops a methodology to design biological targets of supramolecular self-assembly under external stimuli for cancer research. PMID- 27477037 TI - Made to Hear. PMID- 27477038 TI - Similarities Between Deaf or Hard of Hearing and Hearing Students' Awareness of Affective Words' Valence in Written Language. AB - An affective priming task was used with two cohorts of college students, one deaf or hard of hearing (D/HH), the other hearing, in two experiments. The same set of affective-word targets, preceded by "??" in Experiment 1 but by affective-word primes of the same valence as the targets in Experiment 2, were presented vertically above or below the screen center. Stimuli that preceded the targets were shown at the screen center. D/HH participants generally performed more poorly than hearing participants, but both groups performed similarly in that both did better on the positive targets than on the negative in both experiments, and on supporting metaphorical associations between valence and vertical positions (Meier & Robinson, 2004), as indicated by reaction times, in Experiment 2. The researchers concluded that D/HH and hearing college students perform similarly in developing cognition-grounded representations of affective words in written language. PMID- 27477039 TI - Understanding the Relationship Between Teacher Behavior and Motivation in Students with Acquired Deafblindness. AB - Because little is known about teacher-student relationships that involve students with acquired deafblindness, the authors performed a multiple case study with a multiple-method design to investigate the relationship between need-supportive teaching behaviors and student engagement. Using self-determination theory (Deci & Ryan, 2000), they analyzed video observations of interactions. It was found that teachers' provision of structure, autonomy support, and involvement often cooccurs with higher levels of student engagement. Moreover, varying degrees of need support over time seem to result in varying levels of student engagement. Examples are provided of need-supportive teaching behaviors that can be used to foster the motivation of students with acquired deafblindness. PMID- 27477040 TI - Analysis of Interaction and Attention Processes in a Child With Congenital Deafblindness. AB - Children with deafblindness need support to be able to understand the world and to have access to information. The authors analyzed a dyad consisting of a child with congenital deafblindness and a specialized teacher. The study included participant observations and audiovisual recordings. It was found that the child showed attention to the teacher in activities involving music and rhythm. As potential forms of nonverbal communication, the child presented vocalization, touch, body contact, body movements, facial expressions, and tears. The teacher's forms of communication were verbal, touch, visual, rhythm, and sign language. It was concluded that a significant communication partner is essential to identify, interpret, and respond to attention and communicative behaviors. Use of other forms of communication must comply with individual characteristics so that the child with deafblindness can receive information from the environment through these senses and thus be guaranteed access to the world. PMID- 27477041 TI - The English-Language and Reading Achievement of a Cohort of Deaf Students Speaking and Signing Standard English: A Preliminary Study. AB - Research suggests that English-language proficiency is critical if students who are deaf or hard of hearing (D/HH) are to read as their hearing peers. One explanation for the traditionally reported reading achievement plateau when students are D/HH is the inability to hear insalient English morphology. Signing Exact English can provide visual access to these features. The authors investigated the English morphological and syntactic abilities and reading achievement of elementary and middle school students at a school using simultaneously spoken and signed Standard American English facilitated by intentional listening, speech, and language strategies. A developmental trend (and no plateau) in language and reading achievement was detected; most participants demonstrated average or above-average English. Morphological awareness was prerequisite to high test scores; speech was not significantly correlated with achievement; language proficiency, measured by the Clinical Evaluation of Language Fundamentals-4 (Semel, Wiig, & Secord, 2003), predicted reading achievement. PMID- 27477042 TI - Perceptions of Social Networks by Adults Who Are Deafblind. AB - Findings are presented from a descriptive qualitative study of 10 adults who were deafblind who were interviewed about their social lives. Additional data were collected from a discussion board and e-mails from the study participants. Three findings emerged from the data: (a) Navigating adaptations was a significant part of socialization. (b) Gaps existed in work, family, and formal support networks. PMID- 27477043 TI - Employment and Adults Who Are Deaf or Hard of Hearing: Current Status and Experiences of Barriers, Accommodations, and Stress in the Workplace. AB - In an integrative review of the literature covering the period 2004-2016, the author presents a current picture of the situation of people who are deaf or hard of hearing (DHH) relative to employment and careers-particularly the barriers, facilitators, and stress levels experienced by working DHH adults. First, an overview is provided of findings from recent reports on employment outcomes for people who are DHH. Second, the author reviews the literature on employment and workplace barriers, facilitators, and accommodations for people who are DHH, and relates findings about DHH people's workplace-related stress and fatigue levels and the associated issues of job demand, job control, and social support in the workplace. The article concludes with a discussion of the implications of these findings, in particular the ways in which barriers to full participation of DHH people in the labor market can be addressed. PMID- 27477044 TI - Are the Most Prestigious Medical Journals Transparent Enough? AB - The International Committee of Medical Journal Editors (ICMJE) has played a critical role in enhancing medical science reporting. Transparency in research is one of its most important objectives and the ICMJE has issued requirements for various stakeholders. However, ICMJE member journals have repeatedly failed to fully comply with a few transparency requirements. PMID- 27477045 TI - Detection of Polyclonal Increases in Immunoglobulin G4 Subclass by Distinct Patterns on Capillary Serum Protein Electrophoresis: Diagnostic Pitfalls and Clinical Observations in a Study of 303 Cases. AB - OBJECTIVES: Autoimmunity, hypersensitivity, and the recently recognized set of syndromes collectively termed immunoglobulin G4-related disease (IgG4-RD) may be associated with increased serum IgG4 levels. We reviewed our experience detecting increased IgG4 by distinct serum protein electrophoresis (SPEP) patterns. METHODS: We studied 303 capillary SPEP cases with dome-like anodal gamma changes and increased measured serum IgG4. RESULTS: IgG4 ranged from 208 to 6,670 mg/dL (normal, <201 mg/dL). Seventeen of 91 cases evaluated by immunosubtraction appeared monotypic (16 kappa, 1 lambda), but all five cases further analyzed by isoelectric focusing appeared polyclonal. Six cases with markedly increased IgG4 had presumptive evidence of IgG4-RD. Sixteen of 45 assessed patients had autoantibodies. CONCLUSIONS: Increased polyclonal IgG4 has a characteristic SPEP pattern that may mimic monoclonal gammopathy, even on immunosubtraction. kappa Pseudo-restriction might reflect the naturally high kappa/lambda ratio of the IgG4 subclass. Autoantibodies were common, and the greatest IgG4 increases had clinical features of IgG4-RD. PMID- 27477046 TI - The best medicine? The influence of physical activity and inactivity on Parkinson's disease. AB - The incidence of Parkinson's disease (PD) is expected to increase as our population ages and will likely strain the projected capacity of our health care system. Despite being the most common movement disorder, there have been few noninvasive therapeutic advances for people with PD since the first levodopa clinical trial in 1961. The study of PD pathogenesis, combined with an appreciation for the biochemical mechanisms by which physical activity and exercise may impact physiology, has resulted in emerging hypotheses for new modifiable risk factors for PD. Physical activity and exercise as a means of preventing PD, or maintaining the functionality of people with PD, are a promising area of investigation. Conversely, physical inactivity is implicated in many disease states, some of which are also correlated with the development of PD, such as metabolic syndrome. The primary relationship between these diseases is likely rooted in heightened inflammation and oxidative stress at the cellular level. Physical activity and exercise as a means of attenuating inflammation have led to increased interest in related potential therapeutic targets for PD. Ultimately, these findings may translate into low-cost, universally available therapies for PD disease modification or prevention. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27477047 TI - A metered intake of milk following exercise and thermal dehydration restores whole-body net fluid balance better than a carbohydrate-electrolyte solution or water in healthy young men. AB - Appropriate rehydration and nutrient intake in recovery is a key component of exercise performance. This study investigated whether the recovery of body net fluid balance (NFB) following exercise and thermal dehydration to -2 % of body mass (BM) was enhanced by a metered rate of ingestion of milk (M) compared with a carbohydrate-electrolyte solution (CE) or water (W). In randomised order, seven active men (aged 26.2 (sd 6.1) years) undertook exercise and thermal dehydration to -2 % of BM on three occasions. A metered replacement volume of M, CE or W equivalent to 150 % of the BM loss was then consumed within 2-3 h. NFB was subsequently measured for 5 h from commencement of rehydration. A higher overall NFB in M than CE (P=0.001) and W (P=0.006) was observed, with no difference between CE and W (P=0.69). After 5 h, NFB in M remained positive (+117 (sd 122) ml) compared with basal, and it was greater than W (-539 (sd 390) ml, P=0.011) but not CE (-381 (sd 460) ml, P=0.077, d=1.6). Plasma osmolality (Posm) and K remained elevated above basal in M compared with CE and W. The change in Posm was associated with circulating pre-provasopressin (r s 0.348, P<0.001), a biomarker of arginine vasopressin, but could not account fully for the augmented NFB in M compared with CE and W. These data suggest that a metered approach to fluid ingestion acts in synergy with the nutrient composition of M in the restoration of NFB following exercise and thermal dehydration. PMID- 27477048 TI - Structure-Based Insights into the Role of the Cys-Tyr Crosslink and Inhibitor Recognition by Mammalian Cysteine Dioxygenase. AB - In mammals, the non-heme iron enzyme cysteine dioxygenase (CDO) helps regulate Cys levels through converting Cys to Cys sulfinic acid. Its activity is in part modulated by the formation of a Cys93-Tyr157 crosslink that increases its catalytic efficiency over 10-fold. Here, 21 high-resolution mammalian CDO structures are used to gain insight into how the Cys-Tyr crosslink promotes activity and how select competitive inhibitors bind. Crystal structures of crosslink-deficient C93A and Y157F variants reveal similar ~1.0-A shifts in the side chain of residue 157, and both variant structures have a new chloride ion coordinating the active site iron. Cys binding is also different from wild-type CDO, and no Cys-persulfenate forms in the C93A or Y157F active sites at pH6.2 or 8.0. We conclude that the crosslink enhances activity by positioning the Tyr157 hydroxyl to enable proper Cys binding, proper oxygen binding, and optimal chemistry. In addition, structures are presented for homocysteine (Hcy), D-Cys, thiosulfate, and azide bound as competitive inhibitors. The observed binding modes of Hcy and D-Cys clarify why they are not substrates, and the binding of azide shows that in contrast to what has been proposed, it does not bind in these crystals as a superoxide mimic. PMID- 27477049 TI - Nanoscale mechanics guides cellular decision making. AB - This study used novel, force-limited nanoscale tension gauges to investigate how force and substrate stiffness guide cellular decision-making during initial cell attachment and spreading on deformable substrates. The well-established dependence of cell traction and spreading on substrate stiffness has been attributed to levels of force exerted on molecular components in focal contacts. The molecular tension gauges used in this study enabled direct estimates of threshold, pico Newton forces that instructed decision-making at different stages of cell attachment, spreading, and adhesion maturation. Results show that the force thresholds controlling adhesion and spreading transitions depend on substrate stiffness. Reported findings agree qualitatively with a proposed model that attributes rigidity-dependent differences in cell spreading to stiffness dependent rates of competing biochemical processes. Moreover, estimated magnitudes of force thresholds governing transitions in cell attachment and spreading, based on these in situ measurements, were in remarkable agreement with prior less direct measurements. PMID- 27477050 TI - The role of sociodemographic risk and maternal behavior in the prediction of infant attachment disorganization. AB - Predictors of infant attachment disorganization were examined among 203 primiparous mothers (52% European American, 48% African American) and their infants (104 female). The Strange Situation Procedure was administered at one year. Global maternal insensitivity and overtly negative maternal behavior were observed during distress-eliciting tasks when infants were six months and one year old. Mothers reported on their demographics to yield a measure of sociodemographic risk (i.e., age, education, income-to-needs). Overtly negative maternal behavior was positively associated with the infant attachment disorganization rating scale score, but did not predict being classified as disorganized. Global maternal insensitivity was associated with higher attachment disorganization, both the rating and the classification, when sociodemographic risk was high but not when sociodemographic risk was low. The pattern of results did not vary by maternal race. The results provide some support for the view that negative maternal behavior and the combination of sociodemographic risk and global maternal insensitivity play a role in the development of infant attachment disorganization. PMID- 27477051 TI - Wide recognition of Culex pipiens and lack of detection of Culex torrentium through biomolecular differentiation of mosquitoes in the Emilia-Romagna region, Northern Italy. AB - The Culex pipiens complex includes species with reported differences in vector competence for arthropod-borne viruses, many of which are of significant importance to human health such as the West Nile virus and the Sindbis virus. This group of mosquitoes is difficult to distinguish morphologically; particularly as adult females. In Europe, the two species of the complex, Culex pipiens Linnaeus 1758 and Culex torrentium Martini 1925, are often found sympatrically. With the aim to characterize the presence and spread of both species in the Emilia-Romagna region, Northern Italy, mosquitoes of the complex - collected during the West Nile virus surveillance plans - were tested by multiplex real-time PCR for the detection of the two species Cx. pipiens and Cx. torrentium. A total of 24 165 mosquitoes, collected between 2012 and 2014 from 105 sites, and sorted in 204 pools, were tested. All tested pools were found to be composed of Cx. pipiens, whereas Cx. torrentium was not detected. These results indicate a likely absence of Cx. torrentium mosquitoes within the surveyed territory, whereas Cx. pipiens is widely distributed in the area mentioned. This is in line with previous reports, which describe a pre-alpine distribution of Cx. torrentium in Italy. PMID- 27477052 TI - Cold Spots in Protein Binding. AB - Understanding the energetics and architecture of protein-binding interfaces is important for basic research and could potentially facilitate the design of novel binding domains for biotechnological applications. It is well accepted that a few key residues at binding interfaces (binding hot spots) are responsible for contributing most to the free energy of binding. In this opinion article, we introduce a new concept of 'binding cold spots', or interface positions occupied by suboptimal amino acids. Such positions exhibit a potential for affinity enhancement through various mutations. We give several examples of cold spots from different protein-engineering studies and argue that identification of such positions is crucial for studies of protein evolution and protein design. PMID- 27477053 TI - Characteristics of Residual Atrial Posterior Wall and Roof-Dependent Atrial Tachycardias after Pulmonary Vein Isolation. AB - BACKGROUND: Roof-dependent atrial tachycardia (roof AT) sometimes occurs after pulmonary vein isolation (PVI) of atrial fibrillation (AF). This study aimed to investigate the relationship between the anatomy of the residual left atrial posterior wall and occurrence of roof AT. METHODS: A total of 265 patients with AF who underwent PVI were enrolled. After the PVI, induced or recurrent roof AT was confirmed by an entrainment maneuver or activation mapping using a three dimensional (3D) mapping system. To identify the predictors of roof AT, the minimum distance between both PVI lines (d-PVI) was measured by a 3D mapping system and the anatomical parameters, including the left atrial (LA) diameter, left atrial volume index (LAVi), and shape of the left atrial roof, were analyzed by 3D computed tomography. RESULTS: Roof AT was documented in 11 (4.2%) of 265 patients. A multivariable analysis demonstrated that the d-PVI, Deep V shape of the LA roof, and LAVi were associated with roof AT occurrences (d-PVI: odds ratio: 0.72, confidence interval [CI]: 0.61-0.86, P < 0.001; Deep V shape: odds ratio: 0.19, CI: 0.04-0.82, P = 0.03; LAVi: odds ratio: 1.05, CI: 1.02-1.07, P = 0.001). A receiver-operating characteristic curve analysis yielded an optimal cut off value of 15.5 mm and 55.7 mL/m2 for the d-PVI and LAVi, respectively. CONCLUSION: The shorter d-PVI at the LA roof, greater LAVi, and Deep V shape were associated with the occurrence of a roof AT. PMID- 27477054 TI - A single amino acid (Asp159) from the dog prion protein suppresses the toxicity of the mouse prion protein in Drosophila. AB - Misfolding of the prion protein (PrP) is the key step in the transmission of spongiform pathologies in humans and several animals. Although PrP is highly conserved in mammals, a few changes in the sequence of endogenous PrP are proposed to confer protection to dogs, which were highly exposed to prion during the mad-cow epidemics. D159 is a unique amino acid found in PrP from dogs and other canines that was shown to alter surface charge, but its functional relevance has never been tested in vivo. Here, we show in transgenic Drosophila that introducing the N159D substitution on mouse PrP decreases its turnover. Additionally, mouse PrP-N159D demonstrates no toxicity and accumulates no pathogenic conformations, suggesting that a single D159 substitution is sufficient to prevent PrP conformational change and pathogenesis. Understanding the mechanisms mediating the protective activity of D159 is likely to lessen the burden of prion diseases in humans and domestic animals. PMID- 27477056 TI - China's One-Child Policy and U.S. Long-Term Care. PMID- 27477057 TI - Sensitivity enhanced (14)N/(14)N correlations to probe inter-beta-sheet interactions using fast magic angle spinning solid-state NMR in biological solids. AB - (14)N/(14)N correlations are vital for structural studies of solid samples, especially those in which (15)N isotopic enrichment is challenging, time consuming and expensive. Although (14)N nuclei have high isotopic abundance (99.6%), there are inherent difficulties in observing (14)N/(14)N correlations due to limited resolution and sensitivity related to: (i) low (14)N gyromagnetic ratio (gamma), (ii) large (14)N quadrupolar couplings, (iii) integer (14)N spin quantum number (I = 1), and (iv) very weak (14)N-(14)N dipolar couplings. Previously, we demonstrated a proton-detected 3D (14)N/(14)N/(1)H correlation experiment at fast magic angle spinning (MAS) on l-histidine.HCl.H2O utilizing a through-bond (J) and residual dipolar-splitting (RDS) based heteronuclear multiple quantum correlation (J-HMQC) sequence mediated through (1)H/(1)H radio frequency driven recoupling (RFDR). As an extension of our previous work, in this study we show the utility of dipolar-based HMQC (D-HMQC) in combination with (1)H/(1)H RFDR mixing to obtain sensitivity enhanced (14)N/(14)N correlations in more complex biological solids such as a glycyl-l-alanine (Gly-l-Ala) dipeptide, and parallel (P) and antiparallel (AP) beta-strand alanine tripeptides (P-(Ala)3 and AP-(Ala)3, respectively). These systems highlight the mandatory necessity of 3D (14)N/(14)N/(1)H measurements to get (14)N/(14)N correlations when the amide proton resonances are overlapped. Moreover, the application of long selective (14)N pulses, instead of short hard ones, is shown to improve the sensitivity. Globally, we demonstrate that replacing J-scalar with dipolar interaction and hard- with selective-(14)N pulses allows gaining a factor of ca. 360 in experimental time. On the basis of intermolecular NH/NH distances and (14)N quadrupolar tensor orientations, (14)N/(14)N correlations are effectively utilized to make a clear distinction between the parallel and antiparallel arrangements of the beta-strands in (Ala)3 through the observation of inter-beta sheet correlations. PMID- 27477055 TI - The number of alpha-synuclein proteins per vesicle gives insights into its physiological function. AB - Although it is well established that the protein alpha-synuclein (alphaS) plays an important role in Parkinson's disease, its physiological function remains largely unknown. It has been reported to bind membranes and to play a role in membrane remodeling processes. The mechanism by which alphaS remodels membranes is still debated; it may either affect its physical properties or act as a chaperone for other membrane associated proteins. To obtain insight into the role of alphaS in membrane remodeling we investigated the number of alphaS proteins associated with single small vesicles in a neuronal cell model. Using single molecule microscopy and photo-bleaching approaches, we most frequently found 70 alphaS-GFPs per vesicle. Although this number is high enough to modulate physical membrane properties, it is also strikingly similar to the number of synaptobrevins, a putative interaction partner of alphaS, per vesicle. We therefore hypothesize a dual, synergistic role for alphaS in membrane remodeling. PMID- 27477058 TI - Extended carrier lifetimes and diffusion in hybrid perovskites revealed by Hall effect and photoconductivity measurements. AB - Impressive performance of hybrid perovskite solar cells reported in recent years still awaits a comprehensive understanding of its microscopic origins. In this work, the intrinsic Hall mobility and photocarrier recombination coefficient are directly measured in these materials in steady-state transport studies. The results show that electron-hole recombination and carrier trapping rates in hybrid perovskites are very low. The bimolecular recombination coefficient (10( 11) to 10(-10) cm(3) s(-1)) is found to be on par with that in the best direct band inorganic semiconductors, even though the intrinsic Hall mobility in hybrid perovskites is considerably lower (up to 60 cm(2) V(-1) s(-1)). Measured here, steady-state carrier lifetimes (of up to 3 ms) and diffusion lengths (as long as 650 MUm) are significantly longer than those in high-purity crystalline inorganic semiconductors. We suggest that these experimental findings are consistent with the polaronic nature of charge carriers, resulting from an interaction of charges with methylammonium dipoles. PMID- 27477061 TI - Reverse surface-polariton cherenkov radiation. AB - The existence of reverse Cherenkov radiation for surface plasmons is demonstrated analytically. It is shown that in a metal-insulator-metal (MIM) waveguide, surface plasmon polaritons (SPPs) excited by an electron moving at a speed higher than the phase velocity of SPPs can generate Cherenkov radiation, which can be switched from forward to reverse direction by tuning the core thickness of the waveguide. Calculations are performed in both frequency and time domains, demonstrating that a radiation pattern with a backward-pointing radiation cone can be achieved at small waveguide core widths, with energy flow opposite to the wave vector of SPPs. Our study suggests the feasibility of generating and steering electron radiation in simple plasmonic systems, opening the gate for various applications such as velocity-selective particle detections. PMID- 27477060 TI - Differential evolution algorithm based photonic structure design: numerical and experimental verification of subwavelength lambda/5 focusing of light. AB - Photonic structure designs based on optimization algorithms provide superior properties compared to those using intuition-based approaches. In the present study, we numerically and experimentally demonstrate subwavelength focusing of light using wavelength scale absorption-free dielectric scattering objects embedded in an air background. An optimization algorithm based on differential evolution integrated into the finite-difference time-domain method was applied to determine the locations of each circular dielectric object with a constant radius and refractive index. The multiobjective cost function defined inside the algorithm ensures strong focusing of light with low intensity side lobes. The temporal and spectral responses of the designed compact photonic structure provided a beam spot size in air with a full width at half maximum value of 0.19lambda, where lambda is the wavelength of light. The experiments were carried out in the microwave region to verify numerical findings, and very good agreement between the two approaches was found. The subwavelength light focusing is associated with a strong interference effect due to nonuniformly arranged scatterers and an irregular index gradient. Improving the focusing capability of optical elements by surpassing the diffraction limit of light is of paramount importance in optical imaging, lithography, data storage, and strong light-matter interaction. PMID- 27477059 TI - Executive function mediates prospective relationships between sleep duration and sedentary behavior in children. AB - Childhood sedentary behavior has been linked to increased obesity risk. Prior work has identified associations between sedentary behavior, executive function (EF), and sleep. This study tested the hypothesis that reduced sleep duration may adversely impact EF and lead to increased childhood sedentary behavior. Southern California schoolchildren participating in the school-based health promotion program Pathways to Health (N=709) were assessed annually from 4th through 6th grades (2010-2013) on self-report measures of sedentary behavior, sleep duration, and executive function. A series of path models were specified treating average nightly sleep duration and weekend wake/bed-time shift at 4th grade as predictors of 6th grade sedentary behavior. Four EF subdomains were tested as potential mediators of longitudinal associations at 5th grade. Significant associations between average nightly sleep duration, EF and sedentary behavior were identified (p<0.05), adjusting for participant gender, physical activity, SES, ethnicity, program group assignment, and the presence/absence of parental screen time rules. Fifth grade overall EF (p<0.05)-and in particular the subdomains of inhibitory control (p<0.05) and organization of materials (p<0.01)-significantly mediated the relationship between 4th grade sleep duration and 6th grade sedentary behavior (p<0.05). Furthermore, delay of weekend bed- or wake-times relative to weekdays was prospectively associated with decreased overall EF (p<0.05), but not increased sedentary behavior (p=0.35 for bed-time delay; p=0.64 for wake-time delay), irrespective of average nightly sleep duration. Findings suggest that sleep promotion efforts may reduce children's sedentary behavior both directly and indirectly through changes in EF. PMID- 27477063 TI - North American Forum on Family Planning Scientific Abstracts Denver, CO, November 5-7, 2016. PMID- 27477062 TI - Elvitegravir concentrations in seminal plasma in HIV-1-infected men. AB - OBJECTIVES: The aim of the study was to quantify elvitegravir (EVG) concentrations in the semen of HIV-1-infected men receiving antiretroviral therapy (ART) consisting of an elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) single-tablet regimen. METHODS: A phase IV, cross-sectional study was carried out including HIV-1-infected male adults with suppressed plasma HIV-1 RNA who switched ART to EVG/COBI/FTC/TDF. Total EVG concentrations at the end of the dosing interval (C24 h ) and HIV-1 RNA were measured in paired seminal plasma (SP) and blood plasma (BP) samples 4 weeks after switching to EVG/COBI/FTC/TDF. Validated liquid chromatography-tandem mass spectrometry (LC MS/MS) was used to quantify EVG concentrations, and HIV-1 RNA was determined by real-time polymerase chain reaction (PCR). RESULTS: Ten men were included. Their median age was 40 years (range 24-47 years), the median time on ART was 50 months (range 10-186 months), the median time with plasma HIV-1 RNA < 40 copies/mL was 37 months (range 7-113 months), and the median CD4 count was 737 cells/MUL (range 190-1122 cells/MUL). Four weeks after switching to EVG/COBI/FTC/TDF, all subjects had HIV-1 RNA < 40 copies/mL in both BP and SP. Median EVG C24 h was 277 ng/mL (range 64.8-1790 ng/mL) in BP and 169 ng/mL (range 12.8-792 ng/mL) in SP. A significant correlation was observed between BP and SP EVG concentrations (Spearman rho 0.952; P < 0.001). The median SP:BP EVG concentration ratio was 0.39 (range 0.20-0.92). EVG C24 h in SP was at least 23-fold the in vitro protein unbound 50% effective response (EC50 ) of HIV-1 clinical isolates (0.04-0.55 ng/mL). In all but one individual, EVG C24 h in SP was also higher than the blood plasma protein binding-adjusted 95% inhibitory concentration (IC95 ) of wild-type HIV-1 (45 ng/mL). CONCLUSIONS: Seminal EVG concentrations in HIV-infected men treated with EVG/COBI/FTC/TDF sufficed to contribute to maintaining HIV-1 RNA suppression in this compartment. PMID- 27477064 TI - "It was as if society didn't want a woman to get an abortion": a qualitative study in Istanbul, Turkey. AB - INTRODUCTION: In 1983, abortion without restriction as to reason was legalized in Turkey. However, at an international conference in 2012, the Prime Minister condemned abortion and announced his intent to draft restrictive abortion legislation. As a result of public outcry and protests, the law was not enacted, but media reports suggest that barriers to abortion access have since worsened. OBJECTIVES: We aimed to conduct a qualitative study exploring women's recent abortion experiences in Istanbul, Turkey. STUDY DESIGN: In 2015, we conducted 14 semi-structured in-depth interviews with women aged 18 or older who had obtained abortion care in Istanbul on/after January 1, 2009. We employed a multimodal recruitment strategy and analyzed these interviews for content and themes using deductive and inductive techniques. RESULTS: Women reported on a total of 19 abortions. Although abortion care is available in private facilities, only one public hospital provides abortion services without restriction as to reason. Women who had multiple abortions in different facility types described quality of care more positively in the private sector. Unmarried women considered their marital status when making the decision to seek an abortion and reported challenges obtaining comprehensive sexual and reproductive health services. All participants were familiar with the Turkish government's antiabortion discourse and believed that this was reflective of an overarching desire to restrict women's rights. CONCLUSION: Public abortion services in Istanbul are currently limited, and private abortion services are accessible but relatively expensive to obtain. Recent antiabortion political rhetoric appears to have negatively impacted access and service quality. IMPLICATIONS: This is the first qualitative study exploring women's experiences obtaining abortion services in Turkey since the proposed abortion restriction in 2012. Further research exploring the experiences of unmarried women and abortion accessibility in other regions of the country is warranted. PMID- 27477065 TI - Featured research at the 2016 North American Forum on Family Planning. PMID- 27477066 TI - Genome-Wide Assessment of the Binding Effects of Artificial Transcriptional Activators by High-Throughput Sequencing. AB - One of the major goals in DNA-based personalized medicine is the development of sequence-specific small molecules to target the genome. SAHA-PIPs belong to such class of small molecule. In the context of the complex eukaryotic genome, the differential biological effects of SAHA-PIPs are unclear. This question can be addressed by identifying the binding regions across the genome; however, it is a challenge to enrich small-molecule-bound DNA without chemical crosslinking. Here, we developed a method that employs high-throughput sequencing to map the binding area of small molecules throughout the chromatinized human genome. Analysis of the sequenced data confirmed the presence of specific binding sites for SAHA-PIPs from the enriched sequence reads. Mapping the binding sites and enriched regions on the human genome clarifies the reason for the distinct biological effects of SAHA-PIP. This approach will be useful for identifying the function of other small molecules on a large scale. PMID- 27477067 TI - Bioinspired Functionalized Melanin Nanovariants with a Range of Properties Provide Effective Color Matched Photoprotection in Skin. AB - Melanin and related polydopamine hold great promise; however, restricted fine tunabilility limits their usefulness in biocompatible applications. In the present study, by taking a biomimetic approach, we synthesize peptide-derived melanin with a range of physicochemical properties. Characterization of these melanin polymers indicates that they exist as nanorange materials with distinct size distribution, shapes, and surface charges. These variants demonstrate similar absorption spectra but have different optical properties that correlate with particle size. Our approach enables incorporation of chemical groups to create functionalized polyvalent organic nanomaterials and enables customization of melanin. Further, we establish that these synthetic variants are efficiently taken up by the skin keratinocytes, display appreciable photoprotection with minimal cytotoxicity, and thereby function as effective color matched photoprotective agents. In effect we demonstrate that an array of functionalized melanins with distinct properties could be synthesized using bioinspired green chemistry, and these are of immense utility in generating customized melanin/polydopamine like materials. PMID- 27477068 TI - Oil residue contamination of continental shelf sediments of the Gulf of Mexico. AB - We have investigated the distribution of a heavy oil residue in the coastal sediments of the Gulf of Mexico. The amount of the contamination was determined by high-temperature pyrolysis coupled with the Gas Chromatography-Mass Spectrometry (GCMS) of air-dried sediments. The pyrolysis products contain straight-chain saturated and unsaturated hydrocarbons, such as dodecane and 1 dodecene, resulting in a very characteristic pattern of double peaks in the GCMS. Hydrocarbons containing 8 to 23 carbon atoms were detected in the pyrolysis products. Using thermal pyrolysis we have found that the sediment samples collected along Texas, Louisiana, and Mississippi shores contain no detectable traces of oil residue, but most of the samples collected along Alabama and Florida shores contain ~200ppm of heavy oil residue. PMID- 27477069 TI - Review of the partitioning of chemicals into different plastics: Consequences for the risk assessment of marine plastic debris. AB - Marine plastic debris are found worldwide in oceans and coastal areas. They degrade only slowly and contain chemicals added during manufacture or absorbed from the seawater. Therefore, they can pose a long-lasting contaminant source and potentially transfer chemicals to marine organisms when ingested. In order to assess their risk, the contaminant concentration in the plastics needs to be estimated and differences understood. We collected from literature plastic water partition coefficients of various organic chemicals for seven plastic types: polydimethylsiloxane (PDMS), high-density, low-density and ultra-high molecular weight polyethylene (LDPE, HDPE, UHMWPE), polystyrene (PS), polypropylene (PP), and polyvinyl chloride (PVC). Most data was available for PDMS (1060) and LDPE (220), but much less for the remaining plastics (73). Where possible, regression models were developed and the partitioning was compared between the different plastic types. The partitioning of chemicals follows the order of LDPE~HDPE>=PP>PVC~PS. Data describing the impact of weathering are urgently needed. PMID- 27477070 TI - The Effects of Amplitudes Ultrasound-Assisted Solvent Extraction and Pretreatment Time on the Yield and Quality of Pistacia Khinjuk Hull Oil. AB - In this study, the effect of three amplitudes of ultrasound-assisted solvent extraction (UASE) (0, 25 and 50 %; 100 W, 30 kHz; the 0% treatment serving as control) on yield and quality of extracted oil from P. khinjuk hull at various pretreatment times (15, 30 and 45 min) was evaluated. The highest oil yields at the three amplitude levels tested were 24.4, 29.8 and 37.8% for 0, 25 and 50 %, respectively. Although increase in pretreatment time increased oil yield, pretreatment time at 30 and 45 min did not significantly different for both 25 and 50% amplitude. Furthermore, UASE did not significantly affect fatty acid composition, peroxide value (PV), conjugated diene value (CDV) and anisidine value (AnV) of extracted oils. UASE also increased tocopherols and tocoterienols content of oils but pretreatment time at 30 and 45 min did not significantly different for them. Therefore, UASE increase yield and quality of extracted oil and reduce extraction time. All these advantages make UASE a good substitute for the extraction of oil. PMID- 27477071 TI - Diester-containing Zwitterionic Gemini Surfactants with Different Spacer and Its Impact on Micellization Properties and Viscosity of Aqueous Micellar Solution. AB - A series of diester containing zwitterionic gemini surfactants, N,N-dimethyl-N alkyl-2-[[hydroxy (alkoxy) phosphinyl]oxy]-alkylammonium designated as C8(-)-S Cn(+), S = 2 and 3, n = 12, 14 and 16, were synthesized and characterized by instrumental techniques namely FT-IR, (1)H NMR, (13)C NMR, (31)P NMR and Mass spectral studies. These new gemini surfactants further investigated for their various surfactant properties. The critical micelle concentration (cmc) and the effectiveness of surface tension reduction (Picmc) were determined as a function of surfactant concentration by means of surface tension measurement. Micellization and viscosity properties were investigated by surface tension, electrical conductivity, dye micellization and rheology techniques. The findings of the aqueous surfactant system obtained were impacted by polarity, size and the nature of zwitterions as the surface. The thermodynamic and viscosity properties of these surfactants found to be based on the structures of gemini surfactants. PMID- 27477072 TI - Thermal Losses of Tertiary Butylhydroquinone (TBHQ) and Its Effect on the Qualities of Palm Oil. AB - The rules and patterns of thermal losses of tertiary butylhydroquinone (TBHQ) in palm oil (PO) and its effect on the qualities of PO were investigated by oven heating method. Volatilization and transformation products of TBHQ in PO were also studied in detail under heating treatment. Results showed that at low temperature (< 135 degrees C), TBHQ had better antioxidative properties, while its antioxidative potency to PO was significantly weakened at high temperature (>= 135 degrees C). In addition, as heating temperatures increased and heating time prolonged, losses of TBHQ significantly increased in PO. Volatilization was the major pathway for losses of TBHQ in PO under heating treatment. Meanwhile, a small portion of TBHQ was transformed and the major transformation product was 2 tertbutyl-1,4- benzoquinone (TQ). Moreover, TQ and several decomposition products of PO were also observed in the volatilization products of TBHQ. PMID- 27477073 TI - Enhanced Enzymatic Preparation of Biodiesel Using Ricinoleic Acid as Acyl Donor: Optimization Using Response Surface Methodology. AB - Castor oil methyl ester is a kind of biodiesel from castor oil. However, in those previous methods for biodiesel preparation using castor oil as feedstock, glycerol was the main by-product, which had a strong blocking effect on the immobilized enzyme activity and affected the mass transfer of reaction system. For avoiding the negative effect of glycerol on the enzymatic esterification, biodiesel was prepared using ricinoleic acid (RA) as acyl donor. Enzyme screening was also studied, and the effects of reaction temperature, molar ratio of ricinoleic acid and methanol, enzyme load, and reaction time, on the preparation of castor methyl ester were also evaluated. Response surface methodology (RSM) was used to optimize the interaction effect of reaction variables (reaction temperature (30-70 degrees C), enzyme load (2-7%; relative to the weight of total substrates), molar ratio of methanol to ricinoleic acid (2:1-10:1), and reaction time (0.5-2.5 h)) on the acid value (AV) and the degree of esterification (DE). Validation of the RSM model was verified by the good agreement between the experimental and the predicted values of AV and DE. The optimum preparation conditions were as follows: reaction temperature, 48.2 degrees C; enzyme load, 5.8%; molar ratio of methanol to ricinoleic acid, 5.56:1; reaction time, 2.36 h. Under these conditions, the AV and DE of the esterification reaction are 10.36+/ 1.05 mgKOH/g and 94.03+/-0.60%, respectively. The relationship between initial reaction rate and temperature was also established, and the activation energy (Ea) of the enzymatic esterification is 33.87 KJ/mol. PMID- 27477074 TI - Inhibitory Effect of Dihydrosphingosine with alpha-Tocopherol on Volatile Formation during the Autoxidation of Polyunsaturated Triacylglycerols. AB - The effect of dihydrosphingosine (d18:0) on triacylglycerol (TAG) oxidation was examined with and without alpha-tocopherol. Three types of TAG from fish, linseed, and soybean oil were oxidized at 50 degrees C to determine the effect of dihydrosphingosine (d18:0) with or without alpha-tocopherol on triacylglycerol (TAG) oxidation. The analysis of oxygen consumption and total volatile formation demonstrated a small effect of d18:0 on TAG oxidation in the absence of alpha tocopherol. On the other hand, the combination of d18:0 with alpha-tocopherol showed strong antioxidant activity and completely inhibited volatile formation within 1400 h for soybean oil TAG, 650 h for linseed oil TAG, and 380 h for fish oil TAG. PMID- 27477075 TI - Incorporation of Palmitic Acid or Stearic Acid into Soybean Oils Using Enzymatic Interesterification. AB - Incorporations of nature fatty acids which were palmitic acid and stearic acid into the end positions of soybean oils were done using sn-1,3 specific immobilised lipase from Rhizomucor miehei at different ratios in order to produce symmetrical triglycerides without changing the fatty acids at sn-2 position. The optimum ratio for the process was 25:75 w/w. There were 19.2% increase of SFA for P25 and 16% increase for S25 at the sn-1,3 positions. The research findings indicated that the structured lipids produced from enzymatic interesterification possessed a higher oxidative stability than soybean oil. The newly formed structured lipids (SUS type) could be good sources for various applications in food industry. PMID- 27477077 TI - Circadian oscillations of KaiA-KaiC and KaiB-KaiC complex formations in an in vitro reconstituted KaiABC clock oscillator. AB - The circadian clock is an endogenous biological mechanism that generates autonomous daily cycles in physiological activities. The phosphorylation levels of KaiC oscillated with a period of 24 h in an ATP-dependent clock oscillator reconstituted in vitro from KaiA, KaiB and KaiC. We examined the complex formations of KaiA and KaiB with KaiC in the KaiABC clock oscillator by fluorescence correlation spectrometry (FCS) analysis. The formation of KaiB containing protein complex(es) oscillated in a circadian manner, with a single peak at 12 h and single trough at 24 h in the circadian cycle, whereas that of KaiA-containing protein complex(es) oscillated with two peaks at 12 and 24 h. FCS and surface plasmon resonance analyses showed that the binding affinity of KaiA for a mutant KaiC with Ala substitutions at the two phosphorylation sites considered to mimic the nonphosphorylated form of KaiC (np-KaiC) was higher than that for a mutant KaiC with Asp substitutions at the two phosphorylation sites considered to mimic the completely phosphorylated form of KaiC (cp-KaiC). The results from the study suggest that a KaiA-KaiB-cp-KaiC ternary complex and a KaiA-np-KaiC complex were formed at 12 and 24 h, respectively. PMID- 27477078 TI - Dual-modulation, dual-wavelength, optical polarimetry system for glucose monitoring. AB - A dual modulation optical polarimetry system utilizing both laser intensity and polarization modulation was designed, built, and tested. The system was designed to reduce complexity and enhance the speed in order to facilitate the reduction of motion-induced time-varying birefringence, which is one of the major limitations to the realization of polarimetry for glucose monitoring in the eye. The high-speed less complex technique was tested using in vitro phantom studies with and without motion artifact introduced. The glucose concentration ranged from 0 to 600 mg/dl and the glucose measurements demonstrated a standard error of prediction to within 8.1 mg/dl without motion and to within 13.9 mg/dl with motion. Our feedback control systems took less than 10 ms to reach stabilization, which is adequately fast to eliminate the effect of time-varying birefringence. The results indicate that this new optical polarimetric approach has improved the speed and reduced the complexity, showing the potential for it to be used for noninvasive glucose measurements. PMID- 27477076 TI - Photoredox Catalysis in Organic Chemistry. AB - In recent years, photoredox catalysis has come to the forefront in organic chemistry as a powerful strategy for the activation of small molecules. In a general sense, these approaches rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single electron transfer with organic substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon-carbon and carbon-heteroatom bonds. PMID- 27477079 TI - Hypertensive patients exhibit an altered metabolism. A specific metabolite signature in urine is able to predict albuminuria progression. AB - Hypertension (HTN) is increasing in prevalence, and albuminuria is a strong indicator of cardiovascular risk and renal damage progression. Despite blood pressure control with chronic treatment, a relevant subgroup of patients develop albuminuria. However, the biological factors responsible for albuminuria development and progression are underexplored. We aimed to identify key metabolic targets and biological pathways involved in the negative progression of cardiovascular and renal damage in hypertensives undergoing chronic treatment. A series of 1533 patients were followed for 5 years to investigate the evolution of albuminuria. Patients were classified as: (1) patients with persistent normoalbuminuria; (2) patients developing de novo albuminuria; and (3) patients with maintained albuminuria. At the end of follow-up, urine from 30 nonhypertensive subjects (control group) and a representative cohort of 118 patients was collected for metabolomic analysis. Metabolic patterns of interest were identified in a first discovery phase by nuclear magnetic resonance and further confirmed by liquid chromatography-mass spectrometry. Metabolites corresponding to HTN or albuminuria were measured in a prospective study carried out in 35 individuals still in normoalbuminuria, to evaluate their potential as predictors of albuminuria development. Nine metabolites were significantly altered, linking beta-alanine metabolism, arginine and proline metabolism, and tricarboxylic acid cycle. The prospective study revealed a panel composed of guanidinoacetate, glutamate, and pantothenate, which was able to predict development of albuminuria. These metabolic signatures open new possibilities in hypertensive therapy and cardiovascular risk control, providing prompt and more efficient intervention, particularly in patients with worse cardiovascular prognosis. PMID- 27477081 TI - Overexpression of miR-29b reduces collagen biosynthesis by inhibiting heat shock protein 47 during skin wound healing. AB - Skin scar formation is characterized by excessive synthesis and aberrant deposition of collagens during wound healing. MicroRNAs are endogenous gene regulators critically involved in diverse biological events including skin scar formation and hold considerable promise as therapeutic targets. However, the detailed molecular mechanisms responsible for collagen production during skin wound repair and scar formation remain incompletely known. Here our data revealed that significant downregulation of miR-29b and upregulation of heat shock protein 47 (HSP47) were observed during wound healing in both excisional and burn wound models and also detected in facial skin scar as compared to adjacent healthy skin. HSP47, a specific chaperon for collagen production and secretion, was identified as a novel and direct post-transcriptional target of miR-29b in skin fibroblasts via bioinformatics prediction and experimental validation. Moreover, the regulatory functions of miR-29b in collagen biosynthesis are partially achieved through modulating HSP47 expression in skin fibroblasts. Furthermore, the profibrotic growth factor TGF-beta1 inhibited miR-29b transcription by activating TGF-beta/Smads signaling and in turn depressed HSP47 and enhanced collagen 1 production. In contrast, the proinflammatory cytokines IL-1beta and TNF-alpha significantly induced miR-29b transcription via activating NF-kappaB signaling but had no significant effect on HSP47 and collagen production in skin fibroblasts. Importantly, local delivery of miR-29b lentiviral particles inhibited HSP47 expression and collagen biosynthesis as well as suppressed angiogenesis, thus reducing scar formation in an excisional wound splinting model. Collectively, our data reveal that miR-29b can reduce collagen biosynthesis during skin wound healing likely via post-transcriptional inhibition of HSP47 expression. These findings also suggest that therapeutic targeting of miR-29b/HSP47 might be a viable alternative strategy to prevent or reduce scar formation. PMID- 27477080 TI - Gut microbiome and liver disease. AB - Gut microbiota changes are important in determining the occurrence and progression of chronic liver disease related to alcohol, nonalcoholic fatty liver disease, and cirrhosis. Specifically, the systemic inflammation, endotoxemia, and the vasodilation that leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy could be related to the gut milieu. Given the poor prognosis of these events, their prevention and early management are essential. Microbiota may be an essential component of the gut milieu that can impact these clinical events, and the study of their composition and function in a culture-independent manner could help understand the prognosis. Recent human and animal studies have shown that the relative abundance and the functional changes of microbiota in the stool, colonic mucosa, and saliva have varying consequences on the presence and prognosis of chronic liver disease and cirrhosis. The impact of therapies on the microbiota is slowly being understood and will likely lead to a more targeted approach to gut microbiota modification in chronic liver disease and cirrhosis. PMID- 27477082 TI - Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. AB - Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process. PMID- 27477084 TI - Feasibility of nurses measuring gait speed in older community-dwelling Emergency Department patients. AB - Gait speed assessment is a rapid, simple and objective measure for predicting risk of unfavorable outcomes which may provide better prognostic and reliable information than existing geriatric ED (Emergency Department) screening tools. This descriptive pilot project was designed to determine feasibility of implementing gait speed screening into routine nursing practice by objectively identifying patients with sub-optimal gait speeds. Participants included community-dwelling adults 65 years and older with plans for discharge following ED treatment. Patients with a gait speed <1.0 m/s were identified as "high-risk" for an adverse event, and referred to the ED social worker for individualized resources prior to discharge. Thirty-five patients were screened and nurse initiated gait speed screens were completed 60% of the time. This project demonstrates ED gait speed screening may be feasible. Implications for practice should consider incorporating gait speed screening into routine nursing assessment to improve provider ED decision-making and disposition planning. PMID- 27477083 TI - Does the vaginal microbiota play a role in the development of cervical cancer? AB - Persistent infection with oncogenic human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the VM and the presence of an HPV infection using next generation sequencing techniques identified higher microbial diversity in HPV positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with preinvasive disease (squamous intraepithelial neoplasia [SIL]) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host's innate immune response, susceptibility to infection, and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks. PMID- 27477085 TI - INFOSA intervention for caregivers of the elderly, an experimental study. AB - An experimental study was carried out in a geriatric hospital unit (pre-discharge at home) with repeated observations taken at baseline, on study completion and six months post-intervention to analyze the impact of a psychoeducational intervention INFOSA addressed to caregivers who support dependent elderly people, on burden, psychological distress and perceived support. Univariate regression models showed that the participants in the experimental group had less burden (OR 35, IC 95% 7.47-163.99) and emotional distress (OR 149.5, IC 95% 15. 57-1435.52) than participants in the control group. Odds ratios effect were statistically significant at post-test and six-month follow-up. The INFOSA intervention reduced burden and emotional distress and enhanced caregivers' perceived social support in the short-term, suggesting that applying the intervention for an extended period could maintain the positive effect in the long-term. PMID- 27477086 TI - Caregivers for older adults: Prevalence, characteristics, and health care utilization and expenditures. AB - The purpose of this study was to provide an overview of caregiver prevalence and characteristics and to estimate the impact of caregiving on health care utilization and expenditures among AARP(r) Medicare Supplement insureds to inform caregiver intervention strategies. A subgroup with live-in partners was used to investigate the additional effect of live-in health status on caregiver health. Multivariate regression models were utilized to determine caregivers' characteristics and associated impacts on their health care utilization and expenditures. Among respondents (n = 18,928), 14.9% self-identified as caregivers. The strongest characteristics included being younger, healthier, but reporting depression or loneliness. Caregivers of sicker live-ins were female, older and indicated moderate loneliness; caregivers of healthier live-ins were younger, healthier, but reported severe loneliness. Caregivers had significantly lower inpatient admissions and medical and prescription drug expenditures. These results indicated an adverse impact on psychological health associated with caregiving but no evidence of a negative impact on physical health. PMID- 27477087 TI - Ultrasound-guided central venous cannulation: Seeing clearer, being safer. PMID- 27477088 TI - A subchronic toxicity study of Radix Dipsaci water extract by oral administration in F344 rats. AB - Radix Dipsaci, the dried root of Dipsacus asperoides C.Y. Cheng & T.M.Ai, has therapeutic effects on various disorders, and in particular, bone and joint disease. Despite such ethnomedicinal benefits, there is very little information regarding its in vivo toxicity or adverse effects. This study was conducted to evaluate the potential toxicity of the Radix Dipsaci water Extract (RD-wE) by using F344 rats. The RD-wE was administered orally to rats at doses of 0, 125, 250, 500, 1000, and 2000 mg/kg body weight (bw)/day for 13 weeks. During the treatment period there were no mortalities attributed to RD-wE. Moreover, no toxic effects were observed with regard to body weight, clinical pathology (hematology, clinical biochemistry, and urinalysis), and anatomic pathology (gross findings, organ weight, and microscopic examination). The changes related to the treatment were excessive salivation at the mouth and soft feces, observed in male and female rats at 1000 or 2000 mg/kg bw/day, but these were not accompanied by any microscopic correlate or other pathophysiological changes. Based on these results, the oral no-observed-adverse-effect level of the RD-wE was considered to be 2000 mg/kg bw/day in both genders, although the target organs were not determined under the current experimental conditions. PMID- 27477089 TI - Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 3. Apparent discrepancies between LLNA and GPMT sensitisation potential: False positives or differences in sensitivity? AB - The Local Lymph Node Assay (LLNA) is the gold standard regulatory toxicology test for skin sensitisation along with the guinea pig maximisation test (GPMT). Compared with the GPMT, LLNA uses fewer animals, it is quantitative, and it gives a numerical prediction of potency. However several concerns have been raised with this assay, mainly related to false positives and false negatives. Over the years, many authors, including the developers of the assay, have presented cases where there have been discrepancies between the GMPT and LLNA results. Several theories have been put forward for these discrepancies, the main one being the "over-sensitivity" of the GPMT. This paper analyses the data from a systematic study, published in three papers from 2008 to 2011, covering several classes of chemicals, in particular unsaturated fatty acids, sugar surfactants and ethoxylated alcohols, with many cases of chemicals testing positive in the LLNA being negative in the GPMT. Based on consideration of reaction chemistry and structural alerts, it is concluded that these discrepancies are not LLNA false positives, but can be rationalised in terms of the different protocols of the assays. PMID- 27477090 TI - Recommendations for pharmacological clinical trials in children with irritable bowel syndrome: the Rome foundation pediatric subcommittee on clinical trials. AB - BACKGROUND: There is little published evidence of efficacy for the most commonly used treatments. Thus, there is an urgent need to conduct clinical trials on existing and novel therapies. PURPOSE: In order to address these issues the Rome Foundation and members of the Pediatric Committee of the European Medicines Agency formed a subcommittee on clinical trials to develop guidelines for the design of clinical trials in children with irritable bowel syndrome (IBS). The following recommendations are based on evidence from published data when available and expert opinion. KEY RECOMMENDATIONS: The subcommittee recommends randomized, double-blind, placebo-controlled, parallel-group, clinical trials to assess the efficacy of new drugs. The combined endpoints for abdominal pain are a decrease in intensity of at least 30% compared with baseline and to meet or exceed the Reliable Change Index (RCI) for the sample. Stool consistency is measured with the Bristol Stool Scale Form (BSFS). The subcommittee recommends as entry criteria for abdominal pain a weekly average of worst abdominal pain in past 24 h of at least 3.0 on a 0-10 point scale or at least 30 mm in 100 mm Visual Analog Scale. For stool endpoints the committee recommends an average stool consistency lower than 3 in the BSFS during the run-in period for clinical trials on IBS-C and an average stool consistency greater than 5 in the BSFS during the run-in period for clinical trials on IBS-D. Changes in stool consistency are the primary endpoints for both IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). PMID- 27477091 TI - Partitioning MOF-5 into Confined and Hydrophobic Compartments for Carbon Capture under Humid Conditions. AB - Metal-organic frameworks (MOFs), by virtue of their remarkable uptake capability, selectivity, and ease of regeneration, hold great promise for carbon capture from fossil fuel combustion. However, their stability toward moisture together with the competitive adsorption of water against CO2 drastically dampens their capacity and selectivity under real humid flue gas conditions. In this work, an effective strategy was developed to tackle the above obstacles by partitioning the channels of MOFs into confined, hydrophobic compartments by in situ polymerization of aromatic acetylenes. Specifically, polynaphthylene was formed via a radical reaction inside the channels of MOF-5 and served as partitions without altering the underlying structure of the framework. Compared with pristine MOF-5, the resultant material (PN@MOF-5) exhibits a doubled CO2 capacity (78 vs 38 cm(3)/g at 273 K and 1 bar), 23 times higher CO2/N2 selectivity (212 vs 9), and significantly improved moisture stability. The dynamic CO2 adsorption capacity can be largely maintained (>90%) under humid conditions during cycles. This strategy can be applied to other MOF materials and may shed light on the design of new MOF-polymer materials with tunable pore sizes and environments to promote their practical applications. PMID- 27477092 TI - Existing and Developing Approaches for QSAR Analysis of Mixtures. AB - This review is devoted to the critical analysis of advantages and disadvantages of existing mixture descriptors and their usage in various QSAR/QSPR tasks. We describe good practices for the QSAR modeling of mixtures, data sources for mixtures, a discussion of various mixture descriptors and their application, recommendations about proper external validation specific for mixture QSAR modeling, and future perspectives of this field. The biggest problem in QSAR of mixtures is the lack of reliable data about the mixtures' properties. Various mixture descriptors are used for the modeling of different endpoints. However, these descriptors have certain disadvantages, such as applicability only to 1 : 1 binary mixtures, and additive nature. The field of QSAR of mixtures is still under development, and existing efforts could be considered as a foundation for future approaches and studies. The usage of non-additive mixture descriptors, which are sensitive to interaction effects, in combination with best practices of QSAR model development (e.g., thorough data collection and curation, rigorous external validation, etc.) will significantly improve the quality of QSAR studies of mixtures. PMID- 27477093 TI - Molecular Dynamics Simulations of G Protein-Coupled Receptors. AB - G protein-coupled receptors (GPCRs) constitute the largest family of membrane bound receptors with more than 800 members encoded by 351 genes in humans. It has been estimated that more than 50 % of clinically available drugs act on GPCRs, with an amount of 400, 50 and 25 druggable proteins for the class A, B and C, respectively. Furthermore, Class A GPCRs with approximately 25 % of marketed small drugs represent the most attractive pharmaceutical class. The recent availability of high-resolution 3-dimensional structures of some GPCRs supports the notion that GPCRs are dynamically versatile, and their functions can be modulated by several factors. In this scenario, molecular dynamics (MD) simulations techniques appear to be crucial when studying GPCR flexibility associated to functioning and ligand recognition. A general overview of biased and unbiased MD techniques is here presented with special emphasis on the recent results obtained in the GPCRs field. PMID- 27477094 TI - QSAR Prediction of Passive Permeability in the LLC-PK1 Cell Line: Trends in Molecular Properties and Cross-Prediction of Caco-2 Permeabilities. AB - A QSAR model for predicting passive permeability (Papp ) was derived from Papp values measured in the LLC-PK1 cell line. The QSAR method and descriptor set that performed best in terms of cross-validation was random forest with a combination of AP, DP, and MOE_2D descriptors. The QSAR model was used to predict the Caco-2 cell permeability for 313 compounds described in the literature with good success. We find that passive permeability for different cell lines can be predicted with similar molecular properties and descriptors. It is shown that the variation in experimental measurements of Papp is smaller than the error in QSAR predictions indicating that predictions are not quantitatively perfect, although qualitatively useful. We get better predictions if the training set is large and diverse, rather than smaller and more internally consistent. This is because prediction accuracy falls off quickly with decreasing similarity to the training set and it is therefore better to have as large a training set as possible. While single physical parameters are not as good as a full QSAR model in predicting Papp , logD seems the most important parameter. Intermediate values of logD are associated with higher Papp . PMID- 27477095 TI - Consensus Computational Ligand-Based Design for the Identification of Novel Modulators of Human Estrogen Receptor Alpha. AB - We describe the first targeted validation of fFLASH, a molecular similarity program from IBM that has been previously proposed as suitable for the virtual screening (VS) of compound libraries based on explicit 3D flexible superimpositions, as part of its deployment within a novel consensus ligand-based virtual screening cascade. A virtual screening protocol using fFLASH for the human estrogen receptor alpha (ERalpha) was advanced and benchmarked against screens completed using established commercial screening softwares - Catalyst and ROCS. The optimised protocol was applied to a ~6000 member physical screening collection and virtual 'hits' sourced and biologically assayed. The approach identified a novel, potent and highly selective partial antagonist of the ERalpha. This study firstly validates the clique detection algorithm utilised by fFLASH and secondly, emphasises the benefits of the consensus approach of employing more than one program in a VS protocol. PMID- 27477096 TI - Towards a Realistic Representation in Surface-Based Pseudoreceptor Modeling: a PDB-Wide Analysis of Binding Pockets. AB - Surface-based pseudoreceptor methods are expansions of 3D-QSAR techniques placing physico-chemical information onto a 3D surface surrounding a set of aligned compounds that bind into the same binding site of a common protein target. With this mapping pseudoreceptor methods attempt to create models of the target protein binding site around the ligand ensemble. The surface points of the pseudoreceptor model are typically independent descriptors and property mapping onto the surface points is prone to overfitting. In this article, we developed surface descriptors based on 2D Gaussian functions that can model the physico chemical properties of binding sites of proteins. Binding pocket surfaces of a large set of experimentally determined protein-ligand complex structures are analyzed and 2D Gaussian functions are used to fit the surface properties. The fitted property values differ from the original values on average by 15-25 %, and on average six Gaussian functions are necessary to model each surface property. These descriptors allow for a realistic representation of the binding site and will limit the number of descriptors used throughout the QSAR optimization phase. PMID- 27477097 TI - QSPR Prediction of Lipophilicity for Organic Compounds Using Random Forest Technique on the Basis of Simplex Representation of Molecular Structure. AB - The relationship between the octanol-water partition coefficient for more than twelve thousand organic compounds and their structures was investigated using a QSPR approach based on Simplex Representation of Molecular Structure (SiRMS). The dataset used in our study included 10973 compounds with experimental values of lipophilicity (LogKow ) for different chemical compounds. Random Forest (RF) method was used for statistical modeling at the 2D level of representation of molecular structure. Developed models are adequate and successfully validated with external test sets. Proposed models have clear interpretation due to the use of simplex representation of molecular structure and predict the LogKow values with the accuracy of the best modern models. Thus QSPR models proposed in this study represent powerful and easy-to use virtual screening tool that can be recommended for prediction of octanol-water partition coefficient. PMID- 27477098 TI - Deorphanization of Malonyl CoA:ACP Transacylase Drug Target in Plasmodium falciparum (PfFabD) Using Bacterial Antagonists: A 'Piggyback' Approach for Antimalarial Drug Discovery. AB - Quest for new drug targets in Plasmodium sp. has underscored malonyl CoA:ACP transacylase (PfFabD) of fatty acid biosynthetic pathway in apicoplast. In this study, a "piggyback" approach was employed for the receptor deorphanization using inhibitors of bacterial FabD enzymes. Due to the lack of crystal structure, theoretical model was constructed using the structural details of homologous enzymes. Sequence and structure analysis has localized the presence of two conserved pentapeptide motifs: GQGXG and GXSXG and five key invariant residues viz., Gln109, Ser193, Arg218, His305 and Gln354 characteristic of FabD enzyme. Active site mapping of PfFabD using substrate molecules has disclosed the spatial arrangement of key residues in the cavity. As structurally similar molecules exhibit similar biological activities, signature pharmacophore fingerprints of FabD antagonists were generated using 0D-3D descriptors for molecular similarity based cluster analysis and to correlate with their binding profiles. It was observed that antagonists showing good geometrical fitness score were grouped in cluster-1, whereas those exhibiting high binding affinities in cluster-2. This study proves important to shed light on the active site environment to reveal the hotspot for binding with higher affinity and to narrow down the virtual screening process by searching for close neighbors of the active compounds. PMID- 27477099 TI - Generative Topographic Mapping (GTM): Universal Tool for Data Visualization, Structure-Activity Modeling and Dataset Comparison. AB - Here, the utility of Generative Topographic Maps (GTM) for data visualization, structure-activity modeling and database comparison is evaluated, on hand of subsets of the Database of Useful Decoys (DUD). Unlike other popular dimensionality reduction approaches like Principal Component Analysis, Sammon Mapping or Self-Organizing Maps, the great advantage of GTMs is providing data probability distribution functions (PDF), both in the high-dimensional space defined by molecular descriptors and in 2D latent space. PDFs for the molecules of different activity classes were successfully used to build classification models in the framework of the Bayesian approach. Because PDFs are represented by a mixture of Gaussian functions, the Bhattacharyya kernel has been proposed as a measure of the overlap of datasets, which leads to an elegant method of global comparison of chemical libraries. PMID- 27477100 TI - Multiple Kernel Learning for Drug Discovery. AB - The support vector machine (SVM) methodology has become a popular and well-used component of present chemometric analysis. We assess a relatively recent development of the algorithm, multiple kernel learning (MKL), on published structure-property relationship (SPR) data. The MKL algorithm learns a weighting across multiple kernel-based representations of the data during supervised classifier creation and, thereby, may be used to describe the influence of distinct groups of structural descriptors upon a single structure-property classifier without explicitly omitting any of them. We observe a statistically significant performance improvement over a conventional, single kernel SVM on all three SPR data sets analysed. Furthermore, MKL output is observed to provide useful information regarding the relative influence of five distinct descriptor subsets present in each data set. PMID- 27477101 TI - Efficient production of nanoparticle-loaded orodispersible films by process integration in a stirred media mill. AB - Orodispersible films possess a great potential as a versatile platform for nanoparticle-loaded oral dosage forms. In this case, poorly water-soluble organic materials were ground in a stirred media mill and embedded into a polymer matrix. The aim of this study was the shortening of this manufacturing process by the integration of several process steps into a stirred media mill without facing disadvantages regarding the film quality. Furthermore, this process integration is time conserving due to the high stress intensities provided in the mill and applicable for high solids contents and high suspension viscosities. Two organic materials, the model compound Anthraquinone and the active pharmaceutical ingredient Naproxen were investigated in this study. Besides the impact of the film processing on the crystallinity of the particles in the orodispersible film, a particle load of up to 50% was investigated with the new developed processing route. Additionally, a disintegration test was developed, combining an appropriate amount of saliva substitute and a clear endpoint determination. In summary, high nanoparticle loads in orodispersible films with good particle size preservation after film redispersion in water as well as a manufacturing of the film casting mass within a few minutes in a stirred media mill was achieved. PMID- 27477102 TI - Nanoencapsulated budesonide in self-stratified polyurethane-polyurea nanoparticles is highly effective in inducing human tolerogenic dendritic cells. AB - The design of innovative strategies to selectively target cells, such antigen presenting cells and dendritic cells, in vivo to induce immune tolerance is gaining interest and relevance for the treatment of immune-mediated diseases. A novel loaded-nanosystem strategy to generate tolerogenic dendritic cells (tol DCs) was evaluated. Hence budesonide (BDS) was encapsulated in multiwalled polyurethane-polyurea nanoparticles (PUUa NPs-BDS) based on self-stratified polymers by hydrophobic interactions at the oil-water interface. DCs treated with encapsulated BDS presented a prominent downregulation of costimulatory molecules (CD80, CD83 and MHCII) and upregulation of inhibitory receptors. Moreover, DCs treated with these PUUa NPs-BDS also secreted large amounts of IL-10, a crucial anti-inflammatory cytokine to induce tolerance, and inhibited T lymphocyte activation in a specific manner compared to those cells generated with free BDS. These results demonstrate that PUUa NPs-BDS are a highly specific and efficient system through which to induce DCs with a tolerogenic profile. Given the capacity of PUUa NPs-BDS, this delivery system has a clear advantage for translation to in vivo studies. PMID- 27477103 TI - Controlled release of diclofenac sodium in glycolipid incorporated micro emulsions. AB - The effect of the glycolipid, hexadecyl-beta-d-glucopyranoside, incorporated in microemulsions (ME(1)) towards the enhancement of skin absorption and skin permeation of Diclofenac sodium (DS(2)) was evaluated. A Franz diffusion cell with a piece of pig's ear epidermis indicated that the optimized ME formulation with glycolipid (0.05wt%) exhibited significantly higher permeability than the conventional formulations. The releasing profiles of DS from ME formulations exhibited first order release kinetics resembling a diffusion controlled release model for the first 8h. Incorporating hexadecyl-beta-D glucopyranoside in ME formulations shows significant potential as a delivery vehicle in the cosmetics and pharmaceutical industry. PMID- 27477104 TI - Preparation of lipid nanoemulsions by premix membrane emulsification with disposable materials. AB - The possibility to prepare nanoemulsions as drug carrier systems on small scale was investigated with disposable materials. For this purpose premix membrane emulsification (premix ME) as a preparation method for nanoemulsions with narrow particle size distributions on small scale was used. The basic principle of premix ME is that the droplets of a coarse pre-emulsion get disrupted by the extrusion through a porous membrane. In order to implement the common preparation setup for premix ME with disposable materials, the suitability of different syringe filters (made from polyethersulfone, cellulose acetate, cellulose ester and nylon) and different pharmaceutically relevant emulsifiers (phospholipids, polysorbate 80 and sucrose laurate) for the preparation of nanoemulsions was investigated. Already the preparation of the premix could be realized by emulsification with the help of two disposable syringes. As shown for a phospholipid-stabilized emulsion, the polyethersulfone filter was the most appropriate one and was used for the study with different emulsifiers. With this syringe filter, the median particle size of all investigated emulsions was below 500nm after 21 extrusion cycles through a 200nm filter and a subsequent extrusion cycle through a 100nm filter. Furthermore, the particle size distribution of the polysorbate 80- and sucrose laurate-stabilized emulsions prepared this way was very narrow (span value of 0.7). PMID- 27477105 TI - Effects of BMP-9 and BMP-2 on the PI3K/Akt Pathway in MC3T3-E1 Preosteoblasts. AB - The bone morphogenetic proteins (BMPs), which are involved in bone formation and repair, play an important role in tissue engineering. For example, BMP-9 and BMP 2, which are members of different BMP subfamilies, are osteoinductive factors. However, several studies have recently shown that BMP-9 is more osteogenic than BMP-2. We have previously shown that fetal bovine serum (FBS) strongly enhances the osteoblast differentiation of murine preosteoblasts (MC3T3-E1) to BMP-9 but not to BMP-2. This effect is mimicked by IGF-2, which primarily activates the PI3K/Akt pathway, but how Akt phosphorylation sites are implicated in such differentiation is unclear. The effects of BMP-9 and BMP-2 with or without FBS or IGF-2 on Akt phosphorylation sites and subsequent osteoblastic differentiation were determined, respectively, by western blot analysis and alkaline phosphatase activity measurements. The involvement of phosphorylated Akt at Thr308 and/or Ser473 on BMP-mediated osteoblast differentiation was further studied using specific inhibitors. In MC3T3-E1 incubated with or without FBS, BMP-9 and BMP-2 activate Akt on Ser473 and Thr308 very differently in a time and dose-dependent manner. Using inhibitors specific to each Akt phosphorylation site, we showed that both Ser473 and Thr308 must be phosphorylated for BMP-9 and/or IGF-2-induced osteoblast differentiation, whereas BMP-2 requires phosphorylation of only Ser473. Furthermore, cells stimulated with BMP-2 in the presence of FBS require the phosphorylation of Akt at Ser473 and the dephosphorylation of Akt at Thr308 to increase the osteoblast differentiation with alkaline phosphatase activity similar to that of BMP-9 plus FBS. These results provide a better understanding into how BMP-9 induces osteoblast differentiation and its synergy with IGF-2 at the signaling level. This knowledge is essential for preparing the serum-free osteogenic media required for bone tissue engineering or developing growth factor delivery systems to improve bone formation. PMID- 27477106 TI - Hijacking microglial glutathione by inorganic arsenic impels bystander death of immature neurons through extracellular cystine/glutamate imbalance. AB - Arsenic-induced altered microglial activity leads to neuronal death, but the causative mechanism remains unclear. The present study showed, arsenic-exposed (10 MUM) microglial (N9) culture supernatant induced bystander death of neuro-2a (N2a), which was further validated with primary microglia and immature neuronal cultures. Results indicated that arsenic-induced GSH synthesis by N9 unfavorably modified the extracellular milieu for N2a by lowering cystine and increasing glutamate concentration. Similar result was observed in N9-N2a co-culture. Co exposure of arsenic and 250 MUM glutamate, less than the level (265 MUM) detected in arsenic-exposed N9 culture supernatant, compromised N2a viability which was rescued by cystine supplementation. Therefore, microglia executes bystander N2a death by competitive inhibition of system Xc(-) (xCT) through extracellular cystine/glutamate imbalance. We confirmed the role of xCT in mediating bystander N2a death by siRNA inhibition studies. Ex-vivo primary microglia culture supernatant from gestationally exposed mice measured to contain lower cystine and higher glutamate compared to control and N-acetyl cysteine co-treated group. Immunofluorescence staining of brain cryosections from treated group showed more dead immature neurons with no such effect on microglia. Collectively, we showed, in presence of arsenic microglia alters cystine/glutamate balance through xCT in extracellular milieu leading to bystander death of immature neurons. PMID- 27477107 TI - Bem Sex Role Inventory Validation in the International Mobility in Aging Study. AB - This study investigated the measurement structure of the Bem Sex Role Inventory (BSRI) with different factor analysis methods. Most previous studies on validity applied exploratory factor analysis (EFA) to examine the BSRI. We aimed to assess the psychometric properties and construct validity of the 12-item short-form BSRI in a sample administered to 1,995 older adults from wave 1 of the International Mobility in Aging Study (IMIAS). We used Cronbach's alpha to assess internal consistency reliability and confirmatory factor analysis (CFA) to assess psychometric properties. EFA revealed a three-factor model, further confirmed by CFA and compared with the original two-factor structure model. Results revealed that a two-factor solution (instrumentality-expressiveness) has satisfactory construct validity and superior fit to data compared to the three-factor solution. The two-factor solution confirms expected gender differences in older adults. The 12-item BSRI provides a brief, psychometrically sound, and reliable instrument in international samples of older adults. PMID- 27477108 TI - Fatty Acid Diversity is Not Associated with Neutral Genetic Diversity in Native Populations of the Biodiesel Plant Jatropha curcas L. AB - Jatropha curcas L. (Euphorbiaceae) is a shrub native to Mexico and Central America, which produces seeds with a high oil content that can be converted to biodiesel. The genetic diversity of this plant has been widely studied, but it is not known whether the diversity of the seed oil chemical composition correlates with neutral genetic diversity. The total seed oil content, the diversity of profiles of fatty acids and phorbol esters were quantified, also, the genetic diversity obtained from simple sequence repeats was analyzed in native populations of J. curcas in Mexico. Using the fatty acids profiles, a discriminant analysis recognized three groups of individuals according to geographical origin. Bayesian assignment analysis revealed two genetic groups, while the genetic structure of the populations could not be explained by isolation-by-distance. Genetic and fatty acid profile data were not correlated based on Mantel test. Also, phorbol ester content and genetic diversity were not associated. Multiple linear regression analysis showed that total oil content was associated with altitude and seasonality of temperature. The content of unsaturated fatty acids was associated with altitude. Therefore, the cultivation planning of J. curcas should take into account chemical variation related to environmental factors. PMID- 27477109 TI - The Genome of Undifilum oxytropis Provides Insights into Swainsonine Biosynthesis and Locoism. AB - Undifilum oxytropis is a fungal endophyte of locoweeds. It produces swainsonine, which is the principal toxic ingredient of locoweeds. However, the genes, pathways and mechanisms of swainsonine biosynthesis are not known. In this study, the genome of U. oxytropis was firstly sequenced and assembled into a 70.05 megabases (Mb) draft genome, which encoded 11,057 protein-coding genes, and 54% of them were similar to current publicly available sequences. U. oxytropis genes were annotated and 164 putative genes were annotated into enzymes, such as Saccharopine dehydrogenase, Saccharopine oxidase, and Pyrroline-5-carboxylate reductase, hypothesized to be involved in the biosynthesis pathway of swainsonine. The genome sequence and gene annotation of U. oxytropis will provide new insights into functional analyses. The characterization of genes in swainsonine biosynthesis will greatly facilitate locoweed poisoning research and help direct locoism management. PMID- 27477110 TI - Treatment of periodontal intrabony defects using autologous platelet-rich fibrin and titanium platelet-rich fibrin: a randomized, clinical, comparative study. AB - AIM: The aim of the present study was to compare the effectiveness of open flap debridement (OFD) alone and OFD with either autologous platelet-rich fibrin (PRF) or titanium PRF (TPRF) in the treatment of intrabony defects (IBD). METHODS: The study was conducted on patients reporting to the Department of Periodontics, The Oxford Dental College and Hospital, Bangalore, India. Thirty-eight patients with 90 periodontal IBD of moderate-severe periodontitis were selected and assigned to the OFD alone group (group I), the OFD with autologous PRF group (group II), or the OFD with TPRF group (group III). In each patient, a minimum number of two sextants were present, with probing pocket depths (PPD) >=5 mm in at least three teeth. RESULTS: At 9 months' postoperatively, upon comparing the PPD reduction, defect depth reduction, and clinical attachment level gains, it was noted that groups II and III showed statistically-significant improvements compared with group I, but no statistically-significant difference was noted between groups II and III. CONCLUSION: The present study demonstrated that marked improvements in the clinical parameters and radiographic outcomes were noted with both autologous PRF and TPRF in the treatment of IBD. PMID- 27477111 TI - Prenatal exposure to antidepressants and risk of epilepsy in childhood. AB - PURPOSE: This study aimed to estimate the association between prenatal exposure to antidepressants and risk of epilepsy in childhood, taking maternal depression into account. METHODS: We conducted a population-based cohort study including all Danish singletons born alive between 1997 and 2008 (n = 734 237). Information on antidepressant medication and diagnosis of depression and epilepsy was obtained from Danish National Registers. The exposed group comprised children of mothers who used antidepressants from 30 days before pregnancy until the date of birth. The reference group comprised children of mothers who used no antidepressants from 6 months before pregnancy to birth. We estimated the hazard ratios (HR) of epilepsy and 95% confidence intervals (CI) using Cox proportional hazard models. RESULTS: We identified 12 438 (1.7%) children exposed to antidepressants during pregnancy (including 30 days before pregnancy) and 5829 (0.8%) children diagnosed with epilepsy in the follow-up time (mean: 6.7 years). Children exposed to antidepressants during pregnancy had a 27% higher risk of epilepsy (aHR: 1.27; 95%CI: 1.05-1.54) than children in the reference group. The estimate of this association was 1.71 (95%CI: 1.10-2.66) if their mothers also had a registry based hospital diagnosis of depression in the 6 months before pregnancy or during pregnancy and 1.14 (95%CI: 0.91-1.43) if their mothers had no registry-based hospital diagnosis of depression. Children of mothers who used antidepressants from 2 to 6 months before pregnancy (but not during pregnancy) had an increased risk of epilepsy (aHR: 1.36; 95%CI: 1.07-1.73). CONCLUSIONS: Antidepressant use during pregnancy was associated with a higher risk of epilepsy among children whose mothers had also a registry-based hospital diagnosis of depression during pregnancy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27477112 TI - 24-h monitoring devices and nyctohemeral rhythms of intraocular pressure. AB - Intraocular pressure (IOP) is not a fixed value and varies over both the short term and periods lasting several months or years. In particular, IOP is known to vary throughout the 24-h period of a day, defined as a nyctohemeral rhythm in humans. In clinical practice, it is crucial to evaluate the changes in IOP over 24 h in several situations, including the diagnosis of ocular hypertension and glaucoma (IOP is often higher at night) and to optimize the therapeutic management of glaucoma. Until recently, all evaluations of 24-h IOP rhythm were performed using repeated IOP measurements, requiring individuals to be awakened for nocturnal measurements. This method may be imperfect, because it is not physiologic and disturbs the sleep architecture, and also because it provides a limited number of time point measurements not sufficient to finely asses IOP changes. These limitations may have biased previous descriptions of physiological IOP rhythm. Recently, extraocular and intraocular devices integrating a pressure sensor for continuous IOP monitoring have been developed and are available for use in humans. The objective of this article is to present the contributions of these new 24-h monitoring devices for the study of the nyctohemeral rhythms. In healthy subjects and untreated glaucoma subjects, a nyctohemeral rhythm is consistently found and frequently characterized by a mean diurnal IOP lower than the mean nocturnal IOP, with a diurnal bathyphase - usually in the middle or at the end of the afternoon - and a nocturnal acrophase, usually in the middle or at the end of the night. PMID- 27477113 TI - NODDI reproducibility and variability with magnetic field strength: A comparison between 1.5 T and 3 T. AB - Diffusion models are advantageous for examining brain microstructure non invasively and their validation is important for transference into the clinical domain. Neurite Orientation Dispersion and Density Imaging (NODDI) is a promising model for estimating multiple diffusion compartments from MRI data acquired in a clinically feasible time. As a relatively new model, it is necessary to examine NODDI under certain experimental conditions, such as change in magnetic field strength, and assess it in relation to diffusion tensor imaging (DTI), an established model that is largely understood by the neuroimaging community. NODDI measures (intracellular volume fraction, nuic , and orientation distribution, OD) were compared with DTI at 1.5 and 3 T data in healthy adults in whole-brain tissue masks and regions of white- and deep grey-matter. Within-session reproducibility and between-subject differences of NODDI with field-strength were also investigated. Field-strength had a significant effect on NODDI measures, suggesting careful interpretation of results from data acquired at 1.5 and 3 T. It was demonstrated that NODDI is feasible at 1.5 T, but with lower nuic in white matter regions compared with 3 T. Furthermore, the advantages of NODDI over DTI in a region of complex microstructure were shown. Specifically, in the centrum semiovale where FA is typically as low as in grey-matter, nuic was comparable to other white-matter regions yet accompanied by an OD similar to deep grey-matter. In terms of reproducibility, NODDI measures varied more than DTI. It may be that NODDI is more susceptible to noisier parameter estimates when compared with DTI, conversely it may have greater sensitivity to true within- and between-subject heterogeneity. Hum Brain Mapp 37:4550-4565, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27477114 TI - Influence of low temperature on structure and dynamics of spermatogenesis during culture of Oreochromis niloticus. AB - Understanding the influence of different temperature conditions on the spermatogenesis is important for improvement of the fish aquaculture. This study evaluated the influence of low temperature on structural and quantitative dynamics of the spermatogenesis in Oreochromis niloticus. Adult males were cultivated with room temperature water (20.28-22.46 degrees C) and testes were collected for histological, ultrastructural and morphometric analyses. This species has unrestricted lobular testis with cystic spermatogenesis and type I spermiogenesis that results in a single anacrosomal aquasperm. Seminiferous lobules and spermatogenic cells had a radial arrangement toward the spermatic duct. Superior and central portions of testes had a greater lobular area than the inferior portion in all samplings. Spermatogonia (9.3%) were distributed in the inferior portion of testes, spermatocytes (25.3%) and spermatids (34.4%) in the central portion, while spermatozoids (39.4%) and secretory cells (4.6%) in the superior portion. Throughout the study, correlation between water temperature and lobular area characteristics was significant only in the inferior portion of testes (r(2)=0.95), although the lobular area in the other testicular portions increased when the water temperature increased by 2 degrees C. Correlation between the water temperature and spermatogenic cells was significant for undifferentiated spermatogonia (r(2)=0.54) and number of spermatids (r(2)=0.67). It is concluded that low cultivation temperatures may positively influence the generation of primary spermatogonia in the inferior periphery of O. niloticus testes. In addition, males maintain reservoirs of germ cells at low temperatures and the radial zonation of spermatogenesis has an important role in the renewal and production of germ cells. PMID- 27477115 TI - Melatonin modulates the functions of porcine granulosa cells via its membrane receptor MT2 in vitro. AB - Melatonin (N-acetyl-5-methoxytryptamine) is documented as a hormone involved in the circadian regulation of physiological and neuroendocrine function in mammals. Herein, the effects of melatonin on the functions of porcine granulosa cells in vitro were investigated. Porcine granulosa cells were cultivated with variable concentrations of melatonin (0, 0.001, 0.01, 0.1, 1.0, and 10ng/mL) for 48h. Melatonin receptor agonist (IIK7) and antagonist (Luzindole, 4P-PDOT) were used to further examine the action of melatonin. The results showed optimum cell viability and colony-forming efficiency of porcine granulosa cells at 0.01ng/mL melatonin for 48-h incubation period. The percentage of apoptotic granulosa cells was significantly reduced by 0.01 and 0.1ng/mL melatonin within the 48-h incubation period as compared with the rest of the treatments. Estradiol biosynthesis was significantly stimulated by melatonin supplementation and suppressed for the progesterone secretion; the minimum ratio of progesterone to estradiol was 1.82 in 0.01ng/mL melatonin treatment after 48h of cultivation. Moreover, the expression of BCL-2, CYP17A1, CYP19A1, SOD1, and GPX4 were up regulated by 0.01ng/mL melatonin or combined with IIK7, but decreased for the mRNA levels of BAX, P53, and CASPASE-3, as compared with control or groups treated with Luzindole or 4P-PDOT in the presence of melatonin. In conclusion, the study demonstrated that melatonin mediated proliferation, apoptosis, and steroidogenesis in porcine granulosa cells predominantly through the activation of melatonin receptor MT2 in vitro, which provided evidence of the beneficial role of melatonin as well as its functional mechanism in porcine granulosa cells in vitro. PMID- 27477116 TI - PPAR ligand association with prostaglandin F2alpha and E2 synthesis in the pig corpus luteum-An in vitro study. AB - The present study evaluated the involvement of PPARs in prostaglandin (PG) E2 and F2alpha production in the corpus luteum (CL) of pigs on days 10-12 and 14-16 of the estrous cycle or pregnancy. The tissue explants were incubated for 6h in the presence of PPARalpha, PPARbeta, PPARgamma ligands. The concentration of PGs in the incubation media was determined by radioimmunoassay, while mRNA abundance of PG synthetases (PGES and PGFS) was analyzed by quantitative real-time PCR. It was found that L-165,045 and rosiglitazone stimulated PGES synthesis on days 10-12 of the estrous cycle, whereas all factors that were assessed did not affect PGE2 release. The PGFS mRNA abundance in the CL did not change in the presence of PPAR ligands during the assessment periods. However, PPARbeta agonist inhibited PGF2alpha secretion on days 10-12 of the estrous cycle and on days 14-16 of pregnancy. Interestingly, PPAR antagonists, MK 886, GW 9662 or T0070907 decreased PGF2alpha release by the slices on days 10-12 of the estrous cycle. It is concluded that the CL has a different susceptibility (greatest during mid-luteal phase of the estrous cycle) to the PPAR ligands, which is related to the physiological status of animal. The inhibition of PGF2alpha release and augmentation of PGES mRNA concentration during mid-luteal phase of the estrous cycle might suggest luteotropic properties of PPAR ligands. PMID- 27477118 TI - Magnetic study on biodistribution and biodegradation of oral magnetic nanostructures in the rat gastrointestinal tract. AB - We have undertaken a magnetic study on the oral biodistribution and biodegradation of nude maghemite nanoparticles of 10 nm average size (MNP) and probiotic bacteria, Lactobacillus fermentum, containing thousands of these same nanoparticles (MNP-bacteria). Using AC magnetic susceptibility measurements of the stomach, small intestine, cecum and large intestine obtained after rat sacrifice, and iron content determination by ICP-OES, we have monitored the biodistribution and biodegradation of the maghemite nanoparticles along the gastrointestinal tract, after oral administration of both MNP and MNP-bacteria. The results revealed that the amount of magnetic nanoparticles accumulated in intestines is sensibly higher when MNP-bacteria were administered, in comparison with MNP. This confirms our initial hypothesis that the use of probiotic bacteria is a suitable strategy to assist the magnetic nanoparticles to overcome the stomach medium, and to achieve their accumulation in intestines. This finding opens doors to different applications. Since iron absorption in humans takes place precisely in the intestines, the use of MNP-bacteria as an iron supplement is a definite possibility. We have actually illustrated how the administration of MNP-bacteria to iron-deficient rats corrects the iron levels after two weeks of treatment. PMID- 27477119 TI - Current pharmacotherapy of depression - focused on multimodal/multifunctional antidepressants. PMID- 27477117 TI - Travelling-wave ion mobility mass spectrometry and negative ion fragmentation of hybrid and complex N-glycans. AB - Nitrogen collisional cross sections (CCSs) of hybrid and complex glycans released from the glycoproteins IgG, gp120 (from human immunodeficiency virus), ovalbumin, alpha1-acid glycoprotein and thyroglobulin were measured with a travelling-wave ion mobility mass spectrometer using dextran as the calibrant. The utility of this instrument for isomer separation was also investigated. Some isomers, such as Man3 GlcNAc3 from chicken ovalbumin and Man3 GlcNAc3 Fuc1 from thyroglobulin could be partially resolved and identified by their negative ion fragmentation spectra obtained by collision-induced decomposition (CID). Several other larger glycans, however, although existing as isomers, produced only asymmetric rather than separated arrival time distributions (ATDs). Nevertheless, in these cases, isomers could often be detected by plotting extracted fragment ATDs of diagnostic fragment ions from the negative ion CID spectra obtained in the transfer cell of the Waters Synapt mass spectrometer. Coincidence in the drift times of all fragment ions with an asymmetric ATD profile in this work, and in the related earlier paper on high-mannose glycans, usually suggested that separations were because of conformers or anomers, whereas symmetrical ATDs of fragments showing differences in drift times indicated isomer separation. Although some significant differences in CCSs were found for the smaller isomeric glycans, the differences found for the larger compounds were usually too small to be analytically useful. Possible correlations between CCSs and structural types were also investigated, and it was found that complex glycans tended to have slightly smaller CCSs than high-mannose glycans of comparable molecular weight. In addition, biantennary glycans containing a core fucose and/or a bisecting GlcNAc residue fell on different mobility-m/z trend lines to those glycans not so substituted with both of these substituents contributing to larger CCSs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27477120 TI - Magnesium isotopic homogeneity of San Carlos olivine: a potential standard for Mg isotopic analysis by multi-collector inductively coupled plasma mass spectrometry. AB - RATIONALE: Previous analyses on San Carlos olivine from Arizona (USA) have shown inter-laboratory delta(26) Mg differences of up to 0.670/00, while mantle olivine samples worldwide are homogeneous at a current analytical uncertainty of ~0.10/00. The differing measurements on San Carlos olivine may be attributable to analytical artifacts or sample heterogeneity. The latter must be ruled out before using it as a standard for Mg isotopic analysis. METHODS: To examine sample homogeneity, two different batches of San Carlos olivine from a lherzolite and four batches from a harzburgite have been analyzed together with coexisting harzburgitic pyroxene. In addition, the effect of acid purity on resin performance and the reusability of AG50W-X8 resin for Mg separation have been evaluated by processing another batch of lherzolitic San Carlos olivine and Hawaiian seawater through both new and used resins cleaned with different acids. RESULTS: Six different batches of olivine grains from two San Carlos peridotite xenoliths show homogeneous delta(26) Mg values to within 0.030/00, and all the mineral phases in the harzburgite are in Mg isotope equilibrium. Furthermore, there is no resolvable delta(26) Mg shift in either lherzolitic San Carlos olivine or Hawaiian seawater by using either new or used resins that were cleaned with single-distilled or double-distilled acids. CONCLUSIONS: The new data are consistent with the narrow delta(26) Mg range of mantle olivine worldwide, while they stand in contrast to the wide range measured on the same San Carlos olivine powder in different laboratories. Therefore, previous inter-laboratory discrepancies reflect analytical artifacts instead of sample heterogeneity, and San Carlos olivine is a suitable standard for Mg isotopic analysis. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27477121 TI - Rapid killing of bed bugs (Cimex lectularius L.) on surfaces using heat: application to luggage. AB - BACKGROUND: The resistance of bed bugs (Cimex lectularius L.) to chemical insecticides has motivated the development of non-chemical control methods such as heat treatment. However, because bed bugs tend to hide in cracks or crevices, their behavior incidentally generates a thermally insulated microenvironment for themselves. Bed bugs located on the outer surface of luggage are less insulated and potentially more vulnerable to brief heat treatment. RESULTS: Soft-sided suitcases with adult male bed bugs on the outside were exposed to an air temperature of 70-75 degrees C. It took 6 min to kill all of the bed bugs, even those that had concealed themselves under zipper flaps or decorative piping. During heating, only one bed bug (out of 250 in total) moved into the luggage (through a closed zipper). Over long periods of time (24 h) at room temperature, adult male bed bugs on the exterior of luggage only infrequently moved inside; only 3% (5/170) had moved inside during 24 h. CONCLUSIONS: Brief exterior heat treatment of luggage is a promising way to reduce the spread of bed bugs being transported on the outer surface of luggage. This treatment will not kill bed bugs inside the luggage, but could be a component of integrated management for this pest. (c) 2016 Society of Chemical Industry. PMID- 27477122 TI - MiR-146a rs2910164 polymorphism increases the risk of digestive system cancer: A meta-analysis. AB - AIM: There is merging evidence suggesting that the miR-146a polymorphism might be associated with susceptibility to digestive system cancer. However, previous published studies have failed to achieve a definitive conclusion. To address this issue, an updated meta-analysis was performed. METHODS: A comprehensive electronic search was conducted using the following source to identify the eligible studies: PubMed, Embase, China BioMedicine, the Cochrane Library, and Google Scholar. Odds ratios and its corresponding 95% confidence interval (CI) was used in the quantitative synthesis. RESULTS: The database search identified 1344 eligible studies, of which 32 (comprising 12,541 cases and 15,925 controls) were included. The results indicate that the miR-146a rs2910164 polymorphism was significantly associated with increased risk of digestive system cancer in heterozygote comparison (GC vs. CC: OR=1.15, 95% CI: 1.02-1.30, P=0.02), and recessive model (GG vs. GC+CC: OR=1.11, 95% CI: 1.04-1.17, P=0.006). Subgroup analysis by cancer site revealed increased risk in gastric cancer above heterozygote comparison (GG vs. GC: OR=1.13, 95% CI: 1.02-1.25, P=0.02), and recessive model (GG vs. GC+CC: OR=1.15, 95% CI: 1.04-1.26, P=0.006). Similarly, increased cancer risk was observed in hepatocellular carcinoma when compared with homozygote comparison (GG vs. CC: OR=1.21, 95% CI: 1.04-1.42, P=0.02), heterozygote comparison (GC vs. CC: OR=1.15, 95% CI: 1.02-1.29, P=0.02), and dominant model (GG+GC vs. CC: OR=1.16, 95% CI: 1.04-1.29, P=0.009). When stratified by ethnicity and quality score, increased cancer risks were also observed among Asians, Caucasians and high quality studies subgroup. CONCLUSION: The current study revealed that miR-146a G/C genetic polymorphism was more likely to be associated with digestive system cancer risk. PMID- 27477123 TI - Response to 'High Risk of Neutropenia for Hormone-naive Prostate Cancer Patients Receiving STAMPEDE-style Upfront Docetaxel Chemotherapy in Usual Clinical Practice', by Tanguay et al. PMID- 27477124 TI - Reply to Goodare et al. Re: Do Patient-reported Outcome Measures Agree with Clinical and Photographic Assessments of Normal Tissue Effects after Breast Radiotherapy? PMID- 27477125 TI - Recombination control in high-performance quantum dot-sensitized solar cells with a novel TiO2/ZnS/CdS/ZnS heterostructure. AB - Charge recombination occurring at the TiO2/QDs/electrolyte interface is a crucial factor that limits the power conversion efficiency (eta) of quantum dot sensitized solar cells (QDSSCs). This paper presents a new approach by inserting a ZnS layer between the TiO2 and CdS/ZnS to prepare a TiO2/ZnS/CdS/ZnS sensitized photoelectrode for QDSSC applications. The CdS QDs and ZnS passivation layers were deposited using a reproducible and controlled successive ionic layer adsorption and reaction method. The TiO2/ZnS/CdS/ZnS based QDSSCs exhibited a power conversion efficiency (eta) value of 3.69%, which is significantly higher than the 3.02% and 2.09% observed for solar cells with a TiO2/CdS/ZnS device and without a passivation layer (TiO2/CdS), respectively. The elevated performance of the TiO2/ZnS/CdS/ZnS-based QDSSCs was attributed to the pre-assembled ZnS layer enhancing the light harvesting and acting as a blocking layer to shield the TiO2 core from the outer QDs and the electrolyte, thereby retarding the interfacial recombination of electrons from the TiO2 with the electrolyte or with the QDs. Electrochemical impedance spectroscopy and open circuit voltage decay measurements showed that the TiO2/ZnS/CdS/ZnS-based QDSSCs inhibit charge recombination remarkably at the photoanode/electrolyte interface and prolong the electron lifetime. PMID- 27477126 TI - Elie Metchnikoff (1845-1916): celebrating 100 years of cellular immunology and beyond. AB - The year 2016 marks 100 years since the death of Elie Metchnikoff (1845-1916), the Russian zoologist who pioneered the study of cellular immunology and who is widely credited with the discovery of phagocytosis, for which he was jointly awarded the Nobel Prize in Physiology or Medicine in 1908. However, his long scientific career spanned many disciplines and has had far-reaching effects on modern immunology beyond the study of phagocytosis. In this Viewpoint article, five leading immunologists from the fields of phagocytosis, macrophage biology, leukocyte migration, the microbiota and intravital imaging tell Nature Reviews Immunology how Metchnikoff's work has influenced past, present and future research in their respective fields. PMID- 27477128 TI - Autoimmunity: Infection stimulates self-antigen presentation. PMID- 27477129 TI - Genetic correlations and sex-specific adaptation in changing environments. AB - Females and males have conflicting evolutionary interests. Selection favors the evolution of different phenotypes within each sex, yet divergence between the sexes is constrained by the shared genetic basis of female and male traits. Current theory predicts that such "sexual antagonism" should be common: manifesting rapidly during the process of adaptation, and slow in its resolution. However, these predictions apply in temporally stable environments. Environmental change has been shown empirically to realign the direction of selection acting on shared traits and thereby alleviate signals of sexually antagonistic selection. Yet there remains no theory for how common sexual antagonism should be in changing environments. Here, we analyze models of sex-specific evolutionary divergence under directional and cyclic environmental change, and consider the impact of genetic correlations on long-run patterns of sex-specific adaptation. We find that environmental change often aligns directional selection between the sexes, even when they have divergent phenotypic optima. Nevertheless, some forms of environmental change generate persistent sexually antagonistic selection that is difficult to resolve. Our results reinforce recent empirical observations that changing environmental conditions alleviate conflict between males and females. They also generate new predictions regarding the scope for sexually antagonistic selection and its resolution in changing environments. PMID- 27477130 TI - Mechanisms of mast seeding: resources, weather, cues, and selection. AB - 546 I. 546 II. 547 III. 548 IV. 552 V. 554 VI. 556 VII. 558 VIII. 558 IX. 559 559 References 559 SUMMARY: Mast seeding is a widespread and widely studied phenomenon. However, the physiological mechanisms that mediate masting events and link them to weather and plant resources are still debated. Here, we explore how masting is affected by plant resource budgets, fruit maturation success, and hormonal coordination of cues including weather and resources. There is little empirical support for the commonly stated hypothesis that plants store carbohydrates over several years to expend in a high-seed year. Plants can switch carbohydrates away from growth in high-seed years, and seed crops are more probably limited by nitrogen or phosphorus. Resources are clearly involved in the proximate mechanisms driving masting, but resource budget (RB) models cannot create masting in the absence of selection because some underlying selective benefit is required to set the level of a 'full' seed crop at greater than the annual resource increment. Economies of scale (EOSs) provide the ultimate factor selecting for masting, but EOSs probably always interact with resources, which modify the relationship between weather cues and reproduction. Thus, RB and EOS models are not alternative explanations for masting - both are required. Experiments manipulating processes that affect mast seeding will help clarify the physiological mechanisms that underlie mast seeding. PMID- 27477131 TI - The influence of cartilage surface topography on fluid flow in the intra articular gap. AB - Self-lubrication of a diarthrodial joint is largely attributed to interstitial fluid pressurisation. However, the retention of synovial fluid within the intra articular gap may also contribute to lubrication. Fluid flow in the intra articular gap between two micro-rough cartilage surfaces was simulated with a three-dimensional numerical model. Representative surface roughness parameters were incorporated and their relative influence on gap flow resistance was quantified. Resistance changes with decreasing gap height were explored. Cartilage surface micro-topography improves the retention of viscous synovial fluid in the gap, through increased resistance to tangential flow. Local asperity contact greatly increases resistance through tortuosity of the flow path. PMID- 27477127 TI - Regulation of pattern recognition receptor signalling in plants. AB - Recognition of pathogen-derived molecules by pattern recognition receptors (PRRs) is a common feature of both animal and plant innate immune systems. In plants, PRR signalling is initiated at the cell surface by kinase complexes, resulting in the activation of immune responses that ward off microorganisms. However, the activation and amplitude of innate immune responses must be tightly controlled. In this Review, we summarize our knowledge of the early signalling events that follow PRR activation and describe the mechanisms that fine-tune immune signalling to maintain immune homeostasis. We also illustrate the mechanisms used by pathogens to inhibit innate immune signalling and discuss how the innate ability of plant cells to monitor the integrity of key immune components can lead to autoimmune phenotypes following genetic or pathogen-induced perturbations of these components. PMID- 27477132 TI - The Triple Play: Pubescent Boys, Pot, and Paranoia. PMID- 27477133 TI - The Strange Case of Smoking and Schizophrenia-The Epidemiology Detectives Are on the Trail. PMID- 27477134 TI - Overt and Hidden Bias in Large Observational Studies. PMID- 27477135 TI - Further Investigation of Ketamine. PMID- 27477136 TI - Late-Life Depression: A Role for Accelerometer Technology in Diagnosis and Management. PMID- 27477137 TI - Personality Disorders in the Basque Region of Spain: Applicability of DSM-5's Alternative Criteria for Personality Disorders. PMID- 27477138 TI - Addressing Difficulties in the Study of Dose-Response Relationships of SSRIs in Depression: Response to Hieronymus and Eriksson. PMID- 27477139 TI - Inclusion of Flexible-Dose Trials in the Meta-Analysis of SSRI Dose-Dependency. PMID- 27477140 TI - Challenges Facing the Identification of Neurobiologically Distinct Psychosis Subtypes: Response to Neuhaus. PMID- 27477141 TI - Importance of Control Biotypes to Distinguish Distinct Psychosis Biotypes. PMID- 27477146 TI - 2015 Annual Report of the American Board of Psychiatry and Neurology, Inc. AB - The following is an edited version of the 2015 Report of the American Board of Psychiatry and Neurology, Inc. The full report can be obtained from the American Board of Psychiatry and Neurology ( www.abpn.com ). PMID- 27477142 TI - Persistent Depersonalization/Derealization Disorder Induced by Synthetic Cannabinoids. PMID- 27477147 TI - Living in colour--American children, race, and wellbeing. PMID- 27477148 TI - Towards elimination of viral hepatitis by 2030. PMID- 27477149 TI - Protocol disparities and research governance. PMID- 27477150 TI - The wisdom of crowds. PMID- 27477152 TI - Concerns raised over future of Medicare in Australia. PMID- 27477153 TI - Peru's transgender community: the battle for rights. PMID- 27477154 TI - Uncertain future for initiative against FGM in the UK. PMID- 27477155 TI - Zika virus epidemic: Africa should not be neglected. PMID- 27477156 TI - Could clinical symptoms be a predictor of complications in Zika virus infection? PMID- 27477157 TI - Could clinical symptoms be a predictor of complications in Zika virus infection? Authors' reply. PMID- 27477158 TI - Haemodialysis is a major risk factor for infective endocarditis. PMID- 27477159 TI - Haemodialysis is a major risk factor for infective endocarditis - Authors' reply. PMID- 27477160 TI - Outcomes in the trial registry should match those in the protocol. PMID- 27477161 TI - Outcomes in the trial registry should match those in the protocol - Authors' reply. PMID- 27477162 TI - Trial registration records, updates, and protocols. PMID- 27477163 TI - Department of Error. PMID- 27477164 TI - Department of Error. PMID- 27477166 TI - Department of Error. PMID- 27477165 TI - Control of gonorrhoea and chlamydia in the UK. PMID- 27477167 TI - Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial. AB - We performed a subgroup analysis of the phase III UK National Cancer Research Institute R-CHOP-14 versus R-CHOP-21 (two- versus three-weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B-cell lymphoma identified from the trial database. At a median follow-up of 7.2 years the 5-year progression-free survival and overall survival was 79.8% and 83.8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R-CHOP-14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients. PMID- 27477168 TI - Openness to experience, work experience and patient safety. AB - AIMS: The purpose of this study is to examine how the interaction between nurse openness and work experience is related to patient safety. BACKGROUND: No study has yet examined the interactions between these, and how openness and work experience jointly impact patient safety. METHODS: This study adopts a cross sectional design, using self-reported work experience, perceived time pressure and measures of patient safety, and was conducted in a major medical centre. The sample consisted of 421 full-time nurses from all available units in the centre. Proportionate random sampling was used. Patient safety was measured using the self-reported frequency of common adverse events. Openness was self-rated using items identified in the relevant literature. RESULTS: Nurse openness is positively related to the patient safety construct (B = 0.08, P = 0.03). Moreover, work experience reduces the relation between openness and patient safety (B = -0.12, P < 0.01). CONCLUSIONS: The relationship between openness, work experience and patient safety suggests a new means of improving patient care in a health system setting. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers may enhance patient safety by assessing nurse openness and assigning highly open nurses to duties that make maximum use of that trait. PMID- 27477169 TI - The Role of Impaired Epidermal Barrier Function in Atopic Dermatitis. AB - Atopic dermatitis (AD) is a chronic, inflammatory, pruritic skin disease with increasing prevalence. The etiopathogenesis of atopic dermatitis is multifactorial and involves a complex interplay of environmental and genetic factors that induce derangements in the structure and function of the epidermal barrier and immune system. Due to great heterogeneity of etiopathogenesis, there is also great variability of clinical presentation, and diagnosis can sometimes be challenging and difficult. Diagnosis mostly relies on clinical features and laboratory tests, but morphology alone cannot reliably establish the diagnosis, so the spectrum of features associated with AD must be considered. Traditionally, patients with AD have been separated into two different subgroups, i.e. intrinsic and extrinsic. Today, most of authors prefer the outside to inside and back to outside hypothesis, suggesting that the primary disorder lies in epidermal structure and function, resulting in inflammation and immunological downstream activation which further provokes secondary barrier abnormalities. In this review, we discuss the structure and function of the epidermal barrier and the role of impaired barrier function in etiopathogenesis of atopic dermatitis. PMID- 27477170 TI - Atopic and Non-atopic Eczema. AB - Atopic dermatitis is a common term used in the medical literature, but according to The Nomenclature Review Committee Of The World Allergy Organization the name which should be used is eczema. Eczema is divided into two subtypes: atopic and non-atopic. These subtypes differ in the level of total immunoglobulin E (IgE) in serum, response to allergens in skin prick tests, and detection of specific IgE antibodies. Non-atopic eczema is characterized by a low level of total IgE, negative skin prick tests, and undetectable specific IgE antibodies. It is estimated that 10-45% cases of eczema are non-atopic ones. In recent studies, other features differentiating these two subtypes have been identified, such as female predominance in non-atopic eczema. A more severe course, damage of the epidermal barrier, predominance of Th2 (T helper cells 2) response, and a lower positive reaction to metal patch tests are the characteristics of the atopic subtype. In our opinion, new diagnostic criteria taking into account the non atopic subtype of eczema need to be established. PMID- 27477171 TI - Keratinization Disorders and Genetic Aspects in Palmar and Plantar Keratodermas. AB - Palmoplantar keratoderma (PPK) is a heterogeneous group of hereditary and acquired disorders characterized by abnormal thickening of the palms and soles. There are three clinical patterns: diffuse, focal, and punctuate. Palmoplantar keratodermas can be divided into the following functional subgroups: disturbed gene functions in structural proteins (keratins), cornified envelope (loricrin, transglutaminase), cohesion (plakophilin, desmoplakin, desmoglein 1), cell-to cell communication (connexins) and transmembrane signal transduction (cathepsin C). Unna-Thost disease is the most common variety of hereditary PPK. Mutations in keratin 1 have been reported in Unna-Thost disease. We report 12 cases in which Unna-Thost disease was diagnosed. Genealogical study demonstrated that the genodermatosis was a familial disease inherited as an autosomal dominant disorder. Dermatological examination revealed yellowish hyperkeratosis on the palms and soles. Oral mucosa, teeth, and nails remained unchanged. Histopathological examination of the biopsy sample taken from the soles of the patients showed orthokeratotic keratosis, hypergranulosis, and acanthosis without epidermolysis. PMID- 27477172 TI - Evaluation of the Clinical and Sociodemographic Features of Turkish Patients with Vitiligo. AB - Vitiligo is an acquired, pigmentary skin disorder that affects about 0.1-4.0% of the population. In this study, we aimed to investigate the disease features such as age of onset, disease duration, clinical and sociodemographic characteristics, and laboratory parameters of patients with vitiligo. A hundred patients who were in follow-up for vitiligo between the period of June 2013 and May 2014 were included in the study. The clinical features and laboratory parameters were retrospectively obtained from the records of the patients. The mean age was 34.9+/-16.8 years. The most common clinical types were focal and acrofacial. Facial involvement was the most common localization. Forty-five (45%) patients had an associated systemic disease. Autoimmune thyroid disease, essential hypertension, and alopecia areata, which were observed in 28%, 8%, and 5% of patients, respectively, were the most common associated diseases. Twenty-one percent of the patients had low ferritin levels, 20% had low iron levels, 12% had low vitamin B12 levels, and 1% had low folic acid levels. The prevalence of anti TG (anti-thyroglobulin) and anti-TPO (anti-thyroid peroxidase) antibodies were found 17% and 27% of the patients, respectively. We found that the clinical characteristics of vitiligo in our patients were similar to those in other studies. We observed laboratory abnormalities and accompanying diseases associated with vitiligo. Therefore we conclude that laboratory examinations including thyroid antibodies and regular follow-up of these patients are essential. PMID- 27477173 TI - Clinical and Demographic Characteristics of Patients with Molluscum Contagiosum Treated at the University Dermatology Clinic Maribor in a 5-year period. AB - Molluscum contagiosum virus (MCV) is a common skin pathogen in both adults and children. In this prospective study, we clinically evaluated consecutive patients with molluscum contagiosum (MC) who had been examined during a 5-year period at the second-largest dermatology clinic in Slovenia and described their main demographic and clinical characteristics, concomitant diseases, and treatment success. The study included 188 patients, of which 121 (64%) were men and 67 (36%) were women. A total of 135 (72%) patients were adults, with lesions that were most commonly located in the anogenital region (98%) and were probably sexually acquired. Two adult patients were diagnosed with concurrent human immunodeficiency virus (HIV) infection. Fifty-three (28%) patients were children with a mean age of 5.7 years, most commonly presenting with lesions on the torso and extremities (85%). In adults, the infection most commonly occurred in male patients, while in children it was slightly more common in female patients. At presentation, 58% of patients had more than 5 MC lesions. A total of 30% of the included children had concomitant atopic dermatitis. We did not observe an increased occurrence of MCV infection in patients with atopic dermatitis. All patients were treated with curettage of the lesions. The cure rate at the first follow-up visit after 2 months was relatively high (63%), and recurrences were not associated with the number or site of lesions at presentation or with concomitant atopic dermatitis. PMID- 27477174 TI - A Different Presentation of Mal De Meleda: New Skin Lesions in a Residual Limb after Traumatic Amputation. AB - Mal de Meleda is a rare autosomal recessive skin disease which is known as keratoderma palmoplantaris transgradiens. Here we report a case of Mal de Meleda who had skin lesions in the residual limb and pseudoainhum in the thigh after traumatic lower leg amputation. A 71-year-old female was admitted to our tertiary hospital for prosthetic rehabilitation. On the physical examination, thickening of the skin on palms, left sole and residual limb was present. The patient reported that she had these skin lesions since infancy and she realized new skin lesions after amputation in the residual limb. We requested dermatology consultation and she was diagnosed as Mal de Meleda. To our knowledge, this is the first Mal de Meleda case in the literature with new lesions at the residual limb. Although exact pathophysiological mechanisms are not well known in Mal de Meleda, prosthesis use might have accelerated disease process in our patient. PMID- 27477175 TI - Cutis Verticis Gyrata - A Case Report. AB - Cutis verticis gyrata (CVG) is a skin condition characterized by excessive growth of the skin of the scalp, resulting in furrows and folds which are similar to the gyri of the brain cortex. CVG can be classified into two forms: primary (essential and non-essential) and secondary. We report the case of a 53-year-old male patient with the primary type of CVG. The patient did not present with any cutaneous complication. His main complaint was the unaesthetic aspect of his scalp related to a psychological inferiority complex. PMID- 27477176 TI - Dermatoscopic Findings of Seborrheic Keratosis in Melanoma. AB - Cutaneous melanoma may in some instances be confused with seborrheic keratosis, which is a very common neoplasia, more often mistaken for actinic keratosis and verruca vulgaris. Melanoma may clinically resemble seborrheic keratosis and should be considered as its possible clinical simulator. We report a case of melanoma with dermatoscopic characteristics of seborrheic keratosis and emphasize the importance of the dermatoscopy algorithm in differentiating between a melanocytic and a non-melanocytic lesion, of the excisional biopsy for the establishment of the diagnosis of cutaneous tumors, and of the histopathologic examination in all surgically removed samples. PMID- 27477177 TI - Zosteriform Collagen Nevus in an Infant. AB - Connective tissue nevi (CTN) are dermal hamartomas characterized by an imbalance in the amount and distribution of the normal components of the extracellular dermal matrix, specifically collagen, elastin, and/or proteoglicans. The term "CTN" was first mentioned by Lewandowsky in 1921 (1), although it was not accepted until the review by Gutmann in 1926 (2). Classification of CTN was established by Uitto et al. (3) in 1980 according to clinical, genetic, and histopathological features. But this classification did not include zosteriform nevi. The more recent Pierard and Lapiere (4) classification seems to be a more suitable method of classification for zosteriform nevi. They classified CTN into two groups: (1) reticular and (2) adventitial. Zosteriform nevus is a rare form of reticular CTN that is diagnosed according to its clinical distribution. Here we report a collagen nevus in an infant that followed a zosteriform pattern. An 8 month-old girl presented with flesh-colored plaques on the right buttock in a zosteriform distribution, which had been present since birth. The plaques appeared to be well-defined cobblestone-like nodules on palpation (Figure 1). Systemic examination, laboratory tests and radiologic examinations did not reveal any abnormalities. The patient had no associated disease and no history of similar skin findings among family members. A skin punch biopsy was performed from one of the nodules. The histopathologic examination showed significantly increased density of thickened collagen fibers in the lower dermis and subcutaneous tissue. Verhoeff-van Gieson and orcein stains demonstrated the presence of dense collagen fibers with diminished elastic fibers (Figure 2). Four subtypes of collagen tissue nevus have been described: (I) familial cutaneous collagenoma, (II) shagreen patches in tuberous sclerosis, (III) eruptive collagenoma, (IV) and isolated collagenoma (5). Isolated collagenoma with lack of family history is fairly rare. It is sporadic, localized to only one body region, and not associated with any disease. In confluent plaques it has the appearance of "peau de chagrin" or a cobblestone-like pattern. The reported presentations include paving stone nevi, plantar fibromatosis, papulolinear lesions, and zosteriform lesions (5). Zosteriform distribution is an extremely rare variety of connective tissue nevus. Steiner (6) was the first to describe the condition in 1944, in a 5-year-old girl who presented with nevi in a zosteriform distribution. The histopathology of the lesion revealed an abnormality in both collagen and elastin fibers. Only 11 other cases have been reported as zosteriform CTN in dermatological literature. To the best of our knowledge, only 3 collagen nevi in a zosteriform distribution have been previously described in the literature. De et al. (7) described the first case in a 25-year-old man presenting a collagen tissue nevus with zosteriform distribution located over the lower back. Subsequently, Kumari et al. (8) described the second case in a 20-year-old man presenting a large, flesh-colored, well-defined plaque in a zosteriform distribution on his right buttock since birth. Topal et al. (9) reported another case of a 10-year-old boy with a zosteriform collagen tissue nevus on his right arm as sclerotic papules and plaques. Clinically, zosteriform CTN has similar morphology and distribution to nevus lipomatosus superficialis (NLS) or segmental neurofibromatosis. The latter differential possibility needs to be excluded due to its association with gliomas. The histopathologic findings of NLS make it easy to differentiate from zosteriform CTN. The peculiar finding of ectopic fat in the dermis is considered to be almost pathognomonic of NLS (10). In conclusion, the zosteriform distribution of CTN is very rare, especially in the variety with collagen predominance. As the lesion remains asymptomatic, with only cosmetic effects, the condition needs no specific treatment. The present case is a rare type of isolated collagenoma with zosteriform distribution presenting over the right buttock with no associated abnormalities and family history. PMID- 27477178 TI - Trichotillomania: Bizzare Patern of Hair Loss at 11-Year-old Girl. AB - Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient's repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2 month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient's personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2 4% of the general psychiatric outpatient population meet the criteria for TTM (2 5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising <1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with "playing" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are "high-risk" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one's own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one's hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a "hair ball" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated. PMID- 27477179 TI - Folliculotropic Cutaneous Metastases and Lymphangitis Carcinomatosa: When Cutaneous Metastases of Breast Carcinoma Are Mistaken for Cutaneous Infections. AB - Dear Editor, Cutaneous metastases (CM) are detected in about 0.6-10.4% of patients with an internal malignancy (1-3). Excluding melanoma, breast and lung carcinomas are the main source of CM in women and men, respectively (1,4,5). CM can have different clinical features, and a diagnosis of CM is usually suspected before performing a biopsy. However, this can be a pitfall for clinicians when the clinical presentation is not the typical inflammatory nodule or mass. Herein we report 2 cases of cutaneous metastases of breast carcinoma, initially treated as a common skin infection. Case 1 A 51-year-old Caucasian woman presented to our Institute with a four-month history of diffuse and erythematous pustular, lesions on the right arm that were painless and non pruritic (Figure 1). The patient had undergone excision for a breast adenocarcinoma (stage IIIA) 5 years earlier. An initial diagnosis of folliculitis was established, and the patient started systemic and topical antibiotics without any improvement. Based on the clinical features and the patient medical history, we performed a skin biopsy. Pathologically dermal nests of tumor cells, arranged in a glandular-like pattern and involving the perifollicular and follicular areas (Figure 2, Figure 3), were highlighted. The tumor cells were positive to cytokeratin (CK) 7, CK19, and carcinoembryonic antigen (CEA) and negative for CK20, CK5/6, CD10, and thyroid transcription factor-1 (TTF-1) (Figure 4). According to the clinical history and pathology, a final diagnosis of folliculotropic metastatic breast carcinoma was established. Unfortunately, the patient died after 10 months. Case 2 A 61-year old Caucasian woman presented to our Department with a two-month history of pink/violet macular lesions with diffuse telangiectasia on the left breast and arm (Figure 5, Figure 6). Five years earlier she had undergone excision for a breast adenocarcinoma (stage II A). A previous diagnosis of cellulitis had been made, and systemic antibiotic therapy had been started without any improvement. Based on the clinical features and the patient medical history, a punch biopsy was performed. Examination of skin biopsy showed a diffuse, sclerotic, and mixoid stroma with several dense ectatic lymphatic vessels (Figure 7, Figure 8). The dermal and hypodermal lymphatic lumens were filled with neoplastic cells. Thus, a diagnosis of cutaneous lymphangitis carcinomatosa (CLC) was established. Unfortunately, the patient died after 8 months. Discussion CM are present after breast carcinoma in about 23.9% of patients, often involving the chest and abdomen and manifesting on average 5 years after surgical removal of the first malignancy (1,6). CM of breast cancer are usually solitary or multiple nodular pinkish lesions (ranging between 1 and 3 cm) (1). However, several clinical features have been reported in the literature, including telangiectatic carcinoma, erythema-like, erythema annulare centrifugum-like, morphea-like, erysipelas-like, dermatofibroma-like, herpes-zoster-like, and alopecia-like lesions (1,7-10). Clinical and pathological images of folliculitis-like metastases are rarely reported in the literature, especially after breast cancer (11,13) Clinically, folliculitis-like metastases could resemble a zosteriform like metastatic lesion (7,14,15) although they do not follow a dermatome and are pustular lesions rather than violaceous indurate papules and/or nodules (13,14) Pathologically, our cases showed an infiltration of the dermis and pilosebaceous units growing through the pilosebaceous unit in a "pseudo-eruptive way". In this regard, folliculitis-like CM could be similar to alopecia neoplastica, where the metastatic process involves and destroys the pilosebaceous units completely, leading to scarring alopecia (9,10). However, in our case, the pilosebaceous unit was still slightly recognizable, and clinically there were no scar-like features. The mechanism of folliculitis-like metastasis formation is currently unknown. As reported in zosteriform-like metastases, the lymphatic and hematogenous spread of malignant cells or the koebnerization at the site of a previous viral and/or bacterial infection could lead to metastasis (7,14-16). However, unlike zosteriform-like metastases, the spread of neoplastic cells from the dorsal root ganglia was not a plausible mechanism of metastasization in our cases because of the absence of dermatome involvement. Furthermore, there were no signs of possible koebnerization in a previous bacterial and/or viral infection site (7,13) In our opinion, folliculitis-like metastasis may be a result of the skin extruding malignant cells through the pilosebaceous unit to limit the neopalstic proliferation. This could explain the clinical and pathological features of folliculitis-like metastasis. Alternatively, the adnexotropic behavior of malignant cells may be explained by homing mechanisms, involving the up regulation of the intercellular adhesion molecule 1 (ICAM-1) on the follicular epithelium, such as folliculotropic mycosis fungoides (17). In our patient, the folliculitis-like eruption was the first sign of recurrence after 5 years of disease-free survival. It is evident that the unusual folliculitis-like eruption of CM led to a delay in the diagnosis. CLC is a rare presentation of skin metastasis, characterized by an occlusion of dermic lymphatic vessels by neoplastic cells (18). CLC has been reported in the literature in association with several malignancies, including lung, breast, and ovarian cancer (19). CLC shows pink/violet macular lesions with diffuse telangiectasias, often associated with itching and burning sensation. The main differential diagnoses are erysipelas and cellulitis. However, CLC is not associated with fever, chills, and leukocytosis. Furthermore, CLC shows no response to antibiotic therapies. Several clinicopathological types of cutaneous metastasis have been reported in the literature, including telangiectatic metastatic breast carcinoma (TMBC) and carcinoma erysipelatous (CE). TMBC is characterized by yellowish/reddish or violaceous papulo-vesicular lesions. CE usually shows blistering erythematous eruptions resembling erysipelas. However, CLC, TMBC, and CE are different clinical expressions of the same metastatic process, pathologically characterized by edema of the dermis and ectatic lymphatic vessels. Positivity to CD31 and podoplanin in the endothelial cells shows that the tumor metastatises predominantly via lymphatic vessels (20). In conclusion, we stress that every cutaneous lesion should be studied and examined carefully in patients with a personal history of cancer. Indeed, a correct diagnosis remains the pivotal point for a better management of these patients. PMID- 27477180 TI - Dermoscopy of Skin Adnexal Neoplasms:A Continuous Challenge. AB - Dear Editor, Apocrine hidradenoma is a rare benign adnexal tumor related to the more common poroma, as they both originate from sweat glands. Hidradenoma usually has an eccrine differentiation, but an apocrine differentiation is possible. Due to its rarity and non-specific clinical appearance it is difficult to differentiate it from other malignant cutaneous lesions. In this challenging task, dermatoscopy could be particularly helpful to better describe, recognize, and differentiate these lesions. Unfortunately, the literature offers only few dermatoscopic descriptions of this rare cutaneous neoplasm. A 70-year-old woman in fair general condition was referred to our Department for an asymptomatic 10*8 mm single nodule on her left scapula. This nodule was red, dome shaped, well circumscribed, firm, and mildly tender (Figure 1). The patient reported that it had been present since approximately 7 months. The lesion was neither painful nor itchy and there was no bleeding. A skin examination did not show any other lesions with the same features or other suspicious lesions. Dermatoscopy revealed milky-pinkish areas with dotted vessels, linear-irregular vessels, and hairpin vessels: some of these aspects can also be found in amelanotic melanoma (1). There were also homogeneous blue areas similar to lacunae, characteristic but not exclusive to vascular or sarcomatous neoplasms and basal cell carcinoma (1,2). Furthermore, small ulcerations covered by an amber crust were identified, which can usually be found in basal cell carcinoma. Regarding the background of the lesion, we noticed peculiar, translucent, pinkish, soft, large lobular areas (Figure 2). On the basis of this analysis, we suspected an atypical presentation of a basal cell carcinoma, an amelanotic melanoma, or a sarcomatous skin neoplasm. A metastasis of an unknown solid tumor was also taken into consideration. The histological examination revealed an adnexal neoplasm and specifically an apocrine hidradenoma. The neoplasm had variably sized nests and nodules of neoplastic epithelial cells, with a small ductular lumens confined within the upper dermis. The lesion was composed mainly of two cell types: polygonal and smaller, elongated, and darker cells. The cuboidal/polygonal cells were seen lining the duct-like spaces and slots and resembled those of poroma (Figure 3). The adnexal skin tumors group includes a complex variety of uncommon tumors that can be distinguished only histologically, and most of them are benign (3). Searching the literature for "hidradenoma dermoscopy" and "adnexal dermoscopy" yields multiple descriptions of poromas but few dermatoscopic descriptions of hidradenoma (4). There was only one report of the presence of "arborizing vessels"(5), and another described "reddish purple areas and some linear or hairpin-like vessels on the surface of the tumor" (6). In another paper we found: "irregular scar like whitish areas and a polymorphous vascular pattern including irregular reddish-purple areas mimicking lacunar appearance of hemangiomas with thick hairpin vessels at the periphery" (7). It is very difficult make use of such scant data especially in order to detect a leading pattern for a specific diagnosis. Moreover, the described structures lack in specificity, being also present in many other lesions. Analyzing our dermatoscopic image and comparing it to the other ones available in the literature, we identified a peculiar background. It consisted in the presence of multilobular translucent and pinkish soft areas, which fit the previously described dermatoscopic criteria. We hypothesize there is a correlation between this feature and the histopathological presentation with variably sized nests and nodules. Of course, further case reports of hidradenoma are needed to identify the soft lobular background as a distinctive dermatoscopic feature. Due to the lack of specific features both clinically than dermatoscopically, histopathological analysis remains the only gold standard for diagnosis of these benign mimicking lesions. PMID- 27477182 TI - New microscopies, biomaterials: Two new axes for Morphologie. PMID- 27477181 TI - Analysis of cell-free fetal DNA for non-invasive prenatal diagnosis in a family with neonatal diabetes. AB - AIMS: An early genetic diagnosis of neonatal diabetes guides clinical management and results in improved treatment in ~ 40% of patients. In the offspring of individuals with neonatal diabetes, a prenatal diagnosis allows accurate estimation of the risk of developing diabetes and, eventually, the most appropriate treatment for the baby. In this study, we performed non-invasive prenatal genetic testing for a fetus at risk of inheriting a paternal KCNJ11 p.R201C mutation causing permanent neonatal diabetes. METHODS: A droplet digital polymerase chain reaction assay was used to detect the presence of the mutation in cell-free circulating DNA (cfDNA) extracted from maternal plasma at 12 and 16 weeks' gestation. RESULTS: The mutation was not detected in the cfDNA samples, suggesting that the fetus had not inherited the KCNJ11 mutation. The fetal DNA fraction was estimated at 6.2% and 10.7%, which is above the detection limit of the assay. The result was confirmed by Sanger sequencing after the baby's birth, confirming that the baby's risk of developing neonatal diabetes was reduced to that of the general population. CONCLUSIONS: We report the first case of non invasive prenatal testing in a family with neonatal diabetes. A prenatal diagnosis in families at high risk of monogenic diabetes informs both prenatal and postnatal management. Although the clinical impact of this novel technology still needs to be assessed, its implementation in clinical practice (including cases at risk of inheriting mutations from the mother) will likely have a positive impact upon the clinical management of families affected by monogenic diabetes. PMID- 27477183 TI - Imaging of MELAS. AB - Mitochondrial diseases are multisystem disorders that frequently involve the central nervous system. The clinical presentation of these disorders may be challenging to differentiate from cerebrovascular disorders. Various imaging techniques are now available that provide a wide range of imaging modalities during initial clinical evaluation and throughout the disease course. Recent technological advancements have introduced advanced neuroimaging modalities that provide detailed information of metabolic disorders at the tissue level. Imaging findings, though diverse, usually have characteristic features that support differentiating these disorders from vascular syndromes. This article provides an overview of various neuroimaging modalities available along with the advent of new imaging techniques being utilized in these disorders. PMID- 27477184 TI - Smad4 is required for the development of cardiac and skeletal muscle in zebrafish. AB - Transforming growth factor-beta (TGF-beta) regulates cellular functions and plays key roles in development and carcinogenesis. Smad4 is the central intracellular mediator of TGF-beta signaling and plays crucial roles in tissue regeneration, cell differentiation, embryonic development, regulation of the immune system and tumor progression. To clarify the role of smad4 in development, we examined both the pattern of smad4 expression in zebrafish embryos and the effect of smad4 suppression on embryonic development using smad4-specific antisense morpholino oligonucleotides. We show that smad4 is expressed in zebrafish embryos at all developmental stages examined and that embryonic knockdown of smad4 results in pericardial edema, decreased heartbeat and defects in the trunk structure. Additionally, these phenotypes were associated with abnormal expression of the two heart-chamber markers, cmlc2 and vmhc, as well as abnormal expression of three makers of myogenic terminal differentiation, mylz2, smyhc1 and mck. Furthermore, a notable increase in apoptosis was apparent in the smad4 knockdown embryos, while no obvious reduction in cell proliferation was observed. Collectively, these data suggest that smad4 plays an important role in heart and skeletal muscle development. PMID- 27477185 TI - Reply to: "Effect of weight loss induced by energy restriction on measures of arterial compliance: A systematic review and meta-analysis". PMID- 27477187 TI - NecroX-7 may appear as a new molecule to stabilize atherosclerotic plaques. PMID- 27477186 TI - PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement. AB - BACKGROUND AND AIMS: Proprotein convertase subtilisin kexin type 9 (PCSK9) induces degradation of the low-density lipoprotein-receptor (LDLR). Smooth muscle cells (SMCs) in human atherosclerotic plaques and cultured SMCs express PCSK9. The present study aimed at defining the role of PCSK9 on vascular response to injury. METHODS: Carotid neointimal lesions were induced by positioning a non occlusive collar in PCSK9 knock-out (PCSK9-/-) and wild type littermate (PCSK9+/+) mice. RESULTS: In PCSK9-/- mice, we observed a significantly less intimal thickening (p < 0.05), a lower intimal media ratio (p < 0.02), and a tendency to higher lumen area, compared to PCSK9+/+ mice. When compared with PCSK9-/-, lesions of PCSK9+/+ mice had a higher content of SMCs (p < 0.05) and collagen (p < 0.05), while no difference was observed in the accumulation of macrophages. PCSK9 was detectable in both left and right carotids artery in regions occupied by medial and neointimal SMCs. SMCs freshly isolated from PCSK9 /-, when compared to PCSK9+/+ cells, showed higher levels of alpha-smooth muscle actin (alpha-SMA; 2.24 +/- 0.36 fold; p < 0.01) and myosin heavy chain II (MHC II; 8.65 +/- 1.55 fold; p < 0.01), and lower levels of caldesmon mRNA(-54 +/- 14%; p < 0.01). PCSK9-/- cells also showed a slower proliferation rate, and an impaired migratory capacity and G1/S progression of the cell cycle. The reconstitution of PCSK9 expression, by retroviral infection of PCSK9-/- SMCs, led to a downregulation of alpha-SMA (-56 +/- 2%; p < 0.01), MHC-II (-45% +/- 25.5 fold: p = 0.06) and calponin (-25% +/- 0.8 fold: p < 0.05) and induction of caldesmon mRNA (1.46 +/- 0.3 fold; p < 0.05). Proliferation rate of SMCs PCSK9-/- was significantly lower compared to PCSK9 reconstituted cells. CONCLUSIONS: Taken together, the present results suggest that PCSK9, by sustaining SMC synthetic phenotype, proliferation, and migration, may play a pro-atherogenic role in the arterial wall. PMID- 27477188 TI - Alloying ZnS in the hexagonal phase to create high-performing transparent conducting materials. AB - Alloyed zinc sulfide (ZnS) has shown promise as a relatively inexpensive and earth-abundant transparent conducting material (TCM). Though Cu-doped ZnS has been identified as a high-performing p-type TCM, the corresponding n-doped ZnS has, to date, been challenging to synthesize in a controlled manner; this is because the dopant atoms compete with hole-inducing zinc vacancies near the conduction band minimum as the most thermodynamically stable intrinsic point defects. We thus aim to identify the most promising n-type ZnS-based TCM, with the optimal combination of physical stability, transparency, and electrical conductivity. Using a relatively new method for calculating the free energy of both the sphalerite (cubic) and wurtzite (hexagonal) phases of undoped and doped ZnS, we find that doped ZnS is more stable in the hexagonal structure. This, for the first time, fundamentally explains previous experimental observations of the coexistence of both phases in doped ZnS; hence, it profoundly impacts future work on sulfide TCMs. We also employ hybrid density functional theory calculations and a new carrier transport model, AMSET (ab initio model for mobility and Seebeck coefficient using the Boltzmann transport equation), to analyze the defect physics and electron mobility of the different cation- (B, Al, Ga, In) and anion doped (F, Cl, Br, I) ZnS, in both the cubic and hexagonal phases, at various dopant compositions, temperatures, and carrier concentrations. Among all doped ZnS candidates, Al-doped ZnS (AZS) exhibits the highest dopant solubility, largest electronic band gap, and highest electrical conductivity of 3830, 1905, and 321 S cm(-1), corresponding to the possible carrier concentrations of n = 10(21), 10(20), and 10(19) cm(-3), respectively, at the optimal 6.25% dopant concentration of Al and the temperature of 300 K. PMID- 27477189 TI - Corrigendum to "Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer" [Gynecol. Oncol. 141 (2016) 588-591]. PMID- 27477190 TI - Immunologic challenges of human reproduction: an evolving story. AB - Characterization of the implanting human fetus as an allograft prompted a field of research in reproductive immunology that continues to fascinate and perplex scientists. Paternal- or partner-derived alloantigens are present in the maternal host at multiple times during the reproductive process. They begin with exposure to semen, continue through implantation and placentation, and may persist for decades in the form of fetal microchimerism. Changes in maternal immune responses that allow allogenic fertilization and survival of semiallogenic concepti to delivery must be balanced with a continued need to respond appropriately to pathogenic invaders, commensals, cell or tissue damage, and any tendency toward malignant transformation. This complex and sophisticated balancing act is essential for survival of mother, fetus, and the species itself. We will discuss concepts of alloimmune recognition, tolerance, and ignorance as they pertain to mammalian reproduction with a focus on human reproduction, maternal immune modulation, and the very earliest events in the reproductive process, fertilization and implantation. PMID- 27477191 TI - Between Moral Relativism and Moral Hypocrisy: Reframing the Debate on "FGM". AB - The spectrum of practices termed "Female Genital Mutilation" (or FGM) by the World Health Organization is sometimes held up as a counterexample to moral relativism. Those who advance this line of thought suggest the practices are so harmful in terms of their physical and emotional consequences, as well as so problematic in terms of their sexist or oppressive implications, that they provide sufficient, rational grounds for the assertion of a universal moral claim -namely, that all forms of FGM are wrong, regardless of the cultural context. However, others point to cultural bias and moral double standards on the part of those who espouse this argument, and have begun to question the received interpretation of the relevant empirical data on FGM as well. In this article I assess the merits of these competing perspectives. I argue that each of them involves valid moral concerns that should be taken seriously in order to move the discussion forward. In doing so, I draw on the biomedical "enhancement" literature in order to develop a novel ethical framework for evaluating FGM (and related interventions--such as female genital "cosmetic" surgery and nontherapeutic male circumcision) that takes into account the genuine harms that are at stake in these procedures, but which does not suffer from being based on cultural or moral double standards. PMID- 27477192 TI - Equality Now in Genital Reshaping: Brian Earp's Search for Moral Consistency. PMID- 27477193 TI - Moral Hypocrisy or Intellectual Inconsistency?: A Historical Perspective on Our Habit of Placing Male and Female Genital Cutting in Separate Ethical Boxes. PMID- 27477194 TI - Relativists and Hypocrites: Earp on Genital Cutting. PMID- 27477195 TI - On Physician-Industry Relationships and Unreasonable Standards of Proof for Harm: A Population-Level Bioethics Approach. AB - The primary claim of this paper is that a widely used argument against obstructing, curtailing, or eliminating deep physician-industry relationships is deficient. The typical argument critiqued requires that proof that physician industry relationships cause harm flows from randomized controlled trials. Chief among the deficiencies in this claim is the fact that this specific demand for proof of harm essentially guts the precautionary principle. In so doing, the typical argument neuters the basic justification for public health action. In place of this fallacious move, the paper argues that proof of harm can be demonstrated via evidentiary standards widely accepted within the knowledge communities of public health scientists and epidemiologists. The paper concludes by noting that while there may be good reasons to oppose curtailment of deep physician-industry relationships, the typical argument described here is not among them. PMID- 27477196 TI - Nonegalitarian Social Responsibility for Health: A Confucian Perspective on Article 14 of the UNESCO: Declaration on Bioethics and Human Rights. AB - This essay offers a Confucian evaluation of Article 14 of the UNESCO Declaration on Bioethics and Human Rights, with a focus given to its statement that "the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being." It indicates that "a right to health" contained in the statement is open to two different interpretations, one radically egalitarian, another a decent minimum. It shows that Confucianism has strong moral considerations to reject the radical egalitarian interpretation, and argues that a Confucian nonegalitarian health distribution ethics of differentiated and graded love and obligation can reasonably be supported with a right to the decent minimum of health at the international level. PMID- 27477198 TI - Editorial Note. PMID- 27477200 TI - Problems with traffic ahead: Synaptic vesicles in Parkinson's disease. PMID- 27477201 TI - The identification of risk and essential elements along the strobila of the rat tapeworm Hymenolepis diminuta. AB - The rat tapeworm Hymenolepis diminuta can bioconcentrate several elements to conspicuously higher concentrations than tissues of their definitive host. The main aim of this study was to locate parts of the tapeworm into which lead, cadmium, zinc, copper, manganese and iron are accumulated. Male Wistar rats were experimentally infected with H. diminuta and worms were exposed to two different forms of lead for 6 weeks through the oral exposure of their rat hosts. After the exposure period, the element levels were determined in the posterior and anterior proglottids of the tapeworm. In all cases, lead concentrations were higher in the anterior parts than the posterior parts. Concentrations of cadmium, copper, iron, manganese and zinc were also significantly higher in the anterior parts. Zinc concentrations showed an opposite trend, with higher zinc levels detected in the posterior part of the strobila, in the control group. The present study demonstrates that risk and essential elements are accumulated mainly into the anterior part of H. diminuta. PMID- 27477199 TI - Social Preference and Glutamatergic Dysfunction: Underappreciated Prerequisites for Social Dysfunction in Schizophrenia. AB - Impaired social functioning is pervasive in schizophrenia. Unfortunately, existing treatments have limited efficacy, and possible psychological or neurobiological mechanisms underlying social dysfunction in this disorder remain obscure. Here, we evaluate whether social preference, one key aspect of social processing that has been largely overlooked in schizophrenia research, and N methyl-d-aspartate receptor (NMDAR) dysfunction can provide insights into the mechanism underlying social dysfunction in schizophrenia. Based on evidence from developmental psychology, and behavioral and clinical neuroscience, we propose a heuristic model in which reduced NMDAR function may induce disrupted social preference that can subsequently lead to social cognitive impairment and social disability. We discuss its implications in terms of the pathophysiology of schizophrenia, other disorders with marked social disability, and potential treatments. PMID- 27477202 TI - Monitoring invasive pathogens in plant nurseries for early-detection and to minimise the probability of escape. AB - The global increase in the movement of plant products in recent years has triggered an increase in the number of introduced plant pathogens. Plant nurseries importing material from abroad may play an important role in the introduction and spread of diseases such as ash dieback and sudden oak death which are thought to have been introduced through trade. The economic, environmental and social costs associated with the spread of invasive pathogens become considerably larger as the incidence of the pathogen increases. To control the movement of pathogens across the plant trade network it is crucial to develop monitoring programmes at key points of the network such as plant nurseries. By detecting the introduction of invasive pathogens at low incidence, the control and eradication of an epidemic is more likely to be successful. Equally, knowing the likelihood of having sold infected plants once a disease has been detected in a nursery can help designing tracing plans to control the onward spread of the disease. Here, we develop an epidemiological model to detect and track the movement of an invasive plant pathogen into and from a plant nursery. Using statistical methods, we predict the epidemic incidence given that a detection of the pathogen has occurred for the first time, considering that the epidemic has an asymptomatic period between infection and symptom development. Equally, we calculate the probability of having sold at least one infected plant during the period previous to the first disease detection. This analysis can aid stakeholder decisions to determine, when the pathogen is first discovered in a nursery, the need of tracking the disease to other points in the plant trade network in order to control the epidemic. We apply our method to high profile recent introductions including ash dieback and sudden oak death in the UK and citrus canker and Huanglongbing disease in Florida. These results provide new insight for the design of monitoring strategies at key points of the trade network. PMID- 27477204 TI - The Pennsylvania Anatomy Act of 1883: Weighing the Roles of Professor William Smith Forbes and Senator William James McKnight. AB - Effective Anatomical Acts transformed medical education and curtailed grave robbing. William S. Forbes, Demonstrator of Anatomy at Jefferson Medical College in Philadelphia, authored the Pennsylvania Anatomy Act of 1867, but it was ineffective. In December of 1882, Forbes and accomplices were charged with grave robbing. Forbes was acquitted in early 1883, but his accomplices were all convicted; nevertheless, these events precipitated a strengthened Anatomy Act in 1883. Forbes was crowned the Father of the Pennsylvania Anatomy Act and was revered by the Philadelphia medical community for his personal sacrifices for medical education; they even paid his legal fees. Over the remainder of his life, Forbes received many honors. However, there was a second major player, rural doctor William J. McKnight, a convicted grave-robber and State Senator. The evidence shows that Forbes precipitated the crisis, which was a racial powder keg, and then primarily focused on his trial, while McKnight, creatively working behind the scenes in collaboration with Jefferson, Anatomy Professor William H. Pancoast, used the crisis to draft and pass transformative legislation enabling anatomical dissection at Pennsylvania medical schools. While not minimizing Forbes suffering throughout these events, McKnight should be appropriately recognized for his initiative and contributions, which far exceeded those of Forbes. PMID- 27477203 TI - Quantitative analysis of B-lymphocyte migration directed by CXCL13. AB - B-lymphocyte migration, directed by chemokine gradients, is essential for homing to sites of antigen presentation. B cells move rapidly, exhibiting amoeboid morphology like other leukocytes, yet quantitative studies addressing B-cell migration are currently lacking relative to neutrophils, macrophages, and T cells. Here, we used total internal reflection fluorescence (TIRF) microscopy to characterize the changes in shape (morphodynamics) of primary, murine B cells as they migrated on surfaces with adsorbed chemokine, CXCL13, and the adhesive ligand, ICAM-1. B cells exhibited frequent, spontaneous dilation and shrinking events at the sides of the leading membrane edge, a phenomenon that was predictive of turning versus directional persistence. To characterize directed B cell migration, a microfluidic device was implemented to generate gradients of adsorbed CXCL13 gradients. Haptotaxis assays revealed a modest yet consistently positive bias of the cell's persistent random walk behavior towards CXCL13 gradients. Quantification of tactic fidelity showed that bias is optimized by steeper gradients without excessive midpoint density of adsorbed chemokine. Under these conditions, B-cell migration is more persistent when the direction of migration is better aligned with the gradient. PMID- 27477205 TI - Pacing in age-group freestyle swimmers at The XV FINA World Masters Championships in Montreal 2014. AB - Pacing strategies have been investigated for elite-standard freestyle swimmers, but little is known about pacing in age-group freestyle swimmers. We investigated changes in swimming time across distances in 4,481 women and men swimmers who competed in 100, 200, 400, and 800 m freestyle age groups from 25-29 years to 90 94 years in the FINA World Masters Championships 2014. In 100 to 800 m, there was a small lap*sex interaction (P < 0.001, 0.033 <= eta2 <= 0.045) whereby women had larger lap-to-lap changes in swimming time than men. From 100 to 800 m, there were moderate to large lap*age group interactions (P < 0.001, 0.054 <= eta2 <= 0.235), i.e., pacing patterns differed by age groups. There were small main effects of lap on time in 100, 200, 400 and 800 m freestyle events (P < 0.001, 0.033 <= eta2 <= 0.045). In summary, (i) the largest increase in swimming time occurred during the second lap and a decrease in time occurred during the last lap, except in the 100 m, and (ii) the effect of participants' sex on lap time indicated larger percentage changes of pacing in women than in men. These findings should help coaches to develop age- and event-tailored pacing strategies. PMID- 27477206 TI - Passage of irinotecan and its active metabolite, SN-38, into human milk. AB - WHAT IS KNOWN AND OBJECTIVE: We measured the levels of irinotecan and its active metabolite, SN-38, in human milk after the administration of irinotecan to assess the potential risks when women treated with irinotecan nurse their infants. CASE SUMMARY: Human milk was collected for 6 days starting on the day after irinotecan was administered. The levels of irinotecan and SN-38 in human milk were measured using liquid chromatography-mass spectrometry. Irinotecan was detected on Days 2 and 3 but not after Day 4. A strong signal indicating the presence of SN-38 was detected on Day 2 and the signal was readily detected until Day 7, indicating that SN-38 remained in human milk. WHAT IS NEW AND CONCLUSION: Intravenously administered CPT-11 continues to pass into human milk over a prolonged period in the form of its active metabolite, SN-38. The relationship between administration of CPT-11 and SN-38 exposure and toxicity is still not well defined, so patients should avoid nursing their infants while they are being treated with CPT-11. PMID- 27477207 TI - Design and development of new class of Mycobacterium tuberculosisl-alanine dehydrogenase inhibitors. AB - Mycobacterium tuberculosisl-alanine dehydrogenase (MTB l-AlaDH) is one of the important drug targets for treating latent/persistent tuberculosis. In this study we used crystal structure of the MTB l-AlaDH bound with cofactor NAD(+) as a structural framework for virtual screening of our in-house database to identified new classes of l-AlaDH inhibitor. We identified azetidine-2,4-dicarboxamide derivative as one of the potent inhibitor with IC50 of 9.22+/-0.72MUM. Further lead optimization by synthesis leads to compound 1-(isonicotinamido)-N(2),N(4) bis(benzo[d]thiazol-2-yl)azetidine-2,4-dicarboxamide (18) with l-AlaDH IC50 of 3.83+/-0.12MUM, 2.0log reduction in nutrient starved dormant MTB model and MIC of 11.81MUM in actively replicative MTB. PMID- 27477208 TI - Ventriculoatrial Intervals <=70 ms in Orthodromic Atrioventricular Reciprocating Tachycardia. AB - BACKGROUND: Although a ventriculoatrial interval (VAI) of <=70 ms is used to distinguish atrioventricular nodal reentrant tachycardia from orthodromic atrioventricular reciprocating tachycardia (AVRT), a VAI of <=70 ms is sometimes observed in cases of AVRT. The study aimed to evaluate the short VAI that is seen in AVRT and to understand its underlying mechanism. METHODS: Electrophysiologic studies of 46 consecutive patients with AVRT involving an accessory pathway (AP) were examined retrospectively. RESULTS: AP was right sided in seven patients and left sided in 39. A VAI (interval from QRS onset to the earliest intracardiac atrial electrogram recorded by any mapping catheter during AVRT) <=70 ms during AVRT (short VAI) was observed in eight patients: six with a left lateral AP and two with a left posteroseptal AP. During AVRT involving a left-sided AP, the QRS V interval (from the earliest QRS onset to the local ventricular electrogram at a site which showed earliest atrial electrogram recorded from the coronary sinus catheter) was significantly shorter (37 +/- 7 ms vs 54 +/- 13 ms, P = 0.001) and supernormal conduction (QRS duration or the QRS-V interval shortening by >=10 ms during AVRT) was more frequently seen (63% vs 6%, P = 0.02) in the short VAI group than in the normal VAI group. Furthermore, these parameters were shown to be determinants for short VAI. CONCLUSIONS: A short VAI is sometimes observed during AVRT involving a left-sided AP. The short VAI may be caused by rapid propagation or supernormal conduction between the proximal Purkinje-muscle junction and basal left ventricular myocardium. PMID- 27477209 TI - De Garengeot hernia: an uncommon presentation of acute appendicitis. AB - We present a case of a 78-year-old female patient with an uncommon presentation of acute appendicitis. She was found to have a perforated appendicitis which developed in a femoral hernia sack. An appendix present in a femoral hernia is called a De Garengeot Hernia, which is a rare form of femoral hernia. Clinical presentation, diagnosis and management are discussed. PMID- 27477210 TI - BioVLAB-mCpG-SNP-EXPRESS: A system for multi-level and multi-perspective analysis and exploration of DNA methylation, sequence variation (SNPs), and gene expression from multi-omics data. AB - Measuring gene expression, DNA sequence variation, and DNA methylation status is routinely done using high throughput sequencing technologies. To analyze such multi-omics data and explore relationships, reliable bioinformatics systems are much needed. Existing systems are either for exploring curated data or for processing omics data in the form of a library such as R. Thus scientists have much difficulty in investigating relationships among gene expression, DNA sequence variation, and DNA methylation using multi-omics data. In this study, we report a system called BioVLAB-mCpG-SNP-EXPRESS for the integrated analysis of DNA methylation, sequence variation (SNPs), and gene expression for distinguishing cellular phenotypes at the pairwise and multiple phenotype levels. The system can be deployed on either the Amazon cloud or a publicly available high-performance computing node, and the data analysis and exploration of the analysis result can be conveniently done using a web-based interface. In order to alleviate analysis complexity, all the process are fully automated, and graphical workflow system is integrated to represent real-time analysis progression. The BioVLAB-mCpG-SNP-EXPRESS system works in three stages. First, it processes and analyzes multi-omics data as input in the form of the raw data, i.e., FastQ files. Second, various integrated analyses such as methylation vs. gene expression and mutation vs. methylation are performed. Finally, the analysis result can be explored in a number of ways through a web interface for the multi level, multi-perspective exploration. Multi-level interpretation can be done by either gene, gene set, pathway or network level and multi-perspective exploration can be explored from either gene expression, DNA methylation, sequence variation, or their relationship perspective. The utility of the system is demonstrated by performing analysis of phenotypically distinct 30 breast cancer cell line data set. BioVLAB-mCpG-SNP-EXPRESS is available at http://biohealth.snu.ac.kr/software/biovlab_mcpg_snp_express/. PMID- 27477211 TI - Disease types discovery from a large database of inpatient records: A sepsis study. AB - Data-driven phenotype discoveries on Electronic Health Records (EHR) data have recently drawn benefits across many aspects of clinical practice. In the method described in this paper, we map a very large EHR database containing more than a million inpatient cases into a low dimensional space where diseases with similar phenotypes have similar representation. This embedding allows for an effective segmentation of diseases into more homogeneous categories, an important task of discovering disease types for precision medicine. In particular, many diseases have heterogeneous nature. For instance, sepsis, a systemic and progressive inflammation, can be caused by many factors, and can have multiple manifestations on different human organs. Understanding such heterogeneity of the disease can help in addressing many important issues regarding sepsis, including early diagnosis and treatment, which is of huge importance as sepsis is one of the main causes of in-hospital deaths in the United States. This study analyzes state of the art embedding models that have had huge success in various fields, applying them to disease embedding from EHR databases. Particular interest is given to learning multi-type representation of heterogeneous diseases, which leads to more homogeneous groups. Our results show evidence that such representations have phenotypes of higher quality and also provide benefit when predicting mortality of inpatient visits. PMID- 27477212 TI - Facile fabrication of large-grain CH3NH3PbI3-xBrx films for high-efficiency solar cells via CH3NH3Br-selective Ostwald ripening. AB - Organometallic halide perovskite solar cells (PSCs) have shown great promise as a low-cost, high-efficiency photovoltaic technology. Structural and electro-optical properties of the perovskite absorber layer are most critical to device operation characteristics. Here we present a facile fabrication of high-efficiency PSCs based on compact, large-grain, pinhole-free CH3NH3PbI3-xBrx (MAPbI3-xBrx) thin films with high reproducibility. A simple methylammonium bromide (MABr) treatment via spin-coating with a proper MABr concentration converts MAPbI3 thin films with different initial film qualities (for example, grain size and pinholes) to high quality MAPbI3-xBrx thin films following an Ostwald ripening process, which is strongly affected by MABr concentration and is ineffective when replacing MABr with methylammonium iodide. A higher MABr concentration enhances I-Br anion exchange reaction, yielding poorer device performance. This MABr-selective Ostwald ripening process improves cell efficiency but also enhances device stability and thus represents a simple, promising strategy for further improving PSC performance with higher reproducibility and reliability. PMID- 27477213 TI - Biotrauma and Ventilator-Induced Lung Injury: Clinical Implications. AB - The pathophysiological mechanisms by which mechanical ventilation can contribute to lung injury, termed "ventilator-induced lung injury" (VILI), is increasingly well understood. "Biotrauma" describes the release of mediators by injurious ventilatory strategies, which can lead to lung and distal organ injury. Insights from preclinical models demonstrating that traditional high tidal volumes drove the inflammatory response helped lead to clinical trials demonstrating lower mortality in patients who underwent ventilation with a lower-tidal-volume strategy. Other approaches that minimize VILI, such as higher positive end expiratory pressure, prone positioning, and neuromuscular blockade have each been demonstrated to decrease indices of activation of the inflammatory response. This review examines the evolution of our understanding of the mechanisms underlying VILI, particularly regarding biotrauma. We will assess evidence that ventilatory and other "adjunctive" strategies that decrease biotrauma offer great potential to minimize the adverse consequences of VILI and to improve the outcomes of patients with respiratory failure. PMID- 27477214 TI - Adverse bone health and abnormal bone turnover among perinatally HIV-infected Asian adolescents with virological suppression. AB - OBJECTIVES: This study aimed to determine the prevalence of low bone mass and assess its relationship with abnormal bone turnover among HIV-infected Asian adolescents. METHODS: A multicentre, cross-sectional study was conducted at four paediatric HIV centres in Thailand and Indonesia. Perinatally HIV-infected adolescents aged 10-18 years receiving antiretroviral therapy (ART) with virological suppression (HIV RNA < 400 copies/mL) were enrolled. Study assessments included lumbar spine (L2-L4) dual-energy X-ray absorptiometry and measurement of bone turnover markers. Bone mineral density (BMD) and bone mineral apparent density (BMAD) Z-scores were calculated based on Thai normative age- and sex-matched references. Low bone mass was defined as BMD or BMAD Z-scores <= -2. RESULTS: Of 396 participants, 57% were female. The median age was 15.0 [interquartile range (IQR) 13.3-16.9] years, and 73% were in Tanner stage 3-5. At enrolment, the median CD4 T-cell count was 734 (IQR 581-907) cells/MUL, and 37% were on protease inhibitor (PI)-based regimens. The overall prevalence of lumbar spine BMD and BMAD Z-scores <= -2 were 16.4% and 8.3%, respectively. Z-scores were lower with older age, female sex, body mass index (BMI) <5th percentile, boosted PI exposure and CD4 T-cell percentage < 15% before ART initiation. Increased bone turnover markers were inversely associated with BMD and BMAD Z scores. CONCLUSIONS: Low bone mass was linked to older age, female sex, low BMI, boosted PI exposure, and poor immunological status before ART commencement in our cohort of perinatally HIV-infected Asian adolescents. Dysregulation of bone turnover was associated with bone demineralization. Screening for low bone mass should be implemented to identify individuals who might benefit from interventions to preserve bone health. PMID- 27477216 TI - Photofragmentation mechanisms in protonated chiral cinchona alkaloids. AB - The photo-stability of protonated cinchona alkaloids is studied in the gas phase by a multi-technique approach. A multi-coincidence technique is used to demonstrate that the dissociation is a direct process. Two dissociation channels are observed. They result from the C8-C9 cleavage, accompanied or not by hydrogen migration. The branching ratio between the two photo-fragments is different for the two pseudo-enantiomers quinine and quinidine. Mass spectrometry experiments coupling UV photo-dissociation of the reactants and structural characterization of the ionic photo-products by Infra-Red Multiple Photo-Dissociation (IRMPD) spectroscopy provide unambiguous information on their structure. In addition, quantum chemical calculations allow proposing a reactive scheme and discussing it in terms of the ground-state geometry of the reactant. PMID- 27477215 TI - Minimalist Antibodies and Mimetics: An Update and Recent Applications. AB - The immune system utilizes antibodies to recognize foreign or disease-relevant receptors, initiating an immune response to destroy unwelcomed guests. Because researchers can evolve antibodies to bind virtually any target, it is perhaps unsurprising that these reagents, and their small-molecule conjugates, are used extensively in clinical and basic research environments. However, virtues of antibodies are countered by significant challenges. Foremost among these is the need for expression in mammalian cells (largely due to often necessary post translational modifications). In response to these challenges, researchers have developed an array of minimalist antibodies and mimetics, which are smaller, more stable, simpler to express in Escherichia coli, and amendable to laboratory evolution and protein engineering. Here we describe these scaffolds and discuss recent applications of minimalist antibodies and mimetics. PMID- 27477217 TI - Diagnosis and clinical management of melanoma patients at higher risk of a new primary melanoma: A population-based study in New South Wales, Australia. AB - BACKGROUND/OBJECTIVES: To describe the method of diagnosis, clinical management and adherence to clinical practice guidelines for melanoma patients at high risk of a subsequent primary melanoma, and compare this with melanoma patients at lower risk. METHODS: The Melanoma Patterns of Care study was a population-based, observational study based on doctors' reported clinical management of melanoma patients in New South Wales, Australia, diagnosed with in situ or invasive melanoma over a 12-month period from October 2006. Of 2605 patients with localised melanoma, 1019 (39%) were defined as at higher risk due to the presence of one or more of the following factors: a family history of melanoma (11%), multiple primary melanomas (17%), or many naevi (24%). RESULTS: Compared to patients at lower risk, high risk patients were more likely to receive their initial care from a primary care physician (56% vs 50%, P = 0.002), have their melanoma detected during a routine skin check (40% vs 33%, P < 0.001), have their lesion assessed with dermoscopy (63% vs 56%, P = 0.002), and be encouraged to have skin surveillance (84% vs 77%, P < 0.001) and skin self-examination (87% vs 83%, P = 0.03). Higher socioeconomic status and urban residence were associated with patients at higher risk receiving initial treatment from a specialist doctor. CONCLUSIONS: Clinical management of higher risk patients was more likely to conform to clinical practice guidelines for diagnosis and skin surveillance than to melanoma patients at lower risk. PMID- 27477219 TI - Antimicrobial dental implant functionalization strategies -A systematic review. AB - Biofilm formation on dental implant surfaces is a serious threat. Up to 50% of all implants show signs of irreversible tissue destruction. The aim of the present systematic review was to summarize the state of the art of strategies to functionalize antimicrobial dental implant surfaces. We searched the following electronic database: SCOPUS, MEDLINE and GOOGLE SCHOLAR and identified relevant controlled trials that evaluated the efficiency of new biomaterial strategies to modify dental implant surfaces, in such a way that biofilm formation was inhibited. The search yielded 2,990 potentially relevant publications. A total of 142 publications met the inclusion criteria. Analysis found that it may be concluded that silver-implanted surfaces, drug-loaded surfaces, surfaces with antimicrobial peptides, bioactive and biopassive polymer coatings as well as nanoscale or UV-activatable surfaces enhance antimicrobial activity compared to commercial pure titanium. PMID- 27477218 TI - Influential and theoretical analysis of nano-defect in the stub resonator. AB - We investigate a classic optical effect based on plasmon induced transparency (PIT) in a metal-insulator-metal (MIM) bus waveguide coupled with a single defective cavity. With the coupled mode theory (CMT), a theoretical model, for the single defective cavity, is established to study spectral features in the plasmonic waveguide. We can achieve a required description for the phenomenon, and the theoretical results also agree well with the finite-difference time domain (FDTD) method. Our researches show that the defect's position and size play important roles in the PIT phenomenon. By adjusting the position and size of the defect, we can realize the PIT phenomenon well and get the required slow light effect. The proposed model and findings may provide guidance for fundamental research of the control of light in highly integrated optical circuits. PMID- 27477220 TI - Diametral tensile strength of novel fast-setting calcium silicate cement. AB - Novel fast-setting calcium silicate cement with fluoride (CSC) has been developed for potential applications in tooth crown. The aim of this study was to test the diametral tensile strength (DTS) of different CSC compositions in humid condition on day1, 28, and 180. We tested 'bond CSC' with 3.5% fluoride and no radiocontrast, 'CSC' with 3.5% fluoride and 10% radiocontrast, 'ultrafast CSC' with 3.5% fluoride and 20% radiocontrast, 'high fluoride CSC' with 15% fluoride and 25% radiocontrast, Biodentine, and MTA. We filled the cements after mixing to cylindrical molds. Specimens were stored in >95% humidity. DTS was measured at each time point. CSC compositions had statistically higher DTS compared to MTA and Biodentine on day1. Bond CSC showed higher DTS versus all cements, except CSC, at all time points. DTS of all cements, except Biodentine, significantly increased in humid condition on day28 and day180 compared to day1. PMID- 27477221 TI - Mechanical properties and microstructures of dental cast Ti-6Nb-4Cu, Ti-18Nb-2Cu, and Ti-24Nb-1Cu alloys. AB - The mechanical properties -tensile strength, yield strength, elongation after fracture, and Vickers hardness- and alloy phases of the dental cast alloys Ti 6%Nb-4%Cu, Ti-18%Nb-2%Cu, and Ti-24%Nb-1%Cu were investigated. Ti-6%Nb-4%Cu consisted of a single alpha-phase, while Ti-18%Nb-2%Cu and Ti-24%Nb-1%Cu consisted of alpha- and beta-phases. The tensile strengths, yield strengths, and hardnesses of these alloys were higher than those of Ti-5%Cu and Ti-30%Nb; however, their breaking elongations were smaller. These differences in the mechanical properties are attributable to solid-solution strengthening or to precipitation strengthening by the dual-phase (alpha+beta) structure. Thus, Ti-Nb Cu alloys are suitable for use in high-strength dental prostheses, such as implantretained superstructures and narrow-diameter implants. PMID- 27477222 TI - Translucency and low-temperature degradation of silica-doped zirconia: A pilot study. AB - The purpose of this study was to examine the translucency and low-temperature degradation of silica-doped experimental Y-TZP (Yttria-stabilized tetragonal zirconia polycrystal) containing almost no alumina. The experimental Y-TZP samples were sintered at either 1,450 or 1,500 degrees C. The samples of commercially available translucent Y-TZP and conventional Y-TZP were used as controls. The contrast ratio (CR) and translucency parameter (TP) were obtained to compare the translucencies. In addition, the specimens were also subjected to an accelerated aging test. The results showed that the experimental Y-TZP sintered at 1,500 degrees C and translucent Y-TZP exhibited almost the same level of translucency. During the accelerated aging test, the translucent Y-TZP underwent a substantial increase in monoclinic content, an index of degradation after the aging test. However, neither the experimental Y-TZP nor the conventional Y-TZP exhibited any appreciable change. It was concluded that the silica-doped Y-TZP will develop translucency and resistance to degradation when sintered at 1,500 degrees C. PMID- 27477223 TI - Wear characteristics of trimethylolpropane trimethacrylate filler-containing resins for the full crown restoration of primary molars. AB - Although the demand for aesthetic restoration of primary molars has increased, the full-crown restorations using resin and the details of the wear characteristics of trimethylolpropane trimethacrylate (TMPT) filler containing resins for primary molars are not well understood. This study was conducted to determine whether new light-cured composite resin (Fantasista) and 4-META/MMATBB resin (Bondfill SB) are appropriate for full crown restoration of primary molars by evaluating their wear characteristics. Both resins products contain TMPT filler. The properties of the resins were evaluated through in vitro impacting sliding wear tests; the wear properties of the opposing enamel specimens used in the tests were also studied. The properties of the resins were compared with those of Litefill, MetafilC, and Clearfil FII, which had been evaluated previously. Fantasista exhibited simple shape of wear that was suggestive of a higher wear resistance than that of Litefill. Fantasista caused the least damage to the antagonistic primary enamel. PMID- 27477224 TI - Retention force of differently fabricated telescopic PEEK crowns with different tapers. AB - To assess the retention force between primary and secondary PEEK crowns made by different fabrication methods. Primary crowns with different tapers (0 degrees , 1 degrees , and 2 degrees ) were fabricated and secondary crowns that were either milled from breCam BioHPP blanks, pressed from pellets (BioHPP Pellet) or granules (BioHPP Granulat) were produced. Each specimen was measured 20 times in a pulloff-test and results were analyzed using 2-/1-way ANOVA and linear regression analyses (p<0.05). Within 0 degrees tapered crowns milled secondary crowns showed lower retention forces compared to pressed pellet crowns. Crowns with a 1 degrees taper, however, showed no impact of the fabrication method on retention force. At a 2 degrees taper, granular pressed crowns displayed lower values than their milled counterparts. Within the milled group, a 0 degrees taper showed lower retention values than the higher tapers, whereas in the pressed groups, no impact of taper angle on retention force was found. PMID- 27477225 TI - The in vitro and in vivo effects of a fast-dissolving mucoadhesive bi-layered strip as topical anesthetics. AB - To overcome pain on injection, the dentist can apply a topical anesthetic spray. Despite the convenience, it is not easy to apply it locally. So, we developed an oral mucoadhesive bi-layer film containing an anesthetic. We used polyvinylpyrrolidone (PVP)/hydroxypropyl methylcellulose (HPMC) and HPMC-only layer as the drug-containing layer and ethyl cellulose (EC) as the backing layer. The lidocaine released was tested in vitro together with the adhesion time and cytotoxicity of the film. Mucosa permeability was tested in vivo. Statistical analysis was performed, with p at 0.05 taken to be significant. The lidocaine was released significantly faster in the PVP/HPMC than HPMC-only group and 80% of the drug was released within 1 min (p<0.05) and they attached at least 3 h. The test groups showed no toxicity and the drug effectively permeated the mucosa (p<0.05). We suggest this new mucoadhesive anesthetic may reduce dental phobia. PMID- 27477226 TI - Comparative study of the dentin bond strength of a new universal adhesive. AB - This study compared the dentin bond strength of a new universal adhesive with that of contemporary multi-step dentin adhesives. Six experimental groups were prepared according to the adhesives used and their application modes: Optibond FL (OB), Adper Single Bond Plus (SB), One-Step Plus (OS), Clearfil SE Bond (CS), All Bond Universal using etch-and-rinse mode (ABE), and AllBond Universal using self etch mode (ABS). Micro-tensile bond strength (uTBS) and failure mode were evaluated for each group. The bonded interface was analyzed using transmission electron microscopy (TEM). As a result, uTBS of 6 experimental groups was followed as: OB=ABE=SE=ABS>SB>OS group. TEM micrographs of ABE and ABS groups revealed a homogenous adhesive layer formation. In conclusion, a new universal adhesive can make reliable bond to dentin, regardless of the application mode. PMID- 27477227 TI - Effects of brushing timing after erosive challenge on enamel loss in situ: White light interferometer and nanoindentation study. AB - This in situ study aimed to evaluate effects of waiting periods after erosive challenge before toothbrushing on enamel abrasion and nanoindentation hardness. Ten subjects wore intraoral appliances each with a set of 4 bovine enamel blocks. The enamel blocks were subjected to 2 cycles a day for 3 days as follows; intraoral exposure to form acquired pellicle and extraoral erosion followed by either 0, 3, 30 or 60 min intraoral exposure and then brushing, which was performed using an automatic brushing machine. Abrasive loss was assessed by white light interferometry. Nanoindentation was performed to calculate relative hardness. Abrasion and relative hardness were statistically analyzed by ANOVA. Abrasive loss was significantly less in groups exposed to saliva compared with 0 min (p<0.05); there was no significant difference between 30 and 60 min (p>0.05). Relative hardness was statistically higher after intraoral exposure, but no differences existed among any intraoral exposure periods (p>0.05). PMID- 27477228 TI - Effect of alcoholic beverages on surface roughness and microhardness of dental composites. AB - The aim of this study was to evaluate the microhardness and surface roughness of composite resins immersed in alcoholic beverages. Three composite resins were used: Durafill (Heraeus Kulzer), Z250 (3M-ESPE) and Z350 XT (3M-ESPE). The inital surface roughness and microhardness were measured. The samples were divided into four groups (n=30): G1-artificial saliva; G2-beer; G3-vodka; G4-whisky. The samples were immersed in the beverages 3* a day for 15 min and 30 days. The surface roughness and microhardness assays were repeated after immersion period. The data were statistically analyzed by two-way ANOVA and Tukey-HSD test (p<0.05). Surface roughness increased for all composite resins immersed in beer and whisky. Microhardness of all groups decreased after immersion in alcoholic beverages. The effect of these beverages on dental composites is depended upon the chemical composition, immersion time, alcohol content and pH of solutions. PMID- 27477229 TI - Effect of strontium ions on calcification of preosteoblasts cultured on porous calcium- and phosphate-containing titanium oxide layers formed by micro-arc oxidation. AB - Strontium (Sr) ions were added to calcium- and phosphate-containing porous titanium oxide layers formed by micro-arc oxidation (MAO) of titanium (Ti) substrates to improve their osseointegration. An MC3T3-E1 preosteoblast was used to evaluate the effect of the incorporated Sr species on cell calcification. Similar surface microporous morphologies of the oxide layers were observed for all specimens produced by MAO, while the contents of the incorporated Sr ions increased with increasing Sr concentrations in MAO electrolytes. The calcium- and phosphate-containing porous layers promoted the cell alkaline phosphatase (ALP) activity, while cell calcification was promoted by the Sr addition. In particular, the ALP activity significantly increased after 10 days of culture, and larger areas of calcified deposits were observed for the specimens treated with MAO electrolytes containing 0.15 mol L(-1) of Sr species. The effect of Sr addition on the calcification of the MAO-treated Ti oxide layers was established in this study. PMID- 27477230 TI - Application of addition-cured silicone denture relining materials to adjust mouthguards. AB - The purposes of this study were to examine the shock absorption capability of addition-cured silicone denture relining materials and the bonding strength of addition-cured silicone denture relining materials and a commercial mouthguard material to determine its applicability to mouthguard adjustment. Two addition cured silicone denture relining materials and eleven commercial mouthguard materials were selected as test materials. The impact test was applied by a free falling steel ball. On the other hand, bonding strength was determined by a delamination test. After prepared surface treatments using acrylic resin on MG sheet surface, 2 types of addition-cured silicone denture relining materials were glued to MG surface. The peak intensity, the time to peak intensity from the onset of the transmitted force and bonding strength were statistically analyzed using ANOVA and Tukey's honest significant difference post hoc test (p<0.05). These results suggest that the silicone denture relining materials could be clinically applicable as a mouthguard adjustment material. PMID- 27477231 TI - Comparison of root canal filling quality by mineral trioxide aggregate and gutta percha cones/AH plus sealer. AB - The aims of this study were to evaluate the quality of canal filling using mineral trioxide aggregate (MTA) and gutta-percha (GP) in root canals, and to investigate the differences in the percentage of voids between mesial and distal canals by using microcomputed tomography. Twenty-two extracted human mandibular molars were instrumented using rotary files. Two teeth without canal fillings served as negative controls, and the other teeth were obturated with either ProRoot((r)) MTA or gutta-percha and AH Plus((r)) sealer. Obturated teeth were scanned with microcomputed tomography, and the percentage of voids (V%) was calculated. These specimens were also examined under a scanning electron microscope. The MTA group showed a significantly higher V% than the GP groups (p<0.05). The mesial canal groups showed significantly higher V% than did the distal canal groups (p<0.05). In orthograde filling, MTA exhibited significantly lower filling quality than did GP. PMID- 27477232 TI - Adsorption and desorption behaviors of cetylpyridinium chloride on hydroxyapatite nanoparticles with different morphologies. AB - Application of hydroxyapatite (HAp) nanoparticles to repair damaged enamel has attracted recent attention. In this study, HAp nanoparticles with various morphologies (spherical, short-rod, long-rod and fiber morphologies) were synthesized via chemical precipitation methods without the addition of template molecules, and the adsorption/desorption behaviors of a cationic antibacterial agent, cetylpyridinium chloride (CPC), on the HAp nanoparticles were evaluated. The adsorption of CPC on each HAp nanoparticle showed Langmuir-type adsorption, and the short-rod/long-rod HAp nanoparticles showed thermodynamically more stable adsorption of CPC than that with the spherical/fiber HAp nanoparticles. The desorption rate of CPC from the short-rod/long-rod HAp nanoparticles was slower than that of the spherical/fiber HAp nanoparticles. The HAp nanoparticles with different CPC release profiles presented here have potential applications as nanoparticulate enamel repair agents with antibacterial properties. PMID- 27477233 TI - The anti-bacterial activity of titanium-copper sintered alloy against Porphyromonas gingivalis in vitro. AB - This study investigates the anti-bacterial property of Ti-Cu sintered alloys against Porphyromonas gingivalis. The anti-anaerobic property of Ti-Cu sintered alloys against P. gingivalis was investigated by antibacterial activity test, DNA measurement, DAPI staining and morphology observation. The antibacterial rates of the Ti-5Cu against P. gingivalis after 18 and 24 h incubation were 36.04 and 54.39%, and those of Ti-10Cu were 68.69 and 75.39%, which were lower than their anti-aerobic abilities. The concentration of P. gingivalis DNA gradually decreased with the increasing Cu content, which was nearly 50% after 24 h incubation on Ti-10Cu. SEM results showed that the shape of P. gingivalis changed and the bacteria broke apart with the addition of Cu and the extension of the culture time. Ti-Cu sintered alloys could not only kill anaerobic bacteria but also reduce the activity of the survived bacteria. The anti-anaerobic mechanism was thought to be in associated with the Cu ion released from Ti-Cu alloy. PMID- 27477234 TI - Effect of surface pretreatments on resin composite bonding to PEEK. AB - This study evaluated the effect of surface pretreatments on resin composite bonding to polyetheretherketone (PEEK). Four groups of surface pretreatment (no pretreatment, etched with 98% sulfuric acid, etched with piranha solution and sandblasting with 50 um alumina) were performed on PEEK. Surface roughness, Scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) analysis were examined. Shear bond strength (SBS) and interface characteristics were also evaluated after the specimens were bonded with resin materials. Two-way ANOVA analysis revealed significance on two main effects and interactions. Tukey's multiple comparisons test showed that the SBS of resin composite on PEEK were the highest in the group etched with 98% sulfuric acid and bonded with Heliobond((r)) (p<0.05). All pretreatments produced similar spectra of FTIR patterns. SEM demonstrated porosities and pitting from chemical etching, which suggested a significant influence on the adhesion between PEEK and resin materials. PMID- 27477235 TI - Effect of enamel margin configuration on color change of resin composite restoration. AB - This study aimed to investigate the effect of enamel margin configuration on color change of resin composite restoration. Enamel disks of 1.0 mm-thick were sliced from sixty bovine anterior teeth and divided into three groups by margin configuration (non-bevel, 45-degree bevel and 45-degree reverse-bevel). The color measurements (L*C*h* values) at the restored bovine enamel disk with resin composite (Estelite Asteria, Estelite Pro, Kalore, Clearfil Majesty) were performed using a digital camera with CIE XYZ color gamut (RC500). All the resin composite restorations with non-beveled and beveled cavities significantly increased L* values compared with the control composite disks (p<0.05). The bevel preparation increased L* values toward the enamel-composite border with gentle inclination, while the reverse-bevel preparation was significantly lower L* values at the enamel-composite border than the non-bevel preparation (p<0.05). Enamel margin configuration affected color shifting of resin composite restoration and color adjustment of the border. PMID- 27477236 TI - Stress Wave Isolation by Purely Mechanical Topological Phononic Crystals. AB - We present an active, purely mechanical stress wave isolator that consists of short cylindrical particles arranged in a helical architecture. This phononic structure allows us to change inter-particle stiffness dynamically by controlling the contact angles of the cylinders. We use torsional travelling waves to control the contact angles, thereby imposing a desired spatio-temporal stiffness variation to the phononic crystal along the longitudinal direction. Such torsional excitation is a form of parametric pumping in the system, which results in the breakage of the time-reversal symmetry. We report that, in quasi-static sense, the system shows topologically non-trivial band-gaps. However, in a dynamic regime where the pumping effect is significant, these band-gaps become asymmetric with respect to the frequency and wavenumber domains in the dispersion relationship. By using numerical simulations, we show that such asymmetry has a direct correspondence to the topological invariant, i.e., Chern number, of the system. We propose that this asymmetry, accompanied by selective inter-band transition, can be utilized for directional isolation of the stress wave propagating along the phononic crystal. PMID- 27477237 TI - Efficient Visible Light-Driven Splitting of Alcohols into Hydrogen and Corresponding Carbonyl Compounds over a Ni-Modified CdS Photocatalyst. AB - Splitting of alcohols into hydrogen and corresponding carbonyl compounds has potential applications in hydrogen production and chemical industry. Herein, we report that a heterogeneous photocatalyst (Ni-modified CdS nanoparticles) could efficiently split alcohols into hydrogen and corresponding aldehydes or ketones in a stoichiometric manner under visible light irradiation. Optimized apparent quantum yields of 38%, 46%, and 48% were obtained at 447 nm for dehydrogenation of methanol, ethanol, and 2-propanol, respectively. In the case of dehydrogenation of 2-propanol, a turnover number of greater than 44 000 was achieved. To our knowledge, these are unprecedented values for photocatalytic splitting of liquid alcohols under visible light to date. Besides, the current catalyst system functions well with other aliphatic and aromatic alcohols, affording the corresponding carbonyl compounds with good to excellent conversion and outstanding selectivity. Moreover, mechanistic investigations suggest that an interface between Ni nanocrystal and CdS plays a key role in the reaction mechanism of the photocatalytic splitting of alcohol. PMID- 27477238 TI - Pickering Emulsions Responsive to CO2/N2 and Light Dual Stimuli at Ambient Temperature. AB - A dual stimuli-responsive n-octane-in-water Pickering emulsion with CO2/N2 and light triggers is prepared using negatively charged silica nanoparticles in combination with a trace amount of dual switchable surfactant, 4-butyl-4-(4-N,N dimethylbutoxyamine) azobenzene bicarbonate (AZO-B4), as stabilizers. On one hand, the emulsion can be transformed between stable and unstable at ambient temperature rapidly via the N2/CO2 trigger, and on the other hand, a change in droplet size of the emulsion can occur upon light irradiation/rehomogenization cycles without changing the particle/surfactant concentration. The dual responsiveness thus allows for a precise control of emulsion properties. Compared with emulsions stabilized by specially synthesized stimuli-responsive particles or by stimuli-responsive surfactants, the method reported here is much easier and requires a relatively low concentration of surfactant (~1/10 cmc), which is important for potential applications. PMID- 27477239 TI - Comment on "Partially Cystic Thyroid Nodules on Ultrasound: Probability of Malignancy and Sonographic Differentiation". PMID- 27477240 TI - Evaluation of the spectral accuracy of mass spectrometers using compounds containing Cl or Br atoms. AB - Current procedures for the evaluation of spectral accuracy of mass spectrometers are limited by the lack of certified isotopic reference materials and the high uncertainty in the isotopic composition of natural abundance molecules. The calculated uncertainties in the ratio M + 1/M for natural abundance molecules containing any number of C, H, N and/or O atoms are close to 5% relative because of the natural variability of the isotopic composition of carbon. So, we have developed two alternative measurement procedures with much lower theoretical uncertainties for a better evaluation of spectral accuracy in both single and triple quadrupole analysers. The first method is based on the measurement of the M + 2/M, M + 4/M + 2, etc. ratios for halogenated organic compounds containing either Cl or Br. The theoretical uncertainties for these ratios because of natural variability are in the order of 0.3 to 1.0% making them suitable for the evaluation of spectral accuracy with the additional advantage that there is no need to take into account other limitations such as cluster purity or poor mass resolution. This procedure was applied to the evaluation of a single quadrupole GC-MS instruments using natural abundance PCB and PBDE standards with satisfactory results. The second method can be applied to tandem instruments and takes advantage of the loss of two halogen atoms when PCB and PBDE standards are fragmented by Collision Induced Dissociation. Theoretical SRM transition ratios can be calculated as a pure combinatorial probability with theoretical uncertainties lower than 0.1%. By combining PCBs and PBDEs with different number of halogen atoms, a mass range from 100 to 700 u and abundance ratios from 0.1 to 10 can be evaluated. The use of penta-chlorinated PCBs and/or penta-brominated PBDEs is finally recommended for the evaluation of spectral accuracy of mass spectrometers with the EI source. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27477241 TI - Phenyl trimethyl ammonium tribromide mediated robust one-pot synthesis of spiro oxacycles - an economic route - stereoselective synthesis of oxaspirohexacyclodieneones. AB - This paper entails the first recognition of Phenyl Trimethyl Ammonium Tribromide (PTAB) as an effective reagent for spiro-cyclizations proceeding via oxidative dearomatization. The experiment exhibits economical, metal and ligand free one pot accomplishment of these significant transformations. The described protocol presents the first generalised methodology of spiro-oxacycle synthesis which can be applied towards various directions. A stereoselective synthesis of oxa spirocyclooxadieneones has been accomplished. PMID- 27477242 TI - Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study. AB - OBJECTIVE: To investigate the real-world safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Japanese patients (>=65 years old) who were first prescribed ipragliflozin within 3 months after its launch in April 2014 were registered in this post-marketing surveillance (PMS). Final data collection was in July 2015. Survey items included demographics, treatments, adverse drug reactions (ADRs), vital signs, and laboratory variables. RESULTS: The PMS included 8505 patients (4181 males/4324 females). The mean age and diabetes duration were 72.3 years and 10.6 years, respectively. In 84.3% of patients, ipragliflozin was prescribed at 50 mg/day, which was continued unchanged. Overall, 16.91% of patients experienced 1880 ADRs, and 165 ADRs were classified as serious in 127 patients (1.49%). ADRs of special interest included skin complications, volume depletion, polyuria/pollakiuria, genital infection, urinary tract infection, renal disorders, hypoglycemia, cerebrovascular disease, cardiovascular disease, malignant tumor, fracture, and ketone body-related events. CONCLUSIONS: This 1 year PMS revealed probable ADRs in elderly Japanese patients with T2DM prescribed ipragliflozin in real-world settings, with no new safety concerns. The risk factors for ADRs varied but could be rationalized. The results should help physicians to identify possible treatment-emergent ADRs in ipragliflozin-treated patients. PMID- 27477244 TI - Preparation and sulfation of an alpha-glucan from Actinidia chinensis roots and their potential activities. AB - In this study, one homopolysaccharide (ACPA1) with a molecular weight (Mw) of 5.5*103g/mol was prepared from the roots of Actinidia chinensis. It was characterized as an alpha-d-glucan consisting of predominant 4-linked alpha-d Glcp residues branched at O-6. Three sulfated derivatives of ACPA1 (SA1, SA2 and SA3) with different degrees of sulfation (DS) were obtained by SO3-pyridine procedure. Moisture-preserving tests demonstrated that the sulfated derivatives with the highest DS values, SA1 and SA2, exhibited better moisture-preserving abilities than ACPA1 and SA3. All sulfated derivatives exerted stimulatory effects on phagocytosis activity and nitric oxide production by RAW 264.7 macrophages while ACPA1 did not. These findings suggested that the sulfated derivatives of ACPA1 might be used as moisture-preserving or immunopotentiating reagents. PMID- 27477245 TI - Protective effect of carboxytmethylpachymaran on TNF-alpha-induced damage in Caco 2 cell monolayers. AB - This study was carried out to study the protective effect of carboxytmethylpachymaran (CMP) on TNF-alpha-induced intestinal epithelial barrier dysfunction in Caco-2 cell monolayers and the underlying mechanism. The Caco-2 cell monolayers were pretreated with 50, 100 or 150MUg/mL CMP for 72h, and then they were exposed to 100ng/mL tumor necrosis factor alpha (TNF-alpha) for 72h. The results showed that CMP alleviated the drop of trans-epithelial electrical resistance (TEER) and the increase of phenol red flux induced by TNF-alpha. CMP also ameliorated TNF-alpha-induced decrease of mRNA/protein expression and distribution of Occludin and ZO-3 which were chosen as makers of tight junction (TJ). Additionally, the increased protein expressions of MLCK, phosphorylation level of myosin light chain (p-MLC), NF-kappaB p-P65 and p-IkappaBalpha induced by TNF-alpha were significantly inhibited by CMP. This study demonstrates the protective effect of CMP on TNF-alpha-induced damage of intestinal epithelial barrier in Caco-2 monolayers and discovers that the suppression of MLCK-p-MLC signaling regulated by NF-kappaB might be one of the mechanisms underlying the protective effect of CMP. PMID- 27477243 TI - Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans. AB - The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson's disease. PMID- 27477246 TI - Interfacial activation of lipases on hydrophobic support and application in the synthesis of a lubricant ester. AB - n-Octyl oleate was synthetized by enzymatic esterification reaction of oleic acid and n-octanol. Lipases from porcine pancreatic (PPL), Mucor javanicus (MJL), Candida sp. (CALA), Rhizomucor miehei (RML) and Thermomyces lanuginosus (TLL) were immobilized via interfacial activation on poly-methacrylate particles (PMA) and tested as biocatalysts. Their catalytic properties were determined in the hydrolysis of olive oil emulsion. Among them, TLL-PMA was the biocatalyst that yielded the highest hydrolytic activity (217.8+/-1.1 IU/g) and immobilized protein loading (37.5+/-0.4mg/g). This biocatalyst was also the most active in n octyl oleate synthesis, thus selected for further studies. Maximum conversion percentage of 95.1+/-1.3% was observed after 60min of reaction at 45 degrees C, 10% m/v of TLL-PMA, and molar ratio oleic acid:n-octanol of 1:1.5 in a solvent free system. The biocatalyst fully retained its original activity after twelve cycles of reaction of 60min each. The product was confirmed by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy analysis and their physico-chemical properties were determined according to ASTM standard methods. These results show that the immobilization of an alkalophilic and thermostable lipase (TLL) on PMA particles allowed the preparation of a highly active biocatalyst in hydrolysis and esterification reactions. PMID- 27477247 TI - Physicochemical properties and in vitro digestibility of sorghum starch altered by high hydrostatic pressure. AB - A nonthermal processing technology, high hydrostatic pressure (HHP) treatment, was investigated to assess its influence on the physicochemical properties and in vitro digestibility of sorghum starch (SS). There was no change in the 'A'-type crystalline pattern of SS after the pressure treatments at 120-480MPa. However, treatment at 600MPa produced a pattern similar to 'B'-type crystalline. HHP treatment also resulted in SS granules with rough surfaces. Measured amylose content, water absorption capacity, alkaline water retention, pasting temperature and thermostability increased with increasing pressure levels, while the oil absorption capacity, swelling power, relative crystallinity and viscosity decreased. Compared with native starch, HHP-modified SS samples had lower in vitro hydrolysis, reduced amount of rapidly digestible starch, as well as increased levels of slowly digestible starch and resistant starch. These results indicate that HHP treatment is an effective modification method for altering in vitro digestibility and physicochemical properties of SS. PMID- 27477248 TI - Photodynamic therapy for onychomycosis: A systematic review. AB - Other than a cosmetic concern, Onychomycosis is also a prevalent nail disease, which is extremely difficult to treat, and sometimes is refractory to conventional therapy. Moreover, many patients are not eligible to take oral antifungals owing to polypharmacy and comorbidities. Systemic side effects seen with oral antifungals have lead to patient nonadherence and adverse events. Therefore, newer therapies are being investigated for onychomycosis that would be free of systemic complications posed by oral therapy. Photodynamic therapy (PDT) is one of those being currently studied, which involves the use of photosensitizer and a light source to excite the photosensitizer to generate reactive oxygen species. The present review will put some light on PDT as an upcoming treatment modality for onychomycosis. We performed a systematic review of the literature to find the articles relevant to the use of PDT for onychomycosis. From the primary search of 43 articles, 17 papers are included in this review. PMID- 27477249 TI - Commentary on 'Risk of Recurrent Stroke in Patients with Symptomatic Mild (20-49% NASCET) Carotid Stenosis'. PMID- 27477250 TI - Genre, travail et vieillissement. PMID- 27477251 TI - A requirement for cell elongation protein RodZ and cell division proteins FtsN and DedD to maintain the small rod morphology of Escherichia coli at growth temperatures near 8 degrees C. AB - As similarly observed in nutrient-poor media at 37 degrees C, Escherichia coli forms small rods in nutrient-rich media at temperatures near 8 degrees C, the minimum temperature of growth. A study was initiated to identify proteins required to facilitate the small rod morphology at low temperature. E. coli contains three nonessential SPOR domain proteins (DamX, RlpA, and DedD) that have been demonstrated to bind to the septal ring. In contrast to the normal growth and small rod morphology of damX and rlpA null mutants at 10 degrees C, the dedD null mutant exhibited reduced growth and formed filamentous cells. The presence of plasmid-encoded DedD restored growth and small rods. Plasmid-encoded FtsN, an essential SPOR domain protein that functions to stabilize the septal ring and to initiate septation, in the dedD null mutant resulted in increased growth and the formation of shorter chained cells. However, plasmid-encoded DedD failed to restore growth and cell division of cells lacking FtsN at 10 degrees C. In contrast to cell division protein DedD, RodZ is a cell elongation protein particularly required for growth at 30 degrees C. However, the rodZ null mutant grew similarly as the wild type strain and produced cocci in LB broth at 10 degrees C. Moreover at 10 degrees C, the concerted deletion of dedD and rodZ resulted in severe inhibition of growth accompanied with the formation of swollen prolate ellipsoids due to a block in septal ring assembly and cell elongation. The data indicate the cellular requirement of both FtsN and DedD for septation as well as RodZ for cell elongation to maintain the small rod morphology at temperatures near 8 degrees C. In comparison to the growth and small rods of the wild type in M9-glucose minimal media at 37 degrees C, the dedD null mutant grew at the same rate and produced elongated cells while the rodZ null mutant grew at a slightly slower rate and produced cocci. The data indicate that DedD and RodZ are also required to maintain the small rod morphology in nutrient-poor media, but there is a higher cellular requirement of DedD for growth and cell division in nutrient-rich media at low temperature. PMID- 27477252 TI - Analyses of the cell-wall peptidoglycan structures in three genera Micromonospora, Catenuloplanes, and Couchioplanes belonging to the family Micromonosporaceae by derivatization with FDLA and PMP using LC/MS. AB - It is the major characteristic of the cell-wall peptidoglycan structure in members of the family Micromonosporaceae that N-acetylmuramic acid (MurNAc) of glycan strand is replaced with N-glycolylmuramic acid (MurNGlyc). Consequently, it is difficult to use enzymatic methods for their peptidoglycan analyses. We therefore developed analysis method of peptidoglycan without using cell wall lytic enzymes as example to take the 3 genera, Micromonospora, Catenuloplanes, and Couchioplanes belonging to the family Micromonosporaceae, and their peptidoglycans were partially hydrolyzed with 4 M HCl at 60 degrees C for 16 h followed by derivatization with N(alpha)-(5-fluoro-2,4-dinitrophenyl)-D leucinamide (FDLA) or 1-phenyl-3-methyl-5-pyrazolone (PMP) and LC/MS analysis. Peptidoglycan of the genus Micromonospora consisted of a MurNGlyc-Gly-D-Glu-meso diaminopimelyl (DAP)-D-Ala peptide stem and direct linkage between D-Ala and meso DAP. In contrast, peptidoglycans of the genera Catenuloplanes and Couchioplanes consisted of a MurNGlyc-Gly-D-Glu-L-Lys-D-Ala peptide stem, and cross-linkage between D-Ala and L-Lys was mediated by an L-Ser residue. This method can be used to analyze the cell-wall peptidoglycan structure of other bacteria as well. By derivatization with FDLA or PMP followed by LC/MS analysis, the structure can be determined using only 0.2 mg of purified peptidoglycan. PMID- 27477253 TI - Effect of Adding McKenzie Syndrome, Centralization, Directional Preference, and Psychosocial Classification Variables to a Risk-Adjusted Model Predicting Functional Status Outcomes for Patients With Lumbar Impairments. AB - Study Design Retrospective cohort. Background Patient-classification subgroupings may be important prognostic factors explaining outcomes. Objectives To determine effects of adding classification variables (McKenzie syndrome and pain patterns, including centralization and directional preference; Symptom Checklist Back Pain Prediction Model [SCL BPPM]; and the Fear-Avoidance Beliefs Questionnaire subscales of work and physical activity) to a baseline risk-adjusted model predicting functional status (FS) outcomes. Methods Consecutive patients completed a battery of questionnaires that gathered information on 11 risk adjustment variables. Physical therapists trained in Mechanical Diagnosis and Therapy methods classified each patient by McKenzie syndromes and pain pattern. Functional status was assessed at discharge by patient-reported outcomes. Only patients with complete data were included. Risk of selection bias was assessed. Prediction of discharge FS was assessed using linear stepwise regression models, allowing 13 variables to enter the model. Significant variables were retained in subsequent models. Model power (R(2)) and beta coefficients for model variables were estimated. Results Two thousand sixty-six patients with lumbar impairments were evaluated. Of those, 994 (48%), 10 (<1%), and 601 (29%) were excluded due to incomplete psychosocial data, McKenzie classification data, and missing FS at discharge, respectively. The final sample for analyses was 723 (35%). Overall R(2) for the baseline prediction FS model was 0.40. Adding classification variables to the baseline model did not result in significant increases in R(2). McKenzie syndrome or pain pattern explained 2.8% and 3.0% of the variance, respectively. When pain pattern and SCL BPPM were added simultaneously, overall model R(2) increased to 0.44. Although none of these increases in R(2) were significant, some classification variables were stronger predictors compared with some other variables included in the baseline model. Conclusion The small added prognostic capabilities identified when combining McKenzie or pain-pattern classifications with the SCL BPPM classification did not significantly improve prediction of FS outcomes in this study. Additional research is warranted to investigate the importance of classification variables compared with those used in the baseline model to maximize predictive power. Level of Evidence Prognosis, level 4. J Orthop Sports Phys Ther 2016;46(9):726-741. Epub 31 Jul 2016. doi:10.2519/jospt.2016.6266. PMID- 27477254 TI - Is Extracorporeal Shockwave Therapy Combined With Isokinetic Exercise More Effective Than Extracorporeal Shockwave Therapy Alone for Subacromial Impingement Syndrome? A Randomized Clinical Trial. AB - Study Design Single-blind randomized trial. Background Extracorporeal shockwave therapy (ESWT) has been shown to produce good results in the treatment of subacromial impingement syndrome (SAIS). The efficacy of a combined administration of ESWT and isokinetic exercise (IE) has not yet been studied. Objectives To evaluate the efficacy of focused ESWT combined with IE for the rotator cuff versus focused ESWT alone in the treatment of SAIS. The secondary objective was to assess the isokinetic torque recovery (external rotation at 210 degrees /s, 180 degrees /s, and 120 degrees /s). Methods Thirty participants with SAIS were randomly assigned to a focused-ESWT group or focused ESWT-plus-IE group. Subjects of both groups received 3 treatment sessions of focused ESWT over a period of 10 days. Participants in the second group also received IE for 10 therapy sessions. Outcome measures were the Constant-Murley score (CMS), the visual analog scale (VAS), and isokinetic parameters (peak torque and total work calculated from 5 repetitions) measured with the isokinetic test. Subjects were assessed at baseline, 10 days after the last treatment session with focused ESWT, and after 2 months of follow-up. Results At 2 months posttreatment, participants in the focused ESWT-plus-IE group showed significantly less pain (focused-ESWT VAS, 3.4 +/- 0.8 versus focused ESWT-plus-IE VAS, 1.5 +/- 0.5; P<.001) and greater improvement in functionality (focused-ESWT CMS, 75.9 +/- 6.7 versus focused ESWT-plus-IE CMS, 92.1 +/- 6.3; P<.001) and muscle endurance than the subjects in the focused-ESWT group. Conclusion In subjects with SAIS, combined administration of focused ESWT and IE for the rotator cuff resulted in greater reduction of pain, as well as superior functional recovery and muscle endurance in the short to medium term, compared with ESWT alone. Level of evidence Therapy, 2b. TRIAL REGISTRATION: unregistered 2011 trial. J Orthop Sports Phys Ther 2016;46(9):714-725. Epub 5 Aug 2016. doi:10.2519/jospt.2016.4629. PMID- 27477255 TI - Copper-Catalyzed 2,2,2-Trifluoroethylthiolation of Aryl Halides. AB - Herein, a copper-catalyzed 2,2,2-trifluoroethylthiolation reaction of aryl bromides and iodides with elemental sulfur, and 1,1,1-trifluoro-2-iodoethane is described. The reaction showed excellent functional group tolerance and allowed the synthesis of various substituted aryl 2,2,2-trifluoroethyl thioethers with good to excellent yields. This transformation constitutes a one-pot synthesis of 2,2,2-trifluoroethylthiolated compounds from inexpensive, readily available starting materials. Utility of the protocol was further demonstrated in the late stage synthesis of the pirfenidone derivative. The copper thiolate species were prepared and proposed as key intermediates in the catalytic cycle. PMID- 27477258 TI - Clot Retraction: A Miniaturized Hemoretractometer for Blood Clot Retraction Testing (Small 29/2016). AB - Whole blood coagulation testing provides valuable diagnostic information on diseases such as bleeding disorders, heart attack, deep venous thrombosis, etc. On page 3926, J. Fu and co-workers develop a miniaturized hemoretractometer to measure clot contraction upon blood coagulation with good reproducibility and robustness. This device design shows great application potential in point-of-care testing. Photo credit: David Peyer from University of Michigan. PMID- 27477261 TI - Role of particle shape anisotropy on crack formation in drying of colloidal suspension. AB - Cracks in a colloidal film formed by evaporation induced drying can be controlled by changing drying conditions. We show, for the first time that the crack morphologies in colloidal films are dependent on shape of constituting particles apart from the microstructure and particle assembly. In order to investigate the particle shape effect on crack patterns, monodispered spherical and ellipsoidal particles are used in sessile drop experiments. On observing the dried sessile drop we found cracks along the radial direction for spherical particle dispersions and circular crack patterns for ellipsoidal particle dispersions. The change in crack pattern is a result of self assembly of shape anisotropic particles and their ordering. The ordering of particles dictate the crack direction and the cracks follow the path of least resistance to release the excess stress stored in the particle film. Ellipsoids having different aspect ratio (~3 to 7) are used and circular crack patterns are repeatedly observed in all experiments. PMID- 27477262 TI - Synthesis and isolation of non-chromophore cage-rearranged silsesquioxanes from base-catalyzed reactions. AB - The nucleophilicity of both ortho- and meta-nitrophenolate anions is strong enough to give substituted products, but their basicity also facilitates cage rearrangement reactions in polyhedral oligomeric silsesquioxanes (POSS). Anions having a stronger basicity, but weaker nucleophilicity, such as CO32-, gave products only from cage-rearrangement, with the cage expansion products being isolable in multi-gram quantities using conventional column chromatography. PMID- 27477263 TI - Molecular Modelling of G Protein-Coupled Receptors Through the Web. AB - With the recent crystallization of several G Protein-Coupled receptors (GPCRs), homology modelling and all atom molecular dynamics (MD) simulations have proven their usefulness for exploring the structure and function of this superfamily of membrane receptors. Subsequently, automated computational protocols have been implemented as web-based servers in the recent years to produce reliable models of GPCRs, providing partial or global solutions for the structural characterization and molecular simulation of GPCRs. These dedicated modelling services represent an attractive tool for the broader community of public researchers and pharmaceutical companies, in order to assist in the structure based drug design of GPCRs. We here collect and analyze the existing web servers, among which a previously unreported service, GPCR-ModSim, offers for the first time full atom MD simulations in the pipeline for GPCR molecular modelling. PMID- 27477264 TI - Networks of Protein?Protein Interactions: From Uncertainty to Molecular Details. AB - Proteins are the bricks and mortar of cells. The work of proteins is structural and functional, as they are the principal element of the organization of the cell architecture, but they also play a relevant role in its metabolism and regulation. To perform all these functions, proteins need to interact with each other and with other bio-molecules, either to form complexes or to recognize precise targets of their action. For instance, a particular transcription factor may activate one gene or another depending on its interactions with other proteins and not only with DNA. Hence, the ability of a protein to interact with other bio-molecules, and the partners they have at each particular time and location can be crucial to characterize the role of a protein. Proteins rarely act alone; they rather constitute a mingled network of physical interactions or other types of relationships (such as metabolic and regulatory) or signaling cascades. In this context, understanding the function of a protein implies to recognize the members of its neighborhood and to grasp how they associate, both at the systemic and atomic level. The network of physical interactions between the proteins of a system, cell or organism, is defined as the interactome. The purpose of this review is to deepen the description of interactomes at different levels of detail: from the molecular structure of complexes to the global topology of the network of interactions. The approaches and techniques applied experimentally and computationally to attain each level are depicted. The limits of each technique and its integration into a model network, the challenges and actual problems of completeness of an interactome, and the reliability of the interactions are reviewed and summarized. Finally, the application of the current knowledge of protein-protein interactions on modern network medicine and protein function annotation is also explored. PMID- 27477265 TI - Prospective Prediction of Antitarget Activity by Matched Molecular Pairs Analysis. AB - Matched molecular pairs analysis (MMPA)1,2 is an inverse quantitative structure activity relationship (QSAR) technique that is rapidly gaining popularity in the retrospective analysis of large experimental datasets.3,4 While much of the recent focus has been on the differences in properties between structurally related groups of existing compounds, attempts to extend this methodology to the de-novo design of novel structures have been limited. To our knowledge the aggregate effect of multiple transformations, all suggesting the same molecular structure, has only ever being considered within a very limited dataset.5 We therefore sought to test this exciting new approach to the design (and absolute property prediction - effectively QSAR-by-MMPA) of novel chemical entities based on a larger, more diverse dataset, and couple these designs to MMPA-based predictions of antitarget activity. PMID- 27477266 TI - Disease-Specific Differentiation Between Drugs and Non-Drugs Using Principal Component Analysis of Their Molecular Descriptor Space. AB - The physicochemical descriptor space has been extensively mapped and described in the literature for orally administered drugs and lead compounds. However, consideration of negative examples (non-drugs) or disease pathophysiology is not common in many studies. In the present work, a principal component analysis was carried out using drugs and non-drugs taking into account disease- and organ specific categories, as well as different administration routes in addition to oral. The study involves 1386 relevant small-molecules including natural and synthetic products. Drug-specific as well as disease-category-specific or organ specific regions and their respective threshold sets (ranges of descriptors) relative to non-drugs were elucidated on the scores plot and validated with external, independent sets of drugs and non-drugs. The respective loadings plot of molecular descriptors was rationalized in terms of physicochemically relevant groups related to the components of solvation free energy. The results of this analysis can contribute to the improved profiling of drug candidates and libraries making use of disease- and organ-specificity coded by physicochemical descriptors and ligand binding efficiency. PMID- 27477267 TI - A Novel QSPR Model for Prediction of Gas to Dimethyl Sulfoxide Solvation Enthalpy of Organic Compounds Based on Support Vector Machine. AB - In this study, a quantitative structure?property relationship (QSPR) study is developed for the prediction of gas to dimethyl sulfoxide solvation enthalpy (DeltaHSolv ) of organic compounds based on molecular descriptors calculated solely from molecular structure considerations. Diverse types of molecular descriptors were calculated to represent the molecular structures of the various compounds studied. Multiple linear regression (MLR) was employed to select an optimal subset of descriptors that have significant contributions to the DeltaHSolv overall property. Our investigation revealed that the dependence of physicochemical properties on solvation enthalpy is a nonlinear observable fact and that MLR method is unable to model the solvation enthalpy accurately. It has been observed that support vector machine (SVM) and artificial neural network (ANN) demonstrates better performance compared with MLR. The standard error value of the test set for SVM is 1.731 kJ mol(-1) , while it is 2.303 kJ mol(-1) and 5.146 kJ mol(-1) for ANN and MLR, respectively. The results showed that the calculated DeltaHSolv values by SVM were in good agreement with the experimental data, and the performance of the SVM model was superior to those of MLR and ANN ones. PMID- 27477269 TI - Changes in the Immune Components of Preterm Human Milk and Associations With Maternal and Infant Characteristics. AB - OBJECTIVE: To describe difference in cytokines, chemokines, and growth factors (CCGFs) and secretory immunoglobulin A (sIgA) in the breast milk of mothers who gave birth preterm and maternal or infant characteristics related to these immune components. DESIGN: A prospective, repeated-measures, one-group design. SETTING: Data were collected at an 82-bed NICU in West Central Florida. PARTICIPANTS: Seventy-six very-low-birth-weight infants weighing less than 1,500 g and their mothers. METHODS: Daily aliquots of breast milk from mothers of preterm infants were collected from the daily infants' feedings and pooled at the end of each week, and CCGFs and sIgA were measured weekly with MagPix multiplexing (Luminex, Austin, TX) and enzyme-linked immunosorbent assay. RESULTS: The CCGFs showed high individual variability, but the levels of most CCGFs and sIgA fell over time. Immune variables were generally greater in milk from mothers of infants smaller than 1,000 g. The breast milk of mothers of male preterm infants had significantly greater sIgA than the breast milk of mothers of female preterm infants. We found relationships between age, body mass index, parity, sIgA, and some of the CCGFs in the breast milk of women who gave birth preterm. CONCLUSION: Immune molecules declined in concentration over time in the breast milk of mothers who give birth preterm during the NICU stay, and maternal and infant factors appeared to play some role in the levels of these immune molecules. Further exploration of this relationship is warranted. PMID- 27477268 TI - Genetically Encoded Fluorescent Indicators for Organellar Calcium Imaging. AB - Optical Ca(2+) indicators are powerful tools for investigating intracellular Ca(2+) signals in living cells. Although a variety of Ca(2+) indicators have been developed, deciphering the physiological functions and spatiotemporal dynamics of Ca(2+) in intracellular organelles remains challenging. Genetically encoded Ca(2+) indicators (GECIs) using fluorescent proteins are promising tools for organellar Ca(2+) imaging, and much effort has been devoted to their development. In this review, we first discuss the key points of organellar Ca(2+) imaging and summarize the requirements for optimal organellar Ca(2+) indicators. Then, we highlight some of the recent advances in the engineering of fluorescent GECIs targeted to specific organelles. Finally, we discuss the limitations of currently available GECIs and the requirements for advancing the research on intraorganellar Ca(2+) signaling. PMID- 27477270 TI - miR-17-92 Cluster Regulates Adult Hippocampal Neurogenesis, Anxiety, and Depression. AB - Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors. PMID- 27477271 TI - Identification of Nucleolus-Associated Chromatin Domains Reveals a Role for the Nucleolus in 3D Organization of the A. thaliana Genome. AB - The nucleolus is the site of rRNA gene transcription, rRNA processing, and ribosome biogenesis. However, the nucleolus also plays additional roles in the cell. We isolated nucleoli using fluorescence-activated cell sorting (FACS) and identified nucleolus-associated chromatin domains (NADs) by deep sequencing, comparing wild-type plants and null mutants for the nucleolar protein NUCLEOLIN 1 (NUC1). NADs are primarily genomic regions with heterochromatic signatures and include transposable elements (TEs), sub-telomeric regions, and mostly inactive protein-coding genes. However, NADs also include active rRNA genes and the entire short arm of chromosome 4 adjacent to them. In nuc1 null mutants, which alter rRNA gene expression and overall nucleolar structure, NADs are altered, telomere association with the nucleolus is decreased, and telomeres become shorter. Collectively, our studies reveal roles for NUC1 and the nucleolus in the spatial organization of chromosomes as well as telomere maintenance. PMID- 27477272 TI - MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload. AB - MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1(-/-) mitochondria demonstrate altered calcium uptake, and deletion of MICU1 results in significant, but not complete, perinatal mortality. Similar to afflicted patients, viable MICU1(-/-) mice manifest marked ataxia and muscle weakness. Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP. Older MICU1(-/-) mice show marked, spontaneous improvement coincident with improved mitochondrial calcium handling and an age-dependent reduction in EMRE expression. Remarkably, deleting one allele of EMRE helps normalize calcium uptake while simultaneously rescuing the high perinatal mortality observed in young MICU1(-/-) mice. Together, these results demonstrate that MICU1 serves as a molecular gatekeeper preventing calcium overload and suggests that modulating the calcium uniporter could have widespread therapeutic benefits. PMID- 27477273 TI - Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling Driven Glioblastoma Growth. AB - Dysregulated lipid metabolism is a characteristic of malignancies. Sterol regulatory element binding protein 1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is highly activated in malignancies. Here, we unraveled a link between miR-29 and the SCAP (SREBP cleavage-activating protein)/SREBP-1 pathway in glioblastoma (GBM) growth. Epidermal growth factor receptor (EGFR) signaling enhances miR-29 expression in GBM cells via upregulation of SCAP/SREBP-1, and SREBP-1 activates miR-29 expression via binding to specific sites in its promoter. In turn, miR-29 inhibits SCAP and SREBP-1 expression by interacting with their 3' UTRs. miR-29 transfection suppressed lipid synthesis and GBM cell growth, which were rescued by the addition of fatty acids or N-terminal SREBP-1 expression. Xenograft studies showed that miR-29 mimics significantly inhibit GBM growth and prolong the survival of GBM-bearing mice. Our study reveals a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling mediated by miR-29 and suggests that miR-29 treatment may represent an effective means to target GBM. PMID- 27477274 TI - The ID1-CULLIN3 Axis Regulates Intracellular SHH and WNT Signaling in Glioblastoma Stem Cells. AB - Inhibitor of differentiation 1 (ID1) is highly expressed in glioblastoma stem cells (GSCs). However, the regulatory mechanism responsible for its role in GSCs is poorly understood. Here, we report that ID1 activates GSC proliferation, self renewal, and tumorigenicity by suppressing CULLIN3 ubiquitin ligase. ID1 induces cell proliferation through increase of CYCLIN E, a target molecule of CULLIN3. ID1 overexpression or CULLIN3 knockdown confers GSC features and tumorigenicity to murine Ink4a/Arf-deficient astrocytes. Proteomics analysis revealed that CULLIN3 interacts with GLI2 and DVL2 and induces their degradation via ubiquitination. Consistent with ID1 knockdown or CULLIN3 overexpression in human GSCs, pharmacologically combined control of GLI2 and beta-CATENIN effectively diminishes GSC properties. A ID1-high/CULLIN3-low expression signature correlates with a poor patient prognosis, supporting the clinical relevance of this signaling axis. Taken together, a loss of CULLIN3 represents a common signaling node for controlling the activity of intracellular WNT and SHH signaling pathways mediated by ID1. PMID- 27477276 TI - The Pseudomonas aeruginosa Type VI Secretion PGAP1-like Effector Induces Host Autophagy by Activating Endoplasmic Reticulum Stress. AB - Pseudomonas aeruginosa is an opportunistic pathogen that regularly causes nosocomial infections in hospitalized patients. The type VI secretion system (T6SS) is responsible for the secretion of numerous virulence effector proteins that can both interfere with competing microbes and manipulate host cells. Here, we report a detailed investigation of a P. aeruginosa H2-T6SS-dependent phospholipase effector, TplE, which acts as a trans-kingdom toxin. Delivery of TplE to the periplasmic space of rival bacteria leads to growth inhibition. Importantly, TplE, also contains a eukaryotic PGAP1-like domain, which targets the host ER apparatus, ultimately leading to disruption of the ER. TplE activity leads to the activation of the unfolded protein response (UPR) through the IRE1alpha-XBP1 pathway, enhancing autophagic flux. These findings indicate that this T6SS-delivered phospholipase effector is active against both prokaryotic and eukaryotic cellular targets, highlighting the T6SS as a versatile weapon in the Pseudomonas arsenal. PMID- 27477275 TI - A Transcript-Specific eIF3 Complex Mediates Global Translational Control of Energy Metabolism. AB - The multi-subunit eukaryotic translation initiation factor eIF3 is thought to assist in the recruitment of ribosomes to mRNA. The expression of eIF3 subunits is frequently disrupted in human cancers, but the specific roles of individual subunits in mRNA translation and cancer remain elusive. Using global transcriptomic, proteomic, and metabolomic profiling, we found a striking failure of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d to synthesize components of the mitochondrial electron transport chain, leading to a defect in respiration, endogenous oxidative stress, and premature aging. Energy balance was maintained, however, by a switch to glycolysis with increased glucose uptake, upregulation of glycolytic enzymes, and strict dependence on a fermentable carbon source. This metabolic regulatory function appears to be conserved in human cells where eIF3e binds metabolic mRNAs and promotes their translation. Thus, via its eIF3d-eIF3e module, eIF3 orchestrates an mRNA-specific translational mechanism controlling energy metabolism that may be disrupted in cancer. PMID- 27477277 TI - Selective Maturation of Temporal Dynamics of Intracortical Excitatory Transmission at the Critical Period Onset. AB - Although the developmental maturation of cortical inhibitory synapses is known to be a critical factor in gating the onset of critical period (CP) for experience dependent cortical plasticity, how synaptic transmission dynamics of other cortical synapses are regulated during the transition to CP remains unknown. Here, by systematically examining various intracortical synapses within layer 4 of the mouse visual cortex, we demonstrate that synaptic temporal dynamics of intracortical excitatory synapses on principal cells (PCs) and inhibitory parvalbumin- or somatostatin-expressing cells are selectively regulated before the CP onset, whereas those of intracortical inhibitory synapses and long-range thalamocortical excitatory synapses remain unchanged. This selective maturation of synaptic dynamics results from a ubiquitous reduction of presynaptic release and is dependent on visual experience. These findings provide an additional essential circuit mechanism for regulating CP timing in the developing visual cortex. PMID- 27477278 TI - Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone. AB - The autophagic clearance of 26S proteasomes (proteaphagy) is an important homeostatic mechanism within the ubiquitin system that modulates proteolytic capacity and eliminates damaged particles. Here, we define two proteaphagy routes in yeast that respond to either nitrogen starvation or particle inactivation. Whereas the core autophagic machineries required for Atg8 lipidation and vesiculation are essential for both routes, the upstream Atg1 kinase participates only in starvation-induced proteaphagy. Following inactivation, 26S proteasomes become extensively modified with ubiquitin. Although prior studies with Arabidopsis implicated RPN10 in tethering ubiquitylated proteasomes to ATG8 lining the autophagic membranes, yeast proteaphagy employs the evolutionarily distinct receptor Cue5, which simultaneously binds ubiquitin and Atg8. Proteaphagy of inactivated proteasomes also requires the oligomeric Hsp42 chaperone, suggesting that ubiquitylated proteasomes are directed by Hsp42 to insoluble protein deposit (IPOD)-type structures before encapsulation. Together, Cue5 and Hsp42 provide a quality control checkpoint in yeast directed at recycling dysfunctional 26S proteasomes. PMID- 27477279 TI - Transcriptionally Driven DNA Replication Program of the Human Parasite Leishmania major. AB - Faithful inheritance of eukaryotic genomes requires the orchestrated activation of multiple DNA replication origins (ORIs). Although origin firing is mechanistically conserved, how origins are specified and selected for activation varies across different model systems. Here, we provide a complete analysis of the nucleosomal landscape and replication program of the human parasite Leishmania major, building on a better evolutionary understanding of replication organization in Eukarya. We found that active transcription is a driving force for the nucleosomal organization of the L. major genome and that both the spatial and the temporal program of DNA replication can be explained as associated to RNA polymerase kinetics. This simple scenario likely provides flexibility and robustness to deal with the environmental changes that impose alterations in the genetic programs during parasitic life cycle stages. Our findings also suggest that coupling replication initiation to transcription elongation could be an ancient solution used by eukaryotic cells for origin maintenance. PMID- 27477280 TI - Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. AB - KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and beta-oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and beta-oxidation of fatty acids in lung cancer cells in an ACSL3-dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain. PMID- 27477282 TI - TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors. AB - Deregulated cathepsin proteolysis occurs across numerous cancers, but in vivo substrates mediating tumorigenesis remain ill-defined. Applying 8-plex iTRAQ terminal amine isotopic labeling of substrates (TAILS), a systems-level N terminome degradomics approach, we identified cathepsin B, H, L, S, and Z in vivo substrates and cleavage sites with the use of six different cathepsin knockout genotypes in the Rip1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis. Among 1,935 proteins and 1,114 N termini identified by TAILS, stable proteolytic products were identified in wild-type tumors compared with one or more different cathepsin knockouts (17%-44% of 139 cleavages). This suggests a lack of compensation at the substrate level by other cathepsins. The majority of neo-N termini (56%-83%) for all cathepsins was consistent with protein degradation. We validated substrates, including the glycolytic enzyme pyruvate kinase M2 associated with the Warburg effect, the ER chaperone GRP78, and the oncoprotein prothymosin-alpha. Thus, the identification of cathepsin substrates in tumorigenesis improves the understanding of cathepsin functions in normal physiology and cancer. PMID- 27477281 TI - Suppression of Resting Metabolism by the Angiotensin AT2 Receptor. AB - Activation of the brain renin-angiotensin system (RAS) stimulates energy expenditure through increasing of the resting metabolic rate (RMR), and this effect requires simultaneous suppression of the circulating and/or adipose RAS. To identify the mechanism by which the peripheral RAS opposes RMR control by the brain RAS, we examined mice with transgenic activation of the brain RAS (sRA mice). sRA mice exhibit increased RMR through increased energy flux in the inguinal adipose tissue, and this effect is attenuated by angiotensin II type 2 receptor (AT2) activation. AT2 activation in inguinal adipocytes opposes norepinephrine-induced uncoupling protein-1 (UCP1) production and aspects of cellular respiration, but not lipolysis. AT2 activation also opposes inguinal adipocyte function and differentiation responses to epidermal growth factor (EGF). These results highlight a major, multifaceted role for AT2 within inguinal adipocytes in the control of RMR. The AT2 receptor may therefore contribute to body fat distribution and adipose depot-specific effects upon cardio-metabolic health. PMID- 27477283 TI - Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1. AB - SAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutieres syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1 deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway. We provide genetic evidence that cell-autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of co-stimulatory markers. This program of myeloid cell activation required reverse transcription, cGAS and STING, and signaling through the IFN receptor. Furthermore, SAMHD1 reduced the induction of virus-specific cytotoxic T cells in vivo. Therefore, virus restriction by SAMHD1 limits the magnitude of IFN and T cell responses. This demonstrates a competition between cell-autonomous virus control and subsequent innate and adaptive immune responses, a concept with important implications for the treatment of infection. PMID- 27477284 TI - Nucleolin-Mediated RNA Localization Regulates Neuron Growth and Cycling Cell Size. AB - How can cells sense their own size to coordinate biosynthesis and metabolism with their growth needs? We recently proposed a motor-dependent bidirectional transport mechanism for axon length and cell size sensing, but the nature of the motor-transported size signals remained elusive. Here, we show that motor dependent mRNA localization regulates neuronal growth and cycling cell size. We found that the RNA-binding protein nucleolin is associated with importin beta1 mRNA in axons. Perturbation of nucleolin association with kinesins reduces its levels in axons, with a concomitant reduction in axonal importin beta1 mRNA and protein levels. Strikingly, subcellular sequestration of nucleolin or importin beta1 enhances axonal growth and causes a subcellular shift in protein synthesis. Similar findings were obtained in fibroblasts. Thus, subcellular mRNA localization regulates size and growth in both neurons and cycling cells. PMID- 27477285 TI - Distinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions. AB - Recent studies have suggested that human pluripotent stem cells (hPSCs) depend primarily on glycolysis and only increase oxidative metabolism during differentiation. Here, we demonstrate that both glycolytic and oxidative metabolism can support hPSC growth and that the metabolic phenotype of hPSCs is largely driven by nutrient availability. We comprehensively characterized hPSC metabolism by using (13)C/(2)H stable isotope tracing and flux analysis to define the metabolic pathways supporting hPSC bioenergetics and biosynthesis. Although glycolytic flux consistently supported hPSC growth, chemically defined media strongly influenced the state of mitochondrial respiration and fatty acid metabolism. Lipid deficiency dramatically reprogramed pathways associated with fatty acid biosynthesis and NADPH regeneration, altering the mitochondrial function of cells and driving flux through the oxidative pentose phosphate pathway. Lipid supplementation mitigates this metabolic reprogramming and increases oxidative metabolism. These results demonstrate that self-renewing hPSCs can present distinct metabolic states and highlight the importance of medium nutrients on mitochondrial function and development. PMID- 27477286 TI - Tissue-Resident CD169(+) Macrophages Form a Crucial Front Line against Plasmodium Infection. AB - Tissue macrophages exhibit diverse functions, ranging from the maintenance of tissue homeostasis, including clearance of senescent erythrocytes and cell debris, to modulation of inflammation and immunity. Their contribution to the control of blood-stage malaria remains unclear. Here, we show that in the absence of tissue-resident CD169(+) macrophages, Plasmodium berghei ANKA (PbA) infection results in significantly increased parasite sequestration, leading to vascular occlusion and leakage and augmented tissue deposition of the malarial pigment hemozoin. This leads to widespread tissue damage culminating in multiple organ inflammation. Thus, the capacity of CD169(+) macrophages to contain the parasite burden and its sequestration into different tissues and to limit infection induced inflammation is crucial to mitigating Plasmodium infection and pathogenesis. PMID- 27477287 TI - BRD4 Phosphorylation Regulates HPV E2-Mediated Viral Transcription, Origin Replication, and Cellular MMP-9 Expression. AB - Post-translational modification can modulate protein conformation and alter binding partner recruitment within gene regulatory regions. Here, we report that bromodomain-containing protein 4 (BRD4), a transcription co-factor and chromatin regulator, uses a phosphorylation-induced switch mechanism to recruit E2 protein encoded by cancer-associated human papillomavirus (HPV) to viral early gene and cellular matrix metalloproteinase-9 (MMP-9) promoters. Enhanced MMP-9 expression, induced upon keratinocyte differentiation, occurs via BRD4-dependent recruitment of active AP-1 and NF-kappaB to their target sequences. This is triggered by replacement of AP-1 family members JunB and JunD by c-Jun and by re-localization of NF-kappaB from the cytoplasm to the nucleus. In addition, BRD4 phosphorylation is critical for E2- and origin-dependent HPV DNA replication. A class of phospho BRD4-targeting compounds, distinct from the BET bromodomain inhibitors, effectively blocks BRD4 phosphorylation-specific functions in transcription and factor recruitment. PMID- 27477288 TI - Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling. AB - Amino acid availability activates signaling by the mammalian target of rapamycin (mTOR) complex 1, mTORC1, a master regulator of cell growth. The class III PI-3 kinase Vps34 mediates amino acid signaling to mTORC1 by regulating lysosomal translocation and activation of the phospholipase PLD1. Here, we identify leucyl tRNA synthetase (LRS) as a leucine sensor for the activation of Vps34-PLD1 upstream of mTORC1. LRS is necessary for amino acid-induced Vps34 activation, cellular PI(3)P level increase, PLD1 activation, and PLD1 lysosomal translocation. Leucine binding, but not tRNA charging activity of LRS, is required for this regulation. Moreover, LRS physically interacts with Vps34 in amino acid-stimulatable non-autophagic complexes. Finally, purified LRS protein activates Vps34 kinase in vitro in a leucine-dependent manner. Collectively, our findings provide compelling evidence for a direct role of LRS in amino acid activation of Vps34 via a non-canonical mechanism and fill a gap in the amino acid-sensing mTORC1 signaling network. PMID- 27477289 TI - Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts. AB - The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma. PMID- 27477290 TI - Chx10 Consolidates V2a Interneuron Identity through Two Distinct Gene Repression Modes. AB - During development, two cell types born from closely related progenitor pools often express identical transcriptional regulators despite their completely distinct characteristics. This phenomenon implies the need for a mechanism that operates to segregate the identities of the two cell types throughout differentiation after initial fate commitment. To understand this mechanism, we investigated the fate specification of spinal V2a interneurons, which share important developmental genes with motor neurons (MNs). We demonstrate that the paired homeodomain factor Chx10 functions as a critical determinant for V2a fate and is required to consolidate V2a identity in postmitotic neurons. Chx10 actively promotes V2a fate, downstream of the LIM-homeodomain factor Lhx3, while concomitantly suppressing the MN developmental program by preventing the MN specific transcription complex from binding and activating MN genes. This dual activity enables Chx10 to effectively separate the V2a and MN pathways. Our study uncovers a widely applicable gene regulatory principle for segregating related cell fates. PMID- 27477291 TI - Growth development in children with congenital hypothyroidism: the effect of screening and treatment variables-a comprehensive longitudinal study. AB - Investigating the screening and early treatment factors potentially affects the growth status of the patients with congenital hypothyroidism. In a longitudinal study, 760 (45 % girl) neonates born in 2002-2009 with congenital hypothyroidism diagnosed by neonatal screening in Isfahan-Iran were followed up to 5 years from the time of diagnosis (i.e., 3-4 records for the first year of age and 2-3 records after that). During follow-up, height, weight, and head circumferences of the patients were measured. Diagnostic and therapeutic factors included serum thyroxine and thyroid stimulating hormone concentration at diagnosis and after treatment initiation, the age at onset of treatment, the first therapeutic dosage, and age at first normalization of thyroxine and thyroid stimulating hormone. Quantile regression for longitudinal data was used for determining the effects of main factors on growth development. Longitudinal growth in height and weight was significantly correlated with the age at onset of treatment and the first therapeutic dosage (p < 0.01), while head circumference only with first therapeutic dosage (p < 0.05). Growth in weight and head circumference was affected by thyroid stimulating hormone at the time of diagnosis (p < 0.05). Also the age of thyroxine normalization had heterogeneous significant impact over the proposed quantiles on weight (p < 0.05), height (p < 0.01), and head circumference (p < 0.001). Among studied factors, the first therapeutic dosage, age at onset of treatment and age of thyroxine normalization seem to be more important for anthropometric development, suggesting that more optimal outcome might be achievable through earlier treatment and appropriate levothyroxine dosage. PMID- 27477292 TI - Diabetes mellitus as a risk factor for incident chronic kidney disease and end stage renal disease in women compared with men: a systematic review and meta analysis. AB - Diabetes mellitus is a strong risk factor for chronic kidney disease and end stage renal disease. Whether sex differences in chronic kidney disease and end stage renal disease incidence exist among diabetic patients remains unclear. This systematic review and meta-analysis was conducted to evaluate the relative effect of diabetes on chronic kidney disease and end-stage renal disease risk in women compared with men. We systematically searched Embase, PubMed, and the Cochrane Library for both cohort and case-control studies until October 2015. Studies were selected if they reported a sex-specific relationship between diabetes mellitus and chronic kidney disease or end-stage renal disease. We generated pooled estimates across studies using random-effects meta-analysis after log transformation with inverse variance weighting. Ten studies with data from more than 5 million participants were included. The pooled adjusted risk ratio of chronic kidney disease associated with diabetes mellitus was 3.34 (95 % CI 2.27, 4.93) in women and 2.84 (95 % CI 1.73, 4.68) in men. The data showed no difference in diabetes-related chronic kidney disease risk between the sexes (pooled adjusted women-to-men relative risk ratio was 1.14 [95 % CI 0.97, 1.34]) except for end-stage renal disease-the pooled adjusted women-to men relative risk ratio was 1.38 (95 % CI 1.22, 1.55; p = 0.114, I2 = 38.1 %). The study found no evidence of a sex difference in the association between diabetes mellitus and chronic kidney disease. However, the excess risk for end-stage renal disease was higher in women with diabetes than in men with the same condition, from which we assume that the female gender could accelerate the disease progression. Further studies are needed to support this notion and elucidate the underlying mechanisms. PMID- 27477294 TI - Cerebral venous thrombosis: A single disease with different approaches. PMID- 27477293 TI - Continuous subcutaneous insulin infusion versus multiple daily injections in individuals with type 1 diabetes: a systematic review and meta-analysis. AB - The relative efficacy of continuous subcutaneous insulin infusion and multiple daily injections in individuals with type 1 diabetes is unclear. We sought to synthesize the existing evidence about the effect of continuous subcutaneous insulin infusion on glycosylated hemoglobin, hypoglycemic events, and time spent in hypoglycemia compared to multiple daily injections. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus from January 2008 through November 2015 for randomized controlled trials that enrolled children or adults with type 1 diabetes. Trials identified in a previous systematic review and published prior to 2008 were also included. We included 25 randomized controlled trials at moderate risk of bias. Meta-analysis showed a significant reduction in glycosylated hemoglobin in patients treated with continuous subcutaneous insulin infusion compared to multiple daily injections (mean difference 0.37; 95 % confidence interval, 0.24 0.51). This effect was demonstrated in both children and adults. There was no significant difference in minor or severe hypoglycemic events. Continuous subcutaneous insulin infusion was associated with lower incidence of nocturnal hypoglycemia. There was no significant difference in the time spent in hypoglycemia. In children and adults with type 1 diabetes and compared to multiple daily injections, continuous subcutaneous insulin infusion is associated with a modest reduction in glycosylated hemoglobin. There was no difference in severe or minor hypoglycemia, but likely a lower incidence of nocturnal hypoglycemia with continuous subcutaneous insulin infusion. PMID- 27477295 TI - Fracture of an unossified humeral medial epicondyle: use of magnetic resonance imaging for diagnosis. AB - Fracture of the humeral medial epicondyle is a relatively common injury in children. Surgery is a good option for treatment, but correct diagnosis is important. Most fractures occur after the ossification of the medial epicondylar apophysis. If a fracture occurs before the ossification of the medial epicondyle, it is undetectable by radiographs. Here we report a case of an unossified medial epicondyle fracture of the humerus. A 9-year-old boy had persistent pain in the medial side of the right elbow after a fall. Despite his pain, he could move his injured elbow with a range from 60 to 90 degrees . Radiographs and computed tomography showed neither fracture nor dislocation in the injured elbow, and soft tissue swelling was the only finding. Neither the trochlea nor the medial epicondyle was ossified. Magnetic resonance imaging showed that the medial epicondyle was separated from the medial metaphysis and displaced. This clear finding led us to surgical fixation. Under general anesthesia, valgus stress showed gross instability of the injured elbow. Two years after the operation, he had no complaints and could play sports with the same range of motion as the left elbow. It is important to keep in mind that medial epicondylar fractures may be hidden in a normal radiograph before the ossification of the medial epicondylar apophysis. PMID- 27477297 TI - Nrf2 knockdown attenuates the ameliorative effects of ligustrazine on hepatic fibrosis by targeting hepatic stellate cell transdifferentiation. AB - Hepatic fibrosis is a frequent reparative process in response to chronic liver injury and inflammation, which is mainly attributed to hepatic stellate cell (HSC) activation. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was recently highlighted for its negative regulation of HSC behaviors. Our previous studies have revealed the potent antifibrotic effects of ligutrazine without elaborating potential molecular mechanisms. In this work, our in vitro results showed that ligustrazine significantly enhanced Nrf2 expression and nuclear translocation in HSC. Mechanistic investigations using RNAi technology demonstrated that Nrf2 knockdown abolished the ameliorative effects of ligustrazine on serum enzyme activities, hepatic histological architecture, levels of proinflammatory cytokines in serum and liver, intrahepatic inflammatory cell infiltration. Nrf2 shRNA also abrogated the antifibrotic effects of ligustrazine evidenced by increased serum fibrotic biomarkers, hepatic hydroxyproline, profibrogenetic factors in serum and liver, and intrahepatic collagen deposition. Ligustrazine inhibited the induction of CCl4 on beta-catenin in HSC, which was cancelled by Nrf2 shRNA lentivirus. In vitro experiments also showed that Nrf2 siRNA abrogated the inhibition of ligustrazine on beta-catenin expression. Nrf2 siRNA and IWR-1 endo (a specific antagonist of beta-catenin) were applied to investigate the correlation between Nrf2 and beta-catenin in mediating the effects of ligustrazine. Results suggested that ligustrazine not only suppressed the viability, contraction, and migration of human HSC but also alleviated lipid droplet loss and extracellular matrix production. Nrf2 siRNA yet weakened the inhibitory action of ligustrazine on HSC behaviors while IWR-1-endo further impaired the suppression of Nrf2 siRNA and restored the capacity of ligustrazine. Collectively, we drew a conclusion that the favorable antifibrotic effects of ligustrazine were attributed to its negative modulation on HSC behaviors by interrupting Nrf2/beta-catenin pathway. The findings broaden the width and depth of molecular mechanisms involved in the ligustrazine action, facilitating the development of ligustrazine in antifibrotic therapies. PMID- 27477298 TI - Changing markets - Medicinal plants in the markets of La Paz and El Alto, Bolivia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Given the importance of local markets as a source of medicinal plants for both healers and the population, literature on market flows and the value of the plant material traded is rather scarce. This stands in contrast to wealth of available information for other components of Bolivian ethnobotany. The present study attempts to remedy this situation by providing a detailed inventory of medicinal plant markets in the La Paz-El Alto metropolitan area, hypothesizing that both species composition, and medicinal applications, have changed considerably over time. MATERIALS AND METHODS: From October 2013 October 2015 semi-structured interviews were conducted with 39 plant vendors between October 2013 and October 2015 in the Mercado Rodriguez, Mercado Calle Santa Cruz, Mercado Cohoni, Mercado Cota Cota, and Mercado Seguencoma and Mercado El Alto in order to elucidate more details on plant usage and provenance. The results of the present study were then compared to previous inventories of medicinal plants in La Paz and El Alto studies to elucidate changes over time and impact of interview techniques. RESULTS: In this study we encountered 163 plant species belonging to 127 genera and 58 families. In addition, 17 species could not be identified. This species richness is considerably higher than that reported in previous studies (2005, 129 species of 55 families; 2015, 94 identified species). While the overall distribution of illness categories is in line with older reports the number of species used per application, as well as the applications per species, were much higher in the present study. Overall, informant consensus was relatively low, which might be explained by the large number of new species that have entered the local pharmacopoeia in the last decade, although some species might simply have been missed by previous studies. In course of the present study it became apparent that even well known species might often be replaced by other apparently similar but botanically unrelated species due to environmental and market forces CONCLUSIONS: The present study indicated that, while the floristic composition of markets in the La Paz metropolitan area remained relatively constant over the last decade, with this inventory adding about 20% of species to previous studies, the number of indications for which certain species were used increased tremendously, and that profound differences exist even between markets in close proximity. The dramatic increase in previously not used species used per indication might pose serious risks for consumers. We found serious problems due to species replacements. Even plants that have a well established vernacular name, and are easily recognizable botanically, can be replaced by other species that can pose a serious health risk. Vendor education and stringent identification of the material sold in public markets are clearly needed. PMID- 27477296 TI - A decade of e-cigarettes: Limited research & unresolved safety concerns. AB - It is well known that tobacco consumption is a leading cause of preventable deaths worldwide and has been linked to major diseases ranging from cancer to chronic obstructive pulmonary disease, atherosclerosis, stroke and a host of neurological/neurodegenerative disorders. In the past decade a number of alternative vaping products have hit the market, rapidly gaining consumers especially among the younger population. Electronic nicotine delivery systems or e-cigarettes have become the sought-after product due to the belief that they are much safer than traditional cigarettes. However, inadequate research and lack of regulatory guidelines for both the manufacturing process and the content of the vaping solution of the e-cigarette has become a major concern. Highly debated and unresolved questions such as whether e-cigarettes may help smokers quit and whether e-cigarettes will promote the use of nicotine among non-smokers add to the confusion of the safety of e-cigarettes. In this review article, we summarize the current understanding (and lack thereof) of the potential health impacts of e cigarettes. We will also highlight the most recent studies (in vivo/in vitro) which seem to conflict with the broad safety claims put forward by the manufacturers. Finally, we provide potential solutions to overcome the research gap of the short and long-term health impact of e-cigarettes. PMID- 27477299 TI - Bacterial toxins: Strain competition keeps a lid on gut pathogens. PMID- 27477300 TI - Bacterial physiology: Salmonella get attached. PMID- 27477301 TI - Bacterial genetics: SMRT-seq reveals an epigenetic switch. PMID- 27477302 TI - Choosing to engage and choosing to persist: The role of non-specific factors in health-promoting activities. AB - OBJECTIVE: Non-specific factors play an important role in determining benefits from health-promoting activities. Previous studies have focussed on beneficial outcomes of motivation during engagement. There are two aims of this project. First, we investigated whether expectancy and intrinsic motivation influence people's decisions to engage with health-promoting activities in the first instance and then subsequently adhere to them. Second, we examined the effects of providing information on health-promoting activities as a method of influencing expectancy and intrinsic motivation. METHOD: In two studies, participants were informed about a health-promoting activity (Study 1: A breathing exercise for well-being; Study 2: A gratitude exercise for smoking cessation) and told that it has either a 'known' or 'unknown' effectiveness. Participants were then given the opportunity to engage with the activity over the following days. Expectancy and intrinsic motivation were measured after reading the information and prior to engagement with the activity. Adherence to the activity was measured at follow up. RESULTS: In both studies, intrinsic motivation positively predicted willingness to engage with the activities as well as subsequent adherence. Expectancy predicted adherence in Study 1 and choices to engage in Study 2, but not after controlling for intrinsic motivation. Describing the gratitude exercise as having a known effectiveness in Study 2 enhanced motivation and adherence to the activity. CONCLUSIONS: The non-specific benefit brought by intrinsic motivation plays an important role in choosing to engage with health-promoting activities as well as subsequent adherence. Our results also show that simple statements about the potential benefits of a health-promoting activity can motivate engagement and adherence. Statement of contribution What is already known on this subject? Previous studies have established that non-specific factors, namely expectancies and intrinsic motivation, play an important role in determining benefit when engaging in health-promoting activities. These studies have neglected how non-specific factors relate to initial choices to engage in health-promoting activities in the first instance. Intrinsic motivation has been found to be more strongly related to benefit than expectancies in real-world health-promoting activities. What does this study add? Intrinsic motivation predicts choices to engage with a health-promoting activity. Simple statements about benefits of a health-promoting activity motivate engagement. PMID- 27477303 TI - Potential Use of Classroom Response Systems (CRS, Clickers) in Foods, Nutrition, and Dietetics Higher Education. AB - Although hundreds of articles have been published about the use of classroom response systems (CRS, clickers) in higher education, few address the use in foods, nutrition, and dietetics courses, especially upper-division, major courses. This technology has the potential to increase student engagement, motivation, assessment, and, possibly, learning. Thoughtfully designed questions may stimulate discussions, especially about challenging nutrition topics. This article presents the viability and potential benefits for the use of CRS in foods, nutrition, and dietetics classes through a brief literature summary, overview of the author's experiences, and guidance for implementing this technology. PMID- 27477304 TI - Ventricular fibrillation with intracoronary adenosine during fractional flow reserve assessment. AB - Fractional flow reserve (FFR) measurement provides useful hemodynamic assessment of intermediate coronary stenoses affecting long term outcomes. While the gold standard remains intravenous adenosine, intracoronary (IC) bolus administration of adenosine is routinely used in clinical practice because of its ease of use and lower dose providing comparative hyperemia with the most common side effect being a transient atrioventricular block. A 62year old male underwent left heart catheterization after ruling in for non-ST elevation myocardial infarction (NSTEMI). Presenting electrocardiogram (ECG) showed an old left bundle branch block and T-wave inversions in lateral leads (QTc 494ms) with no significant electrolyte abnormalities. Coronary angiography revealed an intermediate lesion in mid left anterior descending coronary artery. FFR assessment with IC adenosine (24MUg/mL of normal saline) was performed inducing ventricular fibrillation (VF). He was successfully defibrillated with a single 200J shock and no further arrhythmias were noticed during rest of his hospital stay. PMID- 27477305 TI - Immediate and intermediate-term results of optical coherence tomography guided atherectomy in the treatment of peripheral arterial disease: Initial results from the VISION trial. AB - BACKGROUND: Long-term patency rates for percutaneous peripheral arterial interventions are suboptimal. Optical coherence tomography (OCT) guided atherectomy may yield superior patency by optimizing plaque removal while preserving the tunica media and adventitia. METHODS: The VISION study is a multicenter prospective study of patients with peripheral arterial disease undergoing OCT guided atherectomy with the PantherisTM device. In 11 patients enrolled in a single center, we report procedural and clinical outcomes, at 30days and 6months. RESULTS: The mean age was 63+/-11years and 73% (n=8) were men. The target lesion was in the superficial femoral artery in 82% (n=9) of the patients. Mean stenosis severity was 87%+/-10% and mean lesion length was 39+/ 31mm. Procedural success was observed in all patients with no device related complications. Mean post-atherectomy stenosis was 18%+/-15%. Almost all excised tissue consisted of intimal plaque (94%). At 30days, significant improvements in Rutherford class, VascuQoL scores and ABI were observed, 0.9+/-0.8 vs. 3.1+/-0.7 (p=0.01), 4.9+/-1.9 vs. 3.6+/-1.5 (p=0.03) and 1.04+/-0.19 vs. 0.80+/-0.19 (p<0.01) respectively. At 6months, there were significant improvements in Rutherford class (1.0+/-1.0 vs. 3.1+/-0.7, p=0.01) and ABI (0.93+/-0.19 versus 0.80+/-0.19, p=0.02) but not in VascuQoL scores (3.7+/-1.4 versus 3.6+/-1.5, p=0.48). Target lesion revascularization occurred in 18% (n=2) of the patients. CONCLUSION: OCT guided atherectomy resulted in high procedural success, no device related complications and encouraging results up to 6months. Histological analysis suggested little injury to the media and adventitia. Larger studies are needed to confirm the efficacy of this approach. PMID- 27477307 TI - Enhanced spin Hall effect of tunneling light in hyperbolic metamaterial waveguide. AB - Giant enhancement of spin Hall effect of tunneling light (SHETL) is theoretically proposed in a frustrated total internal reflection (FTIR) structure with hyperbolic metamaterial (HMM). We calculate the transverse shift of right circularly polarized light in a SiO2-air-HMM-air-SiO2 waveguide and analyze the physical mechanism of the enhanced SHETL. The HMM anisotropy can greatly increase the transverse shift of polarized light even though HMM loss might reduce it. Compared with transverse shift of transmitted light through a single HMM slab with ZnAlO/ZnO multilayer, the maximum transverse shift of tunneling light through a FTIR structure with identical HMM can be significantly enlarged by more than three times which reaches -38 MUm without any amplification method. PMID- 27477306 TI - Long-term use of dual antiplatelet therapy for the secondary prevention of atherothrombotic events: Meta-analysis of randomized controlled trials. AB - BACKGROUND: The potential benefit of long-term dual antiplatelet therapy (DAPT) for secondary prevention of atherothrombotic events is unclear. Data from different randomized controlled trials (RCT) using different agents in different subgroups showed inconsistent results. METHODS: We performed a systematic review and meta-analysis from RCTs that tested different prolonged durations of DAPT for secondary prevention. Long term DAPT arm was defined as those receiving DAPT for more than 12months. Long-term aspirin arm was defined as those receiving either aspirin alone long term or DAPT for less than 12months. RESULTS: The use of long term DAPT was associated with a significant decrease in composite of death, myocardial infarction (MI) and stroke (6.08% vs. 6.71%; odds ratio OR=0.86 [0.78 0.94]; P=0.001). This reduction of death, MI and stroke was mainly noticed in patients with prior MI or stroke, but not with PAD or multiple risk factors. The reduction was seen with post PCI patients with prasugrel and only in those with prior MI with clopidogrel and ticagrelor. Long-term use of DAPT was associated with significant increase in major bleeding (1.47% vs. 0.88%; OR=1.65 [1.23 2.21]; P=0.001). CONCLUSION: Long-term use of DAPT for secondary prevention is associated with lower risk of death, MI and stroke beneficial especially in patients with prior MI and stroke, but it is associated with increased risk of bleeding. Prolonging DAPT requires careful assessment of the trade-off between ischemic and bleeding complications and should probably be reserved for patients with higher risk for atherothrombotic events. PMID- 27477308 TI - Cold-inducible RNA-binding protein mediates airway inflammation and mucus hypersecretion through a post-transcriptional regulatory mechanism under cold stress. AB - Acute or chronic cold exposure exacerbates chronic inflammatory airway diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Cold-inducible RNA-binding protein (CIRP) is a cold-shock protein and is induced by various environmental stressors, such as hypothermia and hypoxia. In this study, we showed that CIRP gene and protein levels were significantly increased in patients with COPD and in rats with chronic airway inflammation compared with healthy subjects. Similarly, inflammatory cytokine production and MUC5AC secretion were up-regulated in rats following cigarette smoke inhalation. Cold temperature induced CIRP overexpression and translocation were shown to be dependent on arginine methylation in vitro. CIRP overexpression promoted stress granule (SG) assembly. In the cytoplasm, the stability of pro-inflammatory cytokine mRNAs was increased through specific interactions between CIRP and mediator mRNA 3'-UTRs; these interactions increased the mRNA translation, resulting in MUC5AC overproduction in response to cold stress. Conversely, CIRP silencing and a methyltransferase inhibitor (adenosine dialdehyde) promoted cytokine mRNA degradation and inhibited the inflammatory response and mucus hypersecretion. These findings indicate that cold temperature can induce an airway inflammatory response and excess mucus production via a CIRP-mediated increase in mRNA stability and protein translation. PMID- 27477309 TI - TLR2 ligation induces corticosteroid insensitivity in A549 lung epithelial cells: Anti-inflammatory impact of PP2A activators. AB - Corticosteroids are effective anti-inflammatory therapies widely utilized in chronic respiratory diseases. But these medicines can lose their efficacy during respiratory infection resulting in disease exacerbation. Further in vitro research is required to understand how infection worsens lung function control in order to advance therapeutic options to treat infectious exacerbation in the future. In this study, we utilize a cellular model of bacterial exacerbation where we pretreat A549 lung epithelial cells with the synthetic bacterial lipoprotein Pam3CSK4 (a TLR2 ligand) to mimic bacterial infection and tumor necrosis factor alpha (TNFalpha) to simulate inflammation. Under these conditions, Pam3CSK4 induces corticosteroid insensitivity; demonstrated by substantially reduced ability of the corticosteroid dexamethasone to repress TNFalpha-induced interleukin 6 secretion. We then explored the molecular mechanism responsible and found that corticosteroid insensitivity induced by bacterial mimics was not due to altered translocation of the glucocorticoid receptor into the nucleus, nor an impact on the NF-kappaB pathway. Moreover, Pam3CSK4 did not affect corticosteroid-induced upregulation of anti-inflammatory MAPK deactivating phosphatase-MKP-1. However, Pam3CSK4 can induce oxidative stress and we show that a proportion of the MKP-1 produced in response to corticosteroid in the context of TLR2 ligation was rendered inactive by oxidation. Thus to combat inflammation in the context of bacterial exacerbation we sought to discover effective strategies that bypassed this road-block. We show for the first time that known (FTY720) and novel (theophylline) activators of the phosphatase PP2A can serve as non-steroidal anti-inflammatory alternatives and/or corticosteroid-sparing approaches in respiratory inflammation where corticosteroid insensitivity exists. PMID- 27477311 TI - Cardiac dysfunction, mitochondrial architecture, energy production, and inflammatory pathways: Interrelated aspects in endotoxemia and sepsis. AB - Septic patients with myocardial dysfunction have a 3-fold increase in mortality compared with patients without cardiovascular impairment, and usually show myocarditis, disruption of the contractile apparatus, increased amounts of interstitial collagen, and damaged mitochondria. The presence of nitric oxide and cytokines in cardiac tissue constitute the molecular markers and the intracellular messengers of inflammatory conditions in the heart due to the onset of sepsis and endotoxemia, derived from the nuclear factor-kappaB pathway activation and proinflammatory gene transcription. Sepsis occurs with an exacerbated inflammatory response that damages tissue mitochondria and impaired bioenergetic processes. The heart consumes 20-30 times its own weight in adenosine triphosphate every day, and 90% of this molecule is derived from mitochondrial oxidative phosphorylation. Cardiac energy management is comprised in sepsis and endotoxemia; both a deficit in energy production and alterations in the source of energy substrates are believed to be involved in impaired cardiac function. Although several hypotheses try to explain the molecular mechanisms underlying the complex condition of sepsis and endotoxemia, the current view is that these syndromes are the result of an intricate balance between prevailing levels of mitochondrial stress, biogenesis/autophagy signaling and mitochondria quality control processes, rather on a single factor. The aim of this review is to discuss current hypothesis of cardiac dysfunction related to energy metabolism and mitochondrial function in experimental models of sepsis and endotoxemia, and to introduce the importance of lipids (mainly cardiolipin) in the mechanism of cardiac energy mismanagement in these inflammatory conditions. PMID- 27477310 TI - Quercetin sensitizes pancreatic cancer cells to TRAIL-induced apoptosis through JNK-mediated cFLIP turnover. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that can selectively kill cancer cells. Nonetheless, many cancers are resistant to TRAIL, and the molecular mechanisms of TRAIL resistance in cancer, particularly pancreatic cancer, are still unclear. In this study, we tested the hypothesis that quercetin, a flavonoid, induces apoptosis in TRAIL resistant pancreatic cancer cells. Although quercetin alone had no significant cytotoxic effect, when combined with TRAIL, it promoted TRAIL-induced apoptosis that required mitochondrial outer membrane permeabilization. A BH3-only protein BID knockdown dramatically attenuated TRAIL/quercetin-induced apoptosis. The expression levels of cellular FLICE-like inhibitory protein (cFLIP) decreased in a dose-dependent manner in the presence of quercetin, and overexpression of cFLIP was able to robustly rescue pancreatic cancer cells from TRAIL/quercetin-induced apoptosis. Additionally, quercetin activated c-Jun N-terminal kinase (JNK) in a dose-dependent manner, which in turn induced the proteasomal degradation of cFLIP, and JNK activation also sensitized pancreatic cancer cells to TRAIL induced apoptosis. Thus, our results suggest that quercetin induces TRAIL-induced apoptosis via JNK activation-mediated cFLIP turnover. PMID- 27477312 TI - Hepatitis C virus suppresses Hepatocyte Nuclear Factor 4 alpha, a key regulator of hepatocellular carcinoma. AB - Hepatitis C Virus (HCV) infection presents with a disturbed lipid profile and can evolve to hepatic steatosis and hepatocellular carcinoma (HCC). Hepatocyte Nuclear Factor 4 alpha (HNF4alpha) is the most abundant transcription factor in the liver, a key regulator of hepatic lipid metabolism and a critical determinant of Epithelial to Mesenchymal Transition and hepatic development. We have previously shown that transient inhibition of HNF4alpha initiates transformation of immortalized hepatocytes through a feedback loop consisting of miR-24, IL6 receptor (IL6R), STAT3, miR-124 and miR-629, suggesting a central role of HNF4alpha in HCC. However, the role of HNF4alpha in Hepatitis C Virus (HCV) related hepatocarcinoma has not been evaluated and remains controversial. In this study, we provide strong evidence suggesting that HCV downregulates HNF4alpha expression at both transcriptional and translational levels. The observed decrease of HNF4alpha expression correlated with the downregulation of its downstream targets, HNF1alpha and MTP. Ectopic overexpression of HCV proteins also exhibited an inhibitory effect on HNF4alpha levels. The inhibition of HNF4alpha expression by HCV appeared to be mediated at transcriptional level as HCV proteins suppressed HNF4alpha gene promoter activity. HCV also up-regulated IL6R, activated STAT3 protein phosphorylation and altered the expression of acute phase genes. Furthermore, as HCV triggered the loss of HNF4alpha a consequent change of miR-24, miR-629 or miR-124 was observed. Our findings demonstrated that HCV-related HCC could be mediated through HNF4alpha-microRNA deregulation implying a possible role of HNF4alpha in HCV hepatocarcinogenesis. HCV inhibition of HNF4alpha could be sustained to promote HCC. PMID- 27477313 TI - Nestin regulates neural stem cell migration via controlling the cell contractility. AB - Neural stem cells (NSCs) migration is essential for neurogenesis and neuroregeneration after brain injury. Nestin, a widely used marker of NSCs, is expressed abundantly in several cancers, where it may correlate with tumor migration and invasion. However, it is not yet known whether nestin participates in NSC migration. Here, we show that nestin down-regulation significantly inhibits the migration and contraction of murine neural stem cells, but does not obviously influence the proliferation, filamentous actin (F-actin) content, distribution or focal adhesion assembly of these cells. Mechanistically, nestin knockdown was found to affect the phosphorylation state of myosin regulatory light chain (MRLC) and regulate the activity of myosin light chain kinase (MLCK). Co-immunoprecipitation experiments showed that it interacts with MLCK and MRLC. Together, our results indicate that nestin may increase NSC motility via elevating MLCK activity through direct binding and provide new insight into the roles of nestin in NSC migration and repair. PMID- 27477314 TI - Intracellular metabolic changes of Clostridium acetobutylicum and promotion to butanol tolerance during biobutanol fermentation. AB - During the fermentation process, Clostridium acetobutylicum cells are often inhibited by the accumulated butanol. However, the mechanism underlying response of C. acetobutylicum to butanol stress remains poorly understood. This study was performed to clarify such mechanism through investigating the butanol stress associated intracellular biochemical changes at acidogenesis phase (i.e., middle exponential phase) and solventogenesis phase (i.e., early stationary phase) by a gas chromatography-mass spectrometry-based metabolomics strategy. With the aid of partial least-squares-discriminant analysis, a pairwise discrimination between control group and butanol-treated groups was revealed, and 27 metabolites with variable importance in the projection value greater than 1 were identified. Under butanol stress, the glycolysis might be inhibited while TCA cycle might be promoted. Moreover, changes of lipids and fatty acids compositions, amino acid metabolism and osmoregulator concentrations might be the key factors involved in C. acetobutylicum metabolic response to butanol stress. It was suggested that C. acetobutylicum cells might change the levels of long acyl chain saturated fatty acids and branched-chain amino acids to maintain the integrity of cell membrane through adjusting membrane fluidity under butanol stress. The increased level of glycerol was considered to be correlated with osmoregulation and regulating redox balance. In addition, increased levels of some amino acids (i.e., threonine, glycine, alanine, phenylalanine, tyrosine, tryptophan, aspartate and glutamate) might also confer butanol tolerance to C. acetobutylicum. These results highlighted our knowledge about the response or adaptation of C. acetobutylicum to butanol stress, and would contribute to the construction of feasible butanologenic strains with higher butanol tolerance. PMID- 27477315 TI - Ultra-high field MRI: what is in full bloom and what is sprouting? PMID- 27477316 TI - Set the pace of bone healing - Treatment of a bilateral sacral stress fracture using teriparatide in a long-distance runner. PMID- 27477317 TI - Segond fracture. PMID- 27477318 TI - Sulfate-reducing bacteria slow intestinal transit in a bismuth-reversible fashion in mice. AB - BACKGROUND: Hydrogen sulfide (H2 S) serves as a mammalian cell-derived gaseous neurotransmitter. The intestines are exposed to a second source of this gas by sulfate-reducing bacteria (SRB). Bismuth subsalicylate binds H2 S rendering it insoluble. The aim of this study was to test the hypothesis that SRB may slow intestinal transit in a bismuth-reversible fashion. METHODS: Eighty mice were randomized to five groups consisting of Live SRB, Killed SRB, SRB+Bismuth, Bismuth, and Saline. Desulfovibrio vulgaris, a common strain of SRB, was administered by gavage at the dose of 1.0 * 109 cells along with rhodamine, a fluorescent dye. Intestinal transit was measured 50 minutes after gavage by euthanizing the animals, removing the small intestine between the pyloric sphincter and the ileocecal valve and visualizing the distribution of rhodamine across the intestine using an imaging system (IVIS, Perkin-Elmer). Intestinal transit (n=50) was compared using geometric center (1=minimal movement, 100=maximal movement). H2 S concentration (n=30) was also measured when small intestinal luminal content was allowed to generate this gas. KEY RESULTS: The Live SRB group had slower intestinal transit as represented by a geometric center score of 40.2 +/- 5.7 when compared to Saline: 73.6 +/- 5.7, Killed SRB: 77.9 +/- 6.9, SRB+Bismuth: 81.0 +/- 2.0, and Bismuth: 73.3 +/- 4.2 (P<.0001). Correspondingly, the Live SRB group had the highest luminal H2 S concentration of 4181.0 +/- 968.0 ppb compared to 0 +/- 0 ppb for the SRB+Bismuth group (P<.0001). CONCLUSIONS & INFERENCES: Live SRB slow intestinal transit in a bismuth reversible fashion in mice. Our results demonstrate that intestinal transit is slowed by SRB and this effect could be abolished by H2 S-binding bismuth. PMID- 27477319 TI - A systems biology-led insight into the role of the proteome in neurodegenerative diseases. AB - INTRODUCTION: Multifactorial disorders are the result of nonlinear interactions of several factors; therefore, a reductionist approach does not appear to be appropriate. Proteomics is a global approach that can be efficiently used to investigate pathogenetic mechanisms of neurodegenerative diseases. AREAS COVERED: Here, we report a general introduction about the systems biology approach and mechanistic insights recently obtained by over-representation analysis of proteomics data of cellular and animal models of Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders, as well as of affected human tissues. Expert commentary: As an inductive method, proteomics is based on unbiased observations that further require validation of generated hypotheses. Pathway databases and over-representation analysis tools allow researchers to assign an expectation value to pathogenetic mechanisms linked to neurodegenerative diseases. The systems biology approach based on omics data may be the key to unravel the complex mechanisms underlying neurodegeneration. PMID- 27477321 TI - Assessment of the classification abilities of the CNS multi-parametric optimization approach by the method of logistic regression. AB - Assessment of "CNS drugs/CNS candidates" classification abilities of the multi parametric optimization (CNS MPO) approach was performed by logistic regression. It was found that the five out of the six separately used physical-chemical properties (topological polar surface area, number of hydrogen-bonded donor atoms, basicity, lipophilicity of compound in neutral form and at pH = 7.4) provided accuracy of recognition below 60%. Only the descriptor of molecular weight (MW) could correctly classify two-thirds of the studied compounds. Aggregation of all six properties in the MPOscore did not improve the classification, which was worse than the classification using only MW. The results of our study demonstrate the imperfection of the CNS MPO approach; in its current form it is not very useful for computer design of new, effective CNS drugs. PMID- 27477322 TI - Test-retest reliability and agreement of the SPI-Questionnaire to detect symptoms of digital ischemia in elite volleyball players. AB - The Shoulder posterior circumflex humeral artery Pathology and digital Ischemia - questionnaire (SPI-Q) has been developed to enable periodic surveillance of elite volleyball players, who are at risk for digital ischemia. Prior to implementation, assessing reliability is mandatory. Therefore, the test-retest reliability and agreement of the SPI-Q were evaluated among the population at risk. A questionnaire survey was performed with a 2-week interval among 65 elite male volleyball players assessing symptoms of cold, pale and blue digits in the dominant hand during or after practice or competition using a 4-point Likert scale (never, sometimes, often and always). Kappa (kappa) and percentage of agreement (POA) were calculated for individual symptoms, and to distinguish symptomatic and asymptomatic players. For the individual symptoms, kappa ranged from "poor" (0.25) to "good" (0.63), and POA ranged from "moderate" (78%) to "good" (97%). To classify symptomatic players, the SPI-Q showed "good" reliability (kappa = 0.83; 95%CI 0.69-0.97) and "good" agreement (POA = 92%). The current study has proven the SPI-Q to be reliable for detecting elite male indoor volleyball players with symptoms of digital ischemia. PMID- 27477320 TI - NTRK3 kinase fusions in Spitz tumours. AB - Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cgamma1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27477324 TI - Re: Microvascular free flaps are a safe and suitable training procedure during structured plastic surgery residency: A comparative cohort study with 391 patients. PMID- 27477323 TI - Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease. AB - While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27477325 TI - Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia. AB - BACKGROUND: Episodic ataxia type 1 is a rare autosomal dominant neurological disorder caused by mutations in the KCNA1 gene that encodes the alpha subunit of voltage-gated potassium channel Kv1.1. The functional consequences of identified mutations on channel function do not fully correlate with the clinical phenotype of patients. METHODS: A clinical and genetic study was performed in a family with 5 patients with episodic ataxia type 1, with concurrent epilepsy in 1 of them. Protein expression, modeling, and electrophysiological analyses were performed to study Kv1.1 function. RESULTS: Whole-genome linkage and candidate gene analyses revealed the novel heterozygous mutation p.Arg324Thr in the KCNA1 gene. The encoded mutant Kv1.1 channel displays reduced currents and altered activation and inactivation. CONCLUSIONS: Taken together, we provide genetic and functional evidence that mutation p.Arg324Thr in the KCNA1 gene is pathogenic and results in episodic ataxia type 1 through a dominant-negative effect. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27477326 TI - Kinetics of charged antibiotic penetration into human intervertebral discs: A numerical study. AB - Little quantitative information exists on the kinetics of charged antibiotic penetration into human intervertebral discs (IVD). This information is crucial for determining the dosage to use, timing of administration, and duration of treatment for infected IVDs. The objective of this study was to quantitatively analyze the transport of various charged antibiotics into human lumbar IVDs. Penetration of charged and uncharged antibiotics into a human lumbar disc was analyzed using a 3D finite element model. The valence (z) of the electrical charge of antibiotics varied from z=+2 (positively charged) to z=-2 (negatively charged). An uncharged antibiotic (z=0) was used as a control. Cases with intravenous (IV) administrations of different charged antibiotics were simulated. Our results showed that the electrical charge had great effects on kinetics of an antibiotic penetration into the IVD; with higher concentrations and uptakes for positively charged antibiotics than those for negatively charged ones. This study provides quantitative information on selecting antibiotics for treating intervertebral disc infections. PMID- 27477327 TI - Accuracy of radiographic measurements for implant planning using cone-beam and helical computer tomography. AB - AIM: The aim of the present study was to compare the accuracy of radiographic measurements for dental implants planning using cone-beam computed tomography (CBCT) and helical computed tomography (HCT). METHODS: Six pig ribs were wrapped by putty impression material, with radiographic markers placed. Two CBCT and an HCT were taken following the standard protocols. Twenty-five locations were selected, with vertical and horizontal dimensions measured using the default software, as well as on the processed HCT films by a digital caliper. The actual dimensions of the ribs measured by the digital caliper served as the control. Differences between radiographic dimensions and the actual dimensions were tested by two-way analysis of variance. RESULTS: No differences were found between measurements made by CBCT and HCT images using the default software (P > 0.05). However, both measurements were statistically-significantly lower than the control (P < 0.001), and the mean difference was 0.3 mm. Measurements made on HCT films were statistically-significantly greater than the control (P < 0.001), and the mean difference was 0.5 mm. CONCLUSION: The accuracy of CBCT and HCT are similar, and both are reliable tools for implant planning. It is preferable to perform the planning using default software, rather than making direct measurements on films. PMID- 27477329 TI - Ectodermal dysplasia with immunodeficiency caused by a branch-point mutation in IKBKG/NEMO. PMID- 27477330 TI - Nasal airflow and brain activity: is there a link? AB - BACKGROUND: Over the past few decades, evidence has emerged suggesting that nasal airflow asymmetry and brain asymmetry are linked. The nose exhibits asymmetrical airflow, with the dominant airflow alternating from one nasal passage to the other over a period of hours. Some authors have suggested a correlation between cerebral hemisphere dominance and nostril dominance. Others have proposed an association between rhythmic fluctuations in nasal airflow and corresponding fluctuations in cerebral hemisphere activity. Based on ancient yoga breathing techniques, newer evidence suggests that altering nasal airflow can influence brain activity, with reports of improved cognitive function caused by unilateral forced nostril breathing. It seems that a nasal airflow stimulus may have an activating effect on the brain, as it has also been shown to trigger seizure activity in epileptic patients. OBJECTIVES: This article explores these theories in detail, reviews the evidence, and presents new models linking nasal airflow and brain activity. PMID- 27477332 TI - The experiences of families living with the anticipatory loss of a school-age child with spinal muscular atrophy - the parents' perspectives. AB - AIMS AND OBJECTIVES: To probe into parents' anticipatory loss of school-age children with Type I or II spinal muscular atrophy. BACKGROUND: Spinal muscular atrophy is a rare disorder that causes death. Children die early due to either gradual atrophy or an infection of the lungs. Therefore, family members experience anticipatory loss, which causes grief before the actual loss. Family members feel physically and mentally exhausted, which results in a family crisis. Therefore, it is important to explore their experiences related to anticipatory loss to assist with the adjustment of the families to their circumstances. DESIGN: This study applied a phenomenology method and purposive sampling. PARTICIPANTS: The 19 parents who participated in this study were referred to us by two medical centers in Taiwan. Their average age was 32-49 years. METHODS: Using in-depth interviews, this study explored parents' anticipatory loss. The interviews were recorded and transcribed. Meanings were extracted using Giorgi analysis, and precision was assessed according to Guba and Lincoln, which was treated as the evaluation standard. RESULTS: Four themes were identified from the parents' interviews. The themes included enduring the helplessness and pressure of care, suffering due to the child's rare and unknown condition, loss of hope and a reinforcement of the parent-child attachment, and avoiding the pressure of death and enriching the child's life. CONCLUSIONS: The research findings help nurses identify anticipatory loss among parents of school-age children with type I or II spinal muscular atrophy. They enhance health professionals' understanding of the panic that occurs in the society surrounding the families, family members' dynamic relationships, and the families' demands for care. RELEVANCE TO CLINICAL PRACTICE: In an attempt to providing intersubjective empathy and support with family having a child with type I and II SMA, nurses may recognize relevant family reactions and enhancing their hope and parent-child attachment. Encourage family members and child go beyond the pressure of death and create customized care plans meeting families' emotional and medical needs. PMID- 27477328 TI - Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells. AB - BACKGROUND: Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. OBJECTIVES: Because regulation of the phosphoinositide 3 kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). METHODS: Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3)+ Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse. RESULTS: Autoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4+ T-cell reduction, and changes in T- and B-cell subsets. Although total CD4+FOXP3+ Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3+ T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse. CONCLUSION: Heterozygous loss of function of PTEN in human subjects has a significant effect on T- and B cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency. PMID- 27477333 TI - Pyrylium-based dye and charge tagging in proteomics. AB - The pyrylium group is a selective reagent for epsilon-amino groups in proteins. In particular, for fluorescence labeling, a number of advantages over traditional N-hydroxysuccinimidyl ester chemistry were recognized such as the rapid prestaining procedure. Here, we have investigated the labeling reaction for the fluorogenic pyrylium dye Py-1 using liquid chromatography coupled to MS with the aim of determining its specificity and possible side products. Peptides containing no, one, and two lysine residue and a choice of no or one cysteine residue were labeled with Py-1 at yields > 30%. Gas phase fragmentation proved both labeling of lysine residues as well as that of the N-terminus also in peptides that contained a lysine residue. Evidence for cysteine labeling was not found, but several other products were detected such as the results of rearrangements with adjacent acidic amino acids. Apart from the use as a fluorogenic label, Py-1 recommends itself for N-terminal charge tagging as alternative to the commonly used quaternary ammonium salts. Predominantly a- and b-type ion series were observed for N-terminally labeled peptides. Further applications include chromophore tagging since the labeled product is not only fluorescent but also colored red. PMID- 27477334 TI - Dissociative electron transfer in polychlorinated aromatics. Reduction potentials from convolution analysis and quantum chemical calculations. AB - Formal potentials of the first reduction leading to dechlorination in dimethylformamide were obtained from convolution analysis of voltammetric data and confirmed by quantum chemical calculations for a series of polychlorinated benzenes: hexachlorobenzene (-2.02 V vs. Fc(+)/Fc), pentachloroanisole (-2.14 V), and 2,4-dichlorophenoxy- and 2,4,5-trichlorophenoxyacetic acids (-2.35 V and 2.34 V, respectively). The key parameters required to calculate the reduction potential, electron affinity and/or C-Cl bond dissociation energy, were computed at both DFT-D and CCSD(T)-F12 levels. Comparison of the obtained gas-phase energies and redox potentials with experiment enabled us to verify the relative energetics and the performance of various implicit solvent models. Good agreement with the experiment was achieved for redox potentials computed at the DFT-D level, but only for the stepwise mechanism owing to the error compensation. For the concerted electron transfer/C-Cl bond cleavage process, the application of a high level coupled cluster method is required. Quantum chemical calculations have also demonstrated the significant role of the pi*ring and sigma*C-Cl orbital mixing. It brings about the stabilisation of the non-planar, C2v-symmetric C6Cl6( ) radical anion, explains the experimentally observed low energy barrier and the transfer coefficient close to 0.5 for C6Cl5OCH3 in an electron transfer process followed by immediate C-Cl bond cleavage in solution, and an increase in the probability of dechlorination of di- and trichlorophenoxyacetic acids due to substantial population of the vibrational excited states corresponding to the out of-plane C-Cl bending at ambient temperatures. PMID- 27477336 TI - Informal pre-exposure prophylaxis use in France: results from the Flash PrEP survey (2014). PMID- 27477335 TI - Metallothionein Prevents Age-Associated Cardiomyopathy via Inhibiting NF-kappaB Pathway Activation and Associated Nitrative Damage to 2-OGD. AB - AIMS: Cardiac-specific metallothionein (MT) overexpression extends lifespan, but the mechanism underlying the effect of MT protection against age-associated cardiovascular diseases (CVD) remains elusive. To elucidate this, male wild-type and two lines of MT-transgenic (MT-TG) mice, MM and MT-1 (cardiac-specific overexpressing MT about 10- and 80-fold, respectively) at three representative ages (2-3, 9-10, and 18-20 months), were utilized. A stable human MT2A overexpressing cardiomyocytes (H9c2MT7) was also introduced. RESULTS: Histomorphology and echocardiographic analysis revealed that age-associated cardiac hypertrophy, remodeling, and dysfunction were ameliorated in MT-TG mice. Also, aging-accompanied NF-kappaB activation, characterized by increased nuclear p65 translocation, elevated DNA-binding activity, and upregulation of inflammatory cytokines, was largely attenuated by MT overexpression. Treatment of H9c2 cardiomyocytes with tumor necrosis factor-alpha (TNF-alpha), which mimicked an inflammatory environment, significantly increased NF-kappaB activity, and some age-related phenotypes appeared. The NF-kappaB activation was further proved to be pivotal for both age-associated and TNF-alpha-induced nitrative damage to cardiac 2-oxoglutarate dehydrogenase (2-OGD) by virtue of NF-kappaB p65 gene silencing. MT inhibited NF-kappaB activation and associated nitrative damage to cardiac 2-OGD in both old MT-TG hearts and TNF-alpha-treated H9c2MT7 cardiomyocytes; these protective effects were abolished in H9c2MT7 cardiomyocytes by MT-specific gene silencing. Innovation and Conclusion: Together, these findings indicate that the protective effects of MT against age-associated CVD can be attributed mainly to its role in NF-kappaB inhibition and resultant alleviation of nitrative damage to 2-OGD. Antioxid. Redox Signal. 25, 936-952. PMID- 27477337 TI - Naltrexone/Bupropion extended release-induced weight loss is independent of nausea in subjects without diabetes. AB - Naltrexone/bupropion extended release (NB) is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of >=30 or >=27 kg m(-2) and >=1 weight-related comorbidity (e.g. hypertension, type 2 diabetes and dyslipidaemia). In phase 3 clinical studies, nausea occurred in significantly higher proportions of subjects randomized to NB vs. placebo (PBO). In this pooled analysis of three phase 3, 56-week, PBO-controlled studies, we characterized nausea and weight loss in NB- and PBO-treated subjects without diabetes. Subjects receiving NB (n = 1778) lost significantly more weight than those receiving PBO (n = 1160). Weight change was not significantly different between subjects reporting and not reporting nausea in either treatment arm. Severity of nausea was mild to moderate in >=95% of all cases. In the NB arm, the highest incidence of nausea onset (9%) was reported during week 1. The median duration of mild, moderate and severe nausea in subjects receiving NB was 14, 9 and 13 days, respectively. Our results demonstrate that nausea associated with NB is rarely severe, primarily occurs early in treatment and is not a contributor to weight loss. PMID- 27477339 TI - Fecal Immunochemical Testing: A Sensitive and Sustainable Approach for Population Colorectal Cancer Screening? PMID- 27477338 TI - Expanding the genetic code of Escherichia coli with phosphotyrosine. AB - Protein phosphorylation is one of the most important post-translational modifications in nature. However, the site-specific incorporation of O phosphotyrosine into proteins in vivo has not yet been reported. Endogenous phosphatases present in cells can dephosphorylate phosphotyrosine as a free amino acid or as a protein residue. Therefore, we deleted the genes of five phosphatases from the genome of Escherichia coli with the aim of stabilizing phosphotyrosine. Together with an engineered aminoacyl-tRNA synthetase (derived from Methanocaldococcus jannaschii tyrosyl-tRNA synthetase) and an elongation factor Tu variant, we were able to cotranslationally incorporate O phosphotyrosine into the superfolder green fluorescent protein at a desired position in vivo. This system will facilitate future studies of tyrosine phosphorylation. PMID- 27477340 TI - Estimating negative binomial parameters from occurrence data with detection times. AB - The negative binomial distribution is a common model for the analysis of count data in biology and ecology. In many applications, we may not observe the complete frequency count in a quadrat but only that a species occurred in the quadrat. If only occurrence data are available then the two parameters of the negative binomial distribution, the aggregation index and the mean, are not identifiable. This can be overcome by data augmentation or through modeling the dependence between quadrat occupancies. Here, we propose to record the (first) detection time while collecting occurrence data in a quadrat. We show that under what we call proportionate sampling, where the time to survey a region is proportional to the area of the region, that both negative binomial parameters are estimable. When the mean parameter is larger than two, our proposed approach is more efficient than the data augmentation method developed by Solow and Smith (, Am. Nat. 176, 96-98), and in general is cheaper to conduct. We also investigate the effect of misidentification when collecting negative binomially distributed data, and conclude that, in general, the effect can be simply adjusted for provided that the mean and variance of misidentification probabilities are known. The results are demonstrated in a simulation study and illustrated in several real examples. PMID- 27477341 TI - 2015 Arthur O. Lovejoy Lecture The Boys on the Beach: Children's Games and Baptismal Grace in Medieval Thought. AB - This paper tracks the fortunes of the debate on whether children playing at baptism can actually administer and receive a valid sacramental baptism from Rufinus of Aquileia (late 4th to early 5th century) through ca. 1300. Theologians and canonists who addressed this question arrived at no consensus. They often disagreed with their own masters, applied Rufinus to a range of issues he never took up, used him to support or criticize Augustine on this topic, and viewed as acceptable more than one position on it within orthodox Christianity. PMID- 27477342 TI - Democritus Junior as Reader of Auctoritates: Robert Burton's Method and The Anatomy of Melancholy. AB - This essay analyzes Robert Burton's methodological approach to the subject of melancholy and draws comparisons between Burton's method of inquiry and the 17th century scientific method at large. Burton's sources are hence examined and two epistemological lines of influence are singled out, one being characterized by deductive procedures (Galen, Ramus), and the other by inductivism (Hippocrates, pseudo-Hippocratic representation of Democritus). Combined by Burton, these traditions inspired the structure of Burton's Anatomy, which allowed the concurrence of multiple opinions that mutually interact and automatically correct one another within a cento-like text. PMID- 27477343 TI - John Punch, Scotist Holy War, and the Irish Catholic Revolutionary Tradition in the Seventeenth Century. AB - During the 1640s, the Irish Franciscan theologian John Punch taught his theology students in Rome that war against Protestants was made just by their religion alone. Jesuits like Luis de Molina identified the holy war tradition in which Punch stood as a Scotist one, and insisted that the Scotists had confused the natural and supernatural spheres. Among Irishmen, Punch was unusual. The main Irish Catholic revolutionary tradition employed Jesuit and Thomist theory. They argued that the Stuarts had lost the right to rule Ireland for natural reasons, not supernatural ones; because the Stuarts were tyrants, not because they were Protestants. PMID- 27477344 TI - Pufendorf on Passions and Sociability. AB - Samuel Pufendorf is known for his normative natural law philosophy, and particularly for his theory of sociability. This article concentrates on a topic that has received very little attention - his theory of the motivating character of passions in social life. It will demonstrate that individually and politically governed passions play a central role in Pufendorf's description of the structure of human societies. I argue that for Pufendorf the norms of sociability are effective in social life because social interaction, guided by political governance, enables people to moderate their antisocial passions and habituate themselves to sociable passions. PMID- 27477345 TI - Free Will, Predestination, and the Fate of the Ottoman Empire. AB - Although European travelers to the Ottoman Empire often noted the inhabitants' "fatalism," historians have never seriously examined this intellectual phenomenon. Whether or not we can credit such sources, the testimony of seventeenth-and eighteenth-century Turkish and Arabic sources points to a robust debate over fate, free will, and predestination. What were the reasons behind these discussions? What issues were at stake? This article outlines the context and content of the debate. It then offers some observations about the wider significance of free will and predestination in the Ottoman intellectual universe - particularly their relation to early modern bureaucratic and military reform. PMID- 27477346 TI - Bergson's Philosophy of Will and the War of 1914-1918. AB - In his wartime discourses of 1914, Henri Bergson mobilizes his philosophy of creative evolution: France is a nation of creative life able to replenish itself, whereas Germany, for all its technological might, is a mechanistic power bound to wear itself out. This paper shows that this moblization is made possible by Bergson's philosophy of will: life as a creative principle is will, and it is a controllable and commandable willpower that he opposes to Germany. Grasping this is crucial for understanding not only the war discourses but also Bergson's later reflections on technology, modernity, and mysticism. PMID- 27477347 TI - Wheeler and Whitehead: Process Biology and Process Philosophy in the Early Twentieth Century. AB - The case of William Morton Wheeler and Alfred North Whitehead represents a striking example of how biologists and philosophers engaged in a common enterprise in the early twentieth century. Both challenge the notion that the living world is composed of distinct organisms. Based on his studies of the behavior of social insects, Wheeler developed a concept of superorganisms that paved the way for a theory of emergent evolution. This paper argues that Whitehead, whose relation to academic biology has been largely ignored, drew on Wheeler's findings and integrated them into a universal philosophical cosmology. PMID- 27477350 TI - Evaluation of the role of risk perception in stakeholder engagement to prevent lead exposure in an urban setting. AB - Stakeholder engagement is a vital sustainable remediation practice for obtaining useful feedback and identifying societal needs. Evaluating and integrating risk perception of stakeholders into remediation and outreach efforts allows for greater insight, increases the likelihood of success and ultimately, benefits the community by protecting its members from environmental hazards. In this study, we identified risk perception factors that influenced residents' level of concern for mitigating their exposure to elevated concentrations of lead in household paint and historic fill material. Risk perception factors were assessed by an in person survey conducted in public green spaces. The analysis of survey participants' responses indicated that their perception of risk to exposed lead was mostly influenced by the presence of hazardous materials in close proximity to their residence, the ability to address pollution, and awareness, interest, and individual accountability in mitigating environmental risks. Responses also revealed that residents considered risk of lead and soil pollution as less menacing than the presence of more immediate and perceptible risks posed by factors such as air and water pollution. In addition, the community seemed to exhibit "optimism bias" and did not identify itself at high risk to susceptible and immediate hazards, including lead exposure. This lack of concern over lead exposure created a significant obstacle to community participation in state-led education and outreach programs. By integrating risk perception analysis and increasing stakeholder engagement, we can bring more attention to this issue, educate the public about the threat of lead pollution, and efficiently use financial resources to implement a more sustainable solution. PMID- 27477351 TI - Vitamin D2 suppresses amyloid-beta 25-35 induced microglial activation in BV2 cells by blocking the NF-kappaB inflammatory signaling pathway. AB - AIMS: Present emerging world is emphasizing the implication of vitamin D deficiency associated with development of inflammation and neurodegenerative disorder like Alzheimer's disease (AD). The chief neuropathological hallmark of AD is aggregation of amyloid-beta (Abeta) peptides surrounding microglial cells in human brain. Microglial activation plays a key role in inflammatory response and neuronal injury. Naturally abundant vitamin D2 (VD2) exhibiting anti inflammatory activities are yet to explore more. This study has investigated the inhibitory effect of VD2 on inflammatory activities of BV2 microglial cells. MAIN METHODS: Cellular compatibility of VD2 and Abeta25-35 protein in treated BV2 microglial cells were measured by CCK-8 assay. Induction of iNOS, COX-2 and NF kappaB signaling cascade were measured by western blotting, whereas pro inflammatory cytokines were measured by ELISA. In addition, generation of ROS was detected by fluorescence intensity. KEY FINDINGS: Morphological observations showed that Abeta25-35 induced BV2 cells stimulation noticeably got reduced in VD2 pre-treated group at 24h time period. Anti-inflammatory activities of VD2 was observed demonstrating the inhibition of up-regulated iNOS and COX-2 protein expression further confirmed by attenuating the activated microglia released pro inflammatory cytokines IL-1beta, IL-6, TNF- alpha and ROS, while blocking the phosphorylation of NF-kappaB p65 in nucleus by preventing IkappaB-alpha degradation and phosphorylation in cytosol. SIGNIFICANCE: The present study revealed that VD2 blocked the phosphorylation of NF-kappaB inflammatory signaling pathway in Abeta25-35 induced activated BV2 microglial cells by suppressing ROS generation and inflammatory cytokines. Our finding suggests that vitamin D2 has therapeutic potential against inflammation and Alzheimer's disease. PMID- 27477352 TI - Radotinib inhibits acute myeloid leukemia cell proliferation via induction of mitochondrial-dependent apoptosis and CDK inhibitors. AB - Radotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the second-line treatment of chronic myeloid leukemia. However, effects of radotinib on acute myeloid leukemia (AML) are unclear. In the present study, we observed that radotinib exerted cytotoxic effects on AML cells. Of the various AML cell lines examined (NB4, HL60, HEL 92.1.7, and THP-1), Kasumi-1 was the most sensitive to radotinib. Results of microarray analysis showed that 417 and 595 genes associated with apoptosis and cell cycle regulation, respectively, were differently expressed (i.e., showed >2-fold difference in expression). Radotinib induced apoptosis involved the mitochondrial pathway. Moreover, radotinib increased the apoptosis of and induced caspase-3 activity in both Kasumi-1 cells and bone marrow cells (BMCs) obtained from patients with AML. Radotinib also increased cleaved caspase-3, caspase-7, and caspase-9 levels and decreased the number of proliferating Kasumi-1 cells and BMCs from patients with AML. In addition, radotinib induced G0/G1 phase arrest by inducing CDKIs p21 and p27 and by inhibiting CDK2, CDK4, and CDK6. These results indicate that radotinib induces caspase-dependent apoptosis and G0/G1 phase arrest in AML cells by regulating CDKI-CDK-cyclin cascade. Moreover, these results indicate that radotinib inhibits AML cell proliferation by inducing mitochondria-dependent apoptosis and CDKIs p21 and p27. To our knowledge, this is the first study to show that radotinib can be potentially used for the anti-leukemic therapy of patients with AML. PMID- 27477353 TI - Taraxasterol inhibits cigarette smoke-induced lung inflammation by inhibiting reactive oxygen species-induced TLR4 trafficking to lipid rafts. AB - Taraxasterol, a pentacyclic-triterpene isolated from Taraxacum officinale, has been demonstrated to have anti-inflammatory effects. However, the protective effects of taraxasterol against cigarette smoke (CS)-induced lung inflammation have not been reported. This study aimed to investigate the protective effects and mechanism of taraxasterol on CS-induced lung inflammation in mice. CS-induced mouse lung inflammation model was used to investigate the protective effects of taraxasterol in vivo. Human bronchial epithelial cells (HBECs) were used to investigate the protective mechanism of taraxasterol in vitro. The results showed that taraxasterol attenuated CS-induced lung pathological changes, inflammatory cells infiltration, inflammatory cytokines TNF-alpha, IL-6 and IL-1beta production. Taraxasterol also up-regulated CS-induced glutathione (GSH) production. In vitro, taraxasterol was found to inhibit CS-induced reactive oxygen species production, recruitment of TLR4 into lipid rafts, NF-kappaB activation, and IL-8 production. Furthermore, our results showed that antioxidant N-acetyl-L-cysteine (NAC) significantly inhibited CS-induced recruitment of TLR4 into lipid rafts as well as IL-8 production. In conclusion, our results suggested that taraxasterol had protective effects of CS-induced lung inflammation. PMID- 27477354 TI - Activin A stimulates the proliferation and differentiation of cardiac fibroblasts via the ERK1/2 and p38-MAPK pathways. AB - Activin A is a key regulator of cardiac fibrosis. However, little is known about the mechanisms by which it contributes to cardiac fibrosis. Our study explored the effects of activin A on proliferation and differentiation of adult rat cardiac fibroblasts (CFs) via the activin A receptor, activin receptor-like kinase 4 (ALK4). CF proliferation was measured by CCK8 and EdU assays, while differentiation, fibrosis and signaling were measured by western blot analysis of alpha-smooth muscle actin, collagen type I, phosphorylated extracellular signal regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (p38-MAPK) expression. Activin A levels were measured by ELISA and western blot analysis. We demonstrated that CFs express activin A and its expression was significantly enhanced by angiotensin II (Ang II), but follistatin (activin A inhibitor) significantly reversed Ang II-induced activin A upregulation, CF proliferation, differentiation, collagen type I expression as well as ERK1/2 and p38-MAPK pathways activation. Conversely, recombinant activin A largely increased these parameters in both the presence and absence of Ang II. Interestingly, p38-MAPK (SB203580) and ALK4 (SB431542) inhibitors significantly reduced all activin A mediated responses; however, an ERK1/2 inhibitor (PD98059) could only significantly reduce CF proliferation and collagen type I expression but not differentiation. Importantly, the most significant effects were observed in the presence vs. absence of Ang II. Thus, activin A promotes basal and Ang II-induced CF proliferation and differentiation via ALK4, and the effects are partly mediated through the ERK1/2 and p38-MAPK pathways. These data suggest that activin A is a potential therapeutic target for cardiac fibrosis. PMID- 27477355 TI - The vitamin D receptor agonist, calcipotriol, modulates fibrogenic pathways mitigating liver fibrosis in-vivo: An experimental study. AB - Vitamin D was found to be involved in liver fibrosis modulation through binding to its receptor (VDR) halting many fibrotic pathways. Targeting vitamin D-VDR axis using vitamin D analogs may represent an efficient strategy for liver fibrosis treatment . The study aims at testing the potential ability of the VDR agonist, calcipotriol, to stop fibrosis progression and/or regeneration of hepatocytes in an experimental model of liver fibrosis. Mice (CD-1) were injected with thioacetamide (TAA, 100mg/kg, i.p., 3 times/week) for 8 weeks to induce fibrosis and were treated with calcipotriol (20, 60 or 80ug/kg, i.p., daily) concurrently with TAA during the last 4 weeks. Liver function and oxidative stress biomarkers were measured by the end of the study and hepatic sections were examined for inflammation, necrosis and fibrosis percentage. Additionally, liver contents of collagen-1-alpha-1 (COL1a1), transforming growth factor (TGF)-beta1 and phospho-Smad2 (Ser456/467)/Smad3 (Ser423/425) were measured. Finally, expression of TGF-beta1, tissue inhibitor metalloproteinase (TIMP)-1, Smad2/3 and Smad1/5/9 were scored using immunohistochemistry techniques. Mainly, calcipotriol (80ug/kg) significantly (P<0.001) reduced fibrosis percentage and improved TAA effect on transaminases, alkaline phosphatase, COL1a1 level, malondialdehyde, albumin and reduced glutathione (GSH). It also decreased the profibrogenic cytokine TGF-beta1, TIMP-1, Smad2/3, Smad1/5/9 and phospoSmad2/3 significantly (P<0.01) when compared to TAA group. Calcipotriol attenuates TAA induced liver fibrosis and can stop its progression through limiting stellate cells activity by decreasing TGF-beta1 level and modulating TGF-beta1/Smad signaling pathway. It also can help fibrolysis through decreasing TIMP-1 and restoring the balance between metalloproteinases and their inhibitors. PMID- 27477356 TI - Cliff Dive or Slippery Slope: Trajectories of Kidney Function Decline and Implications for Survival After Hemodialysis Initiation. PMID- 27477357 TI - Reconciling and Closing the Loop Between Evidence-Based and Practice-Based Medicine: The Case for Hemodiafiltration. PMID- 27477358 TI - Hemodialysis Prescription for Incident Patients: Twice Seems Nice, But Is It Incremental? PMID- 27477359 TI - Retraction Notice to "Kidney Function and Rate of Bone Loss at the Hip and Spine: The Canadian Multicentre Osteoporosis Study" [Am J Kidney Dis. 55(2):291-299]. PMID- 27477360 TI - Cause Unknown, Treatment Uncertain, Outcome Poor: An Encounter With Kidney Failure in the Developing World. PMID- 27477361 TI - Quiz Page August 2016: Skin Lesions in a Dialysis Patient. PMID- 27477362 TI - AJKD Atlas of Renal Pathology: Subacute Bacterial Endocarditis-Associated Glomerulonephritis. PMID- 27477363 TI - AJKD Atlas of Renal Pathology: HIV-Associated Nephropathy (HIVAN). PMID- 27477364 TI - AJKD Atlas of Renal Pathology: HIV-Associated Immune Complex Kidney Disease (HIVICK). PMID- 27477365 TI - Joint society statement for the elimination of viral hepatitis. PMID- 27477366 TI - From the Editor: Biology and culture. PMID- 27477367 TI - Guest Editorial: Equity in sexual and reproductive health - an ongoing challenge. PMID- 27477368 TI - A proposed Primary Health Early Warning Score (PHEWS) with emphasis on early detection of sepsis in the elderly. AB - There are several secondary care early warning scores which alert for severe illness including sepsis. None are specifically adjusted for primary care. A Primary Health Early Warning Score (PHEWS) is proposed which incorporates practical parameters from both secondary and primary care. PMID- 27477369 TI - New Zealand needs a Practice Based Research Network. AB - Practice Based Research Networks (PBRNs) are groups of general practices collaborating to produce research. Contemporary New Zealand health information technology systems are ideal for electronic data extraction for PBRN research. Stakeholders have a valuable, but typically underutilised, part to play in research. Development of an e-participation platform will facilitate stakeholder engagement. New Zealand is in a unique position to create an innovative, low cost, stakeholder-engaged PBRN. This type of PBRN would offer unparalleled research opportunities, and would strengthen New Zealand's general practice research capacity. The more research information we have based on our New Zealand population, the more appropriate care we can provide. Establishing a stakeholder engaged PBRN in New Zealand will promote and support transformational change within our health system. PMID- 27477370 TI - New Zealand women's experience during their first year of Jadelle(r) contraceptive implant. AB - INTRODUCTION Subsidisation of the levonorgestrel-releasing Jadelle(r) contraceptive implant in 2010 resulted in a rapid uptake. Clinicians had little prior experience of client satisfaction, side effect profile, and removal rate of this contraceptive method. AIM To obtain information on satisfaction, bleeding patterns, continuation rates and reasons for removal for New Zealand women during their first year of use of a subsidised contraceptive implant, Jadelle(r). METHODS Women having a Jadelle(r) implant inserted in New Zealand Family Planning clinics were recruited to be followed up by phone, text or email at 1, 3, 6, 9 and 12 months. They were asked about their bleeding pattern, satisfaction and their views on benefits of, or problems with, implant use. RESULTS 252 women were recruited. The three common bleeding patterns in the cohort were regular periods, amenorrhoea and irregular bleeding. Eighteen percent had their implant removed within the first year with more than half of those being unhappy with their bleeding pattern. This was usually prolonged bleeding. Otherwise satisfaction rates were high throughout the year. DISCUSSION The majority of New Zealand women using Jadelle(r) were satisfied with this method of contraception during their first year of use. Implant removals were most likely to be related to prolonged bleeding. However the commonest bleeding pattern was regular periods. KEYWORDS Contraceptive implant; progestin; bleeding; satisfaction; continuation rate; reducing reproductive health inequalities. PMID- 27477371 TI - International sore throat guidelines and international medical graduates: a mixed methods systematic review. AB - AIM To examine national and international guidelines on sore throat management and subsequently, to explore the phenomenon of international medical graduates working in general and rural practice in New Zealand. METHOD Two separate systematic reviews were conducted that resulted in a contingent methodology. Contingent methodologies involve syntheses of data that are derived sequentially. The initial review for this study examined international sore throat guidelines and their key points. The results of this initial review resulted in the theory that international medical graduates may be unaware of the New Zealand specific sore throat guidelines and the problem of acute rheumatic fever in this country. The subsequent review examined the phenomenon of international medical graduates working in general or rural practice in New Zealand. Data sources were Medline, Google Scholar, Trip Database, and NHS Evidence, Embase and Scopus. Electronic databases were searched for relevant data published January 2000-December 2013. Additional hand searches found key references from articles and websites. RESULTS International guidelines for the management of sore throats differ from New Zealand guidelines. Of resource rich countries, New Zealand has the second highest number of international medical graduates: they may not use New Zealand specific sore throat guidelines. DISCUSSION Acute rheumatic fever is virtually eradicated in most resource rich countries. Rheumatic fever rates of among indigenous Maori and Pacifika people in New Zealand have failed to reduce over the last three decades. Knowledge and actions of international medical graduates in relation to sore throat management needs investigating. KEYWORDS Sore throats; acute rheumatic fever; clinical guidelines; international medical graduates; mixed methods review. PMID- 27477372 TI - Sunscreen compliance with regional clinical practice guidelines and product labeling standards in New Zealand. AB - INTRODUCTION For general practitioners, practice nurses and community pharmacists in New Zealand, a core duty is to educate patients about sun protection. We aimed to evaluate compliance of locally available sunscreens with regional clinical practice guidelines and sunscreen labelling standards, to assist clinicians in advising consumers on sunscreen selection. METHODS We audited all sunscreens available at two Auckland stores for three New Zealand sunscreen retailers. We then assessed compliance with accepted regional clinical practice guidelines for sun protection from the New Zealand Guidelines Group. We further assessed compliance with regional Australia/New Zealand consumer standards for sunscreen labelling. RESULTS All sunscreens satisfied clinical guidelines for broad spectrum protection, and 99% of sunscreens met or exceeded clinical guidelines for minimal Sun Protection Factor. Compliance with regional standardized labelling guidelines is voluntary in New Zealand and 27% of audited sunscreens were not fully compliant with SPF labelling standards. DISCUSSION Sunscreens were generally compliant with clinical guidelines for minimal sun protection. However there was substantial noncompliance with regional recommendations for standardized sunscreen labelling. Primary health care clinicians should be aware that this labelling noncompliance may mislead patients into thinking some sunscreens offer more sun protection than they do. Mandatory compliance with the latest regional labelling standards would simplify sunscreen selection by New Zealand consumers. KEYWORDS Sunscreen; Sun Protection Factor; SPF; Skin Neoplasms; Melanoma; Skin Cancer Prevention. PMID- 27477374 TI - Shoulder pain in primary care: frozen shoulder. AB - BACKGROUND AND CONTEXT Frozen shoulder is a painful condition that follows a protracted clinical course. We aim to review the management of patients with a diagnosis of frozen shoulder who are referred for specialist orthopaedic evaluation against existing guidelines in primary care. ASSESSMENT OF PROBLEM Referrals and clinical records were reviewed for all patients referred for orthopaedic specialist assessment who received a specialist diagnosis of frozen shoulder. Diagnostic, investigation and management practices from a regional primary health care setting in New Zealand were compared with guideline recommended management. RESULTS Eighty patients with frozen shoulder were referred for orthopaedic evaluation in the 13 month study period, mostly from general practice. Fifteen patients (19%) were identified as having a frozen shoulder in their medical referral. Most (99%) had received previous imaging. Seven patients (12%) had received guideline recommended treatment. STRATEGIES FOR IMPROVEMENT Education of all clinicians involved in patient management is important to ensure an understanding of the long natural history of frozen shoulder and provide reassurance that outcomes are generally excellent. HealthPathways now include more information regarding diagnosis, imaging and evidence-based management for frozen shoulder. LESSONS Frozen shoulder may be under-diagnosed among patients referred for orthopaedic review. Ultrasound imaging is commonly used and may identify occult and unrelated pathology in this age-group. When managed according to clinical guidelines, patients report significant clinical and functional improvement with most reporting 80% function compared with normal after 1 year. KEYWORDS Adhesive capsulitis; bursitis; injections; practice guideline; primary health care; ultrasound. PMID- 27477373 TI - Stakeholder views on factors influencing the wellbeing and health sector engagement of young Asian New Zealanders. AB - INTRODUCTION In New Zealand, while the term 'Asians' in popular discourse means East and South-east Asian peoples, Statistics New Zealand's definition includes people of many nationalities from East, South and South-east Asia, all with quite different cultural norms, taboos and degrees of conservatism. In a context where 'Asian' youth data are typically presented in aggregate form, there are notable gaps in knowledge regarding the contextual determinants of health in this highly heterogeneous group. This qualitative study explored key stakeholder views on issues that would be most useful to explore on the health and wellbeing of Asian youth and processes that would foster engagement of Asian youth in health research. METHODS Interviews were conducted with six key stakeholders whose professional activities were largely focused on the wellbeing of Asian people. The general inductive approach was used to identify and analyse themes in the qualitative text data. FINDINGS Six broad themes were identified from the key stakeholder interviews framed as priority areas that need further exploration: cultural identity, integration and acculturation; barriers to help-seeking; aspects to consider when engaging Asian youth in research (youth voice, empowerment and participatory approach to research); parental influence and involvement in health research; confidentiality and anonymity; and capacity building and informing policy. CONCLUSION With stakeholders strongly advocating the engagement of Asian youth in the health research agenda this study highlights the importance of engaging youth alongside service providers to collaborate on research and co-design responsive primary health care services in a multicultural setting. KEYWORDS Asian youth; New Zealand; health research; minority health; Community and social participation. PMID- 27477375 TI - Pounamu: E Hine: access to contraception for indigenous Maori teenage mothers. AB - INTRODUCTION Timely and equitable access to contraception enables teenage mothers to make informed choices about their sexual and reproductive health. This study aimed to identify barriers and facilitators to contraception for Maori teenagers who become mothers. METHODS 'E Hine' is a longitudinal qualitative Kaupapa Maori (by Maori for Maori) study involving Maori women (aged 14-19 years), following them through pregnancy (n = 44) and the birth of their babies until their babies' first birthdays (n = 41). This analysis focusses on contraception access pre-and post-pregnancy. FINDINGS Pre-pregnancy most participants accessed contraception or advice. Contraception use was compromised by a lack of information, negative side effects, and limited follow up. All reported their subsequent pregnancies as unplanned. Participants gave considerable thought to post-pregnancy contraception. Despite this many experienced clinical and service delays, financial barriers, and negative contraceptive side effects. There was little focus on contraception initiation and a lack of integrated care between midwives and other primary care services, leaving many participants without timely effective contraception. The system worked well when there was a contraception plan that included navigation, free access, and provision of contraception. CONCLUSION The majority of participants actively sought contraception pre- and post-conception. Despite a publicly funded system, a lack of health sector integration resulted in multiple missed opportunities to meet the needs of these teenagers for effective contraception. Health service funding formulas should define the goal as initiation of contraception rather than advice and provide funding to improve timely access to long acting reversible contraception. KEYWORDS Indigenous teenage pregnancy; contraception; barriers to contraception; Maori mothers. PMID- 27477376 TI - Pounamu: Integration of kaupapa Maori concepts in health research: a way forward for Maori cardiovascular health? PMID- 27477377 TI - Vaikoloa: Understanding depression in Tokelauan people in New Zealand. AB - BACKGROUND The Tokelauan language lacks a word for 'depression' and this can make diagnosing and treating depression in Tokelauan patients difficult for general practitioners. AIMS To describe the experience of depression in Tokelauans and thereby assist diagnosis and treatment of the illness. METHOD Ten semi-structured in-depth interviews were conducted. The transcripts were thematically analysed using an immersion crystallisation technique. RESULTS An illness involving profound sadness exists in the Tokelauan culture. Tokelauans recognise isolation and withdrawal from family and community activities as indicators of extreme sadness. Privacy and pride are important cultural characteristics, which may be barriers to recognising sadness. Often the smiling Tokelauan face becomes the mask hiding sadness. CONCLUSION This research demonstrates the complexity of relationships between patients, their illness and their culture, that impacts on how depression manifests. This research indicates that therapy must have a whole person approach involving family, church, community and patients' spiritual beliefs. KEYWORDS Depression; Pacific health. PMID- 27477379 TI - Cochrane Corner: Will increasing the amount of fibre in your diet help prevent cardiovascular disease? PMID- 27477378 TI - Ethics support for GPs: what should it look like? AB - INTRODUCTION Ethics support services for hospital clinicians have become increasingly common globally but not as yet in New Zealand. However, an initiative to change this is gathering momentum. Its slogan 'Clinical ethics is everyone's business' indicates that the aim is to encompass all of health care, not just the hospital sector. General Practitioners (GPs) deal with ethical issues on a daily basis. These issues are often quite different from ethical issues in hospitals. To make future ethics support relevant for primary care, local GPs were interviewed to find out how they might envisage ethics support services that could be useful to them. METHODS A focus group interview with six GPs and semi-structured individual interviews with three GPs were conducted. Questions included how they made decisions on ethical issues at present, what they perceived as obstacles to ethical reflection and decision-making, and what support might be helpful. FINDINGS Three areas of ethics support were considered potentially useful: Formal ethics education during GP training, access to an ethicist for assistance with analysing an ethical issue, and professional guidance with structured ethics conversations in peer groups. CONCLUSION The complex nature of general practice requires GPs to be well educated and supported for handling ethical issues. The findings from this study could serve as input to the development of ethics support services. KEYWORDS General practice; primary care; ethics; support; education. PMID- 27477380 TI - Nuggets of Knowledge: COPD - targeting the use of inhaled corticosteroids. PMID- 27477381 TI - Ageing positively. PMID- 27477382 TI - Not Our Problem - Ian Cowan. PMID- 27477384 TI - Microvillus inclusion disease: a subtotal enterectomy as a bridge to transplantation. AB - BACKGROUND: Microvillus inclusion disease (MVID) is a known congenital cause of intractable diarrhea resulting in permanent intestinal failure. There is need for a lifelong total parenteral nutrition (TPN) from diagnosis and the prognosis is poor. Most patients die by the second decade of life as a result of complications of parenteral alimentation including liver failure or sepsis. The only available treatment at this moment is a small bowel transplantation. But before that moment, the patients often suffer from a persistent failure to thrive and electrolyte disturbances despite continuous TPN. METHODS AND RESULTS: We report what we believe is a first case of an extensive small bowel resection in a 5 month-old boy with proven MVID to act as a bridge to (liver-) intestinal transplantation to treat failure to thrive and intractable diarrhea. CONCLUSIONS: An extensive small bowel resection can be done to enhance the chance of survival leading up to the transplantation by managing fluid and electrolyte imbalance. It facilitates medical management of these patients and makes a bowel transplantation possible at a later stage. PMID- 27477386 TI - The Human Centriolar Protein CEP135 Contains a Two-Stranded Coiled-Coil Domain Critical for Microtubule Binding. AB - Centrioles are microtubule-based structures that play important roles notably in cell division and cilium biogenesis. CEP135/Bld10p family members are evolutionarily conserved microtubule-binding proteins important for centriole formation. Here, we analyzed in detail the microtubule-binding activity of human CEP135 (HsCEP135). X-ray crystallography and small-angle X-ray scattering in combination with molecular modeling revealed that the 158 N-terminal residues of HsCEP135 (HsCEP135-N) form a parallel two-stranded coiled-coil structure. Biochemical, cryo-electron, and fluorescence microscopy analyses revealed that in vitro HsCEP135-N interacts with tubulin, protofilaments, and microtubules and induces the formation of microtubule bundles. We further identified a 13 amino acid segment spanning residues 96-108, which represents a major microtubule binding site in HsCEP135-N. Within this segment, we identified a cluster of three lysine residues that contribute to the microtubule bundling activity of HsCEP135 N. Our results provide the first structural information on CEP135/Bld10p proteins and offer insights into their microtubule-binding mechanism. PMID- 27477385 TI - Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies. AB - Antibody somatic hypermutation (SHM) and affinity maturation enhance antigen recognition by modifying antibody paratope structure to improve its complementarity with the target epitope. SHM-induced changes in paratope dynamics may also contribute to antibody maturation, but direct evidence of this is limited. Here, we examine two classes of HIV-1 broadly neutralizing antibodies (bNAbs) for SHM-induced changes in structure and dynamics, and delineate the effects of these changes on interactions with the HIV-1 envelope glycoprotein (Env). In combination with new and existing structures of unmutated and affinity matured antibody Fab fragments, we used hydrogen/deuterium exchange with mass spectrometry to directly measure Fab structural dynamics. Changes in antibody structure and dynamics were positioned to improve complementarity with Env, with changes in dynamics primarily observed at the paratope peripheries. We conclude that SHM optimizes paratope complementarity to conserved HIV-1 epitopes and restricts the mobility of paratope-peripheral residues to minimize clashes with variable features on HIV-1 Env. PMID- 27477387 TI - A global meta-analysis of soil phosphorus dynamics after afforestation. AB - Afforestation significantly affects soil chemistry and biota, but its effects on the potentially growth-limiting nutrient phosphorus (P) had not to our knowledge been analyzed globally. We conducted a comprehensive meta-analysis of 220 independent sampling sites from 108 articles to evaluate global patterns and controls of soil P change following afforestation. Overall, total P concentration decreased by 11% and total P stock by 12% in the top 20 cm of mineral soil following afforestation, with no change in available P. Time since afforestation had no consistent effect on total P, while available P tended to increase with time. Prior land cover was the most influential factor for soil P change after afforestation, with available P increasing on native vegetation but decreasing on cropland. Afforestation increased available P by 22% without decreasing total P on formerly 'degraded' land, but depleted total P by 15% at nondegraded sites. Climate also influenced soil P response to afforestation, with larger P loss in the tropics. Afforestation did not appear to directly induce P limitation, as available P only decreased on cropland. However, substantial declines in total P may drive tropical plantations toward greater P limitation as the capacity to replenish available P decreases. PMID- 27477388 TI - High-throughput acoustic separation of platelets from whole blood. AB - Platelets contain growth factors which are important in biomedical and clinical applications. In this work, we present an acoustic separation device for high throughput, non-invasive platelet isolation. In particular, we separated platelets from whole blood at a 10 mL min(-1) throughput, which is three orders of magnitude greater than that of existing acoustic-based platelet separation techniques. Without sample dilution, we observed more than 80% RBC/WBC removal and platelet recovery. High throughput, high separation efficiency, and biocompatibility make this device useful for many clinical applications. PMID- 27477390 TI - Adsorption of alkanes on stoichiometric and oxygen-rich RuO2(110). AB - We investigated the molecular adsorption of methane, ethane, propane and n-butane on stoichiometric and oxygen-rich RuO2(110) surfaces using temperature-programmed desorption (TPD) and dispersion-corrected density functional theory (DFT-D3) calculations. We find that each alkane adsorbs strongly on the coordinatively unsaturated Ru (Rucus) atoms of s-RuO2(110), with desorption from this state producing a well-defined TPD peak at low alkane coverage. As the coverage increases, we find that alkanes first form a compressed layer on the Rucus atoms and subsequently adsorb on the bridging O atoms of the surface until the monolayer saturates. DFT-D3 calculations predict that methane preferentially adsorbs on top of a Rucus atom and that the C2 to C4 alkanes preferentially adopt bidentate configurations in which each molecule aligns parallel to the Rucus atom row and datively bonds to neighboring Rucus atoms. DFT-D3 predicts binding energies that agree quantitatively with our experimental estimates for alkane sigma-complexes on RuO2(110). We find that oxygen atoms adsorbed on top of Rucus atoms (Oot atoms) stabilize the adsorbed alkane complexes that bind in a given configuration, while also blocking the sites needed for sigma-complex formation. This site blocking causes the coverage of the most stable, bidentate alkane complexes to decrease sharply with increasing Oot coverage. Concurrently, we find that a new peak develops in the C2 to C4 alkane TPD spectra with increasing Oot coverage, and that the desorption yield in this TPD feature passes through a maximum at Oot coverages between ~50% and 60%. We present evidence that the new TPD peak arises from C2 to C4 alkanes that adsorb in upright, monodentate configurations on stranded Rucus sites located within the Oot layer. PMID- 27477389 TI - The ATPase hCINAP regulates 18S rRNA processing and is essential for embryogenesis and tumour growth. AB - Dysfunctions in ribosome biogenesis cause developmental defects and increased cancer susceptibility; however, the connection between ribosome assembly and tumorigenesis remains unestablished. Here we show that hCINAP (also named AK6) is required for human 18S rRNA processing and 40S subunit assembly. Homozygous CINAP(-/-) mice show embryonic lethality. The heterozygotes are viable and show defects in 18S rRNA processing, whereas no delayed cell growth is observed. However, during rapid growth, CINAP haploinsufficiency impairs protein synthesis. Consistently, hCINAP depletion in fast-growing cancer cells inhibits ribosome assembly and abolishes tumorigenesis. These data demonstrate that hCINAP reduction is a specific rate-limiting controller during rapid growth. Notably, hCINAP is highly expressed in cancers and correlated with a worse prognosis. Genome-wide polysome profiling shows that hCINAP selectively modulates cancer associated translatome to promote malignancy. Our results connect the role of hCINAP in ribosome assembly with tumorigenesis. Modulation of hCINAP expression may be a promising target for cancer therapy. PMID- 27477391 TI - Cooperative behavior of a sacrificial bond network and elastic framework in providing self-healing capacity in mussel byssal threads. AB - The dissipative and self-healing properties of mussel byssal threads are critical for their function as anchoring fibers in wave-battered habitats and central to their emergence as an exciting model system for bio-inspired polymers. Much is now understood about the structure-function relationships defining this remarkable proteinaceous bio-fiber; however, the molecular mechanisms underlying the distinctive tough, viscoelastic and self-healing behavior are still unclear. Here, we investigate elastic and dissipative contributions from the primary load bearing proteins in the distal region of byssal threads (the preCols) using X-ray diffraction (XRD) combined with in situ tensile testing. Specifically, we identified cross beta-sheet structure in the preCol flanking domains that functions as an elastic framework, providing hidden length. Dissipative behavior was associated with a strain-rate dependent phase transition of a sacrificial network stabilized by strong, reversible cross-links. Based on these findings, we posit a new model for byssal thread deformation and self-healing. PMID- 27477392 TI - Unusual sequence length-dependent gold nanoparticles aggregation of the ssDNA sticky end and its application for enzyme-free and signal amplified colorimetric DNA detection. AB - It is known that the adsorption of short single-stranded DNA (ssDNA) on unmodified gold nanoparticles (AuNPs) is much faster than that for long ssDNA, and thus leads to length-dependent AuNPs aggregation after addition of salt, the color of the solutions sequentially changed from red to blue in accordance with the increase of ssDNA length. However, we found herein that the ssDNA sticky end of hairpin DNA exhibited a completely different adsorption behavior compared to ssDNA, an inverse blue-to-red color variation was observed in the colloid solution with the increase of sticky end length when the length is within a certain range. This unusual sequence length-dependent AuNPs aggregation might be ascribed to the effect of the stem of hairpin DNA. On the basis of this unique phenomenon and catalytic hairpin assembly (CHA) based signal amplification, a novel AuNPs-based colorimetric DNA assay with picomolar sensitivity and specificity was developed. This unusual sequence length-dependent AuNPs aggregation of the ssDNA sticky end introduces a new direction for the AuNPs based colorimetric assays. PMID- 27477393 TI - Microengineered 3D cell-laden thermoresponsive hydrogels for mimicking cell morphology and orientation in cartilage tissue engineering. AB - Mimicking the zonal organization of native articular cartilage, which is essential for proper tissue functions, has remained a challenge. In this study, a thermoresponsive copolymer of chitosan-g-poly(N-isopropylacrylamide) (CS-g PNIPAAm) was synthesized as a carrier of mesenchymal stem cells (MSCs) to provide a support for their proliferation and differentiation. Microengineered three dimensional (3D) cell-laden CS-g-PNIPAAm hydrogels with different microstripe widths were fabricated to control cellular alignment and elongation in order to mimic the superficial zone of natural cartilage. Biochemical assays showed six- and sevenfold increment in secretion of glycosaminoglycans (GAGs) and total collagen from MSCs encapsulated within the synthesized hydrogel after 28 days incubation in chondrogenic medium. Chondrogenic differentiation was also verified qualitatively by histological and immunohistochemical assessments. It was found that 75 +/- 6% of cells encapsulated within 50 MUm wide microstripes were aligned with an aspect ratio of 2.07 +/- 0.16 at day 5, which was more organized than those observed in unpatterned constructs (12 +/- 7% alignment and a shape index of 1.20 +/- 0.07). The microengineered constructs mimicked the cell shape and organization in the superficial zone of cartilage whiles the unpatterned one resembled the middle zone. Our results suggest that microfabrication of 3D cell laden thermosensitive hydrogels is a promising platform for creating biomimetic structures leading to more successful multi-zonal cartilage tissue engineering. Biotechnol. Bioeng. 2017;114: 217-231. (c) 2016 Wiley Periodicals, Inc. PMID- 27477394 TI - Comparative Proteome Analysis in Schizosaccharomyces pombe Identifies Metabolic Targets to Improve Protein Production and Secretion. AB - Protein secretion in yeast is a complex process and its efficiency depends on a variety of parameters. We performed a comparative proteome analysis of a set of Schizosaccharomyces pombe strains producing the alpha-glucosidase maltase in increasing amounts to investigate the overall proteomic response of the cell to the burden of protein production along the various steps of protein production and secretion. Proteome analysis of these strains, utilizing an isobaric labeling/two dimensional LC-MALDI MS approach, revealed complex changes, from chaperones and secretory transport machinery to proteins controlling transcription and translation. We also found an unexpectedly high amount of changes in enzyme levels of the central carbon metabolism and a significant up regulation of several amino acid biosyntheses. These amino acids were partially underrepresented in the cellular protein compared with the composition of the model protein. Additional feeding of these amino acids resulted in a 1.5-fold increase in protein secretion. Membrane fluidity was identified as a second bottleneck for high-level protein secretion and addition of fluconazole to the culture caused a significant decrease in ergosterol levels, whereas protein secretion could be further increased by a factor of 2.1. In summary, we show that high level protein secretion causes global changes of protein expression levels in the cell and that precursor availability and membrane composition limit protein secretion in this yeast. In this respect, comparative proteome analysis is a powerful tool to identify targets for an efficient increase of protein production and secretion in S. pombe Data are available via ProteomeXchange with identifiers PXD002693 and PXD003016. PMID- 27477395 TI - Distribution, Partitioning and Bioaccumulation of Substituted Diphenylamine Antioxidants and Benzotriazole UV Stabilizers in an Urban Creek in Canada. AB - Substituted diphenylamine antioxidants (SDPAs) and benzotriazole UV stabilizers (BZT-UVs), previously under reported classes of organic contaminants, were determined in sediment, water, and freshwater biota in an urban creek in Canada. SDPAs and BZT-UVs were frequently detected in all matrices including upstream of the urban area in a rural agricultural/woodlot region, suggesting a ubiquitous presence and bioaccumulation of these emerging contaminants. Spatial comparisons were characterized by higher levels of SDPAs downstream compared with the upstream, implying a possible influence of the urban activities on the antioxidant contamination in the sampling area. In sediment, 4,4'-bis(alpha,alpha dimethylbenzyl)-diphenylamine (diAMS), dioctyl-diphenylamine (C8C8), and dinonyl diphenylamine (C9C9) were the most dominant congeners of SDPAs, with concentrations up to 191 ng/g (dry weight, d.w.). Benthic invertebrates Crayfish (Orcoescties spp.) had larger body burdens of SDPAs and BZT-UVs compared to pelagic fish (hornyhead chub (Nocomis biguttatus) and common shiner (Luxilus cornutus)) in the creek and partitioning coefficients demonstrated that sediment was the major reservoir of these contaminants. This is the first report of bioaccumulation and partitioning behaviors of SDPAs and BZT-UVs in freshwater environments. PMID- 27477396 TI - Relationship between Non-alcoholic Fatty Liver Disease and Thyroid Dysfunction. PMID- 27477397 TI - The Effect of Low Frame Rate Fluoroscopy on the X-ray Dose during Coronary Intervention. AB - Objective The aim of this study was to investigate whether the use of low frame rate fluoroscopy at 7.5 frames per second during coronary intervention could reduce radiation exposure in Japanese patients. Methods From December 10, 2014 to March 20, 2015, 84 consecutive patients with coronary artery disease who underwent coronary intervention in our institution were retrospectively collected and then divided into two groups: the LR group (fluoroscopy at 7.5 frames per second) and the OR group (fluoroscopy at 15 frames per second), according to the frame rate of fluoroscopy that was used in their treatment. Results There were no differences in the patient backgrounds or the procedural characteristics of the two groups. Although there were no differences in the contrast volume or fluoroscopy time, the total air kerma at the interventional reference point, which is used to monitor the patient's radiation dose, was significantly lower in the LR group than in the OR group (701.4+/-427.9 vs. 936.8+/-623.9 mGy, p=0.02). Conclusion Low frame rate fluoroscopy at 7.5 frames per second is safe and feasible for use during coronary interventions and an easy and useful strategy for reducing the radiation to which patients are exposed during coronary intervention. PMID- 27477398 TI - Orthostatic Hypotension Predicts a Poor Prognosis in Elderly People with Dementia. AB - Objective The purpose of the present study was to assess the prevalence of orthostatic hypotension (OH) and elucidate its associations with the demographic characteristics and the prognosis in elderly subjects with dementia who visited a hospital for elderly daycare. Methods A total of 64 outpatients (44 females) with a mean age of 84+/-6 years who visited a hospital for daycare were enrolled in the study. The prevalence of OH and demographic characteristics were examined. Then, the subjects were followed up for 1 year. The blood pressure was measured in the supine position and immediately, 1, 3 and 5 minutes after standing. Poor outcome measures included death, hospitalization for any reason, and admission to a nursing home or geriatric facility. Results OH was present in 17 patients (26.6%). The presence of OH was associated with a higher supine systolic blood pressure. The increase in heart rate in the standing position was also reduced in subjects with OH compared with those without. The presence of OH was associated with faster time in the timed up-and-go test compared with those without OH. During the follow-up period, 22 patients (34.4%) had a poor prognosis, of which 8 (36.4%) had OH, which tended to be higher than those with a favorable prognosis. The event-free survival rate appeared to be lower in subjects with OH than in those without. Conclusion OH is relatively common in frail elderly patients with dementia, and it also appears to be associated with a poor prognosis. PMID- 27477399 TI - The Efficacy and Safety of Oral Rivaroxaban in Patients with Non-Valvular Atrial Fibrillation Scheduled for Electrical Cardioversion. AB - Objective Electrical cardioversion (EC) is associated with an increased risk of thrombotic events in patients with non-valvular atrial fibrillation (NVAF). Patients who experience AF for a period of >48 hours therefore require adequate anticoagulation therapy for at least 3 weeks before and 4 weeks after EC. While the guidelines address the management of vitamin K antagonists (VKAs), there are limited data on the use of novel oral anticoagulants (NOAC). One NOAC, rivaroxaban, has a rapid onset of action and might therefore shorten the time for which anti-coagulant treatment is required before a patient undergoes EC. Methods This study included 91 patients with NVAF of >48 hours in duration or in whom the time of onset was unknown who were undergoing EC after pretreatment with rivaroxaban. All of the patients were pretreated with rivaroxaban for at least 2 hours before EC and the same dose of rivaroxaban was prescribed for 4 weeks after EC. The primary endpoint was a successful EC without any thrombotic events or bleeding complications within 30 days after EC. The secondary endpoint was the time to EC. Results The mean age was 63+/-12 years and 70 of the 91 patients were male. The CHADS2 and HAS-BLED scores were 1.0+/-1.0 and 1.7+/-1.3, respectively. Although there were no thrombotic events, minor bleeding (gingival hemorrhage) occurred 20 days after the initiation of rivaroxaban treatment in one patient. The average time to EC was 11.9+/-11.1 days. Conclusion Rivaroxaban is safe and effective drug for NVAF patients who are scheduled for an EC. Furthermore, since VKAs take a substantial amount of time to establish adequate anticoagulation, pretreatment with rivaroxaban could shorten the time to the EC. PMID- 27477400 TI - Association of the Elevated Red Blood Cell Distribution Width with the Risk of Developing Diabetes Mellitus. AB - Objective The aim of this study was to determine whether elevated levels of RDW coefficient of variation (CV) are associated with the development of diabetes mellitus (DM) in a population of healthy middle- and old-aged individuals. Method We conducted a retrospective cohort study. A total of 2,688 individuals (aged 49 66 years) without a DM diagnosis, impaired fasting glucose, or anemia at baseline were grouped according to the RDW-CV quartile, and the onset of DM during a 4 year period was recorded for each group. Results The correlation coefficients for the RDW-CV and waist circumference and for the RDW-CV and HbA1c were 0.114 and 0.133, respectively. The relative risks of future DM in RDW-CV quartiles II, III, and IV (high) compared with RDW-CV quartile I (low) were 1.9 [95% confidence interval (CI) 1.0-3.6, p=0.057], 1.6 (95% CI 0.8-3.0, p=0.157), and 2.2 (95% CI 1.2-4.0, p=0.015), respectively. After adjusting for sex, age, waist circumference, hemoglobin A1c, triglycerides, high density lipoprotein cholesterol (HDL-C), and high-sensitivity C-reactive protein, the multivariate relative risk for the highest vs. the lowest RDW-CV quartile was 1.8 (95% CI, 1.1 3.4, p=0.046). Conclusion These data indicate that an elevated RDW-CV is associated with an increased incidence of DM. PMID- 27477401 TI - Hypo-high-density Lipoprotein Cholesterolemia Caused by Evacuation after the Fukushima Daiichi Nuclear Power Plant Accident: Results from the Fukushima Health Management Survey. AB - Objective The Great East Japan Earthquake and the Fukushima Daiichi nuclear disaster forced the evacuation of residents and led to many changes in the lifestyle of the evacuees. A comprehensive health check was implemented to support the prevention of lifestyle-related disease, and we analyzed changes in lipid metabolism before and after these disasters. Methods Subjects included Japanese men and women living near the Fukushima Daiichi nuclear power plant in Fukushima Prefecture. Annual health checkups, focusing on metabolic syndromes, were conducted for persons >=40 years of age by the Heath Care Insures. Results A total of 27,486 subjects underwent a follow-up examination after the disaster, with a mean follow-up of 1.6 years. Following the disaster, the prevalence of hypo-high-density lipoprotein (HDL) cholesterolemia increased significantly from 6.0% to 7.2%. In the hypo-HDL cholesterolemia group, the body mass index (BMI), blood pressure, and LDL-C level increased significantly in men after the disaster. On the other hand, in the normal HDL-C level group, the BMI, blood pressure, glucose and lipid metabolism, and liver function were adversely affected. The decrease in HDL-C was significantly greater in evacuees than non evacuees in the normal HDL-C level group. Furthermore, a multivariate logistic regression analysis showed that the evacuation was significantly associated with the incidence of hypo-HDL cholesterolemia. Conclusion This is the first study to evaluate how the evacuation affected the incidence of hypo-HDL cholesterolemia and led to an increase in cardiovascular disease. This information may be important in the follow-up and lifestyle change recommendations for evacuees. PMID- 27477402 TI - Frequency of Calreticulin (CALR) Mutation and Its Clinical Prognostic Significance in Essential Thrombocythemia and Primary Myelofibrosis: A Meta analysis. AB - Objective As the calreticulin (CALR) mutation frequency is significantly associated with essential thrombocythemia (ET) and primary myelofibrosis (PMF), this mutation may be an important biomarker in patients with ET and PMF. Methods We performed a literature search until April 2015 and obtained 21 relevant studies. The outcome was pooled as the effect size by using the Stata software program. Results The CALR mutation frequencies in patients with ET and PMF were 19% and 22%, respectively. The CALR mutation ratio in Asian patients with ET was 23% and higher than that in European-American patients (16%). Moreover, the mutation ratio in Asian patients with PMF was lower (21%) than that in European American patients (23%). A slight trend toward fibrotic transformation was found in ET with CALR mutations, whereas leukemic transformation was not significant in patients with ET or PMF with CALR mutations. Conclusion CALR mutations significantly influence the incident of ET as demonstrated by the meta-analysis. PMID- 27477403 TI - A Potential Link between Amyotrophic Lateral Sclerosis and Bullous Pemphigoid: Six New Cases and a Systematic Review of the Literature. AB - Objective Bullous pemphigoid in amyotrophic lateral sclerosis (BP-ALS) is rare and poorly understood. We herein assessed the association between ALS and BP using clinical and biological findings. Methods The clinical features of six new BP-ALS cases were described and collated with cases from a systematic literature review. Results Our six cases were combined with three other published cases. The mean disease duration (from ALS onset to the occurrence of BP) was 5.6+/-3.1 years. All patients had limb-onset ALS. Four of the 9 patients received riluzole, with the use of riluzole ranging from a few days to 3 years. When BP occurred, the status of the ALS patients was paretic and/or bedridden in all cases. BP occurred throughout the body, and we confirmed that the bullous lesions were located not only at the compression site, but also at the anterior part of the chest, abdomen, and limbs. Treatment for BP was successful, as oral prednisone and/or local corticosteroids were effective in 8 cases. Conclusion These six new cases, in combination with previous cases, expand our knowledge of the relationship between dermatological lesions and ALS. The pathogenesis of BP-ALS is poorly understood, however, some immunological aberrance is likely. PMID- 27477404 TI - Functional Outcomes of Decompressive Craniectomy in Patients with Malignant Middle Cerebral Artery Infarction and Their Association with Preoperative Thalamus Deformation: An Analysis of 12 Patients. AB - Objective Decompressive craniectomy (DC) in patients with malignant middle cerebral artery (MCA) infarction is known to decrease the mortality rate. However, the functional outcomes (communication and oral intake) of this procedure remain unclear. Most patients with malignant MCA infarction exhibit a loss of consciousness, which may be principally governed by the thalamus. We herein investigated the functional outcomes of DC at 90 days after the onset of malignant MCA infarction and their association with preoperative thalamus deformation, which can occur due to pressure and edema. Methods Twelve of 2,692 patients with acute cerebral infarction were diagnosed with malignant MCA infarction and underwent DC. We evaluated preoperative thalamus damage using brain computed tomography and its association with communication and oral intake abilities and the modified Rankin Scale (mRS) and Barthel index scores at 90 days after stroke onset. Results The mRS score at 90 days was 0-4 in five patients. Seven patients could communicate immediately after surgery, while five could do so by 90 days. Five patients were able to resume the oral intake of food at 90 days. All patients with preoperative thalamus deformation showed a poor recovery, while those with absent or slight preoperative thalamus deformation showed a good recovery. Conclusion Patients with preoperative thalamus deformation caused by pressure and edema show a poor oral intake and communication abilities after DC, suggesting that preoperative thalamus deformation is a predictor of poor functional outcomes after DC in patients with malignant MCA infarction. PMID- 27477405 TI - Efficacy of Vitamin K2 for Glucocorticoid-induced Osteoporosis in Patients with Systemic Autoimmune Diseases. AB - Objective Vitamin K2 (menatetrenone) is an effective treatment for patients with postmenopausal osteoporosis. We herein performed a subanalysis of patients with systemic autoimmune diseases undergoing glucocorticoid therapy in our previous prospective study. Methods Sixty patients were categorized into a group with vitamin K2 treatment (n=20, Group A) and a group without vitamin K2 treatment (n=40, Group B). All patients were treated with bisphosphonates. Results Serum levels of osteocalcin and undercarboxylated osteocalcin decreased significantly after the start of glucocorticoid therapy in both groups, while the serum osteocalcin level was significantly higher in Group A than Group B during the third (p=0.0250) and fourth weeks (p=0.0155). The serum level of the N-terminal peptide of type I procollagen, a bone formation marker, decreased during glucocorticoid therapy, but was significantly higher in Group A than Group B during the fourth week (p=0.0400). The bone mineral density and fracture rate showed no significant differences between the two groups. Conclusion Although vitamin K2 improves bone turnover markers in patients with osteoporosis on glucocorticoid therapy, it has no significant effect on the bone mineral density and fracture rate after 1.5 years of treatment. PMID- 27477406 TI - Improvement in Severe Mycophenolic Acid-associated Gastrointestinal Symptoms after Changing Enteric-coated Mycophenolate Sodium to Mizoribine in Renal Transplant Recipients: Two Case Reports. AB - Clinical results point to a better gastrointestinal tolerability with enteric coated mycophenolate sodium as compared to mycophenolate mofetil. However, some transplant recipients who are treated with enteric-coated mycophenolate sodium still experience gastrointestinal symptoms. We herein present two cases of renal transplant recipients with severe gastrointestinal symptoms who were switched from enteric-coated mycophenolate sodium to mizoribine, and the symptom reversal effects were evaluated using the Gastrointestinal Symptom Rating Scale. The results of this study showed a significant improvement in severe gastrointestinal symptoms in renal transplant recipients after converting from enteric-coated mycophenolate sodium to mizoribine. PMID- 27477407 TI - Onset of Tuberculosis from a Pulmonary Latent Tuberculosis Infection during Antiviral Triple Therapy for Chronic Hepatitis C. AB - A 62-year-old man was diagnosed with the onset of tuberculosis (Tb) from a pulmonary latent tuberculosis infection (LTBI) during triple therapy with pegylated interferon alpha2a, ribavirin, and telaprevir for a chronic hepatitis C infection in 2013 before interferon (IFN)-free anti-viral therapy was introduced in Japan. A liver biopsy before IFN treatment revealed the presence of epithelioid cell granulomas (ECGs). IFN may also be employed for chronic hepatitis B infection and malignant tumors, thus, special attention must be paid to the development of Tb from a LTBI when ECGs are observed before treatment. It is also necessary to review the significance of the liver biopsy. PMID- 27477408 TI - Hyperthyroidism Improves the Pathological Condition of Nonalcoholic Steatohepatitis: A Case of Nonalcoholic Steatohepatitis with Graves' Disease. AB - 3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH. PMID- 27477409 TI - Coronary Intramural Hematoma Presenting as Acute Coronary Syndrome. AB - We herein report a case of intramural hematoma without ongoing myocardial ischemia that healed spontaneously with conservative treatment. A 37-year-old woman was admitted due to chest pain. Acute coronary syndrome was diagnosed by electrocardiography and echocardiography. Coronary angiography showed 90% stenosis in the distal portion of the left anterior descending coronary artery, where intravascular ultrasound showed a hematoma, but optical coherence tomography could not detect the entry point. Therefore, we identified the intramural hematoma as the etiology. Because the coronary flow was maintained and chest pain disappeared, we chose conservative treatment. Fifteen days after admission, coronary computed tomography showed an improvement in the intramural hematoma. PMID- 27477410 TI - Adrenocortical Carcinoma Treated by CyberKnife. AB - Adrenocortical carcinoma is a rare malignancy with a poor prognosis. The effective treatment for advanced cancer remains unknown. A 61-year-old woman underwent CyberKnife treatment on a large adrenocortical carcinoma and tumor emboli in both pulmonary arteries. Follow-up positron emission tomography scanning with fluorodeoxyglucose (FDG) revealed that the FDG uptake was greatly decreased in all the tumors, and the hormone levels were also decreased. CyberKnife is a safe and effective treatment option for the non-operative large advanced adrenocortical carcinoma. PMID- 27477411 TI - Superior Mesenteric Artery Syndrome Complicated by Diabetic Ketoacidosis and Graves' Disease in Slowly Progressive Insulin Dependent Diabetes Mellitus (SPIDDM): A Case Report and a Review of the Literature. AB - A 48-year-old woman with a history of diabetes was admitted for nausea and vomiting with body weight loss. A blood examination revealed high plasma glucose and thyroid hormone levels and metabolic acidosis. She was therefore diagnosed with both diabetic ketoacidosis (DKA) and hyperthyroidism. Nausea and vomiting continued intermittently despite the administration of saline and insulin. The patient was further diagnosed with superior mesenteric artery syndrome (SMAS) after abdominal computed tomography revealed that a horizontal portion of the duodenum was sandwiched between the aorta and the superior mesenteric artery. Clinicians should be vigilant for SMAS in patients with both DKA and hyperthyroidism who present body weight loss. PMID- 27477412 TI - Myeloperoxidase Antineutrophil Cytoplasmic Antibody (MPO-ANCA) Associated Crescentic and Necrotizing Glomerulonephritis (GN) with Membranoproliferative GN Features. AB - A 77-year-old man presented with a fever, non-productive cough, and edema formation. A laboratory analysis showed an elevated creatinine level (2.5 mg/dL), a high titer of myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) (99 U/mL), positive reaction for antinuclear antibody (*320), hematuria, and massive proteinuria (3.33 g/day). A renal biopsy revealed crescentic and necrotizing glomerulonephritis (GN) with membranoproliferative GN features [double contour appearance of the glomerular basement membrane, granular deposition of immunoglobulin (Ig) G, IgM, and C3 along the capillary wall, subendothelial and subepithelial deposits with mesangial interposition]. A potential relationship between MPO-ANCA associated GN and membranoproliferative GN is discussed. PMID- 27477413 TI - Sarcoid Myositis with Anti-Ku Antibody Consistent with both Sarcoidosis and Polymyositis. AB - We herein describe a case of sarcoid myositis with anti-Ku antibody positivity. Pathological findings of the muscle were compatible with sarcoidosis, but could not be completely distinguished from myositis diseases that arise from other causes. According to a physical examination, pathological findings, the detection of anti-Ku antibody and the human leukocyte antigen (HLA)-DPB1 allele, we strongly suspected that the patient developed both sarcoidosis and polymyositis. Sarcoidosis is often complicated by autoimmune diseases. This case suggests the possibility that sarcoidosis and other autoimmune diseases may have common causal genetic factors. PMID- 27477414 TI - Endoscopic Bronchial Occlusion with Silicon Spigots for the Treatment of an Alveolar-pleural Fistula during Anti-tuberculosis Therapy for Tuberculous Empyema. AB - A prolonged air leak caused by pulmonary tuberculosis is difficult to treat, and little is known about optimal treatment strategies. We herein report the case of a 60-year-old man who demonstrated tuberculous empyema with a fistula. An air leak from a tuberculous cavity in his left upper lobe persisted for approximately 4 months; surgical repair could not be performed due to a poor physical status and undernourishment. However, the air leak was successfully treated with endobronchial occlusion using two silicone spigots in left B3b and B4, without any adverse effects or aggravation of the infection. PMID- 27477415 TI - Rituximab-induced Acute Thrombocytopenia in High Tumor Burden Follicular Lymphoma. AB - Rituximab-induced acute thrombocytopenia (RIAT), a rare complication of rituximab administration, has not yet been described in follicular lymphoma (FL). A 65-year old man received rituximab for the treatment of high tumor burden follicular lymphoma in the leukemic phase. The next day, his platelet count abruptly dropped from 85,000 to 5,000/MUL, which spontaneously recovered in a few days without specific treatment. We speculate that the occurrence of infusion-related cytokine release syndrome in rituximab-sensitive high tumor burden FL contributed to the development of RIAT. Frequent monitoring of the platelet count is advisable for select patients considered to be at a high risk for RIAT. PMID- 27477416 TI - Dialysis-induced Subdural Hematoma in an Arachnoid Cyst Associated with Autosomal Dominant Polycystic Kidney Disease. AB - Arachnoid cyst (AC) is a neurological complication of autosomal dominant polycystic kidney disease (ADPKD). Although an AC can increase the risk of a subdural hematoma, the clinical presentation of bleeding into an AC associated with ADPKD is not well known. We herein report the case of a 59-year-old woman in whom the initiation of hemodialysis for renal failure led to AC bleeding. A change of anticoagulant from heparin to nafamostat mesilate allowed dialysis to continue without rebleeding. These findings suggest that hemodialysis in patients with an AC associated with ADPKD may increase the risk of bleeding. Nafamostat mesilate may be useful in such cases. PMID- 27477417 TI - Pneumococcal Pyomyositis of the Neck Muscles. AB - High fever, severe neck pain and neck stiffness can result from meningitis. We report a case of pneumococcal pyomyositis of the neck muscles. A 72-year-old man developed high fever and severe neck pain. His chief complaint mimicked bacterial meningitis. Although his condition was initially suspected to be bacterial meningitis, his cerebrospinal fluid did not show pleocytosis. MRI showed areas of high intensity in the posterior deep neck muscles on short tau inversion recovery (STIR) sequences and gadolinium-enhanced T1-weighted images. Pneumococcal myositis should therefore be included in the differential diagnosis of severe neck pain with fever. PMID- 27477418 TI - Alternating Hemiplegia with Ipsilateral Supranuclear Facial Palsy and Abducens Nerve Palsy Caused by Pontine Infarction. AB - A 62-year-old right-handed man was diagnosed with a cerebral infarction in the ventromedial region of the left lower pons. He showed left abducens nerve palsy, left-sided supranuclear palsy of the lower part of the face and right hemiparesis. We hypothesized that the mechanism underlying the patient's ipsilateral supranuclear facial palsy involved the corticofacial fibers after they crossed the midline. PMID- 27477419 TI - Giant Cell Arteritis with Facial Edema Presenting with Delayed Jugular Venous Flow. AB - The detection of abnormalities of the cranial arteries on magnetic resonance imaging (MRI) is useful for the diagnosis of giant cell arteritis (GCA). However, reports on the veins of GCA patients are rare. We report the case of an elderly woman with GCA who presented with facial edema. She presented with a one month history of headache and facial edema. After MRI and enhanced computed tomography revealed delayed blood flow in the left jugular vein, a temporal artery biopsy was performed. She was diagnosed with GCA based on the biopsy findings. Following corticosteroid therapy, her symptoms and venous flow improved. The present case indicates that delayed jugular venous flow can occur in GCA patients with facial edema. PMID- 27477420 TI - Strongyloides stercoralis Infection Causing Obstructive Jaundice and Refractory Pancreatitis: A Lesson Learned from a Case Study. AB - A 58-year-old Japanese woman came to our institution because of leg edema and abdominal distention. She had developed acute pancreatitis 5 times in the past 3 years. Dilation of the bile duct and main pancreatic duct without obstruction was observed on computed tomography and magnetic resonance cholangiopancreatography. The presence of Strongyloides stercoralis was highly suspected from the biopsy sample from the duodenal papilla. Polymerase chain reaction amplification and sequencing of small subunit rDNA from paraffin-embedded specimens identified the worm as S. stercoralis. All of the symptoms were considered to be associated with S. stercoralis infection. Therefore, the patient was treated with oral administration of ivermectin. Subsequently, symptoms and laboratory data improved. There has been no recurrence of the symptoms to date. PMID- 27477421 TI - Bloodstream Infections Caused by Klebsiella pneumoniae Carbapenemase 2-producing K. pneumoniae at a Hematology Department in Wenzhou, China. AB - The increasing prevalence of Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae (KPC-2-KP) infections can become a new life-threatening complication for hematological patients. Five cases of KPC-2-KP bloodstream infections have been identified in our hematology department over the past 10 years. The current treatment options do not show satisfactory efficacy, especially for bloodstream infections. The treatment of these five cases was unsuccessful, mainly due to the high minimum inhibitory concentrations of carbapenem, fosfomycin resistance, or the inaccessibility of polymyxin. Further investigations into the optimal treatment modalities are therefore imperative. The present study provides insights into the epidemiology and clinical challenges of treating KPC-2-KP bloodstream infections. PMID- 27477422 TI - Successful Treatment of Aspergillus Empyema Using Open Window Thoracostomy Salvage Treatment and the Local Administration of an Antifungal Agent. AB - A 76-year-old woman received long-term immunosuppressive treatment for collagen vascular disease-associated interstitial pneumonia. The patient developed a cavitary mass lesion in the right lower lung field, and both nontuberculous mycobacteria and Aspergillus spp. were isolated after bronchial washing. The patient underwent a right lower lobectomy but developed Aspergillus empyema. Empyema due to Aspergillus spp. is a rare and life-threatening condition; however, the standard therapeutic strategies for treating Aspergillus empyema are not clear. We herein report a case of Aspergillus empyema that was successfully treated with a combination therapy which included open-window thoracostomy and the administration of antifungal agents (systemic micafungin and local amphotericin-B). PMID- 27477423 TI - Streptococcus pneumoniae Meningitis Presenting with Acute Urinary Retention and Emphysematous Cystitis. AB - A combination of acute urinary retention and aseptic meningitis has occasionally been described, which is referred to as meningitis-retention syndrome. In contrast, acute urinary retention has rarely been reported in bacterial meningitis. We herein report a case of Streptococcus pneumoniae meningitis presenting with acute urinary retention which led to emphysematous cystitis in an elderly woman. She presented with impaired consciousness and a distended lower abdomen. She was diagnosed with pneumococcal meningitis by lumbar puncture. Abdominal computed tomography revealed the presence of emphysematous cystitis. She completely recovered with antibiotic therapy without any complications. Acute urinary retention can occur secondary to pneumococcal meningitis. PMID- 27477425 TI - Pancreatitis due to Radiolucent Pancreatolithiasis Mimicking Gallstone Pancreatitis. PMID- 27477426 TI - Localized Amyloid Deposition at the Ampulla of Vater. PMID- 27477424 TI - Systemic Inflammatory Syndrome Associated with a Case of Jugular Paraganglioma. AB - Jugular paraganlioma is a benign, slow-growing tumor originating from the paraganglion cells and it is associated with catecholamine secretion. Paragangliomas can secrete Interleukin-6 (IL-6) and present as a systemic inflammatory syndrome; these characteristics have not been previously associated with jugular paragangliomas. A 63-year-old man with a jugular tumor in the skull base was referred to our hospital for an evaluation of pyrexia, back pain, and acute inflammation. His serum IL-6 level was elevated on admission and it decreased after radiotherapy. This is the first known case of a jugular paraganglioma exhibiting systemic inflammatory syndrome. PMID- 27477427 TI - Multiple Coronary Artery Fistulas in the Left Ventricle. PMID- 27477428 TI - Unilateral Renal Cystic Disease with an Impaired Renal Function. PMID- 27477429 TI - Haemoptysis as a Presenting Symptom of Thoracic Aneurysm Dissection. PMID- 27477430 TI - Esophageal Malignancy with an Esophagorespiratory Fistula Masquerading as Pneumonia. PMID- 27477432 TI - Helicobacter cinaedii in Urine. PMID- 27477431 TI - A Necrotized Eyelid. PMID- 27477433 TI - Idiopathic Nonsurgical Pneumoperitoneum Accompanied by a Pneumomediastinum. PMID- 27477434 TI - Is May and Thurner's Original Article Appropriate for Characterizing the Iliac Vein Compression Syndrome? PMID- 27477435 TI - May-Thurner Syndrome: Authors' Reply. PMID- 27477436 TI - Does Catheter Removal not Matter in Candidemia Patients? PMID- 27477437 TI - Catheter Removal Does Matter but Should Be Individualized for Patients with Candidemia. PMID- 27477438 TI - Corrigendum: Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes. PMID- 27477439 TI - Microwetting of pH-Sensitive Surface and Anisotropic MoS2 Surfaces Revealed by Femtoliter Sessile Droplets. AB - Understanding the microwettability of anisotropic molybdenum disulfide crystal is critically important in separation and processing of this material in liquid. In this work, static microwetting properties of MoS2 face (MF) and MoS2 edge (ME) surfaces in water are revealed by the morphology of femtoliter interfacial droplets. The oil droplets with different size distribution were produced from heterogeneous nucleation and growth of nanodroplets during the solvent exchange under controlled flow and solution conditions, and were polymerized for droplet morphology characterization to reveal the relative wettability of the droplets on surfaces. We first demonstrate that the shape of the nanodroplets is responsive to the surface charges on a model pH sensitive substrate of gold coated with a self-assembled monolayer of two types of thiol. The experimental results on MoS2 substrates indicate that (1) oil contact angle of the droplets on ME surface is much larger than that on MF surface at pH 3.0, suggesting that the ME surface is more hydrophilic than MF; (2) the droplets are pinned by the layered nanostructure on MoS2 edge. The fundamental understanding of microwettability elucidated in this study may allow for an improved control of the interaction between anisotropic MoS2 surfaces and the surrounding liquid environment, which is critically important for many industrial applications such as flotation and catalysis systems. PMID- 27477440 TI - Nationwide firefighter survey: the prevalence of lower back pain and its related psychological factors among Korean firefighters. AB - The main objective of this study was to assess the prevalence of lower back pain (LBP) and clarify the effect of work-related psychological factors on LBP. Nationwide survey data collected from male Korean firefighters (FIFS) were used. To identify the risk factors (work-related psychological factors such as job stress and depression) affecting LBP, the chi2 test and multivariate logistic regression analyses were conducted. The prevalence of LBP was 19.3% and was highest in the emergency medical service (31.8%) part of FF job types. Within job stress, an uncomfortable physical environment, high mental job demand and organizational injustice were associated with LBP. However, inadequate social support inversely associated with LBP. Depression and high-risk alcohol drinking were related to LBP. LBP was closely related to job stress, depression and alcohol intake. Proper interventions of psychological factors should therefore be addressed to control LBP in FIFS. PMID- 27477441 TI - Incidence of Guillain-Barre syndrome in Chile: a population-based study. AB - The Guillain-Barre syndrome (GBS) incidence rate (IR) varies between 0.16 and 3.00 cases per 100,000 inhabitants. Little data exist on the epidemiology of GBS in Latin American countries. Our objective was to describe GBS epidemiology based on a national database in a Latin American country and to contribute to the global map of GBS epidemiology. This was a retrospective study that included all reported GBS cases in Chile between 2001 and 2012. Gender, age, seasonal occurrence, and geographical distribution were analyzed. A total of 4,158 GBS cases were identified from 19,513,655 registries. The mean age was 37 +/- 24 years, and 59% of patients were male (male to female ratio of 1.5 : 1). Gender IR was 2.53/100,000 for males and 1.68/100,000 for females. The overall standardized IR was 2.1/100,000, although this varied between 1.61/100,000 (2001) and 2.35/100,000 (2010). The seasonal distribution was as follows: autumn 22%; winter 25%; spring 27%; and summer 26%. The geographical IR were as follows: far North 1.49/100,000; North 1.94/100,000; Central 1.97/100,000; South 3.18/100,000; and far South 2.78/100,000. The reported IR of GBS in Chile was similar to other studies based on national databases. In Chile, IR was greater in men and in the south. PMID- 27477442 TI - New technologies in diagnostic bronchoscopy - an age of meta-analyses. PMID- 27477443 TI - Grounding meaning in experience: A broad perspective on embodied language. AB - This work reviews key behavioural, neurophysiological and neuroimaging data on the neural substrates for processing the meaning of linguistic material, and tries to articulate the picture emerging from those findings with the notion of meaning coming from specific approaches in philosophy of language (the "internalist" view) and linguistics (words point at experiential clusters). The reviewed findings provide evidence in favour of a causal role of brain neural structures responsible for sensory, motor and even emotional experiences in attributing meaning to words expressing those experiences and, consequently, lend substantial support to an embodied and "internalist" conception of linguistic meaning. Key evidence concern verbs, nouns and adjectives with a concrete content, but the challenge that abstract domains pose to the embodied approach to language is also discussed. This work finally suggests that the most fundamental role of embodiment might be that of establishing commonalities among individual experiences of different members of a linguistic community, and that those experiences ground shared linguistic meanings. PMID- 27477445 TI - The neurobiological nature of syntactic hierarchies. AB - The review focuses on the neurobiological literature concerning the specific human ability to process linguistic hierarchies. First, we will discuss current ethological studies dedicated to the comparison between human and non-human animals for the processing of different grammar types. We will inspect the functional neuroanatomical structures of human and non-human primates more closely, including human developmental data, thereby suggesting interesting phylogenetic and ontogenetic differences. We then examine the neural reality of the Merge computation, being the most fundamental mechanism regulating natural language syntax, and offer new evidence for a possible localization of Merge in the most ventral anterior portion of BA 44. We conclude that BA 44, with its strong neural connection to the posterior temporal cortex, provides a recent evolutionary neurobiological basis for the unique human faculty of language. PMID- 27477446 TI - Orexin, Stress and Central Cardiovascular Control. A Link with Hypertension? AB - Orexin, the arousal peptide, originates from neurons located in an area of the dorsal hypothalamus well known for integrating defense responses and their cardiovascular component. Orexin neurons, which are driven in large part by the limbic forebrain, send projections to many regions in the brain, including regions involved in cardiovascular control, as far down as sympathetic preganglionic neurons in the spinal cord. Central injections of orexin evoke sympathetically mediated cardiovascular responses. Conversely, blockade of orexin receptors reduce the cardiovascular responses to acute stressors, preferentially of a psychological nature. More importantly, lasting upregulation of orexin signaling can lead to a hypertensive state. This can be observed in rats exposed to chronic stress as well as in strains known to display spontaneous hypertension such as the spontaneously hypertensive rat (SHR) or the hypertensive BPH/2J Schlager mouse. Thus, there is a link between orexin, stress and hypertension, and orexin upregulation could be a factor in the development of essential hypertension. Orexin receptor antagonists have anti-hypertensive effects that could be of clinical use. PMID- 27477447 TI - Erythropoietin and TRPV1 together in new formation. PMID- 27477444 TI - The role of experience in adolescent cognitive development: Integration of executive, memory, and mesolimbic systems. AB - Adolescence marks a time of unique neurocognitive development, in which executive functions reach adult levels of maturation. While many core facets of executive function may reach maturation in childhood, these processes continue to be refined and stabilized during adolescence. We propose that this is mediated, in part, by interactions between the hippocampus and prefrontal cortex. Specifically, we propose that development of this circuit refines adolescents' ability to extract relevant information from prior experience to support task relevant behavior. In support of this model, we review evidence for protracted structural and functional development both within and across the hippocampus and prefrontal cortex. We describe emerging research demonstrating the refinement of adolescents' ability to integrate prior experiences to support goal-oriented behavior, which parallel hippocampal-prefrontal integration. Finally, we speculate that the development of this circuit is mediated by increases in dopaminergic neuromodulation present in adolescence, which may underlie memory processing, plasticity, and circuit integration. This model provides a novel characterization of how memory and executive systems integrate throughout adolescence to support adaptive behavior. PMID- 27477448 TI - Amide bond-containing monodisperse polyethylene glycols beyond 10 000 Da. AB - Although monodisperse polyethylene glycols (M-PEGs) above 4000 Da are especially valuable in biomedical applications, their synthesis remains a long-standing challenge. To this end, a peptide-based strategy for such M-PEGs was developed. With macrocyclic sulfates as the key intermediates, a panel of oligoethylene glycol (OEG) containing omega-amino acids were prepared with high efficiency. Through solid phase peptide synthesis (SPPS), these amino acids were conveniently assembled into a series of amide bond-containing M-PEGs with high flexibility in molecular weight and amide density selection. With this strategy, an M-PEG of 10 262 Da was prepared on a gram scale and its biocompatibility was assessed in a mice model. PMID- 27477450 TI - A gene browser of colorectal cancer with literature evidence and pre-computed regulatory information to identify key tumor suppressors and oncogenes. AB - Colorectal cancer (CRC) is a cancer of growing incidence that associates with a high mortality rate worldwide. There is a poor understanding of the heterogeneity of CRC with regard to causative genetic mutations and gene regulatory mechanisms. Previous studies have identified several susceptibility genes in small-scale experiments. However, the information has not been comprehensively and systematically compiled and interpreted. In this study, we constructed the gbCRC, the first literature-based gene resource for investigating CRC-related human genes. The features of our database include: (i) manual curation of experimentally-verified genes reported in the literature; (ii) comprehensive integration of five reliable data sources; and (iii) pre-computed regulatory patterns involving transcription factors, microRNAs and long non-coding RNAs. In total, 2067 genes associating with 2819 PubMed abstracts were compiled. Comprehensive functional annotations associated with all the genes, including gene expression profiles, homologous genes in other model species, protein protein interactions, somatic mutations, and potential methylation sites. These comprehensive annotations and this pre-computed regulatory information highlighted the importance of the gbCRC with regard to the unexplored regulatory network of CRC. This information is available in a plain text format that is free to download. PMID- 27477449 TI - Personalized Computer Simulation of Diastolic Function in Heart Failure. AB - The search for a parameter representing left ventricular relaxation from non invasive and invasive diagnostic tools has been extensive, since heart failure (HF) with preserved ejection fraction (HF-pEF) is a global health problem. We explore here the feasibility using patient-specific cardiac computer modeling to capture diastolic parameters in patients suffering from different degrees of systolic HF. Fifty eight patients with idiopathic dilated cardiomyopathy have undergone thorough clinical evaluation, including cardiac magnetic resonance imaging (MRI), heart catheterization, echocardiography, and cardiac biomarker assessment. A previously-introduced framework for creating multi-scale patient specific cardiac models has been applied on all these patients. Novel parameters, such as global stiffness factor and maximum left ventricular active stress, representing cardiac active and passive tissue properties have been computed for all patients. Invasive pressure measurements from heart catheterization were then used to evaluate ventricular relaxation using the time constant of isovolumic relaxation Tau (tau). Parameters from heart catheterization and the multi-scale model have been evaluated and compared to patient clinical presentation. The model parameter global stiffness factor, representing diastolic passive tissue properties, is correlated significantly across the patient population with tau. This study shows that multi-modal cardiac models can successfully capture diastolic (dys) function, a prerequisite for future clinical trials on HF-pEF. PMID- 27477451 TI - Assessment of Self-Contamination During Removal of Personal Protective Equipment for Ebola Patient Care. AB - OBJECTIVE Ebola virus disease (EVD) places healthcare personnel (HCP) at high risk for infection during patient care, and personal protective equipment (PPE) is critical. Protocols for EVD PPE doffing have not been validated for prevention of viral self-contamination. Using surrogate viruses (non-enveloped MS2 and enveloped Phi6), we assessed self-contamination of skin and clothes when trained HCP doffed EVD PPE using a standardized protocol. METHODS A total of 15 HCP donned EVD PPE for this study. Virus was applied to PPE, and a trained monitor guided them through the doffing protocol. Of the 15 participants, 10 used alcohol based hand rub (ABHR) for glove and hand hygiene and 5 used hypochlorite for glove hygiene and ABHR for hand hygiene. Inner gloves, hands, face, and scrubs were sampled after doffing. RESULTS After doffing, MS2 virus was detected on the inner glove worn on the dominant hand for 8 of 15 participants, on the non dominant inner glove for 6 of 15 participants, and on scrubs for 2 of 15 participants. All MS2 on inner gloves was observed when ABHR was used for glove hygiene; none was observed when hypochlorite was used. When using hypochlorite for glove hygiene, 1 participant had MS2 on hands, and 1 had MS2 on scrubs. CONCLUSIONS A structured doffing protocol using a trained monitor and ABHR protects against enveloped virus self-contamination. Non-enveloped virus (MS2) contamination was detected on inner gloves, possibly due to higher resistance to ABHR. Doffing protocols protective against all viruses need to incorporate highly effective glove and hand hygiene agents. Infect Control Hosp Epidemiol 2016;1-6. PMID- 27477452 TI - Easy and inexpensive molecular detection of dengue, chikungunya and zika viruses in febrile patients. AB - Dengue (DENV), chikungunya (CHIKV) and zika (ZIKV) are arthropod-borne viruses (arboviruses) sharing a common vector, the mosquito Aedes aegypti. At initial stages, patients infected with these viruses have similar clinical manifestations, however, the outcomes and clinical management of these diseases are different, for this reason early and accurate identification of the causative virus is necessary. This paper reports the development of a rapid and specific nested-PCR for detection of DENV, CHIKV and ZIKV infection in the same sample. A set of six outer primers targeting the C-preM, E1, and E gene respectively was used in a multiplex one-step RT-PCR assay, followed by the second round of amplification with specific inner primers for each virus. The specificity of the present assay was validated with positive and negative serum samples for viruses and supernatants of infected cells. The assay was tested using clinical samples from febrile patients. In these samples, we detected mono and dual infections and a case of triple co-infection DENV-CHIKV-ZIKV. This assay might be a useful and an inexpensive tool for detection of these infections in regions where these arboviruses co-circulate. PMID- 27477453 TI - Treatment with an orally bioavailable prodrug of 17beta-estradiol alleviates hot flushes without hormonal effects in the periphery. AB - Estrogen deprivation has a profound effect on the female brain. One of the most obvious examples of this condition is hot flushes. Although estrogens relieve these typical climacteric symptoms, many women do not want to take them owing to unwanted side-effects impacting, for example, the uterus, breast and blood. Therefore, there is a need for developing safer estrogen therapies. We show here that treatment with 10beta,17beta-dihydroxyestra-1,4-dien-3-one (DHED), a novel brain-targeting bioprecursor prodrug of the main human estrogen, 17beta estradiol, alleviates hot flushes in rat models of thermoregulatory dysfunction of the brain. Oral administration of DHED elicits a significant reduction of tail skin temperature (TST) rise representing hot flushes in the morphine-dependent ovariectomized rat model and results in the restoration of estrogen deprivation induced loss of diurnal rhythm in TST. These beneficial effects occur without detrimental peripheral hormonal exposure; thus, the treatment avoids potentially harmful stimulation of estrogen-sensitive peripheral organs, including the uterus and the anterior pituitary, or the proliferation of MCF-7a breast cancer cell xenografts. Our promising preclinical assessments warrant further considerations of DHED for the development of a brain-selective 17beta-estradiol therapy to relieve hot flushes without undesirable peripheral side-effects. PMID- 27477454 TI - Role of anti-domain 1-beta2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome: reply. PMID- 27477455 TI - Toward the development of an in silico human model for indoor environmental design. AB - In modern society where people spend more than 90% of their time in indoor spaces, the indoor air quality (IAQ) created by buildings has the potential of greatly influencing quality of life. Because the time spent by workers/residents in indoor spaces has increased over time, the importance of IAQ issues in terms of public health is also increasing. Additionally, the quality of the indoor thermal environment also has great impact on human comfort and performance; hence, the development of a comprehensive prediction method integrating indoor air quality/thermal environment assessment and human physiological responses, is crucial for creating a healthy, comfortable, and productive indoor environment. Accordingly, the overarching objective of this study was to develop a comprehensive and universal computer simulated person (i.e., in silico human model), integrating computational fluid dynamics (CFD), to be used in indoor environmental design and quality assessment. This paper presents and discusses the development of this computer-simulated person and its application to indoor environmental design. PMID- 27477456 TI - What can we learn from noise? - Mesoscopic nonequilibrium statistical physics. AB - Mesoscopic systems - small electric circuits working in quantum regime - offer us a unique experimental stage to explorer quantum transport in a tunable and precise way. The purpose of this Review is to show how they can contribute to statistical physics. We introduce the significance of fluctuation, or equivalently noise, as noise measurement enables us to address the fundamental aspects of a physical system. The significance of the fluctuation theorem (FT) in statistical physics is noted. We explain what information can be deduced from the current noise measurement in mesoscopic systems. As an important application of the noise measurement to statistical physics, we describe our experimental work on the current and current noise in an electron interferometer, which is the first experimental test of FT in quantum regime. Our attempt will shed new light in the research field of mesoscopic quantum statistical physics. PMID- 27477457 TI - Overview on poly(ADP-ribose) immuno-biomedicine and future prospects. AB - Poly(ADP-ribose), identified in 1966 independently by three groups Strassbourg, Kyoto and Tokyo, is synthesized by poly(ADP-ribose) polymerases (PARP) from NAD(+) as a substrate in the presence of Mg(2+). The structure was unique in that it has ribose-ribose linkage. In the early-1970s, however, its function in vivo/in vitro was still controversial and the antibody against it was desired to help clear its significance. Thereupon, the author tried to produce antibody against poly(ADP-ribose) in rabbits and succeeded in it for the first time in the world. Eventually, this success has led to the following two groundbreaking papers in Nature: "Naturally-occurring antibody against poly(ADP-ribose) in patients with autoimmune disease SLE", and "Induction of anti-poly(ADP-ribose) antibody by immunization with synthetic double-stranded RNA, poly(A).poly(U)".On the way to the publication of the first paper, a reviewer gave me a friendly comment that there is "heteroclitic" fashion as a mechanism of the production of natural antibody. This comment was really a God-send for me, and became a train of power for publication of another paper, as described above. Accordingly, I thought this, I would say, episode is worth describing herein. Because of its importance in biomedical phenomena, a certain number of articles related to "heteroclitic" have become to be introduced in this review, although they were not always directly related to immuno-biological works on poly(ADP-ribose). Also, I tried to speculate on the future prospects of poly(ADP-ribose), product of PARP, as an immuno-regulatory molecule, including either induced or naturally occurring antibodies, in view of "heteroclitic". PMID- 27477458 TI - Microglial phospholipase D4 deficiency influences myelination during brain development. AB - Phospholipase D4 (PLD4) is expressed in activated microglia that transiently appear in white matter during postnatal brain development. Previous knockdown experiments using cultured microglia showed PLD4 involvement in phagocytosis and proliferation. To elucidate the role of PLD4 in vivo, PLD4-deficient mice were generated and the cerebella were examined at postnatal day 5 (P5) and P7, when PLD4 expression is highest in microglia. Wild type microglia showed strong immunoreactivity for microglial marker CD68 at P5, whereas CD68 signals were weak in PLD4-deficient microglia, suggesting that loss of PLD4 affects microglial activation. At P5 and P7, immunostaining for anti-myelin basic protein (MBP) antibody indicated a mild but significant delay in myelination in PLD4-deficient cerebellum. Similar change was also observed in the corpus callosum at P7. However, this difference was not apparent at P10, suggesting that microglial PLD4 deficiency primarily influences the early myelination stage. Thus, microglia may have a transient role in myelination via a PLD4-related mechanism during development. PMID- 27477459 TI - Hippocampal calcifications are not associated with dementia and seem to be an incidental age-related finding. PMID- 27477460 TI - Orthogonal PLS (OPLS) Modeling for Improved Analysis and Interpretation in Drug Design. AB - Partial least squares (PLS) regression is a flexible data analytical approach, which can be made even more versatile and useful by various modifications. In this article we describe the extension into orthogonal PLS modeling, in terms of two new methods, called OPLS and O2PLS, with similar prediction capacity but improved model interpretation. PMID- 27477461 TI - Computational Insights into ADAMTS4, ADAMTS5 and MMP13 Inhibitor Selectivity. AB - The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Analysis on ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastat and two cis-1(S)2(R)-amino-2-indanol ligands suggest that determinant characteristics for ligand binding and selectivity among the three enzymes are to be found in the different protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymes has been investigated for the first time in this work. The results obtained suggest that the influence of the TS-domain on the S1' loop fluctuations of ADAMTS4 and ADAMTS5 could be exploited for the design of therapeutics for chronic osteoarthritis diseases. PMID- 27477462 TI - Comparative Occupancy Analysis (CoOAn) - A Straightforward and Directly Applicable 3D-QSAR Formalism to Extract Molecular Features Obligatory for Designing Potent Leads. AB - A simple and directly applicable 3D-QSAR method, termed Comparative Occupancy Analysis (CoOAn), has been developed. The method is based on the comparison of local occupancies of fragments of an aligned set of molecules in a 3D-grid space. The formalism commendably extracts the crucial position-specific molecular features and correlates them quantitatively to their biological endpoints. The method has been effectively applied and efficaciously validated on three large and diverse datasets?thrombin, glycogen phosphorylase b (GPB), and thermolysin inhibitors. Several robust and statistically significant predictive 3D-QSAR models were developed while simultaneously considering the influence of grid spacing on the accuracy of the results. The models, generated by the G/PLS chemometric method, not only unswervingly identified the obligatory chemical features but advantageously detected those that are unfavourable or detrimental for the molecular activity. The CoOAn models can profitably be used to optimize existing molecules as well as to design new leads with more desirable (and/or less detrimental) features. The activity-modulating features (together with their distance-constraints) extracted by the methodology can also be incorporated into a pharmacophore-type query to search a chemical database for novel leads. PMID- 27477463 TI - Fingerprint Kernels for Protein Structure Comparison. AB - A key task in structural biology is to define a meaningful similarity measure for the comparison of protein structures. Recently, the use of graphs as modeling tools for molecular data has gained increasing importance. In this context, kernel functions have attracted a lot of attention, especially since they allow for the application of a rich repertoire of methods from the field of kernel based machine learning. However, most of the existing graph kernels have been designed for unlabeled and/or unweighted graphs, although proteins are often more naturally and more exactly represented in terms of node-labeled and edge-weighted graphs. Here we analyze kernel-based protein comparison methods and propose extensions to existing graph kernels to exploit node-labeled and edge-weighted graphs. Moreover, we propose an instance of the substructure fingerprint kernel suitable for the analysis of protein binding sites. By using fuzzy fingerprints, we solve the problem of discontinuity on bin-boundaries arising in the case of labeled graphs. PMID- 27477464 TI - QSAR, QSPR and QSRR in Terms of 3-D-MoRSE Descriptors for In Silico Screening of Clofibric Acid Analogues. AB - A series of 27 analogues of clofibric acid, mostly heteroarylalkanoic derivatives, have been analyzed by a novel high-throughput reversed-phase HPLC method employing combined gradient of eluent's pH and organic modifier content. The such determined hydrophobicity (lipophilicity) parameters, log kw , and acidity constants, pKa , were subjected to multiple regression analysis to get a QSRR (Quantitative Structure?Retention Relationships) and a QSPR (Quantitative Structure-Property Relationships) equation, respectively, describing these pharmacokinetics-determining physicochemical parameters in terms of the calculation chemistry derived structural descriptors. The previously determined in vitro log EC50 values - transactivation activity towards PPARalpha (human Peroxisome Proliferator-Activated Receptor alpha) - have also been described in a QSAR (Quantitative Structure?Activity Relationships) equation in terms of the 3-D MoRSE descriptors (3D-Molecule Representation of Structures based on Electron diffraction descriptors). The QSAR model derived can serve for an a priori prediction of bioactivity in vitro of any designed analogue, whereas the QSRR and the QSPR models can be used to evaluate lipophilicity and acidity, respectively, of the compounds, and hence to rational guide selection of structures of proper pharmacokinetics. PMID- 27477465 TI - Molecular Docking Study Based on Pharmacophore Modeling for Novel PhosphodiesteraseIV Inhibitors. AB - In this study, pharmacophore modelling was carried out for novel PhosphodiesteraseIV (PDEIV) inhibitors. A pharmacophore-based virtual screening, which resulted in 1959 hit compounds was performed with six chemical databases. The pharmacophore screening was proven to be successful in discriminating active and inactive inhibitors using a set of compounds with known activity obtained from ChEMBL database. Furthermore, the Lipinski's rule of five was applied for physicochemical filtering of the hit molecules and this yielded 1840 compounds. Three docking software tools, AutoDock 4.0, AutoDock Vina, and Gold v5.1 were used for the docking process. All 1840 compounds and the known selective inhibitor, rolipram, were docked into the active site of the target protein. A total of 234 compounds with all three scoring values higher than those of rolipram were determined with the three docking tools. The interaction maps of 14 potent inhibitors complexed with PDEIV B and D isoforms have been analyzed and seven key residues (Asn 395, Gln 443, Tyr 233, Ile 410, Phe 446, Asp 392, Thr 407) were found to interact with more than 80 % of the potent inhibitors. For each one of the 234 hit compounds, using the bound conformation with the highest AutoDock score, the interacting residues were determined. 117 out of 234 compounds are found to interact with at least five of the seven key residues and these were selected for further evaluation. The conformation with the highest AutoDock score for each 117 compounds were rescored using the DSX scoring function. This yielded a total of 101 compounds with better score values than the natural ligand rolipram. For ADME/TOX calculations, the FAF-Drugs2 server was used and 32 out of 101 compounds were found to be non-toxic. PMID- 27477466 TI - Application of GQSAR for Scaffold Hopping and Lead Optimization in Multitarget Inhibitors. AB - Many literature reports suggest that drugs against multiple targets may overcome many limitations of single targets and achieve a more effective and safer control of the disease. However, design of multitarget drugs presents a great challenge. The present study demonstrates application of a novel Group based QSAR (GQSAR) method to assist in lead optimization of multikinase (PDGFR-beta, FGFR-1 and SRC) and scaffold hopping of multiserotonin target (serotonin receptor 1A and serotonin transporter) inhibitors. For GQSAR analysis, a wide variety of structurally diverse multikinase inhibitors (225 molecules) and multiserotonin target inhibitors (162 molecules) were collected from various literature reports. Each molecule in the data set was divided into four fragments (kinase inhibitors) and three fragments (serotonin target inhibitors) and their corresponding two dimensional fragment descriptors were calculated. The multiresponse regression GQSAR models were developed for both the datasets. The developed GQSAR models were found to be useful for scaffold hopping and lead optimization of multitarget inhibitors. In addition, the developed GQSAR models provide important fragment based features that can form the building blocks to guide combinatorial library design in the search for optimally potent multitarget inhibitors. PMID- 27477467 TI - QSPR Approach to Predict Nonadditive Properties of Mixtures. Application to Bubble Point Temperatures of Binary Mixtures of Liquids. AB - This paper is devoted to the development of methodology for QSPR modeling of mixtures and its application to vapor/liquid equilibrium diagrams for bubble point temperatures of binary liquid mixtures. Two types of special mixture descriptors based on SiRMS and ISIDA approaches were developed. SiRMS-based fragment descriptors involve atoms belonging to both components of the mixture, whereas the ISIDA fragments belong only to one of these components. The models were built on the data set containing the phase diagrams for 167 mixtures represented by different combinations of 67 pure liquids. Consensus models were developed using nonlinear Support Vector Machine (SVM), Associative Neural Networks (ASNN), and Random Forest (RF) approaches. For SVM and ASNN calculations, the ISIDA fragment descriptors were used, whereas Simplex descriptors were employed in RF models. The models have been validated using three different protocols: "Points out", "Mixtures out" and "Compounds out", based on the specific rules to form training/test sets in each fold of cross validation. A final validation of the models has been performed on an additional set of 94 mixtures represented by combinations of novel 34 compounds and modeling set chemicals with each other. The root mean squared error of predictions for new mixtures of already known liquids does not exceed 5.7 K, which outperforms COSMO RS models. Developed QSAR methodology can be applied to the modeling of any nonadditive property of binary mixtures (antiviral activities, drug formulation, etc.). PMID- 27477468 TI - Nearly no Scoring Function Without a Hansch-Analysis. AB - Corwin Hansch is well-known as the father, inventor, and promoter of quantitative structure-activity relationships. Usually, QSAR is seen as a ligand-based design method correlating molecular structure or property descriptors to biological activity. QSAR is seldom mentioned in relation to structure-based approaches, although it is the centerpiece of nearly every empirical scoring function. QSAR techniques are applied on various levels, from the fitting of scoring terms to biological affinity data in empirical scoring functions up to the fine-tuning of individual aspects of protein-ligand interactions. In the following, we report on current findings for our scoring approach HYDE, which are based upon both the idea of QSAR and Hansch's historical logP data. We relate the molecular surface area of 594 diverse compounds to their experimental octanol/water partition coefficients aiming at new insights in hydrogen bonding and dehydration energies of solutes. Donors and acceptors which are far from each other contribute with nearly constant increments to the logP value. The solubility in the aqueous phase is however not increased with the number of hydrogen bonds a polar group is able to form. Although signs are found that these facts have been known for many years, they have implications for modern scoring function design. PMID- 27477469 TI - Large-Scale QSAR in Target Prediction and Phenotypic HTS Assessment. AB - The advent of in silico compound target prediction offers a potential paradigm shift in how large compound collections are understood and used strategically in high-throughput screens (HTS). Specifically, phenotypic HTS hits may be annotated both with known targets and predicted targets using large-scale QSAR models, enabling a more sophisticated hit assessment. Efforts in massive bioactivity data integration and standardization is empowering such compound-target annotations. These approaches differ fundamentally from the traditional role of QSAR in lead optimization and binding affinity predictions to global, probabilistic target predictions for thousands of human proteins. PMID- 27477470 TI - A unified set of experimental organometallic data used to evaluate modern theoretical methods. AB - We applied a test set of ligand dissociation enthalpies derived entirely from a unified experimental approach to evaluate the efficacy of various methods for modeling organometallic chemistry. This differs from most benchmarking studies, as it is common to evaluate theoretical methods by using more computationally expensive calculations to provide the "target" values. With an aim of presenting the 'best suited functional/functionals' for calculations involving the metal ligand bond dissociation enthalpies (BDEs) of organometallic complexes, we utilized a database of 30 experimental metal-ligand bond dissociation enthalpies, and tested for 101 density functionals and 2 ab initio methods, all with a large basis set. We find the most accurate functional is M06 with a mean unsigned error (MUE) of 1.6 kcal mol(-1), followed closely by M06L, omegaB97XD, PW91PW91 and MPWB95 with MUEs of 1.7, 1.8, 2.0, and 2.1 kcal mol(-1) respectively. Other top performers are B3LYP-GD3, BLYP-GD3, PBEPBE, CAM-B3LYP-GD3, CAM-B3LYP-GD3BJ, B3LYP GD3BJ and MN12L; all predict BDEs with MUEs in the range of 2.2 to 2.5 kcal mol( 1). Adding solvent corrections to the gas-phase BDE calculations for these top twelve functionals do not significantly change the MUE value. The well-known and widely used functional B3LYP shows very poor performance for this specific property. However, the empirical dispersion correction to the B3LYP functional has significantly improved its performance in predicting BDEs. It is also worth noting that several modern range-separated functionals predict the bond dissociation enthalpies with an error of 2-3 kcal mol(-1). PMID- 27477471 TI - Growth and Consequences. AB - In response to the growth of JOSPT, Editor-in-Chief J. Haxby Abbott introduces 3 new Associate Editors to the JOSPT Editorial Board, and announces the promotion of 1 outstanding Editorial Board member to an Editor role. J Orthop Sports Phys Ther 2016;46(8):610-612. doi:10.2519/jospt.2016.0111. PMID- 27477472 TI - Sport-Related Concussion: Optimizing Treatment Through Evidence-Informed Practice. AB - Concussion is one of the most common injuries in sport and recreation today. Reports of concussion have increased in recent years, likely due to increased societal awareness and the risk of longer-term sequelae. Presently, treatment includes a period of prescribed rest in the acute period following injury, followed by a protocol of graded exertion. Despite an initial period of rest and attempts at a gradual return to play, up to 30% of individuals may have ongoing symptoms past the acute period. The goal of this viewpoint is to introduce the reader to the most common symptoms of concussion and the need for a new, more active paradigm during treatment. J Orthop Sports Phys Ther 2016;46(8):613-616. doi:10.2519/jospt.2016.0607. PMID- 27477473 TI - Cervicothoracic Manual Therapy Plus Exercise Therapy Versus Exercise Therapy Alone in the Management of Individuals With Shoulder Pain: A Multicenter Randomized Controlled Trial. AB - Study Design Multicenter randomized controlled trial. Background Cervicothoracic manual therapy has been shown to improve pain and disability in individuals with shoulder pain, but the incremental effects of manual therapy in addition to exercise therapy have not been investigated in a randomized controlled trial. Objectives To compare the effects of cervicothoracic manual therapy and exercise therapy to those of exercise therapy alone in individuals with shoulder pain. Methods Individuals (n = 140) with shoulder pain were randomly assigned to receive 2 sessions of cervicothoracic range-of-motion exercises plus 6 sessions of exercise therapy, or 2 sessions of high-dose cervicothoracic manual therapy and range-of-motion exercises plus 6 sessions of exercise therapy (manual therapy plus exercise). Pain and disability were assessed at baseline, 1 week, 4 weeks, and 6 months. The primary aim (treatment group by time) was examined using linear mixed-model analyses and the repeated measure of time for the Shoulder Pain and Disability Index (SPADI), the numeric pain-rating scale, and the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH). Patient-perceived success was assessed and analyzed using the global rating of change (GROC) and the Patient Acceptable Symptom State (PASS), using chi-square tests of independence. Results There were no significant 2-way interactions of group by time or main effects by group for pain or disability. Both groups improved significantly on the SPADI, numeric pain-rating scale, and QuickDASH. Secondary outcomes of success on the GROC and PASS significantly favored the manual therapy-plus-exercise group at 4 weeks (P = .03 and P<.01, respectively) and on the GROC at 6 months (P = .04). Conclusion Adding 2 sessions of high-dose cervicothoracic manual therapy to an exercise program did not improve pain or disability in patients with shoulder pain, but did improve patient-perceived success at 4 weeks and 6 months and acceptability of symptoms at 4 weeks. More research is needed on the use of cervicothoracic manual therapy for treating shoulder pain. Level of Evidence Therapy, level 1b. Prospectively registered March 30, 2012 at www.ClinicalTrials.gov (NCT01571674). J Orthop Sports Phys Ther 2016;46(8):617-628. doi:10.2519/jospt.2016.6319. PMID- 27477474 TI - Long-Lever-Arm Manipulation Under Anesthesia With Resultant Traumatic Anterior Shoulder Dislocation. AB - The patient was a 61-year-old woman who underwent long-lever manipulation under anesthesia (MUA) for adhesive capsulitis. Two weeks following MUA, the constellation of clinical findings raised concern for possible adverse outcomes. Radiographs were obtained, as well as subsequent magnetic resonance imaging and computed tomography scans. Images revealed anterior shoulder dislocation with Bankart and Hill-Sachs lesions, and an anterior rotator cuff tear. J Orthop Sports Phys Ther 2016;46(8):707. doi:10.2519/jospt.2016.0412. PMID- 27477475 TI - Rotator Cuff Tear Consequent to Glenohumeral Dislocation. AB - The patient was a 21-year-old collegiate running back who was tackled during a football game and sustained a posterior glenohumeral dislocation. He was referred to an orthopaedist and presented 3 weeks after the injury, and, following examination, further imaging was ordered by the orthopaedist due to rotator cuff weakness. Magnetic resonance imaging showed a complete tear of the supraspinatus and infraspinatus, as well as a posterior Bankart lesion, a subscapularis tear, and a dislocation of the biceps long head tendon into the reverse Hill-Sachs lesion. J Orthop Sports Phys Ther 2016;46(8):708. doi:10.2519/jospt.2016.0413. PMID- 27477476 TI - Effectiveness of an intervention to improve diabetes self-management on clinical outcomes in patients with low educational level. AB - OBJECTIVE: To determine whether an intervention based on patient-practitioner communication is more effective than usual care in improving diabetes self management in patients with type 2 diabetes with low educational level. METHODS: 12-month, pragmatic cluster randomised controlled trial. Nine physicians and 184 patients registered at two practices in a deprived area of Granada (Andalusia, Spain) participated in the study. Adult patients with type 2 diabetes, low educational level and glycated haemoglobin (HbA1c) > 7% (53.01 mmol/mol) were eligible. The physicians in the intervention group received training on communication skills and the use of a tool for monitoring glycaemic control and providing feedback to patients. The control group continued standard care. The primary outcome was difference in HbA1c after 12 months. Dyslipidaemia, blood pressure, body mass index and waist circumference were also assessed as secondary outcomes. Two-level (patient and provider) regression analyses controlling for sex, social support and comorbidity were conducted. RESULTS: The HbA1c levels at 12 months decreased in both groups. Multilevel analysis showed a greater improvement in the intervention group (between-group HbA1c difference= 0.16; p=0.049). No statistically significant differences between groups were observed for dyslipidaemia, blood pressure, body mass index and waist circumference. CONCLUSIONS: In this pragmatic study, a simple and inexpensive intervention delivered in primary care showed a modest benefit in glycaemic control compared with usual care, although no effect was observed in the secondary outcomes. Further research is needed to design and assess interventions to promote diabetes self-management in socially vulnerable patients. PMID- 27477477 TI - [Changes in tobacco consumption: boom of roll-your-own cigarettes and emergence of e-cigarettes]. AB - OBJECTIVE: To assess changes in smoking prevalence and study roll-your-own (RYO) tobacco and e-cigarette use in the Galician population between 2007 and 2015. METHODS: Data were obtained from five independent, cross-sectional studies carried out in Galicia (Spain) between 2007-2015 in the population aged 16 and over (n=8,000/year). Prevalence of use was estimated, with 95% confidence intervals, overall, according to sex and by age group, area of residence and level of education. RESULTS: Smoking prevalence decreased from 25.4% in 2007 to 21.8% in 2015. In 2007, 1.8% of current smokers declared that they had smoked RYO tobacco, compared to 18.6% in 2015. Among smokers, RYO tobacco consumption increased across all demographic groups. In both 2014 and 2015, ever use of e cigarettes was 0.7%. E-cigarette use was more frequent in urban settings. CONCLUSION: Smoking prevalence decreased in Galicia between 2007 and 2015, and there has been rapid growth in the prevalence of RYO tobacco use. Although smokers are more likely to use e-cigarettes, both former and never smokers declared their use. The boom of RYO cigarettes and the emergence of e-cigarettes highlight the importance of having continuous surveillance systems to identify smoking behavioural changes. PMID- 27477478 TI - Erratum to: Fanconi-Bickel Syndrome - Mutation in SLC2A2 Gene. PMID- 27477479 TI - Carfilzomib: a rare cause of posterior reversible encephalopathy syndrome. PMID- 27477480 TI - Tropical Medicine & International Health. PMID- 27477482 TI - Functional classification of CATH superfamilies: a domain-based approach for protein function annotation. PMID- 27477481 TI - Alterations in ribosomal protein L19 that decrease the fidelity of translation. AB - Ribosomal protein L19 is an essential ribosomal protein and is a component of bridge B8, one of the protein-RNA bridges linking the large and small ribosomal subunits. Bridge B8 also contributes to the accuracy of translation by affecting GTPase activation by ribosome-bound aminoacyl tRNA-EF-Tu*GTP ternary complexes. Previous work has identified a limited number of accuracy-altering alterations in protein L19 of Salmonella enterica and Thermus thermophilus. Here, we have targeted the Escherichia coli rplS gene encoding L19 for mutagenesis and have screened for mutants with altered levels of miscoding. We have recovered 14 distinct L19 mutants, all of which promote increased stop codon readthrough, but do not have major effects on subunit association or cell growth. Examination of the E. coli 70S ribosome structure indicates that the amino acid substitutions cluster in three distinct regions of L19 and thereby potentially affect its interactions with L14 and 16S rRNA. PMID- 27477484 TI - Enhanced mitochondrial glutamine anaplerosis suppresses pancreatic cancer growth through autophagy inhibition. AB - Cancer cells use precursors derived from tricarboxylic acid (TCA) cycle to support their unlimited growth. However, continuous export of TCA cycle intermediates results in the defect of mitochondrial integrity. Mitochondria glutamine metabolism plays an essential role for the maintenance of mitochondrial functions and its biosynthetic roles by refilling the mitochondrial carbon pool. Here we report that human pancreatic ductal adenocarcinoma (PDAC) cells have a distinct dependence on mitochondrial glutamine metabolism. Whereas glutamine flux into mitochondria contributes to proliferation of most cancer cells, enhanced glutamine anaplerosis results in a pronounced suppression of PDAC growth. A cell membrane permeable alpha-ketoglutarate analog or overexpression of glutamate dehydrogenase lead to decreased proliferation and increased apoptotic cell death in PDAC cells but not other cancer cells. We found that enhanced glutamine anaplerosis inhibits autophagy, required for tumorigenic growth of PDAC, by activating mammalian TORC1. Together, our results reveal that glutamine anaplerosis is a crucial regulator of growth and survival of PDAC cells, which may provide novel therapeutic approaches to treat these cancers. PMID- 27477483 TI - TNFA gene variants related to the inflammatory status and its association with cellular aging: From the CORDIOPREV study. AB - BACKGROUND: Several single nucleotide polymorphisms have been proposed as potential predictors of the development of age-related diseases. OBJECTIVE: To explore whether Tumor Necrosis Factor Alpha (TNFA) gene variants were associated with inflammatory status, thus facilitating the rate of telomere shortening and its relation to cellular aging in a population with established cardiovascular disease from the CORDIOPREV study (NCT00924937). MATERIALS AND METHODS: SNPs (rs1800629 and rs1799964) located at the TNFA gene were genotyped by OpenArray platform in 840 subjects with established cardiovascular disease. Relative telomere length was determined by real time PCR and plasma levels of C-reactive protein by ELISA. In a subgroup of 90 subjects, the gene expression profiles of TNFA, IKKbeta, p47phox, p40phox, p22phox and gp91phox were determined by qRT-PCR. RESULTS: GG subjects for the SNP rs1800629 at the TNFA gene showed shorter relative telomere length and higher plasma levels of hs-CRP than A-allele subjects (p<0.05). Consistent with these findings, the expression of pro inflammatory (TNFA) and pro-oxidant (p47phox and the gp91phox) genes was higher in GG subjects than A allele subjects (p<0.05). CONCLUSION: Subjects carrying the GG genotype for the SNP rs1800629 at the TNFA gene show a greater activation of the proinflammatory status than A-allele carriers, which is related to ROS formation. These ROS could induce DNA damage especially in the telomeric sequence, by decreasing the telomere length and inducing cellular aging. This effect may also increase the risk of the development of age-related diseases. PMID- 27477485 TI - Effects of scFOS on the composition of fecal microbiota and anxiety in patients with irritable bowel syndrome: a randomized, double blind, placebo controlled study. AB - BACKGROUND: Short-chain fructooligosaccharides (scFOS) have beneficial effects in subjects with minor digestive complaints, but the potential mechanisms involved have not been elucidated. The aim of the study was to evaluate changes in rectal sensitivity related to the clinical effects of scFOS in a selected group of patients with irritable bowel syndrome (IBS) and rectal hypersensitivity. METHODS: In 79 IBS patients (defined by Rome III criteria) with rectal hypersensitivity (defined as discomfort threshold <=44 g) a parallel, placebo controlled, randomized, and double-blind study was performed to assess the effects of dietary supplementation (5 g d-1 ) with scFOS vs placebo for 4 weeks on rectal sensitivity (primary outcome: tolerance to increasing wall tension applied by a tensostat), clinical outcomes (IBS, anxiety/depression and quality of life scores) and composition of fecal microbiota. KEY RESULTS: Rectal discomfort threshold, and IBS and quality of life scores, significantly improved during treatment, but in a similar manner in both scFOS and placebo groups; a post-hoc analysis showed that the effect of scFOS on rectal sensitivity was more pronounced in constipation-predominant-IBS patients (P=.051 vs placebo). Contrary with placebo, scFOS significantly reduced anxiety scores and increased fecal Bifidobacteria (P<.05 for both) without modifying other bacterial groups. CONCLUSIONS & INTERFENCES: The effect of scFOS on anxiety may be related to modulation of the gut microbiota; demonstration of effects of scFOS on rectal sensitivity may require higher doses and may depend on the IBS subgroup. PMID- 27477486 TI - DNA-encoded chemical libraries: foundations and applications in lead discovery. AB - DNA-encoded chemical libraries have emerged as a powerful tool for hit identification in the pharmaceutical industry and in academia. Similar to biological display techniques (such as phage display technology), DNA-encoded chemical libraries contain a link between the displayed chemical building block and an amplifiable genetic barcode on DNA. Using routine procedures, libraries containing millions to billions of compounds can be easily produced within a few weeks. The resulting compound libraries are screened in a single test tube against proteins of pharmaceutical interest and hits can be identified by PCR amplification of DNA barcodes and subsequent high-throughput sequencing. PMID- 27477487 TI - GPCRs - Pivotal Players in Metabolism. PMID- 27477488 TI - Patterns of Distant Metastases After Surgical Management of Non-Small-cell Lung Cancer. AB - BACKGROUND: Patients with limited metastases, oligometastases (OMs), might have improved outcomes compared with patients with widespread distant metastases (DMs). The incidence and behavior of OMs from non-small-cell lung cancer (NSCLC) need further characterization. PATIENTS AND METHODS: The medical records of patients who had undergone surgery for stage I-III NSCLC from 1995 to 2009 were retrospectively reviewed. All information pertaining to development of the first metastatic progression was recorded and analyzed. Patients with DMs were categorized into OMs (1-3 lesions potentially amenable to local therapy) and DM subgroups. RESULTS: Of 1719 patients reviewed, 368 (21%) developed DMs with a median follow-up period of 39 months. A single lesion was diagnosed in 115 patients (31%) and 69 (19%) had 2 to 3 lesions (50% oligometastatic). The median survival from the DM diagnosis for oligometastatic and diffuse DM was 12.4 and 6.1 months, respectively (hazard ratio, 0.54; 95% confidence interval, 0.42-0.68; P < .001). Patients with a single metastasis had the longest median survival at 14.7 months. Younger age, OM, the use of chemotherapy for the primary tumor, and DM detection by surveillance imaging were independently associated with improved survival. CONCLUSION: DMs and OMs are common in surgically managed NSCLC. Overall survival appears to be prolonged with OM. PMID- 27477489 TI - CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. AB - Ankyrin repeat and sterile alpha motif domain-containing protein 1B (ANKS1B, also known as AIDA-1) is a major component of the postsynaptic density (PSD) in excitatory neurons where it concentrates at the electron-dense core under basal conditions and moves out during activity. This study investigates the molecular mechanism underlying activity-induced displacement of AIDA-1. Experiments with PSD fractions from brain indicate phosphorylation of AIDA-1 upon activation of endogenous CaMKII. Immuno-electron microscopy studies show that treatment of hippocampal neurons with NMDA results in an ~ 30 nm shift in the median distance of the AIDA-1 label from the postsynaptic membrane, an effect that is blocked by the CaMKII inhibitor tatCN21. CaMKII-mediated redistribution of AIDA-1 is similar to that observed for SynGAP. CaMKII-mediated removal of two abundant PSD-95 binding proteins from the PSD core during activity is expected to initiate a molecular reorganization at the PSD. PMID- 27477492 TI - Cell biology: Vasopressin-independent AQP2 trafficking. PMID- 27477493 TI - Dialysis: Bioengineered vessels for dialysis access: soon to be a reality? PMID- 27477491 TI - Insights into kidney diseases from genome-wide association studies. AB - Over the past decade, genome-wide association studies (GWAS) have considerably improved our understanding of the genetic basis of kidney function and disease. Population-based studies, used to investigate traits that define chronic kidney disease (CKD), have identified >50 genomic regions in which common genetic variants associate with estimated glomerular filtration rate or urinary albumin to-creatinine ratio. Case-control studies, used to study specific CKD aetiologies, have yielded risk loci for specific kidney diseases such as IgA nephropathy and membranous nephropathy. In this Review, we summarize important findings from GWAS and clinical and experimental follow-up studies. We also compare risk allele frequency, effect sizes, and specificity in GWAS of CKD defining traits and GWAS of specific CKD aetiologies and the implications for study design. Genomic regions identified in GWAS of CKD-defining traits can contain causal genes for monogenic kidney diseases. Population-based research on kidney function traits can therefore generate insights into more severe forms of kidney diseases. Experimental follow-up studies have begun to identify causal genes and variants, which are potential therapeutic targets, and suggest mechanisms underlying the high allele frequency of causal variants. GWAS are thus a useful approach to advance knowledge in nephrology. PMID- 27477494 TI - Impairment in subcortical suppression in schizophrenia: Evidence from the fBIRN Oddball Task. AB - Schizophrenia patients show widespread impairments in brain activity during oddball tasks, which involve responding to infrequent target stimuli while refraining from responding during continuous non-target stimuli. In a network based investigation comparing schizophrenia or schizoaffective patients to healthy controls, we sought to clarify which networks were specifically associated with target detection using a multivariate analysis technique that identifies task-specific functional brain networks. We acquired data from the publicly available function biomedical informatics research network collaboration, including 58 patients and 50 controls. Two task-based functional brain networks were identified: (1) a response modulation network including bilateral temporal pole, supramarginal gyrus, striatum, and thalamus, on which patients showed decreased activity relative to controls; and (2) an auditory motor response activation network, on which patients showed a slower return to baseline than controls, but no difference in peak activation. For both groups, baseline to peak activation of the response modulation network correlated negatively with peak to baseline activity in the response activation network, suggesting a role in suppressing the motor response following targets. Patients' impaired activity in the response modulation network, and subsequent longer return to baseline in the response activation network, correspond with their later and less accurate behavioral performance, suggesting that impairment in suppression of the auditory-motor response activation network could underlie oddball task deficits in schizophrenia. In addition, the magnitude of the activity in the response modulation network was correlated with intensity of delusions of reference, supporting the notion that increased referential ideation is associated with hyperactivity within the subcortical striatal-limbic network. Hum Brain Mapp 37:4640-4653, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27477495 TI - The role of minimally invasive interval debulking surgery in advanced epithelial ovarian cancer. PMID- 27477496 TI - Greater carotid intima media thickness at a younger age in HIV-infected patients compared with reference values for an uninfected cohort. AB - OBJECTIVES: In contrast to the general population, no decline in cardiovascular disease (CVD) has been noted in HIV-infected patients over the last 10 years. We compared the carotid artery intima media thickness (CIMT) of HIV-infected patients to that of age- and gender-matched reference values and determined the relationship between CVD risk factors and CIMT. METHODS: A total of 292 HIV infected patients were enrolled in the study. Data collected included vascular screening data, data obtained using a questionnaire, data obtained from laboratory assessments and CIMT measurement. Using linear regression (adjusted for age/gender/known HIV), the association between HIV-specific and classical cardiovascular risk factors and CIMT was evaluated. RESULTS: The cohort comprised for 91% of male patients, aged 49.4 +/- 10.5 years, with a known duration of HIV infection of 8.8 +/- 6.7 years. The mean with standard deviation (mean +/- SD) CIMT was 0.77 +/- 0.19 mm, compared with 0.58 +/- 0.05 mm in the controls. A steeper increase of CIMT per age was seen in the HIV-infected patients. A significant relationship between CIMT and hypertension, diabetes mellitus, smoking, systolic blood pressure, HbA1c (glycated hemoglobin) and ankle brachial index was found. Of the HIV-specific variables, only a relationship between CIMT and length of cART use and between CIMT and (inversely) current cART use was seen. CONCLUSIONS: A greater CIMT was found in HIV-infected patients compared with controls. In contrast to HIV-specific variables, classical CVD risk factors were associated with a greater CIMT and should therefore be the focus of preventive measures. PMID- 27477497 TI - Optimization of Internally Deleted Dystrophin Constructs. AB - Duchenne muscular dystrophy (DMD) is a severe, genetic muscle disease caused by the absence of the sarcolemmal protein dystrophin. Gene replacement therapy is considered a potential strategy for the treatment of DMD, aiming to restore the missing protein. Although the elements of the dystrophin molecule have been identified and studies in transgenic mdx mice have explored the importance of a number of these structural domains, the resulting modified dystrophin protein products that have been developed so far are only partially characterized in relation to their structure and function in vivo. To optimize a dystrophin cDNA construct for therapeutic application we designed and produced four human minidystrophins within the packaging capacity of lentiviral vectors. Two novel minidystrophins retained the centrally located neuronal nitric oxide synthase (nNOS)-anchoring domain in order to achieve sarcolemmal nNOS restoration, which is lost in most internally deleted dystrophin constructs. Functionality of the resulting truncated dystrophin proteins was investigated in muscle of adult dystrophin-deficient mdx mice followed by a battery of detailed immunohistochemical and morphometric tests. This initial assessment aimed to determine the overall suitability of various constructs for cloning into lentiviral vectors for ex vivo gene delivery to stem cells for future preclinical studies. PMID- 27477490 TI - Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. AB - The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation. Studies involving selective gene targeting of mTOR complexes (mTORC1 and mTORC2) in renal cell populations and/or pharmacologic mTOR inhibition have revealed important roles of mTOR in podocyte homeostasis and tubular transport. Important advances have also been made in understanding the role of mTOR in renal injury, polycystic kidney disease and glomerular diseases, including diabetic nephropathy. Novel insights into the roles of mTORC1 and mTORC2 in the regulation of immune cell homeostasis and function are helping to improve understanding of the complex effects of mTOR targeting on immune responses, including those that impact both de novo renal disease and renal allograft outcomes. Extensive experience in clinical renal transplantation has resulted in successful conversion of patients from calcineurin inhibitors to mTOR inhibitors at various times post-transplantation, with excellent long-term graft function. Widespread use of this practice has, however, been limited owing to mTOR-inhibitor- related toxicities. Unique attributes of mTOR inhibitors include reduced rates of squamous cell carcinoma and cytomegalovirus infection compared to other regimens. As understanding of the mechanisms by which mTORC1 and mTORC2 drive the pathogenesis of renal disease progresses, clinical studies of mTOR pathway targeting will enable testing of evolving hypotheses. PMID- 27477499 TI - The expression analysis of Bmpr1a and Bmp2 during hindgut development in rat embryos with anorectal malformations. AB - The aim of this study was to determine Bmpr1a and Bmp2 expression patterns during anorectal development in normal and anorectal malformation (ARM) embryos with a view to establishing the possible role of Bmpr1a and Bmp2 in ARM pathogenesis. ARM was induced with ethylenethiourea on the 10th gestational day (GD10) in rat embryos. The embryos were harvested by Cesarean deliveries. The expression of Bmpr1a and Bmp2 was evaluated in normal rat embryos (n=213) and ARM embryos (n=236) from GD14 to GD16. Immunohistochemical staining revealed, in normal embryos, that Bmpr1a and Bmp2 was mainly expressed on the epithelium of the urorectal septum (URS) and the cloacal membrane (CM) on GD14 and GD15. When the rectum separated from the urogenital sinus (UGS) on GD16, Bmpr1a- and Bmp2 immunolabeled cells were observed on the anorectal epithelium. In ARM embryos, the epithelium of the hindgut and URS demonstrated faint immunostaining for Bmpr1a and Bmp2. Analyses by Western blot and Real-time PCR revealed that Bmpr1a and Bmp2 protein and mRNA expression were significantly decreased in the ARM hindgut compared with normal hindgut on GD14 and GD15 (P<0.05). In ARM embryos, an imbalance in the spatiotemporal expression of Bmpr1a and Bmp2 was noted during anorectal morphogenesis from GD14 to GD16. Therefore, downregulation of Bmpr1a and Bmp2 at the time of cloacal separation into the primitive rectum and UGS might be related to the development of ARM. PMID- 27477498 TI - Sexual identity development: relationship with lifetime suicidal ideation in sexual minority women. AB - AIMS AND OBJECTIVES: This study draws on a life course perspective to evaluate in a sample of sexual minority women: (1) the relationship between age at reaching sexual identity milestones and risk of suicidal ideation, (2) developmental stages or stages of sexual identity development that represent greatest risk and (3) the relationship between age of reaching milestones and parental support. BACKGROUND: Research shows higher rates of suicidal ideation among sexual minority women than heterosexual women. Evidence suggests this is partly accounted for by risk factors including sexual identity development and parental support. However, it remains unclear whether there are stages of particularly high risk. DESIGN: This is a cross-sectional study. Data come from a prospective study of sexual minority women that used convenience and respondent-driven sampling methods. METHODS: Using logistic regression, we examined associations among age at sexual identity developmental milestones, parental support and suicidal ideation in a large (N = 820), ethnically diverse sample of sexual minority women. RESULTS: Compared with women who first wondered about their sexual identity in adulthood, those who first wondered in early, middle or late adolescence had greater odds of lifetime suicidal ideation. Younger age at subsequent milestones (first decided or first disclosed) was not associated with heightened risk of suicidal ideation. Parental support was independently associated with suicidal ideation. CONCLUSIONS: Findings suggest that where one is in the process of identifying as a sexual minority may be more important than age in understanding risk of suicidal ideation in this population. As individuals come to accept and integrate their sexual minority identity risks associated with younger age diminish. RELEVANCE TO CLINICAL PRACTICE: Nurses and other healthcare providers who work with youth should routinely ask about sexual orientation and suicidal ideation and be aware that youth in the earliest stages of coming out as sexual minority may be at particularly high risk of suicide. PMID- 27477500 TI - Future occupational health services, policies and regulations of Japan, in view of re-examining latest global occupational health developments - The summary report of the Policies and Regulations Committee Symposium at the 88(th) Japan Society for Occupational Health Conference. PMID- 27477501 TI - Apparent seroprevalence, isolation and identification of risk factors for brucellosis among dairy cattle in Goa, India. AB - Brucellosis is a highly contagious zoonotic infection affecting livestock and human beings. The disease has been reported worldwide except in few countries where it has been eradicated. The prevalence of brucellosis among cattle from 11 farms having a history of abortions was studied. A total of 481 samples comprising of blood, milk, vaginal swabs, vaginal discharges, placental tissues and fetal tissues were collected from 296 animals. Clinical samples were processed for the isolation of Brucella. Serum samples (n=296) were tested by Rose Bengal Plate Test (RBPT) and indirect ELISA. A total of 90 (30.40%) and 123 (41.55%) samples were positive by RBPT and indirect ELISA, respectively. Also 27.02% samples were positive by both the tests. Brucella isolates (n= 8) were recovered from clinical samples using Brucella selective media. All the isolates demonstrated PCR amplification for the bcsp31 and IS711 genes. Amplification of Brucella abortus specific primer was demonstrated by all the isolates in AMOS PCR indicating isolates to be of either B. abortus biotype 1, 2 or 4. Risk factors for transmission of brucellosis among cattle population were studied by field surveys. It was observed that lack of awareness about brucellosis (OR=8.739, P=0.138) and inadequate floor space (OR=0.278, P=0.128) were crucial risk factors for transmission of bovine brucellosis. PMID- 27477502 TI - Evolutionary characteristics of morbilliviruses during serial passages in vitro: Gradual attenuation of virus virulence. AB - The genus Morbillivirus is classified into the family Paramyxoviridae, and is composed of 6 members, namely measles virus (MV), rinderpest virus (RPV), peste des-petits-ruminants virus (PPRV), canine distemper virus (CDV), phocine distemper virus (PDV) and cetacean morbillivirus (CeMV). The MV, RPV, PPRV and CDV have been successfully attenuated through their serial passages in vitro for the production of live vaccines. It has been demonstrated that the morbilliviral virulence in animals was progressively attenuated with their consecutive passages in vitro. However, only a few reports were involved in explanation of an attenuation-related mechanism on them until many years after the establishment of a quasispecies theory. RNA virus quasispecies arise from rapid evolution of viruses with high mutation rate during genomic replication, and play an important role in gradual loss of viral virulence by serial passages. Here, we overviewed the development of live-attenuated vaccine strains against morbilliviruses by consecutive passages in vitro, and further discussed a related mechanism concerning the relationship between virulence attenuation and viral evolution. PMID- 27477503 TI - Serological and molecular evidence of Q fever among small ruminant flocks in Algeria. AB - Q fever, a commonly reported zoonosis worldwide, is caused by infection with Coxiella burnetii, an obligate intracellular bacterium. The infection is often asymptomatic in ruminants, but it can lead to reproductive disorders with bacterial shedding into the environment. Between 2011 and 2013, a study was undertaken in small ruminant flocks in different regions of Algeria. A total of 35 flocks were visited and 227 sera and 267 genital swabs were collected from females after abortions or the lambing period to investigate Q fever infection. Indirect ELISA was used to detect specific antibodies against C. burnetii and real-time PCR for detecting bacterial DNA. Our survey indicated that 58% (95% CI=40-76%) of flocks had at least one positive animal (17 seropositive flocks) and individual seroprevalence was estimated at 14.1% (95% CI=11.8-16.4%) (32 seropositive animals). Bacterial excretion was observed in 21 flocks (60%), and 57 females showed evidence of C. burnetii shedding (21.3%). These results suggest that C. burnetii distribution is high at the flock level and that seropositive and infected (shedder) animals can be found all over the country. Further studies are needed in other regions and on different animal species to better understand the distribution and incidence of Q fever, as well as human exposure, and to develop an adequate prophylaxis program. PMID- 27477504 TI - Role of the suppressor of cytokine signaling 2 (SOCS2) during meningoencephalitis caused by Bovine herpesvirus 5 (BoHV-5). AB - The role of suppressors of cytokine signaling (SOCS) in meningoencephalitis caused by Bovine herpesvirus 5 (BoHV-5) was evaluated by intracranial infection in C57BL/6 wild-type mice (WT) and SOCS2 deficient mice (SOCS2(-/-)). Both infected groups presented weight loss, ruffled fur and hunched posture. Additionally, infected SOCS2(-/-) mice showed swollen chamfer and progressive depression. Infected WT animals developed mild meningitis, characterized by infiltration of mononuclear cells. Moreover, viral DNA was detected in liver and lung from infected WT group. This group also showed elevated brain levels of IFN gamma, IL-10, CXCL1 and CCL5, when compared with non-infected WT animals. Brain inflammation was exacerbated in infected SOCS2(-/-) mice with widespread distribution of the virus and increased brain levels of TNF-alpha, IFN-gamma, IL 10, IL-12, CXCL1 and CCL5, when compared with WT infected mice. Moreover, infected SOCS2 deficient mice exhibited reduced brain mRNA expression of IFNalpha and IFNbeta and increased expression of mRNA of SOCS1, compared with infected WT mice. Taken together, our study provides an insight into the role of SOCS2 in modulating the immune response to BoHV-5 infection. PMID- 27477505 TI - Molecular identification and comparative transcriptional analysis of myxovirus resistance GTPase (Mx) gene in goose (Anser cygnoide) after H9N2 AIV infection. AB - Interferon (IFN)-induced myxovirus resistance (Mx) GTPases belong to the family of dynamin-like GTPases and control a diverse range of viruses. In this study, the identified goose Mx (goMx) mRNA is 2009bp long, shares partially conserved exons with other homologues, and shares highly conserved domains in its primary structure. The amino acid position 629 (629aa) of the goMx protein was identified as serine (Ser), in contrast to the Ser located at 631aa in chicken Mx, which is considered to be responsible for the lack of chicken Mx antiviral activity. In addition, the goMx 142aa residue in the dynamin family signature differs from that of other functional Mx proteins. Transcriptional analysis revealed that goMx was mainly expressed in the digestive, respiratory and immune systems in an age specific manner. GoMx transcript levels in goose peripheral blood mononuclear cells (PBMCs) were found to be significantly up-regulated by various agonists and avian viruses. Furthermore, a time course study of the effects of H9N2 avian influenza virus (AIV) on goMx expression in infected goslings suggested that H9N2 AIV affected goMx expression. However, significant changes in goMx expression were observed in the trachea, lung and small intestine of infected birds. Altogether, these results indicate that goMx protein may have acquired its broad antiviral activity by changing only a few amino acids at select sites, even as it shares a conserved architectures with species. PMID- 27477506 TI - Characterization of tuberculous granulomas in different stages of progression and associated tertiary lymphoid tissue in goats experimentally infected with Mycobacterium avium subsp. hominissuis. AB - Oral infection of goats with Mycobacterium avium subsp. hominissuis (MAH) resulted in a large variety of granulomas in organized gut-associated lymphatic tissues and intestinal lymph nodes. To characterize the cellular composition of granulomas, CD4(+), CD8(+), gammadelta, B lymphocytes and plasma, CD25(+), CD68(+), MHC-II(+), Ki67(+) and endothelial cells were labeled in consecutive frozen sections by immunohistochemistry and acid fast bacilli (AFB) by Kinyoun stain. Granulomas with extensive necrosis, little mineralization and variable numbers of AFB surrounded by many CD4(+) T cells, but only few epitheloid macrophages were observed in severely sick goats at 2-3mpi. They were interpreted as exuberant immune reaction. Organized granulomas with very few AFB were seen in clinically healthy goats at 13mpi. The necrotic cores were surrounded by a zone of granulomatous infiltrate with many epitheloid macrophages and few lymphocytes. This zone was initially wide and highly vascularized and became progressively smaller. It was enclosed by an increasing layer of connective tissue. All organized granulomas were surrounded by compartimentalized tertiary lymphoid tissue. The granulomas in experimental infection of goats with MAH reflect the heterogeneity of lesions seen in mycobacterial infections of humans and ruminants and are therefore valuable for comparative research. PMID- 27477508 TI - Efficacy of selected biocides in the decontamination of common nosocomial bacterial pathogens in biofilm and planktonic forms. AB - The efficacy and use of biocides to eliminate pathogens in the health care environment are based on their testing against planktonic bacteria. In the environment, bacteria exist in biofilms, as they do on medical devices, and as planktonic or viable non-culturable forms as well. This work aimed to evaluate the efficacy of four biocides against the biofilm and planktonic phases of nine common nosocomial bacteria. The bactericidal activity of the biocides against bacteria in the planktonic form was assessed using a broth microdilution technique. The killing activity of the biocides against biofilms was evaluated using cells grown on polyethylene tubes under a dynamic flow-cell system that was designed for biofilm growth. All biocides completely killed the planktonic bacteria at all concentrations; however, they did not eradicate the biofilms of the same pathogens. Our study highlights the need for an alternative strategy, one that utilizes chemicals that have been tested to disrupt or prevent biofilm growth, in order to enhance current disinfection practice. PMID- 27477507 TI - Characterization of the immune response and evaluation of the protective capacity of rSsnA against Streptococcus suis infection in pigs. AB - The efforts made to develop vaccines against Streptococcus suis have failed because of lack of common antigens cross-reactive against different serotypes of this species. The cell wall-anchored proteins can be good vaccine candidates due to their high expression and accessibility to antibodies, among these, a cell wall protein, DNA-nuclease (SsnA), present in most of the S. suis serotypes and clinical isolates collected from infected pigs, was selected. An experimental challenge against S. suis serotype 2 in a pig model was used to validate the efficacy of recombinant SsnA combined with aluminium hydroxide plus Quil A as adjuvants, previously tested in mice by our research group with good results. In our study, clinical characteristics, bacterial load and spread, haematological and immunological parameters and the antibody response, including the opsonophagocytosis analysis of the sera were evaluated. Moreover the composition of peripheral blood leukocyte populations was studied in infected animals. The results show that the immunization of piglets with rSsnA elicits a significant humoral antibody response. However, the antibody response is not reflected in protection of pigs that are challenged with a virulent strain in our conventional vaccination model. Further studies are necessary to evaluate the use of rSsnA as a vaccine candidate for swine. PMID- 27477509 TI - Serological and molecular detection of Theileria equi in sport horses of northeastern Brazil. AB - Theileriosis is a worldwide protozoal tick-borne disease caused by Theileria equi, which may produce a variety of clinical signs and turn infected horses into lifetime carriers. This study has aimed to perform a serological and molecular detection of T. equi and associated factors in sports horses from six areas of northeastern Brazil. In overall, 59.6% horses were positive by indirect immunofluorescence assay and 50.4% by polymerase chain reaction. No significant association was found when presence of ticks, age, gender, anemia or total plasma proteins was analyzed with seropositivity and molecular techniques. Although a significant association of infection was found in two cities. Thus, local risk factors other than presence of ticks, horse age, gender, anemia and total plasmatic proteins may dictate prevalence of T. equi infection in sports horses, even in highly endemic areas with no control of infection prior to horse competitions. PMID- 27477510 TI - Molecular survey on the presence of zoonotic arthropod-borne pathogens in wild red deer (Cervus elaphus). AB - To estimate the prevalence of some zoonotic tick-borne pathogens in red deer (Cervus elaphus) living in Italian areas with high risk of arthropod exposure, blood samples from 60 red deer were tested by PCR for A. phagocytophilum, Borrelia burgdorferi s.l., Coxiella burnetii, Francisella tularensis, and piroplasms. Thirty-four (56.67%) animals resulted positive for one or more pathogens. In particular, 24 (40%) red deer were positive for A. phagocytophilum, 16 (26.67%) for Babesia divergens, 6 (10%) for C. burnetii, 2 (3.33%) for B. burgdorferi s.l. No positive reaction was observed for F. tularensis. Thirteen (21.67%) animals resulted co-infected by two or three pathogens. Red deer is confirmed as competent reservoir of A. phagocytophilum and B. divergens, but not of B. burgdorferi. This is the first report of C. burnetii-positive red deer in central Italy. Hunters may be at risk of infection both through infected ticks and during the infected cervids carcasses dressing. PMID- 27477512 TI - UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome. AB - Clearance of misfolded and aggregated proteins is central to cell survival. Here, we describe a new pathway for maintaining protein homeostasis mediated by the proteasome shuttle factor UBQLN2. The 26S proteasome degrades polyubiquitylated substrates by recognizing them through stoichiometrically bound ubiquitin receptors, but substrates are also delivered by reversibly bound shuttles. We aimed to determine why these parallel delivery mechanisms exist and found that UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. We further show that this process is active in the cell nucleus, where another system for aggregate clearance, autophagy, does not act. Finally, we found that mutations in UBQLN2, which lead to neurodegeneration in humans, are defective in chaperone binding, impair aggregate clearance, and cause cognitive deficits in mice. PMID- 27477511 TI - NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. AB - Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease. PMID- 27477513 TI - Coupled Sensing of Hunger and Thirst Signals Balances Sugar and Water Consumption. AB - Hunger and thirst are ancient homeostatic drives for food and water consumption. Although molecular and neural mechanisms underlying these drives are currently being uncovered, less is known about how hunger and thirst interact. Here, we use molecular genetic, behavioral, and anatomical studies in Drosophila to identify four neurons that modulate food and water consumption. Activation of these neurons promotes sugar consumption and restricts water consumption, whereas inactivation promotes water consumption and restricts sugar consumption. By calcium imaging studies, we show that these neurons are directly regulated by a hormone signal of nutrient levels and by osmolality. Finally, we identify a hormone receptor and an osmolality-sensitive ion channel that underlie this regulation. Thus, a small population of neurons senses internal signals of nutrient and water availability to balance sugar and water consumption. Our results suggest an elegant mechanism by which interoceptive neurons oppositely regulate homeostatic drives to eat and drink. PMID- 27477515 TI - A multi-technique comparison of the electronic properties of pristine and nitrogen-doped polycrystalline SnO2. AB - Nitrogen doped tin(iv) oxide (SnO2) materials in the form of nanometric powders have been prepared by precipitation with ammonia. Their properties have been compared with those of undoped materials obtained in a similar way using various physical techniques such as photoelectron spectroscopies (XPS and UPS), UV-Vis NIR spectroscopy and electron paramagnetic resonance (EPR). Nitrogen doping leads to the formation of various nitrogen containing species, the more relevant of which is a nitride-type ionic species, based on the substitution of a lattice oxygen atom with a nitrogen atom. This species exists in two forms, paramagnetic (hole centre, formally N(2-)) and diamagnetic (N(3-)). The mutual ratio of the two species varies according to the oxidation state of the material. The doped solid, like most of the semiconducting oxides, tends to lose oxygen forming oxygen vacancies upon annealing under vacuum and leaving an excess of electrons in the solid. The stoichiometry of the solid can thus be markedly changed depending on the external conditions. Excess electrons are present both as itinerant electrons in the conduction band and as Sn(ii) states lying close to the valence band maximum. The presence of nitride-type centres, which are low energy states located below the top of the valence band, decreases the energy cost for the formation of oxygen vacancies by O2 release from the lattice. This particular feature of the doped system represents a severe limit to the preparation of a p-type SnO2via nitrogen doping. PMID- 27477514 TI - Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages. AB - Small immune complexes cause type III hypersensitivity reactions that frequently result in tissue injury. The responsible mechanisms, however, remain unclear and differ depending on target organs. Here, we identify a kidney-specific anatomical and functional unit, formed by resident macrophages and peritubular capillary endothelial cells, which monitors the transport of proteins and particles ranging from 20 to 700 kDa or 10 to 200 nm into the kidney interstitium. Kidney-resident macrophages detect and scavenge circulating immune complexes "pumped" into the interstitium via trans-endothelial transport and trigger a FcgammaRIV-dependent inflammatory response and the recruitment of monocytes and neutrophils. In addition, FcgammaRIV and TLR pathways synergistically "super-activate" kidney macrophages when immune complexes contain a nucleic acid. These data identify a physiological function of tissue-resident kidney macrophages and a basic mechanism by which they initiate the inflammatory response to small immune complexes in the kidney. PMID- 27477516 TI - Does body mass index impact on muscle wasting and recovery following critical illness? A pilot feasibility observational study. AB - BACKGROUND: Critical illness is associated with muscle loss, weakness and poor recovery. The impact that illness and the ensuing metabolic response has on obese patients is not known. Objectives were to test if obese patients lose less muscle depth compared to non-obese patients; if a reduction in muscle depth was associated with reduced strength and recovery; and to assess the feasibility of these methods with a range of body mass index's (BMI). METHODS: A prospective observational pilot study of muscle depth in critically ill patients categorised by BMI was performed. Muscle depth changes were assessed by ultrasound on study days 1, 3, 5, 7, 12 and 14. Strength was measured via handgrip dynamometry and Medical Research Council (MRC) sum score on waking and at discharge from the intensive care unit. Level of dependency was measured with the Barthel index. RESULTS: 44 critically ill patients; 17 had normal BMI, 10 were overweight and 17 were obese. The three groups did not differ in baseline characteristics, except obese patients had significantly greater initial muscle depth. Muscle depth loss was similar between the BMI groups at each of the time points. Handgrip and MRC sum score were only possible in a small number of patients because of reduced alertness and weakness. Majority were deemed fully dependent based on the Barthel index. CONCLUSIONS: Obese patients lost muscle depth in a comparable manner to non-obese patients, suggesting that BMI may not prevent muscle depth loss. It was not possible to determine the effect on strength because the clinical condition of patients precluded reliable measurements. PMID- 27477517 TI - Retention behavior of alkyl-substituted polycyclic aromatic sulfur heterocycles in reversed-phase liquid chromatography. AB - Retention indices for 79 alkyl-substituted polycyclic aromatic sulfur heterocycles (PASHs) were determined by using reversed-phase liquid chromatography (LC) on a monomeric and polymeric octadecylsilane (C18) stationary phase. Molecular shape parameters [length, breadth, thickness (T), and length-to breadth ratio (L/B)] were calculated for all the compounds studied. Based on separations of isomeric methylated polycyclic aromatic hydrocarbons on polymeric C18 phases, alkyl-substituted PASHs are expected to elute based on increasing L/B ratios. However, the correlation coefficients had a wide range of values from r=0.43 to r=0.93. Several structural features besides L/B ratios were identified to play an important role in the separation mechanism of PASHs on polymeric C18 phases. First, the location of the sulfur atom in a bay-like-region results in alkylated-PASHs being more retentive than non-bay-like-region alkylated-PASHs, and they elute later than expected based on L/B value. Second, the placement of the alkyl group in the k region of the structure resulted in a later elution than predicted by L/B. Third, highly nonplanar methyl-PASHs (i.e., 1-Me and 11 MeBbN12T) elute prior to the parent PASH (BbN12T). PMID- 27477518 TI - Determination of dimethyl trisulfide in rabbit blood using stir bar sorptive extraction gas chromatography-mass spectrometry. AB - Cyanide poisoning by accidental or intentional exposure poses a severe health risk. The current Food and Drug Administration approved antidotes for cyanide poisoning can be effective, but each suffers from specific major limitations concerning large effective dosage, delayed onset of action, or dependence on enzymes generally confined to specific organs. Dimethyl trisulfide (DMTS), a sulfur donor that detoxifies cyanide by converting it into thiocyanate (a relatively nontoxic cyanide metabolite), is a promising next generation cyanide antidote. Although a validated analytical method to analyze DMTS from any matrix is not currently available, one will be vital for the approval of DMTS as a therapeutic agent against cyanide poisoning. Hence, a stir bar sorptive extraction (SBSE) gas chromatography - mass spectrometry (GC-MS) method was developed and validated for the analysis of DMTS from rabbit whole blood. Following acid denaturation of blood, DMTS was extracted into a polydimethylsiloxane-coated stir bar. The DMTS was then thermally desorbed from the stir bar and analyzed by GC-MS. The limit of detection of DMTS using this method was 0.06MUM with dynamic range from 0.5-100MUM. For quality control standards, the precision, as measured by percent relative standard deviation, was below 10%, and the accuracy was within 15% of the nominal concentration. The method described here will allow further investigations of DMTS as a promising antidote for cyanide poisoning. PMID- 27477519 TI - Effect of cadence selection on peak power and time of power production in elite BMX riders: A laboratory based study. AB - The aims of this study were to analyse the optimal cadence for peak power production and time to peak power in bicycle motocross (BMX) riders. Six male elite BMX riders volunteered for the study. Each rider completed 3 maximal sprints at a cadence of 80, 100, 120 and 140 revs . min-1 on a laboratory Schoberer Rad Messtechnik (SRM) cycle ergometer in isokinetic mode. The riders' mean values for peak power and time of power production in all 3 tests were recorded. The BMX riders produced peak power (1105 +/- 139 W) at 100 revs . min-1 with lower peak power produced at 80 revs . min-1 (1060 +/- 69 W, (F(2,15) = 3.162; P = .266; eta2 = 0.960), 120 revs . min-1 (1077 +/- 141 W, (F(2,15) = 4.348; P = .203; eta2 = 0.970) and 140 revs . min-1 (1046 +/- 175 W, (F(2,15) = 12.350; P = 0.077; eta2 = 0.989). The shortest time to power production was attained at 120 revs . min-1 in 2.5 +/- 1.07 s. Whilst a cadence of 80 revs . min 1 (3.5 +/- 0.8 s, (F(2,15) = 2.667; P = .284; eta2 = 0.800) 100 revs . min-1 (3.00 +/- 1.13 s, (F(2,15) = 24.832; P = .039; eta2 = 0.974) and 140 revs . min-1 (3.50 +/- 0.88 s, (F(2,15) = 44.167; P = .006; eta2 = 0.967)) all recorded a longer time to peak power production. The results indicate that the optimal cadence for producing peak power output and reducing the time to peak power output are attained at comparatively low cadences for sprint cycling events. These findings could potentially inform strength and conditioning training to maximise dynamic force production and enable coaches to select optimal gear ratios. PMID- 27477520 TI - Isolation of rugosin A, B and related compounds as dipeptidyl peptidase-IV inhibitors from rose bud extract powder. AB - Dipeptidyl peptidase-IV (DPP-IV) is a protease responsible for the degradation of the incretin hormone. A number of DPP-IV inhibitors have been approved for use in the treatment of type 2 diabetes. While these inhibitors are effective for this treatment, methods for the prevention of this disease are also required as diabetes patient numbers are currently increasing rapidly worldwide. We screened the DPP-IV inhibitory activities of edible plant extracts with the intention of using these extracts in a functional food supplement for the prevention of diabetes. Rose (Rosa gallica) bud extract powder was a promising material with high inhibitory activity. In this study, seven ellagitannins were isolated as active compounds through activity-guided fractionations, and their DPP-IV inhibitory activities were measured. Among them, rugosin A and B showed the highest inhibitory activities and rugosin B was shown as the major contributing compound in rose bud extract powder. PMID- 27477521 TI - A model for flexi-bar to evaluate intervertebral disc and muscle forces in exercises. AB - This study developed and validated a lumped parameter model for the FLEXI-BAR, a popular training instrument that provides vibration stimulation. The model which can be used in conjunction with musculoskeletal-modeling software for quantitative biomechanical analyses, consists of 3 rigid segments, 2 torsional springs, and 2 torsional dashpots. Two different sets of experiments were conducted to determine the model's key parameters including the stiffness of the springs and the damping ratio of the dashpots. In the first set of experiments, the free vibration of the FLEXI-BAR with an initial displacement at its end was considered, while in the second set, forced oscillations of the bar were studied. The properties of the mechanical elements in the lumped parameter model were derived utilizing a non-linear optimization algorithm which minimized the difference between the model's prediction and the experimental data. The results showed that the model is valid (8% error) and can be used for simulating exercises with the FLEXI-BAR for excitations in the range of the natural frequency. The model was then validated in combination with AnyBody musculoskeletal modeling software, where various lumbar disc, spinal muscles and hand muscles forces were determined during different FLEXI-BAR exercise simulations. PMID- 27477522 TI - Thermally-assisted ultrasonic separation of giant vesicles. AB - We report on a newly-developed membrane stiffness-based separation of vesicles using a thermally-assisted acoustophoretic approach. By tuning the temperature, we achieved the separation of vesicles of the same size, shape, and charge but with different stiffness values. It was observed that at a specific transition point, the acoustic contrast factor of vesicles changed sign from positive to negative. This change was mainly due to the change in the acoustic compressibility of the vesicles, which is inversely proportional to stiffness. The acoustic contrast temperature, corresponding to the temperature at which the acoustic contrast factor switches sign, was determined to be unique to the composition of the vesicles. This unique temperature signature allowed us to develop a separation method of vesicles with distinct membrane stiffness with target outlet purities exceeding 95%. Our studies suggest that this method may be applied for the separation of cells affected by diseases that affect the cellular stiffness. PMID- 27477523 TI - Editorial Comment to Role of routine computed tomography scan in the oncological follow up of patients treated by radical cystectomy for bladder cancer. PMID- 27477524 TI - Underlying chronic inflammation alters the profile and mechanisms of acute neutrophil recruitment. AB - Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders. We have developed a novel model of chronic ischaemia of the mouse cremaster muscle that is characterized by a persistent population of monocyte-derived cells (MDCs), and capillary angiogenesis. These tissues also show elevated acute neutrophil recruitment in response to locally administered inflammatory stimuli. We determined that Gr1low MDCs, which are widely considered to have anti inflammatory and reparative functions, amplified acute inflammatory reactions via the generation of additional proinflammatory signals, changing both the profile and magnitude of the tissue response. Similar vascular and inflammatory responses, including activation of MDCs by transient ischaemia-reperfusion, were observed in mouse hindlimbs subjected to chronic ischaemia. This response demonstrates the relevance of the findings to peripheral arterial disease, in which patients experience transient exercise-induced ischaemia known as claudication.These findings demonstrate that chronically inflamed tissues show an altered profile and altered mechanisms of acute inflammatory responses, and identify tissue-resident MDCs as potential therapeutic targets. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 27477525 TI - Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. AB - : Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naive metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p<0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67-0.88; p=0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9-22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1-5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2-not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8-34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. PATIENT SUMMARY: According to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer. PMID- 27477526 TI - Re: Delivering Safe and Effective Analgesia for Management of Renal Colic in the Emergency Department: A Double-blind, Multigroup, Randomised Controlled Trial. PMID- 27477527 TI - Re: The Effect of Anastomosis Time on Outcome in Recipients of Kidneys Donated After Brain Death: A Cohort Study. PMID- 27477528 TI - Oncologic Outcomes of Kidney-sparing Surgery Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the EAU Non-muscle Invasive Bladder Cancer Guidelines Panel. AB - CONTEXT: There is uncertainty regarding the oncologic effectiveness of kidney sparing surgery (KSS) compared with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). OBJECTIVE: To systematically review the current literature comparing oncologic outcomes of KSS versus RNU for UTUC. EVIDENCE ACQUISITION: A computerised bibliographic search of the Medline, Embase, and Cochrane databases was performed for all studies reporting comparative oncologic outcomes of KSS versus RNU. Approaches considered for KSS were segmental ureterectomy (SU) and ureteroscopic (URS) or percutaneous (PC) management. Using the methodology recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, we identified 22 nonrandomised comparative retrospective studies published between 1999 and 2015 that were eligible for inclusion in this systematic review. A narrative review and risk-of-bias (RoB) assessment were performed using cancer-specific survival (CSS) as the primary end point. EVIDENCE SYNTHESIS: Seven studies compared KSS overall (n=547) versus RNU (n=1376). Information on the comparison of SU (n=586) versus RNU (n=3692), URS (n=162) versus RNU (n=367), and PC (n=66) versus RNU (n=114) was available in 10, 5, and 2 studies, respectively. No significant difference was found between SU and RNU in terms of CSS or any other oncologic outcomes. Only patients with low-grade and noninvasive tumours experienced similar CSS after URS or PC when compared with RNU, despite an increased risk of local recurrence following endoscopic management of UTUC. The RoB assessment revealed, however, that the analyses were subject to a selection bias favouring KSS. CONCLUSIONS: Our systematic review suggests similar survival after KSS versus RNU only for low-grade and noninvasive UTUC when using URS or PC. However, selected patients with high-grade and invasive UTUC could safely benefit from SU when feasible. These results should be interpreted with caution due to the risk of selection bias. PATIENT SUMMARY: We reviewed the studies that compared kidney sparing surgery versus radical nephroureterectomy for upper tract urothelial carcinoma. We found similar oncologic outcomes for favourable tumours when using ureteroscopic or percutaneous management, whereas indications for segmental ureterectomy could be extended to selected cases of aggressive tumours. PMID- 27477529 TI - Prevalence and Prognostic Significance of PTEN Loss in African-American and European-American Men Undergoing Radical Prostatectomy. AB - : African-American (AA) men have a higher risk of lethal prostate cancer (PCa) compared to European-American (EA) men. However, the molecular basis of this difference, if any, remains unclear. In EA PCa, PTEN loss, but not ERG rearrangement, has been associated with poor outcomes in most studies. Although ERG rearrangement is less common in AA compared to EA PCa, the relative frequency of PTEN loss and the association of PTEN/ERG molecular subtypes with outcomes is unknown for AA PCa. We examined PTEN/ERG status by immunohistochemistry in self identified AA patients undergoing radical prostatectomy at Johns Hopkins with tumor tissue available on tissue microarray (TMA; n=169) and matched these cases by pathologic parameters to 169 EA patients from the same TMAs. The rate of PTEN loss was significantly lower in AA compared to EA PCa (18% vs 34%; p=0.001), similar to the lower rate of ERG expression (25% vs 51%; p<0.001). To examine the association of PTEN/ERG status with oncologic outcomes, we created an additional TMA of 87 AA tumors with Gleason score > 4 + 3 = 7. Among the total population of AA men with outcome data from all TMAs (n=222), PTEN loss was associated with higher risk of biochemical recurrence (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.82) and metastasis (HR 3.90, 95% CI 1.46-10.4) in multivariable models. PATIENT SUMMARY: PTEN and ERG alterations in prostate cancer are less likely in African-American than in European-American men. However, PTEN loss remains associated with poor prostate cancer outcomes among African-American men. PMID- 27477530 TI - Prior event rate ratio adjustment for hidden confounding in observational studies of treatment effectiveness: a pairwise Cox likelihood approach. AB - Observational studies provide a rich source of information for assessing effectiveness of treatment interventions in many situations where it is not ethical or practical to perform randomized controlled trials. However, such studies are prone to bias from hidden (unmeasured) confounding. A promising approach to identifying and reducing the impact of unmeasured confounding is prior event rate ratio (PERR) adjustment, a quasi-experimental analytic method proposed in the context of electronic medical record database studies. In this paper, we present a statistical framework for using a pairwise approach to PERR adjustment that removes bias inherent in the original PERR method. A flexible pairwise Cox likelihood function is derived and used to demonstrate the consistency of the simple and convenient alternative PERR (PERR-ALT) estimator. We show how to estimate standard errors and confidence intervals for treatment effect estimates based on the observed information and provide R code to illustrate how to implement the method. Assumptions required for the pairwise approach (as well as PERR) are clarified, and the consequences of model misspecification are explored. Our results confirm the need for researchers to consider carefully the suitability of the method in the context of each problem. Extensions of the pairwise likelihood to more complex designs involving time varying covariates or more than two periods are considered. We illustrate the application of the method using data from a longitudinal cohort study of enzyme replacement therapy for lysosomal storage disorders. (c) 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID- 27477531 TI - Association of obesity with hypertension and dyslipidemia in type 2 diabetes mellitus subjects. AB - AIM: Obesity and diabetes are contributed to cardiovascular disease risk. The current study was performed to evaluate the association of central and general obesity and cardio-metabolic risk factors, including dyslipidemia and hypertension in T2DM patients. METHODS: This was a cross-sectional study in T2DM adults. Body mass index (BMI) was used to identify general obesity and waist circumference (WC) was measured to define abdominal obesity (based on ATP III). Biochemical analyses, and anthropometric and blood pressure measurements were done for all participants. RESULTS: Participants with central obesity showed significantly higher systolic (132.5mmHg vs. 125.4mmHg, p=0.024) and diastolic blood pressures (84.9mmHg vs. 80mmHg, p=0.007) than participants without obesity. Dyslipidemia was more prevalent in all participants either by BMI (98.3% vs. 97%, 95% CI: 0.18-17.53) or by WC (97.2% vs. 98%, 95% CI: 0.07-7.19). Abdominal adiposity in diabetic subjects showed significant reverse association with high level of physical activity (OR=0.22, 95% CI: 0.06-0.85). Hypertriglyceridemia rate was increased with both central (OR=2.11; p=0.040) and general obesity (OR=2.68; p=0.021). After adjustment for energy intake and age, females had higher risk of general (OR=4.57, 95% CI=1.88-11.11) and central obesity (OR=7.93, 95% CI=3.48-18.08). CONCLUSIONS: Females were more susceptible to obesity. Hypertension was associated with both obesity measures. Dyslipidemia, except for hypertriglyceridemia, was correlated to neither abdominal nor general obesity. PMID- 27477532 TI - Parenting a child with metabolic diseases: Impact on health related quality of life of parents. AB - The study was conducted to assess the health related quality of life of the parents of children with inborn errors of metabolism (IEM). The study was conducted at the Genetic and metabolic outpatient department of Sultan Qaboos University Hospital, Oman. The parents of children with metabolic diseases who were accompanying their children to the outpatient clinics were the samples. An explorative descriptive survey design and Convenient sampling technique were used to select the sample. Study included 72 parents of children with metabolic diseases aged between 20 and 55 years. The RAND 36-Item Health Survey version was used to assess the health related quality of life of parents. The results shows lower mean scores in subscales of 'general health' and vitality. Parents with higher educational levels showed higher levels of PCS and MCS scores than parents with lower educational levels. Parents with higher monthly income and younger age showed higher quality of life. A significant association was found between supporting persons and HQoL in the dimensions of the "role limitations due to physical" (p<0.03), and social functioning (p<0.04). Empowering the parents by helping them to actively seek and maintain social support is an important step in improving the health related quality of life. PMID- 27477534 TI - Effectiveness of 3 per cent boric acid in 70 per cent alcohol versus 1 per cent clotrimazole solution in otomycosis patients: a randomised, controlled trial. AB - OBJECTIVES: To compare the clinical effectiveness and adverse events for 3 per cent boric acid in 70 per cent alcohol versus 1 per cent clotrimazole solution in the treatment of otomycosis. METHODS: A total of 120 otomycosis patients were randomly assigned to receive either 1 per cent clotrimazole solution (intervention group) or 3 per cent boric acid in 70 per cent alcohol (control group) at the Khon Kaen Hospital ENT out-patient department. Treatment effectiveness was determined based on the otomicroscopic absence of fungus one week after therapy, following a single application of treatment. RESULTS: After 1 week of treatment, there were data for 109 participants, 54 in the clotrimazole group and 55 in the boric acid group. The absolute difference in cure rates between 1 per cent clotrimazole solution and 3 per cent boric acid in 70 per cent alcohol was 17.9 per cent (95 per cent confidence interval, 2.3 to 33.5; p = 0.028) and the number needed to treat was 6 (95 per cent confidence interval, 3.0 to 43.4). Adverse events for the two agents were comparable. CONCLUSION: One per cent clotrimazole solution is more effective than 3 per cent boric acid in 70 per cent alcohol for otomycosis treatment. PMID- 27477533 TI - Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus induced deficits in the novel object recognition task in rats. AB - Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6-12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP. PMID- 27477535 TI - The Virtual Epileptic Patient: Individualized whole-brain models of epilepsy spread. AB - Individual variability has clear effects upon the outcome of therapies and treatment approaches. The customization of healthcare options to the individual patient should accordingly improve treatment results. We propose a novel approach to brain interventions based on personalized brain network models derived from non-invasive structural data of individual patients. Along the example of a patient with bitemporal epilepsy, we show step by step how to develop a Virtual Epileptic Patient (VEP) brain model and integrate patient-specific information such as brain connectivity, epileptogenic zone and MRI lesions. Using high performance computing, we systematically carry out parameter space explorations, fit and validate the brain model against the patient's empirical stereotactic EEG (SEEG) data and demonstrate how to develop novel personalized strategies towards therapy and intervention. PMID- 27477536 TI - How to avoid mismodelling in GLM-based fMRI data analysis: cross-validated Bayesian model selection. AB - Voxel-wise general linear models (GLMs) are a standard approach for analyzing functional magnetic resonance imaging (fMRI) data. An advantage of GLMs is that they are flexible and can be adapted to the requirements of many different data sets. However, the specification of first-level GLMs leaves the researcher with many degrees of freedom which is problematic given recent efforts to ensure robust and reproducible fMRI data analysis. Formal model comparisons that allow a systematic assessment of GLMs are only rarely performed. On the one hand, too simple models may underfit data and leave real effects undiscovered. On the other hand, too complex models might overfit data and also reduce statistical power. Here we present a systematic approach termed cross-validated Bayesian model selection (cvBMS) that allows to decide which GLM best describes a given fMRI data set. Importantly, our approach allows for non-nested model comparison, i.e. comparing more than two models that do not just differ by adding one or more regressors. It also allows for spatially heterogeneous modelling, i.e. using different models for different parts of the brain. We validate our method using simulated data and demonstrate potential applications to empirical data. The increased use of model comparison and model selection should increase the reliability of GLM results and reproducibility of fMRI studies. PMID- 27477537 TI - A qualitative study looking at informed choice in the context of non-invasive prenatal testing for aneuploidy. AB - OBJECTIVE: To explore women's attitudes towards non-invasive prenatal testing (NIPT) and determine factors influencing their decisions around uptake of NIPT. METHOD: We conducted qualitative interviews to assess knowledge, attitude and deliberation amongst women offered NIPT in a public health service. In total, 45 women took part in telephone interviews (79% participation rate). RESULTS: Most women could recount the key aspects of NIPT discussed during pre-test counselling but had variable knowledge about Down syndrome. Analysis of women's attitudes towards undergoing NIPT revealed three dominant factors they considered when reflecting on the test: (1) how NIPT compared with alternative testing options, (2) reflections on coping and (3) moral or religious values. Exploring the deliberative process revealed the different paths women take when making decisions. For some, it was an extension of the decision to have Down syndrome screening; some considered it early on following the booking-in appointment; others made step-wise decisions about NIPT when it became relevant to them. CONCLUSION: Our findings support the importance of personalised counselling, whereby women and their partners have the opportunity to reflect on the implications of the test results in the context of their own lives and values. Our data highlight the influence of personal circumstances on decision-making. (c) 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. PMID- 27477538 TI - Extracorporeal delivery of a therapeutic enzyme. AB - To remove circulating harmful small biochemical(s)/substrates causing/deteriorating certain chronic disease, therapeutic enzyme(s) delivered via vein injection/infusion suffer(s) from immunoresponse after repeated administration at proper intervals for a long time and short half-lives since delivery. Accordingly, a novel, generally-applicable extracorporeal delivery of a therapeutic enzyme is proposed, by refitting a conventional hemodialysis device bearing a dialyzer, two pumps and connecting tubes, to build a routine extracorporeal blood circuit but a minimal dialysate circuit closed to circulate the therapeutic enzyme in dialysate. A special quantitative index was derived to reflect pharmacological action and thus pharmacodynamics of the delivered enzyme. With hyperuricemic blood in vitro and hyperuricemic geese, a native uricase via extracorporeal delivery was active in the dialysate for periods much longer than that in vivo through vein injection, and exhibited the expected pharmacodynamics to remove uric acid in hyperuricemic blood in vitro and multiple forms of uric acid in hyperuricemic geese. Therefore, the extracorporeal delivery approach of therapeutic enzymes was effective to remove unwanted circulating small biochemical(s)/substrates, and was expected to avoid immunogenicity problems of therapeutic enzymes after repeated administration at proper intervals for a long time due to no contacts with macromolecules and cells in the body. PMID- 27477540 TI - MSA-C or SCA 17? A clinicopathological case update. PMID- 27477544 TI - Readiness to accept Western standard of beauty and body satisfaction among Muslim girls with and without hijab. AB - The purpose of this paper was to determine whether there is a difference in the readiness to accept Western standards of beauty in which thinness is an ideal of beauty and attractiveness, as well in body and appearance satisfaction between Muslim adolescent girls attending madrassa and dressing in accordance with tradition, that is to say wearing hijab, and Muslim adolescent girls who do not wear hijab and who follow contemporary Western-influenced fashion trends. Both of these groups were also compared to a non-Muslim group of adolescent girls. The sample consisted of 75 Muslim adolescent girls with hijab, 75 Muslim adolescent girls without hijab and 75 Orthodox adolescent girls. The following instruments were used: the Eating Attitudes Test (EAT-26), the Sociocultural Attitudes towards Appearance Questionnaire (SATAQ-3) and the Contour Drawing Rating Scale (CDRS). The highest level of body satisfaction (despite this group having the highest body weight in the sample) was evident among Muslim adolescent girls attending madrassa and wearing hijab. They also showed significantly less pressure to attain the Western thin-ideal standards of beauty than adolescent girls who accept Western way of dressing. Research results indicate a significant role of socio-cultural factors in one's attitude towards the body image, but also opens the question of the role of religion as a protective factor when it comes to the body and appearance attitude among Muslim women who wear hijab. PMID- 27477539 TI - Cellular tagging as a neural network mechanism for behavioural tagging. AB - Behavioural tagging is the transformation of a short-term memory, induced by a weak experience, into a long-term memory (LTM) due to the temporal association with a novel experience. The mechanism by which neuronal ensembles, each carrying a memory engram of one of the experiences, interact to achieve behavioural tagging is unknown. Here we show that retrieval of a LTM formed by behavioural tagging of a weak experience depends on the degree of overlap with the neuronal ensemble corresponding to a novel experience. The numbers of neurons activated by weak training in a novel object recognition (NOR) task and by a novel context exploration (NCE) task, denoted as overlapping neurons, increases in the hippocampal CA1 when behavioural tagging is successfully achieved. Optical silencing of an NCE-related ensemble suppresses NOR-LTM retrieval. Thus, a population of cells recruited by NOR is tagged and then preferentially incorporated into the memory trace for NCE to achieve behavioural tagging. PMID- 27477545 TI - Seasonal Changes in the Immunolocalization of Cytoskeletal Proteins and Laminin in the Testis of the Black-Backed Jackal (Canis mesomelas). AB - Manipulation of the reproductive activity of jackals is dependent on a thorough understanding of the reproductive biology of this species. This study describes seasonal morphological changes in the adult testis of the black-backed jackal in relation to the immunoexpression of the basement membrane marker, laminin and the cytoskeletal proteins, cytokeratin, smooth muscle actin and vimentin. Laminin was immunolocalized in basement membranes surrounding seminiferous tubules, as well as in basement membranes associated with Leydig, peritubular myoid and vascular smooth muscle cells. Scalloped basement membranes enclosed seminiferous tubules in regressing testes. The seminiferous epithelium and interstitial tissue in all animals studied were cytokeratin immunonegative. Smooth muscle actin was demonstrated in vascular smooth muscle cells, as well as in peritubular myoid cells encircling seminiferous tubules. Vimentin immunoreactivity was exhibited in the cytoplasm of Sertoli cells, Leydig cells, vascular endothelial cells, vascular smooth muscle cells and fibrocytes. Vimentin immunostaining in Sertoli, Leydig and peritubular myoid cells varied depending on the functional state of the testis. The results of the study have shown that dramatic seasonal histological changes occur in the testes of the jackal. In addition, the use of immunohistochemistry accentuates these morphological changes. PMID- 27477546 TI - Editorial Comment. PMID- 27477547 TI - Room-temperature switching of magnetic hysteresis by reversible single-crystal-to single-crystal solvent exchange in imidazole-inspired Fe(ii) complexes. AB - The recent upsurge in molecular magnetism reflects its application in the areas of sensors and molecular switches. Thermal hysteresis is crucial to the molecular bistability and information storage, a wide hysteresis near room temperature is expected to be of practical sense for the molecular compound. In this work, spin crossover iron(ii) complexes [Fe(Liq)2](BF4)2.(CH3CH2)2O (1-Et2O) and [Fe(Liq)2](BF4)2.3H2O (1-3H2O) were prepared and structurally and magnetically analysed. The single-crystal-to-single-crystal (SCSC) solvation transformation and the influence on the crystal structures and magnetic hysteresis were investigated in an etherification-hydration cycle. At room temperature, X-ray diffraction experiments indicated a transformation from one crystal (1-Et2O, P21212) to another crystal (1-3H2O, P212121) upon humidity exposure and reversible recovery of its crystallinity upon exposure to ether vapor. The etherified phase 1-Et2O exhibits room temperature spin crossover (T1/2 = 305 K) but negligible thermal hysteresis, however the hydrated phase 1-3H2O exhibits the apparent hysteresis loop (T1/2? = 346 K, T1/2? = 326 K) which expands to room temperature. This effect is associated with the change of intermolecular cooperativity in the etherification-hydration recyclability. PMID- 27477548 TI - From the Editor: He aha te mea nui o te ao? PMID- 27477549 TI - Guest Editorial: Improving the general practice discipline through higher degree study. PMID- 27477550 TI - New Zealand among global social media initiative leaders for primary care advocacy. AB - The international '#1WordforFamilyMedicine' initiative explores the identity of General Practitioners (GPs) and Family Physicians (FPs) by allowing the international Family Medicine community to collaborate on advocating for the discipline via social media. The New Zealand version attracted 83 responses on social media. Thematic analysis was performed on the responses and a 'word cloud' image was created based on an image identifying the country around the world - that of the silver fern. The '#1WorldforFamilyMedicine' project was promoted by WONCA (World Organisation of Family Doctors) globally to help celebrate World Family Doctor Day on 19 May 2015. To date, over 80 images have been created in 60 different countries on six continents. The images represent GPs' love for their profession and the community they serve. We hope that this initiative will help inspire current and future Family Medicine and Primary Care providers. PMID- 27477551 TI - Vocational thresholds: developing expertise without certainty in general practice medicine. AB - INTRODUCTION This paper argues that particular experiences in the workplace are more important than others and can lead to transformational learning. This may enable practitioners to cross 'vocational thresholds' to new ways of being. AIM A notion of 'vocational thresholds' is developed, aiming to help build an understanding of the most powerful learning experiences of general practitioners (GPs). Vocational thresholds takes its cue from the idea of 'threshold concepts' concepts that transform perspectives and integrate previously disconnected or hidden knowledge, sometimes in ways that are 'troublesome' to previously held beliefs. METHODS The paper is based on a thematic analysis of 57 GPs' brief written accounts of a particularly powerful learning experience during their development. Accounts were provided in a conference session about an ongoing study of workplace-based structured learning arrangements in the fields of general practice medicine, engineering, and building. FINDINGS Most GPs' accounts focused on development of dispositional attributes that moved them to a new understanding of themselves in relation to their work and patients. Just under two-thirds picked out informal and formal collegial relationships within purposeful learning arrangements as pivotal. A third picked out direct experiences with patients as shifting their perspective. CONCLUSION The emergent idea of vocational thresholds is offered as a way to frame the most important learning experiences identified by GPs. It supports a focus in early and ongoing development beyond accumulating clinical expertise and skills (knowing and doing), to dispositional capability (being) - vital for practitioners negotiating inherent and daily uncertainty. KEYWORDS General practitioners; Medical education; Vocational education; Identity; Learning experiences; Threshold concepts. PMID- 27477552 TI - Master of Primary Health Care degree: who wants it and why? AB - INTRODUCTION The Department of General Practice and Primary Health Care at the University of Auckland is considering developing a Master of Primary Health Care (MPHC) programme. Masters level study entails considerable investment of both university and student time and money. AIM To explore the views of potential students and possible employers of future graduates to discover whether there is a market for such a programme and to inform the development of the programme. METHODS Semi-structured interviews were conducted with 30 primary health care stakeholders. Interviews were digitally recorded, transcribed and analysed using a general inductive approach to identify themes. FINDINGS Primary care practitioners might embark on MPHC studies to develop health management and leadership skills, to develop and/or enhance clinical skills, to enhance teaching and research skills, or for reasons of personal interest. Barriers to MPHC study were identified as cost and a lack of funding, time constraints and clinical workload. Study participants favoured inter-professional learning and a flexible delivery format. Pre-existing courses may already satisfy the post-graduate educational needs of primary care practitioners. Masters level study may be superfluous to the needs of the primary care workforce. CONCLUSIONS Any successful MPHC programme would need to provide value for PHC practitioner students and be unique. The postgraduate educational needs of New Zealand primary care practitioners may be already catered for. The international market for a MPHC programme is yet to be explored. PMID- 27477553 TI - Educating vocationally trained family physicians: a survey of graduates from a postgraduate medical education programme. AB - INTRODUCTION Since 1991 the University of Otago, Dunedin, New Zealand has offered postgraduate qualifications specifically designed to educate general practitioners (GPs) about their unique work environment. AIM To determine motivations and impacts of postgraduate education for practising GPs. METHODS Survey of the 100 graduates of the University of Otago, Dunedin postgraduate general practice programme. Ninety five living graduates were approached and 70 (73.7%) responded. Quantitative data about disposition of respondents before enrolling and after completion of the programme were analysed using chi-square and paired t-tests. Free text responses about motivations, impacts and outcomes of the program were thematically analysed. RESULTS 64 GPs graduated with a postgraduate diploma and 36 with a masters degree in general practice. Although the mean number of graduates was 3.5 and 2.0 (respectively), annual enrolments averaged 25.1. Most graduates (60.9%) were aged in their 40s when they started studying and most (94.3%) had a spouse and/or children at home. DISCUSSION This voluntary postgraduate medical education complements traditional medical training but has low external value despite personal, practising and professional benefits. Graduates valued engagement above completion of a qualification. KEYWORDS Medical education; general practitioners; scholarship; professionalism. PMID- 27477554 TI - The care work of general practice receptionists. AB - INTRODUCTION The care work of general practice receptionists has received limited research attention, despite receptionists position at the beginning of patients' journeys in many health care systems. We examine receptionists' perceptions of their work and the opportunities and constraints they experience in caring for patients while providing administrative support to practices. METHODS Data were collected in focus group interviews with 32 receptionists from urban and rural general practices in the Auckland and Northland regions of New Zealand. We employed tools from inductive thematic analysis and Straussian grounded theory in interpreting the data. FINDINGS We found that the way receptionists identified with a caring role strongly challenged the pejorative view of them in public discourse. Receptionists provide care in two key ways: for the practice and for patients. The juggling they do between the demands of the practice and of patients creates considerable work tensions that are often invisible to other staff members. CONCLUSION Receptionists have a critical role as the first step in the patient care pathway, bridging health care system and community. For general practice to be patient-centred and improve accessibility for the most vulnerable, the care work of receptionists must be considered core. KEYWORDS Receptionists; general practice; care; New Zealand. PMID- 27477555 TI - Outcomes of a community-based lifestyle programme for adults with diabetes or pre diabetes. AB - INTRODUCTION Diabetes, a long-term condition increasing in prevalence, requires ongoing healthcare management. Exercise alongside lifestyle education and support is effective for diabetes management. AIM To investigate clinical outcomes and acceptability of a community-based lifestyle programme for adults with diabetes/prediabetes at programme completion and 3-month follow-up. METHODS The 12-week community programme included twice-weekly sessions of self-management education and exercise, supervised by a physiotherapist, physiotherapy students and a nurse. Clinical outcomes assessed were cardiorespiratory fitness, waist circumference, exercise behaviour and self-efficacy. A standardised evaluation form was used to assess programme acceptability. RESULTS Clinically significant improvements were found from baseline (n = 36) to programme completion (n = 25) and 3-months follow-up (n = 20) for the six minute walk test (87 m (95%CI 65-109; p <= 0.01), 60 m (95%CI 21-100; p <= 0.01)), waist circumference (-3 cm (95%CI -6 to -1), -3 cm (95%CI -6 to 1)), exercise behaviour (aerobic exercise 53 min/week (95%CI 26 to 81; p <= 0.01), 71 min/week (95%CI 25 to 118; p <= 0.01)) and self efficacy (0.7 (95%CI -0.2 to 1.6), 0.8 (95%CI 0.04 to 1.5)). Good programme acceptability was demonstrated by themes suggesting a culturally supportive, motivating, friendly, informative atmosphere within the programme. The attrition rate was 30% but there were no adverse medical events related to the programme. DISCUSSION The programme was safe and culturally acceptable and outcomes demonstrated clinical benefit to participants. The attrition rate was largely due to medical reasons unrelated to the programme. This model of a community-based lifestyle programme has the potential to be reproduced in other regions and in adults with similar long-term conditions. KEYWORDS Diabetes Mellitus Type II; Prediabetic state; Co-morbidity; Exercise; Self-management. PMID- 27477556 TI - Patient awareness, knowledge and use of colchicine: an exploratory qualitative study in the Counties Manukau region, Auckland, New Zealand. AB - INTRODUCTION Treatment of gout, specifically with colchicine, varies globally. Colchicine can be fatal due to its narrow therapeutic index and potential for interactions. In New Zealand, cases of intentional and unintentional colchicine overdose have been documented. AIMS To explore patients' knowledge on the use of gout medicines, and in particular their awareness of the maximum dose of colchicine, the dangers of colchicine overdose, and their opinions on restricting colchicine dispensing. The study also investigates where patients receive gout information. METHODS Thirty people with gout presenting to their regular gout clinic in Auckland currently or previously taking colchicine were invited to participate in a 30-min semi-structured interview. Data were analysed using a general inductive thematic approach. FINDINGS Overall, participants had a lack of knowledge regarding colchicine and used variable doses during an acute gout attack. Participants were unsure of the maximum dose of colchicine and several took more than prescribed. The prophylactic use of colchicine and allopurinol varied from 3 weeks to 15 years. Mixed views were reported on restricting colchicine supply. Most participants received gout information from their general practitioner (GP). CONCLUSION Poor understanding of colchicine contributed to inappropriate use and highlights the need for targeted patient education. Considerable inter-patient variability exists in the use of colchicine for acute gout, suggesting the efficacy of low dose regimens be explored. The length of adjunctive colchicine use, as part of a prophylaxis regimen, needs to be regularly reviewed and tailored to each patient. Further research is required on limiting the amount of colchicine dispensed. PMID- 27477557 TI - A qualitative study to explore health professionals' experience of treating gout: understanding perceived barriers to effective gout management. AB - INTRODUCTION The management of gout is challenging and mainly occurs in primary care. This study aims to explore the experience of treating gout among primary care clinicians and understand the perceived barriers to effective therapy. METHODS Fourteen health professionals from primary care practices in South Auckland were recruited. Each participated in a semi-structured interview exploring their experience of treating and managing gout patients were analysed thematically. FINDINGS Participants described the large burden of gout in their communities and the importance of the clinician-patient relationship in gout management. Four themes summarise the perceived barriers to effective urate lowering therapy (ULT); unique gout factors, eg its intermittent nature and potential for stigmatisation; systemic barriers to optimal treatment, or barriers that emerge from working within a certain organisation; uncertainty about ownership, or who should carry responsibility for overcoming barriers to optimal treatment; and cultural barriers to optimal treatment. CONCLUSION Clinicians in primary practice perceive gout management to be mainly acute rather than preventive care. Patients may be stigmatised and management difficult particularly when diet is emphasised over ULT. Practice nurses are a group potentially available and willing to assist in educating patients. These findings may be helpful in planning for and improving healthcare in gout. KEYWORDS Gout; general practice; uric acid; primary health care; allopurinol; primary prevention. PMID- 27477558 TI - Symptoms and signs of acromegaly: an ongoing need to raise awareness among healthcare practitioners. AB - INTRODUCTION Chronic excess growth hormone production results in acromegaly, a condition associated with widespread physical changes, including soft tissue and bony overgrowth. When untreated, acromegaly reduces life expectancy. Patients usually remain undiagnosed for years after the onset of symptoms, by which stage irreversible physical changes have often occurred. METHOD A cross-sectional questionnaire study involving patients with acromegaly from the Waikato Endocrine Unit and the New Zealand Acromegaly Society evaluated features of acromegaly that were present before diagnosis. The aim of this study was to identify acromegaly features that were most prevalent to promote increased awareness about the disease by healthcare providers. RESULTS 81 participants were included. The main pre-diagnosis physical changes participants reported were acral changes, alterations in facial features and oral symptoms. For some, these features were present for more than 10 years before the acromegaly diagnosis. Multiple co morbidities associated with acromegaly were reported. Two-thirds of the participants felt that an earlier diagnosis was possible. Most participants were in contact with General Practitioners (GPs) and/or dentists before diagnosis. Endocrinologists had the highest diagnosis rate, followed by GPs. Dentists had a low diagnosis rate despite a high prevalence of oral symptoms among study participants. CONCLUSION Increased awareness of acromegaly among primary care clinicians is important as they are the first-point-of-contact with the healthcare system for most patients. Health professionals' early recognition of symptoms and signs of acromegaly would reduce delays in time-to-diagnosis, enable earlier treatment and may improve outcomes for patients with acromegaly. MESH KEYWORDS Acromegaly; symptoms; delayed diagnosis; clinicians; primary healthcare. PMID- 27477559 TI - Deprescribing in a family health team: a study of chronic proton pump inhibitor use. AB - BACKGROUND Proton pump inhibitors (PPIs) are often used inappropriately, without an indication, or for longer durations than recommended. Few tools exist to guide reassessment of their continued use and deprescribing if required. We aimed to reduce inappropriate drug use by developing and implementing a PPI deprescribing tool and process in a family medicine unit. ASSESSMENT OF PROBLEM Primary care providers of adults taking a PPI for 8 weeks with an upcoming periodic health examination were reminded to reassess therapy via electronic medical record (EMR) messaging. A PPI Deprescribing Tool was uploaded into the EMR as a second reminder and to guide reassessment and deprescribing where indicated. Ten weeks after the examination a chart review assessed changes to PPI use. A follow up survey of providers assessed the utility and barriers to implementing the Deprescribing Tool. RESULTS Forty-three of 46 patients on PPIs (93%) had their PPI reassessed, resulting in 11 patients (26%) having their PPI deprescribed. Strategies for Improvement Routine reassessment of long-term medications is often overlooked because of extensive demands on primary care providers' time. Deprescribing likely improved because potentially eligible patients were identified to the provider and a tool was provided at the time of the encounter to guide the deprescribing process. LESSONS Reassessment and deprescribing of PPIs can be supported by implementing a standardised process and use of guidance tools for clinicians. Providers found the timely and selective reminder message to deprescribe the most useful component of the intervention. KEYWORDS proton pump inhibitor; deprescribing; reassessment; primary care; medication therapy management; gastroesophageal reflux disease. PMID- 27477560 TI - Using run charts for cardiovascular disease risk assessments in general practice. AB - INTRODUCTION Run charts are quality improvement tools. AIM To investigate the feasibility and acceptability of run charts displaying weekly cardiovascular disease (CVD) risk assessments in general practice and assess their impact on CVD risk assessments. METHODS A controlled non-randomised observational study in nine practices using run charts and nine control practices. We measured the weekly proportion of eligible patients with completed CVD risk assessments for 19 weeks before and after run charts were introduced into intervention practices. A random coefficients model determined changes in CVD risk assessment rates (slope) from pre- to post- intervention by aggregating and comparing intervention and control practices' mean slopes. We interviewed staff in intervention practices about their use of run charts. RESULTS Seven intervention practices used their run chart; six consistently plotting weekly data for >12 weeks and positioning charts in a highly visible place. Staff reported that charts were easy to use, a visual reminder for ongoing team efforts, and useful for measuring progress. There were no significant differences between study groups: the mean difference in pre- to post-run chart slope in the intervention group was 0.03% more CVD risk assessments per week; for the control group the mean difference was 0.07%. The between group difference was 0.04% per week (95% CI: -0.26 to 0.35, P = 0.77). DISCUSSION Run charts are feasible in everyday general practice and support team processes. There were no differences in CVD risk assessment between the two groups, likely due to national targets driving performance at the time of the study. PMID- 27477561 TI - Cochrane Corner: Will topical NSAIDs help with chronic musculoskeletal pain? PMID- 27477562 TI - PEARLS: a locally-produced resource for New Zealand primary care with a global reach. PMID- 27477563 TI - String of PEARLS about Heart health. PMID- 27477564 TI - Potion of Poison? Cannabis oil. PMID- 27477566 TI - Successful mechanical thrombectomy in a three-year-old boy with cardioembolic occlusion of both the basilar artery and the left middle cerebral artery. AB - BACKGROUND: Paediatric stroke is a potentially life-threatening emergency and requires immediate treatment to improve clinical outcome. In contrast to adult treatment recommendations, little is known about safety and efficacy of thrombolysis and mechanical thrombectomy in children. CASE DESCRIPTION AND CONCLUSION: We report on a three-year-old boy with a cardioembolic intracranial two-vessel occlusion and successful therapy with thrombolysis and mechanical thrombectomy. Furthermore, this case emphasizes the need of standardized protocols for acute management of paediatric stroke. PMID- 27477568 TI - A comparison of risk factors and prognosis between intra and extracranial acute atherosclerotic stroke in the Turkish population: a prospective study. AB - BACKGROUND: The aim of this study was to compare the differences in risk factors and prognosis between acute stroke caused by definitive intracranial atherosclerosis (ICAS) or extracranial atherosclerosis (ECAS) in the Turkish population. METHODS: This study was prospectively designed in a single centre and conducted with patients who were hospitalised due to acute ischaemic stroke. Inclusion criteria were the diagnosis of atherosclerotic ischaemic stroke, defined as more than 50% stenosis or occlusion in the arterial structure supplying the ischaemic area, having excluded other possible causes. RESULTS: Information on 58 ICAS and 57 ECAS stroke patients was collected in a 13-month period. The ECAS patients had male gender predominance (p = 0.003). Ageing, stroke history and hyperlipidaemia were related with stroke severity in ECAS, and gender was associated with severity in ICAS. Hypertension and being female were related with poor prognosis in ICAS (p = 0.081 vs. 0.087). Congestive heart failure (p = 0.002) was associated with poor prognosis and alcohol with a favourable outcome (p = 0.087) in ECAS. Stroke severity was related with poor prognosis in both groups (p < 0.001). CONCLUSIONS: The prevalence of risk factors differs between ICAS and ECAS, and their influence differs for stroke severity and prognosis. PMID- 27477567 TI - Relationship Between Process of Care and a Subsequent Increase in Damage in Systemic Lupus Erythematosus. AB - OBJECTIVE: To evaluate whether low ratings of interactions with providers and health plans in 2013 were associated with increased systemic lupus erythematosus (SLE) damage in 2015. METHODS: Data were derived from the Lupus Outcomes Study (LOS) annual surveys and include items from the Consumer Assessment of Health Plans and Interpersonal Processes of Care Scale measuring dimensions of health care interactions. We used ordinary least squares regression to model the change in disease damage over a 2-year period, 2013-2015, as a function of ratings of multiple dimensions of interactions with providers and health plans, with and without adjustment for demographic characteristics, socioeconomic status, and SLE and overall health status, and logistic regression to estimate the effect of the same matrix of variables on the probability of experiencing a minimum clinically important increase in damage. RESULTS: There were 566 LOS respondents who were followed from 2013-2015 and who rated their providers and health plans in 2013. After adjustment, persons with SLE rating their providers poorly in patient provider communication experienced a significantly greater accrual of disease damage (odds ratio [OR] 0.23 [95% confidence interval (95% CI) 0.09-0.38]) and were more likely to experience a minimum clinically important increase in damage (OR 2.35 [95% CI 1.25-4.39]). After adjustment, those rating their health plan poorly on care coordination experienced a significantly greater accrual of disease damage (OR 0.19 [95% CI 0.03-0.35]) and were more likely to experience a minimum clinically important increase in damage (OR 2.20 [95% CI 1.12-4.34]). CONCLUSION: Poor patient-provider communication and care coordination may result in increased disease damage. PMID- 27477570 TI - Optimal use of CT imaging in pediatric congenital cholesteatoma. AB - OBJECTIVE: This study aimed to determine the radiation dose of temporal bone computed tomography (TBCT) to detect pediatric congenital cholesteatoma (CC), and suggests strategy for lowering perioperative radiation dose. METHODS: Fifty-three CC patients followed up for more than 12 months after surgery. Perioperative clinical findings and the effective radiation dose (ERD) of TBCT were investigated. Patients' mean age at initial TBCT was 60 months; the mean follow up period was 43 months. RESULTS: In 33 (62.3%) of 53 patients, only one TBCT was performed postoperatively. Postoperative CT imaging was performed to evaluate before second-stage ossiculoplasty, due to suspicion of CC recurrence on examinations, or as part of follow-up. When TBCT was performed on more than two occasions after surgery as a part of follow-up, there was no difference in the distribution of stage or type of CC compared to patients subjected to TBCT on less than three occasions (p=0.093 and p=0.744, respectively). During the most recent follow-up of these 53 cases, there was no CC recurrence. The mean ERD of a single TBCT was 1.2mSv, and the mean cumulative ERD of TBCT was 2mSv per patient. CONCLUSION: Mean and cumulative ERD of TBCT performed in CC cases was not too high to consider radiation hazard. However, efforts to minimize the number of CT scans should be taken basically. PMID- 27477569 TI - Intravascular Inflammation Triggers Intracerebral Activated Microglia and Contributes to Secondary Brain Injury After Experimental Subarachnoid Hemorrhage (eSAH). AB - Activation of innate immunity contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH). Microglia accumulation and activation within the brain has recently been shown to induce neuronal cell death after eSAH. In isolated mouse brain capillaries after eSAH, we show a significantly increased gene expression for intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Hence, we hypothesized that extracerebral intravascular inflammatory processes might initiate the previously reported microglia accumulation within the brain tissue. We therefore induced eSAH in knockout mice for ICAM-1 (ICAM-1-/-) and P-selectin glycoprotein ligand-1 (PSGL-1-/-) to find a significant decrease in neutrophil-endothelial interaction within the first 7 days after the bleeding in a chronic cranial window model. This inhibition of neutrophil recruitment to the endothelium results in significantly ameliorated microglia accumulation and neuronal cell death in knockout animals in comparison to controls. Our results suggest an outside-in activation of the CNS innate immune system at the vessel/brain interface following eSAH. Microglia cells, as part of the brain's innate immune system, are triggered by an inflammatory reaction in the microvasculature after eSAH, thus contributing to neuronal cell death. This finding offers a whole range of new research targets, as well as possible therapy options for patients suffering from eSAH. PMID- 27477571 TI - Cerebral infarction in right pons during the course of mobile mitral annular calcification-related calcified amorphous tumor during a long time hemodialysis. AB - We report here a 70 year-old male on maintenance hemodialysis who presented non paralytic pontine exotropia. Brain MRI showed new right pons infarct. Transthoracic and transesophageal echocardiography revealed a mobile calcification at posterior mitral leaflet with rapid growing compared to 14 days ago. Neurological symptoms disappeared at least 10 days by a treatment with aspirin. Calcification reduced by a follow-up transthoracic echocardiography after 90 days from the beginning of neurological symptoms. We diagonosed him with cerebral infarction during the course of mobile mitral annular calcification related calcified amorphous tumor. Mobile mitral annular calcification-related calcified amorphous tumor would be a cause of cerebral infarction, we need to be careful to check a transthoracic echocardiography regularly because of necessity. PMID- 27477572 TI - A case of midbrain infarction with acute bilateral cerebellar ataxia visualized by diffusion tensor imaging. AB - An 85-year-old woman with hypertension was admitted with a sudden onset of gait disturbance and dysarthria. On admission, the patient showed severe bilateral cerebellar ataxia with moderate right medial longitudinal fasciculus (MLF) syndrome. Magnetic resonance (MR) imaging showed an acute infarction in the lower and medial part of midbrain. Diffusion tensor imaging (DTI) started from both cerebellar peduncles revealed that the lesion of the acute infarction matched the decussation of superior cerebellar peduncle where crossing of tract was seen and a part of its tract was interrupted at the site. Interruption of the cerebellum red nuclear path at the medial part of midbrain was considered to be the reason for bilateral cerebellar ataxia and visualization of cerebellum red nuclear path by DTI can give better understanding of the neurological symptom. PMID- 27477573 TI - A case of neuromyelitis optica presenting marked pleocytosis and hypoglycorrhachia. AB - A 57-year-old man initially developed chest discomfort, nausea, vomiting, headache and low-grade fever, followed by paraplegia, sensory disturbance below level Th5 and bilateral visual loss. He was admitted to our hospital on the 15th day of illness. MRI short T1 inversion recovery image showed multiple longitudinal lesions in the spinal cord below C3, and T2-weighted image showed abnormal hyperintensity within the left optic nerve. Cerebrospinal fluid (CSF) analysis revealed marked pleocytosis (1,719/MUl) and hypoglycorrhachia (CSF glucose; 20 mg/dl). Intensive immunosuppressive therapy combined with antibiotics and antiviral agent were started immediately, resulting in relatively good visual outcome but no improvement of paraplegia and sensory disturbance. The patient's serum sample on admission was subsequently reported to be positive for anti aquaporin-4 antibody. With no evidence of infectious diseases, neuromyelitis optica (NMO) was diagnosed. It should be borne in mind that marked hypogylcorrhachia may also be seen in NMO. PMID- 27477574 TI - A case of anti-nuclear matrix protein 2 antibody positive myopathy associated with lung cancer. AB - Myositis-specific autoantibodies (MSAs) are associated with myositis. Anti nuclear matrix protein 2 (NXP-2) antibody was recently identified as a major MSA and was observed mostly in juvenile dermatomyositis. We report the case of a 44 year-old man who presented with myopathy with anti-NXP-2 antibody and large cell carcinoma of the lung. He was hospitalized because of myalgia and edema of limbs. Neurological examination revealed mild proximal-dominant weakness in all four extremities, and laboratory studies showed elevated creatine kinase level (6,432 IU/l). Needle electromyography showed myogenic patterns. MRI of the lower limbs demonstrated inflammatory lesions in the thighs. Biopsied specimen from the left quadriceps femoris muscle showed mild mononuclear inflammatory infiltrate surrounding muscle fibres but no fiber necrosis. He was diagnosed with myopathy based on neurological examinations and clinical symptoms. His chest X-ray and CT showed tumor shadow on the right upper lung field, but CT didn't indicate the findings of interstitial lung disease. This was surgically removed, and a histological diagnosis of non-small cell lung cancer was suspected. He was also treated with definitive chemoradiotherapy before and after operation. His symptoms of myopathy promptly remitted with the preoperative chemotherapy. His serum analysis was positive for the anti-NXP-2. Further investigation and experience of MSAs are necessary to evaluate the therapeutic strategy against cancer-associated myopathy/myositis. PMID- 27477575 TI - Subacute autonomic and sensory neuropathy closely related to cytomegalovirus infection preceded by frequent syncopal attacks. AB - A 73-year-old woman who had hypertension developed a slight fever and general malaise with laboratory-proven hepatic dysfunction as well as frequent syncopal attacks 3 months before admission to our hospital. One month later, she developed urinary retention and distal limb numbness. Upon admission, her neurological examination showed reduced limb tendon reflexes, glove and stocking-type numbness, and diminished senses of touch, temperature, pain, and distal leg vibration and position. Serum cytomegalovirus (CMV) IgM antibody and CMV IgG antibody were elevated on admission, and both decreased thereafter, confirming CMV infection. No serum anti-ganglioside antibody was detected. Cerebrospinal fluid revealed a mild pleocytosis and elevated proteins. Compound muscle action potential (CMAP) amplitudes of the tibial and peroneal nerve were slightly reduced. Sensory nerve action potential (SNAP) amplitudes of the median and ulnar nerves were reduced, and sural SNAP was not evoked. Systolic blood pressure dropped 48 mmHg when the patient assumed a standing position from a supine one, demonstrating orthostatic hypotension, and a cold pressor test was abnormal, both indicating an obvious hypofunction of the sympathetic nerve. The postganglionic autonomic nerve appeared to be damaged because the accumulation of [(123)I] meta iodobenzylguanidine was reduced on myocardial scintigraphy. These findings combined together led us to make a diagnosis of subacute autonomic and sensory neuropathy associated with CMV infection in this case. Following an eventless administration of oral fludrocortisones, intravenous immuno-globulin (IVIg) was given after one month of the hospitalization with a remarkable reduction of the syncope. This case is instructive in two points. One is that there may be a couple of months with syncope alone before the sensory disturbance appearance, and the other is that IVIg may be considerably effective for the patient-annoying syncopes. To our knowledge, this is the first report of subacute autonomic and sensory neuropathy caused by CMV infection. PMID- 27477576 TI - Guillan-Barre syndrome following scrub typus: two case reports. AB - Case 1: A 66-year-old man was admitted because of progressive gait disturbance and dysphagia after developing red rash. He was diagnosed as Guillain-Barre syndrome (GBS) and treated by intravenous immunoglobulin therapy (IVIg). Two weeks later, he could swallow and walk without any abnormalities. Case 2: A 58 year-old woman was admitted because of gait disturbance, bilateral peripheral facial nerve palsies, and respiratory failure one week after developing fever and rash. She was diagnosed as GBS and treated with IVIg. She underwent mechanical ventilation, while she could wean off it one month later and her limb strengths improved. We confirmed both patients had scrub typhus by serological studies. Peripheral neuropathy is one of the complications of scrub typhus. In addition, this disease sometimes leads to severe GBS. GBS should be included in differential diagnosis when peripheral neuropathies develop in the course of treating scrub typhus, and we should keep in mind that scrub typhus is one of the causes of GBS. PMID- 27477577 TI - Dysphagia in Parkinson's disease. AB - Although dysphagia is an important symptom associated with prognosis in patients with Parkinson's disease (PD), dysphagia tends to be overlooked until swallowing difficulties reach an advanced phase. We assessed dysphagia with videofluoroscopic examination of swallowing in 31 patients with mainly mild or moderate PD. Swallowing problems were observed in the pharyngeal phase in 28 patients, oral phase in 19 patients, esophageal phase in 15 patients, and oral preparatory phase in 1 patient. Therefore, dysphagia in the pharyngeal phase was observed in almost all patients with mild or moderate PD. In contrast, no dysfunction was detected in most patients when screening was conducted via questionnaire or other methods. Assessment of clinical parameters in the present study suggests that latent swallowing dysfunction may be present even in the early disease stage in PD. A future prospective study to follow swallowing functions in a pre-symptomatic phase in PD would be fruitful to find whether swallowing dysfunction is one of the prodromal symptoms. PMID- 27477578 TI - Sleep related movement and behavior disorders. AB - Movement and behavior disorders developing during sleep or in the transitional state from sleep to wakefulness are mostly unfamiliar to Japanese neurologists, primarily because these disorders are objects of basic research. In addition, the patients with sleep related movement and behavior disorders (SRMBD) show no signs and symptoms in our consulting rooms, and cannot be identified without polysomnography (PSG) attended by trained sleep technologists. Although attended PSG is not widely available in Japan, some kinds of SRMBD ought to be clinical targets for neurologists, and they are the scope of this review. PMID- 27477579 TI - An elderly man with progressive ataxia and palatal tremor presenting with dizziness and oculopalatal tremor. AB - A 74-year-old man was referred to our department for dizziness and progressive unsteady gait over 6 years. His family history was unremarkable. Neurological examination showed dysarthria, saccadic eye movement, palatal tremor (1.7 Hz) synchronous with rotational ocular movement, and truncal ataxia. T2-weighted magnetic resonance imaging (MRI) of the brain revealed hyperintense and hypertrophic bilateral inferior olivary nuclei at the medulla and mild cerebellar atrophy. On the basis of neurological findings of oculopalatal tremor and cerebellar ataxia with brain MRI findings, the diagnosis of progressive ataxia and palatal tremor (PAPT) was made. PAPT should be included in differential diagnosis of dizziness observed in elderly individuals. PMID- 27477580 TI - Meta-analysis on the effect of text message reminders for HIV-related compliance. AB - For the treatment of HIV, compliance in regard to appointment attendance and medication usage is critical. Various methods have been attempted to increased HIV care compliance, and a method that has inspired many published studies is text message reminders. We conducted a meta-analysis of the literature from inception through May 2016 using the following databases: Pubmed, Embase, CINAHL, Web of Science, and Cochrane. Examples of terms used in the search included exploded versions of "HIV, "AIDS", "cell phone", "SMS", "text message", "reminder". After abstract and manuscript review, articles were discussed with co author and included based on consensus. We excluded qualitative analyses, observational studies without an intervention, and studies without a control or pre-intervention group. We used random-effects models to calculate odds ratios (OR) and standardized mean differences (SMDs) for the text message intervention. Thirty-four unique studies were found and included in the meta-analysis. For the seven articles relating to non-attendance, text message reminders significantly reduced the rates of non-attendance (OR, 0.66; 95% CI, 0.48-0.92; P = .01; I2 = 52%). For the 20 articles on drug adherence, text message reminders significantly increased adherence (SMD, 0.87; 95% CI, 0.06-1.68; P = .04; I2 = 99%). For the 11 articles with physiologic measures (CD4 count or viral load), text message reminders led to significant improvement (SMD, 1.53; 95% CI, 0.52-2.55; P = .003; I2 = 99%). This meta-analysis reveals that text message reminders are a promising intervention that can be used to increase HIV care compliance when logistically feasible. Further study should focus on which populations benefit the most from this intervention, and successful implementers could create an established technological infrastructure for other clinics to adopt when seeking to boost compliance. PMID- 27477582 TI - Ultrasonographic Evaluation of the Radial Nerves in Patients with Unilateral Refractory Lateral Epicondylitis. AB - Objective: To evaluate the possible radial nerve entrapment of patients with unilateral refractory lateral epicondylitis (LE) by using ultrasound (US) and electroneuromyography. Design: Cross-sectional study. Setting: Three physical medicine and rehabilitation departments. Subjects: Consecutive 44 patients (15 M, 29 F) with unilateral refractory LE. Methods: All patients underwent detailed clinical, electrophysiological and ultrasonographic evaluations. Ultrasound imaging was used to evaluate thickness and presence of abnormal findings of the common extensor tendon (CET) and cross-sectional area (CSA) of the radial nerve (at spiral groove and before bifurcation) bilaterally. Unaffected sides of the patients were taken as controls. Results: When compared with the unaffected sides, CET thickness and radial nerve CSAs (at both levels) were higher, and abnormal US findings regarding LE (47.7% vs. 6.8%) were more common on the affected sides than nonaffected sides (all P < 0.001). Grip strength values were lower on the affected sides ( P < 0.001). Electrophysiological studies were all normal, and similar between the two sides (all P > 0.05). When subgroup analyses were performed after taking into account the hand dominance, affected and dominant sides were found to be the same in 31 and different in 13 patients. In subgroups, CETs and radial nerve CSAs at both levels were higher on the affected sides (all P < 0.01). Conclusions: Radial nerves and the CETs seem to be swollen on the affected sides, independent from the hand dominance of the patients with refractory LE. These results morphologically support the previous literature that attributes some of the chronic complaints of these patients actually to radial nerve entrapment. PMID- 27477581 TI - Factors Associated with Opioid Dose Increases: A Chart Review of Patients' First Year on Long-Term Opioids. AB - Objective: To examine encounter-level factors associated with opioid dose increases during patients' first year on opioid therapy for chronic pain. Design: Case-control study analyzing all opioid prescriptions for patients with chronic pain during their first year after opioid initiation. Cases were patients who experienced an overall dose escalation of >= 30 mg morphine equivalents over the 1-year period; controls did not experience overall dose escalation. Main measures were encounter type, opioid dose change, documented prescribing rationale, documentation of guideline-concordant opioid-prescribing practices. Two coders reviewed all encounters associated with opioid prescriptions. Analysis of factors associated with dose increases and provider documentation of prescribing rationale was conducted using multiple logistic regression. Results: There were 674 encounters coded for 66 patients (22 cases, 44 controls). Fifty-three percent of opioid prescriptions were associated with telephone encounters; 13% were associated with e-mail encounters. No prescribing rationale was documented for 43% of all opioid prescriptions and 25% of dose increases. Likelihood of dose increase and documentation of prescribing rationale did not significantly differ for cases versus controls. Compared with face-to-face encounters, dose increases were significantly less likely for telephone (OR 0.18, 95% CI 0.11-0.28) and e mail (OR 0.23, 95% CI 0.12-0.47) encounters; documentation of prescribing rationale was significantly more likely for e-mail (OR 5.06, 95% CI 1.87-13.72) and less likely for telephone (OR 0.30, 95% CI 0.18-0.51) encounters. Conclusion: Most opioid prescriptions were written without face-to-face encounters. One quarter of dose increases contained no documented prescribing rationale. Documented encounter-level factors were not significantly associated with overall opioid dose escalation. PMID- 27477584 TI - Mobile health in cardiology: a review of currently available medical apps and equipment for remote monitoring. AB - INTRODUCTION: Recent developments in implantable cardioverter-defibrillators (ICDs) and smartphone technology have increased the possibilities for remote monitoring. It is the purpose of this review to give an overview of these new possibilities. AREAS COVERED: Remote monitoring in ICD allows for early detection of lead fractures and remote follow-up of patients. Possible limitations are the lack of standardization and the possible unsafety of the data stored on the ICD. Secondly, remote monitoring of health parameters using smartphone compatible wearables and smartphone medical apps is addressed. Possible limitations include the fact that the majority of smartphone apps are unregulated by the regulatory authorities and privacy issues such as selling of app-generated data to third parties. Lastly, clinical studies with smartphone apps are discussed. Expert commentary: New technologies in ICDs and smartphones have the potential to be used for remote monitoring. However, unreliability of smartphone technology, inadequate legislation and lack of reimbursement impede implementation. PMID- 27477585 TI - Artifactual mutations resulting from DNA lesions limit detection levels in ultrasensitive sequencing applications. AB - The need in cancer research or evolutionary biology to detect rare mutations or variants present at very low frequencies (<10-5) poses an increasing demand on lowering the detection limits of available methods. Here we demonstrated that amplifiable DNA lesions introduce important error sources in ultrasensitive technologies such as single molecule PCR (smPCR) applications (e.g. droplet digital PCR), or next-generation sequencing (NGS) based methods. Using templates with known amplifiable lesions (8-oxoguanine, deaminated 5-methylcytosine, uracil, and DNA heteroduplexes), we assessed with smPCR and duplex sequencing that templates with these lesions were amplified very efficiently by proofreading polymerases (except uracil), leading to G->T, and to a lesser extent, to unreported G->C substitutions at 8-oxoguanine lesions, and C->T transitions in amplified uracil containing templates. Long heat incubations common in many DNA extraction protocols significantly increased the number of G->T substitutions. Moreover, in ~50-80% smPCR reactions we observed the random amplification preference of only one of both DNA strands explaining the known 'PCR jackpot effect', with the result that a lesion became indistinguishable from a true mutation or variant. Finally, we showed that artifactual mutations derived from uracil and 8-oxoguanine could be significantly reduced by DNA repair enzymes. PMID- 27477586 TI - Identification of Biomarkers of Exposure to FTOHs and PAPs in Humans Using a Targeted and Nontargeted Analysis Approach. AB - Although historic perfluorinated compounds are currently under scrutiny and growing regulatory control in the world, little is known about human exposure to other polyfluorinated compounds presently in use. Fluorotelomer alcohols (FTOHs) and polyfluoroalkyl phosphate esters (PAPs) are known to degrade to terminal perfluorinated acids and toxic reactive intermediates through metabolic pathways. Therefore, it is important to characterize their human exposure by the identification of unique biomarkers. With the use of liquid chromatography-mass spectrometry-time-of-flight analysis (LC-MS-TOF), we developed a workflow for the identification of metabolites for the 8:2 FTOH and 8:2 diPAP. Analysis of serum and urine of dosed rats indicated the 8:2 FTOH-sulfate and the 8:2 diPAP as potential biomarkers. These compounds, as well as 25 other fluorinated compounds and metabolites, were analyzed in human serum and urine samples from the general population (n = 100) and office workers (n = 30). The 8:2 FTOH-sulfate was measured for the first time in human samples in 5 to 10% of the serum samples, ranging from 50 to 80 pg/mL. The 8:2 diPAP was measured in 58% of the samples, ranging from 100 to 800 pg/mL. This study indicates the FTOH-sulfate conjugate as a biomarker of exposure to FTOHs and PAPs in humans. PMID- 27477587 TI - Alterations in the Fecal Microbiota of Patients with HIV-1 Infection: An Observational Study in A Chinese Population. AB - The available evidence suggests that alterations in gut microbiota may be tightly linked to the increase in microbial translocation and systemic inflammation in patients with human immunodeficiency virus 1 (HIV-1) infection. We profiled the fecal microbiota as a proxy of gut microbiota by parallel barcoded 454 pyrosequencing in 67 HIV-1-infected patients (32 receiving highly active antiretroviral therapy [HAART] and 35 HAART naive) and 16 healthy controls from a Chinese population. We showed that alpha-diversity indices did not differ significantly between the healthy control and HIV-1-infected patients. The ratio of Firmicutes/Bacteroidetes increased significantly in HIV-1-infected patients. Several key bacterial phylotypes, including Prevotella, were prevalent in HIV-1 infected patients; whereas Phascolarctobacterium, Clostridium XIVb, Dialister and Megamonas were significantly correlated with systemic inflammatory cytokines. After short-term, effective HAART, the viral loads of HIV-1 were reduced; however, the diversity and composition of the fecal microbiota were not completely restored. and the dysbiosis remained among HIV-1-infected subjects undergoing HAART. Our detailed analysis demonstrated that dysbiosis of fecal microbiota might play an active role in HIV-1 infection. Thus, new insights may be provided into therapeutics that target the microbiota to attenuate the progression of HIV disease and to reduce the risk of gut-linked disease in HIV-1 infected patients. PMID- 27477588 TI - Heterotrophs are key contributors to nitrous oxide production in activated sludge under low C-to-N ratios during nitrification-Batch experiments and modeling. AB - Nitrous oxide (N2 O), a by-product of biological nitrogen removal during wastewater treatment, is produced by ammonia-oxidizing bacteria (AOB) and heterotrophic denitrifying bacteria (HB). Mathematical models are used to predict N2 O emissions, often including AOB as the main N2 O producer. Several model structures have been proposed without consensus calibration procedures. Here, we present a new experimental design that was used to calibrate AOB-driven N2 O dynamics of a mixed culture. Even though AOB activity was favoured with respect to HB, oxygen uptake rates indicated HB activity. Hence, rigorous experimental design for calibration of autotrophic N2 O production from mixed cultures is essential. The proposed N2 O production pathways were examined using five alternative process models confronted with experimental data inferred. Individually, the autotrophic and heterotrophic denitrification pathway could describe the observed data. In the best-fit model, which combined two denitrification pathways, the heterotrophic was stronger than the autotrophic contribution to N2 O production. Importantly, the individual contribution of autotrophic and heterotrophic to the total N2 O pool could not be unambiguously elucidated solely based on bulk N2 O measurements. Data on NO would increase the practical identifiability of N2 O production pathways. Biotechnol. Bioeng. 2017;114: 132-140. (c) 2016 Wiley Periodicals, Inc. PMID- 27477589 TI - Can Cerebrospinal Fluid Pressure Detect Catheter Complications in Patients Who Experience Loss of Effectiveness With Intrathecal Baclofen Therapy? AB - OBJECTIVE: The catheter status of patients who presented with loss of intrathecal baclofen (ITB) therapy effectiveness was investigated using measurements of cerebrospinal fluid (CSF) pressure transmitted through the catheter fluid path to the pump. The aim of the study was to estimate the appropriate threshold separating catheter complications from "normal" catheter function, and to compare catheter status based on CSF pressure with the clinical diagnosis. METHODS: This was a prospective, masked nonsignificant risk, research study. Patients (N = 47) received ITB for the treatment of severe spasticity and presented with symptoms of catheter malfunction. CSF pressure data were recorded using an external sensor connected to a needle inserted into the catheter access port. An algorithm calculated the energy of the variations in CSF pressure caused by respiration and heartbeat within the intrathecal space. These data were evaluated against a threshold that separated normal from abnormal catheter function. Catheter status based on the algorithm was compared with the clinical diagnosis. RESULTS: Complete data were available for 37 patients. Mean CSF pressure energy was significantly higher (p = 0.025; student t-test) for patients diagnosed with normal catheter function vs. catheters with complications. The CSF pressure algorithm matched the clinical diagnosis in 16 of 18 patients with catheter complications (sensitivity = 89%), and 13 of 19 patients with normal catheter function (specificity = 68%). CONCLUSION: In-clinic CSF pressure data acquisition is technically feasible. Overall, catheter status based on the algorithm demonstrated concordance with the clinical diagnosis in 29 of 37 patients (78.4%). PMID- 27477590 TI - Characterization of a Monoclonal Antibody against Syringate Derivatives: Application of Immunochemical Detection of Methyl Syringate in Honey. AB - Syringic acid is one of the key skeletal structures of plant-derived chemicals. The derivatives of syringic acid have certain biological functions. In this study, a monoclonal antibody to syringic acid-based phytochemicals was prepared and characterized. The obtained antibody reacted with methyl syringate, syringic acid, and leonurine. Methyl syringate is a characteristic compound found in manuka honey, other honey varieties, and plants. Manuka honey was fractionated using HPLC, and the reactivity of the fractions with the antibody was examined. The antibody reacted with the fraction in which methyl syringate was eluted. The amount of methyl syringate in honeys as estimated by ELISA using the antibody had a good linearity compared with that estimated by HPLC. These results suggest that the antibody is applicable for the immunochemical detection of syringic acid derivatives in plants and foods. PMID- 27477591 TI - Peptides interfering with protein-protein interactions in the ethylene signaling pathway delay tomato fruit ripening. AB - The plant hormone ethylene is involved in the regulation of several processes with high importance for agricultural applications, e.g. ripening, aging and senescence. Previous work in our group has identified a small peptide (NOP-1) derived from the nuclear localization signal of the Arabidopsis ethylene regulator ETHYLENE INSENSITIVE-2 (EIN2) C-terminal part as efficient inhibitor of ethylene responses. Here, we show that NOP-1 is also able to efficiently disrupt EIN2-ETR1 complex formation in tomato, indicating that the NOP-1 inhibition mode is conserved across plant species. Surface application of NOP-1 on green tomato fruits delays ripening similar to known inhibitors of ethylene perception (MCP) and ethylene biosynthesis (AVG). Fruits treated with NOP-1 showed similar ethylene production as untreated controls underlining that NOP-1 blocks ethylene signaling by targeting an essential interaction in this pathway, while having no effect on ethylene biosynthesis. PMID- 27477592 TI - Psychophysiological whole-brain network clustering based on connectivity dynamics analysis in naturalistic conditions. AB - We introduce a novel method for delineating context-dependent functional brain networks whose connectivity dynamics are synchronized with the occurrence of a specific psychophysiological process of interest. In this method of context related network dynamics analysis (CRNDA), a continuous psychophysiological index serves as a reference for clustering the whole-brain into functional networks. We applied CRNDA to fMRI data recorded during the viewing of a sadness-inducing film clip. The method reliably demarcated networks in which temporal patterns of connectivity related to the time series of reported emotional intensity. Our work successfully replicated the link between network connectivity and emotion rating in an independent sample group for seven of the networks. The demarcated networks have clear common functional denominators. Three of these networks overlap with distinct empathy-related networks, previously identified in distinct sets of studies. The other networks are related to sensorimotor processing, language, attention, and working memory. The results indicate that CRNDA, a data-driven method for network clustering that is sensitive to transient connectivity patterns, can productively and reliably demarcate networks that follow psychologically meaningful processes. Hum Brain Mapp 37:4654-4672, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27477593 TI - Speech audiometry findings from HIV+ and HIV- adults in the MACS and WIHS longitudinal cohort studies. AB - The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5 dB steps from 0 to 25dB hearing level (HL) with one category as >=30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores <90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication. PMID- 27477594 TI - Long-Term Use and Safety of Migraine Preventive Medications. AB - Migraine preventive medications are used to reduce the frequency, severity, and disability of migraine attacks. Once migraine preventive therapy is initiated, the question of how long to maintain this therapy arises. This article will explore the literature pertaining to the long-term use of migraine preventive medications, including length of treatment and safety with long-term exposure. PMID- 27477595 TI - Design, synthesis and biological evaluation of 6-aryl-1,6-dihydro-1,3,5-triazine 2,4-diamines as antiplasmodial antifolates. AB - The design, synthesis and biological evaluation of a series of 6-aryl-1,6-dihydro 1,3,5-triazine-2,4-diamines is described. These compounds exhibited in vitro antiplasmodial activity in the low nanomolar range against both drug sensitive and drug resistant strains of P. falciparum, with 1-(3-(2,4 dichlorophenoxy)propyl)-6-phenyl-1,6-dihydro-1,3,5-triazine-2,4-diamine hydrochloride identified as the most potent compound from this series against the drug resistant FCR-3 strain (IC50 2.66 nM). The compounds were not toxic to mammalian cells at therapeutic concentrations and were shown to be inhibitors of parasitic DHFR in a biochemical enzyme assay. PMID- 27477598 TI - Open Innovation in Drug Discovery. PMID- 27477596 TI - Immunophenotyping of T cells in the peripheral circulation in psoriasis. AB - BACKGROUND: Psoriasis is a T-helper (Th)-1/Th17-mediated chronic inflammatory disease. Cytokine mediated interaction between T lymphocytes and keratinocytes lead to keratinocyte hyper-proliferation, which leads to further inflammation in the psoriatic plaques. There is an increased population of T-helper cells in the skin lesions as well as in the peripheral circulation in psoriasis. However, the relative percentage of each T-cell phenotype in the disease pathogenesis is understudied. Our aim was to study the immune-phenotype of the different T helper/T-reg cell subsets in patients with psoriasis, with respect to healthy controls. MATERIALS AND METHODS: A total of 189 cases of psoriasis and 189 age- and gender-matched healthy controls were recruited in this cross-sectional study. Disease severity was determined by psoriasis area severity index (PASI) scoring. Peripheral blood mononuclear cells were isolated by Ficoll-Paque density centrifugation, and T-cell immunophenotyping was done by flow cytometric analysis. RESULTS: In psoriasis, we observed an imbalance in T-cell immunophenotype, characterised by an increase in Th1/Th17 cells and a relative decrease in Th2/T-reg cells, as compared to the healthy controls. We also found that the percentage of Th1/Th17 cells showed a linear trend, increasing with increasing disease severity (PASI). CONCLUSION: Our results suggest an immune dysregulation in psoriasis associated with a predominance of Th1/Th17 phenotype, especially with increasing severity of the disease. PMID- 27477597 TI - Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse. AB - The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID- 27477599 TI - Tumor or abnormality identification from magnetic resonance images using statistical region fusion based segmentation. AB - In this article, a statistical fusion based segmentation technique is proposed to identify different abnormality in magnetic resonance images (MRI). The proposed scheme follows seed selection, region growing-merging and fusion of multiple image segments. In this process initially, an image is divided into a number of blocks and for each block we compute the phase component of the Fourier transform. The phase component of each block reflects the gray level variation among the block but contains a large correlation among them. Hence a singular value decomposition (SVD) technique is adhered to generate a singular value of each block. Then a thresholding procedure is applied on these singular values to identify edgy and smooth regions and some seed points are selected for segmentation. By considering each seed point we perform a binary segmentation of the complete MRI and hence with all seed points we get an equal number of binary images. A parcel based statistical fusion process is used to fuse all the binary images into multiple segments. Effectiveness of the proposed scheme is tested on identifying different abnormalities: prostatic carcinoma detection, tuberculous granulomas identification and intracranial neoplasm or brain tumor detection. The proposed technique is established by comparing its results against seven state-of the-art techniques with six performance evaluation measures. PMID- 27477600 TI - Natural chymotrypsin-like-cleaved human mitochondrial peptides confirm tetra-, pentacodon, non-canonical RNA translations. AB - Mass spectra of human mitochondrial peptides match non-canonical transcripts systematically (a) deleting mono/dinucleotides after trinucleotides (delRNA), (b) exchanging nucleotides (swinger RNA), translated according to tri, (c) tetra- and pentacodons (codons expanded by a 4th (and 5th) silent nucleotide(s)). Swinger transcriptions are 23 bijective transformations, nine symmetric (X<->Y, e.g. A< >C) and fourteen asymmetric exchanges (X->Y->Z->X, e.g. A->C->G->A). Here, proteomic analyses assuming cleavage after W,Y, F (chymotrypsin-like, for trypsinized samples) detect fewer chymotrypsinized than trypsinized peptides. Detected non-canonical peptides map preferentially on detected non-canonical RNAs for chymotrypsinized peptides, as previously found for trypsinized peptides. This suggests residual natural chymotrypsin-like digestion detectable within experimentally trypsinized peptide data. Some trypsinized peptides are detected twice, by analyses assuming trypsin, and those assuming chymotrypsin cleavages. They have higher spectra counts than peptides detected only once, meaning that abundant peptides are more frequently detected, but detection certainties resemble those for peptides detected only once. Analyses assuming 'incorrect' digestions are inadequate negative controls for digestion enzymes naturally active in biological samples. Chymotrypsin-analyses confirm non-canonical transcriptions/translations independently of results obtained assuming trypsinization, increase non-canonical peptidome coverage, indicating mitogenome encoding of yet undetected proteins. PMID- 27477601 TI - Chronic constipation: improved understanding offers a new therapeutic approach. PMID- 27477602 TI - PET imaging of glucose movement into tissues in vivo sheds new light on an old problem. PMID- 27477603 TI - Counter-regulatory control of homeostasis during hypoglycaemia: adrenaline hits the sweet spot in the controversy concerning carotid body glucose sensing. PMID- 27477604 TI - Challenging dogma: is hepatic lipid accumulation in type 2 diabetes due to mitochondrial dysfunction? PMID- 27477605 TI - hERG long QT syndrome type 2 mutants need more than a chaperone to dance. PMID- 27477606 TI - Lost your nerve? Modulating the parasympathetic nervous system to treat inflammatory bowel disease. PMID- 27477607 TI - Gaseous regulation of Ca(2+) homeostasis; for better or worse? PMID- 27477608 TI - Non-selective cationic channels in chemical and physical stress. PMID- 27477610 TI - A giant negative magnetoresistance effect in an iron tetrabenzoporphyrin complex. AB - By measuring the electrical resistivity in TPP[FeIII(tbp)(CN)2]2 (TPP = tetraphenylphosphonium and tbp = tetrabenzoporphyrin) under the application of a static magnetic field, a giant negative magnetoresistance (MR) effect with high anisotropy is observed. More specifically, the MR ratio at 13 K under a field of 9 T perpendicular to the c axis is -70%, whereas the MR ratio under a field parallel to the c axis is -40%. Furthermore, electron spin resonance (ESR) measurements indicate large anisotropy in the principal g-values of d spin (S = 1/2) in the [FeIII(tbp)(CN)2] unit; the g1 value almost perpendicular to the tbp plane and the g2 and g3 values almost parallel to the tbp plane are 3.60, 1.24, and 0.39, respectively. It is revealed that the anisotropy in the MR effect arises from the anisotropy in the d spin, suggesting that the d spins in TPP[FeIII(tbp)(CN)2]2 affect the pi-conduction electron via the intramolecular pi d interaction. The anisotropy and magnitude in the giant negative MR effect for TPP[FeIII(tbp)(CN)2]2 are smaller than the corresponding values for the isostructural phthalocyanine (Pc) analogue TPP[FeIII(Pc)(CN)2]2. This is consistent with the fact that the intermolecular antiferromagnetic d-d interaction in TPP[FeIII(tbp)(CN)2]2 (suggested by the Weiss temperature: Theta = -8.0 K) is weaker than that in TPP[FeIII(Pc)(CN)2]2 (Theta = -12.3 K). This indicates that the minor modification in coordination complexes can significantly affect the MR effect via tuning the intermolecular d-d interaction as well as the intermolecular pi-pi overlap. PMID- 27477609 TI - Activation of lysosomal P2X4 by ATP transported into lysosomes via VNUT/SLC17A9 using V-ATPase generated voltage gradient as the driving force. AB - KEY POINTS: SLC17A9 proteins function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation. P2X4 receptors act as lysosomal ion channels activated by luminal ATP. SLC17A9-mediated ATP transport across the lysosomal membrane is suppressed by Bafilomycin A1, the V-ATPase inhibitor. SLC17A9 mainly uses voltage gradient but not pH gradient generated by the V-ATPase as the driving force to transport ATP into the lysosome to activate P2X4. ABSTRACT: The lysosome contains abundant ATP which plays important roles in lysosome functions and in cell signalling. Recently, solute carrier family 17 member 9 (SLC17A9, also known as VNUT for vesicular nucleotide transporter) proteins were suggested to function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation, and P2X4 receptors were suggested to be lysosomal ion channels that are activated by luminal ATP. However, the molecular mechanism of SLC17A9 transporting ATP and the regulatory mechanism of lysosomal P2X4 are largely unknown. In this study, we report that SLC17A9-mediated ATP transport across lysosomal membranes is suppressed by Bafilomycin A1, the V-ATPase inhibitor. By measuring P2X4 activity, which is indicative of ATP transport across lysosomal membranes, we further demonstrated that SLC17A9 mainly uses voltage gradient but not pH gradient as the driving force to transport ATP into lysosomes. This study provides a molecular mechanism for lysosomal ATP transport mediated by SLC17A9. It also suggests a regulatory mechanism of lysosomal P2X4 by SLC17A9. PMID- 27477611 TI - Genetic diversity of Klebsiella pneumoniae isolates during an outbreak in a non human primate research colony. AB - BACKGROUND: Klebsiella pneumoniae can be a serious pathogen in non-human primates, particularly Neotropical monkeys. METHODS: During a K. pneumoniae outbreak in an owl monkey research colony, 13 K. pneumoniae isolates were DNA fingerprinted by automated repetitive extragenic palindromic-polymerase chain reaction and the profiles compared to isolates obtained from other non-human primate species during the same time period and isolates from previous outbreaks. RESULTS: Eleven different types of K. pneumoniae were circulating in the owl monkey colony at the time of the outbreak. When comparing owl monkey isolates relatedness to previous colony outbreak isolates and squirrel monkey and capuchin monkey isolates, all were different. CONCLUSIONS: These results agree with recent reports where K. pneumoniae nosocomial isolates in hospital settings can have high genetic diversity, and multiple strains can be circulating simultaneously. This potential genetic diversity should be considered when designing strategies for controlling K. pneumoniae outbreaks in captive non-human primate colonies. PMID- 27477613 TI - Biparental immune priming in the pipefish Syngnathus typhle. AB - The transfer of immunity from parents to offspring (trans-generational immune priming (TGIP)) boosts offspring immune defence and parasite resistance. TGIP is usually a maternal trait. However, if fathers have a physical connection to their offspring, and if offspring are born in the paternal parasitic environment, evolution of paternal TGIP can become adaptive. In Syngnathus typhle, a sex-role reversed pipefish with male pregnancy, both parents invest into offspring immune defence. To connect TGIP with parental investment, we need to know how parents share the task of TGIP, whether TGIP is asymmetrically distributed between the parents, and how the maternal and paternal effects interact in case of biparental TGIP. We experimentally investigated the strength and differences but also the costs of maternal and paternal contribution, and their interactive biparental influence on offspring immune defence throughout offspring maturation. To disentangle maternal and paternal influences, two different bacteria were used in a fully reciprocal design for parental and offspring exposure. In offspring, we measured gene expression of 29 immune genes, 15 genes associated with epigenetic regulation, immune cell activity and life-history traits. We identified asymmetric maternal and paternal immune priming with a dominating, long-lasting paternal effect. We could not detect an additive adaptive biparental TGIP impact. However, biparental TGIP harbours additive costs as shown in delayed sexual maturity. Epigenetic regulation may play a role both in maternal and paternal TGIP. PMID- 27477612 TI - Direct-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV coinfected patients: real-life safety and efficacy. AB - OBJECTIVES: Clinical trials of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection reported high response rates in HCV/HIV coinfection, similar to those obtained in HCV monoinfection. We evaluated the safety and efficacy of these regimens in a clinical practice setting. METHODS: In this prospective observational study, all the HCV-monoinfected and HCV/HIV coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting from December 2014 to December 2015 were included in the analysis. Sustained virological response 12 weeks after the end of therapy (SVR12) and reported adverse events (AEs) were evaluated. Resistance-associated variants (RAVs) were analysed in a subgroup of patients at baseline and at the time of viral rebound in those with virological failure. RESULTS: One-hundred and nine patients (51 HCV-infected and 58 HCV/HIV-coinfected) were enrolled in the study. Sixty per cent had cirrhosis and 52% were pegylated interferon and ribavirin (pegIFN/RBV)-experienced. Thirty-six per cent received ombitasvir + paritaprevir/ritonavir + dasabuvir, 25% sofosbuvir + daclatasvir, 16% sofosbuvir + simeprevir, 17% sofosbuvir + ribavirin and 6% sofosbuvir + ledipasvir; ribavirin was used in 57% of subjects. The SVR12 rate was 91% and 96% in HIV infected and uninfected patients, respectively (P = 0.44). The 4-week HCV viral decline was similar in the two groups. RAVs were found at baseline in 23 of 49 patients and did not affect SVR12. No predictors of SVR12 were identified in our cohort. CONCLUSIONS: Treatment with all-oral DAA combinations of patients infected with HCV and with HCV/HIV under real-life conditions led to high and similar rates of SVR12. Moreover, the historical factors associated with a sustained virological response to pegIFN/RBV were not predictive of the response to all-oral DAAs. PMID- 27477614 TI - Implementation of Telemedicine Consultation to Assess Unplanned Transfers in Rural Long-Term Care Facilities, 2012-2015: A Pilot Study. AB - INTRODUCTION: Public and private entities in the United States spend billions of dollars each year on potentially avoidable hospitalizations. This is a common occurrence in long-term care (LTC) facilities, especially in rural jurisdictions. This article details the creation of a telemedicine approach to assess residents from rural LTC facilities for potential transfer to hospitals. METHODS: An electronic LTC (eLTC) pilot was conducted in 20 pilot LTC facilities from 2012 2015. Each site underwent technologic assessment and upgrading to ensure that 2 way video communication was possible. A new central "hub" was staffed with advanced practice providers and registered nurses. Long-term care pilot sites were trained and rolled out over 3 years. This article reports development and implementation of the pilot, as well as descriptive statistics associated with provider assessments and averted transfers. RESULTS: Over 3 years, 736 eLTC consultations occurred in pilot sites. One-quarter of consultations occurred between 10 pm and 9 am. Overall, approximately 31% of cases were transferred. This decreased from 54% of cases in 2013 to 17% in 2015. Rural pilot facilities had an average of 23 eLTC consults per site per year. DISCUSSION: Averted transfers represent a dramatic benefit to the residents, as potentially avoidable hospitalizations cause undue stress and allow for nosocomial infections, among other risks. In addition, averting these unnecessary transfers likely saved the taxpayers of the United States over $5 million in admission-related charges to Centers for Medicare and Medicaid Services (511 avoided transfers * $11,000 per average hospitalization from a LTC facility). CONCLUSIONS: Overall, the eLTC pilot showed promise as a proof-of-concept. The pilot's implementation resulted in increasing utilization and promising reductions in unnecessary transfers to emergency departments and hospitalizations. PMID- 27477615 TI - Is It Ethical Not to Precribe Physical Activity for the Elderly Frail? PMID- 27477616 TI - Characteristics of Telephone Crisis Hotline Callers with Suicidal Ideation in Japan. AB - Hotline callers do not always have suicidal ideation and previous studies have noted that the rate of such callers is limited. Crisis hotline counselors must be able to identify high-risk callers in order to provide appropriate support. This study investigated the characteristics of Japanese crisis hotline callers in 2012 (N = 541,694) and is the first to analyze crisis hotline data for all parts of Japan over 1 year. About 14% of the callers had suicidal ideation and 6% had a history of attempted suicide. The odds ratio for suicidal ideation among those with a history of attempted suicide was 15.5. The suicidal ideation rate was much smaller compared to previous studies in other countries. There is a psychological barrier that must be broken for high-risk people to use support hotlines. In addition, attempted suicide is a strong exclusive predisposing factor for death due to suicide; therefore, counselors should pay careful attention to callers with a history of attempted suicide. The characteristics of Japanese crisis hotline callers and the features of suicidal ideation revealed in the present study are expected to be useful in developing telephone crisis hotline strategies. PMID- 27477617 TI - Comparison of three preclinical models for nausea and vomiting assessment. AB - INTRODUCTION: Nausea is a subjective sensation often preceding emesis in humans. Drug-induced nausea remains difficult to predict in preclinical tests. The aim of this study was to compare the effects of emetic agents in rats (pica behavior), ferrets (acute and delayed phases of emesis) or dogs (emesis and cardiovascular endpoints). METHODS: Rats and ferrets were administered cisplatin (+/ aprepitant/ondansetron or aprepitant) or apomorphine (+/-domperidone). Telemetered dogs were administered apomorphine (+/-domperidone). Food and kaolin intake was measured in rats whereas the number of emetic events was counted in ferrets and dogs. Cardiovascular changes were also monitored in dogs. RESULTS: In rats, cisplatin (6mg/kg, i.p.) increased kaolin intake (+2257%, p<0.001). The cisplatin effects were not reversed by the combination of aprepitant/ondansetron (2mg/kg, p.o./2mg/kg, i.p.) or by aprepitant (30mg/kg, p.o.). Apomorphine (10mg/kg, i.p.) did not induce pica behavior. In ferrets, cisplatin (8mg/kg, i.p.) induced acute and delayed emesis (371.8+/-47.8 emetic events over 72h) which was antagonized by aprepitant (1mg/kg, p.o.). Apomorphine (0.25mg/kg, s.c.) induced acute emesis (38.8+/-8.7 emetic events over 2h) which was abolished by domperidone (0.1mg/kg, s.c.). In dogs, apomorphine (100MUg/kg, s.c.) induced emesis and tachycardia which were decreased by domperidone (0.2mg/kg, i.v.). CONCLUSIONS: The assessment of emesis in the ferret or in the dog displays a strong predictive value. In contrast, assessing nausea remains challenging in all animal species and the use of pica behavior remains questionable in the context of antiemetic drug development. PMID- 27477618 TI - Fates of nickel and fluoranthene during the bioremediation by Pleurotus eryngii in three different soils. AB - This study focused on the bioremediation role of Pleurotus eryngii in different characteristics soils contaminated with nickel (Ni) and fluoranthene. The results of bioremediation experiments showed that fluoranthene had a positive effect on the growth of P. eryngii, whereas Ni exerted a negative influence. The concentration of fluoranthene significantly decreased in inoculated soil accounting for 86.39-91.95% of initial concentration in soils and 71.46-81.76% in non-inoculated soils, which showed that the dissipation of fluoranthene was enhanced by mushroom inoculating. The highest removal rates of fluoranthene in sandy loam, loamy clay, and sandy soils reached to 87.81, 86.39, and 91.95%, respectively, which demonstrated that P. eryngii was more suitable for the bioremediation of sandy soil contaminated with fluoranthene. In addition, the presence of Ni tended to decrease the dissipation of fluoranthene in inoculated soil. Higher ligninolytic enzymes activities were detected in inoculated soils, resulting in the enhanced dissipation of fluoranthene in inoculated soils. Furthermore, P. eryngii had the ability to uptake Ni (4.88-39.53 mg kg-1 ) in co contamination soil. In conclusion, the inoculating of P. eryngii was effective in remediating of Ni-fluoranthene co-contaminated soils. PMID- 27477619 TI - Insulin sensitivity, body composition and adipose depots following 12 w combined endurance and strength training in dysglycemic and normoglycemic sedentary men. AB - CONTEXT: Insulin resistance and dysglycemia are associated with physical inactivity and adiposity, and may be improved by exercise. OBJECTIVE: Investigate the effect of exercise on insulin sensitivity, body composition and adipose depots in sedentary men with (n = 11) or without (n = 11) overweight and dysglycemia. MATERIAL AND METHODS: Euglycemic-hyperinsulinemic clamp, ankle-to neck MRI, MRS, muscle and adipose tissue biopsies before and after 12 weeks combined strength and endurance exercise. RESULTS: Insulin sensitivity, VO2max, strength, whole-body and muscle fat content, and abdominal adipose depots were improved without obvious differences between normo- and dysglycemic men. Hepatic fat, waist circumference and subcutaneous adipose tissue were reduced in the dysglycemic group. For both groups plasma adiponectin was reduced, whereas IL-6 was unchanged. Visceral fat was preferentially lost compared with other adipose depots. DISCUSSION AND CONCLUSION: Body composition, fat distribution and insulin sensitivity improved following training in sedentary middle-aged men with and without dysglycemia. PMID- 27477620 TI - Considering Ranolazine as a Potential Treatment for K+ Channel Linked Short QT Syndrome. PMID- 27477621 TI - Event related desynchronisation predicts functional propriospinal myoclonus. AB - OBJECTIVE: Recent diagnostic criteria for functional movement disorders have proposed a "laboratory supported" level of diagnostic certainty where the clinical diagnosis is supported by a positive test. For functional myoclonus the Bereitschaftspotential (BP) is generally accepted as a positive laboratory test. We hypothesised that a different EEG measure, event-related desynchronisation (ERD), might be more effective. METHODS: We analysed 20 patients with functional propriospinal myoclonus (fPSM) and 9 controls with organic myoclonus and performed back-averaging for BPs plus time-frequency decomposition to assess ERD and calculated sensitivity and specificity for both techniques. RESULTS: The BP was present in only 25% of patients with fPSM while the majority showed a significant ERD (mean 38 Hz; sensitivity 65%). ERD was significant at the group level (p < 0.001), but not the BP (p > 0.05). Both BP and ERD were absent in our control group. CONCLUSION: ERD in high-beta may be a useful new test for positive diagnosis of functional myoclonus. PMID- 27477622 TI - Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls. AB - BACKGROUND: An increasing number of rare, functionally relevant non c.907_909delGAG (non-DeltaGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts. METHODS: We screened the entire coding sequence and the 5'-UTR region of TOR1A for rare non DeltaGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-DeltaGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset. RESULTS: In the case cohort, we identified a rare 5'-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-DeltaGAG variants was 0.4%. CONCLUSIONS: Our study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia. PMID- 27477623 TI - Sensitivity to biomechanical limitations during postural decision-making depends on the integrity of posterior superior parietal cortex. AB - Most object-directed limb movements can be carried out with a comfortable grasp posture. However, the orientation of an object relative to our bodies can sometimes lead us to select an uncomfortable or awkward grasp posture due to limitations imposed by the biomechanics of the arm. In a series of experiments, we identified a network of cortical areas that are engaged during the selection of movement strategies. Neurologically intact participants and two brain-damaged patients with overlapping lesions in the right posterior superior parietal lobule (pSPL) performed a grasp posture selection task in which biomechanical constraints were the primary consideration for selecting an action. The task induced states of bistable actions whereby the same stimulus gave rise to categorically different grasp postures. In a behavioral experiment, the two patients displayed a large range of manual bistability with the contralesional hand, resulting in a higher incidence of awkward grasping postures. In neurologically intact participants, a separate functional magnetic resonance imaging (fMRI) experiment revealed activation of a parieto-frontal network, which included the posterior intraparietal sulcus (pIPS) along the banks of the pSPL that was parametrically modulated by the degree of bistability in grasp posture selection. Superimposing this activation over the patients' structural MRIs revealed that the pIPS/pSPL activation in the neurologically intact participants overlapped with lesioned cortical tissue in both patients; all other areas of activation overlapped with intact cortical tissue in the patients. These results provide converging evidence that the posterior parietal cortex plays a critical role in selecting biomechanically appropriate postures during reach-to-grasp behaviors. PMID- 27477624 TI - The use of volunteers to help older medical patients mobilise in hospital: a systematic review. AB - AIMS AND OBJECTIVES: To review current evidence for the use of volunteers to mobilise older acute medical in-patients. BACKGROUND: Immobility in hospital is associated with poor healthcare outcomes in older people, but maintaining mobility is frequently compromised due to time pressures experienced by clinical staff. Volunteers are established in many hospitals, usually involved in indirect patient care. Recent evidence suggests that trained mealtime volunteers had a positive impact on patients and hospital staff. It is unclear whether volunteers can help older inpatients to mobilise. DESIGN: Systematic review. METHODS: We searched Cochrane, Medline, Embase, CINAHL, AMED and Google databases using MeSH headings and keywords within six key themes: inpatients, older, mobility/exercise, delirium, falls and volunteers. Full texts of relevant articles were retrieved and reference lists reviewed. RESULTS: Of the 2428 articles that were identified, two scientific studies and three reports on quality improvement initiatives were included in the final review. One study included volunteer assisted mobilisation as part of a delirium prevention intervention (HELP). The second study has not reported yet (MOVE ON). The contribution of volunteers in both is unclear. Three quality improvement initiatives trained volunteers to help mobilise patients. They were not formally evaluated but report positive effects of the volunteers on patient and staff satisfaction. CONCLUSIONS: This review has identified a lack of scientific evidence for the use of volunteers in mobilising older medical inpatients, but quality improvement initiatives suggest that volunteers can be employed in this role with reports of staff and patient satisfaction: this is an area for further development and evaluation. RELEVANCE TO CLINICAL PRACTICE: This review outlines the evidence for the involvement of volunteers in maintaining patients' mobility, identifies mobilisation protocols that have been used, the need to train volunteers and for formal evaluation of volunteers in this role. Prospero registration number: CRD42014010388. PMID- 27477625 TI - Association of Musculoskeletal Joint Pain With Obstructive Sleep Apnea, Daytime Sleepiness, and Poor Sleep Quality in Men. AB - OBJECTIVE: To investigate the association of musculoskeletal pain with objectively determined obstructive sleep apnea (OSA) and subjective sleep measures in a population-based sample. METHODS: Participants were community dwelling men (n = 360) age >=35 years from the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. Shoulder, back, hip, knee, hand, and foot pain were assessed by computer-assisted telephone interview or self completed questionnaire. OSA was determined with full in-home unattended polysomnography (Embletta X100) scored by 2007 American Academy of Sleep Medicine alternative criteria. The Epworth Sleepiness Scale assessed daytime sleepiness and the Pittsburgh Sleep Quality Index assessed sleep quality. RESULTS: OSA was not associated with the presence of any joint pain (adjusted odds ratio [OR] 1.03 [95% confidence interval (95% CI) 0.61-1.76]). There was no association between OSA and pain in any specific joint (shoulder, back, hip, knee, hand, or foot), nor was the number of joints in pain associated with OSA. There was, similarly, no association between pain variables and excessive daytime sleepiness, except for hand pain (OR 3.10 [95% CI 1.50-6.39]). However, pain was associated with poor sleep quality: any pain (OR 2.19 [95% CI 1.25-3.82]), shoulder pain (OR 2.16 [95% CI 1.25-3.75]), back pain (OR 2.24 [95% CI 1.41-3.55]), and foot pain (OR 2.47 [95% CI 1.43-4.26]). The number of painful joints was also associated with poor sleep quality (5-6 joints versus no joints OR 7.34 [95% CI 2.30-23.42]). CONCLUSION: No association between OSA and pain or between daytime sleepiness and pain was found. Consistent with previous reports, poor sleep quality was associated with musculoskeletal pain in this population sample. The etiologic differences between OSA-related sleep disruption and poor subjective sleep quality require further investigation. PMID- 27477626 TI - A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic anticoagulation: reply. PMID- 27477627 TI - Computed Tomography-Based Bone Density Assessment for Men With Prostate Cancer: Not Ready for Prime Time. PMID- 27477628 TI - Brain structural changes following adaptive cognitive training assessed by Tensor Based Morphometry (TBM). AB - Tensor-Based Morphometry (TBM) allows the automatic mapping of brain changes across time building 3D deformation maps. This technique has been applied for tracking brain degeneration in Alzheimer's and other neurodegenerative diseases with high sensitivity and reliability. Here we applied TBM to quantify changes in brain structure after completing a challenging adaptive cognitive training program based on the n-back task. Twenty-six young women completed twenty-four training sessions across twelve weeks and they showed, on average, large cognitive improvements. High-resolution MRI scans were obtained before and after training. The computed longitudinal deformation maps were analyzed for answering three questions: (a) Are there differential brain structural changes in the training group as compared with a matched control group? (b) Are these changes related to performance differences in the training program? (c) Are standardized changes in a set of psychological factors (fluid and crystallized intelligence, working memory, and attention control) measured before and after training, related to structural changes in the brain? Results showed (a) greater structural changes for the training group in the temporal lobe, (b) a negative correlation between these changes and performance across training sessions (the greater the structural change, the lower the cognitive performance improvements), and (c) negligible effects regarding the psychological factors measured before and after training. PMID- 27477629 TI - Using fMRI to understand event construction in developmental amnesia. AB - Recently, neuroimaging and patient-lesion methods have been combined to explain anomalies such as patients' intact performance on tasks on which they would be predicted to perform poorly. In some cases, preserved performance has been attributed to activation of residual tissue within the damaged region. However, activation of remnant tissue can also occur in relation to impaired performance and, thus, may not necessarily correspond to successful recruitment. To constrain these neuroimaging interpretations, what is needed is a paradigm with closely matched conditions that yields intact and impaired performance in the same patient. We investigated this in H.C., an amnesic person with congenital abnormalities of the hippocampus and its connections, who was scanned during remembering and imagining, abilities known to depend on the hippocampus. Specifically, we examined whether differences in activation and/or functional connectivity would explain H.C.'s compromised ability to construct events relating to herself in autobiographical memory (SELF condition) and events relating to personally familiar others (FAMILIAR condition) versus her intact ability to construct events relating to unknown others (UNFAMILIAR condition). Despite behavioral dissociations in H.C., the pattern of activation and functional connectivity supporting her performance was strikingly similar to that of controls across conditions. Most notably, like controls, H.C. showed robust hippocampal activation and functional connectivity to the hippocampus, both when her performance was intact and impaired. Across all conditions, H.C. activated several extra-hippocampal regions to a greater extent than did controls, and modest differences were observed in functional connectivity between extra hippocampal regions. Taken together, these findings urge caution when drawing conclusions about the functional integrity of a structurally compromised brain region even when it is activated and/or co-activated with other regions. PMID- 27477631 TI - Visuomotor priming of action preparation and motor programming is similar in visually guided and memory-guided actions. AB - The present study examined whether the planning and execution of a reach-to-grasp movement is susceptible to visuomotor priming, and whether the strength of the priming effect depends on the availability of visual feedback. Participants grasped a target object as quickly as possible with either a whole-hand grip or a precision grip upon hearing an auditory stimulus. Prior to the auditory cue, a prime stimulus was presented. The prime stimulus depicted an object that was either congruent, incongruent, or ambiguous with respect to the required grasp, or it showed no object at all. In addition, participants performed the grasping task in one of three vision conditions: participants' vision was either occluded during both the motor programming and online-control phase (no-vision), participants had vision only during the motor programming phase (partial-vision), or they had vision available throughout task performance (full-vision). Results revealed the presence of two discrete priming effects. First, we found a facilitative effect of congruent compared to incongruent prime-grip combinations that influenced reaction times and kinematic parameters. Second, we found that movements were initiated slower during the no prime compared to all other conditions. However, this effect did not affect movement kinematics. Importantly, the size of both effects was similar regardless of vision. Together, these results suggest that visuomotor priming effects exhibit a similar influence on memory-guided and visually guided actions, indicating the same underlying object representations for those actions, and thus further challenging the real-time view of motor programming. Furthermore, the two different priming effects suggest the presence of functionally distinct, yet related modules or processes related to action preparation and motor programming, and hint towards possible ventrodorsal interactions. PMID- 27477630 TI - Willing to wait: Elevated reward-processing EEG activity associated with a greater preference for larger-but-delayed rewards. AB - While almost everyone discounts the value of future rewards over immediate rewards, people differ in their so-called delay-discounting. One of the several factors that may explain individual differences in delay-discounting is reward processing. To study individual-differences in reward-processing, however, one needs to consider the heterogeneity of neural-activity at each reward-processing stage. Here using EEG, we separated reward-related neural activity into distinct reward-anticipation and reward-outcome stages using time-frequency characteristics. Thirty-seven individuals first completed a behavioral delay discounting task. Then reward-processing EEG activity was assessed using a separate reward-learning task, called a reward time-estimation task. During this EEG task, participants were instructed to estimate time duration and were provided performance feedback on a trial-by-trial basis. Participants received monetary-reward for accurate-performance on Reward trials, but not on No-Reward trials. Reward trials, relative to No-Reward trials, enhanced EEG activity during both reward-anticipation (including, cued-locked delta power during cue evaluation and pre-feedback alpha suppression during feedback-anticipation) and reward-outcome (including, feedback-locked delta, theta and beta power) stages. Moreover, all of these EEG indices correlated with behavioral performance in the time-estimation task, suggesting their essential roles in learning and adjusting performance to maximize winnings in a reward-learning situation. Importantly, enhanced EEG power during Reward trials, as reflected by stronger 1) pre-feedback alpha suppression, 2) feedback-locked theta and 3) feedback-locked beta, was associated with a greater preference for larger-but-delayed rewards in a separate, behavioral delay-discounting task. Results highlight the association between a stronger preference toward larger-but-delayed rewards and enhanced reward-processing. Moreover, our reward-processing EEG indices detail the specific stages of reward-processing where these associations occur. PMID- 27477632 TI - Predictive decision making driven by multiple time-linked reward representations in the anterior cingulate cortex. AB - In many natural environments the value of a choice gradually gets better or worse as circumstances change. Discerning such trends makes predicting future choice values possible. We show that humans track such trends by comparing estimates of recent and past reward rates, which they are able to hold simultaneously in the dorsal anterior cingulate cortex (dACC). Comparison of recent and past reward rates with positive and negative decision weights is reflected by opposing dACC signals indexing these quantities. The relative strengths of time-linked reward representations in dACC predict whether subjects persist in their current behaviour or switch to an alternative. Computationally, trend-guided choice can be modelled by using a reinforcement-learning mechanism that computes a longer term estimate (or expectation) of prediction errors. Using such a model, we find a relative predominance of expected prediction errors in dACC, instantaneous prediction errors in the ventral striatum and choice signals in the ventromedial prefrontal cortex. PMID- 27477633 TI - Beneficial effects of diazepin-quinazolin-amine derivative (BIX-01294) on preimplantation development and molecular characteristics of cloned mouse embryos. AB - Somatic cell nuclear transfer is frequently associated with abnormal epigenetic modifications that may lead to the developmental failure of cloned embryos. BIX 01294 (a diazepine-quinazoline-amine derivative) is a specific inhibitor of the histone methyltransferase G9a. The aim of the present study was to investigate the effects of BIX-01294 on development, dimethylation of histone H3 at lysine 9 (H3K9), DNA methylation and the expression of imprinted genes in cloned mouse preimplantation embryos. There were no significant differences in blastocyst rates of cloned embryos treated with or without 0.1MUM BIX-01294. Relative to clone embryos treated without 0.1MUM BIX-01294, exposure of embryos to BIX-01294 decreased histone H3K9 dimethylation and DNA methylation in cloned embryos to levels that were similar to those of in vivo-fertilised embryos at the 2-cell and blastocyst stages. Cloned embryos had lower expression of octamer-binding transcription factor 4 (Oct4) and small nuclear ribonucleoprotein N (Snrpn), but higher expression of imprinted maternally expressed transcript (non-protein coding) (H19) and growth factor receptor-bound protein 10 (Grb10) compared with in vivo-fertilised counterparts. The addition of 0.1MUM BIX-01294 to the activation and culture medium resulted in lower H19 expression and higher cyclin dependent kinase inhibitor 1C (Cdkn1c) and delta-like 1 homolog (Dlk1) expression, but had no effect on the expression of Oct4, Snrpn and Grb10. The loss of methylation at the Grb10 cytosine-phosphorous-guanine (CpG) islands in cloned embryos was partially corrected by BIX-01294. These results indicate that BIX-01294 treatment of cloned embryos has beneficial effects in terms of correcting abnormal epigenetic modifications, but not on preimplantation development. PMID- 27477634 TI - The origin and evolution of assessment criteria for persistent, bioaccumulative and toxic (PBT) chemicals and persistent organic pollutants (POPs). AB - General public concern over the effects of persistent chemicals began in the early 1960s. Since then, significant scientific advances have increased our understanding of persistent, bioaccumulative, and toxic (PBT) chemicals and the properties and processes that influence their fates in, and adverse effects on, human health and the environment. In addition to the scientific advances, a number of legislations and agreements for national, international, and global identification and control of PBT chemicals have been adopted. However, some of the rationales and thoughts that were relied upon when the first criteria were developed to identify and categorize PBT chemicals and then POPs (persistent organic pollutants) have not been carried forward. Criteria have been based upon available data of neutral hydrophobic substances as reference chemicals, derived under laboratory conditions. They evolved over the last decades due to the diversification of the protection aims under various national regulatory frameworks and international agreements, advances in methods for estimation of physical/chemical properties, and the identification of chemicals which are non traditional POPs. Criteria are not defined purely by science; they also are subject to the aims of policy. This paper offers a historical perspective on the development of criteria for PBT chemicals and POPs. It also offers suggestions for rationalization of protection goals, describes some emerging procedures for identification of compounds of concern, and proposes information that needs to be considered when applying criteria to screening and/or evaluation of new chemicals. PMID- 27477635 TI - H3K27me3 Does Not Orchestrate the Expression of Lineage-Specific Markers in hESC Derived Hepatocytes In Vitro. AB - Although pluripotent stem cells can be differentiated into the hepatocyte lineages, such cells retain an immature phenotype. As the chromatin state of regulatory regions controls spatiotemporal gene expression during development, we evaluated changes in epigenetic histone marks in lineage-specific genes throughout in vitro hepatocyte differentiation from human embryonic stem cells (hESCs). Active acetylation and methylation marks at promoters and enhancers correlated with progressive changes in gene expression. However, repression associated H3K27me3 marks at these control regions showed an inverse correlation with gene repression during transition from hepatic endoderm to a hepatocyte-like state. Inhibitor of Enhancer of Zeste Homolog 2 (EZH2) reduced H3K27me3 decoration but did not improve hepatocyte maturation. Thus, H3K27me3 at regulatory regions does not regulate transcription and appears dispensable for hepatocyte lineage differentiation of hESCs in vitro. PMID- 27477637 TI - Did exposure to a severe outbreak of pandemic influenza in 1918 impact on long term survival? AB - There is some suggestion that infection with pandemic influenza may increase long term mortality risks. Therefore we aimed to determine if exposure to a severe outbreak of pandemic influenza on a troopship in 1918 impacted on lifespan in the survivors. The troopship with the outbreak cohort had 1107 personnel and the comparison cohort was from two contemporaneous troopships (1108 randomly selected personnel). Data were collected from online individual military files. The main finding was that there was no statistically significant difference in the lifespan of the outbreak cohort and the comparison cohort (means of 71.5 and 71.0 years, respectively). Indeed, the outbreak cohort was actually more likely to survive into the period from 1950 onwards (P = 0.036) and to participate in the Second World War (P = 0.043). There were no significant differences between the cohorts in terms of occupational class, but the comparison cohort had a higher proportion of rural occupations (33.3% vs. 27.0%, P < 0.001) and was very slightly older in mid-1918 (27.8 vs. 27.2 years, P = 0.028). In conclusion, this study found no support for the hypothesis that exposure to the 1918 influenza pandemic adversely impacted on the lifespan in the survivors, at least in this male and military-age population. PMID- 27477636 TI - Esophageal dysfunction in different stages of Parkinson's disease. AB - BACKGROUND: Dysphagia is a clinically relevant symptom in patients with Parkinson's disease (PD) leading to pronounced reduction in quality of life and other severe complications. Parkinson's disease-related dysphagia may affect the oral and pharyngeal, as well as the esophageal phase of swallowing. METHODS: To examine the nature and extend of esophageal dysphagia in different stages of PD and their relation to oropharyngeal dysfunction, we examined 65 PD patients (mean age 66.3+/-9.7 years, mean disease duration 7.9+/-5.8 years, mean Hoehn & Yahr [H&Y] stage 2.89+/-0.91) and divided into three groups (early [H&Y I+II; n=21], intermediate [H&Y III; n=25], and advanced stadium [H&Y IV+V; n=19]), using esophageal high-resolution manometry (HRM) to detect esophageal motor disorders. Oropharyngeal impairment was assessed using fiberoptic endoscopic evaluation of swallowing. KEY RESULTS: Major esophageal motor disorders were detected in nearly one third of the PD patients. Minor impairment of the esophageal body was present in 95% of participants and throughout all disease stages with pathological findings especially in peristalsis and intrabolus pressure (IBP). The IBP was found to significantly increase in the advanced stadium. Although dysfunction of the upper and lower esophageal sphincters was observed in individual patients, alterations in these esophageal segments revealed no statistical significance compared with normative data. No clear association was found between the occurrence of oropharyngeal dysphagia and esophageal impairment. CONCLUSIONS & INFERENCES: Esophageal body impairment in PD is a frequent phenomenon during all disease stages, which possibly reflects alpha-synucleinopathy in the enteric nervous system. PMID- 27477638 TI - Editorial: Centennial Celebration - A Focus on Endocrine Disrupting Chemicals... One Hundred Years in the Making. PMID- 27477639 TI - Editorial: Centennial Celebration - An Interview With Dr Ana Soto on 25 Years of Research on Endocrine-Disrupting Chemicals. PMID- 27477641 TI - Retraction. PMID- 27477644 TI - Search for New Bioactive Marine Natural Products and Application to Drug Development. AB - Natural products are well recognized as an important source of lead compounds in drug development. During the past >30 years, we have discovered >1000 novel bioactive natural products from Okinawan marine organisms (sponges, tunicates, cone shells, etc.) and microorganisms (fungi, bacteria, dinoflagellates, etc.). Some of them are used as bioprobes useful for basic studies of life sciences, while others are expected to be candidates of drug leads. PMID- 27477640 TI - Minireview: Endocrine Disruptors: Past Lessons and Future Directions. AB - Within the past few decades, the concept of endocrine-disrupting chemicals (EDCs) has risen from a position of total obscurity to become a focus of dialogue, debate, and concern among scientists, physicians, regulators, and the public. The emergence and development of this field of study has not always followed a smooth path, and researchers continue to wrestle with questions about the low-dose effects and nonmonotonic dose responses seen with EDCs, their biological mechanisms of action, the true pervasiveness of these chemicals in our environment and in our bodies, and the extent of their effects on human and wildlife health. This review chronicles the development of the unique, multidisciplinary field of endocrine disruption, highlighting what we have learned about the threat of EDCs and lessons that could be relevant to other fields. It also offers perspectives on the future of the field and opportunities to better protect human health. PMID- 27477645 TI - Deposits from Creams Containing 20% (w/w) Urea and Suppression of Crystallization (Part 1): Rate of Crystallization from Cream Containing 20% (w/w) Urea and Evaluation of the Properties of the Deposit. AB - Two creams containing 20% (w/w) urea and various emulsifiers, a nonionic surfactant (NS) and lecithin (LEC), were prepared, and the rate of crystallization following application of the cream and differences in the properties of the deposits were investigated. Post-application crystallization was slower with the LEC formulation. Differences in the crystals obtained from the two formulations and from a 20% aqueous solution of urea were evaluated by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), powder X-ray-DSC (PXRD-DSC) and Fourier transform infrared spectrophotometry (FT-IR). PXRD and PXRD-DSC measurements showed that the diffraction patterns of both formulations differed from that of urea. The NS formulation provided diffraction peaks for urea and a urea composite, whereas only the urea composite was evident in the LEC formulation. DSC scans of urea showed an endotherm at around 134 degrees C, whereas the deposits from both formulations provided an endotherm 23 25 degrees C below that of urea; the NS formulation also showed a peak at around 140 degrees C. These results indicate a tendency for urea crystallization in the NS formulation. FT-IR measurements showed that both deposits have a urea-based structure. The effects of the LEC formulation components on the physical properties of urea were investigated by PXRD and showed that all diffraction peaks were evenly weakened, suggesting that urea tends to be amorphous and that the formulation impacts post-application urea crystallization. Consequently, the amorphous state of urea can be maintained post-application by optimizing the formulation, thereby increasing the clinical efficacy of the cream. PMID- 27477646 TI - Deposits from Creams Containing 20% (w/w) Urea and Suppression of Crystallization (Part 2): Novel Analytical Methods of Urea Accumulated in the Stratum Corneum by Tape stripping and Colorimetry. AB - The transfer of urea from a urea formulation to the stratum corneum varies with the formulation base and form, and impacts the formulation's therapeutic effect. Consequently, determining the amount of urea transferred is essential for developing efficient formulations. This study assessed a simple method for measuring the amount of urea accumulated in the stratum corneum. Conventional methods rely on labeling urea used in the formulation with radiocarbon ((14)C) or other radioactive isotopes (RIs), retrieving the transferred urea from the stratum corneum by tape stripping, then quantitating the urea. The handling and use of RIs, however, is subject to legal regulation and can only be performed in sanctioned facilities, so methods employing RIs are neither simple nor convenient. We therefore developed a non-radiolabel method "tape stripping colorimetry (T-C)" that combines tape stripping with colorimetry (urease glutamate dehydrogenase (GLDH)) for the quantitative measurement of urea. Urea in the stratum corneum is collected by tape stripping and measured using urease GLDH, which is commonly used to measure urea nitrogen in blood tests. The results indicate that accurate urea measurement by the T-C method requires the application of 1400 mg (on hairless rats) of a 20% urea solution on a 50 cm(2) (5*10 cm) area. Further, we determined the amount of urea accumulated in the stratum corneum using formulations with different urea concentrations, and the time course of urea accumulation from formulations differing in the rate of urea crystallization. We demonstrate that the T-C method is simple and convenient, with no need for (14)C or other RIs. PMID- 27477647 TI - Deposits from Creams Containing 20% (w/w) Urea and Suppression of Crystallization (Part 3): Novel Analytical Methods Based on Raman Spectroscopy for the Characterization of Deposits and Deposition Phenomena of Creams Containing 20% (w/w) Urea. AB - In drug formulations for external application, variations in the state of pharmaceutical agents within the base formulation may affect the transfer of agents to the skin. Here, we use Raman spectroscopic methods to acquire more detailed information on the state of the active pharmaceutical ingredients within an externally applied formulation. The combination of wide-field Raman spectroscopy with an experimental method in which drug formulations are applied to glass surfaces provided a new method for characterizing the state of pharmaceutical agents within drug formulations. Here, we demonstrate the usefulness of this new method, called application to glass-wide-field Raman spectroscopy (AG-WRS). In addition to allowing rapid and easy wide-field observations, the use of WRS allows Raman imaging in a manner that is insensitive to variations in the thickness of the formulations applied to sample slides. We consider two types of urea-compound creams with different crystal deposition rates, using AG-WRS to characterize the post-application time-evolving state of deposited crystals. Differences in the base pharmaceutical produce different spectra for the deposits, indicating that the deposits differ in composition and structure. In addition, we use microscopic laser Raman measurements to demonstrate that the process of crystal formulation differs significantly for formulations with different compositions. Our results demonstrate that the combination of AG-WRS with existing analytical techniques such as powder X-ray diffraction or thermal analysis yields more detailed and timely post-application information on the state of pharmaceuticals in external application. We believe this will be a valuable analytical tool for future studies related to the development of external application. PMID- 27477648 TI - Formulation and Evaluation of a Self-microemulsifying Drug Delivery System Containing Bortezomib. AB - The purposes of the present study were to develop a self-microemulsifying drug delivery system (SMEDDS) containing bortezomib, a proteasome inhibitor. The solubility of the drug was evaluated in 15 pharmaceutical excipients. Combinations of oils, surfactants and cosurfactants were screened by drawing pseudo-ternary phase diagrams. The system exhibiting the largest region of microemulsion was considered optimal. Bortezomib SMEDDS spontaneously formed a microemulsion when diluted with an aqueous medium with a median droplet size of approximately 20-30 nm. In vitro release studies showed that the SMEDDS had higher initial release rates for the drug when compared with the raw drug material alone. Measurement of the viscosity, size, and ion conductivity indicated that a phase inversion from water in an oil system to oil in a water system occurred when the weight ratio of the water exceeded 30% of the entire microemulsion system. In a pharmacokinetics study using rats, the bortezomib microemulsion failed to improve the bioavailability of the drug. The reason was assumed to be degradation of the drug in the microemulsion in the gastrointestinal tract. However, bortezomib in Labrasol((r)) solution (an aqueous solution containing 0.025% Labrasol((r))) showed significantly increased area under the curve from 0-24 h (AUC0-24 h) and maximum plasma concentration (Cmax) values compared to the drug suspension. The findings of this study imply that oral delivery of a bortezomib and colloidal system containing Labrasol((r)) could be an effective strategy for the delivery of bortezomib. PMID- 27477649 TI - The Safety and Immunological Effects of rAd5-EBV-LMP2 Vaccine in Nasopharyngeal Carcinoma Patients: A Phase I Clinical Trial and Two-Year Follow-Up. AB - Epstein-Barr virus (EBV)-encoded latent membrane protein 2 (LMP2) promotes nasopharyngeal carcinoma (NPC) progression. Previously, we reported that the dendritic cells (DCs) transfected with EBV-LMP2 recombinant serotype 5 adenoviruses (rAd5) induced anti-tumor effect by eliciting cytotoxic T lymphocytes (CTLs)-mediated immune response in vitro and the adenoviral vaccine of EBV-LMP2 (rAd5-EBV-LMP2) stimulated antigen-specific cellular immunity in mice. However, the safety and immunological effect of rAd5-EBV-LMP2 vaccine in human still remained unknown. Here we conducted a single-center, non-randomized, open-label, single-arm phase I clinical trial to clarify this unsolved issue. A total of 24 patients with regional advanced NPC were sequentially enrolled into three dose level groups (2*10(9), 2*10(10), 2*10(11) vp). The rAd5-EBV-LMP2 vaccines were intramuscularly injected for four times within 28 d (D0, D7, D14, D28). Blood samples were harvested immediately before every vaccination, one week and one month after the last vaccination (D0, D7, D14, D28, D35, D58). All the vaccine inoculation-related toxicities presented as grade I/II adverse events. The most frequent systemic adverse reactions were fatigue (33.0%, 8/24), myalgia (29.2%, 7/24) and cough (29.2%, 7/24), while the most common regional adverse reaction was tenderness in the inoculation site (54.2%, 13/24). In addition, proportion of CD(3+)CD(4+) cells in peripheral blood was significantly increased in the high dose group (2*10(11) vp). The rAd5-EBV-LMP2 vaccine was generally well-tolerated and the high dose (2*10(11) vp) is recommended to be adopted in phase II studies. The long-term outcome of rAd5-EBV-LMP2 vaccine inoculation is required to be determined in following placebo-controlled trials. PMID- 27477650 TI - False HDAC Inhibition by Aurone Compound. AB - Fluorescence assays are useful tools for estimating enzymatic activity. Their simplicity and manageability make them suitable for screening enzyme inhibitors in drug discovery studies. However, researchers need to pay attention to compounds that show auto-fluorescence and quench fluorescence, because such compounds lower the accuracy of the fluorescence assay systems by producing false positive or negative results. In this study, we found that aurone compound 7, which has been reported as a histone deacetylase (HDAC) inhibitor, gave false positive results. Although compound 7 was identified by an in vitro HDAC fluorescence assay, it did not show HDAC inhibitory activity in a cell-based assay, leading us to suspect its in vitro HDAC inhibitory activity. As a result of verification experiments, we found that compound 7 interferes with the HDAC fluorescence assay by quenching the HDAC fluorescence signal. Our findings underscore the faults of fluorescence assays and call attention to careless interpretation. PMID- 27477651 TI - Quantification of Pharmaceutical Compounds Based on Powder X-Ray Diffraction with Chemometrics. AB - We propose an approach for the simultaneous determination of multiple components in pharmaceutical mixed powder based on powder X-ray diffraction (PXRD) method coupled with chemometrics. Caffeine anhydrate, acetaminophen and lactose monohydrate were mixed at various ratios. The samples were analyzed by PXRD method in the ranges of 2theta=5.00-30.0 and 35.0-45.0 degrees. Obtained diffractograms were analyzed by conventional peak intensity method, multi curve resolution (MCR)-alternating least squares (ALS) method and partial least squares (PLS) method. Constructed PLS models can most accurately predict the concentrations among different methods used. Each regression vector of PLS correlates not only to the compound of interest but also to the coexisting compounds. The combination of PXRD and PLS methods is concluded to be powerful approach for analyzing multi components in pharmaceutical formulations. PMID- 27477653 TI - Mechanical Stress Simulation of Scored Tablets Based on the Finite Element Method and Experimental Verification. AB - Scored tablets can be divided into equal halves for individual treatment of patients. However, the relationships between scored shapes and tablet characteristics such as the dividing strength, halving equality, and breaking strength are poorly understood. The purpose of this study was to simulate the mechanical stress distribution of scored tablets by using the finite element method (FEM). A runnel of triangle pole on the top surface of flat tablets was fabricated as the score shape. The depth and angle of the scores were selected as design variables. Elastic parameters such as a Young's modulus and a Poisson ratio for the model powder bed were measured. FEM simulation was then applied to the scored tablets, represented as a continuum elastic model. Stress distributions in the inner structure of the tablets were simulated after applying external force. The adequacy of the simulation was evaluated in experiments using scored tablets. As a result, we observed a relatively good agreement between the FEM simulation and the experiments, suggesting that FEM simulation is advantageous for designing scored tablets. PMID- 27477652 TI - Synthesis and Biological Evaluation of 1-(2-Aminophenyl)-3-arylurea Derivatives as Potential EphA2 and HDAC Dual Inhibitors. AB - A series of 1-(2-aminophenyl)-3-arylurea novel derivatives were synthesized and evaluated against Ephrin type-A receptor 2 (EphA2) and histone deacetylases (HDACs) kinase. Most of the compounds exhibited inhibitory activity against EphA2 and HDAC. The antiproliferative activities were evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (thiazolyl blue, tetrazolium blue) against the human cancer cell lines HCT116, K562 and MCF7. Compounds 5a and b showed the most potent inhibitory activity against EphA2 and HDAC. However, compound 5b exhibited higher potency against HCT116 (IC50=5.29 uM) and MCF7 (IC50=7.42 uM). 1-(2-Aminophenyl)-3-arylurea analogues may serve as new EphA2-HDAC dual inhibitors. PMID- 27477654 TI - Convergent Synthesis of Dronedarone, an Antiarrhythmic Agent. AB - We have developed a convergent synthesis of dronedarone, an antiarrhythmic agent. The key steps of the process are the construction of a benzofuran skeleton by iodocyclization and the carbonylative Suzuki-Miyaura cross-coupling for biaryl ketone formation. This synthetic route required only eight steps from 2-amino-4 nitrophenol in 23% overall yield. PMID- 27477655 TI - Development of a Sulfur-Modified Glass-Supported Pd Nanoparticle Catalyst for Suzuki-Miyaura Coupling. AB - A safe, facile and low-leaching (up to 0.17 ppm) sulfur-modified glass-supported palladium nanoparticle catalyst has been developed for the Suzuki-Miyaura coupling of aryl halides with aryl boronic acids. Most notably, this catalyst was highly recyclable and could be used up to 10 times without any discernible decrease in its activity. PMID- 27477656 TI - Preparation and Characterization of Four Stereoisomers of Monatin. AB - Monatin is a naturally occurring, sweet amino acid comprising four stereoisomers due to its two asymmetric centers at C2 and C4. However, the characteristics of each stereoisomer have not yet been fully investigated. To obtain a sufficient amount of racemic monatin for optical resolution, a synthetic method was developed by modifying a possible biosynthetic pathway, i.e., a cross-aldol reaction and subsequent transamination. The key intermediate, 4-hydroxy-4-(3 indolylmethyl)-2-ketoglutaric acid, was obtained via the cross-aldol reaction of pyruvic acid and indole-3-pyruvic acid. Subsequently, the carbonyl group was converted to a hydroxyimino group through reaction with hydroxylamine and then to an amino group via hydrogenation to produce monatin. Next, the racemic monatin was divided into mixtures of two pairs of enantiomers through recrystallization. Finally, both enantiomers of the N-carbobenzoxy-gamma-lactone derivatives of monatin were separated by preparative HPLC and deprotected. It was found that all optically pure stereoisomers exhibited a sweet taste. The isomer that displayed the most intense sweetness was the (2R,4R)-isomer, as determined by single crystal X-ray structure analysis of the monatin potassium salt, whereas the least sweet isomer was the (2S,4S)-isomer, which demonstrated a far lower sweetness than was previously reported. PMID- 27477657 TI - Design, Synthesis and Biological Evaluation of Some 5-Arylthieno[2,3 d]pyrimidines as Potential Anti-cancer Agents. AB - Structure-based design, synthesis and biological evaluation of new small molecules anti-cancer agents were described. On continuation of applying scaffold hopping theory, a series of 5-arylthieno[2,3-d]pyrimidines based on the structural features of lapatinib was designed, synthesized and characterized using IR, (1)H-NMR, (13)C-NMR, mass and microanalyses. Biological evaluation of the cytotoxic activity against MCF-7 cell line and the inhibition of the enzymatic activity of epidermal growth factor tyrosine kinase were carried out in vitro for the target compounds. Substituting the 4-anilino-5-arylthieno[2,3 d]pyrimidines with different pharmacophoric groups at ortho, meta and/or para positions led to discovery of two potent lead compounds 3b and f with excellent cytotoxic activity and enzymatic inhibition activity. PMID- 27477658 TI - Structure-CaSR-Activity Relation of Kokumi gamma-Glutamyl Peptides. AB - Modulation of the calcium sensing receptor (CaSR) is one of the physiological activities of gamma-glutamyl peptides such as glutathione (gamma glutamylcysteinylglycine). gamma-Glutamyl peptides also possess a flavoring effect, i.e., sensory activity of kokumi substances, which modifies the five basic tastes when added to food. These activities have been shown to be positively correlated, suggesting that kokumi gamma-glutamyl peptides are perceived through CaSRs in humans. Our research is based on the hypothesis that the discovery of highly active CaSR agonist peptides will lead to the creation of practical kokumi peptides. Through continuous study of the structure-CaSR activity relation of a large number of gamma-glutamyl peptides, we have determined that the structural requirements for intense CaSR activity of gamma glutamyl peptides are as follows: existence of an N-terminal gamma-L-glutamyl residue; existence of a moderately sized, aliphatic, neutral substituent at the second residue in an L-configuration; and existence of a C-terminal carboxylic acid, preferably with the existence of glycine as the third constituent. By the sensory analysis of gamma-glutamyl peptides selected by screening using the CaSR activity assay, gamma-glutamylvalylglycine was found to be a potent kokumi peptide. Furthermore, norvaline-containing gamma-glutamyl peptides, i.e., gamma glutamylnorvalylglycine and gamma-glutamylnorvaline, possessed excellent sensory activity of kokumi substances. A novel, practical industrial synthesis of regiospecific gamma-glutamyl peptides is also required for their commercialization, which was achieved through the ring opening reaction of N alpha-carbobenzoxy-L-glutamic anhydride and amino acids or peptides in the presence of N-hydroxysuccinimide. PMID- 27477659 TI - Synthesis of Diastereomers of 1,3-cis-25-Dihydroxy-19-norvitamin D3. AB - 1beta,3beta,25-Dihydroxy-19-norvitamin D3 (4a) and 1alpha,3alpha,25-dihydroxy-19 norvitamin D3 (4b) were synthesized by employing a new A-ring synthon, (1R,3S)-3 ((tert-butyldimethylsilyl)oxy)-5-oxocyclohexyl benzoate (19), which was derived from D-(-)-quinic acid in 12 steps. The A-ring was coupled with the circular dichroism (CD) ring by means of Julia-Kocienski olefination to construct the diene unit. The structures of the products were confirmed by (1)H-NMR and nuclear Overhauser effect (NOE) experiments. PMID- 27477660 TI - Statistical Analysis of the Impact of Molecular Descriptors on Cytotoxicity of Thiourea Derivatives Incorporating 2-Aminothiazole Scaffold. AB - Chemical reactivity descriptors and lipophilicyty (log P) were evaluated via semi empirical method for the quantum calculation of molecular electronic structure (PM3) in order to clarify the structure-cytotoxic activity relationships of disubstutited thioureas. Analysed compounds were obtained by the linkage of 2 aminothiazole ring, thiourea and substituted phenyl ring. The detailed examination was carried out to establish correlation between descriptors and cytotoxic activity against the MT-4 cells for 11 compounds. For the most active compounds (6 compounds) cytotoxic activity against three cancer cell lines (CCRF CEM, WIL-2NS, CCRF-SB) and normal human cell (HaCaT) was determined. 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release were assessed. Regression analysis revealed that electrophilicity index and chemical potential significantly contributed to expain the thioureas cytotoxic potential. PMID- 27477661 TI - Synthesis and Biological Evaluation of 3-Benzylidene-4-chromanone Derivatives as Free Radical Scavengers and alpha-Glucosidase Inhibitors. AB - A series of 3-benzylidene-4-chromanone derivatives (3-20) were synthesized and the structure-activity relationships for antioxidant and alpha-glucosidase inhibitory activities were evaluated. Among synthesized compounds, compounds 5, 13, 18, which contain catechol moiety, showed the potent 1,1-diphenyl-2 picrylhydrazyl (DPPH) free radical scavenging activity (5: EC50 13 uM; 13: EC50 14 uM; 18: EC50 13 uM). The compounds 12, 14, 18 showed higher alpha-glucosidase inhibitory activity (12: IC50 15 uM; 14: IC50 25 uM; 18: IC50 28 uM). The compound 18 showed both of potent DPPH radical scavenging and alpha-glucosidase inhibitory activities. These data suggest that 3-benzylidene-4-chromanone derivatives, such as compound 18, may serve as the lead compound for the development of novel alpha-glucosidase inhibitors with antioxidant activity. PMID- 27477662 TI - Photostable Solid Dispersion of Nifedipine by Porous Calcium Silicate. AB - Nifedipine (NIF) is a typical light-sensitive drug requiring protection from light during manufacture, storage, and handling of its dosage forms. The purpose of this study was to evaluate the utility of porous calcium silicate (PCS) for maintaining the photostability of NIF in a solid dispersion formulation. Adsorption solid dispersion (ASD) prepared using NIF and PCS as an amorphous formulation was more stable to light irradiation than a physical mixture of NIF and microcrystalline cellulose (a control physical mixture) as a crystalline formulation. In addition, PCS in physical mixtures with NIF adequately protected NIF from photodegradation, suggesting that this protective effect could be because of some screening effect by the porous structure of PCS blocking the passage of light reaching NIF in pores of PCS. These findings suggest that PCS is useful for improving the solubility and photostability of NIF in solid dispersion formulation. PMID- 27477663 TI - New 3,4-seco-Grayanane Diterpenoids from the Flowers of Pieris japonica. AB - Three new 3,4-seco-grayanane diterpenoids, neopierisoids D-F (2-4), and a new natural one, neopierisoid C (1), were isolated from the flowers of Pieris japonica. Their structures were elucidated on the basis of extensive spectroscopic analysis, including one and two dimensional (1- and 2D)-NMR, as well as high resolution-electron ionization (HR-EI)-MS. PMID- 27477664 TI - Quantitative Appearance Inspection for Film Coated Tablets. AB - The decision criteria for the physical appearance of pharmaceutical products are subjective and qualitative means of evaluation that are based entirely on human interpretation. In this study, we have developed a comprehensive method for the quantitative analysis of the physical appearance of film coated tablets. Three different kinds of film coated tablets with considerable differences in their physical appearances were manufactured as models, and their surface roughness, contact angle, color measurements and physicochemical properties were investigated as potential characteristics for the quantitative analysis of their physical appearance. All of these characteristics were useful for the quantitative evaluation of the physical appearances of the tablets, and could potentially be used to establish decision criteria to assess the quality of tablets. In particular, the analysis of the surface roughness and film coating properties of the tablets by terahertz spectroscopy allowed for an effective evaluation of the tablets' properties. These results indicated the possibility of inspecting the appearance of tablets during the film coating process. PMID- 27477665 TI - Morinlongosides A-C, Two New Naphthalene Glycoside and a New Iridoid Glycoside from the Roots of Morinda longissima. AB - Two new naphthalene glycosides, morinlongosides A and B (1, 2) and a new iridoid glycoside, morinlongoside C (3), together with four known ones, geniposidic acid (4), (3R)-3-O-[beta-D-xylopyranosyl-(1->6)-beta-D-glucopyranosyl]-l-octen-3-ol (5), lucidin-3-O-beta-primeveroside (6), and morindone-6-O-beta-gentiobioside (7), were isolated from the roots of Morinda longissima Y. Z. RUAN. The structures of all isolated compounds (1-7) were elucidated on the basis of spectroscopic data (high resolution (HR)-MS, one and two dimensional (1/2D)-NMR). PMID- 27477666 TI - Reaction of Thymidine with Hypobromous Acid in Phosphate Buffer. AB - When thymidine was treated with hypobromous acid (HOBr) in 100 mM phosphate buffer at pH 7.2, two major product peaks appeared in the HPLC chromatogram. The products in each peak were identified by NMR and MS as two isomers of 5-hydroxy 5,6-dihydrothymidine-6-phosphate (a novel compound) and two isomers of 5,6 dihydroxy-5,6-dihydrothymidine (thymidine glycol) with comparable yields. 5 Hydroxy-5,6-dihydrothymidine-6-phosphate was relatively stable, and decomposed with a half-life of 32 h at pH 7.2 and 37 degrees C generating thymidine glycol. The results suggest that 5-hydroxy-5,6-dihydrothymidine-6-phosphate in addition to thymidine glycol may have importance for mutagenesis by the reaction of HOBr with thymine residues in nucleotides and DNA. PMID- 27477667 TI - Concise Synthesis of (2R,4R)-Monatin. AB - Monatin, 4-hydroxy-4-(3-indolylmethyl)-glutamic acid, is a naturally occurring sweet amino acid. The (2R,4R)-monatin isomer has been found to be the sweetest among its four stereoisomers. A concise and efficient synthesis of (2R,4R) monatin was accomplished by the alkylation of (4R)-N-tert-butoxycarbonyl (tBoc)-4 tert-butyldimethylsilyoxy-D-pyroglutamic acid methyl ester with tert-butyl 3 (bromomethyl)-1H-indole-1-carboxylate to give (4R)-N-tBoc-4-tert butyldimethylsilyloxy-4-(N-tBoc-3-indolylmethyl)-D-pyroglutamic acid methyl ester, i.e., the lactam form of (2R,4R)-monatin with protecting groups. This was followed by the hydrolysis of the lactam ring and deprotection. The 4-hydroxyl D pyroglutamic acid derivative was demonstrated to be a suitable precursor for the efficient preparation of (2R,4R)-monatin in high optical purity because the alkylation proceeded in regioselective and stereoselective manners at C4 to form appropriate asymmetric tetra-substituted carbon center; the resulting alkylated pyroglutamic acid derivative was then easily converted into the linear form of monatin. PMID- 27477668 TI - The Extent of Myocardial Injury During Prolonged Targeted Temperature Management After Out-of-Hospital Cardiac Arrest. AB - AIM: The aim of this study is to evaluate the extent of myocardial injury by cardiac biomarkers during prolonged targeted temperature management of 24 hours vs 48 hours after out-of-hospital cardiac arrest. METHODS: This randomized Scandinavian multicenter study compares the extent of myocardial injury quantified by area under the curve (AUC) of cardiac biomarkers during prolonged targeted temperature management at 33 degrees C +/- 1 degrees C of 24 hours and 48 hours, respectively. Through a period of 2.5 years, 161 comatose out-of hospital cardiac arrest patients were randomized to targeted temperature management for 24 hours (n = 77) or 48 hours (n = 84). The AUC was calculated using both high-sensitivity cardiac troponin T (hs-cTnTAUC) and creatine kinase myocardial band (CK-MBAUC) that were based upon measurements of these biomarkers every 6 hours upon admission until 96 hours after reaching target temperature. RESULTS: The median hs-cTnTAUC of 33,827 ng/L/h (interquartile range [IQR] 11,366 117,690) of targeted temperature management at 24 hours did not differ significantly from that of 28,973 ng/L/h (IQR 10,656-163,655) at 48 hours. In contrast, the median CK-MBAUC of 1829 MUg/L/h (IQR 800-6799) during targeted temperature management at 24 hours was significantly lower than that of 2428 MUg/L/h (IQR 1163-10,906) within targeted temperature management at 48 hours, P <.05. CONCLUSION: This study of comatose out-of-hospital cardiac arrest survivors showed no difference between the extents of myocardial injury estimated by hs cTnTAUC of prolonged targeted temperature management of 48 hours vs 24 hours, although the CK-MBAUC was significantly higher during 48 hours vs 24 hours. Hence, it seems unlikely that the duration of targeted temperature management has a beneficial effect on the extent of myocardial injury after out-of-hospital cardiac arrest, and may even have a worsening effect. PMID- 27477669 TI - Anticoagulation Is Associated with Decreased Inferior Vena Cava Filter-Related Complications in Patients with Metastatic Carcinoma. AB - OBJECTIVES: Patients with metastatic carcinoma and venous thromboembolism commonly have contraindications to anticoagulation that prompt the use of retrievable inferior vena cava filters. The aim of this study was to compare the pattern of inferior vena cava filter use, anticoagulation management, and development of inferior vena cava filter-related complications in patients with localized versus metastatic carcinoma. METHODS: We conducted a retrospective cohort study of inferior vena cava filter use at a tertiary referral hospital between January 1, 2009, and December 31, 2011. Including only patients with cancer and carcinomas, both metastatic and localized, we recorded the indications for inferior vena cava filter, postfilter practices including anticoagulation use, filter retrieval rates, and filter-related complications. RESULTS: Overall, 154 patients with carcinoma underwent inferior vena cava filter placement. Basic demographics and indication for filter placement were similar between the metastatic and localized groups. Metastatic patients had more filter-related complications (25% vs 11%, P = .03) and underwent filter retrieval less often (31% vs 58%, P = .01). Time to reinitiating anticoagulation was longer in metastatic patients (5.5 vs 2 days, P = .05). In multivariate analysis, metastatic disease was associated with reduced inferior vena cava filter retrieval (odds ratio, 0.3; P = .003). Anticoagulation use was associated with a lower rate of filter-related complications (odds ratio, 0.3; P = .005). CONCLUSIONS: Patients with metastatic carcinoma with an indwelling inferior vena cava filter had a higher rate of filter-related complications, a lower filter retrieval rate, and a greater median time to initiating anticoagulation. When possible, early reinitiation of anticoagulation may reduce inferior vena cava filter-related complications. PMID- 27477670 TI - Rectal prolapse in Winnie mice with spontaneous chronic colitis: changes in intrinsic and extrinsic innervation of the rectum. AB - Rectal prolapse is associated with diminished anal sensitivity and rectal motor activity. Both sensory and motor functions are controlled by the extrinsic and intrinsic (enteric nervous system) innervation of the gastrointestinal tract. Studies of changes in intestinal innervation in humans and in animal models with rectal prolapse are extremely scarce. The Winnie mouse model of spontaneous chronic colitis closely represents human inflammatory bowel disease and is prone to develop rectal prolapse. We have investigated changes in the myenteric and inhibitory motor neurons and evaluated changes in the density of sensory afferent, sympathetic, and parasympathetic fibers in the rectal colon of Winnie mice with and without rectal prolapse. Our results demonstrate that rectal prolapse in Winnie mice with chronic colitis is correlated with enhanced levels of inflammation, gross morphological damage, and muscular hypertrophy of the rectum. Animals with prolapse have more severe damage to the rectal innervation compared with Winnie mice without prolapse. This includes more severe neuronal loss in the myenteric plexus, involving a decrease in nNOS-immunoreactive neurons (not observed in Winnie mice without prolapse) and a more pronounced loss of VAChT-immunoreactive fibers. Both Winnie mice with and without prolapse have comparable levels of noradrenergic and sensory fiber loss in the rectum. This is the first study providing evidence that the damage and death of enteric neurons, including nitrergic neurons in myenteric ganglia and the loss of cholinergic nerve fibers, are important factors in structural changes in the rectum of mice with rectal prolapse. PMID- 27477671 TI - Influence of wheel size on muscle activity and tri-axial accelerations during cross-country mountain biking. AB - This study aimed to investigate the influence of different mountain bike wheel diameters on muscle activity and whether larger diameter wheels attenuate muscle vibrations during cross-country riding. Nine male competitive mountain bikers (age 34.7 +/- 10.7 years; stature 177.7 +/- 5.6 cm; body mass 73.2 +/- 8.6 kg) participated in the study. Riders performed one lap at race pace on 26, 27.5 and 29 inch wheeled mountain bikes. sEMG and acceleration (RMS) were recorded for the full lap and during ascent and descent phases at the gastrocnemius, vastus lateralis, biceps brachii and triceps brachii. No significant main effects were found by wheel size for each of the four muscle groups for sEMG or acceleration during the full lap and for ascent and descent (P > .05). When data were analysed between muscle groups, significant differences were found between biceps brachii and triceps brachii (P < .05) for all wheel sizes and all phases of the lap with the exception of for the 26 inch wheel during the descent. Findings suggest wheel diameter has no influence on muscle activity and vibration during mountain biking. However, more activity was observed in the biceps brachii during 26 inch wheel descending. This is possibly due to an increased need to manoeuvre the front wheel over obstacles. PMID- 27477672 TI - Impact of Abiotic Factors on Onion Thrips (Thysanoptera: Thripidae) Aerial Dispersal in an Onion Ecosystem. AB - Onion thrips, Thrips tabaci Lindeman, is a significant pest of onion crops worldwide, but little is known about its patterns of aerial dispersal in the context of abiotic environmental factors. Thrips tabaci adults were passively collected from the air column above onion fields in western New York using clear sticky cards over a series of sampling periods in 2012, 2013, and 2014 while on site weather conditions were recorded. Results indicated that T. tabaci adult densities on aerial traps during daylight averaged 279 times greater per hour than densities on similar traps at night. Adult dispersal also tended to spike during presunset, indicating that thrips initiated flight diurnally and within 1 h before sunset. Densities of T. tabaci on aerial traps increased significantly as temperature increased above 17 degrees C and 90% of the thrips were captured between 20.8 and 27.7 degrees C; no thrips were captured above 30.6 degrees C. Densities of T. tabaci on aerial traps decreased significantly as wind speed increased, with no thrips captured at winds exceeding 3.8 m/s (13.7 kph). In 2013 and 2014, T. tabaci densities on aerial traps prior to the passage of a cold front (relatively high atmospheric pressure and temperature with low wind speed) were significantly greater than densities after passage of the front, suggesting that T. tabaci disperses on synoptic weather systems. PMID- 27477673 TI - Transitioning from multi-phase to single-phase microfluidics for long-term culture and treatment of multicellular spheroids. AB - When compared to methodologies based on low adhesion or hanging drop plates, droplet microfluidics offers several advantages for the formation and culture of multicellular spheroids, such as the potential for higher throughput screening and the use of reduced cell numbers, whilst providing increased stability for plate handling. However, a drawback of the technology is its characteristic compartmentalisation which limits the nutrients available to cells within an emulsion and poses challenges to the exchange of the encapsulated solution, often resulting in short-term cell culture and/or viability issues. The aim of this study was to develop a multi-purpose microfluidic platform that combines the high throughput characteristics of multi-phase flows with that of ease of perfusion typical of single-phase microfluidics. We developed a versatile system to upscale the formation and long-term culture of multicellular spheroids for testing anticancer treatments, creating an array of fluidically addressable, compact spheroids that could be cultured in either medium or within a gel scaffold. The work provides proof-of-concept results for using this system to test both chemo- and radio-therapeutic protocols using in vitro 3D cancer models. PMID- 27477675 TI - Advances in sensor and wearable technologies for Parkinson's disease. PMID- 27477674 TI - Assessing treatment efficacy in the presence of diagnostic errors. AB - This paper investigates estimating and testing treatment effects in randomized control trials where imperfect diagnostic device is used to assign subjects to treatment and control group(s). The paper focuses on pre-post design and proposes two new methods for estimating and testing treatment effects. Furthermore, methods for computing sample sizes for such design accounting for misclassification of the subjects are devised. The methods are compared with each other and with a traditional method that ignores the imperfection of the diagnostic device. In particular, the likelihood-based approach shows a significant advantage in terms of power, coverage probability and, consequently, in reduction of the required sample size. The application of the results are illustrated with data from an aging trial for dementia and data from electroencephalogram (EEG) recordings of alcoholic and non-alcoholic subjects. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27477677 TI - Mitochondrial contact sites as platforms for phospholipid exchange. AB - Mitochondria are unique organelles that contain their own - although strongly reduced - genome, and are surrounded by two membranes. While most cellular phospholipid biosynthesis takes place in the ER, mitochondria harbor the whole spectrum of glycerophospholipids common to biological membranes. Mitochondria also contribute to overall phospholipid biosynthesis in cells by producing phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. Considering these features, it is not surprising that mitochondria maintain highly active exchange of phospholipids with other cellular compartments. In this contribution we describe the transport of phospholipids between mitochondria and other organelles, and discuss recent developments in our understanding of the molecular functions of the protein complexes that mediate these processes. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum. PMID- 27477676 TI - SCD1 deficiency protects mice against ethanol-induced liver injury. AB - Stearoyl-CoA desaturase 1 (SCD1) is a delta-9 fatty acid desaturase that catalyzes the synthesis of mono-unsaturated fatty acids (MUFA). SCD1 is a critical control point regulating hepatic lipid synthesis and beta-oxidation. Scd1 KO mice are resistant to the development of diet-induced non-alcoholic fatty liver disease (NAFLD). Using a chronic-binge protocol of ethanol-mediated liver injury, we aimed to determine if these KO mice are also resistant to the development of alcoholic fatty liver disease (AFLD). Mice fed a low-fat diet (especially low in MUFA) containing 5% ethanol for 10days, followed by a single ethanol (5g/kg) gavage, developed severe liver injury manifesting as hepatic steatosis. This was associated with an increase in de novo lipogenesis and inflammation. Using this model, we show that Scd1 KO mice are resistant to the development of AFLD. Scd1 KO mice do not show accumulation of hepatic triglycerides, activation of de novo lipogenesis nor elevation of cytokines or other pro-inflammatory markers. Incubating HepG2 cells with a SCD1 inhibitor induced a similar resistance to the effect of ethanol, confirming a role for SCD1 activity in mediating ethanol-induced hepatic injury. Taken together, our study shows that SCD1 is a key player in the development of AFLD and associated deleterious effects, and suggests SCD1 inhibition as a therapeutic option for the treatment of this hepatic disease. PMID- 27477678 TI - Development of smart cell-free and cell-based assay systems for investigation of leukotriene C4 synthase activity and evaluation of inhibitors. AB - Cysteinyl leukotrienes (cys-LTs) cause bronchoconstriction in anaphylaxis and asthma. They are formed by 5-lipoxygenase (5-LOX) from arachidonic acid (AA) yielding the unstable leukotriene A4 (LTA4) that is subsequently conjugated with glutathione (GSH) by LTC4 synthase (LTC4S). Cys-LT receptor antagonists and LTC4S inhibitors have been developed, but only the former have reached the market. High structural homology to related enzymes and lack of convenient test systems due to instability of added LTA4 have hampered the development of LTC4S inhibitors. We present smart cell-free and cell-based assay systems based on in situ-generated LTA4 that allow studying LTC4S activity and investigating LTC4S inhibitors. Co incubations of microsomes from HEK293 cells expressing LTC4S with isolated 5-LOX efficiently converted exogenous AA to LTC4 (~1.3MUg/200MUg protein). Stimulation of HEK293 cells co-expressing 5-LOX and LTC4S with Ca2+-ionophore A23187 and 20MUM AA resulted in strong LTC4 formation (~250ng/106 cells). MK-886, a well known 5-LOX activating protein (FLAP) inhibitor that also acts on LTC4S, consistently inhibited LTC4 formation in all assay types (IC50=3.1-3.5MUM) and we successfully confirmed TK04a as potent LTC4S inhibitor in these assay systems (IC50=17 and 300nM, respectively). We demonstrated transcellular LTC4 biosynthesis between neutrophils or 5-LOX-expressing HEK293 cells that produce LTA4 from AA and HEK293 cells expressing LTC4S that transform LTA4 to LTC4. In conclusion, our assay approaches are advantageous as the substrate LTA4 is generated in situ and are suitable for studying enzymatic functionality of LTC4S including site-directed mutations and evaluation of LTC4S inhibitors. PMID- 27477679 TI - In memory of Christina Enroth-Cugell, distinguished vision scientist. PMID- 27477680 TI - The use of imaging techniques in understanding lower urinary tract (dys)function. AB - The ability to store urine in the bladder and to void at an appropriate time depends on several complex mechanisms in the lower urinary tract (LUT) and its neural control. Normal LUT function requires coordination of the urinary bladder, urethra, pelvic floor, efferent and afferent neurons and specific spinal cord and brain areas. These structures can be visualised using different imaging modalities, such as ultrasound, X-ray and magnetic resonance imaging. The supraspinal neural control of the LUT can be studied using functional brain imaging. During the last two decades, the many technological improvements of these imaging techniques have increased our knowledge of voiding dysfunction. Here, we review the different imaging modalities of the LUT and its neural control and discuss their importance for diagnosing and understanding voiding dysfunction. PMID- 27477681 TI - Origination and Establishment of a Trigenic Reproductive Isolation System in Rice. PMID- 27477682 TI - Ins(1,4,5)P3 Suppresses Protein Degradation in Plant Vacuoles by Regulating SNX Mediated Protein Sorting. PMID- 27477683 TI - Control of Leaf Senescence by an MeOH-Jasmonates Cascade that Is Epigenetically Regulated by OsSRT1 in Rice. AB - Although considerable progress has been made in identifying the genes regulating accumulation of hormones that are involved in leaf senescence, only a few studies have focused on natural variations in jasmonates content and much less on the underlying genetic basis. Moreover, the epigenetic regulation of jasmonate mediated leaf senescence remains largely unknown. In this study, we carried out metabolic profiling of a worldwide collection of rice accessions and demonstrated that there are substantial variations in jasmonate levels among these accessions. A subsequent metabolite-based genome-wide association study identified candidates for two major quantitative genes (QTGs), OsPME1 and OsTSD2, affecting the content of jasmonates. Further investigations using a series of relevant mutants and transgenic lines revealed the MeOH-jasmonate cascade plays an important role in regulating leaf senescence. Moreover, we showed that OsSRT1, one of the two Sir2 (silent information regulator 2) homologs in rice, negatively regulates leaf senescence by repressing expression of the biosynthetic genes of this metabolic cascade and at least particially through histone H3K9 deacetylation of OsPME1. Taken together, our results indicate that the MeOH-jasmonates cascade and its epigenetic regulation are crucial for controlling leaf senescence process in rice. PMID- 27477684 TI - The DNA Topoisomerase VI-B Subunit OsMTOPVIB Is Essential for Meiotic Recombination Initiation in Rice. PMID- 27477686 TI - Genome-wide Identification and Structural, Functional and Evolutionary Analysis of WRKY Components of Mulberry. AB - Mulberry is known to be sensitive to several biotic and abiotic stresses, which in turn have a direct impact on the yield of silk, because it is the sole food source for the silk worm. WRKYs are a family of transcription factors, which play an important role in combating various biotic and abiotic stresses. In this study, we identified 54 genes with conserved WRKY motifs in the Morus notabilis genome. Motif searches coupled with a phylogenetic analysis revealed seven sub groups as well as the absence of members of Group Ib in mulberry. Analyses of the 2K upstream region in addition to a gene ontology terms enrichment analysis revealed putative functions of mulberry WRKYs under biotic and abiotic stresses. An RNA-seq-based analysis showed that several of the identified WRKYs have shown preferential expression in the leaf, bark, root, male flower, and winter bud of M. notabilis. Finally, expression analysis by qPCR under different stress and hormone treatments revealed genotype-specific responses. Taken together, our results briefs about the genome-wide identification of WRKYs as well as their differential response to stresses and hormones. Importantly, these data can also be utilized to identify potential molecular targets for conferring tolerance to various stresses in mulberry. PMID- 27477688 TI - Spin-polarized transport in hydrogen-passivated graphene and silicene nanoribbons with magnetic transition-metal substituents. AB - We present a systematic theoretical study of the electronic transport in hydrogen passivated zigzag graphene and silicene nanoribbons with between zero and four neighboring H atoms on one edge replaced by magnetic transition metals (Fe, Co, and Ni). The calculations were performed using equilibrium transport and density functional theory with the generalized gradient approximation to exchange and correlation. We considered the magnetic moments of the two edges aligned both ferromagnetically (Ferro-F form) and antiferromagnetically (Ferro-A form). The Ferro-A graphene-based ribbons were all semiconducting and would support moderate spin-polarized currents of either sign by applying positive or negative gate voltages. The Ferro-F graphene-based ribbons were all metallic; the most interesting for possible spintronic applications being that with a single Ni atom, in which strong spin-filtering at low bias resulted from a deep trough in the transmission of one spin component around the Fermi level. By contrast, in the Si-based analog this trough was split, partially eliminating the polarization of the current. This splitting was found to be related to the buckled structure of the Si-based nanoribbon, which has its origin in its preference for sp(3)-like hybridization. PMID- 27477687 TI - Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti inflammatory and neuroprotective properties. AB - The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in vitro studies on neuronal HT-22 cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration. PMID- 27477690 TI - Nurse-based monitoring and management of breakthrough pain in an acute pain relief and palliative care unit. AB - OBJECTIVES: To assess the nurses' performance in assessing, treating, and documenting breakthrough pain (BTP) in a palliative care unit where traditionally there is continuous training. METHODS: The study was performed in an acute palliative care unit. Once a week, a research nurse examined the documentation regarding all the episodes of BTP registered in a specific pain chart, designed by the institutional nurse board, as part of the routine nurse activity. RESULTS: The charts of 50 consecutive eligible patients (32 M/18 F), were analysed. The mean number of episodes/patient was 3.3 (SD 1.61; range 1-7). 166 episodes occurred. The main BTP pain intensity was 7.06 (SD 0.82). In 7 episodes, pain intensity was not evaluated at T0. The pain intensity after 15 minutes after BTP medication was 3.01 (SD1.19). In 28 episodes, pain intensity was not evaluated at T15. The change in pain intensity was highly significant (P < 0.0005). BTP episodes were distributed normally through different day intervals. No relevant adverse event attributable to BTP medication was reported in the nurse diary. CONCLUSION: Training in a research environment allows a good nurse capability in evaluating and treating BTP, and above all, providing documentation for each BTP episode. The theoretical work and recommendations around BTP need to be translated into day-to-day clinical practice. PMID- 27477685 TI - Redox-based therapeutics in neurodegenerative disease. AB - : This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research. LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. PMID- 27477689 TI - The Application of Failure Modes and Effects Analysis Methodology to Intrathecal Drug Delivery for Pain Management. AB - OBJECTIVE: This study aimed to utilize failure modes and effects analysis (FMEA) to transform clinical insights into a risk mitigation plan for intrathecal (IT) drug delivery in pain management. METHODS: The FMEA methodology, which has been used for quality improvement, was adapted to assess risks (i.e., failure modes) associated with IT therapy. Ten experienced pain physicians scored 37 failure modes in the following categories: patient selection for therapy initiation (efficacy and safety concerns), patient safety during IT therapy, and product selection for IT therapy. Participants assigned severity, probability, and detection scores for each failure mode, from which a risk priority number (RPN) was calculated. Failure modes with the highest RPNs (i.e., most problematic) were discussed, and strategies were proposed to mitigate risks. RESULTS: Strategic discussions focused on 17 failure modes with the most severe outcomes, the highest probabilities of occurrence, and the most challenging detection. The topic of the highest-ranked failure mode (RPN = 144) was manufactured monotherapy versus compounded combination products. Addressing failure modes associated with appropriate patient and product selection was predicted to be clinically important for the success of IT therapy. CONCLUSIONS: The methodology of FMEA offers a systematic approach to prioritizing risks in a complex environment such as IT therapy. Unmet needs and information gaps are highlighted through the process. Risk mitigation and strategic planning to prevent and manage critical failure modes can contribute to therapeutic success. PMID- 27477691 TI - The relationship of platelet-to-lymphocyte ratio with clinical outcome and final infarct core in acute ischemic stroke patients who have undergone endovascular therapy. AB - OBJECTIVES: Of all strokes, 85% are ischemic and intracranial artery occlusion accounts for 80% of these ischemic strokes. Endovascular therapy for acute ischemic stroke was a new modality aiming at resolution of clots in occluded cerebral arteries. The platelet-to-lymphocyte ratio (PLR) was introduced as a potential marker to determine increased inflammation, which is a result of releasing many mediators from the platelets. In this study we aimed to evaluate whether the PLR had a prognostic role in stroke patients undergoing thrombectomy and attempted to determine the effect that this ratio had on their survival. METHODS: Over a three-year period, demographic, clinical, and angiographic findings of 57 consecutive patients with acute ischemic stroke who underwent mechanical thrombectomy were evaluated. RESULTS: The patients were divided into two groups on the basis of a PLR level cut-off value of 145 based on receiver operating characteristic (ROC) curve. Successful revascularization (mTICI 2b and 3) was achieved in 42 of 57 (73.7%) patients; a mTICI 3 state was observed in 21 of 23 patients with low-PLR values (p = .015). Patients with higher PLR values had significantly a score of less than six on the ASPECT scale compared to patients with lower PLR values (p = .005). The patients with low-PLR values had better functional outcomes (mRS <= 2) compared with the patients with high-PLR values [respectively, p = .004 (at first month) and p = .014 (at third month)]. DISCUSSION: The platelet-to-lymphocyte ratio could represent pro-thrombotic inflammatory state in acute ischemic stroke patients because having a high-PLR values increased the poor prognosis, the rate of insufficient recanalization, and the size of infarcted area. PMID- 27477692 TI - CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells. AB - Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells. Loss of CBP/p300 decreased the basal cell surface expression of human ligands and reduced the upregulation of MICA/B and ULBP2 in response to histone deacetylase inhibitors or DNA damage. Furthermore, CBP/P300 deficiency abrogated the sensitivity of stressed cells to NK cell mediated killing. CBP/p300 were also identified as major regulators of mouse NKG2D ligand RAE-1 in vitro and in vivo using the EMU-Myc lymphoma model. Mechanistically, we observed an enhanced activation of the CBP/p300 binding transcription factor CREB (cAMP response element-binding protein) correlating to the NKG2D-L upregulation. Moreover, increased binding of CREB and CBP/p300 to NKG2D-L promoters and elevated histone acetylation were detectable. This study provides strong evidence for a major role of CBP and p300 in orchestrating NKG2D L induction and consequently immunosurveillance of tumors in mice and humans. These findings might help to develop novel immunotherapeutic approaches against cancer. PMID- 27477694 TI - Identification of latent biomarkers in hepatocellular carcinoma by ultra-deep whole-transcriptome sequencing. PMID- 27477693 TI - Overexpression of PDGFRA cooperates with loss of NF1 and p53 to accelerate the molecular pathogenesis of malignant peripheral nerve sheath tumors. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, frequently metastatic sarcomas that are associated with neurofibromatosis type 1 (NF1), a prominent inherited genetic disease in humans. Although loss of the NF1 gene predisposes to MPNST induction, relatively long tumor latency in NF1 patients suggests that additional genetic or epigenetic abnormalities are needed for the development of these nerve sheath malignancies. To study the molecular pathways contributing to the formation of MPNSTs in NF1 patients, we used a zebrafish tumor model defined by nf1 loss in a p53-deficient background together with the overexpression of either wild-type or constitutively activated PDGFRA (platelet derived growth factor receptor-alpha) under control of the sox10 neural crest specific promoter. Here we demonstrate the accelerated onset and increased penetrance of MPNST formation in fish overexpressing both the wild-type and the mutant PDGFRA transgenes in cells of neural crest origin. Interestingly, overexpression of the wild-type PDGFRA was even more potent in promoting transformation than the mutant PDGFRA, which is important because ~78% of human MPNSTs have expression of wild-type PDGFRA, whereas only 5% harbor activating mutations of the gene encoding this receptor. Further analysis revealed the induction of cellular senescence in zebrafish embryos overexpressing mutant, but not wild-type, PDGFRA, suggesting a mechanism through which the oncogenic activity of the mutant receptor is tempered by the activation of premature cellular senescence in an NF1-deficient background. Taken together, our study suggests a model in which overexpression of wild-type PDGFRA associated with NF1 deficiency leads to aberrant activation of downstream RAS signaling and thus contributes importantly to MPNST development-a prediction supported by the ability of the kinase inhibitor sunitinib alone and in combination with the MEK inhibitor trametinib to retard MPNST progression in transgenic fish overexpressing the wild-type receptor. PMID- 27477695 TI - MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy. PMID- 27477697 TI - Cyclin G2 inhibits epithelial-to-mesenchymal transition by disrupting Wnt/beta catenin signalling. PMID- 27477696 TI - microRNAs with AAGUGC seed motif constitute an integral part of an oncogenic signaling network. AB - microRNA (miRNA) dysregulation is a common feature of cancer cells, but the complex roles of miRNAs in cancer are not fully elucidated. Here, we used functional genomics to identify oncogenic miRNAs in non-small cell lung cancer and evaluate their impact on response to epidermal growth factor (EGFR)-targeting therapy. Our data demonstrate that miRNAs with an AAGUGC motif in their seed sequence increase both cancer cell proliferation and sensitivity to EGFR inhibitors. Global transcriptomics, proteomics and target prediction resulted in the identification of several tumor suppressors involved in the G1/S transition as AAGUGC-miRNA targets. The clinical implications of our findings were evaluated by analysis of AAGUGC-miRNA expression in multiple cancer types, supporting the link between this miRNA seed family, their tumor suppressor targets and cancer cell proliferation. In conclusion, we propose the AAGUGC seed motif as an oncomotif and that oncomotif-miRNAs promote cancer cell proliferation. These findings have potential therapeutic implications, especially in selecting patients for EGFR-targeting therapy. PMID- 27477699 TI - Re: Incidence and risk factors for acute kidney injury after radical cystectomy. PMID- 27477698 TI - Plk1-mediated stabilization of 53BP1 through USP7 regulates centrosome positioning to maintain bipolarity. AB - Although 53BP1 has been established well as a mediator in DNA damage response, its function in mitosis is not clearly understood. We found that 53BP1 is a mitotic-binding partner of the kinases Plk1 and AuroraA, and that the binding with Plk1 increases the stability of 53BP1 by accelerating its interaction with the deubiquitinase USP7. Depletion of 53BP1 induces mitotic defects such as chromosomal missegregation, misorientation of spindle poles and the generation of extra centrosomes, which is similar phenotype to USP7-knockdown cells. In addition, 53BP1 depletion reduces the levels of p53 and centromere protein F (CENPF), interacting proteins of 53BP1. These phenotypes induced by 53BP1 depletion were rescued by expression of wild-type or phosphomimic mutant 53BP1 but not by expression of a dephosphomimic mutant. We propose that phosphorylation of 53BP1 at S380 accelerates complex formation with USP7 and CENPF to regulate their stability, thus having a crucial role in proper centrosome positioning, chromosomal alignment, and centrosome number. PMID- 27477700 TI - The association between intersegmental coordination in the lower limb and gait speed in elderly females. AB - Human multi-segmental motion is a complex task requiring motor coordination. Uncoordinated motor control may contribute to the decline in mobility; however, it is unknown whether the age-related decline in intersegmental coordination relates to the decline in gait performance. The aim of this study was to clarify the association between intersegmental coordination and gait speed in elderly females. Gait measurements were performed in 91 community-dwelling elderly females over 60 years old. Foot, shank, and thigh sagittal motions were assessed. Intersegmental coordination was analyzed using the mean value of the continuous relative phase (mCRP) during four phases of the gait cycle to investigate phase differences in foot-shank and shank-thigh motions during a normal gait. The results showed that foot-shank mCRP at late stance had negative correlations with gait speed (r=-0.53) and cadence (r=-0.54) and a positive correlation with age (r=0.25). In contrast, shank-thigh mCRP at late stance had positive correlations with gait speed (r=0.37) and cadence (r=0.56). Moreover, partial correlation, controlling age, height, and weight, revealed that foot-shank mCRP at late stance had negative correlations with gait speed (r=-0.52) and cadence (r=-0.54). Shank thigh mCRP at late stance had a positive correlation with gait speed (r=0.28) and cadence (r=0.51). These findings imply that the foot-shank and shank-thigh coordination patterns at late stance relate to gait speed, and uncoordinated lower limb motion is believed to be associated with the age-related decline in cadence. PMID- 27477701 TI - Split-belt locomotion in Parkinson's disease links asymmetry, dyscoordination and sequence effect. AB - BACKGROUND: The pathophysiology behind gait impairments seen in Parkinson's disease (PD), in particular freezing of gait (FOG), is not fully understood. Here we study the interplay between several gait features related to FOG during different split-belt treadmill (SBTM) conditions. METHODS: We investigated the spatiotemporal properties, the phenomenon of sequence effect and the inter-limb symmetry and temporal coordination of gait during different split-belt conditions in 20 patients with advanced Parkinson's disease and different severities of freezing. Subjects were tested in four belt configurations: tied, split while reducing the velocity of leg with the shorter (worst side reduction, WSR) and longer (best side reduction, BSR) step length, and tied again to measure the after-effect. RESULTS: We found that in spite of an improvement of spatial symmetry, the BSR led to a worsening of coordination (i.e. the left-right anti phased stepping) and an increased sequence effect (i.e. progressive shortening of the step length). By contrast, in spite of a worsened spatial symmetry, WSR improved inter-limbs coordination and reduced the sequence effect. After prolonged split-belt walking gait was differently modulated according to the reduction of the best or worst leg velocity: BSR led to positive after effects in symmetry, bilateral coordination and sequence effect. CONCLUSIONS: These findings support the hypothesis that the irregularity of inter-limb coordination and defective amplitude generation leading to sequence effect might be coupled and result from the same maladaptive motor behavior. Furthermore, our results show that SBTM can be an effective tool to improve parkinsonian gait. PMID- 27477703 TI - Center of pressure during stance and gait in subjects with or without persistent complaints after a lateral ankle sprain. AB - STUDY AIM: To investigate differences in the center of pressure (COP) during gait and single leg stance between subjects with persistent complaints (PC) and without persistent complaints (NPC) after a lateral ankle sprain. METHODS: 44 patients who consulted the general practitioner, 6-12 months prior to inclusion, with a lateral ankle sprain were included for the current study purpose. Using a 7-point Likert scale patients were divided into the PC or NPC group. All subjects filled out an online questionnaire, walked along a walkway and performed a single leg stance, both on the RSscan. Primary outcomes included the COP displacement, range and percentage used in mediolateral and anterioposterior direction. RESULTS: There was a trend (p<0.05) towards a more medially COP trajectory during walking at 34-46% and 83-96% and more anteriorly at 21-31% and 91-100% of the stance phase in the PC group compared to NPC group. Additionally, the COP was more laterally located in the sprained leg compared to the non-sprained leg in the PC group in the loading response phase (p<0.05). An interaction was found for the percentage of anterior-posterior range used in single leg stance without vision. CONCLUSION: The COP trajectory discriminates between patients with PC and NPC. This indicates that roll off during gait might play an important role in the recovery of patients after a lateral ankle sprain and could be used to monitor treatment. PMID- 27477702 TI - The effect of tibiotalar alignment on coronal plane mechanics following total ankle replacement. AB - BACKGROUND: Gait mechanics following total ankle replacement (TAR) have reported improved ankle motion following surgery. However, no studies have addressed the impact of preoperative radiographic tibiotalar alignment on post-TAR gait mechanics. We therefore investigated whether preoperative tibiotalar alignment (varus, valgus, or neutral) resulted in significantly different coronal plane mechanics or ground reaction forces post-TAR. METHODS: We conducted a non randomized study of 93 consecutive end-stage ankle arthritis patients. Standard weight-bearing radiographs were obtained preoperatively to categorize patients as having neutral (+/-4 degrees ), varus (>=5 degrees of varus), or valgus (>=5 degrees of valgus) coronal plane tibiotalar alignment. All patients underwent a standard walking assessment including three-dimensional lower extremity kinetics and kinematics preoperatively, 12 and 24 months postoperatively. RESULTS: A significant group by time interaction was observed for the propulsive vertical ground reaction force (vGRF), coronal plane hip range of motion (ROM) and the peak hip abduction moment. The valgus group demonstrated an increase in the peak knee adduction angle and knee adduction angle at heel strike when compared to the other groups. Coronal plane ankle ROM, knee and hip angles at heel strike, and the peak hip angle exhibited significant increases across time. Peak ankle inversion moment, peak knee abduction moment and the weight acceptance vGRF also exhibited significant increases across time. Neutral ankle alignment was achieved for all patients by 2 years following TAR. CONCLUSIONS: Restoration of neutral ankle alignment at the time of TAR in patients with preoperative varus or valgus tibiotalar alignment resulted in biomechanics similar to those of patients with neutral preoperative tibiotalar alignment by 24-month follow-up. PMID- 27477704 TI - Validation of hip joint center localization methods during gait analysis using 3D EOS imaging in typically developing and cerebral palsy children. AB - Localization of the hip joint center (HJC) is essential in computation of gait data. EOS low dose biplanar X-rays have been shown to be a good reference in evaluating various methods of HJC localization in adults. The aim is to evaluate predictive and functional techniques for HJC localization in typically developing (TD) and cerebral palsy (CP) children, using EOS as an image based reference. Eleven TD and 17 CP children underwent 3D gait analysis. Six HJC localization methods were evaluated in each group bilaterally: 3 predictive (Plug in Gait, Bell and Harrington) and 3 functional methods based on the star arc technique (symmetrical center of rotation estimate, center transformation technique and geometrical sphere fitting). All children then underwent EOS low dose biplanar radiographs. Pelvis, lower limbs and their corresponding external markers were reconstructed in 3D. The center of the femoral head was considered as the reference (HJCEOS). Euclidean distances between HJCs estimated by each of the 6 methods and the HJCEOS were calculated; distances were shown to be lower in predictive compared to functional methods (p<0.0001). Contrarily to findings in adults, functional methods were shown to be less accurate than predictive methods in TD and CP children, which could be mainly due to the shorter thigh segment in children. Harrington method was shown to be the most accurate in the prediction of HJC (mean error~18mm, SD=9mm) and quasi-equivalent to the Bell method. The bias for each method was quantified, allowing its correction for an improved HJC estimation. PMID- 27477705 TI - Validity of FitBit, Jawbone UP, Nike+ and other wearable devices for level and stair walking. AB - BACKGROUND: Increased physical activity can provide numerous health benefits. The relationship between physical activity and health assumes reliable activity measurements including step count and distance traveled. This study assessed step count and distance accuracy for Nike+ FuelBand, Jawbone UP 24, Fitbit One, Fitbit Flex, Fitbit Zip, Garmin Vivofit, Yamax CW-701, and Omron HJ-321 during level, upstairs, and downstairs walking in healthy adults. METHODS: Forty subjects walked on flat ground (400m), upstairs (176 steps), and downstairs (176 steps), and a subset of 10 subjects performed treadmill walking trials to assess the influence of walking speed on accuracy. Activity monitor measured step count and distance values were compared with actual step count (determined from video recordings) and distance to determine accuracy. RESULTS: For level walking, step count errors in Yamax CW-701, Fitbit Zip, Fitbit One, Omron HJ-321, and Jawbone UP 24 were within 1% and distance errors in Fitbit Zip and Yamax CW-701 were within 5%. Garmin Vivofit and Omron HJ-321 were the most accurate in estimating step count for stairs with errors less than 4%. An important finding is that all activity monitors overestimated distance for stair walking by at least 45%. CONCLUSION: In general, there were not accuracy differences among activity monitors for stair walking. Accuracy did not change between moderate and fast walking speeds, though slow walking increased errors for some activity monitors. Nike+ FuelBand was the least accurate step count estimator during all walking tasks. Caution should be taken when interpreting step count and distance estimates for activities involving stairs. PMID- 27477706 TI - The effect of standing desks on manual control in children and young adults. AB - The aim of the present study was to establish if and how the additional postural constraint of standing affects accuracy and precision of goal directed naturalistic actions. Forty participants, comprising 20 young adults aged 20-23 years and 20 children aged 9-10 years completed 3 manual dexterity tasks on a tablet laptop with a handheld stylus during two separate conditions (1) while standing and (2) while seated. The order of conditions was counterbalanced across both groups of participants. The tasks were (1) a tracking task, where the stylus tracked a dot in a figure of 8 at 3 speeds, (2) an aiming task where the stylus moved from dot to dot with individual movements creating the outline of a pentagram and (3) a tracing task, where participants had to move the stylus along a static pathway or maze. Root mean squared error (RMSE), movement time and path accuracy, respectively, were used to quantify the effect that postural condition had on manual control. Overall adults were quicker and more accurate than children when performing all 3 tasks, and where the task speed was manipulated accuracy was better at slower speeds for all participants. Surprisingly, children performed these tasks more quickly and more accurately when standing compared to when sitting. In conclusion, standing at a desk while performing goal directed tasks did not detrimentally affect children's manual control, and moreover offered a benefit. PMID- 27477707 TI - Disturbances of automatic gait control mechanisms in higher level gait disorder. AB - The underlying mechanisms responsible for the gait changes in frontal gait disorder (FGD), a form of higher level gait disorders, are poorly understood. We investigated the relationship between stride length and cadence (SLCrel) in people with FGD (n=15) in comparison to healthy older adults (n=21) to improve our understanding of the changes to gait in FGD. Gait data was captured using an electronic walkway system as participants walked at five self-selected speed conditions: preferred, very slow, slow, fast and very fast. Linear regression was used to determine the strength of the relationship (R(2)), slope and intercept. In the FGD group 9 participants had a strong SLCrel (linear group) (R(2)>0.8) and 6 a weak relationship (R(2)<0.8) (nonlinear group). The linear FGD group did not differ to healthy control for slope (p>0.05) but did have a lower intercept (p<0.001). The linear FGD group modulated gait speed by adjusting stride length and cadence similar to controls whereas the nonlinear FGD participants adjusted stride length but not cadence similar to controls. The non-linear FGD group had greater disturbance to their gait, poorer postural control and greater fear of falling compared to the linear FGD group. Investigation of the SLCrel resulted in new insights into the underlying mechanisms responsible for the gait changes found in FGD. The findings suggest stride length regulation was disrupted in milder FGD but as the disorder worsened, cadence control also became disordered resulting in a break down in the relationship between stride length and cadence. PMID- 27477708 TI - Effects of running-induced fatigue on plantar pressure distribution in novice runners with different foot types. AB - This study aimed to assess the effects of running-induced fatigue on plantar pressure parameters in novice runners with low and high medial longitudinal arch. Plantar pressure data from 42 novice runners (21 with high, and 21 with low arch) were collected before and after running-induced fatigue protocol during running at 3.3m/s along the Footscan((r)) platform. Peak plantar pressure, peak force and force-time integral (impulse) were measured in ten anatomical zones. Relative time for foot roll-over phases and medio-lateral force ratio were calculated before and after the fatigue protocol. After the fatigue protocol, increases in the peak pressure under the first-third metatarsal zones and reduction under the fourth-fifth metatarsal regions were observed in the low arch individuals. In the high arch group, increases in peak pressure under the fourth-fifth metatarsal zones after the running-induced fatigue was observed. It could be concluded that running-induced fatigue had different effects on plantar pressure distribution pattern among novice runners with low and high medial longitudinal foot arch. These findings could provide some information related to several running injuries among individuals with different foot types. PMID- 27477709 TI - Active vision task and postural control in healthy, young adults: Synergy and probably not duality. AB - In upright stance, individuals sway continuously and the sway pattern in dual tasks (e.g., a cognitive task performed in upright stance) differs significantly from that observed during the control quiet stance task. The cognitive approach has generated models (limited attentional resources, U-shaped nonlinear interaction) to explain such patterns based on competitive sharing of attentional resources. The objective of the current manuscript was to review these cognitive models in the specific context of visual tasks involving gaze shifts toward precise targets (here called active vision tasks). The selection excluded the effects of early and late stages of life or disease, external perturbations, active vision tasks requiring head and body motions and the combination of two tasks performed together (e.g., a visual task in addition to a computation in one's head). The selection included studies performed by healthy, young adults with control and active - difficult - vision tasks. Over 174 studies found in Pubmed and Mendeley databases, nine were selected. In these studies, young adults exhibited significantly lower amplitude of body displacement (center of pressure and/or body marker) under active vision tasks than under the control task. Furthermore, the more difficult the active vision tasks were, the better the postural control was. This underscores that postural control during active vision tasks may rely on synergistic relations between the postural and visual systems rather than on competitive or dual relations. In contrast, in the control task, there would not be any synergistic or competitive relations. PMID- 27477710 TI - A simplified marker set to define the center of mass for stability analysis in dynamic situations. AB - The extrapolated center of mass (XCoM), a valuable tool to assess balance stability, involves defining the whole body center of mass (CoMWB). However, accurate three-dimensional estimation of the CoMWB is time consuming, a severe limitation in certain applications. In this study, twenty-four subjects (young and elderly, male and female) performed three different balance tasks: quiet standing, gait and balance recovery. Three different models, based on a segmental method, were used to estimate the three-dimensional CoMWB absolute position during these movements: a reference model based on 38 markers, a simplified 13 marker model and a single marker (sacral) model. CoMWB and XCoM estimations from the proposed simplified model came closer to the reference model than estimations from the sacral marker model. It remained accurate for dynamic tasks, where the sacral marker model proved inappropriate. The simplified model proposed here yields accurate three-dimensional estimation of both the CoMWB and the XCoM with a limited number of markers. Importantly, using this model would reduce the experimental and post-processing times for future balance studies assessing dynamic stability in humans. PMID- 27477711 TI - Muscle co-contraction during gait in individuals with articular cartilage defects in the knee. AB - Increased muscle co-contraction during gait is common in individuals with knee pathology, and worrisome as it is known to amplify tibiofemoral compressive forces. While knees with articular cartilage defects (ACD) are more vulnerable to compressive forces, muscle co-contraction has never been reported in this population. The purpose of this study was to evaluate the extent to which individuals with ACDs in the knee demonstrate elevated quadriceps to hamstrings muscle co-contraction on the involved limb during gait compared to the uninvolved limb and to healthy controls. We also explored the impact of participant characteristics and knee impairments on co-contraction. Twenty-nine individuals with full-thickness knee ACDs (ACD group) and 19 healthy adults (control group) participated in this study. Participants performed five gait trials at self selected speed, during which activity of the quadriceps and hamstrings muscles were collected with surface electromyography. Three-dimensional motion capture was used to define phases of gait. Quadriceps strength and self-reported outcomes were also assessed in the same session. There were no differences in quadriceps: hamstrings co-contraction between the ACD and control groups, or between the involved and uninvolved limb for the ACD group. For both ACD and control groups, co-contraction was highest in early stance and lowest in late stance. Quadriceps strength was consistently the strongest predictor of muscle co-contraction in both the ACD and the control groups, with individuals with lower strength demonstrating greater co-contraction. Further study is needed to understand the effect of increased muscle co-contraction on joint compressive forces in the presence of varied quadriceps strength. PMID- 27477712 TI - Vision, visuo-cognition and postural control in Parkinson's disease: An associative pilot study. AB - INTRODUCTION: Impaired postural control (PC) is common in patients with Parkinson's disease (PD) and is a major contributor to falls, with significant consequences. Mechanisms underpinning PC are complex and include motor and non motor features. Research has focused predominantly on motor and sensory inputs. Vision and visuo-cognitive function are also integral to PC but have largely been ignored to date. The aim of this observational cross-sectional pilot study was to explore the relationship of vision and visuo-cognition with PC in PD. METHODS: Twelve people with PD and ten age-matched healthy controls (HC) underwent detailed assessments for vision, visuo-cognition and postural control. Vision assessments included visual acuity and contrast sensitivity. Visuo-cognition was measured by visuo-perception (object identification), visuo-construction (ability to copy a figure) and visuo-spatial ability (judge distances and location of object within environment). PC was measured by an accelerometer for a range of outcomes during a 2-min static stance. Spearman's correlations identified significant associations. RESULTS: Contrast sensitivity, visuo-spatial ability and postural control (ellipsis) were significantly impaired in PD (p=0.017; p=0.001; and p=0.017, respectively). For PD only, significant correlations were found for higher visuo-spatial function and larger ellipsis (r=0.64; p=0.024) and impaired attention and reduced visuo-spatial function (r=-0.62; p=0.028). CONCLUSIONS: Visuo-spatial ability is associated with PC deficit in PD, but in an unexpected direction. This suggests a non-linear pattern of response. Further research is required to examine this novel and important finding. PMID- 27477713 TI - Directional acuity of whole-body perturbations during standing balance. AB - The ability to perceive the direction of whole-body motion during standing may be critical to maintaining balance and preventing a fall. Our first goal was to quantify kinesthetic perception of whole-body motion by estimating directional acuity thresholds of support-surface perturbations during standing. The directional acuity threshold to lateral deviations in backward support-surface motion in healthy, young adults was quantified as 9.5+/-2.4 degrees using the psychometric method (n=25 subjects). However, inherent limitations in the psychometric method, such as a large number of required trials and the predetermined stimulus set, may preclude wider use of this method in clinical populations. Our second goal was to validate an adaptive algorithm known as parameter estimation by sequential testing (PEST) as an alternative threshold estimation technique to minimize the required trial count without predetermined knowledge of the relevant stimulus space. The directional acuity threshold was estimated at 11.7+/-3.8 degrees from the PEST method (n=11 of 25 subjects, psychometric threshold=10.1+/-3.1 degrees ) using only one-third the number of trials compared to the psychometric method. Furthermore, PEST estimates of the direction acuity threshold were highly correlated with the psychometric estimates across subjects (r=0.93) suggesting that both methods provide comparable estimates of the perceptual threshold. Computational modeling of both techniques revealed similar variance in the estimated thresholds across simulations of about 1 degrees . Our results suggest that the PEST algorithm can be used to more quickly quantify whole-body directional acuity during standing in individuals with balance impairments. PMID- 27477714 TI - An evaluation of 3D head pose estimation using the Microsoft Kinect v2. AB - The Kinect v2 sensor supports real-time non-invasive 3D head pose estimation. Because the sensor is small, widely available and relatively cheap it has great potential as a tool for groups interested in measuring head posture. In this paper we compare the Kinect's head pose estimates with a marker-based record of ground truth in order to establish its accuracy. During movement of the head and neck alone (with static torso), we find average errors in absolute yaw, pitch and roll angles of 2.0+/-1.2 degrees , 7.3+/-3.2 degrees and 2.6+/-0.7 degrees , and in rotations relative to the rest pose of 1.4+/-0.5 degrees , 2.1+/-0.4 degrees and 2.0+/-0.8 degrees . Larger head rotations where it becomes difficult to see facial features can cause estimation to fail (10.2+/-6.1% of all poses in our static torso range of motion tests) but we found no significant changes in performance with the participant standing further away from Kinect - additionally enabling full-body pose estimation - or without performing face shape calibration, something which is not always possible for younger or disabled participants. Where facial features remain visible, the sensor has applications in the non-invasive assessment of postural control, e.g. during a programme of physical therapy. In particular, a multi-Kinect setup covering the full range of head (and body) movement would appear to be a promising way forward. PMID- 27477715 TI - Effects of mid-foot contact area ratio on lower body kinetics/kinematics in sagittal plane during stair descent in women. AB - The mid-foot contact area relative to the total foot contact area can facilitate foot arch structure evaluation. A stair descent motion consistently provides initial fore-foot contact and utilizes the foot arch more actively for energy absorption. The purpose of this study was to compare ankle and knee joint angle, moment, and work in sagittal plane during stair descending between low and high Mid-Foot-Contact-Area (MFCA) ratio group. The twenty-two female subjects were tested and classified into two groups (high MFCA and low MFCA) using their static MFCA ratios. The ground reaction force (GRF) and kinematics of ankle and knee joints were measured while stair descending. During the period between initial contact and the first peak in vertical GRF (early absorption phase), ankle negative work for the low MFCA ratio group was 33% higher than that for the high MFCA ratio group (p<0.05). However, ankle negative work was not significantly different between the two groups during the period between initial contact and peak dorsiflexion angle (early absorption phase+late absorption phase). The peak ankle dorsiflexion angle was smaller in the low MFCA ratio group (p<0.05). Our results suggest that strategy of energy absorption at the ankle and foot differs depending upon foot arch types classified by MFCA. The low MFCA ratio group seemed to absorb more impact energy using strain in the planar fascia during early absorption phase, whereas the high MFCA ratio group absorbed more impact energy using increased dorsiflexion during late absorption phase. PMID- 27477716 TI - Cognitive loading-induced sway alterations are similar in those with chronic ankle instability and uninjured controls. AB - Performing a cognitive task while balancing can result in either increased or decreased sway depending on the nature of the cognitive task, and is commonly used in pathologic populations to evaluate postural performance. A total of 39 participants were recruited into two groups: uninjured controls (n=20, age: 21.9+/-2.1 years, height: 175.0+/-11.2cm, mass: 71.3+/-14.9kg) and chronic ankle instability (n=19, age: 22.1+/-5.6 years, height: 169.7+/-7.7cm, mass: 72.9+/ 17.3kg). Participants were asked to perform one of three cognitive tasks while maintaining single limb balance. Cognitive tasks included backwards counting by 3 (BC), the manikin test (MAN), and random number generation (RNG). Time-to boundary minima, mean, and standard deviations were calculated and compared between groups as pre to post change scores. Effect sizes and 95% confidence intervals were also calculated to test for group differences and the effect of task performance on sway. No significant main effects of Group or Group by Task interactions were identified (p>0.05). However, a significant multivariate main effect of Task was identified in BC (p=0.001, F(6, 32)=4.804) and RNG (p<0.001, F(6, 32)=6.233) but not for MAN (p=0.117). The results suggest that those with chronic ankle instability and uninjured controls have similar postural suprapostural interactions across multiple cognitive task domains. Both the BC and RNG tasks resulted in less sway for all participants. Our results suggest that dual-task interference in the CAI population may not be present as previous research would suggest. PMID- 27477717 TI - Control conditions for footwear insole and orthotic research. AB - Footwear insoles/orthotics alter variables associated with musculoskeletal injury; however, their clinical effectiveness is inconclusive. One explanation for this is the possibility that control conditions may actually produce biomechanical changes that induce clinical responses. The purpose of this study was to compare insole/orthotic control conditions to identify if variables at the ground, ankle and knee that are associated with injury are altered relative to what participants would normally experience in their own shoes. Gait analysis was performed on 15 participants during walking and running while wearing (1) their own shoes, (2) #1 with a 3mm flat insole, (3) a standardized shoe, and (4) #3 with a 3mm flat insole, where external knee adduction moments, external knee adduction angular impulses, internal ankle inversion moments, and vertical ground reaction force loading rates were determined. Conditions 2-4 were expressed as percent changes relative to condition 1, and tests of proportions assessed if there were a significant number of individuals experiencing a biomechanically relevant change for each variable. Repeated-measures ANOVAs were used to identify group differences between conditions. The majority of movement-footwear-variable combinations contained a proportion of individuals experiencing biomechanically relevant changes compared to condition 1 that was significantly greater than the expected proportion of 20%. No systematic differences were found between conditions. This suggests that conditions 2-4 may alter biomechanics relative to baseline for many participants, but not in a consistent way across participants. It is recommended that participant's own footwear be used as control conditions in future trials where biomechanics are primary variables of interest. PMID- 27477718 TI - Accuracy and reliability of the RGB-D camera for measuring walking speed on a treadmill. AB - AIM: RGB-D cameras (Red Green Blue+Depth) are widely employed in exergames designed to physically stimulate elderly people. Nevertheless, the intensity of the physical activity reached with the existing solutions is rarely sufficient to obtain a real impact on the physical fitness and thus on the health status of this population. In this context, a Point Cloud Based System (PCBS) has been developed to interface ordinary motorized treadmills with exergames through a simple RGB-D camera, to induce players to perform physical activities at higher intensities. The goal of this study was to assess the accuracy and reliability of PCBS to measure the walking speed of a subject on a standard motorized treadmill based on the image streams of an RGB-D camera. METHODS: 36 participants performed three 10min walking exercises, divided in 5 blocks of 2min at the following constant ordered speeds: 0.42, 0.69, 0.97, 1.25 and 1.53ms(-1). The measured walking speeds are compared to those obtained through a Marker Based Control System (MBCS). RESULTS: Results showed a high system accuracy (bias: 0.013+/ 0.015ms(-1)), a good reliability (ICC=0.63-0.91) and a low variability (SEM=1-5%; MD=2.7-14%). DISCUSSION: Accuracy and reliability of PCBS are consistent with those obtained in similar existing systems measuring gait parameters. CONCLUSION: Within the context of the development of exergames, PCBS may be combined with exergames to perform physical activities at sufficiently high intensities in the elderly population, in order to improve their physical health and possibly prevent/delay cognitive impairment. PMID- 27477719 TI - Development of Magnetic Resonance Based Functional Imaging Techniques Heading Up to Theranostics ~Creating Next Generation Functional Contrast Agents~. PMID- 27477720 TI - Development of Magnetic Resonance-based Functional Imaging: The Past, the Present, and the Future. AB - The term "theranostics" is a compound word combining "therapeutics" and "diagnostics". Discovery of the X-ray made an extraordinary contribution to the field of medical science. Development of computer science after World War II has been absolutely imperative for the development of medical imaging technology to date. The invention of X-ray computed tomography (CT) has revolutionized medical image diagnostic systems. Several functional imaging modalities emerged not only in the radiological field but also in magnetic resonance and ultrasonic fields. The fusion of three digital imaging techniques, MR Redox imaging, electron paramagnetic resonance (EPR) oxygen mapping, and hyperpolarized (13)C MRI techniques in the magnetic resonance field, contribute to the newly-termed theranostics. Future development of a suitable contrast agent for each imaging modality will be a key for the success of theranositics. PMID- 27477721 TI - Evaluation of Brain Redox Status and Its Association with Cognitive Dysfunction in Diabetic Animal Models by Redox Molecular Imaging (ReMI). AB - Oxidative stress contributes to the development of diabetic complications. Increasing epidemiologic evidence suggests that diabetes mellitus is associated with dementia and cognitive decline. However, the underlying mechanisms are not fully understood. We have evaluated brain redox status and its association of cognitive dysfunction in diabetic animal models by dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) and other oxidative stress markers. In this review, we discuss the role of oxidative stress in the development of diabetes related dementia and clinical regulation of the redox state in new approaches to augmenting diabetes-related dementia. PMID- 27477722 TI - Nano-theranostics and Nitroxyl Radical-labeled Antitumor Agents for Magnetic Resonance Imaging. AB - The advent of functional contrast agents and nanoparticle drug delivery systems (nano-DDS) is opening new pathways to understanding pathophysiology using magnetic resonance imaging (MRI). Nitroxyl radical compounds are promising functional contrast agents for redox evaluation. We have developed a novel nitroxyl radical theranostic compound for noninvasive real-time imaging of blood brain barrier-permeable antitumor drugs. Divalent manganese ions (Mn(2+)) can also be used as an intracellular functional MRI contrast agent. Manganese enhanced MRI (MEMRI) provides a unique opportunity to study neuronal activation and architecture. Extracellular Mn(2+) can enter cells through NMDA receptors for glutamate and/or voltage-gated calcium channels. Thus, Mn(2+) can behave as a functional contrast agent depending on the cellular activity/viability. This paper summarizes the recent progress in MEMRI for neuroimaging and cancer research. Nanocarriers for DDS can contain multiple functional elements, such as therapeutic drugs, MRI contrast agents, fluorescent dyes, and radioisotopes, without significant changes in the particle kinetics/dynamics. Various materials have also been reported as nano-DDS carriers, including micelles, liposomes, dendrimers, quantum dots, and carbon materials such as fullerenes, with each material providing a different set of characteristics as a nano-DDS carrier. Our recent research into nano-DDS-based contrast agents and the theranostic applications is also outlined. PMID- 27477723 TI - Development of a Functional Contrast Agent for Targeting Lipid-derived Radicals. AB - Lipid derived radicals and their metabolic products are closely involved in the pathogenesis of oxidative stress diseases, such as inflammation and angiogenesis, through the formation of a protein or DNA complex. The starting point of lipid peroxide generation is lipid-derived radicals, which increase explosively via radical chain reaction. Therefore, the trapping of lipid-derived radicals is useful in understanding the mechanism of the formation of oxidative stress diseases, and in suppressing the following chain reaction. On the other hand, nitroxides with a stable unpaired electron allow for spin trapping with carbon centered radicals. Hence, we focused on the following points to develop lipid radical detection methods. 1) Fluorescence will be quenched through interaction with nitroxide's unpaired electron. 2) Nitroxide can react with lipid-derived radicals via radical-radical reaction. 3) Fluorescence will recover from the loss of an unpaired electron in nitroxide, after reaction with the lipid-derived radicals, by using a profluorescent nitroxide. In this paper, I will discuss the development of a lipid-derived detection method using profluorescent nitroxide switching methods, and discuss its application to cell imaging. PMID- 27477724 TI - Prediction of Cancer Treatment Response by Physiologic and Metabolic Imaging. AB - Tumors develop a characteristic microenvironment depending on their specific genetic mutations. The direct products of mutant genes and the resulting microenvironmental changes provoke metabolic changes in the tumor. If noninvasive imaging techniques including magnetic resonance imaging (MRI) could be used to detect such microenvironmental and metabolic changes in tumors, we might be able to provide more effective treatment strategies for individual tumors in patients. In addition to conventional imaging techniques, this review article introduces quantitative 3D oxygen imaging using electron paramagnetic resonance imaging (EPRI) and hyperpolarized (13)C metabolic MRI and shows how these imaging techniques can help to monitor and predict tumor response to various treatments including radiation therapy and antiangiogenic agents. Hyperpolarization is a method for enhancing the MRI signal of (13)C in a molecule by 10000-fold, which makes it possible to trace the metabolic reaction of externally administered molecules in the body noninvasively. For example, a precise cancer diagnosis can be made in a 3-min scan with a [1-(13)C] pyruvate as a metabolic tracer. The first clinical trial on the use of hyperpolarized (13)C MRI in patients with prostate cancer was conducted at the University of California San Francisco (UCSF), and we plan to start the second clinical trial on this technique in the near future. PMID- 27477725 TI - Development of Redox Metabolic Imaging Using Endogenous Molecules. AB - Redox metabolism plays a central role in maintaining homeostasis in living organisms. The electron transfer system in mitochondria produces ATP via endogenous redox molecules such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), and coenzyme Q10 (CoQ10), which have flavin or quinone moieties. One-electron transfer reactions convert FMN, FAD, and CoQ10 to the free radical intermediates FMNH and FADH, and CoQ10H, respectively. Dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) allows us to visualize free radicals in vitro and in vivo. We present a spectroscopic imaging technology with DNP-MRI, which enables the imaging of multiple free radical intermediates such as FADH and CoQH. DNP-MRI can also identify various endogenous free radical intermediates derived from redox transformations. PMID- 27477726 TI - Collaborative Approach to Heart Failure Care. PMID- 27477727 TI - Team Medicine for CHF Treatment. AB - The mortality associated with end stage heart failure (HF) is high, despite the development of new and increasingly effective drugs and non-pharmacological therapies. Repetitive hospitalizations predict fatal outcomes, and each hospitalization should prompt individual conversations with the patient, the family and the caregivers. A multidisciplinary disease management program promotes the education of patients and their families, and modifies their behaviour, with a view to ultimately improving the prognosis and quality of life. Beginning with the earliest stages of HF, on through the late stages, a multidisciplinary disease management program should be implemented. PMID- 27477728 TI - Roles of Cardiology Pharmacists. AB - Inpatients with heart failure take a number of high-risk drugs such as anti thrombotic and anti-arrhythmic drugs, in addition to other drug types, including diuretics and cardioprotective agents. Pharmacists should support the pharmacological management of these patients by evaluating their clinical condition and laboratory data, due to the frequency of renal failure. Furthermore, it is known that poor adherence to a drug regimen is one of the aggravating factors for heart failure. It is necessary to conduct regular patient education to facilitate early hospital discharge and to prevent the recurrence of heart failure. In Chiba University Hospital, a single pharmacist is in charge of both the cardiac care unit (CCU) and the cardiovascular ward. In the course of a patient's hospital stay, from admission to discharge, the pharmacist performs various duties such as evaluating and proposing a medication plan after checking the patient's regular medications, conducting patient education, promoting appropriate prescriptions, overseeing the preparation of injection drugs, and providing drug information to medical staff. There are many cases in which avoidance of drug interactions or overdose, in order to prevent renal failure, is needed. Thus, pharmacists play important roles in the management of patients with heart failure by ensuring the efficacy and safety of each patient's drug therapy. PMID- 27477729 TI - Role of the Pharmacist within the Heart Failure Team. AB - Hyogo Prefectural Amagasaki General Medical Center has formed a heart failure team. Here, I report on the role of the pharmacist in this heart failure team at this hospital. Patient education is one of the roles of the pharmacist. It is the pharmacist's responsibility to improve medication adherence among patients. For this purpose, the pharmacist uses a brochure created by the heart failure team. The brochure outlines drug information in an easy-to-understand manner. The roles of a pharmacist were addressed in a lecture presented to the heart failure team. These lectures helped improve the pharmaceutical knowledge of the team, allowing the team to prescribe medicines more safely and appropriately. Maintaining co operation between hospital and community pharmacies is another important role of a hospital pharmacist. This allows patients to be properly educated by pharmacists even after discharge from the hospital. PMID- 27477730 TI - Roles of Nurses in Home Medical Care. AB - Some patients of advanced age with heart failure (HF) require repeated hospital care. In an aging society, the importance of medical and social care support systems for patients with HF further increases. In Onomichi-city, a comprehensive community care system has been in place since its introduction in 1997. The system is called "Onomichi Type". This is an interprofessional care system in which a variety of healthcare professionals, with common basic knowledge of disease prevention, treatment and welfare, collaborate with other care professionals. These professionals gain shared knowledge in regard to care management, and fulfill their respective roles at Care Conferences held during a patient's hospital stay. Elderly patients also often have multiple comorbidities and take a lot of medicines. Some patients might forget to take their medicine, whereas others might take an overdose. Thus, sharing a patient's complete medical information with pharmacists is also necessary. We began to collaborate with pharmacists in hospitals and at pharmacies in 2014. The pharmacist plays a great role in providing comprehensive community medical care. PMID- 27477731 TI - Home Medical Care for Heart Failure. AB - As heart failure progresses to the end stage, it becomes more difficult to maintain the same level of quality of life using the established therapy for the heart failure patients. We believe that an innovative home medical care for heart failure therapy that focuses on the individual's quality of daily living and early intervention is necessary. The roles of home medical care include: early discharge to home as opposed to long hospitalization; the prevention of re hospitalization; the provision of good care; treatment of any exacerbations; and options available at the end of the patient's life at home. Being able to provide all of the above will allow heart failure patients to live at their home. Home medical care for heart failure requires collaborative teamwork among multiple institutions and medical professionals. Among this collaborative group, the role of pharmacists is critical. Since many of the elderly with heart failure are taking multiple medications, it is important to evaluate the compliance and to intervene for improvement. Pharmacists visiting the patient's home will be able to check the patient's living environment, to evaluate medication compliance, to reconsider the necessary medications for the specific patient, and to consult physicians. Pharmacists can also explain clearly to patients and their family members any changes in medical therapy, as the conditions for an end-stage heart failure patient may change drastically in a short time. By achieving all of the above, it may be possible to prevent re-hospitalization and to help maintain the quality of life for heart failure patients. PMID- 27477732 TI - Team-based Medical Care for Cardiac Failure-The Pharmacist's Expected Role. AB - The pharmacist's role in home care is increasingly important. We are required to collaborate with multiple other professions. As home care pharmaceutical managers, pharmacists verify the timeline of side effects and the onset of expected effects. It is also important to verify all prescriptions from the pharmaceutical viewpoint, and to point out potential negative interactions or consequences of each prescribed medication, suggesting changes or dosage reduction in drugs as appropriate. Additionally, we verify the cause of unused drugs (i.e. patient non-compliance) and take action. As an effort to provide quality home care, pharmacists share information with other professions for collaborative management of a patient's needs. We act as a bridge between related government, agencies and citizens, assisting in creating a healthy lifestyle for the residents of our community. The days when pharmacists just sit in their pharmacies and dispense drugs are gone. Therefore, we need to collaborate more with medical, nursing care, and governmental professionals in our communities. PMID- 27477733 TI - A New Horizon in Vitamin K Research. AB - Vitamin K is a cofactor for gamma-glutamyl carboxylase, which catalyzes the posttranslational conversion of specific glutamyl residues to gamma carboxyglutamyl residues in a variety of vitamin K-dependent proteins (VKDPs) involved in blood coagulation, bone and cartilage metabolism, signal transduction, and cell proliferation. Despite the great advances in the genetic, structural, and functional studies of VKDPs as well as the enzymes identified as part of the vitamin K cycle which enable it to be repeatedly recycled within the cells, little is known of the identity and roles of key regulators of vitamin K metabolism in mammals and humans. This review focuses on new insights into the molecular mechanisms underlying the intestinal absorption and in vivo tissue conversion of vitamin K1 to menaquinone-4 (MK-4) with special emphasis on two major advances in the studies of intestinal vitamin K transporters in enterocytes and a tissue MK-4 biosynthetic enzyme UbiA prenyltransferase domain-containing protein 1 (UBIAD1), which participates in the in vivo conversion of a fraction of dietary vitamin K1 to MK-4 in mammals and humans, although it remains uncertain whether UBIAD1 functions as a key regulator of intracellular cholesterol metabolism, bladder and prostate tumor cell progression, vascular integrity, and protection from oxidative stress. PMID- 27477734 TI - Effects of Food Thickeners on the Inhibitory Effect of Voglibose Oral disintegrating Tablets on Post-prandial Elevation of Blood Sugar Levels. AB - The aim of this study was to examine the effects of food thickeners on the pharmacodynamics of voglibose, an alpha-glucosidase inhibitor. The pharmacodynamics of voglibose were examined in an open-label study in 9 healthy participants after the ingestion of a single oral dose of a voglibose oral disintegrating tablet, with and without food thickener immersion. The area under the incremental blood sugar concentration-time curve was larger and the rate of increments in the blood sugar concentration was higher with the voglibose oral disintegrating tablets immersed in the food thickener than with the tablets that were not immersed. Immersing the voglibose oral-disintegrating tablets in the food thickener possibly delayed their disintegration rate. This suggests that commercially available food thickeners may be associated with changes in the disintegration of voglibose oral-disintegrating tablets and should therefore be used carefully in certain clinical situations. PMID- 27477736 TI - Clarification of the Relationship between Awareness of Doping of Competitive Sports Coaches and Their Instructions to Prevent Doping. AB - It has been 6 years since the establishment of the position of "sports pharmacist" as one type of pharmacist. In the sporting world of Japan, sports pharmacists are expected to promote athletes' awareness of antidoping regulations and provide them with relevant education. However, currently, these pharmacists' main duty is to provide athletes and their coaches with guidance on medication. Using a model for the prediction of athletes' actions, we have worked to promote athletes' awareness of antidoping regulations and encourage sports pharmacists to perform relevant activities, such as antidoping education. As a result, we clarified that athletes' awareness regarding antidoping rules influences their actions when experiencing minor illnesses. In addition, we have proposed approaches to encourage athletes to undertake antidoping activities. The present study aimed to clarify competitive sports coaches' awareness of antidoping regulations, the instructions that those coaches give athletes when they experience minor illnesses, and coaches' awareness of athletes' usage of drugs and supplements. Analysis using a model for the prediction of actions revealed that to promote coaches' awareness of antidoping regulations, education aimed at raising their level of knowledge of doping is warranted. Furthermore, coaches were aware of the necessity of continuously providing athletes with antidoping instructions, but they did not keep sufficient track of athletes' usage of drugs and supplements. To encourage sports coaches to perform antidoping activities, it is effective to provide them with opportunities to develop their knowledge of doping prevention in their areas. PMID- 27477735 TI - Correlations between Plasma Levels of Anionic Uremic Toxins and Clinical Parameters in Hemodialysis Patients. AB - When the kidney is seriously impaired, various uremic toxins (UTs) accumulate in the body, often exerting unfavorable effects on physiological functions and drug pharmacokinetics. To prevent this, it is important to determine plasma UT levels accurately in chronic kidney disease patients. Although attempts to predict plasma UT levels using biomarkers have been made, the correlation between UT levels and the markers is not yet fully understood. In this study, we assessed the correlations among plasma levels of indoxyl sulfate (IS), indoleacetic acid (IA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) in 20 hemodialysis patients and evaluated the relationship between the plasma levels of UTs and clinical parameters, such as serum creatinine (Scr), blood urea nitrogen, and estimated glomerular filtration rate (eGFR), with special focus on IS. There were no correlations among the plasma levels of the three UTs before and immediately after hemodialysis. However, a significant correlation was observed between plasma IS levels and Scr before hemodialysis (r=0.643, p=0.002), with the correlation becoming much stronger when using the data obtained immediately after hemodialysis (r=0.744, p<0.001). Further, plasma IS levels showed a significant negative correlation with eGFR (r=-0.558, p=0.011). However, no correlations were observed for IA or CMPF. The results obtained from this study suggest that plasma IS levels can be predicted from Scr values, although the precise mechanism behind the correlation remains to be clarified. PMID- 27477737 TI - Recent developments in transition metal catalysis for quinazolinone synthesis. AB - Quinazolinones are an important class of heteroaromatic compound, and they are prevalent in a variety of important bio-active scaffolds. Traditionally, their synthesis has been achieved via classical condensation procedures, however over recent years catalytic methodologies have emerged as effective alternatives. This review examines recent developments in the employment of catalytic approaches towards this highly important heterocyclic motif. PMID- 27477738 TI - The effect of mountain bike wheel size on cross-country performance. AB - The purpose of this study was to determine the influence of different wheel size diameters on indicators of cross-country mountain bike time trial performance. Nine competitive male mountain bikers (age 34.7 +/- 10.7 years; stature 177.7 +/- 5.6 cm; body mass 73.2 +/- 8.6 kg) performed 1 lap of a 3.48 km mountain bike (MTB) course as fast as possible on 26", 27.5" and 29" wheeled MTB. Time (s), mean power (W), cadence (revs . min-1) and velocity (km . h-1) were recorded for the whole lap and during ascent and descent sections. One-way repeated measure ANOVA was used to determine significant differences. Results revealed no significant main effects for any variables by wheel size during all trials, with the exception of cadence during the descent (F(2, 16) = 8.96; P = .002; P2 = .53). Post hoc comparisons revealed differences lay between the 26" and 29" wheels (P = .02). The findings indicate that wheel size does not significantly influence performance during cross-country when ridden by trained mountain bikers, and that wheel choice is likely due to personal choice or sponsorship commitments. PMID- 27477739 TI - Generation of Perfluoroalkyl Acids from Aerobic Biotransformation of Quaternary Ammonium Polyfluoroalkyl Surfactants. AB - The aerobic biotransformation over 180 days of two cationic quaternary ammonium compounds (QACs) with perfluoroalkyl chains was determined in soil microcosms, and biotransformation pathways were proposed. This is the first time that polyfluoroalkyl cationic surfactants used in aqueous film-forming foam (AFFF) formulations were studied for their environmental fate. The biotransformation of perfluorooctaneamido quaternary ammonium salt (PFOAAmS) was characterized by a DT50 value (time necessary to consume half of the initial mass) of 142 days and significant generation of perfluoroalkyl carboxylic acid (PFOA) at a yield of 30 mol % by day 180. The biotransformation of perfluorooctane sulfonamide quaternary ammonium salt (PFOSAmS) was very slow with unobservable change of the spiked mass; yet the generation of perfluorooctanesulfonate (PFOS) at a yield of 0.3 mol % confirmed the biotransformation of PFOSAmS. Three novel biotransformation intermediates were identified for PFOAAmS and three products including perfluorooctane sulfonamide (FOSA) for PFOSAmS through high-resolution mass spectrometry (MS) analysis and t-MS(2) fragmentation. The significantly slower PFOSAmS biotransformation is hypothesized to be due to its stronger sorption to soil owing to a longer perfluoroalkyl chain and a bulkier sulfonyl group, when compared to PFOAAmS. This study has demonstrated that despite overall high stability of QACs and their biocide nature, the ones with perfluoroalkyl chains can be substantially biotransformed into perfluoroalkyl acids in aerobic soil. PMID- 27477740 TI - 13 C-metabolic flux analysis of human adenovirus infection: Implications for viral vector production. AB - Adenoviruses are human pathogens increasingly used as gene therapy and vaccination vectors. However, their impact on cell metabolism is poorly characterized. We performed carbon labeling experiments with [1,2-13 C]glucose or [U-13 C]glutamine to evaluate metabolic alterations in the amniocyte-derived, E1 transformed 1G3 cell line during production of a human adenovirus type 5 vector (AdV5). Nonstationary 13 C-metabolic flux analysis revealed increased fluxes of glycolysis (17%) and markedly PPP (over fourfold) and cytosolic AcCoA formation (nearly twofold) following infection of growing cells. Interestingly, infection of growth-arrested cells increased overall carbon flow even more, including glutamine anaplerosis and TCA cycle activity (both over 1.5-fold), but was unable to stimulate the PPP and was associated with a steep drop in AdV5 replication (almost 80%). Our results underscore the importance of nucleic and fatty acid biosynthesis for adenovirus replication. Overall, we portray a metabolic blueprint of human adenovirus infection, highlighting similarities with other viruses and cancer, and suggest strategies to improve AdV5 production. Biotechnol. Bioeng. 2017;114: 195-207. (c) 2016 Wiley Periodicals, Inc. PMID- 27477760 TI - Growth Mechanism and Luminescent Properties of Amorphous SiOx Structures via Phase Equilibrium in Binary System. AB - Balloon whisk-like and flower-like SiOx tubes with well-dispersed Sn and joining countless SiOx loops together induce intense luminescence characteristics in substrate materials. Our synthetic technique called "direct substrate growth" is based on pre-contamination of the surroundings without the intended catalyst and source powders. The kind of supporting material and pressure of the inlet gases determine a series of differently functionalized tube loops, i.e., the number, length, thickness, and cylindrical profile. SiOx tube loops commonly twist and split to best suppress the total energy. Photoluminescence and confocal laser measurements based on quantum confinement effect of the embedded Sn nanoparticles in the SiOx tube found substantially intense emissions throughout the visible range. These new concepts related to the synthetic approach, pre-pollution, transitional morphology, and permeable nanoparticles should facilitate progress in nanoscience with regard to tuning the dimensions of micro-/nanostructure preparations and the functionalization of customized applications. PMID- 27477761 TI - The relationship between the positions of the left ventricular papillary muscles and the direction of the QRS axis. PMID- 27477763 TI - Call for papers: The development of mathematical cognition. PMID- 27477762 TI - The ability of mitral papillary muscle positions to explain QRS complex characteristics in humans. AB - Anatomical location of the conduction system may influence the characteristics of the depolarization and thus characteristics of the QRS complex. It is known that in the heart, there are electro-anatomical relationships, such as relationships among the molecular, genetic and anatomic components of the conduction system and papillary muscles. This review aims to discuss how knowledge of the electro anatomical developmental relationships helps in understanding the known variability to be observed in the human electrocardiograms. PMID- 27477764 TI - Clinical Response with intralesional Amphotericin B in the treatment of old world cutaneous leishmaniasis: a preliminary report. AB - Cutaneous leishmaniasis (CL) is a vector-borne tropical disease caused by a heterogeneous group of protozoan parasites that belong to the genus Leishmania. With an annual incidence of 1.5 million new cases, CL is a global health concern mainly in developing countries. The treatment options for CL are numerous but none is optimal. Pentavalent antimonials despite their side effects remain the preferred choice since decades. Alternate new treatment options are being explored to expand the therapeutic armamentarium of CL. In this study, we intend to describe our therapeutic experience with intralesional amphotericin B in the treatment of CL in a series of Indian patients, hitherto not commonly used in old world CL (OWCL). We also endeavour to review the literature on the use of amphotericin B in OWCL. Five consecutive patients diagnosed with cutaneous leishmansis at the out-patient department of Dermatology, Government Medical College, Jammu were treated with weekly injections of intralesional amphotericin B (2.5 mg/mL). Treatment response was assessed at each visit and the cases were followed up for 6 months. All the five patients responded well to the treatment and remained recurrence-free during follow-up. Intralesional amphotericin B was found to be safe and effective treatment for OWCL. Large randomized control trials need to be conducted to establish its efficacy. PMID- 27477765 TI - To be, or not to be biodegradable... that is the question for the bio-based plastics. AB - Global warming, market and production capacity are being the key drivers for selecting the main players for the next decades in the market of bio-based plastics. The drop-in bio-based polymers such as the bio-based polyethylene terephtalate (PET) or polyethylene (PE), chemically identical to their petrochemical counterparts but having a component of biological origin, are in the top of the list. They are followed by new polymers such as PHA and PLA with a significant market growth rate since 2014 with projections to 2020. Research will provide improved strains designed through synthetic and systems biology approaches; furthermore, the use of low-cost substrates will contribute to the widespread application of these bio- based polymers. The durability of plastics is not considered anymore as a virtue, and interesting bioprospecting strategies to isolate microorganisms for assimilating the recalcitrant plastics will pave the way for in vivo strategies for plastic mineralization. In this context, waste management of bio-based plastic will be one of the most important issues in the near future in terms of the circular economy. There is a clear need for standardized labelling and sorting instructions, which should be regulated in a coordinated way by policymakers and material producers. PMID- 27477766 TI - Heterodimers of heterometallic rings. AB - Nine new complexes are reported involving linked heterometallic rings; one ring is designed as a ligand for the second, and the compounds produced can be regarded as molecular prototypes for implementing quantum gates featuring two subtly different qubits. PMID- 27477768 TI - Nummular Headache Associated With Linear Scleroderma. PMID- 27477767 TI - The endoderm indirectly influences morphogenetic movements of the zebrafish head kidney through the posterior cardinal vein and VegfC. AB - Integration of blood vessels and organ primordia determines organ shape and function. The head kidney in the zebrafish interacts with the dorsal aorta (DA) and the posterior cardinal vein (PCV) to achieve glomerular filtration and definitive hematopoiesis, respectively. How the head kidney co-develops with both the axial artery and vein remains unclear. We found that in endodermless sox32 deficient embryos, the head kidney associated with the PCV but not the DA. Disrupted convergent migration of the PCV and the head kidney in sox32-deficient embryos was rescued in a highly coordinated fashion through the restoration of endodermal cells. Moreover, grafted endodermal cells abutted the host PCV endothelium in the transplantation assay. Interestingly, the severely-disrupted head kidney convergence in the sox32-deficient embryo was suppressed by both the cloche mutation and the knockdown of endothelial genes, indicating that an interaction between the endoderm and the PCV restricts the migration of the head kidney. Furthermore, knockdown of either vegfC or its receptor vegfr3 suppressed the head kidney convergence defect in endodermless embryos and perturbed the head kidney-PCV association in wild-type embryos. Our findings thus underscore a role for PCV and VegfC in patterning the head kidney prior to organ assembly and function. PMID- 27477770 TI - The complement component C5 promotes liver steatosis and inflammation in murine non-alcoholic liver disease model. AB - Non-Alcoholic Fatty Liver Disease (NALD) is considering a hepatic manifestation of metabolic syndrome. Although the pathogenesis of NALD is not completely understood, insulin resistance and inflammatory cytokines are implicated. Considering that component C5 is a central mediator of inflammation, we investigated the role of C5 in the establishment of NALD. Eight to ten-week old B6 C5(+) and A/J C5(-) male mice were fed a high fat diet containing glucose (HFDG) for 6 and 10 weeks. We observed that B6 C5(+) mice HFDG-fed for 10 weeks developed hepatomegaly, triglycerides (TG) accumulation, steatosis and enhanced liver TNF-alpha, IL-6, IL-12p70 and IL-17 levels when compared to A/J C5(-) mice. Next, B6 C5(+) mice were compared with congenic B6 C5(-) mice. Again, B6 C5(+) HFDG-fed mice developed more steatosis, liver centro-lobular inflammation and presented higher levels of liver IL-1beta, IL-12p70, IL-17 and TFG-beta than B6 C5(-) mice under the same conditions. B6 C5(+) mice HFDG-fed also presented lower concentrations of serum albumin, serum cholesterol, blood leukocytes and liver NO production when compared with B6 C5(-) mice. We concluded that murine C5 contributes effectively to liver steatosis and inflammation in NALD pathogenesis. In addition, C5 is also important to control serum cholesterol and albumin levels in the C57BL/6 genetic background. PMID- 27477769 TI - Visual Function of Moderately Hyperopic 4- and 5-Year-Old Children in the Vision in Preschoolers - Hyperopia in Preschoolers Study. AB - PURPOSE: To compare visual performance between emmetropic and uncorrected moderately hyperopic preschool-age children without strabismus or amblyopia. DESIGN: Cross-sectional study. METHODS: setting: Multicenter, institutional. patient or study population: Children aged 4 or 5 years. intervention or observation procedures: Visual functions were classified as normal or reduced for each child based on the 95% confidence interval for emmetropic individuals. Hyperopic (>=3.0 diopters [D] to <=6.0 D in the most hyperopic meridian; astigmatism <=1.50 D; anisometropia <=1.0 D) and emmetropic status were determined by cycloplegic autorefraction. MAIN OUTCOME MEASURES: Uncorrected monocular distance and binocular near visual acuity (VA); accommodative response; and near random dot stereoacuity. RESULTS: Mean (+/- standard deviation) logMAR distance visual acuity (VA) among 248 emmetropic children was better than among 244 hyperopic children for the better (0.05 +/- 0.10 vs 0.14 +/- 0.11, P < .001) and worse eyes (0.10 +/- 0.11 vs 0.19 +/- 0.10, P < .001). Mean binocular logMAR near VA was better in emmetropic than in hyperopic children (0.13 +/- 0.11 vs 0.21 +/- 0.11, P < .001). Mean accommodative response for emmetropic children was lower than for hyperopic subjects for both Monocular Estimation Method (1.03 +/- 0.51 D vs 2.03 +/- 1.03 D, P < .001) and Grand Seiko (0.46 +/- 0.45 D vs 0.99 +/- 1.0 D, P < .001). Median near stereoacuity was better in emmetropic than in than hyperopic children (40 sec arc vs 120 sec arc, P < .001). The average number of reduced visual functions was lower in emmetropic than in hyperopic children (0.19 vs 1.0, P < .001). CONCLUSIONS: VA, accommodative response, and stereoacuity were significantly reduced in moderate uncorrected hyperopic preschool children compared to emmetropic subjects. Those with higher hyperopia (>=4 D to <=6 D) were at greatest risk, although more than half of children with lower magnitudes (>=3 D to <4 D) demonstrated 1 or more reductions in function. PMID- 27477771 TI - Multi-functional lectin-like transcript-1: A new player in human immune regulation. AB - Lectins and C-type lectins are a heterogeneous group of proteins with a diverse range of functions. Two C-type lectins, found in the Natural Killer gene Complex (NKC), Lectin-like transcript 1 (LLT1) and CD161, have recently gained interest from a broad range of immunological and non-immunological fields. LLT1 in particular has a diverse functional repertoire, from NK cell and B cell regulation to bone metabolism. This review seeks to bring together nearly two decades of research on these receptors and describe their importance in the immune system. PMID- 27477772 TI - Knowing what we do not know: statin therapy in advanced chronic kidney disease. PMID- 27477773 TI - Impact of renal function on the effects of LDL cholesterol lowering with statin based regimens: a meta-analysis of individual participant data from 28 randomised trials. AB - BACKGROUND: Statin therapy is effective for the prevention of coronary heart disease and stroke in patients with mild-to-moderate chronic kidney disease, but its effects in individuals with more advanced disease, particularly those undergoing dialysis, are uncertain. METHODS: We did a meta-analysis of individual participant data from 28 trials (n=183 419), examining effects of statin-based therapy on major vascular events (major coronary event [non-fatal myocardial infarction or coronary death], stroke, or coronary revascularisation) and cause specific mortality. Participants were subdivided into categories of estimated glomerular filtration rate (eGFR) at baseline. Treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol. FINDINGS: Overall, statin-based therapy reduced the risk of a first major vascular event by 21% (RR 0.79, 95% CI 0.77-0.81; p<0.0001) per mmol/L reduction in LDL cholesterol. Smaller relative effects on major vascular events were observed as eGFR declined (p=0.008 for trend; RR 0.78, 99% CI 0.75-0.82 for eGFR >=60 mL/min per 1.73 m(2); 0.76, 0.70-0.81 for eGFR 45 to <60 mL/min per 1.73 m(2); 0.85, 0.75-0.96 for eGFR 30 to <45 mL/min per 1.73 m(2); 0.85, 0.71-1.02 for eGFR <30 mL/min per 1.73 m(2) and not on dialysis; and 0.94, 0.79-1.11 for patients on dialysis). Analogous trends by baseline renal function were seen for major coronary events (p=0.01 for trend) and vascular mortality (p=0.03 for trend), but there was no significant trend for coronary revascularisation (p=0.90). Reducing LDL cholesterol with statin-based therapy had no effect on non-vascular mortality, irrespective of eGFR. INTERPRETATION: Even after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits. FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme, Australian National Health and Medical Research Council, Australian National Heart Foundation. PMID- 27477774 TI - Developmental neuropathology of brainstem respiratory centers in unexplained stillbirth: What's the meaning? AB - Stillbirth is one of the most stressful life events affecting over 3 million pregnancies per year throughout the world. An accurate autopsy of the stillborn fetus, including the placenta and umbilical cord examination, should be performed promptly after delivery. A thorough maternal history also should be taken, including exposures to risk factors. In many cases a death cause, attributable to fetal, maternal, or placental pathology, is clearly identified. However, in 50% or more of cases the cause remains unknown. The purpose of this study is to highlight possible developmental alterations of the autonomic nervous system in unexplained stillbirths to provide an explanation of the pathogenetic mechanism of their death. We conducted a careful neuropathological study of the brainstem, where the main vital centers are located, in 85 unexplained stillbirths and 52 age-matched controls died of known cause. Information on the maternal lifestyle, including the smoking habit, was collected in all cases. Hypodevelopment of neuronal centers involved in breathing control, all connected together in a "respiratory network", precisely hypoplasia of the facial/parafacial complex, Kolliker-Fuse nucleus, pre-Botzinger nucleus and intermediolateral nucleus, were frequently observed in unexplained deaths, significantly related to maternal cigarette smoking. We support the hypothesis of a strong action of maternal smoking during pregnancy on the development of brainstem respiratory nuclei and suggest an explanation of the high incidence of the respiratory network alterations in unexplained fetal death, when breathing not represents a vital function. PMID- 27477776 TI - Seasonal variation of whole blood copper levels in children aged 0-14 years. PMID- 27477777 TI - Comparison of robot-assisted and open partial nephrectomy for completely endophytic renal tumours: a single centre experience. AB - OBJECTIVE: To compare outcomes between robot-assisted partial nephrectomy (RAPN) and open PN (OPN) for completely endophytic renal tumours. PATIENTS AND METHODS: We retrospectively reviewed 1 230 consecutive cases, consisting of 823 RAPNs and 407 OPNs, performed for renal mass at a single academic tertiary centre between 2011 and 2016. Of these, data on 87 RAPN and 56 OPN cases for completely endophytic renal tumours were analysed. Patient and tumour characteristics, operative, postoperative, functional, and oncological outcomes were compared between groups. RESULTS: Apart from a higher prevalence of solitary kidney among OPN cases (RAPN, 5.7% vs OPN, 21.4%; P = 0.005), demographic characteristics were similar between the groups. There were no statistically significant differences in tumour size (P = 0.07), tumour stage (P = 0.3), margin status (P = 0.48), malignant tumour subtypes (P = 0.51), and grades (P = 0.61) between the groups. Also, there were no statistically significant differences among the groups for warm ischaemia time (P = 0.15), cold ischaemia time (P = 0.28), and intraoperative (P = 0.75) or postoperative (Clavien-Dindo Grade I-V, P = 0.08; Clavien-Dindo Grade III-V, P = 0.85) complication rates. The patients in the RAPN group had a shorter length of stay (P < 0.001), less estimated blood loss (P < 0.001), and lower intraoperative transfusion rates (0% vs 7.1%, P = 0.02). No local recurrences occurred during a median (interquartile range) follow-up of 15.2 (7-27.2) and 18.1 (8.2-30.9) months in the RAPN and OPN groups, respectively. There was no difference in estimated glomerular filtration rate preservation rates between groups for the early (P = 0.26) and latest (P = 0.22) functional follow-up. CONCLUSION: For completely endophytic renal tumours, both OPN and RAPN have excellent outcomes when performed by experienced surgeons at a high-volume centre. For skilled robotic surgeons, RAPN is a safe and effective alternative to OPN with the advantages of shorter length of stay and less blood loss. PMID- 27477775 TI - Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia. AB - BACKGROUND: Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brain's white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age-related decline in FA values. In the largest mega-analysis to date, we tested if differences in the trajectories of WM tract development influenced patient-control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging. METHODS: Three cohorts of schizophrenia patients (total n = 177) and controls (total n = 249; age = 18 61 years) were ascertained with three 3T Siemens MRI scanners. Whole-brain and regional FA values were extracted using ENIGMA-DTI protocols. Statistics were evaluated using mega- and meta-analyses to detect effects of diagnosis and age-by diagnosis interactions. RESULTS: In mega-analysis of whole-brain averaged FA, schizophrenia patients had lower FA (P = 10-11 ) and faster age-related decline in FA (P = 0.02) compared with controls. Tract-specific heterochronicity measures, that is, abnormal rates of adolescent maturation and aging explained approximately 50% of the regional variance effects of diagnosis and age-by diagnosis interaction in patients. Interactive, three-dimensional visualization of the results is available at www.enigma-viewer.org. CONCLUSION: WM tracts that mature later in life appeared more sensitive to the pathophysiology of schizophrenia and were more susceptible to faster age-related decline in FA values. Hum Brain Mapp 37:4673-4688, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27477779 TI - Engineering Protein Hydrogels Using SpyCatcher-SpyTag Chemistry. AB - Constructing hydrogels from engineered proteins has attracted significant attention within the material sciences, owing to their myriad potential applications in biomedical engineering. Developing efficient methods to cross link tailored protein building blocks into hydrogels with desirable mechanical, physical, and functional properties is of paramount importance. By making use of the recently developed SpyCatcher-SpyTag chemistry, we successfully engineered protein hydrogels on the basis of engineered tandem modular elastomeric proteins. Our resultant protein hydrogels are soft but stable, and show excellent biocompatibility. As the first step, we tested the use of these hydrogels as a drug carrier, as well as in encapsulating human lung fibroblast cells. Our results demonstrate the robustness of the SpyCatcher-SpyTag chemistry, even when the SpyTag (or SpyCatcher) is flanked by folded globular domains. These results demonstrate that SpyCatcher-SpyTag chemistry can be used to engineer protein hydrogels from tandem modular elastomeric proteins that can find applications in tissue engineering, in fundamental mechano-biological studies, and as a controlled drug release vehicle. PMID- 27477778 TI - IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo. AB - To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNgamma upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts. Pre-treatment of WASp KO NK cells with IL 2 ex vivo restored degranulation, IFNgamma production, and killing of MHC class I negative hematopoietic grafts. Moreover, WASp KO mice controlled growth of A20 lymphoma cells that naturally produced IL-2. WASp KO NK cells showed increased expression of DNAM-1, LAG-3, and KLRG1, all receptors associated with cellular exhaustion and NK cell memory. NK cells isolated from WAS patient spleen cells showed increased expression of DNAM-1 and had low to negative expression of CD56, a phenotype associated with NK cells exhaustion. Finally, in a cohort of neuroblastoma patients we identified a strong correlation between WASp, IL-2, and patient survival. PMID- 27477780 TI - Ascarosides coordinate the dispersal of a plant-parasitic nematode with the metamorphosis of its vector beetle. AB - Insect vectors are required for the transmission of many species of parasitic nematodes, but the mechanisms by which the vectors and nematodes coordinate their life cycles are poorly understood. Here, we report that ascarosides, an evolutionarily conserved family of nematode pheromones, are produced not only by a plant-parasitic nematode, but also by its vector beetle. The pinewood nematode and its vector beetle cause pine wilt disease, which threatens forest ecosystems world-wide. Ascarosides secreted by the dispersal third-stage nematode LIII larvae promote beetle pupation by inducing ecdysone production in the beetle and up-regulating ecdysone-dependent gene expression. Once the beetle develops into the adult stage, it secretes ascarosides that attract the dispersal fourth-stage nematode LIV larvae, potentially facilitating their movement into the beetle trachea for transport to the next pine tree. These results demonstrate that ascarosides play a key role in the survival and spread of pine wilt disease. PMID- 27477781 TI - SNAREs and cholesterol movement for steroidogenesis. AB - Steroidogenesis is a complex process through which cholesterol traffics to mitochondria and is converted via a series of enzymatic steps to steroid hormones. Although the rate-limiting step in this process is the movement of cholesterol from the outer to the inner mitochondrial membrane via the actions of StAR, a continuous supply of cholesterol must be delivered to the outer mitochondrial membrane during active steroidogenesis and this is derived from multiple sources, including lipoprotein uptake, endogenous cholesterol synthesis and release from stores within cytoplasmic lipid droplets. A number of mechanisms have been suggested to contribute to cholesterol trafficking to mitochondria; however, there is no definitive consensus and this is particularly so in regards to trafficking from cytoplasmic lipid droplets. In this paper we review experiments in which we have surveyed the expression of SNARE proteins in steroidogenic tissue and cells and examined the role of SNAREs in mediating cholesterol movement from lipid droplets to the mitochondria based on multiple studies that identified SNAREs as components of cytoplasmic lipid droplets. We established and characterized an in vitro mitochondria reconstitution assay system that enabled us to examine the impact of adding recombinant SNARE proteins specifically on the movement of cholesterol from model lipid droplets to the outer mitochondrial membrane. Using this reconstitution assay system in combination with siRNA knockdown experiments in rat primary granulosa cells or in steroidogenic cell lines, we showed that several SNARE proteins are important components in the trafficking of cholesterol from lipid droplets to the mitochondria for steroidogenesis. PMID- 27477782 TI - Role of the Kiss1/Kiss1r system in the regulation of pituitary cell function. AB - Kisspeptin (Kiss1) is an amidated neurohormone that belongs to the RF-amide peptide family, which has a key role in the control of reproduction. Specifically, kisspeptin regulates reproductive events, including puberty and ovulation, primarily by activating the surface receptor Kiss1r (aka GPR54), at hypothalamic gonadotropin-releasing hormone (GnRH) neurons. More recently, it has been found that kisspeptin peptide is present in the hypophyseal portal circulation and that the Kiss1/Kiss1r system is expressed in pituitary cells, which suggest that kisspeptin could exert an endocrine, paracrine or even autocrine role at the pituitary gland level. Indeed, mounting evidence is pointing towards a direct role of kisspeptin in the control of not only gonadotropins but also other pituitary secretions such as growth hormone or prolactin. In this review, we summarize the most recent advances in the study of the role that the Kiss/Kiss1r system plays in the control of pituitary gland function, paying special attention to the direct role of this neuropeptide on pituitary cells and its interactions with other relevant regulators. PMID- 27477783 TI - Calcium-sensing-receptor (CaSR) controls IL-6 secretion in metastatic breast cancer MDA-MB-231 cells by a dual mechanism revealed by agonist and inverse agonist modulators. AB - IL-6 is a tightly controlled pleiotropic cytokine with hormone-like properties whose levels are frequently altered in cancer and inflammatory diseases. In highly invasive MDA-MB-231 breast cancer cells, basal activity of endogenously expressed calcium sensing receptor (CaSR) promotes IL-6 secretion. Interestingly, upon agonist stimulation, CaSR reduces IL-6 levels whereas it promotes secretion of various other cytokines and growth factors, raising intriguing questions about how CaSR signaling modulates IL-6 secretion. Here, using NPS-2143, which acted as an inverse agonist, we show that IL-6 secretion promoted by constitutive activity of CaSR is mechanistically linked to Galphas/PKC, MEK1/2 and mTORC1 signaling pathways, integrated by transactivated EGFR. On the other hand, agonist stimulated CaSR engages in a Rab11a-dependent trafficking pathway critical to inhibit constitutive IL-6 secretion via the PI3K/AKT and PKC signaling pathways. These results support the emerging potential of CaSR as a therapeutic target in metastatic breast cancer whose pharmacological modulation would reduce IL-6. PMID- 27477784 TI - Mumps virus induces innate immune responses in mouse ovarian granulosa cells through the activation of Toll-like receptor 2 and retinoic acid-inducible gene I. AB - Mumps virus (MuV) infection may lead to oophoritis and perturb ovarian function. However, the mechanisms underlying the activation of innate immune responses to MuV infection in the ovary have not been investigated. This study showed that Toll-like receptor 2 (TLR2) and retinoic acid-inducible gene I (RIG-I) cooperatively initiate innate immune responses to MuV infection in mouse ovarian granulosa cells. Ovarian granulosa cells infected with MuV significantly produced pro-inflammatory cytokines and chemokines, including interleukin-1beta (IL 1beta), tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and type 1 interferons (IFN-alpha and IFN-beta). Knockdown of RIG-I significantly decreased MuV-induced cytokine expression. TLR2 deficiency reduced the expression of IL-1beta, TNF-alpha, and MCP-1 but did not affect the expression of IFN-alpha and IFN-beta in granulosa cells after infection with MuV. Intraperitoneal injection of MuV induced the ovarian innate immune responses in vivo, which suppressed estradiol synthesis and induced granulosa cell apoptosis. The results provide novel insights into the mechanisms underlying MuV-induced innate immune responses in the mouse ovary. PMID- 27477785 TI - Effect of Sodium Chloride on alpha-Dicarbonyl Compound and 5-Hydroxymethyl-2 furfural Formations from Glucose under Caramelization Conditions: A Multiresponse Kinetic Modeling Approach. AB - This study aimed to investigate the kinetics of alpha-dicarbonyl compound formation in glucose and glucose-sodium chloride mixture during heating under caramelization conditions. Changes in the concentrations of glucose, fructose, glucosone, 1-deoxyglucosone, 3-deoxyglucosone, 3,4-dideoxyglucosone, 5 hydroxymethyl-2-furfural (HMF), glyoxal, methylglyoxal, and diacetyl were determined. A comprehensive reaction network was built, and the multiresponse model was compared to the experimentally observed data. Interconversion between glucose and fructose became 2.5 times faster in the presence of NaCl at 180 and 200 degrees C. The effect of NaCl on the rate constants of alpha-dicarbonyl compound formation varied across the precursor and the compound itself and temperature. A decrease in rate constants of 3-deoxyglucosone and 1 deoxyglucosone formations by the presence of NaCl was observed. HMF formation was revealed to be mainly via isomerization to fructose and dehydration over cyclic intermediates, and the rate constants increase 4-fold in the presence of NaCl. PMID- 27477787 TI - Describing and Measuring the Pathway to Suicide Attempts: A Preliminary Study. AB - To die by suicide, one must think about suicide, make a plan, and then carry it out. Prior research has examined the presence and predictors of these outcomes; however, virtually no studies have characterized how these steps unfold along the pathway to suicide. A novel instrument was administered to 30 recent suicide attempters. Results revealed that although the median onset for suicidal ideation occurs 1 to 5 years prior to attempting, the median for 6 of the 10 steps measured was within 6 hours of attempting. Overall, 86.5% of proximal planning steps took place within 1 week of attempting and 66.6% occurred within 12 hours. PMID- 27477786 TI - Erosion protection benefits of stabilized SnF2 dentifrice versus an arginine sodium monofluorophosphate dentifrice: results from in vitro and in situ clinical studies. AB - OBJECTIVES: The aim of these investigations was to assess the ability of two fluoride dentifrices to protect against the initiation and progression of dental erosion using a predictive in vitro erosion cycling model and a human in situ erosion prevention clinical trial for verification of effectiveness. MATERIALS AND METHODS: A stabilized stannous fluoride (SnF2) dentifrice (0.454 % SnF2 + 0.077 % sodium fluoride [NaF]; total F = 1450 ppm F) [dentifrice A] and a sodium monofluorophosphate [SMFP]/arginine dentifrice (1.1 % SMFP + 1.5 % arginine; total F = 1450 ppm F) [dentifrice B] were tested in a 5-day in vitro erosion cycling model and a 10-day randomized, controlled, double-blind, two-treatment, four-period crossover in situ clinical trial. In each study, human enamel specimens were exposed to repetitive product treatments using a standardized dilution of test products followed by erosive acid challenges in a systematic fashion. RESULTS: Both studies demonstrated statistically significant differences between the two products, with dentifrice A providing significantly better enamel protection in each study. In vitro, dentifrice A provided a 75.8 % benefit over dentifrice B (p < 0.05, ANOVA), while after 10 days in the in situ model, dentifrice A provided 93.9 % greater protection versus dentifrice B (p < 0.0001, general linear mixed model). CONCLUSION: These results support the superiority of stabilized SnF2 dentifrices for protecting human teeth against the initiation and progression of dental erosion. CLINICAL RELEVANCE: Stabilized SnF2 dentifrices may provide more significant benefits to consumers than conventional fluoride dentifrices. PMID- 27477788 TI - More than just recruitment: the X-domain influences catalysis of the first phenolic coupling reaction in A47934 biosynthesis by Cytochrome P450 StaH. AB - Glycopeptide antibiotic biosynthesis involves a complex cascade of reactions centred on a non-ribosomal peptide synthetase and modifiying proteins acting in trans, such as Cytochrome P450 enzymes. These P450s are responsible for cyclisation of the peptide via cross-linking aromatic amino acid side chains, which are a hallmark of the glycopeptide antibiotics. Here, we analysed the first cyclisation reaction in the biosynthesis of the glycopeptide antibiotic A47934. Our results demonstrate that the P450 StaH is recruited to the NRPS machinery through interaction with the X-domain present in the last A47934 NRPS module. We determined the crystal structure of StaH and showed that it is responsible for the first cyclisation in A47934 biosynthesis and additionally exhibits flexible substrate specificity. Our results further point out that the X-domain has an impact on the efficiency of the in vitro cyclisation reaction: hybrid PCP-X constructs obtained by domain exchange between A47934 and teicoplanin biosynthesis NRPS modules reveal that the X-domain from A47934 leads to decreased P450 activity and alternate stereochemical preference for the substrate peptide. We determined that a tight interaction between StaH and the A47934 X-domain correlates with decreased in vitro P450 activity: this highlights the need for glycopeptide antibiotic cyclisation to be a dynamic system, with an overly tight interaction interfering with substrate turnover in vitro. PMID- 27477790 TI - Evidence-based policy? The re-medicalization of cannabis and the role of expert committees in the UK, 1972-1982. AB - BACKGROUND: Cannabis was introduced to the UK as a medical product in the nineteenth century. However, with questions over its safety, efficacy, and possible harms its medical role diminished and by the 1950s it was viewed as a drug of misuse. Nonetheless, scientific and lay knowledge around cannabis expanded from the 1960s and cannabis re-appeared in different therapeutic forms. In re-medicalizing cannabis, science-policy transfer proved important and was enabled by the developing mechanism of expert committees, most notably the Advisory Council on the Misuse of Drugs (ACMD). METHODS: This article draws upon previously unknown archival material on the ACMD held at the National Archives and covers the period 1972-1982. It considers how expert groups were established, their membership, and the evolving discussion over therapeutic cannabis within the broader drug policy debate. RESULTS: Three distinct periods emerged: 1972 1976 with the creation of the Working Group on Cannabis; 1977-1979 when the Working Group focused on potential amendments to the Misuse of Drugs Act and recommended downgrading cannabis from Class B to Class C; 1980-1982 when the Expert Group on the Effects of Cannabis recommended downgrading cannabis and encouraged research into cannabis as a medicine. Sources reveal that driven by drug control imperatives the ACMD stimulated research on cannabis leading to increased research on medical applications. CONCLUSION: Expert advice was critical in the process of re-medicalization. Initially, discourse occurred in the closed expert committees of the ACMD. The drug problem had been framed under the criminal justice system but as the limitations of this were revealed, and there was continuing uncertainty over cannabis' impact, new approaches to cannabis were sought. It was this combination of more relaxed attitudes towards cannabis, research incentives, as well as a developing desire to draw medical needs away from discussion of drug control that was to allow re-medicalization to develop. PMID- 27477789 TI - Study of six patients with complete F9 deletion characterized by cytogenetic microarray: role of the SOX3 gene in intellectual disability. AB - : Essentials Some hemophilia B (HB) patients with complete F9 deletion present with intellectual disability (ID). We delineate six F9 complete deletions and investigate genotype/phenotype correlation. We identify SOX3 as a candidate gene for ID, acting through haploinsufficiency, in HB patients. All complete F9 deletions in ID patients should be explored with cytogenetic microarrays. SUMMARY: Background Large deletions encompassing both the complete F9 gene and contiguous genes have been detected in patients with severe hemophilia B (HB). Some of these patients present other clinical features, such as intellectual disability (ID). Objectives/Methods In this study, we characterized six unrelated large deletions encompassing F9, by cytogenetic microarray analysis (CMA), to investigate genotype/phenotype correlation. Results Five of the six patients included in this study presented with ID associated with HB. CMA showed that the six large deletions, ranging in size from approximately 933 kb to 9.19 Mb, were located within the Xq26.3 to Xq28 bands. In all cases, the complete deletion of F9 was associated with the loss of various neighboring genes (5-28 other genes). The smallest region of overlap for ID was a 1.26-Mb region encompassing seven OMIM genes (LOC389895, SOX3, LINC00632, CDR1, SPANXF1, LDOC1, SPANXC). SOX3, our candidate gene for ID, encodes an early transcription factor involved in pituitary development. All of the patients studied who had both HB and ID had deletion of the SOX3 gene. Conclusions All HB patients with an atypical phenotype, especially if complete deletion of F9 is suspected, should be referred to a geneticist for possible pangenomic assessment, because haploinsufficiency of genes flanking F9, such as SOX3 in particular, may result in a broader phenotype, including ID. Such assessment would be of particular value for the genetic counseling of female carriers with F9 deletions, as it would facilitate analysis of the risk of transmitting HB associated with ID. PMID- 27477791 TI - Factors associated with caries: a survey of students from southern Brazil. AB - OBJECTIVE: To describe the factors associated with dental caries among students from Santa Cruz do Sul, Rio Grande do Sul, Brazil. METHODS: A cross-sectional study was conducted in a random sample of 623 students of both genders, aged 10 17 years old. Tooth decay was performed using the index of the World Health Organization (1997), DMFT (permanent dentition) that expresses the sum of decayed, missing and filled teeth per person. The maternal educational level was rated using criteria of the Brazilian Association of Market Research Companies. The remaining variables were obtained by a structured questionnaire. Poisson regression analysis was used to test the association between variables using robust models and a subsequently adjusted model. Data were expressed as prevalence ratio (PR). RESULTS: Multivariate analysis identified the following factors related to the experience of dental caries: residence in rural municipalities (PR: 1.15; 95%CI: 1.0-1.3), attending a city school (PR: 3.30; 95%CI: 1.1-9.4) or a state school (PR: 3.40; 95%CI: 1.1-9.6); and having an illiterate mother or a mother that only attended up to the 4th year of school (PR: 1.67; 95%CI: 1.1-2.4) or high school (PR: 1.54; 95%CI: 1.1-2.2). CONCLUSIONS: The presence of caries in students in southern Brazil was associated with residence in rural areas, mother with little education and attendance to a public school. PMID- 27477792 TI - Environmental implications and applications of engineered nanoscale magnetite and its hybrid nanocomposites: A review of recent literature. AB - This review focuses on environmental implications and applications of engineered magnetite (Fe3O4) nanoparticles (MNPs) as a single phase or a component of a hybrid nanocomposite that exhibits superparamagnetism and high surface area. MNPs are synthesized via co-precipitation, thermal decomposition and combustion, hydrothermal process, emulsion, microbial process, and green approaches. Aggregation/sedimentation and transport of MNPs depend on surface charge of MNPs and geochemical parameters such as pH, ionic strength, and organic matter. MNPs generally have low toxicity to humans and ecosystem. MNPs are used for constructing chemical/biosensors and for catalyzing a variety of chemical reactions. MNPs are used for air cleanup and carbon sequestration. MNP nanocomposites are designed as antimicrobial agents for water disinfection and flocculants for water treatment. Conjugated MNPs are widely used for adsorptive/separative removal of organics, dyes, oil, arsenic, phosphate, molybdate, fluoride, selenium, Cr(VI), heavy metal cations, radionuclides, and rare earth elements. MNPs can degrade organic/inorganic contaminants via chemical reduction or catalyze chemical oxidation in water, sediment, and soil. Future studies should further explore mechanisms of MNP interactions with other nanomaterials and contaminants, economic and green approaches of MNP synthesis, and field scale demonstration of MNP utilization. PMID- 27477793 TI - Hepatobiliary scintigraphy for early diagnosis of biliary atresia. AB - INTRODUCTION: The aim of this study was to evaluate the validity of (99m)Technetium-trimethylbromo-iminodiacetic acid hepatobiliary scintigraphy (HS) for the diagnosis of biliary atresia (BA). METHODS: From January 2005 to December 2009, a total of 47 infants with conjugated hyperbilirubinaemia (> 20 micromol/l total bilirubin of which 20% is conjugated) underwent HS. BA was suspected if no tracer was visualised in the gut 24 hours post-injection. The results of the HSs were compared with the gold standard, laparotomy with antegrade cholangiography findings. RESULTS: Considering the final diagnosis based on the gold standard, the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the HS in the diagnosis of BA was 100%, 63.6%, 53.8%, and 100%, respectively. The accuracy was 74.5%. BA patients with non-draining HS had significantly higher levels of gamma-glutamyl transpeptidase (GGTP) than non-BA patients with non-draining HS (p = 0.019) or draining HS (p = 0.0001). CONCLUSIONS: HS plays an important role in the diagnostic strategy of infantile jaundice due to conjugated hyperbilirubinaemia. It is a non-invasive method that only seldomly calls for sedation. A high sensitivity and NPV prevent un-necessary surgery. Because of the low specificity of HS in diagnosing BA, it should be part of a multimodality imaging strategy when the result supports a clinical suspicion of BA. In cases with non-draining HS and normal GGTP blood levels, supplemental imaging modalities are especially needed. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 27477794 TI - Secondary oesophageal or gastric cancer in patients treated for head and neck squamous cell carcinoma. AB - INTRODUCTION: Patients with head and neck squamous cell carcinoma (HNSCC) are at an elevated risk of developing second primary malignancies (SPM). Our objectives were to estimate the excess risk of oesophageal and gastric SPMs in patients with malignancies of the pharynx or larynx and, additionally, to examine possible risk factors of developing SPMs. METHODS: Data on all patients treated for HNSCC with curative intent in the Region of Southern Denmark in the period between 1 January 2000 and 31 December 2010 were reviewed. A total of 1,172 patients were identified. The combined data from the DAHANCA database, the Danish National Pathology Registry and the patient charts were analysed. RESULTS: A total of 27 patients developed an SPM in the oesophagus or stomach corresponding to a standardised incidence ratio of 9.5 (95% confidence interval (CI): 6.5-13.9). Supraglottic (odds ratio (OR) = 6.9; p < 0.004) and hypopharyngeal (OR = 3.9; p < 0.049) index tumour sites were significant risk factors for developing SPM. The median survival of patients with SPM was 3.6 years (95% CI: 1.6-5.1; range: 0.7 12.4) from diagnosis of the index cancer compared with 3.4 years (95% CI: 3.1 4.3; range: 0.04-13.7) for patients without SPM. CONCLUSION: In this study, we confirm that there is an elevated risk of developing oesophageal and gastric cancer in the Danish population of patients with a cancer in the supraglottic or hypopharyngeal region. Therefore, we recommend close follow-up of these patients and a low threshold for examination of the oesophagus and stomach. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 27477795 TI - A nationwide analysis of socioeconomic outcomes after hip and knee replacement. AB - INTRODUCTION: Total hip and knee replacement (THA and TKA) are successful operations based on patient-reported outcomes and short-term socioeconomic evaluations. However, other data have shown problems regarding persistent pain and function. No detailed large-scale, long-term socioeconomic data exist on income and total health expenses before and after THA and TKA compared with a matched reference population (RP). METHODS: From the unique nationwide Danish registers, a total of 128,109 patients undergoing primary THA and TKA were followed from up to 12 years before to up to 12 years after surgery. The economic analysis of the total costs before and after surgery were divided into annual healthcare costs (outpatient services, inpatient admissions, prescription drugs and physician office visits), home care and loss of income and compared with a matched RP. RESULTS: Healthcare costs increased by about 10,000 ? in the year of surgery followed by an increase of about 6,000 ?/yr/patient in both operations due to a loss of employment income, a need for home care and the use of medications, also compared with an RP. Survival was slightly better for patients than for the RP, suggesting that severe co-morbidities have only a limited role in explaining the increased costs. CONCLUSIONS: The healthcare costs and income of patients undergoing THA and TKA are comparable to those of their matched RP until three years before the operation, but TKA and THA patients continuously have higher healthcare costs and lower income levels than the RP after surgery. These data should be taken into account in future studies of patient expectations and strategies for enhanced rehabilitation. FUNDING: none. TRIAL REGISTRATION: none. PMID- 27477796 TI - Laparoscopic appendectomy during pregnancy is safe for both the mother and the fetus. AB - INTRODUCTION: The diagnosis and treatment of acute appendicitis during pregnancy is still debated. While laparoscopic appendectomy in general has become the gold standard, this procedure has not generally been implemented for pregnant women. METHODS: We retrospectively reviewed the patient charts of all patients who underwent appendectomy during pregnancy in the period from 2000 to 2012. Open appendectomy (OA) was performed in 25 cases and laparoscopic (LA) in 19. RESULTS: We observed a significantly longer operation time (69 versus 49 min., p = 0.002), but fewer complications, a shorter hospital stay (2.6 versus 5.5 days, p = 0.004) and a lower rate of negative appendectomies (16% versus 52%, p = 0.02) in the LA group compared with the OA group. The mean gestation age at appendectomy was significantly lower in the LA group. There were no significant differences in gestational age at birth, Apgar score, birth weight or height between the two groups. Five births (11%) were categorised as mildly to moderately preterm. There were no cases of fetal loss. CONCLUSION: Laparoscopic appendectomy is safe for both the mother and the fetus during pregnancy irrespective of gestational age, and the procedure is associated with a low risk of post-operative complications. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 27477797 TI - Preoperative steroid in abdominal wall reconstruction: protocol for a randomised trial. AB - INTRODUCTION: Preoperative administration of high-dose glucocorticoid leads to improved recovery and decreased length of stay after abdominal surgery. Even so, studies on administration of glucocorticoids for patients undergoing abdominal wall reconstruction (AWR) for giant ventral hernia repair are lacking, perhaps due to a fear of impaired wound healing. We hypothesised that patients undergoing AWR would benefit from preoperative glucocorticoids and aimed at examining this in a randomised controlled trial. METHODS: A total of 40 patients scheduled to undergo AWR for ventral hernias with a fascial defect exceeding 10 cm will be randomised for intravenous administration of either 125 mg methylprednisolone or saline at the induction of anaesthesia. The primary endpoint is pain at rest on the first post-operative day. Patients will be followed until 30 days post operatively, and secondary outcomes include subjective measures, wound complications and analysis of blood and wound fluids. CONCLUSIONS: This is the first trial on the effect of preoperative glucocorticoid administration in patients undergoing AWR. Due to long post-operative stays and a high rate of post operative complications, this patient group can potentially benefit much from any post-operative optimisation. Furthermore, insight into any impact of glucocorticoids on wound healing in hernia patients may provide important information. FUNDING: none. TRIAL REGISTRATION: This study was registered with Clinicaltrials.gov (NCT02594241) and Eudra-CT (2015-004916-39). PMID- 27477798 TI - Fluorescence versus X-ray cholangiography during laparoscopic cholecystectomy: protocol for a randomised trial. AB - INTRODUCTION: Intraoperative fluorescent cholangiography is a novel non-invasive imaging technique to visualise the extrahepatic biliary tract during laparoscopic cholecystectomy. It has been proven feasible, fast and cost effective. Never theless, there is only sparse data on the capacity of fluorescent cholangiography to visualise the biliary anatomy. METHODS: Based on a non-inferiority design, patients with complicated gallstone disease are randomised to either intraoperative conventional X-ray cholangiography (reference group, n = 60) or intraoperative fluorescent cholangiography (n = 60). The primary outcome is visualisation of the junction between the cystic duct, the common hepatic duct and the common bile duct. CONCLUSION: The present study may show that fluorescent cholangiography is as valid for visualisation of important structures of the extrahepatic biliary tract as conventional X-ray cholangiography. This may lead to the introduction of online imaging of the extrahepatic tract during dissection of the gallbladder during cholecystectomy. FUNDING: none. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov (No. NCT02344654), with the National Committee on Health Research Ethics (Reg. no. H-15000817) and with the Danish Data Protection Agency (Reg no. AHH- 2015-005). PMID- 27477799 TI - Personalized therapy with TNF-inhibitors in Crohn's disease: optimizing treatment outcomes by monitoring drug levels and anti-drug antibodies. AB - Therapeutic monoclonal antibodies (Abs) targeting the proinflammatory cytokine, TNF-alpha have revolutionized the treatment of inflammatory bowel disease (IBD), and raised treatment goals from symptom control to maintenance of clinical remission with mucosal healing. However, clinicians are challenged by a significant proportion of patients not responding to TNF-inhibitors or losing effect over time, and by the high costs of these drugs along with their potential side effects. The aim of this dissertation was therefore to examine if anti-TNF treatment outcomes can be improved by tailoring therapy on an individual patient basis by considering relevant prognostic variables. The main finding is that personalized treatment with TNF-inhibitors by use of an algorithm defined by measurements of anti-TNF drug and anti-drug Abs to guide interventions at therapeutic failure can be useful to secure optimal clinical, economic, and patient reported outcomes. Furthermore, the present studies have documented the key role of measurements of anti-TNF drug and anti-drug Abs to elucidate conditions related to pharmacokinetics and pharmacodynamics of these agents in individual patients, and to serve as prognostic markers of anti-TNF treatment outcomes. In addition, knowledge has been provided on how to interpret and integrate measurements of anti-TNF drug and anti-drug Abs in the clinical management of individual IBD patients taking into account potential pit-falls and biases. Hence, the studies forming the basis for this dissertation have yielded novel insights into the technical, temporal, and methodological complexities and challenges related to application of personalized anti-TNF treatment strategies based on measurements of anti-TNF drug and anti-drug Abs, and established measures to proactively address and accommodate these - both technically and clinically. Although not yet completely resolved, this dissertation has also laid a foundation for individually tailored anti-TNF therapy by use of algorithms based on measurements of anti-TNF drug and anti-drug Abs involving different clinical scenarios than treatment failure, for example in the context of drug withdrawal among selected subgroups in remission. Finally, this dissertation has demonstrated that personalized anti-TNF therapy cannot at this time be done on the basis of prognostic variables related to specific characteristics of individual patients, their disease and the anti-TNF treatment regimen, but that management decisions integrating knowledge of these factors can aid improving the overall benefit-risk ratio of anti-TNF treatment outcomes in individual patients. In conclusion, this dissertation has brought personalized anti-TNF therapy in IBD from bench to bedside. PMID- 27477800 TI - Low-grade disease activity in early life precedes childhood asthma and allergy. AB - Asthma and allergies are today the most common chronic diseases in children and the leading causes of school absences, chronic medication usage, emergency department visits and hospitalizations, which affect all members of the family and represent a significant societal and scientific challenge. These highly prevalent disorders are thought to originate from immune distortion in early childhood, but the etiology and heterogeneity of the disease mechanisms are not understood, which hampers preventive initiatives and makes treatment inadequate. The objective of this thesis is to investigate the presence of an early life disease activity prior to clinical symptoms to understand the anteceding pathophysiological steps towards childhood asthma and allergy. The thesis is built on seven studies from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) birth cohort examining biomarkers of disease activity in 411 asymptomatic neonates in cord blood (I-II), urine (III), exhaled breath (IV V) and infant lung function (VI-VII) in relation to the subsequent development of asthma and allergy during the first seven years of life. In papers I-II, we studied cord blood chemokines and 25(OH)-vitamin D, which represent a proxy of the inborn immature immune system, the intrauterine milieu, and the maternal immune health during pregnancy. High levels of the Th2-related chemokine CCL22 and high CCL22/CXCL11 ratio were positively correlated with total IgE level during preschool age (II). This suggests an inborn Th2 skewing of the immune system in healthy newborns subsequently developing elevated total IgE antibodies, which is considered to increase the risk of asthma and allergies later in life. Additionally, deficient cord blood 25(OH)-vitamin D levels were associated with a 2.7-fold increased risk of recurrent wheeze at age 0-7 years (I). Together, these findings support the concept that early life immune programming in the pre symptomatic era plays an essential role for promotion of or protection against asthma and allergies. Therefore, preventive initiatives to restore immune health, such as vitamin D supplementation, should be directed to the fetus and the earliest postnatal life. The eosinophil granulocyte has a major role in the allergic inflammatory cascade and eosinophilia is considered a hallmark of many allergic phenotypes. In paper III, we examined neonatal urinary biomarkers including eosinophil protein X (u-EPX), which is contained in the eosinophil granules. Elevated u-EPX in asymptomatic neonates was associated with development of allergic sensitization and nasal eosinophilia, but not with wheezing or asthma (III). These findings suggest the presence of an ongoing low-grade disease process in early life characterized by eosinophil activation prior to appearance of allergy-related conditions. In papers IV-V, we investigated perinatal and genetic predictors of neonatal fractional exhaled nitric oxide (FeNO) and the relationship between neonatal FeNO and wheezing later in child-hood. The a priori selected determinants encompassed asthma genetic risk variants, anthropometrics, demographics, socioeconomics, parental asthma and allergy, maternal smoking, paracetamol and antibiotic usage during pregnancy, and neonatal bacterial airway colonization. Among those, only the DENND1B risk allele and paternal history of asthma and allergy were associated with increased FeNO values (V) suggesting that raised FeNO in neonatal life is primarily an inherited trait. The neonatal FeNO levels were widely dispersed (1-67 ppb) and children with values in the upper quartile were at increased risk of recurrent wheezing in early childhood, but not persistent wheezing, reduced lung function or allergy-related endpoints (IV). This suggests that elevated neonatal FeNO represents an early asymptomatic low grade disease process other than congenitally small airway calibre contributing to a transient wheezing phenotype. Reduced lung function in neonates is associated with wheezing and asthma proneness, but it is unknown if such host factor also confers a risk of acute bronchiolitis, which is considered an index event of asthma persisting into school age. In paper VI, we investigated neonatal forced flow, volume, and responsiveness to methacholine in relation to occurrence of acute severe bronchiolitis at age 0-2 years. Children developing bronchiolitis had a 2.5-fold increased bronchial responsiveness as neonates (VI) suggesting a preexisting joint propensity of the airways to react adversely to common respiratory viruses and to develop asthma. This finding proposes airway hyperresponsiveness as yet another marker of low-grade disease activity among asymptomatic neonates on a trajectory towards childhood asthma. In paper VII, we examined whether neonates with impaired pulmonary capacity also had signs of systemic inflammation prior to clinical symptoms. Reduced FEV0.5 was significantly associated with elevated serum hs-CRP and other blood inflammatory markers (VII) suggesting presence of systemic low-grade inflammation from the beginning of life. Chronic low-grade inflammation is a common nominator of virtually all the major non-communicable welfare diseases (NCDs) of modernity whereof asthma and allergies are the earliest debuting disorders. The novel finding of systemic low-grade inflammation among neonates at increased risk of asthma and allergy, therefore implies that exploring the origins of asthma and allergy may also unravel disease mechanisms involved in other NCDs. In conclusion, the series of papers presented in this thesis (I-VII) evidence the presence of a pre-symptomatic disease process measurable in several body compartments, which supports the notion of low-grade disease activity in early life as a generic trait among neonates developing asthma and allergy. This hypothesis piggybacking on single biomarker assessments could be enforced and refined by applying novel global omics approaches. In particular, metabolomic analyses of serum, urine, and airway lining fluid from neonates as well as neonatal VOC profiling of exhaled breath may facilitate a broader understanding of the early low-grade disease activity preceding clinical symptoms. Disentangling the introductory pathophysiological mechanisms and underlying endotypes of disease is paramount for generating successful preventive measures to alleviate the major global burden of asthma, allergy, and other NCDs of modern time. PMID- 27477801 TI - Cardiac time intervals by tissue Doppler imaging M-mode echocardiography: reproducibility, reference values, association with clinical characteristics and prognostic implications. AB - BACKGROUND: The preservation of normal cardiac time intervals is intimately related to normal cardiac physiology and function. In the ailing myocardium, the cardiac time intervals will change during disease progression. As left ventricular (LV) systolic function deteriorates, the time it takes for myocardial myocytes to achieve an LV pressure equal to that of aorta increases, resulting in a prolongation of the isovolumic contraction time (IVCT). Furthermore, the ability of myocardial myocytes to maintain the LV pressure decreases, resulting in reduction in the ejection time (ET). As LV diastolic function declines further, early diastolic relaxation proceeds more slowly, explaining the prolongation of isovolumic relaxation time (IVRT). Consequently, the IVRT/ET and the myocardial performance index (MPI), defined as (IVCT + IVRT)/ET, will detect cardiac dysfunction with an increase, irrespective of whether the LV is suffering from impaired systolic or diastolic function. A novel method of evaluating the cardiac time intervals has recently evolved. Using tissue Doppler imaging (TDI) M mode through the mitral valve (MV) to estimate the cardiac time intervals may be an improved method reflecting global cardiac time intervals and eliminating beat to-beat variation and regional differences. However, little is known about the usability of the cardiac time intervals obtained by this novel method. OBJECTIVE: To compare the reproducibility, association with clinical characteristics, association with established echocardiographic and invasive measures of systolic and diastolic function, and the usefulness in predicting all-cause mortality in the general population, for the MPI obtained by the conventional method (MPIConv) and by the novel method of obtaining the MPI (MPITDI). Furthermore, to define normal values of the cardiac time intervals obtained by TDI M-mode through the MV. In addition, to investigate if the cardiac time intervals are able to identify miniscule cardiac impairments in individuals with hypertension, which are unrecognized by conventional echocardiography. Lastly, to evaluate the prognostic value of the cardiac time intervals and the combined indexes of systolic and diastolic performance, IVRT/ET and MPI, obtained by TDI M-mode method in low risk participants from the general population and in highrisk patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). METHOD: The research involved three prospective observational studies. Within the Copenhagen City Heart Study, a large community based study of cardiovascular risk factors, the cardiac time intervals were obtained by TDI M-mode in 1,915 participants. Additionally, in the present thesis the cardiac time intervals were also obtained in 391 patients who were admitted with a STEMI and treated with pPCI at Gentofte Hospital. All patients were examined by echocardiography median two days (IQR 1-3) after the STEMI. Lastly, we also included a population (n = 44) of patients who underwent left heart ventricular catheterization and had the MPITDI and MPIConv measured. In all cohorts baseline data and an assessment of cardiac function were obtained by conventional echocardiography. Follow-up data on admission were obtained from the Danish National Board of Health's National Patient Registry and from the national Danish Causes of Death Registry. RESULTS: MPITDI had superior reproducibility, was less confounded by association with clinical characteristics, and provided superior prognostic information in a low-risk population as compared to MPIConv. Additionally, the MPITDI (but not MPIConv) was significantly associated with most invasive and established echocardiographic measures of systolic and diastolic function. The cardiac time intervals displayed a significant dose-response relationship, with increasing severity of elevated blood pressure and increasing left ventricular mass index. They identified impaired cardiac function in participants with hypertension, not only independent of conventional risk factors, but also in participants with a normal conventional echocardiographic examination. The combined cardiac time intervals which include information on both the systolic and diastolic function in one index (IVRT/ET and MPI) provided independent prognostic information, regardless of rhythm, incremental to conventional and novel echocardiographic parameters of systolic and diastolic function both in the general population and in patients with STEMI treated with pPCI. CONCLUSION: The novel TDI M-mode method is superior to the conventional method of obtaining the MPI, both when comparing reproducibility, validity, prognostic power and the ability to display both the systolic and diastolic function in one index. The cardiac time intervals obtained by TDI M mode reveal impaired cardiac function in persons with hypertension even when conventional echocardiography gives the impression of normal cardiac function. The combined cardiac time intervals which include information on both the systolic and diastolic function in one index (IVRT/ET and MPI) provide prognostic information incremental to conventional and novel echocardiographic parameters of systolic and diastolic function both in the general population and in patients with STEMI treated with pPCI. PMID- 27477802 TI - Hamartomatous polyps - a clinical and molecular genetic study. AB - Hamartomatous polyps (HPs) in the gastrointestinal (GI) tract are rare compared to other types of GI polyps, yet they are the most common type of polyp in children. The symptoms are usually rectal bleeding, abdominal pain, obstipation, anaemia, and/or small bowel obstruction. The polyps are typically removed concurrently with endoscopy when located in the colon, rectum, or stomach, whereas polyps in the small bowel are removed during push-enteroscopy, device assisted enteroscopy, or by surgery. HPs can be classified as juvenile polyps or Peutz-Jeghers polyps based on their histopathological appearance. Patients with one or a few juvenile polyps are usually not offered clinical follow-up as the polyp(s) are considered not to harbour any malignant potential. Nevertheless, it is important to note that juvenile polyps and HPs are also found in patients with hereditary hamartomatous polyposis syndromes (HPS). Patients with HPS have an increased risk of cancer, recurrences of polyps, and extraintestinal complications. The syndromes are important to diagnose, as patients should be offered surveillance from childhood or early adolescence. The syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and the PTEN hamartoma tumour syndrome. Currently, the HPS diagnoses are based on clinical criteria and are often assisted with genetic testing as candidate genes have been described for each syndrome. This thesis is based on six scientific papers. The overall aim of the studies was to expand the knowledge on clinical course and molecular genetics in patients with HPs and HPS, and to investigate research participants' attitude towards the results of extensive genetic testing. Paper I: In the first paper we investigated the occurrence, anatomic distribution, and other demographics of juvenile polyps in the colon and rectum in Denmark in 1995-2014. Based on the Danish Pathology Data Bank we found that 1772 patients had 2108 JPs examined in the period, and we calculated the incidence of juvenile polyps to be between 1:45,000 and 1:65,000. The majority of patients with juvenile polyps were adults and 1% fulfilled to diagnostic criteria of JPS. The majority of patients had a single juvenile polyp. Paper II: In this paper we conducted a review of the HPS based on the current literature. Paper III: We investigated the hypothesis that patients with one or few HPs may have a HPS based on genetic screening. We de-signed a panel of 26 genes associated with HPS and used targeted next generation sequencing in 77 patients with mainly one juvenile polyp. We detected several germ line variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be classified as definitely pathogenic or likely pathogenic according to our variant classification scheme and thus we concluded that genetic screening of patients with one or few JPs are not indicated. Paper IV: In Paper IV we investigated one of the ethical aspects of next generation sequencing: the issue whether research participants in NGS studies should be offered the possibility of not re-ceiving information on incidental genetic findings (the "opting out possibility"). We conducted semi-structures interviews in 127 research participants, and found that the majority (61%) wanted information on all incidentals findings, while 36% wanted information on actionable incidental findings. Only 3% did not want information on incidental findings at all. Paper V: In this paper we wanted to gather information on all Danish patients with Peutz-Jeghers syndrome in order to investigate the phenotype and genotype. Through Danish registers we detected 43 patients of which 14 had deceased. We calculated the prevalence of Peutz-Jeghers syndrome to be approximately one in 195,000 individuals. The median age at diagnosis was 29 years with obstruction of the small bowel as the most frequent presenting symptom. We noted 18 cancer occurrences in the population in both the GI tract and at extraintestinal sites, demonstrating that these patients are predisposed to cancer at various anatomical sites. The study also underlined the wide phenotypic expression of the syndrome. Paper VI: In the last paper we identified patients with juvenile polyposis syndrome, who carry a SMAD4 mutation, and described their genotype and phenotype. We especially investigated whether these patients have symptoms of both juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. We identified 14 Danish patients. Most of these had symptoms of both conditions and one had aortic root dilatation. Thus, this group of patients requires a multidisciplinary follow up program. PMID- 27477803 TI - Virtual reality simulation training of mastoidectomy - studies on novice performance. AB - Virtual reality (VR) simulation-based training is increasingly used in surgical technical skills training including in temporal bone surgery. The potential of VR simulation in enabling high-quality surgical training is great and VR simulation allows high-stakes and complex procedures such as mastoidectomy to be trained repeatedly, independent of patients and surgical tutors, outside traditional learning environments such as the OR or the temporal bone lab, and with fewer of the constraints of traditional training. This thesis aims to increase the evidence-base of VR simulation training of mastoidectomy and, by studying the final-product performances of novices, investigates the transfer of skills to the current gold-standard training modality of cadaveric dissection, the effect of different practice conditions and simulator-integrated tutoring on performance and retention of skills, and the role of directed, self-regulated learning. Technical skills in mastoidectomy were transferable from the VR simulation environment to cadaveric dissection with significant improvement in performance after directed, self-regulated training in the VR temporal bone simulator. Distributed practice led to a better learning outcome and more consolidated skills than massed practice and also resulted in a more consistent performance after three months of non-practice. Simulator-integrated tutoring accelerated the initial learning curve but also caused over-reliance on tutoring, which resulted in a drop in performance when the simulator-integrated tutor-function was discontinued. The learning curves were highly individual but often plateaued early and at an inadequate level, which related to issues concerning both the procedure and the VR simulator, over-reliance on the tutor function and poor self assessment skills. Future simulator-integrated automated assessment could potentially resolve some of these issues and provide trainees with both feedback during the procedure and immediate assessment following each procedure. Standard setting by establishing a proficiency level that can be used for mastery learning with deliberate practice could also further sophisticate directed, self-regulated learning in VR simulation-based training. VR simulation-based training should be embedded in a systematic and competency-based training curriculum for high quality surgical skills training, ultimately leading to improved safety and patient care. PMID- 27477805 TI - Defining criteria for rheumatoid arthritis patient-derived disease activity score that correspond to Disease Activity Score 28 and Clinical Disease Activity Index based disease states and response criteria. AB - OBJECTIVE: Two versions of a patient-based DAS (PDAS) 1 and 2 (with and without ESR) have been developed and validated in RA. The objective of this study was to define PDAS1- and PDAS2-based criteria for remission, low, moderate and high disease activity and responses to treatment. METHOD: Using receiver operating characteristic curves, the optimal thresholds for PDAS1 and PDAS2 that correspond to validated assessor-based DAS (DAS28) and Clinical Disease Activity Index (CDAI) disease statuses were determined. Data from RA patients initiated on disease-modifying drugs were used to determine optimal thresholds for PDAS1 and PDAS2 that corresponded to EULAR good and moderate responses. Agreement with DAS28, CDAI and EULAR response criteria was assessed by Cohen's kappa statistic. RESULTS: Threshold for PDAS1 and PDAS2 demonstrated fair to moderate agreement with DAS28 [kappa = 0.44 (95% CI: 0.40, 0.50) and 0.31 (95% CI: 0.25, 0.38)] and CDAI [kappa = 0.27 (95% CI: 0.22, 0.33) and 0.42 (95% CI: 0.35, 0.49)] disease statuses, respectively, which was similar to agreement between DAS28 and CDAI [kappa = 0.54 (95% CI: 0.46, 0.61)] within this group. Agreement of EULAR good and moderate response with PDAS1 and PDAS2 was kappa = 0.46 (95% CI: 0.27, 0.64) and 0.38 (95% CI: 0.20, 0.56), respectively. CONCLUSION: Thresholds for disease activity statuses and response to treatment for PDAS1 and PDAS2 have been established. They have comparable agreement to assessor-based criteria. PMID- 27477804 TI - Combined Treatment With Chondroitin Sulfate and Glucosamine Sulfate Shows No Superiority Over Placebo for Reduction of Joint Pain and Functional Impairment in Patients With Knee Osteoarthritis: A Six-Month Multicenter, Randomized, Double Blind, Placebo-Controlled Clinical Trial. AB - OBJECTIVE: To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis (OA). METHODS: A multicenter, randomized, double-blind, placebo-controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate-to severe knee pain (mean +/- SD global pain score 62.1 +/- 11.3 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy. RESULTS: Intriguingly, in the modified intent-to-treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean +/- SD change in VAS global pain score over 6 months -11.8 +/- 2.4 mm [19% reduction] in patients receiving CS plus GS versus -20.5 +/- 2.4 mm [33% reduction] in patients receiving placebo; peak between-group difference in global pain score at 6 months 8.7 mm [14.2%], P < 0.03), but no between-group differences were seen in the per-protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per-protocol completers. Neither the OMERACT-OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed. CONCLUSION: The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA. PMID- 27477807 TI - Treatment preferences of patients with early rheumatoid arthritis: a discrete choice experiment. AB - OBJECTIVE: To quantify the preferences of patients with early RA (ERA) with the benefits and harms of DMARDs. METHODS: We assessed patients' preferences using a discrete-choice experiment, an experimentally designed survey to measure trade offs. Consecutive adult patients with ERA (<2 years since diagnosis) were presented 13 different sets of three treatment options described by eight attributes (clinical outcomes, risks and dosing regimens) and asked to choose one. From patients' responses we estimated the average importance of each attribute and explored preference heterogeneity through latent-class analysis. RESULTS: A total of 152 patients completed the survey (86% response rate): mean age 52 years, 63% female, disease duration 7.8 months. Treatment benefits (increasing the chance of a major symptom improvement and reducing the chance of serious joint damage) were most important. Of potential adverse events, a small risk of serious infections/possible increased risk of cancer was most important. Patients were willing to accept this risk for a 15% absolute increase in the chance of a major symptom improvement. Patients had an aversion to i.v. therapy, but were relatively indifferent to other dosing regimens. Through latent-class analysis, we identified two patient groups: 54% who were more risk averse, particularly to a possible risk of cancer/infection, and others who were highly benefit-driven. CONCLUSION: On average, patients with ERA were risk tolerant, but important differences in preferences were identified. In particular, a subgroup of patients may prefer to avoid treatments with a possible increased risk of cancer/infection if other effective options are available. PMID- 27477808 TI - Placebo-related effects: a meta-narrative review of conceptualization, mechanisms and their relevance in rheumatology. AB - For decades in medicine, the placebo effect has been conceptualized as a subjective psychological effect associated with an inert substance and considered to be a nuisance noise in the assessment of therapeutic effects in clinical trials. However, research on placebo has undergone substantial developments since the mid-1980s in several fields of knowledge (including methodology, psychology and neurosciences) that challenge this traditional view. Using a meta-narrative approach, this review of conceptualizations, determinants, mechanisms and models of placebo effects shows that placebo effects are genuine biopsychosocial phenomena strongly affected by context and factors surrounding the patient and treatments. Psychological experiments and neurobiological and neuroimaging studies have identified various types of placebo responses, driven by different mechanisms (especially but not only expectation and conditioning) and associated with different chemical, structural and functional features. Insights into the mechanisms involved in placebo responses have led to opportunities for ethical enhancements of these mechanisms in clinical practice, notably by improving the patient-doctor interaction and refining the therapeutic ritual. These developments should be carefully considered in rheumatology settings, in which placebo effects are both prevalent and significant, with the potential to improve patient care. PMID- 27477806 TI - Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans. AB - OBJECTIVES: Cigarette smoking is a major risk factor for RA and has been associated with increased disease severity and lower rates of disease remission. We hypothesized that inflammation and disease activity would be associated with smoking status and this would be related to levels of ACPA. METHODS: RA patients from the Veterans Affairs RA registry were studied (n = 1466): 76.9% anti-CCP2 positive, 89% male, median age 63 years (interquartile range 57-72), median disease duration 8.45 years (interquartile range 2.8-18). Baseline serum samples were evaluated for levels of anti-CCP2, RF, 19 distinct ACPAs and 17 cytokines. Smoking status at baseline was recorded as current, former or never. The association of smoking status with cytokines, autoantibodies and disease activity (DAS28) was evaluated. RESULTS: Among anti-CCP-positive RA patients, RA associated cytokines (false-discovery rates q < 0.1%) and DAS28 (P < 0.01) were higher in current smokers compared with former or never smokers. DAS28 and cytokine levels were similar between former and never smokers. In contrast, ACPA concentrations were higher among both current and former smokers compared with never smokers, and levels of ACPA were not associated with DAS28 or cytokine levels. CONCLUSION: Among anti-CCP2-positive RA patients, current smoking status is associated with elevations in pro-inflammatory cytokines and increased RA disease activity. Similar levels of inflammation and disease activity among former and never smokers suggests that the detrimental effects of smoking could be ameliorated through tobacco cessation. The effect of tobacco cessation on RA disease activity should be evaluated prospectively. PMID- 27477809 TI - Sodium Selenite Inhibits Proliferation of Gastric Cancer Cells by Inducing SBP1 Expression. AB - Selenium is an essential trace element with an inhibitory effect on many types of human cancers, including gastric cancer. Selenium-binding protein 1 (SBP1) has been shown as a possible mediator of selenium's anti-cancer functions. Indeed, SBP1 was downregulated in gastric cancer, which is related with poor prognosis. However, the molecular mechanisms underlying the anti-tumor effects of SBP1 remain poorly understood. In this study, we aimed to assess the effects of selenium and/or SBP1 on the proliferation of gastric cancer cells. We used SGC7901 and N87 human gastric cancer cell lines and nude mice carrying subcutaneously implanted SGC7901 cells. Treatment with sodium selenite for 48 h caused the inhibition of cell proliferation and the increase in apoptosis of SGC7901 and N87 cells. Furthermore, sodium selenite increased the expression level of SBP1 and decreased the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and the Wnt pathway components and its downstream targets, including beta-catenin, GSK-3beta, c-myc and cyclinD1 in these cell lines. However, these effects of sodium selenite were attenuated in SGC7901 and N87 cells by knockdown of SBP1 expression. Thus, the sodium selenite-induced SBP1 expression is associated with the inhibition of cell proliferation and with the induced apoptosis. Importantly, sodium selenite treatment retarded the growth of the transplanted SGC7901 cells in nude mice, with the induction of SBP1 expression, which was associated with the decrease of Nrf2 expression and the inactivation of the Wnt/beta-catenin signaling pathway. We suggest that sodium selenite may have a potential application in gastric cancer treatment. PMID- 27477810 TI - Editorial: Molecular Informatics Gaining Impact. PMID- 27477811 TI - Advances in the Prediction of Turn Structures in Peptides and Proteins. AB - Turns are essential for protein structure as they allow the polypeptide chain to fold backup on itself. They also occur within protein binding sites, at protein?protein interfaces and in small bioactive peptides, where they can play a crucial role for molecular recognition. Turn structures are an important class of protein secondary structure, although relatively little attention is paid to them with respect to helices and beta-sheets. Protein structure prediction, functional analysis of proteins and peptides, and computer-aided drug design could all benefit from making use of accurately predicted turn structures from amino acid sequence. Here, recent advances of turn structure prediction and the underlying turn classification will be discussed together with their applications. PMID- 27477812 TI - Impact of X-Ray Structure on Predictivity of Scoring Functions: PPARgamma Case Study. PMID- 27477813 TI - Homology Modeling and Validation of the Human M1 Muscarinic Acetylcholine Receptor. PMID- 27477814 TI - Interpretability of SAR/QSAR Models of any Complexity by Atomic Contributions. PMID- 27477815 TI - Harnessing Human N-type Ca(2+) Channel Receptor by Identifying the Atomic Hotspot Regions for Its Structure-Based Blocker Design. AB - The voltage dependent N-type Ca(2+) channel (NCC) receptor was identified to have therapeutic potential for the treatment of neuropathic pain and stroke disease. The Ca(2+) ion transport through the transmembrane influx is mainly dependent on the closing, opening, or intermediate state gating mechanism of NCC. Harnessing this dynamic gating mechanism at the structural level is an important and challenging physiological phenomenon. The three dimensional (3D) structure of this membrane receptor is not yet experimentally determined to understand its mechanism of action. Based on these observations, we have developed for the first time the structure of the closed state of the NCC receptor at the pore forming domains which mainly involve three transmembrane helices (TMhs) S5, P and S6. Hot spot binding site residues of this receptor model were identified by molecular docking technique using amlodipine, cilnidipine and nifedipine compounds known to be potent Ca(2+) channel antagonists. Further, the Ca(2+) ion permeability and the hydrophobic gating mechanism provided better structural and functional insights on the NCC receptor. These results are in consonance with other Ca(2+) channel receptors and would provide guidance for further biochemical investigations. PMID- 27477816 TI - Structural Basis of Amino Pyrimidine Derivatives for Inhibitory Activity of PKC theta: 3D-QSAR and Molecular Docking Studies. AB - In the present study, 3D-QSAR analysis was performed on a set of 56 amino pyrimidine PKC-theta inhibitors utilizing docking based alignment. The best 3D QSAR model exhibited the highest value of Q(2) (0.825) and also displayed high values of R(2) (0.937), F (184.600) and low SD (0.240). The selected model was validated by determining the Pearson-r (0.915) for test set molecules. Docking simulation was carried out to explore the binding interactions of the molecules with active site amino acid residues of the receptor and subsequently to validate the generated 3D-QSAR model. The results of 3D-QSAR and docking analysis exerted complementary fit that strengthen the stability and reliability of the generated model. Therefore, the combined study of 3D-QSAR and docking analysis may successfully be used for the rational designing of new potent congeners. PMID- 27477817 TI - QSAR Modelling of CYP3A4 Inhibition as a Screening Tool in the Context of Drug?Drug Interaction Studies. AB - Drug?drug interaction potential (DDI), especially cytochrome P450 (CYP) 3A4 inhibition potential, is one of the most important parameters to be optimized before preclinical and clinical pharmaceutical development as regard to the number of marketed drug metabolized mainly by this CYP and potentially co administered with the future drug. The present study aims to develop in silico models for CYP3A4 inhibition prediction to help medicinal chemists during the discovery phase and even before the synthesis of new chemical entities (NCEs), focusing on NCEs devoid of any inhibitory potential toward this CYP. In order to find a relevant relationship between CYP3A4 inhibition and chemical features of the screened compounds, we applied a genetic-algorithm-based QSAR exploratory tool SQS (Stochastic QSAR Sampler) in combination with different description approaches comprising alignment-independent Volsurf descriptors, ISIDA fragments and Topological Fuzzy Pharmacophore Triplets. The experimental data used to build models were extracted from an in-house database. We derived a model with good prediction ability that was confirmed on both newly synthesized compound and public dataset retrieved from Pubchem database. This model is a promising efficient tool for filtering out potentially problematic compounds. PMID- 27477818 TI - Probability Based hERG Blocker Classifiers. AB - The US Food and Drug Administration (FDA) require in vitro human ether-a-go-go related (hERG) ion channel affinity tests for all drug candidates prior to clinical trials. In this study, probabilistic-based methods were employed to develop prediction models on hERG inhibition prediction, which are different from traditional QSAR models that are mainly based on supervised 'hard point' (HP) classification approaches giving 'yes/no' answers. The obtained models can 'ascertain' whether or not a given set of compounds can block hERG ion channels. The results presented indicate that the proposed probabilistic-based method can be a valuable tool for ranking compounds with respect to their potential cardio toxicity and will be promising for other toxic property predictions. PMID- 27477819 TI - Use of Rasch analysis to investigate structural validity of a set of movement control tests for the neck. AB - BACKGROUND: Movement control abilities are often reduced in persons with neck pain. In physiotherapeutic practice observational tests are frequently used to assess the impaired abilities. Several tests for movement control abilities are available, but no evidence exists on how to combine and interpret them. OBJECTIVE: The aim was to investigate structural validity of a set of movement control tests with Rasch analysis. DESIGN: Cross-sectional study. METHODS: Thirty persons with and thirty without neck pain were recruited for this study. All persons performed ten movement control tests. A partial credit model was applied to investigate item fit, ordering of the item response functions, dimensionality and hierarchy of the tests. RESULTS: The majority of persons with neck pain had moderate disabilities and the mean value in the Neck disability index was 10.7. Functioning of the movement control tests to measure the construct "movement control abilities" was adequate for the majority of tests. Three movement control tests showed considerable misfit. Possible explanations were a reactive movement control instead of an active control and a more challenging test position. Test difficulties and person abilities could be estimated for the complete sample. The most difficult test was "sitting rocking forward" (1.13 logits) and the least difficult test was "lifting the right arm" (-1.30 logits). The highest person ability estimate was 3.61 logits indicating that movement control tests are missing to evaluate persons with moderate neck disabilities. CONCLUSION: Modifying the existing set of tests is required to evaluate the complete spectrum of persons with neck pain. PMID- 27477820 TI - Increased CD4+CXCR5+T follicular helper cells in diabetic nephropathy. AB - BACKGROUND: T follicular helper (Tfh) cells are known to regulate humoral immune response. In this study we examined the correlation of different subsets of peripheral blood Tfh cells in patients with diabetic nephropathy (DN). METHODS: A total of 23 DN patients and 15 healthy controls (HC) were investigated for various subsets of Tfh cells by flow cytometry. The molecules ICOS+, PD-1+, CD28+, CD154+, IL-21+, IFN-gamma+, IL-4+, IL-17+ Tfh cells were examined. The subsets of B cells were investigated by flow cytometry. The levels of 24 h urinary protein and estimated glomerular filtration rate (eGFR) were calculated. A potential correlation between the number of different subsets of Tfh cells, B cells and DN, was assessed. RESULTS: The circulating CD4+CXCR5+PD-1+, PD 1+CD154+, PD-1+CD28+, PD-1+IL-21+, PD-1+IL-4+, PD-1+-IL-17+-Tfh cell counts, CD38+CD19+, CD38+CD19+CD40+ B cells and plasma levels of IL-21 were significantly increased in DN patients (p < 0.05), as compared to that in the HC group. Furthermore, the circulating CD4+CXCR5+PD-1+ Tfh cell counts negatively correlated with eGFR; Tfh cell counts positively correlated with 24 h urinary protein concentration in DN patients. Post-treatment, there was a significant reduction in the CD4+CXCR5+PD-1+ Tfh cell counts and its subsets, with a corresponding decrease in plasma levels of IL-6 and IL-17A (p < 0.05) in DN patients, as compared to the HCs. CONCLUSION: An increased number of CD4+CXCR5+PD 1+ Tfh cells were observed in DN patients, which may be new targets for intervention in DN. PMID- 27477821 TI - 13 C and 15 N NMR spectra of high-energy polyazidocyanopyridines. AB - 13 C and 15 N NMR spectra of high-energy 2,4,6-triazidopyridine-3,5 dicarbonitrile, 2,3,5,6-tetraazidopyridine-4-carbonitrile and 3,4,5,6 tetraazidopyridine-2-carbonitrile are reported. The assignment of signals in the spectra was performed on the basis of density functional theory calculations. The molecular geometries were optimized using the M06-2X functional with the 6 311+G(d,p) basis set. The magnetic shielding tensors were calculated by the gauge independent atomic orbital method with the Tao-Perdew-Staroverov-Scuseria hybrid functional known as TPSSh. In all the calculations, a polarizable continuum model was used to simulate solvent effects. This approach provided accurate predictions of the 13 C and 15 N chemical shifts for all the three compounds despite complications arising due to non-coplanar arrangement of the azido groups in the molecules. It was found that the 15 N chemical shifts of the Nalpha atoms in the azido groups of 2,4,6-triazidopyridines correlate with the 13 C chemical shifts of the carbon atoms attached to these azido groups. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27477822 TI - Prognostic Significance of Progesterone Receptor Expression in Estrogen-Receptor Positive, HER2-Negative, Node-Negative Invasive Breast Cancer With a Low Ki-67 Labeling Index. AB - INTRODUCTION: We showed the clinical implications of the Ki-67 labeling index (LI) in hormone receptor (HR)-positive, HER2-negative (HER2-) breast cancer patients with lower risk (luminal A [LA]-like) and higher risk (luminal B [LB] like) subtypes. PATIENTS AND METHODS: Three hundred sixty-nine patients with HR+, HER2- cancers were eligible and we dichotomized these patients into LA-like and LB-like according to Ki-67 LI (14% cutoff) and analyzed prognostic significance of progesterone receptor (PR) expression. RESULTS: Of 205 LA-like and 163 LB-like subtypes, PR was positive in 149 (73%) and 103 (63%). PR expression was a prognostic factor in the LA-like subtype but not in the LB-like subtype. In LA/PR+, LA/PR-, and LB-like subtypes, the 12-year disease-free survival (DFS) rates were 94.8%, 81.6%, and 79.7% (P = .03), and breast cancer-specific survival (BCSS) rates were 98.4%, 97.4%, and 92.0%, respectively (P = .05). Late recurrence occurred in LA/PR- subtype, and differences in prognosis between LA/PR+ and LA/PR- subtypes emerged >5 years after surgery. Twelve-year DFS rates of the LA/PR- subtype were almost equal to those of the LB-like subtype, whereas 12-year BCSS of the LA/PR- subtype was superior to that of the LB-like subtype. In multivariate analysis, PR expression and tumor size were significant or nearly significant prognostic factors. CONCLUSION: PR expression and tumor size were independent prognostic factors in the LA-like subtype, and the LA/PR- subtype had the higher risk of recurrence, especially late recurrence, than the LA/PR+ subtype. In LA-like breast cancers, stratification of prognosis according to PR expression and tumor size is important. PMID- 27477823 TI - Epidemiological impact of a syphilis vaccine: a simulation study. AB - Despite the availability of inexpensive antimicrobial treatment, syphilis remains prevalent worldwide, affecting millions of individuals. Furthermore, syphilis infection is suspected of increasing both susceptibility to, and tendency to transmit, HIV. Development of a syphilis vaccine would be a potentially promising step towards control, but the value of dedicating resources to vaccine development should be evaluated in the context of the anticipated benefits. Here, we use a detailed mathematical model to explore the potential impact of rolling out a hypothetical syphilis vaccine on morbidity from both syphilis and HIV and compare it to the impact of expanded 'screen and treat' programmes using existing treatments. Our results suggest that an efficacious vaccine has the potential to sharply reduce syphilis prevalence under a wide range of scenarios, while expanded treatment interventions are likely to be substantially less effective. Our modelled interventions in our simulated study populations are expected to have little effect on HIV, and in some scenarios lead to small increases in HIV incidence, suggesting that interventions against syphilis should be accompanied with interventions against other sexually transmitted infections to prevent the possibility that lower morbidity or lower perceived risk from syphilis could lead to increases in other sexually transmitted diseases. PMID- 27477824 TI - Uncovering the Stabilization Mechanism in Bimetallic Ruthenium-Iridium Anodes for Proton Exchange Membrane Electrolyzers. AB - Proton exchange membrane (PEM) electrolyzers are attracting an increasing attention as a promising technology for the renewable electricity storage. In this work, near ambient pressure X-ray photoelectron spectroscopy (NAP-XPS) is applied for in situ monitoring of the surface state of membrane electrode assemblies with RuO2 and bimetallic Ir0.7Ru0.3O2 anodes during water splitting. We demonstrate that Ir protects Ru from the formation of an unstable hydrous Ru(IV) oxide thereby rendering bimetallic Ru-Ir oxide electrodes with higher corrosion resistance. We further show that the water splitting occurs through a surface Ru(VIII) intermediate, and, contrary to common opinion, the presence of Ir does not hinder its formation. PMID- 27477825 TI - Cytogenetics in the management of "chronic myeloid leukemia": an update by the Groupe francophone de cytogenetique hematologique (GFCH). AB - Cytogenetic evaluation is one the most important criteria for diagnosis and response to treatment in chronic myeloid leukemia, and recent baseline prognostic factors including particular additional clonal cytogenetic abnormalities have been established. The French cytogenetic group in hematology GFCH proposes here an updating of recommendations for cytogenetic assessment of CML in the era of tyrosine kinase inhibitors. PMID- 27477826 TI - Validation of criteria for the definition of transient lower esophageal sphincter relaxations using high-resolution manometry. AB - BACKGROUND: Criteria for transient lower esophageal sphincter relaxations (TLESRs) are well-defined for Dentsleeve manometry. As high-resolution manometry (HRM) is now the gold standard to assess esophageal motility, our aim was to propose a consensus definition of TLESRs using HRM. METHODS: Postprandial esophageal HRM combined with impedance was performed in 10 patients with gastroesophageal reflux disease. Transient lower esophageal sphincter relaxations identification was performed by 17 experts using a Delphi process. Four investigators then characterized TLESR candidates that achieved 100% agreement (TLESR events) and those that achieved less than 25% agreement (non-events) after the third round. Logistic regression and decision tree analysis were used to define optimal diagnostic criteria. KEY RESULTS: All diagnostic criteria were more frequently encountered in the 57 TLESR events than in the 52 non-events. Crural diaphragm (CD) inhibition and LES relaxation duration >10 seconds had the highest predictive value to identify TLESR. Based on decision tree analysis, reflux on impedance, esophageal shortening, common cavity, upper esophageal sphincter relaxation without swallow and secondary peristalsis were alternate diagnostic criteria. CONCLUSION & INFERENCES: Using HRM, TLESR might be defined as LES relaxation occurring in absence of swallowing, lasting more than 10 seconds and associated with CD inhibition. PMID- 27477827 TI - Considering Ranolazine as a Potential Treatment for K+ Channel Linked Short QT Syndrome. PMID- 27477828 TI - Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families. AB - Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the gamma-glutamyl cycle, affecting either glutathione synthetase or 5 oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology. PMID- 27477830 TI - Upregulation of lipocalin-2 (LCN2) in osteoarthritic cartilage is not necessary for cartilage destruction in mice. AB - OBJECTIVE: Lipocalin-2 (LCN2) is a recently characterized adipokine that is upregulated in chondrocytes treated with pro-inflammatory mediators and in the synovial fluid of osteoarthritis (OA) patients. Here, we explored the in vivo functions of LCN2 in OA cartilage destruction in mice. METHODS: The expression levels of LCN2 were determined at the mRNA and protein levels in primary cultured mouse chondrocytes and in human and mouse OA cartilage. Experimental OA was induced in wild-type (WT) or Lcn2-knockout (KO) mice by destabilization of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing hypoxia-inducible factor (HIF)-2alpha (Ad-Epas1), ZIP8 (Ad-Zip8), or LCN2 (Ad-Lcn2). The effect of LCN2 overexpression on the cartilage of WT mice was examined by IA injection of Ad-Lcn2. RESULTS: LCN2 mRNA levels in chondrocytes were markedly increased by the pro-inflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha), and by previously identified catabolic regulators of OA, such as HIF-2alpha and components of the zinc-ZIP8 MTF1 axis. LCN2 protein levels were also markedly increased in human OA cartilage and cartilage from various experimental mouse models of OA. However, overexpression of LCN2 in chondrocytes did not modulate the expression of cartilage matrix molecules or matrix-degrading enzymes. Furthermore, LCN2 overexpression in mouse cartilage via IA injection of Ad-Lcn2 did not cause OA pathogenesis, and Lcn2 KO mice showed no alteration in DMM-induced OA cartilage destruction. CONCLUSIONS: Our observations collectively suggest that upregulation of LCN2 in OA cartilage is not sufficient or necessary for OA cartilage destruction in mice. PMID- 27477831 TI - Psychological and behavioral acculturation in a social network of Mexican Americans in the United States and use of dental services. AB - OBJECTIVES: We used data from the TalaSurvey study to examine associations between dental health experiences, social network characteristics, and levels of behavioral and psychological acculturation in one location in the American Midwest. METHODS: Starting in parishes and community organizations, we identified adults of Mexican origin living in Indianapolis, who were 1st- or 2nd-generation immigrants from Tala, Mexico. Using a social networks methodology and following extensive formative research, we created an egocentric social network survey and administered it via face-to-face interviews. We identified the peers (alters) in interviewees' (egos) personal networks. We asked egos about multiple oral health and dental care variables for self and for alters. Acculturation (psychological and behavioral) was measured with a validated tool. Through logistic and negative binomial regression, we examined the effects of acculturation and network composition on ego's dental insurance status, dental office visits, and the reason for most recent dental office visit. RESULTS: A total of 332 egos (mean age 36; 63% female) were interviewed: 90% were born in Mexico; 45% had completed elementary school or lower; and most had low income. Each ego named 3.9 (SD+/ 1.9) alters in his/her personal network, for a total of 1299 alters (mean age 39; 61% female). Both behavioral acculturation and psychological acculturation were moderately associated with dental insurance coverage, and greater behavioral acculturation predicted more frequent dental care. More psychologically acculturated egos were more likely to seek preventive care. Further, egos with more highly educated networks sought care more frequently and for preventive purposes, net of ego's own education and acculturation. CONCLUSIONS: This study contextualizes acculturation of Mexican Americans within the personal networks in which oral health discussion takes place. The findings underscore the critical importance of acculturation and social network factors in shaping a subgroup of Latinos' orientation toward dental care. PMID- 27477832 TI - Overlap between dental anxiety, gagging and Blood-Injection-Injury related fears A spectrum of one multidimensional phenomenon. AB - BACKGROUND AND OBJECTIVES: Dental anxiety (DA) and gagging (GAG) are prevalent problems that severely impact social behavior and quality of life. Furthermore, because dental phobia is considered a Blood-Injection-Injury (B-I-I) phobia, the present study contrasted DA, GAG and control subjects regarding the severity of dental anxiety and investigated the comorbidity of GAG, DA and B-I-I fears. METHODS: Demographics, Verbal Pain Scale (VPS), Oral Health Impact Profile-14 (OHIP-14), Decay, Missing and Filled Teeth (DMFT), Dental Anxiety Scale (DAS) and response to phobic stimuli were collected from 53 GAG, 68 DA and 80 control subjects. RESULTS: GAGs exhibited results between DA and controls regarding the likelihood to have high-anxiety/phobia (DA group: OR=55.56; GAG group: OR=17.24), self-assessed dental anxiety (OR=29.14; OR=17.48), fear of dental injections (OR=8.51; OR=2.91) and dental drills (OR=12.02; OR=5.82). DA and GAG had similar results regarding: DAS score (p=0.13), fear of blood tests (OR=4.68; OR=4.09) and blood donations (OR=3.13; OR=3.10). Overlap between GAG, DA and a B-I-I fear was observed. GAG and DA patients and worse maximal VPS and OHIP-14 scores retained their significant positive association with the DAS score in the multivariate analysis. CONCLUSIONS: The co-occurrence of DA, GAG and B-I-I-related fears suggests these entities are linked. However, different anxiety levels, symptoms and triggers, reflect the broad spectrum of fear of medical/dental situations. PMID- 27477833 TI - Conscious distance monitoring and perceived exertion in light-deprived cycling time trial. AB - The monitoring of distance is crucial to calculate the metabolic requirement and the ratings of perceived exertion (RPE) for a given exercise bout. Visual cues provide valuable information for distance estimation, navigation and orientation. The present study investigated if light deprivation may affect the conscious monitoring of distance, RPE and associative thoughts to exercise (ATE) during a 20-km cycling time trial (TT20km). Eleven male, endurance cyclists performed two TT20km in illuminated-control and light-deprived laboratory. They were asked to self-report RPE and ATE when they perceived they had completed each 2km. RESULTS: The light deprivation resulted in elongated perceived distance at each actual 2km, rather than in illuminated-control trial (P<0.05). Although there was no difference in RPE when it was plotted as a function of the perceived distance, RPE was lowered in light-deprived environment when it was plotted as a function of the actual distance (P<0.05). Additionally, ATE was lowered during TT20km in light deprivation (P<0.01); however, pacing and performance were unaffected in light-deprived environment. CONCLUSION: Results suggest that pacing and performance were regulated through a system which was unaffected in light deprived environment, despite the altered conscious distance monitoring and perceptive responses. PMID- 27477829 TI - 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative. AB - INTRODUCTION: There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. METHODS: Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism - Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed. RESULTS: The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2MUmol/L (median 8.6, range 0.36 43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A>G ACADM gene mutation or compound heterozygous for the c.985A>G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A>G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities. CONCLUSIONS: This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system. PMID- 27477834 TI - "I Serve 2": Meeting the needs of military children in civilian practice. AB - The American Academy of Nursing launched the "Have You Ever Served in the Military?" campaign in 2013 in conjunction with the Joining Forces campaign spearheaded by First Lady Michelle Obama and Dr. Jill Biden. The "Have You Ever Served in the Military?" campaign provides guidance and resources for nurses outside the Military Health System and Veterans Health Administration where upwards of 80% of veterans receive care. However, most military personnel do not serve alone. More than half of the 2.2 million active duty, National Guard, and Reserve service members currently serving in the armed forces have families and many military children experience stress and anxiety secondary to parental military service. Although strides have been made to improve identification and treatment of the visible and invisible wounds of war for service members, little to no information exists regarding the impact parental service has on the physical, psychological, and behavioral health of military children. In addition, there is no mechanism in place to identify military children in civilian practice nor resources providing evidence-based best practices when caring for these children. PMID- 27477835 TI - Bridge to recovery using extracorporeal membrane oxygenation for critical tracheal stenosis complicating refractory bronchospasm. PMID- 27477837 TI - Using concept hierarchies to improve calculation of patient similarity. AB - OBJECTIVE: We introduce a new distance measure that is better suited than traditional methods at detecting similarities in patient records by referring to a concept hierarchy. MATERIALS AND METHODS: The new distance measure improves on distance measures for categorical values by taking the path distance between concepts in a hierarchy into account. We evaluate and compare the new measure on a data set of 836 patients. RESULTS: The new measure shows marked improvements over the standard measures, both qualitatively and quantitatively. Using the new measure for clustering patient data reveals structure that is otherwise not visible. Statistical comparisons of distances within patient groups with similar diagnoses shows that the new measure is significantly better at detecting these similarities than the standard measures. CONCLUSION: The new distance measure is an improvement over the current standard whenever a hierarchical arrangement of categorical values is available. PMID- 27477836 TI - Combined with Bone Marrow-Derived Cells and rhBMP-2 for Osteonecrosis after Femoral Neck Fractures in Children and Adolescents: A case series. AB - Osteonecrosis of the femoral head (ONFH) following femoral neck fractures is a rare, yet severe, disorder in children and adolescents. This study evaluated the effectiveness of core decompression (CD) combined with implantation of bone marrow-derived cells (BMDC) and rhBMP-2 for osteonecrosis of femoral head (ONFH) after femoral neck fractures in children and adolescents. This study included 51 patients, aged 11.4-18.1 years, with ARCO stages I-III ONFH after femoral neck fractures between 2004 and 2010. The hips were divided into two groups based on whether the lateral pillar of the femoral head (LPFH) was preserved: LPFH and non LPFH groups. All patients were followed up clinically and radiographically for a minimum of 5 years. 44 patients (86.3%) had improved clinical outcome. Radiologically, 9 of the 51 hips (17.6%) exhibited collapse onset or progression of the femoral head or narrowing of the hip joint space, and one patient in the non-LPFH group required hip arthroplasty due to the worsened syndrome. The technique provided an effective therapeutic option for children and adolescents with ONFH following femoral neck fractures. It relieves hip pain and prevents the progression of osteonecrosis in young patients lasting more than 5 years after surgery. PMID- 27477838 TI - An approach for deciphering patient-specific variations with application to breast cancer molecular expression profiles. AB - Several studies have successfully used molecular expression profiling in conjunction with classification techniques for discerning distinct disease groups. However, a majority of these studies do not provide sufficient insights into potential patient-specific variations within the disease groups. Such variations are ubiquitous and manifests across multiple scales with varying resolution. There is an urgent need for novel approaches that falls within the objective of precision medicine and provide novel insights into patient-specific variations and sub-populations within disease groups while discerning the disease groups of interest so as to enable timely and targeted intervention of select subjects. This study presents a selective-voting ensemble classification approach (SVA) for discerning good and poor-prognosis breast cancer samples from their 70 gene molecular expression profile revealing patient-specific variations within the poor-prognosis group. In contrast to traditional classification, SVA adapts the feature sets in a sample-specific manner capturing the proclivity of the samples to each of the disease groups. Correlation between normalized vote counts from SVA and clinical outcomes of the subjects is elucidated. Performance of Support Vector Machine and Naive Bayes classifier is investigated within the SVA framework and compared to established clinical criteria (Nottingham Prognostic Index, Adjuvant Online, St. Gallen) and Mammaprint approach. Weighted undirected graph abstractions of the ensemble sets of the poor-prognosis test samples is also shown to exhibit markedly different topologies with varying proclivities. These patient-specific networks may reflect inherent variations in underlying signaling mechanisms in the poor-prognosis subjects and reveal potential targets for personalized therapeutic intervention. PMID- 27477839 TI - Decision support environment for medical product safety surveillance. AB - We have developed a Decision Support Environment (DSE) for medical experts at the US Food and Drug Administration (FDA). The DSE contains two integrated systems: The Event-based Text-mining of Health Electronic Records (ETHER) and the Pattern based and Advanced Network Analyzer for Clinical Evaluation and Assessment (PANACEA). These systems assist medical experts in reviewing reports submitted to the Vaccine Adverse Event Reporting System (VAERS) and the FDA Adverse Event Reporting System (FAERS). In this manuscript, we describe the DSE architecture and key functionalities, and examine its potential contributions to the signal management process by focusing on four use cases: the identification of missing cases from a case series, the identification of duplicate case reports, retrieving cases for a case series analysis, and community detection for signal identification and characterization. PMID- 27477840 TI - Lanolin for the treatment of nipple pain in breastfeeding women: a randomized controlled trial. AB - Nipple pain and damage are commonly experienced by breastfeeding women and are associated with negative breastfeeding outcomes. Health care providers often recommend the application of lanolin to treat painful/damaged nipples, yet no randomized controlled trial has evaluated the effectiveness of lanolin on nipple pain and breastfeeding outcomes. The purpose of this study was to evaluate the effect of lanolin on nipple pain among breastfeeding women with damaged nipples. A randomized, single-blind, controlled trial was conducted at a tertiary care hospital in Hamilton, Ontario, Canada. Breastfeeding women (N = 186) identified as having nipple pain/damage were randomized to apply lanolin (intervention group; n = 93) or to receive usual postpartum care (control group; n = 93). The primary outcome was nipple pain at 4 days post-randomization measured by the Numeric Rating Scale. Additional outcomes included nipple pain measured by the Short Form McGill Pain Questionnaire, breastfeeding duration/exclusivity, breastfeeding self-efficacy, and maternal satisfaction with lanolin treatment versus usual care. The results revealed no significant group differences in mean pain scores at 4 days post-randomization. Women in both groups experienced clinically relevant decreases in nipple pain by 7 days post-randomization. Significantly, more women in the lanolin group reported that they were satisfied with treatment compared with those receiving usual care. No significant group differences were found for other secondary outcomes. While more women were satisfied using lanolin, its application to sore/damaged nipples was ineffective for reducing nipple pain or improving breastfeeding outcomes. PMID- 27477841 TI - Heterodyne mixing of millimetre electromagnetic waves and sub-THz sound in a semiconductor device. AB - We demonstrate heterodyne mixing of a 94 GHz millimetre wave photonic signal, supplied by a Gunn diode oscillator, with coherent acoustic waves of frequency ~100 GHz, generated by pulsed laser excitation of a semiconductor surface. The mixing takes place in a millimetre wave Schottky diode, and the intermediate frequency electrical signal is in the 1-12 GHz range. The mixing process preserves all the spectral content in the acoustic signal that falls within the intermediate frequency bandwidth. Therefore this technique may find application in high-frequency acoustic spectroscopy measurements, exploiting the nanometre wavelength of sub-THz sound. The result also points the way to exploiting acoustoelectric effects in photonic devices working at sub-THz and THz frequencies, which could provide functionalities at these frequencies, e.g. acoustic wave filtering, that are currently in widespread use at lower (GHz) frequencies. PMID- 27477842 TI - Knowledge, Attitudes and Practices of Law Enforcement Officers on Rabies and Animal Control Issues in Kansas. AB - Rabies is a deadly zoonoses endemic in the United States, including Kansas. Animal control programmes that emphasize vaccination of dogs and cats, removal of stray animals and enforcement of licensure programmes have historically been essential in reducing the risk of rabies exposures to humans (Beran, 1991). Kansas does not mandate the use of animal control officers [ACOs] and in areas where there is no designated animal control officer, law enforcement officers [LEOs] are required to fill that role. Little is known about LEOs' knowledge of rabies, their current practices in responding to animal-related calls or if they receive any specialized training to perform the duties of an ACO. A web-based, voluntary and anonymous survey was sent to law enforcement officers in Kansas in January 2014. The survey included questions about animal control practices and a self-assessment of rabies knowledge. The response rate was 16.2%. All respondents indicated LEOs will respond to animal-related calls, even if there was an ACO available in their department or jurisdiction. A majority of respondents indicated they had not received training on safe animal handling (62.9%, 61/97) or zoonoses prevention (85.6%, 83/97), even though a strong majority considered such training important (89.7% and 79.4%, respectively). Most respondents (>80%) were able to correctly identify animals capable of transmitting rabies but were less aware of how rabies was transmitted or the severity of rabies in humans. Our results demonstrate that Kansas LEOs perform animal control duties, many without the proper training, even though most consider such training to be important to be able to perform their duties safely. Training on safe animal handling and zoonoses prevention should be provided to all LEOs in Kansas to enable them to safely execute their duties and provide timely and accurate information to citizens regarding rabies prevention. PMID- 27477843 TI - Association of echocardiographic parameters with mortality in hospitalized patients with lupus nephritis. AB - AIM: Increasing evidence shows that the cardiac involvement attributes to the mortality of patients with lupus nephritis (LN) and echocardiography provides a valid measurement for cardiac disease. However, the association between echocardiographic parameters and mortality in LN patients without cardiac disease history remains unclear. The aim of this study was to explore the relationship between echocardiographic parameters and the mortality in hospitalized LN patients without cardiac disease history. METHODS: A total of 436 LN patients without cardiac disease history who underwent echocardiography at Sun Yat-sen Memorial Hospital, between 1 January 2000 and 31 December 2014, were enrolled into this study. The association between echocardiographic parameters and all cause and cardiac mortality of LN patients was examined by the Cox proportional hazards model. RESULTS: In this cohort study, the median duration of follow-up was 18 months. Among 436 hospitalized LN patients, 88 patients (20.2%) died. Of them, 38 patients (43.2%) died of cardiac disease. Cardiac symptoms, high systolic blood pressure, high serum levels of C-reactive protein, low serum albumin, low estimated glomerular filtration rate (eGFR), and decreased left ventricular ejection fraction (LVEF) were found to be independently associated with increased all-cause mortality. Furthermore, the cardiac symptoms, low eGFR, increased left ventricular mass index (LVMI), and decreased LVEF were independently correlated with an increased cardiac mortality risk. CONCLUSIONS: Decreased LVEF was associated with increased all-cause and cardiac mortality and increased LVMI was an independent risk factor for cardiac mortality in hospitalized LN patients without cardiac disease history. PMID- 27477845 TI - Predictors and Clinical Impacts of Aggravated Left Ventricular Diastolic Dysfunction After Off-Pump Coronary Artery Bypass Grafting. AB - BACKGROUND: To determine the predictors of aggravated left ventricular diastolic dysfunction (LVDD) in patients undergoing off-pump coronary artery bypass grafting (OPCAB) and to compare late outcomes according to the aggravated LVDD. METHODS AND RESULTS: OPCAB was performed in 1,101 patients (2001-2013). LVDD was classified as normal, mild, moderate or severe. Patients were divided into 2 groups: non-aggravated LVDD (group I) and aggravated LVDD (group II). The primary endpoint was aggravation of LVDD. The secondary endpoint was late mortality and morbidity such as major adverse cardiac and cerebrovascular events (MACCE) related to LVDD aggravation postoperatively. There were 894 patients in group I and 207 in group II. Multivariate analysis revealed that preoperative peripheral artery obstructive disease (PAOD) (P=0.04), renal failure (P<0.01), and A' velocity (P<0.01) anticipated aggravated LVDD. The Cox hazards model revealed that aggravated LVDD was a poor prognostic factor for MACCE (P<0.01) and overall survival (P<0.01). The Kaplan-Meier survival curve showed that aggravated LVDD was related to poor late outcomes (freedom from MACCE, P=0.01; overall survival, P<0.01). CONCLUSIONS: Aggravated LVDD significantly affects late clinical outcomes after OPCAB and preoperative PAOD, renal failure, and A' velocity might be predictors. (Circ J 2016; 80: 1937-1945). PMID- 27477844 TI - A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children. AB - BACKGROUND: GMZ2 is a recombinant protein malaria vaccine, comprising two blood stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda. METHODS: Children 12-60months old were randomized to receive three injections of either 100MUg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ?5000/MUL. RESULTS: A cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value=0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value=0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%). CONCLUSIONS: GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role. PMID- 27477847 TI - Endomyocardial Fibrosis Associated With Apical Calcification and High Uptake on Myocardial Gallium-67 Scintigraphy. PMID- 27477846 TI - Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells. AB - BACKGROUND: Substantial evidence indicates that molecular hydrogen (H2) has beneficial vascular effects because of its antioxidant and/or anti-inflammatory effects. Thus, hydrogen-rich water may prove to be an effective anti-aging drink. This study examined the effects of H2on endothelial senescence and clarified the mechanisms involved. METHODS AND RESULTS: Hydrogen-rich medium was produced by a high-purity hydrogen gas generator. Human umbilical vein endothelial cells (HUVECs) were incubated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for various time periods in normal or hydrogen-rich medium. The baseline H2concentration in hydrogen-rich medium was 0.55+/-0.07 mmol/L. This concentration gradually decreased, and H2was almost undetectable in medium after 12 h. At 24 h after TCDD exposure, HUVECs treated with TCDD exhibited increased 8OHdG and acetyl-p53 expression, decreased nicotinamide adenine dinucleotide (NAD(+))/NADH ratio, impaired Sirt1 activity, and enhanced senescence-associated beta-galactosidase. However, HUVECs incubated in hydrogen-rich medium did not exhibit these TCDD-induced changes accompanying Nrf2 activation, which was observed even after H2was undetectable in the medium. Chrysin, an inhibitor of Nrf2, abolished the protective effects of H2on HUVECs. CONCLUSIONS: H2has long lasting antioxidant and anti-aging effects on vascular endothelial cells through the Nrf2 pathway, even after transient exposure to H2. Hydrogen-rich water may thus be a functional drink that increases longevity. (Circ J 2016; 80: 2037 2046). PMID- 27477848 TI - Genome-wide transcriptome induced by nickel in human monocytes. AB - Nickel-containing alloys are frequently used in the biomedical field, although, owing to corrosive processes metal ion leaching is inevitable. Due to nickel ion (Ni(2+)) leaching several adverse effects are described in the literature. However, only a few studies evaluated the genetic profile of Ni(2+) in human cells which is of great importance since nickel-induced effects differ between humans and mice as a result of species-specific receptor variability. Thus, we investigated gene expression induced by Ni(2+)in human monocytes using a transcriptome-wide approach determining new target genes implicated in nickel induced pathologies. Monocytes were isolated from healthy volunteers of Central European origin using stringent inclusion criteria. Cells were challenged with different Ni(2+) concentrations. Array-based gene expression analysis was performed comprising more than 47,000 transcripts followed by pathway analyses. Transcriptional data were validated by protein and cell surface markers. Ni(2+) significantly influenced the expression of 1385 transcripts in a dose-dependent manner. Apart from known targets (CCL20?, PTGS2?, MTs?, SLCs?), we identified new candidates implicated in Ni(2+)-elicited processes (various microRNAs?, INSIG1?, NAMPT?, MS4A6A?, DHRS9?). Several of these transcripts correspond to immunity, inflammation and were shown to be involved in cellular reactions related to hypersensitivity, cancer, colitis, and encephalitis. Moreover, 459 canonical pathways/signaling, 500 pathologies and 2687 upstream regulators were detected. Protein results validated our findings. To our knowledge, the present systematic transcriptome-wide expression study is the first which explored Ni(2+)-elicited cell responses in human primary monocytes identifying new target genes, pathways and upstream regulators of relevance to diagnostic and therapeutic strategies. STATEMENT OF SIGNIFICANCE: Nickel is widely applied in the biomedical field, although several adverse effects are documented in the literature due to nickel ion (Ni(2+)) leaching. In humans, allergic reactions like contact dermatitis are the most common adverse effect to Ni(2+), whereas serious concerns relate to possible systemic and carcinogenic activities. Using a systematic genome-wide transcriptional approach in human primary monocytes unveil new target genes, pathways and upstream regulators implicated in nickel-elicited immune response which are of significance to diagnostic and therapeutic strategies. This approach provides new information of how host-derived immune response contributes to the interaction with antigens and supports the interplay between metal ions and systemic diseases. PMID- 27477849 TI - Nanofiber-mediated microRNA-126 delivery to vascular endothelial cells for blood vessel regeneration. AB - As manipulation of gene expression by virtue of microRNAs (miRNAs) is one of the emerging strategies for cardiovascular disease remedy, local delivery of miRNAs to a specific vascular tissue is challenging. In this work, we developed an efficient delivery system composed of electrospun fibrous membranes and target carriers for the intracellular delivery of miRNA-126 (miR-126) to vascular endothelial cells (VECs) in the local specific vascular environment. A bilayer vascular scaffold was specially prepared via emulsion electrospinning of poly(ethylene glycol)-b-poly(l-lactide-co-epsilon-caprolactone) (PELCL) and dual power electrospinning of poly(epsilon-caprolactone) (PCL) and gelatin. The inner layer of PELCL, which was loaded with complexes of miR-126 in REDV peptide modified trimethyl chitosan-g-poly(ethylene glycol), regulated the response of VECs, while the outer layer of PCL/gelatin contributed to the mechanical stability. Biological activities of the miR-126-loaded electrospun membranes were evaluated by cell proliferation and SPRED-1 expression of a miR-126 target gene. By encapsulating targeting complexes of miR-126 in the electrospun membranes, a sustained release profile of miRNA was obtained for 56days. Significant down regulation of SPRED-1 gene expression in VECs was detected on day 3, and it was found that miR-126 released from the electrospun membranes accelerated VEC proliferation in the first 9days. The bilayer vascular scaffold loaded with miR 126 complexes could also improve endothelialization in vivo. These results demonstrated the potential of this approach towards a new and more effective delivering system for local delivery of miRNAs to facilitate blood vessel regeneration. STATEMENT OF SIGNIFICANCE: Tissue engineering of small-diameter blood vessels is still challenging because of thrombosis and low long-term patency. The manipulation of gene expression by miRNAs could be a novel strategy in vascular regeneration. Here, we report an efficient delivery system of electrospun fibrous scaffold combined with REDV peptide-modified trimethyl chitosan for targeted intracellular delivery of miR-126 to VECs in the local vascular environment. Results exhibited that miR-126 released from the electrospun membrane could modulate VEC proliferation via down-regulation of SPRED-1 gene expression. The electrospun scaffolds loaded with target-delivery carriers may serve as an ideal platform for local delivery of miRNAs in the vascular tissue engineering. PMID- 27477850 TI - Hypoxia-mimicking Co doped TiO2 microporous coating on titanium with enhanced angiogenic and osteogenic activities. AB - Advanced titanium (Ti) based bone implant with both angiogenesis and osteogenesis stimulating activities for enhanced clinical performance is stringently needed. In the present work, TiO2/calcium-phosphate (TCP) coatings on Ti doped with cobalt (Co) of various amounts (designated as C2-TCP, C7-TCP, and C13-TCP where the Arabic numbers indicate the mean Co contents) are developed by a simple micro arc oxidation procedure. The Co doped TCP coatings possess a microporous structure (pore size of 3-4MUm in average diameter) which is evenly covered by nano-grains of 30-60nm in size. Successful Co incorporation in TCP is determined by X-ray photoelectron spectroscopy. The microstructure, TiO2 phase compositions, surface roughness, and wettability of TCP are not apparently affected by the Co incorporation. The Co doped coatings bond firmly to the Ti substrate and show good long-term adhesion strength stability in biological environment. Then the behaviors of rat bone marrow stem cells (MSCs) on the Co-incorporated TCP are evaluated. The Co incorporation leads to enhanced expression of the markers for both angiogenesis and osteogenesis, and the effects are positively related to the incorporated Co amount. Overdose of Co incorporation (C13-TCP) can induce certain cytotoxicity and an optimal dose of Co incorporation is essential to get the enhanced angiogenic and osteogenic activities without showing cytotoxicity. Between C2-TCP and C7-TCP that show no significant cytotoxicity, C7-TCP exhibits higher angiogenic and osteogenic activities. In conclusion, the Co doping is feasible to enhance the angiogenic and osteogenic activities of orthopedic and dental Ti implants for potentially improved clinical performance. STATEMENT OF SIGNIFICANCE: TiO2/calcium-phosphate coatings on Ti doped with cobalt are developed by a simple micro-arc oxidation procedure. The Co doped coatings bond firmly to the Ti substrate and show good long-term adhesion strength stability in biological environment. Furthermore, the cobalt doping is feasible to enhance the angiogenic and osteogenic activities of orthopedic and dental Ti implants for potentially improved clinical performance. PMID- 27477852 TI - Student nurses' knowledge and attitudes towards domestic violence: results of survey highlight need for continued attention to undergraduate curriculum. AB - AIMS AND OBJECTIVES: To gain a comprehensive understanding of undergraduate nursing student attitudes and views towards domestic violence, and employ the findings to inform undergraduate curriculum development. BACKGROUND: Nurses have an important role in identifying people who are victims of domestic violence through screening and facilitating their access to assistance and support. Undergraduate nursing education is key to shaping attitudes and facilitating the development of a comprehensive understanding of domestic violence. Little research has been undertaken exploring nursing students' attitudes towards domestic violence. METHODS: A cross-sectional survey of undergraduate nursing students enrolled in a three-year Bachelor of Nursing programme across three campuses of a regional university in NSW, Australia. Students completed a pen and paper survey during class time and descriptive and comparative analysis was undertaken. RESULTS: The majority of respondents were female, first year students females aged 17-26 years. Many students understood the nature and consequences of domestic violence, yet others across the course of the programme demonstrate attitudes that reflect a lack of understanding and misconceptions of domestic violence. Stereotypical and gendered attitudes that normalise violence within intimate partner relationships and sustain victim-blaming attitudes were evident across the cohort. CONCLUSIONS: It is important for nurses to understand the relationship between exposure to violence and women's ill health, and be able to respond appropriately. Undergraduate programmes need to highlight the important role of nurses around domestic violence and address stereotypical conceptions about domestic violence. RELEVANCE TO CLINICAL PRACTICE: Continued effort is required to address domestic violence in undergraduate nursing education so that nursing graduates understand the association between violence exposure and poor health and are able to assess exposure and respond appropriately in the clinical environment. PMID- 27477851 TI - Demands and challenges for patients with sickle-cell disease requiring hematopoietic stem cell transplantation in Saudi Arabia. AB - Allogeneic HSCT is the only curative treatment for SCD. In this study, we estimated the number of Saudi patients with SCD who are candidates for HSCT. We used the presence of overt stroke, recurrent ACS, and frequent severe pain crisis as indications for HSCT. We calculated the frequencies of these complications among a Saudi SCD cohort of 376 patients with SCD, 250 from SW and 126 from Eastern (E) provinces. We found that 59 (23.6%) of SW patients were transplant candidates compared to 22 (17.4%) from E province. It is estimated that about 61 000 patients with SCD live in Saudi Arabia. Thus, the projected number of Saudi patients with SCD who are candidates for HSCT is 10 536 patients. Of those, 2148 are children. The burden of SCD on HSCT centers in Saudi Arabia is substantial and is difficult currently to meet the demand. We recommend recruiting/training more transplant physicians and nurses, expand current capacity of centers if feasible, and open new transplant centers to make HSCT a practical therapeutic option for patients with severe SCD in Saudi Arabia. PMID- 27477853 TI - Exposure to waterpipe smoke induces renal functional and oxidative biomarkers variations in mice. AB - CONTEXT: Waterpipe smoking (WPS) has been known for over 400 years. It has been spread widely especially between youth because of the addition of pleasant flavor and because it was misconsidered to be less harmful than cigarette. OBJECTIVE: In this study, we investigated the effect of waterpipe smoking on renal oxidative and functional parameters and compared that at acute and chronic exposure time in mice. MATERIALS AND METHODS: Mice were divided into three groups, namely acute, chronic and fresh air control. Acute group was exposed to waterpipe smoke for one hour daily for six days using whole-body exposure system, while chronic group was exposed to waterpipe smoke for one hour daily for 30 days using whole-body exposure system. RESULT: Exposure to waterpipe smoke has shown significant changes on the mice kidney functional parameters such as creatinine and blood urea nitrogen. Both exposures (acute and chronic) has shown a significant reduction in superoxide dismutase (SOD) activity (p < 0.05), whereas the activity of other antioxidant enzymes (catalase and GPx) reduced only with chronic exposure to waterpipe smoke (p < 0.05). Additionally, the level of thiobarbituric acid reactive substances (TBARS) in mice kidney homogenates has shown a significant elevation following chronic exposure to waterpipe smoke (p < 0.05). DISCUSSION AND CONCLUSION: In conclusion, chronic waterpipe smoke affects the kidney parameter and antioxidant markers, therefore affecting its functionality of detoxifying and removal of poisonous material from the body. PMID- 27477854 TI - Significance of the isolation of Staphylococcus aureus from a central venous catheter tip in the absence of concomitant bacteremia: a clinical approach. AB - The optimal approach following the isolation of Staphylococcus aureus from an intravascular catheter tip in the absence of concomitant bacteremia remains unclear. We aimed to determine the rate of delayed complications in these patients. We performed a retrospective observational study (during the period 2002-2012) including patients with a catheter tip culture yielding S. aureus. Patients were followed up for >=6 months. The primary endpoint was the occurrence of delayed staphylococcal complications (either bacteremia and/or metastatic distant infections). A total of 113 patients were included (75 % male, median age 61 years): 46 and 67 with negative and positive blood cultures, respectively. We found a lower rate of delayed staphylococcal complications in cases with no bacteremia within 48 h since catheter removal than in cases of confirmed S. aureus catheter-related bacteremia (0.0 % vs. 25.4 %; p-value < 0.001). In the group without bacteremia, there was a subgroup of 15 patients (32.6 %) who did not receive antimicrobial treatment. Again, delayed complications occurred less commonly in this subgroup of patients without bacteremia (0.0 % vs. 25.4 %; p value = 0.033). In contrast to patients with S. aureus catheter-related bacteremia, no delayed infectious complications were observed in patients with an isolated catheter tip culture yielding S. aureus and negative blood cultures within 48 h of catheter removal. Futures studies are needed to assess if the therapeutic approach could be different for this group of patients. PMID- 27477856 TI - Colloidal heat engines: a review. AB - Stochastic heat engines can be built using colloidal particles trapped using optical tweezers. Here we review recent experimental realizations of microscopic heat engines. We first revisit the theoretical framework of stochastic thermodynamics that allows to describe the fluctuating behavior of the energy fluxes that occur at mesoscopic scales, and then discuss recent implementations of the colloidal equivalents to the macroscopic Stirling, Carnot and steam engines. These small-scale motors exhibit unique features in terms of power and efficiency fluctuations that have no equivalent in the macroscopic world. We also consider a second pathway for work extraction from colloidal engines operating between active bacterial reservoirs at different temperatures, which could significantly boost the performance of passive heat engines at the mesoscale. Finally, we provide some guidance on how the work extracted from colloidal heat engines can be used to generate net particle or energy currents, proposing a new generation of experiments with colloidal systems. PMID- 27477857 TI - Biofilm Thickness Influences Biodiversity in Nitrifying MBBRs-Implications on Micropollutant Removal. AB - In biofilm systems for wastewater treatment (e.g., moving bed biofilms reactors MBBRs) biofilm thickness is typically not under direct control. Nevertheless, biofilm thickness is likely to have a profound effect on the microbial diversity and activity, as a result of diffusion limitation and thus substrate penetration in the biofilm. In this study, we investigated the impact of biofilm thickness on nitrification and on the removal of more than 20 organic micropollutants in laboratory-scale nitrifying MBBRs. We used novel carriers (Z-carriers, AnoxKaldnes) that allowed controlling biofilm thickness at 50, 200, 300, 400, and 500 MUm. The impact of biofilm thickness on microbial community was assessed via 16S rRNA gene amplicon sequencing and ammonia monooxygenase (amoA) abundance quantification through quantitative PCR (qPCR). Results from batch experiments and microbial analysis showed that (i) the thickest biofilm (500 MUm) presented the highest specific biotransformation rate constants (kbio, L g(-1) d(-1)) for 14 out of 22 micropollutants; (ii) biofilm thickness positively associated with biodiversity, which was suggested as the main factor for the observed enhancement of kbio; (iii) the thinnest biofilm (50 MUm) exhibited the highest nitrification rate (gN d(-1) g(-1)), amoA gene abundance and kbio values for some of the most recalcitrant micropollutants (i.e., diclofenac and targeted sulfonamides). Although thin biofilms favored nitrification activity and the removal of some micropollutants, treatment systems based on thicker biofilms should be considered to enhance the elimination of a broad spectrum of micropollutants. PMID- 27477855 TI - Molecular characterisation and antifungal susceptibility of clinical Cryptococcus deuterogattii (AFLP6/VGII) isolates from Southern Brazil. AB - Cryptococcosis, caused by Cryptococcus gattii sensu lato, is an emerging disease that was initially found in (sub)tropical regions but recently expanded to temperate regions. Cryptococcus gattii s.l. infections are mostly encountered in healthy individuals, frequently affecting both lungs and the central nervous system (CNS). Usually, C. gattii s.l. is less susceptible to antifungal compounds than its counterpart, C. neoformans s.l. We studied 18 clinical C. gattii s.l. isolates with amplified fragment length polymorphism (AFLP) fingerprinting, mating-typing, multi-locus sequence typing (MLST) and antifungal susceptibility testing. All isolates were C. deuterogattii (genotype AFLP6/VGII), 14 were mating type alpha and four were type a. Amphotericin B, itraconazole, voriconazole, posaconazole and isavuconazole showed high activity, with minimum inhibitory concentration (MIC) ranges of 0.063-0.25, 0.031-0.25, 0.031-0.25, 0.031-0.25 and <0.016-0.25 MUg mL-1, respectively. Fluconazole and flucytosine had high geometric mean MICs of 2.07 and 3.7 MUg mL-1, respectively. Most cases occurred in immunocompetent patients (n = 10; 55.6 %) and CNS involvement was the most common clinical presentation (n = 14; 77.8 %). Three patients (16.7 %) showed sequelae, hyperreflexia, dysarthria, diadochokinesia, anosmia and upper limb weakness. In conclusion, all infections were caused by C. deuterogattii (AFLP6/VGII) and the majority of patients were immunocompetent, with the CNS as the most affected site. All antifungal drugs had high in vitro activity against C. deuterogattii isolates, except fluconazole and flucytosine. PMID- 27477858 TI - Influence of developmental nicotine exposure on glutamatergic neurotransmission in rhythmically active hypoglossal motoneurons. AB - Developmental nicotine exposure (DNE) is associated with increased risk of cardiorespiratory, intellectual, and behavioral abnormalities in neonates, and is a risk factor for apnea of prematurity, altered arousal responses and Sudden Infant Death Syndrome. Alterations in nicotinic acetylcholine receptor signaling (nAChRs) after DNE lead to changes in excitatory neurotransmission in neural networks that control breathing, including a heightened excitatory response to AMPA microinjection into the hypoglossal motor nucleus. Here, we report on experiments designed to probe possible postsynaptic and presynaptic mechanisms that may underlie this plasticity. Pregnant dams were exposed to nicotine or saline via an osmotic mini-pump implanted on the 5th day of gestation. We used whole-cell patch clamp electrophysiology to record from hypoglossal motoneurons (XIIMNs) in thick medullary slices from neonatal rat pups (N=26 control and 24 DNE cells). To enable the translation of our findings to breathing-related consequences of DNE, we only studied XIIMNs that were receiving rhythmic excitatory drive from the respiratory central pattern generator. Tetrodotoxin was used to isolate XIIMNs from presynaptic input, and their postsynaptic responses to bath application of l-glutamic acid (glutamate) and alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) were studied under voltage clamp. DNE had no influence on inward current magnitude evoked by either glutamate or AMPA. However, in cells from DNE animals, bath application of AMPA was associated with a right shift in the amplitude distribution (P=0.0004), but no change in the inter-event interval distribution of miniature excitatory postsynaptic currents (mEPSCs). DNE had no influence on mEPSC amplitude or frequency evoked by glutamate application, or under (unstimulated) baseline conditions. Thus, in the presence of AMPA, DNE is associated with a small but significant increase in quantal size, but no change in the probability of glutamate release. PMID- 27477859 TI - A new clinically relevant model for intracranial atherosclerosis in rats. AB - INTRODUCTION: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We developed a new rat model to study intracranial atherosclerosis. METHODS: Twelve-week-old male Sprague-Dawley rats were divided into a control (on a maintain diet) and a high-cholesterol group (on a daily 1% cholesterol diet) for up to 6 weeks. During the first two weeks, NG nitro-L-arginine methylester (L-NAME, 3 mg/mL) was added to the drinking water in the high-cholesterol group to induce intimal changes making the rats susceptible to atherosclerosis. Blood lipids, including low-density lipoprotein (LDL), cholesterol (CHO), triglycerides (TG), and high-density lipoprotein (HDL), were measured after 3 and 6 weeks. Histological sections of the brains, including internal carotid artery (ICA), middle cerebral artery (MCA), and basilar artery (BA), were prepared to study intracranial artery morphometry and intimal thickening. The levels of CD68, an inflammatory marker, within the vessel walls as determined by immunohistochemistry were also measured. RESULTS: The high cholesterol diet increased the levels of classic blood markers of atherosclerosis, LDL, CHO, and TG as well as decreased HDL, which became progressively more intensive with time. Rats showed increased intimal thickening in the ICA, MCA, and BA. This protocol also increased the levels of CD68 immunoreactivity within the vessel walls. CONCLUSIONS: A rat model of intracranial atherosclerosis was effectively developed by high-cholesterol diet and L-NAME administration. This clinically relevant model would be beneficial for studying ICAS. PMID- 27477860 TI - The Endocrine Society Centennial: No Longer a Surprise: Estrogenic Chemicals in a Multitude of Places. AB - Nowadays, we are bombarded with information on a large number of endocrine disrupting chemicals. We hear and read about endocrine-disrupting chemicals on blogs, the web, news stories, television specials, advertisements, and of course scientific articles. Reports claim these ubiquitous compounds are responsible for increased rates of cancer, autism, obesity, hypospadias, and infertility, just to name a few. But it was not always this way. In fact, the scientific study of endocrine-disrupting chemicals is relatively new: a recent PubMed search found a total of 6184 hits for the term, 739 articles in 2015 as compared with 4, 20 years ago in 1995. PMID- 27477861 TI - Do the Effects of the Triorganotin Tributyltin on the Hypothalamic-Pituitary Adrenal Axis In Vivo Contribute to Its Environmental Toxicity? PMID- 27477862 TI - The Enhancement of Muscle Insulin Sensitivity After Exercise: A Rac1-Independent Handoff to Some Other Player? PMID- 27477865 TI - Three-Dimensional Echocardiographic Assessment of Left Heart Chamber Size and Function with Fully Automated Quantification Software in Patients with Atrial Fibrillation. AB - BACKGROUND: Echocardiographic determination of left heart chamber volumetric parameters by using manual tracings during multiple beats is tedious in atrial fibrillation (AF). The aim of this study was to determine the usefulness of fully automated left chamber quantification software with single-beat three-dimensional transthoracic echocardiographic data sets in patients with AF. METHODS: Single beat full-volume three-dimensional transthoracic echocardiographic data sets were prospectively acquired during consecutive multiple cardiac beats (>=10 beats) in 88 patients with AF. In protocol 1, left ventricular volumes, left ventricular ejection fraction, and maximal left atrial volume were validated using automated quantification against the manual tracing method in identical beats in 10 patients. In protocol 2, automated quantification-derived averaged values from multiple beats were compared with the corresponding values obtained from the indexed beat in all patients. RESULTS: Excellent correlations of left chamber parameters between automated quantification and the manual method were observed (r = 0.88-0.98) in protocol 1. The time required for the analysis with the automated quantification method (5 min) was significantly less compared with the manual method (27 min) (P < .0001). In protocol 2, there were excellent linear correlations between the averaged left chamber parameters and the corresponding values obtained from the indexed beat (r = 0.94-0.99), and test-retest variability of left chamber parameters was low (3.5%-4.8%). CONCLUSIONS: Three dimensional transthoracic echocardiography with fully automated quantification software is a rapid and reliable way to measure averaged values of left heart chamber parameters during multiple consecutive beats. Thus, it is a potential new approach for left chamber quantification in patients with AF in daily routine practice. PMID- 27477867 TI - Spectroscopic study on the active site of a SiO2 supported niobia catalyst used for the gas-phase Beckmann rearrangement of cyclohexanone oxime to epsilon caprolactam. AB - NbOx/SiO2 with a very high catalytic activity for the gas-phase Beckmann rearrangement of cyclohexanone oxime to epsilon-caprolactam, was investigated by different spectroscopic methods in order to obtain new insights in the formation and nature of the active sites. FT-IR spectroscopy in combination with pyridine adsorption measurements revealed that the catalyst material contains Lewis-acidic sites, most probably related to the Nb[double bond, length as m-dash]O groups of isolated tetrahedral NbO4 surface species, whereas no Bronsted-acidic sites were observed. Results from in situ Raman and complementary FT-IR measurements strongly suggest that Bronsted-acidic Nb-OH sites can be generated from Nb[double bond, length as m-dash]O groups by reaction with ethanol. This is in agreement with the observation that ethanol is essential for obtaining a very good catalyst performance. However, the Bronsted-acidic sites can be detected in significant amounts in particular in the presence of a Lewis-base, e.g. pyridine, most probably because the formation and/or the stability of these Bronsted-acidic sites are enhanced by a basic molecule. Assuming that cyclohexanone oxime, being a base, can play a similar role as pyridine, we propose on the basis of the spectroscopic findings obtained in this work and our kinetic results published recently, a reaction scheme for the formation of the active site at the Nb[double bond, length as m-dash]O group as well as for the recovery of the Nb[double bond, length as m-dash]O site during the final stage of the gas-phase Beckmann rearrangement. PMID- 27477866 TI - Do Emergency Medicine Residency Graduates Feel Prepared to Manage Closed Fractures After Training? AB - OBJECTIVES: Fractures comprise 3% of all emergency department (ED) visits. Although emergency physicians are often responsible for managing most of the initial care of these patients, many report a lack of proficiency and comfort with these skills. The primary objective was to assess how prepared recent emergency medicine (EM) residency graduates felt managing closed fractures upon completion of residency. Secondary objectives included whether residency training or independent practice contributed most to the current level of comfort with these procedures and which fractures were most commonly reduced without orthopedic consultation. METHODS: An anonymous online survey was sent to graduates from seven EM residency programs over a 3-month period to evaluate closed fracture reduction training, practice, and comfort level. Each site primary investigator invited graduates from 2010 to 2014 to participate and followed a set schedule of reminders. RESULTS: The response rate was 287/384 (74.7%) and included 3-year (198/287, 69%) and 4-year (89/287, 31%) programs. Practice in community, academic, and hybrid ED settings was reported by 150/287 (52.3%), 64/287 (22.3%), and 73/287 (25.4%), respectively. It was indicated by 137/287 (47.7%) that they reduce closed fractures without a bedside orthopedic consultation greater than 75% of the time. The majority of graduates felt not at all prepared (35/287, 12.2%) or somewhat prepared (126/287, 43.9%) upon residency graduation. Postresidency independent practice contributed most to the current level of comfort for 156/287 (54.4%). The most common fractures requiring reduction were wrist/distal radius and/or ulna, next finger/hand, and finally, ankle/distal tibia and/or fibula. CONCLUSIONS: Although most recent graduates feel at least "somewhat" prepared to manage closed fractures in the ED, most felt that independent practice was a greater contributor to their current level of comfort than residency training. Recent graduates indicate that fracture reduction without orthopedic consultation is common in today's clinical practice. This survey identifies common fractures requiring reduction which EM residencies may wish to consider prioritizing in their emergency orthopedic curricula to better prepare their residents for independent clinical practice. PMID- 27477868 TI - Patient satisfaction and alliance as a function of the physician's self regulation, the physician's stress, and the content of consultation in cancer care. AB - OBJECTIVE: To investigate which characteristics of the physician and of the consultation are related to patient satisfaction with communication and working alliance. METHODS: Real-life consultations (N = 134) between patients (n = 134) and their physicians (n = 24) were audiotaped. All of the patients were aware of their cancer diagnosis and consulted their physician to discuss the results of tests (CT scans, magnetic resonance imaging, or tumor markers) and the progression of their cancer. The consultations were transcribed and coded with the "Defense Mechanisms Rating Scale-Clinician." The patients and physicians completed questionnaires about stress, satisfaction, and alliance, and the data were analyzed using robust linear modeling. RESULTS: Patient satisfaction with communication and working alliance was high. Both were significantly (negatively) related to the physician's neurotic and action defenses-in particular to the defenses of displacement, self-devaluation, acting out, and hypochondriasis-as well as to the physician's stress level. The content of the consultation was not significantly related to the patient outcomes. CONCLUSIONS: Our study shows that patient satisfaction with communication and working alliance is not influenced by the content of the consultation but is significantly associated with the physician's self-regulation (defense mechanisms) and stress. The results of this study might contribute to optimizing communication skills training and to improving communication and working alliance in cancer care. PMID- 27477869 TI - Real-time monitoring of amyloid growth in a rigid gel matrix. AB - We demonstrate the real-time monitoring of the growth of amyloid-protein aggregates in a semi-rigid gel environment constructed from a 5% w/v gelatin solution. The kinetics of amyloid fibril growth from reduced and carboxy methylated kappa-casein occurring in the gel medium was contrasted against that obtained in a regular solution assay. Aggregation kinetics were recorded using Thioflavin T fluorescence. Transmission electron microscopy was used to confirm the aggregates' existence and morphology. The current demonstration of controlled amyloid growth in a gel environment represents the first step towards development of an experimental model for investigating the role of spatial and medium factors in the kinetics of aggregation-based proteopathies. PMID- 27477870 TI - Resistin reinforces interferon lambda-3 to eliminate hepatitis C virus with fine tuning from RETN single-nucleotide polymorphisms. AB - The effect of resistin (RETN) on the response to anti-HCV therapy remains unclear. A prospective cohort study was performed using 655 consecutive HCV patients, of whom 513 had completed a course of interferon-based therapy. Multivariate and GEE analyses revealed four RETN single-nucleotide polymorphisms (SNPs), rs34861192, rs3219175, rs3745367 and rs1423096, to be synergistically associated with resistin levels. After adjusting for co-factors such as interferon lambda-3 (IFNL3)-rs12979860, the resistin level and the hyper resistinemic genotype at the 4 RETN SNPs were positively and negatively associated with a sustained virological response (SVR), respectively. RETN rs3745367 was in linkage disequilibrium with IFNL3-rs12979860. Compared to non SVR patients, SVR patients had higher levels of pre-therapy resistin, primarily originating from intrahepatic lymphocytes, stellate cells, Kupffer cells, hepatic progenitor cells and hepatocytes. This difference diminished over the course of therapy, as only SVR patients exhibited a 24-week post-therapy decrease in resistin. Both resistin and IFNL3 mRNAs were upregulated, but only resistin mRNA was upregulated by recombinant resistin in peripheral blood mononuclear cells with and without hyper-resistinemic genotypes of the 4 RETN SNPs, respectively. Fine-tuned by RETN SNPs, intrahepatic, multi-cellular resistin reinforced IFNL3 in eliminating HCV via immunomodulation to counteract pro-inflammation. These results encourage the development of novel resistin-targeted anti-viral agents. PMID- 27477871 TI - Idarucizumab: Clinical Role of a Novel Reversal Agent for Dabigatran. AB - Atrial fibrillation (AF), a common cardiac arrhythmia associated with increased risk of heart failure, thromboembolic phenomena and death, is a leading cause of hospitalization of adults. A major complication of AF is an increased risk of ischemic stroke leading to long-term disability and in severe cases, death. Historically, Coumadin has been the drug of choice for chronic anticoagulation and stroke prevention in AF patients however, given the need for constant monitoring and multiple drug interactions, newer anticoagulants have been developed. One such drug is dabigatran, with the promise of less frequent monitoring and decreased bleeding tendencies as compared to Coumadin. The main disadvantage of dabigatran has been the lack of a reversal agent in case of severe bleeding or emergent surgical intervention. This was until the recent The Food and Drug Administration approval of idarucizumab, a potential reversal agent for dabigatran. In this article, we discuss the evidence addressing idarucizumab safety, tolerability and its efficacy for reversing effect of dabigatran. PMID- 27477872 TI - Magnetism and variable temperature and pressure crystal structures of a linear oligonuclear cobalt bis-semiquinonate. AB - The crystal structure of the first oligomeric cobalt dioxolene complex, Co3(3,5 DBSQ)2((t)BuCOO)4(NEt3)2, 1, where DBSQ is 3,5-di-tert-butyl-semiquinonate, has been studied at various temperatures between 20 and 200 K. Despite cobalt dioxolene complexes being generally known for their extensive ability to exhibit valence tautomerism (VT), we show here that the molecular geometry of compound 1 is essentially unchanged over the full temperature range, indicating the complete absence of electron transfer between ligand and metal. Magnetic susceptibility measurements clearly support the lack of VT between 8 and 300 K. The crystal structure is also determined at elevated pressures in the range from 0 to 2.5 GPa. The response of the crystal structure is surprisingly dependent on the dynamics of pressurisation: following rapid pressurization to 2 GPa, a structural phase transition occurs; yet, this is absent when the pressure is increased incrementally to 2.6 GPa. In the new high pressure phase, Z' is 2 and one of the two molecules displays changes in the coordination of one bridging carboxylate from MU2:kappaO:kappaO' to MU2:kappa(2)O,O':kappaO', while the other molecule remains unchanged. Despite the significant changes to the molecular connectivity, analysis of the crystal structures shows that the phase transition leaves the spin and oxidation states of the molecules unaltered. Intermolecular interactions in the high pressure crystal structures have been analysed using Hirshfeld surfaces but they cannot explain the origin of the phase transition. The lack of VT in this first oligomeric Co-dioxolene complex is speculated to be due to the coordination geometry of the terminal Co-atoms, which are trigonal bipyramidally coordinated, different from the more common octahedral coordination. The energy that is gained by a hs-to-ls change in Oh is equal to Delta, while in the case of the trigonal bipyramidal (C3v), the energy gain is equal to the splitting between d(z(2)) and degenerate d(x(2) - y(2))/d(xy), which is significantly less. PMID- 27477873 TI - Dose-dependent and cell type-specific cell death and proliferation following in vitro exposure to radial extracorporeal shock waves. AB - Radial extracorporeal shock wave (rESW) therapy is widely used in musculoskeletal disorders and wound repair. However, the mechanisms of action are still largely unknown. The current study compared the effects of rESWs on two cell types. Human fetal foreskin fibroblasts (HFFF2) and human placental choriocarcinoma cell line JEG-3 were exposed to 0, 100, 200, 500 or 5000 rESWs generated with a Swiss DolorClast device (2.5 bar, 1 Hz). FACS analysis immediately after rESW exposure showed that initially, rESWs rather induced mechanical cell destruction than regulated or programmed cell death. Cell damage was nearly negated by reducing cavitation. Furthermore, cell viability decreased progressively with higher numbers of rESWs. Exposure to rESWs had no impact on growth potential of JEG-3 cells, but dose-dependently increased growth potential of HFFF2 cells. Cultivation of cells that were initially exposed to sham-rESWs in conditioned media increased the growth potential of HFFF2 cells, nevertheless, an even stronger effect was achieved by direct exposure to rESWs. Additionally, cell cycle distribution analysis demonstrated a shift in proportion from G0/G1 to G2/M phase in HFFF2 cells, but not in JEG-3 cells. These data demonstrate that rESWs leads to initial and subsequent dose-dependent and cell type-specific effects in vitro. PMID- 27477874 TI - Is anti-viral defence the evolutionary origin of mRNA turnover? (Comment on DOI 10.1002/bies.201600100). PMID- 27477875 TI - Corrigendum to "Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer" [Drug Discov. Today 20 (11) (2015) 1391-1397]. PMID- 27477876 TI - Risk Factors for Prolonged Hospitalization in Pediatric Appendicitis Patients with Medical Treatment. AB - BACKGROUND: With effective antibiotics against enteric flora and computed tomography-guided drainage for abscesses, the initial use of nonoperative therapy for children with appendicitis has increased both in recent reports and at our hospital. However, it has been reported that these patients have a relatively longer hospital stay and that their treatment is more expensive than those who undergo aggressive surgical intervention. METHODS: This was a retrospective cohort study based in a single medical center. A systemic chart review was conducted to identify risk factors for prolonged hospitalization in pediatric appendicitis patients not initially undergoing surgical treatment. Patient demographics, clinical symptoms, duration of symptoms, laboratory findings, imaging findings, complications, and length of hospital stay were analyzed. Logistic regression analysis was used to identify significant predictors of prolonged hospitalization (>=15 days) and readmission. RESULTS: One hundred and twenty-five patients were recruited in this study, of whom 53 (42.4%) had prolonged hospitalization. The values of serum C-reactive protein (CRP) were significantly higher in patients with prolonged hospitalization compared with those without prolonged hospitalization (203 +/- 108.6 mg/L vs. 140 +/- 93.0 mg/L, p = 0.001). Risk factors of prolonged hospitalization were serum CRP >150 mg/L (35/53 vs. 28/72, p = 0.001), abscess formation (38/53 vs. 35/72, p = 0.008), and multiple abscesses (10/53 vs. 1/72, p = 0.001). Under multivariate analysis, CRP >150 mg/L (odds ratio=1.004, p = 0.0334) and multiple abscesses (odds ratio = 8.788, p = 0.044) were two independent predictors for prolonged hospitalization. CONCLUSION: Marked elevation of serum CRP (>150 mg/L) and multiple abscesses are two independent risk factors for prolonged hospitalization in children with appendicitis who are initially treated nonoperatively. PMID- 27477877 TI - Use of an absorbable embolization material for reversible portal vein embolization in an experimental model. AB - BACKGROUND: Portal vein embolization (PVE) is used to increase future remnant liver size in patients requiring major hepatic resection. PVE using permanent embolization, however, predisposes to complications and excludes the use of PVE in living donor liver transplantation. In the present study, an absorbable embolization material containing fibrin glue and different concentrations of the fibrinolysis inhibitor aprotinin was used in an experimental animal model. METHODS: PVE of the cranial liver lobes was performed in 30 New Zealand White rabbits, which were divided into five groups, fibrin glue + 1000, 700, 500, 300 or 150 kunits/ml aprotinin, and were compared with a previous series of permanent embolization using the same experimental set-up. Caudal liver lobe hypertrophy was determined by CT volumetry, and portal recanalization was identified on contrast-enhanced CT images. Animals were killed after 7 or 42 days, and the results were compared with those of permanent embolization. RESULTS: PVE using fibrin glue with aprotinin as embolic material was effective, with 500 kunits/ml providing the optimal hypertrophic response. Lower concentrations of aprotinin (150 and 300 kunits/ml) led to reduced hypertrophy owing to early recanalization of the embolized segments. The regeneration rate over the first 3 days was higher in the group with 500 kunits/ml aprotinin than in the groups with 300 or 150 kunits/ml or permanent embolization. In the 500-kunits/ml group, four of five animals showed recanalization 42 days after embolization, with minimal histological changes in the cranial lobes following recanalization. CONCLUSION: Fibrin glue combined with 500 kunits/ml aprotinin resulted in reversible PVE in 80 per cent of animals, with a hypertrophy response comparable to that achieved with permanent embolization material. Surgical relevance Portal vein embolization (PVE) is used to increase future remnant liver volume in patients scheduled for major liver resection who have insufficient future remnant liver size to perform a safe resection. The current standard is PVE with permanent embolization materials, which renders patients found to have unresectable disease prone to complications owing to the permanently deportalized liver segments. Absorbable embolization might prevent the PVE-associated morbidity and lower the threshold for its application. In this study, PVE using fibrin glue and aprotinin resulted in an adequate hypertrophy response with 80 per cent recanalization after 42 days. Considering the minor histological changes following recanalization of embolized segments and potentially preserved function, reversible PVE might also be applied in living donor liver transplantation. PMID- 27477878 TI - A quantitative assessment of Arctic shipping in 2010-2014. AB - Rapid loss of sea ice is opening up the Arctic Ocean to shipping, a practice that is forecasted to increase rapidly by 2050 when many models predict that the Arctic Ocean will largely be free of ice toward the end of summer. These forecasts carry considerable uncertainty because Arctic shipping was previously considered too sparse to allow for adequate validation. Here, we provide quantitative evidence that the extent of Arctic shipping in the period 2011-2014 is already significant and that it is concentrated (i) in the Norwegian and Barents Seas, and (ii) predominantly accessed via the Northeast and Northwest Passages. Thick ice along the forecasted direct trans-Arctic route was still present in 2014, preventing transit. Although Arctic shipping remains constrained by the extent of ice coverage, during every September, this coverage is at a minimum, allowing the highest levels of shipping activity. Access to Arctic resources, particularly fisheries, is the most important driver of Arctic shipping thus far. PMID- 27477879 TI - The Differential Impact of User-Fee Exemption Compared to Conditional Cash Transfers on Safe Deliveries in Nepal. AB - OBJECTIVE: To assess the differential impact of a copayment exemption compared to a cash incentive on increasing skilled birth attendance (i.e., birth attended by a skilled health worker) in Nepal. DATA SOURCES/STUDY SETTING: This study used data on 8,785 children born between July 2005 and December 2008, obtained from the nationally representative Demographic and Health Surveys, 2006 and 2011. STUDY DESIGN: Twenty-five districts received both the policy interventions, and the remaining 50 control districts received only the cash incentive. We employed a difference-in-differences model to compare children born in districts with both interventions to those in districts with conditional cash transfers only. Average marginal effects of the difference-in-difference coefficient on skilled birth attendance measures are estimated. PRINCIPAL FINDINGS: Skilled birth attendance in districts with both interventions was no higher on average than in districts with only the cash incentive. In areas with adequate road networks, however, significantly higher skilled birth attendance was observed in districts with both interventions compared to those with only the cash incentive. CONCLUSIONS: The added incentive of the user-fee exemption did not significantly increase skilled birth attendance relative to the presence of the cash incentive. User-fee exemptions may not be effective in areas with inadequate road infrastructure. PMID- 27477880 TI - Monitoring of adherent live cells morphology using the undecimated wavelet transform multivariate image analysis (UWT-MIA). AB - Cell morphology is an important macroscopic indicator of cellular physiology and is increasingly used as a mean of probing culture state in vitro. Phase contrast microscopy (PCM) is a valuable tool for observing live cells morphology over long periods of time with minimal culture artifact. Two general approaches are commonly used to analyze images: individual object segmentation and characterization by pattern recognition. Single-cell segmentation is difficult to achieve in PCM images of adherent cells since their contour is often irregular and blurry, and the cells bundle together when the culture reaches confluence. Alternatively, pattern recognition approaches such as the undecimated wavelet transform multivariate image analysis (UWT-MIA), allow extracting textural features from PCM images that are correlated with cellular morphology. A partial least squares (PLS) regression model built using textural features from a set of 200 ground truth images was shown to predict the distribution of cellular morphological features (major and minor axes length, orientation, and roundness) with good accuracy for most images. The PLS models were then applied on a large dataset of 631,136 images collected from live myoblast cell cultures acquired under different conditions and grown in two different culture media. The method was found sensitive to morphological changes due to cell growth (culture time) and those introduced by the use of different culture media, and was able to distinguish both sources of variations. The proposed approach is promising for application on large datasets of PCM live-cell images to assess cellular morphology and growth kinetics in real-time which could be beneficial for high throughput screening as well as automated cell culture kinetics assessment and control applications. Biotechnol. Bioeng. 2017;114: 141-153. (c) 2016 Wiley Periodicals, Inc. PMID- 27477881 TI - Increased Risk of Depression Recurrence After Initiation of Prescription Opioids in Noncancer Pain Patients. PMID- 27477882 TI - Response to Ruan et al. Letter to the Editor: Increased Risk of Depression Recurrence After Initiation of Prescription Opioids in Noncancer Pain Patients. PMID- 27477883 TI - Erratum. PMID- 27477884 TI - Phase evolution, characterisation, and performance of cement prepared in an oxy fuel atmosphere. AB - Cement manufacture is one of the major contributors (7-10%) to global anthropogenic CO2 emissions. Carbon capture and storage (CCS) has been identified as a vital technology for decarbonising the sector. Oxy-fuel combustion, involving burning fuel in a mixture of recycled CO2 and pure O2 instead of air, makes CO2 capture much easier. Since it combines a theoretically lower energy penalty with an increase in production, it is attractive as a CCS technology in cement plants. However, it is necessary to demonstrate that changes in the clinkering atmosphere do not reduce the quality of the clinker produced. Clinkers were successfully produced in an oxy-fuel atmosphere using only pure oxides as raw materials as well as a mixture of oxides and clay. Then, CEM I cements were prepared by the addition of 5 wt% gypsum to the clinkers. Quantitative XRD and XRF were used to obtain the phase and elemental compositions of the clinkers. The particle size distribution and compressive strength of the cements at 3, 7, 14, and 28 days' ages were tested, and the effect of the particle size distribution on the compressive strength was investigated. Additionally, the compressive strength of the cements produced in oxy-fuel atmospheres was compared with those of the cement produced in air and commercially available CEMEX CEM I. The results show that good-quality cement can be successfully produced in an oxy-fuel atmosphere and it has similar phase and chemical compositions to CEM I. Additionally, it has a comparable compressive strength to the cement produced in air and to commercially available CEMEX CEM I. PMID- 27477885 TI - Locked doors or therapeutic relationships? PMID- 27477886 TI - Suicide risk and absconding in psychiatric hospitals with and without open door policies: a 15 year, observational study. AB - BACKGROUND: Inpatient suicide and absconding of inpatients at risk of self endangering behaviour are important challenges for all medical disciplines, particularly psychiatry. Patients at risk are often admitted to locked wards in psychiatric hospitals to prevent absconding, suicide attempts, and death by suicide. However, there is insufficient evidence that treatment on locked wards can effectively prevent these outcomes. We did this study to compare hospitals without locked wards and hospitals with locked wards and to establish whether hospital type has an effect on these outcomes. METHODS: In this 15 year, naturalistic observational study, we examined 349 574 admissions to 21 German psychiatric inpatient hospitals from Jan 1, 1998, to Dec 31, 2012. We used propensity score matching to select 145 738 cases for an analysis, which allowed for causal inference on the effect of ward type (ie, locked, partly locked, open, and day clinic wards) and hospital type (ie, hospitals with and without locked wards) on suicide, suicide attempts, and absconding (with and without return), despite the absence of an experimental design. We used generalised linear mixed effects models to analyse the data. FINDINGS: In the 145 738 propensity score matched cases, suicide (OR 1.326, 95% CI 0.803-2.113; p=0.24), suicide attempts (1.057, 0.787-1.412; p=0.71), and absconding with return (1.288, 0.874-1.929; p=0.21) and without return (1.090, 0.722-1.659; p=0.69) were not increased in hospitals with an open door policy. Compared with treatment on locked wards, treatment on open wards was associated with a decreased probability of suicide attempts (OR 0.658, 95% CI 0.504-0.864; p=0.003), absconding with return (0.629, 0.524-0.764; p<0.0001), and absconding without return (0.707, 0.546-0.925; p=0.01), but not completed suicide (0.823, 0.376-1.766; p=0.63). INTERPRETATION: Locked doors might not be able to prevent suicide and absconding. FUNDING: None. PMID- 27477888 TI - Facile fabrication of high-quality Ag/PS coaxial nanocables based on the mixed mode of soft/hard templates. AB - A new kind of high-quality Ag/PS coaxial nanocables can be facilely synthesized by using soft/hard templates method. In order to effectively introduce Ag sources into porous polystyrene (PS) nanotubes which were trapped in porous anodic aluminum oxide (AAO) hard template, Pluronic F127 (F127) was used as guiding agent, soft template and reductant. Meanwhile, ethylene glycol solution was also used as solvent and co-reducing agent to assist in the formation of silver nanowires. The influences of concentration of F127 and reducing reaction time on the formation of Ag/PS coaxial nanocables were discussed. Results indicated that the high-quality Ag/PS coaxial nanocables can be obtained by the mixed mode of soft/hard templates under optimized conditions. This strategy is expected to be extended to design more metal/polymer coaxial nanocables for the benefit of creation of complex and functional nanoarchitectures and components. PMID- 27477887 TI - NMR investigation of magnesium chelation and cation-induced signal shift effect of testosterone. AB - We have previously reported that testosterone (Tes) is able to interact with magnesium chloride dissolved in methanol. In this study, we have applied 1H and 13C NMR spectroscopies to a series of Tes solutions containing Mg2+ at various concentrations. High-resolution 13C NMR spectra of Tes/Mg2+ revealed well resolved 13C signals, and the intensities of those arising from C3, C5, C16, and C17 decreased linearly with increasing Mg2+ concentration. The magnitude of the chelation affinity could be deduced from the slopes of the 13C intensity variations; typically, the greater the slope the higher the chelation affinity. The results revealed Tes/Mg2+ chelation to be mediated by the oxygen atom attached to C3 in ring A, and the hydroxyl group attached to C17 in ring D. With regard to the chelation specificity, we showed that Tes chelates Mg2+, but not Ca2+ or Zn2+. We also explored the cation-induced signal shift effects of Tes in the presence of Mg2+, Ca2+, or Zn2+. We demonstrate that high-resolution 13C NMR spectroscopy provides a better probe than 1H NMR for the detection of cation chelation and cation-induced signal shift effects for steroid compounds such as Tes. PMID- 27477889 TI - Accumulation, Persistence, and Effects of Indospicine Residues in Camels Fed Indigofera Plant. AB - Indospicine (l-2-amino-6-amidinohexanoic acid) is a natural hepatotoxin found in all parts of some Indigofera plants such as Indigofera linnaei and Indigofera spicata. Several studies have documented a susceptibility to this hepatotoxin in different species of animals, including cattle, sheep, dogs, and rats, which are associated with mild to severe liver disease after prolonged ingestion. However, there is little published data on the effects of this hepatotoxin in camels, even though Indigofera plants are known to be palatable to camels in central Australia. The secondary poisoning of dogs after prolonged dietary exposure to residual indospicine in camel muscle has raised additional food safety concerns. In this study, a feeding experiment was conducted to investigate the in vivo accumulation, excretion, distribution, and histopathological effects of dietary indospicine on camels. Six young camels (2-4 years old), weighing 270-390 kg, were fed daily a roughage diet consisting of Rhodes grass hay and lucerne chaff, supplemented with Indigofera and steam-flaked barley. Indigofera (I. spicata) was offered at 597 mg DM/kg body weight (bw)/day, designed to deliver 337 MUg indospicine/kg bw/day, and fed for a period of 32 days. Blood and muscle biopsies were collected over the period of the study. Concentrations of indospicine in the plasma and muscle biopsy samples were quantitated by validated ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The highest concentrations in plasma (1.01 mg/L) and muscle (2.63 mg/kg fresh weight (fw)) were found at necropsy (day 33). Other tissues were also collected at necropsy, and analysis showed ubiquitous distribution of indospicine, with the highest indospicine accumulation detected in the pancreas (4.86 +/- 0.56 mg/kg fw) and liver (3.60 +/- 1.34 mg/kg fw), followed by the muscle, heart, and kidney. Histopathological examination of liver tissue showed multiple small foci of predominantly mononuclear inflammatory cells. After cessation of Indigofera intake, indospicine present in plasma in the remaining three camels had a longer terminal elimination half-life (18.6 days) than muscle (15.9 days), and both demonstrated monoexponential decreases. PMID- 27477890 TI - Hypophosphataemia and parenteral nutrition; biochemical monitoring, incidence and outcomes. PMID- 27477891 TI - Effect of PEG-PDMAEMA Block Copolymer Architecture on Polyelectrolyte Complex Formation with Heparin. AB - Heparin is a naturally occurring polyelectrolyte consisting of a sulfated polysaccharide backbone. It is widely used as an anticoagulant during major surgical operations. However, the associated bleeding risks require rapid neutralization after the operation. The only clinically approved antidote for heparin is protamine sulfate, which is, however, ineffective against low molecular weight heparin and can cause severe adverse reactions in patients. In this study, the facile synthesis of cationic-neutral diblock copolymers and their effective heparin binding is presented. Poly(ethylene glycol)-poly(2 (dimethylamino)ethyl methacrylate) (PEG-PDMAEMA) block copolymers were synthesized in two steps via atom-transfer radical polymerization (ATRP) using PEG as a macroinitiator. Solution state binding between heparin and a range of PEG-PDMAEMA block copolymers and one homopolymer was studied with dynamic light scattering and methylene blue displacement assay. Also in vitro binding in plasma was studied by utilizing a chromogenic heparin anti-Xa assay. Additionally, quartz crystal microbalance and multiparametric surface plasmon resonance were used to study the surface adsorption kinetics of the polymers on a heparin layer. It was shown that the block copolymers and heparin form electrostatically bound complexes with varying colloidal properties, where the block lengths play a key role in controlling the heparin binding affinity, polyelectrolyte complex size and surface charge. With the optimized polymers (PEG114PDMAEMA52 and PEG114PDMAEMA100), heparin could be neutralized in a dose-dependent manner, and bound efficiently into small neutral complexes, with a hydrodynamic radius less than 100 nm. These complexes had only a limited effect on cell viability. Based on these studies, our approach paves the way for the development of new polymeric heparin binding agents. PMID- 27477892 TI - Copayments and physicians visits: A panel data study of Swedish regions 2003 2012. AB - OBJECTIVE: This paper analyzes how primary care physician visits are affected by the level of copayment in Sweden. DATA SOURCE: We use data between the years 2003 2012 from 21 Swedish health care regions that have the mandate to set their own level of copayment. The copayment per visit varies between ?10 and ?20 for these years and regions. STUDY DESIGN: Our strategy to identify the causal effect and deal with unobserved endogeneity of price changes on physician visits is based on a panel data model using fixed effects to control for region and time and regional-variation in time trends. PRINCIPAL FINDING: We cannot reject that the copayment has no statistical or economic effect of significance, and we estimate the "zero effect" with very high precision. CONCLUSION: In a setting with sub national regions with autonomy to set co-payments the results points to that the copayment is not an important predictor for the number of health care visits. The result is in line with some previous studies on European data where the range of copayments used tends to be relatively low. PMID- 27477893 TI - Exploring the origin of the catalytic power and product specificity of SET domain protein methyltransferase. AB - Herein, we used computer simulation to evaluate the free energy activation barriers of the first and second methyl transfer for native SET8 PKMT and its Y334F mutant. The results suggest that the origin of SET8 catalytic power is mainly due to electrostatic preorganization. PMID- 27477894 TI - Insufficient global health education in European neurological post-graduate training: a European Association of Young Neurologists and Trainees survey. AB - BACKGROUND AND PURPOSE: The awareness of and demand for neurological expertise in global health (GH) have emerged over recent years and have become more relevant due to the increasing numbers of refugees from developing countries arriving in Europe. This study aimed to assess the provision of GH education and opportunities for international exchange during neurology post-graduate training with a focus on Europe. METHODS: We developed a questionnaire covering different aspects of and interest in GH education on behalf of the European Association of Young Neurologists and Trainees. Residents in neurology and junior neurologists (RJN) were approached to complete this survey. RESULTS: Completed questionnaires were returned by 131 RJNs, of whom 65.7% were women and 84.0% were between 26 and 35 years old. In total, almost one-third (29.0%) of RJNs reported that their residency programs offered training in GH. Limited education was reported for women's or children's health and neurological disorders of immigrants and refugees, as only 22.1%, 25.2% and 22.1% of RJNs reported that such training was offered, respectively. The curriculum rarely included coverage of the global impact of neurological disorders. Definite plans to volunteer in a developing country were reported by 7.6%. The majority of the participants acknowledged the importance of GH training and international exchange during post-graduate education. CONCLUSION: This survey corroborates the interest in and appreciation of GH education by European RJNs. However, there are shortcomings in training and opportunities for international exchange. Academic neurology and international bodies, including the European Academy of Neurology, are requested to address this. PMID- 27477895 TI - Mesenchymal stem cells for fistulising Crohn's disease. PMID- 27477896 TI - Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. AB - BACKGROUND: Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease. METHODS: We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (>=18 years) with Crohn's disease and treatment refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579. FINDINGS: 212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15.2%, 97.5% CI 0.2-30.3; p=0.024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15.8%, 0.5-31.2; p=0.021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine). INTERPRETATION: Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both. FUNDING: TiGenix. PMID- 27477897 TI - Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. AB - Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cystine or glutamine excess induced ferroptosis of both cisplatin sensitive and -resistant HNC cells without any apparent changes to necrosis and apoptosis markers. The cystine/glutamate antiporter inhibitors erastin and sulfasalazine inhibited HNC cell growth and accumulated lipid reactive oxygen species, thereby inducing ferroptosis. Genetic silencing of cystine/glutamate antiporter with siRNA or shRNA treatment also induced effective ferroptotic cell death of resistant HNC cells and enhanced the cisplatin cytotoxicity of resistant HNC cells. Pharmacological and genetic inhibition of cystine/glutamate antiporter significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Pharmacological and genetic inhibition of cystine/glutamate antiporter overcomes the cisplatin resistance of HNC cells by inducing ferroptosis. PMID- 27477898 TI - "Cell identity" crisis: Another call for immediate action. AB - Comment on: J. Wei, J. Zhang, Y. Si, M. Kanada, Z. Zhang, S. Terakawa, H. Watanabe, Blockage of LMP1-modulated store-operated Ca(2+) entry reduces metastatic potential in nasopharyngeal carcinoma cell, Cancer Lett. 360 (2015) 234-244. doi:10.1016/j.canlet.2015.02.032. PMID- 27477899 TI - Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of clonogenic resistance in breast cancer cells by combined cisplatin and FK228. AB - Safe and effective combination chemotherapy regimens against breast cancer are lacking. We used our cellular system, consisting of the non-cancerous human breast epithelial MCF10A cell line and its derived tumorigenic, oncogenic H-Ras expressing, MCF10A-Ras cell line, to investigate the effectiveness of a combination chemotherapy regimen in treating breast cancer cells using two FDA approved agents, cisplatin and FK228. Cisplatin and FK228 significantly, synergistically, and preferentially induced death and reduced drug resistance of MCF10A-Ras versus MCF10A cells. The ERK-Nox-ROS pathway played a major role in both synergistic cell death induction and GSH-level reduction, which contributed to the synergistic suppression of drug resistance in cells. Enhancement of the Ras-ERK-Nox pathway by combined cisplatin and FK228 significantly increased ROS levels, leading to induction of death, reduction of drug resistance, and induction of DNA damage and oxidation in cancerous MCF10A-Ras cells. Furthermore, synergistic induction of cell death and reduction of drug resistance by combined cisplatin and FK228 in breast cells is independent of their estrogen receptor status. Our study suggests that combined cisplatin and FK228 should be considered in clinical trials as a new regimen for therapeutic control of breast cancers. PMID- 27477900 TI - BARD1 splice variants display mislocalization in breast cancer cells and can alter the apoptotic response to cisplatin. AB - We previously showed that BARD1 is a shuttling protein with pro-apoptotic activity in MCF-7 breast cancer cells. BARD1 is expressed as splice variant isoforms in breast cancer. Here we characterized YFP-tagged BARD1 splice variants (beta, omega, phi, DeltaRIN, epsilon) for subcellular localization and apoptotic efficacy. We found that loss of nuclear localization (NLS) or export (NES) sequences influenced cellular distribution. The beta and omega variants (+NLS/ NES) shifted exclusively to the nucleus. In contrast, BARD1-epsilon (-NLS/+NES) was mostly cytoplasmic. Variants that lacked both NLS and NES were evenly distributed. Interestingly, the more nuclear isoforms (omega and beta) were least apoptotic in MCF-7 cells as measured by FACS. The cytoplasmic localization of BARD1 isoforms correlated with increased apoptosis. This relationship held in cells exposed to low dose (5 uM) of cisplatin. At 20 uM cisplatin, the main observation was a protective effect by the omega isoform. Similar analyses of HCC1937 cells revealed less pronounced changes but a significant protective influence by BARD1-epsilon. Thus BARD1 variants differ in localization and apoptotic ability, and their expression profile may aid prediction of drug efficacy in breast cancer. PMID- 27477901 TI - Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells. AB - Head and neck cancer is the sixth most common cancer worldwide. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, exhibits a wide range of biological roles including a highly efficient and specific anti tumor activity. Here, we aimed to examine the effect of DHA on head and neck carcinoma cells and elucidate the potential mechanisms. We used five head and neck carcinoma cell lines and two non-tumorigenic normal epithelial cell lines to achieve our goals. Cells were exposed to DHA and subjected to cellular activity assays including viability, cell cycle analysis, cell death, and angiogenic phenotype. Our results show that DHA causes cell cycle arrest which is mediated through Forkhead box protein M1 (FOXM1). We also demonstrate that DHA induces ferroptosis and apoptosis in head and neck carcinoma cells. Lastly, our results show that DHA alters the angiogenic phenotype of cancer cells by reducing the expression of angiogenic factors and the ability of cancer cells to support endothelial cell tubule formation. Our study suggests that DHA specifically causes head and neck cancer cell death through contribution from both ferroptosis and apoptosis. DHA may represent an effective strategy in head and neck cancer treatment. PMID- 27477902 TI - Recent advances in brain development. PMID- 27477903 TI - Psychometric assessment of the short-form Child Perceptions Questionnaire: an international collaborative study. AB - OBJECTIVE: To examine the factor structure and other psychometric characteristics of the most commonly used child oral-health-related quality-of-life (OHRQoL) measure (the 16-item short-form CPQ11-14 ) in a large number of children (N = 5804) from different settings and who had a range of caries experience and associated impacts. METHODS: Secondary data analyses used subnational epidemiological samples of 11- to 14-year-olds in Australia (N = 372), New Zealand (three samples: 352, 202, 429), Brunei (423), Cambodia (244), Hong Kong (542), Malaysia (439), Thailand (220, 325), England (88, 374), Germany (1055), Mexico (335) and Brazil (404). Confirmatory factor analysis (CFA) was used to examine the factor structure of the CPQ11-14 across the combined sample and within four regions (Australia/NZ, Asia, UK/Europe and Latin America). Item impact and internal reliability analysis were also conducted. RESULTS: Caries experience varied, with mean DMFT scores ranging from 0.5 in the Malaysian sample to 3.4 in one New Zealand sample. Even more variation was noted in the proportion reporting only fair or poor oral health; this was highest in the Cambodian and Mexican samples and lowest in the German sample and one New Zealand sample. One in 10 reported that their oral health had a marked impact on their life overall. The CFA across all samples revealed two factors with eigenvalues greater than 1. The first involved all items in the oral symptoms and functional limitations subscales; the second involved all emotional well-being and social well-being items. The first was designated the 'symptoms/function' subscale, and the second was designated the 'well-being' subscale. Cronbach's alpha scores were 0.72 and 0.84, respectively. The symptoms/function subscale contained more of the items with greater impact, with the item 'Food stuck in between your teeth' having greatest impact; in the well-being subscale, the 'Felt shy or embarrassed' item had the greatest impact. Repeating the analyses by world region gave similar findings. CONCLUSION: The CPQ11-14 performed well cross-sectionally in the largest analysis of the scale in the literature to date, with robust and mostly consistent psychometric characteristics, albeit with two underlying factors (rather than the originally hypothesized four-factor structure). It appears to be a sound, robust measure which should be useful for research, practice and policy. PMID- 27477904 TI - Barriers and Facilitators to Adolescents' Use of Long-Acting Reversible Contraceptives. AB - Most pregnancies among teenagers are unintended and many can be attributed to contraception misuse or nonuse. The etonogestrel implant and intrauterine devices, referred to as long-acting reversible contraceptives, or LARCs, are the most effective reversible contraceptive methods. These methods are safe for use by adolescents, yet the number of LARC users remains low among adolescents in the United States. In this review we examine recent literature about barriers and facilitators to LARC use among adolescent women. Factors that influence decision making and provision are organized into 4 categories: (1) cost and clinical operations; (2) adolescent awareness and attitudes; (3) confidentiality, consent, and parental attitudes; and (4) health care provider knowledge, attitudes, and counseling. Knowledge deficits and misconceptions among adolescents and their health care providers are key barriers to adolescent LARC use. PMID- 27477905 TI - Patch testing - a valuable tool for investigating non-immediate cutaneous adverse drug reactions to antibiotics. AB - BACKGROUND: Antibiotics are among the most frequent causes of cutaneous adverse drug reactions (CADR); patch testing may be an important tool in their evaluation and management. We assessed the role of patch testing as a diagnostic tool in non immediate CADR to antibiotics, and evaluated cross-reactivity among them. METHODS: We reviewed data from all patients with non-immediate CADR attributed to antibiotics, which were patch tested between 2000 and 2014 at our dermatology department. RESULTS: Patch tests were performed in 260 patients, and showed overall reactivity to antibiotics of 21.5%, especially in the context of drug reactions with eosinophilia and systemic symptoms (DRESS) (31.6%), maculopapular exanthema (MPE) (21.8%), Stevens-Johnson syndrome/toxic epidermal necrolysis (20%) and acute generalized exanthematous pustulosis (AGEP) (18.1%). Patch test reactivity was higher for amoxicillin, mainly in DRESS (44.4%) and MPE (25.6%), and dicloxacillin (50% in AGEP and 37.5% in MPE). Reactivity to clindamycin occurred, especially in the setting of MPE (23.2%). In AGEP and DRESS, patch tests were useful in detecting reactivity to quinolones (50-100%). Overall reactivity was lower for vancomycin (9.1%), co-trimoxazole (8.6%), macrolides (4.8%) and cephalosporins (4.4%). Positive patch tests for more than one antibiotic occurred in 29/56 cases (51.8%), mostly explained by cross-reactions. Twenty of 24 cases reacted to both amoxicillin and ampicillin. All five cases reacting to ciprofloxacin cross-reacted with other quinolones. CONCLUSION: Although oral rechallenge is considered the gold standard for confirming drug imputability in CADR, patch testing could be suggested as a first choice in the study of non-immediate reactions, since it is a safe and valuable procedure. PMID- 27477906 TI - ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes. AB - Histone acetylation, including acetylated H3K14 (H3K14ac), is generally linked to gene activation. Monomethylated histone H3 lysine 4 (H3K4me1), together with other gene-activating marks, denotes active genes. In contrast to usual gene activating functions of H3K14ac and H3K4me1, we here show that the dual histone modification mark H3K4me1-H3K14ac is recognized by ZMYND8 (also called RACK7) and can function to counteract gene expression. We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D. ZMYND8 antagonized the expression of metastasis-linked genes, and its knockdown increased the cellular invasiveness in vitro and in vivo. The plant homeodomain (PHD) and Bromodomain cassette in ZMYND8 mediated the combinatorial recognition of H3K4me1 H3K14ac and H3K4me0-H3K14ac by ZMYND8. These findings uncover an unexpected role for the signature H3K4me1-H3K14ac in attenuating gene expression and reveal a metastasis-suppressive epigenetic mechanism in which ZMYND8's PHD-Bromo cassette couples H3K4me1-H3K14ac with downregulation of metastasis-linked genes. PMID- 27477907 TI - Engineered Covalent Inactivation of TFIIH-Kinase Reveals an Elongation Checkpoint and Results in Widespread mRNA Stabilization. AB - During transcription initiation, the TFIIH-kinase Kin28/Cdk7 marks RNA polymerase II (Pol II) by phosphorylating the C-terminal domain (CTD) of its largest subunit. Here we describe a structure-guided chemical approach to covalently and specifically inactivate Kin28 kinase activity in vivo. This method of irreversible inactivation recapitulates both the lethal phenotype and the key molecular signatures that result from genetically disrupting Kin28 function in vivo. Inactivating Kin28 impacts promoter release to differing degrees and reveals a "checkpoint" during the transition to productive elongation. While promoter-proximal pausing is not observed in budding yeast, inhibition of Kin28 attenuates elongation-licensing signals, resulting in Pol II accumulation at the +2 nucleosome and reduced transition to productive elongation. Furthermore, upon inhibition, global stabilization of mRNA masks different degrees of reduction in nascent transcription. This study resolves long-standing controversies on the role of Kin28 in transcription and provides a rational approach to irreversibly inhibit other kinases in vivo. PMID- 27477909 TI - A Highly Sensitive and Robust Method for Genome-wide 5hmC Profiling of Rare Cell Populations. AB - We present a highly sensitive and selective chemical labeling and capture approach for genome-wide profiling of 5-hydroxylmethylcytosine (5hmC) using DNA isolated from ~1,000 cells (nano-hmC-Seal). Using this technology, we assessed 5hmC occupancy and dynamics across different stages of hematopoietic differentiation. Nano-hmC-Seal profiling of purified Tet2-mutant acute myeloid leukemia (AML) murine stem cells allowed us to identify leukemia-specific, differentially hydroxymethylated regions that harbor known and candidate disease specific target genes with differential 5hmC peaks compared to normal stem cells. The change of 5hmC patterns in AML strongly correlates with differential gene expression, demonstrating the importance of dynamic alterations of 5hmC in regulating transcription in AML. Together, covalent 5hmC labeling offers an effective approach to study and detect DNA methylation dynamics in in vivo disease models and in limited clinical samples. PMID- 27477908 TI - A Long Noncoding RNA Regulates Sister Chromatid Cohesion. AB - Long noncoding RNAs (lncRNAs) are involved in diverse cellular processes through multiple mechanisms. Here, we describe a previously uncharacterized human lncRNA, CONCR (cohesion regulator noncoding RNA), that is transcriptionally activated by MYC and is upregulated in multiple cancer types. The expression of CONCR is cell cycle regulated, and it is required for cell-cycle progression and DNA replication. Moreover, cells depleted of CONCR show severe defects in sister chromatid cohesion, suggesting an essential role for CONCR in cohesion establishment during cell division. CONCR interacts with and regulates the activity of DDX11, a DNA-dependent ATPase and helicase involved in DNA replication and sister chromatid cohesion. These findings unveil a direct role for an lncRNA in the establishment of sister chromatid cohesion by modulating DDX11 enzymatic activity. PMID- 27477910 TI - DNA Breaks and End Resection Measured Genome-wide by End Sequencing. AB - DNA double-strand breaks (DSBs) arise during physiological transcription, DNA replication, and antigen receptor diversification. Mistargeting or misprocessing of DSBs can result in pathological structural variation and mutation. Here we describe a sensitive method (END-seq) to monitor DNA end resection and DSBs genome-wide at base-pair resolution in vivo. We utilized END-seq to determine the frequency and spectrum of restriction-enzyme-, zinc-finger-nuclease-, and RAG induced DSBs. Beyond sequence preference, chromatin features dictate the repertoire of these genome-modifying enzymes. END-seq can detect at least one DSB per cell among 10,000 cells not harboring DSBs, and we estimate that up to one out of 60 cells contains off-target RAG cleavage. In addition to site-specific cleavage, we detect DSBs distributed over extended regions during immunoglobulin class-switch recombination. Thus, END-seq provides a snapshot of DNA ends genome wide, which can be utilized for understanding genome-editing specificities and the influence of chromatin on DSB pathway choice. PMID- 27477911 TI - Cdk1 Triggers Association of RNA Polymerase to Cell Cycle Promoters Only after Recruitment of the Mediator by SBF. PMID- 27477913 TI - Social Media and Language Processing: How Facebook and Twitter Provide the Best Frequency Estimates for Studying Word Recognition. AB - Corpus-based word frequencies are one of the most important predictors in language processing tasks. Frequencies based on conversational corpora (such as movie subtitles) are shown to better capture the variance in lexical decision tasks compared to traditional corpora. In this study, we show that frequencies computed from social media are currently the best frequency-based estimators of lexical decision reaction times (up to 3.6% increase in explained variance). The results are robust (observed for Twitter- and Facebook-based frequencies on American English and British English datasets) and are still substantial when we control for corpus size. PMID- 27477912 TI - Endoscopic detection of cancer with lensless radioluminescence imaging and machine vision. AB - Complete removal of residual tumor tissue during surgical resection improves patient outcomes. However, it is often difficult for surgeons to delineate the tumor beyond its visible boundary. This has led to the development of intraoperative detectors that can image radiotracers accumulated within tumors, thus facilitating the removal of residual tumor tissue during surgical procedures. We introduce a beta imaging system that converts the beta radiation from the radiotracer into photons close to the decay origin through a CdWO4 scintillator and does not use any optical elements. The signal is relayed onto an EMCCD chip through a wound imaging fiber. The sensitivity of the device allows imaging of activity down to 100 nCi and the system has a resolution of at least 500 MUm with a field of view of 4.80 * 6.51 mm. Advances in handheld beta cameras have focused on hardware improvements, but we apply machine vision to the recorded images to extract more information. We automatically classify sample regions in human renal cancer tissue ex-vivo into tumor or benign tissue based on image features. Machine vision boosts the ability of our system to distinguish tumor from healthy tissue by a factor of 9 +/- 3 and can be applied to other beta imaging probes. PMID- 27477914 TI - Species-specific differentiation of variola, monkeypox, and varicella-zoster viruses by multiplex real-time PCR assay. AB - A method of one-stage rapid detection and differentiation of epidemiologically important variola virus (VARV), monkeypox virus (MPXV), and varicella-zoster virus (VZV) utilizing multiplex real-time TaqMan PCR assay was developed. Four hybridization probes with various fluorescent dyes and the corresponding fluorescence quenchers were simultaneously used for the assay. The hybridization probes specific for the VARV sequence contained FAM/BHQ1 as a dye/quencher pair; MPXV-specific, JOE/BHQ1; VZV-specific, TAMRA/BHQ2; and internal control-specific, Cy5/BHQ3. The specificity and sensitivity of the developed method were assessed by analyzing DNA of 32 strains belonging to orthopoxvirus and herpesvirus species. PMID- 27477915 TI - Correlation analysis of the natural radionuclides in soil and indoor radon in Vojvodina, Province of Serbia. AB - The most dominant source of indoor radon is the underlying soil, so the enhanced levels of radon are usually expected in mountain regions and geology units with high radium and uranium content in surface soils. Laboratory for radioactivity and dose measurement, Faculty of Sciences, University of Novi Sad has rich databases of natural radionuclides concentrations in Vojvodina soil and also of indoor radon concentrations for the region of Vojvodina, Northern Province of Serbia. In this paper we present the results of correlative and multivariate analysis of these results and soil characteristics in order to estimate the geogenic radon potential. The correlative and multivariate analysis were done using Toolkit for Multivariate Analysis software package TMVA package, within ROOT analysis framework, which uses several comparable multivariate methods for our analysis. The evaluation ranking results based on the best signal efficiency and purity, show that the Boosted Decision Trees (BDT) and Multi Layer Preceptor (MLP), based on Artificial Neural Network (ANN), are multivariate methods which give the best results in the analysis. The BDTG multivariate method shows that variables with the highest importance are radio-nuclides activity on 30 cm depth. Moreover, the multivariate regression methods give a good approximation of indoor radon activity using full set of input variables. On several locations in the city of Novi Sad the results of indoor radon concentrations, radon emanation from soil, gamma spectrometry measurements of underlying soil and geology characteristics of soil were analyzed in detail in order to verify previously obtained correlations for Vojvodina soil. PMID- 27477916 TI - Effect of the van der Waals interaction on the electron energy-loss near edge structure theoretical calculation. AB - The effect of the van der Waals (vdW) interaction on the simulation of the electron energy-loss near edge structure (ELNES) by a first-principles band structure calculation is reported. The effect of the vdW interaction is considered by the Tkatchenko-Scheffler scheme, and the change of the spectrum profile and the energy shift are discussed. We perform calculations on systems in the solid, liquid and gaseous states. The transition energy shifts to lower energy by approximately 0.1eV in the condensed (solid and liquid) systems by introducing the vdW effect into the calculation, whereas the energy shift in the gaseous models is negligible owing to the long intermolecular distance. We reveal that the vdW interaction exhibits a larger effect on the excited state than the ground state owing to the presence of an excited electron in the unoccupied band. Moreover, the vdW effect is found to depend on the local electron density and the molecular coordination. In addition, this study suggests that the detection of the vdW interactions exhibited within materials is possible by a very stable and high resolution observation. PMID- 27477917 TI - Patient-centered communication in the era of electronic health records: What does the evidence say? AB - OBJECTIVE: Patient-physician communication is essential for patient-centered health care. Physicians are concerned that electronic health records (EHRs) negatively affect communication with patients. This study identified a framework for understanding communication functions that influence patient outcomes. We then conducted a systematic review of the literature and organized it within the framework to better understand what is known. METHOD: A comprehensive search of three databases (CINAHL, Medline, PsycINFO) yielded 41 articles for analysis. RESULTS: Results indicated that EHR use improves capture and sharing of certain biomedical information. However, it may interfere with collection of psychosocial and emotional information, and therefore may interfere with development of supportive, healing relationships. Patient access to the EHR and messaging functions may improve communication, patient empowerment, engagement, and self management. CONCLUSION: More rigorous examination of EHR impacts on communication functions and their influences on patient outcomes is imperative for achieving patient-centered care. By focusing on the role of communication functions on patient outcomes, future EHRs can be developed to facilitate care. PRACTICE IMPLICATIONS: Training alone is likely to be insufficient to address disruptions to communication processes. Processes must be improved, and EHRs must be developed to capture useful data without interfering with physicians' and patients' abilities to effectively communicate. PMID- 27477918 TI - Aerobic Degradation of Sulfadiazine by Arthrobacter spp.: Kinetics, Pathways, and Genomic Characterization. AB - Two aerobic sulfadiazine (SDZ) degrading bacterial strains, D2 and D4, affiliated with the genus Arthrobacter, were isolated from SDZ-enriched activated sludge. The degradation of SDZ by the two isolates followed first-order decay kinetics. The half-life time of complete SDZ degradation was 11.3 h for strain D2 and 46.4 h for strain D4. Degradation kinetic changed from nongrowth to growth-linked when glucose was introduced as the cosubstrate, and accelerated biodegradation rate was observed after the adaption period. Both isolates could degrade SDZ into 12 biodegradation products via 3 parallel pathways, of which 2-amino-4 hydroxypyrimidine was detected as the principal intermediate product toward the pyrimidine ring cleavage. Compared with five Arthrobacter strains reported previously, D2 and D4 were the only Arthrobacter strains which could degrade SDZ as the sole carbon source. The draft genomes of D2 and D4, with the same completeness of 99.7%, were compared to other genomes of related species. Overall, these two isolates shared high genomic similarities with the s-triazine degrading Arthrobacter sp. AK-YN10 and the sulfonamide-degrading bacteria Microbacterium sp. C448. In addition, the two genomes contained a few significant regions of difference which may carry the functional genes involved in sulfonamide degradation. PMID- 27477919 TI - Heme dampens T-cell sequestration by modulating glial cell responses during rodent cerebral malaria. AB - Cerebral malaria is the deadliest complication of Plasmodium falciparum infection. Its pathophysiology is associated with a strong pro-inflammatory reaction and the activation of glial cells. Among modulators released during the infection, heme seems to play a controversial role in the pathophysiology of malaria. Herein, we first investigated the phenotype of glial cells during cerebral malaria in C57BL/6 mice infected with P. berghei ANKA. Given the fact that high levels of heme were associated with cerebral malaria, we then investigated its impact on microglial, astrocyte, and T cell responses to further clarify its contribution in the neuropathophysiology. Surprisingly, we found that administration of heme twice a day from day three of infection induced the expression of the Heme oxygenase-1 (Hmox1) gene and prevented brain damages. More specifically, heme inhibited the M1 phenotype of microglia, hampered the activation of astrocytes, and decreased the cerebral expression of Ifng, Tnfa and Ip10. Heme might that way alter the migration of pathogenic CD4 and CD8 T lymphocytes within the brain observed during cerebral malaria. Taking into account that cerebral malaria results from a complex interplay between host- and parasite-derived factors, it is possible that genetic polymorphisms of Hmox1, which could be associated with the control of systemic levels of heme during P. falciparum infection, might explain its dual role and its contribution to the resistance to cerebral malaria. PMID- 27477920 TI - NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury. AB - Following traumatic brain injury (TBI), activation of microglia and peripherally derived inflammatory macrophages occurs in association with tissue damage. This neuroinflammatory response may have beneficial or detrimental effects on neuronal survival, depending on the functional polarization of these cells along a continuum from M1-like to M2-like activation states. The mechanisms that regulate M1-like and M2-like activation after TBI are not well understood, but appear in part to reflect the redox state of the lesion microenvironment. NADPH oxidase (NOX2) is a critical enzyme system that generates reactive oxygen species in microglia/macrophages. After TBI, NOX2 is strongly up-regulated in M1-like, but not in M2-like polarized cells. Therefore, we hypothesized that NOX2 drives M1 like neuroinflammation and contributes to neurodegeneration and loss of neurological function after TBI. In the present studies we inhibited NOX2 activity using NOX2-knockout mice or the selective peptide inhibitor gp91ds-tat. We show that NOX2 is highly up-regulated in infiltrating macrophages after injury, and that NOX2 deficiency reduces markers of M1-like activation, limits tissue loss and neurodegeneration, and improves motor recovery after moderate level control cortical injury (CCI). NOX2 deficiency also promotes M2-like activation after CCI, through increased IL-4Ralpha signaling in infiltrating macrophages, suggesting that NOX2 acts as a critical switch between M1- and M2 like activation states after TBI. Administration of gp91ds-tat to wild-type CCI mice starting at 24h post-injury reduces deficits in cognitive function and increased M2-like activation in the hippocampus. Collectively, our data indicate that increased NOX2 activity after TBI drives M1-like activation that contributes to inflammatory-mediated neurodegeneration, and that inhibiting this pathway provides neuroprotection, in part by altering M1-/M2-like balance towards the M2 like neuroinflammatory response. PMID- 27477921 TI - Running for REST: Physical activity attenuates neuroinflammation in the hippocampus of aged mice. AB - Exercise improves mental health and synaptic function in the aged brain. However, the molecular mechanisms involved in exercise-induced healthy brain aging are not well understood. Evidence supports the role of neurogenesis and neurotrophins in exercise-induced neuroplasticity. The gene silencing transcription factor neuronal RE1-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) and an anti-inflammatory role of exercise are also candidate mechanisms. We evaluate the effect of 8weeks of physical activity on running wheels (RW) on motor and depressive-like behavior and hippocampal gene expression of brain-derived neurotrophic factor (BDNF), REST, and interleukins IL-1beta and IL-10 of adult and aged C57BL/6 mice. The aged animals exhibited impaired motor function and a depressive-like behavior: decreased mobility in the RW and open field and severe immobility in the tail suspension test. The gene expression of REST, IL-1beta, and IL-10 was increased in the hippocampus of aged mice. Physical activity was anxiolytic and antidepressant and improved motor behavior in aged animals. Physical activity also boosted BDNF and REST expression and decreased IL 1beta and IL-10 expression in the hippocampus of aged animals. These results support the beneficial role of REST in the aged brain, which can be further enhanced by regular physical activity. PMID- 27477922 TI - Maternal serum cytokine levels and risk of bipolar disorder. AB - Prenatal exposure to influenza has previously been associated with increased risk of bipolar disorder (BD), an association that may be mediated by maternal cytokines. The objective of this study was to determine the association between maternal levels of cytokines measured during each trimester of pregnancy and the risk of BD in offspring. We conducted a case-control study nested in the Child Health and Development Study, a birth cohort that enrolled pregnant women in 1959 1966. Potential cases with DSM-IV-TR bipolar I disorder, bipolar II disorder, BD not otherwise specified, and BD with psychotic features were ascertained through electronic medical records, a public agency database, and a mailing to the cohort. Diagnoses were confirmed by clinical interview. Nine cytokines (IL-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha and GM-CSF) were measured simultaneously by Luminex assays in archived prenatal maternal serum samples from 85 cases and 170 matched controls. Data were analyzed using conditional logistic regression. In the overall study sample, there were no significant associations between prenatal maternal cytokine levels and BD after adjustment for confounders. The risk of BD without psychotic features was decreased among subjects with higher maternal levels of first trimester log-transformed IL-4 (OR (95% CI)=0.76 (0.58, 0.98); p=0.04) and third trimester log-transformed IL-6 (OR (95% CI)=0.64 (0.42, 0.98); p=0.04). In conclusion, higher levels of prenatal maternal cytokines were not associated with increased risk for BD. Further studies with larger samples are necessary to confirm the finding. PMID- 27477924 TI - Progress in cell culture systems for pathological research. AB - Cell culture is a well-established standard technique and a fundamental tool in biology and medicine. Establishment of a novel culture method by meeting various challenges can sometimes open up new fields of cell biology and medicine. An artificial microenvironment for cultured cells is made up of complicated factors, including cytokines, scaffold material type, cell-cell interactions, and physical stress. To replicate the tissue architecture, cell-cell interactions, and specific physical microenvironment, we previously demonstrated the effectiveness of a three-dimensional culture system, and further established two simple culture systems: air-liquid interface (ALI) and fluid flow stress (FFS). A three dimensional collagen gel culture system can replicate cell-cell interactions in vitro. As skin is constantly exposed to air, the ALI system closely mimicked the skin microenvironment and maintained the homeostasis of the epidermis and dermis. The ALI culture system also revealed the possibility of skin regeneration through ectopic mesenchymal cell involvement. Fluid streaming and shear stress were recently demonstrated to constitute the critical microenvironment for various cell types. The FFS system demonstrated that fluid streaming induced epithelial mesenchymal transition of mesothelial cells, leading to peritoneal fibrosis. Our novel culture systems will hopefully open up new fields of regenerative medicine and pathological research. PMID- 27477925 TI - Pharmacokinetic profiles of the active metamizole metabolites in healthy horses. AB - Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs. MT is rapidly hydrolysed to the active primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared with other minor metabolites. Among the other secondary metabolites, 4 aminoantipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.) and intramuscular (i.m.) routes in healthy horses. Six horses were randomly allocated to two equally sized treatment groups according to a 2 * 2 crossover study design. Blood was collected at predetermined times within 24 h, and plasma was analysed by a validated HPLC-UV method. No behavioural changes or alterations in health parameters were observed in the i.v. or i.m. groups of animals during or after (up to 7 days) drug administration. Plasma concentrations of MAA after i.v. and i.m. administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time, but in smaller amounts. Maximum concentration (Cmax ), time to maximum concentration (Tmax ) and AUMC0-last of MAA were statistically different between the i.v. and i.m. groups. The AUCIM /AUCIV ratio of MAA was 1.06. In contrast, AUC0-last of AA was statistically different between the groups (P < 0.05) with an AUCIM /AUCIV ratio of 0.54. This study suggested that the differences in the MAA and AA plasma concentrations found after i.m. and i.v. administrations of MT might have minor consequences on the pharmacodynamics of the drug. PMID- 27477923 TI - A Catalogue of Altered Salivary Proteins Secondary to Invasive Ductal Carcinoma: A Novel In Vivo Paradigm to Assess Breast Cancer Progression. AB - The objective of this manuscript is to introduce a catalogue of salivary proteins that are altered secondary to carcinoma of the breast. The catalogue of salivary proteins is a compilation of twenty years of research by the authors and consists of 233 high and low abundant proteins which have been identified by LC-MS/MS mass spectrometry, 2D-gel analysis and by enzyme-linked immunosorbent assay. The body of research suggests that saliva is a fluid suffused with solubilized by-products of oncogenic expression and that these proteins may be useful in the study of breast cancer progress, treatment efficacy and the tailoring of individualized patient care. PMID- 27477926 TI - FAMA: A Molecular Link between Stomata and Myrosin Cells. AB - Plants use sophisticated defense strategies against herbivores, including the myrosinase-glucosinolate system in Brassicales plants. This system sequesters myrosinase in myrosin cells, which are idioblasts in inner leaf tissues, and produces a toxic compound when cells are damaged by herbivores. Although the molecular mechanisms underlying myrosin cell development are largely unknown, recent studies have revealed that two key components, a basic helix-loop-helix (bHLH) transcription factor (FAMA) and vesicle trafficking factors (such as SYNTAXIN OF PLANTS 22), regulate the differentiation and fate determination of myrosin cells. FAMA also functions as a master regulator of guard cell (GC) differentiation. In this review, we discuss how FAMA operates two distinct genetic programs: the generation of myrosin cells in inner plant tissue and GCs in the epidermis. PMID- 27477927 TI - The Evolution of Cell Division: From Streptophyte Algae to Land Plants. AB - The mechanism of cell division has undergone significant alterations during the evolution from aquatic streptophyte algae to land plants. Two new structures evolved, the cytokinetic phragmoplast and the preprophase band (PPB) of microtubules, whereas the ancestral mechanism of cleavage and the centrosomes disappeared. We map cell biological data onto the recently emerged phylogenetic tree of streptophytes. The tree suggests that, after the establishment of the phragmoplast mechanism, several groups independently lost their centrosomes. Surprisingly, the phragmoplast shows reductions in the Zygnematophyceae (the sister to land plants), many of which returned to cleavage. The PPB by contrast evolved stepwise and, most likely, originated in the algae. The phragmoplast/PPB mechanism established in this way served as a basis for the 3D development of land plants. PMID- 27477928 TI - What tendon pathology is seen on imaging in people who have taken fluoroquinolones? A systematic review. AB - Fluoroquinolones (FQs) are highly effective broad-spectrum antibiotics. Clinical data reveal an increased incidence of tendon pain and rupture in those taking FQs, yet little is known about tendon structural changes. This review synthesises published data on tendon structural changes in people who have taken FQs. Eight databases were searched for potentially relevant articles (Medline, CINAHL, Biological Abstracts, AMED, Web of Knowledge, SCOPUS, SportDiscus and EMBASE) using MeSH and free-text searches. Inclusion and exclusion criteria determined which articles were used for this review. Twenty-six papers met the eligibility criteria. The Achilles tendon was most commonly affected, and ciprofloxacin and levofloxacin were the most commonly implicated FQs. Mean time to onset of symptoms was 16 days following first FQ dose. Imaging modalities used included magnetic resonance imaging (MRI), B-mode ultrasound (US) and computed tomography (CT). Tendon measurements were rarely reported, and intratendinous imaging findings were not reported in a consistent manner. Few studies imaged tendons bilaterally, and only two studies were longitudinal in design. Future studies should report imaging measures such as thickness and cross-sectional area and use consistent descriptions of intratendinous changes during and post-FQ treatment. PMID- 27477929 TI - Quality of life in breast cancer sufferers. AB - Purpose - The purpose of this paper is to measure health-related quality of life (QOL) among patients with early stage cancer breast under curative treatment at department of oncology and nuclear medicine at Ain Shams University Hospitals. Identify factors affecting QOL among these patients. Design/methodology/approach A cross-sectional study measured QOL among early stage female breast cancer (BC) patients and determined the main factors affecting their QOL. Three interviewer administered questionnaires were used. Findings - The physical domain mostly affected in BC patients and the functional domain least. Socio-demographic factors that significantly affected BC patients QOL scores were patient age, education, having children and family income. Specific patient characteristics include caregiver presence - a factor that affected different QOL scores. Age at diagnosis, affection in the side of the predominant hand, post-operative chemotherapy and difficulty in obtaining the medication were the disease-related factors that affected QOL scores. Originality/value - The final model predicting QOL for early stage female BC patients included age, education and difficulty in obtaining the medication as determinants for total QOL score. Carer presence was the specific patient characteristic that affected different QOL scores. PMID- 27477930 TI - Improving outpatient phlebotomy service efficiency and patient experience using discrete-event simulation. AB - Purpose - The purpose of this paper is to present a simulation modeling application to reconfigure the outpatient phlebotomy service of an acute regional and teaching hospital in Hong Kong, with an aim to improve service efficiency, shorten patient queuing time and enhance workforce utilization. Design/methodology/approach - The system was modeled as an inhomogeneous Poisson process and a discrete-event simulation model was developed to simulate the current setting, and to evaluate how various performance metrics would change if switched from a decentralized to a centralized model. Variations were then made to the model to test different workforce arrangements for the centralized service, so that managers could decide on the service's final configuration via an evidence-based and data-driven approach. Findings - This paper provides empirical insights about the relationship between staffing arrangement and system performance via a detailed scenario analysis. One particular staffing scenario was chosen by manages as it was considered to strike the best balance between performance and workforce scheduled. The resulting centralized phlebotomy service was successfully commissioned. Practical implications - This paper demonstrates how analytics could be used for operational planning at the hospital level. The authors show that a transparent and evidence-based scenario analysis, made available through analytics and simulation, greatly facilitates management and clinical stakeholders to arrive at the ideal service configuration. Originality/value - The authors provide a robust method in evaluating the relationship between workforce investment, queuing reduction and workforce utilization, which is crucial for managers when deciding the delivery model for any outpatient-related service. PMID- 27477931 TI - Clinical Assessment of Risk Management: an INtegrated Approach (CARMINA). AB - Purpose - The European Union recommendations for patient safety calls for shared clinical risk management (CRM) safety standards able to guide organizations in CRM implementation. The purpose of this paper is to develop a self-evaluation tool to measure healthcare organization performance on CRM and guide improvements over time. Design/methodology/approach - A multi-step approach was implemented including: a systematic literature review; consensus meetings with an expert panel from eight Italian leader organizations to get to an agreement on the first version; field testing to test instrument feasibility and flexibility; Delphi strategy with a second expert panel for content validation and balanced scoring system development. Findings - The self-assessment tool - Clinical Assessment of Risk Management: an INtegrated Approach includes seven areas (governance, communication, knowledge and skills, safe environment, care processes, adverse event management, learning from experience) and 52 standards. Each standard is evaluated according to four performance levels: minimum; monitoring; outcomes; and improvement actions, which resulted in a feasible, flexible and valid instrument to be used throughout different organizations. Practical implications This tool allows practitioners to assess their CRM activities compared to minimum levels, monitor performance, benchmarking with other institutions and spreading results to different stakeholders. Originality/value - The multi-step approach allowed us to identify core minimum CRM levels in a field where no consensus has been reached. Most standards may be easily adopted in other countries. PMID- 27477932 TI - Outpatient clinic waiting time, provider communication styles and satisfaction with healthcare in India. AB - Purpose - The purpose of this paper is to evaluate the impact of extended waiting time on patients' perceptions of provider communication skills and in-clinic satisfaction, in three major cities in India. Design/methodology/approach - In total, 625 patients were interviewed. The multivariate general linear model was used to determine the causality and relationship between the independent and the dependent variable. A moderation analysis was also conducted to assess waiting time role as a potential moderator in doctor-patient communication. Findings - Results show that patients with higher waiting time were less satisfied with health care quality. Male patients and patients of male providers were more affected by extended waiting time than female patients and patients of female providers. The advanced regression analysis, however, suggests weak support for waiting time and its effect on overall satisfaction with clinic quality. Waiting time did not moderate the relationship between satisfaction with dominant communication style, and overall satisfaction at the outpatient clinic. Research limitations/implications - A cross-sectional study does not easily lend itself to explaining causality with certainty. Thus, sophisticated techniques, such as structural equation modelling may also be utilized to assess the influence of extended waiting time on satisfaction with healthcare at outpatient clinics. Practical implications - Findings are relevant for providers as the onus is on them to ensure patient satisfaction. They should initiate a workable waiting time assessment model at the operational level. Originality/value - There has been a relatively lesser focus on patient waiting time in patient-provider satisfaction studies. In India, this aspect is still vastly unexplored especially in the context of outpatient clinics. Gender wise pattern of patient satisfaction and waiting time is also missing in most studies. PMID- 27477933 TI - Survival probability in patients with liver trauma. AB - Purpose - The purpose of this paper is to assess the survival probability among patients with liver trauma injury using the anatomical and psychological scores of conditions, characteristics and treatment modes. Design/methodology/approach - A logistic model is used to estimate 173 patients' survival probability. Data are taken from patient records. Only emergency room patients admitted to University Hospital of Trauma (former Military Hospital) in Tirana are included. Data are recorded anonymously, preserving the patients' privacy. Findings - When correctly predicted, the logistic models show that survival probability varies from 70.5 percent up to 95.4 percent. The degree of trauma injury, trauma with liver and other organs, total days the patient was hospitalized, and treatment method (conservative vs intervention) are statistically important in explaining survival probability. Practical implications - The study gives patients, their relatives and physicians ample and sound information they can use to predict survival chances, the best treatment and resource management. Originality/value - This study, which has not been done previously, explores survival probability, success probability for conservative and non-conservative treatment, and success probability for single vs multiple injuries from liver trauma. PMID- 27477934 TI - Managing healthcare information: analyzing trust. AB - Purpose - The purpose of this paper is to analyze two case studies with a trust matrix tool, to identify trust issues related to electronic health records. Design/methodology/approach - A qualitative research approach is applied using two case studies. The data analysis of these studies generated a problem list, which was mapped to a trust matrix. Findings - Results demonstrate flaws in current practices and point to achieving balance between organizational, person and technology trust perspectives. The analysis revealed three challenge areas, to: achieve higher trust in patient-focussed healthcare; improve communication between patients and healthcare professionals; and establish clear terminology. By taking trust into account, a more holistic perspective on healthcare can be achieved, where trust can be obtained and optimized. Research limitations/implications - A trust matrix is tested and shown to identify trust problems on different levels and relating to trusting beliefs. Future research should elaborate and more fully address issues within three identified challenge areas. Practical implications - The trust matrix's usefulness as a tool for organizations to analyze trust problems and issues is demonstrated. Originality/value - Healthcare trust issues are captured to a greater extent and from previously unchartered perspectives. PMID- 27477935 TI - Performance indicators: healthcare professionals' views. AB - Purpose - The purpose of this paper is to capture factors behind professional views of indicator usefulness as a common structure for assessing healthcare performance and their important characteristics to design limited key performance indicators (PIs) for holistic hospital management. Design/methodology/approach - Two surveys were conducted using self-administered questionnaires, in which hospital manager/staff respondents were asked to rate the 52 PIs' usefulness. In total, 228 manager and 894 staff responses were collected. Findings - Eight factors were elicited from manager and staff responses as performance measures with 72 percent cumulative variance accounted for. Hospital managers and staff showed similar performance measure perceptions: high-utility acknowledgment on safety, operational efficiency and patient/employee satisfaction but relatively low-employee development concerns. Manager indicator usefulness perceptions were rather homogeneous and significantly higher than staff for almost all performance measures. Practical implications - Homogeneous manager views mean that a single key PI set for hospital management may be established regardless of hospital attributes. The following aspects may be measures that should be managed in a healthcare organization based on their key PIs: patient/employee safety, operational efficiency, financial effectiveness and patient/employee satisfaction. Originality/value - This is a pilot study on hospital management PIs in Japan. The eight-dimensional factor structure and findings about healthcare provider perceptions may be useful for healthcare management. PMID- 27477937 TI - Hypoxia Promotes Osteogenesis of Human Placental-Derived Mesenchymal Stem Cells. AB - Placental-derived mesenchymal stem cells (pMSCs) are promising candidates for regenerative medicine because they possess high proliferative capacity and multi differentiation potential. Human pMSCs are residing in an environment with low oxygen tension in the body. Heme oxygenase-1 (HO-1) is known to participate in the regulation of MSC differentiation. The present study aimed to investigate the impact of hypoxia on the osteogenic differentiation of human pMSCs, and to elucidate the role of HO-1 in the osteogenic differentiation of hypoxic pMSCs. Human pMSCs were cultured under normoxia (21% O2) or hypoxia (5% O2) for 3 days. We found that hypoxia maintained the morphology and immunophenotype of human pMSCs. The expression of stemness markers Oct4, Nanog, and Sox2 was increased under hypoxia. After a 5-day hypoxic culture, the proliferation ability of pMSCs was increased, which might be correlated with the increased expression of stem cell factor. During osteogenic induction, hypoxia increased the expression of osteogenic genes including osteopontin, osteocalcin, and alkaline phosphatase (ALP). Moreover, hypoxia increased the mineralization and ALP levels of human pMSCs as evidenced by Alizarin Red staining and ALP staining. Upregulation of HO 1 by cobalt-protoporphyrin treatment increased the osteogenic differentiation of pMSCs under hypoxia, while inhibition of HO-1 by Zn-protoporphyrin reduced the osteogenic differentiation of hypoxic pMSCs. Taken together, our data suggest that hypoxia can promote the osteogenic differentiation of human pMSCs. Upregulation of HO-1 can further increase the osteogenesis of human pMSCs under hypoxia. Our findings will highlight the therapeutic potential of MSCs in the tissue engineering of bones. PMID- 27477936 TI - Acid-Sensing Ion Channel 2a (ASIC2a) Promotes Surface Trafficking of ASIC2b via Heteromeric Assembly. AB - Acid-sensing ion channels (ASICs) are proton-activated cation channels that play important roles as typical proton sensors during pathophysiological conditions and normal synaptic activities. Among the ASIC subunits, ASIC2a and ASIC2b are alternative splicing products from the same gene, ACCN1. It has been shown that ASIC2 isoforms have differential subcellular distribution: ASIC2a targets the cell surface by itself, while ASIC2b resides in the ER. However, the underlying mechanism for this differential subcellular localization remained to be further elucidated. By constructing ASIC2 chimeras, we found that the first transmembrane (TM1) domain and the proximal post-TM1 domain (17 amino acids) of ASIC2a are critical for membrane targeting of the proteins. We also observed that replacement of corresponding residues in ASIC2b by those of ASIC2a conferred proton-sensitivity as well as surface expression to ASIC2b. We finally confirmed that ASIC2b is delivered to the cell surface from the ER by forming heteromers with ASIC2a, and that the N-terminal region of ASIC2a is additionally required for the ASIC2a-dependent membrane targeting of ASIC2b. Together, our study supports an important role of ASIC2a in membrane targeting of ASIC2b. PMID- 27477938 TI - The role of osmotic self-inflatable tissue expanders in intestinal transplant candidates. AB - Intestinal transplantation (ITx) is often associated with decreased abdominal domain, rendering abdominal closure difficult. Pre-transplant placement of tissue expanders (TE) can overcome this challenge; however it can be associated with life-threatening complications. This review aimed to comprehensively summarize all available literature on TE in ITx candidates and include the technical details of osmotic, self-inflatable TE -a technique undescribed before. PubMed, EMBASE and CCTR were searched until April 30, 2016. Based on structured data abstraction and detailed analysis, eighteen cases of TE (inflatable) in ITx candidates were found. Localisation of placement was: subcutaneously in 11; intraperitoneally in 4; 1 patient had 1 TE placed retromuscularly and 1 intraperitoneally; 1 patient had biplanar TE (intraperitoneally placed and extending retromuscularly) and in 1 localisation was unreported. Complication rate was high (61%), injection- or intraperitoneal-related, resulting in life threatening infections/hematoma. With successful expansion, physiological graft protection -by skin+/-fascia- was always achieved. In completion of this review, we describe our own experience with two patients (7.5-, 34-year-old females), in whom osmotic TE were placed subcutaneously pre-ITx. No TE-related complications occurred and both patients underwent uncomplicated ITx with respectively primary skin and skin + fascia closure. The pros and cons of each TE type and placement are discussed, resulting in the overall conclusions that TE offer an important benefit in graft-protection following ITx. Osmotic TE are safer than conventional prostheses by avoiding percutaneous injections. Subcutaneous placement seems to be safer and more reliable. PMID- 27477939 TI - A 2:1 Atrioventricular Tachycardia Recorded by an Implantable Cardioverter Defibrillator: What Is the Mechanism? PMID- 27477940 TI - Inflammation-Induced Expression and Secretion of MicroRNA 122 Leads to Reduced Blood Levels of Kidney-Derived Erythropoietin and Anemia. AB - BACKGROUND & AIMS: Anemia is associated commonly with acute and chronic inflammation, but the mechanisms of their interaction are not clear. We investigated whether microRNA 122 (MIR122), which is generated in the liver and is secreted into the blood, is involved in the development of anemia associated with inflammation. METHODS: We characterized the primary transcript of the human liver-specific MIR122 using Northern blot, quantitative real-time polymerase chain reaction, and 3' and 5' rapid amplification of cDNA ends analyses. We studied regulation of MIR122 in human hepatocellular carcinoma cell lines (Huh7 and HepG2) as well as in C57BL/6 and mice with disruption of the tumor necrosis factor (Tnf) gene. Liver tissues were collected and analyzed by bioluminescence imaging or immunofluorescence. Inflammation in mice was induced by lipopolysaccharide (LPS) or by cerulein injections. Mice were given 4 successive injections of LPS, leading to inflammation-induced anemia. Steatohepatitis was induced with a choline-deficient, high-fat diet. Hemolytic anemia was stimulated by phenylhydrazine injection. MIR122 was inhibited in mice by tail-vein injection of an oligonucleotide antagonist of MIR122. MicroRNA and messenger RNA levels were determined by quantitative real-time polymerase chain reaction. RESULTS: The primary transcript of MIR122 spanned 5 kb, comprising 3 exons; the third encodes MIR122. Within the MIR122 promoter region we identified a nuclear factor-kappaB binding site and showed that RELA (NF-kappaB p65 subunit), as well as activators of NF-kappaB (TNF and LPS), increased promoter activity of MIR122. Administration of LPS to mice induced secretion of MIR122 into blood, which required TNF. Secreted MIR122 reached the kidney and reduced expression of erythropoietin (Epo), which we identified as a MIR122 target gene. Injection of mice with an oligonucleotide antagonist of MIR122 increased blood levels of EPO, reticulocytes, and hemoglobin. We found an inverse relationship between blood levels of MIR122 and EPO in mice with acute pancreatitis or steatohepatitis, and also in patients with acute inflammation. CONCLUSION: In mice, we found that LPS induced inflammation increases blood levels of MIR122, which reduces expression of Epo in the kidney; this is a mechanism of inflammation-induced anemia. Strategies to block MIR122 in patients with inflammation could reduce the development or progression of anemia. PMID- 27477941 TI - Synthesis and biological activity of FGLamide allatostatin analogs with Phe(3) residue modifications. AB - A FGLamide allatostatin neuropeptide mimic (H17) is a potential insect growth regulator which inhibits the production of juvenile hormone by the corpora allata. To find more evidence to reveal the structure-activity relationships of the Phe(3) residue in the C-terminal conserved pentapeptide and search for novel analogs with high activity, a series of Phe(3) residue-modified analogs were designed and synthesized using H17 as the lead compound. Bioassay using juvenile hormone (JH) production by corpora allata of the cockroach Diploptera punctata indicated that analogs 4, 11, and 13 showed strong ability to inhibit JH production in vitro, with IC50 of 38.5, 22.5, and 26 nM, respectively. As well, the activity of analog 2 (IC50 : 89.5 nM) proved roughly equivalent to that of H17. Based on the primary structure-activity relationships of Phe(3) residue, we suggest that for analogs containing six-membered aromatic rings, removing the methylene group of Phe(3) or an o-halogen or p-halogen-substituted benzene ring could increase the ability to inhibit biosynthesis of JH. This study will be useful for the design of new allatostatin analogs for insect management. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27477942 TI - Hyperpolarized 129Xe for investigation of mild cystic fibrosis lung disease in pediatric patients. AB - BACKGROUND: Cystic fibrosis (CF) is a genetic disease which carries high morbidity and mortality from lung-function decline. Monitoring disease progression and treatment response in young patients is desirable, but serial imaging via CT is often considered prohibitive, and detailed functional information cannot be obtained using conventional imaging techniques. Hyperpolarized 129Xe magnetic resonance imaging (MRI) can depict and quantify regional ventilation, but has not been investigated in pediatrics. We hypothesized that 129Xe MRI is feasible and would demonstrate ventilation defects in mild CF lung disease with greater sensitivity than FEV1. METHODS: 11 healthy controls (age 6-16years) and 11 patients with mild CF (age 8-16years, Forced Expiratory Volume (FEV1) percent predicted >70%) were recruited for this study. Nine CF patients had an FEV1>85%. Each subject was imaged via hyperpolarized 129Xe MRI, and the ventilation defect percentage (VDP) was measured. FEV1 and VDP were compared between the groups. RESULTS: FEV1 for controls was 100.3%+/-8.5% (mean+/-sd) and for CF patients was 97.9%+/-16.0% (p=0.67). VDP was 6.4%+/-2.8% for controls and 18.3%+/-8.6% for CF (p<0.001). When considering the 9 CF patients with normal FEV1 (>85%), the mean FEV1 was 103.1%+/-12.3% (p=0.57 compared to controls) and VDP was 15.4%+/-6.3% (p=0.002). CONCLUSIONS: Hyperpolarized 129Xe MRI demonstrated ventilation defects in CF patients with normal FEV1 and more effectively discriminated CF from controls than FEV1. Thus 129Xe may be a useful outcome measure to detect mild CF lung disease, to investigate regional lung function in pediatric lung diseases, and to follow disease progression. PMID- 27477943 TI - Presumptive keratoglobus in a great horned owl (Bubo virginianus). AB - A juvenile to young adult, male, great horned owl (Bubo virginianus,GHOW) was presented to the wildlife rehabilitation hospital at Lindsay Wildlife Museum (WRHLWM) due to trauma to the right patagium from barbed wire entanglement. On presentation, both corneas were irregular, dry, and no movement of the third eyelid was noted. A severe corneal enlargement/globoid appearance was the predominant ophthalmic feature. The fundus was normal in both eyes (OU). Over the course of several days, both corneas developed edema combined with further dessication at the ocular surface associated with diffuse dorsal fluorescein stain uptake. Repeated ophthalmic examinations found normal intraocular pressures and an inability to move the third eyelid over the enlarged corneas. The bird was deemed nonreleasable due to severe wing damage and poor prognosis associated with eye abnormalities and was humanely euthanized. Postmortem CT, enucleation, and histopathology were performed to evaluate the ocular anatomical abnormality and confirm the suspected diagnosis of keratoglobus. This GHOW represents the first reported case of presumptive keratoglobus in a raptor. PMID- 27477944 TI - Susceptibility of Pigs to Zoonotic Hepatitis E Virus Genotype 3 Isolated from a Wild Boar. AB - In Europe, zoonotic hepatitis E virus (HEV) genotype 3 strains mainly circulate in humans, swine and wild boar. The aim of this study was to investigate the potential transmission of a wild boar originating HEV strain (WbHEV) to swine by intravenous or oral inoculation and to study the consequences of infection of a WbHEV strain, a WbHEV strain previously passaged in a pig and a swine HEV strain after oral inoculation. Firstly, an intravenous infection was performed for which five piglets were divided into two groups with three pigs inoculated with a WbHEV field strain and two pigs inoculated with a HEV-negative swine liver homogenate. All pigs were necropsied 8, 9 and 10 days post-inoculation. Secondly, an oral infection of 56 days was performed on 12 piglets divided into four groups inoculated with a WbHEV strain, a WbHEV strain previously passaged in swine, a swine HEV strain or a HEV-negative swine liver homogenate. After intravenous inoculation, HEV RNA was detected in serum, bile, liver, spleen, duodenum, jejunum, colon, lung, gastro-hepatic lymph nodes and faeces in all infected piglets. After oral inoculation, HEV RNA was detected in serum, bile, liver, gastro-hepatic lymph nodes and faeces. Most of HEV-inoculated pigs became seropositive at day 15. This study provides experimental evidence of early viral spread throughout the organism after intravenous infection with a WbHEV strain and supports the notion that such a zoonotic strain could be transmitted via the natural faecal-oral route of infection between wild boar and pigs but also between pigs. PMID- 27477946 TI - Cytogenetics in the management of Philadelphia-negative myeloproliferative neoplasms: an update by the Groupe francophone de cytogenetique hematologique (GFCH). AB - The recent years have witnessed tremendous progress in the molecular characterization of Philadelphia-negative myeloproliferative neoplasms (MPN). Beside a better understanding of pathophysiology, these abnormalities often constitute very useful diagnostic markers in diseases where exclusion of reactive states used to be the strongest argument. However, conventional and molecular cytogenetics keep a major interest in MPN, either as a second line exploration, in cases where no molecular marker is available, for differential diagnosis or as a proof of clonality or in first line for cases with hyperleukocytosis, for differential diagnosis (CML), to evidence druggable targets (ABL1, RET, PDGFR...) or as a prognosis marker. In this article, we will review the interest of cytogenetic techniques in myeloproliferative neoplasms. PMID- 27477945 TI - A high-throughput in vitro ring assay for vasoactivity using magnetic 3D bioprinting. AB - Vasoactive liabilities are typically assayed using wire myography, which is limited by its high cost and low throughput. To meet the demand for higher throughput in vitro alternatives, this study introduces a magnetic 3D bioprinting based vasoactivity assay. The principle behind this assay is the magnetic printing of vascular smooth muscle cells into 3D rings that functionally represent blood vessel segments, whose contraction can be altered by vasodilators and vasoconstrictors. A cost-effective imaging modality employing a mobile device is used to capture contraction with high throughput. The goal of this study was to validate ring contraction as a measure of vasoactivity, using a small panel of known vasoactive drugs. In vitro responses of the rings matched outcomes predicted by in vivo pharmacology, and were supported by immunohistochemistry. Altogether, this ring assay robustly models vasoactivity, which could meet the need for higher throughput in vitro alternatives. PMID- 27477947 TI - Cellulose-Microtubule Uncoupling Proteins Prevent Lateral Displacement of Microtubules during Cellulose Synthesis in Arabidopsis. AB - Cellulose is the most abundant biopolymer on Earth and is the major contributor to plant morphogenesis. Cellulose is synthesized by plasma membrane-localized cellulose synthase complexes (CSCs). Nascent cellulose microfibrils become entangled in the cell wall, and further catalysis therefore drives the CSC forward through the membrane: a process guided by cortical microtubules via the protein CSI1/POM2. Still, it is unclear how the microtubules can withstand the forces generated by the motile CSCs to effectively direct CSC movement. Here, we identified a family of microtubule-associated proteins, the cellulose synthase microtubule uncouplings (CMUs), that located as static puncta along cortical microtubules. Functional disruption of the CMUs caused lateral microtubule displacement and compromised microtubule-based guidance of CSC movement. CSCs that traversed the microtubules interacted with the microtubules via CSI1/POM2, which prompted the lateral microtubule displacement. Hence, we have revealed how microtubules can withstand the propulsion of the CSCs during cellulose biosynthesis and thus sustain anisotropic plant cell growth. PMID- 27477948 TI - Corrigendum to "Implications of mercury concentrations in umbilical cord tissue in relation to maternal hair segments as biomarkers for prenatal exposure to methylmercury" by Sakamoto et al. [Environ. Res. 149 (2016) 282-287]. PMID- 27477950 TI - Obtaining consensus regarding international transplantation continues to be difficult for pediatric centers in the United States. AB - Organ transplant is life-saving and any given organ may be valuable to a multitude of potential recipients. An allocation system must be used to reconcile the difference between supply and demand, and this system must take into account the impact that accepting international patients may have on the local system. The principles for allocation must be clear, equitable, provide utility and must be monitored so as to maintain public trust. The impact of the system on metrics deemed to be critical must be measured. Finally, strategies must take into account the local culture, size of the region to be supported, the number and experience of transplant centers, and the resources of the healthcare delivery system. Our focus is on the United States, recognizing that strategies and challenges may vary across countries. PMID- 27477949 TI - Salvage resection for recurrent or metastatic hepatocellular carcinoma after percutaneous ablation therapy. AB - INTRODUCTION: To retrospectively evaluate the efficacy and safety of salvage resection(SR) for recurrence or metastasis of hepatocellular carcinoma (HCC) after initial percutaneous ablation therapy (PAT). METHODS: From September 2006 to September 2013, 50 consecutive patients who received SR for recurrent or metastatic HCC undergone initial PAT were enrolled. Safety and efficacy of SR for these patients were analyzed. RESULTS: No treatment-related death occurred. Curative outcome was achieved in all the patients. The median overall survival after SR was 40 months, and the 1-, 3-, 5-year overall survival rate after SR was 85.2%, 46.4% and 34.8%, respectively. The disease-free survival was 38.6% at 1 year and 12.1% at 3 years after SR. CONCLUSION: SR is an effective and safe method for patients with recurrent or metastatic HCC after initial PAT treatment. PMID- 27477951 TI - Five-year outcomes following a randomized trial of femorofemoral and femoropopliteal bypass grafting with heparin-bonded or standard polytetrafluoroethylene grafts. AB - BACKGROUND: Cohort studies suggest superior long-term patency of luminal heparin bonded polytetrafluoroethylene (Hb-PTFE) bypass grafts compared with standard PTFE grafts. The aim of this study was to compare the outcomes of Hb-PTFE grafts with those of standard PTFE grafts 5 years after a randomized trial. METHODS: Patients with intermittent claudication or critical limb ischaemia requiring femorofemoral or femoropopliteal bypass grafting were randomized in a clinical trial of Hb-PTFE versus standard PTFE in 11 Scandinavian centres between 2005 and 2009. Patients were followed up for 5 years with clinical assessment and surveillance Duplex ultrasound imaging. The primary endpoint of this study was primary patency. Secondary endpoints included major amputation and mortality. RESULTS: Overall, 569 patients were enrolled in the randomized trial. Some 552 had follow-up data available for analysis of the primary outcome. Use of Hb-PTFE significantly improved patency by 37 per cent at 2 years, but 5 years after randomization there was no difference in primary patency (adjusted hazard ratio (HR) 0.95, 95 per cent c.i. 0.71 to 1.28; P = 0.748). In patients with critical limb ischaemia the use of Hb-PTFE reduced the 5-year risk of loss of primary patency by 37 per cent (HR 0.63, 0.40 to 0.99; P = 0.049). CONCLUSION: In this study there was no difference in primary graft patency between Hb-PTFE and standard PTFE grafts. Patients receiving Hb-PTFE grafts for critical limb ischaemia were more likely to have a patent graft at 5 years than those with standard PTFE grafts. PMID- 27477952 TI - Psychometric validation of the Chinese version of the Johns Hopkins Fall Risk Assessment Tool for older Chinese inpatients. AB - AIMS AND OBJECTIVES: To culturally adapt and evaluate the reliability and validity of the Chinese version of the Johns Hopkins Fall Risk Assessment Tool among older inpatients in the mainland of China. BACKGROUND: Patient falls are an important safety consideration within hospitals among older inpatients. Nurses need specific risk assessment tools for older inpatients to reliably identify at risk populations and guide interventions that highlight fixable risk factors for falls and consequent injuries. In China, a few tools have been developed to measure fall risk. However, they lack the solid psychometric development necessary to establish their validity and reliability, and they are not widely used for elderly inpatients. DESIGN: A cross-sectional study. METHODS: A convenient sampling was used to recruit 201 older inpatients from two tertiary level hospitals in Beijing and Xiamen, China. The Johns Hopkins Fall Risk Assessment Tool was translated using forward and backward translation procedures and was administered to these 201 older inpatients. Reliability of the tool was calculated by inter-rater reliability and Cronbach's alpha. Validity was analysed through content validity index and construct validity. RESULTS: The Inter-rater reliability of Chinese version of Johns Hopkins Fall Risk Assessment Tool was 97.14% agreement with Cohen's Kappa of 0.903. Cronbach's alpha was 0.703. Content of Validity Index was 0.833. Two factors represented intrinsic and extrinsic risk factors were explored that together explained 58.89% of the variance. CONCLUSION: This study provided evidence that Johns Hopkins Fall Risk Assessment Tool is an acceptable, valid and reliable tool to identify older inpatients at risk of falls and falls with injury. Further psychometric testing on criterion validity and evaluation of its advanced utility in geriatric clinical settings are warranted. RELEVANCE TO CLINICAL PRACTICE: The Chinese version of Johns Hopkins Fall Risk Assessment Tool may be useful for health care personnel to identify older Chinese inpatients at risk of falls and falls with injury. PMID- 27477953 TI - Epidemiological features and spatio-temporal clusters of hand-foot-mouth disease at town level in Fuyang, Anhui Province, China (2008-2013). AB - Hand-foot-mouth disease (HFMD) is a frequently occurring epidemic and has been an important cause of childhood mortality in China. Given the disease's significant impact nationwide, the epidemiological characteristics and spatio-temporal clusters in Fuyang from 2008 to 2013 were analysed in this study. The disease exhibits strong seasonality with a rising incidence. Of the reported HFMD cases, 63.7% were male and 95.2% were preschool children living at home. The onset of HFMD is age-dependent and exhibits a 12-month periodicity, with 12-, 24- and 36 month-old children being the most frequently affected groups. Across the first 60 months of life, children born in April [relative risk (RR) 8.18], May (RR 9.79) and June (RR 8.21) exhibited an elevated infection risk of HFMD relative to January-born children; the relative risk compared with the reference (January born) group was highest for children aged 24 months born in May (RR 34.85). Of laboratory-confirmed cases, enterovirus 71 (EV71), coxsackie A16 (Cox A16) and other enteroviruses accounted for 60.1%, 7.1% and 32.8%, respectively. Spatio temporal analysis identified one most likely cluster and several secondary clusters each year. The centre of the most likely cluster was found in different regions in Fuyang. Implications of our findings for current and future public health interventions are discussed. PMID- 27477954 TI - Pregnancy Characteristics and Outcomes among Women at Risk for Disability from Health Conditions Identified in Medical Claims. AB - BACKGROUND: Women with disabilities are at risk for poor birth outcomes. Little is known about specific potentially disabling health conditions and their effects on pregnancies. Using hospital claims, we identified women at risk for disability and evaluated the relationship between disability risk and demographic characteristics, pregnancy risks, and infant and maternal outcomes. METHODS: The 2006 through 2009 Massachusetts Pregnancy to Early Life Longitudinal data system linked birth certificate and hospital claims one year pre-pregnancy through delivery. Access Risk Classification System categorized International Classification of Diseases, Ninth Revision, Clinical Modification/Current Procedural Terminology codes into disability risk groups (no/limited vs. medium/high). Generalized estimating equations evaluated the association between disability risk and infant and maternal outcomes. RESULTS: Of 221,867 women, 14,701 (6.6%) were at medium or high risk of disability. Health conditions were classified as circulatory (23%), musculoskeletal (10%), nervous system/sensory (13%), other physical (19%), two or more physical (5%), mental illness (24%), and comorbid mental/physical (6%). Women at risk of disability were more likely than others to have socioeconomic and pregnancy risks, and adverse infant and maternal outcomes. Socioeconomic and risk profile varied by health condition category. Adjusted risk ratios for preterm birth ranged from 1.2 (95% confidence interval [CI], 1.1-1.4) for women with nervous system/sensory diagnoses to 1.6 (95% CI, 1.4-1.9) for women with two or more physical diagnoses; risk ratios for maternal delivery hospitalization for more than 5 days ranged from 1.5 (95% CI, 1.2-1.9) for women with musculoskeletal diagnoses to 3.0 (95% CI, 2.5-3.6) for women with comorbid mental/physical diagnoses. CONCLUSIONS: Disability risk identified through claims is associated with poor infant and maternal outcomes. Risk profiles vary by underlying health condition. PMID- 27477956 TI - Crystallization kinetics of binary colloidal monolayers. AB - Experiments and simulations are used to study the kinetics of crystal growth in a mixture of magnetic and nonmagnetic particles suspended in ferrofluid. The growth process is quantified using both a bond order parameter and a mean domain size parameter. The largest single crystals obtained in experiments consist of approximately 1000 particles and form if the area fraction is held between 65-70% and the field strength is kept in the range of 8.5-10.5 Oe. Simulations indicate that much larger single crystals containing as many as 5000 particles can be obtained under impurity-free conditions within a few hours. If our simulations are modified to include impurity concentrations as small as 1-2%, then the results agree quantitatively with the experiments. These findings provide an important step toward developing strategies for growing single crystals that are large enough to enable follow-on investigations across many subdisciplines in condensed matter physics. PMID- 27477955 TI - Type 2 diabetes, but not obesity, prevalence is positively associated with ambient temperature. AB - Cold exposure stimulates energy expenditure and glucose disposal. If these factors play a significant role in whole body energy balance, and glucose homeostasis, it is predicted that both obesity and type 2 diabetes prevalence would be lower where it is colder. Previous studies have noted connections between ambient temperature and obesity, but the direction of the effect is confused. No previous studies have explored the link of type 2 diabetes to ambient temperature. We used county level data for obesity and diabetes prevalence across the mainland USA and matched this to county level ambient temperature data. Average ambient temperature explained 5.7% of the spatial variation in obesity and 29.6% of the spatial variation in type 2 diabetes prevalence. Correcting the type 2 diabetes data for the effect of obesity reduced the explained variation to 26.8%. Even when correcting for obesity, poverty and race, ambient temperature explained 12.4% of the variation in the prevalence of type 2 diabetes, and this significant effect remained when latitude was entered into the model as a predictor. When obesity prevalence was corrected for poverty and race the significant effect of temperature disappeared. Enhancing energy expenditure by cold exposure will likely not impact obesity significantly, but may be useful to combat type 2 diabetes. PMID- 27477957 TI - Familial Hypercholesterolemia: Advances in Recognition and Therapy. AB - Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease. It is under-diagnosed, yet early detection and treatment are critical to limit premature atherosclerotic disease. High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults. Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants. Lipoprotein apheresis is used when pharmacotherapy is inadequate, especially for those with homozygous FH and some patients with severe heterozygous FH. Mipomersen and lomitapide are also indicated for patients with homozygous FH. The recently approved PCSK9 inhibitors, alirocumab and evolocumab, are a promising treatment and outcome studies are ongoing. This article reviews the pathophysiology, diagnosis, and management of FH. PMID- 27477958 TI - The effect of introducing small cavities on the allosteric inhibition of phosphofructokinase from Bacillus stearothermophilus. AB - The allosteric coupling free energy between ligands fructose-6-phosphate (Fru-6 P) and phospho(enol)pyruvate (PEP) for phosphofructokinase-1 (PFK) from the moderate thermophile, Bacillus stearothermophilus (BsPFK), results from compensating enthalpy and entropy components. In BsPFK the positive coupling free energy that defines inhibition is opposite in sign from the negative enthalpy term and is therefore determined by the larger absolute value of the negative entropy term. Variants of BsPFK were made to determine the effect of adding small cavities to the structure on the allosteric function of the enzyme. The BsPFK Ile -> Val (cavity containing) mutants have varied values for the coupling free energy between PEP and Fru-6-P, indicating that the modifications altered the effectiveness of PEP as an inhibitor. Notably, the mutation I153V had a substantial positive impact on the magnitude of inhibition by PEP. Van't Hoff analysis determined that this is the result of decreased entropy-enthalpy compensation with a larger change in the enthalpy term compared to the entropy term. PMID- 27477959 TI - Decreased expression of the vitamin D receptor in women with recurrent pregnancy loss. AB - The multiple functions of vitamin D3 have stimulated interest in the role that this vitamin may play during pregnancy. The present study investigated the expression of the vitamin D receptor (VDR) in women during the first trimester of pregnancy in order to determine whether VDR is associated with recurrent pregnancy loss (RPL). Forty women at 7-10 weeks gestation with RPL and 40 women of similar gestational age with a healthy pregnancy were recruited. VDR mRNA and protein in chorionic villi and decidua were evaluated by immunohistochemistry, confocal laser scanning microscopy (CLSM), western blot, and quantitative real time polymerase chain reaction. The serum levels of VDR were measured by an enzyme-linked immunosorbent assay. Women with RPL had a significantly weaker expression of VDR mRNA in villi and decidual tissues compared with the control women (both p < 0.0001). Western blot analysis showed an approximately 46% decrease in VDR expression in villi and a 52% decrease in decidua in the RPL vs. the controls. Serum VDR levels were also significantly lower in the RPL group than in the control group (p = 0.003). Compared with the controls, immunohistochemical and CLSM analysis revealed significantly lower VDR expression in villous cytotrophoblasts and stromal cells, as well as in decidual glandular epithelial and stromal cells (all p < 0.05). In conclusion, these observations show that women with RPL have lower levels of VDR expression in chorionic villi, decidua and serum compared with normal pregnant women, suggesting that decreased VDR expression in the first trimester pregnancy may be associated with RPL. PMID- 27477960 TI - Association between chronic periodontitis and oral health-related quality of life in Sri Lankan adults. AB - OBJECTIVE: To determine the impact of chronic periodontitis on oral health related quality of life in Sri Lankan adults. METHODS: A cross-sectional study was conducted among 1,400 participants, 35-60 years of age, residing in the Colombo district of Sri Lanka. Data were collected using two interviewer administered questionnaires and an oral examination. RESULTS: The prevalence, extent and severity of oral impacts increased with the increase in severity of chronic periodontitis. The most commonly experienced impacts were within the domain of physical pain. The adjusted Poisson regression model indicated that chronic periodontitis was significantly associated with the prevalence of oral impacts. The prevalence of oral impacts was 48% and 69% higher in those with moderate and severe periodontitis, respectively, compared with those with no/mild periodontitis. CONCLUSIONS: Oral health-related quality of life deteriorates with the increase in severity of chronic periodontitis. PMID- 27477961 TI - Quantitative Comparison Between Amyloid Deposition Detected by (99m)Tc Diphosphonate Imaging and Myocardial Deformation Evaluated by Strain Echocardiography in Transthyretin-Related Cardiac Amyloidosis. AB - BACKGROUND: Management of cardiac amyloidosis (CA) is related to amyloid deposition. Our aim was to assess the effect of amyloid deposition on myocardial function. METHODS AND RESULTS: Twenty-eight patients with transthyretin mutation and a group of 14 controls underwent echocardiography to quantify left ventricular (LV) dimensions, function, and global (G) longitudinal (L), radial (R) and circumferential (C) strain (S). (99m)Tc-3,3-diphosphono-1,2 propanodicarboxylic-acid-scintigraphy ((99m)Tc-DPD) was used to quantify CA. (99m)Tc-DPD revealed accumulation in 14/28 patients (CA group) and no accumulation (no-CA group) in 14. Cardiac accumulation was lower-than-bone uptake in 5 (mild-CA group) and higher-than-bone uptake in 9 (severe-CA group). Ejection fraction was similar among groups. GLS was lower (P<0.001) in the severe-CA group (-12.2+/-4.5) with respect to the no-CA group (-19.3+/-3.0) and to the control group (-20.9+/-2.5). Conversely, GCS and GRS were lower (P<0.05) in the mild-CA group (-10.8+/-4.1 and 9.5+/-5.7, respectively) with respect to the severe-CA group (-18.9+/-5.1 and 23.9+/-6.3 respectively), no-CA group (-19.2+/-4.1 and 28.4+/-10.2, respectively) and the control group (-23.9+/-4.4 and 29.9+/-8.7, respectively). A correlation was found between the scintigraphic heart retention index (HRI) and LV septal thickness (rho=0.72), E/E' (rho=0.46) and GLS (rho= 0.40). CONCLUSIONS: Myocardial deformation is impaired in a different stage of CA. The (99m)Tc-DPD HRI correlated well with morphologic, diastolic and strain abnormalities. (Circ J 2016; 80: 1998-2003). PMID- 27477962 TI - Fast and selective separation of carbon dioxide from dilute streams by pressure swing adsorption using solid ionic liquids. AB - The need to create a new approach to carbon capture processes that are economically viable has led to the design and synthesis of sorbents that selectively capture carbon dioxide by physisorption. Solid Ionic Liquids (SoILs) were targeted because of their tunable properties and solid form under operational conditions. Molecular modelling was used to identify candidate SoILs and a number of materials based on the low cost, environmentally friendly acetate anion were selected. The materials showed excellent selectivity for carbon dioxide over nitrogen and oxygen and moderate sorption capacity. However, the rate of capture was extremely fast, in the order of a few seconds for a complete adsorb-desorb cycle, under pressure swing conditions from 1 to 10 bar. This showed the importance of rate of sorption cycling over capacity and demonstrates that smaller inventories of sorbents and smaller process equipment are required to capture low concentration CO2 streams. Concentrated CO2 was isolated by releasing the pressure back to atmospheric. The low volatility and thermal stability of SoILs mean that both plant costs and materials costs can be reduced and plant size considerably reduced. PMID- 27477963 TI - Internal pH regulation facilitates in situ long-term acclimation of massive corals to end-of-century carbon dioxide conditions. AB - The resilience of tropical corals to ocean acidification depends on their ability to regulate the pH within their calcifying fluid (pHcf). Recent work suggests pHcf homeostasis under short-term exposure to pCO2 conditions predicted for 2100, but it is still unclear if pHcf homeostasis can be maintained throughout a corals lifetime. At CO2 seeps in Papua New Guinea, massive Porites corals have grown along a natural seawater pH gradient for decades. This natural gradient, ranging from pH 8.1-7.4, provides an ideal platform to determine corals' pHcf (using boron isotopes). Porites maintained a similar pHcf (~8.24) at both a control (pH 8.1) and seep-influenced site (pH 7.9). Internal pHcf was slightly reduced (8.12) at seawater pH 7.6, and decreased to 7.94 at a site with a seawater pH of 7.4. A growth response model based on pHcf mirrors the observed distribution patterns of this species in the field. We suggest Porites has the capacity to acclimate after long-time exposure to end-of-century reduced seawater pH conditions and that strong control over pHcf represents a key mechanism to persist in future oceans. Only beyond end-of-century pCO2 conditions do they face their current physiological limit of pH homeostasis and pHcf begins to decrease. PMID- 27477964 TI - Effect of thrombin preconditioning on migration of subventricular zone-derived cells after intracerebral hemorrhage in rats. AB - OBJECTIVE: To investigate the effect of thrombin preconditioning (TPC) on the intracerebral hemorrhage (ICH)-induced proliferation, migration, and function of subventriclular zone (SVZ) cells and to find new strategies that enhance endogenous neurogenesis after ICH. METHODS: Male Sprague-Dawley rats were randomly divided into 3 groups (ICH, TPC, and control group). Rats of each group were randomly divided into 5 subgroups (3-d, 7-d, 14-d, 21-d, and 28-d subgroup). ICH was caused by intrastrial stereotactic administration of collagenase type IV. Brdu was used to label newborn SVZ cells. Organotypic brain slices were cultured to dynamically observe the migration of SVZ cells at living brain tissue. Migration of Dil-labeled SVZ cells in living brain slices was traced by time lapse microscopy. To assess whether SVZ cells migrating to injured striatum had the ability to form synapses with other cells, brain slices from each group were double immunolabeled with Brdu and synapsin I. RESULTS: The number of Brdu positive cells markedly increased in the ipsilateral SVZ and striatum 3 days after TPC, peaked at 14 days (P < 0.01), continued to 21 days, and then gradually decreased at 28 days with significant difference compared to the ICH group at each time point (P < 0.01). Migration of Dil-labeled SVZ cells in brain slices in each group was observed and imaged during a 12-h period. Dil-labeled SVZ cells in the TPC group were observed to migrate laterally toward striatum with time with a faster velocity compared to the ICH group (P < 0.01). Our study also demonstrated that TPC induced strong colocalization of Brdu and synapsin I in the ipsilateral striatum between 3 and 28 days after injury.TPC made colocalization of Brdu and synapsin I appear earlier and continue for a longer time compared to the ICH group. CONCLUSIONS: Our results demonstrated that TPC could promote proliferation, migration, and function of SVZ cells after ICH, which may provide a new idea for enhancing endogenous neurogenesis and developing new therapeutic strategies against ICH-induced brain injury. PMID- 27477965 TI - Migration and health. PMID- 27477966 TI - SAGE committee advice on dengue vaccine. PMID- 27477967 TI - The risks behind Dengvaxia recommendation. PMID- 27477968 TI - Engaging health-care workers to reduce tuberculosis transmission. PMID- 27477969 TI - Corrections. PMID- 27477970 TI - The VITAL study: case control studies are hypothesis-generating. PMID- 27477971 TI - The VITAL study: case control studies are hypothesis-generating - Authors' reply. PMID- 27477972 TI - Procalcitonin to guide antibiotic stewardship in intensive care. PMID- 27477973 TI - Procalcitonin to guide antibiotic stewardship in intensive care. PMID- 27477974 TI - Procalcitonin to guide antibiotic stewardship in intensive care - Authors'reply. PMID- 27477975 TI - Procalcitonin to guide antibiotic stewardship in intensive care. PMID- 27477976 TI - Tenofovir resistance and first-line antiretroviral therapy. PMID- 27477977 TI - Changing epidemiology of HIV-associated cryptococcosis in sub-Saharan Africa. PMID- 27477978 TI - Sertraline-induced increase in VEGF brain levels and its activity in cryptococcal meningitis. PMID- 27477979 TI - Former first-line antibiotics for treatment of enteric fever. PMID- 27477980 TI - Mycobacterium tuberculosis and prosthetic joint infection. PMID- 27477981 TI - Zika virus in semen of a patient returning from a non-epidemic area. PMID- 27477982 TI - Mycobacterium tuberculosis and prosthetic joint infection. PMID- 27477983 TI - Yellow fever in Africa: a disaster waiting to happen. PMID- 27477984 TI - Highlights from ASM Microbe 2016. PMID- 27477985 TI - Congenital cytomegalovirus-a neglected health problem. PMID- 27477988 TI - Abdominal aortitis and aneurysm impending rupture during pneumococcal meningitis. PMID- 27477989 TI - Bilateral Idiopathic Carpal Tunnel Syndrome in a 4-Year-Old Girl. AB - Carpal tunnel syndrome (CTS), the most common entrapment neuropathy in adulthood, is rare in childhood. The symptoms may differ to those in adults, or may be misinterpreted owing to children's difficulties in expressing themselves. Cases of idiopathic, bilateral CTS under the age of 5 are rare. A 4-year-old girl presented with pain in both hands and difficulty opening them in the morning. Bilateral severe CTS was determined at electroneuromyography (ENMG). Bilateral wrist splints were advised for both hands. Improvement in ENMG was seen at 2 weeks following conservative treatment. PMID- 27477990 TI - Successful endoscopic submucosal dissection for early gastric cancer adjacent to gastric cardia varix. AB - A 58-year-old man with liver cirrhosis and renal failure was diagnosed with esophageal varices (EVs) and a gastric cardia varix (GCV) by esophagogastroduodenoscopy (EGD). The patient also exhibited early gastric cancer (EGC) in the upper gastric body adjacent to the GCV. The EVs and GCV were treated using endoscopy before endoscopic submucosal dissection (ESD) of the EGC to prevent variceal bleeding during ESD. Endoscopic variceal ligation (EVL) was performed to treat the EVs. In addition, extra-variceal polidocanol injection and argon plasma coagulation (APC) were performed after EVL. Follow-up EGD two months after APC revealed that the GCV had diminished in size. Then, ESD was performed with polidocanol injection into the submucosa around the GCV to prevent bleeding. During ESD, the EGC was resected en bloc without severe bleeding. Complications were not observed after ESD. Histopathological examination of the ESD specimens indicated that the resection was curative. PMID- 27477991 TI - An evidence-based medicine approach to the laparoscopic treatment of colorectal cancer. AB - During the 1990s, laparoscopic resection was established as a treatment for gastrointestinal malignant tumors. A number of randomized controlled trials comparing laparoscopic-assisted colorectal surgery with conventional open colorectal surgery for colon cancer have been conducted. These trials have shown short-term benefits, and the vast majority demonstrated no significant difference in long-term outcomes. Laparoscopic-assisted colorectal surgery is widely performed for the treatment of colon cancer, whereas laparoscopic-assisted colorectal surgery for rectal cancer is less commonly performed. In recent years, there have been an increasing number of reports of laparoscopic-assisted colorectal surgery for rectal cancer, where improving short-term outcomes was shown, but no definitive effect on long-term survival has been shown to date. Randomized controlled trials focusing on long-term survival are currently ongoing. PMID- 27477993 TI - Strain-induced electrostatic enhancements of BiFeO3 nanowire loops. AB - Semiconductor nanowires (NWs), due to their intriguing structural and physical properties, offer tremendous potential for future technological applications. The existence of strain in NWs can greatly affect, for instance, their mechanical, electrical and optical properties. Here, we report an extraordinary electrostatic response of semiconductor BiFeO3 NW loops, based on Kelvin probe force microscopy (KPFM) and electrostatic force microscopy (EFM). A substantial ~300 mV surface potential difference, accompanied by an ~29% higher surface charge density, was found on the NW loop. We also found that the electrostatic enhancement is strongly related to the strain present at the curvature of the NW loops. We propose that the electric polarization coupled with mechanical strain (piezoelectric effect) or strain gradient (flexoelectricity) as possible reasons to account for our observation. These findings provide new insights into multiferroic based semiconductor NWs under external stimuli as well as significant inspiration towards strain sensors and electromechanical devices with multifunctional sensing abilities. PMID- 27477992 TI - Surgical treatment options for septic non-union of the tibia: two staged operation, Flow-through anastomosis of FVFG, and continuous local intraarterial infusion of heparin. AB - BACKGROUND: The treatment of septic non-union of the tibia is a challenging area. The objective of this clinical study was to improve the treatment outcomes in patients with a highly active infection by the three strategies consisting of a two-staged operation, a flow-through technique for vascular anastomosis of a free vascularized fibular graft (FVFG), and continuous local intra-arterial infusion of heparin. PATIENTS & METHOD: Five patients with septic non-union of the tibia who were treated with an FVFG (mean age: 52.8 years) were enrolled. The mean postoperative follow-up period was 47.2 months, and the mean length of the bone defect was 111 mm. A two-staged operation, in which polymethylmethacrylate (PMMA) beads containing antibiotics were inserted into a bone defect followed by bone reconstruction performed with an FVFG later. Vascular anastomosis was performed with the flow-through technique in all patients. Immediately after FVFG, heparin was continuously infused through a femoral arterial catheter for 1 week. RESULT: Bone union was confirmed an average of 18.8 weeks after-surgery in all patients without reoperation for thrombus. CONCLUSION: Our attempt to apply the strategies appears to be a viable treatment option for septic non-union of the tibia. PMID- 27477994 TI - Awareness and use of nonoccupational post-exposure prophylaxis among men who have sex with men in Vancouver, Canada. AB - OBJECTIVES: Nonoccupational post-exposure prophylaxis (nPEP) is a strategy to reduce the risk of HIV infection in those with high-risk exposure. This study characterized nPEP awareness among gay, bisexual and other men who have sex with men (MSM) in Metro Vancouver, British Columbia, Canada after a pilot nPEP programme established in 2012. METHODS: Momentum Health Study participants were MSM aged >=16 years recruited via respondent-driven sampling (RDS) who completed a computer-assisted self-interview. Stratifying patients by HIV status, we used multivariable logistic regression with backward selection to identify factors associated with nPEP awareness. All analyses were RDS-adjusted. RESULTS: A total of 51.9% (112 of 173) of HIV-positive and 48.5% (272 of 500) of HIV-negative participants had heard of nPEP. Only 3% (five of 106) of HIV-negative participants who reported recent high-risk sex used nPEP. Generally, nPEP awareness was higher for participants who engaged in sexual activities with increased HIV transmission potential. Factors associated with greater awareness among HIV-negative participants included recent alcohol use, higher communal sexual altruism, previous sexually transmitted infection diagnosis, and greater perceived condom use self-efficacy. Other factors associated with greater awareness among HIV-negative participants included white race/ethnicity, gay sexual identity, more formal education, lower personal sexual altruism, and Vancouver residence. Greater nPEP awareness among HIV-positive participants was associated with greater perceived agency to ask sexual partners' HIV status and more frequently reporting doing so, a higher number of lifetime receptive sex partners, and greater access to condoms. CONCLUSIONS: Following implementation of an nPEP pilot programme, nPEP awareness among HIV-negative MSM was 51% and use was 3%. These data support the need to expand access to and actively promote nPEP services. PMID- 27477995 TI - What is the mechanism of formation of hydroxyaluminosilicates? AB - The formation of hydroxyaluminosilicates is integral to the biogeochemical cycles of aluminium and silicon. The unique inorganic chemistry which underlies their formation explains the non-essentiality in biota of both of these elements. However, the first steps in the formation of hydroxyaluminosilicates were hitherto only theoretical and plausibly only accessible in silico. Herein we have used computational chemistry to identify and define for the first time these unique and ultimately critically important reaction steps. We have used density functional theory combined with solvent continuum models to confirm first, the nature of the reactants, an aluminium hydroxide dimer and silicic acid, second, the reaction products, two distinct hydroxyaluminosilicates A and B and finally, how these are the precursors to highly insoluble hydroxyaluminosilicates the role of which has been and continues to be to keep inimical aluminium out of biota. PMID- 27477996 TI - To the Editor- Implantation of permanent devices in patients with Takotsubo syndrome. PMID- 27477997 TI - To the Editor- How to manage patients with Takotsubo cardiomyopathy and a previous pacemaker implantation? PMID- 27477998 TI - Life's utilization of B vitamins on early Earth. AB - Coenzymes are essential across all domains of life. B vitamins (B1 -thiamin, B2 riboflavin, B3 -niacin, B5 -pantothenate, B6 -pyridoxine, B7 -biotin, and B12 cobalamin) represent the largest class of coenzymes, which participate in a diverse set of reactions including C1 -rearrangements, DNA repair, electron transfer, and fatty acid synthesis. B vitamin structures range from simple to complex heterocycles, yet, despite this complexity, multiple lines of evidence exist for their ancient origins including abiotic synthesis under putative early Earth conditions and/or meteorite transport. Thus, some of these critical coenzymes likely preceded life on Earth. Some modern organisms can synthesize their own B vitamins de novo while others must either scavenge them from the environment or establish a symbiotic relationship with a B vitamin producer. B vitamin requirements are widespread in some of the most ancient metabolisms including all six carbon fixation pathways, sulfate reduction, sulfur disproportionation, methanogenesis, acetogenesis, and photosynthesis. Understanding modern metabolic B vitamin requirements is critical for understanding the evolutionary conditions of ancient metabolisms as well as the biogeochemical cycling of critical elements such as S, C, and O. PMID- 27477999 TI - Rare ACL enthesis tears treated by suture in children. A report of 14 cases after a mean 15 years follow-up. AB - INTRODUCTION: ACL enthesis tears are rare in children and there are very few reports in the literature. Characterized by avulsion of the ligament that tears off a very thin piece of cartilage or a bone fragment at the ACL epiphyseal insertion site, we hypothesize that conservative treatment by suture could reduce the number of patients requiring later ligament reconstruction. MATERIALS AND METHODS: Fourteen patients underwent surgery between 1986 and 2014 and were included in this retrospective study. Patients were selected according to the following criteria: suture failure requiring ligament reconstruction, reoperation free survival for secondary injury and the subjective and objective IKDC scores by comparative laximetry. RESULTS: After almost 15 years of mean follow-up, reoperation-free survival was approximately 85%. Three patients required one or more additional surgeries; one for suture failure requiring 2 additional ligament reconstructions, one for a meniscal tear with a mechanical block requiring partial meniscectomy and one patient with secondary pain requiring arthroscopic surgery that was inconclusive. DISCUSSION: Rare and often misdiagnosed, ACL enthesis tears in children can be treated by suture with satisfactory results. Careful analysis of plain films and an X-ray centered on the intercondylar notch often provide the diagnosis. In case of doubt, MRI, which is now more accessible, can prevent missing this entity. Improved standard surgical techniques and careful patient selection could make conservative treatment an option once again while avoiding the risks associated with ligament reconstruction technique. LEVEL OF EVIDENCE: 4. PMID- 27478000 TI - A pilot trial comparing the tear-out behavior in screw-sockets and cemented polyethylene acetabular components - a cadaveric study. AB - BACKGROUND: The removal of well-fixed acetabular components following THA (total hip arthroplasty) is a difficult operation and could be accompanied by the loss of acetabular bone stock. The optimal method for fixation is still under debate. The aim of this pilot study was to compare the tear-out resistance and failure behavior between osseo-integrated and non-integrated screw cups. Furthermore, we examined whether there are differences in the properties mentioned between screw sockets and cemented polyethylene cups. HYPOTHESIS: Tear-out resistance and related mechanical work required for the tear-out of osseo-integrated screw sockets are higher than in non-integrated screw sockets. PATIENTS AND METHODS: Ten human coxal bones from six cadavers with osseo-integrated screw sockets (n=4), non-integrated (implanted post-mortem, n=3) screw sockets and cemented polyethylene cups (n=3) were used for tear-out testing. The parameters axial failure load and mechanical work for tear-out were introduced as measures for determining the stability of acetabular components following THA. RESULTS: The osseo-integrated screw sockets yielded slightly higher tear-out resistance (1.61+/-0.26kN) and related mechanical work compared to the non-integrated screw sockets (1.23+/-0.39kN, P=0.4). The cemented polyethylene cups yielded the lowest tear-out resistance with a failure load of 1.18+/-0.24kN. Compared to the screw cups implanted while alive, they also differ on a non-significant level (P=0.1). Osseous failure patterns differed especially for the screw sockets compared to the cemented polyethylene cups. DISCUSSION: Osseo-integration did not greatly influence the tear-out stability in cementless screw sockets following axial loading. Furthermore, the strength of the bone-implant-interface of cementless screw sockets appears to be similar to cemented polyethylene cups. However, given the high failure load, high mechanical load and because of the related bone failure patterns, removal should not be performed by means of tear-out but rather by osteotomes or other curved cutting devices to preserve the acetabular bone stock. LEVEL OF EVIDENCE: Level III, case-control-study. PMID- 27478001 TI - Acidic Deep Eutectic Solvents As Hydrolytic Media for Cellulose Nanocrystal Production. AB - In this study, a new method to fabricate cellulose nanocrystals (CNCs) based on DES pretreatment of wood cellulose fibers with choline chloride and organic acids are reported. Oxalic acid (anhydrous and dihydrate), p-toluenesulfonic acid monohydrate, and levulinic acid were studied as acid components of DESs. DESs were formed at elevated temperatures (60-100 degrees C) by combining choline chloride with organic acids and were then used to hydrolyze less ordered amorphous regions of cellulose. All the DES treatments resulted in degradation of wood fibers into microsized fibers and after mechanically disintegrating, CNCs were successfully obtained from choline chloride/oxalic acid dihydrate-treated fibers, whereas no liberation of CNCs was observed with other DESs. The DES produced CNCs had a width and length of 9-17 and 310-410 nm, respectively. The crystallinity indexes (CrIs) and carboxylic acid content of the CNCs were 66-71% and 0.20-0.28 mmol/g, respectively. CNCs exhibited good thermal stabilities (the onset thermal degradation temperatures ranged from 275-293 degrees C). The demonstrated acidic DES method exhibits certain advantages over previously reported CNC productions, namely, milder processing conditions and easily obtainable and relatively inexpensive biodegradable solvents with low toxicity (compared, e.g., to ILs). PMID- 27478002 TI - Evaluation of Internal Construct Validity and Unidimensionality of the Brachial Assessment Tool, A Patient-Reported Outcome Measure for Brachial Plexus Injury. AB - OBJECTIVE: To evaluate the internal construct validity and dimensionality of a new patient-reported outcome measure for people with traumatic brachial plexus injury (BPI) based on the International Classification of Functioning, Disability and Health definition of activity. DESIGN: Cross-sectional study. SETTING: Outpatient clinics. PARTICIPANTS: Adults (age range, 18-82y) with a traumatic BPI (N=106). INTERVENTIONS: There were 106 people with BPI who completed a 51-item 5 response questionnaire. Responses were analyzed in 4 phases (missing responses, item correlations, exploratory factor analysis, and Rasch analysis) to evaluate the properties of fit to the Rasch model, threshold response, local dependency, dimensionality, differential item functioning, and targeting. MAIN OUTCOME MEASURES: Not applicable, as this study addresses the development of an outcome measure. RESULTS: Six items were deleted for missing responses, and 10 were deleted for high interitem correlations >.81. The remaining 35 items, while demonstrating fit to the Rasch model, showed evidence of local dependency and multidimensionality. Items were divided into 3 subscales: dressing and grooming (8 items), arm and hand (17 items), and no hand (6 items). All 3 subscales demonstrated fit to the model with no local dependency, minimal disordered thresholds, no unidimensionality or differential item functioning for age, time postinjury, or self-selected dominance. Subscales were combined into 3 subtests and demonstrated fit to the model, no misfit, and unidimensionality, allowing calculation of a summary score. CONCLUSIONS: This preliminary analysis supports the internal construct validity of the Brachial Assessment Tool, a unidimensional targeted 4-response patient-reported outcome measure designed to solely assess activity after traumatic BPI regardless of level of injury, age at recruitment, premorbid limb dominance, and time postinjury. Further examination is required to determine test-retest reliability and responsiveness. PMID- 27478003 TI - Reduced glyoxalase 1 activity in carotid artery plaques of nondiabetic patients with increased hemoglobin A1c level. AB - OBJECTIVE: Glyoxalase 1 (GLO1) is ubiquitously expressed in the cytosol of the cell and is the major opponent against the reactive metabolite methylglyoxal, which is involved in the development of atherosclerosis. Nondiabetic individuals with an increased hemoglobin A1c (HbA1c) level are at higher risk for development of cardiovascular diseases. As such, this study investigated whether there was an association between reduced GLO1 activity in atherosclerotic lesions of nondiabetic patients with an increased HbA1c level. METHODS: HbA1c level was determined in venous blood of patients with carotid artery disease. Protein level of GLO1 was measured in endarterectomy-derived carotid artery plaques by Western blotting. Activity was measured by spectrophotometric assay in the plaques as well as in the erythrocytes; GLO1 activity in erythrocytes was compared with that in a cohort of healthy individuals (n = 15; 33% men; average age, 60 years). RESULTS: There were 36 patients with carotid artery disease (69% men; average age, 69 years) included in this study and divided into two equal groups: group I, HbA1c < 5.7% (<39 mmol/mol); and group II, 5.7% <= HbA1c < 6.5% (39 mmol/mol <= HbA1c < 48 mmol/mol). GLO1 activity in carotid plaques was reduced by 29% in group II compared with group I (P = .048), whereas protein expression was unchanged (P = .25). Analysis of GLO1 activity in erythrocytes revealed no difference between the groups (P = .36) or in comparison to healthy controls (P = .15). Examination of clinical parameters showed an increased amount of patients with concomitant peripheral arterial disease in group II (44% vs 10%; P = .020). CONCLUSIONS: Reduction of GLO1 activity in atherosclerotic lesions of nondiabetic patients with increased HbA1c is associated with a functional involvement of this protective enzyme in atherogenesis. Systemic GLO1 activity seems to be independent of both HbA1c and localized atherosclerosis as it was unchanged between group I and group II as well as compared with healthy controls, respectively. PMID- 27478005 TI - Drug-eluting balloon angioplasty versus uncoated balloon angioplasty in patients with femoropopliteal arterial occlusive disease. AB - OBJECTIVE: The optimal percutaneous treatment for femoropopliteal arterial occlusive disease has yet to be assessed. This systematic review and meta analysis assessed the efficacy of drug-eluting balloons (DEBs) compared with uncoated balloons (UCBs) for the treatment of femoropopliteal arterial occlusive disease. METHODS: We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement (PRISMA) standards to systematically search the electronic databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for trials comparing DEBs vs UCBs in the femoropopliteal arteries. All articles were critically assessed for relevance, validity, and availability of data regarding patient and lesion characteristics and outcomes. All data were systematically pooled, and meta-analysis was performed on binary restenosis, late lumen loss (LLL), target lesion revascularization (TLR), major amputation, mortality, and changes in the ankle brachial index and the Rutherford-Baker classification. RESULTS: From 364 screened articles, we included nine trials, all of which had a low risk of bias. We found a significant reduction of binary restenosis at 6 months (14.3% vs 40.1%; P < .0001), binary restenosis at 1 year (26.6% vs 47.4%; P = .008), LLL at 6 months (-0.80 mm; P < .00001), TLR at 1 year (10.4% vs 26.9; P = .0008), and TLR at 2 years (13.8% vs 40.7%; P = .0003) after DEB angioplasty compared with UCB angioplasty. The difference in amputation rate and mortality was not significant. Definitions on changes in ankle-brachial index and Rutherford classifications were heterogeneous and, therefore, could not be pooled in sufficient numbers. CONCLUSIONS: Compared with UCB angioplasty, the use of DEBs increases the durability of the treatment effect in femoropopliteal arterial disease, expressed by a significant decrease of binary restenosis, LLL, and TLR at short-term and midterm follow-up. PMID- 27478004 TI - Renal dysfunction and the associated decrease in survival after elective endovascular aneurysm repair. AB - OBJECTIVE: The reported frequency of renal dysfunction after elective endovascular aneurysm repair (EVAR) varies widely in current surgical literature. Published research establishes pre-existing end-stage renal disease as a poor prognostic indicator. We intend to quantify the mortality effect associated with renal morbidity developed postoperatively and to identify modifiable risk factors. METHODS: All elective EVAR patients with preoperative and postoperative renal function data captured by the Vascular Quality Initiative between January 2003 and December 2014 were examined. The primary study end point was long-term mortality. Preoperative, intraoperative, and postoperative parameters were analyzed to estimate mortality stratified by renal outcome and to describe independent risk factors associated with post-EVAR renal dysfunction. RESULTS: This study included 14,475 elective EVAR patients, of whom 96.8% developed no post-EVAR renal dysfunction, 2.9% developed acute kidney injury, and 0.4% developed a new hemodialysis requirement. Estimated 5-year survival was significantly different between groups, 77.5% vs 53.5%, respectively, for the no dysfunction and acute kidney injury groups, whereas the new hemodialysis group demonstrated 22.8% 3-year estimated survival (P < .05). New-onset postoperative congestive heart failure (odds ratio [OR], 3.50; 95% confidence interval [CI], 1.18-10.38), return to the operating room (OR, 3.26; 95% CI, 1.49-7.13), and postoperative vasopressor requirement (OR, 2.68; 95% CI, 1.40-5.12) predicted post-EVAR renal dysfunction, whereas a preoperative estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m2 was protective (OR, 0.33; 95% CI, 0.21 0.53). Volume of contrast material administered during elective EVAR varies 10 fold among surgeons in the Vascular Quality Initiative database, but the average volume administered to patients is statistically similar, regardless of preoperative eGFR. Multivariable logistic regression demonstrated nonsignificant correlation between contrast material volume and postoperative renal dysfunction. CONCLUSIONS: Any renal dysfunction developing after elective EVAR is associated with decreased estimated long-term survival. Protecting renal function with a rational dosing metric for contrast material linked to preoperative eGFR may better guide treatment. PMID- 27478006 TI - Hybrid external iliac selective endarterectomy surgical technique and outcomes. AB - OBJECTIVE: Long or multisegmental external iliac-to-femoral arterial lesions treated by angioplasty and stenting have achieved disappointing results. Conventional, open approaches are often complicated by significant morbidity, and endovascular stenting alone typically requires additional outflow procedures. We hypothesized that a hybrid approach, combining endovascular techniques with remote selective external iliac endarterectomy, produces superior outcomes in terms of patency compared with stenting alone, with minimal associated morbidity. METHODS: We performed a retrospective review of all patients having undergone hybrid-based retrograde iliofemoral endarterectomy from 2010 to 2014 at St. Joseph Mercy in Ann Arbor, Michigan. Patient demographics, presenting complaints, operative details, and complications were analyzed. Postoperative patency was assessed by comparison of ankle-brachial index values and qualitative patient improvement. Data were analyzed by way of paired Student t-test with significance defined as P < .05. RESULTS: A total of 40 limbs were intervened upon on 33 patients. In 20 limbs, the procedure was performed for critical limb ischemia (rest pain, n = 9; tissue loss/gangrene, n = 11). By TransAtlantic Inter-Society Consensus II criteria, 83% of iliac lesions were class D. A more even distribution was noted in TransAtlantic Inter-Society Consensus II classification for femoral and popliteal disease. Seventeen percent of patients had one-vessel infrageniculate runoff. In 21 limbs (54%), external iliac artery (EIA) stenting was performed at the time of procedure, 18 (46%) had common iliac artery (CIA) stenting, and 7 (18%) had a bridging stent from the CIA to EIA. The modal EIA stent diameter was 10 mm (range, 8-10 mm), modal CIA stent diameter 8 mm (range, 7-9 mm). The preintervention ankle-brachial index was 0.45 +/- 0.24 (n = 33 limbs) and significantly improved to 0.75 +/- 0.27 (n = 29 limbs; P < .001). In addition, preintervention toe pressure of 34 +/- 28 (n = 28 limbs) improved to 58 +/- 26 (n = 23 limbs; P < .001). No intraoperative complications occurred, which necessitated abdominal or retroperitoneal exposure. Average follow-up after the intervention was 13 +/- 14.6 months. One limb (3%) required an additional outflow bypass. The incidence of ipsilateral hypogastric occlusion increased from 35% to 55% postoperatively; however, no patients reported pelvic or buttock ischemia. One patient who had the procedure done bilaterally presented 655 days after the procedure with bilateral iliac artery thrombosis and underwent aortobifemoral bypass. No other patient needed subsequent primary assisted patency or additional infrainguinal revascularization. CONCLUSIONS: Hybrid-based external iliac and femoral endarterectomy provides a minimally invasive approach to EIA occlusive disease comparable with aortofemoral bypass. Dramatic inflow improvement was observed in our series, and the need for additional outflow revascularization was minimal. The procedure was deemed technically feasible and safe, with a low number of adverse sequela and excellent primary patency achieved more than 1 year after the intervention. PMID- 27478008 TI - Discussion. PMID- 27478007 TI - Access-related hand ischemia and the Hemodialysis Fistula Maturation Study. AB - OBJECTIVE: Access-related hand ischemia (ARHI) is a major complication after hemodialysis access construction. This study was designed to prospectively describe its incidence, predictors, interventions, and associated access maturation. METHODS: The Hemodialysis Fistula Maturation Study is a multicenter prospective cohort study designed to identify predictors of autogenous arteriovenous access (arteriovenous fistula [AVF]) maturation. Symptoms and interventions for ARHI were documented, and participants who received interventions for ARHI were compared with other participants using a nested case control design. Associations of ARHI with clinical, ultrasound, vascular function, and vein histologic variables were each individually evaluated using conditional logistic regression; the association with maturation was assessed by relative risk, Pearson chi(2) test, and multiple logistic regression. RESULTS: The study cohort included 602 participants with median follow-up of 2.1 years (10th-90th percentiles, 0.7-3.5 years). Mean age was 55.1 +/- 13.4 (standard deviation) years; the majority were male (70%), white (47%), diabetic (59%), smokers (55%), and on dialysis (64%) and underwent an upper arm AVF (76%). Symptoms of ARHI occurred in 45 (7%) participants, and intervention was required in 26 (4%). Interventions included distal revascularization with interval ligation (13), ligation (7), banding (4), revision using distal inflow (1), and proximalization of arterial inflow (1). Interventions were performed <=7 days after AVF creation in 4 participants (15%), between 8 and 30 days in 6 (23%), and >30 days in 16 (63%). Female gender (odds ratio, 3.17; 95% confidence interval, 1.27-7.91; P = .013), diabetes (13.62 [1.81-102.4]; P = .011), coronary artery disease (2.60 [1.03-6.58]; P = .044), higher preoperative venous capacitance (per %/10 mm Hg, 2.76 [1.07-6.52]; P = .021), and maximum venous outflow slope (per [mL/100 mL/min]/10 mm Hg, 1.13 [1.03-1.25]; P = .011) were significantly associated with interventions; a lower carotid-femoral pulse wave velocity and the outflow vein diameter in the early postoperative period (days 0-3) approached significance (P < .10). Intervention for ARHI was not associated with AVF maturation failure (unadjusted risk ratio, 1.18 [0.69-2.04], P = .56; adjusted odds ratio, 0.97 [0.41-2.31], P = .95). CONCLUSIONS: Remedial intervention for ARHI after AVF construction is uncommon. Diabetes, female gender, capacitant outflow veins, and coronary artery disease are all associated with an increased risk of intervention. These higher risk patients should be counseled preoperatively, their operative plans should be designed to reduce the risk of hand ischemia, and they should be observed closely. PMID- 27478009 TI - Barriers to physical activity participation in colorectal cancer survivors at high risk of cardiovascular disease. AB - BACKGROUND: Lifestyle factors including inadequate physical activity may contribute to increased risk of developing cardiovascular disease in colorectal cancer survivors. Identification of the barriers to physical activity is important for forming an evidence base of factors to target in future physical activity programs aimed at improving cardiovascular health in this population. METHODS: Colorectal cancer survivors (N = 24) from St. John of God Subiaco Hospital participated in semi-structured interviews about their current physical activity behaviors and perceived barriers to physical activity. RESULTS: Inductive thematic analysis of interviews revealed 5 overarching themes relating to barriers to physical activity: psychological barriers, environmental barriers, knowledge of guidelines, lack of practitioner support, and energy/age barriers. CONCLUSIONS: Novel findings revealed participants' dependence on practitioner support, including a reliance on practitioners to recommend lifestyle change. Survivors also revealed that regular checkups to monitor cardiovascular risk replaced the need for healthy lifestyle changes. IMPLICATIONS: With survivors holding the advice of clinicians in high regard, an opportunity exists for clinicians to facilitate lifestyle change. Health care professionals such as nurses can implement motivational strategies and provide additional health information during follow-up visits, to ensure long-term adherence. Individuals who reported psychological, motivational, and environmental barriers may benefit from interventions to improve self-regulation, planning, and problem-solving skills. PMID- 27478010 TI - The present and future of withdrawal period calculations for milk in the European Union: dealing with data below the limit of quantification. AB - The assessment of withdrawal periods for milk is affected by the occurrence of data below the lower analytical quantification limit (BLQ data) and the resulting uncertainty. The current regulatory approach for dealing with BLQ residues is simple and easy: BLQ data (and missing data) are arbitrarily reassigned a value of one-half the LOQ before any calculation on the data with one of the three currently applicable methods. Here, we reconsider the determination of the withdrawal period of milk with data below the limit of quantification. Theoretical background on analytical limits and pharmacometric considerations will be established. Then, we analyze the uncertainty problems caused by the current approach and propose a calculation solution (maximum-likelihood estimation handling left-censored data) included in nonlinear mixed-effects modeling. Finally, we illustrate this issue using a case example. PMID- 27478012 TI - Survival outcomes scores (SOFT, BAR, and Pedi-SOFT) are accurate in predicting post-liver transplant survival in adolescents. AB - SOFT and BAR scores utilize recipient, donor, and graft factors to predict the 3 month survival after LT in adults (>=18 years). Recently, Pedi-SOFT score was developed to predict 3-month survival after LT in young children (<=12 years). These scoring systems have not been studied in adolescent patients (13-17 years). We evaluated the accuracy of these scoring systems in predicting the 3-month post LT survival in adolescents through a retrospective analysis of data from UNOS of patients aged 13-17 years who received LT between 03/01/2002 and 12/31/2012. Recipients of combined organ transplants, donation after cardiac death, or living donor graft were excluded. A total of 711 adolescent LT recipients were included with a mean age of 15.2+/-1.4 years. A total of 100 patients died post-LT including 33 within 3 months. SOFT, BAR, and Pedi-SOFT scores were all found to be good predictors of 3-month post-transplant survival outcome with areas under the ROC curve of 0.81, 0.80, and 0.81, respectively. All three scores provided good accuracy for predicting 3-month survival post-LT in adolescents and may help clinical decision making to optimize survival rate and organ utilization. PMID- 27478011 TI - Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation. AB - To determine the association of somatic mutations in acute myeloid leukemia (AML) with risk of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT), we retrospectively studied pre-transplantation genetic profiles obtained from next-generation sequencing of 26 genes in 112 adult patients with AML who underwent alloHSCT. Univariable and multivariable regression analyses were used to assess the association between the presence of a pathogenic mutation and risk of relapse after alloHSCT. Eighty-six percent (96 of 112) of patients had at least 1 pathogenic mutation. Mutations in TP53, WT1, and FLT3-internal tandem duplication (ITD) were associated with an increased risk of relapse after alloHSCT (adjusted hazard ratio [aHR], 2.90; P = .009; aHR, 2.51; P= .02; and aHR, 1.83; P = .07, respectively). DNMT3A mutation in the absence of FLT3-ITD and NPM1 mutations was associated with a lower relapse risk (aHR, .22; P = .04). Comparison of pre-alloHSCT and post-alloHSCT genetic profiles showed clonal evolution in 6 of 6 patients, including acquisition of actionable mutations in 4 patients. In summary, genetic profiling is useful for assessing relapse risk in patients with AML undergoing alloHSCT and may identify patients in need of strategies to reduce this risk. Clonal evolution is present at post-alloHSCT relapse and repeat genetic profiling may uncover acquired actionable mutations. PMID- 27478013 TI - Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury. AB - Problems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between alpha-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p=0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p=0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation. PMID- 27478014 TI - Effect of SOCS1 overexpression on RPE cell activation by proinflammatory cytokines. AB - The purpose of this study was to investigate the in vitro effect of Suppressor Of Cytokine Signaling 1 (SOCS1) overexpression in retinal pigment epithelium (RPE) cells on their activation by pro-inflammatory cytokines IFNgamma, TNFalpha and IL 17. Retinal pigment epithelium cells (ARPE-19) were stably transfected with the control plasmid pIRES2-AcGFP1 or the plasmid pSOCS1-IRES2-AcGFP1. They were stimulated by IFNgamma (150ng/ml), TNFalpha (30ng/ml) or IL-17 (100ng/ml). The levels of SOCS1 mRNA were measured by real-time PCR. Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation and IkappaBalpha expression were analysed by western Blot (WB). IL-8 secretion was analysed by ELISA and expression of MHCII molecules and ICAM-1/CD54 by flow cytometry. Our data show that SOCS1 mRNA overexpression in RPE cells prevents IFNgamma-induced SOCS1 mRNA increase and IFNgamma-mediated STAT1 phosphorylation. Moreover, SOCS1 overexpression in RPE cells inhibits IFNgamma-induced decrease of IL-8 secretion and prevents IFNgamma-induced MHC II and ICAM1/CD54 upregulation. However, SOCS1 overexpression does not affect TNFalpha-induced IkappaBalpha degradation nor block TNFalpha-induced or IL-17-induced IL-8 secretion. On the contrary, IL-17 induced secretion is increased by SOCS1 overexpression. In conclusion, SOCS1 overexpression in RPE cells inhibits some IFNgamma-mediated responses that lead to uveitis development. This notion raises the possibility that SOCS1 overexpression could be a novel target for treating non-infectious uveitis. However, some proinflammatory effects of TNFalpha and IL-17 stimulation on RPE are not blocked by SOCS1 overexpression. PMID- 27478015 TI - CD29/CD184 expression analysis provides a signature for identification of neuronal like cells differentiated from PBMSCs. AB - In vitro study was used as a helpful model to investigate the role of different growth factors in differentiation of stem cells. The aim of this study was to find an easy and robust method for confirmation of Peripheral Blood-Mesenchymal Stem Cells (PB-MSCs) differentiation into neuronal cells. A set of CD markers as well as neural markers were used to elucidate their differentiation. In the present study, PB-MSCs were isolated by density centrifugation. Isolated cells were divided into four groups: (i) untreated PB-MSCs as control cells, (ii) cells treated with 50ng/ml Noggin [N50], (iii) cells treated with 75ng/ml Noggin [N75], (iv) cells treated with 100ng/ml Noggin [N100]. These cells were cultured for 14days. Expression of CD24, CD29 and CD184 markers was evaluated by flow cytometry. Furthermore, the neural markers as well as BMP genes expression were analyzed by Real time PCR. Our in vitro studies demonstrated that Noggin had diverse effects on neural differentiation of PB-MSCs depending on the concentration. N75 treatment induced neuronal differentiation of PB-MSCs more strongly than N50 treatment. Furthermore, differentiation of PB-MSCs into neuronal lineage was inhibited by N100 treatment. Our result showed that exposure of PB-MSCs to Noggin with 75ng/ml concentration was associated with changes in pattern of CD29/CD184 expression. The expression profile of CD29(+/-)/CD184(-) can be suggested as a robust signature for tracing differentiation of Peripheral Blood-Mesenchymal Stem Cells (PB-MSCs) into neuronal cells. PMID- 27478016 TI - Distinct Subthreshold Mechanisms Underlying Rate-Coding Principles in Primate Auditory Cortex. AB - A key computational principle for encoding time-varying signals in auditory and somatosensory cortices of monkeys is the opponent model of rate coding by two distinct populations of neurons. However, the subthreshold mechanisms that give rise to this computation have not been revealed. Because the rate-coding neurons are only observed in awake conditions, it is especially challenging to probe their underlying cellular mechanisms. Using a novel intracellular recording technique that we developed in awake marmosets, we found that the two types of rate-coding neurons in auditory cortex exhibited distinct subthreshold responses. While the positive-monotonic neurons (monotonically increasing firing rate with increasing stimulus repetition frequency) displayed sustained depolarization at high repetition frequency, the negative-monotonic neurons (opposite trend) instead exhibited hyperpolarization at high repetition frequency but sustained depolarization at low repetition frequency. The combination of excitatory and inhibitory subthreshold events allows the cortex to represent time-varying signals through these two opponent neuronal populations. PMID- 27478017 TI - Satb2 Is Required for the Development of a Spinal Exteroceptive Microcircuit that Modulates Limb Position. AB - Motor behaviors such as walking or withdrawing the limb from a painful stimulus rely upon integrative multimodal sensory circuitry to generate appropriate muscle activation patterns. Both the cellular components and the molecular mechanisms that instruct the assembly of the spinal sensorimotor system are poorly understood. Here we characterize the connectivity pattern of a sub-population of lamina V inhibitory sensory relay neurons marked during development by the nuclear matrix and DNA binding factor Satb2 (ISR(Satb2)). ISR(Satb2) neurons receive inputs from multiple streams of sensory information and relay their outputs to motor command layers of the spinal cord. Deletion of the Satb2 transcription factor from ISR(Satb2) neurons perturbs their cellular position, molecular profile, and pre- and post-synaptic connectivity. These alterations are accompanied by abnormal limb hyperflexion responses to mechanical and thermal stimuli and during walking. Thus, Satb2 is a genetic determinant that mediates proper circuit development in a core sensory-to-motor spinal network. PMID- 27478018 TI - Expression of C1ql3 in Discrete Neuronal Populations Controls Efferent Synapse Numbers and Diverse Behaviors. AB - C1ql3 is a secreted neuronal protein that binds to BAI3, an adhesion-class GPCR. C1ql3 is homologous to other gC1q-domain proteins that control synapse numbers, but a role for C1ql3 in regulating synapse density has not been demonstrated. We show in cultured neurons that C1ql3 expression is activity dependent and supports excitatory synapse density. Using newly generated conditional and constitutive C1ql3 knockout mice, we found that C1ql3-deficient mice exhibited fewer excitatory synapses and diverse behavioral abnormalities, including marked impairments in fear memories. Using circuit-tracing tools and conditional ablation of C1ql3 targeted to specific brain regions, we demonstrate that C1ql3 expressing neurons in the basolateral amygdala project to the medial prefrontal cortex, that these efferents contribute to fear memory behavior, and that C1ql3 is required for formation and/or maintenance of these synapses. Our results suggest that C1ql3 is a signaling protein essential for subsets of synaptic projections and the behaviors controlled by these projections. PMID- 27478019 TI - The Basis of Food Texture Sensation in Drosophila. AB - Food texture has enormous effects on food preferences. However, the mechanosensory cells and key molecules responsible for sensing the physical properties of food are unknown. Here, we show that akin to mammals, the fruit fly, Drosophila melanogaster, prefers food with a specific hardness or viscosity. This food texture discrimination depends upon a previously unknown multidendritic (md-L) neuron, which extends elaborate dendritic arbors innervating the bases of taste hairs. The md-L neurons exhibit directional selectivity in response to mechanical stimuli. Moreover, these neurons orchestrate different feeding behaviors depending on the magnitude of the stimulus. We demonstrate that the single Drosophila transmembrane channel-like (TMC) protein is expressed in md-L neurons, where it is required for sensing two key textural features of food hardness and viscosity. We propose that md-L neurons are long sought after mechanoreceptor cells through which food mechanics are perceived and encoded by a taste organ, and that this sensation depends on TMC. VIDEO ABSTRACT. PMID- 27478020 TI - Effects of aerobic and anaerobic biological processes on leaching of heavy metals from soil amended with sewage sludge compost. AB - The risk from leaching of heavy metals is a major factor hindering land application of sewage sludge compost (SSC). Understanding the change in heavy metal leaching resulting from soil biological processes provides important information for assessing long-term behavior of heavy metals in the compost amended soil. In this paper, 180days aerobic incubation and 240days anaerobic incubation were conducted to investigate the effects of the aerobic and anaerobic biological processes on heavy metal leaching from soil amended with SSC, combined with chemical speciation modeling. Results showed that leaching concentrations of heavy metals at natural pH were similar before and after biological process. However, the major processes controlling heavy metals were influenced by the decrease of DOC with organic matter mineralization during biological processes. Mineralization of organic matter lowered the contribution of DOC-complexation to Ni and Zn leaching. Besides, the reducing condition produced by biological processes, particularly by the anaerobic biological process, resulted in the loss of sorption sites for As on Fe hydroxide, which increased the potential risk of As release at alkaline pH. PMID- 27478021 TI - Metal removal from Municipal Solid Waste Incineration fly ash: A comparison between chemical leaching and bioleaching. AB - Bio- and hydrometallurgical experimental setups at 2-l reactor scale for the processing of fly ash from municipal waste incinerators were explored. We aimed to compare chemical H2SO4 leaching and bioleaching; the latter involved the use of H2SO4 and a mixed culture of acidophilic bacteria. The leaching yields of several elements, including some of those considered as critical (Mg, Co, Ce, Cr, Ga, Nb, Nd, Sb and Sm), are provided. At the end of the experiments, both leaching methods resulted in comparable yields for Mg and Zn (>90%), Al and Mn (>85%), Cr (~65%), Ga (~60%), and Ce (~50%). Chemical leaching showed the best yields for Cu (95%), Fe (91%), and Ni (93%), whereas bioleaching was effective for Nd (76%), Pb (59%), and Co (55%). The two leaching methods generated solids of different quality with respect to the original material as we removed and significantly reduced the metals amounts, and enriched solutions where metals can be recovered for example as mixed salts for further treatment. Compared to chemical leaching the bioleaching halved the use of H2SO4, i.e., a part of agent costs, as a likely consequence of bio-produced acid and improved metal solubility. PMID- 27478022 TI - Evaluation of concrete recycling system efficiency for ready-mix concrete plants. AB - The volume of waste generated annually in concrete plants is quite large and has important environmental and economic consequences. The use of fresh concrete recyclers is an interesting way for the reuse of aggregates and water in new concrete production. This paper presents a study carried out for over one year by one of the largest ready-mix concrete producers in Brazil. This study focused on the evaluation of two recyclers with distinct material separation systems, herein referred to as drum-type and rotary sieve-type equipment. They were evaluated through characterization and monitoring test programs to verify the behaviour of recovered materials (aggregates, water, and slurry). The applicability of the recovered materials (water and aggregates) was also evaluated in the laboratory and at an industrial scale. The results obtained with the two types of recyclers used were equivalent and showed no significant differences. The only exception was in terms of workability. The drum-type recycler generated fewer cases that required increased pumping pressure. The analysis concluded that the use of untreated slurry is unfeasible because of its intense negative effects on the strength and workability of concrete. The reclaimed water, pre-treated to ensure that its density is less than 1.03g/cm(3), can be used on an industrial scale without causing any harm to the concrete. The use of recovered aggregates consequently induces an increase in water demand and cement consumption to ensure the workability conditions of concrete that is proportional to the concrete strength level. Therefore, the viability of their use is restricted to concretes with characteristic strengths lower than 25MPa. PMID- 27478023 TI - Removal of humic substances from reverse osmosis (RO) and nanofiltration (NF) concentrated leachate using continuously ozone generation-reaction treatment equipment. AB - Concentrated leachate from membrane treatment process, which contains large amount of difficult-to-degrade humic substances, can induce potential hazards to ecological environment. In this study, the concentrated leachates from reverse osmosis (RO) and nanofiltration (NF) were treated by continuous ozone generating reaction integrated equipment, and the removal characteristics of humic substances were analyzed using gel filtration chromatography (GFC), excitation emission matrix fluorescence spectroscopy (EEM), XAD-8 resin fractionation, and Fourier transform infrared spectroscopy (FTIR). The results of XRD-8 fractionation and SUVA254 showed that the humic substances including humic acid (HA) and fulvic acid (FA), were effectively removed along with the breakdown of aromatic hydrocarbons and decrease in the degree of humification during the ozonation process. After 110min of reaction, HA in both concentrated leachates was completely removed. GFC analysis indicated that both concentrated leachates had much broader distribution after the degradation. The high molecular weight (MW) organic matter was transformed into low molecular weight of <10kDa. The majority of high MW organics in NF concentrate were converted to low MW molecules of 10kDa-1kDa, while those in RO concentrate were decomposed to small MW molecules of <1kDa. The results of EEM analysis implied that the degradation of HA and FA led to a significant decrease in the fluorescence intensity. Though the effluent of two concentrated leachate did not meet the maximum allowable criterion for leachate direct or indirect discharge standard in China, the composition and properties of organic matters in concentrated leachate were changed significantly after entire ozonation reaction, which would be conducive to the further biological treatment or other advanced treatment. PMID- 27478024 TI - Analysis and interpretation of the leaching behaviour of waste thermal treatment bottom ash by batch and column tests. AB - This paper investigates the leaching behaviour of specific types of waste thermal treatment bottom ash (BA) as a function of both pH and the liquid-to-solid ratio (L/S). Specifically, column percolation tests and different types of batch tests (including pH-dependence) were applied to BA produced by hospital waste incineration (HW-I), Refuse Derived Fuel (RDF) gasification (RDF-G) and RDF incineration (RDF-I). The results of these tests were interpreted applying an integrated graphical and modelling approach aimed at identifying the main mechanisms (solubility, availability or time-controlled dissolution and diffusion) governing the release of specific constituents from each type of BA. The final aim of this work was in fact to gain insight on the information that can be provided by the leaching tests applied, and hence on which ones may be more suitable to apply for assessing the leaching concentrations expected in the field. The results of the leaching tests showed that the three samples of analysed BA presented differences of orders of magnitude in their leaching behaviour, especially as a function of pH, but also in terms of the L/S. These were mainly related to the differences in mineralogy of the samples. In addition, for the same type of bottom ash, the comparison between the results of batch and percolation column tests, expressed in terms of cumulative release, showed that for some constituents (e.g. Mg for HW-I BA and Cu for RDF-G BA) differences of over one order of magnitude were obtained due to variations in pH and DOC release. Similarly, the eluate concentrations observed in the percolation tests, for most of the investigated elements, were not directly comparable with the results of the pH-dependence tests. In particular, in some cases the percolation test results showed eluate concentrations of some constituents (e.g. K and Ca in HW-I BA) of up to one order of magnitude higher than the values obtained from the pH-dependence experiments at the same pH value. This was attributed to a rapid washout from the column of the soluble phases present in the BA. In contrast, for other constituents (e.g. Mg and Ba for the RDF-G BA), especially at high L/S ratios, the concentrations in the column tests were of up to one order of magnitude lower than the solubility value, indicating release under non equilibrium conditions. In these cases, batch pH-dependence tests should be preferred, since column tests results could underestimate the concentrations expected in the field. PMID- 27478025 TI - Separation of plastics by froth flotation. The role of size, shape and density of the particles. AB - Over the last few years, new methods for plastic separation in mining have been developed. Froth flotation is one of these techniques, which is based on hydrophobicity differences between particles. Unlike minerals, most of the plastics are naturally hydrophobic, thus requiring the addition of chemicals that promote the selective wettability of one of its components, for a flotation separation. The floatability of six granulated post-consumer plastic - Polystyrene (PS), Polymethyl methacrylate (PMMA), Polyethylene Terephthalate (PET S, PET-D) and Polyvinyl Chloride (PVC-M, PVC-D) - in the presence of tannic acid (wetting agent), and the performance of the flotation separation of five bi component plastic mixtures - PS/PMMA, PS/PET-S, PS/PET-D, PS/PVC-M and PS/PVC-D - were evaluated. Moreover, the effect of the contact angle, density, size and shape of the particles was also analysed. Results showed that all plastics were naturally hydrophobic, with PS exhibiting the highest floatability. The contact angle and the flotation recovery of six plastics decreased with increasing tannic acid concentration, occurring depression of plastics at very low concentrations. Floatability differed also with the size and shape of plastic particles. For regular-shaped plastics (PS, PMMA and PVC-D) floatability decreased with the increase of particle size, while for lamellar-shaped particles (PET-D) floatability was slightly greater for coarser particles. Thus, plastic particles with small size, lamellar shape and low density present a greater floatability. The quality of separation varied with the mixture type, depending not only on the plastics hydrophobicity, but also on the size, density and shape of the particles, i.e. the particle weight. Flotation separation of plastics can be enhanced by differences in hydrophobicity. In addition, flotation separation improves if the most hydrophobic plastic, that floats, has a lamellar shape and lower density and if the most hydrophilic plastic, that sinks, has a regular shape and higher density. The results obtained show that froth flotation is a potential method for plastics separation, in particular for plastics with particle size greater than 2.0mm. PMID- 27478026 TI - Life cycle assessment of capital goods in waste management systems. AB - The environmental importance of capital goods (trucks, buildings, equipment, etc.) was quantified by LCA modelling 1 tonne of waste treated in five different waste management scenarios. The scenarios involved a 240L collection bin, a 16m(3) collection truck, a composting plant, an anaerobic digestion plant, an incinerator and a landfill site. The contribution of capital goods to the overall environmental aspects of managing the waste was significant but varied greatly depending on the technology and the impact category: Global Warming: 1-17%, Stratospheric Ozone Depletion: 2-90%, Ionising Radiation, Human Health: 2-91%, Photochemical Ozone Formation: 2-56%, Freshwater Eutrophication: 0.05-99%, Marine Eutrophication: 0.03-8%, Terrestrial Acidification: 2-13%, Terrestrial Eutrophication: 1-8%, Particulate Matter: 11-26%, Human Toxicity, Cancer Effect: 10-92%, Human Toxicity, non-Cancer Effect: 1-71%, Freshwater Ecotoxicity: 3-58%. Depletion of Abiotic Resources - Fossil: 1-31% and Depletion of Abiotic Resources - Elements (Reserve base): 74-99%. The single most important contribution by capital goods was made by the high use of steel. Environmental impacts from capital goods are more significant for treatment facilities than for the collection and transportation of waste and for the landfilling of waste. It is concluded that the environmental impacts of capital goods should always be included in the LCA modelling of waste management, unless the only impact category considered is Global Warming. PMID- 27478027 TI - Recovery of valuable metals from electronic scraps by clays and organo-clays: Study on bi-ionic model solutions. AB - The demand of valuable metals, as precious metals and rare earths, is constantly increasing in the global market, as many and different technological applications exploit these materials because of their unique properties. Since natural resources are located just in focused areas, an interesting possibility could be the recovery of metals from Waste Electrical and Electronic Equipment (WEEE). The aim of this work is to evaluate the recovery potentialities of clays and organo clay based systems towards the metals contained in the solutions of electronic scraps dissolved in strong acid, by preliminary tests on bi-ionic model solutions. Lanthanum has been chosen as representative of the rare earths while copper has been considered since it is by far the most used metal in electric and electronic equipment. The considered sorbents are a montmorillonitic clay and two polyamine based organo-clays. Uptake and release processes have been carried out in order to assess the performances of these solids and to evaluate the uptake and release mechanisms. The results showed that the cationic exchange is the prevailing mechanism in the case of pristine clay, while both coordinating effect due to amino groups and cationic exchange occur in the case of modified clays, respectively accounting for copper and lanthanum uptake. Furthermore the pH was found having a great influence in both the adsorption and desorption phenomena. PMID- 27478028 TI - Gastric per-oral endoscopic myotomy with antropyloromyotomy in the treatment of refractory gastroparesis: clinical experience with follow-up and scintigraphic evaluation (with video). AB - BACKGROUND AND AIMS: Gastroparesis is a chronic, debilitating condition. We report an experience conducting gastric per-oral endoscopic pyloromyotomy (G POEM) with objectives to assess clinical efficacy, gastric emptying evolution, and procedural adverse events. METHODS: This was a clinical pilot series on 12 consecutive patients who underwent G-POEM for refractory gastroparesis in our tertiary center between February 2014 and August 2015. Patients included had severe disease as defined by elevated Gastroparesis Cardinal Symptoms Index (GCSI) score and delayed gastric emptying scintigraphy (GES). G-POEM was performed by mucosal incision upstream the pylorus followed by submucosal tunnel and antropyloromyotomy with subsequent access closure. Efficacy was assessed at 5 days, 1 month, and 3 months, based on GCSI score, and individualizing (Likert scale) the main symptoms (nausea, vomiting, abdominal pain, early satiety, and anorexia). GES was performed 2 months after the procedure. RESULTS: G-POEM was successfully performed in all 12 patients, yielding a technical success rate of 100%. Significant improvements in GCSI were observed: 3.5 +/- .8 versus .9 +/- .9 (1 month) and 1.1 +/- 1.5 (3 months), respectively (P < .001), as well as the severity of main symptoms at 3 months. Clinical efficacy was 85% (10/12). GES normalized in 75% of cases, with improvement of half emptying time (222 +/- 90 minutes vs 133 +/- 90 minutes; P = .03) and retention at 2 hours (76% +/- 20% vs 44% +/- 26%; P = .009). There were no adverse events related to the procedure. CONCLUSION: We report a single-center study evaluating G-POEM for refractory gastroparesis, demonstrating its feasibility, reproducibility, and safety with promising clinical and scintigraphic efficacy. PMID- 27478029 TI - Risk of infection transmission in curvilinear array echoendoscopes: results of a prospective reprocessing and culture registry. AB - BACKGROUND AND AIMS: The complex design of the elevator mechanism in duodenoscopes has been recognized as a challenge for disinfection and recently implicated as a potential source of persistent bacterial contamination. Curvilinear array (CLA) echoendoscopes also have an elevator mechanism; however, there are no recommendations or data regarding the risk of persistent bacterial contamination of echoendoscopes. Here we hoped to determine the yield of microbial growth with routine bacterial surveillance cultures of reprocessed CLA echoendoscopes. METHODS: Beginning in February 2015 to February 2016, CLA echoendoscopes at a single tertiary care center underwent prospective bacterial surveillance cultures after reprocessing. Any growth of gram-negative bacilli was considered to be critical. Echoendoscopes with a positive result underwent quarantine followed by repeat disinfection and culture. RESULTS: During the study period, 540 cultures were obtained; 521 (96.5%) were primary cultures obtained from 18 CLA echoendoscopes. Twenty-two primary cultures (4.2%) were positive for gram-negative bacilli after high-level disinfection reprocessing. Eleven different bacteria were isolated: Klebsiella pneumoniae, Citrobacter freundii, Escherichia coli, Pseudomonas aeruginosa, Klebsiella oxytoca, Sphingomonas paucimobilis, Acinetobacter baumanii, Enterobacter cloacae, Hafnia alvei, Pseudomonas putida, and Stenotrophomonas maltophilia. Antibiotic sensitivity data on 19 of 24 bacteria (79.2%) isolated from positive primary cultures revealed no documented cases of carbapenem-resistant enterobacteriaceae, cephalosporin resistant-Klebsiella, or multidrug-resistant Acinetobacter. There have been no documented cases of patient-to-patient transmission. CONCLUSIONS: After following standard high-level disinfection and reprocessing, CLA echoendoscopes can remain culture positive for high-concern organisms. Recommendations regarding infection risk should take into consideration elevator-containing echoendoscopes in addition to duodenoscopes to ensure patient safety and endoscope reprocessing efficacy. PMID- 27478030 TI - NT-proBNP <95 ng/l can exclude pulmonary hypertension on echocardiography at diagnostic workup in patients with interstitial lung disease. AB - BACKGROUND: Pulmonary hypertension (PH) is a serious complication to interstitial lung disease (ILD) and has a poor prognosis. PH is often diagnosed by screening with echocardiography followed by right heart catheterisation. A previous study has shown that a value of NT-pro-brain natriuretic peptide (NT-proBNP) <95 ng/l could be used to rule out PH in patients with ILD. AIM: To evaluate this rule-out test for PH in a new cohort of incident patients with ILD. METHODS: An established database with data from 148 consecutive patients referred from January 2012 to October 2014 was used to identify patients and obtain data from echocardiography, NT-proBNP, diagnosis and lung function. Signs of PH on echocardiography were defined as a tricuspid pressure gradient (TR) >=40 mmHg, decreased right ventricular systolic function or dilatation. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of NT-proBNP >95 ng/l for signs of PH on echocardiography were calculated. The study was approved by the Danish Health Authority. RESULTS: In 118 patients, data from both echocardiography and measurements of NT-proBNP were available. Eleven of these were screened positive for PH on echocardiography. Sensitivity, specificity, NPV and PPV of NT-proBNP <95 ng/l for PH were 100, 44, 16 and 100%, respectively. Furthermore, no patients with left heart failure as the cause of dyspnoea were missed using this cut-off value. CONCLUSION: NT-proBNP <95 ng/l precludes a positive echocardiographic screen for PH in ILD patients at referral for diagnostic workup. PMID- 27478031 TI - Activity of bis(7-hydroxycoumarin) Mannich bases against bovine viral diarrhoea virus. AB - Some Mannich bases of 7-hydroxycoumarins (3-6) with piperazine or other amines bearing two secondary amine groups were prepared and tested against viruses representative of RNA families. All compounds were symmetrical and possessed two identical coumarin moieties with respect to one diamine. In the series of 7 hydroxy derivatives, 3a was endowed with a significant activity against BVDV. Then, some of these double Mannich bases were alkylated and acylated. Among the propyloxy derivatives, only 3f showed a modest activity against BVDV. Among the acyl derivatives, the p-nitrobenzoyl derivative 3i emerged as the most active compound; in this series, the p-nitrobenzoyl derivative 3j also exhibited good action against BVDV and modest activity against CVB-5. On the whole, the compounds presented here show some differences, with respect to previous studies in terms of SAR from similar Mannich bases of 7-hydroxycoumarin. PMID- 27478034 TI - C-type lysozyme gene haplotypes in Rhode Island Red layer chickens are associated with hatchability and survival. PMID- 27478032 TI - Discovery of cyclosporine A and its analogs as broad-spectrum anti-influenza drugs with a high in vitro genetic barrier of drug resistance. AB - As the number of drug-resistant influenza viruses continues to increase, antivirals with novel mechanisms of action are urgently needed. Among the two classes of FDA-approved antiviral drugs, neuraminidase (NA) inhibitors, oseltamivir, zanamivir, and peramivir, are currently the only choice for the prevention and treatment of influenza virus infection. Due to the antigenic drift and antigenic shift, it will only be a matter of time before influenza viruses become completely resistant to these NA inhibitors. In pursuing the next generation of antiviral drugs with complementary mechanisms of action to those of the NA inhibitors, we have identified a natural product, cyclosporine A (CsA) (1), as a desired drug candidate. In this study, we discovered that CsA (1) and its analogs have broad-spectrum antiviral activity against multiple influenza A and B strains, including strains that are resistant to either NA or M2 inhibitors or both. Moreover, CsA (1) displays a high in vitro genetic barrier of drug resistance than oseltamivir carboxylate Mechanistic studies revealed that CsA (1) acts at the intermediate step of viral replication post viral fusion. Its antiviral mechanism is independent of inhibiting the isomerase activity of cyclophilin A (CypA), and CsA (1) has no effect on the viral polymerase activity The potent antiviral efficacy of CsA (1), coupled with the high in vitro genetic barrier of drug resistance and novel mechanism of action, renders CsA (1) a promising anti-influenza drug candidate for further development. PMID- 27478035 TI - Spontaneous resolution of a central giant cell lesion: case report. PMID- 27478033 TI - Macromolecular crowding meets oxygen tension in human mesenchymal stem cell culture - A step closer to physiologically relevant in vitro organogenesis. AB - Modular tissue engineering is based on the cells' innate ability to create bottom up supramolecular assemblies with efficiency and efficacy still unmatched by man made devices. Although the regenerative potential of such tissue substitutes has been documented in preclinical and clinical setting, the prolonged culture time required to develop an implantable device is associated with phenotypic drift and/or cell senescence. Herein, we demonstrate that macromolecular crowding significantly enhances extracellular matrix deposition in human bone marrow mesenchymal stem cell culture at both 20% and 2% oxygen tension. Although hypoxia inducible factor - 1alpha was activated at 2% oxygen tension, increased extracellular matrix synthesis was not observed. The expression of surface markers and transcription factors was not affected as a function of oxygen tension and macromolecular crowding. The multilineage potential was also maintained, albeit adipogenic differentiation was significantly reduced in low oxygen tension cultures, chondrogenic differentiation was significantly increased in macromolecularly crowded cultures and osteogenic differentiation was not affected as a function of oxygen tension and macromolecular crowding. Collectively, these data pave the way for the development of bottom-up tissue equivalents based on physiologically relevant developmental processes. PMID- 27478036 TI - A low-fidelity, high-functionality, inexpensive ultrasound-guided nerve block model. PMID- 27478037 TI - A differing bidirectional impact on the recognition accuracy of facial expression. AB - This study explored a bidirectional impact on the recognition accuracy of various facial expressions deriving from both the observer and sender in a sample of Chinese participants. A facial manipulation task was used to examine the ability of an observer's facial feedback to modulate the recognition of various facial expressions. Furthermore, the effect of a sender's facial expression with an open or closed mouth on recognition accuracy was investigated. The results showed that only recognition accuracy of a sad facial expression was influenced simultaneously by bidirectional sources from a sender and observer. Moreover, the impact of the unidirectional cue of a sender's facial feature (i.e., mouth openness) on happy and neutral faces was found to influence the recognition accuracy of these faces, but not the observer's bodily state. These findings indicate that the bidirectional impact derived from an observer and sender on facial expression recognition accuracy differs for emotional and neutral expressions. PMID- 27478038 TI - Lower and reduced expression of EphA4 is associated with advanced TNM stage, lymph node metastasis, and poor survival in breast carcinoma. AB - The expression of EphA4 has been well documented in the development of nerve and in certain types of human cancer. Few studies of EphA4, however, have focused on breast carcinoma. In this study, a set of breast carcinomas was subjected to immunohistochemical staining. In normal luminal cells, EphA4 was weakly detected in 11 (14.3 %), moderately detected in 15 (19.5 %) and highly detected in 51 out of 77 (66.2 %) samples, while in breast carcinoma cells, EphA4 was weakly detected in 42 (54.5 %), moderately detected in 19 (24.7 %) and highly detected in 16 out of 77 (20.8 %) samples (P < 0.001). The expression of EphA4 protein was significantly reduced in 68.8 % of breast carcinoma samples comparing with normal cells. The expression of EphA4 was significantly associated with tumor grade (P = 0.003), TNM stage (P = 0.034), lymph node metastasis (P = 0.034) and Ki-67 (P < 0.001). No significant relationship was found between the expression of EphA4 and age, molecular subtypes, and HER2 status. Survival analysis showed that significant association of low expression of EphA4 in tumor cells with short overall survival (P = 0.048) and disease-free survival (P = 0.051). Our data show that EphA4 was reduced in breast carcinoma, which is associated with high grade, advanced TNM stage, lymph node metastasis, and poor outcome of patients. PMID- 27478039 TI - Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development. AB - Hepatocellular carcinoma (HCC) represents a classic example of inflammation linked cancer. To characterize the role of the immune system in hepatic injury and tumor development, we comparatively studied the extent of liver disease and hepatocarcinogenesis in immunocompromised versus immunocompetent Fah-deficient mice. Strikingly, chronic liver injury and tumor development were markedly suppressed in alymphoid Fah(-/-) mice despite an overall increased mortality. Mechanistically, we show that CD8(+) T cells and lymphotoxin beta are central mediators of HCC formation. Antibody-mediated depletion of CD8(+) T cells as well as pharmacological inhibition of the lymphotoxin-beta receptor markedly delays tumor development in mice with chronic liver injury. Thus, our study unveils distinct functions of the immune system, which are required for liver regeneration, survival, and hepatocarcinogenesis. PMID- 27478040 TI - High-throughput Phenotyping of Lung Cancer Somatic Mutations. AB - Recent genome sequencing efforts have identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood. Here we characterize 194 somatic mutations identified in primary lung adenocarcinomas. We present an expression-based variant-impact phenotyping (eVIP) method that uses gene expression changes to distinguish impactful from neutral somatic mutations. eVIP identified 69% of mutations analyzed as impactful and 31% as functionally neutral. A subset of the impactful mutations induces xenograft tumor formation in mice and/or confers resistance to cellular EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and multiple BRAF variants, demonstrating that rare mutations can be functionally important in cancer. PMID- 27478043 TI - Cytosolic pH as a messenger signal used in brain information processing. PMID- 27478044 TI - A new transgenic mouse model revealed a role of astrocytic calcium in vivo. PMID- 27478042 TI - Conferring biological activity to native spider silk: A biofunctionalized protein based microfiber. AB - Spider silk is an extraordinary material with physical properties comparable to the best scaffolding/structural materials, and as a fiber it can be manipulated with ease into a variety of configurations. Our work here demonstrates that natural spider silk fibers can also be used to organize biological components on and in devices through rapid and simple means. Micron scale spider silk fibers (5 10 MUm in diameter) were surface modified with a variety of biological entities engineered with pentaglutamine tags via microbial transglutaminase (mTG). Enzymes, enzyme pathways, antibodies, and fluorescent proteins were all assembled onto spider silk fibers using this biomolecular engineering/biofabrication process. Additionally, arrangement of biofunctionalized fiber should in of itself generate a secondary level of biomolecular organization. Toward this end, as proofs of principle, spatially defined arrangement of biofunctionalized spider silk fiber was shown to generate effects specific to silk position in two cases. In one instance, arrangement perpendicular to a flow produced selective head and neck carcinoma cell capture on silk with antibodies complexed to conjugated protein G. In a second scenario, asymmetric bacterial chemotaxis arose from asymmetric conjugation of enzymes to arranged silk. Overall, the biofabrication processes used here were rapid, required no complex chemistries, were biologically benign, and also the resulting engineered silk microfibers were flexible, readily manipulated and functionally active. Deployed here in microfluidic environments, biofunctional spider silk fiber provides a means to convey complex biological functions over a range of scales, further extending its potential as a biomaterial in biotechnological settings. Biotechnol. Bioeng. 2017;114: 83-95. (c) 2016 Wiley Periodicals, Inc. PMID- 27478041 TI - Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche. AB - The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is overexpressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2. Activated SIK2 plays a dual role in augmenting AMPK-induced phosphorylation of acetyl-CoA carboxylase and in activating the PI3K/AKT pathway through p85alpha-S154 phosphorylation. These findings identify SIK2 at the apex of the adipocyte-induced signaling cascades in cancer cells and make a compelling case for targeting SIK2 for therapy in ovarian cancer. PMID- 27478045 TI - Visualization of diversity of calcium signals in astrocytes. PMID- 27478046 TI - Neurogenic microglia in the early postnatal subventricular zone found by a simple stereological imaging method. PMID- 27478047 TI - Future prospects for the development of a novel medical therapy for intracranial aneurysm. PMID- 27478048 TI - SPring-8 synchrotron radiation imaging for analyzing cardiovascular function in anesthetized small animals. PMID- 27478049 TI - Design of antisense oligonucleotides. PMID- 27478050 TI - Immunomodulatory effects of glatiramer acetate as they relate to stage-specific immune dysregulation in multiple sclerosis. PMID- 27478051 TI - Autism spectrum disorders and epilepsy. PMID- 27478052 TI - What senses shear stress? PMID- 27478053 TI - A Novel scoring system for distinguishing keratoconus from normal eyes. AB - PURPOSE: To evaluate the accuracy of a novel scoring system in differentiation of keratoconus (KC) eyes from normal eyes using a Scheimpflug camera system tomography. SETTING: Marmara University Hospital, Istanbul, Turkey and Birinci Eye Hospital, Istanbul, Turkey. DESIGN: Retrospective case-control study. METHODS: The study included 624 keratoconus eyes and 512 healthy eyes. Thirty nine significant parameters obtained from the Scheimpflug imaging system (Pentacam-Oculus Optikgerate GmbH, Wetzlar, Germany) were studied. The cut-off value and area under receiver operating characteristic (AUROC) curve analysis for each studied parameter were established in the previous study. Minus three and plus three standard deviations of the cut-off value were scored after multiplication of AUROC for each parameter. The sum of all scores (TKS; Total Keratoconus Score) was compared between keratoconus and normal eyes. RESULTS: Average TKS value was -29.57+/-5.65 (Range from -43.11 to -7.09) in normal eyes and 36.23+/-24.3 (Range from -16.82 to 97.45) in keratoconus eyes (p<0.001). Receiver operating characteristic curve analyses showed perfect predictive accuracy for TKS (ROC 1.0 (95% CI: 0.999-1.0)). The TKS distinguished the keratoconus group from the normal group with 99% sensitivity and 99% specificity at the best cut-off point of -12.45. CONCLUSIONS: The new scoring system measured by the Scheimpflug imaging system provides perfect discrimination of keratoconus from normal corneas. PMID- 27478054 TI - Influence and management of diabetes mellitus in patients with heart failure with reduced ejection fraction. PMID- 27478055 TI - Respiratory syncytial virus infection in adults diagnosed in Valencian Region of Spain. PMID- 27478056 TI - Encumbered by vulnerability and temporality - the meanings of trigger situations when learning to live with diabetes. AB - AIMS AND OBJECTIVES: The aim of the study was to illuminate the meanings of trigger situations experienced in everyday life when learning to live with diabetes. BACKGROUND: Adults become active learners when faced with situations they do not know how to manage, triggering a need to understand something in a different way than before. Knowing more about experiential learning for persons living with diabetes is important for understanding how learning can be supported by health care. DESIGN: A life-world approach with a phenomenological hermeneutical method, inspired by the philosophy of Paul Ricoeur. METHODS: This method was used for interpreting transcriptions of interviews and consists of three stages: naive understanding, structural analysis and a comprehensive understanding. Participants (n = 13), with either type I or type II diabetes, were interviewed on three different occasions over a three-year period after being diagnosed with diabetes. RESULTS: When learning to live with diabetes, the meanings of trigger situations were described as 'the unpredictable body heightens insecurity with awareness of one's own dependability', 'losing control in unsustainable situations' and 'encumbered by vulnerability and temporality in earlier familiar situations'. CONCLUSION: The meanings of trigger situations were to lose the smooth, unreflected way of managing an everyday life situation, interlaced with feelings of lost control of how to live with new insights of being vulnerable. Trigger situations meant an opportunity for learning, as well as being demanding, unplanned and with limited freedom of choice. Trigger situations presented life and body as unpredictable. RELEVANCE TO CLINICAL PRACTICE: If healthcare professionals can identify the worries and questions raised in trigger situations, knowledge gaps can be identified and reflected on to stimulate learning. PMID- 27478057 TI - Stakeholder Experiences in a Stepped Collaborative Care Study Within U.S. Army Clinics. AB - OBJECTIVE: This article examines stakeholder experiences with integrating treatment for posttraumatic stress disorder (PTSD) and depression within primary care clinics in the U.S. Army, the use-of-care facilitation to improve treatment, and the specific therapeutic tools used within the Stepped Treatment Enhanced PTSD Services Using Primary Care study. METHODS: We conducted a series of qualitative interviews with health care providers, care facilitators, and patients within the context of a large randomized controlled trial being conducted across 18 Army primary care clinics at 6 military installations. RESULTS: Most of stakeholders' concerns clustered around the need to improve collaborative care tools and care facilitators and providers' comfort and abilities to treat behavioral health issues in the primary care setting. CONCLUSIONS: Although stakeholders generally recognize the value of collaborative care in overcoming barriers to care, their perspectives about the utility of different tools varied. The extent to which collaborative care mechanisms are well understood, navigated, and implemented by providers, care facilitators, and patients is critical to the success of the model. Improving the design of the web based therapy tools, increasing the frequency of team meetings and case presentations, and expanding training for primary care providers on screening and treatment for PTSD and depression and the collaborative care model's structure, processes, and offerings may improve stakeholder perceptions and usage of collaborative care. PMID- 27478058 TI - The late-presenting HIV-infected patient 30 years after the introduction of HIV testing: spectrum of opportunistic diseases and missed opportunities for early diagnosis. AB - OBJECTIVES: The aim of the study was to describe the characteristics of HIV infected late presenters, opportunistic diseases at diagnosis and missed opportunities to diagnose HIV infection earlier. METHODS: In a retrospective cohort study, we reviewed the medical records of all adults with newly diagnosed HIV infection admitted to the Department of Infectious Diseases of the Vivantes Auguste-Viktoria Hospital, Berlin, Germany. RESULTS: In the 5-year period from 2009 to 2013, 270 late presenters were identified. The most common AIDS-defining conditions were oesophageal candidiasis (n = 136; 51%), wasting syndrome (n = 106; 40%) and pneumocystis pneumonia (n = 91; 34%). Fifty-five patients (21%) had presented with at least one HIV indicator condition on prior contact with health care services without being offered testing for HIV. Female patients and heterosexual men [not men who have sex with men ('non-MSM')] had a significantly higher chance of being among patients previously presenting with indicator conditions and not being tested [odds ratio (OR) 4.7; 95% confidence interval (CI) 2.2-10.0; P < 0.001; and OR 2.4; 95% CI 1.2-5.1; P < 0.01, respectively]. The most commonly missed indicator conditions were leucocytopenia (n = 13; 24%), thrombocytopenia (n = 12; 22%), oral candidiasis (n = 9; 16%), unexplained weight loss (n = 7; 13%), herpes zoster (n = 5; 9%) and cervical dysplasia/cancer (n = 4; 20% of women). The median time between presentation with an indicator condition and the diagnosis of HIV infection was 158.5 days [interquartile range (IQR) 40-572 days]. Patients with oral candidiasis and unexplained weight loss had the shortest time between the "missed opportunity" and the diagnosis of HIV infection. Fifty-five hospital admissions with a total cost of over EUR 500 000 and - most importantly - six in-hospital deaths might have been prevented if HIV testing had been performed in patients with documented indicator conditions. CONCLUSIONS: Indicator conditions are still missed by clinicians. Women and 'non MSM' are at highest risk of presenting with an indicator condition but not being tested for HIV infection. PMID- 27478059 TI - Introduction. PMID- 27478060 TI - Ensembles of Deep Learning Architectures for the Early Diagnosis of the Alzheimer's Disease. AB - Computer Aided Diagnosis (CAD) constitutes an important tool for the early diagnosis of Alzheimer's Disease (AD), which, in turn, allows the application of treatments that can be simpler and more likely to be effective. This paper explores the construction of classification methods based on deep learning architectures applied on brain regions defined by the Automated Anatomical Labeling (AAL). Gray Matter (GM) images from each brain area have been split into 3D patches according to the regions defined by the AAL atlas and these patches are used to train different deep belief networks. An ensemble of deep belief networks is then composed where the final prediction is determined by a voting scheme. Two deep learning based structures and four different voting schemes are implemented and compared, giving as a result a potent classification architecture where discriminative features are computed in an unsupervised fashion. The resulting method has been evaluated using a large dataset from the Alzheimer's disease Neuroimaging Initiative (ADNI). Classification results assessed by cross validation prove that the proposed method is not only valid for differentiate between controls (NC) and AD images, but it also provides good performances when tested for the more challenging case of classifying Mild Cognitive Impairment (MCI) Subjects. In particular, the classification architecture provides accuracy values up to 0.90 and AUC of 0.95 for NC/AD classification, 0.84 and AUC of 0.91 for stable MCI/AD classification and 0.83 and AUC of 0.95 for NC/MCI converters classification. PMID- 27478061 TI - Serotonin neuron abnormalities in the BTBR mouse model of autism. AB - The inbred mouse strain BTBR T+ Itpr3tf /J (BTBR) is studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. Autism Res 2017, 10: 66-77. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27478062 TI - Baicalin increases developmental competence of mouse embryos in vitro by inhibiting cellular apoptosis and modulating HSP70 and DNMT expression. AB - Scutellaria baicalensis has been effectively used in Chinese traditional medicine to prevent miscarriages. However, little information is available on its mechanism of action. This study is designed specifically to reveal how baicalin, the main effective ingredient of S. baicalensis, improves developmental competence of embryos in vitro, using the mouse as a model. Mouse pronuclear embryos were cultured in KSOM medium supplemented with (0, 2, 4 and 8 MUg/ml) baicalin. The results demonstrated that in vitro culture conditions significantly decreased the blastocyst developmental rate and blastocyst quality, possibly due to increased cellular stress and apoptosis. Baicalin (4 ug/ml) significantly increased 2- and 4-cell cleavage rates, morula developmental rate, and blastocyst developmental rate and cell number of in vitro-cultured mouse embryos. Moreover, baicalin increased the expression of Gja1, Cdh1, Bcl-2, and Dnmt3a genes, decreased the expression of Dnmt1 gene, and decreased cellular stress and apoptosis as it decreased the expression of HSP70, CASP3, and BAX and increased BCL-2 expression in blastocysts cultured in vitro. In conclusion, baicalin improves developmental competence of in vitro-cultured mouse embryos through inhibition of cellular apoptosis and HSP70 expression, and improvement of DNA methylation. PMID- 27478064 TI - Nuclear translocation of PKCalpha isoenzyme is involved in neurogenic commitment of human neural crest-derived periodontal ligament stem cells. AB - Stem cells isolated from human adult tissue niche represent a promising source for neural differentiation. Human Periodontal Ligament Stem Cells (hPDLSCs) originating from the neural crest are particularly suitable for induction of neural commitment. In this study, under xeno-free culture conditions, in undifferentiated hPDLSCs and in hPDLSCs induced to neuronal differentiation by basic Fibroblast Growth Factor, the level of some neural markers have been analyzed. The hPDLSCs spontaneously express Nestin, a neural progenitor marker. In these cells, the neurogenic process induced to rearrange the cytoskeleton, form neurospheres and express higher levels of Nestin and Tyrosine Hydroxylase, indicating neural induction. Protein Kinase C (PKC) is highly expressed in neural tissue and has a key role in neuronal functions. In particular the Ca(2+) and diacylglycerol-dependent activation of PKCalpha isozyme is involved in the regulation of neuronal differentiation. Another main component of the pathways controlling neuronal differentiation is the Growth Associated Protein-43 (GAP 43), whose activity is strictly regulated by PKC. The aim of this study is to investigate the role of PKCalpha/GAP-43 nuclear signal transduction pathway during neuronal commitment of hPDLSCs. During hPDLSCs neurogenic commitment the levels of p-PKC and p-GAP-43 increased both in cytoplasmic and nuclear compartment. PKCalpha nuclear translocation induced GAP-43 movement to the cytoplasm, where it is known to regulate growth cone dynamics and neuronal differentiation. Moreover, the degree of cytosolic Ca(2+) mobilization appeared to be more pronounced in differentiated hPDLSCs than in undifferentiated cells. This study provides evidences of a new PKCalpha/GAP-43 nuclear signalling pathway that controls neuronal differentiation in hPDLSCs, leading the way to a potential use of these cells in cell-based therapy in neurodegenerative diseases. PMID- 27478063 TI - The roles of kisspeptin revisited: inside and outside the hypothalamus. AB - Kisspeptin, encoded by KISS1/Kiss1 gene, is now considered a master regulator of reproductive functions in mammals owing to its involvement in the direct activation of gonadotropin-releasing hormone (GnRH) neurons after binding to its cognate receptor, GPR54. Ever since the discovery of kisspeptin, intensive studies on hypothalamic expression of KISS1/Kiss1 and on physiological roles of hypothalamic kisspeptin neurons have provided clues as to how the brain controls sexual maturation at the onset of puberty and subsequent reproductive performance in mammals. Additionally, emerging evidence indicates the potential involvement of extra-hypothalamic kisspeptin in reproductive functions. Here, we summarize data regarding kisspeptin inside and outside the hypothalamus and revisit the physiological roles of central and peripheral kisspeptins in the reproductive functions of mammals. PMID- 27478065 TI - APPL1 promotes glucose uptake in response to mechanical stretch via the PKCzeta non-muscle myosin IIa pathway in C2C12 myotubes. AB - Expression of adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1 (APPL1) promoted glucose transporter 4 (GLUT4) translocation and glucose uptake in adipose and muscle tissues in response to stimulation with insulin, adiponectin, or exercise. In response to mechanical stretch, knockdown of APPL1 in C2C12 myotubes suppressed glucose uptake. APPL1-induced increased glucose uptake was mediated by protein kinase C (PKC) zeta but not AKT, AMPK, or calmodulin-dependent protein kinase. In myotubes overexpressing APPL1, PKCzeta was phosphorylated and translocated to the plasma membrane (PM) in response to mechanical stretch. Phosphorylated PKCzeta co immunoprecipitated with protein phosphatase 2A (PP2A) under basal conditions, but dissociated upon myotube stretching. Moreover, stretch-induced phosphorylated PKCzeta co-immunoprecipitated with non-muscle myosin IIa. Blebbistatin, an inhibitor of myosin II ATPase activity, suppressed APPL1-mediated stretch-induced glucose uptake and PKCzeta translocation. Taken together these data demonstrate that in response to mechanical stretch, APPL1 enhances glucose uptake by modulating the activation and localization of PKCzeta, as well as its functional interaction with both PP2A and myosin IIa. These findings support a new function for non-muscle myosin IIa in differentiated myotubes. PMID- 27478066 TI - Do Innate Immune Gene Variations Contribute to Susceptibility and Severity of Pneumococcal Meningitis? PMID- 27478067 TI - The distally based, venous supercharged anterolateral thigh flap. PMID- 27478069 TI - Intermittent Capture of the Left Bundle With Permanent His Bundle Pacing: Mechanistic Insights and Implications for an Emerging Field. AB - We present a case of a patient with elevated His lead capture thresholds and intermittent recruitment of the left bundle. The patient underwent a noninvasive electrophysiology study and was determined to have a left bundle branch block due to postrepolarization refractoriness. The nature of bundle branch block can have important implications for optimal patient selection and device programming in the emerging field of His bundle pacing. PMID- 27478068 TI - Sequencing Structural Variants in Cancer for Precision Therapeutics. AB - The identification of mutations that guide therapy selection for patients with cancer is now routine in many clinical centres. The majority of assays used for solid tumour profiling use DNA sequencing to interrogate somatic point mutations because they are relatively easy to identify and interpret. Many cancers, however, including high-grade serous ovarian, oesophageal, and small-cell lung cancer, are driven by somatic structural variants that are not measured by these assays. Therefore, there is currently an unmet need for clinical assays that can cheaply and rapidly profile structural variants in solid tumours. In this review we survey the landscape of 'actionable' structural variants in cancer and identify promising detection strategies based on massively-parallel sequencing. PMID- 27478070 TI - A proteomic approach to compare saliva from individuals with and without oral leukoplakia. AB - BACKGROUND: Oral leukoplakia is the most common potentially malignant disorder in the oral cavity and can precede carcinoma. This study aimed to identify possible oral leukoplakia salivary biomarkers. METHODS: Unstimulated saliva was collected from participants and protein concentration was determined. Proteins were then precipitated with cold acetone and separated using 2DE over a pH range of 3-10. Spot demarcation and matching were performed and protein identification was done through MS analysis. Oral leukoplakia tissues were submitted to immunohistochemistry analysis for keratin 10 (CK10). A complementary analysis of oral leukoplakias that were not included previously was performed in addition. RESULTS: 226+/-10 spots were identified in oral leukoplakia 2DE gels, and 262+/ 12 spots were identified in volunteers. Twenty-two spots were highly abundant in oral leukoplakias or not detected in the control group, such as apolipoprotein A1, alpha amylase, cystatins, keratin 10, and lysozyme precursor. All were identified. All oral leukoplakia cases were immunopositive for CK10, mainly in the superficial epithelial layers. CONCLUSIONS: The 2DE salivary protein profiles of individuals with and without oral leukoplakia were observably different. CK10 appears to be an interesting protein and should be further studied in oral carcinogenesis. SIGNIFICANCE: MS-based proteomics enables large-scale analysis of proteins. Proteomics can provide detailed descriptions of proteomes of cells and tissues, including body fluids, and appears as a powerful tool to study human disorders. Saliva is readily accessible through non invasive collection and can mirror diverse disease states. Saliva from both diseased and healthy subjects can be analyzed through 2DE and differences between groups could be found. Routine immunohistochemistry analysis confirmed one of these findings, with CK10 being positive tissues from individuals with oral leukoplakia. Therefore, the present study allows insights into development of an important potential oral cancer precursor, named oral leukoplakia. However, the results can be extrapolated and tested in other precancer states, such as proliferative verrucous leukoplakia, patients at risk of oral cancer due to lifestyle behavior and/or cancer history in the family or even those who are under surveillance after a treated primary oral cancer. PMID- 27478071 TI - Secretome profiling of apheresis platelet supernatants during routine storage via antibody-based microarray. AB - : Platelet storage lesions (PSLs) occur during platelet concentrate (PC) storage. Adverse transfusion reactions (ATRs) have been demonstrated to be more frequent in older PCs and removal of the supernatant prior to transfusion reduces their occurrence. Proteomic profiling of PC supernatants was thus performed to identify proteins associated with PSLs and ATRs. Twenty-four PCs were investigated daily from day 0 to day 9 for platelet pre-activation (PPA), platelet-derived extracellular vesicles (PEVs), and platelet function. Using antibody microarrays, 673 extracellular proteins were analysed in PC supernatants on days 0, 3, 5, 7, and 9. During 5days of storage, PPA and PEVs continuously increased (P<0.0001). Platelet function was observed to remain stable within the first 5days (P=0.1751) and decreased thereafter. Comparison of all time points to day 0 revealed the identification of 136 proteins that were significantly changed in abundance during storage, of which 72 were expressed by platelets. Network analysis identified these proteins to be predominantly associated with exosomes (P=4.61*10 8, n=45 genes) and two clusters with distinct functions were found with one being associated with haemostasis and the other with RNA binding. These findings may provide an explanation for ATRs. SIGNIFICANCE: Changes in platelet concentrate (PC) supernatants during storage have been so far only poorly addressed and high abundant proteins burden the identification of quantitative changes in the secretome. We applied a high-throughput antibody microarray allowing for the sensitive quantification of 673 extracellular factors. PCs account for the highest number of adverse transfusion reactions (ATRs). ATRs have been demonstrated to be more frequent in older PCs and removal of the supernatant prior to transfusion reduces their occurrence. Comprehensive interpretation of the changing proteins in the secretome during platelet storage under blood banking conditions may help to identify mechanisms leading to the occurrence of adverse transfusion reactions. PMID- 27478072 TI - Baltic lineage of tick-borne encephalitis virus: A putative evolutionary pathway. AB - Tick-borne encephalitis virus (TBEV) is transmitted by ixodid ticks and has three subtypes. The most genetically heterogeneous and widely distributed is the Siberian subtype which is subdivided into two main phylogenetic lineages, Asian (TBEV-SibAsia) and Baltic (TBEV-SibBaltic). According to the hypothesis of quantum evolution of TBEV (Kovalev et al., 2014b), TBEV-SibAsia originated about 370 years ago in Siberia, but the question concerning the time and place of origin of TBEV-SibBaltic is still to be solved. In the present paper, the sequences of a gene E fragment of 20 newly obtained TBEV-SibBaltic strains and 164 sequences of TBEV-SibBaltic from GenBank were analysed. The clusteron approach applied to TBEV-SibBaltic allowed the identification of three new clusterons. We revealed three clades of TBEV-SibBaltic, each characterized by a certain geographical distribution, and estimated their evolutionary ages. The oldest clade was Balt I, which presumably originated in North-West Russia and the Baltic countries about 300 years ago as a result of human activity, and then gave rise to the other clades in the Urals and West Siberia. The European subtype of TBEV and TBEV-SibBaltic may have originated simultaneously from the clusteron founder 3A of TBEV-SibAsia, the former through the adaptation of the virus to Ixodes ricinus, the latter - to a European subpopulation of Ixodes persulcatus. The use of the clusteron approach complemented with the results of phylogenetic analysis, data on the geographical distribution of the virus, the population structure of ticks, and the historical evidence allow us to estimate evolutionary pathways of the subtypes and phylogenetic lineages of TBEV. PMID- 27478073 TI - Dual phase high-temperature membranes for CO2 separation - performance assessment in post- and pre-combustion processes. AB - Dual phase membranes are highly CO2-selective membranes with an operating temperature above 400 degrees C. The focus of this work is to quantify the potential of dual phase membranes in pre- and post-combustion CO2 capture processes. The process evaluations show that the dual phase membranes integrated with an NGCC power plant for CO2 capture are not competitive with the MEA process for post-combustion capture. However, dual phase membrane concepts outperform the reference Selexol technology for pre-combustion CO2 capture in an IGCC process. The two processes evaluated in this work, post-combustion NGCC and pre-combustion IGCC, represent extremes in CO2 partial pressure fed to the separation unit. Based on the evaluations it is expected that dual phase membranes could be competitive for post-combustion capture from a pulverized coal fired power plant (PCC) and pre-combustion capture from an Integrated Reforming Cycle (IRCC). PMID- 27478074 TI - Cancer survivors and return to work: current knowledge and future research. PMID- 27478075 TI - Neuraminidase enhances in vitro expansion of human erythroid progenitors. AB - In spite of recent key improvements, in vitro mass production of erythrocytes from human stem cells is still limited by difficulties in obtaining sufficient numbers of erythroid progenitors. In fact, such progenitors are as scarce in the bone marrow as in peripheral blood. We used a two-step culture model of human cord blood-derived erythroid progenitors in the presence or absence of high purity neuraminidase, in a serum-free, defined culture medium. Granulocytic and megakaryocytic progenitor cell expansions were also studied. We show that significant enhancement of erythroid cell generation is obtained when CD34(+) human hematopoietic progenitors are cultured in the presence of neuraminidase. Interestingly, in so doing, expanded red cell progenitors remained erythropoietin dependent for further expansion and survival, and cells thus generated displayed a normal phenotype. Moreover, the activity of neuraminidase on these cells can be reversed by simple cell washing. Finally, growth of cells of the other myeloid lineages (granulocytes and megakaryocytes) is either decreased or unchanged in the presence of neuraminidase. This specific feature of neuraminidase, that of stimulation of human red cell progenitor proliferation, provides a safe technique for producing greater numbers of in vitro-generated red blood cells for both basic research and transfusion use. PMID- 27478076 TI - Effect of pro-inflammatory interleukin-17A on epithelial cell phenotype inversion in HK-2 cells in vitro. AB - Renal interstitial fibrosis (RIF) is a pathological change common to a variety of chronic renal diseases, ultimately progressing to end-stage renal failure. It is believed that epithelial cell phenotype inversion plays an important role in RIF, which is characterized by expression of the mesenchymal maker alpha-SMA, loss of the epithelial maker E-cadherin, and enhanced secretion of extracellular matrix. IL-17, a newly discovered pro-inflammatory cytokine, has recently been reported to play an important role in tissue fibrosis, involving pulmonary, liver, intestine and skin tissues. This study aimed to investigate whether IL-17A, a member of the IL-17 family, can induce epithelial cell phenotype inversion, and to explore the molecular mechanism of this phenotype inversion, in vitro. HK-2 cells were cultured and incubated with IL-17A. Cell proliferation was measured by CCK-8 assay, and the secretion of types I and III collagen was detected by ELISA in dose-dependent and time-dependent experiments. To find out whether IL-17A can induce epithelial cell phenotype inversion, HK-2 cells were stimulated with 80 ng/mL of IL-17A and 10 ng/mL of TGF-beta1 as a positive control, for 72 h. To explore the potential signaling pathway, anti-TGF-beta1 antibody was added before IL-17A treatment. At the same time, anti-TGF-beta1 antibody alone was added to the medium as the negative control group. The expression of types I and III collagen, alpha-SMA and E-cadherin proteins, and mRNA was measured by real-time PCR, western blotting and immuno-histochemistry. IL-17A promoted the proliferation of HK-2 cells and secretion of types I and III collagen in a dose dependent and time-dependent manner. Compared with the normal control, IL-17A could stimulate the expression of alpha-SMA, types I and III collagen, and suppressed the expression of E-cadherin in HK-2 cells. Incubation of IL-17A with TGF-beta1 antibody decreased significantly the expression of alpha-SMA, but increased the expression of E-cadherin in HK-2 cells. Our results suggest that IL 17A might promote the proliferation of HK-2 cells and secretion of extracellular matrix, and induce epithelial cell phenotype inversion via a TGF-beta1-dependent pathway. Blocking the pro-inflammatory cytokine IL-17A might be a potential target for the treatment of fibrotic kidney disease. PMID- 27478077 TI - The role of CXCR3 and its ligands in renal transplant outcome. AB - Chemokines and their corresponding receptors serve as pro-inflammatory and migratory signals for immune cells. CXCR3 and its corresponding ligands, CXCL9, CXCL10 and CXCL11, participate in the induction of immune responses against several foreign antigens. Numerous cells, including macrophages, NK cells and T lymphocytes, express CXCR3 and thus, expression of the receptor and its ligands can induce activity of these important immune cells against foreign antigens, including allogeneic grafts. Several parameters of the immune system participate in the induction and stimulation of powerful immune responses against allogeneic grafts. A thorough understanding of the parameters that regulate these responses can provide insights into new methods for immunotherapy during organ transplantation. The aim of this review is to address the most recent information regarding the roles played by CXCR3 and its corresponding ligands in the outcome of renal transplantation. PMID- 27478078 TI - Experimental colitis in rats induces de novo synthesis of cytokines at distant intestinal sites: role of capsaicin-sensitive primary afferent fibers. AB - Increased levels of pro- and anti-inflammatory cytokines were observed in various segments of histologically-intact small intestine in animal models of acute and chronic colitis. Whether these cytokines are produced locally or spread from the inflamed colon is not known. In addition, the role of gut innervation in this upregulation is not fully understood. To examine whether cytokines are produced de novo in the small intestine in two rat models of colitis; and to investigate the role of capsaicin-sensitive primary afferents in the synthesis of these inflammatory cytokines. Colitis was induced by rectal instillation of iodoacetamide (IA) or trinitrobenzene sulphonic acid (TNBS) in adult Sprague Dawley rats. Using reverse transcriptase (RT) and real-time PCR, TNF-alpha, and IL-10 mRNA expression was measured in mucosal scrapings of the duodenum, jejunum, ileum and colon at different time intervals after induction of colitis. Capsaicin sensitive primary afferents (CSPA) were ablated using subcutaneous injections of capsaicin at time 0, 8 and 32 h, and the experiment was repeated at specific time intervals to detect any effect on cytokines expression. TNF-alpha mRNA expression increased by 3-40 times in the different intestinal segments (p<0.05 to p<0.001), 48h after IA-induced colitis. CSPA ablation completely inhibited this upregulation in the small intestine, but not in the colon. Similar results were obtained in TNBS-induced colitis at 24 h. Intestinal IL-10 mRNA expression significantly decreased at 12 h and then increased by 6-43 times (p<0.05 to p<0.001) 48h after IA administration. This increase was abolished in rats subjected to CSPA ablation except in the colon, where IL-10 further increased by twice (p<0.05). In the TNBS group, there was 4-12- and 4-7-fold increases in small intestinal IL-10 mRNA expression at 1 and 21 days after colitis induction, respectively (both p<0.01). This increase was not observed in rats pretreated with capsaicin. Capsaicin-treated and untreated rats had comparable visual ulcer scores after colitis induction. Inflammatory cytokines are produced de novo in distant intestinal segments in colitis. CSPA fibers play a key role in the upregulation of this synthesis. PMID- 27478079 TI - The effect of 1,25-dihydroxyvitamin D3 on TSLP, IL-33 and IL-25 expression in respiratory epithelium. AB - Airway epithelium is an active and important component of the immunological response in the pathophysiology of obstructive lung diseases. Recent studies suggest an important role for vitamin D3 in asthma severity and treatment response. Our study evaluated the influence of an active form of vitamin D3 on the expression of selected mediators of allergic inflammation in the respiratory epithelium. Primary nasal and bronchial epithelial cells were exposed to1,25D3 for 1 hour and were then stimulated or not with IL-4, TNF-alpha, LPS, and poly I:C. After 24 hours TSLP, IL-33, and IL-25 protein levels were measured in culture supernatants using ELISA and mRNA levels in cells by real time PCR. 1,25D3 increased TSLP concentration in unstimulated nasal epithelial cells, but did not influence IL-33 and IL-25 expression. In IL-4-stimulated epithelial cell cultures 1,25D3 mostly inhibited TSLP and IL-33 expression. In LPS-treated cultures 1,25D3 decreased IL-33 expression. Simultaneously 1,25D3 augmented IL-25 production in the same model of stimulation. Our study revealed the dual nature of vitamin D3 manifested in both pro- and anti-inflammatory properties observed in airway epithelial cells. PMID- 27478080 TI - Patients with severe accidental tetanus admitted to an intensive care unit in Northeastern Brazil: clinical-epidemiological profile and risk factors for mortality. AB - INTRODUCTION: Tetanus, an acute infectious disease, is highly prevalent worldwide, especially in developing countries. Due to respiratory failure and hemodynamic instability associated with dysautonomia, severe cases require intensive care, but little has been published regarding the management in the Intensive Care Unit. OBJECTIVE: To draw a 10-year clinical-epidemiological profile of Intensive Care Unit patients with severe tetanus, observe their evolution in the Intensive Care Unit and identify risk factors for mortality. METHODS: In this retrospective study, we used a standardized questionnaire to collect information from the records of patients with severe tetanus admitted to the intensive care unit of a referral hospital for infectious and contagious diseases in Northeastern Brazil. RESULTS: The initial sample included 144 patients, of whom 29 were excluded due to incomplete information, leaving a cohort of 115 subjects. The average age was 49.6+/-15.3 years, most patients had no (or incomplete) vaccination against tetanus, and most were male. The main intensive care-related complications were pneumonia (84.8%) and dysautonomia (69.7%). Mortality (44.5%) was higher than expected from the mean APACHE II score (11.8), with shock/multiple organ failure as the main cause of death (72.9%). The independent factors most predictive of mortality were APACHE II score, dysautonomia, continuous neuromuscular blockade and age. CONCLUSION: A high mortality rate was observed in our cohort of Intensive Care Unit patients with severe tetanus and a number of risk factors for mortality were identified. Our results provide important insights for the development of intervention protocols capable of reducing complications and mortality in this patient population. PMID- 27478081 TI - Transition Metal Dichalcogenides: Morphological Engineering of CVD-Grown Transition Metal Dichalcogenides for Efficient Electrochemical Hydrogen Evolution (Adv. Mater. 29/2016). AB - On page 6207, Y. Zhang, Z. Liu and co-workers describe morphologically engineered 2D-MoS2 for the facilitation of efficient hydrogen evolution reaction. Two pathways to achieve such a purpose are highlighted, either by non-equilibrium growth of MoS2 dendrites or by high-density nucleation of MoS2 nanoflakes directly on the electrode materials. Future research directions are also proposed and discussed to further enhance the efficiency of such unique catalysts. PMID- 27478083 TI - Chemical Approaches to 2D Materials. AB - Chemistry plays an ever-increasing role in the production, functionalization, processing and applications of graphene and other 2D materials. This special issue highlights a selection of enlightening chemical approaches to 2D materials, which nicely reflect the breadth of the field and convey the excitement of the individuals involved in it, who are trying to translate graphene and related materials from the laboratory into a real, high-impact technology. PMID- 27478084 TI - Carbon Nanomembranes: Carbon Nanomembranes (Adv. Mater. 29/2016). AB - Carbon nanomembranes (CNMs), made by radiation-induced crosslinking of aromatic self-assembled monolayers, are described by A. Turchanin and A. Golzhauser on page 6075. The image shows a large-area CNM with a thickness of 1 nm, spanning a hexagonal metal grid. This is a microscopy image made by a novel imaging technique - helium-ion microscopy. PMID- 27478085 TI - Graphene Films: Synthesis of Graphene Films on Copper Foils by Chemical Vapor Deposition (Adv. Mater. 29/2016). AB - Synthesis of graphene films on copper foils is discussed by X. Li, L. Colombo, and R. S. Ruoff on page 6247. Graphene can grow on metal substrates by chemical vapor deposition of hydrocarbons. Hydrocarbons crack on a metal surface, nucleate, grow, and finally merge to form a continuous graphene film. Copper is one of the best candidates for graphene growth due to the advantages of good control over the graphene thickness, the growth of high-quality graphene, and the ease for graphene transfer, and has been widely used for production of large-area graphene films in both academia and industry. PMID- 27478087 TI - Phase separation driven by density-dependent movement: A novel mechanism for ecological patterns. AB - Many ecosystems develop strikingly regular spatial patterns because of small scale interactions between organisms, a process generally referred to as spatial self-organization. Self-organized spatial patterns are important determinants of the functioning of ecosystems, promoting the growth and survival of the involved organisms, and affecting the capacity of the organisms to cope with changing environmental conditions. The predominant explanation for self-organized pattern formation is spatial heterogeneity in establishment, growth and mortality, resulting from the self-organization processes. A number of recent studies, however, have revealed that movement of organisms can be an important driving process creating extensive spatial patterning in many ecosystems. Here, we review studies that detail movement-based pattern formation in contrasting ecological settings. Our review highlights that a common principle, where movement of organisms is density-dependent, explains observed spatial regular patterns in all of these studies. This principle, well known to physics as the Cahn-Hilliard principle of phase separation, has so-far remained unrecognized as a general mechanism for self-organized complexity in ecology. Using the examples presented in this paper, we explain how this movement principle can be discerned in ecological settings, and clarify how to test this mechanism experimentally. Our study highlights that animal movement, both in isolation and in unison with other processes, is an important mechanism for regular pattern formation in ecosystems. PMID- 27478088 TI - Neurologists cannot ignore global health issues. An initiative from young neurologists. PMID- 27478090 TI - Giant spontaneous exchange bias triggered by crossover of superspin glass in Sb doped Ni50Mn38Ga12 Heusler alloys. AB - A spontaneous exchange bias (SEB) discovered by Wang et al. [Phys. Rev. Lett. 106 (2011) 077203.] after zero-field cooling (ZFC) has attracted recent attention due to its interesting physics. In this letter, we report a giant SEB tuned by Sb doping in Ni50Mn38Ga12-xSbx Heusler alloys. Such an SEB was switched on below the blocking temperature of approximately 50 K. The maximum exchange bias HE can arrive at 2930 Oe in a Ni50Mn38Ga10Sb2 sample after ZFC to 2 K. Further studies showed that this SEB was attributable to interaction of superspin glass (SSG) and antiferromagnetic matix, which was triggered by the crossover of SSG from canonical spin glass to a cluster spin glass. Our results not only explain the underlying physics of SEB, but also provide a way to tune and control the SEB performance. PMID- 27478089 TI - Attenuation of transcriptional and signaling responses limits viability of rho(0)Saccharomyces cerevisiae during periods of glucose deprivation. AB - BACKGROUND: The maintenance of viability during periods when a glycolytic carbon source is limited (or absent) is a major obstacle for cells whose mitochondrial DNA (mtDNA) has been damaged or lost. METHODS: We utilized genome wide transcriptional profiling and in gel mobility analyses to examine the transcriptional response and characterize defects in the phosphorylation dependent signaling events that occur during acute glucose starvation in rho(0) cells that lack mtDNA. Genetic and pharmacological interventions were employed to clarify the contribution of nutrient responsive kinases to regulation of the transcription factors that displayed abnormal phosphoregulation in rho(0) cells. RESULTS: The transcriptional response to glucose deprivation is dampened but not blocked in rho(0) cells. Genes regulated by the transcription factors Mig1, Msn2, Gat1, and Ume6 were noticeably affected and phosphorylation of these factors in response to nutrient depletion is abnormal in rho(0) cells. Regulation of the nutrient responsive kinases PKA and Snf1 remains normal in rho(0) cells. The phosphorylation defect results from ATP depletion and loss of the activity of kinases including GSK3beta, Rim15, and Yak1. Interventions which rescue phosphoregulation of transcription factors bolster maintenance of viability in rho(0) cells during subsequent glucose deprivation. CONCLUSIONS: A subset of nutrient responsive kinases is especially sensitive to ATP levels and their misregulation may underlie regulatory defects presented by rho(0) cells. GENERAL SIGNIFICANCE: Abnormal regulation of mitochondrial function is implicated in numerous human disorders. This work illustrates that some signaling pathways are more sensitive than others to metabolic defects caused by mitochondrial dysfunction. PMID- 27478091 TI - Robust analysis of an underwater navigational strategy in electrically heterogeneous corridors. AB - Obstacles and other global stimuli provide relevant navigational cues to a weakly electric fish. In this work, robust analysis of a control strategy based on electrolocation for performing obstacle avoidance in electrically heterogeneous corridors is presented and validated. Static output feedback control is shown to achieve the desired goal of reflexive obstacle avoidance in such environments in simulation and experimentation. The proposed approach is computationally inexpensive and readily implementable on a small scale underwater vehicle, making underwater autonomous navigation feasible in real-time. PMID- 27478092 TI - Ensemble ecosystem modeling for predicting ecosystem response to predator reintroduction. AB - Introducing a new or extirpated species to an ecosystem is risky, and managers need quantitative methods that can predict the consequences for the recipient ecosystem. Proponents of keystone predator reintroductions commonly argue that the presence of the predator will restore ecosystem function, but this has not always been the case, and mathematical modeling has an important role to play in predicting how reintroductions will likely play out. We devised an ensemble modeling method that integrates species interaction networks and dynamic community simulations and used it to describe the range of plausible consequences of 2 keystone-predator reintroductions: wolves (Canis lupus) to Yellowstone National Park and dingoes (Canis dingo) to a national park in Australia. Although previous methods for predicting ecosystem responses to such interventions focused on predicting changes around a given equilibrium, we used Lotka-Volterra equations to predict changing abundances through time. We applied our method to interaction networks for wolves in Yellowstone National Park and for dingoes in Australia. Our model replicated the observed dynamics in Yellowstone National Park and produced a larger range of potential outcomes for the dingo network. However, we also found that changes in small vertebrates or invertebrates gave a good indication about the potential future state of the system. Our method allowed us to predict when the systems were far from equilibrium. Our results showed that the method can also be used to predict which species may increase or decrease following a reintroduction and can identify species that are important to monitor (i.e., species whose changes in abundance give extra insight into broad changes in the system). Ensemble ecosystem modeling can also be applied to assess the ecosystem-wide implications of other types of interventions including assisted migration, biocontrol, and invasive species eradication. PMID- 27478093 TI - Incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study. AB - OBJECTIVE: To assess whether quadrivalent human papillomavirus (qHPV) vaccination is associated with increased incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease. METHODS: This register-based open cohort study included all girls and women between 10 and 30 years of age in Sweden in 2006-2012 diagnosed with at least one of 49 prespecified autoimmune diseases (n = 70 265). Incidence rate ratios were estimated for new-onset autoimmune disease within 180 days of qHPV vaccination using Poisson regression adjusting for, country of birth, parental country of birth, parental income and parental education. RESULTS: A total of 70 265 girls and women had at least one of the 49 predefined autoimmune diseases; 16% of these individuals received at least one dose of qHPV vaccine. In unvaccinated girls and women, 5428 new-onset autoimmune diseases were observed during 245 807 person-years at a rate of 22.1 (95% CI 21.5-22.7) new events per 1000 person-years. In vaccinated girls and women, there were 124 new events during 7848 person-years at a rate of 15.8 (95% CI 13.2-18.8) per 1000 person-years. There was no increase in the incidence of new-onset autoimmune disease associated with qHPV vaccination during the risk period; on the contrary, we found a slightly reduced risk (incidence rate ratio 0.77, 95% CI 0.65-0.93). CONCLUSION: In this nationwide study, qHPV vaccination was not associated with increased incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease. PMID- 27478095 TI - Recent advances in phytochemistry and pharmacology of C21 steroid constituents from Cynanchum plants. AB - Cynanchum is one of the most important genera in Asclepiadaceae family, which has long been known for its therapeutic effects. In this genus, 16 species are of high medicinal value. The extracts of the root and/or rhizome parts have been applied in traditional Chinese medicines (TCM) for the prevention and treatment of various illnesses for centuries. C21 steroids, as the typical constituents of Cynanchum species, possess a variety of structures and pharmacological activities. This review summarizes the comprehensive information on phytochemistry and pharmacology of C21 steroid constituents from Cynanchum plants, based on reports published between 2007 and 2015. Our aim is to provide a rationale for their therapeutic application, and to discuss the future trends in research and development of these compounds. A total of 172 newly identified compounds are reviewed according to their structural classifications. Their in vitro and in vivo pharmacological studies are also reviewed and discussed, focusing on antitumor, antidepressant, antifungal, antitaging, Na(+)/K(+)-ATPase inhibitory, appetite suppressing and antiviral activities. Future research efforts should concentrate on in vitro and in vivo biological studies and structure activity relationship of various C21 steroid constituents. PMID- 27478094 TI - Systematic review of published Phase 3 data on anti-PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. AB - AIMS: Two anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, have been approved for the treatment of hypercholesterolaemia in certain patients. We reviewed data from Phase 3 studies to evaluate the efficacy and safety of these antibodies. METHODS: We systematically reviewed Phase 3 English-language studies in patients with hypercholesterolaemia, published between 1 January 2005 and 20 October 2015. Congress proceedings from 16 November 2012 to 16 November 2015 were also reviewed. RESULTS: We identified 12 studies of alirocumab and nine of evolocumab, including over 10 000 patients overall. Most studies enrolled patients with hypercholesterolaemia and used anti-PCSK9 antibodies with statins. The ODYSSEY FH I, FH II and HIGH FH alirocumab studies and the RUTHERFORD-2 evolocumab study exclusively recruited patients with heterozygous familial hypercholesterolaemia. Two evolocumab studies focused mainly on homozygous familial hypercholesterolaemia (HoFH): TESLA Part B and TAUSSIG (a TESLA sub-study); only those data for HoFH are reported here. All comparator studies demonstrated a reduction in LDL cholesterol (LDL-C) with the anti-PCSK9 antibodies. No head-to head studies were conducted between alirocumab and evolocumab. Up to 87% of patients receiving alirocumab and up to 98% receiving evolocumab reached LDL-C goals. Both antibodies were effective and well tolerated across a broad population of patients and in specific subgroups, such as those with type 2 diabetes. CONCLUSIONS: Using anti-PCSK9 antibodies as add-on therapy to other lipid-lowering treatments or as monotherapy for patients unable to tolerate statins may help patients with high cardiovascular risk to achieve their LDL-C goals. PMID- 27478096 TI - Anti-aging properties of Ribes fasciculatum in Caenorhabditis elegans. AB - The present study investigated the effects and underlying mechanism of ethylacetate fraction of Ribes fasciculatum (ERF) on the lifespan and stress tolerance using a Caenorhabditis elegans model. The longevity activity of ERF was determined by lifespan assay under normal culture condition. The survival rate of nematodes under various stress conditions was assessed to validate the effects of ERF on the stress tolerance. To determine the antioxidant potential of ERF, the superoxide dismutase (SOD) activities and intracellular reactive oxygen species (ROS) levels were investigated. The ERF-mediated change in SOD-3 expression was examined using GFP-expressing transgenic strain. The effects of ERF on the aging related factors were investigated by reproduction assay and pharyngeal pumping assay. The intestinal lipofuscin levels of aged nematodes were also measured. The mechanistic studies were performed using selected mutant strains. Our results indicated that ERF showed potent lifespan extension effects on the wild-type nematode under both normal and various stress conditions. The ERF treatment also enhanced the activity and expression of superoxide dismutase (SOD) and attenuated the intracellular ROS levels. Moreover, ERF-fed nematodes showed decreased lipofuscin accumulation, indicating ERF might affect age-associated changes in C. elegans. The results of mechanistic studies indicated that there was no significant lifespan extension in ERF-treated daf-2, age-1, sir-2.1, and daf-16 null mutants, suggesting that they were involved in ERF-mediated lifespan regulation. In conclusion, R. fasciculatum confers increased longevity and stress resistance in C. elegans via SIR-2.1-mediated DAF-16 activation, dependent on the insulin/IGF signaling pathway. PMID- 27478097 TI - Anti-neuro-inflammatory effects of Nardostachys chinensis in lipopolysaccharide and lipoteichoic acid-stimulated microglial cells. AB - Excessive microglial cell activation is related to the progression of chronic neuro-inflammatory disorders. Heme oxygenase-1 (HO-1) expression mediated by the NFE2-related factor (Nrf-2) pathway is a key regulator of neuro-inflammation. Nardostachys chinensis is used as an anti-malarial, anti-nociceptive, and neurotrophic treatment in traditional Asian medicines. In the present study, we examined the effects of an ethyl acetate extract of N. chinensis (EN) on the anti neuro-inflammatory effects mediated by HO-1 up-regulation in Salmonella lipopolysaccharide (LPS)- or Staphylococcus aureus lipoteichoic acid (LTA) stimulated BV2 microglial cells. Our results indicated that EN suppressed pro inflammatory cytokine production and induced HO-1 transcription and translation through Nrf-2/antioxidant response element (ARE) signaling. EN markedly inhibited LPS- and LTA-induced activation of nuclear factor-kappa B (NF-kappaB) as well as phosphorylation of mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT). Furthermore, EN protected hippocampal HT22 cells from indirect neuronal toxicity mediated by LPS- and LTA treated microglial cells. These results suggested that EN impairs LPS- and LTA induced neuro-inflammatory responses in microglial cells and confers protection against indirect neuronal damage to HT22 cells. In conclusion, our findings indicate that EN could be used as a natural anti-neuro-inflammatory and neuroprotective agent. PMID- 27478098 TI - Brazilein inhibits neuronal inflammation induced by cerebral ischemia and oxygen glucose deprivation through targeting NOD2 expression. AB - Brazilein is reported to have immunosuppressive effect on cardiovascular and cerebral-vascular diseases. The essential roles of innate immunity in cerebral ischemia are increasingly identified, but no studies concerning the influence of brazilein on the innate immunity receptors have been reported. The present study was designed to investigate the regulation of NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) by brazilein for its protection of neuron in cerebral ischemia in vivo and oxygen-glucose deprivation in vitro. The results showed that brazilein could reverse the elevated expression of NOD2 and TNFalpha (tumor necrosis factor alpha) elicited by cerebral ischemia and reperfusion. This reduction could also be detected in normal mice and C17.2 cells, indicating that this suppressive effect of brazilein was correlated with NOD2. The results from GFP reporter plasmid assay suggested brazilein inhibited NOD2 gene transcription. In conclusion, brazilein could attenuate NOD2 and TNFalpha expression in cerebral ischemia and NOD2 may be one possible target of brazilein for its immune suppressive effect in neuro-inflammation. PMID- 27478099 TI - Antagonistic effects of extracts from Artemisia rupetris L. and Leontopodium leontopodioides to CC chemokine receptor 2b (CCR2b). AB - The present study was designed to establish a suitable assay to explore CCR2b receptor antagonists from the natural products of Artemisia rupetris and Leontopodium leontopodioides. An aequorin assay was developed as a cell-based assay suitable for 384-well microplate and used for screening CCR2b receptor antagonists from natural products. Through establishing suitable conditions, the assay was shown to be suitable for screening of CCR2b receptor antagonists. Seven compounds were identified in preliminary screening. Five of them showed evident dose-response relationship in secondary screening. The structure-activity relationship study suggested that 7-position hydroxyl group of flavonoids was necessary, a polar group should be introduced on the 3-position, and the substituents on 2-position benzene ring of flavonoids have little influence on the potentency of the inhibition activity on CCR2b receptor. The ortho-position dihydroxyl structure in quinic acid compounds may be important. In conclusion, Compounds HR-1, 5, 7, and AR-20, 35 showed activity as antagonist of CCR2b receptor, which shed lights on the development of novel drugs as CCR2b receptor antagonists for preventing inflammation related diseases. PMID- 27478100 TI - A polysaccharide purified from Radix Adenophorae promotes cell activation and pro inflammatory cytokine production in murine RAW264.7 macrophages. AB - Radix Adenophorae, a traditional Chinese medicine, has been reported to have a variety of biological functions. In the present study, a polysaccharide component, Radix Adenophorae Polysaccharide (RAPS), was purified from Radix Adenophorae by decoloring with ADS-7 macroporous adsorption resin, DEAE-52 cellulose ion-exchange chromatography, and Sephacryl S-300HR gel chromatography, with the purity of 98.3% and a molecular weight of 1.8 * 10(4) Da. The cell viability assay and microscopic examination revealed that RAPS promoted the proliferation and activation of macrophages. At 400 MUg.mL(-1), RAPS stimulated RAW264.7 cell proliferation by 1.91-fold compared with the control. Meanwhile, RAPS significantly increased the secretion of pro-inflammatory cytokines (TNF alpha and IL-6) in a dose-dependent manner in the supernatant of RAW264.7 cell culture as determined by ELISA. At 400 MUg.mL(-1), the production of TNF-ialpha was 20.8-fold higher than that of the control. Simultaneously, the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS) were increased in RAW264.7 cells incubated with RAPS, as measured by Griess assay and Western blot analysis. The NO production of cells treated with RAPS (400 MUg.mL(-1)) reached 15.8 MUmol.L(-1), which was 30.4-fold higher than that of the control (0.53 MUmol.L(-1)). These data suggested that RAPS may enhance the immune function and protect against exogenous pathogens by activating macrophages. PMID- 27478101 TI - Triterpenoids from the roots of Rubus parvifolius. AB - Two new oleanane-type triterpenoids, parvifolactone A (1) and rubuside P (2), together with 11 known triterpenoids, fupenzic acid (3), 18,19-seco,2alpha,3alpha dihydroxyl-19-oxo-urs-11,13(18)-dien-28-oic acid (4), euscaphic acid (5), maslinic acid (6), 1beta- hydroxyeuscaphic acid (7), 2alpha,3alpha,19alpha,23 tetrahydroxyolean-12-en-28-oic acid (8), 2alpha,3beta,19alpha,23-tetrahydroxyurs 12-en-28-oic acid (9), glucosyl pinfaensate (10), rubuside J (11), 2alpha,3alpha,19alpha,23-tetrahydroxyurs-12-en-24,28-dioic acid (12), and 2alpha,3beta,19alpha- trihydroxyurs-12-en-23,28-dioic acid (13), were isolated from the roots of Rubus parvifolius. PMID- 27478102 TI - Synthesis and evaluation of benzylisoquinoline derivatives for their inhibition on pancreatic lipase and preadipocyte proliferation. AB - The present study was designed to synthesize and evaluate a series of benzylisoquinoline derivatives. These compounds were synthesized by Bischler Napieralski cyclization to yield 1-benzyl-3,4-dihydroisoquinolines, and the products were obtained by reductions. All these compounds were identified by MS, (1)H NMR and (13)C NMR. The inhibitory activities on pancreatic lipase and preadipocyte proliferation for the synthesized compounds and alkaloids from Nulembo nucifera were assessed in vitro. Most of the compounds showed inhibitory activities on both pancreatic lipase and preadipocyte proliferation. Particularly, compounds 7p-7u and 9d-9f exhibited significant inhibitory activity on pancreatic lipase while compounds 7c, 7d, 7f, 7g, 7i, and 7j potently inhibited the proliferation of 3T3-L1 preadipocytes. Our results provided a basis for future evaluation and development of these compounds as leads for therapeutics for human diseases. PMID- 27478103 TI - Integrating qualitative and quantitative characterization of Prunellae Spica by HPLC-QTOF/MS and HPLC-ELSD. AB - The present study was designed to analyze the major constituents in Prunellae Spica and establish a method for simultaneous determination of two constituents contained in Prunellae Spica. High performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC-QTOF-MS/MS) technique was used to identify the constituents in the extractive of Prunellae Spica. High performance liquid chromatography coupled with evaporative light scattering detection (HPLC-ELSD) was used to simultaneously quantify two kinds of constituents contained in Prunellae Spica. Principal component analysis (PCA) was applied to compare the similarity and difference among samples from different regions of China. In the present study, 22 compounds were identified and some new fragmental pathways of triterpenic acids were discovered. An accurate and reliable HPLC-ELSD method was developed and validated for the first time to simultaneously quantify multiple constituents, including rosmarinic acid, maslinic acid, corosolic acid, betulin, oleanolic acid, and ursolic acid in the extract of Prunellae Spica. (PCA) revealed some similarities and differences among different samples from different regions of China. In conclusion, our results from this study would be helpful in establishing a scientific and rational quality control method for Prunellae Spica. PMID- 27478104 TI - Effect of cartilaginous matrix components on the chondrogenesis and hypertrophy of mesenchymal stem cells in hyaluronic acid hydrogels. AB - The microenvironment of the extracellular matrix (ECM) plays a key role in directing the viability and subsequent differentiation of the encapsulated stem cells by the specific integration between the hydrated biomolecules and cell surface receptors. Herein, we developed a hydrogel platform based on hyaluronic acid (HA) that presents cartilage ECM molecules as a form of developmental cues. The hybrid hydrogels were generated by coupling photo-cross-linkable methacrylated HA (MeHA) with selected cartilaginous ECM molecules including chondroitin sulfate (CS) and type I collagen (Col I), and we studied the decoupled function of these cues in regulating the initial chondrogenesis, subsequent hypertrophy, and tissue mineralization by hMSCs. The results indicate upregulated mRNA expression of the chondrogenesis markers in the HA hydrogels that contain Col I or CS, and decreased expression of the hypertrophic markers compared with the control MeHA group. The quantification results also show that glycosaminoglycans accumulation increases in the hybrid hydrogels containing cartilaginous ECM molecules, both in vitro and in vivo. We hypothesize that these additional ECM components in the HA hydrogels further regulate the hMSCs chondrogenesis and hypertrophy by coordination. The understanding obtained in this study may guide biomaterial scaffold design, thereby facilitating manipulation of the differentiation and mineralization of induced hMSCs for application in the repair of different musculoskeletal defects. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2292-2300, 2017. PMID- 27478105 TI - Microwave assisted synthesis of tyrosine protected gold nanoparticles for dual (colorimetric and fluorimetric) detection of spermine and spermidine in biological samples. AB - In this work, tyrosine-protected gold nanoparticles (Tyr-Au NPs) were fabricated by one-step reduction of Au3+ ion using Tyr as a reducing and capping agent under microwave irradiation. The Tyr-Au NPs were successfully used as a dual probe for colorimetric and fluorescence turn-on assays of spermine and spermidine in biological samples. Upon addition of spermine and spermidine, the characteristic surface plasmon resonance (SPR) band of Tyr-Au NPs was red-shifted to 596 and 616nm and the emission peak (Tyr) at 410nm was gradually increased with increasing concentration of both analytes, confirming the aggregation of Tyr-Au NPs induced by spermine and spermidine, which results to restore fluorescence of Tyr on the surfaces of Au NPs. In addition, it shows high selectivity for sensitive detection of prostatic cancer biomarkers spermine and spermidine in real clinical applications with reduced sample preparations. PMID- 27478106 TI - Candida albicans colonisation, continence status and incontinence-associated dermatitis in the acute care setting: a pilot study. AB - Candida albicans is the most prevalent human fungal commensal organism and is reported to be the most frequent aetiological organism responsible for infection associated with incontinence-associated dermatitis. However, it remains unclear whether incontinence predisposes a patient to increased Candida colonisation or whether incontinence acts as a trigger for Candida infection in those already colonised. The purpose of this observational cross-sectional study was to estimate colonisation rates of C. albicans in continent, compared to incontinent patients, and patients with incontinence-associated dermatitis. Data were collected on 81 inpatients of a major Australian hospital and included a pelvic skin inspection and microbiological specimens to detect C. Albicans at hospital admission. The mean age of the sample was 76 years (SD = 12.22) with 53% being male. Incontinent participants (n = 53) had a non-significant trend towards greater Candida colonisation rates at the perianal site (43% versus 28%) chi2 (1, N = 81) = 4.453, p = .638 and the inguinal site (24% versus 14%) chi2 (1, N = 81) = 6.868, p = .258 compared to continent patients (n = 28). The incontinent subgroup with incontinence-associated dermatitis (n = 22) showed no difference in colonisation rates compared to those without incontinence-associated dermatitis. Understanding the epidemiology of colonisation may have implications for the prevention of Candida infection in these patients. PMID- 27478108 TI - An enzyme-responsive conjugate improves the delivery of a PI3K inhibitor to prostate cancer. AB - An enzyme-responsive peptide drug conjugate was developed for TGX-D1, a promising PI3K inhibitor for prostate cancer therapy. LNCaP-specific KYL peptide was used as the targeting ligand and the prostate specific antigen (PSA) cleavable peptide (SSKYQSL) was used as the enzyme-responsive linker. SSKYQSL is cleaved by recombinant human PSA at 10-250 MUg/mL. By contrast, the linker is stable in the serum of prostate cancer patients with high PSA levels (>500 ng/mL), indicating that this linker can survive the systemic circulation in prostate cancer patients but be cleaved in the tumor microenvironment. Cellular uptake of the peptide drug conjugate in prostate cancer cells is improved by about nine times. Biodistribution study reveals significant tumor accumulation of the peptide drug conjugate in nude mice bearing C4-2 tumor xenografts. Meanwhile, distribution of the conjugate in other major tissues is the same as the parent drug, indicating a high specificity of the conjugate to prostate cancers in vivo. PMID- 27478107 TI - Synthetic mimetics of the endogenous gastrointestinal nanomineral: Silent constructs that trap macromolecules for intracellular delivery. AB - Amorphous magnesium-substituted calcium phosphate (AMCP) nanoparticles (75-150nm) form constitutively in large numbers in the mammalian gut. Collective evidence indicates that they trap and deliver luminal macromolecules to mucosal antigen presenting cells (APCs) and facilitate gut immune homeostasis. Here, we report on a synthetic mimetic of the endogenous AMCP and show that it has marked capacity to trap macromolecules during formation. Macromolecular capture into AMCP involved incorporation as shown by STEM tomography of the synthetic AMCP particle with 5nm ultra-fine iron (III) oxohydroxide. In vitro, organic cargo-loaded synthetic AMCP was taken up by APCs and tracked to lysosomal compartments. The AMCP itself did not regulate any gene, or modify any gene regulation by its cargo, based upon whole genome transcriptomic analyses. We conclude that synthetic AMCP can efficiently trap macromolecules and deliver them to APCs in a silent fashion, and may thus represent a new platform for antigen delivery. PMID- 27478109 TI - Electrospray ionization mass spectrometric detection of low polar compounds by adding NaAuCl4. AB - Liquid chromatography electrospray ionization mass spectrometry (LC/ESI/MS) has been widely used for various analyses. However, it is difficult to use LC/ESI/MS for the analysis of low polar compounds, such as polycyclic aromatic hydrocarbons. It is well known that AuCl4- ion decomposes to AuCl3 by heating, and AuCl3 is a strong pi-electrophilic Lewis acid. Low polar compounds (pyrene, benzo[a]pyrene, perylene, benzo[ghi]perylene, dibenzothiophene and p dimethoxybenzene) were detected by ESI/MS in the positive ion mode by adding NaAuCl4 . The low polar compound interacts with AuCl3 formed at the ESI interface, and undergoes electron transfer to AuCl3 . The radical cation of the low polar compound was then detected by MS. In addition, the LC/ESI/MS determination of polycyclic aromatic hydrocarbons by the post-column addition of NaAuCl4 was studied. (c) 2016 The Authors Journal of Mass Spectrometry Published by John Wiley & Sons Ltd. PMID- 27478110 TI - Medication Persistence, Duration of Treatment, and Treatment-switching Patterns Among Canadian Patients Taking Once-daily Extended-release Methylphenidate Medications for Attention-Deficit/Hyperactivity Disorder: A Population-based Retrospective Cohort Study. AB - PURPOSE: We conducted a retrospective cohort study to compare medication use patterns of a long-acting extended-release methylphenidate (Osmotic Release Oral System [OROS((r))] methylphenidate, CONCERTA((r))) and Teva-methylphenidate (methylphenidate ER-C), a generic drug determined by the Canadian regulatory authority, Health Canada, to be bioequivalent to OROS((r)) methylphenidate. METHODS: We established an OROS((r)) methylphenidate-experienced and new-user population cohort to compare medication use patterns, including medication persistence, duration of therapy, and treatment-switching patterns. Multivariable log-binomial regression was used to adjust for confounders of the associations with persistence. FINDINGS: In the OROS((r)) methylphenidate-experienced cohort (n = 21,940), OROS((r)) methylphenidate was associated with a 70% higher rate of medication persistence at 12 months relative to methylphenidate ER-C (adjusted relative risk = 1.70; 95% CI, 1.64-1.77). In the new-user cohort (n = 20,410), OROS((r)) methylphenidate had a 58% higher rate of medication persistence relative to methylphenidate ER-C (adjusted relative risk = 1.58; 95% CI, 1.51 1.65). Median duration of therapy was significantly longer in patients taking OROS((r)) methylphenidate compared with those taking methylphenidate ER-C, and treatment-switching occurred significantly more frequently in patients taking methylphenidate ER-C compared with those taking OROS((r)) methylphenidate. IMPLICATIONS: Significant differences were observed in how the medications were used by patients in the real-world setting. Because the data sources were administrative databases, it was not possible to control for all potentially important confounding variables. Although differences in medication persistence may not directly reflect differences in treatment efficacy, the findings are important because these products are used interchangeably in a number of Canadian provinces. PMID- 27478111 TI - Opioid Use Among Metastatic Prostate Cancer Patients With Skeletal-related Events. AB - PURPOSE: The development of skeletal-related events (SREs) (pathologic fracture, need for surgery and/or radiation to bone, spinal cord compression, and hypercalcemia of malignancy) in metastatic prostate cancer (MPC) is associated with worsened pain and compromised quality of life. Opioids are frequently used throughout the course of SRE treatment. This study describes the treatment patterns and incremental use of opioids in MPC patients diagnosed with SREs. METHODS: PC patients with bone metastases newly diagnosed with an SRE between January 1, 2005, and September 30, 2014, were identified using MarketScan Commercial and Medicare databases. Included patients were aged >=40 years, had medical/pharmacy benefits for >=12 months before (preindex) and >=6 months after (postindex) diagnosis, and were without evidence of other primary cancers. Patients were categorized as nonusers of opioids (<10 days), short-term users (>=10 and <60 days), or long-term users (>=60 days) and further by SRE type. Opioid type, proportion of time on opioids, morphine-equivalent dose, adjuvant medications, and radiation use before and after SRE diagnosis were evaluated. FINDINGS: A total of 1071 eligible patients were identified (mean age, 71 years; 10.8% had chronic pain at baseline). The most common SRE types present were radiation (60.2%), radiation and bone surgery (15.0%), pathologic fracture (7.2%), and bone surgery (6.5%). Opioid use increased from 49.9% preindex to 53.3% postindex (P < 0.0001). The proportion of time on opioids doubled after SRE (pre, 0.3 vs post, 0.6; P < 0.0001). A greater percentage of patients used only opioids after an SRE (pre, 11.0%; post, 46.1% [P < 0.0001]), while a lesser percentage of patients used only radiation after an SRE (pre, 36.0%; post, 4.7% [P < 0.0001]). An increase was observed in patients using neither radiation nor opioids (pre, 14.5%; post, 42.0% [P < 0.0001]). An increase of ~50% was noted in long-term opioid users (from 22.1% to 32.1%). The use of monotherapy with a short acting opioid decreased (pre, 35.1%; post, 32.5% [P < 0.0001]), while use of mixed opioids increased (pre, 13.7%; post, 19.1% [P < 0.0001]). Mean morphine equivalent dose increased from pre- to post-SRE (9.1 vs 13.1 mg). Bisphosphonate and NSAID users decreased from before to after an SRE diagnosis (bisphosphonates, 40.2% vs 8.6%; NSAIDs, 26.7% vs 17.5% [both, P < 0.0001]). IMPLICATIONS: Long term opioid use and dose were significantly increased after SRE development in MPC. The high percentage of patients not treated with an opioid or radiation potentially supports the need for additional treatment options for controlling pain if medically necessary and/or to prevent SREs. PMID- 27478112 TI - Can Coronary Stent Implantation Complexity Become an Intuitive and Useful Factor to Tailor DAPT Duration? PMID- 27478113 TI - Sex-Based Differences in Cessation of Dual-Antiplatelet Therapy Following Percutaneous Coronary Intervention With Stents. AB - OBJECTIVES: The aim of this study was to compare the incidence and impact of cessation of dual-antiplatelet therapy (DAPT) in women and men treated with percutaneous coronary intervention. BACKGROUND: Nonadherence to cardiovascular medications and female sex are associated with worse outcomes. However, the patterns and impact of DAPT cessation in women compared with men following percutaneous coronary intervention have not been studied. METHODS: Baseline characteristics, patterns of DAPT cessation, and 2-year clinical outcomes were compared in 5,031 patients (1,279 women, 3,739 men) enrolled following successful percutaneous coronary intervention with stents in the PARIS (Patterns of Non Adherence to Antiplatelet Regimens in Stented Patients) study. DAPT cessation was adjudicated as physician-guided discontinuation, interruption for surgery, or disruption due to bleeding or noncompliance. Clinical endpoints were major adverse cardiac events (a composite of cardiac death, definite or probable stent thrombosis, spontaneous myocardial infarction, or clinically indicated target lesion revascularization), a second restricted definition of major adverse cardiac events excluding target lesion revascularization, and bleeding. RESULTS: DAPT cessation was more common in women than men (59.1% vs. 55.9%, p = 0.007) and comprised increased rates of discontinuation, disruption for bleeding, and disruption due to noncompliance. The impact of DAPT cessation was similar regardless of sex and varied according the mode; in particular, disruption was associated with increased risk for both ischemic and bleeding events. After adjusting for differences in baseline and treatment characteristics as well as DAPT cessation events, female sex remained an independent predictor of bleeding but not of ischemic events. CONCLUSIONS: DAPT cessation was more common in women, but its impact was similar in women and men. Female sex was an independent predictor of bleeding but not of ischemic events after adjustment for differences in DAPT cessation and baseline and treatment characteristics. PMID- 27478114 TI - Dual-Antiplatelet Therapy: Why Stop Now? PMID- 27478116 TI - Walking the Tightrope Between Suppressing Ischemia and Minimizing Bleeding. PMID- 27478115 TI - Duration of Triple Antithrombotic Therapy and Outcomes Among Patients Undergoing Percutaneous Coronary Intervention. AB - OBJECTIVES: The aim of this study was to compare clinical outcomes in relation to the duration of triple antithrombotic therapy (TAT) among patients with indications for oral anticoagulation undergoing percutaneous coronary intervention (PCI). BACKGROUND: TAT is recommended for patients undergoing PCI with a firm indication for oral anticoagulation. Duration of TAT may influence outcomes, but the optimal period of TAT remains uncertain. METHODS: Between 2009 and 2013, 8,772 consecutive patients undergoing PCI for stable coronary artery disease or acute coronary syndrome were prospectively included in the Bern PCI Registry (NCT02241291). Of 568 patients with indications for oral anticoagulation, 245 (43%) were discharged on a regimen of 1-month TAT and 323 (57%) on a regimen >1-month TAT (mean 5.1 +/- 3.3 months, median 3 months). The primary endpoint was a composite of cardiac death, myocardial infarction, stroke, definite stent thrombosis, or TIMI (Thrombolysis in Myocardial Infarction) major bleeding within 1 year. RESULTS: Patients on 1-month compared with >1-month TAT were more commonly women, with stable coronary artery disease, had higher HAS BLED scores, and less frequently received drug-eluting stents. In multivariate analyses, the primary endpoint did not differ between groups (adjusted hazard ratio: 1.07; 95% confidence interval: 0.56 to 2.06; p = 0.84). Results were consistent in stratified analyses in relation to clinical presentation with acute coronary syndrome (38%) and PCI with drug-eluting stents (79%) (p for interaction = 0.18 and 0.95, respectively). There were no differences in the secondary bleeding endpoint, Bleeding Academic Research Consortium >=3 bleeding (adjusted hazard ratio: 0.62; 95% confidence interval: 0.21 to 1.80; p = 0.37) and the secondary composite ischemic endpoint (cardiac death, myocardial infarction, stroke, or definite stent thrombosis) (adjusted hazard ratio: 1.12; 95% confidence interval: 0.55 to 2.29; p = 0.76). CONCLUSIONS: One-month TAT, used preferentially in patients with higher estimated bleeding risk in this observational study, was associated with similar net clinical outcomes compared with longer TAT durations throughout 1 year following PCI. PMID- 27478117 TI - "One-Stop Shop": Safety of Combining Transcatheter Aortic Valve Replacement and Left Atrial Appendage Occlusion. AB - OBJECTIVES: The aim of this study was to investigate the safety and efficacy of combining transcatheter valve replacement (TAVR) and left atrial appendage occlusion (LAAO) versus TAVR alone. BACKGROUND: Patients with severe aortic stenosis and atrial fibrillation undergoing TAVR are at increased risk for stroke and bleeding complications. METHODS: A cohort of 52 patients undergoing concomitant TAVR and LAAO were compared with 52 patients undergoing isolated TAVR. A primary safety endpoint at 30 days, a clinical efficacy endpoint from day 30 to last follow-up, and an LAAO efficacy endpoint from the first post interventional day to the last follow-up were chosen. RESULTS: The mean age of the study population was 85 +/- 5 years. The mean CHA2DS2-VASc score and HAS-BLED score were 3.9 +/- 1.1 and 2.6 +/- 0.9, respectively. The mean Society of Thoracic Surgeons score was 7.8 +/- 5.5. The median follow-up duration of the study population was 9.4 months (range 0 to 48 months). The primary safety endpoint occurred in 10 patients in the concomitant group and in 7 patients in the isolated TAVR group (19% vs. 14%; 95% confidence interval: 0.59 to 4.06). The clinical and LAAO efficacy endpoints were achieved in 81 (79%) (75% vs. 82%; 95% confidence interval: 0.49 to 2.92) and 75 (73%) patients (69% vs. 76%; 95% confidence interval: 0.54 to 2.51), respectively. CONCLUSIONS: This pilot study shows that concomitant TAVR and LAAO is feasible and seems to be safe among patients with severe aortic stenosis and atrial fibrillation. Larger trials and longer follow-up are needed to confirm the safety and efficacy of such an approach. PMID- 27478118 TI - Opening and Closing in Tandem. PMID- 27478119 TI - Prevalence and Clinical Impact of Tissue Protrusion After Stent Implantation: An ADAPT-DES Intravascular Ultrasound Substudy. AB - OBJECTIVES: The aim of this study was to evaluate the prevalence and long-term clinical impact of tissue protrusion (TP) after stent implantation. BACKGROUND: Stent implantation may be associated with tissue (plaque or thrombus) protrusion, especially in unstable lesions, but its clinical impact is unknown. METHODS: ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective multicenter study of 8,663 patients undergoing percutaneous coronary intervention (PCI) using drug-eluting stents. In a pre-specified intravascular ultrasound (IVUS) substudy, 2,072 patients with 2,446 culprit lesions underwent post-PCI IVUS (among whom some also underwent pre-PCI IVUS) and were classified according to the presence or absence of post-stent TP. RESULTS: After PCI, 34.3% of lesions displayed TP on IVUS. Median maximum TP was 0.7 mm(2) (interquartile range: 0.5 to 1.2 mm(2)) in area and 3.0 mm (interquartile range: 1.4 to 6.7 mm) in length. Patients with TP more often presented with ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction but less often with unstable angina or stable ischemic heart disease. In 893 culprit lesions that were also examined pre-PCI, TP was associated with larger reference luminal area, greater plaque burden, and more plaque ruptures, attenuated plaque, and virtual histology thin-cap fibroatheromas. Because a larger stent or post-dilation balloon was used, post-PCI luminal area was significantly larger in lesions with versus without TP. At 2-year follow-up, there was less clinically driven target lesion revascularization in lesions with TP and no significant difference in major adverse cardiac events (defined as cardiac death, myocardial infarction, or stent thrombosis) in patients with versus without TP. CONCLUSIONS: IVUS-detected TP after drug-eluting stent implantation was not associated with worse long-term clinical outcomes, in part because of greater stent expansion in lesions with TP. PMID- 27478120 TI - Intrastent Tissue Prolapse and Late Cardiac Events: Innocent Bystander or Culprit? PMID- 27478121 TI - Do Bioresorbable Scaffold Particles Created by Rotablation Pulverization Come to a Safe End? PMID- 27478122 TI - Drug-Eluting Stents Are Effective in Women: Only Part of the Story? PMID- 27478123 TI - Reply: Drug-Eluting Stents Are Effective in Women: Only Part of the Story? PMID- 27478124 TI - Validity of Randomized Trials Comparing Radial Versus Femoral Access in Acute Coronary Syndrome. PMID- 27478125 TI - Reply: Validity of Randomized Trials Comparing Radial Versus Femoral Access in Acute Coronary Syndrome. PMID- 27478127 TI - Correction. PMID- 27478126 TI - What Is the Journal Looking For? PMID- 27478128 TI - Compression of a Woven Self-Expanding Femoropopliteal Stent Leading to Occlusion. PMID- 27478129 TI - Production of Spherical Ablations Using Nonthermal Irreversible Electroporation: A Laboratory Investigation Using a Single Electrode and Grounding Pad. AB - PURPOSE: To mathematically model and test ex vivo a modified technique of irreversible electroporation (IRE) to produce large spherical ablations by using a single probe. MATERIALS AND METHODS: Computed simulations were performed by using varying voltages, electrode exposure lengths, and tissue types. A vegetable (potato) tissue model was then used to compare ablations created by conventional and high-frequency IRE protocols by using 2 probe configurations: a single probe with two collinear electrodes (2EP) or a single electrode configured with a grounding pad (P+GP). The new P+GP electrode configuration was evaluated in ex vivo liver tissue. RESULTS: The P+GP configuration produced more spherical ablation volumes than the 2EP configuration in computed simulations and tissue models. In prostate tissue, computed simulations predicted ablation volumes at 3,000 V of 1.6 cm(3) for the P+GP configurations, compared with 0.94 cm(3) for the 2EP configuration; in liver tissue, the predicted ablation volumes were 4.7 times larger than those in the prostate. Vegetable model studies verify that the P+GP configuration produces larger and more spherical ablations than those produced by the 2EP. High-frequency IRE treatment of ex vivo liver with the P+GP configuration created a 2.84 * 2.21-cm ablation zone. CONCLUSIONS: Computer modeling showed that P+GP configuration for IRE procedures yields ablations that are larger than the 2EP configuration, creating substantial ablation zones with a single electrode placement. When tested in tissue models and an ex vivo liver model, the P+GP configuration created ablation zones that appear to be of clinically relevant size and shape. PMID- 27478130 TI - Treatment with infliximab for pediatric Crohn's disease: Nationwide survey of Japan. AB - BACKGROUND AND AIM: Childhood-onset inflammatory bowel disease (IBD) is characterized by extensive intestinal involvement and rapid early progression. Infliximab (IFX), cyclosporin (CYA), and tacrolimus (FK506) are increasingly used to treat pediatric IBD; however, their long-term effects and adverse events have not been properly investigated in pediatric patients. The aim of this study was to characterize the effects of these biologics and immunomodulators on pediatric IBD patients in Japan. Additionally, we assessed IFX use in pediatric patients with Crohn's disease (CD). METHODS: A national survey of IFX, adalimumab, CYA, and FK506 use in pediatric IBD patients (< 17 years of age) was sent to 683 facilities in Japan from December 2012 to March 2013. Secondary questionnaires were sent to pediatric and adult practitioners with the aim of assessing the effectiveness and safety of IFX for pediatric CD patients. RESULTS: The response rate for the primary survey was 61.2% (N = 418). Among 871 pediatric CD patients, 284 (31.5%), 24, 4, and 15 received IFX (31.5%), adalimumab, CYA, and FK506, respectively, from 2000 to 2012. According to the secondary survey, extensive colitis (L3, Paris classification) was diagnosed in 69.4% of pediatric CD patients who received IFX. Regarding the effectiveness of IFX in this population, 54.7% (99/181) of patients were in remission, and 42.0% (76/181) were on maintenance therapy. However, 32.0% (58/181) of patients experienced adverse events, and one patient died of septic shock. CONCLUSIONS: Infliximab is reasonably safe and effective in pediatric CD patients and should therefore be administered in refractory cases. PMID- 27478131 TI - Identification of Natural Infections in Sheep/Goats with HoBi-like Pestiviruses in China. AB - The natural infections of HoBi-like pestiviruses in cattle have been reported in South America, Europe and Asia. In China, although the detections of HoBi-like pestivirus have been reported, the epidemiological investigation was limited. From January 2014 to October 2015, several flocks of sheep/goats in Henan province in central China suffered respiratory diseases which were recovered slowly after antibiotics treatment. To test whether it is the HoBi-like pestivirus caused this symptom, 49 serum samples and 22 nasal swabs were then collected for analysis by serology and RT-PCR. Serological result revealed that prevalence of pestivirus in small ruminants was 12.2% (6/49) in central China. Sequence analysis of partial 5'-UTR nucleotides of pestivirus-positive samples suggested that HoBi-like pestivirus might have circulated in sheep/goats of China for a period and have evolved into new genotype clusters. It is apparent that the study provides the molecular evidence of natural infections in goat/sheep species with HoBi-like pestiviruses in China. PMID- 27478132 TI - Glioblastoma in the elderly - How do we choose who to treat? AB - OBJECTIVE: Glioblastoma (GBM) is the commonest primary malignant brain tumour amongst the adult population. Incidence peaks in the 7th and 8th decades of life and as our global population ages, rates are increasing. GBM is an almost universally fatal disease with life expectancy in the range of 3-5months amongst the elderly. MATERIALS AND METHODS: The assessment of elderly GBM patients prior to treatment decisions is poorly researched and unstandardised. In order to begin tackling this issue we performed a cross-sectional survey across all UK based consultant neuro-oncologists to review their current practice in assessing elderly GBM patients. RESULTS: There were 56 respondents from a total of 93 recipients (60% response rate). All respondents confirmed that at least some patients aged 70 or over were referred to their clinics from the local multidisciplinary team meeting (MDT). Only 18% of consultants routinely performed a cognitive or frailty screening test at initial consultation. Of those who performed a screening test, the majority reported that the results of the test changed their treatment decision in approximately 50% of cases. Participants ranked performance status as the most important factor in determining treatment decisions. CONCLUSIONS: Considering the heterogeneity of this patient population, we argue that performance status is a crude measure of vulnerability within this cohort. Elderly GBM patients represent a unique clinical scenario because of the complexity of distinguishing neuro-oncology related symptoms from general frailty. There is a need for specific geriatric assessment models tailored to the elderly neuro-oncology population in order to facilitate treatment decisions. PMID- 27478133 TI - Physical resilience of older cancer survivors: An emerging concept. AB - OBJECTIVES: To characterize factors contributing to physical resilience in older cancer survivors, as demonstrated by resistance to decline or recovery (resilience). MATERIALS AND METHODS: We conducted a secondary analysis of data from a randomized controlled trial of cancer survivors >=65years old and >=5years from cancer diagnoses. Physical function was assessed quarterly over 2years, with Short-Form 36 physical function subscale. Participants with >=2 follow-up assessments (n=594) were evaluated for physical resilience: 1) Resistance was defined as lack of any decline, where decline was a drop of >=13 points, and 2) resilience (i.e., recovery) was defined as regaining >=50% of lost function, subsequent to decline. RESULTS: Mean age was 73.1years and 89.1% were Caucasian. Forty-nine percent (n=289) were resistant to decline in function; these individuals were younger, had higher education and income, were more likely to be Caucasian, and had higher baseline physical function (mean difference [MD] 7.8 points, 95% CI 5.0-10.8) and general health (MD 7.5 points, 95% CI 4.9-10.1). Fifty-seven percent (n=137 of 239) demonstrated resilience, with 91.2% (n=125) recovering within 6months of declines; these participants had higher baseline physical function (MD 6.6 points, 95% CI 1.8-11.4), but similar pre-decline function. More participants who were resistant, and more who showed resilience, reported high self-efficacy and social support. CONCLUSIONS: The majority of older cancer survivors exhibited physical resilience; this was associated with high baseline health, physical function, self-efficacy, and social support. Assessing and targeting psychosocial factors may be important for interventions seeking to promote physical resilience. PMID- 27478135 TI - The effects of dose and diet on the pharmacokinetics of omeprazole in the horse. AB - This study aimed to investigate the effect of diet and dose on the pharmacokinetics of omeprazole in the horse. Six horses received two doses (1 and 4 mg/kg) of omeprazole orally once daily for 5 days. Each dose was evaluated during feeding either a high-grain/low-fibre (HG/LF) diet or an ad libitum hay (HAY) diet in a four-way crossover design. Plasma samples were collected for pharmacokinetic analysis on days 1 and 5. Plasma omeprazole concentrations were determined by ultra-high pressure liquid chromatography-mass spectrometry. In horses being fed the HG/LF diet, on day 1, the area under the curve (AUC) and maximal plasma concentration (Cmax ) were higher on the 4 mg/kg dose than on the 1 mg/kg dose. The AUC was higher on day 5 compared to day 1 with the 4 mg/kg dose on the HG/LF diet. On days 1 and 5, the AUC and Cmax were higher in horses being fed the HG/LF diet and receiving the 4 mg/kg dose than in horses being fed the HAY diet and receiving the 1 mg/kg dose. These findings suggest that both dose and diet may affect pharmacokinetic variables of omeprazole in the horse. PMID- 27478134 TI - Coherent microwave generation by spintronic feedback oscillator. AB - The transfer of spin angular momentum to a nanomagnet from a spin polarized current provides an efficient means of controlling the magnetization direction in nanomagnets. A unique consequence of this spin torque is that the spontaneous oscillations of the magnetization can be induced by applying a combination of a dc bias current and a magnetic field. Here we experimentally demonstrate a different effect, which can drive a nanomagnet into spontaneous oscillations without any need of spin torque. For the demonstration of this effect, we use a nano-pillar of magnetic tunnel junction (MTJ) powered by a dc current and connected to a coplanar waveguide (CPW) lying above the free layer of the MTJ. Any fluctuation of the free layer magnetization is converted into oscillating voltage via the tunneling magneto-resistance effect and is fed back into the MTJ by the CPW through inductive coupling. As a result of this feedback, the magnetization of the free layer can be driven into a continual precession. The combination of MTJ and CPW behaves similar to a laser system and outputs a stable rf power with quality factor exceeding 10,000. PMID- 27478136 TI - Effect of injection rate on contrast-enhanced MR angiography image quality: Modulation transfer function analysis. AB - PURPOSE: Contrast-enhanced (CE)-MRA optimization involves interactions of sequence duration, bolus timing, contrast recirculation, and both R1 relaxivity and R2*-related reduction of signal. Prior data suggest superior image quality with slower gadolinium injection rates than typically used. METHODS: A computer based model of CE-MRA was developed, with contrast injection, physiologic, and image acquisition parameters varied over a wide gamut. Gadolinium concentration was derived using Verhoeven's model with recirculation, R1 and R2* calculated at each time point, and modulation transfer curves used to determine injection rates, resulting in optimal resolution and image contrast for renal and carotid artery CE-MRA. Validation was via a vessel stenosis phantom and example patients who underwent carotid CE-MRA with low effective injection rates. RESULTS: Optimal resolution for renal and carotid CE-MRA is achieved with injection rates between 0.5 to 0.9 mL/s and 0.2 to 0.3 mL/s, respectively, dependent on contrast volume. Optimal image contrast requires slightly faster injection rates. Expected signal to-noise ratio varies with both contrast volume and cardiac output. Simulated vessel phantom and clinical carotid CE-MRA exams at an effective contrast injection rate of 0.4 to 0.5 mL/s demonstrate increased resolution. CONCLUSION: Optimal image resolution is achieved at intuitively low, effective injection rates (0.2-0.9 mL/s, dependent on imaging parameters and contrast injection volume). Magn Reson Med 78:357-369, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27478137 TI - Lithium lengthens circadian period of cultured brain slices in area specific manner. AB - Lithium has been used for the treatment of bipolar disorder (BD). However, the mechanisms how lithium exerts its mood stabilizing effects remain to be studied. The disorder in circadian pacemaking has been suggested as an underlying mechanism of the characteristic mood instability of the BD. Lithium is also known to lengthen the circadian periods. We recently proposed that chronic methamphetamine treatment induced circadian oscillation as a complex oscillator including multiple dopaminergic brain areas, and the complex oscillator regulates behavior rhythm independent from the central circadian oscillator in the suprachiasmatic nucleus (SCN). Sleep-wake pattern of rapid cycling BD exhibits similar rhythm disorganization to methamphetamine treated animals. Therefore, we hypothesized that the dysregulated circadian rhythm in BD patients is caused by desynchronization of sleep-wake rhythms from the central clock in the SCN, and that mood stabilizing effect of lithium is achieved through their resynchronization. In the present experiment, we examined how lithium affects the circadian rhythms of brain areas involved in the complex oscillator as well as the SCN. Here we report that lithium lengthens the circadian periods in the SCN, olfactory bulb, median eminence and substantia nigra with dose and area specific manner. The effective lithium dose was much higher than the plasma levels that are required for lengthening the circadian behavior rhythms as well for therapeutic use. Low dose of lithium did not lengthen the period but enhanced the amplitude of circadian rhythms, which may exert therapeutic effects on BD. PMID- 27478138 TI - Differential activation and tyrosine hydroxylase distribution in the hippocampal, pallial and midbrain brain regions in response to cognitive performance in Indian house crows exposed to abrupt light environment. AB - Disruption of the cyclic feature of the day-night environment can cause negative effects on daily activity and advanced brain functions such as learning, memory and decision-making behaviour. These functions in songbirds, including corvids, involve the hippocampus, pallium and midbrain, as revealed by ZENK (a neuronal activation marker) and tyrosine hydroxylase (TH) expressions. TH is rate-limiting marker enzyme of the biosynthesis of dopamine, widely implicated in learning and memory. Here, we measured ZENK and TH immunoreactivity in the hippocampal, pallial and midbrain regions in response to cognitive performance (learning memory retrieval) tests in Indian house crows (Corvus splendens) exposed to constant light environment (LL) with controls on 12h light:12h darkness. Along with the decay of circadian rhythm in activity behaviour, LL caused a significant decline in the cognitive performance. There was also a decrease under LL in the activity of neurons in the hippocampus, medial and central caudal nidopallium, and hyperpallium apicale, which are widely distributed with TH-immunoreactive fibres. Further, under LL, TH- immunoreactive neurons were reduced in number in midbrain dopamine synthesis sites, the venteral tegmental area (VTA) and substantia nigra (SN), with a negative correlation of co-localized ZENK/TH- immunoreactive cells on errors during the association tasks. These results show decreased activity of learning and memory neural systems, and underscore the role of dopamine in reduced cognitive performance of diurnal corvids with disrupted circadian rhythms under an abrupt light environment. PMID- 27478139 TI - Divergent effects of isolation rearing on prepulse inhibition, activity, anxiety and hippocampal-dependent memory in Roman high- and low-avoidance rats: A putative model of schizophrenia-relevant features. AB - Social isolation of rats induces a constellation of behavioral alterations known as "isolation syndrome" that are consistent with some of the positive and cognitive symptoms observed in schizophrenic patients. In the present study we have assessed whether isolation rearing of inbred Roman high-avoidance (RHA-I) and Roman low-avoidance (RLA-I) strains can lead to the appearance of some of the key features of the "isolation syndrome", such as prepulse inhibition (PPI) deficits, increased anxious behavior, hyperactivity and memory/learning impairments. Compared to RLA-I rats, the results show that isolation rearing (IR) in RHA-I rats has a more profound impact, as they exhibit isolation-induced PPI deficits, increased anxiety, hyperactivity and long-term reference memory deficits, while isolated RLA-I rats only exhibit deficits in a spatial working memory task. These results give further support to the validity of RHA-I rats as a genetically-based model of schizophrenia relevant-symptoms. PMID- 27478140 TI - Long-lasting impairments in adult neurogenesis, spatial learning and memory from a standard chemotherapy regimen used to treat breast cancer. AB - The negative impact of chemotherapy on cognitive function in cancer patients has gained increasing attention in the last decade. Whilst the short-term acute effects on cognition are expected following chemotherapy, the persistence of such impairments in the long-term is still in question. This is despite clinical evidence indicating cognitive difficulties may persist well beyond treatment and affect quality of life. In the present study, we assessed the long-term (3 months) cognitive impact of chemotherapy in a mouse model intended to mimic the human female post-menopausal population receiving chemotherapy for breast cancer. Ovariectomized, female, C57BL/6J mice received two doses of Doxorubicin, Cyclophosphamide, and 5-Fluorouracil or saline vehicle (control), separated by one week. During this interval, mice received BrdU injections to label dividing cells. Results indicate a persistent impairment in learning and recall (1h, 24h and 48h) on the Morris water maze, reduced survival and differentiation of new neurons (BrdU+/NeuN+), and a persistent decline in proliferation of new cells (Ki67(+)) in the dentate gyrus. Locomotor activity, motor performance, and anxiety-like behavior were unaffected. We further evaluated the efficacy of a diet enriched in omega-3-fatty acids (DHA+EPA+DPA), in reversing long-term chemotherapy deficits but no rescue was observed. The model described produces long-term cognitive and cellular impairments from chemotherapy that mimic those observed in humans. It could be useful for identifying mechanisms of action and to test further the ability of lifestyle interventions (e.g., diet) for ameliorating chemotherapy-induced cognitive impairments. PMID- 27478141 TI - Dopamine antagonism does not impair learning of Pavlovian conditioned approach to manipulable or non-manipulable cues but biases responding towards goal tracking. AB - Dopamine's (DA) role in reward-processing is currently discussed as either providing a teaching signal to guide learning or mediating the transfer of incentive salience (i.e. motivational aspects) from unconditioned stimuli (US) to conditioned stimuli (CS). We used a Pavlovian conditioned approach (PCA) procedure to further investigate DAs contribution to these processes. Experiment 1 assessed the acquisition of PCA to a manipulable lever cue for 7days under DA blockade with Flupenthixol (FLU; 225MUg/kg) or Saline (SAL) treatment, followed by 6-days off-drug testing. FLU decreased the number of conditioned responses (CR) during the treatment phase, but cessation of treatment resulted in an immediate increase in CR to levels comparable to SAL controls; notably, CR in FLU treated rats were restricted to goal tracking behaviour. During continued off drug testing, rats from the FLU group developed sign tracking with a similar temporal pattern as controls. In experiment 2, acquisition of PCA to a non manipulable auditory cue was investigated. FLU reduced the number of CR during treatment, and removing DA antagonism resulted in a similar rapid increase of CR as seen in experiment 1. These data complement other reports by demonstrating that, independently from the physical properties of the CS, DA is not required for learning predictive aspects of a CS-US relationship but for the development of behaviour (namely sign tracking) which is based on the motivational aspects of a CS-US relationship. PMID- 27478143 TI - Drinking water quality in Indigenous communities in Canada and health outcomes: a scoping review. AB - BACKGROUND: Many Indigenous communities in Canada live with high-risk drinking water systems and drinking water advisories and experience health status and water quality below that of the general population. A scoping review of research examining drinking water quality and its relationship to Indigenous health was conducted. OBJECTIVE: The study was undertaken to identify the extent of the literature, summarize current reports and identify research needs. DESIGN: A scoping review was designed to identify peer-reviewed literature that examined challenges related to drinking water and health in Indigenous communities in Canada. Key search terms were developed and mapped on five bibliographic databases (MEDLINE/PubMED, Web of Knowledge, SciVerse Scopus, Taylor and Francis online journal and Google Scholar). Online searches for grey literature using relevant government websites were completed. RESULTS: Sixteen articles (of 518; 156 bibliographic search engines, 362 grey literature) met criteria for inclusion (contained keywords; publication year 2000-2015; peer-reviewed and from Canada). Studies were quantitative (8), qualitative (5) or mixed (3) and included case, cohort, cross-sectional and participatory designs. In most articles, no definition of "health" was given (14/16), and the primary health issue described was gastrointestinal illness (12/16). Challenges to the study of health and well being with respect to drinking water in Indigenous communities included irregular funding, remote locations, ethical approval processes, small sample sizes and missing data. CONCLUSIONS: Research on drinking water and health outcomes in Indigenous communities in Canada is limited and occurs on an opportunistic basis. There is a need for more research funding, and inquiry to inform policy decisions for improvements of water quality and health-related outcomes in Indigenous communities. A coordinated network looking at First Nations water and health outcomes, a database to store and create access to research findings, increased funding and time frames for funding, and more decolonizing and community-based participatory research aimed at understanding the relationship between drinking water quality and health outcomes in First Nations communities in Canada are needed. PMID- 27478142 TI - CREB, cellular excitability, and cognition: Implications for aging. AB - Humans and laboratory animals display cognitive deficits as they age. However, there are currently no effective therapies available to treat these deficits, as the underlying mechanisms are poorly understood. Studies using pharmacological compounds have found a link between cognitive performance and the intrinsic cellular excitability of CA1 hippocampal neurons. Therefore, it is of great interest to identify molecular regulators that may be influencing both cognition and neuronal excitability, which could be changed with age. One possible regulator is the transcription factor cAMP response element binding-protein (CREB). In young adult animals, manipulation of CREB activity has resulted in modulation of both cognitive performance on behavioral tasks, and neuronal excitability. While evidence is sparse, studies also point to a dysfunction in CREB signaling with aging. We propose that CREB may be a viable therapeutic target for the treatment of age-related cognitive deficits, along with potential experiments to test this hypothesis. PMID- 27478144 TI - A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay. AB - The objective of this preliminary study was to evaluate the threshold for immune stimulation in mice following local exposure to metal particles and ions representative of normal-functioning cobalt-chromium (CoCr) metal-on-metal (MoM) hip implants. The popliteal lymph node assay (PLNA) was used in this study to assess immune responses in BALB/c mice following treatment with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3 and NiCl2), or Cr2O3 particles together with metal salts using single-dose exposures representing approximately 10days (0.000114mg), 19years (0.0800mg), and 40years (0.171mg) of normal implant wear. The immune response elicited following treatment with Cr2O3 particles together with metal salts was also assessed at four additional doses equivalent to approximately 1.5months (0.0005mg), 0.6years (0.0025mg), 2.3years (0.01mg), and 9.3years (0.04mg) of normal implant wear. Mice were injected subcutaneously (50MUL) into the right hind foot with the test article, or with the relevant vehicle control. The proliferative response of the draining lymph node cells (LNC) was measured four days after treatment, and stimulation indices (SI) were derived relative to vehicle controls. The PLNA was negative (SI<3) for all Cr2O3 particle doses, and was also negative at the lowest dose of the metal salt mixture, and the lowest four doses of the Cr2O3 particles with metal salt mixture. The PLNA was positive (SI>3) at the highest two doses of the metal salt mixture and the highest three doses of the Cr2O3 particles with the metal salt mixture. The provisional NOAEL and LOAEL values identified in this study for immune activation corresponds to Co and Cr concentrations in the synovial fluid approximately 500 and 2000 times higher than that reported for normal-functioning MoM hip implants, respectively. Overall, these results indicate that normal wear conditions are unlikely to result in immune stimulation in individuals not previously sensitized to metals. PMID- 27478145 TI - Chronic venous disease - Part I: Inflammatory biomarkers in wound healing. AB - Venous leg ulcers (VLUs) produce wound fluid (WF), as a result of inflammatory processes within the wound. It is unclear if WF from different healing phases of VLU has a peculiar biochemical profile and how VLU microenvironment affects the wound healing mechanisms. This study was conducted to evaluate the cytokine/chemokine profiles in WF from distinct VLU phases, in WF- and LPS stimulated monocytes and treated with glycosaminoglycan Sulodexide, a therapeutic option for VLU healing. WF and plasma were collected from patients with VLU during active inflammatory (Infl) and granulating (Gran) phases. Demographics, clinical characteristics and pain measurements were evaluated. WF, plasma, and THP-1 supernatants were analyzed for 27 inflammatory mediators by multiplex immunoassay. Our results demonstrated that: 1) pain was significantly increased in patients with Infl compared to Gran VLU; 2) cytokine profile of Infl WF was found to be statistically different from that Gran WF, as well significantly increased respect to plasma; 3) LPS- and WF-stimulation of THP-1 cells significantly increased the expression of several cytokines compared to untreated cells; 4) Sulodexide treatment of both LPS- and WF-stimulated THP-1 monocytes was able to significantly down-regulate the release of peculiar inflammatory mediators. Our study highlighted the importance to understand biomolecular processes underlying CVI when providing treatment for chronic VLU. Identification of inflammatory biomarkers in leg ulcer microenvironment, may provide useful tools for predicting healing outcome and developing targeted therapies. PMID- 27478146 TI - Tracheomalacia in a patient with tracheobronchial amyloidosis. PMID- 27478147 TI - Stirred, shaken, or stagnant: What goes on at the blood-biomaterial interface. AB - There is a widely recognized need to improve the performance of vascular implants and external medical devices that come into contact with blood by reducing adverse reactions they cause, such as thrombosis and inflammation. These reactions lead to major adverse cardiovascular events such as heart attacks and strokes. Currently, they are managed therapeutically. This need remains unmet by the biomaterials research community. Recognized stagnation of the blood biomaterial interface research translates into waning interest from clinicians, funding agencies, and practitioners of adjacent fields. The purpose of this contribution is to stir things up. It follows the 2014 BloodSurf meeting (74th International IUVSTA Workshop on Blood-Biomaterial Interactions), offers reflections on the situation in the field, and a three-pronged strategy integrating different perspectives on the biological mechanisms underlying blood biomaterial interactions. The success of this strategy depends on reengaging clinicians and on the renewed cooperation of the funding agencies to support long term efforts. PMID- 27478148 TI - CPR-induced consciousness: A cross-sectional study of healthcare practitioners' experience. AB - INTRODUCTION: Consciousness may occur during effective management of cardiac arrest and ranges from eye opening to interfering with rescuers' resuscitation attempts. Reported cases in the medical literature appear scant compared to anecdotal reports. The aim of this study was to evaluate health care providers' experience with consciousness during cardio-pulmonary resuscitation (CPR). METHODS: A cross-sectional survey of 100 experienced health care professionals, including doctors, nurses and paramedics. Participants were asked about their experience with both CPR-non-interfering consciousness (e.g. eye opening, agonal breaths or mild restlessness) and CPR-interfering consciousness (e.g. purposeful movement, withdrawing from CPR, attempting to pull out airway-securing devices). RESULTS: A third of responders reported attending more than 100 cases of arrests, while another third had attended 20 or less arrests. The responders had a mean of 11 (SD 8.7) years of practice. Most responders (59 of 67) to the question had experienced CPR-non-interfering consciousness and reported experiencing it a median of 3 (IQR 1-5) times. CPR-interfering consciousness had been experienced by 51 of the 63 responders and was experienced overall 1 (IQR 1-3) time. Management of these cases varied widely with varied opinion on ideal management ranging from no action to sedation and/or paralysis. A guideline describing the management of this presentation was considered necessary by 40 out of 57 (70%) responders. CONCLUSIONS: Contrasting to a few reports in the medical literature, CPR-induced consciousness appears to be experienced more commonly during resuscitation. Management strategies varied widely and clinician opinion of ideal management was also varied. The desire for consensus guidelines on this topic exists. Acute care nurses are integral members of all resuscitation teams and in conjunction with other clinicians, ideally placed to develop, implement and disseminate such guidelines to delivering evidence based care to this sub-group of patients. PMID- 27478150 TI - Improvement of daptomycin production via increased resistance to decanoic acid in Streptomyces roseosporus. AB - Daptomycin, a cyclic anionic lipopeptide compound produced by Streptomyces roseosporus, is used to treat skin infections caused by multi-drug resistant gram positive pathogens. The biosynthesis of daptomycin is initiated by the condensation of decanoic acid (DA, a 10-carbon unit fatty acid) and the N terminal l-tryptophan. So, the addition of DA to the fermentation medium is essential for increasing daptomycin production. However, increasing of DA concentration in the fermentation medium was not possible due to the high toxicity of DA. The previous studies reported that the cell growth of S. roseosporus was halted from 1 mM DA. In order to improve daptomycin production with increasing DA concentration in the medium, the DA-resistant S. roseosporus was developed via a sequential-adaptation method. The DA-resistant strain (DAR) showed complete resistance to 1 mM DA, and the daptomycin production was increased 1.4-fold (40.5 +/- 0.7 mg/L) compared with the wild-type (28.5 +/- 0.8 mg/L) at 1 mM DA. Additionally, the initial step of the daptomycin biosynthesis was enhanced by the overexpression of dptE and dptF in DAR. The dptEF overexpression DAR showed 3.9-fold (156.3 +/- 8.2 mg/L) increase in the daptomycin production compared with DAR (40.1 +/- 2.6 mg/L) at 1 mM DA. PMID- 27478149 TI - Efficacy of tranexamic acid for the prevention of bleeding in patients with von Willebrand disease and Glanzmann thrombasthenia: a controlled, before and after trial. AB - INTRODUCTION: Reducing bleeding episodes is very important in haematology disorders like von Willebrand disease (VWD) and Glanzmann thrombasthenia (GT). Replacement factors are very expensive although prophylactic drugs are affordable. OBJECTIVE: To study the prophylactic effects of tranexamic acid (TXA) for reduction of bleeding episodes in patients with VWD and GT in non-invasive conditions. METHODS: A controlled, double-blind before and after single-centre trial was performed in Amir-Kabir Hospital (Arak, Iran). The study was done on 17 patients with VWD and three patients with GT with minimum age of 2 years. Patients were received placebo for 6 months to evaluate the frequency and severity of bleeding and also to record the frequency of use of factor concentrates and platelet transfusion. After that, patients were given oral single dose of TXA 25 mg kg(-1) day(-1) for 6 months. The mentioned outcomes were studied and compared between two phases of study. Safety assessment was done in all patients. RESULTS: Tranexamic acid caused a significant reduction in number of Grade 1 and Grade 2 bleeding episodes in VWD patients (P < 0.001 and P < 0.01 respectively). In addition, TXA therapy was associated with significant decrease in the use of factor concentrates (P < 0.05). Number of bleeding episodes decreased in GT patients who used TXA; however, difference between two phases of studies was not significant (P = 0.1). TXA had no effect in the frequency of platelet transfusions in GT patients. TXA therapy was associated with headache, back pain and musculoskeletal pain. No case of allergy or thromboembolic events was seen following treatment. CONCLUSIONS: The results suggest that TXA is safe and effective to reduce bleeding and use of factor concentrates in VWD patients. In addition, TXA therapy can decrease bleeding in GT patients. PMID- 27478151 TI - Antimicrobial activity against Porphyromonas gingivalis and mechanism of action of the cationic octadecapeptide AmyI-1-18 and its amino acid-substituted analogs. AB - The antimicrobial peptide AmyI-1-18 is a cationic alpha-helical octadecapeptide derived from alpha-amylase in rice (Oryza sativa L. japonica) that contains four cationic amino acid residues (two arginines and two lysines). To enhance the antibacterial activity of AmyI-1-18 against Porphyromonas gingivalis (a bacterium associated with periodontal disease), we synthesized 12 analogs bearing substitutions with alanine, leucine, and/or arginine that were designed based on helical wheel projections and investigated their antibacterial properties. The antibacterial properties of four analogs bearing substitution of a single arginine or lysine with alanine were almost similar to those of AmyI-1-18, suggesting that the antibacterial properties depend on the presence of three cationic amino acid residues. Of three single arginine-substituted analogs, AmyI 1-18(G12R) exhibited an antibacterial activity 2.8-fold higher [50% growth inhibitory concentration (IC50): 4.6 MUM] than that of AmyI-1-18 (IC50: 13 MUM). Likewise, the antibacterial properties of two single leucine-substituted analogs were significantly enhanced; in particular, AmyI-1-18(N3L) exhibited an antibacterial activity (IC50: 2.5 MUM) 5.2-fold higher than that of AmyI-1-18. The hemolytic activity of AmyI-1-18(N3L) against mammalian red blood cells was low (2% at 50 MUM). A membrane-depolarization assay using a membrane potential sensitive fluorescent dye revealed that, similar to AmyI-1-18, the antibacterial activity of AmyI-1-18(N3L) was not dependent on its membrane-disrupting activity. Our results demonstrate that the antibacterial properties of AmyI-1-18 against P. gingivalis are significantly improved, without a significant increase in hemolytic activity, by replacing asparagine with leucine at position 3. PMID- 27478152 TI - Adenosine-Guided Pulmonary Vein Antral Isolation for Paroxysmal Atrial Fibrillation: A Randomized Study. AB - OBJECTIVES: The prognostic significance of adenosine-mediated pulmonary vein (PV) dormant conduction and whether such conduction should be eliminated still remain controversial. This randomized study aimed to investigate whether adenosine guided ablation of the reconnection gaps improves the long-term outcomes of pulmonary vein antral isolation (PVAI) for paroxysmal atrial fibrillation (AF). METHODS AND RESULTS: Consecutive patients with paroxysmal AF were randomly assigned to undergo (n = 80, group 1) or not (n = 81, group 2) adenosine testing following PVAI. Adenosine-mediated PV dormant conduction was unmasked in 26 patients (32.5%) of group 1. Successful elimination of the reconnection gaps was subsequently performed in all patients. During a mean follow-up period of 11.39 +/- 5.10 months, 30 patients of group 1 (37.5%), and 27 patients of group 2 (33.3%) experienced arrhythmia recurrence. The Kaplan-Meier arrhythmia free survival curves failed to demonstrate any significant differences between study groups (log rank 0.217, P = 0.642). Fourteen of 26 (53.8%) patients with adenosine-mediated dormant conduction and subsequent elimination of reconnection gaps experienced AF recurrence during follow-up. On the contrary, only 16 of 54 patients without dormant conduction (29.6%) displayed arrhythmia recurrence (P = 0.049). Logistic regression analysis showed that adenosine-mediated PV reconnection (hazard ratio 0.292, 95% confidence interval 0.122-0.483; P = 0.01) was an independent predictor of AF recurrence. CONCLUSION: In this patients' cohort, adenosine-mediated PV reconnection is predictive of future arrhythmic events. Elimination of dormant conduction with additional ablation lesions does not improve the long-term outcome of the procedure compared to the standard PVAI. PMID- 27478154 TI - Spotlights on our sister journals: Chem. Eur. J. 33/2016. PMID- 27478153 TI - The miRNA biogenesis factors, p72/DDX17 and KHSRP regulate the protein level of Ago2 in human cells. AB - MicroRNAs (miRNAs) are short (21-23nt long) RNAs that post-transcriptionally regulate gene expression in plants and animals. They are key regulators in all biological processes. In mammalian cells miRNAs are loaded into one of the four members of the Argonaute (Ago) protein family to form the RNA-induced silencing complex (RISC). RISCs inhibit the translation of mRNAs that share sequence complementarity with their loaded miRNAs. miRNA processing and miRNA-mediated gene regulation are highly regulated processes and involve many RNA-binding proteins as auxiliary factors. Here we show that the two RNA-binding proteins, p72 and KHSRP, both with known roles in promoting miRNA biogenesis, regulate the protein level of human Ago2 in transformed human cells. We determined that p72 and KHSRP influence Ago2 stability by regulating miRNA levels in the cell and that loss of p72/KHSRP results in a decrease of unloaded Ago2. PMID- 27478155 TI - CORRELATION OF ARTICULAR CARTILAGE THICKNESS MEASUREMENTS MADE WITH MAGNETIC RESONANCE IMAGING, MAGNETIC RESONANCE ARTHROGRAPHY, AND COMPUTED TOMOGRAPHIC ARTHROGRAPHY WITH GROSS ARTICULAR CARTILAGE THICKNESS IN THE EQUINE METACARPOPHALANGEAL JOINT. AB - Osteoarthritis of the metacarpophalangeal joint is common cause of lameness in equine athletes, and is hallmarked by articular cartilage damage. An accurate, noninvasive method for measuring cartilage thickness would be beneficial to screen for cartilage injury and allow for prompt initiation of interventional therapy. The objective of this methods comparison study was to compare computed tomographic arthrography (CTA), magnetic resonance imaging (MRI), and magnetic resonance arthrography (MRA) measurements of articular cartilage thickness with gross measurements in the metacarpophalangeal joint of Thoroughbred horses. Fourteen cadaveric, equine thoracic limbs were included. Limbs were excluded from the study if pathology of the metacarpophalangeal articular cartilage was observed with any imaging modality. Articular cartilage thickness was measured in nine regions of the third metacarpal bone and proximal phalanx on sagittal plane MRI sequences. After intra-articular contrast administration, the measurements were repeated on sagittal plane MRA and sagittal CTA reformations. In an effort to increase cartilage conspicuity, the volume of intra-articular contrast was increased from 14.5 ml, to maximal distention for the second set of seven limbs. Mean and standard deviation values were calculated, and linear regression analysis was used to determine correlations between gross and imaging measurements of cartilage thickness. This study failed to identify one imaging test that consistently yielded measurements correlating with gross cartilage thickness. Even with the use of intra-articular contrast, cartilage surfaces were difficult to differentiate in regions where the cartilage surfaces of the proximal phalanx and third metacarpal bone were in close contact with each other. PMID- 27478156 TI - Sub-Millisecond Response Time in a Photorefractive Composite Operating under CW Conditions. AB - Extensive study of photorefractive polymeric composites photosensitized with semiconductor nanocrystals has yielded data indicating that the inclusion of such nanocrystals enhances the charge-carrier mobility, and subsequently leads to a reduction in the photorefractive response time. Unfortunately, the included nanocrystals may also act as a source of deep traps, resulting in diminished diffraction efficiencies as well as reduced two beam coupling gain coefficients. Nonetheless, previous studies indicate that this problem is mitigated through the inclusion of semiconductor nanocrystals possessing a relatively narrow band-gap. Here, we fully exploit this property by doping PbS nanocrystals into a newly formulated photorefractive composite based on molecular triphenyldiamine photosensitized with C60. Through this approach, response times of 399 MUs are observed, opening the door for video and other high-speed applications. It is further demonstrated that this improvement in response time occurs with little sacrifice in photorefractive efficiency, with internal diffraction efficiencies of 72% and two-beam-coupling gain coefficients of 500 cm(-1) being measured. A thorough analysis of the experimental data is presented, supporting the hypothesized mechanism of enhanced charge mobility without the accompaniment of superfluous traps. It is anticipated that this approach can play a significant role in the eventual commercialization of this class of materials. PMID- 27478157 TI - Mitochondrial Chemical Biology: New Probes Elucidate the Secrets of the Powerhouse of the Cell. AB - Mitochondria are energy-producing organelles with essential functions in cell biology, and mitochondrial dysfunction is linked to a wide range of human diseases. Efforts to better understand mitochondrial biology have been limited by the lack of tools for manipulating and detecting processes occurring within the organelle. Here, we highlight recent significant advances in mitochondrial chemical biology that have produced new tools and techniques for studying mitochondria. Specifically, we focus on the development of chemical tools to perturb mitochondrial biochemistry, probes allowing precise measurement of mitochondrial function, and new techniques for high-throughput characterization of the mitochondrial proteome. Taken together, these advances in chemical biology will enable exciting new directions in mitochondrial research. PMID- 27478158 TI - Counter Selection Substrate Library Strategy for Developing Specific Protease Substrates and Probes. AB - Legumain (AEP) is a lysosomal cysteine protease that was first characterized in leguminous seeds and later discovered in higher eukaryotes. AEP upregulation is linked to a number of diseases including inflammation, arteriosclerosis, and tumorigenesis. Thus this protease is an excellent molecular target for the development of new chemical markers. We deployed a hybrid combinatorial substrate library (HyCoSuL) approach to obtain P1-Asp fluorogenic substrates and biotin labeled inhibitors that targeted legumain. Since this approach led to probes that were also recognized by caspases, we introduced a Counter Selection Substrate Library (CoSeSuL) approach that biases the peptidic scaffold against caspases, thus delivering highly selective legumain probes. The selectivity of these tools was validated using M38L and HEK293 cells. We also propose that the CoSeSuL methodology can be considered as a general principle in the design of selective probes for other protease families where selectivity is difficult to achieve by conventional sequence-based profiling. PMID- 27478159 TI - OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity. AB - OptoGluNAM4.1, a negative allosteric modulator (NAM) of metabotropic glutamate receptor 4 (mGlu4) contains a reactive group that covalently binds to the receptor and a blue-light-activated, fast-relaxing azobenzene group that allows reversible receptor activity photocontrol in vitro and in vivo. OptoGluNAM4.1 induces light-dependent behavior in zebrafish and reverses the activity of the mGlu4 agonist LSP4-2022 in a mice model of chronic pain, defining a photopharmacological tool to better elucidate the physiological roles of the mGlu4 receptor in the nervous system. PMID- 27478160 TI - The Evolutionary Origin of Female Orgasm. AB - The evolutionary explanation of female orgasm has been difficult to come by. The orgasm in women does not obviously contribute to the reproductive success, and surprisingly unreliably accompanies heterosexual intercourse. Two types of explanations have been proposed: one insisting on extant adaptive roles in reproduction, another explaining female orgasm as a byproduct of selection on male orgasm, which is crucial for sperm transfer. We emphasize that these explanations tend to focus on evidence from human biology and thus address the modification of a trait rather than its evolutionary origin. To trace the trait through evolution requires identifying its homologue in other species, which may have limited similarity with the human trait. Human female orgasm is associated with an endocrine surge similar to the copulatory surges in species with induced ovulation. We suggest that the homolog of human orgasm is the reflex that, ancestrally, induced ovulation. This reflex became superfluous with the evolution of spontaneous ovulation, potentially freeing female orgasm for other roles. This is supported by phylogenetic evidence showing that induced ovulation is ancestral, while spontaneous ovulation is derived within eutherians. In addition, the comparative anatomy of female reproductive tract shows that evolution of spontaneous ovulation is correlated with increasing distance of clitoris from the copulatory canal. In summary, we suggest that the female orgasm-like trait may have been adaptive, however for a different role, namely for inducing ovulation. With the evolution of spontaneous ovulation, orgasm was freed to gain secondary roles, which may explain its maintenance, but not its origin. PMID- 27478161 TI - Cytological features of lymphoepithelioma-like carcinoma of the breast. PMID- 27478162 TI - Transformation from an easy-plane to an easy-axis antiferromagnetic structure in the mixed rare-earth ferroborates Pr x Y1-x Fe3(BO3)4: magnetic properties and crystal field calculations. AB - The magnetic structure of the mixed rare-earth system Pr x Y1-x Fe3(BO3)4 (x = 0.75, 0.67, 0.55, 0.45, 0.25) was studied via magnetic and resonance measurements. These data evidence the successive spin reorientation from the easy axis antiferromagnetic structure formed in PrFe3(BO3)4 to the easy-plane one of YFe3(BO3)4 associated with the weakening of the magnetic anisotropy of the Pr subsystem due to its diamagnetic dilution by nonmagnetic Y. This reorientation occurs through the formation of an inclined magnetic structure, as was confirmed by our previous neutron research in the range of x = 0.67 / 0.45. In the compounds with x = 0.75 and 0.67 whose magnetic structure is close to the easy axis one, a two-step spin reorientation takes place in the magnetic field H||c. Such a peculiarity is explained by the formation of an interjacent inclined magnetic structure with magnetic moments of Fe ions located closer to the basal plane than in the initial state, with these intermediate states remaining stable in some ranges of the magnetic field. An approach based on a crystal field model for the Pr(3+) ion and the molecular-field approximation is used to describe the magnetic characteristics of the system Pr x Y1-x Fe3(BO3)4. With the parameters of the d-d and f-d exchange interactions, of the magnetic anisotropy of the iron subsystem and of the crystal field parameters of praseodymium thus determined, it is possible to achieve a good agreement between the experimental and calculated temperature and field dependences of the magnetization curves (up to 90 kOe) and magnetic susceptibilities (2-300 K). PMID- 27478163 TI - Potential Surgical and Oncologic Consequences Related to Skin Tattoos in the Treatment of Cervical Cancer. AB - STUDY OBJECTIVE: Skin tattoos on the feet, legs, and lower abdominal wall are progressively gaining popularity. Consequently, the number of tattooed women with cervical cancer has significantly increased in the last decade. However, pigments of tattoo ink can be transported to regional lymph nodes and potentially clog lymphatic pathways that might also be used by sentinel labeling substances. Therefore, here we report whether the presence of tattoo ink affected pelvic lymph nodes in women with early cervical cancer and discuss its potential oncologic and surgical consequences. DESIGN: Prospective observational study. SETTING: University Hospital in Hamburg, Germany (Canadian Task Force classification II2). PATIENTS: Women affected by cervical cancer. INTERVENTIONS: Between January 2014 and May 2016, 267 laparoscopic oncologic operations, including at least a pelvic sentinel or complete lymphadenectomy, were performed in the Department of Advanced Surgical and Oncologic Gynecology, Asklepios Hospital, Hamburg, Germany. Among these, 191 patients were affected by cervical cancer. MEASUREMENTS AND MAIN RESULTS: Data of patients in whom dyed lymph nodes without the use of patent blue as a sentinel marker or different from blue colored pelvic lymph nodes in the case of sentinel procedure were identified and prospectively collected. RESULTS: In 9 patients, skin tattoos localized in the lower extremities caused discoloration of at least 1 pelvic lymph node. This effect was observed in 40% of women (9/23) with tattoos in this area of the body. Mean patient age was 34 years (range, 27-56). All women had cutaneous tattoos on their feet or legs, and in 1 woman an additional tattoo situated on the inferior abdominal wall was observed. The stage of cervical cancer was FIGO IB1 in all cases. One woman was at the 16th week of gestation at the time of cancer diagnosis. On average, 26 pelvic lymph nodes (range, 11-51) were harvested from both pelvic basin sides. None of the removed lymph nodes was tumor involved. Three patients (33%) developed postoperatively infected lymphoceles on the side of the tattooed lymph nodes, and 1 woman had multiple episodes of fever without a clear origin. CONCLUSION: In women affected by cervical cancer with skin tattoos located in the lower limbs, the pelvic lymph nodes can be partially or totally occupied by the ink. This must be taken into consideration, especially for women scheduled exclusively for sentinel node biopsy. Infectious complications related to nodal dissection, in particular infected lymphoceles, may be more frequent in this population. PMID- 27478164 TI - Endometriosis in a Postmenopausal Patient Presenting as an Erythematous Vaginal Plaque. PMID- 27478165 TI - Reduced Mortality With Partial-Breast Irradiation for Early Breast Cancer: A Meta Analysis of Randomized Trials. AB - PURPOSE: With earlier detection and more effective treatment, mortality from breast cancer continues to fall and it has become increasingly important to reduce the toxicity of treatments. Partial-breast radiation therapy, which focuses radiation to the tumor bed, may achieve this aim. We analyzed mortality differences in randomized trials of partial-breast irradiation (PBI). METHODS AND MATERIALS: We included data from published randomized trials of PBI (alone or as part of a risk-adapted approach) versus whole-breast irradiation (WBI) for invasive breast cancer suitable for breast-conserving therapy. We identified trials using PubMed and Google searches with the terms "partial breast irradiation" OR "intraoperative radiotherapy" OR "IMRT" OR ("accelerated" AND "radiation") AND "randomised/randomized," as well as through discussion with colleagues in the field. We calculated the proportion of patients who had events in each randomized arm at 5 years' follow-up and created a forest plot using Stata, version 14.1. RESULTS: We identified 9 randomized trials of PBI versus WBI in invasive breast cancer; 5-year outcomes were available for non-breast cancer mortality in 5 trials (n=4489) and for breast cancer mortality in 4 trials (n=4231). The overall mortality was 4.9%. There was no detectable heterogeneity between the trials for any of the outcomes. There was no difference in the proportion of patients dying of breast cancer (difference, 0.000% [95% confidence interval (CI), -0.7 to +0.7]; P=.999). Non-breast cancer mortality with PBI was lower than with WBI (difference, 1.1% [95% CI, -2.1% to -0.2%]; P=.023). Total mortality with PBI was also lower than with WBI (difference, 1.3% [95% CI, -2.5% to 0.0%]; P=.05). CONCLUSIONS: Use of PBI instead of WBI in selected patients results in a lower 5-year non-breast cancer and overall mortality, amounting to a 25% reduction in relative terms. This information should be included when breast conserving therapy is proposed to a patient. PMID- 27478166 TI - Stereotactic Radiosurgery for Brainstem Metastases: An International Cooperative Study to Define Response and Toxicity. AB - PURPOSE: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses. RESULTS: Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade >=3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 months after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score. CONCLUSIONS: Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS. PMID- 27478167 TI - Survival After Conservative Management Versus External Beam Radiation Therapy in Elderly Patients With Localized Prostate Cancer. AB - PURPOSE: To compare survival in elderly men with clinically localized prostate cancer (PCa) according to treatment type, defined as radiation therapy (RT) with or without androgen deprivation therapy (ADT) versus conservative management (observation). METHODS AND MATERIALS: In the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified 23,790 patients aged 80 years or more with clinically localized PCa treated with either RT or observation between 1991 and 2009. Competing risks analyses focused on cancer-specific mortality and other-cause mortality, after accounting for confounders. All analyses were repeated after stratification according to grade (well differentiated vs moderately differentiated vs poorly differentiated disease), race, and United States region, in patients with no comorbidities and in patients with at least 1 comorbidity. Analyses were repeated within most contemporary patients, namely those treated between 2001 and 2009. RESULTS: Radiation therapy was associated with more favorable cancer-specific mortality rates than observation in patients with moderately differentiated disease (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66-0.94; P=.009) and in patients with poorly differentiated disease (HR 0.58; 95% CI 0.49-0.69; P<.001). Conversely, the benefit of RT was not observed in well-differentiated disease. The benefit of RT was confirmed in black men (HR 0.54; 95% CI 0.35-0.83; P=.004), across all United States regions (all P<=.004), in the subgroups of the healthiest patients (HR 0.67; 95% CI 0.57-0.78; P<.001), in patients with at least 1 comorbidity (HR 0.69; 95% CI 0.56-0.83; P<.001), and in most contemporary patients (HR 0.55; 95% CI 0.46-0.66; P<.001). CONCLUSIONS: Radiation therapy seems to be associated with a reduction in the risk of death from PCa relative to observation in elderly patients with clinically localized PCa, except for those with well-differentiated disease. PMID- 27478168 TI - Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation. AB - PURPOSE: In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development. METHODS AND MATERIALS: Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3 month) and late (6-month) phases, before behavioral testing. RESULTS: Fractional anisotropy in the splenium of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI. CONCLUSIONS: The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches. PMID- 27478169 TI - Fractionation Spares Mice From Radiation-Induced Reductions in Weight Gain But Does Not Prevent Late Oligodendrocyte Lineage Side Effects. AB - PURPOSE: To determine the late effects of fractionated versus single-dose cranial radiation on murine white matter. METHODS AND MATERIALS: Mice were exposed to 0 Gy, 6 * 6 Gy, or 1 * 20 Gy cranial irradiation at 10 to 12 weeks of age. Endpoints were assessed through 18 months from exposure using immunohistochemistry, electron microscopy, and electrophysiology. RESULTS: Weight gain was temporarily reduced after irradiation; greater loss was seen after single versus fractionated doses. Oligodendrocyte progenitor cells were reduced early and late after both single and fractionated irradiation. Both protocols also increased myelin g-ratio, reduced the number of nodes of Ranvier, and promoted a shift in the proportion of small, unmyelinated versus large, myelinated axon fibers. CONCLUSIONS: Fractionation does not adequately spare normal white matter from late radiation side effects. PMID- 27478172 TI - Editorial: Molecular Informatics -- A Leading Discipline in a Complex Emerging Field. PMID- 27478170 TI - Prognostic Value of p16 Status on the Development of a Complete Response in Involved Oropharynx Cancer Neck Nodes After Cisplatin-Based Chemoradiation: A Secondary Analysis of NRG Oncology RTOG 0129. AB - PURPOSE: To determine the relationship between p16 status and the regional response of patients with node-positive oropharynx cancer treated on NRG Oncology RTOG 0129. METHODS AND MATERIALS: Patients with N1-N3 oropharynx cancer and known p16 status who underwent treatment on RTOG 0129 were analyzed. Pathologic complete response (pCR) rates in patients treated with a postchemoradiation neck dissection (with p16-positive or p16-negative cancer) were compared by Fisher exact test. Patients managed expectantly were compared with those treated with a neck dissection. RESULTS: Ninety-nine (34%) of 292 patients with node-positive oropharynx cancer and known p16 status underwent a posttreatment neck dissection (p16-positive: n=69; p16-negative: n=30). The remaining 193 patients with malignant lymphadenopathy at diagnosis were observed. Neck dissection was performed a median of 70 (range, 17-169) days after completion of chemoradiation. Neither the pretreatment nodal stage (P=.71) nor the postradiation, pre-neck dissection clinical/radiographic neck assessment (P=.42) differed by p16 status. A pCR was more common among p16-positive patients (78%) than p16-negative patients (53%, P=.02) and was associated with a reduced incidence of local regional failure (hazard ratio 0.33, P=.003). On multivariate analysis of local regional failure, a test for interaction between pCR and p16 status was not significant (P=.37). One-hundred ninety-three (66%) of 292 of initially node positive patients were managed without a posttreatment neck dissection. Development of a clinical (cCR) was not significantly influenced by p16-status (P=.42). Observed patients with a clinical nodal CR had disease control outcomes similar to those in patients with a pCR neck dissection. CONCLUSIONS: Patients with p16-positive tumors had significantly higher pCR and locoregional control rates than those with p16-negative tumors. PMID- 27478173 TI - Mimicking Peptides... In Silico. AB - Protein-protein interactions (PPIs) play a central and crucial role in almost every cellular process. Understanding the structural basis of protein-protein interactions can lead to the development of new drugs for treatment of various diseases. With this purpose, peptide-based drug design (PBDD) has been extensively explored in the last few decades. Peptidomimetics are compounds which mimic the biological activity of peptides while offering the advantages of improving their pharmacokinetics profiles. In this review, we would like to summarize the state of the art of computational methods which have been recently introduced to design novel peptidomimetics involved in a therapeutically relevant protein-protein recognition processes. PMID- 27478171 TI - Dosimetric and Clinical Outcomes With Intensity Modulated Radiation Therapy After Chemotherapy for Patients With Early-Stage Diffuse Large B-cell Lymphoma of Waldeyer Ring. AB - PURPOSE: To assess the dosimetric benefit, prognosis, and toxicity of intensity modulated radiation therapy (IMRT) for early-stage, diffuse large B-cell lymphoma of Waldeyer ring (WR-DLBCL). METHODS AND MATERIALS: Sixty-one patients with early stage WR-DLBCL who received chemotherapy followed by IMRT were retrospectively reviewed. Dosimetric parameters for the target volume and critical normal structures were evaluated, and survival was calculated. Linear regression analysis was used to assess the effect of the mean dose (Dmean) to the parotid glands on xerostomia. RESULTS: The median conformity index and homogeneity index of the planning target volume (PTV) were 0.83 and 0.90, respectively, demonstrating very good coverage of the target volume. The mean dose to the parotid glands was 24.9 Gy. The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were 94.7%, 93.1%, and 98.3%, respectively. Early and late toxicities were mild, and no patient experienced late grade >=3 toxicities. The Dmean to the parotid glands had a linear correlation with late grade >=2 xerostomia. CONCLUSIONS: IMRT after chemotherapy can provide excellent dose conformity and achieve favorable survival and LRC with mild toxicities in patients with early-stage WR-DLBCL. Dose constraints for the parotid glands should be limited to <24 Gy for early-stage WR-DLBCL. PMID- 27478174 TI - From Virtual Screening to Bioactive Compounds by Visualizing and Clustering of Chemical Space. PMID- 27478175 TI - In Silico Models to Discriminate Compounds Inducing and Noninducing Toxic Myopathy. AB - Toxic myopathy is a muscular disease in which the muscle fibers do not function and which results in muscular weakness. Some drugs, such as lipid-lowering drugs and antihistamines, can cause toxic myopathy. In this work, a dataset containing 232 chemical compounds inducing toxic myopathy (IM-compounds) and 117 drugs not inducing toxic myopathy (notIM-compounds) was collected. The dataset was split into a training set (containing 270 compounds) and a test set (containing 79 compounds). A Kohonen's self-organizing map (SOM) and a support vector machine (SVM) were applied to develop classification models to differentiate IM-compounds and notIM-compounds. Polarizibity related descriptors, electronegativity related descriptors, atom charges related descriptors, H-bonding related descriptor, atom identity and molecular shape descriptors were used to build models. Using the SOM method, classification accuracies of 88.4 % for the training set and 88.2 % for the test set were achieved; using the SVM method, classification accuracies of 95.6 % for the training set and 86.1 % for the test set were achieved. In addition, extended connectivity fingerprints (ECFP_4) were calculated and analyzed to find important substructures of molecules relating to toxic myopathy. PMID- 27478176 TI - An Advanced Group Contribution Method for High-Dimensional, Sparse Data Sets. AB - Today's chemical processes involve many components, and it is necessary to know their basic physical properties for process design and operation. However, it is not always possible to find the property information of all components in the literature. Generally, there are two ways to evaluate properties of chemical compounds when they do not exist in the literature: the experimental measurement and predictive approaches based on empirical models. The latter is called the group contribution method (GCM), and its basic concept is that specific functional groups or fragments of a molecule contribute to the value of its physical property. The advantage of the GCMs is that they reduce the effort and cost compared to experiments. This study proposes a novel GCM method suitable for high-dimensional, sparse data sets. In order to improve its applicability and accuracy, the database is extended and divided into non-ring group compounds and ring group ones. Support vector regression (SVR) is adopted as the regression model, and a derivative-free optimization approach, referred to as particle swarm optimization, is incorporated into the parameter optimization step in learning the SVM model to avoid local optimality. Performance of the proposed model is compared to those of other GCMs. PMID- 27478177 TI - Classification Models for Predicting Cytochrome P450 Enzyme-Substrate Selectivity. AB - Cytochrome P450 (CYP) is an important drug-metabolizing enzyme family. Different CYPs often have different substrate preferences. In addition, one drug molecule may be preferentially metabolized by one or more CYP enzymes. Therefore, the classification and prediction of substrate specificity of CYP enzymes are of importance to the understanding of drug metabolisms and may help guide the development of new drugs. In this study, we used three different machine learning methods to classify CYP substrates for predicting CYP-substrate specificity based solely on structural and physicochemical properties of the substrates. We first built a simple decision tree model to classify substrates of four CYP enzymes, 1A2, 2C9, 2D6 and 3A4 with more than 78 % classification accuracy. We then built a single-label eight-class model and a multilabel five-class model to classify substrates of eight CYP enzymes and to classify substrates that can be metabolized by more than one CYP enzymes, respectively. Above 90 % and >80 % prediction accuracy was achieved for the single-label and multilabel models, respectively. The main improvement of our models over existing ones is the automated and unbiased selection of descriptors by genetic algorithms, which makes our methods applicable for larger data sets and increased number of CYP enzymes. PMID- 27478178 TI - Navigating Drug-Like Chemical Space of Anticancer Molecules Using Genetic Algorithms and Counterpropagation Artificial Neural Networks. AB - A total of 6289 drug-like anticancer molecules were collected from Binding database and were analyzed by using the classification techniques. The collected molecules were encoded to a diverse set of descriptors, spanning different physical and chemical properties of the molecules. A combination of genetic algorithms and counterpropagation artificial neural networks was used for navigating the generated drug-like chemical space and selecting the most relevant molecular descriptors. The proposed method was used for the classification of the molecules according to their therapeutic targets and activities. The selected molecular descriptors in this work define discrete areas in chemical space, which are mainly occupied by particular classes of anticancer molecules. The obtained structure-activity relationship (SAR) patterns and classification rules contain valuable information, which help to screen the large databases of compounds, more precisely. Such rules and patterns can be considered as virtual filters for mining the large databases of compounds and are useful in finding new anticancer candidates. PMID- 27478179 TI - Digital Filters for Molecular Interaction Field Descriptors. AB - Descriptor properties are often neglected when building 3D-QSAR models. The relevance of correlation and distribution profiles is tested in terms of the models' prediction power. A different approach to filter descriptors prior to variable selection is proposed. Additionally, a protocol for molecular interaction field descriptors selection and model validation is presented. The algorithms and protocols presented are quite simple and enable a different and powerful way to create parsimonious interaction field-based models. PMID- 27478180 TI - Linear and Nonlinear Support Vector Machine for the Classification of Human 5 HT1A Ligand Functionality. AB - Upon binding to a receptor, agonists and antagonists can induce distinct biological functions and thus lead to significantly different pharmacological responses. Thus, in silico prediction or in vitro characterization of ligand agonistic or antagonistic functionalities is an important step toward identifying specific pharmacological therapeutics. In this study, we investigated the molecular properties of agonists and antagonists of human 5-hydroxytryptamine receptor subtype 1A (5-HT1A ). Subsequently, intrinsic functions of these ligands (agonists/antagonists) were modeled by support vector machine (SVM), using five 2D molecular fingerprints and the 3D Topomer distance. Five kernel functions, including linear, polynomial, RBF, Tanimoto and a novel Topomer kernel based on Topomer 3D similarity were used to develop linear and nonlinear classifiers. These classifiers were validated through cross-validation, yielding a classification accuracy ranging from 80.4 % to 92.3 %. The performance of different kernels and fingerprints was analyzed and discussed. Linear and nonlinear models were further interpreted through the illustration of underlying classification mechanism. The computation protocol has been automated and demonstrated through our online service. This study expands the scope and applicability of similarity-based methods in cheminformatics, which are typically used for the identification of active molecules against a target protein. Our findings provide a good starting point for further systematic classifications of other GPCR ligands and for the data mining of large chemical libraries. PMID- 27478181 TI - Which CD8+ T-cells in asthma? Attacking or defending? PMID- 27478182 TI - Metabolic consequences of obesity as an "outside in" mechanism of disease severity in asthma. PMID- 27478183 TI - Complex lung function in severe asthma: seeing is believing. PMID- 27478184 TI - Primary ciliary dyskinesia: the patients grow up. PMID- 27478185 TI - Interleukin-1alpha: a key player for epithelial-to-mesenchymal signalling in COPD? PMID- 27478186 TI - Pulmonary arterial hypertension and the Enigma code of smouldering inflammation. PMID- 27478187 TI - The difficult diagnosis of pulmonary vascular disease in heart failure. PMID- 27478188 TI - The difficult diagnosis of pulmonary vascular disease in heart failure. PMID- 27478189 TI - Should we use gait speed in COPD, FEV1 in frailty and dyspnoea in both? PMID- 27478190 TI - Increased use of high-flow nasal oxygen during bronchoscopy. PMID- 27478191 TI - Increased use of high-flow nasal oxygen during bronchoscopy. PMID- 27478192 TI - "Cortical drive to breathe in amyotrophic lateral sclerosis: a dyspnoea-worsening defence?" Marjolaine Georges, Elise Morawiec, Mathieu Raux, Jesus Gonzalez Bermejo, Pierre-Francois Pradat, Thomas Similowski and Capucine Morelot-Panzini. Eur Respir J 2016; 47: 1818-1828. PMID- 27478193 TI - "Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis." Michael Kreuter, Marlies S. Wijsenbeek, Martina Vasakova, Paolo Spagnolo, Martin Kolb, Ulrich Costabel, Derek Weycker, Klaus-Uwe Kirchgaessler and Toby M. Maher. Eur Respir J 2016; 47: 1776-1784. PMID- 27478194 TI - ERJ August Podcast: management of chronic thromboembolic pulmonary hypertension. PMID- 27478195 TI - An open-access endoscopy screen correctly and safely identifies patients for conscious sedation. AB - BACKGROUND AND AIMS: Open-access scheduling is highly utilized for facilitating generally low-risk endoscopies. Preprocedural screening addresses sedation requirements; however, procedural safety may be compromised if screening is inaccurate. We sought to determine the reliability of our open-access scheduling system for appropriate use of conscious sedation. METHODS: We prospectively and consecutively enrolled outpatient procedures booked at an academic center by open access using screening after in-office gastroenterology (GI) consultation. We collected the cases inappropriately booked for conscious sedation and compared the characteristics for significant differences. RESULTS: A total of 8063 outpatients were scheduled for procedures with conscious sedation, and 5959 were booked with open-access. Only 78 patients (0.97%, 78/8063) were identified as subsequently needing anesthesiologist-assisted sedation; 44 (56.4%, 44/78) were booked through open-access, of which chronic opioid (47.7%, 21/44) or benzodiazepine use (34.1%, 15/44) were the most common reasons for needing anesthesiologist-assisted sedation. Patients on chronic benzodiazepines required more midazolam than those not on chronic benzodiazepines (P = .03) of those patients who underwent conscious sedation. Similarly, patients with chronic opioid use required more fentanyl than those without chronic opioid use (P = .04). Advanced liver disease and alcohol use were common reasons for patients being booked after in-office consultation and were significantly higher than those booked with open-access (both P < .01). CONCLUSIONS: We observed that the majority of patients can be triaged for conscious sedation using a multi-tiered screening process. Importantly, few patients (<1.0%) were inappropriately booked for conscious sedation. The most common reasons for considering anesthesiologist assisted sedation were chronic opioid, benzodiazepine and/or alcohol use and advanced liver disease. This suggests that these entities could be included in screening processes for open-access scheduling. PMID- 27478196 TI - Pelvic autonomic nerve preservation in radical rectal cancer surgery: changes in the past 3 decades. AB - The advent of total mesorectal excision (TME) together with minimally invasive techniques such as laparoscopic colorectal surgery and robotic surgery has improved surgical results. However, the incidence of bladder and sexual dysfunction remains high. This may be particularly distressing for the patient and troublesome to manage for the surgeon when it does occur. The increased use of neoadjuvant and adjuvant radiotherapy is also associated with poorer functional outcomes. In this review, we evaluate current understanding of the anatomy of pelvic nerves which are divided into the areas of the inferior mesenteric artery pedicle, the lateral pelvic wall and dissection around the urogenital organs. Surgical techniques in these areas are discussed. We also discuss the results in functional outcomes of the various techniques including open, laparoscopic and robotic over the last 30 years. PMID- 27478197 TI - Recent frustration and innovation in myelodysplastic syndrome. PMID- 27478198 TI - Innovative approach to older patients with malignant hemopathies. PMID- 27478200 TI - Treatment of relapsed and refractory multiple myeloma. PMID- 27478201 TI - Capillary-inertial colloidal catapults upon drop coalescence. AB - Surface energy released upon drop coalescence is known to power the self propelled jumping of liquid droplets on superhydrophobic solid surfaces, and the jumping droplets can additionally carry colloidal payloads toward self-cleaning. Here, we show that drop coalescence on a spherical particle leads to self propelled launching of the particle from virtually any solid surface. The main prerequisite is an intermediate wettability of the particle, such that the momentum from the capillary-inertial drop coalescence process can be transferred to the particle. By momentum conservation, the launching velocity of the particle drop complex is proportional to the capillary-inertial velocity based on the drop radius and to the fraction of the liquid mass in the total mass. The capillary inertial catapult is not only an alternative mechanism for removing colloidal contaminants, but also a useful model system for studying ballistospore launching. PMID- 27478199 TI - The contribution of mouse models to the understanding of constitutional thrombocytopenia. AB - Constitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia. PMID- 27478202 TI - A Mesoscale Model-Based Climatography of Nocturnal Boundary-Layer Characteristics over the Complex Terrain of North-Western Utah. AB - Nocturnal boundary-layer phenomena in regions of complex topography are extremely diverse and respond to a multiplicity of forcing factors, acting primarily at the mesoscale and microscale. The interaction between different physical processes, e.g., drainage promoted by near-surface cooling and ambient flow over topography in a statically stable environment, may give rise to special flow patterns, uncommon over flat terrain. Here we present a climatography of boundary-layer flows, based on a 2-year archive of simulations from a high-resolution operational mesoscale weather modelling system, 4DWX. The geographical context is Dugway Proving Ground, in north-western Utah, USA, target area of the field campaigns of the MATERHORN (Mountain Terrain Atmospheric Modeling and Observations Program) project. The comparison between model fields and available observations in 2012-2014 shows that the 4DWX model system provides a realistic representation of wind speed and direction in the area, at least in an average sense. Regions displaying strong spatial gradients in the field variables, thought to be responsible for enhanced nocturnal mixing, are typically located in transition areas from mountain sidewalls to adjacent plains. A key dynamical process in this respect is the separation of dynamically accelerated downslope flows from the surface. PMID- 27478204 TI - Real-time anti-poaching tags could help prevent imminent species extinctions. PMID- 27478203 TI - Entometabolomics: applications of modern analytical techniques to insect studies. AB - Metabolomic analyses can reveal associations between an organism's metabolome and further aspects of its phenotypic state, an attractive prospect for many life sciences researchers. The metabolomic approach has been employed in some, but not many, insect study systems, starting in 1990 with the evaluation of the metabolic effects of parasitism on moth larvae. Metabolomics has now been applied to a variety of aspects of insect biology, including behaviour, infection, temperature stress responses, CO 2 sedation, and bacteria-insect symbiosis. From a technical and reporting standpoint, these studies have adopted a range of approaches utilising established experimental methodologies. Here, we review current literature and evaluate the metabolomic approaches typically utilised by entomologists. We suggest that improvements can be made in several areas, including sampling procedures, the reduction in sampling and equipment variation, the use of sample extracts, statistical analyses, confirmation, and metabolite identification. Overall, it is clear that metabolomics can identify correlations between phenotypic states and underlying cellular metabolism that previous, more targeted, approaches are incapable of measuring. The unique combination of untargeted global analyses with high-resolution quantitative analyses results in a tool with great potential for future entomological investigations. PMID- 27478205 TI - Prioritizing management actions for invasive populations using cost, efficacy, demography and expert opinion for 14 plant species world-wide. AB - Management of invasive populations is typically investigated case-by-case. Comparative approaches have been applied to single aspects of management, such as demography, with cost or efficacy rarely incorporated.We present an analysis of the ranks of management actions for 14 species in five countries that extends beyond the use of demography alone to include multiple metrics for ranking management actions, which integrate cost, efficacy and demography (cost effectiveness) and managers' expert opinion of ranks. We use content analysis of manager surveys to assess the multiple criteria managers use to rank management strategies.Analysis of the matrix models for managed populations showed that all management actions led to reductions in population growth rate (lambda), with a median 48% reduction in lambda across all management units; however, only 66% of the actions led to declining populations (lambda < 1).Each management action ranked by cost-effectiveness and cost had a unique rank; however, elasticity ranks were often tied, providing less discrimination among management actions. Ranking management actions by cost alone aligned well with cost-effectiveness ranks and demographic elasticity ranks were also well aligned with cost effectiveness. In contrast, efficacy ranks were aligned with managers' ranks and managers identified efficacy and demography as important. 80% of managers identified off-target effects of management as important, which was not captured using any of the other metrics. Synthesis and applications. A multidimensional view of the benefits and costs of management options provides a range of single and integrated metrics. These rankings, and the relationships between them, can be used to assess management actions for invasive plants. The integrated cost effectiveness approach goes well 'beyond demography' and provides additional information for managers; however, cost-effectiveness needs to be augmented with information on off-target effects and social impacts of management in order to provide greater benefits for on-the-ground management. PMID- 27478206 TI - Antimicrobial seafood packaging: a review. AB - Microorganisms are the major cause of spoilage in most seafood products; however, only few microbes, called the specific spoilage organisms (SSOs), contribute to the offensive off-flavors associated with seafood spoilage. In food, microbial degradation manifests itself as spoilage, or changes in the sensory properties of a food product, rendering it unsuitable for human consumption. The use of antimicrobial substances can control the general microflora as well as specific microorganisms related to spoilage to provide products with higher safety and better quality. Many antimicrobial compounds have been evaluated in film structures for use in seafood, especially organic acids and their salts, enzymes, bacteriocins; some studies have considered inorganic compounds such as AgSiO2, zinc oxide, silver zeolite, and titanium oxide. The characteristics of some organic antimicrobial packaging systems for seafood and their antimicrobial efficiency in film structures are reviewed in this article. PMID- 27478207 TI - Volatile composition of Pedro Ximenez and Muscat sweet Sherry wines from sun and chamber dried grapes: a feasible alternative to the traditional sun-drying. AB - Sweet Sherry wines from Pedro Ximenez and Muscat sun and chamber-dried grapes during vintages 2009 and 2010 were aged in American oak wood for 12 months. Their volatile content was periodically analyzed using SBSE-GC-MS. Cluster analysis and principal component analysis demonstrated that the volatile compounds considered can be used to detect grape variety and vintage. Principal component analysis for each grape variety, clearly differentiated aging time and vintage. Drying type was the least significant factor. Sweet wines produced using chamber driers were from Pedro Ximenez and Muscat grapes provides similar in volatile constituents as those produced by traditional process. PMID- 27478208 TI - The adsorption of lead(II) ions by dynamic high pressure micro-fluidization treated insoluble soybean dietary fiber. AB - Insoluble dietary fiber from soybean residue (SIDF) was treated with dynamic high pressure microfluidization (DHPM) and used as adsorbent for Pb(II) ion. The effects of pressure on the Pb(II) adsorption capacity, primary cilia structure and surface topography of SIDF were determined using a gastrointestinal simulated model in vitro. SIDF (at pH 7.0) showed maximum binding capacity (261.42 +/- 2.77 MUmol/g), which was about 1.13 times higher than that of untreated sample (233.47 +/- 1.84 MUmol/g), when pressure reached 80 MPa. However, the net adsorption value of SIDF in a simulated small intestine (~ 9 MUmol/g) was significantly lower than that in the stomach (~ 48 MUmol/g), because of the competitive adsorption of Pb(2+) by pancreatin, cholate and several enzymes in the small intestine. In addition, the adsorption capacity of SIDF exhibited good linear relationship with the physicochemical properties of total negative charges, and the adsorption behavior presumably occurred on the surface area of granules fiber. PMID- 27478209 TI - Influence of copigmentation and phenolic composition on wine color. AB - Chromatic characteristics and their relationships with copigmentation and phenolic composition were studied in 160 bottled red wines. Free anthocyanins, copigmented anthocyanins and polymeric pigments contributing to color were calculated according to Boulton protocol and related to main changes produced in wine visible spectra after destroying any copigmented anthocyanins effect. Color differences between copigmented and non copigmented wines were quantified and related with ageing, cultivar and phenolic profile. Phenomenon of co-pigmentation visually increases the colour at 420, 520 and 620 nm for most of wines. Copigmented wines showed a mean value of 8.26 CIELab units higher than non copigmented (DeltaEab(c-nc)), being this shift deeper for young wines than for aged wines. Copigmentation mostly changed hue and decreased L, a* and b* values therefore resulted into purplish and darker wine. Visual variations in color caused by copigmentation was related to particularly anthocyanins and copigments (mostly flavonols and hydroxycinnamic acids). PMID- 27478210 TI - Dehulling reduces toxicity and improves in vivo biological value of proteins in vegetal milk derived from two mucuna (Mucuna pruriens L.) seeds varieties. AB - The present work was carried out to evaluate the nutritive quality (proximate and antinutrients composition) of vegetable milks prepared from whole and dehulled mucuna bean flours. Casein and mucuna milk diets were fed to rats (four weeks old; n = 8 per group) for 28 days to determine protein efficiency ratio (PER), net protein efficiency ratio (NPER), true and apparent digestibility (TD and AD, respectively), organ-to-body weight ratios and hematological parameters. The experimental design was a factorial design with two variety of mucuna (cochinchinensis and veracruz) and two treatments (whole and dehulled beans). Protein, total sugar, dry matter and ash-content of mucuna milks ranged from 6.40 to 12.13 g/100 mL, 10.52 to 13.08 g/100 mL, 8.59 to 12.88 g/100 g and 0.31 to 0.92 g/100 g, respectively. Milks from dehulled flours had lower contents of tannins (80-87.08 %), phytates (76.67-78.16 %) and L-Dopamine (44.45-66.66 %) than that from whole flours. The PER of dehulled mucuna diets were 22.76-21.74 %, but negative PER and low NPER was observed for whole mucuna milk diets. TD for dehulled mucuna milk (85.15-85.96 %) were higher and similar to casein when compared to that of whole mucuna milk (47.87-51.17 %). Rats fed with diets containing whole mucuna milk lost weight and had higher kidney weight. In addition, the rats fed with milk from whole mucuna flours showed significantly lower levels of lymphocytes, granulocytes, red blood cells, hemoglobin and hematocrit than that fed with dehulled mucuna milk. PMID- 27478211 TI - Comparison of cheese and paneer whey for production of a functional pineapple beverage: Nutraceutical properties and Shelf life. AB - Whey, a dairy byproduct offers a challenging task in terms of its disposal. Two functional beverages were produced by blending pineapple juice with cheese whey (W1B) and paneer whey (W2B) at different concentrations (10 %, 20 % and 30 %). The beverages were compared for physico-chemical, microbial and nutraceutical properties over a period of 60 days. Whey addition significantly improved various physico-chemical parameters of the beverages. Higher protein content in W1B and a higher mineral content in W2B without any adverse effects on antioxidant activity was seen because of blending. Whey based beverages showed higher microbial content, sedimentation values and serum separation values than control at all levels of blending. Although, W1B showed highest protein and microbial count but W2B showed highest mineral content and improved shelf life due to significantly lower values of serum separation and sedimentation. It could be concluded that paneer whey based pineapple beverage enable byproduct utilization with excellent nutrition and nutraceutical quality. PMID- 27478212 TI - Composition and functionality of whole jamun based functional confection. AB - Whole jamun based functional confection (WJFC) was developed from an optimized blend (through response surface methodology) containing 26.585 % paste of jamun pulp with adhering skin, 2 % jamun seed powder, hydrocolloid mixture (2.289 % agar, 1.890 % pectin and 27.236 % polydextrose), antimicrobials (0.022 % benzoic acid and 0.085 % sorbic acid), and 40 % added water. The confection also contained 0.08 % sucralose, 0.06 % citric acid and 100 mg CaCl2.2H2O/g pectin. The confection was found to be rich in minerals like Ca, Mg, K, Na and P, with prebiotic activity and low glycemic index (48.1). Additionally, WJFC had reduced calorie (1.48 kcal/g) and high dietary fiber content (15.49 +/- 0.058 g/100 g (db)). The antioxidant potential measured as DPPH radical scavenging activity and FRAP with different extraction solvents was found to range between 0.26 +/- 0.01 and 0.98 +/- 0.04 mg BHA/g and 2.57 +/- 0.97 and 18.17 +/- 1.30 MUM Fe(2+)/g, respectively, with highest yield obtained for 50 % aq. ethanolic extract. Moreover, the antioxidant potential was observed to be dose dependent with IC50 values as 9.89 and 2.75 mg (db) against DPPH and superoxide anion radicals, respectively. WJFC was found to suppress alpha-amylase activity and retard glucose dialysis depicting the antidiabetic effect. PMID- 27478213 TI - Effects of membrane-filtered soy hull pectin and pre-emulsified fiber/oil on chemical and technological properties of low fat and low salt meat emulsions. AB - The objectives of this study were to determine efficacy of a membrane filtration in soy hull pectin purification and evaluate combined effects of soy hull pectin and pre-emulsified fiber/oil (PE) on chemical composition and technological properties of low fat and low salt meat emulsions. Soy hull pectin was purified through two different methods (alcohol-washed (ASP) and membrane-filtered (MSP)). Insoluble soy hull residues after pectin extraction were incorporated with sunflower oil and water for the PE preparation. Meat emulsion was formulated with 58 % pork, 20 % ice, 20 % pork backfat, and 2 % NaCl as control. A total of six low fat and low salt meat emulsions (1 % NaCl and 10 % backfat) was manufactured with 1 % pectin (with/without ASP or MSP) and 10 % PE (with/without). The pectin content of ASP and MSP was 0.84 and 0.64 g L-galacturonic acid/g dry sample, respectively. The inclusion of soy hull pectin caused similar results on chemical composition, color, cooking loss, and texture of the meat emulsions, regardless of the purification method. In addition, positive impacts of the combined treatments with soy hull pectin and PE compared to single treatments on cooking loss and texture of the meat emulsions were observed. Results suggest that membrane filtration could be an effective alternative method to purify pectin, instead of alcohol-washing, and both soluble pectin and insoluble fiber from soy hulls could be used as a functional non-meat ingredient to manufacture various low fat and low salt meat products. PMID- 27478215 TI - Quality evaluation of peony seed oil spray-dried in different combinations of wall materials during encapsulation and storage. AB - This study aimed at evaluating the performance of peony seed oil microencapsulated by spray drying during encapsulation and storage. Four different combinations of gum arabic (GA), corn syrup (CS), whey protein concentrate (WPC) and sodium caseinate (CAS) were used to encapsulate peony seed oil. The best encapsulation efficiency was obtained for CAS/CS followed by the CAS/GA/CS combination with the encapsulation ratio of 93.71 and 92.80 %, respectively, while the lowest encapsulation efficiency was obtained for WPC/GA/CS (85.96 %). Scanning electron microscopy and confocal laser scanning microscopy revealed that the particles were spherical in shape and did not exhibit apparent cracks or fissures, and gum arabic was uniformly distributed across the wall of the microcapsules. Oxidative stability study indicated that the CAS/GA/CS combination presented the best protection against lipid oxidation and the smallest loss of polyunsaturated fatty acid content among all of the formulas as measured by gas chromatography. Therefore, CAS/GA/CS could be promising materials encapsulate peony seed oil with high encapsulation efficiency and minimal lipid oxidation. PMID- 27478214 TI - Voltammetric determination of polyphenolic content as rosmarinic acid equivalent in tea samples using pencil graphite electrodes. AB - The quasi-reversible, diffusion controlled behavior of rosmarinic acid (RA) on a disposable pencil graphite electrode (PGE) was established by cyclic voltammetry. Using the anodic oxidation peak presented by RA on the PGE a differential pulse voltammetric (DPV) method was developed for the quantitative determination of RA. The linear range was 10(-8) - 10(-5) M RA and the detection and quantification limits were 7.93 * 10(-9) M and 2.64 * 10(-8) M RA, respectively. The applicability of the developed method was tested by recovery studies and by the assessment of the total polyphenolic contents (TPCDPV) of green, white and black Turkish teas, which were found to be 40.74, 30.04 and 23.97 mg rosmarinic acid equivalent/g dry tea, respectively. These results were in good agreement with those obtained by the Folin-Ciocalteu method. The developed method is a sensitive and cheap tool for the rapid and precise evaluation of TPCDPV of tea samples. PMID- 27478216 TI - Effects of plasticizers on sorption and optical properties of gum cordia based edible film. AB - The present study aimed to characterize a biodegradable film produced from the polysaccharide of an indigenous plant Cordia myxa. Effect of plasticizer type (Glycerol, Sorbitol, PEG200 and PEG 400) and concentration (0-30 %) was studied on sorption and optical properties of the casted film. Increase in plasticizer concentration resulted in increase in equilibrium moisture content of the film and was supported by GAB model of sorption indicating that isotherms were of Type II. The monolayer value increased with the increase in plasticizer concentration with a peak of 0.93 g.g-1 for glycerol. Addition of plasticizers improved the total color (DeltaE) with glycerol showing the highest effects. All films showed resistance to UV light in the range of 280-200 nm. The polysaccharide of the fruit of C.myxa can be used to prepare an edible film with improved properties as compared to other available edible coatings. PMID- 27478218 TI - Antilisterial effects of antibacterial formulations containing essential oils, nisin, nitrite and organic acid salts in a sausage model. AB - This study was conducted to evaluate the effects of sixteen antibacterial formulations against Listeria monocytogenes in a sausage model using a standard experimental design with 4 independent factors at 2 levels (2(4)). Four independent factors consisted of nisin (12.5-25 ppm), nitrite (100-200 ppm) and organic acid salts (1.55-3.1 %) and the mixture of Chinese cinnamon and Cinnamon bark Essential Oils (EOs) (0.025-0.05 %). Based on the analysis, utilization of low (0.025 %) or high concentration (0.05 %) of EOs in combination with low concentration of nitrite (100 ppm), organic acid salts (1.55 %), and nisin (12.5 ppm) could reduce respectively 1.5 or 2.6 log CFU/g of L. monocytogenes in sausage at day 7 of storage as compared to the control. A predictive equation was created to predict the growth of L. monocytogenes in sausage. The sensory evaluation was then performed on selected optimized formulations in cooked meat (both pork and beef sausages) with a trained jury consisting of 35 individuals, demonstrated the selected antimicrobial formulations were organoleptically acceptable. The results revealed an important role of hurdle technology to control L. monocytogenes in meat product. PMID- 27478217 TI - In vitro antioxidant, anti-diabetic and antilipemic potentials of quercetagetin extracted from marigold (Tagetes erecta L.) inflorescence residues. AB - Quercetagetin, the major flavonoid in marigold (Tagetes erecta L.) inflorescence residues was extracted and purified. The content of quercetagetin after the purification was 89.91 +/- 0.26 %. The in vitro antioxidant activity of quercetagetin and its potential in controlling diabetes mellitus and obesity were investigated and compared to quercetin and rutin. The 50 % inhibitory concentration (IC50) values of quercetagetin on scavenging 1, 1-diphenyl-2 picrylhydrazyl (DPPH), 2,2-azinobis-(3-ethylbenzothiazolin-6-sulfonic acid) (ABTS) and hydroxyl radicals were 27.12 +/- 1.31 MUmol/L, 12.16 +/- 0.56 MUmol/L and 1833.97 +/- 6.66 MUmol/L, respectively. The IC50 values of quercetagetin on alpha-glucosidase, alpha-amylase and pancreatic lipase were 180.11 +/- 3.68 MUmol/L, 137.71 +/- 3.55 MUmol/L and 2327.58 +/- 12.37 MUmol/L, respectively. These results indicated that quercetagetin exhibited strong in vitro antioxidant, anti-diabetic and antilipemic activities. Lineweaver-Burk plots analysis elucidated that quercetagetin inhibited alpha-glucosidase and alpha-amylase non competitively, while its inhibition against pancreatic lipase was involved in a mixed-type pattern. Moreover, strong correlations were found between ABTS(.+)/DPPH(.) scavenging activities and lipase inhibitory activity (R (2) > 0.90), as well as .OH scavenging activity and alpha-amylase inhibitory activity (R (2) = 0.8967). PMID- 27478219 TI - Extraction and evaluation of natural occurring bioactive compounds and change in antioxidant activity during red winemaking. AB - Phenolic composition of red wines from Stanusina, a grape variety indigenous of the Republic of Macedonia, was compared with the regional Vranec and the international Cabernet Sauvignon. The extent of skin contact (i.e. maceration time) on levels of phenolic compounds and antioxidant activity of wines was evaluated. A total of 19 phenolic compounds were identified and quantified. Among these malvidin-3-glucoside and its derivatives were the major compounds, while caftaric acid was the predominant cinnamic acid derivative, followed by catechin, the main flavan-3-ol. The concentration of hydroxycinnamic acids, anthocyanins and (+)-catechin ranged from 224 to 511 mg/L, 22 to 360 mg/L and 26 20 to 375 mg/L, respectively and peaked at 3rd, 6th and 9th day of maceration, respectively. However, prolong maceration slightly decreased their concentration. Stanusina wines presented high levels of hydroxycinnamic acids and antioxidant activity. PMID- 27478220 TI - Effect of nisin and perilla oil combination against Listeria monocytogenes and Staphylococcus aureus in milk. AB - In the present study, in vitro interaction of nisin and perilla oil (PO) against 20 food-borne isolates of L. monocytogenes and S. aureus were assessed using a checkerboard microdilution method. Synergism was observed in tested strains with the fractional inhibitory concentration indexs (FICIs) ranges from 0.125-0.25 and 0.19-0.375, respectively. Scanning electron microscopy was carried out to investigate the effect of nisin and PO on the integrity of cell wall and membrane of L. monocytogenes and S. aureus. The results showed that nisin and PO were more effective in damaging cell wall and membrane in combination. PMID- 27478221 TI - Stability and microstructure of freeze-dried guava pulp (Psidium guajava L.) with added sucrose and pectin. AB - Freeze-dried guava pulp powders, formulated with the addition of sucrose (0-20 g/100 g pulp) and pectin (0-1.0 g/100 g pulp), were obtained, and their stability was evaluated with respect to the water adsorption isotherms, thermal analysis and microstructure. The GAB (Guggenheim-Anderson-de Boer), Peleg and BET (Brunauer-Emmett-Teller) models were used to evaluate the water adsorption. The microstructure was examined using optical microscopy with polarized light and scanning electron microscopy (SEM). The GAB and BET parameters showed that the moisture content of the monolayer (Xm) increases with increasing pectin concentration in the adsorption isotherms. Optical microscopy micrographs showed that the pulp consisting of sucrose showed crystalline structures present in a higher amount and size, and this behavior is enhanced with increasing relative moisture. SEM showed that the increase in sucrose and pectin concentrations produced powders with lower porosity, providing greater stability to the product. The glass transition temperature increased slightly with increasing pectin concentration and decreased with increasing moisture content in the guava pulp powder. The kinetic curves, ratio of the increase of the water content against the storage time, of the guava pulp treated with 20 g sucrose per 100 g pulp and higher pectin concentration (0.5 or 1.0 g pectin per 100 g pulp) showed reduced adsorption and yielded freeze-dried pulps that were more stable. PMID- 27478222 TI - Germinated, toasted and cooked chickpea as ingredients for breadmaking. AB - The effect of processing (germination, toasting and cooking) of chickpea beans was investigated on the resulting flours characteristics and their potential for obtaining gluten free breads. Rheological properties of dough were recorded using Mixolab((r)) and breads were analyzed for their instrumental quality, nutritional and sensory properties. Chickpea based doughs showed low consistency and their rheological behavior was defined by the starch gelatinization and gelification. The bread made with cooked chickpea flour exhibited the lowest specific volume (0.58 mL/g), brightest crumb (L* = 76.20) and the softest texture, but cooking decreased the content of carbohydrates, ash and protein, although increased the protein digestibility. The highest specific volume was obtained in bread made with toasted chickpea flour, although crumb hardness was higher. Overall, processing of chickpea beans, concretely toasting and cooking led to flours that could be used for obtaining gluten free breads with the nutritional characteristics of the legumes and acceptable sensory characteristics. PMID- 27478223 TI - Effects of removal of surface proteins on physicochemical and structural properties of A- and B-starch isolated from normal and waxy wheat. AB - The effects of protein removal on the physicochemical and structural properties of normal and waxy wheat and their A- and B-type granule fractions were investigated. No evident changes were observed in the morphological, birefringence pattern and X-ray diffraction pattern after treatment, but there was evidence showing that the relative crystallinity, swelling power and percentage syneresis of all samples were significant increased. Protein removal treatment increased the peak, setback, final viscosity, breakdown viscosity of normal and waxy native wheat starch, and their A- and B-type starch granule fractions, whereas it decreased the pasting temperature, peak time and trough viscosity. Meanwhile, the thermal transition temperatures (To, Tp, Tc) and gelatinization temperature range (DeltaTr) of normal and waxy wheat and their isolated A- and B-type granules were increased, but the enthalpy decrease slightly. The different genetic factors and amylose content in normal and waxy wheat starch and their A- and B-type wheat starch granules fractions were related to the different physicochemical and structural characteristics of those starches. PMID- 27478225 TI - Evaluation of molecular weight distribution of unreduced wheat gluten proteins associated with noodle quality. AB - Unreduced gluten proteins of Indian wheat varieties viz.C306, DBW16, HI977 and HW2004 were separated using size-exclusion chromatography (SEC). Statistical correlation of area % of eluted peaks with properties of flour, dough and noodles was elucidated. Chromatograms of gluten proteins were classified primarily into five peaks in decreasing molecular size range and relative proportion were expressed in terms of area % of individual peaks which depicts the quantitative variation in protein eluted at different retention times. Cooking time and cooked weight of noodles depicted positive correlation with peak I and negative correlation with peak II which predominantly composed of glutenins and gliadins, respectively. Oil uptake and cooking loss were negatively association with peak I and positively with peak II. Noodle hardness, springiness, cohesiveness and chewiness were positively correlated with peak I and negatively to peak II, though adhesiveness was unaffected by SEC eluted peaks statistically. PMID- 27478224 TI - Regulation of acylated homoserine lactones (AHLs) in beef by spice marination. AB - Quorum sensing (QS) is a signaling mechanism used by bacteria to communicate each other through the release of auto-inducing signaling molecules. Despite the fact that bacteria regulate its phenotypes by QS mechanism, their potential role in meat spoilage is not yet elucidated. In the current study, beef samples were analyzed for its microbial association and for the presence of N-acyl-homoserine lactone (AHLs) throughout the storage experiments. Isolates were screened for AHLs production and selected spices were screened for their quorum sensing inhibitory (QSI) activity. In addition, effect of spices on AHLs production of Y. enterocolitica was quantified through high performance thin layer chromatography (HP-TLC). Outcome showed that microbial association of beef mainly consists of lactic acid bacteria (LAB) and Enterobacteriaceae. Samples stored at both aerobic and modified atmospheric packaging (MAP) exhibited higher counts whereas; marinated samples stored at MAP exhibited the lowest. It was found that out of 35 isolates Y. enterocolitica induced reporter strain CV026 and its cell-free supernatant contained 26.36 nM/100 ml of AHLs when compared to standard. Among the tested spices, C. cyminum exhibited pronounced results by significantly reducing the AHLs concentration up to 47.75 %. Findings revealed the presence of quorum molecules (AHLs) in beef meat throughout the spoilage process and spices can acts as quorum quenchers to influence the spoilage rate by reducing AHLs production. PMID- 27478226 TI - Soft computing modelling of moisture sorption isotherms of milk-foxtail millet powder and determination of thermodynamic properties. AB - Moisture sorption isotherms of spray-dried milk-foxtail millet powder were determined at 10, 25 and 40 degrees C. Sorption data was fitted using classical and soft-computing approaches. The isotherms were of type II, and equilibrium moisture content (EMC) was temperature dependent. The BET monolayer moisture content decreased from 3.30 to 2.67 % as temperature increased from 10 to 40 degrees C. Amongst the classical models, Ferro-Fontan gave the best fit of EMC-aw data. However, the Sugeno-type adaptive neuro-fuzzy inference system (ANFIS) with generalized bell-shaped membership function performed better than artificial neural network and classical models with RMSE as low as 0.0099. The isosteric heat of sorption decreased from 150.32 kJ mol(-1) at 1 % moisture content to 44.11 kJ mol(-1) at 15 % moisture. The enthalpy-entropy compensation theory was validated, and the isokinetic and harmonic mean temperatures were determined as 333.1 and 297.5 K, respectively. PMID- 27478227 TI - Influence of palm oil and glycerol on properties of fish skin gelatin-based films. AB - Properties of fish skin gelatin film incorporated with palm oil at 50 and 75 % (w/w) as affected by glycerol at 0-30 % (w/w) were investigated. Increases in water vapour permeability and elongation at break along with decrease in tensile strength were noticed when levels of glycerol were increased (p < 0.05). Decrease in L*- and a*-values with coincidental increase in b*- and DeltaE*-values were observed in emulsified films when amount of palm oil incorporated increased (p < 0.05). Light transmittance of all films increased as glycerol levels were increased (p < 0.05). FTIR results suggested that the protein-protein interaction in film matrix decreased when palm oil was incorporated. Films added with palm oil had lower glass transition and degradation temperatures than control films. The addition of 75 % palm oil and 10 % glycerol improved water vapour barrier property of fish skin gelatin films without drastic alteration of mechanical properties. PMID- 27478228 TI - Effect of high hydrostatic pressure on rheological and thermophysical properties of murtilla (Ugni molinae Turcz) berries. AB - Effects of high hydrostatic pressure (HHP) on rheological and thermophysical properties of murtilla berries were evaluated after pressure treatments for 5 min between 100 and 500 MPa. Differential scanning calorimetry was employed to measure specific heat capacity. HHP caused a significant decrease in specific heat and density, while thermal diffusivity did not changed significantly. Thermal conductivity showed a slight increase upon HHP treatment. Apparent viscosity increased significantly above 200 MPa HHP treatment. Apparent viscosity of treated samples between 200 and 400 MPa did not differ significantly and the increase was significant at 500 MPa. Herschel-Bulkley, Bingham and Ostwald de Waele models were used to describe the rheological behaviour of murtilla puree, and Ostwald de Waele model gave the best fit for the experimental data. PMID- 27478229 TI - Improvement of physical properties of gluten-free steamed cake based on black waxy rice flour using different hydrocolloids. AB - This study aimed to compare the effects of 1 % addition of four selected hydrocolloids (xanthan, guar, hypdroxypropylmethylcellulose and carrageenan) on quality characteristics of batter and of black waxy rice steamed cake compared to a control without hydrocolloids. Dynamic frequency sweeps of the batters at 25 degrees C indicated that all formulations exhibited gel-like behaviour with storage moduli (G') higher than loss moduli (G"). Hydrocolloids increased the apparent viscosity and the thixotropic behaviour, depending on the type of hydrocolloids. Xanthan had the greatest effects on both moduli, whereas carrageenan had the smallest effects. During a storage period of 4 days the cakes with xanthan remained softer than control samples. The overall acceptability of cake with xanthan and guar were higher than control. This study is the first report on using black waxy rice flour as a main raw material in gluten free cake. The results of this study provided useful information for selection hydrocolloids as ingredients that can help to improve the physical properties of waxy rice steamed cake. PMID- 27478230 TI - Effect of low temperature plasma on the functional properties of basmati rice flour. AB - The present study deals with the application of low temperature plasma on basmati rice flour and its effect on functional properties such as gel hydrations properties, flour hydration properties, gelatinization temperatures and antioxidant properties. The water holding capacity and water binding capacity were observed to be increased with increase in plasma power and time of treatment as the air plasma is known to make the surface more hydrophilic. XRD analysis revealed there is no significance difference in the crystalline structure after the plasma treatment. DSC shows a decrease in peak temperatures (Tp) after the treatment. Hot paste viscosities were observed to be decease from 692 to 591 BU was corresponded to decrease in peak temperature. The total polyphenolic content and reducing power was observed to be increased. The effects of plasma treatment on functional groups of polyphenols were observed by changes in absorption intensities using FTIR. This study demonstrates that the low temperature plasma treatmentis capable of improving the functional properties of basmati rice. PMID- 27478231 TI - Ultrasound treatment: effect on physicochemical, microbial and antioxidant properties of cherry (Prunus avium). AB - The cherry was treated with ultrasonic waves (33 kHz, 60 W) at different time intervals (10, 20, 30, 40, 60 min) and study was carried out to analyze the change in physico-chemical properties (TSS, pH, color, acidity and firmness), antioxidant potential and microbial load of the fruit during the storage period of 15 days at 4 degrees C. It was observed that ultrasound treatment (US) between 30 and 40 min showed better retention of color of the fruit during the storage period. The antioxidant assays (DPPH, ABTS and TPC) also increased significantly (P <= 0.05) up to 40 min, however the firmness of the fruit was affected and it showed a significant decrease beyond 20 min of US treatment. The sample with 40 min US treatment showed significantly less microbial load than other samples. The 20-40 min US treatment time (33 kHz, 60 W) was suggested for preservation of cherry during the storage at 4 degrees C. PMID- 27478232 TI - Effect of pre-cooking methods on the chemical and sensory deterioration of ready to-eat chicken patties during chilled storage and microwave reheating. AB - The effects of pre-cooking methods, namely, boiling (BL), roasting (RT) and grilling (GR), refrigerated storage (14 days/+4 degrees C) and microwave reheating on chicken patties were studied. Physical, chemical and sensory parameters were evaluated in order to correlate the chemical deterioration of ready-to-eat chicken patties with the acceptance of the odor. Chemical deterioration was evaluated through the chemical composition, Maillard compounds, Thiobarbituric acid-reactive substances (TBARS) and volatiles. Sensory deterioration (odor liking) was performed by an acceptance test with hedonic scale. According to the TBARS values and volatile compounds generated in the head space during the examined stages, the pre-cooking method and the storage time had a significant effect on lipid oxidation, whereas reheating in a microwave had a negligible impact. At each succeeding processing stage, panelists gave lower odor scores to all samples and no significant differences were found between treatments at any stage. RT and GR patties showed less intense chemical changes and presented higher acceptation scores by the sensory panel than BL patties. Thus, the choice of pre-cooking method and control of storage conditions plays a key role in the inhibition of oxidative changes in ready-to-eat chicken patties. PMID- 27478233 TI - Numerical simulation of transient temperature profiles for canned apple puree in semi-rigid aluminum based packaging during pasteurization. AB - Pasteurization of canned apple puree was simulated for a 3-D geometry in a semi rigid aluminum based container which was heated from all sides at 378 K. The computational fluid dynamics code Ansys Fluent 14.0 was used and the governing equations for energy, momentum, and continuity were computed using a finite volume method. The food model was assumed to have temperature-dependent properties. To validate the simulation, the apple puree was pasteurized in a water cascading retort. The effect of the mesh structures was studied for the temperature profiles during thermal processing. The experimental temperature in the slowest heating zone in the container was compared with the temperature predicted by the model and the difference was not significant. The study also investigated the impact of head space (water-vapor) on heat transfer. PMID- 27478234 TI - Evaluation of nutraceutical and antinutritional properties in barnyard and finger millet varieties grown in Himalayan region. AB - Five elite varieties of barnyard (Echinochloa frumentacea) and finger (Eleusine coracana) growing at northwestern Himalaya were investigated for nutraceutical and antinutritional properties. Barnyard millet contained higher amount of crude fiber, total dietary fiber, tryptophan content, total carotenoids, alpha tocopherol compared to the finger millet whereas the finger millet contains higher amount of methionine and ascorbic acid as compared to the barnyard millet. The secondary metabolites of biological functions were analyzed and found that barnyard millet contained the higher amount of polyphenols, tannins and ortho dihydroxy phenol content compared to finger millet. Among antinutitional compounds barnyard millet contained lower phytic acid content compare to finger millet whereas no significant difference in trypsin inhibition activity of barnyard millet and finger millet varieties were found. Barnyard millet contained higher acid phosphatase, alpha-galactosidase and alpha-amylase inhibitor activity compared to finger millet. Finger millet seeds contained about 10-13 folds higher calcium content and double amount of manganese content in comparison to barnyard millet seeds. Present study suggests that barnyard millet varieties studied under present investigation were found nutritionally superior compared to finger millet varieties. PMID- 27478235 TI - Antioxidant protection of proteins and lipids in processed pork loin chops through feed supplementation with avocado. AB - This study was conducted to analyze the impact of dietary avocado on the oxidative stability of lipids and proteins during pork processing. Loins from control (fed basic diet) and treated pigs (fed on avocado-supplemented diet) were roasted (102 degrees C/20 min) and subsequently packed in trays wrapped with oxygen-permeable films and chilled at 4 degrees C for 12 days. At each processing stage (raw, cooked and cooked & chilled), pork samples from both groups were analyzed for the concentration of TBARS, the loss of tryptophan and free thiols, and the formation of protein carbonyls, disulphide bonds and Schiff bases. Processing led to a depletion of tryptophan and sulfur-containing amino acids and an increase of lipid and protein oxidation products. Dietary avocado was not able to protect against the oxidation of tryptophan and thiols but cooked & chilled loins from treated pigs had significantly lower concentration of lipid and protein carbonyls than control counterparts. Likewise, dietary avocado alleviated the formation of Schiff bases during cooking. These results illustrate the benefits of dietary avocado on the oxidative stability of processed pork loins. PMID- 27478236 TI - Near-infrared spectroscopy for rapid classification of fruit spirits. AB - Multivariate analysis combined with near-infrared (NIR) spectral analysis was evaluated to classify fruit spirits. A total of 67 fruit spirits (12 apple, 18 apricot, 19 pear and 18 plum spirits) were analyzed. NIR spectra were collected in the wavenumber range of 4000-10,000 cm(-1). Linear discriminant analysis based on principal component analysis (PCA-LDA) and general discriminant analysis (GDA) based directly on NIR spectral data were used to classify the samples. The prediction performance of models in different wavenumber ranges was also investigated. The best PCA-LDA and GDA models gave a 100 % classification of spirits of the four fruit kinds in the wavenumber range from 5500 to 6050 cm(-1) corresponding to either the C-H stretch of the first overtones of CH3 and CH2 groups, or to compounds containing O-H aromatic groups. The results demonstrated that NIR spectroscopy could be used as a rapid method for classification of fruit spirits. PMID- 27478237 TI - Phytochemical study and antioxidant, antimicrobial and anticancer activities of Melanelia subaurifera and Melanelia fuliginosa lichens. AB - The aim of this study was to investigate antioxidant, antimicrobial and anticancerous activity of Melanelia subaurifera and Melanelia fuliginosa. The phytochemical analysis was determined by HPLC-UV method. Antioxidant activity was evaluated by DPPH and reducing power assay while antimicrobial activity was determined by minimal inhibitory concentration. The cytotoxic activity was tested using MTT method. The method for quantification of 2'-O-methyl anziaic acid and lecanoric acid in these lichens using RF-HPLC was also developed and validated. The depsides (lecanoric acid, gyrophoric acid, atranorin, anziaic acid and 2'-O methyl anziaic acid), and dibenzofurane (usnic acid) were identified in these lichens. The antioxidant activity (IC50) of lichens extracts ranged from 121.52 to 424.51 MUg/ml. 2'-O-Methyl anziaic acid showed the highest antimicrobial activity with MIC ranging from 0.0625 to 1 mg/ml. M. subaurifera extract showed the highest cytotoxic activity against the tested cell lines (IC50 = 9.88 to 31.64 MUg/ml). PMID- 27478238 TI - Preparation of antioxidant active films based on chitosan: diffusivity study of alpha-tocopherol into food simulants. AB - New active films based on chitosan and polycaprolactone blends and containing alpha-tocopherol were designed for food packaging applications. Mechanical properties, stability against temperature and swelling degree in 50 % ethanol (v/v) were evaluated. Migration kinetics of alpha-tocopherol from the developed films into butter and food simulants [50 % ethanol (v/v), 95 % ethanol (v/v), and isooctane] at different temperatures were studied. alpha-Tocopherol was quantified in the food simulants by means of high performance liquid chromatography with diode-array detection at 292 nm. The proposed method exhibited a good sensitivity with a limit of detection of 0.1 mg/L. The kinetics release of alpha-tocopherol was characterized by determining the partition and the diffusion coefficients by using a mathematical modeling based on Fick's Second Law. The diffusion coefficients obtained ranged between 1.03 * 10(-13) and 2.24 * 10(-12) cm(2)/s for 95 % ethanol (v/v) at 4 and 20 degrees C, respectively. Developed films maintained the antioxidant activity for more than 20 days. PMID- 27478239 TI - Effect of cryogenic grinding on volatile and fatty oil constituents of cumin (Cuminum cyminum L.) genotypes. AB - Effect of cryogenic grinding on recovery of volatile oil, fatty oil percentage and their constituents in two cumin (Cuminum cyminum L.) genotypes have been analyzed. Cryogenic grinding not only retains the volatiles but enhanced the recovery by 33.9 % in GC 4 and 43.5 % in RZ 209. A significant increase (29.9 %) over normal grinding in oil percentage was also observed in genotype RZ 209. This increase was, however, less (15.4 %) in genotype GC 4. Nineteen major compounds were identified in the essential oil of both genotypes. The two grinding techniques had significant effects on dependent variables, viz., volatile oil and monoterpenes. Cuminaldehyde was the main constituent in both genotypes, content of which increased from 48.2 to 56.1 % in GC 4 on cryo grinding. Content of terpines were found to decrease in cryo ground samples of GC 4 and either decrease or no change was found in RZ 209. Organoleptic test showed more pleasant aroma in cryo ground seeds of both the genotypes. Significant increase was also reported in fatty oil yield due to cryogenic grinding. Fatty acid methyl ester (FAME) analysis showed oleic acid as major FAME content of which increased from 88.1 to 94.9 % in RZ 209 and from 88.2 to 90.1 % in GC 4 on cryogenic grinding. Other prominent FAME were palmitic, palmitoleic and stearic acid. Results indicated commercial potential of cryogenic grinding technology for cumin in general and spices in particular for better retention of flavour and quality in spices. PMID- 27478240 TI - Development of walnut dehulling machine and assessment of its performance using Ethephon and Tween-80 as pre-treatments for hull loosening. AB - A power- driven walnut dehulling machine was developed and tested. The machine was evaluated for dehulling after applying Ethephon and Tween-80 to green walnuts by dip and spray methods. The results showed that with the increase in dipping time and post dipping/spraying time, the effective throughput capacity, dehulling efficiency and fully dehulled walnut percentage increased, whereas partially dehulled walnut percentage and labour requirement decreased in both manual and mechanical dehulling. Maximum effective throughput capacity, dehulling efficiency and fully dehulled walnut percentage were observed, when green walnuts were subjected to dehulling after 4 days of Ethephon spray treatment (0.3 %). The effective throughput capacity, dehulling efficiency and fully dehulled walnut percentage were found significantly higher in mechanical dehulling than in manual dehulling. PMID- 27478241 TI - Effects of fresh Aloe vera gel coating on browning alleviation of fresh cut wax apple (Syzygium samarangenese) fruit cv. Taaptimjaan. AB - The effect of natural coating by using fresh Aloe vera (A. vera) gel alleviating browning of fresh-cut wax apple fruits cv. Taaptimjaan was investigated. The fresh-cut fruits were dipped in fresh A. vera gel at various concentrations of 0, 25, 75 or 100 % (v/v) for 2 min at 4 +/- 1 degrees C for 6 days. Lightness (L*), whiteness index (WI), browning index (BI), total color difference (DeltaE*), sensorial quality attributes, total phenolic (TP) content, antioxidant activity and polyphenol oxidase (PPO) and peroxidase (POD) activities were determined. During storage, L* and WI of the fresh-cut fruits surface decreased whilst their BI and DeltaE* increased. A. vera coating maintained the L* and WI and delayed the increase in BI and DeltaE*, especially at 75 % A. vera dip. The fresh-cut fruits dipped in 75 % A. vera had the lowest browning score, the highest acceptance score and delayed the increase in TP content and PPO activity. However POD activity was induced by A. vera coating. Antioxidant activity had no effect on browning incidence of the fresh-cut fruits. Consequently, A. vera gel coating could maintain quality and retarded browning of fresh-cut wax apple fruits during storage. PMID- 27478242 TI - Bio-fortification and shelf-life extension of idli batter using curry leaves (Murraya koenigii). AB - Among several traditional foods of India, idli is one of the most popular and commonly consumed steamed products. A new method of adding Murraya koenigii (curry leaves) to idli batter as a vehicle for fortification and extension of shelf-life has been developed. Dried curry leaves powder was incorporated with other ingredients like rice and dehusked black gram in different proportions to optimize the most palatable formulation. Rate of fermentation and microbial changes in the batter; nutritional qualities, texture and sensory properties of the prepared product were assessed. Incorporation of curry leaves powder (5 %) in idli batter increased the shelf-life and also increased the flavour, texture and appearance of the idli. The calcium content of the prepared idli was 10 times more than that of the control idli, while dietary fiber content increased by 18.6 %. Anti-microbial activity of the curry leaves in idli batter extended the shelf life from 2 to 5 days when stored at 30 degrees C. PMID- 27478243 TI - Contribution of crosslinking products in the flavour enhancer processing: the new concept of Maillard peptide in sensory characteristics of Maillard reaction systems. AB - In this study, the flavour-enhancing properties of the Maillard reaction products (MRPs) for different systems consisted of different peptides (sunflower, SFP; corn, CP and soyabean SP) with, xylose and cysteine were investigated. Maillard systems from peptides of sunflower, corn and soyabean with xylose and cysteine were designated as PXC, MCP and MSP, respectively. The Maillard systems were prepared at pH of 7.4 using temperature of 120C for 2 h. Results showed that all systems were significantly different in all sensory attributes. The highest scores for mouthfulness and continuity were observed for MCP with the lowest peptides distribution between 1000 and 5000 Da, known as Maillard peptide. This revealed that the MCP with the lowest Maillard peptide content had the strongest "Kokumi" effect compared to the other MRPsand demonstrated that "kokumi effect" of MRPs was contributed by not only the "Maillard peptide" defined by the molecular weight (1000-5000 Da). Results on sensory evaluation after fractionation of PXC followed by enzymatic hydrolysis showed no significant differences between PXC, P-PXC and their hydrolysates. This observation therefore confirmed that the presence of other contributors attributed to the "Kokumi" effect rather than the Maillard peptide. It can be deduced that the unhydrolyzed crosslinking products might have contributed to the "Kokumi" effect of MRPs. The structures of four probable crosslinking compounds were proposed and the findings have provided new insights in the sensory characteristics of xylose, cysteine and sunflower peptide MRPs. PMID- 27478244 TI - Application of guar-xanthan gum mixture as a partial fat replacer in meat emulsions. AB - The physicochemical, oxidative, texture and microstructure properties were evaluated for low fat meat emulsions containing varying levels of guar/xanthan gum mixture (1:1 ratio) as a fat substitute. Partial replacement of fat with guar/xanthan gum resulted in higher emulsion stability and cooking yield but lower penetration force. Proximate composition revealed that high fat control had significantly higher fat and lower moisture content due to the difference in basic formulation. Colour evaluation revealed that low fat formulations containing gum mixture had significantly lower lightness and higher yellowness values than high fat control formulation. However non-significant difference was observed in redness values between low fat formulations and the high fat control. The pH values of the low fat formulations containing gum mixture were lower than the control formulations (T0 and TC). The MetMb% of the high fat emulsion formulation was higher than low fat formulations. The significant increase of TBARS value, protein carbonyl groups and loss of protein sulphydryl groups in high fat formulation reflect the more oxidative degradation of lipids and muscle proteins during the preparation of meat emulsion than low fat formulations. The SEM showed a porous matrix in the treatments containing gum mixture. Thus, the guar/xanthan gum mixture improved the physicochemical and oxidative quality of low fat meat emulsions than the control formulations. PMID- 27478245 TI - Use of paprika oily extract as pre-extrusion colouring of rice extrudates: impact of processing and storage on colour stability. AB - Suitability of paprika oily extract as a pre-extrusion colouring of rice extrudate was evaluated as a function of extrusion parameters viz. moisture content, screw speed and die temperature. Most acceptable coloured rice extrudates in terms of colour and overall acceptability was achieved with addition of 3 % paprika oily extract and which is extruded at fixed conditions of 25 % feed moisture, 120 degrees C barrel temperature and 100 rpm screw speed. During extrusion, retention of red colour of paprika oily extract added rice extrudates increased with an increase in feed moisture and screw speed while decreased with an increase in barrel temperature. Present study was also undertaken to check effect of addition of butylated hydroxytoluene (BHT) on colour stability of coloured rice extrudates. Coloured rice extrudates were packed in polyethylene, metallised polyethylene and vacuum packaging material and subjected to storage studies for 90 days at 25 and 50 degrees C with 65 % relative humidity conditions. Retention of red colour (a*) of paprika oily extract added rice extrudates follows first order kinetics, showing a faster rate of degradation with half-life of 48 days when packed in metalized polyethylene and stored at higher temperature conditions. PMID- 27478248 TI - Hydrology controls dissolved organic matter export and composition in an Alpine stream and its hyporheic zone. AB - Streams and rivers transport dissolved organic matter (DOM) from the terrestrial environment to downstream ecosystems. In light of climate and global change it is crucial to understand the temporal dynamics of DOM concentration and composition, and its export fluxes from headwaters to larger downstream ecosystems. We monitored DOM concentration and composition based on a diurnal sampling design for 3 years in an Alpine headwater stream. We found hydrologic variability to control DOM composition and the coupling of DOM dynamics in the streamwater and the hyporheic zone. High-flow events increased DOM inputs from terrestrial sources (as indicated by the contributions of humic- and fulvic-like fluorescence), while summer baseflow enhanced the autochthonous imprint of DOM. Diurnal and seasonal patterns of DOM composition were likely induced by biological processes linked to temperature and photosynthetic active radiation (PAR). Floods frequently interrupted diurnal and seasonal patterns of DOM, which led to a decoupling of streamwater and hyporheic water DOM composition and delivery of aromatic and humic-like DOM to the streamwater. Accordingly, DOM export fluxes were largely of terrigenous origin as indicated by optical properties. Our study highlights the relevance of hydrologic and seasonal dynamics for the origin, composition and fluxes of DOM in an Alpine headwater stream. PMID- 27478249 TI - A cautionary note on the use of Ornstein Uhlenbeck models in macroevolutionary studies. AB - Phylogenetic comparative methods are increasingly used to give new insights into the dynamics of trait evolution in deep time. For continuous traits the core of these methods is a suite of models that attempt to capture evolutionary patterns by extending the Brownian constant variance model. However, the properties of these models are often poorly understood, which can lead to the misinterpretation of results. Here we focus on one of these models - the Ornstein Uhlenbeck (OU) model. We show that the OU model is frequently incorrectly favoured over simpler models when using Likelihood ratio tests, and that many studies fitting this model use datasets that are small and prone to this problem. We also show that very small amounts of error in datasets can have profound effects on the inferences derived from OU models. Our results suggest that simulating fitted models and comparing with empirical results is critical when fitting OU and other extensions of the Brownian model. We conclude by making recommendations for best practice in fitting OU models in phylogenetic comparative analyses, and for interpreting the parameters of the OU model. PMID- 27478250 TI - Determining the Effective Density and Stabilizer Layer Thickness of Sterically Stabilized Nanoparticles. AB - A series of model sterically stabilized diblock copolymer nanoparticles has been designed to aid the development of analytical protocols in order to determine two key parameters: the effective particle density and the steric stabilizer layer thickness. The former parameter is essential for high resolution particle size analysis based on analytical (ultra)centrifugation techniques (e.g., disk centrifuge photosedimentometry, DCP), whereas the latter parameter is of fundamental importance in determining the effectiveness of steric stabilization as a colloid stability mechanism. The diblock copolymer nanoparticles were prepared via polymerization-induced self-assembly (PISA) using RAFT aqueous emulsion polymerization: this approach affords relatively narrow particle size distributions and enables the mean particle diameter and the stabilizer layer thickness to be adjusted independently via systematic variation of the mean degree of polymerization of the hydrophobic and hydrophilic blocks, respectively. The hydrophobic core-forming block was poly(2,2,2-trifluoroethyl methacrylate) [PTFEMA], which was selected for its relatively high density. The hydrophilic stabilizer block was poly(glycerol monomethacrylate) [PGMA], which is a well known non-ionic polymer that remains water-soluble over a wide range of temperatures. Four series of PGMA x -PTFEMA y nanoparticles were prepared (x = 28, 43, 63, and 98, y = 100-1400) and characterized via transmission electron microscopy (TEM), dynamic light scattering (DLS), and small-angle X-ray scattering (SAXS). It was found that the degree of polymerization of both the PGMA stabilizer and core-forming PTFEMA had a strong influence on the mean particle diameter, which ranged from 20 to 250 nm. Furthermore, SAXS was used to determine radii of gyration of 1.46 to 2.69 nm for the solvated PGMA stabilizer blocks. Thus, the mean effective density of these sterically stabilized particles was calculated and determined to lie between 1.19 g cm-3 for the smaller particles and 1.41 g cm-3 for the larger particles; these values are significantly lower than the solid-state density of PTFEMA (1.47 g cm-3). Since analytical centrifugation requires the density difference between the particles and the aqueous phase, determining the effective particle density is clearly vital for obtaining reliable particle size distributions. Furthermore, selected DCP data were recalculated by taking into account the inherent density distribution superimposed on the particle size distribution. Consequently, the true particle size distributions were found to be somewhat narrower than those calculated using an erroneous single density value, with smaller particles being particularly sensitive to this artifact. PMID- 27478252 TI - Endoskeletal structure in Cheirolepis (Osteichthyes, Actinopterygii), An early ray-finned fish. AB - As the sister lineage of all other actinopterygians, the Middle to Late Devonian (Eifelian-Frasnian) Cheirolepis occupies a pivotal position in vertebrate phylogeny. Although the dermal skeleton of this taxon has been exhaustively described, very little of its endoskeleton is known, leaving questions of neurocranial and fin evolution in early ray-finned fishes unresolved. The model for early actinopterygian anatomy has instead been based largely on the Late Devonian (Frasnian) Mimipiscis, preserved in stunning detail from the Gogo Formation of Australia. Here, we present re-examinations of existing museum specimens through the use of high-resolution laboratory- and synchrotron-based computed tomography scanning, revealing new details of the neuro-cranium, hyomandibula and pectoral fin endoskeleton for the Eifelian Cheirolepis trailli. These new data highlight traits considered uncharacteristic of early actinopterygians, including an uninvested dorsal aorta and imperforate propterygium, and corroborate the early divergence of Cheirolepis within actinopterygian phylogeny. These traits represent conspicuous differences between the endoskeletal structure of Cheirolepis and Mimipiscis. Additionally, we describe new aspects of the parasphenoid, vomer and scales, most notably that the scales display peg-and-socket articulation and a distinct neck. Collectively, these new data help clarify primitive conditions within ray-finned fishes, which in turn have important implications for understanding features likely present in the last common ancestor of living osteichthyans. PMID- 27478251 TI - Where are the polyps? Molecular identification, distribution and population differentiation of Aurelia aurita jellyfish polyps in the southern North Sea area. AB - For many species of metagenic jellyfish the location of the benthic polyps is unknown. To gain insight in the distribution, species composition and population structure of scyphozoan jellyfish polyps in the southern North Sea area, polyp samples were collected from natural and artificial substrates (settling plates, marina floats and wrecks) at ten inshore locations in the Netherlands, seven offshore locations in the North Sea and in the Gullmar Fjord in Sweden. Polyps were identified to species level by sequencing both a fragment of 18S rDNA and a fragment of mitochondrial COI, and comparing these sequences to reference sequences available in GenBank and to newly obtained sequences from medusae collected in the area. All polyps sequenced did belong to Aurelia aurita. For this species, molecular diversity in mitochondrial COI was high, with 50 haplotypes among 183 polyps. Population differentiation was detected between the Dogger Bank and other-more coastal-locations, indicating extremely low connectivity. No significant differences were found between coastal samples. The location of polyps of Cyanea capillata, Cyanea lamarckii, Chrysaora hysoscella and Rhizostoma octopus in the study area remains unresolved. PMID- 27478253 TI - Cassava brown streak disease and the sustainability of a clean seed system. AB - One method of reducing disease in crops is the dissemination of disease-free planting material from a multiplication site to growers. This study assesses the validity and sustainability of this method for cassava brown streak disease, a threat to cassava crops across East Africa. Using mathematical modelling, the effects of different environmental and control conditions on pathogen spread were determined in a single-field multiplication site. High disease pressure, through large vector populations and disease in the surrounding area, combined with poor roguing practice, resulted in unsuccessful disease suppression. However, fields may produce sufficiently clean material for replanting if these factors can be overcome. Assessing the sustainability of a low-pressure system over multiple harvests, well-managed fields were found to maintain low disease levels, although producing sufficient cuttings may prove challenging. Replanting fields from the previous harvest does not lead to degeneration of planting material, only cutting numbers, and the importation of new clean material is not necessarily required. It is recommended that multiplication sites are only established in areas of low disease pressure and vector population density, and the importance of training in field management is emphasized. Cultivars displaying strong foliar symptoms are to be encouraged, as these allow for effective roguing, resulting in negative selection against the disease and reducing its spread. Finally, efforts to increase plant multiplication rates, the number of cuttings that can be obtained from each plant, have a significant impact on the sustainability of sites, as this represents the primary limiting factor to success. PMID- 27478254 TI - Race, Space, and Cumulative Disadvantage: A Case Study of the Subprime Lending Collapse. AB - In this article, we describe how residential segregation and individual racial disparities generate racialized patterns of subprime lending and lead to financial loss among black borrowers in segregated cities. We conceptualize race as a cumulative disadvantage because of its direct and indirect effects on socioeconomic status at the individual and neighborhood levels, with consequences that reverberate across a borrower's life and between generations. Using Baltimore, Maryland as a case study setting, we combine data from reports filed under the Home Mortgage Disclosure Act with additional loan-level data from mortgage-backed securities. We find that race and neighborhood racial segregation are critical factors explaining black disadvantage across successive stages in the process of lending and foreclosure, controlling for differences in borrower credit scores, income, occupancy status, and loan-to-value ratios. We analyze the cumulative cost of predatory lending to black borrowers in terms of reduced disposable income and lost wealth. We find the cost to be substantial. Black borrowers paid an estimated additional 5 to 11 percent in monthly payments and those that completed foreclosure in the sample lost an excess of $2 million in home equity. These costs were magnified in mostly black neighborhoods and in turn heavily concentrated in communities of color. By elucidating the mechanisms that link black segregation to discrimination we demonstrate how processes of cumulative disadvantage continue to undermine black socioeconomic status in the United States today. PMID- 27478255 TI - Stream water age distributions controlled by storage dynamics and nonlinear hydrologic connectivity: Modeling with high-resolution isotope data. AB - To assess the influence of storage dynamics and nonlinearities in hydrological connectivity on time-variant stream water ages, we used a new long-term record of daily isotope measurements in precipitation and streamflow to calibrate and test a parsimonious tracer-aided runoff model. This can track tracers and the ages of water fluxes through and between conceptual stores in steeper hillslopes, dynamically saturated riparian peatlands, and deeper groundwater; these represent the main landscape units involved in runoff generation. Storage volumes are largest in groundwater and on the hillslopes, though most dynamic mixing occurs in the smaller stores in riparian peat. Both streamflow and isotope variations are generally well captured by the model, and the simulated storage and tracer dynamics in the main landscape units are consistent with independent measurements. The model predicts that the average age of stream water is ~1.8 years. On a daily basis, this varies between ~1 month in storm events, when younger waters draining the hillslope and riparian peatland dominates, to around 4 years in dry periods when groundwater sustains flow. This variability reflects the integration of differently aged water fluxes from the main landscape units and their mixing in riparian wetlands. The connectivity between these spatial units varies in a nonlinear way with storage that depends upon precipitation characteristics and antecedent conditions. This, in turn, determines the spatial distribution of flow paths and the integration of their contrasting nonstationary ages. This approach is well suited for constraining process-based modeling in a range of northern temperate and boreal environments. PMID- 27478256 TI - Water sources and mixing in riparian wetlands revealed by tracers and geospatial analysis. AB - Mixing of waters within riparian zones has been identified as an important influence on runoff generation and water quality. Improved understanding of the controls on the spatial and temporal variability of water sources and how they mix in riparian zones is therefore of both fundamental and applied interest. In this study, we have combined topographic indices derived from a high-resolution Digital Elevation Model (DEM) with repeated spatially high-resolution synoptic sampling of multiple tracers to investigate such dynamics of source water mixing. We use geostatistics to estimate concentrations of three different tracers (deuterium, alkalinity, and dissolved organic carbon) across an extended riparian zone in a headwater catchment in NE Scotland, to identify spatial and temporal influences on mixing of source waters. The various biogeochemical tracers and stable isotopes helped constrain the sources of runoff and their temporal dynamics. Results show that spatial variability in all three tracers was evident in all sampling campaigns, but more pronounced in warmer dryer periods. The extent of mixing areas within the riparian area reflected strong hydroclimatic controls and showed large degrees of expansion and contraction that was not strongly related to topographic indices. The integrated approach of using multiple tracers, geospatial statistics, and topographic analysis allowed us to classify three main riparian source areas and mixing zones. This study underlines the importance of the riparian zones for mixing soil water and groundwater and introduces a novel approach how this mixing can be quantified and the effect on the downstream chemistry be assessed. PMID- 27478257 TI - A review of the potential for competitive cereal cultivars as a tool in integrated weed management. AB - Competitive crop cultivars offer a potentially cheap option to include in integrated weed management strategies (IWM). Although cultivars with high competitive potential have been identified amongst cereal crops, competitiveness has not traditionally been considered a priority for breeding or farmer cultivar choice. The challenge of managing herbicide-resistant weed populations has, however, renewed interest in cultural weed control options, including competitive cultivars. We evaluated the current understanding of the traits that explain variability in competitive ability between cultivars, the relationship between suppression of weed neighbours and tolerance of their presence and the existence of trade-offs between competitive ability and yield in weed-free scenarios. A large number of relationships between competitive ability and plant traits have been reported in the literature, including plant height, speed of development, canopy architecture and partitioning of resources. There is uncertainty over the relationship between suppressive ability and tolerance, although tolerance is a less stable trait over seasons and locations. To realise the potential of competitive crop cultivars as a tool in IWM, a quick and simple-to-use protocol for assessing the competitive potential of new cultivars is required; it is likely that this will not be based on a single trait, but will need to capture the combined effect of multiple traits. A way needs to be found to make this information accessible to farmers, so that competitive cultivars can be better integrated into their weed control programmes. PMID- 27478258 TI - A Nuclear Singlet Lifetime of More than One Hour in Room-Temperature Solution. AB - Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are supremely important techniques with numerous applications in almost all branches of science. However, until recently, NMR methodology was limited by the time constant T1 for the decay of nuclear spin magnetization through contact with the thermal molecular environment. Long-lived states, which are correlated quantum states of multiple nuclei, have decay time constants that may exceed T1 by large factors. Here we demonstrate a nuclear long-lived state comprising two 13C nuclei with a lifetime exceeding one hour in room-temperature solution, which is around 50 times longer than T1. This behavior is well-predicted by a combination of quantum theory, molecular dynamics, and quantum chemistry. Such ultra-long-lived states are expected to be useful for the transport and application of nuclear hyperpolarization, which leads to NMR and MRI signals enhanced by up to five orders of magnitude. PMID- 27478259 TI - trans-Hydrogenation: Application to a Concise and Scalable Synthesis of Brefeldin A. AB - The important biochemical probe molecule brefeldin A (1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium-catalyzed trans-hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch-type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron catalyzed reductive formation of a non-terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring-closing alkyne metathesis catalyzed by a molybdenum alkylidyne. PMID- 27478260 TI - Identification and Spectroscopic Characterization of Nonheme Iron(III) Hypochlorite Intermediates. AB - FeIII-hypohalite complexes have been implicated in a wide range of important enzyme-catalyzed halogenation reactions including the biosynthesis of natural products and antibiotics and post-translational modification of proteins. The absence of spectroscopic data on such species precludes their identification. Herein, we report the generation and spectroscopic characterization of nonheme FeIII-hypohalite intermediates of possible relevance to iron halogenases. We show that FeIII-OCl polypyridylamine complexes can be sufficiently stable at room temperature to be characterized by UV/Vis absorption, resonance Raman and EPR spectroscopies, and cryo-ESIMS. DFT methods rationalize the pathways to the formation of the FeIII-OCl, and ultimately FeIV=O, species and provide indirect evidence for a short-lived FeII-OCl intermediate. The species observed and the pathways involved offer insight into and, importantly, a spectroscopic database for the investigation of iron halogenases. PMID- 27478261 TI - Synthesis of d- and l-Phenylalanine Derivatives by Phenylalanine Ammonia Lyases: A Multienzymatic Cascade Process. AB - The synthesis of substituted d-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization (based on stereoselective oxidation and nonselective reduction). A simple high-throughput solid-phase screening method has also been developed to identify PALs with higher rates of formation of non natural d-phenylalanines. The best variants were exploited in the chemoenzymatic cascade, thus increasing the yield and ee value of the d-configured product. Furthermore, the system was extended to the preparation of those l-phenylalanines which are obtained with a low ee value using PAL amination. PMID- 27478262 TI - 113Cd NMR Experiments Reveal an Unusual Metal Cluster in the Solution Structure of the Yeast Splicing Protein Bud31p. AB - Establishing the binding topology of structural zinc ions in proteins is an essential part of their structure determination by NMR spectroscopy. Using 113Cd NMR experiments with 113Cd-substituted samples is a useful approach but has previously been limited mainly to very small protein domains. Here we used 113Cd NMR spectroscopy during structure determination of Bud31p, a 157-residue yeast protein containing an unusual Zn3Cys9 cluster, demonstrating that recent hardware developments make this approach feasible for significantly larger systems. PMID- 27478263 TI - Hybrid Supramolecular and Colloidal Hydrogels that Bridge Multiple Length Scales. AB - Hybrid nanocomposites were constructed based on colloidal nanofibrillar hydrogels with interpenetrating supramolecular hydrogels, displaying enhanced rheological yield strain and a synergistic improvement in storage modulus. The supramolecular hydrogel consists of naphthyl-functionalized hydroxyethyl cellulose and a cationic polystyrene derivative decorated with methylviologen moieties, physically cross-linked with cucurbit[8]uril macrocyclic hosts. Fast exchange kinetics within the supramolecular system are enabled by reversible cross-linking through the binding of the naphthyl and viologen guests. The colloidal hydrogel consists of nanofibrillated cellulose that combines a mechanically strong nanofiber skeleton with a lateral fibrillar diameter of a few nanometers. The two networks interact through hydroxyethyl cellulose adsorption to the nanofibrillated cellulose surfaces. This work shows methods to bridge the length scales of molecular and colloidal hybrid hydrogels, resulting in synergy between reinforcement and dynamics. PMID- 27478264 TI - Rate and Equilibrium Constants for the Addition of N-Heterocyclic Carbenes into Benzaldehydes: A Remarkable 2-Substituent Effect. AB - Rate and equilibrium constants for the reaction between N-aryl triazolium N heterocyclic carbene (NHC) precatalysts and substituted benzaldehyde derivatives to form 3-(hydroxybenzyl)azolium adducts under both catalytic and stoichiometric conditions have been measured. Kinetic analysis and reaction profile fitting of both the forward and reverse reactions, plus onwards reaction to the Breslow intermediate, demonstrate the remarkable effect of the benzaldehyde 2-substituent in these reactions and provide insight into the chemoselectivity of cross-benzoin reactions. PMID- 27478265 TI - An Inverted-Sandwich Diuranium MU-eta5:eta5-Cyclo-P5 Complex Supported by U-P5 delta-Bonding. AB - Reaction of [U(TrenTIPS)] [1, TrenTIPS=N(CH2CH2NSiiPr3)3] with 0.25 equivalents of P4 reproducibly affords the unprecedented actinide inverted sandwich cyclo-P5 complex [{U(TrenTIPS)}2(MU-eta5:eta5-cyclo-P5)] (2). All prior examples of cyclo P5 are stabilized by d-block metals, so 2 shows that cyclo-P5 does not require d block ions to be prepared. Although cyclo-P5 is isolobal to cyclopentadienyl, which usually bonds to metals via sigma- and pi-interactions with minimal delta bonding, theoretical calculations suggest the principal bonding in the U(P5)U unit is polarized delta-bonding. Surprisingly, the characterization data are overall consistent with charge transfer from uranium to the cyclo-P5 unit to give a cyclo-P5 charge state that approximates to a dianionic formulation. This is ascribed to the larger size and superior acceptor character of cyclo-P5 compared to cyclopentadienyl, the strongly reducing nature of uranium(III), and the availability of uranium delta-symmetry 5f orbitals. PMID- 27478267 TI - Spectroscopic and Crystal Field Consequences of Fluoride Binding by [Yb?DTMA]3+ in Aqueous Solution. AB - Yb?DTMA forms a ternary complex with fluoride in aqueous solution by displacement of a bound solvent molecule from the lanthanide ion. [Yb?DTMA?F]2+ and [Yb?DTMA?OH2]3+ are in slow exchange on the relevant NMR timescale (<2000 s-1), and profound differences are observed in their respective NMR and EPR spectra of these species. The observed differences can be explained by drastic modification of the ligand field states due to the fluoride binding. This changes the magnetic anisotropy of the YbIII ground state from easy-axis to easy-plane type, and this change is easily detected in the observed magnetic anisotropy despite thermal population of more than just the ground state. The spectroscopic consequences of such drastic changes to the ligand field represent important new opportunities in developing fluoride-responsive complexes and contrast agents. PMID- 27478266 TI - A Molecular Nanotube with Three-Dimensional pi-Conjugation. AB - A pi-conjugated twelve-porphyrin tube is synthesized in 32 % yield by a template directed coupling reaction that joins together six porphyrin dimers, forming twelve new C-C bonds. The nanotube has two bound templates, enclosing an internal volume of approximately 4.5 nm3. Its UV/Vis/NIR absorption and fluorescence spectra resemble those of a previously reported six-porphyrin ring, but are red shifted by approximately 300 cm-1, reflecting increased conjugation. Ultrafast fluorescence spectroscopy demonstrates extensive excited-state delocalization. Transfer of electronic excitation from an initially formed state polarized in the direction of the nanotube axis (z axis) to an excited state polarized in the xy plane occurs within 200 fs, resulting in a negative fluorescence anisotropy on excitation at 742 nm. PMID- 27478268 TI - Formation of Ruthenium Carbenes by gem-Hydrogen Transfer to Internal Alkynes: Implications for Alkyne trans-Hydrogenation. AB - Insights into the mechanism of the unusual trans-hydrogenation of internal alkynes catalyzed by {Cp*Ru} complexes were gained by para-hydrogen (p-H2) induced polarization (PHIP) transfer NMR spectroscopy. It was found that the productive trans-reduction competes with a pathway in which both H atoms of H2 are delivered to a single alkyne C atom of the substrate while the second alkyne C atom is converted into a metal carbene. This "geminal hydrogenation" mode seems unprecedented; it was independently confirmed by the isolation and structural characterization of a ruthenium carbene complex stabilized by secondary inter ligand interactions. A detailed DFT study shows that the trans alkene and the carbene complex originate from a common metallacyclopropene intermediate. Furthermore, the computational analysis and the PHIP NMR data concur in that the metal carbene is the major gateway to olefin isomerization and over-reduction, which frequently interfere with regular alkyne trans-hydrogenation. PMID- 27478269 TI - Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis. AB - Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels-Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid-Cu2+ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities. PMID- 27478270 TI - Silica Nanowires Templated by Amyloid-like Fibrils. AB - Many peptides self-assemble to form amyloid fibrils. We previously explored the sequence propensity to form amyloid using variants of a designed peptide with sequence KFFEAAAKKFFE. These variant peptides form highly stable amyloid fibrils with varied lateral assembly and are ideal to template further assembly of non proteinaceous material. Herein, we show that the fibrils formed by peptide variants can be coated with a layer of silica to produce silica nanowires using tetraethyl-orthosilicate. The resulting nanowires were characterized using electron microscopy (TEM), X-ray fiber diffraction, FTIR and cross-section EM to reveal a nanostructure with peptidic core. Lysine residues play a role in templating the formation of silica on the fibril surface and, using this library of peptides, we have explored the contributions of lysine as well as arginine to silica templating, and find that sequence plays an important role in determining the physical nature and structure of the resulting nanowires. PMID- 27478271 TI - Three Aromatic Residues are Required for Electron Transfer during Iron Mineralization in Bacterioferritin. AB - Ferritins are iron storage proteins that overcome the problems of toxicity and poor bioavailability of iron by catalyzing iron oxidation and mineralization through the activity of a diiron ferroxidase site. Unlike in other ferritins, the oxidized di-Fe3+ site of Escherichia coli bacterioferritin (EcBFR) is stable and therefore does not function as a conduit for the transfer of Fe3+ into the storage cavity, but instead acts as a true catalytic cofactor that cycles its oxidation state while driving Fe2+ oxidation in the cavity. Herein, we demonstrate that EcBFR mineralization depends on three aromatic residues near the diiron site, Tyr25, Tyr58, and Trp133, and that a transient radical is formed on Tyr25. The data indicate that the aromatic residues, together with a previously identified inner surface iron site, promote mineralization by ensuring the simultaneous delivery of two electrons, derived from Fe2+ oxidation in the BFR cavity, to the di-ferric catalytic site for safe reduction of O2. PMID- 27478272 TI - Isolation of Elusive HAsAsH in a Crystalline Diuranium(IV) Complex. AB - The HAsAsH molecule has hitherto only been proposed tentatively as a short-lived species generated in electrochemical or microwave-plasma experiments. After two centuries of inconclusive or disproven claims of HAsAsH formation in the condensed phase, we report the isolation and structural authentication of HAsAsH in the diuranium(IV) complex [{U(TrenTIPS)}2(MU-eta2:eta2-As2H2)] (3, TrenTIPS=N(CH2CH2NSiPri3)3; Pri=CH(CH3)2). Complex 3 was prepared by deprotonation and oxidative homocoupling of an arsenide precursor. Characterization and computational data are consistent with back-bonding-type interactions from uranium to the HAsAsH pi*-orbital. This experimentally confirms the theoretically predicted excellent pi-acceptor character of HAsAsH, and is tantamount to full reduction to the diarsane-1,2-diide form. PMID- 27478273 TI - Intermolecular Interactions and Protein Dynamics by Solid-State NMR Spectroscopy. AB - Understanding the dynamics of interacting proteins is a crucial step toward describing many biophysical processes. Here we investigate the backbone dynamics for protein GB1 in two different assemblies: crystalline GB1 and the precipitated GB1-antibody complex with a molecular weight of more than 300 kDa. We perform these measurements on samples containing as little as eight nanomoles of GB1. From measurements of site-specific 15N relaxation rates including relaxation dispersion we obtain snapshots of dynamics spanning nine orders of magnitude in terms of the time scale. A comparison of measurements for GB1 in either environment reveals that while many of the dynamic features of the protein are conserved between them (in particular for the fast picosecond-nanosecond motions), much greater differences occur for slow motions with motions in the >500 ns range being more prevalent in the complex. The data suggest that GB1 can potentially undergo a small-amplitude overall anisotropic motion sampling the interaction interface in the complex. PMID- 27478274 TI - Insights into 6-Methylsalicylic Acid Bio-assembly by Using Chemical Probes. AB - Chemical probes capable of reacting with KS (ketosynthase)-bound biosynthetic intermediates were utilized for the investigation of the model type I iterative polyketide synthase 6-methylsalicylic acid synthase (6-MSAS) in vivo and in vitro. From the fermentation of fungal and bacterial 6-MSAS hosts in the presence of chain termination probes, a full range of biosynthetic intermediates was isolated and characterized for the first time. Meanwhile, in vitro studies of recombinant 6-MSA synthases with both nonhydrolyzable and hydrolyzable substrate mimics have provided additional insights into substrate recognition, providing the basis for further exploration of the enzyme catalytic activities. PMID- 27478275 TI - Highly Unsaturated Platinum and Palladium Carbenes PtC3 and PdC3 Isolated and Characterized in the Gas Phase. AB - Carbenes of platinum and palladium, PtC3 and PdC3, were generated in the gas phase through laser vaporization of a metal target in the presence of a low concentration of a hydrocarbon precursor undergoing supersonic expansion. Rotational spectroscopy and ab initio calculations confirm that both molecules are linear. The geometry of PtC3 was accurately determined by fitting to the experimental moments of inertia of twenty-six isotopologues. The results are consistent with the proposal of an autogenic isolobal relationship between O, Au+, and Pt atoms. PMID- 27478276 TI - Arsenic-Containing Phosphatidylcholines: A New Group of Arsenolipids Discovered in Herring Caviar. AB - A new group of arsenolipids based on cell-membrane phosphatidylcholines has been discovered in herring caviar (fish roe). A combination of HPLC with elemental and molecular mass spectrometry was used to identify five arsenic-containing phosphatidylcholines; the same technique applied to salmon caviar identified an arsenic-containing phosphatidylethanolamine. The arsenic group in these membrane lipids might impart particular properties to the molecules not displayed by their non-arsenic analogues. Additionally, the new compounds have human health implications according to recent results showing high cytotoxicity for some arsenolipids. PMID- 27478277 TI - Photoreduction of Terrigenous Fe-Humic Substances Leads to Bioavailable Iron in Oceans. AB - Humic substances (HS) are important iron chelators responsible for the transport of iron from freshwater systems to the open sea, where iron is essential for marine organisms. Evidence suggests that iron complexed to HS comprises the bulk of the iron ligand pool in near-coastal waters and shelf seas. River-derived HS have been investigated to study their transport to, and dwell in oceanic waters. A library of iron model compounds and river-derived Fe-HS samples were probed in a combined X-ray absorption spectroscopy (XAS) and valence-to-core X-ray emission spectroscopy (VtC-XES) study at the Fe K-edge. The analyses performed revealed that iron complexation in HS samples is only dependent on oxygen-containing HS functional groups, such as carboxyl and phenol. The photoreduction mechanism of FeIII-HS in oceanic conditions into bioavailable aquatic FeII forms, highlights the importance of river-derived HS as an iron source for marine organisms. Consequently, such mechanisms are a vital component of the upper-ocean iron biogeochemistry cycle. PMID- 27478278 TI - X-ray Excited Optical Fluorescence and Diffraction Imaging of Reactivity and Crystallinity in a Zeolite Crystal: Crystallography and Molecular Spectroscopy in One. AB - Structure-activity relationships in heterogeneous catalysis are challenging to be measured on a single-particle level. For the first time, one X-ray beam is used to determine the crystallographic structure and reactivity of a single zeolite crystal. The method generates MUm-resolved X-ray diffraction (MU-XRD) and X-ray excited optical fluorescence (MU-XEOF) maps of the crystallinity and Bronsted reactivity of a zeolite crystal previously reacted with a styrene probe molecule. The local gradients in chemical reactivity (derived from MU-XEOF) were correlated with local crystallinity and framework Al content, determined by MU-XRD. Two distinctly different types of fluorescent species formed selectively, depending on the local zeolite crystallinity. The results illustrate the potential of this approach to resolve the crystallographic structure of a porous material and its reactivity in one experiment via X-ray induced fluorescence of organic molecules formed at the reactive centers. PMID- 27478279 TI - Visible-Light-Driven Hydrogen Evolution Using Planarized Conjugated Polymer Photocatalysts. AB - Linear poly(p-phenylene)s are modestly active UV photocatalysts for hydrogen production in the presence of a sacrificial electron donor. Introduction of planarized fluorene, carbazole, dibenzo[b,d]thiophene or dibenzo[b,d]thiophene sulfone units greatly enhances the H2 evolution rate. The most active dibenzo[b,d]thiophene sulfone co-polymer has a UV photocatalytic activity that rivals TiO2, but is much more active under visible light. The dibenzo[b,d]thiophene sulfone co-polymer has an apparent quantum yield of 2.3 % at 420 nm, as compared to 0.1 % for platinized commercial pristine carbon nitride. PMID- 27478280 TI - Temporal Control of Gelation and Polymerization Fronts Driven by an Autocatalytic Enzyme Reaction. AB - Chemical systems that remain kinetically dormant until activated have numerous applications in materials science. Herein we present a method for the control of gelation that exploits an inbuilt switch: the increase in pH after an induction period in the urease-catalyzed hydrolysis of urea was used to trigger the base catalyzed Michael addition of a water-soluble trithiol to a polyethylene glycol diacrylate. The time to gelation (minutes to hours) was either preset through the initial concentrations or the reaction was initiated locally by a base, thus resulting in polymerization fronts that converted the mixture from a liquid into a gel (ca. 0.1 mm min-1). The rate of hydrolytic degradation of the hydrogel depended on the initial concentrations, thus resulting in a gel lifetime of hours to months. In this way, temporal programming of gelation was possible under mild conditions by using the output of an autocatalytic enzyme reaction to drive both the polymerization and subsequent degradation of a hydrogel. PMID- 27478281 TI - A Bifunctional Electrocatalyst for Oxygen Evolution and Oxygen Reduction Reactions in Water. AB - Oxygen reduction and water oxidation are two key processes in fuel cell applications. The oxidation of water to dioxygen is a 4 H+/4 e- process, while oxygen can be fully reduced to water by a 4 e-/4 H+ process or partially reduced by fewer electrons to reactive oxygen species such as H2O2 and O2-. We demonstrate that a novel manganese corrole complex behaves as a bifunctional catalyst for both the electrocatalytic generation of dioxygen as well as the reduction of dioxygen in aqueous media. Furthermore, our combined kinetic, spectroscopic, and electrochemical study of manganese corroles adsorbed on different electrode materials (down to a submolecular level) reveals mechanistic details of the oxygen evolution and reduction processes. PMID- 27478282 TI - On the size and velocity distribution of cosmic dust particles entering the atmosphere. AB - The size and velocity distribution of cosmic dust particles entering the Earth's atmosphere is uncertain. Here we show that the relative concentrations of metal atoms in the upper mesosphere, and the surface accretion rate of cosmic spherules, provide sensitive probes of this distribution. Three cosmic dust models are selected as case studies: two are astronomical models, the first constrained by infrared observations of the Zodiacal Dust Cloud and the second by radar observations of meteor head echoes; the third model is based on measurements made with a spaceborne dust detector. For each model, a Monte Carlo sampling method combined with a chemical ablation model is used to predict the ablation rates of Na, K, Fe, Mg, and Ca above 60 km and cosmic spherule production rate. It appears that a significant fraction of the cosmic dust consists of small (<5 ug) and slow (<15 km s-1) particles. PMID- 27478283 TI - Ion temperature anisotropy across a magnetotail reconnection jet. AB - A significant fraction of the energy released by magnetotail reconnection appears to go into ion heating, but this heating is generally anisotropic. We examine ARTEMIS dual-spacecraft observations of a long-duration magnetotail exhaust generated by antiparallel reconnection in conjunction with particle-in-cell simulations, showing spatial variations in the anisotropy across the outflow far (>100di ) downstream of the X line. A consistent pattern is found in both the spacecraft data and the simulations: While the total temperature across the exhaust is rather constant, near the boundaries Ti,|| dominates. The plasma is well above the firehose threshold within patchy spatial regions at |BX |?[0.1,0.5]B0, suggesting that the drive for the instability is strong and the instability is too weak to relax the anisotropy. At the midplane ( |BX|?0.1B0), Ti,?>Ti,|| and ions undergo Speiser-like motion despite the large distance from the X line. PMID- 27478284 TI - Diurnal variation of the potassium layer in the upper atmosphere. AB - Measurements of the diurnal cycle of potassium (K) atoms between 80 and 110 km have been made during October (for the years 2004-2011) using a Doppler lidar at Kuhlungsborn, Germany (54.1 degrees N, 11.7 degrees E). A pronounced diurnal variation is observed in the K number density, which is explored by using a detailed description of the neutral and ionized chemistry of K in a three dimensional chemistry climate model. The model captures both the amplitude and phase of the diurnal and semidiurnal variability of the layer, although the peak diurnal amplitude around 90 km is overestimated. The model shows that the total potassium density (~ K + K+ + KHCO3) exhibits little diurnal variation at each altitude, and the diurnal variations are largely driven by photochemical conversion between these reservoir species. In contrast, tidally driven vertical transport has a small effect at this midlatitude location, and diurnal fluctuations in temperature are of little significance because they are small and the chemistry of K is relatively temperature independent. PMID- 27478285 TI - Conduit dynamics and post explosion degassing on Stromboli: A combined UV camera and numerical modeling treatment. AB - Recent gas flux measurements have shown that Strombolian explosions are often followed by periods of elevated flux, or "gas codas," with durations of order a minute. Here we present UV camera data from 200 events recorded at Stromboli volcano to constrain the nature of these codas for the first time, providing estimates for combined explosion plus coda SO2 masses of ~18-225 kg. Numerical simulations of gas slug ascent show that substantial proportions of the initial gas mass can be distributed into a train of "daughter bubbles" released from the base of the slug, which we suggest, generate the codas, on bursting at the surface. This process could also cause transitioning of slugs into cap bubbles, significantly reducing explosivity. This study is the first attempt to combine high temporal resolution gas flux data with numerical simulations of conduit gas flow to investigate volcanic degassing dynamics. PMID- 27478286 TI - A comparative study of dipolarization fronts at MMS and Cluster. AB - We present a statistical study of dipolarization fronts (DFs), using magnetic field data from MMS and Cluster, at radial distances below 12 RE and 20 RE , respectively. Assuming that the DFs have a semicircular cross section and are propelled by the magnetic tension force, we used multispacecraft observations to determine the DF velocities. About three quarters of the DFs propagate earthward and about one quarter tailward. Generally, MMS is in a more dipolar magnetic field region and observes larger-amplitude DFs than Cluster. The major findings obtained in this study are as follows: (1) At MMS ~57 % of the DFs move faster than 150 km/s, while at Cluster only ~35 %, indicating a variable flux transport rate inside the flow-braking region. (2) Larger DF velocities correspond to higher Bz values directly ahead of the DFs. We interpret this as a snow plow like phenomenon, resulting from a higher magnetic flux pileup ahead of DFs with higher velocities. PMID- 27478287 TI - Demographic Strengthening of European Identity. PMID- 27478288 TI - Exceptional Outgroup Stereotypes and White Racial Inequality Attitudes toward Asian Americans. AB - Stereotypes of outgroups help create social identificational boundaries for ingroups. When the ingroup is dominant, members employ individualist sentiments to justify their status. In this study, we build on advances in social psychological research that account for multiple outgroup stereotypes. We argue the Asian American model minority stereotype is analogous to the "cold but competent" position of perceptions toward Asians in Fiske's stereotype content model. Asian Americans are perceived to be exceptional to other minority groups, and we hypothesize that perceived competence is associated with individualist sentiments directed at Blacks and Latinos. Using data from the National Longitudinal Study of Freshmen, we find support for our hypotheses but find that perceived coldness has no relationship to individualist sentiments. We discuss the implications and directions for further research. PMID- 27478289 TI - Mapping Gender and Migration in Sociological Scholarship: Is It Segregation or Integration? AB - A review of the sociological research about gender and migration shows the substantial ways in which gender fundamentally organizes the social relations and structures influencing the causes and consequences of migration. Yet, although a significant sociological research has emerged on gender and migration in the last three decades, studies are not evenly distributed across the discipline. In this article, we map the recent intellectual history of gender and migration in the field of sociology and then systematically assess the extent to which studies on engendering migration have appeared in four widely read journals of sociology (American Journal of Sociology, American Sociological Review, Demography, and Social Forces). We follow with a discussion of these studies, and in our conclusions, we consider how future gender and migration scholarship in sociology might evolve more equitably. PMID- 27478290 TI - The Florentine Archives in Transition: Government, Warfare and Communication (1289-1530 ca.). AB - A turning point in European administrative and documentary practices was traditionally associated, most famously by Robert-Henri Bautier, with the monarchies of the late sixteenth and early seventeenth centuries. By summarizing previous research in this field, as well as by using both published and unpublished sources, this article intends to underline an earlier process of transition connected to the development of significant new techniques for the production and preservation of documents in Renaissance Italian city-states. Focusing on the important case of Florence, the administrative uses of records connected to government, diplomacy and military needs will be discussed, and evidence will be provided that such documentary practices accelerated significantly during the so-called Italian Wars (from 1494 onwards). A particular reason of interest for Florence at this time is that a major role in the production and storage of a large quantity of state papers was played by Niccolo Machiavelli, one of the outstanding political thinkers of the age. This was especially true in connection to the new militia which he himself created in 1506. By stressing the role of information management and the importance of correspondence networks at a time of war and crisis, this article also contributes to recent scholarship which has focused on the growth of public records relating to diplomacy in Italy during the second half of the fifteenth century, as well as to a recent field of historiography which has lately gained importance: namely the 'documentary history of institutions'. PMID- 27478292 TI - Male sexually coercive behaviour drives increased swimming efficiency in female guppies. AB - Sexual coercion of females by males is widespread across sexually reproducing species. It stems from a conflict of interest over reproduction and exerts selective pressure on both sexes. For females, there is often a significant energetic cost of exposure to male sexually coercive behaviours.Our understanding of the efficiency of female resistance to male sexually coercive behaviour is key to understanding how sexual conflict contributes to population level dynamics and ultimately to the evolution of sexually antagonistic traits.Overlooked within this context are plastic physiological responses of traits within the lifetime of females that could moderate the energetic cost imposed by coercive males. Here, we examined whether conflict over the frequency and timing of mating between male and female guppies Poecilia reticulata can induce changes in swimming performance and aerobic capacity in females as they work to escape harassment by males.Females exposed to higher levels of harassment over a 5-month period used less oxygen to swim at a given speed, but displayed no difference in resting metabolic rate, maximal metabolic rate, maximal sustained swimming speed or aerobic scope compared to females receiving lower levels of harassment.The observed increase in swimming efficiency is at least partially related to differences in swimming mechanics, likely brought on by a training effect of increased activity, as highly harassed females spent less time performing pectoral fin-assisted swimming.Sexual conflict results in sexually antagonistic traits that impose a variety of costs, but our results show that females can reduce costs through phenotypic plasticity. It is also possible that phenotypic plasticity in swimming physiology or mechanics in response to sexual coercion can potentially give females more control over matings and affect which male traits are under selection. PMID- 27478291 TI - Quantification of the oxygen uptake rate in a dissolved oxygen controlled oscillating jet-driven microbioreactor. AB - BACKGROUND: Microbioreactors have emerged as a new tool for early bioprocess development. The technology has advanced rapidly in the last decade and obtaining real-time quantitative data of process variables is nowadays state of the art. In addition, control over process variables has also been achieved. The aim of this study was to build a microbioreactor capable of controlling dissolved oxygen (DO) concentrations and to determine oxygen uptake rate in real time. RESULTS: An oscillating jet driven, membrane-aerated microbioreactor was developed without comprising any moving parts. Mixing times of ~7 s, and kLa values of ~170 h-1 were achieved. DO control was achieved by varying the duty cycle of a solenoid microvalve, which changed the gas mixture in the reactor incubator chamber. The microbioreactor supported Saccharomyces cerevisiae growth over 30 h and cell densities of 6.7 gdcw L-1. Oxygen uptake rates of ~34 mmol L-1 h-1 were achieved. CONCLUSION: The results highlight the potential of DO-controlled microbioreactors to obtain real-time information on oxygen uptake rate, and by extension on cellular metabolism for a variety of cell types over a broad range of processing conditions. (c) 2015 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 27478293 TI - RADIANCE AND PHOTON NOISE: Imaging in geometrical optics, physical optics, quantum optics and radiology. AB - A fundamental way of describing a photon-limited imaging system is in terms of a Poisson random process in spatial, angular and wavelength variables. The mean of this random process is the spectral radiance. The principle of conservation of radiance then allows a full characterization of the noise in the image (conditional on viewing a specified object). To elucidate these connections, we first review the definitions and basic properties of radiance as defined in terms of geometrical optics, radiology, physical optics and quantum optics. The propagation and conservation laws for radiance in each of these domains are reviewed. Then we distinguish four categories of imaging detectors that all respond in some way to the incident radiance, including the new category of photon-processing detectors. The relation between the radiance and the statistical properties of the detector output is discussed and related to task based measures of image quality and the information content of a single detected photon. PMID- 27478294 TI - A Tale of Two Joints: The Role of Matrix Metalloproteases in Cartilage Biology. AB - Matrix metalloproteinases are a class of enzymes involved in the degradation of extracellular matrix molecules. While these molecules are exceptionally effective mediators of physiological tissue remodeling, as occurs in wound healing and during embryonic development, pathological upregulation has been implicated in many disease processes. As effectors and indicators of pathological states, matrix metalloproteinases are excellent candidates in the diagnosis and assessment of these diseases. The purpose of this review is to discuss matrix metalloproteinases as they pertain to cartilage health, both under physiological circumstances and in the instances of osteoarthritis and rheumatoid arthritis, and to discuss their utility as biomarkers in instances of the latter. PMID- 27478295 TI - Form, function and phylogeny: comparative morphometrics of Lake Tanganyika's cichlid tribe Tropheini. AB - Lake Tanganyika's cichlid fishes represent one of the most diverse species assemblages of the world. In this study we focused on the tribe Tropheini which occupies several trophic niches, mostly in rocky habitats. We analysed morphological variation of seventeen closely related species by means of geometric morphometric methods and related these data to ecological characteristics and phylogeny of the study species. It turned out that morphology mostly correlated well with ecological parameters, but not always closely with the degree of the phylogenetic relatedness of the species. Overall, body shapes in the tribe Tropheini are of great evolutionary plasticity, but variation is restricted to particular body parts: the preorbital region once again emerged as a key factor that facilitated their impressive radiation. PMID- 27478296 TI - The influence of the starvation-predation trade-off on the relationship between ambient temperature and body size among endotherms. AB - AIM: The tendency for animals at higher latitudes to be larger (Bergmann's rule) is generally explained by recourse to latitudinal effects on ambient temperature and the food supply, but these receive only mixed support and do not explain observations of the inverse to Bergmann's rule. Our aim was to better understand how ecological variables might influence body size and thereby explain this mixed support. LOCATION: World-wide. METHODS: Previous explanations do not allow for the selective pressure exerted by the trade-off between predation and starvation, which we incorporate in a model of optimal body size and energy storage of a generalized homeotherm. In contrast to existing arguments, we concentrate on survival over winter when the food supply is poor and can be interrupted for short periods. RESULTS: We use our model to assess the logical validity of the heat conservation hypothesis and show that it must allow for the roles of both food availability and predation risk. We find that whether the effect of temperature on body size is positive or negative depends on temperature range, predator density, and the likelihood of long interruptions to foraging. Furthermore, changing day length explains differing effects of altitude and latitude on body size, leading to opposite predictions for nocturnal and diurnal endotherms. Food availability and ambient temperature can have counteracting selective pressures on body mass, and can lead to a non-monotonic relationship between latitude and size, as observed in several studies. MAIN CONCLUSIONS: Our work provides a theoretical framework for understanding the relationships between the costs and benefits of large body size and eco-geographical patterns among endotherms world-wide. PMID- 27478297 TI - Impact of agricultural interventions on the nutritional status in South Asia: A review. AB - Nearly half of the malnourished population of the world lives in South Asia, and agriculture is the main source of livelihood of the people in this region. Many review exercises have analysed the available evidences to understand the ways in which agriculture can be leveraged to enhance nutritional status; however, very few of them have employed a systematic approach ensuring internal and external validity. The present paper seeks to fill this gap for strengthening the policy recommendations. It demonstrates an association between agricultural interventions and nutritional outcomes; and it shows that the production of targeted nutrition-rich crops, homestead gardens, and diversification of the agricultural production system towards fruits and vegetables and aquaculture can potentially improve nutrient intake and nutritional outcomes. The empowerment of women and nutrition knowledge play a crucial role in establishing linkage between agriculture and nutritional outcomes. PMID- 27478298 TI - Ecological management of cereal stemborers in African smallholder agriculture through behavioural manipulation. AB - 1. Africa faces serious challenges in feeding its rapidly growing human population owing to the poor productivity of maize and sorghum, the most important staple crops for millions of smallholder farmers in the continent, with yields being among the lowest in the world. 2. A complex of lepidopterous stemborers attack cereals in Africa. However, their effective control is difficult, largely as a result of the cryptic and nocturnal habits of moths, and protection provided by host stem for immature pest stages. Moreover, current control measures are uneconomical and impractical for resource-poor farmers. 3. An ecological approach, based on companion planting, known as 'push-pull', provides effective management of these pests, and involves combined use of inter- and trap cropping systems where stemborers are attracted and trapped on trap plants with added economic value ('pull'), and are driven away from the cereal crop by antagonistic intercrops ('push'). 4. Novel defence strategies inducible by stemborer oviposition have recently been discovered, leading to the attraction of egg and larval parasitoids, in locally adapted maize lines but not in elite hybrids. We also established that landscape complexity did not improve the ecosystem service of biological control, but rather provided a disservice by acting as a 'source' of stemborer pests colonising the crop. 5. Here we review and provide new data on the direct and indirect effects of the push-pull approach on stemborers and their natural enemies, including the mechanisms involved, and highlight opportunities for exploiting intrinsic plant defences and natural ecosystem services in pest management in smallholder farming systems in Africa. PMID- 27478300 TI - Consequences of a warming climate for social organisation in sweat bees. AB - ABSTRACT: The progression from solitary living to caste-based sociality is commonly regarded as a major evolutionary transition. However, it has recently been shown that in some taxa, sociality may be plastic and dependent on local conditions. If sociality can be environmentally driven, the question arises as to how projected climate change will influence features of social organisation that were previously thought to be of macroevolutionary proportions. Depending on the time available in spring during which a foundress can produce worker offspring, the sweat bee Halictus rubicundus is either social or solitary. We analysed detailed foraging data in relation to climate change predictions for Great Britain to assess when and where switches from a solitary to social lifestyle may be expected. We demonstrate that worker numbers should increase throughout Great Britain under predicted climate change scenarios, and importantly, that sociality should appear in northern areas where it has never before been observed. This dramatic shift in social organisation due to climate change should lead to a bigger workforce being available for summer pollination and may contribute towards mitigating the current pollinator crisis. SIGNIFICANCE STATEMENT: The sweat bee Halictus rubicundus is socially polymorphic, expressing both solitary and social forms, and is socially plastic, capable of transitioning from solitary to social forms, depending on local environmental conditions. Here, we analyse detailed foraging data in relation to climate change predictions for Great Britain to show that worker numbers and sociality both increase under predicted climate change scenarios. Especially dramatic will be the appearance of social H. rubicundus nests in the north of Britain, where previously only solitary forms are found. Particularly, if more taxa are found to be socially plastic, environmentally driven shifts in social organisation may help to mitigate future pollinator crises by providing more individuals for pollination. PMID- 27478301 TI - Hyperspectral image analysis for CARS, SRS, and Raman data. AB - In this work, we have significantly enhanced the capabilities of the hyperspectral image analysis (HIA) first developed by Masia et al. 1 The HIA introduced a method to factorize the hyperspectral data into the product of component concentrations and spectra for quantitative analysis of the chemical composition of the sample. The enhancements shown here comprise (1) a spatial weighting to reduce the spatial variation of the spectral error, which improves the retrieval of the chemical components with significant local but small global concentrations; (2) a new selection criterion for the spectra used when applying sparse sampling2 to speed up sequential hyperspectral imaging; and (3) a filter for outliers in the data using singular value decomposition, suited e.g. to suppress motion artifacts. We demonstrate the enhancements on coherent anti Stokes Raman scattering, stimulated Raman scattering, and spontaneous Raman data. We provide the HIA software as executable for public use. (c) 2015 The Authors. Journal of Raman Spectroscopy published by John Wiley & Sons, Ltd. PMID- 27478299 TI - Mother-male bond, but not paternity, influences male-infant affiliation in wild crested macaques. AB - ABSTRACT: In promiscuous primates, interactions between adult males and infants have rarely been investigated. However, recent evidence suggests that male affiliation towards infants has an influence on several aspects of the infants' life. Furthermore, affiliations may be associated with male reproductive strategy. In this study, we examined which social factors influenced male-infant affiliation initiated by either male or infant, in wild crested macaques (Macaca nigra). We combined behavioral data and genetic paternity analysis from 30 infants living in three wild groups in Tangkoko Reserve, Indonesia. Our results indicate that adult males and infants do not interact at random, but rather form preferential associations. The social factors with the highest influence on infant-initiated interactions were male rank and male association with the infant's mother. While infants initiated affiliations with males more often in the absence of their mothers, adult males initiated more affiliations with infants when their mothers were present. Furthermore, males initiated affiliations more often when they were in the same group at the time the infant was conceived, when they held a high dominance rank, or when they had a close relationship with the mother. Interestingly, paternity did not affect male-infant affiliation despite being highly skewed in this species. Overall, our results suggest that adult males potentially associate with an infant to secure future mating with the mother. Infants are more likely to associate with a male to receive better support, suggesting a strategy to increase the chance of infant survival in a primate society with high infant mortality. SIGNIFICANCE STATEMENT: We explore social relationships between males and infants in a promiscuous primate, the wild crested macaque. Our novel approach addresses the nature of affiliations both from males' and infants' perspectives. The results show that males and infants form preferential associations. Male-female affiliation, but not paternity, was a significant predictor of interactions initiated both by males and infants. Males initiated more interactions towards infants when the mother was in proximity, while infants initiated more interactions in her absence. Finally, high-ranking males were more likely to initiate interactions towards infants. We demonstrated that paternity is not a good predictor of male infant affiliations, even in a species with a high reproductive skew and a relatively high confidence of paternity. Our paper is one of the first to show that infants are active agents in establishing and maintaining preferential relationships with males. PMID- 27478302 TI - Pliocene-Pleistocene evolution of sea surface and intermediate water temperatures from the southwest Pacific. AB - Over the last 5 million years, the global climate system has evolved toward a colder mean state, marked by large-amplitude oscillations in continental ice volume. Equatorward expansion of polar waters and strengthening temperature gradients have been detected. However, the response of the mid latitudes and high latitudes of the Southern Hemisphere is not well documented, despite the potential importance for climate feedbacks including sea ice distribution and low high latitude heat transport. Here we reconstruct the Pliocene-Pleistocene history of both sea surface and Antarctic Intermediate Water (AAIW) temperatures on orbital time scales from Deep Sea Drilling Project Site 593 in the Tasman Sea, southwest Pacific. We confirm overall Pliocene-Pleistocene cooling trends in both the surface ocean and AAIW, although the patterns are complex. The Pliocene is warmer than modern, but our data suggest an equatorward displacement of the subtropical front relative to present and a poleward displacement of the subantarctic front of the Antarctic Circumpolar Current (ACC). Two main intervals of cooling, from ~3 Ma and ~1.5 Ma, are coeval with cooling and ice sheet expansion noted elsewhere and suggest that equatorward expansion of polar water masses also characterized the southwest Pacific through the Pliocene-Pleistocene. However, the observed trends in sea surface temperature and AAIW temperature are not identical despite an underlying link to the ACC, and intervals of unusual surface ocean warmth (~2 Ma) and large-amplitude variability in AAIW temperatures (from ~1 Ma) highlight complex interactions between equatorward displacements of fronts associated with the ACC and/or varying poleward heat transport from the subtropics. PMID- 27478303 TI - Asymmetric trends in seasonal temperature variability in instrumental records from ten stations in Switzerland, Germany and the UK from 1864 to 2012. AB - While the rise in global mean temperature over the past several decades is now widely acknowledged, the issue as to whether and to what extent temperature variability is changing continues to undergo debate. Here, variability refers to the spread of the temperature distribution. Much attention has been given to the effects that changes in mean temperature have on extremes, but these changes are accompanied by changes in variability, and it is actually the two together, in addition to all aspects of a changing climate pattern, that influence extremes. Since extremes have some of the largest impacts on society and ecology, changing temperature variability must be considered in tandem with a gradually increasing temperature mean. Previous studies of trends in temperature variability have produced conflicting results. Here we investigated ten long-term instrumental records in Europe of minimum, mean and maximum temperatures, looking for trends in seasonal, annual and decadal measures of variability (standard deviation and various quantile ranges) as well as asymmetries in the trends of extreme versus mean temperatures via quantile regression. We found consistent and accelerating mean warming during 1864-2012. In the last 40 years (1973-2012) trends for Tmax were higher than for Tmin, reaching up to 0.8 degrees C per 10a in spring. On the other hand, variability trends were not as uniform: significant changes occurred in opposing directions depending on the season, as well as when comparing 1864-2012 trends to those of 1973-2012. Moreover, if variability changed, then it changed asymmetrically, that is only in the part above or below the median. Consequently, trends in the extreme high and low quantiles differed. Regional differences indicated that in winter, high-alpine stations had increasing variability trends for Tmax especially at the upper tail compared to no changes or decreasing variability at low altitude stations. In contrast, summer variability increased at all stations studied. PMID- 27478304 TI - Viral ecology of organic and inorganic particles in aquatic systems: avenues for further research. AB - Viral abundance and processes in the water column and sediments are well studied for some systems; however, we know relatively little about virus-host interactions on particles and how particles influence these interactions. Here we review virus-prokaryote interactions on inorganic and organic particles in the water column. Profiting from recent methodological progress, we show that confocal laser scanning microscopy in combination with lectin and nucleic acid staining is one of the most powerful methods to visualize the distribution of viruses and their hosts on particles such as organic aggregates. Viral abundance on suspended matter ranges from 105 to 1011 ml-1. The main factors controlling viral abundance are the quality, size and age of aggregates and the exposure time of viruses to aggregates. Other factors such as water residence time likely act indirectly. Overall, aggregates appear to play a role of viral scavengers or reservoirs rather than viral factories. Adsorption of viruses to organic aggregates or inorganic particles can stimulate growth of the free-living prokaryotic community, e.g. by reducing viral lysis. Such mechanisms can affect microbial diversity, food web structure and biogeochemical cycles. Viral lysis of bacterio- and phytoplankton influences the formation and fate of aggregates and can, for example, result in a higher stability of algal flocs. Thus, viruses also influence carbon export; however, it is still not clear whether they short circuit or prime the biological pump. Throughout this review, emphasis has been placed on defining general problems and knowledge gaps in virus-particle interactions and on providing avenues for further research, particularly those linked to global change. PMID- 27478305 TI - Effects of Traumeel (Tr14) on Exercise-Induced Muscle Damage Response in Healthy Subjects: A Double-Blind RCT. AB - The present double-blind, randomized, placebo-controlled clinical trial intended to test whether ingestion of a natural combination medicine (Tr14 tablets) affects serum muscle damage and inflammatory immune response after downhill running. 96 male subjects received Tr14 tablets, which consist of 14 diluted biological and mineral components, or a placebo for 72 h after the exercise test, respectively. Changes in postexercise levels of various serum muscle damage and immunological markers were investigated. The area under the curve with respect to the increase (AUCi) of perceived pain score and creatine kinase (CK) were defined as primary outcome measures. While for CK the p value of the difference between the two groups is borderline, the pain score and muscle strength were not statistically significant. However, a trend towards lower levels of muscle damage (CK, p = 0.05; LDH, p = 0.06) in the Tr14 group was shown. Less pronounced lymphopenia (p = 0.02), a trend towards a lower expression of CD69 count (p = 0.07), and antigen-stimulated ICAM-1 (p = 0.01) were found in the verum group. The Tr14 group showed a tendentially lower increase of neutrophils (p = 0.10), BDNF (p = 0.03), stem cell factor (p = 0.09), and GM-CSF (p = 0.09) to higher levels. The results of the current study indicate that Tr14 seems to limit exercise-induced muscle damage most likely via attenuation of both innate and adaptive immune responses. This study was registered with ClinicalTrials.gov (NCT01912469). PMID- 27478306 TI - The Expression of T Cell FOXP3 and T-Bet Is Upregulated in Severe but Not Euthyroid Hashimoto's Thyroiditis. AB - Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disorder characterized by progressive thyroid failure. Th1 and Treg subset of CD4(+) cells have been implicated in the pathogenesis; however, less is known about their respective roles across the spectrum of HT clinical presentations. To shed more light on CD4(+) subsets role in HT, we investigated the mRNA expression levels of several Th1/Treg-associated transcription factors (T-bet/ETS1, HIF1alpha/BLIMP1/FOXP3) in peripheral blood T cells of 10 hypothyroid, untreated HT patients, 10 hypothyroid patients undergoing hormone replacement therapy, 12 euthyroid HT subjects, and 11 healthy controls by the qRT-PCR. Compared to euthyroid HT patients and controls, both hypothyroid (2.34-fold difference versus controls, P < 0.01) and thyroxine-supplemented patients (2.5-fold, P < 0.001) showed an increased FOXP3 mRNA expression in T cells. Similarly, mRNA expression levels of T-bet were upregulated in severely affected but not in euthyroid HT subjects (2.37-fold and 3.2-fold, hypothyroid and thyroxine-supplemented HT patients versus controls, resp., P < 0.01). By contrast, no differences in mRNA expression levels of ETS1, BLIMP1, and HIF1alpha were observed across the study groups. In summary, severe but not euthyroid HT was associated with robust upregulation of T-bet and FOXP3 mRNA in peripheral T cells, independent of the thyroid hormone status but proportional to disease activity. PMID- 27478307 TI - Inhibition of TLR4 Signalling-Induced Inflammation Attenuates Secondary Injury after Diffuse Axonal Injury in Rats. AB - Increasing evidence suggests that secondary injury after diffuse axonal injury (DAI) damages more axons than the initial insult, but the underlying mechanisms of this phenomenon are not fully understood. Recent studies show that toll-like receptor 4 (TLR4) plays a critical role in promoting adaptive immune responses and have been shown to be associated with brain damage. The purpose of this study was to investigate the role of the TLR4 signalling pathway in secondary axonal injury in the cortices of DAI rats. TLR4 was mainly localized in microglial cells and neurons, and the levels of TLR4 downstream signalling molecules, including TLR4, myeloid differentiation primary response gene 88, toll/IR-1-(TIR-) domain containing adaptor protein inducing interferon-beta, interferon regulatory factor 3, interferon beta, nuclear factor kappaB (NF-kappaB) p65, and phospho-NF-kappaB p65, significantly increased and peaked at 1 d after DAI. Inhibition of TLR4 by TAK-242 attenuated apoptosis, neuronal and axonal injury, and glial responses. The neuroprotective effects of TLR4 inhibition were associated with decreases in the levels of TLR4 downstream signalling molecules and inflammatory factors, including interleukin-1beta, interleukin-6, and tumour necrosis factor-alpha. These results suggest that the TLR4 signalling pathway plays an important role in secondary injury and may be an important therapeutic target following DAI. PMID- 27478308 TI - Serotonin-Exacerbated DSS-Induced Colitis Is Associated with Increase in MMP-3 and MMP-9 Expression in the Mouse Colon. AB - Background. 5-HT enhances dextran sulfate sodium- (DSS-) induced colitis and is involved in inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) play roles in the process of intestinal inflammation. Aims. To examine whether 5 HT induces MMPs expression in mouse colon to enhance DSS-induced colitis. Materials and Methods. C57BL/6J (B6) mice were treated with either low-dose (1.0 mg/kg) or high-dose (2.0 mg/kg) 5-HT by enema, low-dose (1.0%) or high-dose (2.5%) DSS, or combined low-dose (1.0%) DSS and (1.0 mg/kg) 5-HT. Mouse colitis was analyzed. MMPs and tissue inhibitors of MMPs (TIMPs) mRNA were measured by real-time quantitative RT-PCR in mouse colon and in human Caco-2 cells and neutrophils. MMP-3 and MMP-9 protein levels were quantified from immunohistochemistry (IHC) images of mouse colons. Results. 5-HT exacerbated DSS induced colitis, low-dose 5-HT induces both MMP-3 and MMP-9, and high-dose 5-HT only increased MMP-3 mRNA expression in mouse colon. Mouse colon MMP-3 and MMP-9 protein levels were also elevated by 5-HT treatment. The MMP-2, TIMP-1, and TIMP 2 mRNA levels were increased in the inflamed colon. 5-HT induced MMP-3 and MMP-9 mRNA expression in Caco-2 and human neutrophils, respectively, in vitro. Conclusion. 5-HT induced MMP-3 and MMP-9 expression in mouse colon; these elevated MMPs may contribute to DSS-induced colitis. PMID- 27478309 TI - Herbal Medicines for Asthmatic Inflammation: From Basic Researches to Clinical Applications. AB - Asthma is one of the most common chronic inflammatory disorders, associated with reversible airflow obstruction, airway hyperresponsiveness, and airway remodeling. This disease has a significant impact on individuals, their families, and society. Standardized therapeutics such as inhaled corticosteroid in combination with long acting beta2 agonist have been applied for asthma control; however, complementary and alternative medicines, especially herbal medicines, are still widely used all over the world. A growing body of literature suggests that various herbals or related products might be effective in inhibiting asthmatic inflammation. In this review, we summarize recent advances about the mechanistic studies of herbal medicines on allergic airway inflammation in animal models and their potential application into clinic for asthma control. PMID- 27478310 TI - Systemic and Local Administration of Antimicrobial and Cell Therapies to Prevent Methicillin-Resistant Staphylococcus epidermidis-Induced Femoral Nonunions in a Rat Model. AB - S. epidermidis is responsible for biofilm-related nonunions. This study compares the response to S. epidermidis-infected fractures in rats systemically or locally injected with vancomycin or bone marrow mesenchymal stem cells (BMSCs) in preventing the nonunion establishment. The 50% of rats receiving BMSCs intravenously (s-rBMSCs) died after treatment. A higher cytokine trend was measured in BMSCs locally injected rats (l-rBMSCs) at day 3 and in vancomycin systemically injected rats (l-VANC) at day 7 compared to the other groups. At day 14, the highest cytokine values were measured in l-VANC and in l-rBMSCs for IL 10. uCT showed a good bony bridging in s-VANC and excellent both in l-VANC and in l-rBMSCs. The bacterial growth was lower in s-VANC and l-VANC than in l-rBMSCs. Histology demonstrated the presence of new woven bone in s-VANC and a more mature bony bridging was found in l-VANC. The l-rBMSCs showed a poor bony bridging of fibrovascular tissue. Our results could suggest the synergic use of systemic and local injection of vancomycin as an effective treatment to prevent septic nonunions. This study cannot sustain the systemic injection of BMSCs due to high risks, while a deeper insight into local BMSCs immunomodulatory effects is mandatory before developing cell therapies in clinics. PMID- 27478311 TI - Simultaneous Inhibition of PGE2 and PGI2 Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models. AB - Prostaglandin E2 (PGE2) is well known as a mediator of inflammatory symptoms such as fever, arthritis, and inflammatory pain. In the present study, we evaluated the analgesic effect of our selective PGE2 synthesis inhibitor, compound I, 2 methyl-2-[cis-4-([1-(6-methyl-3-phenylquinolin-2-yl)piperidin-4-yl]carbonyl amino)cyclohexyl] propanoic acid, in rat yeast-induced acute and adjuvant-induced chronic inflammatory pain models. Although this compound suppressed the synthesis of PGE2 selectively, no analgesic effect was shown in both inflammatory pain models. Prostacyclin (PGI2) also plays crucial roles in inflammatory pain, so we evaluated the involvement of PGI2 signaling in rat inflammatory pain models using prostacyclin receptor (IP) antagonist, RO3244019. RO3244019 showed no analgesic effect in inflammatory pain models, but concomitant administration of compound I and RO3244019 showed analgesic effects comparable to celecoxib, a specific cyclooxygenase- (COX-) 2 inhibitor. Furthermore, coadministration of PGE2 receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE2 signaling, especially through the EP4 receptor, and PGI2 signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia. PMID- 27478312 TI - Cancer incidence and mortality in Shandong province, 2012. AB - OBJECTIVE: Population-based cancer registration data in 2012 from all available cancer registries in Shandong province were collected by Shandong Center for Disease Control and Prevention (SDCDC). SDCDC estimated the numbers of new cancer cases and cancer deaths in Shandong province with compiled cancer incidence and mortality rates. METHODS: In 2015, there were 21 cancer registries submitted data of cancer incidence and deaths occurred in 2012. All the data were checked and evaluated based on the National Central Cancer Registry (NCCR) criteria of data quality. Qualified data from 15 registries were used for cancer statistics analysis as provincial estimation. The pooled data were stratified by area (urban/rural), gender, age group (0, 1.4, 5.9, 10.14, ..., 85+ years) and cancer type. New cancer cases and deaths were estimated using age-specific rates and corresponding provincial population in 2012. The Chinese census data in 2000 and Segi's population were applied for age-standardized rates. All the rates were expressed per 100,000 person-year. RESULTS: Qualified 15 cancer registries (4 urban and 11 rural registries) covered 17,189,988 populations (7,486,039 in urban and 9,703,949 in rural areas). The percentage of cases morphologically verified (MV%) and death certificate-only cases (DCO%) were 66.12% and 2.93%, respectively, and the mortality to incidence rate ratio (M/I) was 0.60. A total of 253,060 new cancer cases and 157,750 cancer deaths were estimated in Shandong province in 2012. The incidence rate was 263.86/100,000 (303.29/100,000 in males, 223.23/100,000 in females), the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 192.42/100,000 and 189.50/100,000 with the cumulative incidence rate (0.74 years old) of 22.07%. The cancer incidence, ASIRC and ASIRW in urban areas were 267.64/100,000, 195.27/100,000 and 192.02/100,000 compared to 262.32/100,000, 191.26/100,000 and 188.48/100,000 in rural areas, respectively. The cancer mortality was 164.47/100,000 (207.42/100,000 in males, 120.23/100,000 in females), the age-standardized incidence rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 117.54/100,000 and 116.90/100,000, and the cumulative mortality rate (0.74 years old) was 13.53%. The cancer mortality, ASMRC and ASMRW were 141.59/100,000, 101.17/100,000 and 100.33/100,000 in urban areas, and 173.79/100,000, 124.20/100,000 and 123.64/100,000 in rural areas, respectively. Cancers of the lung, stomach, liver, esophagus, colorectum, female breast, brain, leukemia, bladder and pancreas were the most common cancers, accounting for about 82.12% of all cancer new cases. Lung cancer, stomach cancer, liver cancer, esophageal cancer, colorectal cancer, female breast cancer, pancreatic cancer, brain tumor, leukemia and lymphoma were the leading causes of cancer death, accounting for about 89.01% of all cancer deaths. The cancer spectrum showed difference between urban and rural, males and females both in incidence and mortality rates. CONCLUSIONS: Cancer surveillance information in Shandong province is making great progress with the increasing number of cancer registries, population coverage and the improving data quality. Cancer registration plays a fundamental role in cancer control by providing basic information on population-based cancer incidence, mortality, survival and time trend. The disease burden of cancer is serious in Shandong province, and so cancer prevention and control in Shandong province should be enhanced including health education, health promotion, cancer screening and cancer care services. PMID- 27478313 TI - Cancer incidence and mortality in Henan province, 2012. AB - OBJECTIVE: Population-based cancer registration data in 2012 from all available cancer registries in Henan province were collected by Henan Office for Cancer Research and Control. The numbers of new cancer cases and cancer deaths in Henan province with compiled cancer incidence and mortality rates were estimated. METHODS: In 2015, all registries' data in Henan province were qualified for the national cancer registry annual report in 2012. The pooled data were stratified by area (urban/rural), gender, age group (0, 1.4, 5.9, 10.14, ..., 85+) and cancer type. New cancer cases and deaths were estimated using age-specific rates and corresponding population of Henan province in 2012. The Chinese census data in 2000 and Segi's population were applied for age-standardized rates. All the rates were expressed per 100,000 person-years. RESULTS: Qualified 19 cancer registries (4 urban and 15 rural registries) covered 16,082,688 populations of Henan province in 2012. The percentage of cases with morphologically verified (MV%) and death certificateonly cases (DCO%) were 69.84% and 2.30%, respectively, and the mortality to incidence rate ratio (M/I) was 0.64. It was estimated that there were 248,510 new cancer cases and 158,630 cancer deaths in Henan province in 2012. The incidence rate was 266.17/100,000 (288.61/100,000 in males and 241.86/100,000 in females), the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 208.95/100,000 and 206.41/100,000 with the cumulative incidence rate (0.74 years old) of 24.30%. The crude incidence rate in urban areas was higher than that in rural areas. However, after adjusted by age, the cancer incidence rate in rural was higher than that in urban areas. The crude mortality of all cancers in Henan province was 169.90/100,000 (201.23/100,000 in males and 135.95/100,000 in females). The age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 131.20/100,000 and 130.80/100,000, respectively. Among the patients aged 0.74 years, the cumulative mortality rate was 15.03%. The crude cancer mortality rate in urban areas was higher than that of rural areas. However, the age-standardized rate in rural areas was higher than that of urban areas. Cancers of lung, stomach, esophagus, liver, female breast, colorectum, cervix, brain, uterus and ovary were the most common cancers, accounting for about 82.80% of all cancer new cases. Lung cancer, stomach cancer, esophageal cancer, liver cancer, colorectal cancer, female breast cancer, brain cancer, leukemia, pancreatic cancer and cervix cancer were the leading causes of cancer deaths, accounting for about 88.50% of all cancer deaths. The burden between urban and rural, males and females were different. CONCLUSIONS: Registration data of Henan province was qualified to provide basic information on population-based cancer incidence, mortality for cancer prevention and control. The upper digestive tract cancer burden in Henan province, especially for males in rural areas, was higher. The incidence rate of female breast cancer was higher in urban areas. Targeted prevention, early detection and treatment programs should be carried out by health department to control the cancer burden. PMID- 27478314 TI - Estimated cancer incidence and mortality in Hebei province, 2012. AB - OBJECTIVE: This study estimates the numbers of new cancer cases and cancer deaths in Hebei province using incidence and mortality data from 9 population-based cancer registries in 2012. METHODS: The data of new diagnosed cancer cases and cancer deaths in 2012 were collected from 9 population-based cancer registries of Hebei province in 2015. All the data met the National Central Cancer Registry of China (NCCR) criteria of data quality. The pooled data analysis was stratified by areas (urban/rural), gender, age group (0, 1.4, 5.9, 10.14, ..., 85+) and cancer type. New cancer cases and deaths in Hebei province were estimated using age specific rates and corresponding provincial population in 2012. The 10 most common cancers in different groups and the cumulative rates were calculated. Chinese population census in 2000 and Segi's population were used for age standardized incidence/mortality rates. RESULTS: All cancer registries covered 4,986,847 populations, 6.84% of Hebei provincial population (2,098,547 in urban and 2,888,300 in rural areas). The percentage of cases morphologically verified (MV%) and death certificate-only cases (DCO%) were 76.40% and 4.72%, respectively. The mortality to incidence rate ratio (M/I) was 0.64. In 2012, it is estimated that there were about 187,900 new diagnosed cancer cases and 119,800 cancer deaths in Hebei province. The incidence rate of cancer was 258.12/100,000 (275.75/100,000 in males, 239.78/100,000 in females), and the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 210.65/100,000 and 208.50/100,000, with the cumulative incidence rates (0.74 years old) of 24.46%. The cancer incidence and ASIRC were 256.99/100,000 and 211.32/100,000 in urban areas and 258.94/100,000 and 209.99/100,000 in rural areas, respectively. The cancer mortality rate was 164.63/100,000 (201.85/100,000 in males, 125.92/100,000 in females). Agestandardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 137.30/100,000 and 137.39/100,000 with the cumulative mortality rate (0.74 years old) of 14.58%, respectively. The cancer mortality rate in rural areas (167.16/100,000) was higher than that in urban areas (161.16/100,000). The most common cancers were lung cancer, stomach cancer, breast cancer, esophageal cancer, liver cancer and colorectal cancer, which accounted for 72.31% of all cancer cases. Lung cancer, stomach cancer, liver cancer, esophageal cancer and colorectal cancer were the major causes of cancer death in Hebei province, which accounted for 75.24% of all cancer deaths. The cancer spectrum differs between urban and rural, males and females in both incidence and mortality rates. CONCLUSIONS: The most common cancers were lung cancer, stomach cancer, esophageal cancer, breast cancer, liver cancer and colorectal cancer in Hebei province. PMID- 27478315 TI - Cancer incidence and mortality in Gansu province, 2012. AB - OBJECTIVE: Population-based cancer registration data in 2012 from all available cancer registries in Gansu province were collected by the Central Cancer Registry of Gansu. The numbers of new cancer cases and cancer deaths in Gansu province with compiled cancer incidence and mortality rates were estimated. METHODS: In 2015, data from 7 registries in Gansu province were qualified. The pooled data were stratified by area (urban/rural), gender, age group (0, 1.4, 5.9, 10.14, ..., 85+) and cancer type. New cancer cases and deaths were estimated using age specific rates and corresponding population of Gansu province in 2012. The Chinese census data in 2000 and Segi's population were applied for age standardized rates. All the rates were expressed per 100,000 person-years. RESULTS: Qualified 7 cancer registries (3 urban and 4 rural registries) covered 2,956,560 populations of Gansu province in 2012. The percentage of cases morphologically verified (MV%) and death certificate-only cases (DCO%) were 72.41% and 1.65%, respectively, and the mortality to incidence rate ratio (M/I) was 0.63. It was estimated that there were 575,600 new cancer cases and 331,300 cancer deaths in Gansu province in 2012. The incidence rate was 223.29/100,000 (244.14/100,000 in males and 201.50/100,000 in females), the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 208.95/100,000 and 206.41/100,000 with the cumulative incidence rate (0.74 years old) of 22.49%. The crude incidence rate in urban areas was equal to that in rural areas. However, after adjusted by age, the cancer incidence rate in urban was the same as that of rural areas. The crude mortality in Gansu province was 128.54/100,000 (135.04/100,000 in males and 124.43/100,000 in females), the age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 109.54/100,000 and 108.44/100,000, respectively, and the cumulative mortality rate (0.74 years old) was 12.91%. The crude cancer mortality rate in urban areas was higher than that of rural areas. However, the agestandardized rate in urban areas was the same as that of rural areas. Cancers of stomach, liver, lung, esophagus, female breast, colorectum, cervix, brain, pancreas and ovary were the most common cancers, accounting for about 83.56% of all cancer new cases. Stomach cancer, liver cancer, lung cancer, esophageal cancer, female breast cancer, colorectal cancer, brain cancer, lymphoma, pancreatic cancer and cervix cancer were the leading causes of cancer death, accounting for about 85.58% of all cancer deaths. The burden between urban and rural, males and females was different. CONCLUSIONS: Registration data of Gansu province were qualified to provide basic information on population-based cancer incidence, mortality for cancer prevention and control. The digestive tract cancer burden in Gansu province, especially for males in rural areas, was higher. The incidence rate of female breast cancer was higher in urban areas. Targeted prevention, early detection and treatment programs should be carried out by health department to control the cancer burden. PMID- 27478316 TI - Cancer incidence and mortality in Guangdong province, 2012. AB - OBJECTIVE: To estimate the cancer incidence and mortality in 2012 in Guangdong province by analyzing the cancer data of selected population-based cancer registries in Guangdong province in 2012. METHODS: Eight of nine population-based cancer registries submitted cancer data to the Guangdong Provincial Centre for Disease Control and Prevention (Guangdong CDC), whose data met the data quality criteria were included for analysis. The statistics of selected registries, stratified by areas, gender, age and cancer types, were used to estimate the cancer incidence and mortality in 2012 in Guangdong province according to the population data in Guangdong province. Segi's population and the national census population in 2000 were used for calculating the age-standardized rates (ASR). RESULTS: A total of 15,084,942 people, accounted for 17.47% of all population in Guangdong province, were covered in 8 selected population-based cancer registries in 2012. The percentage of cases morphologically verified (MV%) and the percentage of death certificate-only cases (DCO%) were 72.84% and 0.87%, respectively, and the mortality/incidence (M/I) ratio was 0.56. It was estimated that there were 211,300 new cancer cases and 117,300 cancer deaths. The incidence crude rate (CR), the ASR by Chinese standard population (ASRC) and by world standard population (ASRW), and the accumulated rate (AR) (0.74 years) were 250.20/100,000 (265.39/100,000 in males, 234.29/100,000 in females), 207.04/100,000, 201.34/100,000 and 22.91%, respectively, in Guangdong province in 2012. The incidence CR and ASRC were 267.25/100,000 and 221.43/100,000 in urban areas, and 215.51/100,000 and 178.77/100,000 in rural areas, respectively. The death CR, ASRC, ASRW and AR (0.74 years) were 148.44/100,000 (190.95/100,000 in males, 105.06/100,000 in females), 103.73/100,000, 102.44/100,000 and 11.68%, respectively, in Guangdong province in 2012. The death CR and ASRC were 164.57/100,000 and 105.46/100,000 in urban areas, and 124.63/100,000 and 99.97/100,000 in rural areas, respectively. Top 5 cancers were lung cancer, liver cancer, female breast cancer, colon cancer and nasopharyngeal cancers (NPC), and top 5 death cancers were lung cancer, liver cancer, colon cancer, stomach cancer, and NPC in Guangdong province in 2012. CONCLUSIONS: Lung cancer, liver cancer, female breast cancer, colon cancer and NPC were the major economic cancer burdens and health concerns in Guangdong province in 2012. Early prevention, diagnosis and treatment of different cancers, survival quality improvement and cancer burden reduction, are important issues we faced in cancer control and prevention. PMID- 27478317 TI - Incidence, mortality and survival of female breast cancer during 2003-2011 in Jiangsu province, China. AB - OBJECTIVE: To assess the incidence, mortality and survival status of female breast cancer in Jiangsu province of China. METHODS: Population-based cancer registry data in Jiangsu province were collected during 2003-2011. Crude rates, age-specific rates, age-standardized rates and annual percent changes of incidence and mortality were calculated to describe the epidemiologic characteristics and time trends. Patients diagnosed from 2003 to 2005 were chosen for analyzing the survival status of breast cancer. RESULTS: From 2003 to 2011, 17,605 females were diagnosed with breast cancer and 4,883 died in selected registry areas in Jiangsu province. The crude incidence rate was 25.18/100,000, and the age-standardized rates by Chinese population (ASRC) and by world population (ASRW) were 19.03/100,000 and 17.92/100,000, respectively. During the same period, the crude mortality rate was 6.98/100,000 and the ASRC and ASRW were 4.93/100,000 and 4.80/100,000, respectively. From 2003 to 2011, the incidence and mortality increased with annual percent change of 11.37% and 5.78%, respectively. For survival analysis, 1,392 patients in 7 areas were identified in 2003-2005 and finished 5 years of follow-up. Survival rates were found to decrease with survival years, the 5-year observed survival rate was 45.9% and the relative survival rate was 52.0%. We also found that the survival rate varied across the province, which was lower in the north and higher in the south of Jiangsu province. CONCLUSIONS: Breast cancer has become a significant public health problem in Jiangsu province and China. More resources should be invested in primary prevention, earlier diagnosis and better health services in order to increase survival rates among Chinese females. PMID- 27478318 TI - Efficacy and safety of trastuzumab combined with chemotherapy for first-line treatment and beyond progression of HER2-overexpressing advanced breast cancer. AB - OBJECTIVE: To observe the efficacy and safety of trastuzumab combined with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. METHODS: A total of 90 patients with HER2 overexpressing advanced breast cancer were enrolled in this study. All patients were diagnosed with ductal invasive breast cancer by pathological analysis, and were aged between 31-73 years with a median of 51 years. HER2-positivity was defined as 3(+) staining in immunochemistry or amplification of fluorescence in situ hybridization (FISH, ratio >=2.0). Trastuzumab was administered in combination with chemotherapy as first-line treatment and beyond progression as a secondline, third-line, and above treatment in 90, 34, 14, and 6 patients, respectively. The chemotherapy regimen was given according to normal clinical practice. The response rate was evaluated every two cycles, and the primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival curves were estimated by using Kaplan-Meier graphs and were compared by using log-rank test statistics. Multivariate analysis was done using Cox's proportional hazards regression model, and the level of significance was P<0.05. RESULTS: All 90 patients received at least one dose of trastuzumab, and efficacy could be evaluated in 85 patients. The median follow-up was 50 months. In total, 72 (80.00%) patients had visceral metastasis, and 43 (47.78%) patients had progressed after one or more extensive chemotherapy regimens for metastatic diseases. The median PFS for first-line trastuzumab was 10 months (range, 2-59 months), and the median OS after metastasis or initially local advanced disease was 22 months (range, 2-116 months). CONCLUSIONS: Trastuzumab combined with chemotherapy was active and well-tolerated as a first-line treatment and even beyond progression in HER2-overexpressing advanced breast cancer as a second-line or third-line treatment. However, its efficacy is certainly less beyond this point. PMID- 27478319 TI - Comparing overall survival between first generation EGFR-TKIs and chemotherapy in lung cancer patients with Del19/L858R. AB - OBJECTIVE: Combined overall survival (OS) analysis of Lux-Lung 3 and Lux-Lung 6 demonstrated that patients with epidermal growth factor receptor (EGFR) exon 19 deletions (Del19) would benefit from first-line second generation EGFR tyrosine kinase inhibitors (TKIs) afatinib but not for those with L858R. This study was to investigate the survival difference between first-line first generation EGFR-TKIs and chemotherapy in patients with either Del19 or L858R, and to directly compare OS in these two mutation groups. METHODS: Eligibles were all prospective and retrospective studies comparing EGFR-TKIs with conventional chemotherapy or receiving single agent EGFR-TKIs and demonstrating survival analysis based on mutation types. The primary outcome was OS measured as pooled hazard ratios (HRs). All measures were pooled using randomeffects models and 95% confidential interval (95% CI) was calculated. RESULTS: A total of 14 studies incorporating 1,706 patients with either Del19 or L858R were included. Enrolling patients with Del19 or L858R in randomized controlled trials (RCTs), first-line first generation EGFR-TKIs were associated with no OS benefit, compared with chemotherapy (pooled HRTKI/Chemo for Del19: 0.82, 95% CI: 0.64-1.06, P = 0.14; pooled HRTKI/Chemo for L858R: 1.15, 95% CI: 0.85-1.56, P = 0.38). Direct comparison of Del19 with L858R receiving with first-line first generation EGFR TKIs demonstrated no significant survival difference (pooled HR19/21: 0.88, 95% CI: 0.67-1.16, P = 0.37). CONCLUSIONS: Among patients with advanced non-small cell lung cancer (NSCLC) harboring Del19 and L858R, first-line first generation EGFR-TKIs demonstrated no survival benefit comparing with chemotherapy. Direct comparison between Del19 and L858R revealed no significant survival difference after first-line first generation EGFR-TKIs. PMID- 27478320 TI - Expanded endoscopic therapy criteria should be cautiously used in intramucosal gastric cancer. AB - OBJECTIVE: Accurate estimation of lymph node metastasis (LNM) in intramucosal gastric cancer is essential to select less invasive treatment options and even avoid surgery. The aim of this study was to evaluate combined clinicopathological features to predict the presence of LNM. METHODS: A retrospective review of data from 386 intramucosal gastric cancer patients who underwent gastrectomy with extended lymphadenectomy from 2003 to 2010 was conducted. The mutual relation between clinicopathological characteristics and LNM was analyzed. RESULTS: LNM was detected in 40 (10.4%) of the 386 patients. Histological type and vascular or lymphatic invasion presence showed a positive correlation with LNM occurrence by univariate analysis. Multivariate analysis revealed that histological type was the only factor associated with LNM. Combined clinicopathologic characteristics would be more predictable for LNM. We found no LNM when we used combined clinicopathological characteristics conforming to Japanese absolute indications for endoscopic therapy. The LNM rate was as high as 8.7% when Japanese expanded criteria were used. Univariate analysis in cancer conformity to expand endoscopic submucosal dissection (ESD) indication also revealed that the undifferential type was the only significant factor for LNM. CONCLUSIONS: It was possible to predict intramucosal gastric cancer cases without LNM using combined clinicopathological characteristic analysis. Extended indication for ESD should be cautiously used for intramucosal gastric cancer patients. PMID- 27478321 TI - Prognostic significance of X-ray cross-complementing gene 1 expression in gastric cancer. AB - OBJECTIVE: The aim of this study is to identify the prognostic significance of X ray cross-complementing gene 1 (XRCC1) in patients with gastric cancer undergoing surgery and platinum-based adjuvant chemotherapy. METHODS: Immunohistochemistry (IHC) was used to evaluate XRCC1 protein expression profiles on surgical specimens of 612 gastric cancer patients. The relationship between XRCC1 expression and existing prognostic factors, platinum-based adjuvant chemotherapy, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: Among 612 patients staged II/III in our study, 182 (29.74%) were evaluated as XRCC1 IHC positive. XRCC1 expression was not significantly related to OS (P = 0.347) or DFS (P = 0.297). Compared with surgery only, platinum-based adjuvant chemotherapy significantly improved the OS (P = 0.031). And the patients with negative XRCC1 expression benefited more from platinum-based adjuvant chemotherapy (P = 0.049). Multivariate analysis demonstrated that tumor size, T category, N category, vascular or nerve invasion and platinum-based chemotherapy were good prognostic factors for OS (P < 0.05). Though XRCC1 plays an important role in DNA repair pathways, no significant relationship is found in XRCC1 expression and OS among gastric cancer in our study. CONCLUSIONS: XRCC1 might be an alternative prognostic marker for the patients of gastric cancer after radical resection. The patients with negative XRCC1 expression can benefit more from platinum-based adjuvant chemotherapy. PMID- 27478322 TI - Influence of chelator and near-infrared dye labeling on biocharacteristics of dual-labeled trastuzumab-based imaging agents. AB - OBJECTIVE: To investigate the effect of fluorescent dye labeling on the targeting capabilities of 111In- (DTPA)n-trastuzumab-(IRDye 800)m. METHODS: Trastuzumab based conjugates were synthesized and conjugated with diethylenetriaminepentaacetic acid (DTPA) at molar ratios of 1, 2, 3 and 5 and with a fluorescent dye (IRDye 800CW) at molar ratios of 1, 3 and 5. Immunoreactivity and internalization were assessed on SKBR-3 cells, overexpressing human epidermal growth factor receptor 2. The stability in human serum and phosphate-buffered saline (PBS) was evaluated. The biodistribution of dual-labeled conjugates was compared with that of 111In-(DTPA)2-trastuzumab in a SKBR-3 xenograft model to evaluate the effect of dye-to-protein ratio. RESULTS: All trastuzumab-based conjugates exhibited a high level of chemical and optical purity. Flow cytometry results showed that increasing dye-to-protein ratios were associated with decreased immunoreactivity. Stability studies revealed that the conjugate was stable in PBS, while in human serum, increased degradation and protein precipitation were observed with increasing dye-to-protein ratios. At 4 h, the percentages of internalization of dual-labeled conjugates normalized by dye-to-protein ratio (m) were 24.88%+/-2.10%, 19.99%+/-0.59%, and 17.47%+/-1.26% for "m" equal to 1, 3, and 5, respectively. A biodistribution study revealed a progressive decrease in tumor uptake with an increase in the dye-to-protein ratios. The liver, spleen and kidney showed a marked uptake with increased dye-to protein ratios, particularly in the latter. CONCLUSIONS: With non-specific-site conjugation of the fluorescent dye with a protein based on imaging agent, the increase in dye-to-protein ratios negatively impacted the immunoreactivity and stability, indicating a reduced tumor uptake. PMID- 27478323 TI - A mini-review on factors and countermeasures associated with false-negative sentinel lymph node biopsies in breast cancer. AB - Sentinel lymph node biopsy (SLNB) is a new surgical technique for local axillary lymph nodes (ALNs) of breast cancer. Large-scale clinical trials have confirmed that undergoing SLNB and ALN dissection (ALND) showed no significant difference for sentinel lymph node (SLN)-negative patients in terms of disease-free survival, overall survival and recurrence-free survival. However, false-negative results are still the main concern of physicians as well as patients who undergo SLNB instead of ALND. The American Society of Breast Surgeons established a task force to suggest acceptable standards for SLNB. In 2000, the task force recommended that the identification rate for SLNB be 85% or higher and the false negative rate be 5% or lower. This review focuses on clinical factors (tumor volume, multifocal/multi-center cancers, neoadjuvant chemotherapy and skip metastasis), tracer techniques and pathological factors affecting SLNB and explores methods for reducing the false-negative rate. PMID- 27478324 TI - CD147/Basigin: a Warburg oncogene in hepatocellular carcinoma? PMID- 27478325 TI - Making cancer fat: reprogramming of lipid metabolism by CD147 in hepatocellular carcinoma. PMID- 27478326 TI - Forecasting Cause-Specific Mortality in Korea up to Year 2032. AB - Forecasting cause-specific mortality can help estimate the future burden of diseases and provide a clue for preventing diseases. Our objective was to forecast the mortality for causes of death in the future (2013-2032) based on the past trends (1983-2012) in Korea. The death data consisted of 12 major causes of death from 1983 to 2012 and the population data consisted of the observed and estimated populations (1983-2032) in Korea. The modified age-period-cohort model with an R-based program, nordpred software, was used to forecast future mortality. Although the age-standardized rates for the world standard population for both sexes are expected to decrease from 2008-2012 to 2028-2032 (males: 31.4%, females: -32.3%), the crude rates are expected to increase (males: 46.3%, females: 33.4%). The total number of deaths is also estimated to increase (males: 52.7%, females: 41.9%). Additionally, the largest contribution to the overall change in deaths was the change in the age structures. Several causes of death are projected to increase in both sexes (cancer, suicide, heart diseases, pneumonia and Alzheimer's disease), while others are projected to decrease (cerebrovascular diseases, liver diseases, diabetes mellitus, traffic accidents, chronic lower respiratory diseases, and pulmonary tuberculosis). Cancer is expected to be the highest cause of death for both the 2008-2012 and 2028-2032 time periods in Korea. To reduce the disease burden, projections of the future cause-specific mortality should be used as fundamental data for developing public health policies. PMID- 27478327 TI - Clinical Evaluation of Rapid Diagnostic Test Kit for Scrub Typhus with Improved Performance. AB - Diagnosis of scrub typhus is challenging due to its more than twenty serotypes and the similar clinical symptoms with other acute febrile illnesses including leptospirosis, murine typhus and hemorrhagic fever with renal syndrome. Accuracy and rapidity of a diagnostic test to Orientia tsutsugamushi is an important step to diagnose this disease. To discriminate scrub typhus from other diseases, the improved ImmuneMed Scrub Typhus Rapid Diagnostic Test (RDT) was evaluated in Korea and Sri Lanka. The sensitivity at the base of each IgM and IgG indirect immunofluorescent assay (IFA) in Korean patients was 98.6% and 97.1%, and the specificity was 98.2% and 97.7% respectively. The sensitivity and specificity for retrospective diagnosis at the base of IFA in Sri Lanka was 92.1% and 96.1%. ImmuneMed RDT was not reactive to any serum from seventeen diseases including hemorrhagic fever with renal syndrome (n = 48), leptospirosis (n = 23), and murine typhus (n = 48). ImmuneMed RDT shows superior sensitivity (98.6% and 97.1%) compared with SD Bioline RDT (84.4% at IgM and 83.3% at IgG) in Korea. The retrospective diagnosis of ImmuneMed RDT exhibits 94.0% identity with enzyme linked Immunosorbent assay (ELISA) using South India patient serum samples. These results suggest that this RDT can replace other diagnostic tests and is applicable for global diagnosis of scrub typhus. This rapid and accurate diagnosis will be beneficial for diagnosing and managing scrub typhus. PMID- 27478328 TI - IgE Sensitization Patterns to Commonly Consumed Foods Determined by Skin Prick Test in Korean Adults. AB - Offending food allergens can vary with regional preferences in food consumption. In this study, we analysed sensitization rates to commonly consumed foods in Korean adults suspected of having food allergy. One hundred and thirty four subjects underwent a skin prick test (SPT) with 55 food allergens, of which 13 were made by our laboratory and the rest were commercially purchased. Of the 134 patients, 73 (54.5%) were sensitized to one or more food allergens. Sensitization to chrysalis was detected most frequently, at a rate of 25.4%. Sensitization rates to other food allergens were as follows: maize grain (13.4%), shrimp (11.9%), almond (11.1%), wheat flour (8.2%), lobster (8.2%), buckwheat (8.2%), mackerel (5.2%), pollack (5.2%), halibut (4.5%), peanut (4.5%), anchovy (4.4%), squid (3.7%), saury (3.0%), common eel (3.0%), yellow corvina (3.0%), hairtail (2.2%), octopus (2.2%), and others. In addition to well-known food allergens, sensitivity to mackerel, chrysalis, pollack, and halibut, which are popular foods in Korea, was observed at high rates in Korean adults. We suggest that the SPT panel for food allergy in Korea should include these allergens. PMID- 27478329 TI - Cross-Reactivity between Oak and Birch Pollens in Korean Tree Pollinosis. AB - Oak and birch trees belong to Fagales order. Specific IgE to pollen allergens of both trees are frequently found in Korea pollinosis patients. Oak trees which comprise 40% of forest area are common in Korea. However, birch trees are sparse. We compared the allergenicity of pollen extracts of white oak, sawtooth and Mongolian oaks which are prevalent species in Korea, with the pollen extract of birch. The cross-reactivity of four pollen extracts was examined with pooled sera of 12 patients by ELISA, immunoblotting and CAP inhibitions. A protein of 17 kDa, putatively homologous to a major birch allergen Bet v 1, displayed strong IgE reactivity from white oak and sawtooth oak pollen extract but not from Mongolian oak pollen. Notably, a 23-kDa protein from sawtooth and white oaks showed strong IgE reactivity and inhibited by Bet v 1. IgE binding to white oak was inhibited a maximum of 94.6% by white oak, 93.4% by sawtooth oak, 83.2% by Mongolian oak, and 68.8% by birch. Furthermore, sawtooth oak, white oak, and Mongolian oak extracts were able to inhibit up to 78.5%, 76.6% and 67.3% of IgE binding to birch extract, while birch extract itself inhibited up to 94.3%. Specific IgE to Bet v 1 was inhibited a maximum of 79.1% by sawtooth oak, 77.4% by white oak, and 72.7% by Mongolian oak, while 81.5% inhibition was shown by birch. Bet v 1 was able to partially inhibit its homologous molecules from sawtooth oak and white oak in immunoblotting. Birch pollen extract was found to be cross-reactive primarily with Bet v 1-homologous allergen from oak pollens in Korea pollinosis patients. Considering the sparseness of birch tree in Korea, oak, especially sawtooth oak may be the main cause of tree pollinosis in Korea, rather than birch. PMID- 27478330 TI - Immunohistochemical Analysis of ATRX, IDH1 and p53 in Glioblastoma and Their Correlations with Patient Survival. AB - Glioblastoma (GBM) can be classified into molecular subgroups, on the basis of biomarker expression. Here, we classified our cohort of 163 adult GBMs into molecular subgroups according to the expression of proteins encoded by genes of alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase (IDH) and TP53. We focused on the survival rate of molecular subgroups, depending on each and various combination of these biomarkers. ATRX, IDH1 and p53 protein expression were evaluated immunohistochemically and Kaplan Meier analysis were carried out in each group. A total of 15.3% of enrolled GBMs demonstrated loss of ATRX expression (ATRX-), 10.4% expressed an aberrant IDH1 R132H protein (IDH1+), and 48.4% exhibited p53 overexpression (p53+). Survival differences were statistically significant when single protein expression or different combinations of expression of these proteins were analyzed. In conclusion, in the case of single protein expression, the patients with each IDH1+, or ATRX-, or p53- GBMs showed better survival than patients with counterparts protein expressed GBMs. In the case of double protein pairs, the patients with ATRX-/p53-, ATRX-/IDH1+, and IDH1+/p53- GBMs revealed better survival than the patients with GBMs with the remained pairs. In the case of triple protein combinations, the patients with ATRX-/p53-/IDH+ showed statistically significant survival gain than the patients with remained combination of proteins-expression status. Therefore, these three biomarkers, individually and as a combination, can stratify GBMs into prognostically relevant subgroups and have strong prognostic values in adult GBMs. PMID- 27478331 TI - OTX1 Contributes to Hepatocellular Carcinoma Progression by Regulation of ERK/MAPK Pathway. AB - Orthodenticlehomeobox 1 (OTX1) overexpression had previously been associated with the progression of several tumors. The present study aimed to determine the expression and role of OTX1 in human hepatocellular carcinoma (HCC). The expression level of OTX1 was examined by quantitative real-time PCR (qRT-PCR) in 10 samples of HCC and paired adjacent non-cancerous tissues, and by immunohistochemistry (IHC) analysis in 128 HCC samples and matched controls. The relationship between OTX1 expression and the clinicopathological features werealso analyzed. Furthermore, the effects of OTX1 knockdown on cell proliferation and migration were determined in HCC cell lines. Axenograft mouse model was also established to investigate the role of OTX1 in HCC tumor growth. TheqRT-PCR and IHC analyses revealed that OTX1 was significantly elevated in HCC tissues compared with the paired non-cancerous controls. Expression of OTX1 was positively correlated with nodal metastasis status (P = 0.009) and TNM staging (P = 0.001) in HCC tissues. In addition, knockdown of OTX1 by shRNA significantly inhibited the proliferation and migration, and induced cell cycle arrest in S phase in vitro. Tumor growth was markedly inhibited by OTX1 silencing in the xenograft. Moreover, OTX1 silencing was causable for the decreased phosphorylation level of ERK/MAPK signaling. In conclusion, OTX1 contributes to HCC progression possibly by regulation of ERK/MAPK pathway. OTX1 may be a novel target for molecular therapy towards HCC. PMID- 27478332 TI - Detection of EGFR and KRAS Mutation by Pyrosequencing Analysis in Cytologic Samples of Non-Small Cell Lung Cancer. AB - EGFR and KRAS mutations are two of the most common mutations that are present in lung cancer. Screening and detecting these mutations are of issue these days, and many different methods and tissue samples are currently used to effectively detect these two mutations. In this study, we aimed to evaluate the testing for EGFR and KRAS mutations by pyrosequencing method, and compared the yield of cytology versus histology specimens in a consecutive series of patients with lung cancer. We retrospectively reviewed EGFR and KRAS mutation results of 399 (patients with EGFR mutation test) and 323 patients (patients with KRAS mutation test) diagnosed with lung cancer in Konkuk University Medical Center from 2008 to 2014. Among them, 60 patients had received both EGFR and KRAS mutation studies. We compared the detection rate of EGFR and KRAS tests in cytology, biopsy, and resection specimens. EGFR and KRAS mutations were detected in 29.8% and 8.7% of total patients, and the positive mutation results of EGFR and KRAS were mutually exclusive. The detection rate of EGFR mutation in cytology was higher than non cytology (biopsy or resection) materials (cytology: 48.5%, non-cytology: 26.1%), and the detection rate of KRAS mutation in cytology specimens was comparable to non-cytology specimens (cytology: 8.3%, non-cytology: 8.7%). We suggest that cytology specimens are good alternatives that can readily substitute tissue samples for testing both EGFR and KRAS mutations. Moreover, pyrosequencing method is highly sensitive in detecting EGFR and KRAS mutations in lung cancer patients. PMID- 27478333 TI - News Portrayal of Cancer: Content Analysis of Threat and Efficacy by Cancer Type and Comparison with Incidence and Mortality in Korea. AB - How the news media cover cancer may have profound significance for cancer prevention and control; however, little is known about the actual content of cancer news coverage in Korea. This research thus aimed to examine news portrayal of specific cancer types with respect to threat and efficacy, and to investigate whether news portrayal corresponds to actual cancer statistics. A content analysis of 1,138 cancer news stories was conducted, using a representative sample from 23 news outlets (television, newspapers, and other news media) in Korea over a 5-year period from 2008 to 2012. Cancer incidence and mortality rates were obtained from the Korean Statistical Information Service. Results suggest that threat was most prominent in news stories on pancreatic cancer (with 87% of the articles containing threat information with specific details), followed by liver (80%) and lung cancers (70%), and least in stomach cancer (41%). Efficacy information with details was conveyed most often in articles on colorectal (54%), skin (54%), and liver (50%) cancers, and least in thyroid cancer (17%). In terms of discrepancies between news portrayal and actual statistics, the threat of pancreatic and liver cancers was overreported, whereas the threat of stomach and prostate cancers was underreported. Efficacy information regarding cervical and colorectal cancers was overrepresented in the news relative to cancer statistics; efficacy of lung and thyroid cancers was underreported. Findings provide important implications for medical professionals to understand news information about particular cancers as a basis for public (mis)perception, and to communicate effectively about cancer risk with the public and patients. PMID- 27478334 TI - The Impact of Hemodialysis and Arteriovenous Access Flow on Extracranial Hemodynamic Changes in End-Stage Renal Disease Patients. AB - In this study, we characterized cerebral blood flow changes by assessment of blood flow parameters in neck arteries using carotid duplex ultrasonography and predictive factors for these hemodynamic changes. Hemodynamic variables were measured before and during hemodialysis in 81 patients with an arteriovenous access in their arm. Hemodialysis produced significant lowering in peak systolic velocity and flow volume of neck arteries and calculated total cerebral blood flow (1,221.9 +/- 344.9 [before hemodialysis] vs. 1,085.8 +/- 319.2 [during hemodialysis], P < 0.001). Effects were greater in vessels on the same side as the arteriovenous access and these changes were influenced by arteriovenous access flow during hemodialysis, both in the CCA (r = -0.277, P = 0.015) and the VA (r = -0.239, P = 0.034). The change of total cerebral blood flow during hemodialysis was independently related with age, presence of diabetes, and systemic blood pressure. PMID- 27478335 TI - Online Registry for Nationwide Database of Current Trend of Helicobacter pylori Eradication in Korea: Interim Analysis. AB - Eradication of Helicobacter pylori using first-line therapy is becoming less effective. Subjects who had been treated for H. pylori infection were prospectively enrolled through an on-line database registry from October 2010 to December 2012. Demographic data, detection methods, treatment indication, regimens, durations, compliance, adverse events, and eradication results for H. pylori infection were collected. Data of 3,700 patients from 34 hospitals were analyzed. The overall eradication rate of the first-line therapy was 73.0%. Eradication failure was significantly associated with old age, concomitant medication, and comorbidity. Regional differences in eradication rates were observed. The most common first-line therapy was proton pump inhibitor-based triple therapy (standard triple therapy, STT) for 7 days (86.8%). The eradication rates varied with regimens, being 73% in STT, 81.8% in bismuth-based quadruple therapy, 100% in sequential therapy, and 90.3% in concomitant therapy. The eradication rate in treatment-naive patients was higher than that in patients previously treated for H. pylori infection (73.8% vs. 58.5%, P < 0.001). The overall eradication rate for second-line therapy was 84.3%. There was no statistical difference in eradication rates among various regimens. H. pylori eradication rate using STT is decreasing in Korea and has become sub-optimal, suggesting the need for alternative regimens to improve the efficacy of first line therapy for H. pylori infection. PMID- 27478336 TI - Characteristics and Outcomes of Second Malignant Neoplasms after Childhood Cancer Treatment: Multi-Center Retrospective Survey. AB - This retrospective study investigated the clinical characteristics and outcomes of second malignant neoplasms (SMNs) in survivors of childhood cancer from multiple institutions in Korea. A total of 102 patients from 11 institutions who developed SMN after childhood cancer treatment between 1998 and 2011 were retrospectively enrolled. The most common primary malignant neoplasms (PMNs) were central nervous system (CNS) tumors (n = 17), followed by acute lymphoblastic leukemia (n = 16), non-Hodgkin lymphoma (n = 13), and osteosarcoma (n = 12). The most common SMNs were therapy-related myeloid neoplasms (t-MNs; acute myeloid leukemia [AML], 29 cases; myelodysplastic syndrome [MDS], 12 cases), followed by thyroid carcinomas (n = 15) and CNS tumors (n = 10). The median latency period was 4.9 years (range, 0.5-18.5 years). Among 45 patients with solid tumors defined as an SMN, 15 (33%) developed the lesion in a field previously subjected to radiation. The 5-year overall survival (OS) rate of patients with an SMN was 45% with a median follow-up time of 8.6 years. Patients with AML, MDS, and CNS tumors exhibited the poorest outcomes with 5-year OS rates of 18%, 33%, and 32%, respectively, whereas those with second osteosarcoma showed comparable outcomes (64%) to patients with primary counterpart and those with second thyroid carcinoma had a 100% OS rate. Further therapeutic efforts are recommended to improve the survival outcomes in patients with SMNs, especially in cases with t MNs and CNS tumors. PMID- 27478337 TI - Risk Factors for Functional Constipation in Young Children Attending Daycare Centers. AB - Our objective was to determine the risk factors associated with the development of functional constipation (FC) in young children attending daycare centers. A cross-sectional survey using a questionnaire based on the Rome III criteria was conducted in children aged 25 to 84 months from 3 randomly selected daycare centers in January 2016. The items in a questionnaire were statistically compared in the constipated and non-constipated groups. A total of 212 children were included and FC was found in 8.5%. Multivariate logistic regression analyses revealed that maternal history of constipation (odds ratio [OR] = 4.1, 95% Confidence Interval [CI] 1.2-13.9), history of painful defecation before age 1 (OR = 10.4, 95% CI 1.1-101.3), history of painful defecation during toilet training (OR = 28.9, 95% CI 1.9-423.8), no or difficult defecation at a daycare center (OR = 5,804.6, 95% CI 134.4-250,718.4), no meat consumption (OR = 10.1, 95% CI 1.2-88.1), and 500 mL or less of water intake per day (OR = 9.9, 95% CI 0.9-99.5) were powerful predictors of FC in young children (P < 0.05). Additionally, the constipated group was significantly associated with 2 hours or less of outdoor play activities per day, entry into daycare centers before 24 months age, 6 hours or more of attendance at a daycare center per day, breastfeeding for less than 6 months, 3 meals or less per day, and 3 or fewer servings of fruits and vegetables per day (P < 0.05). The findings of this study can guide parents, daycare teachers, and clinicians in prevention, early recognition and early intervention for the risk factors associated with FC in young children. PMID- 27478338 TI - Clinical Outcomes of Cryopreserved Arterial Allograft Used as a Vascular Conduit for Hemodialysis. AB - This single center cohort study aimed to test the hypothesis that use of a cryopreserved arterial allograft could avoid the maturation or healing process of a new vascular access and to evaluate the patency of this technique compared with that of vascular access using a prosthetic graft. Between April 2012 and March 2013, 20 patients underwent an upper arm vascular access using a cryopreserved arterial allograft for failed or failing vascular accesses and 53 using a prosthetic graft were included in this study. The mean duration of catheter dependence, calculated as the time interval from upper arm access placement to removal of the tunneled central catheter after successful cannulation of the access, was significantly longer for accesses using a prosthetic graft than a cryopreserved arterial allograft (34.4 +/- 11.39 days vs. 4.9 +/- 8.5 days, P < 0.001). In the allograft group, use of vascular access started within 7 days in 16 patients (80%), as soon as from the day of surgery in 10 patients. Primary (unassisted; P = 0.314) and cumulative (assisted; P = 0.673) access survivals were similar in the two groups. There were no postoperative complications related to the use of a cryopreserved iliac arterial allograft except for one patient who experienced wound hematoma. In conclusion, upper arm vascular access using a cryopreserved arterial allograft may permit immediate hemodialysis without the maturation or healing process, resulting in access survival comparable to that of an access using a prosthetic graft. PMID- 27478339 TI - Simvastatin Reduces Capsular Fibrosis around Silicone Implants. AB - Capsular fibrosis and contracture occurs in most breast reconstruction patients who undergo radiotherapy, and there is no definitive solution for its prevention. Simvastatin was effective at reducing fibrosis in various models. Peri-implant capsular formation is the result of tissue fibrosis development in irradiated breasts. The purpose of this study was to examine the effect of simvastatin on peri-implant fibrosis in rats. Eighteen male Sprague-Dawley rats were allocated to an experimental group (9 rats, 18 implants) or a control group (9 rats, 18 implants). Two hemispherical silicone implants, 10 mm in diameter, were inserted in subpanniculus pockets in each rat. The next day, 10-Gy of radiation from a clinical accelerator was targeted at the implants. Simvastatin (15 mg/kg/day) was administered by oral gavage in the experimental group, while animals in the control group received water. At 12 weeks post-implantation, peri-implant capsules were harvested and examined histologically and by real-time polymerase chain reaction. The average capsular thickness was 371.2 MUm in the simvastatin group and 491.2 MUm in the control group. The fibrosis ratio was significantly different, with 32.33% in the simvastatin group and 58.44% in the control group (P < 0.001). Connective tissue growth factor (CTGF) and transforming growth factor (TGF)-beta1 gene expression decreased significantly in the simvastatin group compared to the control group (P < 0.001). This study shows that simvastatin reduces radiation-induced capsular fibrosis around silicone implants in rats. This finding offers an alternative therapeutic strategy for reducing capsular fibrosis and contracture after implant-based breast reconstruction. PMID- 27478340 TI - Effects of High-Intensity-Focused Ultrasound Treatment on Benign Uterine Tumor. AB - In this study, the effects of high-intensity-focused ultrasound (HIFU) treatment on benign uterine tumor patients were examined. A total of 333 patients diagnosed with fibroids or adenomyosis using diagnostic sonography, treated with HIFU between February 4, 2010 and December 29, 2014 at a hospital in Korea, and followed up for three or six months were selected for this study. Their benign uterine tumor volume was measured, and the effects of HIFU treatment on the volume were analyzed according to age, disease, fertility, and treatment duration. The volume of benign tumors of the uterus changed by age in all age groups after conducting HIFU treatment for 3 and 6 months, respectively. The rate of decrease in individuals' in their twenties was the largest, at 64.9%. When the decreasing volume of benign tumors of the uterus was analyzed by type of disease, the treatment efficacy for adenomyosis was the best, with a decrease of 164.83 cm(3) after 6 months. Myoma had the fastest decreasing rate, at 68.5%. When evaluated on the basis of fertility, the volume of benign tumors of the uterus continued to decrease until 6 months after completing all procedures. The volume has continued to decrease for 6 months after all procedures. This study showed that HIFU treatments for uterine fibroid and adenomyosis is an effective non invasive therapy via reducing the benign uterine tumor volume. Therefore, the HIFU method might replace other conventional treatment methods. PMID- 27478342 TI - The Degree of Diabetic Retinopathy in Patients with Type 2 Diabetes Correlates with the Presence and Severity of Coronary Heart Disease. AB - Both diabetic retinopathy (DR) and coronary heart disease (CHD) are clinically significant in diabetic patients. We investigated the correlation between the severity of DR and the presence and severity of CHD among type 2 diabetic patients. A total of 175 patients who were examined at the DR clinic and underwent dual-source computed tomography (DSCT) angiography within 6 months were included. The degree of DR was graded as no DR, nonproliferative DR (NPDR), and proliferative DR (PDR). The severity of CHD and the numbers of significant stenotic coronary artery on DSCT angiography according to DR grade were assessed. The mean Agatston Calcium Score (ACS) in patients with PDR was significantly higher than other groups (P < 0.001). The overall odds of an ACS increase were about 4.7-fold higher in PDR group than in no DR group (P < 0.001). In PDR group, in comparison with in no DR, the odds of having 1 or 2 arterial involvement were 3-fold higher (P = 0.044), and those of having 3 were 17-fold higher (P = 0.011). The c-index, one of the predictability values in regression analysis model, was not significantly increased when PDR was added to classical CHD risk factors (0.671 to 0.706, P = 0.111). Conclusively, patients with PDR develop a greater likelihood of not only having CHD, but being more severe nature. PDR has no additional effect to classical CHD risk factors for predicting CHD. PMID- 27478343 TI - Is There Any Age Cutoff to Treat Elderly Patients with Head and Neck Cancer? Comparing with Septuagenarians and Octogenarians. AB - With the increase in life expectancy, age is no longer considered as a limitation for treatment. Nevertheless, the treatment of elderly patients with head and neck cancer (HNC) remains controversial. Here, we aimed to review our experience with the treatment for elderly patients, while particularly focusing on the differences among older old patients (septuagenarians vs. octogenarians). We retrospectively reviewed the records of 260 elderly patients who were assigned to 3 groups according to age: 70 years old <= group 1 < 75 years old, 75 years old <= group 2 < 80 years old, and group 3 >= 80 years old. The patients were assessed for comorbidities using the Adult Comorbidity Evaluation (ACE)-27, and the American Society of Anesthesia (ASA) physical status was also compared. Group 1, 2, and 3, consisted of 97, 102, and 61 patients, respectively. No significant difference in demographic data was noted among the groups. However, group 3 showed more comorbidities than groups 1 and 2. With regard to the initial treatment for HNC, radiation therapy (RT) was more frequently performed in group 3 than in groups 1 and 2. Among 7 patients of non-compliant to treatment in group 3, 6 patients had have performed RT. In group 3, a total of 18 patients underwent surgery, including microvascular free flap reconstruction and no significant difference in complications was observed postoperatively compared with group 1 and 2. Moreover, no significant difference was noted in overall survival between the groups, regardless of the treatment modality chosen. In conclusion, octogenarians with HNC should be more carefully managed than septuagenarians with HNC. Surgical treatment can be considered in octogenarians with HNC, if it can be tolerated. PMID- 27478341 TI - Differences in Utilization Patterns among Medications in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: a 36-Month Retrospective Study Using the Korean Health Insurance Review and Assessment Claims Database. AB - We evaluated the differences in utilization patterns including persistence and adherence among medications in children and adolescents with attention deficit hyperactivity disorder (ADHD). The current study was performed using data from the Korean Health Insurance Review and Assessment claims database from January 1, 2009 to December 31, 2013. Our study sample consisted of 10,343 children and adolescents with ADHD who were not given their newly prescribed medication in 360 days before the initial claim in 2010. Data were followed up from the initiation of treatment with ADHD medications in 2010 to December 31, 2013. Discontinuation rates for 4 ADHD medications in our sample ranged from 97.7% for immediate release methylphenidate to 99.4% for atomoxetine using refill gap more than 30 days and from 56.7% for immediate-release methylphenidate to 62.3% for extended release methylphenidate using refill gap more than 60 days. In the number of discontinued, we found significant differences among medications using refill gap more than 30 days. Among 4 ADHD medications, extended-release methylphenidate and atomoxetine had more days than immediate-release methylphenidate and osmotic controlled oral delivery system methylphenidate. In logistic regression analyses, extended-release methylphenidate, osmotic-controlled oral delivery system methylphenidate, and atomoxetine showed less discontinuation compared to immediate-release methylphenidate group when a refill gap more than 30 days was used. In logistic regression analysis of adherence, we could not find any differences among 4 medication types. We suggest that the utilization patterns should be assessed regularly in order to improve future outcomes in children and adolescents with ADHD. PMID- 27478344 TI - Skin Barrier Function Is Not Impaired and Kallikrein 7 Gene Polymorphism Is Frequently Observed in Korean X-linked Ichthyosis Patients Diagnosed by Fluorescence in Situ Hybridization and Array Comparative Genomic Hybridization. AB - X-linked ichthyosis (XLI) is a recessively inherited ichthyosis. Skin barrier function of XLI patients reported in Western countries presented minimally abnormal or normal. Here, we evaluated the skin barrier properties and a skin barrier-related gene mutation in 16 Korean XLI patients who were diagnosed by fluorescence in situ hybridization and array comparative genomic hybridization analysis. Skin barrier properties were measured, cytokine expression levels in the stratum corneum (SC) were evaluated with the tape stripped specimen from skin surface, and a genetic test was done on blood. XLI patients showed significantly lower SC hydration, but normal basal trans-epidermal water loss and skin surface pH as compared to a healthy control group. Histopathology of ichthyosis epidermis showed no acanthosis, and levels of the pro-inflammatory cytokines in the corneal layer did not differ between control and lesional/non-lesional skin of XLI patients. Among the mutations in filaggrin (FLG), kallikrein 7 (KLK7), and SPINK5 genes, the prevalence of KLK7 gene mutations was significantly higher in XLI patients (50%) than in controls (0%), whereas FLG and SPINK5 prevalence was comparable. Korean XLI patients exhibited unimpaired skin barrier function and frequent association with the KLK7 gene polymorphism, which may differentiate them from Western XLI patients. PMID- 27478345 TI - Preventing Venous Thromboembolism with Use of Intermittent Pneumatic Compression after Total Hip Arthroplasty in Korean Patients. AB - Intermittent Pneumatic Compression (IPC) device has been used to prevent venous thromboembolism (VTE). This study investigated the effectiveness of IPC device. We evaluated incidences of deep vein thrombosis (DVT) and pulmonary embolism (PE) in total hip arthroplasty (THA) patients after use of IPC device, and compared with historical incidences from our institution. We applied IPC device in 741 patients who underwent 870 elective primary THAs from January 2010 to December 2013, DVT was detected in 3 patients (0.3%) by sonography, and one (0.1%) of them was symptomatic. Symptomatic PE occurred in 1 patient (0.1%) and there were no cases of fatal PE. The incidence of symptomatic DVT was significantly lower than the historical control (P = 0.042). The IPC is a safe and effective prophylaxis of VTE after primary THA in Korea. PMID- 27478346 TI - Comparative Effectivenesses of Pulsed Radiofrequency and Transforaminal Steroid Injection for Radicular Pain due to Disc Herniation: a Prospective Randomized Trial. AB - Transforaminal Epidural steroid injections (TFESI) have been widely adopted to alleviate and control radicular pain in accord with current guidelines. However, sometimes repeated steroid injections have adverse effects, and thus, this prospective randomized trial was undertaken to compare the effectivenesses of pulsed radiofrequency (PRF) administered to a targeted dorsal root ganglion (DRG) and TFESI for the treatment of radicular pain due to disc herniation. Subjects were recruited when first proved unsuccessful (defined as a score of > 4 on a visual analogue scale (VAS; 0-10 mm) and of > 30% according to the Oswestry Disability Index (ODI) or the Neck Disability Index (NDI)). Forty-four patients that met the inclusion criteria were enrolled. The 38 subjects were randomly assigned to receive either PRF (PRF group; n = 19) or additional TFESI (TFESI group; n = 19) and were then followed for 2, 4, 8, and 12 weeks. To evaluate pain intensity were assessed by VAS. ODI and NDI were applied to evaluate functional disability. Mean VAS scores for cervical and lumbar radicular pain were significantly lower 12 weeks after treatment in both study groups. NDI and ODI scores also declined after treatment. However, no statistically significant difference was observed between the PRF and TFESI groups in terms of VAS, ODI, or NDI scores at any time during follow-up. PRF administered to a DRG might be as effective as TFESI in terms of attenuating radicular pain caused by disc herniation, and its use would avoid the adverse effects of steroid. PMID- 27478348 TI - Influence of Daily Fluid Balance prior to Continuous Renal Replacement Therapy on Outcomes in Critically Ill Patients. AB - Positive fluid balance is a risk factor for mortality in critically ill patients, especially those requiring continuous renal replacement therapy (CRRT). However, the association between daily fluid balance and various organ impairments remains unclear. This study investigated the impacts of daily fluid balance prior to CRRT on organ dysfunction, as well as mortality in critically ill patients. We identified daily fluid balance between intensive care unit (ICU) admission and CRRT initiation. According to daily fluid balance, the time to CRRT initiation and the rate of organ failure based on the sequential organ failure assessment (SOFA) score were assessed. We recruited 100 patients who experienced CRRT for acute kidney injury. CRRT was initiated within 2 [0, 4] days. The time to CRRT initiation was shortened in proportion to daily fluid balance, even after the adjustment for the renal SOFA score at ICU admission (HR 1.14, P = 0.007). Based on the SOFA score, positive daily fluid balance was associated with respiratory, cardiovascular, nervous, and coagulation failure, independent of each initial SOFA score at ICU admission (HR 1.36, 1.26, 1.24 and 2.26, all P < 0.05). Ultimately, we found that positive fluid balance was related with an increase in the rate of 28-day mortality (HR 1.14, P = 0.012). Positive daily fluid balance may accelerate the requirement for CRRT, moreover, it can be associated with an increased risk of multiple organ failure in critically ill patients. PMID- 27478347 TI - Emergency Department Crowding Disparity: a Nationwide Cross-Sectional Study. AB - In this study, we evaluated national differences in emergency department (ED) crowding to identify factors significantly associated with crowding in institutes and communities across Korea. This was a cross-sectional nationwide observational study using data abstracted from the National Emergency Department Information System (NEDIS). We calculated mean occupancy rates to quantify ED crowding status and divided EDs into three groups according to their occupancy rates (cutoffs: 0.5 and 1.0). Factors potentially related to ED crowding were collected from the NEDIS. We performed a multivariate regression analysis to identify variables significantly associated with ED crowding. A total of 120 EDs were included in the final analysis. Of these, 73 were categorized as 'low crowded' (LC, occupancy rate < 0.50), 37 as 'middle crowded' (MC, 0.50 <= occupancy rate < 1.00), 10 EDs as 'high crowded' (HC, 1.00 <= occupancy rate). The mean ED occupancy rate varied widely, from 0.06 to 2.33. The median value was 0.39 with interquartile ranges (IQRs) from 0.20 to 0.71. Multivariate analysis revealed that after adjustment, ED crowding was significantly associated with the number of visits, percentage of patients referred, number of nurses, and ED disposition. This nationwide study observed significant variety in ED crowding. Several input, throughput, and output factors were associated with crowding. PMID- 27478349 TI - Hypopituitarism Presenting as Adrenal Insufficiency and Hypothyroidism in a Patient with Wilson's Disease: a Case Report. AB - Wilson's disease typically presents symptoms associated with liver damage or neuropsychiatric disturbances, while endocrinologic abnormalities are rare. We report an unprecedented case of hypopituitarism in a patient with Wilson's disease. A 40-year-old woman presented with depression, general weakness and anorexia. Laboratory tests and imaging studies were compatible with liver cirrhosis due to Wilson's disease. Basal hormone levels and pituitary function tests indicated secondary hypothyroidism and adrenal insufficiency due to hypopituitarism. Brain MRI showed T2 hyperintense signals in both basal ganglia and midbrain but the pituitary imaging was normal. She is currently receiving chelation therapy along with thyroid hormone and steroid replacement. There may be a relationship between Wilson's disease and hypopituitarism. Copper deposition or secondary neuronal damage in the pituitary may be a possible explanation for this theory. PMID- 27478350 TI - Preoperative Computed Tomography Findings for Patients with Nasolacrimal Duct Obstruction or Stenosis. AB - PURPOSE: To identify and analyze the role of preoperative computed tomography (CT) in patients with tearing symptoms with nasolacrimal duct obstruction (NLDO). METHODS: We retrospectively reviewed the medical records and CT results on 218 patients who complained of tearing symptoms with NLDO between January 2014 and December 2014. All patients were recruited from Kim's Eye Hospital's outpatient clinic and assessed by clinical history, examination, and CT to evaluate periocular pathology and nasolacrimal drainage system. Patients with abnormal findings assessed by preoperative CT were further reviewed. RESULTS: CT was performed on 218 patients (average age, 58.2 +/- 11.9 years). Of these, 196 (89.9%) had endonasal dacryocystorhinostomy, 14 (6.4%) declined surgery, and 8 (3.7%) were inoperable due to abnormal CT findings. Soft tissue opacity was the most common finding which 243 cases (85.9%) of 283 obstructed nasolacrimal duct and 89 cases (81.7%) of 109 non-obstructed nasolacrimal duct showed it. Thirty nine (17.8%) of 218 patients showed either maxillary sinusitis or ethmoidal sinusitis and 32 (14.7%) of 218 patients presented with periocular inflammation. Other abnormal CT findings included septal deviations, previous fractures, masses, and structural abnormalities of nasal cavity. CONCLUSIONS: Preoperative CT imaging is useful in the assessment of both nasolacrimal drainage and nearby anatomical structures. This information will be helpful in planning surgical interventions and management of NLDO. PMID- 27478351 TI - Evaluation of Anterior Segment Parameter Changes Using the Sirius after Uneventful Phacoemulsification. AB - PURPOSE: To investigate changes in anterior chamber depth (ACD), corneal volume (CV), anterior chamber angle (ACA), anterior chamber volume (ACV), central corneal thickness (CCT), horizontal visible iris diameter (HVID), pupil diameter (PD), and intraocular pressure (IOP) after uneventful phacoemulsification cataract surgery with intraocular lens implantation. METHODS: A total of 132 eyes of 132 patients (87 men and 45 women) that underwent uneventful phacoemulsification cataract surgery and intraocular lens implantation were prospectively studied. The mean age of the patients was 63.68 +/- 12.51 years. All patients were evaluated preoperatively and at 1 month postoperatively with the Sirius 3D Rotating Scheimpflug camera topography system. The ACD, CV, ACA, ACV, CCT, HVID, and PD measurements were recorded. IOP was measured using the Goldmann applanation tonometer, which was corrected for CCT of the Sirius device using Ehlers' formula. RESULTS: The preoperative mean ACD, ACV, ACA, CCT, CV, PD, HVID, and IOP were 2.79 +/- 0.45 mm, 124.73 +/- 25.72 mm(3), 42.09 +/- 7.49(0), 523.87 +/- 41.97 microns, 55.37 +/- 4.89 mm(3), 3.98 +/- 1.23 mm, 11.72 +/- 0.67 mm, and 14.74 +/- 2.59 mmHg, respectively. Three months postoperatively, the mean ACD, ACV, ACA, CCT, CV, PD, HVID, and IOP were 3.45 +/- 0.6 mm, 162.52 +/- 23.79 mm(3), 51.46 +/- 5.63(0), 526.21 +/- 44.45 microns, 56.23 +/- 5.12 mm(3), 2.87 +/ 0.45 mm, 11.91 +/- 0.75 mm, and 12.02 +/- 1.83 mmHg, respectively. There was a statistically significant increase in mean postoperative ACD, ACV, ACA, CV, and HVID compared with the corresponding preoperative values (p < 0.05). CCT remained stable after surgery. Postoperative PD and IOP were significantly decreased compared to corresponding preoperative values (p < 0.05). CONCLUSIONS: Preoperative measurements by the Sirius 3D Rotating Scheimpflug camera topography system might help surgeons to predict postoperative changes resulting from phacoemulsification and intraocular lens implantation. This is a noncontact, noninvasive, and comfortable system for patients that is highly reliable and repeatable for anterior segment measurements. PMID- 27478352 TI - Diagnostic Value of the Serum Anti-Toxocara IgG Titer for Ocular Toxocariasis in Patients with Uveitis at a Tertiary Hospital in Korea. AB - PURPOSE: This study evaluated the prevalence of ocular toxocariasis (OT) in patients with uveitis of unknown etiology who visited a tertiary hospital in South Korea and assessed the success of serum anti-Toxocara immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) as a diagnostic test for OT. METHODS: The records of consecutive patients with intraocular inflammation of unknown etiology were reviewed. All participants underwent clinical and laboratory investigations, including ELISA for serum anti-Toxocara IgG. OT was diagnosed based on typical clinical findings. Clinical characteristics, seropositivity, and IgG titers were compared between patients diagnosed with OT and non-OT uveitis. The seropositivity and the diagnostic value of anti-Toxocara IgG was investigated among patients with different types of uveitis. RESULTS: Of 238 patients with uveitis of unknown etiology, 71 (29.8%) were diagnosed with OT, and 80 (33.6%) had positive ELISA results for serum anti-Toxocara IgG. The sensitivity and specificity of the ELISA test were 91.5% (65 / 71) and 91.0% (152 / 167), respectively. The positive predictive value of the serum anti-Toxocara IgG assay was 81.3%. Among patients with anterior, intermediate, posterior, and panuveitis, the prevalence rates of OT were 8.3%, 47.1%, 44.8%, and 7.1%, respectively; the seropositivity percentages were 18.1%, 47.1%, 43.7%, and 17.9%; and the positive predictive values were 38.5%, 95.8%, 92.1%, and 40.0%. The serum anti-Toxocara IgG titer also significantly decreased following albendazole treatment. CONCLUSIONS: OT is a common cause of intraocular inflammation in the tertiary hospital setting. Considering that OT is more prevalent in intermediate and posterior uveitis, and that the positive predictive value of the anti Toxocara IgG assay is high, a routine test for anti-Toxocara IgG might be necessary for Korean patients with intermediate and posterior uveitis. PMID- 27478353 TI - High Dose Intravitreal Bevacizumab for Refractory Pigment Epithelial Detachment in Age-related Macular Degeneration. AB - PURPOSE: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) is the first choice of treatment for age-related macular degeneration. However, quite a few eyes treated using conventional dose anti-VEGF (CDAV) have persistent pigment epithelial detachment (PED) on optical coherence tomography. This study investigated the efficacy and safety of high dose anti-VEGF (HDAV) for refractory PED. METHODS: In this retrospective study, 31 eyes of neovascular age-related macular degeneration patients with persistent PED findings despite six or more intravitreal injections of CDAV (bevacizumab 1.25 mg or ranibizumab 2.5 mg) were analyzed. Changes in visual outcome, central foveal thickness, and PED height were compared before and after HDAV (bevacizumab 5.0 mg) for these refractory PED cases. RESULTS: The mean age of patients was 67.7 years. The number of CDAV injections was 12.1. The number of HDAV injections was 3.39. Best-corrected visual acuity in logarithm of the minimum angle of resolution before and after HDAV was 0.49 and 0.41 (p < 0.001), respectively. Central foveal thickness before and after HDAV was 330.06 and 311.10 um (p = 0.125), respectively. PED height before and after HDAV was 230.28 and 204.07 um (p = 0.014), respectively. There were no serious adverse reactions in all the eyes. CONCLUSIONS: Increasing the dose of bevacizumab in refractory PED may be a possible treatment option. PMID- 27478354 TI - Intravitreal Anti-vascular Endothelial Growth Factor for Treating Polypoidal Choroidal Vasculopathy with Grape-like Polyp Clusters. AB - PURPOSE: To evaluate 12-month outcomes of anti-vascular endothelial growth factor (VEGF) therapy for polypoidal choroidal vasculopathy (PCV) with grape-like polyp clusters. METHODS: This retrospective observational study included 23 eyes of 23 patients who were newly diagnosed with PCV with grape-like polyp clusters, and who were subsequently treated with anti-VEGF monotherapy. The study compares the best-corrected visual acuity (BCVA) of the patients at diagnosis, at 3 months, and at 12 months after diagnosis. In addition, 12-month changes in BCVA values were compared between cases with subfoveal or juxtafoveal polyps and cases with extrafoveal polyps. RESULTS: The baseline, 3-month, and 12-month logarithm of the minimal angle of resolution BCVA was 0.62 +/- 0.35, 0.50 +/- 0.43, and 0.58 +/- 0.48, respectively. Compared to the baseline, patient BCVA was not significantly different at 12 months after diagnosis (p = 0.764). Six eyes (26.1%) gained >=0.2 logarithm of the minimal angle of resolution BCVA. In cases with subfoveal or juxtafoveal polyps, BCVA values at baseline and at 12 months after diagnosis were 0.66 +/- 0.37 and 0.69 +/- 0.53, respectively. In cases with extrafoveal polyps, the values were 0.54 +/- 0.33 and 0.37 +/- 0.31, respectively. Changes in BCVA values were significantly different between the two groups (p = 0.023). CONCLUSIONS: Although anti-VEGF therapy has favorable short-term efficacy for treating PCV with grape-like polyp clusters, long-term visual improvements are generally limited in the majority of afflicted eyes. The presence of subfoveal or juxtafoveal polyps may suggest unfavorable treatment outcomes. PMID- 27478355 TI - Influence of Biometric Variables on Refractive Outcomes after Cataract Surgery in Angle-closure Glaucoma Patients. AB - PURPOSE: To evaluate the influence of biometric variables on refractive outcomes after cataract surgery in angle-closure glaucoma (ACG) patients. METHODS: In this case-control study, 42 ACG patients, 40 open-angle glaucoma (OAG) patients, and 35 controls without glaucoma who had undergone conventional cataract surgery were enrolled consecutively. Electronic medical records, including preoperative biometric variables (keratometric diopter, axial length, anterior chamber depth, and lens thickness), the refractive change (RC), and the absolute value of refractive change (ARC) were reviewed. RESULTS: In the control and OAG patients, the anterior chamber depth was negatively correlated with the ARC (r = -0.344, p = 0.043 and r = -0.431, p = 0.006, respectively), whereas there was no correlation in the ACG patients. Lens thickness was positively correlated with the RC, but not with the ARC, in the control and OAG groups (r = 0.391, p = 0.020 and r = 0.501, p = 0.001, respectively). In contrast, lens thickness in the ACG group was not correlated with the RC but was positively correlated with the ARC (r = 0.331, p = 0.032). CONCLUSIONS: In contrast with the anterior chamber depth, preoperatively measured lens thickness may be a useful predictor of the direction of the RC after cataract surgery in control and OAG patients. However, in ACG patients, a thicker lens was correlated with a larger RC, regardless of the direction of the shift (hyperopic or myopic). PMID- 27478356 TI - Analysis of Fundus Photography and Fluorescein Angiography in Nonarteritic Anterior Ischemic Optic Neuropathy and Optic Neuritis. AB - PURPOSE: We evaluated fundus and fluorescein angiography (FAG) findings and characteristics that can help distinguish nonarteritic anterior ischemic optic neuropathy (NAION) from optic neuritis (ON). METHODS: Twenty-three NAION patients and 17 ON with disc swelling patients were enrolled in this study. We performed fundus photography and FAG. The disc-swelling pattern, hyperemia grade, presence of splinter hemorrhages, cotton-wool spots, artery/vein ratio and degree of focal telangiectasia were investigated. The FAG findings for each patient were compared with respect to the following features: the pattern of disc leakage in the early phase, arteriovenous (artery/vein) transit time (second), and the presence and pattern of the filling delay. RESULTS: Cotton-wool spots, focal telangiectasia, and venous congestion were more common in the affected eyes of NAION patients. Upon FAG, 76.5% of the patients in the ON group exhibited normal choroidal circulation. However, 56.5% of patients in the NAION group demonstrated abnormal filling defects, such as peripapillary, generalized, or watershed zone filling delays. CONCLUSIONS: Fundus findings, including cotton-wool spots, focal telangiectasia, and venous congestion in the affected eye, may be clues that can be used to diagnose NAION. In addition, choroidal insufficiencies on FAG could be also helpful in differentiating NAION from ON. PMID- 27478357 TI - The Application of a New Maximum Color Contrast Sensitivity Test to the Early Prediction of Chiasma Damage in Cases of Pituitary Adenoma: The Pilot Study. AB - PURPOSE: Our objective was to estimate the maximum color contrast sensitivity (MCCS) thresholds in individuals with chiasma opticum damage. METHODS: The pilot study tested 41 people with pituitary adenoma (PA) and 100 age- and gender matched controls. Patients were divided into two groups according to PA size, PA <=1 cm or PA >1 cm. A new MCCS test program was used for color discrimination. RESULTS: The mean total error score (TES) of MCCS was 1.8 in the PA <=1 cm group (standard deviation [SD], 0.38), 3.5 in the PA >1 cm group (SD, 0.96), and 1.4 in the control group (SD, 0.31; p < 0.001). There was a positive correlation between tumor size and MCCS result (r = 0.648, p < 0.01). In the group that had PA producing hormones, the TES was 2.5 (SD, 1.09), compared to 4.2 value in the non functioning PA group of patients that did not have clinically significant hormone excess (SD, 3.16; p < 0.01). In patients with normal visual acuity (VA) or visual field MCCS, the TES was 3.3 (SD, 1.8), while that in patients with VA <0.00 was 4.6 (SD, 2.9). CONCLUSIONS: Results of the MCCS test TES were 1.9 times better in patients with PA <=1 cm compared to patients with PA >1 cm (p < 0.01). In PA patients with normal VA, the TES was 2.35 times worse than that of healthy persons (p < 0.01). PMID- 27478358 TI - The Effect of TNF-alpha Blocker HL036337 and Its Best Concentration to Inhibit Dry Eye Inflammation. AB - PURPOSE: Dry eye syndrome is commonly thought of as an inflammatory disease, and we have previously presented data showing the effectiveness of topical TNF-alpha blocker agents for the treatment of this condition. The purpose of this study was to investigate the effectiveness of the TNF-alpha blocking agent HL036337 compared to cyclosporine A for the treatment of dry eye induced inflammation in order to establish whether HL036337 represents a more effective method for suppressing inflammation. The efficacy of HL036337 and cyclosporine A was determined using an experimental murine dry eye model. METHODS: The TNF-alpha blocker HL036337 is a modified form of TNF receptor I. Using dry eye induced C57BL/6 mice (n = 45), corneal erosion was measured at day 4 and 7 after topical treatment with cyclosporine A or HL036337. To determine the effective treatment dose, 0.25, 0.5, 1, 2.5, and 5 mg/mL of HL036337 were topically administered twice per day to dry eye induced murine corneas for 1 week. RESULTS: The optimal concentration of the TNF-alpha blocker HL036337 for treatment of dry eye induced corneal erosion was determined to be 1 mg/mL. Dry eye induced corneal erosion was improved after 1 week with topically applied cyclosporine A and HL036337 at 1 mg/mL. CONCLUSIONS: HL036337 administered topically at 1 mg/mL effectively improved corneal erosion induced by dry eye. This finding may also suggest that inhibition of TNF-alpha can improve dry eye syndrome. PMID- 27478359 TI - Verrucous Carcinoma of the Eyelid. PMID- 27478360 TI - Successful Treatment with Chronic Conjunctivitis: Removal of Tarsoconjunctival Crypt. PMID- 27478361 TI - A Case of Ocular Decompression Retinopathy Mimicking Central Retinal Vein Occlusion. PMID- 27478362 TI - Recurrent Ophthalmoplegia Presenting Different Clinical Features in a Patient with Anti-GQ1b Antibody Syndrome. PMID- 27478363 TI - Fluid Dynamics of Biomimetic Pectoral Fin Propulsion Using Immersed Boundary Method. AB - Numerical simulations are carried out to study the fluid dynamics of a complex shaped low-aspect-ratio pectoral fin that performs the labriform swimming. Simulations of flow around the fin are achieved by a developed immersed boundary (IB) method, in which we have proposed an efficient local flow reconstruction algorithm with enough robustness and a new numerical strategy with excellent adaptability to deal with complex moving boundaries involved in bionic flow simulations. The prescribed fin kinematics in each period consists of the power stroke and the recovery stroke, and the simulations indicate that the former is mainly used to provide the thrust while the latter is mainly used to provide the lift. The fin wake is dominated by a three-dimensional dual-ring vortex wake structure where the partial power-stroke vortex ring is linked to the recovery stroke ring vertically. Moreover, the connection of force production with the fin kinematics and vortex dynamics is discussed in detail to explore the propulsion mechanism. We also conduct a parametric study to understand how the vortex topology and hydrodynamic characteristics change with key parameters. The results show that there is an optimal phase angle and Strouhal number for this complicated fin. Furthermore, the implications for the design of a bioinspired pectoral fin are discussed based on the quantitative hydrodynamic analysis. PMID- 27478364 TI - Singular Value Decomposition Based Features for Automatic Tumor Detection in Wireless Capsule Endoscopy Images. AB - Wireless capsule endoscopy (WCE) is a new noninvasive instrument which allows direct observation of the gastrointestinal tract to diagnose its relative diseases. Because of the large number of images obtained from the capsule endoscopy per patient, doctors need too much time to investigate all of them. So, it would be worthwhile to design a system for detecting diseases automatically. In this paper, a new method is presented for automatic detection of tumors in the WCE images. This method will utilize the advantages of the discrete wavelet transform (DWT) and singular value decomposition (SVD) algorithms to extract features from different color channels of the WCE images. Therefore, the extracted features are invariant to rotation and can describe multiresolution characteristics of the WCE images. In order to classify the WCE images, the support vector machine (SVM) method is applied to a data set which includes 400 normal and 400 tumor WCE images. The experimental results show proper performance of the proposed algorithm for detection and isolation of the tumor images which, in the best way, shows 94%, 93%, and 93.5% of sensitivity, specificity, and accuracy in the RGB color space, respectively. PMID- 27478365 TI - Femtosecond laser-assisted in situ keratomileusis multifocal ablation profile using a mini-monovision approach for presbyopic patients with hyperopia. AB - PURPOSE: To report the visual outcomes of the femtosecond laser-assisted multifocal aspheric corneal ablation profile using a mini-monovision approach and to evaluate if corneal multifocality was effective, and to report the relative benefits of this approach. PATIENTS AND METHODS: Bilateral femtosecond laser assisted in situ keratomileusis using a multifocal aspheric corneal ablation profile was performed on 19 hyperopic patients (38 eyes). They were divided into two groups based on eye dominance: dominant eye (DE) group targeting emmetropia and the nondominant eye (NDE) group targeting -0.5 D slight myopia. The uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), and retreatment rates were reported from baseline to 6 months. RESULTS: The UNVA, UIVA, and UDVA improved significantly in both groups (Kruskal-Wallis test, DE and NDE: P<0.00001, P<0.000005, and P=0.00001, respectively). Corrected distance visual acuity (CDVA) baseline was better in both groups in comparison to UDVA at 6 months (Wilcoxon test, DE: P<0.001, 95% confidence interval (CI) of the median 0.0-0.0 LogMAR and 0.1000-0.1218 LogMAR and NDE: P=0.010, 95% CI of the median 0.0-0.0 LogMAR and 0.00-0.10 LogMAR). There was a significant loss of lines between CDVA baseline and UDVA at 6 months in both groups (DE group: 68% of eyes lost one line or more; NDE group: 58% of eyes lost one line or more). The corrected near visual acuity baseline compared to UNVA at 6 months was not statistically important (Wilcoxon test, DE: P=0.8125, 95% CI of the median 0.0-0.0 LogMAR and 0.0-0.0 LogMAR and NDE: P=0.82, 95% CI of the median 0.0-0.0 LogMAR and 0.0-0.0 LogMAR). The comparison among the UDVA, UIVA, and UNVA between the two groups at baseline and during all follow-ups was not statistically important. Two cases from the DE group were retreated (6%). CONCLUSION: Use of this multifocal aspheric corneal ablation profile in patients with hyperopic presbyopia significantly improved UDVA, UIVA, and UNVA. This improvement was due to created multifocality of the cornea. The mini-monovision seems not to affect UDVA, UIVA, and UNVA between the two groups. The retreatment rates at the 6-month evaluation were significantly less in our study when compared with other studies. This method seems to improve UDVA, UIVA, and UNVA but could result in a significant statistical difference between CDVA baseline and UDVA at 6 months that leads to loss of lines in distance vision. Despite promising results, this is a preliminary evaluation of this new profile, and a larger number of eyes are needed to verify visual outcomes, retreatment rates, and safety. PMID- 27478366 TI - The role of adjunctive dexamethasone in the treatment of bacterial meningitis: an updated systematic meta-analysis. AB - BACKGROUND: Bacterial meningitis is a serious infection in children and adults worldwide, with considerable morbidity, mortality, and severe neurological sequelae. Dexamethasone is often used before antibiotics in cases of this disease, and improves outcomes. OBJECTIVE: Although several studies have identified the role of adjunctive dexamethasone therapy in the treatment of bacterial meningitis, the results are still inconclusive. The aim of this study was to systematically evaluate the therapeutic and adverse effect of adjunctive dexa-methasone in patients with bacterial meningitis. MATERIALS AND METHODS: Relevant randomized, double-blind, placebo-controlled trials of dexamethasone in bacterial meningitis published between 2000 and 2016 were retrieved from the common electronic databases. The odds ratio (OR) and risk ratio (RR) with their 95% confidence interval (CI) were employed to calculate the effect. RESULTS: A total of ten articles including 2,459 bacterial meningitis patients (1,245 in the dex-amethasone group and 1,214 in the placebo group) were included in this meta analysis. Our result found that dexamethasone was not associated with a significant reduction in follow-up mortality (292 of 1,245 on dexamethasone versus 314 of 1,214 on placebo; OR =0.91, 95% CI =0.80-1.03, P=0.14) and severe neurological sequelae (22.4% versus 24.1%, OR =0.84, 95% CI =0.54-1.29, P=0.42). However, dexamethasone seemed to reduce hearing loss among survivors (21.2% versus 26.1%; OR =0.76, 95% CI =0.59-0.98, P=0.03). No significant difference was found between these two groups in adverse events. CONCLUSION: Our results suggested that adjunctive dexamethasone might not be beneficial in the treatment of bacterial meningitis. Future studies with more data are needed to further prove the role of dexamethasone in bacterial meningitis. PMID- 27478367 TI - Molecular Shape Analysis-Guided Virtual Screening Platform for Adenosine Kinase Inhibitors. AB - We propose a new application of molecular shape descriptors in hierarchical selection during virtual screening (VS). Here, a structure-based pharmacophore and docking-guided VS protocol have been evolved to identify inhibitors against adenosine kinase (AK). The knowledge gained on the shape requirements has been extrapolated in classifying active and inactive molecules against this target. This classification enabled us to pick the appropriate ligand conformation in the binding site. We have suggested a set of hierarchical filters for VS, from a simple molecular shape analysis (MSA) descriptor-based recursive models to docking scores. This approach permits a systematic study to understand the importance of spatial requirements and limitations for inhibitors against AK. Finally, the guidelines on how to select compounds for AK to achieve success have been highlighted. The utility of this approach has been suggested by giving an example of database screening for plausible active compounds. PMID- 27478368 TI - PIMADb: A Database of Protein-Protein Interactions in Huge Macromolecular Assemblies. AB - Protein-protein interactions play a very important role in the process of cellular functionality. Intricate details about the interactions between the proteins in a macromolecular assembly are important to understand the function and significance of protein complexes. We are reporting about a database of protein-protein interactions in huge macromolecular assemblies (PIMADb) that records the intrinsic details of 189,532 interchain interactions in 40,049 complexes from the Protein Data Bank. These details include the results of the quantification and analysis of all the interactions in the complex. The availability of interprotomer interaction networks can enable the design of point mutation experiments. PIMADb can be accessed from the URL: http://caps.ncbs.res.in/pimadb. PMID- 27478369 TI - Cluster Analysis of Tumor Suppressor Genes in Canine Leukocytes Identifies Activation State. AB - Cells of the immune system undergo activation and subsequent proliferation in the normal course of an immune response. Infrequently, the molecular and cellular events that underlie the mechanisms of proliferation are dysregulated and may lead to oncogenesis, leading to tumor formation. The most common forms of immunological cancers are lymphomas, which in dogs account for 8%-20% of all cancers, affecting up to 1.2% of the dog population. Key genes involved in negatively regulating proliferation of lymphocytes include a group classified as tumor suppressor genes (TSGs). These genes are also known to be associated with progression of lymphoma in humans, mice, and dogs and are potential candidates for pathological grading and diagnosis. The aim of the present study was to analyze TSG profiles in stimulated leukocytes from dogs to identify genes that discriminate an activated phenotype. A total of 554 TSGs and three gene set collections were analyzed from microarray data. Cluster analysis of three subsets of genes discriminated between stimulated and unstimulated cells. These included 20 most upregulated and downregulated TSGs, TSG in hallmark gene sets significantly enriched in active cells, and a selection of candidate TSGs, p15 (CDKN2B), p18 (CDKN2C), p19 (CDKN1A), p21 (CDKN2A), p27 (CDKN1B), and p53 (TP53) in the third set. Analysis of two subsets suggested that these genes or a subset of these genes may be used as a specialized PCR set for additional analysis. PMID- 27478370 TI - The imaging assessment and specific endograft design for the endovascular repair of ascending aortic dissection. AB - BACKGROUND: Endovascular option has been proposed for a very limited and selected number of Stanford type A aortic dissection (TAAD) patients. We have performed a computed tomography (CT)-based TAAD study to explore appropriate endograft configurations for the ascending aortic pathology. METHODS: TAAD patients treated with optimal CT scans were retrospectively reviewed, and their entry tears (ETs) were identified using three-dimensional and multiplanar reconstructions in an EndoSize workstation. After generating a centerline of flow, measurements, including numerous morphologic characteristics of anatomy, were evaluated and a selected subset of patients were determined to be suitable for endovascular treatments. Proximal diameter and distal diameter of endograft were selected based on diameters measured at the ET level and at the innominate artery (IA) level, with 10% oversizing with respect to the true lumen, but not exceeding the original aortic diameter. The length of the endograft was determined by the distance from the sinotubular junction to IA. RESULTS: This study covered 126 TAAD patients with primary ET in ascending aorta, among which, according to the assumed criteria, 48 (38.1%) patients were deemed to be suitable for endovascular treatment. The diameters of ascending aorta from the sinotubular junction to the IA level presented a downward trend, and the proximal diameters differed significantly from distal diameters of the endograft for TAAD (39.9 versus 36.2 mm, P<0.01), implying that the conical endograft might be compatible with the ascending pathology. In the ascending aorta, lengths of the endograft should be 50, 60, 70, 80, and 90 mm in five (10.4%), 22 (45.9%), 13 (27.1%), six (12.5%), and two (4.2%) patients, respectively. CONCLUSION: In this selected number of Chinese patients, the suitability of endovascular repair has been demonstrated based on the CT imaging. Shorter, larger, and bare spring-free conical endografts were preferred in the ascending aortic pathology. PMID- 27478371 TI - CHADS2 score has a better predictive value than CHA2DS2-VASc score in elderly patients with atrial fibrillation. AB - AIM: The study aims to compare the ability of CHA2DS2-VASc (defined as congestive heart failure, hypertension, age >=75 years [two scores], type 2 diabetes mellitus, previous stroke, transient ischemic attack, or thromboembolism [TE] [doubled], vascular disease, age 65-74 years, and sex category) and CHADS2 (defined as congestive heart failure, hypertension, age >=75 years, type 2 diabetes mellitus, previous stroke [doubled]) scores to predict the risk of ischemic stroke (IS) or TE among patients with nonvalvular atrial fibrillation (NVAF). METHODS: A total of 413 patients with NVAF aged >=65 years, and not on oral anticoagulants for the previous 6 months, were enrolled in the study. The predictive value of the CHA2DS2-VASc and CHADS2 scores for IS/TE events was evaluated by the Kaplan-Meier method. RESULTS: During a follow-up period of 1.99+/-1.29 years, 104 (25.2%) patients died and 59 (14.3%) patients developed IS/TE. The CHADS2 score performed better than the CHA2DS2-VASc score in predicting IS/TE as assessed by c-indexes (0.647 vs 0.615, respectively; P<0.05). Non-CHADS2 risk factors, such as vascular disease and female sex, were not found to be predictive of IS/TE (hazard ratio 1.518, 95% CI: 0.832-2.771; hazard ratio 1.067, 95% CI: 0.599-1.899, respectively). No differences in event rates were found in patients with the CHADS2 scores of 1 and 2 (7.1% vs 7.8%). It was observed that patients with a CHADS2 score of >=3 were most in need of anticoagulation therapy. CONCLUSION: In patients with NVAF aged >=65 years, the CHADS2 score was found to be significantly better in predicting IS/TE events when compared to the CHA2DS2-VASc score. Patients with a CHADS2 score of >=3 were associated with high risk of IS/TE events. PMID- 27478372 TI - Involvement of informal caregivers in supporting patients with COPD: a review of intervention studies. AB - Caregivers of individuals with COPD have a key role in maintaining patient adherence and optimizing patient function. However, no systematic review has examined how the caregiver role has been operationalized in interventions to improve outcomes of individuals with COPD or the quality or effectiveness of these interventions. The aims of this review were to 1) determine whether caregivers have been involved as part of interventions to improve outcomes of individuals with COPD; 2) determine the risk of bias within included intervention studies; and 3) examine the effectiveness of interventions that have involved caregivers in improving outcomes of individuals with COPD. The electronic databases of Medline, Embase, PsycINFO, and Cochrane Library were searched from January 2000 to November 2015. Experimental studies testing interventions that involved a caregiver to improve COPD patient outcomes were eligible. Nine studies involving caregivers met inclusion criteria. No studies reported any intervention components targeted solely at caregivers, with most instead including caregivers in dyadic or group education sessions about COPD delivered by health care professionals. The risk of bias identified in included studies was mixed. Seven of the nine studies were effective in improving a broad range of outcomes. These findings highlight that there is an urgent need for methodologically rigorous interventions to examine the effectiveness of strategies to assist caregivers to provide direct care, encourage adherence to health care provider recommendations, act as a health care advocate, and provide emotional and psychosocial support to individuals with COPD. PMID- 27478373 TI - Phenotypic assessment of pulmonary hypertension using high-resolution echocardiography is feasible in neonatal mice with experimental bronchopulmonary dysplasia and pulmonary hypertension: a step toward preventing chronic obstructive pulmonary disease. AB - Bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD) are chronic lung diseases of human infants and adults, respectively, that are characterized by alveolar simplification. One-third of the infants with severe BPD develop pulmonary hypertension (PH). More importantly, PH increases morbidity and mortality in BPD patients. Additionally, COPD is a common respiratory morbidity in former BPD patients. The lack of an appropriate small animal model wherein echocardiography (Echo) can demonstrate PH is one of the major barriers to understand the molecular mechanisms of the disease and, thereby, develop rational therapies to prevent and/or treat PH in BPD patients. Thus, the goal of this study was to establish a model of experimental BPD and PH and investigate the feasibility of Echo to diagnose PH in neonatal mice. Since hyperoxia-induced oxidative stress and inflammation contributes to the development of BPD with PH, we tested the hypothesis that exposure of newborn C57BL/6J mice to 70% O2 (hyperoxia) for 14 days leads to lung oxidative stress, inflammation, alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and Echo evidence of PH. Hyperoxia exposure caused lung oxidative stress and inflammation as evident by increased malondialdehyde adducts and inducible nitric oxide synthase, respectively. Additionally, hyperoxia exposure caused growth restriction, alveolar and pulmonary vascular simplification, and pulmonary vascular remodeling. At 14 days of age, Echo of these mice demonstrated that hyperoxia exposure decreased pulmonary acceleration time (PAT) and PAT/ejection time ratio and increased right ventricular free wall thickness, which are indicators of significant PH. Thus, we have demonstrated the feasibility of Echo to phenotype PH in neonatal mice with experimental BPD with PH, which can aid in discovery of therapies to prevent and/or treat BPD with PH and its sequelae such as COPD in humans. PMID- 27478374 TI - Inhaled corticosteroids can reduce osteoporosis in female patients with COPD. AB - BACKGROUND: Whether the use of inhaled corticosteroids (ICSs) in patients with COPD can protect from osteoporosis remains undetermined. The aim of this study is to assess the incidence of osteoporosis in patients with COPD with ICS use and without. PATIENTS AND METHODS: This is a retrospective cohort and population based study in which we extracted newly diagnosed female patients with COPD between 1997 and 2009 from Taiwan's National Health Insurance (TNHI) database between 1996 and 2011 (International Classification of Diseases, Ninth Revision - Clinical Modification [ICD-9-CM] 491, 492, 496). The patients with COPD were defined by the presence of two or more diagnostic codes for COPD within 12 months on either inpatient or outpatient service claims submitted to TNHI. Patients were excluded if they were younger than 40 years or if osteoporosis had been diagnosed prior to the diagnosis of COPD and cases of asthma (ICD-9 CM code 493.X) before the index date. These enrolled patients were followed up till 2011, and the incidence of osteoporosis was determined. The Cox proportional hazards regression model was also used to estimate hazard ratios (HRs) for incidences of lung cancer. RESULTS: Totally, 10,723 patients with COPD, including ICS users (n=812) and nonusers (n=9,911), were enrolled. The incidence rate of osteoporosis per 100,000 person years is 4,395 in nonusers and 2,709 in ICS users (HR: 0.73, 95% confidence interval [CI]: 0.63-084). The higher ICS dose is associated with lower risk of osteoporosis (0 mg to <=20 mg, HR: 0.84, 95% CI: 0.69-1.04; >20 mg to <=60 mg, HR: 0.78, 95% CI: 0.59-1.04; and >60 mg, HR: 0.72, 95% CI: 0.55-0.96; P for trend =0.0023) after adjusting for age, income, and medications. The cumulative osteoporosis probability significantly decreased among the ICS users when compared with the nonusers (P<0.001). CONCLUSION: Female patients with COPD using ICS have a dose-response protective effect for osteoporosis. PMID- 27478375 TI - Silencing tumor necrosis factor-alpha in vitro from small interfering RNA decorated titanium nanotube array can facilitate osteogenic differentiation of mesenchymal stem cells. AB - Titanium implants are known for their bone bonding ability. However, the osseointegration may be severely disturbed in the inflammation environment. In order to enhance osseointegration of the implant in an inflamed environment, the small interfering RNA (siRNA) targeting tumor necrosis factor alpha (TNF-alpha) was used to functionalize titanium surface for gene silencing. The chitosan tripolyphosphate-hyaluronate complexes were used to formulate nanoparticles (NPs) with siRNA, which were adsorbed directly by the anodized titanium surface. The surface characterization was analyzed by scanning electron microscope, atomic force microscopy, as well as contact angle measurement. The fluorescence microscope was used to monitor the degradation of the layer. The coculture system was established with mesenchymal stem cells (MSCs) grown directly on functionalized titanium surface and RAW264.7 cells (preactivated by lipopolysaccharide) grown upside in a transwell chamber. The transfection and knockdown efficiency of TNF-alpha in RAW264.7 cells were determined by fluorescence microscope, quantitative polymerase chain reaction, and enzyme linked immunosorbent assay. The cytoskeleton and osteogenic differentiation of MSCs were also analyzed. Regular vertical aligned nanotubes (~100 nm diameter and ~300 nm length) were generated after anodization of polished titanium. After loading with NPs, the nanotubes were filled and covered by a layer of amorphous particles. The surface topography changed and wettability decreased after covering with NPs. As expected, a burst degradation of the film was observed, which could provide sufficient NPs in the released supernatant and result in transfection and knockdown effects in RAW264.7 cells. The cytoskeleton arrangement of MSCs was elongated and the osteogenic differentiation was also significantly improved on NPs loading surface. In conclusion, the siRNA decorated titanium implant could simultaneously suppress inflammation and improve osteogenesis, which may be suitable for peri-implant bone formation under inflammatory conditions. PMID- 27478376 TI - Sol-gel dip coating of yttria-stabilized tetragonal zirconia dental ceramic by aluminosilicate nanocomposite as a novel technique to improve the bonding of veneering porcelain. AB - The aim of this in vitro study was to evaluate the effect of silica and aluminosilicate nanocomposite coating of zirconia-based dental ceramic by a sol gel dip-coating technique on the bond strength of veneering porcelain to the yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) in vitro. Thirty Y-TZP blocks (10 mm *10 mm *3 mm) were prepared and were assigned to four experimental groups (n=10/group): C, without any further surface treatment as the control group; S, sandblasted using 110 MUm alumina powder; Si, silica sol dip coating + calcination; and Si/Al, aluminosilicate sol dip coating + calcination. After preparing Y-TZP samples, a 3 mm thick layer of the recommended porcelain was fired on the coated Y-TZP surface. Fourier transform infrared spectroscopy (FT IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive X-ray analysis were used to characterize the coating and the nature of the bonding between the coating and zirconia. To examine the zirconia-porcelain bond strength, a microtensile bond strength (MUTBS) approach was chosen. FT-IR study showed the formation of silica and aluminosilicate materials. XRD pattern showed the formation of new phases consisting of Si, Al, and Zr in coated samples. SEM showed the formation of a uniform coating on Y-TZP samples. Maximum MUTBS values were obtained in aluminosilicate samples, which were significantly increased compared to control and sandblasted groups (P=0.013 and P<0.001, respectively). This study showed that aluminosilicate sol-gel dip coating can be considered as a convenient, less expensive reliable method for improving the bond strength between dental Y-TZP ceramics and veneering porcelain. PMID- 27478377 TI - ESSENCE-Q - a first clinical validation study of a new screening questionnaire for young children with suspected neurodevelopmental problems in south Japan. AB - BACKGROUND: Early identification of autism spectrum disorder, intellectual developmental disorder, attention-deficit/hyperactivity disorder, and other neurodevelopmental disorders/problems is crucial, yet diagnosis is often delayed for years under the often misguided "wait-and-see" paradigm. The early symptomatic syndromes eliciting neurodevelopmental clinical examinations questionnaire (ESSENCE-Q) is a brief (12-item) screening questionnaire developed specifically for the purpose of speeding up the identification process of a wide variety of neurodevelopmental problems. The aims were to 1) estimate the reliability of the ESSENCE-Q, 2) evaluate the clinical cutoff levels suggested by the author of the ESSENCE-Q, and 3) propose optimal cutoff levels based on receiver operating characteristic analysis. METHODS: The ESSENCE-Q was used for 1 year by a psychiatrist in Kochi, Japan, assessing children under the age of 6 years referred for developmental problems. The children were also clinically assessed with regard to whether or not they met criteria for a developmental disorder (diagnosis positive and diagnosis negative groups). We contrasted the results of the ESSENCE-Q and those of clinical diagnostic assessments in 130 cases. RESULTS: Cronbach's alpha was 0.82, sensitivity was 0.94 (95% confidence interval [CI]: [0.88, 0.98]), and specificity 0.53 (95% CI: [0.28, 0.77]), which are reasonable psychometrics for a first-step screening tool. Based on receiver operating characteristic analysis, we recommended an optimal cutoff level of yes >=2 or maybe/a little >=3 on the ESSENCE-Q (0.87 (95% CI: [0.79, 0.92]) sensitivity and 0.77 (95% CI: [0.50, 0.93]) specificity). CONCLUSION AND IMPLICATION: The ESSENCE-Q can be a good instrument for use as a screening tool for aiding in the process of early identification of neurodevelopmental disorders in clinical settings. To establish the broader validity and reliability of the ESSENCE-Q, case-control studies and general population studies of children in different age groups are needed. PMID- 27478379 TI - Efficient Queries of Stand-off Annotations for Natural Language Processing on Electronic Medical Records. AB - In natural language processing, stand-off annotation uses the starting and ending positions of an annotation to anchor it to the text and stores the annotation content separately from the text. We address the fundamental problem of efficiently storing stand-off annotations when applying natural language processing on narrative clinical notes in electronic medical records (EMRs) and efficiently retrieving such annotations that satisfy position constraints. Efficient storage and retrieval of stand-off annotations can facilitate tasks such as mapping unstructured text to electronic medical record ontologies. We first formulate this problem into the interval query problem, for which optimal query/update time is in general logarithm. We next perform a tight time complexity analysis on the basic interval tree query algorithm and show its nonoptimality when being applied to a collection of 13 query types from Allen's interval algebra. We then study two closely related state-of-the-art interval query algorithms, proposed query reformulations, and augmentations to the second algorithm. Our proposed algorithm achieves logarithmic time stabbing-max query time complexity and solves the stabbing-interval query tasks on all of Allen's relations in logarithmic time, attaining the theoretic lower bound. Updating time is kept logarithmic and the space requirement is kept linear at the same time. We also discuss interval management in external memory models and higher dimensions. PMID- 27478378 TI - Zika virus challenges for neuropsychiatry. AB - Before 2007, Zika virus (ZIKV) was generally considered as an arbovirus of low clinical relevance, causing a mild self-limiting febrile illness in tropical Africa and Southeast Asia. Currently, a large, ongoing outbreak of ZIKV that started in Brazil in 2015 is spreading across the Americas. Virus infection during pregnancy has been potentially linked to congenital malformations, including microcephaly. In addition to congenital malformations, a temporal association between ZIKV infection and an increase in cases of Guillain-Barre syndrome is currently being observed in several countries. The mechanisms underlying these neurological complications are still unknown. Emerging evidence, mainly from in vitro studies, suggests that ZIKV may have direct effects on neuronal cells. The aim of this study was to critically review the literature available regarding the neurobiology of ZIKV and its potential neuropsychiatric manifestations. PMID- 27478380 TI - Relevance of Pathological Complete Response after Neoadjuvant Therapy for Breast Cancer. AB - Breast cancer is a heterogeneous disease, and the different biological subtypes have different prognostic impacts. Neoadjuvant trials have recently become popular as they offer several advantages compared to traditional adjuvant trials. Studies have shown that patients who achieve pathological complete response (pCR) after neoadjuvant treatment have a better long-term outcome. Consequently, increasing the rate of pCR became the end point of neoadjuvant trials with the expectation of translation into improved survival. However, the definition of pCR has lacked uniformity, and the prognostic impact of achievement of pCR on survival in different breast cancer subtypes is uncertain. In this review, we present the controversies associated with the use of pCR as an end point in neoadjuvant trials. PMID- 27478381 TI - Safety and Efficacy of Gadoxetate Disodium-Enhanced Liver MRI in Pediatric Patients Aged >2 Months to <18 Years-Results of a Retrospective, Multicenter Study. AB - PURPOSE: To assess the safety and efficacy of gadoxetate disodium-enhanced liver MR imaging in pediatric patients. MATERIAL AND METHODS: Retrospective, multicenter study including pediatric patients aged >2 months to <18 years who underwent contrast-enhanced liver MRI due to focal liver lesions. A single intravenous bolus injection of 0.025 to 0.05 mmol/kg body weight of gadoxetate disodium was administered. Adverse events (AEs) up to 24 hours after injection were recorded and a one-year follow-up was conducted for all serious and unexpected AEs. Efficacy was defined based on the additional diagnostic information obtained from the combined (pre- and postcontrast) image sets as compared with the precontrast image sets by blinded reading. RESULTS: A total of 52 patients for safety and 51 patients for efficacy analyses were evaluated. Twenty-two patients (42.3%) reported a total of 51 serious AEs (SAEs) and one AE after one year. No SAE or AE was related to gadoxetate disodium injection. Gadoxetate disodium-related effects on vital signs were not seen. Additional diagnostic information was obtained for 86.3% of patients. The three most improved efficacy variables were lesion-to-background contrast, lesion characterization, and improved border delineation in 78.4%, 76.5%, and 70.6% of patients, respectively. CONCLUSION: Gadoxetate disodium in pediatric patients did not raise any clinically significant safety concern. Contrast enhancement provided additional clinically relevant information. PMID- 27478383 TI - Comparison of tumor markers using different detection devices [Retraction]. AB - [This retracts the article on p. 1083 in vol. 8, PMID: 26056472.]. PMID- 27478382 TI - Potential for Extrinsic Incubation Temperature to Alter Interplay Between Transmission Potential and Mortality of Dengue-Infected Aedes aegypti. AB - The extrinsic incubation period is a critical component in the assessment of arboviral transmission potential. It defines the time it takes for a mosquito to become infectious following exposure to an arbovirus. Since this is a temporal process, the lifespan of a mosquito is intimately tied to the extrinsic incubation period and thus transmission potential of these viruses. Temperature is a known effector of both vector competence (the ability of a vector to transmit a pathogen) and mosquito mortality, but the interaction among temperature, vector competence, and mosquito mortality is not well characterized. Herein, we investigate this interaction for dengue virus, serotype 2, and its primary vector Aedes aegypti where we found that at 30 degrees C, infection and/or dissemination shortened the average lifespan of the mosquito and that when considering only mosquitoes with a disseminated infection, those incubated at 26 degrees C lived significantly longer. PMID- 27478384 TI - Theaflavins suppress tumor growth and metastasis via the blockage of the STAT3 pathway in hepatocellular carcinoma. AB - Theaflavins, the major black tea polyphenols, have been reported to exhibit promising antitumor activities in several human cancers. However, the role of theaflavins in hepatocellular carcinoma (HCC) is still unknown. In this study, we found that theaflavins could significantly inhibit proliferation, migration, and invasion, and induce apoptosis in HCC cells in vitro. Furthermore, we found that theaflavins inhibited the growth and metastasis of HCC in an orthotopic model and a lung metastasis model. Immunohistochemical analyses and terminal deoxynucleotidyl transferase dUTP nick end-labeling assays showed that theaflavins could suppress proliferation and induce apoptosis in vivo. Theaflavins also suppressed constitutive and inducible signal transducer and activator of transcription 3 (STAT3) phosphorylation. The downstream proteins regulated by STAT3, including the antiapoptotic proteins (Bcl-2 and Survivin) and the invasion-related proteins (MMP-2, MMP-9), were also downregulated after theaflavins treatment. Theaflavins induced apoptosis by activating the caspase pathway. Together, our results suggest that theaflavins suppress the growth and metastasis of human HCC through the blockage of the STAT3 pathway, and thus may act as potential therapeutic agents for HCC. PMID- 27478385 TI - Pyruvate kinase M2 overexpression and poor prognosis in solid tumors of digestive system: evidence from 16 cohort studies. AB - PURPOSE: The expression of pyruvate kinase M2 (PKM2) has been linked to tumor formation and invasion. Specifically, the relationship between high PKM2 expression and prognosis has been evaluated in solid tumors of digestive system. However, the prognostic value of PKM2 remains controversial. METHODS: A literature search of PubMed, Embase, and Cochrane databases was conducted until October 2015. The end point focused on overall survival (OS). The pooled hazard ratio (HR) or odds ratio and the 95% confidence intervals were calculated to correlate PKM2 overexpression with OS and clinicopathological characteristics by employing fixed- or random-effects models, depending on the heterogeneity of the included studies. RESULTS: We identified 18 cohorts in 16 studies involving 2,812 patients for this meta-analysis. Overall, the combined HR for OS in all tumor types was 1.74 (1.44-2.11; P<0.001). When stratified by tumor type, the influence of PKM2 expression on poor prognosis was also found in gastric cancer (HR =1.54 [1.08-2.21], P=0.018), esophageal squamous cell carcinoma (HR =1.71 [1.38-2.12], P<0.001), hepatocellular cancer (HR =1.92 [1.52-2.42], P<0.001), biliary cancer (HR =2.11 [1.50-2.95], P<0.001), and oral cancer (HR =3.49 [1.97-6.18], P<0.001), but not in pancreatic ductal adenocarcinoma (HR =1.03 [0.28-3.76], P=0.968). Furthermore, PKM2 overexpression had a negative effect on the late clinical stage of all tumor types except for pancreatic ductal adenocarcinoma. The high density of PKM2 overexpression was significantly associated with some clinical characteristics in different cancer types, such as tumor stage, modal metastasis, and tumor size. CONCLUSION: Our findings revealed significant association of PKM2 overexpression with OS and certain clinicopathological features in solid tumors of digestive system, thereby suggesting that PKM2 might be an indicator of poor prognosis in digestive system cancers. PMID- 27478386 TI - Upregulation of MAGEA4 correlates with poor prognosis in patients with early stage of esophageal squamous cell carcinoma. AB - Esophageal cancer is a common type of cancer in the People's Republic of China. Many genes have been reported to be linked with it. Melanoma antigen gene family A (MAGEA) genes are frequently highly expressed in various types of carcinoma. However, the specific role of MAGEA gene expression in esophageal squamous cell carcinoma (ESCC) still remains unclear. MAGEA4 is a member of MAGEA genes. We aimed to investigate the expression and prognosis of MAGEA4 expression in ESCC. MAGEA4 messenger RNA expression levels of 120 pairs of tumor and nontumor tissues of patients with ESCC were measured by quantitative real-time polymerase chain reaction. The results showed that MAGEA4 messenger RNA was significantly elevated in tumor tissues of patients with ESCC compared to nontumor ones. In addition, overexpression of MAGEA4 messenger RNA was significantly correlated with poorer overall survival (P=0.018) in early stage of patients with ESCC (I-IIA). In conclusion, MAGEA4 played an important role in the early stage of ESCC and overexpression of MAGEA4 was expected to become a potential prognostic marker for patients with early stage of ESCC. PMID- 27478387 TI - Amphetamine Withdrawal Differentially Increases the Expression of Organic Cation Transporter 3 and Serotonin Transporter in Limbic Brain Regions. AB - Amphetamine withdrawal increases anxiety and stress sensitivity related to blunted ventral hippocampus (vHipp) and enhances the central nucleus of the amygdala (CeA) serotonin responses. Extracellular serotonin levels are regulated by the serotonin transporter (SERT) and organic cation transporter 3 (OCT3), and vHipp OCT3 expression is enhanced during 24 hours of amphetamine withdrawal, while SERT expression is unaltered. Here, we tested whether OCT3 and SERT expression in the CeA is also affected during acute withdrawal to explain opposing regional alterations in limbic serotonergic neurotransmission and if respective changes continued with two weeks of withdrawal. We also determined whether changes in transporter expression were confined to these regions. Male rats received amphetamine or saline for two weeks followed by 24 hours or two weeks of withdrawal, with transporter expression measured using Western immunoblot. OCT3 and SERT expression increased in the CeA at both withdrawal timepoints. In the vHipp, OCT3 expression increased only at 24 hours of withdrawal, with an equivalent pattern seen in the dorsomedial hypothalamus. No changes were evident in any other regions sampled. These regionally specific changes in limbic OCT3 and SERT expression may partially contribute to the serotonergic imbalance and negative affect during amphetamine withdrawal. PMID- 27478388 TI - Assessing the Causality Factors in the Association between (Abdominal) Obesity and Physical Activity among the Newfoundland Population-A Mendelian Randomization Analysis. AB - A total of 1,263 adults from Newfoundland and Labrador were studied in the research. Body mass index (BMI) and percent trunk fat (PTF) were analyzed as biomarkers for obesity. The Mendelian randomization (MR) approach with two single nucleotide polymorphisms in the fat-mass and obesity (FTO) gene as instruments was employed to assess the causal effect. In both genders, increasing physical activity significantly reduced BMI and PTF when adjusted for age and the FTO gene. The effect of physical activity was stronger on PTF than BMI. Direct observational analyses showed significant increase in BMI/PTF when physical activity decreased. A similar association in MR analyses was not significant. The association between physical activity and BMI/PTF could be due to reversed causality or common confounding factors. Our study provides insights into the causal contributions of obesity to physical activity in adults. Health intervention strategies to increase physical activity among adults should include some other plans such as improving diet for reducing obesity. PMID- 27478389 TI - Reliability of a Proposed Ultrasonographic Grading Scale for Severity of Primary Knee Osteoarthritis. AB - OBJECTIVES: The objective of this study was to examine the concordance of a grading scale (0-4) of medial femoral osteophytes in knee joint detected by ultrasound (US) compared with the corresponding grades (0-4) of Kellgren-Lawrence (K&L) scale of conventional radiography and clinical joint examination. PATIENTS AND METHODS: A cross-sectional observational study included 160 patients with knee pain who fulfilled the American College of Rheumatology (ACR) criteria for knee osteoarthritis (KOA) and 20 patients with knee pain who have not fulfilled the ACR criteria for KOA. All patients were subjected to clinical assessment (Western Ontario and McMaster Universities Index of Osteoarthritis and global visual analog scale) and radiological assessment in the form of X-ray grading according to K&L grading scale and ultrasonographic assessment of medial femoral osteophytes according to a scale that was proposed by the first author and consisted of five grades (0-4), where grade 0 denoted no osteoarthritis and grade 4 denoted the most advanced grade of KOA. Grade 2 was divided into two subgrades A and B with grade 2B considered as a more advanced stage than grade 2A. RESULTS: The proposed US grading scale had high sensitivity and specificity in detecting the different grades of KOA compared with K&L grading scale (a total sensitivity of 94.6% and a total specificity of 93.3%). Intra- and interreader reliability of US was excellent (kappa >0.93 and >0.85, respectively). CONCLUSIONS: US can reliably detect the severity of KOA. Good agreement was found between the proposed US grading scale and K&L grading scale. The proposed US grading scale is simple and reliable. PMID- 27478390 TI - Switching from EPA + DHA (Omega-3-acid Ethyl Esters) to High-Purity EPA (Icosapent Ethyl) in a Statin-Treated Patient with Persistent Dyslipidemia and High Cardiovascular Risk: A Case Study. AB - Cardiovascular (CV) risk may remain despite statin treatment, and there is a need to address this risk with add-on therapy. The lipid effects of two different prescription omega-3 fatty acid therapies are described in a 55-year-old statin- and niacin-treated female with severe dyslipidemia and high CV risk. The patient was initially treated with omega-3-acid ethyl esters (eicosapentaenoic acid [EPA] and docosahexaenoic acid) 4 g/day. Due to persistently elevated low-density lipoprotein cholesterol (LDL-C), she was switched to icosapent ethyl (high-purity EPA ethyl ester) 4 g/day. Approximately 28 months after switching to icosapent ethyl, her LDL-C decreased by 69% to 52 mg/dL, triglycerides decreased by 35% to 119 mg/dL, non-high-density lipoprotein cholesterol (non-HDL-C) decreased by 63% to 76 mg/dL, total cholesterol decreased by 44% to 137 mg/dL, and HDL-C increased by 45% to 61 mg/dL. Total and small dense LDL particle concentrations decreased by 60 and 59%, respectively. Treatment was well tolerated, with improvements maintained over two years. PMID- 27478391 TI - Role of Cytosolic Calcium Diffusion in Murine Cardiac Purkinje Cells. AB - Cardiac Purkinje cells (PCs) are morphologically and electrophysiologically different from ventricular myocytes and, importantly, exhibit distinct calcium (Ca(2+)) homeostasis. Recent studies suggest that PCs are more susceptible to action potential (AP) abnormalities than ventricular myocytes; however, the exact mechanisms are poorly understood. In this study, we utilized a detailed biophysical mathematical model of a murine PC to systematically examine the role of cytosolic Ca(2+) diffusion in shaping the AP in PCs. A biphasic spatiotemporal Ca(2+) diffusion process, as recorded experimentally, was implemented in the model. In this study, we investigated the role of cytosolic Ca(2+) dynamics on AP and ionic current properties by varying the effective Ca(2+) diffusion rate. It was observed that AP morphology, specifically the plateau, was affected due to changes in the intracellular Ca(2+) dynamics. Elevated Ca(2+) concentration in the sarcolemmal region activated inward sodium-Ca(2+) exchanger (NCX) current, resulting in a prolongation of the AP plateau at faster diffusion rates. Artificially clamping the NCX current to control values completely reversed the alterations in the AP plateau, thus confirming the role of NCX in modifying the AP morphology. Our results demonstrate that cytosolic Ca(2+) diffusion waves play a significant role in shaping APs of PCs and could provide mechanistic insights in the increased arrhythmogeneity of PCs. PMID- 27478392 TI - Visual Representation of Body Shape in African-American and European American Women: Clinical Considerations. AB - BACKGROUND: Body mass index (BMI) has been used widely among clinicians to assess obesity in their patients due to its ease and availability. However, BMI has some diagnostic limitations and other measures related to health risks; in particular, body shape may be of greater relevance to health outcomes. OBJECTIVE: The objective of this study was to illustrate the importance of body shape assessments above and beyond BMI and its relationship to health risk among a sample of African-American and European American women. METHODS: African-American and European American women aged 19-78 years (n = 552) in Birmingham, Alabama, were recruited and stratified by menopausal status (ie, pre- or postmenopausal). Pictorial body shapes were derived from digital photographs, while body fat distribution defined by android-gynoid ratio (AGR) and body composition were obtained from dual-energy X-ray absorptiometry. RESULTS: Images of BMI and age matched women illustrate variability in fat distribution. Among both menopausal status groups, more than 50% of women had a pear body shape (AGR < 1). An apple body shape was associated with higher odds of having diabetes (unadjusted odds ratio [OR]: 4.1, 95% confidence interval [CI]: 1.9-9.3), hypertension (unadjusted OR: 3.1, 95% CI: 2.0-4.7), and high cholesterol (unadjusted OR: 3.0, 95% CI: 1.8 5.1). CONCLUSION: Use of visual cues alongside traditional methods of weight status assessment may help to facilitate weight management conversations between physicians and female patients. However, next steps should include the validation of visual assessments of body shape in women for use by physicians. PMID- 27478393 TI - Health Disparity among Latina Women: Comparison with Non-Latina Women. AB - Analyzing the Latino community and focusing on the women that make up this fast growing demographic create a better understanding of the needs and considerations for health-care professionals and social policies. It is important that national health and health-care data on the Latino ethnic group be presented by gender in order to determine areas specific to women. This review focuses on the existing health and health-care data of Latino women (Latinas). The ability to distinguish the health-care experiences of Latinas will increase the understanding of existing barriers to their health care, the initiatives needed to overcome them, and increase the overall quality of health among Latina women. PMID- 27478394 TI - FSI Simulations of Pulse Wave Propagation in Human Abdominal Aortic Aneurysm: The Effects of Sac Geometry and Stiffness. AB - This study aims to quantify the effects of geometry and stiffness of aneurysms on the pulse wave velocity (PWV) and propagation in fluid-solid interaction (FSI) simulations of arterial pulsatile flow. Spatiotemporal maps of both the wall displacement and fluid velocity were generated in order to obtain the pulse wave propagation through fluid and solid media, and to examine the interactions between the two waves. The results indicate that the presence of abdominal aortic aneurysm (AAA) sac and variations in the sac modulus affect the propagation of the pulse waves both qualitatively (eg, patterns of change of forward and reflective waves) and quantitatively (eg, decreasing of PWV within the sac and its increase beyond the sac as the sac stiffness increases). The sac region is particularly identified on the spatiotemporal maps with a region of disruption in the wave propagation with multiple short-traveling forward/reflected waves, which is caused by the change in boundary conditions within the saccular region. The change in sac stiffness, however, is more pronounced on the wall displacement spatiotemporal maps compared to those of fluid velocity. We conclude that the existence of the sac can be identified based on the solid and fluid pulse waves, while the sac properties can also be estimated. This study demonstrates the initial findings in numerical simulations of FSI dynamics during arterial pulsations that can be used as reference for experimental and in vivo studies. Future studies are needed to demonstrate the feasibility of the method in identifying very mild sacs, which cannot be detected from medical imaging, where the material property degradation exists under early disease initiation. PMID- 27478395 TI - A Patient-Held Medical Record Integrating Depression Care into Diabetes Care. AB - PURPOSE: Depression is frequently observed in people with diabetes. The purpose of this study is to develop a tool for individuals with diabetes and depression to communicate their comorbid conditions to health-care providers. METHOD: We searched the Internet to review patient-held medical records (PHRs) of patients with diabetes and examine current levels of integration of diabetes and depression care in Japan. RESULTS: Eight sets of PHRs were found for people with diabetes. All PHRs included clinical follow-up of diabetes and multidisciplinary clinical pathways for diabetes care. No PHRs included depression monitoring and/or treatment. In terms of an integrated PHR for a patient comorbid with diabetes and depression, necessary components include hopes/preferences, educational information on diabetes complications and treatment, medical history, stress and coping, resources, and monitoring diabetes and depression. CONCLUSION: A new PHR may be suitable for comorbid patients with diabetes and depression. PMID- 27478396 TI - EGFR Mutation Analysis of Circulating Tumor DNA Using an Improved PNA-LNA PCR Clamp Method. AB - Introduction. Rebiopsies have become more crucial in non-small cell lung cancer (NSCLC). Instead of invasive biopsies, development of collecting biological data of the tumor from blood samples is expected. We conducted a prospective study to assess the feasibility of detection of epidermal growth factor receptor (EGFR) mutation in plasma samples. Method. NSCLC patients harboring EGFR activating mutations, who were going to receive EGFR-tyrosine kinase inhibitors (TKIs) as first-line treatment, were enrolled in this study. Plasma EGFR activating mutations and the T790M resistance mutation were analyzed by an improved PNA-LNA PCR clamp method, characterized by a 10-fold or more sensitivity compared with the original methods. Result. Six patients with wild-type EGFR and 24 patients with EGFR mutations were enrolled in this study. Pretreatment plasma samples achieved sensitivity of 79%. The 6 patients with wild-type EGFR were all negative for plasma EGFR mutations. At the time of disease progression, plasma T790M mutation was detected in 8 of 16 cases. Absence of T790M before and during TKI treatment and disappearance of activating mutations during TKI treatment were considered as predictors of EGFR-TKIs efficacy. Conclusion. We were able to detect EGFR mutations in plasma samples by using an improved PNA-LNA PCR clamp method. PMID- 27478397 TI - Incidence, Prevalence, and Mortality Trends in Chronic Obstructive Pulmonary Disease over 2001 to 2011: A Public Health Point of View of the Burden. AB - Background. An increase of chronic obstructive pulmonary disease (COPD) prevalence was reported in Canada despite the decline of the main risk factor. Objectives. To estimate incidence, prevalence, and mortality of COPD from 2001 to 2011 and establish the COPD burden by the evaluation of the age-period-cohort effects on incidence trends and the comorbidities prevalence estimations. Methods. A retrospective population-based cohort was built using Quebec health administrative data. Change in trends was measured by relative percentage of changes and by joinpoint regression. After a descriptive analysis of the trends, an age-period-cohort analysis was performed on incidence rates. Results. Overall increase in prevalence along with a decrease of incidence and all-cause mortality was observed. Over time, all age-standardized trends were higher in men than women. Despite higher rates, the number of incident and prevalent cases in women exceeds men since 2004. The curve analysis by age groups showed over time a downshift for both sexes in incidence and all-cause mortality. Further analysis showed the presence of a cohort effect in women. Conclusion. The burden of COPD has risen over time. Women younger than 65 years old have been identified as at risk group for healthcare planning. PMID- 27478398 TI - Rapid Growth of Lung Nodules due to Combined Pulmonary Vasculitis, Silicoanthracosis, and Chondrocalcinosis. AB - Background. Silicoanthracosis is a pneumoconiosis due to occupational inhalation of silica and carbon dusts. Clinically, it can be associated with vasculitis or rheumatoid arthritis. In association with these diseases, silicoanthracosis can present within the lung with multiple pulmonary nodules which, as a differential diagnosis, can mimic metastatic disease or multiple abscesses. Case Presentation. We present the case of a 62-year old former pit worker with pulmonary nodules, chondrocalcinosis due to calcium pyrophosphate deposition (CPPD), and a history of renal cancer. Within a short period of time, pulmonary nodules grew rapidly. Thoracoscopically, the resected lung specimen revealed silicoanthracosis associated with small-to-medium-size vasculitis in the presence of antineutrophil cytoplasmatic autoantibodies (c-ANCA). Conclusion. Pulmonary silicoanthracotic lesions on the base of ANCA-associated vasculitis and CPPD arthritis can rapidly grow. A mutual correlation between silicoanthracosis, ANCA-associated vasculitis, and CPPD seems possible. Apart from this, consideration of metastatic disease should be obligatory in patients with a history of cancer at the same time being immunosuppressed. PMID- 27478399 TI - Dissociable behavioural outcomes of visual statistical learning. AB - Statistical learning refers to the extraction of probabilistic relationships between stimuli and is increasingly used as a method to understand learning processes. However, numerous cognitive processes are sensitive to the statistical relationships between stimuli and any one measure of learning may conflate these processes; to date little research has focused on differentiating these processes. To understand how multiple processes underlie statistical learning, here we compared, within the same study, operational measures of learning from different tasks that may be differentially sensitive to these processes. In Experiment 1, participants were visually exposed to temporal regularities embedded in a stream of shapes. Their task was to periodically detect whether a shape, whose contrast was staircased to a threshold level, was present or absent. Afterwards, they completed a search task, where statistically predictable shapes were found more quickly. We used the search task to label shape pairs as "learned" or "non-learned", and then used these labels to analyse the detection task. We found a dissociation between learning on the search task and the detection task where only non-learned pairs showed learning effects in the detection task. This finding was replicated in further experiments with recognition memory (Experiment 2) and associative learning tasks (Experiment 3). Taken together, these findings are consistent with the view that statistical learning may comprise a family of processes that can produce dissociable effects on different aspects of behaviour. PMID- 27478400 TI - Long-term management changes topsoil and subsoil organic carbon and nitrogen dynamics in a temperate agricultural system. AB - : Soil organic carbon (SOC) and nitrogen (N) contents are controlled partly by plant inputs that can be manipulated in agricultural systems. Although SOC and N pools occur mainly in the topsoil (upper 0.30 m), there are often substantial pools in the subsoil that are commonly assumed to be stable. We tested the hypothesis that contrasting long-term management systems change the dynamics of SOC and N in the topsoil and subsoil (to 0.75 m) under temperate conditions. We used an established field experiment in the UK where control grassland was changed to arable (59 years before) and bare fallow (49 years before) systems. Losses of SOC and N were 65 and 61% under arable and 78 and 74% under fallow, respectively, in the upper 0.15 m when compared with the grass land soil, whereas at 0.3-0.6-m depth losses under arable and fallow were 41 and 22% and 52 and 35%, respectively. The stable isotopes 13C and 15N showed the effects of different treatments. Concentrations of long-chain n-alkanes C27, C29 and C31 were greater in soil under grass than under arable and fallow. The dynamics of SOC and N changed in both topsoil and subsoil on a decadal time-scale because of changes in the balance between inputs and turnover in perennial and annual systems. Isotopic and geochemical analyses suggested that fresh inputs and decomposition processes occur in the subsoil. There is a need to monitor and predict long-term changes in soil properties in the whole soil profile if soil is to be managed sustainably. HIGHLIGHTS: Land-use change affects soil organic carbon and nitrogen, but usually the topsoil only is considered.Grassland cultivated to arable and fallow lost 13 78% SOC and N to 0.6 m depth within decades.Isotopic and biomarker analyses suggested changes in delivery and turnover of plant-derived inputs.The full soil profile must be considered to assess soil quality and sustainability. PMID- 27478401 TI - Realist complex intervention science: Applying realist principles across all phases of the Medical Research Council framework for developing and evaluating complex interventions. AB - The integration of realist evaluation principles within randomised controlled trials ('realist RCTs') enables evaluations of complex interventions to answer questions about what works, for whom and under what circumstances. This allows evaluators to better develop and refine mid-level programme theories. However, this is only one phase in the process of developing and evaluating complex interventions. We describe and exemplify how social scientists can integrate realist principles across all phases of the Medical Research Council framework. Intervention development, modelling, and feasibility and pilot studies need to theorise the contextual conditions necessary for intervention mechanisms to be activated. Where interventions are scaled up and translated into routine practice, realist principles also have much to offer in facilitating knowledge about longer-term sustainability, benefits and harms. Integrating a realist approach across all phases of complex intervention science is vital for considering the feasibility and likely effects of interventions for different localities and population subgroups. PMID- 27478402 TI - Realism and resources: Towards more explanatory economic evaluation. AB - To be successfully and sustainably adopted, policy-makers, service managers and practitioners want public programmes to be affordable and cost-effective, as well as effective. While the realist evaluation question is often summarised as what works for whom, under what circumstances, we believe the approach can be as salient to answering questions about resource use, costs and cost-effectiveness - the traditional domain of economic evaluation methods. This paper first describes the key similarities and differences between economic evaluation and realist evaluation. It summarises what health economists see as the challenges of evaluating complex interventions, and their suggested solutions. We then use examples of programme theory from a recent realist review of shared care for chronic conditions to illustrate two ways in which realist evaluations might better capture the resource requirements and resource consequences of programmes, and thereby produce explanations of how they are linked to outcomes (i.e. explanations of cost-effectiveness). PMID- 27478403 TI - Immediate versus Delayed Sarcoma Reconstruction: Impact on Outcomes. AB - Background. Sarcoma is a rare malignancy, and more recent management algorithms emphasize a multidisciplinary approach and limb salvage, which has resulted in an increase in overall survival and limb preservation. However, limb salvage has resulted in a higher rate of wound complications. Objective. To compare the complications between immediate and delayed (>three weeks) reconstruction in the multidisciplinary limb salvage sarcoma patient population. Methods. A ten-year retrospective review of patients who underwent sarcoma resection was performed. The outcome of interest was wound complication in the postoperative period based on timing of reconstruction. We defined infection as any infection requiring intravenous antibiotics, partial flap failure as any flap requiring a debridement or revision, hematoma/seroma as any hematoma/seroma requiring drainage, and wound dehiscence as a wound that was not completely intact by three weeks postoperatively. Results. 70 (17 delayed, 53 immediate) patients who underwent sarcoma resection and reconstruction met the inclusion criteria. Delayed reconstruction significantly increased the incidence of postoperative wound infection and wound dehiscence. There was no difference in partial or total flap loss, hematoma, or seroma between the two groups. Discussion and Conclusion. Immediate reconstruction results in decreased wound complications may reduce the morbidity associated with multidisciplinary treatment in the limb salvage sarcoma patient. PMID- 27478404 TI - Surveillance Strategies for Sarcoma: Results of a Survey of Members of the Musculoskeletal Tumor Society. AB - Background. Surveillance is crucial to oncology, yet there is scant evidence to guide strategies. Purpose. This survey identified sarcoma surveillance strategies for Musculoskeletal Tumor Society (MSTS) members and rationales behind them. Understanding current practice should facilitate studies to generate evidence based surveillance protocols. Methods. Permission was granted by the Research and Executive Committee of the MSTS to survey members on surveillance strategies. First, the questionnaire requested demographic and clinical practice information. Second, the survey focused on clinicians' specific surveillance soft tissue and bone sarcoma protocols. Results. 20 percent of MSTS members completed the survey. The primary rationale for protocols was training continuation, followed by published guidelines, and finally personal interpretation of the literature. 95% of the respondents believe that additional studies regarding appropriate surveillance protocols are needed. 87% reported patient concerns regarding radiation exposure from surveillance imaging. For soft tissue and bone sarcoma local recurrence, responders identified surgical margin, histologic grade, and tumor size as the most important factors. For metastases, important risk factors identified included histologic grade, tumor size, and histologic type. Protocols demonstrated wide variation. Conclusion. This survey demonstrates that surveillance strategies utilized by MSTS members are not evidence-based, providing rationale for multi-institutional studies. It also confirms the public health issue of excessive radiation exposure. PMID- 27478405 TI - Evaluating the Contributions of Individual Variables to a Quadratic Form. AB - Quadratic forms capture multivariate information in a single number, making them useful, for example, in hypothesis testing. When a quadratic form is large and hence interesting, it might be informative to partition the quadratic form into contributions of individual variables. In this paper it is argued that meaningful partitions can be formed, though the precise partition that is determined will depend on the criterion used to select it. An intuitively reasonable criterion is proposed and the partition to which it leads is determined. The partition is based on a transformation that maximises the sum of the correlations between individual variables and the variables to which they transform under a constraint. Properties of the partition, including optimality properties, are examined. The contributions of individual variables to a quadratic form are less clear-cut when variables are collinear, and forming new variables through rotation can lead to greater transparency. The transformation is adapted so that it has an invariance property under such rotation, whereby the assessed contributions are unchanged for variables that the rotation does not affect directly. Application of the partition to Hotelling's one- and two-sample test statistics, Mahalanobis distance and discriminant analysis is described and illustrated through examples. It is shown that bootstrap confidence intervals for the contributions of individual variables to a partition are readily obtained. PMID- 27478406 TI - Contact mechanics of highly porous oxide nanoparticle agglomerates. AB - Efficient nanopowder processing requires knowledge of the powder's mechanical properties. Due to the large surface area to volume ratio, nanoparticles experience relatively strong attractive interactions, leading to the formation of micron-size porous structures called agglomerates. Significant effort has been directed towards the development of models and experimental procedures to estimate the elasticity of porous objects such as nanoparticle agglomerates; however, none of the existing models has been validated for solid fractions below 0.1. Here, we measure the elasticity of titania (TiO[Formula: see text], 22 nm), alumina (Al[Formula: see text]O[Formula: see text], 8 nm), and silica (SiO[Formula: see text], 16 nm) nanopowder agglomerates by Atomic Force Microscopy, using a 3.75 [Formula: see text]m glass colloid for the stress-strain experiments. Three sample preparations with varying degree of powder manipulation are assessed. The measured Young's moduli are in the same order of magnitude as those predicted by the model of Kendall et al., thus validating it for the estimation of the Young's modulus of structures with porosity above 90 %. PMID- 27478407 TI - Anodic oxide formation on aluminium-terbium alloys. AB - Aluminium terbium alloys were prepared by simultaneous thermal evaporation resulting in a thin film library covering a 5 to 25 at.% Tb compositional spread. Synchrotron x-ray diffraction (XRD) proves all of the alloys to be amorphous. Scanning electron microscopy (SEM) measurements reveal the structural changes upon increase in Tb content with the formation of small, Tb-rich segregations right before a drastic change in morphology around 25 at.% Tb. Anodic oxides were formed systematically in cyclic voltammograms using scanning droplet cell microscopy. Coulometric analysis revealed a linear thickness over formation potential behaviour with film formation factors ranging from 1.2 nm V-1 (5 at.% Tb) to 1.6 nm V-1 (25 % Tb). Electrochemical impedance spectroscopy was performed for each incremental oxidation step resulting in a linear relation between inverse capacity and formation potential with dielectric constants ranging from 8 (5 at.% Tb) to 16 (25 at.% Tb). PMID- 27478408 TI - Healthcare workers' perceptions and experiences on using mHealth technologies to deliver primary healthcare services: a qualitative evidence synthesis. PMID- 27478409 TI - The study of calcified atherosclerotic arteries: an alternative to evaluate the composition of a problematic tissue reveals new insight including metakaryotic cells. AB - BACKGROUND: Calcifications of atherosclerotic plaques represent a controversial issue as they either lead to the stabilization or rupture of the lesion. However, the cellular key players involved in the progression of the calcified plaques have not yet been described. The primary reason for this lacuna is that decalcification procedures impair protein and nucleic acids contained in the calcified tissue. The aim of our study was to preserve the cellular content of heavily calcified plaques with a new rapid fixation in order to simplify the study of calcifications. METHODS: Here we applied a fixation method for fresh calcified tissue using the Carnoy's solution followed by an enzymatic tissue digestion with type II collagenase. Immunohistochemistry was performed to verify the preservation of nuclear and cytoplasmic antigens. DNA content and RNA preservation was evaluated respectively with Feulgen staining and RT-PCR. A checklist of steps for successful image analysis was provided. To present the basic features of the F-DNA analysis we used descriptive statistics, skewness and kurtosis. Differences in DNA content were analysed with Kruskal-Wallis and Dunn's post tests. The value of P < 0.05 was considered significant. RESULTS: Twenty four vascular adult tissues, sorted as calcified (14) or uncalcified (10), were processed and 17 fetal tissues were used as controls (9 soft and 8 hard). Cells composing the calcified carotid plaques were positive to Desmin, Vimentin, Osteocalcin or Ki-67; the cellular population included smooth muscle cells, osteoblasts and osteoclasts-like cells and metakaryotic cells. The DNA content of each cell type found in the calcified carotid artery was successfully quantified in 7 selected samples. Notably the protocol revealed that DNA content in osteoblasts in fetal control tissues exhibits about half (3.0 ng) of the normal nuclear DNA content (6.0 ng). CONCLUSION: Together with standard histology, this technique could give additional information on the cellular content of calcified plaques and help clarify the calcification process during atherosclerosis. PMID- 27478410 TI - Expression of podocalyxin-like protein is an independent prognostic biomarker in resected esophageal and gastric adenocarcinoma. AB - BACKGROUND: Podocalyxin-like protein (PODXL) is a cell surface transmembrane glycoprotein, the expression of which has been associated with poor prognosis in a range of malignancies. The aim of this study was to investigate the impact of PODXL expression on survival in esophageal and gastric adenocarcinoma. METHODS: The study cohort consists of a consecutive series of 174 patients with esophageal (including the gastroesophageal junction) or gastric adenocarcinoma, surgically treated between 2006 and 2010 and not subjected to neoadjuvant treatment. Immunohistochemical expression of PODXL was assessed in tissue microarrays with cores from primary tumors, lymph node metastases, intestinal metaplasia and adjacent normal epithelium. Survival analyses were performed on patients with no distant metastases and no macroscopic residual tumor. RESULTS: In the majority of cases, expression of PODXL was significantly higher in cancer cells compared to normal epithelial cells and was significantly associated with lymph node metastases and high grade tumors. In esophageal adenocarcinoma, Kaplan-Meier analyses revealed that patients with PODXL negative tumors had a superior time to recurrence (TTR) and overall survival (OS) compared to patients with PODXL positive tumors. In gastric adenocarcinoma, patients with PODXL negative tumors had a superior TTR and a trend towards an improved OS. In esophageal and gastric adenocarcinoma combined, the prognostic significance of PODXL expression on TTR was confirmed in unadjusted Cox regression analysis (HR = 5.36, 95 % CI 1.68 17.06, p = 0.005) and remained significant in the adjusted model (HR = 3.39, 95 % CI 1.01-11.35, p = 0.048). Moreover, the impact of PODXL expression on OS was also confirmed in unadjusted analysis (HR = 2.52, 95 % CI 1.31-4.85, p = 0.006) and remained significant in the adjusted model (HR = 2.03, 95 % CI 1.04-3.98, p = 0.039). CONCLUSIONS: In esophageal and gastric adenocarcinoma, PODXL expression is an independent prognostic biomarker for reduced time to recurrence and poor overall survival. This is the first report on the prognostic role of PODXL in esophageal adenocarcinoma and validates recent findings in gastric cancer. PMID- 27478411 TI - PADI2 gene confers susceptibility to breast cancer and plays tumorigenic role via ACSL4, BINC3 and CA9 signaling. AB - BACKGROUND: Peptidylarginine deiminase (PAD) post-translationally converts arginine residues to citrulline residues. Recent studies have suggested that PADI2 (PAD isoform 2), a member of the PAD family, is involved in the tumorigenic process of some tumors, especially breast cancer. However, little is known about the mechanisms of PADI2 in tumorigenesis. This study aimed to elucidate the tumorigenic role and regulatory pathway of PADI2 in breast tumors. METHODS: The Sequenom MassARRAY and TaqMan genotyping methods were used to investigate the correlation between PADI2 gene SNPs and various tumor risks. PCR array analyses, including cancer pathway finder and signal transduction PCR arrays, were performed to investigate the tumorigenic pathway of PADI2 in the MCF-7 breast cancer cell line following treatment with anti-PADI2 siRNA. Cell proliferation, apoptosis and transwell migration assays were performed to observe the effect of PADI2 in MCF-7 cells treated with anti-PADI2 siRNA. RESULTS: Both Sequenom MassARRAY and TaqMan genotyping assays demonstrated that SNP rs10788656 in the PADI2 gene was significantly associated with breast cancer. PCR arrays indicated that inhibiting PADI2 expression significantly increased expression of CA9 and decreased expression of ACSL4 and BIRC3 in MCF-7 cells, which was verified using real-time PCR. Inhibiting PADI2 expression also significantly decreased the migration ability of MCF-7 cells but did not affect cell proliferation or apoptosis. CONCLUSIONS: The PADI2 gene confers susceptibility to breast cancer. PADI2 expression contributes to abnormal migration of breast tumor cells. PADI2 affects tumorigenesis in breast tumor cells by regulating the expression of ACSL4, BINC3 and CA9, which are known to promote abnormal lipid metabolism and cell invasion of tumors. PMID- 27478412 TI - Phenotypic analysis of peripheral B cell populations during Mycobacterium tuberculosis infection and disease. AB - BACKGROUND: Mycobacterium tuberculosis (Mtb) remains an unresolved threat resulting in great annual loss of life. The role of B cells during the protective immunity to Mtb is still unclear. B cells have been described as effector cells in addition to their role as antibody producing cells during disease. Here we aim to identify and characterize the frequency of peripheral B-cell subpopulations during active Tuberculosis and over treatment response. Analysis were done for both class switched (CS) and non-class switched (NCS) phenotypes. METHODS: We recruited participants with active untreated pulmonary Tuberculosis, other lung diseases and healthy community controls. All groups were followed up for one week from recruitment and the TB cases till the end of treatment (month 6). RESULTS: Peripheral blood samples were collected, stained with monoclonal antibodies to CD19(+) cells, Immunoglobulin (Ig) M, plasma cells (CD 138(+)), marker of memory (CD27(+)), immune activation (CD23(+)) and acquired on a flow cytometer. Circulating Marginal zone B cells (CD19(+)IgM(+)CD23(-)CD27(+)) and memory phenotypes are able to distinguish between TB diagnosis and end of treatment. The frequency of mature B cells from TB cases are lower than that of other-lung diseases at diagnosis. A subpopulation of activated memory B cells (CD19(+)IgM(+)CD23(+)CD27(+)) cells are present at the end of TB treatment. CONCLUSIONS: This study identified distinctive B cell subpopulations present during active TB disease and other lung disease conditions. These cell populations warrants further examination in larger studies as it may be informative as cell markers or as effectors/regulators in TB disease or TB treatment response. PMID- 27478413 TI - A comparative study of blood endotoxin detection in haemodialysis patients. AB - BACKGROUND: Endotoxemia is commonly reported in patients receiving haemodialysis and implicated in the pathogenesis of systemic inflammation. The Limulus Amoebocyte Lysate (LAL) assay is the most commonly used blood endotoxin detection assay. Two kinetic variations of the assay are commercially available - the turbidimetric and chromogenic assay, it is unknown which assay is superior for endotoxin detection in uremic patients. Selection of the optimum LAL technique for endotoxin detection in haemodialysis patients is important to further understanding of the sequela of endotoxemia and development of endotoxin-lowering strategies in this population. METHOD: A turbidimetric and chromogenic LAL assay from the same manufacturer were directly compared. We investigated the ability of both LAL assays to detect endotoxin in uremic plasma. Plasma samples from haemodialysis patients and healthy controls were spiked with endotoxin and percentage spike recovery for the chromogenic and turbidimetric assay was determined. Assay accuracy and precision were compared between both LAL assays. RESULTS: The turbidimetric assay had greater accuracy than the chromogenic assay. Spike recovery was 113.8 % vs. 53.8 % for the turbidimetric and chromogenic assay respectively. Assay bias was higher in the chromogenic assay (-0.384EU/mL vs. 0.011EU/mL). The turbidimetric assay demonstrated greater precision compared to the chromogenic assay. Coefficient of variation ranged from 4.5 to 24.1 % for the turbidimetric assay and 25.8-26.5 % for the chromogenic assay. CONCLUSION: The study findings suggest that the kinetic turbidimetric LAL assay has greater accuracy and precision than the chromogenic assay and is the optimum LAL technique for endotoxin detection in haemodialysis patients, though these findings should be verified using LAL reagents from other sources. PMID- 27478415 TI - Edward I. Lee, MD. PMID- 27478414 TI - Visualizing tephra deposits and sedimentary processes in the marine environment: The potential of X-ray microtomography. AB - Localized tephra deposition in marine sequences is the product of many complex primary and secondary depositional processes. These can significantly influence the potential applicability of tephra deposits as isochronous marker horizons and current techniques, used in isolation, may be insufficient to fully unravel these processes. Here we demonstrate the innovative application of X-ray microtomography (uCT) to successfully identify tephra deposits preserved within marine sediments and use these parameters to reconstruct their internal three dimensional structure. Three-dimensional visualizations and animations of tephra dispersal in the sediment permit a more thorough assessment of postdepositional processes revealing a number of complex microsedimentological features that are not revealed by conventional methods. These features include bioturbation burrows and horizontally discontinuous tephra packages, which have important ramifications for the stratigraphic placement of the isochron in a sedimentary sequence. Our results demonstrate the potential for utilizing rigorous two and three-dimensional microsedimentological analysis of the ichnofabric to enhance and support the use of tephra deposits as isochronous marker horizons and to identify the stratigraphic position that best reflects the primary fallout of ash. The application also provides an exceptional insight into the style and rate of sedimentation processes and permits an assessment of the stratigraphic integrity of a tephra deposit. We discuss the possibility of applying these uCT methods to the identification of cryptotephras within various paleoclimatic sequences and to enhance our understanding of marine sedimentation processes. PMID- 27478416 TI - Dermatology for Plastic Surgeons. PMID- 27478417 TI - Common Pediatric Skin Lesions: A Comprehensive Review of the Current Literature. AB - The timely diagnosis and treatment of dermatologic disease in the pediatric population can be challenging. A basic, yet comprehensive knowledge of common lesions is essential for a successful practice in plastic surgery. In this article, the authors describe vascular, cystic, and pigmented cutaneous lesions that are commonly encountered in the pediatric population. Epidemiology, pathogenesis, clinical course, and management options are discussed for each. PMID- 27478418 TI - Common Adult Skin and Soft Tissue Lesions. AB - A strong foundational knowledge of dermatologic disease is crucial for a successful practice in plastic surgery. A plastic surgeon should be able to identify and appreciate common dermatologic diseases that may require medical and/or surgical evaluation and management. In this article, the authors describe epidermal/dermal, infectious, pigmented, and malignant cutaneous lesions that are commonly encountered in practice. Descriptions include the epidemiology, pathogenesis, clinical course, and management options for each type of lesion. PMID- 27478419 TI - Facial Skin Cancer Reconstruction. AB - Nonmelanoma skin cancers are the most common skin cancers in the United States and the most common malignancies afflicting the head and neck region. Reconstruction of resulting defects has significant aesthetic and functional implications, and plastic surgeons are frequently consulted for reconstruction. Reconstruction can be accomplished via a multitude of approaches spanning the reconstructive ladder, and the approach should be individualized based upon both patient-related and defect-related factors. Here the authors propose a simplified approach to facial reconstruction broken down by aesthetic region. PMID- 27478420 TI - Update on Postsurgical Scar Management. AB - Postoperative scar appearance is often a significant concern among patients, with many seeking advice from their surgeons regarding scar minimization. Numerous products are available that claim to decrease postoperative scar formation and improve wound healing. These products attempt to create an ideal environment for wound healing by targeting the three phases of wound healing: inflammation, proliferation, and remodeling. With that said, preoperative interventions, such as lifestyle modifications and optimization of medical comorbidities, and intraoperative interventions, such as adherence to meticulous operative techniques, are equally important for ideal scarring. In this article, the authors review the available options in postoperative scar management, addressing the benefits of multimodal perioperative intervention. Although numerous treatments exist, no single modality has been proven superior over others. Therefore, each patient should receive a personalized treatment regimen to optimize scar management. PMID- 27478421 TI - Noninvasive Facial Rejuvenation. Part 1: Patient-Directed. AB - A proper knowledge of noninvasive facial rejuvenation is integral to the practice of a cosmetic surgeon. Noninvasive facial rejuvenation can be divided into patient- versus physician-directed modalities. Patient-directed facial rejuvenation combines the use of facial products such as sunscreen, moisturizers, retinoids, alpha-hydroxy acids, and various antioxidants to both maintain youthful skin and rejuvenate damaged skin. Physicians may recommend and often prescribe certain products, but the patients are in control of this type of facial rejuvenation. On the other hand, physician-directed facial rejuvenation entails modalities that require direct physician involvement, such as neuromodulators, filler injections, laser resurfacing, microdermabrasion, and chemical peels. With the successful integration of each of these modalities, a complete facial regimen can be established and patient satisfaction can be maximized. This article is the first in a three-part series describing noninvasive facial rejuvenation. The authors focus on patient-directed facial rejuvenation. It is important, however, to emphasize that even in a patient directed modality, a physician's involvement through education and guidance is integral to its success. PMID- 27478422 TI - Noninvasive Facial Rejuvenation. Part 2: Physician-Directed-Neuromodulators and Fillers. AB - A proper knowledge of noninvasive facial rejuvenation is integral to the practice of a cosmetic surgeon. Noninvasive facial rejuvenation can be divided into patient- versus physician-directed modalities. Patient-directed facial rejuvenation combines the use of facial products such as sunscreen, moisturizers, retinoids, alpha-hydroxy acids, and various antioxidants to both maintain youthful skin as well as rejuvenate damaged skin. Physicians may recommend and often prescribe certain products, but patients are in control with this type of facial rejuvenation. On the other hand, physician-directed facial rejuvenation entails modalities that require direct physician involvement, such as neuromodulators, filler injections, laser resurfacing, microdermabrasion, and chemical peels. With the successful integration of each of these modalities, a complete facial regimen can be established and patient satisfaction can be maximized. This article is the second in a three-part series describing noninvasive facial rejuvenation. Here the authors discuss neuromodulators and fillers in detail, focusing on indications for use, techniques, and common side effects. PMID- 27478423 TI - Noninvasive Facial Rejuvenation. Part 3: Physician-Directed-Lasers, Chemical Peels, and Other Noninvasive Modalities. AB - A proper knowledge of noninvasive facial rejuvenation is integral to the practice of a cosmetic surgeon. Noninvasive facial rejuvenation can be divided into patient- versus physician-directed modalities. Patient-directed facial rejuvenation combines the use of facial products such as sunscreen, moisturizers, retinoids, alpha-hydroxy acids, and various antioxidants to both maintain youthful skin and rejuvenate damaged skin. Physicians may recommend and often prescribe certain products, but patients are in control with this type of facial rejuvenation. On the other hand, physician-directed facial rejuvenation entails modalities that require direct physician involvement, such as neuromodulators, filler injections, laser resurfacing, microdermabrasion, and chemical peels. With the successful integration of each of these modalities, a complete facial regimen can be established and patient satisfaction can be maximized. This article is the last in a three-part series describing noninvasive facial rejuvenation. Here the authors review the mechanism, indications, and possible complications of lasers, chemical peels, and other commonly used noninvasive modalities. PMID- 27478424 TI - Use of a Nonexercise Estimate for Prestroke Peak Vo2 During the Acute Stroke Hospital Stay. AB - PURPOSE: For individuals with acute stroke, it is difficult to conduct an exercise test to assess peak oxygen consumption (peak Vo2). Therefore, the purpose of this study was to use a clinically feasible tool for assessing prestroke peak Vo2 using a nonexercise estimation equation to test whether estimated prestroke peak Vo2 was related to the functional outcome measures at discharge from the hospital in individuals after an acute stroke. We hypothesized that the estimated prestroke peak Vo2 would be significantly related to discharge Physical Performance Test (PPT), 6-minute walk test (6MWT), and lower extremity Fugl-Meyer (LEFM) assessment. METHODS: Estimated prestroke peak Vo2 was calculated using a previously validated prediction equation using the following variables: body mass index, age, sex, resting heart rate, and a self-reported measure of physical activity. Outcome measures were assessed 4 days after enrollment or immediately before discharge (whichever occurred first). RESULTS: Thirty-four participants (mean age = 56.0, SD = 12.6 years; 20 men) with acute stroke were enrolled within 48 hours of admission. For all individuals, mean estimated prestroke peak Vo2 was 27.3 (SD = 7.4) mL.kg-1.min-1 and had a weak, nonsignificant relationship with the PPT (r = 0.19; P = .28), 6MWT (r = 0.10; P = .56), and LEFM (r = 0.32; P = .06). However, when considering sex, women, but not men, had a significant relationship with LEFM (r = 0.73; P = .005) and moderate but nonsignificant relationship with PPT (r = 0.53; P = .06) and 6MWT (r = 0.47; P = .10). CONCLUSIONS: Within 48 hours of stroke admission, we were able to administer a nonexercise equation to estimate prestroke peak Vo2. For the entire sample, functional measures conducted at discharge were not related to estimated prestroke peak Vo2. However, when considering sex, the relationship between prestroke Vo2 and the functional measures was strengthened. PMID- 27478425 TI - Interindividual variability in sweat electrolyte concentration in marathoners. AB - BACKGROUND: Sodium (Na(+)) intake during exercise aims to replace the Na(+) lost by sweat to avoid electrolyte imbalances, especially in endurance disciplines. However, Na(+) needs can be very different among individuals because of the great inter-individual variability in sweat electrolyte concentration. The aim of this investigation was to determine sweat electrolyte concentration in a large group of marathoners. METHODS: A total of 157 experienced runners (141 men and 16 women) completed a marathon race (24.4 +/- 3.6 degrees C and 27.7 +/- 4.8 % of humidity). During the race, sweat samples were collected by using sweat patches placed on the runners' forearms. Sweat electrolyte concentration was measured by using photoelectric flame photometry. RESULTS: As a group, sweat Na(+) concentration was 42.9 +/- 18.7 mmol.L(-1) (minimal-maximal value = 7.0-95.5 mmol.L(-1)), sweat Cl(-) concentration was 32.2 +/- 15.6 mmol.L(-1) (7.3-90.6 mmol.L(-1)) and sweat K(+) concentration was 6.0 +/- 0.9 mmol.L(-1) (3.1-8.0 mmol.L(-1)). Women presented lower sweat Na(+) (33.9 +/- 12.1 vs 44.0 +/- 19.1 mmol.L(-1); P = 0.04) and sweat Cl(-) concentrations (22.9 +/- 10.5 vs 33.2 +/- 15.8 mmol.L(-1); P = 0.01) than men. A 20 % of individuals presented a sweat Na(+) concentration higher than 60 mmol.L(-1) while this threshold was not surpassed by any female marathoner. Sweat electrolyte concentration did not correlate to sweat rate, age, body characteristics, experience or training. Although there was a significant correlation between sweat Na(+) concentration and running pace (r = 0.18; P = 0.03), this association was weak to interpret that sweat Na(+) concentration increased with running pace. CONCLUSIONS: The inter-individual variability in sweat electrolyte concentration was not explained by any individual characteristics except for individual running pace and sex. An important portion (20 %) of marathoners might need special sodium intake recommendations due to their high sweat salt losses. PMID- 27478426 TI - Synthesis of Polydopamine Functionalized Reduced Graphene Oxide-Palladium Nanocomposite for Laccase Based Biosensor. AB - Graphene based 2D nanomaterials have attracted increasing attention in biosensing application due to the outstanding physicochemical properties of graphene. In this work, palladium nanoparticles (Pd) loaded reduced graphene oxide (rGO) hybrid (rGO-Pd) was synthesized through a facile method. Laccase (Lac) was immobilized on rGO-Pd by utilizing the self-polymerization of dopamine, which generated polydopamine (PDA). The PDA-Lac-rGO-Pd nanocomposites were further modified on electrode surface to construct novel biosensing platform. The obtained electrochemical biosensor was applied in the detection of catechol, achieving excellent analytic results. Under the optimum condition, this biosensor possessed a linear range from 0.1 uM to 263 uM for catechol detection, the sensitivity reached 18.4 uA mM(-1), and the detection limit was as low as 0.03 uM. In addition, the biosensor also showed good repeatability, reproducibility, anti-interference, and stability. Moreover, the novel Lac based biosensor was successfully used in the trace detection of catechol existing in real water environment. PMID- 27478427 TI - Gynaecological endoscopic surgical education and assessment. A diploma programme in gynaecological endoscopic surgery. AB - In recent years, training and education in endoscopic surgery has been critically reviewed. Clinicians, both surgeons as gynaecologist who perform endoscopic surgery without proper training of the specific psychomotor skills, are at higher risk to increased patient morbidity and mortality. Although the apprentice-tutor model has long been a successful approach for training of surgeons, recently, clinicians have recognised that endoscopic surgery requires an important training phase outside the operating theatre. The Gynaecological Endoscopic Surgical Education and Assessment programme (GESEA) recognises the necessity of this structured approach and implements two separated stages in its learning strategy. In the first stage, a skill certificate on theoretical knowledge and specific practical psychomotor skills is acquired through a high-stake exam; in the second stage, a clinical programme is completed to achieve surgical competence and receive the corresponding diploma. Three diplomas can be awarded: (a) the Bachelor in Endoscopy, (b) the Minimally Invasive Gynaecological Surgeon (MIGS) and (c) the Master level. The Master level is sub-divided into two separate diplomas: the Master in Laparoscopic Pelvic Surgery and the Master in Hysteroscopy. The complexity of modern surgery has increased the demands and challenges to surgical education and the quality control. This programme is based on the best available scientific evidence, and it counteracts the problem of the traditional surgical apprentice-tutor model. It is seen as a major step toward standardisation of endoscopic surgical training in general. PMID- 27478428 TI - Effect of salpingectomy, ovarian cystectomy and unilateral salpingo-oopherectomy on ovarian reserve. AB - Pelvic surgery can affect ovarian reserve, but estimates of the potential effect of different surgical procedures are lacking. This study examines the markers of ovarian reserve after different procedures in order to help the provision of informed consent before surgery. Anti-Mullerian hormone (AMH), antral follicle count (AFC) and follicle-stimulating hormone (FSH) of women with a history of salpingectomy, ovarian cystectomy or unilateral salpingo-oophorectomy were compared to those without history of surgery using cross-sectional data adjusting for patient and clinical factors in multivariable regression model. There were 138 women who had had salpingectomy, 36 unilateral salpingo-oopherectomy, 41 cystectomy for ovarian cysts that are other than endometrioma and 40 women had had excision of endometrioma. There was no significant difference in AMH (9 %; p = 0.33), AFC (-2 %; p = 0.59) or FSH (-14 %; p = 0.21) in women with a history of salpingectomy compared to women without surgery. Women with a history of unilateral salpingo-oophorectomy were found to have significantly lower AMH (-54 %; p = 0.001). These women also had lower AFC (-28 %; p = 0.34) and higher FSH (14 %; p = 0.06), the effect of which did not reach statistical significance. The study did not find any significant associations between a history of cystectomy, for disease other than endometrioma and AMH (7 %; p = 0.62), AFC (13 %; p = 0.18) or FSH. (11 %; p = 0.16). Women with a history of cystectomy for ovarian endometrioma had 66 % lower AMH (p = 0.002). Surgery for endometrioma did not significantly affect AFC (14 %; p = 0.22) or FSH (10 %; p = 0.28). Salpingo oopherectomy and cystectomy for endometrioma cause a significant reduction in AMH levels. Neither salpingectomy nor cystectomy for cysts other than endometrioma has appreciable effects on ovarian reserve. PMID- 27478429 TI - Label-Free and Continuous-Flow Ferrohydrodynamic Separation of HeLa Cells and Blood Cells in Biocompatible Ferrofluids. AB - In this study, a label-free, low-cost, and fast ferrohydrodynamic cell separation scheme is demonstrated using HeLa cells (an epithelial cell line) and red blood cells. The separation is based on cell size difference, and conducted in a custom made biocompatible ferrofluid that retains the viability of cells during and after the assay for downstream analysis. The scheme offers moderate-throughput (~106 cells h-1 for a single channel device) and extremely high recovery rate (>99%) without the use of any label. It is envisioned that this separation scheme will have clinical applications in settings where rapid cell enrichment and removal of contaminating blood will improve efficiency of screening and diagnosis such as cervical cancer screening based on mixed populations in exfoliated samples. PMID- 27478430 TI - Protein adsorption onto nanoparticles induces conformational changes: Particle size dependency, kinetics, and mechanisms. AB - The use of nanomaterials in bioapplications demands a detailed understanding of protein-nanoparticle interactions. Proteins can undergo conformational changes while adsorbing onto nanoparticles, but studies on the impact of particle size on conformational changes are scarce. We have shown that conformational changes happening upon adsorption of myoglobin and BSA are dependent on the size of the nanoparticle they are adsorbing to. Out of eight initially investigated model proteins, two (BSA and myoglobin) showed conformational changes, and in both cases this conformational change was dependent on the size of the nanoparticle. Nanoparticle sizes ranged from 30 to 1000 nm and, in contrast to previous studies, we attempted to use a continuous progression of sizes in the range found in live viruses, which is an interesting size of nanoparticles for the potential use as drug delivery vehicles. Conformational changes were only visible for particles of 200 nm and bigger. Using an optimized circular dichroism protocol allowed us to follow this conformational change with regard to the nanoparticle size and, thanks to the excellent temporal resolution also in time. We uncovered significant differences between the unfolding kinetics of myoglobin and BSA. In this study, we also evaluated the plausibility of commonly used explanations for the phenomenon of nanoparticle size-dependent conformational change. Currently proposed mechanisms are mostly based on studies done with relatively small particles, and fall short in explaining the behavior seen in our studies. PMID- 27478431 TI - Clinicopathological Characteristics, Treatment, and Prognosis of 21 Patients with Primary Gastric Squamous Cell Carcinoma. AB - We performed a retrospective analysis of 21 patients with primary gastric squamous cell carcinoma (PGSCC) who were admitted to our hospital from October 2008 to October 2014. The median age was 67 years and male predominance was observed, the most common tumor locations were the upper third of the stomach, most of the clinical manifestations were identical to those of other types of gastric tumors, and the tumor cells had positive immunoreactivity for p63 and CK5/6. In terms of treatments, surgery (R0 resection) is the main treatment; the effect of other treatments is unclear. The median survival time for the surgery group and nonsurgery group was 46 and 4.5 months, respectively. Probably due to limited number of cases, no significant difference in median survival time was observed between the surgery alone group and the surgery plus adjuvant therapy group (46 versus 51 months, P = 0.310). A standard chemotherapy regimen for this disease has not yet been established; the choice of its chemotherapy regimens tends to follow the principle of the treatment of gastric adenocarcinoma or esophageal cancer. PGSCC generally had a poor prognosis, and early detection, early diagnosis, and early surgical treatment are beneficial to patients. PMID- 27478432 TI - Small Bowel Obstruction due to Anomalous Congenital Bands in Children. AB - Introduction. The aim of the study was to evaluate our children who are operated on for anomalous congenital band while increasing the awareness of this rare reason of intestinal obstruction in children which causes a diagnostic challenge. Patients and Methods. We retrospectively reviewed the records of fourteen children treated surgically for intestinal obstructions caused by anomalous congenital bands. Results. The bands were located between the following regions: the ascending colon and the mesentery of the terminal ileum in 4 patients, the jejunum and mesentery of the terminal ileum in 3 patients, the ileum and mesentery of the terminal ileum in 2 patients, the ligament of Treitz and mesentery of the jejunum in one patient, the ligament of Treitz and mesentery of the terminal ileum in one patient, duodenum and duodenum in one patient, the ileum and mesentery of the ileum in one patient, the jejunum and mesentery of the jejunum in one patient, and Meckel's diverticulum and its ileal mesentery in one patient. Band excision was adequate in all of the patients except the two who received resection anastomosis for intestinal necrosis. Conclusion. Although congenital anomalous bands are rare, they should be considered in the differential diagnosis of patients with an intestinal obstruction. PMID- 27478433 TI - Corticotropin-Releasing Factor and Toll-Like Receptor Gene Expression Is Associated with Low-Grade Inflammation in Irritable Bowel Syndrome Patients with Depression. AB - The mechanism of low-grade inflammation in irritable bowel syndrome (IBS) is unclear; our research concentrates on the involvement of the corticotropin releasing factor (CRF) and Toll-like receptor (TLR) gene expression in the process of low-grade inflammation in IBS patients with depression. This study suggests more IBS patients are presenting with the states of depression and anxiety. IBS patients with depression have shown a lower grade inflammatory response and an imbalance of the inflammatory response. CRF1, CRF2, TLR2, and TLR4 in IBS patients with depression are significantly higher than those without depression and controls. Thus, activation of the CRF-TLR associated pathways produces an inflammatory reaction, which can concurrently affect the digestive tract and the CNS and induce the corresponding digestive and psychiatric symptoms. PMID- 27478434 TI - Effects of Lactobacillus gasseri OLL2716 on Helicobacter pylori-Associated Dyspepsia: A Multicenter Randomized Double-Blind Controlled Trial. AB - Some Lactobacillus spp. suppress Helicobacter pylori in the stomach and have potential therapeutic applications for the treatment of gastrointestinal conditions. In this study, the effects of Lactobacillus strains on functional dyspepsia associated with H. pylori infection were examined. Volunteers were screened using the (13)C-urea breath test (UBT) and H. pylori stool test, and 131 participants who met the selection criteria (mean age: 48.9 years) were randomly given L. gasseri OLL2716-containing yogurt or placebo yogurt once daily for 12 weeks. Gastrointestinal symptoms (epigastric pain, bloating, postprandial fullness, nausea, and heartburn) and the levels of serum pepsinogen (PG), (13)C UBT, and H. pylori stool antigen were assessed. No significant differences were observed between the groups in UBT results, H. pylori stool antigens, or the serum PGI/II ratio. In the L. gasseri group, postprandial fullness was significantly lower at the end of the trial compared to the initial level (p < 0.05) and significantly fewer patients had a VAS score of >10 for bloating compared to the placebo group (p < 0.05). Dietary supplementation with L. gasseri OLL2716-containing yogurt may effectively suppress dyspeptic symptoms in H. pylori-infected patients. This study was registered at the University Hospital Medical Network Clinical Trial Registry (UMIN000016746). PMID- 27478435 TI - Pharmacological Evaluation of Naproxen Metal Complexes on Antinociceptive, Anxiolytic, CNS Depressant, and Hypoglycemic Properties. AB - Purpose. The present study was designed to investigate the antinociceptive, anxiolytic, CNS depressant, and hypoglycemic effects of the naproxen metal complexes. Methods. The antinociceptive activity was evaluated by acetic acid induced writhing method and radiant heat tail-flick method while anxiolytic activity was evaluated by elevated plus maze model. The CNS depressant activity of naproxen metal complexes was assessed using phenobarbitone-induced sleeping time test and the hypoglycemic test was performed using oral glucose tolerance test. Results. Metal complexes significantly (P < 0.001) reduced the number of abdominal muscle contractions induced by 0.7% acetic acid solution in a dose dependent manner. At the dose of 25 mg/kg body weight p.o. copper, cobalt, and zinc complexes exhibited higher antinociceptive activity having 59.15%, 60.56%, and 57.75% of writhing inhibition, respectively, than the parent ligand naproxen (54.93%). In tail-flick test, at both doses of 25 and 50 mg/kg, the copper, cobalt, silver, and zinc complexes showed higher antinociceptive activity after 90 minutes than the parent drug naproxen. In elevated plus maze (EPM) model the cobalt and zinc complexes of naproxen showed significant anxiolytic effects in dose dependent manner, while the copper, cobalt, and zinc complexes showed significant CNS depressant and hypoglycemic activity. Conclusion. The present study demonstrated that copper, cobalt, and zinc complexes possess higher antinociceptive, anxiolytic, CNS depressant, and hypoglycemic properties than the parent ligand. PMID- 27478436 TI - Intubation Success through I-Gel(r) and Intubating Laryngeal Mask Airway(r) Using Flexible Silicone Tubes: A Randomised Noninferiority Trial. AB - Introduction. The study aims to test whether flexible silicone tubes (FST) improve performance and provide similar intubation success through I-Gel as compared to ILMA. Our trial is registered in CTRI and the registration number is "CTRI/2016/06/006997." Methods. One hundred and twenty ASA status I-II patients scheduled for elective surgical procedures needing tracheal intubation were randomised to endotracheal intubation using FST through either I-Gel or ILMA. In the ILMA group (n = 60), intubation was attempted through ILMA using FST and, in the I-Gel group (n = 60), FST was inserted through I-Gel airway. Results. Successful intubation was achieved in 36.67% (95% CI 24.48%-48.86%) on first attempt through I-Gel (n = 22/60) compared to 68.33% (95% CI 56.56%-80.1%) in ILMA (n = 41/60) (p = 0.001). The overall intubation success rate was also lower with I-Gel group [58.3% (95% CI 45.82%-70.78%); n = 35] compared to ILMA [90% (95% CI 82.41%-97.59%); n = 54] (p < 0.001). The number of attempts, ease of intubation, and time to intubation were longer with I-Gel compared to ILMA. There were no differences in the other secondary outcomes. Conclusion. The first pass success rate and overall success of FST through an I-Gel airway were inferior to those of ILMA. PMID- 27478437 TI - Bioinformatics Approach for Prediction of Functional Coding/Noncoding Simple Polymorphisms (SNPs/Indels) in Human BRAF Gene. AB - This study was carried out for Homo sapiens single variation (SNPs/Indels) in BRAF gene through coding/non-coding regions. Variants data was obtained from database of SNP even last update of November, 2015. Many bioinformatics tools were used to identify functional SNPs and indels in proteins functions, structures and expressions. Results shown, for coding polymorphisms, 111 SNPs predicted as highly damaging and six other were less. For UTRs, showed five SNPs and one indel were altered in micro RNAs binding sites (3' UTR), furthermore nil SNP or indel have functional altered in transcription factor binding sites (5' UTR). In addition for 5'/3' splice sites, analysis showed that one SNP within 5' splice site and one Indel in 3' splice site showed potential alteration of splicing. In conclude these previous functional identified SNPs and indels could lead to gene alteration, which may be directly or indirectly contribute to the occurrence of many diseases. PMID- 27478438 TI - The Effect of Metformin on Adolescents with Type 1 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Background. The effect of metformin in combination with insulin in adolescents with type 1 diabetes (T1DM) is controversial. Methods and Results. The PubMed and EMBASE online databases were searched. Five double-blind randomized controlled trials (RCTs) that included 301 adolescents with T1DM were identified. Metformin plus insulin was associated with reduced hemoglobin A1C levels, total daily insulin dosage, body mass index (BMI), and body weight. However, the subgroup analysis demonstrated that HbA1c levels were not significantly changed in overweight/obese adolescents and were significantly reduced in the general patients. On the contrary, BMI and body weight were significantly reduced in overweight/obese adolescents but not in the general patients. Metformin was associated with higher incidence of adverse events. Conclusions. Among adolescents with T1DM, administering adjunctive metformin therapy in addition to insulin was associated with improved HbA1c levels, total daily insulin dosage, BMI, and body weight. However, there may be differences in the effects of this regimen between overweight/obese and nonobese adolescents. The risk of an adverse event may be increased with metformin treatment. These results provide strong evidence supporting future high-quality, large-sample trials. PMID- 27478439 TI - Melatonin in Epilepsy: A New Mathematical Model of Diurnal Secretion. AB - Purpose. The main objective of the study was to create a mathematical model that describes the melatonin circadian secretion and, then the functionality of the model was tested by a comparison of the melatonin secretions in children with and without epilepsy. Material and Methods. The patients were divided into the epilepsy group (EG, n = 52) and the comparison group (CG, n = 30). The melatonin level was assessed by a radioimmunoassay method. The diurnal melatonin secretion was described using a nonlinear least squares method. Spearman's rank correlation coefficient was chosen to estimate the dependence of the acquired data. The model reproduces blood concentration profiles and its parameters were statistically analyzed using the Mann-Whitney-Wilcoxon test and logistic regression. Results. The correlation analysis performed for the EG and CG groups showed moderate correlations between age and the melatonin secretion model parameters. Patients with epilepsy are characterized by an increased phase shift of melatonin release. PMID- 27478440 TI - Factors in Gestational Diabetes Mellitus Predicting the Needs for Insulin Therapy. AB - Objective. To identify factors predicting the need for insulin therapy in pregnancies complicated by gestational diabetes mellitus (GDM). Methods. A total of 1352 patients with GDM diagnosed by the 75-g/2-h oral glucose tolerance test (OGTT) were enrolled in this study. Univariate and multivariate analysis were performed; receiver operating characteristics (ROC) were also drawn. Results. There was a significant difference in factors such as maternal age, pregestational BMI, first visit SBP, first visit DBP, FBG of first visit, FBG at time of OGTT, 75-g OGTT glucose value (fasting, after 1 h and 2 h), and serum HbA1c level at diagnosis between patients with insulin therapy and patients with medical nutrition therapy (MNT) alone. Multivariate analysis showed that higher FBG at time of OGTT, first 75 g OGTT 2 h plasma glucose, and HbA1c concentration at diagnosis lead to more likely need of insulin therapy. Conclusion. The probability of insulin therapy can be estimated in pregnant women with GDM based on fasting and 2 h glucose values during OGTT and HbA1c value at diagnosis of GDM. PMID- 27478441 TI - Precancerous Cervix in Human Immunodeficiency Virus Infected Women Thirty Years Old and above in Northern Uganda. AB - Background. Little is known about precancerous cervical lesion (PCCL), the precursor of cervical cancer among Human Immunodeficiency (HIV) infected women in a postconflict setting of Northern Uganda. Objective. To establish factors associated with PCCL among HIV infected women above thirty years of age in a postconflict setting of Northern Uganda. Method. This retrospective cohort study used electronic data from 995 HIV-positive women that attended cervical cancer screening during June 2014 and December 2015. Data on social, sexual, obstetric, and gynecological factors was analyzed at 95% confidence level. Multivariate analysis determined factors independently associated with positive PCCL. Probability value less than 5% was considered significant. Results. Prevalence of PCCL was 3.0% (95% confidence interval (CI): 2.0-4.3). A positive PCCL was significantly associated with absence of sexually transmitted diseases (STDs) during clinic visits (adjusted odds ratio, aOR = 0.24; 95% confidence interval (CI): 0.09-0.64; P = 0.004) and first pregnancy before the age of 20 years (aOR = 3.09; 95% CI: 1.21-7.89; P = 0.018). Conclusion. The prevalence of PCCL was low in the postconflict setting of Northern Uganda. HIV-positive women presenting with STDs and those with first pregnancy before the age of 20 years were at increased risk of PCCL. PMID- 27478442 TI - A New Total Digital Smile Planning Technique (3D-DSP) to Fabricate CAD-CAM Mockups for Esthetic Crowns and Veneers. AB - Purpose. Recently, the request of patients is changed in terms of not only esthetic but also previsualization therapy planning. The aim of this study is to evaluate a new 3D-CAD-CAM digital planning technique that uses a total digital smile process. Materials and Methods. Study participants included 28 adult dental patients, aged 19 to 53 years, with no oral, periodontal, or systemic diseases. For each patient, 3 intra- and extraoral pictures and intraoral digital impressions were taken. The digital images improved from the 2D Digital Smile System software and the scanner stereolithographic (STL) file was matched into the 3D-Digital Smile System to obtain a virtual previsualization of teeth and smile design. Then, the mockups were milled using a CAM system. Minimally invasive preparation was carried out on the enamel surface with the mockups as position guides. Results. The patients found both the digital smile design previsualization (64.3%) and the milling mockup test (85.7%) very effective. Conclusions. The new total 3D digital planning technique is a predictably and minimally invasive technique, allows easy diagnosis, and improves the communication with the patient and helps to reduce the working time and the errors usually associated with the classical prosthodontic manual step. PMID- 27478443 TI - Physicochemical and Antibacterial Properties of Chitosan Extracted from Waste Shrimp Shells. AB - This research aims to study the production of chitosan from shrimp shell (Litopenaeus vannamei) of waste origin using two chemical methodologies involving demineralization, deproteinization, and the degree of deacetylation. The evaluation of the quality of chitosan from waste shrimp shells includes parameters for the yield, physical chemistry characteristics by infrared spectroscopy (FT-IR), the degree of deacetylation, and antibacterial activity. The results showed (by Method 1) extraction yields for chitin of 33% and for chitosan of 49% and a 76% degree of deacetylation. Chitosan obtained by Method 2 was more efficient: chitin (36%) and chitosan (63%), with a high degree of deacetylation (81.7%). The antibacterial activity was tested against Gram negative bacteria (Stenotrophomonas maltophilia and Enterobacter cloacae) and Gram-positive Bacillus subtilis and the Minimum Inhibitory Concentrations (MIC) and the Minimum Bactericidal Concentration (MBC) were determined. Method 2 showed that extracted chitosan has good antimicrobial potential against Gram-positive and Gram-negative bacteria and that the process is viable. PMID- 27478444 TI - Vague neuroglycopenic complaints camouflage diagnosis of adolescent insulinoma: a case report. AB - BACKGROUND: Insulinoma is a rare diagnosis in the general population with estimates of 1 in 250,000 people per year. Reports of these pancreatic islet cell tumors are even more unusual in children and adolescents. Chronic hypoglycemia due to an insulinoma often presents with neuroglycopenic symptoms that can easily be overlooked, especially in adolescents where nonspecific complaints are common. This may result in delayed diagnosis with prolonged periods of untreated hypoglycemia and associated complications. The rarity of pediatric insulinoma, vagueness of presenting symptoms, and challenge of tumor localization make insulinoma a true diagnostic quandary for clinicians. CASE PRESENTATION: In this report, we present a 15-year-old female who visited her primary care provider complaining of intermittent episodes of altered mental status including fatigue, irritability, and poor concentration. Her outpatient management included routine laboratory studies, drug screening, electroencephalogram (EEG), valproic acid initiation, CT scan of the abdomen, and endoscopic ultrasound with documentation of hypoglycemia, but otherwise inconclusive results. The patient was admitted to a tertiary children's hospital with severe refractory hypoglycemia 8 months after the initial evaluation. A serum critical sample was obtained and magnetic resonance imaging (MRI) of the abdomen performed which confirmed the presence of a pancreatic mass ultimately identified as an insulinoma. She went on to have surgical resection of her tumor resulting in complete resolution of her hypoglycemia and associated symptoms. CONCLUSION: Within this report we demonstrate the importance of being vigilant for fasting hypoglycemia secondary to insulinoma even when the patient presents with nonspecific symptoms such as fatigue, irritability, or problems with concentration. If these neuroglycopenic complaints are unnoticed or misdiagnosed, patients with a potentially curable disease are put at risk of neurologic injury, or even death, due to untreated severe hypoglycemia. PMID- 27478446 TI - First Report of Clostridium lavalense Isolated in Human Blood Cultures. AB - An 88-year-old man was admitted to the hospital with worsening malaise, fever, and weakness. Anaerobic blood culture bottles revealed the presence of an anaerobic, Gram-positive sporulated bacillus. Empirical antibiotherapy with intravenous piperacillin-tazobactam was initiated. The patient defervesced after four days and was switched to oral amoxicillin on his 6th day of antibiotic therapy and later discharged from the hospital. Four months later, he had recovered. The bacterium was initially identified as Clostridium butyricum using anaerobic manual identification panel. 16S rRNA gene sequence and phylogenetic analysis showed the bacterium to be Clostridium lavalense, a recently described species with no previously published case of isolation in human diagnostic samples so far. This is the first report of Clostridium lavalense isolation from human blood cultures. Further studies are needed in order to elucidate the role of Clostridium lavalense in human disease and its virulence factors. PMID- 27478445 TI - Patient engagement and patient support programs in allergy immunotherapy: a call to action for improving long-term adherence. AB - Allergy immunotherapy (AIT) is acknowledged to produce beneficial mid- and long term clinical and immunologic effects and increased quality of life in patients with allergic respiratory diseases (such as allergic rhinoconjunctivitis and allergic asthma). However, poor adherence to AIT (due to intentional and/or non intentional factors) is still a barrier to achieving these benefits. There is an urgent need for patient support programs (PSPs) that encompass communication, educational and motivational components. In the field of AIT, a PSP should be capable of (1) improving adherence, (2) boosting patient engagement, (3) explaining how AIT differs from pharmacological allergy treatments; (4) increasing health literacy about chronic, progressive, immunoglobulin-E-mediated immune diseases, (5) helping the patient to understand and manage local or systemic adverse events, and (6) providing and/or predicting local data on aeroallergen levels. We reviewed the literature in this field and have identified a number of practical issues to be addressed when implementing a PSP for AIT: the measurement of adherence, the choice of technologies, reminders, communication channels and content, the use of "push" messaging and social networks, interactivity, and the involvement of caregivers and patient leaders. A key issue is "hi-tech" (i.e. approaches based mainly on information technology) vs. "hi touch" (based mainly on interaction with humans, i.e. family members, patient mentors and healthcare professionals). We conclude that multistakeholder PSPs (combining patient-, provider and society-based actions) must now be developed and tested with a view to increasing adherence, efficacy and safety in the field of AIT. PMID- 27478447 TI - Prevalence of familial hypercholesterolemia: a meta-analysis of six large, observational, population-based studies in Poland. AB - INTRODUCTION: Familial hypercholesterolemia (FH) is a severely underdiagnosed and undertreated genetic disorder. Little is known about regional variation in the prevalence of FH, and information for Central and Eastern Europe (CEE) is scarce. This paper assesses the prevalence of FH and related cardiovascular disease (CVD) risk factors in Poland. MATERIAL AND METHODS: We performed a meta-analysis of six population-based studies in Poland. The FH was assessed using the Dutch Lipids Clinics Network (DLCN) criteria. The categories "definite" (> 8 points) and "probable" (6-8 points) were combined into "potential FH". Combined estimates of proportions across studies were pooled by meta-analysis with a random effects model. RESULTS: A total of 37,889 persons aged 20-79 years were included in the analysis. The distribution of DLCN scores was skewed, and there were only 7 cases of definite FH. Prevalence of potential FH was 404/100,000 people (95% CI = 277 531/100,000). Familial hypercholesterolemia was more prevalent in women than in men, and the prevalence was the highest in the age group 45-54 years in men and 55-64 years in women. After adjustment for age and sex, compared to participants with normal cholesterol, persons with potential FH had twice the prevalence of hypertension (p < 0.01); smoking was more prevalent by about 80% (p < 0.01) and hypertriglyceridemia was nine times more frequent (p < 0.001). There was no difference in the prevalence of low high-density lipoprotein (HDL)-cholesterol or diabetes. CONCLUSIONS: We believe that our study might facilitate the planning of a strategy to manage the disease at a population level, i.e. to develop a national strategy for the detection, diagnosis, and treatment of FH. PMID- 27478448 TI - Serum paraoxonase 1 activity in patients with iron deficiency anemia. AB - INTRODUCTION: In this study we aimed to detect paraoxonase 1 (PON-1) activity in iron deficiency anemia (IDA) and to compare it with healthy controls by observing the change after iron therapy. MATERIAL AND METHODS: In this study, 50 adult patients with IDA and 40 healthy subjects were enrolled. All patients were analyzed at the beginning and after treatment according to laboratory assessments. RESULTS: Mean paraoxonase and arylesterase activities in the iron deficiency anemia group were significantly lower than mean activities of the control group (102.4 +/-19.2 U/l and 163.3 +/-13.68 U/l, respectively and 157.3 +/-26.4 U/l and 256.1 +/-24.6 U/l, respectively; p = 0.0001 for both). Paraoxonase and arylesterase activities significantly increased after treatment for IDA (143.2 +/-13.9 and 197.6 +/-27.9 U/l, respectively, p = 0.0001). Mean activities after treatment with iron were significantly lower than mean activities in the control group (p = 0.002; p = 0.0001 respectively). CONCLUSIONS: Paraoxonase and arylesterase activities in patients with IDA significantly increased after treatment with iron therapy. In adults IDA may also be one of the factors associated with increased risk of atherosclerosis. PMID- 27478449 TI - Serum CETP and PLTP activity in middle-aged men living in urban or rural area of the Lower Silesia region. PURE Poland sub-study. AB - INTRODUCTION: The dependence of lipid transfer proteins on significant pro atherogenic factors is unclear. The aim of the study was to evaluate serum cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activity in relation to lipid disturbances in men living in an urban or rural area. MATERIAL AND METHODS: A group of 427 men, volunteers for the Prospective Urban Rural Epidemiology (PURE) sub-study - 263 urban inhabitants (aged 51.9 +/-6.0) and 164 residents of villages (aged 51.1 +/-5.9) - were examined. In the multivariable linear regression model, the following factors were included as potential confounders: age, body mass index (BMI), smoking, alcohol consumption, hs-C-reactive protein reaction (hs-CRP) and co-existence of chronic diseases. RESULTS: In multiple linear regression models, site of residence (urban or rural area) was the most important independent and consistent predictor of CETP and PLTP activity; beta coefficients (95% CI) for CETP (0.18) and PLTP (-0.29) were significant at levels of p < 0.001. Three-way analysis of variance showed no effect of smoking or moderate alcohol consumption on lipid transfer proteins; however, CETP activity showed an interaction effect between these risk factors. In the group of all men, CETP activity was significantly and positively correlated with total cholesterol (r = 0.24), low-density lipoprotein cholesterol (r = 0.18), and non-high density lipoprotein cholesterol (r = 0.21), whereas PLTP activity was correlated with BMI (r = 0.12). Body mass index in rural men was higher than in the urban male population. CONCLUSIONS: Increased PLTP activity, recognized as a pro-atherogenic factor, and decreased CETP activity, known as a protective factor, both observed in men living in rural areas, are probably conditioned by nutritional and/or genetic factors. PMID- 27478450 TI - Smoking habits and coenzyme Q10 status in healthy European adults. AB - INTRODUCTION: Coenzyme Q10 (CoQ10) is a lipophilic endogenously synthesised antioxidant that is present in nearly all human tissues and plays an important role in mitochondrial energy production. It has been postulated that smoking has a consumptive effect on CoQ10. MATERIAL AND METHODS: To further define the relation between smoking and the serum CoQ10 status, 276 healthy volunteers aged 19 to 62 years were grouped into non-smokers (n = 113; 77 male, 36 female) and smokers (n = 163; 102 male, 61 female). Serum lipid profile was analysed by standard clinical chemistry. Coenzyme Q10 concentration and redox status were analysed by high-pressure liquid chromatography with electrochemical detection. RESULTS: Male smokers showed higher serum CoQ10 levels than female smokers. This sex-related difference was accounted for when CoQ10 was related to low-density lipoprotein (LDL) cholesterol as the main carrier of CoQ10 in the circulation. Neither LDL-adjusted CoQ10 concentration nor redox status significantly differed when smokers and non-smokers were compared. Regarding the smoking history, the number of cigarettes consumed per day did not significantly affect the CoQ10 status. Interestingly, with increasing time of smoking habit we observed increasing levels of LDL-adjusted serum CoQ10 concentration (Spearman's p < 0.002) and of the reduced form of CoQ10 (Spearman's p < 0.0001). CONCLUSIONS: As an adaptive response to oxidative stress in long-term smokers an increased demand for antioxidant capacity may be covered by increasing levels of LDL-adjusted CoQ10 serum concentrations and by a concomitantly increased availability of the reduced, active form of CoQ10, possibly by induction of enzymes that are involved in converting CoQ10ox to CoQ10red. PMID- 27478451 TI - Vitamin D and inflammation: evaluation with neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio. AB - INTRODUCTION: Association of vitamin D, inflammation and endothelial dysfunction, beside the classic bone metabolism disorders, may explain the pathogenesis of numerous diseases associated with vitamin D deficiency. While large numbers of reports support the relationship of vitamin D with inflammation, several reports fail to confirm this relationship. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel and inexpensive markers of inflammation that can be studied in all centers. The goal of this study was to investigate the association between 25-hydroxy vitamin D (25(OH)D) and inflammation with the novel inflammatory markers NLR and PLR. MATERIAL AND METHODS: This study was performed retrospectively. Results of the simultaneously performed 25(OH)D, parathyroid hormone, albumin, calcium, phosphorus, alkaline phosphatase and creatinine level measurements and complete blood count were recorded. The data of 4120 patients were included in the study. RESULTS: Between vitamin D deficient and non-deficient groups there were significant differences in PLR (p < 0.001) and NLR (p = 0.001). Vitamin D had a significant negative correlation with PLR (p < 0.001) and NLR (p < 0.001). Multiple regression analysis indicated that 25(OH)D was independently and negatively correlated with PLR (OR = 0.994, 95% CI 0.991-0.998, p = 0.02). CONCLUSIONS: Platelet-to lymphocyte ratio and NLR were significantly associated with 25(OH)D levels, and PLR was found to be an independent predictor of 25(OH)D levels. Our study revealed an inverse association of vitamin D levels and inflammation with these inexpensive and universally available markers. PMID- 27478452 TI - Effect of comprehensive cardiovascular disease risk management on longitudinal changes in carotid artery intima-media thickness in a community-based prevention clinic. AB - INTRODUCTION: The aim of the study was to examine changes in carotid intima-media thickness (CIMT) and carotid plaque morphology in patients receiving multifactorial cardiovascular disease (CVD) risk factor management in a community based prevention clinic. Quantitative changes in CIMT and qualitative changes in carotid plaque morphology may be measured non-invasively by ultrasound. MATERIAL AND METHODS: This is a retrospective study on a cohort of 324 patients who received multifactorial cardiovascular risk reduction treatment at a community prevention clinic. All patients received lipid-lowering medications (statin, niacin, and/or ezetimibe) and lifestyle modification. All patients underwent at least one follow-up CIMT measurement after starting their regimen. Annual biomarker, CIMT, and plaque measurements were analyzed for associations with CVD risk reduction treatment. RESULTS: Median time to last CIMT was 3.0 years. Compared to baseline, follow-up analysis of all treatment groups at 2 years showed a 52.7% decrease in max CIMT, a 3.0% decrease in mean CIMT, and an 87.0% decrease in the difference between max and mean CIMT (p < 0.001). Plaque composition changes occurred, including a decrease in lipid-rich plaques of 78.4% within the first 2 years (p < 0.001). After the first 2 years, CIMT and lipid rich plaques continued to decline at reduced rates. CONCLUSION: In a cohort of patients receiving comprehensive CVD risk reduction therapy, delipidation of subclinical carotid plaque and reductions in CIMT predominantly occurred within 2 years, and correlated with changes in traditional biomarkers. These observations, generated from existing clinical data, provide unique insight into the longitudinal on-treatment changes in carotid plaque. PMID- 27478453 TI - Risk factor indicators in offspring of patients with premature coronary heart disease in Banja Luka region/Republic of Srpska/Bosnia and Herzegovina. AB - INTRODUCTION: Risk factor differences among offspring of patients with premature coronary heart disease (CHD) have not been widely studiem. MATERIAL AND METHODS: We examined 161 persons from the region of Banja Luka, including 81 children (mean age: 25.9 years, 45.7% female) with a history of CHD and a control group of 80 persons (mean age: 24.1, 50% female). Medical history interviews and risk factor measurements were performed. RESULTS: There were differences in mean body amss index (BMI) (26.1 kg/m(2) vs. 23.1 kg/m(2), p < 0.0001), waist circumference (87.7 cm vs. 83.9 cm, p = 0.002), hip circumference (99.3 cm vs. 95.84 cm, p < 0.002), systolic blood pressure (BP) (128.09 mm Hg vs. 122.7 mm Hg, p = 0.007), and diastolic BP (99.3 mm Hg vs. 95.8 mm Hg, p = 0.07). Moreover, HDL-cholesterol was significantly lower (1.1 mmol/l vs. 1.4 mmol/l, p = 0.0001), triglycerides significantly higher (2.2 mmol/l vs. 1.6 mmol/l, p = 0.001), and TC/HDL-ratio was significantly higher (5.1 vs. 4.0, p < 0.001) comparing cases and controls, respectively, adjusted for age, gender, and standard CHD risk factors total cholesterol, LDL and HDL cholesterol, smoking, systolic and diastolic BP, and BMI, those with HDL-C > 1.0 mmol/l in men and 1.2 mmol/l in women had a reduced odds (OR = 0.08, 95% CI: 0.02-0.34 of CHD as well as those with change of fat type (OR = 0.26, 95% CI: 0.11-0.60). CONCLUSIONS: Children of parents with premature CHD have a significantly greater burden of CHD risk factors, with low HDL-C, in particular, being associated with an increased likelihood of being a child of a parent with premature CHD. PMID- 27478454 TI - Association of chest pain versus dyspnea as presenting symptom for coronary angiography with demographics, coronary anatomy, and 2-year mortality. AB - INTRODUCTION: The association of chest pain versus dyspnea with demographics, coronary angiographic findings, and outcomes of patients undergoing coronary angiography is unknown. MATERIAL AND METHODS: We studied 1,053 patients who had coronary angiography to investigate the association of chest pain versus dyspnea with demographics, coronary angiographic findings, and outcomes. RESULTS: Of 1,053 patients, 654 (62%) had chest pain, 229 (22%) had dyspnea, and 117 (11%) had chest pain and dyspnea. Patients with dyspnea were older (p < 0.0001) and had higher serum creatinine (p = 0.0011), lower left ventricular ejection fraction (LVEF) (p < 0.0001), more cardiogenic shock (p = 0.0004), less obstructive coronary artery disease (CAD) (p < 0.0001), less percutaneous coronary intervention (p < 0.0001), and similar 2-year mortality. Stepwise Cox regression analysis showed no significant difference in mortality between chest pain and dyspnea. Significant risk factors for time to death were age (hazard ratio (HR) = 1.07, p < 0.0001), serum creatinine (HR = 1.5, p < 0.0001), body mass index (HR = 0.93, p = 0.005), and obstructive CAD graft (HR = 3.2, p = 0.011). CONCLUSIONS: Patients undergoing coronary angiography presenting with dyspnea were older and had higher serum creatinine, lower LVEF, more frequent cardiogenic shock, less obstructive CAD, and less percutaneous coronary intervention compared to patients presenting with chest pain but similar 2-year mortality. PMID- 27478456 TI - Impact of coexisting multivessel coronary artery disease on short-term outcomes and long-term survival of patients treated with carotid stenting. AB - INTRODUCTION: Systemic atherosclerosis can result in both coronary artery disease (CAD) and carotid artery disease. Recently it has been shown that patients with CAD have a higher incidence of microembolization during carotid artery stenting (CAS), and it has been hypothesized that they could be at higher risk in this intervention. MATERIAL AND METHODS: We retrospectively evaluated an institutional registry with 437 consecutive patients who underwent coronary angiography and CAS to evaluate their short-term outcomes and long-term survival with regard to the presence of coexisting multivessel coronary artery disease (MVD). RESULTS: We performed 220 CAS procedures in MVD patients and 318 CAS procedures in non-MVD patients. The incidence of in-hospital CAS-related adverse events was 2.7% and 2.5% in the MVD and non-MVD groups, respectively (p = 0.88). At 30 days, there was no significant difference between the groups in terms of the number of patients with adverse events (hierarchically death/stroke/myocardial infarction; 8.8% vs. 5.5%; p = 0.18). The median duration of follow-up was 4.23 years. Survival free of all-cause mortality at 1, 3 and 5 years was 90% (95% CI: 86 94%), 79% (95% CI: 73-85%) and 70% (95% CI: 64-77%), and 92% (95% CI: 89-95%), 85% (95% CI: 80-90%) and 76% (95% CI: 70-82%) for the MVD and non-MVD groups (p = 0.02), respectively. CONCLUSIONS: These results suggest that patients with MVD combined with carotid artery disease are probably not at higher risk of early post-CAS adverse clinical events, but they have significantly worse long-term survival rates. PMID- 27478455 TI - Cognitive variations among vascular dementia subtypes caused by small-, large-, or mixed-vessel disease. AB - INTRODUCTION: Vascular dementia (VaD) is a heterogeneous disease that can vary in clinical presentation and cognitive profile. The cognitive profiles of different VaD subtypes depend on the anatomical distribution of the vascular insults that have been documented. MATERIAL AND METHODS: We reviewed demographic, cognitive, and imaging data in 402 patients who were clinically diagnosed with VaD between January 2002 and June 2012 at the First Affiliated Hospital of Gan Nan Medical College in Ganzhou, China. RESULTS: Based on magnetic resonance imaging (MRI) results, patients were classified as having large- (24.1%), small- (70.4%), or mixed-vessel VaD (5.5%). Hypertension was the most prevalent risk factor (81%), followed by smoking (37%), hyperlipidemia (35%), and diabetes (27%). Hyperlipidemia, cardiac risk factors (history of cardiovascular disease, heart valve disorder) and carotid stenosis were more frequent in patients with large vessel disease compared to those with small-vessel or mixed-vessel disease (p < 0.001). A median of 4 (maximum 11) cognitive domains were impaired in each VaD patient. After memory dysfunction, executive defects were the most prevalent (68.9%), and neurobehavioral dysfunction was the most rare (13.2%). Patients with small-vessel VaD showed more executive dysfunction than patients with large vessel and mixed-vessel VaD (p < 0.05), whereas patients with large-vessel VaD had a higher prevalence of visuospatial or language dysfunction (p < 0.05). CONCLUSIONS: The results indicate that specific subtypes and underlying vascular mechanisms will help predict clinical courses and produce more focused treatment and prevention of VaD. PMID- 27478457 TI - Timing of coronary artery bypass surgery in patients with non-ST-segment elevation myocardial infarction and postoperative outcomes. AB - INTRODUCTION: The aim of the study was to assess whether a cardiac troponin T (cTnT) level 1 ng/ml or below threshold is safe and to evaluate mid-term follow up results in stable patients with non-ST-segment elevation after acute myocardial infarction. MATERIAL AND METHODS: Among cTnT positive patients who presented to the emergency unit with chest pain and received coronary angiography, 100 patients who underwent isolated coronary artery bypass grafting (CABG) constituted the study group (group 1). The same number of patients (n = 100) who were cTnT negative and underwent an isolated CABG operation under elective conditions were selected as the control group (group 2). RESULTS: Among preoperative criteria, group 1 had significantly higher smoking rates (74% vs. 41%, p = 0.0001), and significantly lower ejection fraction values (47.1 +/-8.25, 54.69 +/-8.73, p = 0.0001). There were no significant differences between the groups with respect to operative parameters. Postoperative follow-up periods were significantly longer in group 1 (23.25 +/-14 vs. 17.55 +/-7.95 months, p = 0.001). Average waiting time for cTnT to drop below the 1 ng/ml threshold value was 5.73 +/-2.95 (1-12) days. Intra-aortic balloon pump use in Groups 1 and 2 was 3% and 1%, respectively. There were no hospital mortalities in either group. Mortality rates at mid term were 6% in both groups. CONCLUSIONS: This study compared two groups positive and negative for preoperative cTnT. The findings show that it is safe to wait until cTnT levels decrease to the 1 ng/ml threshold value in cTnT positive patients having a stable course. This waiting period is not very long, which is significant with respect to potential complications. PMID- 27478458 TI - Preservation of renal function by thyroid hormone replacement in elderly persons with subclinical hypothyroidism. AB - INTRODUCTION: The treatment of subclinical hypothyroidism in elderly persons is controversial. Previous studies have shown that there are interactions between kidney and thyroid function, but data regarding interventions that target thyroid function in elderly patients are scarce. We aimed to investigate the impact of thyroid hormone therapy on the estimated glomerular filtration rate (eGFR) in elderly patients. MATERIAL AND METHODS: Ninety elderly patients aged >= 65 years with subclinical hypothyroidism were followed for 36 months in our case-control study. The changes in the eGFR in patients with and without thyroid hormone replacement therapy were compared. The adverse effects during the treatment period were noted. RESULTS: The eGFR of both groups was similar at the beginning of the study (43.4 +/-6.1 vs. 42.8 +/-5.9 ml/min/1.73 m(2); p = 0.62). With the decline in thyroid stimulating hormone levels after treatment, the eGFR of the treatment group significantly improved compared with the control group (45.8 +/ 4.8 vs. 35.8 +/-5.3 ml/min/1.73 m(2); p < 0.001); the eGFR increased rapidly over the first 6 months and then plateaued. No patients withdrew from the study, but the therapeutic dose was decreased in two patients due to angina pectoris. CONCLUSIONS: Thyroid hormone therapy preserved renal function in elderly patients. Appropriate individual treatment should be considered in elderly patients with subclinical hypothyroidism. PMID- 27478460 TI - Incomplete defect filling after third generation autologous chondrocyte implantation. AB - INTRODUCTION: Third generation autologous chondrocyte implantation (ACI) is a suitable method for the treatment of cartilage defects in the knee joint. However, knowledge about the development of graft thickness and the clinical relevance of incomplete defect filling in the postoperative course is low. This prospective study analyses the graft integration into the surrounding cartilage, with special consideration of the graft thickness. MATERIAL AND METHODS: A total of 71 consecutive patients with 79 cartilage defects were treated with third generation autologous chondrocyte implantation (NOVOCART 3D) in the knee. Follow up magnetic resonance imaging (MRI) was performed at 0.25, 0.5, 1 and 2 years. Graft thickness was measured compared to the surrounding healthy cartilage. The International Knee Documentation Committee (IKDC) scoring system and the visual analogue scale (VAS) were used for clinical evaluation. Cartilage defect filling was classified as the percentage of the surrounding cartilage. RESULTS: The average graft thickness showed a significant increase between 3 and 6 months after autologous chondrocyte implantation. Incomplete defect filling occurred in 44 (55.7%) cases. Of these, 33 cases showed incomplete defect filling grade I (> 75%), 10 cases were grade II (> 50%) and one case grade III (> 25%). Incomplete defect filling grade IV (< 25%) was not observed. Incomplete defect filling occurred significantly more often in women (p = 0.021), without worse clinical results. CONCLUSIONS: Graft thickness after third generation autologous chondrocyte implantation shows increasing graft thickness over the period of 2 years postoperatively. A high rate of incomplete defect filling in the surrounding cartilage was observed, without worse clinical results. PMID- 27478459 TI - Cytokine profiling in exhaled breath condensate after exercise challenge in asthmatic children with post-exercise symptoms. AB - INTRODUCTION: Markers of exhaled breath condensate (EBC) correlate with lung function impairment, airway remodeling and different aspects of the disease such as exercise-induced bronchoconstriction (EIB). Aim of the study was to determine the cytokine profile in EBC of children with asthma after an exercise treadmill challenge in order to obtain clinically useful information about mechanisms of EIB; also, to assess correlations between cytokine concentrations in EBC and clinical characteristics of the patients. MATERIAL AND METHODS: The study population consisted of 25 randomly selected children, aged 8 to 19 years, with asthma and EIB symptoms despite the use of control medications. Patients on the day of the study visit underwent fractional exhaled nitric oxide measurement (FeNO) and baseline spirometry, performed an exercise treadmill challenge (ETC), and EBC samples were obtained at the end of the ETC. RESULTS: In asthmatic children with positive ETC, monocyte hemotactic protein-1 (MCP-1) and IL-16 adjusted to pre-EBC forced expiratory volume in 1 s (FEV1) were significantly higher compared to children with negative ETC (p = 0.022 and p = 0.017 respectively). After adjustment to pre-EBC FEV1 other cytokines (IL-4, IL-5, IL 6, IL-8, MIG, TNF-alpha) were not related to post-exercise changes in FEV1. CONCLUSIONS: We observed a specific inflammatory profile in the airways of asthmatic children with bronchoconstriction induced by exercise. The concentration of cytokines in EBC depended on the post-exercise decrease in FEV1, which was measured by the area under the curve (AUC). MCP-1 and IL-16, adjusted to pre-EBC FEV1, were significantly higher in children with a positive exercise challenge compared to those with a negative one. PMID- 27478461 TI - Sonoelastography in the evaluation of capsule formation after breast augmentation - preliminary results from a follow-up study. AB - INTRODUCTION: There are many indications for breast augmentation, including reconstruction after mastectomy, correction of congenital disorders and cosmetic procedures. The most frequent local complication of this surgery is capsule formation due to fibrosis. The aim of the study was to assess the usefulness of sonoelastography in the evaluation of capsule formation around silicone implants. MATERIAL AND METHODS: The study group included 13 patients aged 20 to 41, who underwent breast augmentation with silicone implants. Their 26 breasts were examined before surgery, 7 and 14 days and a minimum of 8.5 months after surgery. The breast stiffness was assessed with tonometry and shear wave elastography to evaluate elasticity of the breast tissue and capsule formation after surgery. RESULTS: We assessed the correlation between capsular elasticity measured at successive visits and the Baker scale. There were no significant relationships between any pairs of variables (p > 0.05). We also analyzed the correlation between the time of the follow-up and changes in the tissue elasticity of every region - no significant relationship was found. The greatest decrease in pericapsular elasticity was established in lower and inner quadrants. Moreover, there was a significant difference between the elasticity of the tissue before and 1 week after surgery (p < 0.05) and no significant changes in the elasticity before surgery and at the end of the follow-up. CONCLUSIONS: Sonoelastography is precise in evaluation of capsule formation after breast augmentation. It may show changes that cannot be assessed using palpation. PMID- 27478462 TI - Analysis of food advertising to children on Spanish television: probing exposure to television marketing. AB - INTRODUCTION: We aimed to assess longitudinal changes in television (TV) food advertising during 2013 compared to 2007, measuring children's exposure to healthy and unhealthy advertisements, after the new European and Spanish Public Health laws published in 2011. MATERIAL AND METHODS: Two thematic channels for children (TC), and 2 generalist channels (GC) for all ages were recorded, between April and May 2013, on 2 week and 2 weekend days. Food advertisements were classified as core (CFA) (nutrient dense, low energy), non-core (NCFA) (unbalanced energy profile or high in energy), or others (OFA) (supermarkets and special food). RESULTS: One thousand two hundred sixty-three food advertisements were recorded (TC: 579/GC: 684) in 2013. NCFA were the most shown (54.9%) in the regular full day TV programming (p < 0.001). In 2013, children watching GC had a higher relative risk of being exposed to fast food advertisements than when watching TC (RR = 2.133, 95% CI: 1.398-3.255); CFA were broadcast most frequently in 2013 (GC: 23.7%; and TC: 47.2%) vs. 2007 (TC: 22.9%) (p < 0.001). The proportion of broadcasting between NCFA/CFA and OFA food advertisements in children's peak time slots was higher on TC (203/162) during 2013 than on GC (189/140), and significantly higher than that shown on TC in 2007 (180/36, p < 0.001). CONCLUSIONS: Broadcasting of unhealthy TV food advertising on TC is lower today than six years ago; but, children's exposure to TV advertising of unhealthy food is worrying in Spain, and there is more exposure to unhealthy than healthy food by TV. Watching GC in 2013 had higher risk of being exposed to fast food advertisements than watching TC. PMID- 27478463 TI - Perception of barriers to postoperative pain management in elderly patients in Polish hospitals with and without a "Hospital Without Pain" Certificate - a multi center study. AB - INTRODUCTION: In 2005-2050, the global population of elderly people will increase by 12%. This will lead to increased demand for such healthcare services as hospital care or surgical interventions. Pain in elderly patients is a substantial problem. Insufficiently controlled postoperative pain continues to be a widespread phenomenon. Pain management in Poland is usually based on nursing care supervised by an anesthesiologist or surgeon. The aim of the study was to identify barriers to effective nurse-controlled analgesia in postoperative pain management in elderly patients in hospitals with and without a Hospital Without Pain certificate. MATERIAL AND METHODS: The study was conducted after the approval of the study protocol by the Independent Bioethics Committee for Scientific Research of the Medical University of Gdansk. The study project was multicenter and was conducted from July 2012 to December 2013. The research was questionnaire-based and used the Polish version of the Nurses' Perceived Obstacles to Pain Assessment and Management Practices questionnaire. The project included 676 nurses from hospitals awarded the Hospital Without Pain Certificate and 926 respondents from hospitals without the certificate. RESULTS: After calculating the overall average result in particular groups, healthcare system related problems were first among the barriers hindering pain management in elderly patients M = (C = 3.81, N/C = 3.87). Patient-related barriers were second (M = 3.77). Physician- and nurse-related barriers took the subsequent positions, with very similar scores M = (C = 3.47, N/C = 3.44) and M = (C = 3.46, N/C = 3.44), respectively. CONCLUSIONS: The greatest barriers to pain management in elderly patients are related to the healthcare system. Nurses from Hospital Without Pain certified hospitals devoted significantly more time to relieving pain through non-pharmacological methods. PMID- 27478464 TI - Evaluation of the quality of life of postmenopausal osteoporotic and osteopenic women with or without fractures. AB - INTRODUCTION: Most studies concerned with the quality of life (QoL) of women with reduced bone mineral density (BMD) focus on patients with vertebral and non vertebral fractures. Our objective was to evaluate QoL among patients with reduced BMD regardless of their fracture history compared to women with normal BMD. MATERIAL AND METHODS: Eighty-five patients in the study group were classified as osteoporotic, with BMD results measured by densitometry and expressed by T-score <= -2.5 SD, 122 women were osteopenic, with -2.5 < T-score <= -1.0 SD, and 97 subjects were assessed as normal, with T-score > -1.0 SD. Mean ages of women according to groups were 59.90, 57.67 and 55.68, respectively. Assessment of life quality was conducted using the Polish version of the QUALEFFO 41 scale. RESULTS: The ratings in the assessment (QUALEFFO-41) of QoL were lower for osteoporotic and osteopenic women than for the normal BMD group with regard to pain (p = 0.006), social function (p = 0.001), health perception (p = 0.001), and mental function (p = 0.001). For total QUALEFFO-41 the associated factors were: secondary and higher education (OR = 0.49; 95% CI: 0.29-0.82), self perceived deformity of the back (OR = 4.09; 95% CI: 1.88-8.93), previous fractures (OR = 2.52; 95% CI: 1.09-5.82), reduced height (OR = 2.48; 95% CI: 1.13 5.39) and anxiety (OR = 1.42; 95% CI: 1.21-1.66). CONCLUSIONS: It seems necessary to evaluate QoL of women with reduced BMD before fractures occur, to aid development of health education aiming to reduce the incidence of osteoporosis and prevent fractures. PMID- 27478465 TI - Searching for a good model for systemic sclerosis: the molecular profile and vascular changes occurring in UCD-200 chickens strongly resemble the early phase of human systemic sclerosis. AB - INTRODUCTION: Vascular injury and endothelial cell (EC) apoptosis are the earliest events in systemic sclerosis (SSc), before the onset of fibrosis, and stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGFA), endothelin-1 (ET-1) and platelet-derived growth factors (PDGF-BB) represent the key molecules to study the link between vascular injury and fibrosis during SSc. The University of California at Davis line 200 (UCD-200) chickens display the same hallmarks of human SSc: vascular occlusion, perivascular lymphocytic infiltration and fibrosis of skin and internal organs. In this study we assessed both cytokines and growth factors involved in the early phases of the UCD-200 chickens' skin lesions, to determine whether these animals might represent an appropriate experimental model to study the pathogenesis of SSc. MATERIAL AND METHODS: Immunofluorescence analysis was performed on human SSc skin, human healthy control (hHC) skin, UCD-200 combs and HC H.B15 chicken (cHC) combs, using anti-SDF-1, CXCR4, VEGFA, VEGF receptor 1 (VEGFR1), VEGF receptor 2 (VEGFR2), ET-1, ET receptor A (ETAR), ET receptor B (ETBR), PDGF-BB, and PDGF receptor (PDGFR) antibodies. The plasma concentrations of SDF-1, VEGFA, ET-1 and PDGF-BB were determined by ELISA. RESULTS: All the molecules analyzed showed higher levels in SSc patients and UCD-200 chickens than in hHC and cHC. Furthermore, the levels of the assessed molecules paralleled the severity of comb involvement. CONCLUSIONS: The molecular similarities between avian and human SSc, observed in this study, suggest that the UCD-200 chickens are an interesting model for translational approaches to SSc. PMID- 27478466 TI - Subfractions of high-density lipoprotein (HDL) and dysfunctional HDL in chronic kidney disease patients. AB - A number of studies have shown that chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease (CVD). Chronic kidney disease is characterized by significant disturbances in lipoprotein metabolism, including differences in quantitative and qualitative content of high-density lipoprotein (HDL) particles. Recent studies have revealed that serum HDL cholesterol levels do not predict CVD in CKD patients; thus CKD-induced modifications in high density lipoprotein (HDL) may be responsible for the increase in CV risk in CKD patients. Various methods are available to separate several subclasses of HDL and confirm their atheroprotective properties. However, under pathological conditions associated with inflammation and oxidation, HDL can progressively lose normal biological activities and be converted into dysfunctional HDL. In this review, we highlight the current state of knowledge on subfractions of HDL and HDL dysfunction in CKD. PMID- 27478467 TI - The role of prenatal ultrasound assessment in management of fetal cervicofacial tumors. AB - Ultrasound prenatal examination enables one to assess the facial skeleton and the neck from the first weeks of gestation. Cervicofacial tumors detected via prenatal ultrasound are very rarely reported fetal pathologies. They include cystic hygromas, teratomas, epulides, vascular tumors, and thyroid tumors. The tumor category, its location and vascularization pattern allow one to accurately establish a diagnosis which is usually confirmed by clinical examination of the neonate or a pathological examination (surgical specimen, biopsy, autopsy). The prenatal ultrasound diagnosis of cervicofacial tumor in the fetus allows planning of pregnancy management and fetal therapy, preparation of the delivery, and perinatal as well as neonatal treatment. PMID- 27478468 TI - Selected tumor markers in the routine diagnosis of chromophobe renal cell carcinoma. AB - Renal cell carcinoma is one of the most malignant tumors, affecting men more frequently than women and constituting nearly 90% of all kidney tumors. Chromophobe renal cell carcinoma has been described as a new histological type of renal cell carcinoma. Chromophobe renal cell carcinoma constitutes up to 5% of all cases of kidney cancer. It is characterized by a significant number of deletions in many chromosomes, as well as the loss of entire chromosomes. Chromophobe renal cell carcinoma arises from tubular cells or cells of the macula densa. In contrast to other types of kidney cancer, it occurs with equal frequency in men and women, mostly in the sixth decade of life. It is characterized by a relatively good prognosis and exhibits a low degree of malignancy. Histopathologic diagnosis of ChRCC can be a diagnostic challenge because these tumors may resemble oncocytoma or conventional cancer. Research by Mathers et al. proposed the use of cytokeratin 7 as a marker useful in the differentiation of these changes. PMID- 27478469 TI - Botulinum toxin A in the treatment of Raynaud's phenomenon: a systematic review. AB - INTRODUCTION: The management of Raynaud's phenomenon in its most severe form is challenging, and current medical and surgical treatment methods frequently do not lead to optimal symptom control and prevention of ischemic complications. The aim of the study was to critically evaluate all existing evidence on the use of botulinum toxin A in the management of Raynaud's phenomenon. MATERIAL AND METHODS: We adopted the PRISMA methodology and searched Cochrane Library, MEDLINE, SCOPUS, EULAR and ACR congresses abstract archives for Raynaud* AND botulinum toxin OR onabotulinum. All studies that contained reports of botulinum toxin A use and its outcome in Raynaud's phenomenon were included in the review. RESULTS: Eleven studies met our inclusion criteria and involved a total of 125 patients. Two reviewers extracted data from the studies under review and achieved a consensus in their selection. The main outcomes measured were pain reduction and healing of digital ulcers. The level of evidence across studies was very low to moderate. CONCLUSIONS: There is insufficient evidence to assess the efficacy of botulinum toxin A in Raynaud's phenomenon. Despite many promising reports, further research in the form of randomized controlled trials is warranted in order to investigate this new treatment method for Raynaud's phenomenon. PMID- 27478470 TI - Sulforaphane protects against acrolein-induced oxidative stress and inflammatory responses: modulation of Nrf-2 and COX-2 expression. AB - INTRODUCTION: Acrolein (2-propenal) is a reactive alpha, beta-unsaturated aldehyde which causes a health hazard to humans. The present study focused on determining the protection offered by sulforaphane against acrolein-induced damage in peripheral blood mononuclear cells (PBMC). MATERIAL AND METHODS: Acrolein-induced oxidative stress was determined through evaluating the levels of reactive oxygen species, protein carbonyl and sulfhydryl content, thiobarbituric acid reactive species, total oxidant status and antioxidant status (total antioxidant capacity, glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activity). Also, Nrf-2 expression levels were determined using western blot analysis. Acrolein-induced inflammation was determined through analyzing expression of cyclooxygenase-2 by western blot and PGE2 levels by ELISA. The protection offered by sulforaphane against acrolein induced oxidative stress and inflammation was studied. RESULTS: Acrolein showed a significant (p < 0.001) increase in the levels of oxidative stress parameters and down-regulated Nrf-2 expression. Acrolein-induced inflammation was observed through upregulation (p < 0.001) of COX-2 and PGE2 levels. Pretreatment with sulforaphane enhanced the antioxidant status through upregulating Nrf-2 expression (p < 0.001) in PBMC. Acrolein-induced inflammation was significantly inhibited through suppression of COX-2 (p < 0.001) and PGE2 levels (p < 0.001). CONCLUSIONS: The present study provides clear evidence that pre-treatment with sulforaphane completely restored the antioxidant status and prevented inflammatory responses mediated by acrolein. Thus the protection offered by sulforaphane against acrolein-induced damage in PBMC is attributed to its anti oxidant and anti-inflammatory potential. PMID- 27478471 TI - Identification of differentially expressed genes in salivary adenoid cystic carcinoma cells associated with metastasis. AB - INTRODUCTION: Salivary adenoid cystic carcinoma (SACC) is a frequent type of salivary gland cancer which is characterized by slow growth but high incidence of distant metastasis. We aimed to identify therapeutic targets which are associated with metastasis of SACC. MATERIAL AND METHODS: Total RNA was isolated from a low metastatic SACC cell line (ACC-2) and a highly metastatic SACC cell line (ACC-M), which was screened from ACC-2 by combination of in vivo selection and cloning in vitro. Then the total RNA was subjected to microarray analysis. Differentially expressed genes (DEGs) were screened from ACC-M compared with ACC-2, followed by Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Function annotation for DEGs also was performed. A protein protein interaction network (PPI) was constructed for DEGs. RESULTS: A total of 1128 DEGs were identified from ACC-M cells compared with ACC-2 cells. Both up- and down-regulated DEGs were enriched in different functions in biological process (BP), cellular component (CC) and molecular function (MF). Additionally, down-regulated DEGs were mainly enriched in "Apoptosis" and "Cytokine-cytokine receptor interaction" pathways which involved IFN-alpha1, NTRK1 and TGF-beta1. In the PPI network, PIK3CA, PTPN11 and PIK3R1 had a number of nodes greater than 10. CONCLUSIONS: Transforming growth factor beta1 might play a pivotal role during lung metastasis of SACC and be selected as a candidate target for treatment of metastatic SACC. IFNA1, NTRK1 and PIK3CA were also associated with tumor metastasis. PMID- 27478472 TI - Silencing expression of the NANOG gene and changes in migration and metastasis of urinary bladder cancer cells. AB - INTRODUCTION: It has been proved that expression of the NANOG gene is observed not only in embryonic-derived malignancies, but also in breast cancer, ovarian cancer, cervix cancer and bladder cancer. NANOG overexpression is correlated with high activity of MMP-2 and MMP-9. The aim of the study was to evaluate the changes in the malignant phenotype of T24 bladder cancer cells with modulated expression of the NANOG gene. MATERIAL AND METHODS: Human urinary bladder cancer cells T24 (HTB-4) were cultivated under standard conditions. Transfection of the cells with silencing constructions was performed with the application of Lipofectamine 2000 (Invitrogen) reagent. Evaluation of changes in the expression level of individual genes was performed using qRTPCR. Changes in the protein level were evaluated using the Human ELISA Kit (Abcam). The invasion capability of transfected cells was tested using Matrigel Invasion Chambers (BD Biosciences). The changes in cell migration were assessed with a wound-healing assay. RESULTS: The qRTPCR evaluation showed that silencing the NANOG gene in T24 cells led to the decrease of mRNA for the MMP-2 gene to the level of 62.4% and the MMP-9 gene to the level of 76%. The cells with modulated expression of the NANOG gene migrated slower in the Matrigel invasion assay and in the wound healing assay. The immunoenzymatic test showed a decrease in the protein level of MMP-9. CONCLUSIONS: The transcriptional activity of the NANOG gene might be connected with some aspects of bladder cancer cell metastasis in vitro and has an influence on MMP-2 and MMP-9 expression levels. PMID- 27478473 TI - Rosuvastatin intensifies the beneficial effects of rho-kinase inhibitor in reversal of monocrotaline-induced pulmonary hypertension. AB - INTRODUCTION: It remains controversial whether statins have a beneficial effect on pulmonary arterial hypertension (PAH). This study is intended to evaluate whether statin, co-administered with Rho-kinase inhibitor, could enhance its efficacy. Although Rho-kinase inhibitors, including fasudil, have been reported to improve pulmonary hypertension in experimental and clinical studies, the combination of these agents has not been tested in the treatment of pulmonary hypertension (PH). MATERIAL AND METHODS: The effects of such a regimen on hemodynamics, right ventricle hypertrophy, and Rho-associated protein kinase (ROCK) activity in experimental monocrotaline (MCT)-induced pulmonary hypertension were examined. Fourteen days after monocrotaline injection (60 mg/kg), male rats were treated orally for another 14 days with fasudil (15 mg/kg per day), or with a combination of fasudil + rosuvastatin (10 mg/kg per day). RESULTS: The drug combination reversed the MCT-induced increase in right ventricle pressure (RVP) and reduced right ventricular hypertrophy (RV/LV + S ratio) more than Rho kinase inhibitor alone. The simultaneous administration of fasudil and rosuvastatin caused a further decrease of RhoA kinase activity in isolated lung tissues as compared to fasudil alone. CONCLUSIONS: The results indicate that rosuvastatin intensifies the beneficial effects of Rho-kinase inhibitor on the Rho/Rho-kinase pathway and such a combination may represent an option for the treatment of pulmonary arterial hypertension. PMID- 27478474 TI - Effect of feeding a high-fat diet independently of caloric intake on reproductive function in diet-induced obese female rats. AB - INTRODUCTION: Globally, the prevalence of overweight and obesity is increasing, predisposing females to health hazards including compromised reproductive capacity. Our objective was to investigate the effect of ad libitum, isocalorically and hypocalorically restricted high-fat diet (HFD) feeding on reproductive function in diet-induced obese female rats. MATERIAL AND METHODS: Twenty female albino Sprague Dawley rats were used; 5 rats were kept on a standard pellet animal diet to serve as a control group (A) and 15 rats were fed a HFD for 9 weeks to induce obesity. The HFD fed animals were equally divided into three groups: an ad libitum HFD group (B), an isocalorically restricted HFD group (C), and a hypocalorically restricted HFD group (D). Estrous cyclicity, hormonal levels, ovarian histopathology and caspase-3 immunoreactivity were evaluated. RESULTS: The HFD-fed rats in groups B, C and D had significant irregularity in estrous cyclicity Vs group A (p = 0.001, 0.003 and 0.034 respectively). Groups C and D had significant reduction in serum progesterone level (p = 0.006 and 0.018 Vs A). Isocaloric restriction of HFD feeding significantly increased serum LH. Groups B and C had a significant increase in caspase-3 expression in the ovary (p < 0.001). CONCLUSIONS: Ad libitum HFD interfered with the normal estrous cycle and enhanced apoptosis of luteal cells in obese female rats. The HFD restriction interfered with the normal estrous cycle and caused functional insufficiency of the corpus luteum in obese female rats. These results suggest that HFD feeding determinately affects female reproductive function independently of caloric intake. PMID- 27478475 TI - First-in-man near-infrared spectroscopy proof of lipid-core embolization during carotid artery stenting. PMID- 27478476 TI - Thin Layer Chromatography-Bioautography and Gas Chromatography-Mass Spectrometry of Antimicrobial Leaf Extracts from Philippine Piper betle L. against Multidrug Resistant Bacteria. AB - This study isolated and identified the antimicrobial compounds of Philippine Piper betle L. leaf ethanol extracts by thin layer chromatography- (TLC-) bioautography and gas chromatography-mass spectrometry (GC-MS). Initially, TLC separation of the leaf ethanol extracts provided a maximum of eight compounds with R f values of 0.92, 0.86, 0.76, 0.53, 0.40, 0.25, 0.13, and 0.013, best visualized when inspected under UV 366 nm. Agar-overlay bioautography of the isolated compounds demonstrated two spots with R f values of 0.86 and 0.13 showing inhibitory activities against two Gram-positive multidrug-resistant (MDR) bacteria, namely, methicillin-resistant Staphylococcus aureus and vancomycin resistant Enterococcus. The compound with an R f value of 0.86 also possessed inhibitory activity against Gram-negative MDR bacteria, namely, carbapenem resistant Enterobacteriaceae-Klebsiella pneumoniae and metallo-beta-lactamase producing Acinetobacter baumannii. GC-MS was performed to identify the semivolatile and volatile compounds present in the leaf ethanol extracts. Six compounds were identified, four of which are new compounds that have not been mentioned in the medical literature. The chemical compounds isolated include ethyl diazoacetate, tris(trifluoromethyl)phosphine, heptafluorobutyrate, 3-fluoro 2-propynenitrite, 4-(2-propenyl)phenol, and eugenol. The results of this study could lead to the development of novel therapeutic agents capable of dealing with specific diseases that either have weakened reaction or are currently not responsive to existing drugs. PMID- 27478477 TI - Miconia sp. Increases mRNA Levels of PPAR Gamma and Inhibits Alpha Amylase and Alpha Glucosidase. AB - Diabetes mellitus is a public health problem worldwide. For this reason, ethanolic extract of Miconia sp. from Oaxaca, Mexico, was selected in search of an alternative against this disease. The effect of Miconia sp. on mRNA expression of PPARgamma on cell line 3T3-L1, its effect on alpha amylase and alpha glucosidase, lipid accumulation during adipogenesis, and cell viability on VERO cells were evaluated. The mRNA levels of PPARgamma increased on 1.393 +/- 0.008 folds, lipid accumulation was increased by 29.55% with Miconia sp. extract and 34.57% with rosiglitazone, and alpha-amylase and alpha-glycosidase were inhibited with IC50 values from 28.23 +/- 2.15 MUg/mL and 1.95 +/- 0.15 MUg/mL, respectively; the IC50 on antiproliferative activity on VERO cells was 314.54 +/- 45.40 MUg/mL. In case of alpha-amylase and alpha-glycosidase assays, IC50 (inhibitory concentration 50) refers to necessary extract amounts to inhibit 50% of enzymatic activity. On the other hand, on antiproliferative activity, IC50 (inhibitory concentration 50) refers to necessary extract amounts to inhibit 50% of cell proliferation. It was concluded that the compounds present in Miconia sp. ethanolic extract increase mRNA expression of PPARgamma, inhibit alpha-amylase and alpha-glucosidase, and increase lipid accumulation. It constitutes an alternative as adjuvant in diabetes mellitus treatment; therefore, we recommend continuing identifying the compounds responsible for its promising in vivo antidiabetic activity. PMID- 27478478 TI - alpha-Mangostin Induces Apoptosis and Cell Cycle Arrest in Oral Squamous Cell Carcinoma Cell. AB - Mangosteen has long been used as a traditional medicine and is known to have antibacterial, antioxidant, and anticancer effects. Although the effects of alpha mangostin, a natural compound extracted from the pericarp of mangosteen, have been investigated in many studies, there is limited data on the effects of the compound in human oral squamous cell carcinoma (OSCC). In this study, alpha mangostin was assessed as a potential anticancer agent against human OSCC cells. alpha-Mangostin inhibited cell proliferation and induced cell death in OSCC cells in a dose- and time-dependent manner with little to no effect on normal human PDLF cells. alpha-Mangostin treatment clearly showed apoptotic evidences such as nuclear fragmentation and accumulation of annexin V and PI-positive cells on OSCC cells. alpha-Mangostin treatment also caused the collapse of mitochondrial membrane potential and the translocation of cytochrome c from the mitochondria into the cytosol. The expressions of the mitochondria-related proteins were activated by alpha-mangostin. Treatment with alpha-mangostin also induced G1 phase arrest and downregulated cell cycle-related proteins (CDK/cyclin). Hence, alpha-mangostin specifically induces cell death and inhibits proliferation in OSCC cells via the intrinsic apoptosis pathway and cell cycle arrest at the G1 phase, suggesting that alpha-mangostin may be an effective agent for the treatment of OSCC. PMID- 27478479 TI - Artisanal Extraction and Traditional Knowledge Associated with Medicinal Use of Crabwood Oil (Carapa guianensis Aublet.) in a Peri-Urban Varzea Environment in the Amazon Estuary. AB - Varzea forests of the Amazon estuary contain species of importance to riverine communities. For example, the oil extracted from the seeds of crabwood trees is traditionally used to combat various illnesses and as such artisanal extraction processes have been maintained. The objectives of this study were to (1) describe the process involved in artisanal extraction of crabwood oil in the Fazendinha Protected Area, in the state of Amapa; (2) characterise the processes of knowledge transfer associated with the extraction and use of crabwood oil within a peri-urban riverine community; and (3) discern medicinal uses of the oil. The data were obtained using semistructured interviews with 13 community members involved in crabwood oil extraction and via direct observation. The process of oil extraction is divided into four stages: seed collection; cooking and resting of the seeds; shelling of the seeds and dough preparation; and oil collection. Oil extraction is carried out within the home for personal use, with surplus marketed within the community. More than 90% of the members of the community involved in extraction of crabwood oil highlighted the use of the oil to combat inflammation of the throat. Knowledge transfer occurs via oral transmission and through direct observation. PMID- 27478480 TI - Exposure to Music Alters Cell Viability and Cell Motility of Human Nonauditory Cells in Culture. AB - Although music is part of virtually all cultures in the world, little is known about how it affects us. Since the beginning of this century several studies suggested that the response to music, and to sound in general, is complex and might not be exclusively due to emotion, given that cell types other than auditory hair cells can also directly react to audible sound. The present study was designed to better understand the direct effects of acoustic vibrations, in the form of music, in human cells in culture. Our results suggest that the mechanisms of cell growth arrest and/or cell death induced by acoustic vibrations are similar for auditory and nonauditory cells. PMID- 27478481 TI - Berberine Protects Human Umbilical Vein Endothelial Cells against LPS-Induced Apoptosis by Blocking JNK-Mediated Signaling. AB - Endothelial dysfunction is a critical factor during the initiation of atherosclerosis. Berberine has a beneficial effect on endothelial function; however, the underlying mechanisms remain unclear. In this study, we investigated the effects of berberine on lipopolysaccharide- (LPS-) induced apoptosis in human umbilical vein endothelial cells (HUVECs) and the molecular mechanisms mediating the effect. The effects of berberine on LPS-induced cell apoptosis and viability were measured with 5-ethynyl-2'-deoxyuridine staining, flow cytometry, and Cell Counting Kit-8 assays. The expression and/or activation of proapoptotic and antiapoptotic proteins or signaling pathways, including caspase-3, poly(ADP ribose) polymerase, myeloid cell leukemia-1 (MCL-1), p38 mitogen-activated protein kinase, C-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase, were determined with western blotting. The malondialdehyde levels, superoxide dismutase (SOD) activity, and production of proinflammatory cytokines were measured with enzyme-linked immunosorbent assays. The results demonstrated that berberine pretreatment protected HUVECs from LPS-induced apoptosis, attenuated LPS-induced injury, inhibited LPS-induced JNK phosphorylation, increased MCL-1 expression and SOD activity, and decreased proinflammatory cytokine production. The effects of berberine on LPS-treated HUVECs were prevented by SP600125, a JNK-specific inhibitor. Thus, berberine might be a potential candidate in the treatment of endothelial cell injury-related vascular diseases. PMID- 27478482 TI - Spectral Analysis of Chinese Medicinal Herbs Based on Delayed Luminescence. AB - Traditional Chinese medicine (TCM) plays a critical role in healthcare; however, it lacks scientific evidence to support the multidimensional therapeutic effects. These effects are based on experience, and, to date, there is no advanced tool to evaluate these experience based effects. In the current study, Chinese herbal materials classified with different cold and heat therapeutic properties, based on Chinese medicine principles, were investigated using spectral distribution, as well as the decay probability distribution based on delayed luminescence (DL). A detection system based on ultraweak biophoton emission was developed to determine the DL decay kinetics of the cold and heat properties of Chinese herbal materials. We constructed a mathematical model to fit the experimental data and characterize the properties of Chinese medicinal herbs with different parameters. The results demonstrated that this method has good reproducibility. Moreover, there is a significant difference (p < 0.05) in the spectral distribution and the decay probability distribution of Chinese herbal materials with cold and heat properties. This approach takes advantage of the comprehensive nature of DL compared with more reductionist approaches and is more consistent with TCM principles, in which the core comprises holistic views. PMID- 27478483 TI - Structural Aspects of Antioxidant and Genotoxic Activities of Two Flavonoids Obtained from Ethanolic Extract of Combretum leprosum. AB - Combretum leprosum Mart., a member of the Combretaceae family, is a traditionally used Brazilian medicinal plant, although no evidence in the literature substantiates its antioxidant action and the safety of its use. We evaluated the antioxidant properties of the ethanolic extract (EE) from flowers of C. leprosum and its isolated products 5,3'-dihydroxy-3,7,4'-trimethoxyflavone (FCL2) and 5,3',4'-trihydroxy-3,7-dimethoxyflavone (FCL5) in Saccharomyces cerevisiae strains proficient and deficient in antioxidant defenses. Their mutagenic activity was also assayed in S. cerevisiae, whereas cytotoxic and genotoxic properties were evaluated by MTT and Comet Assays, respectively, in V79 cells. We show that the EE, FCL2, and FCL5 have a significant protective effect against H2O2. FCL2 showed a better antioxidant action, which can be related to the activation of the 3'-OH in the presence of a methoxyl group at 4' position in the B-ring of the molecule, while flavonoids did not induce mutagenesis in yeast, and the EE was mutagenic at high concentrations. The toxicity of these compounds in V79 cells increases from FCL2 = FCL5 < EE; although not cytotoxic, FCL5 induced an increase in DNA damage. The antioxidant effect, along with the lower toxicity and the absence of genotoxicity, suggests that FCL2 could be suitable for pharmacological use. PMID- 27478485 TI - Use of magnetic hydrazide-modified polymer microspheres for enrichment of Francisella tularensis glycoproteins. AB - The field of microbial proteomics has currently experienced a boom in the discovery of glycosylated proteins of various pathogenic bacteria as potential mediators of host-pathogen interactions. The presence of glycoproteins has recently been discovered in a Gram-negative pathogenic bacterium Francisella tularensis, utilizing glycoprotein detection and isolation techniques in combination with mass spectrometry. The isolation of glycoproteins is a prerequisite for their subsequent mass-spectrometric identification. Current glycoprotein isolation/enrichment methods comprise lectin affinity chromatography, aminophenylboronic acid and hydrazide-based enrichment. The use of magnetic microspheres containing functional groups is nowadays among state-of art separation methodologies owing to an ease of manipulation, a speed of separation, and a minimum of non-specific protein adsorption. In the present study, novel magnetic hydrazide-modified poly(2-hydroxyethyl methacrylate) (PHEMA) microspheres were developed using a multi-step swelling and polymerization method with subsequent precipitation of magnetic iron oxides within the pores of the particles. The microspheres had a regular shape, size of 4 MUm and contained 0.18 mmol hydrazide groups per g; the magnetic microspheres were employed for specific enrichment of Francisella tularensis glycoproteins. Effectiveness of the newly prepared magnetic microspheres for glycoprotein enrichment was proved by comparison with commercial hydrazide-functionalized microparticles. PMID- 27478484 TI - Exposure to dietary lipid leads to rapid production of cytosolic lipid droplets near the brush border membrane. AB - BACKGROUND: Intestinal absorption of dietary lipids involves their hydrolysis in the lumen of proximal intestine as well as uptake, intracellular transport and re assembly of hydrolyzed lipids in enterocytes, leading to the formation and secretion of the lipoproteins chylomicrons and HDL. In this study, we examined the potential involvement of cytosolic lipid droplets (CLD) whose function in the process of lipid absorption is poorly understood. METHODS: Intestinal lipid absorption was studied in mouse after gavage. Three populations of CLD were purified by density ultracentrifugations, as well as the brush border membranes, which were analyzed by western-blots. Immunofluorescent localization of membranes transporters or metabolic enzymes, as well as kinetics of CLD production, were also studied in intestine or Caco-2 cells. RESULTS: We isolated three populations of CLD (ranging from 15 to 1000 nm) which showed differential expression of the major lipid transporters scavenger receptor BI (SR-BI), cluster of differentiation 36 (CD-36), Niemann Pick C-like 1 (NPC1L1), and the ATP-binding cassette transporters ABCG5/G8 but also caveolin 2 and fatty acid binding proteins. The enzyme monoacylglycerol acyltransferase 2 (MGAT2) was identified in the brush border membrane (BBM) in addition to the endoplasmic reticulum, suggesting local synthesis of triglycerides and CLD at both places. CONCLUSIONS: We show a very fast production of CLD by enterocytes associated with a transfer of apical constituents as lipid transporters. Our findings suggest that following their uptake by enterocytes, lipids can be partially metabolized at the BBM and packaged into CLD for their transportation to the ER. PMID- 27478486 TI - Hyperthymic affective temperament and hypertension are independent determinants of serum brain-derived neurotrophic factor level. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) has neuroprotective, proangiogenic and myogenic effects and, therefore, possibly acts as a psychosomatic mediator. Here, we measured serum BDNF (seBDNF) level in hypertensive patients (HT) and healthy controls (CONT) and its relation to affective temperaments, depression and anxiety scales, and arterial stiffness parameters. METHODS: In this cross-sectional study, affective temperaments, anxiety, and depression were studied with questionnaires (TEMPS-A, HAM-A, and BDI, respectively). SeBDNF level and routine laboratory parameters were measured as well. Arterial stiffness was evaluated with a tonometric method. RESULTS: Allover, 151 HT, and 32 CONT subjects were involved in the study. SeBDNF level was significantly higher in HT compared to CONT (24880 +/- 8279 vs 21202.6 +/- 6045.5 pg/mL, p < 0.05). In the final model of regression analysis, hyperthymic temperament score (Beta = 405.8, p = 0.004) and the presence of hypertension (Beta = 6121.2, p = 0.001) were independent determinants of seBDNF. In interaction analysis, it was found that in HT, a unit increase in hyperthymic score was associated with a 533.3 (95 %CI 241.3-825.3) pg/mL higher seBDNF. This interaction was missing in CONT. CONCLUSIONS: Our results suggest a complex psychosomatic involvement of BDNF in the pathophysiology of hypertension, where hyperthymic affective temperament may have a protective role. BDNF is not likely to have an effect on large arteries. PMID- 27478487 TI - CT genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is protector factor of major depressive disorder in the Tunisian population: a case control study. AB - BACKGROUND: Major depressive disorder (MDD) is a common psychiatric disorder with considerable mortality. Death from unnatural causes, largely suicidal or quasi suicidal, has a particularly high risk for the functional disorders, especially depression and schizophrenia. One of the prospective risk factors for this disease is hyperhomocysteinemia and folate deficiency. The methylenetetrahydrofolate reductase (MTHFR) gene encodes for a 5 methylenetetrahydrofolate reductase involved in folate metabolism and neurotransmitter synthesis. The aim of this research is to study the association between the C677T polymorphism of MTHFR gene and depression in Tunisian population, to explore their relationship with clinical and therapeutic characteristics of this disease. And it may lead to discover a novel marker to identify a patient with a higher risk of development of depressive disorder to be. This marker can be used for better therapeutic management and prevent disease installation. METHODS: Our study included 208 depressive patients, 187 controls aged between 44.1 +/- 13.5 and 38.9 +/- 13.2 years, respectively. MTHFR gene polymorphisms were determined by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). RESULTS: No significant difference was detected in the distribution of the genotype frequencies of MTHFR C677T polymorphisms (chi (2) = 5.443, df = 2, p = 0.066) between patients and controls. But when we study the risk of these genotypes, CT genotype is significantly more frequent in controls compared to patients, it may be a protection from depression (OR = 0.655, CI 95 % = 0.432-0.995, p = 0.047, OR* = 0.638, CI 95 %* = 0.415-0.983, p* = 0.04, before and after adjustment). Women, TT Genotype can increase four times the risk to be depressive. Addictive behavior seems to be associated with CT genotype and there was no significant association between clinical and therapeutic characteristics and this polymorphism. CONCLUSION: This paper is the first study to prove that CT genotype of MTHFR C677T polymorphism may protect from depression and TT genotype seems to be associated with women's depression. Further studies are required with other polymorphisms and biochemical factors that must be investigated to clarify the implication of MTHFR C677T polymorphism in the pathophysiology of depression. PMID- 27478488 TI - A Duty To Warn Relatives in Clinical Genetics: Arguably 'Fair just and reasonable' in English Law? AB - The use of 'next-generation' genetic sequencing technology that allows the sequencing of large parts, or even the entirety, of a patient's genome is advancing rapidly in the UK and around the world. This is set to greatly increase the level of health information that will be of relevance to relatives and the latest medical guidance advises that there is a professional duty to consider warning a patient's relatives of a serious genetic risk in limited circumstances. However, the High Court in ABC v St George's Healthcare NHS Trust [2015] EWHC 1394 (QB), recently found that a legal duty on the part of doctors to warn a patient's daughter of a genetic risk of Huntington's Disease without the patient's consent, was not even 'reasonably arguable' and would not be 'fair, just and reasonable'. This article considers the courts' approach to a duty of care towards 'third parties' in this context and concludes that some form of a duty of care to genetic relatives in clinical genetics is at very least arguably 'fair, just and reasonable'. PMID- 27478490 TI - Recent Work on the Nature and Development of Delusions. AB - In this paper we review two debates in the current literature on clinical delusions. One debate is about what delusions are. If delusions are beliefs, why are they described as failing to play the causal roles that characterise beliefs, such as being responsive to evidence and guiding action? The other debate is about how delusions develop. What processes lead people to form delusions and maintain them in the face of challenges and counter-evidence? Do the formation and maintenance of delusions require abnormal experience alone, or also reasoning biases or deficits? We hope to show that the focus on delusions has made a substantial contribution to the philosophy of the mind and continues to raise issues that are central to defining the concept of belief and gaining a better understanding of how people process information and learn about the world. PMID- 27478489 TI - Rpl22 is required for IME1 mRNA translation and meiotic induction in S. cerevisiae. AB - BACKGROUND: The transition from mitotic cell division to meiotic development in S. cerevisiae requires induction of a transient transcription program that is initiated by Ime1-dependent destruction of the repressor Ume6. Although IME1 mRNA is observed in vegetative cultures, Ime1 protein is not suggesting the presence of a regulatory system restricting translation to meiotic cells. RESULTS: This study demonstrates that IME1 mRNA translation requires Rpl22A and Rpl22B, eukaryotic-specific ribosomal protein paralogs of the 60S large subunit. In the absence of Rpl22 function, IME1 mRNA synthesis is normal in cultures induced to enter meiosis. However, Ime1 protein production is reduced and the Ume6 repressor is not destroyed in rpl22 mutant cells preventing early meiotic gene induction resulting in a pre-meiosis I arrest. This role for Rpl22 is not a general consequence of mutating non-essential large ribosomal proteins as strains lacking Rpl29 or Rpl39 execute meiosis with nearly wild-type efficiencies. Several results indicate that Rpl22 functions by enhancing IME1 mRNA translation. First, the Ime1 protein synthesized in rpl22 mutant cells demonstrates the same turnover rate as in wild-type cultures. In addition, IME1 transcript is found in polysome fractions isolated from rpl22 mutant cells indicating that mRNA nuclear export and ribosome association occurs. Finally, deleting the unusually long 5'UTR restores Ime1 levels and early meiotic gene transcription in rpl22 mutants suggesting that Rpl22 enhances translation through this element. Polysome profiles revealed that under conditions of high translational output, Rpl22 maintains high free 60S subunit levels thus preventing halfmer formation, a translation species indicative of mRNAs bound by an unpaired 40S subunit. In addition to meiosis, Rpl22 is also required for invasive and pseudohyphal growth. CONCLUSIONS: These findings indicate that Rpl22A and Rpl22B are required to selectively translate IME1 mRNA that is required for meiotic induction and subsequent gametogenesis. In addition, our results imply a more general role for Rpl22 in cell fate switches responding to environmental nitrogen signals. PMID- 27478492 TI - Soft Computing in Medical Image Processing. PMID- 27478491 TI - Alternative Confidence Interval Methods Used in the Diagnostic Accuracy Studies. AB - Background/Aim. It is necessary to decide whether the newly improved methods are better than the standard or reference test or not. To decide whether the new diagnostics test is better than the gold standard test/imperfect standard test, the differences of estimated sensitivity/specificity are calculated with the help of information obtained from samples. However, to generalize this value to the population, it should be given with the confidence intervals. The aim of this study is to evaluate the confidence interval methods developed for the differences between the two dependent sensitivity/specificity values on a clinical application. Materials and Methods. In this study, confidence interval methods like Asymptotic Intervals, Conditional Intervals, Unconditional Interval, Score Intervals, and Nonparametric Methods Based on Relative Effects Intervals are used. Besides, as clinical application, data used in diagnostics study by Dickel et al. (2010) has been taken as a sample. Results. The results belonging to the alternative confidence interval methods for Nickel Sulfate, Potassium Dichromate, and Lanolin Alcohol are given as a table. Conclusion. While preferring the confidence interval methods, the researchers have to consider whether the case to be compared is single ratio or dependent binary ratio differences, the correlation coefficient between the rates in two dependent ratios and the sample sizes. PMID- 27478493 TI - Geriatric Assessment as a qualification element for elective and emergency cholecystectomy in older patients. AB - BACKGROUND: Older patients experience a higher incidence of postoperative complications after cholecystectomy compared with younger patients. However, most studies have not considered patient frailty, particularly regarding emergency cholecystectomy. The aim of this prospective study was to evaluate outcomes in frail older patients eligible for elective and emergency cholecystectomy. METHODS: Preoperative Geriatric Assessment (GA) was performed in consecutive patients aged 65+ years, operated for biliary disease. The GA evaluated the functional, cognitive, comorbidity, depressive, nutritional, and polypharmacy status and patients with two or more abnormal domains were considered frail. Outcomes of interest were 30-day postoperative mortality, morbidity, and length of hospital stay (LOS). RESULTS: A total of 126 patients (median age 74; range 65 93 years) were included. There was no difference between elective frail and non frail patients regarding postoperative mortality (0 %) and morbidity (6 % vs. 5 %; p = 0.76). LOS was not significantly longer in the frail group (5.6 vs. 4 days; p = 0.22). In the emergency-admitted patients, almost all complications occurred in the frail population (mortality 5 % vs. 0 %; morbidity 36.7 % vs. 3.3 %, compared with non-frail patients, respectively; p < 0.01) and LOS was significantly longer (10.3 (frail) vs. 6 days (non-frail);p = 0.03). Frail status was a significant independent predictive factor for postoperative complications in the emergency population, only (odds ratio: 3.4 (1.2-9.7); p = 0.02). CONCLUSIONS: Elective laparoscopic cholecystectomy is a safe and effective surgical technique also for older frail patients. In emergency settings, frail patients have significantly more complications and a longer LOS. However, the role of severity of frailty and the most reliable GA tools require further study. TRIAL REGISTRATION: ISRCTN14976998 (retrospectively registered). PMID- 27478495 TI - Phytochemicals and potential health effects of Sambucus williamsii Hance (Jiegumu). AB - Sambucus williamsii Hance (Jiegumu) is traditionally used in Chinese medicine to treat bone and joint diseases. The major phytochemicals in S. williamsii are lignans, terpenoids, and phenolic acids, together with trace amounts of essential oils, minerals, amino acids, and natural pigments. In this review, a database search for studies published from 1990 to November 2015 was conducted using PubMed, the China Academic Journals Full-Text Database, and Google Scholar with the keywords "Sambucus williamsii Hance", "Sambucus williamsii", "Sambucus williamsii + clinic", "Sambucus williamsii + biology", "Sambucus williamsii + chemicals", and "Jiegumu", which covered chemical studies, cell culture studies, animal experiments, and clinical studies. This article reviewed the compounds isolated from S. williamsii that may reduce the risk of cancer, and exert antifungal, antioxidant, anti-inflammatory, bone fracture healing, and antiosteoporotic effects. PMID- 27478496 TI - Conservation and sustainable use of medicinal plants: problems, progress, and prospects. AB - Medicinal plants are globally valuable sources of herbal products, and they are disappearing at a high speed. This article reviews global trends, developments and prospects for the strategies and methodologies concerning the conservation and sustainable use of medicinal plant resources to provide a reliable reference for the conservation and sustainable use of medicinal plants. We emphasized that both conservation strategies (e.g. in situ and ex situ conservation and cultivation practices) and resource management (e.g. good agricultural practices and sustainable use solutions) should be adequately taken into account for the sustainable use of medicinal plant resources. We recommend that biotechnical approaches (e.g. tissue culture, micropropagation, synthetic seed technology, and molecular marker-based approaches) should be applied to improve yield and modify the potency of medicinal plants. PMID- 27478494 TI - WSES Guidelines for the management of acute left sided colonic diverticulitis in the emergency setting. AB - Acute left sided colonic diverticulitis is one of the most common clinical conditions encountered by surgeons in acute setting. A World Society of Emergency Surgery (WSES) Consensus Conference on acute diverticulitis was held during the 3rd World Congress of the WSES in Jerusalem, Israel, on July 7th, 2015. During this consensus conference the guidelines for the management of acute left sided colonic diverticulitis in the emergency setting were presented and discussed. This document represents the executive summary of the final guidelines approved by the consensus conference. PMID- 27478497 TI - Course of self-reported symptoms of 342 outpatients receiving medium- versus long term psychodynamic psychotherapy. AB - BACKGROUND: The course of self-reported symptoms during medium- versus long-term psychodynamic psychotherapy has rarely been documented for outpatient settings. This observational study describes routine practice of ambulatory treatment in Germany and explores self-reported symptoms of a broad patient sample undergoing one (medium-term) versus two years (long-term) of psychodynamic psychotherapy. METHODS: Over four and a half years, longitudinal self-report symptom data were collected from 342 outpatients as part of a standardized documentation system. Self-report data were compared between patients receiving either medium-term or long-term psychodynamic psychotherapy. RESULTS: Routine care significantly decreased disease burden as reported by patients by small to medium effect sizes (ES) for depression (ES = 0.58), anxiety (ES = 0.49), obsessive-compulsive disorder (ES = 0.54), somatoform disorder (ES = 0.32), eating disorder (ES = 0.38). The majority of patients completed treatment after one year and showed medium-size changes. For a subgroup of patients with depressive and/or obsessive compulsive disorder symptoms for whom two years of therapy were deemed necessary, additional benefits were reported during the second year of treatment (ES = 0.61 and ES 0.47, respectively). CONCLUSIONS: Our findings suggest that both medium- and long-term psychodynamic psychotherapy decrease self-reported disease burden of patients with depression, anxiety, obsessive-compulsive, somatoform and/or eating disorders. For a subgroup of patients, additional benefits were gained in the second year of treatment. PMID- 27478498 TI - Inhibition of emotional needs and emotional wellbeing predict disease progression of chronic hepatitis C patients: an 8-year prospective study. AB - BACKGROUND: The role of psycosocial factors in the disease progression of chronic hepatitis C (CHC) patients remains unclear. The aim of the present study was to prospectively evaluate the prognostic value of behavioral patterns and the quality of life (QOL) of patients with CHC. METHODS: Two hundred and forty Japanese CHC patients (mean age 62.4 years) were assessed for behavioral patterns (Stress Inventory), QOL (Functional Assessment of Chronic Illness Therapy Spiritual), and known prognostic factors at baseline then followed for a maximum of 8 years for disease progression, defined as either the first diagnosis of hepatocellular carcinoma (HCC) or hepatitis-related death. RESULTS: Forty-nine events occurred during the study period (46 newly diagnosed HCC cases, three hepatitis-related deaths). In a Cox proportional hazard model including known prognostic factors and treatment-related factors as time-dependent variables, behavioral patterns associated with inhibition of emotional needs (hazard ratio (HR): 1.35; 95 % confidence interval (CI): 1.02-1.77; p = 0.036) and QOL, representing emotional wellbeing (HR 0.60; 95 % CI 0.37-0.98; p = 0.041), were each associated with the risk of disease progression. CONCLUSION: Psychosocial factors such as behavioral patterns relevant to the inhibition of emotional needs and emotional wellbeing independently affect the clinical course of patients with CHC. PMID- 27478499 TI - Erratum to: Neonatal outcomes of Syrian refugees delivered in a tertiary hospital in Ankara, Turkey. AB - [This corrects the article DOI: 10.1186/s13031-015-0066-1.]. PMID- 27478500 TI - Cesium-containing triple cation perovskite solar cells: improved stability, reproducibility and high efficiency. AB - Today's best perovskite solar cells use a mixture of formamidinium and methylammonium as the monovalent cations. With the addition of inorganic cesium, the resulting triple cation perovskite compositions are thermally more stable, contain less phase impurities and are less sensitive to processing conditions. This enables more reproducible device performances to reach a stabilized power output of 21.1% and ~18% after 250 hours under operational conditions. These properties are key for the industrialization of perovskite photovoltaics. PMID- 27478501 TI - Cell-free synthesis of functional phospholipase A1 from Serratia sp. AB - BACKGROUND: Phospholipase A1 is an enzyme that hydrolyzes phospholipids at the sn 1 position. It has potential applications across diverse fields including food, pharmaceutical, and biofuel industries. Although there has been increasing interest in the use of phospholipase A1 for degumming of plant oils during biodiesel production, production of recombinant phospholipase A1 has been hampered by low efficiency of gene expression and its toxicity to the host cell. RESULTS: While expression of phospholipase A1 in Escherichia coli resulted in extremely low productivity associated with inhibition of transformed cell growth, drastically higher production of functional phospholipase A1 was achieved in a cell-free protein synthesis system where enzyme expression is decoupled from cell physiology. Compared with expression in E. coli, cell-free synthesis resulted in an over 1000-fold higher titer of functional phospholipase A1. Cell-free produced phospholipase A1 was also used for successfully degumming crude plant oil. CONCLUSIONS: We demonstrate successful production of Serratia sp. phospholipase A1 in a cell-free protein synthesis system. Including the phospholipase A1 investigated in this study, many industrial enzymes can interfere with the regular physiology of cells, making cellular production of them problematic. With the experimental results presented herewith, we believe that cell-free protein synthesis will provide a viable option for rapid production of important industrial biocatalysts. PMID- 27478502 TI - A balanced chromosomal translocation involving chromosomes 3 and 16 in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome reveals new candidate genes at 3p22.3 and 16p13.3. AB - BACKGROUND: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, or the congenital absence of uterus and vagina, is the most severe anomaly of the female reproductive tract. It affects 1 in 5,000 females, and is the second most common cause of primary amenorrhea. The etiology remains unknown in most patients, although four single gene defects and some repetitive copy number variants (CNVs) have been identified. Translocations in MRKH patients are very rare, and reported only in three patients previously without breakpoint mapping. We have identified the fourth MRKH translocation patient and are the first to characterize the breakpoints mapped by molecular methods. RESULTS: The proband is a 17- year old white female with agenesis of the uterus and vagina who had a peripheral blood karyotype revealing a de novo balanced translocation 46,XX,t(3;16)(p22.3;p13.3)dn. There were no known related anomalies present in the proband or her family. No CNVs were found by chromosomal microarray analysis, and no genes were directly disrupted by the translocation. DNA sequencing of six nearby candidate genes-TRIM71, CNOT10, ZNF200, OR1F1, ZNF205, and ZNF213-did not reveal any mutations. RT-qPCR of proband lymphoblast RNA for 20 genes near the breakpoints of 3p22.3 and 16p13.3 showed significantly altered expression levels for four genes in the proband compared to three white female controls, after correction for multiple comparisons. Reduced expression was seen for CMTM7 and CCR4 on 3p22.3, while increased expression was observed for IL32 and MEFV on 16p13.3. CONCLUSION: We have mapped the breakpoints of our t(3;16)(p22.3;p13.3) translocation patient using molecular methods to within 13.6 kb at 3p22.3 and within 1.9 kb for 16p13.3 and have suggested 10 nearby genes that become plausible candidate genes for future study. PMID- 27478503 TI - Joint analysis of multiple high-dimensional data types using sparse matrix approximations of rank-1 with applications to ovarian and liver cancer. AB - BACKGROUND: Technological advances enable the cost-effective acquisition of Multi Modal Data Sets (MMDS) composed of measurements for multiple, high-dimensional data types obtained from a common set of bio-samples. The joint analysis of the data matrices associated with the different data types of a MMDS should provide a more focused view of the biology underlying complex diseases such as cancer that would not be apparent from the analysis of a single data type alone. As multi modal data rapidly accumulate in research laboratories and public databases such as The Cancer Genome Atlas (TCGA), the translation of such data into clinically actionable knowledge has been slowed by the lack of computational tools capable of analyzing MMDSs. Here, we describe the Joint Analysis of Many Matrices by ITeration (JAMMIT) algorithm that jointly analyzes the data matrices of a MMDS using sparse matrix approximations of rank-1. METHODS: The JAMMIT algorithm jointly approximates an arbitrary number of data matrices by rank-1 outer products composed of "sparse" left-singular vectors (eigen-arrays) that are unique to each matrix and a right-singular vector (eigen-signal) that is common to all the matrices. The non-zero coefficients of the eigen-arrays identify small subsets of variables for each data type (i.e., signatures) that in aggregate, or individually, best explain a dominant eigen-signal defined on the columns of the data matrices. The approximation is specified by a single "sparsity" parameter that is selected based on false discovery rate estimated by permutation testing. Multiple signals of interest in a given MDDS are sequentially detected and modeled by iterating JAMMIT on "residual" data matrices that result from a given sparse approximation. RESULTS: We show that JAMMIT outperforms other joint analysis algorithms in the detection of multiple signatures embedded in simulated MDDS. On real multimodal data for ovarian and liver cancer we show that JAMMIT identified multi-modal signatures that were clinically informative and enriched for cancer-related biology. CONCLUSIONS: Sparse matrix approximations of rank-1 provide a simple yet effective means of jointly reducing multiple, big data types to a small subset of variables that characterize important clinical and/or biological attributes of the bio-samples from which the data were acquired. PMID- 27478505 TI - Effectiveness of percutaneous flexor tenotomies for the management and prevention of recurrence of diabetic toe ulcers: a systematic review. AB - BACKGROUND: Diabetic toe ulcers are a potentially devastating complication of diabetes. In recent years, the percutaneous flexor tenotomy procedure for the correction of flexible claw and hammer-toe contraction deformities has been proposed as a safe and effective technique for facilitating the healing of toe deformity related diabetic ulcers. The aim of this review is to critically appraise the evidence for the effectiveness of this surgical procedure in achieving ulcer healing, prevention of re-ulceration, and to summarise the rate of post-operative complications. METHOD: A search of medical databases, was performed to locate relevant literature. Titles were screened prior to abstract and full text review to identify articles relevant to the research question. Search terms included truncations of "tenotomy", "toe", "hallux", "digit", "diabetes" and "ulcer". Peer reviewed primary research study designs specified as suitable for systematic reviews by the Centre for Reviews and Dissemination were included. Studies were excluded if they used a concurrent secondary procedure or included non-diabetic patients without reporting outcomes separately. Included studies were appraised for quality using the Methodological Index for Non Randomised Studies tool. Levels of evidence were subsequently assigned to each outcome of interest (healing rate and prevention of re-ulceration). RESULTS: From a total search yield of 42 articles, 5 eligible studies (all case series designs) were identified for inclusion. Included studies were of low-to-moderate methodological quality when assessed using the MINORS tool. A total of 250 flexor tenotomy procedures were performed in a total of 163 patients. Included studies generally reported good healing rates (92-100 % within 2 months) post-op follow up), relatively few recurrences (0-18 % at 22 months median post-op follow-up), and low incidences of infection or new deformity. Transfer ulcers developing on adjacent areas as a result of shifted pressure were reported by several authors. The validity of these results is undermined by methodological limitations inherent to case series designs such as a lack of control groups, non-randomised designs, as well as inconsistent reporting of post-intervention follow-up periods. There was level 4 evidence for the flexor tenotomy procedure in facilitating ulcer healing and preventing re-ulceration. CONCLUSION: More definitive research evidence is needed in this area to determine whether or not the flexor tenotomy is a safe and effective treatment option for people with, or at risk of developing diabetic toe ulcers. Whilst the available literature reports that the procedure may be associated with high healing rates, relatively low recurrence rates and low incidences of post-op complications, methodological limitations restrict the value of these findings. PMID- 27478504 TI - Epigenetic dynamics of monocyte-to-macrophage differentiation. AB - BACKGROUND: Monocyte-to-macrophage differentiation involves major biochemical and structural changes. In order to elucidate the role of gene regulatory changes during this process, we used high-throughput sequencing to analyze the complete transcriptome and epigenome of human monocytes that were differentiated in vitro by addition of colony-stimulating factor 1 in serum-free medium. RESULTS: Numerous mRNAs and miRNAs were significantly up- or down-regulated. More than 100 discrete DNA regions, most often far away from transcription start sites, were rapidly demethylated by the ten eleven translocation enzymes, became nucleosome free and gained histone marks indicative of active enhancers. These regions were unique for macrophages and associated with genes involved in the regulation of the actin cytoskeleton, phagocytosis and innate immune response. CONCLUSIONS: In summary, we have discovered a phagocytic gene network that is repressed by DNA methylation in monocytes and rapidly de-repressed after the onset of macrophage differentiation. PMID- 27478506 TI - Improving rural and remote practitioners' knowledge of the diabetic foot: findings from an educational intervention. AB - BACKGROUND: This study aimed to determine knowledge of national guidelines for diabetic foot assessment and risk stratification by rural and remote healthcare professionals in Western Australia and their implementation in practice. Assessment of diabetic foot knowledge, availability of equipment and delivery of foot care education in a primary healthcare setting at baseline enabled evaluation of the effectiveness of a diabetic foot education and training program for generalist healthcare professionals. METHODS: This study employed a quasi experimental pre-test/post-test study design. Healthcare practitioners' knowledge, attitudes and practice of diabetic foot assessment, diabetic foot risks, risk stratification, and use of the 2011 National Health and Medical Research Council Guidelines were investigated with an electronic pre-test survey(.) Healthcare professionals then undertook a 3-h education and training workshop before completing the electronic post-test knowledge, attitudes and practice survey. Comparison of pre-test/post-test survey findings was used to assess the change in knowledge, attitudes and intended practice due to the workshops. RESULTS: Two hundred and forty-six healthcare professionals from two rural and remote health regions of Western Australia participated in training workshops. Monofilaments and diabetes foot care education brochures, particularly brochures for Aboriginal people, were reported as not readily available in rural and remote health services. For most participants (58 %), their post-test knowledge score increased significantly from the pre-test score. Use of the Guidelines in clinical settings was low (19 %). The healthcare professionals' baseline diabetic foot knowledge was adequate to correctly identify the high risk category. However, stratification of the intermediate risk category was poor, even after training. CONCLUSION: This study reports the first assessment of Western Australia's rural and remote health professionals' knowledge, attitudes and practices regarding the diabetic foot. It shows that without training, generalists' levels of knowledge concerning the diabetic foot was low and they were unlikely to assess foot risk. The findings from this study in a rural and remote setting cast doubt on the ability of generalist healthcare professionals to stratify risk appropriately, especially for those at intermediate risk, without clinical decision support tools. PMID- 27478507 TI - Screening for coeliac disease in adult patients with type 1 diabetes mellitus: myths, facts and controversy. AB - This review aims at summarizing the present knowledge on the clinical consequences of concomitant coeliac disease (CD) in adult patients with type 1 diabetes mellitus (T1DM). The cause of the increased prevalence of CD in T1DM patients is a combination of genetic and environmental factors. Current screening guidelines for CD in adult T1DM patients are not uniform. Based on the current evidence of effects of CD on bone mineral density, diabetic complications, quality of life, morbidity and mortality in patients with T1DM, we advise periodic screening for CD in adult T1DM patients to prevent delay in CD diagnosis and subsequent CD and/or T1DM related complications. PMID- 27478509 TI - The relationship between HbA1c values and the occurrence of hypoglycemia as assessed by continuous glucose monitoring in patients with type 1 diabetes. AB - BACKGROUND: We aimed to examine the relationship between the occurrence of hypo /hyperglycemia and HbA1c values, as assessed by continuous glucose monitoring (CGM) in patients with type 1 diabetes. METHODS: The study subjects comprised 101 type 1 diabetic patients on basal-bolus insulin therapy, who were put on masked CGM immediately after admission. The subjects were divided into four groups equally by HbA1c values and the 24-h CGM data were compared among the groups. RESULTS: Groups A to D comprised 24 patients with HbA1c <=7.2 %, 26 patients with 7.2 % 9.2 %, respectively. The higher the HbA1c values, the significantly higher the 24-h mean glucose levels [median (25-75 percentiles)], with the HbA1c in groups A to D being 133 (114-155), 158 (132-188), 182 (152-206), and 186 (143 215) mg/dL, respectively (P < 0.001). Conversely, the higher the HbA1c values, the significantly shorter the time in hypoglycemia (<70 mg/dL), with the time in groups A to D being 170 (58-341), 78 (0-210), 45 (0-105), and 20 (0-105) min, respectively (P = 0.014); and the higher the HbA1c values, the significantly shorter the time in nocturnal hypoglycemia, with the time in groups A to D being 120 (5-269), 25 (0-120), 0 (0-60), and 0 (0-89) min, respectively (P = 0.019). No significant difference was seen between groups A to D in the standard deviations (SDs) of 24-h glucose values at 53 (40-65), 54 (45-70), 64 (55-76), and 58 (48 80), respectively. CONCLUSION: In type 1 diabetic patients, lower HbA1c was not associated with lower SD of 24-h glucose values, but may result in increased hypoglycemia. Trial Registration Current controlled trials UMIN000019190. PMID- 27478508 TI - Association of cardiac NT pro-beta-type natriuretic peptide with metabolic and endothelial risk factors in young obese hypertensive patients: a perspective on the hypothalamic pituitary adrenal axis activation. AB - BACKGROUND: In practice, there is increasing recognition of the importance of hypothalamic pituitary adrenal axis in the cardiovascular disease progression. The association of brain natriuretic peptide with obesity and characteristics of the metabolic syndrome in adults and aged patients is well established, but that in pediatrics needs thorough elucidation. AIM: The aim of this study was to assess the association of hypothalamic pituitary adrenal axis mediators (cortisol and aldosterone) with plasma NT-pro beta-type natriuretic peptide (NT-proBNP) levels on metabolic, immune-inflammatory and endothelial markers in young obese pediatric patients. METHODS: This is achieved by recruitment of 60 young (13-17 years) obese pediatric cohorts who are further subclassified according to their stage of hypertension; normotensive, prehypertensive and hypertensive patients. RESULTS: The study showed significant differences in the metabolic parameters (glucose, insulin and HOMA-index) among the three obese young patient groups. Levels of cortisol and aldosterone, as well as NT-proBNP levels are positively associated with characteristics of the metabolic syndrome; blood pressure, BMI, HOMA index in all three obese groups. However, their association to the lipid profile was insignificant. These increases aligned harmonically with the assessed immune-inflammatory markers; CRP, TNF-alpha, and IL-23, as well as levels of sICAM, sVCAM and p-selectin, reflecting the involvement of mast cells and inflammatory effects on the vascular endothelium. ROC analysis revealed their beneficial addition as promising biomarkers for a better prognostic profile of hypertension-induced cardiovascular risk. CONCLUSION: Early detection of NT proBNP, cortisol and aldosterone levels in pre-hypertension stage added to the immune-inflammatory mediators may improve the coronary risk assessment in young Egyptian patients. PMID- 27478510 TI - Comparison between adherence assessments and blood glucose monitoring measures to predict glycemic control in adults with type 1 diabetes: a cross-sectional study. AB - BACKGROUND: Adherence to treatment has been defined as the degree to which a patient's behavior corresponds to medical or health advice; however, the most appropriate method to evaluate adherence to diabetes care has yet to be identified. We conducted analyses to compare adherence assessments and blood glucose monitoring measures with regard to their ability to predict glycemic control in adults with type 1 diabetes. METHODS: We analyzed four instruments to evaluate adherence: Self-Care Inventory-Revised, a self-administered survey; Diabetes Self-Monitoring Profile (DSMP), administered by trained researchers; a categorical (yes/no/sometimes) adherence self-evaluation; and a continuous (0 100) adherence self-evaluation. Blood glucose monitoring frequency was evaluated by self-report, diary, and meter download. RESULTS: Participants (n = 82) were aged 39.0 +/- 13.1 years with a mean diabetes duration of 21.2 +/- 11.1 years; 27 % monitored blood glucose >4 times/day. The DSMP score was the strongest predictor of glycemic control (r = -0.32, P = 0.004) among adherence assessments, while blood glucose monitoring frequency assessed by meter download was the strongest predictor among blood glucose monitoring measures (r = -40, P < 0.001). All the self-report assessments had a significant but weak correlation with glycemic control (r <= 0.28, P <= 0.02). The final adjusted model identified the assessment of blood glucose monitoring frequency by meter download as the most robust predictor of HbA1c (estimate effect size = -0.58, P = 0.003). CONCLUSIONS: In efforts to evaluate adherence, blood glucose monitoring frequency assessed by meter download has the strongest relationship with glycemic control in adults with type 1 diabetes. PMID- 27478511 TI - Methylation quantitative trait loci within the TOMM20 gene are associated with metabolic syndrome-related lipid alterations in severely obese subjects. AB - BACKGROUND: The TOMM20 gene was previously identified as differentially expressed and methylated between severely obese subjects with and without metabolic syndrome (MS). Since metabolic complications do not affect all obese patients to the same extent, the aim of this study was to identify methylation quantitative trait loci (meQTL) potentially associated with MS-related complications within the TOMM20 locus. METHODS: Methylation profiling, SNP genotyping and meQTL association tests (general linear models) were performed in a population of 48 severely obese subjects. Genotyping was extended to a larger population of 1720 severely obese subjects with or without MS, where genotype- and diplotype-based association tests were assessed by logistic regression. In silico analyses were performed using TRAP. RESULTS: Four SNPs were identified as significant meQTLs for the differentially methylated site cg16490124. Individuals carrying rare alleles of rs4567344 (A > G) (P = 4.9 * 10(-2)) and rs11301 (T > C) (P = 5.9 * 10(-3)) showed decreased methylation levels at this site, whereas those carrying rare alleles of rs4551650 (T > C) (P = 3.5 * 10(-15)) and rs17523127 (C > G) (P = 3.5 * 10(-15)) exhibited a significant increase in methylation. rs4567344 and rs11301 were associated with increased susceptibility to exhibit high plasma triglycerides (TG >= 1.69 mmol/L), while rare alleles of rs4551650 and rs17523127 were significantly more represented in the low plasma total-C group (total-C <= 6.2 mmol/L). Haplotype reconstruction with the four meQTLs (rs4567344, rs11301, rs4551650, rs17523127) led to the identification of ten different diplotypes, with H1/H2 (GCGG/ACGG) exhibiting a nearly absence of methylation at cg16490124, and showing the highest risk of elevated plasma TG levels [OR = 2.03 (1.59 3.59)], a novel association with elevated LDL-cholesterol [OR = 1.86 (1.06-3.27)] and the complete inversion of the protective effect on total-C levels [OR = 2.03 (1.59-3.59)], especially in men. In silico analyses revealed that rs17523127 overlapped the CpG site cg16490124 and encompassed the core binding sites of the transcription factors Egr 1, 2 and 3, located within the TOMM20 promoter region. CONCLUSION: This study demonstrates that TOMM20 SNPs associated with MS-related lipid alterations are meQTLs potentially exerting their action through a CpG methylation-dependent effect. The strength of the diplotype-based associations may denote a novel meQTL additive action and point to this locus as particularly relevant in the inter-individual variability observed in the metabolic profiles of obese subjects. PMID- 27478512 TI - Identification of polymorphic SVA retrotransposons using a mobile element scanning method for SVA (ME-Scan-SVA). AB - BACKGROUND: Mobile element insertions are a major source of human genomic variation. SVA (SINE-R/VNTR/Alu) is the youngest retrotransposon family in the human genome and a number of diseases are known to be caused by SVA insertions. However, inter-individual genomic variations generated by SVA insertions and their impacts have not been studied extensively due to the difficulty in identifying polymorphic SVA insertions. RESULTS: To systematically identify SVA insertions at the population level and assess their genomic impact, we developed a mobile element scanning (ME-Scan) protocol we called ME-Scan-SVA. Using a nested SVA-specific PCR enrichment method, ME-Scan-SVA selectively amplify the 5' end of SVA elements and their flanking genomic regions. To demonstrate the utility of the protocol, we constructed and sequenced a ME-Scan-SVA library of 21 individuals and analyzed the data using a new analysis pipeline designed for the protocol. Overall, the method achieved high SVA-specificity and over >90 % of the sequenced reads are from SVA insertions. The method also had high sensitivity (>90 %) for fixed SVA insertions that contain the SVA-specific primer-binding sites in the reference genome. Using candidate locus selection criteria that are expected to have a 90 % sensitivity, we identified 151 and 29 novel polymorphic SVA candidates under relaxed and stringent cutoffs, respectively (average 12 and 2 per individual). For six polymorphic SVAs that we were able to validate by PCR, the average individual genotype accuracy is 92 %, demonstrating a high accuracy of the computational genotype calling pipeline. CONCLUSIONS: The new approach allows identifying novel SVA insertions using high-throughput sequencing. It is cost-effective and can be applied in large-scale population study. It also can be applied for detecting potential active SVA elements, and somatic SVA retrotransposition events in different tissues or developmental stages. PMID- 27478513 TI - Core functionalization of semi-crystalline polymeric cylindrical nanoparticles using photo-initiated thiol-ene radical reactions. AB - Sequential ring-opening and reversible addition-fragmentation chain transfer (RAFT) polymerization was used to form a triblock copolymer of tetrahydropyran acrylate (THPA), 5-methyl-5-allyloxycarbonyl-1,3-dioxan-2-one (MAC) and l lactide. Concurrent deprotection of the THPA block and crystallization-driven self-assembly (CDSA) was undertaken and allowed for the formation of cylindrical micelles bearing allyl handles in a short outer core segment. These handles were further functionalized by different thiols using photo-initiated thiol-ene radical reactions to demonstrate that the incorporation of an amorphous PMAC block within the core does not disrupt CDSA and can be used to load the cylindrical nanoparticles with cargo. PMID- 27478515 TI - The Anophthalmic Socket - Reconstruction Options. AB - Keeping the eye is impossible, functionality is lost and aesthetic requirements are high. What do we do? Which approach is right? This is the dilemma we face whenenucleation or evisceration are unavoidable. The patient loses a sensory organ with a very important function and, at the same time, is faced with a major aesthetic defect, leading to significant anxiety. The purpose of this article is to describe the different reconstruction techniques for anophthalmic sockets. In preparing the anopthalmic socket for prosthesis fitting we have several options: dermis-fat graft with a very good biocompatibility, the Guthoff artificial implant, which provides better motility or the methyl methacrylate implant inside the muscle cone. Each option has advantages and disadvantages but the choice of technique should be adapted to the needs and expectations of the patient, taking into account both time and cost. PMID- 27478514 TI - Physical activity, nutritional status, and dietary habits of students of a medical university. AB - Nutritional habits and physical activity influence the health status of young adults. In this study, we engaged a group of 151 students from a medical university (90 female and 61 male subjects). Anthropometric parameters, dietary habits (a 7-day dietary recall), and level of physical activity were measured. It was found that the daily food rations of female (F) and male (M) students were improperly balanced and characterized by high amount of total and animal protein, phosphorus, vitamin A, cholesterol, and insufficient intake of carbohydrates, dietary fiber, and vitamin C. Female subjects consumed low amounts of total fat and calcium. The intake of protein (total and animal), fat, phosphorus, and cholesterol correlated with higher body mass. The physical activity of the students was found to be higher than the average physical activity of the European Union populations, and a general tendency of lowering level of physical activity with age was observed. Students with the highest level of physical activity (MET > 1500) consumed lower amounts of simple carbohydrates (galactose and saccharose) when compared to students with lower physical activity (MET < 600, p < 0.05). Therefore, this study concluded that the dietary habits should be modified to prevent the development of diet-dependent diseases. Various forms of physical activity should be proposed to students and they should be encouraged to participate in high level of physical activity so as to promote good health status. PMID- 27478516 TI - Informed Consent in Asymmetrical Relationships: an Investigation into Relational Factors that Influence Room for Reflection. AB - In recent years, informed consent has been suggested as a way to deal with risks posed by engineered nanomaterials. We argue that while we can learn from experiences with informed consent in treatment and research contexts, we should be aware that informed consent traditionally pertains to certain features of the relationships between doctors and patients and researchers and research participants, rather than those between producers and consumers and employers and employees, which are more prominent in the case of engineered nanomaterials. To better understand these differences, we identify three major relational factors that influence whether valid informed consent is obtainable, namely dependency, personal proximity, and existence of shared interests. We show that each type of relationship offers different opportunities for reflection and therefore poses distinct challenges for obtaining valid informed consent. Our analysis offers a systematic understanding of the possibilities for attaining informed consent in the context of nanomaterial risks and makes clear that measures or regulations to improve the obtainment of informed consent should be attuned to the specific interpersonal relations to which it is supposed to apply. PMID- 27478517 TI - Responsible, Inclusive Innovation and the Nano-Divide. AB - Policy makers from around the world are trying to emulate successful innovation systems in order to support economic growth. At the same time, innovation governance systems are being put in place to ensure a better integration of stakeholder views into the research and development process. In Europe, one of the most prominent and newly emerging governance frameworks is called Responsible Research and Innovation (RRI). This article aims to substantiate the following points: (1) The concept of RRI and the concept of justice can be used to derive similar ethical positions on the nano-divide. (2) Given the ambitious policy aims of RRI (e.g. economic competitiveness enhancer), the concept may be better suited to push for ethical outcomes on access to nanotechnology and its products rather than debates based on justice issues alone. It may thus serve as a mediator concept between those who push solely for competitiveness considerations and those who push solely for justice considerations in nano-technology debates. (3) The descriptive, non-normative Systems of Innovation approaches (see below) should be linked into RRI debates to provide more evidence on whether the approach advocated to achieve responsible and ethical governance of research and innovation (R&I) can indeed deliver on competitiveness (in nano-technology and other fields). PMID- 27478518 TI - Comparison Between Pathogen Associated Laboratory and Clinical Parameters in Early-Onset Sepsis of the Newborn. AB - OBJECTIVES: To identify laboratory and clinical characteristics of different pathogens associated with early-onset sepsis (EOS) of the newborn. METHODS: Newborns with EOS were retrospectively analyzed regarding laboratory and clinical parameters associated with the identified pathogen. RESULTS: We identified 125 newborns having diagnosis of culture proven EOS between 1993 and 2011. One hundred cases had diagnosis of group B streptococci (GBS) infection (80%), 11 had Escherichia coli (8.8%), eight enterococci (6.4%), and six other pathogens (4.8%). White blood cell count (WBC), immature to total neutrophil (IT) ratio, and C-reactive protein (CRP) values did not differ between groups within the first 72 hours of life. Presence of high (>30000/uL) and low (<9000/ul) WBC was significantly less found compared with IT-ratio >0.2 in GBS and E.coli EOS. High WBC were more common found than low WBC in all groups. Gram positive pathogens were more common found in late preterm and term infants (84%), and gram negative pathogens more common in very low birth weight infants (64%). E. coli was significantly associated with lower gestational age and birth weight, respectively. CONCLUSION: An abnormal IT-ratio was a more common finding than an abnormal WBC in GBS and E. coli EOS. E. coli was significantly associated with prematurity. PMID- 27478519 TI - Biomedical Big Data Training Collaborative (BBDTC): An effort to bridge the talent gap in biomedical science and research. AB - The BBDTC (https://biobigdata.ucsd.edu) is a community-oriented platform to encourage high-quality knowledge dissemination with the aim of growing a well informed biomedical big data community through collaborative efforts on training and education. The BBDTC collaborative is an e-learning platform that supports the biomedical community to access, develop and deploy open training materials. The BBDTC supports Big Data skill training for biomedical scientists at all levels, and from varied backgrounds. The natural hierarchy of courses allows them to be broken into and handled as modules. Modules can be reused in the context of multiple courses and reshuffled, producing a new and different, dynamic course called a playlist. Users may create playlists to suit their learning requirements and share it with individual users or the wider public. BBDTC leverages the maturity and design of the HUBzero content-management platform for delivering educational content. To facilitate the migration of existing content, the BBDTC supports importing and exporting course material from the edX platform. Migration tools will be extended in the future to support other platforms. Hands-on training software packages, i.e., toolboxes, are supported through Amazon EC2 and Virtualbox virtualization technologies, and they are available as: (i) downloadable lightweight Virtualbox Images providing a standardized software tool environment with software packages and test data on their personal machines, and (ii) remotely accessible Amazon EC2 Virtual Machines for accessing biomedical big data tools and scalable big data experiments. At the moment, the BBDTC site contains three open Biomedical big data training courses with lecture contents, videos and hands-on training utilizing VM toolboxes, covering diverse topics. The courses have enhanced the hands-on learning environment by providing structured content that users can use at their own pace. A four course biomedical big data series is planned for development in 2016. PMID- 27478520 TI - The Method of Randomization for Cluster-Randomized Trials: Challenges of Including Patients with Multiple Chronic Conditions. AB - Cluster-randomized clinical trials (CRT) are trials in which the unit of randomization is not a participant but a group (e.g. healthcare systems or community centers). They are suitable when the intervention applies naturally to the cluster (e.g. healthcare policy); when lack of independence among participants may occur (e.g. nursing home hygiene); or when it is most ethical to apply an intervention to all within a group (e.g. school-level immunization). Because participants in the same cluster receive the same intervention, CRT may approximate clinical practice, and may produce generalizable findings. However, when not properly designed or interpreted, CRT may induce biased results. CRT designs have features that add complexity to statistical estimation and inference. Chief among these is the cluster-level correlation in response measurements induced by the randomization. A critical consideration is the experimental unit of inference; often it is desirable to consider intervention effects at the level of the individual rather than the cluster. Finally, given that the number of clusters available may be limited, simple forms of randomization may not achieve balance between intervention and control arms at either the cluster- or participant-level. In non-clustered clinical trials, balance of key factors may be easier to achieve because the sample can be homogenous by exclusion of participants with multiple chronic conditions (MCC). CRTs, which are often pragmatic, may eschew such restrictions. Failure to account for imbalance may induce bias and reducing validity. This article focuses on the complexities of randomization in the design of CRTs, such as the inclusion of patients with MCC, and imbalances in covariate factors across clusters. PMID- 27478522 TI - Extra dissipation and flow uniformization due to elastic instabilities of shear thinning polymer solutions in model porous media. AB - We study flows of hydrolized polyacrylamide solutions in two dimensional porous media made using microfluidics, for which elastic effects are dominant. We focus on semi-dilute solutions (0.1%-0.4%) which exhibit a strong shear thinning behavior. We systematically measure the pressure drop and find that the effective permeability is dramatically higher than predicted when the Weissenberg number is greater than about 10. Observations of the streamlines of the flow reveal that this effect coincides with the onset of elastic instabilities. Moreover, and importantly for applications, we show using local measurements that the mean flow is modified: it appears to be more uniform at high Weissenberg number than for Newtonian fluids. These observations are compared and discussed using pore network simulations, which account for the effect of disorder and shear thinning on the flow properties. PMID- 27478521 TI - Microfluidic viscometers for shear rheology of complex fluids and biofluids. AB - The rich diversity of man-made complex fluids and naturally occurring biofluids is opening up new opportunities for investigating their flow behavior and characterizing their rheological properties. Steady shear viscosity is undoubtedly the most widely characterized material property of these fluids. Although widely adopted, macroscale rheometers are limited by sample volumes, access to high shear rates, hydrodynamic instabilities, and interfacial artifacts. Currently, microfluidic devices are capable of handling low sample volumes, providing precision control of flow and channel geometry, enabling a high degree of multiplexing and automation, and integrating flow visualization and optical techniques. These intrinsic advantages of microfluidics have made it especially suitable for the steady shear rheology of complex fluids. In this paper, we review the use of microfluidics for conducting shear viscometry of complex fluids and biofluids with a focus on viscosity curves as a function of shear rate. We discuss the physical principles underlying different microfluidic viscometers, their unique features and limits of operation. This compilation of technological options will potentially serve in promoting the benefits of microfluidic viscometry along with evincing further interest and research in this area. We intend that this review will aid researchers handling and studying complex fluids in selecting and adopting microfluidic viscometers based on their needs. We conclude with challenges and future directions in microfluidic rheometry of complex fluids and biofluids. PMID- 27478523 TI - Microfluidic converging/diverging channels optimised for homogeneous extensional deformation. AB - In this work, we optimise microfluidic converging/diverging geometries in order to produce constant strain-rates along the centreline of the flow, for performing studies under homogeneous extension. The design is examined for both two dimensional and three-dimensional flows where the effects of aspect ratio and dimensionless contraction length are investigated. Initially, pressure driven flows of Newtonian fluids under creeping flow conditions are considered, which is a reasonable approximation in microfluidics, and the limits of the applicability of the design in terms of Reynolds numbers are investigated. The optimised geometry is then used for studying the flow of viscoelastic fluids and the practical limitations in terms of Weissenberg number are reported. Furthermore, the optimisation strategy is also applied for electro-osmotic driven flows, where the development of a plug-like velocity profile allows for a wider region of homogeneous extensional deformation in the flow field. PMID- 27478524 TI - Rheology of clustering protein solutions. AB - High viscosity is a major challenge with protein therapeutics at extremely high concentrations. To overcome this obstacle, it is essential to understand the relationship between the concentration of a protein solution and its viscosity as a function of shear rate and temperature. Here, lysozyme is a model charged globular protein having both short-ranged attraction (SA) and long-ranged repulsion (LR) that promote the formation of dynamic clusters at high concentrations. We report viscosity measurements from a micro-capillary rheometer (using only several microliters of solution) over a wide range of lysozyme solution concentrations, shear rates, and temperatures. Solution structural relaxation dynamics are also probed by dynamic light scattering (DLS). As a result of lysozyme's SALR interactions, the viscosity increased dramatically across all shear rates with increasing concentration and decreasing temperature. While most of the solutions exhibited Newtonian behavior, shear thinning was exhibited at the highest concentration (480 g/l) and lowest temperatures at shear rates above approximately 10(4 )s(-1). The onset shear rate for thinning and a structural relaxation rate estimated from a slow-mode measured by DLS are compared. These measurements provide insights into the properties of protein solutions and their microscopic structural origins. PMID- 27478525 TI - Introducing natural thermoplastic shellac to microfluidics: A green fabrication method for point-of-care devices. AB - We present a sustainable fabrication method for cheap point-of-care microfluidic systems, employing hot embossing of natural shellac as a key feature of an energy efficient fabrication method that exclusively uses renewable materials as consumables. Shellac is a low-cost renewable biomaterial that features medium hydrophilicity (e.g., a water contact angle of ca. 73 degrees ) and a high chemical stability with respect to common solvents such as cyclohexane or toluene, rendering it an interesting candidate for low-cost microfluidics and a competitor to well-known systems such as paper-based or polydimethylsiloxane based microfluidics. Moreover, its high replication accuracy for small features down to 30 MUm lateral feature size and its ability to form smooth surfaces (surface roughness Ra = 29 nm) at low embossing temperatures (glass transition temperature Tg = 42.2 degrees C) enable energy-efficient hot embossing of microfluidic structures. Proof-of-concept for the implementation of shellac hot embossing as a green fabrication method for microfluidic systems is demonstrated through the successful fabrication of a microfluidic test setup and the assessment of its resource consumption. PMID- 27478526 TI - An integrative microfluidically supported in vitro model of an endothelial barrier combined with cortical spheroids simulates effects of neuroinflammation in neocortex development. AB - The development of therapeutic substances to treat diseases of the central nervous system is hampered by the tightness and selectivity of the blood-brain barrier. Moreover, testing of potential drugs is time-consuming and cost intensive. Here, we established a new microfluidically supported, biochip-based model of the brain endothelial barrier in combination with brain cortical spheroids suitable to detect effects of neuroinflammation upon disruption of the endothelial layer in response to inflammatory signals. Unilateral perfusion of the endothelial cell layer with a cytokine mix comprising tumor necrosis factor, IL-1beta, IFNgamma, and lipopolysaccharide resulted in a loss of endothelial von Willebrand factor and VE-cadherin expression accompanied with an increased leakage of the endothelial layer and diminished endothelial cell viability. In addition, cytokine treatment caused a loss of neocortex differentiation markers Tbr1, Tbr2, and Pax6 in the cortical spheroids concomitant with reduced cell viability and spheroid integrity. From these observations, we conclude that our endothelial barrier/cortex model is suitable to specifically reflect cytokine induced effects on barrier integrity and to uncover damage and impairment of cortical tissue development and viability. With all its limitations, the model represents a novel tool to study cross-communication between the brain endothelial barrier and underlying cortical tissue that can be utilized for toxicity and drug screening studies focusing on inflammation and neocortex formation. PMID- 27478527 TI - Magnetofluidic concentration and separation of non-magnetic particles using two magnet arrays. AB - The present paper reports the use of diluted ferrofluid and two arrays of permanent magnets for the size-selective concentration of non-magnetic particles. The micro magnetofluidic device consists of a straight channels sandwiched between two arrays of permanent magnets. The permanent magnets create multiple capture zones with minimum magnetic field strength along the channel. The complex interaction between magnetic forces and hydrodynamic force allows the device to operate in different regimes suitable for concentration of non-magnetic particles with small difference in size. Our experimental results show that non-magnetic particles with diameters of 3.1 MUm and 4.8 MUm can be discriminated and separated with this method. The results from this study could be used as a guide for the design of size-sensitive separation devices for particle and cell based on negative magnetophoresis. PMID- 27478528 TI - Embedding objects during 3D printing to add new functionalities. AB - A novel method for integrating and embedding objects to add new functionalities during 3D printing based on fused deposition modeling (FDM) (also known as fused filament fabrication or molten polymer deposition) is presented. Unlike typical 3D printing, FDM-based 3D printing could allow objects to be integrated and embedded during 3D printing and the FDM-based 3D printed devices do not typically require any post-processing and finishing. Thus, various fluidic devices with integrated glass cover slips or polystyrene films with and without an embedded porous membrane, and optical devices with embedded Corning((r)) FibranceTM Light Diffusing Fiber were 3D printed to demonstrate the versatility of the FDM-based 3D printing and embedding method. Fluid perfusion flow experiments with a blue colored food dye solution were used to visually confirm fluid flow and/or fluid perfusion through the embedded porous membrane in the 3D printed fluidic devices. Similar to typical 3D printed devices, FDM-based 3D printed devices are translucent at best unless post-polishing is performed and optical transparency is highly desirable in any fluidic devices; integrated glass cover slips or polystyrene films would provide a perfect optical transparent window for observation and visualization. In addition, they also provide a compatible flat smooth surface for biological or biomolecular applications. The 3D printed fluidic devices with an embedded porous membrane are applicable to biological or chemical applications such as continuous perfusion cell culture or biocatalytic synthesis but without the need for any post-device assembly and finishing. The 3D printed devices with embedded Corning((r)) FibranceTM Light-Diffusing Fiber would have applications in display, illumination, or optical applications. Furthermore, the FDM-based 3D printing and embedding method could also be utilized to print casting molds with an integrated glass bottom for polydimethylsiloxane (PDMS) device replication. These 3D printed glass bottom casting molds would result in PDMS replicas with a flat smooth bottom surface for better bonding and adhesion. PMID- 27478529 TI - Single cell functional analysis of multiple myeloma cell populations correlates with diffusion profiles in static microfluidic coculture systems. AB - Microfluidic cell culture systems are becoming increasingly useful for studying biology questions, particularly those involving small cell populations that are cultured within microscale geometries mimicking the complex cellular microenvironment. Depending on the geometry and spatial organization of these cell populations, however, paracrine signaling between cell types can depend critically on spatial concentration profiles of soluble factors generated by diffusive transport. In scenarios where single cell data are acquired to study cell population heterogeneities in functional response, uncertainty associated with concentration profiles can lead to interpretation bias. To address this issue and provide important evidence on how diffusion develops within typical microfluidic cell culture systems, a combination of experimental and computational approaches were applied to measure and predict concentration patterns within microfluidic geometries, and characterize the functional response of culture cells based on single-cell resolution transcription factor activation. Using a model coculture system consisting of multiple myeloma cells (MMCs) and neighboring bone marrow stromal cells (BMSCs), we measured concentrations of three cytokines (IL-6, VEGF, and TNF-alpha) in conditioned media collected from separate culture compartments using a multiplex ELISA system. A 3D numerical model was developed to predict biomolecular diffusion and resulting concentration profiles within the tested microsystems and compared with experimental diffusion of 20 kDa FITC-Dextran. Finally, diffusion was further characterized by controlling exogenous IL-6 diffusion and the coculture spatial configuration of BMSCs to stimulate STAT3 nuclear translocation in MMCs. Results showed agreement between numerical and experimental results, provided evidence of a shallow concentration gradient across the center well of the microsystem that did not lead to a bias in results, and demonstrated that microfluidic systems can be tailored with specific geometries to avoid spatial bias when desired. PMID- 27478530 TI - Ankle Spatting Compared to Bracing or Taping during Maximal-Effort Sprint Drills. AB - The purpose of this study was to compare the influences of 4 ankle conditions (no support, bracing, taping, taping + spatting; all in football cleats) during 2 maximal-effort field drills (40-yd dash and 34-yd cutting drill) on perceptions of comfort and stability and performance outcomes. Fourteen young adult males participated. Subjects' perceptions of comfort and stability were assessed by visual analogue scales after each drill for each ankle condition. Time-to completion and post-completion heart rate were recorded. For both drills, significant differences in comfort perception were found such that subjects perceived no support as equivocal to bracing but more comfortable than either taping or spatting + taping. Stability results differed by drill. For the dash, significant differences in stability perception were found such that subjects perceived no support as equivocal to bracing but less stable than either taping or spatting + taping. By contrast, for the cutting drill significant differences in stability perception were found such that subjects perceived their ankles as less stable during the no support condition as compared to all 3 other conditions. Generally, bracing was perceived as equivocal to all 3 other conditions for comfort and stability. There were no significant differences in time-to-completion or heart rate for any comparison. Compared to bracing or taping, spatting + taping (a) did not influence performance time in explosive/sprint-type drills, (b) was perceived as equivalent to taping alone in terms of ankle comfort and stability, and PMID- 27478532 TI - Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones. AB - Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H2S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H2S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H2S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H2S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H2S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H2S in hepatic glucose output and adipose glucose uptake. The mechanism of H2S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H2S in other metabolic and glucoregulatory hormone secreting tissues are proposed. PMID- 27478533 TI - Mitochondrial Health in Aging and Age-Related Metabolic Disease. PMID- 27478534 TI - Protective Effects of Soy Oligopeptides in Ultraviolet B-Induced Acute Photodamage of Human Skin. AB - Aim. We explored the effects of soy oligopeptides (SOP) in ultraviolet B- (UVB-) induced acute photodamage of human skin in vivo and foreskin ex vivo. Methods. We irradiated the forearm with 1.5 minimal erythemal dose (MED) of UVB for 3 consecutive days, establishing acute photodamage of skin, and topically applied SOP. Erythema index (EI), melanin index, stratum corneum hydration, and transepidermal water loss were measured by using Multiprobe Adapter 9 device. We irradiated foreskin ex vivo with the same dose of UVB (180 mJ/cm(2)) for 3 consecutive days and topically applied SOP. Sunburn cells were detected by using hematoxylin and eosin staining. Apoptotic cells were detected by using terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Cyclobutane pyrimidine dimers (CPDs), p53 protein, Bax protein, and Bcl-2 protein were detected by using immunohistochemical staining. Results. Compared with UVB group, UVB-irradiated skin with topically applied SOP showed significantly decreased EI. Compared with UVB group, topical SOP significantly increased Bcl-2 protein expression and decreased CPDs-positive cells, sunburn cells, apoptotic cells, p53 protein expression, and Bax protein expressions in the epidermis of UVB-irradiated foreskin. Conclusion. Our study demonstrated that topical SOP can protect human skin against UVB-induced photodamage. PMID- 27478536 TI - New horizon for radical cure of chronic hepatitis B virus infection. AB - About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalently-closed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-gamma and tumor necrosis factor-alpha, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection. PMID- 27478535 TI - Bioactivity of Polyphenols: Preventive and Adjuvant Strategies toward Reducing Inflammatory Bowel Diseases-Promises, Perspectives, and Pitfalls. AB - Inflammatory bowel diseases (IBDs) are characterized by autoimmune and inflammation-related complications of the large intestine (ulcerative colitis) and additional parts of the digestive tract (Crohn's disease). Complications include pain, diarrhoea, chronic inflammation, and cancer. IBD prevalence has increased during the past decades, especially in Westernized countries, being as high as 1%. As prognosis is poor and medication often ineffective or causing side effects, additional preventive/adjuvant strategies are sought. A possible approach is via diets rich in protective constituents. Polyphenols, the most abundant phytochemicals, have been associated with anti-inflammatory, antioxidant, immunomodulatory, and apoptotic properties. Locally reducing oxidative stress, they can further act on cellular targets, altering gene expression related to inflammation, including NF-kappaB, Nrf-2, Jak/STAT, and MAPKs, suppressing downstream cytokine formation (e.g., IL-8, IL-1beta, and TNF alpha), and boosting the bodies' own antioxidant status (HO-1, SOD, and GPx). Moreover, they may promote, as prebiotics, healthy microbiota (e.g., Bifidobacteria, Akkermansia), short-chain fatty acid formation, and reduced gut permeability/improved tight junction stability. However, potential adverse effects such as acting as prooxidants, or perturbations of efflux transporters and phase I/II metabolizing enzymes, with increased uptake of undesired xenobiotics, should also be considered. In this review, we summarize current knowledge around preventive and arbitrary actions of polyphenols targeting IBD. PMID- 27478537 TI - Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria. AB - Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria (MC) (single HCC <= 5 cm or up to 3 HCCs <= 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy (LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCC-LT criteria models and pre-LT treatment strategies are required. PMID- 27478538 TI - Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma. AB - Alpha-fetoprotein (AFP) is the main tumor biomarker available for the management of hepatocellular carcinoma (HCC). Although it is neither a good screening test nor an accurate diagnostic tool for HCC, it seems to be a possible prognostic marker. However, its contribution in liver transplantation for HCC has not been fully determined, although its use to predict recurrence after liver transplantation has been underlined by international societies. In an era of organ shortages, it could also have a key role in the selection of patients eligible for liver transplantation. Yet unanswered questions remain. First, the cut-off value of serum AFP above which liver transplantation should not be performed is still a subject of debate. We show that a concentration of 1000 ng/mL could be an exclusion criterion, whereas values of < 15 ng/mL indicate patients with an excellent prognosis whatever the size and number of tumors. Monitoring the dynamics of AFP could also prove useful. However, evidence is lacking regarding the values that should be used. Today, the real input of AFP seems to be its integration into new criteria to select patients eligible for a liver transplantation. These recent tools have associated AFP values with morphological criteria, thus refining pre-existing criteria, such as Milan, University of California, San Francisco, or "up-to-seven". We provide a review of the different criteria submitted within the past years. Finally, AFP can be used to monitor recurrence after transplantation, although there is little evidence to support this claim. Future challenges will be to draft new international guidelines to implement the use of AFP as a selection tool, and to determine a clear cut-off value above which liver transplantation should not be performed. PMID- 27478540 TI - Anti-hepatitis C virus potency of a new autophagy inhibitor using human liver slices model. AB - AIM: To evaluate the antiviral potency of a new anti-hepatitis C virus (HCV) antiviral agent targeting the cellular autophagy machinery. METHODS: Non-infected liver slices, obtained from human liver resection and cut in 350 MUm-thick slices (2.7 * 10(6) cells per slice) were infected with cell culture-grown HCV Con1b/C3 supernatant (multiplicity of infection = 0.1) cultivated for up to ten days. HCV infected slices were treated at day 4 post-infection with GNS-396 for 6 d at different concentrations. HCV replication was evaluated by strand-specific real time quantitative reverse transcription - polymerase chain reaction. The infectivity titers of supernatants were evaluated by foci formation upon inoculation into naive Huh-7.5.1 cells. The cytotoxic effect of the drugs was evaluated by lactate dehydrogenase leakage assays. RESULTS: The antiviral efficacy of a new antiviral drug, GNS-396, an autophagy inhibitor, on HCV infection of adult human liver slices was evidenced in a dose-dependent manner. At day 6 post-treatment, GNS-396 EC50 was 158 nmol/L without cytotoxic effect (compared to hydroxychloroquine EC50 = 1.17 MUmol/L). CONCLUSION: Our results demonstrated that our ex vivo model is efficient for evaluation the potency of autophagy inhibitors, in particular a new quinoline derivative GNS-396 as antiviral could inhibit HCV infection in a dose-dependent manner without cytotoxic effect. PMID- 27478539 TI - Acute renal injury after partial hepatectomy. AB - Currently, partial hepatectomy is the treatment of choice for a wide variety of liver and biliary conditions. Among the possible complications of partial hepatectomy, acute kidney injury (AKI) should be considered as an important cause of increased morbidity and postoperative mortality. Difficulties in the data analysis related to postoperative AKI after liver resections are mainly due to the multiplicity of factors to be considered in the surgical patients, moreover, there is no consensus of the exact definition of AKI after liver resection in the literature, which hampers comparison and analysis of the scarce data published on the subject. Despite this multiplicity of risk factors for postoperative AKI after partial hepatectomy, there are main factors that clearly contribute to its occurrence. First factor relates to large blood losses with renal hypoperfusion during the operation, second factor relates to the occurrence of post-hepatectomy liver failure with consequent distributive circulatory changes and hepatorenal syndrome. Eventually, patients can have more than one factor contributing to post operative AKI, and frequently these combinations of acute insults can be aggravated by sepsis or exposure to nephrotoxic drugs. PMID- 27478541 TI - Moral Chivalry: Gender and Harm Sensitivity Predict Costly Altruism. AB - Moral perceptions of harm and fairness are instrumental in guiding how an individual navigates moral challenges. Classic research documents that the gender of a target can affect how people deploy these perceptions of harm and fairness. Across multiple studies, we explore the effect of an individual's moral orientations (their considerations of harm and justice) and a target's gender on altruistic behavior. Results reveal that a target's gender can bias one's readiness to engage in harmful actions and that a decider's considerations of harm-but not fairness concerns-modulate costly altruism. Together, these data illustrate that moral choices are conditional on the social nature of the moral dyad: Even under the same moral constraints, a target's gender and a decider's gender can shift an individual's choice to be more or less altruistic, suggesting that gender bias and harm considerations play a significant role in moral cognition. PMID- 27478542 TI - Adenophora remotiflora protects human skin keratinocytes against UVB-induced photo-damage by regulating antioxidative activity and MMP-1 expression. AB - BACKGROUND/OBJECTIVES: Chronic ultraviolet (UV) exposure-induced reactive oxygen species (ROS) are commonly involved in the pathogenesis of skin damage by activating the metalloproteinases (MMP) that break down type I collagen. Adenophora remotiflora (AR) is a perennial wild plant that inhabits Korea, China, and Japan. The present study investigated the protective effects of AR against UVB-induced photo-damage in keratinocytes. MATERIALS/METHODS: An in vitro cell free system was used to examine the scavenging activity of 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radical and nitric oxide (NO). The effect of AR on ROS formation, antioxidant enzymes, elastase, MMP-1 level, and mRNA expression of MMP 1 were determined in UVB-irradiated human keratinocyte HaCaT cells. RESULTS: AR demonstrated strong DPPH free radical and NO scavenging activity in a cell-free system exhibiting IC50 values of 1.88 mg/mL and 6.77 mg/mL, respectively. AR pretreatment dose-dependently attenuated the production of UVB-induced intracellular ROS, and antioxidant enzymes (catalase and superoxide dismutase) were enhanced in HaCaT cells. Furthermore, pretreatment of AR prevented UVB induced elastase and collagen degradation by inhibiting the MMP-1 protein level and mRNA expression. Accordingly, AR treatment elevated collagen content in UVB irradiated HaCaT cells. CONCLUSION: The present study provides the first evidence of AR inhibiting UVB-induced ROS production and induction of MMP-1 as a result of augmentation of antioxidative activity in HaCaT human keratinocytes. These results suggest that AR might act as an effective inhibitor of UVB-modulated signaling pathways and might serve as a photo-protective agent. PMID- 27478543 TI - Involvement of miR-Let7A in inflammatory response and cell survival/apoptosis regulated by resveratrol in THP-1 macrophage. AB - BACKGROUND/OBJECTIVES: Resveratrol, a natural polyphenol, has multiple functions in cellular responses including apoptosis, survival, and differentiation. It also participates in the regulation of inflammatory response and oxidative stress. MicroRNA-Let-7A (miR-Let7A), known as a tumor suppressor miRNA, was recently reported to play a crucial role in both inflammation and apoptosis. Therefore, we examined involvement of miR-Let7A in the modulation of inflammation and cell survival/apoptosis regulated by resveratrol. MATERIALS/METHODS: mRNA expression of pro-/anti-inflammatory cytokines and sirtuin 1 (SIRT1), and protein expression of apoptosis signal-regulating kinase 1 (ASK1), p-ASK1, and caspase-3 and cleaved caspase-3 were measured, and cell viability and Hoechst/PI staining for apoptosis were observed in Lipopolysaccharide (LPS)-stimulated human THP-1 macrophages with the treatment of resveratrol and/or miR-Let7A overexpression. RESULTS: Pre treatment with resveratrol (25-200 uM) resulted in significant recovery of the reduced cell viabilities under LPS-induced inflammatory condition and in markedly increased expression of miR-Let7A in non-stimulated or LPS-stimulated cells. Increased mRNA levels of tumor necrosis factor-alpha and interleukin (IL)-6 induced by LPS were significantly attenuated, and decreased levels of IL-10 and brain-derived neurotrophic factor were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. Decreased expression of IL-4 mRNA by LPS stimulation was also significantly increased by miR-Let7A overexpression co-treated with resveratrol. In addition, decreased SIRT1 mRNA levels, and increased p-ASK1 levels and PI-positive cells by LPS stimulation were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. CONCLUSIONS: miR-Let7A may be involved in the inflammatory response and cell survival/apoptosis modulated by resveratrol in human THP-1 macrophages. PMID- 27478544 TI - Effects of disturbed liver growth and oxidative stress of high-fat diet-fed dams on cholesterol metabolism in offspring mice. AB - BACKGROUND/OBJECTIVES: Changes in nutritional status during gestation and lactation have detrimental effects on offspring metabolism. Several animal studies have shown that maternal high-fat diet (HFD) can predispose the offspring to development of obesity and metabolic diseases, however the mechanisms underlying these transgenerational effects are poorly understood. Therefore, we examined the effect of maternal HFD consumption on metabolic phenotype and hepatic expression of involved genes in dams to determine whether any of these parameters were associated with the metabolic outcomes in the offspring. MATERIALS/METHODS: Female C57BL/6 mice were fed a low-fat diet (LFD: 10% calories from fat) or a high-fat diet (HFD: 45% calories from fat) for three weeks before mating, and during pregnancy and lactation. Dams and their male offspring were studied at weaning. RESULTS: Dams fed an HFD had significantly higher body and adipose tissue weights and higher serum triglyceride and cholesterol levels than dams fed an LFD. Hepatic lipid levels and mRNA levels of genes involved in lipid metabolism, including LXRalpha, SREBP-2, FXR, LDLR, and ABCG8 were significantly changed by maternal HFD intake. Significantly lower total liver DNA and protein contents were observed in dams fed an HFD, implicating the disturbed liver adaptation in the pregnancy-related metabolic demand. HFD feeding also induced significant oxidative stress in serum and liver of dams. Offspring of dams fed an HFD had significantly higher serum cholesterol levels, which were negatively correlated with liver weights of dams and positively correlated with hepatic lipid peroxide levels in dams. CONCLUSIONS: Maternal HFD consumption induced metabolic dysfunction, including altered liver growth and oxidative stress in dams, which may contribute to the disturbed cholesterol homeostasis in the early life of male mice offspring. PMID- 27478545 TI - Therapeutic effects of dihydroartemisinin and transferrin against glioblastoma. AB - BACKGROUND/OBJECTIVES: Artemisinin, a natural product isolated from Gaeddongssuk (artemisia annua L.) and its main active derivative, dihydroartemisinin (DHA), have long been used as antimalarial drugs. Recent studies reported that artemisinin is efficacious for curing diseases, including cancers, and for improving the immune system. Many researchers have shown the therapeutic effects of artemisinin on tumors such as breast cancer, liver cancer and kidney cancer, but there is still insufficient data regarding glioblastoma (GBM). Glioblastoma accounts for 12-15% of brain cancer, and the median survival is less than a year, despite medical treatments such as surgery, radiation therapy, and chemotherapy. In this study, we investigated the anti-cancer effects of DHA and transferrin against glioblastoma (glioblastoma multiforme, GBM). MATERIALS/METHODS: This study was performed through in vitro experiments using C6 cells. The toxicity dependence of DHA and transferrin (TF) on time and concentration was analyzed by MTT assay and cell cycle assay. Observations of cellular morphology were recorded with an optical microscope and color digital camera. The anti-cancer mechanism of DHA and TF against GBM were studied by flow cytometry with Annexin V and caspase 3/7. RESULTS: MTT assay revealed that TF enhanced the cytotoxicity of DHA against C6 cells. An Annexin V immune-precipitation assay showed that the percentages of apoptosis of cells treated with TF, DHA alone, DHA in combination with TF, and the control group were 7.15 +/- 4.15%, 34.3 +/- 5.15%, 66.42 +/- 5.98%, and 1.2 +/- 0.15%, respectively. The results of the Annexin V assay were consistent with those of the MTT assay. DHA induced apoptosis in C6 cells through DNA damage, and TF enhanced the effects of DHA. CONCLUSION: The results of this study demonstrated that DHA, the derivative of the active ingredient in Gaeddongssuk, is effective against GBM, apparently via inhibition of cancer cell proliferation by a pharmacological effect. The role of transferrin as an allosteric activator in the GBM therapeutic efficacy of DHA was also confirmed. PMID- 27478531 TI - Role of ROS and RNS Sources in Physiological and Pathological Conditions. AB - There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis. PMID- 27478546 TI - Associations among plasma vitamin C, epidermal ceramide and clinical severity of atopic dermatitis. AB - BACKGROUND/OBJECTIVES: Atopic dermatitis (AD), a chronic inflammatory skin disease, is accompanied by disruption of the epidermal lipid barrier, of which ceramide (Cer) is the major component. Recently it was reported that vitamin C is essential for de novo synthesis of Cer in the epidermis and that the level of vitamin C in plasma is decreased in AD. The objective of this study was to determine the associations among clinical severity, vitamin C in either plasma or epidermis, and Cer in the epidermis of patients with AD. SUBJECTS/METHODS: A total of 17 patients (11 male and 6 female) aged 20-42 years were enrolled. The clinical severity of AD was assessed according to the SCORAD (SCORing Atopic Dermatitis) system. Levels of vitamin C were determined in plasma and biopsies of lesional epidermis. Levels of epidermal lipids, including Cer, were determined from tape-stripped lesional epidermis. RESULTS: The clinical severity of patients ranged between 0.1 and 45 (mild to severe AD) based on the SCORAD system. As the SCORAD score increased, the level of vitamin C in the plasma, but not in the epidermis, decreased, and levels of total Cer and Cer2, the major Cer species in the epidermis, also decreased. There was also a positive association between level of vitamin C in the plasma and level of total Cer in the epidermis. However, levels of epidermal total lipids including triglyceride, cholesterol, and free fatty acid (FFA) were not associated with either SCORAD score or level of vitamin C in the plasma of all subjects. CONCLUSIONS: As the clinical severity of AD increased, level of vitamin C in the plasma and level of epidermal Cer decreased, and there was a positive association between these two parameters, implying associations among plasma vitamin C, epidermal Cer, and the clinical severity of AD. PMID- 27478547 TI - Dietary inflammatory index is associated with serum C-reactive protein and protein energy wasting in hemodialysis patients: A cross-sectional study. AB - BACKGROUND/OBJECTIVE: Malnutrition and inflammation are reported as the most powerful predictors of mortality and morbidity in hemodialysis (HD) patients. Diet has a key role in modulating inflammation and dietary inflammatory index (DII) is a new tool for assessment of inflammatory potential of diet. The aim of this study was to evaluate the application of DII on dietary intake of HD patients and examine the associations between DII and malnutrition-inflammation markers. SUBJECTS/METHODS: A total of 105 subjects were recruited for this cross sectional study. Anthropometric measurements, 3-day dietary recall, and pre dialysis biochemical parameters were recorded for each subject. Subjective global assessment (SGA), which was previously validated for HD patients, and malnutrition inflammation score (MIS) were used for the diagnosis of protein energy wasting. DII was calculated according to average of 3-day dietary recall data. RESULTS: DII showed significant correlation with reliable malnutrition and inflammation indicators including SGA (r = 0.28, P < 0.01), MIS (r = 0.28, P < 0.01), and serum C-reactive protein (CRP) (r = 0.35, P < 0.001) in HD patients. When the study population was divided into three subgroups according to their DII score, significant increasing trends across the tertiles of DII were observed for SGA score (P = 0.035), serum CRP (P = 0.001), dietary energy (P < 0.001), total fat (P < 0.001), saturated fatty acids (P < 0.001), polyunsaturated fatty acids (P = 0.006), and omega-6 fatty acids (P = 0.01) intakes. CONCLUSION: This study shows that DII is a good tool for assessing the overall inflammatory potential of diet in HD patients. PMID- 27478548 TI - Leptin and uric acid as predictors of metabolic syndrome in jordanian adults. AB - BACKGROUND/OBJECTIVES: Metabolic syndrome (MetS) is a set of interrelated metabolic risk factors that increase the risk of cardiovascular morbidity and mortality. Studies regarding the specificity and sensitivity of serum levels of leptin and uric acid as predictors of MetS are limited. The aim of this study was to evaluate the serum levels of leptin and uric acid in terms of their specificity and sensitivity as predictors of MetS in the studied Jordanian group. SUBJECTS/METHODS: In this cross sectional study, 630 adult subjects (308 men and 322 women) were recruited from the King Hussein Medical Center (Amman, Jordan). The diagnosis of MetS was made according to the 2005 International Diabetes Federation criteria. Receiver operating characteristic curves were used to determine the efficacy of serum levels of leptin and uric acid as predictors of MetS in the studied Jordanian group. RESULTS: Study results showed that for identification of subjects with MetS risk, area under the curve (AUC) for leptin was 0.721 and 0.683 in men and women, respectively. Serum uric acid levels in men showed no significant association with any MetS risk factors and no significant AUC, while uric acid AUC was 0.706 in women. CONCLUSION: Serum leptin levels can be useful biomarkers for evaluation of the risk of MetS independent of baseline obesity in both men and women. On the other hand, serum uric acid levels predicted the risk of MetS only in women. PMID- 27478549 TI - The influence of obesity on the effects of spirulina supplementation in the human metabolic response of Korean elderly. AB - BACKGROUND/OBJECTIVES: Spirulina, a blue-green alga, is widely produced and commercialized as a dietary supplement with bio- and immune-modulatory functions. We have previously shown that spirulina had favorable effects on lipid profiles, immune functions, and antioxidant capacity in healthy Korean elderly. Despite favorable effect of spirulina supplementation, some sub-populations have shown a poor response to supplementation. Obesity is a factor related to poor-response. Therefore, the purpose of this study was to determine the immuno-modulation, antioxidant capacity, and lipid-lowering effect of spirulina in obese and non obese Korean elderly. SUBJECTS/METHODS: The subjects were 78 elderly aged 60-87 years. In a randomized double blind, placebo-controlled study, subjects were fed either placebo or spirulina daily, at 8 g for 12 weeks. Subjects were divided into the non-obese group and the obese group based on body mass index (BMI) criteria for Asians suggested by the International Obesity Task Force: BMI < 25 kg/m(2) (non-obese) and BMI >= 25 kg/m(2) (obese). RESULTS: In the non-obese group, spirulina supplementation showed a significant lowering effect on plasma concentration of total cholesterol and LDL-cholesterol, a significant increase in interleukin (IL)-2 concentration (P < 0.01) and a significant increment (P < 0.05) in IL-2/IL-6 ratio, and a significant increase in total antioxidant status level and a significant decrease in thiobarbituric acid reactive substances level. However, these effects were not observed in the obese group. CONCLUSIONS: These results demonstrated that blood lipid lowering and immune and antioxidant improving response for spirulina supplement was affected by obesity in Korean elderly. PMID- 27478550 TI - Perception and practice regarding allergen labeling: focus on food-related employees. AB - BACKGROUND/OBJECTIVES: Most consumers are able to recognize allergenic foods. However, the frequency of checking such foods is reportedly low, resulting in higher prevalence of food-related allergic reactions in Korea compared to other countries. Thus, this study was performed to investigate the overall perception of allergenic food labeling and its practice level in food manufacturing company employees. SUBJECTS/METHODS: The survey was administered to food safety employees and food development teams at food companies located in metropolitan areas. A total of 399 (93.8%) valid samples were used in the final analysis. Statistical analyses, including Frequency Analysis, t-test, Anova, PCA (Principal Component Analysis), and Pearson Correlation Analysis using SPSS ver. 21.0, were performed. RESULTS: The correct answer rate in the analysis of allergy-related knowledge level ranged from 15.0% to 89.7%. Analysis of differences in allergy-related perception by knowledge level showed significant differences in introduction of a food recall system, strengthening of relevant laws and regulations, content labeling, description of substitutional food, and differentiated package by age. CONCLUSIONS: It can be concluded that labeling of allergenic foods should be made easier and more convenient for checking by employees, developers, and consumers, and it is necessary to provide contents through the development of publicity, guidelines, or APP along with labeling. PMID- 27478551 TI - Development and evaluation of a dish-based semiquantitative food frequency questionnaire for Korean adolescents. AB - BACKGROUND/OBJECTIVES: The purpose of this study was to develop a dish-based semiquantitative food frequency questionnaire s(FFQ) for Korean adolescents and evaluate its reproducibility and validity. SUBJECTS/METHODS: Based on 24-hour dietary recall data from the 4th Korean National Health and Nutrition Examination Survey (KNHANES), we developed a FFQ with 71 items. From a quota sample of 160 adolescents recruited using gender and age group as stratification variables, 153 participated in the complete data collection process. The FFQ was administered to each subject twice, at an interval of 3-4 weeks, to evaluate the test-retest reliability. The validity of the FFQ was assessed relative to 8-day food record data. RESULTS: The study findings demonstrated the FFQ's satisfactory reproducibility. Spearman correlation coefficients ranged from 0.64(for beta carotene) to 0.81(for protein). From cross-classification analyses, the proportion of subjects in the same intake quartile was highest for protein (65.4%) and lowest for vitamin A(47.1%). With regard to validity analysis, Spearman correlation coefficients ranged from 0.27(for vitamin A and fiber) to 0.90 (for energy). The proportions of subjects in the opposite categories between the first FFQ and the 8-day food record data were generally low within the range from 0.74% (for energy and carbohydrate) to 13.2% (for alpha-carotene). CONCLUSIONS: In conclusion, the dish-based semiquantitative FFQ developed in this study can be useful for grouping Korean adolescents according to major macro- and micronutrient intakes with reasonable reproducibility and validity. PMID- 27478552 TI - A study on blood lipid profiles, aluminum and mercury levels in college students. AB - BACKGROUND/OBJECTIVES: College students are in a period of transition from adolescence to adulthood, in which proper dietary habits and balanced nutritional intake are very important. However, improper dietary habits and lifestyles can bring several health problems. This study was performed to investigate blood lipid profiles, blood aluminum and mercury in college students and the relationships among them. SUBJECTS/METHODS: The subjects were 80 college students (43 males and 37 females) in Gyeonggi-do. General characteristics, anthropometric measurements, blood pressure, blood lipids, SGOT, SGPT, and blood aluminum and mercury of the subjects were measured and analyzed, and their relationship was studied. RESULTS: The BMI was significantly higher in males, 23.69 +/- 3.20 kg/m(2), than in females, 20.38 +/- 2.37 kg/m(2) (P < 0.001). The blood pressure was significantly higher in males with 128.93 +/- 12.92 mmHg systolic pressure and 77.14 +/- 10.31 mmHg diastolic pressure compared to females with 109.78 +/- 11.97 mmHg and 65.95 +/- 6.92 mmHg, respectively (P < 0.001). HDL cholesterol in males, 61.88 +/- 13.06 mg/dl, was lower than 64.73 +/- 12.16 mg/dl in females, but other blood lipid levels were higher in males. Blood aluminum was significantly higher in males, 9.12 +/- 2.11 ug/L, than in females, 8.03 +/- 2.14 ug/L (P < 0.05), and blood mercury was higher in males, 3.08 +/- 1.55 ug/L, than in females, 2.64 +/- 1.49 ug/L. The blood lipids showed positive correlation with obesity and blood pressure. CONCLUSIONS: The degree of obesity, blood pressure, triglycerides, and LDL cholesterol were higher in males, suggesting possible association with chronic disease incidence such as hyperlipidemia and hypertension. Thus, it is considered that a systematic health education is needed for college students, especially for males. PMID- 27478553 TI - Nutritional aspects of night eating and its association with weight status among Korean adolescents. AB - BACKGROUND/OBJECTIVES: A growing body of research has indicated that night eating could be associated with poor diet quality and negative health outcomes. This study examined the nutritional aspects of night eating, its related factors, and the association between night eating and body weight among Korean adolescents. SUBJECTS/METHODS: This study analysed the data from a one day 24-hour dietary recall as well as a demographic survey of 1,738 Korean adolescents aged 12 to 18 years-old obtained from the 2010-2012 Korea National Health and Nutrition Examination Survey. 'Night eating' was defined as consuming 25% or more of one's daily energy intake between 21:00 and 06:00. Subjects complying with the preceding condition were classified as 'night eaters', whereas the rest were considered 'non-night eaters'. Logistic regression analysis examined factors related to night eating. Multiple linear regression analyses were used to examine the relationship between night eating and BMI z-scores, whereas multinomial logistic regression analysis was used to examine the relationship between night eating and weight status. RESULTS: About 21% of Korean adolescents appeared to be night eaters. Night eaters showed increased breakfast skipping (P = 0.001), higher energy intake from snacks (P < 0.001), greater proportion of energy intake from fat (P = 0.029), and lower Dietary Diversity Scores (P = 0.008) than non night eaters. Male adolescents presented 1.9 times higher odds of being night eaters than females. Adolescents whose both parents were night eaters were 4.4 times as likely to be night eaters as those whose neither parents were. Female adolescents showed a significant relationship between night eating and BMI z scores (beta = 0.28, P = 0.004). However, night eating did not increase odds of being overweight or obese in adolescents. CONCLUSIONS: Night eating in Korean adolescents was related to undesirable dietary behaviours and low diet quality in general as well as higher BMI z-scores in females. Male gender and parental night eating appeared to be the factors that significantly increased odds of night eating. These results suggest that night eating should be considered when designing nutrition education or intervention programs targeting adolescents. PMID- 27478555 TI - The Effects of industrial workers' food choice attribute on sugar intake pattern and job satisfaction with Structural Equcation Model. AB - BACKGROUND/OBJECTIVES: This research analyzes the effects of the food choices of industrial workers according to their sugar intake pattern on their job satisfaction through the construction of a model on the relationship between sugar intake pattern and job satisfaction. SUBJECTS/METHODS: Surveys were collected from May to July 2015. A statistical analysis of the 775 surveys from Kyungsangnam-do was conducted using SPSS13.0 for Windows and SEM was performed using the AMOS 5.0 statistics package. RESULTS: The reliability of the data was confirmed by an exploratory factor analysis through a Cronbach's alpha coefficient, and the measurement model was proven to be appropriate by a confirmatory factor analysis in conjunction with AMOS. The results of factor analysis on food choice, sugar intake pattern and job satisfaction were categorized into five categories. The reliability of these findings was supported by a Cronbach's alpha coefficient of 0.6 and higher for all factors except confection (0.516) and dairy products (0.570). The multicollinearity results did not indicate a problem between the variables since the highest correlation coefficient was 0.494 (P < 0.01). In an attempt to study the sugar intake pattern in accordance with the food choices and job satisfaction of industrial workers, a structural equation model was constructed and analyzed. CONCLUSIONS: All tests confirmed that the model satisfied the recommended levels for the goodness of fit index, and thus, the overall research model was proven to be appropriate. PMID- 27478554 TI - Evaluation of emotion-based messages designed to motivate Hispanic and Asian parents of early adolescents to engage in calcium-rich food and beverage parenting practices. AB - BACKGROUND/OBJECTIVES: Setting healthful beverage expectations, making calcium rich foods and beverages (CRF/B) available, and role modeling are parenting practices promoting calcium intake among early adolescents. This study aimed to evaluate emotion-based messages designed to motivate parents of early adolescents to perform these practices. SUBJECTS/METHODS: Emotion-based messages were developed for each parenting practice and tested in 35 parents from 5 states. Findings were used to modify messages and develop a survey administered via Amazon MechanicalTurk to a convenience sample of Asian (n = 166) and Hispanic (n = 184) parents of children 10-13 years. Main outcome measures were message comprehension, motivation, relevance, acceptability, and novelty. Engagement in the parenting practices was also assessed. RESULTS: Message comprehension was acceptable for the majority of parents. Most also agreed that messages were motivational (setting healthful beverage expectations (69.0%), making CRF/B available (67.4%), and role modeling (80.0%)), relevant and acceptable. About 30 50% indicated they had not seen the information before. Many parents indicated they were already engaging in the practices (> 70%). No racial/ethnic differences were observed for responses to messages or engaging in parenting practices. CONCLUSIONS: Results indicate that emotion-based messages designed to motivate parents to engage in parenting practices that promote calcium intake among early adolescents were motivating, relevant, and acceptable. PMID- 27478556 TI - Enteroviral Meningitis in Neonates and Children of Mashhad, Iran. AB - BACKGROUND: The highest incidence of meningitis occurs during the neonatal period and (then) infancy. Although Bacterial agents are the most dangerous cause of neonatal and childhood meningitis yet viruses especially, enteroviruses (EV), are by far the most common cause of meningitis in this age group. OBJECTIVES: The aim of the current study was to evaluate the role of EVs in neonatal and childhood meningitis in the Mashhad city of Iran. MATERIALS AND METHODS: This was a descriptive study that was performed at Imam Reza hospital in a period of six months (March to September 2007), during which all of the cerebral spinal fluid (CSF) samples from the neonatal intensive care unit (NICU) and pediatrics ward were collected and real time-polymerase chain reaction (RT-PCR) for EVs was done on these samples. Clinical data were collected retrospectively from hospital files. RESULTS: We collected 58 CSF samples (35 neonates and 23 children) during six months. Pleocytosis of CSF was seen in 51.1% of the subjects (28% of neonates, and 66.6% of infants and children). Enteroviruses PCR was positive in 37.1% (13) of neonates and 34.7% (8) of children. Pleocytosis of CSF was seen in 23% and 75% of EV positive neonates and children, respectively. Polymorphonuclear (PMN) dominance (PMN > 50%) of CSF was seen in 50% and 33% of EV positive neonates and children, respectively. There were three cases of bacterial meningitis in our group; EV PCR result was positive for one of these subjects. Concomitant bacterial infection (meningitis and sepsis) was seen in 9.5% (two cases) of EV positive CSFs in our study. Almost half of the available neonates (four of nine) with pure enteroviral meningitis (EVM) were discharged (in good condition) with final diagnosis of culture negative sepsis (CNS) and mean length of hospital stay (MLOS) of 4.3 days. One (12.5%) of the neonates with EVM, who had a very low birth weight (< 1500 mg), was expired, and two (25%) cases were discharged with brain damage and final diagnosis of severe asphyxia. The MLOS for children with pure EVM was 1.6 days (one to four days); they didn't have any sign of brain damage or mortality. Qualitative c-reactive protein (CRP) of serum was negative in 72.7% and 37.5% of EV positive neonates and children, respectively. The mean white blood cell count and PMN percentage in the peripheral blood was 11416/mm(3) and 60.8% for EV positive neonates, and 14500/mm(3) and 77.1% for EV positive children, respectively. Hyponatremia, due to possible syndrome of inappropriate antidiuretic hormone (SIADH), was seen in 30% of neonates and 57% of children with EVM. CONCLUSIONS: Enteroviruses were a common cause (> 30%) of meningitis in our study group. Concomitant bacterial infection is not rare in neonates and children with EVM. Many of the neonates (50%) and almost all of the children with EVM did not require prolonged hospitalization. Both normal CSF and PMN dominancy of CSF was common in neonates and children with EVM. Positive qualitative CRP of serum (up to two plus) was common especially in children with EVM. Non-symptomatic mild hyponatremia/SIADH was common in early life EVM. PMID- 27478557 TI - Observation of Network Dynamics of Ryanodine Receptors on Skeletal Muscle Sarcoplasmic Reticulum Membranes. AB - Rabbit muscle vesicles derived from sarcoplasmic reticulum were used as a material in studying networks of ryanodine receptors by cryo electron tomography. Three-dimensional analysis reveals the dynamical features of these networks. It was found that the connection angles were rotated along the transmembrane axis of ryanodine receptors. Majority of the connections was observed at domains 6/6 of ryanodine receptors while a small group of connections were showed at domains 9/10. The flexible rotation and connection shift seem to facilitate the extension of an annular network on the wall of the sarcoplasmic reticulum in a triad. PMID- 27478558 TI - Extensive Functional Evaluations to Monitor Aerobic Training in Becker Muscular Dystrophy: A Case Report. AB - Low-intensity aerobic training seems to have positive effects on muscle strength, endurance and fatigue in Becker Muscular Dystrophy (BMD) patients. We describe the case of a 33-year old BMD man, who performed a four-week aerobic training. Extensive functional evaluations were executed to monitor the efficacy of the rehabilitative treatment. Results evidenced an increased force exertion and an improvement in muscle contraction during sustained exercise. An improvement of walk velocity, together with agility, endurance capacity and oxygen consumption during exercise was observed. Moreover, an enhanced metabolic efficiency was evidenced, as shown by reduced lactate blood levels after training. Interestingly, CK showed higher levels after the training protocol, revealing possible muscle damage. In conclusion, aerobic training may represent an effective method improving exercise performance, functional status and metabolic efficiency. Anyway, a careful functional assessment should be taken into account as a useful approach in the management of the disease's rehabilitative treatment. PMID- 27478559 TI - Severely Atrophic Human Muscle Fibers With Nuclear Misplacement Survive Many Years of Permanent Denervation. AB - Likewise in rodents, after complete spinal cord injury (SCI) the lower motor neuron (LMN) denervated human muscle fibers lose completely the myofibrillar apparatus and the coil distribution of myonuclei that are relocated in groups (nuclear clumps) in the center of severely atrophic muscle fibers. Up to two years of LMN denervation the muscle fibers with nuclear clumps are very seldom, but in this cohort of patients the severely atrophic muscle fibers are frequent in muscle biopsies harvested three to six years after SCI. Indeed, the percentage increased to 27 +/- 9% (p< 0.001), and then abruptly decreased from the 6th year onward, when fibrosis takes over to neurogenic muscle atrophy. Immunohistochemical analyses shown that nuclear misplacements occurred in both fast and slow muscle fibers. In conclusion, human muscle fibers survive permanent denervation much longer than generally accepted and relocation of nuclei is a general behavior in long term denervated muscle fibers. PMID- 27478560 TI - Physical Activity Counteracts Tumor Cell Growth in Colon Carcinoma C26-Injected Muscles: An Interim Report. AB - Skeletal muscle tissue is a rare site of tumor metastasis but is the main target of the degenerative processes occurring in cancer-associated cachexia syndrome. Beneficial effects of physical activity in counteracting cancer-related muscle wasting have been described in the last decades. Recently it has been shown that, in tumor xeno-transplanted mouse models, physical activity is able to directly affect tumor growth by modulating inflammatory responses in the tumor mass microenvironment. Here, we investigated the effect of physical activity on tumor cell growth in colon carcinoma C26 cells injected tibialis anterior muscles of BALB/c mice. Histological analyses revealed that 4 days of voluntary wheel running significantly counteracts tumor cell growth in C26-injected muscles compared to the non-injected sedentary controls. Since striated skeletal muscle tissue is the site of voluntary contraction, our results confirm that physical activity can also directly counteract tumor cell growth in a metabolically active tissue that is usually not a target for metastasis. PMID- 27478561 TI - Serum Response Factor in Muscle Tissues: From Development to Ageing. AB - Skeletal, cardiac and smooth muscle cells share various common characteristic features. During development the embryonic mesodermal layer contribute at different proportions to the formation of these tissues. At the functional level, contractility as well as its decline during ageing, are also common features. Cytoskeletal components of these tissues are characterized by various actin isoforms that govern through their status (polymerised versus monomeric) and their interaction with the myosins the contractile properties of these muscles. Finally, at the molecular level, a set of different transcription factors with the notable exception of Serum Response Factor SRF- which is commonly enriched in the 3 types of muscle- drive and maintain the differentiation of these cells (Myf5, MyoD, Myogenin for skeletal muscle; Nkx2.5, GATA4 for cardiomyocytes). In this review, we will focus on the transcription factor SRF and its role in the homeostasis of cardiac, smooth and skeletal muscle tissues as well as its behaviour during the age related remodelling process of these tissues with a specific emphasis on animal models and human data when available. PMID- 27478562 TI - Quantitative Computed Tomography and Image Analysis for Advanced Muscle Assessment. AB - Medical imaging is of particular interest in the field of translational myology, as extant literature describes the utilization of a wide variety of techniques to non-invasively recapitulate and quantity various internal and external tissue morphologies. In the clinical context, medical imaging remains a vital tool for diagnostics and investigative assessment. This review outlines the results from several investigations on the use of computed tomography (CT) and image analysis techniques to assess muscle conditions and degenerative process due to aging or pathological conditions. Herein, we detail the acquisition of spiral CT images and the use of advanced image analysis tools to characterize muscles in 2D and 3D. Results from these studies recapitulate changes in tissue composition within muscles, as visualized by the association of tissue types to specified Hounsfield Unit (HU) values for fat, loose connective tissue or atrophic muscle, and normal muscle, including fascia and tendon. We show how results from these analyses can be presented as both average HU values and compositions with respect to total muscle volumes, demonstrating the reliability of these tools to monitor, assess and characterize muscle degeneration. PMID- 27478563 TI - Comparison of Proximally Versus Distally Placed Spatially Distributed Sequential Stimulation Electrodes in a Dynamic Knee Extension Task. AB - Spatially distributed sequential stimulation (SDSS) has demonstrated substantial power output and fatigue benefits compared to single electrode stimulation (SES) in the application of functional electrical stimulation (FES). This asymmetric electrode setup brings new possibilities but also new questions since precise placement of the electrodes is one critical factor for good muscle activation. The aim of this study was to compare the power output, fatigue and activation properties of proximally versus distally placed SDSS electrodes in an isokinetic knee extension task simulating knee movement during recumbent cycling. M. vastus lateralis and medialis of seven able-bodied subjects were stimulated with rectangular bi-phasic pulses of constant amplitude of 40 mA and at an SDSS frequency of 35 Hz for 6 min on both legs with both setups (i.e. n=14). Torque was measured during knee-extension movement by a dynamometer at an angular velocity of 110 deg/s. Mean power, peak power and activation time were calculated and compared for the initial and final stimulation phases, together with an overall fatigue index. Power output values (Pmean, Ppeak) were scaled to a standardised reference input pulse width of 100 MUs (Pmean,s, Ppeak,s). The initial evaluation phase showed no significant differences between the two setups for all outcome measures. Ppeak and Ppeak,s were both significantly higher in the final phase for the distal setup (25.4 +/- 8.1 W vs. 28.2 +/- 6.2 W, p=0.0062 and 34.8 +/- 9.5 W vs. 38.9 +/- 6.7 W, p=0.021, respectively). With distal SDSS, there was modest evidence of higher Pmean and Pmean,s (p=0.071, p=0.14, respectively) but of longer activation time (p=0.096). The rate of fatigue was similar for both setups. For practical FES applications, distal placement of the SDSS electrodes is preferable. PMID- 27478564 TI - Modeling and Simulations in Time Domain of a Stimulation Set-up for Cortical Applications. AB - Electrical stimulation is used for example to treat neuronal disorders and depression with deep brain stimulation or transcranial electrical stimulation. Depending on the application, different electrodes are used and thus different electrical characteristics exist, which have to be handled by the stimulator. Without a measuring device the user would have to rely on the stimulator being able to deliver the needed stimulation signal. Therefore, the objective of this paper is to present a method to increase the level of confidence with characterization and modelling of the electrical behavior by using the example of one channel of our stimulation device for experimental use. In several simulation studies with an electrode model with values in a typical range for cortical applications the influence of the load onto the stimulator and the possibility to pre-estimate measuring signals in complex networks are shown. PMID- 27478565 TI - Effects of Sensitive Electrical Stimulation Based Cueing in Parkinson's Disease: A Preliminary Study. AB - This study aims to investigate the effect of a sensitive cueing on Freezing of Gait (FOG) and gait disorders in subjects suffering from Parkinson's disease (PD). 13 participants with Parkinson's disease were equipped with an electrical stimulator and a foot mounted inertial measurement unit (IMU). An IMU based algorithm triggered in real time an electrical stimulus applied on the arch of foot at heel off detection. Starting from standing, subjects were asked to walk at their preferred speed on a path comprising 5m straight, u-turn and walk around tasks. Cueing globally decreased the time to achieve the different tasks in all the subjects. In "freezer" subjects, the time to complete the entire path was reduced by 19%. FOG events occurrence was lowered by 12% compared to baseline before and after cueing. This preliminary work showed a positive global effect of an electrical stimulation based cueing on gait and FOG in PD. PMID- 27478566 TI - Design and Implementation of a Less Invasive Gastrostimulator. AB - Gastrointestinal stimulator implants have recently shown positive results in helping obese patients lose weight. However, to place the implant, the patient currently needs to undergo an invasive surgical procedure. Our team is aiming for a less invasive procedure to stimulate the stomach with a gastrostimulator. Attempts covered fully endoscopic implantation and, more recently, we have focussed on a single incision laparoscopic procedure. Whatever the chosen implantation solution, the electronic design of the implant system shares many challenges. This paper covers the work achieved to meet these. PMID- 27478567 TI - A New Semi-Automatic Approach to Find Suitable Virtual Electrodes in Arrays Using an Interpolation Strategy. AB - Functional Electrical Stimulation via electrode arrays enables the user to form virtual electrodes (VEs) of dynamic shape, size, and position. We developed a feedback-control-assisted manual search strategy which allows the therapist to conveniently and continuously modify VEs to find a good stimulation area. This works for applications in which the desired movement consists of at least two degrees of freedom. The virtual electrode can be moved to arbitrary locations within the array, and each involved element is stimulated with an individual intensity. Meanwhile, the applied global stimulation intensity is controlled automatically to meet a predefined angle for one degree of freedom. This enables the therapist to concentrate on the remaining degree(s) of freedom while changing the VE position. This feedback-control-assisted approach aims to integrate the user's opinion and the patient's sensation. Therefore, our method bridges the gap between manual search and fully automatic identification procedures for array electrodes. Measurements in four healthy volunteers were performed to demonstrate the usefulness of our concept, using a 24-element array to generate wrist and hand extension. PMID- 27478568 TI - Audio-Visual Stimulation in Conjunction with Functional Electrical Stimulation to Address Upper Limb and Lower Limb Movement Disorder. AB - Neurological disorders often manifest themselves in the form of movement deficit on the part of the patient. Conventional rehabilitation often used to address these deficits, though powerful are often monotonous in nature. Adequate audio visual stimulation can prove to be motivational. In the research presented here we indicate the applicability of audio-visual stimulation to rehabilitation exercises to address at least some of the movement deficits for upper and lower limbs. Added to the audio-visual stimulation, we also use Functional Electrical Stimulation (FES). In our presented research we also show the applicability of FES in conjunction with audio-visual stimulation delivered through VR-based platform for grasping skills of patients with movement disorder. PMID- 27478569 TI - Engagement Sensitive Visual Stimulation. AB - Stroke is one of leading cause of death and disability worldwide. Early detection during golden hour and treatment of individual neurological dysfunction in stroke using easy-to-access biomarkers based on a simple-to-use, cost-effective, clinically-valid screening tool can bring a paradigm shift in healthcare, both urban and rural. In our research we have designed a quantitative automatic home based oculomotor assessment tool that can play an important complementary role in prognosis of neurological disorders like stroke for the neurologist. Once the patient has been screened for stroke, the next step is to design proper rehabilitation platform to alleviate the disability. In addition to the screening platform, in our research, we work in designing virtual reality based rehabilitation exercise platform that has the potential to deliver visual stimulation and in turn contribute to improving one's performance. PMID- 27478570 TI - An Intermediate Animal Model of Spinal Cord Stimulation. AB - Spinal cord injuries (SCI) result in the loss of movement and sensory feedback as well as organs dysfunctions. For example, nearly all SCI subjects loose their bladder control and are prone to kidney failure if they do not proceed to intermittent (self-) catheterization. Electrical stimulation of the sacral spinal roots with an implantable neuroprosthesis is a promising approach, with commercialized products, to restore continence and control micturition. However, many persons do not ask for this intervention since a surgical deafferentation is needed and the loss of sensory functions and reflexes become serious side effects of this procedure. Recent results renewed interest in spinal cord stimulation. Stimulation of existing pre-cabled neural networks involved in physiological processes regulation is suspected to enable synergic recruitment of spinal fibers. The development of direct spinal stimulation strategies aiming at bladder and bowel functions restoration would therefore appear as a credible alternative to existent solutions. However, a lack of suitable large animal model complicates these kinds of studies. In this article, we propose a new animal model of spinal stimulation -pig- and will briefly introduce results from one first acute experimental validation session. PMID- 27478571 TI - Exploring Selective Neural Electrical Stimulation for Upper Limb Function Restoration. AB - This article introduces a new approach of selective neural electrical stimulation of the upper limb nerves. Median and radial nerves of individuals with tetraplegia are stimulated via a multipolar cuff electrode to elicit movements of wrist and hand in acute conditions during a surgical intervention. Various configurations corresponding to various combinations of a 12-poles cuff electrode contacts are tested. Video recording and electromyographic (EMG) signals recorded via sterile surface electrodes are used to evaluate the selectivity of each stimulation configuration in terms of activated muscles. In this abstract we introduce the protocol and preliminary results will be presented during the conference. PMID- 27478572 TI - Inductive Powering of Subcutaneous Stimulators: Key Parameters and Their Impact on the Design Methodology. AB - Inductive powering of implantable medical devices involves numerous factors acting on the system efficiency and safety in adversarial ways. This paper lightens up their role and identifies a procedure enabling the system design. The latter enables the problem to be decoupled into four principal steps: the frequency choice, the magnetic link optimization, the secondary circuit and then finally the primary circuit designs. The methodology has been tested for the powering system of a device requirering a power of 300mW and implanted at a distance of 15 to 30mm from the outside power source. It allowed the identification of the most critical parameters. A satisfying efficiency of 34% was reached at 21mm and tend to validate the proposed design procedure. PMID- 27478573 TI - A Study on the Effect of Electrical Stimulation as a User Stimuli for Motor Imagery Classification in Brain-Machine Interface. AB - Functional Electrical Stimulation (FES) provides a neuroprosthetic interface to non-recovered muscle groups by stimulating the affected region of the human body. FES in combination with Brain-machine interfacing (BMI) has a wide scope in rehabilitation because this system directly links the cerebral motor intention of the users with its corresponding peripheral muscle activations. In this paper, we examine the effect of FES on the electroencephalography (EEG) during motor imagery (left- and right-hand movement) training of the users. Results suggest a significant improvement in the classification accuracy when the subject was induced with FES stimuli as compared to the standard visual one. PMID- 27478574 TI - Local Muscle Metabolic Demand Induced by Neuromuscular Electrical Stimulation and Voluntary Contractions at Different Force Levels: A NIRS Study. AB - Functional Muscle metabolic demand during contractions evoked by neuromuscular electrical stimulation (NMES) has been consistently documented to be greater than voluntary contractions (VOL) at the same force level (10-50% maximal voluntary contraction-MVC). However, we have shown using a near-infrared spectroscopy (NIRS) technique that local muscle metabolic demand is similar between NMES and VOL performed at MVC levels, thus controversy exists. This study therefore compared biceps brachii muscle metabolic demand (tissue oxygenation index-TOI and total hemoglobin volume-tHb) during a 10s isometric contraction of the elbow flexors between NMES (stimulation frequency of 30Hz and current level to evoke 30% MVC) and VOL at 30% MVC (VOL-30%MVC) and MVC (VOL-MVC) level in 8 healthy men (23-33-y). Greater changes in TOI and tHb induced by NMES than VOL-30%MVC confirm previous studies of a greater local metabolic demand for NMES than VOL at the same force level. The same TOI and tHb changes for NMES and VOL-MVC suggest that local muscle metabolic demand and intramuscular pressure were similar between conditions. In conclusion, these findings indicate that NMES induce a similar local muscle metabolic demand as that of maximal VOL. PMID- 27478576 TI - Editorial Ejtm Special: 20(th) Conference of the International Functional Electrical Stimulation Society, IFESS. PMID- 27478575 TI - Evolution of Surface Motor Activation Zones in Hemiplegic Patients During 20 Sessions of FES Therapy with Multi-pad Electrodes. AB - The purpose of this study was to examine surface motor activation zones for wrist, fingers and thumb extension movements and their temporal change during 20 therapy sessions using advanced multi-pad functional electrical stimulation system. Results from four hemiplegic patients indicate that certain zones have higher probability of eliciting each of the target movements. However, mutual overlap and variations of the zones are present not just between the subjects, but also on the intrasubject level, reflected through these session to session transformations of the selected virtual electrodes. The obtained results could be used as a priori knowledge for semi-automated optimization algorithm and could shorten the time required for calibration of the multi-pad electrode. PMID- 27478577 TI - Triorchidism: Presenting as Undescended Testis in a Case of Indirect Inguinal Hernia. AB - Triorchidism is the commonest variety of polyorchidism, an entity with more than two testis is an extremely rare congenital anomaly of the testis. Although excision of the abnormal testis is a safer alternative proposed, recent literature suggests more conservative approach in normal testes with watchful regular follow up to screen for malignancy. This case presented as a left inguinal swelling diagnosed as indirect left inguinal hernia. The left side testis was of smaller size (about half) with normal sperm count, morphology and motility. Intraoperatively indirect inguinal hernia was noted with supernumerary testis at deep ring in addition to normal left testis in left scrotal sac. The ectopic testis were small (2.5*2.5*1 cm) lacking epididymis and with short vas deferens. An evident normal semen analysis and varied anatomy, the decision for orchidectomy of ectopic testis was taken. The histopathological finding was consistent with arrest in germ cell development. PMID- 27478578 TI - Sandwich Wound Closure Reduces the Risk of Cerebrospinal Fluid Leaks in Posterior Fossa Surgery. AB - Posterior fossa surgery is demanding and hides a significant number of obstacles starting from the approach to the wound closure. The risk of cerebrospinal fluid (CSF) leakage in posterior fossa surgery given in the literature is around 8%. The present study aims to introduce a sandwich closure of the dura in posterior fossa surgery, which reduces significantly the number of CSF leaks (3.8%) in the patients treated in our department. Three hundred and ten patients treated in our hospital in the years 2009-2013 for posterior fossa pathologies were retrospectively evaluated. The dura closure method was as following: lyophilized dura put under the dura and sealed with fibrin glue and sutures, dura adapting stitches, TachoSil(r) (Takeda Pharma A/S, Roskilde, Denmark), Gelfoam(r) (Pfizer Inc., New York, NY, USA) and polymethylmethacrylate (osteoclastic craniotomy). The incidence of postsurgical complications associated with the dural closure like CSF leakage, infections, bleeding is evaluated. Only 3.8% of patients developed CSF leakage and only 0.5% needed a second surgery for CSF leakage closure. Two percent had a cerebellar bleeding with no need for re-operation and 3% had a wound infection treated with antibiotics. The sandwich wound closure we are applying for posterior fossa surgery in our patients correlates with a significant reduction of CSF leaks compared to the literature. PMID- 27478579 TI - Transient Superficial Peroneal Nerve Palsy After Anterior Cruciate Ligament Reconstruction. AB - A 19-year-old male subject was diagnosed with medial meniscal, lateral meniscal and anterior cruciate ligament (ACL) tear. The symptoms did not subside after 4 months of physical therapy, and he underwent arthroscopic partial medial and lateral meniscectomy and ACL reconstruction. Immediately after the patient woke up from general anesthesia, he started experience loss of sensation in the area of superficial peroneal nerve with inverted dorsiflexion of foot and ankle. Instantly, the bandage and knee brace was removed and a diagnosis of compartment syndrome was ruled out. After eight hours, post-operatively, the patient started receiving physiotherapy. He complained of numbness and tingling in the same area. After 24 h, post-operatively, the patient started to regain dorsiflexion and eversion gradually. Two days after the surgery, the patient exhibited complete recovery of neurological status. PMID- 27478580 TI - Acute, Severe Cryptosporidiosis in an Immunocompetent Pediatric Patient. AB - Severe diarrheal illness in children can be attributed to a number of different microbiological agents. Without appropriate microbiological testing of stool samples, patients who present with multiple days of severe diarrhea might have a delay in proper diagnosis and treatment. Here, we report a case of an immunocompetent pediatric patient presenting with acute cryptosporidiosis. Humans and bovine species are known hosts of cryptosporidium and several studies have evaluated the zoonotic transmission of cryptosporidium from cattle to humans. Adding diagnostic tests for cryptosporidium like Ziehl-Neelsen staining of stool or fecal rapid antigen detection techniques should be considered in the workup of patients presenting with undifferentiated, severe diarrheal illness, especially in those who have close contact with livestock. PMID- 27478581 TI - Exercise-Triggered Chest Pain as an Isolated Symptom of Myocarditis in Children. AB - In childhood, chest pain occurring at exercise is a common complaint. A cardiac etiology for it is exceptionally found, explaining that most children do not undergo systematic cardiological investigation. However, chest pain at exercise may manifest as the unique symptom of a viral myocarditis. Recognizing this form of myocardial injury, however, might help to avoid clinical deterioration by providing adequate care. In this paper, we report on two children presenting with the unique clinical symptom of chest pain related to physical activity and in whom laboratory and cardiac investigations suggested transient myocardial damage related to myocarditis. PMID- 27478582 TI - A Rare Association of Hepatitis A Virus Infection with Type-1 Diabetes. AB - Patients with type-1 diabetes are predisposed to develop a spectrum of liver diseases, which includes fatty liver, steatohepatitis and cirrhosis. The association of hepatitis A infection with type-1 diabetes is extremely rare. To the best of our knowledge, our case is the first case report in children. We described a nine year-old girl who had type-1 diabetes and developed hepatitis A virus infection without complications. A review of the literature is also provided. PMID- 27478583 TI - Huge Aneurysm of the Proper Hepatic Artery. AB - Hepatic artery aneurysms are rarely diagnosed. It is mainly because of non specific symptoms. They are generally an incidental findings during imaging studies. They are usually detected in the sixth decade, predominantly in men. We report herein a case of an 80 year-old man with a huge hepatic artery aneurysm revealed by abdominal pain and chronic anemia. It was treated by embolisation. Hepatic artery aneurysms are second among visceral aneurysms. They may cause abdominal pain, jaundice and hemorrhagic events. PMID- 27478584 TI - Metastatic Clear Cell Renal Cell Carcinoma Presenting with a Gingival Metastasis. AB - Metastatic deposits to the oral cavity are exceptionally rare. The commonest tumor types metastasizing to the oral cavity include lung and breast carcinoma. Renal cell carcinoma is believed to be the third most common infra clavicular tumor to metastasize to the head and neck. We report a case where an oral cavity deposit was the initial presentation for an occult clear cell renal carcinoma. Additional therapeutic options, including immunotherapy, tyrosine kinase inhibitors, and participation in a clinical trial, should be discussed with the patient despite the poor overall prognosis. PMID- 27478585 TI - Further Effort is Needed to Improve Management of Chronic Pain in Primary Care. Results from the Arkys Project. AB - Treatment of chronic pain is challenging. The Arkys project was initiated in Italy to assist general practitioners (GPs) in the management of chronic pain. The main objective of this study was to determine the usefulness of Arkys for selecting new therapeutic strategies. An online interactive questionnaire for assessing pain and guiding therapeutic decisions was made available to GPs participating to Arkys. The GPs were invited to complete the questionnaire for each patient who presented moderate-severe chronic pain, and to decide on a new analgesic treatment based on the information provided by the questionnaire. Two hundred and forty four GPs participated with a total of 3035 patients. Patients (mean age 68.9 years) had mostly chronic non-cancer pain (87.7%). In 42.3%, pain had neuropathic components. Only 53.6% of patients were in treatment with analgesics (strong opioids, 38.9%; NSAIDs, 32.6%; weak opioids, 25.6%; anti epileptics, 17.3%; paracetamol, 14.9%). Use of the questionnaire resulted in the prescription of analgesics to all patients and in increased prescription of strong opioids (69.7%). NSAID prescription decreased (12.8%), while anti epileptics use remained stable. These findings show that current management of chronic pain in primary care is far from optimal and that efforts are needed to educate GPs and improve guideline implementation. PMID- 27478586 TI - Ultrasound-Guided Greater Auricular Nerve Block as Sole Anesthetic for Ear Surgery. AB - A greater auricular nerve (GAN) block was used as the sole anesthetic for facial surgery in an 80-year-old male patient with multiple comorbidities which would have made general anesthesia challenging. The GAN provides sensation to the ear, mastoid process, parotid gland, and angle of the mandible. In addition to anesthesia for operating room surgery, the GAN block can be used for outpatient or emergency department procedures without the need for a separate anesthesia team. Although this nerve block has been performed using landmark-based techniques, the ultrasound-guided version offers several potential advantages. These advantages include increased reliability of the nerve block, as well as prevention of inadvertent vascular puncture or blockade of the phrenic nerve, brachial plexus, or deep cervical plexus. The increasing access to ultrasound technology for medical care providers outside the operating room makes this ultrasound guided block an increasingly viable alternative. PMID- 27478587 TI - Increasing the power of genome wide association studies in natural populations using repeated measures - evaluation and implementation. AB - Genomewide association studies (GWAS) enable detailed dissections of the genetic basis for organisms' ability to adapt to a changing environment. In long-term studies of natural populations, individuals are often marked at one point in their life and then repeatedly recaptured. It is therefore essential that a method for GWAS includes the process of repeated sampling. In a GWAS, the effects of thousands of single-nucleotide polymorphisms (SNPs) need to be fitted and any model development is constrained by the computational requirements. A method is therefore required that can fit a highly hierarchical model and at the same time is computationally fast enough to be useful.Our method fits fixed SNP effects in a linear mixed model that can include both random polygenic effects and permanent environmental effects. In this way, the model can correct for population structure and model repeated measures. The covariance structure of the linear mixed model is first estimated and subsequently used in a generalized least squares setting to fit the SNP effects. The method was evaluated in a simulation study based on observed genotypes from a long-term study of collared flycatchers in Sweden.The method we present here was successful in estimating permanent environmental effects from simulated repeated measures data. Additionally, we found that especially for variable phenotypes having large variation between years, the repeated measurements model has a substantial increase in power compared to a model using average phenotypes as a response.The method is available in the r package RepeatABEL. It increases the power in GWAS having repeated measures, especially for long-term studies of natural populations, and the R implementation is expected to facilitate modelling of longitudinal data for studies of both animal and human populations. PMID- 27478589 TI - Demographic and socio-economic influences on community-based care and caregivers of people with dementia in China. AB - BACKGROUND: Dementia is a major public health challenge and China has the largest population with dementia in the world. However, dementia care and caregivers for Chinese are less investigated. OBJECTIVES AND DESIGN: To evaluate demographic and socio-economic influences on dementia care, management patterns and caregiver burden in a household community-dwelling-based survey, using participants' care receipts and Zarit scale. SETTING AND PARTICIPANTS: Rural and urban communities across six provinces of China comprising 4837 residents aged >=60 years, in whom 398 had dementia and 1312 non-dementia diseases. RESULTS: People with dementia were less likely to receive care if they were living in rural compared to urban areas (Odd ratio (OR) = 0.20; 95%CI: 0.10-0.41), having education level below compared to above secondary school (OR = 0.24; 95%CI: 0.08-0.70), manual labourer compared to non-manual workers (OR = 0.27; 95%CI: 0.13-0.55), having personal annual income below RMB 10,000 yuan (L1000) compared to above (OR = 0.37; 95%CI: 0.13-0.74) or having four or more than compared to less four children (OR = 0.52; 95%CI: 0.27-1.00). Caregivers for dementia compared with those for non-dementia diseases were younger and more likely to be patients' children or children in law, had lower education and spent more caring time. Caregiver burden increased with low education, cutback on work and caring for patients who were younger or living in rural areas, and this caregiver burden was three-fold greater than that for non-dementia diseases. CONCLUSIONS: There are a number of inequalities in dementia care and caregiver burden in China. Reducing the socio-economic gap and increasing education may improve community care for people with dementia and preserve caregivers' well-being. PMID- 27478590 TI - Formulas for fixing serum sodium: curb your enthusiasm. AB - A variety of formulas have been proposed to predict changes in serum sodium concentration. All are based on an experiment done over 50 years ago by Edelman, who derived a formula relating the plasma sodium concentration to isotopically measured body sodium, potassium, and water. Some of these formulas fail because they do not include urinary losses of electrolytes and water. Even those that include these essential variables are not accurate enough for clinical use because it is impractical to adjust calculations to rapid changes in urinary composition, and because the formulas do not account for changes in serum sodium caused by internal exchanges between soluble and bound sodium stores or shifts of water into or out of cells resulting from changes in intracellular organic osmolytes. Nephrologists should curb their enthusiasm for predictive formulas and rely instead on frequent measurements of the serum sodium when correcting hyponatremia and hypernatremia. PMID- 27478591 TI - The utility and accuracy of four equations in predicting sodium levels in dysnatremic patients. AB - BACKGROUND: Improper correction of hyponatremia can cause severe complications, including osmotic demyelination syndrome (ODS). The Adrogue-Madias equation (AM), the Barsoum-Levine (BL) equation, the Electrolyte Free Water Clearance (EFWC) equation and the Nguyen-Kurtz (NK) equation are four derived equations based on the empirically derived Edelman equation for predicting sodium at a later time (Na2) from a known starting sodium (Na1), fluid/electrolyte composition and input and output volumes. METHODS: Our retrospective study included 43 data points from 31 mostly hyponatremic patients. We calculated Na2 based on five sets of rules that were progressively more precisely calculated. Sets A-D included all 31 patients and 43 data points and set E was based on 15 patients and 27 data points. RESULTS: The root mean square error was calculated and found to be between 4.79 and 6.37 mmol/L (mEq/L) for all sets. Bland-Altman analysis showed high variability and discrepancies between the predicted and actual Na2. CONCLUSIONS: Like similar studies in hypernatremic patients, the data suggest that hyponatremic modeling equations are not reliably accurate in predicting Na2 from Na1 and available clinical data regarding sodium, potassium and fluid balance over longer time frames (12-30 h). Our study was retrospective and was done in an inpatient setting and thus was subject to limitations and laboratory measurement variability, but showed that all four equations are not able to reliably predict Na2 from Na1 and inputs across a 12-30 h period. PMID- 27478592 TI - Continuous venovenous hemofiltration using customized replacement fluid for acute kidney injury with severe hypernatremia. AB - The initiation of continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) with severe hypernatremia is challenging since sodium concentrations in commercial replacement fluid (RF) and dialysate solutions are usually fixed at 140 mEq/L. We present a case of AKI with severe hypernatremia successfully treated with CRRT using commercial RF solutions customized to prevent rapid correction of hypernatremia. None of the few case reports published on hypernatremia and AKI requiring CRRT have included formulas to help modulate the sodium content in the solutions. We present an equation to facilitate adjustment of the sodium concentration in this setting. PMID- 27478593 TI - Kaliopenic nephropathy revisited. AB - In the 'older' literature, a definitive renal pathology was described in patients with long-standing hypokalaemia and depletion of the body's potassium reserves. The topic is relevant because possibly a quite cheaply reversible element in the course of chronic kidney disease progression could be addressed. Earlier, pathologists drew attention to vacuolar changes in renal tubular epithelium accompanied by inflammatory interstitial changes in patients with potassium losses. The diagnostic term 'kaliopenic nephropathy' was coined to describe such patients. Kaliopenic nephropathy now receives less emphasis than in earlier times. However, with eating disorders, laxative abuse and other potential causes, we suggest that the syndrome should be resurrected. PMID- 27478594 TI - Current and novel biomarkers in anti-neutrophil cytoplasm-associated vasculitis. AB - Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is characterized by a variable disease course, with up to 50% of patients having one relapse within 5 years and many progressing to end-stage organ damage despite modern treatment strategies. Moreover, complications arising from treatment dominate the causes of mortality and morbidity both early and late during disease, especially in the elderly and those with severe renal involvement, and there is additional uncertainty as to how long treatment should be continued. There is, therefore, an urgent clinical need to identify robust biomarkers to better predict treatment responses, risk of disease relapse and eventual complete clinical and immunological quiescence. To date, no such biomarkers exist, but better understanding of disease pathogenesis and the underlying immune dysfunction has provided some potential candidates linked to the discovery of new antibodies, different leukocyte activation states, the role of the alternative complement pathway and markers of vascular activation. With all promising new biomarkers, there is the need to rapidly replicate and validate early findings using large biobanks of samples that could be brought together by leaders in the field. PMID- 27478595 TI - Ofatumumab treatment in lupus nephritis patients. AB - Rituximab is frequently used in systemic lupus erythematosus; however, side effects such as infusion-related reactions limit its use. In this case report, we describe, for the first time, treatment with ofatumumab in four patients with lupus nephritis. The treatment was well tolerated in three of the patients, and a reduction of proteinuria was seen in all cases. This emphasizes the importance of alternative B-cell-depleting therapies in patients with an initial good response to rituximab, but who develop side effects. PMID- 27478596 TI - Granulomatous interstitial nephritis and Crohn's disease. AB - Granulomatous interstitial nephritis has been observed in <1% of native renal biopsies. Here, we describe two patients with granulomatous interstitial nephritis in relation to Crohn's disease. Circulating helper and cytotoxic T cells were highly activated, and both cell types predominated in the interstitial infiltrate, indicating a cellular autoimmune response. After immunosuppressive treatment, renal function either improved or stabilized in both patients. In conclusion, granulomatous interstitial nephritis is a genuine extraintestinal manifestation of Crohn's disease, the treatment of which should include immunosuppressive agents. PMID- 27478597 TI - The risk of acute kidney injury following transapical versus transfemoral transcatheter aortic valve replacement: a systematic review and meta-analysis. AB - BACKGROUND: The aim of this systematic review is to examine the literature for the risk of acute kidney injury (AKI) in patients who underwent transcatheter aortic valve replacement (TAVR) based on transapical (TA) versus transfemoral (TF) approaches. METHODS: A literature search was conducted utilizing Embase, Medline, Cochrane Database of Systematic Reviews and ClinicalTrials.gov from inception through December 2015. Studies that reported relative risk, odds ratio or hazard ratio comparing the AKI risk in patients who underwent TA-TAVR versus TF-TAVR were included. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated using a random effect, generic inverse variance method. RESULTS: Seventeen cohort studies with 5085 patients were enrolled in the analysis to assess the risk of AKI in patients undergoing TA-TAVR versus TF-TAVR. The pooled RR of AKI in patients who underwent TA-TAVR was 2.26 (95% CI 1.79-2.86) when compared with TF-TAVR. When meta-analysis was confined to the studies with adjusted analysis for confounders evaluating the risk of AKI following TAVR, the pooled RR of TA-TAVR was 2.89 (95% CI 2.12-3.94). The risk for moderate to severe AKI [RR 1.02 (95% CI 0.57-1.80)] in patients who underwent TA-TAVR compared with TF-TAVR was not significantly higher. CONCLUSIONS: Our meta-analysis demonstrates an association between TA-TAVR and a higher risk of AKI. Future studies are required to assess the risks of moderate to severe AKI and mortality following TA TAVR versus TF-TAVR. PMID- 27478598 TI - Provider acceptance of an automated electronic alert for acute kidney injury. AB - BACKGROUND: Clinical decision support systems, including electronic alerts, ideally provide immediate and relevant patient-specific information to improve clinical decision-making. Despite the growing capabilities of such alerts in conjunction with an expanding electronic medical record, there is a paucity of information regarding their perceived usefulness. We surveyed healthcare providers' opinions concerning the practicality and efficacy of a specific text based automated electronic alert for acute kidney injury (AKI) in a single hospital during a randomized trial of AKI alerts. METHODS: Providers who had received at least one electronic AKI alert in the previous 6 months, as part of a separate randomized controlled trial (clinicaltrials.gov #01862419), were asked to complete a survey concerning their opinions about this specific AKI alert system. Individual approval of the alert system was defined by a provider's desire to continue receiving the alert after termination of the trial. RESULTS: A total of 98 individuals completed the survey, including 62 physicians, 27 pharmacists and 7 non-physician providers. Sixty-nine percent of responders approved the alert, with no significant difference among the various professions (P = 0.28). Alert approval was strongly correlated with the belief that the alerts improved patient care (P < 0.0001), and negatively correlated with the belief that alerts did not provide novel information (P = 0.0001). With each additional 30 days of trial duration, odds of approval decreased by 20% (3-35%) (P = 0.02). CONCLUSIONS: The alert system was generally well received, although approval waned with time. Approval was correlated with the belief that this type of alert improved patient care. These findings suggest that perceived efficacy is critical to the success of future alert trials. PMID- 27478599 TI - Pneumococcal hemolytic uremic syndrome and steroid resistant nephrotic syndrome. AB - Pneumococcal-associated hemolytic uremic syndrome (pHUS) is a rare but severe complication of invasive Streptococcus pneumoniae infection. We report the case of a 12-year-old female with steroid-resistant nephrotic syndrome treated with adrenocorticotrophic hormone (H.P. Acthar((r)) Gel), who developed pneumococcal pneumonia and subsequent pHUS. While nephrotic syndrome is a well-known risk factor for invasive pneumococcal disease, this is the first reported case of pHUS in an adolescent patient with nephrotic syndrome, and reveals novel challenges in the diagnosis, treatment and potential prevention of this complication. PMID- 27478600 TI - Thrombotic microangiopathy and human immunodeficiency virus in the era of eculizumab. AB - Thrombotic microangiopathies (TMAs) include thrombotic thromobocytopenic purpura and hemolytic uremic syndrome (HUS). Among these conditions, atypical HUS is now recognized to be a disease of alternative complement pathway dysregulation. Eculizumab is a recombinant humanized monoclonal antibody that binds to the complement protein C5 and prevents the cleavage of C5 to C5a and C5b. Eculizumab has been used as a novel treatment for complement-mediated TMA. We present a case of a patient with human immunodeficiency virus infection who developed TMA and was successfully treated with eculizumab. The effect of long-term treatment with this new medication is unknown, and further studies are needed to establish guidelines in the management of this condition. PMID- 27478601 TI - Relapsing thrombotic microangiopathy and intravenous sustained-release oxycodone. AB - Thrombotic microangiopathy (TMA) associated with injecting sustained-release oxymorphone, an opioid intended for oral use, has previously been reported. We report a case of TMA secondary to intravenous use of sustained-release oxycodone, and the first case to demonstrate relapsing disease due to persistent intravenous opioid use. In cases such as these, TMA is suspected to be due to a polyethylene oxide (PEO) coating found on these drugs, and the disease is likely due to a directly toxic effect of PEO to endothelial cells. We hypothesize that there are unidentified genetic predispositions causing some persons to be susceptible to developing this disease. PMID- 27478603 TI - Short-term effects of the DASH diet in adults with moderate chronic kidney disease: a pilot feeding study. AB - BACKGROUND: Although the Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure (BP) for adults with normal kidney function, evidence is lacking regarding its safety and efficacy in chronic kidney disease (CKD). We aimed to test the effects of the DASH diet on serum electrolytes and BP in adults with moderate CKD. METHODS: In a prospective before-after feeding study, 11 adults with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m(2) and medication-treated hypertension were provided a reduced-sodium, run-in diet for 1 week followed by a reduced-sodium, DASH diet for 2 weeks. Changes in serum electrolytes and BP were compared pre-post DASH. RESULTS: Eleven participants underwent feeding; 1 completed 1 week and 10 completed 2 weeks of DASH. Compared with baseline, DASH modestly increased serum potassium at 1 week (mean +/- standard deviation, +0.28 +/- 0.4 mg/dL; P = 0.043) but had no significant effect on potassium at 2 weeks (+0.15 +/- 0.28 mg/dL; P = 0.13). Serum bicarbonate was reduced (-2.5 +/- 3.0 mg/dL; P = 0.03) at 2 weeks. Neither incident hyperkalemia nor new onset metabolic acidosis was observed. Clinic BP and mean 24-h ambulatory BP was unchanged. DASH significantly reduced mean nighttime BP (-5.3 +/- 5.8 mmHg; P = 0.018), and enhanced percent declines in both nocturnal systolic BP ( 2.1% to -5.1%; P = 0.004) and diastolic BP (-3.7% to -10.0%; P = 0.008). CONCLUSIONS: These pilot data suggest that a reduced-sodium DASH dietary pattern does not cause acute metabolic events in adults with moderate CKD and may improve nocturnal BP. Definitive studies are needed to determine long-term effects of DASH in CKD. PMID- 27478602 TI - Chronic kidney disease in children. AB - Chronic kidney disease (CKD) is a major health problem worldwide. Although relatively uncommon in children, it can be a devastating illness with many long term consequences. CKD presents unique features in childhood and may be considered, at least in part, as a stand-alone nosologic entity. Moreover, some typical features of paediatric CKD, such as the disease aetiology or cardiovascular complications, will not only influence the child's health, but also have long-term impact on the life of the adult that they will become. In this review we will focus on the unique issues of paediatric CKD, in terms of aetiology, clinical features and treatment. In addition, we will discuss factors related to CKD that start during childhood and require appropriate treatments in order to optimize health outcomes and transition to nephrologist management in adult life. PMID- 27478604 TI - Pure red cell aplasia induced by epoetin zeta. AB - Pure red cell aplasia (PRCA) may develop in patients with chronic kidney disease receiving erythropoiesis-stimulating agents (ESA). We report on a 72-year-old patient who developed hypo-proliferative anaemia unresponsive to ESA following the administration of epoetin zeta subcutaneously for 7 months. On the basis of severe isolated hypoplasia of the erythroid line in the bone marrow and high titre neutralizing anti-erythropoietin antibodies (Ab), a diagnosis of Ab mediated PRCA was made. Epoetin zeta was discontinued and the patient was given steroids. This was associated with anaemia recovery. To our knowledge this is the first PRCA case related to epoetin zeta. PMID- 27478605 TI - Post renal transplant pure red cell aplasia-is tacrolimus a culprit? AB - Anemia is not uncommon in the post-renal transplant period and has been reported in up to 40% of renal transplant recipients. It is commonly due to drugs and infections. While post-transplantation anemia is usually due to graft dysfunction and drugs such as mycophenolate and cotrimoxazole, tacrolimus is an uncommon cause. Tacrolimus is usually not believed to be significantly myelosuppressive, but it can cause anemia due to thrombotic microangiopathy. A literature review shows a very small number of reported cases of pure red cell aplasia (PRCA) where tacrolimus seemed to be a causative agent. We report a case series of three renal transplant recipients who were on tacrolimus and presented with chronic transfusion requiring anemia due to PRCA. PMID- 27478588 TI - Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5). AB - Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing. PMID- 27478606 TI - Discriminative value of frailty screening instruments in end-stage renal disease. AB - BACKGROUND: Numerous frailty screening instruments are available, but their applicability for identifying frailty in patients with end-stage renal disease (ESRD) is unknown. We aimed to investigate the diagnostic accuracy of three instruments used for frailty screening in an ESRD population. METHODS: The study was conducted in 2013 in a teaching hospital in The Netherlands and included patients receiving haemodialysis, peritoneal dialysis and pre-dialysis care. We determined the sensitivity and specificity of three screening instruments: the Groningen Frailty Indicator (GFI), the Identification of Seniors at Risk Hospitalized Patients (ISAR-HP) and the Veiligheidsmanagementsysteem (VMS), which is a safety management system for vulnerable elderly patients. The Frailty Index was the gold standard used. RESULTS: The prevalence of frailty was 37% in a total of 95 participants with ESRD [mean age 65.2 years (SD 12.0), 57% male]. Frailty prevalence in participants >=65 years of age and <65 years of age was 44% and 28%, respectively (P = 0.11). Sensitivity and specificity for frailty of the GFI were 89% and 57%, respectively; ISAR-HP 83% and 77%, respectively; and VMS 77% and 67%, respectively. CONCLUSIONS: Although the GFI showed the highest sensitivity, it is not yet possible to propose a firm choice for one of these screening instruments or specific items due to the small scale of the study. Since there is a high prevalence of frailty in ESRD patients, translation and testing of the effectiveness of screening using the GFI in the prognostication and prevention of development or deterioration of frailty in this population should be the next step. PMID- 27478607 TI - Nephrologists' likelihood of referring patients for kidney transplant based on hypothetical patient scenarios. AB - BACKGROUND: There is wide variation in referral for kidney transplant and preemptive kidney transplant (PKT). Patient characteristics such as age, race, sex and geographic location have been cited as contributing factors to this disparity. We hypothesize that the characteristics of nephrologists interplay with the patients' characteristics to influence the referral decision. In this study, we used hypothetical case scenarios to assess nephrologists' decisions regarding transplant referral. METHODS: A total of 3180 nephrologists were invited to participate. Among those interested, 252 were randomly selected to receive a survey in which nephrologists were asked whether they would recommend transplant for the 25 hypothetical patients. Logistic regression models with single covariates and multiple covariates were used to identify patient characteristics associated with likelihood of being referred for transplant and to identify nephrologists' characteristics associated with likelihood of referring for transplant. RESULTS: Of the 252 potential participants, 216 completed the survey. A nephrologist's affiliation with an academic institution was associated with a higher likelihood of referral, and being '>10 years from fellowship' was associated with lower likelihood of referring patients for transplant. Patient age <50 years was associated with higher likelihood of referral. Rural location and smoking history/chronic obstructive pulmonary disease were associated with lower likelihood of being referred for transplant. The nephrologist's affiliation with an academic institution was associated with higher likelihood of referring for preemptive transplant, and the patient having a rural residence was associated with lower likelihood of being referred for preemptive transplant. CONCLUSIONS: The variability in transplant referral is related to patients' age and geographic location as well as the nephrologists' affiliation with an academic institution and time since completion of training. Future educational interventions should emphasize the benefits of kidney transplant and PKT for all population groups regardless of geographic location and age and should target nephrologists in non-academic settings who are 10 or more years from their fellowship training. PMID- 27478608 TI - Newer antibiotics for the treatment of peritoneal dialysis-related peritonitis. AB - Peritonitis is a debilitating infectious complication of peritoneal dialysis (PD). Drug-resistant bacterial peritonitis typically has a lower response rate to antibiotics. In the past 15 years, newer antibiotics with activities against drug resistant Gram-positive bacteria have been developed. In most circumstances, peritonitis due to methicillin-resistant staphylococci responds to vancomycin. If vancomycin cannot be used due to allergy and/or non-susceptibility, there is increasing evidence that linezolid and daptomycin are the drugs of choice. It is reasonable to start linezolid orally or intravenously, but subsequent dose reduction may be necessary in case of myelosuppression. Daptomycin can be given intravenously or intraperitoneally and has excellent anti-biofilm activity. Other treatment options for drug-resistant Gram-positive bacterial peritonitis include teicoplanin, tigecycline and quinupristin/dalfopristin. Teicoplanin is not available in some countries (e.g. the USA). Tigecycline can only be given intravenously. Quinupristin/dalfopristin is ineffective against Enterococcus faecalis and there is only low-quality evidence to support its efficacy in the treatment of peritonitis. Effective newer antibiotics against drug-resistant Gram negative bacteria are lacking. Polymyxins can be considered, but evidence on its efficacy is limited. In this review, we will discuss the potential use of newer antibiotics in the treatment of drug-resistant bacterial peritonitis in PD patients. PMID- 27478609 TI - Incidence and outcome of encapsulating peritoneal sclerosis. AB - BACKGROUND: Studies report variation in the incidence and outcomes of encapsulating peritoneal sclerosis (EPS). This study reports the incidence and outcome of EPS cases in a national cohort of peritoneal dialysis (PD) patients. METHODS: The incident cohort of adult patients who started PD between 1 January 2000 and 31 December 2007 in Scotland (n = 1238) was identified from the Scottish Renal Registry. All renal units in Scotland identified potential EPS cases diagnosed from 1 January 2000 to 31 December 2014, by which point all patients had a minimum of 7 years follow-up from start of PD. RESULTS: By 31 December 2014, 35 EPS cases were diagnosed in the 1238 patient cohort: an overall incidence of 2.8%. The incidence for subgroups with longer PD duration rises exponentially: 1.1% by 1 year, 3.4% by 3 years, 8.8% at 4 years, 9.4% at 5 years and 22.2% by 7 years. Outcomes are poor with mortality of 57.1% by 1 year after diagnosis. Survival analysis demonstrates an initial above-average survival in patients who later develop EPS, which plummets to well below average after EPS diagnosis. CONCLUSIONS: The incidence of EPS is reassuringly low provided PD exposure is not prolonged and this supports ongoing use of PD. However, continuing PD beyond 3 years results in an exponential rise in the risk of developing EPS and deciding whether this risk is acceptable should be made on an individual patient basis. PMID- 27478610 TI - Low-molecular weight heparin infusion as anticoagulation for haemodialysis. AB - BACKGROUND: Low-molecular weight heparin (LMWH) is commonly used as an anticoagulant for haemodialysis by a single-bolus injection. However, its application in extended haemodialysis has been infrequently studied. In particular, for nocturnal home haemodialysis patients sleeping throughout treatment, the need for additional intradialytic bolus might render the use of LMWH impractical. To overcome this limitation, we changed traditional bolus injections to continuous infusion. We first tested our method among in-centre 4-h haemodialysis patients to establish a feasible and safe infusion regimen before utilizing it in extended dialyses at home. METHODS: Recruited patients were given nadroparin (standardized at 65 IU/kg) as an anticoagulant for haemodialysis. They were first randomized to receive nadroparin either by bolus injection or infusion. Afterwards, the patients underwent crossover to receive the alternate method of LMWH anticoagulation. The degrees of anticoagulation and bleeding complications were compared. RESULTS: Sixteen haemodialysis patients were recruited. After nadroparin administration, anti-Xa levels at the first hour were significantly higher by the bolus than the infusion methods (0.68 +/- 0.10 versus 0.49 +/- 0.10 IU/mL, P < 0.001) and were similar by the second hour (0.56 +/- 0.10 versus 0.55 +/- 0.11 IU/mL, P = 0.64). At the sixth hour, anti-Xa levels by the infusion method were significantly higher (0.35 +/- 0.13 versus 0.25 +/- 0.10 IU/mL, P < 0.001), suggesting the infusion approach required a dosage reduction. There were no bleeding events reported in either method. CONCLUSIONS: LMWH infusion is feasible and safe. The method avoids early excessive anticoagulation caused by bolus injection and reduces the LMWH dose. Future studies should be conducted to evaluate LMWH infusion in extended haemodialysis treatment. PMID- 27478611 TI - Intradialytic hypertension during chronic haemodialysis and subclinical fluid overload assessed by bioimpedance spectroscopy. AB - BACKGROUND: Intradialytic hypertension (IDH) increases morbidity and mortality. The prevalence in South Africa is unknown. The pathogenesis is unclear, but it has been suggested that IDH may be due to subclinical fluid overload. The objective of this study was to determine the prevalence of IDH and to evaluate its association with fluid overload using bioimpedance spectroscopy (BIS). METHODS: A cross-sectional study involving 190 chronic haemodialysis patients in the Western Cape province of South Africa was conducted between January 2013 and May 2014. IDH was defined as a >10 mmHg increase in systolic blood pressure in at least four of six prior consecutive haemodialysis sessions. RESULTS: The prevalence of IDH was 28.4% (n = 54). There was a trend towards pre-dialysis overhydration in the IDH group when compared with controls {2.6 L [95% confidence interval (CI) 1.7-3.4] versus 1.8 L [95% CI 1.4-2.1], respectively; P = 0.06} as measured by BIS, but no difference in mean ultrafiltration (UF) volume (2.4 versus 2.6 L; P = 0.30). A trend towards greater use of antihypertensive drugs was noted in the IDH group [2.5 drugs (95% CI 2.15-2.87) versus 2.1 (95% CI 1.82 2.30); P = 0.05]. More participants in the IDH group received calcium channel blockers (54 versus 36; P = 0.03). CONCLUSIONS: The prevalence of IDH in our treatment centres is much higher than previously reported. Subclinical fluid overload may be a major contributing factor to the mechanism of this condition. The use of BIS identifies patients who may benefit from additional UF. PMID- 27478612 TI - Urinary bile casts in bile cast nephropathy secondary to severe falciparum malaria. AB - BACKGROUND: Severe cholestatic jaundice may complicate with bile cast nephropathy (BCN) causing severe acute kidney injury (AKI). In this study, we investigate BCN in severe falciparum malaria complicated with jaundice and AKI. METHODS: This prospective study was conducted in a tertiary health care institution with high prevalence of malaria. A cohort of 110 patients with falciparum malaria complicated with cerebral malaria, jaundice and AKI were enrolled. Species diagnosis was made from peripheral blood smear or rapid diagnostic test. Severe malaria was diagnosed from WHO criteria. BCN was diagnosed with the detection of bile casts in urine or in biopsy. The recovery pattern and outcome with and without BCN was assessed. RESULTS: Out of 110 patients, 20 (18.2%) patients had BCN and 15 (13.6%) patients had hepato-renal syndrome. Patients with BCN had high conjugated bilirubin (26.5 +/- 4.1 mg/dL), urea (75.9 +/- 10.3 mg/dL) and creatinine (7.2 +/- 0.8 mg/dL), longer duration of illness (6.4 +/- 1.1 days), higher mortality (25.0%) and prolonged recovery time of hepatic (9.6 +/- 2.4 days) and renal dysfunction (15.1 +/- 6.5 days) compared with patients without BCN. CONCLUSIONS: Prolonged duration of illness and increased bilirubin cause BCN among patients with severe falciparum malaria with jaundice and AKI, which is associated with high mortality and morbidity. PMID- 27478613 TI - Erratum: Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma. AB - [This corrects the article on p. 411 in vol. 9, PMID: 27274826.]. PMID- 27478614 TI - High-concentrate feeding upregulates the expression of inflammation-related genes in the ruminal epithelium of dairy cattle. AB - BACKGROUND: The objective of this study was to characterize the mRNA expression profile related to rumen epithelial inflammation through the in vivo and in vitro experiments. In the in vivo experiment, rumen papillae were collected from four dairy cows adapted to either a 40 % (LC) or 70 % (HC) concentrate feeds for microarray analysis. RESULTS: Results showed that 245 differentially expressed genes (DEGs) were detected in the cows fed the HC relative to the LC diet. The DEGs were first annotated, and results revealed that the expression of inflammation-related genes, including IL-1beta, IL-2, IL-22, CCL19, CCL8, CX3CR1, CXCL6, INHBE, LEPR, PRL, and TNFRSF9 found in the cytokine-cytokine receptor pathway were up-regulated in the HC-fed cows, indicating local inflammation in the rumen epithelium was triggered. The expression of IL-1beta, IL-2, and IL-6 was further validated by qRT-PCR. To demonstrate whether there were relationships between cytokine mRNA expression and ruminal factors (pH and LPS), the isolated ruminal epithelial cells were cultured in vitro. Results showed that the mRNA expression of IL-1beta, IL-2, IL-6, and IL-8 increased after the LPS treatment, while low-pH treatment elevated the mRNA expression of TNF-alpha, suggesting that low-pH coupled with higher levels of LPS in rumen of cows fed the HC may be mainly responsible for the triggered local ruminal inflammation. CONCLUSIONS: Our results indicate that ruminal local inflammation response might be triggered during HC feeding, and these findings also enhance the knowledge of rumen epithelial adaptation to HC at the molecular level. PMID- 27478615 TI - Procedural sedation and analgesia for respiratory-gated MR-HIFU in the liver: a feasibility study. AB - BACKGROUND: Previous studies demonstrated both pre-clinically and clinically the feasibility of magnetic resonance-guided high-intensity focused ultrasound (MR HIFU) ablations in the liver. To overcome the associated problem of respiratory motion of the ablation area, general anesthesia (GA) and mechanical ventilation was used in conjunction with either respiratory-gated energy delivery or energy delivery during induced apnea. However, clinical procedures requiring GA are generally associated with increased mortality, morbidity, and complication rate compared to procedural sedation and analgesia (PSA). Furthermore, PSA is associated with faster recovery and an increased eligibility for non- and mini invasive interventions. METHODS: In this study, we investigate both in an animal model and on a small patient group the kinetics of the diaphragm during free breathing, when a tailored remifentanil/propofol-based PSA protocol inducing partial respiratory depression is used. Subsequently, we demonstrate in an animal study the compatibility of the resulting respiratory pattern of the PSA protocol with a gated HIFU ablation in the liver by direct comparison with gated ablations conducted under GA. Wilcoxon signed-rank tests were performed for statistical analysis of non-perfused and necrosed tissue volumes. Duty cycles (ratio or percentage of the breathing cycle with the diaphragm in its resting position, such that acoustic energy delivery with MR-HIFU was allowed) were statistically compared for both GA and PSA using student's t tests. RESULTS: In both animal and human experiments, the breathing frequency was decreased below 9/min, while maintaining stable vital functions. Furthermore an end-exhalation resting phase was induced by this PSA protocol during which the diaphragm is virtually immobile. Median non-perfused volumes, non-viable volumes based on NADH staining, and duty cycles were larger under PSA than under GA or equal. CONCLUSIONS: We conclude that MR-HIFU ablations of the liver under PSA are feasible and potentially increase the non-invasive nature of this type of intervention. PMID- 27478616 TI - Efficient eco-friendly inverted quantum dot sensitized solar cells. AB - Recent progress in quantum dot (QD) sensitized solar cells has demonstrated the possibility of low-cost and efficient photovoltaics. However, the standard device structure based on n-type materials often suffers from slow hole injection rate, which may lead to unbalanced charge transport. We have fabricated efficient p type (inverted) QD sensitized cells, which combine the advantages of conventional QD cells with p-type dye sensitized configurations. Moreover, p-type QD sensitized cells can be used in highly promising tandem configurations with n type ones. QDs without toxic Cd and Pb elements and with improved absorption and stability were successfully deposited onto mesoporous NiO electrode showing good coverage and penetration according to morphological analysis. Detailed photophysical charge transfer studies showed that high hole injection rates (108 s-1) observed in such systems are comparable with electron injection in conventional n-type QD assemblies. Inverted solar cells fabricated with various QDs demonstrate excellent power conversion efficiencies of up to 1.25%, which is 4 times higher than the best values for previous inverted QD sensitized cells. Attempts to passivate the surface of the QDs show that traditional methods of reduction of recombination in the QD sensitized cells are not applicable to the inverted architectures. PMID- 27478617 TI - Early mobilization of mechanically ventilated patients in the intensive care unit. AB - Several recent studies have suggested that the early mobilization of mechanically ventilated patients in the intensive care unit is safe and effective. However, in these studies, few patients reached high levels of active mobilization, and the standard of care among the studies has been inconsistent. The incidence of adverse events during early mobilization is low. Its importance should be considered in the context of the ABCDE bundle. Protocols of early mobilization with strict inclusion and exclusion criteria are needed to further investigate its contributions. PMID- 27478618 TI - A genetic assessment of the English bulldog. AB - BACKGROUND: This study examines genetic diversity among 102 registered English Bulldogs used for breeding based on maternal and paternal haplotypes, allele frequencies in 33 highly polymorphic short tandem repeat (STR) loci on 25 chromosomes, STR-linked dog leukocyte antigen (DLA) class I and II haplotypes, and the number and size of genome-wide runs of homozygosity (ROH) determined from high density SNP arrays. The objective was to assess whether the breed retains enough genetic diversity to correct the genotypic and phenotypic abnormalities associated with poor health, to allow for the elimination of deleterious recessive mutations, or to make further phenotypic changes in body structure or coat. An additional 37 English bulldogs presented to the UC Davis Veterinary Clinical Services for health problems were also genetically compared with the 102 registered dogs based on the perception that sickly English bulldogs are products of commercial breeders or puppy-mills and genetically different and inferior. RESULTS: Four paternal haplotypes, with one occurring in 93 % of dogs, were identified using six Y-short tandem repeat (STR) markers. Three major and two minor matrilines were identified by mitochondrial D-loop sequencing. Heterozygosity was determined from allele frequencies at genomic loci; the average number of alleles per locus was 6.45, with only 2.7 accounting for a majority of the diversity. However, observed and expected heterozygosity values were nearly identical, indicating that the population as a whole was in Hardy Weinberg equilibrium (HWE). However, internal relatedness (IR) and adjusted IR (IRVD) values demonstrated that a number of individuals were the offspring of parents that were either more inbred or outbred than the population as a whole. The diversity of DLA class I and II haplotypes was low, with only 11 identified DLA class I and nine class II haplotypes. Forty one percent of the breed shared a single DLA class I and 62 % a single class II haplotype. Nineteen percent of the dogs were homozygous for the dominant DLA class I haplotype and 42 % for the dominant DLA class II haplotype. The extensive loss of genetic diversity is most likely the result of a small founder population and artificial genetic bottlenecks occurring in the past. The prominent phenotypic changes characteristic of the breed have also resulted in numerous large runs of homozygosity (ROH) throughout the genome compared to Standard Poodles, which were phenotypically more similar to indigenous-type dogs. CONCLUSIONS: English bulldogs have very low genetic diversity resulting from a small founder population and artificial genetic bottlenecks. Although some phenotypic and genotypic diversity still exists within the breed, whether it is sufficient to use reverse selection to improve health, select against simple recessive deleterious traits, and/or to accommodate further genotypic/phenotypic manipulations without further decreasing existing genetic diversity is questionable. PMID- 27478619 TI - Adaptation of community health worker-delivered behavioral activation for torture survivors in Kurdistan, Iraq. AB - BACKGROUND: Growing evidence supports the use of Western therapies for the treatment of depression, trauma, and stress delivered by community health workers (CHWs) in conflict-affected, resource-limited countries. A recent randomized controlled trial (Bolton et al. 2014a) supported the efficacy of two CHW delivered interventions, cognitive processing therapy (CPT) and brief behavioral activation treatment for depression (BATD), for reducing depressive symptoms and functional impairment among torture survivors in the Kurdish region of Iraq. METHODS: This study describes the adaptation of the CHW-delivered BATD approach delivered in this trial (Bolton et al.2014a), informed by the Assessment-Decision Administration-Production-Topical experts-Integration-Training-Testing (ADAPT ITT) framework for intervention adaptation (Wingood & DiClemente, 2008). Cultural modifications, adaptations for low-literacy, and tailored training and supervision for non-specialist CHWs are presented, along with two clinical case examples to illustrate delivery of the adapted intervention in this setting. RESULTS: Eleven CHWs, a study psychiatrist, and the CHW clinical supervisor were trained in BATD. The adaptation process followed the ADAPT-ITT framework and was iterative with significant input from the on-site supervisor and CHWs. Modifications were made to fit Kurdish culture, including culturally relevant analogies, use of stickers for behavior monitoring, cultural modifications to behavioral contracts, and including telephone-delivered sessions to enhance feasibility. CONCLUSIONS: BATD was delivered by CHWs in a resource-poor, conflict affected area in Kurdistan, Iraq, with some important modifications, including low-literacy adaptations, increased cultural relevancy of clinical materials, and tailored training and supervision for CHWs. Barriers to implementation, lessons learned, and recommendations for future efforts to adapt behavioral therapies for resource-limited, conflict-affected areas are discussed. PMID- 27478621 TI - Usefulness of T2*-weighted MRI in the detection of adnexal torsion. AB - BACKGROUND: The usefulness of T2*-weighted (T2*W) imaging for the detection of adnexal torsion has yet to be determined. PURPOSE: To assess the usefulness of T2*W imaging for detecting and differentiating adnexal torsion. MATERIAL AND METHODS: Eight patients with eight ovaries with torsion and 44 patients with 72 ovaries without torsion were included in this study. All patients underwent 1.5-T magnetic resonance imaging (MRI) including T2*W images. The frequency and distribution of hypointensity on T2*W images were compared between ovaries with torsion and ovaries without torsion. RESULTS: Hypointensity on T2*W images was significantly more frequent in ovaries with torsion than in ovaries without torsion (75% vs. 36%; P < 0.05). Among patients with hypointensity on T2*W images, the frequency of diffuse hypointensity was significantly higher in ovaries with torsion than in ovaries without torsion (83% vs. 0%; P < 0.01); whereas the frequency of focal hypointensity was significantly lower in ovaries with torsion than in ovaries without torsion (17% vs. 100%; P < 0.01). CONCLUSION: The presence and distribution of hypointensity on T2*W images may play a supplementary role in the detection of adnexal torsion. PMID- 27478620 TI - Gene expression profiles and neural activities of Kenyon cell subtypes in the honeybee brain: identification of novel 'middle-type' Kenyon cells. AB - In the honeybee (Apis mellifera L.), it has long been thought that the mushroom bodies, a higher-order center in the insect brain, comprise three distinct subtypes of intrinsic neurons called Kenyon cells. In class-I large-type Kenyon cells and class-I small-type Kenyon cells, the somata are localized at the edges and in the inner core of the mushroom body calyces, respectively. In class-II Kenyon cells, the somata are localized at the outer surface of the mushroom body calyces. The gene expression profiles of the large- and small-type Kenyon cells are distinct, suggesting that each exhibits distinct cellular characteristics. We recently identified a novel gene, mKast (middle-type Kenyon cell-preferential arrestin-related gene-1), which has a distinctive expression pattern in the Kenyon cells. Detailed expression analyses of mKast led to the discovery of novel 'middle-type' Kenyon cells characterized by their preferential mKast-expression in the mushroom bodies. The somata of the middle-type Kenyon cells are localized between the large- and small-type Kenyon cells, and the size of the middle-type Kenyon cell somata is intermediate between that of large- and small-type Kenyon cells. Middle-type Kenyon cells appear to differentiate from the large- and/or small-type Kenyon cell lineage(s). Neural activity mapping using an immediate early gene, kakusei, suggests that the small-type and some middle-type Kenyon cells are prominently active in the forager brain, suggesting a potential role in processing information during foraging flight. Our findings indicate that honeybee mushroom bodies in fact comprise four types of Kenyon cells with different molecular and cellular characteristics: the previously known class-I large- and small-type Kenyon cells, class-II Kenyon cells, and the newly identified middle-type Kenyon cells described in this review. As the cellular characteristics of the middle-type Kenyon cells are distinct from those of the large- and small-type Kenyon cells, their careful discrimination will be required in future studies of honeybee Kenyon cell subtypes. In this review, we summarize recent progress in analyzing the gene expression profiles and neural activities of the honeybee Kenyon cell subtypes, and discuss possible roles of each Kenyon cell subtype in the honeybee brain. PMID- 27478623 TI - Effect of mouse strain as a background for Alzheimer's disease models on the clearance of amyloid-beta. AB - Novel animal models of Alzheimer's disease (AD) are relentlessly being developed and existing ones are being fine-tuned; however, these models face multiple challenges associated with the complexity of the disease where most of these models do not reproduce the full phenotypical disease spectrum. Moreover, different AD models express different phenotypes that could affect their validity to recapitulate disease pathogenesis and/or response to a drug. One of the most important and understudied differences between AD models is differences in the phenotypic characteristics of the background species. Here, we used the brain clearance index (BCI) method to investigate the effect of strain differences on the clearance of amyloid beta (Abeta) from the brains of four mouse strains. These mouse strains, namely C57BL/6, FVB/N, BALB/c and SJL/J, are widely used as a background for the development of AD mouse models. Findings showed that while Abeta clearance across the blood-brain barrier (BBB) was comparable between the 4 strains, levels of LRP1, an Abeta clearance protein, was significantly lower in SJL/J mice compared to other mouse strains. Furthermore, these mouse strains showed a significantly different response to rifampicin treatment with regard to Abeta clearance and effect on brain level of its clearance-related proteins. Our results provide for the first time an evidence for strain differences that could affect ability of AD mouse models to recapitulate response to a drug, and opens a new research avenue that requires further investigation to successfully develop mouse models that could simulate clinically important phenotypic characteristics of AD. PMID- 27478624 TI - The Impact of Demographic Factors and Blood Sugar Control on the Incidence of Urinary Tract Infections in Khorramabad in 2013. AB - BACKGROUND: Diabetes is one of the most serious metabolic disorders to affect different organs in the body. Patients with diabetes are hence at risk of developing other problems. Urinary tract infections (UTI) are one of the problems that occur more commonly in diabetic patients than in others. There are several risk factors that lead to the incidence of UTI in diabetic patients. OBJECTIVES: We conducted this study to determine the effect of different factors on the incidence of UTI in diabetic patients in order to decrease the incidence of this problem. PATIENTS AND METHODS: In this cross-sectional study, data concerning 233 patients who were referred to the largest diabetes center in Khorramabad, Lorestan province, Iran, were recorded. The relationships between various factors and the incidence of UTI in these patients were evaluated using SPSS version 16. We used chi-square and logistic regression to analyze the data. A P < 0.05 was considered to be statistically significant. RESULTS: The incidence of UTI increased significantly with increasing age (P = 0.009). The incidence of UTI was higher among females than among males, and it was higher among unemployed people than among those in other occupations. The prevalence of UTI among patients who control their diabetes through diet and exercise was lower than that among those undergoing other types of treatment; however, no significant relationship was found between the different types of oral medication and the incidence of UTI. We did not find any relationship between the incidence of UTI in diabetic patients and other factors such as literacy, marital status, BMI, addiction, history of hospitalization, and level of HbA1c. CONCLUSIONS: We found that age, gender, occupation, and the type of medication used are all risk factors for the incidence of UTI in diabetic patients. Other factors such as literacy, marital status, addiction, and history of hospitalization did not have any significant association with the incidence of UTI in diabetic patients. PMID- 27478625 TI - Females' Attitudes Toward Mental Illness: A Sample From Rural Istanbul, Turkey. AB - BACKGROUND: The beliefs, attitudes and behaviors of the society toward mentally ill patients may prevent these people from seeking help and accessing a successful treatment. OBJECTIVES: The current study aimed to investigate mental illness among Turkish females residing in rural areas and their attitudes toward mental illness. PATIENTS AND METHODS: The current study was inferential cross sectional. The population of this study consisted of 1000 households registered at the primary healthcare centre in Ademyavuz area who met the study inclusion criteria. The sample size was 387 females. Using the simple random sample selection method, certain females living in these households were included in the study. The socioeconomic status of the population in this region is low and middle-class. The adult population of the region is 10,960. Females comprise 39.8% of Ademyavuz population. The prevalence of mental illness in the district is unknown. Data were collected by face-to-face interviews using a researcher made questionnaire and the opinions about mental illness scale (OMI) in autumn 2008. The interviews were conducted at the participants' houses and lasted for 20 - 30 minutes. The females gave their informed consent and were assured that their information would be treated as strictly confidential. RESULTS: The females in the rural research area had negative attitudes and stigmas about mental illness. The subject of the current study exhibited a total mean score of 155.6 +/- 24.5 in terms of their attitudes toward mental illness. Mean scores in the unsophisticated benevolence sub-scale were 42.5 +/- 8.2, 34.2 +/- 7.9 in the authoritarianism sub-scale, 25.5 +/- 6.3 in the mental illness ideology sub scale, 34.0 +/- 7.4 in the social restrictiveness sub-scale, and 20.0 +/- 6.0 for the interpersonal etiology sub-scale. The current study found that individuals exhibited more positive attitudes towards mental illnesses as they got older ((Kvx2) = 19.42; P < 0.0001), married people exhibited a more positive attitude towards mental illnesses than singles did (Kvx(2) = 19.42; P < 0.0001), those who considered themselves to have a good economic status exhibited a more negative attitude towards mental illnesses compared to the ones who thought their economic status as poor or average (Kvx(2) = 5.11; P = 0.024). CONCLUSIONS: Nurses have an important role in creating and maintaining a mentally healthy society. It is advisable to provide the public with training and consultancy services within the context of primary healthcare services, especially during home visits to change the negative attitudes of individuals against the mentally ill and prevent approaches that promote social isolation and denouncement. PMID- 27478626 TI - The in Silico Insight into Carbon Nanotube and Nucleic Acid Bases Interaction. AB - BACKGROUND: To explore practical applications of carbon nanotubes (CNTs) in biomedical fields the properties of their interaction with biomolecules must be revealed. Recent years, the interaction of CNTs with biomolecules is a subject of research interest for practical applications so that previous research explored that CNTs have complementary structure properties with single strand DNA (ssDNA). OBJECTIVES: Hence, the quantum mechanics (QM) method based on ab initio was used for this purpose. Therefore values of binding energy, charge distribution, electronic energy and other physical properties of interaction were studied for interaction of nucleic acid bases and SCNT. MATERIALS AND METHODS: In this study, the interaction between nucleic acid bases and a (4, 4) single-walled carbon nanotube (SCNT) were investigated through calculations within quantum mechanics (QM) method at theoretical level of Hartree-Fock (HF) method using 6-31G basis set. Hence, the physical properties such as electronic energy, total dipole moment, charge distributions and binding energy of nucleic acid bases interaction with SCNT were investigated based on HF method. RESULTS: It has been found that the guanine base adsorption is bound stronger to the outer surface of nanotube in comparison to the other bases, consistent with the recent theoretical studies. In the other words, the results explored that guanine interaction with SCNT has optimum level of electronic energy so that their interaction is stable. Also, the calculations illustrated that SCNT interact to nucleic acid bases by noncovalent interaction because of charge distribution an electrostatic area is created in place of interaction. CONCLUSIONS: Consequently, small diameter SCNT interaction with nucleic acid bases is noncovalent. Also, the results revealed that small diameter SCNT interaction especially SCNT (4, 4) with nucleic acid bases can be useful in practical application area of biomedical fields such detection and drug delivery. PMID- 27478627 TI - Psychometric Evaluation of the Cognitive State Test (COST) in a Sample of Iranian Elderly People. AB - BACKGROUND: An absolute prerequisite to the effective management of dementia is its early diagnosis. Successful dementia screening requires precise and sensitive instruments that can be completed even by illiterate elderly people. OBJECTIVES: The aim of this study was to evaluate the psychometric properties of the Persian version of the cognitive state test (COST). MATERIALS AND METHODS: This methodologic study was conducted in Kashan, Iran, during 2013 - 2014. A purposeful sample of 150 healthy elderly people and 50 elderly patients with dementia was recruited. After translating the instrument by using the standard forward-backward technique, we assessed its qualitative and quantitative face and content validity. The validity of the test was assessed by using the concurrent validity and the exploratory factor analysis. We also calculated Cronbach's alpha and employed the test-retest method for evaluating the internal consistency and the stability of the test, respectively. Study data were analyzed by using the SPSS v16.0, the Spearman-Brown, and the intraclass correlation coefficient tests and the principal components factor analysis with varimax rotation. RESULTS: The Persian COST consists of nineteen items. The impact scores, the content validity ratios and the content validity indices of all test items were greater than 4.5, 0.69, and 0.84, respectively. The COST had a significant correlation with the clinical dementia rating (rS = -0.76, P value < 0.001), indicating an acceptable concurrent validity for the test. The exploratory factor analysis revealed a five factor structure that explained 60.59% of the total variance of the total cognitive state score. The Cronbach's alpha, Spearman-Brown, and interclass correlation coefficients were 0.82, 0.95, and 0.88, respectively (P value < 0.001). CONCLUSIONS: The Persian version of the COST can be used as a valid and reliable instrument for assessing cognitive state and screening dementia in literate and illiterate elderly people. PMID- 27478628 TI - Efficacy of Traditional Medicine Product Henna and Hydrocortisone on Diaper Dermatitis in Infants. AB - BACKGROUND: Diaper dermatitis (DD) is a common inflammatory disorder in infants, including newborns. OBJECTIVES: This study aimed to compare the effects of a traditional medicine product (containing natural henna oil 25%) and hydrocortisone 1% cream on DD in infants. PATIENTS AND METHODS: In a triple blind, randomized trial, 82 children aged two years or less were randomly divided into two groups of 41 children each to receive either hydrocortisone ointment or henna medicinal product. Infants were treated 3 times a day for 5 days. The severity of dermatitis was assessed on the first, third, and fifth days using a six-point scale. The study was conducted in 2013 in a children teaching hospital in Qazvin, Iran. RESULTS: Both groups showed an improvement in the severity of DD (mean DD severity on the first, third and fifth days, respectively, was 3.20, 1.39, and 1.20 in the henna group versus 3.20, 2.05, and 1.90 in the hydrocortisone group; P < 0.001). The henna group showed a better response when compared with the hydrocortisone group: the rate of improvement on the fifth day of treatment was 90.2% (37 of 41 children without erythema) in the former versus 61% (25 of 41 patients) in the latter (P = 0.042). No significant side effects were observed in both the groups. CONCLUSIONS: Henna, a traditional medicine product, can be considered an effective and appropriate treatment for DD in infants and children. PMID- 27478629 TI - Randomized Control Trials on Otago Exercise Program (OEP) to Reduce Falls Among Elderly Community Dwellers in Shahroud, Iran. AB - BACKGROUND: Fall is a worldwide health problem among elderly people and a known leading cause of disabilities. Fall prevention programs have been implemented in various forms. The Otago exercise program (OEP) is one of the most recent home base exercise training program. OBJECTIVES: This study was conducted to examine the effectiveness of OEP to reduce falls among elderly people in Shahroud, IR Iran. MATERIALS AND METHODS: This randomised control trial was conducted among the elderly community dwellers in Shahroud city of the Semnan province, IR Iran, with experience of falls in the last 12 months. Subjects of the study (n = 317) were recruited from elderly senior citizens at public health centers. Block systematic random sampling was applied to categorize the subjects in experimental and control groups. The experimental group (n = 160) received OEP for six months and was compared with the control group (n = 157) who received general health training. This study was registered with the following ID, IRCT2014012016285N1. RESULTS: The findings of the study showed that OEP improved physical performance (Berg-Balance-Score with P > 0.025, and Timed-Up-Go-Test with P > 0.017) and functional capacity (Arm-Curl-Test with P > 0.00 and Chair-Stand-Test with P > 0.01). In addition, OEP significantly reduced the incidence of falls (P <= 0.00) among senior citizens in the experimental group. DISCUSSION: The OEP as a home based exercise is effective for the reduction of the incidence of falls among senior citizens with a history of falls. The OEP can be recommended for elderly homebound people who do not have access to facilities. PMID- 27478630 TI - Intermediate-Term Outcomes of Dual Adult versus Single-Kidney Transplantation: Evolution of a Surgical Technique. AB - Background. Acceptance of dual kidney transplantation (DKT) has proven difficult, due to surgical complexity and concerns regarding long-term outcomes. We herein present a standard technique for ipsilateral DKT and compare outcomes to single kidney transplant (SKT) recipients. Methods. A retrospective single-center comparison of DKT and SKT performed between February 2007 and July 2013. Results. Of 516 deceased donor kidney transplants, 29 were DKT and 487 were SKT. Mean follow-up was 43 +/- 67 months. DKT recipients were older and more likely than SKT recipients to receive an extended criteria graft (p < 0.001). For DKT versus SKT, the rates of delayed graft function (10.3 versus 9.2%) and acute rejection (20.7 versus 22.4%) were equivalent (p = ns). A higher than expected urologic complication rate in the DKT cohort (14 versus 2%, p < 0.01) was reduced through modification of the ureteral anastomosis. Graft survival was equivalent between DKT and SKT groups (p = ns) with actuarial 3-year DKT patient and graft survivals of 100% and 93%. At 3 years, the groups had similar renal function (p = ns). Conclusions. By utilizing extended criteria donor organs as DKT, the donor pool was enlarged while providing excellent patient and graft survival. The DKT urologic complication rate was reduced by modification of the ureteral anastomosis. PMID- 27478631 TI - Clinical Course and Outcomes of Late Kidney Allograft Dysfunction. AB - Background. This study is provided to increase the efficiency of the treatment of kidney transplant recipients by predicting the development of the late allotransplant dysfunction. Methods. 330 patients who have lived for more than one year with functioning kidney allograft were evaluated. To predict the subsequent duration of the well-functioning of allotransplant the prognostic significance of 15 baseline clinical and sociodemographic characteristics on the results of the survey one year after transplantation was investigated. The result was considered to be positive in constructing the regression prognostication model if recipient lived more than 3 years from the time of transplantation. Results. It was established that more late start of renal allograft dysfunction after transplantation correlates with the more time it takes till complete loss of allograft function. Creatinine and hemoglobin blood concentration and the level of proteinuria one year after transplantation within created mathematical model allow predicting the loss of kidney transplant function three years after the transplantation. Patients with kidney transplant dysfunction are advised to renew the program hemodialysis upon reaching plasma creatinine concentration 0.5 0.7 mmol/L. Conclusion. Values of creatinine, hemoglobin, and proteinuria one year after transplantation can be used for subsequent prognostication of kidney transplant function. PMID- 27478632 TI - Success Rates of Vitrectomy in Treatment of Rhegmatogenous Retinal Detachment. AB - Aim. To investigate the anatomical success rates of pars plana vitrectomy (PPV) after primary rhegmatogenous retinal detachment (RRD). Methods. This retrospective study was conducted between December 2008 and October 2014 at Nagasaki University Hospital. The preoperative data recorded included the lens status, location of the retinal tear, whether a tear was visualized, presence of multiple tears, macula status, presence of peripheral lattice retinal degeneration, and best-corrected visual acuity (BCVA). The primary outcome measures were anatomical (primary and final) and functional success (visual acuity better than 6/60). Results. This study evaluated 422 eyes of 411 patients with a mean age of 57.7 +/- 11.2 years. The single-operation reattachment rate (primary anatomical success) was 89.8%. The final anatomical success rate was 100% after 2-6 operations (mean = 3.14 +/- 1.03). Functional success rate after the primary reattachment operation was 96.7%, while it was 97.2% at the end of the follow-up. Multiple logistic regression analysis of the possible risk factors for the primary anatomical failure showed a significant relation with the 25 G instruments (P = 0.002) and the presence of multiple tears (P = 0.01). Conclusion. The primary anatomical success of PPV for primary uncomplicated RRD was 89.8% and the final anatomical success rate was 100%. PMID- 27478633 TI - Long-Term Follow-Up of the Fellow Eye in Patients Undergoing Surgery on One Eye for Treating Myopic Traction Maculopathy. AB - Objective. To observe the fellow eye in patients undergoing surgery on one eye for treating myopic traction maculopathy. Methods. 99 fellow eyes of consecutive patients who underwent unilateral surgery to treat MTM were retrospectively evaluated. All patients underwent thorough ophthalmologic examinations, including age, gender, duration of follow-up, refraction, axial length, intraocular pressure, lens status, presence/absence of a staphyloma, and best-corrected visual acuity (BCVA). Fundus photographs and SD-OCT images were obtained. When feasible, MP-1 microperimetry was performed to evaluate macular sensitivity and fixation stability. Results. At an average follow-up time of 24.7 months, 7% fellow eyes exhibited partial or complete MTM resolution, 68% stabilized, and 25% exhibited progression of MTM. Of the 38 eyes with "normal" macular structure on initial examination, 11% exhibited disease progression. The difference in progression rates in Groups 2, 3, and 4 was statistically significant. Refraction, axial length, the frequency of a posterior staphyloma, chorioretinal atrophy, initial BCVA, final BCVA, and retinal sensitivity all differed significantly among Groups 1-4. Conclusions. Long axial length, chorioretinal atrophy, a posterior staphyloma, and anterior traction contribute to MTM development. Patients with high myopia and unilateral MTM require regular OCT monitoring of the fellow eye to assess progression to myopic pre-MTM. For cases exhibiting one or more potential risk factors, early surgical intervention may maximize the visual outcomes. PMID- 27478634 TI - Impact of Indocyanine Green Concentration, Exposure Time, and Degree of Dissolution in Creating Toxic Anterior Segment Syndrome: Evaluation in a Rabbit Model. AB - Purpose. To investigate the role of indocyanine green (ICG) dye as a causative material of toxic anterior segment syndrome (TASS) in an experimental rabbit model. Method. Eight eyes of four rabbits were allocated to this study. Capsular staining was performed using ICG dye, after which the anterior chamber was irrigated with a balanced salt solution. The effects of different concentrations (control, 0.25, 0.5, and 1.0%), exposure times (10 and 60 seconds), and the degree of dissolution (differently vortexed) were investigated. The analysis involved anterior segment photography, ultrasound pachymetry, prostaglandin assay (PGE2 Parameter Assay, R&D systems, Inc.), and scanning electron microscopy of each iris. Result. There was no reaction in the control eye. A higher aqueous level of PGE2 and more severe inflammatory reaction were observed in cases of eyes with higher concentration, longer exposure time, and poorly dissolved dye. Additionally, scanning electron microscopy revealed larger and coarser ICG particles. Conclusion. TASS occurrence may be associated with the concentration, exposure time, and degree of dissolution of ICG dye during cataract surgery. PMID- 27478635 TI - The Typical Presentation Spectrum of Deep Vein Thrombosis Associated with Inferior Vena Cava Malformations. AB - Congenital malformations of the inferior vena cava (IVC) are rare and underreported. They can be a risk factor for deep venous thrombosis (DVT) as a result of inadequate venous drainage of the lower extremities through collateral circulation. The significant number of cases reported in the literature highlights their importance, warranting investigating their existence in younger individuals with idiopathic DVT of the lower extremities and pelvic veins. In this systematic review, we depict the typical presentation of IVC malformations, their management, and the management of their associated DVT. PMID- 27478636 TI - Interferon-Gamma Improves Macrophages Function against M. tuberculosis in Multidrug-Resistant Tuberculosis Patients. AB - Background. Mycobacterium tuberculosis (M. tuberculosis) that causes tuberculosis (TB) kills millions of infected people annually especially multidrug-resistant tuberculosis (MDR-TB). On infection, macrophages recognize the mycobacteria by toll-like receptor (TLR) followed by phagocytosis and control of mycobacteria. In addition, macrophages also secrete IL-12 to induce IFN-gamma production by T, which, in turn, increases the phagocytosis and oxidative burst. Individuals with defects in innate or adaptive immunity exhibit increased susceptibility to M. tuberculosis. Understanding these immunologic mechanisms will help in TB control. We aimed to investigate the immunopathologic mechanisms in MDR-TB and role of recombinant human interferon-gamma (rhIFN-gamma). Study Design and Methods. Monocyte-derived macrophages (MDMs) were generated from peripheral blood mononuclear cells of MDR-TB patients and healthy subjects and were investigated for immunologic response by ELISA and flow cytometry. Results. Different functional and molecular anomalies were observed in macrophages. In addition, a defective immune response to M. tuberculosis from the patient's MDMs was characterized, which in turn improved by pretreatment with rhIFN-gamma. Conclusion. This work highlights the fact that rhIFN-gamma improves macrophages function against M. tuberculosis and treatment of patients with poor responsiveness to TB therapy may be needed in future to include IFN-gamma as adjuvant therapy after the full characterization of pathological and molecular mechanisms in these and in other more multidrug-resistant TB patients. PMID- 27478637 TI - Hypoxia Associated Proteolytic Processing of OS-9 by the Metalloproteinase Meprin beta. AB - Meprin metalloproteases play a role in the pathology of ischemia/reperfusion- (IR ) induced renal injury. The endoplasmic reticulum-associated protein, osteosarcoma-9 (OS-9), has been shown to interact with the carboxyl-terminal tail of meprin beta. More importantly, OS-9 interacts with the hypoxia inducible factor-1alpha (HIF-1alpha) and the prolyl-hydroxylase, proteins which mediate the cell's response to hypoxia. To determine if OS-9 is a meprin substrate, kidney proteins from meprin alphabeta knockout mice (alphabetaKO) (which lack endogenous meprins) and purified human OS-9 were incubated with activated forms of meprin A and meprin B, and Western blot analysis was used to evaluate proteolytic processing of OS-9. Fragmentation of OS-9 was observed in reactions with meprin B, but not meprin A. To determine whether meprin B cleaves OS-9 in vivo, wild type (WT) and meprin alphabetaKO mice were subjected to IR-induced renal injury. Fragmentation of OS-9 was observed in kidney proteins from WT mice subjected to IR, but not in meprin alphabetaKO counterparts. Transfection of kidney cells (MDCK and HEK293) with meprin beta cDNA prevented accumulation of OS-9 following exposure to the hypoxia mimic, CoCl2. These data suggest that meprin beta interaction with OS-9 plays a role in the hypoxia response associated with IR induced renal injury. PMID- 27478638 TI - Total Protein Profile and Drug Resistance in Candida albicans Isolated from Clinical Samples. AB - This study was done to assess the antifungal susceptibility of clinical isolates of Candida albicans and to evaluate its total protein profile based on morphological difference on drug resistance. Hundred and twenty clinical isolates of C. albicans from various clinical specimens were tested for susceptibility against four antifungal agents, namely, fluconazole, itraconazole, amphotericin B, and ketoconazole. A significant increase of drug resistance in clinical isolates of C. albicans was observed. The study showed 50% fluconazole and itraconazole resistance at 32 MUg mL(-1) with a MIC50 and MIC90 values at 34 and 47 and 36 and 49 MUg mL(-1), respectively. All isolates were sensitive to amphotericin B and ketoconazole. The SDS-PAGE protein profile showed a prevalent band of ~52.5 kDa, indicating overexpression of gene in 72% strains with fluconazole resistance. Since the opportunistic infections of Candida spp. are increasing along with drug resistance, the total protein profile will help in understanding the evolutionary changes in drug resistance and also to characterize them. PMID- 27478639 TI - Health Status and Social Networks as Predictors of Resilience in Older Adults Residing in Rural and Remote Environments. AB - Purpose. Health status and social networks are associated with resilience among older adults. Each of these factors may be important to the ability of adults to remain in rural and remote communities as they age. We examined the association of health status and social networks and resilience among older adults dwelling in a rural and remote county in the Western United States. Methods. We selected a random sample of 198 registered voters aged 65 years or older from a frontier Wyoming county. Hierarchical linear regression was used to examine the association of health status as well as social networks and resilience. We also examined health status as a moderator of the relationship between social networks and resilience. Results. Family networks (p = 0.024) and mental health status (p < 0.001) significantly predicted resilience. Mental health status moderated the relationship of family (p = 0.004) and friend (p = 0.021) networks with resilience. Smaller family and friend networks were associated with greater resilience when mental health status was low, but not when it was high. Conclusion. Efforts to increase mental health status may improve resilience among older adults in rural environments, particularly for those with smaller family and friends networks. PMID- 27478640 TI - The Effects of Exercise on the Physical Fitness of High and Moderate-Low Functioning Older Adult Women. AB - Introduction. Understanding how exercise affects individuals with varying levels of functional ability will provide further insight into the role of exercise during the aging process. It will also aid in the development of exercise programs that are appropriate for a wider spectrum of older adults. Specifically it was the primary aim of this study to determine and compare the effects of 10 weeks of community-based exercise on the cardiovascular endurance, muscular strength, flexibility, and balance fitness components of older adult women with high and moderate-low levels of physical function. Methods. Participants were placed in either the high functioning (n = 13) or moderate/low functioning (n = 17) groups based on their level of physical functioning. Fitness components were measured by the Senior Fitness Test and physical function was determined by the Composite Physical Function scale. Results. The results of the 3 * 2 mixed ANOVA statistical analysis showed no significant interaction effect for time * group for any of the six subtests (chair stand, arm curls, 2-minute step, chair sit-and reach, back scratch, and 6-foot up-and-go) of the SFT. However, the main effect of time was significant for all fitness components and the main effect of group was significant for all fitness components except lower extremity flexibility. Discussion. Community-based exercise programs offering a variety of exercise types to people with varying levels of functional ability can be useful in maintaining or improving fitness and independence. These programs may also be capable of improving the self-efficacy of lower functioning older adults toward performing daily tasks. PMID- 27478641 TI - Simple In-Hospital Interventions to Reduce Door-to-CT Time in Acute Stroke. AB - Background. Intravenous tissue plasminogen activator, a time dependent therapy, can reduce the morbidity and mortality of acute ischemic stroke. This study was designed to assess the effect of simple in-hospital interventions on reducing door-to-CT (DTC) time and reaching door-to-needle (DTN) time of less than 60 minutes. Methods. Before any intervention, DTC time was recorded for 213 patients over a one-year period at our center. Five simple quality-improvement interventions were implemented, namely, call notification, prioritizing patients for CT scan, prioritizing patients for lab analysis, specifying a bed for acute stroke patients, and staff education. After intervention, over a course of 44 months, DTC time was recorded for 276 patients with the stroke code. Furthermore DTN time was recorded for 106 patients who were treated with IV thrombolytic therapy. Results. The median DTC time significantly decreased in the postintervention period comparing to the preintervention period [median (IQR); 20 (12-30) versus 75 (52.5-105), P < 0.001]. At the postintervention period, the median (IQR) DTN time was 55 (40-73) minutes and proportion of patients with DTN time less than 60 minutes was 62.4% (P < 0.001). Conclusion. Our interventions significantly reduced DTC time and resulted in an acceptable DTN time. These interventions are feasible in most hospitals and should be considered. PMID- 27478642 TI - Revisits within 48 Hours to a Thai Emergency Department. AB - Objective. Emergency department (ED) revisits are a common ED quality measure. This study was undertaken to ascertain the contributing factors of revisits within 48 hours to a Thai ED and to explore physician-related, illness-related, and patient-related factors behind those revisits. Methods. This study was a chart review from one tertiary care, urban Thai hospital from October 1, 2009, to September 31, 2010. We identified patients who returned to the ED within 48 hours for the same or related complaints after their initial discharge. Three physicians classified revisit as physician-related, illness-related, and patient related factors. Results. Our study included 172 ED patients' charts. 86/172 (50%) were male and the mean age was 38 +/- 5.6 (SD) years. The ED revisits contributing factors were physician-related factors [86/172 (50.0%)], illness related factors [61/172 (35.5%)], and patient-related factor [25/172 (14.5%)], respectively. Among revisits classified as physician-related factors, 40/86 (46.5%) revisits were due to misdiagnosis and 36/86 (41.9%) were due to suboptimal management. Abdominal pain [27/86 (31.4%)] was the majority of physician-related chief complaints, followed by fever [16/86 (18.6%)] and dyspnea [15/86 (17.4%)]. Conclusion. Misdiagnosis and suboptimal management contributed to half of the 48-hour repeat ED visits in this Thai hospital. PMID- 27478643 TI - Etodolac Containing Topical Niosomal Gel: Formulation Development and Evaluation. AB - The present study aimed to investigate the delivery potential of Etodolac (ETD) containing topical niosomal gel. Niosomal formulations were prepared by thin film hydration method at various ratios of cholesterol and Span 60 and were evaluated with respect to particle size, shape, entrapment efficiency, and in vitro characteristics. Dicetyl phosphate (DCP) was also added in the niosomal formulation. Mean particle size of niosomal formulation was found to be in the range of 2 MUm to 4 MUm. Niosomal formulation N2 (1 : 1) ratio of cholesterol and surfactant displayed good entrapment efficiency (96.72%). TEM analyses showed that niosomal formulation was spherical in shape. Niosomal formulation (N2) displayed high percentage of drug release after 24 h (94.91) at (1 : 1) ratio of cholesterol : surfactant. Further selected niosomal formulation was used to formulate topical gel and was characterized with respect to its various parameters such as pH, viscosity, spreadability, ex vivo study, and in vivo potential permeation. Ex vivo study showed that niosomal gel possessed better skin permeation study than the plain topical gel. Further in vivo study revealed good inhibition of inflammation in case of topical niosomal gel than plain gel and niosomal formulation. The present study suggested that topical niosomal gel formulations provide sustained and prolonged delivery of drug. PMID- 27478644 TI - Epidemiology of Cancers in Kashmir, India: An Analysis of Hospital Data. AB - Cancer is a leading cause of mortality and morbidity in the world. The aim of the present study was to measure the pattern of different cancers in Kashmir, India, a cancer belt with peculiar cancer profile. A hospital based cancer registry was started by the Department of Community Medicine, Government Medical College, Srinagar, in January 2006, wherein information was collected from cancer patients who were diagnosed and treated in the hospital. Data has been analysed for a period extending from January 2006 to December 2012. Descriptive analysis has been done by using statistical software. A total of 1598 cancer patients were admitted during this period. Overall male to female ratio was 1.33 : 1. Stomach cancer was the most commonly reported cancer (25.2%), followed by colorectal cancer (16.4%) and lung cancer (13.2%) among males. For females, colorectal cancer (16.8%), breast cancer (16.1%), and stomach cancer (10.4%) were the most frequently reported cancers in order of frequency. Tobacco related cancers contributed to more than three-fourths of cancers among men and more than half of cancers for women. There is an urgent need to set up a population based cancer registration system to understand the profile of cancers specific to this geographic region. PMID- 27478645 TI - Neuroplasticity: Insights from Patients Harboring Gliomas. AB - Neuroplasticity is the ability of the brain to reorganize itself during normal development and in response to illness. Recent advances in neuroimaging and direct cortical stimulation in human subjects have given neuroscientists a window into the timing and functional anatomy of brain networks underlying this dynamic process. This review will discuss the current knowledge about the mechanisms underlying neuroplasticity, with a particular emphasis on reorganization following CNS pathology. First, traditional mechanisms of neuroplasticity, most relevant to learning and memory, will be addressed, followed by a review of adaptive mechanisms in response to pathology, particularly the recruitment of perilesional cortical regions and unmasking of latent connections. Next, we discuss the utility and limitations of various investigative techniques, such as direct electrocortical stimulation (DES), functional magnetic resonance imaging (fMRI), corticocortical evoked potential (CCEP), and diffusion tensor imaging (DTI). Finally, the clinical utility of these results will be highlighted as well as possible future studies aimed at better understanding of the plastic potential of the brain with the ultimate goal of improving quality of life for patients with neurologic injury. PMID- 27478646 TI - Sleep Spindle Characteristics in Children with Neurodevelopmental Disorders and Their Relation to Cognition. AB - Empirical evidence indicates that sleep spindles facilitate neuroplasticity and "off-line" processing during sleep, which supports learning, memory consolidation, and intellectual performance. Children with neurodevelopmental disorders (NDDs) exhibit characteristics that may increase both the risk for and vulnerability to abnormal spindle generation. Despite the high prevalence of sleep problems and cognitive deficits in children with NDD, only a few studies have examined the putative association between spindle characteristics and cognitive function. This paper reviews the literature regarding sleep spindle characteristics in children with NDD and their relation to cognition in light of what is known in typically developing children and based on the available evidence regarding children with NDD. We integrate available data, identify gaps in understanding, and recommend future research directions. Collectively, studies are limited by small sample sizes, heterogeneous populations with multiple comorbidities, and nonstandardized methods for collecting and analyzing findings. These limitations notwithstanding, the evidence suggests that future studies should examine associations between sleep spindle characteristics and cognitive function in children with and without NDD, and preliminary findings raise the intriguing question of whether enhancement or manipulation of sleep spindles could improve sleep-dependent memory and other aspects of cognitive function in this population. PMID- 27478647 TI - Individual Differences in Behavioural Despair Predict Brain GSK-3beta Expression in Mice: The Power of a Modified Swim Test. AB - While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome. PMID- 27478648 TI - Sleep Spindles Characteristics in Insomnia Sufferers and Their Relationship with Sleep Misperception. AB - Cortical hyperarousal is higher in insomnia sufferers (INS) than in good sleepers (GS) and could be related to an alteration in sleep protection mechanisms, like reduced density or altered characteristics in sleep spindles. The deficient sleep protection mechanisms might in turn enhance underestimation of sleep. This study's objective was to document sleep spindles characteristics in INS compared with GS and to investigate their potential role in sleep consolidation and misperception. Seventeen individuals with paradoxical insomnia (PARA-I), 24 individuals with psychophysiological insomnia (PSY-I), and 29 GS completed four consecutive polysomnographic nights in laboratory. Sleep spindles were detected automatically during stage 2 and SWS (3-4) on night 3. Number, density, duration, frequency, and amplitude of sleep spindles were calculated. A misperception index was used to determine the degree of discrepancy between subjective and objective total sleep times. Kruskal-Wallis H tests and post hoc tests revealed that PARA-I had significantly shorter sleep spindles than GS but that PSY-I and GS did not differ on spindles length. A standard multiple regression model revealed that neither sleep spindles characteristics nor objective sleep measures were predictive of sleep misperception. A longer duration of spindles could reflect a higher gating process but this hypothesis still needs to be confirmed in replication studies. PMID- 27478650 TI - Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine. AB - We present a case of a syncopal episode resulting from significant QT interval prolongation in a patient on hydroxychloroquine for the treatment of systemic lupus erythematosus and end stage renal disease. The patient had been treated with hydroxychloroquine for two years prior to presentation. After thorough workup for secondary causes of QT interval prolongation hydroxychloroquine was discontinued and the patient's QT interval shortened. The patient was treated with mexiletine to prevent sudden ventricular arrhythmias, which was unique compared to other documented cases in which lidocaine was used. The patient was noted to have mild prolongation of the QT interval on electrocardiogram prior to initiation of hydroxychloroquine therapy which was exacerbated by its use and may have been caused due to toxicity from underlying renal failure. PMID- 27478651 TI - Diagnosis Using CCTA and Management of Anomalous Right Coronary Artery from the Opposite Sinus. AB - Coronary anomalies can be observed in 1-1.2% of all angiograms performed. Majority of coronary anomalies are benign and do not lead to cardiac ischemia; however anomalous coronary arteries from the opposite sinus (ACAOS) are often associated with sudden cardiac deaths, typically in 0.11-0.35% of individuals who participate in vigorous physical activity (Penalver et al., 2012). Left and right ACAOS have an incidence of 0.15% and 0.92%, respectively. Left ACAOS are often associated with higher incidence of sudden cardiac death; this could be secondary to greater territory of myocardial perfusion by the left coronary artery. ACAOS are often asymptomatic and initially present as sudden death following exertion in young athletes. The management of left ACAOS is clear and surgery is usually indicated. However there is a lack of consensus on the management of certain cases of right ACAOS. In this paper a case of 20 yo M with right coronary artery from left sinus is going to be presented with a discussion on pathophysiology, diagnosis, and management. PMID- 27478649 TI - Sleep Spindles as an Electrographic Element: Description and Automatic Detection Methods. AB - Sleep spindle is a peculiar oscillatory brain pattern which has been associated with a number of sleep (isolation from exteroceptive stimuli, memory consolidation) and individual characteristics (intellectual quotient). Oddly enough, the definition of a spindle is both incomplete and restrictive. In consequence, there is no consensus about how to detect spindles. Visual scoring is cumbersome and user dependent. To analyze spindle activity in a more robust way, automatic sleep spindle detection methods are essential. Various algorithms were developed, depending on individual research interest, which hampers direct comparisons and meta-analyses. In this review, sleep spindle is first defined physically and topographically. From this general description, we tentatively extract the main characteristics to be detected and analyzed. A nonexhaustive list of automatic spindle detection methods is provided along with a description of their main processing principles. Finally, we propose a technique to assess the detection methods in a robust and comparable way. PMID- 27478652 TI - Arteria Lusoria: An Anomalous Finding during Right Transradial Coronary Intervention. AB - Arteria Lusoria or aberrant right subclavian artery (ARSA) is present in 0.6-1.4% of individuals. It typically remains clinically silent and is often discovered during angiographic procedures. The presence of ARSA can make a right transradial approach for coronary angiography and angioplasty technically more difficult. With the use of catheter support, we describe two cases in which a right transradial approach for catheterization was successful in the setting of ARSA. As such, the presence of ARSA does not warrant abandoning a transradial approach for coronary angiography and angioplasty. PMID- 27478653 TI - Iatrogenic Transient Complete Heart Block in a Preexisting LBBB. AB - Catheter induced cardiac arrhythmia is a well-known complication encountered during pulmonary artery or cardiac catheterization. Injury to the cardiac conducting system often involves the right bundle branch which in a patient with preexisting left bundle branch block can lead to fatal arrhythmia including asystole. Such a complication during central venous cannulation is rare as it usually does not enter the heart. The guide wire or the cannula itself can cause such an injury during central venous cannulation. The length of the guide wire, its rigidity, and lack of set guidelines for its insertion make it theoretically more prone to cause such an injury. We report a case of LBBB that went into transient complete heart block following guide wire insertion during a central venous cannulation procedure. PMID- 27478655 TI - Maxillofacial Changes in Melnick-Needles Syndrome. AB - Background. Melnick-Needles Syndrome is rare congenital hereditary skeletal dysplasia caused by mutations in the FLNA gene, which codifies the protein filamin A. This condition leads to serious skeletal abnormalities, including the stomatognathic region. Case Presentation. This paper describes the case of a 13 year-old girl diagnosed with Melnick-Needles Syndrome presenting with different forms of skeletal dysplasia, such as cranial hyperostosis, short upper limbs, bowed long bones, metaphyseal thickening, genu valgum (knock-knee), shortened distal phalanges, narrow pelvis and shoulders, rib tapering and irregularities, elongation of the vertebrae, kyphoscoliosis, micrognathia, hypoplastic coronoid processes of the mandible, left stylohyoid ligament suggesting ossification, and dental development anomalies. Conclusion. Knowledge of this rare syndrome on the part of dentists is important due to the fact that this condition involves severe abnormalities of the stomatognathic system that cause an impact on the development of the entire face as well as functional and esthetic impairments. PMID- 27478654 TI - Bilateral Postoperative Cyst after Maxillary Sinus Surgery: Report of a Case and Systematic Review of the Literature. AB - Purpose. We present a case of a bilateral postoperative maxillary cyst (PMC) and discuss this with a systemic review. Case Report and Literature Review. A 68-year old female with pain and swelling on the right side of the face. MRI and CT showed a cystic tumors of the right and left maxillary sinus. Radical maxillary surgery via a Caldwell-Luc procedure had been performed 55 years ago and bilateral PMC was diagnosed. The PubMed database was searched for PMC within the last 30 years. Results. Together with the current case, we found 23 reports including 284 patients describing PMC. It was diagnosed at a mean time of 22 years after causal surgery at a mean age of 47 years. Initial symptoms were mostly pain with or without swelling. The main radiological sign was a unilocular radiolucency with a slight preference for the left side. Discussion. PMC is a long-term complication that can occur after maxillary sinus surgery and a second surgical approach is required in order to stop cystic expansion. Therefore, patients' informed consent on this complication as well as a prolonged follow-up is recommended. Simple paranasal ultrasound or paranasal sinus plain radiography may lead to an earlier detection reducing interventional morbidity. PMID- 27478656 TI - Unusual Localisation for Onychomatricoma on the 5th Toenail: A Case Report and Review of the Literature. AB - Onychomatricoma is a rare and benign tumour of the nail matrix but originates rarely from the ventral portion of the proximal nail fold. This tumour is characterised by fingerlike projections that invade the nail plate. This lesion, of unknown aetiology, is typically asymptomatic with slow progression. Localisation on the finger is the most frequently described. We report the case of a 68-year-old woman who has an onychomatricoma in an unusual location, the fifth toe of the left foot. Due to its clinical appearance, the tumour can be confused with and treated as onychomycosis. However, if it is resistant to an oral antifungal well behaved treatment, one must consider onychomatricoma diagnosis. PMID- 27478657 TI - Mugwort-Mustard Allergy Syndrome due to Broccoli Consumption. AB - Pollen-food allergy syndrome (PFAS) is a relatively rare form of food allergy which develops in individuals who are sensitized to pollen. Tree pollens, especially birch pollen, frequently induce PFAS; however, the incidence of PFAS due to grass or weed pollens such as ragweed or mugwort is relatively rare. Mugwort-mustard allergy syndrome (MMAS) is an example of a PFAS in which individuals sensitized to mugwort may develop an allergy to mustard and experience severe reactions. We herein describe a case of MMAS due to broccoli consumption. PMID- 27478658 TI - Iatrogenic Radial Nerve Palsy following Closed Reduction of a Simple Diaphyseal Humeral Fracture: Beware the Perfect X-Ray. AB - Radial nerve injury is a recognised complication associated with humeral shaft fracture. A case of iatrogenic radial nerve injury is presented following fracture reduction. The relevant anatomy, challenges in management of humeral fractures with associated radial nerve injury, and the importance of detailed clinical assessment and documentation are discussed. PMID- 27478659 TI - Successful Control of Massive Bleeding in a Child with Burkitt's Lymphoma via a Biosimilar Recombinant Activated Factor VII (AryoSevenTM). AB - We describe a case of a 4-year-old girl with Burkitt's lymphoma, who suffered from a massive gastrointestinal hemorrhage 3 days after chemotherapy. In spite of applying the common practice in correction of coagulopathy, thrombocytopenia persisted and bleeding became life-threatening. In the present case report, we report a successful control of bleeding with a single-dose administration of a biosimilar recombinant activated human factor VII (AryoSeven). PMID- 27478660 TI - Two Cases of Legionella pneumophila Pneumonia with Prolonged Neurologic Symptoms and Brain Hypoperfusion on Single-Photon Emission Computed Tomography. AB - Cerebral and cerebellar symptoms are frequently associated with Legionnaires' disease. However, corresponding brain lesions are difficult to demonstrate using either computed tomography (CT) or magnetic resonance imaging (MRI). We report here two patients with Legionella pneumophila pneumonia accompanied by prolonged neurologic symptoms. In contrast to brain CT and MRI, which failed to detect any abnormalities, single-photon emission computed tomography (SPECT) showed multiple sites of hypoperfusion within the brains of both patients. These cases suggest that vasculopathy, which is detectable by SPECT, might be one of the causes of neurologic symptoms in patients with Legionnaires' disease. PMID- 27478661 TI - Two Case Reports on Thalamic and Basal Ganglia Involvement in Children with Dengue Fever. AB - There have been increasing numbers of case reports of dengue infection with unusual manifestations. Such unusual manifestations including acute liver failure and encephalopathy could be manifested even in the absence of significant plasma leakage. Further, severe organ involvement including nervous system involvement indicates severe dengue infection. However, neurological manifestations of dengue fever are rare. This is the first case report of dengue infection with thalamic and basal ganglia involvement in Sri Lanka. PMID- 27478662 TI - Acute Disseminated Encephalomyelitis following Vaccination against Hepatitis B in a Child: A Case Report and Literature Review. AB - Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system, which has been associated with several vaccines such as rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese B encephalitis, pertussis, influenza, and the Hog vaccine. Here, we presented a case of 12-year-old child who suffered from ADEM three weeks after hepatitis B vaccination. He was admitted to our hospital with symptoms of weakness of limbs, high fever, and alteration of consciousness. Some abnormalities were also found in CSF. Treatment with high-dose corticosteroids and intravenous immunoglobulin had significant effect, with marked improvement of the clinical symptoms and the results of CSF. The findings of MRI also detected some abnormal lesions located in both brain and spinal cord. The clinical features, the findings of CSF and MRI, and therapeutic effect may contribute to such diagnosis of ADEM. PMID- 27478663 TI - Acute Paraplegia due to Thoracic Hematomyelia. AB - Spontaneous intraspinal intramedullary hemorrhage is a rare entity with the acute onset of neurologic symptoms. The etiology of idiopathic spontaneous hematomyelia (ISH) is unknown, and there are few published case reports. Hematomyelia is mostly associated with trauma, but the other nontraumatic etiologies are vascular malformations, tumors, bleeding disorders, syphilis, syrinx, and myelitis. MRI is a good choice for early diagnosis. Hematomyelia usually causes acute spinal cord syndrome due to the compression and destruction of the spinal cord. A high-dose steroid treatment and surgical decompression and evacuation of hematoma are the urgent solution methods. We present idiopathic spontaneous hematomyelia of a previously healthy 80-year-old male with a sudden onset of back pain and paraplegia. PMID- 27478664 TI - A Case of New-Onset Dermatomyositis in the Second Trimester of Pregnancy: A Case Report and Review of the Literature. AB - Dermatomyositis (DM), a subtype of idiopathic inflammatory myopathies (IIMs), is characterized by skin rash, proximal muscle weakness, and inflammatory infiltrates in the muscle tissue. The peak incidence of the disease is at the age of 50-60 years, and only 14% of the patients with IIMs are estimated to present during reproductive years. Because of the limited pregnancy experience in patients with IIMs, little is known regarding the effects of DM on pregnancy or vice versa. We herein report a 40-year-old woman who developed DM in the second trimester of her pregnancy and did not respond to treatment with methylprednisolone. Her pregnancy was terminated at the 32nd week of gestation, due to preeclampsia and fetal distress. She delivered a healthy baby and improved rapidly after delivery. We have searched PubMed for relevant articles and reviewed previously published cases. PMID- 27478665 TI - Sword-Like Trauma to the Shoulder with Open Head-Splitting Fracture of the Head. AB - Head-splitting fractures occur as a result of violent compression of the head against the glenoid; the head splits and the tuberosities may remain attached to the fragments or split and separate. Isolated humeral head-splitting fractures are rare injuries. Favorable results with osteosynthesis can be difficult to achieve because of the very proximal location of the head fracture and associated poor vascularity. We present a case of a 67-year-old man who sustained a severe, sword-like trauma to his left shoulder after a road traffic accident with associated isolated open Gustilo-Anderson IIIA humeral head-splitting fracture. Bony union was achieved with minimal internal fixation but the clinical outcome deteriorated due to accompanying axillary nerve apraxia. To our knowledge, this type of sword-like injury with associated humeral head-split fracture has not previously been reported. PMID- 27478666 TI - Ultrasound Guidance in Performing a Tendoscopic Surgery to Treat Posterior Tibial Tendinitis: A Useful Tool? AB - A 25-year-old man with a pronation-external rotation type of fracture was surgically treated using a fibular plate. Five years later, he underwent resection of bone hyperplasia because of the ankle pain and limitation of range of motion. Thereafter, the left ankle became intermittently painful, which persisted for about one year. He presented at the age of 43 with persistent ankle pain. Physical and image analysis findings indicated a diagnosis of posttraumatic posterior tibial tendinitis, which we surgically treated using tendoscopy. Endoscopic findings showed tenosynovitis and fibrillation on the tendon surface. We cleaned and removed the synovium surrounding the tendon and deepened the posterior tibial tendon groove to allow sufficient space for the posterior tibial tendon. Full weight-bearing ambulation was permitted one day after surgery and he returned to his occupation in the construction industry six weeks after surgery. The medial aspect of the ankle was free of pain and symptoms at a review two years after surgery. Although tendoscopic surgery for stage 1 posterior tibial tendon dysfunction has been reported, tendoscopic surgery to treat posttraumatic posterior tibial tendinitis has not. Our experience with this patient showed that tendoscopic surgery is useful not only for stage 1 posterior tibial dysfunction, but also for posttraumatic posterior tibial tendinitis. PMID- 27478667 TI - A Case of Legg-Calve-Perthes Disease due to Transient Synovitis of the Hip. AB - Transient synovitis (TS) of the hip develops spontaneously in childhood; it usually has a good prognosis and is a self-limiting disease. However, its pathology is not well known. We describe a case of Legg-Calve-Perthes disease (LCPD) that seemingly developed due to TS. Even if TS is diagnosed on the basis of the patient's medical history and imaging findings, physicians should consider the possibility of LCPD and perform a careful observation if joint effusion continues and/or a symptom does not improve within 4 weeks. PMID- 27478668 TI - Metastatic Malignant Melanoma of Parotid Gland with a Regressed Primary Tumor. AB - Malignant melanoma of the parotid gland is often metastatic and mainly originates from malignant melanomas in the head and neck. Nevertheless, some malignant melanomas may metastasize and subsequently regress. Therefore, it may not be possible to observe a metastatic malignant melanoma and its primary melanoma simultaneously. The investigation of a patient's old photographs may help in the detection of preexisting and regressed pigmented lesions in the facial and neck regions. PMID- 27478669 TI - Vitamin D and Risk for Vitamin A Intoxication in an 18-Month-Old Boy. AB - An 18-month-old boy presented with abdominal pain, vomiting, diarrhea, and poor appetite for 6 days. He had been given a multivitamin preparation once daily, containing 50.000 IU of vitamin D and 10.000 IU of vitamin A for a wide anterior fontanelle for about three months. He presented with hypercalcemia, low levels of parathyroid hormone (PTH), and very high serum 25-hydroxyvitamin D (25-OHD) levels. Renal ultrasound showed nephrocalcinosis. He did not have sign or symptom of vitamin A intoxication. Patient was successfully treated with intravenous hydration, furosemide, and prednisolone. With treatment, serum calcium returned rapidly to the normal range and serum 25-OHD levels were reduced progressively. In conclusion the diagnosis of vitamin D deficiency rickets without checking 25 OHD levels may cause redundant treatment that leads to vitamin D intoxication (VDI). PMID- 27478670 TI - Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion. AB - We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose metabolism. PMID- 27478671 TI - Lessons Learned and Questions Raised by an Atypical Case of Clozapine-Induced Myocarditis. AB - A Caucasian male in his early twenties suffering from treatment resistant schizophrenia was started on clozapine. After three days he developed tachycardia, a common side effect of clozapine induction. He had one temperature spike (38.9 degrees C) on day ten after induction but remained clinically well. An ECG and blood tests were normal. Due to persistent tachycardia and an episode of collapse whilst seated on day 12, he was admitted to hospital for further investigation. A diagnosis of myocarditis was confirmed as a result of elevated cardiac enzyme levels and an echocardiogram. Following withdrawal of clozapine, supportive management, and initiation of cardiac medication, the patient made a successful recovery. He will be followed up with the cardiology team to ensure that his heart function returns to normal. Given the incidence of clozapine induced myocarditis, the associated mortality risk, and diagnostic difficulties, this case raises questions about whether a formal system for identifying myocarditis should be adopted. PMID- 27478672 TI - Bilateral Orchidopexy in a Hypochondriacal (Somatic Symptom Disorder) Patient and Determination of Fitness for Bilateral Orchidectomy. AB - Introduction. DSM-5 identifies two disorders: somatic symptom disorder and illness anxiety disorder, to replace hypochondriasis in DSM-IV. Patients with both disorders are intensely anxious about the possibility of an undiagnosed illness or devote excessive time and energy to health concerns and are not easily reassured. Both disorders cause considerable distress and life disruption, even at moderate levels. However, hypochondriasis (DSM-IV) is an indication for neither orchidopexy nor orchidectomy. This is the rationale for this report which is the first of its kind to the best of available literature. This is an original case report of interest to a particular clinical specialty of mental health but it will have a broader clinical impact across medicine. Case Presentation. A 30 year-old black male presented to a primary care clinic with multiple internet searches on the topic of testicular pain and its differential diagnosis. He had a bilateral orchidopexy for a suspected torsion. He was referred to mental health unit, to determine fitness for further surgery. Conclusions. If hypochondriasis is suspected in a medical or surgical inpatient, a psychological medicine consultation should be performed, to elucidate the diagnosis, to avoid unnecessary procedures, and to optimize patient's care. PMID- 27478673 TI - Primary Pulmonary Amebiasis Complicated with Multicystic Empyema. AB - Amebiasis is a parasitic infection caused by the protozoan Entamoeba histolytica. While most infections are asymptomatic, the disease could manifest clinically as amebic dysentery and/or extraintestinal invasion in the form of amebic liver abscess or other more rare manifestations such as pulmonary, cardiac, or brain involvement. Herein we are reporting a case of a 24-year-old male with history of Down syndrome who presented with severe right side pneumonia complicated with multicystic empyema resistant to regular medical therapy. Further investigation revealed a positive pleural fluid for E. histolytica cysts and trophozoites. The patient was diagnosed with primary pleuropulmonary amebiasis and he responded promptly to surgical drainage and metronidazole therapy. In patients from endemic areas all physicians should keep a high index of suspicion of amebiasis as a cause of pulmonary disease. PMID- 27478674 TI - Painful Os Peroneum Syndrome: Underdiagnosed Condition in the Lateral Midfoot Pain. AB - Os peroneum is an accessory ossicle located within the peroneus longus tendon. The painful os peroneum syndrome (POPS) results from a wide spectrum of conditions, including fractures, diastases, and other causes. POPS can result in tenosynovitis or discontinuity of the peroneus longus tendon with a clinical presentation of pain in the lateral aspect of the midfoot. Authors report a typical case of POPS, illustrating this entity through different imaging methods (radiographs, ultrasound, and magnetic resonance imaging). We emphasize the prevalence of this ossicle and discuss painful complications. PMID- 27478675 TI - Toxic Epidermal Necrolysis-Like Lesions and Systemic Lupus Erythematosus Possibly Triggered by Sulfasalazine. AB - This case report describes a patient with arthritis of the large joints, bilateral sacroiliitis, and positive anti-SSA and anti-dsDNA antibody, who received sulfasalazine and shortly thereafter became critically ill. He developed toxic epidermal necrolysis, hemolytic anemia, lymphopenia, markedly elevated ferritin, and muscle wasting. A diagnosis of systemic lupus erythematosus was made, and mycophenolate mofetil and systemic glucocorticoids brought this severe disease under control. Toxic epidermal necrolysis-like lesions and hemophagocytic syndrome have been reported as manifestations of systemic lupus erythematosus. This patient possibly had spondyloarthritis or an undifferentiated connective tissue disease at presentation, and we suggest, based on the timing of events, that sulfasalazine may have acted as a trigger of the severe disease manifestations. PMID- 27478676 TI - Eculizumab for the Treatment of Severe Antibody-Mediated Rejection: A Case Report and Review of the Literature. AB - In renal transplantation, treatment options for antibody-mediated rejection are limited. Here, we report a case of severe AMR treated with eculizumab. A 50-year old woman known for end stage kidney disease secondary to IgA nephropathy received a kidney transplant from a 50-year-old deceased donor. At 5 months after transplantation, she presented with acute graft dysfunction and biopsy showed a severe antibody-mediated rejection associated with thrombotic microangiopathy. Despite an aggressive conventional immunosuppressive regimen, signs of rejection persisted and the patient was treated with 3 doses of eculizumab. Following the therapy, markers of TMA improved and graft function stabilized. However, ongoing signs of rejection remained in the repeated biopsy. In kidney transplantation, eculizumab is an expensive treatment and its role in the treatment of antibody mediated rejection remains to be determined. PMID- 27478677 TI - The Acceptability and Usefulness of Cognitive Stimulation Therapy for Older Adults with Dementia: A Narrative Review. AB - Cognitive stimulation therapy (CST) is an evidence-based therapy for individuals with mild-to-moderate dementia. Past reviews have only synthesized outcomes obtained through quantitative study which does not fully represent the understanding on the acceptability and usefulness of CST. Therefore, the present review aims to integrate outcomes obtained from both quantitative and qualitative studies to provide a deeper understanding on the acceptability and usefulness of CST for older adults with dementia. Findings of literature were retrieved from searches of computerized databases in relation to CST for people with dementia. Literatures were selected according to selection criteria outlined. Results obtained in previous studies pertaining to the effects of CST were discussed in relation to variables such as cognitive function, quality of life, and family caregivers' wellbeing. The review also explores the use of CST in different cultural context, the perception on its effectiveness, and individualized CST (iCST). There is considerable evidence obtained through quantitative and qualitative studies on the usefulness and acceptability of CST for older adults with dementia. Recommendations for future research are provided to strengthen the evidence of CST's effectiveness. PMID- 27478678 TI - Comparison of Test Your Memory and Montreal Cognitive Assessment Measures in Parkinson's Disease. AB - Background. MoCA is widely used in Parkinson's disease (PD) to assess cognition. The Test Your Memory (TYM) test is a cognitive screening tool that is self administered. Objectives. We sought to determine (a) the optimal value of TYM to discriminate between PD patients with and without cognitive deficits on MoCA testing, (b) equivalent MoCA and TYM scores, and (c) interrater reliability in TYM testing. Methods. We assessed the discriminant ability of TYM and the equivalence between TYM and MoCA scores and measured the interrater reliability between three raters. Results. Of the 135 subjects that completed both tests, 55% had cognitive impairment according to MoCA. A MoCA score of 25 was equivalent to a TYM score of 43-44. The area under the receiver operator characteristic (ROC) curve for TYM to differentiate between PD-normal and PD-cognitive impairment was 0.82 (95% CI 0.75 to 0.89). The optimal cutoff to distinguish PD-cognitive impairment from PD-normal was <=45 (sensitivity 90.5%, specificity 59%) thereby correctly classifying 76.3% of patients with PD-cognitive impairment. Interrater agreement was high (0.97) and TYM was completed in under 7 minutes (interquartile range 5.33 to 8.52 minutes). Conclusions. The TYM test is a useful and less resource intensive screening test for cognitive deficits in PD. PMID- 27478680 TI - Racial Disparity in Stroke Awareness in the US: An Analysis of the 2014 National Health Interview Survey. AB - BACKGROUND/AIMS: Stroke is a leading cause of premature death and disability, and increasing the proportion of individuals who are aware of stroke symptoms is a target objective of the Healthy people 2020 project. METHODS: We used data from the 2014 Supplement of the National Health Interview Survey (NHIS) to assess the prevalence of stroke symptom knowledge and awareness. We also tested, using a logistic regression model, the hypothesis that individuals who have knowledge of all 5 stroke symptoms will be have a greater likelihood to activate Emergency Medical Services (EMS) if a stroke is suspected. RESULTS: From the 36,697 participants completing the survey 51% were female. In the entire sample, the age adjusted awareness rate of stroke symptoms/calling 911 was 66.1%. Knowledge of the 5 stroke symptoms plus importance of calling 911 when a stroke is suspected was higher for females, Whites, and individuals with health insurance. Stroke awareness was lowest for Hispanics, Blacks, and survey participants from Western US region. CONCLUSION: The findings allude to continuing differences in the knowledge of stroke symptoms across race/ethnic and other demographic groups. Further research will confirm the importance of increased health literacy for Stroke management and prevention in minority communities. PMID- 27478679 TI - Alcohol Interactions with Psychostimulants: An Overview of Animal and Human Studies. AB - Alcohol consumption with psychostimulants is very common among drug addicts. There is little known about the possible pharmacological interactions between alcohol and psychostimulants. Among most commonly co-abused psychostimulants with alcohol are methamphetamine, cocaine, 3,4-methylenedioxymethamphetaminen, and nicotine. Co-abuse of alcohol with psychostimulants can lead to several neurophysiological dysfunctions such as decrease in brain antioxidant enzymes, disruption of learning and memory processes, cerebral hypo-perfusion, neurotransmitters depletion as well as potentiation of drug seeking behaviour. Moreover, co-abuse of alcohol and psychostimulants can lead to increase in heart rate, blood pressure, myocardial oxygen consumption and cellular stress, and the risk of developing different types of cancer. Co-abuse of alcohol with psychostimulants during pregnancy can lead to fetal brain abnormalities. Further studies are needed to investigate the pharmacokinetics, pharmacodynamics, and neurochemical changes on co-abuse of alcohol and psychostimulants. PMID- 27478682 TI - Achievement of Climate Planning Objectives among U.S. Member Cities of the International Council for Local Environmental Initiatives (ICLEI). AB - In an effort to address climate change, many cities have joined the International Council for Local Environmental Initiatives (ICLEI) whose members commit to work toward five specific program objectives designed to reduce greenhouse gas emissions. This study examines the extent to which 257 member cities in the US have been successful in achieving these program milestones and identifies factors that may explain variation in the performance of member cities. Potential influences on milestone attainment include socioeconomic, political and ideological characteristics of residents, length of ICLEI membership, existence of other climate programs within the state, and local environmental pressures. Multiple regression results indicate that length of membership is the strongest predictor of milestone attainment, regardless of local socioeconomic conditions, ideological and political orientations of residents, or other climate-related initiatives within the state. This finding supports the general effectiveness of ICLEI's network organizational model and its outreach and education efforts. However, member cities facing more "climate stress", including higher levels of hazardous air pollutants (HAP's) and greater automobile use among residents are making slower progress. The findings yield insight into the conditions under which cities engaged in climate planning are more likely to succeed in reducing local greenhouse gas emissions-relevant information for planners, community stakeholders and administrators of organizations like ICLEI. PMID- 27478681 TI - Impact of Depression and Inflammation on the Progression of HIV Disease. AB - The human immunodeficiency virus type 1 (HIV-1) epidemic has negatively affected over 40 million people worldwide. Antiretroviral therapy (ART) has improved life expectancy and changed the outcome of HIV-1 infection, making it a chronic and manageable disease. However, AIDS and non-AIDS comorbid illnesses persist during the course of infection despite the use of ART. In addition, the development of neuropsychiatric comorbidities (including depression) by HIV-infected subjects significantly affects quality of life, medication adherence, and disease prognosis. The factors associated with depression during HIV-1 infection include altered immune response, the release of pro-inflammatory cytokines, and monoamine imbalance. Elevated plasma pro-inflammatory cytokine levels contribute to the development of depression and depressive-like behaviors in HIV+ subjects. In addition, comorbid depression influences the decline rates of CD4+ cell counts and increases plasma viral load. Depression can manifest in some subjects despite their adherence to ART. In addition, psychosocial factors related to stigma (negative attitudes, moral issues, and abuse of HIV+ subjects) are also associated with depression. Both neurobiological and psychosocial factors are important considerations for the effective clinical management of HIV and the prevention of HIV disease progression. PMID- 27478683 TI - Sleep Disorders and Cardio-Renal Disease: Implications for Minority Populations. AB - Obesity is a major public health problem that is reaching pandemic proportion. Currently two thirds of the American population is either overweight or obese and worldwide, 39% of the population is overweight and 13% are considered obese [1,2]. This rapid rise in obesity is associated with increased in diabetes mellitus type 2 (DM2), hypertension (HTN), chronic kidney disease (CKD) and cardiovascular diseases (CVD), the major killer of adults in the USA. Parallel to this epidemic is the rapid rise of sleep disorders such as Obstructive Sleep Apnea (OSA). These disorders lead to increased morbidity and mortality and generally go undiagnosed and undertreated, particularly among minority groups. Accumulating evidence indicates common pathophysiologic background underlying all of these related disorders. Among these include: increased inflammation, increased oxidative stress, endothelial dysfunction, dyslipidemia and hypercoagulability. We discuss the rising epidemic of sleep disorders and its interrelationship with DM2, HTN, CVD and renal disease highlighting the racial disparity in diagnosis and treatment of these disorders that disproportionately affects minority populations. We also discuss the various treatment modalities and the cutting edge developments in this field. PMID- 27478685 TI - Effects of molecularly targeted therapies on murine thymus: highly selective mTOR inhibitors induce reversible thymic involution. AB - BACKGROUND: Blocking mTOR (molecular target of rapamycin) by sirolimus has been shown to suppress cellular respiration. The bearing of this impaired cellular bioenergetics on the mode-of-action of mTOR inhibitors has yet to be illustrated. METHODS: This study investigated in vitro effects of several molecularly-targeted therapies on O2 consumption in thymic fragments from C57BL/6 mice. RESULTS: Thymocyte respiration (uM O2 min(-1) mg(-1)) was reduced by sirolimus and everolimus (p <= 0.007). In contrast, the dual PI3K (phosphatidylinositol-3 kinase)/mTOR inhibitors BEZ235, GDC0980 and GSK2126458, the highly-selective PI3 K-p110-delta inhibitor idelalisib and the calcineurin inhibitor tacrolimus had no effects on thymocyte respiration. Sirolimus was administered intraperitoneally on Days 0-3 and the thymus was then examined on Days 4 and 14. Cortex involution associated with increased cytochrome c and caspase-3 positive cells (apoptosis) were observed on Day 4; these changes were resolved on Day 14 (10 days after sirolimus treatment). On Day 4, the residual thymus (mostly medulla) had normal cellular respiration, decreased caspase activity and increased glutathione. Intraperitoneal administration of sorafenib (a multikinase inhibitor) or idelalisib had no effects on thymus size. CONCLUSION: Thus, the highly-selective mTOR inhibitors imposed specific effects on the thymus, manifested by suppression of cellular respiration and induction of apoptosis. PMID- 27478684 TI - Acute lymphoblastic leukemia with e1a3 BCR/ABL fusion protein. A report of two cases. AB - B Acute Lymphoblastic leukemia (B-ALL) with Philadelphia chromosome (Ph') is a neoplasm of lymphoblast committed to the B cell lineage. The clinical presentation of B-ALL Ph'+ is similar to B-ALL, but is more common in adults than in children. The e1a3 rare variant is produced by the fusion of BCR exon 1 to ABL exon 3. The presence of this translocation has been associated with good disease outcome for chronic myeloid leukemia in a very small series of only 5 cases; there is no such evidence for B-ALL. We report two new cases of B-ALL Ph+ with the rare e1a3 fusion transcript. The e1a3 and e1a2 (p190) transcripts have been reported to have a similar molecular weight and probably a similar clinical profile, thus in these cases the presence of e1a3 was associated with extramedullary infiltration and disease acceleration. PMID- 27478686 TI - Interosseous Membrane and Its Effect on the Distal Radioulnar Joint. PMID- 27478688 TI - Targeting Human beta-Microglobulin with Monoclonal Antibodies in Multiple Myeloma - A Potential in Treatment. PMID- 27478687 TI - AMPK Activators as a Drug for Diabetes, Cancer and Cardiovascular Disease. AB - The cellular mechanisms of AMP-Activated Protein Kinase (AMPK) activators in the treatment and prevention of diabetes, cancer, and cardiovascular disease. PMID- 27478689 TI - Patient Specific Characteristics Are an Important Factor That Determines the Risk of Acute Grade >= 2 Rectal Toxicity in Patients Treated for Prostate Cancer with IMRT and Daily Image Guidance Based on Implanted Gold Markers. AB - AIM: To model acute rectal toxicity in Intensity Modulated Radiation Therapy (IMRT) for prostate cancer using dosimetry and patient specific characteristics. METHODS: A database of 79 prostate cancer patients treated with image guided IMRT was used to fit parameters of Lyman-Kutcher-Burman (LKB) and logistic regression Normal Tissue Complications Probability (NTCP) models to acute grade >= 2 rectal toxicities. We used a univariate regression model to find the dosimetric index which was most correlated with toxicity and a multivariate logistic regression model with machine learning algorithm to integrate dosimetry with patient specific characteristics. We used Receiver Operating Characteristics (ROC) analysis and the area under the ROC curve (AUC) to quantify the predictive power of models. RESULTS: Sixteen patients (20.3%) developed acute grade>=2 rectal toxicity. Our best estimate (95% confidence interval) of LKB model parameters for acute rectal toxicity are exponent n=0.13 (0.1-0.16), slope m=0.09 (0.08-0.11), and threshold dose TD50=56.8 (53.7-59.9) Gy. The best dosimetric indices in the univariate logistic regression NTCP model were D25% and V50Gy. The best AUC of dosimetry only modeling was 0.67 (0.54, 0.8). In the multivariate logistic regression two patient specific variables were particularly strongly correlated with acute rectal toxicity, the use of statin drugs and PSA level prior to IMRT, while two additional variables, age and diabetes were weakly correlated. The AUC of the logistic regression NTCP model improved to 0.88 (0.8, 0.96) when patient specific characteristics were included. In a group of 79 patients, 40 took Statins and 39 did not. Among patients who took statins, (4/40)=10% developed acute grade >=2 rectal toxicity, compared to (12/39)=30.8% who did not take statins (p=0.03). The average and standard deviation of PSA distribution for patients with acute rectal toxicity was PSAtox = 5.77 +/- 2.27 and it was PSAnotox = 9.5 +/- 7.8 for the remainder (p=0.01). CONCLUSIONS: Patient specific characteristics strongly influence the likelihood of acute grade >= 2 rectal toxicity in radiation therapy for prostate cancer. PMID- 27478691 TI - Food and nutritional security requires adequate protein as well as energy, delivered from whole-year crop production. AB - Human food security requires the production of sufficient quantities of both high quality protein and dietary energy. In a series of case-studies from New Zealand, we show that while production of food ingredients from crops on arable land can meet human dietary energy requirements effectively, requirements for high-quality protein are met more efficiently by animal production from such land. We present a model that can be used to assess dietary energy and quality-corrected protein production from various crop and crop/animal production systems, and demonstrate its utility. We extend our analysis with an accompanying economic analysis of commercially-available, pre-prepared or simply-cooked foods that can be produced from our case-study crop and animal products. We calculate the per-person, per day cost of both quality-corrected protein and dietary energy as provided in the processed foods. We conclude that mixed dairy/cropping systems provide the greatest quantity of high-quality protein per unit price to the consumer, have the highest food energy production and can support the dietary requirements of the highest number of people, when assessed as all-year-round production systems. Global food and nutritional security will largely be an outcome of national or regional agroeconomies addressing their own food needs. We hope that our model will be used for similar analyses of food production systems in other countries, agroecological zones and economies. PMID- 27478690 TI - Applicability of the ReproQ client experiences questionnaire for quality improvement in maternity care. AB - Background. The ReproQuestionnaire (ReproQ) measures the client's experience with maternity care, following the WHO responsiveness model. In 2015, the ReproQ was appointed as national client experience questionnaire and will be added to the national list of indicators in maternity care. For using the ReproQ in quality improvement, the questionnaire should be able to identify best and worst practices. To achieve this, ReproQ should be reliable and able to identify relevant differences. Methods and Findings. We sent questionnaires to 17,867 women six weeks after labor (response 32%). Additionally, we invited 915 women for the retest (response 29%). Next we determined the test-retest reliability, the Minimally Important Difference (MID) and six known group comparisons, using two scorings methods: the percentage women with at least one negative experience and the mean score. The reliability for the percentage negative experience and mean score was both 'good' (Absolute agreement = 79%; intraclass correlation coefficient = 0.78). The MID was 11% for the percentage negative and 0.15 for the mean score. Application of the MIDs revealed relevant differences in women's experience with regard to professional continuity, setting continuity and having travel time. Conclusions. The measurement characteristics of the ReproQ support its use in quality improvement cycle. Test-retest reliability was good, and the observed minimal important difference allows for discrimination of good and poor performers, also at the level of specific features of performance. PMID- 27478692 TI - Members of the methanotrophic genus Methylomarinum inhabit inland mud pots. AB - Proteobacteria capable of converting the greenhouse gas methane to biomass, energy, and carbon dioxide represent a small but important sink in global methane inventories. Currently, 23 genera of methane oxidizing (methanotrophic) proteobacteria have been described, although many are represented by only a single validly described species. Here we describe a new methanotrophic isolate that shares phenotypic characteristics and phylogenetic relatedness with the marine methanotroph Methylomarinum vadi. However, the new isolate derives from a terrestrial saline mud pot at the northern terminus of the Eastern Pacific Rise (EPR). This new cultivar expands our knowledge of the ecology of Methylomarinum, ultimately towards a fuller understanding of the role of this genus in global methane cycling. PMID- 27478693 TI - New insight into the role of MMP14 in metabolic balance. AB - Membrane-anchored matrix metalloproteinase 14 (MMP14) is involved broadly in organ development through both its proteolytic and signal-transducing functions. Knockout of Mmp14 (KO) in mice results in a dramatic reduction of body size and wasting followed by premature death, the mechanism of which is poorly understood. Since the mammary gland develops after birth and is thus dependent for its functional progression on systemic and local cues, we chose it as an organ model for understanding why KO mice fail to thrive. A global analysis of the mammary glands' proteome in the wild type (WT) and KO mice provided insight into an unexpected role of MMP14 in maintaining metabolism and homeostasis. We performed mass spectrometry and quantitative proteomics to determine the protein signatures of mammary glands from 7 to 11 days old WT and KO mice and found that KO rudiments had a significantly higher level of rate-limiting enzymes involved in catabolic pathways. Glycogen and lipid levels in KO rudiments were reduced, and the circulating levels of triglycerides and glucose were lower. Analysis of the ultrastructure of mammary glands imaged by electron microscopy revealed a significant increase in autophagy signatures in KO mice. Finally, Mmp14 silenced mammary epithelial cells displayed enhanced autophagy. Applied to a systemic level, these findings indicate that MMP14 is a crucial regulator of tissue homeostasis. If operative on a systemic level, these findings could explain how Mmp14KO litter fail to thrive due to disorder in metabolism. PMID- 27478694 TI - A preliminary case study of the effect of shoe-wearing on the biomechanics of a horse's foot. AB - Horse racing is a multi-billion-dollar industry that has raised welfare concerns due to injured and euthanized animals. Whilst the cause of musculoskeletal injuries that lead to horse morbidity and mortality is multifactorial, pre existing pathologies, increased speeds and substrate of the racecourse are likely contributors to foot disease. Horse hooves have the ability to naturally deform during locomotion and dissipate locomotor stresses, yet farriery approaches are utilised to increase performance and protect hooves from wear. Previous studies have assessed the effect of different shoe designs on locomotor performance; however, no biomechanical study has hitherto measured the effect of horseshoes on the stresses of the foot skeleton in vivo. This preliminary study introduces a novel methodology combining three-dimensional data from biplanar radiography with inverse dynamics methods and finite element analysis (FEA) to evaluate the effect of a stainless steel shoe on the function of a Thoroughbred horse's forefoot during walking. Our preliminary results suggest that the stainless steel shoe shifts craniocaudal, mediolateral and vertical GRFs at mid-stance. We document a similar pattern of flexion-extension in the PIP (pastern) and DIP (coffin) joints between the unshod and shod conditions, with slight variation in rotation angles throughout the stance phase. For both conditions, the PIP and DIP joints begin in a flexed posture and extend over the entire stance phase. At mid-stance, small differences in joint angle are observed in the PIP joint, with the shod condition being more extended than the unshod horse, whereas the DIP joint is extended more in the unshod than the shod condition. We also document that the DIP joint extends more than the PIP after mid-stance and until the end of the stance in both conditions. Our FEA analysis, conducted solely on the bones, shows increased von Mises and Maximum principal stresses on the forefoot phalanges in the shod condition at mid-stance, consistent with the tentative conclusion that a steel shoe might increase mechanical loading. However, because of our limited sample size none of these apparent differences have been tested for statistical significance. Our preliminary study illustrates how the shoe may influence the dynamics and mechanics of a Thoroughbred horse's forefoot during slow walking, but more research is needed to quantify the effect of the shoe on the equine forefoot during the whole stance phase, at faster speeds/gaits and with more individuals as well as with a similar focus on the hind feet. We anticipate that our preliminary analysis using advanced methodological approaches will pave the way for new directions in research on the form/function relationship of the equine foot, with the ultimate goal to minimise foot injuries and improve animal health and welfare. PMID- 27478695 TI - HIV/STIs risks between migrant MSM and local MSM: a cross-sectional comparison study in China. AB - Background. Internal migration plays a significant role in China's HIV epidemic. However, few studies have directly compared migrant men who have sex with men (MSM) with local MSM with regard to HIV/sexually transmitted infections (STIs) risks. Methods. We conducted a study in Guangzhou, China, with the aim of understanding the differences in HIV/STIs risks between migrant MSM and local MSM. A cross-sectional study was conducted among 273 migrant MSM and 249 local MSM in Guangzhou, China. Their behavioral and serologic data on HIV/syphilis were collected and compared between the two groups. A multivariate logistic regression was used to estimate the associations between HIV/STIs risks and migratory status. Results. Migrant MSM, compared to local MSM, have higher odds of reporting unprotected anal intercourse (UAI) (OR = 1.4; 95% CI [0.9-2.0]) and having multiple homosexual partners (OR = 1.2; 95% CI [0.8-1.8]). A lower rate of condom use at homosexual debut was reported in migrant MSM than in local MSM (OR = 0.7; 95% CI [0.5-0.9]). Migrant MSM have less odds of reporting HIV/STIs testing in the previous 6 months relative to local MSM (OR = 0.5; 95% CI [0.4 0.8]). In addition, migrant MSM demonstrated a lower level of HIV knowledge than local MSM (OR = 0.4; 95% CI [0.2-0.8]). Conclusion. Migrant MSM are more likely to engage in sexual risk behaviors, report a lower level of HIV knowledge and have less access to HIV/STIs testing. Further comprehensive interventions targeting migrant MSM are urged. PMID- 27478696 TI - Characterization of a biofilm-forming Shigella flexneri phenotype due to deficiency in Hep biosynthesis. AB - Deficiency in biosynthesis of inner core of lipopolysaccharide (LPS) rendered a characteristic biofilm-forming phenotype in E. coli. The pathological implications of this new phenotype in Shigella flexneri, a highly contagious enteric Gram-negative bacteria that is closely related to E. coli, were investigated in this study. The DeltarfaC (also referred as waaC) mutant, with incomplete inner core of LPS due to deficiency in Hep biosynthesis, was characteristic of strong biofilm formation ability and exhibited much more pronounced adhesiveness and invasiveness to human epithelial cells than the parental strain and other LPS mutants, which also showed distinct pattern of F actin recruitment. Failure to cause keratoconjunctivitis and colonize in the intestine in guinea pigs revealed that the fitness gain on host adhesion resulted from biofilm formation is not sufficient to offset the loss of fitness on survivability caused by LPS deletion. Our study suggests a clear positive relationship between increased surface hydrophobicity and adhesiveness of Shigella flexneri, which should be put into consideration of virulence of Shigella, especially when therapeutic strategy targeting the core oligosaccharide (OS) is considered an alternative to deal with bacterial antibiotics-resistance. PMID- 27478697 TI - Quantification of coral sperm collected during a synchronous spawning event. AB - Most studies of coral reproductive biology to date have focused on oocyte numbers and sizes. Only one (ex situ) study has enumerated sperm numbers, even though these data have multiple potential applications. We quantified total coral sperm and eggs per gamete bundle collected from six species in situ during a synchronous spawning event in Singapore. Egg-sperm bundles were captured midwater as they floated towards the surface after being released by the colony. For each sample, a semi-transparent soft plastic bottle was squeezed and released to create a small suction force that was used to 'catch' the bundles. This technique provided several advantages over traditional methods, including low cost, ease of use, no diving prior to the night of collection needed, and the ability to target specific areas of the colony. The six species sampled were Echinophyllia aspera, Favites abdita, F. chinensis, Merulina ampliata, M. scabricula and Platygyra pini. The mean number of sperm packaged within one egg-sperm bundle ranged from 2.04 * 10(6) to 1.93 * 10(7). The mean number of eggs per egg-sperm bundle ranged from 26.67 (SE +/- 3.27) to 85.33 (SE +/- 17.79). These data are critical for fertilisation success models, but the collection technique described could also be applied to studies requiring in situ spawning data at the polyp level. PMID- 27478698 TI - Transcription factor organic cation transporter 1 (OCT-1) affects the expression of porcine Klotho (KL) gene. AB - Klotho (KL), originally discovered as an aging suppressor, is a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. Recent reports showed Klotho might play a role in adipocyte maturation and systemic glucose metabolism. However, little is known about the transcription factors involved in regulating the expression of porcine KL gene. Deletion fragment analysis identified KL-D2 (-418 bp to -3 bp) as the porcine KL core promoter. MARC0022311SNP (A or G) in KL intron 1 was detected in Landrace * DIV pigs using the Porcine SNP60 BeadChip. The pGL-D2-A and pGL-D2-G were constructed with KL-D2 and the intron fragment of different alleles and relative luciferase activity of pGL3-D2-G was significantly higher than that of pGL3-D2-A in the PK cells and ST cells. This was possibly the result of a change in KL binding ability with transcription factor organic cation transporter 1 (OCT-1), which was confirmed using electrophoretic mobility shift assays (EMSA) and chromatin immune precipitation (ChIP). Moreover, OCT-1 regulated endogenous KL expression by RNA interference experiments. Our study indicates SNP MARC0022311 affects porcine KL expression by regulating its promoter activity via OCT-1. PMID- 27478699 TI - Different patterns of pfcrt and pfmdr1 polymorphism in Plasmodium falciparum isolates from Tehama region, Yemen. AB - Introduction. Despite the efforts of the malaria control programme, malaria morbidity is still a common health problem in Yemen, with 60% of the population at risk. Plasmodium falciparum is responsible for 99% of malaria cases. The emergence in Yemen of parasite resistance to chloroquine (CQ) prompted the adoption of artemisinin combination therapy (ACT) in 2009, which involves the use of artesunate plus sulphadoxine-pyrimethamine (AS + SP). However, CQ was retained as the drug of choice for vivax malaria. To assess the impact of the change in the malaria treatment policy five years after its introduction, the present study investigated the mutations in the CQ resistance transporter (pfcrt) and multidrug resistance 1 (pfmdr1) genes. Method. A molecular investigation of 10 codons of pfcrt (72-76, 220, 271, 326, 356, and 371) and five codons of pfmdr1 (86, 184, 1034, 1042, and 1246) was conducted on P. falciparum isolates from districts with the highest malaria endemicity in the Hodeidah and Al-Mahwit governorates in Tehama region, Yemen. A total of 86 positive cases of falciparum monoinfection were investigated for the presence of mutations related to CQ and other antimalarials using a PCR-RFLP assay. Results. There was a wide prevalence of pfcrt gene mutations with the pfcrt 76T CQ resistance marker being predominant (97.7%). The prevalence of other pfcrt mutations varied from high (75E: 88%) to moderate (74I: 79.1%, 220S: 69.8%, 271E and 371I: 53.5%) or low (326S: 36%, 72S: 10.5%). Mutated pfcrt 72-76 amino acids haplotypes were highly prevalent (98.8%). Among these, the CVIET classic, old-world African/Southeast Asian haplotype was the most predominant, and was mostly found in the isolates from the Khamis Bani Saad district of Al-Mahwit (93.1%) and the AdDahi district of Hodeidah (88.9%). However, it was only found in 26.3% of the isolates from the Bajil district of Hodeidah. Surprisingly, the SVMNT new-world South American haplotype was exclusively detected in 9.3% of the isolates from the Bajil district of Hodeidah. Mutations at Y184F of pfmdr1 were found in all isolates (100%) from all districts. The mutation for codons 1034C and 86Y were found only in the isolates from the AdDahi and Khamis Bani Saad districts. Overall, the AdDahi and Khamis Bani Saad districts were similar in terms of carrying most of the mutations in the pfcrt and pfmdr1 genes, while there was a lower prevalence of mutation in the isolates from the Bajil district. Conclusion. The high prevalence of mutations in pfcrt 5 years after the official cessation of CQ use against P. falciparum suggests that there is sustained CQ pressure on P. falciparum isolates in the study area. Moreover, the low prevalence of mutations in the pfmdr1 gene could be a good indicator of the high susceptibility of P. falciparum isolates to antimalarials other than CQ. A new strategy to ensure the complete nationwide withdrawal of CQ from the private drug market is recommended. PMID- 27478700 TI - How smartphone usage correlates with social anxiety and loneliness. AB - INTRODUCTION: Early detection of social anxiety and loneliness might be useful to prevent substantial impairment in personal relationships. Understanding the way people use smartphones can be beneficial for implementing an early detection of social anxiety and loneliness. This paper examines different types of smartphone usage and their relationships with people with different individual levels of social anxiety or loneliness. METHODS: A total of 127 Android smartphone volunteers participated in this study, all of which have agreed to install an application (MobileSens) on their smartphones, which can record user's smartphone usage behaviors and upload the data into the server. They were instructed to complete an online survey, including the Interaction Anxiousness Scale (IAS) and the University of California Los Angeles Loneliness Scale (UCLA-LS). We then separated participants into three groups (high, middle and low) based on their scores of IAS and UCLA-LS, respectively. Finally, we acquired digital records of smartphone usage from MobileSens and examined the differences in 105 types of smartphone usage behaviors between high-score and low-score group of IAS/UCLA-LS. RESULTS: Individuals with different scores on social anxiety or loneliness might use smartphones in different ways. For social anxiety, compared with users in low score group, users in high-score group had less number of phone calls (incoming and outgoing) (Mann-Whitney U = 282.50~409.00, p < 0.05), sent and received less number of text messages in the afternoon (Mann-Whitney U = 391.50~411.50, p < 0.05), used health & fitness apps more frequently (Mann-Whitney U = 493.00, p < 0.05) and used camera apps less frequently (Mann-Whitney U = 472.00, p < 0.05). For loneliness, users in low-score group, users in high-score group had less number of phone calls (incoming and outgoing) (Mann-Whitney U = 305.00~407.50, p < 0.05) and used following apps more frequently: health & fitness (Mann-Whitney U = 510.00, p < 0.05), system (Mann-Whitney U = 314.00, p < 0.01), phone beautify (Mann-Whitney U = 385.00, p < 0.05), web browser (Mann-Whitney U = 416.00, p < 0.05) and social media (RenRen) (Mann-Whitney >U = 388.50, p < 0.01). DISCUSSION: The results show that individuals with social anxiety or loneliness receive less incoming calls and use healthy applications more frequently, but they do not show differences in outgoing-call-related features. Individuals with higher levels of social anxiety also receive less SMSs and use camera apps less frequently, while lonely individuals tend to use system, beautify, browser and social media (RenRen) apps more frequently. CONCLUSION: This paper finds that there exists certain correlation among smartphone usage and social anxiety and loneliness. The result may be useful to improve social interaction for those who lack social interaction in daily lives and may be insightful for recognizing individual levels of social anxiety and loneliness through smartphone usage behaviors. PMID- 27478701 TI - Hierarchical organization of a Sardinian sand dune plant community. AB - Coastal sand dunes have attracted the attention of plant ecologists for over a century, but they have largely relied on correlations to explain dune plant community organization. We examined long-standing hypotheses experimentally that sand binding, inter-specific interactions, abiotic factors and seedling recruitment are drivers of sand dune plant community structure in Sardinia, Italy. Removing foundation species from the fore-, middle- and back-dune habitats over three years led to erosion and habitat loss on the fore-dune and limited plant recovery that increased with dune elevation. Reciprocal species removals in all zones suggested that inter-specific competition is common, but that dominance is transient, particularly due to sand burial disturbance in the middle-dune. A fully factorial 2-year manipulation of water, nutrient availability and substrate stability revealed no significant proximate response to these physical factors in any dune zone. In the fore- and middle-dune, plant seeds are trapped under adult plants during seed germination, and seedling survivorship and growth generally increase with dune height in spite of increased herbivory in the back-dune. Sand and seed erosion leads to limited seed recruitment on the fore-dune while high summer temperatures and preemption of space lead to competitive dominance of woody plants in the back-dune. Our results suggest that Sardinian sand dune plant communities are organized hierarchically, structured by sand binding foundation species on the fore-dune, sand burial in the middle-dune and increasingly successful seedling recruitment, growth and competitive dominance in the back dune. PMID- 27478703 TI - Human population and socioeconomic modulators of conservation performance in 788 Amazonian and Atlantic Forest reserves. AB - Protected areas form a quintessential component of the global strategy to perpetuate tropical biodiversity within relatively undisturbed wildlands, but they are becoming increasingly isolated by rapid agricultural encroachment. Here we consider a network of 788 forest protected areas (PAs) in the world's largest tropical country to examine the degree to which they remain intact, and their responses to multiple biophysical and socioeconomic variables potentially affecting natural habitat loss under varying contexts of rural development. PAs within the complex Brazilian National System of Conservation Units (SNUC) are broken down into two main classes-strictly protected and sustainable use. Collectively, these account for 22.6% of the forest biomes within Brazil's national territory, primarily within the Amazon and the Atlantic Forest, but are widely variable in size, ecoregional representation, management strategy, and the degree to which they are threatened by human activities both within and outside reserve boundaries. In particular, we examine the variation in habitat conversion rates in both strictly protected and sustainable use reserves as a function of the internal and external human population density, and levels of land-use revenue in adjacent human-dominated landscapes. Our results show that PAs surrounded by heavily settled agro-pastoral landscapes face much greater challenges in retaining their natural vegetation, and that strictly protected areas are considerably less degraded than sustainable use reserves, which can rival levels of habitat degradation within adjacent 10-km buffer areas outside. PMID- 27478704 TI - -A practical application of reduced-copper antifouling paint in marine biological research. AB - Biofouling of experimental cages and other field apparatuses can be problematic for scientists and has traditionally been addressed using frequent manual removal (e.g., scraping, scrubbing). Recent environmental restrictions and legislative changes have driven the development of less hazardous antifouling products, making antifouling paint a potential alternative option to manual removal. Consequently, the viability of using these newly developed products as a replacement for the manual cleaning of exclusion cages was experimentally investigated. There were six treatments tested, comprising three with settlement tiles in experimental cages coated with antifouling paint, two with settlement tiles in unpainted experimental cages, and one cage-free suspended tile. The three antifouling treatments comprised two reduced-copper paints (21% Cu2O and 40% Cu2O) and one copper-free, Econea (TM)-based paint (labeled "ecofriendly"). Antifouling paints were assessed for performance of preventing fouling of the cages and whether they elicited local effects on settlement tiles contained within them. All three paints performed well to reduce fouling of the cages during the initial six weeks of the experiment, but the efficacy of "ecofriendly" paint began to decrease during an extended deployment that lasted 14 weeks. The macro-community composition, biomass, and percent cover of settled organism on tiles within cages treated with copper-based paints (21% and 40% concentrations) were indistinguishable from tiles within the manually scrubbed cages. In contrast, settlement to tiles from the "ecofriendly" treatment was different in composition of macro-community and lower in biomass, suggesting the presence of local effects and therefore rendering it unsuitable for use in settlement experiments. The results of this study suggest that reduced-copper paints have the potential to serve as an alternative to manual maintenance, which may be useful for deployments in locations that are difficult to access on a frequent schedule. PMID- 27478702 TI - Association between aberrant APC promoter methylation and breast cancer pathogenesis: a meta-analysis of 35 observational studies. AB - Background. Adenomatous polyposis coli (APC) is widely known as an antagonist of the Wnt signaling pathway via the inactivation of beta-catenin. An increasing number of studies have reported that APC methylation contributes to the predisposition to breast cancer (BC). However, recent studies have yielded conflicting results. Methods. Herein, we systematically carried out a meta analysis to assess the correlation between APC methylation and BC risk. Based on searches of the Cochrane Library, PubMed, Web of Science and Embase databases, the odds ratio (OR) with 95% confidence interval (CI) values were pooled and summarized. Results. A total of 31 articles involving 35 observational studies with 2,483 cases and 1,218 controls met the inclusion criteria. The results demonstrated that the frequency of APC methylation was significantly higher in BC cases than controls under a random effect model (OR = 8.92, 95% CI [5.12-15.52]). Subgroup analysis further confirmed the reliable results, regardless of the sample types detected, methylation detection methods applied and different regions included. Interestingly, our results also showed that the frequency of APC methylation was significantly lower in early-stage BC patients than late stage ones (OR = 0.62, 95% CI [0.42-0.93]). Conclusion. APC methylation might play an indispensable role in the pathogenesis of BC and could be regarded as a potential biomarker for the diagnosis of BC. PMID- 27478705 TI - Behavioral flexibility in an invasive bird is independent of other behaviors. AB - Behavioral flexibility is considered important for a species to adapt to environmental change. However, it is unclear how behavioral flexibility works: it relates to problem solving ability and speed in unpredictable ways, which leaves an open question of whether behavioral flexibility varies with differences in other behaviors. If present, such correlations would mask which behavior causes individuals to vary. I investigated whether behavioral flexibility (reversal learning) performances were linked with other behaviors in great-tailed grackles, an invasive bird. I found that behavioral flexibility did not significantly correlate with neophobia, exploration, risk aversion, persistence, or motor diversity. This suggests that great-tailed grackle performance in behavioral flexibility tasks reflects a distinct source of individual variation. Maintaining multiple distinct sources of individual variation, and particularly variation in behavioral flexibility, may be a mechanism for coping with the diversity of novel elements in their environments and facilitate this species' invasion success. PMID- 27478706 TI - Dominant forest tree species are potentially vulnerable to climate change over large portions of their range even at high latitudes. AB - Projecting suitable conditions for a species as a function of future climate provides a reasonable, although admittedly imperfect, spatially explicit estimate of species vulnerability associated with climate change. Projections emphasizing range shifts at continental scale, however, can mask contrasting patterns at local or regional scale where management and policy decisions are made. Moreover, models usually show potential for areas to become climatically unsuitable, remain suitable, or become suitable for a particular species with climate change, but each of these outcomes raises markedly different ecological and management issues. Managing forest decline at sites where climatic stress is projected to increase is likely to be the most immediate challenge resulting from climate change. Here we assess habitat suitability with climate change for five dominant tree species of eastern North American forests, focusing on areas of greatest vulnerability (loss of suitability in the baseline range) in Quebec (Canada) rather than opportunities (increase in suitability). Results show that these species are at risk of maladaptation over a remarkably large proportion of their baseline range. Depending on species, 5-21% of currently climatically suitable habitats are projected to be at risk of becoming unsuitable. This suggests that species that have traditionally defined whole regional vegetation assemblages could become less adapted to these regions, with significant impact on ecosystems and forest economy. In spite of their well-recognised limitations and the uncertainty that remains, regionally-explicit risk assessment approaches remain one of the best options to convey that message and the need for climate policies and forest management adaptation strategies. PMID- 27478707 TI - Shades of yellow: interactive effects of visual and odour cues in a pest beetle. AB - BACKGROUND: The visual ecology of pest insects is poorly studied compared to the role of odour cues in determining their behaviour. Furthermore, the combined effects of both odour and vision on insect orientation are frequently ignored, but could impact behavioural responses. METHODS: A locomotion compensator was used to evaluate use of different visual stimuli by a major coleopteran pest of stored grains (Sitophilus zeamais), with and without the presence of host odours (known to be attractive to this species), in an open-loop setup. RESULTS: Some visual stimuli-in particular, one shade of yellow, solid black and high-contrast black-against-white stimuli-elicited positive orientation behaviour from the beetles in the absence of odour stimuli. When host odours were also present, at 90 degrees to the source of the visual stimulus, the beetles presented with yellow and vertical black-on-white grating patterns changed their walking course and typically adopted a path intermediate between the two stimuli. The beetles presented with a solid black-on-white target continued to orient more strongly towards the visual than the odour stimulus. DISCUSSION: Visual stimuli can strongly influence orientation behaviour, even in species where use of visual cues is sometimes assumed to be unimportant, while the outcomes from exposure to multimodal stimuli are unpredictable and need to be determined under differing conditions. The importance of the two modalities of stimulus (visual and olfactory) in food location is likely to depend upon relative stimulus intensity and motivational state of the insect. PMID- 27478709 TI - Meter scale variation in shrub dominance and soil moisture structure Arctic arthropod communities. AB - The Arctic is warming at twice the rate of the rest of the world. This impacts Arctic species both directly, through increased temperatures, and indirectly, through structural changes in their habitats. Species are expected to exhibit idiosyncratic responses to structural change, which calls for detailed investigations at the species and community level. Here, we investigate how arthropod assemblages of spiders and beetles respond to variation in habitat structure at small spatial scales. We sampled transitions in shrub dominance and soil moisture between three different habitats (fen, dwarf shrub heath, and tall shrub tundra) at three different sites along a fjord gradient in southwest Greenland, using yellow pitfall cups. We identified 2,547 individuals belonging to 47 species. We used species richness estimation, indicator species analysis and latent variable modeling to examine differences in arthropod community structure in response to habitat variation at local (within site) and regional scales (between sites). We estimated species responses to the environment by fitting species-specific generalized linear models with environmental covariates. Species assemblages were segregated at the habitat and site level. Each habitat hosted significant indicator species, and species richness and diversity were significantly lower in fen habitats. Assemblage patterns were significantly linked to changes in soil moisture and vegetation height, as well as geographic location. We show that meter-scale variation among habitats affects arthropod community structure, supporting the notion that the Arctic tundra is a heterogeneous environment. To gain sufficient insight into temporal biodiversity change, we require studies of species distributions detailing species habitat preferences. PMID- 27478708 TI - Molecular characterization of an adiponectin receptor homolog in the white leg shrimp, Litopenaeus vannamei. AB - Adiponectin (AdipoQ) and its receptors (AdipoRs) are strongly related to growth and development of skeletal muscle, as well as glucose and lipid metabolism in vertebrates. Herein we report the identification of the first full-length cDNA encoding an AdipoR homolog (Liv-AdipoR) from the decapod crustacean Litopenaeus vannamei using a combination of next generation sequencing (NGS) technology and bioinformatics analysis. The full-length Liv-AdipoR (1,245 bp) encoded a protein that exhibited the canonical seven transmembrane domains (7TMs) and the inversed topology that characterize members of the progestin and adipoQ receptor (PAQR) family. Based on the obtained sequence information, only a single orthologous AdipoR gene appears to exist in arthropods, whereas two paralogs, AdipoR1 and AdipoR2, have evolved in vertebrates. Transcriptional analysis suggested that the single Liv-AdipoR gene appears to serve the functions of two mammalian AdipoRs. At 72 h after injection of 50 pmol Liv-AdipoR dsRNA (340 bp) into L. vannamei thoracic muscle and deep abdominal muscle, transcription levels of Liv-AdipoR decreased by 93% and 97%, respectively. This confirmed optimal conditions for RNAi of Liv-AdipoR. Knockdown of Liv-AdipoR resulted in significant changes in the plasma levels of ammonia, 3-methylhistine, and ornithine, but not plasma glucose, suggesting that that Liv-AdipoR is important for maintaining muscle fibers. The chronic effect of Liv-AdipoR dsRNA injection was increased mortality. Transcriptomic analysis showed that 804 contigs were upregulated and 212 contigs were downregulated by the knockdown of Liv-AdipoR in deep abdominal muscle. The significantly upregulated genes were categorized as four main functional groups: RNA-editing and transcriptional regulators, molecular chaperones, metabolic regulators, and channel proteins. PMID- 27478710 TI - Characterizing abnormal behavior in a large population of zoo-housed chimpanzees: prevalence and potential influencing factors. AB - Abnormal behaviors in captive animals are generally defined as behaviors that are atypical for the species and are often considered to be indicators of poor welfare. Although some abnormal behaviors have been empirically linked to conditions related to elevated stress and compromised welfare in primates, others have little or no evidence on which to base such a relationship. The objective of this study was to investigate a recent claim that abnormal behavior is endemic in the captive population by surveying a broad sample of chimpanzees (Pan troglodytes), while also considering factors associated with the origins of these behaviors. We surveyed animal care staff from 26 accredited zoos to assess the prevalence of abnormal behavior in a large sample of chimpanzees in the United States for which we had information on origin and rearing history. Our results demonstrated that 64% of this sample was reported to engage in some form of abnormal behavior in the past two years and 48% of chimpanzees engaged in abnormal behavior other than coprophagy. Logistic regression models were used to analyze the historical variables that best predicted the occurrence of all abnormal behavior, any abnormal behavior that was not coprophagy, and coprophagy. Rearing had opposing effects on the occurrence of coprophagy and the other abnormal behaviors such that mother-reared individuals were more likely to perform coprophagy, whereas non-mother-reared individuals were more likely to perform other abnormal behaviors. These results support the assertion that coprophagy may be classified separately when assessing abnormal behavior and the welfare of captive chimpanzees. This robust evaluation of the prevalence of abnormal behavior in our sample from the U.S. zoo population also demonstrates the importance of considering the contribution of historical variables to present behavior, in order to better understand the causes of these behaviors and any potential relationship to psychological wellbeing. PMID- 27478711 TI - Rapid response of arbuscular mycorrhizal fungal communities to short-term fertilization in an alpine grassland on the Qinghai-Tibet Plateau. AB - BACKGROUND: The Qinghai-Tibet Plateau (QTP) is home to the vast grassland in China. The QTP grassland ecosystem has been seriously degraded by human land use practices and climate change. Fertilization is used in this region to increase vegetation yields for grazers. The impact of long-term fertilization on plant and microbial communities has been studied extensively. However, the influence of short-term fertilization on arbuscular mycorrhizal fungal (AMF) communities in the QTP is largely unknown, despite their important functional role in grassland ecosystems. METHODS: We investigated AMF community responses to three years of N and/or P addition at an experimental field site on the QTP, using the Illumina MiSeq platform (PE 300). RESULTS: Fertilization resulted in a dramatic shift in AMF community composition and NP addition significantly increased AMF species richness and phylogenetic diversity. Aboveground biomass, available phosphorus, and NO3 (-) were significantly correlated with changes in AMF community structure. Changes in these factors were driven by fertilization treatments. Thus, fertilization had a large impact on AMF communities, mediated by changes in aboveground productivity and soil chemistry. DISCUSSION: Prior work has shown how plants often lower their reliance on AMF symbioses following fertilization, leading to decrease AMF abundance and diversity. However, our study reports a rise in AMF diversity with fertilization treatment. Because AMF can provide stress tolerance to their hosts, we suggest that extreme weather on the QTP may help drive a positive relationship between fertilizer amendment and AMF diversity. PMID- 27478712 TI - Comparison of buckwheat, red clover, and purple tansy as potential surrogate plants for use in semi-field pesticide risk assessments with Bombus impatiens. AB - Background. Bumble bees (Bombus spp.) are important wild and managed pollinators. There is increased interest in incorporating data on bumble bees into risk assessments for pesticides, but standardized methods for assessing hazards of pesticides in semi-field and field settings have not yet been established for bumble bees. During semi-field studies, colonies are caged with pesticide-treated flowering surrogate plants, which must be attractive to foragers to ensure colony exposure to the test compound, and must produce an ample nectar and pollen to sustain colonies during testing. However, it is not known which plant(s) are suitable for use in semi-field studies with bumble bees. Materials and Methods. We compared B. impatiens foraging activity and colony development on small plots of flowering buckwheat (Fagopyrum esculentum, var. common), red clover (Trifolium pratense), and purple tansy (Phacelia tanacetifolia) under semi-field conditions to assess their suitability as surrogate plants for pesticide risk assessment studies with bumble bees. We also compared the growth characteristics and input requirements of each plant type. Results. All three plant types generally established and grew well. Red clover and purple tansy experienced significant weed pressure and/or insect pest damage. In contrast, pest pressure was extremely low in buckwheat. Overall, B. impatiens foraging activity was significantly greater on buckwheat plots than red clover or purple tansy, but plant type had no effect on number of individuals produced per colony or colony weight. Discussion. Because of the consistently high foraging activity and successful colony development observed on buckwheat plots, combined with its favourable growth characteristics and low maintenance requirements, we recommend buckwheat as a surrogate plant for use in semi-field pesticide toxicity assessments with B. impatiens. PMID- 27478713 TI - A simple, sufficient, and consistent method to score the status of threats and demography of imperiled species. AB - Managers of large, complex wildlife conservation programs need information on the conservation status of each of many species to help strategically allocate limited resources. Oversimplifying status data, however, runs the risk of missing information essential to strategic allocation. Conservation status consists of two components, the status of threats a species faces and the species' demographic status. Neither component alone is sufficient to characterize conservation status. Here we present a simple key for scoring threat and demographic changes for species using detailed information provided in free-form textual descriptions of conservation status. This key is easy to use (simple), captures the two components of conservation status without the cost of more detailed measures (sufficient), and can be applied by different personnel to any taxon (consistent). To evaluate the key's utility, we performed two analyses. First, we scored the threat and demographic status of 37 species recently recommended for reclassification under the Endangered Species Act (ESA) and 15 control species, then compared our scores to two metrics used for decision-making and reports to Congress. Second, we scored the threat and demographic status of all non-plant ESA-listed species from Florida (54 spp.), and evaluated scoring repeatability for a subset of those. While the metrics reported by the U.S. Fish and Wildlife Service (FWS) are often consistent with our scores in the first analysis, the results highlight two problems with the oversimplified metrics. First, we show that both metrics can mask underlying demographic declines or threat increases; for example, ~40% of species not recommended for reclassification had changes in threats or demography. Second, we show that neither metric is consistent with either threats or demography alone, but conflates the two. The second analysis illustrates how the scoring key can be applied to a substantial set of species to understand overall patterns of ESA implementation. The scoring repeatability analysis shows promise, but indicates thorough training will be needed to ensure consistency. We propose that large conservation programs adopt our simple scoring system for threats and demography. By doing so, program administrators will have better information to monitor program effectiveness and guide their decisions. PMID- 27478714 TI - Psychometric properties and Confirmatory structure of the Strengths and difficulties questionnaire in a sample of adolescents in Nigeria. AB - Though the SDQ has been used in selected studies in Nigeria, its theoretical structure has not been fully and appropriately investigated in the setting. The present study employs Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) to investigate the theoretical structure of the self-reported version of the SDQ in a sample of adolescents in Benue state, Nigeria. A total of 1,244 adolescents from different categories of secondary schools in Makurdi and Vandekya Local government areas of Benue state participated in the study. Preliminary data analyses were performed using descriptive statistics while the theoretical structure of the SDQ was assessed using EFA and CFA. Model fits were assessed using Chi-square test and other fit indices at 5% significance level. Participants were 14.19+/-2.45 (Vandekya) and 14.19+/-2.45 (Makurdi) years old. Results of the EFA and CFA revealed a 3-factor oblique model as the best model for the sample of adolescents studied (chi2/df =2.20, p<0.001) with all fit indices yielding better results. A correlated 3-factor model fits the present data better than the 5-factor theoretical model of the SDQ. The use of the original 5-factor model of the SDQ in the present setting should be interpreted with caution. PMID- 27478715 TI - Importance of nondiffusive transport for soil CO2 efflux in a temperate mountain grassland. AB - Soil respiration and its biotic and abiotic drivers have been an important research topic in recent years. While the bulk of these efforts has focused on the emission of CO2 from soils, the production and subsequent transport of CO2 from soil to atmosphere received far less attention. However, to understand processes underlying emissions of CO2 from terrestrial ecosystems, both processes need to be fully evaluated. In this study, we tested to what extent the transport of CO2 in a grassland site in the Austrian Alps could be modeled based on the common assumption that diffusion is the main transport mechanism for trace gases in soils. Therefore, we compared the CO2 efflux calculated from the soil CO2 concentration gradient with the CO2 efflux from chamber measurements. We used four commonly used diffusion-driven models for the flux-gradient approach. Models generally underestimated the soil chamber effluxes and their amplitudes, indicating that processes other than diffusion were responsible for the transport of CO2. We further observed that transport rates correlated well with irradiation and, below a soil moisture content of 33%, with wind speed. This suggests that mechanisms such as bulk soil air transport, due to pressure pumping or thermal expansion of soil air due to local surface heating, considerably influence soil CO2 transport at this site. Our results suggest that nondiffusive transport may be an important mechanism influencing diel and day-to-day dynamics of soil CO2 emissions, leading to a significant mismatch (10-87% depending on the model used) between the two approaches at short time scales. PMID- 27478716 TI - The near-global mesospheric potassium layer: Observations and modeling. AB - The meteoric metal layers act as unique tracers of chemistry and dynamics in the upper atmosphere. Existing lidar studies from a few locations show that K exhibits a semiannual seasonality (winter and summer maxima), quite unlike the annual seasonality (winter maximum and summer minimum) seen with Na and Fe. This work uses spaceborne observations made with the Optical Spectrograph and InfraRed Imager System instrument on the Odin satellite to retrieve the near-global K layer for the first time. The satellite data (2004 to mid-2013) are used to validate the implementation of a recently proposed potassium chemistry scheme in a whole atmosphere chemistry climate model, which provides a chemical basis for this semiannual seasonal behavior. The satellite and model data show that this semiannual seasonality is near global in extent, with the strongest variation at middle and high latitudes. The column abundance, centroid layer height, and root mean-square width of the K layer are consistent with the limited available lidar record. The K data set is then used to investigate the impact of polar mesospheric clouds on the metal layers at high latitudes during summer. Finally, the occurrence frequency of sporadic K layers and their possible link to sporadic E layers are examined. PMID- 27478717 TI - Adjustment of regional climate model output for modeling the climatic mass balance of all glaciers on Svalbard. AB - Large-scale modeling of glacier mass balance relies often on the output from regional climate models (RCMs). However, the limited accuracy and spatial resolution of RCM output pose limitations on mass balance simulations at subregional or local scales. Moreover, RCM output is still rarely available over larger regions or for longer time periods. This study evaluates the extent to which it is possible to derive reliable region-wide glacier mass balance estimates, using coarse resolution (10 km) RCM output for model forcing. Our data cover the entire Svalbard archipelago over one decade. To calculate mass balance, we use an index-based model. Model parameters are not calibrated, but the RCM air temperature and precipitation fields are adjusted using in situ mass balance measurements as reference. We compare two different calibration methods: root mean square error minimization and regression optimization. The obtained air temperature shifts (+1.43 degrees C versus +2.22 degrees C) and precipitation scaling factors (1.23 versus 1.86) differ considerably between the two methods, which we attribute to inhomogeneities in the spatiotemporal distribution of the reference data. Our modeling suggests a mean annual climatic mass balance of 0.05 +/- 0.40 m w.e. a-1 for Svalbard over 2000-2011 and a mean equilibrium line altitude of 452 +/- 200 m above sea level. We find that the limited spatial resolution of the RCM forcing with respect to real surface topography and the usage of spatially homogeneous RCM output adjustments and mass balance model parameters are responsible for much of the modeling uncertainty. Sensitivity of the results to model parameter uncertainty is comparably small and of minor importance. PMID- 27478718 TI - Crustal anisotropy across northern Japan from receiver functions. AB - Northern Japan is a tectonically active area, with the presence of several volcanoes, and with frequent earthquakes among which the destructive Mw = 8.9 9.0 Tohoku-oki occurred on 11 March 2011. Tectonic activity leaves an imprint on the crustal structures, on both the upper and the lower layers. To investigate the crust in northern Japan, we construct a receiver function data set using teleseismic events recorded at 58 seismic stations belonging to the Japanese National (Hi-net) network. We isolate the signals, in the receiver function wavelet, that witness the presence of anisotropic structures at depth, with the aim of mapping the variation of anisotropy across the northern part of the island. This study focuses on the relation among anisotropy detected in the crust, stresses induced by plate convergence across the subduction zone, and the intrinsic characteristics of the rocks. Our results show how a simple velocity model with two anisotropic layers reproduces the observed data at the stations. We observe a negligible or small amount of signal related to anisotropy in the eastern part of the study area (i.e., the outer arc) for both upper and lower crust. Distinct anisotropic features are observed at the stations on the western part of the study area (i.e., the inner arc) for both upper and lower crust. The symmetry axes are mostly E-W oriented. Deviation from the E-W orientation is observed close to the volcanic areas, where the higher geothermal gradient might influence the deformation processes. PMID- 27478719 TI - Geoeffective jets impacting the magnetopause are very common. AB - The subsolar magnetosheath is penetrated by transient enhancements in dynamic pressure. These enhancements, also called high-speed jets, can propagate to the magnetopause, causing large-amplitude yet localized boundary indentations on impact. Possible downstream consequences of these impacts are, e.g., local magnetopause reconnection, impulsive penetration of magnetosheath plasma into the magnetosphere, inner magnetospheric and boundary surface waves, drop outs and other variations in radiation belt electron populations, ionospheric flow enhancements, and magnetic field variations observed on the ground. Consequently, jets can be geoeffective. The extend of their geoeffectiveness is influenced by the amount of mass, momentum, and energy they transport, i.e., by how large they are. Their overall importance in the framework of solar wind-magnetosphere coupling is determined by how often jets of geoeffective size hit the dayside magnetopause. In this paper, we calculate such jet impact rates for the first time. From a large data set of Time History of Events and Macroscale Interactions during Substorms (THEMIS) multispacecraft jet observations, we find distributions of scale sizes perpendicular and parallel to the direction of jet propagation. They are well modeled by an exponential function with characteristic scales of 1.34RE (perpendicular) and 0.71RE (parallel direction), respectively. Using the distribution of perpendicular scale sizes, we derive an impact rate of jets with cross-sectional diameters larger than 2RE on a reference area of about 100RE2 of the subsolar magnetopause. That rate is about 3 per hour in general, and about 9 per hour under low interplanetary magnetic field cone angle conditions (<30 degrees ), which are favorable for jet occurrence in the subsolar magnetosheath. PMID- 27478721 TI - EBSJ Evidence Assessment. PMID- 27478720 TI - Updates from Global Spine Congress. PMID- 27478722 TI - Competitive kinetics versus stopped flow method for determining the degradation rate constants of steroids by ozonation. AB - Steroids are classified as endocrine disrupting chemicals; they are persistent with low biodegradability and are hardly degraded by conventional methods. Ozonation process has been effective for steroids degradation and the determination of the kinetics is a fundamental aspect for the design and operation of the reactor. This study assessed two methods: competitive kinetics and stopped flow, for determining the degradation kinetics of two steroids, estradiol (E2) and ethinylestradiol (EE2) in spiked water. Experiments were performed at pH 6, 21 degrees C, and using tertbutyl alcohol as scavenger of hydroxyl radicals; competitive kinetics method used sodium phenolate as reference compound. For the stopped flow, the experiments were performed in a BioLogic SFM 3000/S equipment. For both methods, the second order rate constants were in the order of 10(6) and 10(5) M(-1) s(-1) for E2 and EE2 respectively. The competitive kinetics can be applied with assurance and reliability but needing an additional analysis method to measure the residual concentrations. Stopped flow method allows the evaluation of the degradation kinetics in milliseconds and avoids the use of additional analytical methodologies; this method allows determining the reaction times on line. The methods are applicable for degradation of other emerging contaminants or other steroids and could be applied in water treatment at industrial level. Finally, it is important to consider the resources available to implement the most appropriate method, either competitive kinetics or the stopped-flow method. PMID- 27478723 TI - The "exaptation" of linguistic implicit strategies. AB - Implicit strategies are known to increase persuasion performances. Implicits of content (vagueness, implicatures) and implicits of responsibility (presuppositions, topics) will be compared semiotically to non-linguistic implicits such as images and sounds. The results of psycholinguistic and neurolinguistic experiments will be used to propose that presuppositions and topics arose in language as means to spare addressees processing effort on already known contents, but they were subsequently "exapted" to spare effort on unknown marginal contents, and eventually to reduce the probability for doubtful contents to be processed thoroughly and rejected. This will be shown by many examples from commercial advertising and political propaganda. PMID- 27478724 TI - Can China afford rapid aging? AB - China's rapid aging has caused widespread concern, but it seems that the situations and consequences of rapid aging are not adequately acknowledged. This study analyzed the problem of ageing in China from the aspects of elderly people's health status, income source, daily care, suicide, the weak social security system in terms of pension, health expenses, and long-term care costs as well as incoming accelerating ageing process in China. All these factors indicate that it is difficult for China to afford the issue of a rapidly aging population. PMID- 27478726 TI - Fast permutation preconditioning for fractional diffusion equations. AB - In this paper, an implicit finite difference scheme with the shifted Grunwald formula, which is unconditionally stable, is used to discretize the fractional diffusion equations with constant diffusion coefficients. The coefficient matrix possesses the Toeplitz structure and the fast Toeplitz matrix-vector product can be utilized to reduce the computational complexity from [Formula: see text] to [Formula: see text], where N is the number of grid points. Two preconditioned iterative methods, named bi-conjugate gradient method for Toeplitz matrix and bi conjugate residual method for Toeplitz matrix, are proposed to solve the relevant discretized systems. Finally, numerical experiments are reported to show the effectiveness of our preconditioners. PMID- 27478727 TI - A two-hop based adaptive routing protocol for real-time wireless sensor networks. AB - One of the most important and challenging issues in wireless sensor networks (WSNs) is to optimally manage the limited energy of nodes without degrading the routing efficiency. In this paper, we propose an energy-efficient adaptive routing mechanism for WSNs, which saves energy of nodes by removing the much delayed packets without degrading the real-time performance of the used routing protocol. It uses the adaptive transmission power algorithm which is based on the attenuation of the wireless link to improve the energy efficiency. The proposed routing mechanism can be associated with any geographic routing protocol and its performance is evaluated by integrating with the well known two-hop based real time routing protocol, PATH and the resulting protocol is energy-efficient adaptive routing protocol (EE-ARP). The EE-ARP performs well in terms of energy consumption, deadline miss ratio, packet drop and end-to-end delay. PMID- 27478725 TI - Worldwide research productivity on tramadol: a bibliometric analysis. AB - BACKGROUND: Pain management and safe use of analgesics is an important medical issue. Tramadol is an old analgesic with controversial properties. Evaluation of worldwide scientific output on tramadol has not been explored. Therefore, the main objective of this study was to give a bibliometric overview of global research productivity on tramadol. METHODS: SciVerse Scopus was used to retrieve and quantitatively and qualitatively analyze worldwide publications on tramadol. RESULTS: A total of 2059 original and review research articles on tramadol were retrieved from Scopus. Forty-six documents (2.23 %) were published in Anesthesia and Analgesia Journal whereas 30 (1.46 %) were published in Arzneimittel Forschung Drug Research Journal. Retrieved tramadol documents were published from 71 countries and appeared in 160 peer reviewed journals. Although the United States of America (259; 12.86 %) had the largest contribution to tramadol publications; the contribution by other countries like Turkey (232; 11.27) India (189; 8.09 %) and Germany (176; 8.56 % was not far away from that of USA. The most productive institution was Grunenthal, Germany (47; 2.28 %) followed by Tehran University of Medical Sciences, Iran (29; 1.41 %), and, Ortho-McNeil Pharmaceutical Incorporated, USA (25; 1.21 %). Of the 2059 documents, there were 370 documents about dependence. The leading institution in documents pertaining to tramadol dependence was Grunenthal GmbH (18; 4.86 %) followed by Ortho-McNeil Pharmaceutical Incorporated (17; 4.59 %). CONCLUSIONS: The current study showed that there is an obvious interest in tramadol research. More efforts are needed to clarify the abuse potential and safety profile of tramadol to help in determining the legal status of tramadol. Collaboration among pharmaceutical industry, clinical researchers and academic institutions can improve research quantity and quality on tramadol. PMID- 27478728 TI - Risk for cardiovascular disease in Japanese patients with rheumatoid arthritis: a large-scale epidemiological study using a healthcare database. AB - OBJECTIVES: To study risk for cardiovascular disease (CVD) in Japanese patients with rheumatoid arthritis (RA). METHODS: We used a Medical Data Vision database mainly composed of health insurance claim data and diagnosis-procedure combination data from Japan. Patients with RA diagnosed from April 2011 to March 2014 at 71 hospitals were identified with the International Classification of Diseases 10th revision (ICD-10) and history of anti-RA drug prescription. Hospitalizations for CVD including ischemic heart disease, heart failure, and stroke were identified by a combination of diagnosis (ICD-10) and diagnostic procedures. CVD incidence rate ratio (IRR) for RA versus osteoarthritis was calculated. Risk factors were analyzed using univariate and multivariate Cox proportional hazard models with baseline C-reactive protein (CRP) and traditional risk factors as covariates. RESULTS: We identified 8658 patients with RA. The age sex adjusted IRR for RA versus osteoarthritis was high for total CVD [2.12; 95 % confidence interval (CI) 1.93-2.32], ischemic heart disease (2.16; 95 % CI 1.86 2.50), heart failure (2.34; 95 % CI 2.07-2.65), and stroke (1.68; 95 % CI 1.41 2.00). Risk factor analysis showed a tendency for cardiovascular risk to increase with higher baseline CRP, although the difference was not statistically significant (hazard ratio 1.43; 95 % CI 0.99-2.07). CONCLUSION: Our study indicates an increased risk for CVD and an association between systemic inflammation and CVD in Japanese RA patients. PMID- 27478729 TI - Anaphylactoid purpura triggered by cellulitis as a favorable prognosis: case report and literature review. AB - BACKGROUND: An anaphylactoid purpura affects small capillaries in the skin and other organs. Although two cases of anaphylactoid purpura exacerbated by cellulitis have been reported in Japanese literatures, its prognosis remains still unclear. Because cellulitis exacerbates various cutaneous inflammations, it has been speculated that cellulitis might also exacerbate cutaneous inflammation, such as vasculitis. FINDINGS: In this article, we report that 78-year-old woman exhibited anaphylactoid purpura, following cellulitis. We also reviewed the literature concerning about this subject. CONCLUSIONS: This type of anaphylactoid purpura is thought to have a favorable prognosis dependent on the treatment for cellulitis. PMID- 27478730 TI - Modeling Ghanaian cocoa farmers' decision to use pesticide and frequency of application: the case of Brong Ahafo Region. AB - Pesticides are a significant component of the modern agricultural technology that has been widely adopted across the globe to control pests, diseases, weeds and other plant pathogens, in an effort to reduce or eliminate yield losses and maintain high product quality. Although pesticides are said to be toxic and exposes farmers to risk due to the hazardous effects of these chemicals, pesticide use among cocoa farmers in Ghana is still high. Furthermore, cocoa farmers do not apply pesticide on their cocoa farms at the recommended frequency of application. In view of this, the study assessed the factors influencing cocoa farmers' decision to use pesticide and frequency of pesticide application. A total of 240 cocoa farmers from six cocoa growing communities in the Brong Ahafo Region of Ghana were selected for the study using the multi-stage sampling technique. The Probit and Tobit regression models were used to estimate factors influencing farmers' decision to use pesticide and frequency of pesticide application, respectively. Results of the study revealed that the use of pesticide is still high among farmers in the Region and that cocoa farmers do not follow the Ghana Cocoa Board recommended frequency of pesticide application. In addition, cocoa farmers in the study area were found to be using both Ghana Cocoa Board approved/recommended and unapproved pesticides for cocoa production. Gender, age, educational level, years of farming experience, access to extension service, availability of agrochemical shop and access to credit significantly influenced farmers' decision to use pesticides. Also, educational level, years of farming experience, membership of farmer based organisation, access to extension service, access to credit and cocoa income significantly influenced frequency of pesticide application. Since access to extension service is one key factor that reduces pesticide use and frequency of application among cocoa farmers, it is recommended that policies by government and non-governmental organisations should be aimed at mobilizing resources towards the expansion of extension education. In addition, extension service should target younger farmers as well as provide information on alternative pest control methods in order to reduce pesticide use among cocoa farmers. Furthermore, extension service/agents should target cocoa farmers with less years of farming experience and encourage cocoa farmers to join farmer based organisations in order to decrease frequency of pesticide application. PMID- 27478731 TI - Interobserver reliability of the 'Welfare Quality((r)) Animal Welfare Assessment Protocol for Growing Pigs'. AB - The present paper focuses on evaluating the interobserver reliability of the 'Welfare Quality((r)) Animal Welfare Assessment Protocol for Growing Pigs'. The protocol for growing pigs mainly consists of a Qualitative Behaviour Assessment (QBA), direct behaviour observations (BO) carried out by instantaneous scan sampling and checks for different individual parameters (IP), e.g. presence of tail biting, wounds and bursitis. Three trained observers collected the data by performing 29 combined assessments, which were done at the same time and on the same animals; but they were carried out completely independent of each other. The findings were compared by the calculation of Spearman Rank Correlation Coefficients (RS), Intraclass Correlation Coefficients (ICC), Smallest Detectable Changes (SDC) and Limits of Agreements (LoA). There was no agreement found concerning the adjectives belonging to the QBA (e.g. active: RS: 0.50, ICC: 0.30, SDC: 0.38, LoA: -0.05 to 0.45; fearful: RS: 0.06, ICC: 0.0, SDC: 0.26, LoA: -0.20 to 0.30). In contrast, the BO showed good agreement (e.g. social behaviour: RS: 0.45, ICC: 0.50, SDC: 0.09, LoA: -0.09 to 0.03 use of enrichment material: RS: 0.75, ICC: 0.68, SDC: 0.06, LoA: -0.03 to 0.03). Overall, observers agreed well in the IP, e.g. tail biting (RS: 0.52, ICC: 0.88; SDC: 0.05, LoA: -0.01 to 0.02) and wounds (RS: 0.43, ICC: 0.59, SDC: 0.10, LoA: -0.09 to 0.10). The parameter bursitis showed great differences (RS: 0.10, ICC: 0.0, SDC: 0.35, LoA: -0.37 to 0.40), which can be explained by difficulties in the assessment when the animals moved around quickly or their legs were soiled. In conclusion, the interobserver reliability was good in the BO and most IP, but not for the parameter bursitis and the QBA. PMID- 27478732 TI - On explicatures, cancellability and cancellation. AB - Within the Gricean framework only what is conversationally implicated is cancellable, whereas what is conventionally implicated and what is said cannot be cancelled without giving rise to contradiction. In the relevance-theoretic framework, however, the question is whether explicatures, which replace the Gricean notion of what is said, are cancellable. In recent years, various objections to the cancellability of explicatures have been raised. The aim of the present paper is to demonstrate that these objections are due to a misinterpretation of the Gricean cancellability test. In particular, they disregard the fact that this test is merely one of several diagnostic tools that are used by Grice to distinguish between conventional and conversational implicatures. Once we have recognized the essence of the cancellability test, the objections to the cancellability of explicatures turn out to be unwarranted. PMID- 27478733 TI - Multiple positive solutions to a coupled systems of nonlinear fractional differential equations. AB - In this article, we study existence, uniqueness and nonexistence of positive solution to a highly nonlinear coupled system of fractional order differential equations. Necessary and sufficient conditions for the existence and uniqueness of positive solution are developed by using Perov's fixed point theorem for the considered problem. Further, we also established sufficient conditions for existence of multiplicity results for positive solutions. Also, we developed some conditions under which the considered coupled system of fractional order differential equations has no positive solution. Appropriate examples are also provided which demonstrate our results. PMID- 27478734 TI - Clinical effects of cyclosporine A on reperfusion injury in myocardial infarction: a meta-analysis of randomized controlled trials. AB - Reperfusion therapy is the most crucial strategy for rescuing ischemic myocardium and reducing infarction size. Cyclosporine A (CsA) can protect against reperfusion-induced myocardial necrosis. However, the clinical effects of CsA on myocardial infarction (MI) remain uncertain. This study investigated the effects of CsA on reperfusion injury (RI) in MI. We searched for and included articles regarding randomized controlled trials investigating the effect of CsA in patients with MI from PubMed, EMBASE, and Cochrane Library databases for an analysis. We then performed quality assessment, subgroup, sensitivity, and publication bias analyses. Of the 277 potentially relevant articles retrieved from the databases, only five were eligible for our meta-analysis. Compared with the placebos used in these studies, CsA did not reduce all-cause mortality [rate ratio (RR) 1.10, 95 % confidence interval (CI) 0.75-1.61; P = 0.533; I (2) = 0 %) or adverse clinical events (RR 1.0, 95 % CI 0.89-1.13; P = 0.381; I (2) = 6.5 %). In the CsA treatment groups, improvement in left ventricular ejection fraction (weighted mean difference = 1.91; 95 % CI 0.89, 2.92; P = 0.064) and reduction in MI size (standard mean difference = -0.41, 95 % CI -0.84 to 0.02; P = 0.519; I (2) = 0.0 %) were minimal. The current meta-analysis indicates that CsA treatment does not reduce all-cause mortality and adverse clinical events in MI and that CsA may not have significant clinical effects on RI in MI. PMID- 27478735 TI - Cross-cultural adaptation and validation of the Chinese version of Toronto Extremity Salvage Score for patients with extremity sarcoma. AB - OBJECTIVE: As a widely used instrument for patients with extremity sarcoma, the Toronto Extremity Salvage Score (TESS) has never been cross-culturally adapted for Chinese population. The objective of our study was to investigate the comprehensibility, reliability and validity of the Chinese version of TESS for use in patients with extremity sarcoma. METHODS: A consensus version of the Chinese TESS was developed under the review of a committee according to international guidelines. 64 patients were recruited to complete the Chinese TESS, the Musculoskeletal Tumor Society (MSTS) Rating Scale, and the Quality of Life Questionnaire Core 30 (QLQ-C30). Reliability was assessed using the intra class correlation coefficient (ICC) and Cronbach's alpha. Validity was assessed with Pearson's correlation between the similar domains of the two questionnaires. RESULTS: The ICCs for the test-retest reliability was 0.932 for the upper extremity questionnaire and 0.893 for lower extremity questionnaire, respectively. The Cronbach's alpha was 0.953 for the lower extremity questionnaire and 0.921 for the upper extremity questionnaire, respectively. Convergent validity of the TESS based on Pearson correlation coefficients indicated significantly moderate to high correlations between the TESS and the MSTS as well as the QLQ-C30, with r ranging from 0.535 to 0.782. CONCLUSIONS: The Chinese TESS is a comprehensible, reliable, and valid instrument that can be utilized for future cross-cultural international studies of extremity sarcoma. PMID- 27478736 TI - Effects of a warming trend on cool climate viticulture in Michigan, USA. AB - Historically, Michigan's climate had mainly three challenges for grape production: growing season temperatures were too low, the growing season was too short and there was too much rain near harvest. However, climate change in the past decades has led to a vastly different landscape that is evolving to meet the new climate. Recently, there has been a significant move from Vitis labrusca (North American) grape plantings to Vitis vinifera (wine grapes) as a consequence of Michigan's shifting climate. The goal of this study was to analyze the historical shift in climate and its potential future impact on the grape industry. We obtained data climate model projection data from two greenhouse gas (GHG) emission scenarios. First, a multi-linear regression model was built to predict future grape yields (t/ac) using data from the climate model projections. Second, trends in the severity of the three challenges (temperature, season length, precipitation timing) were analyzed. In both GHG scenarios grape yields are seen to improve, but to different extents. The improvement is likely a response to warmer season temperatures canceling out losses to early season frost. Model projections recommend that Michigan's future climate will be more accommodating for all varieties of grapes. This suggests that grape production will continue to grow, but the landscape will continue to evolve with more emphasis on varieties that are more climatically sensitive to cold temperatures. Climate change has greatly affected Michigan's viticultural landscape, and will continue to do so in the coming decades. PMID- 27478737 TI - The role of school desk on the learning of graphic skills in early childhood education in Brazil. AB - The role of two different layouts of school furniture was investigated in the pattern legibility and spatial-temporal parameters of a graphic skill acquisition. Thirty children from the first grade of elementary school (mean age = 6 years) practiced a graphic task according to a criterion figure. They were assigned to two groups, Group of Fixed School Desk (GF) and Group with Adjustable School Desk (GA). Each child practiced the task on a digital tablet for 25 trials. The software Movalyser 2.3 processed the data from which the following measures were obtained: pattern legibility, linear spatial error and speed of execution. Two expert teachers also judged legibility. Children in the GA showed more number of legible patterns, they were slower to complete the task but they were more accurate in its reproduction. The adjustable school desk facilitates the acquisition of legible graphic patterns. Since stable graphic skills are positively correlated to the production of creative texts, studies unraveling the role of school desks to facilitate handwriting and drawing skills will contribute ultimately children's literacy and overall educational development. PMID- 27478738 TI - Binding interaction of a gamma-aminobutyric acid derivative with serum albumin: an insight by fluorescence and molecular modeling analysis. AB - gamma-Aminobutyric acid (GABA) is a naturally occurring inhibitory neurotransmitter and some of its derivatives showed potential to act as neuroprotective agents. With the aim of developing potential leads for anti Alzheimer's drugs, in this study we synthesized a novel GABA derivative, methyl 4 (4-((2-(tert-butoxy)-2-oxoethyl)(4-methoxyphenyl)amino)benzamido)butanoate by a unique method of Buchwald-Hartwig cross coupling synthesis; with some modification the yield was significant (97 %) and spectroscopic analysis confirmed that the compound was highly pure (98.8 % by HPLC). The druglikeness properties such as logP, logS, and polar surface area were 3.87, -4.86 and 94.17 A(2) respectively and it satisfied the Lipinski's rule of five. We examined the binding behavior of the molecule to human serum albumin (HSA) and bovine serum albumin (BSA) which are known as universal drug carrier proteins. The molecule binds to the proteins with low micromolar efficiency and the calculated binding constants were 3.85 and 2.75 micromolar for BSA and HSA, respectively. Temperature dependent study using van't Hoff equation established that the binding was thermodynamically favorable and the changes in the Gibb's free energy, DeltaG for the binding process was negative. However, the binding of the molecule to HSA was enthalpy driven and the change of enthalpy (DeltaH) was 10.63 kJ/mol, whereas, the binding to BSA was entropy driven and the change in entropy DeltaS was 222 J/mol. The molecular docking analysis showed that the binding sites of the molecule lie in the groove between domain I and domain III of BSA, whereas it is within the domain I in case of HSA, which also supported the different thermodynamic nature of binding with HSA and BSA. Molecular dynamics analysis suggested that the binding was stable with time and provided further details of the binding interaction. Molecular dynamics study also highlighted the effect of this ligand binding on the serum albumin structure. PMID- 27478739 TI - In silico analysis of enantioselective binding of immunomodulatory imide drugs to cereblon. AB - BACKGROUND: Thalidomide and its analogs, lenalidomide and pomalidomide (referred to as immunomodulatory imide drugs or IMiDs) have been known to treat multiple myeloma and other hematologic malignancies as well as to cause teratogenicity. Recently the protein cereblon was identified as the primary target of IMiDs, and crystallographic studies of the cereblon-IMiDs complex showed strong enantioselective binding for the (S)-enantiomer of IMiDs. RESULTS: Using the structures of cereblon and IMiDs [both (S)-enantiomers and (R)-enantiomers] we performed docking simulations in order to replicate this enantiomeric selectivity and to identify the region(s) contributing to this selectivity. We confirmed the enantioselective binding of IMiDs to cereblon with high accuracy, and propose that the hairpin connecting the beta10-beta11 region of cereblon (residues 351 355) contributes to this selectivity and to the increased affinity with IMiDs. CONCLUSIONS: Our docking results provide novel insights into the binding mode of IMiD-like molecules and contribute to a deeper understanding of cereblon-related biology. PMID- 27478740 TI - Duplication of the right vertebral artery: MRA findings and review of the literature. AB - INTRODUCTION: Duplication of the vertebral artery (VA) is a rare vascular variant. To the best our knowledge, only fourteen cases have been reported with angiographic findings that they have dual origin of the VA from ipsilateral subclavian artery. Herein, we present a case of duplication of right VA which was incidentally detected by magnetic resonance (MR) angiography. CASE DESCRIPTION: A 69-year-old female patient presented with headache for 30 days. She underwent brain MR imaging with MR angiography for evaluating possible intracranial cause. There was a dual origin of the right vertebral artery (VA) as an incidental finding without other significant abnormalities. DISCUSSION AND EVALUATION: Diagnosis of duplicated VA can be difficult due to its rarity and misinterpreted as the vascular dissection. In addition, a detailed knowledge of this variation is potentially important to prevent inadvertent challenges during endovascular procedure. Because duplicated VA has smaller lumen and usually enters the higher transverse foramen than those of normal side, it can be influence the choice or route of endovascular treatment. CONCLUSIONS: We suggested that the understanding of embryologic background about VA can be helpful to identify unexpected vascular findings on imaging studies in clinical practice. PMID- 27478741 TI - UAV formation control design with obstacle avoidance in dynamic three-dimensional environment. AB - This paper considers the artificial potential field method combined with rotational vectors for a general problem of multi-unmanned aerial vehicle (UAV) systems tracking a moving target in dynamic three-dimensional environment. An attractive potential field is generated between the leader and the target. It drives the leader to track the target based on the relative position of them. The other UAVs in the formation are controlled to follow the leader by the attractive control force. The repulsive force affects among the UAVs to avoid collisions and distribute the UAVs evenly on the spherical surface whose center is the leader UAV. Specific orders or positions of the UAVs are not required. The trajectories of avoidance obstacle can be obtained through two kinds of potential field with rotation vectors. Every UAV can choose the optimal trajectory to avoid the obstacle and reconfigure the formation after passing the obstacle. Simulations study on UAV are presented to demonstrate the effectiveness of proposed method. PMID- 27478742 TI - Expression of a mitochondrial gene orfH79 from CMS-Honglian rice inhibits Escherichia coli growth via deficient oxygen consumption. AB - Cytoplasmic male sterility (CMS) has often been associated with abnormal mitochondrial open frames (ORF), orfH79 is a mitochondrial chimeric gene responsible for the CMS trait in Honglian (HL) rice. In this study, the weakly produced ORFH79 protein significantly inhibited the growth of E. coli in an oxygen culture, however, the growth of the transformants producing ORFH79 was indistinguishable from the control under anaerobic incubation conditions. In addition, a lower respiration rate, wrinkled bacterial surfaces, and decreased pyruvate kinase and alpha-ketoglutarate dehydrogenase activities were observed in the ORFH79 produced E. coli. These results indicate that ORFH79 impairs the oxygen respiration of E. coli, which may inhibit E. coli growth. PMID- 27478743 TI - Some properties of the Catalan-Qi function related to the Catalan numbers. AB - In the paper, the authors find some properties of the Catalan numbers, the Catalan function, and the Catalan-Qi function which is a generalization of the Catalan numbers. Concretely speaking, the authors present a new expression, asymptotic expansions, integral representations, logarithmic convexity, complete monotonicity, minimality, logarithmically complete monotonicity, a generating function, and inequalities of the Catalan numbers, the Catalan function, and the Catalan-Qi function. As by-products, an exponential expansion and a double inequality for the ratio of two gamma functions are derived. PMID- 27478744 TI - A stochastic frontier analysis of technical efficiency of fish cage culture in Peninsular Malaysia. AB - Cage culture plays an important role in achieving higher output and generating more export earnings in Malaysia. However, the cost of fingerlings, feed and labour have increased substantially for cage culture in the coastal areas in Peninsular Malaysia. This paper uses farm level data gathered from Manjung, Perak and Kota Tinggi, Johor to investigate the technical efficiency of brackish water fish cage culture using the stochastic frontier approach. The technical efficiency was estimated and specifically the factors affecting technical inefficiencies of fish cage culture system in Malaysia was investigated. On average, 37 percent of the sampled fish cage farms are technically efficient. The results suggest very high degrees of technical inefficiency exist among the cage culturists. This implies that great potential exists to increase fish production through improved efficiency in cage culture management in Peninsular Malaysia. The results indicate that farmers obtained grouper fingerlings from other neighboring countries due to scarcity of fingerlings from wild sources. The cost of feeding for grouper (Epinephelus fuscoguttatus) requires relatively higher costs compared to seabass (Lates calcarifer) production in cage farms in the study areas. Initiatives to undertake extension programmes at the farm level are needed to help cage culturists in utilizing their resources more efficiently in order to substantially enhance their fish production. PMID- 27478745 TI - A characterization of some alternating groups A p+8 of degree p + 8 by OD. AB - Let [Formula: see text] be an alternating group of degree n. We know that [Formula: see text] is 2-fold OD-characterizable and [Formula: see text] is 6 fold OD-characterizable. In this note, we first show that [Formula: see text] and [Formula: see text] are 14-fold and 7-fold OD-characterizable, respectively, and second show that certain groups [Formula: see text] with that [Formula: see text] and [Formula: see text], are OD-characterizable. The first gives a negative answer to Open Problem of Kogani-Moghaddam and Moghaddamfar. PMID- 27478746 TI - Molecular cloning, expression analysis and subcellular localization of four DELLA genes from hybrid poplar. AB - Gibberellic acid (GA) signaling regulates diverse aspects of plant growth and developmental processes. The DELLA repressors of GA signaling are named for an N terminal conserved DELLA domain. In this study, four genes encoding DELLA proteins, PeRGA1, PeRGA2, PeGAI1 and PeGAI2, were isolated and characterized in poplar. A gene structural analysis revealed that the DELLA genes were all intron free. Multiple protein sequence alignments revealed that these proteins contained seven highly conserved domains: the DELLA domain, the TVHYNP domain, leucine heptad repeat I (LHR I), the VHIID domain, leucine heptad repeat II (LHR II), the PFYRE domain, and the SAM domain. Temporal expression patterns of these genes were profiled during the adventitious root development of poplar. The four DELLA genes were expressed in root, stem and leaf in a dynamic manner. The subcellular localization demonstrated that these DELLA genes were mainly localized to the nucleus. These results suggest that the four DELLA genes may play diverse regulatory roles in the adventitious root, stem and leaf development of poplar, and contribute to improving our understanding of conserved and divergent aspects of DELLA proteins that restrain GA signaling in various species. PMID- 27478747 TI - Intestinal microbiota and chronic constipation. AB - Chronic constipation is a prevalent, burdensome gastrointestinal disorder whose aetiology and pathophysiology remains poorly understood and is most likely multifactorial. Differences in the composition of the intestinal microbiota have been demonstrated when constipated patients and healthy controls have been compared. Growing evidence indicates that alterations of intestinal microbiota may contribute to constipation and constipation-related symptoms. The intestinal microbiota is a collection of microorganisms that live within the gastrointestinal tract, and perform many important health-promoting functions. The intestinal microbiota aids in the breakdown of food products into absorbable nutrients, stimulates the host immune system, prevents growth of pathogenic bacteria and produces a great variety of biologically important compounds. In this review, we will summarize the current evidence supporting roles of the intestinal microbiota in the pathogenesis and management of chronic constipation. The discussion will shed light on the novel mechanisms of intestinal microbiota and gut function interactions, which is invaluable in ultimately developing new therapeutic tools for the treatment of chronic constipation. PMID- 27478748 TI - The genetic diversity of soil bacteria affected by phytoremediation in a typical barren rare earth mined site of South China. AB - The soil bacterial diversity is one of the most important indicators to evaluate the effect of phytoremediation. In this study, the technologies of Sequence Related Amplified Polymorphism (SRAP) and 16S rRNA gene sequence analysis were used to evaluate the soil bacterial diversity after phytoremediation in a barren rare earth mined area. The results showed that the plant density was remarkably increased after the phytoremediation. The SRAP analysis suggested that the soil bacterial diversity declined dramatically after mining, while increased significantly in second and third year of the phytoremediation. A total of eight bacterial genera were identified by using 16S rRNA gene sequence analysis, with Arthrobacter and Bacillus as the dominant species before the mining, and Brevibacillus as the dominant species after the mining and during the first year of the phytoremediation. The Bacillus, which was a dominant type of bacteria before the mining, disappeared after mining and appeared again in the second and third years of the phytoremediation, other bacterial genera present. Principal component analysis and 16S rRNA gene analysis revealed a new bacterial type after phytoremediation that was not existed in the original mined area. The results of the present study indicated that the soil bacterial richness and genetic diversity significantly increased after the phytoremediation in the mined site. PMID- 27478749 TI - Hydrothermal derived nitrogen doped SrTiO3 for efficient visible light driven photocatalytic reduction of chromium(VI). AB - In this work, we report on the synthesis of nitrogen doped SrTiO3 nanoparticles with efficient visible light driven photocatalytic activity toward Cr(VI) by the solvothermal method. The samples are carefully characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, UV Vis diffuse reflectance spectroscopy and photocatalytic test. It is found that nitrogen doping in SrTiO3 lattice led to an apparent lattice expansion, particle size reduction as well as subsequent increase of Brunner-Emmet-Teller surface area. The visible light absorption edge and intensity can be modulated by nitrogen doping content, which absorption edge extends to about 600 nm. Moreover, nitrogen doping can not only modulate the visible light absorption feature, but also have consequence on the enhancement of charge separation efficiency, which can promote the photocatalytic activity. With well controlled particle size, Brunner-Emmet-Teller surface area, and electronic structure via nitrogen doping, the photocatalytic performance toward Cr(VI) reduction of nitrogen doped SrTiO3 was optimized at initial hexamethylenetetramine content of 2. PMID- 27478750 TI - The class inclusion question: a case study in applying pragmatics to the experimental study of cognition. AB - For more than 70 years, Piaget's class-inclusion task (given, e.g., five asters and three tulips, the child is asked whether "there are more asters or more flowers") has been the object of experimental investigation. Inclusion is of considerable importance for cognitive science as it is a key concept for logical operations and knowledge representation. It is shown that the question can be characterised by a kind of privative ambiguity which is at the source of the younger children's answer, "more asters". A relevance-theoretic explanation of children's interpretation of the question and of the subsequent responses is expounded. This account can explain the effect of all the factors that are known to influence performance (e.g., role of collections, counting, typicality, qualification, syntax, etc.), a review of which is presented. It is further tested experimentally. The development of performance is explained on the basis of the way children disambiguate the question. This study exemplifies the two ways in which pragmatic analysis is pertinent to the study of children's (as well as adults') reasoning and judgement, namely in explaining and predicting participants' comprehension of the statements and questions, and in taking into account attribution processes that occur in the experimental setting. PMID- 27478751 TI - Farmers' perceptions and attitudes towards the development of the sheep and goat sector in the Greek region of Evros. AB - The present study endeavors to investigate the attitudes, opinions and perceptions of livestock farmers regarding the main problems they face and confine the development of livestock in the Greek region of Evros. Primary data were collected through a quantitative survey (structured questionnaire) with livestock farmers in the region. The analysis of the survey data was carried out with the use of descriptive statistics, Friedman's test and factor analysis. The results indicate that strategies for livestock development in the region should take into account the great dissatisfaction that exists towards public authorities and the level of satisfaction as regards the non-governmental bodies. Furthermore, the economic objectives are of primary importance for livestock farmers, whereas they stress their interest in training and know-how. Particularly on issues pertaining to dairy livestock management, improving sanitation conditions and enhancing the quality, digestibility and production of animal feed. PMID- 27478752 TI - Crop diversification and livelihoods of smallholder farmers in Zimbabwe: adaptive management for environmental change. AB - This paper demonstrates how crop diversification impacts on two outcomes of climate smart agriculture; increased productivity (legume and cereal crop productivity) and enhanced resilience (household income, food security, and nutrition) in rural Zimbabwe. Using data from over 500 smallholder farmers, we jointly estimate crop diversification and each of the outcome variables within a conditional (recursive) mixed process framework that corrects for selectivity bias arising due to the voluntary nature of crop diversification. We find that crop diversification depends on the land size, farming experience, asset wealth, location, access to agricultural extension services, information on output prices, low transportation costs and general information access. Our results also indicate that an increase in the rate of adoption improves crop productivity, income, food security and nutrition at household level. Overall, our results are indicative of the importance of crop diversification as a viable climate smart agriculture practice that significantly enhances crop productivity and consequently resilience in rural smallholder farming systems. We, therefore, recommend wider adoption of diversified cropping systems notably those currently less diversified for greater adaptation to the ever-changing climate. PMID- 27478753 TI - North American Skull Base Society 26th Annual Meeting: Innovation and Creativity in Skull Base Surgery. PMID- 27478754 TI - Albert L. Rhoton, Jr., M.D., 1932-2016. PMID- 27478755 TI - Prof. Rhoton: Master and Mentor. PMID- 27478756 TI - Dr. Al Rhoton, Jr.: Friend, Mentor, and Colleague. PMID- 27478757 TI - The Rhoton Collection. PMID- 27478758 TI - Alcohol management plans in Indigenous communities in Queensland (Australia) may have unintended implications for the care of children. AB - BACKGROUND: Indigenous children in Australia are more likely than non-Indigenous children to be in contact with the child safety system. A large number of Queensland's Indigenous population live in remote and isolated communities in north Queensland where the state government's Alcohol Management Plans (AMPs) are in effect. In these communities it is an offence to have in one's possession more than the regulated amount and type of alcohol. A breach of these restrictions can result in convictions under the Liquor Act 1992. FINDINGS: During an evaluation of AMPs, influential stakeholders and key service providers voiced their belief that a conviction for a breach of the AMP would impact a person's eligibility to hold a Positive Notice Blue Card (PNBC). On its own, however, a breach of the Liquor Act 1992 will not impact a person's eligibility for a PNBC. A PNBC is required for any person volunteering or working with children. Without a PNBC, a person is ineligible to work in child-related employment, volunteer at child related activities or provide out-of-home care for children. CONCLUSION: This misconception needs to be addressed in these already-disadvantaged communities to ensure that Indigenous community members have every opportunity to hold a PNBC. Focused strategies with evaluation and research are needed in this important policy area. PMID- 27478759 TI - Increasing Independence Within Adult Services: a Program for Reducing Staff Completion of Daily Routines for Consumers with Developmental Disabilities. PMID- 27478760 TI - Constrained VPH+: a local path planning algorithm for a bio-inspired crawling robot with customized ultrasonic scanning sensor. AB - This paper aims to develop a local path planning algorithm for a bio-inspired, reconfigurable crawling robot. A detailed description of the robotic platform is first provided, and the suitability for deployment of each of the current state of-the-art local path planners is analyzed after an extensive literature review. The Enhanced Vector Polar Histogram algorithm is described and reformulated to better fit the requirements of the platform. The algorithm is deployed on the robotic platform in crawling configuration and favorably compared with other state-of-the-art local path planning algorithms. PMID- 27478761 TI - Body Mass Changes Across a Variety of Running Race Distances in the Tropics. AB - BACKGROUND: Current literature evaluating body mass (BM) changes across a variety of running race distances is limited. The primary objective of this study was to profile the range of BM changes across race distances. The secondary objective was to evaluate the prevalence of exercise-associated hyponatremia (EAH) in runners admitted to the on-site medical tent following participation of race events of different distances. METHODS: A total of 1934 runners across seven footrace categories (10-, 21-, 25-, 42-, 50-, 84-, and 100-km) were included in the study. One thousand eight hundred eighty-seven runners had their BM measured before and after each race. Blood sodium concentrations were measured from the remaining 47 symptomatic runners admitted to the on-site medical tents and did not complete the race. RESULTS: In terms of hydration status, 106 (6 %) were overhydrated, 1377 (73 %) were euhydrated, and 404 (21 %) were dehydrated. All race distances exhibited similar percentage of overhydrated runners (5 % in 10 km, 3 % in 21 km, 5 % in 25 km, 6 % in 42 km, 8 % in 50 km, 7 % in 84 km, and 6 % in 100 km). Forty-seven runners were admitted to the medical tents. Eight (17 %) were diagnosed with EAH (4 from 42 km, 2 from 84 km, 2 from 100 km), 38 (81 %) were normonatremic, and 1 (2 %) was hypernatremic. The % DeltaBM across all races ranged from -8.0 to 4.1 % with a greater decrement noted in the 42-, 50-, 84-, and 100-km categories. CONCLUSIONS: Approximately 3-8 % runners had increased post-race BM, suggesting overhydration regardless of race distance. Symptomatic EAH was seen at race distances at or above 42 km, where BM changes demonstrated the widest range of values. PMID- 27478763 TI - Cerebral toxoplasmosis and anti-TNFalpha: a case report. AB - We report a case that documents the second known patient treated by anti-TNFalpha who has been diagnosed a cerebral toxoplasmosis. PMID- 27478762 TI - WHEN ONSET MEETS DESISTANCE: COGNITIVE TRANSFORMATION AND ADOLESCENT MARIJUANA EXPERIMENTATION. AB - PURPOSE: Desistance scholars primarily focus on changing social roles, cognitive transformations, and shifting identities to understand the cessation of serious crime and illicit drug use in adulthood. In the current study, we move the spotlight away from adulthood and toward adolescence, the developmental stage when the prevalence of offending and substance use peak and desistance from most of these behaviors begins. Our primary hypothesis is that changes in perceived psychic rewards surrounding initial forays into marijuana use strongly predict adolescents' decisions to cease or persist that behavior. In addition, based on social learning expectations, we hypothesize that peer perceptions and behaviors provide mechanisms for perceptual change. METHODS: We test these hypotheses using longitudinal data of marijuana use, perceptions, and peer networks from the PROmoting School-community-university Partnerships to Enhance Resilience (PROSPER) study. We estimate hazard models of marijuana initiation and within person models of perceptual updating for youth from grades 6 to 12 (n=6,154). RESULTS: We find that changes in marijuana's perceived psychic rewards surrounding initiation differentiated experimenters from persisters. Experimenters had significantly lower updated perceptions of marijuana as a fun behavior compared to persisters and these perceptions dropped after the initiation wave. In contrast, persisters updated their perceptions in upward directions and maintained more positive perceptions over time. Inconsistent with social learning expectations, initiators' updated perceptions of marijuana as a fun activity were not explained by peer-reported behaviors or attitudes. PMID- 27478764 TI - Clostridium subterminale septicemia in an immunocompetent patient. AB - Clostridium subterminale is a Clostridium species that has been rarely isolated in the blood of immunocompromised patients. We report a case of C. subterminale septicemia in an immunocompetent patient who presented with acute mediastinitis following spontaneous esophageal rupture. PMID- 27478765 TI - Challenges of Genetic Screening of In Vitro Fertilized Human Embryos Using Current Technologies. PMID- 27478766 TI - Survival Assessment of Mouse Preimplantation Embryos After Exposure to Cell Phone Radiation. AB - BACKGROUND: Using cellular phone has rapidly increased all over the world. Also, the concern on the possible health hazards of electromagnetic fields (EMF) induced from cell phones to reproduction has been growing in many countries. The aim of this study was to assess the consequences and effects of exposure to the cell phone radiation on the quality and survival rates of preimplantation embryos in mice. METHODS: A total of 40 mice (20 females and 20 males), 6 weeks old and sexually mature BALB/c, were used for control and experimental groups. The ovary burses were removed and the zygotes were dissected in the morning after mating. Next, 2-cell embryos were divided into two groups of control (n=150) and experimental (n=150). EMF (900-1800 MHz) was used for four days in experimental group for 30 min/day in culture at 37 degrees C in a CO 2 incubator. The quality of embryos was recorded daily and the fluorescent staining was used for identification of viable blastocysts. All data were compared by Student's t-test and Mann-Whitney test (p<0.05). RESULTS: The rate of embryo survival to the blastocysts stage was similar in both groups. However, the percentage of dead embryos at the 2-cell stage was significantly higher in EMF-exposed group compared with controls (p=0.03). Also, the loss of cell viability significantly increased in experimental blastocysts (p=0.002). CONCLUSION: The normal embryonic development up to the blastocyst stage indicates that EMF-exposure commonly did not have adverse effect on embryo development in mice. But, it caused loss of blastocysts cell viability. PMID- 27478767 TI - The Effect of Ammonium Chloride Concentration in In Vitro Maturation Culture on Ovine Embryo Development. AB - BACKGROUND: Ammonium is produced in culture medium due to amino acids degradation and has adverse effect on in vitro culture of embryo. In the current study, the purpose was to evaluate the effects of ammuniom chloride (AC) on in vitro oocyte maturation rate and early embryo development in the sheep and its effect on the expression of Bcl-2. METHODS: In vitro maturation (IVM) was performed in the presence of various concentrations (0, 29, 88,132,176 MUM/ml) of ammonium chloride (NH 4 CL) (AC). Meiotic maturation, embryonic development and expression of Bcl2 gene in Blastocyst cells were determined. The data were analyzed by one way ANOVA and Tukey post HOC test, and values with p<0.05 were considered statistically significant. RESULTS: The highest concentration (176 MUM) of AC significantly decreased the rate of fully expanded cumulus cells 24 hr after IVM compared with the control group (p<0.05). Moreover, significantly lower rates of MII oocytes were found in the 176 MUM AC group compared with the 29 MUM AC group. The percentage of zygotes developing to blastocysts in 176 MUM AC was lower than the other group. Also, supplementation of the oocyte maturation media with 176 MUM AC decreased Bcl2 expression. CONCLUSION: Our results suggested that significant increase in IVM rate could be obtained with supplementation maturation medium with AC in a dose dependent manner. Increased AC concentration led to lower blastocyst rate under normal condition. However, regulation of pro apoptotic (Bcl-2) gene did not change with different concentrations of AC supplementing. PMID- 27478768 TI - Association of the +49 A/G Polymorphism of CTLA4 Gene with Idiopathic Recurrent Spontaneous Abortion in Women in Southwest of Iran. AB - BACKGROUND: Survival of the semi-allograft fetus during pregnancy opens a new area for the immunological based causes of recurrent spontaneous abortion (RSA). Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a negative regulator of the T-cell activation, which may modulate peripheral self-tolerance of the allogeneic fetus. The present study aimed to investigate the +49 A/G CTLA4 genetic polymorphism and predisposition to RSA. METHODS: The total participants were 120 women with at least two miscarriages and 120 healthy post-menopausal women as the control group. The +49 A/G polymorphism was genotyped using PCR-RFLP method. Required demographic information was collected through filling out a questionnaire. The obtained data were fed into SPSS software version 16. RESULTS: The results showed a significant association between the minor alleles (G) with the decreased risk of the RSA. The frequency of the G allele in controls and patients was 25% and 12%, respectively. A GG genotype in the co-dominance model (OR: 0.25, 95%CI: 0.09-0.66) and in the dominant model for allele G (GG+AG vs. AA) (OR: 0.84, 95%CI: 0.8-0.87) showed significant association with RSA by imposing the protective role. The frequency of miscarriage is significantly (p=0.04) higher among the relatives of RSA women (33.3%) in comparison with the women in the control group (21.7%). CONCLUSION: It can be concluded that +49G allele may act as a dominant allele and reduce the risk of RSA. Family history of miscarriage increased the risk of RSA among women. PMID- 27478769 TI - Effect of Acetylcholinesterase and Butyrylcholinesterase on Intrauterine Insemination, Contribution to Inflammations, Oxidative Stress and Antioxidant Status; A Preliminary Report. AB - BACKGROUND: Oxidative stress affects women fertility and influences on the sperm quality by alterating activities of cholinesterases, a molecular marker of stress related infertility. The aim of the present study was to investigate the role of acetyl-cholinesterase (AChE), butyrylcholinesterase (BuChE) activities and phenotypes in patients with unexplained infertility (idiopathic). It's possible association with inflammation marker C-reactive protein (CRP) and other oxidative stress markers, i.e. before and after intra uterine insemination (IUI). METHODS: In this study, blood samples of 60 patients with unexplained infertility were collected the day before and 24 hr after IUI (between 8 AM and 9 AM after the overnight fasting) and activities of BuChE, AChE, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GpX) and serum levels of thiol proteins (TP), C-reactive protein (CRP), total antioxidant capacity (TAC) were measured. Statistical significance was assumed at p<0.05. RESULTS: Before IUI, there was a significant (p=0.048) positive correlation between BuChE activity and plasma TAC and a significant difference in the CAT activity between various BuChE (UU and non-UU) phenotypes. However, after IUI, a significant negative correlation between the AChE activity and BuChE activity was found (p=0.045) and the level of RBC AChE activity was significantly reduced (382.4+/- 163.19 vs. 586.7+/-384 IU/grHb, p=0.025). Meanwhile, after IUI, the activities of SOD (1568+/-847.5 IU/grHb vs. 1126+/-229.3, p=0.031) and CAT (310+/-53.4 IU/grHb vs. 338+/-73, p=0.025) were increased. CONCLUSION: This study suggests that decline in cholinesterases activities may be responsible for stimulation of oxidative stress and inflammation and reduction in fertility rates by IUI. PMID- 27478770 TI - Microdose Flare-up Gonadotropin-releasing Hormone (GnRH) Agonist Versus GnRH Antagonist Protocols in Poor Ovarian Responders Undergoing Intracytoplasmic Sperm Injection. AB - BACKGROUND: Microdose flare-up GnRH agonist and GnRH antagonist have become more popular in the management of poor ovarian responders (POR) in recent years; however, the optimal protocol for POR patients undergoing in vitro fertilization has still been a challenge. METHODS: In this observational study design, two hundred forty four poor ovarian responders were retrospectively evaluated for their response to GnRH agonist protocol (group-1, n=135) or GnRH antagonist protocol (group-2, n=109). Clinical pregnancy rate was the primary end point and was compared between the groups. Student t-test, Mann Whitney U test and chi (2) test were used to compare the groups. The p<0.05 was considered to show a statistically significant result. RESULTS: The mean total gonadotropin doses were 3814+/-891 IU in group 1 and 3539+/-877 IU in group 2 (p=0.02). The number of metaphase-II oocytes (3.6+/-2.4 vs. 2.8+/-1.9, p=0.005) and implantation rates (27.8% vs. 18.8%, p=0.04) in group 1 and group 2, respectively were significantly different. The fertilization rate in group 1 and group 2 was 73% vs. 68%, respectively (p=0.5) and clinical pregnancy rate was 19.8% vs. 14.4%, respectively (p=0.13). CONCLUSION: The GnRH agonist microdose flare-up protocol has favorable outcomes with respect to the number of oocytes retrieved and implantation rate; nevertheless, the clinical pregnancy rate was found to be similar in comparison to GnRH antagonist protocol in poor ovarian responders. GnRH antagonist protocol appears to be promising with significantly lower gonadotropin requirement and lower treatment cost in poor ovarian responders. PMID- 27478771 TI - Sex-Reassignment Rules in Shiite Jurisprudence. AB - BACKGROUND: The "Sex-Reassignment Surgery" is a solution that besides behavioral therapy has been suggested to people suffering from gender identity disorders in recent years. In Iran, this trend has become more popular over the past years due to the inclination to reach to the goal rapidly with less effort and also the surgery has attracted many patients with the problem. Religious clerics have tried to determine the religious doctrines for this practice and as a result a group of them favor an absolute permission while others choose prohibition and some of them favor a middle path. The aim of this study was to determine the religious doctrines for Sex-Reassignment and legitimate treatment for GID. METHODS: The research method was a library research based on which an investigation was done by analyzing the relevant books, articles and dissertations. Primary documents of Islamic sources (Quran and tradition) along with scientific, medical and psychological materials were used in this research. RESULTS: In this study, the survey shows that none of the reasons have the power to deliver a definitive and religious ruling on this issue because the validity of its reasons is related to the reality of "Sex-Reassignment". CONCLUSION: The results demonstrate that Sex-Reassignment is prohibited and it is not authorized. In case of urgency for doing the surgery, the gender of the person should not be changed. PMID- 27478772 TI - Can a Short Term of Repeated Ejaculations Affect Seminal Parameters? AB - BACKGROUND: The aim of the study was to assess the effect of four repeated ejaculations on the same day at two-hour intervals on conventional and functional semen parameters. METHODS: Three healthy men (32+/-3.6 years) donated the first semen samples after 3-4 days of sexual abstinence followed by three subsequent samples on the same day at two-hour interval each. Semen samples were processed and analyzed according to the World Health Organization (WHO) 2010 guidelines. Furthermore, intracellular reactive oxygen (ROS) production, sperm DNA fragmentation and mitochondrial function were evaluated by flow cytometry. RESULTS: An overall decreasing trend was noted in the conventional semen parameters at second, third and fourth evaluations after two hours of abstinence in comparison to first evaluation after 3-4 days of abstinence. The statistical comparison of the conventional semen parameters at fourth evaluation after 2 hr of abstinence revealed significant reduction (p<0.05) in the parameters of concentration, total sperm count and total motile sperm count at fourth evaluation. The functional parameter of intracellular ROS production showed a decreasing trend with each subsequent evaluation, the difference being significant (p<0.05) at fourth evaluation in comparison to first evaluation. An increasing trend was noted for DNA fragmentation index (DFI), although it remained within acceptable levels (<29%). The DeltaPsim (high) permatozoa and the integrity of the plasma membrane remained stable throughout the evaluations. CONCLUSION: The findings of the present study indicate the potential use of additional semen samples with repeated ejaculations at short abstinence times in assisted reproduction procedures particularly from severe oligospermic men. PMID- 27478773 TI - Homozygosity for a Robertsonian Translocation (13q;14q) in a Phenotypically Normal 44, XX Female with a History of Recurrent Abortion and a Normal Pregnancy Outcome. AB - BACKGROUND: Robertsonian translocations are structural chromosomal abnormalities caused by fusion of two acrocentric chromosomes. In carriers of such translocations, different modes of segregations would result in the formation of either balanced (alternate segregation mode) or unbalanced (adjacent 1, adjacent 2, and 3:1 segregation modes) gametes. In addition, there is an increased risk for imprinting disorders in their offspring. Although it has been estimated that 1/1000 healthy persons carry a Robertsonian translocation, homozygosity for this type of structural chromosomal abnormality has been reported rarely. Most of reported cases are phenotypically normal but experience adverse pregnancy outcomes. CASE PRESENTATION: In this paper, a report was made on a normal female with a history of 4 consecutive first trimester fetal losses and a normal son referred to Center for Comprehensive Genetics Services, Tehran, Iran, in summer 2015. Cytogenetic analyses of proband and her infant showed 44, XX, der(13;14) (q10;q10)x2 and 45, XY, der(13;14)(q10;q10), respectively. Parents of proband have been shown to have 45, XY, der(13q;14q) and 45, XX, der(13q;14q) karyotypes, respectively. CONCLUSION: The present report was in agreement with the few reports of homozygosity for Robertsonian translocation which demonstrated normal phenotypes for such persons and possibility of giving birth to phenotypically normal heterozygote carriers of Robertsonian translocations. PMID- 27478774 TI - A Case of Primary Hypogonadism with Features of Albright's Syndrome. AB - BACKGROUND: McCune Albright syndrome is rare with an estimated prevalence of 1 in 100,000 to 1 in 1,000,000 persons. The classical clinical triad consists of fibrous dysplasia of the bone, cafe-au-lait skin spots and precocious puberty. However, in rare cases, there may be primary hypogonadism and amenorrhea. CASE PRESENTATION: An eighteen-year-old female presented with amenorrhea. She had a short stature, round face, thick neck, and short fourth metacarpals and metatarsals. The secondary sexual characters were absent. Serum calcium, phosphorus and parathyroid concentrations were normal, but gonadotropin hormones were very low. X-ray examination revealed short fourth and fifth metacarpals, short left metatarsal, and short fibula. CONCLUSION: These local bony abnormalities along with the biochemical findings helped us to diagnose this case as an unusual presentation of primary hypogonadism with features of McCune Albright's syndrome where there was amenorrhea rather than preocious puberty. PMID- 27478776 TI - Key Immune Cell Cytokines Affects the Telomere Activity of Cord Blood Cells In vitro. AB - PURPOSE: Telomere is a nucleoprotein complex at the end of eukaryotic chromosomes and its length is regulated by telomerase. The number of DNA repeat sequence (TTAGGG)n is reduced with each cell division in differentiated cells. The aim of this study was to evaluate the effect of SCF (Stem Cell Factor), Flt3 (Fms- Like tyrosine kinase-3), Interleukin-2, 7 and 15 on telomere length and hTERT gene expression in mononuclear and umbilical cord blood stem cells (CD34+ cells) during development to lymphoid cells. METHODS: The mononuclear cells were isolated from umbilical cord blood by Ficoll-Paque density gradient. Then cells were cultured for 21 days in the presence of different cytokines. Telomere length and hTERT gene expression were evaluated in freshly isolated cells, 7, 14 and 21 days of culture by real-time PCR. The same condition had been done for CD34+ cells but telomere length and hTERT gene expression were measured at initial and day 21 of the experiment. RESULTS: Highest hTERT gene expression and maximum telomere length were measured at day14 of MNCs in the presence of IL-7 and IL-15. Also, there was a significant correlation between telomere length and telomerase gene expression in MNCs at 14 days in a combination of IL-7 and IL-15 (r = 0.998, p =0.04). In contrast, IL-2 showed no distinct effect on telomere length and hTERT gene expression in cells. CONCLUSION: Taken together, IL-7 and IL-15 increased telomere length and hTERT gene expression at 14 day of the experiment. In conclusion, it seems likely that cells maintain naive phenotype due to prolonged exposure of IL-7 and IL-15. PMID- 27478775 TI - The Impact of Variables on Particle Size of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers; A Comparative Literature Review. AB - During the past decade, pharmaceutical science has seen rapid growth in interest for nanoscale materials. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are popular research topics recently introduced as nano scale drug carriers; they have shown numerous merits in drug delivery. Size is the most important index in a nanocarrier affecting its drug delivery efficiency. The influence of preparation conditions and type of lipidic components on the size of SLN and NLC in comparable states seems to be interesting for researchers who investigate these types of carriers. This review highlights the results of SLN and NLC particle size and size distribution comparisons. PMID- 27478777 TI - Essential Oil from Flowers and Leaves of Elaeagnus Angustifolia (Elaeagnaceae): Composition, Radical Scavenging and General Toxicity Activities. AB - PURPOSE: The aim of this work was to identify the chemical composition of the essential oils obtained from the flowers and leaves of Elaeagnus angostifolia (Elaeagnaceae) along with evaluate the radical scavenging and general toxicity activities. METHODS: A combination of GC-MS and GC-FID were utilized for analyzing the chemical profile of the essential oils extracted by hydro distillation from the leaves and flowers of E. angustifolia. The essential oils were subjected to general toxicity and radical scavenging assays using brine shrimp lethality test and DPPH method, respectively. RESULTS: In total, 53 and 25 components were identified and quantified in the essential oils of flowers and leaves, accounting for 96.59% and 98.97% of the oil, respectively. The both oils were observed to be rich in ester compounds. The most abundant components of the oil from flowers were E-ethyl cinnamate (60.00%), hexahydrofarnesyl acetone (9.99%), palmitic acid (5.20%) and phytol (3.29%). The major constituents of the oil from leaves were E-ethyl cinnamate (37.27%), phytol (12.08%), nonanal (10.74%) and Z-3-hexenyl benzoate (7.65%). Both oils showed moderate activity in DPPH assay; however, they exhibited potent tocixity in brine shrimp lethality test. CONCLUSION: The remarkable toxicity effects of the oils are worthy to further investigation to find the probable mechanisms of action accountable for the noticeable toxic effect of these essential oils. PMID- 27478778 TI - Silencing of High Mobility Group Isoform I-C (HMGI-C) Enhances Paclitaxel Chemosensitivity in Breast Adenocarcinoma Cells (MDA-MB-468). AB - PURPOSE: HMGI-C (High Mobility Group protein Isoform I-C) protein is a member of the high-mobility group AT-hook (HMGA) family of small non-histone chromosomal protein that can modulate transcription of an ample number of genes. Genome-wide studies revealed up regulation of the HMGI-C gene in many human cancers. We suggested that HMGI-C might play a critical role in the progression and migration of various tumors. However, the exact role of HMGI-C in breast adenocarcinoma has not been cleared. METHODS: The cells were transfected with siRNAs using transfection reagent. Relative HMGI-C mRNA and protein levels were measured by quantitative real-time PCR and Western blotting, respectively. The cytotoxic effects of HMGI-C siRNA, Paclitaxel alone and combination on breast adenocarcinoma cells were determined using MTT assay. The migration after treatment by HMGI-C siRNA, Paclitaxel alone and combination were detected by wound-healing respectively. RESULTS: HMGI-C siRNA significantly reduced both mRNA and protein expression levels in a 48 hours after transfection and dose dependent manner. We observed that the knockdown of HMGI-C led to the significant reduced cell viability and inhibited cells migration in MDA-MB-468 cells in vitro. CONCLUSION: These results propose that HMGI-C silencing and Paclitaxel treatment alone can inhibit the proliferation and migration significantly, furthermore, synergic effect of HMGI-C siRNA and Paclitaxel showed higher inhibition compared to mono treatment. Taken together, HMGI-C could be used as a promising therapeutic agent in the treatment of human breast adenocarcinoma. Therefore HMGI C siRNA may be an effective adjuvant in human breast adenocarcinoma. PMID- 27478779 TI - Evaluating Effect of Mesenchymal Stem Cells on Expression of TLR2 and TLR4 in Mouse DCs. AB - PURPOSE: Mesenchymal stem cells (MSCs) are multipotent cells and recent findings suggest immunomodulatory effect of them on immune cells including T cells and dendritic cells (DCs). DCs are the most potent antigen presenting cells. It seems because of immunoregulatory properties of MSCs, they can affect the maturation and differentiation of DCs. DCs express a kind of surface receptors called toll like receptors (TLRs) and play a key role in maturation process and activation of DCs. The aim of this study was to evaluate expression of TLR2 and TLR4 on DCs after exposure to mesenchymal stem cell's supernatant in culture media containing LPS and devoid of it. METHODS: In this experimental study, MSCs and DCs were extracted from adult Balb/c mouse bone marrow and spleen, respectively. MSCs supernatant were collected 24 and 48 h after 5(th) passage, and in adjusted with DCs culture. Isolated DCs were co-cultured with MSCs supernatant, incubation time were 24 and 48 hours. mRNA levels of TLR2 and TLR4 were evaluated using real time PCR technique. RESULTS: The results demonstrated that although, expressions of these two receptors were up-regulated in culture media lacking LPS in comparison with the control group but the increase was not significant. There were no significant associations between LPS stimulated DCs with and without MSCs supernatants. CONCLUSION: According to the results presented here, it appears that TLR2 and TLR4 gene expressions on the DCs are not affected by MSCs supernatant. PMID- 27478780 TI - Cloning and Expression of Recombinant Human Endostatin in Periplasm of Escherichia coli Expression System. AB - PURPOSE: Recombinant human endostatin (rhEs) is an angiogenesis inhibitor which is used as a specific drug in the treatment of non-small-cell lung cancer. In the current research, we developed an efficient method for expressing soluble form of the rhEs protein in the periplasmic space of Escherichia coli via fusing with pelB signal peptide. METHODS: The human endostatin (hEs) gene was amplified using synthetic (hEs) gene as a template; then, cloned and expressed under T7 lac promoter. IPTG was used as an inducer for rhEs expression. Next, the osmotic shock was used to extraction of protein from the periplasmic space. The presence of rhEs in the periplasmic space was approved by SDS-PAGE and Western blotting. RESULTS: The results show the applicability of pelB fusion protein system usage for secreting rhEs in the periplasm of E. coli in the laboratory scale. The rhEs represents approximately 35 % (0.83mg/l) of the total cell protein. CONCLUSION: The present study apparently is the first report of codon-optimized rhEs expression as a fusion with pelB signal peptide. The results presented the successful secretion of soluble rhEs to the periplasmic space. PMID- 27478781 TI - Development of Floating-Mucoadhesive Microsphere for Site Specific Release of Metronidazole. AB - PURPOSE: The purpose of this study was to develop and evaluate metronidazole loaded floating-mucoadhesive microsphere for sustained drug release at the gastric mucosa. METHODS: Alginate gastroretentive microspheres containing metronidazole were prepared by ionic gelation method using sodium bicarbonate as gas forming agent, guar gum as mucoadhesive polymer, and Eudragit L100 as drug release modifier. Carbopol was used for increasing the bead strength. The microspheres were characterized by scanning electron microscopy and evaluated by means of drug entrapment efficiency, in vitro buoyancy, and swelling studies. In vitro mucoadhesion and drug release studies were carried out in order to evaluate site specific sustained drug release. RESULTS: All formulations showed 100% buoyancy in vitro for a prolonged period of time. Amount of guar gum influenced the properties of different formulations. The formulation containing drug and guar gum at a ratio of 1:0.5 showed the best results with 76.3% drug entrapment efficiency, 61.21% mucoadhesion, and sustained drug release. Carbopol was found to increase surface smoothness of the microspheres. CONCLUSION: Metronidazole mucoadhesive-floating microspheres can be effectively used for sustained drug release to the gastric mucosa in treatment of upper GIT infection. PMID- 27478782 TI - Lactobacillus Casei Decreases Organophosphorus Pesticide Diazinon Cytotoxicity in Human HUVEC Cell Line. AB - PURPOSE: Exposure to diazinon can trigger acute and chronic toxicity and significantly induces DNA damage and proapoptotic effects in different human cells. Due to the significance of probiotic bacteria antitoxin effect, this study aimed to investigate the effect of Lactobacillus casei on diazinon (DZN) cytotoxicity in human umbilical vein endothelial cells (HUVEC) in vitro. METHODS: The cytotoxicity assessments were performed by MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) test, DAPI (4',6-diamidino-2-phenylindole) staining and flow cytometric methodologies. RESULTS: Cytotoxic assessments through flow cytometry/ DAPI staining demonstrated that apoptosis is the main cytotoxic mechanism of diazinon in HUVEC cells and L. casei could decrease the diazinon cytotoxic effects on toxicants. CONCLUSION: the screen of total bacterial secreted metabolites can be considered as a wealthy source to find the new active compounds to introduce as reducing agricultural remained pesticide cytotoxicity effects on the human food chain. PMID- 27478783 TI - D-optimal Design for Preparation and Optimization of Fast Dissolving Bosentan Nanosuspension. AB - PURPOSE: Bosentan is a drug currently taken orally for the treatment of pulmonary arterial hypertension. However, the water solubility of bosentan is very low, resulting in low bioavailability. The aim of this study was preparation and optimization of bosentan nanosuspension to improve solubility and dissolution rate. METHODS: The different formulations designed by Design Expert(r) software. Nanosuspensions were prepared using precipitation method and the effects of stabilizer type and content and drug content on the particle size, polydispersity (PDI) and yield of nanosuspensions were investigated. RESULTS: Particle size, PDI and yield of the optimal nanosuspension formulation were 200.9 nm, 0.24 and 99.6%, respectively. Scanning electron microscopy (SEM) results showed spherical morphology for bosentan nanoparticles. Thermal analysis indicated that there was a partial crystalline structure and change in the pholymorphism of bosentan in the nanoparticles. In addition, reduction of particle size, significantly increased in vitro dissolution rate of the drug. CONCLUSION: Optimization by design expert software was shown to be a successful method for optimization and prediction of responses by less than 10% error and formulation with 15.8 mg span 85 as an internal stabilizer and 45 mg drug content were introduced as the optimum formulation. The solubility of bosentan in the optimal formulation was 6.9 times higher than coarse bosentan and could be suggested as promising drug delivery systems for improving the dissolution rate and possibly the pharmacokinetic of bosentan. PMID- 27478784 TI - Prediction of Optimum Combination of Eudragit RS/Eudragit RL/Ethyl Cellulose Polymeric Free Films Based on Experimental Design for Using as a Coating System for Sustained Release Theophylline Pellets. AB - PURPOSE: The physicochemical properties of free films made from different mixtures of sustained release polymers were investigated, and an optimum formulation coating on drug containing pellets, based on the study of free film was evaluated. METHODS: In order to determine the effect of different variables on the permeability and swelling of films and procedure optimization, the experimental design was fulfilled based on the statistical method of a 3(3) full factorial design, and according to this method 27 formulations were prepared. The films were prepared using casting-solvent evaporation method. Water vapor permeability, the swelling and permeability of free films in both acidic and buffer media, were carried out. Then, the pellets containing theophylline were coated with the optimum formulation. RESULTS: The results of this study demonstrated that an increase in the free film thickness and Eurdragit RS ratio in films lowered the water vapor transmission (WVT), the swelling and the permeability of all formulations, while an increase in the quantity of ethylcellulose, up to a specific ratio (approximately 40%), decreased the permeability and swelling. The most optimum free film formulation was made up of 60% Eudragit RS and 40% ethylcellulose. CONCLUSION: Pellets coated with a 10% coating level of ethylcellulose and Eudragit RS (4:6) showed suitable release properties and could serve as a favorable sustained release system for theophylline. PMID- 27478786 TI - Formulation and Physicochemical Characterization of Lycopene-Loaded Solid Lipid Nanoparticles. AB - PURPOSE: Lycopene belongs to the carotenoids that shows good pharmacological properties including antioxidant, anti-inflammatory and anticancer. However, as a result of very low aqueous solubility, it has a limited systemic absorption, following oral administration. METHODS: Here, we prepared a stable lycopene loaded solid lipid nanoparticles using Precirol(r) ATO5, Compritol 888 ATO and myristic acid by hot homogenization method with some modification. The size and morphological characteristics of nanoparticles were evaluated using Scanning Electron Microscopy (SEM). Moreover, zeta potential and dispersity index (DI) were measured using zeta sizer. In addition, encapsulation efficiency (EE%), drug loading (DL) and cumulative drug release were quantified. RESULTS: The results showed that the size and DI of particles was generally smaller in the case of SLNs prepared with precirol when compared to SLNs prepared with compritol. Scanning electron microscopy (SEM) and particle size analyses showed spherical SLNs (125 +/- 3.89 nm), monodispersed distribution, and zeta potential of -10.06 +/- 0.08 mV. High EE (98.4 +/- 0.5 %) and DL (44.8 +/- 0.46 mg/g) were achieved in the case of nanoparticles prepared by precirol. The stability study of the lycopene-SLNs in aqueous medium (4 degrees C) was showed that after 2 months there is no significant differences seen in size and DI compared with the fresh formulation. CONCLUSION: Conclusively, in this investigation we prepared a stable lycopene-SLNs with good physicochemical characteristic which candidate it for the future in vivo trials in nutraceutical industries. PMID- 27478785 TI - Interactions Between Sirolimus and Anti-Inflammatory Drugs: Competitive Binding for Human Serum Albumin. AB - PURPOSE: The aim of the present study was investigating the effects of three anti inflammatory drugs, on Sirolimus protein biding. The binding site of Sirolimus on human serum albumin (HSA) was also determined. METHODS: Six different concentrations of Sirolimus were separately exposed to HSA at pH 7.4 and 37 degrees C. Ultrafiltration method was used for separating free drug; then free drug concentrations were measured by HPLC. Finally, Sirolimus protein binding parameters was calculated using Scatchard plots. The same processes were conducted in the presence of NSAIDs at lower concentration of albumin and different pH conditions. To characterize the binding site of Sirolimus on albumin, the free concentration of warfarin sodium and Diazepam, site I and II specific probes, bound to albumin were measured upon the addition of increasing Sirolimus concentrations. RESULTS: Based on the obtained results presence of Diclofenac, Piroxicam and Naproxen, could significantly decrease the percentage of Sirolimus protein binding. The Binding reduction was the most in the presence of Piroxicam. Sirolimus-NSAIDs interactions were increased in higher pH values and also in lower albumin concentrations. Probe displacement study showed that Sirolimus may mainly bind to site I on albumin molecule. CONCLUSION: More considerations in co-administration of NSAIDs and Sirolimus is recommended. PMID- 27478787 TI - Vitamin C for the Prevention of Postoperative Atrial Fibrillation after Cardiac Surgery: A Meta-Analysis. AB - PURPOSE: Several studies have investigated the administration of vitamin C (vitC) for the prevention of postoperative atrial fibrillation (AF) after cardiac surgery. However, their findings were inconsistent. The purpose of this meta analysis was to evaluate the efficacy of vitC as prophylaxis for the prevention of postoperative AF in cardiac surgery. METHODS: A systematic search of PubMed, EMBASE, Google Scholar, the Cochrane Library, and clinical trial registries, was performed. 9 studies, published from August 2001 to May 2015, were included, with a total of 1,037 patients. Patients were randomized to receive vitC, or placebo. RESULTS: Cardiac surgery patients who received vitC as prophylaxis, had a significantly lower incidence of postoperative AF (random effects OR=0.478, 95% CI 0.340 - 0.673, P < 10(-4)). No significant heterogeneity was detected across the analyzed studies (I(2)=21.7%), and no publication bias or other small study related bias was found. CONCLUSION: Our findings suggest that VitC is effective as prophylaxis for the prevention of postoperative AF. The administration of vitC may be considered in all patients undergoing cardiac surgery. PMID- 27478788 TI - A Simple, Fast, Low Cost, HPLC/UV Validated Method for Determination of Flutamide: Application to Protein Binding Studies. AB - PURPOSE: The main goal of this study was development of a reverse phase high performance liquid chromatography (RP-HPLC) method for flutamide quantitation which is applicable to protein binding studies. METHODS: Ultrafilteration method was used for protein binding study of flutamide. For sample analysis, flutamide was extracted by a simple and low cost extraction method using diethyl ether and then was determined by HPLC/UV. Acetanilide was used as an internal standard. The chromatographic system consisted of a reversed-phase C8 column with C8 pre column, and the mobile phase of a mixture of 29% (v/v) methanol, 38% (v/v) acetonitrile and 33% (v/v) potassium dihydrogen phosphate buffer (50 mM) with pH adjusted to 3.2. RESULTS: Acetanilide and flutamide were eluted at 1.8 and 2.9 min, respectively. The linearity of method was confirmed in the range of 62.5 16000 ng/ml (r(2) > 0.99). The limit of quantification was shown to be 62.5 ng/ml. Precision and accuracy ranges found to be (0.2-1.4%, 90-105%) and (0.2-5.3 %, 86.7-98.5 %) respectively. Acetanilide and flutamide capacity factor values of 1.35 and 2.87, tailing factor values of 1.24 and 1.07 and resolution values of 1.8 and 3.22 were obtained in accordance with ICH guidelines. CONCLUSION: Based on the obtained results a rapid, precise, accurate, sensitive and cost-effective analysis procedure was proposed for quantitative determination of flutamide. PMID- 27478789 TI - The Effect of Spacer Morphology on the Aerosolization Performance of Metered-Dose Inhalers. AB - PURPOSE: Respiratory drug delivery has been attracted great interest for the past decades, because of the high incidence of pulmonary diseases. However, despite its invaluable benefits, there are some major drawbacks in respiratory drug delivery, mainly due to the relatively high drug deposition in undesirable regions. One way to improve the efficiency of respiratory drug delivery through metered-dose inhalers (MDI) is placing a respiratory spacer between the inhaler exit and the mouth. The aim of this study was to assess the effect of type and shape of spacer on the aerosolization performance of MDIs. METHODS: A commercial Beclomethasone Dipropionate (BDP) MDI alone or equipped with two different spacer devices (roller and pear type) widely distributed in the world pharmaceutical market was used. The effect of spacers was evaluated by calculating aerosolization indexes such as fine particle fraction (FPF), mass median aerodynamic diameters (MMAD) and geometric standard deviation (GSD) using the next generation impactor. RESULTS: Although one of the spacers resulted in superior outcomes than the other one, but it was not statistically significant. CONCLUSION: The results confirmed that the type and shape of spacer did not substantially influence the aerosolization performance of MDIs. PMID- 27478790 TI - Comparative Evaluation of RUT, PCR and ELISA Tests for Detection of Infection with Cytotoxigenic H. pylori. AB - PURPOSE: Helicobacter pylori is one of the most prevalent infectious agents in the world which causes a variety of gastrointestinal diseases including gastritis, peptic ulcer and gastric carcinoma. The objective of this study was to comparatively evaluate invasive (rapid urease test and polymerase chain reaction) and non-invasive (enzyme-linked immunosorbent assay) tests in diagnosis of infection with cytotoxigenic H. pylori. METHODS: Biopsy specimens and sera were collected from 105 patients with gastric disorders. The presence of H. pylori infection in gastric biopsies was evaluated by RUT and PCR methods using chemotaxis signal transduction protein gene (CSTP), Urea C and HP-16srRNA primers. Serum samples were used for the ELISA test. Detection of infection with cag A-positive strains was performed by PCR and cag A-IgG ELISA kit. RESULTS: Patients with at least two out of three positive results were regarded as infected. The sensitivity, specificity, predictive value and accuracy of the three different methods were evaluated. Of the 105 gastric biopsies, H. pylori were positive in 51 patients (48.57%). The best sensitivity (92.16%) belonged to RUT. The sensitivities of other tests including PCR and ELISA test were 88.24% and 90.20%, respectively. PCR showed the best specificity (94.44%), and the specificities of the other tests including RUT and ELISA test, were 90.74 % and 61.11%, respectively. Furthermore, results of PCR and cag A-IgG ELISA showed high prevalence of cag A-positive strain in the study population. CONCLUSION: Based on our findings, serum ELISA is a rapid noninvasive test for screening of H. pylori infection in the absence of endoscopy indication. In addition, considering the high prevalence of cytotoxigenic H. pylori strains, cag A is suggested as a promising target for PCR and non- invasive ELISA tests for detection of infection with toxigenic strains. PMID- 27478791 TI - Fisetin Protects DNA Against Oxidative Damage and Its Possible Mechanism. AB - PURPOSE: The paper tries to assess the protective effect of fisetin against *OH induced DNA damage, then to investigate the possible mechanism. METHODS: The protective effect was evaluated based on the content of malondialdehyde (MDA). The possible mechanism was analyzed using various antioxidant methods in vitro, including *OH scavenging (deoxyribose degradation), *O2 (-) scavenging (pyrogallol autoxidation), DPPH* scavenging, ABTS*(+) scavenging, and Cu(2+) reducing power assays. RESULTS: Fisetin increased dose-dependently its protective percentages against *OH-induced DNA damage (IC50 value =1535.00+/-29.60 uM). It also increased its radical-scavenging percentages in a dose-dependent manner in various antioxidants assays. Its IC50 values in *OH scavenging, *O2(-) scavenging, DPPH* scavenging, ABTS*(+) scavenging, and Cu(2+)-reducing power assays, were 47.41+/-4.50 uM, 34.05+/-0.87 uM, 9.69+/-0.53 uM, 2.43+/-0.14 uM, and 1.49+/-0.16 uM, respectively. CONCLUSION: Fisetin can effectively protect DNA against *OH-induced oxidative damage possibly via reactive oxygen species (ROS) scavenging approach, which is assumed to be hydrogen atom (H*) and/or single electron (e) donation (HAT/SET) pathways. In the HAT pathway, the 3',4' dihydroxyl moiety in B ring of fisetin is thought to play an important role, because it can be ultimately oxidized to a stable ortho-benzoquinone form. PMID- 27478792 TI - Spices Mixture Containing Garlic, Ginger and Nutmeg Has Protective Effects on the Kidneys and Liver of Cadmium Exposed Rats. AB - PURPOSE: To determine the potential protective effect of spice mixture containing garlic, ginger and nutmeg on the liver and kidney of cadmium exposed rats. METHODS: Male albino rats (n=30) weighing 120 - 180 g, grouped into five (1-5) of 6 rats/group were studied. Group 1 (NC) rats were administered distilled water (1 ml) orally for 4 weeks and served as the negative control while group 2 (PC) rats were administered low dose (LD) cadmium (25 mg/kg body weight) orally for 4 weeks and served as positive control. Group 3 (TBE) rats were treated with spice mixture (SM); 300 mg/kg body weight orally for 2 weeks and then administered LD cadmium for 4 weeks. While group 4 (CET) rats were concurrently administered LD cadmium and SM for 4 weeks, group 5 (TAE) rats were administered LD cadmium for 4 weeks and then treated with SM for 2 weeks. The whole experiment lasted for 42 day after which the animals were sacrificed and blood collected for determination of biochemical parameters using standard procedures and techniques. RESULTS: Exposure to Cd produced greater increases in the liver function parameters. However treatment with SM significantly (p<0.05) reduced ALT in animals treated after exposure, AST and bilirubin in those treated before exposure and significant (p<0.05) increased serum albumin in animals treated before exposure to Cd. The altered renal function parameters and total serum cholesterol were restored to near normal values following treatment with SM. CONCLUSION: It may be concluded that concurrent intake of garlic, ginger and nutmeg at culinary dose in the diet has both therapeutic and prophylactic effect at mitigating Cd toxicity and reaffirms the safely of spices combinations as being currently practiced. PMID- 27478793 TI - Anti-Inflammatory and Antioxidant Activity of Acalypha hispida Leaf and Analysis of its Major Bioactive Polyphenols by HPLC. AB - PURPOSE: Inflammation and oxidative stress can lead to different chronic diseases including cancer and atherosclerosis. Many medicinal plants have the potential to show as anti-inflammatory activity. Present investigation was performed to investigate anti-inflammatory, antioxidant activity, and quantification of selected bioactive plant polyphenols of the ethanol (EAH) and aqueous (AAH) extracts of Acalypha hispida (Euphorbiaceae) leaves. METHODS: Anti-inflammatory activity was evaluated by carragenan and histamine induced rat paw edema models while antioxidant capacity was evaluated by DPPH free radical scavenging, Fe+2 chelating ability, reducing power, NO scavenging, total phenolic and total flavonoid content assay. Identification and quantification of bioactive polyphenols was done by HPLC. RESULTS: At the doses of 200 and 400 mg/kg, both EAH and AAH showed statistically significant inhibition of paw volume in the anti inflammatory activity test. Both the extracts showed DPPH scavenging (IC50: 14 and 17 ug/ml, respectively), Fe+2 ion chelating (IC50: 40 and 46 ug/ml, respectively), NO scavenging activity (65.49 and 60.66% inhibition at 100 ug/ml), and concentration dependent reducing power ability. For EAH and AAH, flavonoid content was 126.30 and 149.72 mg QE/g dry extract, while phenolic content was 130.51 and 173.80 mg GAE/g dry extract, respectively. HPLC analysis of EAH and AAH indicated the presence of high content of ellagic acid along with other phenolic constituents. CONCLUSION: High content of ellagic acid along with other phenolic constituents might have played an important role in the observed anti inflammatory and antioxidant activity. PMID- 27478794 TI - Qualitative and Quantitative Content Determination of Macro-Minor Elements in Bryonia Alba L. Roots using Flame Atomic Absorption Spectroscopy Technique. AB - PURPOSE: To determine the elements in Bryonia alba L. roots, collected from the Crimean Peninsula region in Ukraine. METHODS: Dry ashing was used as a flexible method and all elements were determined using atomic absorption spectrometry (AAS) equipped with flame and graphite furnace. RESULTS: The average concentrations of the determined elements, expressed as mg/100 g dry weight of the sample, were as follow: 13.000 for Fe, 78.000 for Si, 88.000 for P, 7.800 for Al, 0.130 for Mn, 105.000 for Mg, 0.030 for Pb, 0.052 for Ni, 0.030 for Mo, 210.000 for Ca, 0.130 for Cu, 5.200 for Zn, 13.000 for Na, 1170.000 for K, 0.780 for Sr, 0.030 for Co, 0.010 for Cd, 0.010 for As, and 0.010 for Hg. Toxic elements such as Cd and Pb were also found but at very low concentration. Among the analyzed elements, K was the most abundant followed by Ca, Mg, P, Si, Fe, Na, and Zn, whereas Hg, As, Cd, Co, Mo, and Pb were found in low concentration. CONCLUSION: The results suggest that the roots of Bryonia alba L. plant has potential medicinal property through their high element contents present. Moreover, it showed that the AAS method is a simple, fast, and reliable for the determination of elements in plant materials. The obtained results of the current study provide justification for the usage of such fruit in daily diet for nutrition and for medicinal usage in the treatment of various diseases. PMID- 27478795 TI - Reader's Forum. PMID- 27478796 TI - Stress distributions in peri-miniscrew areas from cylindrical and tapered miniscrews inserted at different angles. AB - OBJECTIVE: The purpose of this study was to analyze stress distributions in the roots, periodontal ligaments (PDLs), and bones around cylindrical and tapered miniscrews inserted at different angles using a finite element analysis. METHODS: We created a three-dimensional (3D) maxilla model of a dentition with extracted first premolars and used 2 types of miniscrews (tapered and cylindrical) with 1.45-mm diameters and 8-mm lengths. The miniscrews were inserted at 30 degrees , 60 degrees , and 90 degrees angles with respect to the bone surface. A simulated horizontal orthodontic force of 2 N was applied to the miniscrew heads. Then, the stress distributions, magnitudes during miniscrew placement, and force applications were analyzed with a 3D finite element analysis. RESULTS: Stresses were primarily absorbed by cortical bone. Moreover, very little stress was transmitted to the roots, PDLs, and cancellous bone. During cylindrical miniscrew insertion, the maximum von Mises stress increased as insertion angle decreased. Tapered miniscrews exhibited greater maximum von Mises stress than cylindrical miniscrews. During force application, maximum von Mises stresses increased in both groups as insertion angles decreased. CONCLUSIONS: For both cylindrical and tapered miniscrew designs, placement as perpendicular to the bone surface as possible is recommended to reduce stress in the surrounding bone. PMID- 27478797 TI - The Improvement and Completion of Outcome index: A new assessment system for quality of orthodontic treatment. AB - OBJECTIVE: Given the considerable disagreement between the Peer Assessment Rating (PAR) index and the American Board of Orthodontics Cast-Radiograph Evaluation, we aimed to develop a novel assessment system-the Improvement and Completion of Outcome (ICO) index-to evaluate the outcome of orthodontic treatment. METHODS: Sixteen criteria from 4 major categories were established to represent the pretreatment malocclusion status, as well as the degree of improvement and level of completion of outcome during/after treatment: dental relationship (arch length discrepancy, irregularity, U1-SN, and IMPA); anteroposterior relationship (overjet, right and left molar position, ANB); vertical relationship (anterior overbite, anterior open-bite, lateral open-bite, SN-MP); and transverse relationship (dental midline discrepancy, chin point deviation, posterior cross bite, occlusal plane cant). The score for each criterion was defined from 0 or -1 (worst) to 5 (ideal value or normal occlusion) in gradations of 1. The sum of the scores in each category indicates the area and extent of the problems. Improvement and completion percentages were estimated based on the pre- and post treatment total scores and the maximum total score. If the completion percentage exceeded 80%, treatment outcome was considered successful. RESULTS: Two cases, Class I malocclusion and skeletal Class III malocclusion, are presented to represent the assessment procedure using the ICO index. The difference in the level of improvement and completion of treatment outcome can be clearly explained by using 2 percentage values. CONCLUSIONS: Thus, the ICO index enables the evaluation of the quality of orthodontic treatment objectively and consecutively throughout the entire treatment process. PMID- 27478798 TI - Treatment effects of mandibular total arch distalization using a ramal plate. AB - OBJECTIVE: The purpose of this study was to evaluate treatment effects after distalization of the mandibular dentition using ramal plates through lateral cephalograms. METHODS: Pre- and post-treatment lateral cephalograms and dental casts of 22 adult patients (11 males and 11 females; mean age, 23.9 +/- 5.52 years) who received ramal plates for mandibular molar distalization were analyzed. The treatment effects and amount of distalization of the mandibular molars were calculated and tested for statistical significance. The significance level was set at p < 0.001. RESULTS: The mandibular first molar distalization at the crown and root were 2.10 mm (p < 0.001) and 0.81 mm (p = 0.011), respectively. In the evaluation of skeletal variables, there was a significant increase in the Wits appraisal (p < 0.001). In the evaluation of the soft tissue, there was no significant effect on upper lip position, but the lower lips showed a significant retraction of 2.2 mm (p < 0.001). CONCLUSIONS: The mandibular molars showed a significant amount of distalization accompanied by limited extrusion and mesiobuccal rotation of the crowns. A ramal plate may be a viable device for mandibular total arch distalization in Class III patients who are reluctant to undergo orthognathic surgery. PMID- 27478799 TI - Translation and validation of the Turkish version of the Psychosocial Impact of Dental Aesthetics Questionnaire. AB - OBJECTIVE: The aim of this study was to translate the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) into Turkish, validate the questionnaire, and provide a cross-cultural adaptation. METHODS: The translation process included the following steps, which were performed by a translation committee: (1) translation into Turkish, (2) back translation into English, (3) pretesting, and (4) cross-cultural adaptation. The Turkish version of the PIDAQ was produced subsequent to the translation process. Validity and reliability were measured using the Perception of Occlusion Scale and the aesthetic component of the Index of Orthodontic Treatment Need. The questionnaire was administered to 260 individuals (age range, 18-30 years; mean age, 20.50 +/- 1.9 years). Structural validity was assessed via factor analysis, and internal consistency was measured using Cronbach's alpha coefficient. RESULTS: Factor analysis revealed a four factor structure, with factor loadings for included items ranging from 0.380 to 0.868. Few questions were shuffled among domains various factor loadings. Cronbach's alphas for the Turkish version of the PIDAQ ranged from 0.534 to 0.904. Mean scores for the PIDAQ subscale and total scores differed significantly according to Index of Orthodontic Treatment Need and Perception of Occlusion Scale scores. CONCLUSIONS: This study provided a Turkish version of the PIDAQ, which could be a useful tool in the evaluation of the psychosocial impact of malocclusion in young Turkish adults. PMID- 27478800 TI - Comparisons of orthodontic root resorption under heavy and jiggling reciprocating forces during experimental tooth movement in a rat model. AB - OBJECTIVE: Root mobility due to reciprocating movement of the tooth (jiggling) may exacerbate orthodontic root resorption (ORR). "Jiggling" describes mesiodistal or buccolingual movement of the roots of the teeth during orthodontic treatment. In the present study, buccolingual movement is described as "jiggling." We aimed to investigate the relationship between ORR and jiggling and to test for positive cell expression in odontoclasts in resorbed roots during experimental tooth movement (jiggling) in vivo. METHODS: Male Wistar rats were divided into control, heavy force (HF), optimal force (OF), and jiggling force (JF) groups. The expression levels of cathepsin K, matrix metalloproteinase (MMP) 9 protein, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant 1 (CINC-1; an IL-8-related protein in rodents), receptor activator of nuclear factor kappaB ligand (RANKL), and osteoprotegerin protein in the dental root were determined using immunohistochemistry. RESULTS: On day 21, a greater number of root resorption lacunae, which contained multinucleated odontoclasts, were observed in the palatal roots of rats in the JF group than in rats from other groups. Furthermore, there was a significant increase in the numbers of cathepsin K-positive and MMP-9-positive odontoclasts in the JF group on day 21. Immunoreactivities for IL-6, CINC-1, and RANKL were stronger in resorbed roots exposed to jiggling than in the other groups on day 21. Negative reactivity was observed in the controls. CONCLUSIONS: These results suggest that jiggling may induce ORR via inflammatory cytokine production during orthodontic tooth movement, and that jiggling may be a risk factor for ORR. PMID- 27478801 TI - Finite element analysis of maxillary incisor displacement during en-masse retraction according to orthodontic mini-implant position. AB - OBJECTIVE: Orthodontic mini-implants (OMI) generate various horizontal and vertical force vectors and moments according to their insertion positions. This study aimed to help select ideal biomechanics during maxillary incisor retraction by varying the length in the anterior retraction hook (ARH) and OMI position. METHODS: Two extraction models were constructed to analyze the three-dimentional finite element: a first premolar extraction model (Model 1, M1) and a residual 1 mm space post-extraction model (Model 2, M2). The OMI position was set at a height of 8 mm from the arch wire between the second maxillary premolar and the first molar (low OMI traction) or at a 12-mm height in the mesial second maxillary premolar (high OMI traction). Retraction force vectors of 200 g from the ARH (-1, +1, +3, and +6 mm) at low or high OMI traction were resolved into X , Y-, and Z-axis components. RESULTS: In M1 (low and high OMI traction) and M2 (low OMI traction), the maxillary incisor tip was extruded, but the apex was intruded, and the occlusal plane was rotated clockwise. Significant intrusion and counter-clockwise rotation in the occlusal plane were observed under high OMI traction and -1 mm ARH in M2. CONCLUSIONS: This study observed orthodontic tooth movement according to the OMI position and ARH height, and M2 under high OMI traction with short ARH showed retraction with maxillary incisor intrusion. PMID- 27478802 TI - Nonsurgical correction of a severe anterior deep overbite accompanied by a gummy smile and posterior scissor bite using a miniscrew-assisted straight-wire technique in an adult high-angle case. AB - In the present report, we describe the successful use of miniscrews to achieve vertical control in combination with the conventional sliding MBTTM straight-wire technique for the treatment of a 26-year-old Chinese woman with a very high mandibular plane angle, deep overbite, retrognathic mandible with backward rotation, prognathic maxilla, and gummy smile. The patient exhibited skeletal Class II malocclusion. Orthodontic miniscrews were placed in the maxillary anterior and posterior segments to provide rigid anchorage and vertical control through intrusion of the incisors and molars. Intrusion and torque control of the maxillary incisors relieved the deep overbite and corrected the gummy smile, while intrusion of the maxillary molars aided in counterclockwise rotation of the mandibular plane, which consequently resulted in an improved facial profile. After 3.5 years of retention, we observed a stable, well-aligned dentition with ideal intercuspation and more harmonious facial contours. Thus, we were able to achieve a satisfactory occlusion, a significantly improved facial profile, and an attractive smile for this patient. The findings from this case suggest that nonsurgical correction using miniscrew anchorage is an effective approach for camouflage treatment of high-angle cases with skeletal Class II malocclusion. PMID- 27478803 TI - A Bioinformatics Approach to Prioritize Single Nucleotide Polymorphisms in TLRs Signaling Pathway Genes. AB - It has been suggested that single nucleotide polymorphisms (SNPs) in genes involved in Toll-like receptors (TLRs) pathway may exhibit broad effects on function of this network and might contribute to a range of human diseases. However, the extent to which these variations affect TLR signaling is not well understood. In this study, we adopted a bioinformatics approach to predict the consequences of SNPs in TLRs network. The consequences of non-synonymous coding SNPs (nsSNPs) were predicted by SIFT, PolyPhen, PANTHER, SNPs&GO, I-Mutant, ConSurf and NetSurf tools. Structural visualization of wild type and mutant protein was performed using the project HOPE and Swiss PDB viewer. The influence of 5'-UTR and 3'- UTR SNPs were analyzed by appropriate computational approaches. Nineteen nsSNPs in TLRs pathway genes were found to have deleterious consequences as predicted by the combination of different algorithms. Moreover, our results suggested that SNPs located at UTRs of TLRs pathway genes may potentially influence binding of transcription factors or microRNAs. By applying a pathway based bioinformatics analysis of genetic variations, we provided a prioritized list of potentially deleterious variants. These findings may facilitate the selection of proper variants for future functional and/or association studies. PMID- 27478804 TI - Carcinoembryonic Antigen Expression and Resistance to Radiation and 5 Fluorouracil-Induced Apoptosis and Autophagy. AB - Understanding the mechanism of tumor resistance is critical for cancer therapy. In this study, we investigated the effect of carcinoembryonic antigen (CEA) overexpression on UV-and 5-fluorouracil (5-FU)-induced apoptosis and autophagy in colorectal cancer cells. We used histone deacetylase (HDAC) inhibitor, NaB and DNA demethylating agent, 5-azacytidine (5-AZA) to induce CEA expression in HT29/219 and SW742 colorectal cancer cell lines. MTT assay was used to measure IC50 value of the cells exposed to graded concentrations of 5- FU with either 0.1 mM NaB or 1 MUM 5-AZA for 72 h . Using CHO- and SW742-CEA transfectants, we also investigated the effect of CEA expression on UV- and 5-FU-induced apoptosis and autophagy. Treatment of HT29/219 cell line with NaB and 5-AZA increased CEA expression by 29% and 31%, respectively. Compared with control cells, the IC50 value for 5-FU of NaB and 5-AZA-treated cells increased by 40% and 57%, respectively. Treatment of SW742 cells with NaB or 5-AZA increased neither CEA expression nor the IC50 value for 5-FU. In comparison to parental cells, CEA expression also significantly protected transfected cells against UV-induced apoptosis. Decreased proportions of autophagy and apoptosis were also observed in 5-FU treated SW742- and CHO-CEA transfectants. We conclude that CEA expression can effectively protect colorectal cancer cells against radiation and drug induced apoptosis and autophagy. PMID- 27478805 TI - Gene Expression and Methylation Pattern in HRK Apoptotic Gene in Myelodysplastic Syndrome. AB - Myelodysplastic syndromes (MDSs) are a clonal bone marrow (BM) disease characterized by ineffective hematopoiesis, dysplastic maturation and progression to acute myeloid leukemia (AML). Methylation silencing of HRK has been found in several human malignancies. In this study, we explored the association of HRK methylation status with its expression, clinical parameters and MDS subtypes in MDS patients. To study the methylation status of HRK gene, we applied Methylation Sensitive-High Resolution Melting Curve Analysis (MS-HRM) in MDS patients, as well as healthy controls and EpiTect(r)PCR Control DNA. Real time RT-PCR was used for gene expression analysis. Methylation frequency in promoter region of HRK in patient samples was 20.37%. Methylation of HRK was significantly related to transcriptional downregulation (P=0.023). The difference in frequency of hypermethylated HRK gene was significant between good (10%) and poor (71.42%) cytogenetic risk groups (P= 0.001), advanced stage MDS patients (66.66%) in comparison with early stage MDS patients (2.56%) (P= 0.00), higher- risk MDS group (61.53%) and lower- risk MDS group (7.31%) (P= 0.00). HRK hypermethylation was associated with advanced- stage MDS and downregulation of HRK gene may play a role in the progression of MDS. PMID- 27478806 TI - The Relation Between GABA and L-Arginine Levels With Some Stroke Risk Factors in Acute Ischemic Stroke Patients. AB - Changes in extra and intracellular neurotransmitter amino acids concentration in the early stage of acute cerebral ischemia have been reported. In this the study, serum level of gamma aminobutyric acid (GABA) and L-Arginine in acute ischemic stroke patients was assessed. 60 patients with acute ischemic stroke and sixthy healthy volunteers as a control group were assessed. Serum GABA was measured with modified enzymatic method and serum L- Arginine was measured by modified Sakaguchi method. Serum GABA level in stroke cases was lower than that of the control group. There was no relationship between GABA level and age or gender. Also, no significant correlation was observed between GABA levels with ischemic stroke risk factors such as smoking, diabetes mellitus, and hypertension. Serum L Arginine level in patients was slightly increased in comparison with control group. There was a positive relationship between serum L- Arginine level and acute ischemic stroke risk factors. Serum GABA level was reduced in patients and had no correlation with acute ischemic stroke risk factors. PMID- 27478807 TI - Expression of HCA2 Receptors in Femoral Epiphysis and Metaphysis of Rats with Dexamethasone-Induced Osteoporosis. AB - The present study describes the changes in expression of hydroxy- carboxylic acid receptor 2 (HCA2 receptor) in femoral epiphysis and metaphysis of rats with glucocorticoid-induced osteoporosis (GIO). 16 growing male Sprauge dawley rats were randomly divided into two equal groups consisting of normal control and rats that were rendered osteoporotic by receiving 0.1 mg/kg/day dexamethasone subcutaneously. After 4 weeks, all rats were sacrificed and immediately right and left femoral bones were removed for RT-qPCR and histological examination, respectively. Immunohistochemical parameters using a primary rabbit polyclonal GPR109A antibody in hematoxylin and eosin- counter stained slides were determined. HCA2 receptor expression was evaluated using RT- qPCR. Qualitative and histomorphometric evaluation of slides revealed the establishment of glucocorticoid- induced osteoporosis (GIO) in rats treated with dexamethasone. In immunohistochemical study, dexamethasone administration appreciably reduced receptor density in all evaluated cell types and in total slides as compared to control. mRNA level of HCA2 receptor gene was reduced in dexamethasone- treated group. GIO may be associated with down regulation of HCA2 receptors in proximal femoral bone of rats at mRNA as well as protein level in no- cell type-specific manner, although reduction in protein expression needs to be further confirmed by western blotting. PMID- 27478808 TI - Mutation Screening of BRCA Genes in 10 Iranian Males with Breast Cancer. AB - Male breast cancer is a rare disease with an increasing trend. Due to limited information especially about the genetic basis of the disease in Iran and the lower age of its onset, the disease requires more attention. The aim of this study was to screen the male patients with breast cancer for BRCA mutations as well as tissue markers of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER-2) and cytokeratin 5/6 (CK5/6). Ten Iranian males with breast cancer were selected regardless of their histologic subtypes, age and family history from patients referred to Mehrad, Day and Parsian hospitals in Tehran, Iran, during a two-year period. Paraffin blocks of the tumoral regions were tested for ER, PR, HER-2 and CK5/6 immunostaining. DNA extraction was carried out on the EDTA blood samples followed by Sanger sequencing. Immunohistochemistry results for ER, and PR were negative in 2 out of 10 patients, while the results of HER-2 and CK5/6 were negative in all the cases. A missense mutation in exon 18 of BRCA1 and a nonsense mutation in exon 25 of in BRCA2 were detected in one patient each. Both patients belonged to luminal A subtype. Despite the low number of patients in this study, it could be concluded that mutations in BRCA1 and BRCA2 occur in male breast cancer patients of luminal A subtype. The negative status of the tissue markers could not be used for the prediction of BRCA mutations. PMID- 27478809 TI - A Novel PKD1 Mutation in a Patient with Autosomal Dominant Polycystic Kidney Disease. PMID- 27478810 TI - Two-port laparoscopic appendectomy assisted with needle grasper comparison with conventional laparoscopic appendectomy. AB - PURPOSE: The 2-port laparoscopic appendectomy technique (TLA) is between the conventional 3-port and single-port laparoscopic appendectomy surgeries. We compared postoperative pain and cosmetic results after TLA with conventional laparoscopic appendectomy (CLA) by a 3-port device. METHODS: Patients undergoing TLA were matched with patients undergoing CLA between February 2015 and November 2015 at the same institution. Thirty-two patients underwent TLA with a needle grasper. The appendix was secured by a percutaneous organ-holding device (needle grasper), then removed through a puncture at McBurney's point. Another 38 patients underwent CLA. Patient demographics, operative details, and postoperative outcomes were collected and evaluated. RESULTS: One patient in the TLA group developed a wound infection and 1 patient in the CLA group developed a postoperative intra-abdominal abscess and 3 wound infections. There was no significant difference between the groups when comparing the length of hospital stay, time until oral intake, and other complications. The pain score in the first 12 hours after surgery was significanly higher in CLA group than the TLA group (P < 0.001). Operative time was significantly shorter in the CLA group compared to the TLA group (P < 0.001). CONCLUSION: TLA using a needle grasper was associated with a significantly lower pain score 12 hours after surgery, better cosmetic results, and lower cost, than the CLA 3-port procedure because of the fewer number of ports. PMID- 27478811 TI - Does Korea's current diagnosis-related group-based reimbursement system appropriately classify appendectomy patients? AB - PURPOSE: As several years have passed since the implementation of the Korean diagnosis-related group (DRG) payment system for appendicitis, its early outcomes should be assessed to determine if further improvements are warranted. METHODS: We retrospectively analyzed clinical data from Korean patients who underwent appendectomy, dividing the sample into 2 groups of those who received services before and after implementation of the DRG system. Based on the DRG code classification, patient data were collected including the amount of DRG reimbursement and the total in-patient costs. We subsequently performed univariate and multivariate analyses to identify independent factors contributing to higher total in-patient cost. RESULTS: Although implementation of the DRG system for appendicitis significantly reduced postoperative length of stay (2.8 +/- 1.0 days vs. 3.4 +/- 1.9 days, P < 0.001), it did not reduce total in hospital cost. The independent factors related to total inhospital cost included patient age of 70 years or more (odds ratio [OR], 3.214; 95% confidence interval [CI], 1.769-5.840; P < 0.001) and operation time longer than 100 minutes (OR, 3.690; 95% CI, 2.007-6.599, P < 0.001). In addition, older patients (>=70 years) showed a nearly 10 times greater relative risk for having a comorbid condition (95% CI, 5.141-20.214; P < 0.001) and a 3.255 times greater relative risk for having higher total in-hospital cost (95% CI, 1.731-6.119, P < 0.001). CONCLUSION: It appears that older patients (>70 years) have greater comorbidities, which contribute to higher inpatient costs. Thus, our study suggests that patient age be considered as a DRG classification variable. PMID- 27478812 TI - Feasibility of single-incision laparoscopic appendectomy in a small hospital. AB - PURPOSE: This study aimed to compare clinical outcomes for single-incision laparoscopic appendectomy (SILA) and conventional laparoscopic appendectomy (CLA) for the treatment of acute appendicitis and to assess the feasibility of performing SILA in a small hospital with limited surgical instruments and staff experience. METHODS: Retrospective record review identified 133 patients who underwent laparoscopic appendectomy from December 2013 to April 2015. Patients were categorized according to the type of appendectomy performed (SILA or CLA). Patient characteristics and surgical outcomes were compared between the 2 groups. Postoperative complication rates were compared using the Clavien-Dindo classification. Postoperative pain was assessed using a visual analog scale immediately postsurgery; at 12, 24, 36, and 48 hours postoperatively, and at 7 days postoperatively. RESULTS: Record review identified 38 patients who had undergone SILA and 95 patients who had undergone CLA. No significant differences in clinical characteristics were found between the 2 groups. There were no significant differences in operation time, time to flatus, or length of hospital stay. Overall complication rates were not significantly different between the 2 groups. No complications worse than grade IIIa occurred in the SILA group. Postoperative pain scores were not significantly different between the 2 groups at any time point. CONCLUSION: We found comparable surgical outcomes for SILA compared to CLA. Even in a small hospital with limited surgical instruments and staff experience, SILA may be a feasible and safe technique. PMID- 27478813 TI - Transumbilical laparoscopic-assisted appendectomy is a useful surgical option for pediatric uncomplicated appendicitis: a comparison with conventional 3-port laparoscopic appendectomy. AB - PURPOSE: Transumbilical laparoscopic-assisted appendectomy (TULA) is a single incision technique that uses a combined intra- and extracorporeal method. The aim of this study was to compare surgical outcomes of TULA with conventional 3-port laparoscopic appendectomy (LA). METHODS: A retrospective review of medical records between 2010 and 2014 identified 303 pediatric patients who underwent LA with uncomplicated acute appendicitis. Of these, 85 patients underwent TULA and 218 patients underwent conventional LA. Demographic data, clinical characteristics, perioperative outcomes and postoperative complications were compared between the 2 groups. RESULTS: The mean operation time in the TULA group was 30.39 minutes, which was significantly shorter than that of the LA group (47.83 minutes) (P < 0.001). The first day of oral intake after surgery was earlier (1.05 days vs. 1.32 days; P < 0.001) and the length of hospital stay was also shorter (2.54 days vs. 3.22 days; P < 0.001) for the TULA group than the LA group. Furthermore, the postoperative complication rate was lower in the TULA group (1 of 85, 1.25%) compared to the LA group (19 of 218, 8.7%) (P = 0.018). CONCLUSION: In conclusion, TULA procedure is recommended for uncomplicated appendicitis in children due to its simplicity and better postoperative outcomes. PMID- 27478814 TI - Effect of surgical timing and outcomes for appendicitis severity. AB - PURPOSE: This study was aimed to evaluate the effect of time of surgery for acute appendicitis on surgical outcomes to optimize the timing of appendectomies. METHODS: Medical records of patients who underwent an appendectomy were reviewed to obtain data on time of symptom onset, time of hospital presentation, and start times of surgery. Surgical findings were used to define appendicitis as either uncomplicated or complicated. The uncomplicated group included patients with simple, focal, or suppurative appendicitis, and the complicated group included patients with gangrenous, perforated appendicitis or periappendiceal abscess formation. The 2 groups were analyzed by age, sex, and time. RESULTS: A total of 192 patients were analyzed. The mean time from symptom onset to start of operation showed a significant difference between both groups (1,652.9 minutes vs. 3,383.8 minutes, P < 0.001). The mean time from hospital visit to start of operation showed no difference between both groups (398.7 minutes vs. 402.0 minutes, P = 0.895). Operating within 24 hours of symptom onset had a relative risk of 1.738 (95% confidence interval, 1.319-2.425) for complications. Operating more than 36 hours after symptom onset was associated with an increased risk of postoperative ileus and a longer hospital stay. CONCLUSION: Complicated appendicitis is associated with a delay in surgery from symptom onset rather than a delay at hospital arrival. Surgeons should take into account the time from symptom onset when deciding on the timing of appendectomy. We recommend that appendectomy be performed within 36 hours from symptom onset. PMID- 27478815 TI - Meckel diverticulum in exomphalos minor. AB - A congenital hernia into the base of the umbilical cord is known as an exomphalos and when the size of the defect is 5 cm or less and containing only bowel, it is called as exomphalos minor. We present a case of a newborn with an exomphalos minor within a Meckel diverticulum. He underwent surgical resection of the Meckel diverticulum and repair of the abdominal wall defect. To our knowledge, this is the first reported case of Meckel diverticulum in an exomphalos minor in Korea. PMID- 27478816 TI - Appendiceal transection associated with seat belt restraint. AB - The seat belt is designed for safety in a motor vehicle and should be worn to prevent severe injuries. But, the seat belt itself can be an injury factor in combination with deceleration forces applied to fixation points of mobile viscera. Here, we present a 23-year-man with traumatic transection of the appendix, highly mobile viscera, following seat belt injury. PMID- 27478817 TI - Similar Clinical and Surgical Outcomes Achieved with Early Compared to Late Anti TNF Induction in Mild-to-Moderate Ulcerative Colitis: A Retrospective Cohort Study. AB - Background. Biologic agents targeting tumor necrosis factor alpha are effective in the management of ulcerative colitis (UC), but their use is often postponed until after failure of other treatment modalities. Objectives. We aim to determine if earlier treatment with infliximab or adalimumab alters clinical and surgical outcomes in UC patients. Methods. A retrospective cohort study was conducted evaluating UC outpatients treated with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first anti-TNF exposure; early initiation was defined as starting treatment within three years of diagnosis. Primary outcomes were colectomy, UC-related hospitalization, and clinical secondary loss of response. Kaplan-Meier analysis was used to assess time to the primary outcomes. Results. 115 patients were included (78 infliximab, 37 adalimumab). Median follow-up was 175.6 weeks (IQR 72.4-228.4 weeks). Fifty-seven (49.6%) patients received early anti-TNF therapy; median time to treatment in this group was 38.1 (23.3-91.0) weeks compared to 414.0 (254.0-561.3) weeks in the late initiator cohort (p < 0.0001). Patients treated with early anti-TNF therapy had more severe endoscopic disease at induction (mean Mayo endoscopy subscore 2.46 (SD +/- 0.66) versus 1.86 (+/-0.67), p < 0.001) and trended towards increased risk of colectomy (17.5% versus 8.6%, p = 0.16) and UC-related hospitalization (43.9% versus 27.6%, p = 0.07). In multivariate regression analysis, early anti-TNF induction was not associated with colectomy (HR 2.02 [95% CI: 0.57-7.20]), hospitalization (HR 1.66 [0.84-3.30]), or secondary loss of response (HR 0.86 [0.52-1.42]). Conclusions. Anti-TNF therapy is initiated earlier in patients with severe UC but earlier treatment does not prevent hospitalization, colectomy, or secondary loss of response. PMID- 27478818 TI - Comorbid Illness, Bowel Preparation, and Logistical Constraints Are Key Reasons for Outpatient Colonoscopy Nonattendance. AB - Background. Colonoscopy nonattendance is a challenge for outpatient clinics globally. Absenteeism results in a potential delay in disease diagnosis and loss of hospital resources. This study aims to determine reasons for colonoscopy nonattendance from a Canadian perspective. Design. Demographic data, reasons for nonattendance, and patient suggestions for improving compliance were elicited from 49 out of 144 eligible study participants via telephone questionnaire. The 49 nonattenders were compared to age and sex matched controls for several potential contributing factors. Results. Nonattendance rates were significantly higher in winter months; the OR of nonattendance was 5.2 (95% CI, 1.6 to 17.0, p < 0.001) in winter versus other months. Being married was positively associated with attendance. There was no significant association between nonattendance and any of the other variables examined. The top 3 reasons for nonattendance were being too unwell to attend the procedure, being unable to complete bowel preparation, or experiencing logistical challenges. Conclusions. Colonoscopy attendance rates appear to vary significantly by season and it may be beneficial to book more colonoscopies in the summer or overbook in the winter. Targets for intervention include more tailored teaching sessions, reminders, taxi chits, and developing a hospital specific colonoscopy video regarding procedure and bowel preparation requirements. PMID- 27478820 TI - Endoscopic Ultrasound-Guided Radiofrequency Ablation of the Pancreatic Tumors: A Promising Tool in Management of Pancreatic Tumors. AB - Objective. Radiofrequency ablation is a well-established antitumor treatment and is recognized as one of the least invasive therapeutic modalities for pancreatic neoplasm. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) delivery can be used to treat both pancreatic cancer and asymptomatic premalignant pancreatic neoplasms and may serve as a less invasive alternative to surgical resection. This is an appealing option that may result in less morbidity and mortality. The aim of this review was to summarize and evaluate the clinical and technical effectiveness of EUS-guided RFA of pancreatic neoplasms. Methods. A through literature review was performed to identify the studies describing this novel technique. In this review article, we have summarized human case series. The indications, techniques, limitations, and complications reported are discussed. Results. A total of six studies were included. Overall, a 100% technical success rate was reported in human studies. Complications related to endoscopic ultrasound-guided radiofrequency ablation delivery have been described; however, few cases have presented life-threatening outcomes. Conclusion. We believe that this novel technique can be a safe and effective alternative approach in the management of selected patients. PMID- 27478819 TI - The Utility of Endoscopic Biopsies in Patients with Normal Upper Endoscopy. AB - Background and Aims. Upper endoscopy is a valuable tool in the workup of gastrointestinal (GI) complaints. The purpose of this study is to determine cost and yield of taking biopsies in a normal upper GI tract. Methods. This is a retrospective study where all upper GI biopsies were identified between May 2012 and April 2013, at a tertiary care center. Clinical, procedural, and pathology reports were reviewed to identify patient demographics, procedure information, and pathology diagnosis. Results. Biopsies of the upper GI tract were taken in 1297 patients with normal upper endoscopies. In patients with normal upper endoscopy, 22% of esophageal, 44% of gastric, and 12% of duodenal biopsies were abnormal. The most frequent abnormality was reflux esophagitis in 16% of esophageal biopsies, chronic gastritis in 23% of gastric biopsies, and increased intraepithelial lymphocytes in 6% of duodenal biopsies. The additional cost for taking biopsies in a normal upper GI tract for a diagnosis of eosinophilic esophagitis was $2963 Canadian (CAD), H. pylori associated gastritis was $1404 CAD, and celiac disease was $3024 CAD. Conclusions. The yield of biopsy in normal upper endoscopy varied with location, but the additional expense can be costly and should be tailored to appropriate clinical situations. PMID- 27478821 TI - Management of Inflammatory Bowel Disease in Pregnancy: A Practical Approach to New Guidelines. PMID- 27478822 TI - Small Worldness in Dense and Weighted Connectomes. AB - The human brain is a heterogeneous network of connected functional regions; however, most brain network studies assume that all brain connections can be described in a framework of binary connections. The brain is a complex structure of white matter tracts connected by a wide range of tract sizes, which suggests a broad range of connection strengths. Therefore, the assumption that the connections are binary yields an incomplete picture of the brain. Various thresholding methods have been used to remove spurious connections and reduce the graph density in binary networks. But these thresholds are arbitrary and make problematic the comparison of networks created at different thresholds. The heterogeneity of connection strengths can be represented in graph theory by applying weights to the network edges. Using our recently introduced edge weight parameter, we estimated the topological brain network organization using a complimentary weighted connectivity framework to the traditional framework of a binary network. To examine the reproducibility of brain networks in a controlled condition, we studied the topological network organization of a single healthy individual by acquiring 10 repeated diffusion-weighted magnetic resonance image datasets, over a 1-month period on the same scanner, and analyzing these networks with deterministic tractography. We applied a threshold to both the binary and weighted networks and determined that the extra degree of freedom that comes with the framework of weighting network connectivity provides a robust result as any threshold level. The proposed weighted connectivity framework provides a stable result and is able to demonstrate the small world property of brain networks in situations where the binary framework is inadequate and unable to demonstrate this network property. PMID- 27478823 TI - Accurate Identification of Cancerlectins through Hybrid Machine Learning Technology. AB - Cancerlectins are cancer-related proteins that function as lectins. They have been identified through computational identification techniques, but these techniques have sometimes failed to identify proteins because of sequence diversity among the cancerlectins. Advanced machine learning identification methods, such as support vector machine and basic sequence features (n-gram), have also been used to identify cancerlectins. In this study, various protein fingerprint features and advanced classifiers, including ensemble learning techniques, were utilized to identify this group of proteins. We improved the prediction accuracy of the original feature extraction methods and classification algorithms by more than 10% on average. Our work provides a basis for the computational identification of cancerlectins and reveals the power of hybrid machine learning techniques in computational proteomics. PMID- 27478825 TI - Elderly and Nonelderly Use of a Dedicated Ambulance Corps' Emergency Medical Services in Taiwan. AB - Backgrounds and Aim. Taiwan's population is gradually aging; however, there are no comparative data on emergency medical services (EMS) use between the elderly and nonelderly. Methods. We analyzed the emergency calls dealt with between January 1 and April 4, 2014, by EMS in one city in Taiwan. All calls were divided into two groups: elderly (>=65 years) and nonelderly (<65 years). Nontransport and transport calls were compared between the groups for demographic characteristics, transport time, reasons for calling EMS, vital signs, and emergency management. Results. There were 1,001 EMS calls: 226 nontransport and 775 transport calls. The elderly accounted for significantly (P < 0.05) fewer (28 (9.2%)) nontransport calls than did the nonelderly (136 (21.4%)). In the transport calls, 276 (35.6%) were the elderly. The elderly had a higher proportion of histories for cardiovascular disease, cerebrovascular disease, hypertension, diabetes, end-stage renal disease, cancer, Parkinson's disease, and Alzheimer's disease. In addition, the elderly had significantly longer total transport time, more nontrauma reasons, and poorer consciousness levels and lower oxygen saturation and needed more respiratory management and more frequent resuscitation during transport than did the nonelderly. Conclusion. The elderly have more specific needs than do the nonelderly. Adapting EMS training, operations, and government policies to aging societies is mandatory and should begin now. PMID- 27478824 TI - Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions. AB - Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1alpha, 25-dihydroxy vitamin D3 activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-alpha, FXR, LXR-alpha play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and microfluidic organs-on chips, which mimic the physiology of a multicellular environment, will likely replace the current cell-based workflow. PMID- 27478826 TI - Mitochondria Biogenesis and Bioenergetics Gene Profiles in Isogenic Prostate Cells with Different Malignant Phenotypes. AB - Background. The most significant hallmarks of cancer are directly or indirectly linked to deregulated mitochondria. In this study, we sought to profile mitochondria associated genes in isogenic prostate cell lines with different tumorigenic phenotypes from the same patient. Results. Two isogenic human prostate cell lines RC77N/E (nonmalignant cells) and RC77T/E (malignant cells) were profiled for expression of mitochondrial biogenesis and energy metabolism genes by qRT-PCR using the Human Mitochondria and the Mitochondrial Energy Metabolism RT(2) PCR arrays. Forty-seven genes were differentially regulated between the two cell lines. The interaction and regulatory networks of these genes were generated by Ingenuity Pathway Analysis. UCP2 was the most significantly upregulated gene in primary adenocarcinoma cells in the current study. The overexpression of UCP2 upon malignant transformation was further validated using human prostatectomy clinical specimens. Conclusions. This study demonstrates the overexpression of multiple genes that are involved in mitochondria biogenesis, bioenergetics, and modulation of apoptosis. These genes may play a role in malignant transformation and disease progression. The upregulation of some of these genes in clinical samples indicates that some of the differentially transcribed genes could be the potential targets for therapeutic interventions. PMID- 27478827 TI - Subclinical Hypothyroidism in PCOS: Impact on Presentation, Insulin Resistance, and Cardiovascular Risk. AB - Aim of Study. To assess status of thyroid function and thyroid disorders particularly subclinical hypothyroidism (SCH) in subjects with polycystic ovarian syndrome (PCOS) and impact of SCH on various clinical and biochemical parameters and cardiovascular risk in PCOS. Methods. Hundred females diagnosed with PCOS as per Rotterdam criteria and 100 normal controls were recruited and were subjected to elaborate anthropometric, clinical, and biochemical assessment. Results. Notable findings included significantly higher frequency of subjects with subclinical hypothyroidism (p = 0.0002), autoimmune thyroiditis (p < 0.001), and goitre (p = 0.02) in polycystic ovarian syndrome subjects compared to control subjects. Further SCH PCOS subjects were found to harbor significantly higher HOMA-IR (p < 0.05) and frequency of subjects with dyslipidemia (p < 0.05) compared to both euthyroid PCOS and euthyroid control subjects. Though frequency of subjects with cardiovascular risk factors was higher in SCH PCOS group than euthyroid PCOS group, it failed to reach statistical significance. Conclusion. We concluded that PCOS is associated with high incidence of SCH and AIT compared to normal population and SCH poses increased risk of cardiovascular disorder in PCOS. PMID- 27478828 TI - Soft Tissue Augmentation with Autologous Platelet Gel and beta-TCP: A Histologic and Histometric Study in Mice. AB - Background. Facial aging is a dynamic process involving both soft tissue and bony structures. Skin atrophy, with loss of tone, elasticity, and distribution of facial fat, coupled with gravity and muscle activity, leads to wrinkling and folds. Purpose. The aim of the study was to evaluate microporous tricalcium phosphate (beta-TCP) and autologous platelet gel (APG) mix in mice for oral and maxillofacial soft tissue augmentation. The hypothesis was that beta-TCP added with APG was able to increase the biostimulating effect on fibroblasts and quicken resorption. Materials and Methods. Ten female, 6-8-week-old black-haired mice were selected. beta-TCP/APG gel was injected into one cheek; the other was used as control. The animals were sacrificed at 8 weeks and histologically evaluated. Results. The new fibroblast was intensively stained with acid fuchsin and presented in contact with beta-TCP. At higher magnification, actively secreting fibroblasts were observed at the periphery of beta-TCP with a well differentiated fibroblast cell line and blood vessels. Acid fuchsin stained cutaneous structures in pink: no epidermal/dermal alterations or pathological inflammatory infiltrates were detected. The margins of beta-TCP granules were clear and not diffused near tissues. Conclusion. APG with beta-TCP preserves skin morphology, without immune response, with an excellent tolerability and is a promising scaffold for cells and biomaterial for soft tissue augmentation. PMID- 27478829 TI - Gene-Disease Interaction Retrieval from Multiple Sources: A Network Based Method. AB - The number of gene-related databases has been growing largely along with the research on genes of bioinformatics. Those databases are filled with various gene functions, pathways, interactions, and so forth, while much biomedical knowledge about human diseases is stored as text in all kinds of literatures. Researchers have developed many methods to extract structured biomedical knowledge. Some study and improve text mining algorithms to achieve efficiency in order to cover as many data sources as possible, while some build open source database to accept individual submissions in order to achieve accuracy. This paper combines both efforts and biomedical ontologies to build an interaction network of multiple biomedical ontologies, which guarantees its robustness as well as its wide coverage of biomedical publications. Upon the network, we accomplish an algorithm which discovers paths between concept pairs and shows potential relations. PMID- 27478830 TI - Interplay between Tumor Microenvironment and Cancer Cells. PMID- 27478831 TI - N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development In Vivo and In Vitro. AB - Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs) are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR's expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E) 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801's influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA's direct effect on fetal lung development was observed using fetal lung organ culture in vitro. Results. All seven NMDARs are expressed in fetal rat lungs. Intrauterine hypoxia upregulated NMDARs expression in fetal lungs and decreased fetal body weight, lung weight, lung-weight-to-body weight ratio, and radial alveolar count, whereas MK-801 alleviated this damage in vivo. In vitro experiments showed that NMDA decreased saccular circumference and area per unit and downregulated thyroid transcription factor-1 and surfactant protein-C mRNA expression. Conclusions. The excessive activation of NMDARs contributed to hypoxia-induced fetal lung development retardation and appropriate blockade of NMDAR might be a novel therapeutic strategy for minimizing the negative outcomes of prenatal hypoxia on lung development. PMID- 27478832 TI - Accuracy and Precision of Three-Dimensional Low Dose CT Compared to Standard RSA in Acetabular Cups: An Experimental Study. AB - Background and Purpose. The gold standard for detection of implant wear and migration is currently radiostereometry (RSA). The purpose of this study is to compare a three-dimensional computed tomography technique (3D CT) to standard RSA as an alternative technique for measuring migration of acetabular cups in total hip arthroplasty. Materials and Methods. With tantalum beads, we marked one cemented and one uncemented cup and mounted these on a similarly marked pelvic model. A comparison was made between 3D CT and standard RSA for measuring migration. Twelve repeated stereoradiographs and CT scans with double examinations in each position and gradual migration of the implants were made. Precision and accuracy of the 3D CT were calculated. Results. The accuracy of the 3D CT ranged between 0.07 and 0.32 mm for translations and 0.21 and 0.82 degrees for rotation. The precision ranged between 0.01 and 0.09 mm for translations and 0.06 and 0.29 degrees for rotations, respectively. For standard RSA, the precision ranged between 0.04 and 0.09 mm for translations and 0.08 and 0.32 degrees for rotations, respectively. There was no significant difference in precision between 3D CT and standard RSA. The effective radiation dose of the 3D CT method, comparable to RSA, was estimated to be 0.33 mSv. Interpretation. Low dose 3D CT is a comparable method to standard RSA in an experimental setting. PMID- 27478834 TI - A Five-Gene Expression Signature Predicts Clinical Outcome of Ovarian Serous Cystadenocarcinoma. AB - Ovarian serous cystadenocarcinoma is a common malignant tumor of female genital organs. Treatment is generally less effective as patients are usually diagnosed in the late stage. Therefore, a well-designed prognostic marker provides valuable data for optimizing therapy. In this study, we analyzed 303 samples of ovarian serous cystadenocarcinoma and the corresponding RNA-seq data. We observed the correlation between gene expression and patients' survival and eventually established a risk assessment model of five factors using Cox proportional hazards regression analysis. We found that the survival time in high-risk patients was significantly shorter than in low-risk patients in both training and testing sets after Kaplan-Meier analysis. The AUROC value was 0.67 when predicting the survival time in testing set, which indicates a relatively high specificity and sensitivity. The results suggest diagnostic and therapeutic applications of our five-gene model for ovarian serous cystadenocarcinoma. PMID- 27478833 TI - Impact of Dental Implant Surface Modifications on Osseointegration. AB - Objective. The aim of this paper is to review different surface modifications of dental implants and their effect on osseointegration. Common marketed as well as experimental surface modifications are discussed. Discussion. The major challenge for contemporary dental implantologists is to provide oral rehabilitation to patients with healthy bone conditions asking for rapid loading protocols or to patients with quantitatively or qualitatively compromised bone. These charging conditions require advances in implant surface design. The elucidation of bone healing physiology has driven investigators to engineer implant surfaces that closely mimic natural bone characteristics. This paper provides a comprehensive overview of surface modifications that beneficially alter the topography, hydrophilicity, and outer coating of dental implants in order to enhance osseointegration in healthy as well as in compromised bone. In the first part, this paper discusses dental implants that have been successfully used for a number of years focusing on sandblasting, acid-etching, and hydrophilic surface textures. Hereafter, new techniques like Discrete Crystalline Deposition, laser ablation, and surface coatings with proteins, drugs, or growth factors are presented. Conclusion. Major advancements have been made in developing novel surfaces of dental implants. These innovations set the stage for rehabilitating patients with high success and predictable survival rates even in challenging conditions. PMID- 27478835 TI - Demographics and Personality Factors Associated with Burnout among Nurses in a Singapore Tertiary Hospital. AB - Background. The aim of the study was to evaluate the prevalence and extent of burnout among nurses in Singapore and investigate the influence of demographic factors and personal characteristics on the burnout syndrome. Methods. A cross sectional survey design was adopted. All registered nurses working in Singapore General Hospital were approached to participate. A questionnaire eliciting data on demographics, burnout (measured using the Maslach Burnout Inventory, MBI), and personality profile (measured using the NEO Five-Factor Inventory, NEO-FFI) was used. Results. 1830 nurses out of 3588 responded (response rate: 51%). Results from 1826 respondents were available for analysis. The MBI identified 39% to have high emotional exhaustion (EE, cut-off score of >27), 40% having high depersonalization (DP, cut-off score of >10), and 59% having low personal accomplishment (PA, cut-off score of <33). In multivariable analysis, age, job grade, and neuroticism were significantly associated with each of the 3 components of the MBI. Staff nurses less than 30 years with high to very high neuroticism were more likely to experience high EE, high DP, and low PA. Conclusion. Younger nurses in Singapore are at increased risk of burnout. Personality traits also played a significant role in the experience of burnout. PMID- 27478836 TI - A Recombinant Adenovirus Expressing P12A and 3C Protein of the Type O Foot-and Mouth Disease Virus Stimulates Systemic and Mucosal Immune Responses in Mice. AB - Foot-and-mouth disease (FMD) is a highly contagious livestock disease of cloven hoofed animals which causes severe economic losses. The replication-deficient, human adenovirus-vectored FMD vaccine has been proven effective against FMD. However, the role of T-cell-mediated antiviral responses and the mucosae-mediated antiviral responses induced by the adenovirus-vectored FMD vaccine was rarely examined. Here, the capsid protein precursor P1-2A and viral protease 3C of the type O FMDV were expressed in replicative-deficient human adenovirus type 5 vector. BALB/c mice immunized intramuscularly and intraperitoneally with recombinant adenovirus rAdv-P12A3C elicited higher FMDV-specific IgG antibodies, IFN-gamma, and IL-4 cytokines than those in mice immunized with inactivated FMDV vaccine. Moreover, BALB/c mice immunized with recombinant adenovirus rAdv-P12A3C by oral and intraocular-nasal immunization induced high FMDV-specific IgA antibodies. These results show that the recombinant adenovirus rAdv-P12A3C could resist FMDV comprehensively. This study highlights the potential of rAdv-P12A3C to serve as a type O FMDV vaccine. PMID- 27478837 TI - The HPV16 E7 Oncoprotein Disrupts Dendritic Cell Function and Induces the Systemic Expansion of CD11b(+)Gr1(+) Cells in a Transgenic Mouse Model. AB - Objective. The aim of this study was to analyze the effects of the HPV16 E7 oncoprotein on dendritic cells (DCs) and CD11b(+)Gr1(+) cells using the K14E7 transgenic mouse model. Materials and Methods. The morphology of DCs was analyzed in male mouse skin on epidermal sheets using immunofluorescence and confocal microscopy. Flow cytometry was used to determine the percentages of DCs and CD11b(+)Gr1(+) cells in different tissues and to evaluate the migration of DCs. Results. In the K14E7 mouse model, the morphology of Langerhans cells and the migratory activity of dendritic cells were abnormal. An increase in CD11b(+)Gr1(+) cells was observed in the blood and skin of K14E7 mice, and molecules related to CD11b(+)Gr1(+) chemoattraction (MCP1 and S100A9) were upregulated. Conclusions. These data suggest that the HPV16 E7 oncoprotein impairs the function and morphology of DCs and induces the systemic accumulation of CD11b(+)Gr1(+) cells. PMID- 27478838 TI - Involvement of the Nonneuronal Cholinergic System in Bone Remodeling in Rat Midpalatal Suture after Rapid Maxillary Expansion. AB - Few studies sought to analyze the expression and function of the nonneuronal acetylcholine system in bone remodeling in vivo due to the lack of suitable models. We established a rat maxilla expansion model in which the midline palatine suture of the rat was rapidly expanded under mechanical force application, inducing tissue remodeling and new bone formation, which could be a suitable model to investigate the role of the nonneuronal acetylcholine system in bone remodeling in vivo. During the expansion, the expression pattern changes of the nonneuronal cholinergic system components and the mRNA levels of OPG/RANKL were detected by immunohistochemistry or real-time PCR. The value of the RANKL/OPG ratio significantly increased after 1 day of expansion, indicating dominant bone resorption induced by the mechanical stimulation; however after 3 days of expansion, the value of the RANKL/OPG ratio significantly decreased, suggesting a dominant role of the subsequent bone formation process. Increasing expression of Ach was detected after 3 days of expansion which indicated that ACh might play a role in bone formation. The mRNA expression levels of other components also showed observable changes during the expansion which confirmed the involvement of the nonneuronal cholinergic system in the process of bone remodeling in vivo. Further researches are still needed to figure out the detailed functions of the nonneuronal cholinergic system and its components. PMID- 27478839 TI - Cognitive Performance during a 24-Hour Cold Exposure Survival Simulation. AB - Survivor of a ship ground in polar regions may have to wait more than five days before being rescued. Therefore, the purpose of this study was to explore cognitive performance during prolonged cold exposure. Core temperature (T c) and cognitive test battery (CTB) performance data were collected from eight participants during 24 hours of cold exposure (7.5 degrees C ambient air temperature). Participants (recruited from those who have regular occupational exposure to cold) were instructed that they could freely engage in minimal exercise that was perceived to maintaining a tolerable level of thermal comfort. Despite the active engagement, test conditions were sufficient to significantly decrease T c after exposure and to eliminate the typical 0.5-1.0 degrees C circadian rise and drop in core temperature throughout a 24 h cycle. Results showed minimal changes in CTB performance regardless of exposure time. Based on the results, it is recommended that survivors who are waiting for rescue should be encouraged to engage in mild physical activity, which could have the benefit of maintaining metabolic heat production, improve motivation, and act as a distractor from cold discomfort. This recommendation should be taken into consideration during future research and when considering guidelines for mandatory survival equipment regarding cognitive performance. PMID- 27478840 TI - An Ultrasound Simulation Model for the Pulsatile Blood Flow Modulated by the Motion of Stenosed Vessel Wall. AB - This paper presents an ultrasound simulation model for pulsatile blood flow, modulated by the motion of a stenosed vessel wall. It aims at generating more realistic ultrasonic signals to provide an environment for evaluating ultrasound signal processing and imaging and a framework for investigating the behaviors of blood flow field modulated by wall motion. This model takes into account fluid structure interaction, blood pulsatility, stenosis of the vessel, and arterial wall movement caused by surrounding tissue's motion. The axial and radial velocity distributions of blood and the displacement of vessel wall are calculated by solving coupled Navier-Stokes and wall equations. With these obtained values, we made several different phantoms by treating blood and the vessel wall as a group of point scatterers. Then, ultrasound echoed signals from oscillating wall and blood in the axisymmetric stenotic-carotid arteries were computed by ultrasound simulation software, Field II. The results show better consistency with corresponding theoretical values and clinical data and reflect the influence of wall movement on the flow field. It can serve as an effective tool not only for investigating the behavior of blood flow field modulated by wall motion but also for quantitative or qualitative evaluation of new ultrasound imaging technology and estimation method of blood velocity. PMID- 27478841 TI - Roles and Clinical Applications of Biomarkers in Cardiovascular Disease. PMID- 27478842 TI - Leukocyte-Reduced Platelet-Rich Plasma Treatment of Basal Thumb Arthritis: A Pilot Study. AB - A positive effect of intra-articular platelet-rich plasma (PRP) injection has been discussed for osteoarthritic joint conditions in the last years. The purpose of this study was to evaluate PRP injection into the trapeziometacarpal (TMC) joint. We report about ten patients with TMC joint osteoarthritis (OA) that were treated with 2 intra-articular PRP injections 4 weeks apart. PRP was produced using the Double Syringe System (Arthrex Inc., Naples, Florida, USA). A total volume of 1.47 +/- 0.25 mL PRP was injected at the first injection and 1.5 +/- 0.41 mL at the second injection, depending on the volume capacity of the joint. Patients were evaluated using VAS, strength measures, and the Mayo Wrist score and DASH score after 3 and 6 months. VAS significantly decreased from 6.2 +/- 1.6 to 5.4 +/- 2.2 at six-month follow-up (P < 0.05). The DASH score was unaffected; however, the Mayo Wrist score significantly improved from 46.5 +/- 18.6 to 67.5 +/- 19.0 at six-month follow-up (P = 0.05). Grip was unaffected, whereas pinch declined from 6.02 +/- 2.99 to 3.96 +/- 1.77 at six-month follow-up (P < 0.05). We did not observe adverse events after the injection of PRP, except one occurrence of a palmar wrist ganglion, which resolved without treatment. PRP injection for symptomatic TMC OA is a reasonable therapeutic option in early stages TMC OA and can be performed with little to no morbidity. PMID- 27478843 TI - Success and Recurrence Rate after Radial Extracorporeal Shock Wave Therapy for Plantar Fasciopathy: A Retrospective Study. AB - Background and Aims. The exploration of an individualised protocol of radial extracorporeal shock wave therapy (rESWT) for plantar fasciopathy, assessing success rates and the recurrence rate over a 1-year period after treatment, is not yet identified in literature. Methods and Results. Between 2006 and 2013, 68 patients (78 heels) were assessed for plantar fasciopathy. An individualised rESWT treatment protocol was applied and retrospectively analysed. Heels were analysed for mean number of shock wave impulses, mean pressure, and mean frequency applied. Significant mean pain reductions were assessed through Visual Analogue Scale (VAS) after 1-month, 3-month, and 1-year follow-up. Success rates were estimated as the percentage of patients having more than 60% VAS pain decrease at each follow-up. 1-year recurrence rate was estimated. The mean VAS score before treatment at 6.9 reduced to 3.6, 1 month after the last session, and to 2.2 and 0.9, after 3 months and 1 year, respectively. Success rates were estimated at 19% (1 month), 70% (3 months), and 98% (1 year). The 1-year recurrence rate was 8%. Moderate positive Spearman's rho correlation (r = 0.462, p < 0.001) was found between pretreatment pain duration and the total number of rESWT sessions applied. Conclusions. Individualised rESWT protocol constitutes a suitable treatment for patients undergoing rESWT for plantar fasciitis. PMID- 27478844 TI - Comparison of Three Chemotherapy Regimens in Elderly Patients with Diffuse Large B Cell Lymphoma: Experience at a Single National Reference Center in Mexico. AB - Background. Although chemotherapy added to rituximab is a standard of care for diffuse large B cell lymphoma (DLBCL), treatment of patients >=65 years of age remains controversial due to comorbidities. Methods. This is a retrospective, comparative, nonrandomized study of patients >=65 years of age, who were diagnosed with DLBCL but not previously treated. Demographic characteristics and comorbidities were analyzed. Three rituximab-containing treatment regimens (standard RCHOP, anthracycline dose-reduced RChOP, and RCOP) were compared. Descriptive analyses were conducted. Survival was calculated with the Kaplan Meier method, and differences were compared with the log-rank test. Results. In total, 141 patients with a median age of 73.9 years were studied. The three treatment groups had comparable demographic characteristics. The overall response was 77%, 72.5%, and 59% in groups treated with RCHOP, RChOP, and RCOP, respectively. After multivariate analysis, the factors influencing the overall survival were the presence of B symptoms, poor performance status (ECOG >= 3), and febrile neutropenia. Factors influencing disease-free survival were febrile neutropenia, high-intermediate and high-risk IPI scores, and treatment without anthracycline. Conclusion. A higher ORR (overall response rate) was achieved with standard RCHOP, which influenced DFS and OS, although it was not statistically significant compared with the other groups. Interventional phase 3 trials testing new molecules in patients aged 70 to 80 years and older are required to improve the prognosis within this growing population. PMID- 27478845 TI - Evaluating the Effect of Knowledge, Attitude, and Practice on Self-Management in Type 2 Diabetic Patients on Dialysis. AB - Background. Type 2 diabetes is an increasingly common condition with several preventable microvascular complications such as kidney damage. Nephropathy is expensive to manage, especially as hospital dialysis treatment. Improving patients' knowledge, attitude, and practice (KAP) toward their condition can achieve better control, delay complications, and improve their quality of life. This study evaluated the KAP and self-care behaviors of diabetic patients on dialysis and variables that affect it. Methods. This cross-sectional study was conducted at Shahid Beheshti academic hospitals of Tehran, Iran. Face-to-face interviews were held to fill five validated questionnaires: three evaluating KAP, one evaluating self-management, and one evaluating quality of life. Result. 117 diabetic patients on hemodialysis (42 females) with mean (SD) age of 68.70 +/- 9.26 years were enrolled in the survey. The scores for patient's KAP, self-care, and quality of life were 59.90 +/- 11.23, 44.27 +/- 8.35, 45.06 +/- 12.87, 46.21 +/- 10.23, and 26.85 +/- 13.23, respectively. There was significant negative correlation between patients' knowledge and attitude with their glycosylated hemoglobin level and their fasting blood sugar. There was significant correlation between patients' knowledge and practice with their self-care activities. Conclusion. The present study suggests that patients' KAP scores have a practical effect upon self-care behavior. This highlights the needs for effective diabetes education programs in developing countries like Iran. PMID- 27478846 TI - Smoking Cessation Carries a Short-Term Rising Risk for Newly Diagnosed Diabetes Mellitus Independently of Weight Gain: A 6-Year Retrospective Cohort Study. AB - Background. The effects of smoking on human metabolism are complex. Although smoking increases risk for diabetes mellitus, smoking cessation was also reported to be associated with weight gain and incident diabetes mellitus. We therefore conducted this study to clarify the association between smoking status and newly diagnosed diabetes mellitus. Methods. An analysis was done using the data of a mass health examination performed annually in an industrial park from 2007 to 2013. The association between smoking status and newly diagnosed diabetes mellitus was analyzed with adjustment for weight gain and other potential confounders. Results. Compared with never-smokers, not only current smokers but also ex-smokers in their first two years of abstinence had higher odds ratios (ORs) for newly diagnosed diabetes mellitus (never-smokers 3.6%, OR as 1; current smokers 5.5%, OR = 1.499, 95% CI = 1.147-1.960, and p = 0.003; ex-smokers in their first year of abstinence 7.5%, OR = 1.829, 95% CI = 0.906-3.694, and p = 0.092; and ex-smokers in their second year of abstinence 9.0%, OR = 2.020, 95% CI = 1.031-3.955, and p = 0.040). Conclusion. Smoking cessation generally decreased risk for newly diagnosed diabetes mellitus. However, increased odds were seen within the first 2 years of abstinence independently of weight gain. PMID- 27478847 TI - Xerostomia, Hyposalivation, and Salivary Flow in Diabetes Patients. AB - The presence of xerostomia and hyposalivation is frequent among diabetes mellitus (DM) patients. It is not clear if the presence of xerostomia and hyposalivation is greater in DM than non-DM patients. The aims of this systematic review are (1) to compare the prevalence rates of xerostomia, (2) to evaluate the salivary flow rate, and (3) to compare the prevalence rates of hyposalivation in DM versus non DM population. This systematic review was conducted according to the PRISMA group guidelines by performing systematic literature searches in biomedical databases from 1970 until January 18th, 2016. All studies showed higher prevalence of xerostomia in DM patients in relation to non-DM population, 12.5%-53.5% versus 0 30%. Studies that analyzed the quantity of saliva in DM population in relation to non-DM patients reported higher flow rates in non-DM than in DM patients. The variation flow rate among different studies in each group (DM/CG) is very large. Only one existing study showed higher hyposalivation prevalence in DM than non-DM patients (45% versus 2.5%). In addition, quality assessment showed the low quality of the existing studies. We recommend new studies that use more precise and current definitions concerning the determination and diagnosis of DM patients and salivary flow collection. PMID- 27478849 TI - Topical Administration of Pirfenidone Increases Healing of Chronic Diabetic Foot Ulcers: A Randomized Crossover Study. AB - Only 30 percent of chronic diabetic foot ulcers heal after 20 weeks of standard treatment. Pirfenidone is a drug with biological, anti-inflammatory, and antifibrotic effects. The aim of this study was to evaluate the effect of topical pirfenidone added to conventional treatment in noninfected chronic diabetic foot ulcers. This was a randomized crossover study. Group 1 received topical pirfenidone plus conventional treatment for 8 weeks; after this period, they were switched to receive conventional treatment only for 8 more weeks. In group 2, the order of the treatments was the opposite. The end points were complete ulcer healing and size reduction. Final data were obtained from 35 ulcers in 24 patients. Fifty-two percent of ulcers treated with pirfenidone healed before 8 weeks versus 14.3% treated with conventional treatment only (P = 0.025). Between 8 and 16 weeks, 30.8% ulcers that received pirfenidone healed versus 0% with conventional treatment (P = 0.081). By week 8, the reduction in ulcer size was 100% [73-100] with pirfenidone versus 57.5% with conventional treatment [28.9-74] (P = 0.011). By week 16, the reduction was 93% [42.7-100] with pirfenidone and 21.8% [8-77.5] with conventional treatment (P = 0.050). The addition of topical pirfenidone to conventional treatment significantly improves the healing of chronic diabetic noninfected foot ulcers. PMID- 27478848 TI - Oxidative Damage to the Salivary Glands of Rats with Streptozotocin-Induced Diabetes-Temporal Study: Oxidative Stress and Diabetic Salivary Glands. AB - Objective. This study evaluated oxidative damage caused to the salivary glands in streptozotocin-induced diabetes (DM). Materials and Methods. Rats were divided into 4 groups: groups 1 and 2, control rats, and groups 3 and 4, DM rats. 8 Hydroxy-2'-deoxyguanosine (8-OHdG), protein carbonyl (PC), 4-hydroxynonenal protein adduct (4-HNE), oxidized and/or MDA-modified LDL-cholesterol (oxy LDL/MDA), 8-isoprostanes (8-isoP), and oxidative stress index (OSI) were measured at 7 (groups 1 and 3) and 14 (groups 2 and 4) days of experiment. Results. The unstimulated salivary flow in DM rats was reduced in the 2nd week, while the stimulated flow was decreased throughout the duration of the experiment versus control. OSI was elevated in both diabetic glands in the 1st and 2nd week, whereas 8-isoP and 8-OHdG were higher only in the parotid gland in the second week. PC and 4-HNE were increased in the 1st and 2nd week, whereas oxy-LDL/MDA was increased in the 2nd week in the diabetic parotid glands. Conclusions. Diabetes induces oxidative damage of the salivary glands, which seems to be caused by processes taking place in the salivary glands, independently of general oxidative stress. The parotid glands are more vulnerable to oxidative damage in these conditions. PMID- 27478850 TI - Analysis of Inflammatory Mediators in Prediabetes and Newly Diagnosed Type 2 Diabetes Patients. AB - This study evaluated the inflammatory markers in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM). Inflammatory markers levels were analyzed using one-way analysis of covariance and the association with prediabetes or T2DM risks was examined by logistic regression models. Our data showed increased levels of hypersensitivity C-reactive protein (hs-CRP), interleukin (IL-4), IL-10, and tryptase in prediabetes subjects and hs-CRP, immunoglobulin E (IgE), IL-4, and IL 10 in T2DM subjects. We concluded that Hs-CRP, IgE, IL-4, IL-10, and tryptase were positively associated with prediabetes or T2DM. Further large prospective studies are warranted to assess a temporal relation between inflammatory biomarkers and incidence of prediabetes or T2DM and its associated chronic diseases. PMID- 27478852 TI - Texas Occurrence of Lyme Disease and Its Neurological Manifestations. AB - Today, Lyme disease is the most commonly reported tick-borne disease in the United States and Europe. The culprits behind Lyme disease are the Borrelia species of bacteria. In the USA, Borrelia burgdorferi causes the majority of cases, while in Europe and Asia Borrelia afzelii and Borrelia garinii carry the greatest burden of disease. The clinical manifestations of Lyme disease have been identified as early localized, early disseminated, and late chronic. The neurological effects of Lyme disease include both peripheral and central nervous systems involvement, including focal nerve abnormalities, cranial neuropathies, painful radiculoneuritis, meningitis, and/or toxic metabolic encephalopathy, known as Lyme encephalopathy. Given the geographic predominance of Lyme disease in the Northeast and Midwest of the USA, no major studies have been conducted regarding Southern states. Between 2005 and 2014, the Center for Disease Control has reported 582 confirmed cases of Lyme disease in Texas. Because of the potential for increased incidence and prevalence in Texas, it has become essential for research and clinical efforts to be diverted to the region. The Texas A&M College of Veterinary Medicine and Biomedical Sciences Lyme Lab has been investigating the ecology of Lyme disease in Texas and developing a pan specific serological test for Lyme diagnosis. This report aimed to exposure materials and raise awareness of Lyme disease to healthcare providers. PMID- 27478851 TI - Does Hsp60 Provide a Link between Mitochondrial Stress and Inflammation in Diabetes Mellitus? AB - The focus of this review is to summarise the known relationships between the expression of heat shock protein 60 (Hsp60) and its association with the pathogenesis of Type 1 and Type 2 diabetes mellitus. Hsp60 is a mitochondrial stress protein that is induced by mitochondrial impairment. It is known to be secreted from a number of cell types and circulating levels have been documented in both Types 1 and 2 diabetes mellitus patients. The biological significance of extracellular Hsp60, however, remains to be established. We will examine the links between Hsp60 and cellular anti- and proinflammatory processes and specifically address how Hsp60 appears to affect immune inflammation by at least two different mechanisms: as a ligand for innate immune receptors and as an antigen recognised by adaptive immune receptors. We will also look at the role of Hsp60 during immune cell activation in atherosclerosis, a significant risk factor during the pathogenesis of diabetes mellitus. PMID- 27478853 TI - The Evolution and Challenge of the Zika virus and its Uncharted Territory in the Neurological Realm. PMID- 27478855 TI - Storage Conditions of Conjugated Reagents Can Impact Results of Immunogenicity Assays. AB - Consistent performance of anti-drug antibody (ADA) assays through all stages of clinical development is critical for the assessment of immunogenicity and interpretation of PK, PD, safety, and efficacy. The electrochemiluminescent assays commonly employed for ADA measurement use drug conjugated with ruthenium and biotin to bind ADA in samples. Here we report an association between high nonspecific ADA responses in certain drug-naive individuals and the storage buffer of the conjugated reagents used in a monoclonal antibody ADA assay. Ruthenylated reagents stored in phosphate-buffered saline (PBS) buffer had increased levels of aggregate and produced variable and high baseline responses in some subjects. Reagents stored in a histidine-sucrose buffer (HSB) had lower aggregate levels and produced low sample responses. In contrast to PBS, conjugated reagents formulated in HSB remained low in aggregate content and in sample response variability after 5 freeze/thaw cycles. A reagent monitoring control (RMC) serum was prepared for the real-time evaluation of conjugated reagent quality. Using appropriate buffers for storage of conjugated reagents together with RMCs capable of monitoring of reagent aggregation status can help ensure consistent, long-term performance of ADA methods. PMID- 27478854 TI - Monocyte Heterogeneity: Consequences for Monocyte-Derived Immune Cells. AB - Blood monocytes are precursors of dendritic cells, macrophages, and osteoclasts. They are a heterogeneous cell population with differences in size, phenotype, and function. Although monocytes maintain several tissue-specific populations of immune cells in homeostasis, their contribution to populations of dendritic cells, macrophages, and osteoclasts is significantly increased in inflammation. Identification of a growing number of functionally different subsets of cells within populations of monocyte-derived immune cells has recently put monocyte heterogeneity into sharp focus. Here, we summarize recent findings in monocyte heterogeneity and their differentiation into dendritic cells, macrophages, and osteoclasts. We also discuss these advances in the context of the formation of functionally different monocyte-derived subsets of dendritic cells, macrophages, and osteoclasts. PMID- 27478857 TI - Associations between Obesity, Body Fat Distribution, Weight Loss and Weight Cycling on Serum Pesticide Concentrations. AB - OBJECTIVE: Preliminary studies suggest pesticides may be linked to increased cancer risk. Since most pesticides are lipophilic and stored within adipose tissue, serum levels of organochlorines are affected not only by environmental exposures, but also by factors related to lipid turnover and storage. Our objective was to investigate whether serum organochlorines are influenced by weight loss, body fat distribution, and weight cycling. METHODS: Ten overweight women were recruited upon entry into a weight loss program and surveyed regarding weight history, childbearing/lactation, and exposure to environmental contaminants. Anthropometric measures and phlebotomy were conducted at baseline and at four weeks (mean weight loss=5.1 kg). Serum was analyzed for 19 common polychlorinated pesticides and metabolites and 10 PCB congeners. RESULTS: Organochlorine levels were not significantly affected by weight loss nor associated with body mass index (BMI). Strong positive correlations were noted between levels of DDE/DDT and age (DDE beta=0.6986/p=0.0246/DDT beta=0.6536/p=0.0404) and between DDE/DDT and waist-to-hip ratio (WHR) (DDE beta=0.4356/p=0.0447/DDT beta=0.8108/p=0.0044). Trends were noted for decreased levels of DDT in women who reported more episodes of weight cycling. CONCLUSION: Serum organochlorine levels may be affected not only by age, but also factors related to lipid turnover (i.e., episodes of weight cycling and WHR), and warrants further study. PMID- 27478856 TI - Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo. AB - Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction with alpha 4 beta 1 integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated, in vitro, their effect on human cells and in vivo in EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects both in vitro and in vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases. PMID- 27478858 TI - Standard manual capsulorhexis / Ultrasound phacoemulsification compared to femtosecond laser-assisted capsulorhexis and lens fragmentation in clear cornea small incision cataract surgery. AB - BACKGROUND: Femtosecond-laser assisted clear cornea cataract surgery may hold promise in safer and more effective procedures. We decided to perform a comparative study to standard manual incision phacoemulsification surgery. METHODS: This is a single-center, single-intervention, and prospective comparative data evaluation of 133 consecutive cases subjected to cataract surgery. Group-A (Phaco), manual capsulorhexis & ultrasound phacoemulsification (n = 66); Group-B femtosecond-laser assisted capsulorhexis and lens fragmentation (n = 67), employing the LenSx laser (Alcon Surgical, Ft. Worth, TX). All cases were evaluated for refraction, visual acuity, keratometry, tomography, pachymetry, endothelial cell counts, intraocular pressure, and type of intraocular lens (IOL) implanted. The groups were matched for age, gender, pre operative vision metrics, and cataract grade, and were followed up to 1 year. RESULTS: In group-A post-operative uncorrected distance visual acuity (UDVA) was 20/20 or better in 61.5 % and 20/25 or better in 78.5 % of the eyes. The femtosecond laser group-B had improved outcomes (p = 0.075 and p = 0.042, respectively): post-operative UDVA was 20/20 or better in 62.7 % of the eyes and 20/25 or better in 85.1 %. Linear regression scatterplots of achieved versus attempted spherical equivalent had excellent regression coefficients (r (2) = 0.983 in group-A and 0.979 in group-B). There were 75.2 % cases in group-A and 80.6 % in group-B (p = 0.8732) within +/-0.50 D of targeted refractive equivalent. Slight trend of under-correction was noted in group-A. Average residual manifest cylinder in the toric subgroup-A was -0.50 D (95 % Limit-of Agreement (LoA) = -0.78 D), and in toric subgroup-B -0.45 D (LoA = -0.45 D). CONCLUSIONS: Mean spherical equivalent refraction and visual acuity are comparable with laser cataract surgery compared with manual capsulorhexis & ultrasound phacoemulsification. Improved astigmatism correction may be among the benefits of femtosecond laser-assisted cataract surgery. Transient corneal edema may be a first day transient disadvantage in femtosecond laser-assisted cataract surgery. PMID- 27478859 TI - Calculation of x-ray scattering patterns from nanocrystals at high x-ray intensity. AB - We present a generalized method to describe the x-ray scattering intensity of the Bragg spots in a diffraction pattern from nanocrystals exposed to intense x-ray pulses. Our method involves the subdivision of a crystal into smaller units. In order to calculate the dynamics within every unit, we employ a Monte-Carlo molecular dynamics-ab-initio hybrid framework using real space periodic boundary conditions. By combining all the units, we simulate the diffraction pattern of a crystal larger than the transverse x-ray beam profile, a situation commonly encountered in femtosecond nanocrystallography experiments with focused x-ray free-electron laser radiation. Radiation damage is not spatially uniform and depends on the fluence associated with each specific region inside the crystal. To investigate the effects of uniform and non-uniform fluence distribution, we have used two different spatial beam profiles, Gaussian and flattop. PMID- 27478860 TI - Pulmonary Myeloperoxidase Activity. AB - Neutrophils are considered one of the first responders of the innate immune response. Their primary activities are to migrate to sites of infection by chemotaxis and trans-migration across the endothelium (Gaines et al., 2005). Once at the site of infection, they phagocytize microbes and kill them. Critical to the neutrophil's ability to kill microbes are the multiple degradative enzymes contained within granules. The activity of these enzymes is non-specific, and therefore, neutrophils also contribute to tissue damage at the site of infection (Gaines and Berliner, 2005). Measurement of neutrophil infiltration into tissues is one way to gauge the severity of infection, inflammation, and tissue damage (Ayala et al., 2002). Myeloperoxidase is found in the primary granules of neutrophils and is an effective measure of neutrophil infiltration into tissues (Gaines and Berliner, 2005). PMID- 27478861 TI - Mesenchymal Stem Cell (MSC) Aggregate Formation in vivo. AB - Human mesenchymal stem/progenitor cells (MSCs) isolated from various adult tissues show remarkable therapeutic potential and are being employed in clinical trials for the treatment of numerous diseases (Prockop et al., 2010). While routes of cell administration vary, profound beneficial effects of MSCs in animal models have been observed following intraperitoneal injections of the cells (Roddy et al., 2011). Similar to MSC spheres formed in culture under conditions where attachment to plastic is not permitted (Bartosh et al., 2010), MSCs injected into the peritoneum of mice spontaneously aggregate into 3D sphere-like structures (Bartosh et al., 2013). During the process of sphere assembly and compaction, MSCs upregulate expression of numerous therapeutic anti-inflammatory and immune modulatory factors. Here we describe the method we previously used for the generation of human bone marrow-derived MSC aggregates/spheres in vivo (Bartosh et al., 2013). By tagging the MSCs with green fluorescent protein (GFP), the aggregates formed can be easily visualized, collected and analyzed for changes in cellular properties and interactions with host immune cells. PMID- 27478862 TI - Quantification of Total and 2-LTR (Long terminal repeat) HIV DNA, HIV RNA and Herpesvirus DNA in PBMCs. AB - Almost all individuals infected with human immunodeficiency virus (HIV) are also infected with cytomegalovirus (CMV) and Epstein Barr virus (EBV). The aims of our studies have included characterizing and measuring the latent HIV reservoir and understanding the association between asymptomatic replication of CMV (and other herpesvirus, including EBV) and this HIV reservoir (Gianella et al., 2014). This protocol was designed to simultaneously co-extract DNA and RNA from the same peripheral blood mononuclear cell (PBMC) aliquot and quantify HIV, CMV and EBV DNA, as well as HIV RNA using droplet digital PCR (ddPCR). For collection and processing of male genital secretions and quantification of HIV RNA and DNA from seven human herpesviruses from seminal plasma, refer to protocol "Quantification of HIV RNA and Human Herpesvirus DNA in Seminal Plasma" (Vargas-Meneses et al., 2015). PMID- 27478863 TI - Smartphone applications to reduce alcohol consumption and help patients with alcohol use disorder: a state-of-the-art review. AB - Hazardous drinking and alcohol use disorder (AUD) are substantial contributors to USA and global morbidity and mortality. Patient self-management and continuing care are needed to combat these public health threats. However, services are rarely provided to patients outside of clinic settings or following brief intervention. Smartphone applications ("apps") may help narrow the divide between traditional health care and patient needs. The purpose of this review is to identify and summarize smartphone apps to reduce alcohol consumption or treat AUD that have been evaluated for feasibility, acceptability, and/or efficacy. We searched two research databases for peer-reviewed journal articles published in English that evaluated smartphone apps to decrease alcohol consumption or treat AUD. We identified six apps. Two of these apps (A-CHESS and LBMI-A) promoted self reported reductions in alcohol use, two (Promillekoll and PartyPlanner) failed to promote self-reported reductions in alcohol use, and two (HealthCall-S and Chimpshop) require further evaluation and testing before any conclusions regarding efficacy can be made. In summary, few evaluations of smartphone apps to reduce alcohol consumption or treat AUD have been reported in the scientific literature. Although advances in smartphone technology hold promise for disseminating interventions among hazardous drinkers and individuals with AUD, more systematic evaluations are necessary to ensure that smartphone apps are clinically useful. PMID- 27478864 TI - Spatiotemporal Gait Parameters as Predictors of Lower-Limb Overuse Injuries in Military Training. AB - The study objective was to determine whether spatiotemporal gait parameters could predict lower-limb overuse injuries in cohort of combat soldiers during first year of military service. Newly recruited infantry soldiers walked on a treadmill at a 15 degrees incline with a fixed speed of 1.67 m/sec while wearing a standard military vest with a 10 kg load. Stride time variability, stride length variability, step length asymmetry, and the duration of the loading response phase of the gait cycle were measured. Injury data on 76 soldiers who did not report musculoskeletal complaints at initial screening were collected one year after recruitment. Multiple logistic regression analyses were conducted to determine the predictive effect of the gait parameters on lower-limb injuries. Twenty-four soldiers (31.6%) had overuse injuries during the first year after recruitment. Duration of the loading response was a significant predictor of general lower-limb injury (p < 0.05), as well as of foot/ankle and knee injuries (p < 0.05, p < 0.01, resp.). A cutoff value of less than 12.15% for loading response duration predicted knee injuries with 83% sensitivity and 67% specificity. This study demonstrates the utility of spatiotemporal gait evaluation, a simple screening tool before military training, which may help to identify individuals at risk of lower-limb overuse injuries. PMID- 27478865 TI - An Economic Analysis of Pigeonpea Seed Production Technology and Its Adoption Behavior: Indian Context. AB - The present study was based on primary data collected from 100 farmers in Gulbarga district of Karnataka, India, during the agricultural year 2013-2014. Study shows that average land holding size of pigeonpea seed farmers was higher in comparison to grain farmers and district average. The study illustrates a ratio of 32 : 68 towards fixed and variable costs in pigeonpea certified seed production with a total cost of ? 39436 and the gross and net returns were ? 73300 and ? 33864 per hectare, respectively. The total cost of cultivation, gross return, and net return in pigeonpea seed production were higher by around 23, 32, and 44 percent than grain production, respectively. Hence, production of certified seed has resulted in a win-win situation for the farmers with higher yield and increased returns. The decision of the farmer on adoption of seed production technology was positively influenced by his education, age, land holding, irrigated land, number of crops grown, and extension contacts while family size was influencing negatively. Higher yield and profitability associated with seed production can be effectively popularized among farmers, resulting in increased certified seed production. PMID- 27478866 TI - The Negligible Influence of Chronic Obesity on Hospitalization, Clinical Status, and Complications in Elective Posterior Lumbar Interbody Fusion. AB - Background. Posterior lumbar interbody fusion (PLIF) is a common surgical treatment for degenerative spinal instability, but many surgeons consider obesity a contraindication for elective spinal fusion. The aim of this study was to analyze whether obesity has any influence on hospitalization parameters, change in clinical status, or complications. Methods. In this prospective study, regression analysis was used to analyze the influence of the body mass index (BMI) on operating time, postoperative care, hospitalization time, type of postdischarge care, change in paresis or sensory deficits, pain level, wound complications, cerebrospinal fluid leakage, and implant complications. Results. Operating time increased only 2.5 minutes for each increase of BMI by 1. The probability of having a wound complication increased statistically with rising BMI. Nonetheless, BMI accounted for very little of the variation in the data, meaning that other factors or random chances play a much larger role. Conclusions. Obesity has to be considered a risk factor for wound complications in patients undergoing elective PLIF for degenerative instability. However, BMI showed no significant influence on other kinds of peri- or postoperative complications, nor clinical outcomes. So obesity cannot be considered a contraindication for elective PLIF. PMID- 27478867 TI - Mycobacterial Protein Tyrosine Phosphatases A and B Inhibitors Augment the Bactericidal Activity of the Standard Anti-tuberculosis Regimen. AB - Novel drugs are required to shorten the duration of treatment for tuberculosis (TB) and to combat the emergence of drug resistance. One approach has been to identify and target Mycobacterium tuberculosis (Mtb) virulence factors, which promote the establishment of TB infection and pathogenesis. Mtb produces a number of virulence factors, including two protein tyrosine phosphatases (PTPs), mPTPA and mPTPB, to evade the antimicrobial functions of host macrophages. To assess the therapeutic potential of targeting the virulent Mtb PTPs, we developed highly potent and selective inhibitors of mPTPA (L335-M34) and mPTPB (L01-Z08) with drug like properties. We tested the bactericidal activity of L335-M34 and L01-Z08 alone or together in combination with the standard antitubercular regimen of isoniazid-rifampicin-pyrazinamide (HRZ) in the guinea pig model of chronic TB infection, which faithfully recapitulates some of the key histological features of human TB lesions. Following a single dose of L335-M34 50mg/kg and L01-Z08 20 mg/kg, plasma levels were maintained at levels 10-fold greater than the biochemical IC50 for 12-24 hours. Although neither PTP inhibitor alone significantly enhanced the antibacterial activity of HRZ, dual inhibition of mPTPA and mPTPB in combination with HRZ showed modest synergy, even after 2 weeks of treatment. After 6 weeks of treatment, the degree of lung inflammation correlated with the bactericidal activity of each drug regimen. This study highlights the potential utility of targeting Mtb virulence factors, and specifically the Mtb PTPs, as a strategy for enhancing the activity of standard anti-TB treatment. PMID- 27478868 TI - Bioautography with TLC-MS/NMR for Rapid Discovery of Anti-tuberculosis Lead Compounds from Natural Sources. AB - While natural products constitute an established source of lead compounds, the classical iterative bioassay-guided isolation process is both time- and labor intensive and prone to failing to identify active minor constituents. (HP)TLC bioautography-MS/NMR, which combines cutting-edge microbiological, chromatographic, and spectrometric technologies, was developed to accelerate anti tuberculosis (TB) drug discovery from natural sources by acquiring structural information at a very early stage of the isolation process. Using the avirulent, bioluminescent Mtb strain mc27000 luxABCDE, three variations of bioautography were evaluated and optimized for sensitivity in detecting anti-TB agents, including established clinical agents and new leads with novel mechanisms of action. Several exemplary applications of this approach to microbial extracts demonstrate its potential as a routine method in anti-TB drug discovery from natural sources. PMID- 27478869 TI - Developmental exposure to endocrine disrupting chemicals alters the epigenome: Identification of reprogrammed targets. AB - Endocrine disruptions induced by environmental toxicants have placed an immense burden on society to properly diagnose, treat and attempt to alleviate symptoms and disease. Environmental exposures during critical periods of development can permanently reprogram normal physiological responses, thereby increasing susceptibility to disease later in life - a process known as developmental reprogramming. During development, organogenesis and tissue differentiation occur through a continuous series of tightly-regulated and precisely-timed molecular, biochemical and cellular events. Humans may encounter endocrine disrupting chemicals (EDCs) daily and during all stages of life, from conception and fetal development through adulthood and senescence. Though puberty and perimenopausal periods may be affected by endocrine disruption due to hormonal effects, prenatal and early postnatal windows are most critical for proper development due to rapid changes in system growth. Developmental reprogramming is shown to be caused by alterations in the epigenome. Development is the time when epigenetic programs are 'installed' on the genome by 'writers', such as histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), which add methyl groups to lysine and arginine residues on histone tails and to CpG sites in DNA, respectively. A number of environmental compounds, referred to as estrogenic endocrine disruptors (EEDs), are able to bind to estrogen receptors (ERs) and interfere with the normal cellular development in target tissues including the prostate and uterus. These EEDs, including diethylstilbestrol (DES), bisphenol A (BPA), and genistein (a phytoestrogen derived from soybeans), have been implicated in the malformation of reproductive organs and later development of disease. Due to the lack of fully understanding the underlying mechanisms of how environmental toxicants and their level of exposure affect the human genome, it can be challenging to create clear clinical guidance to address the potential health effects of lower-level exposures commonly experienced within the general population. In addition, human studies concerning environmental exposures are limited in feasibility by ethical concerns for human safety. Therefore, studies in animal models provide great opportunities to reveal links between early-life exposure to EDCs and related diseases. It has been shown that developmental exposure to EDCs, such as diethylstilbestrol (DES) and genistein, during reproductive tract development increases the incidence, multiplicity and overall size of uterine fibroids in the Eker rat model, concomitantly reprogramming estrogen-responsive gene expression. Importantly, EDC exposure represses enhancer of zeste 2 (EZH2) and reduces levels of the histone 3 lysine 27 trimethylation (H3K27me3) repressive mark through Estrogen receptor / Phosphatidylinositide 3-kinases / Protein kinase B non genomic signaling in the developing uterus. More recent research identified a developmental reprogramming target, Scbg2a1 gene, whose epigenetic status can be altered by early exposure to BPA in the rat prostate. Molecular analyses revealed markedly increased expression (greater than 100 fold) of Scgb2a1, a secretaglobin gene in response to developmental exposure to BPA. This increase in Scgb2a1 expression is concomitantly associated with increased enrichment of acetylated H3K9 (H3K9Ac representing active chromatin status) and hypomethylation of DNA for a CpG island upstream of the transcription start site of Scgb2a1. These data suggest that expression of Scgb2a1 in the adult prostate could be epigenetically reprogrammed by BPA exposure during prostate development. Further studies are needed to create more targeted preventative interventions as well as specific, effective therapeutics to decrease the incidence of diseases. PMID- 27478870 TI - Gas Phase UTE MRI of Propane and Propene. AB - 1H MRI of gases can potentially enable functional lung imaging to probe gas ventilation and other functions. In this work, 1H MR images of hyperpolarized and thermally polarized propane gas were obtained using UTE (ultrashort echo time) pulse sequence. A 2D image of thermally polarized propane gas with ~0.9*0.9 mm2 spatial resolution was obtained in less than 2 seconds, demonstrating that even non-hyperpolarized hydrocarbon gases can be successfully utilized for conventional proton MRI. The experiments were also performed with hyperpolarized propane gas and demonstrated acquisition of high-resolution multi-slice FLASH 2D images in ca. 510 s and non slice-selective 2D UTE MRI images in ca. 2 s. The UTE approach adopted in this study can be potentially used for medical lung imaging. Furthermore, the possibility to combine UTE with selective suppression of 1H signals from one of the two gases in a mixture is demonstrated in this MRI study. The latter can be useful for visualizing industrially important processes where several gases may be present, e.g., gas-solid catalytic reactions. PMID- 27478871 TI - Imaging Sensitivity of Quiescent Cancer Cells to Metabolic Perturbations in Bone Marrow Spheroids. AB - Malignant cells from breast cancer and other common cancers such as prostate and melanoma may persist in bone marrow as quiescent, non-dividing cells that remain viable for years or even decades before resuming proliferation to cause recurrent disease. This phenomenon, referred to clinically as tumor dormancy, poses tremendous challenges to curing patients with breast cancer. Quiescent tumor cells resist chemotherapy drugs that predominantly target proliferating cells, limiting success of neo-adjuvant and adjuvant therapies. We recently developed a 3D spheroid model of quiescent breast cancer cells in bone marrow for mechanistic and drug testing studies. We combined this model with optical imaging methods for label-free detection of cells preferentially utilizing glycolysis versus oxidative metabolism to investigate the metabolic state of co-culture spheroids with different bone marrow stromal and breast cancer cells. Through imaging and biochemical assays, we identified different metabolic states of bone marrow stromal cells that control metabolic status and flexibilities of co-cultured breast cancer cells. We tested metabolic stresses and targeted inhibition of specific metabolic pathways to identify approaches to preferentially eliminate quiescent breast cancer cells from bone marrow environments. These studies establish an integrated imaging approach to analyze metabolism in complex tissue environments to identify new metabolically-targeted cancer therapies. PMID- 27478872 TI - Co-Registration of Bioluminescence Tomography, Computed Tomography, and Magnetic Resonance Imaging for Multimodal In Vivo Stem Cell Tracking. AB - We present a practical approach for co-registration of bioluminescence tomography (BLT), computed tomography (CT), and magnetic resonance (MR) images. To this end, we developed a customized animal shuttle composed of non-fluorescent, MR compatible Delrin plastic that fits a commercially available MR surface coil. Mouse embryonic stem cells (mESCs) were transfected with the luciferase gene and labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Cells were stereotaxically implanted in mouse brain and imaged weekly for 4 weeks with BLI (IVIS Spectrum CT scanner) and MRI (11.7T horizontal bore scanner). Without the use of software co-registration, in vitro phantom studies yielded root-mean square errors (RMSE) of 7.6*10-3, 0.93 mm, and 0.78 mm along the medial-lateral (ML), dorsal-ventral (DV), and anterior-posterior (AP) axes, respectively. Rotation errors were negligible. Software co-registration by translation along the DV and AP axes resulted in consistent agreement between the CT and MR images, without the need for rotation or warping. In vivo co-registered BLT/MRI mouse brain data sets demonstrated a single, diffuse region of BLI photon signal and MRI hypointensity. Over time, the transplanted cells formed tumors as validated by histopathology. Disagreement between BLT and MRI tumor location was greatest along the DV axis (1.4+/-0.2 mm) compared to the ML (0.5+/-0.3 mm) and AP axis (0.6 mm) due to the uncertainty of the depth of origin of the BLT signal. Combining the high spatial anatomical information of MRI with the cell viability/proliferation data from BLT should facilitate pre-clinical evaluation of novel therapeutic candidate stem cells. PMID- 27478873 TI - Multiplexed Nanoplasmonic Temporal Profiling of T-Cell Response under Immunomodulatory Agent Exposure. AB - Immunomodulatory drugs-agents regulating the immune response-are commonly used for treating immune system disorders and minimizing graft versus host disease in persons receiving organ transplants. At the cellular level, immunosuppressant drugs are used to inhibit pro-inflammatory or tissue-damaging responses of cells. However, few studies have so far precisely characterized the cellular-level effect of immunomodulatory treatment. The primary challenge arises due to the rapid and transient nature of T-cell immune responses to such treatment. T-cell responses involve a highly interactive network of different types of cytokines, which makes precise monitoring of drug-modulated T-cell response difficult. Here, we present a nanoplasmonic biosensing approach to quantitatively characterize cytokine secretion behaviors of T cells with a fine time-resolution (every 10 min) that are altered by an immunosuppressive drug used in the treatment of T cell-mediated diseases. With a microfluidic platform integrating antibody conjugated gold nanorod (AuNR) arrays, the technique enables simultaneous multi time-point measurements of pro-inflammatory (IL-2, IFN-gamma, and TNF-alpha) and anti-inflammatory (IL-10) cytokines secreted by T cells. The integrated nanoplasmonic biosensors achieve precise measurements with low operating sample volume (1 MUL), short assay time (~30 min), heightened sensitivity (~20-30 pg/mL), and negligible sensor crosstalk. Data obtained from the multicytokine secretion profiles with high practicality resulting from all of these sensing capabilities provide a comprehensive picture of the time-varying cellular functional state during pharmacologic immunosuppression. The capability to monitor cellular functional response demonstrated in this study has great potential to ultimately permit personalized immunomodulatory treatment. PMID- 27478874 TI - Transplantation of human skin microbiota in models of atopic dermatitis. AB - Atopic dermatitis (AD) is characterized by reduced barrier function, reduced innate immune activation, and susceptibility to Staphylococcus aureus. Host susceptibility factors are suggested by monogenic disorders associated with AD like phenotypes and can be medically modulated. S. aureus contributes to AD pathogenesis and can be mitigated by antibiotics and bleach baths. Recent work has revealed that the skin microbiome differs significantly between healthy controls and patients with AD, including decreased Gram-negative bacteria in AD. However, little is known about the potential therapeutic benefit of microbiome modulation. To evaluate whether parameters of AD pathogenesis are altered after exposure to different culturable Gram-negative bacteria (CGN) collected from human skin, CGN were collected from healthy controls and patients with AD. Then, effects on cellular and culture-based models of immune, epithelial, and bacterial function were evaluated. Representative strains were evaluated in the MC903 mouse model of AD. We found that CGN taken from healthy volunteers but not from patients with AD were associated with enhanced barrier function, innate immunity activation, and control of S. aureus. Treatment with CGN from healthy controls improved outcomes in a mouse model of AD. These findings suggest that a live biotherapeutic approach may hold promise for treatment of patients with AD. PMID- 27478875 TI - Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors. AB - The deubiquitinase-encoding gene Cyld displays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant-syndrome (CYLDm-syndrome). Despite recent advances, little is understood about the molecular mechanisms responsible for this painful and difficult-to-treat skin disease. Here, we generated a conditional mouse model with epidermis-targeted expression of a catalytically deficient CYLDm through K14 Cre-mediated deletion of exon 9 (hereafter refer to CyldEDelta9/Delta9 ). CyldEDelta9/Delta9 mice were born alive but developed hair and sebaceous gland abnormalities and dental defects at 100% and 60% penetrance, respectively. Upon topical challenge with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors resembling human CYLDm-syndrome as opposed to papilloma, which is most commonly induced in WT mice by this treatment. Molecular analysis revealed that TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c-Myc (S62) were markedly elevated in CyldEDelta9/Delta9 skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEDelta9/Delta9 skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that CyldEDelta9/Delta9 mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLDm-syndrome. PMID- 27478876 TI - Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus. AB - Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/ kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 +/- 126 mOsM) was restored to control levels by metformin (2,335 +/- 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na+-K+-2Cl- cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI. PMID- 27478877 TI - A review of volume-area scaling of glaciers. AB - Volume-area power law scaling, one of a set of analytical scaling techniques based on principals of dimensional analysis, has become an increasingly important and widely used method for estimating the future response of the world's glaciers and ice caps to environmental change. Over 60 papers since 1988 have been published in the glaciological and environmental change literature containing applications of volume-area scaling, mostly for the purpose of estimating total global glacier and ice cap volume and modeling future contributions to sea level rise from glaciers and ice caps. The application of the theory is not entirely straightforward, however, and many of the recently published results contain analyses that are in conflict with the theory as originally described by Bahr et al. (1997). In this review we describe the general theory of scaling for glaciers in full three-dimensional detail without simplifications, including an improved derivation of both the volume-area scaling exponent gamma and a new derivation of the multiplicative scaling parameter c. We discuss some common misconceptions of the theory, presenting examples of both appropriate and inappropriate applications. We also discuss potential future developments in power law scaling beyond its present uses, the relationship between power law scaling and other modeling approaches, and some of the advantages and limitations of scaling techniques. PMID- 27478878 TI - A review on regional convection-permitting climate modeling: Demonstrations, prospects, and challenges. AB - Regional climate modeling using convection-permitting models (CPMs; horizontal grid spacing <4 km) emerges as a promising framework to provide more reliable climate information on regional to local scales compared to traditionally used large-scale models (LSMs; horizontal grid spacing >10 km). CPMs no longer rely on convection parameterization schemes, which had been identified as a major source of errors and uncertainties in LSMs. Moreover, CPMs allow for a more accurate representation of surface and orography fields. The drawback of CPMs is the high demand on computational resources. For this reason, first CPM climate simulations only appeared a decade ago. In this study, we aim to provide a common basis for CPM climate simulations by giving a holistic review of the topic. The most important components in CPMs such as physical parameterizations and dynamical formulations are discussed critically. An overview of weaknesses and an outlook on required future developments is provided. Most importantly, this review presents the consolidated outcome of studies that addressed the added value of CPM climate simulations compared to LSMs. Improvements are evident mostly for climate statistics related to deep convection, mountainous regions, or extreme events. The climate change signals of CPM simulations suggest an increase in flash floods, changes in hail storm characteristics, and reductions in the snowpack over mountains. In conclusion, CPMs are a very promising tool for future climate research. However, coordinated modeling programs are crucially needed to advance parameterizations of unresolved physics and to assess the full potential of CPMs. PMID- 27478880 TI - Designing for Temporal Awareness: The Role of Temporality in Time-Critical Medical Teamwork. AB - This paper describes the role of temporal information in emergency medical teamwork and how time-based features can be designed to support the temporal awareness of clinicians in this fast-paced and dynamic environment. Engagement in iterative design activities with clinicians over the course of two years revealed a strong need for time-based features and mechanisms, including timestamps for tasks based on absolute time and automatic stopclocks measuring time by counting up since task performance. We describe in detail the aspects of temporal awareness central to clinicians' awareness needs and then provide examples of how we addressed these needs through the design of a shared information display. As an outcome of this process, we define four types of time representation techniques to facilitate the design of time-based features: (1) timestamps based on absolute time, (2) timestamps relative to the process start time, (3) time since task performance, and (4) time until the next required task. PMID- 27478879 TI - Cocaine Self-Administration Elevates GluN2B within dmPFC Mediating Heightened Cue Elicited Operant Responding. AB - Cue-elicited drug-craving correlates with hyperactivity within prefrontal cortex (PFC), which is theorized to result from dysregulated excitatory neurotransmission. The NMDA glutamate receptor is highly implicated in addiction related neuroplasticity. As NMDA receptor function is regulated critically by its GluN2 subunits, herein, we assayed the relation between incubated cue-elicited cocaine-seeking following extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) and the expression of GluN2A/B receptor subunits within PFC sub regions during early versus late withdrawal (respectively, 3 vs. 30 days). Cocaine-seeking rats exhibited elevated GluN2B expression within the dorsomedial aspect of the PFC (dmPFC); this effect was apparent at both 3 and 30 days withdrawal and occurred in cocaine-experienced rats, regardless of experiencing an extinction test or not. Thus, elevated dmPFC GluN2B expression appears to reflect a pharmacodynamic response to excessive cocaine intake that is independent of the duration of drug withdrawal or re-exposure to drug-taking context. The functional relevance of elevated dmPFC GluN2B expression for drug seeking was assessed by the local infusion of the prototypical GluN2B-selective antagonist ifenprodil (1.0 ug/side). Ifenprodil did not alter cue-elicited responding in animals with a history of saline self-administration. In contrast, ifenprodil lowered cue-elicited cocaine-seeking, while potentiating cue-elicited sucrose-seeking. Thus, the effects of an intra-dmPFC ifenprodil infusion upon cue reactivity are reinforcer-specific, arguing in favor of targeting GluN2B containing NMDA receptors as a pharmacological strategy for reducing behavioral reactivity to drug-associated cues with the potential benefit of heightening the reinforcing properties of cues associated with non-drug primary rewards. PMID- 27478881 TI - BeUpright: Posture Correction Using Relational Norm Intervention. AB - Research shows the critical role of social relationships in behavior change, and the advancement of mobile technologies brings new opportunities of using online social support for persuasive applications. In this paper, we propose Relational Norm Intervention (RNI) model for behavior change, which involves two individuals as a target user and a helper respectively. RNI model uses Negative Reinforcement and Other-Regarding Preferences as motivating factors for behavior change. The model features the passive participation of a helper who will undergo artificially generated discomforts (e.g., limited access to a mobile device) when a target user performs against a target behavior. Based on in-depth discussions from a two-phase design workshop, we designed and implemented BeUpright, a mobile application employing RNI model to correct sitting posture of a target user. Also, we conducted a two-week study to evaluate the effectiveness and user experience of BeUpright. The study showed that RNI model has a potential to increase efficacy, in terms of behavior change, compared to conventional notification approaches. The most influential factor of RNI model in the changing the behavior of target users was the intention to avoid discomforting their helpers. RNI model also showed a potential to help unmotivated individuals in behavior change. We discuss the mechanism of RNI model in relation to prior literature on behavior change and implications of exploiting discomfort in mobile behavior change services. PMID- 27478882 TI - A Component-Based Evaluation Protocol for Clinical Decision Support Interfaces. AB - In this paper we present our experience in designing and applying an evaluation protocol for assessing usability of a clinical decision support (CDS) system. The protocol is based on component-based usability testing, cognitive interviewing, and a rigorous coding scheme cross-referenced to a component library. We applied this protocol to evaluate alternate designs of a CDS interface for a nursing plan of care tool. The protocol allowed us to aggregate and analyze usability data at various granularity levels, supporting both validation of existing components and providing guidance for targeted redesign. PMID- 27478883 TI - Using ILP to Identify Pathway Activation Patterns in Systems Biology. AB - We show a logical aggregation method that, combined with propositionalization methods, can construct novel structured biological features from gene expression data. We do this to gain understanding of pathway mechanisms, for instance, those associated with a particular disease. We illustrate this method on the task of distinguishing between two types of lung cancer; Squamous Cell Carcinoma (SCC) and Adenocarcinoma (AC). We identify pathway activation patterns in pathways previously implicated in the development of cancers. Our method identified a model with comparable predictive performance to the winning algorithm of a recent challenge, while providing biologically relevant explanations that may be useful to a biologist. PMID- 27478884 TI - Functionalization effect on a Pt/carbon nanotube composite catalyst: a first principles study. AB - Chemical interactions between Pt and both pristine and defective carbon nanotubes (CNTs) that were functionalized with various surface functional groups, including atomic oxygen (-O), atomic nitrogen (-N), hydroxyl (-OH) and amine (-NH2) groups, were investigated through first-principles calculations. Our calculations suggest that the oxygen or nitrogen of the surface functional group can promote better structural stability of a Pt/CNT complex in terms of the binding energy enhancement between Pt and CNTs. Enhanced binding of the Pt/CNT complex would improve the long-term durability of the complex and thus enhance the catalytic activity of Pt catalysts supported on CNTs. Among the functional groups investigated, atomic nitrogen resulted in the most consistent increase in the Pt binding energies on pristine or defective CNTs. Moreover, atomic nitrogen decoration on the surface of CNTs rather than substitution into the CNTs appears to be more desirable. A d-band centre analysis and H2 adsorption calculations also revealed that the catalytic activity of Pt can be improved via efficient functionalization of the CNT support. PMID- 27478885 TI - Insoluble layer deposition and dilatational rheology at a microscale spherical cap interface. AB - The dilatational properties of insoluble monolayers are important for understanding the mechanics of biological systems and consumer products, but isolating the dilatational response of an interface is challenging due to the difficulties in separating dilatation from shear and other deformation modes. Oscillations of a microscale bubble radius are useful for generating purely dilatational flows, but the current deposition methods for insoluble layers onto fluid interfaces are not easily scaled down. In this paper, we describe a miscible solvent exchange procedure for generating insoluble layers at an air water interface pinned at the tip of a capillary tens of micrometers in diameter. We show that the amount of surfactant adsorbed at the interface can be controlled by the initial concentration dissolved in isopropanol (the starting solvent) and the volumetric flow rate of solvent exchange. Surface pressure-area isotherms and dilatational moduli are measured concurrently for three insoluble surfactants: palmitic acid (PA), dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC). The isotherms measured on the microscale interface compare well with previous experiments performed on a Langmuir trough. However, the magnitudes of the dilatational moduli differ from those measured on either Langmuir trough or pendant drop apparatuses. Several possible reasons for the observed differences are discussed. A comparison of the dilatational modulus with the Gibbs elasticity is used to determine the presence of dilatational extra stresses at the interface. The isotherm and dilatational modulus of the insoluble component of the industrial surfactant Tween 80 are measured using this approach. The methods developed here also open the possibility for future study of the important role of finite size effects on microstructure formation and the resulting interfacial mechanics. PMID- 27478886 TI - A smart multi-pipette for hand-held operation of microfluidic devices. AB - A smart multi-pipette for hand-held operation of microfluidic devices is presented and applied to cytotoxicity assays and micro-droplet generation. This method enables a continuous-flow and accurate pumping simply by pushing the plunger of the smart multi-pipette, thereby obviating the need for auxiliary equipment and special expertise in microfluidics. We applied the smart multi pipette to a cytotoxicity assay using a gradient-generating device and water droplet generation using a T-junction device. In combination with general microfluidic devices, the smart multi-pipette enables the devices to successfully perform their own functions. PMID- 27478887 TI - A novel spectral multivariate calibration approach based on a multiple fitting method. AB - This paper introduces a novel multivariate regression approach based on a multiple fitting algorithm that combines fitting functions to accordingly configure different regression models for the quantitative analysis of spectra data. The novel regression method employs multivariate fitting functions to characterize the potential functional relationship of spectral information and sample information with the corresponding attributes, and uses single fitting function elements as the independent variables for biased parameters to determine the amplitude of each fitting function. The peak width of the different fitting functions and the biased parameters are optimized by a simulated annealing algorithm. After parameter optimization, the fitting functions are superposed together to form a functional super surface, and a multiple fitting regression model is then used to characterize any functional relationship among the spectral variable information, sample information, and the corresponding analyte information. In this paper, a common fitting function, namely the Gaussian function, is used to create multiple fitting regression models. The simulated dataset and two real near infrared spectral datasets were used to validate the multiple fitting regression model. The results are compared to those obtained using partial least squares regression and least squares support vector regression. It is shown that the proposed multiple fitting regression algorithm achieved an accuracy comparable to the two conventional methods. Therefore, the multiple fitting regression is demonstrated to be a useful tool for spectra multivariate regression analysis and may also be suitable for linear and nonlinear multivariate calibration. PMID- 27478888 TI - Influence of transition metal electronegativity on the oxygen storage capacity of perovskite oxides. AB - The selection of highly efficient oxygen carriers (OCs) is a key step necessary for the practical development of chemical looping combustion (CLC). In this study, a series of ABO3 perovskites, where A = La, Ba, Sr, Ca and B = Cr, Mn, Fe, Co, Ni, Cu, are synthesized and tested in a fixed bed reactor for reactivity and stability as OCs with CH4 as the fuel. We find that the electronegativity of the transition metal on the B-site (lambdaB), is a convenient descriptor for oxygen storage capacity (OSC) of our perovskite samples. By plotting OSC for total methane oxidation against lambdaB, we observe an inverted volcano plot relationship. These results could provide useful guidelines for perovskite OC design and their other energy related applications. PMID- 27478889 TI - Ultrafast Electron Diffraction Tomography for Structure Determination of the New Zeolite ITQ-58. AB - In this work a new ultrafast data collection strategy for electron diffraction tomography is presented that allows reducing data acquisition time by one order of magnitude. This methodology minimizes the radiation damage of beam-sensitive materials, such as microporous materials. This method, combined with the precession of the electron beam, provides high quality data enabling the determination of very complex structures. Most importantly, the implementation of this new electron diffraction methodology is easily affordable in any modern electron microscope. As a proof of concept, we have solved a new highly complex zeolitic structure named ITQ-58, with a very low symmetry (triclinic) and a large unit cell volume (1874.6 A(3)), containing 16 silicon and 32 oxygen atoms in its asymmetric unit, which would be very difficult to solve with the state of the art techniques. PMID- 27478890 TI - Exploring the impact of mindfulness meditation training in pre-licensure and post graduate nurses. AB - The complex, high stress, technologically laden healthcare environment compromises providers' ability to be fully present in the moment; especially during patient interactions. This "pulling away" of attention (mindlessness) from the present moment creates an environment where decision making can take place in the absence of thoughtful, deliberate engagement in the task at hand. Mindfulness, can be cultivated through a variety of mindfulness practices. Few schools of nursing or hospitals offer mindfulness training, despite study findings supporting its effectiveness in improving levels of mindfulness, and perceived connections with patients and families. METHODS: A mindfulness program developed for this study and tailored to nursing was used to provide the mindfulness training. Pre and post training assessments were completed and included administration of the Freiburg Mindfulness Inventory (FMI) and the Defining Issues Test (DIT) of moral judgment version 2. RESULTS: A statistically significant improvement in the FMI scores p=0.003 was found. The pre-licensure group did not show a statistically significant improvement in their FMI scores pre to post training (p=0.281), however the post graduate group did (p=0.004). Statistically significant pre - post scores were found in two schemas of the DIT 2 (P [Post conventional] score, p=0.039 and N2 [Maintaining norms] score, p=0.032). CONCLUSIONS: Mindfulness training improves mindfulness and some aspects of ethical decision making in the groups studied as part of this project. The findings of this study are promising and further demonstrate the merits of a mindfulness practice, however aspects of mindfulness training would need to be addressed prior to launching a full scale attempt to incorporate this into a work life or some other quality improvement program. PMID- 27478891 TI - Chromatic Information and Feature Detection in Fast Visual Analysis. AB - The visual system is able to recognize a scene based on a sketch made of very simple features. This ability is likely crucial for survival, when fast image recognition is necessary, and it is believed that a primal sketch is extracted very early in the visual processing. Such highly simplified representations can be sufficient for accurate object discrimination, but an open question is the role played by color in this process. Rich color information is available in natural scenes, yet artist's sketches are usually monochromatic; and, black-and white movies provide compelling representations of real world scenes. Also, the contrast sensitivity of color is low at fine spatial scales. We approach the question from the perspective of optimal information processing by a system endowed with limited computational resources. We show that when such limitations are taken into account, the intrinsic statistical properties of natural scenes imply that the most effective strategy is to ignore fine-scale color features and devote most of the bandwidth to gray-scale information. We find confirmation of these information-based predictions from psychophysics measurements of fast viewing discrimination of natural scenes. We conclude that the lack of colored features in our visual representation, and our overall low sensitivity to high frequency color components, are a consequence of an adaptation process, optimizing the size and power consumption of our brain for the visual world we live in. PMID- 27478892 TI - Central Projection of Antennal Sensory Neurons in the Central Nervous System of the Mirid Bug Apolygus lucorum (Meyer-Dur). AB - The mirid bug Apolygus lucorum (Meyer-Dur), a polyphagous pest, is dependent on olfactory cues to locate various host plant species and mates. In this study, we traced the projection pathway of the antennal sensory neurons and visualized their projection patterns in the central nervous system of A. lucorum through confocal microscopy and digital reconstructions. We also examined the glomerular organization of the primary olfactory center of the brain, the antennal lobe, and created a three-dimensional model of the glomeruli. We found that the axons of the sensory neurons project into the brain via the ipsilateral antennal nerve, and descend further into the gnathal ganglion, prothoracic ganglion, mesothoracic ganglion, and metathoracic ganglion, and reach as far as to the abdominal ganglion. Such a projection pattern indicates that antennal sensory neurons of A. lucorum may be potentially directly connected to motor neurons. The antennal lobe, however, is the major target area of antennal sensory neurons. The antennal lobe is composed of a large number of glomeruli, i.e. 70-80 glomeruli in one AL of A. lucorum. The results of this study which provide information about the basic anatomical arrangement of the brain olfactory center of A. lucorum, are important for further investigations of chemosensory encoding mechanisms of the mirid bug. PMID- 27478894 TI - Shear Capacity of C-Shaped and L-Shaped Angle Shear Connectors. AB - This paper investigates the behaviour of C-shaped and L-shaped angle shear connectors embedded in solid concrete slabs. An effective finite element model is proposed to simulate the push out tests of these shear connectors that encompass nonlinear material behaviour, large displacement and damage plasticity. The finite element models are validated against test results. Parametric studies using this nonlinear model are performed to investigate the variations in concrete strength and connector dimensions. The finite element analyses also confirm the test results that increasing the length of shear connector increases their shear strength proportionately. It is observed that the maximum stress in L shaped angle connectors takes place in the weld attachment to the beam, whereas in the C-shaped angle connectors, it is in the attached leg. The location of maximum concrete compressive damage is rendered in each case. Finally, a new equation for prediction of the shear capacity of C-shaped angle connectors is proposed. PMID- 27478893 TI - Total Glucosides of Paeony Promote Intestinal Motility in Slow Transit Constipation Rats through Amelioration of Interstitial Cells of Cajal. AB - OBJECTIVES: Using an atropine-diphenoxylate-induced slow transit constipation (STC) model, this study explored the effects of the total glucosides of paeony (TGP) in the treatment of STC and the possible mechanisms. STUDY DESIGN: A prospective experimental animal study. METHODS: The constipation model was set up in rats with an oral gavage of atropine-diphenoxylate and then treated with the TGP. The volume and moisture content of the faeces were observed and the intestinal kinetic power was evaluated. Meanwhile, the colorimetric method and enzyme linked immunosorbent assay (ELISA) were employed to determine the changes of nitric oxide (NO), nitric oxide synthase (NOS), vasoative intestinal peptide (VIP) and the P substance (SP) in the serum, respectively. The protein expressions of c-kit and stem cell factor (SCF) were assessed by immunohistochemical analysis and western blot, respectively, and the mRNA level of c-kit was measured by a reverse transcription polymerase chain reaction (RT PCR). RESULTS: The TGP attenuated STC responses in terms of an increase in the fecal volume and moisture content, an enhancement of intestinal transit rate and the reduction of NO, NOS and VIP in the serum. In addition, the c-kit, a labeling of interstitial cells of Cajal (ICC) increased at both protein and mRNA levels. SCF, which serves as a ligand of c-kit also increased at protein level. CONCLUSION: The analysis of our data indicated that the TGP could obviously attenuate STC through improving the function of ICC and blocking the inhibitory neurotransmitters such as NO, NOS and VIP. PMID- 27478895 TI - Correction: Pyrosequencing Unveils Cystic Fibrosis Lung Microbiome Differences Associated with a Severe Lung Function Decline. AB - [This corrects the article DOI: 10.1371/journal.pone.0156807.]. PMID- 27478896 TI - Differences in Postprandial Lipid Response to Breast- or Formula-feeding in 8 Week-Old Infants. AB - OBJECTIVE: Lipids play important roles in infant growth and development. In this exploratory observational single-center study, we investigated postmeal responses of infants to dietary lipids and differences between breast-feeding (BF) and formula-feeding (FF). METHODS: Two capillary blood samples were collected from each subject, before and randomly assigned at either 30, 60, 90, 120, 180, or 240 minutes after their respective feeding, followed by measurement of lipid-related plasma parameter concentrations using enzyme-linked immunosorbent assay-based or combined enzymatic and colorimetric methods. RESULTS: The intermeal interval before testing was shorter in the BF (182.91 +/- 22.85 minutes, n = 33) versus FF group (214.1 +/- 30.76 minutes, n = 34); BF subjects fed 5 minutes longer (BF 20.27 +/- 7.7 minutes; FF 14.82 +/- 3.57 minutes). Composite postmeal concentration profiles were generated from 59 plasma sample pairs with sufficient volume (BF = 30): triglyceride (TG) baselines were not different. A TG difference was indicated for BF over FF subjects at 30 minutes, for FF over BF subjects at 60 minutes when corrected for baseline. TG responses in both groups appeared and seemed to clear much faster than those reported for adults. The TG:apolipoprotein B48 (ApoB48) ratio suggests that chylomicrons in BF subjects may carry a higher fat load (P < 0.05), compensated by a higher chylomicron number in FF subjects (P < 0.05). Cholesterol in BF subjects was higher and showed an increase after feeding when corrected for baseline. CONCLUSIONS: Our results indicate that lipids from either BF or FF may be handled differently in young healthy infants. PMID- 27478897 TI - Infantile Colic Is Associated With Low-grade Systemic Inflammation. AB - OBJECTIVES: Dysbiosis, an imbalance in the taxonomic composition of the gut bacteria occurring during the critical stages of development, induces lasting shifts in the immunological and metabolic phenotype if accompanied by an inflammatory response. Because altered gut microbiota and successful treatment with probiotics have both been demonstrated in cases of colic, we hypothesized here that infants with colic might have low-grade inflammation. METHODS: In 28 infants with colic and in 12 healthy controls at the age of 1 month, we measured the following serum immunological biomarkers: cytokines interleukin 1beta (IL 1beta); IL-6; IL-10; tumor necrosis factor alpha; interferon gamma (IFN-gamma); chemokines IL-8; monocyte chemotactic protein-1 (MCP-1); macrophage inflammatory protein 1beta (MIP-1beta) and chemokine (C-X-C motif) ligand 16; and intestinal fatty acid-binding protein, a biomarker of enterocyte damage and zonulin, a biomarker of intestinal permeability. In addition, intestinal microbiota composition was correlated with immunological biomarkers. RESULTS: Infants with colic had increased concentrations of IL-8, MCP-1, and MIP-1beta in serum as compared with healthy children. All the other immunological biomarkers were comparable between the groups. Fecal levels of Clostridium leptum correlated negatively with the proinflammatory markers MCP-1 (r = -0.44, P = 0.02), MIP 1beta (r = -0.43, P = 0.02), and tumor necrosis factor alpha (r = -0.38, P = 0.04). In addition, C coccoides group levels correlated negatively with MCP-1 (r = -0.43, P = 0.02) and Bifidobacterium breve levels positively with chemokine (C X-C motif) ligand 16 (r = 0.38, P = 0.04). CONCLUSIONS: In addition to gut microbiota alterations, colic in infants is associated with low-grade systemic inflammation. Specific bacterial species beyond conventional probiotics may have anti-inflammatory properties that may help to modulate microbiota and alleviate colic-related inflammation. PMID- 27478898 TI - Lubrication of Individual Microcontacts by a Self-Assembled Alkyl Phosphonic Acid Monolayer on alpha-Al2O3(0001). AB - We report on the tribological behavior of a self-assembled alkyl phosphonic acid monolayer on the microscale using the colloidal probe technique. Friction-load data and adhesion forces were measured with borosilicate glass particles on uncoated and octadecylphosphonic acid (ODPA) coated alpha-Al2O3(0001) surfaces. A significant decrease in friction force was observed after surface coating, while the adhesion force was only moderately reduced. We assume the lubrication effect of the ODPA self-assembled monolayer (SAM) to be close to the maximum obtainable of alkyl phosphonic acids in the studied system due to the high molecular order which was confirmed by vibrational sum-frequency generation. At small loads, a nonlinear dependence of friction force to load was maintained after surface coating. However, a shift from a contact behavior well described by the DMT model toward the JKR model occurred that is possibly related to the altered elastic properties of the coated surface. With increasing load, a linear friction-load behavior was observed on the coated samples. Molecular plowing and adhesive interactions were identified as responsible mechanisms. In all friction experiments, we could not detect any wear neither of the colloidal probes nor at the surfaces of uncoated and coated samples. This proves the high wear resistivity of the studied ODPA SAM. PMID- 27478899 TI - Visible to short wavelength infrared In2Se3-nanoflake photodetector gated by a ferroelectric polymer. AB - Photodetectors based on two-dimensional (2D) transition-metal dichalcogenides have been studied extensively in recent years. However, the detective spectral ranges, dark current and response time are still unsatisfactory, even under high gate and source-drain bias. In this work, the photodetectors of In2Se3 have been fabricated on a ferroelectric field effect transistor structure. Based on this structure, high performance photodetectors have been achieved with a broad photoresponse spectrum (visible to 1550 nm) and quick response (200 MUs). Most importantly, with the intrinsic huge electric field derived from the polarization of ferroelectric polymer (P(VDF-TrFE)) gating, a low dark current of the photodetector can be achieved without additional gate bias. These studies present a crucial step for further practical applications for 2D semiconductors. PMID- 27478900 TI - When, Where, and Why Are Babies Dying? Neonatal Death Surveillance and Review in Bangladesh. AB - BACKGROUND: Better data on cause of, and factors contributing to, neonatal deaths are needed to improve interventions aimed at reducing neonatal mortality in low- and middle-income countries. METHODS: Community surveillance to identify all neonatal deaths across four districts in Bangladesh. Verbal autopsy for every fifth case and InterVA-4 used to assign likely cause of death. FINDINGS: 6748 neonatal deaths identified, giving a neonatal mortality rate of 24.4 per 1000 live births. Of these, 51.3% occurred in the community and 48.7% at or on the way to a health facility. Almost half (46.1%) occurred within 24 hours of birth with 83.6% of all deaths occurring in the first seven days of life. Birth asphyxia was the leading cause of death (43%), followed by infections (29.3%), and prematurity (22.2%). In 68.3% of cases, care had been provided at a health facility before death occurred. Care-seeking was significantly higher among mothers who were educated (RR 1.18, 95% CI: 1.04-1.35) or who delivered at a health facility (RR 1.48, 95% CI 1.37-1.60) and lower among mothers who had 2-4 previous births (RR 0.89, 95% CI 0.82-0.96), for baby girls (RR 0.87, 95% CI 0.80-0.93), and for low birth weight babies (RR 0.89, 95% CI 0.82-0.96). INTERPRETATION: Most parents of neonates who died had accessed and received care from a qualified healthcare provider. To further reduce neonatal mortality, it is important that the quality of care provided, particularly skilled birth attendance, emergency obstetric care, and neonatal care during the first month of life is improved, such that it is timely, safe, and effective. PMID- 27478901 TI - The Ionomic Study of Vegetable Crops. AB - Soil contains various essential and nonessential elements, all of which can be absorbed by plants. Plant ionomics is the study of the accumulation of these elements (the ionome) in plants. The ionomic profile of a plant is affected by various factors, including species, variety, organ, and environment. In this study, we cultivated various vegetable crop species and cultivars under the same field conditions and analyzed the level of accumulation of each element in the edible and nonedible parts using ionomic techniques. The concentration of each element in the edible parts differed between species, which could be partly explained by differences in the types of edible organs (root, leaf, seed, and fruit). For example, the calcium concentration was lower in seeds and fruit than in other organs because of the higher dependency of calcium accumulation on xylem transfer. The concentration of several essential microelements and nonessential elements in the edible parts also varied greatly between cultivars of the same species, knowledge of which will help in the breeding of vegetables that are biofortified or contain lower concentrations of toxic elements. Comparison of the ionomes of the fruit and leaves of tomato (Solanum lycopersicum) and eggplant (S. melongena) indicated that cadmium and boron had higher levels of accumulation in eggplant fruit, likely because of their effective transport in the phloem. We also found that homologous elements that have been reported to share the same uptake/transport system often showed significant correlation only in a few families and that the slopes of these relationships differed between families. Therefore, these differences in the characteristics of mineral accumulation are likely to affect the ionomic profiles of different families. PMID- 27478902 TI - Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus. AB - Importance: The use of dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon like peptide 1 (GLP-1) analogues-a group of drugs used in the management of type 2 diabetes mellitus-may be associated with an increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association. Objective: To determine whether the use of DPP-4 inhibitors and GLP 1 analogues is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes. Design, Setting, and Participants: A population-based cohort study linked the United Kingdom Clinical Practice Research Datalink with the Hospital Episodes Statistics database, yielding a cohort of 71 369 patients, 18 years or older, initiating an antidiabetic drug (including oral and injectable agents) between January 1, 2007, and March 31, 2014. Exposures: Current use of DPP-4 inhibitors and GLP-1 analogues (alone or in combination therapy) compared with current use of at least 2 oral antidiabetic drugs. Main Outcomes and Measures: Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of incident bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis) causing hospitalization, comparing current use of DPP-4 inhibitors and GLP-1 analogues with current use of at least 2 oral antidiabetic drugs. Results: During 227 994 person-years of follow-up, 853 of the 71 369 patients were hospitalized for bile duct and gallbladder disease (incidence rate per 1000 person-years, 3.7; 95% CI, 3.5-4.0). Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95% CI, 0.75-1.32). In contrast, the use of GLP 1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95% CI, 1.21-2.67). In a secondary analysis, GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02). Conclusions and Relevance: The use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs. PMID- 27478904 TI - Cr(3+) Binding to DNA Backbone Phosphate and Bases: Slow Ligand Exchange Rates and Metal Hydrolysis. AB - The interaction between chromium ions and DNA is of great interest in inorganic chemistry, toxicology, and analytical chemistry. Most previous studies focused on in situ reduction of Cr(VI), producing Cr(3+) for DNA binding. Recently, Cr(3+) was reported to activate the Ce13d DNAzyme for RNA cleavage. Herein, the Ce13d is used to study two types of Cr(3+) and DNA interactions. First, Cr(3+) binds to the DNA phosphate backbone weakly through reversible electrostatic interactions, which is weakened by adding competing inorganic phosphate. However, Cr(3+) coordinates with DNA nucleobases forming stable cross-links that can survive denaturing gel electrophoresis condition. The binding of Cr(3+) to different nucleobases was further studied in terms of binding kinetics and affinity by exploiting carboxyfluorescein-labeled DNA homopolymers. Once binding takes place, the stable Cr(3+)/DNA complex cannot be dissociated by EDTA, attributable to the ultraslow ligand exchange rate of Cr(3+). The binding rate follows the order of G > C > T ~ A. Finally, Cr(3+) gradually loses its DNA binding ability after being stored at neutral or high pH, attributable to hydrolysis. This hydrolysis can be reversed by lowering the pH. This work provides a deeper insight into the bioinorganic chemistry of Cr(3+) coordination with DNA, clarifies some inconsistency in the previous literature, and offers practically useful information for generating reproducible results. PMID- 27478903 TI - Engineering Nucleotide Specificity of Succinyl-CoA Synthetase in Blastocystis: The Emerging Role of Gatekeeper Residues. AB - Charged, solvent-exposed residues at the entrance to the substrate binding site (gatekeeper residues) produce electrostatic dipole interactions with approaching substrates, and control their access by a novel mechanism called "electrostatic gatekeeper effect". This proof-of-concept study demonstrates that the nucleotide specificity can be engineered by altering the electrostatic properties of the gatekeeper residues outside the binding site. Using Blastocystis succinyl-CoA synthetase (SCS, EC 6.2.1.5), we demonstrated that the gatekeeper mutant (ED) resulted in ATP-specific SCS to show high GTP specificity. Moreover, nucleotide binding site mutant (LF) had no effect on GTP specificity and remained ATP specific. However, via combination of the gatekeeper mutant with the nucleotide binding site mutant (ED+LF), a complete reversal of nucleotide specificity was obtained with GTP, but no detectable activity was obtained with ATP. This striking result of the combined mutant (ED+LF) was due to two changes; negatively charged gatekeeper residues (ED) favored GTP access, and nucleotide binding site residues (LF) altered ATP binding, which was consistent with the hypothesis of the "electrostatic gatekeeper effect". These results were further supported by molecular modeling and simulation studies. Hence, it is imperative to extend the strategy of the gatekeeper effect in a different range of crucial enzymes (synthetases, kinases, and transferases) to engineer substrate specificity for various industrial applications and substrate-based drug design. PMID- 27478905 TI - Piezotronic Effect Enhanced Label-Free Detection of DNA Using a Schottky Contacted ZnO Nanowire Biosensor. AB - A sensitive and in situ selective label-free DNA sensor based on a Schottky contacted ZnO nanowire (NW) device has been developed and utilized to detect the human immunodeficiency virus 1 gene in this work. Piezotronic effect on the performance of the DNA sensor is studied by measuring its output current under different compressive strains and target complementary DNA concentrations. By applying a -0.59% compressive strain to a ZnO NW-based DNA sensor, the relative current response is greatly enhanced by 454%. A theoretical model is proposed to explain the observed behaviors of the DNA sensor. This study provides a piezotronically modified method to effectively improve the overall performance of the Schottky-contacted ZnO NW-based DNA sensor. PMID- 27478906 TI - Structure, Energetics, and Dynamics of Screw Dislocations in Even n-Alkane Crystals. AB - Spiral hillocks on n-alkane crystal surfaces were observed immediately after Frank recognized the importance of screw dislocations for crystal growth, yet their structures and energies in molecular crystals remain ill-defined. To illustrate the structural chemistry of screw dislocations that are responsible for plasticity in organic crystals and upon which the organic electronics and pharmaceutical industries depend, molecular dynamics was used to examine heterochiral dislocation pairs with Burgers vectors along [001] in n-hexane, n octane, and n-decane crystals. The cores were anisotropic and elongated in the (110) slip plane, with significant local changes in molecular position, orientation, conformation, and energy. This detailed atomic level picture produced a distribution of strain consistent with linear elastic theory, giving confidence in the simulations. Dislocations with doubled Burgers vectors split into pairs with elementary displacements. These results suggest a pathway to understanding the mechanical properties and failure associated with elastic and plastic deformation in soft crystals. PMID- 27478907 TI - The Biosimilarity Concept: Toward an Integrated Framework for Evidence Assessment. PMID- 27478908 TI - Large-Area Supercapacitor Textiles with Novel Hierarchical Conducting Structures. AB - Supercapacitor textiles with large sizes are developed to satisfy practical applications by designing a novel hierarchical conducting structure. They display remarkable capacitance, power, and energy of 69.3 F, 80.7 mW, and 5.4 mW h, respectively, representing an important step toward real-world applications. PMID- 27478909 TI - Predictive value of p16/Ki-67 immunocytochemistry for triage of women with abnormal Papanicolaou test in cervical cancer screening: a systematic review and meta-analysis. AB - BACKGROUND: The Papanicolaou (Pap) test is one screening strategy used to prevent cervical cancer in developed countries. The p16/Ki-67 immunocytochemistry is a triage test performed on Pap smears in women with atypical squamous cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesion. OBJECTIVE: Our objective was to review studies investigating the diagnostic performance of p16/Ki-67 dual stain for triage of women with abnormal Pap tests. DESIGN: We conducted a systematic review and meta-analysis of diagnostic test accuracy studies. SETTINGS: We followed the protocol of systematic review of diagnostic accuracy studies. PATIENTS AND METHODS: We searched PubMed, The Cochrane Library, BioMed Central, and ClinicalTrials.gov for relevant studies. We included research that assessed the accuracy of p16/Ki-67 dual stain and high risk human papillomavirus testing for triage of abnormal Pap smears. Review articles and studies that provided insufficient data to construct 2.2 tables were excluded. Data synthesis was conducted using a random-effects model. MAIN OUTCOME MEASURES: Sensitivity and specificity. RESULTS: In seven studies encompassing 2628 patients, the pooled sensitivity and specificity of p16/Ki-67 for triage of abnormal Pap smear results were 0.91 (95% CI, 0.89 to 0.93) and 0.64 (95% CI, 0.62 to 0.66), respectively. No study used a case-control design. A subgroup analysis involving liquid-based cytology showed a sensitivity of 0.91 (95%CI, 0.89 to 0.93) and specificity of 0.64 (95%CI, 0.61 to 0.66). CONCLUSIONS: Our meta-analysis of p16/Ki-67 dual stain studies showed that the test achieved high sensitivity and moderate specificity for p16/Ki-67 immunocytochemistry for high grade squamous intraepi.thelial lesion and cervical cancer. We suggest that p16/Ki-67 dual stain might be a reliable ancillary method identifying high-grade squamous intraepithelial lesions in women with abnormal Pap tests. LIMITATIONS: No study in the meta-analysis examined the accuracy of the p16/Ki-67 dual stain for inter.pretation of glandular neoplasms. PMID- 27478910 TI - Assessment of chronic renal injury from melamine-associated pediatric urolithiasis: an eighteen-month prospective cohort study. AB - BACKGROUND: The illegal use of melamine in powdered baby formula resulted in a widespread outbreak of melamine-associated pediatric urolithiasis and kidney damage in China in 2008. We conducted this study because more needs to be known about the long-term effects of melamine-associated urolithiasis and kidney damage. OBJECTIVES: To determine the prognosis and long-term implications of chronic kidney damage in children with urolithiasis resulting from melamine consumption. DESIGN: Prospective cohort study. SETTING: Children's Hospital of Fudan University. PATIENTS AND METHODS: Children six years of age or older with a history of having consumed melamine-contaminated milk powder were voluntarily screened. We measured urinary microprotein profiles [microalbumin (ALBU), immunoglobulin G (IgG), and n-acetyl-beta-d-glucosidase (NAG)] and creatinine (CR) results at 6 and 18 months in children with melamine-associated urolithiasis. This study was conducted from September 17 to October 15, 2008. MAIN OUTCOME MEASURES: Changes in urinary microprotein profiles. RESULTS: Of 8335 children screened, 102 children (1.22%) were diagnosed with melamine-associated urolithiasis. Follow-up rates at 6 and 18 months were 91.4% (96/105) and 89.2% (91/102), respectively. Eighteen months later, 90.3% patients had spontaneously passed a stone. The incidence rates of proteinuria and microscopic hematuria at 6 months were significantly higher than at 18 months (P=.029 and P=.017, respectively). The proportion of patients with abnormal ALBU/CR, IgG/CR and NAG/CR at 6 months (27.6%, 17.1% and 21.1%, respectively) was significantly higher than at 18 months (6.4%, 5.1% and 12.8%, respectively). The high concentration of melamine consumed was the primary factor correlated with the high microprotein levels. Approximately 90% melamine-associated urolithiasis cases can be resolved within 18 months by non-surgical therapy. CONCLUSION: The long-term presence of stones associated with a previous exposure to melanine can cause chronic kidney glomerular and tubular injuries. Passing these stones as soon as possible can reduce kidney injury and accelerate recovery. LIMITATIONS: We could not control for possible selection bias due to more visits to our hospital or visits to our hospital after diagnosis at other hospitals, which might have increased the rate of diagnosis. PMID- 27478911 TI - Emergency department attendance patterns during Ramadan. AB - BACKGROUND: Patient attendance in the emergency department (ED) is inherently variable and unpredictable. Resources might be better allocated if use of the ER could be predicted during the month of fasting (Ramadan), healthy adult Muslims do not eat or drink from dawn to sunset and in the Middle East, social activities occur mostly during night. There is no published data that has reported changes in local ED attendance pattern during Ramadan. OBJECTIVES: Determine if there are differences in tertiary care ed attendance during Ramadan compared to other times of the year. DESIGN: Retrospective, using data from the hospital integrated clinical information system. SETTING: Tertiary care institution in Riyadh, Saudi Arabia. PATIENTS AND METHODS: All ED visits during the Islamic calendar years of 1431-1434 (December 18, 2009-October 13, 2013) were analyzed. MAIN OUTCOME MEASURES: Patient volume, acuity, demographics and admission rate variability between Ramadan and other months. RESULTS: During the study period of 4 years, of 226075 ED patients, 129178 (57.14%) patients were seen during the day shift (07:00 to 18:59). During Ramadan, 10 293 (60%) patients presented during the night shift compared with the day shift (P < .0001). This trend was seen consistently with no statistically significant differences in admissions 7%, triage acuity or when compared with other months. CONCLUSION: During Ramadan, ED attendance changes as more patients present during the night shift. In Saudi Arabia and possibly other Muslim countries, appropriate resources should be allocated during Ramadan to manage the nocturnal ED patient surge. LIMITATIONS: We believe that the majority of our patients fast, but it is not known how many ED patients were actually fasting during the study period. This study was conducted in a tertiary care hospital and the patient population presenting to our ed is predominantly Muslim; therefore, the results may not be generalized to populations that are not predominantly Muslim. PMID- 27478912 TI - Growth reference for Saudi school-age children and adolescents: LMS parameters and percentiles. AB - BACKGROUND: Information on LMS parameters and percentiles reference for Saudi children and adolescents is not available. OBJECTIVE: To report the L, M, and S parameters and percentile reference graphs for growth. DESIGN: Field survey of a population-based sample of Saudi school-age children and adolescents (5-18 years of age). SETTING: A stratified listing of the Saudi population. SUBJECTS AND METHODS: Data from the national study of healthy children were reanalyzed using the Lamba-Mu-Sigma (LMS) methodology. The LMS parameters of percentiles for weight, height, and body mass index for age were calculated for children and adolescents from 5 to 18 years of age. MAIN OUTCOME MEASURE: The main outcomes were the LMS parameters and percentiles of growth. RESULTS: There were 19299 and 9827 (50.9%) were boys. The data for weight, height, and BMI for age for boys and girls are reported for the 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97th percentiles including LMS parameters for each percentile and age. Figures corresponding to each table are color coded (blue for boys and pink for girls). CONCLUSIONS: This report provides a reference for growth and nutrition of Saudi school-age children and adolescents. The detailed LMS and percentile tables and graphs provide essential information for clinical assessment of nutritional status and growth in various clinical conditions and for research. LIMITATIONS: This report does not reflect regional variations in growth. PMID- 27478913 TI - Validity and reliability of a quality-of-life assessment instrument in children aged between 6 and 11 years. AB - BACKGROUND: There is increasing recognition of the importance of obtaining children's reports of their health, but significant challenges remain in accomplishing these goals in a systematic, community-based approach. OBJECTIVES: The aim of study was to evaluate the validity and reliability of the culturally adapted Turkish version of the "Child Health and Illness Profile - Child Edition (CHIP-CE) (6-11) for children 6 to 11 years of age. DESIGN: Cross-sectional analytical study conducted at Eskisehir Osmangazi University, Faculty of Medicine, Department of Pediatrics, Eskisehir, Turkey. SETTING: Children's health and diseases clinic. PATIENTS AND METHODS: For the purpose of this study, face-to face interviews were conducted with inpatients (children aged between 6 and 11 years staying in the hospital) and healthy children (children aged between 6 and 11 years attending a private elementary school in the spring semester of 2010 2011). The Turkish version of CHIP-CE (6-11) was administered after the original version of CHIP-CE in English was translated into Turkish, and then back translated into English. All steps in the cultural adaptation process were undertaken meticulously by an expert committee. Confirmatory factor analysis (CFA) was conducted to test construct validity. The Cronbach's alpha and item total correlations were used to evaluate internal consistency for reliability testing. MAIN OUTCOME MEASURES: Domain scores on the CHIP-CE questionnaire, Cronbach's alpha and item-total correlations. RESULTS: The Turkish version of CHIP-CE (6-11) was administered to 235 children, including 109 (46.4%) girls and 126 (53.6%) boys receiving inpatient treatment in the hospital, and 194 healthy children, including 89 (45.9%) girls and 105 (54.1%) boys. The mean (standard deviation) age was 6.9 (1.6) years in the group of children receiving inpatient treatment, and 9.2 (1.6) years in the healthy children. In the reliability testing of the CHIP-CE form, Cronbach's alpha was 0.79 in children receiving inpatient treatment, and 0.80 in healthy children. These values indicate excellent reliability. The CFA measurement model produced results consistent with standards: c2=185.76 df=160 P=.07986 RMSEA=0.026 in the children receiving inpatient treatment, and c2=180.20 df=109 P=.00002 RMSEA=0.058 in healthy children. CONCLUSION: CHIP-CE proved to be a reliable and valid measurement instrument for children receiving treatment for various diseases and healthy children. The internal consistency of the Turkish version of CHIP-CE is acceptable. LIMITATIONS: The sample, although large and diverse, was self selected and does not represent the population of children in Turkey. PMID- 27478914 TI - Single-incision laparoscopic colorectal surgery: a report of 33 cases in Saudi Arabia. AB - BACKGROUND: Single-incision laparoscopic surgery (SILS) has gained worldwide acceptance as a minimally invasive technique in colorectal procedures since its introduction in 2008. However, case series on its feasibility and safety in Saudi Arabia are lacking. OBJECTIVE: Evaluate the operative results and clinical outcome of single-port laparoscopic procedures in colorectal surgeries. DESIGN: Retrospective. SETTING: This study was conducted at King Khalid university Hospital, Riyadh, Saudi Arabia. PATIENTS AND METHODS: Demographic and clinical data, including pathology, and intraoperative and postoperative outcomes, were prospectively collected in patients undergoing SILS. This study was conducted during the period from January 2010 and October 2014. MAIN OUTCOME MEASURES: Demographic and postoperative outcomes in patients undergoing SILS colectomies. RESULTS: Thirty-three (33) patients underwent SILS. The mean (SD) age was 51 years (18.2 years), and the average body mass index was 26.6 (6.9) kg/m2. Patients were primarily diagnosed with cancer (n=20/33, 61%), inflammatory bowel disease (n=12/33, 36%) and diverticulitis (n=1/33, 3%). Procedures included anterior resection (n=9/33, 27%), ileocecal resection (n=8/33 24%), hemicolectomy (n=7/33, 21%), extended right hemicolectomy (n=5/33, 15%) and total colectomy (n=4/33, 12%). The mean SD operative time was 212 minutes (76.4 minutes). The mean SD size of the extraction incision was 4.2 (1.7) cm. Six percent of the cases were converted to open (n=2/33), and 9% required placement of an extra port (n=3/33). Four (12%) patients had intraoperative complications, and 30% experienced postoperative complications. The average length of hospital stay was 6.4 (4.3) days. COCNLUSIONS: SILS is technically feasible and safe for patients undergoing colorectal surgery with no unusual complications. However, comparative studies are necessary to validate the potential benefits of SILS over conventional colorectal laparoscopic surgery. LIMITATIONS: The study lacked a comparison to conventional open procedures. Additionally, some evaluation criteria were not considered, including cosmesis, pain control, patient satisfaction and cost effectiveness. PMID- 27478915 TI - Elevated alanine aminotransferase levels in HIV-infected persons without hepatitis B or C virus coinfection. AB - BACKGROUND: Mortality related to human immunodeficiency (HIV) has improved with the use of antiretroviral therapy; however, liver disease-related mortality remains a major concern for the HIV population. Elevation of alanine aminotransferase (ALT) has been noted in HIV-infected persons even without viral hepatitis infection. OBJECTIVE: The objective of this study was to determine the incidence and prevalence of chronic alanine ALT elevation among patients infected with HIV who are negative for hepatitis B or C infection. DESIGN: Retrospective chart review. SETTINGS: We reviewed the medical records of all patients infected with HIV who had been treated from November 2002 to December 2010. PATIENTS AND METHODS: Patients with an unknown or positive HBV or HCV infection status were excluded. We identified patient demographics, route of transmission, peak viral load, and nadir CD4 count. RESULTS: We followed 440 patients for up to 2265 person-years. A total of 123 patients developed chronically elevated ALT levels, with an incidence of 5.8 cases per 100 person-years. Chronically elevated ALT levels were associated with high HIV viral load, mean body mass index, and diabetes mellitus. We found exposure to lamivudine in 58% of the patients, efavirenz in 41%, and zidovudine in 38%. Abdominal ultrasounds revealed fatty liver in 20 of 39 (51%) of the patients. CONCLUSION: Among patients without viral hepatitis coinfection, the prevalence and incidence of chronic elevated ALT levels were high and accompanied by high HIV RNA levels and increased BMI. LIMITATIONS: The limitations of this report are its retrospective nature and lack of a control group. PMID- 27478917 TI - Whats your diagnosis? A 72-year-old female with a diffuse mass in the right tonsillar region. PMID- 27478916 TI - Laryngopyocele: report of a rare case and systematic review. AB - A systematic review on laryngopyoceles across Ovid, PubMed, and Google Scholar database was conducted. A total of 61 papers published between 1952 and 2015 were found. Of these, 23 cases written in English, which described the number of cases, surgical approaches, resort to tracheostomy, complications, and outcomes, were shortlisted. Four cases of laryngopyoceles were managed endoscopically using a cold instrument, microdebrider, or laser. Eighteen cases were operated via an external approach, and 1 case applied both approaches. One of 4 endoscopic and 10 of 18 external approaches involved tracheostomy. The present study aimed to report a case of large mixed laryngopyocele that was successfully drained and marsupialized endoscopically using suction diathermy without requiring tracheostomy. Management using suction diathermy for excision and marsupialization of a laryngopyocele has never been reported and can be recommended as a feasible method due to its widespread availability. In the presence of a large laryngopyocele impeding the airway, tracheostomy may be averted in a controlled setting. SIMILAR CASES PUBLISHED: None specified. PMID- 27478918 TI - Prolapse of a feeding jejunostomy. PMID- 27478919 TI - A call for a national ART registry. PMID- 27478920 TI - Effects of sex on naevus body distribution and melanoma risk in two melanoma case control studies at different latitudes. PMID- 27478921 TI - Shrinking of silicon nanocrystals embedded in an amorphous silicon oxide matrix during rapid thermal annealing in a forming gas atmosphere. AB - We report the effect of hydrogen on the crystallization process of silicon nanocrystals embedded in a silicon oxide matrix. We show that hydrogen gas during annealing leads to a lower sub-band gap absorption, indicating passivation of defects created during annealing. Samples annealed in pure nitrogen show expected trends according to crystallization theory. Samples annealed in forming gas, however, deviate from this trend. Their crystallinity decreases for increased annealing time. Furthermore, we observe a decrease in the mean nanocrystal size and the size distribution broadens, indicating that hydrogen causes a size reduction of the silicon nanocrystals. PMID- 27478922 TI - Objective measurement of sedentary behaviour using accelerometers. AB - BACKGROUND: Sedentary behaviour (SB) is an important risk factor for a number of chronic diseases. Although gaps remain in our knowledge of the elements of SB most associated with reduced health outcomes, measuring SB is important, especially in less active patient populations where treatment-related changes may be seen first in changes in SB. METHODS: We review current published work in the measurement of SB to make recommendations for SB measurement in clinical studies. RESULTS: To help move our understanding of the area forward, we propose a set of derived measures of SB that can be easily understood and interpreted. CONCLUSION: Although there is more work required to determine and validate the most clinically relevant and sensitive measures of SB, there is enough understanding of how to measure SB to enable its inclusion in study protocols. PMID- 27478923 TI - Metabolic consequences of snoring in adolescents and younger adults: a population study in Chile. AB - STUDY OBJECTIVES: To investigate the potential association between snoring and other symptoms indicative of sleep-disordered breathing and metabolic syndrome (MetS) in Hispanic adolescents and younger adults using a large population-based survey. METHODS: Sleep-related information, anthropometric measurements and fasting blood samples markers of MetS were obtained from subjects aged 15-40 years collected through the 2nd Chilean Health Survey. Regression models were constructed to evaluate the associations of snoring with MetS, hypertension and serum cholesterol levels. The modulating effect of sleep duration was accounted for in the models. RESULTS: A total of 2147 subjects (42% males, mean age 27.9+/ 7.6 years) were included. Snoring and short sleep duration were present in 43.5 and 25% of the entire population, respectively. MetS was detected in 19.5% of the subjects. In the adjusted regression model, the odds of MetS among snoring subjects were 2.13 times higher (95% confidence interval (CI): 1.52-2.99; P<0.01), and 1.53-fold higher odds of elevated cholesterol also emerged (95% CI: 1.12-2.10; P<0.01). However, the odds of hypertension were not increased by the presence of snoring after adjusting for confounders. In addition, snoring was associated with an increase of 7.26 and 6.56 mg dl-1 for total and low-density lipoprotein cholesterol, respectively, even after adjusting for age, sex and body mass index. Short sleep duration was associated with a small albeit significant risk increase for high systolic blood pressure. CONCLUSIONS: In this large population-based sample of young Hispanic adults and adolescents, snoring, but not sleep duration, emerged as an independent risk factor for dyslipidemia and MetS, but not for hypertension. PMID- 27478924 TI - Serious adverse events reported for antiobesity medicines: postmarketing experiences from the EU adverse event reporting system EudraVigilance. AB - BACKGROUND: Use of antiobesity medicines has been linked with serious cardiac and psychiatric adverse events (AEs). Spontaneous reports can provide information about serious, rare and unknown AEs occurring after the time of marketing. In Europe, information about AEs reported for antiobesity medicines can be accessed in the EudraVigilance (EV) database. Therefore, we aimed to identify and characterise AEs associated with the use of antiobesity medicines in Europe. METHODS: AE reports submitted for antiobesity medicines (Anatomical Therapeutic Chemical (ATC) group A08A) from 2007 to 2014 and located in the EV database were analysed. AE data were categorised with respect to time, age and sex of patient/consumer, type of reporter, category and seriousness of reported AEs and medicines. Consumer AE reports were compared with reports from other types of reporters with respect to age and sex of consumer, seriousness, system organ class and medicine. The unit of analysis was one AE and one AE report, respectively. RESULTS: We located 4941 AE reports corresponding to 13 957 AEs for antiobesity medicines in the EV database. More than 90% of all AE cases were serious, including 159 deaths. The majority of AE cases were reported for female adults. The majority of serious AEs was reported for orlistat (37%) and rimonabant (22%). The largest share of serious AEs was of the type 'cardiac disorders' (19%) and 'psychiatric disorders' (18%). Consumer AEs reporting differed from other sources with respect to share and seriousness of AEs, type of AEs (system organ class) and medicines (ATC level 5). CONCLUSIONS: Many serious AEs were found for antiobesity medicines in EV, and consumers contributed with a relatively high share of reports. Although several products have been withdrawn from the market and new medicines are being marketed, the utilisation of antiobesity medicines is widespread, and therefore systematic monitoring of the safety of these medicines is necessary. PMID- 27478925 TI - Sleep and meal-time misalignment alters functional connectivity: a pilot resting state study. AB - Delayed sleep and meal times promote metabolic dysregulation and obesity. Altered coordination of sleeping and eating times may impact food-reward valuation and interoception in the brain, yet the independent and collective contributions of sleep and meal times are unknown. This randomized, in-patient crossover study experimentally manipulates sleep and meal times while preserving sleep duration (7.05+/-0.44 h for 5 nights). Resting-state functional magnetic resonance imaging scans (2 * 5-minute runs) were obtained for four participants (three males; 25.3+/-4.6 years), each completing all study phases (normal sleep/normal meal; late sleep/normal meal; normal sleep/late meal; and late sleep/late meal). Normal mealtimes were 1, 5, 11 and 12.5 h after awakening; late mealtimes were 4.5, 8.5, 14.5 and 16 h after awakening. Seed-based resting-state functional connectivity (RSFC) was computed for a priori regions-of-interest (seeds) and contrasted across conditions. Statistically significant (P<0.05, whole-brain corrected) regionally specific effects were found for multiple seeds. The strongest effects were linked to the amygdala: increased RSFC for late versus normal mealtimes (equivalent to skipping breakfast). A main effect of sleep and interaction with meal time were also observed. Preliminary findings support the feasibility of examining the effects of sleep and meal-time misalignment, independent of sleep duration, on RSFC in regions relevant to food reward and interoception. PMID- 27478926 TI - Kruppel-like factor 8 promotes cancer stem cell-like traits in hepatocellular carcinoma through Wnt/beta-catenin signaling. AB - Kruppel-like factor 8 (KLF8) is highly expressed in hepatocellular carcinoma (HCC) and contributes to tumor initiation and progression by promoting HCC cell proliferation and invasion. However, the role of KLF8 in liver cancer stem cells (LCSCs) is not known. In the current study, we investigated the role of KLF8 in LCSCs to determine if KLF8 is a novel marker of these cells. We found that KLF8 was highly expressed in primary HCC tumors, distant migrated tissues, and LCSCs. Patients with high KLF8 expression had a poor prognosis. KLF8 promoted stem cell like features through activation of the Wnt/beta-catenin signaling pathway. Cell apoptosis was significantly increased in HCC cells with knockdown of KLF8 compared with the control cells when treated with the same doses of sorafenib or cisplatin. Taken together, our study shows that KLF8 plays a potent oncogenic role in HCC tumorigenesis by maintaining stem cell-like features through activation of the Wnt/beta-catenin signaling pathway and promoting chemoresistance. Thus, targeting KLF8 may provide an effective therapeutic approach to suppress tumorigenicity of HCC. (c) 2016 Wiley Periodicals, Inc. PMID- 27478927 TI - Open-Source Automated Parahydrogen Hyperpolarizer for Molecular Imaging Using (13)C Metabolic Contrast Agents. AB - An open-source hyperpolarizer producing (13)C hyperpolarized contrast agents using parahydrogen induced polarization (PHIP) for biomedical and other applications is presented. This PHIP hyperpolarizer utilizes an Arduino microcontroller in conjunction with a readily modified graphical user interface written in the open-source processing software environment to completely control the PHIP hyperpolarization process including remotely triggering an NMR spectrometer for efficient production of payloads of hyperpolarized contrast agent and in situ quality assurance of the produced hyperpolarization. Key advantages of this hyperpolarizer include: (i) use of open-source software and hardware seamlessly allowing for replication and further improvement as well as readily customizable integration with other NMR spectrometers or MRI scanners (i.e., this is a multiplatform design), (ii) relatively low cost and robustness, and (iii) in situ detection capability and complete automation. The device performance is demonstrated by production of a dose (~2-3 mL) of hyperpolarized (13)C-succinate with %P13C ~ 28% and 30 mM concentration and (13)C-phospholactate at %P13C ~ 15% and 25 mM concentration in aqueous medium. These contrast agents are used for ultrafast molecular imaging and spectroscopy at 4.7 and 0.0475 T. In particular, the conversion of hyperpolarized (13)C-phospholactate to (13)C lactate in vivo is used here to demonstrate the feasibility of ultrafast multislice (13)C MRI after tail vein injection of hyperpolarized (13)C phospholactate in mice. PMID- 27478928 TI - Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation. AB - Hsp104, a conserved AAA+ protein disaggregase, promotes survival during cellular stress. Hsp104 remodels amyloids, thereby supporting prion propagation, and disassembles toxic oligomers associated with neurodegenerative diseases. However, a definitive structural mechanism for its disaggregase activity has remained elusive. We determined the cryo-EM structure of wild-type Saccharomyces cerevisiae Hsp104 in the ATP state, revealing a near-helical hexamer architecture that coordinates the mechanical power of the 12 AAA+ domains for disaggregation. An unprecedented heteromeric AAA+ interaction defines an asymmetric seam in an apparent catalytic arrangement that aligns the domains in a two-turn spiral. N terminal domains form a broad channel entrance for substrate engagement and Hsp70 interaction. Middle-domain helices bridge adjacent protomers across the nucleotide pocket, thus explaining roles in ATP hydrolysis and protein disaggregation. Remarkably, substrate-binding pore loops line the channel in a spiral arrangement optimized for substrate transfer across the AAA+ domains, thereby establishing a continuous path for polypeptide translocation. PMID- 27478929 TI - m(1)A and m(1)G disrupt A-RNA structure through the intrinsic instability of Hoogsteen base pairs. AB - The B-DNA double helix can dynamically accommodate G-C and A-T base pairs in either Watson-Crick or Hoogsteen configurations. Here, we show that G-C(+) (in which + indicates protonation) and A-U Hoogsteen base pairs are strongly disfavored in A-RNA. As a result,N(1)-methyladenosine and N(1)-methylguanosine, which occur in DNA as a form of alkylation damage and in RNA as post transcriptional modifications, have dramatically different consequences. Whereas they create G-C(+) and A-T Hoogsteen base pairs in duplex DNA, thereby maintaining the structural integrity of the double helix, they block base-pairing and induce local duplex melting in RNA. These observations provide a mechanism for disrupting RNA structure through post-transcriptional modifications. The different propensities to form Hoogsteen base pairs in B-DNA and A-RNA may help cells meet the opposing requirements of maintaining genome stability, on the one hand, and of dynamically modulating the structure of the epitranscriptome, on the other. PMID- 27478930 TI - Clathrin-coat disassembly illuminates the mechanisms of Hsp70 force generation. AB - Hsp70s use ATP hydrolysis to disrupt protein-protein associations and to move macromolecules. One example is the Hsc70- mediated disassembly of the clathrin coats that form on vesicles during endocytosis. Here, we exploited the exceptional features of these coats to test three models-Brownian ratchet, power stroke and entropic pulling-proposed to explain how Hsp70s transform their substrates. Our data rule out the ratchet and power-stroke models and instead support a collision-pressure mechanism whereby collisions between clathrin-coat walls and Hsc70s drive coats apart. Collision pressure is the complement to the pulling force described in the entropic pulling model. We also found that self association augments collision pressure, thereby allowing disassembly of clathrin lattices that have been predicted to be resistant to disassembly. These results illuminate how Hsp70s generate the forces that transform their substrates. PMID- 27478932 TI - Evidence for the Propositions of the Interpersonal Theory of Suicide Among a Military Sample. AB - OBJECTIVE: Although the interpersonal theory of suicide may explain the elevated suicide risk among military service members, past explorations have been equivocal. This study aimed to investigate the propositions of the interpersonal theory in a sample of U.S. Army recruiters. METHOD: Participants (N = 3,428) completed self-report measures assessing the interpersonal theory's constructs (i.e., thwarted belongingness (TB), perceived burdensomeness (PB), acquired capability for suicide), current suicidal ideation, agitation, and insomnia. History of depression was obtained from medical records. RESULTS: Hierarchical multiple regression analyses revealed that the interaction between TB and PB was associated with current suicidal ideation, controlling for depression, agitation, and insomnia. This effect was especially notable among those with high capability for suicide. CONCLUSION: Findings provide support for the interpersonal theory in a large, diverse military sample. It may be advantageous to assess and therapeutically address TB and PB among at-risk service members. PMID- 27478934 TI - Incorporation of iron into chloroplasts triggers the restoration of cadmium induced inhibition of photosynthesis. AB - Photosynthetic symptoms of acute Cd stress can be remedied by elevated Fe supply. To shed more light on the most important aspects of this recovery, the detailed Fe trafficking and accumulation processes as well as the changes in the status of the photosynthetic apparatus were investigated in recovering poplar plants. The Cd-free, Fe-enriched nutrient solution induced an immediate intensive Fe uptake. The increased Fe/Cd ratio in the roots initiated the translocation of Fe to the leaf with a short delay that ultimately led to the accumulation of Fe in the chloroplasts. The chloroplast Fe uptake was directly proportional to the Fe translocation to leaves. The accumulation of PSI reaction centers and the recovery of PSII function studied by Blue-Native PAGE and chlorophyll a fluorescence induction measurements, respectively, began in parallel to the increase in the Fe content of chloroplasts. The initial reorganization of PSII was accompanied by a peak in the antennae-based non-photochemical quenching. In conclusion, Fe accumulation of the chloroplasts is a process of prime importance in the recovery of photosynthesis from acute Cd stress. PMID- 27478933 TI - Identification of flavonoid 3'-hydroxylase in the yellow flower of Delphinium zalil. AB - The flowers of delphinium cultivars owe their coloration to anthocyanins such as delphinidin or pelargonidin derivatives. To date, no delphinium cultivars have been found with red flowers due to the presence of cyanidin derivatives. This suggests that delphiniums do not have cyanidin biosynthesis ability because of the loss of function of flavonoid 3' hydroxylase (F3'H). Here, we show that the wild delphinium species Delphinium zalil (synonym semibarbatum) can accumulate quercetin 3-glucosides in its sepals, presumably through F3'H activity. We isolated F3'H cDNA from D. zalil (DzF3'H) and produced a recombinant enzyme from a yeast transformant. The recombinant DzF3'H protein could convert naringenin, apigenin, dihydrokaempferol and kaempferol to eriodictyol, luteolin, dihydroquercetin and quercetin, respectively. An expression analysis confirmed that blue flowered D. grandiflorum does not express F3'H, and also showed that flavonoid 3',5'-hydroxylase and anthocyanidin synthase do not function in D. zalil sepals. DzF3'H can act as a flavonoid hydroxylase to produce cyanidin accumulation. The introduction of the DzF3'H gene into other delphinium species by conventional breeding may enable development of cultivars with novel flower colors. PMID- 27478931 TI - Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV. AB - Structure-based design of vaccines, particularly the iterative optimization used so successfully in the structure-based design of drugs, has been a long-sought goal. We previously developed a first-generation vaccine antigen called DS-Cav1, comprising a prefusion-stabilized form of the fusion (F) glycoprotein, which elicits high-titer protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV protective responses. The resultant second-generation 'DS2'-stabilized immunogens have their F subunits genetically linked, their fusion peptides deleted and their interprotomer movements stabilized by an additional disulfide bond. These DS2 immunogens are promising vaccine candidates with superior attributes, such as their lack of a requirement for furin cleavage and their increased antigenic stability against heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens. PMID- 27478935 TI - Detecting rare and common haplotype-environment interaction under uncertainty of gene-environment independence assumption. AB - Finding rare variants and gene-environment interactions (GXE) is critical in dissecting complex diseases. We consider the problem of detecting GXE where G is a rare haplotype and E is a nongenetic factor. Such methods typically assume G-E independence, which may not hold in many applications. A pertinent example is lung cancer-there is evidence that variants on Chromosome 15q25.1 interact with smoking to affect the risk. However, these variants are associated with smoking behavior rendering the assumption of G-E independence inappropriate. With the motivation of detecting GXE under G-E dependence, we extend an existing approach, logistic Bayesian LASSO, which assumes G-E independence (LBL-GXE-I) by modeling G E dependence through a multinomial logistic regression (referred to as LBL-GXE D). Unlike LBL-GXE-I, LBL-GXE-D controls type I error rates in all situations; however, it has reduced power when G-E independence holds. To control type I error without sacrificing power, we further propose a unified approach, LBL-GXE, to incorporate uncertainty in the G-E independence assumption by employing a reversible jump Markov chain Monte Carlo method. Our simulations show that LBL GXE has power similar to that of LBL-GXE-I when G-E independence holds, yet has well-controlled type I errors in all situations. To illustrate the utility of LBL GXE, we analyzed a lung cancer dataset and found several significant interactions in the 15q25.1 region, including one between a specific rare haplotype and smoking. PMID- 27478936 TI - Self-report of ADHD shows limited agreement with objective markers of persistence and remittance. AB - OBJECTIVE: A controversial issue is whether self-report of symptoms and impairment is sufficient for diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adolescents and adults in the absence of other informants, such as parents. The present study investigated how well self-report is reflected by cognitive-neurophysiological and actigraph measures, which we have previously shown to discriminate between ADHD persisters, remitters and controls using parent-report (Cheung et al., 2015; Brit J Psychiat http://dx.doi.org/10.1192/bjp.bp.114.145185). METHOD: Parent- and self-reported ADHD symptoms and impairment, together with cognitive, electroencephalogram (EEG) frequency, event-related potential (ERP) and actigraph measures were obtained from 108 adolescents and young adults with childhood ADHD and 167 controls. RESULTS: Participants reported lower levels of ADHD symptoms and impairments than parents (p < 0.05) and the ADHD persistence rate based on self-report was low at 44%, compared to the persistence rate of 79% previously reported based on parent report. Regression analyses showed that the objective measures distinguished poorly between ADHD persistent and remittent groups based on self-report, in contrast to findings based on parent-report (Cheung et al., 2015), although the measures differentiated well between ADHD persisters and controls. Correlation analyses revealed that self-reported impairment significantly correlated with fewer of the objective measures, despite parent- and self-reported symptoms showing similar correlations with the measures. CONCLUSIONS: The findings show that self-reported ADHD outcome is not as well reflected by cognitive neurophysiological and movement correlates as we previously found for parent reported ADHD. PMID- 27478937 TI - Molecular polymorphism: microwave spectra, equilibrium structures, and an astronomical investigation of the HNCS isomeric family. AB - The rotational spectra of thioisocyanic acid (HNCS), and its three energetic isomers (HSCN, HCNS, and HSNC) have been observed at high spectral resolution by a combination of chirped-pulse and Fabry-Perot Fourier-transform microwave spectroscopy between 6 and 40 GHz in a pulsed-jet discharge expansion. Two isomers, thiofulminic acid (HCNS) and isothiofulminic acid (HSNC), calculated here to be 35-37 kcal mol(-1) less stable than the ground state isomer HNCS, have been detected for the first time. Precise rotational, centrifugal distortion, and nitrogen hyperfine coupling constants have been determined for the normal and rare isotopic species of both molecules; all are in good agreement with theoretical predictions obtained at the coupled cluster level of theory. On the basis of isotopic spectroscopy, precise molecular structures have been derived for all four isomers by correcting experimental rotational constants for the effects of rotation-vibration interaction calculated theoretically. Formation and isomerization pathways have also been investigated; the high abundance of HSCN relative to ground state HNCS, and the detection of strong lines of SH using CH3CN and H2S, suggest that HSCN is preferentially produced by the radical radical reaction HS + CN. A radio astronomical search for HSCN and its isomers has been undertaken toward the high-mass star-forming region Sgr B2(N) in the Galactic Center with the 100 m Green Bank Telescope. While we find clear evidence for HSCN, only a tentative detection of HNCS is proposed, and there is no indication of HCNS or HSNC at the same rms noise level. HSCN, and tentatively HNCS, displays clear deviations from a single-excitation temperature model, suggesting weak masing may be occurring in some transitions in this source. PMID- 27478941 TI - Effects of Environmental Temperature Change on the Efficiency of Coal- and Natural Gas-Fired Power Plants. AB - Modeling studies predict that droughts and hotter water and air temperatures caused by climate warming will reduce the efficiency (eta) of thermoelectric plants by 0.12-0.45% for each 1 degrees C of warming. We evaluate these predictions using historical performance data for 39 open- and closed-loop coal and natural gas plants from across the U.S., which operated under daily and seasonal temperature fluctuations multiples greater than future average warming projections. Seven to 14 years of hourly water (Tw), dry-bulb air (Ta), and wet bulb air (Twb) temperature recordings collected near each plant are regressed against efficiency to attain estimates of Deltaeta per 1 degrees C increase. We find reductions in eta with increased Tw (for open-loop plants) up to 1 order of magnitude less than previous estimates. We also find that changes in eta associated with changes in Ta (open-loop plants) or Twb (closed-loop plants) are not only smaller than previous estimates but also variable; i.e., eta rises with Ta or Twb for some plants and falls for others. Our findings suggest that thermoelectric plants, particularly closed-loop plants, should be more resilient to climate warming than previously expected. PMID- 27478938 TI - Emerging concepts of epigenetic dysregulation in hematological malignancies. AB - The past decade brought a revolution in understanding of the structure, topology and disease-inducing lesions of RNA and DNA, fueled by unprecedented progress in next-generation sequencing. This technological revolution has also affected understanding of the epigenome and has provided unique opportunities for the analysis of DNA and histone modifications, as well as the first map of the non protein-coding genome and three-dimensional (3D) chromosomal interactions. Overall, these advances have facilitated studies that combine genetic, transcriptomics and epigenomics data to address a wide range of issues ranging from understanding the role of the epigenome in development to targeting the transcription of noncoding genes in human cancer. Here we describe recent insights into epigenetic dysregulation characteristic of the malignant differentiation of blood stem cells based on studies of alterations that affect epigenetic complexes, enhancers, chromatin, long noncoding RNAs (lncRNAs), RNA splicing, nuclear topology and the 3D conformation of chromatin. PMID- 27478939 TI - C13orf31 (FAMIN) is a central regulator of immunometabolic function. AB - Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease. PMID- 27478942 TI - 4-Hydroxy-N-propyl-1,8-naphthalimide esters: New fluorescence-based assay for analysing lipase and esterase activity. AB - Research using 1,8-naphthalimide derivatives has expanded rapidly in recent years owing to their cell-permeable nature, ability to target certain cellular locations and fluorescent properties. Here we describe the synthesis of three new esters of 4-hydroxy-N-propyl-1,8-naphthalimide (NAP) and the development of a simple and sensitive assay protocol to measure the activity of carboxylester hydrolases. The NAP fluorophore was esterified with short (butyrate), medium (octanoate) and long (palmitate) chain fatty acids. The esters were spectroscopically characterised and their properties investigated for their suitability as assay substrates. The esters were found to be relatively stable under the conditions of the assay and levels of spontaneous hydrolysis were negligible. Non-specific hydrolysis by proteins such as bovine serum albumin was also minimal. A simple and rapid assay methodology was developed and used to analyse a range of commercially available enzymes that included enzymes defined as lipases, esterases and phospholipases. Clear differences were observed between the enzyme classes with respect to the hydrolysis of the various chain length esters, with lipases preferentially hydrolysing the medium chain ester, whereas esterases reacted more favourably with the short ester. The assay was found to be highly sensitive with the fluorophore detectable to the low nM range. These esters provide alternate substrates from established coumarin-based fluorophores, possessing distinctly different excitation (447 nm) and emission (555 nm) optima. Absorbing at 440-450 nm also offers the flexibility of analysis by UV-visible spectrophotometry. This represents the first instance of a naphthalimide-derived compound being used to analyse these enzymes. PMID- 27478943 TI - The shared burden of stroke and dementia. PMID- 27478944 TI - Surgery for epilepsy: the need for global acceptance and access. PMID- 27478940 TI - Affinity for self antigen selects Treg cells with distinct functional properties. AB - The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD 1(lo)CD25(lo) (Triple(lo)) Treg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) Tconv cells into induced Treg cells (iTreg cells). Although Foxp3-deficient (Scurfy) mice lacked Treg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells zsuper> T cells infiltrated the skin, whereas Scurfy Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of Treg cells into distinct subsets with non-overlapping regulatory activities. PMID- 27478945 TI - A call for researchers to join the META-MICROBLEEDS Consortium. PMID- 27478946 TI - Phenytoin for neuroprotection. PMID- 27478947 TI - Phenytoin for neuroprotection. PMID- 27478948 TI - Phenytoin for neuroprotection - Authors' reply. PMID- 27478949 TI - Taking a swipe at Africa's epilepsy. PMID- 27478950 TI - Dystonia in a prolific medieval scribe. PMID- 27478951 TI - Sharon Shively. PMID- 27478953 TI - Neurogenic orthostatic hypotension and supine hypertension in Parkinson's disease and related synucleinopathies: prioritisation of treatment targets. AB - Neurogenic orthostatic hypotension and supine hypertension are common manifestations of cardiovascular dysautonomia in Parkinson's disease and related synucleinopathies. Because these disorders are haemodynamic opposites, improvement in one might be achieved at the expense of worsening of the other. Thus, management decisions necessitate assessment of the individual risks for patients with coexistent neurogenic orthostatic hypotension and supine hypertension. Whereas neurogenic orthostatic hypotension poses risks for falls and can be associated with cognitive impairment in the short term, chronic supine hypertension can be associated with stroke and myocardial infarction in the long term. Because few clinical trial data exist for outcomes in patients with coexistent neurogenic orthostatic hypotension and supine hypertension, clinicians need to balance, on the basis of comorbidities and disease staging, the potential immediate benefits of treatment for neurogenic orthostatic hypotension and the long-term risks of supine hypertension treatment in each patient. Future research needs to focus on ascertaining a safe degree of supine hypertension when treating neurogenic orthostatic hypotension; the effectiveness of nocturnal antihypertensive therapy in patients with coexistent neurogenic orthostatic hypotension and supine hypertension; and the prevalence, scope, and therapeutic requirements for managing neurogenic orthostatic hypotension that manifests with falls or cognitive impairment, but without postural lightheadedness or near syncope. PMID- 27478954 TI - Atypical inflammatory demyelinating syndromes of the CNS. AB - Atypical inflammatory demyelinating syndromes are rare disorders that differ from multiple sclerosis owing to unusual clinical or MRI findings or poor response to treatments used for multiple sclerosis. These syndromes include neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis, tumefactive demyelination, Balo's concentric sclerosis, Schilder's disease, and Marburg's multiple sclerosis. The overlapping features of these syndromes with multiple sclerosis and with each other complicate diagnosis and their categorisation as distinct or related conditions. Recognition of these syndromes is crucial because they differ from multiple sclerosis and other demyelinating and non-demyelinating conditions in their prognosis and treatment. Advances in MRI, pathology, and immunobiology are needed to increase understanding of these syndromes, including the extent to which some of them represent distinct entities, and to assist with improvements in their diagnosis and management. PMID- 27478955 TI - Surgical treatment for epilepsy: the potential gap between evidence and practice. AB - Findings from randomised controlled trials, along with more than 100 case series and observational studies, support the efficacy and safety of resective surgery and, more recently, non-resective surgical interventions for the treatment of drug-resistant epilepsy in appropriately selected individuals. There is an argument that epilepsy surgery remains underused, but the evidence to support this assertion is at times unclear. Results from longitudinal studies show a stagnant or declining rate of epilepsy surgery over time, despite the evidence and guidelines supporting its use. Some suggest that this stagnation is due to a decreasing pool of eligible surgical candidates, whereas others emphasise the numerous barriers to epilepsy surgery. Strategies exist to increase access to surgery and to improve communication about the effectiveness of this potentially life-changing procedure. Further investigation into the nature and causes of the presumed underuse of epilepsy surgery and the elaboration of strategies to address this treatment gap are necessary and pressing. PMID- 27478957 TI - Enhancing the biocompatibility of microfluidics-assisted fabrication of cell laden microgels with channel geometry. AB - Microfluidic flow-focusing devices (FFD) are widely used to generate monodisperse droplets and microgels with controllable size, shape and composition for various biomedical applications. However, highly inconsistent and often low viability of cells encapsulated within the microgels prepared via microfluidic FFD has been a major concern, and yet this aspect has not been systematically explored. In this study, we demonstrate that the biocompatibility of microfluidic FFD to fabricate cell-laden microgels can be significantly enhanced by controlling the channel geometry. When a single emulsion ("single") microfluidic FFD is used to fabricate cell-laden microgels, there is a significant decrease and batch-to-batch variability in the cell viability, regardless of their size and composition. It is determined that during droplet generation, some of the cells are exposed to the oil phase which is shown to have a cytotoxic effect. Therefore, a microfluidic device with a sequential ('double') flow-focusing channels is employed instead, in which a secondary aqueous phase containing cells enters the primary aqueous phase, so the cells' exposure to the oil phase is minimized by directing them to the center of droplets. This microfluidic channel geometry significantly enhances the biocompatibility of cell-laden microgels, while maintaining the benefits of a typical microfluidic process. This study therefore provides a simple and yet highly effective strategy to improve the biocompatibility of microfluidic fabrication of cell-laden microgels. PMID- 27478956 TI - Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease. AB - Importance: Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease in children in the United States and is associated with insulin resistance. In adults, NAFLD is also associated with type 2 diabetes. To our knowledge, the prevalence of type 2 diabetes in children with NAFLD is unknown. Objective: To determine the prevalence of type 2 diabetes and prediabetes in children with NAFLD and assess type 2 diabetes and prediabetes as risk factors for nonalcoholic steatohepatitis (NASH). Design, Setting, and Participants: This was a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network. Children younger than 18 years with biopsy-confirmed NAFLD enrolled in the NASH Clinical Research Network. Main Outcomes and Measures: The presence of type 2 diabetes and prediabetes as determined by American Diabetes Association screening criteria using clinical history and fasting laboratory values. Results: There were 675 children with NAFLD included in the study with a mean age of 12.6 years and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 32.5. Most of the children were boys (480 of 675) and Hispanic (445 of 675).The estimated prevalence of prediabetes was 23.4% (95% CI, 20.2%-26.6%), and the estimated prevalence of type 2 diabetes was 6.5% (95% CI, 4.6%-8.4%). Girls with NAFLD had 1.6 (95% CI, 1.04-2.40) times greater odds of having prediabetes and 5.0 (95% CI, 2.49-9.98) times greater odds of having type 2 diabetes than boys with NAFLD. The prevalence of NASH was higher in those with type 2 diabetes (43.2%) compared with prediabetes (34.2%) or normal glucose (22%) (P < .001). The odds of having NASH were significantly higher in those with prediabetes (OR, 1.9; 95% CI, 1.21-2.9) or type 2 diabetes (OR, 3.1; 95% CI, 1.5 6.2) compared with those with normal glucose. Conclusions and Relevance: In this study, nearly 30% of children with NAFLD also had type 2 diabetes or prediabetes. These children had greater odds of having NASH and thus were at greater long-term risk for adverse hepatic outcomes. PMID- 27478958 TI - Adsorption of lysozyme on base metal surfaces in the presence of an external electric potential. AB - The impact of external electric potential on the adsorption of a protein to base metal surfaces was examined. Hen egg white lysozyme (LSZ) and six types of base metal plates (stainless steel SUS316L (St), Ti, Ta, Zr, Cr, or Ni) were used as the protein and adsorption surface, respectively. LSZ was allowed to adsorb on the surface under different conditions (surface potential, pH, electrolyte type and concentration, surface material), which was monitored using an ellipsometer. LSZ adsorption was minimized in the potential range above a certain threshold and, in the surface potential range below the threshold, decreasing the surface potential increased the amount of protein adsorbed. The threshold potential for LSZ adsorption was shifted toward a positive value with increasing pH and was lower for Ta and Zr than for the others. A divalent anion salt (K2SO4) as an electrolyte exhibited the adsorption of LSZ in the positive potential range while a monovalent salt (KCl) did not. A comprehensive consideration of the obtained results suggests that two modes of interactions, namely the electric force by an external electric field and electrostatic interactions with ionized surface hydroxyl groups, act on the LSZ molecules and determine the extent of suppression of LSZ adsorption. All these findings appear to support the view that a base metal surface can be controlled for the affinity to a protein by manipulating the surface electric potential as has been reported on some electrode materials. PMID- 27478959 TI - Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced arthritis model. AB - Rheumatoid arthritis (RA), an autoimmune and inflammatory pathology, is resulted due to the disruption of immune-homeostasis and failure of host immune surveillance mechanism leading to cartilage degradation and bone erosion. Orally and parenterally administered methotrexate (MTX) have had adverse systemic complications in RA therapeutics. Therefore, transdermal application of MTX is recommended for the treatment of RA [1]. Present study is designed to develop MTX loaded nanostructured lipid carriers and chemical enhancer co-incorporated hydrogel (gel-(MTX-NLCs+CE)) for an efficient transdermal delivery of MTX in a Freund's adjuvants induced experimental animal model of RA. A gel-(MTX-NLCs+CE) was formulated and evaluated for its biocompatibility in hyper keratinocytes (HaCaT) and human monocytic cells (U937). Further, systemic and local inflammation was assessed by the estimation of pro-inflammatory cytokines & joint destructive enzymes (TNF-alpha, IL-6, MMP-1 & IL-1beta,; iNOS & COX-2) in the serum and synovial fluid, respectively in an experimentally induced RA animal model. Prepared formulations were also evaluated with respect to arthritis index, arthritis score and histopathology of paw and ankle bones. The biocompatibility study of formulation on U937 and HaCaT is suggestive of safe and greater therapeutic efficacy of the developed formulations. Our results show that transcutaneous ability of MTX loaded nanostructured lipid carries (NLCs) and chemical enhancer (CE) co-incorporated hydrogel significantly (p<0.001) decreases the inflammation in RA animal model. In conclusion, developed NLCs-based gel formulation loaded with MTX opens new avenues for developing novel therapeutic modality for RA patients with the acceptably minimum adverse effects. PMID- 27478960 TI - Supramolecular host-guest polycationic gene delivery system based on poly(cyclodextrin) and azobenzene-terminated polycations. AB - This article describes the supramolecular host-guest polycationic gene delivery system based on poly(beta-cyclodextrin) (PCD) and azobenzene-terminated polycations. The azobenzene-terminated linear (Az-LPDM) and branched (Az-BPDM) cationic polymers were synthesized by atom transfer radical polymerization (ATRP) of 2-dimethylamino ethyl methacrylate (DMAEMA). The formation and photosensitive behavior of the supramolecular polycations of azobenzene-terminated polycations Az-LPDM and Az-BPDM with PCD were confirmed by UV-vis and NMR analysis. The supramolecular PCD/Az-BPDM/DNA and PCD/Az-LPDM/DNA polyplexes showed smaller size and were less positive than those of their corresponding polyplexes without PCD. Moreover, the UV irradiation may promote release of DNA from the photosensitive supramolecular polyplexes due to dissociation of supramoelcular polyplexes. In vitro experiments revealed that the photosensitive supramolecular polycationic polyplexes (PCD/Az-LPDM/DNA and PCD/Az-BPDM/DNA) exhibited enhancement of cellular uptake, higher transfection efficiency, and lower cytoxicity compared to the azobenzene-terminated polycation/DNA polyplexes in the absence of PCD. Branched polycationic polyplexes showed higher transfection efficiency than its linear polycationic polyplexes. Furthermore, after UV irradiation, the transfection efficiency of photosensitive supramolecular polyplexes was improved resulting from more DNAs delivered and released inside of the cell nuclei. Thus this photoresponsive supramolecular host-guest system containing azobenzene terminated branched cationic polymers and PCD is a promising gene vector. PMID- 27478961 TI - Production of lysozyme nanofibers using deep eutectic solvent aqueous solutions. AB - Amyloid fibrils have recently gained a lot of attention due to their morphology, functionality and mechanical strength, allowing for their application in nanofiber-based materials, biosensors, bioactive membranes and tissue engineering scaffolds. The in vitro production of amyloid fibrils is still a slow process, thus hampering the massive production of nanofibers and its consequent use. This work presents a new and faster (2-3h) fibrillation method for hen egg white lysozyme (HEWL) using a deep eutectic solvent based on cholinium chloride and acetic acid. Nanofibers with dimensions of 0.5-1MUm in length and 0.02-0.1MUm in thickness were obtained. Experimental variables such as temperature and pH were also studied, unveiling their influence in fibrillation time and nanofibers morphology. These results open a new scope for protein fibrillation into nanofibers with applications ranging from medicine to soft matter and nanotechnology. PMID- 27478962 TI - Green synthesized cerium oxide nanoparticle: A prospective drug against oxidative harm. AB - Cerium oxide nanoparticle (CeONP) of size 2-3nm was synthesized by a new, simple and green method at ambient temperature, using cerium nitrate as prime precursor and Aloe vera leaf extract as stabilizing agent. Of the two oxidation states (+3) and (+4) of cerium, it was dominantly present in (+3) state in CeONP and cyclic conversion of Ce(III)O->Ce(IV)O->Ce(III)O by reaction with H2O2 implied uninterrupted antioxidant property of CeONP. Moreover, the higher oxygen defect in the crystal lattice produced particles with higher antioxidant activity. CeONP was found to neutralize the deleterious effects of H2O2 viz., cell death, generation of intracellular reactive oxygen species and loss of connectivity in mouse neural cells. Therefore, CeONP might have potential use in future as an anti-oxidant drug. PMID- 27478964 TI - Non-Noble-Metal Nanoparticle Supported on Metal-Organic Framework as an Efficient and Durable Catalyst for Promoting H2 Production from Ammonia Borane under Visible Light Irradiation. AB - In this work, we propose a straightforward method to enhance the catalytic activity of AB dehydrogenation by using non-noble-metal nanoparticle supported on chromium-based metal-organic framework (MIL-101). It was demonstrated to be effective for hydrogen generation from ammonia borane under assistance of visible light irradiation as a noble-metal-free catalyst. The catalytic activity of metal nanoparticles supported on MIL-101 under visible light irradiation is remarkably higher than that without light irradiation. The TOFs of Cu/MIL-101, Co/MIL-101, and Ni/MIL-101 are 1693, 1571, and 3238 h(-1), respectively. The enhanced activity of catalysts can be primarily attributed to the cooperative promoting effects from both non-noble-metal nanoparticles and photoactive metal-organic framework in activating the ammonia borane molecule and strong ability in the photocatalytic production of hydroxyl radicals, superoxide anions, and electron rich non-noble-metal nanoparticle. This work sheds light on the exploration of active non-noble metals supported on photoactive porous materials for achieving high catalytic activity of various redox reactions under visible light irradiation. PMID- 27478963 TI - Diagnostic and treatment strategy for small gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) are considered to be potentially malignant mesenchymal tumors of the gastrointestinal tract. Clinically relevant GISTs are rare; however, subclinical GISTs (mini-GISTs) (1-2 cm) and pathologic GISTs (micro-GISTs) (<1 cm) are frequently reported. Most mini-GISTs and almost all micro-GISTs of the stomach may exhibit benign clinical behavior, and only mini-GISTs with high-risk features may progress. For this review, a provisional algorithm was used to propose diagnostic and treatment strategies for patients with small GISTs. Because surgery is the only potentially curative treatment, in its application for small GISTs, the principles of sarcoma surgery should be maintained, and cost effectiveness should be considered. Indications for surgery include GISTs measuring >=2 cm, symptomatic GISTs, and mini-GISTs with high-risk features (irregular borders, cystic spaces, ulceration, echogenic foci, internal heterogeneity, and tumor progression during follow-up); however, a preoperative pathologic diagnosis is infrequently obtained. For small intestinal and colorectal GISTs, surgery is indicated irrespective of size because of their greater malignant potential. Otherwise, mini-GISTs without high-risk features, micro-GISTs, and small submucosal tumors measuring <5 cm without high-risk features may be followed by periodical endoscopic ultrasonography. Although surgical approaches and operative methods are selected according to tumor size, location, growth pattern, and surgical teams, laparoscopic surgery has produced similar oncologic outcomes and is less invasiveness compared with open surgery. After resection, pathologic examination for diagnosis and risk assessment is mandatory, and genotyping is also recommended for high-risk GISTs. Endoscopic resection techniques, although feasible, are not routinely indicated for most mini-GISTs or micro-GISTs. Cancer 2016;122:3110-8. (c) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID- 27478965 TI - How does prior health status (age, comorbidities and frailty) determine critical illness and outcome? AB - PURPOSE OF REVIEW: Critical illness has a significant impact on an individual's physical and mental health. However, it is less clear to what degree outcomes after critical illness are due to patients' preexisting characteristics, rather than the critical illness itself. In this review, we summarize recent findings regarding the role of age, comorbidity and frailty on long-term outcomes after critical illness. RECENT FINDINGS: Age, comorbidity and frailty are all associated with an increased risk of critical illness. Although severity of illness drives the risk of acute mortality, recent data suggest that longer term outcomes are much more closely aligned with prior health status. There are growing data regarding the important role of noncardiovascular comorbidity, including psychiatric illness and obesity, in determining long-term outcomes. Finally, preadmission frailty is associated with poor long-term outcomes after critical illness; further data are needed to evaluate the attributable impact of critical illness on the health trajectories of frail individuals. SUMMARY: Age, comorbidity and frailty play a critical role in determining the long-term outcomes of patients requiring intensive care. PMID- 27478966 TI - Assessment of adequacy of volume resuscitation. AB - PURPOSE OF REVIEW: It has recently become evident that administration of intravenous fluids following initial resuscitation has a greater probability of producing tissue edema and hypoxemia than of increasing oxygen delivery. Therefore, it is essential to have a rational approach to assess the adequacy of volume resuscitation. Here we review passive leg raising (PLR) and respiratory variation in hemodynamics to assess fluid responsiveness. RECENT FINDINGS: The use of ultrasound enhances the clinician's ability to detect and predict fluid responsiveness, whereas enthusiasm for this modality must be tempered by recent evidence that it is only reliable in apneic patients. SUMMARY: The best predictor of fluid response for hypotensive patients not on vasopressors is a properly conducted passive leg raise maneuver. For more severely ill patients who are apneic, mechanically ventilated and on vasopressors, point of care echocardiography is the best choice. Increases in vena caval diameter induced by controlled positive pressure breaths are insensitive to arrhythmias and can be performed with relatively brief training. Most challenging are patients who are awake and on vasopressors; we suggest that the best method to discriminate fluid responders is PLR measuring changes in cardiac output. PMID- 27478967 TI - Congenital internal hernia through defect in the falciform ligament in adult: A case report and review of the literature. AB - INTRODUCTION: The incidence of occlusion syndrome caused by internal hernia is very rare, in particular when the defect is congenital discovered in adults with no previous abdominal surgery. PRESENTATION OF CASE: We present a case of a 31 year-old female patient who presented with acute abdominal pain and mechanical obstruction. The patient had never undergone abdominal surgery. DISCUSSION: On diagnostic laparoscopy, it was found a herniation of a loop of small bowel through a hole in the falciform ligament. The obstruction was solved by the division of part of falciform ligament without intestinal resection. CONCLUSION: Internal hernia is a very uncommon pathology, most often discovered in pediatric age because of congenital abnormalities, it must be included in the differential diagnosis in adults. Preoperative diagnosis is difficult. The diagnostic laparoscopic approach has shown to be the best. PMID- 27478968 TI - Importance of perioperative management for emergency carotid artery stenting within 24h after intravenous thrombolysis for acute ischemic stroke: Case report. AB - INTRODUCTION: We report a patient treated successfully via endovascular surgery within 24h after intravenous thrombolysis using recombinant tissue plasminogen activator for acute cervical internal carotid artery occlusion. PRESENTATION OF CASE: A 68-year-old man was admitted to our hospital. Neurological examination revealed severe left-sided motor weakness. Magnetic resonance imaging showed no cerebral infarction, but magnetic resonance angiography revealed complete occlusion of the right internal carotid artery. Systemic intravenous injection of recombinant tissue plasminogen activator was performed within 4h after the onset. But, magnetic resonance angiography still revealed complete occlusion. Revascularization of the right cervical internal carotid artery was performed via endovascular surgery. The occluded artery was successfully recanalized using the Penumbra System((r)) and stent placement at the origin of the internal carotid artery. Immediately after surgery, dual antiplatelet therapy (aspirin and clopidogrel) was initiated, and then cilostazol was added on the following day. Carotid ultrasonography and three-dimensional computed tomographic angiography at 14days revealed no further obstruction to flow. DISCUSSION: When trying to perform emergency carotid artery stenting within 24h after intravenous recombinant tissue plasminogen activator administration, several issues require attention, such as the decisions regarding the type of stent and embolic protection device, the selection of antiplatelet therapy and the methods of preventing hyperperfusion syndrome. CONCLUSION: Emergency carotid artery stenting for the acute internal carotid artery occlusion may be considered a safe procedure in preventing early stroke recurrence in selected patients. PMID- 27478969 TI - Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3. AB - Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases (RTKs) regulate a variety of dynamic cellular events, including cell protrusion, migration, proliferation, and cell-fate determination. Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the physiological and pathological roles of Eph. However, there is a lack of small-molecule inhibitors that are selective for individual Eph isoforms due to the high homology within the family. Herein, we report the development of the first potent and specific inhibitors of a single Eph isoform, EphB3. Through structural bioinformatic analysis, we identified a cysteine in the hinge region of the EphB3 kinase domain, a feature that is not shared with any other human kinases. We synthesized and characterized a series of electrophilic quinazolines to target this unique, reactive feature in EphB3. Some of the electrophilic quinazolines selectively and potently inhibited EphB3 both in vitro and in cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed the covalent linkage between the protein and the inhibitors. A "clickable" version of an optimized inhibitor was created and employed to verify specific target engagement in the whole proteome and to probe the extent and kinetics of target engagement of existing EphB3 inhibitors. Furthermore, we demonstrate that the autophosphorylation of EphB3 within the juxtamembrane region occurs in trans using a specific inhibitor. These exquisitely specific inhibitors will facilitate the dissection of EphB3's role in various biological processes and disease contribution. PMID- 27478971 TI - Factors influencing the inclusion of oral health education in individualized education plans of children with autism spectrum disorders in Singapore. AB - BACKGROUND: Prevention of oral diseases in children with autism spectrum disorder (ASD) is possible via incorporation of oral health education (OHE) into individualized education plans. OBJECTIVES: To assess (i) whether training can improve teachers' oral heath knowledge, (ii) whether OHE is taught to children with ASD, and (iii) factors associated with teachers' perceived barriers to the implementation of OHE. DESIGN: Teachers working in special schools were recruited. Two pre-tested questionnaires were administered, before and after a training session. The effectiveness of the intervention was evaluated. Teachers were also surveyed on their teaching of caries prevention and perceived barriers of teaching OHE. RESULTS: There was a significant increase in knowledge scores post-intervention (P < 0.001). Teachers were more likely to incorporate OHE into their teaching if trained by dental professionals (P = 0.022) and provided teaching materials (P = 0.001). Teachers' level of baseline OHE knowledge was a predictor and significantly negatively associated with levels of perceived overall and personal barriers (both P < 0.001). CONCLUSION: OHE is included in the curriculum of the schools surveyed, but this is very limited. The training programme increased teachers' oral health knowledge competence scores. Levels of knowledge, lack of training, and teaching materials are barriers to incorporating OHE in their teaching curriculum. PMID- 27478970 TI - Combinatorial epigenetic mechanisms and efficacy of early breast cancer inhibition by nutritive botanicals. AB - AIM: Aberrant epigenetic events are important contributors to the pathogenesis of different types of cancers and dietary botanicals with epigenetic properties can influence early cancer development leading to cancer prevention effects. We sought to investigate potential combinatorial effects of bioactive dietary components including green tea polyphenols (GTPs) and broccoli sprouts (BSp) on neutralizing epigenetic aberrations during breast tumorigenesis. MATERIALS & METHODS: The combinatorial effects were evaluated in a breast cancer transformation cellular system and breast cancer mouse xenografts. RESULTS & CONCLUSION: Combined treatment with epigallocatechin-3-gallate in GTPs and sulforaphane in BSp resulted in a synergistic inhibition of breast cancer cellular growth. Further studies revealed this combination led to genome-wide epigenetic alterations. Combinatorial diets significantly inhibited tumor growth in breast cancer mouse xenografts. Collectively, these studies indicate that combined GTPs and BSp are highly effective in inhibiting early breast cancer development by, at least in part, regulating epigenetic mechanisms. PMID- 27478972 TI - Stroma Insights: Potential Mechanism for Arsenic-Induced Prostate Cancer. PMID- 27478973 TI - The Roadmap to Value-Based Care. PMID- 27478974 TI - Advanced positive airway pressure modes: adaptive servo ventilation and volume assured pressure support. AB - INTRODUCTION: Volume assured pressure support (VAPS) and adaptive servo ventilation (ASV) are non-invasive positive airway pressure (PAP) modes with sophisticated negative feedback control systems (servomechanism), having the capability to self-adjust in real time its respiratory controlled variables to patient's respiratory fluctuations. However, the widespread use of VAPS and ASV is limited by scant clinical experience, high costs, and the incomplete understanding of propriety algorithmic differences in devices' response to patient's respiratory changes. Hence, we will review and highlight similarities and differences in technical aspects, control algorithms, and settings of each mode, focusing on the literature search published in this area. AREAS COVERED: One hundred twenty relevant articles were identified by Scopus, PubMed, and Embase databases from January 2010 to 2016, using a combination of MeSH terms and keywords. Articles were further supplemented by pearling. Recommendations were based on the literature review and the authors' expertise in this area. Expert commentary: ASV and VAPS differ in their respiratory targets and response to a respiratory fluctuation. The VAPS mode targets a more consistent minute ventilation, being recommended in the treatment of sleep related hypoventilation disorders, while ASV mode attempts to provide a more steady breathing airflow pattern, treating successfully most central sleep apnea syndromes. PMID- 27478975 TI - Cationic Intermixing and Reactivity at the La2 Mo2 O9 /La0.8 Sr0.2 MnO3-delta Solid Oxide Fuel Cell Electrolyte-Cathode Interface. AB - Among standard high-temperature cathode materials for solid oxide fuel cells, La0.8 Sr0.2 MnO3-delta (LSM) displays the least reactivity with the oxide-ion conductor La2 Mo2 O9 (LMO), yet a reaction is observed at high processing temperatures, identified by using XRD and focused ion beam secondary-ion mass spectrometry (FIB-SIMS) after annealing at 1050 and 1150 degrees C. Additionally, Sr and Mn solutions were deposited and annealed on LMO pellets, as well as a Mo solution on a LSM pellet. From these studies several reaction products were identified by using XRD and located by using FIB-SIMS on the surface of pelletised samples. We used depth profiling to show that the reactivity extended up to ~10 MUm from the surface region. If Sr was present, a SrMoO4 -type scheelite phase was always observed as a reaction product, and if Mn was present, LaMnO3+delta single crystals were observed on the surface of the LMO pellets. Additional phases such as La2 MoO6 and La6 MoO12 were also detected depending on the configuration and annealing temperature. Reaction mechanisms and detailed reaction formulae are proposed to explain these observations. The strongest driving force for cationic diffusion appears to originate from Mo(6+) and Mn(3+) cations, rather than from Sr(2+) . PMID- 27478976 TI - The protective effect of a satisfying romantic relationship on women's body image after breast cancer: a longitudinal study. AB - OBJECTIVE: To examine the protective role of relationship satisfaction on body image in women with breast cancer throughout the first year post-surgery. METHODS: Seventy-four Swiss patients engaged in a relationship filled out a questionnaire assessing body image disturbance 2 weeks, 3 months, and 1 year after surgery. A univariate latent change score model was used to analyze the evolution of body image disturbance and the contribution of relationship satisfaction to body image disturbance. RESULTS: Women who were satisfied with their relationship reported less body image disturbance than did dissatisfied women at 2 weeks post-surgery. Being married was also associated with less body image disturbance at that time. The protective effect of these relational variables was still observable 1 year later. Changes in body image disturbance over time were explained by the negative impacts of mastectomy and chemotherapy. CONCLUSIONS: How women perceive the impact of breast cancer treatment on their body may be partly determined by the quality of the relational context in which they live. PMID- 27478977 TI - Good collateral circulation predicts favorable outcomes in intravenous thrombolysis: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Baseline collateral status has been correlated with outcomes of acute ischaemic stroke patients receiving intravenous thrombolysis (IVT) in previous studies. We carried out the current systematic review and meta analysis to synthesize currently available evidence regarding such correlations. METHODS: Full-text articles published since 2000 were retrieved and screened. The overall effect sizes of good versus poor collateral status over a series of outcomes and certain baseline features were estimated by random-effects models and presented in risk ratios (RRs) or mean differences. RESULTS: Overall, 28 (3057 patients) and 14 (1584 patients) studies were included in qualitative and quantitative synthesis, respectively. Compared with poor pre-treatment collateral status, good collaterals showed a beneficial effect over the primary outcome of a favorable functional outcome at 3 or 6 months [RR, 2.45; 95% confidence interval, 1.94-3.09; P < 0.001] in acute ischaemic stroke patients receiving IVT treatment. However, such an effect tended to be different between studies with prescribed time windows of 3, 4.5 and > 4.5 h (up to 7 h), with the RRs being 2.21, 2.48 and 5.00, respectively (I2 = 53%). Good pre-treatment collaterals were also associated with a smaller infarct size at baseline, and a lower rate of symptomatic intracranial hemorrhage and a higher rate of neurological improvement early after IVT treatment. CONCLUSIONS: The present study has demonstrated the prognostic value of baseline collateral circulation for outcomes of acute ischaemic stroke patients receiving intravenous reperfusion therapies, studied with different time windows of up to 7 h after ictus for IVT therapy. PMID- 27478978 TI - Photoresponsive hollow molecularly imprinted polymer for the determination of trace bisphenol A in water. AB - A photoresponsive hollow molecularly imprinted polymer (PHMIP) was fabricated for photoresponsive recognition and determination of trace bisphenol A (BPA) in aqueous media using a water-soluble azo compound as the functional monomer. The PHMIP was prepared on sacrificial silica microspheres by surface imprinting and subsequent removal of the silica core. The PHMIP displayed photocontrolled recognition for BPA. SEM, TEM, FT-IR, TGA and N2 adsorption-desorption analyses confirmed successful formation of the hollow structure. The PHMIP displayed higher binding capacity, a larger specific area, and faster mass transfer rate than its corresponding surface molecularly imprinted polymer. The PHMIP was used to determine trace BPA in real samples with a limit of detection of 0.5ppm. For samples spiked at 0-10ppm, the BPA recoveries were in the range of 93.0%-99.0%. This PHMIP-based method provides convenient and inexpensive detection method for trace BPA in environmental samples. This method is especially suitable for determining materials that do not possess specific spectroscopic or luminescent properties. PMID- 27478979 TI - Spectroscopic, structural and in vitro cytotoxicity evaluation of luminescent, lanthanide doped core@shell nanomaterials GdVO4:Eu(3+)5%@SiO2@NH2. AB - The luminescent GdVO4:Eu(3+)5%@SiO2@NH2 core@shell nanomaterials were obtained via co-precipitation method, followed by hydrolysis and co-condensation of silane derivatives: tetraethyl orthosilicate and 3-aminopropyltriethoxysilane. Their effect on human erythrocytes sedimentation and on proliferation of human lung microvascular endothelial cells was examined and discussed. The luminescent nanoparticles were synthesized in the presence of polyacrylic acid or glycerin in order to minimalize the agglomeration and excessive growth of nanostructures. Surface coating with amine functionalized silica shell improved their biocompatibility, facilitated further organic conjugation and protected the internal core. Magnetic measurements revealed an enhanced T1-relaxivity for the synthesized GdVO4:Eu(3+)5% nanostructures. Structure, morphology and average grain size of the obtained nanomaterials were determined by X-ray diffraction, transmission electron microscopy and dynamic light scattering analysis. The qualitative elemental composition of the nanomaterials was established using energy-dispersive X-ray spectroscopy. The spectroscopic characteristic of red emitting core@shell nanophosphors was completed by measuring luminescence spectra and decays. The emission spectra revealed characteristic bands of Eu(3+) ions related to the transitions (5)D0-(7)F0,1,2,3,4 and (5)D1-(7)F1. The luminescence lifetimes consisted of two components, associated with the presence of Eu(3+) ions located at the surface of the crystallites and in the bulk. PMID- 27478980 TI - Function of Sitka spruce stone cells as a physical defence against white pine weevil. AB - Stone cells are a physical defence of conifers against stem feeding insects such as weevils and bark beetles. In Sitka spruce, abundance of stone cells in the cortex of apical shoot tips is associated with resistance to white pine weevil. However, the mode of action by which stone cells interfere with growth and development of weevil larvae is unknown. We developed a bioassay system for testing potential effects of stone cells, which were isolated from resistant trees, on weevil larvae. Bioassays using artificial diet and controlled amounts of stone cells focused on physical defence. We evaluated the effects of stone cells on establishment of neonate larvae, mandible wear and changes in relative growth rates of third instar larvae. Establishment of neonates and relative growth rates of third instars were significantly reduced by stone cells. Stone cells appeared to be indigestible by weevil larvae. Our results suggest that stone cells affect weevil establishment and development by forming a physical feeding barrier against neonate larvae at the site of oviposition, and by reducing access to nutrients in the cortex of resistant trees, which contain an abundance of stone cells in place of a more nutrient rich tissue in susceptible trees. PMID- 27478981 TI - Sodium chlorite increases production of reactive oxygen species that impair the antioxidant system and cause morphological changes in human erythrocytes. AB - Sodium chlorite (NaClO2 ) is used in the production of chlorine dioxide for bleaching and stripping of textiles, pulp, and paper. It is also used as disinfectant in municipal water treatment and as a component in therapeutic rinses and gels. The effect of NaClO2 on human erythrocytes has been studied under in vitro conditions. Incubation of 5% suspension of erythrocytes with NaClO2 (0.1-2.0 mM) at 37 degrees C for 30 min resulted in marked cell lysis (1.2 3.8 fold) and increased their osmotic fragility. Several parameters were assayed in cell lysates prepared from NaClO2 -treated and -untreated (control) erythrocytes. Compared to controls, exposure to NaClO2 caused significant increase in protein oxidation (1.1-8.07 fold), lipid peroxidation (1.08-4.95 fold) with decrease in total sulfhydryl (-5 to -61%), and glutathione levels (-7 to -86%). Methemoglobin content was tremendously increased, by 5-52 fold when compared to control, while methemoglobin reductase activity decreased (-17 to 93%) upon NaClO2 treatment. NaClO2 enhanced the generation of reactive oxygen species by 3-21 fold and lowered the metal reducing and free radical quenching ability of erythrocytes. It also caused an increase in nitric oxide levels (2.7 15.4 fold) showing generation of nitrosative stress too. The activities of major antioxidant and membrane bound enzymes were significantly altered. Gross morphological changes, from discocytes to echinocytes, were seen in NaClO2 treated erythrocytes under electron microscope. These results show that NaClO2 induces oxidative stress in human erythrocytes, damages the membrane, and impairs the cellular antioxidant defence system. This oxidative damage can shorten the life span of erythrocytes in blood resulting in red cell senescence. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1343-1353, 2017. PMID- 27478982 TI - Diffusing Diffusivity: Survival in a Crowded Rearranging and Bounded Domain. AB - We consider a particle diffusing in a bounded, crowded, rearranging medium. The rearrangement happens on a time scale longer than the typical time scale of diffusion of the particle; as a result, effectively, the diffusion coefficient of the particle varies as a stochastic function of time. What is the probability that the particle will survive within the bounded region, given that it is absorbed the first time it hits the boundary of the region in which it diffuses? This question is of great interest in a variety of chemical and biological problems. If the diffusion coefficient is a constant, then analytical solutions for a variety of cases are available in the literature. However, there is no solution available for the case in which the diffusion coefficient is a random function of time. We discuss a class of models for which it is possible to find analytical solutions to the problem. We illustrate the method for a circular, two dimensional region, but our methods are easy to apply to diffusion in arbitrary dimensions and spherical/rectangular regions. Our solution shows that if the dimension of the region is large, then only the average value of the diffusion coefficient determines the survival probability. However, for smaller-sized regions, one would be able to see the effects of the stochasticity of the diffusion coefficient. We also give generalizations of the results to N dimensions. PMID- 27478983 TI - Group-based parent training programmes for improving emotional and behavioural adjustment in young children. AB - BACKGROUND: Emotional and behavioural problems in children are common. Research suggests that parenting has an important role to play in helping children to become well-adjusted, and that the first few months and years are especially important. Parenting programmes may have a role to play in improving the emotional and behavioural adjustment of infants and toddlers, and this review examined their effectiveness with parents and carers of young children. OBJECTIVES: 1. To establish whether group-based parenting programmes are effective in improving the emotional and behavioural adjustment of young children (maximum mean age of three years and 11 months); and2. To assess whether parenting programmes are effective in the primary prevention of emotional and behavioural problems. SEARCH METHODS: In July 2015 we searched CENTRAL (the Cochrane Library), Ovid MEDLINE, Embase (Ovid), and 10 other databases. We also searched two trial registers and handsearched reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA: Two reviewers independently assessed the records retrieved by the search. We included randomised controlled trials (RCTs) and quasi-RCTs of group-based parenting programmes that had used at least one standardised instrument to measure emotional and behavioural adjustment in children. DATA COLLECTION AND ANALYSIS: One reviewer extracted data and a second reviewer checked the extracted data. We presented the results for each outcome in each study as standardised mean differences (SMDs) with 95% confidence intervals (CIs). Where appropriate, we combined the results in a meta-analysis using a random-effects model. We used the GRADE (Grades of Recommendations, Assessment, Development, and Evaluation) approach to assess the overall quality of the body of evidence for each outcome. MAIN RESULTS: We identified 22 RCTs and two quasi-RCTs evaluating the effectiveness of group-based parenting programmes in improving the emotional and behavioural adjustment of children aged up to three years and 11 months (maximum mean age three years 11 months).The total number of participants in the studies were 3161 parents and their young children. Eight studies were conducted in the USA, five in the UK, four in Canada, five in Australia, one in Mexico, and one in Peru. All of the included studies were of behavioural, cognitive-behavioural or videotape modelling parenting programmes.We judged 50% (or more) of the included studies to be at low risk for selection bias, detection bias (observer-reported outcomes), attrition bias, selective reporting bias, and other bias. As it is not possible to blind participants and personnel to the type of intervention in these trials, we judged all studies to have high risk of performance bias. Also, there was a high risk of detection bias in the 20 studies that included parent-reported outcomes.The results provide evidence that group-based parenting programmes reduce overall emotional and behavioural problems (SMD -0.81, 95% CI -1.37 to -0.25; 5 studies, 280 participants, low quality evidence) based on total parent-reported data assessed at postintervention. This result was not, however, maintained when two quasi-RCTs were removed as part of a sensitivity analysis (SMD -0.67, 95% CI -1.43 to 0.09; 3 studies, 221 participants). The results of data from subscales show evidence of reduced total externalising problems (SMD -0.23, 95% CI -0.46 to -0.01; 8 studies, 989 participants, moderate quality evidence). Single study results show very low quality evidence of reductions in externalising problems hyperactivity inattention subscale (SMD -1.34; 95% CI -2.37 to -0.31; 19 participants), low quality evidence of no effect on total internalising problems (SMD 0.34; 95% CI 0.12 to 0.81; 73 participants), and very low quality evidence of an increase in social skills (SMD 3.59; 95% CI 2.42 to 4.76; 32 participants), based on parent reported data assessed at postintervention. Results for secondary outcomes, which were also measured using subscales, show an impact on parent-child interaction in terms of reduced negative behaviour (SMD -0.22, 95% CI -0.39 to -0.06; 7 studies, 941 participants, moderate quality evidence), and improved positive behaviour (SMD 0.48, 95% CI 0.17 to 0.79; 4 studies, 173 participants, moderate quality evidence) as rated by independent observers postintervention. No further meta analyses were possible. Results of subgroup analyses show no evidence for treatment duration (seven weeks or less versus more than eight weeks) and inconclusive evidence for prevention versus treatment interventions. AUTHORS' CONCLUSIONS: The findings of this review, which relate to the broad group of universal and at-risk (targeted) children and parents, provide tentative support for the use of group-based parenting programmes to improve the overall emotional and behavioural adjustment of children with a maximum mean age of three years and 11 months, in the short-term. There is, however, a need for more research regarding the role that these programmes might play in the primary prevention of both emotional and behavioural problems, and their long-term effectiveness. PMID- 27478987 TI - Positive correlation of HIV infection with Giardia intestinalis assemblage B but not with assemblage A in asymptomatic Kenyan children. AB - A cross-sectional molecular epidemiological study of Giardia intestinalis infection was conducted among asymptomatic Kenyan children with (n = 123) and without (n = 111) HIV infection. G. intestinalis assemblage B infection was positively correlated with HIV infection [HIV (+), 18.7% vs. HIV (-), 11.7%; P = 0.013], whereas assemblage A infection was not [HIV (+), 4.1% vs. HIV (-), 6.3%; P = 0.510]. Thus, HIV infection is a risk factor for G. intestinalis assemblage B infection but not for assemblage A infection. PMID- 27478988 TI - Chronic health conditions in Medicare beneficiaries 65 years old, and older with HIV infection. AB - OBJECTIVES: To examine sociodemographic factors and chronic health conditions of people living with HIV (PLWHIV/HIV+) at least 65 years old and compare their chronic disease prevalence with beneficiaries without HIV. DESIGN: National fee for-service Medicare claims data (parts A and B) from 2006 to 2009 were used to create a retrospective cohort of beneficiaries at least 65 years old. METHODS: Beneficiaries with an inpatient or skilled nursing facility claim, or outpatient claims with HIV diagnosis codes were considered HIV+. HIV+ beneficiaries were compared with uninfected beneficiaries on demographic factors and on the prevalence of hypertension, hyperlipidemia, ischemic heart disease, rheumatoid arthritis/osteoarthritis, and diabetes. Odds ratios (OR), 95% confidence intervals (CIs), and P values were calculated. Adjustment variables included age, sex, race/ethnicity, end stage renal disease (ESRD), and dual Medicare-Medicaid enrollment. Chronic conditions were examined individually and as an index from zero to all five conditions. RESULTS: Of 29 060 418 eligible beneficiaries, 24 735 (0.09%) were HIV+. HIV+ beneficiaries were more likely to be Hispanic, African-American, male, and younger (P > 0.0001) and were 1.5-2.1 times as likely to have a chronic disease [diabetes (adjusted OR) 1.51, 95% CI (1.47, 1.55): rheumatoid arthritis/osteoarthritis 2.14, 95% CI (2.08, 2.19)], and 2.4-7 times as likely to have 1-5 comorbid chronic conditions [1 condition (adjusted OR) 2.38, 95% CI (2.21, 2.57): 5 conditions 7.07, 95% CI (6.61, 7.56)]. CONCLUSION: Our results show that PLWHIV at least 65 years old are at higher risk of comorbidities than other fee-for-service Medicare beneficiaries. This finding has implications for the cost and health management of PLWHIV 65 years and older. PMID- 27478989 TI - Three-Fold Scholl-Type Cycloheptatriene Ring Formation around a Tribenzotriquinacene Core: Toward Warped Graphenes. AB - A nonplanar polycyclic aromatic compound 6 bearing a tribenzotriquinacene (TBTQ) core merged with an o,p,o,p,o,p-hexaphenylene belt was prepared and characterized by NMR spectroscopy and X-ray crystallography. The key synthesis step involves three Scholl-type cycloheptatriene ring formation steps of the 1,4,8-tris(3',4' dimethoxyphenyl)-TBTQ derivative 5. The bridging of each of the three TBTQ bays by 1,2-phenylene units in compound 6 gives rise to an unusual wizard hat shaped structure, which represents a promising key intermediate for the construction of nonplanar nanographene molecules bearing a TBTQ core. PMID- 27478985 TI - Formation of polarity convergences underlying shoot outgrowths. AB - The development of outgrowths from plant shoots depends on formation of epidermal sites of cell polarity convergence with high intracellular auxin at their centre. A parsimonious model for generation of convergence sites is that cell polarity for the auxin transporter PIN1 orients up auxin gradients, as this spontaneously generates convergent alignments. Here we test predictions of this and other models for the patterns of auxin biosynthesis and import. Live imaging of outgrowths from kanadi1 kanadi2 Arabidopsis mutant leaves shows that they arise by formation of PIN1 convergence sites within a proximodistal polarity field. PIN1 polarities are oriented away from regions of high auxin biosynthesis enzyme expression, and towards regions of high auxin importer expression. Both expression patterns are required for normal outgrowth emergence, and may form part of a common module underlying shoot outgrowths. These findings are more consistent with models that spontaneously generate tandem rather than convergent alignments. PMID- 27478990 TI - 3,4-Dialkoxypyrrole for the Formation of Bioinspired Rose Petal-like Substrates with High Water Adhesion. AB - Self-organization is commonly present in nature and can lead to the formation of surface structures with different wettabilities. Indeed, in nature superhydrophobic (low water adhesion) and parahydrophobic (high water adhesion) properties exist, such as in lotus leaves and red roses, respectively. The aim of this work is to prepare parahydrophobic properties by electrodeposition. For this, pyrrole derivatives with two alkoxy groups of various lengths (from 1 to 12) were synthesized in 8 steps by adapting a method developed by Merz et al. We show that the alkyl chain length has a huge influence on the polymer solubility and as a consequence on the surface morphology and hydrophobicity. Moreover, the alkyl chain length should be at least greater than eight carbons in order to obtain parahydrophobic properties. The properties are also controlled by the electrolyte nature. These materials can be used for many potential applications in water harvesting and transportation and separation membranes. PMID- 27478984 TI - Coherent diffraction of single Rice Dwarf virus particles using hard X-rays at the Linac Coherent Light Source. AB - Single particle diffractive imaging data from Rice Dwarf Virus (RDV) were recorded using the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS). RDV was chosen as it is a well-characterized model system, useful for proof-of-principle experiments, system optimization and algorithm development. RDV, an icosahedral virus of about 70 nm in diameter, was aerosolized and injected into the approximately 0.1 MUm diameter focused hard X ray beam at the CXI instrument of LCLS. Diffraction patterns from RDV with signal to 5.9 Angstrom were recorded. The diffraction data are available through the Coherent X-ray Imaging Data Bank (CXIDB) as a resource for algorithm development, the contents of which are described here. PMID- 27478991 TI - Electron Transfer in Bacterial Reaction Centers with the Photoactive Bacteriopheophytin Replaced by a Bacteriochlorophyll through Coordinating Ligand Substitution. AB - The influence of amino acid substitutions at position M214 (M-subunit, residue 214) on the rate and pathway of electron transfer involving the bacteriopheophytin cofactor, HA, in a bacterial photosynthetic reaction center has been explored in a series of Rhodobacter sphaeroides mutants. The M214 leucine (L) residue of the wild type was replaced with histidine (H), glutamine (Q), and asparagine (N), creating the mutants M214LH, M214LQ, and M214LN, respectively. As has been reported previously for M214LH, each of these mutations resulted in a bacteriochlorophyll molecule in place of a bacteriopheophytin in the HA pocket, forming so-called beta-type mutants (in which the HA cofactor is called betaA). In addition, these mutations changed the properties of the surrounding protein environment in terms of charge distribution and the amino acid side chain volume. Electron transfer reactions from the excited primary donor P to the acceptor QA were characterized using ultrafast transient absorption spectroscopic techniques. Similar to that of the previously characterized M214LH (beta mutant), the strong energetic mixing of the P(+)BA(-) and P(+)betaA(-) states (the mixed anion is denoted I(-)) increased the rate of charge recombination between P(+) and I(-) in competition with the I(-) -> QA forward reaction. This reduced the overall yield of charge separation forming the P(+)QA(-) state. While the kinetics of the primary electron transfer forming P(+)I(-) were essentially identical in all three beta mutants, the rates of the betaA(-) (I(-)) -> QA electron transfer in M214LQ and M214LH were very similar but quite different from that of the M214LN mutant. The observed yield changes and the differences in kinetics are correlated more closely with the volume of the mutated amino acid than with their charge characteristics. These results are consistent with those of previous studies of a series of M214 mutants with different sizes of amino acid side chains that did not alter the HA cofactor composition [Pan, J., et al. (2013) J. Phys. Chem. B 117, 7179-7189]. Both studies indicate that protein relaxation in this region of the reaction center plays a key role in stabilizing charge-separated states involving the HA or betaA cofactor. The effect is particularly pronounced for reactions occurring on time scales of tens and hundreds of picoseconds (forward transfer to the QA and charge recombination). PMID- 27478993 TI - Modulating the Electronic Properties of Monolayer Graphene Using a Periodic Quasi One-Dimensional Potential Generated by Hex-Reconstructed Au(001). AB - The structural and electronic properties of monolayer graphene synthesized on a periodically reconstructed substrate can be widely modulated by the generation of superstructure patterns, thereby producing interesting physical properties, such as magnetism and superconductivity. Herein, using a facile chemical vapor deposition method, we successfully synthesized high-quality monolayer graphene with a uniform thickness on Au foils. The hex-reconstruction of Au(001), which is characterized by striped patterns with a periodicity of 1.44 nm, promoted the formation of a quasi-one-dimensional (1D) graphene superlattice, which served as a periodic quasi-1D modulator for the graphene overlayer, as evidenced by scanning tunneling microscopy/spectroscopy. Intriguingly, two new Dirac points were generated for the quasi-1D graphene superlattice located at -1.73 +/- 0.02 and 1.12 +/- 0.12 eV. Briefly, this work demonstrates that the periodic modulation effect of reconstructed metal substrates can dramatically alter the electronic properties of graphene and provides insight into the modulation of these properties using 1D potentials. PMID- 27478992 TI - In Vitro Reconstruction of Nonribosomal Peptide Biosynthesis Directly from DNA Using Cell-Free Protein Synthesis. AB - Genome sequencing has revealed that a far greater number of natural product biosynthetic pathways exist than there are known natural products. To access these molecules directly and deterministically, a new generation of heterologous expression methods is needed. Cell-free protein synthesis has not previously been used to study nonribosomal peptide biosynthesis, and provides a tunable platform with advantages over conventional methods for protein expression. Here, we demonstrate the use of cell-free protein synthesis to biosynthesize a cyclic dipeptide with correct absolute stereochemistry. From a single-pot reaction, we measured the expression of two nonribosomal peptide synthetases larger than 100 kDa, and detected high-level production of a diketopiperazine. Using quantitative LC-MS and synthetically prepared standard, we observed production of this metabolite at levels higher than previously reported from cell-based recombinant expression, approximately 12 mg/L. Overall, this work represents a first step to apply cell-free protein synthesis to discover and characterize new natural products. PMID- 27478994 TI - Protein Chips Compatible with MALDI Mass Spectrometry Prepared by Ambient Ion Landing. AB - We present a technology that allows the preparation of matrix-assisted laser desorption/ionization (MALDI)-compatible protein chips by ambient ion landing of proteins and successive utilization of the resulting protein chips for the development of bioanalytical assays. These assays are based on the interaction between the immobilized protein and the sampled analyte directly on the protein chip and subsequent in situ analysis by MALDI mass spectrometry. The electrosprayed proteins are immobilized on dry metal and metal oxide surfaces, which are nonreactive under normal conditions. The ion landing of electrosprayed protein molecules is performed under atmospheric pressure by an automated ion landing apparatus that can manufacture protein chips with a predefined array of sample positions or any other geometry of choice. The protein chips prepared by this technique are fully compatible with MALDI ionization because the metal-based substrates are conductive and durable enough to be used directly as MALDI plates. Compared to other materials, the nonreactive surfaces show minimal nonspecific interactions with chemical species in the investigated sample and are thus an ideal substrate for selective protein chips. Three types of protein chips were used in this report to demonstrate the bioanalytical applications of ambient ion landing. The protein chips with immobilized proteolytic enzymes showed the usefulness for fast in situ peptide MALDI sequencing; the lectin-based protein chips showed the ability to enrich glycopeptides from complex mixtures with subsequent MALDI analysis, and the protein chips with immobilized antibodies were used for a novel immunoMALDI workflow that allowed the enrichment of antigens from the serum followed by highly specific MALDI detection. PMID- 27478995 TI - Photocatalytic Hydrogen Generation by CdSe/CdS Nanoparticles. AB - The photocatalytic hydrogen (H2) production activity of various CdSe semiconductor nanoparticles was compared including CdSe and CdSe/CdS quantum dots (QDs), CdSe quantum rods (QRs), and CdSe/CdS dot-in-rods (DIRs). With equivalent photons absorbed, the H2 generation activity orders as CdSe QDs ? CdSe QRs > CdSe/CdS QDs > CdSe/CdS DIRs, which is surprisingly the opposite of the electron hole separation efficiency. Calculations of photoexcited surface charge densities are positively correlated with the H2 production rate and suggest the size of the nanoparticle plays a critical role in determining the relative efficiency of H2 production. PMID- 27478996 TI - Reversible Oligonucleotide Chain Blocking Enables Bead Capture and Amplification of T-Cell Receptor alpha and beta Chain mRNAs. AB - Next-generation sequencing (NGS) has proven to be an exceptionally powerful tool for studying genetic variation and differences in gene expression profiles between cell populations. However, these population-wide studies are limited by their inability to detect variation between individual cells within a population, inspiring the development of single-cell techniques such as Drop-seq, which add a unique barcode to the mRNA from each cell prior to sequencing. Current Drop-seq technology enables capture, amplification, and barcoding of the entire mRNA transcriptome of individual cells. NGS can then be used to sequence the 3'-end of each message to build a cell-specific transcriptional landscape. However, current technology does not allow high-throughput capture of information distant from the mRNA poly-A tail. Thus, gene profiling would have much greater utility if beads could be generated having multiple transcript-specific capture sequences. Here we report the use of a reversible chain blocking group to enable synthesis of DNA barcoded beads having capture sequences for the constant domains of the T-cell receptor alpha and beta chain mRNAs. We demonstrate that these beads can be used to capture and pair TCRalpha and TCRbeta sequences from total T-cell RNA, enabling reverse transcription and PCR amplification of these sequences. This is the first example of capture beads having more than one capture sequence, and we envision that this technology will be of high utility for applications such as pairing the antigen receptor chains that give rise to autoimmune diseases or measuring the ratios of mRNA splice variants in cancer stem cells. PMID- 27478998 TI - The Presence and Duration of Overweight Are Associated with Low-Grade Inflammation in Prepubertal Chilean Children. AB - BACKGROUND: Overweight is associated with low-grade inflammation, but it is under debate whether the effect of fat mass accumulation is acute or chronic. We aimed to study the association of overweight duration with low-grade inflammation in children in whom overweight initiation can be established. METHODS: Observational longitudinal study, including a subsample of 250 Chilean children from the Growth and Obesity Cohort Study followed-up yearly since preschool age (n = 1195). At 4 years, 324 children provided blood. From those, 272 participants were evaluated at 7 years. The current analysis includes 250 children with a blood sample at 4 and 7 years of age and C-reactive protein (CRP) <5 mg/L. Anthropometric data (0-4 years) were obtained from health records and measured thereafter; sex- and age specific body mass index Z-scores (BAZ) were computed. Among overweight (BAZ >= 1) participants at 7 years, the duration of overweight (time since diagnosis) was computed and categorized according to tertiles: <36, 36-<72, or >=72 months. The independent association between overweight (diagnosis and duration) and low-grade inflammation (CRP >= 1 mg/L) was studied (logistic regression models). RESULTS: Overweight was associated with CRP >= 1 mg/L at 7 years [odds ratio (OR) = 2.93 confidence interval (95% CI = 1.60-5.38)], but not at 4 years [OR = 1.26 (95% CI = 0.71-2.26)]. An overweight duration <36 m was independently associated with CRP >= 1 mg/L [OR = 3.53 (95% CI = 1.21-10.28)] (reference = normal weight), whereas longer overweight durations (36-<72 or >=72 m) were not associated with CRP >= 1 mg/L [OR = 1.35 (95% CI = 0.41-4.40) and OR = 1.21 (95% CI = 0.35-4.18), respectively]. CONCLUSIONS: Overweight at 7 years of age was associated with low grade inflammation only in the case of recent onset. Inflammatory disturbances may be associated with the early phases of excess weight. PMID- 27478997 TI - Acute Kidney Injury, Risk Factors, and Prognosis in Hospitalized HIV-Infected Adults in South Africa, Compared by Tenofovir Exposure. AB - There are limited data describing acute kidney injury (AKI) in HIV-infected adult patients in resource-limited settings where tenofovir disoproxil fumarate (TDF), which is potentially nephrotoxic, is increasingly prescribed. We describe risk factors for and prognosis of AKI in HIV-infected individuals, stratified by those receiving and those naive to TDF. A prospective case cohort study of hospitalized HIV-infected adults with AKI stratified by TDF exposure. Adults (>=18 years) were recruited: clinical and biochemical data were collected at admission; their renal recovery, discharge, or mortality was ascertained as an in-patient and, subsequently, to a scheduled 3-month follow-up. Among this predominantly female (61%), almost exclusively black African cohort of 175 patients with AKI, 93 (53%) were TDF exposed; median age was 41 years (interquartile range 35-50). Median CD4 count and viral load and creatinine at baseline were 116 cells/mm3 and 110,159 copies/ml, respectively. A greater proportion of the TDF group had severe AKI on admission (61% vs. 43%, p = .014); however, both groups had similar rates of newly diagnosed tuberculosis (TB; 52%) and nonsteroidal anti-inflammatory drug (NSAID; 32%) use. Intravenous fluid was the therapeutic mainstay; only seven were dialyzed. Discharge median serum creatinine (SCr) was higher in the TDF group (p = .032) and fewer in the TDF group recovered renal function after 3 months (p = .043). Three-month mortality was 27% in both groups, but 55% of deaths occurred in hospital. Those that died had a higher SCr and more severe AKI than survivors; TB was diagnosed in 33 (70%) of those who died. AKI was more severe and renal recovery slower in the TDF group; comorbidities, risk factors, and prognosis were similar regardless of TDF exposure. Because TB is linked to higher mortality, TB coinfection in HIV-infected patients with AKI warrants more intensive monitoring. In all those with poor renal recovery, our data suggest that a lower threshold for dialysis is needed. PMID- 27478999 TI - Heterostructures based on graphene and MoS2 layers decorated by C60 fullerenes. AB - Here we present a comprehensive investigation of various novel composite structures based on graphene (G) and molybdenum disulphide (MoS2) monolayers decorated by C60 fullerenes, which can be successfully applied in photovoltaics as a solar cell unit. Theoretical studies of the atomic structure, stability and electronic properties of the proposed G/C60, MoS2/C60 and G/MoS2/C60/G nanostructures were carried out. We show that making the G/MoS2/C60/G heterostructure from the 2D films considered here will lead to the appearance of particular properties suitable for application in photovoltaics due to the broad energetic region of high electronic density of states. PMID- 27479000 TI - Influence of oxygen on nitrogen-doped carbon nanofiber growth directly on nichrome foil. AB - The synthesis of various nitrogen-doped (N-doped) carbon nanostructures has been significantly explored as an alternative material for energy storage and metal free catalytic applications. Here, we reveal a direct growth technique of N-doped carbon nanofibers (CNFs) on flexible nichrome (NiCr) foil using melamine as a solid precursor. Highly reactive Cr plays a critical role in the nanofiber growth process on the metal alloy foil in an atmospheric pressure chemical vapor deposition (APCVD) process. Oxidation of Cr occurs in the presence of oxygen impurities, where Ni nanoparticles are formed on the surface and assist the growth of nanofibers. Energy-dispersive x-ray spectroscopy (EDXS) and x-ray photoelectron spectroscopy (XPS) clearly show the transformation process of the NiCr foil surface with annealing in the presence of oxygen impurities. The structural change of NiCr foil assists one-dimensional (1D) CNF growth, rather than the lateral two-dimensional (2D) growth. The incorporation of distinctive graphitic and pyridinic nitrogen in the graphene lattice are observed in the synthesized nanofiber, owing to better nitrogen solubility. Our finding shows an effective approach for the synthesis of highly N-doped carbon nanostructures directly on Cr-based metal alloys for various applications. PMID- 27479002 TI - Relationship between Anxiety and Burnout among Chinese Physicians: A Moderated Mediation Model. AB - OBJECTIVE: The main goal of this research was to investigate the complex relationships among coping styles, personality, burnout, and anxiety using a moderated mediation analysis. METHODS: A random cluster sampling procedure was used to select a total of 1274 physicians from two tertiary grade A hospitals in Heilongjiang Province, which is located in northeast China. The Zung Self-Rating Anxiety Scale (SAS), Chinese Maslach Burnout Inventory (CMBI), Chinese version of the EPQ-revised Short Scale, and the Trait Coping Style Questionnaire (TCSQ) were used to gather data. Moderated mediation analysis was used in this study; it was executed using the PROCESS macro so that the mediators and moderator could function together in the same model. RESULTS: The prevalence of anxiety symptoms among the physicians was 31%, and there were no differences between the sexes. The results showed that positive and negative coping styles partially mediated the association between burnout and anxiety symptoms in physicians. The mediated effect of positive coping styles was moderated by Eysenck's Psychoticism traits. CONCLUSIONS: Personality traits moderate the strength of the relationships between burnout and anxiety mediated by positive coping styles; however, personality traits do not moderate the strength of the relationships between burnout and anxiety mediated by negative coping styles. PMID- 27479003 TI - Direct Photolysis of Fluoroquinolone Antibiotics at 253.7 nm: Specific Reaction Kinetics and Formation of Equally Potent Fluoroquinolone Antibiotics. AB - Three fluoroquinolone-to-fluoroquinolone antibiotic transformations were monitored during UV-C irradiation processes. In particular, the following reactions were observed: enrofloxacin-to-ciprofloxacin, difloxacin-to sarafloxacin, and pefloxacin-to-norfloxacin. The apparent molar absorptivity and fluence-based pseudo-first-order rate constants for transformation of the six fluoroquinolones by direct photolysis at 253.7 nm were determined for the pH 2-12 range. These parameters were deconvoluted to calculate specific molar absorptivity and fluence-based rate constants for cationic, zwitterionic, and anionic fluoroquinolone species. For a typical disinfection fluence of 40 mJ/cm(2), the apparent transformation efficiencies were inflated by 2-8% when fluoroquinolone products were not considered; moreover, the overall transformation efficiencies at 400 mJ/cm(2) varied by up to 40% depending on pH. The three product antibiotics, namely ciprofloxacin, sarafloxacin, and norfloxacin, were found to be equally or more potent than the parent fluoroquinolones using an Escherichia coli-based assay. UV treatment of a solution containing difloxacin was found to increase antimicrobial activity due to formation of sarafloxacin. These results highlight the importance of considering antibiotic-to-antibiotic transformations in UV-based processes. PMID- 27479001 TI - Diet-Induced Maternal Obesity Alters Insulin Signalling in Male Mice Offspring Rechallenged with a High-Fat Diet in Adulthood. AB - Modern lifestyle has resulted in an increase in the prevalence of obesity and its comorbidities in pregnant women and the young population. It has been well established that the consumption of a high-fat diet (HFD) has many direct effects on glucose metabolism. However, it is important to assess whether maternal consumption of a HFD during critical periods of development can lead to metabolic changes in the offspring metabolism. This study evaluated the potential effects of metabolic programming on the impairment of insulin signalling in recently weaned offspring from obese dams. Additionally, we investigated if early exposure to an obesogenic environment could exacerbate the impairment of glucose metabolism in adult life in response to a HFD. Swiss female mice were fed with Standard Chow (SC) or a HFD during gestation and lactation and tissues from male offspring were analysed at d28 and d82. Offspring from obese dams had greater weight gain and higher adiposity and food intake than offspring from control dams. Furthermore, they showed impairment in insulin signalling in central and peripheral tissues, which was associated with the activation of inflammatory pathways. Adipose tissue was ultimately the most affected in adult offspring after HFD rechallenge; this may have contributed to the metabolic deregulation observed. Overall, our results suggest that diet-induced maternal obesity leads to increased susceptibility to obesity and impairment of insulin signalling in offspring in early and late life that cannot be reversed by SC consumption, but can be aggravated by HFD re-exposure. PMID- 27479004 TI - Manikin-based simulation: online orientation and student anxiety. AB - OBJECTIVE: This study examined changes in anxiety associated with different modes of student orientation to a manikin-based simulation lab. It was purposed that the addition of an online orientation prior to the actual lab would save time for more learning content during the session. METHODS: Anxiety scores were gathered from groups of interns, using a visual analog scale. Some students experienced a 30-minute in-person orientation while others completed an online module. One-way analysis of variance and the Kruskal-Wallis test were used for analysis. RESULTS: Mean anxiety scores were not statistically different (chi2 = 2.51, p = .29) between the group that received a 30-minute in-person orientation and the online group. At the end of the entire introductory phase, there was a significant difference between year cohorts (F = 9.61, p < .001), indicating overall higher anxiety for one of the years receiving in-person orientation. However, when looking at the remaining in-person orientation year vs the online module year, there was no significant difference seen (p = .56). CONCLUSIONS: Successful transition, resulting in substantial gain to learning time, was observed by changing an in-person orientation to an online format. Anxiety levels were noted to fluctuate significantly from year to year regardless of orientation method. PMID- 27479005 TI - New Perspectives on Ebola Virus Evolution. AB - Since the recent devastating outbreak of Ebola virus disease in western Africa, there has been significant effort to understand the evolution of the deadly virus that caused the outbreak. There has been a considerable investment in sequencing Ebola virus (EBOV) isolates, and the results paint an important picture of how the virus has spread in western Africa. EBOV evolution cannot be understood outside the context of previous outbreaks, however. We have focused this study on the evolution of the EBOV glycoprotein gene (GP) because one of its products, the spike glycoprotein (GP1,2), is central to the host immune response and because it contains a large amount of the phylogenetic signal for this virus. We inferred the maximum likelihood phylogeny of 96 nonredundant GP gene sequences representing each of the outbreaks since 1976 up to the end of 2014. We tested for positive selection and considered the placement of adaptive amino acid substitutions along the phylogeny and within the protein structure of GP1,2. We conclude that: 1) the common practice of rooting the phylogeny of EBOV between the first known outbreak in 1976 and the next outbreak in 1995 provides a misleading view of EBOV evolution that ignores the fact that there is a non-human EBOV host between outbreaks; 2) the N-terminus of GP1 may be constrained from evolving in response to the host immune system by the highly expressed, secreted glycoprotein, which is encoded by the same region of the GP gene; 3) although the mucin-like domain of GP1 is essential for EBOV in vivo, it evolves rapidly without losing its twin functions: providing O-linked glycosylation sites and a flexible surface. PMID- 27479006 TI - Enabling N-to-C Ser/Thr Ligation for Convergent Protein Synthesis via Combining Chemical Ligation Approaches. AB - In this article, Ser/Thr ligation(on/off) has been realized to enable N-to-C successive peptide ligations using a salicylaldehyde semicarbazone (SAL(off)) group by in situ activation with pyruvic acid of the peptide SAL(off) ester into the peptide salicylaldehyde (SAL(on)) ester. In addition, a peptide with a C terminal thioester and N-terminal Ser or Thr as the middle peptide segment can undergo one-pot Ser/Thr ligation and native chemical ligation in the N-to-C direction. The utility of this combined ligation strategy in the N-to-C direction has been showcased through the convergent assembly of a human cytokine protein sequence, GlcNAcylated interleukin-25. PMID- 27479007 TI - Melting-Freezing Transition of Monolayer Water Confined by Phosphorene Plates. AB - The two-dimensional material phosphorene has become a focus of the scientific community recently. On the basis of molecular dynamics simulations, we utilize phosphorene as a model material to study the behavior of water molecules confined by two phosphorene plates with nonflat surfaces. As the relative position of the two plates changes, the water molecules first stay in a melting process at 230 K and then exhibit a freezing process. The disparate variations of local confinements induced by the mismatch of the two plates are the key for understanding this extraordinary behavior of water. Our results imply that such nonflat surfaces could be an important factor for understanding or controlling the dynamics of water. The phenomena reported here may enrich the knowledge of water and inspire more applications of similar materials. PMID- 27479008 TI - Characterization of Three Novel Fatty Acid- and Retinoid-Binding Protein Genes (Ha-far-1, Ha-far-2 and Hf-far-1) from the Cereal Cyst Nematodes Heterodera avenae and H. filipjevi. AB - Heterodera avenae and H. filipjevi are major parasites of wheat, reducing production worldwide. Both are sedentary endoparasitic nematodes, and their development and parasitism depend strongly on nutrients obtained from hosts. Secreted fatty acid- and retinol-binding (FAR) proteins are nematode-specific lipid carrier proteins used for nutrient acquisition as well as suppression of plant defenses. In this study, we obtained three novel FAR genes Ha-far-1 (KU877266), Ha-far-2 (KU877267), Hf-far-1 (KU877268). Ha-far-1 and Ha-far-2 were cloned from H. avenae, encoding proteins of 191 and 280 amino acids with molecular masses about 17 and 30 kDa, respectively and sequence identity of 28%. Protein Blast in NCBI revealed that Ha-FAR-1 sequence is 78% similar to the Gp FAR-1 protein from Globodera pallida, while Ha-FAR-2 is 30% similar to Rs-FAR-1 from Radopholus similis. Only one FAR protein Hf-FAR-1was identified in H. filipjevi; it had 96% sequence identity to Ha-FAR-1. The three proteins are alpha helix-rich and contain the conserved domain of Gp-FAR-1, but Ha-FAR-2 had a remarkable peptide at the C-terminus which was random-coil-rich. Both Ha-FAR-1 and Hf-FAR-1 had casein kinase II phosphorylation sites, while Ha-FAR-2 had predicted N-glycosylation sites. Phylogenetic analysis showed that the three proteins clustered together, though Ha-FAR-1 and Hf-FAR-1 adjoined each other in a plant-parasitic nematode branch, but Ha-FAR-2 was distinct from the other proteins in the group. Fluorescence-based ligand binding analysis showed the three FAR proteins bound to a fluorescent fatty acid derivative and retinol and with dissociation constants similar to FARs from other species, though Ha-FAR-2 binding ability was weaker than that of the two others. In situ hybridization detected mRNAs of Ha-far-1 and Ha-far-2 in the hypodermis. The qRT-PCR results showed that the Ha-far-1and Ha-far-2 were expressed in all developmental stages; Ha-far-1 expressed 70 times more than Ha-far-2 in all stages. The highest expression level of Ha-far-1 was observed in fourth-stage juvenile (J4), whereas the highest expression level of Ha-far-2 occurred in second-stage juvenile (J2). In conclusion, we have identified two novel far genes from H. avenae and one from H. filipjevi and have provided further indication that nematode far genes are present in a variety of nematode species, where the FAR proteins share similar basic structure, expression pattern and biochemical activities. PMID- 27479009 TI - The Effect of Aging on Relationships between Lean Body Mass and VO2max in Rowers. AB - Aging is associated with a fall in maximal aerobic capacity as well as with a decline in lean body mass. The purpose of the study was to investigate the influence of aging on the relationship between aerobic capacity and lean body mass in subjects that chronically train both their upper and lower bodies. Eleven older rowers (58+/-5 yrs) and 11 younger rowers (27+/-4 yrs) participated in the study. Prior to the VO2max testing, subjects underwent a dual energy X-ray absorptiometry scan to estimate total lean body mass. Subsequently, VO2max was quantified during a maximal exercise test on a rowing ergometer as well as a semi recumbent cycle ergometer. The test protocol included a pre-exercise stage followed by incremental exercise until VO2max was reached. The order of exercise modes was randomized and there was a wash-out period between the two tests. Oxygen uptake was obtained via a breath-by-breath metabolic cart (VmaxTM Encore, San Diego, CA). Rowing VO2max was higher than cycling VO2max in both groups (p<0.05). Older subjects had less of an increase in VO2max from cycling to rowing (p<0.05). There was a significant relationship between muscle mass and VO2max for both groups (p<0.05). After correcting for muscle mass, the difference in cycling VO2max between groups disappeared (p>0.05), however, older subjects still demonstrated a lower rowing VO2max relative to younger subjects (p<0.05). Muscle mass is associated with the VO2max obtained, however, it appears that VO2max in older subjects may be less influenced by muscle mass than in younger subjects. PMID- 27479011 TI - EBUS-TBNA and EUS-FNA: Risk Assessment for Patients Receiving Clopidogrel. AB - BACKGROUND: Clopidogrel is widely used for the prevention of thrombotic vascular complications. Its primary potential toxicity is bleeding. Management of clopidogrel therapy for patients undergoing invasive procedures is an area of ongoing study. We sought to evaluate the bleeding risk for patients undergoing needle aspiration biopsy by endobronchial ultrasound (EBUS) or esophageal ultrasound (EUS) while taking clopidogrel. METHODS: Retrospective review of sequential cases of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and esophageal ultrasound fine needle aspiration (EUS FNA). RESULTS: Three hundred ninety-five consecutive procedures were reviewed. Thirty-seven patients were taking clopidogrel at time of biopsy. The patients taking clopidogrel were significantly older than those in the control group. Two patients (1%) in the control group were admitted for observation, but neither was found to have a significant bleed. There were no clinically significant bleeding complications in either of the study groups. CONCLUSIONS: It is reasonable to proceed with EBUS-TBNA or EUS-FNA when both, (1) clopidogrel cannot be stopped and, (2) an important diagnostic question is at stake. PMID- 27479010 TI - Persistence of Breakage in Specific Chromosome Bands 6 Years after Acute Exposure to Oil. AB - BACKGROUND: The identification of breakpoints involved in chromosomal damage could help to detect genes involved in genetic disorders, most notably cancer. Until now, only one published study, carried out by our group, has identified chromosome bands affected by exposure to oil from an oil spill. In that study, which was performed two years after the initial oil exposure in individuals who had participated in clean-up tasks following the wreck of the Prestige, three chromosomal bands (2q21, 3q27, 5q31) were found to be especially prone to breakage. A recent follow-up study, performed on the same individuals, revealed that the genotoxic damage had persisted six years after oil exposure. OBJECTIVES: To determine whether there exist chromosome bands which are especially prone to breakages and to know if there is some correlation with those detected in the previous study. In addition, to investigate if the DNA repair problems detected previously persist in the present study. DESIGN: Follow-up study performed six years after the Prestige oil spill. SETTING: Fishermen cooperatives in coastal villages. PARTICIPANTS: Fishermen highly exposed to oil spill who participated in previous genotoxic study six years after the oil. MEASUREMENTS: Chromosome damage in peripheral lymphocytes. For accurate identification of the breakpoints involved in chromosome damage of circulating lymphocytes, a sequential stain/G banding technique was employed. To determine the most break-prone chromosome bands, two statistical methods, the Fragile Site Multinomial and the chi-square tests (where the bands were corrected by their length) were used. To compare the chromosome lesions, structural chromosome alterations and gaps/breaks between two groups of individuals we used the GEE test which takes into account a possible within-individual correlation. Dysfunctions in DNA repair mechanisms, expressed as chromosome damage, were assessed in cultures with aphidicolin by the GEE test. RESULTS: Cytogenetic analyses were performed in 47 exposed individuals. A total of 251 breakpoints in exposed individuals) were identified, showing a non-uniform distribution in the human ideogram. Ten chromosome bands were found to be especially prone to breakage through both statistical methods. By comparing these bands with those observed in certain exposed individuals who had already participated the previous study, it was found in both studies that four bands (2q21, 3q27, 5q31 and 17p11.2) are particularly sensitive to breakage. Additionally, the dysfunction in DNA repair mechanisms was not significantly higher in oil-exposed individuals than in non-exposed individuals. LIMITATIONS: The sample size and the possibility of some kind of selection bias should be considered. Genotoxic results cannot be extrapolated to the high number of individuals who participated occasionally in clean-up tasks. CONCLUSION: Our findings show the existence of at least four target bands (2q21, 3q27, 5q31 and 17p11.2) with a greater propensity to break over time after an acute exposure to oil. The breaks in these bands, which are commonly involved in hematological cancer, may explain the increase of cancer risk reported in chronically benzene exposed individuals. In addition, a more efficiency of the DNA repair mechanisms has been detected six years after in fishermen who were highly exposed to the oil spill. To date, only this study, performed by our group on the previous and present genotoxic effects, has analyzed the chromosomal regions affected by breakage after an acute oil exposure. PMID- 27479012 TI - CD4/CD8 Ratio in Mediastinal Lymph Nodes Involved by Sarcoidosis: Analysis of Flow Cytometry Data Obtained by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. AB - BACKGROUND: Despite mixed results in the literature, some clinicians continue to consider an elevated CD4/CD8 ratio in bronchoalveolar lavage (BAL) fluid to be supportive of a diagnosis of sarcoidosis. However, the CD4/CD8 ratio in mediastinal lymph nodes involved by sarcoidosis has not been extensively studied. The primary aim of this study was to evaluate the utility of the CD4/CD8 ratio in mediastinal lymph node aspirates obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing sarcoidosis. METHODS: Our archives were searched for EBUS-TBNAs in which mediastinal lymph node aspirates had been submitted for flow cytometry (n=160). Clinical and pathologic findings in these cases were reviewed retrospectively. Cases were included in the study if they had (1) a clinical diagnosis of sarcoidosis supported by cytopathologic confirmation of non-necrotizing granulomas in EBUS-TBNA-derived lymph node aspirates (23 cases), or (2) a pathologically confirmed non-neoplastic diagnosis other than sarcoidosis (7 cases). Cases that did not fulfil these criteria were excluded (130 cases). RESULTS: The CD4/CD8 ratios in mediastinal lymph nodes and BAL fluid were compared. The CD4/CD8 ratio was elevated in mediastinal lymph nodes in 12/23 (52%) cases of sarcoidosis and 3/7 (43%) pathologically confirmed nonsarcoid cases. BAL fluid had been concurrently submitted for flow cytometry in 20/23 cases of sarcoidosis and 5/7 nonsarcoid cases. CD4/CD8 was elevated in BAL fluid in 9/20 (45%) cases of sarcoidosis and 2/5 (40%) nonsarcoid cases. CONCLUSION: As in BAL fluid, the CD4/CD8 ratio in mediastinal lymph nodes involved by sarcoid granulomas is highly variable and does not reliably confirm or exclude sarcoidosis. PMID- 27479013 TI - Thoracic Extramedullary Hematopoiesis Mimicking Metastatic Cancer. AB - Thoracic extramedullary hematopoiesis (EMH) is a rare manifestation in patients with myeloproliferative neoplasm. A 76-year-old woman with a long-standing history of polycythemia vera presented with a 2-month history of worsening dyspnea and left-sided wheezing. A chest computed tomography showed an ill defined soft tissue mass encasing the left mainstem bronchus causing airway obstruction, associated with paratracheal and paraesophageal lymphadenopathy. Endobronchial ultrasound-guided fine needle aspiration of the soft tissue mass and mediastinoscopy with excisional biopsy of a paratracheal lymph node demonstrated EMH with increased myeloid blasts. A bone marrow biopsy confirmed postpolycythemic myelofibrosis consistent with progression of polycythemia vera to myelofibrosis. We describe the bronchoscopic management of a case of EMH presenting as a mediastinal mass, mimicking malignancy. PMID- 27479014 TI - An Expectorated "Stent": An Unexpected Complication of EBUS-TBNA. AB - Endobronchial ultrasound-guided transbronchial needle aspiration has a low complication rate and is a cost-effective procedure for mediastinal staging and diagnosis when compared with the more invasive mediastinoscopy. There are increasing case reports of unexpected complications including equipment failures with and without significant medical consequences. Knowledge of complications, including those that are rare, is essential for the physician performing this minimally invasive procedure. We report a case of a retained foreign body from the unexpected separation of a distal spring/coil mechanism from the Olympus ViziShot Aspiration needle following early needle deployment within the working channel of the bronchoscope. PMID- 27479015 TI - The Intranodal Presence of Coexisting Granulomatous Inflammation and Carcinoma During Transbronchial Needle Aspiration of Intrathoracic Lymphadenopathy. AB - The presence of intrathoracic lymphadenopathy in patients with suspected malignancy remains concerning, often prompting further evaluation with tissue sampling. The presence of nodal granulomatous inflammation in patients with underlying malignancy is well reported. However, review of 3 recent large trials of endobronchial ultrasound-guided transbronchial needle aspiration in patients with granulomatous inflammation and malignancy did not identify the presence of coexisting, intranodal malignancy, and granulomatous inflammation, rather these diagnoses remained nodally exclusive. We present a case of coexisting granulomatous inflammation and metastatic carcinoma within the same lymph node aspirates, reviewing the potential diagnostic pitfalls and implications of this rare occurrence. PMID- 27479017 TI - Polytriangulane. PMID- 27479016 TI - Recent advances in epigenomics in NSCLC: real-time detection and therapeutic implications. AB - NSCLC is an aggressive disease with one of the poorer prognosis among cancers. The disappointing response to chemotherapy drives the search for genetic biomarkers aimed at both attaining an earlier diagnosis and choosing the most appropriate chemotherapy. In this scenario, epigenomic markers, such as DNA methylation, histone acetylation and the expression of noncoding RNAs, have been demonstrated to be reliable for the stratification of NSCLC patients. Newest techniques with increased sensitivity and the isolation of nucleic acids from plasma may allow an early diagnosis and then monitoring the efficacy over time. However, prospective confirmatory studies are still lacking. This article presents an overview of the epigenetic markers evaluated in NSCLC and discusses the role of their real-time detection in the clinical management of the disease. PMID- 27479018 TI - Fulminant Liver Failure in a Child With beta-Thalassemia on Deferasirox: A Case Report. AB - Deferesirox (DFX), an oral chelating agent, is used to treat chronic iron overload in several hematological diseases such as beta-thalassemia, sickle cell disease, and myelodysplastic anemia. DFX is generally well tolerated with the exception of gastrointestinal disturbances and rash, although cases of renal toxicity, as well as acute and chronic liver failure, have been reported in adults and children. Here we describe a 3-year-old girl with beta-thalassemia undergoing treatment with DFX who presented with acute liver failure and Fanconi's syndrome. It is important for pediatric gastroenterologists, hepatologists, and hematologists to be aware that the commonly used drug DFX can lead to acute liver failure in children, and liver function should be monitored closely in all patients taking DFX. PMID- 27479019 TI - Sex Differences in Lumbar Disc Herniation: Point of View. PMID- 27479020 TI - Computer-aided design and manufacturing of surgical templates and their clinical applications: a review. AB - INTRODUCTION: The surgical template is a guide aimed at directing the implant placement, tumor resection, osteotomy and bone repositioning. Using it, preoperative planning can be transferred to the actual surgical site, and the precision, safety and reliability of the surgery can be improved. However, the actual workflow of the surgical template design and manufacturing is quite complicated before the final clinical application. AREAS COVERED: The major goal of the paper is to provide a comprehensive reference source of the current and future development of the template design and manufacturing for relevant researchers. Expert commentary: This paper aims to present a review of the necessary procedures in the template-guided surgery including the image processing, 3D visualization, preoperative planning, surgical guide design and manufacturing. In addition, the template-guided clinical applications for various kinds of surgeries are reviewed, and it demonstrated that the precision of the surgery has been improved compared with the non-guided operations. PMID- 27479021 TI - Different People, Different Outcomes: Assessing Genetic Susceptibility to Lead Exposures. PMID- 27479022 TI - A New Volume-Based Approach for Predicting Thermophysical Behavior of Ionic Liquids and Ionic Liquid Crystals. AB - Volume-based prediction of melting points and other properties of ionic liquids (ILs) relies on empirical relations with volumes of ions in these low-melting organic salts. Here we report an accurate way to ionic volumes by Bader's partitioning of electron densities from X-ray diffraction obtained via a simple database approach. For a series of 1-tetradecyl-3-methylimidazolium salts, the volumes of different anions are found to correlate linearly with melting points; larger anions giving lower-melting ILs. The volume-based concept is transferred to ionic liquid crystals (ILs that adopt liquid crystalline mesophases, ILCs) for predicting the domain of their existence from the knowledge of their constituents. For 1-alkyl-3-methylimidazolium ILCs, linear correlations of ionic volumes with the occurrence of LC mesophase and its stability are revealed, thus paving the way to rational design of ILCs by combining suitably sized ions. PMID- 27479023 TI - Integrative Therapies for Women with a High Risk Pregnancy During Antepartum Hospitalization. AB - BACKGROUND: High-risk pregnancies that require lengthy hospitalization can cause anxiety and stress for pregnant women. Integrative medicine therapies may be beneficial for this population, but have not been widely studied. PURPOSE: The purpose of this study was to evaluate potential effects of acupuncture, guided imagery, Healing Touch, massage therapy, and reflexology on pain and anxiety of hospitalized pregnant women. METHODS: A retrospective analysis of the effects of integrative medicine therapies was conducted; N = 554 individual therapies were provided to hospitalized women with high-risk pregnancies. They included acupuncture (n = 83), guided imagery (n = 71), Healing Touch (n = 119), massage therapy (n = 196), and reflexology (n = 85) over an 18-month period. Pain and anxiety were measured pre- and posttherapy using a scale of 0 to 10, where 0 means no pain or no anxiety and 10 means high pain or high anxiety. RESULTS: Analysis of mean scores of pre- and posttherapies for pain and anxiety found a decrease of pain and anxiety after all of the therapies, ranging from an 84.5% to 61.4% decrease for pain (p < .0001) and a 91% to 70. 9% decrease for anxiety (p < .0001). Overall, patients rated their anxiety higher than pain prior to each therapy. CLINICAL IMPLICATIONS: Hospitalized pregnant women responded favorably to the therapies. There were no adverse reactions reported. Results suggest potential benefits of integrative medicine therapies for this group of inpatients. Anxiety was more prevalent than pain among hospitalized pregnant women who received integrative medicine therapy. PMID- 27479024 TI - The human gut microbiome of Latin America populations: a landscape to be discovered. AB - PURPOSE OF REVIEW: The gut microbiome is critical for human health, and its alteration is associated with intestinal, autoimmune and metabolic diseases. Numerous studies have focused on prevention or treatment of dysbiotic microbiome to reduce the risk or effect of these diseases. A key issue is to define the microbiome associated with the state of good health. The purpose of this review is to describe factors influencing the gut microbiome with special emphasis on contributions from Latin America. In addition, we will highlight opportunities for future studies on gut microbiome in Latin America. RECENT FINDINGS: A relevant factor influencing gut microbiome composition is geographical location associated with specific genetic, dietary and lifestyle factors. Geographical specificities suggest that a universal 'healthy microbiome' is unlikely. SUMMARY: Several research programs, mostly from Europe and North America, are extensively sequencing gut microbiome of healthy people, whereas data from Latin America remain scarce yet slowly increasing. Few studies have shown difference in the composition of gut microbiome between their local populations with that of other industrialized countries (North American populations). Latin America is composed of countries with a myriad of lifestyles, traditions, genetic backgrounds and socioeconomic conditions, which may determine differences in gut microbiome of individuals from different countries. This represents an opportunity to better understand the relationship between these factors and gut microbiome. PMID- 27479026 TI - Situation of Sri Lanka, where autochthonous malaria is no longer a problem, and other infections dominate, such as dengue, leptospirosis and rickettsioses. AB - PURPOSE OF REVIEW: Sri Lanka achieved a major milestone in communicable disease control in 2012 by reporting zero incidence of autochthonous malaria. However, reduction of malaria was associated with concurrent increase of several tropical diseases. This review looks into the time trends and epidemiology of these communicable diseases in Sri Lanka. RECENT FINDINGS: Reduction of malaria cases coincides with an increase of dengue, leptospirosis and rickettsioses in Sri Lanka. Although the case fatality rate of dengue has reduced and maintained below 1%, leptospirosis in clinical management is questionable. Despite having national focal points for control and prevention, these emerging diseases are completely out of control. Whether the holding back of vector control activities of malaria after a successful control programme is having an effect on emergence of other vector-borne diseases should be studied. SUMMARY: The communicable disease control programme in Sri Lanka should be further strengthened with availability of proper and rapid diagnostic facilities. Malaria control could not be considered as a great achievement due to the fact that other emerging infectious diseases are replacing malaria. PMID- 27479027 TI - Advances in diagnosis, treatment, and prevention of invasive Salmonella infections. AB - PURPOSE OF REVIEW: Typhoidal and nontyphoidal Salmonella enterica serotypes are among the most common bacterial causes of acute febrile illnesses in the developing world. In this review, we discuss new advances in understanding of the burden, diagnostic approaches, treatment and vaccines for invasive Salmonella infections. RECENT FINDINGS: Recent estimates of the global burden of typhoidal and nontyphoidal Salmonella not only affirm the importance of these infections but also highlight the paucity of systematic incidence data from many regions. New data from Africa indicate that typhoidal Salmonella may be more common than previously considered. Novel diagnostic techniques for Salmonella include new serologic, molecular and metabolomic approaches, but blood culture - although slow and insensitive - remains the primary means of establishing a diagnosis. Antibiotic resistance, particularly to fluoroquinolones, continues to emerge and threatens to undermine treatment success for these infections. New vaccines for typhoid, including conjugate vaccines with longer duration of immunity than prior vaccines, represent a promising tool for prevention of enteric fever. SUMMARY: Invasive Salmonella infections are a major cause of morbidity and mortality worldwide. Increasing antibiotic resistance in Salmonella is concerning, and empiric oral options are being rapidly eroded. Where new effective antimicrobials are lacking, developments in vaccines offer hope for reducing the burden of Salmonella infections globally. PMID- 27479028 TI - Free Energies of Cavity and Noncavity Hydrated Electrons Near the Instantaneous Air/Water Interface. AB - The properties of the hydrated electron at the air/water interface are computed for both a cavity and a noncavity model using mixed quantum/classical molecular dynamics simulation. We take advantage of our recently developed formalism for umbrella sampling with a restrained quantum expectation value to calculate free energy profiles of the hydrated electron's position relative to the water surface. We show that it is critical to use an instantaneous description of the air/water interface rather than the Gibbs' dividing surface to obtain accurate potentials of mean force. We find that noncavity electrons, which prefer to encompass several water molecules, avoid the interface where water molecules are scarce. In contrast, cavity models of the hydrated electron, which prefer to expel water, have a local free-energy minimum near the interface. When the cavity electron occupies this minimum, its absorption spectrum is quite red-shifted, its binding energy is significantly lowered, and its dynamics speed up quite a bit compared with the bulk, features that have not been found by experiment. The surface activity of the electron therefore serves as a useful test of cavity versus noncavity electron solvation. PMID- 27479025 TI - Giardia: a pathogen or commensal for children in high-prevalence settings? AB - PURPOSE OF REVIEW: Giardia is a common intestinal parasite worldwide, and infection can be associated with clear and sometimes persistent symptomatology. However, in children in high-prevalence settings, it is not associated with or is perhaps even protective against acute diarrhea, and the association with long term outcomes has been difficult to discern. RECENT FINDINGS: Recent studies have made progress in helping us disentangle this apparent paradox. First, prospective, well-characterized cohort studies have added to the data on the association between Giardia and diarrhea in these settings and have further characterized associations between Giardia infection and nutrition, gut function, and growth. Second, animal models have further characterized the host response to Giardia and helped elucidate mechanisms by which Giardia could impair child development. Finally, new work has shed light on the heterogeneity of human Giardia strains, which may both explain discrepant findings in the literature and help guide higher-resolution analyses of this pathogen in the future. SUMMARY: The true clinical impact of endemic pediatric giardiasis remains unclear, but recent prospective studies have confirmed a high prevalence of persistent, subclinical Giardia infections and associated growth shortfalls. Integrating how nutritional, microbial, metabolic, and pathogen-strain variables influence these outcomes could sharpen delineations between pathogenic and potentially beneficial attributes of this enigmatic parasite. PMID- 27479029 TI - Dispersion Forces and the Molecular Origin of Internal Friction in Protein. AB - Internal friction in macromolecules is one of the curious phenomena that control conformational changes and reaction rates. It is held here that dispersion interactions and London-van der Waals forces between nonbonded atoms are major contributors to internal friction. To demonstrate this, the flipping motion of aromatic rings of F10 and Y97 amino acid residues of cytochrome c has been studied in glycerol/water mixtures by cross relaxation-suppressed exchange nuclear magnetic resonance spectroscopy. The ring-flip rate is highly overdamped by glycerol, but this is not due to the effect of protein-solvent interactions on the Brownian dynamics of the protein, because glycerol cannot penetrate into the protein to slow the internal collective motions. Sound velocity in the protein under matching solvent conditions shows that glycerol exerts its effect by rather smothering the protein interior to produce reduced molecular compressibility and root-mean-square volume fluctuation (deltaVRMS), implying an increased number of dispersion interactions of nonbonded atoms. Hence, deltaVRMS can be used as a proxy for internal friction. By using the ansatz that internal friction is related to nonbonded interactions by the equation f(n) = f0 + f1n + f2n(2) + ..., where the variable n is the extent of nonbonded interactions with fi coefficients, the barrier to aromatic ring rotation is found to be flat. Also interesting is the appearance of a turnover region in the deltaVRMS dependence of the ring-flip rate, suggesting anomalous internal diffusion. We conclude that cohesive forces among nonbonded atoms are major contributors to the molecular origin of internal friction. PMID- 27479030 TI - Linear Stepper Actuation Driving Drop Resonance and Modifying Hysteresis. AB - In this work, 2 MUL water drops are placed on substrates that are created to have a circular hydrophilic region bounded by superhydrophobicity so that they exhibit high contact angles. When the substrate is translated by a linear stepper actuator, the random force components present in the actuator are shown to cause the drop to rock resonantly. When the substrate is translated downward at inclination angles of up to 6 degrees with respect to the horizontal, the contact angle hysteresis increases progressively to a limiting condition. When the substrate is moved up at inclined angles, alternatively, the contact angle hysteresis increases initially to the limiting condition before it is progressively restored to its static state. These behaviors are accounted for by the reversible micro-Cassie to Wenzel wetting state transformations that are made possible by the hierarchical microscale and nanoscale structures present in the superhydrophobic regions. PMID- 27479031 TI - Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule, Allosteric Inhibitor of FGF Receptor Signaling. PMID- 27479032 TI - CARM1 Methylates Chromatin Remodeling Factor BAF155 to Enhance Tumor Progression and Metastasis. PMID- 27479033 TI - Rab1A Is an mTORC1 Activator and a Colorectal Oncogene. PMID- 27479035 TI - Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance. PMID- 27479034 TI - The Public Repository of Xenografts Enables Discovery and Randomized Phase II like Trials in Mice. PMID- 27479036 TI - Fallout volume and litter type affect 137Cs concentration difference in litter between forest and stream environments. AB - It is important to understand the changes in the 137Cs concentration in litter through leaching when considering that 137Cs is transferred from basal food resources to animals in forested streams. We found that the difference of 137Cs activity concentration in litter between forest and stream was associated with both litter type and 137Cs fallout volume around Fukushima, Japan. The 137Cs activity concentrations in the litter of evergreen conifers tended to be greater than those in the litter of broad-leaved deciduous trees because of the absence of deciduous leaves during the fallout period in March 2011. Moreover, 137Cs activity concentrations in forest litter were greater with respect to the 137Cs fallout volume. The 137Cs activity concentrations in stream litter were much lower than those in forest litter when those in forest litter were higher. The 137Cs leaching patterns indicated that the differences in 137Cs activity concentration between forest and stream litter could change with changes in both fallout volume and litter type. Because litter is an important basal food resource in the food webs of both forests and streams, the 137Cs concentration gradient reflects to possible 137Cs transfer from lower to higher trophic animals. Our findings will improve our understanding of the spatial heterogeneity and variability of 137Cs concentrations in animals resident to the contaminated landscape. PMID- 27479037 TI - Freezing tolerance revisited-effects of variable temperatures on gene regulation in temperate grasses and legumes. AB - Climate change creates new patterns of seasonal climate variation with higher temperatures, longer growth seasons and more variable winter climates. This is challenging the winter survival of perennial herbaceous plants. In this review, we focus on the effects of variable temperatures during autumn/winter/spring, and its interactions with light, on the development and maintenance of freezing tolerance. Cold temperatures induce changes at several organizational levels in the plant (cold acclimation), leading to the development of freezing tolerance, which can be reduced/lost during warm spells (deacclimation) in winters, and attained again during cold spells (reacclimation). We summarize how temperature interacts with components of the light regime (photoperiod, PSII excitation pressure, irradiance, and light quality) in determining changes in the transcriptome, proteome and metabolome. PMID- 27479038 TI - In vivo triarylmethyl radical stabilization through encapsulation in Pluronic F 127 hydrogel. AB - In vivo electron paramagnetic resonance (EPR) imaging and spectroscopy are non invasive technologies used to specifically detect and quantify paramagnetic species. However, the relative instability of spin probes such as triarylmethyl radicals limits their application to conduct oxygen quantification and mapping. In this study we encapsulated tetrathiatriarylmethyl radical (TAM; known as "Finland" probe) in Pluronic F-127 hydrogel (PF-127) in order to limit its degradation and evaluate its in vitro and in vivo EPR properties as a function of oxygen. Our results show that the EPR signal of encapsulated TAM in PF-127 hydrogel is similar to the one in solution. Although it is less sensitive to oxygen, it is suitable for oximetry. We also demonstrated that the incorporation of TAM in PF-127 hydrogel leads to an improved in vivo EPR stability of the radical under anesthesia. This new formulation enables high quality EPR imaging and oximetry and paves the way for the application of TAM radical-based probes in various biomedical fields. PMID- 27479039 TI - Gate-Tunable Spatial Modulation of Localized Plasmon Resonances. AB - We demonstrate localization and field-effect spatial control of the plasmon resonance in semiconductor nanostructures, using scattering-type scanning near field optical microscopy in the mid-infrared region. We adopt InAs nanowires embedding a graded doping profile to modulate the free carrier density along the axial direction. Our near-field measurements have a spatial resolution of 20 nm and demonstrate the presence of a local resonant feature whose position can be controlled by a back-gate bias voltage. In the present implementation, field effect induces a modulation of the free carrier density profile yielding a spatial shift of the plasmon resonance of the order of 100 nm. We discuss the relevance of our electrically tunable nanoplasmonic architectures in view of innovative optoelectronic devices concepts. PMID- 27479040 TI - Arm lymphoedema and upper limb impairments in sentinel node-negative breast cancer patients: A one year follow-up study. AB - PURPOSE: The aim of this study is (1) to investigate the prevalence rate of arm lymphedema, pain, impaired shoulder range of motion, strength and shoulder function one year after a sentinel lymph node biopsy (SLNB) for breast cancer and (2) to determine predictive factors for these complications. METHODS: A longitudinal study was performed. One hundred patients with a sentinel-lymph node negative breast cancer were included. All patients were measured before surgery and one year after. Arm lymphedema was measured with the perimeter, pain with the Visual Analogue Scale, shoulder range of motion with an inclinometer, strength with a handheld dynamometer and shoulder function with the Disability of Arm, Shoulder and Hand questionnaire. Patient-, breast cancer- and treatment-related variables were recorded. RESULTS: One year after surgery 8% of sentinel node negative breast cancer patients had developed arm lymphedema. Fifty percent of patients had pain, 30% had an impaired shoulder range of motion, 8% had a decreased handgrip strength and 49% had an impaired shoulder function. Pain, shoulder range of motion, strength and shoulder dysfunctions changed significantly over one year (p < 0.001). Higher Body Mass Index is a predictive variable for shoulder dysfunctions one year post-SLNB. CONCLUSIONS: Prevalence rate of lymphedema and other upper limb impairments may not be underestimated after SLNB. Pain, shoulder range of motion, handgrip strength and shoulder function change significantly up to one year compared to preoperative values in sentinel node-negative breast cancer patients. PMID- 27479041 TI - Breast cancer in young women: Pathologic features and molecular phenotype. AB - PURPOSE: Controversy exists about the prognosis of breast cancer in young women. Our objective was to describe clinicopathological and prognostic features to improve adjuvant treatment indications. METHODS: We conducted a retrospective multi centre study including fifteen French hospitals. Disease-free survival's data, clinical and pathological criteria were collected. RESULTS: 5815 patients were included, 15.6% of them where between 35 and 40 years old and 8.7% below 35. In 94% of the cases, a palpable masse was found in patients <=35 years old. Triple negative and HER2 tumors were predominantly found in patients <=35 (22.2% and 22.1%, p < 0.01). A young age <=40 years (p < 0.001; hazard ratio [HR]: 2.05; 95% confidence limit [CL]: 1.60-2.63) or <=35 years (p < 0.001; [HR]: 3.86; 95% [CL]: 2.69-5.53) impacted on the indication of chemotherapy. Age <=35 (p < 0.001; [HR]: 2.01; 95% [CL]: 1.36-2.95) was a significantly negative factor on disease free survival. Chemotherapy (p < 0.006; [HR]: 0.6; 95% [CL]: 0.40-0.86) and positive hormone receptor status (p < 0.001; [HR]: 0.6; 95% [CL]: 0.54-0.79) appeared to be protector factors. Patients under 36, had a significantly higher rate of local recurrence and distant metastasis compared to patients >35-40 (21.5 vs. 15.4% and 21.8 vs. 12.6%, p < 0.01). CONCLUSION: Young women present a different distribution of molecular phenotypes with more luminal B and triple negative tumors with a higher grade and more lymph node involvement. A young age, must be taken as a pejorative prognostic factor and must play a part in indication of adjuvant therapy. PMID- 27479042 TI - The impact of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial: An institutional review. AB - BACKGROUND: Axillary dissection (AD) was historically recommended for all patients with breast tumor involvement discovered by sentinel lymph node biopsy (+SLNB). However, after the ACOSOG Z0011 trial, omission of AD became the recommendation for selected patients with a +SLNB. We report the impact of ACOSOG Z0011 on the completion AD rate in patients with +SLNB at our institution. METHODS: We retrospectively reviewed all patients diagnosed with breast cancer between March 2009 and February 2013 (n = 1781). This cohort was divided into two groups: 1) those diagnosed BEFORE Z0011 and 2) those diagnosed AFTER Z0011. We calculated both the percentage of patients with a +SNLB who underwent AD and, from those patients, the percentage who did and did not meet the Z0011 criteria. RESULTS: The BEFORE group contained 849 patients; 144 had +SLNB and from those 113 underwent AD. The AFTER group contained 932 patients: 139 had +SLNB and from those 73 underwent AD. The completion AD rate in the BEFORE group was 78.5%, compared to 52.5% in the AFTER group (p < 0.001). From the patients who met the Z0011 criteria, 75.6% of the BEFORE patients underwent AD, compared to only 2.2%% in the AFTER group (p < 0.001). Among those who did not meet the Z0011 criteria, a similar percentage of patients underwent AD in each group (BEFORE 79.8%, AFTER 74.4%, p = 0.384). CONCLUSION: Following the publication of the ACOSOG Z0011 trial, we experienced a significant decrease in the completion AD rate among patients with a +SLNB who met the Z0011 inclusion criteria. PMID- 27479043 TI - Automated High-Throughput Permethylation for Glycosylation Analysis of Biologics Using MALDI-TOF-MS. AB - Monitoring glycoprotein therapeutics for changes in glycosylation throughout the drug's life cycle is vital, as glycans significantly modulate the stability, biological activity, serum half-life, safety, and immunogenicity. Biopharma companies are increasingly adopting Quality by Design (QbD) frameworks for measuring, optimizing, and controlling drug glycosylation. Permethylation of glycans prior to analysis by matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) is a valuable tool for glycan characterization and for screening of large numbers of samples in QbD drug realization. However, the existing protocols for manual permethylation and liquid liquid extraction (LLE) steps are labor intensive and are thus not practical for high-throughput (HT) studies. Here we present a glycan permethylation protocol, based on 96-well microplates, that has been developed into a kit suitable for HT work. The workflow is largely automated using a liquid handling robot and includes N-glycan release, enrichment of N-glycans, permethylation, and LLE. The kit has been validated according to industry analytical performance guidelines and applied to characterize biopharmaceutical samples, including IgG4 monoclonal antibodies (mAbs) and recombinant human erythropoietin (rhEPO). The HT permethylation enabled glycan characterization and relative quantitation with minimal side reactions: the MALDI-TOF-MS profiles obtained were in good agreement with hydrophilic liquid interaction chromatography (HILIC) and ultrahigh performance liquid chromatography (UHPLC) data. Automated permethylation and extraction of 96 glycan samples was achieved in less than 5 h and automated data acquisition on MALDI-TOF-MS took on average less than 1 min per sample. This automated and HT glycan preparation and permethylation showed to be convenient, fast, and reliable and can be applied for drug glycan profiling and clinical glycan biomarker studies. PMID- 27479045 TI - Editorial Comment: First Impact Factor. PMID- 27479044 TI - Marfan syndrome associated aortic disease in neonates and children: a clinical morphologic review. AB - BACKGROUND: Marfan syndrome (MFS) is a multisystem connective tissue disorder that can lead to aortic dilation requiring aortic root replacement. Neonatal MFS (nMFS) is a rare and severe form of MFS compared to classic MFS (cMFS). Aortic root histology in MFS is thought to demonstrate predominantly medial degeneration (MD) of a translamellar mucoid extracellular matrix accumulation (MEMA-T) vs. the intralamellar mucoid extracellular matrix accumulation (MEMA-I) seen in other aortopathies. The objective of this study was to describe the clinical and histopathologic features of nMFS and cMFS patients undergoing aortic root replacement. METHODS: Children with MFS who underwent aortic root replacement between 2000 and 2012 at a single institution were included. Medical records including clinical details, aortic dimensions (Z scores), and histology including MD type were obtained. Statistics were descriptive with univariate analysis of age at surgery and type of MD. RESULTS: Eleven patients, 3 (27%) with nMFS, were included. Root dilation at time of surgery was greater in nMFS compared to cMFS (Z=12.8 vs. 7.6, P=.005), and nMFS patients were younger at time of surgery (7.3 vs. 18.8 years, P=.002). Histology in the nMFS group demonstrated MEMA-I in one and no MD in two. In the cMFS group, there were three with MEMA-T, four with MEMA I, and one with both types. CONCLUSION: In summary, nMFS has earlier root dilation often in the absence of MD. Both forms of MD were present in our cohort, and there was no correlation between age at surgery and type of MD. PMID- 27479046 TI - Highly sensitive detection of dipicolinic acid with a water-dispersible terbium metal organic framework. AB - The sensitive detection of dipicolinic acid (DPA) is strongly associated with the sensing of bacterial organisms in food and many types of environmental samples. To date, the demand for a sensitive detection method for bacterial toxicity has increased remarkably. Herein, we investigated the DPA detection potential of a water-dispersible terbium-metal organic framework (Tb-MOF) based on the fluorescence quenching mechanism. The Tb-MOF showed a highly sensitive ability to detect DPA at a limit of detection of 0.04nM (linear range of detection: 1nM to 5uM) and also offered enhanced selectivity from other commonly associated organic molecules. The present study provides a basis for the application of Tb-MOF for direct, convenient, highly sensitive, and specific detection of DPA in the actual samples. PMID- 27479047 TI - Amperometric IFN-gamma immunosensors with commercially fabricated PCB sensing electrodes. AB - Lab-on-a-Chip (LoC) technology has the potential to revolutionize medical Point of-Care diagnostics. Currently, considerable research efforts are focused on innovative production technologies that will make commercial upscaling of lab-on chip products financially viable. Printed circuit board (PCB) manufacturing techniques have several advantages in this field. In this paper we focus on transferring a complete IFN-gamma enzyme-linked immune-sorbent assay (ELISA) onto a commercial PCB electrochemical biosensing platform, We adapted a commercially available ELISA to detect the enzyme product TMB/H2O2 using amperometry, successfully reproducing the colorimetry-obtained ELISA standard curve. The results demonstrate the potential for the integration of these components into an automated, disposable, electronic ELISA Lab-on-PCB diagnostic platform. PMID- 27479048 TI - Label-free thioflavin T/G-quadruplex-based real-time strand displacement amplification for biosensing applications. AB - To promote application of strand-displacement amplification (SDA) techniques in biosensing, a label-free, real-time monitoring strategy for isothermal nucleic acid amplification reactions was designed. G-quadruplex structures were introduced into SDA products using specific recognition of G-quadruplexes by the fluorogenic dye thioflavin T. Performance was good for real-time monitoring of traditional SDA by a linear-amplification mechanism and for exponential cross triggered SDA amplification. The strategy worked on a commercial real-time PCR instrument, making it suitable for biosensing platforms. As examples, two highly sensitive and specific biosensors were designed for analysis of the activity of uracil-DNA glycosylase (UDG) and the restriction endonuclease EcoRI. Detection limits were 6*10(-5)U/mL for UDG and 0.016U/mL for EcoRI. Detection of corresponding targets in complex matrices such as cell lysates or human serum was also demonstrated. Compared to traditional end-point detection methods, real-time SDA-based approaches have the advantages of simple, fast operation; high sensitivity; low risk of carryover contamination; and very high throughput. The introduction of real-time monitoring strategies may promote application of SDA reactions in biosensor design. PMID- 27479050 TI - Using Wolbachia Releases to Estimate Aedes aegypti (Diptera: Culicidae) Population Size and Survival. AB - Mosquitoes carrying the endosymbiont bacterium Wolbachia have been deployed in field trials as a biological control intervention due to Wolbachia effects on reducing transmission of arboviruses. We performed mark, release and recapture (MRR) experiments using Wolbachia as an internal marker with daily collections with BG-Traps during the first two weeks of releases in Rio de Janeiro, Brazil. The MRR design allowed us to investigate two critical parameters that determine whether Wolbachia would successful invade a field population: the probability of daily survival (PDS) of Wolbachia-infected Aedes aegypti females, and the wild population density during releases. Released females had a PDS of 0.82 and 0.89 in the first and second weeks, respectively, immediately after releases, which is well within the range of previous estimates of survivorship of wild mosquitoes in Rio de Janeiro. Abundance estimation of wild population varied up to 10-fold higher depending on the estimation method used (634-3565 females on the average difference model to 6365-16188 females according to Lincoln-Petersen). Wolbachia released mosquitoes were lower than the density estimation of their wild counterparts, irrespectively of the model used. Individually screening mosquitoes for the presence of Wolbachia reduced uncertainty on abundance estimations due to fluctuation in capturing per week. A successful invasion into local population requires Ae. aegypti fitness is unaffected by Wolbachia presence, but also reliable estimates on the population size of wild mosquitoes. PMID- 27479049 TI - Novel theranostic nanoporphyrins for photodynamic diagnosis and trimodal therapy for bladder cancer. AB - The overall prognosis of bladder cancer has not been improved over the last 30 years and therefore, there is a great medical need to develop novel diagnosis and therapy approaches for bladder cancer. We developed a multifunctional nanoporphyrin platform that was coated with a bladder cancer-specific ligand named PLZ4. PLZ4-nanoporphyrin (PNP) integrates photodynamic diagnosis, image guided photodynamic therapy, photothermal therapy and targeted chemotherapy in a single procedure. PNPs are spherical, relatively small (around 23 nm), and have the ability to preferably emit fluorescence/heat/reactive oxygen species upon illumination with near infrared light. Doxorubicin (DOX) loaded PNPs possess slower drug release and dramatically longer systemic circulation time compared to free DOX. The fluorescence signal of PNPs efficiently and selectively increased in bladder cancer cells but not normal urothelial cells in vitro and in an orthotopic patient derived bladder cancer xenograft (PDX) models, indicating their great potential for photodynamic diagnosis. Photodynamic therapy with PNPs was significantly more potent than 5-aminolevulinic acid, and eliminated orthotopic PDX bladder cancers after intravesical treatment. Image-guided photodynamic and photothermal therapies synergized with targeted chemotherapy of DOX and significantly prolonged overall survival of mice carrying PDXs. In conclusion, this uniquely engineered targeting PNP selectively targeted tumor cells for photodynamic diagnosis, and served as effective triple-modality (photodynamic/photothermal/chemo) therapeutic agents against bladder cancers. This platform can be easily adapted to individualized medicine in a clinical setting and has tremendous potential to improve the management of bladder cancer in the clinic. PMID- 27479052 TI - Detection and molecular characterization of beta-lactamase genes in clinical isolates of Gram-negative bacteria in Southern Ecuador. AB - This work performed a phenotypic and genotypic characterization of 79 clinical isolates of Enterobacteriaceae and Pseudomonadaceae collected in hospitals of Southern Ecuadorin 2013. Our results showed a high incidence of beta-lactamases and ESBLs with blaTEM and blaCTX-M as the prevalent genes, respectively. By direct sequencing of PCR amplicons, the different beta-lactamases and variants of the genes were also distinguished. Our results revealed a predominance of TEM-1 beta-lactamase and the presence of different CTX-M variants with a prevalence of CTX-M-15. Two infrequent CTX-M variants in South America were also identified. To the best of our knowledge, this is one of the first studies describing the genetic characteristics of beta-lactamases in Ecuador. PMID- 27479054 TI - Repeatable, accurate, and high speed multi-level programming of memristor 1T1R arrays for power efficient analog computing applications. AB - Beyond use as high density non-volatile memories, memristors have potential as synaptic components of neuromorphic systems. We investigated the suitability of tantalum oxide (TaOx) transistor-memristor (1T1R) arrays for such applications, particularly the ability to accurately, repeatedly, and rapidly reach arbitrary conductance states. Programming is performed by applying an adaptive pulsed algorithm that utilizes the transistor gate voltage to control the SET switching operation and increase programming speed of the 1T1R cells. We show the capability of programming 64 conductance levels with <0.5% average accuracy using 100 ns pulses and studied the trade-offs between programming speed and programming error. The algorithm is also utilized to program 16 conductance levels on a population of cells in the 1T1R array showing robustness to cell-to cell variability. In general, the proposed algorithm results in approximately 10* improvement in programming speed over standard algorithms that do not use the transistor gate to control memristor switching. In addition, after only two programming pulses (an initialization pulse followed by a programming pulse), the resulting conductance values are within 12% of the target values in all cases. Finally, endurance of more than 10(6) cycles is shown through open-loop (single pulses) programming across multiple conductance levels using the optimized gate voltage of the transistor. These results are relevant for applications that require high speed, accurate, and repeatable programming of the cells such as in neural networks and analog data processing. PMID- 27479051 TI - Relationship between Parental Feeding Practices and Neural Responses to Food Cues in Adolescents. AB - Social context, specifically within the family, influences adolescent eating behaviours and thus their health. Little is known about the specific mechanisms underlying the effects of parental feeding practices on eating. We explored relationships between parental feeding practices and adolescent eating habits and brain activity in response to viewing food images. Fifty- seven adolescents (15 with type 2 diabetes mellitus, 21 obese and 21 healthy weight controls) underwent fMRI scanning whilst viewing images of food or matched control images. Participants completed the Kids Child Feeding Questionnaire, the Childrens' Dutch Eating Behaviour Questionnaire (DEBQ) and took part in an observed meal. Parents completed the Comprehensive Feeding Practices Questionniare and the DEBQ. We were particularly interested in brain activity in response to food cues that was modulated by different feeding and eating styles. Healthy-weight participants increased activation (compared to the other groups) to food in proportion to the level of parental restriction in visual areas of the brain such as right lateral occipital cortex (LOC), right temporal occipital cortex, left occipital fusiform gyrus, left lateral and superior LOC. Adolescents with type 2 diabetes mellitus had higher activation (compared to the other groups) with increased parental restrictive feeding in areas relating to emotional control, attention and decision-making, such as posterior cingulate, precuneus, frontal operculum and right middle frontal gyrus. Participants with type 2 diabetes mellitus also showed higher activation (compared to the other groups) in the left anterior intraparietal sulcus and angular gyrus when they also reported higher self restraint. Parental restriction did not modulate food responses in obese participants, but there was increased activity in visual (visual cortex, left LOC, left occipital fusiform gyrus) and reward related brain areas (thalamus and parietal operculum) in response to parental teaching and modelling of behaviour. Parental restrictive feeding and parental teaching and modelling affected neural responses to food cues in different ways, depending on motivations and diagnoses, illustrating a social influence on neural responses to food cues. PMID- 27479055 TI - Does Age of Onset of Asthma Influence the Effect of Cigarette Smoking on Lung Function? PMID- 27479053 TI - Distinctive adaptive response to repeated exposure to hydrogen peroxide associated with upregulation of DNA repair genes and cell cycle arrest. AB - Many environmental and physiological stresses are chronic. Thus, cells are constantly exposed to diverse types of genotoxic insults that challenge genome stability, including those that induce oxidative DNA damage. However, most in vitro studies that model cellular response to oxidative stressors employ short exposures and/or acute stress models. In this study, we tested the hypothesis that chronic and repeated exposure to a micromolar concentration of hydrogen peroxide (H2O2) could activate DNA damage responses, resulting in cellular adaptations. For this purpose, we developed an in vitro model in which we incubated mouse myoblast cells with a steady concentration of ~50MUM H2O2 for one hour daily for seven days, followed by a final challenge of a 10 or 20X higher dose of H2O2 (0.5 or 1mM). We report that intermittent long-term exposure to this oxidative stimulus nearly eliminated cell toxicity and significantly decreased genotoxicity (in particular, a >5-fold decreased in double-strand breaks) resulting from subsequent acute exposure to oxidative stress. This protection was associated with cell cycle arrest in G2/M and induction of expression of nine DNA repair genes. Together, this evidence supports an adaptive response to chronic, low-level oxidative stress that results in genomic protection and up-regulated maintenance of cellular homeostasis. PMID- 27479056 TI - Does Undiagnosed Chronic Obstructive Pulmonary Disease Matter? PMID- 27479057 TI - Loud and Clear: Sensory Impairment, Delirium, and Functional Recovery in Critical Illness. PMID- 27479058 TI - Airborne Transmission of Viral Respiratory Pathogens. Don't Stand So Close to Me? PMID- 27479059 TI - Lung Transplant and Extracorporeal Membrane Oxygenation. More Is Better and Better Together? PMID- 27479060 TI - Update in Asthma 2015. PMID- 27479061 TI - Official American Thoracic Society Clinical Practice Guidelines: Diagnostic Evaluation of Infants with Recurrent or Persistent Wheezing. AB - BACKGROUND: Infantile wheezing is a common problem, but there are no guidelines for the evaluation of infants with recurrent or persistent wheezing that is not relieved or prevented by standard therapies. METHODS: An American Thoracic Society-sanctioned guideline development committee selected clinical questions related to uncertainties or controversies in the diagnostic evaluation of wheezing infants. Members of the committee conducted pragmatic evidence syntheses, which followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The evidence syntheses were used to inform the formulation and grading of recommendations. RESULTS: The pragmatic evidence syntheses identified few studies that addressed the clinical questions. The studies that were identified constituted very low-quality evidence, consisting almost exclusively of case series with risk of selection bias, indirect patient populations, and imprecise estimates. The committee made conditional recommendations to perform bronchoscopic airway survey, bronchoalveolar lavage, esophageal pH monitoring, and a swallowing study. It also made conditional recommendations against empiric food avoidance, upper gastrointestinal radiography, and gastrointestinal scintigraphy. Finally, the committee recommended additional research about the roles of infant pulmonary function testing and food avoidance or dietary changes, based on allergy testing. CONCLUSIONS: Although infantile wheezing is common, there is a paucity of evidence to guide clinicians in selecting diagnostic tests for recurrent or persistent wheezing. Our committee made several conditional recommendations to guide clinicians; however, additional research that measures clinical outcomes is needed to improve our confidence in the effects of various diagnostic interventions and to allow advice to be provided with greater confidence. PMID- 27479062 TI - Premature Infants Rehospitalized because of an Apparent Life-Threatening Event Had Distinctive Autonomic Developmental Trajectories. PMID- 27479063 TI - Hypothermia and Meconium Aspiration Syndrome: International Multicenter Retrospective Cohort Study. PMID- 27479064 TI - Myeloid Targets for Pulmonary Arterial Hypertension: Time for Another Look. PMID- 27479065 TI - Reply: Expanded Role for Bone Marrow-derived Hematopoietic Stem and Progenitor Cells in Pulmonary Arterial Hypertension. PMID- 27479066 TI - Reply: Early-Life Exposure to Traffic-related Air Pollution and Lung Function in Adolescence. PMID- 27479067 TI - Early-Life Exposure to Traffic-related Air Pollution and Lung Function in Adolescence. PMID- 27479068 TI - Living with a Tracheostomy. PMID- 27479069 TI - Clinical, Echocardiographic, and Electrocardiographic Predictors of Persistent Atrial Fibrillation after Dual-Chamber Pacemaker Implantation: An Integrated Scoring Model Approach. AB - Persistent atrial fibrillation (PeAF) predictors after dual-chamber pacemaker (PM) implantation remain unclear. We sought to determine these predictors and establish an integrated scoring model. Data were retrospectively reviewed for 649 patients (63.8 +/- 12.3 years, 48.6% male, mean CHA2DS2-VASC score 2.7 +/- 2.0) undergoing dual-chamber PM implantation. PeAF was defined as documented AF on two consecutive electrocardiograms acquired >=7 days apart. During a 7.1-year median follow-up (interquartile range 4.5-10.1 years), 67 (10.3%) patients had PeAF. Multivariable analysis showed the following independent predictors of future PeAF: ischemic stroke or transient ischemic accident history (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.03-3.50, p = 0.040), atrial fibrillation/flutter history (HR 1.80, 95% CI 1.01-3.20, p = 0.046), sinus node disease (HR 2.24, 95% CI 1.16-4.35, p = 0.016), left atrial enlargement (>45 mm, HR 2.14, 95% CI 1.26-3.63, p = 0.005), and time in automatic mode switching >1% at first follow-up interrogation (HR 2.58, 95% CI 1.51-4.42, p < 0.001). An integrated scoring model combining these predictors showed good discrimination performance at the seven-year follow-up. (C-statistic 0.716, 95% CI 0.629-0.802, p < 0.001). Significantly greater seven-year PeAF incidences were seen in patients with higher scores (2-5) than in those with lower scores (0-1) (22.8% +/ 3.8% vs. 5.3% +/- 1.7%, p < 0.001). In conclusion, an integrated scoring model combining clinical, echocardiographic, and electrocardiographic characteristics is useful for predicting future PeAF in patients with a dual-chamber PM. PMID- 27479070 TI - In Vivo Choroidal Vascular Lesions in Diabetes on Swept-Source Optical Coherence Tomography. AB - Diabetes induces microvascular diseases including diabetic retinopathy and choroidopathy which reciprocally promote the pathogenesis, although optical coherence tomography images of diabetic choroidopathy remains to be documented. Here we evaluated the qualitative characteristics of choroidal vascular lesions in patients with diabetes and their association with diabetic retinopathy on swept-source optical coherence tomography (SS-OCT) images. We retrospectively reviewed 110 consecutive eyes of 110 patients with diabetes and 35 eyes of 35 healthy subjects for whom SS-OCT images (6x6-mm scans centered on the fovea) of sufficient quality were acquired. The curve of chorioretinal sections was flattened using Bruch's membrane as a reference surface, followed by generation of en-face images. We characterized choroidal vascular lesions and evaluated their association with the logarithm of the minimum angle of resolution visual acuity (logMAR VA), retinal and choroidal thicknesses, and diabetic retinopathy severity. En-face SS-OCT images showed unvisualized vessels in Sattler's layer in 33 eyes (30.0%). Focal narrowing was seen in choroidal vessels in Haller's layer in 56 eyes (50.9%). The choroidal vessels ended in the superficial or middle portion of Haller's layer, referred to as vascular stumps, in 20 eyes (18.2%). Diabetic eyes had these findings more frequently than nondiabetic eyes. The subfoveal choroid was thicker in eyes with focal vascular narrowing and vascular stumps than in eyes without such lesions. Vascular stumps in Haller's layer were significantly related to diabetic retinopathy severity, logMAR VA, and central retinal and choroidal thicknesses. These novel findings on SS-OCT images would promote the better understanding of complicated pathogenesis in diabetic retinopathy and choroidopathy. PMID- 27479071 TI - Proteomic and Transcriptomic Analyses of Swine Pathogen Erysipelothrix rhusiopathiae Reveal Virulence Repertoire. AB - E. rhusiopathiae is the causative agent of erysipelas in animals and erysipeloid in humans, but its pathogenicity is poorly understood. To identify virulence factors associated with E. rhusiopathiae and screen engineered vaccine candidates, we used proteomics and transcriptomics to compare the highly virulent strain HX130709 with an isogenic avirulent derivative, HX130709a. 1,299 proteins and 1,673 transcribed genes were identified and 1,292 of the proteins could be associated with genes. In a comparison between HX130907 and HX130709a, 168 proteins and 475 genes exhibited differences in regulation level. Among these, levels for 61 proteins and transcripts were positively or negatively correlated. Gene Ontology (GO) analysis suggests that many of the down-regulated proteins in the attenuated strain have catalytic or binding functions. Potential protein protein interactions suggest that some of the down-regulated proteins may regulate PTS, GMP synthase and ribosomal proteins. Morphological results showed that HX130709 and HX130709a have similar colony and capsule morphology. Growth curves and pyruvate measurements suggest that TCA cycle and saccharide phosphorylation levels were decreased and gluconeogenesis was increased in HX130709a. Our study confirms that SpaA and neuraminidase, but not hyaluronidase and capsule, are associated with virulence in E. rhusiopathiae. We conclude that the virulence of E. rhusiopathiae may be associated with slow reactions of the TCA cycle and down-regulation of selected proteins. PMID- 27479072 TI - Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine. AB - Sweet state is a basic physiological sensation of humans and other mammals which is mediated by the broadly acting sweet taste receptor-the heterodimer of Tas1r2 (taste receptor type 1 member 2) and Tas1r3 (taste receptor type 1 member 3). Various sweeteners interact with either Tas1r2 or Tas1r3 and then activate the receptor. In this study, we cloned, expressed and functionally characterized the taste receptor Tas1r2 from a species of Old World monkeys, the rhesus monkey. Paired with the human TAS1R3, it was shown that the rhesus monkey Tas1r2 could respond to natural sugars, amino acids and their derivates. Furthermore, similar to human TAS1R2, rhesus monkey Tas1r2 could respond to artificial sweeteners and sweet-tasting proteins. However, the responses induced by rhesus monkey Tas1r2 could not be inhibited by the sweet inhibitor amiloride. Moreover, we found a species-dependent activation of the Tas1r2 monomeric receptors of human, rhesus monkey and squirrel monkey but not mouse by an intense sweetener perillartine. Molecular modeling and sequence analysis indicate that the receptor has the conserved domains and ligand-specific interactive residues, which have been identified in the characterized sweet taste receptors up to now. This is the first report of the functional characterization of sweet taste receptors from an Old World monkey species. PMID- 27479073 TI - Ag-catalyzed InAs nanowires grown on transferable graphite flakes. AB - Semiconducting nanowires grown by quasi-van-der-Waals epitaxy on graphite flakes are a new class of hybrid materials that hold promise for scalable nanostructured devices within opto-electronics. Here we report on high aspect ratio and stacking fault free Ag-seeded InAs nanowires grown on exfoliated graphite flakes by molecular beam epitaxy. Ag catalyzes the InAs nanowire growth selectively on the graphite flakes and not on the underlying InAs substrates. This allows for easy transfer of the flexible graphite flakes with as-grown nanowire ensembles to arbitrary substrates by a micro-needle manipulator. Besides the possibilities for fabricating novel nanostructure device designs, we show how this method is used to study the parasitic growth and bicrystal match between the graphite flake and the nanowires by transmission electron microscopy. PMID- 27479075 TI - Removal of Antibiotics in Biological Wastewater Treatment Systems-A Critical Assessment Using the Activated Sludge Modeling Framework for Xenobiotics (ASM-X). AB - Many scientific studies present removal efficiencies for pharmaceuticals in laboratory-, pilot-, and full-scale wastewater treatment plants, based on observations that may be impacted by theoretical and methodological approaches used. In this Critical Review, we evaluated factors influencing observed removal efficiencies of three antibiotics (sulfamethoxazole, ciprofloxacin, tetracycline) in pilot- and full-scale biological treatment systems. Factors assessed include (i) retransformation to parent pharmaceuticals from e.g., conjugated metabolites and analogues, (ii) solid retention time (SRT), (iii) fractions sorbed onto solids, and (iv) dynamics in influent and effluent loading. A recently developed methodology was used, relying on the comparison of removal efficiency predictions (obtained with the Activated Sludge Model for Xenobiotics (ASM-X)) with representative measured data from literature. By applying this methodology, we demonstrated that (a) the elimination of sulfamethoxazole may be significantly underestimated when not considering retransformation from conjugated metabolites, depending on the type (urban or hospital) and size of upstream catchments; (b) operation at extended SRT may enhance antibiotic removal, as shown for sulfamethoxazole; (c) not accounting for fractions sorbed in influent and effluent solids may cause slight underestimation of ciprofloxacin removal efficiency. Using tetracycline as example substance, we ultimately evaluated implications of effluent dynamics and retransformation on environmental exposure and risk prediction. PMID- 27479074 TI - Impact of Heterogeneity in Sexual Behavior on Effectiveness in Reducing HIV Transmission with Test-and-Treat Strategy. AB - The WHO's early-release guideline for antiretroviral treatment (ART) of HIV infection based on a recent trial conducted in 34 countries recommends starting treatment immediately upon an HIV diagnosis. Therefore, the test-and-treat strategy may become more widely used in an effort to scale up HIV treatment and curb further transmission. Here we examine behavioural determinants of HIV transmission and how heterogeneity in sexual behaviour influences the outcomes of this strategy. Using a deterministic model, we perform a systematic investigation into the effects of various mixing patterns in a population of men who have sex with men (MSM), stratified by partner change rates, on the elimination threshold and endemic HIV prevalence. We find that both the level of overdispersion in the distribution of the number of sexual partners and mixing between population subgroups have a large influence on endemic prevalence before introduction of ART and on possible long term effectiveness of ART. Increasing heterogeneity in risk behavior may lead to lower endemic prevalence levels, but requires higher coverage levels of ART for elimination. Elimination is only feasible for populations with a rather low degree of assortativeness of mixing and requires treatment coverage of almost 80% if rates of testing and treatment uptake by all population subgroups are equal. In this case, for fully assortative mixing and 80% coverage endemic prevalence is reduced by 57%. In the presence of heterogeneity in ART uptake, elimination is easier to achieve when the subpopulation with highest risk behavior is tested and treated more often than the rest of the population, and vice versa when it is less. The developed framework can be used to extract information on behavioral heterogeneity from existing data which is otherwise hard to determine from population surveys. PMID- 27479077 TI - Charge Transport in Dendrimer Melts Using Multiscale Modeling Simulation. AB - In this article, we present a theoretical calculation of the charge carrier mobility in two different dendrimeric melt systems (dendritic phenylazomethine with a triphenyl amine core and dendritic carbazole with cyclic phenylazomethine as the core), which have recently been reported1 to increase the efficiency of dye-sensitized solar cells by interface modification. Our mobility calculation, which is a combination of molecular dynamics simulation, first-principles calculation, and kinetic Monte Carlo simulation, leads to mobilities that are in quantitative agreement with available experimental data. We also show how the mobility depends on dendrimer generation. Furthermore, we examine the variation of mobility with an external electric field and external reorganization energy. Physical mechanisms behind the observed electric field and generation dependencies of mobility are also explored. PMID- 27479076 TI - Super-resolution Imaging of Live Bacteria Cells Using a Genetically Directed, Highly Photostable Fluoromodule. AB - The rapid development in fluorescence microscopy and imaging techniques has greatly benefited our understanding of the mechanisms governing cellular processes at the molecular level. In particular, super-resolution microscopy methods overcome the diffraction limit to observe nanoscale cellular structures with unprecedented detail, and single-molecule tracking provides precise dynamic information about the motions of labeled proteins and oligonucleotides. Enhanced photostability of fluorescent labels (i.e., maximum emitted photons before photobleaching) is a critical requirement for achieving the ultimate spatio temporal resolution with either method. While super-resolution imaging has greatly benefited from highly photostable fluorophores, a shortage of photostable fluorescent labels for bacteria has limited its use in these small but relevant organisms. In this study, we report the use of a highly photostable fluoromodule, dL5, to genetically label proteins in the Gram-negative bacterium Caulobacter crescentus, enabling long-time-scale protein tracking and super-resolution microscopy. dL5 imaging relies on the activation of the fluorogen Malachite Green (MG) and can be used to label proteins sparsely, enabling single-protein detection in live bacteria without initial bleaching steps. dL5-MG complexes emit 2-fold more photons before photobleaching compared to organic dyes such as Cy5 and Alexa 647 in vitro, and 5-fold more photons compared to eYFP in vivo. We imaged fusions of dL5 to three different proteins in live Caulobacter cells using stimulated emission depletion microscopy, yielding a 4-fold resolution enhancement compared to diffraction-limited imaging. Importantly, dL5 fusions to an intermediate filament protein CreS are significantly less perturbative compared to traditional fluorescent protein fusions. To the best of our knowledge, this is the first demonstration of the use of fluorogen activating proteins for super-resolution imaging in live bacterial cells. PMID- 27479078 TI - MetLab: An In Silico Experimental Design, Simulation and Analysis Tool for Viral Metagenomics Studies. AB - Metagenomics, the sequence characterization of all genomes within a sample, is widely used as a virus discovery tool as well as a tool to study viral diversity of animals. Metagenomics can be considered to have three main steps; sample collection and preparation, sequencing and finally bioinformatics. Bioinformatic analysis of metagenomic datasets is in itself a complex process, involving few standardized methodologies, thereby hampering comparison of metagenomics studies between research groups. In this publication the new bioinformatics framework MetLab is presented, aimed at providing scientists with an integrated tool for experimental design and analysis of viral metagenomes. MetLab provides support in designing the metagenomics experiment by estimating the sequencing depth needed for the complete coverage of a species. This is achieved by applying a methodology to calculate the probability of coverage using an adaptation of Stevens' theorem. It also provides scientists with several pipelines aimed at simplifying the analysis of viral metagenomes, including; quality control, assembly and taxonomic binning. We also implement a tool for simulating metagenomics datasets from several sequencing platforms. The overall aim is to provide virologists with an easy to use tool for designing, simulating and analyzing viral metagenomes. The results presented here include a benchmark towards other existing software, with emphasis on detection of viruses as well as speed of applications. This is packaged, as comprehensive software, readily available for Linux and OSX users at https://github.com/norling/metlab. PMID- 27479079 TI - Mild Alkalization Acutely Triggers the Warburg Effect by Enhancing Hexokinase Activity via Voltage-Dependent Anion Channel Binding. AB - To fully understand the glycolytic behavior of cancer cells, it is important to recognize how it is linked to pH dynamics. Here, we evaluated the acute effects of mild acidification and alkalization on cancer cell glucose uptake and glycolytic flux and investigated the role of hexokinase (HK). Cancer cells exposed to buffers with graded pH were measured for 18F-fluorodeoxyglucose (FDG) uptake, lactate production and HK activity. Subcellular localization of HK protein was assessed by western blots and confocal microscopy. The interior of T47D breast cancer cells was mildly alkalized to pH 7.5 by a buffer pH of 7.8, and this was accompanied by rapid increases of FDG uptake and lactate extrusion. This shift toward glycolytic flux led to the prompt recovery of a reversed pH gradient. In contrast, mild acidification rapidly reduced cellular FDG uptake and lactate production. Mild acidification decreased and mild alkalization increased mitochondrial HK translocation and enzyme activity. Cells transfected with specific siRNA against HK-1, HK-2 and voltage-dependent anion channel (VDAC)1 displayed significant attenuation of pH-induced changes in FDG uptake. Confocal microscopy showed increased co-localization of HK-1 and HK-2 with VDAC1 by alkaline treatment. In isolated mitochondria, acidic pH increased and alkaline pH decreased release of free HK-1 and HK-2 from the mitochondrial pellet into the supernatant. Furthermore, experiments using purified proteins showed that alkaline pH promoted co-immunoprecipitation of HK with VDAC protein. These findings demonstrate that mild alkalization is sufficient to acutely trigger cancer cell glycolytic flux through enhanced activity of HK by promoting its mitochondrial translocation and VDAC binding. This process might serve as a mechanism through which cancer cells trigger the Warburg effect to maintain a dysregulated pH. PMID- 27479080 TI - Insight into the Ligand-Mediated Synthesis of Colloidal CsPbBr3 Perovskite Nanocrystals: The Role of Organic Acid, Base, and Cesium Precursors. AB - While convenient solution-based procedures have been realized for the synthesis of colloidal perovskite nanocrystals, the impact of surfactant ligands on the shape, size, and surface properties still remains poorly understood, which calls for a more detailed structure-morphology study. Herein we have systematically varied the hydrocarbon chain composition of carboxylic acids and amines to investigate the surface chemistry and the independent impact of acid and amine on the size and shape of perovskite nanocrystals. Solution phase studies on purified nanocrystal samples by (1)H NMR and IR spectroscopies have confirmed the presence of both carboxylate and alkylammonium ligands on surfaces, with the alkylammonium ligand being much more mobile and susceptible to detachment from the nanocrystal surfaces during polar solvent washes. Moreover, the chain length variation of carboxylic acids and amines, ranging from 18 carbons down to two carbons, has shown independent correlation to the size and shape of nanocrystals in addition to the temperature effect. We have additionally demonstrated that employing a more soluble cesium acetate precursor in place of the universally used Cs2CO3 results in enhanced processability without sacrificing optical properties, thus offering a more versatile recipe for perovskite nanocrystal synthesis that allows the use of organic acids and amines bearing chains shorter than eight carbon atoms. Overall our studies have shed light on the influence of ligand chemistry on crystal growth and stabilization of the nanocrystals, which opens the door to functionalizable perovskite nanocrsytals through surface ligand manipulation. PMID- 27479081 TI - Nitric Oxide Regulation of H-NOX Signaling Pathways in Bacteria. AB - Nitric oxide (NO) is a freely diffusible, radical gas that has now been established as an integral signaling molecule in eukaryotes and bacteria. It has been demonstrated that NO signaling is initiated upon ligation to the heme iron of an H-NOX domain in mammals and in some bacteria. Bacterial H-NOX proteins have been found to interact with enzymes that participate in signaling pathways and regulate bacterial processes such as quorum sensing, biofilm formation, and symbiosis. Here, we review the biochemical characterization of these signaling pathways and, where available, describe how ligation of NO to H-NOX specifically regulates the activity of these pathways and their associated bacterial phenotypes. PMID- 27479082 TI - Inference of Gene Regulatory Network Based on Local Bayesian Networks. AB - The inference of gene regulatory networks (GRNs) from expression data can mine the direct regulations among genes and gain deep insights into biological processes at a network level. During past decades, numerous computational approaches have been introduced for inferring the GRNs. However, many of them still suffer from various problems, e.g., Bayesian network (BN) methods cannot handle large-scale networks due to their high computational complexity, while information theory-based methods cannot identify the directions of regulatory interactions and also suffer from false positive/negative problems. To overcome the limitations, in this work we present a novel algorithm, namely local Bayesian network (LBN), to infer GRNs from gene expression data by using the network decomposition strategy and false-positive edge elimination scheme. Specifically, LBN algorithm first uses conditional mutual information (CMI) to construct an initial network or GRN, which is decomposed into a number of local networks or GRNs. Then, BN method is employed to generate a series of local BNs by selecting the k-nearest neighbors of each gene as its candidate regulatory genes, which significantly reduces the exponential search space from all possible GRN structures. Integrating these local BNs forms a tentative network or GRN by performing CMI, which reduces redundant regulations in the GRN and thus alleviates the false positive problem. The final network or GRN can be obtained by iteratively performing CMI and local BN on the tentative network. In the iterative process, the false or redundant regulations are gradually removed. When tested on the benchmark GRN datasets from DREAM challenge as well as the SOS DNA repair network in E.coli, our results suggest that LBN outperforms other state-of the-art methods (ARACNE, GENIE3 and NARROMI) significantly, with more accurate and robust performance. In particular, the decomposition strategy with local Bayesian networks not only effectively reduce the computational cost of BN due to much smaller sizes of local GRNs, but also identify the directions of the regulations. PMID- 27479083 TI - Analysis and Implementation of an Electronic Laboratory Notebook in a Biomedical Research Institute. AB - Electronic laboratory notebooks (ELNs) will probably replace paper laboratory notebooks (PLNs) in academic research due to their advantages in data recording, sharing and security. Despite several reports describing technical characteristics of ELNs and their advantages over PLNs, no study has directly tested ELN performance among researchers. In addition, the usage of tablet-based devices or wearable technology as ELN complements has never been explored in the field. To implement an ELN in our biomedical research institute, here we first present a technical comparison of six ELNs using 42 parameters. Based on this, we chose two ELNs, which were tested by 28 scientists for a 3-month period and by 80 students via hands-on practical exercises. Second, we provide two survey-based studies aimed to compare these two ELNs (PerkinElmer Elements and Microsoft OneNote) and to analyze the use of tablet-based devices. We finally explore the advantages of using wearable technology as ELNs tools. Among the ELNs tested, we found that OneNote presents almost all parameters evaluated (39/42) and both surveyed groups preferred OneNote as an ELN solution. In addition, 80% of the surveyed scientists reported that tablet-based devices improved the use of ELNs in different respects. We also describe the advantages of using OneNote application for Apple Watch as an ELN wearable complement. This work defines essential features of ELNs that could be used to improve ELN implementation and software development. PMID- 27479086 TI - Human odontogenic epithelial cells derived from epithelial rests of Malassez possess stem cell properties. AB - Epithelial cell rests of Malassez (ERM) are quiescent epithelial remnants of the Hertwig's epithelial root sheath (HERS) that are involved in the formation of tooth roots. ERM cells are unique epithelial cells that remain in periodontal tissues throughout adult life. They have a functional role in the repair/regeneration of cement or enamel. Here, we isolated odontogenic epithelial cells from ERM in the periodontal ligament, and the cells were spontaneously immortalized. Immortalized odontogenic epithelial (iOdE) cells had the ability to form spheroids and expressed stem cell-related genes. Interestingly, iOdE cells underwent osteogenic differentiation, as demonstrated by the mineralization activity in vitro in mineralization-inducing media and formation of calcification foci in iOdE cells transplanted into immunocompromised mice. These findings suggest that a cell population with features similar to stem cells exists in ERM and that this cell population has a differentiation capacity for producing calcifications in a particular microenvironment. In summary, iOdE cells will provide a convenient cell source for tissue engineering and experimental models to investigate tooth growth, differentiation, and tumorigenesis. PMID- 27479084 TI - An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. AB - Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4ra(R576)) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL 4Ralpha(R576) of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3. Treg cell-specific deletion of genes that regulate TH17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 or Il13, prevented exacerbated airway inflammation in mice expressing Il4ra(R576) (hereafter referred to as Il4ra(R576) mice). Furthermore, treatment of Il4ra(R576) mice with a neutralizing IL-6-specific antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed TH2-TH17 cell inflammation in genetically prone individuals and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies. PMID- 27479085 TI - Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. AB - The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions. PMID- 27479088 TI - Macular Choroidal Thickness and Volume Measured by Swept-source Optical Coherence Tomography in Healthy Korean Children. PMID- 27479087 TI - A survey of changing trends in modelling radiation lung injury in mice: bringing out the good, the bad, and the uncertain. AB - Within this millennium there has been resurgence in funding and research dealing with animal models of radiation-induced lung injury to identify and establish predictive biomarkers and effective mitigating agents that are applicable to humans. Most have been performed on mice but there needs to be assurance that the emphasis on such models is not misplaced. We therefore considered it timely to perform a comprehensive appraisal of the literature dealing with radiation lung injury of mice and to critically evaluate the validity and clinical relevance of the research. A total of 357 research papers covering the period of 1970-2015 were extensively reviewed. Whole thorax irradiation (WTI) has become the most common treatment for studying lung injury in mice and distinct trends were seen with regard to the murine strain, radiation dose, intended pathology investigated, length of study, and assays. Recently, the C57BL/6 strain has been increasingly used in the majority of these studies with the notion that they are susceptible to pulmonary fibrosis. Nonetheless, many of these investigations depend on animal survival as the primary end point and neglect the importance of radiation pneumonitis and the anomaly of lethal pleural effusions. A relatively large variation in survival times of C5BL/6 mice is also seen among different institutions pointing to the need for standardization of radiation treatments and environmental conditions. An analysis of mitigating drug treatments is complicated by the fact that the majority of studies are limited to the C57BL/6 strain with a premature termination of the experiments and do not establish whether the treatment actually prevents or simply delays the progression of radiation injury. This survey of the literature has pointed to several improvements that need to be considered in establishing a reliable preclinical murine model of radiation lung injury. The lethality end point should also be used cautiously and with greater emphasis on other assays such as non-invasive lung functional and imaging monitoring in order to quantify specific pulmonary injury that can be better extrapolated to radiation toxicity encountered in our own species. PMID- 27479089 TI - Federally-Assisted Healthcare Coverage among Male State Prisoners with Chronic Health Problems. AB - Prisoners have higher rates of chronic diseases such as substance dependence, mental health conditions and infectious disease, as compared to the general population. We projected the number of male state prisoners with a chronic health condition who at release would be eligible or ineligible for healthcare coverage under the Affordable Care Act (ACA). We used ACA income guidelines in conjunction with reported pre-arrest social security benefits and income from a nationally representative sample of prisoners to estimate the number eligible for healthcare coverage at release. There were 643,290 US male prisoners aged 18-64 with a chronic health condition. At release, 73% in Medicaid-expansion states would qualify for Medicaid or tax credits. In non-expansion states, 54% would qualify for tax credits, but 22% (n = 69,827) had incomes of <= 100% the federal poverty limit and thus would be ineligible for ACA-mediated healthcare coverage. These prisoners comprise 11% of all male prisoners with a chronic condition. The ACA was projected to provide coverage to most male state prisoners with a chronic health condition; however, roughly 70,000 fall in the "coverage gap" and may require non-routine care at emergency departments. Mechanisms are needed to secure coverage for this at risk group and address barriers to routine utilization of health services. PMID- 27479090 TI - The Uncertain Relationship between Air Pollution and Risk of Preterm Birth: Does Spatial Variation Drive Disparate Findings? PMID- 27479091 TI - Musculoskeletal impact of the use of various types of electronic devices on university students in Hong Kong: An evaluation by means of self-reported questionnaire. AB - INTRODUCTION: Despite the increasingly widespread popularity of electronic devices, there are limited comprehensive studies on the effects of usage and exposure to multiple electronic devices over extended periods of time. Therefore, this study explored the cumulative musculoskeletal implications of exposure to various electronic devices among university students. METHODS: A self-reported questionnaire was administered in the university in Hong Kong and students provided information about the frequency and duration of electronic devices use, including computers, mobile phones and game consoles, and reported on any musculoskeletal pain or discomfort that may relate to electronic devices usage in the immediate 12 months prior to the survey date. RESULTS: A total of 503 university students (59% males and 41% females) aged 18-25 years completed the questionnaire. The results showed that 251 (49.9%) respondents reported upper limb musculoskeletal symptoms, particularly in the neck and shoulder regions. Among these, 155 (61.8%) indicated that their discomfort was related to electronic device usage. Statistically significant differences in exposure to electronic devices and musculoskeletal outcomes between genders were found (p < 0.05). CONCLUSION: The use of electronic devices and habitual postures were associated with musculoskeletal problems among university students in Hong Kong. This phenomenon highlights the urgent need for ergonomics education and recommendations to increase students' awareness of musculoskeletal wellbeing. PMID- 27479093 TI - Assessing the Risk for Diabetes in Patients With Unexpectedly Identified Tumors in the Adrenal Glands. PMID- 27479092 TI - Clinical Experience of Prescribing Dabigatran Etexilate With Dronedarone: The Role of Therapeutic Drug Monitoring. PMID- 27479094 TI - Evaluation of Peripheral Blood Circulation Disorder in Scleroderma Patients Using an Optical Sensor with a Pressurization Mechanism. AB - Blood circulation function of peripheral blood vessels in skin dermis was evaluated employing an optical sensor with a pressurization mechanism using the blood outflow and reflow characteristics. The device contains a light source and an optical sensor. When applied to the skin surface, it first exerts the primary pressure (higher than the systolic blood pressure), causing an outflow of blood from the dermal peripheral blood vessels. After two heartbeats, the pressure is lowered (secondary pressure) and blood reflows into the peripheral blood vessels. Hemoglobin concentration, which changes during blood outflow and reflow, is derived from the received light intensity using the Beer-Lambert law. This method was evaluated in 26 healthy female volunteers and 26 female scleroderma patients. In order to evaluate the blood circulation function of the peripheral blood vessels of scleroderma patients, pressurization sequence which consists of primary pressure followed by secondary pressure was adopted. Blood reflow during the first heartbeat period after applying the secondary pressure of 40mmHg was (mean+/-SD) 0.059+/-0.05%mm for scleroderma patients and 0.173+/-0.104%mm for healthy volunteers. Blood reflow was significantly lower in scleroderma patients than in healthy volunteers (p<0.05). This result indicates that the information necessary for assessing blood circulation disorder of peripheral blood vessels in scleroderma patients is objectively obtained by the proposed method. PMID- 27479096 TI - Treatment Outcome of Bangladeshi UCLP Patients Based on Both Phenotype and Postnatal Treatment Factors using Modified Huddart Bodenham (mHB) Index. AB - OBJECTIVE: To evaluate the dental arch relationship (DAR) of nonsyndromic unilateral cleft lip and palate (UCLP) and to explore the various phenotype and postnatal treatment factors that are responsible for poor DAR. DESIGN: Retrospective study. SETTING: School of Dental Science, Universiti Sains Malaysia. SUBJECTS: Eighty-four Bangladeshi children with nonsyndromic UCLP who received cheiloplasty and palatoplasty. MAIN OUTCOME MEASURES: Dental models were taken at 5 to 12 years of age (man: 7.69), and dental arch relationships were assessed using modified Huddart/Bodenham index (mHB) by two raters. Kappa statistics was used to evaluate the intra- and interexaminer agreements, chi square was used to assess the associations, and logistic regression analysis was used to explore the responsible factors that affect DAR. RESULTS: The total mHB score (mean [SD]) was -8.261 (7.115). Intra- and interagreement was very good. Using crude and stepwise backward regression analysis, significant association was found between positive history of class III (P = .025, P = .030, respectively) and unfavorable DAR. Complete UCLP (P = .003) was also significantly correlated with unfavorable DAR. CONCLUSION: This multivariate study suggested complete type of UCLP and positive history of class III had a significantly unfavorable effect on the DAR. PMID- 27479095 TI - Generation and Characterization of an IgG4 Monomeric Fc Platform. AB - The immunoglobulin Fc region is a homodimer consisted of two sets of CH2 and CH3 domains and has been exploited to generate two-arm protein fusions with high expression yields, simplified purification processes and extended serum half life. However, attempts to generate one-arm fusion proteins with monomeric Fc, with one set of CH2 and CH3 domains, are often plagued with challenges such as weakened binding to FcRn or partial monomer formation. Here, we demonstrate the generation of a stable IgG4 Fc monomer with a unique combination of mutations at the CH3-CH3 interface using rational design combined with in vitro evolution methodologies. In addition to size-exclusion chromatography and analytical ultracentrifugation, we used multi-angle light scattering (MALS) to show that the engineered Fc monomer exhibits excellent monodispersity. Furthermore, crystal structure analysis (PDB ID: 5HVW) reveals monomeric properties supported by disrupted interactions at the CH3-CH3 interface. Monomeric Fc fusions with Fab or scFv achieved FcRn binding and serum half-life comparable to wildtype IgG. These results demonstrate that this monomeric IgG4 Fc is a promising therapeutic platform to extend the serum half-life of proteins in a monovalent format. PMID- 27479097 TI - The DSM-5 social anxiety disorder severity scale: Evidence of validity and reliability in a clinical sample. AB - With DSM-5, the APA began providing guidelines for anxiety disorder severity assessment that incorporates newly developed self-report scales. The scales share a common template, are brief, and are free of copyright restrictions. Initial validation studies have been promising, but the English-language versions of the scales have not been formally validated in clinical samples. Forty-seven individuals with a principal diagnosis of Social Anxiety Disorder (SAD) completed a diagnostic assessment, as well as the DSM-5 SAD severity scale and several previously validated measures. The scale demonstrated internal consistency, convergent validity, and discriminant validity. The next steps in the validation process are outlined. PMID- 27479098 TI - Complicated Grief Treatment for older adults: The critical role of a supportive person. AB - In the wake of the increased interest in treatment for complicated grief (CG) symptoms, research has reported the promising effect of CG treatment (CGT) on CG symptoms. This study compared CGT with supportive counseling (SC) in terms of improvement in CG symptoms. A randomized trial design was used to compare the effectiveness of CGT with that of SC in treating CG symptoms, depressive symptoms, and social impairments. The primary outcome was the Inventory of Complicated Grief. Relative to SC, CGT resulted in improved CG symptoms and depressive symptoms. Among those receiving CGT, participants with a supportive person in their sessions showed more beneficial results in CG and depressive symptoms than those without a supportive person did. This suggests that CGT is superior to SC in reducing CG symptoms and depressive symptoms, and in improving work and social functions during bereavement. Moreover, having a supportive person plays a critical role in the effectiveness of CGT sessions. PMID- 27479099 TI - Specificity of childhood maltreatment and emotion deficit in nonsuicidal self injury in an inpatient sample of youth. AB - The present study investigated the function of two specific emotion-related skills, emotion expressivity and emotion coping, as potential mediators in the relations between childhood sexual, physical, and emotional abuse and NSSI. A robust body of work supports the role of emotion regulation in nonsuicidal self injury, but additional research is warranted to tease apart the role of specific emotion regulation deficits as predictors of NSSI. Participants included 95 youth (Mage=14.22, SDage=1.67; 58% female) hospitalized on one of two acute care psychiatric inpatient units. Participants completed self-report questionnaires related to childhood experiences of trauma, current emotion expressivity and coping, and lifetime frequency of NSSI. Path analytic models indicated that only child emotional abuse was directly associated with NSSI when all abuse subtypes were examined simultaneously. Results also indicated that poor emotion expressivity, but not emotion coping, mediated the relation between childhood experiences of emotional abuse and NSSI. PMID- 27479100 TI - Stigma and its correlates among patients with bipolar disorder: A study from a tertiary care hospital of North India. AB - This study aimed to assess stigma and its sociodemographic and clinical correlates among patients with bipolar disorder while in remission. 185 patients currently in remission were assessed on Internalized Stigma of Mental Illness Scale (ISMIS) for internalized stigma, Explanatory Model Interview Catalogue Stigma Scale for perceived stigma and Participation scale for restriction of activities. About 28% patients reported moderate to high level of self stigma as assessed by ISMIS total score. Discrimination experience (38.9%) was reported to be the most commonly experienced self stigma followed by alienation (28.6%) and social withdrawal (28.6%). On the participation scale, about two-fifth (42%) of the participants had severe restriction of activities. Internalized stigma was higher among those with lower age and lesser income. Higher level of stigma was associated with shorter mean duration of remission, income, mean duration of depressive episodes, higher severity of residual depressive symptoms and current level of functioning. Higher internalized stigma was associated with greater restriction in participation of activities. To conclude, present study suggests that self stigma is highly prevalent among patients with bipolar disorder in India and is associated with clinical variables like duration of depressive episodes and level of functioning. PMID- 27479101 TI - Predictors of improved functioning in patients with psychosis: The role of amotivation and defeatist performance beliefs. AB - Defeatist performance beliefs (DPBs) are associated with the severe impairments in functioning of patients with negative symptoms of schizophrenia. This association has been found to be mediated by amotivation, a core aspect of negative symptoms. Although causality is assumed, longitudinal evidence for this is lacking. The current study aimed to extend previous findings by investigating both cross-sectional and longitudinal associations between DPBs, motivational impairments and functioning in a sample of patients with psychotic disorders (N=58). We hypothesized, that DPBs would be related to functioning in cross sectional and longitudinal analyses and that this link would be mediated by motivational impairments. Data was assessed at baseline and post-treatment in a trial on the effects of cognitive behavior therapy for psychosis. At baseline, amotivation mediated the association between DPBs and functioning. From baseline to post-treatment, reduction of amotivation was associated with improvement of functioning significantly, whereas reduction of DPBs was unrelated to improvements in functioning or amotivation. The findings suggest that improvement in amotivation accounts for favorable treatment outcomes in regard to functioning but question the causal role of DPBs in negative symptoms and functioning. PMID- 27479102 TI - Does body mass index moderate the association between posttraumatic stress disorder symptoms and suicidal ideation in Iraq/Afghanistan veterans? AB - Suicide, PTSD, and obesity co-occur at high rates among returning veterans, yet limited research exists regarding the relationship among these variables. Self report and diagnostic interview data from a longitudinal study of Iraq and Afghanistan veterans (N=130) enrolled in VA healthcare examined these inter relations. As hypothesized, body mass index (BMI) significantly moderated the association between PTSD and suicidal ideation such that the association between PTSD and suicidal ideation was strongest among individuals with a high BMI. Programs that focus on health promotion, trauma treatment, and weight management should continue to monitor suicide risk. PMID- 27479103 TI - Military experience helps setting reasonable personality characteristics but does not alter the criminal behavior-related impression of negative parental experience and alcoholism in a Chinese population. AB - Personalities are determined by convergent factors, including physical environment, culture, special experience, and heredity. It has been shown that abuse of substance and alcohol among individuals with personality disorders predict criminality (Glenn and Raine, 2014; Hernandez-Avila et al., 2000). Thus, it is important to clarify the relationship between psychological characteristics and valence of criminal practice, even in the population without substance abuse. Here, we focused on a population with military experience in Shaanxi province of China to screen the psychological characteristics and correlate these characteristics to criminal behaviors. The study population included incarcerated veterans, incarcerated civilians, and three groups of military troops with different lengths of active duty history (<1 month, 1 year, and 2 years). We used the MAST (Michigan Alcoholism Screening Test), EMBU (Egna Minnen av Barndoms Uppfostran), and 16PF (Sixteen Personality Factor Questionnaire) for the screening purpose. Eight hundred seventy-five valid packets of questionnaires were collected during November 2014-January 2015. Comparison of the mean scores was used to evaluate the difference among the five groups. Incarcerated veterans and incarcerated civilians shared the alcohol abuse-relevant characteristics, including negative parental attitudes during their childhood and decreased emotional stability. Compared to the incarcerated civilians, incarcerated veterans scored higher in emotional stability, self-reliance, and perfectionism, but a lower score in apprehension. Personality characteristics associated with criminal behavior of incarcerated veterans seem to be unrelated to their military service per se as evidenced by the control groups. Conversely, military service may benefit the personnel characteristics even in the incarcerated veteran population. PMID- 27479105 TI - The relationship between change in cognition and change in functional ability in schizophrenia during cognitive and psychosocial rehabilitation. AB - While a wealth of studies have evaluated cross-sectional links between cognition and functioning in schizophrenia, few have investigated the relationship between change in cognition and change in functioning in the context of treatment trials targeted at cognition. Identifying cognitive skills that, when improved, predict improvement in functioning will guide the development of more targeted rehabilitation for this population. The present study identifies the relationship between change in specific cognitive skills and change in functional ability during one year of cognitive rehabilitation. Ninety-six individuals with schizophrenia were assessed with a battery of cognitive measures and a measure of performance-based functioning before and after cognitive training consisting of either drill-and-practice cognitive remediation or computer skills training. Results revealed that while working and episodic memory, problem-solving, and processing speed skills all improved during the trial, only improved working memory and processing speed skills predicted improvement in functional ability. Secondary analyses revealed these relationships were driven by individuals who showed a moderate level (SD>=0.5) of cognitive improvement during the trial. These findings suggest that while a variety of cognitive skills may improve during training targeted at cognition, only improvements in a subset of cognitive functions may translate into functional gains. PMID- 27479104 TI - Wearable devices and mobile technologies for supporting behavioral weight loss among people with serious mental illness. AB - Promoting physical activity is essential for addressing elevated cardiovascular risk and high obesity rates affecting people with serious mental illness. Numerous challenges interfere with exercise participation in this high-risk group including mental health symptoms, low motivation, and limited access to safe and affordable options for physical activity. Wearable devices and mobile health technologies may afford new opportunities for promoting physical activity and supporting behavioral weight loss efforts. This exploratory study examined whether daily step count measured using Fitbit wearable devices was associated with weight loss and improved fitness among individuals with serious mental illness enrolled in a 6-month lifestyle program. Participants (n=34) had a schizophrenia spectrum disorder (23.5%), major depression (50.0%), or bipolar disorder (26.5%), and wore Fitbits most of the days (M=86.2%; SD=18.4%) they were enrolled in the study. At 6-months, higher average daily step count was associated with greater weight loss (F=5.07; df=1,32; p=0.0314), but not improved fitness (F=1.92; df=1,31; p=0.176). These findings demonstrate that encouraging participants with serious mental illness enrolled in lifestyle interventions to collect more steps may contribute to greater weight loss. This suggests that wearable devices may offer a feasible and potentially effective strategy for supporting behavioral weight loss in community mental health settings. PMID- 27479106 TI - E-mail support as an adjunct to cognitive-behavioral group therapy for social anxiety disorder: Impact on dropout and outcome. AB - The present study evaluates the impact of semi-individualized e-mail support as an adjunct to cognitive behavioral group therapy (CBGT) for social anxiety disorder (SAD) on dropout and outcome. The effectiveness of additional semi individualized e-mail support was evaluated for the whole sample and for a subsample of patients at risk of dropping out of therapy. A total of 91 patients with SAD were allocated either to the intervention condition (CBGT with e-mail support), or to the control condition (CBGT without e-mail support). Anxiety symptoms, depression, global symptomatology and life satisfaction were assessed at pretreatment, post-treatment and follow-up (3, 6 and 12 months). From pre treatment to post-treatment, both groups improved significantly on all symptom measures. Therapy gains were maintained at the 1-year follow-up. Subsample analyses showed that CBGT+e-mail was more effective than CGBT alone in reducing symptom severity among patients missing at least two therapy sessions. Additionally, in this subgroup, those receiving additional e-mail support showed a tendency towards lower dropout rates. Based on the results of this study, semi individualized e-mail support between sessions seems to enhance the effectiveness of CBGT for SAD patients at risk of dropping out of treatment and should be considered as an additional tool in clinical practice. PMID- 27479107 TI - Food addiction and the outcome of bariatric surgery at 1-year: Prospective observational study. AB - PURPOSES: The objectives of the current study were to determine the prevalence of food addiction in bariatric surgery candidates and whether food addiction is associated with weight loss after bariatric surgery. METHODS: This prospective observational study was performed on morbidly obese patients who had been found suitable for bariatric surgery. Follow-up was conducted at the 6 and 12 month post-surgery. The Yale Food Addiction Scale (YFAS) was used to determine food addiction. RESULTS: One hundred seventy-eight patients were included. Pre operative food addiction was found in 57.8% of patients. Food addiction prevalence decreased at the 6 and 12 month follow ups, to 7.2% and 13.7% respectively. There were no statistically differences between those with food addiction and those without addiction with regard to weight loss measured as percent of excess BMI at the 12 month follow-up. CONCLUSION: Food addiction as measured by the YFAS decreases significantly after bariatric surgery. The presence of food addiction before surgery was not associated with weight loss as measured EBL%. However, in view of the increase in BMI, 2 years after surgery longer follow up studies are warranted. PMID- 27479109 TI - Factors associated with family violence by persons with psychiatric disorders. AB - Family violence by persons with psychiatric disorders (PD) is a highly under researched area. The primary objective of the present analysis was to identify perpetrator, victim, and interaction/relationship factors associated with this phenomenon. The secondary objective was to examine the extent to which the relationship between caregiving and family violence was mediated by limit-setting practices used towards relatives with PD. 573 adults across the U.S. with an adult relative with PD completed an online survey. Multivariate logistic regression was performed examining the association of factors with the occurrence of family violence. Mediation was assessed with Sobel testing. Family violence was significantly associated with the following factors: perpetrator-income, illegal drug use, psychiatric hospitalization, treatment attendance, and use of medications; victim-age, employment status, income, and mental health status; interaction/relationship-parental relationship, co-residence, use of limit setting practices, representative payeeship, and unofficial money management. Mediation was statistically significant. Increasing access to mental health and/or substance abuse treatment may decrease the risk of family violence. Interventions may benefit from attempting to decrease/modify the use of limit setting practices. Where family representative payeeship or unofficial money management exists, it is advisable for practitioners to assess and address financial coercion and promote greater collaboration in financial decision making. PMID- 27479108 TI - Clinical correlates of plasma brain-derived neurotrophic factor in post-traumatic stress disorder spectrum after a natural disaster. AB - Clinical correlates of plasma Brain-Derived Neurotrophic Factor (BDNF) have been investigated in a clinical population with Post Traumatic Stress Disorder (PTSD) symptoms and healthy control subjects who survived to the L'Aquila 2009 earthquake. Twenty-six outpatients and 14 control subjects were recruited. Assessments included: Structured Clinical Interview for DSM-IV Axis-I disorders Patient Version, Trauma and Loss Spectrum-Self Report (TALS-SR) for post traumatic spectrum symptoms. Thirteen patients were diagnosed as Full PTSD and 13 as Partial PTSD. The subjects with full-blown PTSD showed lower BDNF level than subjects with partial PTSD and controls. Different relationship patterns of BDNF with post-traumatic stress spectrum symptoms have been reported in the three samples. Our findings add more insight on the mechanisms regulating BDNF levels in response to stress and further proofs of the utility of the distinction of PTSD into full and partial categories. PMID- 27479110 TI - Nonsuicidal self-injury disorder: Does Criterion B add diagnostic utility? AB - The current paper evaluates Criterion B for Non-Suicidal Self-Injury Disorder, which states that non-suicidal self-injury (NSSI) must occur for at least one function. The majority of individuals who engage in NSSI report at least one function, so it is unclear if Criterion B provides diagnostic utility in individuals who already meet Criterion A (i.e., NSSI occurring on 5 or more days in the past 12 months). This paper compared individuals meeting Criterion A (threshold group) to those with 1-4 acts of NSSI in the past year (subthreshold group) in two different samples. The first sample included 217 undergraduate students, and the second sample included 1082 individuals from a behavioral health hospital, all with past-year NSSI. The majority of both samples reported at least one function of NSSI (99%). For the undergraduate sample, the number of and level of endorsement of functions were similar across threshold and subthreshold groups. For the behavioral health sample, the threshold group endorsed significantly more functions for NSSI and greater endorsement of affect regulation, self-punishment, and toughness compared to the subthreshold group. While some differences were found between NSSI groups, overall endorsement of functions for NSSI appears to be a universal characteristic regardless of NSSI frequency. PMID- 27479111 TI - Risks of Myocardial Infarction, Death, and Diabetes in Identical Twin Pairs With Different Body Mass Indexes. AB - Importance: Observational studies have shown that obesity is a major risk factor for cardiovascular disease and death. The extent of genetic confounding in these associations is unclear. Objective: To compare the risk of myocardial infarction (MI), type 2 diabetes, and death in monozygotic (MZ) twin pairs discordant for body mass index (BMI). Design, Setting, and Participants: A cohort of 4046 MZ twin pairs with discordant BMIs (difference >0.01) was identified using the nationwide Swedish twin registry. The study was conducted from March 17, 1998, to January 16, 2003, with follow-up regarding incident outcomes until December 31, 2013. Main Outcomes and Measures: The combined primary end point of death or MI and the secondary end point of incident diabetes were evaluated in heavier compared with leaner twins in a co-twin control analysis using multivariable conditional logistic regression. Results: Mean (SD) baseline age for both cohorts was 57.6 (9.5) years (range, 41.9-91.8 years). During a mean follow-up period of 12.4 (2.5) years, 203 MIs (5.0%) and 550 deaths (13.6%) occurred among heavier twins (mean [SD] BMI, 25.9 [3.6] [calculated as weight in kilograms divided by height in meters squared]) compared with 209 MIs (5.2%) and 633 deaths (15.6%) among leaner twins (mean [SD] BMI, 23.9 [3.1]; combined multivariable adjusted odds ratio [OR], 0.75; 95% CI, 0.63-0.91). Even in twin pairs with BMI discordance of 7.0 or more (mean [SE], 9.3 [0.7]), where the heavier twin had a BMI of 30.0 or more (n = 65 pairs), the risk of MI or death was not greater in heavier twins (OR, 0.42; 95% CI, 0.15-1.18). In contrast, in the total cohort of twins, the risk of incident diabetes was greater in heavier twins (OR, 2.14; 95% CI, 1.61-2.84). Finally, increases in BMI since 30 years before baseline were not associated with the later risk of MI or death (OR, 0.97; 95% CI, 0.89-1.05) but were associated with the risk of incident diabetes (OR, 1.13; 95% CI, 1.01-1.26). Conclusions and Relevance: In MZ twin pairs, higher BMI was not associated with an increased risk of MI or death but was associated with the onset of diabetes. These results may suggest that lifestyle interventions to reduce obesity are more effective in decreasing the risk of diabetes than the risk of cardiovascular disease or death. PMID- 27479113 TI - Reference to Out-of-Date Guideline. PMID- 27479112 TI - Ubiquitin-specific peptidase 2 as a potential link between microRNA-125b and psoriasis. AB - BACKGROUND: The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. miR-125b has previously been shown to be strongly associated with psoriasis, and presents as an obvious candidate for further investigation. OBJECTIVES: To elucidate the specific pathway and mechanism of interest in this association. METHODS: A three-step bioinformatical hypothesis-generation pipeline was performed to identify genes of interest. This pipeline was based on miR-125b binding, expression in psoriatic lesions and genome-wide association study-based evidence of involvement. The identified candidate gene was then carefully evaluated using luciferase binding assays, in vitro overexpression, small interfering RNA knock-down and downstream gene readouts. RESULTS: Based on our bioinformatical pipeline, ubiquitin-specific peptidase 2 was selected as a likely candidate for a mechanistic explanation for psoriasis association. After establishing a definite connection to miR-125b, we proceeded to show that modulation of nuclear factor kappa B-mediated inflammation is the likely mechanism through which this miRNA gene pair functioned. CONCLUSIONS: Shedding further light on the multifactorial causes of psoriasis is essential, if the goal is to progress towards finer control of therapeutic tools in disease management. Findings, such as the ones presented herein, are therefore necessary in order to achieve the future of personalized medicine. PMID- 27479116 TI - 7-Year-Old With a Painful Rash. PMID- 27479117 TI - Errors in Reference Citation and Reference. PMID- 27479118 TI - When Your Child Is Referred to a Therapist. PMID- 27479121 TI - From Emotional Tsunami to Empathy. PMID- 27479119 TI - Next-generation personalised medicine for high-risk paediatric cancer patients - The INFORM pilot study. AB - The 'Individualized Therapy for Relapsed Malignancies in Childhood' (INFORM) precision medicine study is a nationwide German program for children with high risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of 'intermediate' or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase-mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re biopsy at relapse. This study demonstrates the feasibility of comprehensive, real time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine. PMID- 27479120 TI - Bat trait, genetic and pathogen data from large-scale investigations of African fruit bats, Eidolon helvum. AB - Bats, including African straw-coloured fruit bats (Eidolon helvum), have been highlighted as reservoirs of many recently emerged zoonotic viruses. This common, widespread and ecologically important species was the focus of longitudinal and continent-wide studies of the epidemiological and ecology of Lagos bat virus, henipaviruses and Achimota viruses. Here we present a spatial, morphological, demographic, genetic and serological dataset encompassing 2827 bats from nine countries over an 8-year period. Genetic data comprises cytochrome b mitochondrial sequences (n=608) and microsatellite genotypes from 18 loci (n=544). Tooth-cementum analyses (n=316) allowed derivation of rare age-specific serologic data for a lyssavirus, a henipavirus and two rubulaviruses. This dataset contributes a substantial volume of data on the ecology of E. helvum and its viruses and will be valuable for a wide range of studies, including viral transmission dynamic modelling in age-structured populations, investigation of seasonal reproductive asynchrony in wide-ranging species, ecological niche modelling, inference of island colonisation history, exploration of relationships between island and body size, and various spatial analyses of demographic, morphometric or serological data. PMID- 27479122 TI - Exploiting Single-Cell Quantitative Data to Map Genetic Variants Having Probabilistic Effects. AB - Despite the recent progress in sequencing technologies, genome-wide association studies (GWAS) remain limited by a statistical-power issue: many polymorphisms contribute little to common trait variation and therefore escape detection. The small contribution sometimes corresponds to incomplete penetrance, which may result from probabilistic effects on molecular regulations. In such cases, genetic mapping may benefit from the wealth of data produced by single-cell technologies. We present here the development of a novel genetic mapping method that allows to scan genomes for single-cell Probabilistic Trait Loci that modify the statistical properties of cellular-level quantitative traits. Phenotypic values are acquired on thousands of individual cells, and genetic association is obtained from a multivariate analysis of a matrix of Kantorovich distances. No prior assumption is required on the mode of action of the genetic loci involved and, by exploiting all single-cell values, the method can reveal non deterministic effects. Using both simulations and yeast experimental datasets, we show that it can detect linkages that are missed by classical genetic mapping. A probabilistic effect of a single SNP on cell shape was detected and validated. The method also detected a novel locus associated with elevated gene expression noise of the yeast galactose regulon. Our results illustrate how single-cell technologies can be exploited to improve the genetic dissection of certain common traits. The method is available as an open source R package called ptlmapper. PMID- 27479123 TI - Urine Protein/Creatinine Ratios during Labor: A Prospective Observational Study. AB - PURPOSE: To evaluate the utility of urine protein/creatinine ratio (uPCR) measurements among healthy parturients at term we performed a prospective cohort study at a community teaching hospital. METHODS: Serial urine samples were collected. Ninety-three women contributed 284 urine samples. uPCRs were determined. Multiple imputation and paired sampled analysis was performed when appropriate. RESULTS: Two-thirds (63/93) of women had at least one measured uPCR >= 0.3. One-third (31/93) had a uPCR >= 0.3 at admission, including 39.1% (9/23) of women not in labor. Median (IQR) uPCRs increased during labor and after delivery: latent phase/no labor, 0.15 (0.06-0.32); active phase, 0.29 (0.10 0.58); early postpartum, 0.45 (0.18-1.36) (all p < 0.04). Median uPCRs were significantly < 0.3 in the latent phase and significantly > 0.3 in the immediate postpartum period (p < 0.01). Women who labored before cesarean delivery had the highest early postpartum uPCRs: median (IQR) 1.16 (0.39-1.80). A negative urine dipstick protein result did not exclude uPCR >= 0.3. uPCRs were similar when compared by method of urine collection. CONCLUSION: uPCR >= 0.3 is common among healthy women with uncomplicated pregnancies at term. uPCR increases during labor and is not a reliable measure of pathologic proteinuria at term or during the peripartum period. PMID- 27479124 TI - Two-dimensional Covalent Organic Framework Thin Films Grown in Flow. AB - Two-dimensional covalent organic frameworks (2D COFs) are crystalline polymer networks whose modular 2D structures and permanent porosity motivate efforts to integrate them into sensing, energy storage, and optoelectronic devices. These applications require forming the material as a thin film instead of a microcrystalline powder, which has been achieved previously by including a substrate in the reaction mixture. This approach suffers from two key drawbacks: COF precipitates form concurrently and contaminate the film, and variable monomer and oligomer concentrations during the polymerization provide poor control over film thickness. Here we address these challenges by growing 2D COF thin films under continuous flow conditions. Initially homogeneous monomer solutions polymerize while pumped through heated tubing for a given residence time, after which they pass over a substrate. When the residence time and conditions are chosen judiciously, 2D COF powders form downstream of the substrate, and the chemical composition of the solution at the substrate remains constant. COF films grown in flow exhibit constant rates of mass deposition, enabling thickness control as well as access to thicker films than are available from previous static growth procedures. Notably, the crystallinity of COF films is observed only at longer residence times, suggesting that oligomeric and polymeric species play an important role in forming the 2D COF lattice. This approach, which we demonstrate for four different frameworks, is both a simple and powerful method to control the formation of COF thin films. PMID- 27479125 TI - The Use of a New CellCollector to Isolate Circulating Tumor Cells from the Blood of Patients with Different Stages of Prostate Cancer and Clinical Outcomes - A Proof-of-Concept Study. AB - BACKGROUND AND METHODS: Circulating tumor cells (CTCs) constitute a useful approach for personalized medicine. Nevertheless, the isolation of these cells remains very challenging because they rarely circulate in the blood. Another current problem is the cancer-specific characterization of these cells, which requires a method that allows for the molecular and immunocytochemical profiling of all captured cells. The purpose of our proof of concept study was to investigate the use of a medical wire (CellCollector, GILUPI) to isolate CTCs in the blood of prostate cancer (PCa) patients, which allowed CTCs to be counted and molecularly characterized. Forty-three PCa patients in different stages and 11 control subjects were studied. Some randomized samples were used to detect tumor associated transcripts, such as prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA) and epidermal growth factor receptor (EGFR), in the isolated CTCs. RESULTS: The mean CTC counts were 4.6 CTCs [range, 0-8] in patients with localized PCa, 16.8 CTCs [range, 10-25] in patients with locally advanced PCa, and 26.8 CTCs [range, 0-98] in patients with metastatic PCa. The median follow-up time was 24 months, and there was a significant difference in the cancer-specific survival rates. Patients with CTC counts under 5 CTCs lived significantly longer (p = 0.035) than patients with more than 5 CTCs. We also demonstrated that the captured CTCs could be molecularly characterized. We detected tumor-associated transcripts of EGFR and PSMA in patients with metastatic PCa in 42.8% and 14.3% of the analyzed samples, respectively. CONCLUSION: Our results indicate that the sensitive isolation and molecular characterization of CTCs can be achieved ex vivo using the wire. Patients with more than 5 CTCs had a mortality risk that was 7.0 times greater that of those with fewer than 5 CTCs (hazard ratio 7.0 95%, CI 1.1-29.39). This proof of concept was required for the approval of the use of the CellCollector in a clinical study for the in vivo isolation of CTCs from the blood stream of PCa patients by the Federal Institute for Drugs and Medical devices (Germany, BfArM). PMID- 27479126 TI - Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation. AB - BACKGROUND: Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated. METHODS AND RESULTS: We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35). CONCLUSIONS: Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV. PMID- 27479127 TI - Fluorescence Concentric Triangles: A Case of Chemical Heterogeneity in WS2 Atomic Monolayer. AB - We report a novel optical property in WS2 monolayer. The monolayer naturally exhibits beautiful in-plane periodical and lateral homojunctions by way of alternate dark and bright band in the fluorescence images of these monolayers. The interface between different fluorescence species within the sample is distinct and sharp. This gives rise to intriguing concentric triangular fluorescence patterns in the monolayer. The novel optical property of this special WS2 monolayer is facilitated by chemical heterogeneity. The photoluminescence of the bright band is dominated by emissions from trion and biexciton while the emission from defect-bound exciton dominates the photoluminescence at the dark band. The discovery of such concentric fluorescence patterns represents a potentially new form of optoelectronic or photonic functionality. PMID- 27479129 TI - Photochromic Dithienylethene-Containing Boron(III) Ketoiminates: Modulation of Photo-Responsive Behavior through Variation of Intramolecular Motion. AB - A series of dithienylethene-containing boron(III) ketoiminates, as well as their corresponding beta-ketoimine ligands, have been synthesized and characterized. The photophysical, electrochemical, and photochromic properties of the compounds have been studied. Photocyclization has been found to be suppressed upon introduction of a phenyl substituent on the nitrogen atom of the beta-ketoiminate core, whereas photochromism could be observed by replacement of the phenyl substituent with a bulky mesityl group. It is believed that the steric effect of the mesityl unit restricts molecular rotation, resulting in such a prominent difference in the photochromic properties. PMID- 27479128 TI - Spectroscopic Studies of the Super Relaxed State of Skeletal Muscle. AB - In the super-relaxed state of myosin, ATPase activity is strongly inhibited by binding of the myosin heads to the core of the thick filament in a structure known as the interacting-heads motif. In the disordered relaxed state myosin heads are not bound to the core of the thick filament and have an ATPase rate that is 10 fold greater. In the interacting-heads motif the two regulatory light chains appear to bind to each other. We have made single cysteine mutants of the regulatory light chain, placed both paramagnetic and fluorescent probes on them, and exchanged them into skinned skeletal muscle fibers. Many of the labeled light chains tended to disrupt the stability of the super-relaxed state, and showed spectral changes in the transition from the disordered relaxed state to the super relaxed state. These data support the putative interface between the two regulatory light chains identified by cryo electron microscopy and show that both the divalent cation bound to the regulatory light chain and the N-terminus of the regulatory light chain play a role in the stability of the super-relaxed state. One probe showed a shift to shorter wavelengths in the super-relaxed state such that a ratio of intensities at 440nm to that at 520nm provided a measure of the population of the super-relaxed state amenable for high throughput screens for finding potential pharmaceuticals. The results provide a proof of concept that small molecules that bind to this region can destabilize the super-relaxed state and provide a method to search for small molecules that do so leading to a potentially effective treatment for Type 2 diabetes and obesity. PMID- 27479130 TI - Intratumoral Genetic Heterogeneity in Rectal Cancer: Are Single Biopsies representative of the entirety of the tumor? AB - OBJECTIVE: Demonstrate intratumoral genetic heterogeneity in rectal cancer. BACKGROUND: Several clinical management decisions in rectal cancer may be influenced by pretreatment biopsy information. However, in the setting of significant intratumoral heterogeneity, biopsies may not be representative of the entirety of the tumor and limit the reliability of the information provided from them for clinical decision management. METHODS: Three fragments from a single rectal adenocarcinoma were chosen for whole-exome sequencing followed by mutation detection analysis. About 25 Gb of unambiguously mapped sequences were generated for each sample resulting in a median fold-coverage of 35x. Captured sequences mapped to the reference human genome were then used for the detection of somatic point mutations. RESULTS: Overall, 193 unique somatic point mutations were identified. Only 53 (27%) of these were shared by all three fragments, including known genes involved in early phases of the adenoma-carcinoma sequence (such as, APC). Approximately, 115 (59%) mutations were exclusively present in only one of the fragments, including mutations in "driver" genes (DNAH12). Jaccard distances showed a median distance of 0.603 for pair-wise comparison of fragments indicating significant heterogeneity between them. CONCLUSIONS: Considerable intratumoral heterogeneity is present among naive rectal cancers. The majority of point mutations detected in different fragments from rectal cancers are frequently unique to a single fragment. These findings support that gene mutations found on single pretreatment biopsies will not necessarily be representative of mutations present in the entirety of the tumor and therefore may limit the utility of the biological information provided by single biopsy fragments for clinical management decisions. PMID- 27479131 TI - Hepatobiliary Scintigraphy in ALPPS: A Response. PMID- 27479132 TI - Reply to "Reducing Nonanastomotic Biliary Strictures in Donation After Circulatory Death Liver Transplantation: Cold Ischemia Matters". PMID- 27479134 TI - Methanol dimer formation drastically enhances hydrogen abstraction from methanol by OH at low temperature. AB - The kinetics of the reaction of methanol with hydroxyl radicals is revisited in light of the reported new kinetic data, measured in cold expansion beams. The rate constants exhibit an approximately 10(2)-fold increase when the temperature decreases from 200 to 50 K, a result that cannot be fully explained by tunneling, as we confirm by new calculations. These calculations also show that methanol dimers are much more reactive to hydroxyl than monomers and imply that a dimer concentration of about 30% of the equilibrium concentration can account quantitatively for the observed rates. The assumed presence of dimers is supported by the observation of cluster formation in these and other cold beams of molecules subject to hydrogen bonding. The calculations imply an important caveat with respect to the use of cold expansion beams for the study of interstellar chemistry. PMID- 27479133 TI - Application of Next-Generation Sequencing to Evaluate the Profile of Noroviruses in Pre- and Post-Depurated Oysters. AB - The development of procedures for the efficient removal or inactivation of noroviruses from contaminated oysters is of great interest in oyster production. However, there is a critical limitation for evaluating the depuration efficacy of presently available procedures, as no suitable cell culture system currently exists to cultivate noroviruses. Thus, we applied a next-generation sequencing (NGS) technique to characterize norovirus genotypes in pre- and post-depurated oysters. As a result, we revealed the diversity of noroviruses in pre- and post depurated oysters. Although the applied depuration procedure could reduce the number of bacterial agents to the level recommended by the Japanese Ministry of Health, Labour and Welfare, no significant changes were observed in the detection rate and the proportion of norovirus group (G) I and GII genotypes. To our knowledge, this is the first report to evaluate the profile of noroviruses in pre and post-depurated oysters, specifically with respect to norovirus removal, using NGS; the findings imply that the removal of noroviruses from oysters through depuration is not presently sufficient. Further studies are needed to develop a more suitable depuration procedure for removing and/or inactivating noroviruses from contaminated oysters. PMID- 27479135 TI - Photoactive Metal-Organic Framework and Its Film for Light-Driven Hydrogen Production and Carbon Dioxide Reduction. AB - The design of a new photocatalytic system and integrating the essential components in a structurally controlled manner to create artificially photosynthetic systems is high desirable. By incorporating a photoactive triphenylamine moiety to assemble a Gd-based metal-organic framework as a heterogeneous photosensitizer, new artificial systems were constructed for the proton and carbon dioxide reduction under irradiation. The assembled MOFs exhibited a one-dimensional metal-oxygen pillar that was connected together by the depronated TCA(3-) ligands to form a three-dimensional noninterpenetrating porous framework. The combining of proton reduction and/or the carbon dioxide reduction catalysts, i.e., the Fe-Fe hydrogenase active site models and the Ni(Cyclam) complexes, initiated a photoinduced single electron transfer from its excited state to the substrate. The system exhibited an initial TOF of 320 h(-1) of hydrogen per catalyst and an overall quantum yield of about 0.21% and is able to reduce carbon dioxide under irradiation. The deposit of the photoactive Gd-TCA into the film of an alpha-Al2O3 plate provided a platform for the practical applications through prolonging the lifetime of the artifical system and allowed the easily operated devices being recyclable as a promising photocatalytic system. PMID- 27479137 TI - The efficacy of intra-alveolar 0.2% chlorhexidine gel on alveolar osteitis: a meta-analysis. AB - OBJECTIVES: The objective of this meta-analysis was to assess the effect of 0.2% chlorhexidine gel in preventing alveolar osteitis following mandibular third molar extraction(s). METHODS: PubMed, Cochrane Library, Embase, Web of Science, Science Direct and the references of identified articles were searched for relevant studies that met our eligibility criteria. Treatment effects were combined by meta-analysis using RevMan 5.3 and Stata 12.0 software. RESULTS: We included 11 trials in this meta-analysis. Compared to the control, 0.2% chlorhexidine gel reduced the risk of alveolar osteitis by 62% (RR = 0.38, 95% CI = 0.28-0.53, P < 0.00001) following mandibular third molar extraction(s). The subgroup analysis results indicated that 0.2% chlorhexidine gel reduced the risk of alveolar osteitis after mandibular third molar extraction(s) by 75% (RR = 0.25, 95% CI = 0.11-0.58) and 56% (RR = 0.44, 95% CI = 0.30-0.63) compared to no treatment and placebo, respectively. However, the occurrence of alveolar osteitis following mandibular third molar extraction(s) was not significantly different between 0.2% chlorhexidine gel and 0.12% chlorhexidine mouthwash (RR = 0.24, 95% CI = 0.06-1.00). CONCLUSION: The results showed that 0.2% chlorhexidine gel was effective in preventing alveolar osteitis after lower third molar extraction(s). PMID- 27479136 TI - Characterisation of the Whole Blood mRNA Transcriptome in Holstein-Friesian and Jersey Calves in Response to Gradual Weaning. AB - Weaning of dairy calves is an early life husbandry management practice which involves the changeover from a liquid to a solid feed based diet. The objectives of the study were to use RNA-seq technology to examine the effect of (i) breed and (ii) gradual weaning, on the whole blood mRNA transcriptome of artificially reared Holstein-Friesian and Jersey calves. The calves were gradually weaned over 14 days (day (d) -13 to d 0) and mRNA transcription was examined one day before gradual weaning was initiated (d -14), one day after weaning (d 1), and 8 days after weaning (d 8). On d -14, 550 genes were differentially expressed between Holstein-Friesian and Jersey calves, while there were 490 differentially expressed genes (DEG) identified on d 1, and 411 DEG detected eight days after weaning (P < 0.05; FDR < 0.1). No genes were differentially expressed within breed, in response to gradual weaning (P > 0.05). The pathways, gene ontology terms, and biological functions consistently over-represented among the DEG between Holstein-Friesian and Jersey were associated with the immune response and immune cell signalling, specifically chemotaxis. Decreased transcription of several cytokines, chemokines, immunoglobulin-like genes, phagocytosis-promoting receptors and g-protein coupled receptors suggests decreased monocyte, natural killer cell, and T lymphocyte, chemotaxis and activation in Jersey compared to Holstein-Friesian calves. Knowledge of breed-specific immune responses could facilitate health management practices better tailored towards specific disease sensitivities of Holstein-Friesian and Jersey calves. Gradual weaning did not compromise the welfare of artificially-reared dairy calves, evidenced by the lack of alterations in the expression of any genes in response to gradual weaning. PMID- 27479138 TI - In Situ Reduction of Silver by Polydopamine: A Novel Antimicrobial Modification of a Thin-Film Composite Polyamide Membrane. AB - We report a facile method for the antimicrobial modification of a thin-film composite polyamide reverse osmosis (RO) membrane. The membrane surface was first coated with polydopamine (PDA), whose reducing catechol groups subsequently immobilized silver ions in situ to form uniformly dispersed silver nanoparticles (AgNPs) inside the coating layer. Agglomeration of AgNPs was not observed despite a high silver loading of 13.3 +/- 0.3 MUg/cm(2) (corresponding to a surface coverage of 18.5% by the nanoparticles). Both diffusion inhibition zone tests and colony formation unit tests showed clear antimicrobial effects of the silver loaded membranes on model bacteria Bacillus subtilis and Escherichia coli. Furthermore, the silver immobilized membrane had significantly enhanced salt rejection compared to the control PDA coated membrane, which is attributed to the preferential formation of AgNPs at defect sides within the PDA layer. This self healing mechanism can be used to prepare antimicrobial RO membranes with improved salt rejection without scarifying the membrane permeability, which provides a new dimension for membrane surface modification. PMID- 27479139 TI - Characterization of the Methylthioadenosine Phosphorylase Polymorphism rs7023954 Incidence and Effects on Enzymatic Function in Malignant Melanoma. AB - Deficiency of methylthioadenosine phosphorylase (MTAP) supports melanoma development and progression through accumulation of its substrate 5' methylthioadenosine (MTA), which leads amongst others to a constitutive inhibition of protein arginine methyltransferases (PRMTs) and activation of the transcription factor AP-1 via the receptor ADORA2B. Genetic association studies have also suggested that genetic polymorphism in MTAP may modulate the risk of melanoma. Here, we investigated the only globally common non-synonymous single nucleotide polymorphism (SNP) reported to date for MTAP. The SNP rs7023954 is located in exon 3 (c.166G>A), and leads to the conservative substitution of one branched-chain amino acid residue (valine) for another (isoleucine) at position 56 (p.Val56Ile). Whereas genotype frequencies in normal and primary melanoma tissues or cell lines were in Hardy-Weinberg equilibrium based on cDNA amplicon sequencing, a marked (P = 0.00019) deviation was observed in metastatic melanoma tissues and cell lines due to a deficit of heterozygotes. Enzyme assays conducted on the co-dominantly expressed alleles revealed no difference in the conversion rate of MTA to adenine and 5-methylthioribose-1-phosphate, indicating that this known enzymatic activity does not modulate the tumor suppressive function of MTAP. PMID- 27479140 TI - The marmoset: An emerging model to unravel the evolution and development of the primate neocortex. AB - Throughout evolution, the neocortex has undergone a dramatic expansion providing the substrate for increasingly complex cognitive abilities, culminating with humans. The enlargement of the neocortex did not affect its' basic organization, which is remarkably conserved from rodents to primates. The mouse has thus proven an advantageous model to decipher the molecular and cellular mechanisms supporting neocortical development. However, it is of limited benefit when studying the mechanisms leading to the inclusion of higher order association areas, which form the largest fraction of the primate neocortex. In the quest for a suitable nonhuman primate model to study the developmental mechanism of neocortical patterning and expansion, researchers focussed on the Old World macaque, routinely employed in functional and behavioral studies. However, the species has many limitations making studies difficult and/or impractical. Therefore, in the past couple of decades, the New World common marmoset (Callithrix jacchus) has drawn much attention and become an accepted model. The marmoset has the advantage of a smooth neocortical sheet, enabling the direct correspondence between developing cortices and the comprehensive map established for the adult, with a significant amount of cortical maturation occurring during the postnatal period. This review presents the contributions of recent marmoset studies to our understanding of the mechanisms regulating corticogenesis in a complex species, the molecular control of neocortical patterning and the sequential maturation of visual cortical areas while commenting on the future of the species in the field. Furthermore, while these new findings are relevant to developmental biology, in order to understand how new cortical areas have emerged to expand cognitive abilities, they also represent a foundation for the better understanding of developmental cognitive disorders. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 263-272, 2017. PMID- 27479141 TI - Increasing Serum Albumin Level Shortly After Gastrostomy Tube Insertion Predicts Longer Survival in Elderly Patients With Dementia. AB - GOAL: To identify factors influencing survival after percutaneous endoscopic gastrostomy (PEG) tube insertion in elderly patients with severe dementia. BACKGROUND: Use of PEG in patients with dementia raises medical and ethical questions. STUDY: The cohort included 189 patients aged >=64 years with severe dementia who underwent PEG tube insertion in 2002 to 2011 at a tertiary hospital and were followed through 2014. Data were collected on background diseases, laboratory tests conducted 14 (+/-10) days before and 90 (+/-10) days after PEG, and date of death. Multivariate Cox regression analysis was performed and cumulative survival curves plotted. RESULTS: Mean baseline serum albumin level was significantly lower in patients who died <=30 days after PEG (n=32, 16.9%) than patients who survived longer (2.9+/-0.5 vs. 3.3+/-0.5 g/dL, P<0.001), and significantly higher in patients who survived 1 year after PEG (n=96, 50.8%) than patients who died earlier (3.4+/-0.5 vs. 3.1+/-0.5 g/dL, P=0.002). No significant differences were found for the other laboratory parameters. After adjustment for background diseases, serum albumin level above the median (3.3 g/dL) was the only predictor of survival (hazard ratio 0.51; 95% confidence interval, 0.37-0.72; P<0.001). Patients with stable/increased serum albumin levels at 90 days after PEG (n=80, 42.3%) survived longer than patients with decreased levels. The only predictor of survival after adjustment for age and background diseases was a stable/increased albumin level at 90 days (hazard ratio 0.59; 95% confidence interval, 0.42-0.85; P=0.004). CONCLUSIONS: Survival after PEG tube insertion is associated with a higher serum albumin level at baseline and a stable/increased serum albumin level during follow-up. PMID- 27479142 TI - Longitudinal Evaluation of Noninvasive Biomarkers for Eosinophilic Esophagitis. AB - BACKGROUND: The diagnosis and management of eosinophilic esophagitis (EoE) often requires multiple endoscopies. Serum biomarkers can be elevated in EoE patients, but their clinical utility in diagnosis and assessing response to treatment is not well established. GOALS: To evaluate serum biomarkers in EoE subjects compared with controls and assess longitudinally in response to treatment. STUDY: We conducted a prospective cohort study of children and adults undergoing esophagogastroduodenoscopy for suspected EoE. After completing an 8-week course of proton-pump inhibitor therapy, esophageal mucosal biopsies were obtained, as well as, serum analysis of absolute eosinophil count (AEC), eotaxin-3, eosinophil derived neurotoxin (EDN), eosinophil cationic protein (ECP) and interleukin-5. Subjects with normal endoscopic and histologic findings constituted controls. Those meeting criteria for EoE underwent repeat esophagogastroduodenoscopy and biomarker measurements following treatment with topical steroids for 8 weeks. RESULTS: Median levels of AEC (263.50 vs. 102 cu/mm, P<0.001), ECP (26.98 vs. 5.20 ng/mL, P<0.001) and EDN (31.70 vs. 14.18 ng/mL, P=0.004) were significantly elevated in EoE subjects compared with controls and correlated with esophageal eosinophilia. Levels of AEC (odds ratio, 1.79; 95% confidence interval, 1.28 2.64) and ECP (odds ratio, 1.61; 95% confidence interval, 1.23-2.36) were associated with a diagnosis of EoE. Among the 5 biomarkers evaluated, only AEC significantly predicted esophageal eosinophilia following topical steroid therapy in EoE subjects (P=0.006). CONCLUSIONS: AEC, ECP, and EDN were higher in EoE subjects compared with controls and correlated with degree of esophageal eosinophilia. Furthermore, AEC predicted post-treatment eosinophilia, suggesting a potential role in monitoring EoE disease activity. PMID- 27479143 TI - Elevated Liver Enzymes and Mortality in Older Individuals: A Prospective Cohort Study. AB - AIM OF THE STUDY: The aim of the study was to determine the excess risk of all cause and cardiovascular mortality in older people with elevated liver enzymes [alanine transaminase (ALT) and gamma glutamyltransferase (GGT)]. METHODS: We utilized data from a large, prospective, population based study of 2061 people aged 50 to 99 years with linkage to a National Death Registry. Participants were categorized as having elevated liver enzymes using standard thresholds (for males, GGT>51 and ALT>40 IU/L, and GGT>33 and ALT>31 IU/L for females). Adjusted Cox proportional hazards models assessed the association of elevated liver enzymes and mortality with long duration follow-up. RESULTS: Over a median follow up of 10 years (20,145 person years), 701 people died, including 203 (34%) from cardiovascular disease. Cox regression models adjusted for sex, age, smoking, and alcohol intake indicated that people with elevated liver enzymes had an increased risk of all-cause mortality that was modified by age (test for interaction P=0.01). Age-stratified analyses demonstrated no increased risk at younger ages [age 59 y and below; hazard ratio (HR): 0.46; 95% confidence interval, 0.06 3.49], but increased risk with age; age 60 to 69, HR: 1.05 (0.53-2.07), age 70 to 79 years, HR: 1.54 (0.81 to 2.93), and age 80 years and above, HR: 3.53 (1.55 to 8.04). Similarly, the risk of cardiovascular mortality with elevated liver enzymes was also modified by, and increased with age (test for interaction P=0.02); age 70 to 79, HR: 3.15 (1.37 to 7.23), age 80 years and above, HR: 6.86 (2.44 to 19.30). CONCLUSIONS: In community-dwelling elderly persons, an elevation in both ALT and GGT are associated with an excess risk of all-cause and cardiovascular mortality which increases with age. PMID- 27479144 TI - Complementary and Alternative Medicine Use in United States Adults With Liver Disease. AB - GOALS: To describe the complementary and alternative medicine (CAM) use in US adults with liver disease. BACKGROUND: The prevalence and patterns of CAM use among US adults with liver disease have not been well characterized. The 2012 National Health Interview Survey is considered the most current and comprehensive source of information on CAM use in US adults. STUDY: Using the results of the 2012 National Health Interview Survey, the prevalence of CAM use, most common modalities used, reasons for CAM use, perceived benefits, perceived helpfulness and importance, and disclosure of CAM to health care providers were compared between adults with and without liver disease. RESULTS: Of the 647 adults with liver disease, 41% reported using CAM in the prior year, compared with 33% of adults without liver disease. The most common modality was herbs and supplements (23%), and 3% of respondents reported consumption of a potentially hepatotoxic substance in the previous 30 days. Only a small proportion of CAM therapies were used specifically for liver disease, with milk thistle being the most common. Among respondents with liver disease, CAM was used more commonly for anxiety or depression, fatigue, and substance use. The majority believed that these therapies improved health. Nearly one-third of therapies were not reported to health care providers, mostly due to failure of the provider to ask. CONCLUSIONS: CAM use, particularly herbs and supplements, is prevalent among US adults with liver disease. Many do not disclose their CAM use to their providers, despite some using potentially hepatotoxic substances. PMID- 27479145 TI - Endoscopic Bubble Trouble: Hyperbaric Oxygen Therapy for Cerebral Gas Embolism During Upper Endoscopy. AB - Gas embolism is a rare but potentially devastating complication of endoscopic procedures. We describe 3 cases of gas embolism which were associated with endoscopic procedures (esophagogastroduodenoscopy and endoscopic retrograde cholangiopancreatography). We treated these at our hyperbaric medicine center with 3 different outcomes: complete resolution, death, and disability. We review the literature regarding this unusual complication of endoscopy and discuss the need for prompt identification and referral for hyperbaric oxygen therapy. Additional adjunctive therapies are also discussed. PMID- 27479146 TI - Capturing Transition States for tRNA Hybrid-State Formation in the Ribosome. AB - In order to quantitatively describe the energetics of biomolecular rearrangements, it is necessary to identify reaction coordinates that accurately capture the relevant transition events. Here, we perform simulations of A-site tRNA movement (~20 A) during hybrid-state formation in the ribosome and quantify the ability of interatomic distances to capture the transition state ensemble. Numerous coordinates are found to be accurate indicators of the transition state, allowing tRNA rearrangements to be described as diffusion across a one dimensional free-energy surface. In addition to providing insights into the physical-chemical relationship between biomolecular structure and dynamics, these results can help enable single-molecule techniques to probe the free-energy landscape of the ribosome. PMID- 27479147 TI - Davydov Splitting and Excitonic Resonance Effects in Raman Spectra of Few-Layer MoSe2. AB - Raman spectra of few-layer MoSe2 were measured with eight excitation energies. New peaks that appear only near resonance with various exciton states are analyzed, and the modes are assigned. The resonance profiles of the Raman peaks reflect the joint density of states for optical transitions, but the symmetry of the exciton wave functions leads to selective enhancement of the A1g mode at the A exciton energy and the shear mode at the C exciton energy. We also find Davydov splitting of intralayer A1g, E1g, and A2u modes due to interlayer interaction for some excitation energies near resonances. Furthermore, by fitting the spectral positions of interlayer shear and breathing modes and Davydov splitting of intralayer modes to a linear chain model, we extract the strength of the interlayer interaction. We find that the second-nearest-neighbor interlayer interaction amounts to about 30% of the nearest-neighbor interaction for both in plane and out-of-plane vibrations. PMID- 27479148 TI - Hyperfine Coupling Constants from Internally Contracted Multireference Perturbation Theory. AB - We present an accurate method for calculating hyperfine coupling constants (HFCCs) based on the complete active space second-order perturbation theory (CASPT2) with full internal contraction. The HFCCs are computed as a first-order property using the relaxed CASPT2 spin-density matrix that takes into account orbital and configurational relaxation due to dynamical electron correlation. The first-order unrelaxed spin-density matrix is calculated from one- and two-body spin-free counterparts that are readily available in the CASPT2 nuclear gradient program [M. K. MacLeod and T. Shiozaki, J. Chem. Phys. 142, 051103 (2015)], whereas the second-order part is computed directly using the newly extended automatic code generator. The relaxation contribution is then calculated from the so-called Z-vectors that are available in the CASPT2 nuclear gradient program. Numerical results are presented for the CN and AlO radicals, for which the CASPT2 values are comparable (or, even superior in some cases) to the ones computed by the coupled-cluster and density matrix renormalization group methods. The HFCCs for the hexaaqua complexes with V(II), Cr(III), and Mn(II) are also presented to demonstrate the accuracy and efficiency of our code. PMID- 27479149 TI - An update on the use of tumor necrosis factor alpha inhibitors in the treatment of ankylosing spondylitis. AB - INTRODUCTION: Ankylosing spondylitis is a chronic immune-mediated disease affecting the sacroiliac joints and the spine manifesting with new bone formation and osteopenia. Over the past decade, tumour necrosis factor alpha (TNF-alpha) inhibitors (TNFi) have become the cornerstone for therapy in improving functional outcomes, and decreasing disease activity in patients with a marginal benefit from non-steroidal anti-inflammatory (NSAID) therapy. At this time, it remains to be determined whether these agents decrease new bone formation, although some studies have recently suggested that. Areas covered: In this review we discuss the factors that favour a good response to these agents both initially and during maintenance, and some of the more recent studies outlining strategies for dose reduction. Expert commentary: Finally, we discuss the importance of using more objective tools for disease activity, such as magnetic resonance imaging, as a complementary tool for clinical assessments in both predicting responses to treatment but also in selecting patients most suited for targeted therapy. PMID- 27479150 TI - Utilizing the Discrete Element Method for the Modeling of Viscosity in Concentrated Suspensions. AB - The rheological behavior of concentrated suspensions is a complicated problem because it originates in the collective motion of particles and their interaction with the surrounding fluid. For this reason, it is difficult to accurately model the effect of various system parameters on the viscosity even for highly simplified systems. We model the viscosity of a hard-sphere suspension subjected to high shear rates using the dynamic discrete element method (DEM) in three spatial dimensions. The contact interaction between particles was described by the Hertz model of elastic spheres (soft-sphere model), and the interaction of particles with flow was accounted for by the two-way coupling approach. The hydrodynamic interaction between particles was described by the lubrication theory accounting for the slip on particle surfaces. The viscosity in a simple shear model was evaluated from the force balance on the wall. The obtained results are in close agreement with literature data for systems with hard spheres. Namely, the viscosity is shown to be independent of shear rate and primary particle size for monodisperse suspensions. In accordance with theory and experimental data, the viscosity grows rapidly with particle volume fraction. We show that this rheological behavior is predominantly caused by the lubrication forces. A novel approach based on the slip of water on a particle surface was developed to overcome the divergent behavior of lubrication forces. This approach was qualitatively validated with literature data from AFM measurements using a colloidal probe. The model presented in this work represents a new, robust, and versatile approach to the modeling of viscosity in suspensions with the possibility to include various interaction models and study their effect on viscosity. PMID- 27479151 TI - Pokemon Go and augmented virtual reality games: a cautionary commentary for parents and pediatricians. AB - PURPOSE OF REVIEW: The recent release of Pokemon Go has ushered in a new set of challenges for parents and pediatricians, highlighting the importance of parents setting guidelines for video game use with their children. Within 1 week of its launch, the game attracted over 65 million users, many of whom are young children. Despite the potential benefits of the game described in our article, this location-based game format poses specific threats to the safety and physical wellbeing of children. RECENT FINDINGS: Reports have discussed both the benefits and adverse effects of this extremely popular video game. Benefits include increased exercise, socialization, and outdoor activity. Negative effects include increased risk of injury, abduction, trespassing, violence, and cost. SUMMARY: Pediatricians play a key role in counseling parents and children about safety precautions and setting appropriate limits for impressionable youth. Parents and pediatricians should be aware of this new and remarkably popular game that appeals to a wide variety of individuals. To protect children from injury, predators, and inappropriate situations, parents and pediatricians must regulate children's participation in this game and maintain vigilance for potentially dangerous circumstances. PMID- 27479152 TI - Heteroleptic Cu-Based Sensitizers in Photoredox Catalysis. AB - Photochemistry is an important tool in organic synthesis that has largely been underdeveloped in comparison to thermal activation. Recent advances in technology have ushered in a new era in synthetic photochemistry. The emergence of photocatalysis, which exploits sensitizers for the absorption of visible light, has provided organic chemists with a new route to the generation of radical intermediates for synthesis. Of particular interest is the development of Cu based complexes for photocatalysis, which possess variable photophysical properties and can display complementary reactivity with common photocatalysts based on heavier transition metals such as Ru or Ir. Heteroleptic Cu-based sensitizers incorporating the presence of both a bisphosphine and diamine ligand bound to the copper center are a promising class of photocatalysts. Their synthesis is a single step, often involving only precipitation for purification. In addition, it was shown that the sensitizers could be formed in situ in the reaction mixture, simplifying the experimental setup. The heteroleptic nature of the Cu-complexes also affords opportunities to fine-tune properties. For example, structurally rigidified bisphosphines reinforce geometries about the metal center to extend the excited state lifetime. Variation of the diamine ligand can influence the excited state oxidation/reduction potentials and optical absorbances. The heteroleptic complex Cu(XantPhos)(neo)BF4 has demonstrated utility in the synthesis of helical polyaromatic carbocycles. The synthesis of [5]helicene, a relatively simple member of the helicene family, was improved from the existing UV-light mediated method by eliminating the formation of unwanted byproducts. In addition, the Cu-based sensitizers also promoted the formation of novel pyrene/helicene hybrids for materials science applications. The synthetic methods that were developed were augmented when combined with continuous flow technology. The irradiation of reaction mixtures as they are pumped through small diameter tubing provides a more homogeneous and increased photon flux compared with irradiation in round-bottom flasks or other batch reactors. The value of continuous flow methods is also evident when examining UV-light photochemistry, where the simple and safe experimental set-ups allow for further exploration of high energy light for synthetic purposes. The synthesis of functionalized complex carbazoles was also studied using both a visible light method exploiting a heteroleptic copper-based sensitizer and a UV-light mediated method. It was demonstrated that both the photocatalysis methods and UV light photochemistries were rendered more user-friendly, safe, and reproducible when using continuous flow methods. Interestingly, the two photochemical methods often afford contrasting selectivities as a result of their inherently different mechanisms. It can be expected that the complementarity of the various photochemical methods will be an asset to synthetic chemists as the field continues to evolve. PMID- 27479153 TI - Quercetin, not caffeine, is a major neuroprotective component in coffee. AB - Epidemiologic studies indicate that coffee consumption reduces the risk of Parkinson's disease and Alzheimer's disease. To determine the factors involved, we examined the protective effects of coffee components. The test involved prevention of neurotoxicity to SH-SY5Y cells that was induced by lipopolysaccharide plus interferon-gamma or interferon-gamma released from activated microglia and astrocytes. We found that quercetin, flavones, chlorogenic acid, and caffeine protected SH-SY5Y cells from these toxins. They also reduced the release of tumor necrosis factor-alpha and interleukin-6 from the activated microglia and astrocytes and attenuated the activation of proteins from P38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NFkappaB). After exposure to toxin containing glial-stimulated conditioned medium, we also found that quercetin reduced oxidative/nitrative damage to DNA, as well as to the lipids and proteins of SH-SY5Y cells. There was a resultant increase in [GSH]i in SH-SY5Y cells. The data indicate that quercetin is the major neuroprotective component in coffee against Parkinson's disease and Alzheimer's disease. PMID- 27479154 TI - Caspase-cleaved Tau-D(421) is colocalized with the immunophilin FKBP52 in the autophagy-endolysosomal system of Alzheimer's disease neurons. AB - Pathologic modifications of the Tau protein leading to neurofibrillary tangle (NFT) formation are a common feature of a wide range of neurodegenerative diseases known as tauopathies, which include Alzheimer's disease (AD). We previously showed that the immunophilin FKBP52 physically and functionally interacts with Tau, and we recently reported that FKBP52 levels are abnormally low in AD patients' brains. To decipher the mechanism of FKBP52 decrease in AD brains, we performed multiple labeling immunohistofluorescence and lysosomal purification using postmortem brain samples of healthy controls (n = 8) and AD (n = 20) patients. Confocal analysis revealed that FKBP52 localizes to the endolysosomal system. We also report FKBP52 colocalization with the truncated Tau D(421) in the autophagy-endolysosomal system in some AD neurons and that the decrease of FKBP52 correlates with NFT formation. Additional experiments of autophagy inhibition in Tau-inducible SH-SY5Y cells allowed demonstrating FKBP52 release in the extracellular milieu. Our findings point out the possibility that FKBP52 could be abnormally released from NFTs negative neurons in AD brains in correlation with the early pathologic Tau-D(421) neuronal accumulation. PMID- 27479155 TI - Electrical detection of spin transport in Si two-dimensional electron gas systems. AB - Spin transport in a semiconductor-based two-dimensional electron gas (2DEG) system has been attractive in spintronics for more than ten years. The inherent advantages of high-mobility channel and enhanced spin-orbital interaction promise a long spin diffusion length and efficient spin manipulation, which are essential for the application of spintronics devices. However, the difficulty of making high-quality ferromagnetic (FM) contacts to the buried 2DEG channel in the heterostructure systems limits the potential developments in functional devices. In this paper, we experimentally demonstrate electrical detection of spin transport in a high-mobility 2DEG system using FM Mn-germanosilicide (Mn(Si0.7Ge0.3)x) end contacts, which is the first report of spin injection and detection in a 2DEG confined in a Si/SiGe modulation doped quantum well structure (MODQW). The extracted spin diffusion length and lifetime are l sf = 4.5 MUm and [Formula: see text] at 1.9 K respectively. Our results provide a promising approach for spin injection into 2DEG system in the Si-based MODQW, which may lead to innovative spintronic applications such as spin-based transistor, logic, and memory devices. PMID- 27479156 TI - "When Grief Breaks Your Heart": A Case Study of Interpersonal Psychotherapy Delivered in a Primary Care Setting. AB - Depression and anxiety, the so-called common mental disorders (CMDs), are highly prevalent and disabling, yet remain largely untreated. This treatment gap is particularly true in low- and middle-income settings, where there is significant scarcity of resources (including human resources) and treatment accessibility is complicated by stigma surrounding mental illness. To address these challenges, the MANAS trial, one of the largest to date randomized, controlled trials, aimed to test the effectiveness of a stepped care intervention led by lay health counselors in primary care settings in Goa, India. Six- and 12-month follow-up outcomes suggest that MANAS was a safe, feasible, effective, and cost-effective intervention for CMDs in that context. This article demonstrates the use of culturally adapted IPT as an intervention to treat CMDs in a 54-year-old Indian primary care patient struggling with depression and heart-related problems after his wife's death. A case formulation is presented based on core IPT principles, followed by detailed delineation of treatment from beginning through termination. PMID- 27479157 TI - Eight-Hour Continuous Normothermic Ex Vivo Kidney Perfusion Is a Safe Preservation Technique for Kidney Transplantation: A New Opportunity for the Storage, Assessment, and Repair of Kidney Grafts. AB - BACKGROUND: Hypothermic kidney storage causes preservation injury and is poorly tolerated by renal grafts. We investigated whether static cold storage (SCS) can be safely replaced with a novel technique of pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) in heart-beating donor kidney transplantation. METHODS: Right kidneys were removed from 30 kg Yorkshire pigs in a model of heart beating donation and either preserved in cold histidine-tryptophan-ketoglutarate solution for 8 hours (n = 5), or subjected to 8 hours of pressure-controlled NEVKP (n = 5) followed by renal heterotopic autotransplantation. RESULTS: During NEVKP, physiologic perfusion conditions were maintained with low intrarenal resistance and normal electrolyte and pH parameters. Aspartate aminotransferase and lactate dehydrogenase as injury markers were below the detectable analyzer range (<4 and <100 U/L, respectively). Perfusate lactate concentration decreased from baseline until the end of perfusion (10.38 +/- 0.76 mmol/L vs 1.22 +/- 0.26 mmol/L; P < 0.001). Posttransplantation, animals transplanted with NEVKP versus SCS grafts demonstrated similar serum creatinine peak levels (NEVKP, 2.0 +/- 0.5 vs SCS 2.7 +/- 0.7 mg/dL; P = 0.11) and creatinine clearance on day 10 (NEVKP, 65.9 +/- 18.8 mL/min vs SCS 61.2 +/- 15.6 mL/min; P = 0.74). After 10 days of follow-up, animals transplanted with NEVKP grafts had serum creatinine and blood urea nitrogen values comparable to their basal levels (P = 0.49 and P = 0.59), whereas animals transplanted with SCS grafts had persistently elevated serum creatinine and blood urea nitrogen when compared with basal levels (P = 0.01 and P = 0.03). CONCLUSIONS: Continuous pressure-controlled NEVKP is feasible and safe in good quality heart-beating donor kidney grafts. It maintains a physiologic environment and excellent graft function ex vivo during preservation without causing graft injury. PMID- 27479158 TI - Cyclooxygenase Inhibitors as a New Therapeutic Strategy in Small Bowel Transplantation. AB - BACKGROUND: The long-term outcome of intestinal transplantations is still not favorable, which is partly due to the intestinal susceptibility to ischemia. There are several indications that the inflammatory response to ischemia reperfusion injury is mediated by cyclooxygenases and that their inhibition may be associated with improved organ function. The aim of this study was to analyze if cyclooxygenase (COX) inhibitors could improve the early posttransplant outcome after orthotopic small bowel transplantation. METHODS: Small bowel transplantation was performed between rats to test the impact of nonselective (Piroxicam), preferential (Meloxicam), and selective COX-2 inhibitors (Parecoxib). The donor intestines were either perfused and stored with inhibitor or had inhibitor administered intravenously after transplantation. RESULTS: Using COX inhibitors, a sequential increase of posttransplantation intestinal integrity could be shown, with Parecoxib the least effective and Meloxicam the most effective treatment. These differences were in line with the downregulation of COX-2 activity by the inhibitors. Functionally, the same tendency could be seen in diminished expression of proinflammatory molecules, decreased leucocyte inflammation, and significantly improved graft microcirculation. In most cases, the intravenous administration was more effective. However, the COX inhibitors used were shown to cause relevant hepatotoxicity under nearly all conditions, but particularly under intravenous administration. Only Meloxicam in histidine tryptophan-ketoglutarate was demonstrated to be a safe drug without hepatotoxic side effects. CONCLUSIONS: The activity of COX contributes to ischemia reperfusion injury after intestinal transplantation. In this comparative study, the administration of the preferential COX-2 inhibitor Meloxicam via histidine tryptophan-ketoglutarate showed the best graft-protective attributes and the lowest hepatotoxic side effects. PMID- 27479159 TI - Establishing Biomarkers in Transplant Medicine: A Critical Review of Current Approaches. AB - Although the management of kidney transplant recipients has greatly improved over recent decades, the assessment of individual risks remains highly imperfect. Individualized strategies are necessary to recognize and prevent immune complications early and to fine-tune immunosuppression, with the overall goal to improve patient and graft outcomes. This review discusses current biomarkers and their limitations, and recent advancements in the field of noninvasive biomarker discovery. A wealth of noninvasive monitoring tools has been suggested that use easily accessible biological fluids such as urine and blood, allowing frequent and sequential assessments of recipient's immune status. This includes functional cell-based assays and the evaluation of molecular expression on a wide spectrum of platforms. Nevertheless, the translation and validation of exploratory findings and their implementation into standard clinical practice remain challenging. This requires dedicated prospective interventional trials demonstrating that the use of these biomarkers avoids invasive procedures and improves patient or transplant outcomes. PMID- 27479161 TI - Kidney Biopsies May Help Predict Renal Function After Liver Transplantation. AB - BACKGROUND: Renal biopsy has been proposed to determine the cause or reversibility of renal failure for patients with end-stage liver disease and may be useful in the kidney allocation. Nevertheless, little data exist to validate the usefulness of kidney biopsies in this patient population. METHODS: We evaluated the utility of renal biopsies in a cohort of 59 consecutive liver transplant candidates with renal impairment of unclear etiology referred to determine the need for simultaneous liver kidney transplantation (SLK) versus liver alone transplantation (LAT). Pathological diagnoses, patient outcomes and the usefulness of biopsy results in predicting renal recovery were analyzed. RESULTS: Our biopsy complication rate was relatively low with only 2.9% and 4.2% serious complications occurring with transjugular and percutaneous renal biopsies, respectively. The most common pathological diagnoses on renal biopsies were membranoproliferative glomerulonephritis (23%) followed by IgA nephropathy (19%) and acute tubular injury (19%). Simultaneous liver kidney transplantation was recommended for patients with greater than 40% global glomerular sclerosis, or with interstitial fibrosis greater than 30% or for patients on hemodialysis for 2 months or longer. The best histological predictor for posttransplant glomerular filtration rate in the LAT group was the extent of global glomerulosclerosis (P = 0.0001). Based on biopsy criteria, we were able to avoid kidney allocation to 70% of our patients with renal dysfunction. Over the first year posttransplant, SLK and LAT patients had comparable estimated glomerular filtration rates. Kaplan-Meier survival analysis did not demonstrate a difference in patient survival between patients who underwent LAT versus SLK. CONCLUSIONS: Renal biopsy can be relatively safe in this population, may help elucidate the etiology of renal failure, may predict post-LAT kidney function, and may be helpful in kidney allocation for liver transplant candidates. PMID- 27479163 TI - FGF-23 Klotho Axis: Will Intervention Improve Kidney Transplant Outcomes? PMID- 27479162 TI - Correlates and Outcomes of Posttransplant Smoking in Solid Organ Transplant Recipients: A Systematic Literature Review and Meta-Analysis. AB - BACKGROUND: Despite smoking being an absolute or relative contraindication for transplantation, about 11% to 40% of all patients continue or resume smoking posttransplant. This systematic review with meta-analysis investigated the correlates and outcomes associated with smoking after solid organ transplantation. METHODS: We searched PubMed, EMBASE, CINAHL, and PsycINFO from inception until January 2016, using state-of-the art methodology. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were computed for correlates/outcomes investigated 5 times or more. RESULTS: Seventy-three studies (43 in kidney, 17 in heart, 12 in liver, 1 in lung transplantation) investigated 95 correlates and 24 outcomes, of which 6 correlates and 4 outcomes could be included in the meta-analysis. The odds of smoking posttransplant were 1.33 times higher in men (95% CI, 1.12-1.57). Older individuals were significantly less likely to smoke (OR, 0.48; 95% CI, 0.38-0.62), as were patients with a higher body mass index (OR, 0.68; 95% CI, 0.52-0.89). Hypertension (OR, 1.16; 95% CI, 0.77-1.75), diabetes mellitus (OR, 0.52; 95% CI, 0.15-1.78), and having a history of cardiovascular disease (OR, 0.92; 95% CI, 0.77-1.09) were not significant correlates. Posttransplant smokers had higher odds of newly developed posttransplant cardiovascular disease (OR, 1.41; 95% CI, 1.02-1.95), nonskin malignancies (OR, 2.58; 95% CI, 1.26-5.29), a shorter patient survival time (OR, 0.59; 95% CI, 0.44-0.79), and higher odds of mortality (OR, 1.74; 95% CI, 1.21 2.48). CONCLUSIONS: Posttransplant smoking is associated with poor outcomes. Our results might help clinicians to understand which patients are more likely to smoke posttransplant, guide interventional approaches, and provide recommendations for future research. PMID- 27479165 TI - How Qualitative Research Informs Clinical and Policy Decision Making in Transplantation: A Review. AB - Patient-centered care is no longer just a buzzword. It is now widely touted as a cornerstone in delivering quality care across all fields of medicine. However, patient-centered strategies and interventions necessitate evidence about patients' decision-making processes, values, priorities, and needs. Qualitative research is particularly well suited to understanding the experience and perspective of patients, donors, clinicians, and policy makers on a wide range of transplantation-related topics including organ donation and allocation, adherence to prescribed therapy, pretransplant and posttransplant care, implementation of clinical guidelines, and doctor-patient communication. In transplantation, evidence derived from qualitative research has been integrated into strategies for shared decision-making, patient educational resources, process evaluations of trials, clinical guidelines, and policies. The aim of this article is to outline key concepts and methods used in qualitative research, guide the appraisal of qualitative studies, and assist clinicians to understand how qualitative research may inform their practice and policy. PMID- 27479167 TI - Surgical Site Infections After Liver Transplantation: Emergence of Multidrug Resistant Bacteria and Implications for Prophylaxis and Treatment Strategies. AB - BACKGROUND: Perioperative antimicrobial prophylaxis is administered to liver transplant (LTx) recipients to prevent surgical site infections (SSIs), but regimens are not standardized, and there are limited effectiveness data. Prevention and treatment of SSIs have been complicated by the emergence of multidrug-resistant (MDR) pathogens. METHODS: We retrospectively reviewed SSIs among 331 LTx recipients at our center in 2010 to 2014. RESULTS: Culture-proven superficial and deep SSIs occurred in 3% and 15% of patients, respectively, at median 12.5 and 13.5 days post-LTx. Recipients with superficial SSIs and those without SSIs were similar in demographics, clinical characteristics, length of hospital stay, and mortality. Deep SSIs included abscesses (58%), peritonitis (28%), deep incisional infections (8%), and cholangitis (6%). Rates of deep SSIs were comparable among patients receiving prophylaxis with ampicillin-sulbactam, aztreonam and vancomycin, or tigecycline (P = 0.61). Independent risk factors for deep SSIs were bile leak (P < 0.001) and operative time (P < 0.001). Enterobacteriaceae (42%), Enterococcus spp. (24%), and Candida spp. (15%) were predominant pathogens. Fifty-three percent of bacteria were MDR, including 95% of Enterococcus faecium and 55% of Enterobacteriaceae; 82% of deep SSIs were caused by bacteria resistant to antimicrobials used for prophylaxis, and 58% of patients were treated with an inactive empiric regimen. Deep SSIs were associated with longer lengths of stay (P < 0.001), and higher 90-day and long-term mortality rates (P < 0.001). CONCLUSIONS: Deep SSIs, including those caused by MDR bacteria, were common after LTx despite prophylaxis with broad-spectrum antimicrobials. Rather than altering prophylaxis regimens, programs should devise empiric treatment regimens that are directed against the most common local pathogens. PMID- 27479166 TI - Survival of Allogeneic Self-Assembled Cultured Skin. AB - BACKGROUND: Deficiency of autologous skin for reconstruction of severe wounds is a major problem in plastic surgery. Autologous substitutes can provide additional coverage, but due to the duration of production, treatment is significantly delayed. The allogeneic approach offers a potential of having an off-the-shelf solution for the immediate application. METHODS: In this study, we assess the engraftment and immunogenicity of allogeneic bilayered bioengineered skin prepared by a self-assembly method. Bioengineered skin has the potential immunological advantage of lacking passenger leukocytes including antigen presenting cells. The skin constructs were transplanted across major histocompatibility complex (MHC) barriers in a porcine animal model. Animals received a second grafting of the same skin construct 7 weeks after the first set of grafts together with MHC-matched constructs to assess for clinical sensitization. RESULTS: All alloconstructs successfully engrafted with histologic evidence of neovascularization by day 4. Complete cellular rejection and tissue loss occurred by day 8 for most grafts. After the second application, accelerated rejection (<4 days) took place with the development of swine MHC-specific cytotoxic alloantibody. CONCLUSIONS: These data demonstrate preclinically that self-assembled allogeneic constructs engraft and reject similar to allogeneic skin despite the absence of professional donor antigen-presenting cells. PMID- 27479168 TI - The Impact of Total Ischemic Time, Donor Age and the Pathway of Donor Death on Graft Outcomes After Deceased Donor Kidney Transplantation. AB - BACKGROUND: Prolonged ischemia is a known risk factor for delayed graft function (DGF) and its interaction with donor characteristics, the pathways of donor death, and graft outcomes may have important implications for allocation policies. METHODS: Using data from the Australian and New Zealand Dialysis and Transplant registry (1994-2013), we examined the relationship between total ischemic time with graft outcomes among recipients who received their first deceased donor kidney transplants. Total ischemic time (in hours) was defined as the time of the donor renal artery interruption or aortic clamp, until the time of release of the clamp on the renal artery in the recipient. RESULTS: A total of 7542 recipients were followed up over a median follow-up time of 5.3 years (interquartile range of 8.2 years). Of these, 1823 (24.6%) experienced DGF and 2553 (33.9%) experienced allograft loss. Recipients with total ischemic time of 14 hours or longer experienced an increased odd of DGF compared with those with total ischemic time less than 14 hours. This effect was most marked among those with older donors (P value for interaction = 0.01). There was a significant interaction between total ischemic time, donor age, and graft loss (P value for interaction = 0.03). There was on average, a 9% increase in the overall risk of graft loss per hour increase in the total ischemic time (adjusted hazard ratio, 1.09; 95% confidence interval, 1.01-1.18; P = 0.02) in recipients with older donation after circulatory death grafts. CONCLUSIONS: There is a clinically important interaction between donor age, the pathway of donor death, and total ischemic time on graft outcomes, such that the duration of ischemic time has the greatest impact on graft survival in recipients with older donation after circulatory death kidneys. PMID- 27479169 TI - The Authors' Reply. PMID- 27479171 TI - Immunological characteristics of renal transplant tolerance in humans. AB - Establishing allograft tolerance is a highly desirable therapeutic goal in kidney transplantation, from which recipients would greatly benefit by withdrawing or minimizing immunosuppression. Identifying biomarkers in predicting tolerance or early diagnosing rejection is essential to direct personalized management. Recent findings have revealed that multiple populations of immune cells have involved in promoting long-term graft function or inducing rejection in renal transplant recipients. Thus, roles of immune cells add another level to predict the renal tolerant state; tailoring their functional and/or phenotypic characteristics would provide insights into mechanism involved in transplant tolerance that may aid in designing new therapies. Here, we review these findings and discuss the current understanding immunological characteristics of renal transplant tolerance in humans, and their potential clinical translation to immune tolerance biomarkers. PMID- 27479170 TI - Financial cost of lymphedema borne by women with breast cancer. AB - OBJECTIVE: Our study examines the financial cost of lymphedema following a diagnosis of breast cancer and addresses a significant knowledge gap regarding the additional impact of lymphedema on breast cancer survivors. METHODS: An online national survey was conducted with 361 women who had either breast cancer without lymphedema (BC) (group 1, n = 209) or breast cancer with lymphedema (BC+LE) (group 2, n = 152). Participant recruitment was supported by the Breast Cancer Network Australia and the Australasian Lymphology Association. RESULTS: Both breast cancer and lymphedema result in significant out-of-pocket financial costs borne by women. Of patients with BC+LE, 80% indicated that their breast cancer diagnosis had affected them financially compared with 67% in the BC group (P < .020). For patients with lymphedema, over half (56%) indicated that this specific additional diagnosis to their breast cancer affected them financially and that costs increased with lymphedema severity. The cost of compression garments formed a large proportion of these costs (40.1%). The average number of attendances to a therapist each year was 5.8 (range, 0-45). Twenty-five patients (16.4%) had an episode of cellulitis in the past year. The incidence of cellulitis was 7.7% in 91 patients with subclinical or mild lymphedema compared with 29.5% of 61 patients with more extensive lymphedema (P < .001). The average out-of-pocket financial cost of lymphedema care borne by women was A$977 per annum, ranging from A$207 for subclinical lymphedema to over A$1400 for moderate or severe lymphedema. CONCLUSIONS: This study identifies an additional detrimental effect of lymphedema on women in terms of financial costs. PMID- 27479172 TI - Chromium-Modified Li4Ti5O12 with a Synergistic Effect of Bulk Doping, Surface Coating, and Size Reducing. AB - Bulk doping, surface coating, and size reducing are three strategies for improving the electrochemical properties of Li4Ti5O12 (LTO). In this work, chromium (Cr)-modified LTO with a synergistic effect of bulk doping, surface coating, and size reducing is synthesized by a facile sol-gel method. X-ray diffraction (XRD) and Raman analysis prove that Cr dopes into the LTO bulk lattice, which effectively inhibits the generation of TiO2 impurities. Transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) verifies the surface coating of Li2CrO4 on the LTO surface, which decreases impedance of the LTO electrode. More importantly, the size of LTO particles can be significantly reduced from submicroscale to nanoscale as a result of the protection of the Li2CrO4 surface layer and the suppression from Cr atoms on the long-range order in the LTO lattice. As anode material, Li4-xCr3xTi5-2xO12 (x = 0.1) delivers a reversible capacity of 141 mAh g(-1) at 10 degrees C, and over 155 mAh g(-1) at 1 degrees C after 1000 cycles. Therefore, the Cr-modified Li4Ti5O12 prepared via a sol-gel method has potential for applications in high power, long-life lithium-ion batteries. PMID- 27479173 TI - Molecular and serological techniques to detect co-circulation of DENV, ZIKV and CHIKV in suspected dengue-like syndrome patients. AB - BACKGROUND: Arboviruses are important emerging viruses worldwide. The signs and symptoms of Zika virus (ZIKV) infection are similar to those presented by infections with dengue virus (DENV) and chikungunya virus (CHIKV). Furthermore, diagnosis of ZIKV infection is particularly challenging in dengue endemic regions and with co-circulation of DENV, CHIKV, and ZIKV, making diagnosis based solely on clinical and epidemiological data unreliable. As these three viral infections share similar clinical manifestations, differential diagnosis is crucial. OBJECTIVES: In this study, diagnoses of ZIKV, CHIKV and DENV infections were investigated in 30 patients with suspected dengue fever residing in the area of co-circulation of these three arboviruses. STUDY DESIGN: The study included whole blood and/or serum samples obtained from 30 patients with suspected dengue fever. All patients were tested for DENV infection as well as for CHIKV and ZIKV infections. Assays for detecting anti-DENV IgM and DENV RNA by semi-nested RT-PCR and ZIKV and CHIKV RNA by real-time RT-PCR were performed. RESULTS: DENV RNA was not detectable in any of the clinical samples, whereas ZIKV RNA was detectable in 17 samples (56.7%). Co-infection by ZIKV and CHIKV was documented in one case. Of the 17 ZIKV-positive individuals, 8 showed reactivity for anti-DENV IgM, which suggested recent DENV infection, cross-reactivity or co-infection. CONCLUSION: Our findings confirm that accurate laboratory testing is of paramount importance for differential diagnosis in areas of simultaneous transmission of different arboviruses with similar clinical presentations. PMID- 27479174 TI - WU and KI polyomavirus infections in Filipino children with lower respiratory tract disease. AB - BACKGROUND: WU and KI are human polyomaviruses initially detected in the respiratory tract, whose clinical significance remains uncertain. OBJECTIVES: To determine the epidemiology, viral load and clinical characteristics of WU and KI polyomaviruses. STUDY DESIGN: We tested respiratory specimens collected during a randomized, placebo-controlled pneumococcal conjugate vaccine trial and related epidemiological study in the Philippines. We analyzed 1077 nasal washes from patients aged 6 weeks to 5 years who developed lower respiratory tract illness using quantitative real-time PCR for WU and KI. We collected data regarding presenting symptoms, signs, radiographic findings, laboratory data and coinfection. RESULTS: The prevalence and co-infection rates for WU were 5.3% and 74% respectively and 4.2% and 84% respectively for KI. Higher KI viral loads were observed in patients with severe or very severe pneumonia, those presenting with chest indrawing, hypoxia without wheeze, convulsions, and with KI monoinfection compared with co-infection. There was no significant association between viral load and clinical presentation for WU. CONCLUSIONS: These findings suggest a potential pathogenic role for KI, and that there is an association between KI viral load and illness severity. PMID- 27479175 TI - Norovirus shedding among food and healthcare workers exposed to the virus in outbreak settings. AB - BACKGROUND: Noroviruses (NoV) are highly contagious and the leading cause of nonbacterial outbreaks of gastroenteritis worldwide. Individuals who are infected asymptomatically may act as reservoirs and facilitate the transmission of NoV, but the likelihood of workers of becoming infected in outbreak settings has not been systematically studied. OBJECTIVES: We evaluated the occurrence of norovirus infections among workers exposed to the virus in different outbreak settings. STUDY DESIGN: We screened feces from food handlers and healthcare workers related with gastroenteritis outbreaks, and shedding concentrations over time were calculated from serial samples of infected individuals. Sequence analyses of the capsid P2 domain and region C were used to evaluate linkage between asymptomatic employees and outbreak cases. RESULTS: Of all employees, 59.1% were positive for NoV, and more than 70% of them were asymptomatic. Asymptomatic infections were significantly more frequent in foodborne compared to person-to-person transmitted outbreaks; and in restaurants and hotels, compared to nursing homes and healthcare institutions. Mean viral loads were similar between symptomatic and asymptomatic individuals, starting at 7.51+/-1.80 and 6.49+/-1.93 log10 genome copies/g, respectively, and decreasing to 5.28+/-0.76 and 4.52+/-1.45 log10 genome copies/g after 19days. CONCLUSIONS: The likelihood of becoming infected when a NoV outbreak occurs at the work place is high and similar between food handlers and healthcare workers, but asymptomatic infections are more frequently identified among food handlers. Since shed amounts of viruses in the absence of symptoms are also high, reinforcement of hygiene practices among workers is especially relevant to reduce the risk of virus secondary transmissions. PMID- 27479176 TI - Epidemiology and etiology of influenza-like-illness in households in Vietnam; it's not all about the kids! AB - BACKGROUND: Household studies provide opportunities to understand influenza-like illness (ILI) transmission, but data from (sub)tropical developing countries are scarce. OBJECTIVE: To determine the viral etiology and epidemiology of ILI in households. STUDY DESIGN: ILI was detected by active case finding amongst a cohort of 263 northern Vietnam households between 2008 and 2013. Health workers collected nose and throat swabs for virus detection by multiplex real-time RT PCR. RESULTS: ILI was detected at least once in 219 (23.7%) of 945 household members. 271 (62.3%) of 435 nose/throat swabs were positive for at least one of the 15 viruses tested. Six viruses predominated amongst positive swabs: Rhinovirus (28%), Influenza virus (17%), Coronavirus (8%), Enterovirus (5%), Respiratory syncytial virus (3%), Metapneumovirus virus (2.5%) and Parainfluenza virus 3 (1.8%). There was no clear seasonality, but 78% of episodes occurred in Winter/Spring for Influenza compared to 32% for Rhinovirus. Participants, on average, suffered 0.49 ILI, and 0.29 virus-positive ILI episodes, with no significant effects of gender, age, or household size. In contrast to US and Australian community studies, the frequency of ILI decreased as the number of household members aged below 5 years increased (p=0.006). CONCLUSION: The findings indicate the need for tailored ILI control strategies, and for better understanding of how local childcare practices and seasonality may influence transmission and the role of children. PMID- 27479179 TI - Vascular events and risk factors for thrombosis in refractory anemia with ring sideroblasts and thrombocytosis. PMID- 27479178 TI - The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia. AB - Immune dysfunctions in chronic lymphocytic leukemia (CLL) contribute to tumor immune escape and attenuate immune-based therapies. Monocytes/macrophages represent key components of cancer immune surveillance and effectors for antibody mediated antitumor effects. Monocytes display an altered subset composition in CLL. Moreover, we find a changed metabolic phenotype: glucose uptake, glucose transporters and expression of glycolytic molecules are reduced. Our data establish a link between glycolytic competence and monocyte-mediated phagocytosis of tumor cells. Furthermore, we report that CLL monocytes express Bruton's tyrosine kinase (BTK). Our observations suggest that using BTK inhibitors in CLL might further aggravate the observed immune metabolic defects in monocytes. Triggering the programmed cell death-1 (PD-1) checkpoint on monocytes hampers glycolysis, phagocytosis and BTK signaling. Conversely, disrupting PD-1/PD-L1 signaling reverses these immune metabolic dysfunctions. Taken together, our findings imply a novel metabolic interplay between CLL cells and monocytes and that blocking PD-1/PD-L1 might restore metabolic together with antitumor activity of CLL monocytes/macrophages. PMID- 27479177 TI - A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. AB - NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK-signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ?50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1-2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion. PMID- 27479180 TI - Protein kinase CK2 regulates AKT, NF-kappaB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia. AB - Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic alpha and regulatory beta subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-kappaB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells. PMID- 27479181 TI - Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms. PMID- 27479182 TI - Survival control of malignant lymphocytes by anti-apoptotic MCL-1. AB - Programmed apoptotic cell death is critical to maintain tissue homeostasis and cellular integrity in the lymphatic system. Accordingly, the evasion of apoptosis is a critical milestone for the transformation of lymphocytes on their way to becoming overt lymphomas. The anti-apoptotic BCL-2 family proteins are pivotal regulators of the mitochondrial apoptotic pathway and genetic aberrations in these genes are associated with lymphomagenesis and chemotherapeutic resistance. Pharmacological targeting of BCL-2 is highly effective in certain indolent B-cell lymphomas; however, recent evidence highlights a critical role for the BCL-2 family member MCL-1 in several lymphoma subtypes. MCL-1 is recurrently highly expressed in various kinds of cancer including non-Hodgkin's lymphoma of B- and T cell origin. Moreover, both indolent and aggressive forms of lymphoma require MCL 1 for lymphomagenesis and for their continued survival. This review summarizes the role of MCL-1 in B- and T-cell lymphoma and discusses its potential as a therapeutic target. PMID- 27479183 TI - HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T cell immunotherapy after allogeneic stem-cell transplantation. AB - Refractory or relapsed acute myeloid leukemia (AML) represents a frequent complication after allogeneic hematopoietic stem-cell transplantation (HSCT). We show herein that primary in vitro stimulation of CD45RA-selected CD4 T cells of stem-cell donors with 10/10 HLA-matched AML blasts results in expansion of cytolytic T-lymphocytes (CTL) that almost all recognize HLA-DPB1 mismatch alleles, which clinically occur in up to 80% of donor-patient pairs. Primary AML blasts were found to strongly express HLA-DPB1, whereas fibroblasts and keratinocytes used as surrogate target cells for graft-versus-host disease did express HLA-DPB1 only upon IFN-gamma pre-treatment. Since patients' AML blasts are rarely available in clinical routine, we developed a protocol based on stimulation of donor-derived CD45RA-selected CD4 T cells with autologous dendritic cells electroporated with RNA encoding patients' HLA-DPB1 mismatch alleles. Short-term stimulated T cell-lines specifically lysed HLA-DPB1 mismatch expressing AML blasts, but not fibroblasts and keratinocytes without IFN-gamma pre-treatment. Notably, these CD4 CTL efficiently eliminated AML blasts upon adoptive transfer into leukemia-engrafted NSG mice. In conclusion, we show strong immunogenicity of HLA-DPB1 mismatch alleles in CD45RA-selected CD4 T cells of stem-cell donors and introduce a novel strategy to reliably generate HLA-DPB1 specific CD4 CTL that might be powerful cellular therapeutics in relapsed or refractory AML after HSCT. PMID- 27479185 TI - Thermal damage suppression of a black phosphorus saturable absorber for high power operation of pulsed fiber lasers. AB - Recent studies of black phosphorus (BP) have shown its future potential in the field of photonics. We determined the optical damage threshold of BP at 21.8 dBm in a fiber ring laser cavity, and demonstrated the high-power operation capacity of an evanescent field interaction-based BP saturable absorber. The long-term stability of a passively mode-locked fiber laser with a saturable absorber operating at the optical power of 23.3 dBm was verified for 168 h without any significant performance degradation. The center wavelength, spectral width, and pulse width of the laser output are 1558.8 nm, 14.2 nm, and 805 fs, respectively. PMID- 27479184 TI - Differentiation stage of myeloma plasma cells: biological and clinical significance. AB - The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal residual-disease samples (n=40) unraveled that in 20% of patients, less differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less differentiated clonal PCs retain high expression of genes related to preceding B cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles. PMID- 27479187 TI - Mistakes to Avoid in Scientific Writing. PMID- 27479186 TI - The dye SYPRO orange binds to amylin amyloid fibrils but not pre-fibrillar intermediates. AB - Amyloid deposition underlies a broad range of diseases including multiple neurodegenerative diseases, systemic amyloidosis and type-2 diabetes. Amyloid sensitive dyes, particularly thioflavin-T, are widely used to detect ex-vivo amyloid deposits, to monitor amyloid formation in vitro and to follow the kinetics of amyloid self-assembly. We show that the dye SYPRO-orange binds to amyloid fibrils formed by human amylin, the polypeptide responsible for islet amyloid formation in type-2 diabetes. No fluorescence enhancement is observed in the presence of pre-fibrillar species or in the presence of non-amyloidogenic rat amylin. The kinetics of human amylin amyloid formation can be monitored by SYPRO orange fluorescence and match the time course determined with thioflavin-T assays. Thus, SYPRO-orange offers an alternative to thioflavin-T assays of amylin amyloid formation. The implications for the interpretation of SYPRO-orange-based assays of protein stability and protein-ligand interactions are discussed. PMID- 27479188 TI - An empirical test of 'universal' biomass scaling relationships in kelps: evidence of convergence with seed plants. AB - Biomass allocation patterns have received substantial consideration, leading to the recognition of several 'universal' interspecific trends. Despite efforts to understand biomass partitioning among embryophytes, few studies have examined macroalgae that evolved independently, yet function ecologically in much the same ways as plants. Kelps allocate photosynthate among three organs (the blade(s), stipe(s) and holdfast) that are superficially convergent with organs of land plants, providing a unique opportunity to test the limits of 'universal' trends. In this study, we used an allometric approach to quantify interspecific biomass partitioning patterns in kelps and assess whether embryophyte-based predictions of biomass scaling can be applied to marine macrophytes that lack root-to-leaf hydraulic transport. Photosynthetic area and dry mass were found to scale to approximately the 3/4 power and kelp biomass allocation patterns were shown to match closely to empirical measures of allometric scaling among woody plants. Larger kelp species were found to have increased relative stipe and holdfast mass than smaller species, highlighting important consequences of size for marine macroalgae. Our study provides insights into the evolution of size in the largest marine macrophytes and corroborates previous work suggesting that the morphology of divergent lineages of photoautotrophs may reflect similar selective pressures. PMID- 27479189 TI - Perioperative Complication Rates in Pediatric Total Joint Arthroplasty Patients Compared With Adults: Results of a Matched Cohort Study. AB - BACKGROUND: One of the least studied areas in orthopaedics is total joint arthroplasty (TJA) in pediatric patients. Recent studies have confirmed that these procedures are being performed on pediatric patients, making it critical to understand the rates of surgical complications in this patient population. We sought to examine the frequency in which surgical complications occur in pediatric patients, aged 20 and younger, undergoing TJA compared with adults. METHODS: Data from the 2003 to 2012 Kids' Inpatient Database (ages 20 and younger) and 2002 to 2013 National Inpatient Sample (ages 21 and over) were analyzed. Pediatric patients were matched to 3 adult controls (1 per age group: 21 to 50, 51 to 65, and over 65 y) using patient characteristics including sex, race, orthopaedic diagnosis, and preoperative loss of function. Comparisons were then made between the rates and relative risks (RRs) of surgical complications between pediatric and adult patients. Finally, we examined patient factors associated with surgical complications, utilizing modified Poisson regression models with robust SEs. RESULTS: Three adult controls (ie, 1 control from each age group) were identified for 1385 pediatric patients, for a total sample of 5540 TJA patients. Approximately 10% of pediatric patients experienced either major or minor surgical complications. The overall rate of major complications in pediatric patients was 5.05%, compared with 4.79% in adult controls [RR: 1.06 (0.81 to 1.38), P=0.69]. The overall rate of minor complications in pediatric patients was 5.78%, compared with 5.68% in adult controls [RR: 1.02 (0.80 to 1.30), P=0.78]. When adjusted for patient demographics, the RR of major complications was 49% higher in pediatric patients compared with ages 21 to 50 [RR: 1.49 (1.03 to 2.16), P=0.03] with no statistically significant differences noted for other age groups. For minor complications, the adjusted RR in pediatric patients, compared with any other age group, did not approach statistical significance. CONCLUSIONS: Pediatric patients undergoing TJA experience major and minor surgical complications at rates comparable with their adult counterparts. Our findings offer important insight on the rates of surgical complications in pediatric TJA patients, which is valuable for preoperative education and consultation with patients and families. LEVEL OF EVIDENCE: Level III therapeutic. PMID- 27479190 TI - Outcome of Conservative Versus Surgical Treatment of Humeral Shaft Fracture in Children and Adolescents: Comparison Between Nonoperative Treatment (Desault's Bandage), External Fixation and Elastic Stable Intramedullary Nailing. AB - BACKGROUND: The main objective of this study was to retrospectively evaluate the clinical and radiographic outcomes of displaced humeral shaft fractures in children treated by Desault's bandage (DB), external fixation (EF), and elastic stable intramedullary nailing (ESIN). METHODS: During the study period, 36 consecutive children with displaced humeral shaft fracture were treated by DB (Group A), EF (Group B) or ESIN (Group C). All the patients underwent full-length preoperative and postoperative anteroposterior and lateral radiographs of the injured humerus. One year after the index surgery, patients were asked to answer the short version of the Disabilities of the Arm, Shoulder and Hand outcome questionnaire (Quick DASH). RESULTS: Ten patients (27.8%) were in Group A, 11 (30%) in Group B, and 15 (41.7%) in Group C. Mean age at the time of injury was 10.8+/-2.3 years (range, 8 to 15.2 y), 11.7+/-2.5 years (range, 6.8 to 15.9 y), and 12.7+/-2.2 years (range, 6.9 to 15.3 y) in Groups A, B, and C, respectively (P=0.08). Groups A, B, and C did not differ significantly in their demographics (P>0.05).Surgical treatment (Groups B and C) provided a better radiologic outcome than nonoperative treatment (Group A) (P=0.05). No statistically significant differences were observed for preoperative, postoperative and at last follow-up mean displacement between Groups B and C (P>0.05).Overall, 9 of 36 patients developed a complication: 2 in Group A (20%), 4 in Group B (37%), and 3 in Group C (20.1) (P=0.92).Mean Quick DASH score was 3+/-8.6 (range, 0 to 27.3), 1.4+/-2.9 (range, 0 to 9), and 1.2+/-4.7 (range, 0 to 18.2) in Groups A, B, and C, respectively. All the patients were able to resume previous physical and sport activities 4 to 6 months after the last fracture reduction procedure. CONCLUSIONS: Surgery is not contraindicated in children with displaced humeral shaft fractures. EF and ESIN provide a better radiologic outcome, less posttreatment pain and faster mobilization than DB. However, numerical differences, although statistically significant, were not clinically relevant for all variables but immobilization time. Nonoperative treatment was as efficacious as surgical treatment apart from the length of time for immobilization. LEVEL OF EVIDENCE: Level III. PMID- 27479191 TI - Elbow Kinematics During Gait Improve With Age in Children With Hemiplegic Cerebral Palsy. AB - BACKGROUND: Children with hemiplegic cerebral palsy (hCP) exhibit a typical posture of elbow flexion during gait. However, the change in elbow kinematics and symmetry during gait across age span in both hCP and typically developing (TD) children is not well described. The aim of this study was to quantify the change in elbow kinematics and symmetry across age span in hCP children compared with TD children. METHODS: Upper extremity kinematic data were extracted and analyzed from a database for gait studies performed between 2009 and 2015. A total of 35 hCP and 51 TD children between the ages of 4 and 18 (mean age: TD=11.2+/-0.6, hCP=9.8+/-0.5) met inclusionary criteria. The groups were further subdivided into 3 age categories: 4 to 7, 8 to 11, 12+ years old. Elbow angles were extracted and peak elbow flexion, overall range of motion during gait, and asymmetry indices were calculated. A 1-way analysis of variance was performed on each group with post hoc Tukey honestly significant difference pairwise comparisons. RESULTS: Peak elbow flexion during gait increased with age in TD children (P<0.05) and decreased with age in hCP children on the affected side (P<0.05). There was no change on the less affected side of hCP children. TD children demonstrated significantly less elbow flexion (mean=51.9+/-2.1 deg.) compared with the affected side in hCP (mean=82.1+/-3.8 deg.) across all age categories (P<0.05). There was no change in elbow asymmetry index (0=perfect symmetry) across age in either controls or hCP children; however, there were differences between hCP and TD groups in younger age groups (TD=28, hCP=62, P<0.05) that resolved by adolescence (TD=32, hCP=40). CONCLUSIONS: During gait, hCP children have greater peak elbow flexion on the affected side than do TD children. Peak elbow flexion angle converged between the 2 groups with age, decreasing in hCP children and increasing in TD children. Furthermore, elbow symmetry during gait improves with age in hCP children, approximating symmetry of TD children by adolescence. These findings have implications for both consideration and optimal timing of surgical intervention to improve elbow flexion in children with hCP. LEVEL OF EVIDENCE: Level III-retrospective case-control study. PMID- 27479192 TI - Zerumbone induces gastric cancer cells apoptosis: Involving cyclophilin A. AB - Gastric cancer is one of the leading causes for cancer death. There is an urgent need to develop new therapeutic approaches targeting metastatic gastric cancer. It has been reported that zerumbone has the anti-cancer effects in various malignant cells. However, the effect and the mechanism of zerumbone on melanoma cells is still largely unknown. In the study, we determined the actions of zerumbone on the human gastric cancer cell line SGC-7901.We also observed the mechanism by which zerumbone induced gastric cancer cell apoptosis. Our data indicated that zerumbone significantly inhibited the growth of human gastric cancer cells in a dose-dependent manner and apoptosis was the main cause of decreased cell viability in zerumbone -treated cells. The treatment with zerumbone downregulated Cyp A and Bcl-2 levels, upregulated Bax levels, and caused Cytochrome c (Cyt-C) to release, activating Caspase-3. In summary, our study suggests that zerumbone mightinduced human gastric cancer cells apoptosis through down-regulating Cyp A and mitochondria-mediated pathways. PMID- 27479193 TI - Multifaceted effects of aluminium in neurodegenerative diseases: A review. AB - Aluminium (Al) is the most common metal and widely distributed in our environment. Al was first isolated as an element in 1827, and its use began only after 1886. Al is widely used for industrial applications and consumer products. Apart from these it is also used in cooking utensils and in pharmacological agents, including antacids and antiperspirants from which the element usually enters into the human body. Evidence for the neurotoxicity of Al is described in various studies, but still the exact mechanism of Al toxicity is not known. However, the evidence suggests that the Al can potentiate oxidative stress and inflammatory events and finally leads to cell death. Al is considered as a well established neurotoxin and have a link between the exposure and development of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), dementia, Gulf war syndrome and Parkinsonism. Here, we review the detailed possible pathogenesis of Al neurotoxicity. This review summarizes Al induced events likewise oxidative stress, cell mediated toxicity, apoptosis, inflammatory events in the brain, glutamate toxicity, effects on calcium homeostasis, gene expression and Al induced Neurofibrillary tangle (NFT) formation. Apart from these we also discussed animal models that are commonly used for Al induced neurotoxicity and neurodegeneration studies. These models help to find out a better way to treat and prevent the progression in Al induced neurodegenerative diseases. PMID- 27479194 TI - Comparative study on the antioxidant capacities of synthetic influenza inhibitors and ellagic acid in model systems. AB - This study compares the antioxidant capacities in vitro of several synthetic and natural compounds applied and researched for influenza treatment - oseltamivir, isoprinosine, ellagic acid, vitamin E and vitamin C. Three chemical systems are utilized for the generation of reactive oxygen species (ROS) at pH 7.4 and pH 8.5: (1) Fenton's (Fe2++H2O2) for OH and -OH species (2) H2O2 (3) NADH phenazinemethosulfat, for superoxide radicals (O2-). The kinetics was evaluated by lucigenin-enhanced chemiluminescence. The calculated constants of inhibition k7 describe the antioxidant capacity at the moment of oxidative burst. Their values do not necessarily correspond to the calculated total antioxidant activity. The obtained results revealed that the synthetic anti-influenza drugs (oseltamivir and isoprinosine) as well as ellagic acid possess pronounced scavenging properties mostly against superoxide radicals, comparable and higher than that of traditional natural antioxidants. Quantitative analysis of the antioxidant effects of the examined synthetic substances was performed. The results compared the corresponding effect of the average physiological concentrations and the applied therapeutic antioxidant dose. With these experiments we registered new aspects of their therapeutic activities, due to antioxidant properties against hydroxyl, superoxide radicals and H2O2 oxidation. PMID- 27479195 TI - Comparison of biomarker expression between proximal and distal colorectal adenomas: The Tennessee-Indiana Adenoma Recurrence Study. AB - It is unclear if proximal and distal traditional adenomas present with differences in molecular events which contribute to cancer heterogeneity by tumor anatomical subsite. Participants from a colonoscopy-based study (n = 380) were divided into subgroups based on the location of their most advanced adenoma: proximal, distal, or "equivalent both sides." Eight biomarkers in the most advanced adenomas were evaluated by immunohistochemistry (Ki-67, COX-2, TGFbetaRII, EGFR, beta-catenin, cyclin D1, c-Myc) or TUNEL (apoptosis). After an adjustment for pathological features, there were no significant differences between proximal and distal adenomas for any biomarker. Conversely, expression levels did vary by other features, such as their size, villous component, and synchronousness. Large adenomas had higher expression levels of Ki-67(P < 0.001), TGFbetaRII (P < 0.0001), c-Myc (P < 0.001), and cyclin D1 (P < 0.001) in comparison to small adenomas, and tubulovillous/villous adenomas also were more likely to have similar higher expression levels in comparison to tubular adenomas. Adenoma location is not a major determinant of the expression of these biomarkers outside of other pathological features. This study suggests similarly important roles of Wnt/beta-catenin and TGF-beta pathways in carcinogenesis in both the proximal and distal colorectum. (c) 2016 Wiley Periodicals, Inc. PMID- 27479196 TI - Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality. AB - Importance: Defining what represents a macronutritionally balanced diet remains an open question and a high priority in nutrition research. Although the amount of protein may have specific effects, from a broader dietary perspective, the choice of protein sources will inevitably influence other components of diet and may be a critical determinant for the health outcome. Objective: To examine the associations of animal and plant protein intake with the risk for mortality. Design, Setting, and Participants: This prospective cohort study of US health care professionals included 131 342 participants from the Nurses' Health Study (1980 to end of follow-up on June 1, 2012) and Health Professionals Follow-up Study (1986 to end of follow-up on January 31, 2012). Animal and plant protein intake was assessed by regularly updated validated food frequency questionnaires. Data were analyzed from June 20, 2014, to January 18, 2016. Main Outcomes and Measures: Hazard ratios (HRs) for all-cause and cause-specific mortality. Results: Of the 131 342 participants, 85 013 were women (64.7%) and 46 329 were men (35.3%) (mean [SD] age, 49 [9] years). The median protein intake, as assessed by percentage of energy, was 14% for animal protein (5th-95th percentile, 9%-22%) and 4% for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was not associated with all-cause mortality (HR, 1.02 per 10% energy increment; 95% CI, 0.98-1.05; P for trend = .33) but was associated with higher cardiovascular mortality (HR, 1.08 per 10% energy increment; 95% CI, 1.01-1.16; P for trend = .04). Plant protein was associated with lower all-cause mortality (HR, 0.90 per 3% energy increment; 95% CI, 0.86-0.95; P for trend < .001) and cardiovascular mortality (HR, 0.88 per 3% energy increment; 95% CI, 0.80-0.97; P for trend = .007). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors. Replacing animal protein of various origins with plant protein was associated with lower mortality. In particular, the HRs for all-cause mortality were 0.66 (95% CI, 0.59 0.75) when 3% of energy from plant protein was substituted for an equivalent amount of protein from processed red meat, 0.88 (95% CI, 0.84-0.92) from unprocessed red meat, and 0.81 (95% CI, 0.75-0.88) from egg. Conclusions and Relevance: High animal protein intake was positively associated with cardiovascular mortality and high plant protein intake was inversely associated with all-cause and cardiovascular mortality, especially among individuals with at least 1 lifestyle risk factor. Substitution of plant protein for animal protein, especially that from processed red meat, was associated with lower mortality, suggesting the importance of protein source. PMID- 27479197 TI - Limited Effects of Type I Interferons on Kyasanur Forest Disease Virus in Cell Culture. AB - BACKGROUND: The tick-borne flavivirus, Kyasanur Forest disease virus (KFDV) causes seasonal infections and periodic outbreaks in south-west India. The current vaccine offers poor protection with reported issues of coverage and immunogenicity. Since there are no approved prophylactic therapeutics for KFDV, type I IFN-alpha/beta subtypes were assessed for antiviral potency against KFDV in cell culture. METHODOLOGY/PRINCIPAL FINDINGS: The continued passage of KFDV infected cells with re-administered IFN-alpha2a treatment did not eliminate KFDV and had little effect on infectious particle production whereas the IFN sensitive, green fluorescent protein-expressing vesicular stomatitis virus (VSV GFP) infection was controlled. Further evaluation of the other IFN-alpha/beta subtypes versus KFDV infection indicated that single treatments of either IFN alphaWA and IFN-alphaKappa appeared to be more effective than IFN-alpha2a at reducing KFDV titres. Concentration-dependent analysis of these IFN-alpha/beta subtypes revealed that regardless of subtype, low concentrations of IFN were able to limit cytopathic effects (CPE), while significantly higher concentrations were needed for inhibition of virion release. Furthermore, expression of the KFDV NS5 in cell culture before IFN addition enabled VSV-GFP to overcome the effects of IFN-alpha/beta signalling, producing a robust infection. CONCLUSIONS/SIGNIFICANCE: Treatment of cell culture with IFN does not appear to be suitable for KFDV eradication and the assay used for such studies should be carefully considered. Further, it appears that the NS5 protein is sufficient to permit KFDV to bypass the antiviral properties of IFN. We suggest that other prophylactic therapeutics should be evaluated in place of IFN for treatment of individuals with KFDV disease. PMID- 27479200 TI - Doubly robust estimator for net survival rate in analyses of cancer registry data. AB - Cancer population studies based on cancer registry databases are widely conducted to address various research questions. In general, cancer registry databases do not collect information on cause of death. The net survival rate is defined as the survival rate if a subject would not die for any causes other than cancer. This counterfactual concept is widely used for the analyses of cancer registry data. Perme, Stare, and Esteve (2012) proposed a nonparametric estimator of the net survival rate under the assumption that the censoring time is independent of the survival time and covariates. Kodre and Perme (2013) proposed an inverse weighting estimator for the net survival rate under the covariate-dependent censoring. An alternative approach to estimating the net survival rate under covariate-dependent censoring is to apply a regression model for the conditional net survival rate given covariates. In this article, we propose a new estimator for the net survival rate. The proposed estimator is shown to be doubly robust in the sense that it is consistent at least one of the regression models for survival time and for censoring time. We examine the theoretical and empirical properties of our proposed estimator by asymptotic theory and simulation studies. We also apply the proposed method to cancer registry data for gastric cancer patients in Osaka, Japan. PMID- 27479198 TI - Acceptability of Robot Assistant in Management of Type 1 Diabetes in Children. AB - BACKGROUND: To find out whether children with type 1 diabetes accept a humanoid robot as an assistant in their diabetes management. In particular, the study aims to determine how the patients feel the robot may contribute to their care and how they respond to advice and education provided by the robot. SUBJECTS AND METHODS: A humanoid robot was used in clinic and its acceptability was tested over 3 months in 37 children (aged 6-16 years) with type 1 diabetes during their clinic visits. RESULTS: The obtained result showed that the overall patients' acceptability is 86.7%. However, the level of acceptability varies depending on the age group; patients aged 6-9 years showed the highest acceptability level of 94.8%, while the older age groups, 10-12 and 13-16 years, showed lower acceptability levels of 85.0% and 83.0%, respectively. There was no difference in the overall acceptability of the robot between the male and female patients (87.0% and 86.5%, respectively). Furthermore, features of the robot that were highly desirable include ability of the robot to give advice on high/low blood glucose (BG) levels (92.0%), how much the patients like the robot (91.4%), and ability of the robot to give advice on BG patterns (90.6%). In contrast, some other features were found least acceptable such as how likely patients want the robot as a companion (81.0%) and calculation of insulin doses with meals (82.53%). Analysis of variance across the responses of different age groups showed that P-value = 0.00003. CONCLUSION: Use of robots as a new device to support diabetes self-management in children was well accepted by patients. PMID- 27479201 TI - Genotype-phenotype correlation in long QT syndrome families. AB - Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction. Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1-4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of "anticipation" in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation. PMID- 27479202 TI - Catheter ablation of recurrent polymorphic tachycardia: Use of sodium channel blockade to organize the tachycardia: A case report. AB - A 55 year old male presented with recurrent implantable cardioverter defibrillator (ICD) shocks due to polymorphic ventricular tachycardia (PMVT). He had undergone prior catheter ablation for VT three years ago. During the prior attempt he underwent voltage guided substrate ablation. With programmed ventricular extrastimulation (PVES), PMVT was repeatedly induced requiring DC shock. Intravenous procainamide was administered and PVES was repeated which induced sustained monomorphic ventricular tachycardia (MMVT). This VT had pseudo delta waves with maximum deflection index of 0.68, suggestive of epicardial origin. Activation mapping was performed epicardially. Presystolic potentials were recorded in mid anterolateral wall of left ventricular epicardial region. Radiofrequency (RF) ablation at this site terminated the VT. Post ablation there was no inducible tachycardia and patient is free of arrhythmias during 2 years of follow-up. PMID- 27479203 TI - Acute outcome of treating patients admitted with electrical storm in a tertiary care centre. AB - BACKGROUND: Electrical storm (ES) is a life threatening emergency. There is little data available regarding acute outcome of ES. AIMS: The study aimed to analyze the acute outcome of ES, various treatment modalities used, and the factors associated with mortality. METHODS: This is a retrospective observational study involving patients admitted with ES at our centre between 1/1/2007 and 31/12/2013. RESULTS: 41 patients (mean age 54.61 +/- 12.41 years; 86.7% males; mean ejection fraction (EF) 44.51 +/- 16.48%) underwent treatment for ES. Hypokalemia (14.63%) and acute coronary syndrome (ACS) (14.63%) were the commonest identifiable triggers. Only 9 (21.95%) patients already had an ICD implanted. Apart from antiarrhythmic drugs (100%), deep sedation (87.8%), mechanical ventilation (24.39%) and neuraxial modulation using left sympathetic cardiac denervation (21.95%) were the common treatment modalities used. Thirty three (80.49%) patients could be discharged after a mean duration of 14.2 +/- 2.31 days. Eight (19.5%) patients died in hospital. The mortality was significantly higher in those with EF < 35% compared to those with a higher EF (8 (42.11% vs 0 (0%), p = 0.03)). There was no significant difference in mortality between those with versus without a structural heart disease (8 (21.1% vs 0 (0%), p = 0.32)). Comparison of mortality an ACS with ES versus ES of other aetiologies (3 (50%) vs 5 (14.29) %, p = 0.076)) showed a trend towards significance. CONCLUSION: With comprehensive treatment, there is reasonable acute survival rate of ES. Hypokalemia and ACS are the commonest triggers of ES. Patients with low EF and ACS have higher mortality. PMID- 27479204 TI - Gold-coated pacemaker implantation for a patient with type IV allergy to titanium. AB - A 65-year-old man was scheduled for pacemaker implantation for symptomatic sick sinus-syndrome (SSS). He suffered from multiple drug-allergies and allergies to several metals like quicksilver and titanium. Gold-coated pacemaker generators and polyurethane leads are effective in avoiding allergic reactions to pacing system components. Therefore, we decided to implant a custom-made gold-coated DDDR-pacemaker generator and polyurethane leads. PMID- 27479205 TI - Electromagnetic Interference in a Private Swimming Pool: Case report. AB - Although current lead design and filtering capabilities have greatly improved, Electromagnetic Interference (EMI) from environmental sources has been increasingly reported in patients with Cardiac Implantable Electronic Device (CIED) [1]. Few cases of inappropriate intracardiac Cardioverter Defibrillator (ICD) associated with swimming pool has been described [2]. Here we present a case of 64 year old male who presented with an interesting EMI signal that was subsequently identified to be related to AC current leak in his swimming pool. PMID- 27479206 TI - Bidirectional ventricular tachycardia of unusual etiology. AB - Bidirectional ventricular tachycardia (BDVT) is a rare form of ventricular arrhythmia, characterized by changing QRS axis of 180 degrees. Digitalis toxicity is considered as commonest cause of BDVT; other causes include aconite toxicity, myocarditis, myocardial infarction, metastatic cardiac tumour and cardiac channelopathies. We describe a case of BDVT in a patient with Anderson-Tawil syndrome. PMID- 27479207 TI - Combination of Hansen Robotic system with cryocatheter in a challenging parahisian accessory pathway ablation. AB - A perceived distinctive feature of cryoablation is the stability (cryoadherence) of the catheter tip during cold temperatures at the desired location, even during tachycardia. We report the case report of a young patient with a parahisian accessory pathway where stability of the ablation catheter was not achieved despite using the cryocatheter with a steerable sheath. Ultimately, stability at the desired location was achieved robotically by means of Hansen system (Hansen Medical, Mountain View, CA, USA). PMID- 27479209 TI - Electrochemical stiffness in lithium-ion batteries. AB - Although lithium-ion batteries are ubiquitous in portable electronics, increased charge rate and discharge power are required for more demanding applications such as electric vehicles. The high-rate exchange of lithium ions required for more power and faster charging generates significant stresses and strains in the electrodes that ultimately lead to performance degradation. To date, electrochemically induced stresses and strains in battery electrodes have been studied only individually. Here, a new technique is developed to probe the chemomechanical response of electrodes by calculating the electrochemical stiffness via coordinated in situ stress and strain measurements. We show that dramatic changes in electrochemical stiffness occur due to the formation of different graphite-lithium intercalation compounds during cycling. Our analysis reveals that stress scales proportionally with the lithiation/delithiation rate and strain scales proportionally with capacity (and inversely with rate). Electrochemical stiffness measurements provide new insights into the origin of rate-dependent chemomechanical degradation and the evaluation of advanced battery electrodes. PMID- 27479208 TI - Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss. AB - Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures. PMID- 27479210 TI - Measuring nonlinear stresses generated by defects in 3D colloidal crystals. AB - The mechanical, structural and functional properties of crystals are determined by their defects, and the distribution of stresses surrounding these defects has broad implications for the understanding of transport phenomena. When the defect density rises to levels routinely found in real-world materials, transport is governed by local stresses that are predominantly nonlinear. Such stress fields however, cannot be measured using conventional bulk and local measurement techniques. Here, we report direct and spatially resolved experimental measurements of the nonlinear stresses surrounding colloidal crystalline defect cores, and show that the stresses at vacancy cores generate attractive interactions between them. We also directly visualize the softening of crystalline regions surrounding dislocation cores, and find that stress fluctuations in quiescent polycrystals are uniformly distributed rather than localized at grain boundaries, as is the case in strained atomic polycrystals. Nonlinear stress measurements have important implications for strain hardening, yield and fatigue. PMID- 27479211 TI - Mixed-dimensional van der Waals heterostructures. AB - The isolation of a growing number of two-dimensional (2D) materials has inspired worldwide efforts to integrate distinct 2D materials into van der Waals (vdW) heterostructures. Given that any passivated, dangling-bond-free surface will interact with another through vdW forces, the vdW heterostructure concept can be extended to include the integration of 2D materials with non-2D materials that adhere primarily through non-covalent interactions. We present a succinct and critical survey of emerging mixed-dimensional (2D + nD, where n is 0, 1 or 3) heterostructure devices. By comparing and contrasting with all-2D vdW heterostructures as well as with competing conventional technologies, we highlight the challenges and opportunities for mixed-dimensional vdW heterostructures. PMID- 27479212 TI - Common Variants in the TBX5 Gene Associated with Atrial Fibrillation in a Chinese Han Population. AB - BACKGROUND: PR interval variations have recently been associated with an increased risk of long-term atrial fibrillation (AF), heart block and all-cause mortality. Genome-wide association studies have linked the PR interval with several common variants in the TBX5 gene. Several variants in the TBX5 gene, including rs7312625 and rs883079, have been associated with AF. The purpose of this study was to determine the association of single-nucleotide polymorphisms (SNPs) in the TBX5 gene, rs7312625 and rs883079, with AF in Chinese Han patients. METHODOLOGY/PRINCIPAL FINDINGS: In this case-control association study, large cohorts of AF patients (n = 1132) and controls (n = 1206) were recruited from different hospitals. The genotyping was performed using a Rotor-Gene TM 6000 high resolution melt system. Rs7312625, rs3825214 and rs883079 were analyzed. We found that SNP 3825214 was significantly associated with AF (P-obs = 0.002, odds ratio [OR] = 0.82), and lone AF (P-obs = 6.77x10-5, odds ratio [OR] = 0.71). SNP rs7312625 was significantly associated with lone AF (P-obs = 0.015, odds ratio [OR] = 1.27), although its association with AF was not significant. No significant association of SNP rs883079 with AF or lone AF was observed. Thus, we analyzed the interaction among these three loci. We demonstrated significant interaction among rs3825214, rs7312625 and rs883079. Four-locus risk alleles showed the highest odds ratio in combined rs3825214 and rs7312625 (P-obs<0.0001, odds ratio [OR] = 2.21). Six-locus risk alleles showed the highest odds ratio in combined rs3825214, rs7312625 and rs 883079(P-obs<0.0001, odds ratio [OR] = 2.35). Significance was established with the trend test (P<0.0001). CONCLUSIONS: For the first time, we report the strong association of SNP rs3825214 in the TBX5 gene with AF and lone AF in a Chinese Han population. Rs7312625 was significantly associated with lone AF, and snp-snp interaction increased the risk of atrial fibrillation. Our data might provide new insights into understanding AF pathogenesis and designing novel genetic therapies for AF patients. PMID- 27479213 TI - Species interactions in occurrence data for a community of tick-transmitted pathogens. AB - Interactions between tick species, their realized range of hosts, the pathogens they carry and transmit, and the geographic distribution of species in the Western Palearctic were determined based on evidence published between 1970-2014. These relationships were linked to remotely sensed features of temperature and vegetation and used to extract the network of interactions among the organisms. The resulting datasets focused on niche overlap among ticks and hosts, species interactions, and the fraction of the environmental niche in which tick-borne pathogens may circulate as a result of interactions and overlapping environmental traits. The resulting datasets provide a valuable resource for researchers interested in tick-borne pathogens, as they conciliate the abiotic and biotic sides of their niche, allowing exploration of the importance of each host species acting as a vertebrate reservoir in the circulation of tick-transmitted pathogens in the environmental niche. PMID- 27479214 TI - Correction: Barcoding Eophila crodabepis sp. nov. (Annelida, Oligochaeta, Lumbricidae), a Large Stripy Earthworm from Alpine Foothills of Northeastern Italy Similar to Eophila tellinii (Rosa, 1888). AB - [This corrects the article DOI: 10.1371/journal.pone.0151799.]. PMID- 27479215 TI - Myocardial Expression Analysis of Osteopontin and Its Splice Variants in Patients Affected by End-Stage Idiopathic or Ischemic Dilated Cardiomyopathy. AB - Osteopontin (OPN) is a phosphoglycoprotein of cardiac extracellular matrix and it is still poorly defined whether its expression changes in failing heart of different origin. The full-length OPN-a and its isoforms (OPN-b, OPN-c) transcriptomic profile were evaluated in myocardium of patients with dilated or ischemic cardiomyopathy (DCM n = 8; LVEF% = 17.5+/-3; ICM n = 8; LVEF% = 19.5+/ 5.2) and in auricle of valvular patients (VLP n = 5; LVEF%>=50), by Real-time PCR analysis. OPN-a and thrombin mRNA levels resulted significantly higher in DCM compared to ICM patients (DCM:31.3+/-7.4, ICM:2.7+/-1.1, p = 0.0002; DCM:19.1+/ 4.9, ICM:5.4+/-2.2, p = 0.007, respectively). Although both genes' mRNA levels increased in patients with LVEF<50% (DCM+ICM) with respect to VLP with LVEF>50%, a significant increase in OPN (p = 0.0004) and thrombin (p = 0.001) expression was observed only in DCM. In addition, a correlation between OPN-a and thrombin was found in patients with LVEF<50% (r = 0.6; p = 0.003). The mRNA pattern was confirmed by OPN-a cardiac protein concentration (VLP:1.127+/-0.26; DCM:1.29+/ 0.22; ICM:1.00+/-0.077 ng/ml). The OPN splice variants expression were detectable only in ICM (OPN-b: 0.357+/-0.273; OPN-c: 0.091+/-0.033) and not in DCM patients. A significant correlation was observed between collagen type I, evaluated by immunohistochemistry analysis, and both OPN-a mRNA expression (r = 0.87, p = 0.002) and OPN protein concentrations (r = 0.77, p = 0.016). Concluding, OPN-a and thrombin mRNA resulted dependent on the origin of heart failure while OPN-b and OPN-c highlighted a different expression for DCM and ICM patients, suggesting their correlation with different clinical-pathophysiological setting. PMID- 27479216 TI - Daily changes of individual gait patterns identified by means of support vector machines. AB - Despite the common knowledge about the individual character of human gait patterns and about their non-repeatability, little is known about their stability, their interactions and their changes over time. Variations of gait patterns are typically described as random deviations around a stable mean curve derived from groups, which appear due to noise or experimental insufficiencies. The purpose of this study is to examine the nature of intrinsic inter-session variability in more detail by proving separable characteristics of gait patterns between individuals as well as within individuals in repeated measurement sessions. Eight healthy subjects performed 15 gait trials at a self-selected speed on eight days within two weeks. For each trial, the time-continuous ground reaction forces and lower body kinematics were quantified. A total of 960 gait patterns were analysed by means of support vector machines and the coefficient of multiple correlation. The results emphasise the remarkable amount of individual characteristics in human gait. Support vector machines results showed an error free assignment of gait patterns to the corresponding individual. Thus, differences in gait patterns between individuals seem to be persistent over two weeks. Within the range of individual gait patterns, day specific characteristics could be distinguished by classification rates of 97.3% and 59.5% for the eight day classification of lower body joint angles and ground reaction forces, respectively. Hence, gait patterns can be assumed not to be constant over time and rather exhibit discernible daily changes within previously stated good repeatability. Advantages for more individual and situational diagnoses or therapy are identified. PMID- 27479217 TI - Gender differences in knee abduction during weight-bearing activities: A systematic review and meta-analysis. AB - BACKGROUND: Increased knee abduction during weight-bearing activities is suggested to be a contributing factor for the high knee injury risk reported in women. However, studies investigating gender difference in knee abduction are inconclusive. OBJECTIVE: To systematically review gender-differences in knee abduction during weight-bearing activities in individuals with or without knee injury. METHODS: A systematic review and meta-analysis were conducted according to the PRISMA guidelines. A search in the databases Medline, CINAHL and EMBASE was performed until September 2015. Inclusion criteria were studies that reported (1) gender differences, (2) healthy individuals and/or those with anterior cruciate ligament (ACL) deficiency or reconstruction or patellofemoral pain PFP, and (3) knee abduction assessed with either motion analysis or visual observation during weight-bearing activity. RESULTS: Fifty-eight articles met the inclusion criteria. Women with PFP had greater peak knee abduction compared to men (Std diff in mean; -1.34, 95%CI; -1.83 to -0.84). In healthy individuals, women performed weight-bearing tasks with greater knee abduction throughout the movement (initial contact, peak abduction, excursion) (Std diff in mean; -0.68 to -0.79, 95%CI; -1.04 to -0.37). In subgroup analyses by task, differences in knee abduction between genders were present for most tasks, including running, jump landings and cutting movements. There were too few studies in individuals with ACL injury to perform meta-analysis. CONCLUSION: The gender difference in knee abduction during weight-bearing activities should be considered in training programs aimed at preventing or treating knee injury. PMID- 27479218 TI - Individuals with multiple sclerosis redistribute positive mechanical work from the ankle to the hip during walking. AB - Individuals with multiple sclerosis (MS) typically walk slower, have reduced cadences and shorter step lengths. While these spatiotemporal gait alterations have been thought to be due to decreased power generation at the ankle, the distribution of mechanical work across the ankle, knee and hip joints during walking is not well understood. By quantifying the mechanical work at each joint, the compensatory mechanisms utilized by individuals with MS to maintain gait speed may be better understood. Fifteen subjects with MS (EDSS: 4.4+/-1.0) and fifteen healthy age-matched control subjects completed a three-dimensional gait analysis. The net mechanical work at the ankle, knee and hip joints was quantified for the stance phase of gait. Our results found that the less impaired leg of the subjects with MS generated a similar amount of mechanical work as the control group; however, the ankle joint produced less positive mechanical work, and the hip joint generated more positive mechanical work. Additionally, the less impaired leg of the subjects with MS and the leg of the control group generated more positive work than the more impaired leg of the subjects with MS. These outcomes suggest that individuals with MS may adopt a hip compensatory strategy with their less impaired leg during gait due to the limited amount of mechanical work generated at the ankle. PMID- 27479219 TI - Striatal functional connectivity changes following specific balance training in elderly people: MRI results of a randomized controlled pilot study. AB - BACKGROUND: Practice-induced effects of specific balance training on brain structure and activity in elderly people are largely unknown. AIM: In the present study, we investigated morphological and functional brain changes following slacking training (balancing over nylon ribbons) in a group of elderly people. METHODS: Twenty-eight healthy volunteers were recruited and randomly assigned to the intervention (mean age: 62.3+/-5.4years) or control group (mean age: 61.8+/ 5.3years). The intervention group completed six-weeks of slackline training. Brain morphological changes were investigated using voxel-based morphometry and functional connectivity changes were computed via independent component analysis and seed-based analyses. All analyses were applied to the whole sample and to a subgroup of participants who improved in slackline performance. RESULTS: The repeated measures analysis of variance showed a significant interaction effect between groups and sessions. Specifically, the Tukey post-hoc analysis revealed a significantly improved slackline standing performance after training for the left leg stance time (pre: 4.5+/-3.6s vs. 26.0+/-30.0s, p<0.038) as well as for tandem stance time (pre: 1.4+/-0.6s vs. post: 4.5+/-4.0s, p=0.003) in the intervention group. No significant changes in balance performance were observed in the control group. The MRI analysis did not reveal morphological or functional connectivity differences before or after the training between the intervention and control groups (whole sample). However, subsequent analysis in subjects with improved slackline performance showed a decrease of connectivity between the striatum and other brain areas during the training period. CONCLUSION: These preliminary results suggest that improved balance performance with slackline training goes along with an increased efficiency of the striatal network. PMID- 27479220 TI - Quantifying six-minute walk induced gait deterioration with inertial sensors in multiple sclerosis subjects. AB - BACKGROUND: The six-minute walk (6MW) is a common walking outcome in multiple sclerosis (MS) thought to measure fatigability in addition to overall walking disability. However, direct evidence of 6MW induced gait deterioration is limited by the difficulty of measuring qualitative changes in walking. OBJECTIVES: This study aims to (1) define and validate a measure of fatigue-related gait deterioration based on data from body-worn sensors; and (2) use this measure to detect gait deterioration induced by the 6MW. METHODS: Gait deterioration was assessed using the Warp Score, a measure of similarity between gait cycles based on dynamic time warping (DTW). Cycles from later minutes were compared to baseline cycles in 89 subjects with MS and 29 controls. Correlation, corrected (partial) correlation, and linear regression were used to quantify relationships to walking and fatigue outcomes. RESULTS: Warp Scores rose between minute 3 and minute 6 in subjects with mild and moderate disability (p<0.001). Statistically significant correlations (p<0.001) to the MS walking scale (MSWS-12), modified fatigue impact scale (MFIS) physical subscale, and cerebellar and pyramidal functional system scores (FSS) were observed even after controlling for walking speed. Regression of MSWS-12 scores on Warp Scores and walking speed explained 73.9% of response variance. Correlations to individual MSWS-12 and MFIS items strongly suggest a relationship to fatigability. CONCLUSION: The Warp Score has been validated in MS subjects as an objective measure of fatigue-related gait deterioration. Progressive changes to gait cycles induced by the 6MW often appeared in later minutes, supporting the importance of sustained walking in clinical assessment. PMID- 27479221 TI - Should We Offer Medication to Reduce Breast Cancer Risk?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center. AB - In November 2013, the U.S. Preventive Services Task Force issued a guideline on medications for risk reduction of primary breast cancer in women. Although mammography can detect early cases, it cannot prevent development of breast cancer. Tamoxifen and raloxifene are selective estrogen receptor modulators that have been shown to reduce the risk for estrogen receptor-positive breast cancer and are approved by the U.S. Food and Drug Administration (FDA) for this indication. However, neither medication reduces the risk for estrogen receptor negative breast cancer or all-cause mortality. The Task Force concluded that postmenopausal women with an estimated 5-year risk for breast cancer of 3% or greater will probably have more net benefit than harm and recommends that clinicians engage in shared, informed decision making about these medications. The American Society of Clinical Oncology issued a practice guideline on use of pharmacologic interventions for breast cancer in 2013. It recommends that women aged 35 years or older at increased risk, defined as a 5-year absolute risk for breast cancer of 1.66% or greater, discuss breast cancer prevention medications with their primary care practitioner. The Society includes the aromatase inhibitor exemestane in addition to tamoxifen and raloxifene as a breast cancer prevention medication, although exemestane is not FDA approved for this indication. Here, an oncologist and an internist discuss how they would balance these recommendations and what they would suggest for an individual patient. PMID- 27479222 TI - Visceral Vistas: Basil Hirschowitz and the Birth of Fiberoptic Endoscopy. AB - Fiberoptic endoscopy was developed at the University of Michigan in the 1950s by gastroenterology fellow Basil Hirschowitz and 2 physicists. Previous methods to visualize the gastrointestinal lumen used rigid instruments that relied on rudimentary optical systems. They were limited in reach and caused patients considerable discomfort. Fiberoptic technology dramatically changed endoscopic practice. The fiberoptic endoscope, or fiberscope, was a flexible instrument that allowed direct inspection of the gastrointestinal lumen. Although many practicing endoscopists initially resisted its adoption, the fiberscope ultimately held sway. Studying the period from the fiberscope's first introduction in the late 1950s to its more widespread acceptance in the late 1960s may help us understand how a new technology makes its way into routine clinical practice. PMID- 27479223 TI - From Kitchen Bench to Bedside. PMID- 27479224 TI - Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus. PMID- 27479225 TI - Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus. PMID- 27479227 TI - Venous Leg Ulcers. AB - This issue provides a clinical overview of venous leg ulcers, focusing on prevention, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers. PMID- 27479228 TI - Web Exclusives. Annals Graphic Medicine - I'd Want a Natural Death. PMID- 27479229 TI - Spin reversal and orbital torques on a viscous fluid Rayleigh sphere located arbitrarily in acoustical Bessel vortex (spiraling) beams. AB - The goal of this work is to demonstrate the emergence of a spin torque singularity (i.e. zero spin torque) and a spin rotation reversal of a small Rayleigh lipid/fat viscous fluid sphere located arbitrarily in space in the field of an acoustical Bessel vortex beam. This counter-intuitive property of negative spin torque generation suggests a direction of spin rotation in opposite handedness of the angular momentum carried by the incident beam. Such effects may open new capabilities in methods of quantitative characterization to determine physical properties such as viscosity, viscoelasticity, compressibility, stiffness, etc., and other techniques for the rotation and positioning using acoustical tractor beams and tweezers, invisibility cloaks, and acoustically engineered composite metamaterials to name a few examples. Based on the descriptions for the velocity potential of the incident beam and the scattering coefficients of the sphere in the long-wavelength approximation limit, simplified expressions for the spin and orbital radiation torque components are derived. For beams with (positive or negative) unit topological charge (m=+/-1), the axial spin torque component for a Rayleigh absorptive sphere is maximal at the center of the beam, while it vanishes for |m|>1 therein. Moreover, the longitudinal orbital torque component, causing the sphere to rotate around the center of the beam is evaluated based on the mathematical decomposition using the gradient, scattering and absorption transverse radiation force vector components. It is shown that there is no contribution of the gradient transverse force to the orbital torque, which is only caused by the scattering and absorption transverse force components. Though the incident acoustical vortex beam carrying angular momentum causes the sphere to rotate in the same orbital direction of the beam handedness, it induces a spin torque singularity (i.e. zero spin torque) and subsequent sign reversal. This phenomenon of negative spin torque generation may be exploited from the standpoint of particle sizing, and possibly other applications in particle manipulation and rotation. In addition, an application of the spin and orbital radiation torque formulations derived here in the Rayleigh limit concerns the inverse determination of the host fluid viscosity from the induced sphere spinning and/or orbital rotation. PMID- 27479230 TI - Development of an ultrasonic linear motor with ultra-positioning capability and four driving feet. AB - This paper presents a novel linear piezoelectric motor which is suitable for rapid ultra-precision positioning. The finite element analysis (FEA) was applied for optimal design and further analysis, then experiments were conducted to investigate its performance. By changing the input signal, the proposed motor was found capable of working in the fast driving mode as well as in the precision positioning mode. When working in the fast driving mode, the motor acts as an ultrasonic motor with maximum no-load speed up to 181.2mm/s and maximum thrust of 1.7N at 200Vp-p. Also, when working in precision positioning mode, the motor can be regarded as a flexible hinge piezoelectric actuator with arbitrary motion in the range of 8MUm. The measurable minimum output displacement was found to be 0.08MUm, but theoretically, can be even smaller. More importantly, the motor can be quickly and accurately positioned in a large stroke. PMID- 27479231 TI - Publication bias in a recent meta-analysis on breastfeeding and IQ. PMID- 27479232 TI - MAIT be different-persisting dysfunction after DAA-mediated clearance of chronic hepatitis C virus infection. AB - MAIT cells are an abundant innate-like T-cell subset that is defined by the invariant T-cell receptor (iTCR) V-alpha chain Valpha7.2-Jalpha33. Little is currently known about their frequency and function in chronic hepatitis C virus (HCV) infection and their fate after therapy-mediated HCV elimination by direct acting antivirals (DAA). In this issue of the European Journal of Immunology, Hengst et al. [Eur. J. Immunol. 2016. 46: 2204-2210] give important novel insights into the biological role of MAIT cells in a relevant human chronic viral infection by showing that first, MAIT cells are only present at low frequencies in chronic HCV infection; second, circulating MAIT cells in HCV patients also display an altered phenotype; third, they are impaired in their MR-1-dependent effector functions and finally, and maybe most importantly, MAIT-cell frequency and function was not restored after HCV elimination by DAA therapy. These results suggest that MAIT cells are severely affected by a chronic human viral infection in their frequency and function and that this impairment is not reversed after HCV elimination. This is in contrast to rapid DAA-mediated restorations of NK cell and CD8(+) T-cell functions, and indicates a differential impact of chronic infection and clearance on different immune cell subsets. PMID- 27479233 TI - Chimeric Antigen Receptor T Cell Therapy Targeting CD19-Positive Leukemia and Lymphoma in the Context of Stem Cell Transplantation. AB - Novel therapies with chimeric antigen receptor (CAR)-transduced T cells (TCs) sparked new hope for patients with relapsed or refractory CD19-positive leukemia or lymphoma even after stem cell therapies. This review focuses on CARs recognizing the B cell antigen CD19. Both retroviral and lentiviral vectors are used, encoding various anti-CD19 CAR constructs comprising costimulatory molecules such as CD28, CD137/4-1BB, and OX40 either alone (second-generation CARs) or in combination (third-generation CARs). Current, up-to-date published studies on anti-CD19 CAR therapy for acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) with observed side effects are discussed and an outlook on 58 ongoing trials is given. Clinical responses were achieved in up to 81% of ALL, 50% of CLL, and 40% of NHL patients. Factors with potential influence on the clinical outcome might be the design of the vector, the preconditioning regimen, and the number and quality of transfused CAR TCs. The applicability of clinical CAR TC therapy might include relapse after allogeneic stem cell transplantation (alloSCT), and ineligibility for or "bridging" until alloSCT. In summary, CAR therapy represents a highly promising treatment option even in heavily pretreated patients. PMID- 27479234 TI - Achieving High Resolution Ion Mobility Separations Using Traveling Waves in Compact Multiturn Structures for Lossless Ion Manipulations. AB - We report on ion mobility (IM) separations achievable using traveling waves (TW) in a Structures for Lossless Ion Manipulations (SLIM) module having a 44 cm path length and 16 90 degrees turns. The performance of the TW-SLIM module was evaluated for ion transmission and IM separations with different RF, TW parameters, and SLIM surface gaps in conjunction with mass spectrometry. In this work, TWs were created by the transient and dynamic application of DC potentials. The module demonstrated highly robust performance and, even with 16 closely spaced turns, achieving IM resolution performance and ion transmission comparable to a similar straight path module. We found an IM peak capacity of ~31 and peak generation rate of 780 s(-1) for TW speeds of ~80 m/s using the current multi turn TW-SLIM module. The separations achieved for isomers of peptides and tetrasaccharides were found to be comparable to those from a ~0.9-m drift tube based IM-MS platform operated at the same pressure (4 Torr). The combined attributes of flexible design, low voltage requirements and lossless ion transmission through multiple turns for the present TW-SLIM module provides a basis for SLIM devices capable of achieving much greater IM resolution via greatly extended ion path lengths and using compact serpentine designs. PMID- 27479235 TI - Dynamical Crossover in Hot Dense Water: The Hydrogen Bond Role. AB - We investigate the terahertz dynamics of liquid H2O as a function of pressure along the 450 K isotherm, by coupled quasielastic neutron scattering and inelastic X-ray scattering experiments. The pressure dependence of the single molecule dynamics is anomalous in terms of both microscopic translation and rotation. In particular, the Stokes-Einstein-Debye equations are shown to be violated in hot water compressed to the GPa regime. The dynamics of the hydrogen bond network is only weakly affected by the pressure variation. The time scale of the structural relaxation driving the collective dynamics increases by a mere factor of 2 along the investigated isotherm, and the structural relaxation strength turns out to be almost pressure independent. Our results point at the persistence of the hydrogen bond network in hot dense water up to ice VII crystallization, thus questioning the long-standing perception that hydrogen bonds are broken in liquid water under the effect of compression. PMID- 27479236 TI - HIV prevention and care-seeking behaviour among female sex workers in four cities in India, Kenya, Mozambique and South Africa. AB - OBJECTIVE: To identify gaps in the use of HIV prevention and care services and commodities for female sex workers, we conducted a baseline cross-sectional survey in four cities, in the context of an implementation research project aiming to improve use of sexual and reproductive health services. METHODS: Using respondent-driven sampling, 400 sex workers were recruited in Durban, 308 in Tete, 400 in Mombasa and 458 in Mysore and interviewed face-to-face. RDS-adjusted proportions were estimated by nonparametric bootstrapping and compared across cities using post hoc pairwise comparison. RESULTS: Condom use with last client ranged from 88.3% to 96.8%, ever female condom use from 1.6% to 37.9%, HIV testing within the past 6 months from 40.5% to 70.9%, receiving HIV treatment and care from 35.5% to 92.7%, care seeking for last STI from 74.4% to 87.6% and having had at least 10 contacts with a peer educator in the past year from 5.7% to 98.1%. Many of the differences between cities remained statistically significant (P < 0.05) after adjusting for differences in FSWs' socio-demographic characteristics. CONCLUSION: The use of HIV prevention and care by FSWs is often insufficient and differed greatly between cities. Differences could not be explained by variations in socio-demographic sex worker characteristics. Models to improve use of condoms and HIV prevention and care services should be tailored to the specific context of each site. Programmes at each site must focus on improving availability and uptake of those services that are currently least used. PMID- 27479237 TI - Simple systems for treating pumped, turbid water with flocculants and a geotextile dewatering bag. AB - Pumping sediment-laden water from excavations is often necessary on construction sites. This water is often treated by pumping it through geotextile dewatering bags. The bags are not designed to filter the fine sediments that create high turbidity, but dosing with a flocculant prior to the bag could result in greater turbidity control. This study compared two systems for introducing flocculant: passive dosing of commercial solid biopolymer (chitosan) and injection of dissolved polyacrylamide (PAM) in a length of corrugated pipe connected to the bag. The biopolymer system consisted of sequential porous socks containing a "charging agent" followed by chitosan in the corrugated pipe with two levels of dosing. The dissolved PAM was injected into turbid water at a flow-weighted concentration at 1 mg L(-1). For each treatment, sediment-laden turbid water in the range of 2000 to 3500 nephelometric turbidity units (NTU) was pumped into the upstream of corrugated pipe and samples were taken from pipe entrance, pipe exit, and dewatering bag exit. Without flocculant treatment, the dewatering bag reduced turbidity by 70% but the addition of flocculant increased the turbidity reduction up to 97% relative to influent. At the pipe exit, the low-dose biopolymer was less effective in reducing turbidity (37%) but it was equally effective as the high-dose biopolymer or PAM injection after the bag. Our results suggest that a relatively simple treatment with flocculants, either passively or actively, can be very effective in reducing turbidity for pumped water on construction sites. PMID- 27479238 TI - The Integrated Scorecard in support of corporate sustainability strategies. AB - Organizations have increasingly recognized the importance and benefits of developing a sustainability strategy that incorporates environmental and social responsibilities. However, the simultaneous integration of the economic, environmental and social aspects remains a major concern for organizations. The Sustainability Balanced Scorecard (SBSC) represents one of the most promising strategic tools to help organizations face these challenges and support their sustainability strategy. However, past research has provided unclear, incomplete and even contradictory SBSC frameworks while offering little knowledge about how to integrate stakeholder management as well as environmental and social performance within the balanced scorecard to successfully support a corporate sustainability strategy. The aim of this study is to address these issues and limitations by proposing the Integrated Scorecard, a specific SBSC that integrates the three pillars of sustainability performance within four different perspectives, namely environmental, social and economic performance, stakeholder management, internal business processes, and skills and capabilities. This study provides a conceptual approach to the Integrated Scorecard and illustrates, through the use of two practical illustrations, the ability of this framework to support the corporate sustainability strategy by identifying the core sustainability objectives that organizations should achieve when creating value, facilitating the understanding of the contribution of environmental and social initiatives on economic performance, allowing the monitoring and measurement of the strategy's level of achievement, and creating synergy between sustainability performance management and reporting. PMID- 27479239 TI - Assessing the effect of different treatments on decomposition rate of dairy manure. AB - Confined animal feeding operations (CAFOs) contribute to greenhouse gas emission, but the magnitude of these emissions as a function of operation size, infrastructure, and manure management are difficult to assess. Modeling is a viable option to estimate gaseous emission and nutrient flows from CAFOs. These models use a decomposition rate constant for carbon mineralization. However, this constant is usually determined assuming a homogenous mix of manure, ignoring the effects of emerging manure treatments. The aim of this study was to measure and compare the decomposition rate constants of dairy manure in single and three-pool decomposition models, and to develop an empirical model based on chemical composition of manure for prediction of a decomposition rate constant. Decomposition rate constants of manure before and after an anaerobic digester (AD), following coarse fiber separation, and fine solids removal were determined under anaerobic conditions for single and three-pool decomposition models. The decomposition rates of treated manure effluents differed significantly from untreated manure for both single and three-pool decomposition models. In the single-pool decomposition model, AD effluent containing only suspended solids had a relatively high decomposition rate of 0.060 d(-1), while liquid with coarse fiber and fine solids removed had the lowest rate of 0.013 d(-1). In the three pool decomposition model, fast and slow decomposition rate constants (0.25 d(-1) and 0.016 d(-1) respectively) of untreated AD influent were also significantly different from treated manure fractions. A regression model to predict the decomposition rate of treated dairy manure fitted well (R(2) = 0.83) to observed data. PMID- 27479240 TI - Climate change adaptation options in rainfed upland cropping systems in the wet tropics: A case study of smallholder farms in North-West Cambodia. AB - While climate change is confirmed to have serious impacts on agricultural production in many regions worldwide, researchers have proposed various measures that farmers can apply to cope with and adapt to those changes. However, it is often the case that not every adaptation measure would be practical and adoptable in a specific region. Farmers may have their own ways of managing and adapting to climate change that need to be taken into account when considering interventions. This study aimed to engage with farmers to: (1) better understand small-holder knowledge, attitudes and practices in relation to perceived or expected climate change; and (2) document cropping practices, climate change perceptions, constraints to crop production, and coping and adaptation options with existing climate variability and expected climate change. This study was conducted in 2015 in Sala Krau village near Pailin (12 degrees 52'N, 102 degrees 45'E) and Samlout (12 degrees 39'N, 102 degrees 36'E) of North-West Cambodia. The methods used were a combination of focus group discussions and one-on-one interviews where 132 farming households were randomly selected. We found that farmers were conscious of changes in climate over recent years, and had a good understanding of likely future changes. While farmers are aware of some practices that can be modified to minimize risk and cope with anticipated changes, they are reluctant to apply them. Furthermore; there are no government agricultural extension services provided at the village level and farmers have relied on each other and other actors in the value chain network for information to support their decision making. There is a lack of knowledge of the principles of conservation agriculture that urgently require agricultural extension services in the region to build farmer ability to better cope and adapt to climate change. PMID- 27479241 TI - In situ remediation and phytotoxicity assessment of lead-contaminated soil by biochar-supported nHAP. AB - In this study, a kind of biochar-supported nano-hydroxyapatite (nHAP@BC) material was used in in-situ remediation of lead-contaminated soil. Column experiments were performed to compare the mobility of nHAP@BC and Bare-nHAP. The immobilization, accumulation and toxic effects of Pb in the after-amended soil were assessed by the in vitro toxicity tests and pot experiments. The column experiments showed a significant improvement in the mobility of nHAP@BC. The immobilization rate of Pb in the soil was 74.8% after nHAP@BC remediation. Sequential extraction procedures revealed that the residual fraction of Pb increased by 66.6% after nHAP@BC remediation, which greatly reduced the bioavailability of Pb in the soil. In addition, pot experiments indicated that nHAP@BC could effectively reduce the upward translocation capacity of Pb in a soil-plant system. The concentration of Pb in the aerial part of the cabbage mustard was 0.1 mg/kg, which is lower than the tolerance limit (0.3 mg/kg). nHAP@BC can remediate Pb-contaminated soil effectively, which can restore soil quality for planting. PMID- 27479243 TI - Applications and stereoselective syntheses of P-chirogenic phosphorus compounds. AB - Phosphorus compounds bearing chirality on the P-center are usually qualified as P chirogenic or P-stereogenic. This chemical class concerns natural products, agrochemistry, molecular materials, biology and pharmacy, although it is certainly in coordination chemistry and in asymmetric catalysis using chiral transition metal complexes that P-chirogenic phosphorus compounds are the most used. The chiral phosphine ligands and their uses in asymmetric metal-catalyzed reactions have been widely reviewed in literature. However, an overview covering the applications as well as the stereoselective syntheses of all classes of phosphorus compounds has not yet been provided. This review reports the best stereoselective or asymmetric syntheses, the most efficient P*-building blocks and functionalisation of P-chirogenic compounds, in the light of chiral phosphorus compound applications. It is an extensive and useful documentation from pioneering work to recent advances in phosphorus stereochemistry. PMID- 27479242 TI - Arsenic and the Placental Epigenome: Unlocking the Secrets of Prenatal Exposure. PMID- 27479244 TI - The Globally Synchronized Switch-Another Milestone Toward Achieving Polio Eradication. PMID- 27479245 TI - Presumed Furosemide-associated Bilateral Angle-Closure Glaucoma. AB - PURPOSE: To report a case of presumed furosemide-associated bilateral angle closure glaucoma. METHODS: Retrospective case report with spectral domain anterior segment optical coherence tomography imaging. RESULTS: A 21-year-old African American woman in her 17th week of pregnancy presented with acute angle closure glaucoma in both eyes after being started on furosemide in her first trimester for fluid overload. Intraocular pressures were elevated in the low 40s mm Hg bilateral (OU) and anterior chambers were shallow with narrow grade 1 angles on gonioscopy (Schaffer classification). Medical history included type 1 diabetes mellitus, chronic kidney disease, and 2 prior failed pregnancies complicated by fluid overload. She was started on 60 mg of prednisone daily along with topical brimonidine in both eyes twice daily. After 3 days, her intraocular pressures normalized. At 1 week, slit-lamp examination showed deepened anterior chambers and gonioscopy confirmed widened angles. Oral prednisone was titrated down slowly for the remainder of her uneventful pregnancy. On follow-up 1 month after delivery, intraocular pressures and best-corrected visual acuities reached preterm baseline values of 15 mm Hg OU and 20/30 OU. CONCLUSIONS: This is the first reported case of furosemide-associated bilateral angle-closure glaucoma. Similar idiosyncratic reactions following exposure to other sulphonamide containing drugs have been described. We propose discontinuation of the offending agent and treatment with oral prednisone in similar clinical settings. PMID- 27479246 TI - Etoxazole is Metabolized Enantioselectively in Liver Microsomes of Rat and Human in Vitro. AB - Acaricide etoxazole belongs to the ovicides/miticides diphenyloxazole class, affecting adults to lay sterile eggs by inhibiting chitin biosynthesis possibly. The reverse-phase HPLC-MS/MS method was used to determine the etoxazole enantiomers. The enantioselective degradation behavior of rac-etoxazole in liver microsomes of rat and human in vitro with NADPH was dramatically different. The t1/2 of (R)-etoxazole was 15.23 min in rat liver microsomes and 30.54 min in human liver microsomes, while 21.73 and 23.50 min were obtained for (S) etoxazole, respectively. The Vmax of (R)-etoxazole was almost 5-fold of (S) etoxazole in liver microsomes of rat in vitro. However, the Vmax of (S)-etoxazole was almost 2-fold of (R)-etoxazole in liver microsomes of human in vitro. The CLint of etoxazole was also shown the enantioselectivity on the contrary in liver microsomes of rat and human. These results indicated that the metabolism of two etoxazole enantiomers was selective in liver microsomes of rat and human in vitro, and enantioselectivity in the two kinds of liver microsomes was in the difference in degradation performance. The reason might be related to the composition and content involved in the enzyme system. PMID- 27479247 TI - Glucagon-like Peptide 1 Drugs as Second-line Therapy for Type 2 Diabetes. PMID- 27479249 TI - BASCULE syndrome, orthostatic cyanosis and postural orthostatic tachycardia syndrome: time for decanting old wine? PMID- 27479248 TI - Vulnerabilities in Older Patients when Cancer Treatment is Initiated: Does a Cognitive Impairment Impact the Two-Year Survival? AB - INTRODUCTION: Dementia is a known predictor of shorter survival times in older cancer patients. However, no empirical evidence is available to determine how much a cognitive impairment shortens survival in older patients when cancer treatment is initiated. PURPOSE: To longitudinally investigate how much a cognitive impairment detected at the initiation of cancer treatment influences survival of older patients during a two-year follow-up duration and to compare the predictive value of a cognitive impairment on patients survival with the predictive value of other vulnerabilities associated with older age. METHODS: Three hundred and fifty-seven consecutive patients (>=65 years old) admitted for breast, prostate, or colorectal cancer surgeries were prospectively recruited. A cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA<26). Socio-demographic, disease-related, and geriatric vulnerabilities were assessed using validated tools. Univariate and subsequent multivariate Cox proportional hazards models stratified for diagnosis (breast/prostate cancer versus colorectal cancer) and disease status (metastatic versus non-metastatic) were used. RESULTS: A cognitive impairment was detected in 46% (n = 163) of patients. Survival was significantly influenced by a cognitive impairment (HR = 6.13; 95% confidence interval [CI] = 2.07-18.09; p = 0.001), a loss in instrumental autonomy (IADL <=7) (HR = 3.06; 95% CI = 1.31-7.11; p = 0.009) and fatigue (Mob-T<5) (HR = 5.98; 95% CI = 2.47-14.44; p <0.001). CONCLUSIONS: During the two years following cancer treatment initiation, older patients with a cognitive impairment were up to six times more likely to die than patients without. Older patients should be screened for cognitive impairments at cancer treatment initiation to enable interventions to reduce morbidity and mortality. Further studies should address processes underlying the relationship between cognitive impairments and an increased risk of dying in older cancer patients. PMID- 27479251 TI - [Not Available]. PMID- 27479250 TI - Genetic Diversity and Association Characters of Bacteria Isolated from Arbuscular Mycorrhizal Fungal Spore Walls. AB - Association between arbuscular mycorrhizal fungi (AMF) and bacteria has long been studied. However, the factors influencing their association in the natural environment is still unknown. This study aimed to isolate bacteria associated with spore walls of AMF and identify their potential characters for association. Spores collected from coastal reclamation land were differentiated based on their morphology and identified by 18S rDNA sequencing as Funneliformis caledonium, Racocetra alborosea and Funneliformis mosseae. Bacteria associated with AMF spore walls were isolated after treating them with disinfection solution at different time intervals. After 0, 10 and 20 min of spore disinfection, 86, 24 and 10 spore associated bacteria (SAB) were isolated, respectively. BOX-PCR fingerprinting analysis showed that diverse bacterial communities were associated to AMF spores. Bacteria belonging to the same genera could associate with different AMF spores. Gram positive bacteria were more closely associated with AMF spores. Isolated SAB were characterized and tested for spore association characters such as chitinase, protease, cellulase enzymes and exopolysaccharide production (EPS). Among the 120 SAB, 113 SAB were able to show one or more characters for association and seven SAB did not show any association characters. The 16S rDNA sequence of SAB revealed that bacteria belonging to the phyla Firmicutes, Proteobacteria, Actinobacteria and Bactereiodes were associated with AMF spore walls. PMID- 27479252 TI - [Not Available]. PMID- 27479253 TI - [Not Available]. PMID- 27479254 TI - [Not Available]. PMID- 27479256 TI - [Not Available]. PMID- 27479255 TI - [Not Available]. PMID- 27479257 TI - [Not Available]. PMID- 27479258 TI - [Cardiac evaluation before non-cardiac surgery]. AB - Before non-cardiac surgery, evaluation of cardiac function is no frequent part of surgical treatment. European societies of anesthesiology and cardiology published consensus-guidelines in 2014 to present a reasonable approach for preoperative evaluation. This paper intends to differentiate the composite of perioperative risk and to display the guidelines methodical approach to handle it. Features to identify patients at risk from an ageing population with comorbidities, are the classification of surgical risk, functional capacity and risk indices. Application of diagnostic means, should be used adjusted to this risk estimation. Cardiac biomarkers are useful to discover risk of complications or mortality, that cannot be assessed by clinical signs. After preoperative optimization and perioperative cardiac protection, the observation of the postoperative period remains, to prohibit complications or even death. In consideration of limited resources of intensive care department, postoperative ward rounds beyond intensive care units are considered to be an appropriate instrument to avoid or recognize complications early to reduce postoperative mortality. PMID- 27479259 TI - [Emergence delirium in children - prophylaxis and treatment]. AB - Emergence Delirium in children after general anesthesia is a common and self limitating event. Although it might be seen as being harmless it can cause other serious complications and might leave both parents and other caregivers with a negative impression behind. Although the cause may still not be clear, potential predictors can be named: preschool age, the use of fast acting volatile anesthestics, higher preoperative anxiety levels and postoperative pain.A child focused approach to reduce preoperative anxiety focusing on distraction methods rather than pharmacological sedation may be the key as well as sufficient postoperative pain control and the use of total intravenous anesthesia. Parenteal presence during induction of anaesthesia (PPIA) may be beneficial to reduce preoperative anxiety levels, but has failed to prove a better outcome regarding ED.The use of age adopted scores/scales to diagnose ED and Pain are mandatory.In the case of an ED event it is most important to protect the child from self injury and the loss of the iv-line. Postoperative pian needs to be ruled out before treating ED. Most cases can be treated by interrupting the situation and putting the child "back to sleep". Short acting drugs as Propofol have been used successfully due to its pharmacodynamics and short acting profile. Alternatively alpha-agonists or ketamin may be preferred by other authors. If potential predictors and a positive history are present, prophylactic treatment should be considered. A TIVA or the use of alpha-2-agonists have proven to be successful in reducing the risk of an ED. Midazolam may reduce preoperative anxiety but not the incidence of ED and should therefore be used carefully and is not a good choice in PACU for the treatment of ED.Parents who witnessed ED in their children should be guided and followed up. Explaining this phenomenon to parents beforehand should be part of the pre anaesthesia clinic talk and written consent.Standard protocols should be in place for treatment in the postoperative period. PMID- 27479260 TI - [Anesthesia and Multiple Sclerosis: What needs to be considered?]. AB - Patients with rare neurological diseases are always a challenge in routine clinical activity. In particular, anesthetic interventions can be fraught with many problems. This article deals with the current state of knowledge on multiple sclerosis in anesthesia. Here, the authors refer to the safe preparation for and implementation of various forms of anesthesia as well as the prevention and if necessary, treatment of possible complications. PMID- 27479261 TI - [Case Report - Bilateral humeral intraosseous access for CPR in a 3-years-old child]. AB - On-scene invasive emergency procedures, such as intraosseous puncture, are often unavoidable, when indicated, and present a challenge for the emergency physician. Personal, temporal or local conditions are often unsuitable. Even with regular intervention by the emergency medical service, "last resort" measures occur very infrequently, particularly in pediatric emergencies. For the first time, this case report presents the use of intraosseous access at the humeral head with children, with reference to indication, implementation, problems and risks. PMID- 27479262 TI - [Not Available]. PMID- 27479263 TI - [Not Available]. PMID- 27479264 TI - [Graduate Medical Education - Structured, competency based training in Anesthesiology]. AB - The "Joint Commission of BDA and DGAI for Graduate Medical Education and Further Education" presents a concept for postgraduate training in anesthesiology. Aiming at a different and demanding generation of young physicians it proposes a new approach to an attractive training in anesthesiology e. g. by simulation as one key concept. It is also intended to meet the guidelines of the German Medical Association of competency based rather than time based or procedure based graduate medical education. A clear structure and the competency based approach shall facilitate a process of professional teaching. The article describes the new concept of graduate medical education by the German Medical Association and the respective aims and objectives of the Scientific Medical Societies in Germany. An existing implementation in a hospital is given as an example of feasibility. PMID- 27479265 TI - [Research activities and Graduate Medical Education in Germany]. AB - Time spent for research activities can count as time spent in GMA (graduate medical education) as long as requirements according to EU directive 2005/36 concerning minimum time in GMA are fulfilled and the necessary knowledge, experience and competencies have been acquired. First results from a project in Westfalia-Lippe are positive. PMID- 27479266 TI - [Are subspecialties and fellowship programs in German Anesthesia required?]. AB - Rapid progress in medical science and technique offer new complex individual treatment modalities. Distinct profile qualifications like echocardiography, electroencephalography are required for anesthesia in high risk populations (cardiovascular, pediatric and neuro surgical patients) to guarantee best patient care and outcome. Accredited subspecialties and distinct fellowship programs are required to improve medical education, training and research. PMID- 27479267 TI - [Graduate Medical Education in intensive care medicine - How can the European concept be integrated in Germany?]. AB - Within the European Union, medical disciplines also have been organized. At the European level, the Union Europeenne des Medecins Specialistes (UEMS) currently represents the interests of 42 medical disciplines and offers support to doctors to work in any European country. For this purpose, guidelines were adopted already in 2005, which, among others, regulate automatic recognition of professional qualifications. This does not apply to intensive care medicine, since in most European countri in the guidelines as a "special competence". For this purpose, a multidisciplinary joint committee of the UEMS formulated the so called "European Training Requirements" (ETR), the aim of which was to raise the professional skills of European doctors working in the field of intensive care to a uniformly high level. The ETR are currently in the process of being voted upon. As things stand, additional training in intensive care medicine in Germany as currently practised would meet the conditions and requirements of the ETR. PMID- 27479268 TI - [Not Available]. PMID- 27479269 TI - [Not Available]. PMID- 27479270 TI - Introduction: Reproductive immunology: checkered past and bright future. AB - The immune system plays a critical role in pregnancy establishment and maintenance, but application of immunological principles to the treatment of infertility and pregnancy loss has had a checkered past. Improving knowledge in this area holds great promise for improving the treatment of subfertile patients. PMID- 27479271 TI - Sense-making under ignorance. AB - Much of cognition allows us to make sense of things by explaining observable evidence in terms of unobservable explanations, such as category memberships and hidden causes. Yet we must often make such explanatory inferences with incomplete evidence, where we are ignorant about some relevant facts or diagnostic features. In seven experiments, we studied how people make explanatory inferences under these uncertain conditions, testing the possibility that people attempt to infer the presence or absence of diagnostic evidence on the basis of other cues such as evidence base rates (even when these cues are normatively irrelevant) and then proceed to make explanatory inferences on the basis of the inferred evidence. Participants followed this strategy in both diagnostic causal reasoning (Experiments 1-4, 7) and in categorization (Experiments 5-6), leading to illusory inferences. Two processing predictions of this account were also confirmed, concerning participants' evidence-seeking behavior (Experiment 4) and their beliefs about the likely presence or absence of the evidence (Experiment 5). These findings reveal deep commonalities between superficially distinct forms of diagnostic reasoning-causal reasoning and classification-and point toward common inferential machinery across explanatory tasks. PMID- 27479272 TI - Bioidentical hormones for women with vasomotor symptoms. AB - BACKGROUND: Various hormone therapies (HT) are available to treat menopausal vasomotor symptoms. Bioidentical hormones are chemically identical to those produced by the human body, and several types are well-tested and available on prescription. Many women have opted for bioidentical hormone therapy (BHT) on the assumption that it is safer than other forms of HT. We evaluated the evidence. OBJECTIVES: To determine the effectiveness and safety of bioidentical hormones compared to placebo or non-bioidentical hormones for the relief of vasomotor symptoms. SEARCH METHODS: In July 2015 we searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS), registers of ongoing trials and the reference lists of articles retrieved. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing bioidentical hormone therapy (BHT) versus placebo or non-bioidentical hormones. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. Our primary outcome was vasomotor symptoms (hot flushes and night sweats). We evaluated the overall quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation criteria (GRADE). MAIN RESULTS: We included 23 RCTs (5779 participants). Most studies (20/23) included only women with moderate to severe hot flushes. All studies compared unopposed 17 beta-estradiol (beta-estradiol) versus placebo or conjugated equine estrogens (CEE). None of the studies reported night sweats as a separate outcome. BHT patch versus placebo Frequency of hot flushesFour RCTs reported data suitable for analysis. There were fewer hot flushes in the BHT group, with a moderate to large effect size (SMD -0.68, 95% CI -0.83 to -0.53, four RCTs, 793 women, I(2) = 67%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. Seven RCTs reported data unsuitable for analysis; all reported a benefit in the intervention group. Symptom intensityTwo RCTs reported analysable data. Measured on a 0-100 visual analogue scale (VAS), hot flush intensity was lower in the BHT group (MD 19.94 points, 95% CI -24.86 to -15.02, two RCTs, 393 women, I(2) = 54%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. Adverse effectsAdverse events (such as headache, vaginal bleeding, breast tenderness and skin reactions) were more common in the intervention group (odds ratio (OR) 2.14, 95% CI 1.29 to 3.54, 9 RCTs, 1822 women, I(2) = 73%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. In one study, five women in the intervention group developed endometrial hyperplasia. BHT gel versus placebo Hot flush frequencyThree RCTs reported this outcome, but the data were unsuitable for analysis. All reported a benefit in the BHT group. Adverse effectsAdverse events were more common in the BHT group (OR 1.41, 95% CI 1.09 to 1.83, 3 RCTs, 1086 women, I(2) = 0%, moderate quality evidence). Oral BHT versus placebo Hot flush frequencyTwo studies reported analysable data. There were fewer hot flushes in the BHT group, with a moderate to large effect size (SMD -0.80, 95% CI -1.03 to -0.57, two RCTs, 356 women, I(2) = 14%, low quality evidence). Adverse effectsThere was no evidence of a difference between the groups (OR 1.28, 95% CI 0.84 to 1.96, 3 RCTs, 433 women, I(2) = 0%, low quality evidence). Topical BHT emulsion versus placebo Hot flush frequencyOne study with data unsuitable for analysis reported a benefit in the intervention group. Adverse effectsThere was no evidence of a difference between the groups (OR 1.46, 95% CI 0.80 to 2.66, one RCT, 200 women, low quality evidence). Intranasal BHT versus placebo Hot flush frequencyOnly one study reported analysable data. There were fewer hot flushes per day in the BHT group (MD -3.04 95% CI -4.05 to -2.03, one study, 458 women, moderate quality evidence) Adverse effectsAdverse events (such as headache, breast tenderness, arthralgia and nausea) were more common in the intervention group (OR 1.96, 95% CI 1.26 to 3.03, one RCT, 458 women, moderate quality evidence). Subgroup analysesSubgroup analyses by dose of BHT suggested that higher doses of BHT may be associated with more effectiveness but also higher risk of adverse effects. BHT patch versus 0.625 mg CEETwo RCTs reported this comparison, but the data were unsuitable for analysis. Hot flush frequencyBoth RCTs reported no evidence of a difference between the groups. Adverse effectsFindings were inconsistent. In one comparison (0.1 mg BHT versus CEE), breast pain and vaginal bleeding were more frequent in the BHT group. Oral BHT versus 0.625 mg CEE Hot flush frequencyOne study with data unsuitable for analysis reported no evidence of a difference between the groups. Adverse effectsThere was no evidence of a difference between the groups (OR 1.20, 95% CI 0.50 to 2.87, one RCT, 103 women, very low quality evidence). AUTHORS' CONCLUSIONS: There was low to moderate quality evidence that BHT in various forms and doses is more effective than placebo for treating moderate to severe menopausal hot flushes. There was low to moderate quality evidence of higher rates of adverse effects such as headache, vaginal bleeding, breast tenderness and skin reactions in the BHT group. There was some evidence to suggest that higher doses of BHT are associated with greater effectiveness but also with higher risk of adverse effects. Although all the included studies used unopposed estrogen, it is recommended best practice to use progestogen therapy in women with a uterus taking estrogen in order to avoid endometrial hyperplasia, regardless of the source of the estrogen. No data are yet available about the safety of BHT with regard to long-term outcomes such as heart attack, stroke and breast cancer.There was no good evidence of a difference in effectiveness between BHT and CEE, and findings with regard to adverse effects were inconsistent. The quality of the evidence was too low to reach any firm conclusions.The main limitations in the quality of the evidence were study risk of bias (mainly due to poor reporting of methods), imprecision and lack of data suitable for analysis. PMID- 27479273 TI - Layer-by-Layer Assembled Architecture of Polyelectrolyte Multilayers and Graphene Sheets on Hollow Carbon Spheres/Sulfur Composite for High-Performance Lithium Sulfur Batteries. AB - In the present work, polyelectrolyte multilayers (PEMs) and graphene sheets are applied to sequentially coat on the surface of hollow carbon spheres/sulfur composite by a flexible layer-by-layer (LBL) self-assembly strategy. Owing to the strong electrostatic interactions between the opposite charged materials, the coating agents are very stable and the coating procedure is highly efficient. The LBL film shows prominent impact on the stability of the cathode by acting as not only a basic physical barrier, and more importantly, an ion-permselective film to block the polysulfides anions by Coulombic repulsion. Furthermore, the graphene sheets can help to stabilize the polyelectrolytes film and greatly reduce the inner resistance of the electrode by changing the transport of the electrons from a "point-to-point" mode to a more effective "plane-to-point'' mode. On the basis of the synergistic effect of the PEMs and graphene sheets, the fabricated composite electrode exhibits very stable cycling stability for over 200 cycles at 1 A g(-1), along with a high average Coulombic efficiency of 99%. With the advantages of rapid and controllable fabrication of the LBL coating film, the multifunctional architecture developed in this study should inspire the design of other lithium-sulfur cathodes with unique physical and chemical properties. PMID- 27479274 TI - Bottom-up Construction of a Primordial Carboxysome Mimic. AB - We have constructed a synthetic mimic of the carboxysome, a cyanobacterial carbon fixing organelle. Using an electrostatic tagging system, we coencapsulated the two key carboxysomal enzymes, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and carbonic anhydrase (CA), in an engineered protein cage based on lumazine synthase. A statistically significant kinetic effect of coencapsulated CA on RuBisCO activity was not observed under ambient or oxygen saturated conditions, suggesting that enzyme proximity alone may not be the key determinant in carboxysome function. The capsid shell protected the enzyme from proteolytic damage, a factor that could have provided early cyanobacteria with an evolutionary benefit. Our strategy to coencapsulate different proteins can easily be extended to other sequentially acting enzymes and lays down principles for developing artificial organelles to control biosynthetic pathways in vivo. PMID- 27479276 TI - In This Issue * August 15, 2016. PMID- 27479275 TI - Atomic resolution of nitrogen-doped graphene on Cu foils. AB - Atomic-level substitutional doping can significantly tune the electronic properties of graphene. Using low-temperature scanning tunneling microscopy and spectroscopy, the atomic-scale crystalline structure of graphene grown on polycrystalline Cu, the distribution of nitrogen dopants and their effect on the electronic properties of graphene were investigated. Both the graphene sheet growth and nitrogen doping were performed using microwave plasma-enhanced chemical vapor deposition. The results indicated that the nitrogen dopants preferentially sit at the grain boundaries of the graphene sheets and confirmed that plasma treatment is a potential method to incorporate foreign atoms into the graphene lattice to tailor the graphene's electronic properties. PMID- 27479277 TI - Veterinarians and physicians on wellness: change can start with one person. PMID- 27479279 TI - Letters to the Editor. PMID- 27479280 TI - What Is Your Diagnosis? PMID- 27479281 TI - Pathology in Practice. PMID- 27479282 TI - Pathology in Practice. PMID- 27479283 TI - Comparison of owner satisfaction between stifle joint orthoses and tibial plateau leveling osteotomy for the management of cranial cruciate ligament disease in dogs. AB - OBJECTIVE To compare owner satisfaction between custom-made stifle joint orthoses and tibial plateau leveling osteotomy (TPLO) for the management of medium- and large-breed dogs with cranial cruciate ligament disease (CCLD). DESIGN Owner survey. SAMPLE 819 and 203 owners of dogs with CCLD that were managed with a custom-made stifle joint orthosis or TPLO, respectively. PROCEDURES Client databases of an orthosis provider and veterinary teaching hospital were reviewed to identify potential survey respondents. An online survey was developed to evaluate owner-reported outcomes, complications, and satisfaction associated with the nonsurgical (orthosis group) and surgical (TPLO group) interventions. Survey responses were compared between groups. RESULTS The response rate was 25% (203/819) and 37% (76/203) for the orthosis and TPLO groups, respectively. The proportion of owners who reported that their dogs had mild or no lameness and rated the intervention as excellent, very good, or good was significantly greater for the TPLO group than for the orthosis group. However, >= 85% of respondents in both groups reported that they would choose the selected treatment again. Of 151 respondents from the orthosis group, 70 (46%) reported skin lesions associated with the device, 16 (11%) reported that the dog subsequently underwent surgery, and 10 (7%) reported that the dog never tolerated the device. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated high owner satisfaction rates for both interventions. Owners considering nonsurgical management with an orthosis should be advised about potential complications such as persistent lameness, skin lesions, patient intolerance of the device, and the need for subsequent surgery. PMID- 27479284 TI - Variable-number tandem-repeat analysis of leptospiral DNA isolated from canine urine samples molecularly confirmed to contain pathogenic leptospires. AB - OBJECTIVE To use variable-number tandem-repeat (VNTR) analysis to determine the infecting serovar and strain for leptospiral DNA isolated from canine urine samples confirmed through PCR testing to contain pathogenic leptospires and to evaluate the sensitivity and specificity of microscopic agglutination testing (MAT) for identifying the infecting serogroup. DESIGN Diagnostic survey and test evaluation. SAMPLE Leptospiral DNA isolated from urine samples from 98 dogs confirmed through PCR testing to have pathogenic leptospires in their urine. PROCEDURES VNTR analysis of DNA isolates was performed to identify the infecting leptospiral serovar and strain by use of primer pairs for the loci 4, 7, 10, and Lb5. Eighteen pathogenic and 2 saprophytic leptospiral serovars were used as reference strains for VNTR analysis. Results of MAT were compared with those of the PCR assay and VNTR analysis to determine the sensitivity and specificity of MAT for diagnosing leptospirosis and identifying the infecting serovar at various reciprocal titers. RESULTS VNTR analysis identified Leptospira kirschneri serovar Grippotyphosa strain DF as the most common infecting serovar in dogs (78/98 [80%]). Thirteen unique VNTR patterns could not be identified by comparison with the Leptospira reference strains used. The MAT had a maximum sensitivity of 41% and a specificity of 100% for identifying Grippotyphosa as the infecting serogroup. CONCLUSIONS AND CLINICAL RELEVANCE Findings confirmed the importance of Leptospira serovar Grippotyphosa among dogs in the United States. Serologic testing had poor sensitivity for identifying the infecting serogroup, and conclusions about emerging serogroups should be cautiously interpreted when serologic data are reported. PMID- 27479285 TI - Use of a Boari flap and renal descensus as treatment for proximal ureteral rupture in a cat. AB - CASE DESCRIPTION A 6-year-old neutered male domestic shorthair cat was evaluated because of signs of abdominal pain and anuria of 12 hours' duration after vehicular trauma. CLINICAL FINDINGS Lethargy, mydriasis, bradycardia, abdominal distension, and signs of pain on abdominal palpation were observed. Abdominal ultrasonography revealed moderate urinary bladder distension without evidence of free abdominal fluid; hematologic evaluation revealed leukocytosis with high BUN and serum creatinine concentrations. TREATMENT AND OUTCOME The patient was hospitalized, medical stabilization was attempted, and an indwelling urinary catheter was placed. Urinary output was < 1 mL/kg/h (< 0.45 mL/lb/h), and signs of abdominal pain persisted despite treatment. The next day, ultrasonographic examination revealed fluid in the retroperitoneal space, and ureteral rupture was suspected. Exploratory laparotomy confirmed retroperitoneal fluid accumulation; a large hematoma surrounded the right kidney and perirenal structures. An abdominal drain was placed to aid patient stabilization. Three days later, IV pyelography revealed rupture of the proximal part of the right ureter. Ureteroneocystostomy was performed with elongated cystoplasty through a Boari flap and caudal transposition of the right kidney (renal descensus). On follow-up examination 18 months after treatment, the cat was free of clinical signs, and results of ultrasonography, CBC, and serum biochemical analysis were unremarkable. CLINICAL RELEVANCE Results suggested that a Boari flap procedure with renal descensus could be a feasible alternative in the management of proximal ureteral rupture in cats, but research is needed in this area. PMID- 27479286 TI - Duration of serum antibody response to rabies vaccination in horses. AB - OBJECTIVE To investigate the impact of age and inferred prior vaccination history on the persistence of vaccine-induced antibody against rabies in horses. DESIGN Serologic response evaluation. ANIMALS 48 horses with an undocumented vaccination history. PROCEDURES Horses were vaccinated against rabies once. Blood samples were collected prior to vaccination, 3 to 7 weeks after vaccination, and at 6 month intervals for 2 to 3 years. Serum rabies virus-neutralizing antibody (RVNA) values were measured. An RVNA value of >= 0.5 U/mL was used to define a predicted protective immune response on the basis of World Health Organization recommendations for humans. Values were compared between horses < 20 and >= 20 years of age and between horses inferred to have been previously vaccinated and those inferred to be immunologically naive. RESULTS A protective RVNA value (>= 0.5 U/mL) was maintained for 2 to 3 years in horses inferred to have been previously vaccinated on the basis of prevaccination RVNA values. No significant difference was evident in response to rabies vaccination or duration of protective RVNA values between horses < 20 and >= 20 years of age. Seven horses were poor responders to vaccination. Significant differences were identified between horses inferred to have been previously vaccinated and horses inferred to be naive prior to the study. CONCLUSIONS AND CLINICAL RELEVANCE A rabies vaccination interval > 1 year may be appropriate for previously vaccinated horses but not for horses vaccinated only once. Additional research is required to confirm this finding and characterize the optimal primary dose series for rabies vaccination. PMID- 27479287 TI - Outcomes assessment of on-site communication skills education in a companion animal practice. AB - OBJECTIVE To evaluate veterinarian-client communication and veterinarian and client satisfaction with veterinary visits before and after veterinarians underwent a 6-month communication skills training program in a practice setting. DESIGN Case-based pretest-posttest intervention study. SAMPLE 1 purposely selected companion-animal practice. PROCEDURES The practice team (3 veterinarians, 5 veterinary technicians, 1 receptionist, and 1 office manager) participated in a 6-month educational program (intervention) that included interactive communication modules, individual coaching, and a communication laboratory. For each of the veterinarians, 6 appointments were video recorded and 30 additional clients completed a visit satisfaction survey both before and after the intervention. The Roter interaction analysis system was used to analyze the video-recorded appointments. RESULTS After the intervention, appointments were 5.4 minutes longer and veterinarians asked 60% fewer closed-ended lifestyle social questions, provided 1.4 times as much biomedically related client education, and used 1.5 and 1.25 times as much facilitative and emotional rapport communication, respectively, compared with before the intervention. Clients provided veterinarians with 1.3 times as much biomedically related information and engaged in twice as much social conversation. After the intervention, veterinarians perceived their clients as complaining less and being more personable and trusting, and clients felt more involved in the appointment and reported that the veterinarian expressed greater interest in their opinion. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the intervention resulted in veterinarians who spent more time educating and building rapport with their clients and facilitating client input in an unhurried environment, which enhanced overall veterinarian visit satisfaction and various aspects of client visit satisfaction. PMID- 27479288 TI - Neural plasticity following lesions of the primate occipital lobe: The marmoset as an animal model for studies of blindsight. AB - For nearly a century it has been observed that some residual visually guided behavior can persist after damage to the primary visual cortex (V1) in primates. The age at which damage to V1 occurs leads to different outcomes, with V1 lesions in infancy allowing better preservation of visual faculties in comparison with those incurred in adulthood. While adult V1 lesions may still allow retention of some limited visual abilities, these are subconscious-a characteristic that has led to this form of residual vision being referred to as blindsight. The neural basis of blindsight has been of great interest to the neuroscience community, with particular focus on understanding the contributions of the different subcortical pathways and cortical areas that may underlie this phenomenon. More recently, research has started to address which forms of neural plasticity occur following V1 lesions at different ages, including work using marmoset monkeys. The relatively rapid postnatal development of this species, allied to the lissencephalic brains and well-characterized visual cortex provide significant technical advantages, which allow controlled experiments exploring visual function in the absence of V1. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 314-327, 2017. PMID- 27479289 TI - Two Magnetic Switching Complexes Based on the Fe(II) Ion. AB - Two neutral mononuclear iron(II) complexes with different spin-crossover (SCO) properties, Fe(L1)2(SCN)2 (1) and Fe(L2)2(SCN)2 (2) (L1 = 2-(thiophen-3-yl)-1H imidazo[4,5-f][1,10]phenanthroline and L2 = 2-(thiophen-2-yl)-1H-imidazo[4,5 f][1,10]phenanthroline), were solvothermally synthesized. With the different substituted position in 1,10-phenanthroline derivatives, 1 exhibits gradual SCO around room temperature with T1/2 = 280 K, while 2 displays abrupt SCO with 10 K hysteresis at T1/2? = 210 K and T1/2? = 220 K. PMID- 27479290 TI - Dyadic associations between psychological distress and sleep disturbance among Chinese patients with cancer and their spouses. AB - BACKGROUND: Patients with cancer and their spouses usually both suffer, but the dyadic effects have not been thoroughly investigated. This study examined the dyadic effects of psychological distress on sleep disturbance in Chinese couples affected by cancer. METHODS: Patients with cancer and their spouses (N = 135) participated in this study. The Hospital Anxiety and Depression Scale and Pittsburgh Sleep Quality Index were used to measure anxiety, depression, and sleep disturbance. RESULTS: There were significant patient-spouse associations on anxiety (r = 0.48, P < .01), depression (r = 0.55, P < .01), and sleep disturbance (r = 0.30, P < .01). Analyses using the actor-partner interdependence model showed that anxiety had significant actor effects, rather than partner effects, on sleep disturbance in both patients and their spouses, but depression had both actor and partner effects. In addition to providing evidence for the concordance in distress and sleep disturbance in patients with cancer and their spouses, the findings indicate a mutual influence of depression on sleep disturbance among the couples. CONCLUSIONS: Clinicians and health care providers are suggested to integrate depression management as a component of sleep therapies and involve both patients and their spouses in treatment programs. PMID- 27479291 TI - [Not Available]. AB - This new paper on chemical risk from anaesthetic agents in operating theatres is the natural progression of that published in this journal in supplement 1-2013, as it constitutes a development and complement of the previous work and an applicative confirmation from the highest organ of administrative justice, the Consiglio di Stato, regarding, in particular, the obligation of adopting the technically most advanced "measures" to eliminate or, at least, minimise risk in the use of new generation and the most commonly-used anaesthetic agents (sevoflurane and desflurane). Therefore, in this paper, the authors commence by referring to the starting point, consisting in the conclusions of the previous study, which highlighted the extraordinary convergence of technical and scientific, legislative and case law data on the same result, constituted by the possibility, and consequent obligation, of implementing, also in operating theatres, the greatest technologically possible safety, starting with the choice of the most suitable equipment, methods and quality systems for avoiding the diffusion, dispersion and /or leakage of volatile hazardous agents that may contribute - together with those chemical reactions that are foreseeable and avoidable, given the characteristics of the materials, substances and relative "packaging" - to workplace pollution, which can, in any case, reach levels that are hazardous due to the concentration of anaesthetic gases. Subsequently, once the "scientific" fruit of the previous contributions has been discussed, the authors evaluate the impact of the result already achieved in practice with concrete cases and the judgement expressed with a series of judgements issued in rapid succession by the Consiglio di Stato, showing the application, not merely of the legislative "data" but also of the references and citations that these "data" contain regarding the "knowledge acquired regarding the relationship with technical progress". Lastly, the Authors provide, as a further, definitive conclusion, the singular unit of the guidelines provided by case law, the result of a univocal and continuous multitude of judgements issued at the highest degree of administrative justice, albeit for very diverse situations and circumstances, which provide, therefore, a direction and an operative guide for which they are called on to adopt roles and responsibilities for the choices of "products", "systems" and "methods" destined to affect - for the use of anaesthetic agents - the health and safety of healthcare staff and of patients themselves. PMID- 27479292 TI - [Not Available]. AB - Protecting healthcare staff against the risk of infection caused by injuries when using sharp or pointed instruments has been placed - as a special, common and difficult type of "biological risk" - at the centre of attention in the investigations, studies and research conducted by various countries and subjects that have led to a convergence between the results able to influence European and supranational legislation. This convergence of results is headed towards the recognition of the great potential of the role of technology and, more specifically, of the "protection devices" of paramount and essential importance, as "technical measures", over the other, nevertheless important "organisational" and "personal" measures. The national and international results of the studies and research, as well as their corresponding conclusions, deserve special space in this journal, given the supranational legislative recognition they received in Directive 2010/32/EU. Indeed, this latter Directive, set forth and classified, with a system of absolutely mandatory regulations, the "Framework agreement" concluded between the organisations that are most representative of the hospital and healthcare sector for the "prevention of cut and prick injuries". On the basis of the "European Union" treaty, Directive 2010/32/EU must be assimilated in the legal system of all the member States of this "Union" with appropriately sanctioned legal provisions in the event of breach by "employers" and/or "directors". In this sense, with Legislative Decree no. 19 of 2014, Italy introduced a dedicated "criminal offence of danger" for the breach of "prevention" regulations intended to prevent the specific "biological risk" in question, regulations that have been incorporated into Legislative Decree 81/08 - "The Occupational Safety and Health Consolidation Act" with a special "Section" (X bis) dedicated exclusively to them. PMID- 27479293 TI - Characterization of soluble microbial products (SMPs) in a membrane bioreactor (MBR) treating synthetic wastewater containing pharmaceutical compounds. AB - This study investigated the behaviour and characteristics of soluble microbial products (SMP) in two anoxic-aerobic membrane bioreactors (MBRs): MBRcontrol and MBRpharma, for treating municipal wastewater. Both protein and polysaccharides measured exhibited higher concentrations in the MBRpharma than the MBRcontrol. Molecular weight (MW) distribution analysis revealed that the presence of pharmaceuticals enhanced the accumulation of SMPs with macro- (13,091 kDa and 1587 kDa) and intermediate-MW (189 kDa) compounds in the anoxic MBRpharma, while a substantial decrease was observed in both MBR effluents. Excitation emission matrix (EEM) fluorescence contours indicated that the exposure to pharmaceuticals seemed to stimulate the production of aromatic proteins containing tyrosine (10.1 32.6%) and tryptophan (14.7-43.1%), compared to MBRcontrol (9.9-29.1% for tyrosine; 11.8-42.5% for tryptophan). Gas chromatography-mass spectrometry (GC MS) analysis revealed aromatics, long-chain alkanes and esters were the predominant SMPs in the MBRs. More peaks were present in the aerobic MBRpharma (196) than anoxic MBRpharma (133). The SMPs identified exhibited both biodegradability and recalcitrance in the MBR treatment processes. Only 8 compounds in the MBRpharma were the same as in the MBRcontrol. Alkanes were the most dominant SMPs (51%) in the MBRcontrol, while aromatics were dominant (40%) in the MBRpharma. A significant decrease in aromatics (from 16 to 7) in the MBRpharma permeate was observed, compared to the aerobic MBRpharma. Approximately 21% of compounds in the aerobic MBRcontrol were rejected by membrane filtration, while this increased to 28% in the MBRpharma. PMID- 27479294 TI - Shielding membrane surface carboxyl groups by covalent-binding graphene oxide to improve anti-fouling property and the simultaneous promotion of flux. AB - Graphene oxide (GO) is an excellent material for membrane surface modification. However, little is known about how and to what extent surface functional groups change after GO modification influence membrane anti-fouling properties. Carboxyl is an inherent functional group on polyamide or other similar membranes. Multivalent cations in wastewater secondary effluent can bridge with carboxyls on membrane surfaces and organic foulants, resulting in serious membrane fouling. In this study, carboxyls of a polydopamine (pDA)/1,3,5-benzenetricarbonyl trichloride (TMC) active layer are shielded by covalently-bound GO. The process is mediated by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC)/N hydroxysuccinimide (NHS). For GO containing low quantities of carboxyls, X-ray photoelectron spectroscopy (XPS) and zeta potential analyzer test results reveal that the carboxyl density decreased by 52.3% compare to the pDA/TMC membrane after GO modification. Fouling experiments shows that the flux only slightly declines in the GO functionalized membrane (19.0%), compared with the pDA/TMC membrane (36.0%) after fouling. In addition, during GO modification process the pDA/TMC active layer also become harder and thinner with the aid of EDC/NHS. So the pure water permeability increases from 56.3 +/- 18.2 to 103.7 +/- 12.0 LMH/MPa. Our results provide new insights for membrane modification work in water treatment and other related fields. PMID- 27479295 TI - Comparative evaluation of iodoacids removal by UV/persulfate and UV/H2O2 processes. AB - To develop a cost-effective method for post-formation mitigation of iodinated disinfection by-products, degradation of iodoacids by UV, UV/PS (persulfate), and UV/H2O2 was extensively investigated in this study. UV direct photolysis of 4 iodoacids followed first-order kinetics with rate constants in the range of 2.43 * 10(-4)-3.02 * 10(-3) cm(2) kJ(-1). The derived quantum yields (F254) of the 4 iodoacids range from 0.13 to 0.34, respectively. A quantitative structure activity relationship (QSAR) model was subsequently established and applied to predict the direct photolysis rates of 6 other structurally similar iodoacids whose standards are commercially unavailable. At a UV dose of 140 mJ cm(-2) which is typically applied for disinfection of drinking water, the removal percentages of 4 iodoacids were only between 3.35% and 34.7%. Thus, ICH2CO2H (IAA), the most photo-recalcitrant species, was selected as the target compound for removal in the UV/PS and UV/H2O2 processes. The IAA degradation rates decreased with increasing pH from 3 to 11 in both processes. Humic acid (HA) and HCO3(-) had inhibitory effects on IAA degradation in both processes. Cl(-) adversely affected the IAA degradation in the UV/PS process but had no effect in the UV/H2O2 process. Generally, in the deionized (DI) water, surface water, treated drinking water, and secondary effluent, UV/PS process is more effective than UV/H2O2 process for IAA removal, based on the same molar ratio of oxidant: IAA. SO4(-) generated in the UV/PS process yields a greater mineralization of IAA than HO in the UV/H2O2 process. IO3(-) was the predominant end-product in the UV/PS process, while I(-) was the major end-product in the UV/H2O2 process. The respective contributions of UV, HO, and SO4(-) for IAA removal in the UV/PS process were 7.8%, 14.7%, and 77.5%, respectively, at a specific condition (1.5 MUM IAA, 60 MUM oxidant, and pH 7). Compared to UV/H2O2 process, UV/PS was also observed as more cost-effective process based on the electrical energy per order (EE/O) and chemical cost. PMID- 27479296 TI - Language: another cause of publication bias. PMID- 27479297 TI - Spatiotemporal Dynamics of Scrub Typhus Transmission in Mainland China, 2006 2014. AB - BACKGROUND: Scrub typhus is endemic in the Asia-Pacific region including China, and the number of reported cases has increased dramatically in the past decade. However, the spatial-temporal dynamics and the potential risk factors in transmission of scrub typhus in mainland China have yet to be characterized. OBJECTIVE: This study aims to explore the spatiotemporal dynamics of reported scrub typhus cases in mainland China between January 2006 and December 2014, to detect the location of high risk spatiotemporal clusters of scrub typhus cases, and identify the potential risk factors affecting the re-emergence of the disease. METHOD: Monthly cases of scrub typhus reported at the county level between 2006 and 2014 were obtained from the Chinese Center for Diseases Control and Prevention. Time-series analyses, spatiotemporal cluster analyses, and spatial scan statistics were used to explore the characteristics of the scrub typhus incidence. To explore the association between scrub typhus incidence and environmental variables panel Poisson regression analysis was conducted. RESULTS: During the time period between 2006 and 2014 a total of 54,558 scrub typhus cases were reported in mainland China, which grew exponentially. The majority of cases were reported each year between July and November, with peak incidence during October every year. The spatiotemporal dynamics of scrub typhus varied over the study period with high-risk clusters identified in southwest, southern, and middle-eastern part of China. Scrub typhus incidence was positively correlated with the percentage of shrub and meteorological variables including temperature and precipitation. CONCLUSIONS: The results of this study demonstrate areas in China that could be targeted with public health interventions to mitigate the growing threat of scrub typhus in the country. PMID- 27479298 TI - Genotypes of rubella virus and the epidemiology of rubella infections in the Democratic Republic of the Congo, 2004-2013. AB - Rubella is a viral infection that may cause fetal death or congenital defects, known as congenital rubella syndrome (CRS), during early pregnancy. The World Health Organization (WHO) recommends that countries assess the burden of rubella and CRS, including the determination of genotypes of circulating viruses. The goal of this study was to identify the genotypes of rubella viruses in the Democratic Republic of the Congo (DRC). Serum or throat swab samples were collected through the measles surveillance system. Sera that tested negative for measles IgM antibody were tested for rubella IgM antibody. Serum collected within 4 days of rash onset and throat swabs were screened by real-time RT-PCR for rubella virus RNA. For positive samples, an amplicon of the E1 glycoprotein gene was amplified by RT-PCR and sequenced. 11733 sera were tested for rubella IgM and 2816 (24%) were positive; 145 (5%) were tested for the presence of rubella RNA by real-time RT-PCR and 10 (7%) were positive. Seventeen throat swabs were analyzed by RT-PCR and three were positive. Sequences were obtained from eight of the positive samples. Phylogenetic analysis showed that the DRC rubella viruses belonged to genotypes 1B, 1E, 1G, and 2B. This report provides the first information on the genotypes of rubella virus circulating in the DRC. These data contribute to a better understanding of rubella burden and the dynamics of rubella virus circulation in Africa. Efforts to establish rubella surveillance in the DRC are needed to support rubella elimination in Africa. J. Med. Virol. 88:1677-1684, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27479299 TI - Phase Transitions in Dipalmitoylphosphatidylcholine Monolayers. AB - A self-assembled phospholipid monolayer at an air-water interface is a well defined model system for studying surface thermodynamics, membrane biophysics, thin-film materials, and colloidal soft matter. Here we report a study of two dimensional phase transitions in the dipalmitoylphosphatidylcholine (DPPC) monolayer at the air-water interface using a newly developed methodology called constrained drop surfactometry (CDS). CDS is superior to the classical Langmuir balance in its capacity for rigorous temperature control and leak-proof environments, thus making it an ideal alternative to the Langmuir balance for studying lipid polymorphism. In addition, we have developed a novel Langmuir Blodgett (LB) transfer technique that allows the direct transfer of lipid monolayers from the droplet surface under well-controlled conditions. This LB transfer technique permits the direct visualization of phase coexistence in the DPPC monolayer. With these technological advances, we found that the two dimensional phase behavior of the DPPC monolayer is analogous to the three dimensional phase transition of a pure substance. This study has implications in the fundamental understanding of surface thermodynamics as well as applications such as self-assembled monolayers and pulmonary surfactant biophysics. PMID- 27479300 TI - The Role of Emotion-Driven Impulse Control Difficulties in the Relation Between Social Anxiety and Aggression. AB - OBJECTIVES: To enhance our understanding of the factors that may account for increased aggression in socially anxious individuals, this study examined associations among emotion-driven impulse control difficulties, social anxiety, and dimensions of aggression (i.e., hostility, anger, physical aggression, verbal aggression). METHOD: Individuals (N = 107; 73.8% male; Mage = 40.8 years) receiving residential substance abuse treatment participated in this cross sectional study. RESULTS: Social anxiety symptoms were significantly positively correlated with emotion-driven impulse control difficulties, anger, and hostility, but not verbal or physical aggression. Separate models for each aggression facet were examined to test the direct and indirect paths. Bootstrapped mediation analyses indicated a significant indirect path from social anxiety symptoms to each facet of aggression through emotion-driven impulse control difficulties (ps < .05). CONCLUSION: Results highlight the potential utility of targeting emotion-driven impulse control difficulties to decrease aggression among socially anxious individuals. PMID- 27479303 TI - ERRATUM. PMID- 27479301 TI - The Evonik-Mainz Eye Care-Study (EMECS): Development of an Expert System for Glaucoma Risk Detection in a Working Population. AB - PURPOSE: To develop an expert system for glaucoma screening in a working population based on a human expert procedure using images of optic nerve head (ONH), visual field (frequency doubling technology, FDT) and intraocular pressure (IOP). METHODS: 4167 of 13037 (32%) employees between 40 and 65 years of Evonik Industries were screened. An experienced glaucoma expert (JW) assessed papilla parameters and evaluated all individual screening results. His classification into "no glaucoma", "possible glaucoma" and "probable glaucoma" was defined as "gold standard". A screening model was developed which was tested versus the gold standard. This model took into account the assessment of the ONH. Values and relationships of CDR and IOP and the FDT were considered additionally and a glaucoma score was generated. The structure of the screening model was specified a priori whereas values of the parameters were chosen post-hoc to optimize sensitivity and specificity of the algorithm. Simple screening models based on IOP and / or FDT were investigated for comparison. RESULTS: 111 persons (2.66%) were classified as glaucoma suspects, thereof 13 (0.31%) as probable and 98 (2.35%) as possible glaucoma suspects by the expert. Re-evaluation by the screening model revealed a sensitivity of 83.8% and a specificity of 99.6% for all glaucoma suspects. The positive predictive value of the model was 80.2%, the negative predictive value 99.6%. Simple screening models showed insufficient diagnostic accuracy. CONCLUSION: Adjustment of ONH and symmetry parameters with respect to excavation and IOP in an expert system produced sufficiently satisfying diagnostic accuracy. This screening model seems to be applicable in such a working population with relatively low age and low glaucoma prevalence. Different experts should validate the model in different populations. PMID- 27479304 TI - Handling and Storage Procedures Have Variable Effects on Fatty Acid Content in Fishes with Different Lipid Quantities. AB - It is commonly assumed that the most accurate data on fatty acid (FA) contents are obtained when samples are analyzed immediately after collection. For logistical reasons, however, this is not always feasible and samples are often kept on ice or frozen at various temperatures and for diverse time periods. We quantified temporal changes of selected FA (MUg FAME per mg tissue dry weight) from 6 fish species subjected to 2 handling and 3 storage methods and compared them to FA contents from muscle tissue samples that were processed immediately. The following species were investigated: Common Carp (Cyprinus carpio), Freshwater Drum (Aplodinotus grunniens), Channel Catfish (Ictalurus punctatus), Antarctic Eelpout (Pachycara brachycephalum), Rainbow Trout (Oncorhynchus mykiss) and Arctic Charr (Salvelinus alpinus). The impact of storage method and duration of storage on FA contents were species-specific, but not FA-specific. There was no advantage in using nitrogen gas for tissue samples held on ice for 1 week; however, holding tissue samples on ice for 1 week resulted in a loss of FA in Charr. In addition, most FA in Trout and Charr decreased in quantity after being stored between 3 and 6 hours on ice. Freezer storage temperature (-80 or -20 degrees C) also had a significant effect on FA contents in some species. Generally, we recommend that species with high total lipid content (e.g. Charr and Trout) should be treated with extra caution to avoid changes in FA contents, with time on ice and time spent in a freezer emerging as significant factors that changed FA contents. PMID- 27479305 TI - Why Hospitals Can, and Should, Do More to Help With Public Health. PMID- 27479306 TI - Politics and Public Health-Engaging the Third Rail. PMID- 27479307 TI - Next Steps for Promoting Evidence-Based Cancer Control. PMID- 27479309 TI - Half an Ocean Away: Health in the US-Affiliated Pacific Islands. PMID- 27479308 TI - Recommendations From the International Colorectal Cancer Screening Network on the Evaluation of the Cost of Screening Programs. AB - Worldwide, colorectal cancer is the fourth leading cause of death from cancer and the incidence is projected to increase. Many countries are exploring the introduction of organized screening programs, but there is limited information on the resources required and guidance for cost-effective implementation. To facilitate the generating of the economics evidence base for program implementation, we collected and analyzed detailed program cost data from 5 European members of the International Colorectal Cancer Screening Network. The cost per person screened estimates, often used to compare across programs as an overall measure, varied significantly across the programs. In addition, there were substantial differences in the programmatic and clinical cost incurred, even when the same type of screening test was used. Based on these findings, several recommendations are provided to enhance the underlying methodology and validity of the comparative economic assessments. The recommendations include the need for detailed activity-based cost information, the use of a comprehensive set of effectiveness measures to adequately capture differences between programs, and the incorporation of data from multiple programs in cost-effectiveness models to increase generalizability. Economic evaluation of real-world colorectal cancer screening programs is essential to derive valuable insights to improve program operations and ensure optimal use of available resources. PMID- 27479310 TI - NACCHO's Baseline Assessment of Disability Inclusion Within Local Health Departments. PMID- 27479311 TI - The 3 Buckets of Prevention Still Need the Public Health Protective Net. PMID- 27479312 TI - Response to Dato. PMID- 27479313 TI - Tobacco User Characteristics and Outcomes Related to Intensity of Quitline Program Use: Results From Minnesota and Pennsylvania. AB - CONTEXT: Tobacco users in all 50 states have access to quitline telephone counseling and cessation medications. While studies show multiple calls relate to quit success, most participants do not complete a full call series. To date, quitline program use studies have analyzed single factors-such as number of calls or counseling minutes. OBJECTIVE: This study combines multiple factors of quitline program use across 2 states to describe how participants use a 5-call program; assess whether intensity of program use is associated with participant subgroups; and assess whether key outcomes (quitting, satisfaction) are associated with intensity. DESIGN, SETTING, AND PARTICIPANTS: This observational study examines data for quitline participants in Minnesota (n = 2844) and Pennsylvania (n = 14 359) in 2011 and 2012. A subset of participants was surveyed 7 months after registration to assess key outcomes (response rates: Minnesota 65%; Pennsylvania 60%). MAIN OUTCOME MEASURES: Quitline utilization data were used to identify program use variables: nicotine replacement therapy provision, number of counseling calls, number of counseling minutes, days from first to last counseling call, and days from registration to first counseling call. Ten program use groups were created using all 5 program use variables, from lowest (1) to highest (10) intensity. RESULTS: Results were similar for both states. Only 11% of Minnesota and 8% of Pennsylvania participants completed all 5 calls. Intensity of quitline program use was associated with several participant characteristics including health conditions and age. Both quit status and program satisfaction were associated with program use intensity. Quit rates peaked in group 9, participants who received the full 5-call program. CONCLUSIONS: Quitlines should focus on engaging participants in multiple calls to improve quit outcomes. In addition, it is important to leverage multiple program use factors for a fuller understanding of how quitline participants use a program. PMID- 27479314 TI - Arginines Plasma Concentration and Oxidative Stress in Mild to Moderate COPD. AB - BACKGROUND: Elevated plasma concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) have been observed in respiratory conditions such as asthma and cystic fibrosis. Since oxidative stress has been shown to increase the activity of arginine methylating enzymes, hence increased ADMA synthesis, and to reduce ADMA degrading enzymes, hence increased ADMA concentrations, we assessed methylated arginines concentrations in chronic obstructive pulmonary disease (COPD), a disease characterized by increased oxidative stress. METHODS: Plasma arginine, ADMA and symmetric dimethylarginine (SDMA), oxidative stress markers (thiobarbituric acid reactive substances, TBARS, and plasma proteins SH, PSH) and antioxidants (taurine and paraoxonase 1, PON1, activity) were measured in 43 COPD patients with mild (n = 29) or moderate (n = 14) disease and 43 age- and sex-matched controls. RESULTS: TBARS significantly increased with COPD presence and severity (median 2.93 vs 3.18 vs 3.64 MUmol/L, respectively in controls, mild and moderate group, p<0.0001 by ANOVA) whereas PSH decreased (6.69+/-1.15 vs 6.04+/-0.85 vs 5.33+/-0.96 MUmol/gr prot, p<0.0001 by ANOVA). Increased ADMA/arginine ratio, primarily due to reduced arginine concentrations, was also observed with COPD presence and severity (median 0.0067 vs 0.0075 vs 0.0100, p<0.0001 by ANOVA). In multiple logistic regression analysis, only TBARS (OR 0.44, 95% CI 0.25-0.77; p = 0.0045) and ADMA/Arginine ratio (OR 1.72, 95% CI 2.27-13.05; p = 0.02) were independently associated with COPD severity. CONCLUSION: COPD presence and severity are associated with increased oxidative stress and alterations in arginine metabolism. The reduced arginine concentrations in COPD may offer a new target for therapeutic interventions increasing arginine availability. PMID- 27479315 TI - Comparative Emulsifying Properties of Octenyl Succinic Anhydride (OSA)-Modified Starch: Granular Form vs Dissolved State. AB - The emulsifying ability of OSA-modified and native starch in the granular form, in the dissolved state and a combination of both was compared. This study aims to understand mixed systems of particles and dissolved starch with respect to what species dominates at droplet interfaces and how stability is affected by addition of one of the species to already formed emulsions. It was possible to create emulsions with OSA-modified starch isolated from Quinoa as sole emulsifier. Similar droplet sizes were obtained with emulsions prepared at 7% (w/w) oil content using OSA-modified starch in the granular form or molecularly dissolved but large differences were observed regarding stability. Pickering emulsions kept their droplet size constant after one month while emulsions formulated with OSA modified starch dissolved exhibited coalescence. All emulsions stabilized combining OSA-modified starch in granular form and in solution showed larger mean droplet sizes with no significant differences with respect to the order of addition. These emulsions were unstable due to coalescence regarding presence of free oil. Similar results were obtained when emulsions were prepared by combining OSA-modified granules with native starch in solution. The degree of surface coverage of starch granules was much lower in presence of starch in solution which indicates that OSA-starch is more surface active in the dissolved state than in granular form, although it led to unstable systems compared to starch granule stabilized Pickering emulsions, which demonstrated to be extremely stable. PMID- 27479316 TI - Molecular interaction fingerprint approaches for GPCR drug discovery. AB - Protein-ligand interaction fingerprints (IFPs) are binary 1D representations of the 3D structure of protein-ligand complexes encoding the presence or absence of specific interactions between the binding pocket amino acids and the ligand. Various implementations of IFPs have been developed and successfully applied for post-processing molecular docking results for G Protein-Coupled Receptor (GPCR) ligand binding mode prediction and virtual ligand screening. Novel interaction fingerprint methods enable structural chemogenomics and polypharmacology predictions by complementing the increasing amount of GPCR structural data. Machine learning methods are increasingly used to derive relationships between bioactivity data and fingerprint descriptors of chemical and structural information of binding sites, ligands, and protein-ligand interactions. Factors that influence the application of IFPs include structure preparation, binding site definition, fingerprint similarity assessment, and data processing and these factors pose challenges as well possibilities to optimize interaction fingerprint methods for GPCR drug discovery. PMID- 27479317 TI - Evaluation of hs-CRP and visseral adiposity index in patients with policystic ovary syndrome by clinical and laboratory findings. AB - AIM: In this study, we aimed to evaluate two cardiovascular risk markers, hs-CRP and visseral adiposity index, in patients with policystic ovary syndrome in association with clinical and laboratory findings. MATERIAL AND METHOD: Study group included 75 patients who were diagnosed as PCOS according to the criteria of AE-PCOS 2006 and control group included 75 non-PCOS patients who were subsequently admitted to outpatient clinic for smear control, with urinary or vaginal symptoms. Physical and sonographic examinations were made to all subjects. Mean arterial pressure, waist/hip ratio and body mass index were calculated. Fasting blood glucose and insulin, HbA1c, lipids, high sensitivity C reactive protein (hs-CRP), estradiol, follicle stimulating hormon, luteinising hormone, tiroid stimulating hormone, prolaktin, total testosteron and sex hormone binding globulin were tested in venous blood samples collected from cases following overnight fast in follicular phase of spontaneous or induced menstruation. Visceral adiposity index was also calculated. FINDINGS: No statistically significant difference was found between PCOS group and control group concerning hs-CRP and VAI (p>0.05). When patients in PCOS group were further grouped as obese and non-obese, hs-CRP and VAI values in obese group were significantly higher than those in non-obese group (p<0.001). However, when control group were further grouped as obese and non-obese, there was no significant difference in terms of hs-CRP between groups (p>0.05), VAI values were significantly higher in obese control group (p<0.05). CONCLUSION: According to the results of our study, hs-CRP stands for a better and more specific marker than VAI to determine metabolic components and predictive risks for cardiovascular diseases in patients with PCOS. Further studies with larger populations are needed in order to determine cardiovascular risks particularly in young PCOS patients. PMID- 27479318 TI - Does intrinsic motivation enhance motor cortex excitability? AB - Intrinsic motivation (IM) is often viewed as a spontaneous tendency for action. Recent behavioral and neuroimaging evidence indicate that IM, in comparison to extrinsic motivation (EM), solicits the motor system. Accordingly, we tested whether IM leads to greater excitability of the motor cortex than EM. To test this hypothesis, we used two different tasks to induce the motivational orientation using either words representing each motivational orientation or pictures previously linked to each motivational orientation through associative learning. Single-pulse transcranial magnetic stimulation over the motor cortex was applied when viewing the stimuli. Electromyographic activity was recorded on the contracted first dorsal interosseous muscle. Two indexes of corticospinal excitability (the amplitude of motor-evoked potential and the length of cortical silent period) were obtained through unbiased automatic detection and analyzed using a mixed model that provided both statistical power and a high level of control over all important individual, task, and stimuli characteristics. Across the two tasks and the two indices of corticospinal excitability, the exposure to IM-related stimuli did not lead to a greater corticospinal excitability than EM related stimuli or than stimuli with no motivational valence (ps > .20). While these results tend to dismiss the advantage of IM at activating the motor cortex, we suggest alternative hypotheses to explain this lack of effect, which deserves further research. PMID- 27479319 TI - Effects of Selective M1 Muscarinic Receptor Activation on Hippocampal Spatial Representations and Neuronal Oscillations. AB - The muscarinic M1 acetylcholine receptor is a key target for drugs aimed at treating cognitive dysfunction, including the memory impairment in Alzheimer's disease. The overall question of the current study was to ask how systemic administration of the bitopic M1 agonist VU0364572, the M1 positive allosteric modulator BQCA, and the acetylcholinesterase inhibitor donepezil (current standard of care for Alzheimer's disease), would impact spatial memory-related hippocampal function in rats. Hippocampal pyramidal neuron spiking and local field potentials were recorded from regions CA1 and CA3 as rats freely foraged in a recording enclosure. To assess the relative stability versus flexibility of the rats' spatial representations, the walls of the recording enclosure were reshaped in 15-m intervals. As compared to the control condition, systemic administration of VU0364572 increased spatial correlations of CA1 and CA3 pyramidal neuron spiking across all enclosure shape comparisons, whereas BQCA and donepezil appeared to decrease these spatial correlations. Further, both VU0364572 and BQCA increased intrahippocampal synchrony as measured by CA3-CA1 field-field coherence in frequency ranges that tended to align with the prominence of those oscillations for the behavioral state (i.e., theta during locomotion and slow gamma during stationary moments). The results indicated that VU0364572 and BQCA influenced hippocampal function differently but in ways that might both be beneficial for treating memory dysfunction. PMID- 27479320 TI - Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups. AB - Conjugate (or 1,4-) additions of carbanionic species to alpha,beta-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates. Nonetheless, catalytic enantioselective 1,6 conjugate additions are uncommon, and ones that incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic alpha,beta,gamma,delta-doubly unsaturated acceptors are unknown. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable because the resulting products could then be subjected to further modifications. However, such reactions, especially when dienoates contain two equally substituted olefins, are scarce and are confined to reactions promoted by a phosphine-copper catalyst (with an alkyl Grignard reagent, dialkylzinc or trialkylaluminium compounds), a diene-iridium catalyst (with arylboroxines), or a bisphosphine-cobalt catalyst (with monosilyl-acetylenes). 1,6-Conjugate additions are otherwise limited to substrates where there is full substitution at the C4 position. It is unclear why certain catalysts favour bond formation at C6, and-although there are a small number of catalytic enantioselective conjugate allyl additions-related 1,6-additions and processes involving a propargyl unit are non-existent. Here we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenyl-boron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 per cent yield, >98:2 diastereomeric ratio (for allyl additions) and 99:1 enantiomeric ratio. We elucidate the mechanistic details, including the origins of high site selectivity (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, by means of density functional theory calculations. The utility of the approach is highlighted by an application towards enantioselective synthesis of the anti-HIV agent (-)-equisetin. PMID- 27479322 TI - Structural biology: Signal locked in. PMID- 27479321 TI - Tempo and mode of genome evolution in a 50,000-generation experiment. AB - Adaptation by natural selection depends on the rates, effects and interactions of many mutations, making it difficult to determine what proportion of mutations in an evolving lineage are beneficial. Here we analysed 264 complete genomes from 12 Escherichia coli populations to characterize their dynamics over 50,000 generations. The populations that retained the ancestral mutation rate support a model in which most fixed mutations are beneficial, the fraction of beneficial mutations declines as fitness rises, and neutral mutations accumulate at a constant rate. We also compared these populations to mutation-accumulation lines evolved under a bottlenecking regime that minimizes selection. Nonsynonymous mutations, intergenic mutations, insertions and deletions are overrepresented in the long-term populations, further supporting the inference that most mutations that reached high frequency were favoured by selection. These results illuminate the shifting balance of forces that govern genome evolution in populations adapting to a new environment. PMID- 27479323 TI - Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. AB - Secondary metabolites synthesized by non-ribosomal peptide synthetases display diverse and complex topologies and possess a range of biological activities. Much of this diversity derives from a synthetic strategy that entails pre- and post assembly oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds. The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis. However, because of the challenges associated with using such oxidative enzymes to carry out chemical transformations in vitro, chemical syntheses guided by these principles have not been fully realized in the laboratory. Here we report that two small-molecule iron catalysts are capable of facilitating the targeted C-H oxidative modification of amino acids and peptides with preservation of alpha-centre chirality. Oxidation of proline to 5-hydroxyproline furnishes a versatile intermediate that can be transformed to rigid arylated derivatives or flexible linear carboxylic acids, alcohols, olefins and amines in both monomer and peptide settings. The value of this C-H oxidation strategy is demonstrated in its capacity for generating diversity: four 'chiral pool' amino acids are transformed to twenty-one chiral unnatural amino acids representing seven distinct functional group arrays; late-stage C-H functionalizations of a single proline-containing tripeptide furnish eight tripeptides, each having different unnatural amino acids. Additionally, a macrocyclic peptide containing a proline turn element is transformed via late-stage C-H oxidation to one containing a linear unnatural amino acid. PMID- 27479324 TI - Circadian neuron feedback controls the Drosophila sleep--activity profile. AB - Little is known about the ability of Drosophila circadian neurons to promote sleep. Here we show, using optogenetic manipulation and video recording, that a subset of dorsal clock neurons (DN1s) are potent sleep-promoting cells that release glutamate to directly inhibit key pacemaker neurons. The pacemakers promote morning arousal by activating these DN1s, implying that a late-day feedback circuit drives midday siesta and night-time sleep. To investigate more plastic aspects of the sleep program, we used a calcium assay to monitor and compare the real-time activity of DN1 neurons in freely behaving males and females. Our results revealed that DN1 neurons were more active in males than in females, consistent with the finding that male flies sleep more during the day. DN1 activity is also enhanced by elevated temperature, consistent with the ability of higher temperatures to increase sleep. These new approaches indicate that DN1s have a major effect on the fly sleep-wake profile and integrate environmental information with the circadian molecular program. PMID- 27479325 TI - DWARF14 is a non-canonical hormone receptor for strigolactone. AB - Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The alpha/beta hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14-D3-ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone. PMID- 27479326 TI - Cytomorphology and flow cytometry of brain biopsy rinse fluid enables faster and multidisciplinary diagnosis of large B-cell lymphoma of the central nervous system. AB - BACKGROUND: Central nervous system lymphomas are aggressive tumors requiring a prompt diagnosis for successful treatment. Stereotactic biopsy remains the standard procedure, but the time needed for histopathology is usually over 2 days. We evaluated the contribution of cytomorphology and flow cytometry to histopathology of the brain biopsy in particular on the rinse fluid usually removed. METHODS: Eighteen patients with suspected localized brain lymphoma underwent stereotactic brain biopsy. Brain biopsy tissue sample and/or brain biopsy rinse fluid were analyzed by cytomorphology combined with flow cytometry. Histopathology was used as a reference. RESULTS: Histopathology characterized ten diffuse large B-cell lymphomas and eight other diseases. Cytomorphology and flow cytometry showed lymphoma cells in nine out of the ten lymphomas. Three cytomorphology or flow cytometry negative results were reported for lymphomas in tissue samples due to low cellularity and biopsy sample conditioning. No lymphomatous cells were found by cytomorphology or flow cytometry in the eight other diseases. Rinse fluid results were consistent with histology in all cases studied (sensitivity and specificity, 100%). The median time to result was 4.5 days (range, 2-10 days) for histopathology, while 5 h (range, 3-20 h) were required for both cytomorphology and flow cytometry. CONCLUSIONS: Brain biopsy rinse fluid alleviates problems of tissue sample distribution compared to tissue sample. Its analysis performs the diagnosis of B-cell lymphoma in a few hours and, associated with histopathology, allows a multidisciplinary diagnosis. This study shows that cytomorphology combined with flow cytometry on brain biopsy rinse fluid is a new, fast, and useful strategy. (c) 2016 International Clinical Cytometry Society. PMID- 27479327 TI - Revealing disease-associated pathways by network integration of untargeted metabolomics. AB - Uncovering the molecular context of dysregulated metabolites is crucial to understand pathogenic pathways. However, their system-level analysis has been limited owing to challenges in global metabolite identification. Most metabolite features detected by untargeted metabolomics carried out by liquid-chromatography mass spectrometry cannot be uniquely identified without additional, time consuming experiments. We report a network-based approach, prize-collecting Steiner forest algorithm for integrative analysis of untargeted metabolomics (PIUMet), that infers molecular pathways and components via integrative analysis of metabolite features, without requiring their identification. We demonstrated PIUMet by analyzing changes in metabolism of sphingolipids, fatty acids and steroids in a Huntington's disease model. Additionally, PIUMet enabled us to elucidate putative identities of altered metabolite features in diseased cells, and infer experimentally undetected, disease-associated metabolites and dysregulated proteins. Finally, we established PIUMet's ability for integrative analysis of untargeted metabolomics data with proteomics data, demonstrating that this approach elicits disease-associated metabolites and proteins that cannot be inferred by individual analysis of these data. PMID- 27479328 TI - A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein. AB - Far-red fluorescent proteins (FPs) are desirable for in vivo imaging because with these molecules less light is scattered, absorbed, or re-emitted by endogenous biomolecules compared with cyan, green, yellow, and orange FPs. We developed a new class of FP from an allophycocyanin alpha-subunit (APCalpha). Native APC requires a lyase to incorporate phycocyanobilin. The evolved FP, which we named small ultra-red FP (smURFP), covalently attaches a biliverdin (BV) chromophore without a lyase, and has 642/670-nm excitation-emission peaks, a large extinction coefficient (180,000 M(-1)cm(-1)) and quantum yield (18%), and photostability comparable to that of eGFP. smURFP has significantly greater BV incorporation rate and protein stability than the bacteriophytochrome (BPH) FPs. Moreover, BV supply is limited by membrane permeability, and smURFPs (but not BPH FPs) can incorporate a more membrane-permeant BV analog, making smURFP fluorescence comparable to that of FPs from jellyfish or coral. A far-red and near-infrared fluorescent cell cycle indicator was created with smURFP and a BPH FP. PMID- 27479329 TI - TRIC: an automated alignment strategy for reproducible protein quantification in targeted proteomics. AB - Next-generation mass spectrometric (MS) techniques such as SWATH-MS have substantially increased the throughput and reproducibility of proteomic analysis, but ensuring consistent quantification of thousands of peptide analytes across multiple liquid chromatography-tandem MS (LC-MS/MS) runs remains a challenging and laborious manual process. To produce highly consistent and quantitatively accurate proteomics data matrices in an automated fashion, we developed TRIC (http://proteomics.ethz.ch/tric/), a software tool that utilizes fragment-ion data to perform cross-run alignment, consistent peak-picking and quantification for high-throughput targeted proteomics. TRIC reduced the identification error compared to a state-of-the-art SWATH-MS analysis without alignment by more than threefold at constant recall while correcting for highly nonlinear chromatographic effects. On a pulsed-SILAC experiment performed on human induced pluripotent stem cells, TRIC was able to automatically align and quantify thousands of light and heavy isotopic peak groups. Thus, TRIC fills a gap in the pipeline for automated analysis of massively parallel targeted proteomics data sets. PMID- 27479330 TI - Virtual microfluidics for digital quantification and single-cell sequencing. AB - We have developed hydrogel-based virtual microfluidics as a simple and robust alternative to complex engineered microfluidic systems for the compartmentalization of nucleic acid amplification reactions. We applied in-gel digital multiple displacement amplification (dMDA) to purified DNA templates, cultured bacterial cells and human microbiome samples in the virtual microfluidics system, and demonstrated whole-genome sequencing of single-cell MDA products with excellent coverage uniformity and markedly reduced chimerism compared with products of liquid MDA reactions. PMID- 27479331 TI - Efficient estimation for accelerated failure time model under case-cohort and nested case-control sampling. AB - Case-cohort (Prentice, 1986) and nested case-control (Thomas, 1977) designs have been widely used as a cost-effective alternative to the full-cohort design. In this article, we propose an efficient likelihood-based estimation method for the accelerated failure time model under case-cohort and nested case-control designs. An EM algorithm is developed to maximize the likelihood function and a kernel smoothing technique is adopted to facilitate the estimation in the M-step of the EM algorithm. We show that the proposed estimators for the regression coefficients are consistent and asymptotically normal. The asymptotic variance of the estimators can be consistently estimated using an EM-aided numerical differentiation method. Simulation studies are conducted to evaluate the finite sample performance of the estimators and an application to a Wilms tumor data set is also given to illustrate the methodology. PMID- 27479332 TI - Science and Public Health on Trial: Warning Notices on Advertisements for Sugary Drinks. PMID- 27479333 TI - Liquid PEG Polymers Containing Antioxidants: A Versatile Platform for Studying Oxygen-Sensitive Photochemical Processes. AB - This article proposes the exploitation of widely available, inexpensive, innocuous "green" liquid polyethylene glycol (PEG) polymers containing the oxygen scavenger oleic acid (OA) as promising media for studying oxygen-sensitive photochemical processes. Here we report the successful application of this media to detailed investigations of triplet-sensitized photochemical upconversion, previously established as being readily poisoned by dissolved oxygen. Three different PEG materials were investigated with increasing molecular weight from 200 to 600 g/mol, coded as PEG-200, PEG-400, and PEG-600. These fluidic polymers facilitate an oxygen-depleted environment in comparison to commonly employed organic solvents while providing high solubility and diffusion for the dissolved chromophores. Moreover, the low oxygen permeation afforded by these PEG solvents allows them to remain deoxygenated in open containers under ambient conditions for extended time periods. OA, 9,10-dimethylanthracene (DMA), and 2,5 dimethylfuran (DMF) are shown to efficiently and quantitatively consume dissolved oxygen in the PEG environment in the presence of the photoactivated triplet sensitizer platinum(II) tetraphenyltetrabenzoporphyrin (PtTPBP). Oxygen consumption was directly correlated with systematically increasing sensitizer excited-state lifetimes that eventually reach the same plateau as achieved through extensive N2 sparging. Diffusion-controlled bimolecular triplet-triplet energy transfer quenching between PtTPBP and the acceptor/annihilator 9,10 bisphenylethynylanthracene (BPEA) was observed in all three PEG formulations investigated. Subsequent triplet-triplet annihilation, between triplet excited BPEA acceptors, achieves bright and stable upconverted singlet fluorescence from BPEA with no decrease in intensity over 20 h under ambient conditions. In the champion composition (PEG 200), the upconversion quantum efficiency reached 31% under conditions where triplet-triplet annihilation was maximized. This is in stark contrast for the same upconverting pair measured in toluene under ambient conditions, which rapidly decomposes upon exposure to visible light. To illustrate that these PEG compositions could be translated into a suitable solid state format, these viscous solutions were embedded in a transparent polyurethane polymer shell yielding a flexible and long-term stable upconverting cell that can be manipulated for possible real-world applications. Although the current investigation focused on photochemical upconversion, the oxygen-depleted environments developed here can be utilized to study a plethora of oxygen intolerant photochemical reactions. PMID- 27479334 TI - Human Papillomavirus Genotyping Testing Practice in 2014: Results of a College of American Pathologists National Survey. AB - CONTEXT: - College of American Pathologists (CAP) surveys are used to establish national benchmarks for laboratories. OBJECTIVE: - To investigate human papillomavirus (HPV) genotyping testing practice patterns in laboratories in 2014. DESIGN: - Data were analyzed from the CAP HPV Genotyping Practices Supplemental Questionnaire distributed to 749 laboratories participating in the CAP Human Papillomavirus (High Risk) for Cytology Program. RESULTS: - Six hundred four of 749 laboratories (80.6%) responded to the survey. More laboratories offered HPV genotyping testing and performed in-house HPV genotyping testing as compared to previous surveys. The Roche cobas HPV test was the most commonly used genotyping method (37.0%; 160 of 433), followed by Hologic Aptima HPV16 18/45 (26.1%; 113 of 433) and Hologic Cervista HPV16/18 (14.3%; 62 of 433). Most laboratories (287 of 399; 71.9%) offered HPV genotyping for high-risk HPV cases regardless of Papanicolaou (Pap) test results and patient age; this pattern was more common in laboratories using cobas. The remaining laboratories specifically offered testing to women with a negative Pap test result at age 30 years and older (65.2%, 73 of 112) or all ages (37.5%, 42 of 112). The median reporting rates of HPV16 and/or HPV18 positivity were 20.6%, 25.7%, 21.1%, and 57.4% for women with positive high-risk HPV adjunctive negative Pap results, atypical squamous cells of undermined significance, low-grade squamous intraepithelial lesion, and high-grade squamous lesion, respectively. CONCLUSIONS: - Human papillomavirus genotyping testing has increased. Roche cobas and Hologic Aptima genotype methods were the most common, and laboratories using cobas usually offered genotyping regardless of Pap test result and age. The data provide a baseline and trend of HPV genotyping test practices in 2014. PMID- 27479335 TI - Common Fluorescence In Situ Hybridization Applications in Cytology. AB - CONTEXT: - Fluorescence in situ hybridization (FISH) is a well-established method for detection of genomic aberrations in diagnostic, prognostic, and predictive marker testing. OBJECTIVE: - To review common applications of FISH in cytology. DATA SOURCES: - The published literature was reviewed. CONCLUSIONS: - Cytology is particularly well suited for all kinds of FISH applications, which is highlighted in respiratory tract cytology with an increasing demand for predictive FISH testing in lung cancer. Fluorescence in situ hybridization is the gold standard for detection of predictive anaplastic lymphoma kinase gene (ALK) rearrangements, and the same evaluation criteria as in histology apply to cytology. Several other gene rearrangements, including ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), are becoming clinically important and share the same underlining cytogenetic mechanisms with ALK. MET amplification is one of the most common mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and can be targeted by crizotinib. As genomic aberrations are a hallmark of malignant cells, FISH is a valuable objective ancillary diagnostic tool. In urinary tract cytology, atypical urothelial cells equivocal for malignancy are a common diagnostic dilemma and multitarget FISH can help clarify such cells. Diagnosis of malignant mesothelioma remains one of the most challenging fields in effusion cytology, and ancillary FISH is useful in establishing the diagnosis. Fluorescence in situ hybridization is a morphology based technique, and the prerequisite for reliable FISH results is a targeted evaluation of the cells in question (eg, cancer or atypical cells). Cytopathologists and cytotechnicians should therefore be involved in molecular testing in order to select the best material and to provide their morphologic expertise. PMID- 27479336 TI - Erlotinib-based targeted dual agent versus erlotinib alone in previously treated advanced non-small-cell lung cancer: a meta-analysis of 13 randomized controlled trials. AB - OBJECTIVES: To compare the effects of an erlotinib-based targeted dual agent with erlotinib alone in previously treated patients with advanced non-small lung cancer (NSCLC). PATIENTS AND METHODS: The PubMed and Embase databases and the Cochrane Central Register of Controlled Trials were searched for publications between January 2005 and March 2016. Hazard ratios (HRs) with their 95% confidence intervals (CIs), or data for calculating HRs with 95% CIs were derived. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity were assessed. RESULTS: Thirteen trials with a total of 4509 patients were included in this meta analysis. Compared with erlotinib alone, combination therapy showed no improvement in OS (HR = 0.95; 95% CI, 0.89-1.02; P = .132) though significantly prolonged PFS (HR = 0.82; 95% CI, 0.75-0.90; P < .001). Combination therapy significantly increased ORR (RR = 1.32; 95% CI, 1.09-1.60; P = .005) and DCR (RR = 1.26; 95% CI, 1.17-1.36, P < .001). Sub-analysis assessment failed to identify any sub-groups which could benefit from combination therapy in terms of OS. Combination therapy was associated with more grade 3 or higher toxic effects (RR = 1.54; 95% CI, 1.22-1.95; P < .001). Patients treated with combination therapy had more grade 3 or greater fatigue (RR = 1.49; 95% CI, 1.16-1.91; P = .002), but did not develop more diarrhea (RR = 2.02; 95% CI, 0.86-4.77; P = .107) or rash (RR = 1.29, 95% CI, 0.90-1.85; P = .172). This study had limitations about heterogeneities among the included trials, and the analysis was not based on individual patient data. CONCLUSIONS: Compared with erlotinib alone, the erlotinib-based targeted dual agent showed a minimal magnitude of improvement in PFS but did not improve OS. The role of erlotinib-based combinations in previously treated patients with NSCLC seemed insignificant. PMID- 27479337 TI - Maxillary Three-Implant Overdentures Opposing Mandibular Two-Implant Overdentures: 10-Year Prosthodontic Outcomes. AB - PURPOSE: This study aimed to evaluate the 10-year prosthodontic outcomes with splinted and unsplinted designs for maxillary overdentures on three implants opposing mandibular two-implant overdentures. MATERIALS AND METHODS: Using two similar implant systems, 40 edentulous participants with existing mandibular two implant overdentures were randomly allocated to two prosthodontic treatment groups (splinted design with bar units; unsplinted design with ball attachments). Participants had three narrow-diameter implants placed in their edentulous maxillae using a one-stage surgical procedure, and they were conventionally loaded with overdentures. Prosthodontic maintenance events were documented at 1-, 2-, 5-, 7-, and 10-year recalls. RESULTS: Progressive attrition of the cohort resulted in 36 participants being seen for the 1-year recall, 31 participants for the 2-year recall, 30 participants for the 3-year recall, 28 participants for the 5-year recall, 26 participants for the 7-year recall, and 23 participants (nearly 60%) for the 10-year recall. Data showed no significant differences in prosthodontic maintenance or success associated with patrices, matrices, or other aspects of the overdentures using the different attachment systems and designs. CONCLUSION: Maxillary three-implant overdentures are a viable treatment option for edentulous patients wearing opposing mandibular two-implant overdentures. There were no differences in prosthodontic maintenance and success between the splinted (bar) and unsplinted (ball) designs. PMID- 27479338 TI - The Resin-Bonded Fixed Partial Denture as the First Treatment Consideration to Replace a Missing Tooth. AB - The resin-bonded fixed partial denture (RB-FPD) is the first restorative treatment option to be considered in cases where one or more teeth are missing. The indications for implants, conventional FPDs, and adhesive FPDs, considering the general and dental conditions of the patient, are discussed in this article. When the RB-FPD is the chosen option, a direct or indirect technique, a cantilever-type or fixed-fixed design, and materials to be used need to be selected. The choice will depend on a variety of factors, such as interproximal space at the connector area, anterior or posterior location, the skills of the dentist, esthetics, and the patient's wishes. The RB-FPD can be made using various techniques and materials. PMID- 27479339 TI - Parallel Randomized Controlled Clinical Trial in Patients with Temporomandibular Disorders Treated with a CAD/CAM Versus a Conventional Stabilization Splint. AB - PURPOSE: This parallel randomized controlled trial (RCT) compared the efficacy of a computer-aided design/computer-assisted manufacture (CAD/CAM) splint versus a conventional stabilization splint in patients with temporomandibular disorders (TMD). MATERIALS AND METHODS: A sample of 48 age-matched TMD patients from the Ludwig Maximilian University Prosthodontic Department in Munich, Germany, were randomly allocated into groups 1 (CAD/CAM splint) and 2 (conventional splint). The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) was used for TMD Axis I (groups I, II, and III) and Axis II (chronic pain grade [CPG]) diagnoses. Numeric scales (TMD/NS, 10 cm) were used to measure headaches, face pain, jaw joint pain, jaw joint noises, mastication pain, neck pain, face tension, limitation of mouth opening, complaints during mastication, and teeth sensitivity at baseline and then monthly for 9 months (T1 to T10). Optical axiography was used to measure right and left condyle movements (mm) at baseline, 3 months, and 6 months (T1, T4, and T7). RESULTS: A total of 32 patients (drop out rate = 33%; 68.75% women; 28.51 +/- 7.13 years old), 16 per group, completed the study. RDC/TMD Axis I showed the following diagnoses: 93.75% muscle disorders, 37.75% disc displacement with reduction, 3.12% disc displacement without reduction, and 56.25% arthralgia. There was a significant reduction in 10 out of 13 items of the TMD/NS in the CAD/CAM splint versus 8 out of 13 in the conventional splint. However, no significant improvement in mandibular movements (ie, increase in range of motion and reduction in asymmetry between right and left condyles) was observed. CONCLUSION: Both treatments were equally efficacious and no difference was found between them. PMID- 27479340 TI - Fit Analysis of Different Framework Fabrication Techniques for Implant-Supported Partial Prostheses. AB - PURPOSE: This study evaluated the vertical misfit of implant-supported frameworks made using different techniques to obtain passive fit. MATERIALS AND METHODS: Thirty three-unit fixed partial dentures were fabricated in cobalt-chromium alloy (n = 10) using three fabrication methods: one-piece casting, framework cemented on prepared abutments, and laser welding. The vertical misfit between the frameworks and the abutments was evaluated with an optical microscope using the single-screw test. Data were analyzed using one-way analysis of variance and Tukey test (alpha = .05). RESULTS: The one-piece casted frameworks presented significantly higher vertical misfit values than those found for framework cemented on prepared abutments and laser welding techniques (P < .001 and P < .003, respectively). CONCLUSION: Laser welding and framework cemented on prepared abutments are effective techniques to improve the adaptation of three-unit implant-supported prostheses. These techniques presented similar fit. PMID- 27479341 TI - Prosthodontic Management and Treatment Considerations for an HIV-Positive Patient with a Nonhealing Lesion of the Maxilla: A Clinical Case History Report. AB - Osteonecrosis of the jaws has recently been associated with HIV infection and requires surgical and prosthetic intervention. The prosthetic management of an HIV patient with a maxillary lesion, as well as medical status-related treatment considerations, are discussed in this article. PMID- 27479342 TI - Preliminary In Vitro Study on O-Ring Wear in Mini-Implant-Retained Overdentures. AB - This preliminary in vitro study evaluated the simulated retention force of O rings used for mini-implant overdenture treatment and the effect of mechanical fatigue corresponding to 6 months of wear. A mandibular overdenture analog device was attached to two mini-implants and underwent a tensile strength test before and after the application of insertion-removal and simulated masticatory cycles. Insertion-removal cycles led to a retention loss of 24%, whereas masticatory cycles did not influence retention. Micro-CT scans showed minor deformation following mechanical cycling, but the changes were milder than those observed in similar clinical specimens. Both experimental loading methods led to physical changes in the O-rings, which explains in part the similar clinically observed wear. PMID- 27479343 TI - Extraoral Cementation Technique to Minimize Cement-Associated Peri-implant Marginal Bone Loss: Can a Thin Layer of Zinc Oxide Cement Provide Sufficient Retention? AB - This report describes the use of laboratory-fabricated crown intaglio replicas for extraorally prepared cementation of fixed restorations to implants. This technique minimizes excess cement and may therefore reduce the risk of cement related marginal peri-implant bone loss. It is unclear whether the remaining thin layer of luting agent provides sufficient retention if low-adhesive zinc oxide (ZnO) cement is used. In 85 consecutive patients, 113 single crowns were cemented to implants using extraoral cementation technique (ECT) and ZnO cement. All patients were followed for 6 months and investigated for decementation. Seven events of decementation (incidence: 6.19%) were found in 7 patients (8.24%). ECT may represent a viable cementation technique for implant-supported single crowns, even using low-adhesion cements. PMID- 27479344 TI - Quality of Life in Patients After Maxillectomy and Placement of Prosthetic Obturator. AB - PURPOSE: The aim of this study was to assess quality of life (QoL) and obturator functioning in patients having undergone a maxillectomy as a tumor ablative resection and rehabilitation with a prosthetic obturator. MATERIALS AND METHODS: The University of Washington Quality of Life scale version 4 (UW-QoLv4) and the Obturator Functioning Scale (OFS) were used to evaluate the self-reported QoL and obturator functioning. The effects of demographic and treatment variables on QoL were assessed using age, defect size, postoperative radiotherapy (RT), neck dissection, and dentition. RESULTS: The study included 16 men and 13 women with a mean age of 48.8 years. Of the 29 patients, 16 had a Brown Class 2a or smaller defect and 13 had a Brown Class 2b or larger defect. The mean OFS score (P = .004) and the physical (P = .001) and social-emotional function scores (P = .001) of the patients who received postoperative RT were significantly lower than those who did not receive postoperative RT. The subscales for swallowing (P = .008), saliva (P = .001), pain (P = .001), and shoulder function (P = .002) correlated strongly with postoperative RT on the UW-QoL. The subscales for pronunciation (P = .007) and saliva (P = .002) correlated significantly with RT on the OFS. The mean OFS scores were significantly lower for the patients with a Brown Class 2a or smaller defect than for Brown Class 2b or larger (P = .005). CONCLUSION: Postoperative RT was the strongest variable affecting QoL in patients with maxillectomy and prosthetic obturator reconstruction. The size of the defect slightly influenced the obturator function; however, it did not influence the overall QoL. PMID- 27479346 TI - Five-Year Retrospective Assay of Implant Treatments and Complications in Private Practice: Restorative Treatment Profiles of Single and Short-Span Implant Supported Fixed Prostheses. AB - PURPOSE: The aim of this study was to describe and analyze the restoration profiles of 5,491 implant-supported single crowns, fixed partial dentures (FPDs), and splinted restorations prescribed between January 2005 and December 2009. MATERIALS AND METHODS: Dental clinicians qualified in or before December 2004, registered in Victoria, and placing and/or restoring implants in private practice were invited to participate in the study. Data was extracted by two trained and calibrated research assistants from dental records. Cross tabulation was carried out in SPSS (IBM) to provide descriptive statistics on clinician profiles, patient demographics, and restoration information. RESULTS: A total of 34 practitioners participated in the study: 25 general dentists and 9 specialists. Clinicians that graduated between 1970 and 1989 (16 to 40 years of experience) prescribed most of the prostheses (82.0%). Female patients were present in higher numbers across most age and restoration groups. Of the implant-supported prostheses, 5,491 fit the criteria for simple basic restorations and were included in this report. The majority of the prostheses (86.7%) were single-tooth restorations. Metal-ceramic was the material of choice for the majority of the restorations (3,382/5,491). The use of single implant-supported crowns in the anterior mandible was rare. More than 65% of the implant-supported restorations in this study were screw retained directly to the implant. The specialist clinicians in this study largely used the screw-retained method to retain single implant-supported crowns (82.0%). General dentists provided 1,066% more cement retained single implant-supported crowns compared with other practitioners. CONCLUSION: This report showed that during the period of January 2005 to December 2009, private practice clinicians in Victoria, Australia favored porcelain-fused to-metal material over all-ceramic for implant restorations. Most implant restorations were single crowns. More female patients received implant-supported restorations in the posterior region of the mouth. The clinicians included in this study, particularly the specialists, generally favored a retrievable design in choosing the retention method for the prostheses. PMID- 27479345 TI - Fracture Strength After Fatigue Loading of Lithium Disilicate Pressed Zirconia Crowns. AB - PURPOSE: The aim of this study was to evaluate the fracture resistance of fatigued lithium disilicate pressed zirconia crowns versus other ceramic crowns. MATERIALS AND METHODS: Lithium disilicate pressed zirconia, fluorapatite pressed zirconia, monolithic lithium disilicate, and monolithic zirconia crowns were fabricated. Cyclic and static loadings were applied to the mesiobuccal cusp tip after thermocycling and fracture strengths were recorded. RESULTS: Fatigued lithium disilicate pressed zirconia crowns were found to have a fracture resistance of 9,117.81 +/- 727.04 N, compared with 9,240.61 +/- 887.21 N for monolithic zirconia crowns, 3,030.18 +/- 1,505.83 N for fluorapatite pressed zirconia crowns, and 4,173.94 +/- 877.46 N for monolithic lithium disilicate crowns (P = .001). CONCLUSION: This in vitro study shows that fatigued lithium disilicate pressed zirconia and monolithic zirconia crowns have better fracture resistance than fluorapatite pressed zirconia and monolithic lithium disilicate crowns. PMID- 27479347 TI - Biofilm Affecting the Mechanical Integrity of Implant-Abutment Joints. AB - PURPOSE: This in vitro study evaluated the effect of biofilms on abutment torque loss and wear of implant internal connection surfaces. MATERIALS AND METHODS: Morse taper abutments were torqued to corresponding implants and then the implant abutment assemblies were immersed in a biofilm medium for 72 hours. After detorque evaluation, the abutments were removed and the inner implant surfaces were observed via scanning electron microscopy and profilometry. RESULTS: The removal torque values and the implant damaged areas decreased after contact with biofilms. CONCLUSION: The lubricating effect of biofilms decreased the friction between contacting surfaces, negatively affecting the mechanical integrity of the implant-abutment connection. PMID- 27479348 TI - Effect of Lithium Disilicate Veneers of Different Thickness on the Degree of Conversion and Microhardness of a Light-Curing and a Dual-Curing Cement. AB - PURPOSE: Various materials and systems for bonding lithium disilicate to the tooth substrate are available to clinicians, who can adapt the materials to each clinical situation to maximize the performance of indirect esthetic restorations. This study aimed to evaluate the degree of conversion (DC) and the microhardness (MH) of a dual-curing and a light-curing cement under lithium disilicate discs of different thicknesses. MATERIALS AND METHODS: A total of 48 lithium disilicate (IPS e.max CAD, Ivoclar Vivadent) samples were prepared and divided into three groups (n = 16) according to the thickness (group A was 0.6 mm; group B was 1.0 mm; group C was 1.5 mm). Each group was further divided into two subgroups (n = 8) according to the resin cement employed, NX3 (Kerr) or Choice 2 (Bisco). A standardized quantity of cement was placed on the sample, and DC was evaluated with an attenuated total reflectance Fourier transformed infrared spectrophotometer (Nicolet IS10, Thermo Scientific). Twenty-four hours after DC was established, Vickers test was performed on the cement with a microindentometer (Leica Microsystems). Results were statistically analyzed with analysis of variance test and significance set at P < .05. RESULTS: Statistical analysis showed cement type had a significant influence (P = .005) on DC. MH results were influenced by thicknesses only between 0.6 and 1.5 mm when light cured cement was employed. CONCLUSION: The light-curing and the dual-curing cements reached comparable DCs between 0.6 and 1.5 mm. However, the light-curing resin showed a higher DC and MH. PMID- 27479349 TI - Missing Teeth and Prosthodontic Replacement in an Institutionalized Dentate Population of 60 Years and Older in Qingdao, China. AB - PURPOSE: The aim of this study was to investigate missing teeth and prosthodontic replacements in an institutionalized elderly population in China, and to assess dental functionality before and after the prosthodontic replacements based on a hierarchical dental functional classification (HDFC) system. MATERIALS AND METHODS: A sample of 512 participants (9% aged 60-69 years; 29% aged 70-79 years; 62% aged >= 80 years) living in eight nursing homes in Qingdao were categorized by the HDFC with and without tooth replacements. A functional dentition in the HDFC meets all the following criteria: >= 10 natural teeth in each jaw; a complete anterior region; 3 or 4 posterior occluding pairs (POPs) in the premolar regions; and >= 1 POP bilaterally in the molar region. Participants with tooth replacements were reclassified. The score for effectiveness of replacements were as follows: 4 for >= 10 teeth in each jaw; 3 for a complete anterior region; 2 for 3 or 4 POPs in premolar regions; and 1 for >= 1 molar POP bilaterally. RESULTS: Twenty percent of the participants had functional dentitions, but 42% met none of the functional criteria. In the branch '>= 10 teeth in each jaw' the mean number of teeth present was 26.3 +/- 2.9, and the mean number of POPs was 6.2 +/- 2.0. In the branch '< 10 teeth in each jaw,' there were 13.4 +/- 5.5 teeth and 1.1 +/- 1.5 POPs. Of the 384 participants with natural teeth in each jaw, 44% had no replacements and 56% had fixed dental prostheses (FDPs), partial removable dental prostheses (PRDPs), or both. FDPs usually replaced 1 or 2 teeth, and PRDPs 3 or more teeth. On the basis of natural teeth plus artificial teeth (214 participants with replacements), 46% had functional dentitions while 18% met none of the functional criteria. In the promoted participants, the mean number of teeth added by FDPs was 3.6 +/- 2.5, and for PRDPs it was 11.9 +/- 6.5. FDPs had a significantly higher mean promotion value per tooth added than PRDPs. CONCLUSION: Approximately half the tooth replacements effectively met all criteria for a functional dentition. PMID- 27479350 TI - Predictors of Tooth Loss in Patients Wearing a Partial Removable Dental Prosthesis. AB - PURPOSE: The partial removable dental prosthesis (PRDP) is used widely to replace missing teeth, but it can disturb the ecology of the mouth. In this retrospective cohort study, the null hypothesis was that there was no difference between tooth loss and the type of edentulous spaces in participants wearing PRDPs. MATERIALS AND METHODS: Participants were selected from patients who were treated consecutively with PRDPs between January 2003 and December 2006 by undergraduate dental students at the University of British Columbia and attended the clinic for at least 5 years following placement of the PRDP. Clinical records were analyzed for 50 men and 52 women aged 19 to 85 years at baseline, before placement of the PRDP (mean age: 63.2 years). Baseline data were obtained from the records on missing teeth and edentulous spaces, and thereafter data were collected on teeth lost over the following 5-year period. Baseline data on age, sex, occlusal contacts, number of dental rests for the dentures, carious teeth, gingival attachment loss, and teeth with endodontic fillings were also obtained. RESULTS: The presence at baseline of teeth with endodontic fillings significantly (P < .05) increased the prediction of tooth loss over the 5 years, but the type of edentulous space did not. CONCLUSION: The risk of tooth loss over a 5-year period was higher in the presence of endodontically treated teeth, but no higher in participants wearing PRDPs with distally extended edentulous spaces rather than tooth-bounded edentulous spaces. PMID- 27479351 TI - Handling of Polyvinylsiloxane Versus Polyether for Implant Impressions. AB - PURPOSE: This study compared polyvinylsiloxane with polyether in handling dental impressions. MATERIALS AND METHODS: Each participant (N = 39) made four impressions, each a combination of pickup and reseating techniques with polyether or polyvinylsiloxane, of one implant cast representing a specific clinical situation (tooth gaps, limited residual dentition, or edentulous jaw). Handling of impressions was subsequently rated by using a 12-item questionnaire with 100 mm visual analog scales. RESULTS: While mean satisfaction scores were higher for polyvinylsiloxane than for polyether (69.5/63.0, P < .001), differences among subgroups were statistically significant only for pickup technique, limited residual dentition, and edentulous jaw. CONCLUSION: Implant impressions made with polyvinylsiloxane using a pickup technique seem to be the best option for most clinical situations. PMID- 27479352 TI - Double-Step Image Superimposition Technique for Fabricating a Drilling Guide to Access the Abutment Screw in Implant Prostheses. AB - Limited retrievability is a major disadvantage of cement-retained implant restorations. Despite great progress in locating the abutment screw within crowns, the existing techniques are based on prior data or prefabricated devices and require significant work. This study introduces a new procedure for fabricating a guide template to drill a screw access hole using a double-step superimposition technique that incorporates intraoral optical scanning, cone beam computed tomography, and dental design software. The double-step superimposition technique with computer-aided design/computer-assisted manufacturing technology can enhance the convenience and accuracy of drilling the screw-access hole. PMID- 27479353 TI - Highly tunable plasmonic nanoring arrays for nanoparticle manipulation and detection. AB - The advancement of trapping and detection of nano-objects at very low laser powers in the near-infra-red region (NIR) is crucial for many applications. Singular visible-light nano-optics based on abrupt phase changes have recently demonstrated a significant improvement in molecule detection. Here, we propose and demonstrate tunable plasmonic nanodevices, which can improve both the trapping field enhancement and detection of nano-objects using singular phase drops in the NIR range. The plasmonic nanostructures, which consist of gaps with dimensions 50 nm * 50 nm connecting nanorings in arrays is discussed. These gaps act as individual detection and trapping sites. The tunability of the system is evident from extinction and reflection spectra while increasing the aperture size in the arrays. Additionally, in the region where the plasmonic nano-array exhibits topologically-protected, near-zero reflection behaviour, the phase displays a rapid change. Our experimental data predict that, using this abrupt phase changes, one can improve the detection sensitivity by 10 times compared to the extinction spectra method. We finally report experimental evidence of 100 nm polystyrene beads trapping using low incident power on these devices. The overall design demonstrates strong capability as an optical, label-free, non-destructive tool for single molecule manipulation where low trapping intensity, minimal photo bleaching and high sensitivity is required. PMID- 27479354 TI - Serial femtosecond crystallography datasets from G protein-coupled receptors. AB - We describe the deposition of four datasets consisting of X-ray diffraction images acquired using serial femtosecond crystallography experiments on microcrystals of human G protein-coupled receptors, grown and delivered in lipidic cubic phase, at the Linac Coherent Light Source. The receptors are: the human serotonin receptor 2B in complex with an agonist ergotamine, the human delta-opioid receptor in complex with a bi-functional peptide ligand DIPP-NH2, the human smoothened receptor in complex with an antagonist cyclopamine, and finally the human angiotensin II type 1 receptor in complex with the selective antagonist ZD7155. All four datasets have been deposited, with minimal processing, in an HDF5-based file format, which can be used directly for crystallographic processing with CrystFEL or other software. We have provided processing scripts and supporting files for recent versions of CrystFEL, which can be used to validate the data. PMID- 27479355 TI - Low-frequency nonsynonymous variants in FKBPL and ARPC1B genes are associated with breast cancer risk in Chinese women. AB - Genome-wide association studies have reported more than 100 independent common loci associated with breast cancer risk. The contribution of low-frequency or rare variants to breast cancer susceptibility has not been well explored. Thus, we applied exome chip to genotype >200 000 low-frequency and rare variants in 1064 breast cancer cases and 1125 cancer-free controls and subsequently validated promising associations in another 1040 breast cancer cases and 1240 controls. We identified two low-frequency nonsynonymous variants at FKBPL (rs200847762, OR = 0.34, 95% CI = 0.20-0.57, P = 4.31 * 10-5 ) and ARPC1B (rs1045012, OR = 0.56, 95% CI = 0.43-0.74, P = 4.30 * 10-5 ) associated with breast cancer risk. In stratification analyses, we found that the protective effect of rs200847762 was stronger in ER-positive breast cancer (OR = 0.18, 95% CI = 0.06-0.42) than that in ER-negative one (OR = 0.59, 95% CI = 0.31-1.05). Our findings indicate that low-frequency variants may also contribute to breast cancer susceptibility and genetic variants in 6p21.33 and 7q22.1 are important in breast carcinogenesis. (c) 2016 Wiley Periodicals, Inc. PMID- 27479356 TI - Formation and fates of nitrosamines and their formation potentials from a surface water source to drinking water treatment plants in Southern Taiwan. AB - Nitrosamines are toxic and emerging disinfection byproducts. In this study, three drinking water treatment plants (DWTPs) in southern Taiwan treating the same source water in Gaoping River with comparable technologies were selected. The objective was to evaluate the formation and fates of six nitrosamines and their formation potentials (FPs) from a surface water source to drinking water. Albeit decreased further downstream in the river, four nitrosamine-FPs were observed in the source water due to anthropogenic pollution in the upstream areas. In the DWTPs, nitrosamines were formed and NDMA was the main species. While high organic carbon concentrations indicated elevated nitrosamine-FPs in the source water, NDMA formation in the DWTPs was more positively associated with reductions of water parameters that quantify organic matters with double bonded ring structures. Although precursor removal via pre-oxidation is a viable approach to limit nitrosamine formation during post-disinfection, this study clearly indicates that a great portion of NDMA in treated water has been formed in the 1st oxidation step of drinking water treatment. The pre-oxidation simulations in the lab demonstrated the impact of pre-chlorination on nitrosamine formation. Given the limited removal in conventional treatment processes, avoiding nitrosamine-FPs in sources and/or nitrosamine formation during pre-oxidation become important issues to control the threats of nitrosamines in drinking water. Under current circumstance in which pre-oxidation is widely used to optimize the treatment effectiveness in many DWTPs, its adverse effect by forming nitrosamines needs to be carefully minimized and using technologies other than pre chlorination (e.g., pre-ozonation) may be considered. PMID- 27479357 TI - Using Discordance in Monozygotic Twins to Understand Causality of Cardiovascular Disease Risk Factors. PMID- 27479358 TI - Micro-scale and rapid expression screening of highly expressed and/or stable membrane protein variants in Saccharomyces cerevisiae. AB - Purification of milligram quantities of target proteins is required for structural and biophysical studies. However, mammalian membrane proteins, many of which are important therapeutic targets, are too unstable to be expressed in heterologous hosts and to be solubilized by detergents. One of the most promising ways to overcome these limitations is to stabilize the membrane proteins by generating variants via introduction of truncated flexible regions, fusion partners, and site-directed mutagenesis. Therefore, an effective screening strategy is a key to obtaining successful protein stabilization. Herein, we report the micro-scale and high-throughput screening of stabilized membrane protein variants using Saccharomyces cerevisiae as a host. All steps of the screening, including cultivation and disruption of cells, solubilization of the target protein, and the pretreatment for fluorescence-detected size exclusion chromatography (FSEC), could be performed in a 96-well microplate format. We demonstrated that the dispersion among wells was small, enabling detection of a small but important improvement in the protein stability. We also demonstrated that the thermally stable mutants of a human G protein-coupled receptor could be distinguished based on an increase of the peak height in the FSEC profile, which was well correlated with increased ligand binding activity of the protein. This strategy represents a significant platform for handling numerous mutants, similar to alanine scanning. PMID- 27479359 TI - Role of W181 in modulating kinetic properties of Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase. AB - Hypoxanthine-guanine-xanthine phosphoribosyltransference (HGXPRT), a key enzyme in the purine salvage pathway of the malarial parasite, Plasmodium falciparum (Pf), catalyses the conversion of hypoxanthine, guanine, and xanthine to their corresponding mononucleotides; IMP, GMP, and XMP, respectively. Out of the five active site loops (I, II, III, III', and IV) in PfHGXPRT, loop III' facilitates the closure of the hood over the core domain which is the penultimate step during enzymatic catalysis. PfHGXPRT mutants were constructed wherein Trp 181 in loop III' was substituted with Ser, Thr, Tyr, and Phe. The mutants (W181S, W181Y and W181F), when examined for xanthine phosphoribosylation activity, showed an increase in Km for PRPP by 2.1-3.4 fold under unactivated condition and a decrease in catalytic efficiency by more than 5-fold under activated condition as compared to that of the wild-type enzyme. The W181T mutant showed 10-fold reduced xanthine phosphoribosylation activity. Furthermore, molecular dynamics simulations of WT and in silico W181S/Y/F/T PfHGXPRT mutants bound to IMP.PPi.Mg2+ have been carried out to address the effect of the mutation of W181 on the overall dynamics of the systems and identify local changes in loop III'. Dynamic cross-correlation analyses show a communication between loop III' and the substrate binding site. Differential cross-correlation maps indicate altered communication among different regions in the mutants. Changes in the local contacts and hydrogen bonding between residue 181 with the nearby residues cause altered substrate affinity and catalytic efficiency of the mutant enzymes. Proteins 2016; 84:1658-1669. (c) 2016 Wiley Periodicals, Inc. PMID- 27479360 TI - Unique Clones of Vibrio cholerae O1 El Tor with Haitian Type ctxB Allele Implicated in the Recent Cholera Epidemics from Nigeria, Africa. AB - BACKGROUND AND OBJECTIVES: The antimicrobial susceptibility patterns and genetic characteristics of Vibrio cholerae O1, which is responsible for several cholera epidemics in Nigeria, are not reported in detail since 2007. In this study, we screened V. cholerae O1 El Tor biotype isolates from cholera cases and water samples from different states to investigate their phenotypic and genetic attributes with special reference to their clonality. RESULTS: All the V. cholerae O1 biotype El Tor isolates isolated during 2007-2013 were susceptible to fluoroquinolones and tetracycline, the drugs currently used in the treatment of cholera cases in Nigeria. Emergence of CT genotype 7 (Haitian type of ctxB allele) was predominantly seen among Ogawa serotype and the CT genotype 1 (classical ctxB allele) was mostly found in Inaba serotype. Overall, V. cholerae O1 from clinical and water samples were found to be closely related as determined by the pulsed-field gel electrophoresis. V. cholerae isolates from Abia, Kano and Bauchi were found to be genetically distinct from the other states of Nigeria. CONCLUSION: Fecal contamination of the water sources may be the possible source of the cholera infection. Combined prevalence of Haitian and classical ctxB alleles were detected in Ogawa and Inaba serotypes, respectively. This study further demonstrated that V. cholerae O1 with the ctxB has been emerged similar to the isolates reported in Haiti. Our findings suggest that the use of fluoroquinolones or tetracycline/doxycycline may help in the effective management of acute cholera in the affected Nigerian states. In addition, strengthening the existing surveillance in the hospitals of all the states and supply of clean drinking water may control cholera outbreaks in the future. PMID- 27479361 TI - Dinuclear metal(ii)-acetato complexes based on bicompartmental 4-chlorophenolate: syntheses, structures, magnetic properties, DNA interactions and phosphodiester hydrolysis. AB - A series of dinuclear metal(ii)-acetato complexes: [Ni2(MU-L(Cl)O)(MU2 OAc)2](PF6).3H2O (1), [Ni2(MU-L(Cl)O)(MU2-OAc)2](ClO4).CH3COCH3 (2), [Cu2(MU L(Cl)O)(MU2-OAc)(ClO4)](ClO4) (3), [Cu2(MU-L(Cl)O)(OAc)2](PF6).H2O (4), [Zn2(MU L(Cl)O)(MU2-OAc)2](PF6) (5) and [Mn2(L(Cl)-O)(MU2-OAc)2](ClO4).H2O (6), where L(Cl)O(-) = 2,6-bis[bis(2-pyridylmethyl)aminomethyl]-4-chlorophenolate, were synthesized. The complexes were structurally characterized by spectroscopic techniques and single crystal X-ray crystallography. Six-coordinate geometries with doubly bridged acetato ligands were found in Ni(ii), Zn(ii) and Mn(ii) complexes 1, 2, 5 and 6, whereas with Cu(ii) complexes a five-coordinate species was obtained with 4, and mixed five- and six-coordinate geometries with a doubly bridged dimetal core were observed in 3. The magnetic properties of complexes 1-4 and 6 were studied at variable temperatures and revealed weak to very weak antiferromagnetic interactions in 1, 2, 4 and 6 (J = -0.55 to -9.4 cm(-1)) and ferromagnetic coupling in 3 (J = 15.4 cm(-1)). These results are consistent with DFT calculations performed at the B3LYP/def2-TZVP(-f) level of theory. Under physiological conditions, the interaction of the dinculear complexes 1-5 with supercoiled plasmid ds-DNA did not show any pronounced nuclease activity, but Ni(ii) complexes 1 and 2 revealed a strong ability to unwind the supercoiled conformation of ds-DNA. The mechanistic studies performed on the interaction of the Ni(ii) complexes with DNA demonstrated the important impact of the nickel(ii) ion in the unwinding process. In combination with the DNA study, the phosphatase activity of complexes 1, 3, and 5 was examined by the phosphodiester hydrolysis of bis(2,4-dinitrophenol)phosphate (BDNPP) in the pH range of 5.5-10.5 at 25 degrees C. The Michaelis-Menten kinetics performed at pH 7 and 10.7 showed that catalytic efficiencies kcat/KM (kcat = catalytic rate constant, KM = substrate binding constant) decrease in the order: Ni(ii), 1 > Zn(ii), 5 > Cu(ii), 3. A similar trend was also observed with the turnover numbers at pH = 7. The results are discussed in relation to the coordination geometry and nature of the metal center as well as the steric environment imposed by the compartmental phenoxido ligand. PMID- 27479362 TI - Having Medicaid insurance negatively impacts outcomes in patients with head and neck malignancies. AB - BACKGROUND: Patients covered by Medicaid insurance appear to have poorer cancer outcomes. Herein, the authors sought to test whether Medicaid was associated with worse outcomes among patients with head and neck cancer (HNC). METHODS: The records of 1698 patients with squamous cell HNC without distant metastatic disease were retrospectively reviewed from an institutional database between 1998 and 2011. At the time of diagnosis, insurance status was categorized as Medicaid, Medicare/other government insurance, or private insurance. Outcomes including locoregional control (LRC) and overall survival (OS) were estimated using the Kaplan-Meier method and Cox regression multivariate analysis (MVA). RESULTS: The median follow-up for all patients was 35 months. Medicaid patients comprised 11% of the population; the remaining patients were privately insured (56%) or had Medicare/government insurance (34%). On MVA, Medicaid patients were younger, were current smokers, had higher tumor T and N classifications, and experienced a longer time from diagnosis to treatment initiation (all P<.005). Medicaid insurance status was associated with a deficit of 13% in LRC (69% vs 82%) and 26% in OS (46% vs 72%) at 3 years (all with P<.001). A time from diagnosis to treatment initiation of >45 days was found to be associated with worse 3-year LRC (77% vs 83%; P = .009) and OS (68% vs 71%; P = .008). On MVA, Medicaid remained associated with a deficit in LRC (P = .002) and OS (P<.001). CONCLUSIONS: Patients with Medicaid insurance more often present with locally advanced HNC and experience a higher rate of treatment delays compared with non-Medicaid patients. Medicaid insurance status appears to be independently associated with deficits in LRC and OS. Improvements in the health care system, such as expediting treatment initiation, may improve the outcomes of patients with HNC. Cancer 2016;122:3529 3537. (c) 2016 American Cancer Society. PMID- 27479363 TI - Methods for the Detection of Autophagy in Mammalian Cells. AB - Macroautophagy (hereafter referred to as autophagy) is a degradation pathway that delivers cytoplasmic materials to lysosomes via double-membraned vesicles designated autophagosomes. Cytoplasmic constituents are sequestered into autophagosomes, which subsequently fuse with lysosomes, where the cargo is degraded. Autophagy is a crucial mechanism involved in many aspects of cell function, including cellular metabolism and energy balance; alterations in autophagy have been linked to various human pathological processes. Thus, methods that accurately measure autophagic activity are necessary. In this unit, we introduce several approaches to analyze autophagy in mammalian cells, including immunoblotting analysis of LC3 and p62, detection of autophagosome formation by fluorescence microscopy, and monitoring autophagosome maturation by tandem mRFP GFP fluorescence microscopy. Overall, we recommend a combined use of multiple methods to accurately assess the autophagic activity in any given biological setting. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479366 TI - Metal Nitrides Grown from Ca/Li Flux: Ca6Te3N2 and New Nitridoferrate(I) Ca6(LixFe1-x)Te2N3. AB - Two new tellurium-containing nitrides were grown from reactions in molten calcium and lithium. The compound Ca6Te3N2 crystallizes in space group R3c (a = 12.000(3)A, c = 13.147(4)A; Z = 6); its structure is an anti-type of rinneite (K3NaFeCl6) and 2H perovskite related oxides such as Sr3Co2O6. The compound Ca6(LixFe1-x)Te2N3 where x ~ 0.48 forms in space group P42/m (a = 8.718(3)A, c = 6.719(2)A; Z = 2) with a new stuffed anti-type variant of the Tl3BiCl6 structure. Band structure calculations and easily observable red/green dichroic behavior indicate that Ca6Te3N2 is a highly anisotropic direct band gap semiconductor (Eg = 2.5 eV). Ca6(LixFe1-x)Te2N3 features isolated linear N-Fe-N units with iron in the rare Fe(1+) state. The magnetic behavior of the iron site was characterized by magnetic susceptibility measurements, which indicate a very high magnetic moment (5.16MUB) likely due to a high degree of spin-orbit coupling. Inherent disorder at the Fe/Li mixed site frustrates long-range communication between magnetic centers. PMID- 27479365 TI - A High-Throughput Screening Assay to Identify Kidney Toxic Compounds. AB - Kidney toxicity due to drugs and chemicals poses a significant health burden for patients and a financial risk for pharmaceutical companies. However, currently no sensitive and high-throughput in vitro method exists for predictive nephrotoxicity assessment. Primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated epithelial cells, making them a desirable model to use in in vitro screening systems. Additionally, heme oxygenase 1 (HO-1) protein expression is upregulated as a protective mechanism during kidney toxicant-induced oxidative stress or inflammation in HPTECs and can therefore be used as a biomarker for nephrotoxicity. In this article, we describe two different methods to screen for HO-1 increase: A homogeneous time resolved fluorescence (HTRF) assay and an immunofluorescence assay. The latter provides lower throughput but higher sensitivity due to the combination of two readouts, HO-1 intensity and cell number. The methods described in the protocol are amendable for other cell types as well. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479364 TI - In Vivo Determination of Mitochondrial Function Using Luciferase-Expressing Caenorhabditis elegans: Contribution of Oxidative Phosphorylation, Glycolysis, and Fatty Acid Oxidation to Toxicant-Induced Dysfunction. AB - Mitochondria are a target of many drugs and environmental toxicants; however, how toxicant-induced mitochondrial dysfunction contributes to the progression of human disease remains poorly understood. To address this issue, in vivo assays capable of rapidly assessing mitochondrial function need to be developed. Here, using the model organism Caenorhabditis elegans, we describe how to rapidly assess the in vivo role of the electron transport chain, glycolysis, or fatty acid oxidation in energy metabolism following toxicant exposure, using a luciferase-expressing ATP reporter strain. Alterations in mitochondrial function subsequent to toxicant exposure are detected by depleting steady-state ATP levels with inhibitors of the mitochondrial electron transport chain, glycolysis, or fatty acid oxidation. Differential changes in ATP following short-term inhibitor exposure indicate toxicant-induced alterations at the site of inhibition. Because a microplate reader is the only major piece of equipment required, this is a highly accessible method for studying toxicant-induced mitochondrial dysfunction in vivo. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479368 TI - Multiple reproductive barriers separate recently diverged sunflower ecotypes. AB - Measuring reproductive barriers between groups of organisms is an effective way to determine the traits and mechanisms that impede gene flow. However, to understand the ecological and evolutionary factors that drive speciation, it is important to distinguish between the barriers that arise early in the speciation process and those that arise after speciation is largely complete. In this article, we comprehensively test for reproductive isolation between recently diverged (<10,000 years bp) dune and nondune ecotypes of the prairie sunflower, Helianthus petiolaris. We find reproductive barriers acting at multiple stages of hybridization, including premating, postmating-prezygotic, and postzygotic barriers, despite the recent divergence. Barriers include extrinsic selection against immigrants and hybrids, a shift in pollinator assemblage, and postpollination assortative mating. Together, these data suggest that multiple barriers can be important for reducing gene flow in the earliest stages of speciation. PMID- 27479367 TI - Rheumatoid arthritis: previously untreated early disease. AB - INTRODUCTION: Rheumatoid arthritis is a chronic autoimmune disease, which most often presents as a symmetrical polyarthritis of the hands and feet. Pharmacological treatments include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs) and other disease-modifying anti-rheumatoid drugs (DMARDs), which may be synthetic (either conventional [csDMARDs] or targeted [tsDMARDs]) or biological (bDMARDs). METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of methotrexate in combination with other csDMARDs versus methotrexate monotherapy in people with rheumatoid arthritis who have not previously received any DMARD treatment (first-line treatment)? What are the effects of bDMARDs as monotherapy versus methotrexate or other csDMARDs in people with rheumatoid arthritis who have not previously received any DMARD treatment (first-line treatment)? What are the effects of bDMARDs in combination with methotrexate versus methotrexate monotherapy or other csDMARDs in people with rheumatoid arthritis who have not previously received any DMARD treatment (first line treatment)? What are the effects of glucocorticoids in combination with methotrexate or with other csDMARDs versus methotrexate or other csDMARDs in people with rheumatoid arthritis who have not previously received any DMARD treatment (first-line treatment)? We searched: Medline, Embase, The Cochrane Library and other important databases up to December 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 2058 studies. Of the full articles evaluated, 10 systematic reviews, 22 RCTs, and one follow-up report were added at this update. We performed a GRADE evaluation for 18 PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for 22 comparisons based on information about the effectiveness and safety of bDMARDs (monotherapy or combined with csDMARDs), csDMARDs (monotherapy or combined with other csDMARDs), glucocorticoids combined with methotrexate or other csDMARDs, and methotrexate (monotherapy or combined with other csDMARDs), identifying interventions which were likely or unlikely to be beneficial. PMID- 27479369 TI - Additive Effect of Risk Factors for Trabeculectomy Failure in Glaucoma Patients: A Risk-group From a Cohort Study. AB - PURPOSE OF THE STUDY: The purpose of the study was to assess the role of significant risk factors and develop a risk-group category related to the trabeculectomy (Trab) failure. MATERIALS AND METHODS: A retrospective cohort study was developed between January 2009 and June 2014. In total, 120 eyes included in this study had a glaucoma diagnosis and undergone to Trab with mitomycin. The main outcome measures were surgical success and failure rate. Multivariate (Cox proportional hazards regression model) analyses were used to examine the predictive value of significant factors. A risk-group category was build based on the number of significant risk factors for patients. The risk group category was tested using the Kaplan-Meier method and log-rank test. RESULTS: With a median follow-up of 33 months (3 to 72 mo), the complete surgical success in 1, 2, 3, and 4 years was 82%, 63.5%, 52%, and 27.6%, respectively. The probability of freedom from a complete surgical failure was 88%, 84.5%, 78%, and 70% in 1, 2, 3, and 4 years, respectively. Glaucoma type (P=0.008), previous ophthalmic surgery (P=0.04), glaucoma medication use >=3 years (P=0.010) and 4 glaucoma medication use pre-Trab (P=0.038) were identified as risk factors for surgical failure. The probability of freedom of surgical failure in 3 years was 93%, 83%, and 37.6% (P=0.003), for low (no factors), intermediate (1 to 2 factors), and high-risk group (3 to 4 factors). CONCLUSIONS: Trab with mitomycin produces satisfactory intraocular pressure control over time. However, several risk factors influence the efficacy of the surgical procedure. Our data show that there seems to exist an additive effect among risk factors with similar pathophysiology. PMID- 27479370 TI - Ethnicity and Deprivation are Associated With Blindness Among Adults With Primary Glaucoma in Nigeria: Results From the Nigeria National Blindness and Visual Impairment Survey. AB - PURPOSE: We explored the risk factors for glaucoma blindness among adults aged 40 years and above with primary glaucoma in Nigeria. PARTICIPANTS AND METHODS: A total of 13,591 participants aged 40 years and above were examined in the Nigeria Blindness Survey; 682 (5.02%; 95 CI, 4.60%-5.47%) had glaucoma by ISGEO's criteria. This was a case-control study (n=890 eyes of 629 persons): glaucoma blind persons were cases and glaucoma not-blind were controls. Education and occupation were used to determine socioeconomic status scores, which were divided into 3 tertiles (affluent, medium, deprived). We assessed sociodemographic, biophysical, and ocular factors by logistic regression analysis for association with glaucoma blindness. Multinomial regression analysis was also performed with nonglaucoma as the reference category. RESULTS: A total of 119/629 (18.9%; 95% CI, 15.9%-22.4%) persons were blind in both eyes; 510 were controls. There was interethnic variation in odds of blindness; age, male sex, socioeconomic status, prior diagnosis of glaucoma, hypertension, intraocular pressure, and lens opacity were associated with glaucoma blindness. Axial length, mean ocular perfusion pressure, and angle-closure glaucoma were associated with blind glaucoma eyes. In multivariate analysis, Igbo ethnicity (OR=2.79; 95% CI, 1.03-7.57) had higher risk as was being male (OR=4.59; 95% CI, 1.73-12.16) and unmarried (OR=2.50; 95% CI, 1.03-6.07). Deprivation (OR=3.57; 95% CI, 1.46-8.72), prior glaucoma diagnosis (OR=5.89; 95% CI, 1.79-19.40), and intraocular pressure (OR=1.07; 95% CI, 1.04-1.09) were also independent risk factors for glaucoma blindness. CONCLUSION: Approximately 1 in 5 people with primary glaucoma were blind. Male sex, ethnicity and deprivation were strongly associated with blindness. Services for glaucoma need to improve in Nigeria, focusing on poor communities and men. PMID- 27479371 TI - Re: Guideline of Guidelines: Follow-up after Nephrectomy for Renal Cell Carcinoma. PMID- 27479372 TI - Re: Urinary Fistula after Robot-Assisted Partial Nephrectomy: A Multicentre Analysis of 1,791 Patients. PMID- 27479373 TI - Re: Prediction of Pulmonary Metastasis in Renal Cell Carcinoma Patients with Indeterminate Pulmonary Nodules. PMID- 27479374 TI - Re: Computed Tomography Contrast Enhancement following Renal Cryoablation-Does it Represent Treatment Failure? PMID- 27479375 TI - Re: Whole-Exome Sequencing of Muscle-Invasive Bladder Cancer Identifies Recurrent Mutations of UNC5C and Prognostic Importance of DNA Repair Gene Mutations on Survival. PMID- 27479376 TI - Re: The Association of ABO Blood Type with Disease Recurrence and Mortality among Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy. PMID- 27479377 TI - Re: Effectiveness of Adjuvant Chemotherapy for Locally Advanced Bladder Cancer. PMID- 27479378 TI - Re: The Correlation of Media Ranking's "Best" Hospitals and Surgical Outcomes following Radical Cystectomy for Urothelial Cancer. PMID- 27479379 TI - Re: Risk Group and Death from Prostate Cancer: Implications for Active Surveillance in Men with Favorable Intermediate-Risk Prostate Cancer. PMID- 27479380 TI - Re: Adverse Health Events following Intermittent and Continuous Androgen Deprivation in Patients with Metastatic Prostate Cancer. PMID- 27479381 TI - Re: Gleason Misclassification Rate is Independent of Number of Biopsy Cores in Systematic Biopsy. PMID- 27479382 TI - Re: Focal Ablation Targeted to the Index Lesion in Multifocal Localised Prostate Cancer: A Prospective Development Study. PMID- 27479383 TI - Re: Molecular Imaging of Prostate Cancer. PMID- 27479384 TI - Re: Cardiovascular Disease Mortality after Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study. PMID- 27479385 TI - Re: Urinary Tract Infections in Older Men. PMID- 27479386 TI - Re: Uropathogenic Escherichia coli Induces Chronic Pelvic Pain. PMID- 27479387 TI - Re: Infections after Fiducial Marker Implantation for Prostate Radiotherapy: Are we Underestimating the Risks? PMID- 27479388 TI - Re: Do Urologists Follow the Golden Rule? A Global Urolithiasis Management Study by the Clinical Research Office of the Endourological Society. PMID- 27479389 TI - Re: Ways of Calcium Reabsorption in the Kidney. PMID- 27479390 TI - Re: Two-Sided Urethra-Sparing Reconstruction Combining Dorsal Preputial Skin plus Ventral Buccal Mucosa Grafts for Tight Bulbar Strictures. PMID- 27479392 TI - Re: Substitution Urethroplasty or Anastomotic Urethroplasty for Bulbar Urethra Strictures? Or Endoscopic Urethrotomy? Opinion: Substitution Urethroplasty. PMID- 27479391 TI - Re: The Vascular and Neurogenic Factors Associated with Erectile Dysfunction in Patients after Pelvic Fractures. PMID- 27479393 TI - Re: The Impact of Transtomal Rigid Endoscopy in Continent Cutaneous Urinary Diversions. PMID- 27479394 TI - Re: Postoperative Care Using a Secure Online Patient Portal: Changing the (Inter)Face of General Surgery. PMID- 27479395 TI - Re: Surgical Checklist Implementation Project: The Impact of Variable WHO Checklist Compliance on Risk-Adjusted Clinical Outcomes after National Implementation: A Longitudinal Study. PMID- 27479396 TI - Re: The Relationship between Urinary Total Polyphenols and the Frailty Phenotype in a Community-Dwelling Older Population: The InCHIANTI Study. PMID- 27479397 TI - Re: Do Surgical Trainees Believe They are Adequately Trained to Manage the Ageing Population? A UK Survey of Knowledge and Beliefs in Surgical Trainees. PMID- 27479398 TI - Re: Cytokines and Postoperative Delirium in Older Patients Undergoing Major Elective Surgery. PMID- 27479399 TI - Re: Cost-Effectiveness of an Internet-Based Treatment Program for Stress Urinary Incontinence. PMID- 27479400 TI - Re: Comparison of Short Term Outcomes of Sacral Nerve Stimulation and Intradetrusor Injection of OnabotulinumtoxinA (Botox) in Women with Refractory Overactive Bladder. PMID- 27479401 TI - Re: Guideline of Guidelines: Urinary Incontinence. PMID- 27479402 TI - Re: Does Defective Volume Sensation Contribute to Detrusor Underactivity? PMID- 27479403 TI - Re: External Urethral Sphincter Electromyography in Asymptomatic Women and the Influence of the Menstrual Cycle. PMID- 27479404 TI - Re: A Review of Detrusor Overactivity and the Overactive Bladder after Radical Prostate Cancer Treatment. PMID- 27479405 TI - Re: Effect of Weight Reduction on the Severity of Lower Urinary Tract Symptoms in Obese Male Patients with Benign Prostatic Hyperplasia: A Randomized Controlled Trial. PMID- 27479406 TI - Re: Long-Term Safety and Efficacy of Single-Tablet Combinations of Solifenacin and Tamsulosin Oral Controlled Absorption System in Men with Storage and Voiding Lower Urinary Tract Symptoms: Results from the NEPTUNE Study and NEPTUNE II Open Label Extension. PMID- 27479407 TI - Re: Comparison of Tamsulosin plus Serenoa repens with Tamsulosin in the Treatment of Benign Prostatic Hyperplasia in Korean Men: 1-Year Randomized Open Label Study. PMID- 27479408 TI - Re: Kidney Retransplantation in the Ipsilateral Iliac Fossa: A Surgical Challenge. PMID- 27479409 TI - Re: Estimated GFR for Living Kidney Donor Evaluation. PMID- 27479410 TI - Re: Trends and Outcomes in Right vs. Left Living Donor Nephrectomy: An Analysis of the OPTN/UNOS Database of Donor and Recipient Outcomes-Should We be Doing More Right-Sided Nephrectomies? PMID- 27479411 TI - Re: Robot-Assisted Laparoscopic Donor Nephrectomy vs Standard Laparoscopic Donor Nephrectomy: A Prospective Randomized Comparative Study. PMID- 27479412 TI - Re: A Prospective, Randomized, Placebo-Controlled Trial of On-Demand vs. Nightly Sildenafil Citrate as Assessed by RigiScan and the International Index of Erectile Function. PMID- 27479413 TI - Re: Simultaneous Detection of Three Phosphodiesterase Type 5 Inhibitors and Eight of Their Analogs in Lifestyle Products and Screening for Adulterants by High Performance Thin-Layer Chromatography. PMID- 27479414 TI - Re: Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction during a 6-Month Observational Study (EDATE): Impact of Patient Characteristics and Comorbidities. PMID- 27479415 TI - Re: Effects of Testosterone Treatment in Older Men. PMID- 27479416 TI - Re: Effect of Lifestyle Intervention on the Hormonal Profile of Frail, Obese Older Men. PMID- 27479417 TI - Re: Effects of Testosterone Replacement Therapy on Lower Urinary Tract Symptoms: A Systematic Review and Meta-Analysis. PMID- 27479418 TI - Re: A Pilot Study Using a Web Survey to Identify Characteristics that Influence Hypogonadal Men to Initiate Testosterone Replacement Therapy. PMID- 27479419 TI - Re: Six Months of Daily Treatment with Vardenafil Improves Parameters of Endothelial Inflammation and of Hypogonadism in Male Patients with Type 2 Diabetes and Erectile Dysfunction: A Randomized, Double-Blind, Prospective Trial. PMID- 27479420 TI - Re: Examining Associations between Sexual Behaviours and Quality of Life in Older Adults. PMID- 27479421 TI - Re: Association between Testosterone Supplementation Therapy and Thrombotic Events in Elderly Men. PMID- 27479422 TI - Re: Use of Suboptimal Sperm Increases the Risk of Aneuploidy of the Sex Chromosomes in Preimplantation Blastocyst Embryos. PMID- 27479423 TI - Re: DNA Fragmentation in Brighter Sperm Predicts Male Fertility Independently from Age and Semen Parameters. PMID- 27479424 TI - Re: Cryopreservation of Testicular Tissue before Long-Term Testicular Cell Culture Does Not Alter In Vitro Cell Dynamics. PMID- 27479425 TI - Re: Molecular Karyotyping of Single Sperm with Nuclear Vacuoles Identifies More Chromosomal Abnormalities in Patients with Testiculopathy than Fertile Controls: Implications for ICSI. PMID- 27479426 TI - Re: Subfertility Increases Risk of Testicular Cancer: Evidence from Population Based Semen Samples. PMID- 27479427 TI - Re: Sperm Freezing to Address the Risk of Azoospermia on the Day of ICSI. PMID- 27479428 TI - Re: Spermatogenesis in Hodgkin's Lymphoma Patients: A Retrospective Study of Semen Quality before and after Different Chemotherapy Regimens. PMID- 27479429 TI - Re: Mediterranean and Western Dietary Patterns are Related to Markers of Testicular Function among Healthy Men. PMID- 27479430 TI - Re: Effect of Male Body Mass Index on Live-Birth Sex Ratio of Singletons after Assisted Reproduction Technology. PMID- 27479431 TI - Re: Psychological Stress and Testicular Function: A Cross-Sectional Study of 1,215 Danish Men. PMID- 27479432 TI - Re: The "Flowerpot" Sign: Inference of Poor Renal Function in High Grade Vesicoureteral Reflux by Calyceal Orientation. PMID- 27479433 TI - Re: Renal Function in Survivors of Nonsyndromic Wilms Tumor Treated with Unilateral Radical Nephrectomy. PMID- 27479434 TI - Re: Overall Survival and Renal Function of Patients with Synchronous Bilateral Wilms Tumor Undergoing Surgery at a Single Institution. PMID- 27479435 TI - Re: Failed Hypospadias Repair: An Algorithm for Secondary Reconstruction Using Remaining Local Tissue. PMID- 27479436 TI - Re: Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis. PMID- 27479437 TI - Re: Renal Tubular Dysfunction in Pediatric Urolithiasis: Proteomic Evidence. PMID- 27479438 TI - Re: Stable Inhibitory Activity of Regulatory T Cells Requires the Transcription Factor Helios. PMID- 27479439 TI - Re: Expression Array Analysis of the Hepatocyte Growth Factor Invasive Program. PMID- 27479440 TI - Re: Dietary Flavonoid Fisetin Binds to beta-Tubulin and Disrupts Microtubule Dynamics in Prostate Cancer Cells. PMID- 27479441 TI - Re: Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy. PMID- 27479443 TI - Continued Questions About Whether Avoidance of Proton Pump Inhibitors Can Reduce Risk of Dementia. PMID- 27479442 TI - Surface Immobilization of Human Arginase-1 with an Engineered Ice Nucleation Protein Display System in E. coli. AB - Ice nucleation protein (INP) is frequently used as a surface anchor for protein display in gram-negative bacteria. Here, MalE and TorA signal peptides, and three charged polypeptides, 6*Lys, 6*Glu and 6*Asp, were anchored to the N-terminus of truncated INP (InaK-N) to improve its surface display efficiency for human Arginase1 (ARG1). Our results indicated that the TorA signal peptide increased the surface translocation of non-protein fused InaK-N and human ARG1 fused InaK-N (InaK-N/ARG1) by 80.7% and 122.4%, respectively. Comparably, the MalE signal peptide decreased the display efficiencies of both the non-protein fused InaK-N and InaK-N/ARG1. Our results also suggested that the 6*Lys polypeptide significantly increased the surface display efficiency of K6-InaK-N/ARG1 by almost 2-fold, while also practically abolishing the surface translocation of non protein fused InaK-N, indicating the interesting roles of charged polypeptides in bacteria surface display systems. Cell surface-immobilized K6-InaK-N/ARG1 presented an arginase activity of 10.7 U/OD600 under the optimized conditions of 40 degrees C, pH 10.0 and 1 mM Mn2+, which could convert more than 95% of L Arginine (L-Arg) to L-Ornithine (L-Orn) in 16 hours. The engineered InaK-Ns expanded the INP surface display system, which aided in the surface immobilization of human ARG1 in E. coli cells. PMID- 27479444 TI - Parents' concerns about future pregnancy after stillbirth: a qualitative study. AB - OBJECTIVES: As stillbirth has a devastating impact, it is imperative to understand the importance of clinical and emotional care after stillbirth and how it influences subsequent pregnancies. The aim of the study was to gain insight into the consideration and planning of a subsequent pregnancy by parents in the weeks following stillbirth. DESIGN: A qualitative semi-structured interview format was utilized. Interpretative phenomenological analysis was employed as the analytic strategy. PARTICIPANTS AND SETTING: The recruitment strategy focused on couples whereby the parents of ten stillborn babies were contacted; however, five men declined to participate in the study. The final sample of 15 parents were all Irish: ten of whom were female and five of whom were male. RESULTS: Findings revealed two superordinate themes relating to a subsequent pregnancy after stillbirth: aspirations for future pregnancy and expectations of future care. Parents disclosed how the prospect of a subsequent pregnancy was daunting with fears about the potential loss of another child. Despite these fears, parents' aspirations differed in the days following stillbirth; mothers wished to plan a future pregnancy while fathers were reluctant to consider any pregnancies. Parents were unsure of what to expect in terms of the level of care that would be provided to them in a subsequent pregnancy. Additional appointments at the maternity hospital were considered crucial to provide reassurance during a subsequent pregnancy. CONCLUSIONS: These findings underscore the far-reaching and contrasting effects of stillbirth on parents. These complex needs highlight the importance of the multidisciplinary team approach. PMID- 27479445 TI - Understanding, Monitoring, and Controlling Biofilm Growth in Drinking Water Distribution Systems. AB - In drinking water distribution systems (DWDS), biofilms are the predominant mode of microbial growth, with the presence of extracellular polymeric substance (EPS) protecting the biomass from environmental and shear stresses. Biofilm formation poses a significant problem to the drinking water industry as a potential source of bacterial contamination, including pathogens, and, in many cases, also affecting the taste and odor of drinking water and promoting the corrosion of pipes. This article critically reviews important research findings on biofilm growth in DWDS, examining the factors affecting their formation and characteristics as well as the various technologies to characterize and monitor and, ultimately, to control their growth. Research indicates that temperature fluctuations potentially affect not only the initial bacteria-to-surface attachment but also the growth rates of biofilms. For the latter, the effect is unique for each type of biofilm-forming bacteria; ammonia-oxidizing bacteria, for example, grow more-developed biofilms at a typical summer temperature of 22 degrees C compared to 12 degrees C in fall, and the opposite occurs for the pathogenic Vibrio cholerae. Recent investigations have found the formation of thinner yet denser biofilms under high and turbulent flow regimes of drinking water, in comparison to the more porous and loosely attached biofilms at low flow rates. Furthermore, in addition to the rather well-known tendency of significant biofilm growth on corrosion-prone metal pipes, research efforts also found leaching of growth-promoting organic compounds from the increasingly popular use of polymer-based pipes. Knowledge of the unique microbial members of drinking water biofilms and, importantly, the influence of water characteristics and operational conditions on their growth can be applied to optimize various operational parameters to minimize biofilm accumulation. More-detailed characterizations of the biofilm population size and structure are now feasible with fluorescence microscopy (epifluorescence and CLSM imaging with DNA, RNA, EPS, and protein and lipid stains) and electron microscopy imaging (ESEM). Importantly, thorough identification of microbial fingerprints in drinking water biofilms is achievable with DNA sequencing techniques (the 16S rRNA gene-based identification), which have revealed a prevalence of previously undetected bacterial members. Technologies are now moving toward in situ monitoring of biomass growth in distribution networks, including the development of optical fibers capable of differentiating biomass from chemical deposits. Taken together, management of biofilm growth in water distribution systems requires an integrated approach, starting from the treatment of water prior to entering the networks to the potential implementation of "biofilm-limiting" operational conditions and, finally, ending with the careful selection of available technologies for biofilm monitoring and control. For the latter, conventional practices, including chlorine-chloramine disinfection, flushing of DWDS, nutrient removal, and emerging technologies are discussed with their associated challenges. PMID- 27479446 TI - An Informatics Approach to Reading the Label: Identifying Common Chemical Mixtures in Personal Care Products. PMID- 27479447 TI - Synthetic Nucleic Acids and Treatment of Neurological Diseases. AB - Importance: The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease. Objective: To review the use of ASOs for the treatment of neurological disorders. Evidence Review: Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich's ataxia) and production of active survival motor neuron 2 (SMN2, spinal muscular atrophy). Findings: Many neurological diseases are caused by inappropriate expression of a protein. Mutations may reduce expression of a wild-type protein, and strategies to activate expression may provide therapeutic benefit. For other diseases, a mutant protein may be expressed too highly and methods that reduce mutant protein expression might form the basis for drug development. Synthetic ASOs can recognize cellular RNA and control gene expression. Antisense oligonucleotides are not a new concept, but successful clinical development has proceeded at a slow pace. Advances in ASO chemistry, biological understanding, and clinical design are making successful applications more likely. Conclusions and Relevance: Both laboratory and clinical studies are demonstrating the potential of ASOs as a source of drugs to treat neurological disease. PMID- 27479448 TI - Electrospray-Differential Mobility Hyphenated with Single Particle Inductively Coupled Plasma Mass Spectrometry for Characterization of Nanoparticles and Their Aggregates. AB - The novel hyphenation of electrospray-differential mobility analysis with single particle inductively coupled plasma mass spectrometry (ES-DMA-spICPMS) was demonstrated with the capacity for real-time size, mass, and concentration measurement of nanoparticles (NPs) on a particle-to-particle basis. In this proof of-concept study, the feasibility of this technique was validated through both concentration and mass calibration using NIST gold NP reference materials. A detection limit of 10(5) NPs mL(-1) was determined under current experimental conditions, which is about 4 orders of magnitude lower in comparison to that of a traditional ES-DMA setup using a condensation particle counter as detector. Furthermore, independent and simultaneous quantification of both size and mass of NPs provides information regarding NP aggregation states. Two demonstrative applications include gold NP mixtures with a broad size range (30-100 nm), and aggregated gold NPs with a primary size of 40 nm. Finally, this technique was shown to be potentially useful for real-world samples with high ionic background due to its ability to remove dissolved ions yielding a cleaner background. Overall, we demonstrate the capacity of this new hyphenated technique for (1) clearly resolving NP populations from a mixture containing a broad size range; (2) accurately measuring a linear relationship, which should inherently exist between mobility size and one-third power of ICPMS mass for spherical NPs; (3) quantifying the early stage propagation of NP aggregation with well-characterized oligomers; and (4) differentiating aggregated NPs and nonaggregated states based on the "apparent density" derived from both DMA size and spICPMS mass. PMID- 27479450 TI - Correction to: J Med Food 2016;19(6):569-577. PMID- 27479449 TI - Access and Binding of H2S to Hemeproteins: The Case of HbI of Lucina pectinata. AB - Hydrogen sulfide (H2S) was recently discovered as a gasotransmitter, capable of coordinating to the heme iron of hemeproteins. H2S is unique for its ability to render varying concentrations of the nucleophilic conjugate bases (HS(-) or S(2 )), either as free or bound species with expected outcomes on its further reactivity. There is no direct evidence about which species (H2S, HS(-), or S(2 )) coordinates to the iron. We performed computer simulations to address the migration and binding processes of H2S species to the hemoglobin I of Lucina pectinata, which exhibits the highest affinity for the substrate measured to date. We found that H2S is the most favorable species in the migration from the bulk to the active site, through an internal pathway of the protein. After the coordination of H2S, an array of clustered water molecules modifies the active site environment, and assists in the subsequent deprotonation of the ligand, forming Fe(III)-SH(-). The feasibility of the second deprotonation of the coordinated ligand is also discussed. PMID- 27479451 TI - Biochemical functionalization of peptide nanotubes with phage displayed peptides. AB - The development of a general approach for the biochemical functionalization of peptide nanotubes (PNTs) could open up existing opportunities in both fundamental studies as well as a variety of applications. PNTs are spontaneously assembled organic nanostructures made from peptides. Phage display has emerged as a powerful approach for identifying selective peptide binding motifs. Here, we demonstrate for the first time the biochemical functionalization of PNTs via peptides identified from a phage display peptide library. The phage-displayed peptides are shown to recognize PNTs. These advances further allow for the development of bifunctional peptides for the capture of bacteria and the self assembly of silver particles onto PNTs. We anticipate that these results could provide significant opportunities for using PNTs in both fundamental studies and practical applications, including sensors and biosensors nanoelectronics, energy storage devices, drug delivery, and tissue engineering. PMID- 27479452 TI - Neonatal central venous catheter thrombosis: diagnosis, management, and outcome. AB - Thrombotic occlusion of central venous catheters (CVCs) is a common problem in newborns. No guideline systematically addresses the diagnosis, management, and prevention of this complication. The objective of this review is to establish evidence-based guidance for the management of CVC thrombosis. A comprehensive literature search was conducted from 1948 to 2012. Twenty-six articles fulfilling four criteria - humans, neonates aged less than 28 days, CVC insertion, and English language - were included for analysis. The incidence of thrombosis was 9.2% (308/3332). Singly inserted umbilical venous catheters (UVCs) and peripherally inserted central catheters accounted for more than 80% of all CVCs. Frequently reported thrombotic sites were the hepatic vein, right atrium, and inferior vena cava. Symptoms included distal swelling of affected areas and thrombocytopenia. Increased length of catheter stay, infusion of blood products, and malpositioned UVCs were identified risk factors. The commonest diagnostic investigations confirming thrombosis were echocardiography and ultrasonography. Spontaneous resolution may occur in UVC-related thrombosis but warrants close monitoring. Thrombolysis with urokinase alone or combined with low molecular weight heparin might be effective and well tolerated. Prophylactic heparin increases the duration of catheter usability (P < 0.005, 95% confidence interval 0.35-0.81), decreases catheter occlusion, but may not uniformly prevent thrombosis. CVC-related thrombosis is an underreported complication because events in the majority occur silently. Currently, solid evidence-based recommendations for diagnosis and treatment are not possible. Well designed prospective studies are urgently required to establish a concrete investigational approach to CVC thrombosis and to institute well tolerated therapeutic modalities. PMID- 27479453 TI - Room-Temperature Synthesis of Thiostannates from {[Ni(tren)]2[Sn2S6]}n. AB - The compound {[Ni(tren)]2[Sn2S6]}n (1) (tren = tris(2-aminoethyl)amine, C6H18N4) was successfully applied as source for the room-temperature synthesis of the new thiostannates [Ni(tren)(ma)(H2O)]2[Sn2S6].4H2O (2) (ma = methylamine, CH5N) and [Ni(tren)(1,2-dap)]2[Sn2S6].2H2O (3) (1,2-dap = 1,2-diaminopropane, C3H10N2). The Ni-S bonds in the Ni2S2N8 bioctahedron in the structure of 1 are analyzed with density functional theory calculations demonstrating significantly differing Ni-S bond strengths. Because of this asymmetry they are easily broken in the presence of an excess of ma or 1,2-dap immediately followed by Ni-N bond formation to N donor atoms of the amine ligands thus generating [Ni(tren)(amine)](2+) complexes. The chemical reactions are fast, and compounds 2 and 3 are formed within 1 h. The synthesis concept presented here opens hitherto unknown possibilities for preparation of new thiostannates. PMID- 27479454 TI - Long-term experiments to investigate irreversibility in sorption of pesticides to soil. AB - Experiments investigated irreversibility in pesticide sorption to soil. Sorption behaviour under abiotic conditions was quantified for chlorotoluron, prometryn and hexaconazole in three soils over periods of up to 274 days. An isotope exchange procedure was used whereby sorption of (12)C- and (14)C-pesticide isotopes in shaken suspensions of three soils (56-168 days shaking) was followed by substitution of the isotopes in the liquid phase and a 14-day exchange phase. This was followed by forced isotope exchange where the sorbed (14)C material was exchanged by adding an excess of non-radiolabelled compound. Experiments were concluded with solvent extraction and soil combustion to determine remaining radioactivity. Under conditions of continuous shaking, the pesticide-soil systems took around four months to approach sorption equilibrium, resulting in strong asymmetry between the profiles of exchange for isotopes of all three compounds. Physically entrapped residues were released back into solution under the steep concentration gradient of forced isotope exchange and small amounts of radioactivity were still being released at the termination of the experiment. The profiles of exchange did not deviate markedly from ideal behaviour based on the assumption that sorption is fully reversible. Whilst the timescales for release of sorbed residues back into solution were very long, soil combustion at study termination only yielded <1-2% of applied radioactivity; this confirms that sorption processes under abiotic soil conditions were overwhelmingly reversible for this set of compounds and soils. PMID- 27479456 TI - Synergistic photoelectrochemical reduction of Cr(VI) and oxidation of organic pollutants by g-C3N4/TiO2-NTs electrodes. AB - The g-C3N4/TiO2-NTs electrodes were synthesized by a dip-coating procedure followed by high-temperature annealing used in photoelectrochemical process. From the results, a simultaneous and rapid reduction of Cr(VI) and degradation of phenol in Cr(VI)/phenol system was observed with photoelectrocatalytic activity under UV-visible light irradiation than photocatalytic and electrocatalytic activities. The different kinds of Cr(VI)/organic pollutants systems were also investigated systematically. In addition, different scavengers were also added in Cr(VI)/phenol and Cr(VI)/benzyl alcohol systems to indicate that the hydroxyl radicals and superoxide radicals were the most major active species for the denomination of Cr(VI) and organic pollutants. The intermediates of phenol and benzyl alcohol were also detected during the reaction in order to deduce the photoelectrocatalysis mechanism underg-C3N4/TiO2-NTs electrodes that the charge separation was improved and subsequently electron-transfer efficiency was higher. PMID- 27479455 TI - Ecological risk analysis of pesticides used on irrigated rice crops in southern Brazil. AB - Based on studies conducted in the past decade in the southern region of Brazil to determine residue levels of the pesticides normally used on irrigated rice crops, changes can be observed in relation to the presence of pesticides in the waters of the main river basins in Santa Catarina State. In previous harvests, the presence of residues of 7 pesticides was determined, with the herbicide bentazon and the insecticide carbofuran being the products showing highest frequency. Following toxicological tests conducted with 8 different test organisms, deterministic and probabilistic risk analysis was performed to assess the situation of the river basins in areas used for the production of irrigated rice. Of the species tested, the herbicide bentazon showed greatest toxicity toward plants, but did not present an ecological risk because in the worst-case scenario the highest concentration of this pesticide in the environment is 37 times lower than the lowest EC50/LC50 value obtained in the tests. The insecticide carbofuran, which had the highest toxicity toward the organisms used in the tests, presented an ecological risk in the deterministic analysis, but without any associated probability. The results highlight the need for increased efforts in training farmers in crop management practices and for the continual monitor of water bodies for the presence of pesticide residues. PMID- 27479457 TI - The fingerprints of dioxin-like bromocarbazoles and chlorocarbazoles in selected forest soils in Germany. AB - The occurrence of bromocarbazoles and chlorocarbazoles was studied in 86 forest soil samples from different regions in Germany. Carbazole, 3-chlorocarbazole, 3 bromocarbazole and 3,6-dibromocarbazole were qualitatively detected in the humic layer of 59 soil samples with bromocarbazoles reported here for the first time in soil. Furthermore, the halogenated carbazoles, PCDD/Fs and PCBs were detected in the humic and mineral soil horizons (0-5 cm and 5-10 cm) of a subset of 11 soil samples subjected to quantitative analysis. Concentrations ranged from 0.6 to 267.6 ng/g (carbazole); 0.2-7.2 ng/g (3-bromocarbazole); 0.0-9.1 ng/g (3 chlorocarbazole); 0.2-19.8 ng/g (3,6-dibromocarbazole); 0.4-67.6 ng/g (3,6 dichlorocarbazole); 0.0-0.7 ng/g (PCDDs); 0.0-0.3 ng/g (PCDFs) and 0.0-33.7 ng/g (PCBs). Concentrations decreased with depth and correlated positively to total organic carbon (TOC). When it was based on TOC%, an increase in concentration with depth was observed in most soil samples. With respect to dioxin-like toxicity, 3-bromocarbazole, 3-chlorocarbazole, 3,6-dibromocarbazole and 3,6 dichlorocarbazoles caused induction of CYP1A1-dependent EROD activity in HII4E rat hepatoma cell line. Their relative effect potency after 72 h exposure ranged from 0.00005 to 0.00013 and was directly related to the degree of halogenation with 2,3,7,8-tetrachlorodibenzo-p-dioxin as reference. Furthermore, their contribution to overall soil dioxin-like toxicity was not significant in comparison to PCDD/Fs and PCBs though the sum toxic equivalency was limited to three halogenated carbazole congeners. Bromocarbazoles and chlorocarbazoles are emerging dioxin-like toxic environmental contaminants with potential for wide distribution occurring simultaneously with PCDD/Fs and PCBs. PMID- 27479458 TI - Effects of Montelukast in an Experimental Model of Acute Pancreatitis. AB - BACKGROUND We evaluated the hematological, biochemical, and histopathological effects of Montelukast on pancreatic damage in an experimental acute pancreatitis model created by cerulein in rats before and after the induction of pancreatitis. MATERIAL AND METHODS Forty rats were divided into 4 groups with 10 rats each. The study groups were: the Cerulein (C) group, the Cerulein + early Montelukast (CMe) group, the Cerulein + late Montelukast (CMl) group, and the Control group. The pH, pO2, pCO2, HCO3, leukocyte, hematocrit, pancreatic amylase, and lipase values were measured in the arterial blood samples taken immediately before rats were killed. RESULTS There were statistically significant differences between the C group and the Control group in the values of pancreatic amylase, lipase, blood leukocyte, hematocrit, pH, pO2, pCO2, HCO3, and pancreatic water content, and also in each of the values of edema, inflammation, vacuolization, necrosis, and total histopathological score (P<0.05). When the CMl group and C group were compared, no statistically significant differences were found in any parameter analyzed. When the CMe group was compared with the C group, pancreatic amylase, lipase, pH, PO2, pCO2, HCO3, pancreatic water content, histopathological edema, inflammation, and total histopathological score values were significantly different between the groups (P<0.05). Finally, when the CMe group and the Control group were compared, significant differences were found in all except 2 (leukocyte and pO2) parameters (P<0.05). CONCLUSIONS Leukotriene receptor antagonists used in the late phases of pancreatitis might not result in any benefit; however, when they are given in the early phases or prophylactically, they may decrease pancreatic damage. PMID- 27479459 TI - Torque-angle-velocity Relationships and Muscle Performance of Professional and Youth Soccer Players. AB - Soccer matches consist of a variety of different activities, including repeated sprints. Time to attain velocity (TTAV), load range (LR) and the torque-angle velocity relationship (TAV3D) represent an important measurement of muscle performance, however there are few related studies. The aim of this study was to compare these outcomes between soccer players of different age category. 17 professional (PRO) and 17 under-17 (U17) soccer players were assessed for concentric knee flexion/extension at 60, 120 and 300 degrees /s. For the extensor muscles, differences were found in favor of the U17 group for TTAV and LR outcomes at 120 degrees /s, however, the PRO group maintained higher torques in both movement directions in comparison to the U17 in TAV3D evaluation. These results suggest that muscle performance of the PRO group is more efficient than the U17 group. PMID- 27479460 TI - Incline Treadmill Interval Training: Short vs. Long Bouts and the Effects on Distance Running Performance. AB - This study compared 6 weeks of incline treadmill interval training (INC) performed on a 10% treadmill grade using either sprint-like efforts or slower, longer bouts. 24 individuals were randomly assigned between 2 groups that each completed 2 INC and one 30-min level-grade sessions?wk-1. Training intensities, bout durations and the number of intervals per INC session were the velocity associated with VO2max (Vmax), 30 s and 10-14 (INCShort n=12), and 68%Vmax, ~3 min and 4-6 (INCLong n=12), respectively. All 30-min sessions were at 65%Vmax. Pre- and post-testing assessed VO2max; lactate threshold (VLT); running economy; and time-to-exhaustion at various conditions including 80%Vmax and 20% grade (CFMod). Both groups improved significantly in all tests; additionally, INCShort improved significantly more so in VLT and CFMod despite INCLong performing more than 2 times the running each INC session (P<0.05). Mean effect size (ES) of the relative improvement in a majority of tests revealed a trivial to very large ES of INCShort vs. INCLong training (ES range: 0.05-4.05). We conclude sprint-like INC better than slower, longer INC at improving a key determinant of distance running performance (VLT), and better at preparing individuals for running on courses with a variety of grades. PMID- 27479461 TI - Metallization of Epitaxial VO2 Films by Ionic Liquid Gating through Initially Insulating TiO2 Layers. AB - Ionic liquid gating has been shown to metallize initially insulating layers formed from several different oxide materials. Of these vanadium dioxide (VO2) is of especial interest because it itself is metallic at temperatures above its metal-insulator transition. Recent studies have shown that the mechanism of ionic liquid gated induced metallization is entirely distinct from that of the thermally driven metal-insulator transition and is derived from oxygen migration through volume channels along the (001) direction of the rutile structure of VO2. Here we show that it is possible to metallize the entire volume of 10 nm thick layers of VO2 buried under layers of rutile titanium dioxide (TiO2) up to 10 nm thick. Key to this process is the alignment of volume channels in the respective oxide layers, which have the same rutile structure with clamped in-plane lattice constants. The metallization of the VO2 layers is accompanied by large structural expansions of up to ~6.5% in the out-of-plane direction, but the structure of the TiO2 layer is hardly affected by gating. The TiO2 layers become weakly conducting during the gating process, but in contrast to the VO2 layers, the conductivity disappears on exposure to air. Indeed, even after air exposure, X-ray photoelectron spectroscopy studies show that the VO2 films have a reduced oxygen content after metallization. Ionic liquid gating of the VO2 films through initially insulating TiO2 layers is not consistent with conventional models that have assumed the gate induced carriers are of electrostatic origin. PMID- 27479462 TI - Influence of Fixture Thread Exposure on Marginal Bone Level Around Different Implant Systems: A Preliminary Study in Dogs. AB - PURPOSE: To evaluate the influence of implant neck structures on marginal bone loss around intentionally exposed implant fixtures by histomorphometric analysis. MATERIALS AND METHODS: Twenty-four implants representing 3 implant systems were placed in three dogs; an implant system with SLA surface without microthreads (group A); one with SLA + calcium surface without microthreads (group B); and one with SLA surface with microthreads (group C). The histomorphometric analyses for vertical defect length (VDL), infrabony defect height (IDH), and defect depth (DD) were performed at the buccal and lingual sides of each fixture. RESULTS: The VDL was lower in group A relative to groups B and C on the buccal and lingual sides. The IDH and DD were higher in group A than group C on the buccal and lingual sides; however, no statistically significant differences were noted between the groups in VDL, IDH, and DD on the buccal and lingual sides of the fixtures. CONCLUSIONS: In this preliminary study, marginal bone resorption pattern in the canine mandible varied according to the neck design of each implant fixture. Further studies with larger sample size are needed to confirm the effect of microthreads and surface roughness on the marginal bone loss at the exposed implant fixture. PMID- 27479463 TI - Use of immunohistochemical staining for p16 in gynecological cytology. PMID- 27479464 TI - A newly developed tracheal tube offering 'pressurised sealing' outperforms currently available tubes in preventing cuff leakage: A benchtop study. AB - BACKGROUND: No currently used tracheal tube offers full protection against aspiration of oropharyngeal secretions into the lower airways. OBJECTIVE: We developed a tracheal tube equipped with two polyvinylchloride (PVC) cuffs with a supplementary port opening between the cuffs through which a continuous positive pressure of 5 cmH2O is provided [double-cuffed PVC (PVCdc)]. We compared this PVCdc with four different cuff types (cylindrical PVC, conical PVC, cylindrical polyurethane and conical polyurethane). DESIGN: A comparison study using an in vitro benchtop model of an artificial rigid trachea. INTERVENTIONS: Tracheal tubes were placed in the artificial trachea. Both cuffs were kept inflated at 25 cmH2O. Total 3 ml dyed water was placed above the cuff and leakage recorded under static and dynamic [5 cmH2O positive end-expiratory pressure (PEEP) alone or positive pressure ventilation plus 5 cmH2O PEEP] conditions. At the end of the dynamic experiments, PEEP was zeroed (PEEP alone) or the tracheal tubes were disconnected from the ventilator (positive pressure ventilation plus PEEP). RESULTS: In the static model, leakage flows [medians (range)] were 9.8 (6.2 to 20) for the cylindrical PVC, 1.3 (0.2 to 3.8) for the conical PVC, 0.03 (0.007 to 0.1) for the cylindrical polyurethane, 0.04 (0.003 to 0.2) for the conical polyurethane and 0.0 (0.0 to 0.0) ml min for the PVCdc cuff (P < 0.001, PVCdc vs. all other cuffs). In the dynamic setting, no leakage was detected for up to 60 min with any of the cuffs studied. Loss of PEEP or tracheal tube disconnection resulted in dye inflow alongside all cuffs except for the PVCdc (P < 0.001, PVCdc vs. all other cuffs). CONCLUSION: A 'pressure seal' incorporated in a double cuffed tracheal tube prevented fluid passage into the lower airways. Clinically, this may translate into absence of inflow of bacteriologically contaminated secretions into the lungs and thus a lower incidence of ventilator-associated infection. PMID- 27479465 TI - Tubulins interact with porcine and human S proteins of the genus Alphacoronavirus and support successful assembly and release of infectious viral particles. AB - Coronavirus spike proteins mediate host-cell-attachment and virus entry. Virus replication takes place within the host cell cytosol, whereas assembly and budding occur at the endoplasmic reticulum-Golgi intermediate compartment. In this study we demonstrated that the last 39 amino acid stretches of Alphacoronavirus spike cytoplasmic domains of the human coronavirus 229E, NL63, and the porcine transmissible gastroenteritis virus TGEV interact with tubulin alpha and beta chains. In addition, a partial co-localization of TGEV spike proteins with authentic host cell beta-tubulin was observed. Furthermore, drug induced microtubule depolymerization led to changes in spike protein distribution, a reduction in the release of infectious virus particles and less amount of spike protein incorporated into virions. These data demonstrate that interaction of Alphacoronavirus spike proteins with tubulin supports S protein transport and incorporation into virus particles. PMID- 27479466 TI - Modeling of pharmaceuticals mixtures toxicity with deviation ratio and best-fit functions models. AB - The present study deals with assessment of ecotoxicological parameters of 9 drugs (diclofenac (sodium salt), oxytetracycline hydrochloride, fluoxetine hydrochloride, chloramphenicol, ketoprofen, progesterone, estrone, androstenedione and gemfibrozil), present in the environmental compartments at specific concentration levels, and their mutual combinations by couples against Microtox(r) and XenoScreen YES/YAS(r) bioassays. As the quantitative assessment of ecotoxicity of drug mixtures is an complex and sophisticated topic in the present study we have used two major approaches to gain specific information on the mutual impact of two separate drugs present in a mixture. The first approach is well documented in many toxicological studies and follows the procedure for assessing three types of models, namely concentration addition (CA), independent action (IA) and simple interaction (SI) by calculation of a model deviation ratio (MDR) for each one of the experiments carried out. The second approach used was based on the assumption that the mutual impact in each mixture of two drugs could be described by a best-fit model function with calculation of weight (regression coefficient or other model parameter) for each of the participants in the mixture or by correlation analysis. It was shown that the sign and the absolute value of the weight or the correlation coefficient could be a reliable measure for the impact of either drug A on drug B or, vice versa, of B on A. Results of studies justify the statement, that both of the approaches show similar assessment of the mode of mutual interaction of the drugs studied. It was found that most of the drug mixtures exhibit independent action and quite few of the mixtures show synergic or dependent action. PMID- 27479467 TI - Profiling of Intracellular Metabolites: An Approach to Understanding the Characteristic Physiology of Mycobacterium leprae. AB - Mycobacterium leprae is the causative agent of leprosy and also known to possess unique features such as inability to proliferate in vitro. Among the cellular components of M. leprae, various glycolipids present on the cell envelope are well characterized and some of them are identified to be pathogenic factors responsible for intracellular survival in host cells, while other intracellular metabolites, assumed to be associated with basic physiological feature, remain largely unknown. In the present study, to elucidate the comprehensive profile of intracellular metabolites, we performed the capillary electrophoresis-mass spectrometry (CE-MS) analysis on M. leprae and compared to that of M. bovis BCG. Interestingly, comparison of these two profiles showed that, in M. leprae, amino acids and their derivatives are significantly accumulated, but most of intermediates related to central carbon metabolism markedly decreased, implying that M. leprae possess unique metabolic features. The present study is the first report demonstrating the unique profiles of M. leprae metabolites and these insights might contribute to understanding undefined metabolism of M. leprae as well as pathogenic characteristics related to the manifestation of the disease. PMID- 27479468 TI - A 2-Year Study of Delta 9-tetrahydrocannabinol Concentrations in Drivers: Examining Driving and Field Sobriety Test Performance,. AB - From November 1, 2010 through November 30, 2012, 1204 whole-blood samples were confirmed to contain THC alone or in combination with other drugs out of nearly 5000 Orange County, California, drivers suspected of driving under the influence of drugs. The goal of this study was to examine police reports and drug recognition expert evaluations of THC-positive samples within this 2-year time frame to determine whether there is a correlation between whole-blood THC concentrations and field sobriety tests performance on DRE and non-DRE evaluations. The FSTs prove to be sensitive to impairment by marijuana although as suspected, the findings of this study did not find a correlation between performance on field sobriety tests and the concentration of THC tested in whole blood samples. Driving behaviors were also examined and found to be similar to those seen in alcohol impairment. Future studies examining DRE findings are needed to confirm the results. PMID- 27479469 TI - Selective Inhibition of STAT3 with Respect to STAT1: Insights from Molecular Dynamics and Ensemble Docking Simulations. AB - STAT3 protein, which is known to be involved in cancer development, is a promising target for anticancer therapy. Successful inhibitors of STAT3 should not affect an activity of closely related protein STAT1, which makes their development challenging. The mechanisms of selectivity of several existing STAT3 inhibitors are not clear. In this work, we studied molecular mechanisms of selectivity of 13 experimentally tested STAT3 inhibitors by means of extensive molecular dynamics and ensemble docking simulations. It is shown that all studied inhibitors bind to the large part of the protein surface in an unspecific statistical manner. The binding to the dimerization interface of the SH2 domain, which is usually considered as the main target region, is not energetically preferable. Binding in this region is remarkably similar for STAT1 and STAT3 proteins and cannot explain experimentally observed selectivity toward STAT3. We propose a new mechanism of selectivity called "selectivity by distraction" for existing STAT3 inhibitors. This mechanism is based on equilibrium statistical partitioning of inhibitor molecules between protein domains. The unspecific binding of inhibitors to the DNA-binding and the coil-coil domains is stronger in STAT1 in comparison to STAT3 while the energies of their binding to SH2 domains are comparable. This "distracts" inhibitor molecules from the SH2 domain of STAT1 and leads to higher effective concentration of inhibitors in the vicinity of the SH2 domain of STAT3. PMID- 27479470 TI - Selective Trapping of DNA Using Glass Microcapillaries. AB - We show experimentally that an inexpensive glass microcapillary can accumulate lambda-phage DNA at its tip and deliver the DNA into the capillary using a combination of electro-osmotic flow, pressure-driven flow, and electrophoresis. We develop an efficient simulation model based on the electrokinetic equations and the finite-element method to explain this phenomenon. As a proof of concept for the generality of this trapping mechanism we use our numerical model to explore the effect of the salt concentration, the capillary surface charge, the applied voltage, the pressure difference, and the mobility of the analyte molecules. Our results indicate that the simple microcapillary system has the potential to capture a wide range of analyte molecules based on their electrophoretic mobility that extends well beyond our experimental example of lambda-phage DNA. Our method for separation and preconcentration of analytes therefore has implications for the development of low-cost lab-on-a-chip devices. PMID- 27479471 TI - What's in a Name?: How Conversant are You With the New Alphabet Soup? PMID- 27479472 TI - Fostering and Experiential Understanding of Addiction: Using the Arts in Nursing. PMID- 27479475 TI - Drugs to Treat Overweight and Obesity. PMID- 27479476 TI - Update on Substance Use in Adolescence. AB - With alarming frequency, an individual's first substance use occurs in childhood or adolescence. However, the use of many types of substances among individuals younger than 18 has been gradually declining over the past 6 years, and our understanding of risk factors for youth substance use has improved. Risk factors identified as possibly contributing to a young individual's first encounter with cigarettes or alcohol include parents' own substance use or mental health problems. Mental disorders of children have been implicated in substance use as well. Screening and interventions are available to reduce the frequency and intensity of adolescent substance use and are suggested in the current article. Nurses are in a position to identify adolescents who are at risk for substance use disorders and link the family system to effective intervention. [Journal of Psychosocial Nursing and Mental Health Services, 54(8), 24-27.]. PMID- 27479477 TI - Genetic and Environmental Influences on the Mental Health of Children: A Twin Study. AB - The current study explored the influences of genetic and environmental factors on the mental health of twins between ages 6 and 16. A total of 41 monozygotic (MZ) twins and 35 dizygotic twins were recruited. The psychological attributes and environmental information of children were evaluated. A significant correlation was found between twins in the diagnostic categories of any psychiatric disorder and attention deficit/hyperactivity disorder (ADHD)/hyperkinesis based on the Strengths and Difficulties Questionnaire scale in MZ twins. Furthermore, fathers' authoritarian parenting style was positively correlated with the probability of any psychiatric disorders and oppositional/conduct disorders, whereas mothers' authoritative parenting style was negatively correlated with the probability of any psychiatric disorders and ADHD/hyperkinesis. The probability of emotional disorders was negatively correlated with scores on the Stressful Life Events Scale. These results collectively suggest that genetic and environmental elements, such as parental rearing style and stressful life events, may influence children's mental health. [Journal of Psychosocial Nursing and Mental Health Services, 54(8), 29-34.]. PMID- 27479478 TI - Nonpharmacological Alternatives to Benzodiazepine Drugs for the Treatment of Anxiety in Outpatient Populations: A Literature Review. AB - Overuse of benzodiazepine drugs to treat anxiety, mood, and sleep disorders is a growing problem in clinical practice. GABAergic medications (benzodiazepine drugs in particular) have side effects, drug interactions, and the potential to create tolerance and dependence in users. GABA-enhancing dietary supplements have similar and unique risks. Natural, non-chemical, anxiolytic treatments exist and can be safely recommended to patients. Three such treatments have been the focus of study in the past 20 years: mindfulness, meditation, and yoga. Growing evidence exists that these treatments can be safely recommended to patients with anxiety. [Journal of Psychosocial Nursing and Mental Health Services, 54(8), 35 42.]. PMID- 27479479 TI - Antidepressant Drugs to Electroconvulsive Therapy: Kristina's Story. AB - A mother of three children experienced depression after each delivery. The worst bout occurred after the birth of her third child. Antidepressant drugs helped initially, but a change in dosage caused severe decompensating symptoms that resulted in feelings and thoughts that life is not worth living. Health care providers would not facilitate entry into an inpatient program for help. She was told that unless actively suicidal or homicidal, she could not be admitted to an inpatient unit. None of the prescribed antidepressant medications seemed to work and the physicians said there was nothing else they could do. Family and friends searched for help and found a psychiatrist who recommended electroconvulsive therapy. Kristina tells her story of experiencing depression and recovery. [Journal of Psychosocial Nursing and Mental Health Nursing, 54(8), 43-47.]. PMID- 27479482 TI - Influence of Ancillary Ligands in Dye-Sensitized Solar Cells. AB - Dye-sensitized solar cells (DSSCs) have motivated many researchers to develop various sensitizers with tailored properties involving anchoring and ancillary ligands. Ancillary ligands carry favorable light-harvesting abilities and are therefore crucial in determining the overall power conversion efficiencies. The use of ancillary ligands having aliphatic chains and/or pi-extended aromatic units decreases charge recombination and permits the collection of a large fraction of sunlight. This review aims to provide insight into the relationship between ancillary ligand structure and DSSC properties, which can further guide the function-oriented design and synthesis of different sensitizers for DSSCs. This review outlines how the new and rapidly expanding class of chelating ancillary ligands bearing 2,2'-bipyridyl, 1,10-phenanthroline, carbene, dipyridylamine, pyridyl-benzimidazole, pyridyl-azolate, and other aromatic ligands provides a conduit for potentially enhancing the performance and stability of DSSCs. Finally, these classes of Ru polypyridyl complexes have gained increasing interest for feasible large-scale commercialization of DSSCs due to their more favorable light-harvesting abilities and long-term thermal and chemical stabilities compared with other conventional sensitizers. Therefore, the main idea is to inspire readers to explore new avenues in the design of new sensitizers for DSSCs based on different ancillary ligands. PMID- 27479483 TI - 6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors. AB - Isoform-selective inhibition of PI3K-alpha has been identified as one of the important strategy to discover effective and safer anticancer agents. Herein, we report discovery of 'quinazoline' as a new chemotype for isoform-selective PI3K alpha inhibitors. The indolyl substituted quinazoline 9u displayed selective inhibition of PI3K-alpha with IC50 value of 0.201 MUM with >49.7 over PI3K-beta, and delta-isoforms. Quinazoline 9u also inhibited PI3K-gamma with IC50 value of 0.750 MUM (3.7 fold selective for alpha-versus gamma-isoform). The isoform selective inhibition was also demonstrated at protein-expression level by western blot analysis in MCF-7 and PC-3 cells. The isoform-selective inhibitor 9u also showed inhibition of phospho-Akt levels in these cells. Quinazoline 9u showed in vitro cytotoxicity in MCF-7 cells with GI50 of 7 MUM, which was highly selective for cancer cells, as it was non-toxic to normal cells fR2, HEK293 and hGF (GI50 > 50 MUM). Compound 9u at 25 mg/kg dose showed 62 and 37% TGI in Ehrlich Ascites Carcinoma and Ehrlich Solid Tumor mice models. In nutshell, our efforts to identify potent and efficacious PI3K inhibitors resulted in the discovery of a new class of isoform-selective PI3K-alpha inhibitors possessing promising in-vivo anticancer activity. PMID- 27479484 TI - Conceptual Knowledge Influences Decision Making Differently in Individuals with High or Low Cognitive Flexibility: An ERP Study. AB - OBJECTIVE: Studies using the Iowa Gambling Task (IGT) have distinguished between good and bad decision makers and have provided an explanation for deficits in decision making. Previous studies have demonstrated a link between Wisconsin Card Sorting Test (WCST) performance and IGT performance, but the results were not consistent and failed to explain why WCST performance can predict IGT performance. The present study aimed to demonstrate that WCST performance can predict IGT performance and to identify the cognitive component of the WCST that affects IGT performance using event-related potentials (ERPs). METHODS: In this study, 39 healthy subjects (5 subjects were excluded) were divided into a high group and a low group based on their global score on the WCST. A single-choice version of the IGT was used to eliminate the impact of retrieval strategies on the choice evaluation process and interference due to uncorrelated decks. Differences in the underlying neural mechanisms and explicit knowledge between the two groups during the three stages of the decision-making process were described. RESULTS: Based on the information processing perspective, we divided the decision-making process into three stages: choice evaluation, response selection, and feedback processing. The behavioral results showed that the highly cognitively flexible participants performed better on the IGT and acquired more knowledge of the task. The ERP results showed that during the choice evaluation stage, the P300 recorded from central and parietal regions when a bad deck appeared was larger in the high group participants than in the low group participants. During the response selection stage, the effect of choice type was significant only in the frontal region in the high group, with a larger effect for passing. During the feedback evaluation stage, a larger FRN was evoked for a loss than for a win in the high group, whereas the FRN effect was absent in the low group. CONCLUSION: Compared with the participants with low cognitive flexibility, the participants with high cognitive flexibility performed better on the IGT, acquired more knowledge of the task, and displayed more obvious somatic markers. The low group participants showed reduced working memory abilities during the choice evaluation stage. The appropriate somatic markers reflected by the DPN is formed only when conceptual knowledge is gained in the response selection stage. The absence of an FRN effect in the subjects who performed poorly on the WCST suggests a significant deficit in feedback learning and reward prediction. PMID- 27479485 TI - Chloroacetamide-Linked Nucleotides and DNA for Cross-Linking with Peptides and Proteins. AB - Nucleotides, 2'-deoxyribonucleoside triphosphates (dNTPs), and DNA probes bearing reactive chloroacetamido group linked to nucleobase (cytosine or 7-deazadaenine) through a propargyl tether were prepared and tested in cross-linking with cysteine- or histidine-containing peptides and proteins. The chloroacetamide modifed dNTPs proved to be good substrates for DNA polymerases in the enzymatic synthesis of modified DNA probes. Modified nucleotides and DNA reacted efficiently with cysteine and cysteine-containing peptides, whereas the reaction with histidine was sluggish and low yielding. The modified DNA efficiently cross linked with p53 protein through alkylation of cysteine and showed potential for cross-linking with histidine (in C277H mutant of p53). PMID- 27479486 TI - Amblyomin-X having a Kunitz-type homologous domain, is a noncompetitive inhibitor of FXa and induces anticoagulation in vitro and in vivo. AB - BACKGROUND: Cancer has long been associated with thrombosis and many of the standard chemotherapeutics used to treat cancer are pro-thrombotic. Thus, the identification of novel selective anticancer drugs that also have antithrombotic properties is of enormous significance. Amblyomin-X is an anticancer protein derived from the salivary glands of the Amblyomma cajennense tick. METHODS: In this work, we determined the inhibition profile of Amblyomin-X and its effect on activated partial thromboplastin time (aPTT) and prothrombin time (PT), using various approaches such as, kinetic analyses, amidolytic assays, SDS-PAGE, and mass spectrometry. RESULTS: Amblyomin-X inhibited factor Xa, prothrombinase and tenase activities. It was hydrolyzed by trypsin and plasmin. MS/MS data of tryptic hydrolysate of Amblyomin-X suggested the presence of Cys(8)-Cys(59) and Cys(19)-Cys(42) but not Cys(34)-Cys(55) disulfide bond. Instead of Cys(34) Cys(55), two noncanonical Cys(34)-Cys(74) and Cys(55)-Cys(74) disulfide bonds were identified. Furthermore, when Amblyomin-X (1mg/kg) injected in rabbits, it prolonged aPTT and PT. CONCLUSION: Amblyomin-X is a noncompetitive inhibitor (Ki=3.9MUM) of factor Xa. It is a substrate for plasmin and trypsin, but not for factor Xa and thrombin. The disulfide Cys(34)-Cys(55) bond probably scrambles with interchain seventh free cysteine residues (Cys(74)) of Amblyomin-X. The prolongation of PT and aPTT is reversible. GENERAL SIGNIFICANCE: In term of anticoagulant property, this is structural and functional characterization of Amblyomin-X. All together, these results and previous findings suggest that Amblyomin-X has a potential to become an anticancer drug with antithrombotic property. PMID- 27479487 TI - New insights about the structural rearrangements required for substrate translocation in the bovine mitochondrial oxoglutarate carrier. AB - The oxoglutarate carrier (OGC) belongs to the mitochondrial carrier family and plays a key role in important metabolic pathways. Here, site-directed mutagenesis was used to conservatively replace lysine 122 by arginine, in order to investigate new structural rearrangements required for substrate translocation. K122R mutant was kinetically characterized, exhibiting a significant Vmax reduction with respect to the wild-type (WT) OGC, whereas Km value was unaffected, implying that this substitution does not interfere with 2 oxoglutarate binding site. Moreover, K122R mutant was more inhibited by several sulfhydryl reagents with respect to the WT OGC, suggesting that the reactivity of some cysteine residues towards these Cys-specific reagents is increased in this mutant. Different sulfhydryl reagents were employed in transport assays to test the effect of the cysteine modifications on single-cysteine OGC mutants named C184, C221, C224 (constructed in the WT background) and K122R/C184, K122R/C221, K122R/C224 (constructed in the K122R background). Cysteines 221 and 224 were more deeply influenced by some sulfhydryl reagents in the K122R background. Furthermore, the presence of 2-oxoglutarate significantly enhanced the degree of inhibition of K122R/C221, K122R/C224 and C224 activity by the sulfhydryl reagent 2-Aminoethyl methanethiosulfonate hydrobromide (MTSEA), suggesting that cysteines 221 and 224, together with K122, take part to structural rearrangements required for the transition from the c- to the m-state during substrate translocation. Our results are interpreted in the light of the homology model of BtOGC, built by using as a template the X-ray structure of the bovine ADP/ATP carrier isoform 1 (AAC1). PMID- 27479488 TI - Do Executive Function and Impulsivity Predict Adolescent Health Behaviour after Accounting for Intelligence? Findings from the ALSPAC Cohort. AB - OBJECTIVE: Executive function, impulsivity, and intelligence are correlated markers of cognitive resource that predict health-related behaviours. It is unknown whether executive function and impulsivity are unique predictors of these behaviours after accounting for intelligence. METHODS: Data from 6069 participants from the Avon Longitudinal Study of Parents and Children were analysed to investigate whether components of executive function (selective attention, attentional control, working memory, and response inhibition) and impulsivity (parent-rated) measured between ages 8 and 10, predicted having ever drunk alcohol, having ever smoked, fruit and vegetable consumption, physical activity, and overweight at age 13, after accounting for intelligence at age 8 and childhood socioeconomic characteristics. RESULTS: Higher intelligence predicted having drunk alcohol, not smoking, greater fruit and vegetable consumption, and not being overweight. After accounting for intelligence, impulsivity predicted alcohol use (odds ratio = 1.10; 99% confidence interval = 1.02, 1.19) and smoking (1.22; 1.11, 1.34). Working memory predicted not being overweight (0.90; 0.81, 0.99). CONCLUSIONS: After accounting for intelligence, executive function predicts overweight status but not health-related behaviours in early adolescence, whilst impulsivity predicts the onset of alcohol and cigarette use, all with small effects. This suggests overlap between executive function and intelligence as predictors of health behaviour in this cohort, with trait impulsivity accounting for additional variance. PMID- 27479490 TI - Spontaneous Changes in Taste Sensitivity of Single Units Recorded over Consecutive Days in the Brainstem of the Awake Rat. AB - A neuron's sensitivity profile is fundamental to functional classification of cell types, and underlies theories of sensory coding. Here we show that gustatory neurons in the nucleus of the solitary tract (NTS) and parabrachial nucleus of the pons (PbN) of awake rats spontaneously change their tuning properties across days. Rats were surgically implanted with a chronic microwire assembly into the NTS or PbN. Following recovery, water-deprived rats had free access to a lick spout that delivered taste stimuli while cellular activity was recorded. In 12 rats for the NTS and 8 rats for the PbN, single units could be isolated at the same electrode on consecutive days (NTS, 14 units for 2-5 consecutive days, median = 2 days; PbN, 23 units for 2-7 days, median = 2.5 days). Waveforms were highly similar (waveform template correlation > 0.99) across days in 13 units in NTS and 13 units in PbN. This degree of similarity was rare (0.3% of pairs in NTS, 1.5% of pairs in PbN) when the waveforms were from presumed-different neurons (units recorded on nonconsecutive days with at least one intervening day in which there were no spikes, or from different wires or rats). Analyses of multi-day recordings that met this criterion for "same unit" showed that responses to taste stimuli appeared, disappeared, or shifted in magnitude across days, resulting in changes in tuning. These data imply, generally, that frameworks for cell classification and, specifically, that theories of taste coding, need to consider plasticity of response profiles. PMID- 27479489 TI - Co-morbidity of PTSD and immune system dysfunction: opportunities for treatment. AB - Posttraumatic stress disorder (PTSD) is defined as a psychiatric disorder; however, PTSD co-occurs with multiple somatic manifestations. People living with PTSD commonly manifest dysregulations in the systems that regulate the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis, and development of a pro-inflammatory state. Additionally, somatic autoimmune and inflammatory diseases and disorders have a high rate of co-morbidity with PTSD. Recognition and understanding of the compounding effect that these disease states can have on each other, evidenced from poorer treatment outcomes and accelerated disease progression in patients suffering from co-morbid PTSD and/or other autoimmune and inflammatory diseases, has the potential to lead to additional treatment opportunities. PMID- 27479492 TI - Proximal femoral growth plate mechanical behavior: Comparison between different developmental stages. AB - In long bones the growth plate is a cartilaginous structure located between the epiphysis and the diaphysis. This structure regulates longitudinal growth and helps determine the structure of mature bone through the process of endochondral ossification. During human growth the femur's proximal growth plate experiences changes in its morphology that may be related to its mechanical environment. Thus, in order to test this hypothesis from a computational perspective, a finite element analysis on a proximal femur was performed on which we modeled different physeal geometries corresponding to the shapes acquired for this structure in a child between the ages of five to eleven. Results show augmented Von Mises stress values with increasing irregularities in physeal geometry, whereas displacement decreased with increased irregularities in the growth plate's morphology. Such observations suggest that growth plate's shape changes follows a possible mechanical adaptation on imposed loads to sustain a person's increasing body mass during growth. PMID- 27479491 TI - Knockdown of Expression of Cdk5 or p35 (a Cdk5 Activator) Results in Podocyte Apoptosis. AB - Podocytes are terminally differentiated glomerular epithelial cells. Podocyte loss has been found in many renal diseases. Cdk5 is a cyclin-dependent protein kinase which is predominantly regulated by p35. To study the role of Cdk5/p35 in podocyte survival, we first applied western blotting (WB) analysis to confirm the time-course expression of Cdk5 and p35 during kidney development and in cultured immortalized mouse podocytes. We also demonstrated that p35 plays an important role in promoting podocyte differentiation by overexpression of p35 in podocytes. To deregulate the expression of Cdk5 or p35 in mouse podocytes, we used RNAi and analyzed cell function and apoptosis assaying for podocyte specific marker Wilms Tumor 1 (WT1) and cleaved caspase 3, respectively. We also counted viable cells using cell counting kit-8. We found that depletion of Cdk5 causes decreased expression of WT1 and apoptosis. It is noteworthy, however, that downregulation of p35 reduced Cdk5 activity, but had no effect on cleaved caspase 3 expression. It did, however, reduce expression of WT1, a transcription factor, and produced podocyte dysmorphism. On the other hand increased apoptosis could be detected in p35-deregulated podocytes using the TUNEL analysis and immunofluorescent staining with cleaved caspase3 antibody. Viability of podocytes was decreased in both Cdk5 and p35 knockdown cells. Knocking down Cdk5 or p35 gene by RNAi does not affect the cycline I expression, another Cdk5 activator in podocyes. We conclude that Cdk5 and p35 play a crucial role in maintaining podocyte differentiation and survival, and suggest these proteins as targets for therapeutic intervention in podocyte-damaged kidney diseases. PMID- 27479494 TI - Toward the influence of temporal attention on the selection of targets in a visual search task: An ERP study. AB - We used ERPs to investigate whether temporal attention interacts with spatial attention and feature-based attention to enhance visual processing. We presented a visual search display containing one singleton stimulus among a set of homogenous distractors. Participants were asked to respond only to target singletons of a particular color and shape that were presented in an attended spatial position. We manipulated temporal attention by presenting a warning signal before each search display and varying the foreperiod (FP) between the warning signal and the search display in a blocked manner. We observed distinctive ERP effects of both spatial and temporal attention. The amplitudes for the N2pc, SPCN, and P3 were enhanced by spatial attention indicating a processing benefit of relevant stimulus features at the attended side. Temporal attention accelerated stimulus processing; this was indexed by an earlier onset of the N2pc component and a reduction in reaction times to targets. Most importantly, temporal attention did not interact with spatial attention or stimulus features to influence visual processing. Taken together, the results suggest that temporal attention fosters visual perceptual processing in a visual search task independently from spatial attention and feature-based attention; this provides support for the nonspecific enhancement hypothesis of temporal attention. PMID- 27479495 TI - Combinatorial Chemical Bath Deposition of CdS Contacts for Chalcogenide Photovoltaics. AB - Contact layers play an important role in thin film solar cells, but new material development and optimization of its thickness is usually a long and tedious process. A high-throughput experimental approach has been used to accelerate the rate of research in photovoltaic (PV) light absorbers and transparent conductive electrodes, however the combinatorial research on contact layers is less common. Here, we report on the chemical bath deposition (CBD) of CdS thin films by combinatorial dip coating technique and apply these contact layers to Cu(In,Ga)Se2 (CIGSe) and Cu2ZnSnSe4 (CZTSe) light absorbers in PV devices. Combinatorial thickness steps of CdS thin films were achieved by removal of the substrate from the chemical bath, at regular intervals of time, and in equal distance increments. The trends in the photoconversion efficiency and in the spectral response of the PV devices as a function of thickness of CdS contacts were explained with the help of optical and morphological characterization of the CdS thin films. The maximum PV efficiency achieved for the combinatorial dip coating CBD was similar to that for the PV devices processed using conventional CBD. The results of this study lead to the conclusion that combinatorial dip coating can be used to accelerate the optimization of PV device performance of CdS and other candidate contact layers for a wide range of emerging absorbers. PMID- 27479493 TI - Pain buddy: A novel use of m-health in the management of children's cancer pain. AB - BACKGROUND: Over 12,000 children are diagnosed with cancer every year in the United States. In addition to symptoms associated with their disease, children undergoing chemotherapy frequently experience significant pain, which is unfortunately often undertreated. The field of m-Health offers an innovative avenue for pain assessment and intervention in the home setting. The current study describes the development and initial evaluation of a tablet-based program, Pain Buddy, aimed to enhance pain management and foster improved quality of life in children ages 8-18 years undergoing cancer treatment. METHODS: An animated avatar-based tablet application was developed using state-of-the-art software. Key aspects of Pain Buddy include daily pain and symptom diaries completed by children, remote monitoring of symptoms by uploading patient's data through internet to a cloud server, cognitive and behavioral skills training, interactive three-dimensional avatars that guide children through the program, and an incentive system to motivate engagement. Twelve children between the ages of 8 and 18 participated in a pilot study of Pain Buddy. RESULTS: Children were highly satisfied with the program. Pain and appetite disturbances were most frequently endorsed. Symptom trigger alerts to outside providers were largely related to clinically significant pain. Children infrequently used analgesics, and reported using some non-pharmacological pain management strategies. CONCLUSION: Pain Buddy appears to be a promising tool to improve pain and symptom management in children undergoing cancer treatment. Results from the current study will inform future improvements to Pain Buddy, in preparation for a randomized controlled trial to assess the efficacy of this innovative treatment. PMID- 27479496 TI - Subpopulations of T Regulatory Cells in Blood Stem Cell Harvests Influence Development of Acute Graft Versus Host Disease in Allogeneic Transplant Recipients. AB - BACKGROUND: CD4+ FoxP3+ regulatory T cells (Tregs) are the potent suppressors of activation and proliferation of conventional T cells. Tregs subdivided by their expression of FoxP3 and CD45RA identify clinically important functional subsets. METHODS: We analyzed Treg subpopulations in hematopoietic stem cell harvests (SCH) from 22 allogeneic (matched unrelated and sibling) donors with flow cytometry by their expression of CD45RA, CD127, CD25, and FoxP3 marker combinations. RESULTS: A high fraction of "activated Tregs", defined as CD4+ FoxP3hi CD45RAlo (aTreg) cells relative to all CD4+ T-cells, in the SCH correlated with no subsequent development of acute graft-versus-host disease (aGVHD) in the corresponding transplant recipients (aTreg 1.29%, range 0.96 1.64%, vs. 0.23%, range 0.14-0.56%, with subsequent aGvHD; P = 0.0015). The "non Treg" cells, defined by CD4+ FoxP3med/lo CD45RAlo , and resting Treg (rTreg) cells, defined by CD4+ FoxP3med CD45RAhi , did not correlate with aGvHD development. We also showed that phenotypic aTregs could be induced in vitro from nonTregs under homeostatic proliferation conditions and that this ability correlated with the CD127 and CD25 expression patterns. CONCLUSIONS: We identified a subset of T CD4+ FoxP3+ cells, i.e., aTregs that were correlated to aGvHD development, and demonstrated plasticity of the nonTreg population to provide phenotypic aTregs. This could have both a predictive clinical relevance in inflammatory conditions as well as support a rationale for development of cell targeted therapy. (c) 2016 International Clinical Cytometry Society. PMID- 27479498 TI - Engineered non-Mendelian inheritance of entire parental genomes in C. elegans. AB - The ability to rewrite the rules of genetic segregation would open new possibilities in diverse areas of biotechnology ranging from breeding to epigenetics. Here we engineer non-Mendelian inheritance of the entire maternal or paternal genome in Caenorhabditis elegans by changing the structure of the mitotic spindle during the first cell division of the zygote. Using germline specific overexpression of a single protein, the conserved microtubule force regulator GPR-1, we increase forces that pull on spindle poles to convert the single bipolar mitotic spindle to two monopolar spindles. This generates two-cell embryos in which one cell contains only the maternal chromosomes and the other cell contains only the paternal chromosomes. As the embryo develops, each cell of the animal, including the germ cells, contains the genetic material of only one parent, resulting in hybrid F1 animals. Progeny of these animals (F2) inherit either only F0 maternal or only F0 paternal chromosomes, and thus descend from only either of their grandparents' gametes. PMID- 27479499 TI - The Effects of an Online Mind-Body Training Program on Stress, Coping Strategies, Emotional Intelligence, Resilience and Psychological State. AB - The goal of this study was to evaluate the effects of an online mind-body training (MBT) program on participants' stress, anger, coping strategies, emotional intelligence, resilience, and positive and negative affect. Forty-two healthy women participated in an online MBT program for approximately 8-10 minutes a day for 8 weeks; a control group of 45 healthy women did not participate in the program. Self-report psychological questionnaires were administered before the beginning of the program and at 4 and 8 weeks following its onset. Data from the MBT group and the control group were compared using repeated measures ANOVA and Student's t-tests. Significant time x group interaction effects were found with respect to stress, coping strategies, anger, emotional intelligence, negative affect and resilience. These results demonstrate beneficial effects of the online MBT program and significant improvements in the psychological capabilities of participants compared with the control group. The effects of online MBT program were similar with those of the previous offline MBT in psychological aspects, suggesting further studies for neuroscientific evidence related stress and emotion of online MBT effects. PMID- 27479500 TI - The Effect of Local Hydration Environment on the Mechanical Properties and Unloaded Temporal Changes of Isolated Porcine Annular Samples. AB - Preventing dehydration during in vitro testing of isolated layers of annulus fibrosus tissue may require different test conditions than functional spine units. The purpose of the study was twofold: (A) to quantify changes in mass and thickness of multilayer annulus samples in four hydration environments over 120 min; and (B) to quantify cycle-varying biaxial tensile properties of annulus samples in the four environments. The environments included a saline bath, air, relative humidity control, and misting combined with controlled humidity. The loading protocol implemented 24 cycles of biaxial tensile loading to 20% strain at a rate of 2%/s with 3-, 8-, and 13-min of intermittent rest. Specimen mass increased an average (standard deviation) 72% (11) when immersed for 120 min (p < 0.0001). The air condition and the combined mist and relative humidity conditions reduced mass by 45% (15) and 25% (23), respectively, after 120 min (p < 0.0014). Stress at 16% stretch in the air condition was higher at cycle 18 (18 min of exposure) and cycle 24 (33 min of exposure) compared to all other environments in both the axial and circumferential directions (p < 0.0460). There was no significant change in mass or thickness over time in the relative humidity condition and the change in circumferential stress at 16% stretch between cycles 6 and 24 was a maximum of 0.099 MPa and not statistically significant. Implementation of a controlled relative humidity environment is recommended to maintain hydration of isolated annulus layers during cyclic tensile testing. PMID- 27479497 TI - Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq. AB - A central challenge in oncology is how to kill tumors containing heterogeneous cell populations defined by different combinations of mutated genes. Identifying these mutated genes and understanding how they cooperate requires single-cell analysis, but current single-cell analytic methods, such as PCR-based strategies or whole-exome sequencing, are biased, lack sequencing depth or are cost prohibitive. Transposon-based mutagenesis allows the identification of early cancer drivers, but current sequencing methods have limitations that prevent single-cell analysis. We report a liquid-phase, capture-based sequencing and bioinformatics pipeline, Sleeping Beauty (SB) capture hybridization sequencing (SBCapSeq), that facilitates sequencing of transposon insertion sites from single tumor cells in a SB mouse model of myeloid leukemia (ML). SBCapSeq analysis of just 26 cells from one tumor revealed the tumor's major clonal subpopulations, enabled detection of clonal insertion events not detected by other sequencing methods and led to the identification of dominant subclones, each containing a unique pair of interacting gene drivers along with three to six cooperating cancer genes with SB-driven expression changes. PMID- 27479502 TI - Separation of Peptides on HALO 2-Micron Particles. AB - Reversed-phase high-performance liquid chromatography (RP-HPLC) is of fundamental importance to the isolation and separation of peptides, proteins, and other biomolecules. Hence, there is a continuing high demand for the development of RP HPLC stationary-phase materials with enhanced separation efficiency. HALO packing materials began the revolution in "core-shell" technology with the advantages of faster separations, higher resolution and peak capacity, high temperature stability, and rugged reliable performance compared to traditional HPLC and UHPLC. These materials are characterized by a solid core surrounded by a thin layer of porous material, and represent a technology for the future with continuing refinements. Such refinements are aided via the use of designed synthetic peptide standards during stationary-phase development. Concomitantly, such standards also enable the researcher to monitor RP-HPLC column performance and develop optimized separation protocols for peptides from a wide array of sources. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479501 TI - Generation of Anti-Murine ADAMTS13 Antibodies and Their Application in a Mouse Model for Acquired Thrombotic Thrombocytopenic Purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy linked to a deficiency in the metalloprotease ADAMTS13. In the current study, a novel mouse model for acquired TTP was generated to facilitate development and validation of new therapies for this disease. Therefore, a large panel (n = 19) of novel anti-mouse ADAMTS13 (mADAMTS13) monoclonal antibodies (mAbs) of mouse origin was generated. Inhibitory anti-mADAMTS13 mAbs were identified using the FRETS-VWF73 assay. Four mAbs strongly inhibited mADAMTS13 activity in vitro (~68-90% inhibition). Injecting a combination of 2 inhibitory mAbs (13B4 and 14H7, 1.25 mg/kg each) in Adamts13+/+ mice resulted in full inhibition of plasma ADAMTS13 activity (96 +/- 4% inhibition, day 1 post injection), leading to the appearance of ultra-large von Willebrand factor (UL VWF) multimers. Interestingly, the inhibitory anti-mADAMTS13 mAbs 13B4 and 14H7 were ideally suited to induce long-term ADAMTS13 deficiency in Adamts13+/+ mice. A single bolus injection resulted in full ex vivo inhibition for more than 7 days. As expected, the mice with the acquired ADAMTS13 deficiency did not spontaneously develop TTP, despite the accumulation of UL-VWF multimers. In line with the Adamts13-/- mice, TTP-like symptoms could only be induced when an additional trigger (rVWF) was administered. On the other hand, the availability of our panel of anti-mADAMTS13 mAbs allowed us to further develop a sensitive ELISA to detect ADAMTS13 in mouse plasma. In conclusion, a novel acquired TTP mouse model was generated through the development of inhibitory anti-mADAMTS13 mAbs. Consequently, this model provides new opportunities for the development and validation of novel treatments for patients with TTP. In addition, these newly developed inhibitory anti-mADAMTS13 mAbs are of great value to specifically study the role of ADAMTS13 in mouse models of thrombo-inflammatory disease. PMID- 27479503 TI - Introduction to Atomic Force Microscopy (AFM) in Biology. AB - The atomic force microscope (AFM) has the unique capability of imaging biological samples with molecular resolution in buffer solution over a wide range of time scales from milliseconds to hours. In addition to providing topographical images of surfaces with nanometer- to angstrom-scale resolution, forces between single molecules and mechanical properties of biological samples can be investigated from the nano-scale to the micro-scale. Importantly, the measurements are made in buffer solutions, allowing biological samples to "stay alive" within a physiological-like environment while temporal changes in structure are measured e.g., before and after addition of chemical reagents. These qualities distinguish AFM from conventional imaging techniques of comparable resolution, e.g., electron microscopy (EM). This unit provides an introduction to AFM on biological systems and describes specific examples of AFM on proteins, cells, and tissues. The physical principles of the technique and methodological aspects of its practical use and applications are also described. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479504 TI - Designing and Applying Proximity-Dependent Hybridization Chain Reaction. AB - Proximity-dependent hybridization chain reaction (proxHCR) is a novel technique for detection of protein interaction, post-translational modifications (PTMs), or protein expression. The method is based upon antibodies targeting the proteins of interest that are covalently conjugated to DNA oligonucleotides, which enables the induction of a hybridization chain reaction (HCR) to generate a fluorescent signal visible under a microscope. In contrast to the in situ proximity ligation assay (in situ PLA), which is another method that utilizes antibody-DNA conjugates to detect protein interactions, proxHCR does not require enzymatic steps. This makes proxHCR an inexpensive alternative to in situ PLA. Another potential advantage might be that proxHCR could more readily be adapted for use in automated staining procedures and in point-of-care devices, as all reagents can be stored at room temperature. This unit describes how the oligonucleotide system for proxHCR can be designed and a protocol for how to perform proxHCR is presented. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479506 TI - Rapid Preparation of a Plasma Membrane Fraction: Western Blot Detection of Translocated Glucose Transporter 4 from Plasma Membrane of Muscle and Adipose Cells and Tissues. AB - Membrane proteins account for 70% to 80% of all pharmaceutical targets, indicating their clinical relevance and underscoring the importance of identifying differentially expressed membrane proteins that reflect distinct disease properties. The translocation of proteins from the bulk of the cytosol to the plasma membrane is a critical step in the transfer of information from membrane-embedded receptors or transporters to the cell interior. To understand how membrane proteins work, it is important to separate the membrane fraction of cells. This unit provides a protocol for rapidly obtaining plasma membrane fractions for western blot analysis. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479505 TI - Correlative Forster Resonance Electron Transfer-Proximity Ligation Assay (FRET PLA) Technique for Studying Interactions Involving Membrane Proteins. AB - This unit provides a guide and detailed protocol for studying membrane protein protein interactions (PPI) using the acceptor-sensitized Forster resonance electron transfer (FRET) method in combination with the proximity ligation assay (PLA). The protocol in this unit is focused on the preparation of FRET-PLA samples and the detection of correlative FRET/PLA signals as well as on the analysis of FRET-PLA data and interpretation of correlative results when using cyan fluorescent protein (CFP) as a FRET donor and yellow fluorescent protein (YFP) as a FRET acceptor. The correlative application of FRET and PLA combines two powerful tools for monitoring PPI, yielding results that are more reliable than with either technique alone. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479507 TI - Use of the SHuffle Strains in Production of Proteins. AB - Escherichia coli continues to be a popular expression host for the production of proteins, yet successful recombinant expression of active proteins to high yields remains a trial and error process. This is mainly due to decoupling of the folding factors of a protein from its native host, when expressed recombinantly in E. coli. Failure to fold could be due to many reasons but is often due to lack of post-translational modifications that are absent in E. coli. One such post translational modification is the formation of disulfide bonds, a common feature of secreted proteins. The genetically engineered SHuffle cells offer an expression solution to proteins that require disulfide bonds for their folding and activity. The purpose of this protocol unit is to familiarize the researcher with the biology of SHuffle cells and guide the experimental design in order to optimize and increase the chances of successful expression of their desired protein of choice. Example of the expression and purification of a model disulfide-bonded protein DsbC is described in detail. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479508 TI - Analysis of proton wires in the enzyme active site suggests a mechanism of c-di GMP hydrolysis by the EAL domain phosphodiesterases. AB - We report for the first time a hydrolysis mechanism of the cyclic dimeric guanosine monophosphate (c-di-GMP) by the EAL domain phosphodiesterases as revealed by molecular simulations. A model system for the enzyme-substrate complex was prepared on the base of the crystal structure of the EAL domain from the BlrP1 protein complexed with c-di-GMP. The nucleophilic hydroxide generated from the bridging water molecule appeared in a favorable position for attack on the phosphorus atom of c-di-GMP. The most difficult task was to find a pathway for a proton transfer to the O3' atom of c-di-GMP to promote the O3'?P bond cleavage. We show that the hydrogen bond network extended over the chain of water molecules in the enzyme active site and the Glu359 and Asp303 side chains provides the relevant proton wires. The suggested mechanism is consistent with the structural, mutagenesis, and kinetic experimental studies on the EAL domain phosphodiesterases. Proteins 2016; 84:1670-1680. (c) 2016 Wiley Periodicals, Inc. PMID- 27479509 TI - Optimal invasive strategy for multivessel coronary artery disease in elderly diabetic patients. PMID- 27479510 TI - A Method to Estimate the Hydraulic Conductivity of the Ground by TRT Analysis. AB - The knowledge of hydraulic properties of aquifers is important in many engineering applications. Careful design of ground-coupled heat exchangers requires that the hydraulic characteristics and thermal properties of the aquifer must be well understood. Knowledge of groundwater flow rate and aquifer thermal properties is the basis for proper design of such plants. Different methods have been developed in order to estimate hydraulic conductivity by evaluating the transport of various tracers (chemical, heat etc.); thermal response testing (TRT) is a specific type of heat tracer that allows including the hydraulic properties in an effective thermal conductivity value. Starting from these considerations, an expeditious, graphical method was proposed to estimate the hydraulic conductivity of the aquifer, using TRT data and plausible assumption. Suggested method, which is not yet verified or proven to be reliable, should be encouraging further studies and development in this direction. PMID- 27479511 TI - Cyanopyridine Based Bipolar Host Materials for Green Electrophosphorescence with Extremely Low Turn-On Voltages and High Power Efficiencies. AB - Low driving voltage and high power efficiency are basic requirements when practical applications of organic light emitting diodes (OLEDs) in displays and lighting are considered. Two novel host materials m-PyCNmCP and 3-PyCNmCP incorporating cyanopyridine moiety as electron-transporting unit are developed for use in fac-tris(2-phenylpyridine)iridium(III) (Ir(ppy)3) based green phosphorescent OLEDs (PhOLEDs). Extremely low turn-on voltages of 2.01 and 2.27 V are realized, which are even lower than the theoretical limit of the emitted photon energy (hv)/electron charge (e) (2.37 V) of Ir(ppy)3. High power efficiency of 101.4 lm/W (corresponding to a maximum external quantum efficiency of 18.4%) and 119.3 lm/W (24.7%) are achieved for m-PyCNmCP and 3-PyCNmCP based green PhOLEDs. The excellent EL performance benefits from the ideal parameters of host materials by combining cyano and pyridine to enhance the n-type feature. The energetic favorable alignment of HOMO/LUMO levels of hosts with adjacent layers and the dopant for easy charge injections and direct charge trapping by dopant, their bipolar feature to balance charge transportations, sufficiently high triplet energy and small singlet/triplet energy difference (0.38 and 0.43 eV) combine to be responsible for the extremely low driving voltages and high power efficiencies of the green PhOLEDs. PMID- 27479512 TI - Organoarsenic Drugs over Time: The Pharmacokinetics of Roxarsone in Chicken Meat. PMID- 27479513 TI - Multiple imputation for cure rate quantile regression with censored data. AB - The main challenge in the context of cure rate analysis is that one never knows whether censored subjects are cured or uncured, or whether they are susceptible or insusceptible to the event of interest. Considering the susceptible indicator as missing data, we propose a multiple imputation approach to cure rate quantile regression for censored data with a survival fraction. We develop an iterative algorithm to estimate the conditionally uncured probability for each subject. By utilizing this estimated probability and Bernoulli sample imputation, we can classify each subject as cured or uncured, and then employ the locally weighted method to estimate the quantile regression coefficients with only the uncured subjects. Repeating the imputation procedure multiple times and taking an average over the resultant estimators, we obtain consistent estimators for the quantile regression coefficients. Our approach relaxes the usual global linearity assumption, so that we can apply quantile regression to any particular quantile of interest. We establish asymptotic properties for the proposed estimators, including both consistency and asymptotic normality. We conduct simulation studies to assess the finite-sample performance of the proposed multiple imputation method and apply it to a lung cancer study as an illustration. PMID- 27479516 TI - Advanced Practice Nurse-Led Statewide Collaborative to Reduce Falls in Hospitals. AB - Thirty-eight hospitals participated in falls prevention team training, followed by coaching and mentoring over 3 months to develop unit-based initiatives to reduce falls. Initiatives centered on fall risk assessment, rounding, or postfall assessment. Paired t test of the pre-/postintervention fall rates of 23 of the hospitals revealed reduced fall rates (P < .01). The estimated mean decrease was 1.7 falls per 1000 patient days (95% confidence limits of 0.7-2.7). PMID- 27479515 TI - Reduction of Medication Errors: A Unique Approach. AB - Medication errors are a source of serious patient harm. A unique approach, Socio Technical Probabilistic Risk Assessment, was used to analyze historical errors in this setting. The goal was to identify a minimal number of steps that would establish increased reliability and decrease errors if these steps were used every time. Three steps were identified that should be taken with every intravenous medication or fluid administration. Preliminary analysis revealed a 22% reduction in errors when using these 3 steps. PMID- 27479517 TI - Patient Perceptions of Sitting Versus Standing for Nurse Leader Rounding. PMID- 27479514 TI - Open data set of live cyanobacterial cells imaged using an X-ray laser. AB - Structural studies on living cells by conventional methods are limited to low resolution because radiation damage kills cells long before the necessary dose for high resolution can be delivered. X-ray free-electron lasers circumvent this problem by outrunning key damage processes with an ultra-short and extremely bright coherent X-ray pulse. Diffraction-before-destruction experiments provide high-resolution data from cells that are alive when the femtosecond X-ray pulse traverses the sample. This paper presents two data sets from micron-sized cyanobacteria obtained at the Linac Coherent Light Source, containing a total of 199,000 diffraction patterns. Utilizing this type of diffraction data will require the development of new analysis methods and algorithms for studying structure and structural variability in large populations of cells and to create abstract models. Such studies will allow us to understand living cells and populations of cells in new ways. New X-ray lasers, like the European XFEL, will produce billions of pulses per day, and could open new areas in structural sciences. PMID- 27479518 TI - Development and Psychometric Analysis of a Nurses' Attitudes and Skills Safety Scale: Initial Results. AB - Health care organizations have incorporated updated safety principles in the analysis of errors and in norms and standards. Yet no research exists that assesses bedside nurses' perceived skills or attitudes toward updated safety concepts. The aims of this study were to develop a scale assessing nurses' perceived skills and attitudes toward updated safety concepts, determine content validity, and examine internal consistency of the scale and subscales. Understanding nurses' perceived skills and attitudes about safety concepts can be used in targeting strategies to enhance their safety practices. PMID- 27479519 TI - Improving the Patient's Experience With a Multimodal Quiet-at-Night Initiative. AB - This project describes a multifaceted noise reduction program on 2 hospital units designed to ensure a quiet hospital environment, with the goal of improving the patient experience. The noise committee in an urban city hospital developed a plan to control noise including scripted leadership rounding, staff education, a nighttime sleep promotion cart, and visual aids to remind staff to be quiet. Postintervention improvement in patient satisfaction scores was noted. PMID- 27479520 TI - Is there a role for pharmacogenetics in the treatment of anorexia nervosa? PMID- 27479521 TI - Group B streptococcus infections in neonates admitted to a German NICU: Emphasis on screening and adherence to pre-analytical recommendations. AB - BACKGROUND: Infections by group B streptococci (GBS), e.g. Streptococcus agalactiae, presenting as early-onset disease (EOD) or late-onset disease (LOD), are leading causes of severe infections in newborn and premature patients. Although screening and intra partum antibiotic prophylaxis are frequently performed, vertically transmitted GBS remain a challenge for pediatrics. AIMS: In order to prevent or reduce potential life-threatening events, this study retrospectively investigated epidemiological, microbiological and clinical aspects of infants admitted to the Division of Neonatology at the Department of Pediatrics at the University Hospital Frankfurt, Germany (UHF). STUDY DESIGN AND SUBJECTS: Between January 2010 and January 2016, perinatal GBS screening status, clinical presentation of EOD or LOD and therapeutic management of neonates admitted to UHF were retrospective analysed. Infants tested positive for GBS within their first three months of life were included; patient data were obtained from the chart report. Severity of neonatal disease was analysed by using the NEOMOD and CRIB score. RESULTS: 108 GBS infected infants born to 105 mothers were observed. N=101 of them (93.5%) presented with EOD, whereof n=9 (10%) primarily presented with pneumonia or pneumothorax. In 82 (78%) mothers of infected infants GBS status was unknown prior to hospitalization of the neonate. 3/108 (2.8%) infants died from GBS septicemia. CONCLUSION: Avoidance of GBS transmission sub partu is the key issue in preventing neonatal GBS infection and should be the focus of preventive strategies. Our results highlight the impact of perinatal screening. PMID- 27479522 TI - The development of effective CaO-based CO2 sorbents via a sacrificial templating technique. AB - A carbon-based sacrificial templating approach was employed to realize single-pot synthesis of cyclically stable CaO-based CO2 sorbents. The sacrificial carbonaceous template was formed through resorcinol-formaldehyde polymerization reaction. The resultant sorbents following the thermal decomposition of the carbonaceous template featured an inverse opal-like macrostructure composed of a highly porous nanostructured backbone. In addition to pure CaO, sorbents supported with Al2O3, MgO, Y2O3, and ZrO2 were synthesized. SEM and XRD were utilized to characterize the morphology and the chemical composition of the synthetic CO2 sorbents, respectively. The cyclic CO2 uptake performance of the synthetic sorbents was assessed by TGA and compared to limestone. All of the synthetic sorbents exhibited an improved CO2 uptake performance when compared to limestone. The performance enhancement became more pronounced in the case of supported sorbents. The sorbent with the best CO2 uptake performance was supported by a mixture of Al2O3 and Y2O3, and exhibited a CO2 uptake of 0.61 g CO2/g CaO after 10 cycles of calcination and carbonation under practically relevant operating temperatures, which exceeded the CO2 uptake of limestone by more than 350%. PMID- 27479523 TI - Unique Strain of Borrelia miyamotoi in Ixodes pacificus Ticks, California, USA. PMID- 27479524 TI - Re: The Timing of Radical Cystectomy for bacillus Calmette-Guerin Failure: Comparison of Outcomes and Risk Factors for Prognosis: C. R. Haas, L. J. Barlow, G. M. Badalato, G. J. DeCastro, M. C. Benson and J. M. McKiernan J Urol 2016;195:1704-1709. PMID- 27479525 TI - Re: More Favorable Pathological Outcomes in Men with Low Risk Prostate Cancer Diagnosed on Repeat versus Initial Transrectal Ultrasound Guided Prostate Biopsy: A. ElShafei, Y. Nyame, O. Kara, A. Badawy, I. Amujiogu, K. Fareed, E. Klein and J. S. Jones J Urol 2016;195:1767-1772. PMID- 27479526 TI - Re: Circadian Rhythm of Glomerular Filtration and Solute Handling Related to Nocturnal Enuresis: L. Dossche, A. Raes, P. Hoebeke, P. De Bruyne and J. Vande Walle J Urol 2016;195:162-167. PMID- 27479527 TI - Reply by Authors. PMID- 27479528 TI - Fabrication of single-crystal silicon nanotubes with sub-10 nm walls using cryogenic inductively coupled plasma reactive ion etching. AB - Single-crystal silicon nanostructures have attracted much attention in recent years due in part to their unique optical properties. In this work, we demonstrate direct fabrication of single-crystal silicon nanotubes with sub-10 nm walls which show low reflectivity. The fabrication was based on a cryogenic inductively coupled plasma reactive ion etching process using high-resolution hydrogen silsesquioxane nanostructures as the hard mask. Two main etching parameters including substrate low-frequency power and SF6/O2 flow rate ratio were investigated to determine the etching mechanism in the process. With optimized etching parameters, high-aspect-ratio silicon nanotubes with smooth and vertical sub-10 nm walls were fabricated. Compared to commonly-used antireflection silicon nanopillars with the same feature size, the densely packed silicon nanotubes possessed a lower reflectivity, implying possible potential applications of silicon nanotubes in photovoltaics. PMID- 27479529 TI - Characterization of low affinity Fcgamma receptor biotinylation under controlled reaction conditions by mass spectrometry and ligand binding analysis. AB - Chemical protein biotinylation and streptavidin or anti-biotin-based capture is regularly used for proteins as a more controlled alternative to direct coupling of the protein on a biosensor surface. On biotinylation an interaction site of interest may be blocked by the biotin groups, diminishing apparent activity of the protein. Minimal biotinylation can circumvent the loss of apparent activity, but still a binding site of interest can be blocked when labeling an amino acid involved in the binding. Here, we describe reaction condition optimization studies for minimal labeling. We have chosen low affinity Fcgamma receptors as model compounds as these proteins contain many lysines in their active binding site and as such provide an interesting system for a minimal labeling approach. We were able to identify the most critical parameters (protein:biotin ratio and incubation pH) for a minimal labeling approach in which the proteins of choice remain most active toward analyte binding. Localization of biotinylation by mass spectrometric peptide mapping on minimally labeled material was correlated to protein activity in binding assays. We show that only aiming at minimal labeling is not sufficient to maintain an active protein. Careful fine-tuning of critical parameters is important to reduce biotinylation in a protein binding site. PMID- 27479530 TI - Regulation of Pancreatic alpha-Cell Function and Proliferation by Bone Morphogenetic Protein 4 (BMP4) In Vitro. AB - Increased expression of bone morphogenetic proteins (BMPs) in several tissues is associated with inflammation and type 2 diabetes mellitus. BMP2 and BMP4 mRNA expression is increased in pancreatic islets from db/db mice and beta-cell proliferation and function are inhibited by BMP4. The effect of BMPs on alpha cells is currently unknown. Here, we investigate the effects of BMP4 on mouse and human alpha-cells in vitro. The effects of BMP4 on alpha-cell proliferation and function were investigated in islets isolated from male mice and from human donors, and in alpha-TC1-6 cells. The effects of BMP4 on alpha-cell function were assessed by determination of glucagon secretion and gene expression. Treatment with BMP4 for 24-96 hours inhibited glucagon secretion in a time-dependent manner in mouse and human islets. Glucagon content, preproglucagon and aristaless related homeobox mRNA expression were reduced after incubation with BMP4 in mouse islets, but not in human islets. The percentage of proliferating alpha-cells was reduced from 7.3 % to 0.2 % in mouse islets incubated with BMP4. alpha-cell proliferation in human islets ranged from 0 to 11.8 %, and BMP4 was found to inhibit proliferation of alpha-cells from all donors when proliferation was present. In agreement with the observations in primary islets, BMP4 decreased glucagon content, preproglucagon, and aristaless related homeobox mRNA expression in alpha-TC1-6 cells. Our findings suggest that BMP4 has an inhibitory role on glucagon secretion, alpha-cell growth, and expression of genes maintaining alpha cell identity. PMID- 27479531 TI - The predictive value of M30 and oxidative stress for left ventricular remodeling in patients with anterior ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. AB - BACKGROUND: Left ventricular (LV) remodeling is an important pathophysiological event that develops following acute myocardial infarction and causes LV systolic dysfunction. Mechanisms such as apoptosis, necrosis, and oxidative stress play an important role in LV remodeling. OBJECTIVES: This study aimed to determine the relationship between the development of LV remodeling and the apoptosis marker M30 in patients with anterior ST-segment elevation myocardial infarction (STEMI) who were treated with primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS: This retrospective study included 255 consecutive patients (210 men, 45 women, mean age 54.9+/-11.8 years) with anterior STEMI who were treated with primary PCI. Blood samples were obtained from each patient at admission and 24 h after admission for measurements of M30, M65, oxidative parameters, and biochemical parameters. Transthoracic echocardiography was performed in each patient within 24 h of infarction and 6 months after infarction. LV remodeling was defined as greater than or equal to 20% increase in end-diastolic volume 6 months after primary PCI. The patients were divided into two groups on the basis of 6 months of post-primary PCI follow-up findings: LV remodeling group and non LV remodeling group. RESULTS: In all, 60 patients received LV remodeling and 195 did not receive LV remodeling at 6 months after primary PCI. Total oxidative stress, M30 and M65 levels, and the oxidative stress index were significantly higher and the total antioxidant capacity and M65/M30 ratio were lower in the LV remodeling group (P<0.05, for all). Brain natriuretic peptide, M30, and oxidative stress index were independent predictors of LV remodeling (P<0.05 for all). Receiver operating characteristic curve analysis showed that the M30 cut-off value for predicting LV remodeling was 144.9 U/l (80% sensitivity and 77% specificity, P<0.001). CONCLUSION: In patients with anterior STEMI treated with primary PCI, the apoptosis marker M30 might be useful for predicting LV remodeling and subsequent LV systolic dysfunction. PMID- 27479532 TI - Antithrombin supplementation and risk of bleeding in patients with sepsis associated disseminated intravascular coagulation. AB - INTRODUCTION: Although antithrombin is commonly used for the treatment of sepsis associated disseminated intravascular coagulation (DIC) in Japan, the factors influencing the incidence of bleeding complications have not been sufficiently studied. The purpose of this survey was to identify the factors that predict clinically relevant bleeding in patients receiving antithrombin for DIC. METHODS: We analyzed data from 1026 sepsis-associated DIC patients with a baseline antithrombin activity <=70% who underwent antithrombin supplementation at two dosages (1500IU/day or 3000IU/day) for three consecutive days. The patients' demographic characteristics, parameters before and after the treatment, and co administered anticoagulants were analyzed in relation to the bleeding events. RESULTS: Overall, 55 patients (5.36%) experienced bleeding events (major bleeding: 1.75%). Logistic regression analysis revealed that sustained DIC>7days was significantly associated with bleeding (odds ratio: 2.761, P=0.001). In contrast, the higher dose of antithrombin or the co-administration of recombinant thrombomodulin or heparins were not associated with bleeding events. CONCLUSION: A higher dose of antithrombin or the concomitant use of other anticoagulants were not associated with bleeding events. On the other hand, sustained DIC lasting more than one week was associated with an increased risk of bleeding in patients with sepsis-associated DIC. PMID- 27479533 TI - Arene C(sp(2))-H Metalation at Ni(II) Modeled with a Reactive PONCPh Ligand. AB - Coordination of the reactive phosphinitopyridylphenyl PONCPh ligand L(H) to NiBr2 initially yields paramagnetic brown NiBr2(L(H)) (1), but addition of triethylamine results in fast and facile cyclometalation at Ni(II), giving NiBr(kappa(3)-P,N,C-L) (2) as well-defined species. This is a rare example of direct cyclometalation at Ni(II) from a C-H bond in a ligand structure other than encumbering ligands (e.g., ECE pincers). Diamagnetic yellow complex 2 reacts instantaneously with HBF4 to give purple [NiBr(kappa(3)-P,N-L(H))]BF4 (3). A very unusual (an)agostic Ni(CPh-H) interaction in the solid-state structure of 3 was unequivocally demonstrated using single-crystal X-ray crystallography and was interpreted by density functional theory calculations (quantum theory of atoms in molecules and electron localization function analysis). These compounds may be viewed as models for key intermediates in the Ni-catalyzed C-H functionalization of arenes. PMID- 27479534 TI - Trait anxiety mediates the effect of stress exposure on post-traumatic stress disorder and depression risk in cardiac surgery patients. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) and depression are common after cardiac surgery. Lifetime stress exposure and personality traits may influence the development of these psychiatric conditions. METHODS: Self-reported rates of PTSD and depression and potential determinants (i.e., trait anxiety and stress exposure) were established 1.5 to 4 years after cardiac surgery. Data was available for 1125 out of 1244 (90.4%) participants. Multivariable linear regressions were conducted to investigate mediating and/or moderating effects of trait anxiety on the relationship between stress exposure, and PTSD and depression. Pre-planned subgroup analyses were performed for both sexes. RESULTS: PTSD and depression symptoms were present in 10.2% and 13.1% of the participants, respectively. Trait anxiety was a full mediator of the association between stress exposure and depression in both the total cohort and female and male subgroups. Moreover, trait anxiety partially mediated the relationship between stress exposure and PTSD in the full cohort and the male subgroup, whereas trait anxiety fully mediated this relationship in female patients. Trait anxiety did not play a moderating role in the total patient sample, nor after stratification on gender. LIMITATIONS: The unequal distribution of male (78%) and female patients (22%) might limit the generalizability of our findings. Furthermore, risk factors were investigated retrospectively and with variable follow-up time. CONCLUSIONS: In cardiac surgery patients, trait anxiety was found to be an important mediator of postoperative PTSD and depression. Prospective research is necessary to verify whether these factors are reliable screening measures of individuals' vulnerability for psychopathology development after cardiac surgery. PMID- 27479535 TI - Emotion dysregulation as a cross-cutting target for inpatient psychiatric intervention. AB - BACKGROUND: This prospective, open effectiveness trial examined trajectories of change in a cross-cutting measure of emotion dysregulation in an intensive multimodal inpatient treatment for adults experiencing serious mental illness (SMI). METHODS: Adult inpatients with SMI (N=994) completed an average of 38.6 days of inpatient treatment. Latent growth curve (LGC) methods were used to model emotion dysregulation trajectories, estimating expected remission based on individual patterns of change. RESULTS: Absolute reductions in experiential avoidance (d=1.03, CI95% [.94, 1.10]) and emotional dysregulation were substantial with large effect size improvements (d=.98, CI95% [.90, 1.05]). Initial scores for experiential avoidance and emotion dysregulation were higher for patients with diagnoses of bipolar, depressive, anxiety, and personality disorders; whereas, male gender was associated with lower initial scores. Substance use diagnoses were associated with rapid improvement in experiential avoidance and specific emotion dysregulation involving goal-directed behavior and impulse control. Presence of a personality disorder predicted rapid improvement in overall emotion dysregulation and clarity of emotional experiences. CONCLUSIONS: Adults with SMI demonstrated substantial improvement in experiential avoidance and emotion dysregulation over the course of intensive inpatient treatment, with significant variability in patterns of change. Substance use and personality disorders were associated with rapid improvements in specific aspects of emotion dysregulation. PMID- 27479536 TI - Characteristics of U.S. Veteran Patients with Major Depressive Disorder who require "next-step" treatments: A VAST-D report. AB - OBJECTIVE: Finding effective and lasting treatments for patients with Major Depressive Disorder (MDD) that fail to respond optimally to initial standard treatment is a critical public health imperative. Understanding the nature and characteristics of patients prior to initiating "next-step" treatment is an important component of identifying which specific treatments are best suited for individual patients. We describe clinical features and demographic characteristics of a sample of Veterans who enrolled in a "next-step" clinical trial after failing to achieve an optimal outcome from at least one well delivered antidepressant trial. METHODS: 1522 Veteran outpatients with nonpsychotic MDD completed assessments prior to being randomized to study treatment. Data is summarized and presented in terms of demographic, social, historical and clinical features and compared to a similar, non-Veteran sample. RESULTS: Participants were largely male and white, with about half unmarried and half unemployed. They were moderately severely depressed, with about one-third reporting recent suicidal ideation. More than half had chronic and/or recurrent depression. General medical and psychiatric comorbidities were highly prevalent, particularly PTSD. Many had histories of childhood adversity and bereavement. Participants were impaired in multiple domains of their lives and had negative self-worth. LIMITATIONS: These results may not be generalizable to females, and some characteristics may be specific to Veterans of US military service. There was insufficient data on age of clinical onset and depression subtypes, and three novel measures were not psychometrically validated. CONCLUSIONS: Characterizing VAST-D participants provides important information to help clinicians understand features that may optimize "next-step" MDD treatments. PMID- 27479537 TI - Suicide behavior as a quantitative trait and its genetic background. AB - INTRODUCTION: Studies have not given yet a clear answer what is the genetic background of suicidal predisposition. The associations between polymorphisms of the TPH1 and 5-HTTLPR genes and violent suicidal behavior was revealed with the least inconsistencies. METHOD: We selected 10 "strong candidate genes" and 35 SNPs, SLC6A4 and ACP1 for replication study. We searched associations between precisely described suicidal phenotype in 825 affective patients and polymorphisms of selected neurobiological pathways genes as well as their interactions that constitute suicidal risk. RESULTS: The results confirm the role of TPH1, TPH2, 5HT2A, CRHR1 and ACP1 variants in the risk of suicidal behavior. LIMITATIONS: In our study we analyzed limited number of candidate genes and only one of them is linked to lithium mechanism of action. We had no data on pharmacological treatment of investigated patients and its relation to the time of suicide attempt. CONCLUSION: Our results indicate that polymorphisms of various signaling pathways are involved in the pathogenesis of suicidal behavior. Non-genetic factors are also involved in the risk of suicidal attempts. PMID- 27479540 TI - Siderophores in Cloud Waters and Potential Impact on Atmospheric Chemistry: Production by Microorganisms Isolated at the Puy de Dome Station. AB - A total of 450 bacteria and yeast strains isolated from cloud waters sampled at the puy de Dome station in France (1465 m) were screened for their ability to produce siderophores. To achieve this, a high-throughput method in 96-well plates was adapted from the CAS (chrome azurol S) method. Notably, 42% of the isolates were siderophore producers. This production was examined according to the phyla of the tested strains and the type of chelating functional groups (i.e., hydroxamate, catechol, and mixed type). The most active bacteria in the clouds belong to the gamma-Proteobacteria class, among which the Pseudomonas genus is the most frequently encountered. gamma-Proteobacteria are produced in the majority of mixed function siderophores, such as pyoverdines, which bear a photoactive group. Finally, siderophore production was shown to vary with the origin of the air masses. The organic speciation of iron remains largely unknown in warm clouds. Our results suggest that siderophores could partly chelate Fe(III) in cloud waters and thus potentially impact the chemistry of the atmospheric aqueous phase. PMID- 27479539 TI - Nanoparticles and intracellular applications of surface-enhanced Raman spectroscopy. AB - Surface-enhanced Raman spectrocopy (SERS) offers ultrasensitive vibrational fingerprinting at the nanoscale. Its non-destructive nature affords an ideal tool for interrogation of the intracellular environment, detecting the localisation of biomolecules, delivery and monitoring of therapeutics and for characterisation of complex cellular processes at the molecular level. Innovations in nanotechnology have produced a wide selection of novel, purpose-built plasmonic nanostructures capable of high SERS enhancement for intracellular probing while microfluidic technologies are being utilised to reproducibly synthesise nanoparticle (NP) probes at large scale and in high throughput. Sophisticated multivariate analysis techniques unlock the wealth of previously unattainable biomolecular information contained within large and multidimensional SERS datasets. Thus, with suitable combination of experimental techniques and analytics, SERS boasts enormous potential for cell based assays and to expand our understanding of the intracellular environment. In this review we trace the pathway to utilisation of nanomaterials for intracellular SERS. Thus we review and assess nanoparticle synthesis methods, their toxicity and cell interactions before presenting significant developments in intracellular SERS methodologies and how identified challenges can be addressed. PMID- 27479538 TI - Genomic characterization of response to chemoradiation in urothelial bladder cancer. AB - BACKGROUND: The authors characterized the genetic landscape of chemoradiation treated urothelial carcinoma of the bladder (UCB) with the objective of identifying potential correlates of response. METHODS: Primary tumors with (n = 8) or without (n = 40) matched recurrent tumors from 48 patients who had non metastatic, high-grade UCB and received treatment primarily with chemoradiation were analyzed using a next-generation sequencing assay enriched for cancer related and canonical DNA damage response (DDR) genes. Protein expression of meiotic recombination 11 homolog (MRE11), a previously suggested biomarker, was assessed in 44 patients. Recurrent tumors were compared with primary tumors, and the clinical impact of likely deleterious DDR gene alterations was evaluated. RESULTS: The profile of alterations approximated that of prior UCB cohorts. Within 5 pairs of matched primary-recurrent tumors, a median of 92% of somatic mutations were shared. A median 33% of mutations were shared between 3 matched bladder-metastasis pairs. Of 26 patients (54%) who had DDR gene alterations, 12 (25%) harbored likely deleterious alterations. In multivariable analysis, these patients displayed a trend toward reduced bladder recurrence (hazard ratio, 0.32; P = .070) or any recurrence (hazard ratio, 0.37; P = .070). The most common of these alterations, ERCC2 (excision repair cross-complementation group 2) mutations, were associated with significantly lower 2-year metastatic recurrence (0% vs 43%; log-rank P = .044). No impact of MRE11 protein expression on outcome was detected. CONCLUSIONS: A similar mutation profile between primary and recurrent tumors suggests that pre-existing, resistant clonal populations represent the primary mechanism of chemoradiation treatment failure. Deleterious DDR genetic alterations, particularly recurrent alterations in ERCC2, may be associated with improved chemoradiation outcomes in patients with UCB. A small sample size necessitates independent validation of these observations. Cancer 2016;122:3715-23. (c) 2016 American Cancer Society. PMID- 27479541 TI - Design, synthesis and biological evaluation of coumarin derivatives as novel acetylcholinesterase inhibitors that attenuate H2O2-induced apoptosis in SH-SY5Y cells. AB - A novel series of coumarin derivatives were designed, synthesized and investigated for inhibition of cholinesterase, including acetyl cholinesterase (AChE) and butyrylcholinesterase (BuChE). This biological study showed that these compounds containing piperazine ring had significant inhibition activities on AChE rather than BuChE. Further study suggested that 9x, as one of this kind of structure derivative, showed the strongest inhibition activity on AChE with an IC50 value of 34nM. Moreover, molecular docking, flow cytometry (FCM), and western blot assay suggested that 9x could induce cytoprotective autophagy to attenuate H2O2-induced cell death in human neuroblastoma SH-SY5Y cells. These findings highlight a new approach for the development of a novel potential neuroprotective compound targeting AChE with autophagy-inducing activity in future Alzheimer's disease (AD) therapy. PMID- 27479542 TI - Metabolic disorders and the risk of nasopharyngeal carcinoma: a case-control study in Italy. AB - The aim of this study is to evaluate the association between metabolic disorders and the risk of nasopharyngeal carcinoma, considering different histological subtypes. Between 1992 and 2008, we carried out a multicentre case-control study in Italy. One-hundred and ninety-seven White patients with histologically confirmed nasopharyngeal carcinoma were enrolled as cases. The control group included 592 cancer-free patients, frequency matched by study centre, area of residence, sex, age and period of interview. Odds ratios (OR) and corresponding 95% confidence intervals (CI), for nasopharyngeal carcinoma according to obesity and self-reported history of other metabolic disorders, were calculated through logistic regression models adjusted for matching variables and tobacco smoking and drinking habits. Obesity (OR=1.44; 95% CI: 0.88-2.36), diabetes mellitus (OR=0.91; 95% CI: 0.42-1.98), hypertension (OR=0.79; 95% CI: 0.48-1.32), hypercholesterolaemia (OR=1.41; 95% CI: 0.84-2.35) and metabolic syndrome (i.e. at least three among the four previously cited metabolic disorders; OR=1.11; 95% CI: 0.86-1.43) were not significantly associated with the overall risk of nasopharyngeal carcinoma. However, the associations observed for diabetes mellitus, hypercholesterolaemia and metabolic syndrome were stronger among differentiated nasopharyngeal carcinomas than among undifferentiated ones. In particular, 21.7% of differentiated nasopharyngeal carcinoma cases and 7.8% of controls reported a history of metabolic syndrome (OR=3.37; 95% CI: 1.05-10.81). The results of the study indicated no overall association between metabolic disorders and nasopharyngeal carcinoma. Nonetheless, although the small sample size calls for caution in interpretation, metabolic disorders could increase the risk of differentiated nasopharyngeal carcinoma. This finding further supports a different aetiology of the two histological subtypes. PMID- 27479543 TI - The Search for Better Patient Handoff Tools. PMID- 27479545 TI - X-ray Structure Analysis of Ozonides by the Crystalline Sponge Method. AB - The crystalline sponge method was used for the X-ray structure analysis of ozonide compounds. As this new technique requires only microgram quantities of the samples, structural analysis can be conducted without product isolation, isomer separation, or crystallization and most importantly without any risk of explosion. PMID- 27479544 TI - Bacterial infections in pediatric hematopoietic stem cell transplantation recipients: incidence, epidemiology, and spectrum of pathogens: report of the Polish Pediatric Group for Hematopoietic Stem Cell Transplantation. AB - BACKGROUND: Infectious complications are a significant cause of hematopoietic stem cell transplantation (HSCT) failure, especially allogeneic HSCT (allo-HSCT) because of delayed immune reconstitution and graft-versus-host disease (GVHD) occurrence. Identifying the factors responsible for bacterial infections (BI) in patients undergoing HSCT will provide much more effective empirical antimicrobial treatment in this group of patients. OBJECTIVE: The aim of this study was to evaluate the epidemiology and profile of BI in patients after HSCT in 5 centers of the Polish Pediatric Group for Hematopoietic Stem Cell Transplantation in 2012 2013. PATIENTS AND METHODS: In 308 HSCT recipients, we retrospectively analyzed 273 episodes of BI in 113 (36.7%) children aged 0.02-22 years (median age: 7 years), 92 after allo-HSCT and 22 after autologous HSCT (auto-HSCT). We assessed incidence of BI in different HSCT types by calculating the Index of Bacterial Infection (IBI) as a ratio of patients with at least 1 BI to all patients who underwent this type of HSCT in the analyzed period. We assessed the profile of BI with particular emphasis on multidrug-resistant organisms, and impact of underlying disease and of graft-versus-host disease on BI episodes. RESULTS: In the studied group, 273 episodes of BI were diagnosed, including 237 episodes after allo-HSCT and 36 after auto-HSCT. Among allo-HSCT recipients diagnosed with at least 1 BI, the IBI was 0.4 (matched sibling donor-HSCT 0.3; matched donor HSCT 0.4; mismatched unrelated donor [MMUD]-HSCT 0.8; P = 0.027) and after auto HSCT 0.3 per 1 transplanted patient. In patient after allo-HSCT because of myelo- or lymphoproliferative diseases and bone marrow failures, the major cause of infections was Enterobacteriaceae, while gram-positive bacteria predominated in the group with primary immunodeficiencies. In all patients after auto-HSCT, the dominant pathogen of BI were Enterobacteriaceae (P = 0.011). Time from each type of HSCT to infection caused by different pathogens did not differ significantly. CONCLUSIONS: The risk of BI does not depend on the underlying disease, but only on HSCT donor type and is the highest after MMUD-HSCT procedure. The profile of BI depends on the underlying disease and HSCT donor type, but does not depend on the occurrence of acute GVHD. Gram-negative bacteria predominated in patients with myelo- and lymphoproliferative diseases, while in patients with primary immunodeficiencies gram-positive strains were predominant. PMID- 27479546 TI - Hydrozoan insights in animal development and evolution. AB - The fresh water polyp Hydra provides textbook experimental demonstration of positional information gradients and regeneration processes. Developmental biologists are thus familiar with Hydra, but may not appreciate that it is a relatively simple member of the Hydrozoa, a group of mostly marine cnidarians with complex and diverse life cycles, exhibiting extensive phenotypic plasticity and regenerative capabilities. Hydrozoan species offer extensive opportunities to address many developmental mechanisms relevant across the animal kingdom. Here we review recent work from non-Hydra hydrozoans - hydromedusae, hydroids and siphonophores - shedding light on mechanisms of oogenesis, embryonic patterning, allorecognition, stem cell regulation and regeneration. We also highlight potential research directions in which hydrozoan diversity can illuminate the evolution of developmental processes at micro- and macro-evolutionary time scales. PMID- 27479547 TI - Glucose- or insulin resistance-mediated beta-cell replication: PKCzeta integrates the proliferative signaling. AB - Glucose- or insulin resistance-mediated beta-cell replication serves as a useful physiological model of beta-cell mass expansion to study the pathophysiology of type 2 diabetes. Lakshmipathi et al. (2016) report that PKCzeta activation is crucial for compensatory beta-cell proliferation induced by glucose stimulation or high-fat diet-feeding. PMID- 27479548 TI - A Young Man With Recurrent Coma and Refractory Status Epilepticus. PMID- 27479549 TI - Oxidized-LDL immunization for the treatment of atherosclerosis: how far are we? PMID- 27479551 TI - Brexit and junior doctors' contracts: the real threats to the NHS. PMID- 27479550 TI - Drug-eluting versus bare metal stent in treatment of patients with saphenous vein graft disease: A meta-analysis of randomized controlled trials. AB - Drug-eluting stent (DES) and bare metal stent (BMS) are effective treatments for preventing vascular disease, but whether using DES is associated with positive clinical outcomes compared with BMS in patients with saphenous vein graft disease (SVGD) has not been established. Three electronic databases including PubMed, EmBase, and the Cochrane Central Register of Controlled Trials were searched to identify potentially includible studies. We did a random-effects meta-analysis of randomized controlled trials (RCTs) to obtain summary effect estimates for the clinical outcomes with the use of relative risk calculated from the raw data of individual trial. Among 812 patients from 4 RCTs, DES was associated with lower risk of short-term major cardiovascular events (MACEs) when compared with BMS, whereas no significant effect on the risk of long-term MACEs. Furthermore, there was no significant difference between DES and BMS for short-term myocardial infarction (MI) and long-term MI. Similarly, DES was not associated with risk of short- and long-term mortality risk as compared with BMS. In addition, DES has no significant effect on the risk of cardiac death and stent thrombosis. Finally, DES therapy significantly reduced the risk of TLR, TVF, and TVR. SVGD patients received DES can minimize the risk of short-term MACEs, TLR, TVF, and TVR when compared with BMS. However, it does not effect on the incidence of long-term MACEs, MI, mortality, cardiac death, and stent thrombosis. PMID- 27479552 TI - The USA's dangerous driving culture. PMID- 27479553 TI - No peace of mind in South Sudan. PMID- 27479555 TI - Human resources for health: time to move out of crisis mode. PMID- 27479554 TI - UN High-Level Meeting on antimicrobials--what do we need? PMID- 27479556 TI - The Lancet Public Health: a new journal and a call for papers. PMID- 27479558 TI - The long road to gun control in America. PMID- 27479559 TI - "Under severe duress": health care in Iraq. PMID- 27479560 TI - Irene Tracey: seeing pain for what it is. PMID- 27479561 TI - Restoring perspective on the doctors' strike. PMID- 27479562 TI - Gun violence prevention. PMID- 27479563 TI - Gun violence prevention. PMID- 27479564 TI - STAMPEDE trial and patients with non-metastatic prostate cancer. PMID- 27479565 TI - Gun violence prevention - Authors' reply. PMID- 27479566 TI - STAMPEDE trial and patients with non-metastatic prostate cancer - Authors' reply. PMID- 27479567 TI - Everolimus in ileum neuroendocrine tumours. PMID- 27479568 TI - Everolimus in ileum neuroendocrine tumours - Authors' reply. PMID- 27479569 TI - Dengue vaccine and the 2016 Olympics. PMID- 27479570 TI - Duplicate publication. PMID- 27479572 TI - Long-Term Outcome and Recurrence of Idiopathic Choroidal Neovascularization Treated with Intravitreal Bevacizumab. AB - PURPOSE: To evaluate the long-term outcome of intravitreal bevacizumab treatment for idiopathic choroidal neovascularization (CNV) and to investigative the influence of CNV recurrence on visual prognosis. METHODS: This retrospective study included 26 patients (26 eyes) who had been diagnosed with idiopathic CNV and followed up for at least 2 years. All the eyes included had been treated with intravitreal bevacizumab. The best-corrected visual acuity (BCVA) at diagnosis was compared with that at final follow-up. The final BCVA of patients who experienced CNV recurrence was compared with that of patients who did not. RESULTS: The mean follow-up period after diagnosis was 33.9 +/- 10.6 months. During this period, a mean of 2.5 +/- 1.7 bevacizumab injections were administered. The mean logarithm of the minimal angle of resolution (logMAR) BCVAs at diagnosis, 6 months, 12 months, and final follow-up was 0.48 +/- 0.38, 0.28 +/- 0.36, 0.25 +/- 0.35, and 0.20 +/- 0.26, respectively. The final BCVA was significantly improved over the baseline value. CNV recurred in 8 patients (30.8%), 3 of whom experienced 2 recurrences; the mean timing of recurrence was 19.7 +/- 15.5 months after diagnosis. The final BCVA in patients who experienced recurrence (mean 0.21 +/- 0.19 logMAR) did not differ from that in patients who did not (mean 0.19 +/- 0.29 logMAR). CONCLUSIONS: The long-term outcome of intravitreal bevacizumab treatment for idiopathic CNV was generally favorable. Although CNV recurrence was noted in 30.8% of patients, the recurrence may not significantly influence long-term visual prognosis. PMID- 27479571 TI - Functional characterization of the Aspergillus nidulans glucosylceramide pathway reveals that LCB Delta8-desaturation and C9-methylation are relevant to filamentous growth, lipid raft localization and Psd1 defensin activity. AB - C8-desaturated and C9-methylated glucosylceramide (GlcCer) is a fungal-specific sphingolipid that plays an important role in the growth and virulence of many species. In this work, we investigated the contribution of Aspergillus nidulans sphingolipid Delta8-desaturase (SdeA), sphingolipid C9-methyltransferases (SmtA/SmtB) and glucosylceramide synthase (GcsA) to fungal phenotypes, sensitivity to Psd1 defensin and Galleria mellonella virulence. We showed that DeltasdeA accumulated C8-saturated and unmethylated GlcCer, while gcsA deletion impaired GlcCer synthesis. Although increased levels of unmethylated GlcCer were observed in smtA and smtB mutants, DeltasmtA and wild-type cells showed a similar 9,Me-GlcCer content, reduced by 50% in the smtB disruptant. The compromised 9,Me GlcCer production in the DeltasmtB strain was not accompanied by reduced filamentation or defects in cell polarity. When combined with the smtA deletion, smtB repression significantly increased unmethylated GlcCer levels and compromised filamentous growth. Furthermore, sdeA and gcsA mutants displayed growth defects and raft mislocalization, which were accompanied by reduced neutral lipids levels and attenuated G. mellonella virulence in the DeltagcsA strain. Finally, DeltasdeA and DeltagcsA showed increased resistance to Psd1, suggesting that GlcCer synthesis and fungal sphingoid base structure specificities are relevant not only to differentiation but also to proper recognition by this antifungal defensin. PMID- 27479573 TI - Enhanced magnetocrystalline anisotropy of Fe30Co70 nanowires by Cu additives and annealing. AB - The use of 3d transition metal-based magnetic nanowires (NWs) for permanent magnet applications requires large magnetocrystalline anisotropy energy (MAE), which in combination with the NWs' magnetic shape anisotropy yields magnetic hardening and an enhancement of the magnetic energy product. Here, we report on the significant increase in MAE by 125 kJ m(-3) in Fe30Co70 NWs with diameters of 20-150 nm embedded in anodic aluminum oxide templates by adding 5 at.% Cu and subsequent annealing at 900 K. Ferromagnetic resonance (FMR) reveals that this enhancement of MAE is twice as large as the enhancement of MAE in annealed, but undoped NWs. X-ray diffraction (XRD) analysis suggests that upon annealing the immiscible Cu in FeCo NWs causes a crystal reorientation with respect to the NW axis with a considerable distortion of the bcc FeCo lattice. This strain is most likely the origin of the strongly enhanced MAE. PMID- 27479574 TI - Investigating the Role of the Stringent Response in Lipid Modifications during the Stationary Phase in E. coli by Direct Analysis with Time-of-Flight-Secondary Ion Mass Spectrometry. AB - Escherichia coli is able to rapidly adjust the biophysical properties of its membrane phospholipids to adapt to environmental challenges including starvation stress. These membrane lipid modifications were investigated in glucose starved E. coli cultures and compared to a DeltarelADeltaspoT (ppGpp(0)) mutant strain of E. coli, deficient in the stringent response, by means of time-of-flight secondary ion mass spectrometry (TOF-SIMS). Recent advances in TOF-SIMS, through the implementation of gas cluster ion beams (GCIBs), now permit the analysis of higher mass species from native, underivatized, biological specimen, i.e., intact bacterial cells. Cultures in stationary phase were found to exhibit a radically different lipid composition as compared to cultures in the exponential growth phase. Wild-type E. coli reacted upon carbon starvation by lipid modifications including elongation, cyclopropanation, and increased cardiolipin formation. Observations are consistent with variants of cardiolipins (CL), phosphatidylglycerols (PG), phosphatidylethanolamines (PE), phosphatidic acids (PA), and fatty acids. Notably, despite having a proteomic profile and a gene expression profile somewhat similar to the wild-type during growth, the ppGpp(0) mutant E. coli strain was found to exhibit modified phospholipids corresponding to unsaturated analogues of those found in the wild-type. We concluded that the ppGpp(0) mutant reacts upon starvation stress by elongation and desaturation of fatty acyl chains, implying that only the last step of the lipid modification, the cyclopropanation, is under stringent control. These observations suggest alternative stress response mechanisms and illustrate the role of the RelA and SpoT enzymes in the biosynthetic pathway underlying these lipid modifications. PMID- 27479575 TI - [Attempted Suicide: One Bullet in Each Orbit?] PMID- 27479576 TI - [Analysis of Anti-VEGF Intravitreal Injection Treatment in Clinical Practice]. AB - BACKGROUND: As AMD patients are very often administered intravitreal operative drugs (IVOM), the relevant procedure in ophthalmological institutes was examined in the present project: A questionnaire was used to collect data on structures, criteria and time expended in the treatment in single or small practices, clinics and (university) departments of ophthalmology. 42 facilities participated in the main study. RESULTS: The patient is usually given an appointment within two weeks of the first contact. If the patient has AMD requiring treatment, the first IVOM is administered within up to two weeks. This often lasts no longer than three hours. The follow-ups after the injection cycle may last up to one hour. If the findings are stable, there is normally a new follow-up after four weeks. The criterion for retreatment is always given as SD-OCT, followed by vision and funduscopy. The next appointment for injection is normally within one week. In diagnostic testing, angiography is almost as important as SD-OCT, funduscopy and vision, but is rarely used as a criterion for retreatment. The main differences in the organisation of the treatment plan are in the time course of the first IVOM and the follow-ups after the injection cycle. In this respect, practice clinics and individual or group practices may be quicker than departments of ophthalmology. One third of the surveyed facilities stated that they cooperated in diagnostic testing. These cooperating facilities repeat many investigations, both in diagnostic testing and in follow-ups. CONCLUSION: Bearing in mind that IVOM patients have a special interest in timely treatment, it would be desirable to shorten the waiting times, both for injection appointments and during treatment. Cooperation between the different service providers is sensible if this shortens the treatment pathways and relieve the patient and ophthalmologist. Moreover, both groups could benefit from standard and efficient treatment pathways, as these simplify patient care, increase the patient's satisfaction with the treatment and therefore tend to increase compliance. PMID- 27479577 TI - [Bruch's Membrane Opening in OCT in Correlation with Corneal Correction - a Pilot Study]. AB - : Background: The measurement by optical coherence tomography (OCT) of the Bruch membrane opening (BMO) and the thinnest retinal fiber nerve layer in relation to it (BMO-MRW) has been performed in clinical routine since 2014. To compensate for astigmatism, or increased or decreased corneal power, a correction is performed through the mean K-value of the measured eye. The aim of this study was to measure the value of this correction and its influence on the measurement results. Methods: The sectors of BMO-MRW and BMO values of the five right eyes of five healthy patients were measured five times each with Heidelberg Spectralis OCT. Corneal compensation was systematically raised with each single measurement (7.1, 7.4, 7.7, 8.0, 8.3 mm). RESULTS: The data showed almost linear dependence on the given corneal compensation values, with intraindividual variability. For the BMO-MRW, only small effects of compensation were found (0.85 up to 1.97 % per K-value difference of 0.3 mm). For BMO, the effect was greater, with a mean change of 7.71 % for every 0.3 mm change in compensation. Conclusion: For BMO MRW, corneal compensation is of low clinical relevance. BMO is more dependent on this correction. In follow-up measurements, the compensation might not account for significant changes, although we recommend using correct corneal compensation values when obtaining single or first-time measurements. PMID- 27479578 TI - [Interaction Between Medical Experts and Professional Associations in Accidents at Work]. PMID- 27479579 TI - [Proliferative Vitreoretinopathy: Therapeutic Strategies]. AB - BACKGROUND: Development of proliferative vitreoretinopathy (PVR) is one of the most important complications of vitreoretinal surgery. Reaching the decision to treat and surgical treatment itself are both challenging. MATERIALS AND METHODS: Our own data and a review of the literature in PubMed are summarised. RESULTS: Pharmacological approaches to the prevention and treatment of proliferative vitreoretinopathy have been limited to concepts that have been investigated in preclinical and a few clinical studies. Anti-inflammatory and antiproliferative substances may be mentioned in this context. Surgical techniques range from scleral buckling to the gold standard pars plana vitrectomy, preferably with silicone oil endotamponade. Applying an encircling band, retinotomy or retinectomy can be useful in reattaching the tractional shortened retina. CONCLUSION: Surgery is still the method of choice for the treatment of PVR. Pharmacological strategies to prevent or treat PVR have not been established. PMID- 27479580 TI - [Stem Cells for Retina Replacement]. AB - In ophthalmology, regenerative medicine is rapidly becoming a reality. Cell based treatment strategies in end stage retinal degeneration may be of therapeutic value, whatever the mechanism of disease mechanism. However, while corneal transplantation is commonly performed with excellent results, many obstacles must be overcome before retinal transplants can become clinically useful. The major problems are the production of appropriate transplants and functional integration in situ. New technologies allow the production of autologous transplants by inducing pluripotency in adult somatic cells. Driven by this development, exciting new research has been conducted on the development of artificial retinal tissue for basic research and transplantation. This article reviews this progress and discusses its clinical utility. PMID- 27479581 TI - [Proliferative Vitreoretinopathy]. AB - Proliferative vitreoretinal retinopathy (PVR) is a very severe complication of vitreoretinal surgery. PVR is characterised by a complex cellular reaction. This corresponds to a vitreoretinal wound healing reaction and leads to tractional retinal detachment fixed by membranes. A rational goal of treatment is the removal of active cells and membranes, particularly the whole vitreous body; this can only be achieved surgically. PMID- 27479582 TI - Disulfide-Bridged (Mo3S11) Cluster Polymer: Molecular Dynamics and Application as Electrode Material for a Rechargeable Magnesium Battery. AB - Exploring novel electrode materials is critical for the development of a next generation rechargeable magnesium battery with high volumetric capacity. Here, we showed that a distinct amorphous molybdenum sulfide, being a coordination polymer of disulfide-bridged (Mo3S11) clusters, has great potential as a rechargeable magnesium battery cathode. This material provided good reversible capacity, attributed to its unique structure with high flexibility and capability of deformation upon Mg insertion. Free-terminal disulfide moiety may act as the active site for reversible insertion and extraction of magnesium. PMID- 27479583 TI - Reverse Stability of Oxyluciferin Isomers in Aqueous Solutions. AB - We investigated the stability of oxyluciferin anions (keto, enol, and enolate isomers) in aqueous solution at room temperature by performing a nanosecond time scale first-principles molecular dynamics simulation. In contrast to all previous quantum chemistry calculations, which suggested the keto-type to be the most stable, we show that the enol-type is slightly more stable than the keto-type, in agreement with some recent experimental studies. The simulation highlights the remarkable hydrophobicity of the keto-type by the cavity formed at the oxyluciferin-water interface as well as a reduction in hydrophobicity with the number of hydrating water molecules. It is therefore predicted that the isomeric form in a hydrated cluster is size-dependent. PMID- 27479585 TI - A Taylor-Affine Arithmetic for analyzing the calculation result uncertainty in accident reconstruction. AB - In order to analyze the uncertainty of a reconstructed result, the Interval Algorithm (IA), the Affine Arithmetic (AA) and the Modified Affine Arithmetic (MAA) were introduced firstly, and then a Taylor-Affine Arithmetic (TAA) was proposed based on the MAA and Taylor series. Steps of the TAA, especially in analyzing uncertainty of a simulation result were given. Through the preceding five numerical cases, its application was demonstrated and its feasibility was validated. Results showed that no matter other methods (The IA, AA, the Upper and Lower bound Method, the Finite Difference Method) work well or bad, the TAA work well, even under the condition that the MAA cannot work in some cases because of the division/root operation in these models. Furthermore, in order to make sure that the result obtained from the TAA can be very close to the accurate interval, a simple algorithm was proposed based on the sub-interval technique, its feasibility was validated by two other numerical cases. Finally, a vehicle pedestrian test was given to demonstrate the application of the TAA in practice. In the vehicle-pedestrian test, the interval [35.5, 39.1]km/h of the impact velocity can be calculated according to steps of the TAA, such interval information will be more useful in accident responsibility identification than a single number. This study will provide a new alternative method for uncertainty analysis in accident reconstruction. PMID- 27479584 TI - An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection. AB - Scrub typhus is a neglected tropical disease, caused by Orientia tsutsugamushi, a Gram-negative bacterium that is transmitted to mammalian hosts during feeding by Leptotrombidium mites and replicates predominantly within endothelial cells. Most studies of scrub typhus in animal models have utilized either intraperitoneal or intravenous inoculation; however, there is limited information on infection by the natural route in murine model skin or its related early host responses. Here, we developed an intradermal (i.d.) inoculation model of scrub typhus and focused on the kinetics of the host responses in the blood and major infected organs. Following ear inoculation with 6 x 104 O. tsutsugamushi, mice developed fever at 11-12 days post-infection (dpi), followed by marked hypothermia and body weight loss at 14-19 dpi. Bacteria in blood and tissues and histopathological changes were detected around 9 dpi and peaked around 14 dpi. Serum cytokine analyses revealed a mixed Th1/Th2 response, with marked elevations of MCP-1/CCL2, MIP 1alpha/CCL3 and IL-10 at 9 dpi, followed by increased concentrations of pro inflammatory markers (IL-6, IL-12, IFN-gamma, G-CSF, RANTES/CCL5, KC/CCL11, IL 1alpha/beta, IL-2, TNF-alpha, GM-CSF), as well as modulatory cytokines (IL-9, IL 13). Cytokine levels in lungs had similar elevation patterns, except for a marked reduction of IL-9. The Orientia 47-kDa gene and infectious bacteria were detected in several organs for up to 84 dpi, indicating persistent infection. This is the first comprehensive report of acute scrub typhus and persistent infection in i.d. inoculated C57BL/6 mice. This is a significant improvement over current murine models for Orientia infection and will permit detailed studies of host immune responses and infection control interventions. PMID- 27479587 TI - Interactions, Structure, and Dynamics of Polymer-Tethered Nanoparticle Blends. AB - We report on the structure, jamming, and dynamics of blends of self-suspended hairy silica nanoparticles grafted with poly(ethylene glycol) (PEG) and poly(methyl methacrylate) (PMMA). We find that favorable enthalpic attraction between tethered PEG and PMMA chains augment previously reported entropic attractions between tethered polymer chains in self-suspended suspensions to enhance particle-particle correlations, increase jamming, and slow down chain dynamics. As with their single-component counterparts, the hairy SiO2-PEG/SiO2 PMMA nanoparticle blends exhibit soft glassy rheological behavior and both the energy dissipated at yielding and the plateau elastic modulus display strong maxima in the symmetric case. A comparison of the small angle X-ray scattering (SAXS) measurements with theoretical analysis from density functional theory (DFT) reveals that the addition of SiO2-PMMA to a self-suspended SiO2-PEG suspension initially leads to a higher degree of stretching of the corona chains, which produces stronger interdigitation of the tethered chains, enhanced jamming, and slower polymer relaxation than observed in the single-component materials. By means of an analysis of the heat of mixing released upon blending tethered and untethered PEG and PMMA chains, we find that the strong enthalpic attraction between the grafted polymer chains enhances entropic attractive forces produced by the space-filling constraint on tethered ligands in self-suspended suspensions to produce entangled-polymer-like physical properties in polymers with molecular weights below the thresholds normally associated with the transition to an entangled state. PMID- 27479586 TI - Detection of Acetaminophen-Protein Adducts in Decedents with Suspected Opioid Acetaminophen Combination Product Overdose. AB - Acetaminophen overdose is a leading cause of drug-induced liver failure in the United States. Acetaminophen-protein adducts have been suggested as a biomarker of hepatotoxicity. The purpose of this study was to determine whether protein derived acetaminophen-protein adducts are quantifiable in postmortem samples. Heart blood, femoral blood, and liver tissue were collected at autopsy from 22 decedents suspected of opioid-acetaminophen overdose. Samples were assayed for protein-derived acetaminophen-protein adducts, acetaminophen, and selected opioids found in combination products containing acetaminophen. Protein-derived APAP-CYS was detected in 17 of 22 decedents and was measurable in blood that was not degraded or hemolyzed. Heart blood concentrations ranged from 11 ng/mL (0.1 MUM) to 7817 ng/mL (28.9 MUM). Protein-derived acetaminophen-protein adducts were detectable in liver tissue for 20 of 22 decedents. Liver histology was also performed for all decedents, and no evidence of centrilobular hepatic necrosis was observed. PMID- 27479589 TI - Correction: Assessing Greater Sage-Grouse Selection of Brood-Rearing Habitat Using Remotely-Sensed Imagery: Can Readily Available High-Resolution Imagery Be Used to Identify Brood-Rearing Habitat Across a Broad Landscape? AB - [This corrects the article DOI: 10.1371/journal.pone.0156290.]. PMID- 27479588 TI - Genome-Wide Association Study Reveals the Genetic Basis of Stalk Cell Wall Components in Maize. AB - Lignin, cellulose and hemicellulose are the three main components of the plant cell wall and can impact stalk quality by affecting cell wall structure and strength. In this study, we evaluated the lignin (LIG), cellulose (CEL) and hemicellulose (HC) contents in maize using an association mapping panel that included 368 inbred lines in seven environments. A genome-wide association study using approximately 0.56 million SNPs with a minor allele frequency of 0.05 identified 22, 18 and 24 loci significantly associated with LIG, CEL and HC at P < 1.0*10-4, respectively. The allelic variation of each significant association contributed 4 to 7% of the phenotypic variation. Candidate genes identified by GWAS mainly encode enzymes involved in cell wall metabolism, transcription factors, protein kinase and protein related to other biological processes. Among the association signals, six candidate genes had pleiotropic effects on lignin and cellulose content. These results provide valuable information for better understanding the genetic basis of stalk cell wall components in maize. PMID- 27479591 TI - Variations of Runoff and Sediment Load in the Middle and Lower Reaches of the Yangtze River, China (1950-2013). AB - On the basis of monthly runoff series obtained in 1950-2013 and annual sediment load measured in 1956--2013 at five key hydrological stations in the middle and lower reaches of the Yangtze River basin, this study used the Mann-Kendall methods to identify trend and abrupt changes of runoff and sediment load in relation to human activities. The results were as follows: (1) The annual and flood season runoffs showed significant decreasing trends at Yichang station, and showed slight downward trends at Hankou and Datong stations, while the abrupt changes of dry season runoff at Yichang, Hankou and Datong stations occurred in about 2007 and the change points were followed by significant increasing trends. The construction of the Three Gorges Dam, which began to operate in 2003, influenced the variations of runoff in the mainstream of Yangtze River, but the effect weakened with the distance along the downstream direction from TGD. (2) Since the 1990s, annual sediment loads at Yichang, Hankou, and Datong stations have been decreasing significantly, and after 2002, the annual sediment load at Yichang dropped below that of Hankou and Datong. The dams and deforestation/forestation contributed to the significant decreasing trend of the sediment load. In addition, the Three Gorges Dam aggravated the downward trend and caused the erosion of the riverbed and riverbanks in the middle and lower reaches. (3) The runoff and sediment load flowing from Dongting Lake into the mainstream of the Yangtze River showed significant decreasing trends at Chenglingji station after 1970s, and in contrast, slight increase in the sediment flow from Poyang Lake to the mainstream of the Yangtze River at Hukou station were detected over the post-TGD period (2003-2013). The result of the study will be an important foundation for watershed sustainable development of the Yangtze River under the human activities. PMID- 27479592 TI - Meaningful Engagement of ACOs With Communities: The New Population Health Management. AB - OBJECTIVES: Population health management (PHM) activities within health care organizations have traditionally focused on coordinating services for populations who present for care in physicians' offices. With the recent proliferation of Accountable Care Organizations (ACOs), however, the reach of PHM has expanded. We aimed to study ACOs' evolving definitions of their patient populations, and how these definitions might be linked to different types of PHM activities pursued by ACOs. METHODS: Over a 2-year period, we conducted in-depth case studies of 4 ACOs operating in the private sector, including 149 interviews with 89 informants. Although the main study focused on the ACO implementation process, our use of both inductive and deductive qualitative methods enabled us to study emergent topics such as we report here about PHM. RESULTS: Interviewees across sites described their ACO populations using terms indicating both panel management and community/neighborhood involvement in the context of PHM. Further, all 4 sites reported conducting PHM activities that extended beyond traditional provider based PHM; these ranged from wellness registries to school-based clinics. Executives at all 4 ACOs also discussed providing, or planning to provide, health care services to all community members in local settings. CONCLUSIONS: Administrators and physicians in private sector ACOs were proponents of ACO-led programs delivered in community settings that provided health care to all members of the community, and reported their ACOs engaged in multisector collaborations designed to improve neighborhood health. These community engagement activities point to a distinction from 90s era managed and integrated care organizations and may contribute to the sustainability of the ACO model. PMID- 27479594 TI - Reference Pricing, Consumer Cost-Sharing, and Insurer Spending for Advanced Imaging Tests. AB - BACKGROUND: Fees charged for similar imaging tests often vary dramatically within the same market, leading to wide variation in insurer spending and consumer cost sharing. Reference pricing is an insurance design that offers good coverage to patients up to a defined contribution limit but requires the patients who select high-priced facilities to pay the remainder out of pocket. OBJECTIVES: To measure the association between implementation of reference pricing and patient choice of facility, test prices, out-of-pocket spending, and insurer spending for advanced imaging (CT and MRI) procedures. RESEARCH DESIGN: Difference-in-differences multivariable analysis of insurance claims data. Study included 4751 employees of a national grocery chain (treatment group) and 23,428 enrollees in the nation's largest private insurance plan (comparison group) that used CT or MRI tests between 2010 and 2013. MEASURES: Patient choice of facility, price paid per test, patient out-of-pocket cost-sharing, and employer spending. RESULTS: Compared with trends in prices paid by insurance enrollees not subject to reference pricing, and after adjusting for characteristics of tests and patients, implementation of reference pricing was associated with a 12.5% (95% CI, -25.0%, 2.1%) reduction in average price paid per test by the end of the second full year of the program for CT scans and a 10.5% (95% CI, -16.9%, 3.6%) for MRIs. Out-of-pocket cost-sharing by patients declined by $71,508 (13.8%). The savings accruing to employees amounted to 45.5% of total savings from reference pricing, with the remainder accruing to the employer. CONCLUSIONS: Implementation of reference pricing led to reductions in payments by both employer and employees. PMID- 27479595 TI - The ACA's Zero Cost-Sharing Mandate and Trends in Out-of-Pocket Expenditures on Well-Child and Screening Mammography Visits. AB - BACKGROUND: Starting in September of 2010, the Patient Protection and Affordable Care Act required most health insurance policies to cover evidence-based preventive care with no cost-sharing (no copays, coinsurance, or deductibles). It is unknown, however, whether declines in out-of-pocket costs for preventive services are large enough to prompt increases in utilization, the ultimate goal of the policy. METHODS: In this study, we use a nationally representative sample of ambulatory care visits to estimate the impact of the zero cost-sharing mandate on out-of-pocket expenditures on well-child and screening mammography visits. Estimates are made using 2-part interrupted time-series models, with well-woman visits serving as the control group because they were not covered under the zero cost-sharing mandate until after our study period. RESULTS: Results indicate a substantial reduction in out-of-pocket costs attributable to the Affordable Care Act. Between January 2011 and September 2012, the zero cost-sharing mandate reduced per-visit out-of-pocket costs for well-child visits from $18.46 to $8.08 (56%) and out-of-pocket costs for screening mammography visits from $25.43 to $6.50 (74%). No reduction was apparent for well-woman visits. CONCLUSIONS: The Affordable Care Act's zero cost-sharing mandate for preventive care has had a large impact on out-of-pocket expenditures for well-child and mammography visits. To increase preventive service use, research is needed to better understand barriers to obtaining preventive care that are not directly related to cost. PMID- 27479596 TI - A Statewide Effort to Implement Collaborative Care for Depression: Reach and Impact for All Patients With Depression. AB - BACKGROUND: Little is known about the reach and impact of collaborative care for depression outside of clinical trials. OBJECTIVE: The objective of this study was to examine the effect of a collaborative care intervention for depression on the rates of depression diagnosis, use of specific depression codes, and treatment intensification. RESEARCH DESIGN: Evaluation of a staggered, multiple baseline implementation initiative. SUBJECTS: Patients receiving depression care in primary care clinics throughout Minnesota from February 2008 through March 2011. MEASURES: Data regarding depression diagnosis rates and codes, and measures of antidepressant intensification were provided by health insurers. RESULTS: Depression Improvement Across Minnesota: Offering a New Direction (DIAMOND) affected neither rates of depression recognition nor use of depression diagnostic codes, and the overall reach of DIAMOND was disappointingly small. Patients in DIAMOND had more episodes of treatment intensification than non-DIAMOND patients, but we were unable to account for depression severity in our analysis. CONCLUSIONS: DIAMOND did not affect depression recognition or diagnostic coding, but may have affected treatment intensification. Our results suggest that even strongly evidence-based interventions may have little contamination effects on patients not enrolled in the new care model. PMID- 27479598 TI - A Perspective on Health Services Research: Comparative Effectiveness Research. PMID- 27479599 TI - Effectiveness of Pay-for-Performance Incentive Designs on Diabetes Care. AB - BACKGROUND: Taiwan's National Health Insurance program implemented a pay-for performance (P4P) program based on process measures in 2001. In late 2006, the P4P was revised to also include achievement of outcome measures. OBJECTIVES: This study examined whether a change in P4P incentive design structure affected diabetes outcomes. RESEARCH DESIGN AND METHOD: We used a longitudinal cohort study design using 2 population-based databases. Newly enrolled P4P patients with diabetes in 2002-2003 (phase 1) and 2007-2008 (phase 2) made up the study cohorts. Propensity score matching was used to match comparable cohorts in each phase. In total, 46,286 matched cohorts in phase 1 and 2 were analyzed. Process measures were defined as the provision of tests of glycosylated hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol, and blood pressure, and outcome measures as changes in those values between baseline and last follow-up within 3 years. Patient-level generalized linear regression models were used and patient characteristics, physician characteristics, and health care facility characteristics were adjusted for. RESULTS: Our results indicated that the process measures of HbA1c and low-density lipoprotein cholesterol tests did not differ significantly between the 2 phases. In addition, better improvements were noted in outcome measures for the phase 2 patients (ie, HbA1c level and lipid profiles), whereas nonincentivized intermediate measures (eg, blood pressure) showed no negative unintended consequences. CONCLUSIONS: Quality of care tended to be better when both process and targeted outcome measures were combined as quality metrics in the P4P program in Taiwan. PMID- 27479600 TI - Constructing Episodes of Inpatient Care: How to Define Hospital Transfer in Hospital Administrative Health Data? AB - BACKGROUND: Hospital administrative health data create separate records for each hospital stay of patients. Treating a hospital transfer as a readmission could lead to biased results in health service research. METHODS: This is a cross sectional study. We used the hospital discharge abstract database in 2013 from Alberta, Canada. Transfer cases were defined by transfer institution code and were used as the reference standard. Four time gaps between 2 hospitalizations (6, 9, 12, and 24 h) and 2 day gaps between hospitalizations [same day (up to 24 h), <=1 d (up to 48 h)] were used to identify transfer cases. We compared the sensitivity and positive predictive value (PPV) of 6 definitions across different categories of sex, age, and location of residence. Readmission rates within 30 days were compared after episodes of care were defined at the different time gaps. RESULTS: Among the 6 definitions, sensitivity ranged from 93.3% to 98.7% and PPV ranged from 86.4% to 96%. The time gap of 9 hours had the optimal balance of sensitivity and PPV. The time gaps of same day (up to 24 h) and 9 hours had comparable 30-day readmission rates as the transfer indicator after defining episode of care. CONCLUSIONS: We recommend the use of a time gap of 9 hours between 2 hospitalizations to define hospital transfer in inpatient databases. When admission or discharge time is not available in the database, a time gap of same day (up to 24 h) can be used to define hospital transfer. PMID- 27479601 TI - Trends in the Treatment of Metastatic Colon and Rectal Cancer in Elderly Patients. PMID- 27479602 TI - Mic13 Is Essential for Formation of Crista Junctions in Mammalian Cells. AB - Mitochondrial cristae are connected to the inner boundary membrane via crista junctions which are implicated in the regulation of oxidative phosphorylation, apoptosis, and import of lipids and proteins. The MICOS complex determines formation of crista junctions. We performed complexome profiling and identified Mic13, also termed Qil1, as a subunit of the MICOS complex. We show that MIC13 is an inner membrane protein physically interacting with MIC60, a central subunit of the MICOS complex. Using the CRISPR/Cas method we generated the first cell line deleted for MIC13. These knockout cells show a complete loss of crista junctions demonstrating that MIC13 is strictly required for the formation of crista junctions. MIC13 is required for the assembly of MIC10, MIC26, and MIC27 into the MICOS complex. However, it is not needed for the formation of the MIC60/MIC19/MIC25 subcomplex suggesting that the latter is not sufficient for crista junction formation. MIC13 is also dispensable for assembly of respiratory chain complexes and for maintaining mitochondrial network morphology. Still, lack of MIC13 resulted in a moderate reduction of mitochondrial respiration. In summary, we show that MIC13 has a fundamental role in crista junction formation and that assembly of respiratory chain supercomplexes is independent of mitochondrial cristae shape. PMID- 27479604 TI - Phage-Directed Synthesis of Photoluminescent Zinc Oxide Nanoparticles under Benign Conditions. AB - Biological systems, especially bacteriophages and peptides, are an attractive green alternative to other known methods of nanoparticle synthesis. In this work, for the first time, bacteriophages were employed to synthesize a specific peptide, capable of producing nanoparticles (NPs). Derivatives of M13 bacteriophage exposing a ZnO-binding peptide (TMGANLGLKWPV) on either pIII or pVIII phage coat protein were constructed and used as a biotemplate. The exposition of the ZnO-binding peptide, synthesized by phages during their propagation in bacteria, on M13 virions provided a groundwork for growing ZnO nanostructures. Depending on the recombinant phage type used (M13-pIII-ZnO or M13 pVIII-ZnO), well separated ZnO NPs or complex 3D structures of ZnO NPs of ca. 20 40 nm were synthesized at room temperature. The synthesized ZnO nanoparticles served as a luminescent material that emitted light near the short wavelength end of the visible region (at ca. 400 nm). The next very low intensity emission band at 530 nm demonstrated that the ZnO material obtained is characterized by a low concentration of surface defects. PMID- 27479605 TI - A systematic review of splenic injuries during colonoscopies: Evolving trends in presentation and management. AB - INTRODUCTION: Although uncommon, the incidence of splenic injury from colonoscopy has been increasing significantly since first being reported in 1974. Early recognition is critical because mortality may be as high as 5%. METHODS: We systematically searched PubMed and EMBASE to identify English-language cases of splenic injury from colonoscopy from inception until January 26, 2015. We used descriptive statistics to characterize the identified cases. RESULTS: A total of 172 cases from 122 reports were included. The mean age was 64 years and 70.8% were females. Prior abdominal or pelvic surgeries were identified in 63.8%. 57.3% of patients underwent polypectomies or biopsies. There was a statistically significant increase in use of computerized tomography for diagnosis in the past 5 years (81.8% versus 65.2%). 76.1% patients received transfusions. Mean inpatient length of stay was 7.83 +/- 5.32 days. A non-significant trend toward conservative management was noted in the past 5 years (37.7% versus 23.1%), and a non-significant drop in mortality was noted (4.9% versus 5.4%). DISCUSSION: Our data support prior literature suggesting a higher incidence of splenic injuries during colonoscopies in females, advanced age, prior history of abdominal/pelvic surgeries and biopsies/polypectomies during the procedure. CONCLUSIONS: Significant mortality associated with splenic injuries during colonoscopies warrants prompt recognition of this potentially life threatening, albeit uncommon, complication. PMID- 27479606 TI - delta(15) N from soil to wine in bulk samples and proline. AB - The feasibility of using delta(15) N as an additional isotopic marker able to link wine to its area of origin was investigated. The whole production chain (soil-leaves-grape-wine) was considered. Moreover, the research included evaluation of the effect of the fermentation process, the use of different types of yeast and white and red vinification, the addition of nitrogen adjuvants and ultrasound lysis simulating wine ageing. The delta(15) N of grapes and wine was measured in bulk samples and compounds, specifically in proline, for the first time. Despite isotopic fractionation from soil to wine, the delta(15) N values of leaves, grapes, wine and particularly must and wine proline conserved the variability of delta(15) N in the growing soil. Fermentation and ultrasound treatment did not affect the delta(15) N values of grape must, which was therefore conserved in wine. The addition of inorganic or organic adjuvants was able to influence the delta(15) N of bulk wine, depending on the amount and the difference between the delta(15) N of must and that of the adjuvant. The delta(15) N of wine proline was not influenced by adjuvant addition and is therefore the best marker for tracing the geographical origin of wine. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27479603 TI - Snail/Slug binding interactions with YAP/TAZ control skeletal stem cell self renewal and differentiation. AB - Bone-marrow-derived skeletal stem/stromal cell (SSC) self-renewal and function are critical to skeletal development, homeostasis and repair. Nevertheless, the mechanisms controlling SSC behaviour, particularly bone formation, remain ill defined. Using knockout mouse models that target the zinc-finger transcription factors Snail or Slug, or Snail and Slug combined, a regulatory axis has been uncovered wherein Snail and Slug cooperatively control SSC self-renewal, osteoblastogenesis and bone formation. Mechanistically, Snail/Slug regulate SSC function by forming complexes with the transcriptional co-activators YAP and TAZ in tandem with the inhibition of the Hippo-pathway-dependent regulation of YAP/TAZ signalling cascades. In turn, the Snail/Slug-YAP/TAZ axis activates a series of YAP/TAZ/TEAD and Runx2 downstream targets that control SSC homeostasis and osteogenesis. Together, these results demonstrate that SSCs mobilize Snail/Slug-YAP/TAZ complexes to control stem cell function. PMID- 27479607 TI - Polymer-Based Organic Batteries. AB - The storage of electric energy is of ever growing importance for our modern, technology-based society, and novel battery systems are in the focus of research. The substitution of conventional metals as redox-active material by organic materials offers a promising alternative for the next generation of rechargeable batteries since these organic batteries are excelling in charging speed and cycling stability. This review provides a comprehensive overview of these systems and discusses the numerous classes of organic, polymer-based active materials as well as auxiliary components of the battery, like additives or electrolytes. Moreover, a definition of important cell characteristics and an introduction to selected characterization techniques is provided, completed by the discussion of potential socio-economic impacts. PMID- 27479609 TI - Sr2OsO5 and Sr7Os4O19, Two Structurally Related, Mott Insulating Osmates(VI) Exhibiting Substantially Reduced Spin Paramagnetic Response. AB - The new osmates(VI), Sr2OsO5 and Sr7Os4O19, feature quasi-1-D polyoxo anions, consisting of corner sharing [OsO6] octahedra. In both compounds, the magnetic moment at T = 300 K is significantly lower (1.2-1.3 MUB/Os-atom) than the value expected for S = 1. For neither of the new osmates(VI) is any evidence for long range magnetic order found. For Sr7Os4O19, magnetic susceptibility suggests an antiferromagnetic ordering at TN = 43(3) K; however, no corresponding anomaly is visible in specific heat. Both compounds are semiconductors. PMID- 27479608 TI - Cellulose and callose synthesis and organization in focus, what's new? AB - Plant growth and development are supported by plastic but strong cell walls. These walls consist largely of polysaccharides that vary in content and structure. Most of the polysaccharides are produced in the Golgi apparatus and are then secreted to the apoplast and built into the growing walls. However, the two glucan polymers cellulose and callose are synthesized at the plasma membrane by cellulose or callose synthase complexes, respectively. Cellulose is the most common cell wall polymer in land plants and provides strength to the walls to support directed cell expansion. In contrast, callose is integral to specialized cell walls, such as the cell plate that separates dividing cells and growing pollen tube walls, and maintains important functions during abiotic and biotic stress responses. The last years have seen a dramatic increase in our understanding of how cellulose and callose are manufactured, and new factors that regulate the synthases have been identified. Much of this knowledge has been amassed via various microscopy-based techniques, including various confocal techniques and super-resolution imaging. Here, we summarize and synthesize recent findings in the fields of cellulose and callose synthesis in plant biology. PMID- 27479610 TI - Schizophrenia in the Era of Brain Complexity. PMID- 27479611 TI - The Psychology of Schizophrenia: Implications for Biological and Psychotherapeutic Treatments. AB - The focus on recent advances in the neurobiology of schizophrenia has pushed aside the psychological understanding of the person with schizophrenia for several decades. However, a useful functional psychology of schizophrenia (in distinction to a psychological approach to symptoms) remains clinically important for several reasons: it is a core part of the bio-psycho-social formulation; it helps us understand and connect with persons with schizophrenia; and it provides a framework by which to organize our treatment efforts (both psychotherapeutic and particularly biological), which can improve adherence and outcomes. A coherent psychological model (the deficit model) based on object relations theory best explains all the biological, psychological, clinical, and sociocultural factors relevant to the understanding and treatment of persons with schizophrenia. A better understanding of a coherent psychology of persons with schizophrenia and provision of psychotherapies improves both the biological and psychotherapeutic treatment of persons with schizophrenia. PMID- 27479612 TI - Levels of Serum Brain-Derived Neurotrophic Factor in Schizophrenia. AB - Recent meta-analyses of serum brain-derived neurotrophic factor (BDNF) have reported lower levels in patients with schizophrenia. However, most studies did not consider the potential confounding effects of time of collection, age, sex, smoking, and obesity. Here, we sought to examine differences in serum BDNF between medicated patients with schizophrenia compared with control subjects, taking into consideration the potential confounders of serum BDNF. Serum was obtained from a sample of fasted blood collected from all participants, and BDNF was assayed on a commercially available kit. After adjusting for potential confounders, there was no statistically significant difference between cases and control subjects (p = 0.261). In the model, body mass index emerged as the most significant predictor of serum BDNF (beta = 0.22, p = 0.009). The present study did not support a role for serum BDNF as a biomarker in schizophrenia. This could be due to the nonspecific nature of serum BDNF and its association with both mental and physical conditions. PMID- 27479613 TI - Lower Urinary and Serum Progesterone-Induced Blocking Factor in Women with Preterm Birth. AB - The aim of the study was to compare urine and serum concentrations of PIBF at 24 28 gestational weeks in women with preterm birth, with those of women who delivered at term and to evaluate the impact of PIBF on the outcome of pregnancy. Case-control study was performed in period from 1.6.2010-31.7.2013. Biological samples (urine and serum) were collected from 126 pregnant women. All biological samples were obtained at 24-28 gestation weeks. We measured PIBF concentration and compared women who delivered preterm and those who delivered at term. Thirteen of 126 pregnant women (10.3%) who were included in the study delivered preterm. Among women that actually delivered preterm, median concentrations of PIBF were significantly lower (12.3ng/ml; 101.3ng/ml) than in women who delivered at term (77.0ng/ml; 412.7ng/ml). The serum and urine 24-28 gestational weeks PIBF in those who delivered preterm were generally low from 24 to 37 gestational weeks, while the serum and urine PIBF concentration reached a peak in those delivering between 37-38 gestational weeks, even significantly different from those delivering at 39 to 40 and after 40 gestational weeks. Preterm birth may be predictable at 24-28 gestational week by lower than normal pregnancy PIBF values and measurement of PIBF concentration in biological fluids at that time may be of importance in clinical practice. PMID- 27479614 TI - Trends in Prevalence of Chronic Kidney Disease in the United States. AB - Background: Trends in the prevalence of chronic kidney disease (CKD) are important for health care policy and planning. Objective: To update trends in CKD prevalence. Design: Repeated cross-sectional study. Setting: NHANES (National Health and Nutrition Examination Survey) for 1988 to 1994 and every 2 years from 1999 to 2012. Participants: Adults aged 20 years or older. Measurements: Chronic kidney disease (stages 3 and 4) was defined as an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2, estimated with the Chronic Kidney Disease Epidemiology Collaboration equation from calibrated serum creatinine measurements. An expanded definition of CKD also included persons with an eGFR of at least 60 mL/min/1.73 m2 and a 1-time urine albumin-creatinine ratio of at least 30 mg/g. Results: The unadjusted prevalence of stage 3 and 4 CKD increased from the late 1990s to the early 2000s. Since 2003 to 2004, however, the overall prevalence has largely stabilized (for example, 6.9% prevalence in 2003 to 2004 and in 2011 to 2012). There was little difference in adjusted prevalence of stage 3 and 4 CKD overall in 2003 to 2004 versus 2011 to 2012 after age, sex, race/ethnicity, and diabetes mellitus status were controlled for (P = 0.26). Lack of increase in CKD prevalence since the early 2000s was observed in most subgroups and with an expanded definition of CKD that included persons with higher eGFRs and albuminuria. Limitation: Serum creatinine and albuminuria were measured only once in each person. Conclusion: In a reversal of prior trends, there has been no appreciable increase in the prevalence of stage 3 and 4 CKD in the U.S. population overall during the most recent decade. Primary Funding Source: American Society of Nephrology Foundation for Kidney Research Student Scholar Grant Program, Centers for Disease Control and Prevention, and National Institutes of Health. PMID- 27479616 TI - Responsiveness to Adenosine Does Not Confirm SVT Diagnosis. PMID- 27479615 TI - Charting moment-to-moment brain signal variability from early to late childhood. AB - Large-scale brain signals exhibit rich intermittent patterning, reflecting the fact that the cortex actively eschews fixed points in favor of itinerant wandering with frequent state transitions. Fluctuations in endogenous cortical activity occur at multiple time scales and index a dynamic repertoire of network states that are continuously explored, even in the absence of external sensory inputs. Here, we quantified such moment-to-moment brain signal variability at rest in a large, cross-sectional sample of children ranging in age from seven to eleven years. Our findings revealed a monotonic rise in the complexity of electroencephalogram (EEG) signals as measured by sample entropy, from the youngest to the oldest age cohort, across a range of time scales and spatial regions. From year to year, the greatest changes in intraindividual brain signal variability were recorded at electrodes covering the anterior cortical zones. These results provide converging evidence concerning the age-dependent expansion of functional cortical network states during a critical developmental period ranging from early to late childhood. PMID- 27479617 TI - Optimal Technique for Application of Corticosteroid Nasal Spray. PMID- 27479618 TI - Correction. PMID- 27479620 TI - How to Prescribe Fewer Unnecessary Antibiotics: Talking Points That Work with Patients and Their Families. PMID- 27479621 TI - Curbing Inappropriate Antibiotic Prescribing: What Works? PMID- 27479624 TI - Vision Loss in Older Adults. AB - Vision loss affects 37 million Americans older than 50 years and one in four who are older than 80 years. The U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in adults older than 65 years. However, family physicians play a critical role in identifying persons who are at risk of vision loss, counseling patients, and referring patients for disease-specific treatment. The conditions that cause most cases of vision loss in older patients are age-related macular degeneration, glaucoma, ocular complications of diabetes mellitus, and age-related cataracts. Vitamin supplements can delay the progression of age-related macular degeneration. Intravitreal injection of a vascular endothelial growth factor inhibitor can preserve vision in the neovascular form of macular degeneration. Medicated eye drops reduce intraocular pressure and can delay the progression of vision loss in patients with glaucoma, but adherence to treatment is poor. Laser trabeculoplasty also lowers intraocular pressure and preserves vision in patients with primary open-angle glaucoma, but long-term studies are needed to identify who is most likely to benefit from surgery. Tight glycemic control in adults with diabetes slows the progression of diabetic retinopathy, but must be balanced against the risks of hypoglycemia and death in older adults. Fenofibrate also slows progression of diabetic retinopathy. Panretinal photocoagulation is the mainstay of treatment for diabetic retinopathy, whereas vascular endothelial growth factor inhibitors slow vision loss resulting from diabetic macular edema. Preoperative testing before cataract surgery does not improve outcomes and is not recommended. PMID- 27479626 TI - Premenstrual Syndrome and Premenstrual Dysphoric Disorder. AB - Premenstrual disorders affect up to 12% of women. The subspecialties of psychiatry and gynecology have developed overlapping but distinct diagnoses that qualify as a premenstrual disorder; these include premenstrual syndrome and premenstrual dysphoric disorder. These conditions encompass psychological and physical symptoms that cause significant impairment during the luteal phase of the menstrual cycle, but resolve shortly after menstruation. Patientdirected prospective recording of symptoms is helpful to establish the cyclical nature of symptoms that differentiate premenstrual syndrome and premenstrual dysphoric disorder from other psychiatric and physical disorders. Physicians should tailor therapy to achieve the greatest functional improvement possible for their patients. Select serotonergic antidepressants are first-line treatments. They can be used continuously or only during the luteal phase. Oral contraceptives and calcium supplements may also be used. There is insufficient evidence to recommend treatment with vitamin D, herbal remedies, or acupuncture, but there are data to suggest benefit from cognitive behavior therapy. PMID- 27479625 TI - Treating Painful Diabetic Peripheral Neuropathy: An Update. AB - Painful diabetic peripheral neuropathy occurs in approximately 25% of patients with diabetes mellitus who are treated in the office setting and significantly affects quality of life. It typically causes burning pain, paresthesias, and numbness in a stocking-glove pattern that progresses proximally from the feet and hands. Clinicians should carefully consider the patient's goals and functional status and potential adverse effects of medication when choosing a treatment for painful diabetic peripheral neuropathy. Pregabalin and duloxetine are the only medications approved by the U.S. Food and Drug Administration for treating this disorder. Based on current practice guidelines, these medications, with gabapentin and amitriptyline, should be considered for the initial treatment. Second-line therapy includes opioid-like medications (tramadol and tapentadol), venlafaxine, desvenlafaxine, and topical agents (lidocaine patches and capsaicin cream). Isosorbide dinitrate spray and transcutaneous electrical nerve stimulation may provide relief in some patients and can be considered at any point during therapy. Opioids and selective serotonin reuptake inhibitors are optional third-line medications. Acupuncture, traditional Chinese medicine, alpha lipoic acid, acetyl-l-carnitine, primrose oil, and electromagnetic field application lack high-quality evidence to support their use. PMID- 27479627 TI - Exercise to Improve Functioning in Patients with Dementia. PMID- 27479628 TI - Acute Onset of Elbow Swelling. PMID- 27479630 TI - Acupuncture for Frequent Tension-Type Headaches. PMID- 27479631 TI - Nerve Pain in Diabetes. PMID- 27479632 TI - Premenstrual Disorders. PMID- 27479633 TI - Measuring Concentrations of Dissolved Methane and Ethane and the 13 C of Methane in Shale and Till. AB - Baseline characterization of concentrations and isotopic values of dissolved natural gases is needed to identify contamination caused by the leakage of fugitive gases from oil and gas activities. Methods to collect and analyze baseline concentration-depth profiles of dissolved CH4 and C2 H6 and delta13 C CH4 in shales and Quaternary clayey tills were assessed at two sites in the Williston Basin, Canada. Core and cuttings samples were stored in Isojars(r) in a low O2 headspace prior to analysis. Measurements and multiphase diffusion modeling show that the gas concentrations in core samples yield well-defined and reproducible depth profiles after 31-d equilibration. No measurable oxidative loss or production during core sample storage was observed. Concentrations from cuttings and mud gas logging (including IsoTubes(r) ) were much lower than from cores, but correlated well. Simulations suggest the lower concentrations from cuttings can be attributed to drilling time, and therefore their use to define gas concentration profiles may have inherent limitations. Calculations based on mud gas logging show the method can provide estimates of core concentrations if operational parameters for the mud gas capture cylinder are quantified. The delta13 C-CH4 measured from mud gas, IsoTubes(r) , cuttings, and core samples are consistent, exhibiting slight variations that should not alter the implications of the results in identifying the sources of the gases. This study shows core and mud gas techniques and, to a lesser extent, cuttings, can generate high resolution depth profiles of dissolved hydrocarbon gas concentrations and their isotopes. PMID- 27479634 TI - Efficiently Enhancing Visible Light Photocatalytic Activity of Faceted TiO2 Nanocrystals by Synergistic Effects of Core-Shell Structured Au@CdS Nanoparticles and Their Selective Deposition. AB - Integrating wide bandgap semiconductor photocatalysts with visible-light-active inorganic nanoparticles (such as Au and CdS) as sensitizers is one of the most efficient methods to improve their photocatalytic activity in the visible light region. However, as for all such composite photocatalysts, a rational design and precise control over their architecture is often required to achieve optimal performance. Herein, a new TiO2-based ternary composite photocatalyst with superior visible light activity was designed and synthesized. In this composite photocatalyst, the location of the visible light sensitizers was engineered according to the intrinsic facet-induced effect of well-faceted TiO2 nanocrystals on the spatial separation of photogenerated carriers. Experimentally, core-shell structured Au@CdS nanoparticles acting as visible light sensitizers were selectively deposited onto photoreductive {101} facets of well-faceted anatase TiO2 nanocrystals through a two-step in situ photodeposition route. Because the combination of Au@CdS and specific {101} facets of TiO2 nanocrystals facilitates the transport of charges photogenerated under visible light irradiation, this well-designed ternary composite photocatalyst exhibited superior activity in visible-light-driven photocatalytic H2 evolution, as expected. PMID- 27479635 TI - Predictors of breast feeding self-efficacy in the immediate postpartum period: A cross-sectional study. AB - OBJECTIVE: to examine breast feeding self-efficacy and identify its predictors among mainland Chinese mothers in the early postpartum period. DESIGN AND SETTING: a cross-sectional descriptive questionnaire survey was conducted in a regional teaching hospital with childbirth rate over 3000 per year at Guangzhou, China from April 1 to July 14, 2014. PARTICIPANTS: a total of 571 Chinese mothers who were within 72-96hours post partum were recruited consecutively to the study. MEASUREMENTS: data were collected by the Chinese version of the Breastfeeding Self-efficacy Scale-Short Form (BSES-SF), the Network Support for Breastfeeding Scale (NSBS) and a socio-demographic data sheet. FINDINGS: a total of 640 eligible women was approached and 571 mothers completed the study with the response rate of 89%. Mothers reported moderate level of breast feeding self efficacy in the immediate postpartum period. The best-fit regression analysis revealed six variables that explained 43.9% of the variance in breast feeding self-efficacy in the immediate postpartum period. They were intention of breast feeding, support from husband, support from nurses/midwives, attending antenatal breast feeding classes, time from childbirth to initiate breast feeding and previous breast feeding experience. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: this study found six predictors of breast feeding self-efficacy in the immediate postpartum period. In order to increase maternal breast feeding self-efficacy level, a more women-centred approach is recommended. Mothers and fathers should be facilitated to attend antenatal classes on breast feeding. New mother' husband could be encouraged in supporting breast feeding. Nurses and midwives could encourage new mothers to initiate breast feeding as soon as possible. Further work to promote early mother-infant contact post birth, such as via skin to skin contact should also be facilitated where possible. PMID- 27479636 TI - Viral RNA in Blood as Indicator of Severe Outcome in Middle East Respiratory Syndrome Coronavirus Infection. AB - We evaluated the diagnostic and clinical usefulness of blood specimens to detect Middle East respiratory syndrome coronavirus infection in 21 patients from the 2015 outbreak in South Korea. Viral RNA was detected in blood from 33% of patients at initial diagnosis, and the detection preceded a worse clinical course. PMID- 27479637 TI - The trickle before the torrent-diffraction data from X-ray lasers. AB - Today Scientific Data launched a collection of publications describing data from X-ray free-electron lasers under the theme 'Structural Biology Applications of X ray Lasers'. The papers cover data on nanocrystals, single virus particles, isolated cell organelles, and living cells. All data are deposited with the Coherent X-ray Imaging Data Bank (CXIDB) and available to the scientific community to develop ideas, tools and procedures to meet challenges with the expected torrents of data from new X-ray lasers, capable of producing billion exposures per day. PMID- 27479639 TI - Accuracy of MR Imaging and MR Spectroscopy for Detection and Quantification of Hepatic Steatosis in Living Liver Donors: A Meta-Analysis. AB - Purpose To determine the accuracy of magnetic resonance (MR) imaging for detection and quantification of hepatic steatosis (HS) in living liver donor candidates. Materials and Methods A systematic search of the literature was performed to find studies on the diagnostic and quantitative accuracy of MR imaging for assessment of HS in liver donors. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used, and patient selection, index text, reference standard, and study flow and timing were assessed to evaluate the quality of each included study. Pooled sensitivity, specificity, positive and negative likelihood ratios, hierarchical summary receiver operating characteristic (ROC) curves, and the area under the curve were estimated by using hierarchical summary ROC and bivariate random-effects models. Results Eight studies involving 934 subjects were eligible for the meta-analysis. For detection of HS with MR imaging and/or MR spectroscopy in living liver donors, the pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio, respectively, were 0.89 (95% confidence interval [CI]: 0.75, 0.95), 0.84 (95% CI: 0.76, 0.89), 5.53 (95% CI: 3.71, 8.25), and 0.14 (95% CI: 0.06, 0.31). The area under the curve was 0.92 (95% CI: 0.89, 0.94). For detection of substantial HS (>10% to >30% HS at liver pathologic examination, as defined in each study), these corresponding diagnostic estimates were 0.91 (95% CI: 0.82, 0.95), 0.89 (95% CI: 0.84, 0.93), 8.30 (95% CI: 5.47, 12.59), 0.10 (95% CI: 0.05, 0.21), and 0.96 (95% CI: 0.93, 0.97), respectively. Moderate heterogeneity was detected. No publication bias was detected (P = .12). Conclusion MR imaging and MR spectroscopy show high sensitivity and specificity for detection of HS, especially when HS is substantial, and may be useful for noninvasive evaluation of HS in living liver donors. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27479638 TI - Integrin Imaging with 99mTc-3PRGD2 SPECT/CT Shows High Specificity in the Diagnosis of Lymph Node Metastasis from Non-Small Cell Lung Cancer. AB - Purpose To evaluate an integrin imaging approach based on single photon emission computed tomography (SPECT)/computed tomography (CT) by using technetium 99m (99mTc)-dimeric cyclic arginine-glycine-aspartic acid (RGD) peptides with three polyethylene glycol spacers (3PRGD2) as the tracer to target the integrin alphavbeta3 expression in lung cancer and lymph node metastasis. Materials and Methods With ethics committee approval and written informed consent, 65 patients (41 male, 24 female; mean age, 60 years +/- 11 [standard deviation]) with suspicious lung lesions were recruited with informed consent. The patients underwent both 99mTc-3PRGD2 SPECT/CT and fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT within 1 week. Finally, 65 lung lesions in 53 patients were pathologically diagnosed as non-small cell lung cancer (NSCLC) and 14 lung lesions in 12 patients were benign. Per-region analysis of lymph nodes included 248 regions with metastasis and 56 negative regions. Twenty specimens from the removed lung lesions or lymph nodes were stained with integrin alphavbeta3, CD34, and Ki-67 to correlate with the image findings. Receiver operating characteristic curve, z statistics, McNemar test, and chi2 analysis were used to compare the diagnostic performance of the two imaging methods. Results 99mTc-3PRGD2 SPECT/CT was found to be more specific than 18F-FDG PET/CT in the per-region diagnosis of lymph node metastasis (specificity, 94.6% vs 75.0%; P = .008) when the sensitivity of the two methods was comparable (88.3% vs 90.7%; P = .557). There was no significant difference between the two methods in the per-lesion diagnosis of lung tumor (z = 0.82, P = .410). The accumulation level of 99mTc-3PRGD2 was found in positive correlation with the integrin alphavbeta3 expression (r = 0.84, P = .001) and microvessel density (r = 0.63, P = .011) in the tumors. Conclusion 99mTc-3PRGD2 SPECT/CT shows high specificity in the diagnosis of lymph node metastasis from NSCLC, which may benefit surgical decision making for the patients. (c) RSNA, 2016. PMID- 27479640 TI - Patterns and Prognostic Importance of Hepatic Involvement in Patients with Serous Ovarian Cancer: A Single-Institution Experience with 244 Patients. AB - Purpose To evaluate the frequency, patterns, and prognostic importance of metastatic hepatic involvement in serous ovarian cancer. Materials and Methods This institutional review board-approved retrospective study, with waived informed consent, included 244 patients with pathologically proven serous ovarian cancer (mean age +/- standard deviation, 59 years +/- 10.7; range 19-93 years). Electronic medical records and all available imaging studies over a median follow up of 44 months (interquartile range [IQR], 27-70) were reviewed to identify the frequency of liver parenchymal invasion (LPI) from perihepatic peritoneal metastasis and hematogenous liver metastases. The associations and prognostic importance of LPI and hematogenous metastases were studied by using univariate and multivariate Cox proportional analysis. Results Eighty-four of 244 patients (34%) developed perihepatic metastases, of whom 55 (23%) developed LPI after median of 43 months (IQR, 25-63). Hematogenous hepatic metastases developed in 38 of 244 patients (16%) after median of 42 months (IQR, 26-64). At multivariate analysis, age (P = .008; hazard ratio [HR]: 1.03; 95% confidence interval [CI]: 1.009, 1.07) and suboptimal cytoreduction (P = .03; HR, 2.13; 95% CI: 1.12, 4.07) were associated with LPI. Increasing age (P = .01; HR, 1.04; 95% CI: 1.008, 1.08), high-grade tumor (P = .01; HR, 6.75; 95% CI: 1.44, 120.5), and advanced stage (P = .03; HR, 3.16; 95% CI: 1.94, 4.56) were associated with hematogenous metastases. Overall survival with and without LPI was similar (median, 80 months; IQR, 50-not reached vs 123 months; IQR, 49-279; P = .6). Hematogenous metastases were associated with significantly shorter survival at univariate (median 63 months, IQR 43-139 vs 145 months, IQR 50-not reached; P = .006) and multivariate analyses (P = .03; HR, 1.88; 95% CI: 1.14, 3.28). Conclusion Differentiating hematogenous metastases and LPI is important for radiologists; hematogenous metastases are associated with shorter survival, while LPI does not adversely affect survival and prognostically behaves like peritoneal disease. (c) RSNA, 2016. PMID- 27479641 TI - Changes in Physician Decision Making after CT: A Prospective Multicenter Study in Primary Care Settings. AB - Purpose To determine the effect of computed tomography (CT) results on physician decision making in three common clinical scenarios in primary care. Materials and Methods This research was approved by the institutional review board (IRB) and was HIPAA compliant. All physicians consented to participate with an opt-in or opt-out mechanism; patient consent was waived with IRB approval. In this prospective multicenter observational study, outpatients referred by primary care providers (PCPs) for CT evaluation of abdominal pain, hematuria, or weight loss were identified. Prior to CT, PCPs were surveyed to elicit their leading diagnosis, confidence in that diagnosis (confidence range, 0%-100%), a rule-out diagnosis, and a management plan if CT were not available. Surveys were repeated after CT. Study measures were the proportion of patients in whom leading diagnoses and management changed (PCP management vs specialist referral vs emergency department transfer), median changes in diagnostic confidence, and the proportion of patients in whom CT addressed rule-out diagnoses. Regression analyses were used to identify associations between study measures and site and participant characteristics. Specifically, logistic regression analysis was used for binary study measures (change in leading diagnosis, change in management), and linear regression analysis was used for the continuous study measure (change in diagnostic confidence). Accrual began on September 5, 2012, and ended on June 28, 2014. Results In total, 91 PCPs completed pre- and post-CT surveys in 373 patients. In patients with abdominal pain, hematuria, or weight loss, leading diagnoses changed after CT in 53% (131 of 246), 49% (36 of 73), and 57% (27 of 47) of patients, respectively. Management changed in 35% (86 of 248), 27% (20 of 74), and 54% (26 of 48) of patients, respectively. Median absolute changes in diagnostic confidence were substantial and significant (+20%, +20%, and +19%, respectively; P <= .001 for all); median confidence after CT was high (90%, 88%, and 80%, respectively). PCPs reported CT was helpful in confirming or excluding rule-out diagnoses in 98% (184 of 187), 97% (59 of 61), and 97% (33 of 34) of patients, respectively. Significant associations between primary measures and site and participant characteristics were not identified. Conclusion Changes in PCP leading diagnoses and management after CT were common, and diagnostic confidence increased substantially. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27479642 TI - Acceptance and Commitment Therapy (ACT) for Chronic Pain: A Systematic Review and Meta-Analyses. AB - OBJECTIVES: Chronic pain places a burden on individuals and the economy. Although there is evidence for the effectiveness of cognitive-behavior therapy, it is recognized that the effects are limited. Acceptance and Commitment Therapy (ACT), which aims to increase valued action in the presence of pain, has been suggested as an alternative approach. The objective of this review was to determine the clinical effectiveness of ACT for chronic pain in adults when compared with control conditions and other active treatments. METHODS: The searches of this systematic review were conducted in the Cochrane library, MEDLINE, EMBASE, CINAHL Plus (EBSCO), and PsycINFO. Grey literature, reference list, and reverse citation searches were also completed. RESULTS: Eleven trials were included. ACT was favored over controls (no alternative intervention or treatment as usual). Significant, medium to large effect sizes were found for measures of pain acceptance and psychological flexibility, which are typically considered processes of ACT. Significant small to medium effect sizes were found for measures of functioning, anxiety, and depression. Measures of pain intensity and quality of life were not significantly different than zero. Generally effect sizes were smaller at follow-up. DISCUSSION: ACT was more clinically effective than controls on a number of outcomes. It is possible that methodological limitations, some of which are common to psychological trials, may have led to overestimated effects. Only a few studies compared ACT to active treatments and while the evidence is promising for ACT in the treatment of chronic pain, further methodologically robust trials are required. PMID- 27479643 TI - Racial Differences in Parental Responses to Children's Chronic Pain. AB - OBJECTIVE: Parental responses to children's pain are related to how youth cope with chronic pain. However, little research has explored cultural differences in the 4 major pain response categories (ie, protect, minimize, distract, and monitor). This study compared parental responses to children's pain between minority parents (ie, black, Hispanic, multiracial) and parents of white children. MATERIALS AND METHODS: Participants included 234 patients, ages 8 to 17, with chronic pain (73.5% female; age M [SD]=13.91 [2.38]; 50% white, 15.39% black, 20.90% Hispanic, 13.68% multiracial). Patients' parents completed the Adult Responses to Children's Symptoms. Parental responses included: protect, monitor, minimize, and distrct. For between-group comparisons, white participants (N=117) were matched on age and sex with black (N=36), Hispanic (N=49), and multiracial (N=32) participants. RESULTS: Paired-samples t tests revealed that protectiveness was higher for parents of black children (t48=-3.84, P<0.001, black M [SD]=1.93 [0.69], white M [SD]=0.94 [0.77], Cohen d=1.09) and parents of Hispanic children (t71=-7.10, P<0.001, Hispanic M [SD]=1.65 [0.76], white M [SD]=0.94 [0.77], Cohen d=1.52) compared with parents of white children. In addition, parents of black children (t40=-2.90, P=0.006, black M [SD]=3.55 [0.49], white M [SD]=2.89 [0.93], Cohen d=0.80) and parents of Hispanic children (t71=-3.62, P<0.001, Hispanic M [SD]=3.35 [0.69], white M [SD]=2.89 [0.93], Cohen d=0.81) were significantly more monitoring their children than were parents of white children. Parents of Hispanic children were also significantly more minimizing than parents of white children (t71=-3.68, P<0.001, Hispanic M [SD]=0.88 [0.75], white M [SD]=0.51 [0.58], Cohen d=0.80). No other significant differences were found. DISCUSSION: Results highlight the need to adapt pediatric chronic pain interventions to family culture and context. Further research is needed to understand pediatric chronic pain from a cross-cultural perspective. PMID- 27479645 TI - Proposing prognostic thresholds for lymph node yield in clinically lymph node negative and lymph node-positive cancers of the oral cavity. AB - BACKGROUND: Prognostic lymph node yield thresholds have been identified and incorporated into treatment guidelines for multiple cancer sites, but not for oral cancer. The objective of this study was to identify optimal thresholds in elective and therapeutic neck dissection for oral cavity cancers. METHODS: Patients with oral cavity cancers in the National Cancer Database (NCDB) were stratified into clinically lymph node-negative (cN0) and clinically lymph node positive (cN+) cohorts to reflect the differing surgical management for these diseases. Univariate and multivariate analyses were performed to assess the relation between lymph node yield and overall survival, adjusting for other prognostic factors. Thresholds derived from the NCDB were validated in the Surveillance, Epidemiology, and End Results database. RESULTS: In patients with cN0 cancers of the oral cavity from the NCDB, those who had <16 lymph nodes had significantly decreased survival. The proportion of positive lymph nodes was higher for patients who had >=16 lymph nodes (27.2% vs 16.3% for < 16 lymph nodes; P < .001). This threshold was validated in 2715 lymph node-negative cancers from SEER, with a mortality hazard ratio of 0.825 for >= 16 lymph nodes (95% confidence interval, 0.764-0.950; P = .004). In patients with cN + oral cavity cancers from the NCDB, groups with <26 lymph nodes had significantly decreased survival. This threshold was validated in 1903 lymph node-positive cancers from SEER, with a mortality hazard ratio of 0.791 (95% confidence interval, 0.692-0.903; P = .001). Academic centers, higher volume centers, and geographic location predicted higher lymph node yields. CONCLUSIONS: More extensive neck dissection (>=16 lymph nodes in cN0, >= 26 lymph nodes in cN+) was associated with better survival. Further evaluation of practice patterns in lymph node yield may represent an opportunity for improved quality of care. Cancer 2016;122:3624-31. (c) 2016 American Cancer Society. PMID- 27479646 TI - Prenatal Use of Acetaminophen and Child IQ: A Danish Cohort Study. AB - BACKGROUND: Acetaminophen (paracetamol) is the most commonly used pain and fever medication during pregnancy, and recently has been linked to hyperactivity and behavioral problems in children. We examine whether prenatal use of acetaminophen affects children's intelligence quotient (IQ). METHODS: We studied 1,491 mothers and children enrolled in the Danish National Birth Cohort (DNBC; 1996-2002). Acetaminophen use in pregnancy was prospectively recorded in three telephone interviews. Child IQ was assessed at age 5 with the Wechsler Primary and Preschool Scales of Intelligence-Revised (WPPSI-R) administered by trained psychologists. We employed linear regression analysis, adjusting for maternal IQ and other confounding factors, and assessed interactions between acetaminophen and indications for use. RESULTS: Both maternal fever in pregnancy and acetaminophen use were associated with child IQ. Children born to mothers using acetaminophen without reporting fever scored on average 3.4 points lower (95% confidence interval [CI]: 0.30 to 6.6 points) on performance IQ compared with offspring of mothers who neither experienced fever nor took acetaminophen. Estimated effects for acetaminophen were stronger for first or second trimester use. Children born to mothers reporting fever without using acetaminophen also scored lower on verbal (2.7 points, 95% CI: -0.19, 5.6) and performance IQ (4.3 points, 95% CI: 0.30, 8.3); IQ scores were not affected if mothers with fever used acetaminophen. CONCLUSIONS: Maternal acetaminophen use during pregnancy was associated with lower performance IQ in 5-year olds. However, acetaminophen treatment of maternal fever in pregnancy showed an apparent compensatory association with child IQ scores. (See video abstract at http://links.lww.com/EDE/B87.). PMID- 27479647 TI - Fine-particulate Air Pollution from Diesel Emission Control and Mortality Rates in Tokyo: A Quasi-experimental Study. AB - BACKGROUND: Evidence linking air pollution with adverse health outcomes is accumulating. However, few studies have adopted a quasi-experimental design to evaluate whether decline in air pollution from regulatory action improves public health. We evaluated the effect of a diesel emission control ordinance introduced in 2003 on mortality rates in 23 wards of the Tokyo metropolitan area, Japan, from October 2000 to September 2012, taking into account change in mortality rates in a reference population (Osaka) with a introduction of such a regulation in 2009. METHODS: We obtained daily counts of all-cause and cause-specific mortality and concentrations of nitrogen dioxide (NO2) and particulate matter less than 2.5 MUm in diameter (PM2.5) during the study period. We employed interrupted time-series analysis to analyze the data. RESULTS: Decline in NO2 during the study period was similar in the two areas, while decline in PM2.5 and the improvement in age-standardized mortality rates were greater in Tokyo's 23 wards compared with Osaka. Even after adjusting for age-standardized mortality rates in Osaka, percent changes in mortality between the first 3-year interval (October 2000 to September 2003) and the last 3-year interval (October 2009 to September 2012) were -6.0% for all causes, -11% for cardiovascular disease, -10% for ischemic heart disease, -6.2% for cerebrovascular disease, -22% for pulmonary disease, and -4.9% for lung cancer. We did not observe a decline in mortality from other causes. CONCLUSIONS: This quasi-experimental study in Tokyo suggests that emission control was associated with improvements in both air quality and health outcomes. PMID- 27479648 TI - Psychological Distress and Risk of Accidental Death in the General Population. PMID- 27479649 TI - Diagnostics for Confounding of Time-varying and Other Joint Exposures. AB - The effects of joint exposures (or exposure regimes) include those of adhering to assigned treatment versus placebo in a randomized controlled trial, duration of exposure in a cohort study, interactions between exposures, and direct effects of exposure, among others. Unlike the setting of a single point exposure (e.g., propensity score matching), there are few tools to describe confounding for joint exposures or how well a method resolves it. Investigators need tools that describe confounding in ways that are conceptually grounded and intuitive for those who read, review, and use applied research to guide policy. We revisit the implications of exchangeability conditions that hold in sequentially randomized trials, and the bias structure that motivates the use of g-methods, such as marginal structural models. From these, we develop covariate balance diagnostics for joint exposures that can (1) describe time-varying confounding, (2) assess whether covariates are predicted by prior exposures given their past, the indication for g-methods, and (3) describe residual confounding after inverse probability weighting. For each diagnostic, we present time-specific metrics that encompass a wide class of joint exposures, including regimes of multivariate time varying exposures in censored data, with multivariate point exposures as a special case. We outline how to estimate these directly or with regression and how to average them over person-time. Using a simulated example, we show how these metrics can be presented graphically. This conceptually grounded framework can potentially aid the transparent design, analysis, and reporting of studies that examine joint exposures. We provide easy-to-use tools to implement it. PMID- 27479650 TI - Classification and Clustering Methods for Multiple Environmental Factors in Gene Environment Interaction: Application to the Multi-Ethnic Study of Atherosclerosis. AB - There has been an increased interest in identifying gene-environment interaction (G * E) in the context of multiple environmental exposures. Most G * E studies analyze one exposure at a time, but we are exposed to multiple exposures in reality. Efficient analysis strategies for complex G * E with multiple environmental factors in a single model are still lacking. Using the data from the Multiethnic Study of Atherosclerosis, we illustrate a two-step approach for modeling G * E with multiple environmental factors. First, we utilize common clustering and classification strategies (e.g., k-means, latent class analysis, classification and regression trees, Bayesian clustering using Dirichlet Process) to define subgroups corresponding to distinct environmental exposure profiles. Second, we illustrate the use of an additive main effects and multiplicative interaction model, instead of the conventional saturated interaction model using product terms of factors, to study G * E with the data-driven exposure subgroups defined in the first step. We demonstrate useful analytical approaches to translate multiple environmental exposures into one summary class. These tools not only allow researchers to consider several environmental exposures in G * E analysis but also provide some insight into how genes modify the effect of a comprehensive exposure profile instead of examining effect modification for each exposure in isolation. PMID- 27479651 TI - The expression of P-glycoprotein in leukemia cells is associated with the upregulated expression of nestin, a class 6 filament protein. AB - Multidrug resistance (MDR) is a serious obstacle to the effective chemotherapeutic treatment of leukemia. Expression of plasma membrane P glycoprotein (P-gp), a transporter involved in drug efflux, is the most frequently observed molecular causality of MDR. We observed the coexpression of P gp and the filament protein nestin in the acute myeloid leukemia (AML) cell lines SKM-1 and MOLM-13 following the induction of P-gp expression using vincristine. Nestin is considered a marker of neural stem cells and neural progenitor cells. The aim of this study was to determine whether there is causal relationship between the expression of P-glycoprotein and the expression of nestin in both of these AML cell lines. The expression of P-gp was induced in SKM-1 cells by selective pressure using vincristine (VCR), mitoxantrone (MTX), azacytidine (AzaC) and lenalidomide (LEN). Whereas the selective pressure of VCR, MTX and AzaC also induced P-gp expression in MOLM-13 cells, LEN was found to be ineffective in this regard. In all cases in which P-gp expression was induced in SKM-1 and MOLM-13 cells, its expression was associated with the induction of nestin mRNA expression and the presence of a 200-220kDa nestin-immunoreactive protein band in western blots. Silencing P-gp expression using s10418 siRNA (known as the P-gp silencer) was associated with the downregulation of the nestin transcript level, demonstrated using RT-PCR. Nestin mRNA was also observed in two P-gp-positive variants of L1210 cells that were obtained either by selection with VCR or by transfection with a retrovirus encoding human P-gp. Detectable levels of nestin transcripts were not observed in P-gp-negative parental L1210 cells. Taken together, these results indicated that the induction of P-gp expression is causally associated with the expression of nestin in leukemia cells. PMID- 27479652 TI - FLOCK cluster analysis of plasma cell flow cytometry data predicts bone marrow involvement by plasma cell neoplasia. AB - We analyzed plasma cell populations in bone marrow samples from 353 patients with possible bone marrow involvement by a plasma cell neoplasm, using FLOCK (FLOw Clustering without K), an unbiased, automated, computational approach to identify cell subsets in multidimensional flow cytometry data. FLOCK identified discrete plasma cell populations in the majority of bone marrow specimens found by standard histologic and immunophenotypic criteria to be involved by a plasma cell neoplasm (202/208 cases; 97%), including 34 cases that were negative by standard flow cytometric analysis that included clonality assessment. FLOCK identified discrete plasma cell populations in only a minority of cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (38/145 cases; 26%). Interestingly, 55% of the cases negative by standard analysis, but containing a FLOCK-identified discrete plasma cell population, were positive for monoclonal gammopathy by serum protein electrophoresis and immunofixation. FLOCK-identified and quantitated plasma cell populations accounted for 3.05% of total cells on average in cases positive for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria, and 0.27% of total cells on average in cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (p<0.0001; area under the curve by ROC analysis=0.96). The presence of a FLOCK identified discrete plasma cell population was predictive of the presence of plasma cell neoplasia with a sensitivity of 97%, compared with only 81% for standard flow cytometric analysis, and had specificity of 74%, PPV of 84% and NPV of 95%. FLOCK analysis, which has been shown to provide useful diagnostic information for evaluating patients with suspected systemic mastocytosis, is able to identify neoplastic plasma cell populations analyzed by flow cytometry, and may be helpful in the diagnostic evaluation of bone marrow samples for involvement by plasma cell neoplasia. PMID- 27479653 TI - Preparedness and response to chemical and biological threats: the role of exposure science. AB - There are multiple components to emergency preparedness and the response to chemical and biological threat agents. The 5Rs framework (rescue, reentry, recovery, restoration, and rehabitation) outlines opportunities to apply exposure science in emergency events. Exposure science provides guidance and refined tools for characterizing, assessing, and reducing risks from catastrophic events, such as the release of hazardous airborne chemicals or biological agents. Important challenges to be met include deployment of assets, including medications, before and after an emergency response situation. Assessment of past studies demonstrates the value of integrating exposure science methods into risk analysis and the management of catastrophic events. PMID- 27479654 TI - Circulating androgens correlate with resting-state MRI in transgender men. AB - Despite mounting evidence regarding the underlying neurobiology in transgender persons, information regarding resting-state activity, particularly after hormonal treatment, is lacking. The present study examined differences between transgender persons on long-term cross-sex hormone therapy and comparisons on two measures of local functional connectivity, intensity of spontaneous resting-state activity (low frequency fluctuations, LFF) and local synchronization of specific brain areas (regional homogeneity, ReHo). Nineteen transgender women (TW, male-to female), 19 transgender men (TM, female-to-male), 21 non-transgender men (NTM) and 20 non-transgender women (NTW) underwent a resting-state MRI scan. The results showed differences between transgender persons and non-transgender comparisons on both LFF and ReHo measures in the frontal cortex, medial temporal lobe, and cerebellum. More interestingly, circulating androgens correlated for TM in the cerebellum and regions of the frontal cortex, an effect that was associated with treatment duration in the cerebellum. By comparison, no associations were found for TW with estrogens. These data provide first evidence for a potential masculinization of local functional connectivity in hormonally treated transgender men. PMID- 27479655 TI - How the prefrontal executive got its stripes. AB - Pathways from cortical and subcortical structures give the prefrontal cortex a panoramic view of the sensory environment and the internal milieu of motives and drives. The prefrontal cortex also receives privileged information from the output of the basal ganglia and cerebellum and innervates widely the inhibitory thalamic reticular nucleus that gates thalamo-cortical communication. Connections, in general, are strongly related to the systematic structural variation of the cortex that can be traced to development. Insights from development have profound implications for the special connections of the prefrontal cortex for executive control, learning and memory, and vulnerability in psychiatric and neurologic diseases. PMID- 27479656 TI - The hunt for the perfect discounting function and a reckoning of time perception. AB - Making decisions that factor the cost of time is fundamental to survival. Yet, while it is readily appreciated that our perception of time is intimately involved in this process, theories regarding intertemporal decision-making and theories regarding time perception are treated, largely, independently. Even within these respective domains, models providing good fits to data fail to provide insight as to why, from a normative sense, those fits should take their apparent form. Conversely, normative models that proffer a rationalization for why an agent should weigh options in a particular way, or to perceive time in a particular way, fail to account for the full body of well-established experimental evidence. Here we review select, yet key advances in our understanding, identifying conceptual breakthroughs in the fields of intertemporal decision-making and in time perception, as well as their limits and failings in the face of hard-won experimental observation. On this background of accrued knowledge, a new conception unifying the domains of decision-making and time perception is put forward (Training-Integrated Maximization of Reinforcement Rate, TIMERR) to provide a better fit to observations and a more parsimonious reckoning of why we make choices, and thereby perceive time, the way we do. PMID- 27479657 TI - Analysis and Purification of Mouse Intestinal Dendritic Cell and Macrophage Subsets by Flow Cytometry. AB - The unit presents a method for analysis of intestinal dendritic cell (DC) and macrophage subsets by flow cytometry in the single cell suspension prepared from the mouse small and large intestine (Basic Protocol). describes a strategy to enrich the hematopoietic cell fraction in the sample by Percoll gradient centrifugation, and describes preparation of single cell suspensions from specific tissue layers of the small intestine, such as the epithelium, villi mucosa, submucosa, and muscularis externa. Finally, Support Protocol explains how to purify specific intestinal DC and macrophage subsets by flow-cytometry-based cell sorting. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479658 TI - Assessment of Inflammasome Formation by Flow Cytometry. AB - Inflammasomes are large protein complexes formed in response to cellular stresses that are platforms for recruitment and activation of caspase 1. Central to most inflammasome functions is the adapter molecule ASC (apoptosis-associated speck like protein containing a caspase-recruitment domain) that links the inflammasome initiator protein to the recruited caspases. ASC is normally diffuse within the cell but within minutes of inflammasome activation relocates to a dense speck in the cytosol. The dramatic redistribution of ASC can be monitored by flow cytometry using parameters of fluorescence peak height and width when immunostained or tagged with a fluorescent protein. This can be used to define cells with active inflammasomes within populations of primary macrophages and monocytes, allowing quantification of responses and flow-sorting of responding cells. Protein structural requirements for ASC speck formation and recruitment of caspases to ASC specks can be assessed by expressing components in HEK293 cells. This provides rapid quantification of responding cell number and correlation with the expression level of inflammasome components within single cells. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479659 TI - TepiTool: A Pipeline for Computational Prediction of T Cell Epitope Candidates. AB - Computational prediction of T cell epitope candidates is currently being used in several applications including vaccine discovery studies, development of diagnostics, and removal of unwanted immune responses against protein therapeutics. There have been continuous improvements in the performance of MHC binding prediction tools, but their general adoption by immunologists has been slow due to the lack of user-friendly interfaces and guidelines. Current tools only provide minimal advice on what alleles to include, what lengths to consider, how to deal with homologous peptides, and what cutoffs should be considered relevant. This protocol provides step-by-step instructions with necessary recommendations for prediction of the best T cell epitope candidates with the newly developed online tool called TepiTool. TepiTool, which is part of the Immune Epitope Database (IEDB), provides some of the top MHC binding prediction algorithms for number of species including humans, chimpanzees, bovines, gorillas, macaques, mice, and pigs. The TepiTool is freely accessible at http://tools.iedb.org/tepitool/. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479660 TI - Immunoblotting and Immunodetection. AB - Immunoblotting (western blotting) is used to identify specific antigens recognized by polyclonal or monoclonal antibodies. This unit provides protocols for all steps, starting with solubilization of the protein samples, usually by means of SDS and reducing agents. Following solubilization, the material is separated by SDS-PAGE and the antigens are electrophoretically transferred to a membrane, a process that can be monitored by reversible staining with Ponceau S. The transferred proteins are bound to the surface of the membrane, providing access to immunodetection reagents. After nonspecific binding sites are blocked, the membrane is probed with the primary antibody and washed. The antibody-antigen complexes are tagged with fluorophores, horseradish peroxidase, or alkaline phosphatase coupled to a secondary anti-IgG antibody, and detected using appropriate fluorescent imaging technologies or with chromogenic or luminescent substrates. Finally, membranes may be stripped and reprobed. (c) 2016 by John Wiley & Sons, Inc. PMID- 27479663 TI - Peripherally Inserted Central Catheters-Improving Appropriateness With a Dedicated and Rigorous Team. PMID- 27479664 TI - Peripherally Inserted Central Catheters-Improving Appropriateness With a Dedicated and Rigorous Team-Reply. PMID- 27479665 TI - Text Messaging and Medication Adherence-Do We Have a Missed Call? PMID- 27479666 TI - Toxic Alcohol Calculations and Misinterpretation of Laboratory Results. PMID- 27479667 TI - Text Messaging and Medication Adherence-Do We Have a Missed Call?-Reply. PMID- 27479668 TI - Toxic Alcohol Calculations and Misinterpretation of Laboratory Results. PMID- 27479669 TI - Toxic Alcohol Calculations and Misinterpretation of Laboratory Results. PMID- 27479670 TI - Toxic Alcohol Calculations and Misinterpretation Of Laboratory Results-Reply. PMID- 27479671 TI - Syncope While Driving in Denmark. PMID- 27479672 TI - Syncope While Driving in Denmark-Reply. PMID- 27479673 TI - Caregiver Perspectives on End-of-Life Experiences of Patients With Left Ventricular Assist Devices. PMID- 27479674 TI - Caregiver Perspectives on End-of-Life Experiences of Patients With Left Ventricular Assist Devices-Reply. PMID- 27479675 TI - Further Limitations of the HOSPITAL Score in US Hospitals. PMID- 27479676 TI - Uncontrolled Hypertension and Risk of Cardiovascular Mortality in China. PMID- 27479677 TI - Further Limitations of the HOSPITAL Score in US Hospitals-Reply. PMID- 27479678 TI - Electronic Health Records Quantify Previously Existing Phenomenon-Physicians Spend Hours Coordinating Care. PMID- 27479679 TI - Uncontrolled Hypertension and Risk of Cardiovascular Mortality in China-Reply. PMID- 27479681 TI - Incorrect Values in a Table. PMID- 27479680 TI - Electronic Health Records Quantify Previously Existing Phenomenon-Physicians Spend Hours Coordinating Care-Reply. PMID- 27479682 TI - A framework for Bayesian nonparametric inference for causal effects of mediation. AB - We propose a Bayesian non-parametric (BNP) framework for estimating causal effects of mediation, the natural direct, and indirect, effects. The strategy is to do this in two parts. Part 1 is a flexible model (using BNP) for the observed data distribution. Part 2 is a set of uncheckable assumptions with sensitivity parameters that in conjunction with Part 1 allows identification and estimation of the causal parameters and allows for uncertainty about these assumptions via priors on the sensitivity parameters. For Part 1, we specify a Dirichlet process mixture of multivariate normals as a prior on the joint distribution of the outcome, mediator, and covariates. This approach allows us to obtain a (simple) closed form of each marginal distribution. For Part 2, we consider two sets of assumptions: (a) the standard sequential ignorability (Imai et al., 2010) and (b) weakened set of the conditional independence type assumptions introduced in Daniels et al. (2012) and propose sensitivity analyses for both. We use this approach to assess mediation in a physical activity promotion trial. PMID- 27479683 TI - High-throughput analysis of 19 endogenous androgenic steroids by ultra performance convergence chromatography tandem mass spectrometry. AB - 11-Oxygenated steroids such as 11-ketotestosterone and 11-ketodihydrotestosterone have recently been shown to play a putative role in the development and progression of castration resistant prostate cancer. In this study we report on the development of a high throughput ultra-performance convergence chromatography tandem mass spectrometry (UPC(2)-MS/MS) method for the analysis of thirteen 11 oxygenated and six canonical C19 steroids isolated from a cell culture matrix. Using an Acquity UPC(2) BEH 2-EP column we found that UPC(2) resulted in superior selectivity, increased chromatographic efficiency and a scattered elution order when compared to conventional reverse phase ultra-performance liquid chromatography (UPLC). Furthermore, there was a significant improvement in sensitivity (5-50 times). The lower limits of quantification ranged between 0.01 10ngmL(-1), while the upper limit of quantification was 100ngmL(-1) for all steroids. Accuracy, precision, intra-day variation, recovery, matrix effects and process efficiency were all evaluated and found to be within acceptable limits. Taken together we show that the increased power of UPC(2)-MS/MS allows the analyst to complete in vitro assays at biologically relevant concentrations for the first time and in so doing determine the routes of steroid metabolism which is vital for studies of androgen responsive cancers, such as prostate cancer, and could highlight new mechanisms of disease progression and new targets for cancer therapy. PMID- 27479684 TI - Pharmacokinetics, tissue distribution, and plasma protein binding study of chicoric acid by HPLC-MS/MS. AB - Chicoric acid is a major active constituent of Echinacea purpurea and has a variety of biological functions. In this study, a liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) approach was developed and validated for the determination of chicoric acid in rat plasma and various tissues using ferulic acid as an internal standard (IS). This method was successfully applied to pharmacokinetics, tissue distribution, and plasma protein binding (PPB) study of chicoric acid in Sprague-Dawley (SD) rats dosed with 50mg/kg by gastric gavage. The pharmacokinetic parameters were determined and showed a half-life (t1/2) of 4.53+/-1.44h, an apparent volume of mean residual time (MRT) of 18.58+/ 4.43h, and an area under the curve (AUC) of 26.14 mghL(-1). The tissue distribution of chicoric acid in rats after gavage administration showed a decreasing tendency in different tissues (liver>lung>kidney>heart>spleen>brain). The PPB rates in rat plasma, human plasma, and bovine serum albumin were 98.3, 96.9, and 96.6%, respectively. These results provide insight for the further pharmacological investigation of chicoric acid. PMID- 27479685 TI - Composition- and Structure-Tunable Gold-Cobalt Nanoparticles and Electrocatalytic Synergy for Oxygen Evolution Reaction. AB - The increasing energy crisis constitutes an inspiring drive seeking alternative energies such as hydrogen from water splitting which is clean and abundant, but a key challenge for water splitting is the need of highly efficient catalysts for oxygen evolution reaction (OER). This report describes findings of an investigation of the synthesis of gold-cobalt (AuCo) nanoparticles by a facile one-pot and injection method and their use as highly efficient catalysts for OER. While particle size depends on the synthesis method, the composition of the nanoparticles is controlled by feeding ratio of Au and Co precursors in the synthesis. Depending on Co content, the nanoparticles exhibit largely phase segregated domains with a core (Au)-shell (Co) type of structure at a high level of Co. Upon the thermochemical treatment of carbon-supported AuCo nanoparticles, the redox activity of Co species in the nanoparticles with cycle number is shown to decrease which changes the surface oxidation state of Co species without changing the composition significantly. The electrocatalytic activity for OER in alkaline electrolytes is shown to depend on the bimetallic composition, displaying a maximum activity for an Au:Co ratio of ~2:3. This dependence is also shown to correlate with the surface oxidation state and redox activities, providing an insight into the electrocatalytic activity. Mechanistic aspects of the electrocataltytic properties are discussed in terms of the bifunctional synergy of Co and Au in the nanoparticle catalysts. PMID- 27479686 TI - Simple Laparoscopic Nephrectomy in Stone Disease: Not Always Simple. AB - OBJECTIVES: Simple nephrectomy is performed for a benign pathology that does not require the excision of either the adrenal gland or any adenopathies. When it is carried out in cases of stone disease, however, it is frequently not a "simple" technique owing to the presence of significant inflammation and infection. METHODS: Ninety-six simple laparoscopic nephrectomies performed because of stone disease between 2006 and 2015 were retrospectively studied. A descriptive statistical analysis was performed, as well as an evaluation of the associated complications. RESULTS: Of the 96 laparoscopic nephrectomies (62 left, 34 right), 7 (7.2%) had to be converted into open surgery owing to the impossibility of dissecting the renal hilum because of xanthogranulomatous pyelonephritis (n = 4) or major associated lesions (n = 3). The indication for nephrectomy was lumbar pain associated with urinary infection, with a partial renal function below 15% assessed by DMSA renal scan. There were three major complications. Pathologic assessment revealed chronic pyelonephritis with kidney atrophy and associated pyonephrosis in 85 cases, xanthogranulomatous pyelonephritis in 10, and pT4 squamous cell carcinoma in 1. CONCLUSIONS: Despite its high technical difficulty, simple laparoscopic nephrectomy for stones is a viable technique for advanced laparoscopists. Its principal advantage compared with open surgery is improved postsurgical recovery, and it is associated with an acceptable complication rate. Xanthogranulomatous pyelonephritis is not an initial contraindication to laparoscopy, but it is the most significant risk factor for conversion to open surgery. PMID- 27479687 TI - Low bone mineral density in adolescents with leukemia after hematopoietic stem cell transplantation: prolonged steroid therapy for GvHD and endocrinopathy after hematopoietic stem cell transplantation might be major concerns? PMID- 27479688 TI - Salvage haploidentical hematopoietic cell transplantation for graft rejection following a prior haploidentical allograft. PMID- 27479689 TI - Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD? AB - A total of 21 patients with severe aplastic anemia (SAA) underwent marrow transplantation from HLA-identical siblings following a standard conditioning regimen with cyclophosphamide (50 mg/kg/day * 4 days) and horse antithymocyte globulin (30 mg/kg/day * 3 days). Post-grafting immunosuppression consisted of a short course of methotrexate (MTX) combined with cyclosporine (CSP). The transplant protocol tested the hypothesis that the incidence of chronic GvHD could be reduced by limiting the marrow grafts to ?2.5 * 108 nucleated marrow cells/kg. None of the patients rejected the graft, all had sustained engraftment and all are surviving at a median of 4 (range 1-8) years after transplantation. Chronic GvHD developed in 16% of patients given ?2.5 * 108 nucleated marrow cells/kg. Post-grafting immunosuppression has been discontinued in 20 of the 21 patients. In conclusion, limiting the number of transplanted marrow cells may have resulted in minimal improvement in the incidence and severity of chronic GvHD. PMID- 27479690 TI - New Insight into GO, Cadmium(II), Phosphate Interaction and Its Role in GO Colloidal Behavior. AB - This study establishes the relationship between the graphene oxide (GO) colloidal behavior and the co-adsorption of Cd(II) and phosphate (P(V)) on GO. Results reveal that the interactions among GO, Cd(II), and P(V) exhibit a significant dependence on solution chemistry and addition sequences and that these interactions subsequently affect the GO colloidal behavior. The GO aggregation is pH-dependent at pH < 4.0 and depends apparently on the binding ability of Cd(II) to GO at pH > 4.0. When the components were added simultaneously, the presence of P(V) enhances the GO binding capacity toward Cd(II), confirmed by theoretical calculation, resulting in the greater destabilizing influence of Cd(II) + P(V) on GO than Cd(II) at pH 3.0-9.5, while the formation of Cd3(PO4)2 precipitate leads to a lower destabilizing influence of Cd(II) + P(V) on GO than Cd(II) at pH > 9.5. Both pH and addition sequence affect the destabilizing ability of Cd(II) + P(V). These new insights are expected to provide valuable information not only for the application of GO as a potential adsorbent in multicomponent systems for heavy metal ion and oxyanion co-removal but also for the fate and risk assessment of GO after serving as heavy metal ion and oxyanion carrier. PMID- 27479691 TI - Cobalt silicate hierarchical hollow spheres for lithium-ion batteries. AB - In this paper, the synthesis of cobalt silicate novel hierarchical hollow spheres via a facile hydrothermal method is presented. With a unique hollow structure, the Co2SiO4 provides a large surface area, which can shorten the lithium ions diffusion length and effectively accommodate the volumetic variation during the lithiation/de-lithiation process. Serving as an anode material in lithium-ion battery application, the Co2SiO4 electrode demonstrates a high reversible specific capacity (first-cycle charge capacity of 948.6 mAh g(-1) at 100 mA g( 1)), a cycling durability (specific capacity of 791.4 mAh g(-1) after 100 cycles at 100 mA g(-1)), and a good rate capability (specific capacity of 349.4 mAh g( 1) at 10 A g(-1)). The results indicate that the cobalt silicate hierarchical hollow sphere holds the potential applications in energy storage electrodes. PMID- 27479692 TI - Microarray-based annotation of the gut transcriptome of the migratory locust, Locusta migratoria. AB - The migratory locust, Locusta migratoria, is a serious agricultural pest and important insect model in the study of insect digestion and feeding behaviour. The gut is one of the primary interfaces between the insect and its environment. Nevertheless, knowledge on the gut transcriptome of L. migratoria is still very limited. Here, 48 802 expressed sequence tags were extracted from publicly available databases and their expression in larval gut and/or brain tissue was determined using microarray hybridization. Our data show 2765 transcripts predominantly or exclusively expressed in the gut. Many transcripts had putative functions closely related to the physiological functions of the gut as a muscular digestive organ and as the first barrier against microorganisms and a wide range of toxins. By means of a ranking procedure based on the relative signal intensity, we estimated 15% of the transcripts to show high expression levels, the highest belonging to diverse digestive enzymes and muscle-related proteins. We also found evidence for very high expression of an allergen protein, which could have important implications, as locusts form a traditional food source in various parts of the world, and were also recently added to the list of insects fit for human consumption in Europe. Interestingly, many highly expressed sequences have as yet unknown functions. Taken together, the present data provide significant insight into locust larval gut physiology, and will be valuable for future studies on the insect gut. PMID- 27479693 TI - Association of a Web-Based Handoff Tool With Rates of Medical Errors. PMID- 27479694 TI - Healthcare resource utilization of second-generation long-acting injectable antipsychotics in schizophrenia: risperidone versus paliperidone palmitate. AB - OBJECTIVE: This retrospective longitudinal cohort study aimed to compare treatment patterns, healthcare resource utilization (HRU), and costs in patients with schizophrenia treated with second-generation antipsychotic long-acting injectables (SGA-LAIs): biweekly risperidone LAI versus once-monthly paliperidone palmitate. METHODS: Patients who initiated risperidone LAI or paliperidone palmitate between 1 July 2007 and 31 December 2012 (index date) were identified from the Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi State insurance databases. Outcomes were assessed 12 months after the index date. Propensity score matching (1:1) based on patients' demographics and comorbidities was conducted. Outcome differences between the two cohorts were evaluated using t tests for continuous variables, chi-square tests for categorical variables, and Wilcoxon rank-sum tests for count and cost variables. Regression models estimated the difference in medication use and adherence, likelihood of HRU, number of HRU events, and healthcare costs when comparing risperidone LAI versus paliperidone palmitate, while further adjusting for patient characteristics and pre-index HRU. RESULTS: Patient characteristics were well balanced between the two cohorts (n = 499 each). Significantly lower discontinuation rates (36.5% vs. 53.3%; p < 0.001) and longer days of LAI coverage (233.6 vs. 131.7 days; p < 0.001) were observed in the paliperidone palmitate cohort versus the risperidone LAI cohort, respectively. Patients treated with paliperidone palmitate were 12.5 (95% confidence interval [CI]: 9.0-17.8) and 11.7 (95% CI: 8.0-17.4) times more likely to be adherent based on medication possession ratio and proportion of days covered, respectively (p < 0.001). Patients treated with paliperidone palmitate had reduced likelihood of hospitalization (adjusted odds ratio [95% CI]: 0.72 [0.55-0.95]), fewer emergency department (ED) visits (adjusted incidence rate ratio [aIRR]: 0.67 [0.61-0.73]) and reduced length of inpatient stay (aIRR: 0.86 [0.82-0.90]), which resulted in lower monthly inpatient hospitalization costs ( $77.58; p = 0.038) and ED visits (-$9.77; p = 0.021) relative to risperidone LAI. LIMITATIONS: Pharmacy costs were derived from health plan payment in the claims data and do not account for any discounts or rebates. This may have overestimated the branded drug costs in this analysis. CONCLUSIONS: These findings highlight the value of once-monthly paliperidone palmitate in the treatment of patients with schizophrenia. PMID- 27479695 TI - Relevance of the transcription factor PdSte12 in Penicillium digitatum conidiation and virulence during citrus fruit infection. AB - Green mould, resulting from Penicillium digitatum, is the most important postharvest disease of citrus. In a previous study, the PdSte12 transcription factor gene was identified, and disruption mutants were obtained. In the present study, the DeltaPdSte12 mutants generated through gene replacement showed significantly reduced virulence during citrus fruit infection. Virulence was affected not only in mature fruit but also in immature fruit, and disease severity was markedly reduced when the oranges were stored at 20 or 4 degrees C. In addition, the DeltaPdSte12 mutants were defective in asexual reproduction, producing few conidia. The conidiophores of these mutants had longer metulae with fewer branches at the tip of the hyphae. Gene expression analysis revealed that PdSte12 might act as a negative regulator of several transporter-encoding genes and a positive regulator of two sterol demethylases, all of which are involved in fungicide resistance and fungal virulence. Moreover, PdSte12 exhibited the negative regulation of another transcription factor PdMut3, putatively involved in fungal pathogenesis but with no effect on the MAPK SLT2 P. digitatum orthologue belonging to different transcription pathways relevant to cell integrity. These results indicate the PdSte12 transcription factor is functionally conserved in P. digitatum for infection and asexual reproduction, similar to other Ste12 fungal plant pathogens. PMID- 27479696 TI - Acetylation control of cardiac fatty acid beta-oxidation and energy metabolism in obesity, diabetes, and heart failure. AB - Alterations in cardiac energy metabolism are an important contributor to the cardiac pathology associated with obesity, diabetes, and heart failure. High rates of fatty acid beta-oxidation with cardiac insulin resistance represent a cardiac metabolic hallmark of diabetes and obesity, while a marginal decrease in fatty acid oxidation and a prominent decrease in insulin-stimulated glucose oxidation are commonly seen in the early stages of heart failure. Alterations in post-translational control of energy metabolic processes have recently been identified as an important contributor to these metabolic changes. In particular, lysine acetylation of non-histone proteins, which controls a diverse family of mitochondrial metabolic pathways, contributes to the cardiac energy derangements seen in obesity, diabetes, and heart failure. Lysine acetylation is controlled both via acetyltransferases and deacetylases (sirtuins), as well as by non enzymatic lysine acetylation due to increased acetyl CoA pool size or dysregulated nicotinamide adenine dinucleotide (NAD+) metabolism (which stimulates sirtuin activity). One of the important mitochondrial acetylation targets are the fatty acid beta-oxidation enzymes, which contributes to alterations in cardiac substrate preference during the course of obesity, diabetes, and heart failure, and can ultimately lead to cardiac dysfunction in these disease states. This review will summarize the role of lysine acetylation and its regulatory control in the context of mitochondrial fatty acid beta oxidation. The functional contribution of cardiac protein lysine acetylation to the shift in cardiac energy substrate preference that occurs in obesity, diabetes, and especially in the early stages of heart failure will also be reviewed. This article is part of a Special Issue entitled: The role of post translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz. PMID- 27479697 TI - Role of sphingomyelinase in mitochondrial ceramide accumulation during reperfusion. AB - Ceramide accumulation in mitochondria has been associated with reperfusion damage, but the underlying mechanisms are not clearly elucidated. In this work we investigate the role of sphingomyelinases in mitochondrial ceramide accumulation, its effect on reactive oxygen species production, as well as on mitochondrial function by using the sphingomyelinase inhibitor, tricyclodecan-9-yl-xanthogenate (D609). Correlation between neutral sphingomyelinase (nSMase) activity and changes in ceramide content were performed in whole tissue and in isolated mitochondria from reperfused hearts. Overall results demonstrated that D609 treatment attenuates cardiac dysfuncion, mitochondrial injury and oxidative stress. Ceramide was accumulated in mitochondria, but not in the microsomal fraction of the ischemic-reperfused (I/R) group. In close association, the activity of nSMase increased, whereas glutathione (GSH) levels diminished in mitochondria after reperfusion. On the other hand, reduction of ceramide levels in mitochondria from I/R+D609 hearts correlated with diminished nSMase activity, coupling of oxidative phosphorylation and with mitochondrial integrity maintenance. These results suggest that mitochondrial nSMase activity contributes to compartmentation and further accumulation of ceramide in mitochondria, deregulating their function during reperfusion. PMID- 27479698 TI - Sensitive and Quantitative Three-Color Protein Imaging in Fission Yeast Using Spectrally Diverse, Recoded Fluorescent Proteins with Experimentally Characterized In Vivo Maturation Kinetics. AB - Schizosaccharomyces pombe is an outstanding model organism for cell biological investigations, yet the range of useful and well-characterized fluorescent proteins (XFPs) is limited. We generated and characterized three recoded fluorescent proteins for 3-color analysis in S.pombe, Super-folder GFP, monomeric Kusabira Orange 2 and E2Crimson. Upon optimization and expression in S. pombe, the three proteins enabled sensitive simultaneous 3-color detection capability. Furthermore, we describe a strategy that combines a pulse-chase approach and mathematical modeling to quantify the maturation kinetics of these proteins in vivo. We observed maturation kinetics in S. pombe that are expected from those described for these proteins in vitro and/or in other cell types, but also unpredicted behaviors. Our studies provide a kinetically-characterized, integrated three-color XFP toolbox for S. pombe. PMID- 27479699 TI - Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration. AB - Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration-QT relationship shows a 24-hour sinusoidal rhythm. Simulations show that the extent of levofloxacin-induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56-1.90) ms per mg/L) and the smallest effect at 06:00 (-0.04 (-0.19 to 0.12) ms per mg/L). These results suggest that a 24-hour variation in the concentration QT relationship could be a potentially confounding factor in the assessment of drug-induced QTc prolongation. PMID- 27479700 TI - Immunological Evidence for the Role of Mycobacteria in Sarcoidosis: A Meta Analysis. AB - BACKGROUND: Sarcoidosis is a granulomatous disease, the etiology of which is currently unknown. The role of mycobacteria in the etiology of sarcoidosis has been extensively investigated. In this meta-analysis, we assessed the immunological evidence of the possible role of mycobacteria in the pathogenesis and development of sarcoidosis. METHODS: We performed a systematic search of relevant articles from PubMed, Embase and Cochrane Library databases published between January 1990 and October 2015. Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). RESULTS: In this meta-analysis, 13 case-control studies (733 participants) were considered eligible according to our criteria. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). The positivity incidence of the immune response (either the cell-mediated response or humoral response) in sarcoidosis patients was significantly higher than that in controls, as determined using fixed-effects model. The odds ratio (OR) of the positivity incidence of T-cell response in the patients with sarcoidosis versus the controls with PPD- or unknown PPD status was 5.54 (95% CI 3.56-8.61); the ORs were 16.70 (95% CI 8.19-34.08) and 1.48 (95% CI 0.74-2.96) for the two subgroups with PPD- controls and unknown PPD status respectively. However, the OR of the positivity incidence in patients with sarcoidosis versus PPD+ controls (latent tuberculosis infection; LTBI) was 0.26 (95% 0.10-0.66). Regarding the humoral response, pooled analysis of the positivity incidence revealed an OR (95%CI) of 20.43 (5.53-75.53) for the patients with sarcoidosis versus controls; the ORs were 11.93 (95% CI 2.15-66.27) and 41.97 (95% CI 5.24-336.15) in two subgroups of controls with PPD- and unknown PPD statuses respectively. Data on heterogeneity and evidence of publication bias were examined. CONCLUSIONS: This meta-analysis confirmed the existence of an association between mycobacteria (especially M.tuberculosis) and sarcoidosis. The current available evidence indicates that some insoluble mycobacterial antigens that preferentially within the body are involved in the pathogenesis of sarcoidosis rather than the whole mycobacteria and that they elicit a type IV immune response. PMID- 27479701 TI - Does Cation Size Affect Occupancy and Electrostatic Screening of the Nucleic Acid Ion Atmosphere? AB - Electrostatics are central to all aspects of nucleic acid behavior, including their folding, condensation, and binding to other molecules, and the energetics of these processes are profoundly influenced by the ion atmosphere that surrounds nucleic acids. Given the highly complex and dynamic nature of the ion atmosphere, understanding its properties and effects will require synergy between computational modeling and experiment. Prior computational models and experiments suggest that cation occupancy in the ion atmosphere depends on the size of the cation. However, the computational models have not been independently tested, and the experimentally observed effects were small. Here, we evaluate a computational model of ion size effects by experimentally testing a blind prediction made from that model, and we present additional experimental results that extend our understanding of the ion atmosphere. Giambasu et al. developed and implemented a three-dimensional reference interaction site (3D-RISM) model for monovalent cations surrounding DNA and RNA helices, and this model predicts that Na(+) would outcompete Cs(+) by 1.8-2.1-fold; i.e., with Cs(+) in 2-fold excess of Na(+) the ion atmosphere would contain an equal number of each cation (Nucleic Acids Res. 2015, 43, 8405). However, our ion counting experiments indicate that there is no significant preference for Na(+) over Cs(+). There is an ~25% preferential occupancy of Li(+) over larger cations in the ion atmosphere but, counter to general expectations from existing models, no size dependence for the other alkali metal ions. Further, we followed the folding of the P4-P6 RNA and showed that differences in folding with different alkali metal ions observed at high concentration arise from cation-anion interactions and not cation size effects. Overall, our results provide a critical test of a computational prediction, fundamental information about ion atmosphere properties, and parameters that will aid in the development of next-generation nucleic acid computational models. PMID- 27479703 TI - Omitted Author Affiliation. PMID- 27479702 TI - A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling. AB - BACKGROUND: Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. METHODS: The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp(r). RESULTS AND DISCUSSION: Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry(r) film to produce pulsatile tablet of amoxicillin. In vitro release study firstly indicated a three-pulse release profile of the tablet. Later the pulse tablet was found to generate the sustained release of amoxicillin in beagle dogs. Furthermore, the Simcyp(r) software was used to simulate the in vivo concentration time curve model of the three-pulse release tablet for amoxicillin in both human and beagle dog. The prediction by PBPK model nicely fitted the observation in human and beagle dog. CONCLUSIONS: This study has demonstrated the interrelation of factors affecting the pulsatile formulation of amoxicillin using a Box-Behnken design. The three-pulse release tablets of amoxicillin were proven to generate pulsatile release in vitro and sustained release in vivo. This formulation was also found to extend the effective plasma concentration in human compared to the tablet of immediate release based on the simulation data by PBPK modeling. This study provides an example of using PBPK to guide the development of pulsatile dosage forms. PMID- 27479704 TI - Phasic Electrodermal Activity During the Standardized Assessment of Concussion (SAC). AB - CONTEXT: The long-term effects of concussion on brain function during cognitive tasks are not fully understood and neuroimaging findings are equivocal. Some images show hyperactivation of prefrontal brain regions in previously concussed individuals relative to controls, suggesting increased cognitive resource allocation. Others show prefrontal hypoactivation and hyperactivation in other regions as a presumed compensatory mechanism. Given the relationship between sympathetic arousal and neural activation, physiologic measures of arousal, such as electrodermal activity, may provide additional insight into the brain's functional changes in those with a history of concussion. OBJECTIVE: To quantify differences in electrodermal activity during a commonly used standardized neurocognitive assessment between individuals with or without a history of concussion. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Seven asymptomatic individuals with a self reported history of physician-diagnosed, sport-related concussion (number of previous concussions = 1.43 +/- 0.53; time since most recent concussion = 0.75 to 6 years, median = 3 years) and 10 individuals without a history of concussion participated in this study. MAIN OUTCOME MEASURE(S): All participants wore bilateral wrist electrodermal activity sensors during the Standardized Assessment of Concussion. We measured normalized phasic (reactive) electrodermal activity during each test element (orientation, immediate recall, concentration, delayed recall). RESULTS: A significant group-by-test element interaction was present (P = .003). Individuals with a history of concussion had greater phasic activity during delayed recall (P < .001). Delayed-recall phasic activity was greater in both groups relative to the other elements. CONCLUSIONS: Delayed recall resulted in greater physiologic arousal in previously concussed individuals relative to healthy control participants, supporting previous neuroimaging findings of increased prefrontal cortex activity during memory tasks after concussion. Given similar task performance and arousal patterns across the test, our results suggest that previously concussed individuals incur additional cognitive demands in a short-delay recall task. PMID- 27479706 TI - Ceramide lipids in alive and thermally stressed mussels: an investigation by hydrophilic interaction liquid chromatography-electrospray ionization Fourier transform mass spectrometry. AB - Hydrophilic interaction liquid chromatography coupled to electrospray ionization Fourier transform mass spectrometry was employed to study ceramide lipids occurring in mussels of sp. Mytilus galloprovincialis. Lipid extracts from alive mussels and mussels deliberately subjected to specific thermal treatments were analyzed. In particular, single and tandem MS measurements were performed on a hybrid quadrupole-Orbitrap mass spectrometer and then complemented by MS(n) analyses (n = 2, 3) achieved by a linear ion trap mass spectrometer. This approach enabled the characterization of 66 ceramide lipids, encompassing ceramide phosphoethanolamines (CPE), ceramide aminoethylphosphonates (CAEP) and N monomethylated CAEP. The sphingoid and acyl chains of each ceramide lipid could be distinctly recognized in terms of numbers of carbon atoms and C=C bonds, and indications on the possible location of the latter on the sphingoid chain could be often inferred from fragmentation patterns. The occurrence of several species hydroxylated on the alpha carbon of the acyl chain was also discovered. On the other hand, the sphingoid chain of ceramide lipids was never found to be involved in oxidation processes, unless forced exposure of the mussel lipid extracts to atmospheric oxygen was performed. CPE(d19:3/16:0) and its hydroxylated form, CPE(d19:3/2-OH-16:0), were found to be the prevailing species among CPE, whereas CAEP(d18:2/16:0), CAEP(d19:3/16:0) and CAEP(d19:3/2-OH-16:0) were the most abundant CAEP. Finally, ceramide lipids showed a remarkably higher stability, compared with glycerophospholipids, in mussels subjected to different thermal treatments. This finding opens interesting perspectives on the role of ceramide based lipids in the adaptation of aquatic organisms to thermal stresses. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27479705 TI - Lactic acid bacteria differentially regulate filamentation in two heritable cell types of the human fungal pathogen Candida albicans. AB - Microorganisms rarely exist as single species in natural environments. The opportunistic fungal pathogen Candida albicans and lactic acid bacteria (LAB) are common members of the microbiota of several human niches such as the mouth, gut and vagina. Lactic acid bacteria are known to suppress filamentation, a key virulence feature of C. albicans, through the production of lactic acid and other metabolites. Here we report that C. albicans cells switch between two heritable cell types, white and opaque, to undergo filamentation to adapt to diversified environments. We show that acidic pH conditions caused by LAB and low temperatures support opaque cell filamentation, while neutral pH conditions and high temperatures promote white cell filamentation. The cAMP signalling pathway and the Rfg1 transcription factor play major roles in regulating the responses to these conditions. This cell type-specific response of C. albicans to different environmental conditions reflects its elaborate regulatory control of phenotypic plasticity. PMID- 27479707 TI - Prussian Blue: A Potential Material to Improve the Electrochemical Performance of Lithium-Sulfur Batteries. AB - The Prussian blue, as a potential adsorbent of polysulfides to suppress the dissolution and shuttle of polysulfides for lithium-sulfur batteries, has been studied in this work. Our results show that Prussian blue improves the electrochemical reaction kinetics during discharge/charge processes. More importantly, the cathode with Prussian blue exhibits better cycling stability and higher discharge capacity retention (722 mAh g-1 at 0.2 A g-1 after 100 cycles) than the one without Prussian blue (151 mAh g-1). These improvements of electrochemical performances are ascribed to the fact that Prussian blue is very effective in suppressing the dissolution of polysulfides into liquid electrolyte by chemical adsorption. PMID- 27479709 TI - Development and Application of Ultra-Performance Liquid Chromatography-TOF MS for Precision Large Scale Urinary Metabolic Phenotyping. AB - To better understand the molecular mechanisms underpinning physiological variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid samples. Hyphenated ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. However, the seemingly inevitable need to analyze large studies in multiple analytical batches for UPLC-MS analysis poses a challenge to data quality which has been recognized in the field. Herein, we describe in detail a fit-for-purpose UPLC-MS platform, method set, and sample analysis workflow, capable of sustained analysis on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed phase chromatography (RPC) and hydrophilic interaction liquid chromatography (HILIC) together with high resolution orthogonal acceleration time-of-flight mass spectrometry (oaTOF-MS), exceptional measurement precision is exemplified with independent epidemiological sample sets of approximately 650 and 1000 participant samples. Evaluation of molecular reference targets in repeated injections of pooled quality control (QC) samples distributed throughout each experiment demonstrates a mean retention time relative standard deviation (RSD) of <0.3% across all assays in both studies and a mean peak area RSD of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extraction was performed followed by data filtration according to feature intensity response to QC sample dilution. Analysis of the remaining features within the repeated QC sample measurements demonstrated median peak area RSD values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each experiment was acquired in a single continuous batch, instances of minor time-dependent intensity drift were observed, highlighting the utility of data correction techniques despite reducing the dependency on them for generating high quality data. These results demonstrate that the platform and methodology presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects. Details of the pipeline used to generate high quality raw data and mitigate the need for batch correction are provided. PMID- 27479710 TI - Accurate Delineation of Glioma Infiltration by Advanced PET/MR Neuro-Imaging (FRONTIER Study): A Diagnostic Study Protocol. AB - BACKGROUND: Glioma imaging, used for diagnostics, treatment planning, and follow up, is currently based on standard magnetic resonance imaging (MRI) modalities (T1 contrast-enhancement for gadolinium-enhancing gliomas and T2 fluid-attenuated inversion recovery hyperintensity for nonenhancing gliomas). The diagnostic accuracy of these techniques for the delineation of gliomas is suboptimal. OBJECTIVE: To assess the diagnostic accuracy of advanced neuroimaging compared with standard MRI modalities for the detection of diffuse glioma infiltration within the brain. METHODS: A monocenter, prospective, diagnostic observational study in adult patients with a newly diagnosed, diffuse infiltrative glioma undergoing resective glioma surgery. Forty patients will be recruited in 3 years. Advanced neuroimaging will be added to the standard preoperative MRI. Serial neuronavigated biopsies in and around the glioma boundaries, obtained immediately preceding resective surgery, will provide histopathologic and molecular characteristics of the regions of interest, enabling comparison with quantitative measurements in the imaging modalities at the same biopsy sites. DISCUSSION: In this clinical study, we determine the diagnostic accuracy of advanced imaging in addition to standard MRI to delineate glioma. The results of our study can be valuable for the development of an improved standard imaging protocol for glioma treatment. EXPECTED OUTCOME: We hypothesize that a combination of positron emission tomography, MR spectroscopy, and standard MRI will have a superior accuracy for glioma delineation compared with standard MRI alone. In addition, we anticipate that advanced imaging will correlate with the histopathologic and molecular characteristics of glioma. ABBREVIATIONS: CHO, [11C-]CholineCRF, case report formsFET, [18F-]Fluoroethyl-tyrosineFLAIR, fluid-attenuated inversion recoveryMETC, Medical Ethical CommitteeMRS, magnetic resonance spectroscopyPET, positron emission tomographyVUmc, VU University Medical Center. PMID- 27479708 TI - A Simple and Versatile Amide Directing Group for C-H Functionalizations. AB - Achieving selective C-H activation at a single and strategic site in the presence of multiple C-H bonds can provide a powerful and generally useful retrosynthetic disconnection. In this context, a directing group serves as a compass to guide the transition metal to C-H bonds by using distance and geometry as powerful recognition parameters to distinguish between proximal and distal C-H bonds. However, the installation and removal of directing groups is a practical drawback. To improve the utility of this approach, one can seek solutions in three directions: 1) Simplifying the directing group, 2) using common functional groups or protecting groups as directing groups, and 3) attaching the directing group to substrates via a transient covalent bond to render the directing group catalytic. This Review describes the rational development of an extremely simple and yet broadly applicable directing group for Pd(II) , Rh(III) , and Ru(II) catalysts, namely the N-methoxy amide (CONHOMe) moiety. Through collective efforts in the community, a wide range of C-H activation transformations using this type of simple directing group have been developed. PMID- 27479711 TI - U.S. domestic cats as sentinels for perfluoroalkyl substances: Possible linkages with housing, obesity, and disease. AB - : Perfluoroalkyl substances (PFAS), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are persistent, globally distributed, anthropogenic compounds. The primary source(s) for human exposure are not well understood although within home exposure is likely important since many consumer products have been treated with different PFAS, and people spend much of their lives indoors. Herein, domestic cats were used as sentinels to investigate potential exposure and health linkages. PFAS in serum samples of 72 pet and feral cats, including 11 healthy and 61 with one or more primary disease diagnoses, were quantitated using high-resolution time-of-flight mass spectroscopy. All but one sample had detectable PFAS, with PFOS and perfluorohexane sulfonate (PFHxS) ranging from 1000ppm CO2 during night. Most residences had notably lower than 2500cfu/m3 airborne culturable fungi and <=100MUg/m3 formaldehyde. More than 70% of the child's bedrooms had <=75MUg/m3 PM2.5 and <=150MUg/m3 PM10. Indoor and outdoor concentrations of particulate matters had strong linear correlations (r=0.891-0.922; p-value <0.001). Most differences between cases and controls were not significant with respect to CO2, culturable fungi, formaldehyde, and particulate matters. Before and after adjusted for potential confounders, indoor averaged concentration of CO2 and particulate matters generally had negative associations with childhood history of doctor-diagnosed asthma in spring, summer, and autumn. Only in winter, indoor CO2 concentration was significantly associated with the increased odds of childhood asthma. Our results indicated that air quality among most residences in Shanghai could meet the national standard for indoor air quality in warm seasons; but household air quality and ventilation status in winter should be greatly improved. We suspected that those "unexpected" negative associations could exist due to changes in lifestyle behaviors regarding indoor air quality after the child being diagnosed asthma by a doctor. PMID- 27479713 TI - Metal assisted focused-ion beam nanopatterning. AB - Focused-ion beam milling is a versatile technique for maskless nanofabrication. However, the nonuniform ion beam profile and material redeposition tend to disfigure the surface morphology near the milling areas and degrade the fidelity of nanoscale pattern transfer, limiting the applicability of the technique. The ion-beam induced damage can deteriorate the performance of photonic devices and hinders the precision of template fabrication for nanoimprint lithography. To solve the issue, we present a metal assisted focused-ion beam (MAFIB) process in which a removable sacrificial aluminum layer is utilized to protect the working material. The new technique ensures smooth surfaces and fine milling edges; in addition, it permits direct formation of v-shaped grooves with tunable angles on dielectric substrates or metal films, silver for instance, which are rarely achieved by using traditional nanolithography followed by anisotropic etching processes. MAFIB was successfully demonstrated to directly create nanopatterns on different types of substrates with high fidelity and reproducibility. The technique provides the capability and flexibility necessary to fabricate nanophotonic devices and nanoimprint templates. PMID- 27479714 TI - Of Phenobarbital for Neonatal Seizures: Response Rate and Refractoriness Predictors. PMID- 27479715 TI - Micro/nanoscale electrohydrodynamic printing: from 2D to 3D. AB - Electrohydrodynamic printing (EHDP), based on the electrohydrodynamically induced flow of materials, enables the production of micro/nanoscale fibers or droplets and has recently attracted extensive interest to fabricate user-specific patterns in a controlled and high-efficiency manner. However, most of the existing EHDP techniques can only print two-dimensional (2D) micropatterns which cannot meet the increasing demands for the direct fabrication of three-dimensional (3D) microdevices. The integration of EHDP techniques with the layer-by-layer stacking principle of additive manufacturing has emerged as a promising solution to this limitation. Here we present a state-of-the-art review on the translation of 2D EHDP technique into a viable micro/nanoscale 3D printing strategy. The working principle, essential components as well as critical process parameters for EHDP are discussed. We highlight recent explorations on both solution-based and melt based 3D EHDP techniques in cone-jet and microdripping modes for the fabrication of multimaterial structures, microelectronics and biological constructs. Finally, we discuss the major challenges as well as possible solutions with regard to translating the 3D EHDP process into a real micro/nanoscale additive manufacturing strategy for the freeform fabrication of 3D structures. PMID- 27479716 TI - Anesthesia on the brain (and spinal cord): progress in neurosurgical anesthesia. PMID- 27479717 TI - Chronic pruritus: evaluation of patient needs and treatment goals with a special regard to differences according to pruritus classification and sex. AB - BACKGROUND: Chronic pruritus (CP) is present in approximately one-third of all dermatological patients. Diagnostics and treatment are challenging and impair patients' quality of life. OBJECTIVES: To analyse therapeutic needs in terms of the importance of treatment goals in a large sample of patients with CP. METHODS: Routine data of 2747 patients with CP were analysed with descriptive methods and significance tests (univariate and multivariate variance analyses). The importance of 27 need items was measured using the Patient Needs Questionnaire of the Patient Benefit Index. RESULTS: The most important needs were to find a clear diagnosis and treatment, to no longer experience itching and to have confidence in the therapy, which were quite or very important to > 90% of the patients. The least important goals concerned a normal working or sex life. Nine needs related mostly to disease and psychological symptoms, and some social needs differed in importance between sexes (P <= 0.05). Patients with pruritus on inflamed skin or with chronic scratch lesions judged more than half of all needs as more important than did patients with pruritus on noninflamed skin (P <= 0.05). In the multivariate model, age, pruritus intensity and quality of life had a significant effect on the importance of therapeutic needs besides sex and pruritus classification. CONCLUSIONS: Patients with CP present high levels of various therapeutic needs with differences by sex and clinical phenotype. The most important needs can be addressed through medical activities such as appropriate itch medication and a trustful doctor-patient relationship. PMID- 27479718 TI - Computational Study of the Radical Mediated Mechanism of the Formation of C8, C5, and C4 Guanine:Lysine Adducts in the Presence of the Benzophenone Photosensitizer. AB - The oxidation of guanine by triplet benzophenone in the presence of lysine has been shown to produce mono- and dilysine-substituted spiroiminodihydantion products, 8-Lys-Sp and 5,8-diLys-Sp. The potential energy surfaces for C8, C5, and C4 nucleophilic addition have been mapped out using the B3LYP/aug-cc pVTZ//B3LYP/6-31+G(d,p) level of density functional theory with the SMD solvation model and employing methylamine as a model for the side chain of lysine. Enthalpies, barrier heights, pKa's, and reduction potentials were calculated for intermediates to find the lowest energy paths. For neutral methylamine plus guanine radical and neutral methylamine radical plus guanine, the barrier for addition at C8 is ca. 10 kcal/mol lower than that for addition at C5 and C4. The barriers for water addition at C8, C5, and C4 of guanine radical are 13-20 kcal/mol higher than that for methylamine addition at C8. Further oxidation and loss of a proton leads to 8-methylaminoguanine, the methylamino analogue of 8-oxo 7,8-dihydroguanine (8-oxoG). The barrier for the addition of a second methylamine at C5 of 8-methylaminoguanine is 4.5 kcal/mol lower than that for the corresponding addition of water. Nevertheless, if the concentration of methylamine (or lysine) is very low, water addition could be competitive with methylamine addition. This would lead to comparable fractions of 8 monosubstituted-Sp and 5-8-disubstituted-Sp, in agreement with the experimental observations. PMID- 27479719 TI - Technical Advances in Oncology Outside of Radiation Medicine. PMID- 27479720 TI - The Stagnation and Decay of Radiation Oncology Resources: Lessons From Nigeria. PMID- 27479721 TI - Dose Specification for NRG Radiation Therapy Trials. PMID- 27479722 TI - How Much of the Future Can Be Read Through the Skin? PMID- 27479724 TI - Postoperative Stereotactic Body Radiation Therapy (SBRT) for Spine Metastases: A Critical Review to Guide Practice. AB - Postoperative stereotactic body radiation therapy (SBRT) for metastatic spinal tumors is increasingly being performed in clinical practice. Whereas the fundamentals of SBRT practice for intact spinal metastases are established, there are as yet no comprehensive practice guidelines for the postoperative indications. In particular, there are unique considerations for patient selection and treatment planning specific to postoperative spine SBRT that are critical for safe and effective management. The purpose of this critical review is to discuss the rationale for treatment, describe those factors affecting surgical decision making, introduce modern surgical trends, and summarize treatment outcomes for both conventional postoperative external beam radiation therapy and postoperative spine SBRT. Lastly, an in-depth practical discussion with respect to treatment planning and delivery considerations is provided to help guide optimal practice. PMID- 27479723 TI - Comparison of the Effectiveness of Radiofrequency Ablation With Stereotactic Body Radiation Therapy in Inoperable Stage I Non-Small Cell Lung Cancer: A Systemic Review and Pooled Analysis. AB - PURPOSE: To performed a systematic review and pooled analysis to compare clinical outcomes of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) for the treatment of medically inoperable stage I non-small cell lung cancer. METHODS AND MATERIALS: A comprehensive literature search for published trials from 2001 to 2012 was undertaken. Pooled analyses were performed to obtain overall survival (OS) and local tumor control rates (LCRs) and adverse events. Regression analysis was conducted considering each study's proportions of stage IA and age. RESULTS: Thirty-one studies on SBRT (2767 patients) and 13 studies on RFA (328 patients) were eligible. The LCR (95% confidence interval) at 1, 2, 3, and 5 years for RFA was 77% (70%-85%), 48% (37%-58%), 55% (47%-62%), and 42% (30%-54%) respectively, which was significantly lower than that for SBRT: 97% (96%-98%), 92% (91%-94%), 88% (86%-90%), and 86% (85%-88%) (P<.001). These differences remained significant after correcting for stage IA and age (P<.001 at 1 year, 2 years, and 3 years; P=.04 at 5 years). The effect of RFA was not different from that of SBRT on OS (P>.05). The most frequent complication of RFA was pneumothorax, occurring in 31% of patients, whereas that for SBRT (grade >=3) was radiation pneumonitis, occurring in 2% of patients. CONCLUSIONS: Compared with RFA, SBRT seems to have a higher LCR but similar OS. More studies with larger sample sizes are warranted to validate such findings. PMID- 27479725 TI - Long-Term Cancer Outcomes From Study NRG Oncology/RTOG 9517: A Phase 2 Study of Accelerated Partial Breast Irradiation With Multicatheter Brachytherapy After Lumpectomy for Early-Stage Breast Cancer. AB - PURPOSE: To examine 10-year rates of local, regional, and distant recurrences, patterns of recurrence, and survival rates for breast cancer patients enrolled on Study NRG Oncology/Radiation Therapy Oncology Group 9517, a multi-institutional prospective trial that studied one of the earliest methods of accelerated partial breast irradiation (APBI), multicatheter brachytherapy (MCT). METHODS AND MATERIALS: Eligibility included stage I/II unifocal breast cancer <3 cm in size after lumpectomy with negative surgical margins and 0 to 3 positive axillary nodes without extracapsular extension. The APBI dose delivered was 34 Gy in 10 twice-daily fractions over 5 days for high-dose-rate (HDR); and 45 Gy in 3.5 to 5 days for low-dose-rate (LDR) brachytherapy. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on long-term ipsilateral breast recurrence (IBR), contralateral breast cancer events (CBE), regional recurrence (RR), and distant metastases (DM), disease-free, and overall survival. RESULTS: The median follow-up was 12.1 years. One hundred patients were accrued from 1997 to 2000; 98 were evaluable; 65 underwent HDR and 33 LDR MCT. Median age was 62 years; 88% had T1 tumors; 81% were pN0. Seventy-seven percent were estrogen receptor and/or progesterone receptor positive; 33% received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 4 isolated IBRs and 1 IBR with RR, for 5.2% 10-year IBR without DM. There was 1 isolated RR, 1 with IBR, and 1 with a CBE, for 3.1% 10-year RR without DM. The 10-year CBE rate was 4.2%, with 5 total events. Eleven patients have developed DM, 8 have died of breast cancer, and 22 have died from other causes. The 10-year DFS and OS rates are 69.8% and 78.0%, respectively. CONCLUSION: This multi-institutional, phase 2 trial studying MCT-APBI continues to report durable in-breast cancer control rates with long-term follow-up. PMID- 27479726 TI - Pitfalls in Prediction Modeling for Normal Tissue Toxicity in Radiation Therapy: An Illustration With the Individual Radiation Sensitivity and Mammary Carcinoma Risk Factor Investigation Cohorts. AB - PURPOSE: To identify the main causes underlying the failure of prediction models for radiation therapy toxicity to replicate. METHODS AND MATERIALS: Data were used from two German cohorts, Individual Radiation Sensitivity (ISE) (n=418) and Mammary Carcinoma Risk Factor Investigation (MARIE) (n=409), of breast cancer patients with similar characteristics and radiation therapy treatments. The toxicity endpoint chosen was telangiectasia. The LASSO (least absolute shrinkage and selection operator) logistic regression method was used to build a predictive model for a dichotomized endpoint (Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer score 0, 1, or >=2). Internal areas under the receiver operating characteristic curve (inAUCs) were calculated by a naive approach whereby the training data (ISE) were also used for calculating the AUC. Cross-validation was also applied to calculate the AUC within the same cohort, a second type of inAUC. Internal AUCs from cross validation were calculated within ISE and MARIE separately. Models trained on one dataset (ISE) were applied to a test dataset (MARIE) and AUCs calculated (exAUCs). RESULTS: Internal AUCs from the naive approach were generally larger than inAUCs from cross-validation owing to overfitting the training data. Internal AUCs from cross-validation were also generally larger than the exAUCs, reflecting heterogeneity in the predictors between cohorts. The best models with largest inAUCs from cross-validation within both cohorts had a number of common predictors: hypertension, normalized total boost, and presence of estrogen receptors. Surprisingly, the effect (coefficient in the prediction model) of hypertension on telangiectasia incidence was positive in ISE and negative in MARIE. Other predictors were also not common between the 2 cohorts, illustrating that overcoming overfitting does not solve the problem of replication failure of prediction models completely. CONCLUSIONS: Overfitting and cohort heterogeneity are the 2 main causes of replication failure of prediction models across cohorts. Cross-validation and similar techniques (eg, bootstrapping) cope with overfitting, but the development of validated predictive models for radiation therapy toxicity requires strategies that deal with cohort heterogeneity. PMID- 27479727 TI - In Regard to Mattonen et al. PMID- 27479728 TI - In Reply to Sun et al. PMID- 27479729 TI - In Regard to Shah and Vicini. PMID- 27479730 TI - In Reply to Chuba and Aref. PMID- 27479731 TI - Erratum to: Nguyen PL. Rethinking the Balance of Risk and Benefit of Androgen Deprivation Therapy for Intermediate-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys 2016;94:975-977. PMID- 27479732 TI - Visualizing the Nonhomogeneous Structure of RAD51 Filaments Using Nanofluidic Channels. AB - RAD51 is the key component of the homologous recombination pathway in eukaryotic cells and performs its task by forming filaments on DNA. In this study we investigate the physical properties of RAD51 filaments formed on DNA using nanofluidic channels and fluorescence microscopy. Contrary to the bacterial ortholog RecA, RAD51 forms inhomogeneous filaments on long DNA in vitro, consisting of several protein patches. We demonstrate that a permanent "kink" in the filament is formed where two patches meet if the stretch of naked DNA between the patches is short. The kinks are readily seen in the present microscopy approach but would be hard to identify using conventional single DNA molecule techniques where the DNA is more stretched. We also demonstrate that protein patches separated by longer stretches of bare DNA roll up on each other and this is visualized as transiently overlapping filaments. RAD51 filaments can be formed at several different conditions, varying the cation (Mg(2+) or Ca(2+)), the DNA substrate (single-stranded or double-stranded), and the RAD51 concentration during filament nucleation, and we compare the properties of the different filaments formed. The results provide important information regarding the physical properties of RAD51 filaments but also demonstrate that nanofluidic channels are perfectly suited to study protein-DNA complexes. PMID- 27479733 TI - The Regional Impacts of Cooking and Heating Emissions on Ambient Air Quality and Disease Burden in China. AB - Exposure to air pollution is a major risk factor globally and particularly in Asia. A large portion of air pollutants result from residential combustion of solid biomass and coal fuel for cooking and heating. This study presents a regional modeling sensitivity analysis to estimate the impact of residential emissions from cooking and heating activities on the burden of disease at a provincial level in China. Model surface PM2.5 fields are shown to compare well when evaluated against surface air quality measurements. Scenarios run without residential sector and residential heating emissions are used in conjunction with the Global Burden of Disease 2013 framework to calculate the proportion of deaths and disability adjusted life years attributable to PM2.5 exposure from residential emissions. Overall, we estimate that 341 000 (306 000-370 000; 95% confidence interval) premature deaths in China are attributable to residential combustion emissions, approximately a third of the deaths attributable to all ambient PM2.5 pollution, with 159 000 (142 000-172 000) and 182 000 (163 000-197 000) premature deaths from heating and cooking emissions, respectively. Our findings emphasize the need to mitigate emissions from both residential heating and cooking sources to reduce the health impacts of ambient air pollution in China. PMID- 27479734 TI - New Reasons to Pursue the Therapeutic Potential of Synthetic Nucleic Acids for Neurological Diseases. PMID- 27479735 TI - Articular Gap and Step-off Revisited: 3D Quantification of Operative Reduction for Posterior Malleolar Fragments. AB - OBJECTIVES: Despite advanced imaging techniques, classic measurements of fracture reduction have not been revisited to date. The purpose of this study was to evaluate the reliability of innovative measurement techniques to quantify operative fragment reduction of posterior malleolar fractures by quantification of three-dimensional computed tomography (Q3DCT). METHODS: Twenty-eight ankle fractures including a posterior malleolar fragment (AO/OTA type 44) were evaluated using 2DCT and Q3DCT to postoperatively quantify fragment reduction. "Classic" maximum gap and step-off of the posterior fragment were measured on 2DCT and Q3DCT. In addition, 2 innovative Q3DCT parameters were introduced and their reliability was tested using intraclass correlations (ICCs): gap surface (mm) and multidirectional 3D-displacement (mm). RESULTS: "Classic" measurements showed a median maximum step-off of 1.1 mm [interquartile range (IQR) 0.0-1.8 mm] on 2DCT versus a median step-off of 0.6 mm (IQR 0.0-1.1) on Q3DCT. Median maximum gap was 1.2 mm (IQR 0.0-3.8) on 2DCT, and its equivalent on Q3DCT showed no median displacement. Q3DCT measurements revealed a median gap surface of 14.5 mm (IQR 4.7-30.0) and a median multidirectional 3D-displacement of 0.7 mm (IQR 0.0 1.1). Interrater reliability of these new Q3DCT parameters of displacement was excellent (ICC 0.92, 95% CI 0.79-0.98) for gap surface and good (ICC 0.64, 95% CI 0.28-0.88) for 3D-displacement. CONCLUSIONS: Q3DCT is a reliable and promising technique for postoperative evaluation of fracture fragment reduction. In addition to "classic" gap and step-off measurements, we propose to explore total gap surface and 3D-displacement as innovative radiographic measurements in future clinical studies. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27479736 TI - Risk of Subluxation or Dislocation After Operative Treatment of Terrible Triad Injuries. AB - OBJECTIVE: The management of terrible triad injuries has evolved over the last 2 decades to include routine radial head fixation or replacement, reattachment of the lateral collateral ligament, with or without coronoid fixation. Our objective was to determine the likelihood of and factors associated with subluxation or dislocation after operative treatment of terrible triad injuries among a large group of surgeons using current techniques. DESIGN: Retrospective cohort study. SETTING: Two level I trauma centers. PATIENTS/PARTICIPANTS: A total of 107 patients with operatively treated terrible triad injuries from January 2000 to June 2015. INTERVENTION: Review of patient- and surgery-related factors during the first postoperative month. MAIN OUTCOME MEASUREMENT: Radiographic subluxation of the ulnohumeral joint. RESULTS: One hundred of the 107 patients (93%) treated with open fixation of terrible triad injuries had no radiographic subluxation or redislocation. Two patients (2%) had slight transient radiographic subluxation ("drop sign") that corrected with active exercises within weeks of surgery. Five patients (5%) had persistent radiographic subluxation, 3 treated with a second surgery (3%). When treated within 2 weeks of injury, recurrent subluxation or dislocation after operative fixation of terrible triad injuries was rare (1%), provided that the radial head was replaced and the lateral collateral ligament reattached. CONCLUSIONS: Radiographic subluxation is very uncommon with current operative management of terrible triad injuries of the elbow within 2 weeks. Patients treated more than 2 weeks after injury might benefit from ancillary fixation to limit subluxation (ie, cross pinning, external fixation, or internal joint stabilizer). LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27479737 TI - The Black Bug Myth: Selective photodestruction of pigmented pathogens. AB - BACKGROUND AND OBJECTIVE: It is commonly believed that pigmented pathogens are selectively targeted by dental lasers. To test this notion optical diffuse reflection spectroscopy (DRS) was used to obtain absorption spectra for the periodontal pathogens, Porphyromonas gingivalis (Pg) and Prevotella intermedia (Pi). MATERIALS AND METHODS: Spectra from 400 to 1,100 nm wavelengths of Pg colonies cultured with different concentrations of hemin were obtained to test the hypothesis that "visual pigmentation" predicts absorption of near-infrared (IR) dental laser energy. Ablation threshold at 1,064 nm [1] was measured for the pathogenic fungus, Candida albicans (Ca). RESULTS: The hypothesis was demonstrated to be true at 810 nm, it was false at 1,064 nm. Diode laser (810 nm) efficacy and "depth of kill" is dependent on hemin availability from 400 to about 900 nm. Pg and Pi absorption at 1,064 nm (ua = 7.7 +/- 2.6 cm(-1) ) is independent of hemin availability but is determined by another unknown chromophore. Ca is non-pigmented but very sensitive to 1,064 nm irradiation. CONCLUSIONS: The amount of visual pigmentation does not necessarily predict sensitivity to dental laser irradiation. Spectra in visible and near-IR wavelengths demonstrate a large difference in absorption between soft tissue and Pg or Pi. This difference represents a host/pathogen differential sensitivity to laser irradiation, the basis for selective photoantisepsis. Lasers Surg. Med. 48:706-714, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27479738 TI - A verbal strength in children with Tourette syndrome? Evidence from a non-word repetition task. AB - Tourette syndrome (TS) is characterized by motor and vocal tics, and frontal/basal-ganglia abnormalities. Whereas cognitive strengths have been found in other neurodevelopmental disorders, less attention has been paid to strengths in TS, or to verbal strengths in any neurodevelopmental disorder. We examined whether the finding of speeded TS production of rule-governed morphological forms (e.g., "slipped") that involve composition (Walenski, Mostofsky, & Ullman, 2007) might extend to another language domain, phonology. Thirteen children with TS and 14 typically-developing (TD) children performed a non-word repetition task: they repeated legal phonological strings (e.g.,"naichovabe"), a task that taps rule governed (de)composition. Parallel to the morphology findings, the children with TS showed speeded production, while the two groups had similar accuracy. The results were not explained by potentially confounding factors, including IQ. Overall, the findings suggest that rule-governed grammatical composition may be speeded in TS, perhaps due to frontal/basal-ganglia abnormalities. PMID- 27479739 TI - Applicability of the dual pathway model in normal and overweight binge eaters. AB - Binge eating is a significant problem in both eating disordered and community populations alike. Extensive support exists for the dual pathway model of binge eating in both adolescent and adult clinical and nonclinical populations. However, the restrained eating pathway to binge eating in particular has failed to be confirmed in some studies. In particular, the dual pathway model may not be applicable to overweight binge eaters. The current study examined the applicability of the dual pathway model in a sample of healthy and overweight binge eaters. A total of 260 (115 healthy weight; 145 overweight or obese) adult binge eaters completed an online survey. Mediation analyses indicated support for both the dietary restraint and negative affect pathways in the healthy weight sample but only the latter pathway was supported in the overweight sample. Therefore, the full dual pathway model may only be applicable to healthy weight binge eaters. PMID- 27479740 TI - Dynamical Excitonic Effects in Doped Two-Dimensional Semiconductors. AB - It is well-known that excitonic effects can dominate the optical properties of two-dimensional materials. These effects, however, can be substantially modified by doping free carriers. We investigate these doping effects by solving the first principles Bethe-Salpeter equation. Dynamical screening effects, included via the sum-rule preserving generalized plasmon-pole model, are found to be important in the doped system. Using monolayer MoS2 as an example, we find that upon moderate doping, the exciton binding energy can be tuned by a few hundred millielectronvolts, while the exciton peak position stays nearly constant due to a cancellation with the quasiparticle band gap renormalization. At higher doping densities, the exciton peak position increases linearly in energy and gradually merges into a Fermi-edge singularity. Our results are crucial for the quantitative interpretation of optical properties of two-dimensional materials and the further development of ab initio theories of studying charged excitations such as trions. PMID- 27479741 TI - Optimal cue combination and landmark-stability learning in the head direction system. AB - Maintaining a sense of direction requires combining information from static environmental landmarks with dynamic information about self-motion. This is accomplished by the head direction system, whose neurons - head direction cells - encode specific head directions. When the brain integrates information in sensory domains, this process is almost always 'optimal' - that is, inputs are weighted according to their reliability. Evidence suggests cue combination by head direction cells may also be optimal. The simplicity of the head direction signal, together with the detailed knowledge we have about the anatomy and physiology of the underlying circuit, therefore makes this system a tractable model with which to discover how optimal cue combination occurs at a neural level. In the head direction system, cue interactions are thought to occur on an attractor network of interacting head direction neurons, but attractor dynamics predict a winner take-all decision between cues, rather than optimal combination. However, optimal cue combination in an attractor could be achieved via plasticity in the feedforward connections from external sensory cues (i.e. the landmarks) onto the ring attractor. Short-term plasticity would allow rapid re-weighting that adjusts the final state of the network in accordance with cue reliability (reflected in the connection strengths), while longer term plasticity would allow long-term learning about this reliability. Although these principles were derived to model the head direction system, they could potentially serve to explain optimal cue combination in other sensory systems more generally. PMID- 27479742 TI - Context-dependent regulation of Th17-associated genes and IFNgamma expression by the transcription factor NFAT5. AB - Stress-activated transcription factors influence T-cell function in different physiopathologic contexts. NFAT5, a relative of nuclear factor kappaB and the calcineurin-activated NFATc transcription factors, protects mammalian cells from hyperosmotic stress caused by the elevation of extracellular sodium levels. In T cells exposed to hypernatremia, NFAT5 not only induces osmoprotective gene products but also cytokines and immune receptors, which raises the question of whether this factor could regulate other T-cell functions in osmostress independent contexts. Here we have used mice with a conditional deletion of Nfat5 in mature T lymphocytes to explore osmostress-dependent and -independent functions of this factor. In vitro experiments with CD4 T cells stimulated in hyperosmotic medium showed that NFAT5 enhanced the expression of IL-2 and the Th17-associated gene products RORgammat and IL-23R. By contrast, NFAT5-deficient CD4 T cells activated in vivo by anti-CD3 antibody exhibited a different activation profile and were skewed towards enhanced interferon gamma (IFNgamma) and IL-17 expression and attenuated Treg responses. Using a model of experimental colitis, we observed that mice lacking NFAT5 in T cells exhibited exacerbated intestinal colitis and enhanced expression of IFNgamma in draining lymph nodes and colon. These results show that NFAT5 can modulate different T-cell responses depending on stress conditions and stimulatory context. PMID- 27479743 TI - Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. AB - Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition. PMID- 27479744 TI - An histidine covalent receptor and butenolide complex mediates strigolactone perception. AB - Strigolactone plant hormones control plant architecture and are key players in both symbiotic and parasitic interactions. They contain an ABC tricyclic lactone connected to a butenolide group, the D ring. The DWARF14 (D14) strigolactone receptor belongs to the superfamily of alpha/beta-hydrolases, and is known to hydrolyze the bond between the ABC lactone and the D ring. Here we characterized the binding and catalytic functions of RAMOSUS3 (RMS3), the pea (Pisum sativum) ortholog of rice (Oryza sativa) D14 strigolactone receptor. Using new profluorescent probes with strigolactone-like bioactivity, we found that RMS3 acts as a single-turnover enzyme that explains its apparent low enzymatic rate. We demonstrated the formation of a covalent RMS3-D-ring complex, essential for bioactivity, in which the D ring was attached to histidine 247 of the catalytic triad. These results reveal an undescribed mechanism of plant hormone reception in which the receptor performs an irreversible enzymatic reaction to generate its own ligand. PMID- 27479745 TI - Expression of p16INK4A in cervical precancerous lesions is unlikely to be preventable by human papillomavirus vaccines. AB - BACKGROUND: Whether higher grade cervical intraepithelial neoplasia (CIN grade 2 or greater [CIN >= 2]) that develops because of human papillomavirus (HPV) genotypes not included in vaccines may progress to cervical cancer is largely unknown. The objectives of this study were to document expression of the cyclin dependent kinase inhibitor 2A (p16) tumor-suppressor protein p16INK4A as a biomarker of cervical carcinogenesis or of malignant potential and to evaluate whether its expression differs between lesions associated with vaccine and nonvaccine high-risk (HR) human papillomavirus (HPV) genotypes. METHODS: The study population consisted of 371 women who had not received HPV vaccines. Women were categorized into vaccine and nonvaccine HR-HPV genotypes and lesions associated with those types. Logistic regression analyses were used to determine the association between positive expression p16INK4A and the risk of being diagnosed with CIN 2 or CIN 3. Differences in the proportion of CIN >=2 lesions that were positive for p16INK4A expression by vaccine-related or nonvaccine related HR-HPV genotype were determined using the Pearson chi-square test. RESULTS: Specimens that were positive for p16INK4A expression were 5.3 and 16.6 times more likely to be diagnosed as CIN 2 and CIN 3 lesions, respectively, compared to CIN 1 lesions. CIN >= 2 lesions that were negative for the bivalent and 9-valent HR-HPV genotypes had similar rates of positive p16INK4A expression compared with lesions that were positive for those HR-HPV genotypes. CONCLUSIONS: Lesions that may develop because of HR-HPV genotypes not included in HPV vaccines are likely to have similar malignant potential, suggesting that well developed screening programs combined with nonvaccine-based approaches may be needed to manage the residual risk of developing cervical cancer in the post-HPV vaccination era. Cancer 2016;122:3615-23. (c) 2016 American Cancer Society. PMID- 27479746 TI - The bright side of dark matter: lncRNAs in cancer. AB - The traditional view of genome organization has been upended in the last decade with the discovery of vast amounts of non-protein-coding transcription. After initial concerns that this "dark matter" of the genome was transcriptional noise, it is apparent that a subset of these noncoding RNAs are functional. Long noncoding RNA (lncRNA) genes resemble protein-coding genes in several key aspects, and they have myriad molecular functions across many cellular pathways and processes, including oncogenic signaling. The number of lncRNA genes has recently been greatly expanded by our group to triple the number of protein coding genes; therefore, lncRNAs are likely to play a role in many biological processes. Based on their large number and expression specificity in a variety of cancers, lncRNAs are likely to serve as the basis for many clinical applications in oncology. PMID- 27479748 TI - 4-Dimensional light-sheet microscopy to elucidate shear stress modulation of cardiac trabeculation. PMID- 27479747 TI - Investigating long noncoding RNAs using animal models. AB - The number of long noncoding RNAs (lncRNAs) has grown rapidly; however, our understanding of their function remains limited. Although cultured cells have facilitated investigations of lncRNA function at the molecular level, the use of animal models provides a rich context in which to investigate the phenotypic impact of these molecules. Promising initial studies using animal models demonstrated that lncRNAs influence a diverse number of phenotypes, ranging from subtle dysmorphia to viability. Here, we highlight the diversity of animal models and their unique advantages, discuss the use of animal models to profile lncRNA expression, evaluate experimental strategies to manipulate lncRNA function in vivo, and review the phenotypes attributable to lncRNAs. Despite a limited number of studies leveraging animal models, lncRNAs are already recognized as a notable class of molecules with important implications for health and disease. PMID- 27479749 TI - Yellow Fever-More a Policy and Planning Problem than a Biological One. PMID- 27479750 TI - Decreasing Prevalence of Chronic Kidney Disease in the United States: A Cause for Optimism. PMID- 27479751 TI - High Performance All-Polymer Solar Cells by Synergistic Effects of Fine-Tuned Crystallinity and Solvent Annealing. AB - Growing interests have been devoted to the design of polymer acceptors as potential replacement for fullerene derivatives for high-performance all polymer solar cells (all-PSCs). One key factor that is limiting the efficiency of all PSCs is the low fill factor (FF) (normally <0.65), which is strongly correlated with the mobility and film morphology of polymer:polymer blends. In this work, we find a facile method to modulate the crystallinity of the well-known naphthalene diimide (NDI) based polymer N2200, by replacing a certain amount of bithiophene (2T) units in the N2200 backbone by single thiophene (T) units and synthesizing a series of random polymers PNDI-Tx, where x is the percentage of the single T. The acceptor PNDI-T10 is properly miscible with the low band gap donor polymer PTB7 Th, and the nanostructured blend promotes efficient exciton dissociation and charge transport. Solvent annealing (SA) enables higher hole and electron mobilities, and further suppresses the bimolecular recombination. As expected, the PTB7-Th:PNDI-T10 solar cells attain a high PCE of 7.6%, which is a 2-fold increase compared to that of PTB7-Th:N2200 solar cells. The FF of 0.71 reaches the highest value among all-PSCs to date. Our work demonstrates a rational design for fine-tuned crystallinity of polymer acceptors, and reveals the high potential of all-PSCs through structure and morphology engineering of semicrystalline polymer:polymer blends. PMID- 27479752 TI - Understanding and predicting protein misfolding and aggregation: Insights from proteomics. AB - Protein misfolding and aggregation are being found to be associated with an increasing number of human diseases and premature aging, either because they promote a loss of protein function or, more frequently, because the aggregated species gain a toxic activity. Despite potentially harmful, aggregation seems to be a generic property of polypeptide chains and aggregation-prone protein sequences seem to be ubiquitous, which, counterintuitively, suggests that they serve evolutionary conserved functions. The in vitro study of individual aggregation reactions of a large number of proteins has provided important insights on the structural and sequential determinants of this process. However, it is clear that understanding the role played by protein aggregation and its regulation in health and disease at the cellular, developmental, and evolutionary levels require more global approaches. The use of model organisms and their proteomic analysis hold the power to provide answers to such issues. In the present review, we address how, initially, computational large-scale analysis and, more recently, experimental proteomics are helping us to rationalize how, why and when proteins aggregate, as well as to decipher the strategies organisms have developed to control proteins aggregation propensities. PMID- 27479753 TI - The impact of aminopyrene trisulfonate (APTS) label in acceptor glycan substrates for profiling plant pectin beta-galactosyltransferase activities. AB - Aminopyrene trisulfonate (APTS)-labelled disaccharides are demonstrated to serve as readily accessible acceptor substrates for galactosyltransferase activities present in Arabidopsis microsome preparations. The reductive amination procedure used to install the fluorophore results in loss of the ring structure of the reducing terminal sugar unit, such that a single intact sugar ring is present, attached via an alditol tether to the aminopyrene fluorophore. The configuration of the alditol portion of the labelled acceptor, as well as the position of alditol galactosylation, substantially influence the ability of compounds to serve as Arabidopsis galactosyltransferase acceptor substrates. The APTS label exhibits an unexpected reaction-promoting effect that is not evident for structurally similar sulfonated aromatic fluorophores ANDS and ANTS. When APTS labelled beta-(1 -> 4)-Gal3 was employed as an acceptor substrate with Arabidopsis microsomes, glycan extension generated beta-(1 -> 4)-galactan chains running to beyond 60 galactose residues. These studies demonstrate the potential of even very short glycan-APTS probes for assessing plant galactosyltransferase activities and the suitability CE-LIF for CAZyme profiling. PMID- 27479755 TI - Planar-Processed Polymer Transistors. AB - Planar-processed polymer transistors are proposed where the effective charge injection and the split unipolar charge transport are all on the top surface of the polymer film, showing ideal device characteristics with unparalleled performance. This technique provides a great solution to the problem of fabrication limitations, the ambiguous operating principle, and the performance improvements in practical applications of conjugated-polymer transistors. PMID- 27479754 TI - Single-shot diffraction data from the Mimivirus particle using an X-ray free electron laser. AB - Free-electron lasers (FEL) hold the potential to revolutionize structural biology by producing X-ray pules short enough to outrun radiation damage, thus allowing imaging of biological samples without the limitation from radiation damage. Thus, a major part of the scientific case for the first FELs was three-dimensional (3D) reconstruction of non-crystalline biological objects. In a recent publication we demonstrated the first 3D reconstruction of a biological object from an X-ray FEL using this technique. The sample was the giant Mimivirus, which is one of the largest known viruses with a diameter of 450 nm. Here we present the dataset used for this successful reconstruction. Data-analysis methods for single-particle imaging at FELs are undergoing heavy development but data collection relies on very limited time available through a highly competitive proposal process. This dataset provides experimental data to the entire community and could boost algorithm development and provide a benchmark dataset for new algorithms. PMID- 27479757 TI - Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. AB - Deterministic lateral displacement (DLD) pillar arrays are an efficient technology to sort, separate and enrich micrometre-scale particles, which include parasites, bacteria, blood cells and circulating tumour cells in blood. However, this technology has not been translated to the true nanoscale, where it could function on biocolloids, such as exosomes. Exosomes, a key target of 'liquid biopsies', are secreted by cells and contain nucleic acid and protein information about their originating tissue. One challenge in the study of exosome biology is to sort exosomes by size and surface markers. We use manufacturable silicon processes to produce nanoscale DLD (nano-DLD) arrays of uniform gap sizes ranging from 25 to 235 nm. We show that at low Peclet (Pe) numbers, at which diffusion and deterministic displacement compete, nano-DLD arrays separate particles between 20 to 110 nm based on size with sharp resolution. Further, we demonstrate the size-based displacement of exosomes, and so open up the potential for on-chip sorting and quantification of these important biocolloids. PMID- 27479756 TI - Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. AB - The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice. Similarly, the subcutaneous co-administration of nanoparticles with adalimumab resulted in the durable inhibition of ADAs, leading to normalized pharmacokinetics of the anti-TNFalpha antibody and protection against arthritis in TNFalpha transgenic mice. Adjunct therapy with tolerogenic nanoparticles represents a novel and broadly applicable approach to prevent the formation of ADAs against biologic therapies. PMID- 27479758 TI - Chemical Short-Range Order in Selenide and Telluride Glasses. AB - The structure of Ge20SbxSe80-x (x = 5, 15, 20) glasses was investigated by neutron diffraction, X-ray diffraction, and extended X-ray fine structure measurements at the Ge, Sb, and Se K-edges. For each composition, large-scale structural models were obtained by fitting simultaneously the experimental data sets in the framework of the reverse Monte Carlo simulation technique. It was found that the structures of these glasses can be described mostly by the chemically ordered network model. Ge-Se and Sb-Se bonds are preferred; Se-Se bonds in the Se-poor composition (x = 20) and M-M (M = Ge, Sb) bonds in strongly Se-rich glass (x = 5) are not needed. The quality of the fits was significantly improved by introducing Ge-Ge bonding in the nearly stoichiometric composition (x = 15), showing a violation of chemical ordering. The structure of Ge20SbxSe80-x was compared to that of several glasses from the three analogous systems (Ge-As Se, Ge-As-Te, Ge-Sb-Te), and it was found that chemical short-range order becomes more pronounced upon substituting As with Sb and Se with Te. Ge-As-Se glasses behave as random covalent networks over a very broad composition range. Chemical short-range order and disorder coexist in both Te-rich and Te-poor Ge-As-Te glasses, whereas amorphous Ge14Sb29Te57 and Ge22Sb22Te56 are governed by strict chemical preferences. PMID- 27479759 TI - Multi-technique approach for qualitative and quantitative characterization of furazidin degradation kinetics under alkaline conditions. AB - Degradation of drug furazidin was studied under different conditions of environmental pH (11-13) and temperature (30-60 degrees C). The novel approach of hybrid hard- and soft-multivariate curve resolution-alternating least squares (HS MCR-ALS) method was applied to UV-vis spectral data to determine a valid kinetic model and kinetic parameters of the degradation process. The system was found to be comprised of three main species and best characterized by two consecutive first-order reactions. Furazidin degradation rate was found to be highly dependent on the applied environmental conditions, showing more prominent differences between both degradation steps towards higher pH and temperature. Complimentary qualitative analysis of the degradation process was carried out using HPLC-DAD-TOF-MS. Based on the obtained chromatographic and mass spectrometric results, as well as additional computational analysis of the species (theoretical UV-vis spectra calculations utilizing TD-DFT methodology), the operating degradation mechanism was proposed to include formation of a 5 hydroxyfuran derivative, followed by complete hydrolysis of furazidin hydantoin ring. PMID- 27479760 TI - Italian medical students quality of life: years 2005-2015. AB - BACKGROUND: Quality of Life (QoL) is a concept used to indicate the general wellness of persons or societies. University students report a low quality of life and a worse perception of their health status, because of a situation of greater discomfort in which they live during the course of the study, especially in faculties with an important emotional burden, such as medical schools. The aim of the study was to evaluate the perceived health status of first year medical students. METHODS: We conducted a cross sectional study in the time span 2005 2015, administering the questionnaire Short Form 36 (SF-36) to first-year students of the School of Medicine of the University of Siena, Italy. In addition to demographic information such as gender and the age we investigated the region of residence, marital status, employment status, and smoking habits; height and weight were required to calculate the body mass index (BMI) to evaluate a possible physical discomfort connected with the perception of health status. The data from the questionnaires were organized and processed by software Stata(r) SE, version 12.1. RESULTS: 1,104 questionnaires were collected. Medical students reported lower SF-36 scores, compared to the Italian population of the same age. Female gender and smoking habits influence negatively the score of several scales. Body Mass Index is positively correlated with the Physical Activity, while Age is negatively correlated with Social Activities. CONCLUSIONS: The perceived quality of life of the Italian medical students is lower when compared to the general population. This confirms that the condition of student implies additional problems, as other studies reports. It would be better to improve it, developing students' resilience. It would be interesting to extend this research to students of other years, from other faculties and other locations, to gain a broader view about the QoL of the Italian students. PMID- 27479761 TI - An experience of field work learning for healthcare providers: new perspectives between disadvantages and critical issues. AB - INTRODUCTION: The learning models used in traditional education are not very effective for the continuing education of healthcare providers. Fieldwork learning is an active learning method that is feasible in the workplace and is also suitable for professionals who possess a style of experiential learning. Guardian Angel 2.0(r) is a fieldwork learning project designed to promote educational skills in nurses to improve the self-care and quality of life in women affected by osteoporosis. The purpose of this article is to present the Guardian Angel 2.0(r) project and its results. METHODS: The Guardian Angel 2.0(r) effort lasted nine months and involved 212 nurses in the north, centre and south of Italy. A socio-demographic questionnaire, an evaluation scale of the learning process and a participants' satisfaction questionnaire were used to evaluate and monitor the fieldwork learning project. RESULTS: Out of the 212 nurses who participated in the project, 119 (70%) completed it. The mean age of these participants was 48 years (+/- 7.98), and 83.5% were female. About half of the participants (52.0%, 55.4% and 45.0%, respectively) were good (a) at respecting deadlines, (b) at using the methodological instruments and (c) the information tools properly. Almost all nurses considered the project to be very relevant (96.4%). In regards to the project's quality, the nurses perceived it as excellent (51.0%) and very good (48.5%). Finally, the project was considered very useful or useful by 100% of nurses. CONCLUSIONS: The general satisfaction of nurses was high. The fieldwork learning was relevant and useful for developing educational skills in nurses. It would therefore be appropriate to use fieldwork learning in clinical settings to improve the existing experience of healthcare providers and thereby reduce the difficulties of transforming the knowledge from a theoretical to a practical level and to promote the development of new behaviours when the existing ones become obsolete or inefficient. PMID- 27479762 TI - The lived experience of adults with heart failure: a phenomenological study. AB - BACKGROUND: Although a number of studies have been conducted on patients with Heart Failure (HF), they have not given a rigorous comprehensive description of what it is like to live with HF. The objective of this study was to describe the lived experience of adults with HF. STUDY DESIGN: A hermeneutic phenomenological design was used. METHODS: Cohen's method was used to conduct the study. Thirty HF patients were enrolled between February and July 2014 from an outpatient cardiovascular clinic in Tuscany, Italy. Phenomenological interviews took place at patients' homes, and the investigators analyzed verbatim transcripts. Once data saturation was achieved, to ensure data trustworthiness, participants were asked to confirm all the extracted themes. Atals.ti vers.7 was used for data analysis. RESULTS: The patients were mostly male (67%) with a mean age of 71 (SD 9.15) and an age range of 48-86. Seven themes emerged from the phenomenological analysis: 1) important life changes; 2) social isolation caused by the illness; 3) anger and resignation associated with the disease; 4) relief from spirituality; 5) will to live; 6) uncertainty about the future and 7) the inescapability of disease and death. CONCLUSIONS: The meaning that patients attribute to their lived experience helps to create their needs, which are important to direct care. Family support and religious beliefs are an important source for HF patients to better manage their fears and cope with the future. Findings of this study provide nurses with a comprehensive description of what it is like to live with HF, which can be useful in helping to meet patients' needs more effectively and in tailoring interventions. PMID- 27479763 TI - Point prevalence surveys on healthcare acquired infections in medical and surgical wards of a teaching hospital in Rome. AB - BACKGROUND: Healthcare acquired infections (HAI) are an important cause of morbidity and mortality in hospitals worldwide. Aim of the study was to analyze nine years surveillance activity, carried out by point prevalence surveys from 2007 to 2015, in a 450-bed teaching hospital in Rome. METHODS: Point prevalence surveys were carried out every year in the medical and surgical wards following the same methodology. In accordance with definitions used by the Centers for Disease Control, all infections occurred more than 48 hours after hospital admission were considered HAI, and included in the study. Baseline characteristics, clinical features, isolated pathogens (only for the period 2011 2015) and antimicrobial resistance were recorded. RESULTS: During the nine years point prevalence surveys a total 2,840 patients were enrolled. Overall 136 (4.79%) patients developed 180 (6.34%) HAI. The most frequent HAI were respiratory tract infections (RTI), which accounted for 35.0% of all HAI, followed by surgical site infections (SSI) 22.2%, urinary tract infections (UTI) 19.4%, bloodstream infections (BSI) 17.2%, and others 6.1%. HAI related to major invasive risk procedures were also evaluated. SSI/patients undergoing surgery 3.99%, UTI/ patients with urinary catheter 4.17% and BSI/patients with CVC 9.42%. Over one-half of all patients surveyed (1,532, 53.9%) were receiving antibiotics at the time of our study. Among them 892 (58.2%) for treatment, 641 (41.8%) for prophylaxis. In the latter group, 109 (17.0%) underwent extra-short term, 89 (13.9%) short term and 443 (69.1%) a long term prophylaxis. During the period 2011-2015 out of 110 HAI episodes 71 (64.5%) were confirmed microbiologically. In total 106 pathogens were isolates, Gram-negative bacteria (63.2%) were isolated more frequently than Gram-positive bacteria (28.3%). CONCLUSIONS: The overall HAI prevalence in our hospital was consistent with those reported in other studies in Italy. The study underlined the role of Gram-negative bacteria in HAI and the need for antimicrobial stewardship. It also provided useful baseline data for rational priorities in allocation of resources, for further infection control activities. PMID- 27479764 TI - Epidemiology of candidemia in neonatal intensive care units: a persistent public health problem. AB - BACKGROUND: Candidemia has become an increasingly important problem in infants hospitalized in the Neonatal Intensive Care Units (NICUs). Candida species are the third most common agents of late-onset infections in critically ill neonates and they are associated with high morbidity and mortality rates. In this study we evaluated the epidemiology of Candida bloodstream infections in the NICU of an Italian university hospital during a 15-year period. Our specific aims were to analyze the change in species distribution and the vitro susceptibility of these yeasts to fluconazole (FCZ) and amphotericin B (AmB). METHODS: A retrospective study of candidemia in the NICU of a university hospital in southern Italy, covering the years 2000-2014 was carried out. The isolates were identified using the VITEK2 yeast identification system and antifungal susceptibility was determined using the E-test method. RESULTS: Among the 57 patients with confirmed candidemia, 60% were males (n = 34 cases) and 82% (n = 47) had a gestational age of 24-32 weeks. Twenty-seven neonates (47%) had a very low birth weight (<1500 g), 20 (35%) an extremely low birth weight (<1000 g), and 10 (18%) a low birth weight (<2500 g). The most important potential risk factors were the placement of a central venous catheter, total parenteral nutrition, and endotracheal intubation (100%, each). Candida albicans was the most frequent yeast (47%), followed by Candida parapsilosis (44%). The proportion of Candida non-albicans increased slightly, from 46% in 2000-2004 to 71% in 2010-2014 (chi2 test for trend, p = 0.030). All isolates were susceptible to FCZ and AmB. CONCLUSIONS: The detection in this epidemiologic study of an increase in Candida non-albicans highlights the importance of correct species-level identification in the rapid diagnosis for an efficient treatment of candidemia. Knowledge of the local epidemiological trends in Candida species isolated in blood cultures will facilitate therapeutic decision-making. PMID- 27479765 TI - Use of a systematic risk analysis method (FMECA) to improve quality in a clinical laboratory procedure. AB - BACKGROUND: Risk management is a set of actions to recognize or identify risks, errors and their consequences and to take the steps to counter it. The aim of our study was to apply FMECA (Failure Mode, Effects and Criticality Analysis) to the Activated Protein C resistance (APCR) test in order to detect and avoid mistakes in this process. METHODS: We created a team and the process was divided in phases and sub phases. For each phase we calculated the probability of occurrence (O) of an error, the detectability score (D) and the severity (S). The product of these three indexes yields the RPN (Risk Priority Number). Phases with a higher RPN need corrective actions with a higher priority. RESULTS: The calculation of RPN showed that more than 20 activities have a score higher than 150 and need important preventive actions; 8 have a score between 100 and 150. Only 23 actions obtained an acceptable score lower than 100. CONCLUSIONS: This was one of the first experience of application of FMECA analysis to a laboratory process, and the first one which applies this technique to the identification of the factor V Leiden, and our results confirm that FMECA could be a simple, powerful and useful tool in risk management and helps to identify quickly the criticality in a laboratory process. PMID- 27479767 TI - Quality Implementation in Health Physics Unit, Cosenza Hospital. Accreditation Program as Quality Improvement instrument. AB - Achieving high levels of quality in healthcare, which could be measurable, is increasingly important at present and is dictated by the radical changes of the welfare system imposed today by the well known economic constraints. However, even in the ongoing legislation, the practices concerning the verification and review of the quality of health care has had a major impact in the galaxy of Health. On the one hand, the citizen is developing an awareness of the possibilities of choice (Empowerment) between a plurality of providers of healthcare services, on the other hand providers themselves are obliged, within the logic of a global market, to retrain their offers to respond satisfactorily to the needs of citizens. The purpose of this study was to demonstrate how the adoption of Operational Procedures, following the granting of a certificate of accreditation to the Unit of Medical Physics, has changed the approach to the work on the part of health workers, in the direction of a dynamic quality improvement. PMID- 27479766 TI - Qualitative and quantitative aspects of drinking water supply in Sardinia, Italy. A descriptive analysis of the ordinances and public notices issued during the years 2010-2015. AB - BACKGROUND: The aim of the study is to analyze the regional district ordinances and the warnings regarding qualitative and quantitavive drinking water abnormalities discovered by the Sardinian Municipalities and the Water Managing Authority between 2010 and 2015 in order to describe and identify the causes leading to an interruption or a limitation of the drinking water supply. METHODS: We carefully reviewed all ordinances and warnings of non-potable water and service interruption published between 2010 and 2015 by the websites of 377 Sardinian Municipalities and by the main regional newspapers, the Water Managing Authority and the Regional Health Trusts. RESULTS: From 2010 to 2015, 738 warnings/ordinances regarding drinking water supply limitation or interruption were issued. The warnings involved more than half (n. 191, 50.7%) of the 377 Sardinian Municipalities. Considering that these Municipalities included the main Sardinian cities we estimated that 80.3% of the population was affected by the issue. During the 6 years we observed a progressive increase of Municipalities involved beginning with 25 and reaching up 110 in 2014. The initial 29 warnings rose to 256 in 2014 along with an increased number of abnormal values, parameters and standards of the drinking water. Regarding the ordinances issued by the 191 Mayors we noticed that the legal limits were exceeded in 23 cases. Among those, we underline the abnormal levels of chlorites and trihalomethanes (22% of cases), the turbidity, the abnormal concentration of total chemical substances and the abnormal level of coliforms, Escherichia coli, manganese, aluminum, nitrites and iron. CONCLUSIONS: According to our observations, the Sardinian drinking water supply system is affected by a major inconvenience and the data suggest that qualitative abnormalities are mainly due to water purification treatments used in addition to the poor water supply network in existence. Considering these results, a cooperation between all Authorities involved would be desirable in order to analyze official data and provide a careful evaluation of population exposure and real risks related to the level of every parameter considered. PMID- 27479768 TI - Femtomole Detection of Proteins Using a Label-Free Nanostructured Porous Silicon Interferometer for Perspective Ultrasensitive Biosensing. AB - Nanostructured porous silicon (PS) is a promising material for label-free optical detection of biomolecules, though it currently suffers of limited clinical diagnostic applications due to insufficient sensitivity. In this regard, here we introduce an ultrasensitive and robust signal processing strategy for PS biosensors that relies on the calculation of the average value over wavelength of spectral interferograms, namely IAW, obtained on PS interferometer by subtraction (wavelength by wavelength) of reflection spectra acquired after adsorption of biomolecules inside the nanopores from a reference reflection spectrum recorded in acetate buffer. As a case study, we choose to monitor bovine serum albumin (BSA) unspecific adsorption, which has been often employed in the literature as a model for proof-of-concept studies of perspective biosensing applications. The proposed IAW signal processing strategy enables reliable detection of BSA at concentrations in the range from 150 pM to 15 MUM (down to 3 orders of magnitude lower than those targeted in the current literature) using a PS interferometer operating in label-free mode without any amplification strategies, with good sample-to-sample reproducibility over the whole range of tested concentrations (%CV = 16% over 5 replicates) and good signal-to-noise ratio also at the lowest tested concentration (S/N ~ 4.6 at 150 pM). A detection limit (DL) of 20 pM (20 femtomoles, 1 mL) is estimated from the sigmoidal function best fitting (R(2) = 0.989) IAW experimental data over the whole range of tested concentrations. This is the lowest DL that has been reported in the literature since the seminal paper of Sailor and co-workers (1997) on the use of PS interferometer for biosensing, and lowers of 4 orders of magnitude DL attained with label-free PS interferometers using conventional effective optical thickness (EOT) calculation through reflective interferometric Fourier transform spectroscopy. Accordingly, the IAW signal processing strategy envisage bringing PS optical transduction at the forefront of ultrasensitive label-free biosensing techniques, especially for point-of-care clinical analysis where low analyte concentrations have to be detected in a small amount of biological samples. PMID- 27479769 TI - Endoscopic Combined Intrarenal Surgery for Simultaneous Renal and Ureteral Stones: A Retrospective Study. AB - PURPOSE: The management of simultaneous renal and ureteral calculi usually require staged procedure or change of position from supine lithotomy for ureterorenoscopic lithotripsy to prone for conventional percutaneous nephrolithotomy (PCNL). We review our experience with endoscopic combined intrarenal surgery (ECIRS) in the management of this condition. MATERIALS AND METHODS: A total of 43 patients with simultaneous renal and ureteral calculi underwent ECIRS in Galdakao-modified supine Valdivia (GMSV) position from June 2012 to March 2016. Relevant demographic and clinical data were analyzed retrospectively. Clinical outcomes such as stone-free rate, complications, and hospital stay were evaluated. Factors predicting stone-free rate were also evaluated. RESULTS: The mean ureteral stone size was 9.79 +/- 2.11 mm and the mean renal stone size was 28.0 +/- 11.4 mm. All patients with ureteral calculus were stone free after first intervention. The overall immediate renal stone success rate was 81.4%, which increased to 97% after auxiliary procedure. The overall complication rate was 32.5% with majority of complications (86%) classified under Clavien grade 1 and 2. Two patients had Clavien grade 3 complication with no grade 4 or 5 complications. The mean operative room occupation time was 132.09 +/- 35.3 minutes. The median hospital stay was 6 days (range: 2-31). On analyzing for risk factors, only the number of involved calices by stone was significantly associated with stone-free rate following ECIRS (p = 0.03). CONCLUSION: ECIRS is a novel and excellent approach for the treatment of simultaneous renal and ureteral calculi with stone clearance and morbidity profile comparable to traditional prone PCNL. We believe that the advantage provided by this approach to the surgeon, patient, and anesthetist may lead to widespread adaptability of this technique in the management of complex urolithiasis. PMID- 27479770 TI - Prolonged Detection of Zika Virus RNA in Pregnant Women. AB - OBJECTIVE: Zika virus infection during pregnancy is a cause of microcephaly and other fetal brain abnormalities. Reports indicate that the duration of detectable viral RNA in serum after symptom onset is brief. In a recent case report involving a severely affected fetus, Zika virus RNA was detected in maternal serum 10 weeks after symptom onset, longer than the duration of RNA detection in serum previously reported. This report summarizes the clinical and laboratory characteristics of pregnant women with prolonged detection of Zika virus RNA in serum that were reported to the U.S. Zika Pregnancy Registry. METHODS: Data were obtained from the U.S. Zika Pregnancy Registry, an enhanced surveillance system of pregnant women with laboratory evidence of confirmed or possible Zika virus infection. For this case series, we defined prolonged detection of Zika virus RNA as Zika virus RNA detection in serum by real-time reverse transcription polymerase chain reaction (RT-PCR) 14 or more days after symptom onset or, for women not reporting signs or symptoms consistent with Zika virus disease (asymptomatic), 21 or more days after last possible exposure to Zika virus. RESULTS: Prolonged Zika virus RNA detection in serum was identified in four symptomatic pregnant women up to 46 days after symptom onset and in one asymptomatic pregnant woman 53 days postexposure. Among the five pregnancies, one pregnancy had evidence of fetal Zika virus infection confirmed by histopathologic examination of fetal tissue, three pregnancies resulted in live births of apparently healthy neonates with no reported abnormalities, and one pregnancy is ongoing. CONCLUSION: Zika virus RNA was detected in the serum of five pregnant women beyond the previously estimated timeframe. Additional real-time RT-PCR testing of pregnant women might provide more data about prolonged detection of Zika virus RNA and the possible diagnostic, epidemiologic, and clinical implications for pregnant women. PMID- 27479771 TI - A sensitive biomarker for the detection of aquatic contamination based on behavioral assays using zebrafish larvae. AB - An effective biological early warning system for the detection of water contamination should employ undemanding species that rapidly react to the presence of contaminants in their environment. The demonstrated reaction should be comprehensible and unambiguously evidential of the contamination event. This study utilized 96h post fertilization zebrafish larvae and tested their behavioral response to acute exposure to low concentrations of cadmium chloride (CdCl2) (5.0, 2.5, 1.25, 0.625mg/L) and permethrin (0.05, 0.029, 0.017, 0.01MUg/L). We hypothesize that the number of larvae that show advanced trajectories in a group corresponds with water contamination, as the latter triggers avoidance behavior in the organisms. The proportion of advanced trajectories in the control and treated groups during the first minute of darkness was designated as a segregation parameter. It was parametrized and a threshold value was set using one CdCl2 trial and then applied to the remaining CdCl2 and permethrin replicates. For all cases, the method allowed distinguishing between the control and treated groups within two cycles of light: dark. The calculated parameter was statistically significantly different between the treated and control groups, except for the lowest CdCl2 concentration (0.625mg/L) in one replicate. This proof-of-concept study shows the potential of the proposed methodology for utilization as part of a multispecies biomonitoring system. PMID- 27479772 TI - Source contributions of Polycyclic Aromatic Hydrocarbons in soils around oilfield in the Brahmaputra Valley. AB - Surface soils from Borholla oilfield in the upper Brahmaputra Valley in India were studied for the USEPA's 16 priority Polycyclic Aromatic Hydrocarbons (PAHs). Analysis of PAHs was carried out by high performance liquid chromatography (HPLC) system equipped with an UV detector. Seasonality in PAHs concentrations was evident and the concentrations were found to be greater in post-monsoon season. There has been a dominance of low molecular weight PAHs (80-90% of total PAHs) indicating recent deposition from combustion sources. The concentration profiles appeared in the decreasing order of 3-ring >2-ring >4-ring >5-ring >6 ring PAHs. The sources of PAHs were identified using isomer pair ratios and Principal Component Analysis-Multiple Linear Regression (PCA-MLR) and Positive Matrix Factorisation (PMF). The ratios of diagnostic pairs indicated for both pyrogenic and petrogenic input of PAHs. The PCA-MLR modelling revealed that the <16% of contribution came from petrogenic origin and the rest 85% was found to be from pyrogenic sources. The PMF model also shown that <19% of PAHs source were petrogenic origin whereas rest from pyrogenic origin. The correlations of black carbon (BC) with PAHs also supported the pyrogenic contribution. The analysis of air mass back trajectories revealed that there has been contribution of both local and distant sources, through long range transport of pollutants, which were deposited to the site. PMID- 27479773 TI - Mineralization of pyrene induced by interaction between Ochrobactrum sp. PW and ryegrass in spiked soil. AB - This study was conducted to investigate the capability of pyrene-degrading bacterium Ochrobactrum sp. PW and ryegrass (Lolium multiflorum) grown alone and in combination on the degradation of pyrene in soil. After 60 days of ryegrass growth, plant biomass, pyrene-degrading microbial mass, soil enzyme activity (catalase activity and polyphenol oxidase activity) and residual concentration of pyrene in soils were determined. Higher dissipation rates were observed in PW inoculation treatments: ryegrass+PW rhizosphere soil (RP-r) and ryegrass+PW non rhizosphere soil (RP-nr), than planting of ryegrass alone, rhizosphere (R-r) or non-rhizosphere (R-nr). The inoculation with PW significantly (p<0.05) increased the dry weight of ryegrass root and shoot, nearly 2.8 and 3.3 times higher than ryegrass treatment. The pyrene-degrading microbial mass indicated that a much larger mass of bacteria, actinobacteria were present in RP treatment. The catalase activity in all different treatments were significantly (p<0.05) higher than in with treatment R-nr, and the polyphenol oxidase activity was also significantly (p<0.05) increased by inoculation with PW, leading to enhanced mineralization of pyrene from soil. Our results suggest that adding of PAHs degrading bacteria to soil can enhance remediation of PAHs contaminated soil, while improving plant growth. PMID- 27479774 TI - Bioremediation potential of diesel-contaminated Libyan soil. AB - Bioremediation is a broadly applied environmentally friendly and economical treatment for the clean-up of sites contaminated by petroleum hydrocarbons. However, the application of this technology to contaminated soil in Libya has not been fully exploited. In this study, the efficacy of different bioremediation processes (necrophytoremediation using pea straw, bioaugmentation and a combination of both treatments) together with natural attenuation were assessed in diesel contaminated Libyan soils. The addition of pea straw was found to be the best bioremediation treatment for cleaning up diesel contaminated Libyan soil after 12 weeks. The greatest TPH degradation, 96.1% (18,239.6mgkg(-1)) and 95% (17,991.14mgkg(-1)) were obtained when the soil was amended with pea straw alone and in combination with a hydrocarbonoclastic consortium respectively. In contrast, natural attenuation resulted in a significantly lower TPH reduction of 76% (14,444.5mgkg(-1)). The presence of pea straw also led to a significant increased recovery of hydrocarbon degraders; 5.7log CFU g(-1) dry soil, compared to 4.4log CFUg(-1) dry soil for the untreated (natural attenuation) soil. DGGE and Illumina 16S metagenomic analyses confirm shifts in bacterial communities compared with original soil after 12 weeks incubation. In addition, metagenomic analysis showed that original soil contained hydrocarbon degraders (e.g. Pseudoxanthomonas spp. and Alcanivorax spp.). However, they require a biostimulant (in this case pea straw) to become active. This study is the first to report successful oil bioremediation with pea straw in Libya. It demonstrates the effectiveness of pea straw in enhancing bioremediation of the diesel contaminated Libyan soil. PMID- 27479775 TI - Ecological risks of trace metals in Guanabara Bay, Rio de Janeiro, Brazil: An index analysis approach. AB - Total concentrations of Ni, Cr, Cu, Pb and Zn were determined in surface sediments from 30 stations in Guanabara Bay in 1999 and 2008. An approach using various environmental indices was used to assess contamination status of metals. This approach allowed the comparison with different coastal areas. Background Enrichment Index, Contamination index and Ecological Risk index (Pollution Load Index; Sediment Quality Guideline Quotient and Ecological Risk Index) were calculated for the metals. Results revealed a great load of organic matter and significant increases in Cu and Pb levels between 1999 and 2008. The concentrations of Cr and Zn were of great concern, surpassing the values of Probable Effect Level reference values. In spite of the differences of each index, results effectively revealed the striking contamination in Guanabara Bay concerning trace metals, and also suggested potential risk to local biota. The contamination of the northwest area was notably higher than the rest of the bay. In comparison with some other coastal bays around the world, Guanabara Bay stood out as a remarkably contaminated environment. PMID- 27479776 TI - Healthcare resource utilization after medium-term residential assessment for epilepsy and psychogenic nonepileptic seizures. AB - INTRODUCTION: Epilepsy and epilepsy mimics may lead to high healthcare resource utilization (HRU) including diagnostic resources. The William Quarrier Scottish Epilepsy Centre (SEC) provides medium-term residential assessment (MTRA; average length of stay: 28days) and treatment for complex presentations of epilepsy and related conditions (principally psychogenic nonepileptic seizures, PNES). We studied the effect of MTRA on HRU in a defined health board area in Scotland. METHODS: A retrospective audit of individuals admitted to the SEC from a defined health board area using SEC and health board medical records. Neurological HRU assessed included emergency department visits, hospital admissions, outpatient clinic appointments, and brain imaging prior to and post-MTRA. Healthcare resource utilization was also compared with individuals referred but not admitted to the SEC because of individual circumstances and choice. RESULTS: Seventy-three individuals (51 female, average age: 37.51; 22 men, average age: 43.72) were identified from three years of admissions (1st April 2010 to 31st March 2013). Final diagnosis was epilepsy (ES), 32; ES and psychogenic nonepileptic seizures (ES+PNES), 17; and PNES alone, 24. Twenty-two individuals were identified as a comparison group (8 men, 14 women; average age: 37.21 and 43.90, respectively). Total average contacts per patient per year (CPY) was significantly different pre and post-MTRA (4.16 vs. 1.32; t(72)=6.11, p<.0001, d=.72). Comparison of HRU in the first year of baseline and last full year of follow-up showed a post-MTRA reduction in HRU for PNES of 92.28%, for ES of 46.81%, and for ES+PNES of 28.3%. During the course of follow-up, PNES CPY continued to drop (1.13 first year vs. 0.10 at 3years post-MTRA). For individuals with epilepsy (with or without PNES), HRU use dropped significantly in the year after admission, and these gains remained stable (total first vs. third postdischarge CPY, 1.74 vs. 1.29). The participants in the comparison group, who were not admitted, had no comparable drop across the study period and were using significantly more resources at each follow-up point than those in the admitted group (F (1, 48)=44.45, p<.01, etap(2)=.49). CONCLUSION: Medium-term residential assessment is associated with sustained reduction in HRU especially in patients with PNES. Overall HRU reduction was 68.27% following admission (d=.72). This suggests benefit from the MTRA model for people with complex presentations. PMID- 27479777 TI - Ictal fear: Associations with age, gender, and other experiential phenomena. AB - PURPOSE: The aim of this study was to determine the relationship of fear to other auras and to gender and age using a large database. METHODS: The Epilepsy Phenome/Genome Project (EPGP) is a multicenter, multicontinental cross-sectional study in which ictal symptomatology and other data were ascertained in a standardized series of questionnaires then corroborated by epilepsy specialists. Auras were classified into subgroups of symptoms, with ictal fear, panic, or anxiety as a single category. RESULTS: Of 536 participants with focal epilepsy, 72 were coded as having ictal fear/panic/anxiety. Reviewing raw patient responses, 12 participants were deemed not to have fear, and 24 had inadequate data, leaving 36 (7%) of 512 with definite ictal fear. In univariate analyses, fear was significantly associated with auras historically considered temporal lobe in origin, including cephalic, olfactory, and visceral complaints; deja vu; and derealization. On both univariate and multivariate stepwise analyses, fear was associated with jamais vu and auras with cardiac symptoms, dyspnea, and chest tightening. Expressive aphasia was associated with fear on univariate analysis only, but the general category of aphasias was associated with fear only in the multivariate model. There was no age or gender relationship with fear when compared to the overall population with focal epilepsy that was studied under the EPGP. Patients with ictal fear were more likely to have a right hemisphere seizure focus. CONCLUSIONS: Ictal fear was strongly associated with other auras considered to originate from the limbic system. No relationship of fear with age or gender was observed. PMID- 27479778 TI - Comparative effectiveness of coronary artery bypass grafting (CABG) surgery and percutaneous coronary intervention (PCI) in elderly patients with diabetes. AB - OBJECTIVE: To compare the relative effectiveness of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) among elderly patients with diabetes regarding acute myocardial infarction (AMI), stroke, repeat revascularization, and all-cause mortality. METHODS: A retrospective cohort study was conducted using the 2006-2008 5% national sample of Medicare claims data. Elderly (>=65 years) beneficiaries with at least two claims of diabetes separated by >=30 days and who had at least one inpatient claim for multi-vessel CABG or PCI between 1 July 2006 and 30 June 2008 were identified. The date of beneficiary's first CABG or PCI was defined as the index date. All patients were followed from the index date to 31 December 2008 for outcomes. CABG and PCI patients were 1:1 matched on propensity scores and index dates. Cox proportional hazards models were used to compare postoperative outcomes between patients undergoing CABG versus PCI. RESULTS: The matched sample consisted of 4430 patients (2215 in each group). The Cox proportional hazards models showed that, compared to patients undergoing PCI, CABG was associated with a lower risk of postoperative AMI (hazard ratio [HR]: 0.494; 95% CI: 0.396-0.616; p < .0001), repeat revascularization (HR: 0.194; 95% CI: 0.149-0.252; p < .0001), the composite outcome (HR: 0.523; 95% CI: 0.460-0.595; p < .0001), and all-cause mortality (HR: 0.775; 95% CI: 0.658-0.914; p = .0024); postoperative risk of stroke was not significantly different between the two groups (HR: 0.965; 95% CI: 0.812-1.148; p = .691). CONCLUSIONS: CABG appears to be the preferred revascularization strategy for elderly patients with diabetes and coronary heart disease. However, this result should be interpreted considering study limitations, for example, several patient clinical variables and physician related factors which may affect procedure outcomes are not available in the data. Clinical decisions should be individualized considering all patient- and physician-related factors. PMID- 27479779 TI - Prevalence, antibiotic resistance, and extended-spectrum and AmpC beta-lactamase productivity of Salmonella isolates from raw meat and seafood samples in Ho Chi Minh City, Vietnam. AB - Salmonellosis is a type of foodborne disease caused by Salmonella enterica and is a frequent cause of childhood diarrhea in Vietnam. Of particular concern is the dissemination of multidrug-resistant Salmonella, as extended-spectrum beta lactamase (ESBL)-positive isolates were recently detected in children in Vietnam. In the present study, the prevalence and antibiotic resistance of Salmonella isolates obtained from 409 raw meat and seafood samples collected between October 2012 and March 2015 from slaughterhouses, wholesale fish market, and retail markets in Ho Chi Minh City, Vietnam were examined. A high rate of Salmonella contamination was detected in the pork (69.7%), poultry (65.3%), beef (58.3%), shrimp (49.1%), and farmed freshwater fish samples (36.6%). A total of 53 Salmonella serovars were found, of which S. Rissen, S. Weltevreden, S. London, S. Anatum, S. Typhimurium, and S. Corvallis were the most prevalent. In addition, 4 monophasic S. Typhimurium strains were identified using a PCR method for the detection of a specific IS200 fragment within the fliB-fliA intergenic region. The Salmonella isolates had a high prevalence (62.2%) of resistance to antimicrobial agents, particularly tetracycline (53.3%), ampicillin (43.8%), chloramphenicol (37.5%), and trimethoprim/sulfamethoxazole (31.3%). Isolates with resistance to three or more classes of antimicrobials were found (41.1%). Especially, isolates such as S. monophasic Typhimurium, S. Schwarzengrund, S. Indiana, S. Newport, S. Saintpaul and S. Bovismorbificans exhibited resistance to 6 classes of antimicrobials (3.3%). All 7 S. Indiana strains were resistant to between 4 and 6 classes of antimicrobials, including ciprofloxacin, which is commonly used for the treatment of human Salmonella infections. Two fish isolates were confirmed to be CTX-M-55 ESBL-producing Salmonella serovars Bovismorbificans and Newport, and five CMY-2 AmpC-producing Salmonella isolates of serovars Braenderup (4) and Typhimurium (1) were detected in poultry samples. The findings from this study, which is the first report of ESBL- and AmpC-producing Salmonella isolates from food in Vietnam, indicate that multidrug-resistant Salmonella are widely disseminated not only in meats, but also in seafood, within the food distribution system of Vietnam. The presence of these multidrug-resistant strains is a public health concern and suggests that the use of antimicrobial agents in both humans and animals in Vietnam should be tightly controlled. PMID- 27479780 TI - Response of Postoperative and Chronic Uveitic Cystoid Macular Edema to a Dexamethasone-Based Intravitreal Implant (Ozurdex). AB - PURPOSE: To survey the clinical responses to treatment of chronic postoperative and uveitic cystoid macular edema (CME) with a dexamethasone-based intravitreal implant (Ozurdex((r))). METHODS: This retrospective, interventional case series reports on patients with chronic CME after uncomplicated vitrectomy for epiretinal gliosis or phacoemulsification (group 1: 12 eyes) or secondary to noninfectious endogenous uveitis (group 2: 36 eyes). Central retinal thickness (CRT), best-corrected visual acuity (BCVA, logMAR), and intraocular pressure (IOP) throughout follow-up were gleaned from the medical records. RESULTS: In group 1, CRT decreased, compared with baseline, from 519 +/- 43 to 297 +/- 23 and 356 +/- 49 MUm by the 1- and 3-month visit (P = 0.02) and to 429 +/- 57 MUm before reimplantation. In group 2, CRT decreased from 460 +/- 31 to 300 +/- 21 and 312 +/- 26 MUm by the 1- and 3-month follow-up, respectively (P = 0.001), and to 373 +/- 32 MUm before reimplantation. Complete resolution of CME was achieved in 67% and 94% (groups 1 and 2, respectively) by 1 month and in 42% and 80% by 3 months after injection. In group 1, BCVA improved from 0.46 +/- 0.08 to 0.27 +/- 0.09 and 0.20 +/- 0.06 (P = 0.01) by the 1- and 3-month follow-up, respectively, and to 0.32 +/- 0.08 before reimplantation. In group 2, BCVA improved from 0.47 +/- 0.06 to 0.34 +/- 0.09, 0.26 +/- 0.07, and 0.29 +/- 0.08 (P < 0.05) at 1 and 3 months of follow-up and before reimplantation, respectively. A significant IOP increase was not observed in either group. Mean time to reimplantation of Ozurdex was 6.4 +/- 5.7 and 6.6 +/- 3.4 months for postoperative and uveitic CME, respectively. CONCLUSION: Ozurdex seems to achieve a sustained effect over up to 6 months in postsurgical and uveitic CME. PMID- 27479782 TI - Model-Based Network Meta-Analysis: A Framework for Evidence Synthesis of Clinical Trial Data. AB - Model-based meta-analysis (MBMA) is increasingly used in drug development to inform decision-making and future trial designs, through the use of complex dose and/or time course models. Network meta-analysis (NMA) is increasingly being used by reimbursement agencies to estimate a set of coherent relative treatment effects for multiple treatments that respect the randomization within the trials. However, NMAs typically either consider different doses completely independently or lump them together, with few examples of models for dose. We propose a framework, model-based network meta-analysis (MBNMA), that combines both approaches, that respects randomization, and allows estimation and prediction for multiple agents and a range of doses, using plausible physiological dose-response models. We illustrate our approach with an example comparing the efficacies of triptans for migraine relief. This uses a binary endpoint, although we note that the model can be easily modified for other outcome types. PMID- 27479783 TI - Magnetic Bistability in a Discrete Organic Radical. AB - Molecular assembly with magnetic bistability has been of considerable interest for application as electronic devices. In contrast to transition-metal complexes, magnetic bistability so far observed in organic radical crystals is mainly caused by intermolecular electron-exchange interaction. We now report that the magnetic bistability in an organic radical can also be caused by intramolecular electron exchange interaction. The diradical salt of 1,4-di(bisphenylamino)-2,3,5,6, tetramethylbenzene undergoes a phase transition with a thermal hysteresis loop over the temperature range from 118 to 131 K. The phases above and below the loop correspond to two different singlet states of the diradical dication. The results provide a novel organic radical material as an unprecedented instance of an intramolecular magnetic bistability revalent to the design of functional materials. PMID- 27479781 TI - Lanthanum carbonate: safety data after 10 years. AB - Despite 10 years of post-marketing safety monitoring of the phosphate binder lanthanum carbonate, concerns about aluminium-like accumulation and toxicity persist. Here, we present a concise overview of the safety profile of lanthanum carbonate and interim results from a 5-year observational database study (SPD405 404; ClinicalTrials.gov identifier: NCT00567723). The pharmacokinetic paradigms of lanthanum and aluminium are different in that lanthanum is minimally absorbed and eliminated via the hepatobiliary pathway, whereas aluminium shows appreciable absorption and is eliminated by the kidneys. Randomised prospective studies of paired bone biopsies revealed no evidence of accumulation or toxicity in patients treated with lanthanum carbonate. Patients treated with lanthanum carbonate for up to 6 years showed no clinically relevant changes in liver enzyme or bilirubin levels. Lanthanum does not cross the intact blood-brain barrier. The most common adverse effects are mild/moderate nausea, diarrhoea and flatulence. An interim Kaplan-Meier analysis of SPD405-404 data from the United States Renal Data System revealed that the median 5-year survival was 51.6 months (95% CI: 49.1, 54.2) in patients who received lanthanum carbonate (test group), 48.9 months (95% CI: 47.3, 50.5) in patients treated with other phosphate binders (concomitant therapy control group) and 40.3 months (95% CI: 38.9, 41.5) in patients before the availability of lanthanum carbonate (historical control group). Bone fracture rates were 5.9%, 6.7% and 6.4%, respectively. After more than 850 000 person years of worldwide patient exposure, there is no evidence that lanthanum carbonate is associated with adverse safety outcomes in patients with end-stage renal disease. PMID- 27479784 TI - Nickel tolerance, accumulation and subcellular distribution in the halophytes Sesuvium portulacastrum and Cakile maritima. AB - It has been shown that halophytes are able to successfully cope with heavy metal toxicity, suggesting their possible use for remediation of metal contaminated soils. In this work, Ni tolerance and accumulation in two halophytes, Sesuvium portulacastrum (L.) L. and Cakile maritima Scop. was investigated. Seedlings of both species were subjected hydroponically during 21 days to 0, 25, 50, and 100 MUM of NiCl2. The growth and photosynthesis parameters revealed that S. portulacastrum tolerates Ni better than C. maritima. The photosynthesis activity, chlorophyll content and photosystem II integrity were less impacted in Ni-treated S. portulacastrum as compared to C. maritima, although, Ni accumulated in higher concentrations in the shoots of S. portulacastrum (1050 MUg g-1 DW) than in those of C. maritima (550 MUg g-1 DW). The subcellular fractionation of Ni in the shoots of both species showed that C. maritima accumulated about 65% of Ni in the soluble fraction, while 28% was associated with the cell walls. In S. portulacastrum 44% of the total cellular Ni was seen in the soluble fraction and 43% was bound to the cell walls. It can be concluded that S. portulacastrum tolerates Ni better than C. maritima, most probably due to a better ability to sequester Ni in the cell walls, restricting its accumulation in the soluble fraction. PMID- 27479785 TI - The selected matrix influences the matrix-assisted laser desorption/ionization time-of-flight mass spectral patterns of partially deuterated glycosaminoglycan disaccharides. AB - RATIONALE: If carbohydrates are investigated by nuclear magnetic resonance (NMR) spectroscopy, they are normally dissolved in deuterated solvents, such as D2 O. The incorporation of deuterium leads to a high complexity of subsequently recorded mass spectra and reduced sensitivity because different deuterated ions become detectable. Here, we demonstrate that the applied matrix-assisted laser desorption/ionization (MALDI) matrix solution has a considerable impact on the observed isotopic distribution. METHODS: Unsaturated disaccharides of chondroitin (CS) and dermatan sulfate (DS) were prepared by enzymatic digestion of the polysaccharides in D2 O and analyzed by MALDI time-of-flight mass spectrometry (TOF MS) using 2,5-dihydroxybenzoic acid (DHB) and 9-aminoacridine (9-AA) according to previously published protocols. RESULTS: The extent of deuteration of a given compound can be easily determined by using the mass shift between the non-deuterated and deuterated ions. However, such a determination is more difficult when considering sugars due to their high content of exchangeable groups. Therefore, both the solvent and the matrix have a considerable impact on the MS patterns. Additionally, there are significant differences if the spectra are recorded at different laser fluences. CONCLUSIONS: Great caution should be taken when the deuterium content of disaccharides is determined by MALDI MS. Aside from the use of non-protic solvents, DHB is the matrix of choice, whereas 9 AA shows a considerable influence on the observed isotope pattern in dependence on the applied laser fluence. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27479786 TI - Evaluation of neuroendocrine tumors with 99mTc-EDDA/HYNIC TOC. AB - BACKGROUND: This paper is the short review of our preliminary results obtained with 99mTc-EDDA/HYNIC-TOC. MATERIAL AND METHODS: The total of 495 patients with different neuroendocrine tumors were investigated during last few years. RESULTS: There have been 334 true positive (TP), 73 true negative (TN), 6 false positive (FP) and 82 false negative findings (FN). Diagnosis was made according to SPECT findings in 122 patients (25%). The mean T/NT ratio for TP cases was significantly higher (p < 0.01) on SPECT (3.12 +/- 1.13) than on whole body scan (2.2 +/- 0.75). According to our results, overall sensitivity of the method is 80%, specificity 92%, positive predictive value 98%, negative predictive value 47% and accuracy 82%. Fifteen TP patients underwent therapy with 90Y-DOTATATE. CONCLUSION: Scintigraphy of neuroendocrine tumors with 99mTc-Tektrotyd is a useful method for diagnosis, staging and follow up of the patients suspected to have neuroendocrine tumors. SPECT had important role in diagnosis. It is also helpful in the appropriate choice of the therapy, including the peptide receptor radionuclide therapy. In the absence of 68Ga-labeled peptides and PET/CT, the special emphasize should be given to application of SPECT/CT as well as to the radioguided surgery. PMID- 27479787 TI - Oxidation of methionine - is it limiting the diagnostic properties of 99mTc labeled Exendin-4, a Glucagon-Like Peptide-1 receptor agonist? AB - BACKGROUND: Preliminary clinical evaluation of 99mTc-EDDA/HYNIC-Met14-Exendin-4 showed that the complex offers new diagnostic possibilities for insulinoma and MTC. Exendin-4 contains methionine at position 14 in the amino acid chain, which may be oxidized to methionine sulfoxide and, from the pharmaceutical point of view, the oxidized moiety becomes an undesired impurity in the final radioactive preparation. Therefore, the aim of this study was to investigate the influence of commonly used methods to eliminate the effect of methionine oxidation in peptides, i.e. the replacement of methionine by norleucine (Nle) and the addition of L-methionine, on the in vitro stability and the biodistribution. MATERIAL AND METHODS: 99mTc-EDDA/HYNIC-Met14-Exendin-4, 99mTc-EDDA/HYNIC-Nle14-Exendin-4, 99mTc-EDDA/HYNIC-Met14-Ex-endin-4 with the addition of L-methionine and an oxidized form of Exendin-4, i.e. 99mTc-EDDA/HYNIC-Met14(ox)-Exendin-4 were compared in vivo with 68Ga-NODAGA-Nle14-Exendin-4 in normal Wistar rats. The stability and lipophilicity were determined in vitro. RESULTS: Biodistribution studies confirmed the specific uptake of all tested complexes in the GLP-1 positive organs: lungs, pancreas and stomach. The uptake of 99mTc-EDDA/HYNIC Met14-Exendin-4 with the addition of L-methionine and for 68Ga-NODAGA-Nle14 Exendin-4 at 1h p.i. was around 2-fold higher than that of 99mTc-EDDA/HYNIC-Met14 Exendin-4 and 99mTc-EDDA/HYNIC-Nle14-Exendin-4. CONCLUSION: Although the substitution of methionine by norleucine in the HYNIC-Exendin-4 did not result in improved bio-distribution, the use of L-methionine, as the excipient that inhibits the oxidation of methionine in the peptide chain resulted in higher lung/blood and stomach/blood uptake ratios. Our results confirmed that methionine at position 14 of amino acid chain of Exendin-4 plays an important role in the interaction with GLP-1 receptor positive tissue. PMID- 27479788 TI - Neuroendocrine neoplasms and somatostatin receptor subtypes expression. AB - Neuroendocrine neoplasms (NENs) show wide spectrum of clinical course - from benign biological potential to recurrences and rapidly progressive disease. Somatostatin analogs that bind to somatostatin receptor are part of the therapy; detection and evaluation of activation of somatostatin receptor subtypes are part of the process of new therapy induction. When using RT-PCR method and immunohistochemistry, it is possible to detect more than two SSTR subtypes in majority or all neuroendo-crine neoplasms regardless tumor origin. Generally with some exceptions, from the viewpoint of tumor grade - apart the site of origin, there is a tendency to decrease the percentage of SSTRs expression; 100% (G1, 2) 85.7% (G3) for SSTR 1; 81.8% (G1, 2)-61.9% (G3) for SSTR 2; 54.5% (G1, 2)-52.4% (G3) for SSTR 3; 9% (G1, 2)-4.8% (G3) for SSTR 5. Different studies indi-cate significant differences in the expression of SSTR 1 and 2A and 2B between NEC G3 small cell type and non-small cell type. Further research on SSTRs expression in NEN could serve as base to development and improvement of somatostatin analogs' pharmacotherapy in patients with unsatisfactory course. PMID- 27479789 TI - NEN - the role of somatostatin receptor scintigraphy in clinical setting. AB - Detection of neuroendocrine neoplasms (NENs) and monitoring of their response to therapy is still challenging due to huge heterogeneity of that group of tumors. Actually, NENs visualization is mainly based on molecular imaging while in the past it was relied on less effective structural imaging including CT and MRI. Molecular imaging techniques in combination with structural imaging (hybrid imaging), especially in patients with well-differentiated NENs, in addition to morphological provide the functional information about tumor which benefits in a more accurate patient management, including more sensitive visualization of primary tumors, more precise staging and better therapy follow-up. Overexpression of somatostatin receptors (SSTR) on NENs' cell membrane was a basis for development of somatostatin receptor scintigraphy (SRS) using single photon emission tomography SPECT, which is today a well-established standard in molecular imaging of NENs, and further imaging improvement in the field of positron emission tomography (PET). Use of hybrid imaging (SPECT/CT, PET/CT) increased sensitivity of examination, mainly resulting in better detection of small lesions. Generally, somatostatin receptor imaging with PET/CT is an emerging technique, although still with limited access, but due to several advantages over SSTR SPECT/CT, should be used if available. It is worth mentioning, that both SSTR PET/CT and SSTR SPECT/CT have some limitations, such as relatively low detection rate of benign insulinomas, poorly differentiated GEP NETs and liver metastases. For that reason further improvement of NETs imaging is necessary. The most promising new tracers' families are based on SSTR antagonists, 64Cu-radiolabeled ligands and glucagon-like peptide-1 receptor (GLP 1R) imaging. Finally, in case of poor-differentiated neuroendocrine cancers 18F FDG PET/CT may be beneficial in comparison with molecular imaging based on somatostatin receptor modalities. PMID- 27479790 TI - Radiopharmaceuticals for somatostatin receptor imaging. AB - The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in clinical routine or in early phase clinical trials. Somatostatin (sst) receptor targeting with radiolabeled peptides has become an integral part in nuclear oncology during the last 20 years. This integration process has been initiated in Europe with the introduction to the market of 111In-DTPA-DPhe1 octreotide [111In-pentetreotide]. Introducing 99mTc in somatostatin receptor targeting radiopeptides resulted in much better image quality, higher sensitivity of tumor detection and lower mean effective dose for the examined patient. The next generation are 68Ga labeled somatostatin analogs. Due to the spatial resolution of PET technique and increasing number of PET scanners, the PET or PET/CT technique became very important in somatostatin receptor imaging. Until up to a couple of years ago the analogs of somatostatin were constructed aiming at their agonistic behavior, expecting that their internalization with the receptor acti-vated by the radiolabeled ligand and its retention within the tumor cell are crucial for efficient imaging and therapy. Recently it has been shown that the antagonists recognize more binding sites at the tumor cell membrane and hence offer an improved diagnostic efficacy, especially when the density of sst receptors is low. This approach may in future improve diagnostic value of somatostatin receptor imaging techniques. The developments in tracer design are followed by the improvements in imaging techniques. The new SPECT scanners offer resolution close to that of PET, which might open a new era for 99mTc and other SPECT radiotracers. PMID- 27479791 TI - Synthesis and Nanofiltration Membrane Performance of Oriented Mesoporous Silica Thin Films on Macroporous Supports. AB - Silica thin films with accessible hexagonal close-packed (HCP) pores have been deposited on macroporous supports to achieve composite nanofiltration membranes. The properties of these pore channels have been characterized through solvent flux and solute diffusion experiments. A chemically neutral surface (provided by a cross-linked layer of P123 copolymer) for silica thin film synthesis on the alumina macroporous support promotes the alignment of HCP channels vertical to the substrate, where the mesopore templating agent is block copolymer P123 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)). Vertical pore alignment is achieved for thin films (less than ~100 nm) on a neutral surface and by sandwiching thicker films (~240 nm) between two chemically neutral surfaces. Solvent flux through the composite membranes is consistent with accessible 10 nm diameter pores. Size selectivity of the membranes is characterized from the permeability of fluorescently tagged solutes (ranging from 4000 to 70 000 Da), where a size cut off occurs at 69 000 Da for the model protein bovine serum albumin. These permeability studies of the nanofiltration membranes serve to demonstrate solute transport in oriented silica thin film membranes and also highlight their versatility for membrane-based separations. PMID- 27479792 TI - Corticosteroids as an adjunct to propranolol for infantile haemangiomas complicated by recalcitrant ulceration. AB - A small subset of patients with infantile haemangiomas (IHs) can present with serious complications, the most common of which is ulceration. Ulcerated IHs can be extremely painful and always result in scarring. Numerous studies support the efficacy and reduced side-effects of propranolol relative to systemic corticosteroids, which led to the adoption of propranolol as the mainstay of IH treatment. However, in certain cases of IH with complex ulceration, propranolol monotherapy may not be sufficient. In this case report, we present two cases that illustrate the effectiveness of the adjunctive use of oral corticosteroids for the treatment of select IHs with recalcitrant painful ulceration, which were refractory to conservative wound care, laser therapy and oral propranolol. We suggest a continuing niche role for the brief use of corticosteroids as an effective adjunct to oral propranolol in managing a subset of complex IHs complicated by intractable ulceration. PMID- 27479793 TI - Influence of 21days of vacuum-aging on color, bloom development, and WBSF of beef semimembranosus. AB - Changes of color, proportions of myoglobin forms, pH, Warner-Bratzler shear force (WBSF) of beef m. semimembranosus (SM) were examined during 21days of vacuum aging. Significant changes in lightness, redness, yellowness, chroma, and hue angle (p<=0.05) of SM during aging were found. Proportions of myoglobin forms changed on the 7th day of aging. Aging decreased WBSF in general, but a significant decrease (p<=0.05) from 67.86N to 55.3N was observed after day 14 of aging. The color parameters (L*, a*, C, DeltaE) and O2Mb in 21-day aged SM were stabilized faster during blooming. Beef SM that had faster stabilization of bright red color during blooming were more tender (correlation of O2Mb with WBSF r=-0.87; p<=0.001). This could be important information for the producers, since the best quality traits could be achieved after sufficient blooming and aging time. PMID- 27479795 TI - Dinuclear and Trinuclear Nickel Complexes as Effective Catalysts for Alternating Copolymerization on Carbon Dioxide and Cyclohexene Oxide. AB - A series of novel nickel complexes 1-9 supported by NNO-tridentate Schiff-base derivatives have been synthesized and characterized. Treatment of the pro-ligands [L(1)-H = 2,4-di-tert-butyl-6-(((2-(dimethylamino)ethyl)imino)methyl)phenol, L(2) H = 2-(((2-(dimethylamino)ethyl)imino)methyl)-4,6-bis(2-phenylpropan-2-yl)phenol, L(3)-H = 2-(((2-(dimethylamino)ethyl)imino)methyl)phenol] with Ni(OAc)2.4H2O in refluxing ethanol afforded mono- or bimetallic nickel complexes {[(L(1))Ni(OAc)] (1); (L(2))Ni(OAc)] (2); (L(3))2Ni2(OAc)2(H2O)] (3)}. Alcohol-solvated trimetallic nickel acetate complexes {[(L(3))2Ni3(OAc)4(MeOH)2] (4); (L(3))2Ni3(OAc)4(EtOH)2] (5)} could be generated from the reaction of L(3)-H and anhydrous nickel(II) acetate with a ratio of 2:3 in refluxing anhydrous MeOH or EtOH. The reaction of nickel acetate tetrahydrate and L(4)-H to L(6)-H [L(4)-H = 2-(((2-(dimethylamino)ethyl)imino)methyl)-5-methoxyphenol, L(5)-H = 2-(((2 (dimethylamino)ethyl)imino)methyl)-4-methoxy-phenol, L(6)-H = 2-(((2 (dimethylamino)ethyl)imino)(phenyl)methyl)phenol] produced, respectively, the alcohol-free trinuclear nickel complexes {[(L(4))2Ni3(OAc)4] (7); [(L(5))2Ni3(OAc)4] (8); [(L(6))2Ni3(OAc)4] (9)} with the same ratio in refluxing EtOH under the atmospheric environment. Interestingly, recrystallization of [(L(3))2Ni3(OAc)4(MeOH)] (4) or [(L(3))2Ni3(OAc)4(EtOH)] (5) in the mixed solvent of CH2Cl2/hexane gives [(L(3))2Ni3(OAc)4] (6), which is isostructural with analogues 7-9. All bi- and trimetallic nickel complexes exhibit efficient activity and good selectivity for copolymerization of CO2 with cyclohexene oxide, resulting in copolymers with a high alternating microstructure possessing >=99% carbonate-linkage content. This is the first example to apply well-defined trinuclear nickel complexes as efficient catalysts for the production of perfectly alternating poly(cyclohexene carbonate). PMID- 27479796 TI - Cobalt-Catalyzed Alkyne Hydrosilylation and Sequential Vinylsilane Hydroboration with Markovnikov Selectivity. AB - A pyridinebis(oxazoline) cobalt complex is a very efficient precatalyst for the hydrosilylation of terminal alkynes with Ph2 SiH2 , providing alpha-vinylsilanes with high (Markovnikov) regioselectivity and broad functional-group tolerance. The vinylsilane products can be further converted into geminal borosilanes through Markovnikov hydroboration with pinacolborane and a bis(imino)pyridine cobalt catalyst. PMID- 27479794 TI - The effects of hippocampal lesions on MRI measures of structural and functional connectivity. AB - Focal lesions can affect connectivity between distal brain regions (connectional diaschisis) and impact the graph-theoretic properties of major brain networks (connectomic diaschisis). Given its unique anatomy and diverse range of functions, the hippocampus has been claimed to be a critical "hub" in brain networks. We investigated the effects of hippocampal lesions on structural and functional connectivity in six patients with amnesia, using a range of magnetic resonance imaging (MRI) analyses. Neuropsychological assessment revealed marked episodic memory impairment and generally intact performance across other cognitive domains. The hippocampus was the only brain structure exhibiting reduced grey-matter volume that was consistent across patients, and the fornix was the only major white-matter tract to show altered structural connectivity according to both diffusion metrics. Nonetheless, functional MRI revealed both increases and decreases in functional connectivity. Analysis at the level of regions within the default-mode network revealed reduced functional connectivity, including between nonhippocampal regions (connectional diaschisis). Analysis at the level of functional networks revealed reduced connectivity between thalamic and precuneus networks, but increased connectivity between the default-mode network and frontal executive network. The overall functional connectome showed evidence of increased functional segregation in patients (connectomic diaschisis). Together, these results point to dynamic reorganization following hippocampal lesions, with both decreased and increased functional connectivity involving limbic-diencephalic structures and larger-scale networks. (c) 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID- 27479797 TI - Improved biomass productivity in algal biofilms through synergistic interactions between photon flux density and carbon dioxide concentration. AB - Algal biofilms were grown to investigate the interaction effects of bulk medium CO2 concentration and photon flux density (PFD) on biomass productivities. When increasing the CO2 concentration from 0.04% to 2%, while maintaining a PFD of 100MUmol/m(2)/s, biomass productivities increased from ~0.5 to 2.0g/m(2)/d; however, the productivities plateaued when CO2 concentrations were incrementally increased above 2-12%. Statistical analysis demonstrates that there is a significant interaction between PFD and CO2 concentrations on biomass productivities. By simultaneously increasing PFD and CO2 concentrations, biomass productivities were significantly increased to 4.0 and 4.1g/m(2)/d in the experimental and modeled data, respectively. The second order model predicted increases in biomass productivities as both PFD and CO2 simultaneously increased yielding an optimum at 440MUmol/m(2)/s and 7.1%; however, when conditions were extended to the highest end of their respective ranges, the conditions were detrimental to growth and productivities decreased. PMID- 27479798 TI - Spatial decision support system to evaluate crop residue energy potential by anaerobic digestion. AB - Implementing anaerobic digestion (AD) in energy production from crop residues requires development of decision tools to assess its feasibility and sustainability. A spatial decision support system (SDSS) was constructed to assist decision makers to select appropriate feedstock according to biomethanation potential, identify the most suitable location for biogas facilities, determine optimum plant capacity and supply chain, and evaluate associated risks and costs. SDSS involves a spatially explicit analysis, fuzzy multi-criteria analysis, and statistical and optimization models. The tool was validated on seven crop residues located in Santander, Colombia. For example, fique bagasse generates about 0.21millionm(3)CH4year(-1) (0.329m(3)CH4kg(-1) volatile solids) with a minimum profitable plant of about 2000tonyear(-1) and an internal rate of return of 10.5%. SDSS can be applied to evaluate other biomass resources, availability periods, and co-digestion potential. PMID- 27479799 TI - Metabolic engineering of Propionibacterium freudenreichii subsp. shermanii for xylose fermentation. AB - Propionibacterium freudenreichii cannot use xylose, the second most abundant sugar in lignocellulosic biomass. Although Propionibacterium acidipropionici can use xylose as a carbon source, it is difficult to genetically modify, impeding further improvement through metabolic engineering. This study identified three xylose catabolic pathway genes encoding for xylose isomerase (xylA), xylose transporter (xylT), and xylulokinase (xylB) in P. acidipropionici and overexpressed them in P. freudenreichii subsp. shermanii via an expression plasmid pKHEM01, enabling the mutant to utilize xylose efficiently even in the presence of glucose without glucose-induced carbon catabolite repression. The mutant showed similar fermentation kinetics with glucose, xylose, and the mixture of glucose and xylose, respectively, as carbon source, and with or without the addition of antibiotic for selection pressure. The engineered P. shermanii thus can provide a novel cell factory for industrial production of propionic acid and other value-added products from lignocellulosic biomass. PMID- 27479800 TI - Long-term production of bioethanol in repeated-batch fermentation of microalgal biomass using immobilized Saccharomyces cerevisiae. AB - Separate hydrolysis fermentation (SHF) and simultaneous saccharification fermentation (SSF) processes were studied for bioethanol production from microalgal biomass. SSF was selected as an efficient process to enhance the bioethanol yield through repeated-batches using immobilized yeast cells. Combined sonication and enzymatic hydrolysis of Chlamydomonas mexicana generated 10.5 and 8.48g/L of ethanol in SSF and SHF, respectively. Yeast utilized maximum portion of total reducing sugar (TRS) reaching a consumption efficiency of 91-98%. A bioethanol yield of 0.5g/g (88.2% of theoretical yield) and volumetric productivity of 0.22g/L/h was obtained after 48h of SSF. Immobilized yeast cells enabled repetitive production of ethanol for 7 cycles displaying a fermentation efficiency up to 79% for five consecutive cycles. The maximum ethanol production was 9.7g/L in 2nd-4th cycles. A total energy recovery of 85.81% was achieved from microalgal biomass in the form of bioethanol. Repeated-batch SSF demonstrated the possibility of cost-effective bioethanol production. PMID- 27479801 TI - Distinctive denitrifying capabilities lead to differences in N2O production by denitrifying polyphosphate accumulating organisms and denitrifying glycogen accumulating organisms. AB - This study aims at investigating the denitrification kinetics in two separate enriched cultures of denitrifying polyphosphate accumulating organisms (dPAO) and denitrifying glycogen accumulating organisms (dGAO) and compare their N2O accumulation potential under different conditions. Two sequencing batch reactors were inoculated to develop dPAO and dGAO enriched microbial communities separately. Seven batch tests with different combinations of electron acceptors (nitrate, nitrite and/or nitrous oxide) were carried out with the enriched biomass from both reactors. Results indicate that in almost all batch tests, N2O accumulated for both cultures, however dPAOs showed a higher denitrification capacity compared to dGAOs due to their higher nitrogen oxides reduction rates. Additionally, the effect of the simultaneous presence of several electron acceptors in the reduction rates of the different nitrogen oxides was also assessed in dPAOs and dGAOs. PMID- 27479802 TI - Highly efficient production of optically pure l-lactic acid from corn stover hydrolysate by thermophilic Bacillus coagulans. AB - A thermophilic strain Bacillus coagulans (NBRC 12714) was employed to produce l lactic acid from corn stover hydrolysate in membrane integrated continuous fermentation. The strain NBRC 12714 metabolized glucose and xylose by the Embden Meyerhof-Parnas pathway (EMP) and the pentose phosphate pathway (PPP), producing l-lactic acid with optical purity >99.5%. The overall l-lactic acid titer of 92g/l with a yield of 0.91g/g and a productivity of 13.8g/l/h were achieved at a dilution rate of 0.15h(-1). The productivity obtained was 1.6-fold than that of conventional continuous fermentation without cell recycling, and also was the highest among the relevant studies ever reported. These results indicated that the process developed had great potential for economical industrial production of l-lactic acid from lignocellulosic biomass. PMID- 27479803 TI - Dendritic cells and adipose tissue. AB - Visceral adipose tissue inflammation in obesity is an established risk factor for metabolic syndrome, which can include insulin resistance, type 2 diabetes, hypertension and cardiovascular diseases. With obesity and related metabolic disorders reaching epidemic proportions globally, an understanding of the mechanisms of adipose tissue inflammation is crucial. Within the immune cell cohort, dendritic cells (DC) play a key role in balancing tolerance and immunity. Despite decades of research into the characterization of DC in lymphoid and non lymphoid organs, their role in adipose tissue function is poorly understood. There is now an increasing interest in identification and characterization of DC in adipose tissue and understanding their function in regulating tissue metabolic homeostasis. This review provides an overview of the study of DC in adipose tissue, focusing on possible mechanisms by which DC may contribute to adipose tissue homeostasis. PMID- 27479805 TI - B1 Field Correction of T1 Estimation Should Be Considered for Breast Dynamic Contrast-enhanced MR Imaging Even at 1.5 T. AB - Purpose To prospectively quantify the effect of T1 estimation in fat by B1 correction in breast magnetic resonance (MR) imaging at 1.5 T and to examine the subsequent quantitative dynamic contrast material-enhanced parameters in breast cancer with and without B1 correction. Materials and Methods This study had institutional review board approval, and informed consent was obtained from 72 patients with breast cancer before breast MR imaging studies were performed between January and July 2015. B1+ field and variable flip angle (FA) mapping were included in the dynamic contrast-enhanced breast MR imaging protocol with a 1.5-T MR imaging system. Precontrast T1 relaxation in fat and breast tumors was computed with and without B1 correction. The pharmacokinetic parameters of breast cancer were calculated by using the Tofts model with T1 values before and after B1 correction. The Mann-Whitney U test and linear regression model were used for statistical analysis. Results The FA was 19% higher in the left breast and 3% lower in the right breast than the prescribed value. This 22% average FA difference created a 43% T1 estimation bias in fat between the breasts. The T1 variation in fat was reduced to 0.96% after B1 correction. There was a 50% overestimation and a 7% underestimation of tumor T1 in the left breast and the right, respectively, associated with B1 error. Assuming T1 after B1 correction represents the true tumor T1, 41% underestimation in the left breast and 10% overestimation in the right without B1 correction were seen in the dynamic contrast-enhanced parameters (including the volume transfer constant, or Ktrans, fraction of extracellular extravascular space, or ve, and blood normalized initial area under the gadolinium concentration curve to 90 seconds, or IAUGCBN90). Conclusion B1 correction for more accurate T1 values should be considered for quantitative dynamic contrast-enhanced breast MR imaging, even at 1.5 T, to offset significant systemic error. (c) RSNA, 2016. PMID- 27479804 TI - Advanced-Stage Nasopharyngeal Carcinoma: Restaging System after Neoadjuvant Chemotherapy on the Basis of MR Imaging Determines Survival. AB - Purpose To evaluate the prognostic value of the restaging system after neoadjuvant chemotherapy (NACT) in patients with advanced-stage nasopharyngeal carcinoma (NPC). Materials and Methods This study was approved by the clinical research committee and a written informed consent was required before enrolling in the study. Prospectively enrolled were 412 consecutive patients with stage III IVb NPC treated with NACT followed by concurrent chemotherapy and radiation therapy. Patients were staged before NACT and restaged after NACT. The progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated with the Kaplan-Meier method, and differences were compared by using the log-rank test. Results Post-NACT T classification (PFS, P = .001) and N classification (PFS, P < .001; DMFS, P = .001) resulted in better survival curve separations than pre-NACT T classification and N classification. Patients downstaged from N2-N3 to N0-N1 disease had a better prognosis than did patients who continued to have N2-N3 diseases (3-year PFS, 83.8% vs 66.6%, P = .001; 3 year DMFS, 88.0% vs 78.4%, P = .026). Multivariate analysis revealed that post NACT T classification (hazard ratio [HR] = 1.67; 95% confidence interval [CI]: 1.18, 2.36; P = .003) and post-NACT N classification (HR = 1.54; 95% CI: 1.17, 2.03; P = .002) were independent prognostic factors for PFS; also, post-NACT N classification (HR = 1.48; 95% CI: 1.05, 2.07; P = .025) was an independent prognostic factor for DMFS. Multivariate analysis in patients with N2-N3 disease demonstrated that the N downstaging effects of NACT was the only independent prognostic factor for PFS (HR = 0.48; 95% CI: 0.29, 0.81; P = .006) and DMFS (HR = 0.52; 95% CI: 0.28, 0.97; P = .039). Conclusion The post-NACT stage is more representative of prognosis than the pre-NACT stage in advanced-stage NPC patients, which suggests that major clinical decisions should be based on the post-NACT stage. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27479806 TI - Evaluation of Paraspinal Fat Pad as an Indicator of Posterior Ligamentous Complex Injury in Cervical Spine Trauma. AB - Purpose To determine if the obliteration of a cervical space, the paraspinal fat pad (PFP), can be used as an indicator at computed tomography (CT) of an injury of cervical spine posterior ligamentous complex (PLC). Materials and Methods This retrospective study was approved by the institutional board review; written informed consent was obtained from healthy subjects and was waived for patients. First, PFP appearance was evaluated in an anatomic specimen and in 10 healthy subjects on spine CT scans by three radiologists (readers 1, 2, and 3) working in consensus. Then, in 85 patients with suspicion of cervical spine trauma following high-velocity trauma, readers 2 and 3 reviewed in consensus the cervical spine CT (reference for fracture and luxation) and 1.5-T magnetic resonance images (T1, T2, and short inversion time inversion-recovery sequences; reference for ligament and disk injuries and contusion or occult fracture) for traumatic injuries. CT appearance of PFP was independently analyzed by readers 1 and 2, and interobserver agreement (weighted kappa) was calculated. Relationships between PFP changes and injuries and descriptive analysis were calculated by using logistic regression and Fisher test, respectively. Results The PFP could be identified as a well-circumscribed fatty area between cervical spine and posterior muscles. Interobserver agreement was 0.76. An abnormal PFP was associated with PLC (P < .001) and arch (P = .006) injuries but not with body (P = .056), longitudinal ligaments (P = .412), or disk (P = .665) injuries. Sensitivity, specificity, positive predictive value, and negative predictive value for PLC injuries were 55% (11 of 20), 97% (38 of 39), 92% (11 of 12), and 81% (38 of 47), respectively. Conclusion PFP changes on CT scans are significantly associated with injuries of PLC in patients with spine cervical trauma. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27479808 TI - States Worse Than Death Among Hospitalized Patients With Serious Illnesses. PMID- 27479807 TI - TGFbeta regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells. AB - Intracerebral levels of Transforming Growth Factor beta (TGFbeta) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGFbeta responsiveness in EAE by targeting the TGFbeta receptor in myeloid cells, determining that Tgfbr2 was specifically targeted in monocyte-derived dendritic cells (moDCs) but not in CNS resident microglia by using bone-marrow chimeric mice. TGFbeta responsiveness in moDCs was necessary for the remission phase since LysM(Cre) Tgfbr2(fl/fl) mice developed a chronic form of EAE characterized by severe demyelination and extensive infiltration of activated moDCs in the CNS. Tgfbr2 deficiency resulted in increased moDC IL-12 secretion that skewed T cells to produce IFN-gamma, which in turn enhanced the production of moDC-derived reactive oxygen species that promote oxidative damage and demyelination. We identified SNPs in the human NOX2 (CYBB) gene that associated with the severity of MS, and significantly increased CYBB expression was recorded in PBMCs from both MS patients and from MS severity risk allele rs72619425-A carrying individuals. We thus identify a novel myeloid cell-T cell activation loop active in the CNS during chronic disease that could be therapeutically targeted. GLIA 2016;64:1925 1937. PMID- 27479810 TI - A multi-layered Fe2O3/graphene composite with mesopores as a catalyst for rechargeable aprotic lithium-oxygen batteries. AB - Aprotic Li-O2 batteries have attracted a huge amount of interest in the past decade owing to their extremely high energy density. However, identifying a desirable cathodic catalyst for this promising battery system is one of the biggest challenges at present. In this work, a multi-layered Fe2O3/graphene nanosheets (Fe2O3/GNS) composite with sandwich structure was synthesized using an easy thermal casting method, and served as a cathodic catalyst for aprotic Li-O2 batteries. The aprotic Li-O2 cell with the Fe2O3/GNS catalyst demonstrated a better reversibility, lower overpotential for oxygen evolution, and a higher Coulombic efficiency (close to 100%) than those of pure GNS. An excellent rate performance and good cycle stability were also confirmed. The results, characterized by ex and in situ methods, revealed that the dominant discharge product Li2O2 was decomposed below 4.35 V. This superior electrochemical performance is mainly attributed to the unique sandwich structure of the Fe2O3/GNS catalyst with mesopores, which can provide substantially more catalytic sites and prevent direct contact between carbon and Li2O2. PMID- 27479809 TI - The daydreamer: Exploring the personality underpinnings of daydreaming styles and their implications for well-being. AB - In the present research, we looked at how positive-constructive daydreaming, guilty-dysphoric daydreaming, and poor attentional control associate with both broad (i.e., openness to experience) and specific (i.e., introspection) personality traits. A second aim was to determine how daydreaming styles were associated with psychological well-being. Across four studies, 1081 undergraduate (studies 1, 2, and 4) and MTurk (study 3) participants completed online questionnaires. A fixed-effect meta-analysis revealed that introspection was a significant predictor of both positive and negative daydreaming styles, but not a consistent predictor of poor attentional control. Positive-constructive daydreaming was more strongly associated with personal growth, purpose in life, and positive affect; guilty-dysphoric daydreaming was associated with depressive symptoms, negative affect, and lower psychological well-being, while poor attentional control was associated with lower positive well-being. Although correlational, these results demonstrate the usefulness of examining the experience and content of recurrent daydreaming and mind-wandering styles to further understand well-being. PMID- 27479811 TI - Intraocular Metastases Secondary to Breast Carcinoma Correlates With Upregulation of Estrogen and Progesterone Receptor Expression in the Primary Tumor. AB - PURPOSE: To compare estrogen (ER), progesterone (PR), and human epidermal growth factor-2 (HER2) receptor expression in the primary tumor of patients affected by choroidal metastases from breast carcinoma (BC) versus those with extraocular metastases. METHODS: Eighteen consecutive patients affected by choroidal metastases from BC were included. We defined ER, PR, and HER2 positivity of the primary tumor following standard guidelines. Breast carcinoma molecular subtypes were also identified (luminal A, luminal B, HER2-enriched, and triple negative). Forty consecutive patients affected by metastatic BC without choroidal involvement were included as a control group. RESULTS: The study group and the control group were similar for age, sex, race, histopathologic classification of the primary tumor (ductal, lobular, others), and American Joint Committee on Cancer Tumor-Node-Metastasis stage at the time of primary tumor diagnosis (P > 0.05). Patients affected by choroidal metastases from BC showed a significantly higher expression of ER (P = 0.009) and PR (P = 0.018) receptors in the primary tumor compared with nonchoroidal metastatic BC. Across all patients, the luminal B molecular subtype was related to the presence of choroidal involvement (P = 0.003). Considering luminal tumors only, the luminal B subclassification was also related to the presence of choroidal involvement (P = 0.009). CONCLUSIONS: Choroidal metastases from BC are associated with ER and PR expression in the primary tumor and the luminal B molecular subtype. PMID- 27479813 TI - A Swine Model of Selective Geographic Atrophy of Outer Retinal Layers Mimicking Atrophic AMD: A Phase I Escalating Dose of Subretinal Sodium Iodate. AB - PURPOSE: To establish the dose of subretinal sodium iodate (NaIO3) in order to create a toxin-induced large animal model of selective circumscribed atrophy of outer retinal layers, the retinal pigment epithelium (RPE), and photoreceptors, by spectral-domain optical coherence tomography (SD-OCT) and immunocytochemistry. METHODS: Fifteen male and female healthy Yorkshire pigs received unilateral subretinal escalating doses of NaIO3 under general anesthesia. In all the animals, volumes of 0.1 to 0.2 mL NaIO3 were injected into the subretinal space of the area centralis through a 23/38-gauge subretinal cannula. Control SD-OCTs were performed 1 and 2 months after the surgery, at which time pigs were euthanized and eyes enucleated. Globes were routinely processed for histologic and immunohistochemical evaluation. RESULTS: Spectral-domain OCT and immunohistochemistry revealed circumscribed and well-demarcated funduscopic lesions, limited to the outer retinal layers in pigs treated with 0.01 mg/mL subretinal sodium iodate. CONCLUSIONS: The swine model of a controlled area of circumscribed retinal damage, with well-delimited borders, and selectively of the outer layers of the retina presented herein shows several clinical and histologic features of geographic atrophy in AMD. Therefore, it may represent a valuable tool in the investigation of new emerging regenerative therapies that aim to restore visual function, such as stem cell transplantation or optogenetics. PMID- 27479812 TI - The Effects of the Relative Strength of Simultaneous Competing Defocus Signals on Emmetropization in Infant Rhesus Monkeys. AB - PURPOSE: We investigated how the relative surface area devoted to the more positive-powered component in dual-focus lenses influences emmetropization in rhesus monkeys. METHODS: From 3 to 21 weeks of age, macaques were reared with binocular dual-focus spectacles. The treatment lenses had central 2-mm zones of zero-power and concentric annular zones that had alternating powers of either +3.0 diopters (D) and 0 D (+3 D/pL) or -3.0 D and 0 D (-3 D/pL). The relative widths of the powered and plano zones varied from 50:50 to 18:82 between treatment groups. Refractive status, corneal curvature, and axial dimensions were assessed biweekly throughout the lens-rearing period. Comparison data were obtained from monkeys reared with binocular full-field single-vision lenses (FF+3D, n = 6; FF-3D, n = 10) and from 35 normal controls. RESULTS: The median refractive errors for all of the +3 D/pL lens groups were similar to that for the FF+3D group (+4.63 D versus +4.31 D to +5.25 D; P = 0.18-0.96), but significantly more hyperopic than that for controls (+2.44 D; P = 0.0002-0.003). In the -3 D/pL monkeys, refractive development was dominated by the zero-powered portions of the treatment lenses; the -3 D/pL animals (+2.94 D to +3.13 D) were more hyperopic than the FF-3D monkeys (-0.78 D; P = 0.004-0.006), but similar to controls (+2.44 D; P = 0.14-0.22). CONCLUSIONS: The results demonstrate that even when the more positive-powered zones make up only one-fifth of a dual-focus lens' surface area, refractive development is still dominated by relative myopic defocus. Overall, the results emphasize that myopic defocus distributed across the visual field evokes strong signals to slow eye growth in primates. PMID- 27479815 TI - A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy. AB - We have recently demonstrated that the transcription factor nuclear factor erythroid 2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of nuclear factor-erythroid 2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. Nuclear factor-erythroid 2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction. We therefore hypothesized that elevated nuclear factor-erythroid 2 levels may lead to increased erythrocyte destruction by interfering with organelle clearance during erythroid maturation. We have previously shown that nuclear factor-erythroid 2 overexpression delays erythroid maturation of human hematopoietic stem cells. Here we report that increased nuclear factor-erythroid 2 levels also impede murine maturation by retarding mitochondrial depolarization and delaying mitochondrial elimination. In addition, ribosome autophagy is delayed in transgenics. We demonstrate that the autophagy genes NIX and ULK1 are direct novel nuclear factor-erythroid 2 target genes, as these loci are bound by nuclear factor-erythroid 2 in chromatin immunoprecipitation assays. Moreover, Nix and Ulk1 expression is increased in transgenic mice and in granulocytes from polycythemia vera patients. This is the first report implying a role for nuclear factor-erythroid 2 in erythroid maturation by affecting autophagy. PMID- 27479814 TI - Residual Foveal Cone Structure in CNGB3-Associated Achromatopsia. AB - PURPOSE: Congenital achromatopsia (ACHM) is an autosomal recessive disorder in which cone function is absent or severely reduced. Gene therapy in animal models of ACHM have shown restoration of cone function, though translation of these results to humans relies, in part, on the presence of viable cone photoreceptors at the time of treatment. Here, we characterized residual cone structure in subjects with CNGB3-associated ACHM. METHODS: High-resolution imaging (optical coherence tomography [OCT] and adaptive optics scanning light ophthalmoscopy [AOSLO]) was performed in 51 subjects with CNGB3-associated ACHM. Peak cone density and inter-cone spacing at the fovea was measured using split-detection AOSLO. Foveal outer nuclear layer thickness was measured in OCT images, and the integrity of the photoreceptor layer was assessed using a previously published OCT grading scheme. RESULTS: Analyzable images of the foveal cones were obtained in 26 of 51 subjects, with nystagmus representing the major obstacle to obtaining high-quality images. Peak foveal cone density ranged from 7,273 to 53,554 cones/mm2, significantly lower than normal (range, 84,733-234,391 cones/mm2), with the remnant cones being either contiguously or sparsely arranged. Peak cone density was correlated with OCT integrity grade; however, there was overlap of the density ranges between OCT grades. CONCLUSIONS: The degree of residual foveal cone structure varies greatly among subjects with CNGB3-associated ACHM. Such measurements may be useful in estimating the therapeutic potential of a given retina, providing affected individuals and physicians with valuable information to more accurately assess the risk-benefit ratio as they consider enrolling in experimental gene therapy trials. (www.clinicaltrials.gov, NCT01846052.). PMID- 27479816 TI - Chronic lymphocytic leukemia development is accelerated in mice with deficiency of the pro-apoptotic regulator NOXA. PMID- 27479818 TI - Maintenance rituximab following induction R-CHOP chemotherapy in patients with composite or discordant, indolent and aggressive, B-cell non-Hodgkin lymphomas. PMID- 27479817 TI - ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres. PMID- 27479819 TI - Identification of a new potential mechanism responsible for severe bleeding in myeloma: immunoglobulins bind the heparin binding domain of antithrombin activating this endogenous anticoagulant. PMID- 27479821 TI - Neutrophil to lymphocyte ratio and future risk of venous thromboembolism and mortality: the Tromso Study. PMID- 27479820 TI - Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma. AB - Classical Hodgkin lymphoma is one of the most common lymphomas and shares clinical and genetic features with primary mediastinal B-cell lymphoma. In this retrospective study, we analyzed the recurrent hotspot mutation of the exportin 1 (XPO1, p.E571K) gene, previously identified in primary mediastinal B-cell lymphoma, in biopsies and plasma circulating cell-free DNA from patients with classical Hodgkin lymphoma using a highly sensitive digital PCR technique. A total of 94 patients were included in the present study. This widely expressed XPO1 E571K mutation is present in one quarter of classical Hodgkin lymphoma patients (24.2%). Mutated and wild-type classical Hodgkin lymphomas were similar regarding the main clinical features. Patients with a detectable XPO1 mutation at the end of treatment displayed a tendency toward shorter progression-free survival, as compared to patients with undetectable mutation in plasma cell-free DNA (2-year progression-free survival: 57.1%, 95% confidence interval: 30.1-100% versus 2-year progression-free survival: 90.5%, 95% confidence interval: 78.8 100%, respectively, P=0.0601). To conclude, the detection of the XPO1 E571K mutation in biopsy and plasma cell-free DNA by digital PCR may be used as a novel biomarker in classical Hodgkin lymphoma for both diagnosis and minimal residual disease, and pinpoints a crucial role of XPO1 in classical Hodgkin lymphoma pathogenesis. The detection of somatic mutation in the plasma cell-free DNA of patients represents a major technological advance in the context of liquid biopsies and noninvasive management of classical Hodgkin lymphoma. PMID- 27479822 TI - Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects. AB - Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11*109/L to 186*109/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified "pathogenic" or "likely pathogenic" variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia. PMID- 27479823 TI - Immunoparesis status in immunoglobulin light chain amyloidosis at diagnosis affects response and survival by regimen type. AB - Clinical tools to guide in the appropriate treatment selection in immunoglobulin light chain (AL) amyloidosis are not well developed. We evaluated the response and outcome for various regimens at first-line treatment (n=681) and first progression (n=240) stratified by the immunoparesis status at diagnosis. Immunoparesis was assessed by the average relative difference of the uninvolved immunoglobulins, classifying patients into a negative average relative difference (i.e. significant immunoparesis) or a positive average relative difference (no/modest immunoparesis). Treatment was categorized as autologous stem cell transplant and four non-transplant regimens (melphalan-based; bortezomib-based, immunomodulatory drug-based and dexamethasone alone). Patients with significant immunoparesis who underwent stem cell transplant had a significantly lower rate of very good partial response or better response (58%), progression-free survival (median 30 months) and overall survival (108 months), compared to those without significant immunoparesis (80%, 127 months, median not reached, respectively; P<0.001 for all comparisons). Among the non-transplant regimens, melphalan resulted in an unfavorable progression-free survival (11 vs. 27 months; P<0.001) and overall survival (30 vs. 74 months; P=0.001) in patients with significant immunoparesis compared to those without significant immunoparesis. In contrast, no significant difference in outcomes between the immunoparesis groups was seen for those treated with bortezomib or immunomodulatory drugs. At first progression, immunoparesis status did not impact response or survival of any regimen. Melphalan at first-line provided poorer outcomes for patients with significant immunoparesis, while bortezomib or immunomodulatory drugs were more likely to overcome the adverse prognosis associated with significant immunoparesis. PMID- 27479824 TI - Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism. AB - Venous thromboembolism occurs frequently in cancer patients. Two variants in the factor 5 gene (F5), rs6025 encoding for the factor V Leiden mutation R506Q, and rs4524 encoding K858R, have been found to be associated with venous thromboembolism. We assessed the joint effect of active cancer and these two F5 variants on venous thromboembolism risk in a case-cohort study. Cases with a first venous thromboembolism (n=609) and a randomly selected age-weighted cohort (n=1,691) were sampled from the general population in Tromso, Norway. Venous thromboembolism was classified as cancer-related if it occurred in the period 6 months before to 2 years after a diagnosis of cancer. Active cancer was associated with an 8.9-fold higher risk of venous thromboembolism (95% CI 7.2 10.9). The risk of cancer-related venous thromboembolism was 16.7-fold (95% CI 9.9-28.0) higher in subjects heterozygous for rs6025 compared with non-carriers of this variant without active cancer. In subjects with active cancer the risk of venous thromboembolism was 15.9-fold higher (95% CI 9.1-27.9) in those with one risk allele at rs4524, and 21.1-fold (95% CI 12.4-35.8) higher in those with two risk alleles compared with non-carriers without active cancer. A synergistic interaction was observed between active cancer and factor V Leiden (relative excess risk due to interaction 7.0; 95% CI 0.5-14.4) and rs4524 (relative excess risk due to interaction 15.0; 95% CI 7.5-29.2). The incidence of venous thromboembolism during the initial 6 months following a diagnosis of cancer was particularly high in subjects with risk alleles at these loci. This implies that the combination of cancer and F5 variants synergistically increases venous thromboembolism risk. PMID- 27479826 TI - Significant functional difference between TNFAIP3 truncation and missense mutants. PMID- 27479825 TI - Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores. AB - This first validation of the International Myeloma Working Group geriatric assessment in 125 newly diagnosed multiple myeloma patients was performed using the International Myeloma Working Group score based on age, the Charlson Comorbidity Index and cognitive and physical conditions (Activities of Daily Living / Instrumental Activities of Daily Living) to classify patients as fit, intermediate-fit or frail. We verified the International Myeloma Working Group score's impact on outcome, and whether additional tools complement it. Since our prior analyses determined renal, lung and Karnofsky performance impairment as multivariate risks, and the inclusion of frailty, age and cytogenetics complements this, we included the revised myeloma comorbidity index, the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index and the Kaplan-Feinstein Index in this assessment. Multivariate analysis confirmed cytogenetics, Activities of Daily Living, Instrumental Activities of Daily Living and the Charlson Comorbidity Index as risks: 3-year overall survival for fit, intermediate-fit and frail patients was 91%, 77% and 47%, respectively. Using the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index, the Kaplan-Feinstein Index and the revised Myeloma Comorbidity Index allowed us to define fit and frail patients with distinct progression-free and overall survival rates, with the most pronounced differences evidenced via the International Myeloma Working Group score, the Charlson Comorbidity Index and the revised Myeloma Comorbidity Index. Since the Charlson Comorbidity Index is included in the International Myeloma Working Group score, we propose the latter and the revised Myeloma Comorbidity Index for future frailty measurements. Both are useful instruments for identifying myeloma patients with a geriatric risk profile and have a strong prognostic value for functional decline and overall survival. The study was registered as: (clinicaltrials.gov Identifier: 00003686). PMID- 27479827 TI - Comparative effectiveness of primary tumor resection in patients with stage IV colon cancer. AB - BACKGROUND: Although the safety of combination chemotherapy without primary tumor resection (PTR) in patients with stage IV colon cancer has been established, questions remain regarding a potential survival benefit with PTR. The objective of this study was to compare mortality rates in patients who had colon cancer with unresectable metastases who did and did not undergo PTR. METHODS: An observational cohort study was conducted among patients with unresectable metastatic colon cancer identified from the National Cancer Data Base (2003 2005). Multivariate Cox regression analyses with and without propensity score weighting (PSW) were performed to compare survival outcomes. Instrumental variable analysis, using the annual hospital-level PTR rate as the instrument, was used to account for treatment selection bias. To account for survivor treatment bias, in situations in which patients might die soon after diagnosis from different reasons, a landmark method was used. RESULTS: In the total cohort, 8641 of 15,154 patients (57%) underwent PTR, and 73.8% of those procedures (4972 of 6735) were at landmark. PTR was associated with a significant reduction in mortality using Cox regression (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.44-0.47) or PSW (HR, 0.46; 95% CI, 0. 44-0.49). However, instrumental variable analysis revealed a much smaller effect (relative mortality rate, 0.91; 95% CI, 0.87-0.96). Although a smaller benefit was observed with the landmark method using Cox regression (HR, 0.6; 95% CI, 0.55-0.64) and PSW (HR, 0.59; 95% CI, 0.54-0.64), instrumental variable analysis revealed no survival benefit (relative mortality rate, 0.97; 95% CI, 0.87-1.06). CONCLUSIONS: Among patients with unresectable metastatic colon cancer, after adjustment for confounder effects, PTR was not associated with improved survival compared with systemic chemotherapy; therefore, routine noncurative PTR is not recommended. Cancer 2017;123:1124-1133. (c) 2016 American Cancer Society. PMID- 27479828 TI - Comparing the Incidence of Febrile Neutropenia Resulting in Hospital Admission Between the Branded Docetaxel and the Generic Formulations. AB - Studies have raised concern about the safety of generic compared with branded drugs. Febrile neutropenia (FN) resulting in hospital admission was compared between the branded docetaxel (Taxotere(r), Sanofi) and 2 generic formulations (docetaxel Ebewe and docetaxel Hospira) in patients with breast cancer. This was a retrospective study that included patients with breast cancer who received docetaxel between January 2012 and December 2014. Patients who had an admission diagnosis of FN and had received docetaxel within 14 days prior to admission were evaluated. The docetaxel brand and dose, patient characteristics, hospital length of stay, admission to the intensive care unit (ICU), and mortality were recorded. During the study period, 2904 cycles of docetaxel were given for 876 patients (1519 cycles of docetaxel Sanofi, 811 cycles of docetaxel Hospira, and 574 cycles of docetaxel Ebewe). Among the cycles given, 130 cycles were associated with FN that required hospital admission. The overall incidence of FN resulting in hospital admission was significantly higher in patients who had received docetaxel Hospira, compared with patients who had received docetaxel Sanofi (47[5.8%] cycles vs 53 [3.5%] cycles, P = .009), but there was no significant difference between docetaxel Ebewe and docetaxel Sanofi (30[5.2%] cycles vs 53 [3.5%] cycles, P = .069). All cases of FN resolved except for 1 patient who died in the ICU after receiving docetaxel Ebewe. There was a significant difference in the incidence of FN between docetaxel Sanofi and docetaxel Hospira, but all cases in both groups resolved completely. PMID- 27479829 TI - Whole-genome duplication as a key factor in crop domestication. AB - Polyploidy is commonly thought to be associated with the domestication process because of its concurrence with agriculturally favourable traits and because it is widespread among the major plant crops(1-4). Furthermore, the genetic consequences of polyploidy(5-7) might have increased the adaptive plasticity of those plants, enabling successful domestication(6-8). Nevertheless, a detailed phylogenetic analysis regarding the association of polyploidy with the domestication process, and the temporal order of these distinct events, has been lacking(3). Here, we have gathered a comprehensive data set including dozens of genera, each containing one or more major crop species and for which sufficient sequence and chromosome number data exist. Using probabilistic inference of ploidy levels conducted within a phylogenetic framework, we have examined the incidence of polyploidization events within each genus. We found that domesticated plants have gone through more polyploidy events than their wild relatives, with monocots exhibiting the most profound difference: 54% of the crops are polyploids versus 40% of the wild species. We then examined whether the preponderance of polyploidy among crop species is the result of two, non-mutually exclusive hypotheses: (1) polyploidy followed by domestication, and (2) domestication followed by polyploidy. We found support for the first hypothesis, whereby polyploid species were more likely to be domesticated than their wild relatives, suggesting that the genetic consequences of polyploidy have conferred genetic preconditions for successful domestication on many of these plants. PMID- 27479830 TI - Providing Orthopaedic Care for the Incarcerated: Obstacles and Challenges. AB - Scant information on healthcare delivery to inmates is available in the medical literature. Healthcare provision to inmates has different rules than that for the general population and presents particular challenges for orthopaedic surgeons because of the nature of this population and restrictions imposed by their confinement. This population is typically of a lower socioeconomic status and is less well educated, has accumulated injuries over a lifetime, and has a considerable prevalence of communicable and blood-borne diseases, along with a high prevalence of smoking and high-risk behavior, such as drug-seeking, abuse, and self-inflicted injury. These variables add levels of complexity of care, including the determination of medical necessity for orthopaedic referral, the logistics of transportation and follow-up, access to durable medical equipment and ancillary services, and the choices the orthopaedic provider must make to optimize care within these limitations. PMID- 27479831 TI - Direct Observation: Assessing Orthopaedic Trainee Competence in the Ambulatory Setting. AB - The Accreditation Council of Graduate Medical Education requires that residency programs teach and assess trainees in six core competencies. Assessments are imperative to determine trainee competence and to ensure that excellent care is provided to all patients. A structured, direct observation program is feasible for assessing nontechnical core competencies and providing trainees with immediate constructive feedback. Direct observation of residents in the outpatient setting by trained faculty allows assessment of each core competency. Checklists are used to document residents' basic communication skills, clinical reasoning, physical examination methods, and medical record keeping. Faculty concerns regarding residents' professionalism, medical knowledge, fatigue, or ability to self-assess are tracked. Serial observations allow for the reinforcement and/or monitoring of skills and attitudes identified as needing improvement. Residents who require additional coaching are identified early in training. Progress in educational milestones is recorded, allowing an individualized educational program that ensures that future orthopaedic surgeons excel across all domains of medical and surgical competence. PMID- 27479832 TI - The Use of MRI in Evaluating Knee Pain in Patients Aged 40 Years and Older. AB - INTRODUCTION: The use of MRI is increasing when evaluating patients with knee pain because it is highly sensitive for detecting intra-articular pathology. However, such changes can be associated with degenerative joint disease, which may be demonstrated with weight-bearing radiographs. The purpose of this study was to determine how often MRI was obtained before orthopaedic referral in patients aged >=40 years with knee pain, how often weight-bearing radiographs were obtained before MRI, and whether such imaging influenced treatment recommendations. METHODS: In a study of 599 new patients, participating physicians documented the presence of a prereferral MRI and/or plain radiographic studies, the results of weight-bearing radiographs, treatment recommendations, and the impact of any prereferral imaging. RESULTS: Prereferral use of MRI occurred in 130 patients (22%). Of these patients, plain radiographic studies were obtained for 58% before MRI and 13% had weight-bearing radiographs. Ultimately, 17% had weight-bearing radiographs that demonstrated >50% loss of joint space. Forty-eight percent of prereferral MRIs did not contribute to treatment recommendations. In patients with >50% loss of joint space, MRI was considered unnecessary in 95% of the cases. DISCUSSION: Many prereferral MRIs do not contribute to clinical decision making. Weight-bearing radiographs can help identify those patients in whom MRI is unlikely to be helpful. LEVEL OF EVIDENCE: Level III. PMID- 27479833 TI - Cervical Spine Injuries in the Athlete. AB - Cervical spine injuries are extremely common and range from relatively minor injuries, such as cervical muscle strains, to severe, life-threatening cervical fractures with spinal cord injuries. Although cervical spine injuries are most common in athletes who participate in contact and collision sports, such as American football and rugby, they also have been reported in athletes who participate in noncontact sports, such as baseball, gymnastics, and diving. Cervical spine injuries in athletes are not necessarily the result of substantial spine trauma; some athletes have chronic conditions, such as congenital stenosis, that increase their risk for a serious cervical spine injury after even minor trauma. Therefore, physicians who cover athletic events must have a thorough knowledge of cervical spine injures and the most appropriate ways in which they should be managed. Although cervical spine injuries can be career-ending injuries, athletes often are able to return to play after appropriate treatment if the potential for substantial re-injury is minimized. PMID- 27479834 TI - Extremity War Injuries X: Return to Health and Function. AB - The symposium Extremity War Injuries X: Return to Health and Function, presented by the American Academy of Orthopaedic Surgeons, the Orthopaedic Trauma Association, the Society of Military Orthopaedic Surgeons, and the Orthopaedic Research Society, was held in Washington, DC, on January 27 and 28, 2015. Course chairs Marc F. Swiontkowski, MD, and COL Jeffrey N. Davila, MD, presided over 2 days of general session lectures focusing on war/trauma-related musculoskeletal injuries resulting in service member disability, followed by small group discussions, with a goal of identifying knowledge gaps in the treatment of these injuries. Recognized civilian and military clinicians and researchers summarized the current state of knowledge in their topic areas and led these discussion groups with meeting participants. Musculoskeletal conditions discussed included posttraumatic osteoarthritis of the knee, foot, and ankle and their relationship to chronic ligament injuries; back disability; peripheral nerve injury; hand transplantation updates; the role of biologics; and prosthetic acceptance and function. A scientific program highlighting research presented by 12 investigators was led by COL (Ret) Romney C. Andersen, MD. Keynote speaker LT GEN Douglas J. Robb, MD, discussed the future of military research funding and the anticipated consolidation of medical care among the three military branches. Additional presentations referencing the impact of military medical care and the government's continued commitment to funding medical research occurred throughout the symposium and were given by five congressional representatives. PMID- 27479835 TI - Management of Osteochondritis Dissecans of the Femoral Condyle. AB - The American Academy of Orthopaedic Surgeons has developed the Appropriate Use Criteria (AUC) document Management of Osteochondritis Dissecans of the Femoral Condyle. Evidence-based information, in conjunction with the clinical expertise of physicians, was used to develop the criteria to improve patient care and obtain the best outcomes while considering the subtleties and distinctions necessary in making clinical decisions. The AUC clinical patient scenarios were derived from patient indications that generally accompany osteochondritis dissecans of the femoral condyle, as well as from current evidence-based clinical practice guidelines and supporting literature. The 64 patient scenarios and 12 treatments were developed by the Writing Panel, a group of clinicians who are specialists in this AUC topic. Lastly, a separate, multidisciplinary Voting Panel (made up of specialists and nonspecialists) rated the appropriateness of treatment of each patient scenario using a 9-point scale to designate a treatment as Appropriate (median rating, 7 to 9), May Be Appropriate (median rating, 4 to 6), or Rarely Appropriate (median rating, 1 to 3). PMID- 27479836 TI - AAOS Appropriate Use Criteria: Management of Osteochondritis Dissecans of the Femoral Condyle. PMID- 27479837 TI - Two Dimensional Host-Guest Metal-Organic Framework Sensor with High Selectivity and Sensitivity to Picric Acid. AB - A dye-sensitized metal-organic framework, TMU-5S, was synthesized based on introducing the laser dye Rhodamine B into the porous framework TMU-5. TMU-5S was investigated as a ratiometric fluorescent sensor for the detection of explosive nitro aromatic compounds and showed four times greater selectivity to picric acid than any state-of-the-art luminescent-based sensor. Moreover, it can selectively discriminate picric acid concentrations in the presence of other nitro aromatics and volatile organic compounds. Our findings indicate that using this sensor in two dimensions leads to a greatly reduced environmental interference response and thus creates exceptional sensitivity toward explosive molecules with a fast response. PMID- 27479838 TI - Photo-sensitization of ZnS nanoparticles with renowned ruthenium dyes N3, N719 and Z907 for application in solid state dye sensitized solar cells: A comparative study. AB - This article presents a comprehensive relative report on the grafting of ZnS with renowned ruthenium ((Ru) dyes i.e. N3, N719 and Z907) and gives insight into their charge transfer interaction and sensitization mechanism for boosting solar cell efficiency. Influence of dye concentration on cell performance is also reported here. ZnS nanoparticles synthesized by a simple coprecipitation method with an average particle size of 15+/-2nm were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), Elemental dispersive X-ray analysis (EDAX), tunneling electron microscopy (TEM) and UV-Visible (UV Vis) spectroscopy. UV-Vis, photoluminescence (PL) and Fourier transform infra-red (FT-IR) spectroscopy confirms the successful grafting of these dyes over ZnS nanoparticles surface. Low-energy metal-to-ligand charge-transfer transition (MLCT) bands of dyes are mainly affected on grafting over the nanoparticle surface. Moreover their current voltage (I-V) results confirm the efficiency enhancement in ZnS solid state dye sensitized solar cells (SSDSSCs) owing to effective sensitization of this material with Ru dyes and helps in finding the optimum dye concentration for nanoparticles sensitization. Highest rise in overall solar cell efficiency i.e. 64% of the reference device has been observed for 0.3mM N719-ZnS sample owing to increased open circuit voltage (Voc) and fill factor (FF). Experimental and proposed results were found in good agreement with each other. PMID- 27479839 TI - Biohydrogen production by purple non-sulfur bacteria Rhodobacter sphaeroides: Effect of low-intensity electromagnetic irradiation. AB - The present work was focused on the effects of low-intensity (the flux capacity was of 0.06mWcm(-2)) electromagnetic irradiation (EMI) of extremely high frequencies or millimeter waves on the growth and hydrogen (H2) photoproduction by purple non-sulfur bacteria Rhodobacter sphaeroides MDC6521 (from Armenian mineral springs). After exposure of R. sphaeroides, grown under anaerobic conditions upon illumination, to EMI (51.8GHz and 53.0GHz) for 15min an increase of specific growth rate by ~1.2-fold, in comparison with control (non-irradiated cells), was obtained. However, the effect of EMI depends on the duration of irradiation: the exposure elongation up to 60min caused the delay of the growth lag phase and the decrease specific growth rate by ~1.3-fold, indicating the bactericidal effect of EMI. H2 yield of the culture, irradiated by EMI for 15min, determined during 72h growth, was ~1.2-fold higher than H2 yield of control cells, whereas H2 production by cultures, irradiated by EMI for 60min was not observed during 72h growth. This difference in the effects of extremely high frequency EMI indicates a direct effect of radiation on the membrane transfer and the enzymes of these bacteria. Moreover, EMI increased DCCD-inhibited H(+) fluxes across the bacterial membrane and DCCD-sensitive ATPase activity of membrane vesicles, indicating that the proton FoF1-ATPase is presumably a basic target for extremely high frequency EMI related to H2 production by cultures. PMID- 27479840 TI - Effect of Cu(2+)-complexation on the scavenging ability of chrysin towards photogenerated singlet molecular oxygen (O2((1)Deltag)). Possible biological implications. AB - Visible-light irradiation of aqueous-ethanolic solutions of Riboflavin (Rf) in the individual presence of the flavone chrysin (Chr) and its complex with Cu(2+) ([Chr2Cu]; 2:1 L:M) generates singlet molecular oxygen O2((1)Deltag), that concomitantly interact with both flavone derivatives. Overall (kt) and reactive (kr) rate constants in the order of 10(7)M(-1)s(-1) were determined for the process. Metal chelation greatly enhances the scavenging ability of [Chr2Cu] towards O2((1)Deltag) through a mechanism dominated, in >80%, by the physical component. In this way, practically all O2((1)Deltag) is deactivated by the complex without significant loss of the quencher. The isolated flavone quenches O2((1)Deltag) in a prevailing reactive fashion. The very low value exhibited by [Chr2Cu] for the kr/kt ratio constitutes a positive quality for antioxidative protectors in biological media, where elevated local concentration and high reactivity of significant molecules make them initial targets for O2((1)Deltag) aggression. Finally, two interesting properties in the field of free radicals scavenging by [Chr2Cu] must be mentioned. In first place metal chelation itself, in the obvious sense of free metal ion withdrawal from the oxidizable medium, prevents the initiation of a free radical-mediated oxidation processes through mechanisms of Fenton or lipid peroxidation. In addition, the incorporation of Cu adds to [Chr2Cu] the ability of a free radical scavenger, already described for similar Cu-chelate compounds. This collection of beneficial properties positions the complex as a remarkably promising bioprotector towards ROS-mediated oxidation. A quantification of the efficiency on the initial anti-oxidative effect exerted by Chr and [Chr2Cu] towards tryptophan was carried out. The amino acid is an archetypal molecular model, commonly employed to monitor oxidative degradation of proteinaceous media. It was efficiently photoprotected against O2((1)Deltag)-mediated photooxidation by [Chr2Cu]. PMID- 27479841 TI - Reductive-degradation of carcinogenic azo dyes using Anacardium occidentale testa derived silver nanoparticles. AB - In the present work, reductive-degradation of azo dyes such as congo red (CR) and methyl orange (MO) was manifested using Anacardium occidentale testa derived silver nanoparticles (AgNPs) as a catalyst. The formation of highly stable AgNPs were visually confirmed by the appearance of yellow color and further substantiated by the existence of surface plasmon resonance (SPR) peak around 425nm. The effect of A. occidentale concentration, reaction time and pH in the formations of AgNPs was corroborated by UV-visible (UV-Vis) spectroscopy. The Fourier transform infrared (FT-IR) spectroscopic results proved that phytoconstituents of A. occidentale testa acts as a capping agent and thereby protects the AgNPs from aggregation. The crystalline nature of the AgNPs was validated from the XRD patterns. The average size of synthesized AgNPs was 25nm, with distorted spherical shape was ascribed from the high resolution transmission electron microscopic (HR-TEM) images. Due to the high stability of the as synthesized AgNPs, they were utilized for the degradation of carcinogenic azo dyes such as CR and MO using NaBH4 and its catalytic activity was studied via UV Vis spectroscopy. The results proved that extraordinary catalytic activity of synthesized AgNPs towards the reductive-degradation of both CR and MO. PMID- 27479843 TI - Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. AB - To identify candidate genes for intellectual disability, we performed a meta analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes. PMID- 27479842 TI - A data set from flash X-ray imaging of carboxysomes. AB - Ultra-intense femtosecond X-ray pulses from X-ray lasers permit structural studies on single particles and biomolecules without crystals. We present a large data set on inherently heterogeneous, polyhedral carboxysome particles. Carboxysomes are cell organelles that vary in size and facilitate up to 40% of Earth's carbon fixation by cyanobacteria and certain proteobacteria. Variation in size hinders crystallization. Carboxysomes appear icosahedral in the electron microscope. A protein shell encapsulates a large number of Rubisco molecules in paracrystalline arrays inside the organelle. We used carboxysomes with a mean diameter of 115+/-26 nm from Halothiobacillus neapolitanus. A new aerosol sample injector allowed us to record 70,000 low-noise diffraction patterns in 12 min. Every diffraction pattern is a unique structure measurement and high-throughput imaging allows sampling the space of structural variability. The different structures can be separated and phased directly from the diffraction data and open a way for accurate, high-throughput studies on structures and structural heterogeneity in biology and elsewhere. PMID- 27479845 TI - Spectrum of Movement Disorders in Mitochondrial Disorders. PMID- 27479844 TI - Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic basis. Yet, only a small fraction of potentially causal genes about 65 genes out of an estimated several hundred-are known with strong genetic evidence from sequencing studies. We developed a complementary machine-learning approach based on a human brain-specific gene network to present a genome-wide prediction of autism risk genes, including hundreds of candidates for which there is minimal or no prior genetic evidence. Our approach was validated in a large independent case-control sequencing study. Leveraging these genome-wide predictions and the brain-specific network, we demonstrated that the large set of ASD genes converges on a smaller number of key pathways and developmental stages of the brain. Finally, we identified likely pathogenic genes within frequent autism-associated copy-number variants and proposed genes and pathways that are likely mediators of ASD across multiple copy-number variants. All predictions and functional insights are available at http://asd.princeton.edu. PMID- 27479846 TI - Modified two-dimensional response as surrogate marker of overall survival in patients with metastatic colorectal cancer. AB - The identification of surrogate markers for long-term outcomes in patients with metastatic colorectal cancer (mCRC) may help in designing treatment regimens. The aim of this study was to assess whether two-dimensional response (2-DR) can serve as a new surrogate marker for overall survival (OS) in patients with mCRC. The study group consisted of 99 patients with mCRC from two independent cohorts who were treated with oxaliplatin-based chemotherapy plus bevacizumab. Two dimensional response was defined as an area enclosed by coordinate points, including early tumor shrinkage at 8 weeks, depth of response at nadir, and 20% increase over nadir at progression. Each variable was weighted by its contribution rate to OS. The model was developed and internally validated in the learning cohort, and the performance of this model was externally verified in the validation cohort. Spearman correlation coefficients for 2-DR and OS in the learning and validation cohorts were 0.593 and 0.661, respectively. The C-indexes in predicting OS were 0.724 (95% confidence interval, 0.623-0.815) in the learning cohort and 0.762 (95% confidence interval, 0.651-0.873) in the validation cohort. Overall survival was significantly longer in patients with high 2-DR values than in patients with low 2-DR values in both the learning (37.0 vs. 24.1 months, P < 0.001) and validation (41.2 vs. 20.4 months, P < 0.001) cohorts. In contrast, differences in early tumor shrinkage and depth of response were not statistically significant. Multivariate analyses showed that 2-DR was an independent prognostic factor for OS. PMID- 27479847 TI - Activity-Related Symptom Exacerbations After Pediatric Concussion. AB - Importance: Recovery from concussion generally follows a trajectory of gradual improvement, but symptoms can abruptly worsen with exertion. This phenomenon is poorly understood. Objectives: To characterize the incidence, course, and clinical significance of symptom exacerbations (spikes) in children after concussion. Design, Setting, and Participants: This secondary analysis of clinical trial data analyzes 63 eligible participants prospectively recruited from an emergency department who were asked to complete a postconcussion symptom scale and record their activities in a structured diary for the next 10 days. They completed standardized assessments of symptoms (postconcussion symptom scale), cognition (Immediate Post-Concussion Assessment and Cognitive Testing), and balance (Balance Error Scoring System) 10 days following the injury. Eligible participants were aged 11 to 18 years and sustained a concussion (according to the Centers for Disease Control and Prevention criteria) that did not result in an abnormal computed tomography scan or require hospital admission. The trial was conducted from May 2010 to December 2012, and the analysis was conducted from November 2015 to February 2016. Main Outcome and Measure: The occurrence of symptom spikes, defined as an increase of 10 or more points on the postconcussion symptom scale over consecutive days. Results: Of the 63 participants, there were 41 boys (65.1%) and 22 girls (34.9%), and the mean (SD) age was 13.8 (1.8) years. Symptom spikes occurred in one-third of the sample (20 participants [31.7%]). Symptom spikes tended to partially resolve within 24 hours. An abrupt increase in mental activity (ie, returning to school and extracurricular activities) from one day to the next increased the risk of a symptom spike (relative risk, 0.81; 95% CI, 0.21-3.21), but most symptom spikes were not preceded by a documented increase in physical or mental activity. Patients with symptom spikes were initially more symptomatic in the emergency department and throughout the observation period but did not differ from the group without symptom spikes on cognition or balance 10 days following injury. Conclusions and Relevance: Certain patients appeared susceptible to high and variable symptom reporting. Symptom spikes may not themselves be detrimental to recovery. The present findings support clinical guidelines for adolescents to return to school and activities gradually after concussion. Trial Registration: clinicaltrials.gov Identifier: NCT01101724. PMID- 27479848 TI - Lewis Acid Based Sorption of Trace Amounts of RuCl3 by Polyaniline. AB - A sorption process of RuCl3 in phosphate buffer by polyaniline (PANI) powder chemically synthesized from phosphoric acid was spectrophotometrically monitored as a function of time. It was determined that the sorption process follows the Langmuir and Freundlich isotherms, and their constants were evaluated. It was determined that chemisorption was the rate-controlling step. By conducting detailed studies, we assigned the chemisorption to Lewis acid based interactions of the sorbent electron pair localized at the benzenoid amine (-NH2) and quinoid imine (?NH) groups, with the sorbate, RuCl3, as the electron acceptor. The stability of the interaction over a period of ~1 week showed that the presence of the Ru(III) in the PANI matrix reverses its state from emeraldine base to emeraldine salt, resulting in a change of conductivity. The partial electron donor based charge transfer is a slow process as compared to the sorption process involving Bronsted acid doping. PMID- 27479849 TI - A day in the life of a district nurse. PMID- 27479850 TI - Exploring quality of life for stoma patients living in the community. PMID- 27479851 TI - RCN backs the district nurse specialist practice qualification. PMID- 27479852 TI - Frailty: a term with many meanings and a growing priority for community nurses. AB - The question of exactly what frailty is and what that may mean for patients is extremely complex. This is a very conceptual problem requiring a broad and long term solution. It is not a disease or a condition that can be treated in isolation. Frailty is a collection of contributing factors that culminate in an individual being susceptible to poorer outcomes following health-care interventions and minor illness. The solution to such a complex problem lies in engaging and empowering staff to understand and champion frailty. Once better understood, it will be possible to educate and enable this workforce to recognise the signs of frailty, poor prognosis and patients requiring more specialised palliative care. Informing staff working within a health-care economy of this issue must be the first step in a shift towards managing patients with frailty more appropriately, and streaming their care towards the correct care pathways sooner. This article discusses what frailty is, what it may mean for patients, and attempts to expand on why the construct of frailty is a prevalent issue for community nurses. The link between frailty and mortality is discussed and how targeted appropriate advanced care planning may be used to address this demographic challenge. PMID- 27479854 TI - Enhancing assertiveness in district nurse specialist practice. AB - District nurse (DN) care delivery has undergone substantial change in recent years due to changing demographics and service delivery demands that have called for a move of care delivery from secondary to primary care. The title District Nurse is recorded with the Nursing and Midwifery Council (NMC) on completion of the Specialist Practice Qualification in District Nursing (SPQ DN), which purports to be a 'transformational' course that prepares future caseload holders to manage their team and prioritise care delivery effectively. This article explores the need for assertiveness skills in this role in response to Australian research, and outlines the pedagogic interventions implemented during the SPQ DN course to enhance this skill. Assertiveness scores were monitored for the duration of the course and demonstrated a significant increase-a topic that is now the subject of a future, funded study. PMID- 27479853 TI - Exploring the barriers to and facilitators of implementing research into practice. AB - District and community nursing roles have changed rapidly in recent years. Community nurses are increasingly being tasked with carrying out multiple roles, which require them to put research into practice and use evidence-based tools and interventions. The implementation of interventions and tools needs to be developed from empirical research, requiring evidence, to be translated into practice. However, this process may be compromised or enhanced by a number of factors. This exploratory, descriptive qualitative study sought to identify barriers and facilitators to community nurses implementing research into practice. Four focus groups were conducted with registered community nurses and district nurses (n=22). Analysis identified four main themes: keeping up to date with evidence; using a clinical tool; education/training and implementation. Findings suggest that there are barriers at a personal, professional and organisational level. Strategies are suggested to overcome these obstacles. PMID- 27479855 TI - The Mental Capacity Act: a review of the current literature. AB - The Mental Capacity Act (MCA) is a piece of statutory legislation which is designed to empower and protect those who are assessed as being unable to make decisions for themselves. At the time of implementation, the legislation was described as visionary and it had the potential to change the lives of many. However, a post-legislative scrutiny report published in 2014 concluded that there is a lack of knowledge among professionals of the MCA, and so it is not embedded into daily clinical practice. This review of literature has identified four key themes: assessment, training, knowledge and empowerment. These appear to concur with the findings of the House of Lords report. The successful integration of the MCA into professionals' everyday practice is high on the political agenda, thus reinforcing the message that following the guidance set out in the MCA legislation is mandatory and not a choice. A shift in culture and improvement in knowledge and understanding of the MCA is required in order for it to be used in the correct manner for which it was designed. PMID- 27479856 TI - District nurses' role in managing medication dysphagia. AB - A survey commissioned by the Patients Association (2015) has shown that the risky practice of altering solid-form medication to assist patients with swallowing difficulties is a daily occurrence in care homes. District nurses and community matrons who provide care to patients and assist staff in care homes are well placed to raise awareness of the impact that tampering with tablets has on patient safety. It is essential that district nurses and community matrons discharge their duty of care to patients in care homes by supporting effective medication management that meets the individual needs of those patients. This article considers the legal and professional standards that must inform a district nurse's support of medication management for a patient with swallowing difficulties residing in a care home. PMID- 27479857 TI - The essential pillars of palliative care. PMID- 27479858 TI - Enteral feeding in community nursing. PMID- 27479859 TI - Nurses making a difference in CCGs. PMID- 27479860 TI - The cross-talk between renal function, inflammation and psoriasis vulgaris. PMID- 27479861 TI - Z-Selective Synthesis of gamma,delta-Unsaturated Ketones via Pd-Catalyzed Ring Opening of 2-Alkylenecyclobutanones with Arylboronic Acids. AB - Pd-catalyzed 1,2-addition (instead of 1,4-addition) of arylboronic acids to 2 alkylenecyclobutanones followed by beta-carbon elimination from the resulting palladium cyclobutanolates to afford gamma,delta-unsaturated ketones was developed. The desired gamma,delta-unsaturated ketones were obtained in good to excellent yields with Z/E selectivities of up to >99:1 and a broad spectrum of functional group tolerability. PMID- 27479863 TI - Diminishing return for mechanistic therapeutics with neurodegenerative disease duration?: There may be a point in the course of a neurodegenerative condition where therapeutics targeting disease-causing mechanisms are futile. AB - The conventional approach to developing disease-modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic driver of age-of-onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals. PMID- 27479862 TI - LSD1: biologic roles and therapeutic targeting. AB - LSD1 (KDM1A; BHC110; AOF2) was the first protein reported to exhibit histone demethylase activity and has since been shown to have multiple essential roles in mammalian biology. Given its enzymatic activity and its high-level expression in many human malignancies, a significant recent focus has been the development of pharmacologic inhibitors. Here we summarize structural and biochemical knowledge of this important epigenetic regulator, with a particular emphasis on the functional and preclinical studies in oncology that have provided justification for the evaluation of tranylcypromine derivative LSD1 inhibitors in early phase clinical trials. PMID- 27479864 TI - Repetition suppression in the medial temporal lobe and midbrain is altered by event overlap. AB - Repeated encounters with the same event typically lead to decreased activation in the medial temporal lobe (MTL) and dopaminergic midbrain, a phenomenon known as repetition suppression. In contrast, encountering an event that overlaps with prior experience leads to increased response in the same regions. Such increased responding is thought to reflect an associative novelty signal that promotes memory updating to resolve differences between current events and stored memories. Here, we married these ideas to test whether event overlap significantly modulates MTL and midbrain responses-even when events are repeated and expected-to promote memory updating through integration. While undergoing high-resolution functional MRI, participants were repeatedly presented with objects pairs, some of which overlapped with other, intervening pairs and some of which contained elements unique from other pairs. MTL and midbrain regions showed widespread repetition suppression for nonoverlapping pairs containing unique elements; however, the degree of repetition suppression was altered for overlapping pairs. Entorhinal cortex, perirhinal cortex (PRc), midbrain, and PRc midbrain connectivity showed repetition-related increases across overlapping pairs. Notably, increased PRc activation for overlapping pairs tracked individual differences in the ability to reason about the relationships among pairs-our behavioral measure of memory integration. Within the hippocampus, activation increases across overlapping pairs were unique to CA1 , consistent with its hypothesized comparator function. These findings demonstrate that event overlap engages MTL and midbrain functions traditionally implicated in novelty processing, even when overlapping events themselves are repeated. Our findings further suggest that the MTL-midbrain response to event overlap may promote integration of new content into existing memories, leading to the formation of relational memory networks that span experiences. Moreover, the results inform theories about the division of labor within MTL, demonstrating that the role of PRc in episodic encoding extends beyond familiarity processing and item-level recognition. (c) 2016 Wiley Periodicals, Inc. PMID- 27479865 TI - Influence of inter-parental conflict on adolescent delinquency via school connectedness: Is impulsivity a vulnerability or plasticity factor? AB - This study examined the mediating effect of school connectedness on the relationship between inter-parental conflict and adolescent delinquency, and impulsivity's moderation of the conditional effect of school connectedness. In total, 1407 Chinese students (mean age = 12.74 years, SD = 0.57) from 4 middle schools completed anonymous questionnaires regarding inter-parental conflict, impulsivity, school connectedness, and delinquency. Path analysis revealed school connectedness was a mediator in the relationship between inter-parental conflict and adolescent delinquency. Furthermore, impulsivity moderated the indirect effect of school connectedness in the relationship between inter-parental conflict and adolescent delinquency. A simple slope plot, together with a proportion affected (PA) index, indicated that impulsivity functioned more as a plasticity, rather than a vulnerability, factor in school connectedness. When school connectedness was low, high impulsivity was associated with more delinquent behaviors; however, when it was high, high impulsivity was associated with fewer delinquent behaviors. PMID- 27479866 TI - Discriminative ability of reflex receptive fields to distinguish patients with acute and chronic low back pain. AB - Low back pain has a life time prevalence of 70% to 85%. Approximately 10% to 20% of all patients experience recurrent episodes or develop chronic low back pain. Sociodemographic, clinical, and psychological characteristics explain the transition from acute to chronic low back pain only to a limited extent. Altered central pain processing may be a contributing mechanism. The measurement of reflex receptive fields (RRF) is a novel method to assess altered central pain processing. The RRF area denotes the area of the foot sole from which spinal nociceptive reflexes can be elicited. It was shown to be enlarged in patients with acute and chronic low back pain compared with pain-free individuals. The aim of the study was to explore the discriminative ability of the RRF to distinguish patients with acute and chronic low back pain with the hypothesis that enlarged RRF are associated with chronic low back pain. We included 214 patients with either acute or chronic low back pain and compared RRF between groups in both univariable and multivariable analyses adjusted for different sociodemographic and clinical characteristics possibly associated with the transition to chronic pain. We found a mean difference between patients with acute and chronic low back pain of -0.01 (95% confidence interval [CI], -0.06 to 0.04) in the crude, -0.02 (95% CI, -0.08 to 0.04) in the age and sex adjusted, and -0.02 (95% CI, -0.09 to 0.05) in the fully adjusted model. Our results suggest that the enlargement of RRF area may not be associated with the transition from acute to chronic low back pain. PMID- 27479867 TI - Subepidermal Calcified Nodules of the Eyelid Differ in Children and Adults. AB - PURPOSE: Subepidermal calcified nodule of the eyelid is considered as one of the types of calcinosis cutis. It generally occurs in children, and is not known to be associated with systemic disease. The authors report histopathological and clinical findings in 14 cases of subepidermal calcified nodule of the eyelid, including 3 older patients with unique microscopic features. METHODS: Clinical records and pathological materials were critically reviewed in each case, including von kossa, CD3, CD20, and CD68 stains. RESULTS: The 14 cases presented clinically as nodular eyelid lesions. All were treated with surgical excision. The authors found 2 distinct histopathological patterns which correlated with the patients' age. In young patients, the authors observed multiple, small calcified bodies within the dermis surrounded by chronic inflammation and granulomatous foreign body reaction. On the other hand, in elderly patients, lesions were characterized by a single, large, well-demarcated amorphous calcified deposit surrounded by fibrous tissue, without chronic inflammation or foreign body reaction. One of these patients, a 70-year-old man, also suffered from gout. The presence of subepidermal calcified nodule was not documented as a preoperative diagnostic possibility in any of the cases. CONCLUSIONS: Subepidermal calcified nodule of the eyelid is a rare condition, but should be considered in any patient presenting with a painless white to yellowish colored nodule of the ocular adnexa, particularly during the teenage years. Clinicians and pathologists should be aware that this entity has a distinct appearance and could be associated with systemic conditions in elderly patients. PMID- 27479868 TI - Ca2+ transients in astrocyte fine processes occur via Ca2+ influx in the adult mouse hippocampus. AB - Astrocytes display complex morphologies with an array of fine extensions extending from the soma and the primary thick processes. Until the use of genetically encoded calcium indicators (GECIs) selectively expressed in astrocytes, Ca2+ signaling was only examined in soma and thick primary processes of astrocytes where Ca2+ -sensitive fluorescent dyes could be imaged. GECI imaging in astrocytes revealed a previously unsuspected pattern of spontaneous Ca2+ transients in fine processes that has not been observed without chronic expression of GECIs, raising potential concerns about the effects of GECI expression. Here, we perform two-photon imaging of Ca2+ transients in adult CA1 hippocampal astrocytes using a new single-cell patch-loading strategy to image Ca2+ -sensitive fluorescent dyes in the cytoplasm of fine processes. We observed that astrocyte fine processes exhibited a high frequency of spontaneous Ca2+ transients whereas astrocyte soma rarely showed spontaneous Ca2+ oscillations similar to previous reports using GECIs. We exploited this new approach to show these signals were independent of neuronal spiking, metabotropic glutamate receptor (mGluR) activity, TRPA1 channels, and L- or T-type voltage-gated calcium channels. Removal of extracellular Ca2+ almost completely and reversibly abolished the spontaneous signals while IP3 R2 KO mice also exhibited spontaneous and compartmentalized signals, suggesting they rely on influx of extracellular Ca2+ . The Ca2+ influx dependency of the spontaneous signals in patch-loaded astrocytes was also observed in astrocytes expressing GCaMP3, further highlighting the presence of Ca2+ influx pathways in astrocytes. The mechanisms underlying these localized Ca2+ signals are critical for understanding how astrocytes regulate important functions in the adult brain. GLIA 2016;64:2093 2103. PMID- 27479869 TI - NOD1 in the modulation of host-microbe interactions and inflammatory bone resorption in the periodontal disease model. AB - Periodontitis is a chronic inflammatory condition characterized by destruction of non-mineralized and mineralized connective tissues. It is initiated and maintained by a dysbiosis of the bacterial biofilm adjacent to teeth with increased prevalence of Gram-negative microorganisms. Nucleotide-binding oligomerization domain containing 1 (NOD1) is a member of the Nod-like receptors (NLRs) family of proteins that participate in the activation of the innate immune system, in response to invading bacteria or to bacterial antigens present in the cytoplasm. The specific activating ligand for NOD1 is a bacterial peptidoglycan derived primarily from Gram-negative bacteria. This study assessed the role of NOD1 in inflammation-mediated tissue destruction in the context of host-microbe interactions. We used mice with whole-genome deletion of the NOD1 gene in a microbe-induced periodontitis model using direct injections of heat-killed Gram negative or Gram-negative/Gram-positive bacteria on the gingival tissues. In vitro experiments using primary bone-marrow-derived macrophages from wild-type and NOD1 knockout mice provide insight into the role of NOD1 on the macrophage response to Gram-negative and Gram-negative/Gram-positive bacteria. Microcomputed tomography analysis indicated that deletion of NOD1 significantly aggravated bone resorption induced by Gram-negative bacteria, accompanied by an increase in the numbers of osteoclasts. This effect was significantly attenuated by the association with Gram-positive bacteria. In vitro, quantitative PCR arrays indicated that stimulation of macrophages with heat-killed Gram-negative bacteria induced the same biological processes in wild-type and NOD1-deficient cells; however, expression of pro-inflammatory mediators was increased in NOD1-deficient cells. These results suggest a bone-sparing role for NOD1 in this model. PMID- 27479870 TI - Bioequivalence of Biosimilar Tumor Necrosis Factor-alpha Inhibitors Compared With Their Reference Biologics: A Systematic Review. AB - Background: Biosimilars are of growing clinical, regulatory, and commercial importance. Purpose: To summarize evidence about the bioequivalence between biosimilar and reference tumor necrosis factor-alpha (TNF-alpha) inhibitors. Data Sources: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS from inception through 13 April 2016 and ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, U.S. Food and Drug Administration, and European Medicines Agency from inception through 30 April 2016. Study Selection: Published English-language studies of any size or design that compared the pharmacokinetics, clinical efficacy, adverse events, or immunogenicity of a biosimilar TNF-alpha inhibitor with a reference biologic in humans. Data Extraction: Two reviewers independently screened titles and abstracts, extracted data from selected studies, and assessed study quality. Data Synthesis: Of 19 eligible studies, 8 were phase 1 randomized trials, 5 were phase 3 randomized trials, and 6 were observational studies. Most phase 1 trials (n = 7) involved healthy volunteers, phase 3 trials involved patients with rheumatoid arthritis, and observational studies involved those with rheumatoid arthritis or inflammatory bowel disease. All phase 1 trials showed that pharmacokinetic parameters of the biosimilar and respective biologic were within the prespecified equivalence margin of 80% to 125%. Phase 3 trials suggested similar clinical responses and adverse events. Adverse events were usually of mild to moderate severity. Two cross-sectional observational studies showed cross-reactivity between products, whereas 4 cohort studies of patients switched from reference to biosimilar products suggested similar efficacy and safety outcomes. Limitation: Possible publication bias, small sample sizes of many studies, and lack of published studies for several biosimilars. Conclusion: Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF-alpha inhibitors. Primary Funding Source: Johns Hopkins Center of Excellence in Regulatory Science and Innovation. (PROSPERO: CRD42015025262). PMID- 27479871 TI - Ultra-sensitive detection of zinc oxide nanowires using a quartz crystal microbalance and phosphoric acid DNA. AB - Recent advancements of nanomaterials have inspired numerous scientific and industrial applications. Zinc oxide nanowires (ZnO NWs) is one of the most important nanomaterials due to their extraordinary properties. However, studies performed over the past decade have reported toxicity of ZnO NWs. Therefore, there has been increasing demand for effective detection of ZnO NWs. In this study, we propose a method for the detection of ZnO NW using a quartz crystal microbalance (QCM) and DNA probes. The detection method is based on the covalent interaction between ZnO NWs and the phosphoric acid group of single-stranded DNA (i.e., linker DNA), and DNA hybridization between the linker DNA and the probe DNA strand on the QCM electrode. Rapid, high sensitivity, in situ detection of ZnO NWs was demonstrated for the first time. The limit of detection was 10(-4) MUg ml(-1) in deionized water, which represents a sensitivity that is 100000 times higher than the toxic ZnO NW concentration level. Moreover, the selectivity of the ZnO NW detection method was demonstrated by comparison with other types of nanowires and the method was able to detect ZnO NWs in tap water sensitively even after stored for 14 d in a refrigerator. The performance of our proposed method was sufficient to achieve detection of ZnO NW in the 'real-world' environment. PMID- 27479872 TI - The potential of ultrasound in cardiac pacing and rhythm modulation. AB - INTRODUCTION: This review examines the potential for ultrasound to induce or otherwise influence cardiac pacing and rhythm modulation. AREAS COVERED: Of particular interest is the possibility of developing new, truly non-invasive, nonpharmacological, acute and chronic, ultrasound-based arrhythmia treatments. Such approaches would not depend upon implanted or indwelling devices of any kind and would use ultrasound at diagnostic exposure levels (so as not to harm the heart or surrounding tissues). It is known that ultrasound can cause cardiomyocyte depolarization and a variety of underlying mechanisms have been proposed. Expert commentary: Questions still remain regarding the effect of exposure parameters and work will also be necessary to identify the optimal target regions within the heart if ultrasound energy is to be used to induce safe and reliable pacing in a clinical setting. PMID- 27479873 TI - Glycemic control: Can nurse practitioners on interprofessional collaborative practice teams enhance clinical outcomes? AB - BACKGROUND AND PURPOSE: Care coordination and specialized knowledge of prescriptive authority are fundamental to advanced nursing practice. Little research documents patient clinical outcomes in primary care when nurse practitioners are members of an interprofessional education and collaborative practice (IPECP) team. This cross-sectional study examined differences in glycemic control among Texas patients who received care by a Family Nurse Practitioner (FNP) and an IPECP team in one calendar year. METHODS: A convenience sample of 120 adult volunteers with diabetes was followed in a community-based clinic by an FNP; of these, 34 received additional care by an IPECP team. Data on selected demographic indices and HgbA1c were derived from the health center's Electronic Medical Record using a retrospective review, and linkage with the federally funded IPECP Project database. CONCLUSIONS: Patients with two or more FNP visits and two or more visits with the IPECP team had statistically significant reductions in HgbA1c levels at the end of 1 year. IMPLICATIONS FOR PRACTICE: Actualizing point-of-care treatment adjustments is a particular strength of advanced practice nurses but potentially a missed opportunity on interprofessional teams. Further study is needed on clinical outcomes of nurse practitioner contributions to IPECP team care. PMID- 27479874 TI - Global oscillation regime change by gated inhibition. AB - The role of sensory inputs in the modelling of synchrony regimes is exhibited by means of networks of spiking cells where the relative strength of the inhibitory interaction is controlled by the activation of a linear unit working as a gating variable. Adaptation to stimulus size is determined by the value of a changing length scale, modelled by the time-varying radius of a circular receptive field. In this set-up, 'consolidation' time intervals relevant to attentional effects are shown to depend on the dynamics governing the evolution of the introduced length scale. PMID- 27479875 TI - Heterogeneous Crystallization on Pairs of Pre-Structured Seeds. AB - Studying the effects of small pre-structured seeds on the crystallization transition in an undercooled monodisperse Lennard-Jones fluid with transition interface path sampling combined with molecular dynamics simulations, we analyze the impact of the simultaneous presence of two seeds with various structures. In the presence of seeds with face- and body-centered cubic structures, we find that decreasing the seed-to-seed distance enhances the probability of the crystalline clusters formed on one of the seeds to grow beyond the critical size, thus, increasing the crystal nucleation rates. In contrast, when seeds have an icosahedral structure, the crystalline clusters form mostly in the bulk. The crystal nucleation rate, however, is also determined by the distance between the seeds with regular structure in which the lattice spacing is equal to the bulk lattice constant, pointing to a heterogeneous crystal nucleation that occurs away from the icosahedrally structured seeds. For slightly squeezed seeds, the effects of the presence of seeds with face- and body-centered cubic structures are reduced in comparison to the regular seeds, and we do not see any effect of the presence of the second seed for seeds with squeezed icosahedral structure. PMID- 27479876 TI - Regulatory T cells and skeletal muscle regeneration. AB - Skeletal muscle regeneration results from the activation and differentiation of myogenic stem cells, called satellite cells, located beneath the basal lamina of the muscle fibers. Inflammatory and immune cells have a crucial role in the regeneration process. Acute muscle injury causes an immediate transient wave of neutrophils followed by a more persistent infiltration of M1 (proinflammatory) and M2 (anti-inflammatory/proregenerative) macrophages. New studies show that injured muscle is also infiltrated by a specialized population of regulatory T (Treg) cells, which control both the inflammatory response, by promoting the M1 to-M2 switch, and the activation of satellite cells. Treg cells accumulate in injured muscle in response to specific cytokines, such as IL-33, and promote muscle growth by releasing growth factors, such as amphiregulin. Muscle repair during aging is impaired due to reduced number of Treg cells and can be enhanced by IL-33 supplementation. Migration of Treg cells could also contribute to explain the effect of heterochronic parabiosis, whereby muscle regeneration of aged mice can be improved by a parabiotically linked young partners. In mdx dystrophin-deficient mice, a model of human Duchenne muscular dystrophy, muscle injury, and inflammation is mitigated by expansion of the Treg-cell population but exacerbated by Treg-cell depletion. These findings support the notion that immunological mechanisms are not only essential in the response to pathogenic microbes and tumor cells but also have a wider homeostatic role in tissue repair, and open new perspectives for boosting muscle growth in chronic muscle disease and during aging. PMID- 27479877 TI - Rheology-sensitive response of zeolite-supported anti-inflammatory drug systems. AB - Drug release from inorganic supports is a challenge for the scientific community for various reasons, related to the low costs of the systems and the possibility of easily regulating the drug release. In the present work, surface-modified zeolite particles are used as carriers for non steroidal antiflammatory drugs (NSAIDs). The release of the drug has been studied in a solution that simulates the intestinal fluid as well as in a gel-like system, based on a surfactant and a binding salt. In the solution case, the quantity of drug released has been tracked via spectrophotometric assay. Release in the gel has been monitored by rheological methods. The molecular conformation of the NSAIDs is fundamental for the interaction with the zeolite surface, whose modified surface has a strong binding energy. It has been proven that the main mechanism for the drug release is anion exchange. It has been found that the NSAIDs, used in their sodic form, can act as binding salts by themselves in the gel-like system, thus changing the viscoelastic response of the overall solution. Drug release kinetics in the solution compare quantitatively well with the released drug in the gel-like fluid, as measured by rheometry. PMID- 27479878 TI - Electrostatic versus Electrochemical Doping and Control of Ferromagnetism in Ion Gel-Gated Ultrathin La0.5Sr0.5CoO3-delta. AB - Recently, electrolyte gating techniques employing ionic liquids/gels in electric double layer transistors have proven remarkably effective in tuning charge carrier density in a variety of materials. The ability to control surface carrier densities at levels above 10(14) cm(-2) has led to widespread use in the study of superconductivity, insulator-metal transitions, etc. In many cases, controversy remains over the doping mechanism, however (i.e., electrostatic vs electrochemical (e.g., redox-based)), and the technique has been less applied to magnetic materials. Here, we discuss ion gel gating of nanoscale 8-unit-cell thick hole-doped La0.5Sr0.5CoO3-delta (LSCO) films, probing in detail the critical bias windows and doping mechanisms. The LSCO films, which are under compressive stress on LaAlO3(001) substrates, are metallic and ferromagnetic (Curie temperature, TC ~ 170 K), with strong anomalous Hall effect and perpendicular magnetic anisotropy. Transport measurements reveal that negative gate biases lead to reversible hole accumulation (i.e., predominantly electrostatic operation) up to some threshold, whereas positive bias immediately induces irreversibility. Experiments in inert/O2 atmospheres directly implicate oxygen vacancies in this irreversibility, supported by atomic force microscopy and X-ray photoelectron spectroscopy. The results are thus of general importance, suggesting that hole- and electron-doped oxides may respond very differently to electrolyte gating. Reversible voltage control of electronic/magnetic properties is then demonstrated under hole accumulation, including resistivity, magnetoresistance, and TC. The sizable anomalous Hall coefficient and perpendicular anisotropy in LSCO provide a particularly powerful probe of magnetism, enabling direct extraction of the voltage-dependent order parameter and TC shift. The latter amounts to ~7%, with potential for much stronger modulation at lower Sr doping. PMID- 27479879 TI - Mitochondrial DNA control region haplotype and haplogroup diversity in South Eastern Turkey. AB - Despite its large geographic and population size only little is known about the mitochondrial (mt)DNA make up of Turkey.orensically relevant data are almost completely absent in the literature. We analyzed the mtDNA control region of 224 volunteers from South Eastern Turkey and compared the data to populations from neighboring countries. The haplotypes will be made available via the EMPOP database (EMP00670) and contribute to the body of forensic mtDNA data. PMID- 27479880 TI - GlobalFiler((r)) Express DNA amplification kit in South Africa: Extracting the past from the present. AB - In this study, the GlobalFiler((r)) Express amplification kit was evaluated for forensic use in 541 South African individuals belonging to the Afrikaaner, amaXhosa,(1) amaZulu,(1) Asian Indian and Coloured population groups. Allelic frequencies, genetic diversity parameters and forensic informative metrics were calculated for each population. A total of 301 alleles were observed ranging between 5 and 44.2 repeat units, 43 were rarely observed partial repeats and seven were novel. The combined match probability (CMP) ranged from 2.21*10(-26) (Coloured) to 5.21*10(-25) (AmaZulu), and the combined power of exclusion (CPE) 0.9999999978 (Afrikaaner) to 0.99999999979 (AmaZulu) respectively. No significant departures from Hardy-Weinberg equilibrium (HWE) were observed after Bonferroni correction. Strong evidence of genetic structure was detected using the coancestry coefficient theta, Analysis of Molecular Variance (AMOVA) and an unsupervised Bayesian clustering method (STRUCTURE). The efficiency of assignment of individuals to population groups was evaluated by applying likelihood ratios with WHICHRUN, and the individual ancestral membership probabilities inferred by STRUCTURE. Likelihood ratios performed the best in the assignment of individuals to population groups. Signs of positive selection were detected for TH01 and D13S317 and purifying/balancing selection for locus SE33. These three loci also displayed the largest informativeness for assignment (In) values. The results of this study supports the use of the GlobalFiler((r)) STR profiling kit for forensic applications in South Africa with the additional capability to predict ethnicity or continental origin of a random sample. PMID- 27479881 TI - Injectable and Cytocompatible Tough Double-Network Hydrogels through Tandem Supramolecular and Covalent Crosslinking. AB - Double-network theory is extended to include guest-host interactions, enabling injectability and cytcompatibility of tough hydrogels. Noncovalent interactions are used as a sacrificial network to toughen covalently crosslinked hydrogels formed from hyaluronic acid. Shear thinning of supramolecular bonds allows hydrogel injection and rapid self-healing, while gentle reaction conditions permit cell encapsulation with high viability. PMID- 27479882 TI - Characterisation of phosphorylated nucleotides by collisional and electron-based tandem mass spectrometry. AB - RATIONALE: Tandem mass spectrometry of phosphorylated ions can often yield a limited number of product ions owing to the labile nature of phosphate groups. Developing techniques to improve dissociation for this type of ion has implications for the structural characterisation of many different phosphorylated ions, such as those from nucleotides, pharmaceutical compounds, peptides and polymers. METHODS: Solutions of adenosine monophosphate, diphosphate and triphosphate (AMP, ADP and ATP) were studied in a hybrid linear ion trap-Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Precursor ions with an overall single positive charge, including protonated nucleotides or nucleotide cations containing one, two or three sodium atoms, were isolated for tandem mass spectrometry. Collision-induced dissociation (CID) was performed in the linear ion trap, with electron-induced dissociation (EID) being conducted in the FTICR cell. RESULTS: EID resulted in many product ions not seen in CID. EID product ion spectra were seen to vary for AMP, ADP and ATP when the nucleotide cation contained zero, one, two or three sodiums. Precursor cations that contain two or three sodiums mainly formed product ions derived from the phosphate group. Conversely, when a precursor ion containing no sodium underwent EID, product ions mainly relating to the non-phosphate end of the ion were observed. The number of phosphate groups was not seen to greatly affect either CID or EID product ion spectra. CONCLUSIONS: The presence of sodium in a precursor ion directs electron induced bond dissociation, thus enabling targeted, and therefore tuneable, fragmentation of groups within that precursor ion. For all precursor ions, the most useful product ion spectra were obtained by EID for a precursor ion containing one sodium, with bond dissociation occurring across the entire nucleotide cation. The findings of this study can be used to improve the structural elucidation of many phosphorylated molecules by broadening the range of product ions achievable. (c) 2016 The Authors. Rapid Communications in Mass Spectrometry Published by John Wiley & Sons Ltd. PMID- 27479883 TI - 99mTc-EDDA/HYNIC-TOC in the diagnosis of differentiated thyroid carcinoma refractory to radioiodine treatment. AB - BACKGROUND: In majority of cases of differentiated thyroid carcinoma (DTC), the ablative radioiodine treatment shows high efficacy. In a small number of patients, mechanism of selective iodine uptake by the DTC cells is insufficient and alternative methods of diagnosis and treatment are needed. As demonstrated in vitro, DTC cells show expression of somatostatin recep-tors. Radiolabeled somatostatin analogs are widely used in the diagnosis of neuroendocrine tumors. The aim of the study was to evaluate the utility of peptide receptor scintigraphy with the use of 99mTc-EDDA/HYNIC-TOC in the diagnosis of DTC in patients with elevated thyroglobulin concentrations (Tg), negative WBS and no effect of the consecutive radioiodine therapies. MATERIAL AND METHODS: Whole body scintigraphy as well as SPECT of neck and chest were performed 3 and 24 h after i.v. administration of 740 MBq 99mTc-EDDA/HYNIC-TOC. The obtained images were compared with other radionuclide and ra-diological imaging methods. Forty-three patients with DTC after surgery and ablative radioiodine treatment with negative WBS and elevated Tg were qualified. Patients' age: 18-83 years (mean 58.0). RESULTS: SRS showed foci of tracer accumulation in 29 cases (67.4%). Sensitivity was 69.0% specificity 78.6%. SRS correctly identified local recurrence in 8 pts., metastatic lymph nodes in 19 pts., lung metastases in 12 pts. and bone metastases in 5 pts. SRS showed high sensitivity in the detection of metastatic lymph nodes (100%) and bone metastases (83.3%) and lung metastases (63.2%). Positive SRS was found in pts. with higher Tg concentrations (130 +/- 144 vs. 30 +/- 54 ng/ml). CONCLUSION: Scintigraphy with the use of the studied technetium-99m-labeled somatostatin analog is useful in the evaluation of patients with advanced DTC. It shows relatively good sensitivity and specificity but not high enough to be recommended as a routine imaging method. The role of somatostatin receptor scintigraphy in DTC is complementary to other imaging modalities. PMID- 27479884 TI - 99mTc-EDDA/HYNIC-TOC in management of patients with head and neck somatostatin receptor positive tumors. AB - BACKGROUND: Aim of this study was to determine the value of technetium-99m hydrazinonicotinyl-Tyr3-octreotide (99mTc-ED-DA/HYNIC-TOC) in patients with somatostatin receptor (SSR) positive tumors of head and neck region. MATERIAL AND METHODS: A total number of 16 patients were enrolled in this study. Planar whole body (WB) and single photon emission computed tomography (SPECT) images were acquired at 2 and 4 hours after the injection of approximately 670 MBq of 99mTc EDDA/HYNIC-TOC. Additional single photon emission computed tomography/computed tomography (SPECT/CT) images of the head and neck region were acquired at 4h post tracer injection. Clinical and imaging follow up were taken as the reference standard. RESULTS: There were 10 female and 6 male patients of age 57.7 +/- 12.9 years (58.5; 32-78) years. 99mTc-EDDA/HYNIC-TOC somatostatin receptor scintigraphy (SRS) was TP in 13 patients, TN in two and FP in one. Follow up period for SRS was 31.1 +/- 19.4 (29; 2-63) months. 99mTc-EDDA/HYNIC-TOC scintigraphy provided additional information in 50% of patients, with impact on patient management in the same percentage of patients. Distant metastases were found in nine out of 16 patients (56%). 99mTc-EDDA/HYNIC-TOC SRS had sensitivity of 100% (75.3-100%), specificity of 66.7% (9.4-99.2%), accuracy of 93.7%, positive predictive value of 92.9% (66.1-99.8%), and negative predictive value of 100% (15.8-100%). CONCLUSION: Somatostatin receptor scintigraphy using 99mTc EDDA/HYNIC-TOC is very useful imaging method in the evalu-ation of patients with SSR positive tumors of head and neck region. PMID- 27479885 TI - Clinical application of SPECT-CT with 99mTc-Tektrotyd in bronchial and thymic neuroendocrine tumors (NETs). AB - Neuroendocrine tumors (NETs) of the thorax including bronchial and thymic tumors belong to foregut NETs. Limited loco-regional thoracic NETs can be resected with surgery, but in extensive metastatic disease the treatment is mainly palliative. A high incidence and density of somatostatin receptors (SSTR2, SSTR3, and SSTR5) are found in thoracic NETs. The purpose of this study was to evaluate the role of SPECT-CT somatostatin receptor scintigraphy (SRS) with 99mTc-Tektrotyd for imaging, staging and follow up of patients with bronchial and thymic neuroendocrine tumors. Forty-one patients with thoracic tumors with neuroendocrine differentiation were studied. Sixty-eight examinations including SPECT-CT studies of the neck and chest and/or abdomen and pelvis were carried out 2-4 hrs. post i.v. administration of aver-age 740 MBq activity dose of 99mTc EDDA/HYNIC-TOC (Tektrotyd, Polatom). In all 41 investigated patients we obtained 81.25% (13/16), 88% (22/25) and 85.36% (35/41) of sensitivity, specificity and accuracy of this diagnostic approach, respectively. Somatostatin-receptor scintigraphy correctly identified all primary NETs located in the lungs and thymus. SPECT-CT studies with 99mTc-EDDA/HYNIC-TOC resulted in exact pre-surgical and pre-treatment N/M staging of bronchial and thymic NETs, except 2 cases with multiple hepatic metastases and 1 with massive suprarenal metastasis. It can be concluded that SPECT-CT with 99mTc-EDDA/HYNIC-TOC is a valuable tool for staging and follow-up of patients with thoracic NETs. PMID- 27479887 TI - Limitations and pitfalls of 99mTc-EDDA/HYNIC-TOC (Tektrotyd) scintigraphy. AB - Tektrotyd kit was developed by Polatom company for 99mTc labeling to make an alternative tracer of somatostatin receptor scintigraphy available. Since 2005, 99mTc-EDDA/HYNIC-Tyr3-Octreotide has been used in clinical imaging and achieved high impact in management of patients with neuroendocrine tumors. Knowing the limitations and pitfalls is essential to provide ac-curate diagnosis. Therefore, the potential pitfalls associated with the use of 99mTc-EDDA/HYNIC-TOC are reviewed on the basis of own experience. Data were analyzed of 310 patients who underwent somatostatin receptor scintigraphy with 99mTc-Tektrotyd. Pitfalls during radiolabeling process or acquisition can worsen the sensitivity of SRS (somatostatin receptor scintigraphy). Recognizing physi-ological and clinical pitfalls, the diagnostic accuracy will improve. PMID- 27479886 TI - Influence of PET/CT 68Ga somatostatin receptor imaging on proceeding with patients, who were previously diagnosed with 99mTc-EDDA/HYNIC-TOC SPECT. AB - BACKGROUND: The aim of this study was the assessment of utility of somatostatin receptor scintigraphy (SRS) by SPECT imaging using 99mTc-EDDA/HYNIC-Tyr3 octreotide (99mTc-EDDA/HYNIC-TOC) in patients with neuroendocrine neoplasm (NEN) or suspected NEN, referred to Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The selected group of patients was referred also to 68Ga PET/CT. The posed question was the ratio of patients for whom PET/CT with 68Ga would change their management. MATERIAL AND METHODS: The distribution of somatostatin receptors was imaged using 99mTc-EDDA/HYNIC-TOC in 61 planar and SPECT studies between 13/05/2010 and 04/02/2013 in Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The patient age was within a range of 17 80, with the average age of 57.6. The average age of women (65% of patients over all) was 55.6 and the average age of men (35% of patients overall) was 61.4. In 46 participants (75% of the study group), that underwent SRS, NEN was documented using pathology tests. Selected patients were referred to PET/CT with 68Ga labeled somatostatin analogs, DOTATATE or DOTANOC. This study group consisted of 14 female and 10 male participants with age range of 35-77 and average age of 55.5 years. Patients were classified into 3 groups, as follows: detection - referral due to clinical symptoms and/or biochemical markers (CgA-Chromogranin A, IAA-indoleacetic acid) with the aim of primary diagnosis, staging - referral with the aim of assessment of tumor spread, and follow-up - assessment of the therapy. RESULTS: Out of 61 patients, 24 underwent both 99mTc-EDDA/HYNIC-Tyr3-octreotide SPECT and 68Ga PET/CT. The result of PET/CT was used as a basis for further evaluation. Therefore, the patients were divided into groups; true positive TP (confirmed presence of tissue somatostatin receptors with 68Ga PET/CT) and TN (68Ga PET/CT did not detect any changes and the results were comparable and had the same influence on treatment protocol). In case of SPECT, the results were assigned as follows: TP, TN (in cases where the results were confirmed by 68Ga PET/CT), FP (patient's scintigraphy demonstrated focal change by SPECT but not PET/CT) and FN (99mTc-EDDA/HYNIC-Tyr3-octreotide SPECT failed to demonstrate any abnormalities; however, the treatment protocol was changed after PET/CT). CONCLUSIONS: The accuracy of SPECT diagnosis was found to be as high as 91.6%. Only in 8.4% of patients the additional PET/CT with 68Ga-labeled somatostatin analog changed the treatment protocol. PMID- 27479889 TI - Lipid diffusion and swelling in a phase separated biocompatible thermoplastic elastomer. AB - Lipid uptake was analyzed via gravimetric measurements in a biocompatible poly(styrene-block-isobutylene-block-styrene) (SIBS) copolymer. Absorption followed Fickian diffusion behavior very closely, although some deviation was noticed once saturation was reached. Diffusion parameters of three different SIBS formulations were calculated and used to predict the behavior of a fourth type based on molecular weight and relative polystyrene content. SIBS with lower polystyrene content and molecular weight showed lower physical stability and developed surface cracks that propagated with exposure to the lipid medium. Saturation lipid content varied from 45% to 63% by weight and was inversely related to polystyrene content, suggesting most of the plasticization is occurring in the isobutylene phase of SIBS. Moreover, swelling of specimens was monitored throughout the immersion in the lipid medium and ranged from 32% to 58%. Swelling in formulations with lower hard phase (polystyrene) was significantly higher than the swelling in SIBS with higher hard phase content. This is consistent with lipid-induced plasticization occurring in the soft (polyisobutylene) segments, relaxing the polymer network and leading to increased swelling and lipid uptake. The biocompatibility and tailorability of SIBS through control of hard/soft phase ratio offer significant advantages for in vivo applications. However, the lipophilic nature of the material and the associated degradation may render the polymer unusable in certain applications. The predictive model of lipid uptake introduced here will allow more accurate evaluation of lipid susceptibility during the preliminary design phase of SIBS based in vivo structures. PMID- 27479888 TI - Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis. AB - BACKGROUND: The clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial. METHODS: The authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event free survival (EFS), and overall survival (OS) between the cohorts. RESULTS: Propensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib. CONCLUSIONS: The clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. (c) 2016 American Cancer Society. PMID- 27479890 TI - Frequency-modulated atomic force microscopy localises viscoelastic remodelling in the ageing sheep aorta. AB - Age-related aortic stiffening is associated with cardiovascular diseases such as heart failure. The mechanical functions of the main structural components of the aorta, such as collagen and elastin, are determined in part by their organisation at the micrometer length scale. With age and disease both components undergo aberrant remodelling, hence, there is a need for accurate characterisation of the biomechanical properties at this length scale. In this study we used a frequency modulated atomic force microscopy (FM-AFM) technique on a model of ageing in female sheep aorta (young: ~18 months, old: >8 years) to measure the micromechanical properties of the medial layer of the ascending aorta. The novelty of our FM-AFM method, operated at 30kHz, is that it is non-contact and can be performed on a conventional AFM using the 'cantilever tune' mode, with a spatial (areal) resolution of around 1.6MUm(2). We found significant changes in the elastic and viscoelastic properties within the medial lamellar unit (elastic lamellae and adjacent inter-lamellar space) with age. In particular, there was an increase in elastic modulus (Young; geometric mean (geometric SD)=42.9 (2.26)kPa, Old=113.9 (2.57)kPa, P<0.0001), G' and G" (storage and loss modulus respectively) (Young; G'=14.3 (2.26)kPa, Old G'=38.0 (2.57)kPa, P<0.0001; Young; G"=14.5 (2.56)kPa, Old G"=32.8 (2.52)kPa, P<0.0001). The trends observed in the elastic properties with FM-AFM matched those we have previously found using scanning acoustic microscopy (SAM). The utility of the FM-AFM method is that it does not require custom AFM hardware and can be used to simultaneously determine the elastic and viscoelastic behaviour of a biological sample. PMID- 27479891 TI - Mechanical properties of anodic titanium films containing ions of Ca and P submitted to heat and hydrothermal treatment. AB - Anodic oxidation is a technique widely used to improve the bioactivity of Ti surface. In this study, micro-arc oxidation (MAO) was used to obtain an anodic film incorporating Ca and P ions to evaluate the effect of heat and hydrothermal treatment on the mechanical and in vitro bioactivity properties of these new layers. The MAO process was carried out using (CH3COO)2Ca.H2O and NaH2PO4.2H2O electrolytes under galvanostatic mode (150mA/cm(2)). The thermal treatments were made at 400 degrees C and 600 degrees C in air atmosphere while hydrothermal treatment was made in an alkaline water solution at 130 degrees C. These surfaces presented desired mechanical properties for biomedical applications owing to the rutile and anatase phases in the anodic film that are more crystalline after thermal treatments; which provided an increase in hardness values and lower elastic modulus. The dry sliding wear resistance increased by performing thermal treatments on the surfaces with one condition still maintaining the film after the test. Bioactivity was investigated by immersion in simulated body fluid during 21 days and hydroxyapatite was formed on all samples. Finally, lower values of contact angle were obtained for heat treated samples. PMID- 27479892 TI - Softened and flexible biodegradable poly(lactic acid) and its electromechanical properties for actuator application. AB - Poly (lactic acid) (PLA) is a biodegradable polymer with high stiffness presenting a limitation for using in actuator applications. Adding a plasticizer is one way to solve this problem to enhance flexibility and improve electromechanical properties of pristine PLA. In this work, the PLA films were prepared via a simple solvent casting method. The influences of plasticizer type and electric field strength on electromechanical behavior of PLA films were investigated by the melt rheometer and bending measurement. For the PLA films filled with dibutyl phthalate (DBP), the storage modulus, G', immediately increased towards its steady state and rapidly recovered to its original value with and without electric field, respectively, which can be referred to a reversible system. On the other hand, the PLA film with Tween 20 processed the highest ?G'/G'0 of 1.34 due to the available amount of polarized groups. In the bending measurement, the dielectrophoresis forces of plasticized PLA films were found to increase with increasing electric field where the deflections occurred towards anode side as the polarized groups generated negative charges. The DBP_PLA1.5D film exhibited the greatest bending and dielectrophoresis force. Thus, the biodegradable PLA along with DBP combine to have a great potential towards actuator application. PMID- 27479893 TI - Functional hydrogel contact lens for drug delivery in the application of oculopathy therapy. AB - Although hydrogel contact lens has attracted increasingly concerns as delivery carriers in the field of oculopathy therapy, traditional hydrogel does not show excellent drug encapsulated and controlled properties due to simple hydrophilic polymer chain lacking extra interaction with drug molecule. Herein, functional hydrogels were synthesized in this research to delivery ophthalmic drug for oculopathy therapy. Functional monomer of mono-GMA-beta-CD and functional crosslinker of MA-beta-CD were incorporated into hydrogel by copolymerization. For hydrogels, equilibrium swelling ratio and contact angle was influenced by mono-GMA-beta-CD ratio and MA-beta-CD ratio, respectively. All hydrogels exhibited similar water loss behavior and good transparency. Hydrogels had rheological characteristic of typical elastomer. Viscoelasticity and surface morphology of hydrogel were also affected by mono-GMA-beta-CD ratio and MA-beta CD ratio. In the aspect of properties, functional hydrogel containing beta-CD domain exhibited better protein resistance capacity and significantly higher equilibrium encapsulated drug amount than traditional hydrogel. Besides the performance, drug release behavior of drug encapsulated hydrogel was adjusted by both mono-GMA-beta-CD ratio and MA-beta-CD ratio. Preliminary in vivo evaluation revealed that functional hydrogel contact lens had better effect and efficacy on lowering intraocular tension than commercial eye drop. It is inferred from all results that functional contact lens has a bright prospect in the application of oculopathy therapy. PMID- 27479894 TI - Elastic-plastic fracture toughness and rising JR-curve behavior of cortical bone is partially protected from irradiation-sterilization-induced degradation by ribose protectant. AB - OBJECTIVE: This study tested the hypothesis that pre-treating cortical bone with ribose would protect the rising fracture resistance curve behavior and crack initiation fracture toughness of both bovine and human cortical bone from the degrading effects of gamma-irradiation sterilization. MATERIALS AND METHODS: A ribose pre-treatment (1.8 M for bovine, and 1.2 M for human, in PBS at 60 degrees C for 24 h) was applied to single-edge notched bending fracture specimens prior to sterilization with a 33 kGy dose of gamma-irradiation. Fracture resistance curves were generated with a single specimen method using an optical crack length measurement technique. The effect of the treatment on overall fracture resistance behavior, crack initiation fracture toughness, and tearing modulus was compared with non-irradiated and conventionally irradiation sterilized controls. Hydrothermal isometric tension testing was used to examine collagen network connectivity and thermal stability to explore relationships between collagen network quality and fracture resistance. RESULTS: The ribose pre treatment successfully protected the crack growth initiation fracture toughness of bovine and human bone by 32% and 63%, respectively. The rising JR-curve behavior was also partially protected. Furthermore, collagen connectivity and thermal stability followed similar patterns to those displayed by fracture toughness. CONCLUSIONS: This paper demonstrates that the fracture toughness of irradiation-sterilized bone tissue can be partially protected with a ribose pre treatment. This new approach shows potential for the production and clinical application of sterilized allografts with improved mechanical performance and durability. PMID- 27479895 TI - Comparative acoustic performance and mechanical properties of silk membranes for the repair of chronic tympanic membrane perforations. AB - The acoustic and mechanical properties of silk membranes of different thicknesses were tested to determine their suitability as a repair material for tympanic membrane perforations. Membranes of different thickness (10-100MUm) were tested to determine their frequency response and their resistance to pressure loads in a simulated ear canal model. Their mechanical rigidity to pressure loads was confirmed by tensile testing. These membranes were tested alongside animal cartilage, currently the strongest available myringoplasty graft as well as paper, which is commonly used for simpler procedures. Silk membranes showed resonant frequencies within the human hearing range and a higher vibrational amplitude than cartilage, suggesting that silk may offer good acoustic energy transfer characteristics. Silk membranes were also highly resistant to simulated pressure changes in the middle ear, suggesting they can resist retraction, a common cause of graft failure resulting from chronic negative pressures in the middle ear. Part of this strength can be explained by the substantially higher modulus of silk films compared with cartilage. This allows for the production of films that are much thinner than cartilage, with superior acoustic properties, but that still provide the same level of mechanical support as thicker cartilage. Together, these in vitro results suggest that silk membranes may provide good hearing outcomes while offering similar levels of mechanical support to the reconstructed middle ear. PMID- 27479896 TI - Crack propagation and the material removal mechanism of glass-ceramics by the scratch test. AB - To eliminate the negative effects of surface flaws and subsurface damage of glass ceramics on clinical effectiveness, crack propagation and the material removal mechanism of glass-ceramics were studied by single and double scratch experiments conducted using an ultra-precision machine. A self-manufactured pyramid shaped single-grit tool with a small tip radius was used as the scratch tool. The surface and subsurface crack propagations and interactions, surface morphology and material removal mechanism were investigated. The experimental results showed that the propagation of lateral cracks to the surface and the interaction between the lateral cracks and radial cracks are the two main types of material peeling, and the increase of the scratch depth increases the propagation angle of the radial cracks and the interaction between the cracks. In the case of a double scratch, the propagation of lateral cracks and radial cracks between paired scratches results in material peeling. The interaction between adjacent scratches depends on the scratch depth and separation distance. There is a critical separation distance where the normalized material removal volume reaches its peak. These findings can help reduce surface flaws and subsurface damage induced by the grinding process and improve the clinical effectiveness of glass-ceramics used as biological substitute and repair materials. PMID- 27479897 TI - Guideline Update for Article on Pharmaceutical Industry-Sponsored Meals. PMID- 27479898 TI - A Common Parvovirus in Deer from California, USA. AB - We characterize the genome of the first reported deer parvovirus, Ungulate tetraparvovirus 5, which we detected by PCR in multiple tissues from 2/9 California mule deer ( Odocoileus hemionus californicus) with hair loss syndrome (HLS) and in 4/12 deer without HLS, suggesting this common infection does not cause HLS. PMID- 27479899 TI - Clinical Evaluation, Hematology, and Serum Chemistry of Ocelots ( Leopardus pardalis ) in the Atlantic Forest of Brazil. AB - During the last three decades, much research has illustrated the potential impact of diseases on wild animal populations. However, few studies focused on establishing parameters to reliably differentiate healthy from sick animals. We present clinical, hematologic, and serum chemistry data from nine healthy ocelots ( Leopardus pardalis ) and one ill ocelot captured in 2012 and 2013 in Brazil. Laboratory results were compared to mean values of captive ocelots and reference ranges for domestic cats ( Felis catus ). Free-ranging ocelots had overall higher white blood cells, aspartate aminotransferase, creatine phosphokinase, lactate dehydrogenase, urea nitrogen, and triglycerides, probably due to handling. Free ranging ocelots also presented hyperproteinemia, hyperglobulinemia, hypoalbuminemia, and hyperuricemia. PMID- 27479901 TI - THE CHALLENGE OF DETECTING CLASSICAL SWINE FEVER VIRUS CIRCULATION IN WILD BOAR (SUS SCROFA): SIMULATION OF SAMPLING OPTIONS. AB - Classical swine fever (CSF) is one of the most important viral diseases of domestic pigs ( Sus scrofa domesticus) and wild boar ( Sus scrofa ). For at least 4 decades, several European Union member states were confronted with outbreaks among wild boar and, as it had been shown that infected wild boar populations can be a major cause of primary outbreaks in domestic pigs, strict control measures for both species were implemented. To guarantee early detection and to demonstrate freedom from disease, intensive surveillance is carried out based on a hunting bag sample. In this context, virologic investigations play a major role in the early detection of new introductions and in regions immunized with a conventional vaccine. The required financial resources and personnel for reliable testing are often large, and sufficient sample sizes to detect low virus prevalences are difficult to obtain. We conducted a simulation to model the possible impact of changes in sample size and sampling intervals on the probability of CSF virus detection based on a study area of 65 German hunting grounds. A 5-yr period with 4,652 virologic investigations was considered. Results suggest that low prevalences could not be detected with a justifiable effort. The simulation of increased sample sizes per sampling interval showed only a slightly better performance but would be unrealistic in practice, especially outside the main hunting season. Further studies on other approaches such as targeted or risk-based sampling for virus detection in connection with (marker) antibody surveillance are needed. PMID- 27479900 TI - SEROSURVEY OF SELECTED ARBOVIRAL PATHOGENS IN FREE-RANGING, TWO-TOED SLOTHS (CHOLOEPUS HOFFMANNI) AND THREE-TOED SLOTHS (BRADYPUS VARIEGATUS) IN COSTA RICA, 2005-07. AB - We screened for antibodies to 16 arboviruses in four populations of free-ranging sloths in Costa Rica. Blood samples were taken from 16 Hoffman's two-toed sloths (HTSs; Choloepus hoffmanni ) and 26 brown-throated sloths (BTSs; Bradypus variegatus ) over a 3-yr period. We used serologic assays to detect antibodies against 10 arboviruses previously described in sloths (St. Louis encephalitis [SLEV], Changuinola, Venezuelan equine encephalitis, Ilheus [ILHV], Oropouche, Mayaro, Utinga, Murutucu, Punta Toro, and vesicular stomatitis [VSV] viruses) and six arboviruses not described in sloths (Rio Grande, West Nile [WNV], eastern equine encephalitis, Piry, Munguba, and La Crosse viruses). Overall, 80% of sloths had detectable antibodies to SLEV, 67% had antibodies to ILHV, 32% to Punta Toro virus, 30% to Changuinola virus, 15% to WNV, 14% to VSV, 11% to Venezuelan equine encephalitis virus, and 10% to Rio Grande virus. No samples had detectable antibodies to the remaining eight viruses. We found a significant increase in prevalence of antibody to VSV in HTSs between 2005 and 2007, and for WNV antibody between 2005 and 2006. We found no significant differences in the prevalences of antibodies to the sampled viruses between the two locations. Antibody prevalences were significantly higher in HTSs than in BTSs for SLEV in 2005. Antibody-positive results for ILHV were likely due to cross-reaction with SLEV. The novel finding of antibodies to Rio Grande virus in sloths could be due to cross-reaction with another phlebovirus. These findings might have implications for land management and domestic animal health. Due to the nature of the study, we could not determine whether sloths could represent amplification hosts for these viruses, or whether they were only exposed and could be used as sentinel species. Further studies are needed to fully characterize arboviral exposure in sloths. PMID- 27479902 TI - Bald Eagle Nestling Mortality Associated with Argas radiatus and Argas ricei Tick Infestation and Successful Management with Nest Removal in Arizona, USA. AB - Eight Bald Eagle ( Haliaeetus leucocephalus ) nestlings heavily infested with larval ticks were found in or under a nest near the confluence of the Verde and Salt rivers in Arizona in 2009-11. The 8-12-wk-old nestlings were slow to respond to stimuli and exhibited generalized muscle weakness or paresis of the pelvic limbs. Numerous cutaneous and subcutaneous hemorrhages were associated with sites of tick attachment. Ticks were identified as Argas radiatus and Argas ricei. Treatment with acaricides and infection with West Nile virus (WNV) may have confounded the clinical presentation in 2009 and 2010. However, WNV-negative birds exhibited similar signs in 2011. One nestling recovered from paresis within 36 h after the removal of all adult and larval ticks (>350) and was released within 3 wk. The signs present in the heavily infested Bald Eagle nestlings resembled signs associated with tick paralysis, a neurotoxin-mediated paralytic syndrome described in mammals, reptiles, and wild birds (though not eagles). Removal of the infested nest and construction of a nest platform in a different tree was necessary to break the cycle of infection. The original nesting pair constructed a new nest on the man-made platform and successfully fledged two Bald Eagles in 2012. PMID- 27479903 TI - Short-term outcome of substance-induced psychotic disorder in a large UK first episode psychosis cohort. AB - OBJECTIVE: The incidence and outcome of first-episode substance-induced psychotic disorder (SIPD) are unclear. The study aimed to compare the 1-year outcomes of those given a SIPD diagnosis by clinicians compared to other psychosis diagnoses in a first-episode cohort. METHOD: Data were from a large (n = 1027) cohort of first-episode psychosis (FEP) patients admitted to early intervention services in the UK (National EDEN). Diagnosis, including that of SIPD, was made by treating psychiatrists at baseline using ICD10 criteria. Details on symptoms, functioning, quality of life, relapse and recovery were available at baseline and 12 months. RESULTS: There were 67 cases of SIPD (6.5% of the cohort). At baseline, SIPD patients were no different to other psychoses on symptoms, functioning and quality of life. At 12 months, there was no difference in SIPD and other psychoses on functioning, quality of life or relapse and recovery rates. Levels of psychotic and general symptomatology were similar but depressive symptoms were higher in the SIPD group. CONCLUSIONS: First-episode psychosis patients with a diagnosis of SIPD do not appear to have better outcomes than those with other primary psychotic diagnoses. The higher levels of depressive symptoms may be a specific marker in these patients. PMID- 27479904 TI - Charge carrier transport and lifetimes in n-type and p-type phosphorene as 2D device active materials: an ab initio study. AB - In this work, we provide a detailed analysis of phosphorene's performance as an n type and p-type active material. This study is based on first principles calculations of the phosphorene electronic structure, and the resulting electron and hole scattering rates and lifetimes. Emphasis is put on extreme regimes commonly found in semiconductor devices, i.e. high electric fields and heavy doping, where impact ionization and Auger recombination can occur. We found that electron-initiated impact ionization is weaker than the hole-initiated process, when compared to carrier-phonon interaction rates, suggesting resilience to impact ionization initiated breakdown. Moreover, calculated minority electron lifetimes are limited by radiative recombination only, not by Auger processes, suggesting that phosphorene could achieve good quantum efficiencies in optoelectronic devices. The provided scattering rates and lifetimes are critical input data for the modeling and understanding of phosphorene-based device physics. PMID- 27479905 TI - Transcription factors as readers and effectors of DNA methylation. AB - Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease. PMID- 27479906 TI - Genetic variation in MHC proteins is associated with T cell receptor expression biases. AB - In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR MHC contacts promote TCR-MHC specificity and, if so, whether differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (eQTL) mapping to test for associations between genetic variation and TCR V gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V gene usage. Fine mapping of the association signals identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR-peptide-MHC complex. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR-MHC interaction. These results provide the first examples of trans-QTL effects mediated by protein-protein interactions and are consistent with intrinsic TCR MHC specificity. PMID- 27479908 TI - Tensor decomposition for multiple-tissue gene expression experiments. AB - Genome-wide association studies of gene expression traits and other cellular phenotypes have successfully identified links between genetic variation and biological processes. The majority of discoveries have uncovered cis-expression quantitative trait locus (eQTL) effects via mass univariate testing of SNPs against gene expression in single tissues. Here we present a Bayesian method for multiple-tissue experiments focusing on uncovering gene networks linked to genetic variation. Our method decomposes the 3D array (or tensor) of gene expression measurements into a set of latent components. We identify sparse gene networks that can then be tested for association against genetic variation across the genome. We apply our method to a data set of 845 individuals from the TwinsUK cohort with gene expression measured via RNA-seq analysis in adipose, lymphoblastoid cell lines (LCLs) and skin. We uncover several gene networks with a genetic basis and clear biological and statistical significance. Extensions of this approach will allow integration of different omics, environmental and phenotypic data sets. PMID- 27479910 TI - Effect of the bimetal ratio on the growth of nickel cobalt sulfide on the Ni foam for the battery-like electrode. AB - The nickel cobalt sulfide is one of the most attractive electroactive materials for battery-like electrodes with multiple oxidation states for Faradaic reactions. Novel structures of the nickel cobalt sulfide with large surface areas and high conductivities have been proposed to improve the performance of the battery-like electrodes. The hydrothermal reaction is the most common used method for synthesizing nickel cobalt sulfide nanostructures due to the simple and cost effective features, but the precursor concentration on the morphology and the resulting electrochemical performance is barely discussed. In this study, various Ni to Co ratios are used in the hydrothermal reaction to make nickel cobalt sulfides on the nickel foam, and the Ni to Co ratio is found to play great roles on the morphology and the electrocapacitive performance for the pertinent battery like electrodes. The sheet-like structures are successfully obtained with large surface area for charge accumulation, and the optimized sample presents the largest nanosheets among all with several wrinkles on the surface. A high specific capacity of 258.2mAh/g measured at the current density of 5A/g and a high-rate charge/discharge capacity are also attended for the optimized battery like electrodes. The excellent cycling stability of 94.5% retention after 2000 cycles repeated charge/discharge process is also obtained for this system. PMID- 27479909 TI - Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. AB - Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 * 10(-5) in the meta-analysis were further analyzed in a replication data set (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint analysis over all three data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics. PMID- 27479911 TI - Nitrogen-doped carbon dots originating from unripe peach for fluorescent bioimaging and electrocatalytic oxygen reduction reaction. AB - This paper reports the robust hydrothermal synthesis of nitrogen doped carbon dots (N-CDs) using the unripe fruit of Prunus persica (peach) as the carbon precursor and aqueous ammonia as the nitrogen source. The optical properties of synthesized N-CDs were characterized by ultraviolet visible (UV-Vis) and fluorescence spectroscopy techniques. The synthesized N-CDs were emitted blue light when excitated with a portable UV lamp. The materials with the optical properties were characterized further by high resolution transmission electron microscope (HRTEM), X-ray diffraction (XRD), Raman, Fourier transform infrared (FT-IR) and X-ray photoelectron spectroscopy (XPS). The mean size of the N-CDs was approximately 8nm, as calculated from the HRTEM image. The d-spacing of N CDs, calculated using Bragg law, was approximately 0.21nm, which was consistent with the interlayer distance calculated from the HRTEM image. FT-IR spectroscopy and XPS revealed the presence of the phytoconstituents functionalities of peach fruit over the N-CDs surface and a high level of nitrogen doping on carbon dots (CDs) was confirmed by XPS studies. These results suggest that the unripe fruit extract of peach is an ideal candidate for the preparation of N-CDs. The resulting N-CDs showed excellent optical properties in water. The synthesized N CDs exhibited a high fluorescence quantum yield and low cytotoxicity, and can be used as fluorescence imaging probes. In addition, the N-CDs were catalytically activite towards the oxygen reduction reaction (ORR). The N-CDs exhibited good catalytic activity in an alkaline medium (0.1M KOH) with a remarkable ORR of approximately 0.72V vs reversible hydrogen electrode (RHE), and O2 reduction follows mainly a 2 electron pathway by being reduced to hydrogen peroxide. The 2 electron reduction pathway is used in industry for H2O2 production. PMID- 27479912 TI - Spectrum of Movement Disorders in Mitochondrial Disorders-Reply. PMID- 27479913 TI - Deletion of FtsH11 protease has impact on chloroplast structure and function in Arabidopsis thaliana when grown under continuous light. AB - The membrane-integrated metalloprotease FtsH11 of Arabidopsis thaliana is proposed to be dual-targeted to mitochondria and chloroplasts. A bleached phenotype was observed in ftsh11 grown at long days or continuous light, pointing to disturbances in the chloroplast. Within the chloroplast, FtsH11 was found to be located exclusively in the envelope. Two chloroplast-located proteins of unknown function (Tic22-like protein and YGGT-A) showed significantly higher abundance in envelope membranes and intact chloroplasts of ftsh11 and therefore qualify as potential substrates for the FtsH11 protease. No proteomic changes were observed in the mitochondria of 6-week-old ftsh11 compared with wild type, and FtsH11 was not immunodetected in these organelles. The abundance of plastidic proteins, especially of photosynthetic proteins, was altered even during standard growth conditions in total leaves of ftsh11. At continuous light, the amount of photosystem I decreased relative to photosystem II, accompanied by a drastic change of the chloroplast morphology and a drop of non-photochemical quenching. FtsH11 is crucial for chloroplast structure and function during growth in prolonged photoperiod. PMID- 27479907 TI - Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. AB - Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD. PMID- 27479914 TI - Global positioning system survey data for active seismic and volcanic areas of eastern Sicily, 1994 to 2013. AB - This work presents and describes a 20-year long database of GPS data collected by geodetic surveys over the seismically and volcanically active eastern Sicily, for a total of more than 6300 measurements. Raw data were initially collected from the various archives at the Istituto Nazionale di Geofisica e Vulcanologia, Sezione di Catania-Osservatorio Etneo and organized in a single repository. Here, quality and completeness checks were performed, while all necessary supplementary information were searched, collected, validated and organized together with the relevant data. Once all data and information collections were completed, raw binary data were converted into the universal ASCII RINEX format; all data are provided in this format with the necessary information for precise processing. In order to make the data archive readily consultable, we developed software allowing the user to easily search and obtain the needed data by simple alphanumeric and geographic queries. PMID- 27479915 TI - Mutations in POGLUT1 in Galli-Galli/Dowling-Degos disease. PMID- 27479916 TI - Downstream effects of hippocampal sharp wave ripple oscillations on medial entorhinal cortex layer V neurons in vitro. AB - The entorhinal cortex (EC) is a critical component of the medial temporal lobe (MTL) memory system. Local networks within the MTL express a variety of state dependent network oscillations that are believed to organize neuronal activity during memory formation. The peculiar pattern of sharp wave-ripple complexes (SPW R) entrains neurons by a very fast oscillation at ~200 Hz in the hippocampal areas CA3 and CA1 and then propagates through the "output loop" into the EC. The precise mechanisms of SPW-R propagation and the resulting cellular input patterns in the mEC are, however, largely unknown. We therefore investigated the activity of layer V (LV) principal neurons of the medial EC (mEC) during SPW-R oscillations in horizontal mouse brain slices. Intracellular recordings in the mEC were combined with extracellular monitoring of propagating network activity. SPW-R in CA1 were regularly followed by negative field potential deflections in the mEC. Propagation of SPW-R activity from CA1 to the mEC was mostly monosynaptic and excitatory, such that synaptic input to mEC LV neurons directly reflected unit activity in CA1. Comparison with propagating network activity from CA3 to CA1 revealed a similar role of excitatory long-range connections for both regions. However, SPW-R-induced activity in CA1 involved strong recruitment of rhythmic synaptic inhibition and corresponding fast field oscillations, in contrast to the mEC. These differences between features of propagating SPW-R emphasize the differential processing of network activity by each local network of the hippocampal output loop. (c) 2016 Wiley Periodicals, Inc. PMID- 27479918 TI - Masking the saccadic smear. AB - Static visual stimuli are smeared across the retina during saccades, but in normal conditions this smear is not perceived. Instead, we perceive the visual scene as static and sharp. However, retinal smear is perceived if stimuli are shown only intrasaccadically, but not if the stimulus is additionally shown before a saccade begins, or after the saccade ends (Campbell & Wurtz, 1978). This inhibition has been compared to forward and backward metacontrast masking, but with spatial relations between stimulus and mask that are different from ordinary metacontrast during fixation. Previous studies of smear masking have used subjective measures of smear perception. Here we develop a new, objective technique for measuring smear masking, based on the spatial localization of a gap in the smear created by very quickly blanking the stimulus at various points during the saccade. We apply this technique to show that smear masking survives dichoptic presentation (suggesting that it is therefore cortical in origin), as well as separations of as much as 6 degrees between smear and mask. PMID- 27479917 TI - Impact of body mass index on outcome in stroke patients treated with intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: The impact of body mass index (BMI) on outcome in stroke patients treated with intravenous thrombolysis (IVT) was investigated. METHODS: In a multicentre IVT-register-based observational study, BMI with (i) poor 3 month outcome (i.e. modified Rankin Scale scores 3-6), (ii) death and (iii) symptomatic intracranial haemorrhage (sICH) based on criteria of the ECASS II trial was compared. BMI was used as a continuous and categorical variable distinguishing normal weight (reference group 18.5-24.9 kg/m2 ) from underweight (<18.5 kg/m2 ), overweight (25-29.9 kg/m2 ) and obese (>=30 kg/m2 ) patients. Univariable and multivariable regression analyses with adjustments for age and stroke severity were done and odds ratios with 95% confidence intervals [OR (95% CI)] were calculated. RESULTS: Of 1798 patients, 730 (40.6%) were normal weight, 55 (3.1%) were underweight, 717 (39.9%) overweight and 295 (16.4%) obese. Poor outcome occurred in 38.1% of normal weight patients and did not differ significantly from underweight (45.5%), overweight (36.1%) and obese (32.5%) patients. The same was true for death (9.5% vs. 14.5%, 9.6% and 7.5%) and sICH (3.9% vs. 5.5%, 4.3%, 2.7%). Neither in univariable nor in multivariable analyses did the risks of poor outcome, death or sICH differ significantly between BMI groups. BMI as a continuous variable was not associated with poor outcome, death or sICH in unadjusted [OR (95% CI) 0.99 (0.97-1.01), 0.98 (0.95-1.02), 0.98 (0.94 1.04)] or adjusted analyses [OR (95% CI) 1.01 (0.98-1.03), 0.99 (0.95-1.05), 1.01 (0.97-1.05)], respectively. CONCLUSION: In this largest study to date, investigating the impact of BMI in IVT-treated stroke patients, BMI had no prognostic meaning with regard to 3-month functional outcome, death or occurrence of sICH. PMID- 27479919 TI - Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden. AB - Importance: Active perinatal care increases the rate of survival of extremely preterm infants, but there are concerns that improved survival might increase the rate of disabled survivors. Objective: To determine the neurodevelopmental outcomes of a national cohort of children 6.5 years of age who had been born extremely preterm (<27 weeks' gestational age) in Sweden. Design, Setting, and Participants: Population-based prospective cohort study of consecutively born extremely preterm infants. All of these infants were born in Sweden during the period from April 1, 2004, to March 31, 2007. Of 707 live-born extremely preterm infants, 486 (68.7%) survived to 6.5 years of age. These children were assessed and compared with matched controls who had been born at term. Comparison estimates were adjusted for demographic differences. Assessments ended in February 2014, and analysis started thereafter. Main Outcomes and Measures: Cognitive ability was measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV), and the mean (SD) scores of the children who had been born extremely preterm were compared with those of the controls. Clinical examinations and parental questionnaires were used for diagnosis of cerebral palsy, hearing and vision impairments, and cognition for the children who were not assessed with the WISC-IV. Results: Of 486 eligible infants who were born extremely preterm, 441 (90.7%) were assessed at 6.5 years of age (59 by medical record review only) alongside 371 controls. The adjusted mean (SD) full-scale WISC-IV score was 14.2 (95% CI, 12.1-16.3) points lower for children who had been born extremely preterm than for controls. Cognitive disability was moderate for 18.8% of extremely preterm children and 2.2% of controls (P < .001), and it was severe for 11.1% of extremely preterm children and 0.3% of controls (P < .001). Cerebral palsy was observed in 9.5% of extremely preterm children and 0.0% of controls (P < .001), blindness was observed in 2.0% of extremely preterm children and 0.0% of controls (P < .001), and hearing impairment was observed in 2.1% of extremely preterm children and 0.5% of controls (P = .07). Overall, 36.1% (95% CI, 31.7%-40.6%) of extremely preterm children had no disability, 30.4% (95% CI 26.3%-34.8%) had mild disability, 20.2% (95% CI, 16.6%-24.2%) had moderate disability, and 13.4% (95% CI, 10.5%-16.9%) had severe disability. For extremely preterm children, moderate or severe overall disability decreased with gestational age at birth (adjusted odds ratio per week, 0.65 [95% CI, 0.54-0.79]; P < .001) and increased from 26.6% to 33.5% (P = .01) for children assessed both at 2.5 and 6.5 years. Conclusions and Relevance: Of the 441 extremely preterm infants who had received active perinatal care, 293 (66.4%) had no or mild disability at 6.5 years; of the 371 controls, 11 (3.0%) had moderate or severe disability. Disability rates at 6.5 years increased relative to the rates at 2.5 years. Results are relevant for health care professionals and planners, and for clinicians counseling families facing extremely preterm births. PMID- 27479921 TI - Voxel-based morphometry to detect effect of APOE on brain gray matter changes in Parkinson's Disease. AB - The goal of the study was to determine association between APOE E4 and gray matter changes in PD patients, with or without dementia. Twenty-five PD patients with the APOE E4 (13 with dementia), 24 without E4 (12 with dementia), and 26 controls were selected. We found no significant differences between PD patients and controls, or between PD patients with and without the APOE E4 allele, with regard to VBM analysis. Our results provide no evidence of an association of the APOE E4 and gray matter degenerative changes in patients with PD, either with or without dementia. PMID- 27479920 TI - T-cell metabolism governing activation, proliferation and differentiation; a modular view. AB - T lymphocytes are a critical component of the adaptive immune system mediating protection against infection and malignancy, but also implicated in many immune pathologies. Upon recognition of specific antigens T cells clonally expand, traffic to inflamed sites and acquire effector functions, such as the capacity to kill infected and malignantly transformed cells and secrete cytokines to coordinate the immune response. These processes have significant bioenergetic and biosynthetic demands, which are met by dynamic changes in T-cell metabolism, specifically increases in glucose uptake and metabolism; mitochondrial function; amino acid uptake, and cholesterol and lipid synthesis. These metabolic changes are coordinate by key cellular kinases and transcription factors. Dysregulated T cell metabolism is associated with impaired immunity in chronic infection and cancer and conversely with excessive T-cell activity in autoimmune and inflammatory pathologies. Here we review the key aspects of T-cell metabolism relevant to their immune function, and discuss evidence for the potential to therapeutically modulate T-cell metabolism in disease. PMID- 27479922 TI - Regional grey matter volume and concentration in at-risk adolescents: Untangling associations with callous-unemotional traits and conduct disorder symptoms. AB - Structural Magnetic Resonance Imaging studies have reported volume reductions in several brain regions implicated in social cognition and emotion recognition in juvenile antisocial populations. However, it is unclear whether these structural abnormalities are specifically related to antisocial features, or to co-occurring callous-unemotional (CU) traits. The present study employed voxel-based morphometry to assess both grey matter volume (GMV) and grey matter concentration (GMC) in a large representative at-risk sample of adolescents (n=134; mean age 17.7yr), characterized by a broad range of CU trait and conduct disorder (CD) symptom scores. There was a significant interaction between CD symptom and CU trait scores in the prediction of GMV in the anterior insula, with a significant positive association between CU traits and GMV in youth low on CD symptoms only. In addition, we found a significant unique positive association between CD symptoms and GMC in the amygdala, and unique negative associations between CU traits and GMC in the amygdala and insula. These findings are in line with accumulating evidence of distinct associations of CD symptoms and CU traits with amygdala and insula GMC in juvenile antisocial populations. PMID- 27479923 TI - White matter correlates of episodic memory encoding and retrieval in schizophrenia. AB - Episodic memory (EM) impairments in schizophrenia (SZ) are predictive of functional outcome and are a potential endophenotype of the disorder. The current study investigated the neuroanatomical correlates of EM encoding and retrieval in SZ with structural magnetic resonance and diffusion tensor imaging (DTI) measures in 22 patients with SZ and 22 age- and gender-matched healthy controls. Tract based Spatial Statistics (TBSS) was used to investigate microstructural alterations in white matter (WM), while FreeSurfer surface-based analysis was used to determine abnormalities in grey matter (GM) and WM volumetrics and cortical thickness. Compared to controls, patients demonstrated GM deficits in temporal and parietal regions and lower fractional anisotropy (FA) of WM in diffuse brain regions. Patients also demonstrated reduced functioning in both encoding and retention of auditory-verbal EM. Among patients but not controls, EM encoding correlated with WM volume in the orbitofrontal cortex and increased radial diffusivity in the fornix, whereas EM retrieval correlated with WM volume in posterior parietal cortex. These findings suggest a differential role for frontal and parietal WM in EM encoding and retrieval processes, while myelin integrity of the fornix may play a specific role in mediating EM encoding processes in SZ. PMID- 27479924 TI - Retrospective evaluation of the incidence and prognostic significance of spontaneous echocardiographic contrast in relation to cardiac disease and congestive heart failure in cats: 725 cases (2006-2011). AB - OBJECTIVE: To determine whether the presence of spontaneous echocardiographic contrast (SEC) in cats with cardiomyopathy is associated with increased mortality. To establish whether specific types of cardiomyopathy are more often associated with SEC in an attempt to provide a risk-stratification scheme for cats with increased risk of thromboembolic events. DESIGN: Retrospective study 2006-2011. SETTING: Tertiary referral and teaching hospital. ANIMALS: Seven hundred twenty-five client-owned cats undergoing echocardiographic evaluation. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, including age, breed, clinical signs, type of cardiovascular disease, presence of SEC, and survival time were recorded. Thyroxine, HCT, and blood pressure were recorded when available. Among cats diagnosed with cardiac abnormalities based on echocardiographic findings, those with SEC were at significantly increased risk of death as compared to those without SEC. Cats with dilated cardiomyopathy, unclassified cardiomyopathy, and hypertrophic cardiomyopathy were significantly more likely to have SEC compared to cats with other types of cardiac disease. CONCLUSIONS: Cats with cardiomyopathy and SEC have an increased risk of death compared to cats without SEC, although other previously identified factors such as the presence of congestive heart failure and increased left atrium to aorta ratio remain important determinants of mortality. Cats with hypertrophic cardiomyopathy, unclassified cardiomyopathy, and dilated cardiomyopathy may benefit from anticoagulant therapy due to the increased risk of SEC in these subpopulations. PMID- 27479925 TI - Evaluation of the ability of Acinetobacter baumannii to form biofilms on six different biomedical relevant surfaces. AB - The human opportunistic pathogen, Acinetobacter baumannii, has the propensity to form biofilms and frequently cause medical device-related infections in hospitals. However, the physio-chemical properties of medical surfaces, in addition to bacterial surface properties, will affect colonization and biofilm development. The objective of this study was to compare the ability of A. baumannii to form biofilms on six different materials common to the hospital environment: glass, porcelain, stainless steel, rubber, polycarbonate plastic and polypropylene plastic. Biofilms were developed on material coupons in a CDC biofilm reactor. Biofilms were visualized and quantified using fluorescent staining and imaged using confocal laser scanning microscopy (CLSM) and by direct viable cell counts. Image analysis of CLSM stacks indicated that the mean biomass values for biofilms grown on glass, rubber, porcelain, polypropylene, stainless steel and polycarbonate were 0.04, 0.26, 0.62, 1.00, 2.08 and 2.70 MUm(3) /MUm(2) respectively. Polycarbonate developed statistically more biofilm mass than glass, rubber, porcelain and polypropylene. Viable cell counts data were in agreement with the CLSM-derived data. In conclusion, polycarbonate was the most accommodating surface for A. baumannii ATCC 17978 to form biofilms while glass was least favourable. Alternatives to polycarbonate for use in medical and dental devices may need to be considered. SIGNIFICANCE AND IMPACT OF THE STUDY: In the hospital environment, Acinetobacter baumannii is one of the most persistent and difficult to control opportunistic pathogens. The persistence of A. baumannii is due, in part, to its ability to colonize surfaces and form biofilms. This study demonstrates that A. baumannii can form biofilms on a variety of different surfaces and develops substantial biofilms on polycarbonate - a thermoplastic material that is often used in the construction of medical devices. The findings highlight the need to further study the in vitro compatibility of medical materials that could be colonized by A. baumannii and allow it to persist in hospital settings. PMID- 27479927 TI - Factors that affect nurse practitioners' implementation of evidence-based practice. AB - BACKGROUND AND PURPOSE: Evidence-based practice (EBP) is a key recommendation to improve patient care outcomes. Factors that influence nurse practitioners' (NPs) ability to implement EBP in the clinical setting have not been fully explored. The study sought to explore NPs' practice, professional, and personal variables with self-reported ability to implement EBP. METHODS: The study was a correlational, cross-sectional design with a survey data collection methodology. A survey was mailed to 1200 randomly selected clinically practicing NPs, which included the Evidence-Based Education Questionnaire (EBEQ). A total of 480 surveys were returned, which represented a 40% response rate. Statistical analyses were performed to explore relationships between NPs' demographics and EBEQ scores. CONCLUSIONS: The DNP appears to have additive benefit for self perceived ability to implement EBP in the clinical setting when compared to the master's degree educated NP. NPs' gender, age, and number of hours worked weekly also correlated to EBEQ scores. NPs' practice settings, such as Magnet status designation and employment at an academic center also significantly correlated to EBEQ scores. Other practice setting variables, such as where the practice is located, did not significantly correlate to EBEQ scores. IMPLICATIONS FOR PRACTICE: The findings of this study provide foundational knowledge to enable increasing NPs' EBP in the clinical setting. PMID- 27479926 TI - "Nonfunctional" Adrenal Tumors and the Risk for Incident Diabetes and Cardiovascular Outcomes: A Cohort Study. AB - Background: Benign adrenal tumors are commonly discovered on abdominal imaging. Most are classified as nonfunctional and are considered to pose no health risk, but some are considered functional because they secrete hormones that increase risk for metabolic and cardiovascular diseases. Objective: To evaluate the hypothesis that nonfunctional adrenal tumors (NFATs) increase risk for cardiometabolic outcomes compared with absence of adrenal tumors. Design: Cohort study. Setting: Integrated hospital system. Participants: Participants with benign NFATs ("exposed"; n = 166) and those with no adrenal tumor ("unexposed"; n = 740), with at least 3 years of follow-up. Measurements: Medical records were reviewed from the time of abdominal imaging for development of incident outcomes (hypertension, composite diabetes [prediabetes or type 2 diabetes], hyperlipidemia, cardiovascular events, and chronic kidney disease) (mean, 7.7 years). Primary analyses evaluated independent associations between exposure status and incident outcomes by using adjusted generalized linear models. Secondary analyses evaluated relationships between NFATs and cortisol physiology. Results: Participants with NFATs had significantly higher risk for incident composite diabetes than those without adrenal tumors (30 of 110 [27.3%] vs. 72 of 615 [11.7%] participants; absolute risk, 15.6% [95% CI, 6.9% to 24.3%]; adjusted risk ratio, 1.87 [CI, 1.17 to 2.98]). No significant associations between NFATs and other outcomes were observed. Higher "normal" postdexamethasone cortisol levels (<=50 nmol/L) were associated with larger NFAT size and higher prevalence of type 2 diabetes. Limitation: Potential bias in the selection of participants and ascertainment of outcomes. Conclusion: Participants with NFATs had a significantly higher risk for diabetes than those without adrenal tumors. These results should prompt a reassessment of whether the classification of benign adrenal tumors as "nonfunctional" adequately reflects the continuum of hormone secretion and metabolic risk they may harbor. Primary Funding Source: National Institutes of Health and Doris Duke Charitable Foundation. PMID- 27479928 TI - Batrachochytrium dendrobatidis in Confiscated Telmatobius in Lima, Peru. AB - The Peruvian Andes are the home of 27 species of frogs of the genus Telmatobius, many of which are critically endangered. Illegal trade of adult frogs for purported medical properties likely represents the major threat facing these species. This activity, besides reducing their populations, may contribute to the dissemination of the fungus Batrachochytrium dendrobatidis (Bd), which causes chytridiomycosis, a disease posing a threat to many populations of amphibians. We screened frogs confiscated by the Administration of Forestry and Wildlife in Lima, Peru, for Bd. We used real-time PCR to diagnose Bd at the Laboratory of Wildlife, Faculty of Veterinary Medicine and Zootecnics, Universidad Peruana Cayetano Heredia, in Lima and Pisces Molecular Laboratory in Boulder, Colorado, US. Of 62 samples collected during this study, 60% (37) were PCR positive for Bd, confirming that illegal trade of amphibians can pose a risk for disseminating Bd. PMID- 27479929 TI - Prevalence of Anaplasma phagocytophilum in North Carolina Eastern Black Bears ( Ursus americanus ). AB - We detected Anaplasma phagocytophilum by DNA amplification in whole blood from free-ranging, hunter-killed American black bears ( Ursus americanus ) from the east coast of North Carolina, US. Molecular prevalence for Anaplasma phagocytophilum was 3% from 68 black bears. No DNA of other Anaplasma or Ehrlichia spp. was identified. PMID- 27479931 TI - Accurate calibration of a molecular beam time-of-flight mass spectrometer for on line analysis of high molecular weight species. AB - RATIONALE: Time-of-Flight (TOF) Mass Spectrometry is a powerful analytical technique, provided that an accurate calibration by standard molecules in the same m/z range of the analytes is performed. Calibration in a very large m/z range is a difficult task, particularly in studies focusing on the detection of high molecular weight clusters of different molecules or high molecular weight species. METHODS: External calibration is the most common procedure used for TOF mass spectrometric analysis in the gas phase and, generally, the only available standards are made up of mixtures of noble gases, covering a small mass range for calibration, up to m/z 136 (higher mass isotope of xenon). In this work, an accurate calibration of a Molecular Beam Time-of Flight Mass Spectrometer (MB TOFMS) is presented, based on the use of water clusters up to m/z 3000. RESULTS: The advantages of calibrating a MB-TOFMS with water clusters for the detection of analytes with masses above those of the traditional calibrants such as noble gases were quantitatively shown by statistical calculations. A comparison of the water cluster and noble gases calibration procedures in attributing the masses to a test mixture extending up to m/z 800 is also reported. In the case of the analysis of combustion products, another important feature of water cluster calibration was shown, that is the possibility of using them as "internal standard" directly formed from the combustion water, under suitable experimental conditions. CONCLUSIONS: The water clusters calibration of a MB-TOFMS gives rise to a ten-fold reduction in error compared to the traditional calibration with noble gases. The consequent improvement in mass accuracy in the calibration of a MB-TOFMS has important implications in various fields where detection of high molecular mass species is required. In combustion products analysis, it is also possible to obtain a new calibration spectrum before the acquisition of each spectrum, only modifying some operative conditions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27479930 TI - Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis. AB - Importance: The association between incretin-based drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, and acute pancreatitis is controversial. Objective: To determine whether the use of incretin-based drugs, compared with the use of 2 or more other oral antidiabetic drugs, is associated with an increased risk of acute pancreatitis. Design, Setting, and Participants: A large, international, multicenter, population-based cohort study was conducted using combined health records from 7 participating sites in Canada, the United States, and the United Kingdom. An overall cohort of 1 532 513 patients with type 2 diabetes initiating the use of antidiabetic drugs between January 1, 2007, and June 30, 2013, was included, with follow-up until June 30, 2014. Exposures: Current use of incretin-based drugs compared with current use of at least 2 oral antidiabetic drugs. Main Outcomes and Measures: Nested case-control analyses were conducted including hospitalized patients with acute pancreatitis matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and follow-up duration. Hazard ratios (HRs) and 95% CIs for hospitalized acute pancreatitis were estimated and compared current use of incretin-based drugs with current use of 2 or more oral antidiabetic drugs. Secondary analyses were performed to assess whether the risk varied by class of drug (DPP-4 inhibitors and GLP-1 agonists) or by duration of use. Site-specific HRs were pooled using random-effects models. Results: Of 1 532 513 patients included in the analysis, 781 567 (51.0%) were male; mean age was 56.6 years. During 3 464 659 person-years of follow-up, 5165 patients were hospitalized for acute pancreatitis (incidence rate, 1.49 per 1000 person-years). Compared with current use of 2 or more oral antidiabetic drugs, current use of incretin-based drugs was not associated with an increased risk of acute pancreatitis (pooled adjusted HR, 1.03; 95% CI, 0.87-1.22). Similarly, the risk did not vary by drug class (DPP-4 inhibitors: pooled adjusted HR, 1.09; 95% CI, 0.86-1.22; GLP-1 agonists: pooled adjusted HR, 1.04; 95% CI, 0.81-1.35) and there was no evidence of a duration-response association. Conclusions and Relevance: In this large population-based study, use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared with other oral antidiabetic drugs. PMID- 27479932 TI - A Flexible and Wearable Lithium-Oxygen Battery with Record Energy Density achieved by the Interlaced Architecture inspired by Bamboo Slips. AB - A flexible and wearable lithium-oxygen (air) battery inspired by Chinese bamboo slips is constructed. In this novel battery, cathodes and anodes are woven without an air diffusion layer and any outer packaging; besides, the woven structure allows oxygen to access the cathodes from both sides freely, endowing the battery with a record energy density of over 523 W h kg-1 . PMID- 27479933 TI - An Integrated Experimental and Computational Approach for Characterizing the Kinetics and Mechanism of Triadimefon Racemization. AB - Enantiomers of chiral molecules commonly exhibit differing pharmacokinetics and toxicities, which can introduce significant uncertainty when evaluating biological and environmental fates and potential risks to humans and the environment. However, racemization (the irreversible transformation of one enantiomer into the racemic mixture) and enantiomerization (the reversible conversion of one enantiomer into the other) are poorly understood. To better understand these processes, we investigated the chiral fungicide, triadimefon, which undergoes racemization in soils, water, and organic solvents. Nuclear magnetic resonance (NMR) and gas chromatography / mass spectrometry (GC/MS) techniques were used to measure the rates of enantiomerization and racemization, deuterium isotope effects, and activation energies for triadimefon in H2 O and D2 O. From these results we were able to determine that: 1) the alpha-carbonyl carbon of triadimefon is the reaction site; 2) cleavage of the C-H (C-D) bond is the rate-determining step; 3) the reaction is base-catalyzed; and 4) the reaction likely involves a symmetrical intermediate. The B3LYP/6-311 + G** level of theory was used to compute optimized geometries, harmonic vibrational frequencies, nature population analysis, and intrinsic reaction coordinates for triadimefon in water and three racemization pathways were hypothesized. This work provides an initial step in developing predictive, structure-based models that are needed to identify compounds of concern that may undergo racemization. Chirality 28:633 641, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27479934 TI - Fair is foul, and foul is fair: reframing neurodevelopmental disorders in the neurodevelopmental perspective. PMID- 27479935 TI - Brassinosteriod Insensitive 2 (BIN2) acts as a downstream effector of the Target of Rapamycin (TOR) signaling pathway to regulate photoautotrophic growth in Arabidopsis. AB - The components of the target of rapamycin (TOR) signaling pathway have been well characterized in heterotrophic organisms from yeast to humans. However, because of rapamycin insensitivity, embryonic lethality in tor null mutants and a lack of reliable ways of detecting TOR protein kinase in higher plants, the key players upstream and downstream of TOR remain largely unknown in plants. Using engineered rapamycin-sensitive Binding Protein 12-2 (BP12-2) plants, the present study showed that combined treatment with rapamycin and active-site TOR inhibitors (asTORis) results in synergistic inhibition of TOR activity and plant growth in Arabidopsis. Based on this system, we revealed that TOR signaling plays a crucial role in modulating the transition from heterotrophic to photoautotrophic growth in Arabidopsis. Ribosomal protein S6 kinase 2 (S6K2) was identified as a direct downstream target of TOR, and the growth of TOR-suppressed plants could be rescued by up-regulating S6K2. Systems, genetic, and biochemical analyses revealed that Brassinosteriod Insensitive 2 (BIN2) acts as a novel downstream effector of S6K2, and the phosphorylation of BIN2 depends on TOR-S6K2 signaling in Arabidopsis. By combining pharmacological with genetic and biochemical approaches, we determined that the TOR-S6K2-BIN2 signaling pathway plays important roles in regulating the photoautotrophic growth of Arabidopsis. PMID- 27479936 TI - Predicting changes in quality of life and emotional distress in Chinese patients with lung, gastric, and colon-rectal cancer diagnoses: the role of psychological resilience. AB - BACKGROUND: Patients with cancer often experience considerable emotional distress, which decreases their quality of life (QOL). Resilience is defined as the psychological characteristics that promote positive adaptation in the face of stress and adversity; however, the relationships among QOL, resilience, and emotional distress in patients with cancer, especially Chinese patients with cancer, are under-researched in the literature. METHODS: Quality of Life Questionnaire Core 30 items, Zung Self-Rating Anxiety Scale, and the Zung Self Rating Depression Scale were applied in this study. Univariate correlated analysis and multivariate logistic regression analysis were used to test the associations among resilience, emotional distress, and QOL with a sample of 276 participants. A Sobel test was conducted to determine whether the indirect effect of resilience was significant. RESULTS: The mean ratings of QOL (59.2), resilience (20.8), anxiety (43.1), and depression (47.7) were reported. The correlations between resilience and QOL in patients with lung cancer were significantly increased compared with patients with gastric or colorectal cancer (Spearman coefficient squares of 0.284, 0.189, and 0.227, respectively). The highest quartile of the resilience level was associated with a 64% (odds ratio = 0.36, 95% confidence interval = 0.17-0.75, P = .006), 70% (odds ratio = 0.30, 95% confidence interval = 0.14-0.63), and 90% (odds ratio = 0.10, 95% confidence interval = 0.04-0.26, P < .001) reduction in the risk of emotional distress compared with the lowest quartile. The Sobel test indicated a buffering effect of resilience that was significant for depression (Sobel value = 2.002, P = .045) but not anxiety (Sobel value = 1.336, P = .182). CONCLUSIONS: The present study suggests that psychological resilience is positively associated with QOL and may comprise a robust buffer between depression and QOL in Chinese patients with cancer. PMID- 27479937 TI - Solid Solution Photocatalyst with Spontaneous Polarization Exhibiting Low Recombination Toward Efficient CO2 Photoreduction. AB - Decreasing the recombination of photogenerated carriers is a major challenge for efficiently converting solar energy into chemical energy by photocatalysis. Here, we have demonstrated that growth of a polar GaN:ZnO solid solution single crystal along its polarization axis is beneficial to efficient separation of photogenerated carriers, owing to the periodic potential barriers and wells generated from the periodically positive and negative atom arrangements in crystal structure. Local charge imbalance caused by replacing Ga(3+) with Zn(2+) leads to a polarization vector in the {0 0 0 1} planes of GaN:ZnO solid solution, thus forming a 1 D electron transport path along [2 1? 1? 0] in the {0 0 0 1} planes of GaN:ZnO solid solution to decrease recombination. Shorting the hole transport distance by synthesizing porous nanoplates can further decrease recombination under the polarization field and improve the performance of polar photocatalyst in photoreduction of CO2 into CH4 . PMID- 27479938 TI - Time of day determines Arabidopsis transcriptome and growth dynamics under mild drought. AB - Drought stress is a major problem for agriculture worldwide, causing significant yield losses. Plants have developed highly flexible mechanisms to deal with drought, including organ- and developmental stage-specific responses. In young leaves, growth is repressed as an active mechanism to save water and energy, increasing the chances of survival but decreasing yield. Despite its importance, the molecular basis for this growth inhibition is largely unknown. Here, we present a novel approach to explore early molecular mechanisms controlling Arabidopsis leaf growth inhibition following mild drought. We found that growth and transcriptome responses to drought are highly dynamic. Growth was only repressed by drought during the day, and our evidence suggests that this may be due to gating by the circadian clock. Similarly, time of day strongly affected the extent, specificity, and in certain cases even direction of drought-induced changes in gene expression. These findings underscore the importance of taking into account diurnal patterns to understand stress responses, as only a small core of drought-responsive genes are affected by drought at all times of the day. Finally, we leveraged our high-resolution data to demonstrate that phenotypic and transcriptome responses can be matched to identify putative novel regulators of growth under mild drought. PMID- 27479939 TI - A new definition of dental sleep medicine. PMID- 27479940 TI - Fluorocarbon Oil Reinforced Triple Emulsion Drops. AB - Fluorocarbon oil reinforced triple emulsion drops are prepared to encapsulate a broad range of polar and non-polar cargoes in a single platform. In addition, it is demonstrated that the fluorocarbon oil within the emulsion drop acts as an effective diffusion barrier, as well as a non-adhesive layer, enabling highly efficient encapsulation and retention of small molecules and active biomolecules in microcapsules. PMID- 27479941 TI - Bone Morphogenetic Protein-7 Regulates Differentially the mRNA Expression of Bone Morphogenetic Proteins and Their Receptors in Rat Achilles and Patellar Tendon Cell Cultures. Yeh, L.-C. C., Tsai, A. D. and Lee, J. C. PMID- 27479942 TI - gamma-Secretase Dependent Nuclear Targeting of Dystroglycan. Daniel Leocadio, Andrew Mitchell, and Steve J. Winder. PMID- 27479944 TI - Joint partially linear model for longitudinal data with informative drop-outs. AB - In biomedical research, a steep rise or decline in longitudinal biomarkers may indicate latent disease progression, which may subsequently cause patients to drop out of the study. Ignoring the informative drop-out can cause bias in estimation of the longitudinal model. In such cases, a full parametric specification may be insufficient to capture the complicated pattern of the longitudinal biomarkers. For these types of longitudinal data with the issue of informative drop-outs, we develop a joint partially linear model, with an aim to find the trajectory of the longitudinal biomarker. Specifically, an arbitrary function of time along with linear fixed and random covariate effects is proposed in the model for the biomarker, while a flexible semiparametric transformation model is used to describe the drop-out mechanism. Advantages of this semiparametric joint modeling approach are the following: 1) it provides an easier interpretation, compared to standard nonparametric regression models, and 2) it is a natural way to control for common (observable and unobservable) prognostic factors that may affect both the longitudinal trajectory and the drop out process. We describe a sieve maximum likelihood estimation procedure using the EM algorithm, where the Akaike information criterion (AIC) and Bayesian information criterion (BIC) are considered to select the number of knots. We show that the proposed estimators achieve desirable asymptotic properties through empirical process theory. The proposed methods are evaluated by simulation studies and applied to prostate cancer data. PMID- 27479946 TI - Non-rigid registration and non-local principle component analysis to improve electron microscopy spectrum images. AB - Image registration and non-local Poisson principal component analysis (PCA) denoising improve the quality of characteristic x-ray (EDS) spectrum imaging of Ca-stabilized Nd2/3TiO3 acquired at atomic resolution in a scanning transmission electron microscope. Image registration based on the simultaneously acquired high angle annular dark field image significantly outperforms acquisition with a long pixel dwell time or drift correction using a reference image. Non-local Poisson PCA denoising reduces noise more strongly than conventional weighted PCA while preserving atomic structure more faithfully. The reliability of and optimal internal parameters for non-local Poisson PCA denoising of EDS spectrum images is assessed using tests on phantom data. PMID- 27479945 TI - Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels. AB - Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=-0.41, p=5.5*10-8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels. PMID- 27479947 TI - Physicians Experiencing Intense Emotions While Seeing Their Patients: What Happens? AB - OBJECTIVES: Physicians often deal with emotions arising from both patients and themselves; however, management of intense emotions when they arise in the presence of patients is overlooked in research. The aim of this study is to inspect physicians' intense emotions in this context, how these emotions are displayed, coping strategies used, adjustment behaviors, and the impact of the emotional reactions on the physician-patient relationship. METHODS: A total of 127 physicians completed a self-report survey, built from a literature review. Participants were recruited in 3 different ways: through a snowball sampling procedure, via institutional e-mails, and in person during service meetings. RESULTS: Fifty-two physicians (43.0%) reported experiencing intense emotions frequently. Although most physicians (88.6%) tried to control their reactions, several reported not controlling themselves. Coping strategies to deal with the emotion at the moment included behavioral and cognitive approaches. Only the type of reaction (but not the emotion's valence, duration, relative control, or coping strategies used) seemed to affect the physician-patient relationship. Choking up/crying, touching, smiling, and providing support were significantly associated with an immediate positive impact. Withdrawing from the situation, imposing, and defending oneself were associated with a negative impact. Some reactions also had an extended impact into future interactions. CONCLUSION: Experiencing intense emotions in the presence of patients was frequent among physicians, and the type of reaction affected the clinical relationship. Because many physicians reported experiencing long-lasting emotions, these may have important clinical implications for patients visiting physicians while these emotions last. Further studies are needed to clarify these results. PMID- 27479948 TI - Evidence-Based Workflows for Thyroid and Parathyroid Surgery. AB - A need exists to reduce care variations by standardizing the practice of thyroid and parathyroid surgery. During the course of a year, a task force developed algorithms representing decision points and workflows based on American Thyroid Association guidelines and three internal studies of surgical practices in the Northern and Southern California Regions of Kaiser Permanente conducted in collaboration with Health Information Technology Transformation & Analytics (HITTA). PMID- 27479949 TI - Recurrence of Epithelioid Hemangioendothelioma during Pregnancy: Case Report and Systematic Review. AB - INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is a family of blood vessel tumors originating in blood vessels, bone, brain, kidney, liver, and lung. EHE is more common in women, and chemotherapy, radiation, and surgery have brought few successes. CASE PRESENTATION: We present a case of a 28-year-old woman whose EHE recurred during pregnancy, suggesting hormonal involvement. We conducted a systematic review to provide analysis and interpretation of the potential significance of her disease recurring, with fatal outcome, during pregnancy. DISCUSSION: Very little research has explored the use of individual hormonal markers. Strongly positive expression of placenta growth factor (PlGF) and 17 beta estradiol receptors have been reported. Expression of PlGF is noteworthy in our case, in that our patient's disease quickly and dramatically flared in the 25th week of pregnancy, near the peak in maternal PlGF production. PlGF binds to vascular endothelial growth factor-1 (VEGF-1), and PlGF may accelerate VEGF induced angiogenesis. Taken together, these factors may explain our patient's EHE recurrence and rapid flare-up during pregnancy. Treatment of EHE with VEGF inhibition, potentially in combination with other antiangiogenic and tumor inhibiting therapies such as lenalidomide, thalidomide, sorafenib, and sunitinib, may also hold promise. PMID- 27479950 TI - Hyperparathyroidism of Renal Disease. AB - Renal hyperparathyroidism (rHPT) is a common complication of chronic kidney disease characterized by elevated parathyroid hormone levels secondary to derangements in the homeostasis of calcium, phosphate, and vitamin D. Patients with rHPT experience increased rates of cardiovascular problems and bone disease. The Kidney Disease: Improving Global Outcomes guidelines recommend that screening and management of rHPT be initiated for all patients with chronic kidney disease stage 3 (estimated glomerular filtration rate, < 60 mL/min/1.73 m(2)). Since the 1990s, improving medical management with vitamin D analogs, phosphate binders, and calcimimetic drugs has expanded the treatment options for patients with rHPT, but some patients still require a parathyroidectomy to mitigate the sequelae of this challenging disease. PMID- 27479953 TI - Switched Fuzzy-PD Control of Contact Forces in Robotic Microbiomanipulation. AB - Force sensing and control are of paramount importance in robotic micromanipulation. A contact force regulator capable of accurately applying mechanical stimuli to a live Drosophila larva could greatly facilitate mechanobiology research on Drosophila and may eventually lead to novel discoveries in mechanotransduction mechanisms of neuronal circuitries. In this paper, we present a novel contact force control scheme implemented in an automated Drosophila larvae micromanipulation system, featuring a switched fuzzy to proportional-differential (PD) controller and a noise-insensitive extended high gain observer (EHGO). The switched fuzzy-PD control law inherits the fast convergence of fuzzy control and overcomes its drawbacks such as large overshoot and steady-state oscillation. The noise-insensitive EHGO can reliably estimate system modeling errors and is robust to force measurement noises, which is advantageous over conventional high gain observers (sensitive to signal noises). Force control experiments show that, compared to a proportional-integral differential (PID) controller, this new force control scheme significantly enhances the system dynamic performance in terms of rising time, overshoot, and oscillation. The developed robotic system and the force control scheme will be applied to mechanical stimulation and fluorescence imaging of Drosophila larvae for identifying new mechanotransduction mechanisms. PMID- 27479951 TI - Safe and Effective Implementation of Telestroke in a US Community Hospital Setting. AB - CONTEXT: There is substantial hospital-level variation in use of tissue plasminogen activator (tPA) for treatment of acute ischemic stroke. Telestroke services can bring neurologic expertise to hospitals with fewer resources. OBJECTIVE: To determine whether implementation of a telestroke intervention in a large integrated health system would lead to increased tPA utilization and would change rates of hemorrhagic complications. DESIGN: A stepped-wedge cluster randomized trial of 11 community hospitals connected to 2 tertiary care centers via telestroke, implemented at each hospital incrementally during a 1-year period. We examined pre- and postimplementation data from July 2013 through January 2015. A 2-level mixed-effects logistic regression model accounted for the staggered rollout. MAIN OUTCOME MEASURES: Receipt of tPA. Secondary outcome was the rate of significant hemorrhagic complications. RESULTS: Of the 2657 patients, demographic and clinical characteristics were similar in pre- and postintervention cohorts. Utilization of tPA increased from 6.3% before the intervention to 10.9% after the intervention, without a significant change in complication rates. Postintervention patients were more likely to receive tPA than were preintervention patients (odds ratio = 2.0; 95% confidence interval = 1.2-3.4). Before implementation, 8 of the 10 community hospitals were significantly less likely to administer tPA than the highest-volume tertiary care center; however, after implementation, 9 of the 10 were at least as likely to administer tPA as the highest-volume center. CONCLUSION: Telestroke implementation in a regional integrated health system was safe and effective. Community hospitals' rates of tPA utilization quickly increased and were similar to the largest-volume tertiary care center. PMID- 27479952 TI - Diagnostic Prevalence of Ankylosing Spondylitis Using Computerized Health Care Data, 1996 to 2009: Underrecognition in a US Health Care Setting. AB - INTRODUCTION: Few studies have assessed the prevalence and features of axial spondyloarthritis (axSpA) and ankylosing spondylitis in diverse, population based, community settings. OBJECTIVES: We used computerized diagnoses to estimate the prevalence of axSpA and ankylosing spondylitis in Kaiser Permanente Northern California (KPNC). METHODS: We identified persons aged 18 years or older with 1 or more International Classification of Diseases, Ninth Revision (ICD-9) diagnosis Code 720.X (ankylosing spondylitis and other inflammatory spondylopathies) in clinical encounter data from 1996 through 2009 to estimate the prevalence of axSpA and ankylosing spondylitis. We reviewed medical records to confirm the diagnosis in a random sample and estimated the positive predictive value of computerized data to identify confirmed cases using various case definitions. RESULTS: In the computerized data, 5568 adults had diagnostic codes indicating axSpA. On the basis of our case-finding approach using a single physician diagnosis code for ICD-9 720.X, the point prevalence of these conditions, standardized to the 2000 US Census, was 2.26 per 1000 persons for axSpA and 1.07 per 1000 for ankylosing spondylitis. Less than half of suspected cases saw a rheumatologist. The most specific algorithm for confirmed ankylosing spondylitis required 2 or more computerized diagnoses assigned by a rheumatologist, with 67% sensitivity (95% confidence interval, 64%-69%) and 81% positive predictive value (95% confidence interval, 79%-83%). CONCLUSIONS: Observed prevalence in the KPNC population, compared with national estimates for axSpA and ankylosing spondylitis, suggests there is substantial underrecognition of these conditions in routine clinical practice. However, use of computerized data is able to identify true cases of ankylosing spondylitis, facilitating population-based research. PMID- 27479954 TI - Spectral Quantification for High-Resolution MR Spectroscopic Imaging With Spatiospectral Constraints. AB - OBJECTIVE: To obtain reliable spectral estimation from magnetic resonance spectroscopic imaging (MRSI) data. METHODS: The proposed method takes advantage of prior knowledge: 1) along the spectral dimension in the form of spectral bases, and 2) along the spatial dimensions in the form of spatial regularizations (e.g., smoothness or transform sparsity) and jointly estimates parameters from all the voxels. RESULTS: Simulation and in vivo studies have been performed to demonstrate the performance of the proposed method. A Cramer-Rao-bound-based analysis is also provided. CONCLUSION: Incorporation of both spatial and spectral constraints can significantly improve spectral quantification of MRSI data. SIGNIFICANCE: The proposed method is expected to be useful for various quantitative MRSI studies. PMID- 27479955 TI - Energy Dissipation in Ex Vivo Porcine Liver During Electrosurgery. AB - This paper explores energy dissipation in ex vivo liver tissue during radiofrequency current excitation with application in electrosurgery. Tissue surface temperature for monopolar electrode configuration is measured using infrared thermometry. The experimental results are fitted to a finite-element model for transient heat transfer taking into account energy storage and conduction in order to extract information about "apparent" specific heat, which encompasses storage and phase change. The average apparent specific heat determined for low temperatures is in agreement with published data. However, at temperatures approaching the boiling point of water, apparent specific heat increases by a factor of five, indicating that vaporization plays an important role in the energy dissipation through latent heat loss. PMID- 27479956 TI - Directional Kernel Density Estimation for Classification of Breast Tissue Spectra. AB - In Breast Conserving Therapy, surgeons measure the thickness of healthy tissue surrounding an excised tumor (surgical margin) via post-operative histological or visual assessment tests that, for lack of enough standardization and reliability, have recurrence rates in the order of 33%. Spectroscopic interrogation of these margins is possible during surgery, but algorithms are needed for parametric or dimension reduction processing. One methodology for tumor discrimination based on dimensionality reduction and nonparametric estimation-in particular, Directional Kernel Density Estimation-is proposed and tested on spectral image data from breast samples. Once a hyperspectral image of the tumor has been captured, a surgeon assists by establishing Regions of Interest where tissues are qualitatively differentiable. After proper normalization, Directional KDE is used to estimate the likelihood of every pixel in the image belonging to each specified tissue class. This information is enough to yield, in almost real time and with 98% accuracy, results that coincide with those provided by histological H&E validation performed after the surgery. PMID- 27479957 TI - Dynamic Electrical Source Imaging (DESI) of Seizures and Interictal Epileptic Discharges Without Ensemble Averaging. AB - We propose an algorithm for electrical source imaging of epileptic discharges that takes a data-driven approach to regularizing the dynamics of solutions. The method is based on linear system identification on short time segments, combined with a classical inverse solution approach. Whereas ensemble averaging of segments or epochs discards inter-segment variations by averaging across them, our approach explicitly models them. Indeed, it may even be possible to avoid the need for the time-consuming process of marking epochs containing discharges altogether. We demonstrate that this approach can produce both stable and accurate inverse solutions in experiments using simulated data and real data from epilepsy patients. In an illustrative example, we show that we are able to image propagation using this approach. We show that when applied to imaging seizure data, our approach reproducibly localized frequent seizure activity to within the margins of surgeries that led to patients' seizure freedom. The same approach could be used in the planning of epilepsy surgeries, as a way to localize potentially epileptogenic tissue that should be resected. PMID- 27479958 TI - Comparative Study of Hydrogen- and Deuterium-Induced Degradation of Ferroelectric (Pb,La)(Zr,Ti)O3 Capacitors Using Time-of-Flight Secondary Ion Measurement. AB - Ferroelectric (Pb,La)(Zr,Ti)O3 (PLZT) capacitors were fabricated with Pt, Al:ZnO (AZO), or Sn:In2O3 (ITO) top electrodes. Hydrogen- or deuterium-induced degradation was investigated for the three capacitors by annealing in a 3% H2/balance N2 or 3% D2/balance N2 ambient environment at 200 degrees C and 1 torr. The remnant polarization of all capacitors decreased after annealing in both H2 and D2 ambient after 45 min, and the remnant polarization of the Pt/PLZT/Pt capacitor significantly decreased after 45-min annealing compared with that of the AZO/PLZT/Pt and ITO/PLZT/Pt capacitors, even though the initial remnant polarization for the Pt/PLZT/Pt capacitor was larger. Time-of-flight secondary ion mass spectrometry showed slight differences in hydrogen content for the three different capacitors after H2 annealing. In contrast, the deuterium content of the Pt/PLZT/Pt and AZO/PLZT/Pt or ITO/PLZT/PT capacitors was significantly different after deuterium annealing. Deuterium depth profiles for the Pt/PLZT/Pt capacitor after annealing showed that deuterium conformally exists in the PLZT layer of the Pt/PLZT/Pt capacitor, and deuterium accumulation under the Pt bottom electrode was also observed. This result suggests that diffusion of deuterium in Pt was much higher than that in PLZT. AZO and ITO top electrodes could act as a hydrogen barrier layer for ferroelectric films. PMID- 27479960 TI - The Dependence of Dielectric and Ferroelectric Properties on Crystal Phase Structures of the Hydrogenized P(VDF-TrFE) Films With Different Thermal Processing. AB - Different thermal treatments were used to obtain various crystal structures of hydrogenated poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] films synthesized by an atom transfer radical chain transfer and controllable elimination reaction route. After analyzing the results of X-ray diffraction and differential scanning calorimeter, we found that these P(VDF-TrFE) samples possessed mixed crystal phases of alpha , beta , and gamma with various compositions depending on the TrFE content and processing temperature, and this characteristic was also demonstrated by the dielectric temperature curves. After polarizing the P(VDF-TrFE) samples at different electric fields, the effect of crystal structure on their ferroelectric and piezoelectric properties was illustrated and conformed by field emission scanning electronic microscopy morphology, which was found that large TrFE content and high temperature processing were responsible for the large remnant polarization. As a result, the annealed P(VDF-TrFE) 80/20 mol% possessed a high remnant polarization of [Formula: see text]/cm2, a large piezoelectric value ( d33 = -25 pC/N), and a favorable electromechanical coupling factor ( kt = 0.26 ), providing a reliable method for the structure design and sample fabrication of this kind of copolymer aimed at the applications in piezoelectric sensors and actuators. PMID- 27479961 TI - The Practicalities of Obtaining and Using Hydrophone Calibration Data to Derive Pressure Waveforms. AB - This paper considers the means by which calibration data are used to convert hydrophone output voltage into pressure. Hydrophone frequency responses are complex-valued quantities, and only by correcting for the magnitude and phase variations, is it possible to accurately recover the original pressure waveform. The limitations of current hydrophone calibration techniques are discussed, and a new method of obtaining hydrophone phase data is presented. Magnitude and phase information is measured via both coarse increment (1 MHz) and fine increment (50 kHz) calibration techniques for three exemplar hydrophones (0.5 mm needle, 0.2 mm needle, and 0.4 mm membrane). Frequently hydrophone calibration data are available at frequency increments that do not match that required by the deconvolution process. Therefore, a variety of methods to interpolate the calibrated system response to obtain correctly spaced data are considered, and two spline interpolation methods are found to offer best performance. Data preconditioning and filtering to address artifacts above and below the 1 to 40 MHz bandwidth of the coarse frequency increment calibration are also investigated, and a simple procedure for selecting an appropriate low-pass filter is presented. The revised calibration data are used to deconvolve the hydrophone frequency response for experimentally derived waveforms. Standard ultrasonic output parameters (such as peak compressional and peak rarefactional pressures, pulse intensity integral, and temporal peak and pulse average acoustic intensities) are calculated from these waveforms. Although the three hydrophones used in this paper are of different types and have a range of active element sizes, all output parameters derived from the deconvolved waveforms have <5% variation from their respective population means (with the majority being within <2%). PMID- 27479962 TI - Small Rodent Cardiac Phantom for Preclinical Ultrasound Imaging. AB - Imaging phantoms play a valuable role in the quality control and quality assurance of medical imaging systems. However, for use in the relatively new field of small-animal preclinical imaging, very few have been described in the literature, and even less or none at all are available commercially. Yet, preclinical small animal phantoms offer the possibility of reducing the need for live animals for test and measurement purposes. Human scale cardiac phantoms, both reported in the literature and available commercially, are typically complex devices. Their designs include numerous flow control valves, pumps, and servo motors. These devices are coupled to tissue mimicking materials (TMMs) shaped to replicate the form of cardiac chambers and valves. They are then operated in such a way as to cause the replica TMM heart to move in a lifelike manner. This paper describes the design and construction of a small rodent preclinical cardiac phantom, which is both of a simple design and construction. Using only readily available materials and components, it can be manufactured without the use of workshop facilities, using only hand-tools. Drawings and pictures of the design are presented along with images of the phantom in operation, using a high frequency preclinical ultrasound scanner. PMID- 27479963 TI - Neutro-Connectedness Cut. AB - Interactive image segmentation is a challenging task and receives increasing attention recently; however, two major drawbacks exist in interactive segmentation approaches. First, the segmentation performance of region of interest (ROI)-based methods is sensitive to the initial ROI: different ROIs may produce results with great difference. Second, most seed-based methods need intense interactions, and are not applicable in many cases. In this paper, we generalize the neutro-connectedness (NC) to be independent of top-down priors of objects and to model image topology with indeterminacy measurement on image regions, propose a novel method for determining object and background regions, which is applied to exclude isolated background regions and enforce label consistency, and put forward a hybrid interactive segmentation method, NC Cut (NC Cut), which can overcome the above two problems by utilizing both pixelwise appearance information and region-based NC properties. We evaluate the proposed NC-Cut by employing two image data sets (265 images), and demonstrate that the proposed approach outperforms the state-of-the-art interactive image segmentation methods (Grabcut, MILCut, One-Cut, MGCmaxsum, and pPBC). PMID- 27479964 TI - Confidence Preserving Machine for Facial Action Unit Detection. AB - Facial action unit (AU) detection from video has been a long-standing problem in the automated facial expression analysis. While progress has been made, accurate detection of facial AUs remains challenging due to ubiquitous sources of errors, such as inter-personal variability, pose, and low-intensity AUs. In this paper, we refer to samples causing such errors as hard samples, and the remaining as easy samples. To address learning with the hard samples, we propose the confidence preserving machine (CPM), a novel two-stage learning framework that combines multiple classifiers following an "easy-to-hard" strategy. During the training stage, CPM learns two confident classifiers. Each classifier focuses on separating easy samples of one class from all else, and thus preserves confidence on predicting each class. During the test stage, the confident classifiers provide "virtual labels" for easy test samples. Given the virtual labels, we propose a quasi-semi-supervised (QSS) learning strategy to learn a person specific classifier. The QSS strategy employs a spatio-temporal smoothness that encourages similar predictions for samples within a spatio-temporal neighborhood. In addition, to further improve detection performance, we introduce two CPM extensions: iterative CPM that iteratively augments training samples to train the confident classifiers, and kernel CPM that kernelizes the original CPM model to promote nonlinearity. Experiments on four spontaneous data sets GFT, BP4D, DISFA, and RU-FACS illustrate the benefits of the proposed CPM models over baseline methods and the state-of-the-art semi-supervised learning and transfer learning methods. PMID- 27479965 TI - Detecting Salient Objects via Color and Texture Compactness Hypotheses. AB - In recent years, the object-level saliency detection has attracted much research attention, due to its usefulness in many high-level tasks. Existing methods are mostly based on the contrast hypothesis, which regards the regions with high contrast in a certain context as salient objects. Although the contrast hypothesis is effective in many scenarios, it cannot handle some difficult cases. As a remedy to address the weakness of contrast hypothesis, we propose a novel compactness hypothesis, which assumes salient regions are more compact than background from the perspectives of both color layout and texture layout. Based on the compactness hypotheses, we implement an effective object-level saliency detection method. In the proposed method, we first construct a weak saliency map based on the compact hypotheses, then collect samples from the weak saliency map to train a dedicated classifier. This classifier is applied on each individual pixel of the input image to produce a confidence score. Finally, the confidence scores are used to form a saliency map. This process is carried out at different scales, and the corresponding results are integrated into the formation of the final saliency map. The proposed approach is evaluated on eight benchmark data sets, where it delivers the competitive performance compared with the state-of the-art methods. PMID- 27479966 TI - Sparse Representation With Spatio-Temporal Online Dictionary Learning for Promising Video Coding. AB - Classical dictionary learning methods for video coding suffer from high computational complexity and interfered coding efficiency by disregarding its underlying distribution. This paper proposes a spatio-temporal online dictionary learning (STOL) algorithm to speed up the convergence rate of dictionary learning with a guarantee of approximation error. The proposed algorithm incorporates stochastic gradient descents to form a dictionary of pairs of 3D low-frequency and high-frequency spatio-temporal volumes. In each iteration of the learning process, it randomly selects one sample volume and updates the atoms of dictionary by minimizing the expected cost, rather than optimizes empirical cost over the complete training data, such as batch learning methods, e.g., K-SVD. Since the selected volumes are supposed to be independent identically distributed samples from the underlying distribution, decomposition coefficients attained from the trained dictionary are desirable for sparse representation. Theoretically, it is proved that the proposed STOL could achieve better approximation for sparse representation than K-SVD and maintain both structured sparsity and hierarchical sparsity. It is shown to outperform batch gradient descent methods (K-SVD) in the sense of convergence speed and computational complexity, and its upper bound for prediction error is asymptotically equal to the training error. With lower computational complexity, extensive experiments validate that the STOL-based coding scheme achieves performance improvements than H.264/AVC or High Efficiency Video Coding as well as existing super-resolution based methods in rate-distortion performance and visual quality. PMID- 27479967 TI - Towards Kilo-Hertz 6-DoF Visual Tracking Using an Egocentric Cluster of Rolling Shutter Cameras. AB - To maintain a reliable registration of the virtual world with the real world, augmented reality (AR) applications require highly accurate, low-latency tracking of the device. In this paper, we propose a novel method for performing this fast 6-DOF head pose tracking using a cluster of rolling shutter cameras. The key idea is that a rolling shutter camera works by capturing the rows of an image in rapid succession, essentially acting as a high-frequency 1D image sensor. By integrating multiple rolling shutter cameras on the AR device, our tracker is able to perform 6-DOF markerless tracking in a static indoor environment with minimal latency. Compared to state-of-the-art tracking systems, this tracking approach performs at significantly higher frequency, and it works in generalized environments. To demonstrate the feasibility of our system, we present thorough evaluations on synthetically generated data with tracking frequencies reaching 56.7 kHz. We further validate the method's accuracy on real-world images collected from a prototype of our tracking system against ground truth data using standard commodity GoPro cameras capturing at 120 Hz frame rate. PMID- 27479968 TI - Spatio-Temporal Point Path Analysis and Optimization of a Galvanoscopic Scanning Laser Projector. AB - Galvanoscopic scanning laser projectors are powerful vector graphic devices offering a tremendous local brightness advantage compared to standard video projection systems. However, such devices have inherent problems, such as temporal flicker and spatially inaccurate rendering. We propose a method to generate an accurate point-based projection with such devices. To overcome the mentioned problems, we present a camera-based method to automatically analyze the laser projector's motion behavior. With this information, a model database is generated that is used to optimize the scanning path of projected point sequences. The optimization considers the overall path length, its angular shape, acceleration behavior, and the spatio-temporal point neighborhood. The method minimizes perceived visual flickering while guaranteeing an accurate spatial point projection at the same time. Comparisons and timing measurements prove the effectiveness of our method. An informal user evaluation shows substantial visual quality improvement as well. PMID- 27479969 TI - A Real-Time Augmented Reality System to See-Through Cars. AB - One of the most hazardous driving scenario is the overtaking of a slower vehicle, indeed, in this case the front vehicle (being overtaken) can occlude an important part of the field of view of the rear vehicle's driver. This lack of visibility is the most probable cause of accidents in this context. Recent research works tend to prove that augmented reality applied to assisted driving can significantly reduce the risk of accidents. In this paper, we present a real-time marker-less system to see through cars. For this purpose, two cars are equipped with cameras and an appropriate wireless communication system. The stereo vision system mounted on the front car allows to create a sparse 3D map of the environment where the rear car can be localized. Using this inter-car pose estimation, a synthetic image is generated to overcome the occlusion and to create a seamless see-through effect which preserves the structure of the scene. PMID- 27479970 TI - Do You See What I See? The Effect of Gaze Tracking on Task Space Remote Collaboration. AB - We present results from research exploring the effect of sharing virtual gaze and pointing cues in a wearable interface for remote collaboration. A local worker wears a Head-mounted Camera, Eye-tracking camera and a Head-Mounted Display and shares video and virtual gaze information with a remote helper. The remote helper can provide feedback using a virtual pointer on the live video view. The prototype system was evaluated with a formal user study. Comparing four conditions, (1) NONE (no cue), (2) POINTER, (3) EYE-TRACKER and (4) BOTH (both pointer and eye-tracker cues), we observed that the task completion performance was best in the BOTH condition with a significant difference of POINTER and EYETRACKER individually. The use of eye-tracking and a pointer also significantly improved the co-presence felt between the users. We discuss the implications of this research and the limitations of the developed system that could be improved in further work. PMID- 27479971 TI - Gaussian Light Field: Estimation of Viewpoint-Dependent Blur for Optical See Through Head-Mounted Displays. AB - We propose a method to calibrate viewpoint-dependent, channel-wise image blur of near-eye displays, especially of Optical See-Through Head-Mounted Displays (OST HMDs). Imperfections in HMD optics cause channel-wise image shift and blur that degrade the image quality of the display at a user's viewpoint. If we can estimate such characteristics perfectly, we could mitigate the effect by applying correction techniques from the computational photography in computer vision as analogous to cameras. Unfortunately, directly applying existing calibration techniques of cameras to OST-HMDs is not a straightforward task. Unlike ordinary imaging systems, image blur in OST-HMDs is viewpoint-dependent, i.e., the optical characteristic of a display dynamically changes depending on the current viewpoint of the user. This constraint makes the problem challenging since we must measure image blur of an HMD, ideally, over the entire 3D eyebox in which a user can see an image. To overcome this problem, we model the viewpoint-dependent blur as a Gaussian Light Field (GLF) that stores spatial information of the display screen as a (4D) light field with depth information and the blur as point spread functions in the form of Gaussian kernels, respectively. We first describe both our GLF model and a calibration procedure to learn a GLF for a given OST HMD. We then apply our calibration method to two HMDs that use different optics: a cubic prism or holographic gratings. The results show that our method achieves significantly better accuracy in Point-Spread Function (PSF) estimations with an accuracy about 2 to 7 dB in Peak SNR. PMID- 27479972 TI - Retargeting Human-Object Interaction to Virtual Avatars. AB - In augmented reality (AR) applications, a virtual avatar serves as a useful medium to represent a human in a different place. This paper deals with the problem of retargeting a human motion to an avatar. In particular, we present a novel method that retargets a human motion with respect to an object to that of an avatar with respect to a different object of a similar shape. To achieve this, we developed a spatial map that defines the correspondences between any points in the 3D spaces around the respective objects. The key advantage of the spatial map is that it identifies the desired locations of the avatar's body parts for any input motion of a human. Once the spatial map is created offline, the motion retargeting can be performed in real-time. The retargeted motion preserves important features of the original motion such as the human pose and the spatial relation with the object. We report the results of a number of experiments that demonstrate the effectiveness of the proposed method. PMID- 27479973 TI - Real-Time Radiometric Compensation for Optical See-Through Head-Mounted Displays. AB - Optical see-through head-mounted displays are currently seeing a transition out of research labs towards the consumer-oriented market. However, whilst availability has improved and prices have decreased, the technology has not matured much. Most commercially available optical see-through head mounted displays follow a similar principle and use an optical combiner blending the physical environment with digital information. This approach yields problems as the colors for the overlaid digital information can not be correctly reproduced. The perceived pixel colors are always a result of the displayed pixel color and the color of the current physical environment seen through the head-mounted display. In this paper we present an initial approach for mitigating the effect of color-blending in optical see-through head-mounted displays by introducing a real-time radiometric compensation. Our approach is based on a novel prototype for an optical see-through head-mounted display that allows the capture of the current environment as seen by the user's eye. We present three different algorithms using this prototype to compensate color blending in real-time and with pixel-accuracy. We demonstrate the benefits and performance as well as the results of a user study. We see application for all common Augmented Reality scenarios but also for other areas such as Diminished Reality or supporting color blind people. PMID- 27479974 TI - A Robotic Exoskeleton for Treatment of Crouch Gait in Children With Cerebral Palsy: Design and Initial Application. AB - Crouch gait, a pathological pattern of walking characterized by excessive knee flexion, is one of the most common gait disorders observed in children with cerebral palsy (CP). Effective treatment of crouch during childhood is critical to maintain mobility into adulthood, yet current interventions do not adequately alleviate crouch in most individuals. Powered exoskeletons provide an untapped opportunity for intervention. The multiple contributors to crouch, including spasticity, contracture, muscle weakness, and poor motor control make design and control of such devices challenging in this population. To our knowledge, no evidence exists regarding the feasibility or efficacy of utilizing motorized assistance to alleviate knee flexion in crouch gait. Here, we present the design of and first results from a powered exoskeleton for extension assistance as a treatment for crouch gait in children with CP. Our exoskeleton, based on the architecture of a knee-ankle-foot orthosis, is lightweight (3.2 kg) and modular. On board sensors enable knee extension assistance to be provided during distinct phases of the gait cycle. We tested our device on one six-year-old male participant with spastic diplegia from CP. Our results show that the powered exoskeleton improved knee extension during stance by 18.1 degrees while total knee range of motion improved 21.0 degrees . Importantly, we observed no significant decrease in knee extensor muscle activity, indicating the user did not rely solely on the exoskeleton to extend the limb. These results establish the initial feasibility of robotic exoskeletons for treatment of crouch and provide impetus for continued investigation of these devices with the aim of deployment for long term gait training in this population. PMID- 27479975 TI - On Modeling Information Spreading in Bacterial Nano-Networks Based on Plasmid Conjugation. AB - In the last years, nano-communications have attracted much attention as a newly promising research field. In particular, molecular communications, which exploit molecular nodes, are a powerful tool to implement communication functionalities in environments where the use of electromagnetic waves becomes critical, e.g., in the human body. In molecular communications, molecules such as proteins, DNA and RNA sequences are used to carry information. To this aim a novel approach relies on the use of genetically modified bacteria to transport enhanced DNA strands, called plasmids, where information can be encoded. Information transfer is thus based on bacteria motility, i.e., self-propelled motion, which under appropriate circumstances is exhibited by certain bacteria. It has been observed that bacteria motility presents many similarities with opportunistic forwarding. Currently the few studies on opportunistic communications among bacteria are based on simulations only. In this paper we propose an analytical model to characterize information spreading in bacterial nano-networks. To this purpose, an epidemic approach, similar to those used to model Delay Tolerant Networks (DTNs), is employed. We also derive two mathematical models which slightly differ. The first describes bacterial nano-networks where a single plasmid is disseminated according to an epidemic approach; the second, takes into account more complex mechanisms where multiple plasmids are disseminated as in realistic bacterial nano-networks. Numerical results being obtained are finally shown and discussed. PMID- 27479976 TI - Tissue P Systems With Channel States Working in the Flat Maximally Parallel Way. AB - Tissue P systems with channel states are a class of bio-inspired parallel computational models, where rules are used in a sequential manner (on each channel, at most one rule can be used at each step). In this work, tissue P systems with channel states working in a flat maximally parallel way are considered, where at each step, on each channel, a maximal set of applicable rules that pass from a given state to a unique next state, is chosen and each rule in the set is applied once. The computational power of such P systems is investigated. Specifically, it is proved that tissue P systems with channel states and antiport rules of length two are able to compute Parikh sets of finite languages, and such P systems with one cell and noncooperative symport rules can compute at least all Parikh sets of matrix languages. Some Turing universality results are also provided. Moreover, the NP-complete problem SAT is solved by tissue P systems with channel states, cell division and noncooperative symport rules working in the flat maximally parallel way; nevertheless, if channel states are not used, then such P systems working in the flat maximally parallel way can solve only tractable problems. These results show that channel states provide a frontier of tractability between efficiency and non-efficiency in the framework of tissue P systems with cell division (assuming P ? NP ). PMID- 27479977 TI - Neural Categorization of Vibrotactile Frequency in Flutter and Vibration Stimulations: An fMRI Study. AB - As the use of wearable haptic devices with vibrating alert features is commonplace, an understanding of the perceptual categorization of vibrotactile frequencies has become important. This understanding can be substantially enhanced by unveiling how neural activity represents vibrotactile frequency information. Using functional magnetic resonance imaging (fMRI), this study investigated categorical clustering patterns of the frequency-dependent neural activity evoked by vibrotactile stimuli with gradually changing frequencies from 20 to 200 Hz. First, a searchlight multi-voxel pattern analysis (MVPA) was used to find brain regions exhibiting neural activities associated with frequency information. We found that the contralateral postcentral gyrus (S1) and the supramarginal gyrus (SMG) carried frequency-dependent information. Next, we applied multidimensional scaling (MDS) to find low-dimensional neural representations of different frequencies obtained from the multi-voxel activity patterns within these regions. The clustering analysis on the MDS results showed that neural activity patterns of 20-100 Hz and 120-200 Hz were divided into two distinct groups. Interestingly, this neural grouping conformed to the perceptual frequency categories found in the previous behavioral studies. Our findings therefore suggest that neural activity patterns in the somatosensory cortical regions may provide a neural basis for the perceptual categorization of vibrotactile frequency. PMID- 27479978 TI - Lagrange Programming Neural Network for Nondifferentiable Optimization Problems in Sparse Approximation. AB - The major limitation of the Lagrange programming neural network (LPNN) approach is that the objective function and the constraints should be twice differentiable. Since sparse approximation involves nondifferentiable functions, the original LPNN approach is not suitable for recovering sparse signals. This paper proposes a new formulation of the LPNN approach based on the concept of the locally competitive algorithm (LCA). Unlike the classical LCA approach which is able to solve unconstrained optimization problems only, the proposed LPNN approach is able to solve the constrained optimization problems. Two problems in sparse approximation are considered. They are basis pursuit (BP) and constrained BP denoise (CBPDN). We propose two LPNN models, namely, BP-LPNN and CBPDN-LPNN, to solve these two problems. For these two models, we show that the equilibrium points of the models are the optimal solutions of the two problems, and that the optimal solutions of the two problems are the equilibrium points of the two models. Besides, the equilibrium points are stable. Simulations are carried out to verify the effectiveness of these two LPNN models. PMID- 27479979 TI - A Binaural Neuromorphic Auditory Sensor for FPGA: A Spike Signal Processing Approach. AB - This paper presents a new architecture, design flow, and field-programmable gate array (FPGA) implementation analysis of a neuromorphic binaural auditory sensor, designed completely in the spike domain. Unlike digital cochleae that decompose audio signals using classical digital signal processing techniques, the model presented in this paper processes information directly encoded as spikes using pulse frequency modulation and provides a set of frequency-decomposed audio information using an address-event representation interface. In this case, a systematic approach to design led to a generic process for building, tuning, and implementing audio frequency decomposers with different features, facilitating synthesis with custom features. This allows researchers to implement their own parameterized neuromorphic auditory systems in a low-cost FPGA in order to study the audio processing and learning activity that takes place in the brain. In this paper, we present a 64-channel binaural neuromorphic auditory system implemented in a Virtex-5 FPGA using a commercial development board. The system was excited with a diverse set of audio signals in order to analyze its response and characterize its features. The neuromorphic auditory system response times and frequencies are reported. The experimental results of the proposed system implementation with 64-channel stereo are: a frequency range between 9.6 Hz and 14.6 kHz (adjustable), a maximum output event rate of 2.19 Mevents/s, a power consumption of 29.7 mW, the slices requirements of 11141, and a system clock frequency of 27 MHz. PMID- 27479980 TI - Toward a Wirelessly Powered On-Lens Intraocular Pressure Monitoring System. AB - This paper presents a wireless on-lens intraocular pressure monitoring system, comprising a capacitance-to-digital converter and a wirelessly powered radio frequency identification (RFID)-compatible communication system, for sensor control and data communication. The capacitive sensor was embedded on a soft contact lens of 200 MUm thickness using commercially available biocompatible lens material, to improve compliance and reduce user discomfort. The sensor chip was shown to achieve effective number of bits greater than 10 over a capacitance range up to 50 pF while consuming only 64-MUW power. The on-lens capacitive sensor could detect dielectric variation caused by changes in water content from a distance of 2 cm by using incident power from an RFID reader at 20 dBm. The maximum detectable distance was 11 cm with 30-dBm incident RF power. The rise in eye tissue temperature under 30-dBm RF exposure over an interval of 1 s was simulated and found to be less than 0.01 degrees C. PMID- 27479981 TI - Characteristic Ratio-Independent Arterial Stiffness-Based Blood Pressure Estimation. AB - Noninvasive blood pressure (BP) measurement is an important tool for managing hypertension and cardiovascular disease. However, automated noninvasive BP measurement devices, which are usually based on the oscillometric method, do not always provide accurate estimation of BP. It has been found that change in arterial stiffness (AS) is an underlying mechanism of disagreement between an oscillometric BP monitor and a sphygmomanometer. This problem is addressed by incorporating parameters related to AS in the algorithm for BP measurement. Pulse transit time (PTT) is first used to estimate AS parameters, which are fixed into a model of the oscillometric envelope. This model can then be used to perform curve fitting to the measured signal using only four parameters: systolic BP, diastolic BP, mean BP, and lumen area at zero transmural pressure. The proposed technique is independent of the experimentally determined characteristic ratios that are commonly used in existing oscillometric methods. The accuracy of the proposed technique was evaluated by comparing with the same model without incorporation of AS, and with reference BP device measurements. The new method achieved standard deviation of error less than 8 mmHg and mean error less than 5 mmHg. The results show consistency with ANSI/AAMI SP-10 standard for noninvasive BP measurement techniques. PMID- 27479982 TI - Segmentation, Splitting, and Classification of Overlapping Bacteria in Microscope Images for Automatic Bacterial Vaginosis Diagnosis. AB - Quantitative analysis of bacterial morphotypes in the microscope images plays a vital role in diagnosis of bacterial vaginosis (BV) based on the Nugent score criterion. However, there are two main challenges for this task: 1) It is quite difficult to identify the bacterial regions due to various appearance, faint boundaries, heterogeneous shapes, low contrast with the background, and small bacteria sizes with regards to the image. 2) There are numerous bacteria overlapping each other, which hinder us to conduct accurate analysis on individual bacterium. To overcome these challenges, we propose an automatic method in this paper to diagnose BV by quantitative analysis of bacterial morphotypes, which consists of a three-step approach, i.e., bacteria regions segmentation, overlapping bacteria splitting, and bacterial morphotypes classification. Specifically, we first segment the bacteria regions via saliency cut, which simultaneously evaluates the global contrast and spatial weighted coherence. And then Markov random field model is applied for high-quality unsupervised segmentation of small object. We then decompose overlapping bacteria clumps into markers, and associate a pixel with markers to identify evidence for eventual individual bacterium splitting. Next, we extract morphotype features from each bacterium to learn the descriptors and to characterize the types of bacteria using an Adaptive Boosting machine learning framework. Finally, BV diagnosis is implemented based on the Nugent score criterion. Experiments demonstrate that our proposed method achieves high accuracy and efficiency in computation for BV diagnosis. PMID- 27479983 TI - A Novel Riemannian Metric Based on Riemannian Structure and Scaling Information for Fixed Low-Rank Matrix Completion. AB - Riemannian optimization has been widely used to deal with the fixed low-rank matrix completion problem, and Riemannian metric is a crucial factor of obtaining the search direction in Riemannian optimization. This paper proposes a new Riemannian metric via simultaneously considering the Riemannian geometry structure and the scaling information, which is smoothly varying and invariant along the equivalence class. The proposed metric can make a tradeoff between the Riemannian geometry structure and the scaling information effectively. Essentially, it can be viewed as a generalization of some existing metrics. Based on the proposed Riemanian metric, we also design a Riemannian nonlinear conjugate gradient algorithm, which can efficiently solve the fixed low-rank matrix completion problem. By experimenting on the fixed low-rank matrix completion, collaborative filtering, and image and video recovery, it illustrates that the proposed method is superior to the state-of-the-art methods on the convergence efficiency and the numerical performance. PMID- 27479984 TI - Active Multitask Learning With Trace Norm Regularization Based on Excess Risk. AB - This paper addresses the problem of active learning on multiple tasks, where labeled data are expensive to obtain for each individual task but the learning problems share some commonalities across multiple related tasks. To leverage the benefits of jointly learning from multiple related tasks and making active queries, we propose a novel active multitask learning approach based on trace norm regularized least squares. The basic idea is to induce an optimal classifier which has the lowest risk and at the same time which is closest to the true hypothesis. Toward this aim, we devise a new active selection criterion that takes into account not only the risk but also the excess risk, which measures the distance to the true hypothesis. Based on this criterion, our proposed algorithm actively selects the instance to query for its label based on the combination of the two risks. Experiments on both synthetic and real-world datasets show that our proposed algorithm provides superior performance as compared to other state of-the-art active learning methods. PMID- 27479985 TI - Consensus for Linear Multiagent Systems With Time-Varying Delays: A Frequency Domain Perspective. AB - This paper investigates the consensus problem for multiagent systems with time varying delays. The bounded delays can be arbitrarily fast time-varying. The communication topology is assumed to be undirected and fixed. With general linear dynamics under average state feedback protocols, the consensus problem is then transformed into the robust control problem. Further, sufficient frequency domain criteria are established in terms of small gain theorem by analyzing the delay dependent gains for both continuous-time and discrete-time systems. The controller synthesis problems can be solved by applying the frequency domain design methods. Numerical examples are demonstrated to verify the effectiveness of the proposed approaches. PMID- 27479986 TI - A Multimedia E-Book-A Story of Health: Filling a Gap in Environmental Health Literacy for Health Professionals. PMID- 27479988 TI - The Exposome: Embracing the Complexity for Discovery in Environmental Health. PMID- 27479989 TI - Erratum: "New Link in the Food Chain? Marine Plastic Pollution and Seafood Safety". PMID- 27479987 TI - Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement. PMID- 27479990 TI - EHP Highlights of the Past Year. PMID- 27479991 TI - India Leads the Way: A Health-Centered Strategy for Air Pollution. PMID- 27479992 TI - Lasting Impact of an Ephemeral Organ: The Role of the Placenta in Fetal Programming. PMID- 27479993 TI - Perfluoropropane (C3F8) injection for Descemet's membrane detachment in cataract surgery. AB - BACKGROUND: Descemet's membrane (DM) detachment is an important cause of surgery related corneal edema that may lead to corneal decompensations and marked reduction in visual acuity if not identified and treated promptly. We prescent a case of postoperative Descemet's membrane detachment that occurred after complicated manual small incisional cataract surgery. Descemetopexy in post cataract surgery descemet's membrane detachment has not yet been reported in Nepal. CASE: A 45 year old female underwent manual small incision cataract surgery of the right eye. Intraoperatively, there was descemet's membrane detachment so: anterior chamber tamponade with air was done. She was discharged with a visual acuity of 6/24. But on the eighth postoperative day, her visual acuity had decreased to 1/60 in right eye with corneal edema, detached descemet's membrane and descemet's folds. Hence was re-admitted for repositioning of descemet's membrane with C3F8 (14% gas mixed with air). The procedure successfully reattached the descemet's membrane. Corneal edema regressed and the gas bubble resolved after 15th day of the surgery. Patient's visual right acuity was 6/36 in right eye and the intraocular pressure was 12mmhg. CONCLUSION: DM detachment should not be taken lightly because of the potential for grave visual outcome. One needs to examine carefully, as the signs of DM detachment can be subtle and may be masked by corneal edema. During the past few years, intracameral injection with perfluoropropane (C3F8) gas has also gained increasing acceptance as an efficient and effective treatment option for Descemet's membrane detachments. PMID- 27479994 TI - Reply. PMID- 27479995 TI - Reply. PMID- 27479996 TI - Genomic research, publics and experts in Latin America: Nation, race and body. AB - The articles in this issue highlight contributions that studies of Latin America can make to wider debates about the effects of genomic science on public ideas about race and nation. We argue that current ideas about the power of genomics to transfigure and transform existing ways of thinking about human diversity are often overstated. If a range of social contexts are examined, the effects are uneven. Our data show that genomic knowledge can unsettle and reinforce ideas of nation and race; it can be both banal and highly politicized. In this introduction, we outline concepts of genetic knowledge in society; theories of genetics, nation and race; approaches to public understandings of science; and the Latin American contexts of transnational ideas of nation and race. PMID- 27479997 TI - Pais de gordos/pais de muertos: Obesity, death and nation in biomedical and forensic genetics in Mexico. AB - This article provides a comparison between genomic medicine and forensic genetics in Mexico, in light of recent depictions of the nation as a 'pais de gordos' (country of the fat) and a 'pais de muertos' (country of the dead). We examine the continuities and ruptures in the public image of genetics in these two areas of attention, health and security, focusing especially on how the relevant publics of genetic science are assembled in each case. Publics of biomedical and forensic genetics are assembled through processes of recruitment and interpellation, in ways that modulate current theorizations of co-production. The comparison also provides a vista onto discussions regarding the involvement of genetics in regimes of governance and citizenship and about the relationship between the state and biopower in a context of perceived health crisis and war like violence. PMID- 27479998 TI - Genetics against race: Science, politics and affirmative action in Brazil. AB - This article analyses interrelations between genetic ancestry research, political conflict and social identity. It focuses on the debate on race-based affirmative action policies, which have been implemented in Brazil since the turn of the century. Genetic evidence of high levels of admixture in the Brazilian population has become a key element of arguments that question the validity of the category of race for the development of public policies. In response, members of Brazil's black movement have dismissed the relevance of genetics by arguing, first, that in Brazil race functions as a social--rather than a biological--category, and, second, that racial classification and discrimination in this country are based on appearance, rather than on genotype. This article highlights the importance of power relations and political interests in shaping public engagements with genetic research and their social consequences. PMID- 27479999 TI - Building the genomic nation: 'Homo Brasilis' and the 'Genoma Mexicano' in comparative cultural perspective. AB - This article explores the relationship between genetic research, nationalism and the construction of collective social identities in Latin America. It makes a comparative analysis of two research projects--the 'Genoma Mexicano' and the 'Homo Brasilis'--both of which sought to establish national and genetic profiles. Both have reproduced and strengthened the idea of their respective nations of focus, incorporating biological elements into debates on social identities. Also, both have placed the unifying figure of the mestizo/mestico at the heart of national identity constructions, and in so doing have displaced alternative identity categories, such as those based on race. However, having been developed in different national contexts, these projects have had distinct scientific and social trajectories: in Mexico, the genomic mestizo is mobilized mainly in relation to health, while in Brazil the key arena is that of race. We show the importance of the nation as a frame for mobilizing genetic data in public policy debates, and demonstrate how race comes in and out of focus in different Latin American national contexts of genomic research, while never completely disappearing. PMID- 27480000 TI - Colombian forensic genetics as a form of public science: The role of race, nation and common sense in the stabilization of DNA populations. AB - Abstract This article examines the role that vernacular notions of racialized regional difference play in the constitution and stabilization of DNA populations in Colombian forensic science, in what we frame as a process of public science. In public science, the imaginations of the scientific world and common-sense public knowledge are integral to the production and circulation of science itself. We explore the origins and circulation of a scientific object--'La Tabla', published in Paredes et al. and used in genetic forensic identification procedures--among genetic research institutes, forensic genetics laboratories and courtrooms in Bogota. We unveil the double life of this central object of forensic genetics. On the one hand, La Tabla enjoys an indisputable public place in the processing of forensic genetic evidence in Colombia (paternity cases, identification of bodies, etc.). On the other hand, the relations it establishes between 'race', geography and genetics are questioned among population geneticists in Colombia. Although forensic technicians are aware of the disputes among population geneticists, they use and endorse the relations established between genetics, 'race' and geography because these fit with common-sense notions of visible bodily difference and the regionalization of race in the Colombian nation. PMID- 27480001 TI - Explaining the visible and the invisible: Public knowledge of genetics, ancestry, physical appearance and race in Colombia. AB - Using data from focus groups conducted in Colombia, we explore how educated lay audiences faced with scenarios about ancestry and genetics draw on widespread and dominant notions of nation, race and belonging in Colombia to ascribe ancestry to collectivities and to themselves as individuals. People from a life sciences background tend to deploy idioms of race and genetics more readily than people from a humanities and race-critical background. When they considered individuals, people tempered or domesticated the more mechanistic explanations about racialized physical appearance, ancestry and genetics that were apparent at the collective level. Ideas of the latency and manifestation of invisible traits were an aspect of this domestication. People ceded ultimate authority to genetic science, but deployed it to work alongside what they already knew. Notions of genetic essentialism co-exist with the strategic use of genetic ancestry in ways that both fix and unfix race. Our data indicate the importance of attending to the different epistemological stances through which people define authoritative knowledge and to the importance of distinguishing the scale of resolution at which the question of diversity is being posed. PMID- 27480002 TI - [Oral medicine in Israel: Current status and future directions]. AB - The oral cavity-body relationships are bi-directional: oral diseases affect the welfare and health of the individual, while diseases and conditions of organs and tissues in the human body affect oral health. The global policy of the World Health Organization is to improve oral health in the 21st century as an integral part of promoting our general health. During the recent years the knowledge of the dental profession has grown exponentially and widened its fields of interest and this has led to impressive advances at both clinical and research levels. Oral medicine, which is a recognized, licensed specialty in Israel, is a definite example that reflects this process. In the last decade residency programs in oral medicine are in the process of constant increased demand. The authors discuss this trend and comment on the need to maintain excellence in this specialty. PMID- 27480003 TI - [The diabetic patient in the dental clinic, update and innovation]. AB - Type 2 Diabetes is a non-curable multi system disease that affect around 9% of the world population. Therefore, the incidence for the general dentist to come across a diabetic patient is very high. The medical treatment in diabetes is graded according to the severity of the disease. In the last decade new drugs and treatment modalities were developed. The implication of diabetes and its complications in the oral cavity are significant. Beside the emergency events that might take place in a diabetic patient, one must take under consideration the influence of the dental treatment on the glycemic control and vis-a-vis the influence of the glycemic control on the oral tissue health and response for treatment. PMID- 27480004 TI - [Biopsy from the oral cavity: Why, when, how and especially what not]. AB - Caries and periodontal disease are the most common pathologies encountered by general dental practitioners on a daily basis. Although less frequently, the oral cavity is also affected by a plethora of pathologic lesions that may represent either a local process or may be a manifestation of systemic conditions. The etiology of these lesions is diverse and ranges from congenital/ developmental, reactive, to neoplastic (benign and malignant), metabolic and hereditary. These lesions are expected to be recognized by the dental clinicians whose main concern would be to achieve a prompt and accurate microscopic diagnosis. The way to a microscopic diagnosis goes through a biopsy procedure. The principles that should guide the dental practitioner for producing a high quality, artefact-free tissue sample from the oral cavity are reviewed in the article together with notes on errors that should be avoided. The patient's life can sometimes depend on a tissue sample as small as 0.5 cm, hence the utmost importance of the strategic and technique-related considerations to be taken by the general dental practitioner prior to performing a biopsy from the oral cavity. In certain cases, the dental practitioner should use the services of specialists in oral medicine or oral and maxillofacial surgery in order to proceed with the biopsy procedure and get a prompt and accurate diagnosis. PMID- 27480005 TI - [Oral carcinoma: From awareness to survivorship]. AB - Oral and oropharyngeal cancer is amongst the most common and fatal malignant diseases worldwide, with oral squamous cell carcinomas constitute more than 90% of all lesions. This article follows the oral cancer patient from the point of view of the oral medicine practitioner; from the stage of the potentially malignant disorders to the diagnosis of cancer, to the management of short-term comlications of the cancer therapy, to the stage of long-term follow up and management of lifelong oral complications of the oncologic treatment. PMID- 27480006 TI - [Maxillofacial imaging in the aid of the clinician]. AB - The rapidly changing field of maxillofacial diagnostic imaging provides the clinician with tools for superior diagnostic capabilities and improved treatment planning improving and thus patient's outcome. There are currently growing number of imaging modalities available in the maxillofacial region, of which a choice must be made according to the least invasive and the most diagnostic option. The introduction of Cone-Beam-Computerized Tomography (CBCT) allows for 3-dimensional imaging volume with improved spatial resolution, along with increased responsibilities of the referring clinician. As various papers showed numerous incidental findings which may be encountered in the imaging data, international organizations advocated the need of both precise, justified and restricted referrals for advanced imaging as well as a need for a radiologic report based on a thorough examination of the entire volume. This paper aims to demonstrate some of the current themes in maxillofacial imaging. it describes the CBCT modality in the maxillofacial region, its application and the various output options. In addition, it introduces the possibility of an imaging consult service. This can be done by either referral of the patient for radiology consult pertaining to findings detected within the region of interest (ROI )or outside the ROI that were not the reason for referral (incidental findings) or by requesting for a written report for an imaging scan. PMID- 27480007 TI - [Rational antibiotic therapy in the dental office: Practical guidelines for decision-making]. AB - Although most dental and periodontal diseases are caused by bacteria, the usual therapy is mechanical/surgical rather than antimicrobial medications. However, sometimes antibiotic administration may be necessary in addition to or as an alternative to the surgical/mechanical treatment. Many studies have shown that the misuse of antibiotics by dentists may be mostly attributed to unnecessity or inefficient regimen, and could contribute to bacterial resistance to antibiotics. The article presents practical guidelines to the administration of antibiotics in the dental office. PMID- 27480008 TI - [Health lips beautiful smile: Conditions to know]. AB - Diagnosis and management of lip pathologies should be part of the dentists' responsibilities. Lip pathologies might affect patient's function, appearance and quality of life. The routine clinical examination of the oral cavity includes lip examination--changes in lip color, size or texture should be recognized during the examination, as well as noticing any habit such as lip licking or mouth breathing.The aim of the review is to present common external lip lesions. Color changes--oral melanotic macule is a localized benign pigmented lesion. It might be similar to early melanoma therefore if it is a new lesion, growing or large it should be excised. White and red changes are usually seen at the lower lip which is exposed to the sun light mainly among light skin individuals. The color changes are showing epithelial and subepithlial permanent changes and is called Solar cheilitis. As a potentially malignant disorder the patient should be carefully examined and under follow- ups. These patients are also advised to reduce sun exposure and use sun screen lipsticks. Lichen planus of the lip can be seen as red and white changes the lips are less prevalent site of the disease and usually the patients will have in intra oral involvement as well. Size changes- angioedema is a quick enlargement of the lip sometimes the face as well. It is an allergic reaction to food drugs and other antigens and resolves spontaneously with 72 hours, but when the upper airway is involved an immediate emergency treatment should be given. A chronic swelling of the lip/lips may be a sign of orofacial granulomatosis--a complicated condition with an unknown etiology, diagnosed by a biopsy and elimination of other diagnoses. Treatment includes steroids in various forms or a combination of surgery. Changes of the epithelial surface of the lip can be a result of dry lips in a hot or dry environment or due to mouth breathing. Lip licking might worsen the situation by secondary infection. Angular cheilitis red and sometimes infected lesion of the commissures should be treated by antifungal and antibiotic and prevention of saliva drooling. Recurrent herpes labialis is a common condition that heals spontaneously but the dentist should be aware to local trauma or treatment that might trigger reactivation. In addition, contact of the vesicle fluid might spread the infection. Chronic ulcer or exophytic lesion is sign of lip carcinoma. The majority of patients in Israel are with lighter skin and sun exposure history. Most patients are over the age of 50. Risk groups should be examined carefully and routinely for any lip change. Israel is an endemic area of Leishmaniasis, and any chronic lip lesion among endemic areas residents or workers should be suspected as Leishmaniasis. PMID- 27480009 TI - [The organization of Jewish dentists in pre-Israel Palestine]. AB - The first modern dental institutes were established in Europe and in the USA during the 1840s. At that period there wasn't a single qualified doctor in Palestine, not to mention a professional dentist. A couple of decades later, as the number of Christian pilgrims grew, some modern hospitals were established and a few non-Jewish dentists opened their clinics in Jerusalem, which was then and in the following decades, the region's largest city. In Europe, dentistry became a popular profession among Jews in general and among Jewish women in particular. The first Jewish dentist settled in Jerusalem in the mid-1880s. Other dentists were slow to arrive and their number began to grow only after the turn of the 20th century. Their professional education varied from those who were trained as apprentices by other dentists to those which studied a couple of years in an academic dental school. The devastation caused by WWI prompted American-Zionist organizations to send a special medical unit to Palestine in 1918. Along medical supplies it also brought a small group of doctors and dentists. The two American dentists that decided to remain in Palestine took upon themselves to spread their medical and scientific knowledge. They also organized the dentists, whose number grew considerably during the 1920s, and called the authorities to regulate the dental profession. In 1926 the British authorities issued a decree regulating all medical professions. It demanded that dental practitioners will be licensed after proving their previous studies and professional knowledge. In 1931, local dentists' organizations decided to establish the Palestine Dental Association. Five years later it was accepted as a member by the International Dental Federation (FDI) and was recognized by the local authorities. Since the 1930s, prominent Jewish dentists from abroad were invited to come to Palestine to lecture, and local dentists participated in international conferences. This prompted the first scientific publications. At the same time dentists published articles in the daily press in which they educated the public on dental hygiene and on modern dental techniques. This momentum was halted in the early 1940s as result of WWII and the Holocaust, but was quick to resume immediately thereafter. 1944 saw the publication of a professional dental Journal, which this issue is a continuation of. By the time the state of Israel was established in 1948, it had more than 900 active dentists, most of them organized in the Israel Dental Association. The only element which was still required to bridge the gap between the dentists in Israel and those in the rest of the modern world was an academic dental school. After more than 20 years in making, the school was opened in 1953 in Jerusalem. From that time on, Israel's dentistry enjoys a worldwide reputation and its dental school graduates teach and lecture in universities and in many dental forums around the globe. PMID- 27480010 TI - Oral medicine. PMID- 27480011 TI - The Psychohistory of Child Maltreatment Among Antebellum Slaveholders. AB - Examining the inner workings of the slaveholder family, including slave caretakers, this article probes the psychodynamics of slaveholder development to assess the extent of child abuse in the Old South. Childcare was haphazard and premised on paternal absence, maternal ambivalence, and the exigencies of slave surrogacy. Corporal punishment, sanctified by southern religion, was the rule. The likelihood of slave negligence and retaliatory attacks against slaveholder children are addressed. Childrearing practices such as swaddling, aunt adoption, and maternal incest are considered, as well as the possible usage of a West African cleansing ritual. The article classifies planter families within the Ambivalent Mode of parent-child relations and suggests the restaging of childhood trauma as the underlying dynamic in the march to civil war. PMID- 27480012 TI - Psychohistorical Hypotheses on Japan's History of Hostility Towards China. AB - The accelerating tensions and military posturing between Japan and China have created a serious crisis with a danger of a catastrophic war. The purpose of this paper is to summarize the events of the current crisis, and to put it in the context of Japan's long history of hostility to China and repeated attempts at conquest. The historical record shows that Japan has attacked China at least seven times, even though China has never attacked Japan. The irrationality of Japan's behavior is demonstrated by the repetition of this hostile behavior despite the enormous human and economic costs that Japan has suffered because of it. The irrationality of Japan's militarism suggests that psychological explanations may be required to understand this phenomenon. Several hypotheses are proposed, including 1) projected paranoid aggression, 2) collective Zeigarnik compulsion, 3) perceived weakness exciting aggression, 4) national inferiority feelings, 5) cultural narcissism, and 6) Oedipal-like hatred of a parent culture. PMID- 27480013 TI - Sacrifice, the Bush Way: From Self to Others. AB - The Walker Bush dynasty has marked the last American century, promoting "corporate democracy" as a means to expand its wealth. As 43rd President of the United States, George Walker Bush's biography illustrates how the members of our powerful elite sacrifice the inner self of their own children for the sake of political success. In his case, the childrearing violence and emotional neglect he experienced created the psychological basis for his later re-enactments as commander-in-chief in the wake of 9/11. From that standpoint, his intergenerational legacy of trauma bears strong affinities with that of the nation as a whole. This paper examines George W. Bush's paternal inheritance, the problem of maternal abuse and its subsequent psychic wounds, as well as the impact of an unresolved grief after the loss of his younger sister, Robin. Restaging childhood traumas as a vengeful young adult at Yale, before getting involved in dirty politics, Bush supported unlawful hazing practices. Then, as Governor of Texas he promoted the death penalty and a zero-tolerance approach to juvenile offenders. Controversial decisions of the Bush administration regarding the Enhanced Interrogation Program, the Guantanamo Bay detention camp and many others are further scrutinized as collective re-enactments of abuse deeply engrained in American society. PMID- 27480014 TI - I Want to Believe: A Short Psychobiography of Mary Baker Eddy. AB - The 18th and 19th centuries were beset with new religious movements in the United States: Shakers, Latter Day Saints, Millerites, and Seventh Day Adventists to name a few. One group, Christian Science, held radically different views than their counterparts and their origins lay in the most unlikely of places, a perpetually ill and poor woman from New Hampshire. Much has been said about Mary Baker Eddy: some say that she was a prophet, others that she was a fraud. Herein no such judgments are made. This study seeks to look into the life of Mary Baker Eddy from a psychological lens in the hopes that insight can be gained into the founding of the First Church of Jesus Christ Scientist and perhaps to allay the binary of Mrs. Eddy as either prophet or fanatic. PMID- 27480015 TI - Live Fast, Die Young: Optimizing Retention Times in High-Rate Contact Stabilization for Maximal Recovery of Organics from Wastewater. AB - Wastewater is typically treated by the conventional activated sludge process, which suffers from an inefficient overall energy balance. The high-rate contact stabilization (HiCS) has been proposed as a promising primary treatment technology with which to maximize redirection of organics to sludge for subsequent energy recovery. It utilizes a feast-famine cycle to select for bioflocculation, intracellular storage, or both. We optimized the HiCS process for organics recovery and characterized different biological pathways of organics removal and recovery. A total of eight HiCS reactors were operated at 15 degrees C at short solids retention times (SRT; 0.24-2.8 days), hydraulic contact times (tc; 8 and 15 min), and stabilization times (ts; 15 and 40 min). At an optimal SRT between 0.5 and 1.3 days and tc of 15 min and ts of 40 min, the HiCS system oxidized only 10% of influent chemical oxygen demand (COD) and recovered up to 55% of incoming organic matter into sludge. Storage played a minor role in the overall COD removal, which was likely dominated by aerobic biomass growth, bioflocculation onto extracellular polymeric substances, and settling. The HiCS process recovers enough organics to potentially produce 28 kWh of electricity per population equivalent per year by anaerobic digestion and electricity generation. This inspires new possibilities for energy-neutral wastewater treatment. PMID- 27480017 TI - Effect of intraoperative high oxygen concentrations on surgical site infection. PMID- 27480016 TI - Clinicopathologic Features of Fatal Non-Anaplastic Follicular Cell-Derived Thyroid Carcinomas. AB - BACKGROUND: The vast majority of thyroid cancers, in particular the non anaplastic follicular cell-derived thyroid carcinomas (non-ANA FCDC), are considered indolent tumors with very low mortality. Hence, it is crucial to analyze the subgroup of these patients who die of disease (DOD) in order to identify clinicopathologic features predictive of disease-specific mortality. METHODS: All non-ANA FCDC operated at a tertiary cancer center between 1985 and 2010 who were DOD were identified and submitted to a meticulous clinicopathologic analysis. RESULTS: Out of 3750 non-ANA FCDC, 58 (1.5%) DOD cases were identified. The DOD group was composed of 33 (57%) poorly differentiated carcinomas (PDTC), 14 (24%) tall-cell variant papillary thyroid carcinomas (TCVPTC), four (7%) Hurthle cell carcinomas, three (5%) papillary microcarcinomas, two (3%) classical variant PTC, and two (3%) follicular variant PTC. Twenty-seven (47%) patients presented with distant metastases (DM), 28 (48%) developed DM during follow-up, while the remaining three (5%) had locally advanced non-resectable recurrence. Gross extension beyond the thyroid (GET) was present in 36 (62%) and extensive vascular invasion (VI) in 21 (36%) of cases. All microcarcinomas had PDTC in their clinically apparent cervical lymph nodes at presentation. Encapsulated thyroid carcinomas were responsible for 17% of DOD cases, and all had extensive VI and/or DM at presentation. All patients had at least one of these high-risk features at diagnosis: DM at presentation, PDTC, GET, and/or extensive VI. The majority of patients died from DM (n = 51; 88%), three (5%) from locoregional disease, three (5%) from both, and one (2%) from unknown cause. CONCLUSIONS: PDTC and TCVPTC are responsible for the vast majority of deaths in differentiated thyroid carcinomas, while the few fatal classical, follicular variant PTC and microcarcinomas all harbor a PDTC component, DM, or GET. Encapsulated differentiated thyroid carcinoma with focal capsular and/or VI without DM at presentation does not seem to cause death. Lack of DM at presentation, PDTC, GET, and extensive VI identify thyroid carcinomas that are at almost no risk of DOD. The vast majority of patients die of DM rather than locoregional invasion, prompting the need for effective systemic treatment. PMID- 27480018 TI - Effect of intraoperative high oxygen fraction on surgical site infection: a meta analysis of randomized controlled trials. PMID- 27480019 TI - Meta-analysis of the DRD5 VNTR in persistent ADHD. AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. DRD5, the gene encoding the dopamine receptor D5, was recently confirmed as a candidate gene for ADHD in children through meta-analysis. In this study, we aimed at studying the association of the ADHD-associated variable number tandem repeat (VNTR) polymorphism upstream of DRD5 with adult ADHD. We compiled data from six sites of the International Multicentre persistent ADHD CollaboraTion (IMpACT) and reached N=6979 (3344 cases and 3635 healthy participants), the largest sample investigated so far. We tested the association of the common DRD5 alleles with categorically defined ADHD and with inattentive and hyperactive/impulsive symptom counts. Our findings provide evidence that none of the common DRD5 alleles are associated with ADHD risk or ADHD symptom counts in adults. PMID- 27480020 TI - Disruption of a dopamine receptor complex amplifies the actions of cocaine. AB - Cocaine-induced increases in dopamine signaling in nucleus accumbens (NAc) play a significant role in cocaine seeking behavior. The majority of cocaine addiction research has focused on neuroanatomically segregated dopamine D1 and D2 receptor expressing neurons, yet an involvement for those NAc neurons coexpressing D1 and D2 receptors in cocaine addiction has never been explored. In situ proximity ligation assay, confocal fluorescence resonance energy transfer and coimmunoprecipitation were used to show native D1 and D2 receptors formed a heteromeric complex in D1/D2 receptor-coexpressing neurons in rat and non-human primate NAc. D1-D2 heteromer expression was lower in NAc of adolescent rats compared to their adult counterparts. Functional disruption of the dopamine D1-D2 receptor heteromer, using a peptide targeting the site of interaction between the D1 and D2 receptor, induced conditioned place preference and increased NAc expression of ?FosB. D1-D2 heteromer disruption also resulted in the promotion, exacerbation and acceleration of the locomotor activating and incentive motivational effects of cocaine in the self-administration paradigm. These findings support a model for tonic inhibition of basal and cocaine-induced reward processes by the D1-D2 heteromer thus highlighting its potential value as a novel target for drug discovery in cocaine addiction. Given that adolescents show increased drug abuse susceptibility, an involvement for reduced D1-D2 heteromer function in the heightened sensitivity to the rewarding effects of cocaine in adolescence is also implicated. PMID- 27480021 TI - Is early vertebroplasty/kyphoplasty justified in multiple myeloma given the rapid vertebral fracture progression? AB - COMMENTARY ON: Xiao R, Miller JA, Margetis K, et al. Radiographic progression of vertebral fractures in patients with multiple myeloma. Spine J 2016:16:822-32 (in this issue). PMID- 27480022 TI - Differences in bone mineral density between cortical bone trajectory and traditional lumbar pedicle screws: commentary. AB - COMMENTARY ON: Mai HT, Mitchell SM, Hashmi SZ, Jenkins TJ, Patel AA, Hsu WK. Differences in bone mineral density of fixation points between lumbar cortical and traditional pedicle screws. Spine J 2016:16:835-41 (in this issue). PMID- 27480023 TI - Introduction of a predictive model for epidural steroid injections leads to inappropriate and inaccurate conclusions. PMID- 27480024 TI - A response to comments by Dr. Manchikanti and Dr. Hirsch. PMID- 27480025 TI - Implementing demand side targeting mechanisms for maternal and child health experiences from national health insurance fund program in Rungwe District, Tanzania. AB - BACKGROUND: Low and middle income countries have adopted targeting mechanisms as a means of increasing program efficiency in reaching marginalized people in the community given the available resources. Design of targeting mechanisms has been changing over time and it is important to understand implementers' experience with such targeting mechanisms since such mechanisms impact equity in access and use of maternal health care services. METHODS: The case study approach was considered as appropriate method for exploring implementers' and decision-makers' experiences with the two targeting mechanisms. In-depth interviews in order to explore implementer experience with the two targeting mechanisms. A total of 10 in-depth interviews (IDI) and 4 group discussions (GDs) were conducted with implementers at national level, regional, district and health care facility level. A thematic analysis approach was adopted during data analysis. RESULTS: The whole process of screening and identifying poor pregnant women resulted in delay in implementation of the intervention. Individual targeting was perceived to have some form of stigmatization; hence beneficiaries did not like to be termed as poor. Geographical targeting had a few cons as health care providers experienced an increase in workload while staff remained the same and poor quality of information in the claim forms. However geographical targeting increase in the number of women going to higher level of care (district/regional referral hospital), increase in facility revenue and insurance coverage. CONCLUSION: Interventions which are using targeting mechanisms to reach poor people are useful in increasing access and use of health care services for marginalized communities so long as they are well designed and beneficiaries as well as all implementers and decision makers are involved from the very beginning. Implementation of demand side financing strategies using targeting mechanisms should go together with supply side interventions in order to achieve project objectives. PMID- 27480026 TI - Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension. AB - Hypertension is a major global health burden and a leading risk factor for cardiovascular diseases. Although its heritability has been documented previously, contributing loci identified to date account for only a small fraction of blood pressure (BP) variation, which strongly suggests the existence of undiscovered variants. To identify novel variants, we conducted a three staged genetic study in 21,990 hypertensive cases and normotensive controls. Four single nucleotide polymorphisms (SNPs) at three new genes (L3MBTL4 rs403814, Pmeta = 6.128 * 10(-9); LOC729251, and TCEANC) and seven SNPs at five previously reported genes were identified as being significantly associated with hypertension. Through functional analysis, we found that L3MBTL4 is predominantly expressed in vascular smooth muscle cells and up-regulated in spontaneously hypertensive rats. Rats with ubiquitous over-expression of L3MBTL4 exhibited significantly elevated BP, increased thickness of the vascular media layer and cardiac hypertrophy. Mechanistically, L3MBTL4 over-expression could lead to down-regulation of latent transforming growth factor-beta binding protein 1 (LTBP1), and phosphorylation activation of the mitogen-activated protein kinases (MAPK) signaling pathway, which is known to trigger the pathological progression of vascular remodeling and BP elevation. These findings pinpointed L3MBTL4 as a critical contributor to the development and progression of hypertension and uncovers a novel target for therapeutic intervention. PMID- 27480027 TI - Characterization of the action of tyrosinase on resorcinols. AB - The action of tyrosinase on resorcinol and some derivatives (4-ethylresorcinol, 2 methylresorcinol and 4-methylresorcinol) was investigated. If the catalytic cycle is completed with a reductant such as ascorbic acid or an o-diphenol such as 4 tert-butylcatechol, these compounds act as substrates of tyrosinase in all cases. The reaction can also be carried out, adding hydrogen peroxide to the medium. All the above compounds were characterized as substrates of the enzyme and their kinetic constants, KM (Michaelis constant) and kcat (catalytic constant) were determined. Measurement of the activity of the enzyme after pre-incubation with resorcinol, 4-ethylresorcinol or 4-methylresorcinol points to an apparent loss of activity at short times, which could correspond to an enzymatic inactivation process. However, if the measurements are extended over longer times, a burst is observed and the enzymatic activity is recovered, demonstrating that these compounds are not suicide substrates of the enzyme. These effects are not observed with 2-methylresorcinol. The docking results indicate that the binding of met-tyrosinase with these resorcinols occurs in the same way, but not with 2 methylresorcinol, due to steric hindrance. PMID- 27480028 TI - Anion inhibition profiles of the complete domain of the eta-carbonic anhydrase from Plasmodium falciparum. AB - We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the eta-CA class and identified in the genome of the malaria producing protozoa. A truncated such enzyme, PfCA1, containing 235 residues was investigated earlier for its catalytic and inhibition profiles. The two enzymes were efficient catalysts for CO2 hydration: PfCAdom showed a kcat of 3.8*10(5)s( 1) and kcat/Km of 7.2*10(7)M(-1)*s(-1), whereas PfCA showed a lower activity compared to PfCAdom, with a kcat of 1.4*10(5)s(-1) and kcat/Km of 5.4*10(6)M( 1)*s(-1). PfCAdom was generally less inhibited by most anions and small molecules compared to PfCA1. The best PfCAdom inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KIs in the range of 9 68MUM, followed by bicarbonate, hydrogensulfide, stannate and N,N diethyldithiocarbamate, which were submillimolar inhibitors, with KIs in the range of 0.53-0.97mM. Malaria parasites CA inhibition was proposed as a new strategy to develop antimalarial drugs, with a novel mechanism of action. PMID- 27480029 TI - Exploring new scaffolds for angiotensin II receptor antagonism. AB - Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes of antihypertensive drugs that modulate the renin-angiotensin system (RAS). Their main uses include also treatment of diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Towards this direction, our study has been focused on the discovery of novel agents bearing different scaffolds which may evolve as a new class of AT1 receptor antagonists. To fulfill this aim, a combination of computational approaches and biological assays were implemented. Particularly, a pharmacophore model was established and served as a 3D search query to screen the ChEMBL15 database. The reliability and accuracy of virtual screening results were improved by using molecular docking studies. In total, 4 compounds with completely diverse chemical scaffolds from potential ARBs, were picked and tested for their binding affinity to AT1 receptor. Results revealed high nanomolar to micromolar affinity (IC50) for all the compounds. Especially, compound 4 exhibited a binding affinity of 199nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities. PMID- 27480030 TI - Solution-phase microwave assisted parallel synthesis, biological evaluation and in silico docking studies of N,N'-disubstituted thioureas derived from 3 chlorobenzoic acid. AB - A facile and robust microwave-assisted solution phase parallel synthesis protocol was exercised for the development of a 38-member library of N,N'-disubstituted thiourea analogues (1-38) by using an identical set of conditions. The reaction time for synthesis of N,N'-disubstituted thiourea analogues was drastically reduced from a reported duration of 8-12h for conventional methods to only 1.5 2.0min. All the derivatives (1-38) were characterized by physico-analytical techniques such as elemental analysis in combination with FT-IR, (1)H, (13)C NMR and by single crystal XRD analysis have also been performed. These compounds were screened for their in vitro urease inhibition activities. Majority of compounds exhibited potent urease inhibition activities, however, the most significant activity was found for 16, with an IC50 value of 1.23+/-0.1MUM. Furthermore, the synthesized compounds were screened for their cytotoxic potential against lungs cancer cell lines. Cell culture studies demonstrated significant toxicity of the compounds on the cell lines, and the levels of toxicity were altered in the presence of various side groups. The molecular docking studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the urease enzymes. These compounds have a great potential and significance for further investigations. PMID- 27480031 TI - Design of cyclic RGD-conjugated Aib-containing amphipathic helical peptides for targeted delivery of small interfering RNA. AB - To achieve the targeted delivery of siRNA, five conjugates of Aib-containing amphipathic helical peptides with mono-, di-, and trivalent cRGDfC [cyclo(-Arg Gly-Asp-d-Phe-Cys-)], which is known to bind to alphaVbeta3 integrin, at several positions of the amphipathic helical peptide were designed and synthesized. Among the five conjugates, the monovalent cRGDfC conjugating at position 20 of the amino acid sequence of the helical peptide through the formation of a disulfide bond (PI) and the divalent cRGDfC conjugating at positions 2 and 14 of the amino acid sequence of the helical peptide through the formation of disulfide bonds (PIII) significantly enhanced the delivery of fluorescence-labeled siRNA into A549 cells as the peptide/siRNA complex formed by electrostatic interaction. The cellular uptake of the PI/siRNA complex was mediated by both endocytic and non endocytic pathways, whereas that of the PIII/siRNA complex was enabled by endocytosis. Furthermore, the cellular uptake of the PI/siRNA complex might involve specific interactions of the RGD group with the alphaVbeta3 integrin receptor. Next, the RNAi effect of the peptide/siRNA complex on luciferase expression in A549-Luc cells was examined. Luciferase expression was significantly decreased in the presence of the complex at the concentration of 1.0MUM PI/10nM siRNA. In contrast, the PIII/siRNA complex did not show the RNAi effect under the same conditions. However, extending the incubation time led to the suppression of the luciferase expression in the presence of the PIII/siRNA complex. Considering that the cellular uptake of the PIII/siRNA complex is mediated by the endocytic pathway, the release of siRNA from the endosome into the cytosol might require a long time. We present herein a useful and unique tool for the delivery of siRNA. PMID- 27480033 TI - Recent progress in nanomaterials for gene delivery applications. AB - Nanotechnology-based gene delivery is the division of nanomedicine concerned with the synthesis, characterization, and functionalization of nanomaterials to be used in targeted-gene delivery applications. Nanomaterial-based gene delivery systems hold great promise for curing fatal inherited and acquired diseases, including neurological disorders, cancer, cardiovascular diseases, and acquired immunodeficiency syndrome (AIDS). However, their use in clinical applications is still controversial. To date, the Food and Drug Administration (FDA) has not approved any gene delivery system because of the unknown long-term toxicity and the low gene transfection efficiency of nanomaterials in vivo. Compared to viral vectors, nonviral gene delivery vectors are characterized by a low preexisting immunogenicity, which is important for preventing a severe immune response. In addition, nonviral vectors provide higher loading capacity and ease of fabrication. For these reasons, this review article focuses on applications of nonviral gene delivery systems, including those based on lipids, polymers, graphene, and other inorganic nanoparticles, and discusses recent advances in nanomaterials for gene therapy. Methods of synthesizing these nanomaterials are briefly described from a materials science perspective. Also, challenges, critical issues, and concerns about the in vivo applications of nanomaterial based gene delivery systems are discussed. It should be noted that this article is not a comprehensive review of the literature. PMID- 27480034 TI - Research digest: NAFLD in the spotlight. PMID- 27480032 TI - Dual and antagonic therapeutic effects of sulfated glycans. AB - Sulfated glycans currently explored in medicine like glycosaminoglycans (GAGs) or those of potential medical application like algal sulfated galactans (SGs) and fucoidans exhibit significant effects in numerous pathophysiological systems. According to the structure of these sulfated glycans, sample concentration and the method utilized in the approach opposite effects can be achieved. The effects aimed at down-regulating the events usually dominate. These effects are expected in most clinical endeavors. However, the effects capable of accelerating the events can be also beneficial in certain circumstances. Besides discoursing about the paradoxical effects of sulfated glycans in coagulation/thrombosis, angiogenesis, inflammation and microbial infections; this report aims primarily at highlighting the possible contribution of the neglected activities of some well-known sulfated glycans in up-regulating the events of these pathophysiological systems. The representative sulfated glycans taken here are the mammalian-derived GAGs, the unique holothurian GAG, the red algal SGs and the brown algal fucoidans. The current discussion is highly relevant in light of the future strategies for developing novel sulfated glycan-based therapies. PMID- 27480036 TI - Pancreatic trauma: Management and literature review. AB - Pancreatic injury is an uncommon event often difficult to diagnose at an early stage. After abdominal trauma, the surgeon must always be aware of the possibility of pancreatic trauma due to the complications associated with missed pancreatic injuries. Due to its retroperitoneal position, asociated organs and vascular injuries are almost always present, which along with frequent extra abdominal injuries explain the high morbidity and mortality. The aim of this study is to present a concise description of the incidence of these injuries, lesional mechanisms, recommended diagnostic methods, therapeutic indications including nonoperative management, endoscopy and surgery, and an analysis of pancreas-specific complications and mortality rates in these patients based on a 60-year review of the literature, encompassing 6,364 patients. Due to pancreatic retroperitoneal position, asociated organs and vascular injuries are almost always present, which along with frequent extraaabdominal injuries explain the high morbidity and mortality of these patients. PMID- 27480037 TI - A critical role for NF2 and the Hippo pathway in branching morphogenesis. AB - Branching morphogenesis is a complex biological process common to the development of most epithelial organs. Here we demonstrate that NF2, LATS1/2 and YAP play a critical role in branching morphogenesis in the mouse kidney. Removal of Nf2 or Lats1/2 from the ureteric bud (UB) lineage causes loss of branching morphogenesis that is rescued by loss of one copy of Yap and Taz, and phenocopied by YAP overexpression. Mosaic analysis demonstrates that cells with high YAP expression have reduced contribution to UB tips, similar to Ret(-/-) cells, and that YAP suppresses RET signalling and tip identity. Conversely, Yap/Taz UB-deletion leads to cyst-like branching and expansion of UB tip markers, suggesting a shift towards tip cell identity. Based on these data we propose that NF2 and the Hippo pathway locally repress YAP/TAZ activity in the UB to promote subsequent splitting of the tip to allow branching morphogenesis. PMID- 27480042 TI - Effect of bandage contact lens wear and postoperative medical therapies on corneal healing rate after diamond burr debridement in dogs. AB - PURPOSE: To determine the effect of bandage contact lens wear and type of post operative medical treatment on corneal healing rates in dogs after diamond burr debridement. ANIMALS STUDIED: 237 client-owned dogs. PROCEDURES: Canine patients having undergone diamond burr debridement (DBD) for treatment of spontaneous chronic corneal epithelial defects (SCCEDs) were included. Patients were put into 1 of 12 different groups based on type of postoperative medical regimen and whether a bandage contact lens (BCL) was utilized. Each dog was examined on a routine basis until the cornea was fluorescein negative. Data points collected included age, sex, breed, diabetic status, eye affected, Schirmer tear test 1, rebound tonometry, type and frequency of topical antibiotic, use of topical sodium chloride, use and retention of BCL, and days until healed. RESULTS: A total of 237 dogs, each contributing one eye to the study, underwent DBD for SCCEDs. All eyes treated had estimated median +/- standard error (SE) days to heal of 9.37 +/- 0.42 days. When sodium chloride and BCL were utilized, ofloxacin had a significantly shorter median healing time when compared to oxytetracycline (adjusted P = 0.0158) and tobramycin (adjusted P = 0.0261). BCL use significantly improved healing times (P = 0.0002). Overall BCL retention rate was 62.02% (80 of 129). PureVision lenses were retained more often compared to Acrivet lenses (P < 0.0001). Overall, BCL retention significantly improved healing rates (P = <0.0001). CONCLUSIONS: Postdebridement antibiotic type or use of sodium chloride ointment had minor effects on healing rates. Bandage contact lens use and retention significantly improves healing times. PMID- 27480043 TI - The olympically mismeasured risk of Zika virus in Rio de Janeiro - Authors' reply. PMID- 27480044 TI - The olympically mismeasured risk of Zika virus in Rio de Janeiro. PMID- 27480045 TI - Muscle volume loss as a prognostic marker in hepatocellular carcinoma patients treated with sorafenib. AB - AIM: To elucidate the clinical significance of muscle wasting in regard to survival of hepatocellular carcinoma (HCC) patients undergoing sorafenib treatment, we evaluated prognostic factors including muscle wasting at the start of sorafenib treatment. METHODS: We enrolled 93 patients with unresectable HCC (68.3 +/- 9.4 years old, 81 men, 12 women, Child-Pugh score 5:6:7 = 69:22:2) who were treated with sorafenib. Muscle wasting was evaluated based on psoas muscle area index (psoas muscle area at level of middle of third lumbar vertebra [cm2 ] / height [m]2 ) calculated from computed tomography findings. Previously reported cut-off values for muscle wasting in men and women (4.24 and 2.50 cm2 /m2 , respectively) were used. Patients were divided into those with (muscle-atrophy group, n = 20) and without (non-atrophy group, n = 73) muscle wasting. RESULTS: There were no significant differences in regard to etiology, Child-Pugh classification, and tumor-node-metastasis stage between the groups. In contrast, body mass index in the muscle-atrophy group was lower (20.9 +/- 2.4 vs. 23.5 +/- 3.4, P = 0.003). Although time to progression was not different (median 2.1 vs. 2.8 months, P = 0.242), the 6-, 12-, and 18-month survival rates were worse in the muscle-atrophy group (62.7%, 32.3%, and 32.3% vs. 78.3%, 64.7% and 48.1%, respectively, P = 0.042). In multivariate Cox hazard analysis, des-gamma-carboxy prothrombin level (>=100 mAU/mL) (hazard ratio, 2.540; P = 0.018) and positive for muscle wasting (hazard ratio, 2.158; P = 0.032) were significant prognostic factors at the start of sorafenib treatment. CONCLUSION: Muscle wasting is an important prognostic factor in patients treated with sorafenib. PMID- 27480046 TI - Popliteal Artery Entrapment and Fibular Angiodysplasia in Siblings. PMID- 27480047 TI - Mechanisms and risk assessment of steroid resistance in acute kidney transplant rejection. AB - Ever since the first successful kidney transplantation, the occurrence of acute rejection has been a dominant risk factor for adverse graft outcome, as it is associated with reduced graft survival and the development of chronic transplant dysfunction. Although the majority of acute renal allograft rejection episodes can be adequately treated with glucocorticoid therapy, 25 to 30% of the rejection episode cannot be reversed with glucocorticoids alone. At present, the diagnosis of steroid resistance primarily relies on post-transplantation follow-up of clinical parameters reflecting renal allograft function. However, it remains difficult to predict the response to the response to antirejection treatment. Prediction of steroid resistance could prevent unnecessary exposure to high-dose corticosteroid therapy and avoid the development and progression of irreversible nephron. This impact of steroid-refractory rejection on graft integrity stresses the need for tools to assess the response to AR treatment in an early stage. Here, we discuss our current understanding of resistance to anti-rejection treatment with glucocorticoids, and provide an overview of biomarkers for the detection and/or prediction of steroid resistance in kidney transplantation. PMID- 27480048 TI - Investigation of lactic acid bacterial strains for meat fermentation and the product's antioxidant and angiotensin-I-converting-enzyme inhibitory activities. AB - In the lactic acid bacteria (LAB) strains screened from our LAB collection, Lactobacillus (L.) sakei strain no. 23 and L. curvatus strain no. 28 degraded meat protein and tolerated salt and nitrite in vitro. Fermented sausages inoculated strains no. 23 and no. 28 showed not only favorable increases in viable LAB counts and reduced pH, but also the degradation of meat protein. The sausages fermented with these strains showed significantly higher antioxidant activity than those without LAB or fermented by each LAB type strain. Angiotensin I-converting-enzyme (ACE) inhibitory activity was also significantly higher in the sausages fermented with strain no. 23 than in those fermented with the type strain. Higher ACE inhibitory activity was also observed in the sausages fermented with strain no. 28, but did not differ significantly from those with the type strain. An analysis of the proteolysis and degradation products formed by each LAB in sausages suggested that those bioactivities yielded fermentation products such as peptides. Therefore, LAB starters that can adequately ferment meat, such as strains no. 23 and no. 28, should contribute to the production of bioactive compounds in meat products. PMID- 27480049 TI - Synaptic transmission despite severe hypoxia in hippocampal slices of the deep diving hooded seal. AB - Brain neurons of the deep-diving hooded seal (Cystophora cristata) are known to be inherently hypoxia tolerant. Here, we have used in vitro field potential recordings in hippocampal slices to compare effects of severe hypoxia on synaptic transmission in hooded seals vs. non-diving mammals. Synaptic responses of mice (Mus musculus) to hypoxia were in accordance with previously published data. Hippocampal slices of reindeer (Rangifer tarandus), an alternative large-mammal non-diving model, behaved in a similar way as mouse slices, in that synaptic activity disappeared rapidly without recovery after >20min in hypoxia. The synaptic activity of hooded seal slices decreased in hypoxia, but unlike mice and reindeer, it remained at >30% of the normoxic amplitude throughout 3h of severe hypoxia. Also, upon reoxygenation, the signal recovered to ~50% of the pre challenge (normoxic) amplitude. The AMPA-type glutamate receptor antagonist CNQX eliminated this signal, showing that it was not an artifact. Paired pulse facilitation (PPF), typically associated with increased presynaptic calcium (Ca2+) levels, was significantly reduced in the seal slices. We propose that the build-up of Ca2+ concentration is limited in seal presynaptic terminals, possibly due to a high Ca2+ buffering capacity, which could explain both the attenuated PPF and the remarkable neural hypoxia tolerance of this species. Although we found no significant hypoxia-induced upregulation of mRNA for the Ca2+ binding proteins calbindin d28k or parvalbumin in hooded seal hippocampal slices, a recent study reports very high transcript levels of the Ca2+ binding protein S100B in this species, which is in support of the hypothesis. PMID- 27480050 TI - Nonalcoholic fatty liver disease and metabolic syndrome: Shared genetic basis of pathogenesis. PMID- 27480051 TI - A selective medium for recovery and enumeration of endolithic bacteria. AB - The study of lithic microbial communities, inhabiting rock substrates has been gathering momentum due to a growing attention of their wide importance as model systems in ecological studies and for their community structure. It is generally accepted that the success of cultivation-based technique is primarily based on suitable culture medium for isolation. The media available for enumeration and recovery of endolithic bacteria are mainly specific to particular type of rock which may not be suitable to isolate endolithic bacterial community from diverse lithobiontic niches. In this study, a new unoptimized medium was formulated, designated LM10 (unoptimized) for enumeration and recovery of endolithic bacteria by addition and/or omission of media components to the basal medium R2G, which was selected after experimental evaluation of five different existing media. The endolithic bacterial count in LM10 medium (unoptimized) was significantly higher than the R2G medium (t=-12.57, p<0.0001). The culture and nutritional parameters associated with unoptimized LM10 medium were optimized using statistical approach to maximize the recovery and enumeration of endolithic bacteria. The first phase of the study comprised of a Plackett-Burman (PB) design experiment conducted to screen thirteen medium components and two culture parameters as variables with effect on bacterial enumeration and recovery. Out of these, Yeast extract, Casein hydrolysate, Glucose, Starch and Sodium thiosulphate were found to be significantly affecting the bacterial count (p<0.05) based on PB design. On keeping rest of the media components and culture conditions at fixed value as per the PB design analyses (p>0.05 and coefficients), further optimization was carried out for significant factors using Box-Behnken design (BBD) of response surface methodology (RSM). Optimized media components obtained by BBD were Yeast extract, Casein hydrolysate, Glucose and Starch in 0.05g/l each and Sodium thiosulphate in 0.047g/l concentrations. The composition of optimized LM10 medium formulated (per litre) is 0.05g Yeast extract, 0.05g Casein hydrolysate, 0.05g Glucose, 0.05g Starch, 0.01g K2HPO4, 0.02g Sodium pyruvate, 0.2g MgSO4, 0.001g FeSO4.7H2O, 0.285g NH4Cl, 0.039g CaCl2.2H2O, 0.047g Na2S2O3.5H2O, 0.002g NaHCO3 and 11g Gellan gum (pH=7.4). Validation of optimized LM10 medium using nine different rock samples from Meghalaya clearly indicated that optimized LM10 medium was better suited for higher recovery and enumeration of endolithic bacteria under both aerobic and anaerobic conditions. PMID- 27480052 TI - Cell-cycle-controlled radiation therapy was effective for treating a murine malignant melanoma cell line in vitro and in vivo. AB - Radiotherapy is a commonly used regimen for treating various types of intractable cancers, although the effects depend on the cell cycle of the targeted cancer cell lines, and for irradiation purposes it is therefore critical to establish a protocol for controlling the cell cycle. Here, we showed that a common murine melanoma cell line B16BL6 was more vulnerable to irradiation during the early S phase, and that synchronisation of the cell cycle greatly increased the therapeutic effects of radiotherapy. Cell-sorting experiments, according to cell cycle phase, using B16BL6 cells demonstrated that cells in the early S phase were the most susceptible to radiotherapy. Gemcitabine, a clinically utilised anti cancer drug, induced cell-cycle arrest during the early S phase in B16BL6 cells, and thus a synergistic therapeutic effect was observed when irradiation was administered at the right time. Human pancreatic cancer cell line PANC-1 exhibited similar properties to B16BL6 in terms of its radiosensitivity during the S/G2/M phase and also demonstrated a synergistic effect of cell cycle synchronisation. These results show the importance of cell-cycle control in the application of irradiation and suggest a suitable time interval between chemotherapy and radiotherapy, as well as providing useful information for treating intractable cancer. PMID- 27480054 TI - Effective anti-leishmanial activity of minimalist squaramide-based compounds. AB - In order to evaluate the in vitro leishmanicidal activity of N,N'-Squaramides derivatives, compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites, against Leishmania infantum, Leishmania braziliensis and Leishmania donovani a series of 18compounds was prepared and assayed on extracellular and intracellular parasite forms. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. Changes in metabolite excretion by 1H-NMR and the ultrastructural alterations occurring in the parasites treated using transmission electron microscopy (TEM), was analyzed. Compounds 1, 7, 11, 14 and 17 were the more active and less toxic. Infection rates showed that the order of effectiveness was 17 > 11 > 14 > 7 for both L. infantum and L. braziliensis and in the same way, the compound 1 for L. donovani. All these compounds have altered the typical structure of the promastigotes, glycosomes and mitochondria. These severe modifications by the compounds are the ultimate reasons for the alterations observed in the excretion products. The Squaramide 17 (3-(butylamino)-4-((3-(dimetilamino)propyl)(methyl)amino)cyclobut-3 en-1,2-dione) was clearly the most efficient of all compounds. The data appear to confirm that the severe modifications generated in organelles such as glycosomes or mitochondria by the compounds are the ultimate reasons for the alterations observed in the excretion products of all species. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-leishmanial agent. PMID- 27480055 TI - Role of H(+)-pyrophosphatase activity in the regulation of intracellular pH in a scuticociliate parasite of turbot: Physiological effects. AB - The scuticociliatosis is a very serious disease that affects the cultured turbot, and whose causal agent is the anphizoic and marine euryhaline ciliate Philasterides dicentrarchi. Several protozoans possess acidic organelles that contain high concentrations of pyrophosphate (PPi), Ca(2+) and other elements with essential roles in vesicular trafficking, pH homeostasis and osmoregulation. P. dicentrarchi possesses a pyrophosphatase (H(+)-PPase) that pumps H(+) through the membranes of vacuolar and alveolar sacs. These compartments share common features with the acidocalcisomes described in other parasitic protozoa (e.g. acid content and Ca(2+) storage). We evaluated the effects of Ca(2+) and ATP on H (+)-PPase activity in this ciliate and analyzed their role in maintaining intracellular pH homeostasis and osmoregulation, by the addition of PPi and inorganic molecules that affect osmolarity. Addition of PPi led to acidification of the intracellular compartments, while the addition of ATP, CaCl2 and bisphosphonates analogous of PPi and Ca(2+) metabolism regulators led to alkalinization and a decrease in H(+)-PPase expression in trophozoites. Addition of NaCl led to proton release, intracellular Ca(2+) accumulation and downregulation of H(+)-PPase expression. We conclude that the regulation of the acidification of intracellular compartments may be essential for maintaining the intracellular pH homeostasis necessary for survival of ciliates and their adaptation to salt stress, which they will presumably face during the endoparasitic phase, in which the salinity levels are lower than in their natural environment. PMID- 27480056 TI - Hypoesthesia of midface by isolated Haller's cell mucocele. PMID- 27480053 TI - What Are We Looking for in Computer-Based Learning Interventions in Medical Education? A Systematic Review. AB - BACKGROUND: Computer-based learning (CBL) has been widely used in medical education, and reports regarding its usage and effectiveness have ranged broadly. Most work has been done on the effectiveness of CBL approaches versus traditional methods, and little has been done on the comparative effects of CBL versus CBL methodologies. These findings urged other authors to recommend such studies in hopes of improving knowledge about which CBL methods work best in which settings. OBJECTIVE: In this systematic review, we aimed to characterize recent studies of the development of software platforms and interventions in medical education, search for common points among studies, and assess whether recommendations for CBL research are being taken into consideration. METHODS: We conducted a systematic review of the literature published from 2003 through 2013. We included studies written in English, specifically in medical education, regarding either the development of instructional software or interventions using instructional software, during training or practice, that reported learner attitudes, satisfaction, knowledge, skills, or software usage. We conducted 2 latent class analyses to group articles according to platform features and intervention characteristics. In addition, we analyzed references and citations for abstracted articles. RESULTS: We analyzed 251 articles. The number of publications rose over time, and they encompassed most medical disciplines, learning settings, and training levels, totaling 25 different platforms specifically for medical education. We uncovered 4 latent classes for educational software, characteristically making use of multimedia (115/251, 45.8%), text (64/251, 25.5%), Web conferencing (54/251, 21.5%), and instructional design principles (18/251, 7.2%). We found 3 classes for intervention outcomes: knowledge and attitudes (175/212, 82.6%), knowledge, attitudes, and skills (11.8%), and online activity (12/212, 5.7%). About a quarter of the articles (58/227, 25.6%) did not hold references or citations in common with other articles. The number of common references and citations increased in articles reporting instructional design principles (P=.03), articles measuring online activities (P=.01), and articles citing a review by Cook and colleagues on CBL (P=.04). There was an association between number of citations and studies comparing CBL versus CBL, independent of publication date (P=.02). CONCLUSIONS: Studies in this field vary highly, and a high number of software systems are being developed. It seems that past recommendations regarding CBL interventions are being taken into consideration. A move into a more student-centered model, a focus on implementing reusable software platforms for specific learning contexts, and the analysis of online activity to track and predict outcomes are relevant areas for future research in this field. PMID- 27480058 TI - Urogenital schistosomiasis and associated determinant factors among senior high school students in the Dutsin-Ma and Safana Local Government Areas of Katsina State, Nigeria. AB - BACKGROUND: Human schistosomiasis is a chronic parasitic disease of poverty caused by the cercariae of digenetic trematodes of the genus Schistosoma. The disease is a major source of morbidity and mortality in 77 low- and middle-income countries in the tropics where 700 million people are at risk. In a bid to provide relevant epidemiological information to boost control of urogenital schistosomiasis at the state level in Nigeria, we conducted this study with the aim of investigating the disease's prevalence and intensity, and the determinant factors responsible for its endemicity. METHODS: Data on risk factors were obtained from a total of 645 students aged 12?25 years using well- designed questionnaires. Samples were collected between 09:45 and 14:00 in universal bottles. Each10MUl centrifuged sample was examined for the eggs of S. haematobium using Motic(r) (Binocular) Light Microscope (model S-10-P) with a x10 objective. Average infection intensity was recorded as number of eggs per 10 ml of urine sample. Survey data were entered into Microsoft Excel 2010 and analyzed using Epi InfoTM 7. Associations among variables were determined using the chi square test and bivariate and multivariate logistic regressions. RESULTS: Prevalence of urogenital schistosomiasis was 30.54 % among the study population, with a mean infection intensity of 30.27 eggs/10 ml of urine. Prevalence and average intensity were higher in males (28.37 % and 32.21 eggs/10 ml of urine respectively) than in females (2.17 % and 5 eggs/10 ml of urine respectively). Water contact activities (X (2) = 29.031, P = 0.0000), sex (male) [X (2) = 109.82; P<0.0001], location (Dutsin?Ma) [X (2) = 7.19; P = 0.0073], age group 18-20 (X (2) = 4.819, P = 0.0281), altitude (531?560 m) [X (2) = 6.84, p = 0.0089], fathers doing other brown?collar jobs (X (2) = 8.449, P = 0.0037) and mothers' occupation (X (2) = 9.470, P = 0.0021) were found to be significantly associated with urogenital schistosomiasis. Boys were six times more likely to be infected with the cercariae of S. haematobium compared to girls [AOR (95 % CI): 6.34 (4.89?8.22)]. CONCLUSIONS: Dutsin-Ma and Safana were classified as moderate risk Local Government Areas for urogenital schistosomiasis. The strong association between the disease and mother's occupation is of utmost importance and suggests a promising control measure: that is, directing health education as well as grassroots mass chemotherapeutic intervention with praziquantel at mothers. A good network including treated pipe-borne water, drainage system, and sewage disposal facilities available should be improved upon. Molluscicides should be provided at highly subsidized rate to help control the disease. PMID- 27480057 TI - Cytotoxic Escherichia coli strains encoding colibactin colonize laboratory mice. AB - Escherichia coli strains have not been fully characterized in laboratory mice and are not currently excluded from mouse colonies. Colibactin (Clb), a cytotoxin, has been associated with inflammation and cancer in humans and animals. We performed bacterial cultures utilizing rectal swab, fecal, and extra intestinal samples from clinically unaffected or affected laboratory mice. Fifty-one E. coli were isolated from 45 laboratory mice, identified biochemically, and selected isolates were serotyped. The 16S rRNA gene was amplified and sequenced for specific isolates, PCR used for clbA and clbQ gene amplification, and phylogenetic group identification was performed on all 51 E. coli strains. Clb genes were sequenced and selected E. coli isolates were characterized using a HeLa cell cytotoxicity assay. Forty-five of the 51 E. coli isolates (88%) encoded clbA and clbQ and belonged to phylogenetic group B2. Mouse E. coli serotypes included: O2:H6, O-:H-, OM:H+, and O22:H-. Clb-encoding O2: H6 mouse E. coli isolates were cytotoxic in vitro. A Clb-encoding E. coli was isolated from a clinically affected genetically modified mouse with cystic endometrial hyperplasia. Our findings suggest that Clb-encoding E. coli colonize laboratory mice and may induce clinical and subclinical diseases that may impact experimental mouse models. PMID- 27480060 TI - MMsDusty: an Alternative InChI-Based Tool to Minimize Chemical Redundancy. PMID- 27480059 TI - Rhizobium anhuiense as the predominant microsymbionts of Lathyrus maritimus along the Shandong Peninsula seashore line. AB - Beach pea [Lathyrus maritimus Bigelow, or Lathyrus japonicus subsp. maritimus (L.) P.W. Ball] is a wild legume distributed on the seashore line, and the rhizobia nodulating with this plant have been reported only rarely. In order to reveal the diversity of beach pea rhizobia on the seashore line of Shandong Peninsula, China, a total of 124 bacterial strains were isolated from the root nodules of beach pea plants collected from five sites. All the isolates were divided into five recA types after screening by recA gene sequence analysis and they consisted of Rhizobium anhuiense covering 122 symbiotic isolates in three recA types, as well as two single isolates Rhizobium sp. and Rhizobium lusitanum representing distinct recA types. The recA genotype III of R. anhuiense (103 isolates) represented by strain YIC11270 was dominant at all five sampling sites. Identical symbiotic genes (nodC and nifH) were detected in the three recA genotypes of R. anhuiense isolates that were closely related to those of the pea and faba rhizobia. This study clarified that R. anhuiense was the main symbiont for beach pea rhizobia on the seashore line of Shandong Peninsula. The low level genetic diversity of beach pea rhizobia revealed by both MLSA and the symbiotic genes might be related to the strong selection pressure produced by the saline alkaline environment and the host plants. PMID- 27480061 TI - GRF: A Greedy Rank Fusion Algorithm for Combining MicroRNA Target Orderings. PMID- 27480062 TI - Prediction of Milk/Plasma Concentration Ratios of Drugs and Environmental Pollutants Using In Silico Tools: Classification and Regression Based QSARs and Pharmacophore Mapping. AB - A large set of 185 compounds with diverse molecular structures and different mechanisms of therapeutic actions was used to develop and validate statistically significant classification and regression based QSTR models for predicting partitioning of drugs/chemicals into breast milk. Pharmacophore mapping was also carried out which showed four important features required for lower risk of secretion into milk: (i) hydrophobic group (HYD), (ii) ring aromatic group (RA), (iii) negative ionizable (NegIon) and (iv) hydrogen bond donor (HBA). QSTR and pharmacophore models were rigorously validated internally as well as externally to check the possibilities of any chance correlation and judge the predictive potential of the models. Pharmacological distribution diagrams (PDDs) were used for the classification model as a visualizing technique for the identification and selection of chemicals with lower partitioning into milk. Our in silico models enable to identify the essential structural attributes and quantify the prime molecular pre-requisites which were chiefly responsible for secretion into milk. The developed models were also implemented to screen milk/plasma partitioning potential for a huge number DrugBank database (http://www.drugbank.ca/) compounds. PMID- 27480063 TI - In Silico and In Vitro Studies of Truncated Forms of Flagellin (FliC) of Enteroaggregative Escherichia coli (EAEC). AB - Enteroaggregative Escherichia coli (EAEC) is an important cause of acute and chronic diarrhea worldwide. It has been shown that flagellin (FliC), a major bacterial surface protein of EAEC, causes IL-8 release from certain epithelial cell lines via activation of TLR-5. Based on the ability of this protein to activate innate immunity, flagellin can be considered as a potent adjuvant in new vaccines and adjuvant effects of native or recombinant forms of flagellin have been demonstrated. In the current study we designed various truncated forms of FliC-EAEC based on its interaction site with TLR-5 and assessed the interactions via docking protocols. Then, the most appropriate truncated forms were PCR amplified, cloned in to pGEX-5X-1 plasmid and expressed. Finally, the expressed proteins were tested for pro-inflammatory properties. Our in silico and in vitro results indicated that two truncated forms of FliC- EAEC (amino acids 79-117 and 477-508) effectively interact with TLR-5, thus could be capable of inducing in vivo immune responses. PMID- 27480064 TI - Modeling Complexes of Transmembrane Proteins: Systematic Analysis of Protein?Protein Docking Tools. AB - Protein?protein docking methodology is frequently used to model complexes of transmembrane proteins, in particular oligomers of G protein-coupled receptors (GPCRs), even if its applicability for these systems has never been fully validated. The aim of this work is to perform a systematic study on the suitability of some widely-used protein?protein docking software for modeling complexes of transmembrane proteins. In this study we tested the programs ZDOCK, ClusPro, HEX, GRAMM-X, PatchDock, SymmDock, and HADDOCK, using a set of membrane protein oligomers for which the 3D structure has been obtained experimentally, including opsin dimer, the recently published chemokine CXCR4 and kappa opioid receptor dimers. The results show that the docking success depends on the applied docking algorithm and scoring functions, but also on inherent structural features of the transmembrane proteins. Thus, proteins with large interface surfaces, rich in surface cavities, high-order symmetry, and small conformational change upon complex formation are well predicted more often than proteins without these features. The results of this systematic analysis provide guidelines that can be used for obtaining reliable models of transmembrane proteins, including GPCRs. Therefore they can be useful for the application of structure-based methods in drug discovery projects involving these targets. PMID- 27480065 TI - In Silico Prediction of Mechanism of Action for Cancer Therapeutics. AB - Cancer is currently the second leading cause of death in the U.S. and is projected to become the principal cause in the near future. While radiation and surgery are common cancer treatment methods, chemotherapy remains a key treatment option, offering distinct advantages over other therapy options, especially in the management of metastasized tumors. Understanding the mechanism of action (MoA) of current and newly developed drugs is crucial to ongoing drug development research. Foreknowledge of how a candidate drug works can yield a wealth of information, including which cancers a drug may treat more effectively based on the susceptibility of the cancer to drugs with the same MoA. Previous studies concerning prediction of MoA have relied on costly experimental measurements as input for their predictions. We have developed an a priori quantitative structure activity relationship (QSAR) for the in silico prediction of MoA without the need for experimental measurements. This model enables us to relate structural features of a chemical to its efficacy with a predictive accuracy of over 80 %, thus identifying the MoA of a candidate drug without costly, time-consuming experimental tests. PMID- 27480066 TI - Integrated One-Against-One Classifiers as Tools for Virtual Screening of Compound Databases: A Case Study with CNS Inhibitors. AB - A total of 21 833 inhibitors of the central nervous system (CNS) were collected from Binding-database and analyzed using discriminant analysis (DA) techniques. A combination of genetic algorithm and quadratic discriminant analysis (GA-QDA) was proposed as a tool for the classification of molecules based on their therapeutic targets and activities. The results indicated that the one-against-one (OAO) QDA classifiers correctly separate the molecules based on their therapeutic targets and are comparable with support vector machines. These classifiers help in charting the chemical space of the CNS inhibitors and finding specific subspaces occupied by particular classes of molecules. As a next step, the classification models were used as virtual filters for screening of random subsets of PUBCHEM and ZINC databases. The calculated enrichment factors together with the area under curve values of receiver operating characteristic curves showed that these classifiers are good candidates to speed up the early stages of drug discovery projects. The "relative distances" of the center of active classes of biosimilar molecules calculated by OAO classifiers were used as indices for sorting the compound databases. The results revealed that, the multiclass classification models in this work circumvent the definition inactive sets for virtual screening and are useful for compound retrieval analysis in Chemoinformatics. PMID- 27480067 TI - HMGB1 facilitates hypoxia-induced vWF upregulation through TLR2-MYD88-SP1 pathway. AB - Increased plasma level of von Willebrand Factor (vWF) is associated with major cardiovascular diseases. We previously reported that multimeric vWF binds to NO synthase and inhibits insulin-induced production of NO, thus promoting insulin resistance during acute hypoxia (AH). However, the transcriptional regulation of vWF during AH is not clearly understood. Here, we investigated the mechanisms underlying the upregulation of vwf in mice. AH significantly upregulates the tlr2, tlr3, myd88, and vwf expression and phosphorylation of specificity protein 1 (SP1). Furthermore, AH significantly upregulates high mobility group box-1 (HMGB1) in a time-dependent manner. Moreover, a TLR2 agonist upregulates vWF but a TLR3 agonist does not. Pretreatment with an HMGB1 inhibitor, TLR2 immunoneutralizing antibody, or SP1 inhibitor significantly inhibits vWF expression. Furthermore, Tlr2 silencing completely inhibited MYD88, vWF expression, and SP1 phosphorylation. However, pretreatment with glycyrrhizic acid or silencing of Tlr2 completely blocks binding of Sp1 to the Vwf promoter, thus inhibiting its expression, and enhances insulin resistance during AH. Patients with type 2 diabetes mellitus also showed significantly elevated levels of HMGB1, TLR2, SP1, and vWF, thereby supporting the results of the murine model of AH. Taken together, HMGB1 upregulates vWF in vivo through the TLR2-MYD88-SP1 pathway in mice. PMID- 27480069 TI - Anemia and stroke: Where do we stand? AB - Anemia seems to have a clear relationship with cerebrovascular events (CVEs), as there is a direct connection between central nervous system, blood supply, and tissue oxygen delivery. Anemia is considered a hyperkinetic state which disturbs endothelial adhesion molecule genes that may lead to thrombus formation. Furthermore, blood flow augmentation and turbulence may result in the migration of this thrombus, thus producing artery-to-artery embolism. It is for this reason that anemia is characterized as "the fifth cardiovascular risk factor." Anemia is consistently present in patients with acute stroke, ranging from 15% to 29%, while the mortality rate was significantly higher in patients suffering from anemia at the time of admission. Different types of anemia (sickle cell disease, beta thalassemia, iron deficiency anemia [IDA]) have been associated with increased cardiovascular and CVE risk. The relation between hemoglobin level and stroke would require further investigation. Unfortunately, treatment of anemia in cardiovascular and cerebrovascular disease still lacks clear targets and specific therapy has not developed. However, packed red blood cell transfusion is generally reserved for therapy in patients with CVEs. What is more, treatment of IDA prevents thrombosis and the occurrence of stroke; although iron levels should be checked, chronic administration favors thrombosis. Regarding erythropoietin (EPO), as there is lack of studies in anemic stroke patients, it would be desirable to utilize both neuroprotective and hematopoietic properties of EPO in anemic stroke patients. This review aims to clarify the poorly investigated and defined issues concerning the relation of anemia and CVEs. PMID- 27480068 TI - Disruption of dmc1 Produces Abnormal Sperm in Medaka (Oryzias latipes). AB - DMC1 is a recombinase that is essential for meiotic synapsis. Experiments in extensive species of eukaryotes have indicated the independent role of DMC1 in repairing double strand breaks (DSBs) produced during meiosis I. Mutation of dmc1 in mice and human often leads to obstacles in spermatogenesis and male sterility. Here, we report on the disruption of dmc1 in male medaka (Oryzias latipes). Synapsis was disturbed in the mutant medaka testis nuclei, as observed in mice and other organisms. Unexpectedly, the mutant medaka could produce a few sperm and, although most of these had multiple tail or multiple head malformations, some of them could swim, and few of them even had insemination ability. Our transcriptome analysis showed that there was not a remarkable change in the expression of most of the genes involved in the pathways associated with the meiotic DNA repair and flagella assembly. Our results provided an indication of the accessory mechanisms that might be involved in the repair of DSBs during meiosis. In a species besides humans, we provided evidence that disorders in meiosis recombination might lead to the malformation of sperm. PMID- 27480070 TI - Circulating T-helper 17 cells and associated cytokines in psoriasis. AB - BACKGROUND: Recently, a new population of IL-17-producing CD4 T helper (Th) cells, named Th17, was identified and shown to be involved in various inflammatory and autoimmune diseases, including psoriasis. AIM: To determine the frequency of Th17 cells and related cytokines in peripheral blood of patients with psoriasis, and to analyse their association with disease severity. METHODS: This was a prospective study comprising 34 patients with psoriasis and 24 healthy controls. Clinicoepidemiological details of patients were recorded, and severity of psoriasis was assessed by means of the Psoriasis Area and Severity Index. Circulating Th1 and Th17 cells in untreated patients with psoriasis and healthy controls were quantified by flow cytometry. In sera collected from patients with psoriasis and healthy controls, concentrations of IL-17A and IL-23 were examined by ELISA. RESULTS: Increased frequencies of CD4+ IL-17A+ T cells were seen in peripheral blood of patients with psoriasis vulgaris (P < 0.001). Although serum IL-17A and IL-23 concentrations were higher in patients with psoriasis than in controls, the results did not reach statistical significance. We could not find any correlation between the studied T cells or related cytokines and the disease severity. CONCLUSION: Increased serum levels of circulating Th17 cells and related cytokines may contribute to the cutaneous pathology of psoriasis, as well as the inflammatory process that is a hallmark of psoriasis. PMID- 27480071 TI - Variations in lung lymphatic drainage into the inferior tracheobronchial lymph nodes junction: Applications in lung cancer. AB - The group of inferior tracheobronchial lymph nodes (ITB) is a lymphatic junction through which the lymph from both lungs is carried. Lymphatic activity in this area can be used to assess the lymphatic spreading of lung cancers. Our aim was to quantify lymph drainage from the lung segments towards the ITB group and to determine the direction of the lymph flow into other mediastinal and abdominal lymph nodes. We injected dye directly into the subpleural lymphatic vessels in 100 lung segments of 25 fresh cadaver subjects; the cadavers were then dissected. Thirty-eight segments (38%) drained into the ITB group in 18 subjects. The drainage into the ITB group involved 15.6% of the upper lobe segments, 87.5% of the middle lobe segments, and 70.6% of the lower lobe segments in the right lung. On the left, 6.9% of the upper lobe segments and 83.3% of the lower lobe segments were drained into the ITB group. For three subjects, the dye did not pass beyond the ITB group. The efferent vessels of the ITB group drained towards the right paratracheal and tracheoesophageal chains in 12 subjects and through the left ascending recurrent chain in five subjects. For six subjects, the efferent channels reached the abdominal lymph nodes. A contralateral drainage involved 14 segments (36%). The size and variety of the segments that drain into the ITB group, coupled with the efferent contralateral mediastinal and abdominal pathways, account for the severity of metastasis to this area. Clin. Anat. 29:955 962, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27480072 TI - Therapeutic Strategies and Pharmacological Tools Influencing S1P Signaling and Metabolism. AB - During the last two decades the study of the sphingolipid anabolic, catabolic, and signaling pathways has attracted enormous interest. Especially the introduction of fingolimod into market as first p.o. therapeutic for the treatment of multiple sclerosis has boosted this effect. Although the complex regulation of sphingosine-1-phosphate (S1P) and other catabolic and anabolic sphingosine-related compounds is not fully understood, the influence on different (patho)physiological states from inflammation to cytotoxicity as well as the availability of versatile pharmacological tools that represent new approaches to study these states are described. Here, we have summarized various aspects concerning the many faces of sphingolipid function modulation by different pharmacological tools up to clinical candidates. Due to the immense heterogeneity of physiological or pharmacological actions and complex cross regulations, it is difficult to predict their role in upcoming therapeutic approaches. Currently, inflammatory, immunological, and/or antitumor aspects are discussed. PMID- 27480074 TI - An enzyme-coupled artificial photosynthesis system prepared from antenna protein mimetic tyrosyl bolaamphiphile self-assembly. AB - An artificial photosynthesis system coupled with an enzyme was constructed using the nanospherical self-assembly of tyrosyl bolaamphiphiles, which worked as a host matrix exhibiting an antenna effect that allowed enhanced energy transfer to the ZnDPEG photosensitizer. The excited electrons from the photosensitizer were transferred to NAD+ to produce NADH, which subsequently initiated the conversion of an aldehyde to ethanol by alcohol dehydrogenase. Production of NADH and ethanol was enhanced by increasing the concentration of tyrosyl bolaamphiphiles. Spectroscopic investigations proved that the photosensitizer closely associated with the surface of the bolaamphiphile assembly through hydrogen bonds that allowed energy transfer between the host matrix and the photosensitizer. This study demonstrates that the self-assembly of bolaamphiphiles could be applicable to the construction of biomimetic energy systems exploiting biochemical activity. PMID- 27480073 TI - Comparison of CT and MRI in Diagnosis of Laryngeal Carcinoma with Anterior Vocal Commissure Involvement. AB - This study aimed to compare the accuracy of CT and MRI in determining the invasion of thyroid cartilage by and the T staging of laryngeal carcinoma with anterior vocal commissure (AVC) involvement. A total of 26 cases of laryngeal carcinomas with AVC involvement from May 2012 to January 2014 underwent enhanced CT and MRI scan, out of whom 6 patients also underwent diffusion-weighted magnetic resonance imaging(DWI). T staging and thyroid cartilage involvement were evaluated. All the surgical specimens underwent serial section and were reviewed by two senior pathologists independently. When compared with pathologic staging, the accuracy was 88.46% (23/26) of MRI scan (with a 95% confidence interval 37~77%) and 57.69% (15/26) of CT scan (with a 95% confidence interval 70~98%), respectively (P < 0.01). We also reported three cases who were misdiagnosed on CT or MRI about either the thyroid cartilage was involved or not, and one case of preliminary study of DWI. Compared to CT, MRI exhibited a higher accuracy rate on T staging of laryngeal carcinomas with AVC involvement. Combined utility of CT and MRI could help improve the accuracy of assessment of thyroid cartilage involvement and T staging of laryngeal carcinomas with AVC involvement. PMID- 27480075 TI - Enhanced Risk of Carotid Atherosclerosis Associated With White-Coat Hypertension. PMID- 27480078 TI - Evaluation of the fetal QT interval using non-invasive fetal ECG technology. AB - Non-invasive fetal electrocardiography (NI-FECG) is a promising alternative continuous fetal monitoring method that has the potential to allow morphological analysis of the FECG. However, there are a number of challenges associated with the evaluation of morphological parameters from the NI-FECG, including low signal to noise ratio of the NI-FECG and methodological challenges for getting reference annotations and evaluating the accuracy of segmentation algorithms. This work aims to validate the measurement of the fetal QT interval in term laboring women using a NI-FECG electrocardiogram monitor. Fetal electrocardiogram data were recorded from 22 laboring women at term using the NI-FECG and an invasive fetal scalp electrode simultaneously. A total of 105 one-minute epochs were selected for analysis. Three pediatric electrophysiologists independently annotated individual waveforms and averaged waveforms from each epoch. The intervals measured on the averaged cycles taken from the NI-FECG and the fetal scalp electrode showed a close agreement; the root mean square error between all corresponding averaged NI-FECG and fetal scalp electrode beats was 13.6 ms, which is lower than the lowest adult root mean square error of 16.1 ms observed in related adult QT studies. These results provide evidence that NI-FECG technology enables accurate extraction of the fetal QT interval. PMID- 27480077 TI - SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features. AB - Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement. We compare that to 13 affected individuals from the literature including five adults allowing us to delineate the features that may develop over time with this disorder including kyphosis, retinitis pigmentosa, and cataracts. (c) 2016 Wiley Periodicals, Inc. PMID- 27480076 TI - MAPK signaling is necessary for neurogenesis in Nematostella vectensis. AB - BACKGROUND: The nerve net of Nematostella is generated using a conserved cascade of neurogenic transcription factors. For example, NvashA, a homolog of the achaete-scute family of basic helix-loop-helix transcription factors, is necessary and sufficient to specify a subset of embryonic neurons. However, positive regulators required for the expression of neurogenic transcription factors remain poorly understood. RESULTS: We show that treatment with the MEK/MAPK inhibitor U0126 severely reduces the expression of known neurogenic genes, Nvath-like, NvsoxB(2), and NvashA, and known markers of differentiated neurons, suggesting that MAPK signaling is necessary for neural development. Interestingly, ectopic NvashA fails to rescue the expression of neural markers in U0126-treated animals. Double fluorescence in situ hybridization and transgenic analysis confirmed that NvashA targets represent both unique and overlapping populations of neurons. Finally, we used a genome-wide microarray to identify additional patterning genes downstream of MAPK that might contribute to neurogenesis. We identified 18 likely neural transcription factors, and surprisingly identified ~40 signaling genes and transcription factors that are expressed in either the aboral domain or animal pole that gives rise to the endomesoderm at late blastula stages. CONCLUSIONS: Together, our data suggest that MAPK is a key early regulator of neurogenesis, and that it is likely required at multiple steps. Initially, MAPK promotes neurogenesis by positively regulating expression of NvsoxB(2), Nvath-like, and NvashA. However, we also found that MAPK is necessary for the activity of the neurogenic transcription factor NvashA. Our forward molecular approach provided insight about the mechanisms of embryonic neurogenesis. For instance, NvashA suppression of Nvath like suggests that inhibition of progenitor identity is an active process in newly born neurons, and we show that downstream targets of NvashA reflect multiple neural subtypes rather than a uniform neural fate. Lastly, analysis of the MAPK targets in the early embryo suggests that MAPK signaling is critical not only to neurogenesis, but also endomesoderm formation and aboral patterning. PMID- 27480080 TI - Antifibrotic Effects of Human Amniotic Membrane Transplantation in Established Biliary Fibrosis Induced in Rats. AB - Liver fibrosis is characterized by excessive accumulation of extracellular matrix components in the liver parenchyma that distorts the normal architecture and hepatic function. Progressive fibrosis could end in the advanced stage known as cirrhosis, resulting in the need to resort to liver transplantation. Amniotic membrane (AM) has emerged as an innovative therapeutic approach for chronic liver diseases due to its anti-inflammatory, antiscarring, and wound-healing effects. We have recently shown that AM can be used as a patch on the liver surface at the same time of fibrosis induction, resulting in significantly reduced progression and severity of biliary fibrosis. Here we investigated the effects of human AM on the established rat model of liver fibrosis, induced by the bile duct ligation (BDL). We also explored the effect of AM on the expression of transforming growth factor-1 (TGF-1), the main profibrogenic factor in hepatic fibrosis, and the proinflammatory cytokines, tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and anti-inflammatory cytokine IL-10. Two weeks after BDL, the liver was covered with a fragment of AM or left untreated. Six weeks later, the fibrosis was first assessed by the semiquantitative Knodell and the METAVIR scoring systems and, thereafter, by CellProfiler digital image analysis to quantify the area occupied by collagen deposition, ductular reactions (DRs), activated myofibroblasts, and TGF-1. The hepatic cytokines were determined by ELISA. AM-treated rats showed a significantly lower score compared to the control BDL rats (2.50.9 vs. 3.50.3, respectively; p0.05). The collagen deposition, DRs, number of activated myofibroblasts, and TGF-1 were all reduced to about 50% of levels observed in untreated BDL rats. These findings suggest that AM, when applied as a patch onto the liver surface, is useful for treating well-established cholestatic fibrosis, and the mechanism was partly by means of downregulating the profibrotic factor TGF-1 and IL-6. PMID- 27480079 TI - Anti-platelet and anti-thrombogenic effects of shikimic acid in sedentary population. AB - This ex vivo study was performed to evaluate the anti-platelet and anti thrombogenic potential of shikimic acid (SA), a plant phenolic metabolite. Fasting blood samples were collected from 22 sedentary participants to analyse the effect of varying concentrations of SA (0.1 mM, 0.2 mM, 0.5 mM, 1 mM and 2 mM) on platelet surface-marker expression, platelet aggregation and biomarkers of thrombogenesis. Monocyte-platelet aggregates (CD14/CD42b) and platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31), effective indicators of thrombus formation were evaluated. Procaspase-activating compound 1 (PAC-1) and P selectin or CD62P were used to assess platelet activation-related thrombogenesis. Adenosine diphosphate (ADP) was used to stimulate the P2Y1/P2Y12 pathway of platelet activation to mimic the in vivo thrombogenic pathway. Platelet aggregation studies utilised both ADP and collagen as exogenous platelet agonists to target both P2Y1/P2Y12 and GPVI pathways of thrombus formation. It was observed with flow cytometry that SA produced a significant antiplatelet effect on PAC-1 (p = 0.03 at 2 mM) and CD62P (p = 0.017, p = 0.036 at 1 mM and 2 mM respectively) expression in addition to lowering monocyte-platelet aggregate formation (p = 0.013, p < 0.01 and p < 0.01 at 0.5 mM, 1 mM and 2 mM respectively). SA at 1 mM concentration reduced PECAM-1 expression (p = 0.035), signifying a reduction to endothelial leucocyte migration during thrombus growth. SA did not demonstrate a platelet aggregation inhibitory effect by targeting the GPVI collagen pathway but reduced ADP induced platelet aggregation at 2 mM concentration (p < 0.01 at 2 mM). The results suggest that SA, an active metabolite of polyphenol-rich food intake, could play an important role in reducing platelet activation, aggregation related thrombus formation and biomarkers of thrombogenesis in sedentary individuals. PMID- 27480081 TI - [Not Available]. PMID- 27480082 TI - Inactivation of the LKB1-AMPK signaling pathway does not contribute to salivary gland tumor development - a short report. AB - PURPOSE: Activation of AMPK by the tumor suppressor LKB1 represents an essential gatekeeping step for cells under energetic stress to prevent their growth and proliferation by inhibiting mTOR activation, until the energy supply normalizes. The LKB1/AMPK pathway is frequently downregulated in various types of cancer, thereby uncoupling tumor cell growth and proliferation from energy supply. As yet, little information is available on the role of the LKB1/AMPK pathway in tumors derived from salivary gland tissues. METHODS: We performed LKB1 protein expression and AMPK and mTOR activation analyses in several salivary gland tumor types and their respective healthy control tissues using immunohistochemistry. RESULTS: No significant downregulation of LKB1 expression or decreased activation of AMPK or mTOR were observed in any of the salivary gland tumors tested. In contrast, we found that the salivary gland tumors exhibited an increased rather than a decreased AMPK activation. Although the PI3K/Akt pathway was found to be activated in most of the analyzed tumor samples, the unchanged robust activity of LKB1/AMPK likely prevents (over)activation of mTOR. CONCLUSION: In contrast to many other types of cancer, inactivation or downregulation of the LKB1/AMPK pathway does not substantially contribute to the pathogenesis of salivary gland tumors. PMID- 27480083 TI - A network including PU.1, Vav1 and miR-142-3p sustains ATRA-induced differentiation of acute promyelocytic leukemia cells - a short report. AB - PURPOSE: Reduced expression of miR-142-3p has been found to be associated with the development of various subtypes of myeloid leukemia, including acute promyelocytic leukemia (APL). In APL-derived cells, miR-142-3p expression can be restored by all-trans retinoic acid (ATRA), which induces the completion of their maturation program. Here, we aimed to assess whether PU.1, essential for ATRA induced gene transcription, regulates the expression of miR-142-3p in APL-derived cells and, based on the established cooperation between PU.1 and Vav1 in modulating gene expression, to evaluate the role of Vav1 in restoring the expression of miR-142-3p. METHODS: ATRA-induced increases in PU.1 and Vav1 expression in APL-derived NB4 cells were counteracted with specific siRNAs, and the expression of miR-142-3p was measured by quantitative real-time PCR (qRT PCR). The recruitment of PU.1 and/or Vav1 to the regulatory region of miR-142 was assessed by quantitative chromatin immunoprecipitation (Q-ChIP). Synthetic inhibitors or mimics for miR-142-3p were used to assess whether this miRNA plays a role in regulating the expression of PU.1 and/or Vav1. RESULTS: We found that the expression of miR-142-3p in differentiating APL-derived NB4 cells is dependent on PU.1, and that Vav1 is essential for the recruitment of this transcription factor to its cis-binding element on the miR-142 promoter. In addition, we found that in ATRA-treated NB4 cells miR-142-3p sustains agonist induced increases in both PU.1 and Vav1. CONCLUSIONS: Our results suggest the existence of a Vav1/PU.1/miR-142-3p network that supports ATRA-induced differentiation in APL-derived cells. Since selective regulation of miRNAs may play a role in the future treatment of hematopoietic malignancies, our results may provide a basis for the development of new therapeutic strategies to restore the expression of miR-142-3p. PMID- 27480085 TI - Another New Esophagitis: The Lymphocyte Gets Its Turn. PMID- 27480084 TI - Safety of Target-Controlled Propofol Infusion by Gastroenterologists in Patients Undergoing Endoscopic Resection. AB - BACKGROUND: A target-controlled infusion (TCI) of a propofol system uses a pharmacokinetic model to achieve and maintain a selected target blood propofol concentration. The aim of this study was to assess whether the propofol TCI system could be safely used by gastroenterologists in patients undergoing endoscopic resection including endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) compared with a manually controlled infusion (MCI) system. METHODS: A total of 431 patients undergoing therapeutic endoscopy (178 ESD and 253 EMR) were consecutively included from November 2011 to August 2014. The patients were divided into the MCI (271) and TCI (160) propofol infusion groups. We compared adverse event rates in MCI and TCI groups and assessed independent risk factors for adverse events. RESULTS: The total sedation related adverse event rate was 5.8 % (25/431). Most of the events were minor, and the rate of major events was 0.5 % (2/431). There was no significant difference in adverse event rate between the MCI and TCI groups [5.5 % (15/271) vs. 6.3 % (10/160); P = 0.759]. In univariate analysis, the propofol infusion time was significantly associated with adverse events (94.88 vs. 59.45 min, P = 0.017). In the multivariate analysis, there were no significant factors associated with adverse events. TCI was not an independent risk factor for adverse events despite the fact that the TCI had a longer duration of infusion and higher total infusion dose (95 % CI, 0.343-2.216; P = 0.773). CONCLUSIONS: TCI of propofol by gastroenterologists may provide safe sedation in patients undergoing ESD and EMR under careful respiratory monitoring. PMID- 27480086 TI - The Increasing Incidence of Colorectal Cancers Diagnosed in Subjects Under Age 50 Among Races: CRaCking the Conundrum. PMID- 27480087 TI - Gluten, Dysbiosis, and Genetics in Celiac Disease: All Are Important. PMID- 27480088 TI - Diabetes Is Associated with Clinical Decompensation Events in Patients with Cirrhosis. AB - OBJECTIVES: Liver cirrhosis is a leading cause of morbidity and mortality in the USA. Diabetes is common and increasing in incidence. Patients with compensated cirrhosis and diabetes may be at greater risk of clinical decompensation. We examined the risk of decompensation among a large sample of working-aged insured patients dually diagnosed with compensated cirrhosis and diabetes. METHODS: This retrospective study used MarketScan(r) Commercial Claims and Encounters and Medicare Supplemental Databases (2000-2013). Decompensation events included incident ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, acute renal failure, and hepatocellular carcinoma. Dually diagnosed patients were defined as patients with cirrhosis and diabetes using previously published ICD-9 coding strategies. Adjusted odds ratios (ORs), hazard ratios (HRs), and confidence intervals (CI) were estimated using logistic regression and Cox proportional hazard models. RESULTS: Of 72,731 patients with compensated cirrhosis, 20,477 patients (28.15 %) were diagnosed with diabetes. After controlling for patient characteristics and medication usage, the odds of developing any decompensation event were 1.14 times higher for patients with cirrhosis and diabetes than for patients with cirrhosis only (95 % CI 1.08-1.21, P value <0.01). In the Cox proportional hazard model, patients who were dually diagnosed with diabetes had a 1.32 times higher HR (95 % CI 1.26-1.39, P value <0.01) after controlling for time-to-event. CONCLUSIONS: Patients dually diagnosed with compensated cirrhosis and diabetes had a higher risk of having decompensation events. Careful management of diabetes in patients with liver disease may reduce the risk of clinical decompensation in this population. PMID- 27480089 TI - Knowledge and Attitudes Regarding Non-Invasive Prenatal Testing (NIPT) and Preferences for Risk Information among High School Students in Sweden. AB - Non-invasive prenatal testing (NIPT) was recently introduced for prenatal testing of genetic disorders. Cell-free fetal DNA is present in maternal blood during pregnancy and enables detection of fetal chromosome aberrations in a maternal blood sample. The public perspective to this new, simple method has not been illuminated. The views of young people (i.e. future parents) are important to develop suitable counseling strategies regarding prenatal testing. The aim was to explore Swedish high school students' attitudes, knowledge and preferences regarding NIPT. A questionnaire was completed by 305 students recruited from one high school in Stockholm, November and December 2014. Most students (80 %) considered prenatal testing as good. The majority (65 %) was positive or very positive towards NIPT and 62 % stated that they potentially would like to undergo the test if they or their partner was pregnant. The vast majority (94 %) requested further information about NIPT. Most students (61 %) preferred verbal information, whereas 20 % preferred information via the Internet. The majority of the high school students was positive towards prenatal testing and most was positive towards NIPT. Further, information was requested by the vast majority before making a decision about NIPT. Most of the students preferred verbal information and to a lesser extent information via the Internet. The attitudes, knowledge and preferences for risk information concerning NIPT in young adults are important, in order to increase knowledge on how to educate and inform future parents. PMID- 27480090 TI - Anti-thymocyte globulin-induced hyperbilirubinemia in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment option for myelofibrosis (MF) despite the emergence of novel targeted therapies. To reduce graft rejection and graft-versus-host disease (GvHD), current allo-HCT protocols often include in vivo T lymphocyte depletion using polyclonal anti-thymocyte globulin (ATG). Shortly after ATG administration, an immediate inflammatory response with fever, chills, and laboratory alterations such as cytopenias, elevation of serum C-reactive protein, bilirubin, and transaminases can develop. Here, we explore whether MF patients, who commonly exhibit extramedullary hematopoiesis in the liver, might be particularly susceptible to ATG-induced liver toxicity. To test this hypothesis, we analyzed 130 control and 94 MF patients from three transplant centers treated with or without ATG during the allo-HCT conditioning regimen. Indeed, hyperbilirubinemia was found in nearly every MF patient treated with ATG (MF-ATG 54/60 = 90 %) as compared to non-ATG treated MF (MF-noATG 15/34 = 44.1 %, p < 0.001) and respectively ATG-treated non-MF patients of the control group (control-ATG, 43/77 = 56 %, p < 0.001). In contrast, transaminases were only inconsistently elevated. Hyperbilirubinemia was in most cases self-limiting and not predictive of increased incidence of non-relapse mortality, hepatic sinusoidal obstruction syndrome (SOS) or liver GvHD. In sum, awareness of this stereotypic bilirubin elevation in MF patients treated with ATG provides a relatively benign explanation for hyperbilirubinemia occurring in these patients during the early transplant. However, attention to drug levels of biliary excreted drugs is warranted, since altered bile flow may influence their clearance and enhance toxicity (e.g., busulfan, antifungal agents). PMID- 27480091 TI - Flushing of the vagina and the prepuce-a cause for contaminated urine cultures in children. AB - OBJECTIVE: An uncontaminated urine culture is a prerequisite for the diagnosis of a urinary tract infection. However, this may be difficult to obtain in small children. We have studied the frequency of ballooning of the prepuce in non circumcised boys and vaginal reflux in girls during voiding as a possible cause of contaminated urine cultures. METHODS: All micturating cystourethrograms (MCUG) performed in our institution over the last 5 years in children aged 0-15 years were reviewed retrospectively for ballooning of the foreskin or vaginal reflux as a potential source of bacterial contamination. The voiding pictures were routinely done with the catheter present for the first voiding cycle and then removed on the second void. RESULTS: A total of 526 children (77.4 % boys, 22.6 % girls) were eligible for the study. Ballooning of the foreskin was identified on the micturition pictures of 115 (38 %) boys, with the frequency significantly higher in boys aged <12 months [odds ratio (OR) 4.1; 95 % confidence interval (CI) 2.1-7.3)] and boys with vesicoureteral reflux (OR 1.6; 95 % CI 1.06-2.4). Seventeen girls (14.3 %) showed vaginal reflux. No correlation with age or vesicoureteral reflux was found in the girls. CONCLUSION: Ballooning of the prepuce or vaginal reflux was seen on a fluoroscopic MCUG in a large proportion of children during their voiding. This normal phenomenon might cause contaminated urine cultures when the urine is obtained by bag or clean catch. PMID- 27480092 TI - Effects of a single bilateral infusion of R-ketamine in the rat brain regions of a learned helplessness model of depression. AB - Effects of a single bilateral infusion of R-enantiomer of ketamine in rat brain regions of learned helplessness model of depression were examined. A single bilateral infusion of R-ketamine into infralimbic (IL) portion of medial prefrontal cortex (mPFC), CA3 and dentate gyrus (DG) of the hippocampus showed antidepressant effects. By contrast, a single bilateral infusion of R-ketamine into prelimbic (PL) portion of mPFC, shell and core of nucleus accumbens, basolateral amygdala and central nucleus of the amygdala had no effect. This study suggests that IL of mPFC, CA3 and DG of hippocampus might be involved in the antidepressant actions of R-ketamine. PMID- 27480093 TI - Propofol Prevents Hippocampal Neuronal Loss and Memory Impairment in Cerebral Ischemia Injury Through Promoting PTEN Degradation. AB - Neuroprotective effect of propofol against cerebral ischemia injury was widely investigated. However, its mechanisms remain unclear. Phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling pathway is supposed as a cell survival pathway, and phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a negative regulator of AKT phosphorylation. Whether PTEN was involved in the protective effect of propofol against cerebral ischemia injury was not elucidated. In this study, the function of PTEN in the acute phase of cerebral ischemia injury was investigated. Our data showed that propofol promoted the PTEN degradation in the acute phase of cerebral ischemia injury and concurrently activated AKT phosphorylation. The increase of ubiquitinated PTEN caused by cerebral ischemia injury were degraded in propofol-pretreated rats. Moreover, we evidenced that proteasome activity was stimulated in propofol-treated rats. These data pointed that PTEN degradation was facilitated in the acute phase after propofol treatment possibly through activating ubiquitin-proteasome system. Therefore, we applied PTEN inhibitor-bpV before cerebral ischemia injury. Like propofol, bpV pretreatment also mitigated cerebral ischemia injury-induced cell loss in CA1 region and memory impairment. Taken together, our data suggest that PTEN degradation is neuroprotective against cerebral ischemia injury and propofol facilitates PTEN degradation to prevent hippocampal neuronal loss and memory deficit in cerebral ischemia injury. PMID- 27480095 TI - Quantification of autonomic nervous activity by heart rate variability and approximate entropy in high ultrafiltration rate during hemodialysis. AB - BACKGROUND: Few studies have focused on the imbalance of the autonomic nervous system in ultrafiltration rate (UFR) subjects without blood pressure variation during maintenance hemodialysis (HD), although the role of autonomic nervous system activation during HD has been proposed to be an important factor for the maintenance of blood pressure. METHODS: Variations over time in autonomic nervous activity due to differences in UFR were evaluated by measuring heart rate variability (HRV) and approximate entropy (ApEn) in 35 HD patients without blood pressure variations during HD session. The subjects were divided into 3 groups, those with UFR <10 ml/h/kg; >=10 ml/h/kg but <=15 ml/h/kg; and >15 ml/h/kg, and Holter ECG was recorded continuously during HD session using frequency analysis of RR intervals. High frequency (HF) and low frequency (LF) spectral components are found to be representative of the parasympathetic nervous system and sympathovagal balance, respectively, with the ratio of LF to HF of HRV providing a measure of sympathetic nervous system. RESULTS: In subjects with UFR >15 ml/h/kg, HF components were significantly lower, and LF/HF and ApEn values were significantly higher, in the latter half of an HD session than before starting HD. CONCLUSION: Removing water from these subjects would promote sustained sympathetic nervous overactivity. These findings indicate that the UFR during HD needs to be set at <=15 ml/h/kg. PMID- 27480094 TI - Association of interactions between dietary salt consumption and hypertension susceptibility genetic polymorphisms with blood pressure among Japanese male workers. AB - BACKGROUND: Blood pressure is influenced by hereditary factors and dietary habits. The objective of this study was to examine the effect of dietary salt consumption and single-nucleotide polymorphisms (SNPs) on blood pressure (BP). METHODS: This was a cross-sectional analysis of 2728 male participants who participated in a health examination in 2009. Average dietary salt consumption was estimated using electronically collected meal purchase data from cafeteria. A multivariate analysis, adjusting for clinically relevant factors, was conducted to examine whether the effect on BP of salt consumption, SNPs, and interaction between salt consumption and each SNP. This study examined the SNPs AGT rs699 (Met235Thr), ADD1 rs4961 (Gly460Trp), NPPA rs5063 (Val32Met), GPX1 rs1050450 (Pro198Leu), and AGTR1 rs5186 (A1166C) in relation to hypertension and salt sensitivity. RESULTS: BP was not significantly associated with SNPs or salt consumption. The interaction between salt consumption and SNPs with systolic BP showed a significant association in NPPA rs5063 (Val32Met) (P = 0.023) and a marginal trend toward significance in rs4961 and rs1050450 (P = 0.060 and 0.067, respectively). CONCLUSION: The effect of salt consumption on BP differed by genotype. Dietary salt consumption and genetic variation can predict a high risk of hypertension. PMID- 27480096 TI - Effect of continuous positive airway pressure (CPAP) on glycemic control and variability in type 2 diabetes. PMID- 27480097 TI - The value of hypercalciuria in patients with osteopenia versus osteoporosis. AB - The aim of this study was to analyze the presence of lithogenic metabolic factors in the blood and urine of patients with osteopenia versus osteoporosis. This is a cross-sectional study including 67 patients who were divided into two groups according to the presence of either osteopenia or osteoporosis as measured by bone densitometry: group 1-40 patients with osteopenia (22 men and 18 women) and group 2-27 patients with osteoporosis (13 men and 14 women). Metabolic studies were performed on the blood and urine; statistical analysis was performed comparing means and conducting linear correlation and multivariate analyses with SPSS. Statistical significance was considered to be p <= 0.05. The mean age of patients in group 1 was 52.9 +/- 12.8 years versus 50.3 +/- 11.4 in group 2; the difference was not statistically significant. In group 2, higher levels of osteocalcin, beta-crosslaps, urinary calcium, fasting urine calcium/creatinine, 24 h urine calcium/creatinine and 24 h oxaluria were observed compared to group 1. In the multivariate analysis, only the beta-crosslaps and urinary calcium were independently associated with osteoporosis. It would be advisable to determine the urinary calcium levels in patients with osteoporosis since altered levels may necessitate modifying the diagnostic and therapeutic approach to osteoporosis. PMID- 27480098 TI - Mosquitoes (Diptera: Culicidae) From the Northwestern Brazilian Amazon: Padauari River. AB - The mosquito fauna (Culicidae) from remote northern areas of the State of Amazonas were sampled using Centers for Disease Control and Prevention, Shannon, Malaise, and Suspended traps, together with net sweeping and immature collections. One hundred and seven collections were performed in five localities along the Padauari River, State of Amazonas, Brazil, during June 2010. The 20,557 mosquitoes collected are distributed in 17 genera, representing 117 different species, of which four are new distributional records for the State of Amazonas. Furthermore, there are 10 morphospecies that may represent undescribed new taxa, eight of which are also new records for the State of Amazonas. The genus Culex had the highest number of species and the largest number of individuals. Aedes and Psorophora both represented 10% of the total sample and had the second highest number of species and individuals. The most abundant species was Culex (Melanoconion) gnomatos Sallum, Hutchings & Ferreira, followed by Aedes (Ochlerotatus) fulvus (Wiedemann), Culex (Melanoconion) vaxus Dyar, Culex (Melanoconion) portesi Senevet & Abonnenc, Psorophora (Janthinosoma) amazonica Cerqueira, Culex (Culex) mollis Dyar & Knab, Psorophora (Janthinosoma) albigenu (Peryassu), and Culex (Melanoconion) theobaldi Lutz. The epidemiological and ecological implications of mosquito species found are discussed and are compared with other mosquito inventories from the Amazon region. The results represent the most diverse standardized inventory of mosquitoes along the Padauari River, with the identification of 127 species-level taxa distributed in five localities, within two municipalities (Barcelos and Santa Isabel do Rio Negro). PMID- 27480099 TI - Rickettsia (Rickettsiales: Rickettsiaceae) Vector Biodiversity in High Altitude Atlantic Forest Fragments Within a Semiarid Climate: A New Endemic Area of Spotted-Fever in Brazil. AB - Rickettsioses are re-emerging vector-borne zoonoses with a global distribution. Recently, Rickettsia sp. strain Atlantic rainforest has been associated with new human spotted-fever (SF) cases in Brazil, featuring particular clinical signs: eschar formation and lymphadenopathy. These cases have been associated with the tick species, Amblyomma ovale From 2010 until 2015, the Brazilian Health Department confirmed 11 human SF cases in the Macico de Baturite region, Ceara, Brazil. The present study reports the circulation of Rickettsia spp. in vectors from this entirely new endemic area for SF. A total of 1,727 ectoparasites were collected in this area from the environment, humans, and wild and domestic animals. Samples (n = 887) were screened by polymerase chain reaction (PCR), targeting the gltA and ompA rickettsial genes. Sequencing and phylogenetic analyses of gltA gene amplicons were carried out for 13 samples positive for both screening PCRs. Fragments of gltA and ompA from three samples were cloned, sequenced, and analyzed further. A. ovale and Rhipicephalus sanguineus specimens, collected from dogs, were found to be infected with Rickettsia sp. str. Atlantic rainforest, suggesting the importance of dogs in the epidemic cycle. Candidatus Rickettsia andeanae, Rickettsia felis, and Rickettsia bellii were also found infecting ticks and fleas in five municipalities, demonstrating the broad diversity of rickettsiae in circulation in the studied area. This study reports, for the first time, evidence of infection with Rickettsia sp. strain Atlantic rainforest in A. ovale and R. sanguineus in Ceara, and Ca. R. andeanae in an Atlantic rainforest environment of Brazil. PMID- 27480100 TI - Hepatitis E virus antibody prevalence, RNA frequency, and genotype among blood donors in Cambodia (Southeast Asia). AB - BACKGROUND: Recent studies conducted in developed countries described hepatitis E virus (HEV) as an emerging infectious threat to blood safety. However, data on HEV among blood donors from southeast Asia are lacking. STUDY DESIGN AND METHODS: Between July and August 2014, we assessed the presence of HEV immunoglobulin (Ig)G and IgM in 301 Cambodian blood donors. All samples were further tested for the presence of HEV RNA using an in-house reverse transcription-polymerase chain reaction. ORF2/ORF3 phylogenetic analysis was performed on positive HEV RNA specimens. RESULTS: We found HEV IgG in 28.2% of blood donors from Cambodia. Three blood donors tested positive for HEV IgM with three distinct patterns: IgM(+)/IgG(-)/RNA(-) (n = 1), IgM(+)/IgG(+)/RNA(-) (n = 1), and IgM(+)/IgG(+)/RNA(+) (n = 1). Thus, the prevalence rates of HEV IgM and HEV RNA were 1.0 and 0.3%. Interestingly, the viremic blood donor harbored a HEV strain that belonged to Genotype 3 (HEV-3) and clustered with a Cambodian riverine HEV-3 isolate. CONCLUSION: Due to the high frequency of Cambodian blood donors with positive HEV IgG, we conclude that HEV is endemic in this country. Large-scale studies must be considered to determine whether Cambodian blood donation screening is warranted to enhance blood safety in regard to HEV. In addition, our findings suggest that river water may be a significant source of exposure to HEV 3. PMID- 27480101 TI - Biomechanical Profiles When Towing a Sled and Wearing a Weighted Vest Once Cleared for Sports Post-ACL Reconstruction. AB - BACKGROUND: Though rehabilitation attempts to correct "stiff knee gait" and control for dynamic limb valgus after anterior cruciate ligament reconstruction (ACLR), impaired biomechanics often persist when an individual is cleared to return to sport (RTS). Reduced knee extension moments (KEMs) and knee flexion angles (KFAs) often continue. While at the hip, increased hip adduction angles (HADDAs) and hip internal rotation angles (HIRAs) often persist in spite of dynamic hip stabilization exercises. Sled towing and weighted vest tasks increase KEM and hip extension moments (HEMs) in healthy individuals, yet biomechanical profiles during these tasks after ACLR are unknown. HYPOTHESIS: Weighted gait will increase KEM, HEM, hip abduction moments (HABDMs), and hip external rotation moments (HERMs) and will not increase unwanted biomechanics (limb asymmetries, HIRA, HADDA) compared with normal gait. STUDY DESIGN: Controlled laboratory study. LEVEL OF EVIDENCE: Level 4. METHODS: Fourteen men and 24 women who were 5 to 12 months after ACLR, had no concomitant ligament injuries, and were cleared to RTS were recruited. Sexes were evaluated independently given the sex-specific incidence to ACL injury, reinjury, and gait responses to certain interventions. Joint moment impulses and peak angles over the first 25% of stance were compared between limbs and across tasks (eg, unweighted gait, sled 50% body weight [BW], and vest 50% BW). RESULTS: Men showed that weighted gait increased KEM, HEM, HERM, HADBM (vest only), HADDA, HIRA (sled only), and KFA. Asymmetrical KEM and KFA existed across tasks. Women showed that weighted gait increased KEM, HEM, HERM, HADBM (vest only), HFA (sled only), HADDA, and KFA. Asymmetrical KEM, HEM, HIRA, and KFA (sled only) existed across tasks. CONCLUSION: Weighted gait generally increased joint moments. Unwanted biomechanics were unique for each weighted gait task. CLINICAL RELEVANCE: Though joint moments increased, both tasks created unwanted biomechanics after ACLR. Persistent hip (women only) and KEM asymmetries across tasks when cleared to RTS are concerning given the relationship among these biomechanics and decreased functional performance. PMID- 27480102 TI - Evaluation and Management of Athletes With Long QT Syndrome. AB - CONTEXT: The congenital long QT syndrome (LQTS) is an inherited channelopathy known for its electrocardiographic manifestations of QT prolongation and its hallmark arrhythmia, torsades de pointes (TdP). TdP can lead to syncope or sudden death and is often precipitated by triggers such as physical exertion or emotional stress. Given that athletes may be at particular risk for adverse outcomes, those suspected of having LQTS should be evaluated, risk stratified, treated, and receive appropriate counseling by providers with sufficient expertise according to the latest guidelines. EVIDENCE ACQUISITION: The following keywords were used to query MEDLINE and PubMed through 2016: LQTS, LQT1, LQT2, LQT3, long QT, long QTc, prolonged QT, prolonged QTc, QT interval, QTc interval, channelopathy, channelopathies, athletes, torsades de pointes, and sudden cardiac death. Selected articles within this primary search, in addition to relevant references from those articles, were reviewed for relevant information and data. Articles with pertinent information regarding pathophysiology, evaluation, diagnosis, genetic testing, treatment, and guidelines for athletes were included, particularly those published in the prior 2 decades. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: Diagnosis of LQTS involves eliciting the patient's family history, clinical history, and evaluation of electrocardiographic findings. Genetic testing for common mutations can confirm suspected cases. beta-Blockers represent the mainstay of treatment, though interventions such as implantable cardioverter-defibrillator placement or left cardiac sympathetic denervation may be required. Properly evaluated and treated athletes with LQTS have a low risk of cardiac events. CONCLUSION: Detection and management of LQTS in the athletic population is crucial given the possibility of adverse outcomes with the stress of athletic participation. Preparticipation screening examinations should include a thorough clinical and family history. Screening electrocardiograms may display key findings consistent with LQTS while genetic testing can confirm the diagnosis. Formerly considered a strict contraindication to athletic participation, LQTS is now an increasingly manageable entity with proper evaluation and treatment by qualified and experienced providers. PMID- 27480103 TI - Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. AB - BACKGROUND: The combination of cobimetinib with vemurafenib improves progression free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. METHODS: In this double-blind, randomised, placebo controlled, multicentre study, adult patients (aged >=18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. FINDINGS: Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14.2 months (IQR 8.5-17.3), the updated investigator-assessed median progression-free survival was 12.3 months (95% CI 9.5-13.4) for cobimetinib and vemurafenib versus 7.2 months (5.6-7.5) for placebo and vemurafenib (HR 0.58 [95% CI 0.46-0.72], p<0.0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22.3 months (95% CI 20.3-not estimable) for cobimetinib and vemurafenib versus 17.4 months (95% CI 15.0-19.8) for placebo and vemurafenib (HR 0.70, 95% CI 0.55-0.90; p=0.005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were gamma-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. INTERPRETATION: These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. FUNDING: F Hoffmann-La Roche-Genentech. PMID- 27480104 TI - Are we there yet? Prolonged MAPK inhibition in BRAF(V600)-mutant melanoma. PMID- 27480105 TI - GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1. AB - Proper hematopoietic cell fate decisions require co-ordinated functions of transcription factors, their associated co-regulators, and histone-modifying enzymes. Growth factor independence 1 (GFI1) is a zinc finger transcriptional repressor and master regulator of normal and malignant hematopoiesis. While several GFI1-interacting proteins have been described, how GFI1 leverages these relationships to carry out transcriptional repression remains unclear. Here, we describe a functional axis involving GFI1, SMYD2, and LSD1 that is a critical contributor to GFI1-mediated transcriptional repression. SMYD2 methylates lysine 8 (K8) within a -(8)KSKK(11)- motif embedded in the GFI1 SNAG domain. Methylation defective GFI1 SNAG domain lacks repressor function due to failure of LSD1 recruitment and persistence of promoter H3K4 di-methyl marks. Methylation defective GFI1 also fails to complement GFI1 depletion phenotypes in developing zebrafish and lacks pro-growth and survival functions in lymphoid leukemia cells. Our data show a discrete methylation event in the GFI1 SNAG domain that facilitates recruitment of LSD1 to enable transcriptional repression and co ordinate control of hematopoietic cell fate in both normal and malignant settings. PMID- 27480106 TI - Hot1 factor recruits co-activator Sub1 and elongation complex Spt4/5 to osmostress genes. AB - Hyperosmotic stress response involves the adaptative mechanisms needed for cell survival. Under high osmolarity conditions, many stress response genes are activated by several unrelated transcription factors that are controlled by the Hog1 kinase. Osmostress transcription factor Hot1 regulates the expression of several genes involved in glycerol biosynthesis, and the presence of this transcription factor in their promoters is essential for RNApol II recruitment. The physical association between Hog1 and Hot1 activates this transcription factor and directs the RNA polymerase II localization at these promoters. We, herein, demonstrate that physical and genetic interactions exist between Hot1 and several proteins involved in transcriptional and posttranscriptional processes: for example, transcription co-activator Sub1 and elongation complex Spt4/5. The results presented in this work demonstrate that Hot1 enrichment is not detected through the coding regions of its target genes and rule out a direct role in transcription elongation. Instead, other data presented herein indicate a key function of the Hot1 transcription factor in the recruitment of these proteins to the promoter or the 5'-coding region of the genes under its control. PMID- 27480108 TI - Barriers to Office-Based Mental Health Care and Interest in E-Communication With Providers: A Survey Study. AB - BACKGROUND: With rising availability and use of Internet and mobile technology in society, the demand and need for its integration into health care is growing. Despite great potential within mental health care and growing uptake, there is still little evidence to guide how these tools should be integrated into traditional care, and for whom. OBJECTIVE: To examine factors that might inform how e-communication should be implemented in our local outpatient mental health program, including barriers to traditional office-based care, patient preferences, and patient concerns. METHODS: We conducted a survey in the waiting room of our outpatient mental health program located in an urban, academic ambulatory hospital. The survey assessed (1) age, mobile phone ownership, and general e-communication usage, (2) barriers to attending office-based appointments, (3) preferences for, and interest in, e-communication for mental health care, and (4) concerns about e-communication use for mental health care. We analyzed the data descriptively and examined associations between the presence of barriers, identifying as a social media user, and interest level in e communication. RESULTS: Respondents (N=68) were predominantly in the age range of 25-54 years. The rate of mobile phone ownership was 91% (62/68), and 59% (40/68) of respondents identified as social media users. There was very low existing use of e-communication between providers and patients, with high levels of interest endorsed by survey respondents. Respondents expressed an interest in using e communication with their provider to share updates and get feedback, coordinate care, and get general information. In regression analysis, both a barrier to care and identifying as a social media user were significantly associated with e communication interest (P=.03 and P=.003, respectively). E-communication interest was highest among people who both had a barrier to office-based care and were a social media user. Despite high interest, there were also many concerns including privacy and loss of in-person contact. CONCLUSIONS: A high burden of barriers to attending office-based care paired with a high interest in e-communication supports the integration of e-communication within our outpatient services. There may be early adopters to target: those with identified barriers to office-based care and who are active on social media. There is also a need for caution and preservation of existing services for those who choose not to, or cannot, access e-services. PMID- 27480107 TI - Structural basis of arginine asymmetrical dimethylation by PRMT6. AB - PRMT6 is a type I protein arginine methyltransferase, generating the asymmetric dimethylarginine mark on proteins such as histone H3R2. Asymmetric dimethylation of histone H3R2 by PRMT6 acts as a repressive mark that antagonizes trimethylation of H3 lysine 4 by the MLL histone H3K4 methyltransferase. PRMT6 is overexpressed in several cancer types, including prostate, bladder and lung cancers; therefore, it is of great interest to develop potent and selective inhibitors for PRMT6. Here, we report the synthesis of a potent bisubstrate inhibitor GMS [6'-methyleneamine sinefungin, an analog of sinefungin (SNF)], and the crystal structures of human PRMT6 in complex, respectively, with S-adenosyl-L homocysteine (SAH) and the bisubstrate inhibitor GMS that shed light on the significantly improved inhibition effect of GMS on methylation activity of PRMT6 compared with SAH and an S-adenosyl-L-methionine competitive methyltransferase inhibitor SNF. In addition, we also crystallized PRMT6 in complex with SAH and a short arginine-containing peptide. Based on the structural information here and available in the PDB database, we proposed a mechanism that can rationalize the distinctive arginine methylation product specificity of different types of arginine methyltransferases and pinpoint the structural determinant of such a specificity. PMID- 27480109 TI - Investigation of the Poisoning Mechanism of Lead on the CeO2-WO3 Catalyst for the NH3-SCR Reaction via in Situ IR and Raman Spectroscopy Measurement. AB - The in situ IR and Raman spectroscopy measurements were conducted to investigate lead poisoning on the CeO2-WO3 catalysts. The deactivation mechanisms were studied with respect to the changes of surface acidity, redox property, nitrate/nitrite adsorption behaviors, and key active sites (note that the results of structure-activity relationship of CeO2-WO3 were based on our previous research). (1) Lewis acid sites originated from CeO2 and crystalline WO3, whereas Bronsted acid sites originated from Ce2(WO4)3. The poisoned catalysts exhibited a lower surface acidity than the fresh catalysts: the number of acid sites decreased, and their thermal stability weakened. (2) The reducibility of catalysts and the amount of active oxygen exhibited a smaller influence after poisoning because lead preferred to bond with surface WOx species rather than CeO2. (3) The quantity of active nitrate species decreased due to the lead coverage on the catalyst and the partial bridged-nitrate species induced by lead exhibited a low degree of activity at 200 degrees C. (4) Crystalline WO3 and Ce2(WO4)3 originated from the transformation of polytungstate sites. These sites were the key active sites during the SCR process. The formation temperatures of polytungstate on the poisoned catalysts were higher than those on the fresh catalysts. PMID- 27480111 TI - Evaluation of an Optimized Injection System for Retinal Gene Therapy in Human Patients. AB - Many retinal gene therapy clinical trials require subretinal injections of small volumes of adeno-associated viral (AAV) vector solutions in patients with retinal dystrophies, using equipment not specifically designed for this purpose. We therefore evaluated an optimized injection system in order to identify variables that might influence the rate of injection and final dose of vector delivered. An optimized injection system was assembled with a 41G polytetrafluoroethylene tip for retinal gene therapy. Flow rate was recorded at relevant infusion pressures (2-22 psi [14-152 kPa]), different target pressures (0.02-30 mm Hg [0.003-4 kPa]) and temperatures (18 degrees C vs. 36 degrees C) using a semiautomated Accurus((r)) Surgical System. Retention of AAV2/8 and AAV2/8(Y733F) vector was quantified after simulating loading/injection with or without 0.001% Pluronic((r)) F-68 (PF-68). The optimized injection system provided a linear flow rate (MUl/s)-to-infusion pressure (psi) relationship (y = 0.62x; r(2) = 0.99), independent of temperature and pressure changes relevant for intraocular surgery (18-36 degrees C, 0.02-30 mm Hg). Differences in length of 41G polytetrafluoroethylene tips caused significant variation in flow rate (p < 0.001). Use of PF-68 significantly (p < 0.001) reduced loss of vector genomes in the injection system by 55% (AAV2/8) and 52% (AAV2/8(Y733F)). A customized subretinal injection system assembled using equipment currently available in the operating room can deliver a controlled volume of vector at a fixed rate across a range of possible clinical parameters encountered in vitreoretinal surgery. The inclusion of 0.001% PF-68 had a significant effect on the final dose of vector genomes delivered. The described technique is currently used successfully in a clinical trial. PMID- 27480110 TI - Management of Invasive Differentiated Thyroid Cancer. AB - BACKGROUND: Invasive disease is a poor prognostic factor for patients with differentiated thyroid cancer (DTC). Uncontrolled central neck disease is a common cause of distressing death for patients presenting in this manner. Advances in assessment and management of such cases have led to significant improvements in outcome for this patient group. This article reviews the patterns of invasion and a contemporary approach to investigation and treatment of patients with invasive DTC. SUMMARY: Aerodigestive tract invasion is reported in around 10% of case series of DTC. Assessment should include not only clinical history and physical examination with endoscopy as indicated, but ultrasound and contrast-enhanced cross-sectional imaging. Further studies including positron emission tomography should be considered, particularly in recurrent cases that are radioactive iodine (RAI) resistant. Both the patient and the extent of disease should be carefully assessed prior to embarking on surgery. The aim of surgery is to resect all gross disease. When minimal visceral invasion is encountered early, "shave" procedures are recommended. In the setting of transmural invasion of the airway or esophagus, however, full thickness excision is required. For intermediate cases in which invasion of the viscera has penetrated the superficial layers but is not evident in the submucosa, opinion is divided. Early reports recommended an aggressive approach. More recently authors have tended to recommend less aggressive resections with postoperative adjuvant therapies. The role of external beam radiotherapy continues to evolve in DTC with support for its use in patients considered to have RAI-resistant tumors. CONCLUSIONS: Patients with invasive DTC require a multidisciplinary approach to investigation and treatment. With detailed assessment, appropriate surgery, and adjuvant therapy when indicated, this patient group can expect durable control of central neck disease, despite the aggressive nature of their primary tumors. PMID- 27480113 TI - Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. AB - Agents targeting B-cell receptor (BCR) signaling-associated kinases such as Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab, or ofatumumab) for treatment of B cell lymphomas and chronic lymphocytic leukemia (CLL). Here we show that interactions between leukemia cells and stromal cells (HS-5) upregulate CD20 on CLL cells and that administering ibrutinib downmodulates CD20 (MS4A1) expression in vivo. We observed that CLL cells that have recently exited the lymph node microenvironment and moved into the peripheral blood (CXCR4(dim)CD5(bright) subpopulation) have higher cell surface levels of CD20 than the cells circulating in the bloodstream for a longer time (CXCR4(bright)CD5(dim) cells). We found that CD20 is directly upregulated by CXCR4 ligand stromal cell-derived factor 1 (SDF 1alpha, CXCL12) produced by stromal cells, and BTK-inhibitor ibrutinib and CXCR4 inhibitor plerixafor block SDF-1alpha-mediated CD20 upregulation. Ibrutinib also downmodulated Mcl1 levels in CLL cells in vivo and in coculture with stromal cells. Overall, our study provides a first detailed mechanistic explanation of CD20 expression regulation in the context of chemokine signaling and microenvironmental interactions, which may have important implications for microenvironment-targeting therapies. PMID- 27480112 TI - EKLF/KLF1-regulated cell cycle exit is essential for erythroblast enucleation. AB - The mechanisms regulating the sequential steps of terminal erythroid differentiation remain largely undefined, yet are relevant to human anemias that are characterized by ineffective red cell production. Erythroid Kruppel-like Factor (EKLF/KLF1) is a master transcriptional regulator of erythropoiesis that is mutated in a subset of these anemias. Although EKLF's function during early erythropoiesis is well studied, its role during terminal differentiation has been difficult to functionally investigate due to the impaired expression of relevant cell surface markers in Eklf(-/-) erythroid cells. We have circumvented this problem by an innovative use of imaging flow cytometry to investigate the role of EKLF in vivo and have performed functional studies using an ex vivo culture system that enriches for terminally differentiating cells. We precisely define a previously undescribed block during late terminal differentiation at the orthochromatic erythroblast stage for Eklf(-/-) cells that proceed beyond the initial stall at the progenitor stage. These cells efficiently decrease cell size, condense their nucleus, and undergo nuclear polarization; however, they display a near absence of enucleation. These late-stage Eklf(-/-) cells continue to cycle due to low-level expression of p18 and p27, a new direct target of EKLF. Surprisingly, both cell cycle and enucleation deficits are rescued by epistatic reintroduction of either of these 2 EKLF target cell cycle inhibitors. We conclude that the cell cycle as regulated by EKLF during late stages of differentiation is inherently critical for enucleation of erythroid precursors, thereby demonstrating a direct functional relationship between cell cycle exit and nuclear expulsion. PMID- 27480114 TI - Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia. AB - Despite advances in the treatment of acute myeloid leukemia (AML), relapse and drug resistance frequently occur. Therefore, detailed mechanisms of refractoriness, including leukemia-initiating cell (LIC) biology, should be elucidated to treat AML. The self-degradative property of cytosolic macromolecules is central to autophagy and can contribute to homeostasis and stress response. Recent reports suggest the importance of autophagy in hematopoietic stem cells and various tumors. Thus, this study investigated the functional role of autophagy in AML maintenance and drug resistance using tamoxifen-inducible conditional knockout mice of Atg5 or Atg7, which are essential genes for autophagy, combined with an mixed lineage leukemia-eleven nineteen leukemia-induced murine AML model. Inactivation of autophagy by deletion of Atg5 or Atg7 prolonged survival in leukemic mice and reduced functional LICs. Atg7-deficient LICs displayed enhanced mitochondrial activity and reactive oxygen species production together with increased cell death. In addition, Atg7 deletion markedly decreased peripheral blood leukemia cells, concurrent with increased apoptosis, suggesting a higher dependency on autophagy compared with bone marrow leukemia cells. Finally, cytarabine (AraC) treatment activated autophagy in LICs, and Atg7 deletion potentiated the therapeutic effects of AraC, which included decreased LICs and prolonged survival, suggesting that autophagy contributes to AraC resistance. Our results highlight the intratumoral heterogeneity related to autophagy in AML and the unique role of autophagy in leukemia development and drug resistance. PMID- 27480115 TI - On the reversibility of parasitism: adaptation to a free-living lifestyle via gene acquisitions in the diplomonad Trepomonas sp. PC1. AB - BACKGROUND: It is generally thought that the evolutionary transition to parasitism is irreversible because it is associated with the loss of functions needed for a free-living lifestyle. Nevertheless, free-living taxa are sometimes nested within parasite clades in phylogenetic trees, which could indicate that they are secondarily free-living. Herein, we test this hypothesis by studying the genomic basis for evolutionary transitions between lifestyles in diplomonads, a group of anaerobic eukaryotes. Most described diplomonads are intestinal parasites or commensals of various animals, but there are also free-living diplomonads found in oxygen-poor environments such as marine and freshwater sediments. All these nest well within groups of parasitic diplomonads in phylogenetic trees, suggesting that they could be secondarily free-living. RESULTS: We present a transcriptome study of Trepomonas sp. PC1, a diplomonad isolated from marine sediment. Analysis of the metabolic genes revealed a number of proteins involved in degradation of the bacterial membrane and cell wall, as well as an extended set of enzymes involved in carbohydrate degradation and nucleotide metabolism. Phylogenetic analyses showed that most of the differences in metabolic capacity between free-living Trepomonas and the parasitic diplomonads are due to recent acquisitions of bacterial genes via gene transfer. Interestingly, one of the acquired genes encodes a ribonucleotide reductase, which frees Trepomonas from the need to scavenge deoxyribonucleosides. The transcriptome included a gene encoding squalene-tetrahymanol cyclase. This enzyme synthesizes the sterol substitute tetrahymanol in the absence of oxygen, potentially allowing Trepomonas to thrive under anaerobic conditions as a free living bacterivore, without depending on sterols from other eukaryotes. CONCLUSIONS: Our findings are consistent with the phylogenetic evidence that the last common ancestor of diplomonads was dependent on a host and that Trepomonas has adapted secondarily to a free-living lifestyle. We believe that similar studies of other groups where free-living taxa are nested within parasites could reveal more examples of secondarily free-living eukaryotes. PMID- 27480116 TI - Gene, Environment and Methylation (GEM): a tool suite to efficiently navigate large scale epigenome wide association studies and integrate genotype and interaction between genotype and environment. AB - BACKGROUND: The interplay among genetic, environment and epigenetic variation is not fully understood. Advances in high-throughput genotyping methods, high density DNA methylation detection and well-characterized sample collections, enable epigenetic association studies at the genomic and population levels (EWAS). The field has extended to interrogate the interaction of environmental and genetic (GxE) influences on epigenetic variation. Also, the detection of methylation quantitative trait loci (methQTLs) and their association with health status has enhanced our knowledge of epigenetic mechanisms in disease trajectory. However analysis of this type of data brings computational challenges and there are few practical solutions to enable large scale studies in standard computational environments. RESULTS: GEM is a highly efficient R tool suite for performing epigenome wide association studies (EWAS). GEM provides three major functions named GEM_Emodel, GEM_Gmodel and GEM_GxEmodel to study the interplay of Gene, Environment and Methylation (GEM). Within GEM, the pre-existing "Matrix eQTL" package is utilized and extended to study methylation quantitative trait loci (methQTL) and the interaction of genotype and environment (GxE) to determine DNA methylation variation, using matrix based iterative correlation and memory efficient data analysis. Benchmarking presented here on a publicly available dataset, demonstrated that GEM can facilitate reliable genome-wide methQTL and GxE analysis on a standard laptop computer within minutes. CONCLUSIONS: The GEM package facilitates efficient EWAS study in large cohorts. It is written in R code and can be freely downloaded from Bioconductor at https://www.bioconductor.org/packages/GEM/ . PMID- 27480117 TI - Loteprednol Etabonate Nanoparticles: Optimization via Box-Behnken Design Response Surface Methodology and Physicochemical Characterization. AB - BACKGROUND: Abstract: The objective of the present work was to prepare and optimize the loteprednoletabonate (LE) loaded poly (D,L-lactide co-glycolide) (PLGA) polymer based nanoparticle carrier. The review on recent patents (US9006241, US20130224302A1, US2012/0028947A1) assisted in the selection of drug and polymer for designing nanoparticles for ocular delivery applications. METHODS: The nanoparticles were prepared by solvent evaporation followed by high speed homogenization. Biodegradable polymer PLGA (50:50) grade was utilized to develop various formulations with different drug:polymer ratio. A Box-Behnken design with 33 factorial design was selected for the present study and 17 runs were carried out in totality. The influence of various process variables (viz., polymer concentration, homogenization speed and sonication time) on the characteristics of nanoparticles including the in vitro drug release profile were studied. RESULTS: The nanoparticulate formulations were evaluated for mean spherical diameter, polydispersity index (PDI), zeta potential, surface morphology, drug entrapment and in-vitro drug release profile. The entrapment efficiency, drug loading and mean particle size were found to be 96.31+/-1.68 %, 35.46+/-0.35 % and 167.6+/-2.1 nm respectively. CONCLUSION: The investigated process and formulation variables were found to have significant effect on the particle size, drug loading (DL), entrapment efficiency (EE), and in vitro drug release profile. A biphasic in vitro drug release profile was apparent from the optimized nanoparticles (NPs) for 24 hours. PMID- 27480118 TI - In vitro and in vivo Evaluation of New Topical Anaesthetic Cream Formulated with Palm Oil Base. AB - BACKGROUND: Topical local anaesthetic cream was reported to be useful for pain relief for cutaneous procedures such as minor surgery and venipuncture. OBJECTIVE: The aim of this study was to evaluate the effectiveness of new formulation of lidocaine topical anaesthetic using palm oil base, HAMIN(r) and to determine how fast this new formulation produces adequate numbness compared to the currently used EMLA cream, in the University of Malaya Medical Centre (UMMC) set-up. METHOD: The skin permeation test was conducted by using Franz type diffusion cell and pain assessment was carried out in healthy subject by using Verbal Rating Score (VRS) and Visual Analogue Score (VAS) evaluation. RESULT: Result of permeation test demonstrated that the cumulative amount of lidocaine released from HAMIN(r) cream was increased with time and slightly higher than EMLA cream. The clinical study showed that HAMIN(r) single lidocaine cream can produces numbness through venepuncture procedure and comparable with EMLA cream which is a combination therapy for local anaesthetic (lidocaine and prilocaine). CONCLUSION: It can be concluded that HAMIN(r) Lidocaine cream is suitable for cream preparation especially for topical application and it can be regarded as an achievement in palm oil and medical industries. PMID- 27480119 TI - A New Application Route of Nitrofurantoin: Preparation and Characterization of Novel Transdermal Formulations. AB - OBJECTIVES: Nitrofurantoin is widely used in the prophylaxis of urinary-tract infections. The aim of this study was to develop and characterize innovative transdermal formulations of nitrofurantoin, to increase the patient compliance and decrease the adverse effects such as nausea and vomiting which limit the drug use in long-term. METHODS: Nitrofurantoin loaded microemulsion, gel (hydrogel, lipogel and DMSO gel) and film formulations were prepared and characterized via several parameters. Ex-vivo drug permeation studies were performed to determine the amount of drug permeated through the rat skin. In in-vivo studies, in order to detect nitrofurantoin in urine, the selected formulations were applied to male Wistar rats transdermally. Also, skin irritation tests (transepidermal water loss and erythema) were performed. RESULTS: All nitrofurantoin loaded formulations were prepared successfully and were stable at +4 degrees C for 3 months. 13%, 16%, 32.5%, 36.5% and 39% of drugs permeated through the rat skin in the 168th hour for hydrogel, lipogel, film, microemulsion and DMSO gel, respectively. Only with film and DMSO gel formulations, nitrofurantoin was detected in urine. Transepidermal water loss was increased compared to basal level in film type formulations (p<0.05). However, in erythema experiments there was no difference (p>0.05). CONCLUSION: There is no approved transdermal formulation of nitrofurantion on the market. Therefore, the prepared film formulations could be an alternative due to their high penetration through the rat skin, the presence of nitrofurantoin in urine and because they cause no irritation on the skin. PMID- 27480120 TI - Autapse-induced multiple coherence resonance in single neurons and neuronal networks. AB - We study the effects of electrical and chemical autapse on the temporal coherence or firing regularity of single stochastic Hodgkin-Huxley neurons and scale-free neuronal networks. Also, we study the effects of chemical autapse on the occurrence of spatial synchronization in scale-free neuronal networks. Irrespective of the type of autapse, we observe autaptic time delay induced multiple coherence resonance for appropriately tuned autaptic conductance levels in single neurons. More precisely, we show that in the presence of an electrical autapse, there is an optimal intensity of channel noise inducing the multiple coherence resonance, whereas in the presence of chemical autapse the occurrence of multiple coherence resonance is less sensitive to the channel noise intensity. At the network level, we find autaptic time delay induced multiple coherence resonance and synchronization transitions, occurring at approximately the same delay lengths. We show that these two phenomena can arise only at a specific range of the coupling strength, and that they can be observed independently of the average degree of the network. PMID- 27480121 TI - Activation of Wnt signaling promotes hippocampal neurogenesis in experimental autoimmune encephalomyelitis. AB - BACKGROUND: Disease progression in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), as one of its animal models, is characterized by demyelination and neuronal damage in white and gray matter structures, including the hippocampus. It is thought that dysfunction of the hippocampus, a primary locus of learning and memory consolidation, may contribute to cognitive impairment in MS patients. Previously, we reported an increased generation of hippocampal neuronal progenitors in the acute stage of EAE, whereas the microenvironmental signals triggering this process remained uninvestigated. RESULTS: In the present study, we used the Wnt signaling reporter mouse Axin2(LacZ), to elucidate the molecular mechanisms underlying the activation of the hippocampal neurogenic niche upon autoimmune neuroinflammation. Histological and enzymatic examinations of beta-gal during the disease course of EAE, allowed us to survey hippocampal Wnt/beta-catenin activity, one of the key signaling pathways of adult neurogenesis. We found that Wnt signaling is transiently upregulated in the acute stage of disease, consistent with a timely induction of canonical Wnt ligands. The enhancement of signaling coincided with hippocampal neuronal damage and local expression of immune cytokines such as TNFalpha and IFNgamma, implicating the role of the inflammatory milieu in activation of the Wnt/beta-catenin pathway. Supporting this finding, we show that transient exposure to pro-inflammatory cytokine TNFalpha triggers Wnt signaling in hippocampal organotypic slice cultures. Importantly, inflammation-mediated activation of the Wnt/beta-catenin pathway was associated with enhanced neurogenesis in vitro and in vivo, indicating its potential role in hippocampal tissue regeneration and repair. CONCLUSIONS: This study raises the possibility that enhancement of Wnt signaling may support neurogenic processes to cope with neuronal deficits upon immune-mediated neuroinflammation. PMID- 27480123 TI - Ferrihydrite Formation: The Role of Fe13 Keggin Clusters. AB - Ferrihydrite is the most common iron oxyhydroxide found in soil and is a key sequester of contaminants in the environment. Ferrihydrite formation is also a common component of many treatment processes for cleanup of industrial effluents. Here we characterize ferrihydrite formation during the titration of an acidic ferric nitrate solution with NaOH. In situ SAXS measurements supported by ex situ TEM indicate that initially Fe13 Keggin clusters (radius ~ 0.45 nm) form in solution at pH 0.12-1.5 and are persistent for at least 18 days. The Fe13 clusters begin to aggregate above ~ pH 1, initially forming highly linear structures. Above pH ~ 2 densification of the aggregates occurs in conjunction with precipitation of low molecular weight Fe(III) species (e.g., monomers, dimers) to form mass fractal aggregates of ferrihydrite nanoparticles (~3 nm) in which the Fe13 Keggin motif is preserved. SAXS analysis indicates the ferrihydrite particles have a core-shell structure consisting of a Keggin center surrounded by a Fe-depleted shell, supporting the surface depleted model of ferrihydrite. Overall, we present the first direct evidence for the role of Fe13 clusters in the pathway of ferrihydrite formation during base hydrolysis, showing clear structural continuity from isolated Fe13 Keggins to the ferrihydrite particle structure. The results have direct relevance to the fundamental understanding of ferrihydrite formation in environmental, engineered, and industrial processes. PMID- 27480122 TI - Global analysis of dorsoventral patterning in the wasp Nasonia reveals extensive incorporation of novelty in a regulatory network. AB - BACKGROUND: Gene regulatory networks (GRNs) underlie developmental patterning and morphogenetic processes, and changes in the interactions within the underlying GRNs are a major driver of evolutionary processes. In order to make meaningful comparisons that can provide significant insights into the evolution of regulatory networks, homologous networks from multiple taxa must be deeply characterized. One of the most thoroughly characterized GRNs is the dorsoventral (DV) patterning system of the Drosophila melanogaster embryo. We have developed the wasp Nasonia as a comparative DV patterning model because it has shown the convergent evolution of a mode of early embryonic patterning very similar to that of the fly, and it is of interest to know whether the similarity at the gross level also extends to the molecular level. RESULTS: We used RNAi to dorsalize and ventralize Nasonia embryos, RNAseq to quantify transcriptome-wide expression levels, and differential expression analysis to identify genes whose expression levels change in either RNAi case. This led to the identification of >100 genes differentially expressed and regulated along the DV axis. Only a handful of these genes are shared DV components in both fly and wasp. Many of those unique to Nasonia are cytoskeletal and adhesion molecules, which may be related to the divergent cell and tissue behavior observed at gastrulation. In addition, many transcription factors and signaling components are only DV regulated in Nasonia, likely reflecting the divergent upstream patterning mechanisms involved in producing the conserved pattern of cell fates observed at gastrulation. Finally, several genes that lack Drosophila orthologs show robust and distinct expression patterns. These include genes with vertebrate homologs that have been lost in the fly lineage, genes that are found only among Hymenoptera, and several genes that entered the Nasonia genome through lateral transfer from endosymbiotic bacteria. CONCLUSIONS: Altogether, our results provide insights into how GRNs respond to new functional demands and how they can incorporate novel components. PMID- 27480124 TI - Decreased expression levels of Ifi genes is associated to the increased resistance to spontaneous arthritis disease in mice deficiency of IL-1RA. AB - BACKGROUND: The mouse strain BALB/c deficient in IL-1 receptor antagonist protein (Il-1ra) develops spontaneous arthritis disease (SAD) while the strain DBA/1 IL1rn (-/-) with the same deficiency does not. Previously, we mapped a QTL on chromosome 1 for SAD and then developed a congenic mouse strain BALB.D1-1(-/-) that contains the QTL genomic fragment associated with resistance from DBA/1(-/-) on a BALB/c(-/-) background. The congenic strain was relatively resistant to spontaneous arthritis and had delayed onset and reduced severity of disease. We obtained whole genome expression profiles from the spleen of the congenic strain BALB.D1-1(-/-) and four other strains, the wild type BALB/c, DBA/1 and the deficient DBA/1 IL1rn (-/-) and the BALB/c IL1rn (-/-). We then compared the similarities and differences between the congenic strain and the four parental strains. Here we report the selected potential causal genes based on differential expression levels as well as function of genes. RESULTS: There is a considerable number of genes that are differentially expressed between the congenic strain and the three parental strains, BALB/c, DBA/1, and DBA/1(-/-). However there only a few differentially expressed genes were identified by comparing the congenic strain and the BALB/c(-/-)strain. These differentially expressed genes are mainly from T-cell receptor beta chain (Tcrb) and interferon-activatable protein (Ifi) genes. These genes are also differentially expressed between congenic strain and BALB/c strains. However, their expression levels in the congenic strain are similar to that in DBA/1 and DBA/1(-/-). The expression level of Tcrb-j gene is positively associated with two genes of Ifi gene 200 cluster. CONCLUSIONS: Decreased expression levels of Ifi genes is associated to the increased resistance to spontaneous arthritis disease and with down regulation of expressions of Tcrb genes in the mouse congenic strain. Ifi genes may play an important role in the susceptibility to SAD in mice. PMID- 27480125 TI - Maternal dietary vitamin D carry-over alters offspring growth, skeletal mineralisation and tissue mRNA expressions of genes related to vitamin D, calcium and phosphorus homoeostasis in swine. AB - Maternal dietary vitamin D carry-over effects were assessed in young pigs to characterise skeletal abnormalities in a diet-induced model of kyphosis. Bone abnormalities were previously induced and bone mineral density (BMD) reduced in offspring from sows fed diets with inadequate vitamin D3. In a nested design, pigs from sows (n 23) fed diets with 0 (-D), 8.125 (+D) or 43.750 (++D) ug D3/kg from breeding through lactation were weaned and, within litter, fed nursery diets arranged as a 2*2 factorial design with 0 (-D) or 7.0 (+D) ug D3/kg, each with 95 % (95P) or 120 % (120P) of P requirements. Selected pigs were euthanised before colostrum consumption at birth (0 weeks, n 23), weaning (3 weeks, n 22) and after a growth period (8 weeks, n 185) for BMD, bone mechanical tests and tissue mRNA analysis. Pigs produced by +D or ++D sows had increased gain at 3 weeks (P<0.05), and at 8 weeks had increased BMD and improved femur mechanical properties. However, responses to nursery diets depended on maternal diets (P<0.05). Relative mRNA expressions of genes revealed a maternal dietary influence at birth in bone osteocalcin and at weaning in kidney 24-hydroxylase (P<0.05). Nursery treatments affected mRNA expressions at 8 weeks. Detection of a maternal and nursery diet interaction (P<0.05) provided insights into the long-term effects of maternal nutritional inputs. Characterising early stages of bone abnormalities provided inferences for humans and animals about maternal dietary influence on offspring skeletal health. PMID- 27480126 TI - Spectral descriptors for bulk metallic glasses based on the thermodynamics of competing crystalline phases. AB - Metallic glasses attract considerable interest due to their unique combination of superb properties and processability. Predicting their formation from known alloy parameters remains the major hindrance to the discovery of new systems. Here, we propose a descriptor based on the heuristics that structural and energetic 'confusion' obstructs crystalline growth, and demonstrate its validity by experiments on two well-known glass-forming alloy systems. We then develop a robust model for predicting glass formation ability based on the geometrical and energetic features of crystalline phases calculated ab initio in the AFLOW framework. Our findings indicate that the formation of metallic glass phases could be much more common than currently thought, with more than 17% of binary alloy systems potential glass formers. Our approach pinpoints favourable compositions and demonstrates that smart descriptors, based solely on alloy properties available in online repositories, offer the sought-after key for accelerated discovery of metallic glasses. PMID- 27480127 TI - The Ethical Implications of the Reclassification of Noninvasive Follicular Variant Papillary Thyroid Carcinoma. AB - BACKGROUND: Several studies have highlighted the lack of consensus in the diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC). An international multidisciplinary panel to address the controversy was assembled at the annual meeting of the Endocrine Pathology Society in March of 2015, leading to the recent publication reclassifying encapsulated (or noninvasive) FVPTC (EFVPTC) as a benign neoplasm. Does this change in histologic taxonomy warrant a change in clinical practice, and how should it affect those who have been given this diagnosis in the past? We consider the financial and psychological impact of this reclassification and discuss the ethical, legal, and practical issues involved with sharing this information with the patients who are affected. SUMMARY: The total direct and indirect cost of thyroid cancer surveillance in patients is significant. High levels of clinically relevant distress affect up to 43% of patients with papillary thyroid carcinoma, as estimated by the Distress Thermometer developed by the National Comprehensive Cancer Network for detecting distress in cancer patients. Although there are currently no legal opinions that establish a precedent for recontacting patients whose clinical status is altered by a change in nomenclature, the prudent course would be to attend to the requirements of medical ethics. CONCLUSION: Informing patients with a previous diagnosis of EFVPTC that the disease has been reclassified as benign is expected to have a dramatic effect on their surveillance needs and to alleviate the psychological impact of living with a diagnosis of cancer. It is important to re evaluate the pathologic slides of those patients at risk to ensure that the invasive nature of the tumor is comprehensively evaluated before notifying a patient of a change in diagnosis. The availability of the entire tumor for evaluation of the capsule may prove to be a challenge for a portion of the population at risk. We believe that it is the clinician's professional duty to make a sincere and reasonable effort to convey the information to the affected patients. We also believe that the cost savings with respect to the need for additional surgery, radioactive iodine, and rigorous surveillance associated with a misinterpretation of the biology of the diagnosis of EFVPTC in less experienced hands will likely more than offset the cost incurred in histologic review and patient notification. PMID- 27480128 TI - Prehospital lung ultrasound for the diagnosis of cardiogenic pulmonary oedema: a pilot study. AB - BACKGROUND: An improved prehospital diagnostic accuracy of cardiogenic pulmonary oedema could potentially improve initial treatment, triage, and outcome. A pilot study was conducted to assess the feasibility, time-use, and diagnostic accuracy of prehospital lung ultrasound (PLUS) for the diagnosis of cardiogenic pulmonary oedema. METHODS: A prospective observational study was conducted in a prehospital setting. Patients were included if the physician based prehospital mobile emergency care unit was activated and one or more of the following two were present: respiratory rate >30/min., oxygen saturation <90 %. Exclusion criteria were: age <18 years, permanent mental disability or PLUS causing a delay in life saving treatment or transportation. Following clinical assessment PLUS was performed and presence or absence of interstitial syndrome was registered. Audit by three physicians using predefined diagnostic criteria for cardiogenic pulmonary oedema was used as gold standard. RESULTS: A total of 40 patients were included in the study. Feasibility of PLUS was 100 % and median time used was 3 min. The gold standard diagnosed 18 (45.0 %) patients with cardiogenic pulmonary oedema. The diagnostic accuracy of PLUS for the diagnosis of cardiogenic pulmonary oedema was: sensitivity 94.4 % (95 % confidence interval (CI) 72.7-99.9 %), specificity 77.3 % (95 % CI 54.6-92.2 %), positive predictive value 77.3 % (95 % CI 54.6-92.2 %), negative predictive value 94.4 % (95 % CI 72.7-99.9 %). DISCUSSION: The sensitivity of PLUS is high, making it a potential tool for ruling-out cardiogenic pulmonary. The observed specificity was lower than what has been described in previous studies. CONCLUSIONS: Performed, as part of a physician based prehospital emergency service, PLUS seems fast and highly feasible in patients with respiratory failure. Due to its diagnostic accuracy, PLUS may have potential as a prehospital tool, especially to rule out cardiogenic pulmonary oedema. PMID- 27480130 TI - Lack of vimentin impairs endothelial differentiation of embryonic stem cells. AB - The cytoskeletal filament vimentin is inherent to the endothelial phenotype and is critical for the proper function of endothelial cells in adult mice. It is unclear, however, if the presence of vimentin is necessary during differentiation to the endothelial phenotype. Here we evaluated gene and protein expression of differentiating wild type embryonic stem cells (WT ESCs) and vimentin knockout embryonic stem cells (VIM -/- ESCs) using embryoid bodies (EBs) formed from both cell types. Over seven days of differentiation VIM -/- EBs had altered morphology compared to WT EBs, with a rippled outer surface and a smaller size due to decreased proliferation. Gene expression of pluripotency markers decreased similarly for EBs of both cell types; however, VIM -/- EBs had impaired differentiation towards the endothelial phenotype. This was quantified with decreased expression of markers along the specification pathway, specifically the early mesodermal marker Brachy-T, the lateral plate mesodermal marker FLK1, and the endothelial-specific markers TIE2, PECAM, and VE-CADHERIN. Taken together, these results indicate that the absence of vimentin impairs spontaneous differentiation of ESCs to the endothelial phenotype in vitro. PMID- 27480131 TI - Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial. AB - BACKGROUND: Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP. METHODS: Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint. DISCUSSION: The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for screening failure include minimal polyp burden (n = 22), withdrawal of consent (n = 9) and extensive polyposis requiring immediate surgical intervention (n = 9). Enrollment is ongoing. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov ( NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register( EudraCT 2012-000427-41 ; May 15, 2014). PMID- 27480133 TI - Serum metabonomics of acute leukemia using nuclear magnetic resonance spectroscopy. AB - Acute leukemia is a critical neoplasm of white blood cells. In order to differentiate between the metabolic alterations associated with two subtypes of acute leukemia, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), we investigated the serum of ALL and AML patients and compared with two controls (healthy and aplastic anemia) using (1)H NMR (nuclear magnetic resonance) spectroscopy. Thirty-seven putative metabolites were identified using Carr-Purcell-Meiboom-Gill (CPMG) sequence. The use of PLS-DA and OPLS-DA models gave results with 84.38% and 90.63% classification rate, respectively. The metabolites responsible for classification are mainly lipids, lactate and glucose. Compared with controls, ALL and AML patients showed serum metabonomic differences involving aberrant metabolism pathways including glycolysis, TCA cycle, lipoprotein changes, choline and fatty acid metabolisms. PMID- 27480132 TI - SIRT1 and SIRT7 expression in adipose tissues of obese and normal-weight individuals is regulated by microRNAs but not by methylation status. AB - BACKGROUND/OBJECTIVE: Given their importance in the regulation of metabolism, sirtuins (SIRTs) constitute promising subjects of research on the pathogenesis of obesity and the metabolic syndrome. The aim of this study was to assess whether obesity in humans is associated with changes in the expression of SIRT genes in adipose tissue and whether epigenetic mechanisms, DNA methylation and microRNA (miRNA) interference, mediate in this phenomenon. SUBJECTS/METHODS: The expression of SIRTs and of SIRT1 and SIRT7 mRNA-interacting miRNAs was evaluated by real-time PCR in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 58 obese (body mass index (BMI) >40 kg m-2) and 31 normal-weight (BMI 20 24.9 kg m-2) individuals. The methylation status of SIRTs was studied by the methylation-sensitive digestion/real-time PCR method. RESULTS: SIRT1 mRNA levels were lower in adipose tissues of obese patients than of normal-weight controls (VAT: P=0.0002, SAT: P=0.008). In contrast, expression of SIRT7 was higher in adipose tissues of obese patients than in the control group (VAT: P=0.001, SAT: P=0.008). The mean methylation of the SIRT1 and SIRT7 CpG islands was similar in tissues with high and low expression of these genes, and there was no correlation between the level of expression and the level of methylation. On the other hand, expression of SIRT1 in VAT of obese subjects correlated negatively with the expression of miR-22-3p (P<0.0001, rs=-0.514), miR-34a-5p (P=0.01, rs=-0.326) and miR-181a-3p (P<0.0001, rs=-0.536). In turn, expression of SIRT7 in VAT of slim individuals correlated negatively with the expression of miR-125a-5p (P=0.003, rs=-0.562) and miR-125b-5p (P=0.018, rs=-0.460). CONCLUSIONS: We observed obesity associated downregulation of SIRT1 and upregulation of SIRT7 mRNA levels that were not associated with the methylation status of their promoters. We found a negative correlation between mRNA levels of SIRT1 in VAT of obese individuals and SIRT7 in VAT of the normal-weight subjects and expression of the relevant miRNAs. PMID- 27480134 TI - PTH/SDF-1alpha cotherapy induces CD90+CD34- stromal cells migration and promotes tissue regeneration in a rat periodontal defect model. AB - Stromal cell-derived factor-1alpha (SDF-1alpha) is a key stem cell homing factor that is crucial for recruitment of stem cells to many diseased organs. However, the therapeutic activity of SDF-1alpha is potentially limited by N-terminal cleavage at position-2 proline by a cell surface protein CD26/dipeptidyl peptidase-IV (DPP-IV). Parathyroid hormone (PTH) is a DPP-IV inhibitor and has been suggested as a promising agent for periodontal tissue repair. The purpose of this study was to explore the effects of a cell-free system comprising SDF-1alpha and scaffold plus PTH systemic application on periodontal tissue regeneration in vivo. The results showed that PTH/SDF-1alpha cotherapy improved the quantity of regenerated bone and resulted in better organization of ligament interface. We further investigated the possible mechanisms, and found that PTH/SDF-1alpha cotherapy enhanced CD90+CD34- stromal cells migration in vivo, increased the number of CXCR4 + cells in periodontal defects, induced early bone osteoclastogenesis and enhanced the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and collagen I (Col I) in newly formed bone tissue. In conclusion, this cell-free tissue engineering system with local administration of SDF-1alpha and systemic application of PTH could be employed to induce CD90+CD34- stromal cells recruitment and promote periodontal tissue regeneration. PMID- 27480135 TI - Ion Current-Based Proteomic Profiling for Understanding the Inhibitory Effect of Tumor Necrosis Factor Alpha on Myogenic Differentiation. AB - Despite a demonstrated role for TNF-alpha in promoting muscle wasting and cachexia, the associated molecular mechanisms and signaling pathways of myoblast differentiation dysregulated by TNF-alpha remain poorly understood. This study presents well-controlled proteomic profiling as a means to investigate the mechanisms of TNF-alpha-regulated myogenic differentiation. Primary human muscle precursor cells (MPCs) cultured in growth medium (GM), differentiation medium (DM) to induce myogenic differentiation, and DM with 20 ng/mL of TNF-alpha (n = 5/group) were comparatively analyzed by an ion current-based quantitative platform consisting of reproducible sample preparation/on-pellet digestion, a long-column nano-LC separation, and ion current-based differential analysis. The inhibition of myogenic differentiation by TNF-alpha was confirmed by reduced formation of multinucleated myotubes and the recovered expression of altered myogenic proteins such as MYOD and myogenin during myogenic differentiation. Functional analysis and validation by immunoassay analysis suggested that the cooperation of NF-kappaB and STAT proteins is responsible for dysregulated differentiation in MPCs by TNF-alpha treatment. Increased MHC class I components such as HLA-A, HLA-B, HLA-C, and beta-2-microglobulin were also observed in cultures in DM treated with TNF-alpha. Interestingly, inhibition of the cholesterol biosynthesis pathway during myogenic differentiation induced by serum starvation was not recovered by TNF-alpha treatment, which combined with previous reports, implies that this process may be an early event of myogenesis. This finding could lay the foundation for the potential use of statins in modulating myogenesis through cholesterol, for example, in stem cell-based myocardial infarction treatment, where differentiation of myoblasts and stem cells into force-generating mature muscle cells is a key step to the therapeutic capacity. In conclusion, the landscapes of altered transcription regulators, metabolic processes, and signaling pathways in MPCs are revealed in the regulation of myogenic differentiation by TNF-alpha, which is valuable for myogenic cellular therapeutics. PMID- 27480136 TI - Co-crystal engineering: a novel method to obtain one-dimensional (1D) carbon nanocrystals of corannulene-fullerene by a solution process. AB - In this study, 1D nanocrystals composed of C60 and corannulene were synthesized efficiently through cocrystallization by a solution process. These 1D nanocrystals display high electron transport characteristics of up to 0.11 cm(2) V(-1) s(-1) and good photoresponse of 0.09 A W(-1), indicating their potential applications in optoelectronics. The results suggest that co-crystal engineering provides a novel strategy for the rational design of new carbon-based crystalline nanomaterials. PMID- 27480142 TI - A Highly Crystalline and Wide-Bandgap Polydiarylfluorene with beta-Phase Conformation toward Stable Electroluminescence and Dual Amplified Spontaneous Emission. AB - Bulky conjugated polymers with high crystallinity is the prerequisite for the overall improvement of performance in wide-bandgap semiconductors, including charge transport, photoluminescence quantum yield, processing reliability, and stability. Herein, we report a stable beta-phase film of bulky polydiarylfluorene (PODPF) preparing by thermal annealing at ~220 degrees C. The beta-phase conformation and regular molecular packing are confirmed by UV-vis, photoluminescence (PL), Raman spectra, and grazing incidence X-ray diffraction (GIXD), respectively. Polymer light-emitting diodes (PLEDs) with crystalline and beta-phase film serving as the active layer exhibit higher current efficiency of 1.8 cd/A (6.0 V) and more stable electroluminescence over the amorphous one. Surprisingly, mixed conformations in PODPF film produce dually tunable amplified spontaneous emission (ASE) at 463 and 482 nm. Polydiarylfluorenes with quasi planar conformation will be a promising candidate for the next-generation gain medium toward a broadly tunable lasing and dual-wavelength laser. PMID- 27480143 TI - An unusual and malignant intussusception in a child. AB - Intussusception is a common cause of bowel obstruction in the pediatric population. Malignant lesions account for up to 30 % of all cases of intussusception in the small intestine. We herein report an interesting case of ileo-colic intussusception caused by diffuse large B-cell lymphoma, in a child. The patient underwent laparoscopic right hemicolectomy. Pathologic evaluation revealed a diffuse large B-cell lymphoma.In cases of intussusception, especially in the older age group of children, a high index of suspicion for malignant lymphoma of the bowel should be observed. PMID- 27480144 TI - Popular Nutrition-Related Mobile Apps: A Feature Assessment. AB - BACKGROUND: A key challenge in human nutrition is the assessment of usual food intake. This is of particular interest given recent proposals of eHealth personalized interventions. The adoption of mobile phones has created an opportunity for assessing and improving nutrient intake as they can be used for digitalizing dietary assessments and providing feedback. In the last few years, hundreds of nutrition-related mobile apps have been launched and installed by millions of users. OBJECTIVE: This study aims to analyze the main features of the most popular nutrition apps and to compare their strategies and technologies for dietary assessment and user feedback. METHODS: Apps were selected from the two largest online stores of the most popular mobile operating systems-the Google Play Store for Android and the iTunes App Store for iOS-based on popularity as measured by the number of installs and reviews. The keywords used in the search were as follows: calorie(s), diet, diet tracker, dietician, dietitian, eating, fit, fitness, food, food diary, food tracker, health, lose weight, nutrition, nutritionist, weight, weight loss, weight management, weight watcher, and ww calculator. The inclusion criteria were as follows: English language, minimum number of installs (1 million for Google Play Store) or reviews (7500 for iTunes App Store), relation to nutrition (ie, diet monitoring or recommendation), and independence from any device (eg, wearable) or subscription. RESULTS: A total of 13 apps were classified as popular for inclusion in the analysis. Nine apps offered prospective recording of food intake using a food diary feature. Food selection was available via text search or barcode scanner technologies. Portion size selection was only textual (ie, without images or icons). All nine of these apps were also capable of collecting physical activity (PA) information using self-report, the global positioning system (GPS), or wearable integrations. Their outputs focused predominantly on energy balance between dietary intake and PA. None of these nine apps offered features directly related to diet plans and motivational coaching. In contrast, the remaining four of the 13 apps focused on these opportunities, but without food diaries. One app-FatSecret-also had an innovative feature for connecting users with health professionals, and another-S Health-provided a nutrient balance score. CONCLUSIONS: The high number of installs indicates that there is a clear interest and opportunity for diet monitoring and recommendation using mobile apps. All the apps collecting dietary intake used the same nutrition assessment method (ie, food diary record) and technologies for data input (ie, text search and barcode scanner). Emerging technologies, such as image recognition, natural language processing, and artificial intelligence, were not identified. None of the apps had a decision engine capable of providing personalized diet advice. PMID- 27480146 TI - When Do Late Effects in Childhood Cancer Survivors Cease Emerging? The Endocrine Answer. PMID- 27480145 TI - Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three Arm Phase III Trial. AB - PURPOSE: Total mesorectal excision with fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy is a standard treatment of locally advanced rectal cancer. This study investigated the addition of oxaliplatin with and without preoperative radiotherapy. METHODS: In this multicenter, open-label, phase III trial, we randomly assigned (1:1:1) Chinese adults (age 18 to 75 years) with locally advanced stage II/III rectal cancer to three treatments: five 2-week cycles of infusional fluorouracil (leucovorin 400 mg/m(2), fluorouracil 400 mg/m(2), and fluorouracil 2.4 g/m(2) over 48 h) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 through 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m(2) on day 1 of each cycle (modified FOLFOX6 [mFOLFOX6]), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Random assignment was performed by using computer-generated block randomization codes. The primary end point was 3 year disease-free survival. Secondary end points of histopathologic response and toxicity are reported. RESULTS: A total of 495 patients were enrolled from June 2010 to February 2015; 475 were evaluable (fluorouracil-radiotherapy, n = 155; mFOLFOX6-radiotherapy, n = 157; mFOLFOX6, n = 163). In the fluorouracil radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, the rate of pathologic complete response (pCR) was 14.0%, 27.5%, and 6.6%, and downstaging (ypStage 0 to 1) was achieved by 37.1%, 56.4%, and 35.5% of patients, respectively. Higher toxicity and more postoperative complications were observed in patients who received radiotherapy. CONCLUSION: mFOLFOX6-based preoperative chemoradiotherapy results in a higher pCR rate than fluorouracil-based treatment. Perioperative mFOLFOX6 alone had inferior results and a lower pCR rate than chemoradiotherapy but led to a similar downstaging rate as fluorouracil-radiotherapy, with less toxicity and fewer postoperative complications. PMID- 27480148 TI - Final Survival Analysis of ROSE/TRIO-012. PMID- 27480147 TI - The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer. AB - PURPOSE: By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. PATIENTS AND METHODS: Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK 2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. RESULTS: Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). CONCLUSION: Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed. PMID- 27480149 TI - Lymph Node Count From Neck Dissection Predicts Mortality in Head and Neck Cancer. AB - Purpose Multiple smaller studies have demonstrated an association between overall survival and lymph node (LN) count from neck dissection in patients with head and neck cancer. This is a large cohort study to examine these associations by using a national cancer database. Patients and Methods The National Cancer Database was used to identify patients who underwent upfront nodal dissection for mucosal head and neck squamous cell carcinoma between 2004 and 2013. Patients were stratified by LN count into those with < 18 nodes and those with >= 18 nodes on the basis of prior work. A multivariable Cox proportional hazards regression model was constructed to predict hazard of mortality. Stratified models predicted hazard of mortality both for patients who were both node negative and node positive. Results There were 45,113 patients with >= 18 LNs and 18,865 patients with < 18 LNs examined. The < 18 LN group, compared with the >= 18 LN group, had more favorable tumor characteristics, with a lower proportion of T3 and T4 lesions (27.9% v 39.8%), fewer patients with positive nodes (46.6% v 60.5%), and lower rates of extracapsular extension (9.3% v 15.1%). Risk-adjusted Cox models predicting hazard of mortality by LN count showed an 18% increased hazard of death for patients with < 18 nodes examined (hazard ratio [HR] 1.18; 95% CI, 1.13 to 1.22). When stratified by clinical nodal stage, there was an increased hazard of death in both groups (node negative: HR, 1.24; 95% CI, 1.17 to 1.32; node positive: HR, 1.12; 95% CI, 1.05 to 1.19). Conclusion The results of our study demonstrate a significant overall survival advantage in both patients who are clinically node negative and node positive when >= 18 LNs are examined after neck dissection, which suggests that LN count is a potential quality metric for neck dissection. PMID- 27480150 TI - Reply to L.E. Daly et al. PMID- 27480152 TI - Can We Define and Reach Precise Goals for Precision Medicine in Cancer Care? PMID- 27480151 TI - A Space to Heal. PMID- 27480153 TI - Improved Metastasis-Free and Survival Outcomes With Early Salvage Radiotherapy in Men With Detectable Prostate-Specific Antigen After Prostatectomy for Prostate Cancer. AB - Purpose To describe outcomes of salvage radiotherapy (SRT) for men with detectable prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer and identify associations with outcomes. Patients and Methods A total of 1,106 patients received SRT between January 1987 and July 2013, with median follow-up 8.9 years. Outcomes were estimated using Kaplan-Meier for overall survival (OS) and cumulative incidence for biochemical recurrence (BcR), distant metastases (DM), and cause-specific mortality (CSM). Variable associations with outcomes used Cox or Fine-Gray methods, as appropriate. Multiple variable analyses used backward selection with P < .05 for retention. Results In multiple variable analyses, pathologic tumor stage, Gleason score, and pre-SRT PSA were associated with BcR, DM, CSM, and OS; androgen suppression and SRT doses > 68 Gy were associated with BcR; and age was associated with OS. Each pre-SRT PSA doubling increased significantly the relative risk of BcR (hazard ratio [HR], 1.30; P < .001), DM (HR, 1.32; P < .001), CSM (HR, 1.40; P < .001), and all-cause mortality (HR, 1.12; P = .02). Using a pre-SRT PSA cutoff <= 0.5 versus > 0.5 ng/mL, 5-year and 10-year cumulative incidences for BcR were 42% versus 56% and 60% versus 68% ( P < .001), DM 7% versus 14% and 13% versus 25% ( P < .001), CSM 1% versus 4% and 6% versus 13% ( P < .001), and OS of 94% versus 92% and 83% versus 73% ( P > .05). Conclusion SRT outcomes are in part affected by factors associated with prostatectomy findings but may be positively affected by using SRT at lower PSA levels, including reductions in BcR, DM, CSM, and all cause mortality. These findings argue against prolonged monitoring of detectable postprostatectomy PSA levels that delay initiation of SRT. PMID- 27480154 TI - Response to "Loss of Muscle Mass During Chemotherapy Is Predictive for Poor Survival of Patients With Metastatic Colorectal Cancer". PMID- 27480155 TI - Subtype-Dependent Relationship Between Young Age at Diagnosis and Breast Cancer Survival. AB - PURPOSE: Young women are at increased risk for developing more aggressive subtypes of breast cancer. Although previous studies have shown a higher risk of breast cancer recurrence and death among young women with early-stage breast cancer, they have not adequately addressed the role of tumor subtype in outcomes. METHODS: We examined data from women with newly diagnosed stage I to III breast cancer presenting to one of eight National Comprehensive Cancer Network centers between January 2000 and December 2007. Multivariable Cox proportional hazards models were used to assess the relationship between age and breast cancer specific survival. RESULTS: A total of 17,575 women with stage I to III breast cancer were eligible for analysis, among whom 1,916 were <= 40 years of age at diagnosis. Median follow-up time was 6.4 years. In a multivariable Cox proportional hazards model controlling for sociodemographic, disease, and treatment characteristics, women <= 40 years of age at diagnosis had greater breast cancer mortality (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.7). In stratified analyses, age <= 40 years was associated with statistically significant increases in risk of breast cancer death among women with luminal A (HR, 2.1; 95% CI, 1.4 to 3.2) and luminal B (HR 1.4; 95% CI, 1.1 to 1.9) tumors, with borderline significance among women with triple-negative tumors (HR, 1.4; 95% CI, 1.0 to 1.8) but not among those with human epidermal growth factor receptor 2 subtypes (HR, 1.2; 95% CI, 0.8 to 1.9). In an additional model controlling for detection method, young age was associated with significantly increased risk of breast cancer death only among women with luminal A tumors. CONCLUSION: The effect of age on survival of women with early breast cancer seems to vary by breast cancer subtype. Young age seems to be particularly prognostic in women with luminal breast cancers. PMID- 27480156 TI - Development and molecular-genetic characterization of a stable Brassica allohexaploid. AB - KEY MESSAGE: We report first-time synthesis of a stable Brassica allohexaploid. It may evolve into a new species and also advance our understanding of pairing regulation and genome evolution in complex allopolyploids. Crop Brassicas include both monogenomic and digenomic species. A trigenomic Brassica (AABBCC) is not known to exist in nature. Past attempts to synthesize a stable allohexaploid were not successful due to aberrant meiosis and very high proportion of aneuploid plants in the selfed progenies. We report the development of a stable allohexaploid Brassica (2n = 54; AABBCC). Genomic in situ hybridization confirmed the complete assemblage of three genomes. Only allohexaploids involving B. rapa cv. R01 (2n = 20; AA) as pollinator with a set of B. carinata (2n = 34; BBCC) were stable. These exhibited a high proportion (0.78-0.94) of pollen mother cells with normal meiosis and an excellent hexaploid ratio (0.80-0.94) in the selfed progenies. Stability of two allohexaploid combinations was demonstrated from H1 to H4 generations at two very diverse locations in India. Graphical genotyping of allohexaploids allowed detection of chromosome fragment exchanges among three genomes. These were much smaller for meiotically stable allohexaploids as compared to unstable ones. The putative hexaploids were morphologically closer to the female donor, B. carinata, for leaf morphology, inflorescence structure and flower shape. The newly formed allohexaploid may also provide unique opportunities to investigate the immediate genetic and genomic consequences of a Brassica allohexaploid with three resident genomes. PMID- 27480157 TI - Model training across multiple breeding cycles significantly improves genomic prediction accuracy in rye (Secale cereale L.). AB - KEY MESSAGE: Genomic prediction accuracy can be significantly increased by model calibration across multiple breeding cycles as long as selection cycles are connected by common ancestors. In hybrid rye breeding, application of genome based prediction is expected to increase selection gain because of long selection cycles in population improvement and development of hybrid components. Essentially two prediction scenarios arise: (1) prediction of the genetic value of lines from the same breeding cycle in which model training is performed and (2) prediction of lines from subsequent cycles. It is the latter from which a reduction in cycle length and consequently the strongest impact on selection gain is expected. We empirically investigated genome-based prediction of grain yield, plant height and thousand kernel weight within and across four selection cycles of a hybrid rye breeding program. Prediction performance was assessed using genomic and pedigree-based best linear unbiased prediction (GBLUP and PBLUP). A total of 1040 S2 lines were genotyped with 16 k SNPs and each year testcrosses of 260 S2 lines were phenotyped in seven or eight locations. The performance gap between GBLUP and PBLUP increased significantly for all traits when model calibration was performed on aggregated data from several cycles. Prediction accuracies obtained from cross-validation were in the order of 0.70 for all traits when data from all cycles (N CS = 832) were used for model training and exceeded within-cycle accuracies in all cases. As long as selection cycles are connected by a sufficient number of common ancestors and prediction accuracy has not reached a plateau when increasing sample size, aggregating data from several preceding cycles is recommended for predicting genetic values in subsequent cycles despite decreasing relatedness over time. PMID- 27480158 TI - Worse Breast Cancer Outcomes for Southern Nevadans, Filipina and Black Women. AB - Breast cancer is the second deadliest cancer for women in the demographically unique mountainous west state of Nevada. This study aims to accurately characterize breast cancer survival among the diverse women of the flourishing Silver State. Nevada Central Cancer Registry data was linked with the National Death Index and the Social Security Administration Masterfile. Overall 5-year age adjusted cause-specific survival, survival stratified by race/ethnicity, and stage-specific survival stratified by region of Nevada were calculated. Adjusted hazard ratios were computed with Cox proportional hazards regression. 11,111 cases of breast cancer were diagnosed from 2003 to 2010. Overall 5-year breast cancer survival in Nevada was 84.4 %, significantly lower than the US, at 89.2 %. Black and Filipina women had a higher risk of death than white women. Poor survival in the racially and ethnically diverse Las Vegas metropolitan area, with a large foreign-born population, drives Nevada's low overall survival. System wide changes are recommended to reduce the racial/ethnic disparities seen for black and Filipina women and improve outcomes for all. PMID- 27480159 TI - Vaccination Coverage Disparities Between Foreign-Born and U.S.-Born Children Aged 19-35 Months, United States, 2010-2012. AB - Healthy People 2020 targets high vaccination coverage among children. Although reductions in coverage disparities by race/ethnicity have been described, data by nativity are limited. The National Immunization Survey is a random-digit-dialed telephone survey that estimates vaccination coverage among U.S. children aged 19 35 months. We assessed coverage among 52,441 children from pooled 2010-2012 data for individual vaccines and the combined 4:3:1:3*:3:1:4 series (which includes >=4 doses of diphtheria, tetanus, and acellular pertussis vaccine/diphtheria and tetanus toxoids vaccine/diphtheria, tetanus toxoids, and pertussis vaccine, >=3 doses of poliovirus vaccine, >=1 dose of measles-containing vaccine, >=3 or >=4 doses of Haemophilus influenzae type b vaccine (depending on product type of vaccine; denoted as 3* in the series name), >=3 doses of hepatitis B vaccine, >=1 dose of varicella vaccine, and >=4 doses of pneumococcal conjugate vaccine). Coverage estimates controlling for sociodemographic factors and multivariable logistic regression modeling for 4:3:1:3*:3:1:4 series completion are presented. Significantly lower coverage among foreign-born children was detected for DTaP, hepatitis A, hepatitis B, Hib, pneumococcal conjugate, and rotavirus vaccines, and for the combined series. Series completion disparities persisted after control for demographic, access-to-care, poverty, and language effects. Substantial and potentially widening disparities in vaccination coverage exist among foreign-born children. Improved immunization strategies targeting this population and continued vaccination coverage monitoring by nativity are needed. PMID- 27480160 TI - What kind of processing is survival processing? : Effects of different types of dual-task load on the survival processing effect. AB - Words judged for their relevance in a survival context are remembered better than words processed in non-survival contexts. This phenomenon is known as the survival processing effect. Recently, inconsistent results were reported on whether the size of the survival processing effect is affected by cognitive load. Whereas Kroneisen, Rummel, and Erdfelder (Memory 22: 92-102, 2014) observed that the survival processing effect vanishes under dual-task conditions, Stillman, Coane, Profaci, Howard, and Howard (Memory & Cognition 42: 175-185, 2014, Experiment 1) found that the size of survival processing effect is essentially unaffected by a cognitively demanding secondary task. In three experiments, we investigated the differences between these studies to achieve a better understanding of dual-task effects on the survival-processing advantage. In the first experiment, we replicated Stillman et al.'s results using their dual-task conditions combined with a sample more than twice as large as theirs. In the second experiment, we compared dual-task conditions that differed regarding how strongly the secondary task taxed (a) working memory load (maintenance of one vs. several items) and (b) processing demands (switching vs. time-sharing between tasks). A third experiment focussed on low (i.e., single-item) load under time sharing processing conditions. Results consistently showed that the survival processing effect persisted under low load but vanished when the number of items held in working memory increased beyond one, irrespective of processing demands. Implications of these findings for explanations of the survival-processing advantage are discussed. PMID- 27480161 TI - Community attitudes towards a Jewish community BRCA1/2 testing program. AB - About 2.5 % of the Ashkenazi-Jewish population carry one of three "founder" mutations in BRCA1 and BRCA2 (BRCA1/2). Currently, testing is offered to Jewish people with a personal and/or family history of breast and/or ovarian cancer; however less than half of BRCA1/2 carriers within the Jewish population are aware of their family history. Population-based testing in other countries has shown to greatly increase the number of mutation carriers identified, compared to targeted testing of people with a family history. We aimed to assess the Australian Jewish community's attitudes towards such a program, including acceptability and interest in having education and testing offered online. Members of Sydney-based Jewish organisations who self-identified as being Jewish were invited by e-mail to participate in an online survey. Of 370 individuals who completed the survey, 96.8 % supported a Jewish community-based BRCA1/2 testing program, and 65.6 % reported being personally interested in undergoing the test. Younger adults aged below 50 years were more interested in undergoing the test than those aged 50 years and above. Almost half (42.9 %) were aware of a family member with breast and/or ovarian cancer; however, of these, 77.1 % had not yet undergone testing. Sixty-five (65.1 %) percent were satisfied with providing consent online, while only 39.6 % of participants' first preference for method of information provision was online. Given the high level of support, and interest in a community testing program, the development and evaluation of a cost-effective and interactive, online BRCA1/2 community testing program appears warranted. PMID- 27480162 TI - Pharmaceutical Residues Affecting the UNESCO Biosphere Reserve Kristianstads Vattenrike Wetlands: Sources and Sinks. AB - This study is the first to investigate the pharmaceutical burden from point sources affecting the UNESCO Biosphere Reserve Kristianstads Vattenrike, Sweden. The investigated Biosphere Reserve is a >1000 km(2) wetland system with inflows from lakes, rivers, leachate from landfill, and wastewater-treatment plants (WWTPs). We analysed influent and treated wastewater, leachate water, lake, river, and wetland water alongside sediment for six model pharmaceuticals. The two WWTPs investigated released pharmaceutical residues at levels close to those previously observed in Swedish monitoring exercises. Compound-dependent WWTP removal efficiencies ranging from 12 to 100 % for bendroflumethiazide, oxazepam, atenolol, carbamazepine, and diclofenac were observed. Surface-water concentrations in the most affected lake were >=100 ng/L for the various pharmaceuticals with atenolol showing the highest levels (>300 ng/L). A small risk assessment showed that adverse single-substance toxicity on aquatic organisms within the UNESCO Biosphere Reserve is unlikely. However, the effects of combinations of a large number of known and unknown pharmaceuticals, metals, and nutrients are still unknown. PMID- 27480163 TI - Impact of aging on leaching characteristics of recycled concrete aggregate. AB - The focus of this study was to evaluate the effects of stockpiling (aging) on leaching of elements in recycled concrete aggregate (RCA) that may contribute to tufaceous constituent formation. Speciation and leaching controlling mechanisms of these elements were identified via geochemical modeling. The effects of stockpiling were simulated by comparing freshly produced RCA with RCA aged as part of this study for 1 year both in the laboratory and in the field. Leachate samples were generated following batch water leach test (WLT) and US Geological Survey leach test (USGSLT) methods. USGSLTs were conducted both on the laboratory and field samples while WLT was only conducted on laboratory samples. During the laboratory aging, it is observed that the carbonate content of RCA, measured as calcite equivalent, increased 20 % (i.e., from ~100 to 120 mg/g) within a year time frame. The leachate extracted from RCA showed minor changes in pH and more significant decreases in electrical conductivity (i.e., ~300 to 100 MUS/cm). A comparison between laboratory and field samples revealed that the RCA aged much slower in the field than in the laboratory within a year. Comparisons between two leach extraction methods on the laboratory conditions showed that the total leached concentrations (TLCs) of most of the constituents from USGSLT were appreciably lower than the ones measured via WLT method. The results of geochemical modeling analyses showed that Al, Si, Fe, Ca, Mg, and Cu exist in their oxidized forms as Al3+, Fe3+, Si4+, Ca2+, Mg2+, and Cu2+ and results revealed that these elements are primarily controlled by the solubility of gibbsite, hematite, silica gel, calcite, magnesite, and tenorite solid phases, respectively. One of the significant findings of the study was to identify the changes in leaching behavior of Ca, Si, Mg, Al, Fe, and Cu due to carbonation. PMID- 27480164 TI - Impacts of rapeseed dregs on Cd availability in contaminated acid soil and Cd translocation and accumulation in rice plants. AB - The objective of the present study was to investigate the effects of rapeseed dregs (RSD, a commonly organic fertilizer in rural China) at application rates of 0, 0.75, 1.5, and 3.0 % on Cd availability in soil and its accumulation in rice plants (Oryza sativa L., Xiangwanxian 12#, and Weiyou 46#) by means of a pot experiment. The results showed that application of RSD resulted in a sharp decrease in the soil TCLP-extractable Cd content. However, the soil TCLP extractable Cd content in amended soil gradually increased during the rice growing period. Application of RSD significantly increased Cd transport from root to shoot and the amount of Cd accumulated in the aerial part. RSD was an effective organic additive for increasing rice grain yield, but total Cd content in rice grain was also increased. At an application rate of 1.5-3.0 % RSD, the total Cd content in Weiyou 46# brown rice was 0.27-0.31 mg kg-1, which exceeded the standard safe limit (0.2 mg kg-1) and was also higher than that of Xiangwanxian 12# (0.04-0.14 mg kg-1). Therefore, Weiyou 46# had a higher dietary risk than Xiangwanxian 12# with RSD application. We do not recommend planting Weiyou 46# and applying more than 0.75 % RSD in Cd-contaminated paddy fields. PMID- 27480165 TI - Socio-economic deprivation: a significant determinant affecting stage of oral cancer diagnosis and survival. AB - BACKGROUND: Many factors contribute to socioeconomic status (SES), yet in most survival studies only income is used as a measure for determining SES. We used a complex, composite, census-based metric for socioeconomic deprivation to better distinguish individuals with lower SES and assess its impact on survival and staging trends of oral cancers. METHODS: Oropharyngeal (OPC) and oral cavity cancer (OCC) cases were identified from the British Columbia cancer registry between 1981-2009 and placed into affluent and deprived neighborhoods using postal codes linked to VANDIX (a composite SES index based on 7 census variables encompassing income, housing, family structure, education, and employment). Stage and cancer-specific survival rates were examined by sex, SES, and time period. RESULTS: Approximately 50 % of OPC and OCC cases of both sexes resided in SES deprived neighborhoods. Numbers of cases have increased in recent years for all but OCC in men. The deprivation gap in survival between affluent and deprived neighborhoods widened in recent years for OPC and OCC in men, while decreasing for OPC and increasing slightly for OCC in women. Greater proportions of OCC cases were diagnosed at later stage disease for both sexes residing in deprived neighborhoods, a trend not seen for OPC. CONCLUSION: SES remains a significant independent determinant of survival for both OPC and OCC when using a composite metric for SES. OPC survival rates among men have improved, albeit at slower rates in deprived communities. OCC screening programs need to be targeted towards SES-deprived neighborhoods where greater proportions of cases were diagnosed at a later stage and survival rates have significantly worsened in both sexes. PMID- 27480166 TI - Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. AB - Progress in the treatment of patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) has been limited. An improvement in the understanding of tumor immunosurveillance has resulted in the development of the immune checkpoint inhibitors such as nivolumab. Nivolumab (Opdivo((r))), a human immunoglobulin (Ig)G4 anti-programmed death (PD)-1 monoclonal antibody, was the first PD-1 inhibitor approved in the treatment of patients with advanced stage squamous cell NSCLC following platinum-based chemotherapy. CHECKMATE 017, a randomized phase III study of second-line nivolumab versus docetaxel, significantly improved overall survival (OS), progression-free survival (PFS), patient reported outcomes and the safety and tolerability favored patients treated with nivolumab. The ligand (PD-L1) expression did not predict for outcome. In this paper, we review the role of nivolumab in the treatment of NSCLC with particular attention on recent studies, ongoing combination studies, toxicity profile, current and potential predictive biomarkers. PMID- 27480167 TI - Ubiquitin ligase gene neurl3 plays a role in spermatogenesis of half-smooth tongue sole (Cynoglossus semilaevis) by regulating testis protein ubiquitination. AB - E3 ubiquitin ligases are a large gene family that plays a diversity of roles in spermatogenesis. In this study, the functional characterization of a neuralized E3 ubiquitin protein ligase 3 (neurl3) revealed its potential participation in spermatogenesis. Firstly, we found that neurl3 exhibited male-biased transcription and that its translation was predominant in testis germ cells. The knockdown of neurl3 by RNA interference caused increased transcription of spermatogenesis-related genes. These results corroborate previous studies indicating a role for neurl3 in spermatogenesis. Moreover, the levels of neurl3 transcription and testis protein ubiquitination were closely correlated. Based on these findings, we speculate that neurl3 modulates testis protein ubiquitination in a dosage-dependent manner and that this influences spermatogenesis. PMID- 27480169 TI - L60m scheme will cover GPs' rising indemnity costs. PMID- 27480168 TI - N-linked glycosylation of N48 is required for equilibrative nucleoside transporter 1 (ENT1) function. AB - Human equilibrative nucleoside transporter 1 (hENT1) transports nucleosides and nucleoside analogue drugs across cellular membranes and is necessary for the uptake of many anti-cancer, anti-parasitic and anti-viral drugs. Previous work, and in silico prediction, suggest that hENT1 is glycosylated at Asn(48) in the first extracellular loop of the protein and that glycosylation plays a role in correct localization and function of hENT1. Site-directed mutagenesis of wild type (wt) hENT1 removed potential glycosylation sites. Constructs (wt 3xFLAG hENT1, N48Q-3xFLAG-hENT1 or N288Q-3xFLAG-hENT2) were transiently transfected into HEK293 cells and cell lysates were treated with or without peptide-N-glycosidase F (PNGase-F), followed by immunoblotting analysis. Substitution of N48 prevents hENT1 glycosylation, confirming a single N-linked glycosylation site. N48Q-hENT1 protein is found at the plasma membrane in HEK293 cells but at lower levels compared with wt hENT1 based on S-(4-nitrobenzyl)-6-thioinosine (NBTI) binding analysis (wt 3xFLAG-ENT1 Bmax, 41.5+/-2.9 pmol/mg protein; N48Q-3xFLAG-ENT1 Bmax, 13.5+/-0.45 pmol/mg protein) and immunofluorescence microscopy. Although present at the membrane, chloroadenosine transport assays suggest that N48Q-hENT1 is non functional (wt 3xFLAG-ENT1, 170.80+/-44.01 pmol/mg protein; N48Q-3xFLAG-ENT1, 57.91+/-17.06 pmol/mg protein; mock-transfected 74.31+/-19.65 pmol/mg protein). Co-immunoprecipitation analyses suggest that N48Q ENT1 is unable to interact with self or with wt hENT1. Based on these data we propose that glycosylation at N48 is critical for the localization, function and oligomerization of hENT1. PMID- 27480170 TI - A gene encoding a potential adenosine 5'-phosphosulphate kinase is necessary for timely development of Myxococcus xanthus. PMID- 27480172 TI - Stem Cells and Regeneration in the Digestive System: Keystone Meeting. PMID- 27480171 TI - The DAU cluster: a comparative analysis of 18 RHD alleles, some forming partial D antigens. AB - BACKGROUND: The Rh system is the most complex and polymorphic blood group system in humans with more than 460 alleles known for the RHD gene. The DAU cluster of RHD alleles is characterized by the single-nucleotide change producing the p.Thr379Met amino acid substitution. It is called the DAU-0 allele and has been postulated to be the primordial allele, from which all other alleles of the DAU cluster have eventually evolved. STUDY DESIGN AND METHODS: For two novel DAU alleles, the nucleotide sequences of all 10 exons as well as adjacent intronic regions, including the 5' and 3' untranslated regions (UTR), were determined for the RHD and RHCE genes. A phylogenetic tree for all DAU alleles was established using the neighbor-joining method with Pan troglodytes as root. Standard hemagglutination and flow cytometry tests were performed. RESULTS: We characterized two DAU alleles, DAU-11 and DAU-5.1, closely related to DAU-3 and DAU-5, respectively. A phylogenetic analysis of the 18 known DAU alleles indicated point mutations and interallelic recombination contributing to diversification of the DAU cluster. CONCLUSIONS: The DAU alleles encode a group of RhD protein variants, some forming partial D antigens known to permit anti-D in carriers; all are expected to cause anti-D alloimmunization in recipients of red blood cell transfusions. The DAU alleles evolved through genomic point mutations and recombination. These results suggest that the cluster of DAU alleles represent a clade, which is concordant with our previous postulate that they derived from the primordial DAU-0 allele. PMID- 27480174 TI - Circadian Rhythms in Gastrointestinal Health and Diseases. PMID- 27480175 TI - Genetic Transformation of Hordeum vulgare ssp. spontaneum for the Development of a Transposon-Based Insertional Mutagenesis System. AB - Domestication and intensive selective breeding of plants has triggered erosion of genetic diversity of important stress-related alleles. Researchers highlight the potential of using wild accessions as a gene source for improvement of cereals such as barley, which has major economic and social importance worldwide. Previously, we have successfully introduced the maize Ac/Ds transposon system for gene identification in cultivated barley. The objective of current research was to investigate the response of Hordeum vulgare ssp. spontaneum wild barley accessions in tissue culture to standardize parameters for introduction of Ac/Ds transposons through genetic transformation. We investigated the response of ten wild barley genotypes for callus induction, regenerative green callus induction and regeneration of fertile plants. The activity of exogenous Ac/Ds elements was observed through a transient assay on immature wild barley embryos/callus whereby transformed embryos/calli were identified by the expression of GUS. Transient Ds expression bombardment experiments were performed on 352 pieces of callus (3-5 mm each) or immature embryos in 4 genotypes of wild barley. The transformation frequency of putative transgenic callus lines based on transient GUS expression ranged between 72 and100 % in wild barley genotypes. This is the first report of a transformation system in H. vulgare ssp. spontaneum. PMID- 27480173 TI - Protective Actions of Epithelial 5-Hydroxytryptamine 4 Receptors in Normal and Inflamed Colon. AB - BACKGROUND & AIMS: The 5-hydroxytryptamine receptor 4 (5-HT4R or HTR4) is expressed in the colonic epithelium but little is known about its functions there. We examined whether activation of colonic epithelial 5-HT4R protects colons of mice from inflammation. METHODS: The 5-HT4R agonist tegaserod (1 mg/kg), the 5-HT4R antagonist GR113808 (1 mg/kg), or vehicle (control) were delivered by enema to wild-type or 5-HT4R knockout mice at the onset of, or during, active colitis, induced by administration of dextran sodium sulfate or trinitrobenzene sulfonic acid. Inflammation was measured using the colitis disease activity index and by histologic analysis of intestinal tissues. Epithelial proliferation, wound healing, and resistance to oxidative stress induced apoptosis were assessed, as was colonic motility. RESULTS: Rectal administration of tegaserod reduced the severity of colitis compared with mice given vehicle, and accelerated recovery from active colitis. Rectal tegaserod did not improve colitis in 5-HT4R knockout mice, and intraperitoneally administered tegaserod did not protect wild-type mice from colitis. Tegaserod increased proliferation of crypt epithelial cells. Stimulation of 5-HT4R increased Caco-2 cell migration and reduced oxidative stress-induced apoptosis; these actions were blocked by co-administration of the 5-HT4R antagonist GR113808. In noninflamed colons of wild-type mice not receiving tegaserod, inhibition of 5-HT4Rs resulted in signs of colitis within 3 days. In these mice, epithelial proliferation decreased and bacterial translocation to the liver and spleen was detected. Daily administration of tegaserod increased motility in inflamed colons of guinea pigs and mice, whereas administration of GR113808 disrupted motility in animals without colitis. CONCLUSIONS: 5-HT4R activation maintains motility in healthy colons of mice and guinea pigs, and reduces inflammation in colons of mice with colitis. Agonists might be developed as treatments for patients with inflammatory bowel diseases. PMID- 27480176 TI - Endoplasmic Reticulum Chaperones Are Potential Active Factors in Thyroid Tumorigenesis. AB - The study aimed to evaluate the proteomic changes in benign follicular adenoma versus malignant follicular variant of papillary thyroid carcinoma. Tumor and nontumor adjacent samples were analyzed by liquid nanochromatography mass spectrometry, and protein abundance was evaluated by label-free quantification. Western blotting and quantitative real-time polymerase chain reaction were used to validate and complement the mass spectrometry data. The results demonstrated deregulated expression of four endoplasmic reticulum chaperones (78 kDa glucose regulated protein, endoplasmin, calnexin, protein disulfide-isomerase A4), glutathione peroxidase 3 and thyroglobulin, all of them involved in thyroid hormone synthesis pathway. The altered tissue abundance of endoplasmic reticulum chaperones in thyroid cancer was correlated with serum expression levels. The identified proteins significantly discriminate between adenoma and carcinoma in both thyroid tissue and corresponding sera. Data are available via ProteomeXchange with identifier PXD004322. PMID- 27480177 TI - Long-term outcomes of sutureless 25-G+ pars-plana vitrectomy for the management of diabetic tractional retinal detachment. AB - PURPOSE: To evaluate the short- and long-term surgical and clinical outcomes in eyes with diabetic tractional retinal detachment (TRD) undergoing 25-G+ pars plana vitrectomy (PPV). METHODS: A total of 238 patients were reviewed for inclusion in this study. A retrospective cohort study of 109 eyes of 73 patients operated on for diabetic TRD were included. All eyes received intraocular tamponade of air, sulfur hexafluoride, octofluropropane or silicone oil. All patients were followed up for a minimum period of one year. RESULTS: The mean age of all patients at surgery was 53.9 years +/- 9.2, while the mean duration of diabetes was 18.7 +/- 10.4 years. The mean length of follow-up was 923 +/- 87 days after surgery (range, 432-1792 days). Thirty-two cases (29.3 %) had an associated rhegmatogenous component. Mean BCVA improved from logarithm minimum angle of resolution (logMAR) 1.17 (20/300) to 0.812 (20/130) (p < 0.05). All eyes underwent intraoperative laser photocoagulation. Primary, single-surgery anatomic reattachment was achieved in 99 eyes (91 %). Final anatomic attachment was achieved in 107 eyes (98 %). There was no statistically significant difference in primary or secondary re-attachment rate in terms of type of tamponade agent used. There were five cases of post-operative hypotony (<=5 mmHg) on postoperative day 1, while 11 eyes had IOP >= 30 mmHg. There were no cases of endophthalmitis in our cohort. CONCLUSIONS: 25G+ PPV provides for safe and effective repair of diabetic TRDs. Patients experienced positive functional and anatomic outcomes, with no significant intraoperative complications and minimal postoperative sequelae. PMID- 27480178 TI - Comparison of hyperbaric oxygen versus iloprost treatment in an experimental rat central retinal artery occlusion model. AB - PURPOSE: Central retinal artery occlusion (CRAO) is one of the serious ophthalmological emergencies with poor visual prognosis. Iloprost is a stable prostacyclin analogue and has prominent anti-edema, anti-inflammatory, vasodilatory, and antiagregant effects. The main objective of this work was to investigate iloprost as an alternative agent versus hyperbaric oxygen (HBO) in the treatment of CRAO. METHODS: Twenty-eight healthy Wistar albino male rats were randomly assigned into control (n = 7, sham operation), HBO (n = 7), iloprost (n = 7), and sham groups (n = 7). CRAO model was created through optic nerve exploration and ligation. Full-thickness retina (FTR), outer nuclear layer (ONL), inner nuclear layer (INL) and ganglion cell layer (GCL) thickness were measured on Hematoxylin/Eosin (H&E) stained retinal sections and immunohistochemical analysis including terminal deoxynucleotidyl transferase-mediated biotindeoxyuridine triphosphate nick-end labeling (TUNEL) assay was performed to determine the apoptotic index (AI). RESULTS: AI values of HBO (0.204 +/- 0.067) and iloprost (0.197 +/- 0.052) groups were significantly lower than sham (0.487 +/- 0.046) group (p < 0.001). Any significant difference was found between the HBO and iloprost groups in terms of AI (p = 0.514). A statistically significant increase in thickness of FTR, ONL, INL and GCL was detected in HBO, iloprost and sham groups compared to the control group (p = 0.002). FTR, ONL, INL and GCL thickness were significantly thinner in HBO and iloprost groups than in the sham group (p = 0.002). A significant lesser increase was observed in all the retinal layers thickness in iloprost group versus HBO group (p = 0.002) except for INL (p = 0.665). CONCLUSIONS: The study results demonstrated anti-edema, neuroprotective, and anti-apoptotic effects of iloprost quantitatively; thus, iloprost may be a beneficial alternative agent in the treatment of CRAO. PMID- 27480179 TI - The molecular mechanism of action of superactive human leptin antagonist (SHLA) and quadruple leptin mutein Lan-2 on human ovarian epithelial cell lines. AB - INTRODUCTION: A number of leptin receptor antagonists have been synthesised for therapeutic use, with pre-clinical tests suggesting their future use in anticancer therapy. To our knowledge, there are no data concerning the possible application of leptin receptor blockers in ovarian cancer. METHODS: In this study, we evaluated two leptin receptor antagonists: superactive human leptin antagonist (SHLA) and quadruple leptin mutein, Lan-2 (L39A/D40A/F41A/I42A), on cell proliferation (Alamar Blue test, BrdU assay), cell cycle gene (qPCR) and protein expression (Western blot) and cell signalling pathways (Western blot) in three different types of cell lines: OVCAR-3, CaOV-3 and HOSEpiC. RESULTS: Both receptor blockers had no effect on non-cancerous HOSEpiC cell line proliferation; however, both reversed the stimulatory effect of leptin on CaOV-3 cell line proliferation to control levels and to below control levels in OVCAR-3 cells. In metastatic carcinoma CaOV-3, both ObR antagonists had an inhibitory effect on the cdk2/cyclin D1 complex, while in serous carcinoma, OVCAR-3, they only had an effect on cdk2 and cdk4 protein expression. SHLA had an inhibitory effect on all investigated signalling pathways in OVCAR-3, while only on Stat3 in CaOV-3. Lan-2 had an inhibitory effect on Stat3 and ERK1/2 in CaOV-3, while in OVCAR-3 it only affected Akt protein phosphorylation. CONCLUSION: Based on these results, we conclude that SHLA and Lan-2 are promising leptin receptor inhibitors which could be used to block leptin activity, eliminating its negative effects on activities related to carcinogenesis. However, the selection of a specific antagonist should be related to tumour type. PMID- 27480180 TI - Is antihistaminergic H2 really useful in prevention of hypersensitivity induced by paclitaxel? PMID- 27480181 TI - Erratum: Erratum to: Effectiveness of tapentadol prolonged release for the management of painful mucositis in head and neck cancers during intensity modulated radiation therapy. PMID- 27480183 TI - [Obligation of guideline recommendations: Perception survey among guideline developers]. AB - INTRODUCTION: Specific recommendations form the centerpiece of medical guidelines. The intended strength of a recommendation is usually expressed by the use of different wordings. Recent investigations showed that guideline users (recipients) interpret the binding character of wordings in different ways. The perception of different wording and their binding character of the strength of guideline recommendations among guideline developers (sender) have so far not been investigated in the German-speaking area. METHODS: German-speaking guideline developers were invited online and at specialist meetings to participate in a survey investigating 13 different terms used in guideline recommendations. The aim was to measure their perceived binding character on a visual analog scale (VAS: 0-100). Additional demographic and occupational data were collected. The results were compared with data from a previous survey among guideline users. RESULTS: Overall, 136 guideline developers with an average of 4.2 (median 3) guideline (co-) authorships participated in the survey. While guideline developers interpreted the two imperative recommendations "must" and "must not" with a similarly high level of obligation, the level of obligation was not rated homogenously for strong and weak recommendations like "shall" or "should". Two out of five negative formulations were perceived as more binding than their corresponding positive formulations. In comparisons with the ratings of the guideline users the terms "darf nicht" (must not), (-5.8 VAS, p<=0.0001) and "muss" (must), (-2.9 VAS, p<=0.0006) were perceived as less binding by the guideline developers, as was "sollte nicht"(should not) (-6.6 VAS, p<=0.0001) and "kann nicht empfohlen werden" (cannot be recommended) (-9.4 VAS, p<=0.0001). Only "soll" (shall) was perceived as more binding (+8.7 VAS, p<=0.0001). DISCUSSION: The current survey demonstrates that guideline developers perceive the binding character of terms used in guideline recommendations in a similar way as it was found for guideline users in a previous survey. Negative recommendations are more often rated as more binding by guideline developers as the corresponding positive terms. The discordant ratings by the guideline developers can be explained by their methodological knowledge regarding formulations of recommendations. It would be desirable that efforts be made to identify wordings in guidelines which better discriminate the intended level of obligation of guideline recommendations with regard to these results. PMID- 27480182 TI - The effect of different volumes of high-intensity interval training on proinsulin in participants with the metabolic syndrome: a randomised trial. AB - AIMS/HYPOTHESIS: The continuous demand for insulin in the face of insulin resistance, coupled with the glucolipotoxic environment associated with the metabolic syndrome (MetS), adversely affects the quality of insulin produced and secreted by the pancreatic beta cells. This is depicted by increased circulating intact proinsulin concentration, which is associated with increased MetS severity and risk of cardiovascular (CV) mortality. High-intensity interval training (HIIT) has been shown to reduce insulin resistance and other CV disease risk factors to a greater degree than moderate-intensity continuous training (MICT). We therefore aimed to investigate the impact of MICT and different volumes of HIIT on circulating intact proinsulin concentration. METHODS: This was a substudy of the 'Exercise in prevention of Metabolic Syndrome' (EX-MET) multicentre trial. Sixty-six individuals with MetS were randomised to 16 weeks of: (1) MICT (n = 21, 30 min at 60-70% peak heart rate [HRpeak], five times/week); (2) 4HIIT (n = 22, 4 * 4 min bouts at 85-95% HRpeak, interspersed with 3 min of active recovery at 50 70% HRpeak, three times/week); or (3) 1HIIT (n = 23, 1 * 4 min bout at 85-95% HRpeak, three times/week). A subanalysis investigated the differential impact of these training programmes on intact proinsulin concentration in MetS individuals with type 2 diabetes (MICT, n = 6; 4HIIT, n = 9; 1HIIT, n = 12) and without type 2 diabetes (MICT, n = 15; 4HIIT, n = 13; 1HIIT, n = 11). Intact proinsulin, insulin and C-peptide concentrations were measured in duplicate via ELISA, following a 12 h fast, before and after the exercise programme. Fasting intact proinsulin concentration was also expressed relative to insulin and C-peptide concentrations. RESULTS: Following the exercise training, there were no significant (p > 0.05) changes in fasting intact proinsulin concentration indices in all participants (pre- vs post-programme proinsulin, proinsulin:insulin, proinsulin:C-peptide: MICT 19% decrease, 6% increase, 4% increase; 4HIIT 19% decrease, 8% decrease, 11% decrease; 1HIIT 34% increase, 49% increase, 36% increase). In participants who did not have type 2 diabetes, only 4HIIT significantly (p < 0.05) reduced fasting intact proinsulin concentration indices from pre to post intervention (pre- vs post-programme proinsulin, proinsulin:insulin, proinsulin:C-peptide: 4HIIT 32% decrease, 26% decrease, 32% decrease, p < 0.05; 1HIIT, 14% increase, 32% increase, 16% increase, p > 0.05; MICT 27% decrease, 17% decrease, 11% decrease), with a group * time interaction effect, indicating a greater reduction in intact proinsulin indices following 4HIIT compared with MICT and 1HIIT. There were no significant (p > 0.05) changes in intact proinsulin concentration indices in participants with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Higher-volume HIIT (4HIIT) improved insulin quality in MetS participants without type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01676870 FUNDING: The study was funded by the Norwegian University of Science and Technology and from an unrestricted research grant from the Coca-Cola company. Funding for the collection of physical activity data was derived from a 'UQ New Staff Start Up' grant awarded to B. Clark. PMID- 27480184 TI - Who is responsible for a safe discharge from hospital? A prospective risk analysis in the German setting. AB - BACKGROUND: A representative national survey on risk management in German hospitals has recently identified hospital discharge as a key area of attention. Based on the consensus in the literature about the need to address patient safety at system level, this paper does not only look at the processes of discharge designed by single hospitals, but also takes account of the broader legal and regulatory framework. METHODS: Failure Mode and Effects Analysis (FMEA) was applied for risk identification and assessment. For the analysis of the current status in hospitals, three hospitals were interviewed about their discharge processes. For the system perspective, the legislative and self-administrative framework specific for the German setting was reviewed. RESULTS: The FMEA allowed the identification of a number of actions for risk control in the responsibility of the hospitals and within the framework. Some risks are mainly caused by the legal framework, whereas others can only be addressed by the hospitals themselves. The continuity of drug treatment and the lack of back-up systems after discharge were identified as posing relevant risks to patient safety. CONCLUSION: Rich interaction was found between the hospitals and the framework they work in impacting patient safety at hospital discharge. The contribution of the legal and regulatory framework to patient safety needs to be taken into account more actively by policy makers in the future. PMID- 27480185 TI - [Systematic pressure ulcer risk management.: Results of implementing multiple interventions at Charite-Universitatsmedizin Berlin]. AB - Pressure ulcers impose a high burden of disease on both the affected individual and society. Demographic change and multimorbidity aggravate the problem. The present study describes the systematic implementation of a comprehensive approach to reduce the incidence of pressure ulcers in an inpatient setting. The introduction of systematic risk assessment and the subsequent risk-adjusted application of evidence-based prevention, combined with continuous feedback of outcomes as well as tailored training, were associated with a significant decline in the incidence of pressure ulcers. Especially the occurrence of high-grade ulcers could be minimized by this systems approach. PMID- 27480186 TI - [Assessment of polypharmacy: A question of definition and underlying data]. AB - BACKGROUND: Older persons are often subjected to polypharmacy. There is a large degree of variability in the definitions used, the underlying data sources and the medications included. Our aim was to analyse the influence of different definitions on the prevalence of polypharmacy. METHODS: We used data of the study "Inappropriate Medication in patients with REnal insufficiency in Nursing homes" (IMREN) conducted in nursing homes in Bremen and the surrounding area. Anonymised data were collected by nursing staff. Prescription drugs and over-the-counter drugs as well as scheduled and as-needed medications were assessed. RESULTS: 852 residents from 21 nursing homes were recruited (mean age: 83.5 years; 76.5% female). Each resident received an average of 8.8 scheduled and as-needed medications, the prevalence of polypharmacy (>=5 medications) was 83.5%. When including scheduled medications only, residents received an average of 6.3 medications (polypharmacy 69.7%). When restricting the analysis to prescription only medicines, the results were comparable (6.3 medications per resident; polypharmacy 69.1%). However, the two analyses included different drugs. A total of 74.3% received at least one over-the-counter drug as scheduled medication (59.7% on an as-needed basis). CONCLUSIONS: In studies investigating polypharmacy, the methods used should be reported in a transparent manner. This is particularly important when addressing the question of which drugs were included in the study. PMID- 27480187 TI - [Healthcare services for people in Lower Saxony (Germany) suffering from a rare disease: Findings from a survey among medical professionals]. AB - BACKGROUND: In the European Union, about 30 million people are affected by one of the 7,000 to 8,000 diseases being defined as rare. In Germany alone, an estimated 4 million people suffer from a rare disease. In many cases, therapeutic options and knowledge of specific rare diseases are strongly limited. OBJECTIVE: The aim of this study was to identify the deficits and challenges confronting healthcare services for people suffering from a rare disease from the medical professional's perspective. METHOD: As many as 530 medical professionals were invited to complete an online questionnaire, which was also available on the website of the General Medical Council of Lower Saxony. The questionnaire focused on questions in the following fields: structure of the medical care system; diagnosis and therapy; information sources and information exchange; and improvement of healthcare situation. Data were analyzed using IBM SPSS 22. RESULT: We received 65 completed questionnaires. The evaluation indicates deficits in the medical services provided for people with a rare disease and shortcomings in the communication between clinical disciplines. In addition, diagnostic and therapeutic options are limited, and quality-tested information is rare. CONCLUSION: Many of the identified deficits have already been addressed in the German national plan of action for people affected by rare diseases. Furthermore, newly discovered deficits have been evaluated. The German government implemented healthcare structures to improve healthcare services for people with rare diseases. However, budget deficits for specialized structures have occurred inhibiting the expansion of healthcare services. Moreover, many patients need systemic treatment requiring the further development of interdisciplinary care. PMID- 27480188 TI - [Evaluation of preliminary grades and credits in nurse training programs]. AB - In the federal state of Bremen preliminary grades were included to the extent of 25 % in written, oral and practical final grades during the time period 2009 2014. The evaluation focuses on the effects of preliminary grades on the scale of final grades and the performance of learners as well as on the assessment of the appropriateness of final grades. A mixed-methods design was employed that consisted of a quasi-experimental study comprising of surveys of students and teachers of comparative and model courses as well as a qualitative study using group discussions. The results confirm that preliminary grades lead to a minimal improvement of the final grades of some exclusively low-achieving students. The assessment of appropriateness hardly changed. From both learners' and teachers' point of view there is still great dissatisfaction concerning the practical final grades. With regard to learning habits an increased willingness to learn new skills on the one hand and a partly increased performance pressure on the other hand were demonstrated. On the basis of these research results, the authors recommend the regular introduction of preliminary marks into the nursing training. PMID- 27480189 TI - [Not Available]. PMID- 27480190 TI - [Evaluation of GP specialty training in Bavaria - An online survey among postgraduate trainees]. AB - BACKGROUND: Statistical projections suggest that by 2020 the number of general practitioners (GPs) in Germany will have decreased by about 13 %, which will lead to a risk of medical undersupply, especially in rural areas. This study was conducted on behalf of the Bavarian Ministry of Environment and Health in order to answer the following questions: How satisfied are young Bavarian physicians in GP specialty training with their training situation? To what extent are they willing to start a private practice, in general and, in particular, in rural areas? METHOD: The study's online questionnaire contained items concerning the context of GP specialty training and the willingness to set up a private practice. In addition, the "Heidelberger Niederlassungsbarometer", a structured questionnaire illustrating self-assessment of competencies of GPs in training, was included in the survey. We asked GP specialty trainees to participate by e maiI, directly or via their GP trainers. RESULTS: In total, 99 questionnaires were returned, whereof 95 fulfilled the criteria for analysis. In 76 % of the cases participants were female, 63 % working in practice and 37 % in a structured training programme. The majority of participants (58 %) preferred to work in a practice with more than one GP, followed by those preferring to work as a salaried GP (26 %). Their disposition to work in rural areas after having passed their specialty certificate examination was high or very high (59 %). Feedback on a regular basis was given to 29 % of the study participants. Almost every second participant received a structured initial training programme. Most of the participating GP trainees (59%) were satisfied or very satisfied with their training. CONCLUSION: In general, there is a high level of motivation among study participants to become an independent and self-employed GP, also in rural areas. Despite the fact that not even every second received central training elements like individual feedback and structured initial training, the participants were mostly satisfied with their GP specialty training. PMID- 27480191 TI - Adaptation, psychometric properties and feasibility of the Professionalism Scale Germany. AB - INTRODUCTION: Pre- and postgraduate education is meant to be competency-based. Over the last two decades various competency frameworks have been published. An important aspect of competency is professionalism, being discussed widely in the literature while a clear-cut definition is still lacking. The purpose of this study was to translate the Nijmegen Professionalism Scale into the German language, to adapt the scale to the German setting and to examine the psychometric properties, test-retest reliability and feasibility of the culturally adapted instrument designed to assess professionalism in general practice, in addition to the validity of the concept of professionalism and to testify the transfer across linguistic, cultural and societal differences. METHOD: After translating the Nijmegen Professional Scale into German, we conducted its cultural adaptation, the German Professionalism Scale (Pro-D). Its psychometric properties were assessed using Cronbach's alpha, descriptive statistics, and test-retest reliability. The validation of the construct was analysed by confirmatory factor analysis. Feasibility was confirmed in interviews with GP trainees and their trainers. RESULTS: A total of 133 trainees completed the Pro-D. The Pro-D showed high internal consistency (Cronbach's alpha 0.93) and good test-retest reliability (Spearman's rank correlation and Wilcoxon's matched pairs test) for the different domains. Confirmatory factor analysis was unable to establish construct validity. Change in sensitivity of the instrument was good. Statements of interviews confirmed the feasibility of the new instrument. CONCLUSIONS: We found good psychometric properties for the Pro-D. This might indicate transferability of the concept across linguistic, cultural and societal differences although the concept of professionalism was not replicated in a confirmatory factor analysis. PMID- 27480192 TI - Effektives Schreiben und Publizieren wissenschaftlicher Artikel - Teil III: Einleitung. PMID- 27480194 TI - A Typical Vascular and Pigmentary Dermoscopic Pattern of Capillary Malformations in Capillary Malformation-Arteriovenous Malformation Syndrome: Report of Four Cases. AB - We report dermoscopic characteristics of cutaneous capillary malformations in four patients with capillary malformation-arteriovenous malformation (CM-AVM) syndrome. We observed a mixed vascular and pigmentary pattern with branched linear vessels and an underlying homogeneous brown background. Disappearance of the vascular pattern on pressure revealed an underlying faint pigmentary reticular pattern. Our results suggest that this typical biphasic pattern on dermoscopy may be useful for the diagnosis of CM-AVM syndrome. PMID- 27480195 TI - Antidepressant drugs can modify cytotoxic action of temozolomide. AB - Cancer patients often require antidepressant treatment due to comorbid depressive disorder. However, recent studies have demonstrated that antidepressant drugs affect the efficacy of chemotherapy and promote progression of cancer. Apart from the main mood-improving effect, antidepressant drugs also produce analgesic, anxiolytic, hypnotic and pro-cognitive actions. Patients suffering from brain cancer constitute the greatest percentage of depressive cancer patients. However, vital safety and efficacy issues related to combined therapy with temozolomide, the first-line cytostatic in patients diagnosed with glioblastoma multiforme, and antidepressant drugs have yet to be addressed. The aim of the present studies was to evaluate the effect of three antidepressant drugs (imipramine, fluoxetine and tranylcypromine) on the cytotoxic efficacy of temozolomide on T98G cells, a human glioblastoma cell line. In our experiments, we used a complex experimental in vitro system to mimic the instability of a tumour's oxygen supply, thereby reproducing conditions that occur inside the tumour. The effect of the interaction between temozolomide and antidepressant drugs on viability, apoptosis and intensity of divisions of glioblastoma cells was evaluated under different oxygen conditions. The results of our studies demonstrated that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects. PMID- 27480193 TI - A Numerical Approach for Kinetic Analysis of the Nonexponential Thermoinactivation Process of Uricase. AB - Prior to the exponential decrease of activity of a uricase from Candida sp. during storage at 37 degrees C, there was a plateau period of about 4 days at pH 7.4, 12 days at pH 9.2, and about 22 days in the presence of 30 MUM oxonate at pH 7.4 or 9.2, but no degradation of polypeptides and no activity of resolved homodimers. To reveal determinants of the plateau period, a dissociation model involving a serial of conformation intermediates of homotetramer were proposed for kinetic analysis of the thermoinactivation process. In the dissociation model, the roles of interior noncovalent interactions essential for homotetramer integrity were reflected by an equivalent number of the artificial weakest noncovalent interaction; to avoid covariance among parameters, the rate constant for disrupting the artificial weakest noncovalent interaction was fixed at the minimum for physical significance of other parameters; among thermoinactivation curves simulated by numerical integration with different sets of parameters, the one for least-squares fitting to an experimental one gave the solution. Results found that the equivalent number of the artificial weakest noncovalent interaction primarily determined the plateau period; kinetics rather than thermodynamics for homotetramer dissociation determined the thermoinactivation process. These findings facilitated designing thermostable uricase mutants. PMID- 27480196 TI - Investigation of DNA damage in cells exposed to poly (lactic-co-glycolic acid) microspheres. AB - Poly (lactic-co-glycolic acid) (PLGA)-based materials are widely investigated for drug delivery and tissue engineering applications. Despite their popularity the genotoxic potential of PLGA has not been investigated. In this study, the comet assay, a sensitive assay for DNA damage, was used to evaluate potential genotoxicity in model cell types exposed to PLGA microspheres. Human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs) cells were exposed to PLGA microspheres (0.4-6 mg/mL) and DNA damage assessed at 24 h, 4 days, and 7 days. DNA damage was not identified after 24 h. However, after 4 and 7 days of exposure to 2 and 6 mg/mL of PLGA microspheres a significant elevation of DNA damage in both cell types was observed. The PLGA microspheres did not exhibit any cytotoxic effects on the cells under the conditions tested. Our results suggest that PLGA may have a genotoxic effect on cells. A broader investigation of the PLGA genotoxic profile in biological systems is needed. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 284-291, 2017. PMID- 27480197 TI - Safety of the Manchester Triage System to Detect Critically Ill Children at the Emergency Department. AB - OBJECTIVE: To assess the safety of the Manchester Triage System in pediatric emergency care for children who require admission to the intensive care unit (ICU). STUDY DESIGN: Between 2006 and 2013, 50 062 consecutive emergency department visits of children younger than the age of 16 years were included. We determined the percentage of undertriage, defined as the proportion of children admitted to ICU triaged as low urgent according to the Manchester Triage System, and diagnostic performance measures, including sensitivity, specificity, and diagnostic OR. Characteristics of undertriaged patients were compared with correctly triaged patients. In a logistic regression model, risk factors for undertriage were determined. RESULTS: In total, 238 (28.7%) of the 830 children admitted to ICU during the study period were undertriaged. Sensitivity of high Manchester Triage System urgency levels to detect ICU admission was 71% (95% CI 68%-74%) and specificity 85% (95% CI 85%-85%). Severity of illness was lower in undertriaged children than correctly triaged children admitted to ICU. Risk factors for undertriage were age <3 months, medical presenting problem, comorbidity, referral by a medical specialist or emergency medical services, and presentation during the evening or night shift. CONCLUSION: The Manchester Triage System misclassifies a substantial number of children who require ICU admission. Modifications targeted at young children and children with a comorbid condition could possibly improve safety of the Manchester Triage System in pediatric emergency care. PMID- 27480199 TI - Phonics Training Improves Reading in Children with Neurofibromatosis Type 1: A Prospective Intervention Trial. AB - OBJECTIVE: To examine the efficacy of a phonics-training program in children with neurofibromatosis type 1 (NF1) and reading difficulties. STUDY DESIGN: Thirty children (7-12 years of age) with NF1 completed a double-baseline, 24-week intervention trial. Literacy outcome measures were assessed at 4 time points: (1) at baseline; (2) after an 8-week no-treatment period; (3) immediately post treatment; and (4) at follow-up 8 weeks post-treatment. Repeated-measures ANOVA were conducted to examine change over time for all outcome measures, and significant main effects were explored with planned comparisons. Predictors of treatment effects were examined by linear regressions. RESULTS: Ninety percent of participants completed the intervention. Intervention-specific improvements were observed across a range of literacy outcomes, including reading accuracy (nonword reading, Cohen d = 1.10; regular-word reading, Cohen d = 0.32), letter-sound knowledge (Cohen d = 0.80), blending (Cohen d = 0.88), repetition of nonsense words (Cohen d = 0.94), phonemic decoding fluency (Cohen d = 0.55), and reading comprehension (Cohen d = 0.31). Improvements were maintained 8 weeks post treatment. Age (P = .03) and working memory (P = .02) significantly influenced efficacy, with greatest improvements observed in older children with stronger verbal working memory capacity. CONCLUSIONS: Home-based, computerized reading intervention was effective in improving the reading and reading-related abilities of children with NF1 and reading difficulty. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12611000779976. PMID- 27480198 TI - Breast Milk Feeding, Brain Development, and Neurocognitive Outcomes: A 7-Year Longitudinal Study in Infants Born at Less Than 30 Weeks' Gestation. AB - OBJECTIVES: To determine the associations of breast milk intake after birth with neurological outcomes at term equivalent and 7 years of age in very preterm infants STUDY DESIGN: We studied 180 infants born at <30 weeks' gestation or <1250 grams birth weight enrolled in the Victorian Infant Brain Studies cohort from 2001-2003. We calculated the number of days on which infants received >50% of enteral intake as breast milk from 0-28 days of life. Outcomes included brain volumes measured by magnetic resonance imaging at term equivalent and 7 years of age, and cognitive (IQ, reading, mathematics, attention, working memory, language, visual perception) and motor testing at 7 years of age. We adjusted for age, sex, social risk, and neonatal illness in linear regression. RESULTS: A greater number of days on which infants received >50% breast milk was associated with greater deep nuclear gray matter volume at term equivalent age (0.15 cc/d; 95% CI, 0.05-0.25); and with better performance at age 7 years of age on IQ (0.5 points/d; 95% CI, 0.2-0.8), mathematics (0.5; 95% CI, 0.1-0.9), working memory (0.5; 95% CI, 0.1-0.9), and motor function (0.1; 95% CI, 0.0-0.2) tests. No differences in regional brain volumes at 7 years of age in relation to breast milk intake were observed. CONCLUSION: Predominant breast milk feeding in the first 28 days of life was associated with a greater deep nuclear gray matter volume at term equivalent age and better IQ, academic achievement, working memory, and motor function at 7 years of age in very preterm infants. PMID- 27480200 TI - Attitudes of Parents and Health Care Workers to Major Surgery for High-Risk Preterm Infants. AB - OBJECTIVES: To assess preferences of health care workers (HCWs) and parents of term and preterm infants to adverse health outcomes, and how perceived surgical mortality influences decision-making. STUDY DESIGN: A total of 536 participants (157 HCWs, 201 parents of term infants, and 178 parents of preterm infants) were recruited to take part in a structured interview. Preferences related to treatment of a critically ill preterm infant with necrotizing enterocolitis were measured by health state rank permutation analysis and pivotal risk analysis. Between-group and subgroup comparisons were performed. RESULTS: HCWs rank adverse health states less favorably than parents of preterm infants, consistently ranking 2 of the most adverse health states worse than death. Pivotal risk values of HCWs for all health states were consistently the lowest of the 3 groups. High operative mortality was associated uniformly with reduction in pivotal risks for all groups both in favorable and adverse health states. Subgroup analyses revealed significant discrepancies in preferences between fathers and mothers as well as doctors and nurses. Regular religious practice was significantly associated with increased pivotal risks in parental subgroups. CONCLUSIONS: As discrepancies in health state preferences existed between subgroups (ie, doctors vs nurses, mothers vs fathers) and perceived operative mortality consistently biased parental and HCW health state preferences, we recommend that HCWs should first identify differences regarding patient management before interviewing the parents together. HCWs should be aware of inadvertently biasing parents when discussing the risks and outcomes of surgery in conjunction with the overall long term prognosis of the underlying condition. PMID- 27480201 TI - Pharmacological effect of a new idebenone formulation in a model of carrageenan induced inflammatory pain. AB - Considerable evidence demonstrated that the central role of reactive oxygen species and reactive nitrogen species (ROS and RNS) in the development of thermal hyperalgesia is associated to acute and chronic inflammation. Idebenone (IDE), a synthetic analogue of the endogenous cellular antioxidant coenzyme Q10 (CoQ10), is an active drug in the central nervous system which shows a protection in a variety of neurological disorders. Since it is lipophilic, poorly water soluble and highly bound to plasma proteins, different technological approaches have been explored to increase its solubility and new pharmaceutical properties. Therefore, it has been complexed with HP-beta-cyclodextrins (HP) and its efficacy has been assessed in an animal model of carrageenan-induced thermal hyperalgesia. All male rats used for this study received a subplantar injection of carrageenan into the right hindpaw in the presence or absence of IDE alone and IDE/HP complex. We observed that IDE poorly reduced painful carrageenan effects whereas IDE/HP complex was able to prevent carrageenan-induced hyperalgesia and edema in a dose dependent manner, reducing spinal MDA levels and protein nitration. Hence, our results demonstrated that when complexed with HP, idebenone exerts a potent analgesic and anti-inflammatory efficacy. PMID- 27480202 TI - Protection of neonatal rat cardiac myocytes against radiation-induced damage with agonists of growth hormone-releasing hormone. AB - Despite the great clinical significance of radiation-induced cardiac damage, experimental investigation of its mechanisms is an unmet need in medicine. Beneficial effects of growth hormone-releasing hormone (GHRH) agonists in regeneration of the heart have been demonstrated. The aim of this study was the evaluation of the potential of modern GHRH agonistic analogs in prevention of radiation damage in an in vitro cardiac myocyte-based model. Cultures of cardiac myocytes isolated from newborn rats (NRVM) were exposed to a radiation dose of 10Gy. The effects of the agonistic analogs, JI-34 and MR-356, of human GHRH on cell viability, proliferation, their mechanism of action and the protein expression of the GHRH/SV1 receptors were studied. JI-34 and MR-356, had no effect on cell viability or proliferation in unirradiated cultures. However, in irradiated cells JI-34 showed protective effects on cell viability at concentrations of 10 and 100nM, and MR-356 at 500nM; but no such protective effect was detected on cell proliferation. Both agonistic analogs decreased radiation-induced ROS level and JI-34 interfered with the activation of SAFE/RISK pathways. Using Western blot analysis, a 52kDa protein isoform of GHRHR was detected in the samples in both irradiated and unirradiated cells. Since GHRH agonistic analogs, JI-34 and MR-356 alleviated radiation-induced damage of cardiac myocytes, they should be tested in vivo as potential protective agents against radiogenic heart damage. PMID- 27480203 TI - A Pragmatic Randomized Evaluation of a Nurse-Initiated Protocol to Improve Timeliness of Care in an Urban Emergency Department. AB - STUDY OBJECTIVE: Emergency department (ED) crowding is a common and complicated problem challenging EDs worldwide. Nurse-initiated protocols, diagnostics, or treatments implemented by nurses before patients are treated by a physician or nurse practitioner have been suggested as a potential strategy to improve patient flow. METHODS: This is a computer-randomized, pragmatic, controlled evaluation of 6 nurse-initiated protocols in a busy, crowded, inner-city ED. The primary outcomes included time to diagnostic test, time to treatment, time to consultation, or ED length of stay. RESULTS: Protocols decreased the median time to acetaminophen for patients presenting with pain or fever by 186 minutes (95% confidence interval [CI] 76 to 296 minutes) and the median time to troponin for patients presenting with suspected ischemic chest pain by 79 minutes (95% CI 21 to 179 minutes). Median ED length of stay was reduced by 224 minutes (95% CI -19 to 467 minutes) by implementing a suspected fractured hip protocol. A vaginal bleeding during pregnancy protocol reduced median ED length of stay by 232 minutes (95% CI 26 to 438 minutes). CONCLUSION: Targeting specific patient groups with carefully written protocols can result in improved time to test or medication and, in some cases, reduce ED length of stay. A cooperative and collaborative interdisciplinary group is essential to success. PMID- 27480205 TI - White-Coat Isolated Systolic Hypertension Is a Risk Factor for Carotid Atherosclerosis. AB - The clinical importance of white-coat hypertension (WCH) remains a controversial issue. The aim of this study was to evaluate the association of isolated systolic, isolated diastolic, and systolic/diastolic WCH with common carotid artery intima-media thickness (CCA-IMT) and to compare each subgroup of WCH against other blood pressure (BP) phenotypes in terms of CCA-IMT values. A total of 1382 consecutive patients underwent 24-hour ambulatory BP monitoring and carotid artery ultrasonographic measurements. According to the type of elevated office BP, WCH was divided into three groups: isolated systolic, isolated diastolic, and systolic/diastolic WCH. Patients with isolated systolic WCH (n=112) had significantly higher CCA-IMT values (0.737 mm) than those with isolated diastolic WCH (n=66) (0.685 mm) and nonsignificantly greater compared with those with systolic/diastolic WCH (n=228) (0.708 mm). Patients with isolated systolic WCH had CCA-IMT values similar to those with hypertension, patients with isolated diastolic WCH had similar values to those with normotension, and patients with systolic/diastolic WCH had an intermediate risk between normotension and hypertension. PMID- 27480204 TI - ATF3 controls proliferation of osteoclast precursor and bone remodeling. AB - Bone homeostasis is maintained by the sophisticated coupled actions of bone resorbing osteoclasts and bone-forming osteoblasts. Here we identify activating transcription factor 3 (ATF3) as a pivotal transcription factor for the regulation of bone resorption and bone remodeling under a pathological condition through modulating the proliferation of osteoclast precursors. The osteoclast precursor-specific deletion of ATF3 in mice led to the prevention of receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL)-induced bone resorption and bone loss, although neither bone volume nor osteoclastic parameter were markedly altered in these knockout mice under the physiological condition. RANKL dependent osteoclastogenesis was impaired in vitro in ATF3-deleted bone marrow macrophages (BMM). Mechanistically, the deficiency of ATF3 impaired the RANKL induced transient increase in cell proliferation of osteoclast precursors in bone marrow in vivo as well as of BMM in vitro. Moreover, ATF3 regulated cyclin D1 mRNA expression though modulating activator protein-1-dependent transcription in the osteoclast precursor, and the introduction of cyclin D1 significantly rescued the impairment of osteoclastogenesis in ATF3-deleted BMM. Therefore, these findings suggest that ATF3 could have a pivotal role in osteoclastogenesis and bone homeostasis though modulating cell proliferation under pathological conditions, thereby providing a target for bone diseases. PMID- 27480206 TI - Effect of persistent pulmonary hypertension on brain oxygenation in asphyxiated term newborns treated with hypothermia. AB - OBJECTIVE: To better understand the impact of persistent pulmonary hypertension (PPHN) on brain oxygenation in term asphyxiated newborns treated with hypothermia. METHODS: The regional cerebral oxygenation saturation (rSO2) measured by near-infrared spectroscopy was compared to pre/post-ductal oxygen saturation and mean arterial blood pressure in three term asphyxiated newborns with documented PPHN during their first 4 days of life while they were being treated with hypothermia. RESULTS: The cerebral oxygen saturation remained relatively stable when oxygen saturation was more than 92% and when there was no difference between pre- and post-ductal oxygen saturations. Episodes of desaturations with a difference between pre- and post-ductal saturations, as well as episodes of hypotension, caused a significant decrease in rSO2 in these newborns. CONCLUSION: This case series demonstrates that PPHN has a profound impact on brain oxygenation in term asphyxiated newborns treated with hypothermia during the first days of life after birth. PPHN may represent an additional risk factor for brain injury in these newborns during the first days of life. PMID- 27480207 TI - Association between isolated abnormal levels of maternal serum unconjugated estriol in the second trimester and adverse pregnancy outcomes. AB - OBJECTIVE: To determine the association between maternal serum unconjugated estriol (uE3) levels in the second trimester and adverse pregnancy outcomes. PATIENTS AND METHODS: The prospective database of our fetal Down screening program was assessed and reviewed for maternal serum uE3 levels. Pregnancies with medical diseases, abnormal levels of beta-human chorionic gonadotropin, alpha fetoprotein and fetal chromosomal or structural abnormalities were excluded. The recruited women were categorized into three groups: high (>95th percentile), normal (5-95th percentile) and low (<5th percentile) uE3 levels. RESULTS: Of 14 212 screened women, 9183 (high; 455, normal; 8271 and low; 457) levels group, were available for outcome analysis. The rates of most adverse outcomes, including preterm birth, low Apgar scores, fetal death, placental abruption, preeclampsia and gestational diabetes mellitus, of the high and normal groups were comparable. Nevertheless, low uE3 levels increased risk of fetal growth restriction (FGR) (RR: 2.36, 95% CI: 1.79-3.10) and low birth weight (LBW) (RR: 1.87, 95% CI: 1.45-2.39), but not preterm birth. Logistic regression analysis indicated that low uE3 level was an independent risk factor for FGR and LBW. CONCLUSIONS: High uE3 levels in the second trimester are not associated with poor outcomes, whereas low levels significantly increase risk of FGR and LBW but not other adverse outcomes. PMID- 27480208 TI - Maternal pre-eclampsia as a risk factor for necrotizing enterocolitis. AB - OBJECTIVE: Similar pro-inflammatory responses are present in pre-eclampsia (PE) and necrotizing enterocolitis (NEC). We hypothesized that maternal PE is an independent risk factor for the development of NEC. METHODS: A retrospective database of all live births (2008-2011) at a tertiary center was constructed. Infant and maternal characteristics were gathered. Babies born to mothers with or without PE were compared. Data were analyzed using Mann-Whitney U, Pearson's chi(2), binary logistic regression and relative risks. RESULTS: Incidence of NEC was 1.5% in non-PE and 4.6% in the PE group (p < 0.001), but once controlled for gestational age and birth weight, the difference lost statistical significance. PE babies were more frequently preterm (41.4% versus 14.5%, p < 0.001) and had intrauterine growth restriction (IUGR) (10.2% versus 6.3%, p < 0.001). Within preterm babies, 9.0% of non-PE and 10.8% of PE babies developed NEC (p = 0.25). Effect of PE was significant in sub-group of IUGR babies, with NEC in 1.5% of non PE and 13.6% in PE babies (p < 0.001). CONCLUSIONS: Maternal PE is an independent risk factor for the development of NEC in some sub-groups of babies, most notably with IUGR. Fetal hypoxia caused by abnormal placentation in PE leads to restricted growth, and may be the underlying mechanism that predisposes the newborn to NEC. PMID- 27480209 TI - Bayesian comparative model of CT scan and ultrasonography in the assessment of acute appendicitis: results from the Acute Care Diagnostic Collaboration project. AB - The objective of this study was to develop a comparative diagnostic model for computed tomography (CT) and ultrasound (US) in the assessment of acute appendicitis using Alvarado risk score as a predictor of pretest probability and Bayesian statistical model as a tool to calculate posttest probabilities for both diagnostic test. Stratification was made by applying the Alvarado score for the prediction of acute appendicitis. Likelihood ratios were calculated using sensitivity and specificity of both CT and US from a Meta-analysis. Posttest probabilities were obtained after inserting Alvarado score and likelihood ratios into Bayesian nomogram. Absolute and relative gains were calculated. ANOVA was used to assess statistical association. 4341 patients from 31 studies yielded a pooled sensitivity and specificity US of 83% (95% CI, 78%-87%) and 93% (95% CI, 90%-96%) and 94% (95% CI, 92%-95%) and 94% (95% CI, 94%-96%), respectively, for CT studies. Positive likelihood ratios (LR) for US were 12 and negative LR was 0.18; for CT +LR was 16 and -LR 0.06. Bayesian statistical modeling posttest probabilities for +LR and low Alvarado risk results yielded a posttest probability for US of 83.72% and 87.27% for CT, intermediate risk gave 95.88% and 96.88%, high risk 99.37% and 99.53 respectively. No statistical differences were found between Ultrasound and CT. This Bayesian analysis demonstrated slight superiority of CT scan over US low-risk patients, whereas no significant advantage was seen when evaluating intermediate and high risk patients. This study also favored elevated accuracy of the Alvarado score. PMID- 27480210 TI - Effects of immobilization and whole-body vibration on rat serum Type I collagen turnover. AB - OBJECTIVE: The aim of this study was to investigate the effects of short-term, high-magnitude whole-body vibration (WBV) on serum type I collagen turnover in immobilized rats. MATERIALS AND METHODS: Thirty Wistar albino rats were randomly divided into the following 5 groups: immobilization (IS), immobilization + remobilization (IR), immobilization + WBV (IV), control (C), and WBV control (CV). Immobilization was achieved by casting from the crista iliaca anterior superior to the lower part of the foot for 2 weeks. The applied WBV protocol involved a frequency of 45 Hz and amplitude of 3 mm for 7 days starting a day after the end of the immobilization period. Serum type I collagen turnover markers were measured by using ELISA kits. RESULTS: Serum NH2-terminal propeptide of type I collagen (PINP) levels were significantly lower in the immobilization groups (p < 0.02) compared with the control groups. Although WBV improved PINP levels in the control groups, there were no differences in PINP levels among the immobilization groups. Similarly, serum COOH-terminal telopeptide of type I collagen (CTX) levels were higher in the WBV controls than their own controls (p < 0,05). Immobilization led to deterioration of tendon tissue, as observed by histopathological analysis with a transmission electron microscope. CONCLUSION: Although 1 week of WBV had a positive effect on type I collagen turnover in controls, it is not an efficient method for repairing tissue damage in the early stage following immobilization. PMID- 27480212 TI - Natural Selection, Adaptive Topographies and the Problem of Statistical Inference: The Moraba scurra Controversy Under the Microscope. AB - This paper gives a detailed narrative of a controversial empirical research in postwar population genetics, the analysis of the cytological polymorphisms of an Australian grasshopper, Moraba scurra. This research intertwined key technical developments in three research areas during the 1950s and 1960s: it involved Dobzhansky's empirical research program on cytological polymorphisms, the mathematical theory of natural selection in two-locus systems, and the building of reliable estimates of natural selection in the wild. In the mid-1950s the cytologist Michael White discovered an interesting case of epistasis in populations of Moraba scurra. These observations received a wide diffusion when theoretical population geneticist Richard Lewontin represented White's data on adaptive topographies. These topographies connected the information on the genetic structure of these grasshopper populations with the formal framework of theoretical population genetics. As such, they appeared at the time as the most successful application of two-locus models of natural selection to an empirical study system. However, this connection generated paradoxical results: in the landscapes, all grasshopper populations were located on a ridge (an unstable equilibrium) while they were expected to reach a peak. This puzzling result fueled years of research and triggered a controversy attracting contributors from Australia, the United States and the United Kingdom. While the original problem seemed, at first, purely empirical, the subsequent controversy affected the main mathematical tools used in the study of two-gene systems under natural selection. Adaptive topographies and their underlying mathematical structure, Wright's mean fitness equations, were submitted to close scrutiny. Suspicion eventually shifted to the statistical machinery used in data analysis, reflecting the crucial role of statistical inference in applied population genetics. In the 1950s and 1960s, population geneticists were not simply in search for new generalizations about the evolutionary process and for new evidence about genetic variation: struggling against statistical artifacts, they were searching for reliable tests and descriptors to analyze their data. PMID- 27480211 TI - Dual plating for fixation of humeral shaft fractures: A mechanical comparison of various combinations of plate lengths. AB - OBJECTIVE: The role of plate configuration was found inconclusive on the biomechanical effects of the plate size and hole number for dual plate constructions in humeral shaft fractures. The purpose of this study was to test the biomechanical stability of various dual plate constructions. METHODS: Twenty four left humeri (4th Generation Composite Humerus, Sawbones, Malmo, Sweden) with comminuted midshaft humeral fracture were used. Four groups of plate constructs were tested: laterally fixed 8-hole locking plate and screws were combined with anteriorly locking plates containing 0, 4, 6, or 8 holes in groups I, II, III, and IV, respectively. The alterations in axial, bending, and torsional angles were recorded. RESULTS: There were no fixation failures during axial, bending, or torsional stiffness testing within the elastic behavior limits. Axial stiffness was highest in Group IV. Torsional stiffness, posterior-to-anterior bending stiffness, lateral-to-medial bending stiffness, and medial-to-lateral bending stiffness were lowest in Group I. CONCLUSION: The similar stiffness values for the 8-to-4 hole and 8-to-6 hole plate constructions indicate that the 8-to-4 hole construction is an option in young adults, while the stiffest 8-to-8 hole combination may be an option for osteoporotic patients. PMID- 27480213 TI - Nitric Oxide Synthase and Cyclooxygenase Pathways: A Complex Interplay in Cellular Signaling. AB - The cellular reaction to external challenges is a tightly regulated process consisting of integrated processes mediated by a variety of signaling molecules, generated as a result of modulation of corresponding biosynthetic systems. Both, nitric oxide synthase (NOS) and cyclooxygenase (COX) systems, consist of constitutive forms (NOS1, NOS3 and COX-1), which are mostly involved in housekeeping tasks, and inducible forms (NOS2 and COX-2), which shape the cellular response to stress and variety of bioactive agents. The complex interplay between NOS and COX pathways can be observed at least at three levels. Firstly, products of NOS and Cox systems can mediate the regulation and the expression of inducible forms (NOS2 and COX-2) in response of similar and dissimilar stimulus. Secondly, the reciprocal modulation of cyclooxygenase activity by nitric oxide and NOS activity by prostaglandins at the posttranslational level has been shown to occur. Mechanisms by which nitric oxide can modulate prostaglandin synthesis include direct S-nitrosylation of COX and inactivation of prostaglandin I synthase by peroxynitrite, product of superoxide reaction with nitric oxide. Prostaglandins, conversely, can promote an increased association of dynein light chain (DLC) (also known as protein inhibitor of neuronal nitric oxide synthase) with NOS1, thereby reducing its activity. The third level of interplay is provided by intracellular crosstalk of signaling pathways stimulated by products of NOS and COX which contributes significantly to the complexity of cellular signaling. Since modulation of COX and NOS pathways was shown to be principally involved in a variety of pathological conditions, the dissection of their complex relationship is needed for better understanding of possible therapeutic strategies. This review focuses on implications of interplay between NOS and COX for cellular function and signal integration. PMID- 27480214 TI - Nitric Oxide-Releasing Biomaterials for Biomedical Applications. AB - Nitric oxide (NO), as an essential signaling molecule, participates in various physiological processes such as cardiovascular homeostasis, neuronal transmission, immunomodulation, and tumor growth. The multiple role of NO in physiology and pathophysiology has triggered a massive interest in the strategies of delivering exogenous NO for biomedical applications. Hence, different kinds of NO prodrugs have been developed up to date, including diazeniumdiolates, S nitrosothiol, metal-nitrosyl, nitrobenzene, and so on. However, the clinical application of these low molecular weight NO donors has been restricted due to the problems of burst release, low payloads, and untargeted delivery. The delivery of NO by biomaterialbased carrier offers a beneficial strategy to realize the controlled and sustained delivery of NO to the targeted tissues or organs. In detail, NO-donor prodrugs have been attached and loaded to diverse biomaterials to fabricate nanoparticles, hydrogels, and coating platforms by means of physical, chemical, or supramolecular techniques. These NO-releasing biomaterials hold promise for a number of biomedical applications ranging from therapy of the ischemic disease and several types of cancer to cardiovascular devices and wound dressing. First, surface coating with NO-releasing biomaterials could mimic the physiological function of vascular endothelium, therefore promoting vascularization and improving the patency of cardiovascular implants. Next, because NO also mediates many important processes that take place after cutaneous injury, NO-releasing biomaterials could serve as ideal wound dressing to accelerate tissue regeneration. Finally, biomaterials enable localized delivery of high dose of NO to tumors in a sustained manner, thus generating potent tumoricidal effect. In this review, we will summarize the progress of different NO-releasing biomaterials, and highlight their biomedical applications with a hope to inspire new perspectives in the area of biomaterial-based NO delivery systems. PMID- 27480215 TI - Peanut allergy and isotretinoin. PMID- 27480217 TI - The double-edged role of 12/15-lipoxygenase during inflammation and immunity. AB - 12/15-Lipoxygenase (12/15-LOX) mediates the enzymatic oxidation of polyunsaturated fatty acids, thereby contributing to the generation of various bioactive lipid mediators. Although 12/15-LOX has been implicated in the pathogenesis of multiple chronic inflammatory diseases, its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation associated tissue damage. This review aims to give a comprehensive overview about our current knowledge on the role of this enzyme during the regulation of inflammation and immunity. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder. PMID- 27480218 TI - Electrocatalytic water oxidation by a macrocyclic Cu(ii) complex in neutral phosphate buffer. AB - A single-site copper complex, [Cu(TMC)(H2O)](NO3)2 (1, TMC = 1,4,8,11-tetramethyl 1,4,8,11-tetraazacyclotetradecane), was found to be the most active copper-based catalyst towards electrocatalytic water oxidation in neutral aqueous solution. Complex 1 leads to a cathodic shift of approximately 200 mV in potential to reach a current density of 1 mA cm(-2) in comparison with that of the previously reported dinuclear copper complex under the same conditions. Upon immobilization of complex 1 on carbon cloth, it shows greatly improved activity than other copper-based WOCs including CuOx and Cu(2+). PMID- 27480219 TI - Who helps whom? Pollination strategy of Iris tuberosa and its relationship with a sexually deceptive orchid. AB - Reproductive success of plants may be affected by interactions with co-flowering species either negatively, through competition for pollinators, or positively, by means of a magnet species effect and floral mimicry. In this study, potential interactions between Iris tuberosa, a rewarding species, and Ophrys fusca, a sexually deceptive orchid, were explored in four populations in southern Italy. In each population plots showing different ratios of the examined species were arranged in the field, and in each plot the number of pollinators and fruit set were assessed. In addition, flower size and floral hydrocarbons produced by the two species were analysed. Morphological and scent data pointed out that flower size and aliphatic compounds did not differ significantly between the two species. Interestingly, both species shared tricosane and 11-nonacosene, electrophysiologically active compounds in the shared dominant pollinator Adrena. We have found that fruit production and number of pollinators in I. tuberosa varied significantly among plots, while percentage of capsules and number of pollinators of O. fusca captured showed no significant differences across plots. These results suggested, that the presence of O. fusca contributes differentially to pollinator attraction, and thus, to total reproductive success of I. tuberosa, according to a different ratio of aggregation. These findings suggest that I. tuberosa profits from the greater abundance of insects attracted by the presence of orchid specimens, and that a sexually deceptive orchid may be a magnet species in pollination strategy. PMID- 27480220 TI - Light self-focusing in the atmosphere: thin window model. AB - Ultra-high power (exceeding the self-focusing threshold by more than three orders of magnitude) light beams from ground-based laser systems may find applications in space-debris cleaning. The propagation of such powerful laser beams through the atmosphere reveals many novel interesting features compared to traditional light self-focusing. It is demonstrated here that for the relevant laser parameters, when the thickness of the atmosphere is much shorter than the focusing length (that is, of the orbit scale), the beam transit through the atmosphere in lowest order produces phase distortion only. This means that by using adaptive optics it may be possible to eliminate the impact of self-focusing in the atmosphere on the laser beam. The area of applicability of the proposed "thin window" model is broader than the specific physical problem considered here. For instance, it might find applications in femtosecond laser material processing. PMID- 27480216 TI - Lipids, oxidized lipids, oxidation-specific epitopes, and Age-related Macular Degeneration. AB - Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly in western societies. While antioxidant micronutrient treatment is available for intermediate non-neovascular disease, and effective anti-vascular endothelial growth factor treatment is available for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. The role of lipids, which accumulate in the macula, and their oxidation, has emerged as an important factor in disease development. These oxidized lipids can either directly contribute to tissue injury or react with amine on proteins to form oxidation-specific epitopes, which can induce an innate immune response. If inadequately neutralized, the inflammatory response from these epitopes can incite tissue injury during disease development. This review explores how the accumulation of lipids, their oxidation, and the ensuing inflammatory response might contribute to the pathogenesis of AMD. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder . PMID- 27480222 TI - Comment on 'Anav et al. (2016) Comparing concentration-based (AOT40) and stomatal uptake (PODY) metrics for ozone risk assessment to European forests' Global Change Biology, 22(4), 1608-1627, doi:10.1111/gcb.13138. PMID- 27480221 TI - Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy. AB - Imatinib (Gleevec), a non-receptor tyrosine kinase inhibitor (nRTKI), is one of the most successful anti-neoplastic drugs in clinical use. However, imatinib resistant mutations are increasingly prevalent in patient tissues and driving development of novel imatinib analogs. We present a detailed study of the conformational dynamics, in the presence and absence of bound imatinib, for full length human c-Src using hydrogen-deuterium exchange and mass spectrometry. Our results demonstrate that imatinib binding to the kinase domain effects dynamics of proline-rich or phosphorylated peptide ligand binding sites in distal c-Src SH3 and SH2 domains. These dynamic changes in functional regulatory sites, distal to the imatinib binding pocket, show similarities to structural transitions involved in kinase activation. These data also identify imatinib-sensitive, and imatinib-resistant, mutation sites. Thus, the current study identifies novel c Src allosteric sites associated with imatinib binding and kinase activation and provide a framework for follow-on development of TKI binding modulators. PMID- 27480223 TI - Estimation of nutrient excretion factors of broiler and layer chickens in Japan. AB - We estimated the nitrogen (N), phosphorus (P), potassium (K) and magnesium (Mg) excretion factors of broiler and layer chickens in Japan, using two approaches and the latest data available. In the top-down approach, we determined the nutrient amounts in the feeds and those in the products (i.e. the liveweight gain, eggs), and the national nutrient excretions were determined as the difference between these amounts. We then calculated the nutrient excretion factors by dividing the national excretions by the number of animals. In the bottom-up approach, we calculated the amounts of nutrients in the feed and product per head using productivity parameters (feed conversion ratio, etc.). The differences between these amounts were considered the nutrient excretion factors. The average nutrient excretion factors of broilers (g/day/head) estimated using the top-down and bottom-up approaches were: N, 1.40 and 1.87; P, 0.36, 0.50; K, 0.54, 0.77; Mg, 0.13, 0.18, respectively. The excretion factors obtained by the top-down approach can be used to calculate the national/regional excretions. The two approaches resulted in almost the same excretion factors for layers, and the average nutrient excretion factors of layers (g/day/head) estimated were: N, 2.20; P, 0.55; K, 0.68; Mg, 0.23. The estimated excretion factors for N (only) are smaller than the reported factors. PMID- 27480224 TI - Nogo-B receptor deficiency increases liver X receptor alpha nuclear translocation and hepatic lipogenesis through an adenosine monophosphate-activated protein kinase alpha-dependent pathway. AB - : Nogo-B receptor (NgBR) was identified as a specific receptor for binding Nogo-B and is essential for the stability of Niemann-Pick type C2 protein (NPC2) and NPC2-dependent cholesterol trafficking. Here, we report that NgBR expression levels decrease in the fatty liver and that NgBR plays previously unrecognized roles in regulating hepatic lipogenesis through NPC2-independent pathways. To further elucidate the pathophysiological role of NgBR in mammals, we generated NgBR liver-specific knockout mice and investigated the roles of NgBR in hepatic lipid homeostasis. The results showed that NgBR knockout in mouse liver did not decrease NPC2 levels or increase NPC2-dependent intracellular cholesterol levels. However, NgBR deficiency still resulted in remarkable cellular lipid accumulation that was associated with increased free fatty acids and triglycerides in hepatocytes in vitro and in mouse livers in vivo. Mechanistically, NgBR deficiency specifically promotes the nuclear translocation of the liver X receptor alpha (LXRalpha) and increases the expression of LXRalpha-targeted lipogenic genes. LXRalpha knockout attenuates the accumulation of free fatty acids and triglycerides caused by NgBR deficiency. In addition, we elucidated the mechanisms by which NgBR bridges the adenosine monophosphate-activated protein kinase alpha signaling pathway with LXRalpha nuclear translocation and LXRalpha mediated lipogenesis. CONCLUSION: NgBR is a specific negative regulator for LXRalpha-dependent hepatic lipogenesis. Loss of NgBR may be a potential trigger for inducing hepatic steatosis. (Hepatology 2016;64:1559-1576). PMID- 27480225 TI - A New Poisson-Nernst-Planck Model with Ion-Water Interactions for Charge Transport in Ion Channels. AB - In this work, we propose a new Poisson-Nernst-Planck (PNP) model with ion-water interactions for biological charge transport in ion channels. Due to narrow geometries of these membrane proteins, ion-water interaction is critical for both dielectric property of water molecules in channel pore and transport dynamics of mobile ions. We model the ion-water interaction energy based on realistic experimental observations in an efficient mean-field approach. Variation of a total energy functional of the biological system yields a new PNP-type continuum model. Numerical simulations show that the proposed model with ion-water interaction energy has the new features that quantitatively describe dielectric properties of water molecules in narrow pores and are possible to model the selectivity of some ion channels. PMID- 27480226 TI - The Threat and Response to Infectious Diseases (Revised). AB - The threat from microorganisms is complex, and the approaches for reducing the challenges the world is facing are also multifaceted, but a combination approach including several simple steps can make a difference and reduce morbidity and mortality and the economic cost of fighting infectious diseases. This paper discusses the continually evolving infectious disease landscape, contributing factors in the rise of the threat, reasons for optimism, and the policies, technologies, actions, and institutions that might be harnessed to further reduce the dangers introduced by pathogens. It builds upon and updates the work of other authors that have recognized the dangers of emerging and re-emerging pathogens and have explored and documented potential solutions. PMID- 27480228 TI - Emotion effects within frontal alpha oscillation in a picture oddball paradigm. AB - In the current study we measured frontal alpha band oscillation in an oddball paradigm with emotional pictures as target stimuli. Within these emotional target pictures we varied valence and arousal separately. Irrespective of this emotional connotation, participants were asked to respond to the occurrence of any picture that deviates from the standard picture (a checkerboard). All stimuli were presented briefly and target stimuli were easily distinguishable from the standard stimulus based on mere perceptive features. Thus, the procedure reduces the probability that participants intentionally process or evaluate the emotional content of the pictures. With these incidental procedural conditions we yet observed a relative shift of alpha power to the right frontal site with increasing pleasantness of the pictures. Furthermore, frontal alpha band oscillation decreased with increasing picture arousal. These patterns were also evident when we controlled for valence and arousal of the pictures at the individual level. The results suggest that changes in frontal alpha band oscillation reflect reliable emotion correlates of incidental picture processing in the oddball paradigm. PMID- 27480227 TI - Diversity and Distribution of Heavy Metal-Resistant Bacteria in Polluted Sediments of the Araca Bay, Sao Sebastiao (SP), and the Relationship Between Heavy Metals and Organic Matter Concentrations. AB - Heavy metals influence the population size, diversity, and metabolic activity of bacteria. In turn, bacteria can develop heavy metal resistance mechanisms, and this can be used in bioremediation of contaminated areas. The purpose of the present study was to understand how heavy metals concentration influence on diversity and distribution of heavy metal-resistant bacteria in Araca Bay, Sao Sebastiao, on the Sao Paulo coast of Brazil. The hypothesis is that activities that contribute for heavy metal disposal and the increase of metals concentrations in environment can influence in density, diversity, and distribution of heavy metal-resistant bacteria. Only 12 % of the isolated bacteria were sensitive to all of the metals tested. We observed that the highest percentage of resistant strains were in areas closest to the Sao Sebastiao channel, where port activity occurs and have bigger heavy metals concentrations. Bacterial isolated were most resistant to Cr, followed by Zn, Cd, and Cu. Few strains resisted to Cd levels greater than 200 mg L(-1). In respect to Cr, 36 % of the strains were able to grow in the presence of as much as 3200 mg L(-1). Few strains were able to grow at concentrations of Zn and Cu as high as 1600 mg L( 1), and none grew at the highest concentration of 3200 mg L(-1). Bacillus sp. was most frequently isolated and may be the dominant genus in heavy metal-polluted areas. Staphylococcus sp., Planococcus maritimus, and Vibrio aginolyticus were also isolated, suggesting their potential in bioremediation of contaminated sites. PMID- 27480229 TI - Prediction for Rational Synthesis Based on Weighted Feature Selection Method. AB - In this paper, a novel integrated feature selection model is proposed to analyze the relationship between the synthesis factors and the specific resulting structure on the database of AlPO synthesis. Concretely, the proposed model can select the most significant synthesis factors affecting the formation of a (6,12) ring-containing structure by combining multiple feature selection methods. Firstly, eight feature selection methods are employed to prerank the synthesis factors based on the predictive performance of support vector machine. Then, a weighted fusion mechanism is presented to rerank the results. Finally, sequential forward floating search method is utilized to select the most significant synthesis factors in view of the highest predictive performance. A large number of experimental results show that the proposed model is efficient and feasible. The predictive accuracy can reach 86.47 % with the selected 10 factors among 21 synthesis factors. The selection and ranking results also give a rational understanding for AlPO synthesis. More specifically, a proportional relationship among gel composition parameters is recommended based on the result of feature selection, which has important guiding significance for the rational design and synthesis. PMID- 27480230 TI - Protein Remote Homology Detection by Combining Chou's Pseudo Amino Acid Composition and Profile-Based Protein Representation. AB - Protein remote homology detection is a key problem in bioinformatics. Currently the discriminative methods, such as Support Vector Machine (SVM) can achieve the best performance. The most efficient approach to improve the performance of SVM based methods is to find a general protein representation method that is able to convert proteins with different lengths into fixed length vectors and captures the different properties of the proteins for the discrimination. The bottleneck of designing the protein representation method is that native proteins have different lengths. Motivated by the success of the pseudo amino acid composition (PseAAC) proposed by Chou, we applied this approach for protein remote homology detection. Some new indices derived from the amino acid index (AAIndex) database are incorporated into the PseAAC to improve the generalization ability of this method. Finally, the performance is further improved by combining the modified PseAAC with profile-based protein representation containing the evolutionary information extracted from the frequency profiles. Our experiments on a well known benchmark show this method achieves superior or comparable performance with current state-of-the-art methods. PMID- 27480231 TI - Development of QSAR-Improved Statistical Potential for the Structure-Based Analysis of Protein?Peptide Binding Affinities. AB - Protein?peptide interactions have recently been found to play an essential role in constructing intracellular signaling networks. Understanding the molecular mechanism of such interactions and identification of the interacting partners would be of great value for developing peptide therapeutics against many severe diseases such as cancer. In this study, we describe a structure-based, general purpose strategy for fast and reliably predicting protein?peptide binding affinities. This strategy combines unsupervised knowledge-based statistical potential derived from 505 interfacially diverse, non-redundant protein?peptide complex structures and supervised quantitative structure-activity relationship (QSAR) modeling trained by 250 protein?peptide interactions with known structure and affinity data. The built partial least squares (PLS) model is confirmed to have high stability and predictive power by using internal 5-fold cross validation and rigorous Monte Carlo cross-validation (MCCV). The model is further employed to analyze two large groups of HLA- and SH3-binding peptides based upon computationally modeled structures. Satisfactorily, although the PLS model is originally trained with dissociation constants (Kd ) of protein?peptide binding, it shows a good correlation with other two affinity qualities, i.e. SPOT signal intensities (BLU) and half maximal competitive concentrations (IC50 ). Furthermore, we perform systematic comparisons of our method with several widely used, representative affinity predictors, including molecular mechanics-based MM PB/SA, knowledge-based DFIRE and docking score HADDOCK, on a small panel of elaborately selected protein?peptide systems. It is demonstrated that (i) the QSAR-improved statistical potential exhibits a comparable predictive performance with but can work faster than these traditional methods, and (ii) the crystal structure-derived statistical potential also supports the modeled and solution structures of protein?peptide complexes. We expect that this hybrid method can be exploited as a new scoring tool to facilitate, for example, peptide docking and virtual screening. PMID- 27480232 TI - Subchronic Oral and Inhalation Toxicities: a Challenging Attempt for Modeling and Prediction. AB - The article deals with a challenging attempt to model and predict "difficult" properties as long-term subchronic oral and inhalation toxicities (90 days) using nonlinear QSAR approach. This investigation is one of the first to tackle such multicomplex properties where we have employed nonlinear models based on artificial neural network for the prediction of NOAEL (no observable adverse effect level). Despite the complex nature of the NOAEL property based on in vivo rat experiments, the successful models can be used as alternative tools to non animal tests for the initial assessment of these chronic toxicities. The model for oral subchronic toxicity is able to describe 88 %, and the inhalation model 87 % of the statistical variance. For the sake of future predictions, we have also defined in a quantitative way the applicability domain of all neural network models. PMID- 27480233 TI - Virtual Screening of Anti-Mycobacterial Plant Compounds. AB - Deaths from tuberculosis have long gripped people and threatened human health. The need for new drug compounds are critically sensed by medical scientists and practitioners due to the emergence of new strains and the slow rate of discovering novel medicines for this disease. Since plants are a rich source of diverse drug compounds, they are among the best choices to achieve new ones. The study of all plants or their compounds is an almost impossible scenario; hence bio/cheminformatics methodology can be used to reduce time and cost spent in drug discovery. For this purpose, we made several databases of anti-mycobacterial plant compounds and further found filter criteria which were able to describe more predicted bioactive compounds by the established algorithm. Also, we present the survey of the developed resource by using bio/cheminformatics tools. The presence of several anti-mycobacterial compounds in the predicted algorithm and introduction of new active compounds represent the high potential of this method. In addition, the general profile of such bioactive molecules is pinpointed using molecular descriptors and cheminformatics approach. PMID- 27480234 TI - Support Vector Machine (SVM) Models for Predicting Inhibitors of the 3' Processing Step of HIV-1 Integrase. AB - Inhibition of the 3' processing step of HIV-1 integrase by small molecule inhibitors is one of the most promising strategies for the treatment of AIDS. Using a support vector machine (SVM) approach, we developed six classification models for predicting 3'P inhibitors. The models are based on up to 48 selected molecular descriptors and a comprehensive data set of 1253 molecules, with measured activities ranging from nanomolar to micromolar IC50 values. Model B2, the most robust SVM model, obtains a prediction accuracy, sensitivity, specificity and Matthews correlation coefficient (MCC) of 93 %, 81 %, 94 % and 0.67 on the test set, respectively. The presence of hydrogen bonding features and hydrophilicity in general were identified as key determinants of inhibitory activity. Further important properties include molecular refractivity, pi atom charge, total charge, lone pair electronegativity, and effective atom polarizability. Comparative fragment-based analysis of the active and inactive molecules corroborated these observations and revealed several characteristic structural elements of 3'P inhibitors. The models built in this study can be obtained from the authors. PMID- 27480235 TI - Using Graph Indices for the Analysis and Comparison of Chemical Datasets. AB - In cheminformatics, compounds are represented as points in multidimensional space of chemical descriptors. When all pairs of points found within certain distance threshold in the original high dimensional chemistry space are connected by distance-labeled edges, the resulting data structure can be defined as Dataset Graph (DG). We show that, similarly to the conventional description of organic molecules, many graph indices can be computed for DGs as well. We demonstrate that chemical datasets can be effectively characterized and compared by computing simple graph indices such as the average vertex degree or Randic connectivity index. This approach is used to characterize and quantify the similarity between different datasets or subsets of the same dataset (e.g., training, test, and external validation sets used in QSAR modeling). The freely available ADDAGRA program has been implemented to build and visualize DGs. The approach proposed and discussed in this report could be further explored and utilized for different cheminformatics applications such as dataset diversification by acquiring external compounds, dataset processing prior to QSAR modeling, or (dis)similarity modeling of multiple datasets studied in chemical genomics applications. PMID- 27480236 TI - Universal Approach for Structural Interpretation of QSAR/QSPR Models. AB - In this paper we offer a novel approach for the structural interpretation of QSAR models. The major advantage of our developed methodology is its universality, i.e., it can be applied to any QSAR/QSPR model irrespective of chemical descriptors and machine learning methods applied. This universality was achieved by using only the information obtained from substructures of the compounds of interest to interpret model outcomes. Reliability of the offered approach was confirmed by the results of three case studies, including end-points of different types (continuous and binary classification) and nature (solubility, mutagenicity, and inhibition of Transglutaminase 2), various fragment and whole molecule descriptors (Simplex and Dragon), and multiple modeling techniques (partial least squares, random forest, and support vector machines). We compared the global contributions of molecular fragments obtained using our methodology with known SAR rules derived experimentally. In all cases high concordance between our interpretation and results published by others was observed. Although the proposed interpretation approach could be easily extended to any type of descriptors, we would recommend using Simplex descriptors to achieve a larger variety of investigated molecular fragments. The developed approach is a good tool for interpretation of such "black box" models like random forest, neural networks, etc. Analysis of fragment global contributions and their deviation across a dataset could be useful for the identification of key fragments and structural alerts. This information could be helpful to maximize the positive influence of structural surroundings on the given fragment and to decrease the negative effects. PMID- 27480237 TI - Physicochemical vs. Vibrational Descriptors for Prediction of Odor Receptor Responses. AB - Responses of olfactory receptors (ORs) can be predicted by applying machine learning methods on a multivariate encoding of an odorant's chemical structure. Physicochemical descriptors that encode features of the molecular graph are a popular choice for such an encoding. Here, we explore the EVA descriptor set, which encodes features derived from the vibrational spectrum of a molecule. We assessed the performance of Support Vector Regression (SVR) and Random Forest Regression (RFR) to predict the gradual response of Drosophila ORs. We compared a 27-dimensional variant of the EVA descriptor against a set of 1467 descriptors provided by the eDragon software package, and against a 32-dimensional subset thereof that has been proposed as the basis for an odor metric consisting of 32 descriptors (HADDAD). The best prediction performance was reproducibly achieved using SVR on the highest-dimensional feature set. The low-dimensional EVA and HADDAD feature sets predicted odor-OR interactions with similar accuracy. Adding charge and polarizability information to the EVA descriptor did not improve the results but rather decreased predictive power. Post-hoc in vivo measurements confirmed these results. Our findings indicate that EVA provides a meaningful low dimensional representation of odor space, although EVA hardly outperformed "classical" descriptor sets. PMID- 27480238 TI - SALM4 suppresses excitatory synapse development by cis-inhibiting trans-synaptic SALM3-LAR adhesion. AB - Synaptic adhesion molecules regulate various aspects of synapse development, function and plasticity. These functions mainly involve trans-synaptic interactions and positive regulations, whereas cis-interactions and negative regulation are less understood. Here we report that SALM4, a member of the SALM/Lrfn family of synaptic adhesion molecules, suppresses excitatory synapse development through cis inhibition of SALM3, another SALM family protein with synaptogenic activity. Salm4-mutant (Salm4(-/-)) mice show increased excitatory synapse numbers in the hippocampus. SALM4 cis-interacts with SALM3, inhibits trans-synaptic SALM3 interaction with presynaptic LAR family receptor tyrosine phosphatases and suppresses SALM3-dependent presynaptic differentiation. Importantly, deletion of Salm3 in Salm4(-/-) mice (Salm3(-/-); Salm4(-/-)) normalizes the increased excitatory synapse number. These results suggest that SALM4 negatively regulates excitatory synapses via cis inhibition of the trans synaptic SALM3-LAR adhesion. PMID- 27480239 TI - Comparison between indocyanine green angiography and fluorescein angiography in normal cats. AB - OBJECTIVE: To study a new approach to indocyanine green (ICG) angiography for contrasting the ocular fundus in cats. ANIMALS STUDIED: Six healthy laboratory cats. PROCEDURES: Fluorescein (FLUO) and ICG angiography were performed using an infrared-sensitive charged coupled device-equipped fundus camera on sedated cats. RESULTS: At 12.3 +/- 3.4 s after ICG administration, the choroidal arteries could be seen extending radially from the optic disk. The choroidal veins became apparent at 16.2 +/- 4.1 s alongside the choroidal arteries. Gradual fading of the choroidal vessels began 5.8 +/- 1.5 min postdye administration and diffuse fluorescence of the fundus appeared. Diffuse fluorescence of the optic disk faded at about 18.8 +/- 2.9 min. Mean arterial blood pressure at 1 and 3 min after ICG administration showed no significant change when compared to pre-administration (P > 0.05). However, 5 min (P = 0.054) and 10 min (P < 0.05) postadministration, a significant drop in blood pressure occurred. The time lapse between FLUO administration and its appearance in the ocular fundus was 15.7 +/- 3.8 s. Retinal veins became apparent at 22.0 +/- 3.6 s alongside retinal arteries. At 31.2 +/- 4.1 s, full venous fluorescence was visualized throughout the entire fundus. CONCLUSIONS: While FLUO angiography shows only the retinal vessels, ICG angiography enabled visualization of the choroidal vasculature. ICG angiography provides clear resolution while remaining reliable and simple; thus, a combination of ICG and FLUO angiography shows promise as a diagnostic aid for clinical evaluation of various chorioretinal diseases in cats. PMID- 27480240 TI - Swine cysticercosis in the Karangasem district of Bali, Indonesia: An evaluation of serological screening methods. AB - A serological assessment was undertaken on pigs from the Kubu and Abang sub districts of Karangasem on the island of Bali, Indonesia, where earlier studies had detected patients with cysticercosis. Antigens purified from Taenia solium cyst fluid by cation-exchange chromatography were used to evaluate antibody responses in the pigs and the serological tests were also evaluated using sera from pigs experimentally infected with T. solium eggs. A total of 392 serum samples from naturally exposed pigs were tested using an ELISA that could be read based on both a colour change perceptible by the naked eye and an ELISA based on absorbance values. Twenty six (6.6%) pigs were found seropositive by the naked eye ELISA and were categorized into three groups: strongly positive (absorbance values >0.8, n=6), moderately positive (absorbance values between 0.2 and 0.8, n=7), and weakly positive (absorbance values <0.2, n=13). Necropsies performed on 11 strongly and moderately positive pigs revealed that six strongly positive pigs were infected either solely with T. solium cysticerci (n=3), or co-infected with both T. solium and Taenia hydatigena (n=3). Four moderately positive pigs were infected solely with T. hydatigena. No cysticerci were found in one pig that was moderately positive by the naked-eye ELISA. Two experimentally infected pigs became antibody positive by 6 weeks post-infection, whereas eight control pigs remained negative. An additional 60 pigs slaughtered at authorized abattoirs on Bali were tested using the same ELISA. All 60 pigs were seronegative with no evidence of Taenia infection at necropsy. The results confirm the presence of porcine cysticercosis on Bali and, while the serological responses seen in T. solium infected animals were much stronger than those infected with T. hydatigena, the diagnostic antigens are clearly not species specific. Further studies are necessary to confirm if it is possible to draw a cut off line for differentiation of pig infected with T. solium from those infected with T. hydatigena. PMID- 27480241 TI - Pathological findings of condemned bovine liver specimens and associated economic loss at Nyabugogo abattoir, Kigali, Rwanda. AB - There are no published abattoir bovine hepatic lesion prevalence studies in cattle in Rwanda. This study estimated that 12.3% of the livers (n=4751) examined at Nyabugogo slaughterhouse in Kigali were condemned. Condemnation prejudiced the nation of 3492.00kg of meat with attendant economic losses of US$8932.40 during the study period. Risk factors for these lesions were also assessed. Male and female animals from 11 districts were used in this study. Hepatic lesions were higher in females (14.6%; n=1494) than in males (11.1%; n=3257). About 78.7% of the condemnations were due to fascioliasis, followed by abscesses (5.7%), hepatitis (5.3%), cirrhosis (4%) and other lesions (6.3%). Female animal livers showed more fascioliasis and abscesses (82.2% and 9.5%) than male animal livers (73.3% and 3.3%). The highest rate of condemnation was observed from Kayonza (40.2%; n=413) and the least was from Gakenke district (0.9%; n=1031). Cattle from the Eastern Province showed significantly (P<0.05) higher prevalence of condemnations (26.8%) than the rest of the provinces. Liver specimens of animals below 3 years and above 6 years of age had a significantly higher (P<0.05) condemnation rate (14.4%) (n=3000 and n=769) than the 3-6year age-group at 4.1% (n=982). We conclude that fascioliasis was responsible for a significant proportion of the liver condemnations at Nyabugogo slaughterhouse. Being a zoonosis, we recommend an epidemio-surveillance, implementation of control measures and anthelmintic resistance investigation for fascioliasis in Rwanda. PMID- 27480242 TI - Effect of resistance training on liver fat and visceral adiposity in adults with obesity: A randomized controlled trial. AB - AIM: Regular aerobic exercise reduces visceral adipose tissue (VAT) and liver fat, however, not all individuals are able to adopt and adhere to such programs. Progressive resistance training (PRT) may be an alternative therapy, but there is limited available evidence. We examined the efficacy of PRT as per current exercise guidelines, compared with sham exercise placebo on liver fat and VAT. METHODS: Twenty-nine inactive and overweight/obese (body mass index >=25 kg/m2 ) adults (age 29-59) were randomized to receive 8 weeks of PRT (n = 15, 10 exercises per session, 8-12 repetitions, 2-3 sets per exercise at 80-85% of one repetition maximum, 3 days per week) or a sham exercise placebo control (CON) (n = 14). Change in liver fat, VAT, and abdominal s.c. adipose tissue (SAT) were assessed by magnetic resonance spectroscopy and imaging). RESULTS: There were no significant group by time interactions for change in liver fat in PRT versus CON groups (-0.07 +/- 0.31% vs. 0.55 +/- 0.77%, respectively, P = 0.19), VAT (-175 +/ 85 cm3 vs. 10 +/- 64 cm3 , respectively, P = 0.11), or abdominal SAT (-436 +/- 245 cm3 vs. 127.29 +/- 182 cm3 , respectively, P = 0.10) despite a significant increase in muscle volume (55 +/- 78 cm3 vs. -0.04 +/- 8 cm3 , respectively, P = 0.03). CONCLUSION: Traditional PRT is not effective for reducing liver fat in overweight/obese adults compared with placebo control. Although PRT has known metabolic benefits, an adequate volume of aerobic exercise should be promoted if liver fat is the therapeutic target. PMID- 27480243 TI - Cellular Functions of Optineurin in Health and Disease. AB - Optineurin (OPTN) was initially identified as a regulator of NF-kappaB and interferon signaling, but attracted most attention because of its association with various human disorders such as glaucoma, Paget disease of bone, and amyotrophic lateral sclerosis. Importantly, OPTN has recently been identified as an autophagy receptor important for the autophagic removal of pathogens, damaged mitochondria, and protein aggregates. This activity is most likely compromised in patients carrying OPTN mutations, and contributes to the observed phenotypes. In this review we summarize recent studies describing the molecular mechanisms by which OPTN controls immunity and autophagy, and discuss these findings in the context of several diseases that have been associated with OPTN (mal)function. PMID- 27480245 TI - Cooperation-mediated plasticity in dispersal and colonization. AB - Kin selection theory predicts that costly cooperative behaviors evolve most readily when directed toward kin. Dispersal plays a controversial role in the evolution of cooperation: dispersal decreases local population relatedness and thus opposes the evolution of cooperation, but limited dispersal increases kin competition and can negate the benefits of cooperation. Theoretical work has suggested that plasticity of dispersal, where individuals can adjust their dispersal decisions according to the social context, might help resolve this paradox and promote the evolution of cooperation. Here, we experimentally tested the hypothesis that conditional dispersal decisions are mediated by a cooperative strategy: we quantified the density-dependent dispersal decisions and subsequent colonization efficiency from single cells or groups of cells among six genetic strains of the unicellular Tetrahymena thermophila that differ in their aggregation level (high, medium, and low), a behavior associated with cooperation strategy. We found that the plastic reaction norms of dispersal rate relative to density differed according to aggregation level: highly aggregative genotypes showed negative density-dependent dispersal, whereas low-aggregation genotypes showed maximum dispersal rates at intermediate density, and medium-aggregation genotypes showed density-independent dispersal with intermediate dispersal rate. Dispersers from highly aggregative genotypes had specialized long-distance dispersal phenotypes, contrary to low-aggregation genotypes; medium-aggregation genotypes showing intermediate dispersal phenotype. Moreover, highly aggregation genotypes showed evidence for beneficial kin-cooperation during dispersal. Our experimental results should help to resolve the evolutionary conflict between cooperation and dispersal: cooperative individuals are expected to avoid kin competition by dispersing long distances, but maintain the benefits of cooperation by dispersing in small groups. PMID- 27480244 TI - Protein arginine methyltransferase 5 regulates multiple signaling pathways to promote lung cancer cell proliferation. AB - BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of symmetrical dimethylation of arginine residues in proteins. WD repeat domain 77 (WDR77), also known as p44, MEP50, or WD45, forms a stoichiometric complex with PRMT5. The PRMT5/p44 complex is required for cellular proliferation of lung and prostate epithelial cells during earlier stages of development and is re activated during prostate and lung tumorigenesis. The molecular mechanisms by which PRMT5 and p44 promote cellular proliferation are unknown. METHODS: Expression of PRMT5 and p44 in lung and prostate cancer cells was silenced and their target genes were identified. The regulation of target genes was validated in various cancer cells during lung development and tumorigenesis. Altered expression of target genes was achieved by ectopic cDNA expression and shRNA mediated silencing. RESULTS: PRMT5 and p44 regulate expression of a specific set of genes encoding growth and anti-growth factors, including receptor tyrosine kinases and antiproliferative proteins. Genes whose expression was suppressed by PRMT5 and p44 encoded anti-growth factors and inhibited cell growth when ectopically expressed. In contrast, genes whose expression was enhanced by PRMT5 and p44 encoded growth factors and increased cell growth when expressed. Altered expression of target genes is associated with re-activation of PRMT5 and p44 during lung tumorigenesis. CONCLUSIONS: Our data provide the molecular basis by which PRMT5 and p44 regulate cell growth and lay a foundation for further investigation of their role in lung tumor initiation. PMID- 27480246 TI - Inhaled nitric oxide therapy for pulmonary disorders of the term and preterm infant. AB - The 21st century began with the FDA approval of inhaled nitric oxide therapy for the treatment of neonatal hypoxic respiratory failure associated with pulmonary hypertension in recognition of the 2 randomized clinical trials demostrating a significant reduction in the need for extracorporeal support in the term and near term infant. Inhaled nitric oxide is one of only a few therapeutic agents approved for use through clinical investigations primarily in the neonate. This article provides an overview of the pertinent biology and chemistry of nitric oxide, discusses potential toxicities, and reviews the results of pertinent clinical investigations and large randomized clinical trials including neurodevelopmental follow-up in term and preterm neonates. The clinical investigations conducted by the Eunice Kennedy Shriver NICHD Neonatal Research Network will be discussed and placed in context with other pertinent clinical investigations exploring the efficacy of inhaled nitric oxide therapy in neonatal hypoxic respiratory failure. PMID- 27480248 TI - Copper-catalyzed synthesis of benzoxazoles via tandem cyclization of 2 halophenols with amidines. AB - This work reports a simple, efficient and alternative synthetic route for the preparation of benzoxazoles via tandem cyclization of 2-halophenols with amidines. The developed methodology is free from ligands and uses inexpensive and easily available CuCl as a catalyst. This protocol avoids the use of any oxidant or inorganic acids. Various benzoxazole derivatives were synthesized in good to excellent yields. To the best of our knowledge, this is the first time that the synthesis of benzoxazoles from 2-halophenols with both aromatic and aliphatic amidines is reported. Owing to the simplicity of this protocol, the preparation of benzoxazoles could be achieved at a gram scale level. PMID- 27480249 TI - Spreading Winge and flying high: The evolutionary importance of polyploidy after a century of study. PMID- 27480250 TI - Analysis of the interaction between transcription factor 7-like 2 genetic variants with nopal and wholegrain fibre intake: effects on anthropometric and metabolic characteristics in type 2 diabetes patients. AB - The transcription factor 7-like 2 (TCF7L2) genetic variants have shown differential effect on low-fat and high-fat diet in obese subjects. Nopal is a Mexican variety of cactus that is a traditional food and has been used in the treatment of diabetes. Its hypoglycaemic effect may be because of its soluble fibre (mucopolysaccharide) content. This study analysed the effects of the rs7903146 and rs12255372 TCF7L2 variants on anthropometric, metabolic and hormonal parameters in type 2 diabetes mellitus patients who consumed fibre from either nopal tortilla or wholegrain bread for 8 weeks. We followed-up seventy four patients who consumed an individualised isoenergetic diet that included nopal tortilla (Diet 1) and sixty-three patients with a diet that included wholegrain bread (Diet 2). Anthropometric, metabolic and hormonal measures were collected at baseline and final intervention. The size effect and carry-over effect were estimated. To assess the interaction of genotype and diets, we used a general linear model repeated-measures analysis. Minor allele frequency of rs7903146T was 0.27 and for rs12255372T it was 0.13. At 8 weeks after Diet 1 intake, weight, BMI, waist and hip circumference decreased (P=0.00015) in rs7903146CC and rs12255372GG genotypes. In particular, patients carrying of the rs7903146CC and consuming Diet 1 showed a reduction in waist circumference of more than 2.5 cm compared with Diet 2 (P<0.001). No significant interaction between rs7903146 or rs12255372 and diet was seen in this study. In conclusion, in the carriers of the rs7903146CC and rs12255372GG wild types, significant changes in all anthropometric measures were observed, and had better response to both diets. PMID- 27480247 TI - Technology-Enabled Remote Monitoring and Self-Management - Vision for Patient Empowerment Following Cardiac and Vascular Surgery: User Testing and Randomized Controlled Trial Protocol. AB - BACKGROUND: Tens of thousands of cardiac and vascular surgeries (CaVS) are performed on seniors in Canada and the United Kingdom each year to improve survival, relieve disease symptoms, and improve health-related quality of life (HRQL). However, chronic postsurgical pain (CPSP), undetected or delayed detection of hemodynamic compromise, complications, and related poor functional status are major problems for substantial numbers of patients during the recovery process. To tackle this problem, we aim to refine and test the effectiveness of an eHealth-enabled service delivery intervention, TecHnology-Enabled remote monitoring and Self-MAnagemenT-VIsion for patient EmpoWerment following Cardiac and VasculaR surgery (THE SMArTVIEW, CoVeRed), which combines remote monitoring, education, and self-management training to optimize recovery outcomes and experience of seniors undergoing CaVS in Canada and the United Kingdom. OBJECTIVE: Our objectives are to (1) refine SMArTVIEW via high-fidelity user testing and (2) examine the effectiveness of SMArTVIEW via a randomized controlled trial (RCT). METHODS: CaVS patients and clinicians will engage in two cycles of focus groups and usability testing at each site; feedback will be elicited about expectations and experience of SMArTVIEW, in context. The data will be used to refine the SMArTVIEW eHealth delivery program. Upon transfer to the surgical ward (ie, post-intensive care unit [ICU]), 256 CaVS patients will be reassessed postoperatively and randomly allocated via an interactive Web randomization system to the intervention group or usual care. The SMArTVIEW intervention will run from surgical ward day 2 until 8 weeks following surgery. Outcome assessments will occur on postoperative day 30; at week 8; and at 3, 6, 9, and 12 months. The primary outcome is worst postop pain intensity upon movement in the previous 24 hours (Brief Pain Inventory-Short Form), averaged across the previous 14 days. Secondary outcomes include a composite of postoperative complications related to hemodynamic compromise-death, myocardial infarction, and nonfatal stroke- all-cause mortality and surgical site infections, functional status (Medical Outcomes Study Short Form-12), depressive symptoms (Geriatric Depression Scale), health service utilization-related costs (health service utilization data from the Institute for Clinical Evaluative Sciences data repository), and patient-level cost of recovery (Ambulatory Home Care Record). A linear mixed model will be used to assess the effects of the intervention on the primary outcome, with an a priori contrast of weekly average worst pain intensity upon movement to evaluate the primary endpoint of pain at 8 weeks postoperation. We will also examine the incremental cost of the intervention compared to usual care using a regression model to estimate the difference in expected health care costs between groups. RESULTS: Study start-up is underway and usability testing is scheduled to begin in the fall of 2016. CONCLUSIONS: Given our experience, dedicated industry partners, and related RCT infrastructure, we are confident we can make a lasting contribution to improving the care of seniors who undergo CaVS. PMID- 27480251 TI - Original Research: miR-194 inhibits proliferation and invasion and promotes apoptosis by targeting KDM5B in esophageal squamous cell carcinoma cells. AB - Increasing evidence suggests that miR-194 is down-regulated in esophageal squamous cell carcinoma tumor tissue. However, the role and underlying mechanism of miR-194 in esophageal squamous cell carcinoma have not been well defined. We used DIANA, TargetScan and miRanda to perform target prediction analysis and found KDM5B is a potential target of miR-194. Based on these findings, we speculated that miR-194 might play a role in esophageal squamous cell carcinoma development and progression by regulation the expression of KDM5B. We detected the expression of miR-194 and KDM5B by quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot assays, respectively, and found down regulation of miR-194 and up-regulation of KDM5B existed in esophageal squamous cell carcinoma cell lines. By detecting proliferation, invasion and apoptosis of TE6 and TE14 cells transfected with miR-194 mimics or mimic control, miR-194 was found to inhibit proliferation and invasion and promote apoptosis of esophageal squamous cell carcinoma cells. miR-194 was further verified to regulate proliferation, apoptosis and invasion of esophageal squamous cell carcinoma cells by directly targeting KDM5B. Furthermore, animal studies were performed and showed that overexpression of miR-194 inhibited the growth of esophageal squamous cell carcinoma tumors in vivo. These results confirmed our speculation that miR 194 targets KDM5B to inhibit esophageal squamous cell carcinoma development and progression. These findings offer new clues for esophageal squamous cell carcinoma development and progression and novel potential therapeutic targets for esophageal squamous cell carcinoma. PMID- 27480254 TI - Stimulation of electrocatalytic oxygen reduction activity on nitrogen doped graphene through noncovalent molecular functionalisation. AB - Molecular doping on graphene, through noncovalent functionalization offers a great opportunity to tune charge density on graphene for catalytic applications. Although enhanced oxygen reduction activity has been reported in heteroatom doped graphene, the synergistic advantage of molecular and heteroatom co-doping has not yet been studied. Here, we report the remarkably enhanced catalytic activity of benzoate or 1-pyrenebutyrate functionalized N-doped graphene (BA-NrGO/PB-NrGO) towards the oxygen reduction reaction (ORR) in alkaline medium. An efficient 4e( ) reduction process with a more positive onset potential (Eonset = 0.85 V vs. RHE) and high ORR activity (Jk = 3.16 mA cm(-2) at 0.65 V) has been observed in BA-NrGO. DFT studies show that the stimulated ORR activity is due to functionalisation induced increased charge density on active sites. PMID- 27480253 TI - Nuclear alpha spectrin: Critical roles in DNA interstrand cross-link repair and genomic stability. AB - Non-erythroid alpha spectrin (alphaIISp) is a structural protein which we have shown is present in the nucleus of human cells. It interacts with a number of nuclear proteins such as actin, lamin, emerin, chromatin remodeling factors, and DNA repair proteins. alphaIISp's interaction with DNA repair proteins has been extensively studied. We have demonstrated that nuclear alphaIISp is critical in DNA interstrand cross-link (ICL) repair in S phase, in both genomic (non telomeric) and telomeric DNA, and in maintenance of genomic stability following ICL damage to DNA. We have proposed that alphaIISp acts as a scaffold aiding to recruit repair proteins to sites of damage. This involvement of alphaIISp in ICL repair and telomere maintenance after ICL damage represents new and critical functions for alphaIISp. These studies have led to development of a model for the role of alphaIISp in DNA ICL repair. They have been aided by examination of cells from patients with Fanconi anemia (FA), a repair-deficient genetic disorder in which a deficiency in alphaIISp leads to defective ICL repair in genomic and telomeric DNA, telomere dysfunction, and chromosome instability following DNA ICL damage. We have shown that loss of alphaIISp in FA cells is due to increased breakdown by the protease, u-calpain. Importantly, we have demonstrated that this deficiency can be corrected by knockdown of u-calpain and restoring alphaIISp levels to normal. This corrects a number of the phenotypic deficiencies in FA after ICL damage. These studies suggest a new and unexplored direction for therapeutically restoring genomic stability in FA cells and for correcting numerous phenotypic deficiencies occurring after ICL damage. Developing a more in depth understanding of the importance of the interaction of alphaIISp with other nuclear proteins could significantly enhance our knowledge of the consequences of loss of alphaIISp on critical nuclear processes. PMID- 27480252 TI - Entropy-based divergent and convergent modular pattern reveals additive and synergistic anticerebral ischemia mechanisms. AB - Module-based network analysis of diverse pharmacological mechanisms is critical to systematically understand combination therapies and disease outcomes. We first constructed drug-target ischemic networks in baicalin, jasminoidin, ursodeoxycholic acid, and their combinations baicalin and jasminoidin as well as jasminoidin and ursodeoxycholic acid groups and identified modules using the entropy-based clustering algorithm. The modules 11, 7, 4, 8 and 3 were identified as baicalin, jasminoidin, ursodeoxycholic acid, baicalin and jasminoidin and jasminoidin and ursodeoxycholic acid-emerged responsive modules, while 12, 8, 15, 17 and 9 were identified as disappeared responsive modules based on variation of topological similarity, respectively. No overlapping differential biological processes were enriched between baicalin and jasminoidin and jasminoidin and ursodeoxycholic acid pure emerged responsive modules, but two were enriched by their co-disappeared responsive modules including nucleotide-excision repair and epithelial structure maintenance. We found an additive effect of baicalin and jasminoidin in a divergent pattern and a synergistic effect of jasminoidin and ursodeoxycholic acid in a convergent pattern on "central hit strategy" of regulating inflammation against cerebral ischemia. The proposed module-based approach may provide us a holistic view to understand multiple pharmacological mechanisms associated with differential phenotypes from the standpoint of modular pharmacology. PMID- 27480256 TI - Acute kidney injury in critically ill cancer patients: an update. AB - Patients with cancer represent a growing group among actual ICU admissions (up to 20 %). Due to their increased susceptibility to infectious and noninfectious complications related to the underlying cancer itself or its treatment, these patients frequently develop acute kidney injury (AKI). A wide variety of definitions for AKI are still used in the cancer literature, despite existing guidelines on definitions and staging of AKI. Alternative diagnostic investigations such as Cystatin C and urinary biomarkers are discussed briefly. This review summarizes the literature between 2010 and 2015 on epidemiology and prognosis of AKI in this population. Overall, the causes of AKI in the setting of malignancy are similar to those in other clinical settings, including preexisting chronic kidney disease. In addition, nephrotoxicity induced by the anticancer treatments including the more recently introduced targeted therapies is increasingly observed. However, data are sometimes difficult to interpret because they are often presented from the oncological rather than from the nephrological point of view. Because the development of the acute tumor lysis syndrome is one of the major causes of AKI in patients with a high tumor burden or a high cell turnover, the diagnosis, risk factors, and preventive measures of the syndrome will be discussed. Finally, we will briefly discuss renal replacement therapy modalities and the emergence of chronic kidney disease in the growing subgroup of critically ill post-AKI survivors. PMID- 27480257 TI - Immunohistochemical techniques for the human inner ear. AB - In this review, we provide a description of the recent methods used for immunohistochemical staining of the human inner ear using formalin-fixed frozen, paraffin and celloidin-embedded sections. We also show the application of these immunohistochemical methods in auditory and vestibular endorgans microdissected from the human temporal bone. We compare the advantages and disadvantages of immunohistochemistry (IHC) in the different types of embedding media. IHC in frozen and paraffin-embedded sections yields a robust immunoreactive signal. Both frozen and paraffin sections would be the best alternative in the case where celloidin-embedding technique is not available. IHC in whole endorgans yields excellent results and can be used when desiring to detect regional variations of protein expression in the sensory epithelia. One advantage of microdissection is that the tissue is processed immediately and IHC can be made within 1 week of temporal bone collection. A second advantage of microdissection is the excellent preservation of both morphology and antigenicity. Using celloidin-embedded inner ear sections, we were able to detect several antigens by IHC and immunofluorescence using antigen retrieval methods. These techniques, previously applied only in animal models, allow for the study of numerous important proteins expressed in the human temporal bone potentially opening up a new field for future human inner ear research. PMID- 27480258 TI - Formation of keratinocyte multilayers on filters under airlifted or submerged culture conditions in medium containing calcium, ascorbic acid, and keratinocyte growth factor. AB - Three-dimensional (3D) cell culture is a powerful in vitro technique to study the stratification and differentiation of keratinocytes. However, culture conditions, including culture media, supplements, and scaffolds (e.g., collagen gels with or without fibroblasts), can vary considerably. Here, we evaluated the roles of calcium, L-ascorbic acid phosphate magnesium salt n-hydrate (APM), and keratinocyte growth factor (KGF) in a chemically defined medium, EpiLife, in 3D cultures of primary human epidermal keratinocytes directly plated on polycarbonate filter inserts under airlifted or submerged conditions. Eight culture media containing various combinations of these three supplements were examined. Calcium was necessary for the stratification and differentiation of keratinocytes based on the localization of keratins and involucrin. However, the localization patterns of keratins and integrin beta4 were partially disrupted and Ki67-positive basal cells almost disappeared 3 weeks after airlift. The addition of KGF, but not APM, prevented these changes. Further addition of APM markedly improved the tissue architecture, including basal cell morphology and the appearance of keratohyalin granules and localized involucrin in the upper suprabasal cells, even after 1 week. Although the submerged culture also formed cornified epithelium-like multilayers, involucrin was localized in the cornified layer, where nuclei were often found. Based on these results, it is most effective to culture keratinocytes at the air-liquid interface in EpiLife medium supplemented with calcium, APM, and KGF to form well-organized and orthokeratinized multilayers as skin analogues. PMID- 27480260 TI - Young people in Asia carry high risk for non-communicable diseases, finds report. PMID- 27480259 TI - Association of TGFbeta signaling with the maintenance of a quiescent stem cell niche in human oral mucosa. AB - A dogma in squamous epithelial biology is that proliferation occurs in the basal cell layer. Notable exceptions are squamous epithelia of the human oral cavity, esophagus, ectocervix, and vagina. In these human epithelia, proliferation is rare in the basal cell layer, and the vast majority of cells positive for Ki67 and other proliferation markers are found in para- and suprabasal cell layers. This unique human feature of a generally quiescent basal cell layer overlaid by highly proliferative cells offers the rare opportunity to study the molecular features of undifferentiated, quiescent, putative stem cells in their natural context. Here, we show that the quiescent human oral mucosa basal cell layer expresses putative markers of stemness, while para- and suprabasal cells are characterized by cell cycle genes. We identified a TGFbeta signature in this quiescent basal cell layer. In in vitro organotypic cultures, human keratinocytes could be induced to express markers of these quiescent basal cells when TGFbeta signaling is activated. The study suggests that the separation of basal cell layer and proliferation in human oral mucosa may function to accommodate high proliferation rates and the protection of a quiescent reserve stem cell pool. Psoriasis, an epidermal inflammatory hyperproliferative disease, exhibits features of a quiescent basal cell layer mimicking normal oral mucosa. Our data indicate that structural changes in the organization of epithelial proliferation could contribute to longevity and carcinogenesis. PMID- 27480261 TI - Validating a Scale of Health Beliefs in Preventive Health Screenings Among Chinese Older Adults. AB - We aimed to examine the psychometric properties of a modified 16-item Attitudinal Index (AI), a measure of Chinese older adults' beliefs about preventive health screenings. We used the 2013 Shanghai Elderly Life and Opinion data including 3,418 respondents age 60+ who were randomly split into training and validation samples. We examined the validity and reliability of the modified AI. Psychometric evaluation of the modified AI revealed good response patterns. The overall scale had good reliability (Cronbach's alpha = .835). Exploratory factor analysis yielded four factors: barriers, fatalism, unnecessary, and detects (Cronbach's alpha = .815-.908). Confirmatory factor analysis of the modified AI's factor structure verified its four-factor structure (comparative fit index = 0.913, standardized root mean square residual = 0.048). The validity and reliability of the modified AI support its cultural appropriateness in measuring health beliefs among Chinese elderly. Further psychometric evaluation should focus on testing concurrent and criterion validity. PMID- 27480262 TI - Neurophysiological prediction of neurological good and poor outcome in post anoxic coma. AB - OBJECTIVE: Investigation of the utility of association between electroencephalogram (EEG) and somatosensory-evoked potentials (SEPs) for the prediction of neurological outcome in comatose patients resuscitated after cardiac arrest (CA) treated with therapeutic hypothermia, according to different recording times after CA. METHODS: Glasgow Coma Scale, EEG and SEPs performed at 12, 24 and 48-72 h after CA were assessed in 200 patients. Outcome was evaluated by Cerebral Performance Category 6 months after CA. RESULTS: Within 12 h after CA, grade 1 EEG predicted good outcome and bilaterally absent (BA) SEPs predicted poor outcome. Because grade 1 EEG and BA-SEPs were never found in the same patient, the recording of both EEG and SEPs allows us to correctly prognosticate a greater number of patients with respect to the use of a single test within 12 h after CA. At 48-72 h after CA, both grade 2 EEG and BA-SEPs predicted poor outcome with FPR=0.0%. When these neurophysiological patterns are both present in the same patient, they confirm and strengthen their prognostic value, but because they also occurred independently in eight patients, poor outcome is predictable in a greater number of patients. SIGNIFICANCE: The combination of EEG/SEP findings allows prediction of good and poor outcome (within 12 h after CA) and of poor outcome (after 48-72 h). Recording of EEG and SEPs in the same patients allows always an increase in the number of cases correctly classified, and an increase of the reliability of prognostication in a single patient due to concordance of patterns. PMID- 27480263 TI - Patient Profile of Drop-Outs From a Pulmonary Rehabilitation Program. AB - INTRODUCTION: While the benefits of pulmonary rehabilitation programs (PR) in COPD have been demonstrated, poor adherence, related with worse clinical outcomes, is common. OBJECTIVE: The purpose of this study was to examine causes for drop-out during a 12-week multidisciplinary pulmonary rehabilitation program and to investigate the characteristics of patients with poor adherence, with special emphasis on functional and clinical characteristics. METHOD: A prospective study was performed between February and November 2015in 83 COPD patients enrolled in an outpatient program of 36 strength +resistance training sessions. Ambulances were provided to facilitate access to the clinic. Patients were divided into: adherent (A) (attended at least 70% of the program) or non adherent (NA) (at least one session). RESULTS: A total of 83 patients were evaluated and 26 excluded; 15.7% refused to participate. The drop-out rate was 38.5%. The main causes were low motivation and transport problems. Lower forced vital capacity (NA, 58.9% vs A, 67.8%; P=.03), worse results on submaximal exercise test (NA, 6.2minutes vs A, 9.2minutes; P=.02), in total distance walked (NA, 42.6 vs A, 56.5; P=.03) and VO2 in ml/min/kg (NA, 11.4 vs A, 13.6; P=.03) and in ml/min (NA, 839 vs A, 1020; P=.04) were found in the non-adherent group. This group also showed higher use of oral steroids (NA, 23.8% vs A, 2.9%; P=.01). CONCLUSIONS: More than 1/3 of patients leave programs. The main causes are related to motivation and transport. The patients who dropout are those with worse functional tests, more exacerbations, steroids and smoking habit. PMID- 27480265 TI - Chronic low back pain in relation to Modic changes, bony endplate lesions, and disc degeneration in a prospective MRI study. AB - PURPOSE: To clarify the significance of Modic changes, bony endplate lesions, and disc degeneration as predictors of chronic low back pain (LBP) during 1-year follow-up. METHODS: 49 patients with severe, non-specific, chronic LBP, and Modic 1 lesion (M1) were prospectively studied with MRI and questionnaire. Changes in grade of disc degeneration, severity of Modic changes, Schmorl lesions, and bony endplate irregularities were evaluated and changes assessed in LBP intensity on numeric rating scale 0-10 and severity with Oswestry disability index 0-100 (ODI). Association between change in MRI findings and symptoms was computed using generalized estimating equations analysis. RESULTS: Although pain decreased in most patients during 1-year follow-up, it increased or persisted in 36 %. Change in M1, M2, bony endplate lesions, and signal intensity (SI) and height of the disc associated with change of pain intensity, while change in M1, bony endplate lesions, and disc height associated with change of ODI. Not only persistent M1s, increasing bony endplate lesions, decreasing disc height, and M2s, but also new M2s predicted persistence of pain, while decrease of M1s and SI of the disc and increase of size of M2s predicted decrease of pain. Changes in disc bulges did not associate with pain. CONCLUSIONS: In patients with chronic non-specific LBP, persisting M1, decreasing disc height, and increasing bony endplate lesions associated with persisting pain while decrease of SI of the disc with decrease of pain. Such changing MRI findings in the same disc space have earlier been shown to progress abnormally fast. They may be signs or biomarkers of a prolonged pain causing, deforming degenerative process, and should lead to considering early intervention or specific treatments to affect that process. PMID- 27480266 TI - Simultaneous Detection of Brown Rot- and Soft Rot-Causing Bacterial Pathogens from Potato Tubers Through Multiplex PCR. AB - Ralstonia solanacearum (Smith) Yabuuchi et al. and Erwinia carotovora subsp. carotovora (Jones) Bergey et al. (Pectobacterium carotovorum subsp. carotovorum) are the two major bacterial pathogens of potato causing brown rot (wilt) and soft rot diseases, respectively, in the field and during storage. Reliable and early detection of these pathogens are keys to avoid occurrence of these diseases in potato crops and reduce yield loss. In the present study, multiplex polymerase chain reaction (PCR) protocol was developed for simultaneous detection of R. solanacearum and E. carotovora subsp. carotovora from potato tubers. A set of oligos targeting the pectatelyase (pel) gene of E. carotovora subsp. carotovora and the universal primers based on 16S r RNA gene of R. solanacearum were used. The standardized multiplex PCR protocol could detect R. solanacearum and E. carotovora subsp. carotovora up to 0.01 and 1.0 ng of genomic DNA, respectively. The protocol was further validated on 96 stored potato tuber samples, collected from different potato-growing states of India, viz. Uttarakhand, Odisha, Meghalaya and Delhi. 53.1 % tuber samples were positive for R. solanacearum, and 15.1 % of samples were positive for E. carotovora subsp. carotovora, and both the pathogens were positive in 26.0 % samples when BIO-PCR was used. This method offers sensitive, specific, reliable and fast detection of two major bacterial pathogens from potato tubers simultaneously, particularly pathogen-free seed certification in large scale. PMID- 27480267 TI - Probabilistic model-based approach for heart beat detection. AB - Nowadays, hospitals are ubiquitous and integral to modern society. Patients flow in and out of a veritable whirlwind of paperwork, consultations, and potential inpatient admissions, through an abstracted system that is not without flaws. One of the biggest flaws in the medical system is perhaps an unexpected one: the patient alarm system. One longitudinal study reported an 88.8% rate of false alarms, with other studies reporting numbers of similar magnitudes. These false alarm rates lead to deleterious effects that manifest in a lower standard of care across clinics. This paper discusses a model-based probabilistic inference approach to estimate physiological variables at a detection level. We design a generative model that complies with a layman's understanding of human physiology and perform approximate Bayesian inference. One primary goal of this paper is to justify a Bayesian modeling approach to increasing robustness in a physiological domain. In order to evaluate our algorithm we look at the application of heart beat detection using four datasets provided by PhysioNet, a research resource for complex physiological signals, in the form of the PhysioNet 2014 Challenge set-p1 and set-p2, the MIT-BIH Polysomnographic Database, and the MGH/MF Waveform Database. On these data sets our algorithm performs on par with the other top six submissions to the PhysioNet 2014 challenge. The overall evaluation scores in terms of sensitivity and positive predictivity values obtained were as follows: set-p1 (99.72%), set-p2 (93.51%), MIT-BIH (99.66%), and MGH/MF (95.53%). These scores are based on the averaging of gross sensitivity, gross positive predictivity, average sensitivity, and average positive predictivity. PMID- 27480264 TI - Coherent and Contradictory Facts, Feats and Fictions Associated with Metal Accumulation in Parkinson's Disease: Epicenter or Outcome, Yet a Demigod Question. AB - Unwarranted exposure due to liberal use of metals for maintaining the lavish life and to achieve the food demand for escalating population along with an incredible boost in the average human life span owing to orchestrated progress in rejuvenation therapy have gradually increased the occurrence of Parkinson's disease (PD). Etiology is albeit elusive; association of PD with metal accumulation has never been overlooked due to noteworthy similitude between metal exposure symptoms and a few cardinal features of disease. Even though metals are entailed in the vital functions, a hysterical shift, primarily augmentation, escorts the stern nigrostriatal dopaminergic neurodegeneration. An increase in the passage of metals through the blood brain barrier and impaired metabolic activity and elimination system could lead to metal accumulation in the brain, which eventually makes dopaminergic neurons quite susceptible. In the present article, an update on implication of metal accumulation in PD/Parkinsonism has been provided. Moreover, encouraging and paradoxical facts and fictions associated with metal accumulation in PD/Parkinsonism have also been compiled. Systematic literature survey of PD is performed to describe updated information if metal accumulation is an epicenter or merely an outcome. Finally, a perspective on the association of metal accumulation with pesticide-induced Parkinsonism has been explained to unveil the likely impact of the former in the latter. PMID- 27480268 TI - Fixation durations in scene viewing: Modeling the effects of local image features, oculomotor parameters, and task. AB - Scene perception requires the orchestration of image- and task-related processes with oculomotor constraints. The present study was designed to investigate how these factors influence how long the eyes remain fixated on a given location. Linear mixed models (LMMs) were used to test whether local image statistics (including luminance, luminance contrast, edge density, visual clutter, and the number of homogeneous segments), calculated for 1 degrees circular regions around fixation locations, modulate fixation durations, and how these effects depend on task-related control. Fixation durations and locations were recorded from 72 participants, each viewing 135 scenes under three different viewing instructions (memorization, preference judgment, and search). Along with the image-related predictors, the LMMs simultaneously considered a number of oculomotor and spatiotemporal covariates, including the amplitudes of the previous and next saccades, and viewing time. As a key finding, the local image features around the current fixation predicted this fixation's duration. For instance, greater luminance was associated with shorter fixation durations. Such immediacy effects were found for all three viewing tasks. Moreover, in the memorization and preference tasks, some evidence for successor effects emerged, such that some image characteristics of the upcoming location influenced how long the eyes stayed at the current location. In contrast, in the search task, scene processing was not distributed across fixation durations within the visual span. The LMM-based framework of analysis, applied to the control of fixation durations in scenes, suggests important constraints for models of scene perception and search, and for visual attention in general. PMID- 27480270 TI - Corrigendum. AB - Interleukin-1beta transfer across the blood-brain barrier in the ovine fetusGrazyna B Sadowska, Xiaodi Chen, Jiyong Zhang, Yow-Pin Lim, Erin E Cummings, Oleksandr Makeyev, Walter G Besio, John Gaitanis, James F Padbury, William A Banks and Barbara S StonestreetJournal of Cerebral Blood Flow & Metabolism 2015; 35: 1388-1395. PMID- 27480269 TI - Species-specific escape of Plasmodium sporozoites from oocysts of avian, rodent, and human malarial parasites. AB - BACKGROUND: Malaria is transmitted when an infected mosquito delivers Plasmodium sporozoites into a vertebrate host. There are many species of Plasmodium and, in general, the infection is host-specific. For example, Plasmodium gallinaceum is an avian parasite, while Plasmodium berghei infects mice. These two parasites have been extensively used as experimental models of malaria transmission. Plasmodium falciparum and Plasmodium vivax are the most important agents of human malaria, a life-threatening disease of global importance. To complete their life cycle, Plasmodium parasites must traverse the mosquito midgut and form an oocyst that will divide continuously. Mature oocysts release thousands of sporozoites into the mosquito haemolymph that must reach the salivary gland to infect a new vertebrate host. The current understanding of the biology of oocyst formation and sporozoite release is mostly based on experimental infections with P. berghei, and the conclusions are generalized to other Plasmodium species that infect humans without further morphological analyses. RESULTS: Here, it is described the microanatomy of sporozoite escape from oocysts of four Plasmodium species: the two laboratory models, P. gallinaceum and P. berghei, and the two main species that cause malaria in humans, P. vivax and P. falciparum. It was found that sporozoites have species-specific mechanisms of escape from the oocyst. The two model species of Plasmodium had a common mechanism, in which the oocyst wall breaks down before sporozoites emerge. In contrast, P. vivax and P. falciparum sporozoites show a dynamic escape mechanism from the oocyst via polarized propulsion. CONCLUSIONS: This study demonstrated that Plasmodium species do not share a common mechanism of sporozoite escape, as previously thought, but show complex and species-specific mechanisms. In addition, the knowledge of this phenomenon in human Plasmodium can facilitate transmission-blocking studies and not those ones only based on the murine and avian models. PMID- 27480271 TI - Discrepancies in Autonomy and Relatedness Promoting Behaviors of Substance Using Mothers and Their Children: The Effects of a Family Systems Intervention. AB - Parents' and children's autonomy and relatedness behaviors are associated with a wide range of child outcomes. Yet, little is known about how parents and children's autonomy and relatedness behaviors jointly influence child outcomes. The current study captured this joint influence by exploring the longitudinal trajectory of mother-child discrepancies in autonomy and relatedness behaviors and its association with child problem behaviors. The effects of a family systems intervention on the trajectory of mother-child discrepancies were also examined. The sample included 183 substance using mothers and their children (M age = 11.54 years, SD = 2.55, range 8-16; 48 % females). Both the mother and child completed an assessment at baseline, 6- and 18-month post-baseline. A person-centered analysis identified subgroups varying in mother-child discrepancy patterns in their autonomy and relatedness behaviors. The results also showed that participation in the family systems therapy was associated with decreased mother child discrepancies, and also a synchronous increase in mother's and child's autonomy and relatedness. Additionally, increased mother-child discrepancies and mother-child dyads showing no change in autonomy and relatedness was associated with higher levels of children's problem behaviors. The findings reveal a dynamic process of mother-child discrepancies in autonomy and relatedness behaviors related to child outcomes. The findings also support the effectiveness of the family systems therapy, and highlight the importance of understanding the complexities in family interactions when explaining children's problem behaviors. PMID- 27480272 TI - Parental Knowledge: Examining Reporter Discrepancies and Links to School Engagement Among Middle School Studies. AB - It is well established that parental knowledge contributes to adolescents' well being and school success and scholars have noted that parents and adolescents report different levels of knowledge. Discrepancies in parental knowledge have implications for adolescent outcomes such as risk behaviors, but little is known about the implications of knowledge discrepancies for adolescents' school outcomes. The present study examined discrepancies in parent and adolescent reports of parental knowledge and investigated the extent to which knowledge discrepancies were linked to school engagement. Participants were early adolescents (N = 174; 53 % female) and their parents (90 % mothers). Adolescents (57 % African American/Black, 18 % multiracial, 17 % White/Caucasian, 7 % Hispanic/Latino and 1 % Asian American) attended a Midwestern, Title 1, urban, public middle school. Adolescents completed surveys in their homerooms and parents completed paper-pencil surveys at home or surveys via telephone. Results showed that parents reported more knowledge of adolescents' activities and whereabouts compared to adolescents' reports. Knowledge discrepancies were associated with school bonding and school self-esteem such that dyads in which adolescents reported more knowledge than their parents reported had significantly higher levels of school bonding and school self-esteem compared to dyads in which parents reported much more knowledge. PMID- 27480273 TI - Sexual Orientation Discordance and Young Adult Mental Health. AB - During the course of sexual development, many people experience dissonance between dimensions of sexual orientation, including attraction, behavior, and identity. This study assesses the relationship between sexual orientation discordance and mental health. Data were obtained from the National Longitudinal Study of Adolescent to Adult Health (n = 8,915; female = 54.62 %; non-Hispanic black = 18.83 %, Hispanic = 14.91 %, other race (non-white) = 10.79 %). Multivariable linear regression evaluated the correlation between sexual orientation discordance and perceived stress and depressive symptomatology. Models were stratified by sex and sexual identity. Among self-identified heterosexual females and mostly heterosexual males, sexual orientation discordance predicted significantly increased depressive symptomatology. No other subpopulation demonstrated a significant correlation between sexual orientation discordance and depressive symptomatology or perceived stress. The association between sexual orientation discordance and depressive symptomatology suggests a link between sexuality, self-concept, and mental health. PMID- 27480274 TI - RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation. AB - RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormone-dependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. (c)2016 AACR. PMID- 27480275 TI - CCN concentrations and BC warming influenced by maritime ship emitted aerosol plumes over southern Bay of Bengal. AB - Significant quantities of carbon soot aerosols are emitted into pristine parts of the atmosphere by marine shipping. Soot impacts the radiative balance of the Earth-atmosphere system by absorbing solar-terrestrial radiation and modifies the microphysical properties of clouds. Here we examined the impact of black carbon (BC) on net warming during monsoon season over southern Bay-of-Bengal, using surface and satellite measurements of aerosol plumes from shipping. Shipping plumes had enhanced the BC concentrations by a factor of four around the shipping lane and exerted a strong positive influence on net warming. Compiling all the data, we show that BC atmospheric heating rates for relatively-clean and polluted shipping corridor locations to be 0.06 and 0.16 K/day respectively within the surface layer. Emissions from maritime ships had directly heated the lower troposphere by two-and-half times and created a gradient of around 0.1 K/day on either side of the shipping corridor. Furthermore, we show that ship emitted aerosol plumes were responsible for increase in the concentration of cloud condensation nuclei (CCN) by an order of magnitude that of clean air. The effects seen here may have significant impact on the monsoonal activity over Bay-of Bengal and implications for climate change mitigation strategies. PMID- 27480277 TI - The syndrome dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL): Report of two additional patients. AB - We have recently described a newly recognized syndromic form of congenital microcephaly as part of a large cohort of apparently novel dysmorphic syndromes. The reported Saudi Arabian patients have severe primary microcephaly, ambiguous male genitalia, dysmorphic facies, polydactyly, and renal agenesis. The same homozygous CTU2 mutation was identified in all patients. Although the nucleotide change c.873G>A does not change the codon, it completely abolishes a consensus donor site resulting in frameshift and premature truncation ((NM_001012762.1): p.Thr247Alafs*21). In this report, we describe two cousins from United Arab Emirates whose clinical presentation was consistent with this recently described syndrome and both were found to have the same mutation on the same haplotypic background. We propose the acronym DREAM-PL to highlight the main clinical features of this syndrome, which we believe is underdiagnosed by exome sequencing based on the high carrier frequency, most likely due to the apparently synonymous nature of the mutation. (c) 2016 Wiley Periodicals, Inc. PMID- 27480278 TI - SB203580 inhibits epithelial-mesenchymal transition and pulmonary fibrosis in a rat silicosis model. AB - To investigate the role of p38 MAPK in silicosis, we explored the effects of SB203580 as a specific inhibitor of p38 MAPK in the silicosis model in rats. Rats were exposed to 50mg/ml silica intratracheally. From the first day after instillation, rats were injected with SB203580 1mg/kg/d. Rats were sacrificed at 7 and 15days after exposure of silica. The results demonstrated SB203580 could prevent the activation of p38. TGF-beta1 in bronchoalveolar lavage fluid, the expression of vimentin and alpha-SMA in the lung tissue was down-regulated and E cadherin was up-regulated after intervention with SB203580 at 7days and 15days. The percentage of the cells staining with SP-C and vimentin doubly was lower in SB203580 treated group than in silica group at 7days and 15days. SB203580 also inhibited the increase of ZEB-1, ZEB-2 and Twist at 7days. Histopathologic examination showed the decrease in the number of nodules and the blue areas of collagen fibers in the lung after SB203580 treatment. The content of hydroxyproline and the expression of collagen I and III decreased in SB203580 treated group than in silica group. These results suggested that p38 MAPK/ZEB-1 (ZEB-2, Twist) pathway was involved at 7days after silica instillation and p38 MAPK was pivotal for EMT in silicosis fibrosis in rats. PMID- 27480276 TI - The evolving role of adiponectin as an additive biomarker in HFrEF. AB - Heart failure (HF) is a growing health problem. Despite improved management and outcome, the number of patients with HF is expected to keep rising in the following years. In recent research, adiponectin was shown to exert beneficial effects in the cardiovascular system, but the protein was also implicated in the development and progression of HF. The objective of this review is to provide an overview of current knowledge on the role of adiponectin in HF with reduced ejection fraction. We discuss the cardioprotective and (anti-) inflammatory actions of adiponectin and its potential use in clinical diagnosis and prognosis. PMID- 27480279 TI - In vitro model adapted to the study of skin ageing induced by air pollution. AB - More than a barrier against environmental agents, skin reflects individual health and is a visible sign of ageing with the progressive loss of skin integrity. In order to evaluate the consequences of an environmental complex mixture, with tobacco smoke (TS) as model, on cellular and morphological changes, a 3D skin model was used. Morphologically, tissue integrity was intact after one TS exposure while the superficial layers were drastically reduced after two TS exposures. However, TS modified epidermal organisation at the molecular level after just one exposure. A decrease in loricrin protein staining was showed in the epidermis, while production of inflammatory cytokines (IL-8, IL-1alpha, IL 18) and metalloproteinase (MMP-1, MMP-3) were stimulated. Oxidative stress was also illustrated with an increase in 4-HNE protein staining. Moreover, terminal differentiation, cell-cell junction and anchorage gene expression was down regulated in our model after one TS-exposure. In conclusion, tobacco smoke impacted the fundamental functions of skin, namely tissue anchorage, cornification and skin desquamation. Oxidative stress resulted in skin ageing. The tissue was even reactive with the inflammatory pathways, after one TS exposure. The 3D-RHE model is appropriate for evaluating the impact of environmental pollutants on skin ageing. PMID- 27480280 TI - Bardoxolone methyl modulates efflux transporter and detoxifying enzyme expression in cisplatin-induced kidney cell injury. AB - Cisplatin is prescribed for the treatment of solid tumors and elicits toxicity to kidney tubules, which limits its clinical use. Nuclear factor erythroid 2-related factor 2 (Nrf2, NFE2L2) is a critical transcription factor that has been shown to protect against kidney injury through activation of antioxidant mechanisms. We aimed to evaluate the ability of short-term treatment with the Nrf2 activator bardoxolone methyl (CDDO-Me) to protect against cisplatin-induced kidney cell toxicity. Cell viability was assessed in human kidney proximal tubule epithelial cells (hPTCs) exposed to low, intermediate, and high cisplatin concentrations in the presence and absence of CDDO-Me, administered either prior to or after cisplatin. Treatment with cisplatin alone resulted in reductions in hPTC viability, while CDDO-Me administered prior to or after cisplatin exposure yielded significantly higher cell viability (17%-71%). Gene regulation (mRNA expression) studies revealed the ability of CDDO-Me to modify protective pathways including Nrf2 induced detoxifying genes [GCLC (increased 1.9-fold), NQO1 (increased 9.3-fold)], and an efflux transporter [SLC47A1 (increased 4.5-fold)] at 12h. Protein assessments were in agreement with gene expression. Immunofluorescence revealed localization of GCLC and NQO1 to the nucleus and cytosol, respectively, with CDDO-Me administered prior to or after cisplatin exposure. The findings of enhanced cell viability and increased expression of detoxifying enzymes (GCLC and NQO1) and the multidrug and toxin extrusion protein 1 (MATE1) efflux transporter (SLC47A1) in hPTCs exposed to CDDO-Me, suggest that intermittent treatment with CDDO-Me prior to or after cisplatin exposure may be a promising approach to mitigate acute kidney injury. PMID- 27480281 TI - Symmetry of Charge Partitioning in Collisional and UV Photon-Induced Dissociation of Protein Assemblies. AB - Tandem mass spectrometry can provide structural information on intact protein assemblies, generating mass fingerprints indicative of the stoichiometry and quaternary arrangement of the subunits. However, in such experiments, collision induced dissociation yields restricted information due to simultaneous subunit unfolding, charge rearrangement, and subsequent ejection of a highly charged unfolded single subunit. Alternative fragmentation strategies can potentially overcome this and supply a deeper level of structural detail. Here, we implemented ultraviolet photodissociation (UVPD) on an Orbitrap mass spectrometer optimized for native MS and benchmark its performance to HCD fragmentation using various protein oligomers. We investigated dimeric beta-lactoglobulin, dimeric superoxide dismutase, dimeric and tetrameric concanavalin A, and heptameric GroES and Gp31; ranging in molecular weight from 32 to 102 kDa. We find that, for the investigated systems, UVPD produces more symmetric charge partitioning than HCD. While HCD spectra show sporadic fragmentation over the full protein backbone sequence of the subunits with a bias toward fragmenting labile bonds, UVPD spectra provided higher sequence coverage. Taken together, we conclude that UVPD is a strong addition to the toolbox of fragmentation methods for top-down proteomics experiments, especially for native protein assemblies. PMID- 27480283 TI - The alpha/beta Hydrolase Fold Proteins of Mycobacterium tuberculosis, with Reference to their Contribution to Virulence. AB - The alpha/beta hydrolase fold superfamily is an ancient and widely diversified group of primarily hydrolytic enzymes. In this review, the adaptations of these proteins to the pathogenic lifestyle of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, are examined. Of the 105 alpha/beta hydrolases identified in Mtb, many are associated with lipid metabolism, particularly in the biosynthesis and maintenance of the Mtb's unique cell envelope, as well in the large number of extracellular lipases that are likely responsible for degradation of host lipid material. alpha/beta hydrolase fold proteins are also involved in the evasion and modulation of the immune response, detoxification and metabolic adaptations, including growth, response to acidification of the intracellular environment and dormancy. A striking feature of Mtb's alpha/beta hydrolases is their diversification into virulence-associated niches. It is clear that the alpha/beta hydrolase fold family has made a significant contribution to Mtb's remarkable success as a pathogen. PMID- 27480284 TI - The production of digital and printed resources from multiple modalities using visualization and three-dimensional printing techniques. AB - PURPOSE: Virtual digital resources and printed models have become indispensable tools for medical training and surgical planning. Nevertheless, printed models of soft tissue organs are still challenging to reproduce. This study adopts open source packages and a low-cost desktop 3D printer to convert multiple modalities of medical images to digital resources (volume rendering images and digital models) and lifelike printed models, which are useful to enhance our understanding of the geometric structure and complex spatial nature of anatomical organs. MATERIALS AND METHODS: Neuroimaging technologies such as CT, CTA, MRI, and TOF-MRA collect serial medical images. The procedures for producing digital resources can be divided into volume rendering and medical image reconstruction. To verify the accuracy of reconstruction, this study presents qualitative and quantitative assessments. Subsequently, digital models are archived as stereolithography format files and imported to the bundled software of the 3D printer. The printed models are produced using polylactide filament materials. RESULTS: We have successfully converted multiple modalities of medical images to digital resources and printed models for both hard organs (cranial base and tooth) and soft tissue organs (brain, blood vessels of the brain, the heart chambers and vessel lumen, and pituitary tumor). Multiple digital resources and printed models were provided to illustrate the anatomical relationship between organs and complicated surrounding structures. Three-dimensional printing (3DP) is a powerful tool to produce lifelike and tangible models. CONCLUSIONS: We present an available and cost-effective method for producing both digital resources and printed models. The choice of modality in medical images and the processing approach is important when reproducing soft tissue organs models. The accuracy of the printed model is determined by the quality of organ models and 3DP. With the ongoing improvement of printing techniques and the variety of materials available, 3DP will become an indispensable tool in medical training and surgical planning. PMID- 27480285 TI - Electrochemical impedance spectroscopy for black lipid membranes fused with channel protein supported on solid-state nanopore. AB - Black lipid membranes (BLMs) have been used for detecting single-channel activities of pore-forming peptides and ion channels. However, the short lifetimes and poor mechanical stability of suspended bilayers limit their applications in high throughput electrophysiological experiments. In this work, we present a synthetic solid-state nanopore functionalized with BLM fused with channel protein. A nanopore with diameter of ~180 nm was electrochemically fabricated in a thin silicon membrane. Folding and painting techniques were demonstrated for production of stable suspended BLMs followed by incorporation of transmembrane protein, ENaC. Membrane formation was confirmed by employing electrochemical impedance spectroscopy (EIS) in the frequency regime of 10-2-105 Hz. Results show that electrochemically fabricated solid state nanopore support resulted in excellent membrane stability, with >1 GOmega of up to 72 and 41 h for painting and folding techniques, respectively. After fusion of ENaC channel protein, the BLM exhibits the stability of ~5 h. We anticipate that such a solid state nanopore with diameter in the range of 150-200 nm and thickness <1 um could be a potential platform to enhance the throughput of ion-channel characterization using BLMs. PMID- 27480286 TI - Efficient Perovskite Solar Cells Depending on TiO2 Nanorod Arrays. AB - Perovskite solar cells (PSCs) with TiO2 materials have attracted much attention due to their high photovoltaic performance. Aligned TiO2 nanorods have long been used for potential application in highly efficient perovskite solar cells, but the previously reported efficiencies of perovskite solar cells based on TiO2 nanorod arrays were underrated. Here we show a solvothermal method based on a modified ketone-HCl system with the addition of organic acids suitable for modulation of the TiO2 nanorod array films to fabricate highly efficient perovskite solar cells. Photovoltaic measurements indicated that efficient nanorod-structured perovskite solar cells can be achieved with the length of the nanorods as long as approximately 200 nm. A record efficiency of 18.22% under the reverse scan direction has been optimized by avoiding direct contact between the TiO2 nanorods and the hole transport materials, eliminating the organic residues on the nanorod surfaces using UV-ozone treatment and tuning the nanorod array morphologies through addition of different organic acids in the solvothermal process. PMID- 27480287 TI - Post-crizotinib management of effective ceritinib therapy in a patient with ALK positive non-small cell lung cancer. AB - BACKGROUND: We report the re-biopsied diagnosis of a patient with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive lung adenocarcinoma successfully treated with ceritinib 450 mg/day taken with food following disease progression and gastrointestinal intolerance to crizotinib. CASE PRESENTATION: A 74-year old female patient initially diagnosed with ALK-negative lung adenocarcinoma responded to initial standard chemotherapy. The patient was subsequently re tested by next generation sequencing (NGS) and found to have ALK EIF2AK3-ALK fusion, and responded to crizotinib, but ultimately progressed and showed intolerance to this ALK inhibitor. She was then successfully treated with ceritinib 450 mg/day taken with food, has not suffered from any further gastrointestinal side-effects, and remains on ceritinib treatment after 12 months. CONCLUSIONS: Second-line ceritinib treatment, when administered at 450 mg/day with food, is both well tolerated and efficacious in a patient with previously treated lung adenocarcinoma who had discontinued crizotinib due to disease progression and gastrointestinal adverse effects (AEs). PMID- 27480289 TI - Evaluation of a novel tablet application for improvement in colonoscopy training and mentoring (with video). AB - BACKGROUND AND AIMS: Endoscopic training can be challenging for the trainee and preceptor. Frustration can result from ineffective communication regarding areas of interest. Our team developed a novel tablet application for real-time mirroring of the colonoscopy examination that allows preceptors to make annotations directly on the viewing monitor. The potential for improvement in team proficiency and satisfaction is unknown. METHODS: The on-screen endoscopic image is mirrored to an Android tablet and permits real-time annotation directly on the in-room endoscopic image display. Preceptors can also "freeze-frame" an image and provide visual on-screen instruction (telestration). Trainees, precepted by a GI attending, were 1:1 randomized to perform colonoscopy on a training phantom using the application with traditional precepting or traditional precepting alone. Magnetized polyps (size < 5 mm) were placed in 1 of 5 preset location scenarios. Each trainee performed a total of 10 colonoscopies and completed each location scenario twice. During withdrawal, the trainee and the attending identified polyps. Outcome measures included number of polyps missed and participant satisfaction after each trial. RESULTS: Fifteen trainees (6 novice and 9 GI fellows) performed a total of 150 colonoscopies where 330 polyps in total were placed. Fellows missed fewer polyps using the tablet versus traditional precepting alone (4.2% vs 12.5%; P = .04). There was no significant difference in missed polyps for novices (12.5% vs 18.8%; P = .66). Overall, fellows missed fewer polyps when compared with novices regardless of the precepting method (P = .01). The attending and all trainees reported reduced stress with improved communication using the tablet. CONCLUSIONS: Fellows missed fewer polyps using the tablet when compared with traditional endoscopy precepting. All trainees reported reduced stress, quicker identification of polyps, and improved educational satisfaction using the tablet. Our application has the potential to improve trainee plus attending team lesion detection and to enhance the endoscopy training experience for both the trainee and attending preceptor. PMID- 27480288 TI - Maneuverability and safety of a magnetic-controlled capsule endoscopy system to examine the human colon under real-time monitoring by colonoscopy: a pilot study (with video). AB - BACKGROUND AND AIMS: Colon capsule endoscopy has become an alternative method to evaluate the colonic mucosa without pain, sedation, and gas insufflation in recent years. The magnetic-controlled capsule endoscopy (MCCE) system is an innovative ingestible colon capsule. We performed a pilot study to assess its maneuverability and safety among subjects who volunteered to undergo colorectal cancer screening. METHODS: Fifty-seven volunteers underwent both MCCE and colonoscopy procedures. The position of the MCCE was monitored after the capsule was swallowed. When the MCCE reached the cecum, it was controlled by a magnetic manipulator to observe the colonic mucosa under real-time monitoring by colonoscopy. The primary measurements included maneuverability, the level of cleanliness, lesions, and safety. RESULTS: Five volunteers (8.78%) were excluded because of bowel preparation protocol deviations or failure to reach the cecum before the battery was exhausted. There was no capsule retention. Maneuverability of the MCCE to match the guidance of the magnetic manipulator was graded as good in 49 subjects (94.23%) and moderate in 3 (5.77%). It took 3.63 +/- 1.14 hours for the MCCE to reach the cecum. In 52 subjects (100%) the MCCE reached the transverse colon positively, and in 41 subjects (78.84%) the MCCE reached the rectosigmoid colon within a limited time of 25 minutes. The bowel preparation for MCCE was rated as good or excellent in 84.61% of the volunteers. Six positive findings were identified by the MCCE in the colon, which were also confirmed by colonoscopy. CONCLUSIONS: The MCCE showed promising maneuverability under real time monitoring by colonoscopy. (Clinical trial registration number: NCT02536144.). PMID- 27480290 TI - Diagnostic services in Australia: service rates and characteristics of patients. AB - BACKGROUND: Diagnostic services are the most common area of dental service in Australia. The objective was to investigate differences in services per visit for examinations and radiographs in relation to the characteristics of patients receiving these services in terms of age and gender, aspects of visiting such as dental insurance and reasons for visit, and oral health such as number of teeth and presence of decay. METHODS: A random sample of Australian dentists was surveyed in 2009-2010. Data on diagnostic services and patient characteristics were collected from a service log. RESULTS: A total of 1148 dentists responded (response rate = 67%). Models adjusted for age and gender of patients showed that rates [Rate Ratio, 95% CI] of examinations were higher for insured patients [1.13; 1.06-1.21], while rates of radiographs were higher for emergency visits [1.25; 1.11-1.48]. Patients with 20 or more teeth had higher rates for examinations [1.15; 1.01-1.32] and radiographs [1.28; 1.02-1.60]. Decayed teeth were associated with lower examination rates [0.70; 0.65-0.76] but higher rates of radiographs [1.34; 1.16-1.55]. CONCLUSIONS: The finding that number of teeth was associated with higher rates of examinations and radiographs suggests that retention of teeth could be influencing the increasing rates of diagnostic services in Australia. PMID- 27480291 TI - The impact of ligation of proximal side branches on blood flow and functional status of the internal thoracic artery in coronary anastomosis. AB - BACKGROUND: The effect of proximal side branches on the patency of the internal thoracic artery (ITA) is controversial. We used echocardiography and Doppler to verify the effect of ligation of branches on the flow and coronary flow reserve (CFR) of the grafted ITA in patients after coronary artery bypass grafting (CABG). METHODS: We prospectively investigated 53 patients with preserved left ventricular ejection fraction (LVEF >50%) who underwent CABG of the ITA. In Group I (25 patients), major branches were ligated during ITA anastomosis to the left anterior descending (LAD) coronary artery, whereas no ligation was performed in Group II (28 patients). Systolic flow (SF), diastolic flow (DF), and total flow (TF = SF + DF) were measured by Doppler echocardiography at the proximal level of the ITA preoperatively, at early postoperative stage, and 6 months after surgery. Dobutamine stress echocardiography (DSE) was performed at 6 months to determine CFR. RESULTS: The ITA flow was predominantly systolic before surgery and diastolic in the postoperative period. We found no differences between the groups in DF. On DSE, SF (19.5+/-9 mL/min vs 32.7+/-19 mL/min; P=.003) and TF (79+/-21 mL/min vs 101+/-47 mL/min; P=.037) were higher in Group II. There were no differences in CFR (1.9+/-0.46 vs 2.11+/-0.56; P=.143). CONCLUSION: In patients with preserved LVEF, ligation of major side branches during anastomosis to the LAD does not alter ITA flow or CFR. PMID- 27480292 TI - Management of spinal infections in children with cerebral palsy. AB - Cerebral palsy patients who undergo posterior spinal instrumentation for scoliosis are at a greater risk of surgical site infection compared to adolescents with idiopathic scoliosis. Many infecting organisms are reported. Risk factors include patients' specific factors, nutritional status as well as surgery related factors. Although surgical management is still controversial, it is always based on irrigation and debridement followed or not by implant removal. The purpose of this paper is to review the pathophysiology of surgical site infection in this patient population and to propose a treatment algorithm, based on a thorough review of the current literature and personal experience. PMID- 27480294 TI - [A proper view of the position and roles of multidisciplinary treatment of head neck squamous cell carcinomas]. PMID- 27480293 TI - Evaluation of Different N-Glycopeptide Enrichment Methods for N-Glycosylation Sites Mapping in Mouse Brain. AB - N-Glycosylation of proteins plays a critical role in many biological pathways. Because highly heterogeneous N-glycopeptides are present in biological sources, the enrichment procedure is a crucial step for mass spectrometry analysis. Five enrichment methods, including IP-ZIC-HILIC, hydrazide chemistry, lectin affinity, ZIC-HILIC-FA, and TiO2 affinity were evaluated and compared in the study of mapping N-glycosylation sites in mouse brain. On the basis of our results, the identified N-glycosylation sites were 1891, 1241, 891, 869, and 710 and the FDR values were 3.29, 5.62, 9.54, 9.54, and 20.02%, respectively. Therefore, IP-ZIC HILIC enrichment method displayed the highest sensitivity and specificity. In this work, we identified a total of 3446 unique glycosylation sites conforming to the N-glycosylation consensus motif (N-X-T/S/C; X ? P) with (18)O labeling in 1597 N-glycoproteins. N-glycosylation site information was used to confirm or correct the transmembrane topology of the 57 novel transmembrane N-glycoproteins. PMID- 27480295 TI - [Analyses of clinicopathologic factors affecting neck control after postoperative radiation as adjuvant treatment for lymph node metastasis in head and neck squamous cell carcinoma]. AB - OBJECTIVE: To investigate the clinicopathologic factors associated with neck control and distant metastasis in patients with neck metastases in head and neck squamous cell carcinoma (HNSCC) after postoperative radiation as adjuvant treatment. METHODS: Clinicopathologic data of 208 pathologic N+ (pN+ ) patients with HNSCC initially treated with neck dissection and postoperative radiation in Bethune International Peace Hospital of China from January 2004 to December 2009 were reviewed. The clinicopathologic factors, includeding age, sex, primary tumor site, pathologic T and N stage, tumor growth pattern, histological grade, tumor resection margin, size and number of positive lymph node, number of levels with positive lymph node, and extracapsular nodal spread (ECS), were evaluated for their association with neck control and distant metastasis in patients with HNSCC after postoperative radiation. Univariate chi(2) test and multiple stepwise logistic regression model were used for the analysis. RESULTS: Overall 5-year neck control rate after postoperative radiotherapy was 72.6% (151/208), with 84.0% (63/75) for SND, 72.9% (78/107) for MRND, and 38.5% (10/26) for RND, respectively. Univariate analysis showed that neck control after postoperative radiation was related with following factors: primary tumor site, pathologic N stage, size of positive node, number of levels with positive node, number of positive node, and ECS. Pathologic N stage and number of levels with positive lymph node were associated with distant metastasis. Multivariate analysis indicated that ECS was the most significant risk factor for neck metastasis after surgery and postoperative radiotherapy and the number of levels with positive node was the most significant risk factor for distant metastasis. CONCLUSIONS: ECS is the most important pathologic factor in planning postoperative adjuvant treatment for pN+ patients with HNSCC, therefore ECS should be evaluated routinely after neck dissection. The value of postoperative radiotherapy in controlling the ECS-related recurrence after surgery is limited. Postoperative concurrent chemoradiotherapy and targeted therapy can be considered in HNSCC patients with ECS. PMID- 27480296 TI - [Clinical features of patients with head and neck malignant tumor concurrent with multiple primary carcinoma]. AB - OBJECTIVE: To analyze the clinical characteristics of multiple primary cancers (MPC) associated with head and neck. METHODS: A total of 71 patients with MPC associated with head and neck treated from January 2008 to November 2015 were included in the retrospective study, of them 20 patients were synchronous MPC and 51 patients were metachronous MPC; 45 (63.4%) patients were field cancerization of head neck (FCHN) and 26 (36.6%) patients were non-field cancerization of head neck (NFCHN). For the synchronous MPC patients with an interval of 0 month, the lesion sites of FCHN were treated with combined chemotherapy and radiotherapy, the site of severe lesion of NFCHN received firstly a standard treatment. Other types of MPC were treated according to international guide lines or experts consensus. RESULTS: With the mean follow-up of 63.4 months, the 3-year and 5-year overall survival (OS) were 84.6% and 75.7% respectively. The 3-year and 5-year OS were 56.4% and 37.6% respectively in patients with synchronous MPC, and were 92.2% and 84.2% respectively in patients with metachronous MPC. There was significant difference in the OS between patients with metachronous MPC and patients with synchronous MPC (P=0.0002). The 3-year and 5-year OS were 85.7% and 77.9% respectively in patients with FCHN, and were 82.9% and 72.8% respectively in patients with NFCHN, with no significant difference between the two groups (P=0.297). CONCLUSION: With correct diagnosis and effective curative treatment, some of patients with MPC can get long-term survival, showing the better prognosis in metachronous MPC compared to synchronous MPC. PMID- 27480297 TI - [Clinical analysis of multimodal treatment for orbital organ preservation in T4b squamous cell carcinoma of nasal cavity and paranasal sinuses]. AB - OBJECTIVE: To investigate the efficacy of induction chemotherapy (ICT) followed by concurrent chemotherapy and helical tomotherapy (HT) in the patients with T4b squamous cell carcinoma of nasal cavity and paranasal sinus (SCCNP) for orbital organ preservation and high quality of life. METHODS: A total of 26 patients with the orbital involvement of T4b SCCNP between May 2008 and March 2013 were analyzed retrospectively. There were 17 males and 9 females; the average age was 54.7 years. The median follow-up time was 25 months (range 4-77 months). The patients received 1-2 cycles ICT with TP (docetaxel 70 mg/m(2) on day 1 and cisplatin 40 mg/m(2) on day 1-2, every 3 weeks) or TPF (docetaxel 70 mg/m(2) on day 1 and cisplatin 70 mg/m(2) on day 1-2, 5-fu 700 mg/m(2) on day 1-5, every 3 weeks), followed by concurrent HT (60-70 Gy) and chemotherapy with TP and/or epidermal growth factor receptor (EGFR) inhibitor. The Kaplan-Meier method was used to determine the 3-year overall survival rate and local control rate. Side effects were evaluated with the established common terminology criteria for adverse events (CTCAE) version 4.0 criteria. RESULTS: All patients completed the planned chemotherapy and 96.2%(25/26)patients completed the planned radiotherapy. The 3-year overall survival rate, the local control rate and real orbital preservation rate were 56.7%, 79.5% and 80.0% respectively. The most common acute side effects higher than grade 2 were oral mucositis, radiodermatitis and dry eye syndrome. CONCLUSION: The strategy including ICT followed by CCRT and/or EGFR inhibitor is an effective treatment for T4b SCCNP patients, with minimal toxicities, higher 3-year OS rate and orbital preservation rate, and also provides a new treatment option for T4b SCCNP patients. PMID- 27480298 TI - [A preliminary analysis on potentially targeted genes of induced chemotherapy in supraglottic laryngeal squamous cell carcinoma]. AB - OBJECTIVE: To analyze the differentially expressed genes produced by paclitaxel, cisplatin and 5-fluorouracil(TPF) regimen induction chemotherapy and the potentially functionally targeted genes of the induced chemotherapy in supraglottic laryngeal squamous cell carcinoma. METHODS: A total of 11 tissue samples from patients diagnosed as supraglottic carcinoma who didn't receive any treatment before were analyzed with microarray. The patients were divided into two groups based on their responses to the induction chemotherapy: 7 were sensitive to chemotherapy and 4 were non-sensitive. Gene expressions were detected by Illumina Human HT-12 BeadChip. The bioinformatics analysis online was used to analyze the differentially expressed genes. RESULTS: A total of 1 554 differentially expressed genes related to chemosensitivity were found. Analyzed with GO database, the up-regulated genes included the functional sets of biological adhesion, immune system development and stem cell proliferation, and the down-regulated genes included the functional sets of cell junction organization, phosphorus metabolic process and cell morphogenesis involved in differentiation. Analyzed with KEGG database, the up-regulated pathways included p53, cell adhesion and Ras signaling pathways, and the down-regulated pathways included focal adhesion, endocytosis and ErbB signaling pathways. There were statistically significant differences in the expressions of MAPK10, PIK3R5 and JUN genes, which had biological significance, between sensitive patients and non sensitive patients. CONCLUSION: MAPK10, PIK3R5 and JUN may be considered as potentially functional genes of the induced chemotherapy in supraglottic carcinoma. PMID- 27480299 TI - [Measuring facial paralysis using the three-dimensional dynamic quantitative analysis system of facial motion: correlation with subjective grading systems]. AB - OBJECTIVE: The aim of this study was to measure the facial motion of patients with facial paralysis using a three-dimensional dynamic quantitative analysis system of facial motion (3D ASFM) and analyze its correlation with subjective grading systems. METHODS: We included 30 healthy volunteers and 50 patients with unilateral facial paralysis. After placing landmarks on the faces, the facial motions of the patients were measured using the 3D ASFM. The regional symmetry ratios(SRs) and gross scores of different parameters were calculated. Then a comparison with four subjective grading systems(House-Brackmann, Sunnybrook, Facial Nerve Grading System 2.0, Fisch) was performed. RESULTS: The entire test could be completed within five minutes. The normal range of healthy volunteers were obtained, the gross score of which was 91.9+/-1.5. The SRs of the maximal moving distance(MMD) were most strongly correlated with regional subjective grading systems, followed by the SRs of the maximal moving velocity (MMV). The SRs of the maximal moving acceleration (MMA) were either poorly correlated or uncorrelated with the subjective grading systems. Moreover, the Spearman coefficients with four subjective grading systems were -0.630(House-Brackmann), 0.728(Facial Nerve Grading System 2.0), 0.697(Sunnybrook), and 0.617(Fisch)respectively(P<0.05). CONCLUSIONS: The 3D ASFM is a convenient method to rapidly assess facial paralysis. It not only overcomes the shortcomings of conventional subjective grading systems, but also correlates well with them. PMID- 27480300 TI - [The spontaneous herniation of temporomandibular joint into external auditory canal: diagnosis of otoscopy, CT and MRI]. AB - OBJECTIVE: To summarize the otoscopy, CT and MRI features of spontaneous herniation of the temporomandibular joint(TMJ) into the external auditory canal(EAC) through the persistence Huschke's foramen(PHF). METHODS: The otoscopy, CT and MRI images of three cases with the herniation of the TMJ into the EAC through the PHF were analyzed retrospectively. RESULTS: Otoscopy revealed the masses located in the antero-inferior aspect of the bony EAC, and the mass displayed an alternative of forward and backward motion during opening and closing of the mouth.CT of the temporal bone showed a bony defect and a consecutive soft mass in the antero-inferior wall of the bony EAC. The margin of the bony defects were well-defined in all cases, the bone adjacent to PHF was pressed and partially wrapped around the soft mass as 'holding ball' in two cases, partly peripheral pseudo bony shell of the soft mass were showed in two cases. The soft mass in EAC appeared equal attenuated with the soft tissue of TMJ, and on enhanced CT scans showed no enhancement of the soft mass. On MRI scans, the imaging displayed a bony defect in the antero-inferior wall of the EAC with a soft mass which was formed by the capsule of the TMJ, and the mass showed iso-signal to the capsule of the TMJ on all sequences, and there was no enhancement after contrast administration. CONCLUSION: The otoscopy, CT and MRI features of the spontaneous herniation of the TMJ into the EAC through the PHF is special, and the above examinations are valuable for diagnosis of the disease. PMID- 27480301 TI - [Rosenmuller valve during endoscopic dacryocystorhinostomy in treating refractory nasolacrimal duct obstruction]. AB - OBJECTIVE: The objective of this study was to assess the efficacy of exposing Rosenmuller valve during endonasal endoscopic dacryocystorhinostomy (EES-DCR) in treating refractory nasolacrimal duct obstruction. METHODS: Thirty six patients (47 eyes) with refractory nasolacrimal duct obstruction were entered into this study, including 13 patients (15 eyes) underwent nasal lacrimal duct intubation before, 18 patients (26 eyes) with small lacrimal sac, 2 patients underwent DCR before, 1 patient with functional nasal lacrimal duct obstruction, 1 patient with lacrimal mucocele, 1 patient with nasal trauma. During the DCR, the bone window was enlarged as wide as possible and the valve of Rosenmuller was exposed. The intubation of the lacrimal apparatus was performed if the lacrimal sac was very small and the Rosenmuller valve was tight. Functional endoscopic sinus surgery and septoplasty were performed simultaneously if necessary. Postoperatively, each patient was assessed by the symptom and nasal endoscopy. RESULTS: The postoperative follow-up period ranged from 3 to 36 months. Thirty two patients(89.4%, 42/47 eyes) were cured, which presented as the disappearance of symptoms, the patency of the lacrimal ostium and the lacrimal duct irrigation was clear. One patient (2.1%, 1/47 eyes) was improved, which presented as the improvement of symptoms, a few hypertrophic scar around the lacrimal ostium and the lacrimal duct irrigation was clear. Four cases failed (8.5%, 4/47), which presented as symptomatic and obstruction of the lacrimal ostium. The total effective rate reached to 91.5%. No serious postoperative complications were found in all cases. CONCLUSIONS: To expose Rosenmuller valve during endoscopic DCR in treating patients with refractory nasolacrimal duct obstruction could obviously increase the operative success rate, fewer complications, with no facial surgical scar. It is an ideal way to treat the refractory nasolacrimal duct obstruction. PMID- 27480302 TI - [Evaluation of blood eosinophil in the diagnosis of eosinophilic chronic rhinosinusitis]. AB - OBJECTIVE: To evaluate the practice of peripheral blood eosinophil in the diagnosis of eosinophilic chronic rhinosinusitis(ECRS). METHODS: The correlation between eosinophil count and percentage in peripheral blood and that in topic tissue in 787 patients (the first affiliated hospital of Wenzhou medical university, from Jan. 2013 to Jun. 2016) with chronic rhinosinusitis (CRS) were retrospectively analysed. The optimal cutoff value of blood eosinophil count and percentage as predictors for ECRS was determined by receiver operating characteristic curves (ROC) and their diagnostic ability was compared. RESULTS: The positive correlation between eosinophil count and percentage in blood and that in tissue was found respectively in 787 patients with CRS (r=0.450, 0.499, 0.463, 0.465, P<0.01). Although the significant correlation between blood eosinophil count and its count and percentage in tissue was not found after blood leukocyte and tissue eosinophilic inflammation was controlled respectively (r=0.041, P=0.380; r=0.046, P=0.329 and r=0.023, P=0.618; r=0.032, P=0.499), blood eosinophil percentage still showed significant correlation with tissue eosinophil count and percentage, but reduced unequally after that(r=0.383, 0.436 and r=0.153, 0.169, P<0.01). With ROC analysis, the diagnostic ability of optimal cut off values of eosinophil count and percentage varied as the histological criteria for ECRS differed. CONCLUSIONS: Eosinophil in peripheral blood showed significant positive correlation with its tissue infiltration, which may be not strong and easily effected by individual factors.Theoretically, blood eosinophil may have a diagnostic significance as a predictor for ECRS but not practically. PMID- 27480303 TI - [A murine model of local allergic rhinitis]. AB - OBJECTIVE: To establish the murine models of local allergic rhinitis (LAR) and allergic rhinitis (AR) by using ovalbumin (OVA), and to investigate the relationship between them. METHODS: Thirty BALB/c mice were divided into 5 groups, (1) the nasally sensitized group (group A1) that was challenged with OVA by a 10 d procedure, (2) the control group of A1 that was challenged with phosphate-buffered saline (PBS), (3) the nasally sensitized group (group A2) that was challenged with OVA by a 25 d procedure, (4)the control group of A2 that was challenged with PBS, (5) the intraperitoneally sensitized group (group B) .The numbers of sneezing after final challenge were counted, and the serum OVA specific immunoglobulin E (OVA-sIgE), interleukin (IL) -4, IL-13, IL-5 levels in nasal lavage fluid were measured by ELISA. Hematoxylin-eosin staining was performed to evaluate the histological change of nose and lung tissues. Graph Pad Prism 6 software was used to analyze the data. RESULTS: Nasally sensitized group A1 displayed LAR symptoms of sneezing and eosinophilic infiltrating, but without increased OVA-sIgE in serum on day 10 compared with the control group of A1(t=0.697, P>0.05), OVA-sIgE in serum of group A2(2.710+/-1.406)ng/ml reached to statistical significance and with airway remodeling on day 25 compared with the control group of A2((0.221+/-0.080)ng/ml, t=4.329, P<0.05). IL-5 and IL-13 in nasal fluid showed a significant increase in the nasally sensitized group A1, compared with the group A2(t values were 2.442, 2.804, P values were less then 0.05). CONCLUSIONS: A short time intranasal instillation with OVA could establish LAR murine model, continuing OVA challenge could increase serum sIgE level and with airway remodeling. LAR mice show a unique characteristic by expressing higher IL-5 and IL-13 in nose than AR mice, but sIgE in serum remains at a normal level. PMID- 27480304 TI - [Genotype-phenotype correlations in multiple endocrine neoplasia type 2]. AB - OBJECTIVE: To evaluate the relationship between different RET mutations and the aggressiveness of hereditary medullary thyroid cancer (HMTC) or the presentation of other endocrine disorders in patients with multiple endocrine neoplasia type 2 (MEN2). METHODS: A total of 73 thyroid medullary carcinoma patients from 22 Chinese kindreds who were treated in our center from 2010 to 2015 were enrolled. RET genes in the patients and their relatives were screened. RESULTS: According to the clinical data and 2015 American Thyroid Association (ATA) guidelines, patients were classified into 3 RET mutation risk groups: Modest, 24 cases; High, 48 cases; and Highest, 1 case. Multivariate analysis showed an increased likelihood of MTC stage III or IV at diagnosis with increasing of age and risk. The likelihood increased 11.6% per year of age at surgery (95% confidence interval, 1.040-1.198; P=0.002). The likelihood in patients with high risk was 7.9 times higher than patients with modest risk (95% confidence interval, 1.607 38.717; P=0.003). Aside from one patient with MEN2B, other 72 patients were MEN2A, of them, 28 cases from 7 kindreds with classical MEN2A (codon 634 & 618), 14 cases from 3 kindreds with cutaneous lichen amyloidosis (codon 634), 4 cases from 1 kindred with Hirschsprung's disease (codon 620), and 26 cases from 10 kindreds with familial MTC. CONCLUSION: The aggressiveness of HMTC and the presentation of other endocrine diseases are related to specific RET mutations. For RET mutation carriers, MTC and other endocrine diseases should be diagnosed and treated early based on the RET genotypes. PMID- 27480305 TI - [Treatment experience on ICU patients with percutaneous dilational tracheotomy and subsequent delayed bleeding]. PMID- 27480306 TI - [Minutes of VI international workshop on endoscopic ear surgery]. PMID- 27480307 TI - [Present status of concurrent chemoreadiotherapy in squamous cell carcinoma of head and neck]. AB - Head neck squamous cell carcinoma (HNSCC) is a common kind of malignancies in human body. For HNSCC in early stage, either surgical operation or radiotherapy can acquire satisfactory treatment results. However, any single treatment modality such as surgery alone or single radiation is insufficient to gain satisfactory tumor control. Multidisciplinary treatment (MDT) has become a mainstay and important therapeutic strategy in the management of HNSCC. Among various approaches in the MDT, concurrent chemoradiotheraqpy (CCR) constitutes a major progress, which implicates a lot in improving outcomes and organ preservations in managing HNSCC. In the present review, the history, mechanisms, indications along with side effects and drawbacks, and perspectives of CCR are to be described and discussed, in the hope of providing effective guidance for the domestic MDT, especially CCR in the management of HNSCC. PMID- 27480309 TI - [Application of narrow band imaging endoscopy in the diagnosis of primary tuberculosis of vocal cord]. PMID- 27480308 TI - [The progress of stem cells in the treatment of olfactory dysfunction]. AB - Olfactory dysfunction is one of the common diseases in the Department of Otorhinolaryngology. Although the olfactory nerve has ability to regenerate in human central nervous system, if the damage involves nerve, only a few patients can restore the olfactory function. At present, there is no satisfactory treatment for sensorineural olfactory dysfunction. Therefore, it is urgent to explore new and effective method for treating sensorineural olfactory dysfunction. The progress of stem cells in the treatment of olfactory dysfunction is reviewed in this article. PMID- 27480310 TI - [Principles and stragegies in the management of post-therapeutic recurrence of hypopharyngeal cancer]. PMID- 27480311 TI - Heterotrimeric G proteins control stem cell proliferation through CLAVATA signaling in Arabidopsis. PMID- 27480312 TI - Collaborative Patient-Centered Quality Improvement: A Cross-Sectional Survey Comparing the Types and Numbers of Quality Initiatives Selected by Patients and Health Professionals. AB - Identification of patients' and health professionals' quality improvement preferences is an essential first step in collaborative improvement models. This includes experience-based codesign (EBCD), where service change is strategically introduced following stakeholder consultation. This study compared the number and types of improvement initiatives selected by outpatients and health professionals. Using electronic surveys designed to inform EBCD studies, 541 outpatients (71.1% consent) and 124 professionals (47.1% response) selected up to 23 general initiatives. On average, outpatients selected 2.4 (median = 1, interquartile range = 1-3) initiatives and professionals selected 10.7 (median = 10; interquartile range = 6-15) initiatives. Outpatients demonstrated a strong preference for improvements to clinic organization, such as appointment scheduling and clinic contact. Outpatients selected relatively fewer initiatives potentially reducing the complexity of service change and resources required to address preferences. Comparatively, professionals indicated a greater degree of change is needed and selected initiatives related to communication with patients and other professionals, including coordinating multidisciplinary care. Improvements to information provision were commonly selected by both groups and offered a strategic opportunity to address patients' and professionals' preferences. By quantifying the ways in which preferences differed, this study emphasizes the need for collaborative approaches to health service change and may be used to initiate an informed discussion on patients' and professionals' quality improvement preferences in tertiary care. PMID- 27480313 TI - The role of interpersonal sensitivity, social support, and quality of life in rural older adults. AB - The mental health of elderly individuals in rural areas is increasingly relevant as populations age and social structures change. While social support satisfaction is a well-established predictor of quality of life, interpersonal sensitivity symptoms may diminish this relation. The current study extends the findings of Scogin et al by investigating the relationship among interpersonal sensitivity, social support satisfaction, and quality of life among rural older adults and exploring the mediating role of social support in the relation between interpersonal sensitivity and quality of life (N = 128). Hierarchical regression revealed that interpersonal sensitivity and social support satisfaction predicted quality of life. In addition, bootstrapping resampling supported the role of social support satisfaction as a mediator between interpersonal sensitivity symptoms and quality of life. These results underscore the importance of nurses and allied health providers in assessing and attending to negative self perceptions of clients, as well as the perceived quality of their social networks. PMID- 27480314 TI - Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol alone or a sedation protocol and daily interruption. AB - BACKGROUND: Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation. METHODS: This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation. RESULTS: Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356 mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, and was at target (3.2 vs 3.3, 95 % CI -0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the night and day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were more unintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases in nighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and the decision not to extubate the patient despite successful SBT. CONCLUSION: Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses were associated with SBT failure and delayed extubation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00675363 . Registered 7 May 2008. PMID- 27480315 TI - Post-exercise blood flow restriction attenuates muscle hypertrophy. AB - PURPOSE: Applying blood flow restriction during low-load resistance training has been shown to augment muscle hypertrophy which has been attributed to metabolic accumulation. It remains unknown, however, whether metabolites can augment muscle growth when maintained post-exercise. METHODS: Thirteen untrained individuals (6 males and 7 females) performed 24 training sessions. The control arm performed one set of elbow flexion (70 % 1RM) to volitional fatigue, while the experimental arm performed the same protocol immediately followed by 3 min of blood flow restriction (70 % arterial occlusion). Muscle growth (ultrasound) was measured at 50, 60, and 70 % of the distance between the lateral epicondyle and acromion process. RESULTS: Both conditions completed the same exercise volume [3678 (95 % CI 2962, 4393) vs. 3638 kg (95 % CI 2854, 4423)]. There was a condition by time interaction (p = 0.031) demonstrating an attenuation of muscle growth at the 60 % site in the experimental [pre 3.1 (95 % CI 2.8, 3.5), post 3.1 (95 % CI 2.7, 3.5) cm] vs. control [pre 3.1 (95 % CI 2.6, 3.6), post 3.3 (95 % CI 2.8, 3.7) cm] condition. Muscle growth at the 50 % and 70 % sites was similar at the group level, although there were attenuations at the individual level. Exploratory analyses of pre-post mean (95 % CI) changes in muscle thickness suggested that this attenuation in the experimental condition occurred only in females [50 % site 0.0 (-0.2, 0.0) cm; 60 % site -0.1 (-0.3, 0.0) cm; 70 % site 0.0 (-0.1, 0.1) cm]. CONCLUSIONS: The application of blood flow restriction post high-load training did not augment muscle growth for either sex, and appeared to attenuate muscle growth among females. PMID- 27480316 TI - Moral distress in ICU nurses. PMID- 27480317 TI - An Agent-Based Approach to Dynamically Represent the Pharmacokinetic Properties of Baicalein. AB - Baicalein, a typical flavonoid presented in Scutellariae radix, exhibits a unique metabolic profile during first-pass metabolism: parallel glucuronidation and sulfation pathways, with possible substrate inhibition in both pathways. In this project, we aimed to construct an agent-based model to dynamically represent baicalein pharmacokinetics and to verify the substrate inhibition hypothesis. The model consisted of three 3D spaces and two membranes: apical space (S1), intracellular space (S2), basolateral space (S3), apical membrane (M1), and basolateral membrane (M2). In silico enzymes (UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs)) and binder components were placed in S2. The model was then executed to simulate one-pass metabolism experiments of baicalein. With the implementation of a two-site enzyme design, the simulated results captured the preset qualitative and quantitative features of the wet-lab observations. The feasible parameter set showed that substrate inhibition happened in both conjugation pathways of baicalein. The simulation results suggested that the sulfation pathway was dominant at low concentrations and that SULT was more inclined to substrate inhibition than UGT. Cross-model validation was satisfactory. Our findings were consistent with a previously reported catenary model. We conclude that the mechanisms represented by our model are plausible. Our novel modeling approach could dynamically represent the metabolic pathways of baicalein in a Caco-2 system. PMID- 27480318 TI - Nanomedicines: From Bench to Bedside and Beyond. AB - Advancing nanomedicines from concept to clinic requires integration of new science with traditional pharmaceutical development. The medical and commercial success of nanomedicines is greatly facilitated when those charged with developing nanomedicines are cognizant of the unique opportunities and technical challenges that these products present. These individuals must also be knowledgeable about the processes of clinical and product development, including regulatory considerations, to maximize the odds for successful product registration. This article outlines these topics with a goal to accelerate the combination of academic innovation with collaborative industrial scientists who understand pharmaceutical development and regulatory approval requirements-only together can they realize the full potential of nanomedicines for patients. PMID- 27480319 TI - Regulatory Experience with In Vivo In Vitro Correlations (IVIVC) in New Drug Applications. AB - In the past two decades, in vitro in vivo correlation (IVIVC) has been considered an important tool for supporting biowaivers, setting dissolution acceptance criteria, and more recently in the Quality by Design (QbD) framework promoting the establishment of clinically meaningful drug product specifications using dissolution as the endpoint. Based on our review experience at the FDA, for the purposes of this article, we analyzed the current state of regulatory submissions containing IVIVC approaches and discussed the successes and failures from the perspectives of study design to methodology. In the past decade, the overall acceptance rate of the IVIVC submissions is about 40%. Moreover, the number of IVIVC studies seen in the submissions per year is not increasing. Establishing clinically meaningful drug product specifications through the linkages between the identified critical quality attributes and in vivo performance is key for developing a quality drug product. To achieve this goal, there is an imminent need for addressing the issues behind a low success rate in IVIVC development. The results from the current analysis revealed that special considerations should be taken in areas such as (1) selection of appropriate number/kind of formulations for IVIVC development/validation, (2) construction of exploratory plots to guide model building and selection, (3) investigation of the reasons of inconclusive predictability, (4) improvement on the quality and richness of the data, and (5) avoidance of over parameterization. The development and incorporation of biopredictive dissolution methods and the use of non conventional approaches, including mechanistic/physiologically based approaches, should be explored to increase the likelihood of IVIVC success. PMID- 27480320 TI - Intermediates, catalysts, persistence, and boundary steady states. AB - For dynamical systems arising from chemical reaction networks, persistence is the property that each species concentration remains positively bounded away from zero, as long as species concentrations were all positive in the beginning. We describe two graphical procedures for simplifying reaction networks without breaking known necessary or sufficient conditions for persistence, by iteratively removing so-called intermediates and catalysts from the network. The procedures are easy to apply and, in many cases, lead to highly simplified network structures, such as monomolecular networks. For specific classes of reaction networks, we show that these conditions for persistence are equivalent to one another. Furthermore, they can also be characterized by easily checkable strong connectivity properties of a related graph. In particular, this is the case for (conservative) monomolecular networks, as well as cascades of a large class of post-translational modification systems (of which the MAPK cascade and the n-site futile cycle are prominent examples). Since one of the aforementioned sufficient conditions for persistence precludes the existence of boundary steady states, our method also provides a graphical tool to check for that. PMID- 27480321 TI - Four in Florida are infected with Zika from local mosquitoes. PMID- 27480322 TI - Magnetic Resonance-Guided High-Intensity-Focused Ultrasound for Palliation of Painful Skeletal Metastases: A Pilot Study. AB - BACKGROUND: Bone is one of the most common sites of metastases, with bone metastases-related pain representing a significant source of morbidity among patients with cancer. Magnetic resonance-guided focused ultrasound is a noninvasive, outpatient modality with the potential for treating painful bone metastases. The aim of this study is to report our initial experience with magnetic resonance-guided focused ultrasound in the treatment of bone metastases and our preliminary analysis of urinary cytokine levels after therapy. METHODS: This was a single-center pilot study of 10 patients with metastatic cancer to investigate the feasibility of magnetic resonance-guided focused ultrasound for primary pain control in device-accessible skeletal metastases. Treatments were performed on a clinical magnetic resonance-guided focused ultrasound system using a volumetric ablation technique. Primary efficacy was assessed using Brief Pain Inventory scores and morphine equivalent daily dose intake at 3 time points: before, day 14, and day 30 after the magnetic resonance-guided focused ultrasound treatment. Urine cytokines were measured 3 days before treatment and 2 days after the treatment. RESULTS: Of the 10 patients, 8 were followed up 14 days and 6 were followed up 30 days after the treatment. At day 14, 3 patients (37.5%) exhibited partial pain response and 4 patients (50%) exhibited an indeterminate response, and at day 30 after the treatment, 5 patients (83%) exhibited partial pain response. No treatment-related adverse events were recorded. Of the urine cytokines measured, only Transforming growth factor alpha (TGFalpha) demonstrated an overall decrease, with a trend toward statistical significance ( P = .078). CONCLUSION: Our study corroborates magnetic resonance-guided focused ultrasound as a feasible and safe modality as a primary, palliative treatment for painful bone metastases and contributes to the limited body of literature using magnetic resonance-guided focused ultrasound for this clinical indication. PMID- 27480323 TI - Inhibition of autophagy ameliorates pulmonary microvascular dilation and PMVECs excessive proliferation in rat experimental hepatopulmonary syndrome. AB - Hepatopulmonary syndrome (HPS) is a defective liver-induced pulmonary vascular disorder with massive pulmonary microvascular dilation and excessive proliferation of pulmonary microvascular endothelial cells (PMVECs). Growing evidence suggests that autophagy is involved in pulmonary diseases, protectively or detrimentally. Thus, it is interesting and important to explore whether autophagy might be involved in and critical in HPS. In the present study, we report that autophagy was activated in common bile duct ligation (CBDL) rats and cultured pulmonary PMVECs induced by CBDL rat serum, two accepted in vivo and in vitro experimental models of HPS. Furthermore, pharmacological inhibition of autophagy with 3-methyladenine (3-MA) significantly alleviated pathological alterations and typical symptom of HPS in CBDL rats in vivo, and consistently 3 MA significantly attenuated the CBDL rat serum-induced excessive proliferation of PMVECs in vitro. All these changes mediated by 3-MA might explain the observed prominent improvement of pulmonary appearance, edema, microvascular dilatation and arterial oxygenation in vivo. Collectively, these results suggest that autophagy activation may play a critical role in the pathogenesis of HPS, and autophagy inhibition may have a therapeutic potential for this disease. PMID- 27480324 TI - Multivariate models for prediction of human skin sensitization hazard. AB - One of the Interagency Coordinating Committee on the Validation of Alternative Method's (ICCVAM) top priorities is the development and evaluation of non-animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays - the direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSensTM assay - six physicochemical properties and an in silico read-across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches, logistic regression and support vector machine, to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three logistic regression and three support vector machine) with the highest accuracy (92%) used: (1) DPRA, h-CLAT and read-across; (2) DPRA, h-CLAT, read-across and KeratinoSens; or (3) DPRA, h-CLAT, read-across, KeratinoSens and log P. The models performed better at predicting human skin sensitization hazard than the murine local lymph node assay (accuracy 88%), any of the alternative methods alone (accuracy 63-79%) or test batteries combining data from the individual methods (accuracy 75%). These results suggest that computational methods are promising tools to identify effectively the potential human skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. PMID- 27480326 TI - Investigating obesity as a risk factor for influenza-like illness during the 2009 H1N1 influenza pandemic using the Health Survey for England. AB - BACKGROUND: Following the 2009 H1N1 influenza pandemic, obesity was shown to be associated with severe influenza outcomes. It remains unclear whether obesity was a risk factor for milder influenza-like illness (ILI). OBJECTIVES: To determine whether obesity was associated with an increased risk of self-reported ILI during the 2009 H1N1 influenza pandemic using Health Survey for England (HSE) 2010 cross sectional data. METHODS: This study used HSE data collected from English households between January and December 2010. Weight and height measurements were taken by trained fieldworkers to determine obesity. ILI was defined as a positive response to the question "Have you had a flu-like illness where you felt feverish and had a cough or sore throat?" with illness occurring between May and December 2009. Multivariable logistic regression was used to evaluate the association between obesity and ILI. RESULTS: The study comprised 8407 participants (6984 adults, 1436 children), among whom 24.7% (95% CI: 23.6-25.9) were classified as obese. Of obese participants, 12.8% (95% CI: 11.1-14.8) reported ILI compared to 11.8% (95% CI: 10.8-12.8) of non-obese participants. The adjusted OR for ILI associated with obesity was 1.16 (95% CI: 0.98-1.38, P=.093). For adults and children, the adjusted ORs were 1.16 (95% CI: 0.97-1.38, P=.101) and 1.26 (95% CI: 0.72-2.21, P=.422), respectively. CONCLUSION: Household survey data showed no evidence that obesity was associated with an increase in self-reported ILI during the 2009 H1N1 influenza pandemic in England. Further studies using active prospective ILI surveillance combined with laboratory reporting would reduce bias and improve accuracy of outcome measurements. PMID- 27480327 TI - Selective directed self-assembly of coexisting morphologies using block copolymer blends. AB - Directed self-assembly (DSA) of block copolymers is an emergent technique for nano-lithography, but is limited in the range of structures possible in a single fabrication step. Here we expand on traditional DSA chemical patterning. A blend of lamellar- and cylinder-forming block copolymers assembles on specially designed surface chemical line gratings, leading to the simultaneous formation of coexisting ordered morphologies in separate areas of the substrate. The competing energetics of polymer chain distortions and chemical mismatch with the substrate grating bias the system towards either line/space or dot array patterns, depending on the pitch and linewidth of the prepattern. This is in contrast to the typical DSA, wherein assembly of a single-component block copolymer on chemical templates generates patterns of either lines/spaces (lamellar) or hexagonal dot arrays (cylinders). In our approach, the chemical template encodes desired local spatial arrangements of coexisting design motifs, self-assembled from a single, sophisticated resist. PMID- 27480325 TI - Defining the Epidemiology and Burden of Severe Respiratory Syncytial Virus Infection Among Infants and Children in Western Countries. AB - INTRODUCTION: The REGAL (RSV [respiratory syncytial virus] Evidence-a Geographical Archive of the Literature) series provides a comprehensive review of the published evidence in the field of RSV in Western countries over the last 20 years. This first of seven publications covers the epidemiology and burden of RSV infection. METHODS: A systematic review was undertaken for articles published between Jan 1, 1995 and Dec 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov. Studies reporting data for hospital visits/admissions for RSV infection among children (<=18 years of age), as well as studies reporting RSV-associated morbidity, mortality, and risk factors were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. RESULT: 2315 studies were identified of which 98 were included. RSV was associated with 12-63% of all acute respiratory infections (ARIs) and 19-81% of all viral ARIs causing hospitalizations in children (high SOE). Annual RSV hospitalization (RSVH) rates increased with decreasing age and varied by a factor of 2-3 across seasons (high SOE). Studies were conflicting on whether the incidence of RSVH has increased, decreased, or remained stable over the last 20 years (moderate SOE). Length of hospital stay ranged from 2 to 11 days, with 2 12% of cases requiring intensive care unit admission (moderate SOE). Case fatality rates were <0.5% (moderate SOE). Risk factors associated with RSVH included: male sex; age <6 months; birth during the first half of the RSV season; crowding/siblings; and day-care exposure (high SOE). CONCLUSION: RSV infection remains a major burden on Western healthcare systems and has been associated with significant morbidity. Further studies focusing on the epidemiology of RSV infection (particularly in the outpatient setting), the impact of co-infection, better estimates of case-fatality rates and associated risk factors (all currently moderate/low SOE) are needed to determine the true burden of disease. FUNDING: Abbvie. PMID- 27480329 TI - [Onychomadesis and hand-foot-mouth disease]. PMID- 27480330 TI - [Traditional tattoos among the Lu people of RDP Lao]. PMID- 27480328 TI - Elastic, silk-cardiac extracellular matrix hydrogels exhibit time-dependent stiffening that modulates cardiac fibroblast response. AB - Heart failure is the leading cause of death in the United States and rapidly becoming the leading cause of death worldwide. While pharmacological treatments can reduce progression to heart failure following myocardial infarction, there still exists a need for new therapies that promote better healing postinjury for a more functional cardiac repair and methods to understand how the changes to tissue mechanical properties influence cell phenotype and function following injury. To address this need, we have optimized a silk-based hydrogel platform containing cardiac tissue-derived extracellular matrix (cECM). These silk-cECM hydrogels have tunable mechanical properties, as well as rate-controllable hydrogel stiffening over time. In vitro, silk-cECM scaffolds led to enhanced cardiac fibroblast (CF) cell growth and viability with culture time. cECM incorporation improved expression of integrin an focal adhesion proteins, suggesting that CFs were able to interact with the cECM in the hydrogel. Subcutaneous injection of silk hydrogels in rats demonstrated that addition of the cECM led to endogenous cell infiltration and promoted endothelial cell ingrowth after 4 weeks in vivo. This naturally derived silk fibroin platform is applicable to the development of more physiologically relevant constructs that replicate healthy and diseased tissue in vitro and has the potential to be used as an injectable therapeutic for cardiac repair. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3058-3072, 2016. PMID- 27480331 TI - The photophysics of phenylenevinylene oligomers and self-absorption of their fluorescence in polymer films. AB - The fluorescence spectra, quantum yields and lifetimes of a series of alkoxy substituted phenylenevinylene molecules, which serve as short chain oligomer models for poly(p-phenylenevinylene), have been determined in fluid solvents and in a high viscosity polymer matrix. The effects of solvent polarity and a high viscosity molecular environment on the fluorescence yields and spectral shapes have been established. Alkoxy group substitution on the phenyl ring moieties of the molecules has an important effect on the vibronic structures and profiles of the absorption spectra. This was interpreted in terms of hot-band, ground to excited singlet state transitions from energetically closely-spaced torsional vibrational levels of the vinylene double bond in the ground state. The shapes of the absorption bands affect the overlaps of the absorption and fluorescence spectra. This has been quantified as the probability of fluorescence reabsorption in solid polymer films as a function of pathlength. This is an important determinant of the efficacies of these compounds for "harvesting" solar energy in luminescent solar concentrator systems. The reabsorption probabilities of these compounds are lower for all pathlengths than those determined in the same polymer film for the fluorophores, perylene and perylene diimide, which have been considered for concentrating spatially diffuse sunlight. PMID- 27480333 TI - In Memoriam: William E. Harmon, MD 1943-2016. PMID- 27480332 TI - Generalized estimation of the ventilatory distribution from the multiple-breath nitrogen washout. AB - BACKGROUND: This work presents a generalized technique to estimate pulmonary ventilation-to-volume (v/V) distributions using the multiple-breath nitrogen washout, in which both tidal volume (V T ) and the end-expiratory lung volume (EELV) are allowed to vary during the maneuver. In addition, the volume of the series dead space (v d ), unlike the classical model, is considered a common series unit connected to a set of parallel alveolar units. METHODS: The numerical solution for simulated data, either error-free or with the N2 measurement contaminated with the addition of Gaussian random noise of 3 or 5 % standard deviation was tested under several conditions in a computational model constituted by 50 alveolar units with unimodal and bimodal distributions of v/V. Non-negative least squares regression with Tikhonov regularization was employed for parameter retrieval. The solution was obtained with either unconstrained or constrained (V T , EELV and v d ) conditions. The Tikhonov gain was fixed or estimated and a weighting matrix (WM) was considered. The quality of estimation was evaluated by the sum of the squared errors (SSE) (between reference and recovered distributions) and by the deviations of the first three moments calculated for both distributions. Additionally, a shape classification method was tested to identify the solution as unimodal or bimodal, by counting the number of shape agreements after 1000 repetitions. RESULTS: The accuracy of the results showed a high dependence on the noise amplitude. The best algorithm for SSE and moments included the constrained and the WM solvers, whereas shape agreement improved without WM, resulting in 97.2 % for unimodal and 90.0 % for bimodal distributions in the highest noise condition. CONCLUSIONS: In conclusion this generalized method was able to identify v/V distributions from a lung model with a common series dead space even with variable V T . Although limitations remain in presence of experimental noise, appropriate combination of processing steps were also found to reduce estimation errors. PMID- 27480336 TI - Multiple intraretinal cilia following spring coil injury. PMID- 27480337 TI - Elemental composition, distribution and control of biogenic silica in the anthropogenically disturbed and pristine zone inter-tidal sediments of Indian Sundarbans mangrove-estuarine complex. AB - Spatial distribution and interrelationship among organic nutrients - silica and carbon - and various lithogenic elements were investigated in the surficial sediments of Matla estuary and Core Zone of Indian Sundarbans Reserve Forest using spatial analysis and multivariate statistics. Biogenic silica (BSi), an important parameter for coastal biogeochemisry, was measured using Si-time alkaline leaching method. BSi concentration ranged from 0.01% to 0.85% with higher concentrations in upstream region of Matla estuary and attenuated values towards the bay, seemingly due to changes in hydrodynamics and land use conditions. Spatial distribution of BSi did not exhibit significant correlation with sediment parameters of organic carbon (OC), elemental composition and clay content. However, it showed significant contrasting trends with total phosphorus (TP) and total silica of human influenced Matla estuary sediments as well as the dissolved silica (DSi) of its surface waters. Anthropogenic influence on sediment geochemistry is discernable with the presence of higher concentrations of organic and inorganic elements in Matla estuary than in Core Zone sediments. Spatial variation trends are often challenging to interpret due to multiple sources of input, varying energy and salinity conditions and constant physical, chemical and biological alterations occurring in the environment. Nonetheless, it is certain that anthropogenic activities have a substantial influence on biogeochemical processes of Sundarbans mangrove-estuarine complex and potentially the coastal ocean. PMID- 27480335 TI - Activation of toxoplasma retinochoroiditis during pregnancy and evaluation of ocular findings in newborns. AB - The purpose of this study was to evaluate patients with activation of toxoplasma retinochoroiditis during pregnancy and ocular findings in newborns. A total of 17 pregnant patients who were clinically and serologically diagnosed with ocular toxoplasmosis were retrospectively reviewed. After birth, ocular findings for all infants were recorded. The mean age of the patients was 29.08 +/- 5.71 years. In all cases, activation was present in only one eye. In 13 cases, anterior uveitis was associated with posterior uveitis. Visual acuity in all cases prior to treatment was 0.3 +/- 0.21 and increased to 0.55 +/- 0.29 after treatment. The mean gestational age of the patients was 19.76 +/- 8.71 weeks at the time of hospital admission. No case of toxoplasmic ocular involvement was identified in the infants on postnatal examination. In the case of toxoplasma retinochoroiditis during pregnancy, appropriate treatment and follow-up is very important to protect the newborns and to prevent impaired vision in mothers. PMID- 27480338 TI - Optimization of thermoreversible poloxamer gel system using QbD principle. AB - The objective of this study was to optimize thermoreversible gel formulations with respect to their gelation temperature and solubilizing capacity, using quality by design (QbD) principles based on design of experiment (DoE). Independent variables, X1, X2 and X3, represent the weight percentages of poloxamer 407 (P407), poloxamer 188 (P188) and the polyethylene glycol 400, respectively (these polymers are either thermoreversible gelling agents or solubilizers). Emodin, a poorly water-soluble compound, was used as a model drug. Fifteen gel formulations were prepared based on the compositions generated by an extreme vertices type of mixture design using a DoE software, in which their gelation temperatures (Y1) and emodin solubility (Y2) were measured. The gelation temperature and emodin solubility were each described adequately using a full cubic model and a quadratic model, respectively. Theoretical and experimental responses showed linearity with R2=0.9943 for the gelation temperature and R2=0.9629 for emodin solubility. The design space was established from the models describing the gelation temperature (test accuracy: 104.5%) and emodin solubility (test accuracy: 96.6%). This study demonstrates successful application of DoE for prediction of gelation temperature and solubility of emodin thermoreversible poloxamer gel (PG). In conclusion, the present DoE approach has led to the establishment of a design space and manufacturing control strategy for gel formulations. PMID- 27480339 TI - Optimal treatment regimes for survival endpoints using a locally-efficient doubly robust estimator from a classification perspective. AB - A treatment regime at a single decision point is a rule that assigns a treatment, among the available options, to a patient based on the patient's baseline characteristics. The value of a treatment regime is the average outcome of a population of patients if they were all treated in accordance to the treatment regime, where large values are desirable. The optimal treatment regime is a regime which results in the greatest value. Typically, the optimal treatment regime is estimated by positing a regression relationship for the outcome of interest as a function of treatment and baseline characteristics. However, this can lead to suboptimal treatment regimes when the regression model is misspecified. We instead consider value search estimators for the optimal treatment regime where we directly estimate the value for any treatment regime and then maximize this estimator over a class of regimes. For many studies the primary outcome of interest is survival time which is often censored. We derive a locally efficient, doubly robust, augmented inverse probability weighted complete case estimator for the value function with censored survival data and study the large sample properties of this estimator. The optimization is realized from a weighted classification perspective that allows us to use available off the shelf software. In some studies one treatment may have greater toxicity or side effects, thus we also consider estimating a quality adjusted optimal treatment regime that allows a patient to trade some additional risk of death in order to avoid the more invasive treatment. PMID- 27480340 TI - Cyclooxygenase-2 (COX-2) inhibition for prostate cancer chemoprevention: double blind randomised study of pre-prostatectomy celecoxib or placebo. AB - OBJECTIVE: To evaluate the biological effects of selective cyclooxygenase-2 inhibition on prostate tissue in patients undergoing radical prostatectomy (RP). PATIENTS AND METHODS: Patients with localised prostate cancer were randomised to receive either celecoxib 400 mg twice daily or placebo for 4 weeks before RP. Specimens were analysed for levels of apoptosis, prostaglandins, and androgen receptor (AR). Effects on serum prostate-specific antigen (PSA) and postoperative opioid use were also measured. RESULTS: In all, 28 of 44 anticipated patients enrolled and completed treatment. One patient in the celecoxib arm had a myocardial infarction postoperatively. For this reason, and safety concerns in other studies, enrolment was halted. The apoptosis index (AI) in tumour cells was 0.29% [95% confidence interval (CI) 0.11-0.47%] vs 0.39% (95% CI 0.00-0.84%) in the celecoxib and placebo arms, respectively (P = 0.68). The AI in benign cells was 0.18% (95% CI 0.03-0.32%) vs 0.13% (95% CI 0.00-0.28%) in the celecoxib and placebo arms, respectively (P = 0.67). Prostaglandin E2 and AR levels were similar in cancerous and benign tissues when comparing the two arms. The median baseline PSA level was 6.0 and 6.2 ng/mL for the celecoxib and placebo groups, respectively, and did not significantly change after celecoxib treatment. There was no difference in postoperative opiate usage between arms. CONCLUSION: Celecoxib had no effect on apoptosis, prostaglandins or AR levels in cancerous or benign prostate tissues. These findings coupled with drug safety concerns should serve to limit interest in these selective drugs as chemopreventive agents. PMID- 27480341 TI - Acclimation settings with identical or similar sensation and functional thresholds. AB - Hypoglossal nerve stimulation with an activated implanted device does not awaken individuals from sleep once they have acclimated to the new sensation of the resulting tongue movement. This case report illustrates the importance of an acclimation period, allowing a patient to become accustomed to stimulation settings below the level at which there is gross tongue movement. Laryngoscope, 126:S20-S21, 2016. PMID- 27480342 TI - Microcarrier-based platforms for in vitro expansion and differentiation of human pluripotent stem cells in bioreactor culture systems. AB - Human pluripotent stem cells (hPSC) have attracted a great attention as an unlimited source of cells for cell therapies and other in vitro biomedical applications such as drug screening, toxicology assays and disease modeling. The implementation of scalable culture platforms for the large-scale production of hPSC and their derivatives is mandatory to fulfill the requirement of obtaining large numbers of cells for these applications. Microcarrier technology has been emerging as an effective approach for the large scale ex vivo hPSC expansion and differentiation. This review presents recent achievements in hPSC microcarrier based culture systems and discusses the crucial aspects that influence the performance of these culture platforms. Recent progress includes addressing chemically-defined culture conditions for manufacturing of hPSC and their derivatives, with the development of xeno-free media and microcarrier coatings to meet good manufacturing practice (GMP) quality requirements. Finally, examples of integrated platforms including hPSC expansion and directed differentiation to specific lineages are also presented in this review. PMID- 27480343 TI - Development of a new method for d-xylose detection and quantification in urine, based on the use of recombinant xylose dehydrogenase from Caulobacter crescentus. AB - The gene xylB from Caulobacter crescentus has been cloned and expressed in Escherichia coli providing a high yield of xylose dehydrogenase (XylB) production and excellent purity (97%). Purified recombinant XylB showed an absolute dependence on the cofactor NAD(+) and a strong preference for d-xylose against other assayed mono and disaccharides. Additionally, XylB showed strong stability when stored as freeze-dried powder at least 250days both at 4 degrees C and room temperature. In addition, more than 80% of the initial activity of rehydrated freeze-dried enzyme remained after 150days of incubation at 4 degrees C. Based on these characteristics, the capability of XylB in d-xylose detection and quantification was studied. The linearity of the method was maintained up to concentrations of d-xylose of 10mg/dL and the calculated limits of detection (LoD) and quantification (LoQ) of xylose in buffer were 0.568mg/dL and 1.89mg/dL respectively. Thus, enzymatic detection was found to be an excellent method for quantification of d-xylose in both buffer and urine samples. This method can easily be incorporated in a new test for the diagnosis of hypolactasia through the measurement of intestinal lactase activity. PMID- 27480344 TI - Complete genome sequence of Lactobacillus plantarum LZ227, a potential probiotic strain producing B-group vitamins. AB - B-group vitamins play an important role in human metabolism, whose deficiencies are associated with a variety of disorders and diseases. Certain microorganisms such as Lactic acid bacteria (LAB) have been shown to have capacities for B-group vitamin production and thus could potentially replace chemically synthesized vitamins for food fortification. A potential probiotic strain named Lactobacillus plantarum LZ227, which was isolated from raw cow milk in this study, exhibits the ability to produce B-group vitamins. Complete genome sequencing of LZ227 was performed to gain insights into the genetic elements involved in B-group vitamin production. The genome of LZ227 contains a circular 3,131,750-bp chromosome, three circular plasmids and two predicted linear plasmids. LZ227 also contains gene clusters for biosynthesis of both riboflavin and folate. This genome sequence provides a basis for further elucidation of its molecular genetics and probiotic functions, and will facilitate its applications as starter cultures in food industry. PMID- 27480345 TI - Heritability of Batrachochytrium dendrobatidis burden and its genetic correlation with development time in a population of Common toad (Bufo spinosus). AB - Despite the important threat that emerging pathogens pose for the conservation of biodiversity as well as human health, very little is known about the adaptive potential of host species to withstand infections. We studied the quantitative genetic architecture responsible for the burden of the fungal pathogen Batrachochytrium dendrobatidis in a population of common toads in conjunction with other life-history traits (i.e., body size and development rate) that may be affected by common selective pressures. We found a significant heritable component that is associated with fungal burden, which may allow for local adaptation to this pathogen to proceed. In addition, the high genetic correlation found between fungal burden and development time suggests that both traits have to be taken into account in order to assess the adaptive response of host populations to this emerging pathogen. PMID- 27480346 TI - Nanoforging Single Layer MoSe2 Through Defect Engineering with Focused Helium Ion Beams. AB - Development of devices and structures based on the layered 2D materials critically hinges on the capability to induce, control, and tailor the electronic, transport, and optoelectronic properties via defect engineering, much like doping strategies have enabled semiconductor electronics and forging enabled introduction the of iron age. Here, we demonstrate the use of a scanning helium ion microscope (HIM) for tailoring the functionality of single layer MoSe2 locally, and decipher associated mechanisms at the atomic level. We demonstrate He(+) beam bombardment that locally creates vacancies, shifts the Fermi energy landscape and increases the Young's modulus of elasticity. Furthermore, we observe for the first time, an increase in the B-exciton photoluminescence signal from the nanoforged regions at the room temperature. The approach for precise defect engineering demonstrated here opens opportunities for creating functional 2D optoelectronic devices with a wide range of customizable properties that include operating in the visible region. PMID- 27480347 TI - Lingual Abscess in the Setting of Recent Periodontal Antibiotic Injections. AB - BACKGROUND: Lingual abscess is a rare clinical entity, with posterior involvement being much less common than anterior involvement. Typical inciting events include trauma or direct inoculation to the area. The clinical diagnosis can be difficult, and early imaging and specialist consultation should be pursued to make a definitive diagnosis and to prevent patient deterioration. CASE REPORT: We present a case of posterior lingual abscess in a 62-year-old man after he received antibiotic injections to the lower molars for periodontal disease. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Lingual abscess is a rare condition that is difficult to diagnose clinically. Misdiagnosis or delayed diagnosis can lead to acute airway compromise and increased morbidity. PMID- 27480348 TI - Safely Managing Acute Osteoarthritis in the Emergency Department: An Evidence Based Review. AB - BACKGROUND: Joint pain caused by acute osteoarthritis (OA) is a common finding in the emergency department. Patients with OA often have debilitating pain that limits their function and ability to complete their activities of daily living. In addition, OA has been associated with a high percentage of arthritis-related hospital admissions and an increased risk of all-cause mortality. Safely managing OA symptoms in these patients can present many challenges to the emergency provider. OBJECTIVES: We review the risks and benefits of available treatment options for acute OA-related pain in the emergency department. In addition, evidence-based recommendations will be made for safely managing pain and disability associated with OA in patients with comorbidities, including cardiovascular disease, renal insufficiency, and risk factors for gastrointestinal bleeding. DISCUSSION: Commonly used treatments for OA include acetaminophen, oral nonsteroidal anti-inflammatory drugs, and opioids, each with varying degrees of efficacy and risk depending on the patient's underlying comorbidities. Effective alternative therapies, such as topical preparations, intra-articular corticosteroid injections, bracing, and rehabilitation are likely underused in this setting. CONCLUSIONS: Emergency providers should be aware of the risks and benefits of all treatment options available for acute OA pain, including oral medications, topical preparations, corticosteroid injections, bracing, and physical therapy. PMID- 27480349 TI - Pyuria and Urine Cultures in Patients with Acute Renal Colic. AB - BACKGROUND: Renal colic caused by stone(s) is common in the emergency department. Often, urinalysis reveals white blood cells, but it is unknown how frequently pyuria is sterile or infectious. OBJECTIVES: We sought to determine the incidence of pyuria in patients with renal colic and to correlate the incidence with a positive urine culture. METHODS: A 1-year retrospective review of adult patients with renal colic presenting to three community emergency departments was performed. Patients without confirmed renal stone(s) or completed urinalysis were excluded. Hematuria is defined as >=5 red blood cells per high power field (RBC/HPF) and pyuria as >10 white blood cells per high power field (WBC/HPF). A positive urine culture is defined as >100,000 colony forming units per milliliter. Student's t-test, chi square, or Fisher's exact tests were performed as appropriate, with significance set at 0.05. RESULTS: There were 339 patients who satisfied the inclusion and exclusion criteria, and 14.2% of these patients had associated pyuria. There were 153 (45.1%) urine cultures performed, and 16 (10.5%) were positive. Patients with pyuria were more likely to have a positive urine culture (36.4% vs. 3.3%, respectively; p < 0.001). The percentage of positive urine cultures increased (p < 0.001) with increasing pyuria from 9.1% (10-20 WBC/HPF) to 60.0% (>50 WBC/HPF). Positive cultures also increased (p < 0.001) with increased leukocyte esterase observed on macroscopic samples, from 1.6% (small or less leukocyte esterase) to 77.8% (large-volume leukocyte esterase). CONCLUSION: Pyuria was found in 14.2% of patients with renal colic. Patients with pyuria had 36.4% positive cultures compared to 3.3% of patients without pyuria. The degree of pyuria or leukocyte esterase was significantly associated with the risk of a positive culture. Urine cultures are recommended for all patients with renal colic and pyuria. PMID- 27480350 TI - Gas-Forming Iliopsoas Abscess: A Klebsiella Pneumoniae-Mediated Invasive Syndrome. PMID- 27480351 TI - Bilateral Quadriceps Femoris Tendon Rupture in a Patient With Chronic Renal Insufficiency: A Case Report. AB - BACKGROUND: Simultaneous bilateral quadriceps femoris tendon rupture is a relatively rare occurrence. As such, patients frequently experience a delay in receiving an accurate diagnosis. It is often associated with significant morbidity and loss of function. We report a case of simultaneous bilateral quadriceps tendon ruptures in a patient with chronic renal insufficiency. CASE REPORT: A 46-year-old white man presented to the Emergency Department (ED) via ambulance, reporting sudden onset of bilateral lower limb weakness. He had a medical history of renal insufficiency due to immunoglobulin-A-induced glomerulopathy, with secondary hyperparathyroidism and gout. Examination of his lower limbs revealed significant swelling in his distal thighs anteriorly and suprapatellar defects at the insertion of the quadriceps tendon. No other palpable deficits were identified. The patella was in a normal position and there was minimal tenderness on palpation. He had complete loss of active knee extension. Bilateral patella reflexes were absent. Lower-limb sensation was intact bilaterally and no other neurovascular deficits were elicited. Thompson test was negative and the rest of the clinical examination was unremarkable. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The inability to walk is a common ED presentation. The differential diagnosis is vast and includes but is not limited to: spinal cord injury, Guillain-Barre syndrome, myopathies, and even malingering. This case report details an uncommon cause for a common ED presentation. Furthermore, this case illustrates the importance of a detailed clinical history and physical examination, which narrowed the differential diagnosis and ultimately led to the clinical diagnosis. Knowledge of the patient's past medical history combined with simple imaging modalities permitted a prompt clinical diagnosis of an uncommon condition, which facilitated early operative management. PMID- 27480352 TI - Endotracheal Intubation for Toxicologic Exposures: A Retrospective Review of Toxicology Investigators Consortium (ToxIC) Cases. AB - BACKGROUND: Endotracheal intubation remains a cornerstone of early resuscitation of the poisoned patient, but little is known about which substances are associated with intubation. OBJECTIVES: Our objective was to describe patient exposures to substances reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC) that were managed with intubation between 2010 and 2014. METHODS: We performed a retrospective review of cases managed with endotracheal intubation in the ACMT ToxIC Registry from January 1, 2010 through December 31, 2014. Descriptive statistics were used to describe patient exposures. RESULTS: A total of 2724 exposures to substances were managed with endotracheal intubation. Intubated patients were 52% male and 82% adults. For all ages taken together, the most common known single-substance exposures managed with intubation were sedative hypnotics (9.8%), antidepressants (8.7%), and opioids (8.0%). The most common single ingestions associated with intubation in various age groups were: opioids (<2 years old), alpha-2 agonists (2-6 years old), antidepressants (7-18 years old), sedative-hypnotics (19-65 years old), and cardiac medications (>65 years old). Multiple substances were involved in 29.0% of exposures. Decontamination and elimination processes were used in 12.8% of patients. CONCLUSIONS: The most common substances involved in single- and multiple-substance exposures managed with intubation varied by age group. Most patients were managed with supportive care. Knowledge of substances commonly involved in exposures managed with intubation may inform triage and resource planning in the emergency department resuscitation of critically ill poisoned patients. PMID- 27480353 TI - Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy. AB - Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation. PMID- 27480355 TI - Prognostic Significance of Tumor Necrosis in Hilar Cholangiocarcinoma. AB - BACKGROUND: Tumor necrosis and peritumoral fibrosis have both been suggested to have a prognostic value in selected solid tumors. However, little is known regarding their influence on tumor progression and prognosis in hilar cholangiocarcinoma (HC). METHODS: Surgically resected tumor specimens of HC (n = 47) were analyzed for formation of necrosis and extent of peritumoral fibrosis. Tumor necrosis and grade of fibrosis were assessed histologically and correlated with clinicopathological characteristics, tumor recurrence, and patients' survival. Univariate Kaplan-Meier analysis and a stepwise multivariable Cox regression model were applied. RESULTS: Mild peritumoral fibrosis was evident in 12 tumor samples, moderate peritumoral fibrosis in 20, and high-grade fibrosis in 15. Necrosis was evident in 19 of 47 tumor samples. Patients with tumors characterized by necrosis showed a significantly decreased 5-year recurrence-free survival (37.9 vs. 25.7 %; p < .05) and a significantly decreased 5-year overall survival (42.6 vs. 12.4 %; p < .05), when compared with patients with tumors showing no necrosis. R status, tumor recurrence, and tumor necrosis were of prognostic value in the univariate analysis (all p < .05). Multivariate survival analysis confirmed tumor necrosis (p = .038) as the only independent prognostic variable. CONCLUSIONS: The assessment of tumor necrosis appears as a valuable additional prognostic tool in routine histopathological evaluation of HC. These observations might have implications for monitoring and more individualized multimodal therapeutic strategies. PMID- 27480356 TI - Outcome of Melanoma Patients Who Did Not Proceed to Sentinel Node Biopsy After Preoperative Lymphoscintigraphy. AB - BACKGROUND: At our institution, a planned sentinel node biopsy (SNB) procedure is occasionally canceled after preoperative lymphoscintigraphy. This study reports the frequency of this, the reasons, and the management and outcomes of these patients. METHODS: All patients with clinically localized cutaneous melanoma treated at Melanoma Institute Australia between 2000 and 2009 whose planned SNB procedure was not undertaken after lymphoscintigraphy were included in this retrospective study. RESULTS: Of the 3148 patients in whom the procedure had been planned, 203 patients (6.4 %) did not have a SNB. The main reason for not proceeding with SNB (in 84 % of cases) was the lymphoscintigraphic demonstration of multiple drainage fields and/or multiple sentinel nodes (SNs). Patients who did not proceed to SNB were significantly older than those who did, more often had melanomas of the head or neck, and had more SNs and more nodal drainage fields. Of the 203 patients, 181 (89 %) were followed with high-resolution ultrasound of their SNs, which identified 33 % of the nodal recurrences before they were clinically apparent. Patients whose SNB was canceled had significantly worse recurrence-free survival and regional node disease-free survival, but melanoma-specific survival was similar. Compared to SN-positive patients, node positive patients without SNB had significantly more involved nodes when a delayed lymphadenectomy was performed, but melanoma-specific survival was not significantly different after a median follow-up of 42 months. CONCLUSIONS: Lymphoscintigraphy with ultrasound follow-up of previously identified SNs is an acceptable management strategy for patients in whom a SNB procedure is likely to be challenging. PMID- 27480354 TI - Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group. AB - INTRODUCTION: Retroperitoneal soft tissue sarcomas (RPS) are rare tumors. Surgery is the mainstay of curative therapy, but local recurrence is common. No recommendations concerning the best management of recurring disease have been developed so far. Although every effort should be made to optimize the initial approach, recommendations to treat recurring RPS will be helpful to maximize disease control at recurrence. METHODS: An RPS transatlantic working group was established in 2013. The goals of the group were to share institutional experiences, build large multi-institutional case series, and develop consensus documents on the approach to this difficult disease. The outcome of this document applies to recurrent RPS that is nonvisceral in origin. Included are sarcomas of major veins, undifferentiated pleomorphic sarcoma of psoas, ureteric leiomyosarcoma (LMS). Excluded are desmoids-type fibromatosis, angiomyolipoma, gastrointestinal stromal tumors, sarcomas arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma. RESULTS: Recurrent RPS management was evaluated from diagnosis to follow-up. It is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, but some patients may experience prolonged disease control also at recurrence, when the approach is optimized and follows the recommendations contained herein. CONCLUSIONS: International collaboration is critical for adding to the present knowledge. A transatlantic prospective registry has been established. PMID- 27480357 TI - Tailoring Surgical Therapy for Extremity Soft Tissue Sarcoma. PMID- 27480358 TI - ypN0: Does It Matter How You Get There? Nodal Downstaging in Esophageal Cancer. AB - BACKGROUND: ypN0 following induction treatment for advanced esophageal cancer improves survival. Importance of how ypN0 is achieved is unknown. This study evaluates survival in "natural" N0 (cN0/ypN0) and "downstaged" N0 (cN+/ypN0) patients. METHODS: Among patients treated with induction treatment and surgery, 83 CT scans were retrieved in digital format and re-evaluated by a radiologist, blinded to pathological nodal status: 28 natural N0, 37 downstaged N0, and 18 ypN+. Impact of N0 classification on survival and associations with survival were identified. RESULTS: Survival varied with ypN: 3-year survival was 84 % for natural N0 patients, 59 % for downstaged N0, and 20 % for ypN+ (p < .001). Compared with natural N0 patients, risk of cancer mortality was 3.8 for downstaged N0 and 7.6 for ypN+ (p = .01). Survival was also stratified by ypT: compared with ypT0 natural N0, who had the best survival, intermediate survival was seen in ypT+ natural N0 [hazard ratio (HR), 1.3] and ypT0 downstaged N0 (HR, 1.8), and poor survival in ypT+ downstaged N0 (HR, 9.5) and ypN+ (HR, 12.0) (p = .026). CONCLUSIONS: Natural N0 and downstaged N0 patients are different clinical entities: downstaging cN+ with induction treatment producing downstaged N0 improves survival only if there is concomitant primary cancer downstaging to ypT0. Intermediate survival is seen in downstaged N0 patients with complete tumor response. Natural N0 patients experience intermediate survival with incomplete response (ypT+). Complete response in natural N0 patients produces the best survival. Means of obtaining ypN0 status matters and requires a complete response for downstaged N0 patients to benefit from induction treatment. PMID- 27480359 TI - Influence of electrode positioning on accuracy and reproducibility of electrical velocimetry cardiac output measurements. AB - Electrical velocimetry (EV) is one of the most recent adaptions of impedance cardiography. Previous studies yielded diverging results identifying several factors negatively influencing accuracy. Although electrode arrangement is suspected to be an influencing factor for impedance cardiography in general, no data for EV is available. We aimed to prospectively assess the influence of electrode position on the accuracy and reproducibility of cardiac output (CO) measurements obtained by EV. Two pairs of standard electrocardiographic electrodes were placed at predefined positions of the thorax in 81 patients. The inter-electrode gap was varied between either 5 or 15 cm by caudal movement of the lowest electrode. Measurements were averaged over 20 s and performed twice at each electrode position. Reference values were determined using cardiac magnetic resonance imaging (CMR). Mean bias was 1.2 +/- 1.6 l min(-1) (percentage error 22 +/- 28%) between COCMR and COEV at the 5 cm gap significantly improving to 0.5 +/- 1.6 l min(-1) (8 +/- 28%) when increasing the gap (p < 0.0001). The mean difference between repeated measurements was 0.0 +/- 0.3 l min(-1) for the 5 cm and 0.1 +/- 0.3 l min(-1) for the 15 cm gap, respectively (p = 0.3). The accuracy of EV can be significantly improved when increasing the lower inter electrode gap still exceeding the Critchley and Critchley recommendations. Therefore, absolute values should not be used interchangeably in clinical routine. As the reproducibility was not negatively affected, serial hemodynamic measurements can be reliably acquired in stable patients when the electrode position remains unchanged. PMID- 27480360 TI - Dynamics of early stem cell recruitment in skin flaps subjected to ischemia reperfusion injury. AB - OBJECTIVE: Bone marrow-derived stromal cell (BMSCs) therapy improves survival of skin flaps subject to ischemia/reperfusion (I/R) injury. However, very little is known about the trafficking and distribution of BMSCs in post-ischemic skin tissue following intravenous administration. The aim of this study was to assess the behavior of BMSCs in post-ischemic skin flaps and to compare the magnitude and kinetics of accumulation of BMSCs and leukocytes following I/R. METHODS: Cutaneous flaps perfused by the inferior epigastric vessels were created in C57Bl6 mice. The flaps were subjected to 3.5h of ischemia followed by reperfusion. Wound healing and vascular perfusion were assessed in 3 groups of mice (sham, I/R, and I/R+BMSCs treatment) on days 3, 5, 7 and 14 post reperfusion. The kinetics and magnitude of BMSCs and leukocyte recruitment were quantified in additional 2 groups (Sham and I/R) after I/R using intravital fluorescence microscopy at 2 and 4h after the intravenous injection of fluorescently labeled BMSCs. RESULTS: Wound healing after I/R was significantly enhanced in skin flaps of mice treated with BMSCs, compared to controls. The rolling velocity of BMSCs was higher compared to leukocytes both in control mice (32.4+/-3.7MUm/s vs 24.0+/-2.2MUm/s, p<0.05) and in I/R mice (34.6+/-3.8MUm/s vs 20.2+/-2.3MUm/s, p<0.005). However, the rolling velocity of both cell populations was not altered by I/R. The firm adhesion and transendothelial migration of BMSCs did not differ from the values detected for leukocytes for both control and I/R mice. CONCLUSIONS: The magnitude and kinetics of BMSCs recruitment in skin flaps subjected to I/R are not significantly different from the responses noted for leukocytes, suggesting that similar mechanisms may be involved in the recruitment of both cell populations following I/R. PMID- 27480361 TI - Contents: Macromol. Rapid Commun. 15/2016. PMID- 27480362 TI - Polysiloxane-Based Autonomic Self-Healing Elastomers Obtained Through Dynamic Boronic Ester Bonds Prepared by Thiol-Ene "Click" Chemistry. PMID- 27480364 TI - Cystic malignant myoepithelioma of the mons pubis. PMID- 27480365 TI - Persistent Parasitism: The Adaptive Biology of Malariae and Ovale Malaria. AB - Plasmodium malariae causes malaria in humans throughout the tropics and subtropics. Plasmodium ovale curtisi and Plasmodium ovale wallikeri are sympatric sibling species common in sub-Saharan Africa and also found in Oceania and Asia. Although rarely identified as the cause of malaria cases in endemic countries, PCR detection has confirmed all three parasite species to be more prevalent, and persistent, than previously thought. Chronic, low-density, multispecies asymptomatic infection is a successful biological adaptation by these Plasmodium spp., a pattern also observed among malaria parasites of wild primates. Current whole-genome analyses are illuminating the species barrier separating the ovale parasite species and reveal substantial expansion of subtelomeric gene families. The evidence for and against a quiescent pre-erythrocytic form of P. malariae is reviewed. PMID- 27480366 TI - Reply. PMID- 27480367 TI - The role of administrative data in the big data revolution in social science research. AB - The term big data is currently a buzzword in social science, however its precise meaning is ambiguous. In this paper we focus on administrative data which is a distinctive form of big data. Exciting new opportunities for social science research will be afforded by new administrative data resources, but these are currently under appreciated by the research community. The central aim of this paper is to discuss the challenges associated with administrative data. We emphasise that it is critical for researchers to carefully consider how administrative data has been produced. We conclude that administrative datasets have the potential to contribute to the development of high-quality and impactful social science research, and should not be overlooked in the emerging field of big data. PMID- 27480369 TI - Liking and hyperlinking: Community detection in online child sexual exploitation networks. AB - The online sexual exploitation of children is facilitated by websites that form virtual communities, via hyperlinks, to distribute images, videos, and other material. However, how these communities form, are structured, and evolve over time is unknown. Collected using a custom-designed webcrawler, we begin from known child sexual exploitation (CE) seed websites and follow hyperlinks to connected, related, websites. Using a repeated measure design we analyze 10 networks of 300 + websites each - over 4.8 million unique webpages in total, over a period of 60 weeks. Community detection techniques reveal that CE-related networks were dominated by two large communities hosting varied material -not necessarily matching the seed website. Community stability, over 60 weeks, varied across networks. Reciprocity in hyperlinking between community members was substantially higher than within the full network, however, websites were not more likely to connect to homogeneous-content websites. PMID- 27480370 TI - Economic performance and public concerns about social class in twentieth-century books. AB - What is the association between macroeconomic conditions and public perceptions of social class? Applying a novel approach based on the Google Books N-gram corpus, this study addresses the relationship between public concerns about social class and economic conditions throughout the twentieth century. The usage of class-related words/phrases, or "literary references to class," in American English-language books is related to US economic performance and income inequality. The findings of this study demonstrate that economic conditions play a significant role in literary references to class throughout the century, whereas income inequality does not. Similar results are obtained from further analyses using alternative measures of class concerns as well as different corpora of English Fiction and the New York Times. We add to the social class literature by showing that the long-term temporal dynamics of an economy can be exhibited by aggregate class concerns. The application of massive culture-wide content analysis using data of unprecedented size also represents a contribution to the literature. PMID- 27480368 TI - Opportunities and challenges of big data for the social sciences: The case of genomic data. AB - In this paper, we draw attention to one unique and valuable source of big data, genomic data, by demonstrating the opportunities they provide to social scientists. We discuss different types of large-scale genomic data and recent advances in statistical methods and computational infrastructure used to address challenges in managing and analyzing such data. We highlight how these data and methods can be used to benefit social science research. PMID- 27480371 TI - Selective responsiveness: Online public demands and government responsiveness in authoritarian China. AB - The widespread use of information and communication technology (ICT) has reshaped the public sphere in the digital era, making online forums a new channel for political participation. Using big data analytics of full records of citizen government interactions from 2008 to early 2014 on a nationwide political forum, we find that authoritarian China is considerably responsive to citizens' demands with a rapid growth of response rate; however, government responsiveness is highly selective, conditioning on actors' social identities and the policy domains of their online demands. Results from logistic and duration models suggest that requests which made by local citizens, expressed collectively, focused on the single task issue, and are closely related to economic growth are more likely to be responded to. These strategies adopted by Chinese provincial leaders reveal the scope and selectivity of authoritarian responsiveness. PMID- 27480372 TI - Using crowdsourced online experiments to study context-dependency of behavior. AB - We use Mechanical Turk's diverse participant pool to conduct online bargaining games in India and the US. First, we assess internal validity of crowdsourced experimentation through variation of stakes ($0, $1, $4, and $10) in the Ultimatum and Dictator Game. For cross-country equivalence we adjust the stakes following differences in purchasing power. Our marginal totals correspond closely to laboratory findings. Monetary incentives induce more selfish behavior but, in line with most laboratory findings, the particular size of a positive stake appears irrelevant. Second, by transporting a homogeneous decision situation into various living conditions crowdsourced experimentation permits identification of context effects on elicited behavior. We explore context-dependency using session level variation in participants' geographical location, regional affluence, and local social capital. Across "virtual pools" behavior varies in the range of stake effects. We argue that quasi-experimental variation of the characteristics people bring to the experimental situation is the key potential of crowdsourced online designs. PMID- 27480373 TI - Using small data to interpret big data: 311 reports as individual contributions to informal social control in urban neighborhoods. AB - Informal social control is considered a vital component of the well-being of urban communities. Though some argue that the actions that constitute this social process are often said to reflect territoriality, little else is known about how individuals contribute to it. The current study leverages a database of over 600,000 requests for government services received by the city of Boston, MA's 311 system as a way to answer such questions, focusing particularly on reports of issues in the public space arising from incivilities. In order to establish construct validity for the "big data" of the 311 system, they are combined with the "small data" of a survey of 311 users, permitting the simultaneous analysis of objective reporting behaviors with self-report attitudes. The analysis occurs in two parts. First, reporting of incivilities is distinguished behaviorally from reporting public issues arising from natural deterioration, and people are found to specialize in one or the other. Second, the survey is used to test whether the reports are a reflection of territoriality. Reports of incivilities were unique in their association with a desire to enforce local social norms. They were also associated with a second territorial motivation to benefit the community. Implications for future research are discussed. PMID- 27480374 TI - Measuring structural similarity in large online networks. AB - Structural similarity based on bipartite graphs can be used to detect meaningful communities, but the networks have been tiny compared to massive online networks. Scalability is important in applications involving tens of millions of individuals with highly skewed degree distributions. Simulation analysis holding underlying similarity constant shows that two widely used measures - Jaccard index and cosine similarity - are biased by the distribution of out-degree in web scale networks. However, an alternative measure, the Standardized Co-incident Ratio (SCR), is unbiased. We apply SCR to members of Congress, musical artists, and professional sports teams to show how massive co-following on Twitter can be used to map meaningful affiliations among cultural entities, even in the absence of direct connections to one another. Our results show how structural similarity can be used to map cultural alignments and demonstrate the potential usefulness of social media data in the study of culture, politics, and organizations across the social and behavioral sciences. PMID- 27480375 TI - Fitting ERGMs on big networks. AB - The exponential random graph model (ERGM) has become a valuable tool for modeling social networks. In particular, ERGM provides great flexibility to account for both covariates effects on tie formations and endogenous network formation processes. However, there are both conceptual and computational issues for fitting ERGMs on big networks. This paper describes a framework and a series of methods (based on existent algorithms) to address these issues. It also outlines the advantages and disadvantages of the methods and the conditions to which they are most applicable. Selected methods are illustrated through examples. PMID- 27480376 TI - The spatial structure of transnational human activity. AB - Starting from conflictive predictions of hitherto disconnected debates in the natural and social sciences, this article examines the spatial structure of transnational human activity (THA) worldwide (a) across eight types of mobility and communication and (b) in its development over time. It is shown that the spatial structure of THA is similar to that of animal displacements and local scale human motion in that it can be approximated by Levy flights with heavy tails that obey power laws. Scaling exponent and power-law fit differ by type of THA, being highest in refuge-seeking and tourism and lowest in student exchange. Variance in the availability of resources and opportunities for satisfying associated needs appears to explain these differences. Over time (1960-2010), the Levy-flight pattern remains intact and remarkably stable, contradicting the popular notion that socio-technological trends lead to a "death of distance." Humans have not become more "global" over time, they rather became more mobile in general, i.e. they move and communicate more at all distances. Hence, it would be more adequate to speak of "mobilization" than of "globalization." Longitudinal change occurs only in some types of THA and predominantly at short distances, indicating regional rather than global shifts. PMID- 27480377 TI - Spatio-temporal filtering techniques for the detection of disaster-related communication. AB - Individuals predominantly exchange information with one another through informal, interpersonal channels. During disasters and other disrupted settings, information spread through informal channels regularly outpaces official information provided by public officials and the press. Social scientists have long examined this kind of informal communication in the rumoring literature, but studying rumoring in disrupted settings has posed numerous methodological challenges. Measuring features of informal communication-timing, content, location-with any degree of precision has historically been extremely challenging in small studies and infeasible at large scales. We address this challenge by using online, informal communication from a popular microblogging website and for which we have precise spatial and temporal metadata. While the online environment provides a new means for observing rumoring, the abundance of data poses challenges for parsing hazard-related rumoring from countless other topics in numerous streams of communication. Rumoring about disaster events is typically temporally and spatially constrained to places where that event is salient. Accordingly, we use spatio and temporal subsampling to increase the resolution of our detection techniques. By filtering out data from known sources of error (per rumor theories), we greatly enhance the signal of disaster-related rumoring activity. We use these spatio-temporal filtering techniques to detect rumoring during a variety of disaster events, from high-casualty events in major population centers to minimally destructive events in remote areas. We consistently find three phases of response: anticipatory excitation where warnings and alerts are issued ahead of an event, primary excitation in and around the impacted area, and secondary excitation which frequently brings a convergence of attention from distant locales onto locations impacted by the event. Our results demonstrate the promise of spatio-temporal filtering techniques for "tuning" measurement of hazard-related rumoring to enable observation of rumoring at scales that have long been infeasible. PMID- 27480378 TI - Thumbs up for privacy?: Differences in online self-disclosure behavior across national cultures. AB - This study investigates relationships between national-level culture and online self-disclosure behavior. We operationalize culture through the GLOBE dimensions, a set of nine variables measuring cultural practices and another nine measuring values. Our observations of self-disclosure come from the privacy settings of approximately 200,000 randomly sampled Facebook users who designated a geographical network in 2009. We model privacy awareness as a function of one or more GLOBE variables with demographic covariates, evaluating the relative influence of each factor. In the top-performing models, we find that the majority of the cultural dimensions are significantly related to privacy awareness behavior. We also find that the hypothesized directions of several of these relationships, based largely on cultural attitudes towards threat mitigation, are confirmed. PMID- 27480379 TI - Lysophosphatidylcholine acts in the constitutive immune defence against American foulbrood in adult honeybees. AB - Honeybee (Apis mellifera) imagines are resistant to the Gram-positive bacterium Paenibacillus larvae (P. larvae), causative agent of American foulbrood (AFB), whereas honeybee larvae show susceptibility against this pathogen only during the first 48 h of their life. It is known that midgut homogenate of adult honeybees as well as a homogenate of aged larvae exhibit strong anti-P. larvae activity. A bioactivity-guided LC-HRMS analysis of midgut homogenate resulted in the identification of 1-oleoyl-sn-glycero-3-phosphocholine (LPC) pointing to a yet unknown immune defence in adult honeybees against P. larvae. Antimicrobial activity of LPC was also demonstrated against Melissococcus plutonius, causative agent of European Foulbrood. To demonstrate an AFB-preventive effect of LPC in larvae, artificially reared larvae were supplemented with LPC to evaluate its toxicity and to assess whether, after infection with P. larvae spores, LPC supplementation prevents AFB infection. 10 MUg LPC per larva applied for 3 d significantly lowered mortality due to AFB in comparison to controls. A potential delivery route of LPC to the larvae in a colony via nurse bees was assessed through a tracking experiment using fluorescent-labelled LPC. This yet undescribed and non-proteinous defense of honeybees against P. larvae may offer new perspectives for a treatment of AFB without the utilization of classic antibiotics. PMID- 27480380 TI - Oxidative stress and nitric oxide are increased in obese children and correlate with cardiometabolic risk and renal function. AB - Oxidative stress and nitric oxide (NO) appear to represent important links between obesity and cardiovascular, metabolic and/or renal disease. We investigated whether oxidative stress and NO production/metabolism are increased in overweight and obese prepubertal children and correlate with cardiometabolic risk and renal function. We performed a cross-sectional evaluation of 313 children aged 8-9 years. Anthropometrics, 24-h ambulatory blood pressure, pulse wave velocity (PWV), insulin resistance (homoeostasis model assessment index (HOMA-IR)), inflammatory/metabolic biomarkers, estimated glomerular filtration rate (eGFR), plasma total antioxidant status (TAS), plasma and urinary isoprostanes (P-Isop, U-Isop), urinary hydrogen peroxide (U-H2O2), and plasma and urinary nitrates and nitrites (P-NOx, U-NOx) were compared among normal weight, overweight and obese groups, according to WHO BMI z-score reference. U-Isop were increased in the obese group, whereas U-NOx were increased in both overweight and obese children. U-Isop were positively correlated with U-H2O2, myeloperoxidase (MPO), high-sensitivity C-reactive protein, HOMA-IR and TAG. TAS correlated negatively with U-Isop and MPO and positively with PWV. HOMA-IR and U-H2O2 were associated with higher U-Isop, independently of BMI and eGFR, and total cholesterol and U-H2O2 were associated with U-NOx, independently of BMI, eGFR values and P-NOx concentration. In overweight and obese children, eGFR decreased across P-NOx tertiles (median: 139.3 (25th, 75th percentile 128.0, 146.5), 128.0 (25th, 75th percentile 121.5, 140.4), 129.5 (25th, 75th percentile 119.4, 138.3), P for linear trend=0.003). We conclude that oxidant status and NO are increased in relation to fat accumulation and, even in young children, they translate into higher values of cardiometabolic risk markers and affect renal function. PMID- 27480381 TI - DeF-GPU: Efficient and effective deletions finding in hepatitis B viral genomic DNA using a GPU architecture. AB - Hepatitis B viral (HBV) infection is strongly associated with an increased risk of liver diseases like cirrhosis or hepatocellular carcinoma (HCC). Many lines of evidence suggest that deletions occurring in HBV genomic DNA are highly associated with the activity of HBV via the interplay between aberrant viral proteins release and human immune system. Deletions finding on the HBV whole genome sequences is thus a very important issue though there exist underlying the challenges in mining such big and complex biological data. Although some next generation sequencing (NGS) tools are recently designed for identifying structural variations such as insertions or deletions, their validity is generally committed to human sequences study. This design may not be suitable for viruses due to different species. We propose a graphics processing unit (GPU) based data mining method called DeF-GPU to efficiently and precisely identify HBV deletions from large NGS data, which generally contain millions of reads. To fit the single instruction multiple data instructions, sequencing reads are referred to as multiple data and the deletion finding procedure is referred to as a single instruction. We use Compute Unified Device Architecture (CUDA) to parallelize the procedures, and further validate DeF-GPU on 5 synthetic and 1 real datasets. Our results suggest that DeF-GPU outperforms the existing commonly-used method Pindel and is able to exactly identify the deletions of our ground truth in few seconds. The source code and other related materials are available at https://sourceforge.net/projects/defgpu/. PMID- 27480382 TI - Opposite Associations Between the rs3845446 Single-Nucleotide Polymorphism of the CACNA1E Gene and Postoperative Pain-Related Phenotypes in Gastrointestinal Surgery Versus Previously Reported Orthognathic Surgery. AB - Cav2.3 (R-type) voltage-activated Ca(2+) channels (VACCs), encoded by the calcium channel, voltage-dependent, R-type, alpha1E subunit (CACNA1E) gene, are responsible for transmission of somatic inflammatory pain, and activation of antinociception elicited by visceral inflammatory pain stimuli. Carriers of the minor G allele of the rs3845446 single-nucleotide polymorphism (SNP) of the CACNA1E gene reportedly exhibit a decrease in opioid requirements to control typical somatic inflammatory pain after orthognathic surgery (ie, a painful cosmetic surgery), suggesting the downregulation of Cav2.3 VACC function that is responsible for transmission of somatic inflammatory pain in these carriers. Gastrointestinal surgery involves somatic and visceral inflammatory pain, in which visceral inflammatory pain stimuli activate Cav2.3 VACC-mediated antinociception. Unknown is whether pain-related phenotypes after gastrointestinal surgery are affected in these carriers. The present study used a correlational design to examine the effect of the rs3845446 SNP on postoperative pain-related phenotypes in 2 groups of patients who underwent gastrointestinal surgery. Carriers of the minor G allele had greater opioid requirements after laparoscopic colectomy when intravenous patient-controlled analgesia was used, and reported higher pain scores after open gastrointestinal surgery when postoperative analgesia was managed with continuous epidural analgesia and rescue analgesics. These results suggest that pain-related phenotypes after gastrointestinal surgery are enhanced in carriers of the minor G allele of the rs3845446 SNP, possibly through impairment of Cav2.3 VACC function that is responsible for the activation of visceral inflammatory pain stimulus-elicited antinociception. PERSPECTIVE: Carriers of the minor allele of the rs3845446 SNP of the CACNA1E gene required more opioid or reported higher pain scores after gastrointestinal surgery, and required less opioid after orthognathic surgery. The difference may result from the presence of visceral inflammatory pain stimulus that activates Cav2.3 VACCs-mediated antinociception. PMID- 27480384 TI - Synthesis, aggregation-enhanced emission, polymorphism and piezochromism of TPE cored foldamers with through-space conjugation. AB - A series of new folded tetraphenylethene derivatives with different substituents are stereoselectively synthesized, which exhibit interesting through-space conjugation, aggregation-enhanced emission, polymorphism and piezochromism properties. PMID- 27480383 TI - Effects of Prolonged and Acute Muscle Pain on the Force Control Strategy During Isometric Contractions. AB - Musculoskeletal pain is associated with multiple adaptions in movement control. This study aimed to determine whether changes in movement control acquired during acute pain are maintained over days of pain exposure. On day 0, the extensor carpi radialis brevis muscle of healthy participants was injected with nerve growth factor (NGF) to induce persistent movement-evoked pain (n = 13) or isotonic saline as a control (n = 13). On day 2, short-lasting pain was induced by injection of hypertonic saline into extensor carpi radialis brevis muscles of all participants. Three-dimensional force components were recorded during submaximal isometric wrist extensions on day 0, day 4, and before, during, and after saline-induced pain on day 2. Standard deviation (variation of task-related force) and total excursion of center of pressure (variation of force direction) were assessed. Maximal movement-evoked pain was 3.3 +/- .4 (0-10 numeric scale) in the NGF-group on day 2 whereas maximum saline-induced pain was 6.8 +/- .3 cm (10-cm visual analog scale). The difference in centroid position of force direction relative to day 0 was greater in the NGF group than in the control group (P < .05) on day 2 (before saline-induced pain) and day 4, reflecting changes in tangential force direction used to achieve the task. During saline induced pain in both groups, tangential and task-related force variation was greater than before and after saline-induced pain (P < .05). PERSPECTIVE: Persistent movement-evoked pain changes force direction from the pain-free direction. Acute pain leads to increased variation in force direction irrespective of persistent movement-evoked pain preceding the acutely painful event. These differences provide novel insight into the search for and consolidation of new motor strategies in the presence of pain. PMID- 27480385 TI - Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial. AB - Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m2 PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25-65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ?40 years, odds ratio (OR) 18.5 (2.02-169.0), P=0.01; Ph- versus Ph+ disease, OR 13.60 (3.52-52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib. PMID- 27480388 TI - Significance of Comorbid Psychological Stress and Depression on Outcomes After Cardiac Rehabilitation. AB - BACKGROUND: Depression is associated with increased mortality in stable coronary heart disease. Cardiac rehabilitation and exercise training has been shown to decrease depression, psychological stress, and mortality after a coronary heart disease event. The presence of depression at completion of cardiac rehabilitation and exercise training is associated with increased mortality. However, it is unknown if depression with comorbid psychological risk factors such as anxiety or hostility confers an additional mortality disadvantage. We evaluated the mortality effect of anxiety and hostility on depression after cardiac rehabilitation and exercise training. PATIENTS AND METHODS: We studied 1150 patients with coronary heart disease following major coronary heart disease events who had completed formal cardiac rehabilitation and exercise training. Using Kellner questionnaires, stress levels were measured in 1 of 3 domains: anxiety, hostility, and depression (with an aggregated overall psychological stress score) and divided into 3 groups: nondepressed (n = 1072), depression alone (n = 18), and depression with anxiety or hostility (n = 60). Subjects were analyzed for all-cause mortality over 161 months of follow-up (mean 6.4 years) by National Death Index. RESULTS: Depression after cardiac rehabilitation was not common (6.8%; mortality 20.8%) but when present, frequently associated with either anxiety or hostility (77% of depressed patients; mortality 22.0%). After adjustment for age, sex, ejection fraction, and baseline peak oxygen consumption, depression alone (hazard ratio [HR] 1.73, P = .04), as well as depression with comorbid psychological stress, was associated with higher mortality (HR 1.98, P = .03). Furthermore, our data showed an increased mortality when both anxiety and hostility were present in addition to depression after cardiac rehabilitation (HR 2.41, P = .04). CONCLUSIONS: After cardiac rehabilitation, depression, when present, is usually associated with other forms of psychological stress, which confers additional mortality. More measures are needed to address psychological stress after cardiac rehabilitation. PMID- 27480387 TI - Dynamics of microvesicle generation in B-cell chronic lymphocytic leukemia: implication in disease progression. AB - Previously, we reported that B-cell chronic lymphocytic leukemia (CLL) patients contained elevated levels of microvesicles (MVs). However, given the quiescent nature of CLL B-cells and the relative indolence of the disease, the dynamics of MV generation and their unique phenotypes are not clearly defined. In this study, we find that CLL B-cells generate MVs spontaneously and can be further induced by B-cell receptor-ligation. Most interestingly, CLL B-cells predominantly generate CD52+ MVs, but not CD19+ MVs in vitro, suggesting preferential usage of CD52 into leukemic-MVs and that the CLL plasma MV phenotypes corroborate well with the in vitro findings. Importantly, we detected increased accumulation of CD52+ MVs in previously untreated CLL patients with progressive disease. Finally, sequential studies on MVs in pre- and post-therapy CLL patients demonstrate that although the plasma CD52+ MV levels drop significantly after therapy in most and remain at low levels in some patients, a trend of increased accumulation of CD52+ MVs was detected in majority of post-therapy CLL patients (25 of 33). In total, this study emphasizes that dynamic accumulation of CD52+ MVs in plasma can be used to study CLL progression and may be a useful biomarker for patients as they progress and require therapy. PMID- 27480386 TI - Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy. PMID- 27480389 TI - The Department of Medicine in 2030: A Look Ahead. AB - The authors described the features of a hypothetical academic Department of Medicine in 2030 that would be most effective in improving the public health. Future departments of medicine will be compelled to respond to a projected shortage of physicians through augmented training strategies. The clinical programs will be more decentralized and responsive to patient preferences while demonstrating greater value. Departments will create adaptable, accountable structures in which clinicians working in interdisciplinary teams continuously improve processes and outcomes of care, and clinician and patient satisfaction. The restructuring of health care will afford exciting opportunities to align clinical and scholarly activities. The growing ability to link biological and clinical phenotypic information will lead to more effective and efficient clinical care. In view of the funding constraints and the remarkable opportunities for high-impact research, departmental research programs will become increasingly disciplined. Successful research programs will require durable investments in faculty career development, enabling infrastructure, interdisciplinary research teams, and diverse funding sources. The educational programs will demonstrate proficiency of trainees in the 6 current core competencies, as well as in additional areas critical to health care transformation. To improve organizational effectiveness, departments will create more nimble organizational structures led by individuals with diverse backgrounds. Chairs of departments of medicine will be expected to continuously expand their capacity to meet the evolving needs of their departments and institutions. Members of departments of medicine will be continuously fortified by the privilege and obligations of our profession while embracing the risks necessary to meet the extraordinary opportunities in 2030. PMID- 27480390 TI - [Reflection on the psychiatric financial allocation in France]. AB - For 25years work has been underway in France for the implementation of an alternative to public financing of health care. In the absence of progress, some regional health agencies are engaged in work related to the reallocation of public finances between psychiatric institutions. We propose a reflection with suggestion on the method proposed by the Provence Alpes Cote d'Azur Regional Health Agency. Without questioning the need for a reallocation of resources between psychiatric institutions, the method proposed here needs to evolve further to be applied in a legitimate and appropriate manner. There is a kind of urgency for a reallocation of resources between psychiatric institutions in France, but it implies a collective thinking and especially the definition of evaluation procedures for the selected models. These conditions are necessary to guarantee the quality of French psychiatry and equity in access to psychiatric care. PMID- 27480391 TI - Molecular epidemiology of junctional epidermolysis bullosa: discovery of novel and frequent LAMB3 mutations in Chilean patients with diagnostic significance. PMID- 27480392 TI - Comparative Study of Bifunctional Mononuclear and Dinuclear Amidoiridium Complexes with Chiral C-N Chelating Ligands for the Asymmetric Transfer Hydrogenation of Ketones. AB - A series of new bifunctional C-N chelating Ir complexes possessing a metal/NH group was synthesized by cyclometalation of optically active primary benzylic amines such as O-silylated (S)-2-amino-2-phenylethanols (1 a and 1 a'), (R)-5 amino-6,7,8,9-tetrahydro-5H-benzocycloheptene (1 b), and (R)-1-phenyl-2,2 dimethylpropylamine (1 c). Although treatment of KOtBu with the amine complexes originating from 1 a and 1 a' afforded amido-bridged dinuclear complexes (3 a and 3 a'), more sterically hindered complexes were solely transformed into the coordinatively unsaturated mononuclear amido complexes (3 b and 3 c), which can serve as real catalyst species in the asymmetric transfer hydrogenation. The structural difference in the C-N chelate framework markedly affected the catalytic performance. Among them, amido complex 3 c showed a pronounced ability to catalyze the transfer hydrogenation of acetophenone in 2-propanol, even at a low temperature of -30 degrees C. A hydridoiridium complex (4 c) was also identified in the reaction of 3 c in 2-propanol, which provides mechanistic insights into the enantiodiscriminating step in the hydrogen transfer to prochiral ketones. PMID- 27480395 TI - Microtomographic studies of subdivision of modified-release tablets. AB - The uniformity of dosage units within a certain batch is ensured when each unit contains the active pharmaceutical ingredient (API) within a narrow range around the label claim. For tablets containing a score-line authorised for dose reductions, the European Pharmacopoeia (Ph. Eur.) considers that the uniformity of the tablet parts may be based on weight measurements regardless of the tablet type (immediate or modified release). This is because it is up to the regulatory authorities first to assess whether the tablet may contain a score-line for such use. X-ray microtomography was applied to assess the symmetry of 36 modified release tablets, containing 300mg of theophylline. The sum of the volume and surface area of the pellets in the subdivided tablets were compared. Simulations were carried out to identify the optimal amount of pellets in the tablet mass. The maximum difference in the API content between two subdivided halves was 165.18mg vs 133.83mg. If the amount of pellets in the tablet mass would drop below 13% on the basis of the pellet surface area, then the Ph. Eur. requirements would be exceeded. The amount of pellets in the tablet halves resulting in the greatest variability in API content was 38%. The results of this study indicate that the pellets were not distributed uniformly in the tablet mass. Thus, the uniformity of the dose in both halves of a tablet containing pellets cannot be based on the weight measurements i.e. it is necessary to develop further standards for tablet subdivision. Microtomographic methods are a very interesting alternative to expensive and time-consuming pharmacokinetic studies. PMID- 27480393 TI - Investigating shared aetiology between type 2 diabetes and major depressive disorder in a population based cohort. AB - Type II diabetes (T2D) and major depressive disorder (MDD) are often co-morbid. The reasons for this co-morbidity are unclear. Some studies have highlighted the importance of environmental factors and a causal relationship between T2D and MDD has also been postulated. In the present study we set out to investigate the shared aetiology between T2D and MDD using Mendelian randomization in a population based sample, Generation Scotland: the Scottish Family Health Study (N = 21,516). Eleven SNPs found to be associated with T2D were tested for association with MDD and psychological distress (General Health Questionnaire scores). We also assessed causality and genetic overlap between T2D and MDD using polygenic risk scores (PRS) assembled from the largest available GWAS summary statistics to date. No single T2D risk SNP was associated with MDD in the MR analyses and we did not find consistent evidence of genetic overlap between MDD and T2D in the PRS analyses. Linkage disequilibrium score regression analyses supported these findings as no genetic correlation was observed between T2D and MDD (rG = 0.0278 (S.E. 0.11), P-value = 0.79). As suggested by previous studies, T2D and MDD covariance may be better explained by environmental factors. Future studies would benefit from analyses in larger cohorts where stratifying by sex and looking more closely at MDD cases demonstrating metabolic dysregulation is possible. (c) 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID- 27480396 TI - A novel thermo-mechanical system enhanced transdermal delivery of hydrophilic active agents by fractional ablation. AB - The Tixel is a novel device based on a thermo-mechanical ablation technology that combines a sophisticated motion and a temperature control. The fractional technology is used to transfer a very precise thermal energy to the skin thereby creating an array of microchannels, accompanying by no signs of pain or inconvenience. This study aimed to evaluate the effect of the Tixel on the skin permeability of three hydrophilic molecular models: verapamil hydrochloride, diclofenac sodium, and magnesium ascorbyl phosphate. Tixel's gold-platted stainless steel tip heated to a temperature of 400 degrees C was applied on skin for 8ms or 9ms at a protrusion of 400MUm (the distance in which the tip protrudes beyond the distance gauge). The experiments were carried out partly in vivo in humans using a fluorescent dye and a confocal microscopy and partly in vitro using porcine skin and a Franz diffusion cell system. The results obtained in this study have shown that (a) no significant collateral damage to the skin tissue and no necrosis or dermal coagulation have been noted, (b) the microchannels remained open and endured for at least 6h, and (c) the skin permeability of hydrophilic molecules, which poorly penetrate the lipophilic stratum corneum barrier, was significantly enhanced by using Tixel's pretreatment. PMID- 27480397 TI - Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel. AB - Previously, it was shown in Phase I clinical trials that solubility-limited oral absorption of docetaxel and paclitaxel can be drastically improved with a freeze dried solid dispersion (fdSD). These formulations, however, are unfavorable for further clinical research because of limitations in amorphicity of SD and scalability of the production process. To resolve this, a spray drying method for an SD (spSD) containing docetaxel or paclitaxel and subsequently drug products were developed. Highest saturation solubility (Smax), precipitation onset time (Tprecip), amorphicity, purity, residual solvents, yield/efficiency and powder flow of spSDs were studied. Drug products were monitored for purity/content and dissolution during 24 months at +15-25 degrees C. Docetaxel spSD Smax was equal to that of fdSD but Tprecip was 3 times longer. Paclitaxel spSD Smax was 30% increased but Tprecip was equal to fdSD. spSDs were fully amorphous, >99% pure, <5% residual solvents, mean batch yield was 100g and 84%. spSDs had poor powder flow characteristics, which could not be resolved by changing settings, but by using 75% lactose as diluent. The drug product was a tablet with docetaxel or paclitaxel spSD and was stable for at least 24 months. Spray drying is feasible for the production of SD of docetaxel or paclitaxel for upcoming clinical trials. PMID- 27480398 TI - In vitro, ex vivo and in vivo characterization of PLGA nanoparticles loading pranoprofen for ocular administration. AB - Pranoprofen (PF) is a NSAID considered as a safe anti-inflammatory treatment for strabismus and/or cataract surgery. The drug has been formulated in poly (lactic/glycolic) acid (PLGA) nanoparticles (PF-F1NPs with cPF 1.5mg/mL, PF-F2NPs with cPF 1mg/mL) produced by solvent displacement technique and tested the in vitro cytotoxicity, ex vivo corneal permeation, in vivo ocular tolerance and in vivo anti-inflammatory efficacy of PF-F1NPs, PF-F2NPs, in comparison to eye drops conventional dosage form (Oftalar((r)), PF 1mg/mL) and free drug solution (PF dissolved in PBS, 1.5mg/mL). The mean particle size of both formulations was around 350nm, with polydispersity index below 0.1, and a net negative charge of 7.41mV and -8.5mV for PF-F1NPs and PF-F2NPs, respectively. Y-79 human retinoblastoma cell line was used to evaluate the cytotoxicity of PF-F1NPs and PF F2NPs, which were compared to blank NPs and free drug solution (PF dissolved in PBS, 1.5mg/mL). Concentrations up to 75MUg/mL exhibited no toxicity to Y-79 cells, whereas at 150MUg/mL a decrease of about 80% on the cell viability was observed after exposing the cells to PF-F1NPs. When treating the Y-79 cells with concentrations of PF-F2NPs between 1MUg/mL to 100MUg/mL, the cell viability was similar to control values after 24h and 48h of exposure. An ex vivo corneal permeation study was carried out in New Zealand rabbits. A very similar profile has been observed for the permeation of PF through the cornea when administered as eye drops and as free drug solution, which was kept much lower in comparison to PF-NPs formulations. The permeated amount of PF from the PF-F1NPs was slightly smaller than from PF-F2NPs, attributed to the increase of viscosity of the formulations with the increase of cPVA concentration. New Zealand white rabbits were also used to evaluate the irritancy of PF-F1NPs and PF-F2NPs, which demonstrated to be well-tolerated to the eye (i.e. the mean total score (MTS) was 0). PF-F2NPs exhibited the highest QP (amounts of PF permeated in the cornea) and significantly reduced the ocular edema compared to the tested formulations. The QR (amounts of PF retained in the cornea) of the PF-F1NPs was greater than that obtained for PF-F2NPs. PMID- 27480399 TI - Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose. AB - Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat. PMID- 27480400 TI - 193 nm Ultraviolet Photodissociation Mass Spectrometry of Tetrameric Protein Complexes Provides Insight into Quaternary and Secondary Protein Topology. AB - Protein-protein interfaces and architecture are critical to the function of multiprotein complexes. Mass spectrometry-based techniques have emerged as powerful strategies for characterization of protein complexes, particularly for heterogeneous mixtures of structures. In the present study, activation and dissociation of three tetrameric protein complexes (streptavidin, transthyretin, and hemoglobin) in the gas phase was undertaken by 193 nm ultraviolet photodissociation (UVPD) for the characterization of higher order structure. High pulse energy UVPD resulted in the production of dimers and low charged monomers exhibiting symmetrical charge partitioning among the subunits (the so-called symmetrical dissociation pathways), consistent with the subunit organization of the complexes. In addition, UVPD promoted backbone cleavages of the monomeric subunits, the abundances of which corresponded to the more flexible loop regions of the proteins. PMID- 27480401 TI - Effect of micronized progesterone on fetal-placental volume in first-trimester threatened abortion. AB - PURPOSE: To compare the effect of oral micronized progesterone (OMP) on the first trimester fetal and placental volumes using three-dimensional ultrasonography and extended imaging virtual organ computer-aided analysis (XI VOCAL) method in threatened abortion. METHODS: This randomized controlled trial enrolled women with threatened abortion and a singleton pregnancy from 6-8 6/7 weeks of gestation. A total of 60 women with threatened abortion were randomly assigned to one of two groups: OMP (400 mg/day) (n = 30) and control groups (n = 30). The XI VOCAL method was used for all volume measurements using three-dimensional ultrasonography. All patients were evaluated for fetal, amniotic, and placental volumes during the initial diagnosis and after 4 weeks. RESULTS: After treatment, placental volume difference was significantly higher in the OMP group (336%, 67 1,077) than in the control group (141%, 29-900) (p = 0.007). The mean differences in gestational sac, amniotic sac, and embryonic volumes between the OMP and control groups were not statistically significant. CONCLUSIONS: Hormonal support with OMP is associated with increased placental volume in first-trimester threatened abortion when compared with the control group. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:14-19, 2017. PMID- 27480402 TI - Characterization and virulence of Beauveria bassiana associated with auger beetle (Sinoxylon anale) infesting allspice (Pimenta dioica). AB - The incidence of auger beetle, Sinoxylon anale Lesne (Bostrichidae: Coleoptera), a destructive pest of cosmopolitan occurrence is reported for the first time on allspice trees, Pimenta dioica (L.) Merr. in Kerala, India. The insects bored through the basal region of fresh twigs resulting in dieback symptoms. Morphological characterization and sequencing of a partially amplified fragment of the mitochondrial CO1 gene (696bp) revealed the insect to be Sinoxylon anale. An entomopathogenic fungus was isolated from infected cadavers of S. anale that was identified as Beauveria bassiana (Bals.-Criv.) Vuill., sensu stricto (s.s.) (Ascomycota: Hypocreales) based on morphological and molecular studies. The partial sequences of the ITS, TUB, TEF and Bloc gene regions were sequenced. The fungus grew well in ambient room temperature conditions (28-32+/-2 degrees C; 60 70% relative humidity) and the infection process on the insect was documented by scanning electron microscopy. Bioassay studies with the isolate indicated that the fungus was virulent against adult beetles as evidenced by the LC50 (3.6*10(6)conidia/ml) and ST50 values (6.8days at a dose of 1*10(7)conidia/ml and 5.8days at a dose of 1*10(8)conidia/ml, respectively). This is the first record of B. bassiana naturally infecting S. anale and the fungus holds promise to be developed as a mycoinsecticide. PMID- 27480403 TI - Structural classification of insecticidal proteins - Towards an in silico characterisation of novel toxins. AB - The increasing rate of discovery of new toxins with potential for the control of invertebrate pests through next generation sequencing, presents challenges for the identification of the best candidates for further development. A consideration of structural similarities between the different toxins suggest that they may be functionally less diverse than their low sequence similarities might predict. This is encouraging from the prospective of being able to use computational tools to predict toxin targets from their sequences, however more structure/function data are still required to reliably inform such predictions. PMID- 27480404 TI - Specificity determinants for Cry insecticidal proteins: Insights from their mode of action. AB - Insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) are used as active components of biopesticides and as plant incorporated protectants in transgenic crops. One of the most relevant attributes of these Bt protein-based insecticidal technologies is their high specificity, which assures lack of detrimental effects on non-target insects, vertebrates and the environment. The identification of specificity determinants in Bt insecticidal proteins could guide risk assessment for novel insecticidal proteins currently considered for commercialization. In this work we review the available data on specificity determinants of crystal (Cry) insecticidal proteins as the Bt toxins most well characterized and used in transgenic crops. The multi-step mode of action of the Cry insecticidal proteins allows various factors to potentially affect specificity determination and here we define seven levels that could influence specificity. The relative relevance of each of these determinants on efficacy of transgenic crops producing Cry insecticidal proteins is also discussed. PMID- 27480405 TI - Safety considerations derived from Cry34Ab1/Cry35Ab1 structure and function. AB - Insecticidal proteins developed for in-plant protection against crop pests undergo extensive safety testing during the product development process. Safety considerations for insecticidal proteins expressed in crops follow recommended, science-based guidelines and specific studies are conducted on a case by case basis. Corn events expressing Bacillus thuringiensis (Bt) Cry34Ab1 and Cry35Ab1 were developed to protect maize from Diabrotica virgifera virgifera (western corn rootworm) feeding damage. The protein crystal structures of Cry34Ab1 and Cry35Ab1 are different from the more common three-domain Cry or Vip3 proteins expressed in insect resistant maize varieties. Cry34Ab1 is a single domain protein that folds into a beta sandwich structure that resembles membrane-active proteins, including several cytolysins, from a variety of natural sources. Cry35Ab1 has two domains, one domain with structural relatedness to sugar binding motifs and a second domain with an extended beta sheet structure that is clearly related to beta pore forming proteins, some of which are insecticidal, e.g. B. sphaericus BinA/BinB. In this review we discuss Cry34Ab1/Cry35Ab1 structure and function in the context of protein safety studies for insect resistant crops. PMID- 27480406 TI - The aged lymphoid tissue environment fails to support naive T cell homeostasis. AB - Aging is associated with a gradual loss of naive T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naive T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naive T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naive T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naive T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naive T cell pool deteriorate with age. PMID- 27480407 TI - Nontargeted Screening Method for Illegal Additives Based on Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometry. AB - Identification of illegal additives in complex matrixes is important in the food safety field. In this study a nontargeted screening strategy was developed to find illegal additives based on ultrahigh-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). First, an analytical method for possible illegal additives in complex matrixes was established including fast sample pretreatment, accurate UHPLC separation, and HRMS detection. Second, efficient data processing and differential analysis workflow were suggested and applied to find potential risk compounds. Third, structure elucidation of risk compounds was performed by (1) searching online databases [Metlin and the Human Metabolome Database (HMDB)] and an in-house database which was established at the above-defined conditions of UHPLC-HRMS analysis and contains information on retention time, mass spectra (MS), and tandem mass spectra (MS/MS) of 475 illegal additives, (2) analyzing fragment ions, and (3) referring to fragmentation rules. Fish was taken as an example to show the usefulness of the nontargeted screening strategy, and six additives were found in suspected fish samples. Quantitative analysis was further carried out to determine the contents of these compounds. The satisfactory application of this strategy in fish samples means that it can also be used in the screening of illegal additives in other kinds of food samples. PMID- 27480408 TI - Do changes to Quality and Outcomes Framework diabetes clinical indicators affect care as measured in the National Diabetes Audit? PMID- 27480409 TI - Molecular detection and identification of Rickettsiales pathogens in dog ticks from Costa Rica. AB - Although vector-borne diseases are globally widespread with considerable impact on animal production and on public health, few reports document their presence in Central America. This study focuses on the detection and molecular identification of species belonging to selected bacterial genera (Ehrlichia, Anaplasma and Rickettsia) in ticks sampled from dogs in Costa Rica by targeting several genes: 16S rRNA/dsb genes for Ehrlichia; 16S rRNA/groEL genes for Anaplasma, and ompA/gltA/groEL genes for Rickettsia. PCR and sequence analyses provides evidences of Ehrlichia canis, Anaplasma platys, and Anaplasma phagocytophilum infection in Rhipicephalus sanguineus s.l ticks, and allow establishing the presence of Rickettsia monacensis in Ixodes boliviensis. Furthermore, the presence of recently discovered Mediterranean A. platys-like strains is reported for the first time in Central America. Results provide new background on geographical distribution of selected tick-transmitted bacterial pathogens in Costa Rica and on their molecular epidemiology, and are pivotal to the development of effective and reliable diagnostic tools in Central America. PMID- 27480410 TI - A randomized trial of Plasma-Lyte A and 0.9 % sodium chloride in acute pediatric gastroenteritis. AB - BACKGROUND: Compare the efficacy and safety of Plasma-Lyte A (PLA) versus 0.9 % sodium chloride (NaCl) intravenous (IV) fluid replacement in children with moderate to severe dehydration secondary to acute gastroenteritis (AGE). METHODS: Prospective, randomized, double-blind study conducted at eight pediatric emergency departments (EDs) in the US and Canada (NCT#01234883). The primary outcome measure was serum bicarbonate level at 4 h. Secondary outcomes included safety and tolerability. The hypothesis was that PLA would be superior to 0.9 % NaCl in improvement of 4-h bicarbonate. Patients (n = 100) aged >=6 months to <11 years with AGE-induced moderate-to-severe dehydration were enrolled. Patients with a baseline bicarbonate level <=22 mEq/L formed the modified intent to treat (mITT) group. RESULTS: At baseline, the treatment groups were comparable except that the PLA group was older. At hour 4, the PLA group had greater increases in serum bicarbonate from baseline than did the 0.9 % NaCl group (mean +/- SD at 4 h: 18 +/- 3.74 vs 18.0 +/- 3.67; change from baseline of 1.6 and 0.0, respectively; P = .004). Both treatment groups received similar fluid volumes. The PLA group had less abdominal pain and better dehydration scores at hour 2 (both P = .03) but not at hour 4 (P = 0.15 and 0.08, respectively). No patient experienced clinically relevant worsening of laboratory findings or physical examination, and hospital admission rates were similar. One patient in each treatment group developed hyponatremia. Four patients developed hyperkalemia (PLA:1, 0.9 % NaCl:3). CONCLUSION: In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led to more rapid improvement in serum bicarbonate and dehydration score. TRIAL REGISTRATION: NCT#01234883 (Registration Date: November 3, 2010). PMID- 27480412 TI - CD1, MR1, NKT, and MAIT: evolution and origins of non-peptidic antigen recognition by T lymphocytes. PMID- 27480411 TI - SSAT State-of-the-Art Conference: New Frontiers in Liver Surgery. AB - ?. PMID- 27480414 TI - Cytotoxicity and proliferative capacity impairment induced on human brain cell cultures after short- and long-term exposure to magnetite nanoparticles. AB - Since magnetic iron oxide nanoparticles (IONP) as magnetite (Fe3 O4 NPs) have potential applications in life sciences, industrial fields and biomedical care, the risks for occupational, general population and patients rises correspondingly. Excessive IONP accumulation in central nervous system (CNS) cells can lead to a disruption of normal iron metabolism/homeostasis, which is a characteristic hallmark resembling that of several neurodegenerative disorders. Fe3 O4 NPs- versus Fe3 O4 bulk-induced toxic effects have been assessed in two human CNS cells namely astrocytes (D384) and neurons (SH-SY5Y) after short-term exposure (4-24-48 h) to 1-100 MUg ml-1 , and long-term exposure to lower concentrations. Short-term Fe3 O4 NPs induced significant concentration- and time dependent alterations of mitochondrial function in D384 (25-75% cell viability decrease): effects started at 25 MUg ml-1 after 4 h, and 1 MUg ml-1 after 48 h. SH-SY5Y were less susceptible: cytotoxicity occurred after 48 h only with 35-45% mortality (10-100 MUg ml-1 ). Accordingly, a more marked intracellular iron accumulation was observed in astrocytes than neurons. Membrane integrity was unaltered in both CNS cell types. Lowering Fe3 O4 NP concentrations (0.05-10 MUg ml-1 ) and prolonging the exposure time (up to 10 days), D384 toxicity was again observed (colony number decrease at >=0.05 MUg ml-1 , morphology alterations and colony size reduction at >=0.5 MUg ml-1 ). Effects on SH-SY5Y appeared at the highest concentration only. Fe3 O4 bulk was always remarkably toxic toward both cells. In summary, human cultured astrocytes were susceptible to both Fe3 O4 NP and bulk forms following short-term and extended exposure to low concentrations, while neurons were more resistant to NPs. Cellular iron overload may trigger adverse responses by releasing iron ions (particularly in astrocytes) thus compromising the normal functions of CNS. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27480413 TI - Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock. AB - BACKGROUND: Persistent hyperlactatemia during septic shock is multifactorial. Hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation together with impaired lactate clearance have been implicated. An excessive adrenergic response could contribute to persistent hyperlactatemia and adrenergic modulation might be beneficial. We assessed the effects of dexmedetomidine and esmolol on hemodynamics, lactate generation, and exogenous lactate clearance during endotoxin-induced septic shock. METHODS: Eighteen anesthetized and mechanically ventilated sheep were subjected to a multimodal hemodynamic/perfusion assessment including hepatic and portal vein catheterizations, total hepatic blood flow, and muscle microdialysis. After monitoring, all received a bolus and continuous infusion of endotoxin. After 1 h they were volume resuscitated, and then randomized to endotoxin-control, endotoxin-dexmedetomidine (sequential doses of 0.5 and 1.0 MUg/k/h) or endotoxin esmolol (titrated to decrease basal heart rate by 20 %) groups. Samples were taken at four time points, and exogenous lactate clearance using an intravenous administration of sodium L-lactate (1 mmol/kg) was performed at the end of the experiments. RESULTS: Dexmedetomidine and esmolol were hemodynamically well tolerated. The dexmedetomidine group exhibited lower epinephrine levels, but no difference in muscle lactate. Despite progressive hypotension in all groups, both dexmedetomidine and esmolol were associated with lower arterial and portal vein lactate levels. Exogenous lactate clearance was significantly higher in the dexmedetomidine and esmolol groups. CONCLUSIONS: Dexmedetomidine and esmolol were associated with lower arterial and portal lactate levels, and less impairment of exogenous lactate clearance in a model of septic shock. The use of dexmedetomidine and esmolol appears to be associated with beneficial effects on gut lactate generation and lactate clearance and exhibits no negative impact on systemic hemodynamics. PMID- 27480415 TI - Loss of APAF-1 expression is associated with early recurrence in stage I, II, and III colorectal cancer. AB - PURPOSE: Apoptotic protease activating factor-1 (APAF-1) is a key regulator in the mitochondrial apoptotic pathway and an important diagnostic and therapeutic biomarker. Loss of APAF-1 expression has been observed in various tumors including colorectal cancer. The aim of our study was to evaluate the relationship between loss of APAF-1 expression and early recurrence of stage I III colorectal cancer. METHODS: We investigated 165 out of 492 patients who had undergone curative resection for colorectal cancer between 1991 and 2001. Sixty one patients (37.0 %) had early recurrence within 1 year after surgery. Tissue microarrays were used for immunohistochemical detection of APAF-1. RESULTS: The mean age of patients with recurrence was 58 years (range, 24-85); 88 (53.3 %, 88/165) were male. APAF-1 was expressed in 32 (19.4 %, 32/165) cases and was not expressed in 133 (80.6 %, 133/165). In univariate analysis, early recurrence significantly correlated with loss of APAF-1 expression (p = 0.017), tumor stage (p = 0.005), N category (p = 0.001), and lymphatic invasion (p = 0.008). In a logistic regression model, loss of APAF-1 expression (p = 0.015, 95 % CI = 1.280 10.063) and N category (p = 0.001, 95 % CI = 0.004-0.739) proved to be independent risk factors associated with early recurrence. In patients with lymph node metastasis, early recurrence was more frequent in the APAF-1-negative group than in the APAF-1-positive group (46.2 % (54/117) vs. 22.2 % (6/27), p = 0.023). CONCLUSIONS: Loss of APAF-1 expression is associated with early recurrence in stage I-III colorectal cancer, suggesting that APAF-1 may have clinical value as a predictive marker of early recurrence. PMID- 27480416 TI - Complete genome sequence of a novel potyvirus, callistephus mottle virus, identified in Callistephus chinensis. AB - The complete genomic sequence of a novel putative member of the genus Potyvirus was detected from Callistephus chinensis (China aster) in South Korea. The genomic RNA consists of 9,859 nucleotides (excluding the 3' poly(A) tail) and contains the typical open reading frame of potyviruses, encoding a putative large polyprotein of 3,154 amino acids. The Callistephus virus is most closely related to plum pox virus and members of the ApVY subgroup which showed 50-52 % polyprotein amino acid sequence identity. These results suggest that the Callistephus virus is a novel member of the genus Potyvirus, tentatively named "callistephus mottle virus" (CalMV). PMID- 27480417 TI - Critical Evaluation of Delayed Healing of Venous Leg Ulcers: A Retrospective Analysis in Canadian Patients. AB - BACKGROUND: Venous leg ulcers (VLUs) are common but challenging health problems. Better understanding of the risk factors involved in delayed healing of VLUs may therefore guide individualized treatment plans to improve patient outcomes. OBJECTIVE: We sought to identify the risk factors associated with delayed healing of VLUs in patients seen at a tertiary academic wound care clinic. METHODS: A retrospective analysis of 554 patients who presented to the Toronto Regional Wound Healing Clinic for VLUs in a 3-year period was performed. Patient and ulcer characteristics were recorded. Multivariate analyses were performed to compare patients with ulcer resolution and those whose ulcers did not resolve after 12 month follow-up. RESULTS: The average age of the patients was 67.3 +/- 0.7 years, with 56 % being female. The most common comorbidities were hypertension (54 %), dyslipidemia (33 %), a history of smoking (30 %), and diabetes (26 %). Ulcer resolution was associated with a smaller ulcer size (odds ratio [OR] 0.984 [95 % confidence interval (CI) 0.973, 0.996]), shorter ulcer duration (OR 0.704 [95 % CI 0.574, 0.865]), and dyslipidemia (OR 1.848 [95 % CI 1.052, 3.246]). CONCLUSION: Pro-healing factors associated with VLUs were a smaller ulcer size and a shorter ulcer duration. Dyslipidemia was also associated with improved healing, potentially owing to the use of statins. Patients presenting with poorer prognosis VLUs should receive more aggressive treatment with earlier referral to vascular surgery. PMID- 27480418 TI - Nationwide Assessment of Cause-Specific Mortality in Patients with Rosacea: A Cohort Study in Denmark. AB - BACKGROUND: Emerging data suggest that rosacea is associated with several comorbidities; however, the causes of mortality in patients with rosacea have not yet been investigated. OBJECTIVE: We evaluated all-cause and cause-specific death rates in patients with rosacea in a population-based Danish cohort study. METHODS: All Danish individuals aged >=18 years between 1 January 1997 and 31 December 2012 with rosacea diagnosed by hospital dermatologists were linked in nationwide registers and compared with age- and sex-matched general-population subjects (1:5 ratio). Death rates were calculated per 1000 person-years, and hazard ratios (HRs) were estimated using Cox regression models. RESULTS: The total cohort (n = 35,958) included 5993 patients with rosacea and 29,965 age- and sex-matched individuals from the general population. During the maximum 15 years of follow-up, 664 (11.1 %) patients with rosacea and 3121 (10.4 %) patients in the reference population died. The risk of all-cause mortality was similar in patients with rosacea and the reference population [HR 1.06, 95 % confidence interval (CI) 0.98-1.15]. Analyses of cause-specific mortality revealed a significantly increased risk of death due to gastrointestinal diseases in patients with rosacea (HR 1.95, 95 % CI 1.31-2.89), primarily related to hepatic disease. No increased risk of death due to other major disease categories, e.g. cancer, cardiovascular, neurological, or infectious diseases was observed. CONCLUSION: We observed a significantly increased risk of death due to gastrointestinal diseases (primarily hepatic disease) in patients with rosacea; however, we found no increased risk of death due to other causes such as cardiovascular or neurological diseases. Although this does not necessarily imply a causal link, the findings underscore the association between rosacea and gastrointestinal disease, but also that rosacea may be associated with increased risk factors, including alcohol consumption. PMID- 27480421 TI - British scientists seek guarantees for researchers bidding for EU funding. PMID- 27480422 TI - Erratum. AB - Riedel, L. E., Barry, C. L., McGinty, E. E., Bandara, S. N., Webster, D. W., Toone, R. E., et al. (2016). Improving Health Care Linkages for Criminal Justice Involved Persons: The Cook County Jail Medicaid Enrollment Initiative. Journal of Correctional Health Care, 22, 189-199.Original doi: 10.1177/1078345816653199In the July 2016 issue, the title of the article was incorrectly published as "Improving Health Care Linkages for Persons: The Cook County Jail Medicaid Enrollment Initiative".The correct title should read as "Improving Health Care Linkages for Criminal Justice-Involved Persons: The Cook County Jail Medicaid Enrollment Initiative." PMID- 27480420 TI - How Families Make Sense of Their Child's Behaviour When on an Autism Assessment and Diagnosis Waiting List. AB - Families waiting for an Autism Spectrum Condition assessment often experience difficulties explaining, or making sense of, the referred young person's behaviour. Little is known about this sense making, or how clinicians might support this ambiguity. This paper explored finite details of how five families do 'sense-making' in conversations with each other, while on the waiting list for an ASC assessment. A Discursive Psychology analysis of these conversations found that sense making was affected by (1) an interactional pattern of interruptions impeding the progress of sense making narratives; (2) face saving to maintain positive identities and shared understanding; and (3) difficulties in word finding within sense making narratives. These practices challenged the production of a coherent family sense making narrative. PMID- 27480423 TI - Impact of a Neighborhood-Based Curriculum on the Helpfulness of Pediatric Residents' Anticipatory Guidance to Impoverished Families. AB - Introduction Neighborhood location has been shown to impact childhood health and well-being. It follows that neighborhood context-the risks and assets present within a patient's neighborhood-may be an important consideration during provision of primary care. Pediatric residents often serve as the primary care physicians for high risk populations though are often unfamiliar with local neighborhoods. As such, education interventions that deepen residents' understanding of a patient's neighborhood context may allow for targeted care provision. A neighborhood-based curriculum was therefore created to improve residents' familiarity with local neighborhoods. Methods The neighborhood-based curriculum utilized a shared interactive presentation to address the topics of housing, nutrition, safe play, pharmacies, and transportation. Education modules included introduction to readily available on-line resources. A pre-post survey assessed resident self-perceived competence on the curricular topics of interest. Caregivers were interviewed in the post-curriculum period to rate the helpfulness of resident-administered advice. Results Following the curriculum, residents reported improved competence on the topics of safe play and transportation (p < 0.05). When addressed in the clinical setting, the large majority of families felt that residents' advice on curricular topics was helpful; however, individual curricular topics were not consistently addressed during clinical encounters. Discussion A neighborhood-based education curriculum can be effective in teaching pediatric residents about the social determinants of health and local neighborhood resources. As research increasingly demonstrates the impact of neighborhood on health, we expect further educational focus on neighborhood as a means from which to educate residents who often care for an impoverished population. PMID- 27480425 TI - [Why dentists need to learn the epidemiological status and prevention strategy of coronary heart disease in China]. AB - Coronary heart disease(CHD) is the leading cause of death among 235 causes of death in human currently and kills more than 7 million peoples annually worldwide and will continuously be ranked as the top cause of death in next 20 years according the prediction. As the population aging and epidemics of major risk factors of CHD, there are remarkable raising incidence and mortality of CHD in Chinese population with increasing numbers of CHD patients. The CHD patients may visit dental clinics to seek help because of their oral or dental diseases. Some of those CHD patients may not be even aware of that they have CHD or the severity of their disease, and some of them may not know well for the medications they are taking. All of those situations may increase the risk of acute CHD event or other complications during clinical processes either for diagnosis or treatment in dental clinics. Therefore, it is important for dentists to learn basic knowledge of CHD including epidemiology and clinical characteristics and treatments of CHD. PMID- 27480424 TI - C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which causes progressive and eventually fatal loss of motor function. Here, we describe genetic and pathologic characterization of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats (DPRs), and ubiquilin. We identified 2 cases with C9ORF72 repeat expansions. Both harbored phosphorylated TDP-43 and DPR inclusions. We show that DPR inclusions can incorporate or occur independently of ubiquilin. We also identified 1 case with a UBQLN2 mutation, which showed phosphorylated TDP-43 and characteristic ubiquilin protein inclusions. This is the first study of ALS genetics in New Zealand, adding New Zealand to the growing list of countries in which C9ORF72 repeat expansion and UBQLN2 mutations are detected in ALS cases. PMID- 27480426 TI - [Prevention and treatment of cardiovascular complications of oral therapy]. AB - Acute cardiovascular event is common acute complication in oral therapy. This article describes how to assess risk of cardiovascular complications before oral treatment, and elabrates the prevention and treatment of angina, acute myocardial infarction, arrhythmia, cardiac arrest, cardiopulmonary resuscitation and other cardiovascular complications. Detailed assessment and comprehensive management of patients are important guarantee for safe oral treatment. PMID- 27480427 TI - [Risk prevention in patients on antithrombotic therapy for common oral invasive treatment]. AB - The high incidence of cardiovascular diseases makes the dentists have more chance to treat patients who receive antithrombotic therapy. Limited by the profession, many dentists are unfamiliar with the systemic disease that the patients suffer from, especially struggle with whether or not to stop the antithrombotic therapy before the invasive diagnosis and treatment such as tooth extraction, dental implant placement and periodontal treatment. Stopping antithrombotic drugs may lead to thrombosis risk, while sustaining antithrombotic drug treatment may lead to bleeding risk. Through literature review and the experience of oral diagnosis and treatment of patients with cardiovascular diseases in our department for many years, the author aims to discuss preventive measures of bleeding and thrombosis risk of patients with oral antithrombotic therapy in oral invasive diagnosis. PMID- 27480428 TI - [Risk assessment and management of exodontia perioperative patients with cardiovascular diseases]. AB - The number of tooth extraction patients with cardiovascular disease in our country is increasing year by year. Safety is essential for those patients and there is no uniform standard of risk assessment and management for tooth extraction patients with cardiovascular disease during perioperative period. By referring to literatures and with the clinical experience, the author summarized the risk assessment methods for tooth extraction patients with cardiovascular disease during perioperative period. Blood pressure control, cardiac function determination, arrhythmia recognition, blood glucose management, oral antiplatelet or anticoagulant medicine use, etc, were proposed in this article. PMID- 27480429 TI - [Clinical application of titanium plate reconstruction of mandibular defect: 10 years of follow up]. AB - OBJECTIVE: To summarize the postoperative complications of reconstruction of mandible defect with titanium reconstruction plate. METHODS: A total of 111 cases of the mandibular defect caused by various reasons and repaired by titanium reconstruction plate in the Department Oral and Maxillofacial Surgery of the affiliated Hospital of Qingdao University from 2003 to 2012 were collected and followed up. The complications were analyzed. RESULTS: Thirty-seven percent of 111 cases showed long term complications. The titanium fracture was the main complication(16%[18/111]), followed by stress-shielding (9%[10/111]), infection(8%[9/111]), and titanium plate exposure(4%[4/111]). Titanium plate fracture occurred within 8 months and 3 years after surgery. The simple titanium plate reconstruction had the highest rate of plate fracture(30%[15/50]). Stress shielding in non-vascularized bone graft was more significant than that in vascularized bone graft(P<0.05). When replaced by mini-titanium plate, the stress shielding effect disappeared gradually. When the retention of mandibular margin height was less than 1 cm with the use of reconstruction plate, the postoperative complications were prone to occur. CONCLUSIONS: Bone graft is the best way to reconstruct mandibular defect, and simple reconstruction plate repair is applied only as a transitional means for high degree of malignancy, obvious recurrence tendency tumor or special reasons such as age etc, which are not suitable for bone graft. The reconstruction plate fixation is not recommended for bone graft, especially non-vascularized bone graft. The retention of mandibular margin with reconstruction plate fixation is open to discussion. PMID- 27480430 TI - [The anatomy of maxillary sinus in single maxillary posterior edentulous area based on cone-beam CT]. AB - OBJECTIVE: To compare the anatomy of maxillary sinus in single maxillary posterior edentulous area and the contralateral side without loss of tooth, and to investigate the effect of tooth loss on the anatomy of maxillary sinus by cone beam CT(CBCT). METHODS: A total of 128 patients with single unilateral single maxillary tooth loss were included in the study. CBCT was taken in these patients and the thickness of the maxillary lateral wall, mucosa thickness of sinus floor and sinus septa of the maxillary sinus were recorded and compared with the contralateral side. The bone height from the sinus floor to the ridge crest and the distance between maxillary sinus floor and the vascular anastomosis of maxillary lateral wall were analyzed. RESULTS: The thickness of maxillary sinus lateral wall and maxillary sinus mucosa were 1.59 (1.22), 1.61(1.95) mm in the maxillary posterior edentulous area and significantly less than those of the contralateral side(1.76[1.10], 1.91[2.23] mm)(P<0.05), and the data was demonstrated using median(quartile range). The difference of the mean number of maxillary sinus septa between the two sides was not statistically significant(P>0.05). There was a negative correlation between the bone height from the sinus floor to the ridge crest and the distance between maxillary sinus floor and the vascular anastomosis of maxillary lateral wall (r= -0.343, P<0.01). CONCLUSIONS: The changes of the thickness of lateral wall of maxillary sinus and maxillary sinus mucosa are closely related to tooth loss. The change of the number of maxillary sinus septa is not related to tooth loss. There is a negative correlation between the bone height from the sinus floor to the ridge crest and the distance between maxillary sinus floor and the vascular anastomosis of maxillary lateral wall. PMID- 27480431 TI - [A cone-beam CT investigation on the effect of two-phase treatment and fixed appliance treatment only on temporomandibular joint]. AB - OBJECTIVE: To assess the effects of two phase treatment(Herbst and fixed appliance) and fixed appliance treatment only(edgewise appliance) on temporomandibular joint in Cass II patients with mandibular retrusion using cone beam CT(CBCT) analysis. METHODS: Thirty Class II patients with mandibular retrusion in the permanent dentition were divided into two groups. Group A consisted of 15 patients with two phase treatment. Group B consisted of 15 patients with fixed appliance treatment only. CBCT was taken before(T1) and after(T2) treatment. The Invivo Dental software was used to calculate the relevant parameters of temporomandibular joint. Wilcoxon analysis was carried out. RESULTS: In group A, the condylar anterior-posterior diameters(7.41[2.55]) and the condylar head height(3.58[0.86]) increased significantly after treatment(P<0.05). In group B, all skeletal measurements had no significant changes(P> 0.05) after treatment. The changes of condylar head height in group A(0.60[0.48]) showed greater than in group B(0.02[0.21]) (P<0.05). No significant differences in the temporomandibular joint spaces were found before and after treatment, and between the two groups(P>0.05). CONCLUSIONS: Compared with fixed appliance treatment only, except for condylar growth changes, no significant changes of other skeletal morphology of the temporomandibular joint and the condyle position within the glenoid fossa were found between patients with two phase treatment and with fixed appliance treatment only. PMID- 27480432 TI - [Finite element analysis of different load mode on tooth movement for space closure in patient with bimaxillary protrusion]. AB - OBJECTIVE: To investigate the stress distribution on the maxillary anterior teeth retracted with sliding mechanics and micro-implant anchorage using different retraction hook heights and positions. METHODS: DICOM image data including maxilla and upper teeth were obtained with cone-beam CT. The three-dimensional finite element model was constructed using Mimics software. Brackets and archwire model were constructed using Creo software. The models were instantiated using Pro/Engineer software. Abaqus software was used to simulate the sliding mechanics by loading 2 N force on 0, 2, 4, 6, 8, 10 mm retraction hooks and three different positions, repectively. Rotation of the occlusal plane, the initial displacement and stress distribution of teeth were analyzed. RESULTS: Lingual rotation of maxillary central incisor(0.021 degrees ), gingival movement of the maxillary first molar(0.005 mm), and clockwise rotation of the maxillary occlusal plane(0.012 degrees ) were observed when the force application point located at the archwire level (0 mm). In contrast, 0.235 degrees labial rotation of the maxillary central incisor, 0.015 mm occlusal movement of the maxillary first molar, and 0.075 degrees anti-clockwise rotation of the maxillary occlusal plane were observed when the force application point located at the higher level(10 mm retraction hook). The more the force application point was located posteriorly at the archwire level, the less lingual rotation of the maxillary central incisor and the more buccal displacement of maxillary first molar was observed. CONCLUSIONS: Maxillary anterior tooth rotation and retraction, vertical displacement of posterior segment, and rotation of the occlusal plane could be controlled by adjusting the height and position of the retraction hook in space closure using miniscrew and sliding mechanics. PMID- 27480433 TI - [Experimental study on the in vitro osteogenic differentiation of dental pulp stem cells encapsulated in Pluronic F-127 hydrogel]. AB - OBJECTIVE: To evaluate the biocompatibility and viability of nonionic triblock copolymer Pluronic F-127 as a cell scaffold for osteogenic differentiation of dental pulp stem cells(DPSC). METHODS: DPSC were obtained via enzymatic digestion method and purified bylimited dilution method. The freeze dried hydrogel of 20% Pluronic F-127 was prepared and itsstructurewas observed usingscanning electron microscopy(SEM). After the encapsulation of cells of passage 3 in Pluronic F-127, the effects of hydrogel on the proliferations of DPSC were assessed with methyl thiazolyl terazolium(MTT) after one day and 3, 5, 7 days of incubations, respectively. On day 14, osteogenic abilities of DPSC encapsulated in the hydrogel were estimated by means of alizarin red S, immunocytochemical staining and real-time quantitative PCR(RT-qPCR). RESULTS: DPSC were isolated and cultured successfully in the present study. SEM observations showed that porous structures which might be suitable for cell culture. A570 values of MTT were then normalized. A570 values of the cells in 2D cultures were 0.30+/-0.06, 0.30+/ 0.17, 0.35+/-0.04 and 0.25+/-0.06 and A570 values of DPSC in 3D cultures were 0.36+/-0.06, 0.54+/-0.18, 0.70+/-0.10 and 0.32+/-0.10 on day 1, 3, 5 and 7, respectively. A570 value peaks were found on day 5 in both groups. The proliferation of 3D cultured DPSC was higher than that of 2D cultured cells(P<0.05). After 14 days of osteogenic induction, there were no calcium nodules observed in the control group and the numbers of calcium nodulesin the 2D and 3D groups had no significant difference(P>0.05). Inmmunocytochemical staining demonstrated strong expression of osteoblast marker Runt-related transcription factor 2(RUNX2), type I collagen(Col-I) and relatively low expression of osteocalcin(OCN). Moreover, RT-qPCR showed no differences between the relative expression of ALP, RUNX-2, OCN in the 2D and 3D groups (P>0.05), but a higher relative expression of Col-I was observed in the 3D group(P=0.023). CONCLUSIONS: Pluronic F-127 is a promising cell scaffold or cell carrier for the osteobalst differentiation of dental pulp stem cells. PMID- 27480434 TI - [Expression of p75 neurotrophin receptor during the mineralization of ectomesenchymal stem cells in vitro]. AB - OBJECTIVE: To investigate the mineralized capacities of ectomesenchymal stem cells (EMSC) from facial process of Sprague Dawley(SD) rat embryo of different age in vitro and the expression of p75 neurotrophin receptor(p75NTR) in this process. METHODS: The stem cell surface antigens of EMSC from 12.5 d, 15.5 d and 18.5 d SD rat embryonic facial process were tested by flow cytometry technology. E12.5 d EMSC, E15.5 d EMSC and E18.5 d EMSC were incubated under mineralization induction and analysed by alkaline phosphatase(ALP) staining on day 7(d7) and alizarin red staining on day 21(d21). Expression changes of Runt-related transcription factor-2(RUNX2), collagen I (Col I) and p75NTR in each group were measured using Western blotting and real time(RT)-PCR on day 0(d0), day 7(d7), day 14(d14) and day 21(d21). RESULTS: The expression of the special substances CD29, CD146 and p75NTR in E12.5 d EMSC, E15.5 d EMSC and E18.5 d EMSC were positive, and the expression of CD45 was negative. The expression level of p75NTR in E18.5 d EMSC(84.04%) was much higher than that of E12.5 d EMSC (22.53%) and E15.5 d EMSC(81.43%). The mineralized capacities of E18.5 d EMSC was stronger than that of E12.5 d EMSC and E15.5 d EMSC. The higher expression of RUNX2, Col I in E18.5 d EMSC(RUNX2: 1.92+/-0.20, Col I: 1.85+/-0.66) was found compared with E12.5 d EMSC(RUNX2: 0.38+/-0.02, Col I: 0.33+/- 0.94) and E15.5 d EMSC(RUNX2: 0.72+/-0.22, Col I: 0.64+/-0.07) (P<0.05), and p75NTR in the E18.5 d EMSC experimental group(E12.5 d: 0.79+/-0.23, E15.5 d: 0.84+/-0.29, E18.5 d: 1.35+/ 0.22) was significantly higher than the in control group(E12.5 d: 0.42+/-0.12, E15.5 d: 0.43+/-0.13, E18.5 d: 0.48+/-0.15)(P<0.05). RT-PCR further proved the results of the Western blotting. CONCLUSIONS: p75NTR participated in the mineralization differentiation of EMSC. E18.5 d EMSC had a higher expression of p75NTR and stronger mineralization capacity and was the ideal engineering seed cells. PMID- 27480436 TI - [Treatment and 10-year follow-up of a patient with severe combined periodontal endodontic lesions: a case report]. PMID- 27480435 TI - [Evaluation of the quality of three-dimensional data acquired by using two kinds of structure light intra-oral scanner to scan the crown preparation model]. AB - OBJECTIVE: To quantitatively evaluate the quality and accuracy of three dimensional (3D) data acquired by using two kinds of structure intra-oral scanner to scan the typical teeth crown preparations. METHODS: Eight typical teeth crown preparations model were scanned 3 times with two kinds of structured light intra oral scanner(A, B), as test group. A high precision model scanner were used to scan the model as true value group. The data above the cervical margin was extracted. The indexes of quality including non-manifold edges, the self intersections, highly-creased edges, spikes, small components, small tunnels, small holes and the anount of triangles were measured with the tool of mesh doctor in Geomagic studio 2012. The scanned data of test group were aligned to the data of true value group. 3D deviations of the test group compared with true value group were measured for each scanned point, each preparation and each group. Independent-samples Mann-Whitney U test was applied to analyze 3D deviations for each scanned point of A and B group. Correlation analysis was applied to index values and 3D deviation values. RESULTS: The total number of spikes in A group was 96, and that in B group and true value group were 5 and 0 respectively. Trueness: A group 8.0 (8.3) MUm, B group 9.5 (11.5) MUm(P>0.05). Correlation analysis of the number of spikes with data precision of A group was r=0.46. CONCLUSIONS: In the study, the qulity of the scanner B is better than scanner A, the difference of accuracy is not statistically significant. There is correlation between quality and data precision of the data scanned with scanner A. PMID- 27480437 TI - [Oxidative stress and antioxitant therapy of chronic periodontitis]. AB - Chronic periodontitis is a progressive, infectious inflammation disease, caused by the dysbiosis of oral resident flora, leading to the destruction of periodontium. The onset of pathogenic microorganisms is the etiological factor of periodontitis, while the immuno-inflammatory response affects the progression of the disease. Under chronic periodontitis, oxidative stress occurs when excessive reactive oxygen species are produced and exceed the compensative capacity of the organism. Oxidative stress leads to the destruction of periodontium, in a direct way(damaging the biomolecule) or an indirect way(enhancing the produce of inflammatory cytokine and destructive enzymes). Therefore, as the antagonist of the reactive oxygen species, antioxidants may be helpful to treat the chronic periodontitis. This paper reviewed relevant literatures about the destructive role of excessive reactive oxygen species and protective role of antioxidants in chronic periodontitis. PMID- 27480438 TI - Lung perfusion characteristics in pulmonary arterial hypertension (PAH) and peripheral forms of chronic thromboembolic pulmonary hypertension (pCTEPH): Dual energy CT experience in 31 patients. AB - PURPOSE: To compare lung perfusion in PAH and pCTEPH on dual-energy CT (DECT) examinations. MATERIALS AND METHODS: Thirty-one patients with PAH (group 1; n = 19) and pCTEPH (group 2; n = 12) underwent a dual-energy chest CTA with reconstruction of diagnostic and perfusion images. Perfusion alterations were analysed at a segmental level. V/Q scintigraphy was available in 22 patients (group 1: 13/19; group 2: 9/12). RESULTS: CT perfusion was abnormal in 52.6 % of group 1 patients and in 100 % of group 2 patients (p = 0.0051). The patterns of perfusion alteration significantly differed between the two groups (p < 0.0001): (1) in group 1, 96.6 % of segments with abnormal perfusion showed patchy defects; (2) in group 2, the most frequent abnormalities consisted of patchy (58.5 %) and PE-type (37.5 %) defects. Paired comparison of CT perfusion and scintigraphy showed concordant findings in 76.9 % of group 1 (10/13) and 100 % of group 2 (9/9) patients, with a predominant or an exclusive patchy pattern in group 1 and a mixed pattern of abnormalities in group 2. CONCLUSION: Lung perfusion alterations at DECT are less frequent and more homogeneous in PAH than in pCTEPH, with a high level of concordant findings with V/Q scintigraphy. KEY POINTS: * Depiction of chronic pulmonary embolism exclusively located on peripheral arteries is difficult. * The main differential diagnosis of pCTEPH is PAH. * The pattern of DECT perfusion changes can help differentiate PAH and pCETPH. * In PAH, almost all segments with abnormal perfusion showed patchy defects. * In pCTEPH, patchy and PE-type defects were the most frequent abnormalities. PMID- 27480439 TI - Morphological and Crystalline Transitions in Monohydrous and Anhydrous Aripiprazole for a Long-Acting Injectable Suspension. AB - Many formulation and manufacturing processes can lead to morphological and crystalline transitions in many polycrystalline drugs, changing the properties of active pharmaceutical ingredients (APIs) such as solubility and physical stability which influence their therapeutic effects and safety and so limit their usefulness. Here, we report significant changes in crystal forms and morphology, including the shape and size of particles during the manufacture of off-white aripiprazole (APZ) dry powders used for long-acting and injectable suspensions. With the optimal top-down approach, powders were prepared by recrystallizing uniform monohydrous APZ (MA) and polycrystalline anhydrous APZ (AA) form III, characterized by thermal analysis, PXRD, and FT-IR. However, powders involving MA (MAP) with a lower mean size (2.126 MUm), narrower distribution (span = 1.90), and higher stability compared with AA dry powders (AAP) were found to exhibit dehydration behavior and morphological changes after completion of the preparation processes based on the results of thermal analysis. In the case of APZ powders, we wished to obtain more information to guide in the industrial production and experimental design of suspensions in the future. PMID- 27480440 TI - Development and Optimization of an Ex Vivo Colloidal Stability Model for Nanoformulations. AB - Nanotechnology is having a significant impact in the drug delivery systems and diagnostic devices. As most of the nanosystems are intended to be administered in vivo, there is a need for stability models, which could simulate the biological environment. Instability issues could lead to particle aggregation and in turn could affect the release of the drug from the nanosystems and even lead to clogging of the systemic blood circulation leading to life-threatening situation. We have developed an ex vivo colloidal stability model for testing the stability of nanosystems over a period of 48 h, which is the typical residence time of the nanoparticles in vivo. Tissue homogenates of rat spleen, brain, kidney, and liver were stabilized and optimized for the study; additionally, plasma and serum were used for the same. Poly (lactide-co-glycolic acid) nanoparticles were used as model nanosystem, and no significant change was found in the size and polydispersity index of the nanoparticles in the biological solutions. Moreover, no change in morphology was observed after 48 h as observed by TEM microscopy. Hence, the developed model could prevent the failure of the developed nanosystem during clinical and preclinical application by serving as an initial checkpoint to study their interaction with the complex milieu. PMID- 27480441 TI - Eudragit S100-Coated Chitosan Nanoparticles Co-loading Tat for Enhanced Oral Colon Absorption of Insulin. AB - In order to improve oral absorption of insulin, especially the absorption at the colon, Eudragit S100(r) (ES)-coated chitosan nanoparticles loading insulin and a trans-activating transcriptional peptide (Tat) were employed as the vehicle. In vitro releases of insulin and Tat from ES-coated chitosan nanoparticles had a pH dependant characteristic. A small amount of the contents was released from the coated nanoparticles at pH 1.2 simulated gastric fluid, while a fairly fast and complete release was observed in pH 7.4 medium. Caco-2 cell was used as the model of cellular transport and uptake studies. The results showed that the cellular transport and uptake of insulin for ES-coated chitosan nanoparticles co-loading insulin and Tat (ES-Tat-cNPs) were about 3-fold and 4-fold higher than those for the nanoparticles loading only insulin (ES-cNPs), respectively. The evaluations in vivo of ES-Tat-cNPs were conducted on diabetic rats and normal minipigs, respectively. The experimental results on rats revealed that the pharmacodynamical bioavailability of ES-Tat-cNPs had 2.16-fold increase compared with ES-cNPs. After oral administration of nanoparticle suspensions to the minipigs, insulin bioavailability of ES-Tat-cNPs was 1.73-fold higher than that of ES-cNPs, and the main absorption site of insulin was probably located in the colon for the two nanoparticles. In summary, this report provided an exploratory means for the improvement of oral absorption of insulin. PMID- 27480442 TI - Evaluation of Organogel Nanoparticles as Drug Delivery System for Lipophilic Compounds. AB - The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds. PMID- 27480443 TI - Development and Characterization of Multifunctional Directly Compressible Co processed Excipient by Spray Drying Method. AB - The present investigation was carried out to develop and characterize a multifunctional co-processed excipient for improving the compressibility of poorly compressible drugs. Etodolac was used as a model drug. Microcrystalline cellulose (MCC), lactose monohydrate (lactose), and StarCap 1500 (StarCap) were selected as components of the co-processed excipient. The spray drying method was used for co-processing of excipients. D-optimal mixture design was applied to optimize the proportion of component excipients. Statistical analysis of the D optimal mixture design revealed that all response variables were significantly affected by the independent variables (p value < 0.05). Optimized composition was obtained from the desirability function. The optimized composition of the co processed excipient was found to be 30% MCC, 25% lactose, and 45% StarCap. This optimized batch was evaluated for flow properties, compressibility parameters such as Kawakita's and Kuno's equation and Heckel's equation, and dilution potential. Evaluation parameters for flow properties (angle of repose, Carr's index, and Hausner's ratio) suggested excellent flow character. The parameters of Kawakita's and Kuno's equation and Heckel's equation suggested improvement in the compressibility of the model drug. Dilution potential was found to be 40%, and based on that, tablets of the model drug were formulated and evaluated for general evaluation parameters of tablets. All the parameters were found to be within the acceptance criteria which concluded that the multifunctional directly compressible co-processed excipient was prepared successfully that improved the compressibility of the poorly compressible model drug etodolac along with spray drying as an efficient method for the preparation of co-processed excipient. PMID- 27480444 TI - First three-dimensional actinide polyrotaxane framework mediated by windmill-like six-connected oligomeric uranyl: dual roles of the pseudorotaxane precursor. AB - The first 3D actinide polyrotaxane framework (named IHEP-URCP-2) has been obtained based on windmill-like six-connected high-nuclear oligomeric uranyl nodes under hydrothermal conditions. Notably, the in situ formed pseudorotaxane ligand simultaneously plays dual roles of both a bulky pseudorotaxane linker and a supramolecular guest. PMID- 27480445 TI - Reward and relief dimensions of temptation to drink: construct validity and role in predicting differential benefit from acamprosate and naltrexone. AB - Researchers have sought to distinguish between individuals whose alcohol use disorder (AUD) is maintained by drinking to relieve negative affect ('relief drinkers') and those whose AUD is maintained by the rewarding effects of alcohol ('reward drinkers'). As an opioid receptor antagonist, naltrexone may be particularly effective for reward drinkers. Acamprosate, which has been shown to down-regulate the glutamatergic system, may be particularly effective for relief drinkers. This study sought to replicate and extend prior work (PREDICT study; Glockner-Rist et al. ) by examining dimensions of reward and relief temptation to drink and subtypes of individuals with distinct patterns of reward/relief temptation. We utilized data from two randomized clinical trials for AUD (Project MATCH, n = 1726 and COMBINE study, n = 1383). We also tested whether classes of reward/relief temptation would predict differential response to naltrexone and acamprosate in COMBINE. Results replicated prior work by identifying reward and relief temptation factors, which had excellent reliability and construct validity. Using factor mixture modeling, we identified five distinct classes of reward/relief temptation that replicated across studies. In COMBINE, we found a significant class-by-acamprosate interaction effect. Among those most likely classified in the high relief/moderate reward temptation class, individuals had better drinking outcomes if assigned to acamprosate versus placebo. We did not find a significant class-by-naltrexone interaction effect. Our study questions the orthogonal classification of drinkers into only two types (reward or relief drinkers) and adds to the body of research on moderators of acamprosate, which may inform clinical decision making in the treatment of AUD. PMID- 27480446 TI - Excretory and Secretory Proteins of Naegleria fowleri Induce Inflammatory Responses in BV-2 Microglial Cells. AB - Naegleria fowleri, a free-living amoeba that is found in diverse environmental habitats, can cause a type of fulminating hemorrhagic meningoencephalitis, primary amoebic meningoencephalitis (PAM), in humans. The pathogenesis of PAM is not fully understood, but it is likely to be primarily caused by disruption of the host's nervous system via a direct phagocytic mechanism by the amoeba. Naegleria fowleri trophozoites are known to secrete diverse proteins that may indirectly contribute to the pathogenic function of the amoeba, but this factor is not clearly understood. In this study, we analyzed the inflammatory responses in BV-2 microglial cells induced by excretory and secretory proteins of N. fowleri (NfESP). Treatment of BV-2 cells with NfESP induced the expression of various cytokines and chemokines, including the proinflammatory cytokines IL 1alpha and TNF-alpha. NfESP-induced IL-1alpha and TNF-alpha expression in BV-2 cells were regulated by p38, JNK, and ERK MAPKs. NfESP-induced IL-1alpha and TNF alpha production in BV-2 cells were effectively downregulated by inhibition of NF kB and AP-1. These results collectively suggest that NfESP stimulates BV-2 cells to release IL-1alpha and TNF-alpha via NF-kB- and AP-1-dependent MAPK signaling pathways. The released cytokines may contribute to inflammatory responses in microglia and other cell types in the brain during N. fowleri infection. PMID- 27480447 TI - Corrigendum: NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells. PMID- 27480448 TI - 3D morphometry aids facial analysis of individuals with a childhood cancer. AB - A group of patients who had cancer as a child were previously found to have distinct patterns of morphological abnormalities. In this study, we investigated the added value of 3D shape analysis to characterize their facial morphology. Primarily, we showed in an objective and quantitative manner that the overall facial dysmorphism of the individuals who had had a childhood cancer was significantly greater than that of the controls. We also demonstrated how the same approach can be used to detect a similar disparity for a more localized malar region comprising customized disconnected patches defined on both sides of the face. In addition, by comparing original face surfaces to their mirrored forms, we confirmed that the patient group had significantly greater facial asymmetry than the controls. Each of these results made use of surface shape differences not detectable by simple linear or angular characteristics as might be used in analyses based on measures captured manually or derived from landmarks annotating 2D photographic images. We conclude that 3D morphometric analysis of a relatively small heterogeneous patient group can further delineate face shape differences from typically developing individuals that are too subtle or geometrically complex to identify or quantify objectively with conventional clinical and anthropometric approaches. (c) 2016 Wiley Periodicals, Inc. PMID- 27480449 TI - Randomized, double-blind, placebo-controlled trial to evaluate the effect of Helicobacter pylori eradication on glucose homeostasis in type 2 diabetic patients. AB - BACKGROUND AND AIMS: Literature data suggest an association between Helicobacter pylori infection and glucose homeostasis. However, a causative link between them has not been demonstrated yet. The aim of this study is to investigate the effect of H. pylori eradication on glucose homeostasis in patients with type 2 diabetes. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled trial was conducted to investigate the effect of H. pylori eradication on glucose homeostasis in 154 patients with type 2 diabetes and who tested positive for H. pylori infection (mean age (SD), 63.1 (8.1) years). Subjects were assigned to H. pylori eradication treatment or placebo. Metabolic and inflammatory parameters were measured in all subjects at baseline and 4 weeks after the treatment. H. pylori eradication led to an improvement in glucose homeostasis, measured by HOMA IR (p < 0.001) and KITT (0 = 0.041), due to the decrease in fasting insulin levels (p = 0.004). The results also showed that lower levels of inflammatory parameters were present after eradication. CONCLUSION: To our knowledge this is the first randomized, double blind, controlled study where the effect of H. pylori eradication on glucose homeostasis in subjects with type 2 diabetes has been investigated. Our findings demonstrate that H. pylori eradication improves glucose homeostasis in patients with type 2 diabetes through a decrease in pro inflammatory factors. TRIAL REGISTRATION NUMBER: ACTRN12609000255280 (https://www.anzctr.org.au/). PMID- 27480452 TI - Validation and in vivo assessment of an innovative satellite-based solar UV dosimeter for a mobile app dedicated to skin health. AB - We present an innovative satellite-based solar UV (ultraviolet) radiation dosimeter with a mobile app interface that has been validated by exploiting both ground-based measurements and an in vivo assessment of the erythemal effects on some volunteers having controlled exposure to solar radiation. The app with this satellite-based UV dosimeter also includes other related functionalities such as the provision of safe sun exposure time updated in real-time and end exposure visual/sound alert. Both validations showed that the system has a good accuracy and reliability needed for health-related applications. This app will be launched on the market by siHealth Ltd in May 2016 under the name of "HappySun" and is available for both Android and iOS devices (more info on ). Extensive R&D activities are on-going for the further improvement of the satellite-based UV dosimeter's accuracy. PMID- 27480450 TI - Role of nanoparticle size, shape and surface chemistry in oral drug delivery. AB - Nanoparticles find intriguing applications in oral drug delivery since they present a large surface area for interactions with the gastrointestinal tract and can be modified in various ways to address the barriers associated with oral delivery. The size, shape and surface chemistry of nanoparticles can greatly impact cellular uptake and efficacy of the treatment. However, the interplay between particle size, shape and surface chemistry has not been well investigated especially for oral drug delivery. To this end, we prepared sphere-, rod- and disc-shaped nanoparticles and conjugated them with targeting ligands to study the influence of size, shape and surface chemistry on their uptake and transport across intestinal cells. A triple co-culture model of intestinal cells was utilized to more closely mimic the intestinal epithelium. Results demonstrated higher cellular uptake of rod-shaped nanoparticles in the co-culture compared to spheres regardless of the presence of active targeting moieties. Transport of nanorods across the intestinal co-culture was also significantly higher than spheres. The findings indicate that nanoparticle-mediated oral drug delivery can be potentially improved with departure from spherical shape which has been traditionally utilized for the design of nanoparticles. We believe that understanding the role of nanoparticle geometry in intestinal uptake and transport will bring forth a paradigm shift in nanoparticle engineering for oral delivery and non-spherical nanoparticles should be further investigated and considered for oral delivery of therapeutic drugs and diagnostic materials. PMID- 27480451 TI - Coated minispheres of salmon calcitonin target rat intestinal regions to achieve systemic bioavailability: Comparison between intestinal instillation and oral gavage. AB - Achieving oral peptide delivery is an elusive challenge. Emulsion-based minispheres of salmon calcitonin (sCT) were synthesized using single multiple pill (SmPill(r)) technology incorporating the permeation enhancers (PEs): sodium taurodeoxycholate (NaTDC), sodium caprate (C10), or coco-glucoside (CG), or the pH acidifier, citric acid (CA). Minispheres were coated with an outer layer of Eudragit(r) L30 D-55 (designed for jejunal release) or Surelease(r)/Pectin (designed for colonic release). The process was mild and in vitro biological activity of sCT was retained upon release from minispheres stored up to 4months. In vitro release profiles suggested that sCT was released from minispheres by diffusion through coatings due to swelling of gelatin and the polymeric matrix upon contact with PBS at pH6.8. X-ray analysis confirmed that coated minispheres dissolved at the intended intestinal region of rats following oral gavage. Uncoated minispheres at a dose of ~2000I.U.sCT/kg were administered to rats by intra-jejunal (i.j.) or intra-colonic (i.c.) instillation and caused hypocalcaemia. Notable sCT absolute bioavailability (F) values were: 5.5% from minispheres containing NaTDC (i.j), 17.3% with CG (i.c.) and 18.2% with C10 (i.c.). Coated minispheres administered by oral gavage at threefold higher doses also induced hypocalcaemia. A highly competitive F value of 2.7% was obtained for orally-administered sCT-minispheres containing CG (45MUmol/kg) and coated with Eudragit(r). In conclusion, the SmPill(r) technology is a potential dosage form for several peptides when formulated with PEs and coated for regional delivery. PK data from instillations over-estimates oral bioavailability and poorly predicts rank ordering of formulations. PMID- 27480453 TI - Exhaled breath condensate as a source of biomarkers for lung carcinomas. A focus on genetic and epigenetic markers-A mini-review. AB - Lung carcinoma is one of the most common causes of cancer-related mortality worldwide. It is an aggressive tumor, often diagnosed at an advanced stage when treatment options are limited. Currently, the importance of detection and assessment of various genetic alterations in cancer is recognized as they can serve as very helpful markers in early diagnosis and follow-up of treatment regimens. Recently, several therapeutically important genetic markers have been identified. One major problem is that tumor tissue specimens used to assay these genetic biomarkers are not always available, especially in the early stages of the disease. Therefore, exhaled breath condensates (EBC) could represent a good non-invasive source to allow the evaluation of these important genetic markers; these could help in the diagnosis, follow-up of the disease and/or assessment of treatment efficacy. The key aims of this review are first to describe the origin and constituents of EBC, as well as the different methodological procedures used in studying EBC biomarkers, and second, to document genetic and epigenetic markers that have been analyzed in EBC from lung cancer patients and to estimate their diagnostic and prognostic value. (c) 2016 Wiley Periodicals, Inc. PMID- 27480454 TI - Social Network Factors as Correlates and Predictors of High Depressive Symptoms Among Black Men Who Have Sex with Men in HPTN 061. AB - Depression is linked to a range of poor HIV-related health outcomes. Minorities and men who have sex with men (MSM), suffer from high rates of depression. The current study examined the relationship between depressive symptoms and social network characteristics among community-recruited Black MSM in HPTN 061 from 6 US cities. A social network inventory was administer at baseline and depression was assessed with the CES-D at baseline, 6, and 12-months. At baseline, which included 1167 HIV negative and 348 HIV positive participants, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms. In longitudinal mixed models, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms as was the number of network members seen weekly. In the multivariate analyses, size of medical appointment network remained statistically significant (aOR 0.89, CI 0.81-0.98). These findings highlight the importance of network support of medical care on depression and suggest the value of support mobilization. PMID- 27480455 TI - Vitamin D levels in 87 Asian patients with cutaneous lupus erythematosus: a case control study. AB - BACKGROUND: Cutaneous lupus erythematosus (CLE) is an autoimmune disease, often exacerbated by sun exposure. Patients are encouraged to avoid sun exposure, therefore predisposing them to vitamin D deficiency. AIM: To investigate the prevalence of and risk factors for vitamin D deficiency in patients with CLE. METHODS: Total serum 25-hydroxy vitamin D (25(OH)D) was measured in 87 consecutive patients with CLE and in 79 controls. Clinical characteristics, disease severity, medications used and lifestyle factors were analysed and compared to determine risk factors for inadequate (25(OH)D), defined as a serum (25(OH)D) level of < 20 MUg/L. RESULTS: We found that 51% (n = 44) of the patients with CLE had 25(OH)D levels of < 20 MUg/L compared with 73% (n = 58) of the controls (P < 0.01). No significant differences in (25(OH)D) levels were found between cases and controls with regard to age, sex, ethnicity, smoking, sun exposure, sunblock use or vitamin D supplementation. Treatment with antimalarials showed a statistically significant association with lower vitamin D levels. CONCLUSION: Low levels of vitamin D were found in both patients with CLE and controls. Despite being on vitamin D supplementation and living in an equatorial location, our Asian patients with CLE still had low levels of vitamin D. It is therefore important to ensure adequate vitamin D supplementation in patients with CLE, especially for those who are on antimalarial therapy. PMID- 27480457 TI - Special Issue on Research in Biomedical Engineering at the University of Illinois at Chicago: Fifty Years of Excellence. PMID- 27480456 TI - Predictors of patient satisfaction in an emergency care centre in central Saudi Arabia: a prospective study. AB - AIM: This study aimed to (i) assess the level of patient satisfaction and its association with different sociodemographic and healthcare characteristics in an emergency care centre (ECC) in Saudi Arabia and (ii) to identify the predictors of patients' satisfaction. METHODS: A prospective cohort study of 390 adult patients with Canadian triage category III and IV who visited ECC at King Abdulaziz Medical City, Riyadh, Saudi Arabia, between 1 July and end of September 2011 was conducted. All patients were followed up from the time of arrival at the front desk of ECC until being seen by a doctor, and were then interviewed. Patient satisfaction was measured using a previously validated interview questionnaire, within two domains: clarity of medical information and relationship with staff. Patient perception of health status after as compared with before the visit, and overall life satisfaction were also measured. Data on patient characteristics and healthcare characteristics were collected. Multiple linear regression analysis was used, and significance was considered at p<=0.05. RESULTS: One-third (32.8%) of patients showed high level of overall satisfaction and 26.7% were unsatisfied, with percentage mean score of 70.36% (17.40), reflecting moderate satisfaction. After adjusting for all potential confounders, lower satisfaction with the ED visit was significantly associated with male gender (p<0.001), long waiting time (p=0.032) and low perceived health status compared with status at admission (p<0.001). Overall life satisfaction was not a significant predictor of patient satisfaction. CONCLUSIONS: An appreciation of waiting time as the only significant modifiable risk factor of patient satisfaction is essential to improve the healthcare services, especially at emergency settings. PMID- 27480458 TI - Sensory Recalibration from Visually Amplified Rotations While Walking. AB - Recent work has pointed to the advantages of using distorted reality to foster sensorimotor adaptations. Here we evaluate the extent to which a visuomotor discrepancy created within the large CAVE2 Hybrid Reality Environment might induce an adaptive effect in walking. This experiment specifically studied the consequences of exposure to a rotational gain that made it appear as though the subjects were turning more than actual by a ratio of 3 to 2. We then studied subjects' abilities make turns while blindfolded before and after the experience. This brief training period (~5 minutes) resulted in slightly larger turns. Such rapid adaptive responses can be interpreted as an alteration of the motor plan and possibly a recalibration of proprioceptive and vestibular senses caused by the alteration of visual input. This study provides preliminary evidence of the possibilities of using distorted reality to constructively enhance motor training and rehabilitation. PMID- 27480459 TI - Atomic Layer Deposition in Bio-Nanotechnology: A Brief Overview. AB - Atomic layer deposition (ALD) is a technique increasingly used in nanotechnology and ultrathin film deposition; it is ideal for films in the nanometer and Angstrom length scales. ALD can effectively be used to modify the surface chemistry and functionalization of engineering-related and biologically important surfaces. It can also be used to alter the mechanical, electrical, chemical, and other properties of materials that are increasingly used in biomedical engineering and biological sciences. ALD is a relatively new technique for optimizing materials for use in bio-nanotechnology. Here, after a brief review of the more widely used modes of ALD and a few of its applications in biotechnology, selected results that show the potential of ALD in bio-nanotechnology are presented. ALD seems to be a promising means for tuning the hydrophilicity/hydrophobicity characteristics of biomedical surfaces, forming conformal ultrathin coatings with desirable properties on biomedical substrates with a high aspect ratio, tuning the antibacterial properties of substrate surfaces of interest, and yielding multifunctional biomaterials for medical implants and other devices. PMID- 27480460 TI - Biomedical Applications of Quantum Dots, Nucleic Acid-Based Aptamers, and Nanostructures in Biosensors. AB - This review is a survey of the biomedical applications of semiconductor quantum dots, nucleic acid-based aptamers, and nanosensors as molecular biosensors. It focuses on the detection of analytes in biomedical applications using (1) advances in molecular beacons incorporating semiconductor quantum dots and nanoscale quenching elements; (2) aptamer-based nanosensors on a variety of platforms, including graphene; (3) Raman scattering and surface-enhanced Raman scattering (SERS) using nanostructures for enhanced SERS spectra of biomolecules, including aptamers; and (4) the electrical and optical properties of nanostructures incorporated into molecular beacons and aptamer-based nanosensors. Research done at the University of Illinois at Chicago (UIC) is highlighted throughout since it emphasizes the specific approaches taken by the bioengineering department at UIC. PMID- 27480461 TI - Super-Resolution Scanning Laser Microscopy Based on Virtually Structured Detection. AB - Light microscopy plays a key role in biological studies and medical diagnosis. The spatial resolution of conventional optical microscopes is limited to approximately half the wavelength of the illumination light as a result of the diffraction limit. Several approaches-including confocal microscopy, stimulated emission depletion microscopy, stochastic optical reconstruction microscopy, photoactivated localization microscopy, and structured illumination microscopy have been established to achieve super-resolution imaging. However, none of these methods is suitable for the super-resolution ophthalmoscopy of retinal structures because of laser safety issues and inevitable eye movements. We recently experimentally validated virtually structured detection (VSD) as an alternative strategy to extend the diffraction limit. Without the complexity of structured illumination, VSD provides an easy, low-cost, and phase artifact-free strategy to achieve super-resolution in scanning laser microscopy. In this article we summarize the basic principles of the VSD method, review our demonstrated single point and line-scan super-resolution systems, and discuss both technical challenges and the potential of VSD-based instrumentation for super-resolution ophthalmoscopy of the retina. PMID- 27480463 TI - miRs*: Innocent bystanders only? PMID- 27480464 TI - Long-term outcomes of implants placed after vertical alveolar ridge augmentation in partially edentulous patients: a 10-year prospective clinical study. AB - AIM: The aim of this study was to evaluate the long-term clinical results around non-submerged implants placed after vertical alveolar ridge augmentation. MATERIAL AND METHODS: The original population consisted of two groups of partially edentulous patients (Clinical Oral Implants Research, 15, 2004, 73; Clinical Oral Implants Research, 18, 2007, 286), receiving a total of 82 implants, after a vertical bone augmentation of at least 4 mm. Following cementation of the fixed dental prostheses, patients were asked to follow an individualized supportive periodontal therapy (SPT) program for an appropriate clinical and radiographic follow-up. RESULTS: At the 10-year examination, seven of the 41 patients were lost to follow-up. During SPT, additional antibiotic and/or surgical therapy was necessary in 18 implants, and four of these implants were removed for biological complications. The overall implant survival rate was 94.1%. The mean interproximal bone loss (BL) was 0.58 +/- 0.57 mm. CONCLUSIONS: The results of this study confirmed that implants, placed after vertical augmentation and followed by an adequate SPT, offer predictable long-term results. Nevertheless, patients whose bone atrophy was consequence of a previous history of periodontitis presented a statistically significant greater BL. PMID- 27480462 TI - Multiscale Modeling of Cellular Epigenetic States: Stochasticity in Molecular Networks, Chromatin Folding in Cell Nuclei, and Tissue Pattern Formation of Cells. AB - Genome sequences provide the overall genetic blueprint of cells, but cells possessing the same genome can exhibit diverse phenotypes. There is a multitude of mechanisms controlling cellular epigenetic states and that dictate the behavior of cells. Among these, networks of interacting molecules, often under stochastic control, depending on the specific wirings of molecular components and the physiological conditions, can have a different landscape of cellular states. In addition, chromosome folding in three-dimensional space provides another important control mechanism for selective activation and repression of gene expression. Fully differentiated cells with different properties grow, divide, and interact through mechanical forces and communicate through signal transduction, resulting in the formation of complex tissue patterns. Developing quantitative models to study these multi-scale phenomena and to identify opportunities for improving human health requires development of theoretical models, algorithms, and computational tools. Here we review recent progress made in these important directions. PMID- 27480465 TI - New insights into the history of domesticated and wild apricots and its contribution to Plum pox virus resistance. AB - Studying domesticated species and their wild relatives allows understanding of the mechanisms of population divergence and adaptation, and identifying valuable genetic resources. Apricot is an important fruit in the Northern hemisphere, where it is threatened by the Plum pox virus (PPV), causing the sharka disease. The histories of apricot domestication and of its resistance to sharka are however still poorly understood. We used 18 microsatellite markers to genotype a collection of 230 wild trees from Central Asia and 142 cultivated apricots as representatives of the worldwide cultivated apricot germplasm; we also performed experimental PPV inoculation tests. The genetic markers revealed highest levels of diversity in Central Asian and Chinese wild and cultivated apricots, confirming an origin in this region. In cultivated apricots, Chinese accessions were differentiated from more Western accessions, while cultivated apricots were differentiated from wild apricots. An approximate Bayesian approach indicated that apricots likely underwent two independent domestication events, with bottlenecks, from the same wild population. Central Asian native apricots exhibited genetic subdivision and high frequency of resistance to sharka. Altogether, our results contribute to the understanding of the domestication history of cultivated apricot and point to valuable genetic diversity in the extant genetic resources of wild apricots. PMID- 27480467 TI - Evaluation of sexual function in females with exstrophy-epispadias-complex: A survey of the multicenter German CURE-Net. AB - OBJECTIVE: Standardized knowledge about genital function in adult female individuals with exstrophy-epispadias complex (EEC) is scarce. The aim of this study was to investigate sexual function using the standardized Female Sexual Function Index (FSFI), and to assess the influence of bladder and vaginal reconstruction and the presence of incontinence on FSFI results. METHOD: Sixty one females (aged >=18 years) recruited by the German multicenter network for congenital uro-rectal malformations (CURE-Net) were asked to complete the FSFI and a self-designed semi-structured questionnaire assessing comprehensive medical data, gynecological, and psychosocial items. Twenty-one eligible females (34%) returned both questionnaires (mean +/- standard deviation [SD] age of 26 +/- 5.1 years). RESULTS: In 43% of participants, a staged or single-staged approach had been used for reconstruction, and these had their bladder in use. A primary or secondary urinary diversion (UD) after cystectomy had been performed in 38% of participants. Of the participants, 57% lived in a committed partnership, and 62% had sexual intercourse on a regular basis, with a further 19% experiencing pain or discomfort thereby. Introitus plasty was done in 43%. Mean total FSFI for all participants was 21.3 (SD 1.9). Most domain scores of patients after introitus plasty were similar compared with those without an operative vaginal approach, except for satisfaction (p = 0.057) and pain (p = 0.024). Comparing incontinent with continent patients, significant differences were found for desire (mean 4.6 vs. 3.5, p = 0.021), lubrication (mean 3.1 vs. 4.2, p = 0.049), and satisfaction (mean 1.6 vs. 3.6, p = 0.0065). In contrast pain was not significant between groups. CONCLUSIONS: Sexual activity rate in the present study was similar to that reported in the literature (81% vs. 89%), whereas dyspareunia rate was lower in our cohort (19% vs. 24%). The risk for sexual dysfunction seems to be lower in patients reconstructed with primary or secondary UD than patients with bladder in use. It is surprising that lubrification was better after UD than after bladder neck surgery. Incontinence and in some parts the history of an introitus plasty may play an additional role in development of sexual dysfunction in EEC. Although most of the female EEC patients lived in a committed partnership and had sexual intercourse, total FSFI values <26.55 clearly indicate a risk of sexual dysfunction. Although continence itself played a major role, females reconstructed with UD seem to have better sexual function. Further evaluation of sexual outcome and improvement of care for these patients is mandatory. PMID- 27480466 TI - Effect of baseline obesity and postoperative weight gain on the risk of channel revision following continent catheterizable urinary channel surgery. AB - OBJECTIVE: Prior studies suggest that obese patients are at increased risk for complications following continent catheterizable urinary (CCU) channel surgery. We hypothesized that postoperative weight gain increases the risk of channel angulation, difficulty catheterizing, and possible channel perforation requiring subfascial revision. The purpose of this study was to evaluate whether baseline obesity or becoming overweight/obese postoperatively was associated with a greater risk of subfascial revision. METHOD: We reviewed retrospectively an institutional database of patients who underwent CCU channel surgery between the ages of >=2 and <20 years from January 1990 to May 2013, excluding those with continent urinary reservoirs, continent vesicostomies, and those without body mass index (BMI) data. We collected data on patient/procedure characteristics, baseline/most recent BMI, and subfascial revision(s). We used Cox proportional hazard multivariable regression to assess the association of being overweight/obese at baseline (>=85% BMI) with time to first subfascial revision, and Fisher's exact test to compare rates of subfascial revision between those who became overweight/obese and those who did not. RESULTS: Of the patients, 328/501 (65.5%) had baseline and post-baseline BMI data available: 53.4% male, 90.6% white, median age 7.4 years; median follow-up 76.4 months. Of the 328 patients, 38 (11.6%) had subfascial revisions. Baseline BMI data were available for 378 patients, and, of these, 130 (34.4%) were overweight/obese at baseline. Overweight/obese patients were more likely to undergo umbilical Monti (10% vs. 8.1%), non-umbilical spiral Monti (33.8% vs. 13.7%), and spiral umbilical Monti channels (13.8% vs. 7.3%) versus normal/underweight patients (p < 0.0001). From a multivariable Cox proportional hazard model controlling for age, BMI category, diagnosis, and ambulatory status, the hazard of subfascial revision for spiral umbilical Monti channels was 2.1* that of other channels (hazard ratio (HR) 2.1 [95% CI 1.2-3.8], p = 0.01). Fifty-one out of 328 patients (15.6%) became overweight/obese postoperatively, with 7.8% having a subfascial revision vs. 12.3% of those whose weight category decreased or remained stable (p = 0.3) (Table 1). CONCLUSIONS: Patients who were overweight/obese at baseline were more likely to have channels constructed that are at the highest risk of subfascial revision. Patients who became overweight/obese postoperatively were not at greater risk of subfascial revision. Limitations include potential bias because of differential follow-up and inaccuracy of BMI percentile as a measurement of obesity. PMID- 27480469 TI - Commentary to 'Testicular atrophy and catch-up growth rates following paediatric primary orchidopexy: A prospective study'. PMID- 27480468 TI - Unexpected outcome of a modification of Bracka repair for proximal hypospadias: High incidence of diverticula with flaps. AB - INTRODUCTION: Various graft and flap techniques have been proposed for urethral reconstruction in proximal hypospadias repair. The Bracka repair involving the transfer of inner prepuce like a Wolfe graft mostly results in satisfactory results besides a high fistula rate. AIM: The aim was to decrease the high fistula rate with Bracka repair; we wanted to use the advantages of vascularized skin in the Bracka method. The aim of this study was to evaluate our results with this modification. STUDY DESIGN: Our modification involves using a flap instead of a graft. In the first stage, chordee was corrected by transection of the urethral plate and dorsal midline plication when necessary. Instead of a graft as suggested by Bracka, inner preputial skin with ample blood supply was transferred and stitched to the denuded ventral penile surface. In the second stage after 6 months, this flap was tubularized in the Thiersch-Duplay fashion. Hospital records of patients who had undergone two stage modified Bracka repair between June 2007 and July 2012 were reviewed, including complaints, complications, and need for interventions. RESULTS: Thirty-eight patients had undergone this operation. Four patients were lost to follow-up. The main complaint was obstructed urinary flow. Voiding symptoms were first attributed to urethral stenosis, but were, however, found to be due to diverticulum and vortex of the urine in the dilated urethra. Twenty-one patients (61%) had voiding problems and 10 patients (29%) had urinary tract infections. Fistula was observed in 23 and diverticula were observed in 24 patients. Of these, 16 patients had both fistula and diverticula. Only two patients (5%) were free of complications and totally satisfied with the operation, and 23 of the 34 patients had complications requiring intervention (Figure). DISCUSSION: Inner preputial flaps used in proximal hypospadias repairs are prone to diverticula formation. They become redundant in time requiring reoperation, thus decreasing the success rate. Careful fixation of the flap to the corpora and allowing time for additional attachment of the urethral plate substitution through fibrotic activity could not overcome this complication. CONCLUSION: Our modification of the Bracka technique using a flap for the plate resulted in a high rate of complications (in particular diverticulum formation) and was therefore abandoned. We recommend careful use of flaps in hypospadias surgery and long-term follow-up studies to evaluate actual functional and cosmetic results. PMID- 27480470 TI - Pressure or Pain in the Dental Chair? PMID- 27480471 TI - Does Less Frequent Mention in Publications Indicate Less Frequent Use? PMID- 27480472 TI - Changes in Publication-Based Academic Interest in Local Anesthetics Over the Past 50 Years. AB - PURPOSE: To present the history of changes in academic interest in local anesthetics quantitatively. METHODS: The changes in publication-based academic interest in local anesthetics were assessed using information from the database of PubMed. The assessment was mostly based on the following indices: general popularity index (GPI), representing the proportion of articles on a drug relative to all articles in the field of regional anesthesia, and specific popularity index (SPI), representing the proportion of articles on a drug relative to all articles in one of the four forms of regional anesthesia: local anesthesia, spinal anesthesia, epidural anesthesia, and peripheral nerve blocks. RESULTS: The most important general feature of the changes in publication-based academic interest in local anesthetics for the past 50 years was the concentration of this interest on a very limited number of drugs. By 2010-2014, only three anesthetics demonstrated the GPI value above 4.0: bupivacaine (10.1), lidocaine (10.0), and ropivacaine (4.6). All other local anesthetics had GPI declining mostly to less than 1.0 (2010-2014). The rate of change in publication based academic interest was very slow in both its increase and decline. The most profound change in publication-based academic interests was caused by the introduction of bupivacaine. During a 20-year period (from 1965-1969 to 1985 1989), bupivacaine's GPI increased from 1.3 to 12.9. CONCLUSION: A slowly developing concentration of publication-based academic interest on a very limited number of local anesthetics was the dominant feature related to this class of anesthetic agents. PMID- 27480473 TI - A Systematic Review of the Cervical Plexus Accessory Innervation and Its Role in Dental Anesthesia. AB - INTRODUCTION: Accessory innervation (AI) may account for the persistent sensation perceived after successful mandibular anesthesia in the adult patient. The purpose of this systematic review was to record the quality of evidence pertaining to the cervical plexus (CP) AI in dental anesthesia. MATERIALS AND METHODS: Electronic and manual searches were conducted using Ovid and Medline of articles published from 1922 to March of 2015. Studies written in any language were included as long as they involved: (i) humans, animals, and/or cadavers AND (ii) anatomical and/or research anesthetic-technique approaches and/or clinical approaches. Exclusion criteria were (i) maxillary buccal infiltration, (ii) no abstract/paper available, (iii) studies that do not comprise the description of the branches of the CP branches in dentistry and (iv) duplicated articles. The articles were reviewed and graded by levels of evidence (LOE) through a methodological scoring index (MSI). RESULTS: Forty-four out of 185 papers fulfilled the inclusion criteria. One randomized control trial, 3 comprehensive reviews, 1 cohort study, 5 case series/reports, 16 poor-quality cohort and case series/reports and 18 reviews/case, reports/expert opinions were found. Of the 44 publications, there were 4 LOE 1, 1 LOE 2, 5 LOE 3, 20 LOE 4 and 14 LOE 5 studies. CONCLUSIONS: The MSI helped to classify papers LOE in a standardized and objective approach. The objective evidence quality occurrence recorded was found to be LOE 4 (n = 20) > LOE 5 (n = 14) > LOE 3 (n = 5) > LOE 1 (n = 4) > LOE 2 (n = 1). The anatomy of the CP needs to be reexamined and understood in the anatomical literature. PMID- 27480474 TI - Noteworthy Chemistry of Chloroform. AB - Inhaled chloroform anesthesia was introduced in 1847. Soon thereafter, the chemical reactivity of aerobically heated chloroform permitted John Snow and Claude Bernard to do seminal experiments in the assay of drug levels and drug metabolism. However, it was not widely appreciated until a clinical mishap in 1899 that thermal decomposition generated significant levels of toxic phosgene from air-polluting quantities of chloroform in poorly ventilated operating rooms that were illuminated by flames. Phosgene is also generated metabolically from chloroform. A clue appeared in the 1950s when subanesthetic traces of inhaled chloroform proved accidentally lethal to strains of male mice spontaneously expressing high levels of chloroform-metabolizing enzymes. Furthermore, in microbial experiments of 1967, the reactive chloroform molecule was inadvertently discovered to selectively inactivate vitamin B12-dependent enzymes. Chloroform can also activate enzymes. As a solvent, it was serendipitously found in 1903 to activate what is now known as plasminogen to plasmin. PMID- 27480475 TI - Royden McIntosh Muir and His Anesthetic Links Between South Africa, London, and the United States. AB - New Zealand born, Dr. Royden McIntosh Muir, MBChB(Edin), DA(RCS&RCP), emigrated to Cape Town in 1921 having specialized in anesthesia in London after World War 1 and became one of South Africa's earliest and leading anesthesiologists. He was appointed honorary anesthetist and clinical teacher by the University of Cape Town at South Africa's first medical school in 1922, and lecturer in 1927. Aware of Cape Town's isolation at the southern tip of Africa, he undertook extensive tours studying anesthetic practice at major hospitals in London, the United States and Canada in 1933 and 1938. He became a lifelong friend of Ralph Waters in Madison, who coached him in the use of cyclopropane, and he subsequently introduced cyclopropane into England and South Africa. In the United States, he met Richard von Foregger, founder of the New York based Foregger Company, from whom he later commissioned a purpose-built anesthetic machine marketed by Foregger as "The Muir Midget." Muir was a founder member of the South African Society of Anaesthetists in 1943 and was elected as its second president the following year. Based on what he had seen in academic hospitals in the United States and England, he fought until his retirement for the improved recognition of the specialty in South Africa and the establishment of adequately staffed departments of anesthesia at teaching hospitals in that country. PMID- 27480476 TI - The Dose of Intravenously Transplanted Bone Marrow Stromal Cells Determines the Therapeutic Effect on Vascular Remodeling in a Rat Model of Ischemic Stroke. AB - The therapeutic benefits of bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation for ischemic stroke have been extensively demonstrated. However, studies on the optimal cell dose for intravenous administration are still limited. This study aimed to determine an appropriate cell dose for BM-MSC intravenous transplantation and to investigate the effect of cell dose on vascular remodeling in a rat model of ischemic stroke. BM-MSCs at doses of 5104 (low-dose group), 5105 (medium-dose group), and 2106 (high-dose group) were intravenously injected into rats at 72 h after ischemia. The therapeutic efficacy of BM-MSCs was evaluated by measuring infarct volume, vascular diameters, capillary area in the peri-infarct zone, level of basic fibroblast growth factor (bFGF) in the peri-infarct zone, and serum vascular endothelial growth factor (VEGF) level at 7 days after ischemia. Compared with the low-dose and control groups, medium-dose and high-dose BM-MSC transplantation significantly reduced the volume of the infarct area, enlarged the diameters of pial vessels and the basilar artery, and increased the capillary area in the peri-infarct zone of the cerebral cortex. Furthermore, transplanted BM-MSCs elevated the expressions of bFGF in the peri-infarct zone and the serum VEGF level. Administration of 5105 BM MSCs is an appropriate cell dose for ischemic stroke therapy in rats. These findings may be helpful for designing future clinical trials. PMID- 27480477 TI - Investigation of selection bias in the association of race with prevalent atrial fibrillation in a national cohort study: REasons for Geographic And Racial Differences in Stroke (REGARDS). AB - PURPOSE: Atrial fibrillation (AF) is diagnosed more commonly in whites than blacks in the United States. In epidemiologic studies, selection bias could induce a noncausal positive association of white race with prevalent AF if voluntary enrollment was influenced by both race and AF status. We investigated whether nonrandom enrollment biased the association of race with prevalent self reported AF in the US-based REasons for Geographic And Racial Differences in Stroke Study (REGARDS). METHODS: REGARDS had a two-stage enrollment process, allowing us to compare 30,183 fully enrolled REGARDS participants with 12,828 people who completed the first-stage telephone survey but did not complete the second-stage in-home visit to finalize their REGARDS enrollment (telephone-only participants). RESULTS: REGARDS enrollment was higher among whites (77.1%) than among blacks (62.3%) but did not differ by self-reported AF status. The prevalence of AF was 8.45% in whites and 5.86% in blacks adjusted for age, sex, income, education, and perceived general health. The adjusted white/black prevalence ratio of self-reported AF was 1.43 (95% CI, 1.32-1.56) among REGARDS participants and 1.38 (1.22-1.55) among telephone-only participants. CONCLUSIONS: These findings suggest that selection bias is not a viable explanation for the higher prevalence of self-reported AF among whites in population studies such as REGARDS. PMID- 27480478 TI - The muscle quality index and mortality among males and females. AB - PURPOSE: The muscle quality index (MQI) was proposed as a measure to quantify age related alterations in muscle function. It is unknown if the MQI predicts mortality. METHODS: This was a population-based cohort study from the Third National Health and Nutrition Survey (NHANES III; 1988-1994). The MQI was quantified using a timed sit-to-stand test, body mass, and leg length. Vital status was obtained through the National Center for Health Statistics. We fit multivariable-adjusted regression models to estimate the hazard ratio (HR) and 95% confidence interval (CI) between the MQI and mortality. RESULTS: During 14.6 years of follow-up, 3299 (73.1%) of 4510 study participants died. Lower MQI was associated with a higher risk of mortality (Ptrend <.001). The multivariable adjusted HR for mortality was 1.50 (95% CI, 1.15-1.96) for those in the lowest quintile of MQI compared to the highest quintile. The association between MQI and mortality was stronger among males (highest vs. lowest quintile of MQI, HR = 1.37 [95% CI, 1.00-1.87]; Ptrend = .001) compared to females (highest vs. lowest quintile of MQI, HR = 1.27 (95% CI, 0.89-1.83); Ptrend = .044; Pinteraction = .005]. CONCLUSIONS: The MQI predicts mortality and may differ between males and females. Additional research examining the MQI is warranted. PMID- 27480479 TI - A systematic review and meta-analysis of racial and ethnic disparities in hepatitis C antibody prevalence in United States correctional populations. AB - PURPOSE: Hepatitis C virus (HCV) is highly prevalent among correctional populations. We aimed to explore racial and ethnic disparities in hepatitis C antibody (anti-HCV) prevalence in U.S. correctional populations. METHODS: We systematically searched the literature for reports of anti-HCV prevalence among U.S. jail and prison populations, by race and ethnicity. We calculated summary prevalence estimates for non-Hispanic White, non-Hispanic Black, Hispanic, and "Other" race/ethnicity jail detainees and prisoners and determined the proportion of anti-HCV positive persons from racial/ethnic minority backgrounds. RESULTS: Few studies reported anti-HCV prevalence data by race and ethnicity, and they suffered from methodologic weaknesses. Anti-HCV prevalence was highest among non Hispanic Whites (35% [95% CI: 28%, 43%; k = 9], compared to 26% [95% CI: 21%, 32%; k = 10] among racial and ethnic minorities). However, the majority (63%) of persons with anti-HCV were from racial and ethnic minority backgrounds. CONCLUSIONS: Racial and ethnic minority persons appear to comprise the majority of HCV burden in U.S. correctional settings. Universal screening and treatment of HCV infection in correctional settings may impact on community-level health disparities. PMID- 27480480 TI - Optic nerve input-dependent regulation of neural stem cell proliferation in the optic tectum of adult zebrafish. AB - Adult neurogenesis attracts broad attention as a possible cure for neurological disorders. However, its regulatory mechanism is still unclear. Therefore, they have been studying the cell proliferation mechanisms of neural stem cells (NSCs) using zebrafish, which have high regenerative potential in the adult brain. The presence of neuroepithelial-type NSCs in the optic tectum of adult zebrafish has been previously reported. In the present study, it was first confirmed that NSCs in the optic tectum decrease or increase in proportion to projection of the optic nerves from the retina. At 4 days after optic nerve crush (ONC), BrdU-positive cells decreased in the optic tectum's operation side. In contrast, at 3 weeks after ONC, BrdU-positive cells increased in the optic tectum's operation side. To study the regulatory mechanisms, they focused on the BDNF/TrkB system as a regulatory factor in the ONC model. It was found that bdnf was mainly expressed in the periventricular gray zone (PGZ) of the optic tectum by using in situ hybridization. Interestingly, expression level of bdnf significantly decreased in the optic tectum at 4 days after ONC, and its expression level tended to increase at 3 weeks after ONC. They conducted rescue experiments using a TrkB agonist and confirmed that decrease of NSC proliferation in the optic tectum by ONC was rescued by TrkB signal activation, suggesting stimuli-dependent regulation of NSC proliferation in the optic tectum of adult zebrafish. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017. PMID- 27480481 TI - The correlation of clinical and chromosomal alterations of benign meningiomas and their recurrences. AB - Meningiomas (MGs) are the frequent benign intracranial tumors. Their complete removal does not always guarantee relapse-free survival. Recurrence-associated chromosomal anomalies in MGs haves been proposed as prognostic factors in addition to the World Health Organisation (WHO) grading, tumor size and resection rate. The aim of this study was to evaluate the frequency of deletions on chromosomes in sporadic MGs and to correlate them with the clinical findings and tumor behaviour. Along with survival, the tumor recurrence was the main endpoint. Chromosomal loss of heterozygosity (LOH) was studied. 46 benign MGs were subjected to the analysis, complete tumor resection was intended and no early mortalities were observed. Incomplete removal was related to parasagittal location and psammomatous hisptopathology (p<0.01). Chromosomal alterations were present in 82.6% of cases; LOH at 22q (67.4%) and 1p (34.8%) were the most frequent and associated with male sex (p=0.04). Molecular findings were not specific for any of the histopathologic grade. Tumor recurrence (14 of 46) correlated with tumor size (>=35mm), LOH at 1p, 14q, coexistence of LOH at 1p/14q, 10q/14q, 'complex karyotype' status (>=2 LOHs excluding 22q), patient age (younger <35), and Simpson grading of resection rate (>=3 of worse prognosis). The last 3 variables were independent significant prognostic factors in multivariate analysis and of the same importance in recurrence prediction (Receiver Operating Characteristic curves comparison p>0.05). Among the cases of recurrence, tumor progression was observed in 3 of 14. In 2 cases, LOH on 1p and/or coexistence of LOH 1p/14q correlated with anaplastic transformation. PMID- 27480482 TI - Predictors of burden and depression among caregivers of relapsing-remitting MS patients in Spain: MS Feeling study. AB - AIM: To assess potential predictors for burden and depression among caregivers of relapsing-remitting multiple sclerosis patients in Spain. Family functioning and social support were also assessed. PATIENTS & METHODS: Multicenter and cross sectional study in relapsing-remitting multiple sclerosis adult patients and their respective informal caregivers (n = 180). Assessment performed: Zarit Scale (Burden), Center for Epidemiologic Studies Depression-7 Scale (depression), Family APGAR (Adaptation, Partnership, Growth, Affection, Resolve) Questionnaire (family functioning) and Duke UNC-11 Functional Social Support Questionnaire (social support). Multivariate logistic regression analysis assessed burden and depression predictors among caregivers. RESULTS: Caregivers suffered burden (19.4%) and depression (20.6%) and perceived poor social support (9.4%) and family dysfunction (10.6%). Burden predictors were patient's degree of disability, caregiver time and number of medications administered to patient. Depression predictors were patient's age and daily caregiving time. CONCLUSION: The factors reported here could help clinicians to identify caregiver groups particularly at risk of burden and depression for timely intervention. PMID- 27480483 TI - Accessing the biocompatibility of layered double hydroxide by intramuscular implantation: histological and microcirculation evaluation. AB - Biocompatibility of layered double hydroxides (LDHs), also known as hydrotalcite like materials or double metal hydroxides, was investigated by in vivo assays via intramuscular tablets implantation in rat abdominal wall. The tablets were composed by chloride ions intercalated into LDH of magnesium/aluminum (Mg2Al-Cl) and zinc/aluminum (Zn2Al-Cl). The antigenicity and tissue integration capacity of LDHs were assessed histologically after 7 and 28 days post-implantation. No fibrous capsule nearby the LDH was noticed for both materials as well any sign of inflammatory reactions. Sidestream Dark Field imaging, used to monitor in real time the microcirculation in tissues, revealed overall integrity of the microcirculatory network neighboring the tablets, with no blood flow obstruction, bleeding and/or increasing of leukocyte endothelial adhesion. After 28 days Mg2Al Cl promoted multiple collagen invaginations (mostly collagen type-I) among its fragments while Zn2Al-Cl induced predominantly collagen type-III. This work supports previous results in the literature about LDHs compatibility with living matter, endorsing them as functional materials for biomedical applications. PMID- 27480485 TI - A critical review of frameworks used for evaluating reliability and relevance of (eco)toxicity data: Perspectives for an integrated eco-human decision-making framework. AB - Considerable efforts have been invested so far to evaluate and rank the quality and relevance of (eco)toxicity data for their use in regulatory risk assessment to assess chemical hazards. Many frameworks have been developed to improve robustness and transparency in the evaluation of reliability and relevance of individual tests, but these frameworks typically focus on either environmental risk assessment (ERA) or human health risk assessment (HHRA), and there is little cross talk between them. There is a need to develop a common approach that would support a more consistent, transparent and robust evaluation and weighting of the evidence across ERA and HHRA. This paper explores the applicability of existing Data Quality Assessment (DQA) frameworks for integrating environmental toxicity hazard data into human health assessments and vice versa. We performed a comparative analysis of the strengths and weaknesses of eleven frameworks for evaluating reliability and/or relevance of toxicity and ecotoxicity hazard data. We found that a frequent shortcoming is the lack of a clear separation between reliability and relevance criteria. A further gaps and needs analysis revealed that none of the reviewed frameworks satisfy the needs of a common eco-human DQA system. Based on our analysis, some key characteristics, perspectives and recommendations are identified and discussed for building a common DQA system as part of a future integrated eco-human decision-making framework. This work lays the basis for developing a common DQA system to support the further development and promotion of Integrated Risk Assessment. PMID- 27480484 TI - Evaluation of micro Electroretinograms Recorded with Multiple Electrode Array to Assess Focal Retinal Function. AB - Full-field electroretinograms (ERGs) are used to objectively assess the mass function of the retina, whereas focal ERGs are used to evaluate the focal retinal function. The purpose of this study was to determine the usefulness of a multiple electrode array (MEA) system for recording ex vivo micro ERGs (mERGs) together with multiunit spike responses of the retinal ganglion cells (RGCs) to assess focal retinal function in isolated mouse retinas. The a- and b-waves of the full field ERGs were present in the mERG. The b-wave was blocked by L-AP4, an inhibitor of the mGluR6 receptor, and the OFF-component was blocked by exposure to PDA, an antagonist of ionotropic glutamate receptors, with a corresponding RGC responses. mERGs were also recorded from mice with progressive retinal degeneration, the C57BL/6J-Pde6b(rd1-2J)/J (rd1) mice, from which conventional full-field ERGs are non-recordable. A blockade of the glutamate receptors indicated that the negative wave of rd1 mice do not originate from the photoreceptors but from the second or third order neurons. This technique of recording mERGs will be useful in assessing the focal properties of the retinas obtained from eyes with pathology and also to follow the recovery of the physiology of the retina in regenerative studies. PMID- 27480486 TI - Fabrication of white luminescence composite films containing Dy-polyoxometalate and the study of their luminescence switching behaviors. AB - White luminescence composite films containing Dy-polyoxometalate (Dy-POM) were firstly constructed by a layer-by-layer assembly method for the realization of electrically controlled luminescence switching. Additionally, blue-white luminescence could be switched by the choice of POM structural types and control of the concentration ratio of POM/Dy-POM in solution and composite films. PMID- 27480487 TI - Low-factor consumption for major surgery in haemophilia B with long-acting recombinant glycoPEGylated factor IX. AB - INTRODUCTION: Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery. AIM: To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery. METHODS: This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg-1 . Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg-1 , repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events. RESULTS: Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra- or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors. CONCLUSIONS: These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri- and postoperative concentrate consumption and infrequent injections as reported with standard FIX products. PMID- 27480488 TI - Contact Lens-induced Limbal Stem Cell Deficiency. AB - Limbal stem cell deficiency (LSCD) is a pathologic condition caused by the dysfunction and/or destruction of stem cell precursors of the corneal epithelium, typified clinically by corneal conjunctivalization. The purpose of this review is to critically discuss a less well-known cause of limbal stem cell disease: contact lens (CL) wear. A literature search was conducted to include original articles containing patients with CL-induced LSCD. This review describes epidemiology, diagnostic strategies, pathogenesis, differential diagnosis, and treatment modalities for this condition. PMID- 27480489 TI - Reduced pCREB in Alzheimer's disease prefrontal cortex is reflected in peripheral blood mononuclear cells. AB - Cyclic-AMP response element-binding protein (CREB) signaling has a critical role in the formation of memories. CREB signaling is dysfunctional in the brains of mouse models of Alzheimer's disease (AD), and evidence suggests that CREB signaling may be disrupted in human AD brains as well. Here, we show that both CREB and its activated form pCREB-Ser(133) (pCREB) are reduced in the prefrontal cortex of AD patients. Similarly, the transcription cofactors CREB-binding protein (CBP) and p300 are reduced in the prefrontal cortex of AD patients, indicating additional dysfunction of CREB signaling in AD. Importantly, we show that pCREB expression is reduced in peripheral blood mononuclear cells (PBMC) of AD subjects. In addition, pCREB levels in PBMC positively correlated with pCREB expression in the postmortem brain of persons with AD. These results suggest that pCREB expression in PBMC may be indicative of its expression in the brain, and thus offers the intriguing possibility of pCREB as a biomarker of cognitive function and disease progression in AD. PMID- 27480490 TI - Dissecting bipolar disorder complexity through epigenomic approach. AB - In recent years, numerous studies of gene regulation mechanisms have emerged in neuroscience. Epigenetic modifications, described as heritable but reversible changes, include DNA methylation, DNA hydroxymethylation, histone modifications and noncoding RNAs. The pathogenesis of psychiatric disorders, such as bipolar disorder, may be ascribed to a complex gene-environment interaction (G * E) model, linking the genome, environmental factors and epigenetic marks. Both the high complexity and the high heritability of bipolar disorder make it a compelling candidate for neurobiological analyses beyond DNA sequencing. Questions that are being raised in this review are the precise phenotype of the disorder in question, and also the trait versus state debate and how these concepts are being implemented in a variety of study designs. PMID- 27480491 TI - The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015). AB - Deprenyl/Selegiline (DEP), created by Joseph Knoll in the 1960s, registered in more than 60 countries to treat Parkinson's disease, Alzheimer's disease, major depressive disorder; and used as an anti-aging drug, achieved its place in research and therapy as the first selective inhibitor of B-type monoamine oxidase (MAO-B). The demonstration that the DEP analog (-)-1-phenyl-2-propylaminopentane devoid of MAO inhibitory property, enhanced like DEP the activity of the catecholaminergic brain engine revealed that this effect is unrelated to the selective inhibition of MAO-B. beta-Phenylethylamine (PEA), the important trace amine in the mammalian brain, is known to be a releaser of catecholamines. Amphetamine and methamphetamine, the best known synthetic PEA derivatives are also releasers of catecholamines like their parent compound. DEP is a unique synthetic PEA derivative devoid of the catecholamine releasing property. As the releasing effect conceals the catecholaminergic activity enhancer (CAE) effect, it remained undiscovered until DEP uncovered that PEA is a natural CAE substance; and only releases catecholamines in high concentration. Discovering that tryptamine is a natural enhancer of catecholaminergic and serotonergic neurons catalyzed the development of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane (BPAP); the most potent and selective enhancer substance, and it exerts its enhancer effect in 0.0001 mg kg-1. DEP and BPAP initiated an analysis of the enhancer regulation in the mammalian brain. Studies regarding the nature of the enhancer regulation revealed that this regulation is enhanced after weaning and sex hormones return it to the pre-weaning level. Thus, sex hormones elicit the transition of the developmental phase of life into the post-developmental, downhill (aging) period. The aging-related, slow decline in the enhancer regulation of the catecholaminergic brain engine, the main activator of the cortex, is the prime factor of brain aging. The enhancer regulation's decay in the most rapidly aging dopaminergic system is, for example, mainly responsible for the decline in learning ability and sexual activity over time. According to the Knoll concept, based on two longevity studies performed on male rats, to keep the catecholaminergic brain engine, from the beginning of the downhill period of life, via the administration of a small daily dose of a CAE substance (presently DEP is the only available drug) on a higher activity level, thus to fight against the physiological aging-related slow decay of the catecholaminergic system, is a suitable anti-aging therapy. As our present knowledge regarding the enhancer regulation in the mammalian brain is like seeing a peak of an iceberg, the future of this new line of brain research looks promising from both theoretical and practical aspects. PMID- 27480492 TI - Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model. AB - An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia. PMID- 27480493 TI - Long-term electrical stimulation of bed nucleus of stria terminalis for obsessive compulsive disorder. AB - We previously reported that bilateral electrical stimulation in the anterior limb of the internal capsule/bed nucleus of the stria terminalis (IC/BST) effectively reduces symptoms in severe treatment-resistant obsessive-compulsive disorder (OCD) patients. Here we used a linear mixed model to investigate the evolution of symptomatic and functional status of our patients (n=24) and examined if baseline variables could predict this evolution. Data were collected during routine, clinical psychiatric visits. Our analysis showed a long-term, sustained effect of electrical stimulation in the IC/BST. After a fast initial decline of OCD symptoms, these symptoms remain relatively stable. In addition, we found a strong ON/OFF effect of stimulation (e.g., due to battery depletion). Our data also show that it is not the surgical procedure but rather the electrical stimulation that drives the improvement in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores. The Beck Depression Inventory (BDI) at baseline was the only predictor significantly related to the evolution of the Y-BOCS. A higher BDI at baseline seemed to be related to a smaller decrease of the Y-BOCS over time. In conclusion, electrical stimulation in the IC/BST has a fast and sustained effect on OCD and comorbid symptoms and functional status of patients. PMID- 27480494 TI - Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers. AB - A growing body of evidence suggests glutamate excess in schizophrenia and that N methyl-d-aspartate receptor (NMDAR) hypofunction on gamma-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, PFDR<0.05, kE=2198, x= 30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, PFDR<0.05, kE=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia. PMID- 27480495 TI - Novel heart rate parameters for the assessment of autonomic nervous system function in premature infants. AB - Autonomic nervous system (ANS) balance is a key factor in homeostatic control of cardiac activity, breathing and certain reflex reactions such as coughing, sneezing and swallowing and thus plays a crucial role for survival. ANS impairment has been related to many neonatal pathologies, including sudden infant death syndrome (SIDS). Moreover, some conditions have been identified as risk factors for SIDS, such as prone sleep position. There is an urgent need for timely and non-invasive assessment of ANS function in at-risk infants. Systematic measurement of heart rate variability (HRV) offers an optimal approach to access indirectly both sympathetic and parasympathetic influences on ANS functioning. In this paper, data from premature infants collected in a sleep physiology laboratory in the NICU are presented: traditional and novel approaches to HRV analyses are applied and compared in order to evaluate their relative merits in the assessment of ANS activity and the influence of sleep position. Indices from time domain and nonlinear approaches contributed as markers of physiological development in premature infants. Moreover, significant differences were observed as a function of sleep position. PMID- 27480496 TI - Deformation behavior of metallic glasses with shear band like atomic structure: a molecular dynamics study. AB - Molecular dynamics simulations were employed to investigate the plastic deformation within the shear bands in three different metallic glasses (MGs). To mimic shear bands, MG specimens were first deformed until flow localization occurs, and then the volume of the material within the localized regions was extracted and replicated. Homogeneous deformation that is independent of the size of the specimen was observed in specimens with shear band like structure, even at a temperature that is far below the glass transition temperature. Structural relaxation and rapid cooling were employed to examine the effect of free volume content on the deformation behavior. This was followed by detailed atomic structure analyses, employing the concepts of Voronoi polyhedra and "liquid-like" regions that contain high fraction of sub-atomic size open volumes. Results suggest that the total fraction of atoms in liquid-like regions is a key parameter that controls the plastic deformation in MGs. These are discussed in the context of reported experimental results and possible strategies for synthesizing monolithic amorphous materials that can accommodate large tensile plasticity are suggested. PMID- 27480497 TI - Site-specific, covalent immobilization of BirA by microbial transglutaminase: A reusable biocatalyst for in vitro biotinylation. AB - A facile approach for the production of a reusable immobilized recombinant Escherichia coli biotin ligase (BirA) onto amine-modified magnetic microspheres (MMS) via covalent cross-linking catalyzed using microbial transglutaminase (MTG) was proposed in this study. The site-specifically immobilized BirA exhibited approximately 95% of enzymatic activity of the free BirA, and without a significant loss in intrinsic activity after 10 rounds of recycling (P > 0.05). In addition, the immobilized BirA can be easily recovered from the solution via a simple magnetic separation. Thus, the immobilized BirA may be of general use for in vitro biotinylation in an efficient and economical manner. PMID- 27480498 TI - Identification of dually acylated proteins from complementary DNA resources by cell-free and cellular metabolic labeling. AB - To establish a strategy to identify dually fatty acylated proteins from cDNA resources, seven N-myristoylated proteins with cysteine (Cys) residues within the 10 N-terminal residues were selected as potential candidates among 27 N myristoylated proteins identified from a model human cDNA resource. Seven proteins C-terminally tagged with FLAG tag or EGFP were generated and their susceptibility to protein N-myristoylation and S-palmitoylation were evaluated by metabolic labeling with [(3)H]myristic acid or [(3)H]palmitic acid either in an insect cell-free protein synthesis system or in transfected mammalian cells. As a result, EEPD1, one of five proteins (RFTN1, EEPD1, GNAI1, PDE2A, RNF11) found to be dually acylated, was shown to be a novel dually fatty acylated protein. Metabolic labeling experiments using G2A and C7S mutants of EEPD1-EGFP revealed that the palmitoylation site of EEPD1 is Cys at position 7. Analysis of the intracellular localization of EEPD1 C-terminally tagged with FLAG tag or EGFP and its G2A and C7S mutants revealed that the dual acylation directs EEPD1 to localize to the plasma membrane. Thus, dually fatty acylated proteins can be identified from cDNA resources by cell-free and cellular metabolic labeling of N myristoylated proteins with Cys residue(s) close to the N-myristoylated N terminus. PMID- 27480499 TI - Prostate size, nocturia and the digital rectal examination: a cohort study of 30 500 men. AB - OBJECTIVES: To evaluate the utility of the digital rectal examination (DRE) in estimating prostate size and the association of DRE with nocturia in a population based cohort. SUBJECTS AND METHODS: We identified all men randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial for whom DRE results were available. Men were excluded if they had a history of prostate surgery or incident prostate cancer. Prostate posterior surface area was derived from DRE sagittal and transverse estimates. Relationships between prostate posterior surface area, transrectal ultrasonography (TRUS), prostate-specific antigen (PSA) and nocturia were analysed using intraclass correlation coefficients (ICCs), Spearman's rank correlation and multivariable logistic regression. RESULTS: A total of 30 500 men met the inclusion criteria, with 103 275 screening visits containing paired DRE and PSA data. Digital rectal examination posterior surface area estimates had an ICC of 0.547 (95% CI 0.541-0.554) and were significantly yet modestly correlated with elevated PSA level (rs = 0.18, P < 0.001) and TRUS prostate volume (rs = 0.32, P < 0.001). Prostate posterior surface area was significantly associated with nocturia on multivariable analysis, but was not significant in stratified analysis of men with cardiovascular risk factors (hypertension, diabetes, high body mass index, stroke). In men without these risk factors, the highest quintile of DRE posterior surface area had 22% greater odds of nocturia than the lowest quintile (odds ratio 1.216, 95% CI 1.036-1.427). CONCLUSIONS: Digital rectal examination is a modestly accurate tool for measuring prostate volume. While DRE posterior surface area represents a statistically significant predictor of nocturia, the magnitude of effect suggests it has limited clinical utility for assessing this condition, particularly in the presence of cardiovascular risk factors. PMID- 27480500 TI - Osteochondral Lesions of the Ankle. PMID- 27480501 TI - Sagittal Distal Tibial Articular Angle and the Relationship to Talar Subluxation in Total Ankle Arthroplasty. AB - BACKGROUND: Longevity of total ankle replacement (TAR) depends heavily on anatomic alignment. The lateral talar station (LTS) classifies the sagittal position of the talus relative to the tibia. We hypothesized that correcting the sagittal distal tibial articular angle (sDTAA) during TAR would anatomically realign the tibiotalar joint and potentially reduce the risk of prosthesis subluxation. METHODS: The LTS (millimeters) and sDTAA (degrees) were measured twice by 2 blinded observers using weight-bearing lateral ankle radiographs obtained before (n = 96) and after (n = 94) TAR, with excellent interobserver and intraobserver reliability (correlation coefficient >0.9). RESULTS: Preoperative LTS was as follows: anterior (60.4%), posterior (27.1%), and neutral (12.5%). A strong preoperative correlation was found between LTS and sDTAA (r = 0.81; P < .0001). In ankles that were initially anterior and became less anterior postoperatively (n = 41), LTS decreased from an average 8.1 mm to 6.5 mm and the LTS changed 1.1 mm per degree of sDTAA change. In ankles that were initially posterior (n = 25), LTS increased from an average of -5.1 mm to -2.8 mm and the LTS changed 0.6 mm per degree of sDTAA change. The correlation between LTS and sDTAA was reduced postoperatively (r = 0.62; P < .0001). CONCLUSIONS: Our results suggest that rather than following generic recommendations, the surgeon should customize the sagittal distal tibial cut to the individual patient based on the preoperative LTS in order to achieve neutral TAR alignment. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 27480502 TI - Response: food fortification as a means to increase vitamin D intake. PMID- 27480503 TI - Advanced titration to treat a floppy epiglottis in selective upper airway stimulation. AB - The following report presents a case of a patient with high residual apnea hypopnea index at 6 months following implantation of an upper airway stimulation device who improved significantly after advanced titration via drug-induced sedated endoscopy by changing the electrode configuration for stimulation from bipolar to monopolar. This case demonstrates the utility of postsurgical advanced titration to optimize programming settings for improved clinical outcomes. Laryngoscope, 126:S22-S24, 2016. PMID- 27480504 TI - Impact of systemic alitretinoin treatment on skin barrier gene and protein expression in patients with chronic hand eczema. AB - BACKGROUND: Chronic hand eczema (CHE) is a common inflammatory skin disease that affects approximately 10% of the population. Systemic alitretinoin has been shown to be effective in patients with CHE who are refractory to topical corticosteroids. OBJECTIVES: To analyse the impact of alitretinoin on the skin barrier genes and protein expression in the skin lesions of patients with CHE. MATERIALS AND METHODS: Fifteen patients with CHE were treated with 30 mg daily of alitretinoin for up to 27 weeks. Disease severity was assessed using a clinical score. Skin biopsies from all the patients were evaluated before and after therapy for the expression of Ki-67, various skin barrier genes and thymic stromal lymphopoietin (TSLP) by real-time quantitative polymerase chain reaction and immunohistochemistry. RESULTS: After alitretinoin application, an improvement in the clinical severity of CHE was observed in the majority of patients. Analysis of skin biopsies before treatment showed a significant increase in Ki-67 positive cells in the suprabasal layer and a dysregulated expression of various skin barrier genes, such as claudin 1, loricrin, filaggrin and cytokeratin 10, which were normalized after treatment. TSLP was significantly upregulated in patients with CHE and also normalized after alitretinoin treatment and negatively correlated with filaggrin. CONCLUSIONS: Our data indicate that the expression of barrier genes and proteins was normalized following treatment with alitretinoin in patients with CHE. The change in expression levels of these genes correlated with the clinical efficacy, suggesting that alitretinoin exhibits a disease modifying activity. TSLP is upregulated in CHE and seems to counteract filaggrin expression in the skin. PMID- 27480505 TI - Proteomic profiling of Gram-negative bacterial outer membrane vesicles: Current perspectives. AB - Outer membrane vesicles (OMVs) are extracellular vesicles derived from Gram negative bacteria. Recent progress in the studies of Gram-negative bacterial extracellular vesicles implies that OMVs may function as intercellular communicasomes in bacteria-bacteria and bacteria-host interactions. Current MS based high-throughput proteomic analyses of Gram-negative bacterial OMVs have identified thousands of vesicular proteins and provided clues to reveal the biogenesis and pathophysiological functions of Gram-negative bacterial OMVs. The future directions of proteomics of Gram-negative bacterial OMVs may include the isolation strategy of Gram-negative bacterial OMVs to thoroughly exclude nonvesicular contaminants and proteomics of Gram-negative bacterial OMVs derived from diverse conditions as well as body fluids of bacterium-infected hosts. We hope this review will shed light on future research in this emerging field of proteomics of extracellular vesicles derived from Gram-negative bacteria and contribute to the development of OMV-based diagnostic tools and effective vaccines. PMID- 27480507 TI - Au 4f spin-orbit coupling effects in supported gold nanoparticles. AB - Using X-ray photoelectron spectroscopy we examine the Au 4f spin-orbit components in Au 4f spectra of nanosized Au particles on a TiO2 support. In general, the peak ratios of the Au 4f7/2 and 4f5/2 excitations are found to deviate from the statistical ratio of 4 : 3 and their linewidths (FWHM) are not equal. We reveal that both the FWHM and the Au 4f7/2-to-4f5/2 peak ratios increase appreciably as the Au atomic concentration on the surface of the TiO2 support and the size of Au nanoparticles decrease. On the contrary, the Au 4f spin-orbit splitting remains essentially unchanged. Our findings are discussed in terms of alterations in the electronic band structure. PMID- 27480506 TI - A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder. AB - Suicidal behavior has been shown to have a heritable component that is partly driven by psychiatric disorders [Brent and Mann, 2005]. However, there is also an independent factor contributing to the heritability of suicidal behavior. We previously conducted a genome-wide association study (GWAS) of bipolar suicide attempters and bipolar non-attempters to assess this independent factor [Willour et al., 2012]. This GWAS implicated glutamatergic neurotransmission in attempted suicide. In the current study, we have conducted a targeted next-generation sequencing study of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, neurexin, and neuroligin gene families in 476 bipolar suicide attempters and 473 bipolar non-attempters. The goal of this study was to gather sequence information from coding and regulatory regions of these glutamatergic genes to identify variants associated with attempted suicide. We identified 186 coding variants and 4,298 regulatory variants predicted to be functional in these genes. No individual variants were overrepresented in cases or controls to a degree that was statistically significant after correction for multiple testing. Additionally, none of the gene-level results were statistically significant following correction. While this study provides no direct support for a role of the examined glutamatergic candidate genes, further sequencing in expanded gene sets and datasets will be required to ultimately determine whether genetic variation in glutamatergic signaling influences suicidal behavior. (c) 2016 Wiley Periodicals, Inc. PMID- 27480508 TI - Structure based sequence analysis of viral and cellular protein assemblies. AB - It is well accepted that, in general, protein structural similarity is strongly related to the amino acid sequence identity. To analyze in great detail the correlation, distribution and variation levels of conserved residues in the protein structure, we analyzed all available high-resolution structural data of 5245 cellular complex-forming proteins and 293 spherical virus capsid proteins (VCPs). We categorized and compare them in terms of protein structural regions. In all cases, the buried core residues are the most conserved, followed by the residues at the protein-protein interfaces. The solvent-exposed surface shows greater sequence variations. Our results provide evidence that cellular monomers and VCPs could be two extremes in the quaternary structural space, with cellular dimers and oligomers in between. Moreover, based on statistical analysis, we detected a distinct group of icosahedral virus families whose capsid proteins seem to evolve much slower than the rest of the protein complexes analyzed in this work. PMID- 27480509 TI - Loss of the cytostome-cytopharynx and endocytic ability are late events in Trypanosoma cruzi metacyclogenesis. AB - Trypanosoma cruzi epimastigotes uptake nutrients by endocytosis via the cytostome cytopharynx complex - an anterior opening (cytostome) continuous with a funnel shaped invagination (cytopharynx) that extends to the posterior of the cell, accompanied by microtubules. During metacyclogenesis - the transformation of epimastigotes into human-infective metacyclic trypomastigotes - the cytostome cytopharynx complex disappears, as trypomastigotes lose endocytic ability. To date, no studies have examined cytostome-cytopharynx complex disappearance in detail, or determined if endocytic activity persists during metacyclogenesis. Here, we produced 3D reconstructions of metacyclogenesis intermediates (Ia, Ib, Ic) using electron microscopy tomography and focused ion beam-scanning electron microscopy (FIB-SEM), concentrating on the cytostome-cytopharynx complex and adjacent structures, including the preoral ridge (POR). Parasite endocytic potential was examined by incubation of intermediate forms with the endocytic tracer transferrin (Tf)-Au. Ia, Ib and Ic cells were capable of internalizing Tf Au, and had a shorter cytopharynx than that of epimastigotes, with the cytostome/POR progressively displaced towards the posterior, following the movement of the kinetoplast/flagellar pocket. While some Ic cells had a short cytopharynx with an enlarged proximal end (~300nm in diameter, larger than that of the cytostome), other Ic cells had no cytopharynx invagination, but retained the cytopharynx microtubules, which were also present in metacyclics. We conclude that cytostome-cytopharynx disappearance and loss of endocytic ability are late events in metacyclogenesis, during which the cytostome is displaced towards the posterior, probably due to a link to the kinetoplast/flagellar pocket. Retention of the cytopharynx microtubules by metacyclics may allow prompt cytostome cytopharynx reassembly in amastigotes, upon host cell infection. PMID- 27480512 TI - CO Oxidation on Au/TiO2: Condition-Dependent Active Sites and Mechanistic Pathways. AB - We present results of ab initio electronic structure and molecular dynamics simulations (AIMD), as well as a microkinetic model of CO oxidation catalyzed by TiO2 supported Au nanocatalysts. A coverage-dependent microkinetic analysis, based on energetics obtained with density functional methods, shows that the dominant kinetic pathway, activated oxygen species, and catalytic active sites are all strongly depended on both temperature and oxygen partial pressure. Under oxidizing conditions and T < 400 K, the prevalent pathway involves a dynamic single atom catalytic mechanism. This reaction is catalyzed by a transient Au-CO species that migrates from the Au-cluster onto a surface oxygen adatom. It subsequently reacts with the TiO2 support via a Mars van Krevelen mechanism to form CO2 and finally the Au atom reintegrates back into the gold cluster to complete the catalytic cycle. At 300 <= T <= 600 K, oxygen-bound single Oad-Au(+) CO sites and the perimeter Au-sites of the nanoparticle work in tandem to optimally catalyze the reaction. Above 600 K, a variety of alternate pathways associated with both single-atom and the perimeter sites of the Au nanoparticle are found to be active. Under low oxygen pressures, Oad-Au(+)-CO species can be a source of catalyst deactivation and the dominant pathway involves only Au perimeter sites. A detailed comparison of the current model and the existing literature resolves many apparent inconsistencies in the mechanistic interpretations. PMID- 27480511 TI - Metabolomics evaluation of the impact of smokeless tobacco exposure on the oral bacterium Capnocytophaga sputigena. AB - The association between exposure to smokeless tobacco products (STP) and oral diseases is partially due to the physiological and pathological changes in the composition of the oral microbiome and its metabolic profile. However, it is not clear how STPs affect the physiology and ecology of oral microbiota. A UPLC/QTof MS-based metabolomics study was employed to analyze metabolic alterations in oral bacterium, Capnocytophaga sputigena as a result of smokeless tobacco exposure and to assess the capability of the bacterium to metabolize nicotine. Pathway analysis of the metabolome profiles indicated that smokeless tobacco extracts caused oxidative stress in the bacterium. The metabolomics data also showed that the arginine-nitric oxide pathway was perturbed by the smokeless tobacco treatment. Results also showed that LC/MS was useful in identifying STP constituents and additives, including caffeine and many flavoring compounds. No significant changes in levels of nicotine and its major metabolites were found when C. sputigena was cultured in a nutrient rich medium, although hydroxylnicotine and cotinine N-oxide were detected in the bacterial metabolites suggesting that nicotine metabolism might be present as a minor degradation pathway in the bacterium. Study results provide new insights regarding the physiological and toxicological effects of smokeless tobacco on oral bacterium C. sputigena and associated oral health as well as measuring the ability of the oral bacterium to metabolize nicotine. PMID- 27480510 TI - Ultrastructural analysis of bacteriophage Phi29 during infection of Bacillus subtilis. AB - Recent advances in cryo-electron tomography (cryo-ET) have allowed direct visualization of the initial interactions between bacteriophages and their hosts. Previous studies focused on phage infection in Gram-negative bacteria but it is of particular interest how phages penetrate the thick, highly cross-linked Gram positive cell wall. Here we detail structural intermediates of phage Phi29 during infection of Bacillus subtilis. Use of a minicell-producing strain facilitated in situ tomographic reconstructions of infecting phage particles. Phi29 initially contacts the cell wall at an angle through a subset of the twelve appendages, which are attached to the collar at the head proximal portion of the tail knob. The appendages are flexible and switch between extended and downward conformations during this stage of reversible adsorption; appendages enzymatically hydrolyze wall teichoic acids to bring the phage closer to the cell. A cell wall-degrading enzyme at the distal tip of the tail knob locally digests peptidoglycan, facilitating penetration of the tail further into the cell wall, and the phage particle reorients so that the tail becomes perpendicular to the cell surface. All twelve appendages attain the same "down" conformation during this stage of adsorption. Once the tail has become totally embedded in the cell wall, the tip can fuse with the cytoplasmic membrane. The membrane bulges out, presumably to facilitate genome ejection into the cytoplasm, and the deformation remains after complete ejection. This study provides the first visualization of the structural changes occurring in a phage particle during adsorption and genome transfer into a Gram-positive bacterium. PMID- 27480513 TI - The burden of allergic contact dermatitis caused by acrylates. PMID- 27480514 TI - Allergic contact dermatitis caused by topical sirolimus used as an adjuvant for laser treatment of port wine stains. PMID- 27480515 TI - Allergic contact dermatitis caused by copper. PMID- 27480516 TI - Contact dermatitis caused by arbutin contained in skin-whitening cosmetics. PMID- 27480517 TI - Occupational nitrile glove allergy caused by Pigment Blue 15. PMID- 27480518 TI - Airborne allergic contact dermatitis caused by a henna stone. PMID- 27480519 TI - Effect of betamethasone on patch test reactivity in patients with parthenium dermatitis. PMID- 27480520 TI - Applying 3D-FRAP microscopy to analyse gap junction-dependent shuttling of small antisense RNAs between cardiomyocytes. AB - Small antisense RNAs like miRNA and siRNA are of crucial importance in cardiac physiology, pathology and, moreover, can be applied as therapeutic agents for the treatment of cardiovascular diseases. Identification of novel strategies for miRNA/siRNA therapy requires a comprehensive understanding of the underlying mechanisms. Emerging data suggest that small RNAs are transferred between cells via gap junctions and provoke gene regulatory effects in the recipient cell. To elucidate the role of miRNA/siRNA as signalling molecules, suitable tools are required that will allow the analysis of these small RNAs at the cellular level. In the present study, we applied 3 dimensional fluorescence recovery after photo bleaching microscopy (3D-FRAP) to visualise and quantify the gap junctional exchange of small RNAs between neonatal cardiomyocytes in real time. Cardiomyocytes were transfected with labelled miRNA and subjected to FRAP microscopy. Interestingly, we observed recovery rates of 21% already after 13min, indicating strong intercellular shuttling of miRNA, which was significantly reduced when connexin43 was knocked down. Flow cytometry analysis confirmed our FRAP results. Furthermore, using an EGFP/siRNA reporter construct we demonstrated that the intercellular transfer does not affect proper functioning of small RNAs, leading to marker gene silencing in the recipient cell. Our results show that 3D FRAP microscopy is a straightforward, non-invasive live cell imaging technique to evaluate the GJ-dependent shuttling of small RNAs with high spatio-temporal resolution. Moreover, the data obtained by 3D-FRAP confirm a novel pathway of intercellular gene regulation where small RNAs act as signalling molecules within the intercellular network. PMID- 27480522 TI - High-Resolution Inductively Coupled Plasma Optical Emission Spectrometry for (234)U/(238)Pu Age Dating of Plutonium Materials and Comparison to Sector Field Inductively Coupled Plasma Mass Spectrometry. AB - Employing a commercial high-resolution inductively coupled plasma optical emission spectrometry (HR-ICP-OES) instrument, an innovative analytical procedure for the accurate determination of the production age of various Pu materials (Pu powder, cardiac pacemaker battery, (242)Cm heat source, etc.) was developed and validated. This undertaking was based on the fact that the alpha decay of (238)Pu present in the investigated samples produced (234)U and both mother and daughter could be identified unequivocally using HR-ICP-OES. Benefiting from the high spectral resolution of the instrument (<5 pm) and the isotope shift of the emission lines of both nuclides, (234)U and (238)Pu were selectively and directly determined in the dissolved samples, i.e., without a chemical separation of the two analytes from each other. Exact emission wavelengths as well as emission spectra of (234)U centered around lambda = 411.590 nm and lambda = 424.408 nm are reported here for the first time. Emission spectra of the isotopic standard reference material IRMM-199, comprising about one-third each of (233)U, (235)U, and (238)U, confirmed the presence of (234)U in the investigated samples. For the assessment of the (234)U/(238)Pu amount ratio, the emission signals of (234)U and (238)Pu were quantified at lambda = 424.408 nm and lambda = 402.148 nm, respectively. The age of the investigated samples (range: 26.7-44.4 years) was subsequently calculated using the (234)U/(238)Pu chronometer. HR-ICP-OES results were crossed-validated through sector field inductively coupled plasma mass spectrometry (SF-ICPMS) analysis of the (234)U/(238)Pu amount ratio of all samples applying isotope dilution combined with chromatographic separation of U and Pu. Available information on the assumed ages of the analyzed samples was consistent with the ages obtained via the HR-ICP-OES approach. Being based on a different physical detection principle, HR-ICP-OES provides an alternative strategy to the well-established mass spectrometric approach and thus effectively adds to the quality assurance of (234)U/(238)Pu age dates. PMID- 27480521 TI - Small Molecular-Sized Artesunate Attenuates Ocular Neovascularization via VEGFR2, PKCalpha, and PDGFR Targets. AB - Ocular neovascularization (NV) is the primary cause of blindness in many ocular diseases. Large molecular weight anti- vascular endothelial growth factor (VEGF) protein drugs, such as Avastin and Lucentis, have saved the vision of millions. However, approximately 20-30% of patients respond poorly to anti-VEGF treatment. We found that artesunate (ART), a small molecular derivative of artemisinin, had a significant inhibitory effect on ocular NV by downregulating the expression of VEGFR2, PKCalpha, and PDGFR. ART significantly inhibited retinal NV in rabbits and macular edema in monkeys with greater anterior chamber penetrability and more durable efficacy than Avastin. Our pilot study showed that intravitreal injection of 80 MUg ART significantly inhibited iris and corneal NV in a severe retinal detachment case. Our results suggest that ART might be a potential persistent small-molecule drug to manage ocular NV via multi-targets. PMID- 27480523 TI - A Self-assessment Tool for Screening Young Adults at Risk of Type 2 Diabetes Using Strong Heart Family Study Data. AB - PURPOSE: The purpose of this study is to characterize risk factors associated with type 2 diabetes in young adults aged 18 to 29 years to develop a noninvasive risk assessment tool for use with younger American populations. METHODS: The self assessment tool was developed with the Strong Heart Family Study data. A total of 590 young American Indian adults (242 men) who had normoglycemia and were not receiving diabetes treatment were included. Risk factors recommended by the American Diabetes Association were used to assess diabetes risk in these young adults. A logistic regression model was developed to calculate the predicted probability. The area under the receiver operating characteristic curve was used to evaluate the model. RESULTS: The final model showed that parental history of diabetes, obesity level, alcohol consumption, and high fasting glucose, even within normal range, were significantly associated with onset of prediabetes/diabetes in 5 years. The area under the receiver operating characteristic curve value was 0.68 with original and validated data, indicating that the risk assessment tool had reasonably good discrimination ability. CONCLUSIONS: This new noninvasive screening tool, based on data from American Indian young adults, has potential to screen young adults' early-onset diabetes risk. Future studies are warranted to test this risk assessment tool in other racial/ethnic young adults. PMID- 27480524 TI - Evaluating Substance Use and Insulin Misuse in Adolescents With Type 1 Diabetes. AB - PURPOSE: Substance use behaviors often emerge during adolescence, and adolescents with type 1 diabetes (T1D) may be at risk for engaging in traditional substance use (eg, alcohol, tobacco, and illicit substances) as well as a unique form of substance use: insulin misuse. The purpose of this exploratory study was to examine substance use and insulin misuse in adolescents with T1D. METHODS: Sixty adolescents aged 12 to 20 years with T1D (n = 60) completed surveys on substance use, insulin misuse, and diabetes self-management during a routine diabetes appointment. Demographic measures were summarized by mean (SD) or percentage. Prevalence of substance use and insulin misuse was calculated and stratified by demographic and clinical characteristics. Two-sample t test (continuous variables) and chi-square analysis (categorical variables) determined statistically significant differences. RESULTS: The prevalence of ever using substances was 36.7%, and that for ever misusing insulin was 19%. Older participants (17.1 +/- 1.8 vs 15.6 +/- 1.9 years; P < .01) and those with depression (31.8% vs 7.9%; P = .02) were more likely to use substances. Disordered eating behaviors were the most frequently reported reason for insulin misuse. Self-harm intent was reported by one-third of insulin misusers. Substance use and insulin misuse were not related to glycemic control or diabetes self management behaviors. CONCLUSIONS: The diabetes care team should be aware that substance use and insulin misuse are common in adolescents with T1D. Screening for these risky behaviors is critical in those who are older or have mental health disorders. Effective education, prevention, and treatment strategies targeted at these behaviors are needed to improve the overall health of this population. PMID- 27480525 TI - Enhancing Access to Diabetes Self-management Education in Primary Care. AB - PURPOSE: The purpose of this continuous quality improvement project was to improve access to diabetes self-management education (DSME) and to evaluate the impact on glycemic and weight control by translating an academic medical center's DSME program, accredited per the Education Recognition Program (ERP) of the American Diabetes Association, into a program offered at primary care clinics (PCCs). METHODS: Certified diabetes educators from the medical center trained PCC registered dietitian nutritionists, registered nurses, and social workers to provide DSME in their community-based clinic. Main outcomes of this retrospective, pretest/posttest, observational project were to evaluate enrollment in DSME classes and change in A1C and weight as patients underwent a combined intervention of diabetes education classes with or without consultation and support from a PCC registered dietitian nutritionist or registered nurse. RESULTS: PCC DSME was associated with increased enrollment in DSME classes and a significant reduction of A1C and weight at 3 and 6 months post-DSME. Greatest A1C and weight reductions were observed in patients with newly diagnosed diabetes. Reductions were also seen in patients with diabetes duration >=10 years, participants taking insulin, and those with depression. CONCLUSIONS: PCC DSME availability increased access to group diabetes education and resulted in reduced A1C and weight for participants. This model was successful in translating an established academic accredited DSME-ERP into a PCC. Results have implications for increasing access to diabetes education programs and improving diabetes control for patients not located near major hospital-based DSME programs. PMID- 27480526 TI - Colonic anastomoses and non-steroidal anti-inflammatory drugs. AB - Nonsteroidal anti-inflammatory drugs (NSAID) play an important role in the treatment of post-operative pain, particularly in the context of enhanced recovery after colorectal surgery. Several recent articles have suggested that NSAID may have a deleterious effect on colo-colic or colo-rectal anastomoses. The aim of this review is to analyze the evidence based on meta-analyses and cohort studies in the literature. A systematic review of clinical studies identified twelve studies including two meta-analyses and ten comparative cohort studies that included a large number of patients. The data in these studies are heterogeneous, often biased, and do not permit a formal recommendation based on a high level of evidence. The main conclusion of this review is that the balance of benefit vs. risk (analgesic effect/risk of anastomotic disruption) is acceptable; it appears (with a low level of evidence) that a prescription of NSAID for 48h after surgery may be recommended for elective colon surgery. Nevertheless, it is important to respect the specific contra-indications of NSAID and avoid post operative NSAID use if there are risk factors for anastomotic leakage: advanced age, malnutrition, severe co-morbidities, intra-operative difficulties. PMID- 27480527 TI - Repeatability of Heidelberg Retinal Tomography 3 and effect of alignment algorithm on glaucoma suspects. AB - BACKGROUND: The Heidelberg Retina Tomograph (HRT) is a commonly-used clinical instrument for glaucoma diagnosis; however, the repeatability of the two most commonly used analysis tools, Moorfield regression analysis (MRA) and 'glaucoma probability score' (GPS) is not known and could have significant implications for patients at risk or suspected of developing glaucoma. Thus, the intra-visit repeatability of the HRT3 (an objective measure of instrument-induced variability) was investigated in a glaucoma suspect cohort. METHODS: Two repeat 15 degrees * 15 degrees optic nerve head scans were taken from 164 eyes of 84 patients using the HRT (HRT3, software version 3) during a single visit. The variability of global and sectoral rim area, rim volume and GPS were analysed with and without image alignment using SPSS 22.0. Repeatability was evaluated as absolute difference between the two measurements. RESULTS: Repeatability of the global rim area, rim volume and GPS were high with and without image registration. Variability increased by a small, yet significant amount without image alignment (p < 0.001 to p = 0.002). This increase was more prominent for sectoral analysis with the exception of the rim area and volume in the temporal sector (p = 0.034 to p < 0.001). Increase in the variability of the GPS was also significant (p < 0.001). CONCLUSION: HRT3 demonstrated high short-term repeatability, which significantly improved with image registration for all global measurements. Sectoral analysis demonstrated higher repeatability with image registration for some of the sectors in rim area and volume analysis and all sectors for the GPS. Therefore, depending upon the assessed parameters, image registration may play a significant role in the interpretation of results in glaucoma suspects. PMID- 27480528 TI - Supervisor leadership in relation to resident job satisfaction. AB - BACKGROUND: Research from outside the medical field shows that leadership behaviours influence job satisfaction. Whether the same is true for the medical training setting needs to be explored. The aim of this study was to investigate the influence of residents' overall appreciation of their supervisor's leadership and observation of specific supervisor leadership behaviours on job satisfaction. METHODS: We invited residents (N = 117) to rate how often they observed certain task and relation-oriented leadership behaviours in their supervisor and overall appreciation of their supervisor's leadership. Furthermore, they rated their satisfaction with 13 different aspects of their jobs on a 10-point scale. Using exploratory factor analysis we identified four factors covering different types of job satisfaction aspects: personal growth, autonomy, affective, and instrumental job satisfaction aspects. Influence of overall appreciation for supervisor leadership and observation of certain leadership behaviours on these job satisfaction factors were analysed using multiple regression analyses. RESULTS: The affective aspects of job satisfaction were positively influenced by overall appreciation of leadership (B = 0.792, p = 0.017), observation of specific instructions (B = 0.972, p = 0.008) and two-way communication (B = 1.376, p = 0.008) and negatively by mutual decision-making (B = -1.285, p = 0.007). No effects were found for the other three factors of job satisfaction. CONCLUSIONS: We recommend that supervisors become more aware of whether and how their behaviours influence residents' job satisfaction. Especially providing specific instructions and using two-way communication seem important to help residents deal with their insecurities and to offer them support. PMID- 27480529 TI - High-Cost Patients: Hot-Spotters Don't Explain the Half of It. AB - BACKGROUND: Understanding resource utilization patterns among high-cost patients may inform cost reduction strategies. OBJECTIVE: To identify patterns of high cost healthcare utilization and associated clinical diagnoses and to quantify the significance of hot-spotters among high-cost users. DESIGN: Retrospective analysis of high-cost patients in 2012 using data from electronic medical records, internal cost accounting, and the Centers for Medicare and Medicaid Services. K-medoids cluster analysis was performed on utilization measures of the highest-cost decile of patients. Clusters were compared using clinical diagnoses. We defined "hot-spotters" as those in the highest-cost decile with >=4 hospitalizations or ED visits during the study period. PARTICIPANTS AND EXPOSURE: A total of 14,855 Medicare Fee-for-service beneficiaries identified by the Medicare Quality Resource and Use Report as having received 100 % of inpatient care and >=90 % of primary care services at Cleveland Clinic Health System (CCHS) in Northeast Ohio. The highest-cost decile was selected from this population. MAIN MEASURES: Healthcare utilization and diagnoses. KEY RESULTS: The highest cost decile of patients (n = 1486) accounted for 60 % of total costs. We identified five patient clusters: "Ambulatory," with 0 admissions; "Surgical," with a median of 2 surgeries; "Critically Ill," with a median of 4 ICU days; "Frequent Care," with a median of 2 admissions, 3 ED visits, and 29 outpatient visits; and "Mixed Utilization," with 1 median admission and 1 ED visit. Cancer diagnoses were prevalent in the Ambulatory group, care complications in the Surgical group, cardiac diseases in the Critically Ill group, and psychiatric disorders in the Frequent Care group. Most hot-spotters (55 %) were in the "frequent care" cluster. Overall, hot-spotters represented 9 % of the high-cost population and accounted for 19 % of their overall costs. CONCLUSIONS: High-cost patients are heterogeneous; most are not so-called "hot-spotters" with frequent admissions. Effective interventions to reduce costs will require a more multi faceted approach to the high-cost population. PMID- 27480530 TI - Patient adoption of an internet based diabetes medication tool to improve adherence: A pilot study. AB - OBJECTIVE: To investigate the effect of a video intervention, Managing Your Diabetes Medicines, on patient self-efficacy, problems with using medication, and medication adherence in a rural, mostly African American population. METHODS: Patients selected their problem areas in medication use and watched one of nine 2 min videos with a research assistant at a clinic or pharmacy and were given an access code to watch all the videos at their convenience. Outcomes were measured at baseline and 3-month follow-up. RESULTS: Fifty-one patients were enrolled; 84% were African American and 80% were female (mean age: 54 years). Seventy-three percent watched at least one module after the initial visit. Improved self efficacy was associated with a decrease in concerns about medications (r=-0.64). Low literate patients experienced greater improvement in self-efficacy than more literate patients (t=2.54, p=0.02). Patients' mean number of problems declined from 6.14 to 5.03. The number of patients with high or medium adherence rose from 33% at baseline to 43% at 3-month follow-up. CONCLUSIONS: A practical, customized video intervention may help improve patient self-efficacy, reduce problems with medication use, and improve medication adherence in diabetes patients. PRACTICE IMPLICATIONS: Providers should consider implementing technology-based interventions in the clinic to address common problems that patients have with self-management. PMID- 27480532 TI - Understanding the physiological roles of polyhydroxybutyrate (PHB) in Rhodospirillum rubrum S1 under aerobic chemoheterotrophic conditions. AB - Polyhydroxybutyrate (PHB) is an important biopolymer accumulated by bacteria and associated with cell survival and stress response. Here, we make two surprising findings in the PHB-accumulating species Rhodospirillum rubrum S1. We first show that the presence of PHB promotes the increased assimilation of acetate preferentially into biomass rather than PHB. When R. rubrum is supplied with (13)C-acetate as a PHB precursor, 83.5 % of the carbon in PHB comes from acetate. However, only 15 % of the acetate ends up in PHB with the remainder assimilated as bacterial biomass. The PHB-negative mutant of R. rubrum assimilates 2-fold less acetate into biomass compared to the wild-type strain. Acetate assimilation proceeds via the ethylmalonyl-CoA pathway with (R)-3-hydroxybutyrate as a common intermediate with the PHB pathway. Secondly, we show that R. rubrum cells accumulating PHB have reduced ribulose 1,5-bisphosphate carboxylase (RuBisCO) activity. RuBisCO activity reduces 5-fold over a 36-h period after the onset of PHB. In contrast, a PHB-negative mutant maintains the same level of RuBisCO activity over the growth period. Since RuBisCO controls the redox potential in R. rubrum, PHB likely replaces RuBisCO in this role. R. rubrum is the first bacterium found to express RuBisCO under aerobic chemoheterotrophic conditions. PMID- 27480531 TI - Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations. AB - BACKGROUND: The Mouse Genomes Project is an ongoing collaborative effort to sequence the genomes of the common laboratory mouse strains. In 2011, the initial analysis of sequence variation across 17 strains found 56.7 M unique single nucleotide polymorphisms (SNPs) and 8.8 M indels. We carry out deep sequencing of 13 additional inbred strains (BUB/BnJ, C57BL/10J, C57BR/cdJ, C58/J, DBA/1J, I/LnJ, KK/HiJ, MOLF/EiJ, NZB/B1NJ, NZW/LacJ, RF/J, SEA/GnJ and ST/bJ), cataloguing molecular variation within and across the strains. These strains include important models for immune response, leukaemia, age-related hearing loss and rheumatoid arthritis. We now have several examples of fully sequenced closely related strains that are divergent for several disease phenotypes. RESULTS: Approximately 27.4 M unique SNPs and 5 M indels are identified across these strains compared to the C57BL/6 J reference genome (GRCm38). The amount of variation found in the inbred laboratory mouse genome has increased to 71 M SNPs and 12 M indels. We investigate the genetic basis of highly penetrant cancer susceptibility in RF/J finding private novel missense mutations in DNA damage repair and highly cancer associated genes. We use two highly related strains (DBA/1J and DBA/2J) to investigate the genetic basis of collagen-induced arthritis susceptibility. CONCLUSIONS: This paper significantly expands the catalogue of fully sequenced laboratory mouse strains and now contains several examples of highly genetically similar strains with divergent phenotypes. We show how studying private missense mutations can lead to insights into the genetic mechanism for a highly penetrant phenotype. PMID- 27480533 TI - A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk. AB - The approach for predicting the degree of drug-induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. Thirty-eight drugs were classified by DILI risk into five categories based on drug labels approved by the Food and Drug Administration (FDA) as follows: withdrawn (WDN), boxed warning (BW), warnings and precautions (WP), adverse reactions (AR), and no match (NM). Also, WP was classified into two categories: high and low concern. Differentiated HepaRG cells were treated with drugs for 24 h. The maximum concentration was set at 100-fold the therapeutic maximum plasma concentration (Cmax ). After treatment with drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. As modified cut-off values of each parameter, the TC50 (toxic concentration that decreased the response by 50%) and EC200 (effective concentration giving a response equal to 200% of controls) were calculated. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. This modified multiparametric assay showed an 87% sensitivity and 87% specificity for predicting the DILI risk. The toxicity score showed a good predictive performance for WDN, BW and WP (high concern) categories [cut-off: score >= 1; area under a receiver operating characteristic curve (ROC-AUC): 0.88], and for WDN and BW categories (cut-off: score >= 3; ROC-AUC: 0.88). This study newly indicated that the degree of DILI risk might be predictable quantitatively by assessing the toxicity score in the modified multiparametric assay using HepaRG cells. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27480534 TI - Cortistatin inhibits calcification of vascular smooth muscle cells by depressing osteoblastic differentiation and endoplasmic reticulum stress. AB - Accumulating evidence has indicated that vascular smooth muscular cells (VSMCs) play an important role in the development of vascular calcification (VC). Cortistatin (CST), a novel bio-active peptide, has been shown to exert multiple protective effects on the cardiovascular system. However, the role and possible mechanism of CST in VC remain unclear. Therefore, we used beta-glycerophosphoric acid (beta-GP) to induce calcification in rat and human VSMCs to determine the effects of CST on osteoblastic differentiation and VSMC mineralization in vitro. Compared with the control, beta-GP significantly increased alkaline phosphatase (ALP) activity and calcium content in cultured rat and human VSMCs, as well as multicellular node formation and calcium deposition, as confirmed by von Kossa and Alizarin Red S staining assays. After incubating rat and human VSMCs with beta-GP in the presence of different doses of CST (10-8 or 10-7 mol/L), CST clearly reversed the beta-GP-induced increases in ALP activity and calcium content and formation of pathological calcified nodes of VSMCs in a dose independent manner. Moreover, 10-8 and 10-7 mol/L CST inhibited the phenotypic transformation of VSMCs into osteoblastic cells by decreasing the osteocalcin protein levels, increasing the SM-alpha-actin protein levels, and reducing endoplasmic reticulum stress by decreasing the protein expression of glucose regulated protein 94 and CCAAT/enhancer-binding protein homologous protein. In conclusion, CST directly inhibited beta-GP-induced calcification of VSMCs in vitro, probably by suppressing ERS and phenotypic transformation of VSMCs into osteoblastic cells. These results indicate that CST represents a potential target for the prevention and treatment of VC. PMID- 27480535 TI - Nocturnal enuresis: prevalence and associated LUTS in adult women attending a urogynaecology clinic. AB - INTRODUCTION: Nocturnal enuresis (NE) is an underreported symptom with a profound impact on quality of life. The primary objective of this study was to investigate the prevalence of NE and its association with other lower urinary tract symptoms (LUTS). METHODS: A validated pelvic floor questionnaire [electronic Personal Assessment Questionnaire-Pelvic Floor (ePAQ-PF)] was completed by 2302 women attending a urogynaecology clinic over a 3-year period. Association between NE and overactive bladder (OAB), stress incontinence (SUI) and nocturia was assessed using logistic regression. Subgroup analysis was performed on women with NE undergoing transvaginal tape (TVT). Ethical approval was acquired from the University of Sheffield and statistical analysis performed using SPSS version 22. RESULTS: The overall prevalence of NE reported in the cohort was 23 % (536 women). The reporting of NE was significantly associated with OAB (p < 0.005), SUI (p < 0.005) and nocturia (p < 0.005). Of 84 women undergoing TVT, 49 % reported NE preoperatively. These women reported significantly more severe symptoms of SUI and OAB (p < 0.05). Sixty percent reported improvement or cure of NE postoperatively, and this was dependent on improvement or cure of SUI (p < 0.005). The presence of NE was a negative predictor for improvement in symptoms of SUI following TVT (p = 0.037). CONCLUSION: This study provides insight into NE, a commonly reported symptom in women attending urogynaecology clinics. To our knowledge, this is the first study to implicate stress incontinence as an important aetiological factor in women with NE. Further studies are required to better understand the aetiology of NE in adult women and relate this to management and outcome. PMID- 27480536 TI - Route planning with transportation network maps: an eye-tracking study. AB - Planning routes using transportation network maps is a common task that has received little attention in the literature. Here, we present a novel eye tracking paradigm to investigate psychological processes and mechanisms involved in such a route planning. In the experiment, participants were first presented with an origin and destination pair before we presented them with fictitious public transportation maps. Their task was to find the connecting route that required the minimum number of transfers. Based on participants' gaze behaviour, each trial was split into two phases: (1) the search for origin and destination phase, i.e., the initial phase of the trial until participants gazed at both origin and destination at least once and (2) the route planning and selection phase. Comparisons of other eye-tracking measures between these phases and the time to complete them, which depended on the complexity of the planning task, suggest that these two phases are indeed distinct and supported by different cognitive processes. For example, participants spent more time attending the centre of the map during the initial search phase, before directing their attention to connecting stations, where transitions between lines were possible. Our results provide novel insights into the psychological processes involved in route planning from maps. The findings are discussed in relation to the current theories of route planning. PMID- 27480537 TI - Review of Economic Submissions to NICE Medical Technologies Evaluation Programme. AB - The economic evaluation of medical devices is increasingly used to inform decision making on adopting new or novel technologies; however, challenges are inevitable due to the unique characteristics of devices. Cost-consequence analyses are recommended and employed by the English National Institute for Health and Care Excellence (NICE) Medical Technologies Evaluation Programme (MTEP) to help address these challenges. The aim of this work was to review the critiques raised for previous MTEP submissions and explore if there were common problems across submissions. We reviewed a sample of 12 economic submissions to MTEP representing 50 % of 24 sets of guidance issued to July 2015. For each submission, we reviewed the External Assessment Centre's (EAC) report and the guidance document produced by NICE. We identified the main problems raised by the EAC's assessments and the committee's considerations for each submission, and explored strategies for improvement. We found that the identification and measurement of costs and consequences are the main shortcomings within economic submissions to MTEP. Together, these shortcomings accounted for 42 % of criticisms by the EACs among the reviewed submissions. In certain circumstances problems with these shortcomings may be unavoidable, for example, if there is a limited evidence base for the device being appraised. Nevertheless, strategies can often be adopted to improve submissions, including the use of more appropriate time horizons, whilst cost and resource use information should be taken, where possible, from nationally representative sources. PMID- 27480539 TI - Clinical, Economic and Policy Implications of Drug Shortages in the European Union. AB - Drug shortages are an international problem, which seems to worsen. In this paper, the clinical, economic and policy implications of drug shortages are discussed, based on data available for the EU. Research on the clinical impact is scarce. Most data describe that patients will experience more side effects or need to postpone their treatment. However, more detailed research such as case studies and the number of patients affected are lacking. Information on the economic impact is described as an estimation of the time spent by hospital pharmacies. Other stakeholders are also burdened: manufacturers loose part of their profit, patients may pay more for the alternative treatment and society pays for additional health-care costs. However, no data are available. Again more detailed and objective research is necessary to know where the problem is situated and how solutions can be proposed. Policy implications are also rather scarce. However, once more detailed and objective research has been conducted, policy changes will follow. All stakeholders should be involved in the discussions, prior to the implementation of policy measures. PMID- 27480538 TI - Assessing the Effect of Potential Reductions in Non-Hepatic Mortality on the Estimated Cost-Effectiveness of Hepatitis C Treatment in Early Stages of Liver Disease. AB - BACKGROUND: Most cost-effectiveness analyses of hepatitis C (HCV) therapy focus on the benefits of reducing liver-related morbidity and mortality. OBJECTIVES: Our objective was to assess how cost-effectiveness estimates of HCV therapy can vary depending on assumptions regarding the potential impact of HCV therapy on non-hepatic mortality. METHODS: We adapted a state-transition model to include potential effects of HCV therapy on non-hepatic mortality. We assumed successful treatment could reduce non-hepatic mortality by as little as 0 % to as much as 100 %. Incremental cost-effectiveness ratios were computed comparing immediate treatment versus delayed treatment and comparing immediate treatment versus non treatment. RESULTS: Comparing immediate treatment versus delayed treatment, when we included a 44 % reduction in non-hepatic mortality following successful HCV treatment, the incremental cost per quality-adjusted life year (QALY) gained by HCV treatment fell by 76 % (from US$314,100 to US$76,900) for patients with no fibrosis and by 43 % (from US$62,500 to US$35,800) for patients with moderate fibrosis. Comparing immediate treatment versus non-treatment, assuming a 44 % reduction in non-hepatic mortality following successful HCV treatment, the incremental cost per QALY gained by HCV treatment fell by 64 % (from US$186,700 to US$67,300) for patients with no fibrosis and by 27 % (from US$35,000 to US$25,500) for patients with moderate fibrosis. CONCLUSION: Including reductions in non-hepatic mortality from HCV treatment can have substantial effects on the estimated cost-effectiveness of treatment. PMID- 27480542 TI - The place of human rights and the common good in global health policy. AB - This article offers an integrated account of two strands of global health justice: health-related human rights and health-related common goods. After sketching a general understanding of the nature of human rights, it proceeds to explain both how individual human rights are to be individuated and the content of their associated obligations specified. With respect to both issues, the human right to health is taken as the primary illustration. It is argued that (1) the individuation of the right to health is fixed by reference to the subject matter of its corresponding obligations, and not by the interests it serves, and (2) the specification of the content of that right must be properly responsive to thresholds of possibility and burden. The article concludes by insisting that human rights cannot constitute the whole of global health justice and that, in addition, other considerations-including the promotion of health-related global public goods-should also shape such policy. Moreover, the relationship between human rights and common goods should not be conceived as mutually exclusive. On the contrary, there sometimes exists an individual right to some aspect of a common good, including a right to benefit from health-related common goods such as programmes for securing herd immunity from diphtheria. PMID- 27480541 TI - Erratum to: Fibrinogen production is enhanced in an in-vitro model of non alcoholic fatty liver disease: an isolated risk factor for cardiovascular events? PMID- 27480540 TI - What is the contribution of embryo-endometrial asynchrony to implantation failure? AB - PURPOSE: The synchronized development of a viable embryo and a receptive endometrium is critical for successful implantation to take place. The aim of this paper is to review current thinking about the importance of embryo endometrial synchrony in in vitro fertilization (IVF). METHODS: Detailed review of the literature on embryo-endometrial synchrony. RESULTS: By convention, the time when the blastocyst first attaches and starts to invade into the endometrium has been defined as the 'window of implantation'. The term window of implantation can be misleading when it is used to imply that there is a single critical window in time that determines whether implantation will be successful or not. Embryo maturation and endometrial development are two independent continuous processes. Implantation occurs when the two tissues fuse and pregnancy is established. A key concept in understanding this event is developmental 'synchrony', defined as when the early embryo and the uterus are both developing at the same rate such that they will be ready to commence and successfully continue implantation at the same time. Many different events, including controlled ovarian hyperstimulation as routinely used in IVF, can potentially disrupt embryo-endometrial synchrony. There is some evidence in humans that implantation rates are significantly reduced when embryo-endometrial development asynchrony is greater than 3 days (+/ 1.5 days). CONCLUSIONS: Embryo-endometrial synchrony is critical for successful implantation. There is an unmet need for improved precision in the evaluation of endometrial development to permit better synchronization of the embryo and the endometrium prior to implantation. PMID- 27480543 TI - Pressured general practices get L16m support fund. PMID- 27480544 TI - Primary Soft Tissue Lymphomas: Description of Seven Cases and Review of the Literature. AB - The present study describes a series of primary soft tissue lymphomas, including immunohistochemical characterization by tissue microarray and cytogenetic profiling. Formalin-fixed, paraffin-embedded tissue samples were collected from patients who underwent soft tissue biopsy. Cases were selected according to the definition of primary soft tissue lymphoma as a lymphoid malignancy arising in soft tissues without evidence of other nodal or extranodal localization for a period of at least 6 months. Our series comprised seven patients with a mean age of 72 years. There were three diffuse large B-cell lymphomas (DLBCLs); one B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma; one DLBCL derived from follicular lymphoma; one ALK-negative anaplastic large cell lymphoma; and one follicular lymphoma. Immunohistochemical and molecular profiles were consistent with the histological diagnoses. The present study contributes to our knowledge about uncommon presentation of lymphoid neoplasms and confirms previously published clinical-pathological data. We present, for the first time, the complete immunohistochemical profile and molecular cytogenetic studies of these lymphoid neoplasms. A rare case of a primary soft tissue ALK-negative anaplastic large cell lymphoma is described in detail. PMID- 27480545 TI - Can robot-assisted laparoscopic radical prostatectomy (RALP) be performed very soon after biopsy? AB - PURPOSE: To identify the perioperative and oncological impact of different intervals between biopsy and robot-assisted laparoscopic radical prostatectomy (RALP) for localized prostate cancer. METHODS: All consecutive patients with localized prostate cancer who underwent RALP with primary curative intent in January 2008-July 2014 in a large tertiary hospital were enrolled in this retrospective cohort study. The patients were divided into groups according to whether the biopsy-RALP interval was <=2, <=4, <=6, or >6 weeks. Estimated blood loss and operating room time were surrogates for surgical difficulty. Surgical margin status and continence at the 1 year were surrogates for surgical efficacy. Biochemical recurrence (BCR) was defined as two consecutive postoperative prostate serum antigen values of >=0.2 ng/ml. RESULTS: Of the 1446 enrolled patients, the biopsy-RALP interval was <=2, <=4, <=6, and >6 weeks in 145 (10 %), 728 (50.3 %), 1124 (77.7 %), and 322 (22.3 %) patients, respectively. The >6 week group had a significantly longer mean operation time than the <=2, <=4, and <=6 week groups. The groups did not differ significantly in terms of estimated blood loss or surgical margin status. Kaplan-Meier analysis showed that interval did not significantly affect postoperative BCR-free survival. Multivariable Cox proportional hazards model analysis showed that interval duration was not an independent predictor of BCR (<=2 vs. >2 weeks, HR = 0.859, p = 0.474; <=4 vs. >4 weeks, HR = 1.029, p = 0.842; <=6 vs. >6 weeks, HR = 0.84, p = 0.368). CONCLUSION: Performing RALP within 2, 4, or 6 weeks of biopsy does not appear to adversely influence surgical difficulty or efficacy or oncological outcomes. PMID- 27480546 TI - Participatory System Dynamics Modeling: Increasing Stakeholder Engagement and Precision to Improve Implementation Planning in Systems. AB - Implementation planning typically incorporates stakeholder input. Quality improvement efforts provide data-based feedback regarding progress. Participatory system dynamics modeling (PSD) triangulates stakeholder expertise, data and simulation of implementation plans prior to attempting change. Frontline staff in one VA outpatient mental health system used PSD to examine policy and procedural "mechanisms" they believe underlie local capacity to implement evidence-based psychotherapies (EBPs) for PTSD and depression. We piloted the PSD process, simulating implementation plans to improve EBP reach. Findings indicate PSD is a feasible, useful strategy for building stakeholder consensus, and may save time and effort as compared to trial-and-error EBP implementation planning. PMID- 27480547 TI - [Facts building the foundation and good solution from debate: my suggestion on the journal's new special column " Focus Forum"]. PMID- 27480548 TI - [Why new Dietary Guidelines for Americans canceled the limit consumption of dietary cholesterol?]. PMID- 27480549 TI - [The considerations on hot topics of cholesterol-lowering therapies]. PMID- 27480550 TI - [Making clinical decision based on three essential elements of evidence-based medicine]. PMID- 27480551 TI - [Risk factors and prognosis of neurological complications in patients with infective endocarditis]. AB - OBJECTIVE: To identify risk factors of neurological complications (NC) in left sided infective endocarditis (IE) and to assess its impact on the outcome and cardiac surgery. METHODS: Clinical data, NC, treatment and outcome of patients with definite left-sided IE admitted to our hospital during 2001-2012 were retrospectively analyzed. RESULTS: A total of 308 patients with age of (45.3+/ 15.9) years were enrolled. Among them, 65 (21.1%) experienced at least one NC. Independent risk factors associated with NC were large vegetation (HR=1.681, 95%CI 1.013-2.788, P=0.044), non-neurologic embolism (HR=1.820, 95%CI 1.068 3.100, P=0.028), mitral valve involvement (HR=1.888, 95%CI 1.089-3.274, P=0.024), Staphylococcus aureus infection (HR=2.054, 95%CI 1.097-3.846, P=0.044), and uncontrolled infection (HR=4.680, 95%CI 2.563-8.546, P<0.001). During a median follow-up for 17 months, 70 (22.7%) patients died. NC had a negative impact on long-term outcome (HR=2.292, 95%CI 1.274-4.122, P=0.006). Valve replacement surgery was performed in 156(50.6%)patients, which was associated with a lower rate of 1-year IE-related death (HR=0.160, 95%CI 0.063-0.405, P<0.001). Among patients with NC, valve replacement surgery was associated with lower rates of in hospital mortality and 1-year IE-related mortality (14.8% vs 5.3%, 18.5% vs 73.7%, respectively, P<0.001). CONCLUSIONS: Independent risk factors of NC include large vegetation, non-neurologic embolism, mitral valve involvement, Staphylococcus aureus infection, and uncontrolled infection. Neurologic complications link to the poor prognosis in patients with left-sided IE. Valve surgery is considered as a safe procedure and improves the survival. PMID- 27480552 TI - [A survey of correlation between serum 25-hydroxyvitamin D levels and dyslipidemia rlsk among middle-aged individuals in Beijing]. AB - OBJECTIVE: To evaluate vitamin D status in middle-aged subjects in Beijing and explore the correlation between serum 25-hydroxyvitamin D[25(OH)D] levels and dyslipidemia. METHODS: A total of 448 individuals over 40 years old were enrolled in the cross-sectional survey. The general information, blood biochemical and lipid profiles and serum 25(OH)D levels were collected. The subjects were either divided into two groups (the dyslipidemia group and the non-dyslipidemia group) based on the lipid levels, or four groups according to quartiles of 25(OH)D levels. The association between 25(OH)D levels and dyslipidemia risk was analyzed by a logistic regression analysis. RESULTS: A total of 234 cases were in dyslipidemia group, which accounted for 52.23% of the subjects. The serum 25(OH)D levels were significantly lower in the dyslipidemia group than in the non dyslipidemia group both in men and in women (all P<0.05). The median serum 25(OH)D level in the total subjects was 15.7 (12.2, 20.1)MUg/L with 91.1% subjects of serum 25(OH)D level<30 MUg/L. The proportion of subjects with dyslipidemia (high TC, high TG, high LDL-C, or low HDL-C) increased with the decrease of 25(OH)D level quartiles (P<0.05). After adjustment of confounding factors, the logistic regression analysis showed that subjects in the lowest 25(OH) D quartile group had 143% higher risks for dyslipidemia than those in the highest quartile group. CONCLUSION: These findings indicate that 25(OH)D insufficiency is highly prevalent among middle-aged individuals and it may be associated with the risk of dyslipidemia. PMID- 27480553 TI - [A genomic study of adult-onset idiopathic hypoparathyroidism in Chinese by targeted next-generation sequencing]. AB - OBJECTIVE: Several genes have been recognized to be associated with non-surgical hypoparathyroidism. Data about gene mutations in adult-onset hypoparathyroidism patients is lacking. This study was designed to screen gene mutation in adult onset hypoparathyroidism in Chinese through the targeted next-generation sequencing (NGS). METHODS: We recruited 17 patients with adult-onset hypoparathyroidism who were regularly followed or newly diagnosed at our centre during the past one year. Nine of them developed hypercalciuria during the treatment with calcium and vitamin D. Eight of them were newly diagnosed with no treatment. Targeted NGS was performed to screen 11 related genes, including AIRE, AP2S1, CASR, CLDN16, FAM111A, GATA3, GCM2, PTH, TBCE, TBX1 and TRPM6. RESULTS: A novel homozygosis mutation of GCMB gene[c.130G>A (p.G44S)]was identified which was predicted to be deleterious by PolyPhen2. The patient was a 36-year-old woman who suffered from paroxysmal carpopedal spasms for ten years. Before treatment, the serum calcium and phosphorus was 1.48 mmol/L and 2.29 mmol/L, respectively.Parathyroid hormonel (PTH) concentration was lower than 3.0 ng/L. Intracranial calcification and cataract were also identified. She developed hypercalciuria during treatment with calcium and vitamin D. She had no physical deformity or family history of hypoparathyroidism. CONCLUSIONS: In this study, the genetic defect was only identified in 1 patient (5.9%). In adult-onset hypoparathyroidism without other diagnostic clues, the gene mutation screening as the first choice to clarify the etiology was not recommended. PMID- 27480554 TI - [The epidemiology of bloodstream infections in Fuxing Hospital in 2012 in Beijing]. AB - OBJECTIVE: To investigate the etiology, clinical features and outcome of hospitalized patients with bloodstream infections (BSIs) in a tertiary hospital. METHODS: Positive blood cultures were obtained from the microbiological laboratory in Fuxing Hospital, Capital Medical University from January 1, 2012 to December 31, 2012. BSIS events were identified and the epidemiology data were collected. RESULTS: A total of 149 patients and 154 BSIs events were confirmed by pathogenic and clinical evidence. The in-patients' BSIs rate was 0.8% in our hospital in 2012. According to the disease entities of the first BSIs onset, 15 patients (10.1%) were from surgical departments, 83 patients (55.7%) from the medical departments, and 51 patients (34.2%) from ICU. Thirty-three patients (22.1%) were diagnosed as septic shock. Sixty-eight patients died during hospital stay. The in-hospital mortality rate was 45.6%. Among the 154 BSIs events, 125 (81.2%) were nosocomial and 29 (18.8%) were community-acquired. A total of 188 strains were isolated from all BSIs, including 106 strains of (56.4%) gram negative bacilli, 67 (35.6%) strains of gram-positive bacteria, and 15 (8.0%) strains of fungi. One hundred and fifty-nine strains of bacteria (84.6%)were isolated from 125 events of hospital-acquired BSIs. Twenty-six strains of bacteria were from catheter related bloodstream infections (CRBSIs). In gram negative BSIs, there were more enterobacteriaceae in community-acquired BSIs. More non-fermentative bacteria were found in hospital-acquired BSIs than in community-acquired ones. The distribution of gram-negative bacilli was quite different between surgical departments, non-surgical departments and ICU (P=0.049). CONCLUSIONS: Pathogens of BSIs are quite different according to disease entities and where the patients are from. Local epidemiology of BSIs and distribution of related pathogens are helpful to physicians searching the optimal empirical antibiotics and improving the outcome. PMID- 27480555 TI - [An analysis of clinical features of celiac disease patients in different ethnic]. AB - OBJECTIVE: To summarize the clinical features of different racial patients with celiac disease (CD) and analyze the disease prevalence, diagnosis and treatment in Chinese population. METHODS: All the patients were diagnosed as CD and enrolled in Beijing United Family Hospital between January 2005 and July 2015.Clinical data including nationality, age, symptoms, endoscopic and pathological findings, outcome were collected and compared in patients from different countries. RESULTS: A total of 87 patients were enrolled including 63 Caucasians, 18 Asian patients and 6 Middle East patients.The peak age of disease onset was 40-60 years old.Patients with typical symptoms such as chronic diarrhea and weight loss only accounted for 20.7%(18/87) and 9.2%(8/87) respectively.Some patients presented with nonspecific symptoms such as abdominal pain and bloating [32.2%(28/87)], even constipation [5.7%(5/87)].13.8%(12/87) patients were previously diagnosed as irritable bowel syndrome.The incidence of abdominal pain, bloating, diarrhea and constipation between Asians and Caucasians had no statistical significance (P>0.05); but the proportions of weight loss, growth retardation, iron deficiency anemia and dermatitis herpetiformis in Asian group were significantly higher than that in Caucasian group (P<0.05). IgA type of anti gliadin antibody (AGA), endomysium antibody (EMA) and tissue transglutaminase antibody (tTGA) were dominant autoimmune antibodies in patients with CD, which accounted for 58.6%(51/87), 44.8%(39/87) and 36.8%(32/87) respectively.The endoscopy showed that the lesion of CD was mainly located in small intestine, with reducing severity from the proximal to the distal small intestine.The lesions of duodenal bulb and descending duodenum appeared more significant in Asian group.Accordingly pathological intestinal atrophy and the degree of intraepithelial lymphocytosis were more severe in Asian patients.All 87 cases took the gluten-free diet (GFD). Eighty-one cases received serological follow up and 8 with endoscopic intestinal biopsy.The celiac disease antibodies in 47 patients turned negative from 6-9 months after GFD treatment, while 34 patients turned negative from 12-18 months after GFD.All patients reported disease remission to some extent.After 1 year GFD treatment, the pathology of endoscopic intestinal biopsy in 8 patients showed significant improvement of villous atrophy and lymphocyte infiltration. CONCLUSIONS: CD patients with typical clinical manifestations are not the majority.Serological celiac disease antibodies (AGA, EMA and tTGA) have a high diagnostic value.GFD treatment is effective on majority of celiac patients.Clinical manifestations, endoscopy, intestinal pathology, and response to GFD in Chinese patients are not the same as Caucasians.Clinicians need to pay attention to the differential diagnosis. PMID- 27480556 TI - [An analysis of risk factors and prognosis of Epstein-Barr virus infection after allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To analyze the incidence of Epstein-Barr virus (EBV) infection in patients after allogeneic hematopoietic stem cell transplantation (HSCT), and investigate its risk factors and prognosis. METHODS: A total of 402 patients receiving HSCT were retrospectively studied from November 2011 to November 2014 in the 307th Hospital of Chinese People's Liberation Army.The cumulative incidence (CI) of EBV infection and survival rate were analyzed by Kaplan-Meier method, while risk factors were assessed by logistic regression model. RESULTS: The one-year CI of EBV viremia and post-transplant lymphoproliferative disease (PTLD) were 42.0% and 1.5%, respectively.Using antithymocyte globulin (ATG) (P<0.001, OR=9.92) and acute graft-versus-host disease (GVHD) grade III to IV (P<0.01, OR=2.42) were related risk factors of EBV viremia.There was a higher CI of EBV viremia in patients with 2 risk factors compared with those without (87.5% vs 24.6%, P<0.001). Patients with EBV viremia had significant shorter three-year overall survival than patients without (58.5% vs 75.4%, P<0.001). CONCLUSIONS: The incidence of EBV infection in patients undergoing HSCT is high, which poses a threat on prognosis.Risk factors of EBV viremia include administration of ATG and severe acute GVHD. PMID- 27480557 TI - [A multi-center clinical observation on safety and efficacy of a plasma derived coagulator factor VIII for treatment of patients with hemophilia A]. AB - OBJECTIVE: To evaluate the efficacy and safety of homemade plasma derived coagulation factor VIII in patients with hemophilia A. METHODS: Patients with congenital hemophilia A who met the inclusive and exclusive criteria were enrolled in the study after informed consent. The doses of factor VIII were calculated according to the weight, disease severity etc. FVIII activity and infusion efficacy value at 10 min and 60 min after infusion were recorded, as well as adverse events and validity rating according to the improvement of clinical syndromes. Viral infections including HBV, HCV, HIV and FVIII inhibitor were determined after 3 and 6 months. RESULTS: A total of 65 patients were enrolled in this study, all of whom were evaluable for drug safety. Treatment efficacy was evaluated in 60 patients and 57 cases completed the trial finally. In this 57 cases, most (52/57) subjects were of middle and severe hemophilia A mainly characterized by joint bleeding. Overall response rate of acute bleeding events was classified as "excellent" (70.00%) or "better" (30.00%). The non responder was 0. FVIII activity and infusion efficiency value of first administration after 10 min and 60 min improved significantly [10 min: (123.66+/ 47.54)%; 60 min: (108.05+/-43.24)%]. The incidence of adverse events was 1.54%. Neither allergic reaction nor reactivation of HBV, HCV, HIV was detected after treatment of 3 and 6 months. No FVIII inhibitor negative patients converted to positive during follow-up. CONCLUSION: This homemade plasma derived coagulation factor VIII is safe and effective for the treatment of acute bleeding in patients with hemophilia A. PMID- 27480558 TI - [The clinical analysis of fulminant Wilson's disease in patients with hepatitis B virus infection: a report of 13 cases]. AB - To analyze the clinical features and prognosis of fulminant Wilson's disease (FWD) in patients with hepatitis B virus (HBV) infection. Twenty-seven patients were enrolled in Guangzhou Eighth People's Hospital from 2005 to 2015, including 13 FWD patients with HBV infection and 14 FWD patients without HBV infection. Clinical efficacy and survival rate were evaluated. Baseline biochemical data in two groups were comparable(P>0.05), including total bilirubin, prothrombin activity, serum albumin, alpha fetal protein, alanine transaminase, ceruloplasmin and 24 hours urine copper .Treatment in FWD group with HBV infection was ineffective, including 9(9/13) deaths and 4(4/13) patients receiveing liver transplants. However, 7(7/14)cases in the other group did not response to the treatment, including 6(6/14)deaths and 1(1/14)patient receiving liver transplant. The prognosis in the two groups is significantly different(P=0.006), which is much worse in FWD patients with HBV infection. PMID- 27480559 TI - [Septic arthritis in systemic lupus erythematosus: a retrospective analysis of 6 cases]. AB - Base on the clinical characteristics of septic arthritis in a group of systemic lupus erythematosus patients, this study has found out that high systemic lupus erythematosus disease activity index, leucopenia, high cumulative dose of glucocorticoid, methylprednisolone intravenous pulse therapy and joint cavity puncture were closely correlated with septic arthritis. Once septic arthritis is suspected, culture specimens should be collected and appropriate antibiotics are suggested immediately. Also, surgical drainage is a very useful approach. PMID- 27480562 TI - [Imipenem monotherapy for severe abdominal infection caused by Pseudomonas aeruginosa leads to rapid development of imipenem resistance]. PMID- 27480561 TI - [Misdiagnosed as hemorrhagic infarction in anti-neutrophil cytoplasmic antibodies negative Churg-Strauss syndrome with reactive vasculitis: a case report]. PMID- 27480560 TI - [The efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation]. AB - To study the efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 7 cases with FLT3-ITD positive AML have received allo-HSCT in our department from May 2013 to January 2015. Six cases were administrated with sorafenib after hematopoietic reconstruction. Another patient relapsed on day 192 past allo-HSCT, then she started to use sorafenib after remission of re-induction regimens. Five patients survived. The median progression free survival was 280(126-366)day. This study suggests that sorafenib might prevent relapse past allo-HSCT and improve survival in patients with FLT3-ITD positive AML. PMID- 27480563 TI - [Cimetidine in the treatment of recurrent acute intermittent porphyria: a case report]. PMID- 27480564 TI - [Hypereosinophilic syndrome with cerebral infarction: a case report]. PMID- 27480566 TI - [Standardized diagnosis and management in patients with diabetic foot]. PMID- 27480565 TI - [Kaposi's sarcoma following treatment of membranous glomerulonephritis: a case report]. PMID- 27480567 TI - [Early biomarkers of amyotrophic lateral sclerosis]. PMID- 27480568 TI - [Acute myocardial infarction with no coronary atherosclerosis: etiology, diagnosis and therapy]. PMID- 27480569 TI - [The clinical manifestations, imaging and pathological features of IgG4-related disease]. PMID- 27480570 TI - [Autosomal dominant polycystic kidney disease: summary fromKDIGO controversies conference]. PMID- 27480571 TI - Profibrotic up-regulation of glucose transporter 1 by TGF-beta involves activation of MEK and mammalian target of rapamycin complex 2 pathways. AB - TGF-beta plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF beta in fibroblast lines and primary cells and is required for the profibrotic effects of TGF-beta. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis-inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up-regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet-derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGF-beta-driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF-beta signaling and present opportunities for potential therapeutic intervention.-Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.-H., Jung, M.-Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up-regulation of glucose transporter 1 by TGF-beta involves activation of MEK and mammalian target of rapamycin complex 2 pathways. PMID- 27480572 TI - Intravenous self-administration of alcohol in rats-problems with translation to humans. AB - Alcohol is consumed orally by humans, and oral self-administration has been successfully modeled in laboratory animals. Over the last several years, attempts have been made to develop a procedure for the reliable intravenous (IV) self administration of alcohol in rodents. IV self-administration would provide a better tool for investigating neurobiological mechanisms of alcohol reinforcement and dependence because confounding factors associated with oral self administration, such as variations in orosensory sensitivity to alcohol and/or its absorption, are avoided. A review of the literature shows that rats, mice and non-human primates can initiate and maintain IV self-administration of alcohol. However, there are 50- to 100-fold interspecies differences in the reported alcohol infusion doses required. Most surprising is that the infusion dose (1-2 mg/kg) that reliably maintains IV alcohol self-administration in rats results in total alcohol intakes of only 20-25 mg/kg/hour, which are unlikely to have significant pharmacological effects. The evidence to support IV self administration of such low doses of alcohol in rats as well as the potential biological mechanisms underlying such self-administration are discussed. The minute amounts of alcohol shown to reliably maintain IV self-administration behavior in rats challenge the relationship between their blood alcohol levels and the rewarding and reinforcing effects of alcohol. PMID- 27480573 TI - Effect of different implant placement depths on crestal bone levels and soft tissue behavior: a randomized clinical trial. AB - OBJECTIVES: This randomized clinical trial analyzed crestal bone changes and soft tissue dimensions surrounding implants with an internal tapered connection placed in the mandible anterior region at different depths (equicrestal and subcrestal). MATERIALS AND METHODS: Eleven edentulous patients (five implants per patient) were randomly divided in a split-mouth design: G1, 28 equicrestal implants; and G2, 27 subcrestal implants. All implants were immediately loaded. Correlation between keratinized tissue width (KTW) and vertical mucosa thickness (MT) with soft tissue recession was analyzed. Intraoral radiographs were used to evaluate crestal bone changes. Patients were assessed immediately, 4-, and 8-months after implant placement. Rank-based ANOVA-type statistical test was used for comparison between groups (alpha = 0.05). RESULTS: Fifty-five implants (G1 = 28 and G2 = 27) were assessed in 11 patients. Implant survival rate was 100% for both groups. Both tested implant placement depths presented similar crestal bone loss (P > 0.05). Significant crestal bone loss for each group was found in the different measurement times (T4 and T8) (P < 0.05). Implant placement depths, KTW, and vertical MT had no effect on soft tissue recession (P > 0.05). CONCLUSIONS: Different implant placement depths do not influence crestal bone changes. Soft tissue behavior is not influenced by different implant placement depths or by the amount of keratinized tissue. PMID- 27480575 TI - In Sickness and in Health: The Co-Regulation of Inflammation and Social Behavior. AB - Although it has commonly been assumed that the immune system and the processes that govern social behavior are separate, non-communicating entities, research over the past several decades suggests otherwise. Considerable evidence now shows that inflammatory processes and social behavior are actually powerful regulators of one another. This review first summarizes evidence that inflammatory processes regulate social behavior, leading to characteristic changes that may help an individual navigate the social environment during times of sickness. Specifically, this review shows that inflammation: (1) increases threat-related neural sensitivity to negative social experiences (eg, rejection, negative social feedback), presumably to enhance sensitivity to threats to well-being or safety in order to avoid them and (2) enhances reward-related neural sensitivity to positive social experiences (eg, viewing close others and receiving positive social feedback), presumably to increase approach-related motivation towards others who might provide support and care during sickness. Next, this review summarizes evidence showing that social behavior also regulates aspects of inflammatory activity, preparing the body for situations in which wounding and infection may be more likely (social isolation). Here, we review research showing: (1) that exposure to social stressors increases proinflammatory activity, (2) that individuals who are more socially isolated (ie, lonely) show increased proinflammatory activity, and (3) that individuals who are more socially isolated show increased proinflammatory activity in response to an inflammatory challenge or social stressor. The implications of the co-regulation of inflammation and social behavior are discussed. PMID- 27480576 TI - Recombinant human thyrotropin stimulated 131I treatment for multinodular goiter. AB - : The aim of the study was to investigate the effects of rhTSH stimulation before 131I treatment in patients with MNG. METHODS: Sources included the Cochrane Library, MEDLINE, EMBASE, and SCOPUS database (all until January 2016). Randomized controlled trials (RCTs) that assessed the efficacy of rhTSH stimulated 131I treatment compared to placebo or 131I treatment alone were collected. Two authors performed the data extraction independently. RESULTS: Six RCTs involving 294 patients with MNG were included in this review. Altogether 168 patients were randomized to rhTSH-stimulated 131I therapy, and 126 to either placebo and 131I or 131I alone. rhTSH-stimulated 131I vs placebo and 131I or 131I alone for MNG showed no statistically significant difference in quality of life and all-cause mortality. rhTSH- (at a dose of 0.03 mg and above) stimulated 131I treatment for MNG showed significant benefits in thyroid volume reduction. 131I treatment with rhTSH stimulation at high doses (0.03 mg, 0.1 mg, 0.3 mg and 0.45 mg) for MNG caused significantly higher adverse effects and hypothyroidism. CONCLUSIONS: The overall results indicated that using rhTSH at high doses of 0.03 0.45 mg before 131I therapy resulted in a greater TVR than 131I therapy alone for patients with non-toxic MNG. However, an increased incidence of adverse effects and hypothyroidism was observed in patients receiving high-dose of rhTSH pretreatment than in patients who received low-dose rhTSH pretreatment. Therefore, a dose of 0.03 mg rhTSH pretreatment before 131I therapy may be more potent than 131I alone in treating patients with non-toxic MNG who either had a contraindication for or declined surgery. PMID- 27480580 TI - Stealth Engineering for In Vivo Drug Delivery Systems. AB - In generic terms, a drug delivery substrate (DDS) can be described as a vehicle to transport drug to the point of interest. A DDS that would ideally have the capability to control drug dosage and achieve target specificity, localization, and higher therapeutic efficacy has been pursued as a holy grail in pharmaceutical research. Over the years, diverse classes, structures, and modifications of DDS have been proposed to achieve this aim. One of its major deterrents, however, is rapid elimination of drug by the immune system before intended functionality. Stealth engineering is broadly defined as a method of designing a drug carrier to minimize or delay opsonization until the encapsulated drug is delivered to the intended target. Stealth-engineered DDS has been successful in extending drug circulation lifetime from a few minutes to several days. Currently, this field of research has made much progress since its initiation in 1960s with liposomes to DNA boxes. Activity has also benefited several areas of medicine, where it has been applied in cancer, gene therapy, bone regrowth, and infection treatment. This review covers the progress of some types of DDS that have been published and indexed in major databases (including ScienceDirect, PubMed, and Google Scholar) in the scientific literature. PMID- 27480577 TI - Medicare Part D's Effects on Drug Utilization and Out-of-Pocket Costs: A Systematic Review. AB - OBJECTIVE: To update a past systematic review on whether Medicare Part D changed drug utilization and out-of-pocket (OOP) costs overall and within subpopulations, and to identify evidence gaps. DATA SOURCES/STUDY SETTING: Published and gray literature from 2010 to 2015 meeting prespecified screening criteria, including having a comparison group, and utilization or OOP cost outcomes. STUDY DESIGN: We conducted a systematic literature review with a quality assessment. DATA COLLECTION/EXTRACTION METHODS: For each study, we extracted information on study design, data sources, analytic methods, outcomes, and limitations. Because outcome measures vary across studies, we did a qualitative synthesis rather than meta-analysis. PRINCIPAL FINDINGS: Sixty-five studies met screening criteria. Overall, Medicare Part D enrollees have increased drug utilization and decreased OOP costs, but coverage gaps limit the program's impact. Beneficiaries whose insurance becomes more generous after enrollment had disproportionately increased drug utilization and decreased OOP costs. Outcomes among dual-eligibles were mixed. CONCLUSIONS: There is strong evidence on how Medicare Part D and the donut hole coverage gap affect utilization and OOP costs, but weak evidence on how effects vary among dual-eligibles or across diseases. Findings suggest that the Affordable Care Act's provisions to expand coverage and reduce the donut hole should improve patient outcomes. PMID- 27480579 TI - Clinical and molecular analyses of Beckwith-Wiedemann syndrome: Comparison between spontaneous conception and assisted reproduction techniques. AB - Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by an excessive prenatal and postnatal growth, macrosomia, macroglossia, and hemihyperplasia. The molecular basis of this syndrome is complex and heterogeneous, involving genes located at 11p15.5. BWS is correlated with assisted reproductive techniques. BWS in individuals born following assisted reproductive techniques has been found to occur four to nine times higher compared to children with to BWS born after spontaneous conception. Here, we report a series of 187 patients with to BWS born either after assisted reproductive techniques or conceived naturally. Eighty-eight percent of BWS patients born via assisted reproductive techniques had hypomethylation of KCNQ1OT1:TSS-DMR in comparison with 49% for patients with BWS conceived naturally. None of the patients with BWS born via assisted reproductive techniques had hypermethylation of H19/IGF2:IG-DMR, neither CDKN1 C mutations nor patUPD11. We did not find differences in the frequency of multi-locus imprinting disturbances between groups. Patients with BWS born via assisted reproductive techniques had an increased frequency of advanced bone age, congenital heart disease, and decreased frequency of earlobe anomalies but these differences may be explained by the different molecular background compared to those with BWS and spontaneous fertilization. We conclude there is a correlation of the molecular etiology of BWS with the type of conception. (c) 2016 Wiley Periodicals, Inc. PMID- 27480578 TI - Optimized design and analysis of preclinical intervention studies in vivo. AB - Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID- 27480581 TI - Current Concepts in Sports-Related Concussion. AB - Traumatic brain injury, specifically concussion, is prevalent in contact sports. In the United States (US) each year, 170 million adults participate in physical recreational activities, and 38 million children and adolescents participate in organized sports. The Centers for Disease Control estimate that in this group ~1.6 to 3.8 million concussions occur annually. Recent class-action lawsuits in the US filed by professional athletes against their respective leagues allege negligence in protecting them from concussions, and this has contributed to the attention received in the popular media. In response, concussion-related publications have increased exponentially during the past several years. Recent studies have challenged earlier assumptions that the effects of concussion are transient. Stronger links between concussion and neurodegenerative processes such as Alzheimer's disease-like conditions, depression, and heightened risk for suicide are being elucidated. In this article, we explore the current knowledge on concussion, including pathophysiology, management, and long-term effects. We conclude that more evidence-based results regarding guidelines for diagnosis, treatment, and return to play (RTP) are needed and should be the focus of future investigations. Attributing the etiology of certain neurodegenerative conditions to a history of concussion has been suggested in the current literature, but additional quantitative data regarding the pathophysiology and causality are needed as well. Bioengineers can have an important role in measuring the dynamic forces encountered during head impacts and their effects on the brain. These results can be effective in designing better helmets as well as improved playing surfaces to reduce the impact of such injuries. At this time, we believe that groups of people with heightened risk for concussion should be followed closely during longer periods of time and compared to matched controls. Such long-term studies are urgently needed to develop appropriate guidelines for safety and protect our young and adult athletes in the future. PMID- 27480582 TI - Analysis of Long-Term Temperature Variations in the Human Body. AB - Body temperature is a continuous physiological variable. In normal healthy adults, oral temperature is estimated to vary between 36.1 degrees C and 37.2 degrees C. Fever is a complex host response to many external and internal agents and is a potential contributor to many clinical conditions. Despite being one of the foremost vital signs, temperature and its analysis and variations during many pathological conditions has yet to be examined in detail using mathematical techniques. Classical fever patterns based on recordings obtained every 8-12 h have been developed. However, such patterns do not provide meaningful information in diagnosing diseases. Because fever is a host response, it is likely that there could be a unique response to specific etiologies. Continuous long-term temperature monitoring and pattern analysis using specific analytical methods developed in engineering and physics could aid in revealing unique fever responses of hosts and in different clinical conditions. Furthermore, such analysis can potentially be used as a novel diagnostic tool and to study the effect of pharmaceutical agents and other therapeutic protocols. Thus, the goal of our article is to present a comprehensive review of the recent relevant literature and analyze the current state of research regarding temperature variations in the human body. PMID- 27480574 TI - Inflammation Effects on Motivation and Motor Activity: Role of Dopamine. AB - Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation. PMID- 27480584 TI - Guest Editorial: Vascularization in Tissue Engineering. PMID- 27480583 TI - Review of the Multiscale Effects of Female Sex Hormones on Matrix Metalloproteinase-Mediated Collagen Degradation. AB - Collagenases and gelatinases regulate many physiological processes and are involved in the pathogenesis and progression of various disease states, such as osteoarthritis, renal fibrosis, and atherosclerosis. These enzymes belong to the matrix metalloproteinase (MMP) family and are regulated by a number of factors, including sex hormones. Estrogen, relaxin, and progesterone can alter the balance between tissue degradation and repair by modulating MMPs, leading to gender disparities in many MMP-related disease states. In these diseases, MMPs initiate collagen degradation at the nanoscale when they cleave and denature collagen molecules. However, the net effect on tissue is generally observed at the macroscale. To understand how nanoscale events lead to macroscale changes, we must examine the intermediate scales. In this article, we review the literature that examines the effects of estrogen, relaxin, and progesterone on MMP production and activity, connecting the nanoscale, microscale, and macroscale details to relevant disease states. PMID- 27480585 TI - Blood Vessel Maturation in Health and Disease and its Implications for Vascularization of Engineered Tissues. AB - Engineered blood vessels have often been found to be immature and unstable. Similarly, numerous pathologies such as diabetic retinopathy and cancer are characterized by highly abnormal, defective, hypervascular networks, consisting of immature, leaky, and irregular vessels with a marked loss of perivascular cell coverage. An emerging therapeutic concept in treatment of such vascular diseases and their management is the potential to normalize blood vessels by strengthening the cellular components that form the vascular network. Vessel normalization is characterized by the reduction in the number and size of immature vessels, a decrease in interstitial fluid pressure, and increase in perivascular cell coverage. Understanding the molecular and cellular defects associated with abnormal blood vessels will allow us to find appropriate treatment options that can promote normal blood vessel development. These, in turn, can be applied to improve vessel maturation in engineered tissues. In this review, we describe the major perivascular abnormalities associated with various human diseases and engineered vasculatures and the major advances in obtaining mature vasculatures for translational applications. PMID- 27480587 TI - Targeting the Vessel Underdogs: Therapeutic Approaches for Microvessel Dysfunction in the Heart. AB - From an obscure and overlooked beginning, the function of the microvessels in the heart has received increasing attention after the Women's Ischemia Syndrome Evaluation study concluded roughly a decade ago. This review defines the contribution of the coronary microcirculation in the development of heart disease and focuses on the therapeutic methods to reverse coronary microvascular dysfunction. Tissue engineering approaches in the past have largely neglected vascular cells in the attempts to design augmented myocardial tissue, but groups are now making advances that incorporate a functional microcirculation with cardiomyocytes that may advance this line of research. This review covers the definition and classification of coronary microvascular disease, as well as the successful (and unsuccessful) therapeutic approaches in the literature. PMID- 27480588 TI - Reply to "A strong message is needed to address the issue of HCC recurrence after DAA therapy". PMID- 27480586 TI - Establishing Early Functional Perfusion and Structure in Tissue Engineered Cardiac Constructs. AB - Myocardial infarction (MI) causes massive heart muscle death and remains a leading cause of death in the world. Cardiac tissue engineering aims to replace the infarcted tissues with functional engineered heart muscles or revitalize the infarcted heart by delivering cells, bioactive factors, and/or biomaterials. One major challenge of cardiac tissue engineering and regeneration is the establishment of functional perfusion and structure to achieve timely angiogenesis and effective vascularization, which are essential to the survival of thick implants and the integration of repaired tissue with host heart. In this paper, we review four major approaches to promoting angiogenesis and vascularization in cardiac tissue engineering and regeneration: delivery of pro angiogenic factors/molecules, direct cell implantation/cell sheet grafting, fabrication of prevascularized cardiac constructs, and the use of bioreactors to promote angiogenesis and vascularization. We further provide a detailed review and discussion on the early perfusion design in nature-derived biomaterials, synthetic biodegradable polymers, tissue-derived acellular scaffolds/whole hearts, and hydrogel derived from extracellular matrix. A better understanding of the current approaches and their advantages, limitations, and hurdles could be useful for developing better materials for future clinical applications. PMID- 27480589 TI - A strong message is needed to address the issue of HCC recurrence after DAA therapy. PMID- 27480590 TI - Inbreeding effects on gene-specific DNA methylation among tissues of Chinook salmon. AB - Inbreeding depression is the loss of fitness resulting from the mating of genetically related individuals. Traditionally, the study of inbreeding depression focused on genetic effects, although recent research has identified DNA methylation as also having a role in inbreeding effects. Since inbreeding depression and DNA methylation change with age and environmental stress, DNA methylation is a likely candidate for the regulation of genes associated with inbreeding depression. Here, we use a targeted, multigene approach to assess methylation at 22 growth-, metabolic-, immune- and stress-related genes. We developed PCR-based DNA methylation assays to test the effects of intense inbreeding on intragenic gene-specific methylation in inbred and outbred Chinook salmon. Inbred fish had altered methylation at three genes, CK-1, GTIIBS and hsp70, suggesting that methylation changes associated with inbreeding depression are targeted to specific genes and are not whole-genome effects. While we did not find a significant inbreeding by age interaction, we found that DNA methylation generally increases with age, although methylation decreased with age in five genes, CK-1, IFN-gamma, HNRNPL, hsc71 and FSHb, potentially due to environmental context and sexual maturation. As expected, we found methylation patterns differed among tissue types, highlighting the need for careful selection of target tissue for methylation studies. This study provides insight into the role of epigenetic effects on ageing, environmental response and tissue function in Chinook salmon and shows that methylation is a targeted and regulated cellular process. We provide the first evidence of epigenetically based inbreeding depression in vertebrates. PMID- 27480591 TI - Cdk5 is required for the positioning and survival of GABAergic neurons in developing mouse striatum. AB - Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase, and its activity is dependent upon an association with a neuron-specific activating subunit. It was previously reported that Cdk5-/- mice exhibit perinatal lethality and defective neuronal positioning. In this study, they focused on the analysis of neuronal positioning of GABAergic neurons in the forebrain. Defective formation of the ventral striatum, nucleus accumbens, and olfactory tubercles was found in Cdk5-/- embryos. To further study this abnormal development, we generated and analyzed Dlx5/6-Cre p35 conditional KO (cKO); p39-/- mice in which forebrain GABAergic neurons have lost their Cdk5 kinase activity. Defective formation of the nucleus accumbens and olfactory tubercles as well as neuronal loss in the striatum of Dlx5/6-Cre p35cKO; p39-/- mice was found. Elevated levels of phosphorylated JNK were observed in neonatal striatal samples from Dlx5/6-Cre p35cKO; p39-/- mice, suggestive of neuronal death. These results indicate that Cdk5 is required for the formation of the ventral striatum in a cell-autonomous manner, and loss of the kinase activity of Cdk5 causes GABAergic neuronal death in the developing mouse forebrain. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017. PMID- 27480592 TI - Application of randomized response techniques for investigating cannabis use by Spanish university students. AB - Cannabis is the most widely used illicit drug in developed countries, and has a significant impact on mental and physical health in the general population. Although the evaluation of levels of substance use is difficult, a method such as the randomized response technique (RRT), which includes both a personal component and an assurance of confidentiality, provides a combination which can achieve a considerable degree of accuracy. Various RRT surveys have been conducted to measure the prevalence of drug use, but to date no studies have been made of the effectiveness of this approach in surveys with respect to quantitative variables related to drug use. This paper describes a probabilistic, stratified sample of 1146 university students asking sensitive quantitative questions about cannabis use in Spanish universities, conducted using the RRT. On comparing the results of the direct question (DQ) survey and those of the randomized response (RR) survey, we find that the number of cannabis cigarettes consumed during the past year (DQ = 3, RR = 17 approximately), and the number of days when consumption took place (DQ = 1, RR = 7) are much higher with RRT. The advantages of RRT, reported previously and corroborated in our study, make it a useful method for investigating cannabis use. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27480593 TI - The use of esophageal stent in controlling acute refractory variceal bleeding. PMID- 27480594 TI - Impact of co-exposure with butachlor and triadimefon on thyroid endocrine system in larval zebrafish. AB - INTRODUCTION: Butachlor (BTL) and triadimefon (TDF), the widely used herbicide and fungicide, are unavoidable enter into the aquatic environment. However, there were limited study regarding to the joint toxicity of these two pesticides on fish at present. AIM: To evaluate the potential thyroid-disrupting toxicity and exposed to different concentrations of BTL mixed with TDF. MATERIALS AND METHODS: Zebrafish embryo (n=3) were exposed to 0.01 and 0.05 fold of LC50 from the acute joint toxicity test, of which 0.32mg/L (BTL) and 9.41mg/L (TDF) for single or mixture agents (BTL: 0.0064mg/L, 0.032mg/L; TDF: 0.1882mg/L, 0.9410mg/L; co exposure: 0.0032mg/L BTL+0.0941mg/L TDF, 0.016mg/l BTL+0.4705mg/L TDF) after 10 day post-fertilization. Hatching, malformation, survival rates and thyroid hormones (THs), genes expression involved in HPT-axis of embryos were measured and detected in control and separately/co-exposure treatments. THs contents were evaluated by ELISA kit and the expression levels of genes were determined by RT PCR. RESULTS: Hatching, malformation and survival rates of embryos exposed to single BTL exhibited no statistically significant difference from the control besides decreased of high concentration in survival rates. Exposure to TDF reduced hatching, survival rate and increased malformation. The combined exposure to BTL and TDF resulted in greater adverse effects on embryonic development. BTL exposure significantly increased free T3 and T4 contents. Elevated free T3 content was also observed in the larvae exposed with single BTL. Co-exposure of the two pesticides caused greater enhanced of T3 and T4 levels. Furthermore, gene data showed BTL up-regulated the mRNA expression of tpo, tshbeta, tg, ttr, dio2, TDF up-regulated the mRNA expression of tpo, tralpha, ttr, dio2 and down regulated trbeta gene. The mixture of the two pesticides caused up-regulation mRNA expression of tralpha, trbeta, tg, ttr, dio2. CONCLUSION: BTL and TDF resulted in adverse effects on zebrafish embryonic development and caused thyroid endocrine disruption, BTL and TDF have a synergistic effect on development and thyroid endocrine by enhanced level of thyroid hormone. PMID- 27480595 TI - Ultrastructural Comparison of Hepatozoon ixoxo and Hepatozoon theileri (Adeleorina: Hepatozoidae), Parasitising South African Anurans. AB - To date, only two haemogregarine parasite species have been described from South African anurans: Hepatozoon ixoxo, infecting toads of the genus Sclerophrys (syn. Amietophrynus); and Hepatozoon theileri, parasitising the common river frog, Amietia quecketti. Both species have been characterised using limited morphology, and molecular data from PCR amplified fragments of the 18S rRNA gene. However, no ultrastructural work has been performed thus far. The aim of this study was to add descriptive information on the two species by studying their ultrastructural morphology. Mature gamont stages, common in the peripheral blood of infected frogs, were examined by transmission electron microscopy. Results indicate that H. ixoxo and H. theileri share typical apicomplexan characteristics, but differ markedly in their external cellular structure. Hepatozoon ixoxo is an encapsulated parasite presenting a prominent cap at the truncate pole, and shows no visible modifications to the host cell membrane. In comparison, H. theileri does not present a capsule or cap, and produces marked morphological changes to its host cell. Scanning electron microscopy was performed to further examine the cytopathological effects of H. theileri, and results revealed small, knob-like protrusions on the erythrocyte surface, as well as notable distortion of the overall shape of the host cell. PMID- 27480596 TI - Single-Port Total Laparoscopic Hysterectomy in a Patient With Deep Infiltrating Endometriosis. AB - STUDY OBJECTIVE: To present the feasibility of single-port laparoscopic surgery at patients with deep infiltrating endometriosis. DESIGN: Step by step explanation of the surgery using videos (Canadian Task Force classification III c). SETTING: Single-port laparoscopic surgery is an emerging technique and an option for improving the benefits of laparoscopic surgery. The goals of single port laparoscopic surgery is to further enhance the cosmetic benefits of minimally invasive surgery and minimize the potential risk and morbidity associated with multiport surgery [1,2]. This procedure is not without challenges, however, such as instrument crowding and clashing, ergonomic difficulties, loss of instrument triangulation, and the need for advanced laparoscopic skills [1,2]. Despite these challenges, technical advances in optics and instrumentation have led to the widespread use of single-port laparoscopic surgery to treat such gynecologic disorders as endometriosis, uterine myomas, and cancers [2,3]. INTERVENTIONS: A 42-year-old woman was admitted to our clinic with a complaint of chronic pelvic pain dysmenorrhea and deep dyspareunia. Her medical history revealed a cesarean section delivery and a diagnosis of endometriosis. Despite treatment of her endometriosis with dienogest, there has been no decline at her complaints. Ultrasound examination performed at admission revealed a 6 * 6 cm right adnexal mass compatible with endometrioma, with a normal left ovary and uterus. Rectovaginal examination detected no endometriotic nodules. Although all treatment options were explained and discussed and laparoscopic excision of right ovarian endometrioma was recommended, the patient strongly desired removal of the uterus and the ovaries to avoid recurrence of endometriosis and related complaints. Thus, laparoscopic hysterectomy and bilateral salpingo-oophorectomy were planned. Under general anesthesia and endotracheal intubation, the patient was placed in low lithotomy position with the arms tucked. An orogastric tube and a Foley catheter were placed. Abdominal access was performed following an open Hasson technique with a 2.0- to 2.5-cm vertical umbilical incision and a 4 channel (with two 10-mm and two 5-mm channels) access port was placed into the peritoneal cavity. On pelvic examination, a 6 * 6-cm right ovarian endometrioma adherent to the pelvic sidewall was detected, along with severe adhesions on the left side between the left adnex and the pelvic sidewall. The uterus was normal. The adhesion on the left side was released using a Harmonic scalpel (Ethicon Endosurgery, Cinncinnati, OH). The pelvic sidewall peritoneum was opened, and the ureters were identified and isolated at the pelvic brim and followed toward the true pelvis. The internal iliac artery, uterine and obliterated umbilical artery, and infundibulopelvic ligament were dissected and identified. The paravesical, pararectal, and rectouterine spaces were opened. Deep infiltrating endometriosis implants on the right side located in the uterosacral ligment and pararectal space were dissected and excised. After restoration of pelvic anatomy, hysterectomy and bilateral salpingo-oophorectomy were performed. The vaginal cuff was closed with intracorporeal knots. The patient was discharged on postoperative day 1, and reported no problems at follow-up. CONCLUSION: Single-port laparoscopic hysterectomy appears to be a safe and feasible option in patients with deep infiltrating endometriosis, especially when performed by well experienced surgeons. PMID- 27480597 TI - MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice. AB - The microRNA-29 (miR-29) family is known to suppress the activation of hepatic stellate cells (HSCs) and reversibly control liver fibrosis; however, the mechanism of how miR-29a controls liver fibrosis remains largely unknown. This study was conducted to clarify the mechanism of anti-fibrotic effect of miR-29a and to explore if miR-29a is a promising candidate for nucleic acid medicine against liver fibrosis. Two liver fibrosis murine models (carbon tetrachloride or thioacetamide) were used. MiR-29a mixed with atelocollagen was systemically administered. Hepatic fibrosis was evaluated by histological analysis and the expression levels of fibrosis-related genes. We observed that miR-29a treatment dramatically accelerated the reversion of liver fibrosis in vivo. Additionally, miR-29a regulated the mRNA expression of collagen type I alpha 1 (COL1A1) and platelet-derived growth factor C (PDGFC). We also noted that miR-29a significantly suppressed COL1A1 mRNA expression and cell viability and significantly increased caspase-9 activity (P < 0.05) in LX-2 cells. Pretreatment of miR-29a inhibited activation of LX-2 cell by transforming growth factor beta treatment. MiR-29a exhibited anti-fibrotic effect without cell toxicity in vivo and directly suppressed the expression of PDGF-related genes as well as COL1A1 and induced apoptosis of LX-2 cells. MiR-29a is a promising nucleic acid inhibitor to target liver fibrosis. PMID- 27480599 TI - An arsenal of magnetic nanoparticles; perspectives in the treatment of cancer. AB - Nanomedicine is an emerging field, which constitutes a new direction in the treatment of cancer. Magnetic nanoparticles (MNPs) can circumvent vascular tissue to concentrate at the site of the tumor. Under the influence of an external, alternating magnetic field, MNPs generate high temperatures within the tumor and ablate malignant cells while inflicting minimal damage to healthy host tissue. Due to their theranostic properties, they constitute a promising candidate for the treatment of cancer. A critical review of the type, size and therapeutic effect of different MNPs is presented, following an appraisal of the literature in the last 5 years. This is a multibillion dollar industry, with a few studies moving to clinical trials within the next 5 years. PMID- 27480600 TI - Use of Health Services by Maltreated Children in Two Different Sociocultural Contexts: Where Can Doors for Interventions Be Opened? AB - Among maltreated children, elevated use of non-routine (for illness or injury) services may coexist with underutilization of preventive services. Besides physical health problems, lack of contact with primary care may preclude the identification and delivery of appropriate interventions. We examined health service utilization in the longitudinal Boricua Youth Study of Puerto Rican children residing in the South Bronx (SBx), New York City ( n = 901), and San Juan metropolitan area, Puerto Rico ( n = 1,163). Parents and children ( Mage = 9 years) reported on child physical abuse, sexual abuse, and neglect. Parents reported if their child had been to illness, injury, and well-child visits in the past year. In the SBx site, caretakers were more likely to report the children seeing a doctor for a well-child visit (90%) compared with children in Puerto Rico (71%). Children in Puerto Rico were more likely to visit a doctor for an injury in the past year compared with children in the SBx (39% vs. 24%). Twenty one percent of children in the SBx reported maltreatment versus 16% in Puerto Rico. Adjusting for sociodemographic factors, compared with non-maltreated children, those who experienced two or more types of maltreatment were more likely to have an illness visit in Puerto Rico (prevalence ratio [PR] = 1.5, 95% confidence interval [CI] = [1.1, 2.2]) and the SBx (PR = 1.8, 95% CI = [1.1, 3.0]), or an injury visit (PR = 4.1, 95% CI = [1.9, 8.9]) in Puerto Rico only. Children in the SBx who reported only one type of maltreatment were less likely to use services for injuries than non-maltreated children (PR = 0.42, 95% CI = [0.2, 0.9]). No relation between maltreatment and well-child visits was noted. Children who experience maltreatment may frequently come in contact with health care providers, presenting opportunities for intervention and the prevention of further maltreatment. PMID- 27480598 TI - A Phase l Study of a Tumor-targeted Systemic Nanodelivery System, SGT-94, in Genitourinary Cancers. AB - Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy. PMID- 27480601 TI - Fertility outcome after laparoscopic salpingostomy or salpingectomy for tubal ectopic pregnancy A 12-years retrospective cohort study. AB - AIM: To compare the subsequent reproductive outcome after laparoscopic salpingostomy or salpingectomy for tubal ectopic pregnancy (EP). MATERIAL OF STUDY: A retrospective cohort study was conducted between January 2002 and May 2014 on 132 women admitted to Unit of Gynecology and Obstetrics of the Department of Human Pathology in Adulthood and Childhood "G. Barresi", "Gaetano Martino" Hospital, University of Messina (Italy), with EP and who received surgical treatment, including laparoscopic salpingectomy (n=57) or salpingostomy (n=75). Main outcomes included intrauterine pregnancy (IUP), recurrent EP and persistent trophoblastic disease rates. RESULTS: The IUP rates up to 24 months after surgery were 56.1% for salpingectomy and 60% for salpingostomy. The 2-year recurrent EP rates were 5.3% for salpingectomy and 18.7% for salpingostomy. The persistent trophoblastic disease rate were 1.8% for salpingectomy and 12% for salpingostomy. DISCUSSION: Our results show that the reproductive outcomes after laparoscopic salpingectomy are similar to those observed after conservative treatment. CONCLUSIONS: In the surgical treatment of EP, the clinician should choose the best treatment in accordance with the patient, considering the severity of the disease, the clinical characteristics of the patient and her desire to preserve fertility. KEY WORDS: Ectopic pregnancy, Salpingectomy,Salpingostomy. PMID- 27480602 TI - The Lost Worlds of Messmore & Damon: Science, Spectacle & Prehistoric Monsters in early-twentieth century America. AB - In 1924, the model-making company Messmore & Damon, Inc. of New York unleashed their masterpiece: the Amphibious Dinosaurus Brontosaurus, a moving, breathing, roaring animatronic dinosaur, based on displays in the American Museum of Natural History. Over the 1920s and 1930s, this became the focus of an ever-increasing publicity campaign, as Messmore & Damon exhibited prehistoric automata in department stores, the media, and the Chicago World Fair of 1933-34. These displays were hugely popular and widely discussed, drawing from the increasing public appeal of paleontology. Mixing commercial entertainment with invocations of scientific value, Messmore & Damon's prehistoric creations offer a window into the meaning and popularity of the deep time sciences in early-twentieth century America, and the links between science and spectacle in this period. PMID- 27480603 TI - The effect of temperature and humidity on adhesion of a gecko-inspired adhesive: implications for the natural system. AB - The adhesive system of geckos has inspired hundreds of synthetic adhesives. While this system has been used relentlessly as a source of inspiration, less work has been done in reverse, where synthetics are used to test questions and hypotheses about the natural system. Here we take such an approach. We tested shear adhesion of a mushroom-tipped synthetic gecko adhesive under conditions that produced perplexing results in the natural adhesive system. Synthetic samples were tested at two temperatures (12 degrees C and 32 degrees C) and four different humidity levels (30%, 55%, 70%, and 80% RH). Surprisingly, adhesive performance of the synthetic samples matched that of living geckos, suggesting that uncontrolled parameters in the natural system, such as surface chemistry and material changes, may not be as influential in whole-animal performance as previously thought. There was one difference, however, when comparing natural and synthetic adhesive performance. At 12 degrees C and 80% RH, adhesion of the synthetic structures was lower than expected based on the natural system's performance. Our approach highlights a unique opportunity for both biologists and material scientists, where new questions and hypotheses can be fueled by joint comparisons of the natural and synthetic systems, ultimately improving knowledge of both. PMID- 27480604 TI - Long-term outcome of total hip arthroplasty in patients with haemophilia. AB - INTRODUCTION: Besides the target joints (elbow, knee and ankle), the hip is one of the commonly affected joints in haemophilic arthropathy. Hip arthroplasty is the therapy of choice after failure of conservative treatment. There are only limited data on long-term results after primary total hip arthroplasty (THA). AIM: The aim of this retrospective study was to analyse clinical outcome and complication rate after total hip replacement in patients with severe haemophilic arthropathy. METHODS: Forty-three patients with haemophilia (PWH), one patient with von Willebrand disease and one patient with a Factor-VII-deficiency undergoing 49 total hip arthroplasties, were evaluated in a retrospective study. Harris hip score (HHS), range of motion (ROM), pain status (visual analogue scale, VAS) complication rate and patient satisfaction were assessed at a mean follow-up of 11.5 years (range: 3-32). RESULTS: HSS, ROM and VAS improved significantly combined with high patient satisfaction. In total, three (6.1%) periprosthetic infections and five (10.2%) aseptic implant loosenings occurred after THA leading to revision arthroplasty. In two (4.1%) cases, a pseudotumour and one (2.0%) periarticular ossification had to be resected after THA. CONCLUSION: Total hip replacement in PWH leads to a significant increase of function, reduction of pain and a high satisfaction. Due to the relatively high complication rate (infections and aseptic loosening) compared to patients without haemophilia, an individual assessment of the risk-benefit ratio from surgical and haemostaseological point of view is needed. PMID- 27480606 TI - Heat- and pH-induced BSA conformational changes, hydrogel formation and application as 3D cell scaffold. AB - Aggregation and gelation of globular proteins can be an advantage to generate new forms of nanoscale biomaterials based on the fibrillar architecture. Here, we report results obtained by exploiting the proteins' natural tendency to self organize in 3D network, for the production of new material based on BSA for medical application. In particular, at five different pH values the conformational and structural changes of the BSA during all the steps of the thermal aggregation and gelation have been analyzed by FTIR spectroscopy. The macroscopic mechanical properties of these hydrogels have been obtained by rheological measurements. The microscopic structure of the gels have been studied by AFM and SEM images to have a picture of their different spatial arrangement. Finally, the use of the BSA hydrogels as scaffold has been tested in two different cell cultures. PMID- 27480605 TI - Abnormal movement of tropomyosin and response of myosin heads and actin during the ATPase cycle caused by the Arg167His, Arg167Gly and Lys168Glu mutations in TPM1 gene. AB - Amino acid substitutions: Arg167His, Arg167Gly and Lys168Glu, located in a consensus actin-binding site of the striated muscle tropomyosin Tpm1.1 (TM), were used to investigate mechanisms of the thin filament regulation. The azimuthal movement of TM strands on the actin filament and the responses of the myosin heads and actin subunits during the ATPase cycle were studied using fluorescence polarization of muscle fibres. The recombinant wild-type and mutant TMs labelled with 5-IAF, 1,5-IAEDANS-labelled S1and FITC-phalloidin F-actin were incorporated into the ghost muscle fibres to acquire information on the orientation of the probes relative to the fibre axis. The substitutions Arg167Gly and Lys168Glu shifted TM strands into the actin filament centre, whereas Arg167His moved TM towards the periphery of the filament. In the presence of Arg167Gly-TM and Lys168Glu-TM the fraction of actin monomers that were switched on and the number of the myosin heads strongly bound to F-actin were abnormally high even under conditions close to relaxation. In contrast, Arg167His-TM decreased the fraction of switched on actin and reduced the formation of strongly bound myosin heads throughout the ATPase cycle. We concluded that the altered TM-actin contacts destabilized the thin filament and affected the actin-myosin interactions. PMID- 27480607 TI - Selective arterial clamping does not improve outcomes in robot-assisted partial nephrectomy: a propensity-score analysis of patients without impaired renal function. AB - OBJECTIVES: To assess the benefit of selective arterial clamping (SAC) as an alternative to main renal artery clamping (MAC) during robot-assisted partial nephrectomy (RAPN) in patients without underlying chronic kidney disease (CKD). PATIENTS AND METHODS: Our study cohort comprised 665 patients without impaired renal function undergoing MAC (n = 589) or SAC (n = 76) during RAPN from four medical institutions in the period 2008-2015. We compared complication rates, positive surgical margin (PSM) rates, and peri-operative and intermediate-term renal functional outcome between 132 patients undergoing MAC and 66 undergoing SAC after 2-to-1 nearest-neighbour propensity-score matching for age, sex, body mass index, RENAL nephrometry score, tumour size, baseline estimated glomerular filtration rate (eGFR), American Society of Anesthesiologists (ASA) score, Charlson comorbidity index (CCI) and warm ischaemia time (WIT). RESULTS: In propensity-score-matched patients, PSM (5.7 vs 3.0%; P = 0.407) and complication rates (13.8 vs 10.6%; P = 0.727) did not differ between the MAC and SAC groups. The incidence of acute kidney injury for MAC vs SAC (25.0 vs 32.0%; P = 0.315) within the first 30 days was similar. At a median follow-up of 7.5 months, the percentage reduction in eGFR (-9.3 vs -10.4%; P = 0.518) and progression to CKD >= stage 3 (7.2 vs 8.5%; P = 0.792) showed no difference. CONCLUSIONS: Our study findings show no difference in PSM rates, complication rates or intermediate-term renal functional outcomes between patients with unimpaired renal function who underwent SAC vs those who underwent MAC. When expected WIT is low, the routine use of SAC may not be necessary. Further studies will need to determine the role of SAC in patients with a solitary kidney or with significantly impaired renal function. PMID- 27480608 TI - Feeding a diet devoid of choline to lactating rodents restricts growth and lymphocyte development in offspring. AB - The nutrient choline is necessary for membrane synthesis and methyl donation, with increased requirements during lactation. The majority of immune development occurs postnatally, but the importance of choline supply for immune development during this critical period is unknown. The objective of this study was to determine the importance of maternal supply of choline during suckling on immune function in their offspring among rodents. At parturition, Sprague-Dawley dams were randomised to either a choline-devoid (ChD; n 7) or choline-sufficient (ChS, 1 g/kg choline; n 10) diet with their offspring euthanised at 3 weeks of age. In a second experiment, offspring were weaned to a ChS diet until 10 weeks of age (ChD-ChS, n 5 and ChS-ChS, n 9). Splenocytes were isolated, and parameters of immune function were measured. The ChD offspring received less choline in breast milk and had lower final body and organ weight compared with ChS offspring (P<0.05), but this effect disappeared by week 10 with choline supplementation from weaning. ChD offspring had a higher proportion of T cells expressing activation markers (CD71 or CD28) and a lower proportion of total B cells (CD45RA+) and responded less to T cell stimulation (lower stimulation index and less IFN-gamma production) ex vivo (P<0.05). ChD-ChS offspring had a lower proportion of total and activated CD4+ T cells, and produced less IL-6 after mitogen stimulation compared with cells from ChS-ChS (P<0.05). Our study suggests that choline is required in the suckling diet to facilitate immune development, and choline deprivation during this critical period has lasting effects on T cell function later in life. PMID- 27480609 TI - Effect of left ventricular pacing mode and site on hemodynamic, torsional and strain indices. AB - INTRODUCTION: Several reports have indicated that left ventricular (LV) lead placement at an optimal pacing site is an important determinant of short- and long-term outcome. This study investigated the effect of pacing mode (atrioventricular [AV] or ventricular) and site (LV apical or lateral) outside the ischemic region on the LV hemodynamic, torsional and strain indices in the ischemic myocardium. METHODS: Experiments were conducted in anesthetized open chest pigs (n = 15) 30 min after LAD ligation to investigate the hemodynamic effects of temporary epicardial AV and ventricular LV pacing at the LV apical (outside the ischemic region) or lateral wall. LV hemodynamic data were recorded (ejection fraction, stroke volume, dP/dtmax, systolic pressure, cardiac output and e/e? ratio) and torsional (twist, rotation), as well as deformation (radial and circumferential strain), indices of LV function were assessed using two dimensional speckle tracking imaging. RESULTS: The LV function was highly dependent on the pacing mode and site. LV dP/dtmax, systolic pressure and twist decreased significantly during LV pacing in comparison to sinus rhythm (p = 0.004, p<0.001, p = 0.002, respectively). Torsion in sinus rhythm decreased significantly during AV-pacing at the lateral wall (0.11+/-0.04 degrees /mm vs. 0.06+/-0.02 degrees /mm, p = 0.005) but did not change significantly during AV pacing at the apex (0.07+/-0.05 degrees /mm). CONCLUSIONS: LV pacing at the apical or lateral wall, in the ischemic myocardium, leads to a suboptimal response in comparison to sinus rhythm. LV pacing at the apex outside the ischemic area exhibits a better response than pacing at the lateral wall, possibly because pacing from this site leads to a more physiological propagation of electrical conduction. PMID- 27480610 TI - A novel approach to cricoarytenoid joint injections: An anatomic study. AB - OBJECTIVES: To demonstrate a novel approach to cricoarytenoid joint (CAJ) injections. STUDY DESIGN: Anatomic feasibility study. METHODS: Five human cadaveric larynges providing 10 CAJ s were used to obtain trajectory measurements of a 27-gauge 11/2-inch needle placed between the CAJ capsule and the contralateral cricothyroid membrane. Ten additional larynges providing 20 CAJ s were then used to assess the efficacy of applying the previously obtained measurements to guide 0.2-cc methylene blue injections of the CAJ using a 27 gauge 11/2-inch needle. Successful injection was confirmed by direct visualization of methylene blue within the CAJ capsule. RESULTS: The tip of the needle made a 70 +/- 1.87 degree (confidence interval [CI] 95%) angle relative to the plane parallel to the anterior lamella of the cricoid cartilage; the needle was within the cricothyroid membrane 5 +/- 0.77 mm (CI 95%) lateral to the midsagittal plane; the needle was 4 +/- 0.80 mm (CI 95%) anteroinferior from the vocal process of the arytenoid cartilage as measured within the airway; and the distance from the point of airway entry and the CAJ capsule was 17 +/- 2.42 mm (CI 95%). Twenty CAJ injections were attempted using the guidelines established here with an 85% success rate. CONCLUSION: The current approach to CAJ injection utilizes microlaryngoscopy in an operative setting. This study is the first to describe the accessibility of the CAJ through percutaneous injection using reliable landmarks, potentially allowing access to the joint in an office-based setting. LEVEL OF EVIDENCE: NA Laryngoscope, 127:199-203, 2017. PMID- 27480611 TI - A pilot study of unemployment in patients with hidradenitis suppurativa in Denmark. PMID- 27480612 TI - RepB proteins of the multipartite Rhizobium leguminosarum bv. trifolii genome discriminate between centromere-like parS sequences for plasmid segregational stability. AB - The plasmids of the Rhizobiaceae family members and other Alphaproteobacteria are usually large, low copy-number and contain all elements necessary for active segregation and replication located in one operon comprising repABC genes. The genome of Rhizobium leguminosarum bv. trifolii TA1 (RtTA1) consists of a chromosome and four plasmids (pRleTA1a-d) with repABC operons. In this work, centromere-binding RepB proteins of four RtTA1 plasmids were studied. Stability assays of the truncated derivatives of repABC cassettes demonstrated that RepA, RepB proteins and parS-like elements constituted plasmid partitioning systems, while RepC were sufficient for their replication. Individual RepB proteins bound specifically to centromere-like parS elements of the parental plasmids, which was crucial step toward the proper segregation of plasmids into daughter cells. RtTA1 RepB proteins formed dimers and oligomers in the solution. The C-terminal part of RepB was responsible for dimerization, while the domain engaged in parS binding was located in the middle of the protein. It was concluded that the specific interaction between individual RepB proteins and their target sequences together with the substantial diversity of the Rep proteins and parS originating from different plasmids strongly contributed to the coexistence of several plasmids equipped with similar repABC cassettes in the multipartite bacterial genome. PMID- 27480613 TI - Reversible polymorphism-aware phylogenetic models and their application to tree inference. AB - We present a reversible Polymorphism-Aware Phylogenetic Model (revPoMo) for species tree estimation from genome-wide data. revPoMo enables the reconstruction of large scale species trees for many within-species samples. It expands the alphabet of DNA substitution models to include polymorphic states, thereby, naturally accounting for incomplete lineage sorting. We implemented revPoMo in the maximum likelihood software IQ-TREE. A simulation study and an application to great apes data show that the runtimes of our approach and standard substitution models are comparable but that revPoMo has much better accuracy in estimating trees, divergence times and mutation rates. The advantage of revPoMo is that an increase of sample size per species improves estimations but does not increase runtime. Therefore, revPoMo is a valuable tool with several applications, from speciation dating to species tree reconstruction. PMID- 27480614 TI - Warfarin and coumarin-like Murraya paniculata extract down-regulate EpCAM mediated cell adhesion: individual components versus mixture for studying botanical metastatic chemopreventives. AB - We recently defined cancer metastatic chemoprevention as utilizing safe and effective molecules to comprehensively prevent the spark of activation-adhesion extravasation-proliferation metastatic cascade caused by circulating tumor cells (CTCs). The strategy focuses on preventing the most important starting point of the cascade. We identified an extract from a well-known medical plant Murraya paniculata, which inhibited both embryonic implantation to human endometrium as traditionally-used for abortion and CTC adhesion to human endothelium. Here, we separated and characterized five coumarin-containing components (Z1-Z5) from the botanic extract. Flow cytometry revealed that within 1-100 MUg/mL, Z3 and Z5 down regulated EpCAM expression in human colon HCT116, whereas, Z1 and Z2 did oppositely. Warfarin and Z1-Z5 component mixture (CM) also down-regulated EpCAM expression. The down-regulation of EpCAM by Z3, Z5, CM and warfarin was confirmed by western blotting, and caused inhibition on adhesion of cancer cells to human endothelial cells. Rat coagulation study showed that warfarin prolonged prothrombin time, whereas, Z3 did not. The present studies revealed that, for the first time, warfarin and coumarin-like components Z3, Z5 and CM from Murraya paniculata could directly inhibit EpCAM-mediated cell-cell adhesion. PMID- 27480615 TI - Role of robotics in managing mesh and suture complications of prior pelvic organ prolapse surgery. AB - Robotic surgery is proving essential in providing a minimally invasive approach to complex urogynaecological cases. This video highlights the diversity and complexity of cases performed using the robot-assisted approach. The robot assisted approach was utilised for excellent effect in two complex urogynaecological cases. In the first case the entire left arm of an intravesically placed TVT was removed using a combined vaginal and robotic approach. The second case involved removing four paravaginal sutures, one of which breeched the bladder and was encrusted with calculus. These were placed during a laparoscopic paravaginal repair 2 years previously. She had a concomitant vaginal hysterectomy, Mc Calls culdoplasty and anterior wall repair. The robot-assisted approach allows for excellent access to the pelvis and retropubic space facilitating the surgical management of complex urogynaecology cases. PMID- 27480616 TI - Climate Surveys: An Inventory of Understanding Sexual Assault and Other Crimes of Interpersonal Violence at Institutions of Higher Education. AB - Sexual assault, dating/domestic violence, sexual harassment, and stalking are complex crimes and have been a major focus of national attention at institutions of higher education (IHEs). To grasp the extent and nature of these crimes on campuses, institutionally specific climate surveys are being developed and endorsed by the federal government and conducted at IHEs. These climate surveys differ in content and length. This article describes 10 different climate surveys and outlines the variables measured in each tool. Next steps for assessing climate surveys are discussed. PMID- 27480617 TI - Three-dimensional printing for preoperative planning of total hip arthroplasty revision: case report. AB - Three dimensional (3D) printing can be used to create material models to aid preoperative planning of complex orthopedic procedures as exemplified by this case of total hip arthroplasty failure due to infection with resulting severe acetabular bone stock deficiency. The 3D model allowed for trialing of the acetabular component to determine cup size, position, and screw placement. Most importantly, the model confirmed that there was not a pelvic discontinuity and the revision shell would be sufficient for the reconstruction. Previously, the cost and complexity of utilization of 3D printers were prohibitive. Recent improvements in commercially available 3D printers have made rapid prototype model creation a realistic option, which can facilitate difficult surgery. PMID- 27480618 TI - The clinicopathologic findings of a subchondral insufficiency fracture of the femoral head in a male patient: a case report. AB - There are few reports describing the clinicopathologic characteristics of subchondral insufficiency fractures of the femoral head (SIF) in men over 50 years of age. A 59-year-old man experienced a sudden onset of the left hip pain without any antecedent trauma. The hip pain did not improve despite conservative treatments, and he underwent a total hip arthroplasty. The mid-coronal cut section of the resected femoral head revealed a fracture line paralleling the subchondral bone endplate beneath the articular cartilage. In addition, the subchondral fracture broadly underlaid the weight bearing area of the femoral head. Histopathologically, reparative tissue including fracture callus and granulation tissue, as well as thin disconnected bone trabeculae were observed. These clinicopathological findings were similar to those of previously described SIF in women. It is therefore important to consider SIF in cases of acute hip pain, even in middle-aged men. PMID- 27480619 TI - What is the best position for palatal implants? A CBCT study on bone volume in the growing maxilla. AB - OBJECTIVE: The objectives of the present study are the following: (a) to investigate limitations (bone height, proximity to nasopalatine nerve and roots) in juvenile patients, (b) to review the recommended site for surgical insertion (level of the maxillary first premolars), and (c) to reassess the rationale behind the manufacturer's age limitation (12 years). PATIENTS AND METHODS: Cone beam CT images of 100 patients aged 10 to 20 years were analyzed. Vertical bone heights were measured in the median plane as well as 3- and 6-mm paramedian along the prospective axis of insertion, at the level of the first premolars (level 0), 3 mm anterior (level 1) and 3 mm posterior (level 2). The Mann-Whitney U test was used to compare bone heights between gender groups. RESULTS: The risk of damage to the nasopalatine nerve is highest in the median region on level 1 (46 %). The risk was lowest in the midsagittal region on level 0 (recommended insertion site; 3 %) and level 2 (0 %), as well as paramedian on levels 0 and 2. The risk of damaging roots was irrelevant for median insertion at all levels; the only critical region was 6-mm paramedian on level 1. CONCLUSIONS: The recommendation of surgical insertion at the level of the maxillary first premolars is still justified, but a slightly more posterior implant position might improve safety. We found no relevant growth-related changes in the vertical bone heights in the median palatal area. Thus, our data do not support the strict 12-year age restriction for palatal implants. PMID- 27480620 TI - Effect of different gutta-percha solvents on the microtensile bond strength of various adhesive systems to pulp chamber dentin. AB - OBJECTIVES: The aim of this study was to evaluate the effect of different endodontic solvents on the microtensile bond strength (MUTBS) of various adhesives to pulp chamber dentin. MATERIAL AND METHODS: A total of 120 human third molars were selected. Canals were prepared with the ProTaper Universal system and obturated. The access cavities were then restored with resin composite. After 1 week, a retreatment procedure was applied as follows: control, no solvent was applied to the pulp chamber and experimental groups, three different solvents (chloroform, eucalyptol, and orange oil) were applied to the pulp chamber for 2 min. The canal filling was removed and calcium hydroxide (Ca[OH]2) was placed into the canals. After 7 days, the Ca(OH)2 was removed from the canals and the canals were re-obturated. Teeth were then divided into three subgroups according to the adhesive used. The samples were restored with a nanohybrid resin composite using three different adhesives: Clearfil SE Bond (CSE), Adper Easy One (AEO), and Single Bond 2 (SB2). The samples were aged with thermocycling. Teeth were sectioned, and a total of 20 dentin sticks were obtained for each subgroup. MUTBS testing was then performed. The debonded surfaces were evaluated using scanning electron microscopy (SEM) analysis. Data were analyzed using two-way ANOVA and Tukey's post hoc tests. RESULTS: Chloroform showed statistically lower mean MUTBS values (14 +/- 7.2 MPa) than control group did (19.2 +/- 6.1 MPa) (p < 0.05). Orange oil (18.1 +/- 6.3 MPa) and eucalyptol (16.9 +/- 6.8 MPa) did not reduce the mean MUTBS statistically (p > 0.05). Chloroform showed significantly lower bond strength for all adhesives (p < 0.05). Whereas orange oil did not reduce the mean MUTBS values of all adhesive systems significantly (p > 0.05), eucalyptol reduced the MUTBS values of all the groups, but the results were only statistically significant for SB2 (p < 0.05). CSE showed statistically higher bond strength (20.4 +/- 6.8 MPa) than AEO (14.6 +/- 5.3 MPa) and SB2 (16.3 +/- 7.2 MPa) did (p < 0.05). There were no statistical differences between AEO and SB2 (p > 0.05). According to the SEM analysis of the debonded surfaces, adhesive failures were the most common type in all the groups, followed by mixed failures. CONCLUSIONS: While chloroform reduced the mean bond strength of the adhesive resins, orange oil did not affect the bond strength of the adhesives. The effect of eucalyptol on bond strength depended on the type of adhesive system. CLINICAL RELEVANCE: This study shows that endodontic solvents could affect the microtensile bond strength of adhesives to pulp chamber dentin. PMID- 27480621 TI - The essence of crime: Contagious transmission from those who have committed moral transgressions. AB - Across four studies, we investigated the relationship between moral contagion and disgust. Study 1 established that the contamination effect is unique to transgressions that fall within the moral domain. Study 2 replicated this effect and further showed that the underlying mechanism is intimately related to disgust, as disgust was found to uniquely mediate the relationship between moral transgressions and contamination responses. In Study 3, disgust was again found to mediate this relationship. In addition, the results of Study 3 show that the moral contagion effect was not dependent upon the presence of a core disgust cue within the transgression. In Study 4, we investigated whether or not moral contagion leads to behavioural avoidance. Results show that behavioural avoidance only occurred when the moral transgression contained a core disgust cue. Taken together, the results of our studies show that disgust plays a key role in moral contagion processes. However, the difference in findings between the thought experiments (Studies 1-3) and the behavioural experiment (Study 4) identifies a need for further research to examine the conditions under which moral contagion leads to behavioural avoidance. PMID- 27480622 TI - Targeted intervention: Computational approaches to elucidate and predict relapse in alcoholism. AB - Alcohol use disorder (AUD) and addiction in general is characterized by failures of choice resulting in repeated drug intake despite severe negative consequences. Behavioral change is hard to accomplish and relapse after detoxification is common and can be promoted by consumption of small amounts of alcohol as well as exposure to alcohol-associated cues or stress. While those environmental factors contributing to relapse have long been identified, the underlying psychological and neurobiological mechanism on which those factors act are to date incompletely understood. Based on the reinforcing effects of drugs of abuse, animal experiments showed that drug, cue and stress exposure affect Pavlovian and instrumental learning processes, which can increase salience of drug cues and promote habitual drug intake. In humans, computational approaches can help to quantify changes in key learning mechanisms during the development and maintenance of alcohol dependence, e.g. by using sequential decision making in combination with computational modeling to elucidate individual differences in model-free versus more complex, model-based learning strategies and their neurobiological correlates such as prediction error signaling in fronto-striatal circuits. Computational models can also help to explain how alcohol-associated cues trigger relapse: mechanisms such as Pavlovian-to-Instrumental Transfer can quantify to which degree Pavlovian conditioned stimuli can facilitate approach behavior including alcohol seeking and intake. By using generative models of behavioral and neural data, computational approaches can help to quantify individual differences in psychophysiological mechanisms that underlie the development and maintenance of AUD and thus promote targeted intervention. PMID- 27480623 TI - Optimal DSI reconstruction parameter recommendations: Better ODFs and better connectivity. AB - Diffusion Spectrum Imaging (DSI) has been used for tractography in several publicly available software and a number of recent high impact publications. However, there are several important theoretical, numerical and practical considerations that are often ignored. We revisit the theoretical and state-of the-art processing steps necessary to go from the DSI signal to the diffusion orientation distribution function (dODF) used by tractography. We show that the parameters in the reconstruction have huge impact on the reconstruction quality and that, while there is no consensus about what they should be, the parameters we most often see in the literature are not optimal. We provide applicable recommendations that improve the accuracy of extracted local orientations and improve accuracy of global connectivity as measured by the Tractometer, a tractography online evaluation system. These recommendations come for "free" as they are applicable to all existing DSI data and do not require a significant increase in computation time. Hence, this paper highlights the do's and dont's of DSI reconstruction. PMID- 27480624 TI - How do parcellation size and short-range connectivity affect dynamics in large scale brain network models? AB - Recent efforts to model human brain activity on the scale of the whole brain rest on connectivity estimates of large-scale networks derived from diffusion magnetic resonance imaging (dMRI). This type of connectivity describes white matter fiber tracts. The number of short-range cortico-cortical white-matter connections is, however, underrepresented in such large-scale brain models. It is still unclear on the one hand, which scale of representation of white matter fibers is optimal to describe brain activity on a large-scale such as recorded with magneto- or electroencephalography (M/EEG) or functional magnetic resonance imaging (fMRI), and on the other hand, to which extent short-range connections that are typically local should be taken into account. In this article we quantified the effect of connectivity upon large-scale brain network dynamics by (i) systematically varying the number of brain regions before computing the connectivity matrix, and by (ii) adding generic short-range connections. We used dMRI data from the Human Connectome Project. We developed a suite of preprocessing modules called SCRIPTS to prepare these imaging data for The Virtual Brain, a neuroinformatics platform for large-scale brain modeling and simulations. We performed simulations under different connectivity conditions and quantified the spatiotemporal dynamics in terms of Shannon Entropy, dwell time and Principal Component Analysis. For the reconstructed connectivity, our results show that the major white matter fiber bundles play an important role in shaping slow dynamics in large-scale brain networks (e.g. in fMRI). Faster dynamics such as gamma oscillations (around 40 Hz) are sensitive to the short-range connectivity if transmission delays are considered. PMID- 27480625 TI - There is more into 'doing' than 'knowing': The function of the right inferior frontal sulcus is specific for implementing versus memorising verbal instructions. AB - In the present study we examine the mechanism underlying the human ability to implement newly instructed stimulus-response mappings for their future application. We introduce a novel procedure in which we can investigate the processes underlying such implementation while controlling for more general working-memory demands. The results indicate that a region within the dorso lateral prefrontal cortex (DLPFC) in the vicinity of the inferior frontal sulcus (IFS) is specifically recruited when new instructions are implemented compared to when new instructions are memorised. In addition, we observed that this area is more strongly activated when task performance is effective. Together, these findings suggest that the DLPFC, and more specific the IFS, plays an important role during the formation of procedural representations in working memory. PMID- 27480626 TI - Probing the Sudlow binding site with warfarin: how does gold nanocluster growth alter human serum albumin? AB - The search for new fluorescent molecules is vital to the advancement of molecular imaging and sensing for the benefit of medical and biological studies. One such class of new fluorescent molecule is fluorescent gold nanoclusters encapsulated in Human Serum Albumin (HSA-AuNC). In order to use this new fluorescent molecule as a sensor or fluorescent marker in biological imaging both in vitro and in vivo it is important to understand whether/how the proteins function is changed by the synthesis and presence of the gold nanoclusters inside the protein. Natural HSA acts as the main drug carrier in the blood stream, carrying a multitude of molecules in two major binding sites (Sudlow I and II). To test the effects of gold on the ability of HSA to act as a drug carrier we employed warfarin, an anticoagulant drug, as a fluorescent probe to detect changes between natural HSA and HSA-AuNCs. AuNCs are found to inhibit the take up of warfarin by HSA. Evidence for this is found from fluorescence spectral and lifetime measurements. Interestingly, the presence of warfarin bound to HSA also inhibits the formation of gold nanoclusters within protein. This research provides valuable insight into how protein function can change upon synthesis of AuNCs and how that will affect their use as a fluorescent probe. PMID- 27480627 TI - Bisphenol A regulates Snail-mediated epithelial-mesenchymal transition in hemangioma cells. AB - Hemangioma (HA) can be exposed to bisphenol A (BPA) through direct skin absorption. Although numerous studies indicated that BPA can trigger the progression of cancers, there is no study concerning the effects of BPA on development of HA. Our present study revealed that nanomolar BPA can significantly increase the in vitro migration and invasion of HA cells via induction of epithelial-mesenchymal transition (EMT), which was evidenced by the upregulation of vimentin and downregulation of E-cadherin. The BPA treatment also significantly increased the expression and nuclear localization of Snail and the key transcription factor of EMT, while it had no effect on the expression of other transcription factors such as Slug, Twist, or ZEB1. Silencing of Snail by small interfering RNAs attenuated BPA-induced downregulation of cadherin and upregulation of vimentin, suggesting that Snail is essential for BPA-induced EMT. Both estrogen receptor alpha (ERalpha) and G protein-coupled estrogen receptor (GPER) were expressed in HA cells; furthermore, BPA treatment can increase the expression of both ERalpha and GPER. However, only the inhibitor of ERalpha (ICI 182, 780), and not GPER (G15), can abolish BPA-induced upregulation of Snail. It suggested that ERalpha is involved in BPA-induced EMT of HA cells. Collectively, our data suggested that BPA can trigger the EMT of HA cells via ERalpha/Snail signals. It indicated that more attention should be paid to the skin exposure to BPA for HA patients. PMID- 27480628 TI - Vertebral bone attenuation on low-dose chest CT: quantitative volumetric analysis for bone fragility assessment. AB - : This study evaluated the use of low-dose chest computed tomography (LDCT) for detecting bone fragility. LDCT-measured vertebral bone attenuation by volumetric methods showed good correlation with bone mineral density (BMD) measured by dual energy x-ray absorptiometry (DXA, and good diagnostic performance for identifying osteoporosis and compression fractures. The results of this study suggest the feasibility of obtaining comprehensive information on bone health in subjects undergoing LDCT. INTRODUCTION: Osteoporosis is a prevalent but underdiagnosed disease that increases fracture risk. This study evaluated the utility of vertebral attenuation derived from low-dose chest computed tomography (LDCT) compared to dual-energy x-ray absorptiometry (DXA) for detecting bone fragility. METHODS: A total of 232 subjects (78 men and 154 women) aged above 50 years who underwent both LDCT and DXA within 30 days were evaluated. LDCT-measured bone attenuation in Hounsfield units (HU) of four vertebrae (T4, T7, T10, and L1) was evaluated using volumetric methods for correlation with DXA-measured bone mineral density (BMD) and for the diagnosis of compression fractures, osteoporosis, and low BMD (osteoporosis or osteopenia) in men and women, with DXA measurements as the reference standard. RESULTS: The average attenuation of the four vertebrae showed strong correlation with DXA-measured BMD of the lumbar spine (r = 0.726, p < 0.05). In receiver-operating characteristic (ROC) analyses, the area under the curve (AUC) across LDCT-measured thresholds of the average attenuation to distinguish compression fractures was 0.827, and a threshold of 129.5 HU yielded 90.9 % sensitivity and 64.4 % specificity. Similarly, average attenuation showed high AUCs and good diagnostic performance for detecting osteoporosis and low BMD in both men and women. Among 44 subjects with compression fractures, the average bone attenuation showed strong negative correlation with both the worst fracture grade (r = -0.525, p < 0.05) and cumulative fracture grade score (r = -0.633, p < 0.05). CONCLUSION: LDCT-measured bone attenuation by volumetric methods showed good correlation with BMD measured by DXA and good diagnostic performance for identifying bone fragility. PMID- 27480629 TI - Synthesis and antifungal activity of dehydroabietic acid-based 1,3,4-thiadiazole thiazolidinone compounds. AB - In an attempt to search for new natural products-based antifungal agents, a series of novel dehydroabietic acid derivatives bearing a 1,3,4-thiadiazole thiazolidinone moiety were designed and synthesized. The primary bioassay used showed that at a concentration of [Formula: see text], the target compounds 3c, 3f, and 3n exhibited excellent antifungal activity (91.3 % inhibition) against Gibberella zeae, which was equivalent to the commercial antifungal drug azoxystrobin (positive control). PMID- 27480630 TI - Design and synthesis of novel protein kinase R (PKR) inhibitors. AB - Protein kinase RNA-activated (PKR) plays an important role in a broad range of intracellular regulatory mechanisms and in the pathophysiology of many human diseases, including microbial and viral infections, cancer, diabetes and neurodegenerative disorders. Recently, several potent PKR inhibitors have been synthesized. However, the enzyme's multifunctional character and a multitude of PKR downstream targets have prevented the successful transformation of such inhibitors into effective drugs. Thus, the need for additional PKR inhibitors remains. With the help of computer-aided drug-discovery tools, we designed and synthesized potential PKR inhibitors. Indeed, two compounds were found to inhibit recombinant PKR in pharmacologically relevant concentrations. One compound, 6 amino-3-methyl-2-oxo-N-phenyl-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide, also showed anti-apoptotic properties. The novel molecules diversify the existing pool of PKR inhibitors and provide a basis for the future development of compounds based on PKR signal transduction mechanism. PMID- 27480631 TI - Vedolizumab for Treating Moderately to Severely Active Crohn's Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn's disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naive to tumour necrosis factor alpha antagonist (anti-TNF-alpha) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF alpha agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6-52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn's disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be L21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-alpha-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above L30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-alpha-naive and anti-TNF-alpha-failure populations) and in patients who were anti-TNF-alpha naive only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company's model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues. PMID- 27480632 TI - On the study of microbial transcriptomes using second- and third-generation sequencing technologies. AB - Second-generation sequencing technologies transformed the study of microbial transcriptomes. They helped reveal the transcription start sites and antisense transcripts of microbial species, improving the microbial genome annotation. Quantification of genome-wide gene expression levels allowed for functional studies of microbial research. Ever-evolving sequencing technologies are reshaping approaches to studying microbial transcriptomes. Recently, Oxford Nanopore Technologies delivered a sequencing platform called MinION, a third generation sequencing technology, to the research community. We expect it to be the next sequencing technology that enables breakthroughs in life science fields. The studies of microbial transcriptomes will be no exception. In this paper, we review microbial transcriptomics studies using second- generation sequencing technology. We also discuss the prospect of microbial transcriptomics studies with thirdgeneration sequencing. PMID- 27480633 TI - Deinococcus seoulensis sp. nov., a bacterium isolated from sediment at Han River in Seoul, Republic of Korea. AB - Strain 16F1E(T) was isolated from a 3-kGy-irradiated sediment sample collected at Han River in Seoul, Republic of Korea. Cells of this strain were observed to be Gram-positive, pililike structure, and short rod shape, and colonies were red in color. The strain showed the highest degree of 16S rRNA gene sequence similarity to Deinococcus aquaticus PB314(T) (98.8%), Deinococcus depolymerans TDMA-24(T) (98.1%), Deinococcus caeni Ho-08(T) (98.0%), and Deinococcus grandis DSM 3963(T) (97.0%). 16S rRNA gene sequence analysis identified this strain as a member of the genus Deinococcus (Family: Deinococcaceae). The genomic DNA G+C content of strain 16F1ET was 66.9 mol%. The low levels of DNA-DNA hybridization (< 56.2%) with the species mentioned above identified strain 16F1E(T) as a novel Deinococcus species. Its oxidase and catalase activities as well as the production of acid from glucose were positive. Growth of the strain was observed at 10-37 degrees C (optimum: 20-30 degrees C) and pH 4-10 (optimum: pH 7-8). The cells tolerated less than 5% NaCl and had low resistance to gamma radiation (D10 < 4 kGy). Strain 16F1ET possessed the following chemotaxonomic characteristics: C16:0, C15:1 omega6c, and C16:1 omega7c as the major fatty acids; phosphoglycolipid as the predominant polar lipid; and menaquinone-8 as the predominant respiratory isoprenoid quinone. Based on the polyphasic evidence, as well as the phylogenetic, genotypic, phenotypic, and chemotaxonomic characterization results, strain 16F1E(T) (=KCTC 33793(T) =JCM 31404(T)) is proposed to represent the type strain of a novel species, Deinococcus seoulensis sp. nov. PMID- 27480634 TI - Dynamic variation of toxic and non-toxic Microcystis proportion in the eutrophic Daechung Reservoir in Korea. AB - This study was conducted to determine the environmental factors affecting the level of potentially toxic Microcystis. The long-term tendencies of temperature, precipitation, and water quality factors were analyzed to determine the environmental characteristics of the Daechung Reservoir in Korea, and water samples were directly collected to analyze the dynamics of toxic and non-toxic Microcystis at weekly intervals from May to October 2012. Microcystis was the dominant genus during the study period, and it was composed of potentially toxic and non-toxic Microcystis. The fraction of potentially toxic Microcystis ranged from 6.0% to 61.1%. The amount of toxic Microcystis was highly related to the intracellular microcystin concentration (r = 0.760, P < 0.01). Therefore, the fraction of potentially toxic Microcystis is an important concern in Microcystis blooming because the intracellular microcystin concentration may reflect microcystin levels in the water. The prevalence of potentially toxic Microcystis was highly related to water temperature in Daechung Reservoir (r = 0.585, P < 0.01). Thus, temperature increase during Microcystis blooming may lead to more frequent toxic Microcystis blooms in eutrophic water bodies. PMID- 27480635 TI - Epidemiology and resistance features of Acinetobacter baumannii isolates from the ward environment and patients in the burn ICU of a Chinese hospital. AB - Acinetobacter baumannii is an important opportunistic pathogen that causes severe nosocomial infections, especially in intensive care units (ICUs). Over the past decades, an everincreasing number of hospital outbreaks caused by A. baumannii have been reported worldwide. However, little attention has been directed toward the relationship between A. baumannii isolates from the ward environment and patients in the burn ICU. In this study, 88 A. baumannii isolates (26 from the ward environment and 62 from patients) were collected from the burn ICU of the Southwest Hospital in Chongqing, China, from July through December 2013. Antimicrobial susceptibility testing results showed that drug resistance was more severe in isolates from patients than from the ward environment, with all of the patient isolates being fully resistant to 10 out of 19 antimicrobials tested. Isolations from both the ward environment and patients possessed the beta lactamase genes bla OXA-51, bla OXA-23, bla AmpC, bla VIM, and bla PER. Using pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST), these isolates could be clustered into 4 major PFGE types and 4 main sequence types (ST368, ST369, ST195, and ST191) among which, ST368 was the dominant genotype. Epidemiologic and molecular typing data also revealed that a small scale outbreak of A. baumannii infection was underway in the burn ICU of our hospital during the sampling period. These results suggest that dissemination of beta-lactamase genes in the burn ICU might be closely associated with the high level resistance of A. baumannii, and the ICU environment places these patients at a high risk for nosocomial infection. Cross-contamination should be an important concern in clinical activities to reduce hospitalacquired infections caused by A. baumannii. PMID- 27480636 TI - Amino acid residues in the Ler protein critical for derepression of the LEE5 promoter in enteropathogenic E. coli. AB - Enteropathogenic E. coli causes attaching and effacing (A/E) intestinal lesions. The genes involved in the formation of A/E lesions are encoded within a chromosomal island comprising of five major operons, LEE1-5. The global regulator H-NS represses the expression of these operons. Ler, a H-NS homologue, counteracts the H-NS-mediated repression. Using a novel genetic approach, we identified the amino acid residues in Ler that are involved in the interaction with H-NS: I20 and L23 in the C-terminal portion of alpha-helix 3, and I42 in the following unstructured linker region. PMID- 27480637 TI - Mycobacterium tuberculosis gene expression at different stages of hypoxia-induced dormancy and upon resuscitation. AB - The physiology of dormant Mycobacterium tuberculosis was studied in detail by examining the gene expression of 51 genes using quantitative Reverse Transcription Polymerase Chain Reaction. A forty-day period of dormancy in the Wayne culture model depicted four major transcription patterns. Some sigma factors and many metabolic genes were constant, whereas genes belonging to the dormancy regulon were activated on day 9. In particular, alpha-crystallin mRNA showed more than a 1,000-fold increase compared to replicating bacilli. Genes belonging to the enduring hypoxic response were up-regulated at day 16, notably, transcription factors sigma B and E. Early genes typical of log-phase bacilli, esat-6 and fbpB, were uniformly down-regulated during dormancy. Late stages of dormancy showed a drop in gene expression likely due to a lack of substrates in anaerobic respiration as demonstrated by the transcriptional activation observed following nitrates addition. Among genes involved in nitrate metabolism, narG was strongly up-regulated by nitrates addition. Dormant bacilli responded very rapidly when exposed to oxygen and fresh medium, showing a transcriptional activation of many genes, including resuscitation-promoting factors, within one hour. Our observations extend the current knowledge on dormant M. tuberculosis gene expression and its response to nutrients and to aerobic and anaerobic respiration. PMID- 27480638 TI - The Pseudomonas aeruginosa extracellular secondary metabolite, Paerucumarin, chelates iron and is not localized to extracellular membrane vesicles. AB - Proteins encoded by the Pseudomonas aeruginosa pvcA-D operon synthesize a novel isonitrile functionalized cumarin termed paerucumarin. The pvcA-D operon enhances the expression of the P. aeruginosa fimbrial chaperone/usher pathway (cup) genes and this effect is mediated through paerucumarin. Whether pvcA-D and/or paerucumarin affect the expression of other P. aeruginosa genes is not known. In this study, we examined the effect of a mutation in pvcA-D operon the global transcriptome of the P. aeruginosa strain PAO1-UW. The mutation reduced the expression of several ironcontrolled genes including pvdS, which is essential for the expression of the pyoverdine genes. Additional transcriptional studies showed that the pvcA-D operon is not regulated by iron. Exogenously added paerucumarin enhanced pyoverdine production and pvdS expression in PAO1-UW. Iron-chelation experiments revealed that purified paerucumarin chelates iron. However, exogenously added paerucumarin significantly reduced the growth of a P. aeruginosa mutant defective in pyoverdine and pyochelin production. In contrast to other secondary metabolite, Pseudomonas quinolone signal (PQS), paerucumarin is not localized to the P. aeruginosa membrane vesicles. These results suggest that paerucumarin enhances the expression of iron-controlled genes by chelating iron within the P. aeruginosa extracellular environment. Although paerucumarin chelates iron, it does not function as a siderophore. Unlike PQS, paerucumarin is not associated with the P. aeruginosa cell envelope. PMID- 27480639 TI - Quantification of the Electrophilicity of Benzyne and Related Intermediates. AB - The determination of reactivity parameters for short-lived intermediates provides an indispensable tool for synthetic design. Despite that electrophilicity parameters have now been established for more than 250 reactive species, the corresponding parameters for benzyne and related intermediates have not been uncovered. We report a study that has allowed for the quantification of benzyne's electrophilicity parameter. Our approach relies on the strategic use of the diffusion-clock method and also provides electrophilicity parameters E for other substituted arynes. PMID- 27480640 TI - Colour is more than hue: preferences for compiled colour traits in the stingless bees Melipona mondury and M. quadrifasciata. AB - The colour vision of bees has been extensively analysed in honeybees and bumblebees, but few studies consider the visual perception of stingless bees (Meliponini). In a five-stage experiment the preference for colour intensity and purity, and the preference for the dominant wavelength were tested by presenting four colour stimuli in each test to freely flying experienced workers of two stingless bee species, Melipona mondury and Melipona quadrifasciata. The results with bee-blue, bee-UV-blue and bee-green colours offered in four combinations of varying colour intensity and purity suggest a complex interaction between these colour traits for the determination of colour choice. Specifically, M. mondury preferred bee-UV-blue colours over bee-green, bee-blue and bee-blue-green colours while M. quadrifasciata preferred bee-green colour stimuli. Moreover in M. mondury the preferences were different if the background colour was changed from grey to green. There was a significant difference between species where M. mondury preferred UV-reflecting over UV-absorbing bee-blue-green colour stimuli, whereas M. quadrifasciata showed an opposite preference. The different colour preferences of the free flying bees in identical conditions may be caused by the bees' experience with natural flowers precedent to the choice tests, suggesting reward partitioning between species. PMID- 27480641 TI - Morphometric data on severely and morbidly obese deceased, established on forensic and non-forensic autopsies. AB - With the widespread increase in the incidence of obesity, autopsies on severely and morbidly obese deceased have become common in the USA. Standard reference tables for organ weights provide little or no information on individuals with a body mass index greater than 35 kg/m(2). Although several recent reports have provided organ weights for small numbers of morbidly obese persons who died naturally from a variety of causes, these data may have been affected by comorbidities. Furthermore, they did not provide information relative to differences in organ weight based on gender, age, and race. The aim of the present study was to fill this void by developing reference tables for organ weights of severely and morbidly obese individuals. Our study was based on data from 802 forensic and medical autopsies, including 435 cases of death of natural and 367 of non-natural causes. Organ weights were compared between these groups, and reference ranges were generated. Significant variability was found in organ weights especially among deceased older than 40 years who died naturally, suggesting that comorbidities affect organ weight. Reference tables were compiled for organ weights and morphometric data based on gender, age, and race. Since obesity is a pathological condition affecting organ weight, these reference tables do not reflect normal organ weights but only weight as seen in severely and morbidly obese individuals. They should be useful to pathologists who perform forensic and non-forensic autopsies. PMID- 27480642 TI - Photoelectrical Stimulation of Neuronal Cells by an Organic Semiconductor Electrolyte Interface. AB - As a step toward the realization of neuroprosthetics for vision restoration, we follow an electrophysiological patch-clamp approach to study the fundamental photoelectrical stimulation mechanism of neuronal model cells by an organic semiconductor-electrolyte interface. Our photoactive layer consisting of an anilino-squaraine donor blended with a fullerene acceptor is supporting the growth of the neuronal model cell line (N2A cells) without an adhesion layer on it and is not impairing cell viability. The transient photocurrent signal upon illumination from the semiconductor-electrolyte layer is able to trigger a passive response of the neuronal cells under physiological conditions via a capacitive coupling mechanism. We study the dynamics of the capacitive transmembrane currents by patch-clamp recordings and compare them to the dynamics of the photocurrent signal and its spectral responsivity. Furthermore, we characterize the morphology of the semiconductor-electrolyte interface by atomic force microscopy and study the stability of the interface in dark and under illuminated conditions. PMID- 27480646 TI - Issue Information-Declaration of Helsinki. PMID- 27480644 TI - Special Issue: Selected papers from the Topical Problems of Biophotonics conference. PMID- 27480647 TI - Nuclear myosin I regulates cell membrane tension. AB - Plasma membrane tension is an important feature that determines the cell shape and influences processes such as cell motility, spreading, endocytosis and exocytosis. Unconventional class 1 myosins are potent regulators of plasma membrane tension because they physically link the plasma membrane with adjacent cytoskeleton. We identified nuclear myosin 1 (NM1) - a putative nuclear isoform of myosin 1c (Myo1c) - as a new player in the field. Although having specific nuclear functions, NM1 localizes predominantly to the plasma membrane. Deletion of NM1 causes more than a 50% increase in the elasticity of the plasma membrane around the actin cytoskeleton as measured by atomic force microscopy. This higher elasticity of NM1 knock-out cells leads to 25% higher resistance to short-term hypotonic environment and rapid cell swelling. In contrast, overexpression of NM1 in wild type cells leads to an additional 30% reduction of their survival. We have shown that NM1 has a direct functional role in the cytoplasm as a dynamic linker between the cell membrane and the underlying cytoskeleton, regulating the degree of effective plasma membrane tension. PMID- 27480648 TI - Hypocretin/orexin knock-out mice display disrupted behavioral and dopamine responses to cocaine. AB - The hypocretin/orexin (HCRT) system is implicated in reward and reinforcement processes through actions on the mesolimbic dopamine (DA) system. Here we provide evidence for the relationship between HCRT and DA in vivo in anesthetized and freely moving mice. The ability of cocaine to elicit reward-related behaviors in mice lacking the HCRT prepro-peptide (HCRT knock-out; KO) and wild-type controls was determined using conditioned place preference. Using a combination of microdialysis and in vivo fast scan cyclic voltammetry in anesthetized and freely moving mice, we investigated the underlying role of HCRT in the regulation of DA release and uptake. We show that, unlike wild-type mice, HCRT KO mice fail to develop characteristic conditioned place preference for cocaine. These mice also demonstrated reduced DA release and uptake under baseline conditions in both anesthetized and freely moving experiments. Further, diminished DA signaling in HCRT KO mice persists following administration of cocaine. These findings indicate that HCRT is essential for the expression of behaviors associated with the rewarding effects of cocaine, and suggest that HCRT regulation of reward and reinforcement may be related to disruptions to DA neurotransmission. PMID- 27480650 TI - [Enhancing the research, prevention and control of drug-resistant pathogens]. PMID- 27480649 TI - In Vivo Cardioprotective Effects and Pharmacokinetic Profile of N-Propyl Caffeamide Against Ischemia Reperfusion Injury. AB - Caffeic acid derivatives constitute a class of potent anti-inflammatory and cardioprotective drug candidates. We recently synthesized a new caffeic acid derivative N-propyl caffeamide (PCA). Our pilot experiments demonstrated that PCA enhanced the survival of rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and reoxygenation challenge in a concentration-dependent manner. Interestingly, PCA exhibited better cardioprotective potential than caffeic acid phenethyl ester and propyl caffeate. Thus, we hypothesized that PCA could protect heart against ischemia reperfusion (I/R) injury in mice. We first determined the stability and pharmacokinetic profile of PCA in male Sprague-Dawley rats by ultra performance liquid chromatography coupled with UV and MS/MS detections. The stability of PCA in rat plasma was defined by the half-life of 31.39, 7.19 and 1.37 h in rat plasma at 25, 37 and 60 degrees C, respectively. To study the pharmacokinetic profiles, PCA was injected into male SD rats at the dose of 15 mg/kg via intravenous bolus administration. PCA showed the elimination half-life of approximate 235 min in rats. We subsequently evaluated the cardioprotective potential of PCA in mice model of myocardial infarction. Our results demonstrated that PCA effectively reduced infarct size and release of myocardial enzymes (e.g., CK, CK-MB and LDH). Biochemical analyses suggested that PCA increased the activities of antioxidant enzymes (e.g., CAT and SOD) while attenuated lipid peroxidation. Moreover, PCA profoundly reduced the number of apoptotic cells in infarcted myocardium. Consistently, PCA increased the expression level of anti apoptotic protein Bcl2 whereas suppressed the expression of pro-apoptotic protein Bax in cardiac tissues. Collectively, PCA appears to be a novel bioavailable and stable pharmacological treatment for myocardial infarction. PMID- 27480651 TI - [Comparison of intensified myeloablative conditioning regime without antithymocytic globulin (ATG) with myeloablative conditioning regime for single unit unrelated umbilical cord blood transplantation in hematological malignancies]. AB - OBJECTIVE: To campare the effect and tolerance beween intensified myeloablative conditioning regime (IMCR) without antithymocyte globulin (ATG) and myeloablative conditioning regime (MCR) for single-unit unrelated umbilical cord blood transplantation (sUCBT) in hematological malignancies. METHODS: The clinical data of 190 patients with hematological malignancies undergoing sUCBT between April 2000 and December 2013 at Department of Hematology, Anhui Provincial Hospital were retrospectively analyzed, of whom 156 received IMCR without ATG (IMCR group), including 79 patient receiving total body irradiation (TBI)/cytosine arabinoside (Ara-C)/cyclophosphamide (CY) regime, 47 receiving fludarabine (Flu)/busulfan (Bu)/CY regime, and 30 receiving Ara-C/Bu/CY regime, and all of the 156 received a combination of cyclosporine A (CsA) and mycophelonate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD); the remaining 34 patients received MCR (MCR group), 30 patients receiving Bu/CY regime, and 4 receiving TBI/CY regime, all using CsA/MMF+/-ATG or methotrexate (MTX) for the prophylaxis of GVHD. The two groups were compared in disease status at the time of transplantation, characteristics of graft, transplantation effect, and transplantation-related complications. RESULTS: There were no statistically significant differences between the two groups in gender, disease type, human leukocyte antigen match, ABO blood type match, and disease status at the time of transplantation (all P>0.05). The median age and body weight at transplantation in the IMCR group were significantly higher than those in the MCR group (13 years vs 9 years, P=0.003; 44 kg vs 26 kg, P=0.000). The median doses of infused total nucleated cells (*10(7)/kg) and CD34(+) cells (*10(5)/kg) in the IMCR group were significantly lower than in the MCR group (3.87 vs 4.99, P=0.002; 2.00 vs 3.17, P=0.000). The cumulative incidence of myeloid engraftment on the 42th day and platelet engraftment on the 120th day in the IMCR group were remarkably higher than in the MCR group [96.33%(95%CI: 96.27%-96.39%)vs 82.30%(95%CI: 80.67% 83.93%), P=0.000; 86.44%(95%CI: 86.28%-86.60%)vs 51.17%(95%CI: 49.02%-53.32%), P=0.002]. There were no statistically significant differences in the incidences of grade II to IV acute GVHD, grade III to IV acute GVHD, and 2-year chronic GVHD(P=0.482, 0.928, 0.579). The incidence of pre-engraftment syndrome in the IMCR group was higher than in the MCR group(82.70% vs 47.06%, P=0.000). And 180 day transplantation-related mortality (TRM) in the IMCR group was lower than that in the MCR group [20.50%(95%CI: 20.28%-20.71%)vs 42.20% (95%CI: 41.32%-45.09%), P=0.004]. Up to October 2015, with a median follow-up of 44.2(22.7-188.9)months, the estimated 3-year overall survival and disease-free survival in the IMCR group were both significantly higher than those in the MCR group (62.90% vs 34.10%, P=0.000; 58.60% vs 34.10%, P=0.001). CONCLUSION: IMCR without ATG may improve the engraftment without increasing complications, reduce early transplantation related mortality, and improve survival. PMID- 27480652 TI - [Relationship between sleep architecture and blood pressure dynamic change in patients with sleep apnea syndrome]. AB - OBJECTIVE: To investigate sleep architecture and blood pressure dynamic change in patients with Sleep apnea syndrome by electrocardiogram-based cardiopulmonary coupling analysis system. METHODS: Seventy-nine sleep disorder participants (PSQI>=8) were enrolled. Electrocardiogram-based cardiopulmonary coupling analysis device and ambulatory blood pressure monitoring were synchronously used to evaluate sleep architecture and blood pressure circadian rhythm. The patients were divided into SAS group (47 participants) and non-SAS group (32 participants) according to the Apnea Hypopnea Index (AHI) that calculated by CPC device. The data of sleep architecture and blood pressure variability were compared between two groups. RESULTS: Compared with non-SAS group, SAS group have less proportion of deep sleep, more proportion of light sleep, higher mean blood pressure in 24 hours and daytime, lower nocturnal blood pressure dipping, faster mean heart rate in night time (P<0.05). AHI has moderate inverse correlation with deep sleep time, wake/dream time (-0.6<=r<-0.3), moderate positive correlation with light sleep time (0.3= 40 years, especially >= 60 years), and III-IV stage were correlated with reduced 3-year progression-free survival (PFS) and overall survival (OS) (PFS: 70.3 vs 87.7%, 79.2% vs 89.8%, 56.8% vs 91.5%, 70.4% vs 93.2%; OS: 81.0% vs 100%, 92.1% vs 99.4%, 75.4% vs 99.2%, 90.3% vs 100%; all P<0.05); and CD20-positive and not receiving local radiotherapy were associated with reduced PFS (79.7% vs 90.6%, 68.8% vs 90.6%, both P<0.05), not with OS (92.4% vs 98.3%, 94.0% vs 99.4%, both P>0.05). Patients positive in both CD20 expression and EBV-encoded small RNAs (EBER) showed low PFS. CONCLUSIONS: CD20 expression in R-S cells in CHL may be closed related with EBV infection. EBV infection is associated with unfavorable prognosis. The effect of CD20-postitive on prognosis may be mediated by the prognostic effect of EBV infection. PMID- 27480654 TI - [A study on diaphragm function after interscalene brachial plexus block using a fixed dose of ropivacaine with different concentrations]. AB - OBJECTIVE: To compare the effect of interscalene brachial plexus block (ISBPB) on the incidence of diaphragmatic paralysis, respiratory function and post-operative pain control using same dosage of local anesthetics diluted into two different volume and concentrations. METHODS: Approved by the Peking University Third Hospital ethics committee, sixty patients undergoing elective arthroscopic shoulder surgery in Peking University Third Hospital from November 2013 to April 2014 were randomly allocated into two groups according to random number table method: before induction of general anesthesia, ultrasound-guided ISBPB was performed using 0.5% ropivacaine 10 ml (Group A) or 0.25% ropivacaine 20 ml (Group B). The incidence of diaphragmatic paralysis, respiratory function and reduction of pulse oxygen saturation at 30 min post-block were recorded and analyzed.Patients were interviewed at 4, 8 and 24 h after block for numerical rating pain score, rescue analgesics requirement and sleep quality. RESULTS: There were no statistically differences between group A and group B for the incidence of diaphragmatic paralysis at 30 min after block (67% vs 70%, chi(2)=0.077, P>0.05). The change of forced vital capacity ((78+/-16)% vs (80+/ 18)%, t=0.435, P>0.05), the change of forced expiratory volume in 1 second ((85+/ 16)% vs (78+/-22)%, t=1.472, P>0.05) and the reduction of pulse oxygen saturation (1(0-3)% vs 2(0-3)%, Z=-0.538, P>0.05) showed no significant differences between the two groups at 30 min after block.There were no statistically differences in terms of the numerical rating pain score, rescue analgesics requirement and sleep quality at 4, 8 and 24 h after block (all P>0.05). CONCLUSIONS: The use of 0.5% and 0.25% ropivacaine 50 mg for interscalene block provides similar effect on the incidence of diaphragmatic paralysis, changes in respiratory function and postoperative analgesia. PMID- 27480655 TI - [Modified Chevron osteotomy combined distal soft tissue reconstruction to treat high-grade bunionette deformity]. AB - OBJECTIVE: To explore the surgical method of using the modified chevron osteotomy combined distal soft tissue reconstruction to treat high-grade bunionette deformity. METHODS: From June 2013 to June 2015, the modified chevron osteotomy combined distal soft tissue reconstruction was used for surgical treatment of high-grade bunionette deformity in the Department of Hand and Foot Microsurgery in Xuzhou Central Hospital.Twenty-six patients with 28 feet high-grade bunionette deformity were hospitalized for treatment, with 3 male (3 feet) and 23 female (25 feet) cases, aged 22-73 (mean 47.1) years old.The average fourth-fifth intermetatarsal angle, lateral deviation of the fifth metatarsal angle and metatarsophalangeal-fifth angle were measured on the pre-and post- operative anterior to posterior weight-beating X rays of treated feet.The American Orthopaedic Foot and Ankle Society (AOFAS) Lesser Toe Metatarsophalangeal Interphalangeal Scale was used to evaluate the post-operative outcomes. RESULTS: All of 26 patients were followed, with a mean 15.7 months (range 8-25 months). Primarily healing of the wound was achieved in all cases.No postoperative infection and nonunion on the osteotomy site was found during the follow-up time.The fracture healing time was 6-15 (mean 12.2) weeks.All the patients had satisfactory appearance and sensory function without callosum and metastatic metatarsalgia at the final follow-up.The post-operative fourth-fifth intermetatarsal angle, lateral deviation of the fifth metatarsal angle and metatarsophalangeal-fifth angle were significantly lesser than the pre-operative at the 6th week after operation, respectively [(5.5+/-1.7) degrees , (2.1+/-0.8) degrees , (5.7+/-2.6) degrees vs (16.4+/-4.2) degrees , (6.0+/-2.2) degrees , (10.5+/-7.4) degrees ; all P<0.01]. The post-operative AOFAS score was significantly greater than the pre-operative [(87.1+/-6.7) vs (62.3+/-9.8) points, P<0.001]. CONCLUSION: The modified chevron osteotomy combined distal soft tissue reconstruction is a safe and easy treatment option for the high-grade bunionette deformity and provides patient satisfaction results. PMID- 27480656 TI - [A comparative study on treating femal stress urinary incontinence with TVT Abbrevo and TVT-Obturator]. AB - OBJECTIVE: To compare the effectiveness and complications of TVT-Abbrevo (tension free vaginal tape-Abbrevo) and TVT-Obturator (tension-free vaginal tape obturator) for the treatment of female stress urinary incontinence (SUI). METHODS: From Nov.2012 to Nov.2013, 117 patients suffering from SUI were treated with TVT-Abbrebo (n=79) or TVT-Obturator (n=38) procedure, the clinical efficacy and operation-correlated complications were observed. RESULTS: A total of 117 cases, 107 cases of urinary incontinence symptoms disappeared completely, 10 cases were improved. 72 cases (91.1%) were cured and 7 cases (8.9%) were improved in TVT-Abbrevo group; 35 cases (92.1%) were cured and 3 cases (7.9%) were improved in TVT-Obturator group. No significant differences could be found for the curing rates between two groups (P>0.05). Compared with the TVT-Obturator group, the TVT-Abbrevo group had less patients complaining of inner thigh pain at 24 h and 1 w after surgery (P<0.05). No significant differences were observed for the incidence of inner thigh pain at 1m and 1y after surgery between TVT-Abbrevo and TVT-Obturator group (P>0.05). No intraoperative complications such as blood vessel, nerve, bladder damage were recorded and no postoperative retropubic hematoma, tape adjustment and other complications occurred in two goups. No recurrence after 1 year follow-up. CONCLUSIONS: The study shows that TVT-Abbrevo procedure is safe and efficacy in treatment of SUI, and associated with low incidence of recent postoperative inner thigh pain. PMID- 27480657 TI - [Effect of PM2.5 on the level of nuclear factor erythroid-2 related factor 2 in chronic obstructive pulmonary disease mice and its relationship with oxidative stress]. AB - OBJECTIVE: To explore the effects of fine particulate matter on the level of nuclear factor erythroid-2 related factor 2 (Nrf2) in pulmonary tissues of chronic obstructive pulmonary disease (COPD) mouse models and its relationship with oxidative stress. METHODS: Totally 40 BALB/c mice were randomly divided into normal control group, normal PM2.5 group, COPD control group and COPD PM2.5 group.COPD mice were established using exposure of cigarette smoking.PM2.5 (20 mg/kg) was intratracheally instilled in PM2.5 group mice.Mice pulmonary function was measured by mice noninvasive body plethysmograph and lung histopathology was observed in normal control group and normal PM2.5 group mice.The mRNA and protein expression of Nrf2 was measured with real-time polymerase chain reaction (PCR) and Western blot methods.Total antioxidative capacity (TAC) was measured by O phenanthroline colorimetry.Glutathione peroxidase (GSH-PX) was measured by improved Hafeman colorimetry and malondialdehyde (MDA) by thiobarbiturieacid colorimetry. RESULTS: Nrf2 mRNA and protein in normal control group, normal PM2.5 group, COPD control group and COPD PM2.5 group were 1.00, 4.46+/-0.42, 4.93+/ 0.63, 6.41+/-0.35 and 0.92+/-0.08, 1.23+/-0.07, 1.20+/-0.09, 1.43+/-0.10.Nrf2 mRNA and protein in COPD control group were increased than those in normal control group while those in normal PM2.5 group and COPD PM2.5 group were respectively higher than each control group.Comparing to normal PM2.5 group, the Nrf2 mRNA and protein in COPD PM2.5 group were increased (all P<0.01). TAC and GSH-PX in each group were (5.1+/-0.4), (2.9+/-0.4), (3.3+/-0.3), (1.8+/-0.3) and (13.4+/-0.5), (9.9+/-0.7), (9.8+/-0.7), (7.0+/-0.6) U/mgpro.TAC and GSH-PX in COPD control group were decreased than those in normal control group while those in normal PM2.5 group and COPD PM2.5 group were respectively lower than each control group.Comparing to normal PM2.5 group, the Nrf2 mRNA and protein in COPD PM2.5 group were decreased (all P<0.01). MDA in each group were (2.9+/-0.4), (4.8+/-0.5), (4.5+/-0.3), and (6.2+/-0.4) nmol/mgpro.MDA in COPD control group were increased than those in normal control group while those in normal PM2.5 group and COPD PM2.5 group were respectively higher than each control group.Comparing to normal PM2.5 group, the MDA in COPD PM2.5 group were increased (all P<0.01). Positive correlations were observed between Nrf2 mRNA, protein and MDA, while negative correlations were observed between Nrf2 mRNA, protein and TAC, GSH-PX in all groups (all P<0.05). CONCLUSIONS: PM2.5 can induce Nrf2 expression and aggravate oxidative stress in COPD mice.The increased expression of Nrf2 is closely associated with oxidative stress. PMID- 27480658 TI - [The protective effect of alpha-2 adrenergic agonist on cranial nerve in rats with brain injury]. AB - OBJECTIVE: To investigate the neuroprotective effect of alpha2 adrenergic agonist, dexmedetomidine on tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) in brain tissue and serum S-100beta protein level in traumatic brain injury rats. METHODS: Seventy-two male Sprague-Dawley rats were randomly divided into sham operation group (group S), traumatic brain injury group (group C), and dexmedetomidine group (group D), 24 rats in each group; each of which was divided into 6, 12, 24 and 48 hours subgroup, 6 rats in each subgroup. Parietal brain contusion was produced by reformed Feeney method. The group S underwent sham operation without blunt force stroke; group D underwent blunt force stroke, then received loading dose of dexmedetomidine, 3 MUg/kg with common jugular vein injection and continued infusion with 3 MUg.kg(-1).h(-1) for 2 hours. The total dosage of dexmedetomidine was 9 MUg/kg with a volume of 4 ml; group C underwent 0.9% NaCl, 4 ml injection at the same time point with the same method. The S-100 protein activity in arteria cruralis serum was detected at the each time point by ELISA and TNF-alpha, IL-6 in the brain tissue were detected by ELISA. RESULTS: There were no significant difference of TNF-alpha activity among time point of 6, 12, 24 and 48 h in group S ((2.07+/-0.06), (2.01+/-0.03), (2.11+/-0.05), and (2.08+/-0.04) pg/mg, F=1.147, P>0.05), no significant difference of IL-6 activity among the same time point ((4.03+/-0.06), (4.07+/-0.09), (4.06+/-0.04), and (4.55+/-0.09) pg/mg, F=1.176, P>0.05), and no significant difference of serum S 100beta activity among the same time too ((0.37+/-0.07), (0.36+/-0.02), (0.35+/ 0.06), and (0.39+/-0.11) MUg/L, F=1.045, P>0.05). The above indexes in group C were higher than those in group S, and the above indexes in group D were higher than those in group S and lower than those in group C (all P<0.05). CONCLUSION: Alpha-2 adrenergic agonist, dexmedetomidine could dramatically inhibit inflammatory reaction induced by traumatic brain injury in rats and protect brain tissue. PMID- 27480659 TI - [Systematic review of feasibility, safety and efficacy of ex situ liver resection and autotransplantation]. AB - OBJECTIVE: To evaluate the feasibility, safety and efficiency of ex situ liver resection (ESLR)technique in patients with hepatocaval region involvement. METHODS: A systematic research of the data bases CNKI, Wan Fang, CQVIP, PubMed, CENTRAL, Medline, Embase, Cochrane, International Clinical Transplantation Registration Platform and Transplant Library was performed. All the current data regarding the feasibility, safety, and oncological efficiency of ESLR was systematically reviewed. Feasibility, conversion to allo-transplantation rate, complication and 90-day mortality were analyzed. RESULTS: A literature search revealed a total of 46 publications with 191 patients who underwent ex situ liver resection (101 autotransplantation, 90 ante-situm liver resection). The most common indication was hepatocellular carcinoma (49), followed by colorectal liver metastasis (37), hepatic alveolar echinococcosis (33) and cholangiocarcinoma (26). The feasibility rate was 84.5% (CI=76.6%-90.1%), the conversion to allo transplantation rate was 13.5% (CI=8.5%-21.0%). Overall complication rate was 58.1% (CI=48.5%-67.1%), and complications grade IIIa or higher occurred in 43.1% (CI=33.6%-53.1%).90-day mortality was 19.5% (CI=12.7%-28.8%). CONCLUSION: ESLR and autotransplantation technique is an effective surgical approach for hepatic tumor with hepatocaval region involvement. Strict control of surgical indications, preoperative evaluation and precise surgical technique is essential to success. PMID- 27480660 TI - angsd-wrapper: utilities for analysing next-generation sequencing data. AB - High-throughput sequencing has changed many aspects of population genetics, molecular ecology and related fields, affecting both experimental design and data analysis. The software package angsd allows users to perform a number of population genetic analyses on high-throughput sequencing data. angsd uses probabilistic approaches which can directly make use of genotype likelihoods; thus, SNP calling is not required for comparative analyses. This takes advantage of all the sequencing data and produces more accurate results for samples with low sequencing depth. Here, we present angsd-wrapper, a set of wrapper scripts that provides a user-friendly interface for running angsd and visualizing results. angsd-wrapper supports multiple types of analyses including estimates of nucleotide sequence diversity neutrality tests, principal component analysis, estimation of admixture proportions for individual samples and calculation of statistics that quantify recent introgression. angsd-wrapper also provides interactive graphing of angsd results to enhance data exploration. We demonstrate the usefulness of angsd-wrapper by analysing resequencing data from populations of wild and domesticated Zea. angsd-wrapper is freely available from https://github.com/mojaveazure/angsd-wrapper. PMID- 27480661 TI - Ancient landscapes and the relationship with microbial nitrification. AB - Ammonia oxidizing archaea (AOA) and bacteria (AOB) drive nitrification and their population dynamics impact directly on the global nitrogen cycle. AOA predominate in the majority of soils but an increasing number of studies have found that nitrification is largely attributed to AOB. The reasons for this remain poorly understood. Here, amoA gene abundance was used to study the distribution of AOA and AOB in agricultural soils on different parent materials and in contrasting geologic landscapes across Australia (n = 135 sites). AOA and AOB abundances separated according to the geologic age of the parent rock with AOB higher in the more weathered, semi-arid soils of Western Australia. AOA dominated the younger, higher pH soils of Eastern Australia, independent of any effect of land management and fertilization. This differentiation reflects the age of the underlying parent material and has implications for our understanding of global patterns of nitrification and soil microbial diversity. Western Australian soils are derived from weathered archaean laterite and are acidic and copper deficient. Copper is a co-factor in the oxidation of ammonia by AOA but not AOB. Thus, copper deficiency could explain the unexpectedly low populations of AOA in Western Australian soils. PMID- 27480662 TI - Outcomes of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: A single institution experience in Japan. AB - OBJECTIVES: To evaluate the efficacy and toxicity profiles of everolimus in Japanese patients with renal angiomyolipoma associated with tuberous sclerosis complex. METHODS: Patients with a 4-cm or larger angiomyolipoma meeting the diagnostic criteria of tuberous sclerosis complex were selected as participants of our investigation. In each case, we assessed tuberous sclerosis complex associated symptoms, the treatment effect and adverse events. The treatment effect was evaluated by measuring the tumor volume reduction rate using abdominal computed tomography or magneitc resonance imaging. Adverse events were investigated using CTCAE v4.0-JCOG. The dose of everolimus was set at 10 mg once a day for adults. For childhood angiomyolipoma, everolimus administration was initiated at a dose of 5 mg once a day. Blood everolimus level was measured, and the dose was adjusted to maintain this within a range of 5-15 ng/mL. RESULTS: The angiomyolipoma volume decreased in 46 of 47 cases, and the mean reduction rate for all cases was 60% in 12 months. The angiomyolipoma volume markedly decreased in the first 3 months, and the size leveled off after 6 months. The main adverse events related to everolimus treatment were stomatitis (91%) and irregular menstruation (65%). Grade 3 or severer adverse events were noted in three cases (6%). All patients developed some adverse events in the first 6 months. The incidence markedly decreased to 40-50% after 13 months. CONCLUSION: The tumor volume-reducing effect of everolimus in a Japanese population was equivalent to or higher than that in Western populations. A wide variety of everolimus treatment-related adverse events can be observed, but most cases are very mild. Special attention should be given to stomatitis, irregular menstruation and interstitial lung disease as adverse events. PMID- 27480663 TI - BRAT1-associated neurodegeneration: Intra-familial phenotypic differences in siblings. AB - Recessive mutations in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome, a phenotype characterized by neonatal microcephaly, hypertonia, and refractory epilepsy with premature death by age 2 years. Recently, attenuated disease variants have been described, suggesting that a wider clinical spectrum of BRAT1-associated neurodegeneration exists than was previously thought. Here, we report two affected siblings with compound heterozygous truncating mutations in BRAT1 and intra-familial phenotypic heterogeneity, with a less severe disease course in the female sibling. This phenotypic variability should be taken into account when treating patients with BRAT1-associated neurodegenerative disease. Mildly affected individuals with BRAT1 mutations show that BRAT1 must be considered as a cause in childhood refractory epilepsy and microcephaly with survival beyond infancy. (c) 2016 Wiley Periodicals, Inc. PMID- 27480664 TI - Haematological cancer: Anti-BCMA CAR T cells show promise in MM. PMID- 27480665 TI - Sarcoma: Olaratumab - really a breakthrough for soft-tissue sarcomas? PMID- 27480666 TI - Haematological cancer: CTLA-4 blockade after allo-SCT. PMID- 27480667 TI - Melanoma: JAK - opening the door to acquired resistance. PMID- 27480668 TI - Using Prenatal Advocates to Implement a Psychosocial Education Intervention for Posttraumatic Stress Disorder during Pregnancy: Feasibility, Care Engagement, and Predelivery Behavioral Outcomes. AB - BACKGROUND: Pregnant women with posttraumatic stress disorder (PTSD) engage in more high-risk behavior and use less prenatal care. Although treating depression in pregnancy is becoming widespread, options for addressing PTSD are few. This study was designed to test the feasibility of implementing a manualized psychosocial PTSD intervention, Seeking Safety, delivered by prenatal advocates. METHODS: All women entering prenatal care at two federally qualified health centers were screened for current symptoms of PTSD. One site was selected randomly to have prenatal care advocates deliver eight Seeking Safety topics for women that indicated clinical or subclinical PTSD symptoms. Baseline and pre delivery interviews were conducted, which collected background characteristics and assessed PTSD severity and coping skills. Medical records were collected to document care visits. Documentation of participation rates, fidelity to the treatment, and qualitative feedback from advocates and participants was collected. RESULTS: More than one-half (57.3%) of the intervention women received all Seeking Safety sessions and fidelity ratings of the session showed acceptable quality. Using an intent-to-treat analysis, intervention women participated in significantly more prenatal care visits (M = 11.7 versus 8.9; p < .001), and had a significantly higher rate of achieving adequate prenatal care (72.4% vs. 42.9%; p < .001). Although not significant when accounting for baseline differences, intervention women also reduced negative coping skills but not PTSD symptoms. CONCLUSIONS: Using prenatal care advocates to deliver Seeking Safety sessions to women screening positive for PTSD symptoms at entry to prenatal care is a promising intervention that seems to increase prenatal care participation and may reduce negative coping strategies. PMID- 27480669 TI - An Application of Chalcogenide Alloy Other than Storage Memory Field. AB - BACKGROUND: The necessity to handle mechanical functionality at nanoscale has recently motivated the prosperity of the nanoelectromechanical systems (NEMs). The fabrication of NEMS strongly depends on the so-called "topdown" techniques that are however limited by the resolution of electronbeam lithography. Meanwhile, the size of the NEMS needs to be shrunk continuously in order to further enhance the system performance. As a result, current research interest has been dedicated to "bottomup" techniques or even a hybridization of two aforementioned approaches, leading to the presence of the nanowire-based NEMs. Here, we presented some recent patent for nanowire-based NEMS. METHODS: We investigate the resonant frequency and the frequency tuneability of the nanowire based nanoelectromechanical system using Ge2Sb2Te5 media. By varying the nanowire dimensions, corresponding resonant frequencies and frequency tuneability are calculated using an established mechanical model. RESULTS: We theoretically study the frequency tuneability of the nanowire-based NEMs using GST media. The resonant frequencies and the corresponding frequency tuneabilities for different nanowire dimensions are investigated using a developed mechanical model, and a previously established electrothermal model is performed to imitate the frequency tuning behavior of the system along with the phase-change phenomenon. By carefully controlling the amorphous fraction of the active region, a very high resonant frequency can be tuned within an ultra-high adjustable bandwidth. In addition, the merits of the phase-change memories including great scalability, low power consumption, fast transition time, and non-volatility can be also found on the proposed system. These results will open up a route for designing the next generation NEMs, and also pioneer a new application field for the GST media. CONCLUSIONS: Today phase-change materials have received a wide range of applications from nonvolatile memories to neuromorphic networks due to its unique combinations of structural, electrical, and thermal properties. However, as the mechanical properties of phase-change materials exhibits a remarkable difference between the amorphous and crystalline phases, the feasibility of continuously changing the resonant frequency of the nanowires based on phase-change materials becomes viable. PMID- 27480670 TI - Dinitrogen binding, P4-activation and aza-Buchner ring expansions mediated by an isocyano analogue of the CpCo(CO) fragment. AB - Synthetic studies targeting an m-terphenyl isocyanide analogue of the unstable 16e(-), S = 1 complex CpCo(CO) are reported (Cp = eta(5)-C5H5). The m-terphenyl isocyanide CNAr(Dipp2) (Ar(Dipp2) = 2,6-(2,6-(i-Pr)2C6H3)2C6H3) is shown to readily bind to both CpCoI2 and Cp*CoI2 fragments (Cp* = eta(5)-C5Me5) and provide mono-isocyanide starting materials that are suitable for chemical reduction. Treatment of CpCoI2(CNAr(Dipp2)) with KC8 produces the bridging isocyanide dimer, [CpCo(MU-CNAr(Dipp2))]2, thereby indicating that the steric combination of Cp and CNAr(Dipp2) ligands does not allow for the production of mononuclear complexes. However, Cp*CoI2(CNAr(Dipp2)) with KC8 under an N2 atmosphere results in the formation of the complex, Cp*Co(N2)(CNAr(Dipp2)), which is a unique two-legged piano stool complex featuring a coordinated dinitrogen ligand. The N2 ligand in Cp*Co(N2)(CNAr(Dipp2)) is shown to be labile and, upon removal by application of vacuum, leads to the production of an eta(4) coordinated 1-azabenz[b]azulene complex by aza-Buchner cyclization of the CNAr(Dipp2) ligand. This cyclization reaction is rationalized via the intermediacy of the unobserved 16e(-) species [Cp*Co(CNAr(Dipp2))]. While this intramolecular aza-Buchner cyclization prevents isolation of [Cp*Co(CNAr(Dipp2))], the dinitrogen complex Cp*Co(N2)(CNAr(Dipp2)) is shown to serve as a reliable synthon for this 16e(-) species upon reaction with small molecule substrates. Both free CNAr(Dipp2) and diphenylacetylene react with Cp*Co(N2)(CNAr(Dipp2)) to form two-legged piano stool complexes. In addition, Cp*Co(N2)(CNAr(Dipp2)) reacts readily with 0.5 and 1.0 equivalents of P4 to produce poly-phosphorus products resulting from P-P single bond cleavage. PMID- 27480671 TI - Margaret McCartney: Can junior doctors feel safe to blow the whistle? PMID- 27480672 TI - Hydroxychloroquine, a potentially lethal drug. PMID- 27480673 TI - [Therapeutic efficacy. Between scientific medicine and healthcare medicine]. PMID- 27480674 TI - [E-health and treatment adherence]. AB - The medico-economic implications of poor drug compliance are such that improving the adherence could have a considerable impact in terms of public health. Technological tools from the digital revolution are now at the service of health: the connected health. There are already numerous, more or less sophisticated, and many more are under development. Data from the literature suggest that these tools could provide real benefits including improving patient compliance. The digital revolution has changed our daily lives. It will certainly revolutionize the practice of medicine. PMID- 27480675 TI - Crosstalk between insulin and dopamine signaling: A basis for the metabolic effects of antipsychotic drugs. AB - In the setting of rising rates of obesity and metabolic syndrome, characterized in part by hyperinsulinemia, it is increasingly important to understand the mechanisms that contribute to insulin dysregulation. The higher risk for metabolic syndrome imparted by antipsychotic medication use highlights one such mechanism. Though there is great variation in the number and types of signaling pathways targeted by these medications, the one common mechanism of action is through dopamine. Dopamine's effects on insulin signaling begin at the level of insulin secretion from the pancreas and continue through the central nervous system. In a reciprocal fashion, insulin also affects dopamine signaling, with specific effects on dopamine reuptake from the synapse. This review probes the dopamine-insulin connection to provide a comprehensive examination of how antipsychotics may contribute towards insulin resistance. PMID- 27480676 TI - The effect of parental monitoring on trajectories of disordered eating attitudes and behaviors among adolescents: An individual growth curve analysis. AB - The primary aim of the present study was to examine whether parental monitoring, as reported by adolescents and their parents, predicts more or less favorable trajectories of disordered eating behavior and attitudes over the course of one year in a sample of adolescent males and females. An additional aim was to explore whether these trajectories vary when study analyses are limited to females. Participants included 87 adolescents (mean age = 15.5 +/- 1.4) in mental health treatment and their parents. Self-report measures included the Parental Monitoring Questionnaire, completed at baseline, and the Eating Attitudes Test Dieting Subscale, completed at baseline as well as 6-month and 12-month follow ups. Individual growth curve (IGC) analyses were used to examine change in disordered eating behavior and attitudes. Adolescents who reported lower parental monitoring showed trajectories characterized by increases in disordered eating attitudes and behaviors. The same pattern emerged when using parent report of monitoring, though only a trend was evident. When analyses were restricted to females, the main effect of parental and adolescent report of monitoring on disordered eating were equally strong. Results may suggest that parents who are less knowledgeable about their adolescents' daily lives, may be less aware of potential disordered eating attitudes and behaviors, and thus less likely to intervene. Findings could be used to inform family-based interventions for this population. PMID- 27480677 TI - Assuring a strong foundation for our nation's public health systems. AB - BACKGROUND: A strong public health infrastructure is necessary to assure that every community is capable of carrying out core public health functions (assessment of population health, assurance of accessible and equitable health resources, and development of policies to address population health) to create healthy conditions. Yet, due to budget cuts and inconsistent approaches to base funding, communities are losing critical prevention and health promotion services and staff that deliver them. PURPOSE: This article describes key components of and current threats to our public health infrastructure and suggests actions necessary to strengthen public health systems and improve population health. DISCUSSION: National nursing and public health organizations have a duty to advocate for policies supporting strong prevention systems, which are crucial for well-functioning health care systems and are fundamental goals of the nursing profession. CONCLUSION: We propose strengthening alliances between nursing organizations and public health systems to assure that promises of a reformed health system are achieved. PMID- 27480678 TI - Pan-genotypic cell culture system for propagation of hepatitis C virus clinical isolates. PMID- 27480679 TI - Changes in ectomycorrhizal fungal community composition and declining diversity along a 2-million-year soil chronosequence. AB - Ectomycorrhizal (ECM) fungal communities covary with host plant communities along soil fertility gradients, yet it is unclear whether this reflects changes in host composition, fungal edaphic specialization or priority effects during fungal community establishment. We grew two co-occurring ECM plant species (to control for host identity) in soils collected along a 2-million-year chronosequence representing a strong soil fertility gradient and used soil manipulations to disentangle the effects of edaphic properties from those due to fungal inoculum. Ectomycorrhizal fungal community composition changed and richness declined with increasing soil age; these changes were linked to pedogenesis-driven shifts in edaphic properties, particularly pH and resin-exchangeable and organic phosphorus. However, when differences in inoculum potential or soil abiotic properties among soil ages were removed while host identity was held constant, differences in ECM fungal communities and richness among chronosequence stages disappeared. Our results show that ECM fungal communities strongly vary during long-term ecosystem development, even within the same hosts. However, these changes could not be attributed to short-term fungal edaphic specialization or differences in fungal inoculum (i.e. density and composition) alone. Rather, they must reflect longer-term ecosystem-level feedback between soil, vegetation and ECM fungi during pedogenesis. PMID- 27480680 TI - Comparative Biochemistry and In Vitro Pathway Reconstruction as Powerful Partners in Studies of Metabolic Diversity. AB - There are estimated to be >300,000 plant species, producing >200,000 metabolites. Many of these metabolites are restricted to specific plant lineages and are referred to as "specialized" metabolites. These serve varied functions in plants including defense against biotic and abiotic stresses, plant-plant and plant microbe communication, and pollinator attraction. These compounds also have important applications in agriculture, medicine, skin care, and in diverse aspects of human culture. The specialized metabolic repertoire of plants can vary even within and between closely related species, in terms of the number and classes of specialized metabolites as well as their structural variants. This phenotypic variation can be exploited to discover the underlying variation in the metabolic enzymes. We describe approaches for using the diversity of specialized metabolites and variation in enzyme structure and function to identify novel enzymatic activities and understand the structural basis for these differences. The knowledge obtained from these studies will provide new modules for the synthetic biology toolbox. PMID- 27480681 TI - De Novo Deep Transcriptome Analysis of Medicinal Plants for Gene Discovery in Biosynthesis of Plant Natural Products. AB - Study on transcriptome, the entire pool of transcripts in an organism or single cells at certain physiological or pathological stage, is indispensable in unraveling the connection and regulation between DNA and protein. Before the advent of deep sequencing, microarray was the main approach to handle transcripts. Despite obvious shortcomings, including limited dynamic range and difficulties to compare the results from distinct experiments, microarray was widely applied. During the past decade, next-generation sequencing (NGS) has revolutionized our understanding of genomics in a fast, high-throughput, cost effective, and tractable manner. By adopting NGS, efficiency and fruitful outcomes concerning the efforts to elucidate genes responsible for producing active compounds in medicinal plants were profoundly enhanced. The whole process involves steps, from the plant material sampling, to cDNA library preparation, to deep sequencing, and then bioinformatics takes over to assemble enormous-yet fragmentary-data from which to comb and extract information. The unprecedentedly rapid development of such technologies provides so many choices to facilitate the task, which can cause confusion when choosing the suitable methodology for specific purposes. Here, we review the general approaches for deep transcriptome analysis and then focus on their application in discovering biosynthetic pathways of medicinal plants that produce important secondary metabolites. PMID- 27480682 TI - Genomics-Based Discovery of Plant Genes for Synthetic Biology of Terpenoid Fragrances: A Case Study in Sandalwood oil Biosynthesis. AB - Terpenoid fragrances are powerful mediators of ecological interactions in nature and have a long history of traditional and modern industrial applications. Plants produce a great diversity of fragrant terpenoid metabolites, which make them a superb source of biosynthetic genes and enzymes. Advances in fragrance gene discovery have enabled new approaches in synthetic biology of high-value speciality molecules toward applications in the fragrance and flavor, food and beverage, cosmetics, and other industries. Rapid developments in transcriptome and genome sequencing of nonmodel plant species have accelerated the discovery of fragrance biosynthetic pathways. In parallel, advances in metabolic engineering of microbial and plant systems have established platforms for synthetic biology applications of some of the thousands of plant genes that underlie fragrance diversity. While many fragrance molecules (eg, simple monoterpenes) are abundant in readily renewable plant materials, some highly valuable fragrant terpenoids (eg, santalols, ambroxides) are rare in nature and interesting targets for synthetic biology. As a representative example for genomics/transcriptomics enabled gene and enzyme discovery, we describe a strategy used successfully for elucidation of a complete fragrance biosynthetic pathway in sandalwood (Santalum album) and its reconstruction in yeast (Saccharomyces cerevisiae). We address questions related to the discovery of specific genes within large gene families and recovery of rare gene transcripts that are selectively expressed in recalcitrant tissues. To substantiate the validity of the approaches, we describe the combination of methods used in the gene and enzyme discovery of a cytochrome P450 in the fragrant heartwood of tropical sandalwood, responsible for the fragrance defining, final step in the biosynthesis of (Z)-santalols. PMID- 27480683 TI - A Workflow for Studying Specialized Metabolism in Nonmodel Eukaryotic Organisms. AB - Eukaryotes contain a diverse tapestry of specialized metabolites, many of which are of significant pharmaceutical and industrial importance to humans. Nevertheless, exploration of specialized metabolic pathways underlying specific chemical traits in nonmodel eukaryotic organisms has been technically challenging and historically lagged behind that of the bacterial systems. Recent advances in genomics, metabolomics, phylogenomics, and synthetic biology now enable a new workflow for interrogating unknown specialized metabolic systems in nonmodel eukaryotic hosts with greater efficiency and mechanistic depth. This chapter delineates such workflow by providing a collection of state-of-the-art approaches and tools, ranging from multiomics-guided candidate gene identification to in vitro and in vivo functional and structural characterization of specialized metabolic enzymes. As already demonstrated by several recent studies, this new workflow opens up a gateway into the largely untapped world of natural product biochemistry in eukaryotes. PMID- 27480684 TI - Gene Discovery for Synthetic Biology: Exploring the Novel Natural Product Biosynthetic Capacity of Eukaryotic Microalgae. AB - Eukaryotic microalgae are an incredibly diverse group of organisms whose sole unifying feature is their ability to photosynthesize. They are known for producing a range of potent toxins, which can build up during harmful algal blooms causing damage to ecosystems and fisheries. Genome sequencing is lagging behind in these organisms because of their genetic complexity, but transcriptome sequencing is beginning to make up for this deficit. As more sequence data becomes available, it is apparent that eukaryotic microalgae possess a range of complex natural product biosynthesis capabilities. Some of the genes concerned are responsible for the biosynthesis of known toxins, but there are many more for which we do not know the products. Bioinformatic and analytical techniques have been developed for natural product discovery in bacteria and these approaches can be used to extract information about the products synthesized by algae. Recent analyses suggest that eukaryotic microalgae produce many complex natural products that remain to be discovered. PMID- 27480685 TI - cis-Prenyltransferase and Polymer Analysis from a Natural Rubber Perspective. AB - Dolichol and natural rubber are representative cis-polyisoprenoids in primary and secondary metabolism, respectively. Their biosynthesis is catalyzed by cis prenyltransferase (CPT) by sequential condensations of isopentenyl diphosphates (IPPs) to a priming molecule. Although prokaryotic CPTs have been well characterized, the mechanism of eukaryotic CPTs in cis-polyisoprene biosynthesis was only recently revealed. It was shown that eukaryotes have evolved a unique protein complex, comprised of CPT and CPT-binding protein (CBP), to synthesize cis-polyisoprenoids. In the context of this new discovery, we found discrepancies in literature for CPT or CBP biochemical assays and in vivo CPT complementation using rer2 (yeast CPT) yeast mutant. Our study here shows that rer2 revertants occur at a frequency that cannot be disregarded and are likely accountable for the results that cannot be explained by the CPT/CBP heteroprotein complex model. To make a stable mutant, SRT1 gene (secondary CPT expressed at a basal level in yeast) was additionally deleted in the rer2Delta mutant background. This stable rer2Delta srt1Delta strain was then used to individually or simultaneously express Arabidopsis CPT1 (AtCPT1, At2g17570) and CBP (AtLEW1, At1G11755). We found that the simultaneous expression of Arabidopsis CPT1 and AtLEW1 effectively complements the rer2Delta srt1Delta strain, whereas the individual expression of AtCPT1 alone or AtLEW1 alone failed to rescue the yeast mutant. Microsomes from the dual expresser showed an efficient incorporation of IPPs into cis polyisoprenoid (30% in 2h). These results showed that the CPT/CBP heteroprotein complex model is valid in Arabidopsis thaliana. Experimental details of these results are described in this methodology paper. PMID- 27480686 TI - Generation and Functional Evaluation of Designer Monoterpene Synthases. AB - Monoterpene synthases are highly versatile enzymes that catalyze the first committed step in the pathways toward terpenoids, the structurally most diverse class of plant natural products. Recent advancements in our understanding of the reaction mechanism have enabled engineering approaches to develop mutant monoterpene synthases that produce specific monoterpenes. In this chapter, we are describing protocols to introduce targeted mutations, express mutant enzyme catalysts in heterologous hosts, and assess their catalytic properties. Mutant monoterpene synthases have the potential to contribute significantly to synthetic biology efforts aimed at producing larger amounts of commercially attractive monoterpenes. PMID- 27480687 TI - Prequels to Synthetic Biology: From Candidate Gene Identification and Validation to Enzyme Subcellular Localization in Plant and Yeast Cells. AB - Natural compounds extracted from microorganisms or plants constitute an inexhaustible source of valuable molecules whose supply can be potentially challenged by limitations in biological sourcing. The recent progress in synthetic biology combined to the increasing access to extensive transcriptomics and genomics data now provide new alternatives to produce these molecules by transferring their whole biosynthetic pathway in heterologous production platforms such as yeasts or bacteria. While the generation of high titer producing strains remains per se an arduous field of investigation, elucidation of the biosynthetic pathways as well as characterization of their complex subcellular organization are essential prequels to the efficient development of such bioengineering approaches. Using examples from plants and yeasts as a framework, we describe potent methods to rationalize the study of partially characterized pathways, including the basics of computational applications to identify candidate genes in transcriptomics data and the validation of their function by an improved procedure of virus-induced gene silencing mediated by direct DNA transfer to get around possible resistance to Agrobacterium-delivery of viral vectors. To identify potential alterations of biosynthetic fluxes resulting from enzyme mislocalizations in reconstituted pathways, we also detail protocols aiming at characterizing subcellular localizations of protein in plant cells by expression of fluorescent protein fusions through biolistic-mediated transient transformation, and localization of transferred enzymes in yeast using similar fluorescence procedures. Albeit initially developed for the Madagascar periwinkle, these methods may be applied to other plant species or organisms in order to establish synthetic biology platform. PMID- 27480688 TI - Functional Expression and Characterization of Plant ABC Transporters in Xenopus laevis Oocytes for Transport Engineering Purposes. AB - Transport engineering in bioengineering is aimed at efficient export of the final product to reduce toxicity and feedback inhibition and to increase yield. The ATP binding cassette (ABC) transporters with their highly diverse substrate specificity and role in cellular efflux are potentially suitable in transport engineering approaches, although their size and high number of introns make them notoriously difficult to clone. Here, we report a novel in planta "exon engineering" strategy for cloning of full-length coding sequence of ABC transporters followed by methods for biochemical characterization of ABC exporters in Xenopus oocytes. Although the Xenopus oocyte expression system is particularly suitable for expression of membrane proteins and powerful in screening for novel transporter activity, only few examples of successful expression of ABC transporter has been reported. This raises the question whether the oocytes system is suitable to express and characterize ABC transporters. Thus we have selected AtABCG25, previously characterized in insect cells as the exporter of commercially valuable abscisic acid-as case study for optimizing of characterization in Xenopus oocytes. The tools provided will hopefully contribute to more successful transport engineering in synthetic biology. PMID- 27480689 TI - Quantifying the Metabolites of the Methylerythritol 4-Phosphate (MEP) Pathway in Plants and Bacteria by Liquid Chromatography-Triple Quadrupole Mass Spectrometry. AB - The 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway occurs in the plastids of higher plants and in most economically important prokaryotes where it is responsible for the biosynthesis of the isoprenoid building blocks, isopentenyl diphosphate and dimethylallyl diphosphate. These five-carbon compounds are the substrates for the enormous variety of terpenoid products, including many essential metabolites and substances of commercial value. Increased knowledge of the regulation of the MEP pathway is critical to understanding many aspects of plant and microbial metabolism as well as in developing biotechnological platforms for producing these commercially valuable isoprenoids. To achieve this goal, researchers must have the ability to investigate the in vivo kinetics of the pathway by accurately measuring the concentrations of MEP pathway metabolites. However, the low levels of these metabolites complicate their accurate determination without suitable internal standards. This chapter describes a sensitive method to accurately determine the concentrations of MEP pathway metabolites occurring at trace amounts in biological samples using liquid chromatography coupled to triple quadrupole mass spectrometry. In addition, simple protocols are given for producing stable isotope-labeled internal standards for these analyses. PMID- 27480690 TI - Establishing the Architecture of Plant Gene Regulatory Networks. AB - Gene regulatory grids (GRGs) encompass the space of all the possible transcription factor (TF)-target gene interactions that regulate gene expression, with gene regulatory networks (GRNs) representing a temporal and spatial manifestation of a portion of the GRG, essential for the specification of gene expression. Thus, understanding GRG architecture provides a valuable tool to explain how genes are expressed in an organism, an important aspect of synthetic biology and essential toward the development of the "in silico" cell. Progress has been made in some unicellular model systems (eg, yeast), but significant challenges remain in more complex multicellular organisms such as plants. Key to understanding the organization of GRGs is therefore identifying the genes that TFs bind to, and control. The application of sensitive and high-throughput methods to investigate genome-wide TF-target gene interactions is providing a wealth of information that can be linked to important agronomic traits. We describe here the methods and resources that have been developed to investigate the architecture of plant GRGs and GRNs. We also provide information regarding where to obtain clones or other resources necessary for synthetic biology or metabolic engineering. PMID- 27480691 TI - Engineering of Tomato Glandular Trichomes for the Production of Specialized Metabolites. AB - Glandular trichomes are specialized tissues on the epidermis of many plant species. On tomato they synthesize, store, and emit a variety of metabolites such as terpenoids, which play a role in the interaction with insects. Glandular trichomes are excellent tissues for studying the biosynthesis of specialized plant metabolites and are especially suitable targets for metabolic engineering. Here we describe the strategy for engineering tomato glandular trichomes, first with a transient expression system to provide proof of trichome specificity of selected promoters. Using microparticle bombardment, the trichome specificity of a terpene-synthase promoter could be validated in a relatively fast way. Second, we describe a method for stable expression of genes of interest in trichomes. Trichome-specific expression of another terpene-synthase promoter driving the yellow-fluorescence protein-gene is presented. Finally, we describe a case of the overexpression of farnesyl diphosphate synthase (FPS), specifically in tomato glandular trichomes, providing an important precursor in the biosynthetic pathway of sesquiterpenoids. FPS was targeted to the plastid aiming to engineer sesquiterpenoid production, but interestingly leading to a loss of monoterpenoid production in the transgenic tomato trichomes. With this example we show that trichomes are amenable to engineering though, even with knowledge of a biochemical pathway, the result of such engineering can be unexpected. PMID- 27480692 TI - Tomato Fruits-A Platform for Metabolic Engineering of Terpenes. AB - Terpenoids are a large and diverse class of plant metabolites including mono-, sesqui-, and diterpenes. They have numerous functions in basic physiological processes as well as the interaction of plants with their biotic and abiotic environment. Due to the tight regulation of biosynthetic pathways and the resulting limited natural availability of terpenes, there is a strong interest in increasing their production in plants by metabolic engineering for agricultural, pharmaceutical, and industrial applications. The tomato fruit system was developed as a platform for metabolic engineering of terpenes to overcome detrimental effects on overall plant growth and photosynthesis traits, which are affected when terpenoid engineering is performed in vegetative tissues. Here we describe how the use of fruit-specific promoters for transgene expression can avoid these unwanted effects. In addition, targeting the expression of the introduced terpene biosynthetic gene to fruit tissue can take advantage of the large precursor pool provided by the methylerythritol-phosphate (MEP) pathway, which is highly active during tomato fruit ripening to facilitate the accumulation of carotenoids. We also discuss how the production of high levels of target terpene compounds can be achieved in fruits by the expression of individual or a combination of (i) the MEP or mevalonic acid pathway enzymes, (ii) prenyltransferases, and/or (iii) terpene synthases. Finally, we provide a brief outline of how the emitted as well as internal pools of terpenes can be analyzed in transgenic tomato fruits. PMID- 27480693 TI - Libraries of Synthetic TALE-Activated Promoters: Methods and Applications. AB - The discovery of proteins with programmable DNA-binding specificities triggered a whole array of applications in synthetic biology, including genome editing, regulation of transcription, and epigenetic modifications. Among those, transcription activator-like effectors (TALEs) due to their natural function as transcription regulators, are especially well-suited for the development of orthogonal systems for the control of gene expression. We describe here the construction and testing of libraries of synthetic TALE-activated promoters which are under the control of a single TALE with a given DNA-binding specificity. These libraries consist of a fixed DNA-binding element for the TALE, a TATA box, and variable sequences of 19 bases upstream and 43 bases downstream of the DNA binding element. These libraries were cloned using a Golden Gate cloning strategy making them usable as standard parts in a modular cloning system. The broad range of promoter activities detected and the versatility of these promoter libraries make them valuable tools for applications in the fine-tuning of expression in metabolic engineering projects or in the design and implementation of regulatory circuits. PMID- 27480694 TI - Preface. PMID- 27480695 TI - Solid Phase Mesh Enhanced Sorption from Headspace (SPMESH) Coupled to DART-MS for Rapid Quantification of Trace-Level Volatiles. AB - Quantitation of trace-level (MUg/L to ng/L) volatile compounds is routinely performed in a broad range of applications, including analyses of odorants, pesticide residues, or toxins in foodstuffs and related matrices. Conventional analyses based on gas chromatography-mass spectrometry (GC-MS) are limited by low throughput, and ambient approaches to sample introduction have typically had poor sensitivity. We prepared polydimethylsiloxane-coated stainless steel meshes for extraction and preconcentration of volatiles (Solid Phase Mesh Enhanced Sorption from Headspace, SPMESH), which could then be analyzed by Direct Analysis in Real Time (DART)-MS. The SPMESH cards were characterized by electron microscopy, and figures of merit for the approach were determined using two representative volatiles: 2-isobutyl-3-methoxypyrazine (IBMP) and linalool. Using DART-MS/MS and isotopically labeled internal standards, we achieved detection limits of 21 ng/L and 71 MUg/L for IBMP and linalool in water. Good accuracy and precision could also be achieved for IBMP spikes in grape macerate, although accuracy for linalool was compromised by the presence of interferences. Detection limits could be further improved by an order of magnitude through the use of high resolution (HR) MS. Because extraction can be performed inexpensively in parallel and because it requires short data acquisition times (<1 min), SPMESH-DART-MS may be appropriate for high throughput trace level volatile analyses. PMID- 27480696 TI - Docking pose selection by interaction pattern graph similarity: application to the D3R grand challenge 2015. AB - High affinity ligands for a given target tend to share key molecular interactions with important anchoring amino acids and therefore often present quite conserved interaction patterns. This simple concept was formalized in a topological knowledge-based scoring function (GRIM) for selecting the most appropriate docking poses from previously X-rayed interaction patterns. GRIM first converts protein-ligand atomic coordinates (docking poses) into a simple 3D graph describing the corresponding interaction pattern. In a second step, proposed graphs are compared to that found from template structures in the Protein Data Bank. Last, all docking poses are rescored according to an empirical score (GRIMscore) accounting for overlap of maximum common subgraphs. Taking the opportunity of the public D3R Grand Challenge 2015, GRIM was used to rescore docking poses for 36 ligands (6 HSP90alpha inhibitors, 30 MAP4K4 inhibitors) prior to the release of the corresponding protein-ligand X-ray structures. When applied to the HSP90alpha dataset, for which many protein-ligand X-ray structures are already available, GRIM provided very high quality solutions (mean rmsd = 1.06 A, n = 6) as top-ranked poses, and significantly outperformed a state-of-the art scoring function. In the case of MAP4K4 inhibitors, for which preexisting 3D knowledge is scarce and chemical diversity is much larger, the accuracy of GRIM poses decays (mean rmsd = 3.18 A, n = 30) although GRIM still outperforms an energy-based scoring function. GRIM rescoring appears to be quite robust with comparison to the other approaches competing for the same challenge (42 submissions for the HSP90 dataset, 27 for the MAP4K4 dataset) as it ranked 3rd and 2nd respectively, for the two investigated datasets. The rescoring method is quite simple to implement, independent on a docking engine, and applicable to any target for which at least one holo X-ray structure is available. PMID- 27480697 TI - The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrodinger FEP. AB - In drug discovery, protonation states and tautomerization are easily overlooked. Through a Merck-Rutgers collaboration, this paper re-examined the initial settings and preparations for the Thermodynamic Integration (TI) calculation in AMBER Free-Energy Workflows, demonstrating the value of careful consideration of ligand protonation and tautomer state. Finally, promising results comparing AMBER TI and Schrodinger FEP+ are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design. PMID- 27480699 TI - Make Up Your Mind! PMID- 27480698 TI - Intracholecystic papillary-tubular neoplasm in a patient with choledochal cyst: a link between choledochal cyst and gallbladder cancer? AB - BACKGROUND: Intracholecystic papillary-tubular neoplasms are rare precursor lesions of gallbladder cancer. They were proposed as a separate pathologic entity in 2012 by Adsay et al. for the unification of a variety of mass-forming precursor lesions including papillary adenomas, tubulopapillary adenomas, intestinal adenomas, and others. They are considered homologous to intrapapillary mucinous neoplasms of the pancreas and intrabiliary papillary neoplasms of the common bile duct. In contrast with the commoner flat-type precursor gallbladder cancer lesions, they follow a more indolent clinical course and probably different genetic pathways to carcinogenesis. They are largely uninvestigated with only a handful of studies providing biological and clinical information. Choledochal cysts are dilation of the common bile duct. Diagnosis is usually established during childhood, and only a minority of patients are diagnosed at adulthood. They are of major clinical importance as they are known predisposing factors for biliary carcinogenesis. CASE PRESENTATION: The current report describes a patient with a simultaneous diagnosis of choledochal cyst and intracholecystic papillary-tubular neoplasm. The patient underwent excision of the extrahepatic biliary tree for a Todani I choledochal cyst, and histological examination of the specimen revealed an intracholecystic papillary-tubular neoplasm of the gallbladder. Authors describe diagnostic and clinical course of the patient alongside clinical and biological characteristics of these rare lesions. CONCLUSIONS: To the best of our knowledge, this is the first report of a patient with a simultaneous diagnosis of choledochal cyst and intracholecystic papillary-tubular neoplasm. Those rare lesions shed light on different forms of gallbladder cancer carcinogenesis and its relationship with choledochal cysts and cholestasis. PMID- 27480701 TI - A Systematic Review of the Use of Self-Assessment in Preclinical and Clinical Dental Education. AB - A desired outcome of dental and dental hygiene programs is the development of students' self-assessment skills. To that end, the Commission on Dental Accreditation states that "graduates must demonstrate the ability to self assess." However, it is unclear that merely providing opportunity for self assessment actually leads to the desired outcome. The aim of this study was to systematically review the literature on self-assessment in dental education. A search of English-language articles for the past 25 years (January 1, 1990, to June 30, 2015) was performed using MEDLINE Medical Subject Heading terms. Each abstract and/or article was validated for inclusion. The data collected included student classification, self-assessment environment, faculty assessment, training, faculty calibration, predictive value, and student perceptions. A qualitative analysis was also performed. From an initial list of 258 articles, 19 were selected for inclusion; exclusion criteria included studies that evaluated a non-preclinical or non-clinical exercise or whose subjects were not predoctoral dental or dental hygiene students. The results showed limited information regarding any kind of systematic training of students on how to perform a self assessment. The majority of the studies also did not specify the impact of self assessment on student performance. Self-assessment was primarily performed in the second year and in the preclinical environment. Students received feedback through a correlated faculty assessment in 73% of the studies, but 64% did not provide information regarding students' perceptions of self-assessment. There was a trend for students to be better self-assessors in studies in which a grade was connected to the process. In addition, there was a trend for better performing students to underrate themselves and for poorer performing students to overrate themselves and, overall, for students to score themselves higher than did their faculty evaluators. These findings suggest the need for greater attention to systematically teaching self-assessment in dental and dental hygiene curricula and for further research on the impact of self-assessment on desired outcomes. PMID- 27480702 TI - Fostering Dental Students' Academic Achievements and Reflection Skills Through Clinical Peer Assessment and Feedback. AB - Peer assessment is increasingly being encouraged to enhance dental students' learning. The aim of this study was to evaluate the educational impact in terms of academic achievements and reflective thinking of a formative prospective peer assessment and feedback protocol. Volunteer final-year dental students at King's College London Dental Institute, UK, received training on peer assessment, peer feedback, and self-reflection. At the beginning (baseline) and end (resultant) of the 2012-13 academic year, 86 students (55% of the year group) completed a reflection questionnaire (RQ). Sixty-eight of those students used a modified Direct Observation of Procedural Skills (DOPS) as a framework for peer assessment and peer feedback during a complete academic year. End-of-year, high-stakes examination grades and RQ scores from the participants and nonparticipants were statistically compared. The participants completed 576 peer DOPS. Those 22 students who peer assessed each other >=10 times exhibited highly statistically significant differences and powerful positive effect sizes in their high-stakes exam grades (p=0.0001, d=0.74) and critical reflection skills (p=0.005, d=1.41) when compared to those who did not assess one another. Furthermore, only the same 22 students showed a statistically significant increase and positive effect size in their critical reflection skills from baseline to resultant (p=0.003, d=1.04). The results of this study suggest that the protocol used has the potential to impact dental students' academic and reflection skills, provided it is practiced in ten or more peer encounters and ensuring peer feedback is provided followed by self-reflection. PMID- 27480703 TI - The Role of Self- and Peer Assessment in Dental Students' Reflective Practice Using Standardized Patient Encounters. AB - The aim of this study was to gain insight into the nature of the role played by self- and peer assessment in the development of dental students' reflective practice skills and the value gained through structured encounters with standardized patients. Four standardized patient encounters in an objective structured clinical exam (OSCE) format served as a learning experience for students to demonstrate decision making and communication skills in complex scenarios regarding issues of ethics. Self- and peer assessment and peer-to-peer discourse were used to enhance student reflection. A sample of 16 peer pairs was randomly selected from the population of 108 fourth-year students who participated in the 2014 Clinical Dental Ethics OSCE. Data were collected from self- and peer assessment forms. Five overall performance themes (personal affect, verbal communication, professional demeanor, relationship-building, and patient management) and three student learning themes (application and knowledge, ways to change, and impressed with peer/increased confidence in self) were identified. The results showed that peer assessment ratings were consistently higher than those in the self-assessments, but overall the students deemed both their peers' and their own decision making and communication skills to be quite good. These students rated their experience with the OSCE and self- and peer assessments as positive, appreciating the importance of reflection and learning from their peers. These results provide support for the continued formative use of standardized patient OSCEs and self- and peer assessment to help students develop skills in decision making, communication, professionalism, and reflection. PMID- 27480704 TI - A Cavity Preparation Evaluation System in the Skill Assessment of Dental Students. AB - The aim of this study was to compare a computerized, laser-scanning Cavity Preparation Skill Evaluation System (CPSES) with conventional teachers' eye-hand grading assessment of dental students' Class I cavity preparation evaluations. Thirty-eight cavity preparations of lower left first molars made by junior dental students at a dental school in China were tested from September 2013 to November 2014. The outline and retention form, smoothness, depth, wall angulation, and cavity margin index of the preparations were evaluated by CPSES and then by teachers' eye-hand grading. The mean difference in scores for each method was considered, as was the variability of scores within each method. Compared with the teachers' eye-hand grading method, CPSES provided objective evaluation results that had statistically significant differences (p<0.05). A questionnaire was also designed and distributed to the students; the response rate was 100%. The results indicated that most of the students recognized CPSES effects in the preclinical teaching; 92.1% perceived that CPSES provided high simulation and appropriate practice guidance for them; and 94.7% reported that the evaluation results provided by CPSES gave targeted and objective recommendations. These findings suggest that CPSES can consistently and reliably scan a student's tooth preparation, compare it to a theoretically ideal preparation, and provide objective feedback. The application of CPSES in preclinical operative training can help students better understand the desired parameters for occlusal cavity preparation skills and encourage students in their self-paced learning and independent practice. PMID- 27480705 TI - The Development of Dental Anesthesiology As a Discipline and Its Role As a Model of Interdisciplinary Collaboration. AB - The majority of dental procedures can be performed with an awake patient and the use of a local anesthetic, but when deep sedation and general anesthesia are needed, they typically are provided by those dentists with advanced training in anesthesiology, i.e., oral and maxillofacial surgeons and dentist anesthesiologists. Dental anesthesiology began with the discovery of anesthesia by a dentist in 1844 and has been recognized as a separate discipline in dentistry for nearly 70 years. Training over this time evolved from apprenticeships to one-year training programs, and in 2007, the Commission on Dental Accreditation (CODA) began accrediting two-year dental anesthesiology training programs. Since 2015, in recognition of the increasing complexity of the discipline, training has required three years of postgraduate study. The number of dentist anesthesiologists has grown with the increasing demand for anesthesia services by both the public and the profession. However, the present number of dentist anesthesiologists is not sufficient to meet the demand, so additional programs and growth in current programs are needed. Another valuable aspect of this discipline is its role as a positive example of interdepartmental collaboration since dental anesthesiology faculty, as members of a support discipline, typically work across many of the other departments in a dental school. This article reviews the history of the discipline, describes the educational goals and CODA standards for dental anesthesiology programs, using one program as an example, and discusses the needs and challenges that will shape the discipline's development in the future. PMID- 27480706 TI - Critical Thinking Disposition and Skills in Dental Students: Development and Relationship to Academic Outcomes. AB - Critical thinking is a key element of complex problem-solving and professional behavior. An ideal critical thinking measurement instrument would be able to accurately predict which dental students are predisposed to and capable of thinking critically and applying such thinking skills to clinical situations. The aims of this study were to describe critical thinking disposition and skills in dental students at the beginning and end of their first year, examine cohort and gender effects, and compare their critical thinking test scores to their first year grades. Volunteers from three student cohorts at the University of British Columbia were tested using the California Critical Thinking Disposition Inventory and California Critical Thinking Skills instruments at the beginning and end of their first year. Based on the preliminary findings, one cohort was retested at graduation when their final-year grades and clinical advisor rankings were compared to their critical thinking test scores. The results showed that students who entered dental school with higher critical thinking scores tended to complete their first year with higher critical thinking scores, achieve higher grades, and show greater disposition to think critically at the start of the program. Students who demonstrated an ability to think critically and had a disposition to do so at the start of the program were also likely to demonstrate those same attributes at the completion of their training. High critical thinking scores were associated with success in both didactic and clinical settings in dental school. PMID- 27480707 TI - Dental vs. Medical Students' Comfort with Smoking Cessation Counseling: Implications for Dental Education. AB - The aim of this study was to determine if dental and medical students have similar feelings of professional responsibility, comfort, and confidence with counseling patients about smoking cessation during their clinical years. All third- and fourth-year osteopathic medical (N=580) and dental students (N=144) at Western University of Health Sciences were invited to participate in a survey in April-July 2014, either electronically or in person, regarding their perceived professional responsibility, comfort, and confidence in counseling smokers about quitting and major constraints against counseling smokers about quitting. Respondents' demographic characteristics, smoking history, and history of living with a smoker were also assessed. Response rates were 21% (124/580) for medical and 82% (118/144) for dental students. Most of the responding medical (99.2%) and dental (94.9%) students reported feeling it was their professional responsibility to counsel patients about smoking cessation. Medical student respondents were significantly more comfortable and confident counseling patients about smoking cessation than dental student respondents (p<0.001). Students in the third year were just as comfortable and confident counseling patients about smoking cessation as students in the fourth year (p>0.10). There were no differences by age, but students who were former smokers were significantly more comfortable and confident counseling about smoking cessation than were nonsmokers (p=0.001). While almost all of the responding students reported feeling responsible for counseling patients about smoking cessation, the medical students and former smokers were more comfortable and confident performing this counseling. These results suggest the need for additional training in counseling techniques for dental students and nonsmokers. Future studies should assess the impact of medical and dental students' smoking cessation counseling. PMID- 27480708 TI - Cultural Competency Education in Academic Dental Institutions in Australia and New Zealand: A Survey Study. AB - The aim of this study was to assess the status of cultural competency education in Australian and New Zealand dental, dental hygiene, and oral health therapy programs. The study sought to explore the extent to which cultural competence is included in these programs' curricula, building on similar studies conducted in the United States and thus contributing to the international body of knowledge on this topic. A 12-item instrument was designed with questions in four areas (demographics, content of cultural competency education, organization of overall program curriculum, and educational methods used to teach cultural competence) and was sent to all Australian and New Zealand dental, dental hygiene, and oral health therapy educational programs. Of the total 24 programs, 15 responded for a response rate of 62.5%. The results showed that lectures were the most frequent teaching method used in cultural competency education; however, the variation in responses indicated inconsistencies across study participants, as discussions and self-directed learning also featured prominently in the responses. The majority of respondents reported that cultural competence was not taught as a specific course but rather integrated into their programs' existing curricula. The variations in methods may indicate the need for a standardized framework for cultural competency education in these countries. In addition, the notion of cultural competency education in academic dental institutions demands additional evaluation, and further research is required to develop a solid evidence base on which to develop cultural competency education, specifically regarding content, most effective pedagogies, and assessment of student preparedness. PMID- 27480709 TI - Dental Hygiene Faculty Calibration Using Two Accepted Standards for Calculus Detection: A Pilot Study. AB - Faculty calibration studies for calculus detection use two different standards for examiner evaluation, yet the only therapeutic modality that can be used for nonsurgical periodontal treatment is scaling/root debridement or planing. In this study, a pretest-posttest design was used to assess the feasibility of faculty calibration for calculus detection using two accepted standards: that established by the Central Regional Dental Testing Service, Inc. (CRDTS; readily detectible calculus) and the gold standard for scaling/root debridement (root roughness). Four clinical dental hygiene faculty members out of five possible participants at Halifax Community College agreed to participate. The participants explored calculus on the 16 assigned teeth (64 surfaces) of four patients. Calculus detection scores were calculated before and after training. Kappa averages using CRDTS criteria were 0.561 at pretest and 0.631 at posttest. Kappa scores using the scaling/root debridement or planing standard were 0.152 at pretest and 0.271 at posttest. The scores indicated improvement from moderate (Kappa=0.41-0.60) to substantial agreement (Kappa=0.61-0.80) following training using the CRDTS standard. Although this result differed qualitatively and Kappas were significantly different from 0, the differences for pre- to post-Kappas for patient-rater dyads using CRDTS were not statistically significant (p=0.778). There was no difference (p=0.913) in Kappa scores pre- to post-training using the scaling/root debridement standard. Despite the small number of participants in this study, the results indicated that training to improve interrater reliability to substantial agreement was feasible using the CRDTS standard but not using the gold standard. The difference may have been due to greater difficulty in attaining agreement regarding root roughness. Future studies should include multiple training sessions with patients using the same standard for scaling/root debridement used for evaluation of students. PMID- 27480710 TI - Teaching Skill Acquisition and Development in Dental Education. AB - Development of dental faculty members is paramount to providing outstanding education and role modeling for students. With the large number of second career educators in dental schools, an efficient method of acquiring teaching skills is important for new faculty members. Knowing the skill progression and learning experiences identified by dental educators of varying rank may lead to more efficient, effective faculty development. The aims of this study were to identify the perceptions of a group of faculty members about the knowledge, skills, attitudes, and learning experiences that contribute to developing teaching expertise and to compare and contrast the perceptions of new and more senior faculty members on these subjects. The Dreyfus skill acquisition continuum of novice to expert performance was used as a construct reference. The study used a mixed-methods approach in which qualitative and quantitative data were collected concurrently in an electronic survey of faculty members at one U.S. dental school. Of the 492 total faculty members, 80 survey responses were received, for a 16% response rate. Open coding and analysis of responses revealed some common themes. Building rich content knowledge and learning varied methodologies for teaching and assessment, supported by an awareness of peer role models, were perceived to be features of early growth. Content prioritization, clarity, and customization appropriate for the learner characterized mid growth. As theorized in the Dreyfus model, more experienced faculty members described a fluid, less structured teaching process, increased reflection, and appreciation of the strength of the educational community. The results of this study may help increase dental educators' understanding of teaching skill acquisition and inform faculty development and support. PMID- 27480711 TI - Development and Assessment of Discrimination Exercises for Faculty Calibration in Preclinical Operative Dentistry. AB - The aims of this study were to identify the level of interexaminer agreement among preclinical operative dentistry faculty members when grading Class II preparations performed by first-year dental students; to develop discrimination exercises for specific preparation components where interexaminer agreement was poor; and to evaluate if the discrimination exercises were able to improve inter- and intraexaminer agreement. In the preliminary phase of this study, 13 components of 32 Class II cavity preparations were assessed by eight course faculty members at one U.S. dental school. Analysis of average interexaminer agreement on these components revealed that six were below 60%. These were proximal contact clearance, retention groove placement, retention groove depth, preparation walls, preparation margins, and preparation toilet/debris. A 30 minute calibration session was subsequently developed to provide discrimination exercises utilizing 3-D models and digital images of various levels of student performance for five of the six components. Immediately following calibration, the course faculty assessed the same 32 preparations (Phase I) followed by a delayed assessment without calibration (Phase II) approximately six months later. The results showed that overall interexaminer reliability improved after calibration. Although there was a decline in interexaminer reliability after an interval of six months (Phase II), the degree of variation among examiners was lower than in the preliminary assessment. These findings support the use of discrimination exercises for preclinical operative dentistry course faculty to increase interexaminer agreement and thereby improve the consistency of faculty student communication. PMID- 27480712 TI - Effectiveness of Crown Preparation Assessment Software As an Educational Tool in Simulation Clinic: A Pilot Study. AB - The aim of this pilot study was to evaluate the feasibility of a new tooth preparation assessment software, Preppr, as an educational tool for dental students in achieving optimal parameters for a crown preparation. In February 2015, 30 dental students in their fourth year in a five-year undergraduate dental curriculum in New Zealand were randomly selected from a pool of volunteers (N=40) out of the total class of 85. The participants were placed into one of three groups of ten students each: Group A, the control group, received only written and pictorial instructions; Group B received tutor evaluation and feedback; and Group C performed self-directed learning with the aid of Preppr. Each student was asked to prepare an all-ceramic crown on the lower first molar typodont within three hours and to repeat the exercise three times over the next four weeks. The exercise stipulated a 1 mm finish line dimension and total convergence angles (TOC) between 10 and 20 degrees. Fulfillment of these parameters was taken as an acceptable preparation. The results showed that Group C had the highest percentage of students who achieved minimum finish line dimensions and acceptable TOC angles. Those students also achieved the stipulated requirements earlier than the other groups. This study's findings provide promising data on the feasibility of using Preppr as a self-directed educational tool for students training to prepare dental crowns. PMID- 27480713 TI - Peer Education: Reviews of the Literature (PERLs). PMID- 27480714 TI - Fluorescent Labeling of Yeast Cell Wall Components. AB - Yeast cells stained with a fluorescent dye that specifically binds to one of the cell wall components can be observed under a fluorescent microscope. Visualization of the components 1,3-beta-glucan, mannoproteins, and/or chitin not only provides information concerning the cell wall, but also reveals clues about various cellular activities such as cell polarity, vesicular transport, establishment of budding pattern, apical and isotropic bud growth, and replicative cell age. This protocol describes a standard method for visualizing different components of the yeast cell wall. PMID- 27480715 TI - Assay for Spore Wall Integrity Using a Yeast Predator. AB - During the budding yeast life cycle, a starved diploid cell undergoes meiosis followed by production of four haploid spores, each surrounded by a spore wall. The wall allows the spores to survive in harsh environments until conditions improve. Spores are also more resistant than vegetative cells to treatments such as ether vapor, glucanases, heat shock, high salt concentrations, and exposure to high or low pH, but the relevance of these treatments to natural environmental stresses remains unclear. This protocol describes a method for assaying the yeast spore wall under natural environmental conditions by quantifying the survival of yeast spores that have passed through the digestive system of a yeast predator, the fruit fly. PMID- 27480716 TI - Local and Acute Disruption of the Yeast Cell Surface. AB - In nature, the yeast cell barrier encounters threats ranging from physical impact to abrupt changes in osmolality after rainfall. Genetic materials are protected from these environmental attacks by the rigid cell wall. Laboratory methods for challenging cell wall integrity have made an enormous contribution to the study of the yeast cell surface, but most have targeted whole-cell populations in place of single-cell analysis. This protocol describes pulse-laser-based acute disruption of the yeast cell surface, which enables the observation of single cell response to submicron-scale damage. PMID- 27480717 TI - Measuring Survival of Adherent Cells with the Colony-Forming Assay. AB - Measuring cell death with colorimetric or fluorimetric dyes such as trypan blue and propidium iodide (PI) can provide an accurate measure of the number of dead cells in a population at a specific time; however, these assays cannot be used to distinguish cells that are dying or marked for future death. In many cases it is essential to measure the proliferative capacity of treated cells to provide an indirect measurement of cell death. This can be achieved using the colony-forming assay described here. This protocol specifically applies to measurement of HeLa cells but can be used for most adherent cell lines with limited motility. PMID- 27480718 TI - Measuring Survival of Hematopoietic Cancer Cells with the Colony-Forming Assay in Soft Agar. AB - Colony-forming assays measure the ability of cells in culture to grow and divide into groups. Any cell that has the potential to form a colony may also have the potential to cause cancer or relapse in vivo. Colony-forming assays also provide an indirect measurement of cell death because any cell that is dead or dying will not continue to proliferate. The proliferative capacity of adherent cells such as fibroblasts can be determined by growing cells at low density on culture dishes and counting the number of distinct groups that form over time. Cells that grow in suspension, such as hematopoietic cells, cannot be assayed this way because the cells move freely in the media. Assays to determine the colony-forming ability of hematopoietic cells must therefore be performed in solid matrices that restrict large-scale movement of the cells. One such matrix is soft agar. This protocol describes the use of soft agar to compare the colony-forming ability of untreated hematopoietic cells to the colony-forming ability of hematopoietic cells that have been treated with a cytotoxic agent. PMID- 27480719 TI - Synchronizing Progression of Schizosaccharomyces pombe Cells from Prophase through Mitosis and into S Phase with nda3-KM311 Arrest Release. AB - Here, we describe how the rapid reversibility of the nda3-KM311 cold-sensitive beta-tubulin mutation was optimized by Mitsuhiro Yanagida's laboratory to synchronize mitotic progression in an entire cell population. The inability to form microtubules following the loss of beta-tubulin function at 20 degrees C triggers the spindle assembly checkpoint, which arrests mitotic progression. Restoration of beta-tubulin function by rewarming to 30 degrees C (or higher) releases the arrest, generating a highly synchronous progression through mitosis. The viability of nda3-KM311 strains at 30 degrees C makes it feasible to generate double mutants between nda3-KM311 and any temperature-sensitive mutant that can also grow at 30 degrees C. These double mutants can be used in reciprocal shift analyses, in which cold-induced early mitotic arrest is relieved by a shift to 36 degrees C, which then inactivates the product of the second mutant gene. The addition of microtubule depolymerizing drugs before the return to 36 degrees C will maintain checkpoint signaling at 36 degrees C transiently, permitting analysis of the impact of temperature-sensitive mutations on checkpoint function. Silencing the checkpoint of nda3-KM311-arrested cells at 20 degrees C through chemical inhibition of aurora kinase is a powerful way to study checkpoint recovery pathways and mitotic exit without anaphase. PMID- 27480720 TI - Synchronizing Progression of Schizosaccharomyces pombe Cells from G2 through Repeated Rounds of Mitosis and S Phase with cdc25-22 Arrest Release. AB - Transient inactivation of the cdc25(+) gene product by manipulation of the culture temperature for cdc25-22 cells is the most commonly exploited approach to mitotic synchronization in fission yeast. Because Cdc25 removes the inhibitory phosphate placed on Cdk1 by Wee1, inactivation of Cdc25 arrests cells at the G2/M boundary. Incubation at the restrictive temperature of 36 degrees C for just over one generation time forces all cells in the culture to accumulate at the G2/M boundary. Restoration of Cdc25 function via a return to the permissive temperature or chemical inhibition of Wee1 activity at 36 degrees C can then promote a highly synchronous wave of cell division throughout the culture. These approaches can be performed on any scale and thus support simultaneous assessment of numerous events within a single culture. After describing this simple and widely applicable procedure, we discuss frequently overlooked issues that can have a considerable impact on the interpretation of data from cdc25-22 induction synchronized cultures. PMID- 27480721 TI - Single-Channel Recording of Glycine Receptors in Human Embryonic Kidney (HEK) Cells. AB - This protocol describes how to record the single-channel activity of recombinant homomeric glycine receptors expressed in human embryonic kidney (HEK) cells. Cell attached recordings readily reveal the large conductance (90 pS) and distinctive clusters of activations at high glycine concentration. This method for obtaining equilibrium recordings can be adapted to any ion channel receptor. The necessary extensions to outside-out patch for nonequilibrium recordings are also described, as are basic analyses of channel properties and activity. PMID- 27480722 TI - Selecting Female Mice in Estrus and Checking Plugs. AB - The female mouse estrous cycle is divided into four phases: proestrus (development of ovarian follicles), estrus (ovulation), metestrus (formation of corpora lutea), and diestrus (beginning of follicle development for next ovulation and elimination of previous oocytes). The appearance of the epithelium of the external genitalia is used to identify the stage of the estrous cycle of a female mouse. This is usually easier to see in strains with either no or only light skin pigmentation. By examining the color, moistness, and degree of swelling of the vagina, females in estrus can readily be identified. To set up the matings, females are examined in the afternoon, and those in estrus are placed into the cages with males (one or two females in each cage with one male). Usually, 50% or more of the selected females will mate. The presence of a vaginal copulation plug next morning indicates that mating has occurred, but it does not mean that a pregnancy will result even if proven breeder fertile males were used. It is important to check vaginal plugs early in the morning because they fall out or are no longer detectable ~12 h after mating or sometimes earlier. PMID- 27480723 TI - Determining the Stage of the Estrous Cycle in Female Mice by Vaginal Smear. AB - Female mice undergo a 3- to 5-d, hormonally controlled estrous cycle. The estrous cycle is divided into different stages, including diestrus, proestrus, estrus, and metestrus. These stages can easily be determined by examining washes or cell smears of the vagina. Determining the stage of the estrous cycle may be important for setting up matings, identifying receptive females for artificial insemination, and analyzing phenotypes of the female reproductive tract. PMID- 27480724 TI - Examination and Disruption of the Yeast Cell Wall. AB - The cell wall of Saccharomyces cerevisiae is a complicated extracellular organelle. Although the barrier may seem like a technical nuisance for researchers studying intracellular biomolecules or conditions, the rigid wall is an essential aspect of the yeast cell. Without it, yeast cells are unable to proliferate or carry out their life cycle. The chemical composition of the cell wall and the biosynthetic pathways and signal transduction mechanisms involved in cell wall remodeling have been studied extensively, but many unanswered questions remain. This introduction describes techniques for investigating abnormalities in the cell and spore walls and performing cell wall disruption. PMID- 27480725 TI - Single-Channel Recording of Ligand-Gated Ion Channels. AB - Single-channel recordings reveal the microscopic properties of individual ligand gated ion channels. Such recordings contain much more information than measurements of ensemble behavior and can yield structural and functional information about the receptors that participate in fast synaptic transmission in the brain. With a little care, a standard patch-clamp electrophysiology setup can be adapted for single-channel recording in a matter of hours. Thenceforth, it is a realistic aim to record single-molecule activity with microsecond resolution from arbitrary cell types, including cell lines and neurons. PMID- 27480726 TI - Data Formats in Bioinformatics. AB - Here we introduce several interchangeable data formats that are commonly used in bioinformatics. PMID- 27480727 TI - Prevalence and Motivation: Pubic Hair Grooming Among Men in the United States. AB - Pubic hair grooming is a growing phenomenon and is associated with body image and sexual activity. A nationally representative survey of noninstitutionalized adults aged 18 to 65 years residing in the United States was conducted. Differences in demographic and sexual characteristics between groomers and nongroomers were explored. Four thousand one hundred and ninety-eight men completed the survey. Of these men, 2,120 (50.5%) reported regular pubic hair grooming. The prevalence of grooming decreases with age, odds ratio = 0.95 (95% confidence interval [0.94, 0.96]), p < .001. Adjusting for sexual frequency and sexual orientation, grooming is associated with performing and receiving oral sex. The majority of men report grooming in preparation for sexual activity with a peak prevalence of 73% among men aged 25 to 34 years, followed by hygiene (61%) and routine care (44%). The majority of men who remove their pubic hair groom the hair above the penis (87%), followed by the scrotum (66%) and the penile shaft (57%). Overall, pubic hair grooming is common among men aged 18 to 65 years in the United States. Younger ages are associated with greater rates of pubic hair grooming. Many men groom for sex, in particular oral sex, as well as for routine care and hygiene. PMID- 27480728 TI - Effect of implementation of a coded problem list entry subsystem. AB - OBJECTIVES: Complete patient problem lists may improve the quality of care. To improve the completeness of the lists at our institution, we implemented the coded problem list entry subsystem (CPLES) in our electronic medical record system. Subsequently, physicians used the CPLES instead of handwritten notes to document coded problem lists and progress notes. We evaluated the effect of implementing the CPLES on the completeness of problem lists. METHODS: We compared the completeness of coded problem lists input after CPLES implementation with that of problem lists handwritten before CPLES implementation and determined the differences. Moreover, the efficiency and usability of the CPLES were evaluated. RESULTS: The efficiency and usability of CPLES were acceptable. However, the completeness of problem lists was reduced after CPLES implementation. The possible reasons for this reduction, namely system usability, efficacy, incentives, leadership, and education, were crucial for successful CPLES implementation and are discussed in the text. CONCLUSION: CPLES implementation reduced the completeness of problem lists. Institutions may learn from our experience and carefully implement their own coded problem list systems to avoid this consequence. PMID- 27480729 TI - Detection and classification of masses in mammographic images in a multi-kernel approach. AB - BACKGROUND AND OBJECTIVE: According to the World Health Organization, breast cancer is the main cause of cancer death among adult women in the world. Although breast cancer occurs indiscriminately in countries with several degrees of social and economic development, among developing and underdevelopment countries mortality rates are still high due to low availability of early detection technologies. From the clinical point of view, mammography is still the most effective diagnostic technology, given the wide diffusion of the use and interpretation of these images. METHODS: Herein this work we propose a method to detect and classify mammographic lesions using the regions of interest of images. Our proposal consists in decomposing each image using multi-resolution wavelets. Zernike moments are extracted from each wavelet component. Using this approach, we can combine both texture and shape features, which can be applied both to the detection and classification of mammary lesions. We used 355 images of fatty breast tissue of IRMA database, with 233 normal instances (no lesion), 72 benign, and 83 malignant cases. RESULTS: Classification was performed by using SVM and ELM networks with modified kernels in order to optimize accuracy rates, reaching 94.11%. Considering both accuracy rates and training times, we defined the ration between average percentage accuracy and average training time in a reverse order. Our proposal was 50 times higher than the ratio obtained using state-of-the-art approaches. CONCLUSIONS: As our proposed model can combine high accuracy rate with low learning time, whenever a new data is received, our work will be able to save a lot of time, hours, in learning process in relation to the best method of the state-of-the-art. PMID- 27480730 TI - Inter-lead correlation analysis for automated detection of cable reversals in 12/16-lead ECG. AB - BACKGROUND AND OBJECTIVE: A crucial factor for proper electrocardiogram (ECG) interpretation is the correct electrode placement in standard 12-lead ECG and extended 16-lead ECG for accurate diagnosis of acute myocardial infarctions. In the context of optimal patient care, we present and evaluate a new method for automated detection of reversals in peripheral and precordial (standard, right and posterior) leads, based on simple rules with inter-lead correlation dependencies. METHODS: The algorithm for analysis of cable reversals relies on scoring of inter-lead correlations estimated over 4s snapshots with time-coherent data from multiple ECG leads. Peripheral cable reversals are detected by assessment of nine correlation coefficients, comparing V6 to limb leads: (I, II, III, -I, -II, -III, -aVR, -aVL, -aVF). Precordial lead reversals are detected by analysis of the ECG pattern cross-correlation progression within lead sets (V1 V6), (V4R, V3R, V3, V4), and (V4, V5, V6, V8, V9). Disturbed progression identifies the swapped leads. RESULTS: A test-set, including 2239 ECGs from three independent sources-public 12-lead (PTB, CSE) and proprietary 16-lead (Basel University Hospital) databases-is used for algorithm validation, reporting specificity (Sp) and sensitivity (Se) as true negative and true positive detection of simulated lead swaps. Reversals of limb leads are detected with Se = 95.5-96.9% and 100% when right leg is involved in the reversal. Among all 15 possible pairwise reversals in standard precordial leads, adjacent lead reversals are detected with Se = 93.8% (V5-V6), 95.6% (V2-V3), 95.9% (V3-V4), 97.1% (V1 V2), and 97.8% (V4-V5), increasing to 97.8-99.8% for reversals of anatomically more distant electrodes. The pairwise reversals in the four extra precordial leads are detected with Se = 74.7% (right-sided V4R-V3R), 91.4% (posterior V8 V9), 93.7% (V4R-V9), and 97.7% (V4R-V8, V3R-V9, V3R-V8). Higher true negative rate is achieved with Sp > 99% (standard 12-lead ECG), 81.9% (V4R-V3R), 91.4% (V8 V9), and 100% (V4R-V9, V4R-V8, V3R-V9, V3R-V8), which is reasonable considering the low prevalence of lead swaps in clinical environment. CONCLUSIONS: Inter-lead correlation analysis is able to provide robust detection of cable reversals in standard 12-lead ECG, effectively extended to 16-lead ECG applications that have not previously been addressed. PMID- 27480731 TI - Bio mathematical venture for the metallic nanoparticles due to ciliary motion. AB - BACKGROUND AND OBJECTIVES: The present investigation is associated with the contemporary study of viscous flow in a vertical tube with ciliary motion. METHODS/RESULTS/CONCLUSIONS: The main flow problem has been modeled using cylindrical coordinates; flow equations are simplified to ordinary differential equations using longwave length and low Reynold's number approximation; and exact solutions have been obtained for velocity, pressure gradient and temperature. Results acquired are discussed graphically for better understanding. Streamlines for the velocity profile are plotted to discuss the trapping phenomenon. It is seen that with an increment in the Grashof number, the velocity of the governing fluids starts to decrease significantly. PMID- 27480732 TI - An accelerated framework for the classification of biological targets from solid state micropore data. AB - Micro- and nanoscale systems have provided means to detect biological targets, such as DNA, proteins, and human cells, at ultrahigh sensitivity. However, these devices suffer from noise in the raw data, which continues to be significant as newer and devices that are more sensitive produce an increasing amount of data that needs to be analyzed. An important dimension that is often discounted in these systems is the ability to quickly process the measured data for an instant feedback. Realizing and developing algorithms for the accurate detection and classification of biological targets in realtime is vital. Toward this end, we describe a supervised machine-learning approach that records single cell events (pulses), computes useful pulse features, and classifies the future patterns into their respective types, such as cancerous/non-cancerous cells based on the training data. The approach detects cells with an accuracy of 70% from the raw data followed by an accurate classification when larger training sets are employed. The parallel implementation of the algorithm on graphics processing unit (GPU) demonstrates a speedup of three to four folds as compared to a serial implementation on an Intel Core i7 processor. This incredibly efficient GPU system is an effort to streamline the analysis of pulse data in an academic setting. This paper presents for the first time ever, a non-commercial technique using a GPU system for realtime analysis, paired with biological cluster targeting analysis. PMID- 27480733 TI - A multiscale modelling of bone ultrastructure elastic proprieties using finite elements simulation and neural network method. AB - Bone is a living material with a complex hierarchical structure which entails exceptional mechanical properties, including high fracture toughness, specific stiffness and strength. Bone tissue is essentially composed by two phases distributed in approximately 30-70%: an organic phase (mainly type I collagen and cells) and an inorganic phase (hydroxyapatite-HA-and water). The nanostructure of bone can be represented throughout three scale levels where different repetitive structural units or building blocks are found: at the first level, collagen molecules are arranged in a pentameric structure where mineral crystals grow in specific sites. This primary bone structure constitutes the mineralized collagen microfibril. A structural organization of inter-digitating microfibrils forms the mineralized collagen fibril which represents the second scale level. The third scale level corresponds to the mineralized collagen fibre which is composed by the binding of fibrils. The hierarchical nature of the bone tissue is largely responsible of their significant mechanical properties; consequently, this is a current outstanding research topic. Scarce works in literature correlates the elastic properties in the three scale levels at the bone nanoscale. The main goal of this work is to estimate the elastic properties of the bone tissue in a multiscale approach including a sensitivity analysis of the elastic behaviour at each length scale. This proposal is achieved by means of a novel hybrid multiscale modelling that involves neural network (NN) computations and finite elements method (FEM) analysis. The elastic properties are estimated using a neural network simulation that previously has been trained with the database results of the finite element models. In the results of this work, parametric analysis and averaged elastic constants for each length scale are provided. Likewise, the influence of the elastic constants of the tissue constituents is also depicted. Results highlight that intelligent numerical methods are powerful and accurate procedures to deal with the complex multiscale problem in the bone tissue with results in agreement with values found in literature for specific scale levels. PMID- 27480734 TI - Computer-assisted detection of swallowing difficulty. AB - To evaluate classification performance of a support vector machine (SVM) classifier for diagnosing swallowing difficulty based on the hyoid movement data attained from videofluoroscopic swallowing study, the hyoid kinematics during the swallowing of 2 mL of liquid barium solution were analyzed for 90 healthy volunteers and 116 dysphagic stroke patients. SVM was used to classify the kinematic results as normal or dysfunctional swallowing. Various kernel functions and kernel parameters were used for optimization. Features were selected to find an optimal feature subset and to minimize redundancy. Accuracy, sensitivity, specificity, and area under a receiving operating characteristic curve (AUC) were used to assess the discrimination performance. In 19 out of 26 features, mean comparison revealed a significant difference between healthy subjects and dysphagic patients. By reducing the number of features to 10, an AUC of 0.9269 could be reached. Common features showing the best classification in both kernel functions included forward maximum excursion time, upward maximum excursion time, maximum excursion length, upward maximum velocity time, upward maximum acceleration time, maximum acceleration, maximum acceleration time, and mean acceleration. SVM-based classification method with the use of kernel functions showed an outstanding (AUC of 0.9269) discrimination performance for either healthy or dysphagic hyoid movement during swallowing. We expect that this classification method will be useful as an adjunct diagnostic tool by providing automatic detection of swallowing dysfunction as well as a research tool providing deeper understanding of pathophysiology. PMID- 27480735 TI - A robust image registration method based on total variation regularization under complex illumination changes. AB - BACKGROUND AND OBJECTIVE: Image registration is one of the fundamental and essential tasks for medical imaging and remote sensing applications. One of the most common challenges in this area is the presence of complex spatially varying intensity distortion in the images. The widely used similarity metrics, such as MI (Mutual Information), CC (Correlation Coefficient), SSD (Sum of Square Difference), SAD (Sum of Absolute Difference) and CR (Correlation Ratio), are not robust against this kind of distortion because stationarity assumption and the pixel-wise independence cannot be obeyed and captured by these metrics. METHODS: In this paper, we propose a new intensity-based method for simultaneous image registration and intensity correction. We assume that the registered moving image can be reconstructed by the reference image through a linear function that consists of multiplicative and additive coefficients. We also assume that the illumination changes in the images are spatially smooth in each region, so we use weighted Total Variation as a regularization term to estimate the aforesaid multiplicative and additive coefficients. Using weighted Total Variation leads to reduce the smoothness-effect on the coefficients across the edges and causes low level segmentation on the coefficients. For minimizing the reconstruction error, as a dissimilarity term, we use l1norm which is more robust against illumination change and non-Gaussian noises than the l2 norm. Primal-Dual method is used for solving the optimization problem. RESULTS: The proposed method is applied to simulated as well as real-world data consisting of clinically 4-D Computed Tomography, retina, Digital Subtraction Angiography (DSA), and iris image pairs. Then, the comparisons are made to MI, CC, SSD, SAD and RC qualitatively and sometimes quantitatively. CONCLUSIONS: The experiment results are demonstrating that the proposed method produces more accurate registration results than conventional methods. PMID- 27480736 TI - The effect of medication therapy management service combined with a national PharmaCloud system for polypharmacy patients. AB - BACKGROUND: This study evaluated a medication therapy management service using the Taiwan National Health Insurance Administration's PharmaCloud system in a medical center in Taiwan. The new PharmaCloud System, launched in 2013, links a complete list of prescribed and dispensed medication from different hospitals, clinics, and pharmacies for all insured patients. METHOD: The study included patients with polypharmacy (>=5 drugs) at a medication therapy management service from March 2013 to March 2014. A structured questionnaire was designed to collect patients' baseline data and record patients' knowledge, attitudes, and practice scores before and after the service intervention. Phone follow-ups for practice and adherence scores on medication use were performed after 3 months. RESULTS: There were 152 patients recruited in the study. Scores for medication use attitudes and practice significantly increased after the service (attitudes: 40.06 +/- 0.26 to 43.07 +/- 0.19, p <0.001; practice: 33.42 +/- 0.30 to 40.37 +/- 0.30, p <0.001). The scores for medication adherence also increased from 3.02 +/- 0.07 to 3.92 +/- 0.02 (p <0.001). CONCLUSIONS: The PharmaCloud system facilitates accurate and efficient medication reconciliation for pharmacists in the medication therapy management service. The model improved patients' attitudes and practice of the rational use of medications and adherence with medications. Further studies are warranted to evaluate human resources, executing costs, and the cost-benefit ratio of this medication therapy management service with the PharmaCloud system. PMID- 27480737 TI - Mobile personal health records for pregnancy monitoring functionalities: Analysis and potential. AB - BACKGROUND AND OBJECTIVE: Personal Health Records (PHRs) are a rapidly growing area of health information technology. PHR users are able to manage their own health data and communicate with doctors in order to improve healthcare quality and efficiency. Mobile PHR (mPHR) applications for mobile devices have obtained an interesting market quota since the appearance of more powerful mobile devices. These devices allow users to gain access to applications that used to be available only for personal computers. This paper analyzes the functionalities of mobile PHRs that are specific to pregnancy monitoring. METHODS: A well-known Systematic Literature Review (SLR) protocol was used in the analysis process. A questionnaire was developed for this task, based on the rigorous study of scientific literature concerning pregnancy and applications available on the market, with 9 data items and 35 quality assessments. The data items contain calendars, pregnancy information, health habits, counters, diaries, mobile features, security, backup, configuration and architectural design. RESULTS: A total of 33 mPHRs for pregnancy monitoring, available for iOS and Android, were selected from Apple App store and Google Play store, respectively. The results show that none of the mPHRs selected met 100% of the functionalities analyzed in this paper. The highest score achieved was 77%, while the lowest was 17%. CONCLUSIONS: In this paper, these features are discussed and possible paths for future development of similar applications are proposed, which may lead to a more efficient use of smartphone capabilities. PMID- 27480738 TI - Empirical search for factors affecting mean particle size of PLGA microspheres containing macromolecular drugs. AB - BACKGROUND AND OBJECTIVES: Poly(lactic-co-glycolic acid) (PLGA) has become one of the most promising in design, development, and optimization for medical applications polymers. PLGA-based multiparticulate dosage forms are usually prepared as microspheres where the size is from 5 to 100 um, depending on the route of administration. The main objectives of the study were to develop a predictive model of mean volumetric particle size and on its basis extract knowledge of PLGA containing proteins forming behaviour. METHODS: In the present study, a model for the prediction of mean volumetric particle size developed by an rgp package of R environment is presented. Other tools like fscaret, monmlp, fugeR, MARS, SVM, kNNreg, Cubist, randomForest and piecewise linear regression are also applied during the data mining procedure. RESULTS: The feature selection provided by the fscaret package reduced the original input vector from a total of 295 input variables to 10, 16 and 19. The developed models had good predictive ability, which was confirmed by a normalized root-mean-square error (NRMSE) of 6.8 to 11.1% in 10-fold cross validation training procedure. Moreover, the best models were validated using external experimental data. The superior predictiveness had a model obtained by rgp in the form of a classical equation with a normalized root-mean-squared error (NRMSE) of 6.1%. CONCLUSIONS: A new approach is proposed for computational modelling of the mean particle size of PLGA microspheres and rules extraction from tree-based models. The feature selection leads to revealing chemical descriptor variables which are important in predicting the size of PLGA microspheres. In order to achieve better understanding in the relationships between particle size and formulation characteristics, the surface analysis method and rules extraction procedures were applied. PMID- 27480739 TI - Sector mapping method for 3D detached retina visualization. AB - A new sphere-mapping algorithm called sector mapping is introduced to map sector images to the sphere of an eyeball. The proposed sector-mapping algorithm is evaluated and compared with the plane-mapping algorithm adopted in previous work. A simulation that maps an image of concentric circles to the sphere of the eyeball and an analysis of the difference in distance between neighboring points in a plane and sector were used to compare the two mapping algorithms. A three dimensional model of a whole retina with clear retinal detachment was generated using the Visualization Toolkit software. A comparison of the mapping results shows that the central part of the retina near the optic disc is stretched and its edges are compressed when the plane-mapping algorithm is used. A better mapping result is obtained by the sector-mapping algorithm than by the plane mapping algorithm in both the simulation results and real clinical retinal detachment three-dimensional reconstruction. PMID- 27480740 TI - Mask_explorer: A tool for exploring brain masks in fMRI group analysis. AB - BACKGROUND AND OBJECTIVE: Functional magnetic resonance imaging (fMRI) studies of the human brain are appearing in increasing numbers, providing interesting information about this complex system. Unique information about healthy and diseased brains is inferred using many types of experiments and analyses. In order to obtain reliable information, it is necessary to conduct consistent experiments with large samples of subjects and to involve statistical methods to confirm or reject any tested hypotheses. Group analysis is performed for all voxels within a group mask, i.e. a common space where all of the involved subjects contribute information. To our knowledge, a user-friendly interface with the ability to visualize subject-specific details in a common analysis space did not yet exist. The purpose of our work is to develop and present such interface. METHODS: Several pitfalls have to be avoided while preparing fMRI data for group analysis. One such pitfall is spurious non-detection, caused by inferring conclusions in the volume of a group mask that has been corrupted due to a preprocessing failure. We describe a MATLAB toolbox, called the mask_explorer, designed for prevention of this pitfall. RESULTS: The mask_explorer uses a graphical user interface, enables a user-friendly exploration of subject masks and is freely available. It is able to compute subject masks from raw data and create lists of subjects with potentially problematic data. It runs under MATLAB with the widely used SPM toolbox. Moreover, we present several practical examples where the mask_explorer is usefully applied. CONCLUSIONS: The mask_explorer is designed to quickly control the quality of the group fMRI analysis volume and to identify specific failures related to preprocessing steps and acquisition. It helps researchers detect subjects with potentially problematic data and consequently enables inspection of the data. PMID- 27480741 TI - A new thresholding technique based on fuzzy set as an application to leukocyte nucleus segmentation. AB - BACKGROUND AND OBJECTIVES: The main aim of this paper is to segment leukocytes in blood smear images using interval-valued intuitionistic fuzzy sets (IVIFSs). Generally, uncertainties occur in terms of vagueness through brightness levels of image. Processing of such uncertain images can be efficiently handled by using fuzzy sets, particularly IVIFSs. METHODS: Logarithmic membership function is utilized for computing membership values corresponding to intensities of the pixel. Non-membership function of IVIFS is constructed by using Yager generating function. By varying parameters, 256 IVIFSs are generated. An IVIFS is selected from 256 IVIFSs having maximizing ultrafuzziness along with varying threshold. Threshold is determined by finding an IVIFS with maximum similarity between ideal segmented and segmented results obtained from the proposed method. RESULTS: Quantitatively, the segmented images are evaluated using precision-recall, receiver operator characteristic curves, Jaccard coefficient and measure for structural similarity index along with the time taken for segmenting nucleus, and their results are compared with results of existing methods. Performance measures reveal that the proposed method seems to segment leukocytes better than other comparable methods. CONCLUSIONS: Segmentation of leukocytes using the proposed method helps the analyst in differentiating various types of leukocytes and in the determination of leukocyte count, and the counting is essential in finding out diseases related to reduction or surplus quantity of these cells. PMID- 27480742 TI - Prediction of nocturnal hypoglycemia by an aggregation of previously known prediction approaches: proof of concept for clinical application. AB - BACKGROUND AND OBJECTIVE: Nocturnal hypoglycemia (NH) is common in patients with insulin-treated diabetes. Despite the risk associated with NH, there are only a few methods aiming at the prediction of such events based on intermittent blood glucose monitoring data and none has been validated for clinical use. Here we propose a method of combining several predictors into a new one that will perform at the level of the best involved one, or even outperform all individual candidates. METHODS: The idea of the method is to use a recently developed strategy for aggregating ranking algorithms. The method has been calibrated and tested on data extracted from clinical trials, performed in the European FP7 funded project DIAdvisor. Then we have tested the proposed approach on other datasets to show the portability of the method. This feature of the method allows its simple implementation in the form of a diabetic smartphone app. RESULTS: On the considered datasets the proposed approach exhibits good performance in terms of sensitivity, specificity and predictive values. Moreover, the resulting predictor automatically performs at the level of the best involved method or even outperforms it. CONCLUSION: We propose a strategy for a combination of NH predictors that leads to a method exhibiting a reliable performance and the potential for everyday use by any patient who performs self-monitoring of blood glucose. PMID- 27480743 TI - Paroxysmal atrial fibrillation prediction method with shorter HRV sequences. AB - This paper proposes a method that predicts the onset of paroxysmal atrial fibrillation (PAF), using heart rate variability (HRV) segments that are shorter than those applied in existing methods, while maintaining good prediction accuracy. PAF is a common cardiac arrhythmia that increases the health risk of a patient, and the development of an accurate predictor of the onset of PAF is clinical important because it increases the possibility to stabilize (electrically) and prevent the onset of atrial arrhythmias with different pacing techniques. We investigate the effect of HRV features extracted from different lengths of HRV segments prior to PAF onset with the proposed PAF prediction method. The pre-processing stage of the predictor includes QRS detection, HRV quantification and ectopic beat correction. Time-domain, frequency-domain, non linear and bispectrum features are then extracted from the quantified HRV. In the feature selection, the HRV feature set and classifier parameters are optimized simultaneously using an optimization procedure based on genetic algorithm (GA). Both full feature set and statistically significant feature subset are optimized by GA respectively. For the statistically significant feature subset, Mann Whitney U test is used to filter non-statistical significance features that cannot pass the statistical test at 20% significant level. The final stage of our predictor is the classifier that is based on support vector machine (SVM). A 10 fold cross-validation is applied in performance evaluation, and the proposed method achieves 79.3% prediction accuracy using 15-minutes HRV segment. This accuracy is comparable to that achieved by existing methods that use 30-minutes HRV segments, most of which achieves accuracy of around 80%. More importantly, our method significantly outperforms those that applied segments shorter than 30 minutes. PMID- 27480744 TI - Prediction of G-protein coupled receptors and their subfamilies by incorporating various sequence features into Chou's general PseAAC. AB - BACKGROUND AND OBJECTIVE: The G-protein coupled receptors are the largest superfamilies of membrane proteins and important targets for the drug design. G protein coupled receptors are responsible for many physiochemical processes such as smell, taste, vision, neurotransmission, metabolism, cellular growth and immune response. So it is necessary to design a robust and efficient approach for the prediction of G-protein coupled receptors and their subfamilies. METHODS: In this paper, the protein samples are represented by amino acid composition, dipeptide composition, correlation features, composition, transition, distribution, sequence order descriptors and pseudo amino acid composition with total 1497 number of sequence derived features. To address the issue of efficient classification of G-protein coupled receptors and their subfamilies, we propose to use a weighted k-nearest neighbor classifier with UNION of best 50 features, selected by Fisher score based feature selection, ReliefF, fast correlation based filter, minimum redundancy maximum relevancy, and support vector machine based recursive elimination feature selection methods to exploit the advantages of these feature selection methods. RESULTS: The proposed method achieved an overall accuracy of 99.9%, 98.3%, 95.4%, MCC values of 1.00, 0.98, 0.95, ROC area values of 1.00, 0.998, 0.996 and precision of 99.9%, 98.3% and 95.5% using 10-fold cross validation to predict the G-protein coupled receptors and non-G-protein coupled receptors, subfamilies of G-protein coupled receptors, and subfamilies of class A G-protein coupled receptors, respectively. CONCLUSIONS: The high accuracies, MCC, ROC area values, and precision values indicate that the proposed method is better for the prediction of G-protein coupled receptors families and their subfamilies. PMID- 27480745 TI - Computer-aided design, structural dynamics analysis, and in vitro susceptibility test of antibacterial peptides incorporating unnatural amino acids against microbial infections. AB - BACKGROUND AND OBJECTIVE: Antibacterial peptides (ABPs) are essential components of host defense against microbial infections present in all domains of life. The AMPs incorporating unnatural amino acids (uABPs) exhibit several advantages over naturally occurring AMPs based on factors such as bioavailability, metabolic stability and overall toxicity. METHODS: Computer-aided modeling and in vitro susceptibility test were combined to rationally design short uABPs with potent antimicrobial activity. In the procedure, peptide characterization and machine learning modeling were used to develop statistical regression predictors, which were then employed to guide the molecular design and structural optimization of uABPs, to which a number of commercially available unnatural amino acids were introduced. RESULTS: An improved uABP population was obtained, from which several promising candidates were successfully prepared and their antibacterial potencies against three bacterial strains Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli were measured using broth microdilution assay. Consequently, four uABPs with hybrid structure property were determined to have high potency against the tested strains with minimum inhibitory concentration (MIC) of <50 ug/ml. CONCLUSIONS: Molecular dynamics (MD) simulations revealed that the designed uABPs are amphipathic helix in solution but they would largely unfold when spontaneously embedding into an artificial lipid bilayer that mimics microbial membrane. PMID- 27480746 TI - Effect of infusion tests on the dynamical properties of intracranial pressure in hydrocephalus. AB - BACKGROUND AND OBJECTIVE: Hydrocephalus comprises a number of conditions characterised by clinical symptoms, dilated ventricles and anomalous cerebrospinal fluid (CSF) dynamics. Infusion tests (ITs) are usually performed to study CSF circulation and in the preoperatory evaluation of patients with hydrocephalus. The study of intracranial pressure (ICP) signals recorded during ITs could be useful to gain insight into the underlying pathophysiology of this condition and to further support treatment decisions. In this study, two wavelet parameters, wavelet turbulence (WT) and wavelet entropy (WE), were analysed in order to characterise the variability, irregularity and similarity in spectral content of ICP signals in hydrocephalus. METHODS: One hundred and twelve ICP signals were analysed using WT and WE. These parameters were calculated in two frequency bands: B1 (0.15-0.3 Hz) and B2 (0.67-2.5 Hz). Each signal was divided into four artefact-free epochs corresponding to the basal, early infusion, plateau and recovery phases of the IT. We calculated the mean and standard deviation of WT and WE and analysed whether these parameters revealed differences between epochs of the IT. RESULTS: Statistically significant differences (p < 1.70?10(-3), Bonferroni-corrected Wilcoxon signed-rank tests) in pairwise comparisons between phases of ITs were found using the mean and standard deviation of WT and WE. These differences were mainly found in B2. CONCLUSIONS: Wavelet parameters like WT and WE revealed changes in the signal time-scale representation during ITs. Statistically significant differences were mainly found in B2, associated with ICP pulse waves, and included a higher degree of similarity in the spectral content, together with a lower irregularity and variability in the plateau phase with respect to the basal phase. PMID- 27480747 TI - Five multiresolution-based calcium volume measurement techniques from coronary IVUS videos: A comparative approach. AB - BACKGROUND AND OBJECTIVE: Fast intravascular ultrasound (IVUS) video processing is required for calcium volume computation during the planning phase of percutaneous coronary interventional (PCI) procedures. Nonlinear multiresolution techniques are generally applied to improve the processing time by down-sampling the video frames. METHODS: This paper presents four different segmentation methods for calcium volume measurement, namely Threshold-based, Fuzzy c-Means (FCM), K-means, and Hidden Markov Random Field (HMRF) embedded with five different kinds of multiresolution techniques (bilinear, bicubic, wavelet, Lanczos, and Gaussian pyramid). This leads to 20 different kinds of combinations. IVUS image data sets consisting of 38,760 IVUS frames taken from 19 patients were collected using 40 MHz IVUS catheter (Atlantis(r) SR Pro, Boston Scientific(r), pullback speed of 0.5 mm/sec.). The performance of these 20 systems is compared with and without multiresolution using the following metrics: (a) computational time; (b) calcium volume; (c) image quality degradation ratio; and (d) quality assessment ratio. RESULTS: Among the four segmentation methods embedded with five kinds of multiresolution techniques, FCM segmentation combined with wavelet-based multiresolution gave the best performance. FCM and wavelet experienced the highest percentage mean improvement in computational time of 77.15% and 74.07%, respectively. Wavelet interpolation experiences the highest mean precision-of merit (PoM) of 94.06 +/- 3.64% and 81.34 +/- 16.29% as compared to other multiresolution techniques for volume level and frame level respectively. Wavelet multiresolution technique also experiences the highest Jaccard Index and Dice Similarity of 0.7 and 0.8, respectively. Multiresolution is a nonlinear operation which introduces bias and thus degrades the image. The proposed system also provides a bias correction approach to enrich the system, giving a better mean calcium volume similarity for all the multiresolution-based segmentation methods. After including the bias correction, bicubic interpolation gives the largest increase in mean calcium volume similarity of 4.13% compared to the rest of the multiresolution techniques. The system is automated and can be adapted in clinical settings. CONCLUSIONS: We demonstrated the time improvement in calcium volume computation without compromising the quality of IVUS image. Among the 20 different combinations of multiresolution with calcium volume segmentation methods, the FCM embedded with wavelet-based multiresolution gave the best performance. PMID- 27480748 TI - An immune-inspired semi-supervised algorithm for breast cancer diagnosis. AB - Breast cancer is the most frequently and world widely diagnosed life-threatening cancer, which is the leading cause of cancer death among women. Early accurate diagnosis can be a big plus in treating breast cancer. Researchers have approached this problem using various data mining and machine learning techniques such as support vector machine, artificial neural network, etc. The computer immunology is also an intelligent method inspired by biological immune system, which has been successfully applied in pattern recognition, combination optimization, machine learning, etc. However, most of these diagnosis methods belong to a supervised diagnosis method. It is very expensive to obtain labeled data in biology and medicine. In this paper, we seamlessly integrate the state-of the-art research on life science with artificial intelligence, and propose a semi supervised learning algorithm to reduce the need for labeled data. We use two well-known benchmark breast cancer datasets in our study, which are acquired from the UCI machine learning repository. Extensive experiments are conducted and evaluated on those two datasets. Our experimental results demonstrate the effectiveness and efficiency of our proposed algorithm, which proves that our algorithm is a promising automatic diagnosis method for breast cancer. PMID- 27480750 TI - Editorial. PMID- 27480749 TI - A methodology based on openEHR archetypes and software agents for developing e health applications reusing legacy systems. AB - BACKGROUND AND OBJECTIVE: In Pervasive Healthcare, novel information and communication technologies are applied to support the provision of health services anywhere, at anytime and to anyone. Since health systems may offer their health records in different electronic formats, the openEHR Foundation prescribes the use of archetypes for describing clinical knowledge in order to achieve semantic interoperability between these systems. Software agents have been applied to simulate human skills in some healthcare procedures. This paper presents a methodology, based on the use of openEHR archetypes and agent technology, which aims to overcome the weaknesses typically found in legacy healthcare systems, thereby adding value to the systems. METHODS: This methodology was applied in the design of an agent-based system, which was used in a realistic healthcare scenario in which a medical staff meeting to prepare a cardiac surgery has been supported. We conducted experiments with this system in a distributed environment composed by three cardiology clinics and a center of cardiac surgery, all located in the city of Marilia (Sao Paulo, Brazil). We evaluated this system according to the Technology Acceptance Model. RESULTS: The case study confirmed the acceptance of our agent-based system by healthcare professionals and patients, who reacted positively with respect to the usefulness of this system in particular, and with respect to task delegation to software agents in general. The case study also showed that a software agent-based interface and a tools-based alternative must be provided to the end users, which should allow them to perform the tasks themselves or to delegate these tasks to other people. CONCLUSIONS: A Pervasive Healthcare model requires efficient and secure information exchange between healthcare providers. The proposed methodology allows designers to build communication systems for the message exchange among heterogeneous healthcare systems, and to shift from systems that rely on informal communication of actors to a more automated and less error-prone agent-based system. Our methodology preserves significant investment of many years in the legacy systems and allows developers to extend them adding new features to these systems, by providing proactive assistance to the end-users and increasing the user mobility with an appropriate support. PMID- 27480751 TI - The Mental Health Impact of Physical Appearance Concerns in the Context of Other Life Domains Among Australian Gay Men. AB - Previous studies have identified gay men as a high-risk population for body image disturbances. However, little research has examined the mental health impact of gay men's physical appearance concerns in the context of other major life domains. The present study addressed this gap by investigating how mental health outcomes (satisfaction with life, self-esteem, positive well-being, and psychological distress) were associated with satisfaction with and importance of physical appearance, work, family relationships, friendships, health and fitness, and sex life among Australian gay men aged 18-39. The possible moderating role of intimate relationship status was also examined. Results from an online survey revealed that greater satisfaction with physical appearance, work, family, and friendships all had similar positive associations with mental health. However, more importance placed on physical appearance was more consistently associated with poorer mental health compared with the subjective importance of other domains. Findings also indicated the associations between physical appearance satisfaction and life satisfaction, and between physical appearance importance and positive well-being, were weaker for those in relationships. Thus, physical appearance matters in gay men's lives, but was only one factor when considered in the broader context of other life areas that contributed to overall well-being. These findings suggest the need for a nuanced and contextualized understanding of how physical appearance concerns fit into gay men's lives. PMID- 27480752 TI - Accepting Sexual Interest in Children as Unchangeable: One Claim Fits for All? Comments on Grundmann, Krupp, Scherner, Amelung, and Beier's (2016) "Stability of Self-Reported Arousal to Sexual Fantasies Involving Children in a Clinical Sample of Pedophiles and Hebephiles". PMID- 27480753 TI - Sexual Inactivity During Young Adulthood Is More Common Among U.S. Millennials and iGen: Age, Period, and Cohort Effects on Having No Sexual Partners After Age 18. AB - Examining age, time period, and cohort/generational changes in sexual experience is key to better understanding sociocultural influences on sexuality and relationships. Americans born in the 1980s and 1990s (commonly known as Millennials and iGen) were more likely to report having no sexual partners as adults compared to GenX'ers born in the 1960s and 1970s in the General Social Survey, a nationally representative sample of American adults (N = 26,707). Among those aged 20-24, more than twice as many Millennials born in the 1990s (15 %) had no sexual partners since age 18 compared to GenX'ers born in the 1960s (6 %). Higher rates of sexual inactivity among Millennials and iGen also appeared in analyses using a generalized hierarchical linear modeling technique known as age period-cohort analysis to control for age and time period effects among adults of all ages. Americans born early in the 20th century also showed elevated rates of adult sexual inactivity. The shift toward higher rates of sexual inactivity among Millennials and iGen'ers was more pronounced among women and absent among Black Americans and those with a college education. Contrary to popular media conceptions of a "hookup generation" more likely to engage in frequent casual sex, a higher percentage of Americans in recent cohorts, particularly Millennials and iGen'ers born in the 1990s, had no sexual partners after age 18. PMID- 27480754 TI - A surface-grafted thermoresponsive hydrogel in which the surface structure dominates the bulk properties. AB - A surface-grafted hydrogel was successfully synthesized by immobilization of the ATRP initiator at the surface region of the gel and the subsequent ARGET ATRP step. This is the first example of a bulk hydrogel with a dense surface-localized layer of a grafted polymer and "active" permeation control of the gel. PMID- 27480756 TI - Erratum to: Project ACHIEVE - using implementation research to guide the evaluation of transitional care effectiveness. PMID- 27480755 TI - Liver dysfunction as predictor of prognosis in patients with amyloidosis: utility of the Model for End-stage Liver disease (MELD) scoring system. AB - Amyloidosis prognosis is often related to the onset of heart failure and a worsening that is concomitant with kidney-liver dysfunction; thus the Model for End-stage Liver disease (MELD) may be an ideal instrument to summarize renal liver function. Our aim has been to test the MELD score as a prognostic tool in amyloidosis. We evaluated 128 patients, 46 with TTR-related amyloidosis and 82 with AL amyloidosis. All patients had a complete clinical and echocardiography evaluation; overall biohumoral assessment included troponin I, NT-proBNP, creatinine, total bilirubin and INR ratio. The study population was dichotomized at the 12 cut-off level of MELD scores; those with MELD score >12 had a lower survival compared to controls in the study cohort (40.7 vs 66.3 %; p = 0.006). Either as a continuous and dichotomized variable, MELD shows its independent prognostic value at multivariable analysis (HR = 1.199, 95 % CI 1.082-1.329; HR = 2.707, 95 % CI 1.075-6.817, respectively). MELD shows a lower prognostic sensitivity/specificity ratio than troponin I and NT-proBNP in the whole study population and AL subgroup, while in TTR patients MELD has a higher sensitivity/specificity ratio compared to troponin and NT-proBNP (ROC analysis AUC: 0.853 vs 0.726 vs 0.659). MELD is able to predict prognosis in amyloidosis. A MELD score >12 selects a subgroup of patients with a higher risk of death. The predictive accuracy seems to be more evident in TTR patients in whom currently no effective scoring systems have been validated. PMID- 27480758 TI - Child and adolescent psychiatry in ICD-11: an opportunity to overcome mistakes made in DSM-5? PMID- 27480757 TI - Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial PROSPECT: a pilot trial. AB - BACKGROUND: Probiotics are live microorganisms that may confer health benefits when ingested. Randomized trials suggest that probiotics significantly decrease the incidence of ventilator-associated pneumonia (VAP) and the overall incidence of infection in critically ill patients. However, these studies are small, largely single-center, and at risk of bias. The aim of the PROSPECT pilot trial was to determine the feasibility of conducting a larger trial of probiotics to prevent VAP in mechanically ventilated patients in the intensive care unit (ICU). METHODS: In a randomized blinded trial, patients expected to be mechanically ventilated for >=72 hours were allocated to receive either 1 * 10(10) colony forming units of Lactobacillus rhamnosus GG or placebo, twice daily. Patients were excluded if they were at increased risk of L. rhamnosus GG infection or had contraindications to enteral medication. Feasibility objectives were: (1) timely recruitment; (2) maximal protocol adherence; (3) minimal contamination; and (4) estimated VAP rate >=10 %. We also measured other infections, diarrhea, ICU and hospital length of stay, and mortality. RESULTS: Overall, in 14 centers in Canada and the USA, all feasibility goals were met: (1) 150 patients were randomized in 1 year; (2) protocol adherence was 97 %; (3) no patients received open-label probiotics; and (4) the VAP rate was 19 %. Other infections included: bloodstream infection (19.3 %), urinary tract infections (12.7 %), and skin and soft tissue infections (4.0 %). Diarrhea, defined as Bristol type 6 or 7 stools, occurred in 133 (88.7 %) of patients, the median length of stay in ICU was 12 days (quartile 1 to quartile 3, 7-18 days), and in hospital was 26 days (quartile 1 to quartile 3, 14-44 days); 23 patients (15.3 %) died in the ICU. CONCLUSIONS: The PROSPECT pilot trial supports the feasibility of a larger trial to investigate the effect of L. rhamnosus GG on VAP and other nosocomial infections in critically ill patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01782755 . Registered on 29 January 2013. PMID- 27480759 TI - 123I-FP-CIT SPECT findings and its clinical relevance in prodromal dementia with Lewy bodies. AB - PURPOSE: Evidence for the prodromal stage of dementia with Lewy bodies (DLB) is very limited. To address this issue, we investigate the 123I-FP-CIT SPECT measure of dopamine transporter binding finding and its clinical relevance. METHODS: We enrolled subjects into a prodromal DLB group (PRD-DLB) (n = 20) and clinical DLB group (CLIN-DLB) (n = 18) and compared these groups with an Alzheimer's disease control group (AD) (n = 10). PRD-DLB was defined as patients having the non-motor symptoms associated with Lewy body disease (LBD) [i.e. REM sleep behavior disorder (RBD), olfactory dysfunction, autonomic dysfunction, and depression] and showing characteristic diffuse occipital hypometabolism in 18F-FDG PET. CLIN-DLB was defined as patients fulfilling the established criteria of probable DLB. Striatal specific binding ratio (SBR) of 123I-FP-CIT SPECT was used for objective group comparisons. The correlations between SBR and cognitive function (MMSE), motor symptoms (UPDRS3), and duration of LBD-associated non-motor symptoms were compared between the two DLB groups. RESULTS: Mean SBR scores of both PRD-DLB and CLIN-DLB were significantly lower than those of AD. No correlation was found between SBR and MMSE scores. Both in the CLIN-DLB and total DLB groups, SBR scores were negatively correlated with UPDRS3 scores, whereas no correlation was found in PRD-DLB. Among the LBD-related non-motor symptoms, duration of olfactory dysfunction, and RBD demonstrated negative correlation with SBR scores in PRD DLB. CONCLUSION: 123I-FP-CIT SPECT may play a role for detecting DLB among the subjects in prodromal stage. During this stage, long-term olfactory dysfunction and/or RBD may indicate more severe degeneration of the nigro-striatal dopaminergic pathway. PMID- 27480760 TI - Forensic Entomology in Animal Cruelty Cases. AB - Forensic entomology can be useful to the veterinary professional in cases of animal cruelty. A main application of forensic entomology is to determine the minimum postmortem interval by estimating the time of insect colonization, based on knowledge of the rate of development of pioneer colonizers and on insect species succession during decomposition of animal remains. Since insect development is temperature dependent, these estimates require documentation of the environmental conditions, including ambient temperature. It can also aid in the detection and recognition of wounds, as well as estimate the timing of periods of neglect. Knowledge of the geographic distribution of insects that colonize animal remains may suggest that there has been movement or concealment of the carcass or can create associations between a suspect, a victim, and a crime scene. In some instances, it can aid in the detection of drugs or toxins within decomposed or skeletonized remains. During animal cruelty investigations, it may become the responsibility of the veterinary professional to document and collect entomological evidence from live animals or during the necropsy. The applications of forensic entomology are discussed. A protocol is described for documenting and collecting entomological evidence at the scene and during the necropsy, with additional emphasis on recording geographic location, meteorological data, and collection and preservation of insect specimens. PMID- 27480761 TI - Diagnosis of Dermatophytosis Using Molecular Biology. AB - Identification of fungi in dermatological samples using PCR is reliable and provides significantly improved results in comparison with cultures. It is possible to identify the infectious agent when negative results are obtained from cultures. In addition, identification of the infectious agent can be obtained in 1 day. Conventional and real-time PCR methods used for direct fungus identification in collected samples vary by DNA extraction methods, targeted DNA and primers, and the way of analysing the PCR products. The choice of a unique method in a laboratory is complicated because the results expected from skin and hair sample analysis are different from those expected in cases of onychomycosis. In skin and hair samples, one dermatophyte among about a dozen possible species has to be identified. In onychomycosis, the infectious agents are mainly Trichophyton rubrum and, to a lesser extent, Trichophyton interdigitale, but also moulds insensitive to oral treatments used for dermatophytes, which renders fungal identification mandatory. The benefits obtained with the use of PCR methods for routine analysis of dermatological samples have to be put in balance with the relative importance of getting a result in a short time, the price of molecular biology reagents and equipment, and especially the time spent conducting laboratory manipulations. PMID- 27480762 TI - Practical Cooling Strategies During Continuous Exercise in Hot Environments: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Performing exercise in thermally stressful environments impairs exercise capacity and performance. Cooling during exercise has the potential to attenuate detrimental increases in body temperature and improve exercise capacity and performance. OBJECTIVE: The objective of this review was to assess the effectiveness of practical cooling strategies applied during continuous exercise in hot environments on body temperature, heart rate, whole body sweat production, rating of perceived exertion (RPE), thermal perception and exercise performance. METHODS: Electronic database searches of MEDLINE, SPORTDiscus, Scopus and Physiotherapy Evidence Database (PEDro) were conducted using medical subject headings, indexing terms and keywords. Studies were eligible if participants were defined as 'healthy', the exercise task was conducted in an environment >=25 degrees C, it used a cooling strategy that would be practical for athletes to use during competition, cooling was applied during a self-paced or fixed-intensity trial, participants exercised continuously, and the study was a randomised controlled trial with the comparator either a thermoneutral equivalent or no cooling. Data for experimental and comparator groups were meta-analysed and expressed as a standardised mean difference and 95 % confidence interval. RESULTS: Fourteen studies including 135 participants met the eligibility criteria. Confidence intervals for meta-analysed data included beneficial and detrimental effects for cooling during exercise on core temperature, mean skin temperature, heart rate and sweat production during fixed-intensity exercise. Cooling benefited RPE and thermal perception during fixed-intensity exercise and improved self-paced exercise performance. CONCLUSION: Cooling during fixed intensity exercise, particularly before a self-paced exercise trial, improves endurance performance in hot environments by benefiting RPE and thermal perception, but does not appear to attenuate increases in body temperature. PMID- 27480763 TI - How to Prevent Injuries in Alpine Ski Racing: What Do We Know and Where Do We Go from Here? AB - Alpine ski racing is known to be a sport with a high risk of injury and a high proportion of time-loss injuries. In recent years, substantial research efforts with regard to injury epidemiology, injury etiology, potential prevention measures, and measures' evaluation have been undertaken. Therefore, the aims of this review of the literature were (i) to provide a comprehensive overview of what is known about the aforementioned four steps of injury prevention research in the context of alpine ski racing; and (ii) to derive potential perspectives for future research. In total, 38 injury risk factors were previously reported in literature; however, a direct relation to injury risk was proven for only five factors: insufficient core strength/core strength imbalance, sex (depending on type of injury), high skill level, unfavorable genetic predisposition, and the combination of highly shaped, short and wide skis. Moreover, only one prevention measure (i.e. the combination of less-shaped and longer skis with reduced profile width) has demonstrated a positive impact on injury risk. Thus, current knowledge deficits are mainly related to verifying the evidence of widely discussed injury risk factors and assessing the effectiveness of reasonable prevention ideas. Nevertheless, the existing knowledge should be proactively communicated and systematically implemented by sport federations and sport practitioners. PMID- 27480764 TI - High- and Low-Load Resistance Training: Interpretation and Practical Application of Current Research Findings. AB - Our current state of knowledge regarding the load (lighter or heavier) lifted in resistance training programmes that will result in 'optimal' strength and hypertrophic adaptations is unclear. Despite this, position stands and recommendations are made based on, we propose, limited evidence to lift heavier weights. Here we discuss the state of evidence on the impact of load and how it, as a single variable, stimulates adaptations to take place and whether evidence for recommending heavier loads is available, well-defined, currently correctly interpreted or has been overlooked. Areas of discussion include electromyography amplitude, in vivo and in vitro methods of measuring hypertrophy, and motor schema and skill acquisition. The present piece clarifies to trainers and trainees the impact of these variables by discussing interpretation of synchronous and sequential motor unit recruitment and revisiting the size principle, poor agreement between whole-muscle cross-sectional area (CSA) and biopsy-determined changes in myofibril CSA, and neural adaptations around task specificity. Our opinion is that the practical implications of being able to self select external load include reducing the need for specific facility memberships, motivating older persons or those who might be less confident using heavy loads, and allowing people to undertake home- or field-based resistance training intervention strategies that might ultimately improve exercise adherence. PMID- 27480769 TI - Differences in growth rates and pre-hibernation body mass gain between early and late-born juvenile garden dormice. AB - Juvenile hibernators have to allocate energy to both growth and fattening, to survive winter, and to avoid possible disadvantages during their first reproductive season. Being born late in the active season may have important effects on growth and fattening. This study aimed at determining potential differences in rates and maximal level of growth, and in pre-hibernation body fat mass between early and late-born juvenile garden dormice (Eliomys quercinus), and kept in outdoor enclosures with ad libitum food and water. We first assessed mean pup mass in early and late-born litters (n = 31) from birth to their early weaning phase, at which time body composition was determined. Then, growth and body mass of early and late-born individuals (six males and six females, for each group) were measured weekly until hibernation onset (n = 24). We also assessed fat content in a group of juveniles during pre-hibernation fattening (n = 16) and after their first winter hibernation (n = 18). During the pre-weaning phase, young from early and late litters mainly grew structurally and gained mass at similar rates. After weaning, late-born juveniles grew and gained mass twice as fast as early born individuals. Body mass was positively associated with fat content during pre-hibernation fattening. Late-born females reached similar structural sizes, but had lower pre-hibernation fat reserves than early born females. Conversely, late-born males showed lower maximal size and pre hibernation body fat content, compared with early born males. Thus, individuals born late in the season cannot fully compensate the lack of available time before the winter onset. PMID- 27480771 TI - Erratum to: Three-dimensional probability maps of the rhinal and the collateral sulci in the human brain. PMID- 27480770 TI - Oculomotor Impairments in Developmental Dyspraxia. AB - Children with developmental dyspraxia (DD) express impairments in the acquisition of various motor skills and in the development of their social cognition abilities. Although the neural bases of this condition are not fully understood, they are thought to involve frontal cortical areas, subcortical structures, and the cerebellum. Although cerebellar dysfunction is typically difficult to assess and quantify using traditional neurophysiological methods, oculomotor analysis may provide insight into specific cerebellar patterns. The aim of the present study was to investigate, in dyspraxic and typically developing subjects, various oculomotor saccade tasks specifically designed to reveal frontal and cerebellar dysfunction. In addition to evidence supporting prefrontal dysfunction, our results revealed increased variability of saccade accuracy consistent with cerebellar impairments. Furthermore, we found that dyspraxic patients showed decreased velocities of non-visually guided saccades. A closer analysis revealed significant differences in saccade velocity profiles with slightly decreased maximum saccade velocities but markedly prolonged deceleration phases. We show that this pattern was not related to a decreased state of alertness but was suggestive of cerebellar dysfunction. However, the clear predominance of this pattern in non-visually guided saccades warrants alternative hypotheses. In light of previous experimental and anatomical studies, we propose that this unusual pattern may be a consequence of impaired connections between frontal areas and cerebellar oculomotor structures. PMID- 27480774 TI - Macrophage Polarization: Implications on Metabolic Diseases and the Role of Exercise. AB - Macrophages are cells of the innate immune response that trigger inflammation resolution. The phenotype of "classically activated macrophages" (M1) has anti tumoricidal and anti-bactericidal activities. On the other hand, "alternatively activated macrophages" (M2) are involved in tissue remodeling and immunomodulatory functions. The change in the polarization of macrophages varies according to the diversity of cytokines present in the microenvironment or by the stimuli of an antigen. It involves such factors as interferon-regulatory factors, peroxisome proliferator-activated receptors (PPARs), hypoxia-inducible factors (HIFs), and signal transducers and activators of transcription (STATs). Switching the phenotype of macrophages can help attenuate the development of an inflammatory disease. Exercise can promote alterations in the number of innate immune cells and stimulates phagocytic function. Chronic exercise seems to inhibit macrophage infiltration into adipose tissue by attenuating the expression of F4/80 mRNA. Furthermore, exercise may also increase the expression of M2 markers and reduce TNF-alpha and TLR4 mRNA expression, which activates the inflammatory pathway of NF-kappaB. Chronic exercise reduces beta2-adrenergic receptors in monocytes and macrophages by modulating TLR4 signaling as well as suppressing IL-12 production, a stimulator of interferon Y. In this review, we discuss macrophage polarization in metabolic diseases and how exercise can modulate macrophage plasticity. PMID- 27480772 TI - The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing. AB - Therapeutic angiogenesis is a major goal of regenerative medicine, but no clinically approved small molecule exists that enhances new blood vessel formation. Here we show, using a phenotype-driven high-content imaging screen of an annotated chemical library of 1,280 bioactive small molecules, that the retinoid agonist Tazarotene, enhances in vitro angiogenesis, promoting branching morphogenesis, and tubule remodeling. The proangiogenic phenotype is mediated by retinoic acid receptor but not retinoic X receptor activation, and is characterized by secretion of the proangiogenic factors hepatocyte growth factor, vascular endothelial growth factor, plasminogen activator, urokinase and placental growth factor, and reduced secretion of the antiangiogenic factor pentraxin-3 from adjacent fibroblasts. In vivo, Tazarotene enhanced the growth of mature and functional microvessels in Matrigel implants and wound healing models, and increased blood flow. Notably, in ear punch wound healing model, Tazarotene promoted tissue repair characterized by rapid ear punch closure with normal appearing skin containing new hair follicles, and maturing collagen fibers. Our study suggests that Tazarotene, an FDA-approved small molecule, could be potentially exploited for therapeutic applications in neovascularization and wound healing. PMID- 27480775 TI - Ethical Dilemmas for Oocyte Donations: Slippery Slope for Conflicts of Interest. AB - Oocyte donations have increased with improvements in oocyte cryopreservation procedures in recent years. Women with medical conditions that require chemotherapy or radiotherapy have begun to opt for oocyte cryo!preservation prior to their treatment or to enroll in an oocyte donation program. Alternatively, some women apply for "third-party" oocyte donation programs for nonmedical reasons such as delayed childbearing. Although society seems to accept oocyte donations for medical reasons, it appears that there are still some moral issues surrounding nonmedical oocyte donations. In this review, the ethical aspects of oocyte donations and donors' perspectives are discussed. With developing technologies, the genetic screening of donors has expanded to include diseases. This review explores the ethical issues involved in genetic screening of gamete donors. PMID- 27480776 TI - The Impacts of miRNAs in Glioblastoma Progression. AB - miRNAs are short noncoding RNA sequences that cause translational repression or mRNA degradation. A growing number of studies have sought new biomarkers in GBM that will be important in disease progression and prognosis and as potential therapeutic targets. miRNA-profiling studies in glioblastoma patients have found that aberrant miRNA expression can be used as a target to develop new biomarkers for disease detection and for determining prognosis or therapeutic response. In evaluating the tumor or its therapeutic response, genetic abnormalities such as mutations, epigenetic abnormalities, and aberrant miRNA expressions can be useful markers. This review summarizes the known miRNAs according their therapeutic importance and their use as disease progression biomarkers. PMID- 27480773 TI - Clinical Genomics: Challenges and Opportunities. AB - Next-generation sequencing (NGS) approaches are highly applicable to clinical studies. We review recent advances in sequencing technologies, as well as their benefits and tradeoffs, to provide an overview of clinical genomics from study design to computational analysis. Sequencing technologies enable genomic, transcriptomic, and epigenomic evaluations. Studies that use a combination of whole genome, exome, mRNA, and bisulfite sequencing are now feasible due to decreasing sequencing costs. Single-molecule sequencing increases read length, with the MinIONTM nanopore sequencer, which offers a uniquely portable option at a lower cost. Many of the published comparisons we review here address the challenges associated with different sequencing methods. Overall, NGS techniques, coupled with continually improving analysis algorithms, are useful for clinical studies in many realms, including cancer, chronic illness, and neurobiology. We, and others in the field, anticipate the clinical use of NGS approaches will continue to grow, especially as we shift into an era of precision medicine. PMID- 27480777 TI - Recent Investigations for Discovery of Natural Antioxidants: A Comprehensive Review. AB - In the biological system, reactive oxygen species (ROS) play a crucial role in the defense mechanisms of the body. ROS is responsible for the initiation of several cellular responses that can impart the harmful effects on the body, initiating biomolecular damage. Therefore, it is essential to counteract the dangerous effects produced by ROS, which is only possible through the use of antioxidants. Researchers are evaluating medicinal plants to discover and investigate the new antioxidant sources. Using natural antioxidants, beneficial effects on human health can be achieved. In this article, we summarize the recent investigations of the sources of naturally occurring antioxidants. PMID- 27480779 TI - Events of Molecular Changes in Epithelial-Mesenchymal Transition. AB - EMT is the process by which epithelial cells, characterized by well-developed intercellular contacts, transdifferentiate into motile and invasive mesenchymal cells. This process is associated with the loss of transmembrane intercellular adhesion molecule E-cadherin and disruption of cell-cell junctions along with acquisition of migratory properties. EMT is integral in embryonic development, wound healing, and stem cell behavior; however, its aberrant activation by micro environmental alterations and abnormal stimuli can lead to cancer progression. Here, we review the different molecular changes associated with EMT that are responsible for downregulation of epithelial genes. Increased knowledge of the EMT process is essential for therapeutic targeting of cancer cells. PMID- 27480778 TI - Challenges Facing the Use of Endothelial Progenitor Cells in Stem Cell Therapies. AB - The paper summarizes the difficulties to study the rare population of endothelial progenitor cells in clinical trials, based on the experience of our group in many publications in this area. PMID- 27480780 TI - The Changes of Energy Interactions between Nucleus Function and Mitochondria Functions Causing Transmutation of Chronic Inflammation into Cancer Metabolism. AB - Interactions between nucleus and mitochondria functions induce the mechanism of maintenance stability of cellular internal energy according to the first law of thermodynamics in able-bodied cells and changes the mechanisms of maintenance stability of cellular internal energy creating a transition stationary state of ablebodied cells into quasi-stationary pathologic states of acute inflammation transiting then into chronic inflammation and then transmuting into cancer metabolism. The mechanisms' influences of intruding etiologic pathologic agents (microbe, virus, etc.) lead to these changes of energy interactions between nucleus and mitochondria functions causing general acute inflammation, then passing into local chronic inflammation, and reversing into cancer metabolism transmutation. Interactions between biochemical processes and biophysical processes of cellular capacitors' operations create a supplementary mechanism of maintenance stability of cellular internal energy in the norm and in pathology. Discussion of some scientific works eliminates doubts of the authors of these works. PMID- 27480781 TI - Jaw myogenesis in the monk parakeet: evidence of developmental reprogramming in the emergence of novel muscles in Psittaciformes (Aves). AB - Psittaciformes have apomorphies in the muscles of the jaw that include both the adductors m. ethmomandibularis (EM) and m. pseudomasseter (PM), which are responsible for the generation of strong bite forces. While the EM is present in all Psittaciformes, the PM can be absent or present, and even underdeveloped or well-developed. The aim of this study is to identify developmental reprogramming processes by comparing the myogenesis of the jaw of the monk parakeet Myiopsitta monachus with the information available about other species of Psittaciformes. Seventeen specimens including embryos at different developmental stages, and nestlings of different ages were studied through the analysis of serial histological sections. At embryonic stage 24 (S24) the muscle precursor was observed in the first pharyngeal arch. At S27 the muscle precursor was found to be divided into lateral, intermediate and medial portions. At S31 the independent development of the EM as a rostro-dorsal projection of the mm. pterygoidei could be observed. At S36 the individualization of all muscles was complete. Finally, the PM was detected two days after hatching as an aponeurotic dorsal projection of the m. adductor mandibulae externus superficialis, located lateral to the arcus jugalis. Our results suggest that in M. monachus the muscles EM and PM emerge as a result of a process of heterotipy, and variations in the degree of development of the PM are associated to a heterochronic process of post displacement, with M. monachus having an underdeveloped PM with respect to basal Psittaciformes. PMID- 27480782 TI - Successful bleeding control with recombinant porcine factor VIII in reduced loading doses in two patients with acquired haemophilia A and failure of bypassing agent therapy. PMID- 27480783 TI - [Percutaneus coronary interventions for ostial lesions]. AB - An ostial lesion is defined as a lesion near to the ostium (<=3 mm) and is characterized by a rigid fibrotic texture with pronounced sclerosis associated with a very high tendency to recoil. Under certain circumstances this may lead to a modest primary interventional result accompanied by a higher complication rate and in particular a higher rate of restenosis. Ostial lesions of the right coronary artery in particular represent a greater challenge for percutaneous interventions with a higher rate of restenosis despite the introduction of various new techniques. In contrast ostial stenosis of the left main trunk shows very good results after percutaneous interventions and implantation of drug eluting stents. The indications for percutaneous transluminal coronary angioplasty (PTCA) of an ostial lesion correspond to the indications for treatment of all other lesions. The article gives an overview of the experiences and recommendations with respect to the diagnostics and interventional therapy of ostial lesions. PMID- 27480784 TI - Exorcising Grice's ghost: an empirical approach to studying intentional communication in animals. AB - Language's intentional nature has been highlighted as a crucial feature distinguishing it from other communication systems. Specifically, language is often thought to depend on highly structured intentional action and mutual mindreading by a communicator and recipient. Whilst similar abilities in animals can shed light on the evolution of intentionality, they remain challenging to detect unambiguously. We revisit animal intentional communication and suggest that progress in identifying analogous capacities has been complicated by (i) the assumption that intentional (that is, voluntary) production of communicative acts requires mental-state attribution, and (ii) variation in approaches investigating communication across sensory modalities. To move forward, we argue that a framework fusing research across modalities and species is required. We structure intentional communication into a series of requirements, each of which can be operationalised, investigated empirically, and must be met for purposive, intentionally communicative acts to be demonstrated. Our unified approach helps elucidate the distribution of animal intentional communication and subsequently serves to clarify what is meant by attributions of intentional communication in animals and humans. PMID- 27480785 TI - Smart, Sustainable, and Ecofriendly Chemical Design of Fully Bio-Based Thermally Stable Thermosets Based on Benzoxazine Chemistry. AB - A smart synthetic chemical design incorporating furfurylamine, a natural renewable amine, into a partially bio-based coumarin-containing benzoxazine is presented. The versatility of the synthetic approach is shown to be flexible and robust enough to be successful under more ecofriendly reaction conditions by replacing toluene with ethanol as the reaction solvent and even under solventless conditions. The chemical structure of this coumarin-furfurylamine-containing benzoxazine is characterized by FTIR, (1) H NMR spectroscopy and two-dimensional (1) H-(1) H nuclear Overhauser effect spectroscopy (2D (1) H-(1) H NOESY). The thermal properties of the resin toward polymerization are characterized by differential scanning calorimetry (DSC) and the thermal stability of the resulting polymers by thermogravimetric analysis (TGA). The results reveal that the furanic moiety induces a co-operative activating effect, thus lowering the polymerization temperature and also contributes to a better thermal stability of the resulting polymers. These results, in addition to those of natural renewable benzoxazine resins reviewed herein, highlight the positive and beneficial implication of designing novel bio-based polybenzoxazine and possibly other thermosets with desirable and competitive properties. PMID- 27480786 TI - Ammonia Level and Mortality in Acute Liver Failure: A Single-Center Experience. AB - BACKGROUND Acute liver failure (ALF) is an emergent condition that requires intensive care and manifests in particular by significant elevation in serum ammonia level. Patients with ALF with concomitant renal failure experience a further rise in ammonia levels due to decreased kidney excretion. The aim of this study was to evaluate the relationship between elevated ammonia levels and mortality and to characterize the subgroup of ALF patients who develop acute kidney injury (AKI) and require renal replacement therapy. MATERIAL AND METHODS This was a retrospective study of 36 consecutive patients admitted to Johns Hopkins Hospital's intensive care units from December 2008 to May 2013 who presented with grade III and IV hepatic encephalopathy (HE). Patients who developed AKI and required hemodialysis (HD) were compared to those without AKI. Patients with chronic kidney disease were excluded. RESULTS Sixteen patients developed AKI and underwent HD (HD group). Median ammonia levels in the HD and non-HD groups were not significantly different (p=0.95). In the HD group, 4 patients underwent liver transplantation (LT) and 3 of them survived the hospitalization. Among the 12 HD patients who did not receive LT, 6 (50%) survived. Out of 20 non-HD patients, 3 were transplanted, all of whom survived the hospitalization. Among the 17 non-HD patients who did not receive LT, 14 (82%) survived. Admission ammonia level (>120 umol/L) was associated with higher mortality rate (OR=7.188 [95% CI 1.3326-38.952], p=0.026) in all patients. CONCLUSIONS Admission ammonia level is predictive of mortality in ALF patients with grade 3-4 HE. PMID- 27480788 TI - Efficacy of treatment with IL-1RA in Majeed syndrome. PMID- 27480787 TI - Implementation and Quality Control of Lung Cancer EGFR Genetic Testing by MALDI TOF Mass Spectrometry in Taiwan Clinical Practice. AB - Molecular diagnostics in cancer pharmacogenomics is indispensable for making targeted therapy decisions especially in lung cancer. For routine clinical practice, the flexible testing platform and implemented quality system are important for failure rate and turnaround time (TAT) reduction. We established and validated the multiplex EGFR testing by MALDI-TOF MS according to ISO15189 regulation and CLIA recommendation in Taiwan. Totally 8,147 cases from Aug-2011 to Jul-2015 were assayed and statistical characteristics were reported. The intra run precision of EGFR mutation frequency was CV 2.15% (L858R) and 2.77% (T790M); the inter-run precision was CV 3.50% (L858R) and 2.84% (T790M). Accuracy tests by consensus reference biomaterials showed 100% consistence with datasheet (public database). Both analytical sensitivity and specificity were 100% while taking Sanger sequencing as the gold-standard method for comparison. EGFR mutation frequency of peripheral blood mononuclear cell for reference range determination was 0.002 +/- 0.016% (95% CI: 0.000-0.036) (L858R) and 0.292 +/- 0.289% (95% CI: 0.000-0.871) (T790M). The average TAT was 4.5 working days and the failure rate was less than 0.1%. In conclusion, this study provides a comprehensive report of lung cancer EGFR mutation detection from platform establishment, method validation to clinical routine practice. It may be a reference model for molecular diagnostics in cancer pharmacogenomics. PMID- 27480789 TI - Prospective evaluation of Streptococcus pneumoniae serum antibodies in patients with primary immunodeficiency on regular intravenous immunoglobulin treatment. AB - BACKGROUND: This is a prospective study that assessed pneumococcal antibody levels in PID patients under intravenous immunoglobulin (IVIG) treatment using different brands. METHODS: Twenty-one patients receiving regular IVIG every 28 days were invited to participate: 12 with common variable immunodeficiency, six with X-linked agammaglobulinaemia and three with hyper-IgM syndrome. One blood sample was collected from each patient just prior to IVIG administration at a three-month time interval during one year. A questionnaire was filled in with patient's demographic data and history of infections during the study period. Streptococcus pneumoniae antibodies against six serotypes (1, 5, 6B, 9V, 14 and 19F) were assessed by ELISA both in patients' serum (trough levels) and in IVIG samples. RESULTS: Median total IgG trough serum levels were 7.91g/L (range, 4.59 12.20). All patients had antibody levels above 0.35MUg/mL to the six serotypes on all four measurements. However, only 28.6% of patients had pneumococcal antibodies for the six analysed serotypes above 1.3MUg/mL on all four evaluations during the one-year period. No correlation was found between IgG trough levels and pneumococcal specific antibodies. Eighteen of the 21 patients (85.7%) had infections at some point during the 12-month follow-up, 62/64 (96.9%) clinically classified in respiratory tract infections, four of which were pneumonia. CONCLUSIONS: Pneumococcal antibodies are present in a high range of concentrations in sera from PID patients and also in IVIG preparations. Even maintaining a recommended IgG trough level, these patients can be susceptible to these bacteria and that may contribute to recurrent respiratory infections. PMID- 27480790 TI - Matrix effect on baked milk tolerance in children with IgE cow milk allergy. AB - BACKGROUND: Children with IgE-mediated cow's milk allergy (IgE-CMA) often tolerate baked milk within a wheat matrix. In our study we evaluated the impact of wheat matrix and of little standardised cooking procedures on tolerance of baked milk. We also tested tolerance versus parmigiano reggiano (PR) and whey based partially hydrolysed formula (pHF). METHODS: Forty-eight children with IgE CMA were enrolled. They underwent prick-by-prick (PbP) and open oral food challenge (OFC) with baked cow's milk (CM), both within a wheat matrix (an Italian cake named ciambellone) and without (in a liquid form), with PR and with pHF. After a passed OFC, children continued to eat the food tolerated. In particular, after passed OFC with ciambellone, children were allowed to eat any food containing CM within a wheat matrix, with the only condition that it was baked at 180 degrees C for at least 30min. Three months after, parents were asked to answer a survey. RESULTS: 81% of children tolerated ciambellone, 56% liquid baked CM, 78% PR and 82% pHF. Negative predictive value of PbP performed with tested foods was 100%. No IgE-mediated adverse reactions were detected at follow up carried out by the survey. CONCLUSIONS: Wheat matrix effect on tolerance of baked milk was relevant in slightly less than half of cases. If our results are confirmed by larger studies, a negative PbP will allow patients to eat processed CM without undergoing OFC. Moreover, in order to guarantee tolerance towards baked milk, strict standardised cooking procedures do not seem to be necessary. PMID- 27480791 TI - The role of surfaces, chemical interfaces, and disorder on plutonium incorporation in pyrochlores. AB - Pyrochlores, a class of complex oxides with formula A2B2O7, are one of the candidates for nuclear waste encapsulation, due to the natural occurrence of actinide-bearing pyrochlore minerals and laboratory observations of high radiation tolerance. In this work, we use atomistic simulations to determine the role of surfaces, chemical interfaces, and cation disorder on the plutonium immobilization properties of pyrochlores as a function of pyrochlore chemistry. We find that both Pu(3+) and Pu(4+) segregate to the surface for the four low index pyrochlore surfaces considered, and that the segregation energy varies with the chemistry of the compound. We also find that pyrochlore/pyrochlore bicrystals A2B2O7/A2'B2'O7 can be used to immobilize Pu(3+) and Pu(4+) either in the same or separate phases of the compound, depending on the chemistry of the material. Finally, we find that Pu(4+) segregates to the disordered phase of an order/disorder bicrystal, driven by the occurrence of local oxygen-rich environments. However, Pu(3+) is weakly sensitive to the oxygen environment, and therefore only slightly favors the disordered phase. This behavior suggests that, at some concentration, Pu incorporation can destabilize the pyrochlore structure. Together, these results provide new insight into the ability of pyrochlore compounds to encapsulate Pu and suggest new considerations in the development of waste forms based on pyrochlores. In particular, the phase structure of a multi phase pyrochlore composite can be used to independently getter decay products based on their valence and size. PMID- 27480792 TI - Self-Compassion: Evaluation of a Psychoeducational Website - CORRIGENDUM. AB - Please note that the self-compassion Website (www.self-compassion.org) and the Mindfulness Self-Compassion program (MSC) offer some similar self-compassion and guided meditation exercises, but differ in structure and content. As currently described on www.CenterforMSC.org, MSC is an 8-week empirically-supported program targeting non-clinical populations. It is offered in a group format and is not led by therapists necessarily. MSC is not considered by the authors as a form of group therapy. As such, 'resource-building course' should have been used in the original paper in lieu of 'group therapy'. PMID- 27480793 TI - Which better predicts mortality among older men, a prostate cancer (PCa) diagnosis or vulnerability on the Vulnerable Elders Survey (VES-13)? A retrospective cohort study. AB - OBJECTIVES: Older men with a prostate cancer (PCa) diagnosis face competing mortality risks. Little is known about the prevalence of vulnerability and predictors of mortality in this population compared to men without a PCa diagnosis. We examined the predictive utility of the Vulnerable Elders Survey (VES-13) for mortality in older men with a PCa diagnosis as compared to controls. MATERIALS AND METHODS: Men aged >=65years from an urban geriatrics clinic completed the VES-13 between 2003 and 2008. Each patient with a PCa diagnosis was matched by age to five controls, resulting in 59 patients with a PCa diagnosis and 318 controls. Cox proportional hazard models were used to determine the association of a PCa diagnosis and vulnerability on the VES-13 with mortality. RESULTS AND CONCLUSIONS: The mean age for men with a PCa diagnosis and controls was 77.9years and 76.1years, respectively. Of those with a PCa diagnosis, 74.6% had no active disease or a rising PSA only. Regardless of PCa diagnosis, vulnerable individuals on the VES-13 were more likely to die during the study period (VES-13>=3: HR=4.46, p<0.01; VES13>=6: HR=3.77, p<0.01). Men with a PCa diagnosis were not more likely to die compared to age-matched controls (VES 13>=3: HR=1.14, p=0.59; VES13>=6: HR=1.06, p=0.83). Vulnerability for men with a PCa diagnosis was more predictive of mortality. Therefore, the assessment of vulnerability is important for establishing goals of care. PMID- 27480794 TI - Tunable resistive pulse sensing: potential applications in nanomedicine. AB - An accurate characterization of nanomaterials used in clinical diagnosis and therapeutics is of paramount importance to realize the full potential of nanotechnology in medicine and to avoid unexpected and potentially harmful toxic effects due to these materials. A number of technical modalities are currently in use to study the physical, chemical and biological properties of nanomaterials but they all have advantages and disadvantages. In this review, we discuss the potential of a relative newcomer, tunable resistive pulse sensing, for the characterization of nanomaterials and its applications in nanodiagnostics. PMID- 27480795 TI - Loss of GluN2D subunit results in social recognition deficit, social stress, 5 HT2C receptor dysfunction, and anhedonia in mice. AB - The N-methyl-d-aspartate (NMDA) receptor channel is involved in various physiological functions, including learning and memory. The GluN2D subunit of the NMDA receptor has low expression in the mature brain, and its role is not fully understood. In the present study, the effects of GluN2D subunit deficiency on emotional and cognitive function were investigated in GluN2D knockout (KO) mice. We found a reduction of motility (i.e., a depressive-like state) in the tail suspension test and a reduction of sucrose preference (i.e., an anhedonic state) in GluN2D KO mice that were group-housed with littermates. Despite apparently normal olfactory function and social interaction, GluN2D KO mice exhibited a decrease in preference for social novelty, suggesting a deficit in social recognition or memory. Golgi-Cox staining revealed a reduction of the complexity of dendritic trees in the accessory olfactory bulb in GluN2D KO mice, suggesting a deficit in pheromone processing pathway activation, which modulates social recognition. The deficit in social recognition may result in social stress in GluN2D KO mice. Isolation housing is a procedure that has been shown to reduce stress in mice. Interestingly, 3-week isolation and treatment with agomelatine or the 5-hydroxytryptamine-2C (5-HT2C) receptor antagonist SB242084 reversed the anhedonic-like state in GluN2D KO mice. In contrast, treatment with the 5-HT2C receptor agonist CP809101 induced depressive- and anhedonic-like states in isolated GluN2D KO mice. These results suggest that social stress that is caused by a deficit in social recognition desensitizes 5-HT2c receptors, followed by an anhedonic- and depressive-like state, in GluN2D KO mice. The GluN2D subunit of the NMDA receptor appears to be important for the recognition of individuals and development of normal emotionality in mice. 5-HT2C receptor antagonism may be a therapeutic target for treating social stress-induced anhedonia. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. PMID- 27480796 TI - Acute drug-induced spine changes in the nucleus accumbens are dependent on beta adducin. AB - Chronic modifications of dopamine transmission alter striatal dendritic spines. Here, we show that spine density and length are increased in the nucleus accumbens 24 h after a single injection of caffeine or quinpirole, a dopamine D2/D3 dopamine receptors agonist, whereas the dopamine antagonist haloperidol has opposite effects. These effects are absent in mice lacking beta-adducin, a protein that stabilizes actin/spectrin cortical cytoskeleton and modulates synaptic plasticity. Phosphorylation of adducin (Ser713 in beta-adducin), which disrupts actin/spectrin interaction, is increased by quinpirole, haloperidol, or caffeine. We previously demonstrated that DARPP-32 interacts with beta-adducin and facilitates its phosphorylation. Quinpirole increased DARPP-32 phosphorylation at Thr75 and haloperidol at Ser97, two modifications that can have similar consequences on adducin phosphorylation through distinct mechanisms. Experiments in DARPP-32 mutant mice confirmed that the apparently paradoxical similar effects of quinpirole and haloperidol on adducin phosphorylation may result from differential effects of these drugs on DARPP-32 phosphorylation at Thr75 and Ser97. Our data provide novel insights on how a single dose of widely used psychoactive drugs can affect spine plasticity in the nucleus accumbens, a component of the reward system. PMID- 27480798 TI - Graphene-Selenium Hybrid Microballs as Cathode Materials for High-performance Lithium-Selenium Secondary Battery Applications. AB - In this study, graphene-selenium hybrid microballs (G-SeHMs) are prepared in one step by aerosol microdroplet drying using a commercial spray dryer, which represents a simple, scalable continuous process, and the potential of the G SeHMs thus prepared is investigated for use as cathode material in applications of lithium-selenium secondary batteries. These morphologically unique graphene microballs filled with Se particles exhibited good electrochemical properties, such as high initial specific capacity (642 mA h g(-1) at 0.1 C, corresponding to Se electrochemical utilisation as high as 95.1%), good cycling stability (544 mA h g(-1) after 100 cycles at 0.1 C; 84.5% retention) and high rate capability (specific capacity of 301 mA h g(-1) at 5 C). These electrochemical properties are attributed to the fact that the G-SeHM structure acts as a confinement matrix for suppressing the dissolution of polyselenides in the organic electrolyte, as well as an electron conduction path for increasing the transport rate of electrons for electrochemical reactions. Notably, based on the weight of hybrid materials, electrochemical performance is considerably better than that of previously reported Se-based cathode materials, attributed to the high Se loading content (80 wt%) in hybrid materials. PMID- 27480797 TI - Transcriptional dysregulation causes altered modulation of inhibition by haloperidol. AB - Many neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism involve interneuron transcriptional dysregulation. The transcriptional coactivator PGC-1alpha regulates gene expression in GABAergic interneurons, which are important for regulating hippocampal network activity. Genetic deletion of PGC-1alpha causes a decrease in parvalbumin expression, similar to what is observed in schizophrenia postmortem tissue. Our lab has previously shown that PGC-1alpha-/- mice have enhanced GABAergic inhibition onto CA1 pyramidal cells, which increases the inhibition/excitation (I/E) ratio, alters hippocampal circuit function, and impairs hippocampal dependent behavior. The typical antipsychotic haloperidol, a dopamine receptor antagonist with selectivity for D2-like receptors, has previously been shown to increase excitation in the CA1 region of hippocampus. We therefore tested whether haloperidol could normalize the I/E balance in CA1 of PGC-1alpha-/- mice, potentially improving circuit function and behavior. Surprisingly, we discovered instead that interneuron transcriptional dysregulation caused by loss of PGC-1alpha alters the effects of haloperidol on hippocampal synaptic transmission and circuit function. Acute administration of haloperidol causes disinhibition in CA1 and decreases the I/E ratio onto CA1 pyramidal cells in slices from PGC-1alpha+/+ mice, but not PGC-1alpha-/- mice. The spread of activity in CA1, assessed by voltage sensitive dye imaging, is increased by haloperidol in slices from PGC-1alpha+/+ mice; however haloperidol decreases the spread of activity in slices from PGC-1alpha-/- mice. Haloperidol increased the power of hippocampal gamma oscillation in slices from PGC-1alpha+/+ mice but reduced the power of gamma oscillations in slices from PGC-1alpha-/- mice. Nest construction, an innate hippocampal-dependent behavior, is inhibited by haloperidol in PGC-1alpha+/+ mice, but not in PGC-1alpha-/- mice, which already have impaired nest building. The effects of haloperidol are mimicked and occluded by a D2 receptor antagonist in slices from PGC-1alpha+/+ mice, and the effects of blocking D2 receptors are lost in slices from PGC-1alpha-/- mice, although there is no change in D2 receptor transcript levels. Together, our results show that hippocampal inhibitory synaptic transmission, CA1 circuit function, and hippocampal dependent behavior are modulated by the antipsychotic haloperidol, and that these effects of haloperidol are lost in PGC-1alpha-/- mice. These results have implications for the treatment of individuals with conditions involving PGC-1alpha deficiency. PMID- 27480799 TI - Short-term outcomes after surgical resection for colorectal cancer in South Australia. AB - RATIONALE, AIMS AND OBJECTIVE: Short-term outcomes (unplanned readmission, post surgical complication rates, 30-day and 90-day post-surgical mortality) are often used as indicators of quality of surgical care for colorectal cancer (CRC). Differences in these immediate outcomes can highlight disparities in care across patient subpopulations. This study aimed to document short-term outcomes following major surgery for CRC and to identify whether there were any sociodemographic differences across South Australia (SA). METHODS: This population-based study included all CRC resections among SA residents diagnosed with CRC aged 50-79 years in 2003-2008 (n = 3940). Clinical, treatment, comorbidity and outcomes data were compiled through linkage of administrative and surveillance datasets across SA. A retrospective cohort design was used to examine short-term outcomes including post-operative complications, 28-day emergency readmission and 30-day and 90-day mortality. We used multivariable logistic regression to identify factors associated with each outcome. RESULTS: Post-operative complications occurred in 28% of cases. Thirty-day and ninety-day mortality were 1.3% and 3%, respectively. Later stage, older age, multiple comorbidities and emergency admissions were associated with poorer short-term outcomes. Risk of complications was lower among patients from higher socio economic areas (OR = 0.77, 95%CI 0.62-0.98). Risk of 30-day mortality was higher among non-metropolitan patients (OR = 2.33, 95%CI 1.22-4.46). Post-operative complications increased the risk of emergency readmission and short-term mortality. CONCLUSIONS: Short-term outcomes following CRC surgery may be improved through strategies to increase earlier detection and reduce emergency admissions. Socioeconomic and regional disparities require further examination of health system factors. PMID- 27480800 TI - In Vitro Assessment of Plants Growing in Cuba Belonging to Solanaceae Family Against Leishmania amazonensis. AB - In this study, an in vitro antileishmanial assessment of plant extracts from 12 genera and 46 species growing in Cuba belonging to Solanaceae family was performed. A total of 226 extracts were screened against promastigotes of Leishmania amazonensis, and cytotoxicity of active extracts [median inhibitory concentration (IC50 ) promastigotes <100 ug/mL] was determined on peritoneal macrophage from BALB/c mice. Extracts that showed selective index >5 were then assayed against intracellular amastigote. Metabolomics analysis of promissory extracts was performed using chemical profile obtained by ultra performance liquid chromatography. Only 11 extracts (4.9%) from nine plants were selected as potentially actives: Brunfelsia cestroides A. Rich, Capsicum annuum L., Capsicum chinense Jacq., Cestrum nocturnum L., Nicotiana plumbaginifolia Viv., Solanum havanense Jacq., Solanum myriacanthum Dunal, Solanum nudum Dunal and Solanum seaforthianum And., with IC50 < 50 ug/mL and selectivity index >5. Metabolomics analysis demonstrated significant differences in the chemical profiles with an average of 42.8 (range 31-88) compounds from m/z 104 to 1477, which demonstrated the complex mixture of compounds. In addition, no common markers among active extracts were identified. The results demonstrate the importance of the Solanaceae family to search new antileishmanial agents, particularly in unexplored species of this family. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27480801 TI - A critical analysis of melanoma malpractice litigation: Should we biopsy everything? AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate factors raised in malpractice litigation related to the diagnosis and management of melanoma and to further assess issues impacting outcome. STUDY DESIGN: Retrospective chart review. METHODS: The Westlaw legal database was searched for malpractice litigation resolved over the last 20 years relating to melanoma. Cases were evaluated for allegations, defendant specialty, outcome, and other issues raised. RESULTS: Of the 80 cases evaluated, 49% were resolved in the defendants' favor. In greater than 80% of cases, there was alleged misdiagnosis. In 35% of cases, the patient had expired secondary to melanoma at the time of litigation. There was no statistical difference in payments upon comparison of cases with and without mortality. A greater proportion of cases with dermatologists and pathologists as defendants involved alleged misdiagnosis. The most common locations for melanoma were the extremities and the head-and-neck region, at 32.5% and 22.5%, respectively. Location did not significantly impact the outcome of cases. CONCLUSION: Malpractice litigation relating to melanoma involves numerous physicians, including dermatologists, pathologists, and otolaryngologists. Alleged misdiagnosis of a pigmented lesion was the most common cause of litigation and involved physicians from numerous specialties. Patients who were misdiagnosed had a significantly higher likelihood of having active disease at the time of litigation. Ultimately improved methods of detecting concerning pigmented lesions need to be developed. Factors such as death and poor cosmetic outcome did not significantly impact litigation outcome. LEVEL OF EVIDENCE: NA Laryngoscope, 127:134-139, 2017. PMID- 27480802 TI - R- and S-terbutaline activate large conductance and Ca2+ dependent K+ (BKCa) channel through interacting with beta2 and M receptor respectively. AB - This study investigated the effect of the beta2 receptor agonist terbutaline on the single channel activity of BKCa channel. The effects of racemate and two isomers of terbutaline were all assessed. beta2 adrenoceptors were stably overexpressed on HEK293 cells by lentiviral transduction method and chicken BKCa channels were transiently expressed on normal HEK293 cell line or HEK293 cells overexpressing beta2 receptors. Data showed that terbutaline significantly increased the single channel open probability of BKCa channel within 10min. The channel activating effects of terbutaline are stereoselective and mainly stay with the R-enantiomers. The opening probability of BKCa channel at 10min after drug application normalized to that just before drug application (Po10/Po0s) for R- and S-terbutaline were 7.85+/-3.20 and 1.06+/-0.45 respectively at 1MUM concentration, corresponding to 28.37+/-9.96 and 2.68+/-1.09 at the higher concentration of 10MUM. ICI 118551 blocked the effect of R- but not S-terbutaline (10MUM), whereas atropine blocked the channel activating effects of S-terbutaline of higher concentration. In addition, the muscarinic receptor agonist carbachol increased the BKCa channel activity in an atropine-sensitive manner as an positive control experiment, which indicate the involvement of M receptor in the channel activating effect of S-terbutaline. PMID- 27480803 TI - Phospholipid dependent mechanism of smp24, an alpha-helical antimicrobial peptide from scorpion venom. AB - Determining the mechanism of action of antimicrobial peptides (AMPs) is critical if they are to be developed into the clinical setting. In recent years high resolution techniques such as atomic force microscopy (AFM) have increasingly been utilised to determine AMP mechanism of action on planar lipid bilayers and live bacteria. Here we present the biophysical characterisation of a prototypical AMP from the venom of the North African scorpion Scorpio maurus palmatus termed Smp24. Smp24 is an amphipathic helical peptide containing 24 residues with a charge of +3 and exhibits both antimicrobial and cytotoxic activity and we aim to elucidate the mechanism of action of this peptide on both membrane systems. Using AFM, quartz crystal microbalance-dissipation (QCM-D) and liposomal leakage assays the effect of Smp24 on prototypical synthetic prokaryotic (DOPG:DOPC) and eukaryotic (DOPE:DOPC) membranes has been determined. Our data points to a toroidal pore mechanism against the prokaryotic like membrane whilst the formation of hexagonal phase non-lamellar phase structures is seen in eukaryotic like membrane. Also, phase segregation is observed against the eukaryotic membrane and this study provides direct evidence of the same peptide having multiple mechanisms of action depending on the membrane lipid composition. PMID- 27480804 TI - Spectral phasor analysis of LAURDAN fluorescence in live A549 lung cells to study the hydration and time evolution of intracellular lamellar body-like structures. AB - Using LAURDAN spectral imaging and spectral phasor analysis we concurrently studied the growth and hydration state of subcellular organelles (lamellar body like, LB-like) from live A549 lung cancer cells at different post-confluence days. Our results reveal a time dependent two-step process governing the size and hydration of these intracellular LB-like structures. Specifically, a first step (days 1 to 7) is characterized by an increase in their size, followed by a second one (days 7 to 14) where the organelles display a decrease in their global hydration properties. Interestingly, our results also show that their hydration properties significantly differ from those observed in well-characterized artificial lamellar model membranes, challenging the notion that a pure lamellar membrane organization is present in these organelles at intracellular conditions. Finally, these LB-like structures show a significant increase in their hydration state upon secretion, suggesting a relevant role of entropy during this process. PMID- 27480805 TI - Phosphatidic acid binding proteins display differential binding as a function of membrane curvature stress and chemical properties. AB - Phosphatidic acid (PA) is a crucial membrane phospholipid involved in de novo lipid synthesis and numerous intracellular signaling cascades. The signaling function of PA is mediated by peripheral membrane proteins that specifically recognize PA. While numerous PA-binding proteins are known, much less is known about what drives specificity of PA-protein binding. Previously, we have described the ionization properties of PA, summarized in the electrostatic hydrogen bond switch, as one aspect that drives the specific binding of PA by PA binding proteins. Here we focus on membrane curvature stress induced by phosphatidylethanolamine and show that many PA-binding proteins display enhanced binding as a function of negative curvature stress. This result is corroborated by the observation that positive curvature stress, induced by lyso phosphatidylcholine, abolishes PA binding of target proteins. We show, for the first time, that a novel plant PA-binding protein, Arabidopsis Epsin-like Clathrin Adaptor 1 (ECA1) displays curvature-dependence in its binding to PA. Other established PA targets examined in this study include, the plant proteins TGD2, and PDK1, the yeast proteins Opi1 and Spo20, and, the mammalian protein Raf 1 kinase and the C2 domain of the mammalian phosphatidylserine binding protein Lact as control. Based on our observations, we propose that liposome binding assays are the preferred method to investigate lipid binding compared to the popular lipid overlay assays where membrane environment is lost. The use of complex lipid mixtures is important to elucidate further aspects of PA binding proteins. PMID- 27480806 TI - Nanoscale investigation of the interaction of colistin with model phospholipid membranes by Langmuir technique, and combined infrared and force spectroscopies. AB - Colistin (Polymyxin E), an antimicrobial peptide, is increasingly put forward as salvage for severe multidrug-resistant infections. Unfortunately, colistin is potentially toxic to mammalian cells. A better understanding of the interaction with specific components of the cell membranes may be helpful in controlling the factors that may enhance toxicity. Here, we report a physico-chemical study of model phospholipid (PL) mono- and bilayers exposed to colistin at different concentrations by Langmuir technique, atomic force microscopy (AFM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The effect of colistin on chosen PL monolayers was examined. Insights into the topographical and elastic changes in the PL bilayers within time after peptide injection are presented via AFM imaging and force spectra. Finally, changes in the PL bilayers' ATR-FTIR spectra as a function of time within three bilayer compositions, and the influence of colistin on their spectral fingerprint are examined together with the time-evolution of the Amide II and nuCO band integrated intensity ratios. Our study reveals a great importance in the role of the PL composition as well as the peptide concentration on the action of colistin on PL model membranes. PMID- 27480807 TI - Strain and rate-dependent neuronal injury in a 3D in vitro compression model of traumatic brain injury. AB - In the United States over 1.7 million cases of traumatic brain injury are reported yearly, but predictive correlation of cellular injury to impact tissue strain is still lacking, particularly for neuronal injury resulting from compression. Given the prevalence of compressive deformations in most blunt head trauma, this information is critically important for the development of future mitigation and diagnosis strategies. Using a 3D in vitro neuronal compression model, we investigated the role of impact strain and strain rate on neuronal lifetime, viability, and pathomorphology. We find that strain magnitude and rate have profound, yet distinctively different effects on the injury pathology. While strain magnitude affects the time of neuronal death, strain rate influences the pathomorphology and extent of population injury. Cellular injury is not initiated through localized deformation of the cytoskeleton but rather driven by excess strain on the entire cell. Furthermore we find that, mechanoporation, one of the key pathological trigger mechanisms in stretch and shear neuronal injuries, was not observed under compression. PMID- 27480809 TI - Clinical measurement of compensatory torsional eye movement during head tilt. AB - PURPOSE: To measure the degree of compensatory torsional eye movement during head tilt using a fundus photography method. METHODS: We enrolled 55 healthy subjects who were 20-66 years of age. Fundus photographs were obtained in the presumed baseline position and in stepwise head tilt positions to evaluate ocular torsion using a non-mydriatic fundus camera. Horizontal marks on the nose were photographed simultaneously to evaluate head tilt. Images were analysed using Photoshop to measure the degree of ocular torsion and head tilt. RESULTS: A consistent compensatory torsional eye movement was observed in all subjects during head tilt. The degree of compensatory torsional eye movement showed a positive correlation with the angle of head tilt. Ocular torsional disconjugacy was observed during head tilt, with larger excycloductional eye movement than incycloductional eye movement (4.88 +/- 2.91 degrees versus 4.50 +/- 2.76 degrees , p < 0.001). In multiple linear regression analysis, the degree of compensatory torsional eye movement was significantly associated with the degree of head tilt (beta = 0.191, p < 0.001), and the direction of cycloduction (beta = -0.548, p < 0.001). CONCLUSIONS: The fundus photography method is a non-invasive, accurate and objective tool for measuring compensatory torsional eye movement. Considering the availability of fundus photography in clinical ophthalmology practice, the proposed method can be used as a clinical tool to measure compensatory torsional eye movement. PMID- 27480808 TI - Are there specific readers of oxidized 5-methylcytosine bases? AB - 5-methylcytosine (5mC) was long thought to be the only enzymatically created modified DNA base in mammalian cells. The discovery of 5-hydroxymethylcytosine, 5 formylcytosine, and 5-carboxylcytosine as reaction products of the TET family 5mC oxidases has prompted extensive searches for proteins that specifically bind to these oxidized bases. However, only a few of such "reader" proteins have been identified and verified so far. In this review, we discuss potential biological functions of oxidized 5mC as well as the role the presumed reader proteins may play in interpreting the genomic signals of 5mC oxidation products. PMID- 27480810 TI - Diversification in vipers: Phylogenetic relationships, time of divergence and shifts in speciation rates. AB - Snakes of the cosmopolitan family Viperidae comprise around 329 venomous species showing a striking heterogeneity in species richness among lineages. While the subfamily Azemiopinae comprises only two species, 70% of all viper species are arranged in the subfamily Crotalinae or the "pit vipers". The radiation of the pit vipers was marked by the evolution of the heat-sensing pits, which has been suggested to be a key innovation for the successful diversification of the group. Additionally, only crotalines were able to successfully colonize the New World. Here, we present the most complete molecular phylogeny for the family to date that comprises sequences from nuclear and mitochondrial genes representing 79% of all living vipers. We also investigated the time of divergence between lineages, using six fossils to calibrate the tree, and explored the hypothesis that crotalines have undergone an explosive radiation. Our phylogenetic analyses retrieved high support values for the monophyly of the family Viperidae, subfamilies Viperinae and Crotalinae, and 22 out of 27 genera, as well as well supported intergeneric relationships throughout the family. We were able to recover a strongly supported sister clade to the New World pit vipers that comprises Gloydius, Ovophis, Protobothrops and Trimeresurus gracilis. Our results agree in many aspects with other studies focusing on the phylogenetics of vipers, but we recover new relationships as well. Despite the addition of new sequences we were not able to resolve some of the poor supported relationships previously suggested. Time of divergence estimates suggested that vipers started to radiate around the late Paleocene to middle Eocene with subfamilies most likely dating back to the Eocene. The invasion of the New World might have taken place sometime close to the Oligocene/Miocene boundary. Diversification analyses suggested a shift in speciation rates during the radiation of a sub-clade of pit vipers where speciation rates rapidly increased but slowed down toward the present. Thus, the evolution of the loreal pits alone does not seem to explain their explosive speciation rates. We suggest that climatic and geological changes in Asia and the invasion of the New World may have also contributed to the speciation shift found in vipers. PMID- 27480811 TI - Syringomyelia in hereditary multiple exostosis. AB - We describe five children with Hereditary Multiple Exostosis (HME) who also had syringomyelia. Of these, four had a tethered cord/fibrolipoma. No spinal osteochondromas were found in these patients. All had antecedent neurological signs or symptoms that prompted spinal imaging with MRI. Of all patients with HME seen in the Midwest Regional Bone Dysplasia Clinic from 1982 to present, 44% (17/39) of patients had signs or symptoms concerning for possible cord-related neurological findings. However, only 10 of 39 had spinal imaging. Assuming that all individuals with syringomyelia were identified, then 5/39 (13%) were in that way affected. This, of course, is a minimal estimate given that many were not imaged. The incidence of syringomyelia appears to be increased in this population, and seems to be unrelated to spinal osteochondromas. A low threshold for obtaining spinal MRI in patients with Hereditary Multiple Exostosis seems rational. (c) 2016 Wiley Periodicals, Inc. PMID- 27480812 TI - Contribution of the Individual Small Intestinal alpha-Glucosidases to Digestion of Unusual alpha-Linked Glycemic Disaccharides. AB - The mammalian mucosal alpha-glucosidase complexes, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI), have two catalytic subunits (N- and C-termini). Concurrent with the desire to modulate glycemic response, there has been a focus on di-/oligosaccharides with unusual alpha-linkages that are digested to glucose slowly by these enzymes. Here, we look at disaccharides with various possible alpha-linkages and their hydrolysis. Hydrolytic properties of the maltose and sucrose isomers were determined using rat intestinal and individual recombinant alpha-glucosidases. The individual alpha-glucosidases had moderate to low hydrolytic activities on all alpha-linked disaccharides, except trehalose. Maltase (N-terminal MGAM) showed a higher ability to digest alpha-1,2 and alpha 1,3 disaccharides, as well as alpha-1,4, making it the most versatile in alpha hydrolytic activity. These findings apply to the development of new glycemic oligosaccharides based on unusual alpha-linkages for extended glycemic response. It also emphasizes that mammalian mucosal alpha-glucosidases must be used in in vitro assessment of digestion of such carbohydrates. PMID- 27480813 TI - Cognitive-behavioural therapy-based intervention to reduce fear of falling in older people: therapy development and randomised controlled trial - the Strategies for Increasing Independence, Confidence and Energy (STRIDE) study. AB - BACKGROUND: Falls cause fear, anxiety and loss of confidence, resulting in activity avoidance, social isolation and increasing frailty. The umbrella term for these problems is 'fear of falling', seen in up to 85% of older adults who fall. Evidence of effectiveness of physical and psychological interventions is limited, with no previous studies examining the role of an individually delivered cognitive-behavioural therapy (CBT) approach. OBJECTIVES: Primary objective To develop and then determine the effectiveness of a new CBT intervention (CBTi) delivered by health-care assistants (HCAs) plus usual care compared with usual care alone in reducing fear of falling. Secondary objectives To measure the impact of the intervention on falls, injuries, functional abilities, anxiety/depression, quality of life, social participation and loneliness; investigate the acceptability of the intervention for patients, family members and professionals and factors that promote or inhibit its implementation; and measure the costs and benefits of the intervention. DESIGN: Phase I CBTi development. Phase II Parallel-group patient randomised controlled trial (RCT) of the new CBTi plus usual care compared with usual care alone. SETTING: Multidisciplinary falls services. PARTICIPANTS: Consecutive community-dwelling older adults, both sexes, aged >= 60 years, with excessive or undue fear of falling per Falls Efficacy Scale-International (FES-I) score of > 23. INTERVENTIONS: Phase I Development of the CBTi. The CBTi was developed following patient interviews and taught to HCAs to maximise the potential for uptake and generalisability to a UK NHS setting. Phase II RCT. The CBTi was delivered by HCAs weekly for 8 weeks, with a 6-month booster session plus usual care. MAIN OUTCOME MEASURES: These were assessed at baseline, 8 weeks, 6 months and 12 months. Primary outcome measure Fear of falling measured by change in FES-I scores at 12 months. Secondary outcome measures These comprised falls, injuries, anxiety/depression [Hospital Anxiety and Depression Scale (HADS)], quality of life, social participation, loneliness and measures of physical function. There were process and health-economic evaluations alongside the trial. RESULTS: Four hundred and fifteen patients were recruited, with 210 patients randomised to CBTi group and 205 to the control group. There were significant reductions in mean FES I [-4.02; 95% confidence interval (CI) -5.95 to -2.1], single-item numerical fear of falling scale (-1.42; 95% CI -1.87 to 1.07) and HADS (-1; 95% CI -1.6 to -0.3) scores at 12 months in the CBTi group compared with the usual care group. There were no differences in the other secondary outcome measures. Most patients found the CBTi acceptable. Factors affecting the delivery of the CBTi as part of routine practice were identified. There was no evidence that the intervention was cost-effective. CONCLUSIONS: Our new CBTi delivered by HCAs significantly improved fear of falling and depression scores in older adults who were attending falls services. There was no impact on other measures. FURTHER WORK: Further work should focus on a joint CBTi and physical training approach to fear of falling, more rational targeting of CBTi, the possibility of mixed group and individual CBTi, and the cost-effectiveness of provision of CBTi by non-specialists. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78396615. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 56. See the NIHR Journals Library website for further project information. PMID- 27480814 TI - Editorial Comment to Effects of silodosin on bladder activity in rats with frequent urination induced by pelvic venous congestion. PMID- 27480815 TI - Nanobubble-Nanoparticle Interactions in Bulk Solutions. AB - Nanobubbles form stable colloids in supersaturated solutions. Here we demonstrate the ability of these solutions to interact with Au nanoparticle suspensions. The principle goal was to demonstrate particle modification, similar to froth flotation, and we do indeed see bubble-particle interactions. However, unlike in froth flotation, where bubble-particle interactions are driven mainly through collisions, for bulk nanobubble solutions we find that the principle interaction is through nucleation of new nanobubbles on the particles. PMID- 27480817 TI - An Analysis of Quality Measures in Diagnostic Radiology with Suggestions for Future Advancement. AB - Radiology in the United States of America is evolving from a fee-for-service to a value-based, "pay-for-performance" system. Such a system requires objective measures, termed metrics, to grade performance. Current grading systems in health care, not designed with the unique nature of radiology in mind, often emphasize patient outcomes; this can be a challenge for measuring and grading performance in radiology, which is often several steps removed from patient outcome. At the present, while there are hundreds of individual radiology-specific metrics, there is no widely accepted overall standard for quality or value in diagnostic radiology services. This article analyzes the current system of radiology metrics and suggests a new direction for performance-based reimbursement in diagnostic radiology, focusing on a limited number of reasonably measurable outcomes-related factors that are specific to radiology. PMID- 27480816 TI - Longitudinal relationships between glycemic status and body mass index in a multiethnic study: evidence from observational and genetic epidemiology. AB - We investigated the relationship between glycemic status and BMI and its interaction with obesity single-nucleotide polymorphisms (SNPs) in a multi-ethnic longitudinal cohort at high-risk for dysglycemia. We studied 17 394 participants from six ethnicities followed-up for 3.3 years. Twenty-three obesity SNPs were genotyped and an unweighted genotype risk score (GRS) was calculated. Glycemic status was defined using an oral glucose tolerance test. Linear regression models were adjusted for age, sex and population stratification. Normal glucose tolerance (NGT) to dysglycemia transition was associated with baseline BMI and BMI change. Impaired fasting glucose/impaired glucose tolerance to type 2 diabetes transition was associated with baseline BMI but not BMI change. No simultaneous significant main genetic effects and interactions between SNPs/GRS and glycemic status or transition on BMI level and BMI change were observed. Our data suggests that the interplay between glycemic status and BMI trajectory may be independent of the effects of obesity genes. This implies that individuals with different glycemic statuses may be combined together in genetic association studies on obesity traits, if appropriate adjustments for glycemic status are performed. Implementation of population-wide weight management programs may be more beneficial towards individuals with NGT than those at a later disease stage. PMID- 27480818 TI - Focal Neurological Deficit at Onset of Aneurysmal Subarachnoid Hemorrhage: Frequency and Causes. AB - BACKGROUND AND AIM: Focal neurological deficit (FND) is a recognized presenting symptom of aneurysmal subarachnoid hemorrhage (SAH). However, little is known on how often aneurysmal SAH patients present with FND and what the responsible mechanisms are. The aim of this study was to examine the frequency and causes of FND at onset in aneurysmal SAH. METHODS: We reviewed the records of consecutive aneurysmal SAH patients over 5 years and identified those who presented with FND. We developed several potential mechanisms for FND based on consensus between 2 separate evaluating neurologists. We then compared the characteristics of aneurysmal SAH patients who presented with and without FND. Logistic regression models were used to assess for association of FND with poor outcome. RESULTS: Of a total of 213 patients, 10.3% presented with FND. The junction of the internal carotid and posterior communicating arteries was the most common aneurysm location in patients with FND (36.4%). Causes of FND at presentation were intraparenchymal hematoma in 45.5%, early cerebral infarction in 22.7%, parenchymal compression by subarachnoid thrombus in 18.2%, and seizure with Todd's paralysis in 13.6%. Patients with FND were older (P = .001) and had higher rates of in-hospital death and severe disability at discharge (P < .0001), compared to those without focal deficit. FND was independently associated with poor outcome (odds ratio: 4.62, confidence interval: 1.41-15.14; P = .01). CONCLUSION: One in every 10 aneurysmal SAH patients presents with FND. FND at presentation has diverse mechanisms, is not associated with a specific aneurysm location, and is independently associated with poor outcome. PMID- 27480819 TI - Intra-arterial Stroke Treatment prior to the Stent-Retriever Era: High Mortality and Lack of Volume-Outcome Association. AB - BACKGROUND: Mechanical thrombectomy for acute large-vessel occlusive stroke is beneficial when performed with stent-retriever devices; however, little is known about real-world experience with intra-arterial treatment (IAT). We aimed to clarify how hospitals influence outcomes for Medicare thrombectomy patients to inform future delivery of effective mechanical thrombectomy treatment. METHODS: This is a retrospective cohort study that includes a Medicare fee-for-service patient population. Patients with a primary stroke discharge (ICD-9-CM 433.x1, 434.x1, 436) were included; billing codes were used to identify patients receiving IAT, intravenous thrombolytics (IVT), or a combination of these treatments. Characteristics of treated patients were summarized using descriptive statistics; long-term mortality was summarized via Kaplan-Meier curves; and multilevel logistic regression models with random hospital-level intercept were built to determine hospital influence on outcome and whether a volume-outcome association existed. RESULTS: A total of 4557 patients received IAT at 544 hospitals. The mean age of IAT patients was 76 years. IAT patients had longer hospital stay (9.7 versus 6.8 days), longer stay in the ICU (5.5 versus 3.3 days), and greater probability of intubation (36.7% versus 9.5%) compared with IVT patients. Ninety-day mortality was 46% IAT versus 26% IVT. Hospitals had little influence on outcomes (intraclass correlation coefficient, <.01). No association between procedural volume and outcomes was identified. CONCLUSIONS: IAT for 2007-2010 was associated with higher patient mortality than recent and prior clinical trials. Treated Medicare patients were considerably older than clinical trial populations. Hospitals had little influence on mortality, and increased hospital volume was not associated with lower mortality. Future real world experience should monitor these parameters as use of stent retrievers disseminates. PMID- 27480821 TI - Association between Atrial Fibrillation and Three-Year Mortality in Nondiabetic Patients with Acute First-Ever Ischemic Stroke. AB - BACKGROUND: Diabetes mellitus (DM) is a risk factor for atrial fibrillation (AF) and is known to be an important risk factor for death from stroke. The influence of AF on long-term outcomes in patients with ischemic stroke remains controversial. To clarify the exact influence of AF on stroke outcome and exclude the effect from DM, we investigated the influence of AF on the 3-year outcomes of nondiabetic patients with acute first-ever ischemic stroke. METHODS: Five-hundred seventy-four nondiabetic patients with acute first-ever ischemic stroke were enrolled and had been followed for 3 years. Patients were divided into 2 groups according to whether AF was diagnosed or not. Clinical presentations, risk factors for stroke, laboratory data, comorbidities, and outcomes were recorded. RESULTS: A total of 107 patients (18.6%) had AF. The age was significantly older in patients with AF. Total anterior circulation syndrome occurred more frequently among patients with AF (P < .001). The mean length of stay in the acute ward was significantly higher in patients with AF (P < .001). Furthermore, dependent functional status following discharge was higher in patients with AF (P < .001). Multivariate Cox regression revealed that AF is a significant predictor of 3-year all-cause mortality (hazard ratio = 1.98, 95% confidence interval = 1.07-3.67, P = .022). CONCLUSIONS: AF is associated with increased risk of 3-year mortality in nondiabetic patients with acute first-ever ischemic stroke. Careful cardiac evaluation and treatment are essential in patients with AF and stroke. PMID- 27480820 TI - Characteristics of the Drip-and-Ship Paradigm for Patients with Acute Ischemic Stroke in South Korea. AB - BACKGROUND: Data on the drip-and-ship paradigm in Korea are limited. The present study aimed to evaluate the use of the drip-and-ship paradigm and the time delays and outcomes associated with the paradigm in Korea. METHODS: We used data from the Clinical Research Center for Stroke-5 registry between January 2011 and March 2014. Among patients treated with tissue-type plasminogen activator (tPA), the use of the drip-and-ship paradigm was evaluated, and time delays and functional outcomes at 3 months were compared between patients treated with the paradigm and those treated directly at visits. RESULTS: Among 1843 patients who met the eligibility criteria, 244 patients (13.2%) were treated with the drip-and-ship paradigm. Subsequent endovascular recanalization therapy was used in 509 patients (27.6%). The median time from symptom onset to groin puncture was greater in patients treated with the paradigm than in those treated directly at visits (305 versus 200 minutes, P < .001). In multivariate analysis, the risks of unfavorable functional outcomes and symptomatic intracranial hemorrhage were higher inpatients treated with the paradigm than in those directly treated at visits (odds ratio [OR] 2.15; 95% confidence interval [CI], 1.50-3.08; P < .001 and OR 1.78; 95% CI, 1.02-3.12; P = .041, respectively). CONCLUSIONS: In Korea, the drip and-ship paradigm was used in less than 15% of all patients treated with tPA. The use of the paradigm might cause an increase in the onset-to-groin puncture time. Additionally, clinical outcomes might be worse in patients treated with the paradigm than in those treated directly at visits. PMID- 27480823 TI - Endoscopic resection of large gastrointestinal lipomas: Loop-and-let-go technique with some twists. PMID- 27480824 TI - Unicompartmental Knee Arthroplasty in Patients Older Than 75 Results in Better Clinical Outcomes and Similar Survivorship Compared to Total Knee Arthroplasty. A Matched Controlled Study. AB - BACKGROUND: Due to the potential reduction of morbidity and mortality, unicompartmental knee arthroplasty (UKA) may represent an interesting solution for older patients with unicompartmental arthritis. It was our hypothesis that UKA can represent an alternative to total knee arthroplasty (TKA) for patients older than 75. We, thus, aimed to compare in those patients (1) functional results, (2) rates of forgotten joint, and (3) survivorships of UKA vs TKA. METHODS: In this retrospective matched-pair study, 101 patients who underwent UKA in our institution were included and then matched one-to-one with TKA group based on age, gender, body mass index, preoperative Knee Society Score (KSS). Inclusion criteria were age between 75 and 90 years on the day of surgery, knee arthroplasty performed for primary osteoarthritis or osteonecrosis of the knee. All patients were evaluated clinically (using KSS, Knee Injury Osteoarthritis Outcome Score [KOOS], and Forgotten Joint Score) at 1, 2, and every 5 years, thereafter. Survivorships of UKA and TKA implants were also compared. RESULTS: At last follow-up, patients from UKA group had better KSS than in TKA group, (respectively, KSS function 82.8 +/- 12.2 vs 79.2 +/- 13.1 [P = .0448] and KSS knee 88.2 +/- 8.9 vs 82.3 +/- 12.5 [P = .0005]). Knee Injury Osteoarthritis Outcome Scores were also higher in UKA group (all P < .001) as well as the rate of forgotten knees (42% vs 25% P = .01). Sixteen-year survivorships free from revision for any reason were similar in the 2 groups (91.8% vs 94.6% P = .66). CONCLUSION: The results of our study showed that UKA provide higher function and better forgotten joint scores with similar survivorship, compared to TKA, for patients older than 75. PMID- 27480825 TI - Survivorship of Extensor Mechanism Allograft Reconstruction After Total Knee Arthroplasty. AB - BACKGROUND: Extensor mechanism disruption remains a devastating complication after total knee arthroplasty. The purpose of this study is to describe the outcomes of extensor mechanism allograft (EMA) reconstruction in a large single center case series. METHODS: Consecutive patients with a previous total knee arthroplasty undergoing extensor mechanism reconstruction using a fresh-frozen EMA tensioned in full extension were identified retrospectively from single center institutional database (N = 25 patients, 26 knees; mean follow-up 68 months [range 22-113 months]). The primary outcome was initial allograft failure, defined as removal of the allograft or extensor lag >30 degrees at most recent follow-up. RESULTS: Sixty-nine percent (18/26) of knees had retained their initial allograft reconstruction at their latest follow-up despite reoperation rates of 58% (15/26). A younger age was significantly associated with failure of the initial allograft reconstruction. Knee Society Scores increased from 101 (38 standard deviation [SD]) to 116 (40 SD) at most recent follow-up for the group as a whole (P = .4). Patients undergoing a reoperation for any cause had lower Knee Society Scores (101 [SD 38] vs 138 [SD 32], respectively; P = .04) at most recent follow-up. CONCLUSION: EMA reconstruction shows adequate overall intermediate term survival; however, reoperation rates were high and associated with worse functional outcomes. PMID- 27480826 TI - Influence of Total Knee Arthroplasty on Patellar Kinematics and Patellofemoral Pressure. AB - BACKGROUND: Patellofemoral complications are one of the main problems after total knee arthroplasty (TKA). The design of the TKA component may affect the patellar biomechanics, which may be associated with this postoperative complication. The purpose of this study was to assess the influence of TKA and prosthesis designs on the patellar kinematics and patellofemoral pressure. METHODS: Using fresh frozen cadavers, we measured the patellofemoral pressure, patella offset, and patella tilt in the following 4 conditions: normal knee (patella replacement only), cruciate-retaining TKA, condylar-stabilizing TKA, and posterior-stabilized TKA. RESULTS: The patellofemoral pressure increased significantly after the cruciate-retaining TKA and condylar-stabilizing TKA compared with the normal knee. The patella offset in the normal knee decreased with increasing knee flexion angles, while the patella offset in the TKA knees did not change significantly through the full range of motion. The amount of lateral patella tilt in the normal knee was significantly larger than the TKA knees in the full range of motion. CONCLUSION: Although the femoral components are designed to reproduce an anatomical patellar tracking, the physiological patellar kinematics were not observed. Relatively high patellofemoral pressure and kinematic change after TKA may be associated with postoperative complications such as the anterior knee pain. PMID- 27480827 TI - Mid-Term Results and Predictors of Patient-Reported Outcomes of Birmingham Hip Resurfacing. AB - BACKGROUND: Birmingham hip resurfacing (BHR) is the only Food and Drug Administration approved resurfacing option currently available in the United States. While adequate BHR outcomes are established, there is a paucity of US based literature demonstrating factors critical to improve patient reported outcomes (PROs). This study answers: (1) What is the implant survivorship in a large US cohort? (2) Which preoperative factors result in higher PRO scores over 5 years postoperatively? METHODS: A retrospective 541 hip single-surgeon cohort with mean of 6.2 years follow-up (range 5-8.1) was collected. Preoperative patient/implant variables, including postoperative radiographic acetabular inclination and femoral component position, clinical outcomes, and follow-up PRO questionnaire information were collected. Validated PROs included the Hip Disability and Osteoarthritis Outcome Score (HOOS), Veterans Rand-12, and University of California Los Angeles (UCLA) activity. PROs were modeled with ordinary least squares then used to create nomograms. RESULTS: Average patient age was 53 years with 391 (72%) males. Seven hips were revised, resulting in an overall survival of 98.8% at 5 years. Predictive modeling identified preoperative variables (sex, body mass index, smoking, and comorbidity) that had statistically significant associations with HOOS pain (P = .049), HOOS activities of daily living (P = .017), UCLA activity (P < .001), and Veterans Rand-12 physical (P < .001) PROs at latest follow-up. Nomograms predicted follow-up PROs using preoperative patient-specific variables. CONCLUSION: This study documents excellent survival of the largest reported single-center cohort of BHRs in the United States with a mean 6.2 years follow-up. Multivariate modeling shows male nonsmokers with low body mass index, and no comorbidities will have less hip pain, better function in daily life, higher activity, and better general physical health after BHR arthroplasty. PMID- 27480828 TI - Myocardial Infarction Risk in Arthroplasty vs Arthroscopy: How Much Does Procedure Type Matter? AB - BACKGROUND: This study aimed at assessing short-term risk of serious cardiac events after elective total joint arthroplasty (TJA) as compared to a less invasive procedure, knee arthroscopy (KA). METHODS: Patients who underwent elective primary total hip arthroplasty (THA), total knee arthroplasty (TKA), or KA from 2011 to 2014 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. A 1:1 propensity matching was used to generate 2 control cohorts of KA patients with similar characteristics. Bivariate and multivariate analyses were assessed using perioperative variables. RESULTS: A total of 24,203 THA, 21,740 TKA, and 45,943 KA patients were included. Bivariate analysis revealed significantly higher rates of serious 30-day cardiac events (myocardial infarction or cardiac arrest) among THA (0.15% vs 0.05%, P < .001) and TKA patients (0.14% vs 0.05%, P < .03) vs KA controls. In multivariate analysis controlling for patient characteristics and comorbidities, THA and TKA were associated with a 2.61 and 1.98 times odds of serious 30-day cardiac events as compared to controls (P <= .03 for both). Additional independent predictors of serious 30-day cardiac events included age, smoking, cardiac disease, and American Society of Anesthesiologists class 3/4. In the THA and TKA cohorts, serious cardiac events occurred within the first 3 days postoperation compared to 4 days in controls. CONCLUSION: After controlling for patient characteristics and comorbidities, TJA increased the short-term risk of serious cardiac event compared to a less-invasive procedure. This information better quantifies the risk differential for patients considering surgery as they engage in shared decision making with their providers. In addition, our data may have an impact on perioperative management of antithrombotic medications used in patients with cardiac disease. The median time in days to serious cardiac event was 2 in THA and 3 in TKA vs 4 in KA, which may have implications in postoperative monitoring of patients after surgery. PMID- 27480829 TI - Hemiarthroplasty for Displaced Femoral Neck Fractures in the Elderly Has a Low Conversion Rate. AB - BACKGROUND: Hemiarthroplasty (HA) has been a mainstay treatment for displaced femoral neck fractures for many years. The purpose of this study was to report the conversion rate of HA to total hip arthroplasty (THA) for displaced femoral neck fractures and compare outcomes between implant constructs (bipolar vs unipolar), fixation options (cemented vs cementless stems), and age groups (<75 years vs >=75 years). METHODS: We retrospectively reviewed the results of a consecutive cohort of 686 patients who underwent HA for the treatment of femoral neck fractures at our institution between 1999 and 2013 with a minimum of 2-year follow-up. RESULTS: The overall component revision rate, including conversion to THA, revision HA, revision with open reduction internal fixation, and Girdlestone procedure, was 5.6% (39/686). Seventeen patients (2.5%) were converted from HA to THA at an average of 1.9 years after index procedure. A significantly lower conversion rate of 1.4% (7/499 patients) was found in the older patient cohort (>=75 years old) compared to 5.3% (11/187) in the younger cohort. The most common causes for conversion surgery to THA were acetabular wear (5 patients), aseptic loosening (4 patients), and periprosthetic fracture (3 patients). There was a significantly lower rate of periprosthetic fracture (0.4% vs 2.5%, P value .025) in the cemented implant group compared to the cementless group. We observed a higher rate of dislocations in the bipolar vs unipolar group (3.8% vs 1%, P value .02) and no other significant differences between these groups. CONCLUSION: We observed a low reoperation rate for this cohort of patients, relatively higher conversion rates for the younger population, fewer periprosthetic fractures with the use of cemented stems, and no advantage of bipolar over unipolar prostheses. PMID- 27480831 TI - Liposomal Irinotecan in the Treatment of Refractory Pancreatic Cancer. AB - Effective therapies against metastatic pancreatic cancer remain limited, and despite treatment, many will ultimately progress. Previously, few options were available for second line therapy in metastatic pancreatic cancer. Liposomal encapsulated irinotecan, in combination with leucovorin-modulated fluorouracil, was found to significantly increase overall survival in patients who have progressed after gemcitabine- based therapy in a large, international, randomized clinical trial (NAPOLI-1). We reviewed the background of systemic therapy for metastatic pancreatic cancer, examined putative mechanisms for the success of encapsulated drugs, and identified recent patent applications on the use of liposomal irinotecan in pancreatic cancer. The landmark NAPOLI-1 trial established a second-line option for those with metastatic pancreatic cancer refractory to gemcitabine chemotherapy, but effective therapies with long duration of response are still lacking. Alternative techniques targeting key driver genes in pancreatic cancer and novel methods of early detection and targeting drugs are currently being explored. How liposomal irinotecan can be integrated into chemotherapy regimens, including neoadjuvant or first line combinations, are currently being tested in clinical trials and covered by several new patent applications. PMID- 27480832 TI - NHS funding in England: money's too tight to mention. PMID- 27480830 TI - Contemporary management of chronic rhinosinusitis with nasal polyposis in aspirin exacerbated respiratory disease: an evidence-based review with recommendations. AB - BACKGROUND: Chronic rhinosinusitis (CRS) in aspirin-exacerbated respiratory disease (AERD) represents a recalcitrant form of sinonasal inflammation for which a multidisciplinary consensus on patient management has not been reached. Several medical interventions have been investigated, but a formal comprehensive evaluation of the evidence has never been performed. The purpose of this article is to provide an evidence-based approach for the multidisciplinary management of CRS in AERD. METHODS: A systematic review of the literature was performed and the guidelines for development of an evidence-based review with recommendations were followed. Study inclusion criteria included: adult population >18 years old; CRS based on published diagnostic criteria, and a presumptive diagnosis of AERD. We focused on reporting higher-quality studies (level 2 or higher) when available, but reported lower-quality studies if the topic contained insufficient evidence. Treatment recommendations were based on American Academy of Otolaryngology (AAO) guidelines, with defined grades of evidence and evaluation of research quality and risk/benefits associated with each treatment. RESULTS: This review identified and evaluated the literature on 3 treatment strategies for CRS in AERD: dietary salicylate avoidance, leukotriene modification, and desensitization with daily aspirin therapy. CONCLUSION: Based on the available evidence, dietary salicylate avoidance and leukotriene-modifying drugs are options following appropriate treatment with nasal corticosteroids and saline irrigation. Desensitization with daily aspirin therapy is recommended following revision endoscopic sinus surgery (ESS). PMID- 27480834 TI - Preconception Blood Pressure and Risk of Low Birth Weight and Small for Gestational Age: A Large Cohort Study in China. AB - Our objective was to examine whether high blood pressure in the preconception period was associated with low birth weight (LBW) and small-for-gestational age (SGA) in Chinese women. Data were obtained from the China-US Collaborative Project for Neural Tube Defects Prevention, a large population-based cohort study. We included 43 718 singleton live births delivered at gestational ages of 28-45 weeks to women who were registered before pregnancy in 7 counties in southern China. Blood pressure was measured during registration by trained healthcare workers, and other health-related information was recorded prospectively. We used logistic regression to evaluate the associations between preconception blood pressure and the risk of LBW and SGA, adjusting for potential confounders. The prevalence of hypertension in the preconception study population was 4.62% (2019/43 718). The incidences of LBW and SGA were 2.33% and 5.05% for the hypertension group and 2.01% and 5.68% for the nonhypertension group. Compared with the nonhypertension group, the hypertension group did not show significantly increased risk for LBW overall (adjusted risk ratio =1.16, 95% confidence interval 0.86-1.57) or SGA (adjusted risk ratio =0.89, 95% confidence interval 0.73-1.09). When participants with normal blood pressure were used as the reference, the adjusted risk ratio of SGA for prehypertensive women was 1.13 (95% confidence interval 1.03-1.25). Our results do not support an association between hypertension or higher blood pressure before pregnancy and increased risk of LBW or SGA. PMID- 27480833 TI - Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by Angiotensin II. AB - Angiotensin II (AngII) has been strongly implicated in hypertension and its complications. Evidence suggests the mechanisms by which AngII elevates blood pressure and enhances cardiovascular remodeling and damage may be distinct. However, the signal transduction cascade by which AngII specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis, remains insufficiently understood. In vascular smooth muscle cells, a metalloproteinase ADAM17 mediates epidermal growth factor receptor transactivation, which may be responsible for cardiovascular remodeling but not hypertension induced by AngII. Thus, the objective of this study was to test the hypothesis that activation of vascular ADAM17 is indispensable for vascular remodeling but not for hypertension induced by AngII. Vascular ADAM17-deficient mice and control mice were infused with AngII for 2 weeks. Control mice infused with AngII showed cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis. These phenotypes were prevented in vascular ADAM17-deficient mice independent of blood pressure alteration. AngII infusion enhanced ADAM17 expression, epidermal growth factor receptor activation, and endoplasmic reticulum stress in the vasculature, which were diminished in ADAM17-deficient mice. Treatment with a human cross reactive ADAM17 inhibitory antibody also prevented cardiovascular remodeling and endoplasmic reticulum stress but not hypertension in C57Bl/6 mice infused with AngII. In vitro data further supported these findings. In conclusion, vascular ADAM17 mediates AngII-induced cardiovascular remodeling via epidermal growth factor receptor activation independent of blood pressure regulation. ADAM17 seems to be a unique therapeutic target for the prevention of hypertensive complications. PMID- 27480835 TI - Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure. AB - Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt 1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95+/-0.45 mg/g in sFlt-1 knockout mice versus 6.60+/-0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure overloaded heart. PMID- 27480837 TI - Hypertension Editors' Picks: Pulmonary Hypertension. PMID- 27480836 TI - Evacuation and Risk of Hypertension After the Great East Japan Earthquake: The Fukushima Health Management Survey. AB - On March 11, 2011, the Great East Japan Earthquake occurred in Japan, with a nuclear accident subsequently occurring at the Fukushima Daiichi Nuclear Power Plant. The disaster forced many evacuees to change particular aspects of their lifestyles. This study assessed the hypothesis that evacuation may have increased the risk of hypertension among residents in Fukushima. A longitudinal study examined data collected from 31 252 Japanese participants aged 40 to 74 years sourced from general health checkups conducted in 13 communities between 2008 and 2010. Follow-up examinations were conducted from 2011 through 2013. A total of 21 989 participants (follow-up proportion, 70.4%) received follow-up examinations. Mean blood pressure significantly increased in both evacuees and nonevacuees after the disaster, with greater changes in blood pressure among the former. The changes in systolic and diastolic blood pressure among the evacuees and nonevacuees were +5.8/3.4 versus +4.6/2.1 mm Hg (P<0.01/P<0.0001) for men and +4.4/2.8 versus +4.1/1.7 mm Hg (P=0.33/P<0.0001) for women, respectively. Evacuation was associated with an increased risk of hypertension among men, and the age-adjusted hazard ratios of evacuation for incidence of hypertension were 1.24 (95% confidence interval, 1.11-1.39; P<0.001) for men and 1.05 (95% confidence interval, 0.94-1.17; P=0.37) for women, respectively. For men, after adjustment for confounding variables, the hazard ratio slightly decreased to 1.20, but the association was essentially unchanged. Blood pressure increased among residents, especially evacuees, in the evacuation zone of Fukushima prefecture after the Great East Japan Earthquake. Evacuation may be associated with an increased risk of hypertension among men in the 2 years after the disaster. PMID- 27480838 TI - Deleting Vascular ADAM17 Sheds New Light on Hypertensive Cardiac Hypertrophy. PMID- 27480839 TI - Respiratory Network Enhances the Sympathoinhibitory Component of Baroreflex of Rats Submitted to Chronic Intermittent Hypoxia. AB - Chronic intermittent hypoxia (CIH) produces respiratory-related sympathetic overactivity and hypertension in rats. In this study, we tested the hypothesis that the enhanced central respiratory modulation of sympathetic activity after CIH also decreases the sympathoinhibitory component of baroreflex of rats, which may contribute to the development of hypertension. Wistar rats were exposed to CIH or normoxia (control group) for 10 days. Phrenic nerve, thoracic sympathetic nerve, and neurons in the rostral ventrolateral medulla and caudal ventrolateral medulla were recorded in in situ preparations of rats. Baroreflex regulation of thoracic sympathetic nerve, rostral ventrolateral medulla, and caudal ventrolateral medulla neurons activities were evaluated in different phases of respiration in response to either aortic depressor nerve stimulation or pressure stimuli. CIH rats presented higher respiratory-related thoracic sympathetic nerve and rostral ventrolateral medulla presympathetic neurons activities at the end of expiration in relation to control rats, which are indexes of respiratory-related sympathetic overactivity. Baroreflex-evoked thoracic sympathetic nerve inhibition during expiration, but not during inspiration, was enhanced in CIH when compared with control rats. In addition, CIH selectively enhanced the expiratory-related baroreceptor inputs, probably through caudal ventrolateral medulla neurons, to the respiratory-modulated bulbospinal rostral ventrolateral medulla presympathetic neurons. These findings support the concept that the onset of hypertension, mediated by sympathetic overactivity, after 10 days of CIH is not secondary to a reduction in sympathoinhibitory component of baroreflex. Instead, it was observed an increase in the gain of sympathoinhibitory component in in situ preparations of rats, suggesting that changes in the respiratory-related sympathetic network after CIH also play a key role in preventing greater increase in arterial pressure. PMID- 27480840 TI - Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin. AB - Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors. PMID- 27480841 TI - Examining EXAMINE for an Interaction With Angiotensin-Converting Enzyme Inhibition. PMID- 27480842 TI - CTLA-4 and IL-6 gene polymorphisms: Risk factors for recurrent pregnancy loss. AB - The purpose of the present study was to evaluate the possible association between CTLA-4 +49A/G and IL-6 -634C/G polymorphisms, and the risk of recurrent pregnancy loss (RPL). 240 women (120 healthy controls and 120 with RPL) were enrolled in this case-control study. Genotyping was performed using a PCR-RFLP technique. In the case of polymorphic CTLA-4 +49A/G, the wild type allele G was associated with a decreased risk of RPL (OR: 0.42, 95%CI: 0.25-0.69, p=0.001). As to IL-6 -634C/G polymorphism, a highly significant difference was observed, and those women who carry at least one mutant G allele presented a probability of developing RPL about 5 times greater than controls (OR: 5.1, 95%CI: 1.04-25.3, p=0.04). The results indicate that polymorphisms of CTLA-4 and IL-6 genes may influence the risk of developing RPL among Iranian women, suggesting that more research on the immunogenetics of pregnancy should be conducted to confirm our results, and to declare the exact roles of studied molecules in RPL pathogenesis. PMID- 27480843 TI - Systematic review and meta-analysis of the association between maternal smoking in pregnancy and childhood overweight and obesity. AB - BACKGROUND: By 2020, it is predicted that 60 million children worldwide will be overweight. Maternal smoking in pregnancy has been suggested as a contributing factor. Our objective was to systematically review studies on this, thereby expanding the evidence base for this association. METHODS: Systematic review with meta-analysis, Prospero Registration number CRD42012002859. We searched PubMed, Embase, Global Health, Web of Science and the Grey literature. We included prevalence, cohort and cross-sectional studies involving full-term, singleton pregnancies. Published and unpublished studies through to 1 January 2015 in all languages, demonstrating an objective overweight outcome up until 18 years of age and data presented as an OR, were included. Quality assessment was undertaken using an adaption of the Newcastle-Ottawa scale. Statistical analysis was performed using Review Manager V.5.3. FINDINGS: The meta-analysis included 39 studies of 236 687 children from Europe, Australia, North America and South America and Asia. Maternal smoking in pregnancy ranged from 5.5% to 38.7%, with the prevalence of overweight from 6.3% to 32.1% and obesity from 2.6% to 17%. Pooled adjusted ORs demonstrated an elevated odds of maternal smoking in pregnancy for childhood overweight (OR 1.37, 95% CI 1.28 to 1.46, I2 45%) and childhood obesity (OR 1.55, 95% CI 1.40 to 1.73, I2 24%). INTERPRETATION: Our results demonstrate an association between maternal prenatal smoking and childhood overweight. This contributes to the growing evidence for the aetiology of childhood overweight, providing important information for policymakers and health professionals alike in planning cessation programmes or antismoking interventions for pregnant female smokers. PMID- 27480844 TI - Cigarette smoke extract (CSE) induces transient receptor potential ankyrin 1(TRPA1) expression via activation of HIF1alphain A549 cells. AB - We previously found that transient receptor potential ankyrin 1 (TRPA1) in guinea pig tracheal epithelial cells was elevated after 14 days of cigarette smoke (CS) exposure. However, the mechanism underlying CS-induced TRPA1 expression remains unknown. Here, we explored whether cigarette smoke extract (CSE)-induced TRPA1 expression is related with modulation of HIF1alpha in A549 cells. Our results showed that CSE increased TRPA1 expression in A549 cells, decreased Ikappa B, PHD2, and HDAC2, and increased ROS release and nuclear translocation of NF-kappa B and HIF1alpha. Moreover, HIF1alpha siRNA and/or MG132 (a proteasome inhibitor) pretreatment significantly inhibited CSE-induced TRPA1 expression and HIF1alpha nuclear translocation in A549 cells. However, HIF1alpha siRNA pretreatment did not affect CSE-induced NF-kappa B nuclear translocation, suggesting that CSE induced TRPA1 expression in A549 cells is directly mediated by HIF1alpha, but not by NF-kappa B. Similar to CSE treatment, treatment of A549 cells with LPS caused significant increases in nuclear translocation of NF-kappa B and HIF1alpha mRNA expression, but did not alter TRPA1 mRNA expression. However, pretreatment with PHD2 siRNA did result in increased TRPA1 mRNA expression in LPS-treated A549 cells; an effect that was inhibited by SN50 (a NF-kappa B inhibitor). It suggests a role for NF-kappa B to indirectly regulate TRPA1 mRNA expression via modulating HIF1alpha mRNA transcription. In addition, treatment cells with HDAC2 siRNA plus 2%CSE resulted in increased HIF1alpha nuclear translocation and TRPA1 expression, which was significantly inhibited by MG132 and HIF1alpha siRNA. These results suggest that HDAC2 indirectly modulates TRPA1 expression by promoting the DNA binding activity of HIF1alpha. These findings show that CSE increases TRPA1 expression in airway epithelial cells by directly activating HIF1alpha, and that this increase in TRPA1 expression is indirectly regulated via NF-kappa B, PHD2 and HDAC2 modulation of HIF1alpha activity. PMID- 27480845 TI - 4-Hydroxyhexenal and 4-hydroxynonenal are mediators of the anti-cachectic effect of n-3 and n-6 polyunsaturated fatty acids on human lung cancer cells. AB - Cachexia, the most severe paraneoplastic syndrome, occurs in about 80% of patients with advanced cancer; it cannot be reverted by conventional, enteral, or parenteral nutrition. For this reason, nutritional interventions must be based on the use of substances possessing, alongside nutritional and energetic properties, the ability to modulate production of the pro-inflammatory factors responsible for the metabolic changes characterising cancer cachexia. In light of their nutritional and anti-inflammatory properties, polyunsaturated fatty acids (PUFAs), and in particular n-3, have been investigated for treating cachexia; however, the results have been contradictory. Since both n-3 and n-6 PUFAs can affect cell functions in several ways, this research investigated the possibility that the effects of both n-3 and n-6 PUFAs could be mediated by their major aldehydic products of lipid peroxidation, 4-hydroxyhexenal (HHE) and 4 hydroxynonenal (HNE), and by their anti-inflammatory properties. An "in vitro" cancer cachexia model, consisting of human lung cancer cells (A427) and murine myoblasts (C2C12), was used. The results showed that: 1) both n-3 and n-6 PUFAs reduced the growth of lung cancer cells without causing cell death, increased lipid peroxidation and Peroxisome Proliferator-Activated Receptor (PPAR)alpha, and decreased TNFalpha; 2) culture medium conditioned by A427 cells grown in the absence of PUFAs blocked myosin production and the differentiation of C2C12 muscle cells; conversely, muscle cells grown in culture medium conditioned by the same cells in the presence of PUFAs showed myosin expression and formed myotubes; 3) adding HHE or HNE directly to C2C12 cells maintained in culture medium conditioned by A427 cells in the absence of PUFAs stimulated myosin production and myotube formation; 4) putative consensus sequences for (PPARs) have been found in genes encoding fast isoforms of myosin heavy chain, by a bioinformatics approach. The overall results show, first, the ability of both n-3 and n-6 PUFAs and their lipid peroxidation products to prevent the blocking of myosin expression and myotube formation caused in C2C12 cells by medium conditioned by human lung tumour cells. The C2C12 cell differentiation can be due to direct effect of lipid peroxidation products, as evidenced by treating C2C12 cells with HHE and HNE, and to the decrease of pro-inflammatory TNFalpha in A427 cell culture medium. The presence of consensus sequences for PPARs in genes encoding the fast isoforms of myosin heavy chain suggests that the effects of PUFAs, HHE, and HNE are PPAR-mediated. PMID- 27480846 TI - Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation. AB - Isoform 1 of uracil-DNA glycosylase (UNG1) is the major protein for initiating base-excision repair in mitochondria and is in close proximity to the respiratory chain that generates reactive oxygen species (ROS). Effects of ROS on the stability of UNG1 have not been well characterized. In the present study, we found that overexpression of UNG1 enhanced cells' resistance to oxidative stress and protected mitochondrial DNA (mtDNA) from oxidation. Proteomics analysis showed that UNG1 bound to eight proteins in the mitochondria, including PAPSS2, CD70 antigen, and AGR2 under normal growth conditions, whereas UNG1 mainly bound to Peroxiredoxin 3 (PRDX3) via a disulfide linkage under oxidative stress. We further demonstrated that the UNG1-PRDX3 interaction protected UNG1 from ROS mediated degradation and prevented mtDNA oxidation. Moreover, our results show that ROS-mediated UNG1 degradation was Lon protease 1 (LonP1)-dependent and mitochondrial UNG1 degradation was aggravated by knockdown of PRDX3 expression. Taken together, these results reveal a novel function of UNG1 in the recruitment of PRDX3 to mtDNA under oxidative stress, enabling protection of UNG1 and UNG1 bound DNA from ROS damage and enhancing cell resistance to oxidative stress. PMID- 27480847 TI - Ion channel noise can explain firing correlation in auditory nerves. AB - Neural spike trains are commonly characterized as a Poisson point process. However, the Poisson assumption is a poor model for spiking in auditory nerve fibres because it is known that interspike intervals display positive correlation over long time scales and negative correlation over shorter time scales. We have therefore developed a biophysical model based on the well-known Meddis model of the peripheral auditory system, to produce simulated auditory nerve fibre spiking statistics that more closely match the firing correlations observed in empirical data. We achieve this by introducing biophysically realistic ion channel noise to an inner hair cell membrane potential model that includes fractal fast potassium channels and deterministic slow potassium channels. We succeed in producing simulated spike train statistics that match empirically observed firing correlations. Our model thus replicates macro-scale stochastic spiking statistics in the auditory nerve fibres due to modeling stochasticity at the micro-scale of potassium channels. PMID- 27480848 TI - Activity of Ceftazidime-Avibactam against Clinical and Isogenic Laboratory Pseudomonas aeruginosa Isolates Expressing Combinations of Most Relevant beta Lactam Resistance Mechanisms. AB - The activity of ceftazidime-avibactam was compared with that of ceftazidime alone and meropenem against a collection of 190 Pseudomonas aeruginosa clinical isolates recovered from a multicenter study of bloodstream infections. The addition of avibactam increased ceftazidime susceptibility in the complete collection of strains (64.7% to 91.1%) and particularly among subsets of isolates showing AmpC hyperproduction (10.9% to 76.1%) or multidrug resistance (MDR) profiles (27% to 77.8%). The MICs of ceftazidime-avibactam, in contrast with those of ceftazidime or meropenem, remained at <=4 MUg/ml for a panel of 16 P. aeruginosa PAO1 isogenic mutants expressing multiple combinations of the most relevant beta-lactam resistance mechanisms. PMID- 27480849 TI - Validation of the HIV Tropism Test TROCAI Using the Virological Response to a Short-Term Maraviroc Monotherapy Exposure. AB - TROCAI is a phenotypic tropism test developed using the virological response to a short-term exposure to maraviroc monotherapy (Maraviroc Clinical Test [MCT]). It was found that with TROCAI, a cutoff of <0.5% of dual/mixed viruses was needed to predict R5 HIV tropism. Here, we have validated TROCAI, using this cutoff, in a new cohort of 42 patients, finding a very high concordance between TROCAI and MCT (98%), and a good concordance (71 to 87%) with other genotypic/phenotypic methods. PMID- 27480850 TI - Intra- and Interlaboratory Agreement in Assessing the In Vitro Activity of Micafungin against Common and Rare Candida Species with the EUCAST, CLSI, and Etest Methods. AB - The emergence of resistant strains among common and rare Candida species necessitates continuous monitoring of the in vitro susceptibilities of those isolates. We therefore assessed the in vitro activities of micafungin against 1,099 molecularly identified isolates belonging to 5 common and 20 rare Candida species by the EUCAST, CLSI, and Etest methods, assessing both the intralaboratory agreement and the interlaboratory agreement for two centers. The median micafungin EUCAST MICs were as follows, from the lowest to the highest: for Candida albicans, 0.004 mg/liter; for C. glabrata, 0.016 mg/liter; for C. tropicalis, 0.031 mg/liter; for C. krusei, 0.125 mg/liter; for C. parapsilosis, 2 mg/liter. Among rare Candida species, high MICs were found for C. guilliermondii, C. lipolytica, C. orthopsilosis, C. metapsilosis, and C. fermentati. No resistant isolates were found by the CLSI method, whereas resistance rates of 1 to 2% were found by the EUCAST method. Overall, the EUCAST method resulted in MICs 1 to 2 dilutions higher than those found by the CLSI and Etest methods. The intra- and interlaboratory agreement between methods was >92%, except for the interlaboratory agreement between the EUCAST and CLSI methods (81%), where 17 to 31% of the differences were >2 2-fold dilutions for C. albicans, C. glabrata, C. tropicalis, and other rare Candida species and <6% for C. parapsilosis and C. krusei For the other interlaboratory comparisons, the EUCAST method resulted in higher MICs than the Etest method for all species, but <7% of these differences were >2 2-fold dilutions. Overall, the CLSI method resulted in lower MICs than the Etest method, with 11% of all isolates demonstrating >2 2-fold-dilution differences (6 to 20% for C. albicans, C. tropicalis, and rare Candida species; <5% for C. glabrata, C. krusei, and C. parapsilosis) and smaller differences found after 24 h. Despite these differences, categorical agreement was excellent (>97%), with only 1 to 2% very major errors between the EUCAST method and the other two methods. PMID- 27480851 TI - Mutational Consequences of Ciprofloxacin in Escherichia coli. AB - We examined the mutagenic specificity of the widely used antibiotic ciprofloxacin (CPR), which displays weak to moderate mutagenic activity in several bacteria and generates short in-frame deletions in rpoB in Staphylococcus aureus To determine the spectrum of mutations in a system where any gene knockout would result in a recovered mutant, including frameshifts and both short and long deletions, we examined CPR-induced mutations in the thymidylate synthase-encoding thyA gene. Here, any mutation resulting in loss of thymidylate synthase activity generates trimethoprim (Trm) resistance. We found that deletions and insertions in all three reading frames predominated in the spectrum. They tend to be short deletions and cluster in two regions, one being a GC-rich region with potential extensive secondary structures. We also exploited the well-characterized rpoB Rif(r) system in Escherichia coli to determine that cells grown in the presence of sublethal doses of CPR not only induced short in-frame deletions in rpoB, but also generated base substitution mutations resulting from induction of the SOS system. Some of the specific point mutations prominent in the spectrum of a strain that overproduces the dinB-encoded Pol IV were also present after growth in CPR. However, these mutations disappeared in CPR-treated dinB mutants, whereas the deletions remained. Moreover, CPR-induced deletions also occurred in a strain lacking all three SOS-induced polymerases. We discuss the implications of these findings for the consequences of overuse of CPR and other antibiotics. PMID- 27480852 TI - Characterization of In Vitro Resistance Development to the Novel Echinocandin CD101 in Candida Species. AB - CD101 is a novel echinocandin with a long half-life undergoing clinical development for treatment of candidemia/invasive candidiasis and vulvovaginal candidiasis. The potential for and mechanisms underlying the development of resistance to CD101 in Candida species were investigated by using spontaneous resistance and serial passage selection methodologies. Four Candida spp. (C. albicans, C. glabrata, C. parapsilosis, and C. krusei) were chosen for resistance characterization with CD101, anidulafungin, and caspofungin. The frequency of spontaneous, single-step mutations conferring reduced susceptibility to CD101 at 1* the agar growth inhibition concentration was low across all species, with median frequencies ranging from 1.35 * 10(-8) to 3.86 * 10(-9), similar to ranges generated for anidulafungin and caspofungin. Serial passage of Candida spp. on agar plates containing drug gradients demonstrated a low potential for resistance development, with passage 20 CD101-selected strains possessing increases in MICs equivalent to or lower than those for the majority of strains generated under selection with anidulafungin and caspofungin. A total of 12 fks "hot spot" mutations were identified, typically in strains with the highest MIC shifts. Cross-resistance was broadly observed among the 3 echinocandins evaluated, with no CD101-selected mutants (with or without fks hot spot mutations) exhibiting reduced susceptibility to CD101 but not also to anidulafungin and/or caspofungin. Consistent with currently approved echinocandins, CD101 demonstrates a low potential for resistance development, which could be further enhanced in vivo by the high maximum concentration of drug in serum (Cmax)/area under the concentration-time curve (AUC) plasma drug exposure achieved with once-weekly dosing of CD101. PMID- 27480853 TI - Glutamate Racemase Is the Primary Target of beta-Chloro-d-Alanine in Mycobacterium tuberculosis. AB - The increasing global prevalence of drug resistance among many leading human pathogens necessitates both the development of antibiotics with novel mechanisms of action and a better understanding of the physiological activities of preexisting clinically effective drugs. Inhibition of peptidoglycan (PG) biosynthesis and cross-linking has traditionally enjoyed immense success as an antibiotic target in multiple bacterial pathogens, except in Mycobacterium tuberculosis, where it has so far been underexploited. d-Cycloserine, a clinically approved antituberculosis therapeutic, inhibits enzymes within the d alanine subbranch of the PG-biosynthetic pathway and has been a focus in our laboratory for understanding peptidoglycan biosynthesis inhibition and for drug development in studies of M. tuberculosis During our studies on alternative inhibitors of the d-alanine pathway, we discovered that the canonical alanine racemase (Alr) inhibitor beta-chloro-d-alanine (BCDA) is a very poor inhibitor of recombinant M. tuberculosis Alr, despite having potent antituberculosis activity. Through a combination of enzymology, microbiology, metabolomics, and proteomics, we show here that BCDA does not inhibit the d-alanine pathway in intact cells, consistent with its poor in vitro activity, and that it is instead a mechanism based inactivator of glutamate racemase (MurI), an upstream enzyme in the same early stage of PG biosynthesis. This is the first report to our knowledge of inhibition of MurI in M. tuberculosis and thus provides a valuable tool for studying this essential and enigmatic enzyme and a starting point for future MurI targeted antibacterial development. PMID- 27480854 TI - Peak Plasma Concentration of Azithromycin and Treatment Responses in Mycobacterium avium Complex Lung Disease. AB - Macrolides, such as azithromycin (AZM) and clarithromycin, are the cornerstones of treatment for Mycobacterium avium complex lung disease (MAC-LD). Current guidelines recommend daily therapy with AZM for cavitary MAC-LD and intermittent therapy for noncavitary MAC-LD, but the effectiveness of these regimens has not been thoroughly investigated. This study evaluated associations between microbiological response and estimated peak plasma concentrations (Cmax) of AZM. The AZM Cmax was measured in patients receiving daily therapy (250 mg of AZM daily, n = 77) or intermittent therapy (500 mg of AZM three times weekly, n = 89) for MAC-LD and daily therapy for Mycobacterium abscessus complex LD (MABC-LD) (250 mg of AZM daily, n = 55). The AZM Cmax was lower with the daily regimen for MAC-LD (median, 0.24 MUg/ml) than with the intermittent regimen for MAC-LD (median, 0.65 MUg/ml; P < 0.001) or daily therapy for MABC-LD (median, 0.53 MUg/ml; P < 0.001). After adjusting for confounding factors, AZM Cmax was independently associated with favorable microbiological responses in MAC-LD patients receiving a daily regimen (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 1.01 to 2.48; P = 0.044) but not an intermittent regimen (aOR, 0.85; 95% CI, 0.58 to 1.23, P = 0.379). With the daily AZM-based multidrug regimen for MAC-LD, a low AZM Cmax was common, whereas a higher AZM Cmax was associated with favorable microbiologic responses. The results also suggested that the addition of rifampin may lower AZM Cmax When a daily AZM-based multidrug regimen is used for treating severe MAC-LD, such as cavitary disease, the currently recommended AZM dose might be suboptimal. (This study has been registered at ClinicalTrials.gov under identifier NCT00970801.). PMID- 27480855 TI - Characterization of CTX-M-140, a Variant of CTX-M-14 Extended-Spectrum beta Lactamase with Decreased Cephalosporin Hydrolytic Activity, from Cephalosporin Resistant Proteus mirabilis. AB - CTX-M-140, a novel CTX-M-type extended-spectrum beta-lactamase (ESBL), was identified in cephalosporin-resistant clinical isolates of Proteus mirabilis CTX M-140 contained an alanine-to-threonine substitution at position 109 compared to its putative progenitor, CTX-M-14. When it was expressed in an Escherichia coli isogenic background, CTX-M-140 conferred 4- to 32-fold lower MICs of cephalosporins than those with CTX-M-14, indicating that the phenotype was attributable to this single substitution. For four mutants of CTX-M-14 that were constructed by site-directed mutagenesis (A109E, A109D, A109K, and A109R mutants), MICs of cephalosporins were similar to those for the E. coli host strain, which suggested that the alanine at position 109 was essential for cephalosporin hydrolysis. The kinetic properties of native CTX-M-14 and CTX-M-140 were consistent with the MICs for the E. coli clones. Compared with that of CTX-M 14, a lower hydrolytic activity against cephalosporins was observed for CTX-M 140. blaCTX-M-140 is located on the chromosome as determined by I-CeuI pulsed field gel electrophoresis (I-CeuI-PFGE) and Southern hybridization. The genetic environment surrounding blaCTX-M-140 is identical to the sequence found in different plasmids with blaCTX-M-9-group genes among the Enterobacteriaceae Genome sequencing and analysis showed that P. mirabilis strains with blaCTX-M-140 have a genome size of ~4 Mbp, with a GC content of 38.7% and 23 putative antibiotic resistance genes. Our results indicate that alanine at position 109 is critical for the hydrolytic activity of CTX-M-14 against oxyimino-cephalosporins. PMID- 27480856 TI - Comparative Characterization of CTX-M-64 and CTX-M-14 Provides Insights into the Structure and Catalytic Activity of the CTX-M Class of Enzymes. AB - Clinical isolates producing hybrid CTX-M beta-lactamases, presumably due to recombination between the blaCTX-M-15 and blaCTX-M-14 elements, have emerged in recent years. Among the hybrid enzymes, CTX-M-64 and CTX-M-14 display the most significant difference in catalytic activity. This study aims to investigate the mechanisms underlying such differential enzymatic activities in order to provide insight into the structure/function relationship of this class of enzymes. Sequence alignment analysis showed that the major differences between the amino acid composition of CTX-M-64 and CTX-M-14 lie at both the N and C termini of the enzymes. Single or multiple amino acid substitutions introduced into CTX-M-64 and CTX-M-14 were found to produce only minor effects on hydrolytic functions; such a finding is consistent with the notion that the discrepancy between the functional activities of the two enzymes is not the result of only a few amino acid changes but is attributable to interactions between a unique set of amino acid residues in each enzyme. This theory is supported by the results of the thermal stability assay, which confirmed that CTX-M-64 is significantly more stable than CTX-M-14. Our data confirmed that, in addition to the important residues located in the active site, residues distal to the active site also contribute to the catalytic activity of the enzyme through stabilizing its structural integrity. PMID- 27480858 TI - In Vitro Evaluation of the Activity of Imipenem-Relebactam against 451 Recent Clinical Isolates of Bacteroides Group and Related Species. AB - We evaluated the in vitro activity of imipenem-relebactam (imipenem-MK7655) against 451 recent clinical isolates within the Bacteroides group and related species. Relebactam did not enhance or inhibit the activity of imipenem against Bacteroides fragilis or other Bacteroides species. No synergistic or antagonistic effect was observed. The MICs of imipenem-relebactam were equal to or within one dilution of the MICs of these isolates to imipenem. PMID- 27480857 TI - High Prevalence of Hypervirulent Klebsiella pneumoniae Infection in China: Geographic Distribution, Clinical Characteristics, and Antimicrobial Resistance. AB - Hypervirulent Klebsiella pneumoniae (hvKP) is traditionally defined by hypermucoviscosity, but data based on genetic background are limited. Antimicrobial-resistant hvKP has been increasingly reported but has not yet been systematically studied. K. pneumoniae isolates from bloodstream infections, hospital-acquired pneumonia, and intra-abdominal infections were collected from 10 cities in China during February to July 2013. Clinical data were collected from medical records. All K. pneumoniae isolates were investigated by antimicrobial susceptibility testing, string test, extended-spectrum beta lactamase (ESBL) gene detection, capsular serotypes, virulence gene profiles, and multilocus sequence typing. hvKP was defined by aerobactin detection. Of 230 K. pneumoniae isolates, 37.8% were hvKP. The prevalence of hvKP varied among different cities, with the highest rate in Wuhan (73.9%) and the lowest in Zhejiang (8.3%). Hypermucoviscosity and the presence of K1, K2, K20, and rmpA genes were strongly associated with hvKP (P < 0.001). A significantly higher incidence of liver abscess (P = 0.026), sepsis (P = 0.038), and invasive infections (P = 0.043) was caused by hvKP. Cancer (odds ratio [OR], 2.285) and diabetes mellitus (OR, 2.256) appeared to be independent variables associated with hvKP infections by multivariate analysis. Importantly, 12.6% of hvKP isolates produced ESBLs, and most of them carried blaCTX-M genes. Patients with neutropenia (37.5% versus 5.6%; P = 0.020), history of systemic steroid therapy (37.5% versus 5.6%; P = 0.020), and combination therapy (62.5% versus 16.7%; P = 0.009) were more likely to be infected with ESBL-producing hvKP. The prevalence of hvKP is high in China and has a varied geographic distribution. ESBL-producing hvKP is emerging, suggesting an urgent need to enhance clinical awareness, especially for immunocompromised patients receiving combination therapy. PMID- 27480859 TI - HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients. AB - There are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients. We report the pharmacokinetics of rifampin, isoniazid, and pyrazinamide in a cohort of patients being treated for active tuberculosis, the majority of whom were coinfected with HIV-1 and had commenced antiretroviral therapy within 2 months of starting antituberculosis treatment. We also examined the association between antituberculosis drug concentrations and reported drug side effects at the 2-month clinical review. One hundred patients with pulmonary tuberculosis (65% coinfected with HIV-1) were intensively sampled to determine rifampin, isoniazid, and pyrazinamide plasma concentrations after 7 to 8 weeks of a daily quadruple-therapy regimen dosed according to World Health Organization (WHO) weight bands. Pharmacokinetic parameters were determined for each patient by using nonlinear mixed-effects models. HIV-1-coinfected patients had lower clearance rates for rifampin (21% decrease) and isoniazid (23% decrease) than HIV-1-uninfected patients, with resulting higher areas under the concentration-time curve from 0 to 24 h (AUC0 24) and maximum concentrations of drug in serum (Cmax). Antiretroviral therapy (ART) that included double-standard-dose lopinavir/ritonavir further lowered rifampin clearance, by 46%, and increased the AUC0-24 The current uniform dosing (per kilogram of body weight) across WHO weight bands was associated with a trend of decreased pharmacokinetic exposures for the lowest weight band. Use of fat free mass as opposed to total body weight for allometric scaling of clearance significantly improved the model. Ambulant HIV-1-coinfected patients, the majority of whom were coprescribed ART, did not have reduced antituberculosis drug concentrations compared to HIV-1-uninfected patients. PMID- 27480860 TI - Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIalpha. AB - Encephalomyocarditis virus (EMCV), like hepatitis C virus (HCV), requires phosphatidylinositol 4-kinase IIIalpha (PI4KA) for genome replication. Here, we demonstrate that tyrphostin AG1478, a known epidermal growth factor receptor (EGFR) inhibitor, also inhibits PI4KA activity, both in vitro and in cells. AG1478 impaired replication of EMCV and HCV but not that of an EMCV mutant previously shown to escape PI4KA inhibition. This work uncovers novel cellular and antiviral properties of AG1478, a compound previously regarded only as a cancer chemotherapy agent. PMID- 27480861 TI - Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms. AB - Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel beta-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms. Aeromonas hydrophila XS91-4-1, Pseudomonas aeruginosa CGMCC1.2620, and Escherichia coli ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition, P. aeruginosa and E. coli exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of P. aeruginosa was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in P. aeruginosa Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I. PMID- 27480862 TI - Novel Structure of Enterococcus faecium-Originated ermB-Positive Tn1546-Like Element in Staphylococcus aureus. AB - We determined the resistance determinants in 274 erythromycin-resistant methicillin-susceptible Staphylococcus aureus (MSSA) isolates during a 13-year period, 2000 to 2012. The resistance phenotypes, inducible macrolide-lincosamide streptogramin (iMLS), constitutive MLS (cMLS), and macrolide-streptogramin (MS) resistance phenotypes, were examined by a double-disk diffusion D test. The ermB gene was more frequent (35%; 97/274) than ermC (27%; 75/274) or ermA (21%; 58/274). All 97 ermB-positive isolates harbored Tn551 and IS1216V The majority (89/97) of ermB-positive isolates displayed the cMLS phenotype and carried mobile element structure (MES)-like structures, which has been previously reported in sequence type 59 (ST59) methicillin-resistant S. aureus (MRSA). The remaining 8 ermB-carrying isolates, belonging to ST7 (n = 4), ST5 (n = 3), and ST59 (n = 1), were sasK intact and did not carry MES-like structures. Unlike a MES-like structure that was located on the chromosome, the ermB elements on sasK-intact isolates were located on plasmids by S1 nuclease pulsed-field gel electrophoresis (PFGE) analysis and conjugation tests. Sequence data for the ermB-containing region (14,566 bp) from ST59 NTUH_3874 revealed that the best match was a Tn1546 like element in plasmid pMCCL2 DNA (GenBank accession number AP009486) of Macrococcus caseolyticus Tn1546 is recognized as an enterococcal transposon and was known from the vancomycin resistance gene cluster in vancomycin-resistant Enterococcus (VRE). So far, acquisitions of Tn1546 in S. aureus have occurred in clonal complex 5 (CC5) MRSA, but not in MSSA. This is the first report that MSSA harbors an Enterococcus faecium-originated ermB-positive Tn1546-like element located on a plasmid. PMID- 27480863 TI - Clinical Variants of the Native Class D beta-Lactamase of Acinetobacter baumannii Pose an Emerging Threat through Increased Hydrolytic Activity against Carbapenems. AB - The threat posed by the chromosomally encoded class D beta-lactamase of Acinetobacter baumannii (OXA-51/66) has been unclear, in part because of its relatively low affinity and turnover rate for carbapenems. Several hundred clinical variants of OXA-51/66 have been reported, many with substitutions of active-site residues. We determined the kinetic properties of OXA-66 and five clinical variants with respect to a wide variety of beta-lactam substrates. The five variants displayed enhanced activity against carbapenems and in some cases against penicillins, late-generation cephalosporins, and the monobactam aztreonam. Molecular dynamics simulations show that in OXA-66, P130 inhibits the side-chain rotation of I129 and thereby prevents doripenem binding because of steric clash. A single amino acid substitution at this position (P130Q) in the variant OXA-109 greatly enhances the mobility of both I129 and a key active-site tryptophan (W222), thereby facilitating carbapenem binding. This expansion of substrate specificity represents a very worrisome development for the efficacy of beta-lactams against this troublesome pathogen. PMID- 27480864 TI - In Vitro and In Vivo Drug Interaction Study of Two Lead Combinations, Oxantel Pamoate plus Albendazole and Albendazole plus Mebendazole, for the Treatment of Soil-Transmitted Helminthiasis. AB - The current treatments against Trichuris trichiura, albendazole and mebendazole, are only poorly efficacious. Therefore, combination chemotherapy was recommended for treating soil-transmitted helminthiasis. Albendazole-mebendazole and albendazole-oxantel pamoate have shown promising results in clinical trials. However, in vitro and in vivo drug interaction studies should be performed before their simultaneous treatment can be recommended. Inhibition of human recombinant cytochromes P450 (CYPs) CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was tested by exposure to albendazole, albendazole sulfoxide, mebendazole, and oxantel pamoate, as well as albendazole-mebendazole, albendazole sulfoxide-mebendazole, albendazole-oxantel pamoate, and albendazole sulfoxide-oxantel pamoate. A high pressure liquid chromatography (HPLC)-UV/visible spectroscopy method was developed and validated for simultaneous quantification of albendazole sulfoxide, albendazole sulfone, mebendazole, and oxantel pamoate in plasma. Albendazole, mebendazole, oxantel pamoate, albendazole-mebendazole, and albendazole-oxantel pamoate were orally applied to rats (100 mg/kg) and pharmacokinetic parameters calculated. CYP1A2 showed a 2.6-fold increased inhibition by albendazole-oxantel pamoate (50% inhibitory concentration [IC50] = 3.1 MUM) and a 3.9-fold increased inhibition by albendazole sulfoxide-mebendazole (IC50 = 3.8 MUM) compared to the single drugs. In rats, mebendazole's area under the concentration-time curve (AUC) and maximal plasma concentration (Cmax) were augmented 3.5- and 2.8-fold, respectively (P = 0.02 for both) when coadministered with albendazole compared to mebendazole alone. Albendazole sulfone was slightly affected by albendazole mebendazole, displaying a 1.3-fold-elevated AUC compared to albendazole alone. Oxantel pamoate could not be quantified, translating to a bioavailability below 0.025% in rats. Elevated plasma levels of albendazole sulfoxide, albendazole sulfone, and mebendazole in coadministrations are probably not mediated by CYP based drug-drug interaction. Even though this study indicates that it is safe to coadminister albendazole-oxantel pamoate and albendazole-mebendazole, human pharmacokinetic studies are recommended. PMID- 27480865 TI - Rare Spontaneous Loss of Multiresistance Gene Carrying IncI/ST12 Plasmid in Escherichia coli in Pig Microbiota. AB - Resistance to extended-spectrum cephalosporins (ESCs) is a matter of considerable concern for public health. Here, we studied the spontaneous loss of an extended spectrum beta-lactamase (ESBL)-encoding plasmid from a rifampin-resistant Escherichia coli isolate orally inoculated into pigs under controlled conditions. Fecal samples were collected and cultured on rifampin-supplemented medium, and the resistance of the E. coli isolates to ESCs was studied by phenotypic tests, PCR detection of plasmid genes, and complete sequencing. The results showed that only 3 out of 353 rifampin-resistant E. coli isolates were ESC susceptible, and PCR and bioinformatics analysis confirmed the loss of the plasmid. These in vivo experiments indicate that the loss of an ESBL-encoding plasmid seems a rare event in gut microbiota. PMID- 27480866 TI - Efficacy of beta-Lactam-plus-Macrolide Combination Therapy in a Mouse Model of Lethal Pneumococcal Pneumonia. AB - Community-acquired pneumonia is a common disease with considerable morbidity and mortality, for which Streptococcus pneumoniae is accepted as a leading cause. Although beta-lactam-plus-macrolide combination therapy for this disease is recommended in several guidelines, the clinical efficacy of this strategy against pneumococcal pneumonia remains controversial. In this study, we examined the effects of beta-lactam-plus-macrolide combination therapy on lethal mouse pneumococcal pneumonia and explored the mechanisms of action in vitro and in vivo We investigated survival, lung bacterial burden, and cellular host responses in bronchoalveolar lavage fluids obtained from mice infected with pneumonia and treated with ceftriaxone, azithromycin, or both in combination. Although in vitro synergy was not observed, significant survival benefits were demonstrated with combination treatment. Lung neutrophil influx was significantly lower in the ceftriaxone-plus-azithromycin-treated group than in the ceftriaxone-treated group, whereas no differences in the lung bacterial burden were observed on day 3 between the ceftriaxone-plus-azithromycin-treated group and the ceftriaxone treated group. Notably, the analysis of cell surface markers in the ceftriaxone plus-azithromycin combination group exhibited upregulation of presumed immune checkpoint ligand CD86 and major histocompatibility complex class II in neutrophils and CD11b-positive CD11c-positive (CD11b(+) CD11c(+)) macrophages and dendritic cells, as well as downregulation of immune checkpoint receptors cytotoxic-T lymphocyte-associated antigen 4 and programmed death 1 in T helper and T regulatory cells. Our data demonstrate that the survival benefits of ceftriaxone-plus-azithromycin therapy occur through modulation of immune checkpoints in mouse pneumococcal pneumonia. In addition, immune checkpoint molecules may be a novel target class for future macrolide research. PMID- 27480867 TI - A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy. AB - Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens. PMID- 27480870 TI - Correction: MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer. PMID- 27480868 TI - The RTA3 Gene, Encoding a Putative Lipid Translocase, Influences the Susceptibility of Candida albicans to Fluconazole. AB - The RTA3 gene, coding for a member of the Rta1p-like lipid-translocating exporter family, is coordinately upregulated with the ATP-binding cassette transporter genes CDR1 and CDR2 in azole-resistant clinical isolates of Candida albicans that carry activating mutations in the transcription factor Tac1p. We show here that deleting RTA3 in an azole-resistant clinical isolate carrying a Tac1p-activating mutation lowered fluconazole resistance by 2-fold, while overexpressing RTA3 in an azole-susceptible clinical isolate resulted in enhanced fluconazole tolerance associated with trailing growth in a liquid microtiter plate assay. We also demonstrate that an Rta3p-green fluorescent protein (GFP) fusion protein localizes predominantly to the plasma membrane, consistent with a putative function for Rta3p as a lipid translocase. PMID- 27480871 TI - Correction: Prospective Validation of Pooled Prognostic Factors in Women with Advanced Cervical Cancer Treated with Chemotherapy with/without Bevacizumab: NRG Oncology/GOG Study. PMID- 27480872 TI - Correction: Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma. PMID- 27480873 TI - A Bivariate Genetic Analysis of Drug Abuse Ascertained Through Medical and Criminal Registries in Swedish Twins, Siblings and Half-Siblings. AB - Using Swedish nationwide registry data, the authors investigated the correlation of genetic and environmental risk factors in the etiology of drug abuse as ascertained from medical and criminal registries by modeling twin and sibling data. Medical drug abuse was defined using public inpatient and outpatient records, while criminal drug abuse was ascertained through legal records. Twin, full and half sibling pairs were obtained from the national twin and genealogical registers. Information about sibling pair residence within the same household was obtained from Statistics Sweden. Standard bivariate genetic structural equation modeling was applied to the population-based data on drug abuse ascertained through medical and crime registries, using OpenMx. Analyses of all possible pairs of twins (MZ: N = 4482; DZ: N = 9838 pairs), full- (N = 1,278,086) and half siblings (paternal: N = 7767; maternal N = 70,553) who grew up together suggested that factors explaining familial resemblance for drug abuse as defined through medical or criminal registries were mostly the same. Results showed substantial heritability and moderate contributions of shared environmental factors to drug abuse; both were higher in males versus females, and higher for drug abuse ascertained through criminal than medical records. Because of the low prevalence of both assessments of drug abuse, having access to population data was crucial to obtain stable estimates. Using objective registry data, the authors found that drug abuse-whether ascertained through medical versus criminal records-was highly heritable. Furthermore, shared environmental factors contributed significantly to the liability of drug abuse. Genetic and shared environmental risk factors for these two forms of drug abuse were highly correlated. PMID- 27480874 TI - A Pharmacist-Physician Collaboration to Optimize Benzodiazepine Use for Anxiety and Sleep Symptom Control in Primary Care. AB - INTRODUCTION: Benzodiazepines are prescribed inappropriately in up to 40% of outpatients. The purpose of this study is to describe a collaborative team-based care model in which clinical pharmacists work with primary care providers (PCPs) to improve the safe use of benzodiazepines for anxiety and sleep disorders and to assess the preliminary results of the impact of the clinical service on patient outcomes. METHODS: Adult patients were eligible if they received care from the academic primary care clinic, were prescribed a benzodiazepine chronically, and were not pregnant or managed by psychiatry. Outcomes included baseline PCP confidence and knowledge of appropriate benzodiazepine use, patient symptom severity, and medication changes. RESULTS: Twenty-five of 57 PCPs responded to the survey. PCPs reported greater confidence in diagnosing and treating generalized anxiety and panic disorders than sleep disorder and had variable knowledge of appropriate benzodiazepine prescribing. Twenty-nine patients had at least 1 visit. Over 44 total patient visits, 59% resulted in the addition or optimization of a nonbenzodiazepine medication and 46% resulted in the discontinuation or optimization of a benzodiazepine. Generalized anxiety symptom severity scores significantly improved (-2.0; 95% confidence interval (CI): -3.57 to -0.43). CONCLUSION: Collaborative team-based models that include clinical pharmacists in primary care can assist in optimizing high-risk benzodiazepine use. Although these findings suggest improvements in safe medication use and symptoms, additional studies are needed to confirm these preliminary results. PMID- 27480875 TI - Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence, and a Method for its Control. AB - PURPOSE: To verify previously reported findings for the European Medicines Agency's method for Average Bioequivalence with Expanding Limits (ABEL) for assessing highly variable drugs and to extend the assessment for other replicate designs in a wide range of sample sizes and CVs. To explore the properties of a new modified method which maintains the consumer risk <=0.05 in all cases. METHODS: Monte-Carlo simulations of three different replicate designs covering a wide range of sample sizes and intra-subject variabilities were performed. RESULTS: At the switching variability of CV wR 30% the consumer risk is substantially inflated to up to 9.2%, which translates into a relative increase of up to 84%. The critical region of inflated type I errors ranges approximately from CV wR 25 up to 45%. The proposed method of iteratively adjusting alpha maintains the consumer risk at the desired level of <=5% independent from design, variability, and sample size. CONCLUSIONS: Applying the European Medicines Agency's ABEL method at the nominal level of 0.05 inflates the type I error to an unacceptable degree, especially close to a CV wR of 30%. To control the type I error nominal levels <=0.05 should be employed. Iteratively adjusting alpha is suggested to find optimal levels of the test. PMID- 27480876 TI - Vitamin A-retinoid signaling in pulmonary development and disease. AB - Retinoic acid (RA), the active form of vitamin A, regulates key developmental processes in multiple organs. In the developing lung, RA is crucial for normal growth and differentiation of airways. Disruption in RA signaling or vitamin A deficiency (VAD) has been linked to aberrant development of the lung including alterations in the airway smooth muscle (SM) differentiation, development, and function. These alterations have been linked to disease states including asthma in both human and animal models. PMID- 27480878 TI - RETRACTED ARTICLE: TIEG1 suppression enhances the therapeutic efficacy of human adipose-derived mesenchymal stem cells in myocardial infarct repair. PMID- 27480877 TI - Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy? AB - Influenza viruses (IVs) circulate seasonally and are a common cause of respiratory infections in pediatric and adult patients. Additionally, recurrent pandemics cause massive morbidity and mortality worldwide. Infection may result in rapid progressive viral pneumonia with fatal outcome. Since accurate treatment strategies are still missing, research refocuses attention to lung pathology and cellular crosstalk to develop new therapeutic options.Alveolar epithelial cells (AECs) play an important role in orchestrating the pulmonary antiviral host response. After IV infection they release a cascade of immune mediators, one of which is granulocyte and macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to promote differentiation, activation and mobilization of myeloid cells. In the lung, GM-CSF drives immune functions of alveolar macrophages and dendritic cells (DCs) and also improves epithelial repair processes through direct interaction with AECs. During IV infection, AEC-derived GM-CSF shows a lung protective effect that is also present after local GM-CSF application. This mini review provides an overview on GM-CSF-modulated immune responses to IV pneumonia and its therapeutic potential in severe IV pneumonia. PMID- 27480879 TI - The utility of T-wave alternans during the morning in the summer for the risk stratification of patients with Brugada syndrome. AB - The prognostic value of the seasonal variations of T-wave alternans (TWA) and heart rate variability (HRV), and the seasonal distribution of ventricular fibrillation (VF) in Brugada syndrome (Br-S) is unknown. We assessed the utility of seasonal variations in TWA and HRV for risk stratification in Br-S using a 24 h multichannel Holter electrocardiogram (24-M-ECG). We enrolled 81 patients with Br-S (grouped according to their history of VF, n = 12; syncope, n = 8; no symptoms, n = 61) who underwent 24-M-ECG in all four seasons. Precordial electrodes were attached to the third (3L-V2) and fourth (4L-V2, 4L-V5) intercostal spaces. We determined the maximum TWA (max-TWA) values and calculated HRV during night and morning time periods for all seasons. During a follow-up period of 5.8 +/- 2.8 years, 11 patients experienced new VF episodes and there was a peak in new VF episodes in the summer. The VF group had the greatest 3L-V2 max-TWA value during morning time in the summer among the three groups and showed higher 3L-V2 max-TWA value than in the other seasons. The cutoff value for the 3L V2 max-TWA during morning time in the summer was determined to be 42 uV using ROC analysis (82 % sensitivity, 74 % specificity; p = 0.0006). Multivariate analysis revealed that a 3L-V2 max-TWA value >=42 uV during morning time in the summer and previous VF episodes were predictors of future VF episodes. The 3L-V2 max-TWA value during morning time in the summer may be a useful predictor of future VF episodes in Br-S. PMID- 27480880 TI - A theoretical investigation of the interactions between hydroxyl-functionalized ionic liquid and water/methanol/dimethyl sulfoxide. AB - Density functional calculations have been used to investigate the interactions of 1-(2-hydroxyethyl)-3-methylimidazolium ([C2OHmim](+))-based ionic liquids (hydroxyl ILs) with water (H2O), methanol (CH3OH), and dimethyl sulfoxide (DMSO). It was found that the cosolvent molecules interact with the anion and cation of each ionic liquid through different atoms, i.e., H and O atoms, respectively. The interactions between the cosolvent molecules and 1-ethyl-3-methylimizolium ([C2mim](+))-based ionic liquids (nonhydroxyl ILs) were also studied for comparison. In the cosolvent-[nonhydroxyl ILs] systems, a furcated H-bond was formed between the O atom of the cosolvent molecule and the C2-H and C6-H, while there were always H-bonds involving the OH group of the cation in the cosolvent [hydroxyl ILs] systems. Introducing an OH group on the ethyl side of the imidazolium ring may change the order of solubility of the molecular liquids. PMID- 27480881 TI - Multitaxon activity profiling reveals differential microbial response to reduced seawater pH and oil pollution. AB - There is growing concern that predicted changes to global ocean chemistry will interact with anthropogenic pollution to significantly alter marine microbial composition and function. However, knowledge of the compounding effects of climate change stressors and anthropogenic pollution is limited. Here, we used 16S and 18S rRNA (cDNA)-based activity profiling to investigate the differential responses of selected microbial taxa to ocean acidification and oil hydrocarbon contamination under controlled laboratory conditions. Our results revealed that a lower relative abundance of sulphate-reducing bacteria (Desulfosarcina/Desulfococcus clade) due to an adverse effect of seawater acidification and oil hydrocarbon contamination (reduced pH-oil treatment) may be coupled to changes in sediment archaeal communities. In particular, we observed a pronounced compositional shift and marked reduction in the prevalence of otherwise abundant operational taxonomic units (OTUs) belonging to the archaeal Marine Benthic Group B and Marine Hydrothermal Vent Group (MHVG) in the reduced pH-oil treatment. Conversely, the abundance of several putative hydrocarbonoclastic fungal OTUs was higher in the reduced pH-oil treatment. Sediment hydrocarbon profiling, furthermore, revealed higher concentrations of several alkanes in the reduced pH-oil treatment, corroborating the functional implications of the structural changes to microbial community composition. Collectively, our results advance the understanding of the response of a complex microbial community to the interaction between reduced pH and anthropogenic pollution. In future acidified marine environments, oil hydrocarbon contamination may alter the typical mixotrophic and k-/r-strategist composition of surface sediment microbiomes towards a more heterotrophic state with lower doubling rates, thereby impairing the ability of the ecosystem to recover from acute oil contamination events. PMID- 27480882 TI - Regret around fertility choices is decreased with pre-treatment counseling in gynecologic cancer patients. AB - PURPOSE: Data have demonstrated an association between regret and lack of fertility counseling among patients undergoing treatment for non-gynecologic cancers. We sought to determine if fertility-related regret is reduced with pre treatment counseling or fertility-sparing surgery (FSS) in patients with gynecologic cancers. METHODS: A cross-sectional survey was administered to 593 reproductive-age survivors (18-40 years old at diagnosis) of localized cervix, ovarian, or endometrial cancers that were eligible for FSS. A validated decision regret score was used to evaluate regret in patients. RESULTS: Four hundred seventy women completed the survey. Forty-six percent received pre-treatment counseling about treatment's effects on fertility. Having received counseling (adjusted beta-coefficient of -1.24, 95 % CI = -2.29 to -0.18, p = 0.02), satisfactory counseling (adjusted beta-coefficient of -2.71, 95 % CI = -3.86 to 1.57, p < 0.001), and FSS (adjusted beta-coefficient of -1.26, 95 % CI = -2.39 to -0.14, p = 0.03) were associated with lower regret post-treatment, after adjusting for age. Time since diagnosis, prior parity, socioeconomic status and cancer type were not associated with regret (p > 0.05). While 50 % of women reported desiring more children after diagnosis, desire for children after treatment was associated with increased regret (adjusted beta-coefficient of 3.97, 95 % CI = 2.92-5.02, p < 0.001). CONCLUSIONS: Though less than half of study participants received counseling about the effect of cancer treatment on future fertility, both fertility counseling and FSS were associated with decreased regret in reproductive-aged women with gynecologic cancers. The desire for more children after treatment was associated with increased regret. IMPLICATIONS FOR CANCER SURVIVORS: Inquiring about fertility desires and providing counseling regarding reproductive outcomes following cancer treatment should be implemented as part of the treatment process. PMID- 27480883 TI - Factors influencing implementation of a survivorship care plan-a quantitative process evaluation of the ROGY Care trial. AB - PURPOSE: The aim of this study is to investigate the factors that influence implementation of Survivorship Care Plans (SCPs) in the intervention arm of the ROGY Care trial by (1) assessing the level of SCP receipt in the ROGY Care trial and (2) identifying patient- and provider-level factors that influence SCP receipt. METHODS: Between 2011 and 2015, a pragmatic cluster randomized controlled-trial was conducted on the effects of automatically generated SCPs. Endometrial (N = 117) and ovarian (N = 61) cancer patients were allocated to 'SCP care', as provided by their SCP care providers (N = 10). Associations between SCP receipt (self-reported SCP receipt and actually generated SCPs), patient-factors (socio-demographic-, clinical-, and personality factors), and care provider factors (profession and a-priori motivation regarding SCP provision) were tested in univariate analysis. The odds ratios of factors influencing self-reported SCP receipt were estimated with a multivariate regression model. RESULTS: Of all patients in the SCP care arm (N = 178), SCPs were generated by the care provider for 90 % of the patients and 70 % of the patients reported that they had received an SCP. Patients with older age, ovarian cancer, type D (distressed) personality, and patients that completed the questionnaire a longer period of time after the SCP consult were more likely to report no SCP receipt. CONCLUSIONS: SCP receipt was influenced by patient- but not care-provider factors. IMPLICATIONS FOR CANCER SURVIVORS: Certain patient groups were less likely to report SCP receipt. Whether all patients are in need of an SCP, requires further investigation. If they do, more efforts need to be made towards the implementation of SCPs. PMID- 27480884 TI - Associations between Attention Deficit Hyperactivity Disorder and Eating Disorders by Gender: Results from the National Comorbidity Survey Replication. AB - Few studies have assessed the association between attention-deficit hyperactivity disorder (ADHD) and eating disorders (ED) separately in men and women, especially in representative samples. Using data from the National Comorbidity Survey Replication, lifetime and past 12-month prevalence of Diagnostic and Statistical Manual of Mental Disorders IV, ADHD was compared in men and women with and without diagnoses of Diagnostic and Statistical Manual of Mental Disorders IV ED and any binge eating (BE) using logistic regression models adjusted for gender and age. In both sexes, those with lifetime and past 12-month BE and binge eating disorder had significantly higher prevalence of ADHD than those without BE and binge eating disorder, respectively. Women with lifetime and past 12-month bulimia nervosa and lifetime anorexia nervosa also had significantly higher prevalence of ADHD compared with women without these diagnoses. Given that ADHD invariably began earlier than the ED, ADHD may be an important risk factor for subsequent BE and related ED, and there may be opportunities for intervention among youth with ADHD. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27480886 TI - Presumed topiramate retinopathy: a case report. AB - BACKGROUND: We report a case of peripheral pigmentary retinopathy and visual field loss following topiramate use for uncontrolled seizures. Such side effects have not been well documented despite the increasing use of topiramate in the past 10 years. A thorough search of available English literature revealed only a small number of reports of topiramate-induced retinopathy or visual field defects in humans. One similar case has been described. We are concerned about the possible rare instances of this occurrence in future patients and hence would like to propose a presumed correlation. CASE PRESENTATION: A 48-year-old Chinese woman developed blurred vision after 9 months of topiramate use. Her visual acuity dropped from 1.2 to 0.7 in both eyes, with bilateral diffuse pigmentary retinopathy and a constricted visual field. Despite an improvement in visual acuity after cessation of the drug, the other clinical findings remained. The temporal relationship between the initiation of topiramate and the visual disturbance suggests that topiramate could be the cause of such signs and symptoms. CONCLUSION: Topiramate potentially causes pigmentary retinopathy and constricted visual field. PMID- 27480885 TI - MRI with ferumoxytol: A single center experience of safety across the age spectrum. AB - PURPOSE: To summarize our single-center safety experience with the off-label use of ferumoxytol for magnetic resonance imaging (MRI) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium. MATERIALS AND METHODS: Consecutive patients who underwent ferumoxytol-enhanced (FE) MRI exams were included. Adverse events (AEs) were classified according to the Common Terminology Criteria for Adverse Events v4.0. In a subgroup of patients examined under general anesthesia, recording of blood pressure, heart rate, oxygen saturation, and end-tidal CO2 was performed. A comparable group of 23 patients who underwent gadofosveset-enhanced (GE) MRI under anesthesia with similar monitoring was also analyzed. RESULTS: In all, 217 unique patients, ages 3 days to 94 years, underwent FE-MRI. No ferumoxytol related severe, life-threatening, or fatal AEs occurred acutely or at follow-up. Two patients developed ferumoxytol-related nausea. Between-group (FE- vs. GE-MRI) comparisons showed no statistical difference in heart rate (P = 0.69, 95% confidence interval [CI] 96-113 bpm), mean arterial blood pressure (MAP) (P = 0.74, 95% CI 44-52 mmHg), oxygen saturation (P = 0.76, 95% CI 94-98%), and end tidal CO2 (P = 0.73, 95% CI 31-37 mmHg). No significant change in MAP (P = 0.12, 95% CI 50-58 mmHg) or heart rate (P = 0.25, 95% CI 91-105 bpm) was noted between slow infusion of ferumoxytol (n = 113) vs. bolus injection (n = 104). CONCLUSION: In our single-center experience, no serious AEs occurred with the diagnostic use of ferumoxytol across a wide spectrum of age, renal function, and indications. Because of the limited sample size, firm conclusions cannot be drawn about the generalizability of our results. Thus, vigilance and monitoring are recommended to mitigate potential rare adverse reactions. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:804-812. PMID- 27480887 TI - Perception of mind and dehumanization: Human, animal, or machine? AB - Dehumanization is reached through several approaches, including the attribute based model of mind perception and the metaphor-based model of dehumanization. We performed two studies to find different (de)humanized images for three targets: Professional people, Evil people, and Lowest of the low. In Study 1, we examined dimensions of mind, expecting the last two categories to be dehumanized through denial of agency (Lowest of the low) or experience (Evil people), compared with humanized targets (Professional people). Study 2 aimed to distinguish these targets using metaphors. We predicted that Evil and Lowest of the low targets would suffer mechanistic and animalistic dehumanization, respectively; our predictions were confirmed, but the metaphor-based model nuanced these results: animalistic and mechanistic dehumanization were shown as overlapping rather than independent. Evil persons were perceived as "killing machines" and "predators." Finally, Lowest of the low were not animalized but considered human beings. We discuss possible interpretations. PMID- 27480889 TI - Overtreatment of nonpurulent cellulitis. PMID- 27480888 TI - Genetic Characterization of Circulating African Swine Fever Viruses in Nigeria (2007-2015). AB - Sequencing and analysis of three discrete genome regions of African swine fever viruses (ASFV) from archival samples collected in 2007-2011 and active and passive surveillance between 2012 and 2015 in Nigeria were carried out. Analysis was conducted by genotyping of three single-copy African swine fever (ASF) genes. The E183L and B646L genes that encode structural proteins p54 and p72, respectively, were utilized to delineate genotypes before intragenotypic resolution by characterization of the tetrameric amino acid repeat region within the hypervariable central variable region of the B602L gene. The results showed no variation in the p72 and p54 gene regions sequenced. Phylogeny of p72 sequences revealed that all the Nigerian isolates belonged to genotype I, while that of the p54 recovered the Ia genotype. Analysis of B602L gene revealed the differences in the number of tetrameric repeats. Four new variants (Tet-15, Tet 17a, Tet-17b and Tet-48) were recovered, while a fifth variant (Tet-20) was the most widely distributed in the country displacing Tet-36 reported previously in 2003-2006. The viruses responsible for ASF outbreaks in Nigeria are from very closely related but mutated variants of the virus that have been circulating since 1997. A practical implication of the genetic variability of the Nigerian viral isolates in this study is the need for continuous sampling and analysis of circulating viruses, which will provide epidemiological information on the evolution of ASFV in the field versus new incursion for informed strategic control of the disease in the country. PMID- 27480890 TI - [Telemedicine in the ICU - the possibilities and limitations of an innovation]. AB - BACKGROUND: Intensive care medicine is challenged by demographic changes and an increasing number of patient combined with existing shortage of doctors. Telemedicine is a promising approach to ensure patient care in the coming years. Due to a shortage of intensive care physicians in the USA, comprehensive telemedicine coverage has already been established. To date, 11 % of all hospitals are supported by a telemedicine center. The beneficial impact in terms of quality of care, patient safety and economic factors has been confirmed in numerous multicenter studies. RESULTS: In the largest multicenter study by Lilly et al., including 107,432 critically ill patients in the intervention group, telemedicine interventions led to a reduced ICU and hospital mortality. In addition, tele-consulting significantly reduced the ICU- and hospital length of stay. These findings were further supported by following studies and metaanalysis, which confirmed these results. The incidence of ventilator associated pneumonia and catheter-associated infections was significantly reduced, when compared to the preintervention group. Furthermore, patient safety and treatment outcomes were improved by increased guideline adherence. Last, the telemedicine intervention significantly decreased the overall treatment costs. These positive results were reproducible even in larger and academic hospitals. At the same time it should be pointed out that a transfer to other health care systems should be considered cautiously in the context of different local infrastructure and culture. Finally, it has to be investigated to what extent the results can be transferred to the health-care situation in Germany. CONCLUSION: Previous data demonstrated that telemedical support can improve the outcome in critically ill patients, both during hospitalization as well as in the long-term result until the discharge home. Telemedicine is neither a magic bullet nor a replacement for a physician. Instead it is a new type of medical cooperation to further improve the outcomes of critically ill patients. PMID- 27480891 TI - Opponent's comments. PMID- 27480892 TI - Opponent's comments. PMID- 27480895 TI - Understanding the introduction and circulation of environmental methicillin resistant Staphylococcus aureus in a large academic medical center during a nonoutbreak, year-long period. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of health care-associated infections, and the role that the hospital environment might play in the transmission cycle remains undefined. We determined the distribution of environmental MRSA isolates, studied contamination patterns of MRSA clones, and evaluated the association between MRSA patient load and environmental contamination. METHODS: High-contact surfaces were sampled for 12 consecutive months in 2 inpatient wards. Concurrently, aggregated data of MRSA patient infection burden were analyzed. Antimicrobial susceptibility testing and molecular epidemiologic tools were used to characterize and analyze all isolates. RESULTS: Overall, 23.7% of the surfaces were MRSA positive. Handrails (58.3%), the medicine room (50.0%), chart holders (41.7%), and access doors (33.3%) were the most contaminated surfaces. Thirty-four different MRSA pulsotypes were identified. Forty-six percent of the isolates were SCCmecII/USA100. Recurrent introduction and reintroduction of clones and hot spot surfaces frequently contaminated with different MRSA strains were observed. However, long-term contamination (maintenance) was not observed. The burden of clinical MRSA cases was not an indicator of the level of environmental contamination. CONCLUSIONS: MRSA frequently contaminates hospital surfaces during nonoutbreak periods and is not associated with the number of clinical MRSA cases. Monitoring and thorough cleaning and disinfection of hot spot surfaces are necessary to minimize the presence of MRSA in the hospital. PMID- 27480896 TI - Haze and influenza A virus: Coincidence or causation? PMID- 27480897 TI - Erratum. PMID- 27480898 TI - Efficacy of computer-based endoscope cleaning and disinfection using a hospital management information system. AB - BACKGROUND: The present study aimed to assess the efficacy of computer-based endoscope cleaning and disinfection using a hospital management information system (HMIS). METHODS: A total of 2,674 gastroscopes were eligible for inclusion in this study. For the processes of disinfection management, the gastroscopes were randomly divided into 2 groups: gastroscope disinfection HMIS (GD-HMIS) group and manual group. In the GD-HMIS group, an integrated circuit card (IC card) chip was installed to monitor and record endoscope cleaning and disinfection automatically and in real time, whereas the endoscope cleaning and disinfection in the manual group was recorded manually. The overall disinfection progresses for both groups were recorded, and the total operational time was calculated. RESULTS: For the GD-HMIS group, endoscope disinfection HMIS software was successfully developed. The time to complete a single session of cleaning and disinfecting on a gastroscope was 15.6 minutes (range, 14.3-17.2 minutes) for the GD-HMIS group and 21.3 minutes (range, 20.2-23.9 minutes) for the manual group. Failure to record information, such as the identification number of the endoscope, occasionally occurred in the manual group, which affected the accuracy and reliability of manual recording. CONCLUSIONS: Computer-based gastroscope cleaning and disinfection using a hospital management information system could monitor the process of gastroscope cleaning and disinfection in real time and improve the accuracy and reliability, thereby ensuring the quality of gastroscope cleaning and disinfection. PMID- 27480899 TI - Syncope with transient diffuse T-wave inversions. PMID- 27480901 TI - Antigen Receptor-Intrinsic Non-Self: The Key to Understanding Regulatory Lymphocyte-Mediated Idiotypic Control of Adaptive Immune Responses. AB - The clone-specific or idiotypic characters of B as well as T cell antigen receptors (BCRs/TCRs) are associated with (1) the third-complementarity determining regions (CDR3s) that are created during V(D)J recombination (they scarcely occur in antibody light chains) and (2) BCR idiotopes created by somatic hypermutations (SHMs) during immune responses. Therefore, BCR/TCR idiotypic sites are antigen receptor-intrinsic Non-Self (AgR-iNS) portions that fulfill two tasks: serving as a crucial component of the epitope-binding paratope and serving as target sites for anti-idiotypic BCR/TCR paratopes of other anti-Non-Self clones that are contained in both normal repertoires. The antigen-induced immune response is thus directed not only toward the environmental stimulus but also against the AgR-iNS portions of the directly and further activated clones that form a subsiding idiotypic cascade. These idiotypic chain reactions form a completely integrated idiotypic control circuit among B and T cells which contains all regulatory T and B cells. However, this circuit cannot be viewed as a network of fixed interacting nodes but rather uses the genetic Self as reference. Hence, AgR-iNS offers a mechanistic understanding of regulatory lymphocyte-mediated idiotypic control of adaptive immune responses and reconciles clonal selection and idiotypic network theories hitherto believed to be incompatible. PMID- 27480900 TI - Role in Allergic Diseases of Immunological Cross-Reactivity between Allergens and Homologues of Parasite Proteins. AB - Implied under the rubric of the hygiene hypothesis is that helminth infection can protect against allergic disease. It is well known that helminths induce processes associated with type 2 immune responses, but they also induce important regulatory responses that can modulate these type 2-associated responses modulation that influences responses to bystander antigens including allergens. Indeed, most epidemiological studies demonstrate a beneficial effect of helminth infection on atopy, but there are also convincing data to demonstrate that helminth infection can precipitate or worsen allergic inflammation/disease. Reasons for these disparate findings are much debated, but there is a school of thought that suggests that helminth-triggered type 2-associated responses, including IgE to cross-reactive aeroallergens, can offset the regulatory effects imposed by the same organisms. The cross-reactivity among helminths and allergenic tropomyosins dominated the antigen/allergen cross-reactivity field, but recent data suggest that cross-reactivity is much more common than previously appreciated. It has been demonstrated that a high degree of molecular similarity exists between allergens and helminth proteins. Thus, an understanding of the mechanisms underlying the response induced by helminth infection and their impact on the induction of allergic disease in the host are critical for designing therapies using iatrogenic infections or parasite products to treat inflammatory diseases and for developing vaccines against helminth parasites. PMID- 27480902 TI - Clinical and Experimental Sepsis Impairs CD8 T-Cell-Mediated Immunity. AB - Septic patients experience chronic immunosuppression resulting in enhanced susceptibility to infections normally controlled by T cells. Clinical research on septic patients has shown increased apoptosis and reduced total numbers of CD4 and CD8 T cells, suggesting contributing mechanism driving immunosuppression. Experimental models of sepsis, including cecal ligation and puncture, reverse translated this clinical observation to facilitate hypothesis-driven research and allow the use of an array of experimental tools to probe the impact of sepsis on T-cell immunity. In addition to numerical loss, sepsis functionally impairs the antigen-driven proliferative capacity and effector functions of CD4 and CD8 T cells. Sepsis-induced impairments in both the quantity and quality of T cells results in reduced protective capacity and increased susceptibility of mice to new or previously encountered infections. Therefore, the combined efforts of clinical and experimental sepsis research have begun to elucidate the impact of sepsis on T-cell-mediated immunity and potential T-cell-intrinsic and -extrinsic mechanisms driving chronic immunosuppression. Future work will explore the impact of sepsis on the recently appreciated tissue-resident memory (TRM) T cells, which provide robust protection against localized infections, and dendritic cells, which are needed to activate T cells and promote effective T-cell responses. PMID- 27480904 TI - A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors. AB - INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 MUg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 MUg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS: In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors. PMID- 27480905 TI - Human aplastic anaemia-derived mesenchymal stromal cells form functional haematopoietic stem cell niche in vivo. PMID- 27480907 TI - Catheter Ablation of Premature Ventricular Contractions From the Left Ventricular Summit. PMID- 27480903 TI - Metabolic Factors that Contribute to Lupus Pathogenesis. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease in which organ damage is mediated by pathogenic autoantibodies directed against nucleic acids and protein complexes. Studies in SLE patients and in mouse models of lupus have implicated virtually every cell type in the immune system in the induction or amplification of the autoimmune response as well as the promotion of an inflammatory environment that aggravates tissue injury. Here, we review the contribution of CD4+ T cells, B cells, and myeloid cells to lupus pathogenesis and then discuss alterations in the metabolism of these cells that may contribute to disease, given the recent advances in the field of immunometabolism. PMID- 27480908 TI - Prognostic Effect of Body Mass Index in Patients With an Implantable Cardioverter defibrillator for Primary Prevention of Sudden Death. PMID- 27480906 TI - Serum Liver Fibrosis Markers in the Prognosis of Liver Cirrhosis: A Prospective Observational Study. AB - BACKGROUND The prognostic role of serum liver fibrosis markers in cirrhotic patients remains unclear. We performed a prospective observational study to evaluate the effect of amino-terminal pro-peptide of type III pro-collagen (PIIINP), collagen IV (CIV), laminin (LN), and hyaluronic acid (HA) on the prognosis of liver cirrhosis. MATERIAL AND METHODS All patients who were diagnosed with liver cirrhosis and admitted to our department were prospectively enrolled. PIIINP, CIV, LN, and HA levels were tested. RESULTS Overall, 108 cirrhotic patients were included. Correlation analysis demonstrated that CIV (coefficient r: 0.658, p<0.001; coefficient r: 0.368, p<0.001), LN (coefficient r: 0.450, p<0.001; coefficient r: 0.343, p<0.001), and HA (coefficient r: 0.325, p=0.001; coefficient r: 0.282, p=0.004) levels, but not PIIINP level (coefficient r: 0.081, p=0.414; coefficient r: 0.090, p=0.363), significantly correlated with Child-Pugh and MELD scores. Logistic regression analysis demonstrated that HA (odds ratio=1.00003, 95% confidence interval [CI]=1.000004-1.000056, p=0.022) was significantly associated with the 6-month mortality. Receiver operating characteristics analysis demonstrated that the area under the curve (AUC) of HA for predicting the 6-month mortality was 0.612 (95%CI=0.508-0.709, p=0.1531). CONCLUSIONS CIV, LN, and HA levels were significantly associated with the severity of liver dysfunction, but might be inappropriate for the prognostic assessment of liver cirrhosis. PMID- 27480909 TI - Does Apolipoprotein e4 Status Moderate the Association of Family Environment with Long-Term Child Functioning following Early Moderate to Severe Traumatic Brain Injury? A Preliminary Study. AB - OBJECTIVES: To examine whether apolipoprotein e4 (APOE) status moderates the association of family environment with child functioning following early traumatic brain injury (TBI). METHODS: Sixty-five children with moderate to severe TBI and 70 children with orthopedic injury (OI) completed assessments 6, 12, 18 months, and 3.5 and 6.8 years post injury. DNA was extracted from saliva samples and genotyped for APOE e4 status. Linear mixed models examined moderating effects of APOE e4 status on associations between two family environment factors (parenting style, home environment) and three child outcomes (executive functioning, behavioral adjustment, adaptive functioning). RESULTS: Children with TBI who were carriers of the e4 allele showed poorer adaptive functioning relative to non-carriers with TBI and children with OI in the context of low authoritarianism. At high levels of authoritarianism, non-carriers with TBI showed the poorest adaptive functioning among groups. There were no main effects or interactions involving APOE and executive functioning or behavioral adjustment. CONCLUSIONS: The APOE e4 allele was detrimental for long-term adaptive functioning in the context of positive parenting, whereas in less optimal parenting contexts, being a non-carrier was detrimental. We provide preliminary evidence for an interaction of APOE e4 status and parenting style in predicting long-term outcomes following early TBI. (JINS, 2016, 22, 859-864). PMID- 27480910 TI - [Endoscopic treatment of 140 pituitary tumors, results and complications]. AB - OBJECTIVE: To present the clinical and radiographic outcomes of 140 patients with pituitary adenomas treated by an endoscopic endonasal approach (EEA) over a period of 4 years. MATERIAL AND METHODS: A retrospective analysis was performed between 2011 and 2014. Pre and post operative MRI, ophtalmological assessment, endocrinological laboratory evaluation and surgical morbidity and mortality were assessed. RESULTS: 57,9% of the patients had functional tumors (n=81), acromegaly being the most frequent sub-type (29.3%). 78.6% of the lesions were macroadenomas (n=110) of which 56.4% (n=62) involved the cavernous sinus, 61 patients presented with visual field defects (44%) of which 50.8% of patients showed improvement after surgery. Gross total removal was achieved in 60% of the cases. Hormonal remission was achieved in the 75% of the patients with functional tumors. The morbidity rate was 15% and one patient died after surgery (mortality 0.7%). CONCLUSION: EEA is a safe and effective tool to treat pituitary adenomas. The main limitation for complete surgical resection is the cavernous sinus invasion. PMID- 27480911 TI - Sensory reconstruction in different regions of the digits: A review of 151 cases. AB - BACKGROUND: Soft tissue defects of the digits are very common in hand trauma and can result in functional disability. The purpose of the study is to introduce the use of several modified and traditional sensate flaps to reconstruct different regions of the digits and to evaluate the efficacy of these techniques. METHODS: A retrospective study was conducted with 151 patients who had soft tissue defects of the digits treated with the sensate flaps from February 2005 to March 2014. Based on different regions of the soft tissue defects, the patients in the study were divided into four groups [1]: thumb group treated with the dual-innervated and traditional kite flaps [2]; distal finger group treated with the single- and dual-innervated dorsal digital flaps [3]; proximal finger group treated with the heterodigital neurocutaneous island flap; and [4] awkward region group treated with the Litter flap. The main outcomes were static 2PD and Semmes-Weinstein monofilament scores of the flap, pain and patient satisfaction. RESULTS: Significant difference was found between dual-innervated and traditional kite flaps, and between single- and dual-innervated dorsal digital flaps in static 2PD, pain and patient satisfaction (P<0.05). Double nerve repairs presented better discriminatory sensation on the flap, lower incidence of pain in the injured digit and larger satisfaction degree than single nerve repair. CONCLUSIONS: Compared to single-innervated flap, dual-innervated flap exhibited better sensory recovery and lower pain incidence. Being an additional treatment option, Littler flap may be better choice for sensory coverage in some specific situations including border injuries. PMID- 27480912 TI - Complications and outcomes of the transfibular approach for posterolateral fractures of the tibial plateau. AB - OBJECTIVE: Evaluate complication rates and functional outcomes of fibular neck osteotomy for posterolateral tibial plateau fractures. DESIGN: Retrospective case series. SETTING: University hospital. PATIENTS: From January 2013 to October 2014, 11 patients underwent transfibular approach for posterolateral fractures of the tibial plateau and were enrolled in the study. All patients who underwent transfibular approach were invited the return to the hospital for another clinical and imaging evaluation. INTERVENTION: Transfibular approach (fibular neck osteotomy) with open reduction and internal fixation for posterolateral fractures of the tibial plateau. MAIN OUTCOME MEASUREMENTS: Complications exclusively related to the transfibular approach: peroneal nerve palsy; knee instability; loss of reduction; nonunion and malunion of fibular osteotomy; and functional outcomes related to knee function. RESULTS: Two patients failed to follow-up and were excluded from the study. Of the 9 patients included in the study, no patients demonstrated evidence of a peroneal nerve palsy. One patient presented loss of fracture reduction and fixation of the fibular neck osteotomy, requiring revision screw fixation. There were no malunions of the fibular osteotomy. None of the patients demonstrated clinically detectable posterolateral instability of the knee following surgery. American Knee Society Score was good in 7 patients (77.8%), fair in 1 (11.1%), and poor in 1 (11.1%). American Knee Society Score/Function showed 80 points average (60-100, S.D:11). CONCLUSION: The transfibular approach for posterolateral fractures is safe and useful for visualizing posterolateral articular injury. The surgeon must gently protect the peroneal nerve during the entire procedure and fix the osteotomy with long screws to prevent loss of reduction. LEVEL OF EVIDENCE: Therapeutic level IV. PMID- 27480914 TI - Economics, socio-ecological resilience and ecosystem services. AB - The economic process transforms raw materials and energy into economic products and waste. On a finite planet, continued economic growth threatens to surpass critical socio-ecological thresholds and undermine ecosystem services upon which humans and all other species depend. For most systems, whether such thresholds exist, where they lie and whether they are reversible cannot be known with certainty until they are crossed. We argue that our central economic challenge is to maintain the resilience of the current socio-ecological regime. We must reduce net impacts of economic activity to avoid critical ecological thresholds while ensuring economic necessities. Conventional economists pursue continuous growth as the central goal of economic activity, and assume that the price mechanism and technological breakthroughs ensure system resilience. Unfortunately, the price mechanism fails to address ecological thresholds because it ignores unowned ecosystem services, and fails to address economic thresholds because it ignores the needs of the poorest individuals, who live on the edge of them. Panarchy theory suggests that systems go through a cycle of growth, conservation, release and renewal. Managing a subsystem too long for growth or conservation-which many consider to be the goal of sustainability-actually threatens to collapse the higher-level system upon which that subsystem depends. Black Swan theory suggests we should seek to reduce the risk of catastrophic thresholds and promote the likelihood of technological breakthroughs. Economic degrowth, or planned release, is required to avoid catastrophic collapse. At the same time, publicly funded, open source information can help stimulate the technological breakthroughs economists count on to ensure resilience. PMID- 27480913 TI - Metabolomics Profiling for Obstructive Sleep Apnea and Simple Snorers. AB - Few clinical studies have explored altered urinary metabolite levels in patients with obstructive sleep apnea (OSA). Thus, we applied a metabolomics approach to analyze urinary metabolites in three groups of participants: patients with polysomnography (PSG)-confirmed OSA, simple snorers (SS), and normal subjects. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and gas chromatography coupled with time-of-flight mass spectrometry were used. A total of 21 and 31 metabolites were differentially expressed in the SS and OSA groups, respectively. Patients with OSA had 18 metabolites different from those with SS. Of the 56 metabolites detected among the 3 groups, 24 were consistently higher or lower. A receiver operator curve analysis revealed that the combination of 4-hydroxypentenoic acid, arabinose, glycochenodeoxycholate-3-sulfate, isoleucine, serine, and xanthine produced a moderate diagnostic score with a sensitivity (specificity) of 75% (78%) for distinguishing OSA from those without OSA. The combination of 4-hydroxypentenoic acid, 5-dihydrotestosterone sulfate, serine, spermine, and xanthine distinguished OSA from SS with a sensitivity of 85% and specificity of 80%. Multiple metabolites and metabolic pathways associated with SS and OSA were identified using the metabolomics approach, and the altered metabolite signatures could potentially serve as an alternative diagnostic method to PSG. PMID- 27480915 TI - Adsorption kinetics and isotherms of arsenite and arsenate on hematite nanoparticles and aggregates. AB - Iron (Fe) nanoparticles, e.g., zerovalent iron (ZVI) and iron oxide nanoparticles (IONP), have been used for remediation and environmental management of arsenic (As) contamination. These Fe nanoparticles, although originally nanosized, tend to form aggregates, in particular in the environment. The interactions of As with both nanoparticles and micron-sized aggregates should be considered when these Fe nanomaterials are used for mitigation of As issue. The objective of this study was to compare the adsorption kinetics and isotherm of arsenite (As(III)) and arsenate (As(V)) on bare hematite nanoparticles and aggregates and how this affects the fate of arsenic in the environment. The adsorption kinetic process was investigated with regards to the aggregation of the nanoparticles and the type of sorbed species. Kinetic data were best described by a pseudo second-order model. Both As species had similar rate constants, ranging from 3.82 to 6.45 * 10 4 g/(MUg.h), as rapid adsorption occurred within the first 8 h regardless of particle size. However, hematite nanoparticles and aggregates showed a higher affinity to adsorb larger amounts of As(V) (4122 +/- 62.79 MUg/g) than As(III) (2899 +/- 71.09 MUg/g) at equilibrium. We were able to show that aggregation and sedimentation of hematite nanoparticles occurs during the adsorption process and this might cause the immobilization and reduced bioavailability of arsenic. Isotherm studies were described by the Freundlich model and it confirmed that hematite nanoparticles have a significantly higher adsorption capacity for both As(V) and As(III) than hematite aggregates. This information is useful and can assist in predicting arsenic adsorption behavior and assessing the role of iron oxide nanoparticles in the biogeochemical cycling of arsenic. PMID- 27480916 TI - Pinning effect of reactive elements on adhesion energy and adhesive strength of incoherent Al2O3/NiAl interface. AB - The profound effects of reactive elements (REs) on the adhesion energy and adhesive strength of the alpha-Al2O3/beta-NiAl interface in thermal barrier coating (TBC) systems have attracted increasing attention because RE-doping has played a significant role in improving the thermal cycling lifetime of TBCs. However, the fundamental mechanism is, so far, not well understood due to the experimental difficulty and theoretical complexity in interface modelling. For this purpose, in the present study we have performed comprehensive density functional theory calculations and information targeted experiments to underline the origin of the surprising enhancement of interface adhesion, stability and mechanical strength of the alpha-Al2O3/beta-NiAl interface by different RE doping levels. Our results suggest that the interface failure firstly appears within the NiAl layer adjacent to the Al-terminated oxide under mechanical loading, while the formation of O-RE-Ni bond pairs at the interface can effectively hinder the interface de-cohesion, providing a higher mechanical strength. By comparing several typical REs, it is observed that Hf can emerge not only with the highest interface adhesion energy, but also the highest mechanical strength; in agreement with our experimental results. By continuously increasing the dopant concentration, the strengthening effect may increase correspondingly, but is limited by the solute solubility. These results shed light into the effect of REs on the stability and strength of the alpha-Al2O3/beta-NiAl interface, providing theoretical guidance for interface design via a combinational analysis of bond topology and electronic structure. PMID- 27480917 TI - High incidence of group A rotaviruses G4P[6] strains among children in Gyeonggi province of South Korea, from 2009 to 2012. AB - The genotype distribution of group A rotaviruses (RVAs) circulating in Gyeonggi province, South Korea between 2009 and 2012 was investigated. A total of 2619 stool specimens from sporadic acute gastroenteritis cases and 117 acute gastroenteritis outbreaks were analyzed. Among them, RVAs were detected from 263 (10.0%) sporadic cases and 3 (2.6%) outbreaks. The G4P[6] strains predominated (29.7%), followed by G1P[8] (19.4%), G2P[4] (15.6%), G3P[8] (13.3%) and G9P[8] (6.5%) strain. Especially 96.2% of the genotype G4P[6] strains were isolated from children<1year of age. Phylogenetic analysis revealed that genotype G4P[6] strains were members of sub-lineage Ie(G4) and Ia(P[6]). Intensified monitoring of RVAs, especially G4P[6] strains among young children, is essential to control RVA infections. PMID- 27480918 TI - Comparative genomic analysis of two isolates of Vibrio cholerae O1 Ogawa El Tor isolated during outbreak in Mariupol in 2011. AB - Cholera is a water-borne, severe enteric infection essentially caused by toxigenic strains of Vibrio cholera O1 and O139 serogroups. An outbreak of cholera was registered during May-July 2011 in Mariupol, Ukraine, with 33 cholera cases and 25 carriers of cholera. Following this outbreak, the toxigenic strain of V. cholerae 2011EL-301 was isolated from seawater in the recreation area of Taganrog city on the territory of Russia. The aim of our study was to understand genomic features of Mariupol isolates as well as to evaluate hypothesis about possible interconnection between the outbreak of cholera in Mariupol and the single case of isolation of V. cholerae from the Sea of Azov in Russia. Mariupol isolates were phenotypically characterized and subsequently subjected to whole genome sequencing procedure. Phylogenetic analysis based on high-quality SNPs of V. cholera O1 El Tor isolates of the 7th pandemic clade from different regions showed that clinical and environmental isolates from Mariupol outbreak were attributable to a unique phylogenetic clade within wave 3 of V. cholera O1 El Tor isolates and characterized by six clade-specific SNPs. Whereas Taganrog isolate belonged to distantly related clade which allows us to reject the hypothesis of transmission the outbreak strain of V. cholerae O1 from Ukraine to Russia in 2011. Mariupol isolates shared a common ancestor with Haiti?Nepal-4?India clade indicating that outbreak progenitor strain most likely originated in the South Asia region and later was introduced to Ukraine. Moreover, genomic data both based on hqSNPs and similarity of virulence-associated mobile genomic elements of Mariupol isolates suggests that environmental and clinical isolates are a part of joint outbreak which confirms the role of contaminated domestic sewage, as an element of the complex chain of infection spread during cholera outbreak. In general, the genome-wide comparative analysis of both genes and genomic regions of epidemiological importance indicates accessory of this isolates to 'new' clone of toxigenic multiple drug resistance atypical variant of V. cholerae O1 El Tor. PMID- 27480919 TI - Sequence diversity and positive selection at the Duffy-binding protein genes of Plasmodium knowlesi and P. cynomolgi: Analysis of the complete coding sequences of Thai isolates. AB - Plasmodium knowlesi and P. cynomolgi are simian malaria parasites capable of causing symptomatic human infections. The interaction between the Duffy binding protein alpha on P. knowlesi merozoite and the Duffy-antigen receptor for chemokine (DARC) on human and macaque erythrocyte membrane is prerequisite for establishment of blood stage infection whereas DARC is not required for erythrocyte invasion by P. cynomolgi. To gain insights into the evolution of the PkDBP gene family comprising PkDBPalpha, PkDBPbeta and PkDBPgamma, and a member of the DBP gene family of P. cynomolgi (PcyDBP1), the complete coding sequences of these genes were analyzed from Thai field isolates and compared with the publicly available DBP sequences of P. vivax (PvDBP). The complete coding sequences of PkDBPalpha (n=11), PkDBPbeta (n=11), PkDBPgamma (n=10) and PcyDBP1 (n=11) were obtained from direct sequencing of the PCR products. Nucleotide diversity of DBP is highly variable across malaria species. PcyDBP1 displayed the greatest level of nucleotide diversity while all PkDBP gene members exhibited comparable levels of diversity. Positive selection occurred in domains I, II and IV of PvDBP and in domain V of PcyDBP1. Although deviation from neutrality was not detected in domain II of PkDBPalpha, a signature of positive selection was identified in the putative DARC binding site in this domain. The DBP gene families seem to have arisen following the model of concerted evolution because paralogs rather than orthologs are clustered in the phylogenetic tree. The presence of identical or closely related repeats exclusive for the PkDBP gene family suggests that duplication of gene members postdated their divergence from the ancestral PcyDBP and PvDBP lineages. Intragenic recombination was detected in all DBP genes of these malaria species. Despite the limited number of isolates, P. knowlesi from Thailand shared phylogenetically related domain II sequences of both PkDBPalpha and PkDBPgamma with those from Peninsular Malaysia, consistent with their geographic proximity. PMID- 27480920 TI - The influence of silica nanoparticles on small mesenteric arterial function. AB - AIM: To determine the influence of silica nanoparticles (SiNPs) on small arterial function; both ex vivo and in vivo. METHODS: Mono-dispersed dye-encapsulated SiNPs (97.85 +/- 2.26 nm) were fabricated and vasoconstrictor and vasodilator responses of mesenteric arteries assessed. RESULTS: We show that while exposure to SiNPs under static conditions, attenuated endothelial dependent dilator responses ex vivo, attenuation was only evident at lower agonist concentrations, when exposed under flow conditions or after intravenous administration in vivo. Pharmacological inhibition studies suggest that SiNPs may interfere with the endothelial dependent hyperpolarizing factor vasodilator pathway. CONCLUSION: The dosage dependent influence of SiNPs on arterial function will help identify strategies for their safe clinical administration. PMID- 27480921 TI - Coherent emotional perception from body expressions and the voice. AB - Perceiving emotion from multiple modalities enhances the perceptual sensitivity of an individual. This allows more accurate judgments of others' emotional states, which is crucial to appropriate social interactions. It is known that body expressions effectively convey emotional messages, although fewer studies have examined how this information is combined with the auditory cues. The present study used event-related potentials (ERP) to investigate the interaction between emotional body expressions and vocalizations. We also examined emotional congruency between auditory and visual information to determine how preceding visual context influences later auditory processing. Consistent with prior findings, a reduced N1 amplitude was observed in the audiovisual condition compared to an auditory-only condition. While this component was not sensitive to the modality congruency, the P2 was sensitive to the emotionally incompatible audiovisual pairs. Further, the direction of these congruency effects was different in terms of facilitation or suppression based on the preceding contexts. Overall, the results indicate a functionally dissociated mechanism underlying two stages of emotional processing whereby N1 is involved in cross modal processing, whereas P2 is related to assessing a unifying perceptual content. These data also indicate that emotion integration can be affected by the specific emotion that is presented. PMID- 27480922 TI - Colour tuning by the stepwise synthesis of mononuclear and homo- and hetero dinuclear platinum(ii) complexes using a zwitterionic quinonoid ligand. AB - The stepwise reaction of a zwitterionic ligand, 4-methylamino-6-methyliminio-3 oxocyclohexa-1,4-dien-1-olate (QH2) with [Pt2(MU-Cl)2(ppy)2] (Hppy = 2 phenylpyridine) afforded a mononuclear complex, [Pt(ppy)(QH)] (1), and a dinuclear complex, [{Pt(ppy)}2(MU-Q)] (2). Using [Pd2(MU-Cl)2(ppy)2] in the second step resulted in the formation of a heterodinuclear complex, [{Pt(ppy)}(MU Q){Pd(ppy)}] (3), which is the first heterodinuclear complex bridged by a quinonoid ligand. Single crystal X-ray diffraction analysis revealed that all three complexes adopted double-decker structures in the crystal. For 1, intermolecular N-HO interactions between uncoordinated N-H and O groups in two adjacent square-planar mononuclear units led to the formation of hydrogen-bonded dimers, which stacked to form a herringbone structure with a double-decker tetranuclear motif. For 2 and 3, dinuclear units bridged by Q(2-) formed a double decker motif similar to that of 1, but a tetranuclear chain in the herringbone pattern was characteristic of the dinuclear complexes. PtPt (or PtPd) distances were more than 3.5 A, twice the van der Waals radii of Pt, suggesting weak electronic metal-metal interactions in the crystal structures. Thus, the different colours observed (brown, purple, and dark green for 1, 2, and 3, respectively) mainly originated from the molecular structures. In fact, the three complexes exhibited colourful solutions of yellow, red, and green. UV-vis absorption spectroscopy and time-dependent density-functional theory (TD-DFT) calculations revealed that colour variations occurred depending on the electronic states composed of metal ions and the quinonoid ligand. PMID- 27480923 TI - Theoretical study of HgCr2Se3.5Te0.5: a doping-site-dependent semimetal. AB - Weyl semimetals have recently attracted enormous attention due to their unusual features. So far, this novel state has been predicted theoretically and confirmed experimentally in several materials, such as HgTe, LaPtBi, Y2Ir2O7, TaAs, TaP, NbAs, NbP and HgCr2Se4. Doping plays an important role in the research of condensed-matter materials. However, its influence on the Weyl semimetal has been little investigated. Here, we present detailed first-principles and theoretical studies on HgCr2Se4 with doping of Te atoms at the Se sites. A special case where only one pair of crossing points locates at the Fermi level is realized in HgCr2Se3.5Te0.5 where one of the Se atoms in the primitive unit cell is replaced by a Te atom. A further study of k.p theory shows that the two points constitute a pair of Weyl nodes with opposite chiralities in the momentum space, and only one edge state and one single Fermi arc are obtained at each boundary of a film. Moreover, through investigations and analyses of different doping cases of HgCr2Se3.5Te0.5, we find that when the type of doping induces inversion symmetry or positional disorder, the Weyl nodes transform into Dirac points resulting in a change from a Weyl semimetal to a Dirac semimetal. PMID- 27480925 TI - Molecular dynamics simulations on the conformational transitions from the GA 98 (GA 88) to GB 98 (GB 88) proteins. AB - We performed conventional and targeted molecular dynamics simulations to address the dynamic transition mechanisms of the conformational transitions from the GA 98 protein with only 1 mutation of Leu45Tyr to GB 98 and from the GA 88 protein with 7 mutations of Gly24Ala, Ile25Thr, Ile30Phe, Ile33Tyr, Leu45Tyr, Ile49Thr, and Leu50Lys to GB 88. The results show that the conformational transition mechanism from the mutated 3alpha GA 98 (GA 88) state to the alpha+4beta GB 98 (GB 88) state via several intermediate conformations involves the bending of loops at the N and C termini firstly, the unfolding of alphaA and alphaC, then the traversing of alphaB, and the formation of the 4beta layer with the conversion of the hydrophobic core. The bending of loops at the N and C termini and the formation of the crucial transition conformation with the full unfolded structure are key factors in their transition processes. The communication of the interaction network, the bending directions of loops, and the traversing site of alphaB in the transition of GA 98 to GB 98 are markedly different from those in GA 88 to GB 88 because of the different mutated residues. The analysis of the correlations and the calculated mass center distances between some segments further supported their conformational transition mechanisms. These results could help people to better understand the Paracelsus challenge. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27480924 TI - CRMP1 and CRMP2 have synergistic but distinct roles in dendritic development. AB - Collapsin response mediator protein 2, CRMP2, has been identified as an intracellular signaling mediator for Semaphorin 3A (Sema3A). CRMP2 plays a key role in axon guidance, dendritic morphogenesis, and cell polarization. It has been also implicated in a variety of neurological and psychiatric disorders. However, the in vivo functions of CRMP2 remain unknown. We generated CRMP2 gene deficient (crmp2(-/-) ) mice. The crmp2(-/-) mice showed irregular development of dendritic spines in cortical neurons. The density of dendritic spines was reduced in the cortical layer V pyramidal neurons of crmp2(-/-) mice as well as in those of sema3A(-/-) and crmp1(-/-) mice. However, no abnormality was found in dendritic patterning in crmp2(-/-) compared to wild-type (WT) neurons. The level of CRMP1 was increased in crmp2(-/-) , but the level of CRMP2 was not altered in crmp1(-/-) compared to WT cortical brain lysates. Dendritic spine density and branching were reduced in double-heterozygous sema3A(+/-) ;crmp2(+/-) and sema3A(+/-) ;crmp1(+/-) mice. The phenotypic defects had no genetic interaction between crmp1 and crmp2. These findings suggest that both CRMP1 and CRMP2 mediate Sema3A signaling to regulate dendritic spine maturation and patterning, but through overlapping and distinct signaling pathways. PMID- 27480926 TI - Blunt cerebrovascular injury following craniomaxillofacial fractures: A systematic review. AB - OBJECTIVES: Blunt cerebrovascular injury (BCVI) is a known sequela of high-energy craniomaxillofacial (CMF) trauma and can result in stroke or death. The objective of this systematic review is to 1) identify CMF trauma patients who may benefit from BCVI screening and 2) describe the optimal diagnostic and treatment modalities. STUDY DESIGN: Systematic review of the literature (1946-2013). METHODS: An a priori study protocol was created using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The authors conducted a search of Ovid/Medline, PubMed, and Cochrane databases for articles related to BCVI and CMF fractures. All abstracts were reviewed, and data was extracted to determine the incidence of BCVI in the setting of CMF trauma. Individual fracture patterns were analyzed using descriptive statistics. RESULTS: Twenty-one studies met inclusion criteria. The overall incidence of CMF fracture-associated BCVI was 0.45%. The majority of patients (86.6%) sustained BCVI in the setting of high-energy trauma. The distribution of CMF fractures among BCVI patients was the mandible (12.5%), followed by the maxilla (11.8%). Computed tomographic angiography (CTA) was the most common diagnostic modality. A total of 63.1% of patients with BCVI were managed medically. The mortality among CMF patients with BCVI was 23.9%, and stroke rate was 47.1%. CONCLUSION: Blunt cerebrovascular injury is a rare but devastating complication of blunt trauma. The recommended screening modality is CTA, and the most common treatment is antiplatelet/anticoagulant medication. Mandibular and LeFort fractures were the most common isolated CMF injury associated with BCVI, highlighting the need for prospective trials to expand current screening criteria. LEVEL OF EVIDENCE: N/A. Laryngoscope, 127:79-86, 2017. PMID- 27480927 TI - Crystal structure of the kinase domain of human protein tyrosine kinase 6 (PTK6) at 2.33 A resolution. AB - Human Protein tyrosine kinase 6 (PTK6) (EC:2.7.10.2), also known as the breast tumor kinase (BRK), is an intracellular non-receptor Src-related tyrosine kinase expressed in a majority of human breast tumors and breast cancer cell lines, but its expression is low or completely absent in normal mammary glands. In the recent past, several studies have suggested that PTK6 is a potential therapeutic target in cancer. To understand its structural and functional properties, the PTK6 kinase domain (PTK6-KD) gene was cloned, overexpressed in a baculo-insect cell system, purified and crystallized at room temperature. X-ray diffraction data to 2.33 A resolution was collected on a single PTK6-KD crystal, which belonged to the triclinic space group P1. The Matthews coefficient calculation suggested the presence of four protein molecules per asymmetric unit, with a solvent content of ~50%.The structure has been solved by molecular replacement and crystal structure data submitted to the protein data bank under the accession number 5D7V. This is the first report of apo PTK6-KD structure crystallized in DFG-in and alphaC-helix-out conformation. PMID- 27480928 TI - The plasma membrane calcium pumps: focus on the role in (neuro)pathology. AB - The plasma membrane Ca2+ ATPase (PMCA pump) is a member of the superfamily of P type pumps. It is organized in the plasma membrane with ten transmembrane helices and two main cytosolic loops, one of which contains the catalytic center. It also contains a long C-terminal tail that houses the binding site for calmodulin, the main regulator of the activity of the pump. The pump also contains a number of other regulators, among them acidic phospholipids, kinases, and numerous protein interactors. Separate genes code for 4 basic pump isoforms in mammals, additional isoform complexity being generated by the alternative splicing of primary transcripts. Pumps 1 and 4 are expressed ubiquitously, pumps 2 and 3 are tissue restricted, with preference for the nervous system. In essentially all cells, the pump coexists with much more powerful systems that clear Ca2+ from the cytosol, e.g. the SERCA pump and the Na+/Ca2+ exchanger. Its role in the global regulation of cellular Ca2+ homeostasis is thus quantitatively marginal: its main function is the regulation of Ca2+ signaling in selected sub-plasma membrane microdomains where Ca2+ modulated interactors also reside. Malfunctions of the pump linked to genetic mutations are now described with increasing frequency, the disease phenotypes being especially severe in the nervous system where isoforms 2 and 3 predominate. The analysis of the pump defects suggests that the disease phenotypes are likely to be related to the imperfect modulation of Ca2+ signaling in selected sub-plasma membrane microdomains, leading to the defective control of the activity of important Ca2+ dependent interactors. PMID- 27480929 TI - Establishment of the BacMam system using silkworm baculovirus. AB - The BacMam system uses modified insect viruses (baculoviruses) as vehicles to efficiently deliver genes for expression in mammalian cells. The technique can be widely applied to large-scale recombinant protein production with appropriate modifications, high-throughput screening platforms for cell-based assays, and the delivery of large genes. The silkworm system is often employed as a rapid and cost-effective approach for recombinant baculovirus generation. Here we have developed the novel BacMam system using silkworm baculovirus, and shown the successful expression of EGFP in mammalian cells. The transduction to mammalian cells via the BacMam system was improved by adding phosphate-buffered saline and sodium butyrate to the culture medium and lowering the temperature after viral infection. This study provides an alternative gene delivery system for mammalian cells, which has various potential applications, including efficient native protein production and gene therapy. PMID- 27480930 TI - A label-free impedance-based whole cell assay revealed a new G protein-coupled receptor ligand for mouse microglial cell migration. AB - We report the usefulness of an impedance-based label-free whole cell assay to identify new ligands for G protein-coupled receptors (GPCRs) involved in microglial cell migration. Authentic GPCR ligands were subjected to the impedance based cell assay in order to examine the responses of ligands for MG5 mouse microglial cells. Complement component 5 (C5a), adenosine 5'-diphosphate (ADP), uridine 5'-triphosphate (UTP), lysophosphatidic acid (LPA), and lysophosphatidylserine (LysoPS) were found to elicit different cellular impedance patterns, i.e. C5a, ADP, and UTP caused a transient increase in cellular impedance, while LPA and LysoPS decreased it. The responses for C5a and ADP were abolished by pertussis toxin (PTX), but not rho-associated protein kinase inhibitor, Y-27632, indicating that C5a and ADP elicited responses through the Galphai pathway. On the other hand, the response for UTP, LPA or LysoPS was not cancelled by PTX or Y-27632. In a modified Boyden chamber assay, C5a and ADP, but not UTP, LPA, or LysoPS, induced the migration of MG5 cells. These results suggest that PTX-sensitive increase in cellular impedance with the assay is characteristic for ligands of GPCRs involved in microglial cell migration. We found using this assay that 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) is a new chemoattractant inducing microglial cell migration through the activation of Galphai. PMID- 27480931 TI - Experimental validation of non-uniformity effect of the radial electric field on the edge transport barrier formation in JT-60U H-mode plasmas. AB - The turbulent structure formation, where strongly-inhomogeneous turbulence and global electromagnetic fields are self-organized, is a fundamental mechanism that governs the evolution of high-temperature plasmas in the universe and laboratory (e.g., the generation of edge transport barrier (ETB) of the H-mode in the toroidal plasmas). The roles of inhomogeneities of radial electric field (Er) are known inevitable. In this mechanism, whether the first derivative of Er (shear) or the second derivative of Er (curvature) works most is decisive in determining the class of nontrivial solutions (which describe the barrier structure). Here we report the experimental identification of the essential role of the Er-curvature on the ETB formation, for the first time, based on the high-spatiotemporal resolution spectroscopic measurement. We found the decisive importance of Er curvature on ETB formation during ELM-free phase, but there is only a low correlation with the Er-shear value at the peak of normalized ion temperature gradient. Furthermore, in the ELMing phase, the effect of curvature is also quantified in terms of the relationship between pedestal width and thickness of the layer of inhomogeneous Er. This is the fundamental basis to understand the structure of transport barriers in fusion plasmas. PMID- 27480932 TI - The grey fovea sign of macular oedema or subfoveal fluid on non-stereoscopic fundus photographs. AB - PURPOSE: To describe the grey fovea sign of fovea-involving macular oedema or subretinal fluid accumulation in red-free fundus photography. METHODS: A test set of 91 digital fundus photographs of good quality from 100 consecutive eyes in 72 patients with diabetic retinopathy or central serous chorioretinopathy was composed by one of the investigators and evaluated by four masked observers. The photographs were graded as to whether a normal dark fovea was present or absent. The reference method was foveal thickness measurement using optical coherence tomography (OCT). RESULTS: Eyes graded as having a grey fovea on fundus photographs (n = 67) had a median foveal thickness of 279 MUm (interquartile range 130 MUm), whereas eyes graded as having a normal dark fovea (n = 24) had a median foveal thickness of 238 MUm (interquartile range 44.5 MUm, p = 0.025). CONCLUSION: The absence of a dark fovea on red-free greyscale fundus photographs is a sign of foveal thickening or detachment that can be reliably recognized by graders when using OCT as the reference diagnostic method. Awareness of the grey fovea sign may facilitate fundus photographic screening for maculopathy because its absence is a reliable sign that no foveal oedema or detachment is present. Its presence may indicate that such conditions are present, but it can also be induced by various other conditions, for which reason it should prompt further investigations by OCT. PMID- 27480933 TI - Upregulation of Atrogin-1/FBXO32 is not necessary for cartilage destruction in mouse models of osteoarthritis. AB - OBJECTIVE: In a preliminary study, we found that recently identified catabolic regulators of osteoarthritis (OA), including hypoxia-inducible factor (HIF) 2alpha and members of the zinc-ZIP8-MTF1 axis, upregulate the E3 ubiquitin ligase, Atrogin-1 (encoded by Fbxo32), in chondrocytes. As the ubiquitination/proteasomal degradation pathways are tightly regulated to modulate the expression of catabolic factors in chondrocytes, we examined the in vivo functions of Atrogin-1 in mouse models of OA. METHODS: The mRNA and protein levels of Atrogin-1 and other regulators of OA were determined in primary cultured mouse chondrocytes, OA human cartilage, and OA cartilage from wild-type (WT) and Fbxo32-knockout (KO) mice subjected to destabilization of the medial meniscus or intra-articular (IA) injection of adenoviruses expressing HIF-2alpha (Ad-Epas1), ZIP8 (Ad-Zip8), or Atrogin-1 (Ad-Fbxo32). The effect of Atrogin-1 overexpression on the cartilage of WT mice was examined by IA injection of Ad Fbxo32. RESULTS: Atrogin-1 mRNA levels in chondrocytes were markedly increased by treatment with interleukin-1beta, HIF-2alpha, and members of the zinc-ZIP8-MTF1 axis. Atrogin-1 protein levels were also increased in OA cartilage from humans and various mouse OA models. However, the forced overexpression of Atrogin-1 in chondrocytes did not modulate the expression of cartilage matrix molecules or matrix-degrading enzymes. Moreover, overexpression of Atrogin-1 in the mouse joint tissues failed to cause OA pathogenesis, and Fbxo32 knockout failed to affect post-traumatic OA cartilage destruction in mice. CONCLUSIONS: Although Atrogin-1 is upregulated in OA cartilage, overexpression of Atrogin-1 in the joint tissues or knockout of Fbxo32 does not affect OA cartilage destruction in mice. PMID- 27480934 TI - Considerations for the design, analysis and presentation of in vivo studies. AB - OBJECTIVE: To describe, explain and give practical suggestions regarding important principles and key methodological challenges in the study design, statistical analysis, and reporting of results from in vivo studies. CONCLUSIONS: Pre-specifying endpoints and analysis, recognizing the common underlying assumption of statistically independent observations, performing sample size calculations, and addressing multiplicity issues are important parts of an in vivo study. A clear reporting of results and informative graphical presentations of data are other important parts. PMID- 27480936 TI - Outcomes of evaluation and testing of 660 individuals with hearing loss in a pediatric genetics of hearing loss clinic. AB - Hearing loss is a relatively common condition in children, occurring in approximately 2 out of every 1,000 births with approximately 50% of reported diagnoses having a primary genetic etiology. Given the prevalence and genetic component of hearing loss, coupled with a trend toward early diagnosis with the institution of universal newborn hearing screening, The Genetics of Hearing Loss Clinic was established at The Children's Hospital of Philadelphia to manage the diagnosis, testing, and genetic counseling for individuals and families. This paper described a cohort of 660 individuals with a diagnosis of hearing loss evaluated between July 2008 and July 2015 in the Genetics of Hearing Loss Clinic. To elucidate the cause of hearing loss in this cohort for better management and prognostication, testing included single nucleotide polymorphism chromosomal microarray, hearing loss next generation sequencing panel, and additional clinical tests inclusive of thyroid and renal function studies, temporal bone magnetic resonance imaging, and electrocardiogram. Of those evaluated, most had bilateral sensorineural hearing loss, occurring in 489/660 (74%). Additionally, 612/660 (93%) of patients presented with a nonsyndromic form of hearing loss (no other observed clinical findings at the time of exam), of which pathogenic mutations in GJB2 were most prevalent. Of the individuals with syndromic manifestations (48/660), Usher and Waardenburg syndrome were most commonly observed. A family history of hearing loss (first degree relative) was present in 12.6% of families with available information. Through molecular analyses, clinical examination, and laboratory testing, a definitive etiologic diagnosis was established in 157/660 (23.8%) of individuals. (c) 2016 Wiley Periodicals, Inc. PMID- 27480935 TI - The control of the discrimination between dNTP and rNTP in DNA and RNA polymerase. AB - Understanding the origin of discrimination between rNTP and dNTP by DNA/RNA polymerases is important both for gaining fundamental knowledge on the corresponding systems and for advancing the design of specific drugs. This work explores the nature of this discrimination by systematic calculations of the transition state (TS) binding energy in RB69 DNA polymerase (gp43) and T7 RNA polymerase. The calculations reproduce the observed trend, in particular when they included the water contribution obtained by the water flooding approach. Our detailed study confirms the idea that the discrimination is due to the steric interaction between the 2'OH and Tyr416 in DNA polymerase, while the electrostatic interaction is the source of the discrimination in RNA polymerase. Proteins 2016; 84:1616-1624. (c) 2016 Wiley Periodicals, Inc. PMID- 27480938 TI - Ground-State Distortion in N-Acyl-tert-butyl-carbamates (Boc) and N-Acyl tosylamides (Ts): Twisted Amides of Relevance to Amide N-C Cross-Coupling. AB - Amide N-C(O) bonds are generally unreactive in cross-coupling reactions employing low-valent transition metals due to nN -> pi*C?O resonance. Herein we demonstrate that N-acyl-tert-butyl-carbamates (Boc) and N-acyl-tosylamides (Ts), two classes of acyclic amides that have recently enabled the development of elusive amide bond N-C cross-coupling reactions with organometallic reagents, are intrinsically twisted around the N-C(O) axis. The data have important implications for the design of new amide cross-coupling reactions with the N-C(O) amide bond cleavage as a key step. PMID- 27480937 TI - Patient choice, Internet based information sources, and perceptions of health care: Evidence from Sweden using survey data from 2010 and 2013. AB - BACKGROUND: Several countries have increased patients' abilities to choose their health care providers, frequently under the assumption that patients are themselves the best agents to make such decisions. In parallel, national and regional health authorities have enhanced access to Internet based information sources (IBIS) to assist patients in making an informed choice. Relatively little, however, is known about the effect that the use of such sources has on key outcomes, including patients' perceptions of care. The aim of this study is to analyze the role of the Internet for patients' confidence in the provider and perceived access to care in the context of choice based reforms in Sweden. METHODS: The study uses a regional, population health survey from the southern part of Sweden. Non-parametric chi-square tests are used to assess the nature of Internet users, including their gender, age and socioeconomic status. Logistic regression models are specified to analyze the role of IBIS on patient perceptions of care while controlling for other factors. RESULTS: Actual use of Internet based information sources for health care was relatively low in 2010 and only somewhat higher in 2013. The characteristics of IBIS users varied significantly across different population groups, such that they were younger, more educated, female, and also considered themselves to be in better health compared with those who reported not using this source of health care information. Finally, the average IBIS user was less likely to report having a high level of satisfaction with respect to their primary care use; OR 0.69 [95 % CI: 0.54-0,87] and OR 0.52 [95 % CI: 0,41-0,66], for confidence in provider and perceived access to care, respectively, in 2013. CONCLUSIONS: Despite health agencies' attempts to make information on health care providers available on the Internet, this source of health care information is not used to any large extent in the current sample. The fact that some people use this source of information more compared with others suggests the need to consider alternative ways of informing the general public about choice options. The use of Internet based sources may also be linked with the experience of actually using health services, which suggests a need to further analyze this complex consumer behavior process. PMID- 27480940 TI - The AgED Study. Age-related eye disease (AgED) in South Australian general practice: are we blind to early detection and intervention? AB - The AgED Study aimed to evaluate the detection, awareness and management of age related eye disease (AgED) in South Australian general practice. Three South Australian metropolitan general practices were recruited and all patients aged 75 years and older were invited to participate. A cross-sectional postal questionnaire and retrospective audit of consenting patients' medical records was performed. On average, patients had their last eye check 9 months ago; the majority (64.9%) performed by an optometrist. Only 7.6% had visited their GP for their last eye check, mostly (90.5%) for a mandatory 'Fitness to Drive' medical assessment. There were marked differences in GP recording v. self-reported AgED and a marked discrepancy in the prevalence rates of AgED, visual impairment and blindness in this study compared with Australian population-based prevalence surveys. Despite the lack of GP documentation of eye disease, the majority of patients engaged in timely eye checks with either an optometrist or ophthalmologist, and their overall visual function and vision-related quality of life (QoL) were satisfactory. PMID- 27480939 TI - Inhibitory effect of YM-244769, a novel Na+/Ca2+ exchanger inhibitor on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. AB - Recently, YM-244769 (N-(3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy} nicotinamide) has been reported as a new potent and selective Na+/Ca2+ exchange (NCX) inhibitor by using various cells transfected with NCX using the 45Ca2+ fluorescent technique. However, the electrophysiological study of YM-244769 on NCX had not been performed in the mammalian heart. We examined the effects of YM 244769 on NCX current (INCX) in single cardiac ventricular myocytes of guinea pigs by using the whole-cell voltage clamp technique. YM-244769 suppressed the bidirectional INCX in a concentration-dependent manner. The IC50 values of YM 244769 for the bidirectional outward and inward INCX were both about 0.1 MUM. YM 244769 suppressed the unidirectional outward INCX (Ca2+ entry mode) with an IC50 value of 0.05 MUM. The effect on the unidirectional inward INCX (Ca2+ exit mode) was less potent, with 10 MUM of YM-244769 resulting in the inhibition of only about 50 %. At 5 mM intracellular Na+ concentration, YM-244769 suppressed INCX more potently than it did at 0 mM [Na+]i. Intracellular application of trypsin via the pipette solution did not change the blocking effect of YM-244769. In conclusion, YM-244769 inhibits the Ca2+ entry mode of NCX more potently than the Ca2+ exit mode, and inhibition by YM-244769 is [Na+]i-dependent and trypsin insensitive. These characteristics are similar to those of other benzyloxyphenyl derivative NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The potency of YM 244769 as an NCX1 inhibitor is higher than those of KB-R7943 and SN-6 and is similar to that of SEA0400. PMID- 27480943 TI - Xylazine Dependence and Detoxification: A Case Report. PMID- 27480941 TI - Crystal structures of APOBEC3G N-domain alone and its complex with DNA. AB - APOBEC3G (A3G) is a potent restriction factor of HIV-1. The N-terminal domain of A3G (A3G-CD1) is responsible for oligomerization and nucleic acid binding, both of which are essential for anti-HIV activity. As a countermeasure, HIV-1 viral infectivity factor (Vif) binds A3G-CD1 to mediate A3G degradation. The structural basis for the functions of A3G-CD1 remains elusive. Here, we report the crystal structures of a primate A3G-CD1 (rA3G-CD1) alone and in complex with single stranded DNA (ssDNA). rA3G-CD1 shares a conserved core structure with the previously determined catalytic APOBECs, but displays unique features for surface charge, dimerization and nucleic acid binding. Its co-crystal structure with ssDNA reveals how the conformations of loops and residues surrounding the Zn coordinated centre (Zn-centre) change upon DNA binding. The dimerization interface of rA3G-CD1 is important for oligomerization, nucleic acid binding and Vif-mediated degradation. These findings elucidate the molecular basis of antiviral mechanism and HIV-Vif targeting of A3G. PMID- 27480942 TI - Putting patient participation into practice in pediatrics-results from a qualitative study in pediatric oncology. AB - Adequate participation of children and adolescents in their healthcare is a value underlined by several professional associations. However, little guidance exists as to how this principle can be successfully translated into practice. A total of 52 semi-structured interviews were carried out with 19 parents, 17 children, and 16 pediatric oncologists. Questions pertained to participants' experiences with patient participation in communication and decision-making. Applied thematic analysis was used to identify themes with regard to participation. Three main themes were identified: (a) modes of participation that captured the different ways in which children and adolescents were involved in their healthcare; (b) regulating participation, that is, regulatory mechanisms that allowed children, parents, and oncologists to adapt patient involvement in communication and decision-making; and (c) other factors that influenced patient participation. This last theme included aspects that had an overall impact on how children participated. Patient participation in pediatrics is a complex issue and physicians face considerable challenges in facilitating adequate involvement of children and adolescents in this setting. Nonetheless, they occupy a central role in creating room for choice and guiding parents in involving their child. CONCLUSION: Adequate training of professionals to successfully translate the principle of patient participation into practice is required. WHAT IS KNOWN: *Adequate participation of pediatric patients in communication and decision making is recommended by professional guidelines but little guidance exists as to how to translate it into practice. What is New: *The strategies used by physicians, parents, and patients to achieve participation are complex and serve to both enable and restrict children's and adolescents' involvement. PMID- 27480945 TI - Bladder cancer: Targeted agents reverse chemotherapy resistance in urothelial carcinoma. PMID- 27480946 TI - Prostate cancer: 'Equivocal' lymphovascular invasion? PMID- 27480944 TI - Underreporting of Delirium in Statewide Claims Data: Implications for Clinical Care and Predictive Modeling. AB - BACKGROUND: Delirium is an acute neuropsychiatric syndrome that portends poor prognosis and represents a significant burden to the health care system. Although detection allows for efficacious treatment, the diagnosis is frequently overlooked. This underdiagnosis makes delirium an appealing target for translational predictive algorithmic modeling; however, such approaches require accurate identification in clinical training datasets. METHODS: Using the Massachusetts All-Payers Claims Database, encompassing health claims for Massachusetts residents for 2012, we calculated the rate of delirium diagnosis in index hospitalizations by reported ICD-9 diagnosis code. We performed a review of published studies formally assessing delirium to establish an expected rate of delirium when formally assessed. Secondarily, we reported a sociodemographic comparison of cases and noncases. RESULTS: Rates of delirium reported in the literature vary widely, from 3.6-73% with a mean of 23.6%. The statewide claims data (Massachusetts All-Payers Claims Database) identified the rate of delirium among index hospitalizations to be only 2.1%. For Massachusetts All-Payers Claims Database hospitalizations, delirium was coded in 2.8% of patients >65 years old and for 1.2% of patients <=65. CONCLUSION: The lower incidence of delirium in claims data may reflect a failure to diagnose, a failure to code, or a lower rate in community hospitals. The relative absence of the phenotype from large databases may limit the utility of data-driven predictive modeling to the problem of delirium recognition. PMID- 27480947 TI - Infection: Prophylactic ART in HIV serodiscordant couples. PMID- 27480948 TI - Bladder cancer: Accuracy of urethral frozen section. PMID- 27480949 TI - Prostate cancer: 6-monthly PSA test predicts survival. PMID- 27480950 TI - Medical expulsive therapy for ureteral stones: where do we go from here? AB - Despite two decades of clinical use, the effectiveness of medical expulsive therapy (MET) for the noninvasive management of patients with ureteral stones has, in the past year, been called into in question. The primary aim of MET is to expedite stone passage, although it has also shown effectiveness in reducing time to stone passage, thus reducing the incidence of colic episodes, improving stone clearance and improving patients' quality of life. At least 11 systematic reviews and meta-analyses have been published showing clinical benefits of MET; however, the results of these analyses have been challenged by data from two randomized controlled, multicentre trials with large patient cohorts, thus providing higher quality evidence that MET is ineffective in patients with ureteral stones. Results of the various systematic reviews and meta-analyses have suggested that MET is effective, however, such analyses incorporate the biases and limitations of smaller cohort studies, resulting in their conclusions being based upon lower quality evidence. Evidence for the use of MET for small (<5 mm) distal ureteral stones has weakened based on clinical trial data published in 2015. However, MET might remain effective in the management of larger ureteral stones (>5 mm). PMID- 27480952 TI - Assessing the consequences of unrealistic optimism: Challenges and recommendations. AB - Of the hundreds of studies published on unrealistic optimism (i.e., expecting a better personal future than is reasonably likely), most have focused on demonstrating the phenomenon, examining boundary conditions, or documenting causes. Few studies have examined the consequences of unrealistic optimism. In this article, we provide an overview of the measurement of unrealistic optimism, review possible consequences, and identify numerous challenges confronting investigators attempting to understand the consequences. Assessing the consequences of unrealistic optimism is tricky, and ultimately probably impossible when researchers assess unrealistic optimism at the group level (which reveals if a group of people is displaying unrealistic optimism on average) rather than the individual level (which reveals whether a specific individual displays unrealistic optimism). We offer recommendations to researchers who wish to examine the consequences of unrealistic optimism. PMID- 27480954 TI - Heterogeneous production of proteases from Brazilian clinical isolates of Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is an important human pathogen that causes severe infections in a wide range of immunosuppressed patients. Herein, we evaluated the proteolytic profiles of 96 Brazilian clinical isolates of P. aeruginosa recovered from diverse anatomical sites. METHODS: Cell-associated and extracellular proteases were evidenced by gelatin-SDS-PAGE and by the cleavage of soluble gelatin. Elastase was measured by using the peptide substrate N-succinyl Ala-Ala-Ala-p-nitroanilide. The prevalence of elastase genes (lasA and lasB) was evaluated by PCR. RESULTS: Bacterial extracts were initially applied on gelatin SDS-PAGE and the results revealed four distinct zymographic profiles as follows: profile I (composed by bands of 145, 118 and 50kDa), profile II (118 and 50kDa), profile III (145kDa) and profile IV (118kDa). All the proteolytic enzymes were inhibited by EDTA, identifying them as metalloproteases. The profile I was the most detected in both cellular (79.2%) and extracellular (84.4%) extracts. Overall, gelatinase and elastase activities measured in the spent culture media were significantly higher (around 2-fold) compared to the cellular extracts and the production level varied according to the site of bacterial isolation. For instance, tracheal secretion isolates produced elevated amount of gelatinase and elastase measured in both cellular and extracellular extracts. The prevalence of elastase genes revealed that 100% isolates were lasB-positive and 85.42% lasA positive. Some positive/negative correlations were showed concerning the production of gelatinase, elastase, isolation site and antimicrobial susceptibility. CONCLUSION: The protease production was highly heterogeneous in Brazilian clinical isolates of P. aeruginosa, which corroborates the genomic/metabolic versatility of this pathogen. PMID- 27480951 TI - The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function. AB - Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir. PMID- 27480955 TI - In Reply: Supraventricular Tachycardia During Status Epilepticus in Dravet Syndrome: A Link Between Brain and Heart? PMID- 27480956 TI - A Rapid and Optimized LC-MS/MS Method for the Simultaneous Extraction and Determination of Sofosbuvir and Ledipasvir in Human Plasma. AB - A new validated bioanalytical method based on LC tandem MS has been developed for the simultaneous extraction and determination of sofosbuvir and ledipasvir in human plasma using antiviral daclatasvir as an internal standard (IS). Liquid liquid extraction of samples was used for the purification and preconcentration of the analytes from a human plasma matrix. Good and consistent recoveries were obtained, with average extraction recoveries of 91.61 and 88.93% for sofosbuvir and ledipasvir, respectively. The chromatographic separation of the three analytes was achieved within only 2.8 min by an isocratic mobile phase consisting of 10 mM ammonium acetate, which was then adjusted to pH 4.0 by acetic acid acetonitrile-0.1% methanolic formic acid (12 + 25 + 63, v/v/v) flowing through a C18 Zorbax eclipse plus column (5 MUm, 100 * 4.6 mm; Agilent). Multiple reaction monitoring transitions were measured in positive ion mode for sofosbuvir, ledipasvir, and daclatasvir (IS). A detailed validation of the method was performed and the standard curves were found to be linear in the range of 0.5 to 2500 and 5 to 2100 ng/mL for sofosbuvir and ledipasvir, respectively, applying weighted (1/X(2)) linear regression. The developed method was applied to the analysis of the two drugs after a single oral administration of Harvoni 400/90 mg film-coated tablets containing 400 mg sofosbuvir and 90 mg ledipasvir to four healthy volunteers. PMID- 27480958 TI - We Are Standing on the Shoulders of Giants. PMID- 27480959 TI - Commentary on "KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer". PMID- 27480960 TI - Correction: ATF3 Suppresses Metastasis of Bladder Cancer by Regulating Gelsolin Mediated Remodeling of the Actin Cytoskeleton. PMID- 27480961 TI - A comparison of the results from intra-pleural and intra-peritoneal studies with those from inhalation and intratracheal tests for the assessment of pulmonary responses to inhalable dusts and fibres. AB - The aim of this paper is to compare results from inhalation studies with those from intraperitoneal and intrapleural tests, where available, for a number of fibrous and particulate test materials. The objective is to determine how well intraperitoneal/intrapleural studies predict the pathological responses observed in more standard in vivo studies of pulmonary toxicity, with a particular focus on carcinogenicity. Published toxicity data was obtained for a number of materials including asbestos, wollastonite, MMVFs (including glass fibres, stone wools and RCF), silicon carbide whiskers, potassium octatitanate, quartz, kevlar, polypropylene and titanium dioxide. For some of the fibrous material reviewed, there is conformity between the results of intraperitoneal and inhalation tests such that they are either consistently positive or consistently negative. For the remaining fibrous materials reviewed, intraperitoneal and inhalation tests give different results, with positive results in the intraperitoneal test not being reflected by positive inhalation results. It is suggested that the intraperitoneal test can be used to exonerate a dust or fibre (because if negative in the intraperitoneal test it is extremely unlikely to be positive in either inhalation or intratracheal tests) but should not be used to positively determine that a dust or fibre is carcinogenic by inhalation. We would argue against the use of intraperitoneal tests for human health risk assessment except perhaps for the purpose of exoneration of a material from classification as a carcinogen. PMID- 27480962 TI - Meta-analysis on continuous outcomes in minimal important difference units: an application with appropriate variance calculations. AB - OBJECTIVE: To compare results from meta-analyses for mean differences in minimal important difference (MID) units (MDMID), when MID is treated as a random variable vs. a constant. STUDY DESIGN AND SETTING: Meta-analyses of published data. We calculated the variance of MDMID as a random variable using the delta method and as a constant. We assessed performance under different assumptions. We compare meta-analysis results from data originally used to present the MDMID and data from osteoarthritis studies using different domain instruments. RESULTS: Depending on the data set and depending on the values of rho and coefficient of variation of the MID (CoVMID), estimates of treatment effect and P-values between an approach considering the MID as a constant vs. as a random variable may differ appreciably. Using our data sets, we provide examples of the potential magnitude. When rho = 0.5 and CoVMID = 0.8, considering MID as a constant overestimated the treatment effect by 33-110% and decreased the P-value for heterogeneity from above 0.95 to below 0.08. When rho = 0.8 and CoVMID = 0.5, the magnitude of the effects was similar. CONCLUSIONS: Considering MID as a random variable avoids unrealistic assumptions and provides more appropriate treatment effect estimates. PMID- 27480963 TI - Effectiveness of Allograft Reconstruction vs Tenodesis for Irreparable Peroneus Brevis Tears: A Cadaveric Model. AB - BACKGROUND: Irreparable peroneus brevis tendon tears are uncommon, and there is scant evidence on which to base operative treatment. Options include tendon transfer, segmental resection with tenodesis to the peroneus longus tendon, and allograft reconstruction. However, the relative effectiveness of the latter 2 procedures in restoring peroneus brevis function has not been established. METHODS: Custom-made strain gage-based tension transducers were implanted into the peroneus longus and brevis tendons near their distal insertions in 10 fresh frozen cadaver feet. Axial load was applied to the foot, and the peroneal tendons and antagonistic tibialis anterior and posterior tendons were tensioned to 50% and 100% of physiologic load. Distal tendon tension was recorded in this normal condition and after sequential peroneus brevis-to-longus tenodesis and peroneus brevis allograft reconstruction. Measurements were made in 5 foot inversion/eversion and plantarflexion/dorsiflexion positions. RESULTS: Distal peroneus brevis tendon tension after allograft reconstruction significantly exceeded that measured after tenodesis in all tested loading conditions (P <= 0.022). With 50% of physiologic load applied, peroneus brevis tension was 1% to 28% of normal (depending on foot position) after tenodesis and 73% to 101% of normal after allograft reconstruction. Under the 100% loading condition, peroneus brevis tension was 6% to 43% of normal after tenodesis and 88% to 99% of normal after reconstruction with allograft. Distal peroneus longus tension remained within 20% of normal under all operative and loading conditions. CONCLUSION: Allograft reconstruction of a peroneus brevis tendon tear in this model substantially restored distal tension when the peroneal tendons and their antagonists were loaded to 50% and 100% of physiologic load. Tenodesis to the peroneus longus tendon did not effectively restore peroneus brevis tension under the tested conditions. CLINICAL RELEVANCE: Because tenodesis was demonstrated to be ineffective for restoration of peroneus brevis function, this procedure may result in an imbalanced foot clinically. PMID- 27480965 TI - Dilemma of Timing of Administration of Non-Steroidal Anti-inflammatory Agents in Relation to Food in the Prevention of Drug Induced Gastritis: Debusting the Myth. AB - BACKGROUND & OBJECTIVE: We aimed to identify the signals that indicate the possible benefits of administering Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) at the initiation of meal, compared to immediately after food. METHODS: This was a randomized, controlled, pilot study in 160 patients who received only NSAIDs for various pain conditions. Patients were randomized to Group I (control group) NSAID After Food (AF), Group II-NSAID Before Food (BF), Group III-NSAID BF for 2 days and then crossed over to AF for next two days (CO-1) and Group IV-NSAID AF for 2 days and then crossed over to BF for next two days (C0-2 group). Group III & Group IV were given a washout period of 48 hours after the initial two days of treatment. All were followed up for the next 2 drug free days. Patients were observed for the development of gastritis (epigastric distress, epigastric pain, nausea, fullness of stomach, repeated reflux) throughout the study. RESULTS: Symptoms of gastritis were seen in 6.45% (2/31) and 36.11% (13/36) patients in group I and II, respectively. There was no statistically significant difference in the development of gastritis in AF group. However, statistically significant difference (P<0.05) was found between BF group and AF intake of NSAIDs [CO-1 (AF), CO-2 (A.F), AF (control group)] in terms of development of gastritis. INTERPRETATION & CONCLUSION: Administering NSAIDs at the initiation of meal is better tolerated as indicated by the lower incidence of gastritis. If proved in larger population, routine concurrent administration of medication for prevention of gastritis can be avoided. PMID- 27480966 TI - HIV Vaccine for Prevention and Cure, A Mission Possible. AB - HIV/AIDS was once a highly deadly infective disease that killed the global people of a million annually two decades ago. While we are enjoying the HIV therapeutic advances (mostly important from HAART invention), one obvious drawback is still unresolved-unable to clearance all HIV from infected human bodies. As a result, a series of different therapeutic attempts have been proposed based on present knowledge of different features of HIV-induced pathogenesis and human mortalities. Facing this shortcoming, innovative designs and update of HIV vaccines and other types of HIV therapeutic inventions can be a final solution for completely HIV clearance and infection managements in human beings. Owing to these scientific and medical significances, several experimental and clinical attempts have to be made. Among these attempts, part of them (updating HIV vaccine developments and clinical routines) are quite promising and noteworthy. In this article, we offer the general information of this attempt and discuss it separately, especially on the respects of HIV vaccine strategic innovations. PMID- 27480967 TI - Ticagrelor: Long-Term Therapy in Patients with Coronary Artery Disease. AB - INTRODUCTION: Atherothrombosis and coronary artery disease affect more than 13 million individuals only in the United States, about 8 millions in Europe and are the major causes of death worldwide. In particular chronic stable angina impairs patient quality of life, is associated with an important health spending and increased patient mortality; it is a prominent symptom of coronary artery disease (CAD), the latter being prevalent worldwide in patients. A key role in pathophysiology of cardiovascular acute events is played by activated platelets. Aspirin and adenosine diphosphate antagonist in addition to it is recommended for 1 year for reduction of cardiovascular events in patients with prior myocardial infarction with a weak recommendation to continue thereafter. P2Y12 receptor antagonists, in addition to aspirin, have been shown in the last years, to reduce ischemic events in patients with acute coronary syndrome but their role in secondary prevention is still new and unclear. The aim of our paper is to review the long-term effect of therapy with ticagrelor on the basis of recent evidence based data. METHODS: We performed an online search on the major search engines. All the randomized controlled trials were summarized in the table. RESULTS: We included in our paper six randomized controlled trials and we mentioned about ten post - hoc analysis, sub studies and registries. All studies included the type the therapy and a mid or long term clinical follow up. CONCLUSIONS: The studies reported in our paper and in particular PEGASUS - TIMI 54 study showed the merit to placing attention of prevention secondary ischemic events after acute coronary syndrome in the context of treatment with dual anti - platelet therapy; it proved a clinical benefit in patients treated with ticagrelor (60 mg x 2) for 3 years. Nevertheless, the effectiveness of these results cannot be generalized to patients with higher bleeding risk or low ischemic risk. In fact prolonged therapy with ticagrelor 60 mg in combination with aspirin could be considered valuable in patients with repeated acute ischemic events or with several coronary revascularizations over time (especially in patients with lower bleeding risk). PMID- 27480968 TI - The Role of Tai Chi in Mental Health Management-Lessons Learned from Clinical Trials. AB - BACKGROUND: Many people seek alternative treatments to reduce stress and to manage anxiety. To counsel people appropriately, physicians need to understand current evidence and recognize both the value and defects in the facts. OBJECTIVE: To review the effect of Tai Chi interventions on improvement of mental health and to learn lessons from current evidence through various clinical studies. METHODS: A literature search was performed to identify research studies that assessed Tai Chi's mental health benefits. Selected studies were classified according to research design, outcome measures, and results. They were qualitatively assessed based on Tai Chi's significant influence on mental health in the areas of mood, stress, and anxiety level. RESULTS: After screening in citations that mentioned Tai Chi as an intervention, we found 21 clinical studies, all of which included at least one outcome measure of mental health or a testing system that included a mental health component. Our results show low evidence of recommending Tai Chi intervention to all patients who seek improvement in mental health despite that many positive effects of Tai Chi practice on mood and anxiety were found in different clinical trials. CONCLUSION: Considering the fact that Tai Chi is a gentle exercise, well suited for people with various physical capabilities, especially the elderly, health care providers may consider recommending it to people with mental health issues and seek alternative treatment besides routine medical care. Nonetheless, clinicians should be aware of the limitations due to incomplete understanding of Tai Chi as an intervention. Better evidence and stronger clinical trial designs are needed to further investigate Tai Chi's role in improving mental health. PMID- 27480969 TI - UK's first maternity service for rape survivors opens in London. PMID- 27480970 TI - Erratum to: A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson's disease. PMID- 27480971 TI - A Comparison of Novel Entomopathogenic Nematode Application Methods for Control of the Chive Gnat, Bradysia odoriphaga (Diptera: Sciaridae). AB - Bradysia odoriphaga Yang & Zhang (Diptera: Sciaridae) is the most serious pest of Chinese chive, Allium tuberosum Chemical pesticide application has become a necessary step to control B. odoriphaga after each of the four to six harvests during the growing season. We compared the effects of application type (nematode infected cadaver, aqueous nematode suspension, and mixture of cadaver and aqueous suspension) and nematode species (Heterorhabditis bacteriophora vs. Steinernema carpocapsae) on B. odoriphaga control. Nematode species combinations and the use of the cadaver method has only been tested in a relatively few studies, and has not been tested for this target pest, B. odoriphaga. Furthermore, this is the first report of combining application methods (aqueous and cadaver). Results indicated that the cadaver treatment produced higher mortality of B. odoriphaga than the aqueous treatment, and H. bacteriophora caused higher mortality of B. odoriphaga than S. carpocapsae. The mortality of B. odoriphaga was 96.7% in H. bacteriophora cadaver treatment and only 27.5% in control treatment without nematode addition. Cadaver treatments caused higher biomass of A. tuberosum than that of aqueous treatment. The plant biomass in H. bacteriophora cadaver treatment was 10 folds as much as that in the control treatment. The mixed aqueous suspension of H. bacteriophora and S. carpocapsae did not increase the mortality in pot trial. Our findings indicate that entomopathogenic nematodes applied as cadavers might be a potential alternative biological agent in the integrated management of B. odoriphaga for Chinese chive production. PMID- 27480972 TI - Isolation and characterization of butanol-tolerant Staphylococcus aureus. AB - OBJECTIVES: A new solvent-tolerant species, Staphylococcus aureus, was isolated and characterized during the screening of butanol-tolerant microorganisms. RESULTS: Three isolates of S. aureus were obtained as contaminants during improvement of butanol tolerance of E. coli K12. Their cell dry weights were 135 % that of K12 in the absence of butanol stress. S. aureus had a growth advantage over K12 when cultured with various concentrations of butanol. It can tolerate up to 3 % (v/v) butanol, while most solventogenic bacteria can tolerate only 2 % (v/v) butanol. The addition of 10-20 g glucose/l enhanced its butanol tolerance. The relative cell biomass of the S. aureus was 71-306 % that of E. coli under 5.5 10 % (v/v) ethanol stress, indicating ethanol resistance. CONCLUSIONS: This is the first study to observe butanol-tolerant S. aureus. As this organism can be genetically manipulated, it could have a wide array of applications. PMID- 27480974 TI - The "starry sky" liver. PMID- 27480975 TI - Nonmalignant gastric causes of acute abdominal pain on MDCT: a pictorial review. AB - Acute abdominal pain is a common indication for imaging. The stomach may be poorly assessed or overlooked on multidetector computed tomography (MDCT), despite the high prevalence of gastric pathology as the source of abdominal pain. We review the pathophysiology, imaging features, and clinical management of common and uncommon nonmalignant gastric conditions on MDCT. As the stomach is often difficult to assess on MDCT, and pathology overlooked, corresponding increased awareness of gastric causes of pain is critical for radiologists to accurately interpret imaging in the setting of acute abdominal pain. PMID- 27480973 TI - Cardiac molecular imaging to track left ventricular remodeling in heart failure. AB - Cardiac left ventricular (LV) remodeling is the final common pathway of most primary cardiovascular diseases that manifest clinically as heart failure (HF). The more advanced the systolic HF and LV dysfunction, the worse the prognosis. The knowledge of the molecular, cellular, and neurohormonal mechanisms that lead to myocardial dysfunction and symptomatic HF has expanded rapidly and has allowed sophisticated approaches to understanding and management of the disease. New therapeutic targets for pharmacologic intervention in HF have also been identified through discovery of novel cellular and molecular components of membrane-bound receptor-mediated intracellular signal transduction cascades. Despite all advances, however, the prognosis of systolic HF has remained poor in general. This is, at least in part, related to the (1) relatively late institution of treatment due to reliance on gross functional and structural abnormalities that define the "heart failure phenotype" clinically; (2) remarkable genetic-based interindividual variations in the contribution of each of the many molecular components of cardiac remodeling; and (3) inability to monitor the activity of individual pathways to cardiac remodeling in order to estimate the potential benefits of pharmacologic agents, monitor the need for dose titration, and minimize side effects. Imaging of the recognized ultrastructural components of cardiac remodeling can allow redefinition of heart failure based on its "molecular phenotype," and provide a guide to implementation of "personalized" and "evidence-based" evaluation, treatment, and longitudinal monitoring of the disease beyond what is currently available through randomized controlled clinical trials. PMID- 27480976 TI - Prostate cancer bone metastases on staging prostate MRI: prevalence and clinical features associated with their diagnosis. AB - PURPOSE: Bone lesions on prostate MRI often raise concern about metastases. This study aimed to evaluate the prevalence of bone metastases on staging prostate MRI and evaluate associations between their MRI features and clinical/pathologic characteristics. METHODS: Retrospective, IRB-approved study of 3765 patients undergoing prostate MRI for newly diagnosed PCa between 2000 and 2014. The reference standard to calculate the prevalence of bone metastases was bone biopsy and/or >=1-year follow-up after MRI. In a subsample of 228 patients, the MRI characteristics of bone lesions were recorded by two radiologists independently. Associations between MRI and clinical/pathologic findings, including National Comprehensive Cancer Network (NCCN) risk categories, were calculated. RESULTS: 57/3765 patients (1.5%, 95% CI 1.2-2.0%) had bone metastases. No patient with NCCN low-risk PCa (Gleason < 7, PSA < 10 ng/mL, cT1-2a) had bone metastases. In the subsample, >=1 bone lesion was present on MRI in 74% (95% CI 0.67-0.79) and 72% (95% CI 0.66-0.78) of patients (R1 and R2). Larger lesion diameter (OR 1.33/1.19; p < 0.001 for both readers) and the absence of intralesional fat (OR 0.07/0.11; p = 0.004/0.002 for R1/R2) were significantly associated with bone metastases. CONCLUSION: Bone lesions are common in prostate MRI, but only rarely represent metastases. MRI should be interpreted in the context of clinical features that influence the likelihood of metastatic disease. PMID- 27480977 TI - The incidence of sexually acquired reactive arthritis: a systematic literature review. AB - Reactive arthritis (ReA) is an inflammatory spondyloarthritis occurring after infection at a distant site. Chlamydia trachomatis is proposed to be the most common cause of ReA, yet the incidence of sexually acquired ReA (SARA) has not been well established. We therefore carried out a systematic literature review to collate and critically evaluate the published evidence regarding the incidence of SARA. MEDLINE and EMBASE databases were searched using free-text and MeSH terms relating to infection and ReA. The title and abstract of articles returned were screened independently by two reviewers and potentially relevant articles assessed in full. Data was extracted from relevant articles and a risk of bias assessment carried out using a validated tool. Heterogeneity of study methodology and results precluded meta-analysis. The search yielded a total of 11,680 articles, and a further 17 were identified from review articles. After screening, 55 papers were assessed in full, from which 3 met the relevant inclusion criteria for the review. The studies reported an incidence of SARA of 3.0-8.1 % and were found to be of low to moderate quality. More studies are required to address the lack of data regarding the incidence of SARA. Specific and sensitive classification criteria must be developed in order for consistent classification and valid conclusions to be drawn. In clinical practice, it is recommended clinicians discuss the possibility of ReA developing at the time of STI diagnosis and to encourage patients to return if they experience any relevant symptoms. PMID- 27480979 TI - What Is the Critical Value of Glenoid Bone Loss at Which Soft Tissue Bankart Repair Does Not Restore Glenohumeral Translation, Restricts Range of Motion, and Leads to Abnormal Humeral Head Position? AB - BACKGROUND: A general consensus has been formed that glenoid bone loss greater than 20% to 25% is the critical amount at which bony augmentation procedures are needed; however, recent clinical results suggest that the critical levels must be reconsidered to lower values. PURPOSE: This study aimed to find the critical value of anterior glenoid bone loss when a soft tissue repair is not adequate to restore anterior-inferior glenohumeral translation, rotational range of motion, or humeral head position using a biomechanical anterior shoulder instability model. STUDY DESIGN: Controlled laboratory study. METHODS: Eight cadaveric shoulders were tested with a customized shoulder testing system. Range of motion, translation, and humeral head position were measured at 60 degrees of glenohumeral abduction in the scapular plane under a total of 40-N rotator cuff muscle loading in the following 11 conditions: intact; soft tissue Bankart lesion and repair; Bankart lesion with 10%, 15%, 20%, and 25% glenoid bone defects based on the largest anteroposterior width of the glenoid; and soft tissue Bankart repair for each respective glenoid defect. Serial osteotomies for each percentage of bone loss were made parallel to the long axis of the glenoid. RESULTS: There was significantly decreased external rotation (121.2 degrees +/- 2.8 degrees to 113.5 degrees +/- 3.3 degrees ; P = .004), increased anteroinferior translation with an externally applied load (3.0 +/- 1.2 mm to 7.5 +/- 1.1 mm at 20 N; P = .008), and increased posterior (0.2 +/- 0.6 mm to 2.7 +/- 0.8 mm; P = .049) and inferior shift (2.9 +/- 0.7 mm to 6.6 +/- 1.1 mm; P = .018) of the humeral head apex in the position of maximum external rotation after soft tissue Bankart repair of a 15% glenoid defect compared with the repair of a Bankart lesion without a glenoid defect, respectively. CONCLUSION: Glenoid defects of 15% or more of the largest anteroposterior glenoid width should be considered the critical bone loss amount at which soft tissue repair cannot restore glenohumeral translation, restricts rotational range of motion, and leads to abnormal humeral head position. CLINICAL RELEVANCE: The critical level of anterior glenoid bone loss at which bony restorations should be considered is closer to 15% of the largest anteroposterior width of glenoid for defects perpendicular to the superoinferior glenoid axis, which is lower than the commonly accepted threshold of 20% to 25%. PMID- 27480978 TI - Effect of High-Grade Preoperative Knee Laxity on Anterior Cruciate Ligament Reconstruction Outcomes. AB - BACKGROUND: Knee laxity in the setting of suspected anterior cruciate ligament (ACL) injury is frequently assessed through physical examination using the Lachman, pivot-shift, and anterior drawer tests. The degree of laxity noted on these examinations may influence treatment decisions and prognosis. HYPOTHESIS: Increased preoperative knee laxity would be associated with increased risk of subsequent revision ACL reconstruction and worse patient-reported outcomes 2 years postoperatively. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: From an ongoing prospective cohort study, 2333 patients who underwent primary isolated ACL reconstruction without collateral or posterior cruciate ligament injury were identified. Patients reported by the operating surgeons as having an International Knee Documentation Committee (IKDC) grade D for Lachman, anterior drawer, or pivot-shift examination were classified as having high-grade laxity. Multiple logistic regression modeling was used to evaluate whether having high grade preoperative laxity was associated with increased odds of undergoing revision ACL reconstruction within 2 years of the index procedure, controlling for patient age, sex, Marx activity level, level of competition, and graft type. Multiple linear regression modeling was used to evaluate whether having high grade preoperative laxity was associated with worse IKDC score or Knee injury and Osteoarthritis Outcome Score Knee-Related Quality of Life subscale (KOOS-QOL) scores at a minimum 2 years postoperatively, controlling for baseline score, patient age, ethnicity, sex, body mass index, marital status, smoking status, sport participation, competition level, Marx activity rating score, graft type, and articular cartilage and meniscus status. RESULTS: Pre-reconstruction laxity data were available for 2325 patients (99.7%). Two-year revision data were available for 2259 patients (96.8%), and patient-reported outcomes were available for 1979 patients (84.8%). High-grade preoperative laxity was noted in 743 patients (31.9%). The mean postoperative IKDC score was 81.8 +/- 15.9, and the mean KOOS-QOL score was 72.0 +/- 22.0. The presence of high-grade pre reconstruction laxity was associated with significantly increased odds of ACL graft revision (odds ratio [OR] = 1.87 [95% CI, 1.19-2.95]; P = .007). The presence of high-grade pre-reconstruction laxity was not associated with any difference in postoperative IKDC (beta = -0.56, P = .44) or KOOS-QOL (beta = 0.04, P = .97). CONCLUSION: The presence of high-grade pre-reconstruction knee laxity as assessed by manual physical examination under anesthesia is associated with significantly increased odds of revision ACL surgery but has no association with patient-reported outcome scores at 2 years after ACL reconstruction. PMID- 27480980 TI - Generalized Ligamentous Laxity Is an Independent Predictor of Poor Outcomes After the Modified Brostrom Procedure for Chronic Lateral Ankle Instability. AB - BACKGROUND: The modified Brostrom procedure for chronic lateral ankle instability (CLAI) has presented outstanding clinical results. However, after the procedure, some patients with generalized ligamentous laxity have experienced a recurrence of ankle instability. PURPOSE: To understand the effect of generalized ligamentous laxity on prognosis and risk of recurrence in a cohort of patients with CLAI after the modified Brostrom procedure. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 199 ankles from 188 patients underwent the modified Brostrom procedure for CLAI with a mean follow-up of 60.1 months (range, 48-108 months). Generalized ligamentous laxity was assessed in all patients. The Karlsson-Peterson ankle score (Karlsson score), talar tilt angle, and anterior displacement of the talus were used to evaluate clinical and radiological outcomes. Risk factors associated with clinical outcomes were evaluated using bivariate analysis and logistic regression analysis. Survival outcomes were compared using Kaplan-Meier analysis. RESULTS: Generalized ligamentous laxity was evident in 42 cases (21.1%). The average Karlsson score improved from 54.6 +/- 7.1 preoperatively to 87.9 +/- 7.2 at last follow-up (P < .001). The presence of generalized ligamentous laxity was significantly associated with poor clinical and radiological outcomes. The rates of clinical failure were 10.8% and 45.2% in the nonlaxity group and the laxity group, respectively (P < .001). According to bivariate analysis, generalized ligamentous laxity, syndesmosis widening, osteochondral lesion of the talus, high preoperative talar tilt angle (>15 degrees ), and high preoperative anterior displacement of the talus (>10 mm) were significantly associated with clinical failure. Multivariate logistic regression analysis revealed that generalized ligamentous laxity was the most important independent predictor of clinical failure after the modified Brostrom procedure. The cumulative success rates for the nonlaxity group were significantly superior to those for the laxity group in Kaplan-Meier curves (P < .001). CONCLUSION: Generalized ligamentous laxity is an independent predictor of poor outcomes and a risk factor of recurrent instability following the modified Brostrom procedure for CLAI. PMID- 27480981 TI - Sex-specific allelic transmission bias suggests sexual conflict at MC1R. AB - Sexual conflict arises when selection in one sex causes the displacement of the other sex from its phenotypic optimum, leading to an inevitable tension within the genome - called intralocus sexual conflict. Although the autosomal melanocortin-1-receptor gene (MC1R) can generate colour variation in sexually dichromatic species, most previous studies have not considered the possibility that MC1R may be subject to sexual conflict. In the barn owl (Tyto alba), the allele MC1RWHITE is associated with whitish plumage coloration, typical of males, and the allele MC1RRUFOUS is associated with dark rufous coloration, typical of females, although each sex can express any phenotype. Because each colour variant is adapted to specific environmental conditions, the allele MC1RWHITE may be more strongly selected in males and the allele MC1RRUFOUS in females. We therefore investigated whether MC1R genotypes are in excess or deficit in male and female fledglings compared with the expected Hardy-Weinberg proportions. Our results show an overall deficit of 7.5% in the proportion of heterozygotes in males and of 12.9% in females. In males, interannual variation in assortative pairing with respect to MC1R explained the year-specific deviations from Hardy-Weinberg proportions, whereas in females, the deficit was better explained by the interannual variation in the probability of inheriting the MC1RWHITE or MC1RRUFOUS allele. Additionally, we observed that sons inherit the MC1RRUFOUS allele from their fathers on average slightly less often than expected under the first Mendelian law. Transmission ratio distortion may be adaptive in this sexually dichromatic species if males and females are, respectively, selected to display white and rufous plumages. PMID- 27480982 TI - Antihistamines prescribed off-label among paediatric patients at a tertiary care hospital setting in Malaysia. AB - Background Antihistamines are widely prescribed to children but should be used with caution in young children. Objective To determine the paediatric prescribing pattern of antihistamines with a focus on the off-label prescribing and factors that influence such prescribing. Setting Paediatric wards of a tertiary care hospital setting in Malaysia. Methods The pharmacy-based computer system and medical records were used to collect the required data. Labelling status of each antihistamine was determined based on the information provided in the product leaflets. Main outcome measure Antihistamines prescribed off-label and factors associated with such prescribing. Results Of the 176 hospitalised children aged <18 years prescribed with an antihistamine in the year 2012, 60.8 % received it in an off-label manner. Of 292 antihistamine prescription items, 55.5 % were prescribed off-label. Loratadine (35.3 %) was the most frequently prescribed antihistamine and chlorpheniramine maleate (34.0 %) was the most common antihistamine prescribed off-label. The main reason for the off-label prescribing of antihistamines was prescribing at higher than the recommended dose (30.2 %). Binary logistic regression showed that children aged <2 years (OR 12.65; 95 % CI 2.87-55.67) and the number of medications received (OR 1.14; 95 % CI 1.00-1.29) were significant predictors for the off-label prescribing of antihistamines. Conclusion Prescribing antihistamines for children in an off-label manner was prevalent at the studied locations and warrants further investigation on the consequences of such prescribing. PMID- 27480983 TI - Safety in the use of vaseline during oxygen therapy: the pharmacist's perspective. AB - The justification of the combination of vaseline and oxygen has been subject for discussion in many hospitals. Due to the lack of evidence based data in literature, we have provided recommendations from a pharmacist's perspective. The use of petroleum-based products should be avoided when handling patients under oxygen therapy. Whenever a skin moisturizer is needed for lubrication or rehydration of dry nasal passages, the lips or nose when breathing oxygen, consider the use of oil-in water creams or water-based products. PMID- 27480984 TI - Congenital diaphragmatic hernia in neonates: factors related to failure of thoracoscopic repair. AB - PURPOSE: To evaluate factors related to conversion to open repair (OR) during thoracoscopic repair (TR) in congenital diaphragmatic hernia (CDH). METHODS: CDH subjects who were diagnosed prenatally or within 6 h of birth and underwent TR at our institution from 2007 to 2015 were reviewed. Two groups were defined: Group A, subjects who tolerated TR; and Group B, subjects who required conversion to OR. RESULTS: Twenty-nine subjects (Group A, 20; Group B, 9) underwent TR. Patients' demographics were not significantly different between the two groups. In Group A, pre-operative arterial blood gas analysis showed mean PaCO2 37.4 mmHg, mean pH 7.45, and mean PaO2 201.6 mmHg, which were not significantly different from those of Group B (PaCO2 40.6 mmHg, pH 7.43, and PaO2 251.1 mmHg). Two Group B cases required conversion due to cardiopulmonary instability. The remaining seven cases were converted for technical reasons (large defect in two, anterior location of the defect in two, bleeding from short gastric vessels or spleen in two, and insufficient operative view in one). CONCLUSIONS: TR can be performed safely in selected cases of CDH. CDH with a large defect and/or an unusual location of the defect remains a challenge for pediatric surgeons. PMID- 27480985 TI - Surgical management of recto-prostatic and recto-bulbar anorectal malformations. AB - PURPOSE: Laparoscopically assisted anorectoplasty (LAARP) was compared to posterior sagittal anorectoplasty (PSARP) in the treatment of male imperforate anus associated with either recto-prostatic fistula (RPF) or recto-bulbar fistula (RBF). METHOD: 19 RPF patients (12 treated by LAARP and 7 by PSARP) and 26 RBF patients (14 treated by LAARP and 12 by PSARP) between 1995 and 2014 were retrospectively assessed using a fecal continence evaluation questionnaire (FCE) (with a maximum score of 10), an FCE score coefficient variation, as well patients' MRI scores, anorectal angle values (AA), and incidence of postoperative complications. Statistical significance was determined at p < 0.05. RESULTS: Both groups were similar in mean age and mean weight at repair, as well as sacral status. Postoperatively, mean MRI scores, mean AA, and biochemistry were also similar (p = NS). All cases treated with LAARP showed consistently higher and less variable FCES values, fewer wound infection incidence, but greater rectal mucosal prolapse unrelated with sacrum status. Significantly lower doses of postoperative analgesia were needed in all LAARP cases (p < 0.05). CONCLUSION: Technical outcomes appear to be similar based on imaging studies, but FCES assessed functional outcomes appear to favor LAARP for treatment of both RPF and RBF. PMID- 27480986 TI - Decreased expression of hepatocyte growth factor in the nitrofen model of congenital diaphragmatic hernia. AB - PURPOSE: Pleuroperitoneal folds (PPFs) are essential for normal diaphragmatic development, representing the only source of the diaphragm's muscle connective tissue. Hepatocyte growth factor (Hgf), which is secreted in PPFs, plays a crucial role in the formation of the muscular diaphragmatic components by regulating the migration of myogenic progenitor cells into the primordial diaphragm. Hgf is also a known downstream target of Gata4 and it has been demonstrated that the expression of Hgf was significantly downregulated in PPF cells of Gata4 knockouts with congenital diaphragmatic hernia (CDH). Furthermore, mutations in PPF-derived cells have been shown to result in CDH. We hypothesized that Hgf expression is decreased in developing diaphragms of fetal rats with nitrofen-induced CDH. METHODS: Timed-pregnant rats were exposed to either nitrofen or vehicle on gestational day 9 (D9). Fetuses were harvested on selected time-points D13, D15 and D18. Dissected diaphragms (n = 72) were divided into control and nitrofen-exposed specimens (n = 12 per time-point and experimental group, respectively). Diaphragmatic gene expression of Hgf was analyzed by qRT PCR. Immunofluorescence double staining for Hgf and the mesenchymal marker Gata4 or muscular progenitor marker Myogenin was performed to evaluate protein expression and localization in fetal diaphragms. RESULTS: Relative mRNA expression of Hgf was significantly downregulated in PPFs of nitrofen-exposed fetuses on D13 (3.08 +/- 1.46 vs. 5.24 +/- 1.93; p < 0.05), developing diaphragms of nitrofen-exposed fetuses on D15 (2.01 +/- 0.79 vs. 4.10 +/- 1.50; p < 0.05) and fully muscularized diaphragms of nitrofen-exposed fetuses on D18 (1.60 +/- 0.78 vs. 3.21 +/- 1.89; p < 0.05) compared to controls. Confocal laser scanning microscopy revealed markedly diminished diaphragmatic immunofluorescence of Hgf in nitrofen-exposed fetuses on D13, D15 and D18 compared to controls, which was associated with disruptions in muscle connective tissue formation and reduced myogenic progenitor cell invasion. CONCLUSION: Decreased diaphragmatic expression of Hgf may disturb the formation of muscle connective tissue in PPFs and thus prevent essential migration of muscle progenitor cells into the developing diaphragm, leading to diaphragmatic defects in the nitrofen CDH model. PMID- 27480988 TI - Neuropsychological Assessment of Testamentary Capacity and Undue Influence. AB - Neuropsychologists are increasingly requested to perform assessments of testamentary capacity. This article provides an overview of the psycho-legal context in which such assessments are performed. Suggestions for an evaluative methodology for performing these evaluations with both living and deceased testators are provided. PMID- 27480987 TI - Effects of various remineralizing agents on the outcome of post-orthodontic white spot lesions (WSLs): a clinical trial. AB - BACKGROUND: One of the most undesirable side effects of comprehensive orthodontic treatment is white spot lesions (WSLs). Despite many attempts at prevention of WSLs, its prevalence remains very high on debonding. There are many agents like fluoride toothpastes, fluoride varnishes, and fluoride mouth rinses, and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) is frequently used for the remineralization of WSLs. However, there is no consensus in the literature with respect to the success rates of these agents. Thus, the present study was designed to evaluate the efficacy of fluoride toothpaste alone and in combination with fluoride varnish and CPP-ACP plus creme in the remineralization of post orthodontic WSLs. METHODS: Forty-five subjects in the age range of 16-25 years having at least one post-orthodontic WSL were included in the study. All the subjects were randomly divided into three groups (toothpaste group, varnish group, and CPP-ACP group). The efficacy of various remineralizing agents on the remineralization of WSLs was evaluated clinically and by DIAGNOdent immediately after debonding and subsequently after 1, 3, and 6 months of their use. RESULTS: Twice daily use of fluoride toothpaste alone had no significant effect on remineralization of WSLs at various intervals of observations (P = 0.078). Application of fluoride varnish along with twice daily use of fluoride toothpaste for 6 months significantly decreased the severity of WSLs (P < 0.01). Twice daily use of CPP-ACP plus creme along with fluoride toothpaste had significant effect on remineralization of WSLs at the end of 6 months of observation (P < 0.05). Between the group comparison showed that the mean visual and DIAGNOdent scores at various time intervals of observations were decreased more when fluoride varnish and CPP-ACP creme were used in addition to daily use of fluoride toothpaste, but the differences were not statistically significant (P > 0.05). CONCLUSIONS: The use of fluoride varnish and CPP-ACP plus creme in addition to twice daily use of fluoride toothpaste had no additional benefit in the remineralization of post orthodontic WSLs. PMID- 27480989 TI - Sexual Consent Capacity Assessment with Older Adults. AB - Many healthcare providers have a limited knowledge of sexual and intimate expression in later life, often due to attitudinal and informational limitations. Further, the likelihood of an older adult experiencing cognitive decline increases in a long-term care (LTC) setting, complicating the ability of the providers to know if the older adult can make his or her own sexual decisions, or has sexual consent capacity. Thus, the team is left to question if and how to support intimacy and/or sexuality among residents with intimacy needs. Psychologists working with LTC need to be aware and knowledgeable about sexual consent capacity in older adulthood to be prepared to conduct evaluations and participate in planning care. Limited research is available to consult for best practices in sexual consent capacity assessment; however, models of assessment have been developed based on the best available evidence, clinical judgment, and practice. Existing models will be discussed and an integrated model will be illustrated via a case study. PMID- 27480990 TI - Comment on published article in Lupus: Autoimmune myelofibrosis with pancytopenia as a presenting manifestation of systemic lupus erythematosus responsive to mycophenolate mofetil; IVIG in myelofibrosis in SLE. PMID- 27480991 TI - Myelitis in systemic lupus erythematosus: clinical characteristics and effect in accrual damage. A single-center experience. AB - Objective The purpose of this study was to describe the clinical characteristics of acute transverse myelitis, including the time of their presentation, and to evaluate their effect on accrual damage in patients with systemic lupus erythematosus (SLE). Methods Patients with SLE who were hospitalized because of incident, noninfectious myelitis at our institute between January 1997 and December 2013 were identified. As a control group, we selected for each of the patients in the study group one SLE patient hospitalized at the closest date to the case due to other severe non-neuropsychiatric (NP) SLE manifestation, with no history of NP manifestations or noninfectious disease. Clinical characteristics, laboratory results, treatment, disease activity (SLEDAI-2K), and damage (SLICC/ACR-DI) were collected from medical charts at the index hospitalization and one year after hospitalization. Results Demographics and SLE characteristics, including age at SLE diagnosis and time since SLE diagnosis to hospitalization, were comparable in patients with myelitis and controls. At hospitalization, disease activity and cumulative damage were similar in both groups. Patients with myelitis received more aggressive treatment than controls. One year after hospitalization, two of the 15 patients who completed follow-up had symptom improvement without neurologic sequelae, and 13 of them had some improvement of symptoms with neurologic sequelae. Four patients died in the myelitis group, three of them of infectious diseases, and one of alveolar hemorrhage. No patient died because of myelopathy and in the control group no patient died, although three were lost during the follow-up. Disease activity and treatment did not differ between both groups. However, cumulative damage was higher among the patients with myelitis than controls (1.9 +/- 0.9 vs 0.75 +/- 0.9; p = 0.003). Conclusion Patients with myelitis have clinical characteristics similar to those observed in non-NP SLE and receive more aggressive treatment. Furthermore, myelitis is associated with a significant increase in accrual damage compared with severe non-NP manifestations. PMID- 27480992 TI - Removal of the 5-nitro-2-pyridine-sulfenyl protecting group from selenocysteine and cysteine by ascorbolysis. AB - We previously reported on a method for the facile removal of 4-methoxybenzyl and acetamidomethyl protecting groups from cysteine (Cys) and selenocysteine (Sec) using 2,2'-dithiobis-5-nitropyridine dissolved in trifluoroacetic acid, with or without thioanisole. The use of this reaction mixture removes the protecting group and replaces it with a 2-thio(5-nitropyridyl) (5-Npys) group. This results in either a mixed selenosulfide bond or disulfide bond (depending on the use of Sec or Cys), which can subsequently be reduced by thiolysis. A major disadvantage of thiolysis is that excess thiol must be used to drive the reaction to completion and then removed before using the Cys-containing or Sec-containing peptide in further applications. Here, we report a further advancement of this method as we have found that ascorbate at pH 4.5 and 25 degrees C will reduce the selenosulfide to the selenol. Ascorbolysis of the mixed disulfide between Cys and 5-Npys is much less efficient but can be accomplished at higher concentrations of ascorbate at pH 7 and 37 degrees C with extended reaction times. We envision that our improved method will allow for in situ reactions with alkylating agents and electrophiles without the need for further purification, as well as a number of other applications. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27480993 TI - Propensity score-matched analysis of robotic versus open surgical enucleation for small pancreatic neuroendocrine tumours. AB - BACKGROUND: Enucleation of pancreatic neuroendocrine tumours (pNETs) via robotic surgery has rarely been described. This study sought to assess the safety and efficiency of robotic surgery for the enucleation of small pNETs. METHODS: A comparison was conducted of enucleation of pNETs smaller than 2 cm by robotic or open surgery between January 2000 and May 2015. Propensity score matching was used to balance sex, age, BMI, tumour location and tumour diameter. Pathological results, safety-related outcomes (postoperative pancreatic fistula (POPF) rate, estimated blood loss, and short-term mortality and morbidity) and efficiency related outcomes (duration of surgery and postoperative length of hospital stay) were compared between the groups. RESULTS: A cohort of 120 patients with pNET were enrolled in the study (1 : 1 matched for open or robotic surgery, 60 per group). Ninety-three patients (77.5 per cent) had a grade 1 tumour and 114 (95.0 per cent) had an insulinoma. Robotic surgery had a conversion rate of 5 per cent (3 of 60), and was not associated with an increased POPF rate (10 per cent versus 17 per cent after open surgery; P = 0.283) or grade III-V surgical complications according to the Dindo-Clavien classification (3 versus 10 per cent respectively; P = 0.272). Estimated blood loss was reduced with the robotic approach (32.5 versus 80.0 ml in the open group; P = 0.008), as was duration of surgery (117 versus 150 min; P < 0.001). Length of hospital stay after surgery was similar in the two groups (12.0 versus 13.5 days respectively; P = 0.071). CONCLUSION: Robotic surgery for enucleation of pNETs smaller than 2 cm did not increase POPF or major complication rates, and reduced the duration of surgery and estimated blood loss, compared with open surgery. REGISTRATION NUMBER: NCT02125929 ( https://www.clinicaltrials.gov/). PMID- 27480994 TI - A new parameter in the thrombin generation assay, mean velocity to peak thrombin, reflects factor VIII activity in patients with haemophilia A. PMID- 27480995 TI - An in-tether sulfilimine chiral center induces helicity in short peptides. AB - A precisely positioned sulfilimine chiral center in the tether of a stabilized peptide would determine the peptide's secondary structure. Peptide sulfilimines could be prepared by a facile chloramine T oxidation and the two resulting peptide diastereomers showed significant differences in their secondary structures, which were supported by circular dichroism spectroscopy and NMR. PMID- 27480996 TI - Donald L. Morton, MD 1934-2014. PMID- 27480997 TI - Donald L. Morton, MD.... A Legendary Surgical Oncologist and Consummate Investigator. PMID- 27480998 TI - Sentinel Lymph Node Biopsy: Evolution of the Technique Since the Original Description by Morton et al. in 1992. AB - Donald Morton was a truly amazing man: a remarkable scientist and an outstanding, inspirational surgical oncologist. For those of us who had the great fortune to know him personally, it was an experience that we will always remember with warmth and gratitude. Hundreds of thousands, possibly millions, of patients in the future will also be grateful to him when they benefit from his original but simple idea that has so dramatically improved the surgical approach to patients with cancers that may metastasize to regional lymph nodes: the sentinel lymph node biopsy concept. PMID- 27480999 TI - Surgical Lymphadenectomy: The Impact of Sentinel Node Mapping in Breast Cancer. AB - Lymphatic mapping continues to grow in utility both as a diagnostic aid and as a method for performing less morbid, potentially therapeutic lymphadenectomies. Its use in breast cancer has become the standard of care for staging and sentinel lymph node dissection is considered sufficiently therapeutic for low-volume axillary disease. Lymphatic mapping has re-emphasized the importance of adequate lymphatic staging both in terms of the amount of lymph nodes resected and the amount of each lymph node that is assessed. Going forward, these concepts continue to be adopted into other tumors, with active investigations ongoing in gastrointestinal cancers, head and neck cancers, and gynecologic cancers. PMID- 27481000 TI - A Comprehensive Approach to Pediatric Atypical Melanocytic Neoplasms with Comment on the Role of Sentinel Lymph Node Biopsy. AB - Pediatric melanoma has been rising in incidence in recent years and its management poses challenges that are frequently exacerbated by diagnostic uncertainty about the benign or malignant nature of many pediatric melanocytic neoplasms. Sentinel lymph node biopsy (SLNB), originally described by Dr. Donald L. Morton, has been incorporated selectively into the management of pediatric atypical melanocytic neoplasms (AMNs), but its value and significance in this scenario have been controversial. Herein, we describe a comprehensive approach to the evaluation and management of pediatric AMNs that involves SLNB as a diagnostic, staging, and potentially therapeutic tool. We also describe our approach to educating patients and their families about the inherent uncertainties involved in diagnosing and predicting the ultimate behavior of pediatric melanocytic lesions. In addition, we stress the importance of long-term follow-up, as well as ongoing research to improve our understanding of the prognostic factors and histopathologic characteristics that may one day allow us to minimize or eliminate entirely this diagnostically uncertain category of skin lesions. PMID- 27481001 TI - Metastasectomy for Stage IV Melanoma in the Era of Effective Systemic Agents. AB - There is an increasing body of literature that strongly suggests that complete metastasectomy for stage IV melanoma can improve overall survival. Before 2011, the efficacy of systemic therapy for melanoma was poor, making surgical resection the mainstay for treatment and the only realistic chance for cure. Now, in just a short time span (2011-2014), we have six Food & Drug Administration (FDA) approved drugs for patients with stage IV metastatic melanoma. In the absence of prospective clinical trials evaluating the most advantageous sequence and timing for systemic therapy and surgical resection in the setting of stage IV melanoma, the treating surgical and medical oncologists must jointly devise individual treatment plans that take into account the advantages and disadvantages of each modality. This multidisciplinary approach gives the patient the best chance for prolonged survival. This article briefly reviews the FDA-approved systemic therapy options, discusses the data for site-specific metastasectomy, critiques the previous stage IV metastasectomy trials, and presents a view for moving forward with a multidisciplinary approach in mind. PMID- 27481002 TI - Immunology Comes Full Circle in Melanoma While Specific Immunity Is Unleashed to Eliminate Metastatic Disease, Inflammatory Products of Innate Immunity Promote Resistance. AB - Melanoma and many other cancers often express cells and molecular features of inflammation. Intrinsic to melanoma is the expression of a continuous cycle of cytokines and oxidative stress markers. The oxidative stress of inflammation is proposed to drive a metastatic process, not only of DNA adducts and crosslinks, but also of posttranslational oxidative modifications to lipids and proteins that we argue support growth and survival. Fortunately, numerous antioxidant agents are available clinically and we further propose that the pharmacological attenuation of these inflammatory processes, particularly the reactive nitrogen species, will restore the cancer cells to an apoptosis-permissive and growth inhibitory state. Experimental model data using a small-molecule arginine antagonist that prevents enzymatic production of nitric oxide supports this view directly. I propose that the recognition, measurement, and regulation of such carcinogenic inflammation be considered as part of the approach to the treatment of cancer. PMID- 27481003 TI - Intralesional Immunotherapy for Metastatic Melanoma: The Oldest and Newest Treatment in Oncology. AB - The last few years have yielded exciting developments in immunotherapy for cancer. The promise of cancer immunotherapy has been well known for many years, but had generally produced limited or inconsistent benefit to patients. Intralesional therapies, which are in fact one of the oldest forms of immunotherapy, are also demonstrating benefits in the modern age. This review discusses the origins of intralesional immunotherapy and its underlying rationale. It also discusses the reemergence of this mode of therapy into the modern era, which is where Donald L. Morton, subject of this edition of the journal, plays a major role. The review also discusses current areas of investigation. Given the intuitive advantages of this strategy and the demonstrated, expanding areas of clinical responses, it is likely that intralesional immunotherapy will remain a useful component of cancer treatment into the future. PMID- 27481004 TI - Therapeutic Strategies for Human IgM Antibodies Directed at Tumor-Associated Ganglioside Antigens: Discoveries Made During the Morton Era and Future Directions. AB - Tumor-associated gangliosides have been investigated for their potential as antigenic targets for more than 35 years, culminating in the recent Food and Drug Administration approval of dinutuximab (Unituxin), an IgG antibody targeted against GD2, for the treatment of neuroblastoma in children. This review is focused on discoveries and development of therapeutic approaches involving human IgM antibodies directed against gangliosides, which occurred over the past 40 years at University of California-Los Angeles and the John Wayne Cancer Institute, where Dr. Donald Morton led the surgical oncology department until his death. PMID- 27481005 TI - Immune Responses to BRAF-Targeted Therapy in Melanoma: Is Targeted Therapy Immunotherapy? AB - Therapies targeting the mitogen-activated protein kinase signaling pathway can induce profound tumor regression in patients with advanced BRAF-mutated melanoma. Most patients develop resistance after several months of treatment, which is typically followed by rapid disease progression and death. BRAF- and mitogen activated protein kinase kinase (MEK)-targeted therapies were initially thought to exert their therapeutic effects through direct inhibition of signaling within the tumor cell, resulting in cell death. Recent evidence suggests that BRAF targeted therapy also augments the host immune response to melanoma. This is characterized by enhanced expression of melanoma differentiation antigens, reduced levels of immunosuppressive cytokines in the micro environment, and a CD8 T-cell response and T-cell-mediated cytotoxicity. These changes are noted within days of starting therapy, correlate with tumor response, reverse with resistance, and occur in metastatic and advanced, operable disease. Enhanced PDL-1 expression by melanoma cells and increased markers of immune exhaustion, including PD-1 and TIM-1, have been identified, suggesting that the immune response is down modulated before resistance occurs. These findings indicate that BRAF- and MEK targeted therapies have multiple, complex, and interrelated mechanisms of action and validate the investigation of combination treatment strategies with targeted therapy and immune checkpoint inhibitors, as well as other therapies that modulate the immune microenvironment. They also lend support for clinical trials investigating preoperative and adjuvant BRAF-targeted therapy for high-risk, BRAF mutated melanoma. Together, these studies will enhance our understanding of the mechanism of action of BRAF-targeted therapies and may identify additional opportunities to improve the outcome of patients with advanced melanoma. PMID- 27481006 TI - Hepatocellular Carcinoma: The Current Role of Surgical Intervention. AB - As the incidence of hepatocellular carcinoma (HCC) continues to rise, so does our understanding of this disease and the number of available treatment options and strategies. Although surgical intervention often continues to play a central role, it must be placed in the proper context of what has rapidly become a multimodality, multidisciplinary disease. Understanding the nuances of managing HCC and its associations and treatment options are essential for making appropriate surgical decisions. PMID- 27481007 TI - Surgical Resection of Retroperitoneal Sarcomas: Analysis of Factors Determining Outcome. AB - INTRODUCTION: Retroperitoneal sarcomas (RS) are rare malignant tumors characterized by high local recurrence rates and poor survival, Aggressive surgical resection may improve local recurrence rates and disease-specific survival (DSS), The aim of our study was to determine predictors of survival and local recurrence in primary RS. METHODS: We performed a retrospective analysis and identified 68 patients who underwent surgical resection of a primary RS between 1985 and 2010, Clinical and pathologic variables were used to create univariate and multivariate models for both survival and recurrence. RESULTS: 68 patients (37% male) with mean age 59 (range 25-84) underwent surgical resection for RS. Median tumor size was 12.0 cm (range 7.0-18.0 cm). 75% of tumors were intermediate/high grade, Incontinuity organ resection was performed in 29 (43%) patients. Seven patients (10%) underwent vascular resection with graft placement. Overall survival at 5, 10 and 15 years was 55%, 42%, and 33%, respectively. Grade (p<0.007), tumor size (p=0.048) and margin status (p<0.05) were found to significantly affect local recurrence. In a multivariate analysis, recurrent disease (p<0.001), age (p<0.003) and high/intermediate grade (p<0.001) significantly affected DSS. Incontinuity organ resection did not significantly affect recurrence (HR = 1.1, CI 0.63 - 1.85) or survival (HR = 1.4, CI 0.8 - 2.9). CONCLUSION: Surgical resection of RS affords the best chance of survival. Incontinuity organ resection did not affect outcome on multivariate analysis; however, margin status did significantly affect recurrence and could not be achieved without aggressive resection of incontinuity organs. PMID- 27481008 TI - Gene Therapy for Lung Cancer. AB - Gene therapy was originally conceived to treat monogenic diseases. The replacement of a defective gene with a functional gene can theoretically cure the disease. In cancer, multiple genetic defects are present and the molecular profile changes during the course of the disease, making the replacement of all defective genes impossible. To overcome these difficulties, various gene therapy strategies have been adopted, including immune stimulation, transfer of suicide genes, inhibition of driver oncogenes, replacement of tumor-suppressor genes that could mediate apoptosis or anti-angiogenesis, and transfer of genes that enhance conventional treatments such as radiotherapy and chemotherapy. Some of these strategies have been tested successfully in non-small-cell lung cancer patients and the results of laboratory studies and clinical trials are reviewed herein. PMID- 27481009 TI - Circulating Tumor Cells in Breast Cancer Patients. AB - Breast cancer is the most commonly diagnosed cancer among women, resulting in an estimated 40,000 deaths in 2014.1 Metastasis, a complex, multi-step process, remains the primary cause of death for these patients. Although the mechanisms involved in metastasis have not been fully elucidated, considerable evidence suggests that metastatic spread is mediated by rare cells within the heterogeneous primary tumor that acquire the ability to invade into the bloodstream. In the bloodstream, they can travel to distant sites, sometimes remaining undetected and in a quiescent state for an extended period of time before they establish distant metastases in the bone, lung, liver, or brain. These occult micrometastatic cells (circulating tumor cells, CTCs) are rare, yet their prognostic significance has been demonstrated in both metastatic and non metastatic breast cancer patients. Because repeated tumor tissue collection is typically not feasible and peripheral blood draws are minimally invasive, serial CTC enumeration might provide "real-time liquid biopsy" snapshots that could be used to identify early-stage breast cancer patients with micrometastatic disease who are at risk for disease progression and monitor treatment response in patients with advanced disease. In addition, characterizing CTCs might aid in the development of novel, personalized therapies aimed at eliminating micrometastases. This review describes current CTC isolation, detection, and characterization strategies in operable breast cancer. PMID- 27481011 TI - Preface: The Living Legacy of Donald L. Morton. PMID- 27481010 TI - Liquid Biopsies for Assessing Metastatic Melanoma Progression. AB - The field of genomic biomarkers in melanoma has evolved dramatically in the past few decades. Whereas much of the prior focus was on molecular assessment of tumor tissue, circulating tumor cells (CTCs), and cell-free circulating tumor DNA (ctDNA) as sources of a "liquid biopsy" in cancer patients provide promising potential as a method to assess tumor progression, identify targets for therapy, and evaluate clinical response to treatment. Blood biomarker assays have the advantage of being noninvasive, allow for dynamic evaluation of disease over a serial time frame, and help to address the issue of tissue sampling bias and tumor heterogeneity. However, there remains an assortment of technologies and techniques to isolate and detect CTCs and ctDNA and a standardized method has yet to be established. Despite these challenges, multiple studies have already demonstrated the clinical prognostic utility of blood-based genomic biomarker assays. With the advent of next-generation sequencing and genome-wide ctDNA analysis, this will undoubtedly lead to an improved understanding of tumor progression, help to identify new targets for treatment, and improve monitoring of treatment response and development of resistance. PMID- 27481012 TI - Executive Function in Pediatric Sleep-Disordered Breathing: A Meta-analysis. AB - OBJECTIVES: Evaluate the association between pediatric sleep-disordered breathing (SDB) and executive functioning. METHODS: We searched multiple electronic databases for peer-reviewed journal articles related to pediatric SDB and executive functioning. We included studies that assessed SDB via polysomnography, included objective or questionnaire measures of executive function, and had an age-matched control group. Fourteen articles met inclusion criteria with a total sample of 1697 children ages 5 to 17 years (M=9.81 years; SD=0.34). We calculated an overall effect size for each of the five executive domains (vigilance, inhibition, working memory, shifting, and generativity) as well as effect sizes according to SDB severity: mild, moderate, severe. We also calculated effect sizes separately for objective and subjective questionnaires of executive functioning. RESULTS: We found a medium effect size (-0.427) for just one of five executive function domains on objective neuropsychological measures (generativity). In contrast, effect sizes on all three executive domains measured via questionnaire data were significant, with effect sizes ranging from medium ( 0.64) to large (-1.06). We found no difference between executive domains by severity of SDB. CONCLUSIONS: This meta-analysis of executive function separated into five domains in pediatric SDB suggested lower performance in generativity on objective neuropsychological measures. There were no differences associated with SDB severity. Questionnaire data suggested dysfunction across the three executive domains measured (inhibition, working memory, shifting). Overall, limited evidence suggested poorer performance in executive function in children with SDB according to objective testing, and subjective ratings of executive function suggested additional worsened performance. (JINS, 2016, 22, 839-850). PMID- 27481013 TI - Microbial metabolism mediates interactions between dissolved organic matter and clay minerals in streamwater. AB - Sorption of organic molecules to mineral surfaces is an important control upon the aquatic carbon (C) cycle. Organo-mineral interactions are known to regulate the transport and burial of C within inland waters, yet the mechanisms that underlie these processes are poorly constrained. Streamwater contains a complex and dynamic mix of dissolved organic compounds that coexists with a range of organic and inorganic particles and microorganisms. To test how microbial metabolism and organo-mineral complexation alter amino acid and organic carbon fluxes we experimented with (13)C-labelled amino acids and two common clay minerals (kaolinite and montmorillonite). The addition of (13)C-labelled amino acids stimulated increased microbial activity. Amino acids were preferentially mineralized by the microbial community, concomitant with the leaching of other (non-labelled) dissolved organic molecules that were removed from solution by clay-mediated processes. We propose that microbial processes mediate the formation of organo-mineral particles in streamwater, with potential implications for the biochemical composition of organic matter transported through and buried within fluvial environments. PMID- 27481014 TI - Observations from a FIGO Past President on vaginal hysterectomy and related surgery by the vaginal route. PMID- 27481015 TI - Asymptomatic elevated total serum bile acids representing an unusual form of intrahepatic cholestasis of pregnancy. PMID- 27481016 TI - A randomized controlled trial of nitrous oxide for intrauterine device insertion in nulliparous women. AB - OBJECTIVE: To evaluate the effectiveness of inhaled nitrous oxide for pain management among nulliparous women undergoing intrauterine device (IUD) insertion. METHODS: A double-blind, randomized controlled trial was conducted among nulliparous women aged 13-45years who underwent IUD insertion at a US center between October 1, 2013, and August 31, 2014. Using a computer-generated randomization sequence, participants were randomly assigned to inhale either oxygen (O2) or a mixture of 50% nitrous oxide and 50% oxygen (N2O/O2) through a nasal mask for 2minutes before insertion. Only the person administering the inhalation agent was aware of group assignment. The primary outcome was maximum pain assessed 2minutes after insertion via a 100-mm visual analog scale. Analyses were by intention to treat. RESULTS: Forty women were assigned to each group. Mean maximum pain score at the time of insertion was 54.3+/-24.8mm for the N2O/O2 group and 55.3+/-20.9mm for the O2 group (P=0.86). Adverse effects were reported for 6 (15%) women in the N2O/O2 group and 7 (18%) in the O2 group (P=0.32). CONCLUSION: N2O/O2 did not reduce the pain of IUD insertion among nulliparous women. ClinicalTrials.gov: NCT02391714. PMID- 27481018 TI - Editorial: Sustained Success of Molecular Informatics. PMID- 27481017 TI - Factors Predictive of Improved Abdominal Ultrasound Visualization after Oral Administration of Simethicone. AB - Ultrasonography is a non-invasive, accurate and low-cost technique used to study the upper abdomen, but it has reduced reliability in the study of the pancreas and retroperitoneum. Simethicone is a well-known emulsifying agent that has been used to improve ultrasonographic visualization. The aim of this study was to identify anthropometric parameters that are able to predict a good response to simethicone in improving ultrasonographic visualization of abdominal structures. One hundred twenty-seven patients were recruited. After basal examination, their anthropometric parameters were collected. Patients with an incomplete upper abdominal examination because of gastrointestinal gas have greater body mass index, waist circumference and abdominal wall thickness. In our study, the best anthropometric parameter for identifying patients with poor visualization at abdominal ultrasound examination is waist circumference. Using a cutoff of 84 cm, we can identify patients with poor visibility at abdominal ultrasound examination (group B) with a sensitivity of 90%. PMID- 27481019 TI - Guest Editorial: Advances in Computational Toxicology. PMID- 27481020 TI - Quantitative Evaluation and Prediction of Drug Effects and Toxicological Risk Using Mechanistic Multiscale Models. AB - Integrating in vitro and in silico approaches has great potential for reducing experimental effort and delivering know-how and intellectual property in drug development. Here, we focus on a possible framework for multiscale modeling in pharmaceutical drug development. Looking at the modeling frameworks at different scales, it is obvious that choosing the proper level of complexity and abstraction is not a trivial task. At cellular level, we consider that the application of validated kinetic models of cellular toxicity mechanisms of drugs is particularly important for deriving valid predictions. These kinetic models can be applied for integrating inter-individual differences, e.g. obtained from data measured in surgical liver samples, into predictions of drug effects. Challenges identified include (i) the development of sufficiently detailed, structured organ models, (ii) definition of multiscale models that can be efficiently handled by available super-computing facilities, and (iii) availability of validated cell-type and organ-specific kinetic metabolic models. Multiscale models can streamline drug development by facilitating the design of experiments and trials, by providing and testing hypotheses, and by reducing time and costs due to less experiments and improved decision-making. In this review, we discuss the required pieces, possibilities, and challenges in multiscale modeling for the prediction of drug effects. PMID- 27481021 TI - The eTOX Library of Public Resources for in Silico Toxicity Prediction. AB - (1000-1500 characters) In spite of the increasing amount of public access resources that offer original data related to drug toxicology, the successful exploitation of such data for the development of in silico predictive models is still limited by the quality of the data available, its integrability and its coverage for each toxicity endpoint. This work describes the strategy developed by the IMI eTOX consortium for identifying and compiling data and other related resources from the biomedical literature and a wide spectrum of public on-line sources. The main result of this effort is a large web-based structured library containing links to articles of toxicological relevance (data that can be used for modeling purposes, computational models, and toxicity mechanisms), public databases, standardized vocabularies and modeling tools. All this material has been manually reviewed, systematically evaluated and grouped into different categories. The library has been made public at the eTOX website (http://www.etoxproject.eu/), where it is updated on a monthly basis, constituting a useful resource for affording the in silico toxicity prediction of novel drug candidates. PMID- 27481022 TI - Exploiting Pharmacological Similarity to Identify Safety Concerns - Listen to What the Data Tells You. AB - Whilst most new drugs are designed to act on a single target or a small number of targets, many do show broad pharmacological activity. In some cases this can be beneficial and necessary for efficacy and in others it can be detrimental, leading to increased safety liability. To probe off-target pharmacology most drug discovery programs include screening against a broad panel of targets that represent known troublesome pharmacology. Hits against any one of these targets can then be subjected to a risk assessment for potential safety problems in preclinical or clinical studies. In addition, the secondary pharmacology profile can also be thought of as an alternative description of the compound and as such can be used as a method for assessing 'similarity'. Consequently, inspection of the in vivo findings of pharmacological neighbors can give important insights into potential safety liabilities that are neither identified by pure chemical similarity searches nor by risk assessment on individual targets. Here we show that the pharmacological profile contains additional information as compared to chemical similarity, and also demonstrate how this can be used in the hazard assessment done during drug discovery and development. PMID- 27481023 TI - The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing. AB - The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. PMID- 27481024 TI - Towards a Fuzzy Expert System on Toxicological Data Quality Assessment. AB - Quality assessment (QA) requires high levels of domain-specific experience and knowledge. QA tasks for toxicological data are usually performed by human experts manually, although a number of quality evaluation schemes have been proposed in the literature. For instance, the most widely utilised Klimisch scheme1 defines four data quality categories in order to tag data instances with respect to their qualities; ToxRTool2 is an extension of the Klimisch approach aiming to increase the transparency and harmonisation of the approach. Note that the processes of QA in many other areas have been automatised by employing expert systems. Briefly, an expert system is a computer program that uses a knowledge base built upon human expertise, and an inference engine that mimics the reasoning processes of human experts to infer new statements from incoming data. In particular, expert systems have been extended to deal with the uncertainty of information by representing uncertain information (such as linguistic terms) as fuzzy sets under the framework of fuzzy set theory and performing inferences upon fuzzy sets according to fuzzy arithmetic. This paper presents an experimental fuzzy expert system for toxicological data QA which is developed on the basis of the Klimisch approach and the ToxRTool in an effort to illustrate the power of expert systems to toxicologists, and to examine if fuzzy expert systems are a viable solution for QA of toxicological data. Such direction still faces great difficulties due to the well-known common challenge of toxicological data QA that "five toxicologists may have six opinions". In the meantime, this challenge may offer an opportunity for expert systems because the construction and refinement of the knowledge base could be a converging process of different opinions which is of significant importance for regulatory policy making under the regulation of REACH, though a consensus may never be reached. Also, in order to facilitate the implementation of Weight of Evidence approaches and in silico modelling proposed by REACH, there is a higher appeal of numerical quality values than nominal (categorical) ones, where the proposed fuzzy expert system could help. Most importantly, the deriving processes of quality values generated in this way are fully transparent, and thus comprehensible, for final users, which is another vital point for policy making specified in REACH. Case studies have been conducted and this report not only shows the promise of the approach, but also demonstrates the difficulties of the approach and thus indicates areas for future development. PMID- 27481025 TI - Enrichment of True Positives from Structural Alerts Through the Use of Novel Atomic Fragment Based Descriptors. AB - To enhance the discrimination rate for methods applying structural alerts and biotransformation rules in the prediction of toxicity and drug metabolism we have developed a set of novel fragment based atomic descriptors. These atomic descriptors encode the properties of the fragments separating an atom from the closest end of a branch or the molecule. The end of a branch and the end of a molecule, as well as the selection of the fragments, are made by an algorithm that uses only the distance matrix of the molecule. The novel descriptors are applied to a small set of biotransformation rules and are shown to be able to reduce the number of unconfirmed positives by up to 58 %. PMID- 27481026 TI - Effectiveness of CASE Ultra Expert System in Evaluating Adverse Effects of Drugs. AB - Purpose of this pilot study is to test the QSAR expert system CASE Ultra for adverse effect prediction of drugs. 870 drugs from the SIDER adverse effect dataset were tested using CASE Ultra for carcinogenicity, genetic, liver, cardiac, renal and reproductive toxicity. 47 drugs that were withdrawn from market since the 1950s were also evaluated for potential risks using CASE Ultra and compared them with the actual reasons for which the drugs were recalled. For the whole SIDER test set (n=870), sensitivity and specificity of the carcinogenicity predictions are 66.67 % and 82.17 % respectively; for liver toxicity: 78.95 %, 78.50 %; cardiotoxicity: 69.07 %, 57.57 %; renal toxicity: 46.88 %, 67.90 %; and reproductive toxicity: 100.00 %, 61.10 %. For the SIDER test chemicals not present in the training sets of the models, sensitivity and specificity of carcinogenicity predictions are 100.00 % and 88.89 % respectively (n=404); for liver toxicity: 100.00 %, 51.33 % (n=115); cardiotoxicity: 100.00 %, 20.45 % (n=94); renal toxicity: 100.00 %, 45.54 % (n=115); and reproductive toxicity: 100.00 %, 48.57 % (n=246). CASE Ultra correctly recognized the relevant toxic effects in 43 out of the 47 withdrawn drugs. It predicted all 9 drugs that were not part of the training set of the models, as unsafe. PMID- 27481027 TI - Model Suite for Predicting the Aquatic Toxicity of alpha,beta-Unsaturated Esters Triggered by Their Chemoavailability. AB - For a Michael-acceptor set of 45 alpha,beta-unsaturated esters, the 2(nd) -order rate constant of reaction with glutathione, log kGSH , was modeled through the quantum chemical reaction barrier (DeltaE(?) ) employing methane thiol as model nucleophile. Regression of their 48-h toxicity toward the ciliates Tetrahymena pyriformis (log EC50 , 50 % growth inhibition) on log Kow (octanol/water partition coefficient) and log kGSH revealed a variation in the relative weights of hydrophobicity and electrophilic reactivity as determinants of the aquatic toxicity. The difference DKk =log Kow -log kGSH turned out as a suitable means for predictively discriminating between narcosis-level (DKk >3.0) and excess toxic (DKk <2.0) compounds. In the intermediate DKk range (2.0<=DKk <=3.0), both narcosis-level and reactive-toxicity models are applicable for predicting aquatic toxicity. As such, DKk represents the chemoavailability of Michael-acceptor esters, characterizing their likelihood for undertaking covalent reactions with thiol sites of endogenous peptides and proteins. At the same time, DKk introduces a straightforward way for characterizing the applicability domain of QSAR (quantitative structure-activity relationship) models for predicting the toxicity of Michael-acceptor esters. The resultant model suite comprising QSARs for reactive toxicity and baseline narcosis is triggered by the compounds' chemoavailability, and yields predictions superior to existing approaches. PMID- 27481028 TI - Read-Across Prediction of the Acute Toxicity of Organic Compounds toward the Water Flea Daphnia magna. AB - According to the European REACH Directive, the acute daphnid toxicity needs to be assessed for industrial chemicals with market volumes >=1 t/a. Employing a data set of 1365 organic compounds with experimental 48-h LC50 data for Daphnia magna, a read-across approach has been developed that makes use of the atom-centered fragment (ACF) method as quantitative measure for structural similarity. Both quantitative log LC50 predictions and a discrimination between narcosis-level and excess toxicity can be obtained, augmented by similarity-triggered information that characterizes a compound as inside or outside the quantitative or qualitative model domain. Reading across proceeds as interpolation of the toxicity enhancement (Te ) over predicted narcosis-level toxicity, taking experimental log Te values from similarity-selected reference compounds as input. The resultant decision tree model yields r(2) =0.85 and rms=0.66 for the subset of 757 compounds (56 %) identified as inside the quantitative model domain, and can handle further 318 compounds (23 %) with the categorical submodel, with 290 compounds (21 %) being outside its domain. The new in silico approach appears useful as ITS (Integrated Testing Strategy) tool for the daphnid toxicity assessment. The discussion includes a comparison of Kow - and LSER-predicted narcosis-level toxicity in the read-across context. PMID- 27481029 TI - Notification: Construction and Consensus Performance of (Q)SAR Models for Predicting Phospholipidosis Using a Dataset of 743 Compounds. PMID- 27481031 TI - [Coding Causes of Death with IRIS Software. Impact in Navarre Mortality Statistic]. AB - BACKGROUND: There are few studies that analyze changes in mortality statistics derived from the use of IRIS software, an automatic system for coding multiple causes of death and for the selection of the underlying cause of death, compared to manual coding. This study evaluated the impact of the use of IRIS in the Navarre mortality statistic. METHODS: We proceeded to double coding 5,060 death certificates corresponding to residents in Navarra in 2014. We calculated coincidence between the two encodings for ICD10 chapters and for the list of causes of the Spanish National Statistics Institute (INE-102) and we estimated the change on mortality rates. RESULTS: IRIS automatically coded 90% of death certificates. The coincidence to 4 characters and in the same chapter of the CIE10 was 79.1% and 92.0%, respectively. Furthermore, coincidence with the short INE-102 list was 88.3%. Higher matches were found in death certificate of people under 65 years. In comparison with manual coding there was an increase in deaths from endocrine diseases (31%), mental disorders (19%) and disease of nervous system (9%), while a decrease of genitourinary system diseases was observed (21%). CONCLUSIONS: The coincidence at level of ICD10 chapters coding by IRIS in comparison to manual coding was 9 out of 10 deaths, similar to what is observed in other studies. The implementation of IRIS has led to increased of endocrine diseases, especially diabetes and hyperlipidaemia, and mental disorders, especially dementias. PMID- 27481032 TI - Extraction and precipitation of phosphorus from sewage sludge. AB - Raw sewage sludge from East Rand Water Care Association (ERWAT) had high phosphorus (P) content, approximately 15.2% (w/w) P2O5, which indicates a potential resource for the limiting nutrient. Leaching sewage sludge with 1M sulphuric acid at 5% solid loading for 2h resulted in an 82% phosphorus extraction. However, the phosphorus was recovered as iron phosphates, thus a further purification step using ion exchange to remove iron was required to increase the degree of P release. Magnesium oxide and ammonium hydroxide were used as magnesium and nitrogen sources, respectively, as well as pH regulators to precipitate P as struvite. 57% struvite was precipitated and the total phosphorus content of the precipitate was 25.9%. Kinetic studies showed that the leaching of phosphorus follows the Dickinson model for the first 100min with a rate of reaction of about 2*10-5s-1. The rate limiting step is controlled by diffusion. Phosphorus solubility in 2% critic acid was almost 96%, which is the amount of phosphorus available to plants if the precipitate is applied as a fertiliser. Environmental, gram-positive Bacillus subtilis were found in the precipitate, which are harmless to the environment since they already exist in the soil where the precipitate can be applied as a fertiliser. PMID- 27481033 TI - Neuroanatomical changes extend beyond striatal atrophy in X-linked dystonia parkinsonism. AB - BACKGROUND: X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative adult-onset basal ganglia model disease associated with severe striatal atrophy. Anatomical changes exceeding striatal pathology were not yet described in XDP. The present study aimed to assess the microstructure of white matter tracts in XDP using magnetic resonance tomography. METHODS: Diffusion weighted imaging was done in 10 XDP patients, aged 42.2 years (SD 8.1), and 14 ethnicity and age-matched controls, aged 40.2 years (SD 6.4). Based on diffusion tensor images, mean diffusivity (MD) and fractional anisotropy (FA) maps were calculated. RESULTS: Except for in the occipital lobe, XDP patients showed generally increased MD values across the entire white matter. FA map analysis identified four significant clusters with controls showing higher FA values than XDP patients. Involved regions included the fornix, anterior thalamic radiation, corticospinal tract, and superior corona radiata bilaterally. In the fornix and the anterior thalamic radiation, the UPDRSIII total score showed a negative correlation with mean FA values at a trend level (tau = -0.40, p = 0.053). Volumetric analysis revealed significant gray matter volume loss of putamen (F(1,19) = 44.2, p < 0.001), caudate nucleus (F(1,19) = 54.3, p < 0.001), and pallidum (F(1,19) = 8.9, p = 0.007). CONCLUSIONS: The present study confirms striatal atrophy in XDP and provides evidence for a strong involvement of the white matter and the pallidum. This calls into question the previously held concept of exclusive striatal atrophy in this unique movement disorder. The spared occipital region may point towards a lack of anatomical connections with the atrophied striatum. PMID- 27481034 TI - Conjugal parkinsonism - Clinical, pathology and genetic study. No evidence of person-to-person transmission. AB - INTRODUCTION: Neurodegeneration is known basis of several different Parkinson syndromes. The most common Parkinson syndrome is the Parkinson's disease. Distinction between different Parkinson syndromes is based on pathology or genetic findings. Recent studies indicate that several major variants of PS have some characteristics of a prion disease and may therefore be transmissible. Married couples offer a unique opportunity to study person-to-person transmission and the role of shared environments as the cause of parkinsonism. METHODS: Autopsy is offered to patients seen at the Movement Disorders Clinic Saskatchewan at no cost. Five couples seen in our clinic, where each spouse had a clinical diagnosis of parkinsonism, came to autopsy. RESULTS: Median duration of marriage was 42 years before the Parkinson syndrome first manifested in a spouse. Three couples were pathologically or genetically discordant for Parkinson variant. Each spouse in the other two couples had Parkinson's disease. One couple had onset separated by 20 years and one partner had a strong family history of Parkinson's disease. CONCLUSION: Our data indicate that neither of the Parkinson's disease, Progressive Supranuclear Palsy and Multiple System Atrophy are transmitted by sexual or other intimate contact. The data also indicate against shared environments as the cause of these disorders. PMID- 27481035 TI - Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: Rationale and Study Design of a Prospective Randomized Controlled Trial. AB - Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent form of heart failure in developed countries. Regrettably, there is no evidence-based effective therapy for HFpEF. We seek to evaluate whether inspiratory muscle training, functional electrical stimulation, or a combination of both can improve exercise capacity as well as left ventricular diastolic function, biomarker profile, quality of life (QoL), and prognosis in patients with HFpEF. A total of 60 stable symptomatic patients with HFpEF (New York Heart Association class II-III/IV) will be randomized (1:1:1:1) to receive a 12-week program of inspiratory muscle training, functional electrical stimulation, a combination of both, or standard care alone. The primary endpoint of the study is change in peak exercise oxygen uptake; secondary endpoints are changes in QoL, echocardiogram parameters, and prognostic biomarkers. As of March 21, 2016, thirty patients have been enrolled. Searching for novel therapies that improve QoL and autonomy in the elderly with HFpEF has become a health care priority. We believe that this study will add important knowledge about the potential utility of 2 simple and feasible physical interventions for the treatment of advanced HFpEF. PMID- 27481037 TI - Pregnancy in patients with autoimmune disease: A reality in 2016. AB - Autoimmune rheumatic diseases are chronic systemic conditions often affecting young women during their reproductive years, so that pregnancy is a major issue in their management. For a long time pregnancy has been discouraged in these women, mainly for two reasons: gestation could aggravate maternal disease and, vice versa, the disease could negatively influence the gestational outcome. The great improvement in the approach to pregnancy done in the past few decades has allowed a progressively increasing number of affected women to fulfill their family plan. Women should be informed about potential risks related to their disease, but they should also be reassured that a good pregnancy outcome is possible if conception occurs in a stable remission state, teratogenic medications have been properly withdrawn and "safe" drugs have been mantained to prevent disease flare. A brief excursus regarding the main issues regarding SLE/APS, Systemic Sclerosis and Systemic Vasculitis is provided, in the attempt to delineate the main risk factors for adverse pregnancy outcome, the onset of maternal complications and the role played by a close multi-specialistic monitoring. PMID- 27481036 TI - Gut microbiome predictors of treatment response and recurrence in primary Clostridium difficile infection. AB - BACKGROUND: Clostridium difficile infection (CDI) may not respond to initial therapy and frequently recurs, but predictors of response and recurrence are inconsistent. The impact of specific alterations in the gut microbiota determining treatment response and recurrence in patients with CDI is unknown. AIM: To assess microbial signatures as predictors of treatment response and recurrence in CDI. METHODS: Pre-treatment stool samples and clinical metadata including outcomes were collected prospectively from patients with their first CDI episode. Next generation 16s rRNA sequencing using MiSeq Illumina platform was performed and changes in microbial community structure were correlated with CDI outcomes. RESULTS: Eighty-eight patients (median age 52.7 years, 60.2% female) were included. Treatment failure occurred in 12.5% and recurrence after response in 28.5%. Patients who responded to treatment had an increase in Ruminococcaceae, Rikenellaceae, Clostridiaceae, Bacteroides, Faecalibacterium and Rothia compared to nonresponders. A risk-index built from this panel of microbes differentiated responders (mean 0.07 +/- 0.24) from nonresponders (0.52 +/- 0.42; P = 0.0002). Receiver operating characteristic (ROC) curve demonstrated that risk index was a strong predictor of treatment response with an area under the curve (AUC) of 0.85. Among clinical parameters tested, only proton pump inhibitor use predicted recurrent CDI (OR 3.75, 95% CI 1.27-11.1, P = 0.01). Patients with recurrent CDI had statistically significant increases in Veillonella, Enterobacteriaceae, Streptococci, Parabacteroides and Lachnospiraceae compared to patients without recurrence and a risk index was able to predict recurrence (AUC = 0.78). CONCLUSION: Gut microbiota signatures predict treatment response and recurrence potentially, allowing identification of patients with Clostridium difficile infection that may benefit from early institution of alternate therapies. PMID- 27481038 TI - Shrinking lung syndrome associated with systemic lupus erythematosus: A multicenter collaborative study of 15 new cases and a review of the 155 cases in the literature focusing on treatment response and long-term outcomes. AB - INTRODUCTION: Shrinking lung syndrome (SLS) is a rare respiratory manifestation of systemic lupus erythematosus (SLE), characterized by dyspnea, chest pain, elevated hemidiaphragm and a restrictive pattern on pulmonary function tests. Here, we report 15 new observations of SLS during SLE and provide a systematic literature review. We studied the clinical, biological, functional and morphologic characteristics, the treatments used and their efficacy. METHODS: The inclusion criteria were all patients with SLE defined by the American College of Rheumatology criteria Hochberg (1997) , associated with a restrictive pattern on pulmonary function tests. The exclusion criteria were all differential diagnoses of restrictive patterns, including obesity and pulmonary fibrosis. The patients were recruited from local databases through chest physicians, rheumatologists and internists. The data for the literature review were extracted from the Medline database using "shrinking lung syndrome" and "lupus" as key words. RESULTS: All 15 new cases were women with a median age at SLS onset of 27years old (range 17 67years). All of them complained of dyspnea and all but one of chest pain. The antibodies were similar to those found in SLE, although the anti-SS-A was positive in 10 of 13 cases. Thoracic imaging showed elevated hemidiaphragm (12/15) and/or basal atelectasia (8/15). All of the patients had an isolated restrictive pattern on PFT, with a median decrease >50% of lung volume. All of the patients were treated, using corticosteroids (11/15), immunosuppressive drugs (8/15), beta-mimetics (2/15), physiotherapy (3/15) and/or colchicine (1/15). Improvement was described in 9 of 12 patients and stability in 3 of 12. We extracted 155 cases of SLE-associated SLS from the Medline database. The clinical, biological and functional parameters were similar to our cases. Clinical improvement was described in 48 of 52 cases (94%) and PFT improvement in 36 of 47 cases. Worsening occurred in 4 cases. CONCLUSION: SLS is a rare SLE manifestation. Pain and parietal inflammation seem to play important pathogenic roles. Steroids and antalgics are the most commonly used therapies with good responses. There is no proof of efficacy with immunosuppressive drugs for this entity. Rituximab can be discussed after failure of corticosteroids, as well as antalgics, theophylline and beta-mimetics. PMID- 27481039 TI - Does inflammatory bowel disease coexist with systemic lupus erythematosus? AB - BACKGROUND: The data regarding the association between inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) is mostly composed of case reports and case series indicating an infrequent association. OBJECTIVES: To investigate the association between IBD and SLE. METHODS: Patients with SLE were compared with age- and sex-matched controls regarding the prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in a case-control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services. RESULTS: The study included 5018 patients with SLE and 25,090 age- and sex-matched controls. The prevalence of UC was significantly higher in patients with SLE than in controls in a univariate analysis (0.4% and 0.2%, respectively; p<0.017). However, in a multivariate logistic regression model SLE was not associated with UC (OR 1.67, 95% CI 0.99-2.815, p<0.052). The prevalence of CD was higher in patients with SLE than in controls in a univariate analysis (0.7% and 0.3%, respectively; p<0.001). A multivariate logistic regression model confirmed this finding and corroborated that SLE was associated with comorbid CD (OR 2.23, 95% CI 1.46-3.4, p<0.001). CONCLUSIONS: Patients with SLE have a greater prevalence of CD than matched controls. The distinction of IBD from SLE gastrointestinal involvement can be challenging as clinical manifestations, laboratory tests, and radiographic findings may appear similar between the two diseases. Therefore, physicians treating patients with rather IBD or SLE should consider this potential association. PMID- 27481040 TI - The clinical presentation and therapy of diseases related to anti-neutrophil cytoplasmic antibodies (ANCA). AB - Anti-neutrophil cytoplasmic antibodies (ANCA) are a family of autoantibodies that react with proteins predominantly expressed in cytoplasmic granules of polymorphonuclear neutrophil granulocytes (PMNs). ANCA was initially detected using indirect immunofluorescence, allowing for different patterns such as p-ANCA (perinuclear) and c-ANCA (cytoplasmic) to be distinguished. Today it is common to detect the antibodies by immunochemical assays such as ELISA using purified proteins as antigens. The strongest association with ANCA is found in the pauci immune small vessel vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). There is compelling evidence that ANCA contributes to the pathogenesis in these conditions. ANCA also occurs in 30%-40% of patients with eosinophilic granulomatosis with polyangiitis (EGPA) and anti GBM disease, but is uncommon in other forms of vasculitis. ANCA with different specificities have been described with varying frequencies in diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, inflammatory bowel disease, endocarditis, chronic infections and hematopoietic malignancies. ANCA can also develop as an adverse event during pharmacological treatment. These entities are treated quite differently, with therapies ranging from immunosuppressive agents over antibiotics to simply removing the causative drug. A positive ANCA test thus requires a careful diagnostic work-up. PMID- 27481041 TI - The skin in autoimmune diseases-Unmet needs. AB - Treatment of skin manifestations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and dermatomyositis (DM) is based on the results of only few randomized controlled trials. The first-line treatment for disfiguring and widespread cutaneous involvement in SLE is antimalarials, but some patients are therapy resistant. Recently, the monoclonal antibody belimumab was approved for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, intolerance of other treatments, or an unacceptably high need for corticosteroids. However, a validated skin score has not been used to confirm the efficacy of belimumab on mucocutaneous manifestations. In SSc, another multi-systemic progressive disease, involvement of the lung, kidney, and the heart is frequently treated with corticosteroids and immunosuppressives, but therapeutic modalities for cutaneous lesions, such as skin sclerosis and digital ulcers, are limited. In the past years, treatment with the endothelin-receptor antagonist bosentan has been proven to reduce the occurrence of new digital ulcers in SSc patients but has no or limited effect on healing of digital ulcers. DM is an idiopathic autoimmune disease characterized by inflammation of the muscles and skin, which is treated with immunosuppressives. Corticosteroids are the first-line treatment for muscle involvement in DM, but skin lesions often flare by reduction or discontinuation. In summary, there is a high unmet need for new therapeutic strategies focusing on skin involvement in systemic autoimmune diseases. Therefore, innovative designs of randomized controlled trials with validated skin scores are warranted to develop new therapeutic strategies for patients with cutaneous manifestations. PMID- 27481042 TI - Mesenchymal stem cells protect against the tissue fibrosis of ketamine-induced cystitis in rat bladder. AB - Abuse of the hallucinogenic drug ketamine promotes the development of lower urinary tract symptoms that resemble interstitial cystitis. The pathophysiology of ketamine-induced cystitis (KC) is largely unknown and effective therapies are lacking. Here, using a KC rat model, we show the therapeutic effects of human umbilical cord-blood (UCB)-derived mesenchymal stem cells (MSCs). Daily injection of ketamine to Sprague-Dawley rats for 2-weeks resulted in defective bladder function, indicated by irregular voiding frequency, increased maximum contraction pressure, and decreased intercontraction intervals and bladder capacity. KC bladders were characterized by severe mast-cell infiltration, tissue fibrosis, apoptosis, upregulation of transforming growth factor-beta signaling related genes, and phosphorylation of Smad2 and Smad3 proteins. A single administration of MSCs (1 * 10(6)) into bladder tissue not only significantly ameliorated the aforementioned bladder voiding parameters, but also reversed the characteristic histological and gene-expression alterations of KC bladder. Treatment with the antifibrotic compound N-acetylcysteine also alleviated the symptoms and pathological characteristics of KC bladder, indicating that the antifibrotic capacity of MSC therapy underlies its benefits. Thus, this study for the first time shows that MSC therapy might help to cure KC by protecting against tissue fibrosis in a KC animal model and provides a foundation for clinical trials of MSC therapy. PMID- 27481043 TI - Role of 18 F-FDG PET/CT differentiating olfactory neuroblastoma from sinonasal undifferentiated carcinoma. AB - OBJECTIVES: The purpose of this study is to demonstrate the potential contribution of positron emission tomography (PET)/computed tomography (CT) to help differentiate olfactory neuroblastoma (ONB) from sinonasal undifferentiated carcinoma (SNUC). METHODS: Following approval by the institutional review board at the Wexner Medical Center at the Ohio State University, Columbus, Ohio, a pilot study with retrospective review of patients with biopsy-proven diagnosis of ONB s and SNUC s was conducted. Staging PET/CT scans were reviewed to document the maximum standardized uptake value (SUVmax). A statistical comparison of SUVmax was performed. RESULTS: We identified 13 patients (7 with ONBs and 6 with SNUCs) with mean age 60.2 years who had undergone staging F-18 fluorodeoxyglucose (18 F-FDG) PET/CT of the primary tumor at the time of their diagnosis. Mean SUVmax was found to be five-fold higher in SNUC patients (35.63, range 10.8-77.9) than in ONB patients (7.24, range 4.6-10.7) (P <= 0.00169). CONCLUSION: Maximum standardized uptake value of 18 F-FDG PET/CT can be used to initially discriminate between ONB and SNUC. This finding may prove helpful to guide diagnostic and treatment planning when the histopathologic diagnosis is inconclusive. LEVEL OF EVIDENCE: 4. Laryngoscope, 2016 127:321-324, 2017. PMID- 27481045 TI - Advances in Lipid Therapy: The Role of Lipid Treatment in Women in Primary Prevention. AB - Cardiovascular disease (CVD) remains the leading cause of death for women. Given the overall prevalence of CVD and its risk factors in women, primary prevention is an important focus. In 2013, the American College of Cardiology and the American Heart Association released guidelines for men and women on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk (ASCVD) in adults based on randomized-controlled trials. Fixed and appropriate intensity of a statin based on calculation of an individual's risk of ASCVD or in diabetics or those with severely elevated low-density lipoprotein cholesterol patients for primary prevention is recommended rather than cholesterol level goals. A more recent consensus statement regarding the role of non-statin therapies has been released, but like the prior guidelines released in 2013, there were no sex specific recommendations. An evidence-based approach to ASCVD prevention should be used in women. PMID- 27481044 TI - Value-based integrated (renal) care: setting a development agenda for research and implementation strategies. AB - BACKGROUND: Integrated care services are considered a vital strategy for improving the Triple Aim values for people with chronic kidney disease. However, a solid scholarly explanation of how to develop, implement and evaluate such value-based integrated renal care services is limited. The aim of this study was to develop a framework to identify the strategies and outcomes for the implementation of value-based integrated renal care. METHODS: First, the theoretical foundations of the Rainbow Model of Integrated Care and the Triple Aim were united into one overarching framework through an iterative process of key-informant consultations. Second, a rapid review approach was conducted to identify the published research on integrated renal care, and the Cochrane Library, Medline, Scopus, and Business Source Premier databases were searched for pertinent articles published between 2000 and 2015. Based on the framework, a coding schema was developed to synthesis the included articles. RESULTS: The overarching framework distinguishes the integrated care domains: 1) type of integration, 2) enablers of integration and the interrelated outcome domains, 3) experience of care, 4) population health and 5) costs. The literature synthesis indicated that integrated renal care implementation strategies have particularly focused on micro clinical processes and physical outcomes, while little emphasis has been placed on meso organisational as well as macro system integration processes. In addition, evidence regarding patients' perceived outcomes and economic outcomes has been weak. CONCLUSION: These results underscore that the future challenge for researchers is to explore which integrated care implementation strategies achieve better health and improved experience of care at a lower cost within a specific context. For this purpose, this study's framework and evidence synthesis have set a developmental agenda for both integrated renal care practice and research. Accordingly, we plan further work to develop an implementation model for value-based integrated renal services. PMID- 27481046 TI - Type III Hyperlipoproteinemia: Still Worth Considering? AB - Familial type III hyperlipoproteinemia (HLP) was first recognized as a distinct entity over 60 years ago. Since then, it has proven to be instructive in identifying the key role of apolipoprotein E (apoE) in removal of the remnants of very low density lipoproteins and chylomicrons produced by the action of lipoprotein lipase on these triglyceride-transporting lipoproteins. It has additionally shed light on the potent atherogenicity of the remnant lipoproteins. This review describes the history of development of our understanding of type III HLP, discusses the several genetic variants of apoE that play roles in the genesis of type III HLP, and describes the remarkable responsiveness of this fascinating disorder to lifestyle modification, especially carbohydrate restriction and calorie restriction, and, when required, the addition of pharmacotherapy. PMID- 27481048 TI - Cost-effectiveness of treating wet age-related macular degeneration at the Kuopio University Hospital in Finland based on a two-eye Markov transition model. AB - PURPOSE: Wet age-related macular degeneration (AMD) is the leading cause of blindness worldwide, which can be treated with regular intraocular anti-vascular endothelial growth factor (VEGF) injections. In this study, we wanted to evaluate whether less frequent injections of aflibercept would make it more cost-effective when compared with ranibizumab and low priced bevacizumab. METHODS: We used a two eye model to simulate the progression and the treatment of the disease. We selected an 8-year period, 3-month cycles and five health states based on the visual acuity of the better-seeing eye. The transition probabilities and utilities attached to the health states were gathered from previous studies. We conducted the analysis from the hospital perspective and we used the health care costs obtained from Kuopio University Hospital. The costs of intraocular adverse events were taken into account. RESULTS: The incremental cost-effectiveness ratio (ICER) with 3% discount rate (?/QALY) for aflibercept compared with monthly bevacizumab was 1 801 228 and when compared with ranibizumab given as needed, the ICER was minus 3 716 943. The sensitivity analysis showed that a change of 20% of the estimated model parameters or a longer follow-up period did not influence these conclusions. CONCLUSION: A two-eye Markov transition model was developed to analyse the cost-effectiveness of wet AMD treatment, as quality of life years (QALYs) are largely based on the visual acuity of the better-seeing eye. Monthly injected bevacizumab was the most cost-effective treatment and monthly ranibizumab the least effective. PMID- 27481047 TI - Role of the Gut Microbiome in Modulating Arthritis Progression in Mice. AB - Genetics alone cannot explain most cases of rheumatoid arthritis (RA). Thus, investigating environmental factors such as the gut microbiota may provide new insights into the initiation and progression of RA. In this study, we performed 16S rRNA sequencing to characterise the gut microbiota of DBA1 mice that did or did not develop arthritis after induction with collagen. We found that divergence in the distribution of microbiota after induction was pronounced and significant. Mice susceptible to collagen-induced arthritis (CIA) showed enriched operational taxonomic units (OTUs) affiliated with the genus Lactobacillus as the dominant genus prior to arthritis onset. With disease development, the abundance of OTUs affiliated with the families Bacteroidaceae, Lachnospiraceae, and S24-7 increased significantly in CIA-susceptible mice. Notably, germ-free mice conventionalized with the microbiota from CIA-susceptible mice showed a higher frequency of arthritis induction than those conventionalized with the microbiota from CIA resistant mice. Consistently, the concentration of the cytokine interleukin-17 in serum and the proportions of CD8+T cells and Th17 lymphocytes in the spleen were significantly higher in the former group, whereas the abundances of dendritic cells, B cells, and Treg cells in the spleen were significantly lower. Our results suggest that the gut microbiome influences arthritis susceptibility. PMID- 27481049 TI - A population approach to characterise amisulpride pharmacokinetics in older people and Alzheimer's disease. AB - INTRODUCTION: Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. METHODS: This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65-79 years), with a clinical dataset obtained during off label, low-dose (25 75 mg daily) amisulpride prescribing in older people with Alzheimer's disease (AD) (n = 25, 69-92 years), as part of an observational study. RESULTS: After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. DISCUSSION: These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above. PMID- 27481050 TI - Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior. AB - RATIONALE: Contemporary animal models of cocaine addiction focus on increasing the amount of drug consumption to produce addiction-like behavior. However, another critical factor is the temporal pattern of consumption, which in humans is characterized by intermittency, both within and between bouts of use. OBJECTIVE: To model this, we combined prolonged access to cocaine (~70 days in total) with an intermittent access (IntA) self-administration procedure and used behavioral economic indicators to quantify changes in motivation for cocaine. RESULTS: IntA produced escalation of intake, a progressive increase in cocaine demand (incentive-sensitization), and robust drug- and cue-induced reinstatement of drug-seeking behavior. We also asked whether rats that vary in their propensity to attribute incentive salience to reward cues (sign-trackers [STs] vs. goal-trackers [GTs]) vary in the development of addiction-like behavior. Although STs were more motivated to take cocaine after limited drug experience, after IntA, STs and GTs no longer differed on any measure of addiction-like behavior. CONCLUSIONS: Exposure to large quantities of cocaine is not necessary for escalation of intake, incentive-sensitization, or other addiction-like behaviors (IntA results in far less total cocaine consumption than 'long access' procedures). Also, the ST phenotype may increase susceptibility to addiction, not because STs are inherently susceptible to incentive-sensitization (perhaps all individuals are at risk), but because this phenotype promotes continued drug use, subjecting them to incentive-sensitization. Thus, the pharmacokinetics associated with the IntA procedure are especially effective in producing a number of addiction-like behaviors and may be valuable for studying associated neuroadaptations and for assessing individual variation in vulnerability. PMID- 27481051 TI - Structural mutation analysis of PTEN and its genotype-phenotype correlations in endometriosis and cancer. AB - The phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene encodes a tumor suppressor phosphatase that has recently been found to be frequently mutated in patients with endometriosis, endometrial cancer and ovarian cancer. Here, we present the first computational analysis of 13 somatic missense PTEN mutations associated with these phenotypes. We found that a majority of the mutations are associated in conserved positions within the active site and are clustered within the signature motif, which contain residues that play a crucial role in loop conformation and are essential for catalysis. In silico analyses were utilized to identify the putative effects of these mutations. In addition, coarse-grained models of both wild-type (WT) PTEN and mutants were constructed using elastic network models to explore the interplay of the structural and global dynamic effects that the mutations have on the relationship between genotype and phenotype. The effects of the mutations reveal that the local structure and interactions affect polarity, protein structure stability, electrostatic surface potential, and global dynamics of the protein. Our results offer new insight into the role in which PTEN missense mutations contribute to the molecular mechanism and genotypic-phenotypic correlation of endometriosis, endometrial cancer, and ovarian cancer. Proteins 2016; 84:1625-1643. (c) 2016 Wiley Periodicals, Inc. PMID- 27481052 TI - Recurrent chronic histiocytic intervillositis with intrauterine growth restriction, osteopenia, and fractures. AB - Chronic histiocytic intervillositis (CHI) is characterized by the presence of histiocytes within the intervillous space of the placenta. The pathogenesis is unclear but available evidence supports an alloimmune mechanism on the basis of the presence in maternal blood of HLA antibodies directed against paternal HLA antigens. CHI has a high risk of recurrence and of abnormal perinatal outcomes. Little is known about the effects of CHI on the developing fetus, in particular on the growth and development of the skeleton. We have studied a woman whose third pregnancy was terminated after ultrasonography showed severe intrauterine growth restriction, raising the possibility of a lethal skeletal dysplasia. Postmortem radiographs showed multiple fractures and other signs of osteogenesis imperfecta (OI). However, bone histology was not typical of OI and no abnormalities were identified by sequencing OI genes. The subsequent pregnancy was also severely growth restricted and was terminated. The placenta showed chronic histiocytic intervillositis, which, on retrospective review, had also been present in her second and third pregnancies. Her fifth pregnancy was again associated with intrauterine growth restriction and CHI but resulted in a premature birth. CHI can be associated with radiographic features that mimic OI and should be considered when fetal fractures occur in the context of recurrent miscarriage, fetal death in utero, and intrauterine growth restriction. The correct diagnosis can be made by histopathology of the placenta, supported by bone histology and normal results of molecular studies for OI. (c) 2016 Wiley Periodicals, Inc. PMID- 27481053 TI - Molecular Diagnostics for Soil-Transmitted Helminths. AB - Historically, the diagnosis of soil-transmitted helminths (STHs) (e.g., Strongyloides stercoralis, Trichuris trichiura, Ancylostoma duodenale, Necator americanus, and Ascaris lumbricoides) has relied on often-insensitive microscopy techniques. Over the past several years, there has been an effort to use molecular diagnostics, particularly quantitative polymerase chain reaction (qPCR), to detect intestinal pathogens. While some platforms have been approved by regulatory bodies (e.g., Food and Drug Administration) to detect intestinal bacteria, viruses, and protozoa, there are no approved tests currently available for STH. Although studies comparing qPCR to microscopy methods for STH are imperfect, due in large part to a lack of a sufficient gold standard, they do show a significant increase in sensitivity and specificity of qPCR compared with microscopic techniques. These studies, as well as the advantages and disadvantages of using qPCR for STH diagnosis, are discussed. Guidelines for those designing future studies utilizing qPCR are proposed for optimizing results, as is the proposition for using standardized molecular diagnostics routinely for STH in clinical laboratories and for field-based studies when possible. PMID- 27481054 TI - Longevity of Genotype-Specific Immune Responses to Plasmodium falciparum Merozoite Surface Protein 1 in Kenyan Children from Regions of Different Malaria Transmission Intensity. AB - Naturally acquired immunity to Plasmodium falciparum presents a changing landscape as malaria control programs and vaccine initiatives are implemented. Determining which immunologic indicators remain surrogates of past infection, as opposed to mediators of protection, led us to compare stability of immune responses across regions with divergent malaria transmission intensities. A repeat cross-sectional study of Kenyan children from a malaria-holoendemic area and an epidemic-prone area was used to examine longitudinal antibody and interferon-gamma (IFN-gamma) responses to the 3D7 and FVO variants of merozoite surface protein 1 (MSP1). Antibodies to MSP1 were common in both study populations and did not significantly wane over a 21-month time period. IFN-gamma responses were less frequent and rapidly disappeared in children after a prolonged period of no malaria transmission. Antibody and IFN-gamma responses rarely correlated with each other; however, MSP1-specific IFN-gamma response correlated with lack of concurrent P. falciparum parasitemia of the same genotype, though only statistically significantly in the malaria-holoendemic region (odds ratio = 0.31, 95% confidence interval = 0.12-0.84). This study affirms that antimalarial antibodies are informative for evaluation of history of malaria exposure within individuals, whereas cell-mediated immunity, though short lived under natural exposure conditions, might provide an assessment of recent infection and protection from parasitemia. PMID- 27481055 TI - Diagnostic Efficacy of Molecular Techniques for Detection and Identification of Leishmania Species in Human Whole Blood and Skin Samples from Ecuador. AB - Microscopic examination is the standard method for diagnosis of cutaneous and mucocutaneous leishmaniasis despite its low sensitivity. This study compared the diagnosis efficacy of microscopic examination versus polymerase chain reaction (PCR)-based methods and DNA sequencing using whole blood and skin lesion samples from patients with suspected leishmaniasis. The presence of Leishmania was determined by microscopy and amplification of 18S ribosomal RNA gene from blood and skin samples of 22 patients. Twenty individuals were positive for leishmaniasis. Microscopic analysis identified 85%, whereas PCR identified 100% of positive cases from skin and 90% from blood. Cytochrome b gene (cyt-b) amplification and sequencing identified Leishmania guyanensis, Leishmania shawi, and Leishmania naiffi from skin and blood samples. This study demonstrated the usefulness of whole blood and molecular techniques for the diagnosis and species identification of leishmaniasis. PMID- 27481056 TI - Clinical and Laboratory Profile of Persons Living with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome and Histoplasmosis from a Colombian Hospital. AB - Histoplasmosis is common among persons living with human immunodeficiency virus/acquired immune deficiency syndrome (PLWHA) in Latin America, but its diagnosis is difficult and often nonspecific. We conducted prospective screening for histoplasmosis among PLWHA with signs or symptoms suggesting progressive disseminated histoplasmosis (PDH) and hospitalized in Hospital La Maria in Medellin, Colombia. The study's aim was to obtain a clinical and laboratory profile of PLWHA with PDH. During 3 years (May 2008 to August 2011), we identified 89 PLWHA hospitalized with symptoms suggestive of PDH, of whom 45 (51%) had histoplasmosis. We observed tuberculosis (TB) coinfection in a large proportion of patients with PDH (35%), so all analyses were performed adjusting for this coinfection and, alternatively, excluding histoplasmosis patients with TB. Results showed that the patients with PDH were more likely to have Karnofsky score <= 30 (prevalence ratio [PR] = 1.98, 95% confidence interval [CI] = 0.97 4.06), liver compromised with hepatomegaly and/or splenomegaly (PR = 1.77, CI = 1.03-3.06) and elevation in serum of alanine aminotransferase and aspartate aminotransferase to values > 40 mU/mL (PR = 2.06, CI = 1.09-3.88 and PR = 1.53, CI = 0.99-2.35, respectively). Using multiple correspondence analyses, we identified in patients with PDH a profile characterized by the presence of constitutional symptoms, namely weight loss and Karnofsky classification <= 30, gastrointestinal manifestations with alteration of liver enzymes and hepatosplenomegaly and/or splenomegaly, skin lesions, and hematological alterations. Study of the profiles is no substitute for laboratory diagnostics, but identifying clinical and laboratory indicators of PLWHA with PDH should allow development of strategies for reducing the time to diagnosis and thus mortality caused by Histoplasma capsulatum. PMID- 27481057 TI - Inappropriate Feeding Behavior: One of the Important Causes of Malnutrition in 6- to 36-Month-Old Children in Myanmar. AB - The complementary feeding period is an important time for children's growth and development. This study was conducted to 1) determine the feeding behaviors of 6- to 36-month-old children in Myanmar, 2) explore health effects of feeding behaviors, and 3) determine factors associated with feeding behaviors. A total of 807 children and their mothers (N = 642) were recruited from nine villages in Kachin, Shan, and Kokang, Myanmar. Feeding behaviors and sociodemographic characteristics were investigated using a validated questionnaire. Hemoglobin and anthropometric indicators were measured during the fieldwork. In our sample, 18.6%, 72.7%, and 9.8% of children were introduced to complementary foods (CFs) earlier than 4 months of age, between 4 and 8 months of age, and later than 8 months of age, respectively. For different types of CFs, up to the age of 24.1-36 months, there were still 6.5% and 4.1% of the children who had never been introduced to eggs and meat. Introduction of CFs earlier than 4 months of age was a risk factor for being underweight (age-adjusted odds ratio (ORadjust-age) = 1.7, 95% confidence interval (CI) = 1.2-2.5) and for stunting (ORadjust-age = 1.6, 95% CI = 1.1-2.3), whereas introduction of CFs later than 8 months of age was a risk factor for anemia (ORadjust-age = 3.5, 95% CI = 1.7-7.2). Mothers who had anemia (OR = 3.7, 95% CI = 2.0-6.9) tended toward early introduction of CFs. Women with a lower family income tended toward later introduction of CFs (OR = 2.0, 95% CI = 1.3-3.3). This study demonstrated that inappropriate feeding behavior was one of the important causes of malnutrition. PMID- 27481060 TI - Iron, Inflammation, and Malaria in the Pregnant Woman and Her Child: Saving Lives, Saving Brains. PMID- 27481059 TI - Seroprevalence of Sparganosis in Rural Communities of Northern Tanzania. AB - In this study, the seroprevalence of sparganosis and its relationship with sociodemographic factors in northern Tanzania have been assessed. A total of 216 serum samples from two rural districts, Monduli and Babati, were tested for sparganosis using an enzyme-linked immunosorbent assay. The seroprevalence of anti-sparganum IgG antibodies was 62.5% (95% confidence interval [CI] = 56.1 68.9) in all age groups. There were significant associations between district (relative risk [RR] = 1.95, 95% CI = 1.42-2.69), education (RR = 1.40, 95% CI = 1.15-1.70), and pet ownership with seropositivity (RR = 1.48, 95% CI = 1.02-2.16) based on univariate analysis. However, only the district was significantly associated with seropositivity (odds ratio = 4.20, 95% CI = 1.89-9.32) in binary logistic regression analysis. Providing health education to people residing in sparganosis-endemic areas is likely to improve the efficacy of preventative measures and reduce human disease burden. PMID- 27481058 TI - Novel Antigen Detection Assay to Monitor Therapeutic Efficacy of Visceral Leishmaniasis. AB - Visceral leishmaniasis (VL) diagnosis is routinely performed by invasive liver, spleen, bone marrow, or lymph node biopsies, followed by microscopic identification of the parasites. Conventional serological tests cannot distinguish active disease from asymptomatic VL or from cured infection. Here, we report the initial validation of an enzyme-linked immunosorbent assay (ELISA) assembled to detect the Leishmania infantum/donovani antigens iron superoxide dismutase 1 (Li-isd1), tryparedoxin 1 (Li-trx1), and nuclear transport factor 2 (Li-ntf2) as a tool to monitor therapeutic efficacy of VL. The assembled ELISA detected the antigens in the urine samples from seven VL patients before initiation of therapy. Importantly, the antigens were no longer detected in all patients after completion of the treatment. These preliminary observations point to a promising tool to follow treatment efficacy of VL. PMID- 27481061 TI - CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells. AB - Glucose and lipid metabolism disorders as well as oxidative stress (OSS) play important roles in diabetic nephropathy (DN). Glucose and lipid metabolic dysfunctions are the basic pathological changes of chronic microvascular complications of diabetes mellitus, such as DN. OSS can lead to the accumulation of extracellular matrix and inflammatory factors which will accelerate the progress of DN. Casein kinase 2 interacting protein-1 (CKIP-1) mediates adipogenesis, cell proliferation and inflammation under many circumstances. However, whether CKIP-1 is involved in the development of DN remains unknown. Here, we show that CKIP-1 is a novel regulator of resisting the development of DN and the underlying molecular mechanism is related to activating the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidative stress pathway. The following findings were obtained: (1) The treatment of glomerular mesangial cells (GMCs) with high glucose (HG) decreased CKIP-1 levels in a time-dependent manner; (2) CKIP-1 overexpression dramatically reduced fibronectin (FN) and intercellular adhesionmolecule-1 (ICAM-1) expression. Depletion of CKIP-1 further induced the production of FN and ICAM-1; (3) CKIP-1 promoted the nuclear accumulation, DNA binding, and transcriptional activity of Nrf2. Moreover, CKIP-1 upregulated the expression of Nrf2 downstream genes, heme oxygenase (HO-1) and superoxide dismutase 1 (SOD1); and ultimately decreased the levels of reactive oxygen species (ROS). The molecular mechanisms clarify that the advantageous effect of CKIP-1 on DN are well connected with the activation of the Nrf2/ARE antioxidative stress pathway. PMID- 27481064 TI - Acceptability of general practice services for Afghan refugees in south-eastern Melbourne. AB - Over 750000 refugees have resettled in Australia since 1945. Despite complex health needs related to prior traumatic experiences and the challenges of resettlement in a foreign country, refugees experience poor access to primary care. Health and settlement service providers describe numerous cultural, communication, financial and health literacy barriers. This study aimed to investigate the acceptability of general practitioner (GP) services and understand what aspects of acceptability are relevant for Afghan refugees in south-eastern Melbourne. Semi-structured interviews were conducted with two Afghan community leaders and 16 Dari- or English-speaking Afghan refugees who accessed GP services. Two distinct narratives emerged - those of recently arrived refugees and established refugees (living in Australia for 3 years or longer). Transecting these narratives, participants indicated the importance of: (1) a preference for detailed clinical assessments, diagnostic investigations and the provision of prescriptions at the first consultation; (2) 'refugee-friendly' staff; and (3) integrated, 'one-stop-shop' GP clinic features. The value of acceptable personal characteristics evolved over time - GP acceptability was less a consideration for recently arrived, compared with more, established refugees. The findings reinforce the importance of tailoring healthcare delivery to the evolving needs and healthcare expectations of newly arrived and established refugees respectively. PMID- 27481062 TI - Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists. AB - The P2X7 receptor (P2X7R) plays an important role in diverse conditions associated with tissue damage and inflammation, meaning that the human P2X7R (hP2X7R) is an attractive therapeutic target. The crystal structures of the zebrafish P2X4R in the closed and ATP-bound open states provide an unprecedented opportunity for structure-guided identification of new ligands. The present study performed virtual screening of ~100,000 structurally diverse compounds against the ATP-binding pocket in the hP2X7R. This identified three compounds (C23, C40 and C60) out of 73 top-ranked compounds by testing against hP2X7R-mediated Ca(2+) responses. These compounds were further characterised using Ca(2+) imaging, patch clamp current recording, YO-PRO-1 uptake and propidium iodide cell death assays. All three compounds inhibited BzATP-induced Ca(2+) responses concentration dependently with IC50s of 5.1+/-0.3MUM, 4.8+/-0.8MUM and 3.2+/-0.2MUM, respectively. C23 and C40 inhibited BzATP-induced currents in a reversible and concentration-dependent manner, with IC50s of 0.35+/-0.3MUM and 1.2+/-0.1MUM, respectively, but surprisingly C60 did not affect BzATP-induced currents up to 100MUM. They suppressed BzATP-induced YO-PRO-1 uptake with IC50s of 1.8+/-0.9MUM, 1.0+/-0.1MUM and 0.8+/-0.2MUM, respectively. Furthermore, these three compounds strongly protected against ATP-induced cell death. Among them, C40 and C60 exhibited strong specificity towards the hP2X7R over the hP2X4R and rP2X3R. In conclusion, our study reports the identification of three novel hP2X7R antagonists with micromolar potency for the first time using a structure-based approach, including the first P2X7R antagonist with preferential inhibition of large pore formation. PMID- 27481065 TI - The "Fully Catalytic System" in Mitsunobu Reaction Has Not Been Realized Yet. AB - An investigation of the recently reported "fully catalytic Mitsunobu reaction" using catalytic amounts of a phosphine reagent and an azo reagent has shown that although benzyl 4-nitrobenzoate is formed under the fully catalytic conditions, the same result is obtained if the hydrazine catalyst is omitted, indicating that this is not a Mitsunobu reaction. In addition, when the reaction between (-) ethyl lactate and 4-nitrobenzoic acid was carried out using the "fully catalytic" method, the corresponding ester was formed but in very low yield and with predominant retention of configuration. Unfortunately, the system catalytic in phosphine reagent is incompatible with that in the azo reagent. PMID- 27481063 TI - Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5'-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form. AB - Human pyruvate kinase isoform M2 (PKM2) is a glycolytic enzyme isoform implicated in cancer. Malignant cancer cells have higher levels of dimeric PKM2, which is regarded as an inactive form of tetrameric pyruvate kinase. This perceived inactivity has fueled controversy about how the dimeric form of pyruvate kinase might contribute to cancer. Here we investigate enzymatic properties of PKM2(G415R), a variant derived from a cancer patient, which we show by size exclusion chromatography and small-angle X-ray scattering to be a dimer that cannot form a tetramer in solution. Although PKM2(G415R) binds to fructose 1,6 bisphosphate (FBP), unlike the wild type this PKM2 variant shows no activation by FBP. In contrast, PKM2(G415R) is activated by succinyl-5-aminoimidazole-4 carboxamide-1-ribose 5'-phosphate (SAICAR), an endogenous metabolite that we previously showed correlates with an increased level of cell proliferation and promotes protein kinase activity of PKM2. Our results demonstrate an important and unexpected enzymatic activity of the PKM2 dimer that likely has a key role in cancer progression. PMID- 27481066 TI - Public attitudes towards community pharmacy attributes and preferences for methods for promotion of public health services. AB - OBJECTIVE: To identify attitudes towards pharmacy characteristics and promotional methods for selected pharmacy public health services (lifestyle advice and screening for cardiovascular risk factors) among different sectors of the general public. STUDY DESIGN: Cross-sectional survey, using a previously validated questionnaire. METHODS: Three survey methods were used, across 15 areas of England, to maximize diversity: face-to-face; telephone; and self-completion of paper questionnaires. Responses to closed questions regarding characteristics and promotion were quantified and differences among sub-groups explored by univariate and multivariate analysis. RESULTS: In total, 2661 responses were available for analysis: 2047 face-to-face; 301 telephone; and 313 paper. There were strong preferences for a pharmacy near to home or doctor's surgery and for long opening hours, particularly among employed people and non-whites. Fifty percent preferred not to use a pharmacy in a supermarket, particularly older people, the retired, those of lower education and frequent pharmacy users. Personal recommendation by health professionals or family/friends was reported as most likely to encourage uptake of pharmacy public health services, with older people and males being less likely and frequent pharmacy users more likely to perceive any promotional method as influential. Posters/leaflets were preferred over mass-media methods, with fewer than 30% perceiving the latter as potentially influential. CONCLUSION: Pharmacists, pharmacy companies and service commissioners should use promotional methods favoured by potential users of pharmacy public health services and be aware of differences in attitudes when trying to reach specific population sub groups. For personal recommendation to be successful, good inter-professional working and a pro-active approach to existing customers are needed. PMID- 27481067 TI - [Interadministrative collaboration for public health management in municipalities with less than 10,000 residents]. AB - This study analyses which administrative body local councils use to carry out their basic public health responsibilities. The study sample includes data from municipalities with less than 10,000 residents, which we believe is a first for studies published in academic journals in Spain. The data used was obtained by means of a survey administered by trained personnel. 93.7% of all the municipalities in the province of Girona, the area under study, responded to the survey. The analysis shows that there is a statistically significant difference between municipalities with more and less than 10,000 residents with regards to which administrative body local councils use for managing public health responsibilities. The results of this study suggest that in the ongoing debate over the streamlining of local government, the current situation regarding public health responsibilities in municipalities with less than 10,000 residents needs to be taken into account. PMID- 27481068 TI - [Health promotion based on assets: how to work with this perspective in local interventions?] AB - An asset-based approach could be useful to revitalise health promotion or community health interventions combining work with multiple partnerships, positive health, community engagement, equity and orientation of health determinants. We set some recommendations about how to incorporate the assets model in programmes, projects and interventions in health promotion. Some techniques are described for assets mapping and some experiences with this methodology being developed in different regions are systematised. We propose the term "Asset-based Health Promotion/Community Health" as an operational definition to work at the local level with a community engagement and participatory approach, building alliances between different institutions at the state-regional level and trying to create a framework for action with the generation of evaluations and evidence to work on population interventions from the perspective of positive health. PMID- 27481069 TI - [Physicians' attitudes toward the problem of unnecessary tests and procedures]. PMID- 27481070 TI - Gender differences in cancer susceptibility: role of oxidative stress. AB - Cancer is a leading cause of death worldwide and environmental factors, including chemicals, have been suggested as major etiological incitements. Cancer statistics indicates that men get more cancer than women. However, differences in the known risk factors including life style or occupational exposure only offer partial explanation. Using a text mining tool, we have investigated the scientific literature concerning male- and female-specific rat carcinogens that induced tumors only in one gender in NTP 2-year cancer bioassay. Our evaluation shows that oxidative stress, although frequently reported for both male- and female-specific rat carcinogens, was mentioned significantly more in literature concerning male-specific rat carcinogens. Literature analysis of testosterone and estradiol showed the same pattern. Tox21 high-throughput assay results, although showing only weak association of oxidative stress-related processes for male- and female-specific rat carcinogens, provide additional support. We also analyzed the literature concerning 26 established human carcinogens (IARC group 1). Oxidative stress was more frequently reported for the majority of these carcinogens, and the Tox21 data resembled that of male-specific rat carcinogens. Thus, our data, based on about 600000 scientific abstracts and Tox21 screening assays, suggest a link between male-specific carcinogens, testosterone and oxidative stress. This implies that a different cellular response to oxidative stress in men and women may be a critical factor in explaining the greater cancer susceptibility observed in men. Although the IARC carcinogens are classified as human carcinogens, their classification largely based on epidemiological evidence from male cohorts, which raises the question whether carcinogen classifications should be gender specific. PMID- 27481071 TI - On the onset of surface condensation: formation and transition mechanisms of condensation mode. AB - Molecular dynamics simulations have been carried out to investigate the onset of surface condensation. On surfaces with different wettability, we snapshot different condensation modes (no-condensation, dropwise condensation and filmwise condensation) and quantitatively analyze their characteristics by temporal profiles of surface clusters. Two different types of formation of nanoscale droplets are identified, i.e. the formations with and without film-like condensate. We exhibit the effect of surface tensions on the formations of nanoscale droplets and film. We reveal the formation mechanisms of different condensation modes at nanoscale based on our simulation results and classical nucleation theory, which supplements the 'classical hypotheses' of the onset of dropwise condensation. We also reveal the transition mechanism between different condensation modes based on the competition between surface tensions and reveal that dropwise condensation represents the transition states from no-condensation to filmwise condensation. PMID- 27481072 TI - Cytotoxic, genotoxic and biochemical markers of insecticide toxicity evaluated in human peripheral blood lymphocytes and an HepG2 cell line. AB - This study evaluated the cyto- and genotoxic effects of three pesticides: alpha cypermethrin, chlorpyrifos and imidacloprid applied in vitro to human lymphocytes and HepG2 cells for exposure times of 4 and 24 h at concentrations corresponding to OEL, ADI and REL. Assessments were made using oxidative stress biomarkers and the alkaline comet, cytokinesis-block micronucleus cytome and cell viability assays. Low doses of all three pesticides displayed DNA damaging potential, both in lymphocytes and HepG2 cells. At the tested concentrations, all three compounds induced lymphocyte apoptosis, though alpha-cypermethrin and chlorpyrifos were generally more cyto- and genotoxic than imidacloprid. At the tested concentrations, oxidative stress biomarkers were not significantly altered, and the effects mediated indirectly through free radicals may not have a key role in the formation of DNA damage. It is likely that the DNA damaging effects were caused by direct interactions between the tested compounds and/or their metabolites that destabilized the DNA structure. The tested pesticides had the potential for MN, NB and NPB formation and to disturb cell cycle kinetics in both cell types. There were also indications that exposure to alpha-cypermethrin led to the formation of crosslinks in DNA, though this would require more detailed study in the future. PMID- 27481073 TI - Endocrine activity of mycotoxins and mycotoxin mixtures. AB - Reporter gene assays incorporating nuclear receptors (estrogen, androgen, thyroid beta and PPARgamma2) have been implemented to assess the endocrine activity of 13 mycotoxins and their mixtures. As expected, zearalenone and its metabolites alpha zearalenol and beta- zearalenol turned out to have the strongest estrogenic potency (EC50 8,7 10-10 +/- 0,8; 3,1 10-11 +/- 0,5 and 1,3 10-8 +/- 0,3 M respectively). The metabolite of deoxynivalenol, 3-acetyl-deoxynivalenol also had estrogenic activity (EC50 3,8 10-7 +/- 1,1 M). Furthermore, most of the mycotoxins (and their mixtures) showed anti-androgenic effects (15 acetyldeoxynivalenol, 3-acetyl-deoxynivalenol and alpha-zearalenol with potencies within one order of magnitude of that of the reference compound flutamide). In particular, deoxynivalenol and 15-acetyl-deoxynivalenol acted as antagonists for the PPARy2 receptor. When testing mixtures of mycotoxins on the same cell systems, we showed that most of the mixtures reacted as predicted by the concentration addition (CA) theory. Generally, the CA was within the 95% confidence interval of the observed ones, only minor deviations were detected. Although these reporter gene tests cannot be directly extrapolated in vivo, they can be the basis for further research. Especially the additive effects of ZEN and its metabolites are of importance and could have repercussions in vivo. PMID- 27481074 TI - Polydatin ameliorates renal ischemia/reperfusion injury by decreasing apoptosis and oxidative stress through activating sonic hedgehog signaling pathway. AB - Polydatin, a glucoside of resveratrol, recently has been demonstrated possibly to exert its biological effects by targeting sonic hedgehog (Shh). However, whether Shh signaling pathway is involved in the therapeutic effects of polydatin for renal ischemia/reperfusion (I/R) injury has not been evaluated. Our results showed that I/R induced the secretion of Shh, upregulated Patched and Smoothened, and enhanced the nuclear translocation and target gene transcription of Glioblastoma 1 in renal I/R injury models, which were further upregulated after the administration of polydatin significantly and in turn exerted prominent nephroprotective effects against cell apoptosis and oxidative stress. The treatment with cyclopamine (a specific inhibitor of Smoothened) or 5E1 (an anti Shh antibody) not only markedly inhibited the activation of the Shh pathway, but also dramatically suppressed the nephroprotective effects of polydatin above mentioned. These results advance our knowledge that polydatin can provide protection for kidneys against I/R injury by enhancing antioxidant capacity and decreasing cell apoptosis through activating Shh signaling pathway. PMID- 27481075 TI - Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies. AB - INTRODUCTION: To assess the long-term (5 year) efficacy of omalizumab and systemic corticosteroid therapy in allergic and non-allergic asthma that could not be controlled by step 4 therapy, respectively. PATIENTS AND METHODS: This single-center study was based on all consecutive step 4 patients with severe persistent uncontrolled allergic and non-allergic asthma who were given omalizumab and systemic corticosteroid (minimum: 4 mg, maximum: 12 mg, median: 8 mg methyl prednisone), respectively, in 2006-2014 and were followed up for at least 5 years. Asthma control test (ACT), FEV1 and exacerbation rates at initial presentation and 1, 2, and 5 years after step 5 treatment initiation were calculated for both groups. RESULT: There were 17 and 16 allergic and non allergic group patients, respectively. Both groups exhibited significant improvements in ACT at the 1st, 2nd, and 5th years relative to baseline (all p< 0.01). The allergic group had significantly better ACTs at 16 weeks, 1 year, and 2 years than the non-allergic group (all p< 0.01). By the 5th year, the exacerbations in the non-allergic group rose significantly by 39.6% (3.3 on average) compared to baseline (2.38 on average, p< 0.001). By contrast, the allergic group continued to have significantly fewer exacerbations at the 5th year (77.1% fewer relative to baseline, p< 0.001). However, 47% of the allergic group patients still presented with one exacerbation in the 5th year. CONCLUSIONS: Adding omalizumab to step 5 therapy improved the control of severe persistent allergic asthma. However, nearly half of the patients in both groups presented at least one exacerbation in the 5th year. PMID- 27481076 TI - Metered dose inhaler-spacer use education effects on achieve asthma control in children. AB - INTRODUCTION: Improper Metered Dose Inhaler (MDI)-spacer use technique can result in less than optimal delivery of medicine to the lungs and poor asthma outcomes. The aim of this study was to evaluate the influence of standardized education on proper MDI- spacer use and asthma control in children with asthma and to identify the factors associated with these results. MATERIALS AND METHODS: This is a cohort study that evaluated the influence of standardized education about MDI Spacer device use on asthma control in children. Asthmatic children using MDI Spacer device and their parents were enrolled in this study. Children were followed up for two months after standardized education and the change in asthma control was recorded. RESULT: Thirty eight children (14 females and 24 males) aged between 2.5 and 13 years were enrolled in the study. Mean age of the children was 7.5 +/- 2.8 years. Six patients were lost to follow up and thirty two patients completed the study. Mean inhalation technique score was 4.9 +/- 1.3 before education and increased significantly to 7.8 +/- 0.4 after education (p< 0.001). Mean Asthma Control Questionnaire (ACQ) score decreased significantly with education (0.77 +/- 0.9 vs 0.1 +/- 0.1 respectively, p< 0.001). Similarly, mean asthma symptom score (ASS) decreased significantly from 4.3 +/- 3.6 to 0.2 +/- 0.7 with education (p< 0.001). Most common mistake in use of MDI-Spacer device use was detected to be lack of mouth rinsing after use before education in 78.9% of the patients. CONCLUSIONS: Providing standardized education about MDI Spacer device use to children and parents leads to correct MDI-Spacer device use and is associated with improvement in asthma symptom score and asthma control. PMID- 27481077 TI - Compare the efficacy and safety of long-acting anticholinergic and a combination of inhaled steroids and long-acting beta-2 agonist in moderate chronic obstructive pulmonary disease. AB - INTRODUCTION: The treatment of COPD (Chronic Obstructive Pulmonary Disease) aims to improve the patients's well-being and to reduce mortality, morbidity and the development of exacerbations. This study was thus designed to compare the efficacy and tolerability of salmeterol/fluticasone combination with tiotropium in patients with moderate COPD. MATERIALS AND METHODS: This was an open, prospective, randomized trial in COPD patients whose FEV1 (forced expiratory volume in 1 second) levels were between 80% and 50% predicted. A total of 44 patients who met the inclusion and exlusion criteria and who gave written informed consent were included in the study. At the end of the two week wash-out period, the patients were randomized to receive either salmeterol 50 ug/fluticasone 500 ug combination as dry powder inhaler twice daily (SF Group) or tiotropium dry powder inhaler 18 ug once daily (T Group) for one year. These were equally distributed in the two groups (22 patients in each study group). At follow-up, the patients were required to come to the outpatient clinic at the third, sixth, ninth and twelfth months. RESULT: There were no statistically significant difference between the two groups with regards to demographic features and baseline measurements. There were 1.2 +/- 1.7 exacerbations in SF Group and 2.1 +/- 2.2 exacerbations in T Group (p= 0.070). The time to the first exacerbation was 4.2 +/- 4.0 and 4.2 +/- 3.3 months, respectively (p= 0.697). The number of severe exacerbations that resulted in admission to the emergency department or hospital was 0.6 +/- 1.0 and 1.1 +/- 1.4, respectively (p= 0.245). Significant improvements were observed in CAT (CPOD Assessment Test) scores in both groups during the treatment period (p< 0.0001); but there was no difference between the two groups. CONCLUSIONS: This study has shown that in patients with moderate COPD, treatment with combined corticosteroid and long-acting beta-2 agonist provides similar improvements in pulmonary function tests, patient reported outcomes and exercise capacity as compared a long-acting anticholinergics. PMID- 27481079 TI - The relation between the extent of radiological findings and respiratory functions in pneumoconiosis cases of dental technicians who are working in Ankara. AB - INTRODUCTION: In dental technicians, parenchymal changes caused by dust affect pulmonary functions. The evaluation of the relation between radiological scores (chest X-Ray/HRCT) indicating the extent of pulmonary involvement and the severity of functional findings in dental technicians. MATERIALS AND METHODS: 440 dental technicians were evaluated with chest X-Ray, pulmonary function tests (PFTs) and high resolution computed tomography (HRCT). The degree of pulmonary involvement in radiological images was categorized based upon emphysema, the profusion of opacities, ground-glass opacity, honey combing and extent of pleural abnormalities. RESULT: Mean age of the study population was 34.7 +/- 8.5 and mean duration of work was 16.5 +/- 7.9 years. The prevalance of Dental technicians' pneumoconiosis (DTP) was 11.1%. The most common opacity in HRCT was round opacity with a rate of 89.7%. The rate of large opacity was %14.3. There was positive correlation between ILO score and HRCT score. Negative correlation was found between ILO and HRCT scores and all pulmonary function tests (except for FEV1/FVC), while no relation was found with age, overall duration of exposure, smoking and the age ofwork onset. In Multiple regression analysis, the extent of pulmonary involvement (HRCT scores) was found to be an independent predictor of functional impairment. Functional parameter reflecting the extent of pulmonary involvement most accurately was (FEV1%). CONCLUSIONS: It is our suggestion that radiological measurement should be used along with functional measurements in the evaluation of functional impairment in mixed dust exposed dental technicians. PMID- 27481078 TI - [The evaluation of nutritional status of stable COPD patients and to investigate the effect of nutritional status on perception of dyspnea, exercise capacity, body composition, hospitalisation and life quality]. AB - INTRODUCTION: Malnutrition is a comorbidity oftenly seen in COPD patients who have progressive chronic inflammation and severity. In this prospective study, we aimed to determine the nutritional status of stable COPD patients and to investigate the impact of nutritional status on perception of dyspnoea, exercise capacity, body composition, hospitalisation and life quality. MATERIALS AND METHODS: COPD patients were assessed using previous smoking story, physical examination and irreversible airway obstruction. This study was done with 50 COPD patients older than 65 years of age and 30 control subjects. Exclusion criteria were also the co-existance of malignancies, malabsorbtion, DM, neurological diseases, renal failure and unstable cardiac diseases known to influence the nutritional state. The obstruction degree was evaluated by spirometry, nutritional status was classified by the MNA questionnaire, perception of dyspnoea was assessed by the MMRC scale, exercise capacity was assessed by the 6MWT, life quality was assessed by the CAT scale. Body composition parameters FM, FFM and FMI were analyzed and hospitalisations during 6 months after discharge were recorded. RESULT: The COPD patients were divided into three groups as without malnutrition (n= 25,%50), under risk of malnutrition (n= 19,%38) and malnourished (n= 6,%12). The COPD severity, MMRC dyspnoea score, CAT score and hospitalisations during 6 months following were higher among the malnourished patients. On the other hand, body mass index, 6MWT results, FM and FFM were lower in malnourished patients. A positive correlation between FFM and 6MWT and a negative correlation between FFM and hospitalisation were observed. CONCLUSIONS: MNA is a well-developed questionnaire which evaluates malnutrition in COPD patients. We determined that malnourished COPD patients have higher airway obstruction degree, perception of dyspnoea, CAT score and lower exercise capacity and FFM. FFM is an independent predictor of exercise capacity and rehospitalisation during 6 months. PMID- 27481080 TI - Diagnostic yield of conventional transbronchial needle aspiration biopsy (C-TBNA) without an on-site cytopathologist: Experience of 363 procedures in 219 patients. AB - INTRODUCTION: Conventional transbronchial needle aspiration biopsy (C-TBNA) is a technique in evaluating mediastinal/hilar lymph nodes (LN). We aimed to investigate diagnostic yield (DY) and safety of C-TBNAs performed in a single university clinic. PATIENTS AND METHODS: We retrospectively reviewed 363 consecutive C-TBNA procedures in 219 patients. The DY and its relationship with location, shortest diameter, SUVmax of LN, and number of sampled stations were evaluated. RESULT: Procedures were diagnostic in 257 (71%) LNs. The most common diagnoses were malignancy (n= 109.30%) and granulomatous inflammation (n= 68, 18.7%).The ratio of patients with at least one diagnostic cytology result was 77% (n= 168). DY was significantly increased with the increased number of sampled LNs (p= 0.033) and larger LN diameter (p< 0.001). Sensitivity, specificity, positive, and negative predictive values were 83.3%, 43.2%, 79.6%, and 49.3% respectively for cut-off LN diameter of 11.5 mm. There was nearly a significant relationship between DY and SUVmax (p= 0.05, cut-off= 4.8). The highest DY was in subcarinal LN (77.4%). No major complications were recorded. CONCLUSIONS: The DY of C-TBNA was 71%. The ratio of the patients with at least one diagnostic cytology result was 77%. The most common diagnoses were malignancy and granulomatous inflammation. The DY of C-TBNA was increased with the increased number of sampled LNs, larger LN diameter, and increased SUVmax. C-TBNA is a safe procedure. PMID- 27481081 TI - [The effectiveness of smoking cessation program in a workplace with high risk]. AB - INTRODUCTION: Initiatives for smoking cessation (SC) at workplace have become more prominent due to both health and safety risks associated with smoking. We aimed to determine 6-month successful SC rates of a group of employees who participated in a SC program as they worked in a workplace that exhibited high risk of fire and explosion. MATERIALS AND METHODS: Having delivered a compulsory smoking training to the paint manufacturing department with 276 employees, we invited 147 smoker employees to participate in a SC initiative (SCI) program. The SCI program was implemented by the occupational health and safety (OHS) staff. Employees were administered a self-reported questionnaire including the age at starting smoking, number of cigarettes smoked (pack years), family members' attitudes towards smoking, reasons for smoking and harms of smoking. Nicotine addiction levels were assessed with Fagerstrom Nicotine Dependence Test (FNDT). RESULT: 276 employees (270 male and 6 female) had an average age of 36.8 +/- 8.4 years. 144 active smokers presented an average age of 38.4 +/- 6.9 and smoked on average 18.5 +/- 12.8 pack/year. Active smokers started smoking at the age of 19.8 +/- 4.9 on average. Their average score in FNDT was 6.6 +/- 1.9 points. Fifty-one (35.4%) employees participated in the SCIs. The participants in the SCP training exhibited statistically significant differences with respect to the following parameters: chronic disease (p= 0.03), pack/year (p< 0.001), age at starting smoking (p= 0.001), attempted methods to SC (p= 0.002), average score in self-reported harms of smoking (p< 0.001), average FNDT score (p< 0.001), average score of self-reported smoking addiction (p= 0.001), and whether the smoker considers smoking a means of socialization (p<= 0.001). After six months, we observed that 12 (23%) of the participants, and 4 (4%) of the non-participants employees quitted smoking (p< 0.001). CONCLUSIONS: In our study, participants in the SCI exhibited higher SC rates compared to the non-participants. Further studies are required to standardize such initiatives, which improve occupational health. PMID- 27481082 TI - [Evaluation of asthma and COPD awareness in primary care doctors in Turkey]. AB - INTRODUCTION: Chronic pulmonary diseases cause significant morbidity and mortality. However awareness about the risk factors, symptoms, diagnosis and traetment of these disorders is low among patients and health care providers. Our aim was to evaluate the awareness of asthma and chronic obstructive pulmonary disease among primary care doctors. This study was performed by the national Global Alliance Against Chronic Respiratory Diseases programme. MATERIALS AND METHODS: Primary care doctors employed by the Ministry of Healthy were included to the study. Turkish Statistical Institute randomly selected 680 doctors. Questionnaires evaluating the awareness of asthma and COPD which were developed by the Turkish Thoracic Society COPD and asthma assemblies were completed online by these doctors. RESULT: 84% of the doctors described asthma as airway obstruction. Dyspnea was reported as the most common symptom of asthma (78.8%) and inspiratory rhonci was reported as the most common physical exam finding (42.3%). Around 50% of doctors thought impairment of pulmonary function tests (PFT) was important for diagnosis and evaluation of severity of asthma while 24.2% thought physical exam was more important. When treatment options were evaluated 87.6% chose inhaled treatment for asthma. COPD was described as bronchiectasis and chronic bronchitis by 9.1%, chronic bronchitis and emphysema by 61.6%, chronic bronchitis and asthma by 22.2% and asthma and emphysema by 7.1%. 1.2% of the doctors did not consider cigarette smoking as a risk factor for COPD. PFT was recommended for diagnosis by 83%. Most correctly differentiated asthma and COPD. Bronchodilators were the first choice for COPD by 72.5%. CONCLUSIONS: Awareness is low for asthma and COPD among primary care doctors. Awareness should be raised among health care professionals for these diseases with high economical burden to improve outcome. PMID- 27481083 TI - [Lung cancer and epigenetic modifications]. AB - Epigenetic alterations, including DNA methylation, histone modifications, and noncoding RNA expression, have been reported to play a major role in the genesis of lung cancer. DNA methylation, histone modifications, and RNA expression are epigenetic markers in assesment of early detection, prognosis and evaluation of treatment of lung cancer. In this rewiev we summarize the common epigenetic changes associated with lung cancer to give some clarity to its etiology, and to provide an overview of the potential translational applications of these changes, including applications for early detection, diagnosis, prognostication, and therapeutics. PMID- 27481084 TI - A patient with mushroom allergy; a new etiological agent of Kounis syndrome. AB - Kounis syndrome (KS) is a rarely diagnosed condition which should always be kept in mind when an acute myocardial infarction (AMI) happens in the context of anaphylactic reactions. We report a case of a 31-year old female; 2 hours after the ingestion of the mushroom (Pleurotus ostreatus); she experienced nausea, stomachache, vomiting, dyspnea and chest pain. Electrocardiogram (ECG) showed an ST segment elevation in D1, AVL, precordial leads V1-V4. The blood analysis revealed high levels of CK-MB fraction and troponin T values. The diagnosis of Kounis syndrome was made in the catheterization laboratory via the complete resolution of angina, along with electrocardiographic changes that took place after intracoronary nitrate therapy and skin prick to prick test positivism with the mushroom. To the best of our knowledge, this is the first case of a type I variant of Kounis syndrome due to Pleurotus ostreatus allergy reported so far. PMID- 27481085 TI - Endobronchial metastasis of mixed germ cell tumors: two cases. AB - Lung metastases from extrapulmonary malignancies are common however endobronchial metastases (EBM) from nonpulmonary neoplasms are rare. A variety of extrathoracic tumors have a tendency to EBM especially breast, colon, and renal carcinomas are most frequent reported tumors however EBM of germ cell tumors are extremely rare. A 39-year-old and a 27-year-old male patient were admitted to our hospital with hemoptysis and dyspnea at different times. Both of them had a history of left orchiectomy due to mixed germ cell tumor two years and one year ago, respectively. On chest X-Ray and thorax computed tomography, first had a right upper lobe atelectasis and second had right total atelectasis. Fiberoptic bronchoscopy (FOB) performed and a vascularized endobronchial lesion (EBL) which tended to bleed was seen in the orifis of right upper lobe in the first case and right main bronchus was totally obstructed by EBL also in the second. Interventional bronchoscopy was performed via rigid bronchoscopy for biopsy and palliative treatment (argon plasma coagulation and debulking) in both two patients because of tendency to bleeding. A partial aperture was achieved at right upper lobe bronchus in the first case and total atelectasis resolved in the second case. Immunohistochemically, histopathological examinations of both patients biopsies confirmed EBM of mixed germ cell tumors. In conclusion, EBM of the germ cell tumors especially with total or partial atelectasis are extremely rare. We want to present these cases to emphasize the importance of distinguishing EBM from primary lung carcinoma which treatment and survival could be different. PMID- 27481086 TI - A rare case of right sided pulmonary artery agenesis associated with congenital mitral valve prolapse. PMID- 27481087 TI - Indeterminate quantiferon TB Gold in Tube results from Turkey. PMID- 27481089 TI - Clinical features and inpatient rehabilitation outcomes of infection-related myelopathy. AB - STUDY DESIGN: This was a retrospective cohort study. OBJECTIVES: The objectives of this study were to determine clinical features of infection-related myelopathy (IRM) and functional outcomes compared with other nontraumatic and traumatic myelopathies. SETTING: US academic inpatient rehabilitation unit. METHODS: This was a 16-year retrospective review of patients with myelopathy discharged from inpatient rehabilitation between 1 January 1995 and 31 December 2010. Patients comprised three injury groups: IRM, nontraumatic myelopathy (NTM) and traumatic spinal cord injury (TSCI). Information collected includes demographic characteristics, functional data, length of stay, injury completeness and discharge destination. Primary outcome measures were change in Functional Independence Measure (FIM) and daily FIM change. For IRM, data were collected regarding injury characteristics, risk factors, presenting symptoms, neurologic impairment level and treatment. RESULTS: Of the 1601 patients, 40 (2.5%) had IRM, 1105 (69.0%) had NTM and 456 (28.5%) had TSCI. IRM mean (s.d.) age was 58.6 (15.7) years (male gender, 72.5%). The majority in each group had incomplete injuries. IRM had longer lengths of stay (P<0.001), lower admission (P=0.001) and discharge (P=0.005) FIM scores and lower FIM daily change (P=0.002) than NTM. Degree of functional improvement was similar in all groups, and most patients in each group were discharged home. Infectious pathogens were bacterial (80.0%, n=32), viral (7.5%, n=3), tuberculous (7.5%, n=3), parasitic (2.5%, n=1) and multiple types (2.5%, n=1). The most common bacterial cause (65.6%) was Staphylococcus aureus. CONCLUSIONS: Infectious etiologies comprise a small proportion of NTM but represent a unique entity with distinct recovery patterns and outcomes. These patients can achieve similar functional improvements as other NTM patients during inpatient rehabilitation, although over a longer period of time. PMID- 27481090 TI - Cardiovascular response during urodynamics in individuals with spinal cord injury. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVES: To establish the frequency and severity of autonomic dysreflexia (AD) during urodynamics among individuals with chronic spinal cord injury (SCI) and to investigate the possible effect of the number of years since SCI on the severity of AD. SETTING: SCI outpatient clinic. METHODS: A retrospective chart review was undertaken of individuals with SCI who were seen at an outpatient clinic and could potentially develop an episode of AD (T6 and above). Data regarding age, gender, urodynamic examination, lower urinary tract function, cardiovascular parameters and SCI were collected. In addition, information on signs and symptoms of AD were retrieved. RESULTS: A total of 76 individuals with SCI were examined with blood pressure (BP) monitoring. The majority had cervical SCI (79%). The mean age was 47.8+/-13.9 years. The median duration after SCI was 51.5 months. During urodynamics, a total of 48 (63.2%) individuals showed an increase in systolic BP>20 mm Hg, meeting the criteria for AD. Indicators for higher incidences of AD were cervical SCI, being >2 years after SCI, the presence of detrusor sphincter dyssynergia (DSD) and low bladder compliance. AD was more severe in individuals with complete (American Spinal Cord Association (ASIA) impairment scale (AIS) A) injuries, worse with greater time after SCI. CONCLUSION: Individuals with cervical SCI, DSD, poor bladder compliance or >2 years after SCI were associated with a higher possibility of developing AD during urodynamics. Furthermore, AD was more severe in complete (AIS A) individuals and was exacerbated with time after injury. PMID- 27481091 TI - Comparison of QT-interval and variability index methodologies in individuals with spinal cord injury. AB - STUDY DESIGN: Within-group comparison. OBJECTIVES: Individuals with spinal cord injury (SCI) demonstrate an elevated risk for cardiac arrhythmias as indicated by an elevated QT-variability index (QTVI). The methodology measuring the QTVI, however, is not standardized, and therefore the purpose of this investigation is to determine whether the threshold and tangent methods of QT-interval measurement, as well as the electrocardiographic (ECG) epoch duration, influence the QTVI in individuals with SCI. SETTING: Ontario, Canada. METHODS: Ten minutes of resting ECG data were collected and analyzed from 14 individuals with SCI (C2 L3; ASIA Impairment Scale (AIS) A-D; 11.5+/-9.4 years post injury). The QTVI was analyzed via the threshold and tangent methods of QT-interval measurement, as well as from 1-, 5- and 10-min ECG epochs. RESULTS: The threshold method produced significantly higher QTVI values compared with the tangent method. The QTVI from a 1-min epoch was significantly higher compared with that from 5- and 10-min epochs. The QTVI values acquired from the threshold method were shown to have higher reproducibility compared with those from the tangent method. There were no differences in QTVI values between participants with lesions above and below T1, as shown by both methods of QT-interval measurement. CONCLUSION: The method of QT interval measurement and the length of ECG epoch influence QTVI values in individuals with SCI. The methodology of QTVI analysis must be standardized in studies involving SCI individuals to reduce the variability accounted by methodological inconsistency. PMID- 27481092 TI - The effects of early or direct admission to a specialised spinal injury unit on outcomes after acute traumatic spinal cord injury. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: For acute traumatic spinal cord injury (ATSCI), this study aimed to determine differences in outcomes between patient groups stratified by admission time (?24 vs >24 h) to the Spinal Injury Unit (SIU) and by the nature of the admission (direct admission to the SIU vs indirect admission via another hospital). We also aimed to measure the effect on time to admission of a 'non-refusal' policy that triggered immediate acceptance of ATSCI cases to the SIU. SETTING: New South Wales, Australia. METHODS: Study population was all adult SCI patients admitted to the Prince of Wales SIU from 1 January 2001 to 31 December 2012. Patients admitted with chronic stage SCI or with incomplete data for the duration of their stay were excluded. Comparison of outcomes was made between groups according to the setting of admission. Time to admission before and after initiation (2009) of the 'non refusal' policy was compared. The prevalence of complications, lengths of stay (LOSs) and time to admission were compared by Mann-Whitney non-parametric methods. Count modelling was used to control for confounders of age and gender. RESULTS: A total of 460 cases were identified and 76 were excluded. The early group had fewer pressure areas (41.8% vs 63.2%; P<0.001) and shorter LOS (136 vs 172 days; P<0.001) than the late group. The direct group had fewer pressure areas (35.2% vs 54.9%, P<0.001), deep vein thrombosis (9.9% vs 24.6%, P=0.003) and shorter LOS (124 vs 158 days, P=0.007) than those admitted indirectly. Time to admission was reduced after introduction of the 'non-refusal' policy (1.53 vs 0.63 days; P=0.001). CONCLUSIONS: Early and direct admission to SIU reduced complication rates and LOS. A non-refusal policy reduced time to admission. PMID- 27481094 TI - Defining Honors in the Surgery Clerkship. AB - BACKGROUND: Although highly influential, no published criteria exist that define who should receive the highest grade in the core surgery clerkship ("honors"). Therefore, significant variability exists in how this evaluation is assigned. Identifying the critical characteristics of the student receiving this grade can improve its usefulness in residency selection, class standing, and direct students' efforts. The purpose of this study was to attain expert consensus on the characteristics of an honors student in the core surgery clerkship. STUDY DESIGN: A 3-round modified Delphi technique was used in 2 parallel cycles to obtain expert consensus from the major stakeholders-program directors and clerkship directors in surgery. Experts were recruited from across the United States, although not from the same institutions. The 2 consensus lists were evaluated for congruency. RESULTS: All 15 of the invited clerkship directors and 14 of 15 invited program directors participated. A total of 65 unique characteristics were submitted by program directors and consensus was reached on 23. Clerkship directors submitted 62 characteristics and achieved agreement on 22. Ten of the final characteristics were identical between the 2 groups. These were communication skills, "shelf" exam score, synthetic ability (organizing data into meaningful care plans), absence of professionalism issues, outstanding work ethic, taking advantage of learning opportunities, accurate and complete history and physicals, enthusiasm, becoming an essential member of the care team, and outstanding clinical acumen. CONCLUSIONS: Expert consensus on the characteristics of an honors student in the core surgery clerkship was achieved. By using these criteria, the honors grade becomes emblematic of these 10 characteristics. This might reduce grade inflation within and between institutions, provide program directors with a consistent and reliable assessment of excellence, and effectively direct student efforts. PMID- 27481095 TI - Dismounted Complex Blast Injuries: A Comprehensive Review of the Modern Combat Experience. PMID- 27481093 TI - Regulation of B-cell development and tolerance by different members of the miR 17~92 family microRNAs. AB - The molecular mechanisms that regulate B-cell development and tolerance remain incompletely understood. In this study, we identify a critical role for the miR 17~92 microRNA cluster in regulating B-cell central tolerance and demonstrate that these miRNAs control early B-cell development in a cell-intrinsic manner. While the cluster member miR-19 suppresses the expression of Pten and plays a key role in regulating B-cell tolerance, miR-17 controls early B-cell development through other molecular pathways. These findings demonstrate differential control of two closely linked B-cell developmental stages by different members of a single microRNA cluster through distinct molecular pathways. PMID- 27481096 TI - Use of private sector for NHS hip surgery has reduced NHS provision, study finds. PMID- 27481097 TI - Growth differentiation factor 8 induces SKOV3 ovarian cancer cell migration and E cadherin down-regulation. AB - Epithelial ovarian cancer is the most lethal gynecological malignancy because most women present with late stage disseminated disease. Epithelial-mesenchymal transition (EMT) is characterized by the down-regulation of E-cadherin and up regulation of N-cadherin, and is a crucial event in the pathogenesis of ovarian cancer. Transforming growth factor-beta (TGF-beta) is a major regulator of EMT in many normal and neoplastic cell types. Growth differentiation factor 8 (GDF8), which also activates TGF-beta-like SMAD2/3 signaling, is best known for negatively regulating muscle growth. Though recent studies suggest that GDF8 enhances placental trophoblast cell migration, little is known about the role of GDF8 in EMT and cancer metastasis. We hypothesized that GDF8 could enhance ovarian cancer cell migration by inducing EMT. Here we demonstrate for the first time that GDF8 down-regulates E-cadherin but does not alter N-cadherin in SKOV3 ovarian cancer cells. This effect is abolished by the activin receptor-like kinase (ALK)4/5/7 inhibitor SB431542 or siRNA-mediated knockdown of ALK5, whereas knockdown of ALK4 is only partially inhibitory. GDF8 treatment increases the phosphorylation of SMAD2/3 and up-regulates the E-cadherin transcriptional repressors Snail and Slug; and these effects are abolished by pre-treatment with SB431542. Knockdown of common SMAD4 fully reverses the effects of GDF8 on E cadherin and partially attenuates its effects on Snail and Slug. Importantly, GDF8 treatment increases SKOV3 cell migration and this effect is blocked by SB431542. Our study suggests that GDF8 promotes ovarian cancer cell migration via ALK4/5-SMAD2/3-E-cadherin signaling. PMID- 27481098 TI - Garcinol exhibits anti-proliferative activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells. AB - BACKGROUND: Colorectal cancer is the fourth leading cause of death. Various natural compounds are known to have antitumor properties. Garcinol, a polyisoprenylated benzophenone, has antioxidant and anti-inflammatory properties. In the current study, we investigated the anticancer activity of garcinol on human colorectal adenocarcinoma cell line (HT-29) human colon cancer cells. METHODS: HT-29 cells were treated with various concentrations of garcinol for 24 h. The effect of garcinol on HT-29 cells proliferation was assessed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; the mRNA expression of microsomal prostaglandin E synthase-1 (mPGES-1), hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were examined by quantitative real-time polymerase chain reaction; apoptosis was detected by proportion of sub-G1 cell; caspase 3 activity and prostaglandin E2 (PGE2) level were determined by enzyme-linked immunosorbent assay and HT-29 cells migration was assessed using scratch test. RESULTS: Garcinol preconditioning markedly decreased the expression of mPGES-1, HIF-1alpha, VEGF, CXCR4, MMP-2, and MMP-9. The proportion of cells in sub-G1 phase and caspase 3 activity were increased by garcinol treatment whereas the cell proliferation, PGE2 level, and cell migration were decreased in these cells, compared to the control group. CONCLUSION: Our findings suggest that garcinol plays a critical role in elevating apoptosis and inhibiting HT-29 cells proliferation, angiogenesis, and invasion by suppressing the mPGES-1/PGE2/HIF 1alpha signaling pathways. PMID- 27481099 TI - A single aspartate mutation in the conserved catalytic site of Rev3L generates a hypomorphic phenotype in vivo and in vitro. AB - Rev3, the catalytic subunit of yeast DNA polymerase zeta, is required for UV resistance and UV-induced mutagenesis, while its mammalian ortholog, REV3L, plays further vital roles in cell proliferation and embryonic development. To assess the contribution of REV3L catalytic activity to its in vivo function, we generated mutant mouse strains in which one or two Ala residues were substituted to the Asp of the invariant catalytic YGDTDS motif. The simultaneous mutation of both Asp (ATA) phenocopies the Rev3l knockout, which proves that the catalytic activity is mandatory for the vital functions of Rev3L, as reported recently. Surprisingly, although the mutation of the first Asp severely impairs the enzymatic activity of other B-family DNA polymerases, the corresponding mutation of Rev3 (ATD) is hypomorphic in yeast and mouse, as it does not affect viability and proliferation and moderately impacts UVC-induced cell death and mutagenesis. Interestingly, Rev3l hypomorphic mutant mice display a distinct, albeit modest, alteration of the immunoglobulin gene mutation spectrum at G-C base pairs, further documenting its role in this process. PMID- 27481100 TI - In vivo effect of copper status on cisplatin-induced nephrotoxicity. AB - Cisplatin is a widely used antitumor agent; however, tumor resistance and severe side effects limit its use. It is well accepted that cisplatin toxicity can be modulated in vitro in cell cultures by copper salts. In the present work, mice with different blood serum copper status were treated with a single intraperitoneal cisplatin injection at a dose of 5 mg/kg, monitored for 3 days in metabolic cages and analyzed for renal function. Both copper-deficient and copper overloaded mice displayed more severe early proteinuria and retarded platinum excretion than control mice. The effects of copper status on cisplatin-induced nephrotoxicity are discussed. PMID- 27481101 TI - Behavior change interventions: the potential of ontologies for advancing science and practice. AB - A central goal of behavioral medicine is the creation of evidence-based interventions for promoting behavior change. Scientific knowledge about behavior change could be more effectively accumulated using "ontologies." In information science, an ontology is a systematic method for articulating a "controlled vocabulary" of agreed-upon terms and their inter-relationships. It involves three core elements: (1) a controlled vocabulary specifying and defining existing classes; (2) specification of the inter-relationships between classes; and (3) codification in a computer-readable format to enable knowledge generation, organization, reuse, integration, and analysis. This paper introduces ontologies, provides a review of current efforts to create ontologies related to behavior change interventions and suggests future work. This paper was written by behavioral medicine and information science experts and was developed in partnership between the Society of Behavioral Medicine's Technology Special Interest Group (SIG) and the Theories and Techniques of Behavior Change Interventions SIG. In recent years significant progress has been made in the foundational work needed to develop ontologies of behavior change. Ontologies of behavior change could facilitate a transformation of behavioral science from a field in which data from different experiments are siloed into one in which data across experiments could be compared and/or integrated. This could facilitate new approaches to hypothesis generation and knowledge discovery in behavioral science. PMID- 27481102 TI - Visual analogue scale (VAS) measurement of antiretroviral adherence in people living with HIV (PLWH): a meta-analysis. AB - Effective treatment of HIV hinges upon maintaining adequate antiretroviral therapy adherence. Accurate, cost-effective measurement of medication adherence is needed to best respond to the HIV pandemic. The visual analogue scale (VAS) appears to be a simple and easy to use measure of adherence but the current literature on its use is mixed. This meta-analysis (1) describes VAS concordance with other measures of medication adherence and viral load; and (2) examines how research methods moderate the reported strength of the VAS-viral load relationship. Literature searches were conducted electronically and by hand with a total of 20 studies included in the present study. The VAS showed large strength associations with most other measures of adherence and a smaller association with viral load. More rigorous methodological quality significantly improved the VAS-viral load effect size. We conclude with optimization recommendations for VAS use in clinical practice and research design. PMID- 27481103 TI - Increasing the public health impact of evidence-based interventions in behavioral medicine: new approaches and future directions. AB - The dissemination and implementation of evidence-based behavioral medicine interventions into real world practice has been limited. The purpose of this paper is to discuss specific limitations of current behavioral medicine research within the context of the RE-AIM framework, and potential opportunities to increase public health impact by applying novel intervention designs and data collection approaches. The MOST framework has recently emerged as an alternative approach to development and evaluation that aims to optimize multicomponent behavioral and bio-behavioral interventions. SMART designs, imbedded within the MOST framework, are an approach to optimize adaptive interventions. In addition to innovative design strategies, novel data collection approaches that have the potential to improve the public-health dissemination include mHealth approaches and considering environment as a potential data source. Finally, becoming involved in advocacy via policy related work may help to improve the impact of evidence-based behavioral interventions. Innovative methods, if increasingly implemented, may have the ability to increase the public health impact of evidence-based behavioral interventions to prevent disease. PMID- 27481104 TI - Impact of a personalized versus moderate-intensity exercise prescription: a randomized controlled trial. AB - Effective approaches to promote adolescent physical activity are needed. Moreover, a one-size-fits-all approach has been minimally successful to date. This randomized controlled trial evaluates a theory-based personalized exercise prescription to enhance motivation for being active and physical activity participation among adolescent reluctant exercisers. Adolescents were characterized by affective style as reluctant (predisposed to negative affect during exercise) or latent (predisposed to positive affect during exercise) exercisers based on their affective response to an acute exercise task, and then randomly assigned to an exercise prescription of either a personalized or a moderate intensity. Assignment was double-blind. Assessments were pre- and post- the 8-week intervention. Participants were an ethnically diverse group of adolescents (19 % non-Latino White) in a public middle-school. The exercise intensity manipulation and assessments took place at the school site during regular Physical Education. Participants were assigned to either a moderate intensity exercise prescription [target heart rate (HR) range 60-80 % of HR max] or a personalized exercise prescription corresponding to an intensity that "feels good" to the individual for 8 weeks during daily Physical Education. Outcome measures included exercise-related intrinsic motivation (via questionnaire), and daily moderate-to-vigorous physical activity (MVPA; via accelerometer). The exercise intensity manipulation did not yield actual differences in exercise intensity during PE, and had no effect on either Intrinsic Motivation or MVPA. There was no significant interaction between affective style and group assignment in predicting Intrinsic Motivation or MVPA. This study did not find support for a link between affective experiences during exercise and physical activity participation. Providing adolescents with a personalized exercise intensity prescription and asking them to follow the prescription during PE was not an effective strategy to manipulate their affective experience of exercise. A more rigorous test of affective manipulation may require supervised exercise sessions during which exercise intensity can be directly observed and controlled. PMID- 27481105 TI - Comparative analysis of the male reproductive accessory glands of bats Noctilio albiventris (Noctilionidae) and Rhynchonycteris naso (Emballonuridae). AB - In eutherian mammals, the male reproductive accessory glands (RAGs) comprise the prostate, bulbourethral glands, ampullary glands, and the seminal vesicles. Their composition, anatomy and function vary widely between species. This study aimed to characterize histologically and compare the RAGs of bats. The RAGs of Noctilio albiventris (Noctilionidae) and Rhynchonycteris naso (Emballonuridae) were studied using anatomical and histological methods, and were reconstructed three dimensionally. The RAGs of N. albiventris and R. naso are composed of a compact glandular complex that surrounds the urethra and a pair of bulbourethral glands, which are extra-abdominally located in the inguinal region. In both species, the glandular complex is composed of two well-defined prostatic regions (ventral and dorsal). The ventral region showed an atypical epithelium (holocrine), where no obvious cellular limits were observed, and PAS-positive secretion. The dorsal region had a pseudostratified cuboidal epithelium, with basal and secretory cells, and PAS-negative secretion. Noctilio albiventris also had urethral glands (Littre glands) surrounding the urethra, however, R. naso had only muscles. Both species had bulbourethral glands, with simple columnar epithelium and PAS positive secretion. In conclusion, the RAGs of N. albiventris and R. naso comprised a pair of bulbourethral glands and an intra-abdominal complex, composed of a prostate with two different regions (ventral and dorsal), while the ampullary glands and seminal vesicles were missing in both species. This morphology was more closely related between N. albiventris and R. naso, and to species of the family Phyllostomidae than to families Molossidae and Vespertilionidae. J. Morphol. 277:1459-1468, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27481106 TI - Psychometric Properties of the German Version of the Pain Vigilance and Awareness Questionnaire (PVAQ) in Pain-Free Samples and Samples with Acute and Chronic Pain. AB - PURPOSE: The way individuals attend to pain is known to have a considerable impact on the experience and chronification of pain. One method to assess the habitual "attention to pain" is the Pain Vigilance and Awareness Questionnaire (PVAQ). With the present study, we aimed to test the psychometric properties of the German version of the PVAQ across pain-free samples and across patients with acute and chronic pain. METHOD: Two samples of pain-free individuals (student sample (N = 255)/non-student sample (N = 362)) and two clinical pain samples (acute pain patients (N = 105)/chronic pain patients (N = 36)) were included in this cross-sectional evaluation of the German PVAQ. Factor structure was assessed using exploratory and confirmatory factor analyses. Reliability was assessed using internal consistency (Cronbach's alpha). Construct validity was tested by assessing correlations between PVAQ and theoretically related constructs. RESULTS: Exploratory factor analysis (non-student sample) and confirmatory factor analysis (student sample, acute pain patient sample) suggested that a two-factor solution best fitted our data ("attention to pain," "attention to changes in pain"). Internal consistency ranged from acceptable to good in all four samples. As hypothesized, the PVAQ correlated significantly with theoretically related constructs in all four samples, suggesting good construct validity in pain-free individuals and in pain patients. CONCLUSION: The German PVAQ shows good psychometric properties across samples of pain-free individuals and patients suffering from pain that are comparable to PVAQ versions of other languages. Thus, the German PVAQ seems to be a measure of pain vigilance equally valid as found in other countries. PMID- 27481107 TI - The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach. AB - ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8(+) T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT 803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-gamma producing CD8(+)CD44(hi) memory T cells and CD8(+)CD44(hi)CD62L(lo) effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8(+) T cells, CD8(+)CD44(hi) T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment. PMID- 27481109 TI - On August. PMID- 27481108 TI - Reduced potency of cytotoxic T lymphocytes from patients with high-risk myelodysplastic syndromes. AB - INTRODUCTION: Myelodysplastic syndromes (MDS) are a group of clonal bone marrow disorders, with dysplasia, cytopenias and increased risk of progression to acute myeloid leukemia. A dysregulated immune system precipitates MDS, and to gain insights into the relevance of cytotoxic T lymphocyte (CTL) in this process, we examined the frequency and function of CX3CR1- and CD57-positive T lymphocytes from MDS patients. MATERIALS AND METHODS: Peripheral blood and/or bone marrow samples from 31 MDS patients and 12 healthy controls were examined by flow cytometry. Expression of cytotoxic granule constituents, immunological co receptors, adhesion molecules and markers of activation were quantified on unstimulated lymphocytes. Degranulation, cytotoxicity and conjugate formation with target cells following co-culture of CTL with target cell lines or autologous bone marrow-derived CD34(+) cells were quantified by flow cytometry. RESULTS: CX3CR1 expression was increased in bone marrow from high-risk MDS patients compared to healthy controls. Expression of CD57 and CX3CR1 was closely correlated, identifying a CTL subset with high cytotoxic capacity. In vitro, TCR induced redirected cytotoxicity was markedly decreased for high-risk MDS patients compared to controls. CTL from MDS patients with the lowest target cell cytotoxicity had reduced expression of adhesion molecules and formed fewer conjugates with target cells. DISCUSSION: Although phenotypically defined CTL numbers were increased in the bone marrow of MDS patients, we found that CTL from high-risk MDS patients exhibited a lower TCR-induced redirected cytotoxic capacity. Thus, decreased T cell cytotoxicity seems related to reduced adhesion to target cells and may contribute to impaired anti-leukemic immune surveillance in MDS. PMID- 27481110 TI - Association of VEGF gene polymorphisms with sporadic Parkinson's disease in Chinese Han population. AB - Recent evidence indicates that vascular endothelial growth factor (VEGF) is capable of protecting dopaminergic (DA) neurons. Parkinson's disease (PD) is a progressive neurodegenerative disease caused by the degeneration of nigrostriatal dopaminergic neurons. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in PD, we performed a case-control study including 400 PD patients and 400 healthy-matched controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing were used to detect the rs699947, rs2010963 and rs3025039 polymorphisms of the VEGF gene in cases and controls. Our study revealed that T allelic frequency of rs3025039 polymorphism was significantly higher in PD subjects (OR 1.497, 95 % CI 1.099-2.040, P = 0.013) than that in controls. Significant association for rs3025039 could be found in additive model (TT vs. CT vs. CC: OR 1.489, 95 % CI 1.018-2.177, P = 0.040) and dominant model (TT + CT vs. CC: OR 1.538, 95 % CI 1.068-2.216, P = 0.021). Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Moreover, it also demonstrated a significant association in the subgroup of late onset PD (LOPD). However, for rs699947 and rs2010963 polymorphisms, genotype or allele frequencies did not differ between groups. No significant association could be found between rs699947 and rs2010963 polymorphism and PD risk. None of the observed haplotypes showed significant association with PD. Therefore, these results suggested that the VEGF gene might be associated with risk of developing sporadic PD in Han Chinese and the rs3025039 polymorphism may be a risk factor for sporadic PD. PMID- 27481111 TI - Severe reversible cerebral vasoconstriction syndrome after taking a product for slimming. PMID- 27481113 TI - A Simple and Sensitive Voltammetric Method for the Determination of Orange II Based on a Functionalized Graphene-Modified Electrode. AB - A simple and sensitive voltammetric sensor for Orange II was developed, based on a poly(sodium p-styrenesulfonate)-functionalized graphene-modified glassy carbon electrode. This voltammetric sensor showed strong accumulation ability and an excellent voltammetric response for Orange II. The electrochemical behavior of Orange II was systematically investigated in a pH 7.0 phosphate buffer solution. By linear sweep voltammetry, under optimum conditions, a good linear relationship was obtained between peak currents and Orange II concentrations in the wider range of 3 * 10(-8) to 5 * 10(-6) mol/L, with an LOD of 1 * 10(-8) mol/L. In addition, the proposed Orange II sensor was successfully applied to real food samples with satisfactory recovery. PMID- 27481115 TI - 95 Years of Progress. PMID- 27481114 TI - The active microbial diversity drives ecosystem multifunctionality and is physiologically related to carbon availability in Mediterranean semi-arid soils. AB - Biogeochemical processes and ecosystemic functions are mostly driven by soil microbial communities. However, most methods focus on evaluating the total microbial community and fail to discriminate its active fraction which is linked to soil functionality. Precisely, the activity of the microbial community is strongly limited by the availability of organic carbon (C) in soils under arid and semi-arid climate. Here, we provide a complementary genomic and metaproteomic approach to investigate the relationships between the diversity of the total community, the active diversity and ecosystem functionality across a dissolved organic carbon (DOC) gradient in southeast Spain. DOC correlated with the ecosystem multifunctionality index composed by soil respiration, enzyme activities (urease, alkaline phosphatase and beta-glucosidase) and microbial biomass (phospholipid fatty acids, PLFA). This study highlights that the active diversity (determined by metaprotoemics) but not the diversity of the whole microbial community (evaluated by amplicon gene sequencing) is related to the availability of organic C and it is also connected to the ecosystem multifunctionality index. We reveal that DOC shapes the activities of bacterial and fungal populations in Mediterranean semi-arid soils and determines the compartmentalization of functional niches. For instance, Rhizobales thrived at high-DOC sites probably fuelled by metabolism of one-C compounds. Moreover, the analysis of proteins involved in the transport and metabolism of carbohydrates revealed that Ascomycota and Basidiomycota occupied different nutritional niches. The functional mechanisms for niche specialization were not constant across the DOC gradient. PMID- 27481116 TI - On "Responsiveness of the Balance Evaluation Systems Test (BESTest) in people with subacute stroke." Chinsongkram B, Chaikeeree N, Saengsirisuwan V, et al. Phys Ther. doi: 10.2522/ptj.20150621. PMID- 27481112 TI - Cognitive Reserve and the Prevention of Dementia: the Role of Physical and Cognitive Activities. AB - PURPOSE OF REVIEW: The article discusses the two most significant modifiable risk factors for dementia, namely, physical inactivity and lack of stimulating cognitive activity, and their effects on developing cognitive reserve. RECENT FINDINGS: Both of these leisure-time activities were associated with significant reductions in the risk of dementia in longitudinal studies. In addition, physical activity, particularly aerobic exercise, is associated with less age-related gray and white matter loss and with less neurotoxic factors. On the other hand, cognitive training studies suggest that training for executive functions (e.g., working memory) improves prefrontal network efficiency, which provides support to brain functioning in the face of cognitive decline. While physical activity preserves neuronal structural integrity and brain volume (hardware), cognitive activity strengthens the functioning and plasticity of neural circuits (software), thus supporting cognitive reserve in different ways. Future research should examine whether lifestyle interventions incorporating these two domains can reduce incident dementia. PMID- 27481117 TI - On "Treatment-based classification system for low back pain: revision and update." Alrwaily M, Timko M, Schneider M, et al. Phys Ther. 2016;96:1057-1066. PMID- 27481118 TI - [Mesenchymal stem/stroma cells : Therapeutic potential in the treatment of autoimmune diseases]. AB - Mesenchymal stem and stromal cells (MSC) are propagated for the treatment of autoimmune and autoinflammatory processes. These cells can be relatively easily obtained from various tissues. The MSC feature anti-inflammatory and immunosuppressive properties in vitro as well as in animal models. Initial reports on the clinical application of MSC for various diseases are available, some with promising results and so far no reported toxicity; however, data from phase III studies are still lacking and crucial questions are still unanswered. The MSC preparations used are heterogeneous and also differ depending on the source and it is unclear whether autologous (own) or allogeneic (foreign) MSC are more suitable for therapeutic use. Long-term consequences, such as possible malignant transformation and possible endogenous tumor growth stimulation cannot be completely excluded. Ultimately, these questions can only be answered through randomized controlled trials for defined clinical indications with defined MSC. PMID- 27481120 TI - Thermometry of Guided Molecular Beams from a Cryogenic Buffer-Gas Cell. AB - A comprehensive characterisation of cold molecular beams from a cryogenic buffer gas cell, providing insight into the physics of buffer-gas cooling, is presented. Cold molecular beams are extracted from a cryogenic cell by electrostatic guiding, which is also used to measure their velocity distribution. The rotational-state distribution of the molecules is probed by radio-frequency resonant depletion spectroscopy. With the help of complete trajectory simulations, yielding the guiding efficiency for all of the thermally populated states, it is possible to determine both the rotational and the translational temperature of the molecules at the output of the buffer-gas cell. This thermometry method is demonstrated for various regimes of buffer-gas cooling and beam formation as well as for molecular species of different sizes (CH3 F and CF3 CCH). Comparison of the rotational and translational temperatures provides evidence of faster rotational thermalisation for the CH3 F/He system in the limit of low He density. In addition, the relaxation rates for different rotational states appear to be different. PMID- 27481121 TI - Atypical presentation of ascending aortic dissection in an ultracentenarian woman. PMID- 27481122 TI - Populations and outcome measures used in ongoing research in sarcopenia. AB - BACKGROUND: Sarcopenia research may be hampered by the heterogeneity of populations and outcome measures used in clinical studies. AIM: The aim of this study was to describe the inclusion/exclusion criteria and outcome measures used in ongoing research in sarcopenia. METHODS: All active intervention studies registered in the World Health Organization with the keyword sarcopenia were included. Study design, type of intervention, inclusion/exclusion criteria and outcome measures were registered and classified. RESULTS: In April 2014, 151 studies on sarcopenia were registered in the WHO database. One hundred twenty three were intervention studies. Most trials (94.3 %) were single centre and randomized (93.5 %), 51.2 % were double blind. Nutritional interventions (36.6 %), physical exercise (12.2 %) or both (19.5 %) were the most common interventions tested. Only 54.4 % included subjects of both genders, and 46.3 % had an upper age limit. Definition of the target populations was heterogeneous, with 57.7 % including healthy subjects and none using recent definitions of sarcopenia. Lifestyle and the degree of physical activity of subjects were not described or considered in most cases (79.7 %). Subjects with cardiovascular, neuropsychiatric or metabolic disorders and those with physical disability were usually excluded. Muscle mass and muscle strength were the primary outcome variables in 28.5 and 29.5 % of studies and physical performance in 19.5 %, but only 4.1 % used the three variables used the three of them. An additional 26.8 % used biological outcome variables. Little information and agreement existed in the way muscle and physical performance parameters were measured. CONCLUSIONS: We found a large heterogeneity in trial design, definition of populations and outcome measures in present research. PMID- 27481123 TI - [Recommendation on capacity for support of hospitals and other medical facilities by hospital hygienists]. PMID- 27481119 TI - [Full version of the S2e guidelines on gouty arthritis : Evidence-based guidelines of the German Society of Rheumatology (DGRh)]. PMID- 27481124 TI - [Effects on health of the Chernobyl accident: 30 years on]. AB - This paper reflects the current state of research into the short- and long-term effects on health in the former Soviet Union and Europe of the nuclear accident in Chernobyl. It discusses the latest results of epidemiological studies and presents future research perspectives. PMID- 27481125 TI - Misoprostol versus uterine straightening by bladder distension for pain relief in postmenopausal patients undergoing diagnostic office hysteroscopy: a randomised controlled non-inferiority trial. AB - OBJECTIVE: To compare the effectiveness of misoprostol with uterine straightening by bladder distension in minimising the pain experienced by postmenopausal patients during diagnostic office hysteroscopy. STUDY DESIGN: Seventy-six postmenopausal patients were randomly allocated in a 1:1 ratio to the misoprostol group or to the bladder distension group. Patients in the misoprostol group were instructed to insert two misoprostol tablets (400MUg) in the vagina 12h before office hysteroscopy. Patients in the bladder distension group were instructed to drink one litre of water and to avoid urination during a period of 2h before office hysteroscopy. The severity of pain experienced by the patients during and at 30min after the procedure was measured using a 100-mm visual analogue scale (VAS). The ease of passing the hysteroscope through the cervical canal was assessed by the hysteroscopists using a 100-mm VAS. RESULTS: The passage of the hysteroscope through the cervical canal was easier in the misoprostol group [60.37+/-15.78 vs. 50.05+/-19.88, p=0.015]. The mean VAS pain score during the procedure was significantly lower in the misoprostol group [39.47+/-13.96 vs. 50.18+/-15.44, p=0.002]. The mean VAS pain score 30min post-procedure was comparable between both groups [11.82+/-3.71 vs. 12.61+/-4.06, p=0.379]. CONCLUSION: Vaginal misoprostol is more effective than uterine straightening by bladder distension in relieving the pain experienced by postmenopausal patients during office hysteroscopy. TRIAL REGISTRATION: Clinicaltrials.gov [NCT02328495]. https://clinicaltrials.gov/ct2/show/NCT02328495. PMID- 27481126 TI - Satisfaction of health-care providers with electronic health records and perceived barriers to its implementation in the United Arab Emirates. AB - The integration of electronic health records (EHRs) has shown promise in improving health-care quality. In the United Arab Emirates, EHRs have been recently adopted to improve the quality and safety of patient care. A cross sectional survey of 680 health-care providers (HCPs) was conducted to assess the satisfaction of HCPs in the United Arab Emirates with EHRs' impact on access/viewing, documentation and medication administration and to explore the barriers encountered in their use. Data were collected over 6 months from April to September 2014. High overall satisfaction with EHRs was reported by HCPs, suggesting their acceptance. Physicians reported the greatest overall satisfaction with EHRs, although nurses showed significantly higher satisfaction with the impact on medication administration compared with other HCPs. The most significant barriers reported by nurses were lack of belief in the value of EHRs for patients and lack of adequate computer skills. Given the large investment in technology, additional research is necessary to promote the full utilization of EHRs. Nurses need to be aware of the value of EHRs for patient care and be involved in all stages of EHR implementations to maximize its meaningful use for better clinical outcomes. PMID- 27481127 TI - Gynaecological and obstetrical bleeding in women with factor XI deficiency - a systematic review: response to rebuttal. PMID- 27481128 TI - The association between diet quality and subclinical inflammation among children aged 6-18 years in the Eastern Cape, South Africa. AB - OBJECTIVE: The study aimed to investigate, for the first time, the association between diet quality (food variety and dietary diversity), intakes of anti inflammatory nutrients and food groups, and subclinical inflammation as assessed by categories of high-sensitivity C-reactive protein (hs-CRP). DESIGN: Cross sectional study. SETTING: Resource-poor, rural children in the Eastern Cape, South Africa. SUBJECTS: A sample size formula determined a representative sample of 235. Five schools were purposively selected and cluster sampling used to select 240 participants. Measurements included 24 h recall and dietary diversity questionnaires, anthropometric and biochemical measurements. RESULTS: The sample consisted of 50.4 % (n 118) girls and 49.6 % (n 116) boys. No obesity was found, but overweight was prevalent in 4.2 % of the children. The hs-CRP concentration (median (25th, 75th percentile)) of the low, medium and high risk inflammatory categories was 0.6 (0.4, 0.7), 1.6 (1.2, 2.2) and 4.2 (3.4, 6.4) mg/l, respectively. Body composition parameters did not differ between hs-CRP groups. Most of the anti-inflammatory nutrient intakes (dietary Fe, Zn, Mg, vitamin C, folate, linolenic acid, linoleic acid, MUFA and PUFA) differed significantly between the hs-CRP groups, with intakes increasing from low to high hs-CRP groups, with similar results for linolenic acid (P=0.022) intake. No significant relationships between hs-CRP and any of the food groups could be established, but significant relationships were established between hs-CRP levels and the high density of living arrangements and unhygienic ablution facilities. CONCLUSIONS: Although no link could be established between overnutrition and hs-CRP levels, an association was found between hs-CRP and dietary quality, as well as socio economic status. PMID- 27481129 TI - A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells. AB - MicroRNA (miRNA) deficiency impairs the generation of T follicular helper (Tfh) cells, but the contribution of individual miRNAs to this phenotype remains poorly understood. In this study, we performed deep sequencing analysis of miRNAs expressed in Tfh cells and identified a five-miRNA signature. Analyses of mutant mice deficient of these miRNAs revealed that miR-22 and miR-183/96/182 are dispensable, but miR-155 is essential for the generation and function of Tfh cells. miR-155 deficiency led to decreased proliferation specifically at the late stage of Tfh cell differentiation and reduced CD40 ligand (CD40L) expression on antigen-specific CD4(+) T cells. Mechanistically, miR-155 repressed the expression of Peli1, a ubiquitin ligase that promotes the degradation of the NF kappaB family transcription factor c-Rel, which controls cellular proliferation and CD40L expression. Therefore, our study identifies a novel miR-155-Peli1-c-Rel pathway that specifically regulates Tfh cell generation and function. PMID- 27481130 TI - Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis. AB - Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin 2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process. PMID- 27481131 TI - Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis. AB - CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)-susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell-intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches. PMID- 27481132 TI - GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. AB - When SUCNR1/GPR91-expressing macrophages are activated by inflammatory signals, they change their metabolism and accumulate succinate. In this study, we show that during this activation, macrophages release succinate into the extracellular milieu. They simultaneously up-regulate GPR91, which functions as an autocrine and paracrine sensor for extracellular succinate to enhance IL-1beta production. GPR91-deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1beta during antigen-induced arthritis. Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1beta release from macrophages in a GPR91-dependent manner. Together, we reveal a GPR91/succinate-dependent feed-forward loop of macrophage activation and propose GPR91 antagonists as novel therapeutic principles to treat RA. PMID- 27481135 TI - Past, Present, and Future of Chemogenomics. PMID- 27481133 TI - Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community-Dwelling Population. AB - BACKGROUND: Soluble ST2 (sST2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST2 levels are associated with incident heart failure (HF), including subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fraction, and cardiovascular death. METHODS AND RESULTS: Baseline serum sST2 was measured in 3915 older, community-dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac-specific biomarker, N terminal pro-type B natriuretic peptide, these associations were attenuated. In these models, an sST2 level above the US Food and Drug Administration-approved cut-off value (>35 ng/mL) was significantly associated with incident HF (hazard ratio [HR], 1.20; 95% CI, 1.02-1.43) and cardiovascular death (HR, 1.21; 95% CI, 1.02-1.44), and greater sST2 was continuously associated with cardiovascular death (per 1-ln increment: HR, 1.24; 95% CI, 1.02-1.50). sST2 was not associated with the HF subtypes of HFpEF and HFrEF in adjusted analysis. Addition of sST2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk. CONCLUSIONS: The predictive value of sST2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross-sectional associations with risk factors and underlying cardiac pathology. PMID- 27481136 TI - Quality Issues with Public Domain Chemogenomics Data. AB - The key concept in chemogenomics is the similarity principle that states that similar ligands should bind similar targets. Chemogenomic analysis requires large amounts of data and both powerful computational algorithms and computers. Data used for chemogenomics analysis can either be compiled from open sources, or they can be produced in-house as is often done in the pharmaceutical industry. The chemogenomic modeller often has to resort to mixing activity values from different laboratories and even assay types to facilitate chemogenomic analysis. The amount of chemogenomics data available in the public domain has dramatically increased in recent years, allowing fully traceable analysis on a continuously increasing scale. However, some warning flags about the data quality have been raised and because the primary data determine the accuracy of chemogenomic analysis, the quality of the data is one of the key questions in chemogenomics. This mini-review discusses some of the most common issues with public domain biological data related to chemogenomic analysis. The errors in data can originate from problems with the experiments themselves and their interpretation, or from more mundane issues such as data extraction and annotation. These issues are not unique for a certain database but are shared by all the public domain databases and can plague commercial and in-house bioactivity databases as well. PMID- 27481137 TI - Compound?Protein Interaction Prediction Within Chemogenomics: Theoretical Concepts, Practical Usage, and Future Directions. AB - With advancements in high-throughput technologies and open availability of bioassay data, computational methods to generate models, that zoom out from a single protein with a focused ligand set to a larger and more comprehensive description of compound-protein interactions and furthermore demonstrate subsequent translational validity in prospective experiments, are of prime importance. In this article, we discuss some of the new benefits and challenges of the emerging computational chemogenomics paradigm, particularly with respect to compound-protein interaction. Examples of experimentally validated computational predictions and recent trends in molecular feature extraction are presented. In addition, analyses of cross-family interactions are considered. We also discuss the expected role of computational chemogenomics in contributing to increasingly expansive network-level modeling and screening projects. PMID- 27481134 TI - Urinary 11-Dehydro-Thromboxane B2 as a Predictor of Acute Myocardial Infarction Outcomes: Results of Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) Study. AB - BACKGROUND: Urinary 11-dehydro-thromboxane (TX)B2 has been described as a potential predictive biomarker of major adverse cardiovascular events (MACEs) in high cardiac risk patients. This part of LTIMI (Leukotrienes and Thromboxane In Myocardial Infarction) study aimed to evaluate the relationship between 11 dehydro-TXB2 and MACEs in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: LTIMI was an observational, prospective study in 180 consecutive patients with AMI type 1 referred for primary percutaneous coronary intervention. On admission and at follow-up visits (1 month, 1 year), 11-dehydro TXB2 was measured in urinary samples by using high-performance liquid chromatography-tandem mass spectrometry. The primary outcome was occurrence of composite MACEs during 1-year after AMI. Left ventricular ejection fraction was assessed in echocardiography on admission and at 1-year follow-up. Analyses of 11 dehydro-TXB2 (pg/mg creatinine) were performed on log-transformed data and expressed as median with IQR (Q1-Q3). 11-Dehydro-TXB2 level on admission was 7.39 (6.85-8.01) and decreased at 1 month (6.73, 6.27-7.12; P<0.001) and 1-year follow up (6.37, 5.91-6.94; P<0.001). In univariate analysis, baseline 11-dehydro-TXB2 was higher in patients with MACEs (n=60; 7.73, 7.07-8.60) compared with those without MACEs (n=119; 7.28, 6.68-7.79; P=0.002). In multivariate regression model, 11-dehydro-TXB2 and 3 other variables (diabetes, multivessel disease, and left ventricular ejection fraction) were found to be best 1-year cumulative MACE predictors with odds ratio for 11-dehydro-TXB2 of 1.58 (95% CI 1.095-2.33; P=0.017) and area under the curve (in receiver operating characteristic analysis of 0.8). Baseline 11-dehydro-TXB2 negatively correlated with both left ventricular ejection fraction on admission (R=-0.21; P=0.006) and after 1 year (R=-0.346; P<0.001). CONCLUSIONS: 11-Dehydro-TXB2 predicts 1-year cumulative MACEs in AMI patients and provides prognostic information on the left ventricular performance. PMID- 27481138 TI - Kinase-Kernel Models: Accurate Chemogenomic Method for the Entire Human Kinome. AB - Chemogenomic kinase-kernel virtual screening models interpolate between very accurate, empirically-trained Profile-QSAR models of the nearest binding-site homologues with IC50 assay data. Between them, activity has been predicted for the entire human kinome. PMID- 27481139 TI - Computational Study of Drugs by Integrating Omics Data with Kernel Methods. AB - With the rapid development of genomic and chemogenomic techniques, many omics data sources for drugs have been publicly available. These data sources illustrate drug's biological function in the living cell from different levels and different aspects. One straightforward idea is to learn understandable rules via computational models and algorithms to mine and integrate these data sources. Here, we review our recent efforts on developing kernel-based methods to integrate drug related omics data sources. Three promising applications of our framework are shown to predict drug targets, assign drug's ATC-code annotation, and reveal drug repositioning. We demonstrate that data integration does provide more information and improve the accuracy by recovering more experimentally observed target proteins, ATC-codes, and drug repositioning. Importantly, data integration can indicate novel predictions which are supported by database search and functional annotation analysis and worthy of further experimental validation. In conclusion, kernel methods can efficiently integrate heterogeneous data sources to computationally study drugs, and will promote the further research in drug discovery in a low-cost way. PMID- 27481140 TI - Progress in the Visualization and Mining of Chemical and Target Spaces. AB - Chemogenomics is a growing field that aims to integrate the chemical and target spaces. As part of a multi-disciplinary effort to achieve this goal, computational methods initially developed to visualize the chemical space of compound collections and mine single-target structure-activity relationships, are being adapted to visualize and mine complex relationships in chemogenomics data sets. Similarly, the growing evidence that clinical effects are many times due to the interaction of single or multiple drugs with multiple targets, is encouraging the development of novel methodologies that are integrated in multi-target drug discovery endeavors. Herein we review advances in the development and application of approaches to generate visual representations of chemical space with particular emphasis on methods that aim to explore and uncover relationships between chemical and target spaces. Also, progress in the data mining of the structure-activity relationships of sets of compounds screened across multiple targets are discussed in light of the concept of activity landscape modeling. PMID- 27481141 TI - Visualization of Activity Landscapes and Chemogenomics Data. AB - Chemogenomics data are often difficult to analyze, given their large amounts, heterogeneity, and multi-dimensional nature. Network representations and other graphical methods are utilized to aid in data analysis. This review covers several recently introduced visualization methods for multi- or high-dimensional compound activity data that are designed for specific applications. PMID- 27481142 TI - Visual Analysis of Biological Activity Data with Scaffold Hunter. AB - The growing interest in chemogenomics approaches over the last years has led to an increasing amount of data regarding chemical and the corresponding biological activity space. The resulting data, collected in either in-house or public databases, need to be analyzed efficiently to speed-up the increasingly difficult task of drug discovery. Unfortunately, the discovery of new chemical entities or new targets for known drugs ('drug repurposing') is not suitable to a fully automated analysis or a simple drill down process. Visual interactive interfaces that allow to explore chemical space in a systematic manner and facilitate analytical reasoning can help to overcome these problems. Scaffold Hunter is a tool for the visual analysis of chemical compound databases that provides integrated visualization and analysis of biological activity data and fosters the interactive exploration of data imported from a variety of sources. We describe the features and illustrate the use by means of an exemplary analysis workflow. PMID- 27481143 TI - Identification of Similar Binding Sites to Detect Distant Polypharmacology. AB - The ability of small molecules to interact with multiple proteins is referred to as polypharmacology. This property is often linked to the therapeutic action of drugs but it is known also to be responsible for many of their side effects. Because of its importance, the development of computational methods that can predict drug polypharmacology has become an important line of research that led recently to the identification of many novel targets for known drugs. Nowadays, the majority of these methods are based on measuring the similarity of a query molecule against the hundreds of thousands of molecules for which pharmacological data on thousands of proteins are available in public sources. However, similarity-based methods are inherently biased by the chemical coverage offered by the active molecules present in those public repositories, which limits significantly their capacity to predict interactions with proteins structurally and functionally unrelated to any of the already known targets for drugs. It is in this respect that structure-based methods aiming at identifying similar binding sites may offer an alternative complementary means to ligand-based methods for detecting distant polypharmacology. The different existing approaches to binding site detection, representation, comparison, and fragmentation are reviewed and recent successful applications presented. PMID- 27481144 TI - Inferring Chemogenomic Features from Drug-Target Interaction Networks. AB - Drug effects are mainly caused by the interactions between drug molecules and target proteins including primary targets and off-targets. Understanding of the molecular mechanisms behind overall drug?target interactions is crucial in the drug design process. In this paper we review recently developed methods to infer chemogenomic features (the underlying associations between drug chemical substructures and protein domains) which are strongly involved in drug-target interaction networks. We show the usefulness of the methods to detect ligand chemical fragments specific for each protein domain and ligand core substructures important for a wide range of protein families. We also discuss how to use the chemogenomic features for predicting unknown drug-target interactions on a large scale. PMID- 27481145 TI - Practice and Challenges of Building a Semantic Framework for Chemogenomics Research. AB - Effective discovery of new drugs for complex diseases demands an integrative analysis of big data aggregated from diverse sources in chemical and biological domains, to help better understand the mechanism of drug actions and to quickly translate discovery to clinical applications. Conventional approaches are confronting critical challenges in the integration of those huge heterogeneous datasets and the rapid transformation from data to knowledge. Semantic technologies aimed at facilitating the building of a common framework that allows data sharing and utilization across applications and domains in the web, have been developed quickly and have been exhibiting a broad impact in life science. Chemogenomics serves as a bridge to connect various chemical and biological data, thus building a semantic framework for chemogenomics research could not only facilitate the development of this field but also advance the intersection among other domains. During the last few years, such framework has been developed and applied in addressing real problems. In the review, we will describe the major techniques needed to build a semantic framework, and will discuss the challenges of having such framework making a broader impact. PMID- 27481146 TI - Extensions to In Silico Bioactivity Predictions Using Pathway Annotations and Differential Pharmacology Analysis: Application to Xenopus laevis Phenotypic Readouts. AB - The simultaneous increase of computational power and the availability of chemical and biological data have contributed to the recent popularity of in silico bioactivity prediction algorithms. Such methods are commonly used to infer the 'Mechanism of Action' of small molecules and they can also be employed in cases where full bioactivity profiles have not been established experimentally. However, protein target predictions by themselves do not necessarily capture information about the effect of a compound on a biological system, and hence merging their output with a systems biology approach can help to better understand the complex network modulation which leads to a particular phenotype. In this work, we review approaches and applications of target prediction, as well as their shortcomings, and demonstrate two extensions of this concept which are exemplified using phenotypic readouts from a chemical genetic screen in Xenopus laevis. In particular, the experimental observations are linked to their predicted bioactivity profiles. Predicted targets are annotated with pathways, which lead to further biological insight. Moreover, we subject the prediction to further machine learning algorithms, namely decision trees, to capture the differential pharmacology of ligand-target interactions in biological systems. Both methodologies hence provide new insight into understanding the Mechanism of Action of compound activities from phenotypic screens. PMID- 27481147 TI - A Perspective on Computational Chemogenomics. PMID- 27481149 TI - Review of "The Nurse Practitioner in Urology". PMID- 27481148 TI - Towards the Next Generation of Computational Chemogenomics Tools. PMID- 27481150 TI - Obesity as a disability - A representative survey of individuals with obesity from Germany. AB - BACKGROUND: While obesity can be an antecedent of disability and the prevalence of disabilities in increased in individuals with obesity, it has been highly debated whether obesity itself should be considered a disability. The European Court of justice has set a precedent in 2014, ruling that severe forms of obesity qualify for protection under the disability protection legislation. However, attitudes and opinions of those affected have not been investigated yet. OBJECTIVE: To study attitudes of people with obesity regarding the acknowledgment of obesity as a disability. METHODS: Cross-sectional analysis of a population based study from Germany, conducted in 2015, in n = 1000 individuals with obesity. RESULTS: We find that 38.2% of all respondents agreed that obesity ought to be considered a disability. In logistic regression analyses, heavier participants expressed a higher support of obesity seen as a disability, regardless of perceived discrimination experiences (DeltaOR = 1.54, p = 0.427). Experiences of perceived discrimination were associated with a higher approval of obesity as a disability in individuals with class II obesity (OR = 2.07, p = 0.002) compared to respondents with less severe obesity. CONCLUSION: These findings go in line with the European Court of Justice's ruling, where it is stated that only severe forms of obesity qualify for protection under the disability legislation. The results underline the importance of considering adding weight to anti-discrimination legislation. PMID- 27481151 TI - Frequency of psycho-oncologic and social service counseling in cancer centers relative to center site and hospital characteristics: Findings from 879 center sites in Germany, Austria, Switzerland, and Italy. AB - BACKGROUND: There is extensive evidence that patients with cancer and cancer survivors have a strong need for expert support in relation to the psychological and social consequences of the disease. The requirements set out in the German Cancer Society's cancer center certification system include the routine provision of psycho-oncologic care (POC) and social service counseling for every patient. The current study investigated which organizational and structural characteristics in hospitals account for variations in psychosocial care provision in these centers. METHODS: Data routinely collected during the certification process regarding the percentages of psychosocial care provision and characteristics of center sites and hospitals were matched with data with regard to size of the municipality, teaching hospital status, and institutional ownership. Linear multilevel regression analyses were performed to identify the characteristics of hospitals and center sites that were related to psychosocial care provision. RESULTS: Substantial differences were found for different types of cancer (eg, a greater provision of psychosocial care in centers specializing in breast rather than prostate cancer). There was more POC provision in longer certified centers and less in rural areas and university hospitals. Much of the variation between hospitals remains unexplained. CONCLUSIONS: Although the implementation of mandatory psychosocial services generally provides patients with access to POC and social service counseling, the wide differences in the provision of counseling indicate that additional measures are needed to avoid inequalities resulting from the center at which a patient receives cancer treatment. Cancer 2016;122:3538-3545. (c) 2016 American Cancer Society. PMID- 27481152 TI - Immunochemical Cross-Reactivity of beta-Glucan in the Medicinal Plant, Sasa veitchii (Japanese Folk Medicine Kumazasa), and Medicinal Mushrooms. AB - Fungal beta-glucan is a representative pathogen-associated molecular pattern from mushroom, yeast, and fungi and stimulates innate as well as acquired immune systems. This beta-glucan is widely applied in functional food to enhance immunity. Humans and animals generally become sensitized to this beta-glucan and gradually produce specific antibodies to beta-glucans. The extracts of plants have been used as folk medicine and are reported to possess various biological activities that are beneficial for human health, such as antitumor, antiallergic, and anti-inflammatory activities. In the present study, the immunochemical cross reactivity of Sasa extract and fungal beta-glucan was analyzed. We found that the anti-beta-glucan antibody in human sera strongly cross-reacted with the Sasa extract. This result strongly suggested that plant extracts modulate the immunostimulating effects of medicinal mushrooms. The cooperative effects of plants and mushrooms may be an important issue for functional foods. PMID- 27481153 TI - Commercial Sample Identification and Characterization Challenges in Medicinal Mushroom Research. AB - A recent study published in this journal demonstrates the pitfalls faced by researchers who utilize commercial products as their test samples without proper characterization. Labeling of commercial mushroom products is often incorrect, which can lead to erroneous interpretations and conclusions. Nine of the 10 samples of commercially branded products used in the study and identified as ground mushrooms were actually grain spawn: mycelium propagated on grain. PMID- 27481154 TI - Vitamin D and Vitamin D from Ultraviolet-Irradiated Mushrooms (Review). AB - Vitamin D may have an important role in many aspects of human health, from bone fractures to prostate cancer, cardiovascular disease, neuromuscular problems, and diabetes. Vitamin D is produced in the human body by the skin after sunlight absorption, but as human lifestyles change, so does the time of exposure to sunlight, necessitating dietary supplementation of vitamin D. Mushrooms have the advantages that they are the only source of vitamin D in the produce aisle and they are one of the few nonfortified food sources. Here, we review the current literature on enhancement of the vitamin D content in mushrooms and literature evidence on the bioavailability of vitamin D in humans and animals after ingesting ultraviolet (UV)-irradiated mushrooms. We also present available literature on health safety after UV irradiation of mushrooms, and we discuss issues arising in the attempt to incorporate UV irradiation into the mushroom production line. PMID- 27481155 TI - Nutrient Optimization Using Response Surface Methodology for Simultaneous Biomass and Bioactive Compound Production by Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes). AB - Due to the unpleasant side effects of long-term use of commercially available drugs, the discovery and development of natural therapeutic agents to prevent life-debilitating diseases is urgently needed. In the present study, the optimization of medium composition for maximum mycelial biomass and bioactive compounds production by Hericium erinaceus was studied using response surface methodology based on a central composite design. Under the optimal conditions and at a pH of 5.41 +/- 0.28, the maximum mycelial biomass and exopolysaccharide production reached 25.0 +/- 1.38 g/L and 1.73 +/- 0.06 g/L, respectively, compared with 22.65 +/- 0.10 g/L and 1.56 +/- 0.23 g/L in the basal medium, after 7 days of cultivation. Furthermore, we report for the first time the production of adenosine, both intra- and extracellularly in submerged cultures of H. erinaceus. Although most of the adenosine detected existed in the culture medium, the highest intracellular and extracellular adenosine concentrations of 150.84 +/ 1.87 mg/L and 142.48 +/- 3.78 mg/L were achieved after 7 and 6 days of cultivation, respectively. PMID- 27481156 TI - Anti-Inflammatory Effects of Ethanol Extract of Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), in Mice with Ulcerative Colitis. AB - This study investigated the anti-inflammatory activity of ethanol extracts of Hericium erinaceus in the inflammatory bowel disease (IBD) model. Twenty C57BL/6 mice were exposed to 2% (w/v) dextran sulfate sodium (DSS) in their drinking water for 7 d to induce acute intestinal inflammation. Orally administrated ethanol extract of H. erinaceus (HEEE) (250 mg/kg/d and 500 mg/kg/d body weight) could significantly (P < 0.05) improve body weight and colon length and decreased the intestinal bleeding of DSS-treated mice compared with DSS-treated mice not given HEEE. HEEE markedly reduced DSS-induced myeloperoxidase accumulation in colon tissues, attenuated histological change in the neutrophils and lymphocyte infiltration, and protected the mucosal epithelium. Mechanistically, HEEE ameliorated colitis not only by suppressing the production of inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 in colon tissues but also by adjusting the production of nitric oxide, malondialdehyde, and superoxide dismutase in serum to suppress the oxidative stress. These results suggest that HEEE can be applied as a protective agent in the treatment of IBDs. PMID- 27481157 TI - Antioxidant, Anti-Inflammatory, and Antitumor Activities of Cultured Mycelia and Fruiting Bodies of the Elm Oyster Mushroom, Hypsizygus ulmarius (Agaricomycetes). AB - Ethanoic extracts from the fruiting bodies and mycelia of the elm oyster mushroom, Hypsizygus ulmarius, were evaluated for their antioxidant, anti inflammatory, and antitumor properties. Ethnolic extracts of fruiting body and mycelia showed 88%, 85%, 71%, and 85%, 65%, 70% 2,2-diphenyl-1-picrylhydrazyl, hydroxyl (DPPH) and 2,2'-azinobis (3-ethyl benzothiazolin-6-sulfonic acid) (ABTS) radical-scavenging activities, respectively, at a concentration of 1000 ug/mL. The anti-inflammatory activity was determined using carrageenan- and formalin- induced paw edema models. Diclofenac was used as the standard drug. In both models, the mycelia extract showed higher activity than the fruiting body extract. The antitumor effect of the extracts against Dalton's Lymphoma Ascites cell-line-induced tumors showed significant antitumor activity. Mycochemical analysis confirmed the presence of many pharmacologically active compounds such as phenol, alkaloids, proteins, tannins, and polysaccharides. Among these, polysaccharides and phenolic compounds were present at a higher concentration in both extracts. These compounds might be largely responsible for the mushroom's medicinal properties. The results of this study indicate that H. ulmarius possesses significant antioxidant, anti-inflammatory, and antitumor properties. PMID- 27481158 TI - Exploring the Medicinal Potential of the Fruit Bodies of Oyster Mushroom, Pleurotus ostreatus (Agaricomycetes), against Multidrug-Resistant Bacterial Isolates. AB - Bacterial resistance to present-generation antibiotics is increasing drastically, which has become a major public health concern. The present study focuses on demonstrating the antimicrobial potential of fruit bodies of the culinary/medicinal oyster mushroom Pleurotus ostreatus against clinical pathogens. Five bacterial isolates were collected from Sagar Hospital in Bangalore, India. The collected strains were grown on selective and differential media and antibiotic susceptibility testing was applied using 48 antibiotics by disc diffusion assay. The antibacterial efficiency of the mushroom extract against clinical pathogens, which were found to be multidrug resistant (MDR) to most of the tested antibiotics, was studied. The yield of cultivated mushrooms was evident at moist, cooler, and humid conditions. The clinical isolates of Staphylococcus aureus, Salmonella typhi, Acinetobacter sp., Proteus mirabilis, and Proteus spp. were found to be MDR to beta-lactam, fluoroquinolones, sulfonamides, third- and fourth-generation cephalosporins, aminoglycosides, macrolides, tetracyclines, and carbapenems. The methanolic extracts of mushroom fruit bodies were found to be more effective than present-generation antibiotics against methicillin- and vancomycin- resistant S. aureus, S. typhi, Acinetobacter sp., and P. mirabilis at a concentration ranging from 50 to 100 ug/disc or 50 to 100 uL/well. The current study suggests that the methanolic extract of P. ostreatus can be used as a promising antibacterial agent against MDR bacterial pathogens. PMID- 27481159 TI - Morphological and Molecular Analysis Identifies the Associated Fungus ("Xianghui") of the Medicinal White Jelly Mushroom, Tremella fuciformis, as Annulohypoxylon stygium. AB - White jelly mushroom, Tremella fuciformis, is a popular edible mushroom with interesting medicinal properties (e.g., immunostimulating, antidiabetic). The formation of T. fuciformis basidiomes is highly dependent on the presence of a specific host fungus, both in nature and for industrial production. This host has traditionally been indicated as "Xianghui" in China, yet which or how many fungal species Xianghui comprises is unclear, with various authorities claiming different species. At present, Annulohypoxilon archeri is generally assumed to be the main Xianghui species, but this has not yet been confirmed experimentally. The implementation of older, premolecular-based research data (i.e., morphological) with present, sequence-based data to solve the identity remains confusing and studies addressing both identification methods in combination are lacking. The unclear identity of Xianghui is a major obstacle for further understanding of the important relationship between the host(s) and T. fuciformis. In this study, we collected a wild specimen of T. fuciformis together with several nearby stroma of Xianghui, cocultivated T. fuciformis with the Xianghui isolates, and observed basidiome formation. Internal transcribed spacer (ITS) sequence analysis showed that all Xianghui spore isolates belonged to the same species and both morphological analysis of sexual stages and ITS beta tubulin and actin gene sequences of the Xianghui specified it as Annulohypoxylon stygium. The ITS sequences of the newly identified Xianghui further closely matched those of the Xianghui strains used in the mushroom industry, showing that wild and culture spawn Xianghui in China consist of A. stygium. In contrast with previous conclusions, A. stygium, and not A. archeris, seems to be the preferred host of T. fuciformis. PMID- 27481160 TI - Screening for Antimicrobial Activity of Wood Rotting Higher Basidiomycetes Mushrooms from Uruguay against Phytopathogens. AB - In this work, the antimicrobial activity of extracts of wood rotting higher Basidiomycetes mushrooms isolated from Eucalyptus plantations in Uruguay was studied using bacterial and fungal phytopathogens as targets. Fifty-one extracts from mycelia and growth broth were prepared from higher Basidiomycetes mushrooms, from which eight extracts (from Ganoderma resinaceum, Laetiporus sulphureus, Dictyopanus pusillus, and Bjerkandera adusta) showed antimicrobial activity against Xanthomonas vesicatoria, Aspergillus oryzae, Penicillium expansum, Botrytis cinerea, and Rhizopus stolonifer as assayed in the qualitative test. The minimum inhibitory concentration (MIC) for those fungal extracts was determined and the results showed that L. sulphureus deserved further study, with low MIC values against X. vesicatoria. The antimicrobial activity of L. sulphureus culture broth extracts grown under different culture conditions was evaluated against X. vesicatoria. From the results of these assays, larger-scale cultures for the production of the compound(s) with antimicrobial activity should be performed using malt extract broth, at pH 5, at 20 degrees C and static culture conditions. PMID- 27481161 TI - In Memory of Professor Gaston Guzman (1932-2016). PMID- 27481163 TI - Social Welfare Policy and Inequalities in Health. Preconceived Truths in Scientific Research. AB - At the end of the first decade of the present century debates arose in social epidemiology. These debates set those who defend the existence of a relation between the political and/or welfare stage regime and the magnitude of socioeconomic inequalities in health against those who maintain the facts do not support such a relation. These debates are similar to other debates in epidemiology in the 1990s related with theories of how diseases are produced and the factors that determine their distribution in the population. Whereas some authors find it impossible to separate ethical and political aspects and professional values from scientific arguments, others consider that epidemiologists and other scientists should make an effort to distinguish between scientific and unscientific considerations. In this paper the author reflects about the harmony that keep science, politics and ethics in the scientific practice on health inequalities, although the empirical evidence is contrary to that harmonious effect. PMID- 27481162 TI - Addressing proteolytic efficiency in enzymatic degradation therapy for celiac disease. AB - Celiac disease is triggered by partially digested gluten proteins. Enzyme therapies that complete protein digestion in vivo could support a gluten-free diet, but the barrier to completeness is high. Current options require enzyme amounts on the same order as the protein meal itself. In this study, we evaluated proteolytic components of the carnivorous pitcher plant (Nepenthes spp.) for use in this context. Remarkably low doses enhance gliadin solubilization rates, and degrade gliadin slurries within the pH and temporal constraints of human gastric digestion. Potencies in excess of 1200:1 (substrate-to-enzyme) are achieved. Digestion generates small peptides through nepenthesin and neprosin, the latter a novel enzyme defining a previously-unknown class of prolyl endoprotease. The digests also exhibit reduced TG2 conversion rates in the immunogenic regions of gliadin, providing a twin mechanism for evading T-cell recognition. When sensitized and dosed with enzyme-treated gliadin, NOD/DQ8 mice did not show intestinal inflammation, when compared to mice challenged with only pepsin treated gliadin. The low enzyme load needed for effective digestion suggests that gluten detoxification can be achieved in a meal setting, using metered dosing based on meal size. We demonstrate this by showing efficient antigen processing at total substrate-to-enzyme ratios exceeding 12,000:1. PMID- 27481164 TI - Trans-oral robotic surgery (TORS) for the treatment of lingual tonsillitis. When conventional therapies fail. AB - BACKGROUND: Lingual tonsillitis is an underestimated but serious health problem. This paper describes the feasibility and efficacy of the trans-oral robotic surgical approach in cases of lingual tonsillitis. MATERIALS AND METHODS: From February 2012 to April 2014, 10 patients affected by lingual tonsillitis resistant to medical treatments underwent transoral robotic lingual tonsillectomy at the authors' Institution. RESULTS: The surgical robotic procedure was completed in all cases and there was no need to change the operative approach once started. The mean set-up time was 13.2 +/- 5.2 min, while mean operating time was 28 +/- 12 min. The mean amount of tissue removed was 16.5 +/- 13 cm3 . No major intra-operative and post-operative complications were registered. After 15.2 +/- 12 months of follow-up, no relapses were reported and patients did not complain of any further symptoms. CONCLUSION: Lingual tonsillitis seems to be safely and effectively managed by trans-oral robotic surgery. The data are encouraging and worthy of further evaluation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27481165 TI - Crystal structure of the CupB6 adhesive tip from the chaperone-usher family of pili from Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that can cause chronic infection of the lungs of cystic fibrosis patients. Chaperone usher systems in P. aeruginosa are known to translocate and assemble adhesive pili on the bacterial surface and contribute to biofilm formation within the host. Here, we report the crystal structure of the tip adhesion subunit CupB6 from the cupB1-6 gene cluster. The tip domain is connected to the pilus via the N terminal donor strand from the main pilus subunit CupB1. Although the CupB6 adhesion domain bears structural features similar to other CU adhesins it displays an unusual polyproline helix adjacent to a prominent surface pocket, which are likely the site for receptor recognition. PMID- 27481166 TI - Macromolecular crowding favors the fibrillization of beta2-microglobulin by accelerating the nucleation step and inhibiting fibril disassembly. AB - Hemodialysis-associated amyloidosis (HAA) involves the fibrillization of beta2 microglobulin (beta2M) and occurs in crowded physiological environments. However, how macromolecular crowding affects amyloid formation of beta2M remains elusive. Here we study the effects of macromolecular crowding on amyloid formation and fibril disassembly of wild-type human beta2M and its pathogenic mutant DeltaN6. At strongly acidic pH2.5, the presence of a strong crowding agent (Ficoll 70 or dextran 70) not only dramatically accelerates the fibrillization of both wild type beta2M and its DeltaN6 variant by reducing the lag time to a large extent, indicating the acceleration of the nucleation phase, but also remarkably increases the amount of beta2M fibrils. At weakly acidic pH6.2, such an enhancing effect of macromolecular crowding on fibril formation is only observed for pathogenic mutant DeltaN6, but not for wild-type beta2M which does not form amyloid fibrils in the absence and presence of a crowding agent. Thus, we propose that the monomers of beta2M form the nuclei, which is enhanced by macromolecular crowding, followed by the step of fibril elongation. Furthermore, at physiological pH, macromolecular crowding remarkably inhibits beta2M fibril disassembly by decreasing rate constants corresponding to fast and slow stages of fibril disaggregation. Our data demonstrate that macromolecular crowding favors the fibrillization of beta2M by accelerating the nucleation step and inhibiting fibril disassembly. Our findings provide clear evidence for the pathology of HAA that macromolecular crowding should be taken into account. PMID- 27481167 TI - Fluorescent molecularly imprinted polymers as plastic antibodies for selective labeling and imaging of hyaluronan and sialic acid on fixed and living cells. AB - Altered glycosylation levels or distribution of sialic acids (SA) or hyaluronan in animal cells are indicators of pathological conditions like infection or malignancy. We applied fluorescently-labeled molecularly imprinted polymer (MIP) particles for bioimaging of fixed and living human keratinocytes, to localize hyaluronan and sialylation sites. MIPs were prepared with the templates D glucuronic acid (GlcA), a substructure of hyaluronan, and N-acetylneuraminic acid (NANA), the most common member of SA. Both MIPs were found to be highly selective towards their target monosaccharides, as no cross-reactivity was observed with other sugars like N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-glucose and D-galactose, present on the cell surface. The dye rhodamine and two InP/ZnS quantum dots (QDs) emitting in the green and in the red regions were used as fluorescent probes. Rhodamine-MIPGlcA and rhodamine-MIPNANA were synthesized as monodispersed 400nm sized particles and were found to bind selectively their targets located in the extracellular region, as imaged by epifluorescence and confocal microscopy. In contrast, when MIP-GlcA and MIP-NANA particles with a smaller size (125nm) were used, the MIPs being synthesized as thin shells around green and red emitting QDs respectively, it was possible to stain the intracellular and pericellular regions as well. In addition, simultaneous dual color imaging with the two different colored QDs-MIPs was demonstrated. Importantly, the MIPs were not cytotoxic and did not affect cell viability; neither was the cells morphology affected as demonstrated by live cell imaging. These synthetic receptors could offer a new and promising imaging tool to monitor disease progression. PMID- 27481168 TI - Extraction of toxic compounds from saliva by magnetic-stirring-assisted micro solid-phase extraction step followed by headspace-gas chromatography-ion mobility spectrometry. AB - A new sample extraction procedure based on micro-solid-phase extraction (MUSPE) using a mixture of sorbents of different polarities (polymeric reversed-phase sorbent HLB, silica-based sorbent C18, and multiwalled carbon nanotubes) was applied to extract benzene, toluene, butyraldehyde, benzaldehyde, and tolualdehyde present in saliva to avoid interference from moisture and matrix components and enhance sensitivity and selectivity of the ion mobility spectrometry (IMS) methodology proposed. The extraction of target analytes from saliva samples by using MUSPE were followed by the desorption step carried out in the headspace vials placed in the autosampler of the IMS device. Then, 200 MUL of headspace was injected into the GC column coupled to the IMS for its analysis. The method was fully validated in terms of sensitivity, precision, and recovery. The LODs and LOQs obtained, when analytes were dissolved in saliva samples to consider the matrix effect, were within the range of 0.38-0.49 and 1.26-1.66 MUg mL(-1), respectively. The relative standard deviations were <3.5 % for retention time and drift time values, which indicate that the method proposed can be applied to determine toxic compounds in saliva samples. Graphical abstract Summary of steps followed in the experimental set up of this work. PMID- 27481170 TI - Development of an ELISA to detect clenbuterol in swine products using a new approach for hapten design. AB - This research outlines the application of an enzyme-linked immunosorbent assay (ELISA) for the analysis of clenbuterol in animal products. Our assay showed good sensitivity for clenbuterol (0.4 ng/g or 0.4 ppb) and low detection limit (0.09 ng/g or 0.09 ppb). A low cross-reactivity for other beta2-agonist drugs such as salbutamol, terbutaline, and epinephrine led to formatting an ELISA kit considered to have a high specificity for clenbuterol. A survey of Ho Chi Minh City pork market was conducted as part of the validation of our ELISA. ELISA results showed a surprisingly high value of contamination. However, it will be necessary to conduct a more statistically valid replicated survey with evaluation by other instrumental methods to obtain a definite conclusion. This ELISA kit will be used to monitor growth promoter residues in Vietnam's animal products. PMID- 27481169 TI - Determination of serum glucose by isotope dilution liquid chromatography-tandem mass spectrometry: a candidate reference measurement procedure. AB - Accurate and precise glucose measurements are requisite for ensuring appropriate diagnosis and management of diseases related to hyperglycemia or hypoglycemia. It is necessary to have a higher order method to provide an accuracy base to which routine methods can be compared. We developed and evaluated a highly reliable measurement procedure based on isotope dilution liquid chromatography-tandem mass spectrometry (ID LC-MS/MS) with a simple one-step derivatization. An appropriate amount of serum was accurately weighed and spiked with an isotope-labeled internal standard. After protein precipitation, the supernatant was reacted with 1-phenyl-3-methyl-5-pyrazolone for chemical structural transformation. The glucose derivatives were analyzed with LC-MS/MS in positive electrospray ionization mode. The within-run and total CVs ranged from 0.28 to 0.42 % and from 0.42 to 0.76 %, respectively, for a concentration range of 1.691 to 15.676 mmol/L. A regression comparison of the presented method to an existing RMP based on ID GC-MS showed agreement with no statistical difference (Y = 0.9985X-0.008; 95 % CI for the slope, 0.9966 to 1.001; 95 % CI for the intercept, -0.012 to 0.019). The structural analogs of glucose with a molecular mass of 180 were tested, and no significant interference effect was found. The limit of quantification was estimated to 0.8 ng glucose in absolute amount. This method is accurate, simple, and can serve as a candidate reference measurement procedure (RMP) in the establishment of a serum glucose reference system. PMID- 27481171 TI - Head lice in progress: what could/should be done-a report on an in vivo and in vitro field study. AB - Head lice infections are a growing problem in the light of increasing migration of large population as well as the increasing current refugee flows and concomitant poor hygienic conditions. These infections are associated with a significantly reduced quality of life and frequent medical consultations. The approved drugs for the treatment of head lice infections have some disadvantages in the treatment despite their good efficacy. In addition to irritant-toxic substances that can cause adverse reactions in patients, a partial development of resistance has occurred and a double application is necessary to achieve adequate efficacy. For this reason, we have decided to test a product without the aforementioned treatment drawbacks. We examined the effect of Licener(r) on the head lice treatment through individual therapy trials. We identified 65 patients with head lice infections for the treatment with Licener(r). All patients were treated with Licener(r) and visited for a period of 2 weeks. Successfully treated patients had no relapses. Against the background of this study and based on the observations of our applications, we expect that Licener(r) could enhance considerably the therapeutic options for the treatment of head lice infections, as an alternative to classical products. PMID- 27481172 TI - Morphological re-description and new geographical records for three digenean parasites infecting African sharptooth catfish Clarias gariepinus (Pisces: Clariidae) in Egypt. AB - Sixty specimens of African sharptooth catfish Clarias gariepinus (Clariidae) were collected during the period of March 2014-February 2015 from boat landing sites and fishermen of the River Nile at Beni Suef Governorate, Egypt, and examined for the presence of digenean parasites. The morphology of these parasites was studied by using light microscopy to describe morphological and morphometrically measurements for different body parts. Three digenean species belonging to three different genera were collected from various organs within the examined fish species. A certain degree of site specificity was also observed, with Thaparotrema botswanensis being found only in the gall bladder of C. gariepinus, while both Pseudoholorchis clarii and Glossidium pedatum were found only in the intestine and thus seem to occupy a certain niche within their host. This study represent as the first record of T. botswanensis and G. pedatum from C. gariepinus, as well as the first report of the genera from the River Nile in Egypt. In addition, re-description of P. clarii clarifies measurements for some body parts. PMID- 27481173 TI - Is there a group of patients at greater risk for hematoma following thyroidectomy? A systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this study was to perform a systematic review and meta analysis to determine whether a difference exists in hematoma rates following thyroidectomy for any of the following subgroups of patients: Graves disease, toxic nodular goiter (TNG), and malignancy. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic literature search was performed for all relevant English and French language studies (1946-2015) using Ovid MEDLINE, EMBASE, and PubMed. Three authors independently extracted data and analyzed articles for quality using the Newcastle-Ottawa Quality Assessment Scale. Our primary outcome of interest was hematoma requiring re-operation. RESULTS: A total of 301 studies were screened, with 11 studies meeting the inclusion criteria. The results of our analysis demonstrated that Graves disease is the only indication for thyroidectomy that appears to have an increased risk of postoperative hematoma formation, pooled odds ratio = 1.58 (1.09-2.31); P = 0.02. Malignancy and TNG did not demonstrate significantly higher rates of postoperative hematoma formation. CONCLUSION: This study demonstrates that of patients undergoing thyroidectomy, Graves disease is the only indication in which patients are at increased risk of postoperative hematoma formation. This information may help guide future decisions regarding the implementation of outpatient thyroidectomy. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1483-1490, 2017. PMID- 27481174 TI - 68Ga-labeled Prostate-specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Imaging: The New Kid on the Block-Early or Too Early to Draw Conclusions? PMID- 27481175 TI - Association of Radical Local Treatment with Mortality in Men with Very High-risk Prostate Cancer: A Semiecologic, Nationwide, Population-based Study. AB - BACKGROUND: Current guidelines recommend androgen deprivation therapy only for men with very high-risk prostate cancer (PCa), but there is little evidence to support this stance. OBJECTIVE: To investigate the association between radical local treatment and mortality in men with very high-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: Semiecologic study of men aged <80 yr within the Prostate Cancer data Base Sweden, diagnosed in 1998-2012 with very high-risk PCa (local clinical stage T4 and/or prostate-specific antigen [PSA] level 50-200ng/ml, any N, and M0). Men with locally advanced PCa (local clinical stage T3 and PSA level <50ng/ml, any N, and M0) were used as positive controls. INTERVENTION: Proportion of men who received prostatectomy or full-dose radiotherapy in 640 experimental units defined by county, diagnostic period, and age at diagnosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCa and all-cause mortality rate ratios (MRRs). RESULTS AND LIMITATIONS: Both PCa and all-cause mortality were half as high in units in the highest tertile of exposure to radical local treatment compared with units in the lowest tertile (PCa MRR: 0.51; 95% confidence interval [CI], 0.28-0.95; and all-cause MRR: 0.56; 95% CI, 0.33-0.92). The results observed for locally advanced PCa for highest versus lowest tertile of exposure were in agreement with results from randomized trials (PCa MRR: 0.75; 95% CI, 0.60-0.94; and all-cause MRR: 0.85; 95% CI, 0.72-1.00). Although the semiecologic design minimized selection bias on an individual level, the effect of high therapeutic activity could not be separated from that of high diagnostic activity. CONCLUSIONS: The substantially lower mortality in units with the highest exposure to radical local treatment suggests that radical treatment decreases mortality even in men with very high-risk PCa for whom such treatment has been considered ineffective. PATIENT SUMMARY: Men with very high-risk prostate cancer diagnosed and treated in units with the highest exposure to surgery or radiotherapy had a substantially lower mortality. PMID- 27481176 TI - Alternative Splicing Provides a Novel Molecular Mechanism for Prostatic Small cell Neuroendocrine Carcinoma. PMID- 27481177 TI - Male Lower Urinary Tract Symptoms Reveal and Predict Important Cardiovascular Disease. PMID- 27481178 TI - Local Therapy for Gleason 9-10 Prostate Cancer: Looking to the Future. PMID- 27481179 TI - Re: The Initial Detection and Partial Characterization of Circulating Tumor Cells in Neuroendocrine Prostate Cancer. PMID- 27481180 TI - Re: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. PMID- 27481181 TI - Varicocele in a Young Man: Something We Should Be Worried About? PMID- 27481182 TI - Whether heart blocks post perimembranous ventricular septal defect device closure remain threatening: how could Chinese experiences impact the world? AB - Transcatheter closure has become one of the alternations of surgical treatment since 1988. However, cAVB occurred as a threatening incidence of 6.8% after Amplatzer VSD Occluder closure, which was quite higher than the incidence of 1% to 2% post-surgical closure, which leaded this kind of technique, was not approved by FDA. In this commentary, we reviewed the publications of cAVB following the device closure, and summarized current data of Modified Amplatzer type Occluder during long-term follow-up, especially introduced the experiences from China, where this kind of treatment became a routine procedure for VSD children. Moreover, we carried our visualized analysis based on scientific literatures using CiteSpace to draw knowledge burst mapping, which revealed the development procedure on this interested topics, and demonstrated the role of China's works to make contributions in the field, and figured out the limitation of our researches, which supplied a basic understanding on why we could not impact the world. Finally, it concluded that transcatheter closure of pmVSD with Modified Amplatzer-type Occluder would be safe and efficient with low incidence of well controlled complications, but it failed to spread our experiences in a more scientific way. And, we hope this kind of therapy could be accepted in a wider region of the world with the increasing evidence from China. PMID- 27481184 TI - A review of postoperative analgesia for breast cancer surgery. AB - An online database search with subsequent article review was performed in order to review the various analgesic modalities for breast cancer surgery. Of 514 abstracts, 284 full-length manuscripts were reviewed. The effect of pharmacologic interventions is varied (NSAIDS, opioids, anticonvulsants, ketamine, lidocaine). Likewise, data from high-quality randomized, controlled studies on wound infiltration (including liposome encapsulated) and infusion of local anesthetic are minimal and conflicting. Conversely, abundant evidence demonstrates paravertebral blocks and thoracic epidural infusions provide effective analgesia and minimize opioid requirements, while decreasing opioid-related side effects in the immediate postoperative period. Other techniques with promising - but extremely limited - data include cervical epidural infusion, brachial plexus, interfascial plane and interpleural blocks. In conclusion, procedural interventions involving regional blocks are more conclusively effective than pharmacologic modalities in providing analgesia to patients following surgery for breast cancer. PMID- 27481185 TI - Post-translational regulation of RORgammat-A therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune diseases. AB - Retinoic acid-related orphan receptor gamma t (RORgammat) is a nuclear receptor, which is selectively expressed by various lymphocytes. RORgammat is critical for the development of secondary and tertiary lymphoid organs, and for the thymic development of the T cell lineage. RORgammat has been extensively studied as the master transcription factor of IL-17 expression and Th17 cells, which are strongly associated with various inflammatory and autoimmune conditions. Given its essential role in promoting pro-inflammatory responses, it is not surprising that the expression of RORgammat is tightly controlled. By its nature as a nuclear receptor, RORgammat activity is also regulated in a ligand-dependent manner, which makes it an attractive drug target. In addition, multiple post translational mechanisms, including post-translational modifications, such as acetylation and ubiquitinylation, as well as interactions with various co factors, modulate RORgammat function. Here we attempt a comprehensive review of the post-translational regulation of RORgammat, an area that holds the potential to transform the way we target the RORgammat/IL-17 pathway, by enabling the development of safe and highly selective modulators of RORgammat activity. PMID- 27481183 TI - Stress kinases, endoplasmic reticulum stress, and Alzheimer's disease related markers in peripheral blood mononuclear cells from subjects with increased body weight. AB - We aimed to characterize endoplasmic reticulum stress, inflammation, and Alzheimer's disease (AD) related markers in peripheral blood mononuclear cells (PBMCs) from males with varied BMI; and to explore whether high glucose and fatty acids (FFAs) might be critical factors for inducing metabolic alterations in PBMCs under obese condition. Approximately 45 middle-aged men were enrolled with varied BMI. At the protein expression level, compared to the lean, the phosphorylation of AMPK, and p-Akt at serine 473 were significantly reduced from the overweight (OW) and/or obese (OB); while the protein expression of p-JNK, cleaved caspase 3, CHOP and p-eIF2alpha were elevated from the OW and/or OB. At the mRNA expression level, ER stress markers (i.e. GRP78, CHOP and XBP-1), inflammatory markers (i.e.TLR2, TLR4 and CCR2) and AD markers (i.e. APP, PS1 and PS2) were significantly higher in PBMCs from OB compared to lean. In cultured PBMCs, high glucose and FFAs induced GRP78, CHOP and XBP-1 mRNA, and high glucose also induced APP, PS1 and PS2 mRNA. In conclusion, altered markers including AMPK, ER stress and AD related makers under obese condition could be easily obtained from PBMCs. These markers might provide new mechanistic links between obesity and other metabolic complications including AD. PMID- 27481186 TI - Reduced susceptibilities to biocides and resistance to antibiotics in food associated bacteria following exposure to quaternary ammonium compounds. AB - AIMS: Our aim was to assess the effects of step-wise exposure to didecyl dimethyl ammonium chloride (DDAC) on the antimicrobial (antibiotics and biocides) susceptibilities of food-associated bacterial strains. METHODS AND RESULTS: Adaptive responses of bacterial strains were investigated by exposing the strains daily to increasing subinhibitory concentrations of DDAC for 7 days. Following adaptation to DDAC, a threefold increase in the minimum inhibitory concentration (MIC) values for this biocide was observed in 48% of the Escherichia coli and Listeria monocytogenes strains, and 3% of the Salmonella strains. Reduced susceptibility to other biocides was found with the most important increase in MIC for benzalkonium chloride (BC) and a commercial biocide formulation (Galox Horizon) containing DDAC and glutaraldehyde, for all species except Salmonella. Increase in antibiotic MIC values was more pronounced in E. coli in terms of antibiotic numbers and of magnitude (from 4- to 32-fold increase) and, to a lesser extent, in Salmonella strains. Most of these strains had acquired resistance to ampicillin, cefotaxime, ceftazidime, chloramphenicol and ciprofloxacin. CONCLUSIONS: The effects of exposure to DDAC on biocides and antibiotics susceptibilities depend upon the bacteria species. SIGNIFICANCE AND IMPACT OF THE STUDY: Extensive use of DDAC at subinhibitory concentrations may lead to the development of antibiotic-resistant bacteria and may represent a public health issue. PMID- 27481187 TI - Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes. AB - Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern. (c) 2016 Wiley Periodicals, Inc. PMID- 27481188 TI - A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis. AB - STUDY DESIGN: Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) studies. METHODS: The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor. RESULTS: In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%-10.9%] vs 45.6% [28.9%-72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit. CONCLUSION: Bicarbonate markedly enhances the anticancer activity of TACE.Clinical trail registration: ChiCTR-IOR-14005319. PMID- 27481190 TI - Insured Veterans' Use of VA and Non-VA Health Care in a Rural State. AB - PURPOSE: To understand how working-age VA-enrolled veterans with commercial insurance use both VA and non-VA outpatient care, and how rural residence affects dual use, for common diagnoses and procedures. METHODS: We analyzed VA and non-VA outpatient treatment records for any months during 2005-2010 that New Hampshire veterans ages <65 were simultaneously enrolled in VA health care and commercial insurance (per NH's mandatory claims database). Controlling for covariates, we used analysis of variance to compare urban and rural VA users, non-VA users, and dual users on travel burden, diagnosis counts, duration in outpatient care, and visit frequencies, and logistic regressions to assess whether rural veterans were as likely to be seen for common conditions and procedures. FINDINGS: More than half of patients were non-VA users and another third were dual users; rural residents were slightly more likely than urban residents to be dual users. For nearly any common diagnosis or procedure, dual users were more likely to have it at some time during treatment than other patients in either VA or non-VA care, but they seldom had it listed in both care systems. Dual users also were seen most often overall, although within either care system they were seen less often than other patients, particularly if they were rural residents living far from care. Rural residence reduced chances of treatment for a wide variety of conditions, though it also was associated with more musculoskeletal and connective tissue diagnoses. It also reduced chances that patients had some diagnostic and treatment procedures but increased the odds of others that may require fewer visits. CONCLUSIONS: Dual users living in rural areas may have less continuity in their health care. Ensuring that rural dual users are identified in primary care should improve access and care coordination. PMID- 27481189 TI - Place recognition using batlike sonar. AB - Echolocating bats have excellent spatial memory and are able to navigate to salient locations using bio-sonar. Navigating and route-following require animals to recognize places. Currently, it is mostly unknown how bats recognize places using echolocation. In this paper, we propose template based place recognition might underlie sonar-based navigation in bats. Under this hypothesis, bats recognize places by remembering their echo signature - rather than their 3D layout. Using a large body of ensonification data collected in three different habitats, we test the viability of this hypothesis assessing two critical properties of the proposed echo signatures: (1) they can be uniquely classified and (2) they vary continuously across space. Based on the results presented, we conclude that the proposed echo signatures satisfy both criteria. We discuss how these two properties of the echo signatures can support navigation and building a cognitive map. PMID- 27481192 TI - 1'-Acetoxychavicol acetate ameliorates age-related spatial memory deterioration by increasing serum ketone body production as a complementary energy source for neuronal cells. AB - 1'-Acetoxychavicol acetate (ACA) is naturally obtained from the rhizomes and seeds of Alpinia galangal. Here, we examined the effect of ACA on learning and memory in senescence-accelerated mice prone 8 (SAMP8). In mice that were fed a control diet containing 0.02% ACA for 25 weeks, the learning ability in the Morris water maze test was significantly enhanced in comparison with mice that were fed the control diet alone. In the Y-maze test, SAMP8 mice showed decreased spontaneous alterations in comparison with senescence-accelerated resistant/1 (SAMR1) mice, a homologous control, which was improved by ACA pretreatment. Serum metabolite profiles were obtained by GC-MS analysis, and each metabolic profile was plotted on a 3D score plot. Based upon the diagram, it can be seen that the distribution areas for the three groups were completely separate. Furthermore, the contents of beta-hydroxybutyric acid and palmitic acid in the serum of SAMP8 ACA mice were higher than those of SAMP8-control mice and SAMR1-control mice. We also found that SAMR1 mice did not show histological abnormalities, whereas histological damage in the CA1 region of the hippocampus in SAMP8-control mice was observed. However, SAMP8-ACA mice were observed in a similar manner as SAMR1 mice. These findings confirm that ACA increases the serum concentrations of beta hydroxybutyric acid and palmitic acid levels and thus these fuels might contribute to the maintenance of the cognitive performance of SAMP8 mice. PMID- 27481191 TI - Suppressive effects of three diketopiperazines from marine-derived bacteria on polyphosphate-mediated septic responses. AB - Diketopiperazine is a natural products found from bacteria, fungi, marine sponges, gorgonian and red algae. They are cyclic dipeptides possessing relatively simple and rigid structures with chiral nature and various side chains. The compounds in this structure class have been known to possess diverse bioactivities including antibiotic activity, anti-cancer activity, neuroprotective activity, and anti-inflammatory activity. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of diketopiperazine and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Diketopiperazine suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-kappaB, tumor necrosis factor alpha, and interleukin-6. Furthermore, diketopiperazine demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of diketopiperazine on various systemic inflammatory diseases, such as sepsis or septic shock. PMID- 27481193 TI - Ramalin inhibits differentiation of 3T3-L1 preadipocytes and suppresses adiposity and body weight in a high-fat diet-fed C57BL/6J mice. AB - Obesity is a serious global health problem. Natural substances that could be effective remedies for treatment of obesity, and which are relatively safe, are desired. The aim of this study was to examine the anti-obesity effect and the mechanism of ramalin in 3T3-L1 preadipocytes and high fat diet (HFD)-induced obese mice. In this study, 3T3-L1 cells were treated with various concentrations of ramalin (1, 5, and 10 MUg/ml). Ramalin reduced the accumulation of intracellular lipid droplets in 3T3-L1 cells. In addition, ramalin inhibited 3T3 L1 adipocyte differentiation by blocking adipogenic gene expression including CCAAT enhancer binding proteins (C/EBPs), peroxisome proliferator-activated receptors gamma (PPARgamma), adipocyte fatty acid-binding protein (aP2), and leptin. The suppression of adipogenesis by ramalin was mediated through the inhibition of MAPK pathways. Ramalin also reduced the secretion of TNF-alpha and IL-6 in 3T3-L1 adipocytes. Oral administration of ramalin (50 and 100 mg/kg) to HFD-fed mice reduced body weight gain and abdominal fat accumulation without changes in food intake. Ramalin also attenuated organ weight and basal serum level by inhibiting Iiver X receptors (LXRs), sterol regulatory element-binding protein-1c (SREBP-1c), and lipoprotein lipase (LPL) mRNA expression in HFD-fed mice. Taken together, these results indicate that ramalin inhibits adipogenesis in 3T3-L1 preadipocytes and prevents HFD-induced obesity. The present study also provides insight into the mechanisms underlying the anti-obesity activity of ramalin and suggests that ramalin has the potential to prevent obesity. PMID- 27481194 TI - [Angiology is moving forward]. AB - Vascular medicine treats many diseases - ischemic syndromes of different arterial bed (with the specifics of their territorial function), venous and lymphatic diseases. A number of states in angiology are urgent, potentially life-threating. Examples include aneurysm rupture, acute limb ischemia, or deep vein thrombosis and pulmonary embolism.On the other hand, chronic vascular disease (eg., peripheral arterial disease or chronic disease of superficial veins) require a differentiated approach according to the manifestation and the emphasis is given on prevention and treatment of disposing conditions.The optimal care for patients bring the specialist in vascular medicine who is able to build a diagnostic and treatment work-up quickly. He works closely with vascular surgeons and interventional radiologists.The article gives an overview of the major innovations in the field of angiology. PMID- 27481195 TI - [SPRINT study: far lower systolic blood pressure]. AB - There is still no consensus, which blood pressure value is the most profitable for the patients when treating the systolic hypertension in the context of reduction of cardiovascular events and cardiovascular and overall mortality.Researchers of the ACCORD study were comparing intensive treatment of systolic blood pressure bellow 120 mmHg and standard treatment reaching bellow 140 mmHg and showed no influence of intensive treatment on the primary goal in individuals with diabetes mellitus.Last autumn, SPRINT study was presented and published showing the favourable effect of intensive (i. e. bellow 120 mmHg) blood pressure lowering on combined primary goal which was myocardial infarction, other acute coronary syndromes, ischemic stroke, heart failure or death from cardiovascular reasons. On the other hand, intensive treatment also resulted in statistically significant occurrence of adverse events (hypotension, syncope, renal injury of failure). PMID- 27481196 TI - [Matrix Gla protein as natural inhibitor of vascular calcification and potential treatment target]. AB - Vascular calcification was once regarded as an advanced stage of atherosclerosis only. However, calcification is currently considered as highly regulated and potentially reversible process.Matrix Gla protein (MGP) represents natural inhibitor of vascular calcification, whereas vitamin K is key co-factor of its maturation to the active form. There is accumulating evidence that vitamin K status and corresponding MGP activity may influence cardiovascular risk. This review summarizes pathophysiological mechanism and recent evidence relative to MGP. Moreover, available data concerning vitamin K supplementation are depicted. PMID- 27481197 TI - [Functional assessment of coronary stenosis by fractional flow reserve]. AB - Revascularization of coronary artery stenosis should be based on the objective evidence of ischemia. Coronary angiography provides excellent spatial and temporal resolution for the visualization of the coronary arteries, but is of limited value in defining the functional significance of a particular lesion.Fractional flow reserve (FFR) has become routine practice in the cardiac catheterization laboratory and is considered nowadays as the gold standard for invasive assessment of physiologic stenosis significance. This paper reviews the concepts behind the coronary physiology and FFR, its practical application and summarizes current evidence from key clinical trials. PMID- 27481198 TI - [Idiopathic pulmonary fibrosis prognostic factors - analysis of the Czech registry]. AB - Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and usually fatal form of idiopathic interstitial pneumonia. IPF is characterized by failure of alveolar re-epithelization, persistence of fibroblasts, deposition of extracellular matrix, and distortion of lung architecture, which ultimately results in respiratory failure.We analysed 202 consecutive patients with IPF diagnosed at the Departments of Pulmonary Diseases and Tuberculosis in the Czech Republic, who they were included in the nationwide Czech IPF registry. Our aim was to determine prognostic factors of IPF and outcome of the disease.There were 129 males and 73 females who were the median age 67 years. IPF was biopsy-proven in 66 (33 %) of patients. Median time from the first symptom to diagnosis was 12 months. Diagnosis was made in 57 patients (28.3 %) within 6 months from the onset of respiratory symptoms. 8 (4 %) patients had an acute exacerbation during the course of the disease.In uniparametric (univariate) analysis as prognostic factors associated with poorer survival were found: higher age, higher degree dyspnea scores, clubbing fingers, comorbidities (arterial hypertension, osteoporosis), patients without histology biopsy, and bronchoalveolar increased neutrophil count. We found these positive prognostic factors: higher levels of VC (vital capacity), TLC (total lung capacity) and DLCO (diffusing capacity for carbon monooxide).In multiparametric (multivariate) analysis as prognostic factors associated with mortality were found: higher age, higher degree of dyspnoe score. Increased lymphocytes in bronchoalveolar fluid, higher level of VC a DLCO were associated with better survival. There was no difference in survival of patients by sex, by smoking status. No significant difference in survival rates was found between IPF with and without emphysema, between the extent of fibrosis on HRCT (high resolution computed tomography) of thorax and mortality. Median survival was 51.6 months. 58 (28.7 %) patients died. The most frequent reason of dead was IPF progression with respiratory failure. KEY WORDS: Idiopathic pulmonary fibrosis; prognosis; treatment. PMID- 27481199 TI - [Dermatomyositis]. AB - Dermatomyositis is an idiopathic inflammatory disease affecting proximal skeletal muscles and the skin. The manifestation can be acute (over weeks) or chronic (over months to years). Dermatomyositis affects children as well as adults. Very helpful for the diagnosis are laboratory, clinical, EMG and histopathological tests. The disease responds positively to corticosteroid, immunosuppressive or immunoglobulin therapy. Three various cases of DM are described in this article. KEY WORDS: dermatomyositis , symptoms, diagnostic criteria, treatment. PMID- 27481200 TI - [The importance of HPV vaccination in men]. AB - The important goal of immunization programs in many countries is the reduction of the incidence of cervical cancer using either the quadrivalent (Silgard/Gardasil) or the bivalent (Cervarix) HPV (human papillomavirus) vaccine. Nevertheless, HPV infection is associated with the development of cancers of anus, vagina, vulva and penis, and cancers of the head and neck and genital warts, too. Large trials for both vaccines find efficacy against HPV-related infection and different HPV associated diseases.Infection with HPV and diseases caused by HPV are common in boys and men, too. Approximately 5.2 % of all cancers are HPV associated and the burden of HPV associated disease in men is now comparable to that in women in economically developed countries. Randomized control trials demonstrate robust antibody responses and high efficacy also in men. Several countries recommend gender-neutral vaccination.Detailed cost effective modeling has preceded these decisions showing that when the burden of disease in men is included in the models then, depending upon vaccine price, coverage of a vaccinated population, and other factors male vaccination can become cost effective. Vaccine price had a decisive impact on results. However, increasing coverage in girls is substantially more effective and cost-effective than expanding vaccination coverage to boys and should be considered a priority. Since 2012, vaccination of girls at the age of 13-14 years has been covered from the health insurance in the Czech Republic. PMID- 27481201 TI - [Psychiatry in everyday life]. AB - Severe mental disorders including its main representative schizophrenia are chronic lifelong diseases. Most patients like those with somatic disease can live in the society under certain conditions as continuous psychopharmacotherapy and availability of community services. Similarly as in somatic medicine a great attentions is devoted to the individualized treatment.Psychotic disorders have some specific features, like lack of insight associated with poor adherence. Nowadays we have a possibility of an objective adherence evaluation by plasma levels measurement and the depots, long-action injections of antipsychotics (including the second generation antipsychotics), are available. Unfortunately this modern approach is restricted by insurance companies.In spite of the fact that therapeutic drug monitoring is an advantageous tool for treatment optimization this interdisciplinary service is in many faculty and regional hospitals not provided. Providers of health care should realise that accessibility of some services and medication could reduce the danger of untreated psychosis. PMID- 27481202 TI - [End-of-life care in the Czech Republic]. AB - Rapid demographic changes and rising prevalence of chronic disease bring about changing demands on health and social care. Declining mortality in higher age groups and increasing life expectancy results in changing structure of users of health services, the structure of causes of death and, of course, in the age distribution of deaths. The Czech Republic is among the countries with the most rapidly aging populations.Although large majority of people wish to age and also to die at home, in 2012, nearly three-quarters of people died in a hospital or other health and social facilities. Despite the deteriorating health of residents of residential social services and the high and increasing number of people dying in those institutions, the availability and quality of health care in those facilities is very problematic. Palliative care and long-term care should respond to the changing needs of our population, arising from rapidly ageing population and increasing prevalence of chronic diseases, regardless of whether such care is provided in health or social care facilities. PMID- 27481203 TI - [Validation of a questionnaire for standardized-patient assessment of clinical skills]. AB - BACKGROUND: This study was designed in the context of a new educational program based on standardized-patients (SPs). The study objectives were (1) to evaluate the reliability of the assessment form used by SPs and (2) to compare global ratings to checklists reproducibility. METHOD: History taking, physical examination and communication skills were assessed by SPs at the end of clinical encounters with year 3 medical students, using generic global rating scales and case-specific checklists. The validation process followed four steps: (1) correlation analysis between global rating and their relative checklist of specific items, (2) internal consistency estimation, (3) validation of the questionnaire dimensions, (4) estimation of the reliability of SPs' ratings compared to medical teachers' ratings. RESULTS: A total of 3322 consultations have been performed by 444 year 3 medical students. Statistical analysis showed a good internal reliability (Cronbach alpha was greater than 0.7) and an acceptable inter-judge reproducibility except for communication skills. Case-specific checklists did not prove to be more reliable than global ratings. Reproducibility was lower with SPs' than with medical teachers' assessment. CONCLUSION: Global rating-based assessment should be preferred to checklists because they are faster and easier to use (shorter duration of SPs training). As SPs proved to be acceptable examiners, no third person seems to be required as external observer. PMID- 27481204 TI - Hydrothermal Synthesis of a rGO Nanosheet Enwrapped NiFe Nanoalloy for Superior Electrocatalytic Oxygen Evolution Reactions. AB - Graphene-based hybrid nanostructures possess many advantages in the field of electrochemical energy applications. In this work, a facile and efficient hydrothermal approach has been developed for the preparation of NiFe alloy nanoparticles/rGO hybrid nanostructures, in which the nanoparticles are well combined with rGO nanosheets and the size of the nanoparticles is about 100 nm. Moreover, the electrochemical oxygen evolution reaction (OER) tests confirmed that the obtained NiFe/rGO hybrid nanostructures possess notably higher activity than both the rGO-free NiFe nanoparticles and pure Ni/rGO hybrids, and the optimal NiFe ratio is 2:1. The OER overpotential at 20 mA cm(-1-2) with Ni2 Fe/rGO is as low as 0.285 V, which is 96 mV lower than that of pure Ni/rGO hybrids. Meanwhile, the Ni2 Fe/rGO catalyst has excellent stability. Therefore, this work contributes a facile and efficient method to prepare a NiFe alloy nanoparticles/rGO hybrid structure for potential applications in the field of electrochemical energy devices, such as electrochemical water splitting cells, rechargeable metal/air batteries, etc. PMID- 27481205 TI - Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets. AB - BACKGROUND: Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS). OBJECTIVE: To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of distinct circulating T-helper cell subset as well as their innate counterparts. METHODS: Flow cytometric analysis of lymphocytes derived from the peripheral blood of patients with exclusively cerebral (n = 20) or predominantly spinal (n = 12) disease manifestation. RESULTS: Patients with exclusively cerebral or preferential spinal lesion manifestation were associated with increased proportions of circulating granulocyte-macrophage colony stimulating factor (GM-CSF) producing TH1 cells or interleukin (IL)-17-producing TH17 cells, respectively. In contrast, proportions of peripheral IL-17/IL-22 producing lymphoid tissue inducer (LTi), the innate counterpart of TH17 cells, were enhanced in RRMS patients with exclusively cerebral lesion topography. CONCLUSIONS: Distinct T-helper and T-helper-like innate lymphoid cell (ILC) subsets are associated with different lesion topography in RRMS. PMID- 27481206 TI - High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial. AB - BACKGROUND: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). OBJECTIVE: To evaluate a treatment effect of EPO on progressive MS. METHODS: This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks. RESULTS: A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle ( p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences. CONCLUSION: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS. PMID- 27481207 TI - ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis. AB - BACKGROUND: Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate efficacy and safety of abatacept in RRMS. METHODS: ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks. RESULTS: No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated. CONCLUSION: The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS. PMID- 27481208 TI - Improvement of spasticity following intermittent theta burst stimulation in multiple sclerosis is associated with modulation of resting-state functional connectivity of the primary motor cortices. AB - BACKGROUND: Intermittent theta burst stimulation (iTBS) of the primary motor cortex improves transiently lower limbs spasticity in multiple sclerosis (MS). However, the cerebral mechanisms underlying this effect have never been investigated. OBJECTIVE: To assess whether modulation of spasticity induced by iTBS is underlined by functional reorganization of the primary motor cortices. METHODS: A total of 17 patients with MS suffering from lower limbs spasticity were randomized to receive real iTBS or sham iTBS during the first half of a 5 week indoor rehabilitation programme. Spasticity was assessed using the Modified Ashworth Scale and the Visual Analogue Scale at baseline, after the stimulation session and at the end of the rehabilitation programme. Resting-state functional magnetic resonance imaging (fMRI) was performed at the three time points, and brain functional networks topology was analysed using graph-theoretical approach. RESULTS: At the end of stimulation, improvement of spasticity was greater in real iTBS group than in sham iTBS group ( p = 0.026). iTBS had a significant effect on the balance of the connectivity degree between the stimulated and the homologous primary motor cortex ( p = 0.005). Changes in inter-hemispheric balance were correlated with improvement of spasticity (rho = 0.56, p = 0.015). CONCLUSION: This longitudinal resting-state fMRI study evidences that functional reorganization of the primary motor cortices may underlie the effect of iTBS on spasticity in MS. PMID- 27481209 TI - Data quality evaluation for observational multiple sclerosis registries. AB - OBJECTIVE: Objective and reproducible evaluation of data quality is of paramount importance for studies of 'real-world' observational data. Here, we summarise a standardised data quality, density and generalisability process implemented by MSBase, a global multiple sclerosis (MS) cohort study. METHODS: Error rate, data density score and generalisability score were developed using all 35,869 patients enrolled in MSBase as of November 2015. The data density score was calculated across six domains (follow-up, demography, visits, MS relapses, paraclinical data and therapy) and emphasised data completeness. The error rate evaluated syntactic accuracy and consistency of data. The generalisability score evaluated believability of the demographic and treatment information. Correlations among the three scores and the number of patients per centre were evaluated. RESULTS: Errors were identified at the median rate of 3 per 100 patient-years. The generalisability score indicated the samples' representativeness of the known MS epidemiology. Moderate correlation between the density and generalisability scores (rho = 0.58) and a weak correlation between the error rate and the other two scores (rho = -0.32 to -0.33) were observed. The generalisability score was strongly correlated with centre size (rho = 0.79). CONCLUSION: The implemented scores enable objective evaluation of the quality of observational MS data, with an impact on the design of future analyses. PMID- 27481211 TI - The gust-mitigating potential of flapping wings. AB - Nature's flapping-wing flyers are adept at negotiating highly turbulent flows across a wide range of scales. This is in part due to their ability to quickly detect and counterract disturbances to their flight path, but may also be assisted by an inherent aerodynamic property of flapping wings. In this study, we subject a mechanical flapping wing to replicated atmospheric turbulence across a range of flapping frequencies and turbulence intensities. By means of flow visualization and surface pressure measurements, we determine the salient effects of large-scale freestream turbulence on the flow field, and on the phase-average and fluctuating components of pressure and lift. It is shown that at lower flapping frequencies, turbulence dominates the instantaneous flow field, and the random fluctuating component of lift contributes significantly to the total lift. At higher flapping frequencies, kinematic forcing begins to dominate and the flow field becomes more consistent from cycle to cycle. Turbulence still modulates the flapping-induced flow field, as evidenced in particular by a variation in the timing and extent of leading edge vortex formation during the early downstroke. The random fluctuating component of lift contributes less to the total lift at these frequencies, providing evidence that flapping wings do indeed provide some inherent gust mitigation. PMID- 27481210 TI - Association of asymptomatic spinal cord lesions and atrophy with disability 5 years after a clinically isolated syndrome. AB - BACKGROUND: Spinal cord pathology is an important substrate for long-term disability in multiple sclerosis (MS). OBJECTIVE: To investigate longitudinal changes in spinal cord lesions and atrophy in patients with a non-spinal clinically isolated syndrome (CIS), and how they relate to the development of disability. METHODS: In all, 131 patients with a non-spinal CIS had brain and spinal cord imaging at the time of CIS and approximately 5 years later (median: 5.2 years, range: 3.0-7.9 years). Brain magnetic resonance imaging (MRI) measures consisted of T2-hyperintense and T1-hypointense lesion loads plus brain atrophy. Spinal cord MRI measures consisted of lesion number and the upper cervical cord cross-sectional area (UCCA). Disability was measured using the Expanded Disability Status Scale (EDSS). Multiple linear regression was used to identify independent predictors of disability after 5 years. RESULTS: During follow-up, 93 (71%) patients were diagnosed with MS. Baseline spinal cord lesion number, change in cord lesion number and change in UCCA were independently associated with EDSS ( R2 = 0.53) at follow-up. Including brain T2 lesion load and brain atrophy only modestly increased the predictive power of the model ( R2 = 0.64). CONCLUSION: Asymptomatic spinal cord lesions and spinal cord atrophy contribute to the development of MS-related disability over the first 5 years after a non-spinal CIS. PMID- 27481212 TI - Synthesis of Arbitrary Quantum Circuits to Topological Assembly. AB - Given a quantum algorithm, it is highly nontrivial to devise an efficient sequence of physical gates implementing the algorithm on real hardware and incorporating topological quantum error correction. In this paper, we present a first step towards this goal, focusing on generating correct and simple arrangements of topological structures that correspond to a given quantum circuit and largely neglecting their efficiency. We detail the many challenges that will need to be tackled in the pursuit of efficiency. The software source code can be consulted at https://github.com/alexandrupaler/tqec. PMID- 27481213 TI - Nanofiber-expanded stem cells mitigate liver fibrosis: Experimental study. AB - OBJECTIVES: This study examines a pretreatment strategy to strengthen the hepatic lineage divergence of mesenchymal stem cells (MSCs). DESIGN AND METHODS: BMSCs were expanded in the presence or absence of nanofiber (NF) and treated with growth factors (GF) prior to transplantation. Thioacetamide (TA) was used for liver fibrosis induction and transplantation of NF-expanded BMSCs was compared biochemically and histologically to the cells expanded without NF scaffold. RESULTS: The ultraweb NF caused better proliferation and characterization of MSCs. MSCs transplantation significantly improved liver functions, increased hepatic HGF and Bcl-2 levels, whereas decreased serum fibronectin, hepatic TNF alpha and TGF-beta1 levels. Hepatic HNF4alpha, FOXa2, CYP7a1 genes expression were enhanced while beta-5-Tub and AFP genes expression were depressed. Histological study documented these results. Differentiated NF-MSCs showed pronounced enhancement of the aforementioned parameters as compared to differentiated MSCs in the absence of NF. CONCLUSION: pretreatment with growth factors in the presence of NF augment homing, repopulation and hepatic differentiation abilities of MSCs and proves to be a promising approach for the treatment of liver fibrosis. PMID- 27481214 TI - Mechanistic stratification in electroactive biofilms of Geobacter sulfurreducens mediated by pilus nanowires. AB - Electricity generation by Geobacter sulfurreducens biofilms grown on electrodes involves matrix-associated electron carriers, such as c-type cytochromes. Yet, the contribution of the biofilm's conductive pili remains uncertain, largely because pili-defective mutants also have cytochrome defects. Here we report that a pili-deficient mutant carrying an inactivating mutation in the pilus assembly motor PilB has no measurable defects in cytochrome expression, yet forms anode biofilms with reduced electroactivity and is unable to grow beyond a threshold distance (~10 MUm) from the underlying electrode. The defects are similar to those of a Tyr3 mutant, which produces poorly conductive pili. The results support a model in which the conductive pili permeate the biofilms to wire the cells to the conductive biofilm matrix and the underlying electrode, operating coordinately with cytochromes until the biofilm reaches a threshold thickness that limits the efficiency of the cytochrome pathway but not the functioning of the conductive pili network. PMID- 27481216 TI - Highly effective synthesis of NiO/CNT nanohybrids by atomic layer deposition for high-rate and long-life supercapacitors. AB - In this work, we report an atomic layer deposition (ALD) method for the fabrication of NiO/CNT hybrid structures in order to improve electronic conductivity, enhance cycling stability and increase rate capability of NiO used as supercapacitor electrodes. A uniform NiO coating can be well deposited on carbon nanotubes (CNTs) through simultaneously employing O3 and H2O as oxidizing agents in a single ALD cycle of NiO for the first time, with a high growth rate of nearly 0.3 A per cycle. The electrochemical properties of the as-prepared NiO/CNT were then investigated. The results show that the electrochemical capacitive properties are strongly associated with the thickness of the NiO coating. The NiO/CNT composite materials with 200 cycles of NiO deposition exhibit the best electrochemical properties, involving high specific capacitance (622 F g(-1) at 2 A g(-1), 2013 F g(-1) for NiO), excellent rate capability (74% retained at 50 A g(-1)) and outstanding cycling stability. The impressive results presented here suggest a great potential for the fabrication of composite electrode materials by atomic layer deposition applied in high energy density storage systems. PMID- 27481215 TI - Synergies between assisted reproduction technologies and functional genomics. AB - This review, is a synopsis of advanced reproductive technologies in farm animals, including the discussion of their limiting factors as revealed by the study of offspring derived from embryos produced in vitro and through cloning. These studies show that the problems of epigenetic mis-programming, which were reported in the initial stages of assisted reproduction, still persist. The importance of whole-genome analyses, including the methylome and transcriptome, in improving embryo biotechnologies in farm animals, are discussed. Genome editing approaches for the improvement of economically-relevant traits in farm animals are also described. Efficient farm animal embryo biotechnologies, including cloning and the most recent technologies such as genome editing, will effectively complement the latest strategies to accelerate genetic improvement of farm animals. PMID- 27481217 TI - Iron overload-induced calcium signals modulate mitochondrial fragmentation in HT 22 hippocampal neuron cells. AB - Iron is necessary for neuronal functions; however, excessive iron accumulation caused by impairment of iron balance could damage neurons. Neuronal iron accumulation has been observed in several neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nevertheless, the precise mechanisms underlying iron toxicity in neuron cells are not fully understood. In this study, we investigated the mechanism underlying iron overload-induced mitochondrial fragmentation in HT-22 hippocampal neuron cells that were incubated with ferric ammonium citrate (FAC). Mitochondrial fragmentation via dephosphorylation of Drp1 (Ser637) and increased apoptotic neuronal death were observed in FAC-stimulated HT-22 cells. Furthermore, the levels of intracellular calcium (Ca(2+)) were increased by iron overload. Notably, chelation of intracellular Ca(2+) rescued mitochondrial fragmentation and neuronal cell death. In addition, iron overload activated calcineurin through the Ca(2+)/calmodulin and Ca(2+)/calpain pathways. Pretreatment with the calmodulin inhibitor W13 and the calpain inhibitor ALLN attenuated iron overload-induced mitochondrial fragmentation and neuronal cell death. Therefore, these findings suggest that Ca(2+)-mediated calcineurin signals are a key player in iron-induced neurotoxicity by regulating mitochondrial dynamics. We believe that our results may contribute to the development of novel therapies for iron toxicity related neurodegenerative disorders. PMID- 27481218 TI - Polychlorinated biphenyls impair endometrial receptivity in vitro via regulating mir-30d expression and epithelial mesenchymal transition. AB - Polychlorinated biphenyls (PCBs) are ubiquitous legacy persistent pollutants and epidemiological data showed that PCB burdens were associated with failed implantation in human. However, the mechanism how PCB exposure affects the embryo implantation is not clear. Using an in vitro model for human embryo implantation employing the human choriocarcinoma cell line JAR and the human endometrial cell line Ishikawa, we have shown that PCB mixture Aroclor 1254 at environmental relevant concentrations (2.5, 12.5, and 62.5MUM) dose-dependently impaired the endometrial receptivity by reducing the adhesion of JAR spheroid attachment and increasing the spheroid outgrowth. The receptive-up-regulated micro-RNA, mir-30d was also down-regulated in endometrial cells by the exposure. Following transient transfection of mir-30d mimic, the disrupted attachment and outgrowth of JAR spheroids was partially restored in the model. By measurement of cadherin switch and vimentin expression, the PCB exposure also activated epithelial mesenchymal transition (EMT) in endometrial cells. In accordance, mir-30d mimic suppressed the EMT markers induced by PCBs. Luciferase reporter assay confirmed that the EMT regulator Snai1 was targeted by mir-30d, and the expression of Snai1 was dose dependently up-regulated by PCB exposure. Taken together, our study revealed that PCBs may affect the receptivity of endometrial cells by impairing the interaction between receptivity-up-regulated microRNA and EMT process. PMID- 27481220 TI - The influence of sleep on emotional and cognitive processing is primarily trait- (but not state-) dependent. AB - Human studies of sleep and cognition have established thatdifferent sleep stages contribute to distinct aspects of cognitive and emotional processing. However, since the majority of these findings are based on single-night studies, it is difficult to determine whether such effects arise due to individual, between subject differences in sleep patterns, or from within-subject variations in sleep over time. In the current study, weinvestigated the longitudinal relationship between sleep patterns and cognitive performance by monitoring both in parallel, daily, for a week. Using two cognitive tasks - one assessing emotional reactivity to facial expressions and the other evaluating learning abilities in a probabilistic categorization task - we found that between-subjectdifferences in the average time spent in particular sleep stages predicted performance in these tasks far more than within-subject daily variations. Specifically, the typical time individualsspent in Rapid-Eye Movement (REM) sleep and Slow-Wave Sleep (SWS) was correlated to their characteristic measures of emotional reactivity, whereas the typical time spent in SWS and non-REM stages 1 and 2 was correlated to their success in category learning. These effects were maintained even when sleep properties werebased onbaseline measures taken prior to the experimental week. In contrast, within-subject daily variations in sleep patterns only contributed to overnight difference in one particular measure of emotional reactivity. Thus, we conclude that the effects of natural sleep onemotional cognition and categorylearning are more trait-dependent than state-dependent, and suggest ways to reconcile these results with previous findings in the literature. PMID- 27481219 TI - A novel human-specific splice isoform alters the critical C-terminus of Survival Motor Neuron protein. AB - Spinal muscular atrophy (SMA), a leading genetic disease of children and infants, is caused by mutations or deletions of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, fails to compensate for the loss of SMN1 due to skipping of exon 7. SMN2 predominantly produces SMNDelta7, an unstable protein. Here we report exon 6B, a novel exon, generated by exonization of an intronic Alu like sequence of SMN. We validate the expression of exon 6B-containing transcripts SMN6B and SMN6BDelta7 in human tissues and cell lines. We confirm generation of SMN6B transcripts from both SMN1 and SMN2. We detect expression of SMN6B protein using antibodies raised against a unique polypeptide encoded by exon 6B. We analyze RNA-Seq data to show that hnRNP C is a potential regulator of SMN6B expression and demonstrate that SMN6B is a substrate of nonsense-mediated decay. We show interaction of SMN6B with Gemin2, a critical SMN-interacting protein. We demonstrate that SMN6B is more stable than SMNDelta7 and localizes to both the nucleus and the cytoplasm. Our finding expands the diversity of transcripts generated from human SMN genes and reveals a novel protein isoform predicted to be stably expressed during conditions of stress. PMID- 27481221 TI - Effects of the cannabinoid 1 receptor peptide ligands hemopressin, (m)RVD hemopressin(alpha) and (m)VD-hemopressin(alpha) on memory in novel object and object location recognition tasks in normal young and Abeta1-42-treated mice. AB - The cannabinoid system plays an important role in memory processes, many studies have indicated that cannabinoid receptor ligands have ability to modulate memory in rodents. A nonapeptide hemopressin (Hp) derived from rat brain, acts as a peptide antagonist or selective inverse peptide agonist of cannabinoid 1 (CB1) receptor. N-terminally extended forms of Hp isolated from mouse brain, (m)RVD hemopressin(alpha) (RVD) and (m)VD-hemopressin(alpha) (VD) also bind CB1 receptor, however, as peptide agonists. Here, we investigated the roles of Hp, RVD, and VD on memory in mice using novel object recognition (NOR) and object location recognition (OLR) tasks. In normal young mice, intracerebroventricular (i.c.v.) infusion of Hp before training not only improved memory formation, but also prolonged memory retention in the tasks, these effects could be inhibited by RVD or VD at the same dose and intraperitoneal (i.p.) injection of a small molecule agonist of CB1 receptor WIN55, 212-2 15min before administration of Hp inhibited the memory-improving effect of Hp. In addition, under the same experimental conditions, i.c.v. RVD or VD displayed memory-impairing effects, which could be prevented by Hp (i.c.v.) or AM251 (i.p.), a small molecule antagonist of CB1 receptor. Infusion of amyloid-beta (1-42) (Abeta1-42) 14days before training resulted in impairment of memory in mice which could be used as animal model of Alzheimer's disease (AD). In these mice, RVD or VD (i.c.v.) reversed the memory impairment induced by Abeta1-42, and the effects of RVD and VD could be suppressed by Hp (i.c.v.) or AM251 (2mg/kg, i.p.). Separate administration of Hp had no effect in Abeta1-42-treated mice. The above results suggested that Hp, RVD and VD, as CB1 receptor peptide ligands, may be potential drugs to treatment of the memory deficit-involving disease, just as AD. PMID- 27481222 TI - Effects of 7-nitroindazole, a selective neural nitric oxide synthase inhibitor, on context-shock associative learning in a two-process contextual fear conditioning paradigm. AB - Nitric oxide (NO) is an important retrograde neuronal intracellular messenger which plays an important role in synaptic plasticity and is involved in learning and memory. However, evidence that NO is particularly important for the acquisition of contextual fear conditioning is mixed. Also, little is known about at which stages of the contextual fear conditioning does NO make its contribution. In the present study, we used 7-nitroindazole to temporarily inhibit neural nitric oxide synthase at either the pre-exposure stage or conditioning stage in a two-process paradigm and examined the potential contribution that NO makes to the contextually conditioned fear. Results showed that the expression of contextual fear memory was significantly impaired in rats treated with 7-nitroindazole (30mg/kg, i.p.) prior to the pairing of context shock (p=0.034, n=8), but not after the conditioning phase (p=0.846, n=8). In addition, the expression of contextual fear memory and reconsolidation was not significantly impaired by 7-nitroindazole administered prior to the context pre exposure stage or prior to another context-shock learning. These findings suggest that NO is specifically involved in the acquisition but not the consolidation, retrieval or reconsolidation of contextual fear memory. PMID- 27481223 TI - mAChR-dependent decrease in proteasome activity in the gustatory cortex is necessary for novel taste learning. AB - Regulation of protein degradation via the ubiquitin proteasome system is crucial for normal learning and synaptic plasticity processes. While some studies reveal that increased proteasome degradation is necessary for different types of learning, others suggest the proteasome to be a negative regulator of plasticity. We aim to understand the molecular and cellular processes taking place in the gustatory cortex (GC), which underlie appetitive and aversive forms of taste learning. Previously, we have shown that N-methyl d-aspartic acid receptor (NMDAR)-dependent upregulation of proteasome activity 4h after novel taste learning is necessary for the association of novel taste with malaise and formation of conditioned taste aversion (CTA). Here, we first identify a correlative increase in proteasome activity in the GC immediately after novel taste learning and study the upstream and downstream effectors of this modulated proteasome activity. Interestingly, proteasome-mediated degradation was reduced in the GC, 20min after novel taste consumption in a muscarinic acetylcholine receptor (mAChR)-dependent and NMDAR-independent manner. This reduction in protein degradation led to an increased amount of p70 S6 kinase (p70S6k), which was abolished in the presence of mAChR antagonist scopolamine. Infusion of lactacystin, a proteasome inhibitor, to the GC precluded the amnestic effect of scopolamine. This study shows for the first time that following novel taste learning there is a cortical, mAChR-dependent reduced proteasome activity that enables the memory of taste familiarity. Moreover, inhibition of degradation in the GC attenuates novel taste learning and of p70 S6 kinase correlative increased expression. These results shed light on the complex regulation of protein synthesis and degradation machineries in the cortex following novel taste experience. PMID- 27481224 TI - Endocannabinoid signaling and memory dynamics: A synaptic perspective. AB - Memory acquisition is a key brain feature in which our human nature relies on. Memories evolve over time. Initially after learning, memories are labile and sensitive to disruption by the interference of concurrent events. Later on, after consolidation, memories are resistant to disruption. However, reactivation of previously consolidated memories renders them again in an unstable state and therefore susceptible to perturbation. Additionally, and depending on the characteristics of the stimuli, a parallel process may be initiated which ultimately leads to the extinction of the previously acquired response. This dynamic aspect of memory maintenance opens the possibility for an updating of previously acquired memories but it also creates several conceptual challenges. What is the time window for memory updating? What determines whether reconsolidation or extinction is triggered? In this review, we tried to re examine the relationship between consolidation, reconsolidation and extinction, aiming for a unifying view of memory dynamics. Since cellular models of memory share common principles, we present the evidence that similar rules apply to the maintenance of synaptic plasticity. Recently, a new function of the endocannabinoid (eCB) signaling system has been described for associative forms of synaptic plasticity in amygdala synapses. The eCB system has emerged as a key modulator of memory dynamics by adjusting the outcome to stimuli intensity. We propose a key function of eCB in discriminative forms of learning by restricting associative plasticity in amygdala synapses. Since many neuropsychiatric disorders are associated with a dysregulation in memory dynamics, understanding the rules underlying memory maintenance paves the path to better clinical interventions. PMID- 27481226 TI - Enhanced photon management in silicon thin film solar cells with different front and back interface texture. AB - Light trapping and photon management of silicon thin film solar cells can be improved by a separate optimization of the front and back contact textures. A separate optimization of the front and back contact textures is investigated by optical simulations taking realistic device geometries into consideration. The optical simulations are confirmed by experimentally realized 1 MUm thick microcrystalline silicon solar cells. The different front and back contact textures lead to an enhancement of the short circuit current by 1.2 mA/cm(2) resulting in a total short circuit current of 23.65 mA/cm(2) and an energy conversion efficiency of 8.35%. PMID- 27481227 TI - Global transcriptional response to salt shock of the plant microsymbiont Mesorhizobium loti MAFF303099. AB - Soil salinity affects rhizobia both as free-living bacteria and in symbiosis with the host. The aim of this study was to examine the transcriptional response of the Lotus microsymbiont Mesorhizobium loti MAFF303099 to salt shock. Changes in the transcriptome of bacterial cells subjected to a salt shock of 10% NaCl for 30 min were analyzed. From a total of 7231 protein-coding genes, 385 were found to be differentially expressed upon salt shock, among which 272 were overexpressed. Although a large number of overexpressed genes encode hypothetical proteins, the two most frequently represented COG categories are "defense mechanisms" and "nucleotide transport and metabolism". A significant number of transcriptional regulators and ABC transporters genes were upregulated. Chemotaxis and motility genes were not differentially expressed. Moreover, most genes previously reported to be involved in salt tolerance were not differentially expressed. The transcriptional response to salt shock of a rhizobium with low ability to grow under salinity conditions, but enduring a salinity shock, may enlighten us concerning salinity stress response mechanisms. PMID- 27481229 TI - Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients. AB - BACKGROUND: Ursodeoxycholic acid (UDCA) might prevent progression of cystic fibrosis liver disease, but objective parameters for its effect are lacking. METHODS: We used liver stiffness measurements to evaluate the effect of Ursodeoxycholic acid. RESULTS: Paired measurements of liver stiffness were done in 73 patients without UDCA and in 32 patients with UDCA. In the latter group, 6 patients had cirrhosis; in 15 patients, UDCA was started based on Colombo criteria, and in 11 patients for other reasons. In patients without UDCA, liver stiffness increased: 0.19 (-0.03 to 0.59)kPa/year. Liver stiffness also increased in patients with cirrhosis: 4.6 (0.67-12.4)kPa/year. In patients who had UDCA based on Colombo criteria, a decrease of liver stiffness was observed: 0.70 (-1.6 to 0.55)kPa/year (P=0.01). In patients on UDCA for other reasons, liver stiffness increased: 0.23 (-0.20 to 0.51)kPa/year. CONCLUSION: UDCA reduced liver stiffness in patients with well-defined, mild liver disease. PMID- 27481230 TI - Correlation Between Daily Dietary Micronutrients Intake and Mental Health Outcomes in Iranians Living With HIV Infection. AB - In this study, we evaluated the correlation between daily dietary antioxidant micronutrients intake and mental health outcomes in Iranians living with HIV infection. During an organized interview, daily dietary micronutrients intake of people living with HIV (PLWH; N = 100) was evaluated using a 168-item semi quantitative food frequency questionnaire. A reliable psychiatric questionnaire was used to assess depression, anxiety, and stress of the patients as mental health outcomes. Significant negative correlations were found between daily dietary intake of zinc, selenium, and vitamin C with mental health outcomes, including depression, anxiety, and stress scores in Iranian PLWH. In our study, daily dietary intake of some antioxidant micronutrients correlated with the mental health outcomes of Iranian PLWH. PMID- 27481231 TI - Investigating the Interaction Between Sleep Symptoms of Arousal and Acquired Capability in Predicting Suicidality. AB - Heightened arousal significantly interacts with acquired capability to predict suicidality. We explore this interaction with insomnia and nightmares independently of waking state arousal symptoms, and test predictions of the Interpersonal Theory of Suicide (IPTS) and Escape Theory in relation to these sleep arousal symptoms. Findings from our e-survey (n = 540) supported the IPTS over models of Suicide as Escape. Sleep-specific measurements of arousal (insomnia and nightmares) showed no main effect, yet interacted with acquired capability to predict increased suicidality. The explained variance in suicidality by the interaction (1%-2%) using sleep-specific measures was comparable to variance explained by interactions previously reported in the literature using measurements composed of a mix of waking and sleep state arousal symptoms. Similarly, when entrapment (inability to escape) was included in models, main effects of sleep symptoms arousal were not detected yet interacted with entrapment to predict suicidality. We discuss findings in relation to treatment options suggesting that sleep-specific interventions be considered for the long-term management of at-risk individuals. PMID- 27481232 TI - Protective Effect of Astaxanthin on Vocal Fold Injury and Inflammation Due to Vocal Loading: A Clinical Trial. AB - OBJECTIVES: Professional voice users, such as singers and teachers, are at greater risk of developing vocal fold injury from excessive use of voice; thus, protection of the vocal fold is essential. One of the most important factors that aggravates injury is the production of reactive oxygen species at the wound site. The purpose of the current study was to assess the effect of astaxanthin, a strong antioxidant, on the protection of the vocal fold from injury and inflammation due to vocal loading. STUDY DESIGN: This study is an institutional review board-approved human clinical trial. METHODS: Ten male subjects underwent a 60-minute vocal loading session and received vocal assessments prior to, immediately after, and 30 minutes postvocal loading (AST(-) status). All subjects were then prescribed 24 mg/day of astaxanthin for 28 days, after which they received the same vocal task and assessments (AST(+) status). Phonatory parameters were compared between both groups. RESULTS: Aerodynamic assessment, acoustic analysis, and GRBAS scale (grade, roughness, breathiness, asthenia, and strain) were significantly worse in the AST(-) status immediately after vocal loading, but improved by 30 minutes after loading. In contrast, none of the phonatory parameters in the AST(+) status were statistically worse, even when measured immediately after vocal loading. No allergic responses or adverse effects were observed after administration of astaxanthin. CONCLUSIONS: The current results suggest that astaxanthin can protect the vocal fold from injury and inflammation caused by vocal loading possibly through the regulation of oxidative stress. PMID- 27481233 TI - Objective Identification of Prepubertal Female Singers and Non-singers by Singing Power Ratio Using Matlab. AB - BACKGROUND: The field of music is increasingly gaining scope and attracting researchers from varied fields in terms of improvising the art of voice modulation in singing. There has been a lot of competition, and young budding singers are emerging with more talent. This study is aimed to develop software to differentiate a prepubertal voice as that of a singer or a non-singer using an objective tool-singing power ratio (SPR)-as an objective measure to quantify the resonant voice quality. METHOD: Recordings of singing and phonation were obtained from 30 singers and 30 non-singer girls (8-10 years). Three professional singers perceptually evaluated all samples using a rating scale and categorized them as singers or non-singers. Using Matlab, a program was developed to automatically calculate the SPR of a particular sample and classify it into either of two groups based on the normative values of SPR developed manually. RESULTS: Positive correlation for SPR of phonation or singing was found between perceptual and manual ratings, and objective values of SPR. Software could automatically give the SPR values for samples that are fed and could further differentiate them as singer or non-singer. CONCLUSION: Researchers need not depend on professional singers or musicians for the judgment of voice for research purposes. This software uses an objective tool, which serves as an instrument to judge singing talent using singing and phonation samples of children. Also, it can be used as a first line of judgment in any singing audition process, which could ease the work of professionals. PMID- 27481234 TI - The Anticonvulsant and Neuroprotective Effects of Oxysophocarpine on Pilocarpine Induced Convulsions in Adult Male Mice. AB - Epilepsy is one of the prevalent and major neurological disorders, and approximately one-third of the individuals with epilepsy experience seizures that do not respond well to available medications. We investigated whether oxysophocarpine (OSC) had anticonvulsant and neuroprotective property in the pilocarpine (PILO)-treated mice. Thirty minutes prior to the PILO injection, the mice were administrated with OSC (20, 40, and 80 mg/kg) once. Seizures and electroencephalography (EEG) were observed, and then the mice were killed for Nissl and Fluoro-jade B (FJB) staining. The oxidative stress was measured at 24 h after convulsion. Western blot analysis was used to examine the expressions of the Bax, Bcl-2, and Caspase-3. In this study, we found that pretreatment with OSC (40, 80 mg/kg) significantly delayed the onset of the first convulsion and status epilepticus (SE) and reduced the incidence of SE and mortality. Analysis of EEG recordings revealed that OSC (40, 80 mg/kg) significantly reduced epileptiform discharges. Furthermore, Nissl and FJB staining showed that OSC (40, 80 mg/kg) attenuated the neuronal cell loss and degeneration in hippocampus. In addition, OSC (40, 80 mg/kg) attenuated the changes in the levels of Malondialdehyde (MDA) and strengthened glutathione peroxidase and catalase activity in the hippocampus. Western blot analysis showed that OSC (40, 80 mg/kg) significantly decreased the expressions of Bax, Caspase-3 and increased the expression of Bcl-2. Collectively, the findings of this study indicated that OSC exerted anticonvulsant and neuroprotective effects on PILO-treated mice. The beneficial effects should encourage further studies to investigate OSC as an adjuvant in epilepsy, both to prevent seizures and to protect neurons in brain. PMID- 27481235 TI - Commentary : The value of intraoperative neurophysiological monitoring: evidence, equipoise and outcomes. AB - The use of intraoperative neurophysiological monitoring (IONM) has grown despite an absence of randomized controlled trials that might unequivocally demonstrate improved outcomes. At issue is how to demonstrate value when other evidence indicates patient harms (opportunity cost) if IONM is withheld for the sake of randomization. In this article we review other non-randomized methods to assess the effects of IONM on post-operative outcomes. We also examine how clinical equipoise may resolve whether (or not) an anticipated controlled study is ethical. We conclude that the value of IONM in a particular surgical setting should be determined by a benefits/harms analysis based on all the available evidence. PMID- 27481236 TI - Bacteriocins: Not Only Antibacterial Agents. AB - This commentary was aimed at shedding light on the multifunction of bacteriocins mainly those produced by lactic acid bacteria. These antibacterial agents were first used to improve food safety and quality. With the increasing antibiotic resistance concern worldwide, they have been considered as viable agents to replace or potentiate the fading abilities of conventional antibiotics to control human pathogens. Bacteriocins were also shown to have potential as antiviral agents, plant protection agents, and anticancer agents. Bacteriocins were reported to be involved in shaping bacterial communities through inter- and intra specific interactions, conferring therefore to producing strains a probiotic added value. Furthermore, bacteriocins recently were shown as molecules with a fundamental impact on the resilience and virulence of some pathogens. PMID- 27481237 TI - Poly-N-Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect. AB - Poly-N-acetylglucosamine (PNAG) is a major component of the Staphylococcus epidermidis biofilm extracellular matrix. However, it is not yet clear how this polysaccharide impacts the host immune response and infection-associated pathology. Faster neutrophil recruitment and bacterial clearance were observed in mice challenged intraperitoneally with S. epidermidis biofilm cells of the PNAG producing 9142 strain than in mice similarly challenged with the isogenic PNAG defective M10 mutant. Moreover, intraperitoneal priming with 9142 cells exacerbated liver inflammatory pathology induced by a subsequent intravenous S. epidermidis challenge, compared to priming with M10 cells. The 9142-primed mice had elevated splenic CD4(+) T cells producing gamma interferon and interleukin 17A, indicating that PNAG promoted cell-mediated immunity. Curiously, despite having more marked liver tissue pathology, 9142-primed mice also had splenic T regulatory cells with greater suppressive activity than those of their M10-primed counterparts. By showing that PNAG production by S. epidermidis biofilm cells exacerbates host inflammatory pathology, these results together suggest that this polysaccharide contributes to the clinical features associated with biofilm derived infections. PMID- 27481238 TI - Use of a Multiplex Transcript Method for Analysis of Pseudomonas aeruginosa Gene Expression Profiles in the Cystic Fibrosis Lung. AB - The discovery of therapies that modulate Pseudomonas aeruginosa virulence or that can eradicate chronic P. aeruginosa lung infections associated with cystic fibrosis (CF) will be advanced by an improved understanding of P. aeruginosa behavior in vivo We demonstrate the use of multiplexed Nanostring technology to monitor relative abundances of P. aeruginosa transcripts across clinical isolates, in serial samples, and for the purposes of comparing microbial physiology in vitro and in vivo The expression of 75 transcripts encoded by genes implicated in CF lung disease was measured in a variety of P. aeruginosa strains as well as RNA serial sputum samples from four P. aeruginosa-colonized subjects with CF collected over 6 months. We present data on reproducibility, the results from different methods of normalization, and demonstrate high concordance between transcript relative abundance data obtained by Nanostring or transcriptome sequencing (RNA-Seq) analysis. Furthermore, we address considerations regarding sequence variation between strains during probe design. Analysis of P. aeruginosa grown in vitro identified transcripts that correlated with the different phenotypes commonly observed in CF clinical isolates. P. aeruginosa transcript profiles in RNA from CF sputum indicated alginate production in vivo, and transcripts involved in quorum-sensing regulation were less abundant in sputum than strains grown in the laboratory. P. aeruginosa gene expression patterns from sputum clustered closely together relative to patterns for laboratory-grown cultures; in contrast, laboratory-grown P. aeruginosa showed much greater transcriptional variation with only loose clustering of strains with different phenotypes. The clustering within and between subjects was surprising in light of differences in inhaled antibiotic and respiratory symptoms, suggesting that the pathways represented by these 75 transcripts are stable in chronic CF P. aeruginosa lung infections. PMID- 27481239 TI - A Coccidioides posadasii CPS1 Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection. AB - The CPS1 gene was identified as a virulence factor in the maize pathogen Cochliobolus heterostrophus Hypothesizing that the homologous gene in Coccidioides posadasii could be important for virulence, we created a Deltacps1 deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,gammac(null) [NSG]). Only a single colony was recovered from 1 of 60 C57BL/6 mice following intranasal infections of up to 4,400 spores. Following administration of very high doses (10,000 to 2.5 * 10(7) spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 postinfection, but nearly all appeared degraded with infrequent endosporulation. Although the role of CPS1 in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Deltacps1 strain versus C. posadasii is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of the Deltacps1 strain showed slower growth of mycelia with delayed and lower spore production than C. posadasii, and in vitro spherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Deltacps1 spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethal C. posadasii intranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance to C. posadasii infection when used as a vaccine, the Deltacps1 strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals. PMID- 27481240 TI - Acanthamoeba castellanii Genotype T4 Stimulates the Production of Interleukin-10 as Well as Proinflammatory Cytokines in THP-1 Cells, Human Peripheral Blood Mononuclear Cells, and Human Monocyte-Derived Macrophages. AB - Free-living amoebae of the genus Acanthamoeba can cause severe and chronic infections in humans, mainly localized in immune privileged sites, such as the brain and the eye. Monocytes/macrophages are thought to be involved in Acanthamoeba infections, but little is known about how these facultative parasites influence their functions. The aim of this work was to investigate the effects of Acanthamoeba on human monocytes/macrophages during the early phase of infection. Here, THP-1 cells, primary human monocytes isolated from peripheral blood, and human monocyte-derived macrophages were either coincubated with trophozoites of a clinical isolate of Acanthamoeba (genotype T4) or stimulated with amoeba-derived cell-free conditioned medium. Production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin-6 [IL-6], and IL 12), anti-inflammatory cytokine (IL-10), and chemokine (IL-8) was evaluated at specific hours poststimulation (ranging from 1.5 h to 23 h). We showed that both Acanthamoeba trophozoites and soluble amoebic products induce an early anti inflammatory monocyte-macrophage phenotype, characterized by significant production of IL-10; furthermore, challenge with either trophozoites or their soluble metabolites stimulate both proinflammatory cytokines and chemokine production, suggesting that this protozoan infection results from the early induction of coexisting, opposed immune responses. Results reported in this paper confirm that the production of proinflammatory cytokines and chemokines by monocytes and macrophages can play a role in the development of the inflammatory response during Acanthamoeba infections. Furthermore, we demonstrate for the first time that Acanthamoeba stimulates IL-10 production in human innate immune cells, which might both promote the immune evasion of Acanthamoeba and limit the induced inflammatory response. PMID- 27481241 TI - Resistance of Mice of the 129 Background to Yersinia pestis Maps to Multiple Loci on Chromosome 1. AB - Yersinia pestis is a Gram-negative bacterium that is the causative agent of bubonic and pneumonic plague. It is commonly acquired by mammals such as rodents and humans via the bite of an infected flea. We previously reported that multiple substrains of the 129 mouse background are resistant to pigmentation locus negative (pgm(-)) Yersinia pestis and that this phenotype maps to a 30 centimorgan (cM) region located on chromosome 1. In this study, we have further delineated this plague resistance locus to a region of less than 20 cM through the creation and phenotyping of recombinant offspring arising from novel crossovers in this region. Furthermore, our experiments have revealed that there are at least two alleles in this initial locus, both of which are required for resistance on a susceptible C57BL/6 background. These two alleles work in trans since resistance is restored in offspring possessing one allele contributed by each parent. Our studies also indicated that the Slc11a1 gene (formerly known as Nramp1) located within the chromosome1 locus is not responsible for conferring resistance to 129 mice. PMID- 27481242 TI - Neuraminidase A-Exposed Galactose Promotes Streptococcus pneumoniae Biofilm Formation during Colonization. AB - Streptococcus pneumoniae is an opportunistic pathogen that colonizes the nasopharynx. Herein we show that carbon availability is distinct between the nasopharynx and bloodstream of adult humans: glucose is absent from the nasopharynx, whereas galactose is abundant. We demonstrate that pneumococcal neuraminidase A (NanA), which cleaves terminal sialic acid residues from host glycoproteins, exposed galactose on the surface of septal epithelial cells, thereby increasing its availability during colonization. We observed that S. pneumoniae mutants deficient in NanA and beta-galactosidase A (BgaA) failed to form biofilms in vivo despite normal biofilm-forming abilities in vitro Subsequently, we observed that glucose, sucrose, and fructose were inhibitory for biofilm formation, whereas galactose, lactose, and low concentrations of sialic acid were permissive. Together these findings suggested that the genes involved in biofilm formation were under some form of carbon catabolite repression (CCR), a regulatory network in which genes involved in the uptake and metabolism of less preferred sugars are silenced during growth with preferred sugars. Supporting this notion, we observed that a mutant deficient in pyruvate oxidase, which converts pyruvate to acetyl-phosphate under non-CCR-inducing growth conditions, was unable to form biofilms. Subsequent comparative transcriptome sequencing (RNA seq) analyses of planktonic and biofilm-grown pneumococci showed that metabolic pathways involving the conversion of pyruvate to acetyl-phosphate and subsequently leading to fatty acid biosynthesis were consistently upregulated during diverse biofilm growth conditions. We conclude that carbon availability in the nasopharynx impacts pneumococcal biofilm formation in vivo Additionally, biofilm formation involves metabolic pathways not previously appreciated to play an important role. PMID- 27481243 TI - MgtC as a Host-Induced Factor and Vaccine Candidate against Mycobacterium abscessus Infection. AB - Mycobacterium abscessus is an emerging pathogenic mycobacterium involved in pulmonary and mucocutaneous infections, presenting a serious threat for patients with cystic fibrosis (CF). The lack of an efficient treatment regimen and the emergence of multidrug resistance in clinical isolates require the development of new therapeutic strategies against this pathogen. Reverse genetics has revealed genes that are present in M. abscessus but absent from saprophytic mycobacteria and that are potentially involved in pathogenicity. Among them, MAB_3593 encodes MgtC, a known virulence factor involved in intramacrophage survival and adaptation to Mg(2+) deprivation in several major bacterial pathogens. Here, we demonstrated a strong induction of M. abscessus MgtC at both the transcriptional and translational levels when bacteria reside inside macrophages or upon Mg(2+) deprivation. Moreover, we showed that M. abscessus MgtC was recognized by sera from M. abscessus-infected CF patients. The intramacrophage growth (J774 or THP1 cells) of a M. abscessus knockout mgtC mutant was, however, not significantly impeded. Importantly, our results indicated that inhibition of MgtC in vivo through immunization with M. abscessus mgtC DNA, formulated with a tetrafunctional amphiphilic block copolymer, exerted a protective effect against an aerosolized M. abscessus challenge in CF (DeltaF508 FVB) mice. The formulated DNA immunization was likely associated with the production of specific MgtC antibodies, which may stimulate a protective effect by counteracting MgtC activity during M. abscessus infection. These results emphasize the importance of M. abscessus MgtC in vivo and provide a basis for the development of novel therapeutic tools against pulmonary M. abscessus infections in CF patients. PMID- 27481244 TI - Meningococcal Outer Membrane Vesicle Composition-Dependent Activation of the Innate Immune Response. AB - Meningococcal outer membrane vesicles (OMVs) have been extensively investigated and successfully implemented as vaccines. They contain pathogen-associated molecular patterns, including lipopolysaccharide (LPS), capable of triggering innate immunity. However, Neisseria meningitidis contains an extremely potent hexa-acylated LPS, leading to adverse effects when its OMVs are applied as vaccines. To create safe OMV vaccines, detergent treatment is generally used to reduce the LPS content. While effective, this method also leads to loss of protective antigens such as lipoproteins. Alternatively, genetic modification of LPS can reduce its toxicity. In the present study, we have compared the effects of standard OMV isolation methods using detergent or EDTA with those of genetic modifications of LPS to yield a penta-acylated lipid A (lpxL1 and pagL) on the in vitro induction of innate immune responses. The use of detergent decreased both Toll-like receptor 4 (TLR4) and TLR2 activation by OMVs, while the LPS modifications reduced only TLR4 activation. Mutational removal of PorB or lipoprotein factor H binding protein (fHbp), two proteins known to trigger TLR2 signaling, had no effect, indicating that multiple TLR2 ligands are removed by detergent treatment. Detergent-treated OMVs and lpxL1 OMVs showed similar reductions of cytokine profiles in the human monocytic cell line MM6 and human dendritic cells (DCs). OMVs with the alternative penta-acylated LPS structure obtained after PagL-mediated deacylation showed reduced induction of proinflammatory cytokines interleukin-6 (IL-6) and IL-1beta but not of IP-10, a typical TRIF-dependent chemokine. Taken together, these data show that lipid A modification can be used to obtain OMVs with reduced activation of innate immunity, similar to what is found after detergent treatment. PMID- 27481246 TI - Neonatal Fc Receptor Regulation of Lung Immunoglobulin and CD103+ Dendritic Cells Confers Transient Susceptibility to Tuberculosis. AB - The neonatal Fc receptor (FcRn) extends the systemic half-life of IgG antibodies by chaperoning bound Fc away from lysosomal degradation inside stromal and hematopoietic cells. FcRn also transports IgG across mucosal barriers into the lumen, and yet little is known about how FcRn modulates immunity in the lung during homeostasis or infection. We infected wild-type (WT) and FcRn-deficient (fcgrt(-/-)) mice with Pseudomonas aeruginosa or Mycobacterium tuberculosis to investigate whether recycling and transport of IgG via FcRn influences innate and adaptive immunity in the lung in response to bacterial infection. We found that FcRn expression maintains homeostatic IgG levels in lung and leads to preferential secretion of low-affinity IgG ligands into the lumen. Fcgrt(-/-) animals exhibited no evidence of developmental impairment of innate immunity in the lung and were able to efficiently recruit neutrophils in a model of acute bacterial pneumonia. Although local humoral immunity in lung increased independently of the presence of FcRn during tuberculosis, there was nonetheless a strong impact of FcRn deficiency on local adaptive immunity. We show that the quantity and quality of IgG in airways, as well as the abundance of dendritic cells in the lung, are maintained by FcRn. FcRn ablation transiently enhanced local T cell immunity and neutrophil recruitment during tuberculosis, leading to a lower bacterial burden in lung. This novel understanding of tissue-specific modulation of mucosal IgG isotypes in the lung by FcRn sheds light on the role of mucosal IgG in immune responses in the lung during homeostasis and bacterial disease. PMID- 27481245 TI - Neisseria gonorrhoeae Evades Calprotectin-Mediated Nutritional Immunity and Survives Neutrophil Extracellular Traps by Production of TdfH. AB - Neisseria gonorrhoeae successfully overcomes host strategies to limit essential nutrients, termed nutritional immunity, by production of TonB-dependent transporters (TdTs)-outer membrane proteins that facilitate nutrient transport in an energy-dependent manner. Four gonococcal TdTs facilitate utilization of iron or iron chelates from host-derived proteins, including transferrin (TbpA), lactoferrin (LbpA), and hemoglobin (HpuB), in addition to xenosiderophores from other bacteria (FetA). The roles of the remaining four uncharacterized TdTs (TdfF, TdfG, TdfH, and TdfJ) remain elusive. Regulatory data demonstrating that production of gonococcal TdfH and TdfJ are unresponsive to or upregulated under iron-replete conditions led us to evaluate the role of these TdTs in the acquisition of nutrients other than iron. In this study, we found that production of gonococcal TdfH is both Zn and Zur repressed. We also found that TdfH confers resistance to calprotectin, an immune effector protein highly produced in neutrophils that has antimicrobial activity due to its ability to sequester Zn and Mn. We found that TdfH directly binds calprotectin, which enables gonococcal Zn accumulation in a TdfH-dependent manner and enhances bacterial survival after exposure to neutrophil extracellular traps (NETs). These studies highlight Zn sequestration by calprotectin as a key functional arm of NET-mediated killing of gonococci. We demonstrate for the first time that N. gonorrhoeae exploits this host strategy in a novel defense mechanism, in which TdfH production hijacks and directly utilizes the host protein calprotectin as a zinc source and thereby evades nutritional immunity. PMID- 27481248 TI - Leishmania donovani-Induced Prostaglandin E2 Generation Is Critically Dependent on Host Toll-Like Receptor 2-Cytosolic Phospholipase A2 Signaling. AB - Visceral leishmaniasis (VL) is the second-largest parasitic killer disease after malaria. During VL, the protozoan Leishmania donovani induces prostaglandin E2 (PGE2) generation within host macrophages to aid parasite survival. PGE2 significantly influences leishmanial pathogenesis, as L. donovani proliferation is known to be attenuated in PGE2-inhibited macrophages. Here, we report for the first time that signaling via macrophage Toll-like receptor 2 (TLR2) plays an instrumental role in inducing PGE2 release from L. donovani-infected macrophages. This signaling cascade, mediated via the TLR2-phosphatidylinositol 3-kinase (PI3K)-phospholipase C (PLC) signaling pathway, was found to be indispensable for activation of two major enzymes required for PGE2 generation: cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (Cox2). Inhibition of cPLA2, but not secreted phospholipase A2 (sPLA2) or calcium-independent phospholipase A2 (iPLA2), arrested L. donovani infection. During infection, cPLA2 activity increased >7-fold in a calcium-dependent and extracellular signal-regulated kinase (ERK)-dependent manner, indicating that elevation of intracellular calcium and ERK-mediated phosphorylation was necessary for L. donovani-induced cPLA2 activation. For transcriptional upregulation of cyclooxygenase 2, activation of the calcium-calcineurin-nuclear factor of activated T cells (NFAT) signaling was required in addition to the TLR2-PI3K-PLC pathway. Detailed studies by site directed mutagenesis of potential NFAT binding sites and chromatin immunoprecipitation (ChIP) analysis revealed that the binding of macrophage NFATc2, at the -73/-77 site on the cox2 promoter, induced L. donovani-driven cox2 transcriptional activation. Collectively, these findings highlight the contribution of TLR2 downstream signaling toward activation of cPLA2 and Cox2 and illustrate how the TLR2-PI3K-PLC pathway acts in a concerted manner with calcium calcineurin-NFATc2 signaling to modulate PGE2 release from L. donovani-infected macrophages. PMID- 27481247 TI - Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase. AB - Dihydroorotate dehydrogenase (DHODH) mediates the fourth step of de novo pyrimidine biosynthesis and is a proven drug target for inducing immunosuppression in therapy of human disease as well as a rapidly emerging drug target for treatment of malaria. In Toxoplasma gondii, disruption of the first, fifth, or sixth step of de novo pyrimidine biosynthesis induced uracil auxotrophy. However, previous attempts to generate uracil auxotrophy by genetically deleting the mitochondrion-associated DHODH of T. gondii (TgDHODH) failed. To further address the essentiality of TgDHODH, mutant gene alleles deficient in TgDHODH activity were designed to ablate the enzyme activity. Replacement of the endogenous DHODH gene with catalytically deficient DHODH gene alleles induced uracil auxotrophy. Catalytically deficient TgDHODH localized to the mitochondria, and parasites retained mitochondrial membrane potential. These results show that TgDHODH is essential for the synthesis of pyrimidines and suggest that TgDHODH is required for a second essential function independent of its role in pyrimidine biosynthesis. PMID- 27481249 TI - Z-DNA Binding Protein Mediates Host Control of Toxoplasma gondii Infection. AB - Intrinsic to Toxoplasma gondii infection is the parasite-induced modulation of the host immune response, which ensures establishment of a chronic lifelong infection. This manipulation of the host immune response allows T. gondii to not only dampen the ability of the host to eliminate the parasite but also trigger parasite differentiation to the slow-growing, encysted bradyzoite form. We previously used RNA sequencing (RNA-seq) to profile the transcriptomes of mice and T. gondii during acute and chronic stages of infection. One of the most abundant host transcripts during acute and chronic infection was Z-DNA binding protein 1 (ZBP1). In this study, we determined that ZBP1 functions to control T. gondii growth. In activated macrophages isolated from ZBP1 deletion (ZBP1(-/-)) mice, T. gondii has an increased rate of replication and a decreased rate of degradation. We also identified a novel function for ZBP1 as a regulator of nitric oxide (NO) production in activated macrophages, even in the absence of T. gondii infection. Upon stimulation, T. gondii-infected ZBP1(-/-) macrophages display increased proinflammatory cytokines compared to wild-type macrophages under the same conditions. These in vitro phenotypes were recapitulated in vivo, with ZBP1(-/-) mice having increased susceptibility to oral challenge, higher cyst burdens during chronic infection, and elevated inflammatory cytokine responses. Taken together, these results highlight a role for ZBP1 in assisting host control of T. gondii infection. PMID- 27481250 TI - The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO(-)) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection. PMID- 27481251 TI - The Glycolytic Enzyme Triosephosphate Isomerase of Trichomonas vaginalis Is a Surface-Associated Protein Induced by Glucose That Functions as a Laminin- and Fibronectin-Binding Protein. AB - Triosephosphate isomerase of Trichomonas vaginalis (TvTIM) is a 27-kDa cytoplasmic protein encoded by two genes, tvtim1 and tvtim2, that participates in glucose metabolism. TvTIM is also localized to the parasite surface. Thus, the goal of this study was to identify the novel functions of the surface-associated TvTIM in T. vaginalis and to assess the effect of glucose as an environmental factor that regulates its expression and localization. Reverse transcription-PCR (RT-PCR) showed that the tvtim genes were differentially expressed in response to glucose concentration. tvtim1 was overexpressed under glucose-restricted (GR) conditions, whereas tvtim2 was overexpressed under glucose-rich, or high-glucose (HG), conditions. Western blot and indirect immunofluorescence assays also showed that glucose positively affected the amount and surface localization of TvTIM in T. vaginalis Affinity ligand assays demonstrated that the recombinant TvTIM1 and TvTIM2 proteins bound to laminin (Lm) and fibronectin (Fn) but not to plasminogen. Moreover, higher levels of adherence to Lm and Fn were detected in parasites grown under HG conditions than in those grown under GR conditions. Furthermore, pretreatment of trichomonads with an anti-TvTIMr polyclonal antibody or pretreatment of Lm- or Fn-coated wells with both recombinant proteins (TvTIM1r and TvTIM2r) specifically reduced the binding of live parasites to Lm and Fn in a concentration-dependent manner. Moreover, T. vaginalis was exposed to different glucose concentrations during vaginal infection of women with trichomoniasis. Our data indicate that TvTIM is a surface-associated protein under HG conditions that mediates specific binding to Lm and Fn as a novel virulence factor of T. vaginalis. PMID- 27481252 TI - A Zebrafish Model of Cryptococcal Infection Reveals Roles for Macrophages, Endothelial Cells, and Neutrophils in the Establishment and Control of Sustained Fungemia. AB - Cryptococcal meningoencephalitis is a fungal infection that predominantly affects immunocompromised patients and is uniformly fatal if left untreated. Timely diagnosis is difficult, and screening or prophylactic measures have generally not been successful. Thus, we need a better understanding of early, asymptomatic pathogenesis. Inhaled cryptococci must survive the host immune response, escape the lung, and persist within the bloodstream in order to reach and invade the brain. Here we took advantage of the zebrafish larval infection model to assess the process of cryptococcal infection and disease development sequentially in a single host. Using yeast or spores as infecting particles, we discovered that both cell types survived and replicated intracellularly and that both ultimately established a sustained, low-level fungemia. We propose that the establishment and maintenance of this sustained fungemia is an important stage of disease progression that has been difficult to study in other model systems. Our data suggest that sustained fungemia resulted from a pattern of repeated escape from, and reuptake by, macrophages, but endothelial cells were also seen to play a role as a niche for cryptococcal survival. Circulating yeast collected preferentially in the brain vasculature and eventually invaded the central nervous system (CNS). As suggested previously in a mouse model, we show here that neutrophils can play a valuable role in limiting the sustained fungemia, which can lead to meningoencephalitis. This early stage of pathogenesis-a balanced interaction between cryptococcal cells, macrophages, endothelial cells, and neutrophils-could represent a window for timely detection and intervention strategies for cryptococcal meningoencephalitis. PMID- 27481253 TI - Attachment of Actinobacillus suis H91-0380 and Its Isogenic Adhesin Mutants to Extracellular Matrix Components of the Tonsils of the Soft Palate of Swine. AB - Tonsils conduct immune surveillance of antigens entering the upper respiratory tract. Despite their immunological function, they are also sites of persistence and invasion of bacterial pathogens. Actinobacillus suis is a common resident of the tonsils of the soft palate in pigs, but under certain circumstances it can invade, causing septicemia and related sequelae. Twenty-four putative adhesins are predicted in the A. suis genome, but to date, little is known about how they might participate in colonization or invasion. To better understand these processes, swine tonsil lysates were characterized by mass spectrometry. Fifty nine extracellular matrix (ECM) proteins were identified, including small leucine rich proteoglycans, integrins, and other cell surface receptors. Additionally, attachment of the wild type and 3 adhesin mutants to 5 ECM components was evaluated. Exponential cultures of wild-type A. suis adhered significantly more than stationary cultures to all ECM components studied except collagen I. During exponential growth, the A. suis Deltaflp1 mutant attached less to collagen IV while the DeltaompA mutant attached less to all ECMs. The DeltacomE1 strain attached less to collagen IV, fibronectin, and vitronectin during exponential growth and exhibited differential attachment to collagen I over short adherence time points. These results suggest that Flp1, OmpA, and ComE1 are important during early stages of attachment to ECM components found in tonsils, which supports the notion that other adhesins have compensatory effects during later stages of attachment. PMID- 27481255 TI - Experimental Evidence of Bacterial Colonization of Human Coronary Microvasculature and Myocardial Tissue during Meningococcemia. AB - Meningococcal septic shock is associated with profound vasoplegia, early and severe myocardial dysfunction, and extended skin necrosis responsible for a specific clinical entity designated purpura fulminans (PF). PF represents 90% of fatal meningococcal infections. One characteristic of meningococcal PF is the myocardial dysfunction that occurs in the early phase of sepsis. Furthermore, hemodynamic studies have shown that the prognosis of meningococcal sepsis is directly related to the degree of impairment of cardiac contractility during the initial phase of the disease. To gain insight into a potential interaction of Neisseria meningitidis with the myocardial microvasculature, we modified a previously described humanized mouse model by grafting human myocardial tissue to SCID mice. We then infected the grafted mice with N. meningitides Using the humanized SCID mouse model, we demonstrated that N. meningitidis targets the human myocardial tissue vasculature, leading to the formation of blood thrombi, infectious vasculitis, and vascular leakage. These results suggest a novel mechanism of myocardial injury in the course of severe N. meningitidis sepsis that is likely to participate in primary myocardial dysfunction. PMID- 27481254 TI - Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins. AB - Enterotoxigenic Escherichia coli (ETEC) causes ~20% of the acute infectious diarrhea (AID) episodes worldwide, often by producing heat-stable enterotoxins (STs), which are peptides structurally homologous to paracrine hormones of the intestinal guanylate cyclase C (GUCY2C) receptor. While molecular mechanisms mediating ST-induced intestinal secretion have been defined, advancements in therapeutics have been hampered for decades by the paucity of disease models that integrate molecular and functional endpoints amenable to high-throughput screening. Here, we reveal that mouse and human intestinal enteroids in three dimensional ex vivo cultures express the components of the GUCY2C secretory signaling axis. ST and its structural analog, linaclotide, an FDA-approved oral secretagog, induced fluid accumulation quantified simultaneously in scores of enteroid lumens, recapitulating ETEC-induced intestinal secretion. Enteroid secretion depended on canonical molecular signaling events responsible for ETEC induced diarrhea, including cyclic GMP (cGMP) produced by GUCY2C, activation of cGMP-dependent protein kinase (PKG), and opening of the cystic fibrosis transmembrane conductance regulator (CFTR). Importantly, pharmacological inhibition of CFTR abrogated enteroid fluid secretion, providing proof of concept for the utility of this model to screen antidiarrheal agents. Intestinal enteroids offer a unique model, integrating the GUCY2C signaling axis and luminal fluid secretion, to explore the pathophysiology of, and develop platforms for, high-throughput drug screening to identify novel compounds to prevent and treat ETEC diarrheal disease. PMID- 27481257 TI - Impact of poplar-based phytomanagement on soil properties and microbial communities in a metal-contaminated site. AB - Despite a long history of use in phytomanagement strategies, the impacts of poplar trees on the structure and function of microbial communities that live in the soil remain largely unknown. The current study combined fungal and bacterial community analyses from different management regimes using Illumina-based sequencing with soil analysis. The poplar phytomanagement regimes led to a significant increase in soil fertility and a decreased bioavailability of Zn and Cd, in concert with changes in the microbial communities. The most notable changes in the relative abundance of taxa and operational taxonomic units unsurprisingly indicated that root and soil constitute distinct ecological microbial habitats, as exemplified by the dominance of Laccaria in root samples. The poplar cultivar was also an important driver, explaining 12% and 6% of the variance in the fungal and bacterial data sets, respectively. The overall dominance of saprophytic fungi, e.g. Penicillium canescens, might be related to the decomposition activities needed at the experimental site. Our data further highlighted that the mycorrhizal colonization of poplar cultivars varies greatly between the species and genotypes, which is exemplified by the dominance of Scleroderma under Vesten samples. Further interactions between fungal and bacterial functional groups stressed the potential of high-throughput sequencing technologies in uncovering the microbial ecology of disturbed environments. PMID- 27481256 TI - Secretion Chaperones PrsA2 and HtrA Are Required for Listeria monocytogenes Replication following Intracellular Induction of Virulence Factor Secretion. AB - The Gram-positive bacterium Listeria monocytogenes transitions from an environmental organism to an intracellular pathogen following its ingestion by susceptible mammalian hosts. Bacterial replication within the cytosol of infected cells requires activation of the central virulence regulator PrfA followed by a PrfA-dependent induction of secreted virulence factors. The PrfA-induced secreted chaperone PrsA2 and the chaperone/protease HtrA contribute to the folding and stability of select proteins translocated across the bacterial membrane. L. monocytogenes strains that lack both prsA2 and htrA exhibit near-normal patterns of growth in broth culture but are severely attenuated in vivo We hypothesized that, in the absence of PrsA2 and HtrA, the increase in PrfA-dependent protein secretion that occurs following bacterial entry into the cytosol results in misfolded proteins accumulating at the bacterial membrane with a subsequent reduction in intracellular bacterial viability. Consistent with this hypothesis, the introduction of a constitutively activated allele of prfA (prfA*) into DeltaprsA2 DeltahtrA strains was found to essentially inhibit bacterial growth at 37 degrees C in broth culture. DeltaprsA2 DeltahtrA strains were additionally found to be defective for cell invasion and vacuole escape in selected cell types, steps that precede full PrfA activation. These data establish the essential requirement for PrsA2 and HtrA in maintaining bacterial growth under conditions of PrfA activation. In addition, chaperone function is required for efficient bacterial invasion and rapid vacuole lysis within select host cell types, indicating roles for PrsA2/HtrA prior to cytosolic PrfA activation and the subsequent induction of virulence factor secretion. PMID- 27481259 TI - A composite likelihood approach in testing for Hardy Weinberg Equilibrium using family-based genetic survey data. AB - In population-based household surveys, for example, the National Health and Nutrition Examination Survey, households are often sampled by stratified multistage cluster sampling, and multiple individuals related by blood are often sampled within households. Therefore, genetic data collected from these population-based household surveys, called National Genetic Household Surveys, can be correlated because of two levels of correlation. One level of correlation is caused by the multistage geographical cluster sampling and the other is caused by biological inheritance among participants within the same sampled family. In this paper, we develop an efficient Hardy Weinberg Equilibrium (HWE) test utilizing pairwise composite likelihood methods that incorporate the sample weighting effect induced by the differential selection probabilities in complex sample designs, as well as the two-level clustering (correlation) effects described above. Monte Carlo simulation studies show that the proposed HWE test maintains the nominal levels, and is more powerful than existing methods (Li et al. 2011) under various (non)informative sample designs that depend on genotypes (explicitly or implicitly), family relationships or both, especially when within household sampling depends on the genotypes. The developed tests are further evaluated using simulated genetic data based on the Hispanic Health and Nutrition Survey. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27481260 TI - Gendered Innovations in Orthopaedic Science: Family Planning: An Orthopaedic Issue. PMID- 27481258 TI - A combined modality of carboplatin and photodynamic therapy suppresses epithelial mesenchymal transition and matrix metalloproteinase-2 (MMP-2)/MMP-9 expression in HEp-2 human laryngeal cancer cells via ROS-mediated inhibition of MEK/ERK signalling pathway. AB - Photodynamic therapy (PDT) has been developed as a promising treatment modality for laryngeal cancer. 9-Hydroxypheophorbide alpha (9-HPbD), a novel chlorophyll derived photosensitizer, has a longer absorption wavelength, which increases the penetration of light to malignant tissues. Carboplatin (CBDCA), a second generation platinum derivative, also has gained more popularity for the treatment of laryngeal cancer. Our previous studies have elucidated that 9-HPbD-PDT could inhibit the migration and invasion of HEp-2 cells. The objective of this study is to investigate the change of migration and invasion of HEp-2 cells induced by a combined modality of CBDCA and 9-HPbD-PDT in vitro. A wound healing assay, cell migration assay and Matrigel invasion assay were used to evaluate the cellular migration and invasion. Reactive oxygen species (ROS) and Western blots for epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin), MMPs (MMP-2 and MMP-9) and MEK/ERK signalling pathway were performed to investigate the possible mechanisms that may be involved. We observed that CBDCA and 9-HPbD-PDT administration synergistically inhibited the migration and invasion of HEp-2 cells. Moreover, the combined modality cooperatively repressed the EMT process and down-regulated expressions of MMP-2 and MMP-9 via ROS mediated inhibition of phosphorylation in the MEK/ERK signalling pathway. Our results suggested that the combination of CBDCA and 9-HPbD-PDT might be a promising therapeutic strategy for laryngeal cancer metastasis. PMID- 27481262 TI - Trousseau's sign at the emergency department. PMID- 27481261 TI - Cancer arising from the remnant mucosa of the ileoanal anastomosis leading to pouchectomy. AB - Ileal pouch-related adenocarcinoma remains a rarity; thus, guidelines on treatment are currently lacking. We present this case of a 54-year-old man who underwent restorative proctocolectomy with stapled ileal pouch-anal anastomosis formation for familial adenomatous polyposis during the 1980s. Despite undergoing annual surveillance endoscopy, the patient was noted to be anaemic and passing fresh blood per anus Endoscopy and radiological investigation revealed the presence of a pouch-related adenocarcinoma. This was subsequently treated with short-course radiotherapy and pouch excision. The patient remains well until now and will follow six-monthly surveillance protocols with a transition to annual surveillance after 2 years. PMID- 27481263 TI - Fever and haematochezia: an unusual association. PMID- 27481265 TI - Learning the Tricks of the Trade: The Need for Specialty-Specific Supervisor Training Programs in Competency-Based Medical Education. PMID- 27481266 TI - Teaching Dialectical Behavior Therapy to Psychiatry Residents: The Columbia Psychiatry Residency DBT Curriculum. AB - OBJECTIVE: Dialectical behavior therapy (DBT) is an evidence-based psychosocial treatment with efficacy in reducing self-harm behaviors in borderline personality disorder (BPD). This study describes and evaluates a clinical curriculum to teach DBT to psychiatry residents, developed at a large urban university hospital. The curriculum objectives are to (1) have psychiatry residents achieve basic understanding of DBT theory and clinical skill, (2) increase residents' ability and confidence in treating self-harm behaviors (both suicidal behavior and non suicidal self-injury), and (3) enhance residents' willingness to treat individuals with BPD. METHODS: In addition to a 6-week didactic course on DBT offered to all residents (n = 62), 25 elected to enroll in a year-long DBT clinical training curriculum over the course of a 5-year period. The DBT clinical training consisted of 15 h of additional didactics, ongoing conduct of individual therapy and group DBT skills training, videotaping of individual therapy sessions, and weekly supervision meetings utilizing videotape to provide feedback. Residents participating in the clinical training program videotaped baseline and later sessions, which were rated for DBT adherence. All 62 graduates of the program were surveyed regarding the impact of the training on their practice of psychiatry. RESULTS: Upon graduation, a high percentage (87 % in the curriculum and 70 % in the didactic course only) reported incorporating DBT into their psychiatry practice, as well as willingness and confidence in treating BPD and self-harm behaviors. Residents participating in the clinical training demonstrated significant improvement in their ability to utilize DBT interventions, particularly in structuring sessions, problem assessment, problem solving, and using validation and dialectical strategies. CONCLUSION: This DBT curriculum was effective in preparing psychiatrists-in-training to incorporate evidence-based practices for effective treatment of BPD and self-harm behaviors and can serve as a model for teaching DBT during psychiatry residency training. Limitations include a small sample size and lack of baseline survey measurement of attitudes for pre- and post-curriculum comparison. PMID- 27481264 TI - ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1-G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS. PMID- 27481267 TI - [Influence of the learning curve for esophagectomy on patient survival]. PMID- 27481269 TI - Porcine bocavirus NP1 protein suppresses type I IFN production by interfering with IRF3 DNA-binding activity. AB - Type I interferon (IFN) and the IFN-induced cellular antiviral responses are the primary defense mechanisms against viral infection; however, viruses always evolve various mechanisms to antagonize this host's IFN responses. Porcine bocavirus (PBoV) is a newly identified porcine parvovirus. In this study, we found that the nonstructural protein NP1 of PBoV inhibits Sendai virus-induced IFN-beta production and the subsequent expression of IFN-stimulating genes (ISGs). Ectopic expression of NP1 significantly impairs IRF3-mediated IFN-beta production; however, it does not affect the expression, phosphorylation, and nuclear translocation of IRF3, the most important transcription factor for IFN synthesis. Coimmunoprecipitation and Chromatin immunoprecipitation assays suggested that NP1 interacts with the DNA-binding domain of IRF3, which in turn blocks the association of IRF3 with IFN-beta promoter. Together, our findings demonstrated that PBoV encodes an antagonist inhibiting type I IFN production, providing a better understanding of the PBoV immune evasion strategy. PMID- 27481270 TI - Ontogeny of learning walks and the acquisition of landmark information in desert ants, Cataglyphis fortis. AB - At the beginning of their foraging lives, desert ants (Cataglyphis fortis) are for the first time exposed to the visual world within which they henceforth must accomplish their navigational tasks. Their habitat, North African salt pans, is barren, and the nest entrance, a tiny hole in the ground, is almost invisible. Although natural landmarks are scarce and the ants mainly depend on path integration for returning to the starting point, they can also learn and use landmarks successfully to navigate through their largely featureless habitat. Here, we studied how the ants acquire this information at the beginning of their outdoor lives within a nest-surrounding array of three artificial black cylinders. Individually marked 'newcomers' exhibit a characteristic sequence of learning walks. The meandering learning walks covering all directions of the compass first occur only within a few centimeters of the nest entrance, but then increasingly widen, until after three to seven learning walks, foraging starts. When displaced to a distant test field in which an identical array of landmarks has been installed, the ants shift their search density peaks more closely to the fictive goal position, the more learning walks they have performed. These results suggest that learning of a visual landmark panorama around a goal is a gradual rather than an instantaneous process. PMID- 27481271 TI - The relevance of performing exercise test before starting supervised physical exercise in asymptomatic cardiovascular patients with rheumatic diseases. AB - OBJECTIVES: To evaluate the impact and risk factors associated with an abnormal exercise test (ET) in systemic inflammatory rheumatic disease (SIRD) patients before commencing supervised physical exercise. METHODS: A total of 235 SIRD patients were enrolled in three controlled clinical trials, including 103 RA, 42 SLE and 57 AS patients. The control group consisted of 231 healthy, sedentary subjects matched for age, gender and BMI. All performed an ET, according to Bruce's or Ellestad's protocol. Cardiovascular disease risk factors, medications, comorbidities and details of each SIRD were assessed. RESULTS: SIRD patients had a higher percentage of abnormal ETs compared with the control group, especially exercise hypertensive behaviour, higher oxygen consumption, higher resting heart rate and heart rate at the first minute of recovery, and chronotropic incompetence (C-Inc) (P < 0.001). The disease itself was involved with higher likelihood of having an abnormal ET [Odds ratio (OR) = 12.0, 95% CI: 2.5, 56.7; P = 0.002 for SLE; OR = 13.56, 95% CI: 6.16, 29.8; P < 0.001 for RA; and OR = 4.31, 95% CI: 1.17, 15.8; P = 0.028, for AS]. Each 10-year increment of age increased the chance of having an abnormal ET by 13% (P = 0.008) in AS patients, as well as hypertension (OR = 7.14, 95% CI: 1.61, 31.6; P = 0.01). Regarding C-Inc, age played a protective role (OR = 0.88, 95% CI: 0.78, 0.99; P = 0.043) in SLE, and ASDAS-ESR was associated with a higher risk in AS (OR = 2.73, 95% CI: 0.93, 8.0; P = 0.067). CONCLUSION: Our results showed a higher prevalence of abnormal ETs in asymptomatic cardiovascular SIRD patients, and the disease itself was associated with a higher likelihood of having an abnormal test, emphasizing the relevance and need of performing it before starting supervised physical exercise. PMID- 27481268 TI - Robotic approach to hepatobiliary surgery. AB - Robot-assisted hepatobiliary surgery has been steadily growing in recent years. It represents an alternative to the open and laparoscopic approaches in selected patients. Endowristed instruments and enhanced visualization provide important advantages in terms of selective bleeding control, microsuturing, and dissection. Cholecystectomies and minor hepatectomies are being performed with comparable results to open and laparoscopic surgery. Even complex procedures, such as major and extended hepatectomies, can have excellent outcomes, in expert hands. The addition of indocyanine green fluorescence provides an additional advantage for recognition of the vascular and biliary anatomy. Future innovations will allow for expanding its use and indications. Robotic surgery has become a very important component of modern minimally invasive surgery and the development of new robotic technology will facilitate a broader adoption of this technique. PMID- 27481272 TI - The spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of the disease. AB - GCA and PMR are conditions of older persons that frequently overlap. The traditional concept of GCA has focused on cranial symptoms such as headache and visual disturbance, but extra-cranial manifestations such as constitutional symptoms, polymyalgia and limb claudication have also long been recognized. These symptoms may coincide with cranial GCA, occur as an independent clinical subset [large-vessel (LV) GCA] or overlap with PMR. Imaging studies have demonstrated that up to one-third of patients with PMR have subclinical LV inflammation at disease outset. The implication of this finding for PMR management is unclear. Pathophysiological studies have emphasized the pivotal role of dendritic cells (DCs) and T cells in the pathogenesis of GCA, and the activation of certain pattern recognition receptors on DCs may determine the clinical subset of GCA. In patients with only PMR clinically, it is conceivable that transmural arterial inflammation has either not yet started or is prevented by unexplored regulatory pathways. This concept is supported by vasculitis of peri-adventitial small vessels and activated DCs in the adventitia of temporal arteries, in the absence of media-infiltrating T cells. This review examines the clinical and pathophysiological spectrum of GCA and its subsets with PMR, the role of newer imaging techniques for GCA diagnosis and the management of these diseases. PMID- 27481273 TI - 'A foot in each world, a heart in none' - whose responsibility is cultural competence? PMID- 27481274 TI - Driver licensing: descriptive epidemiology of a social determinant of Aboriginal and Torres Strait Islander health. AB - OBJECTIVE: Education, employment and equitable access to services are commonly accepted as important underlying social determinants of health. For most Australians, access to health, education and other services is facilitated by private transport and a driver licence. This study aimed to examine licensing rates and predictors of licensing in a sample of Aboriginal and Torres Strait Islander people, as these have previously been poorly described. METHODS: Interviewer-administered surveys were conducted with 625 people 16 years or older in four Aboriginal Community Controlled Health Services in New South Wales and South Australia over a two-week period in 2012-2013. RESULTS: Licensing rates varied from 51% to 77% by site. Compared to not having a licence, having a driver licence was significantly associated with higher odds of full-time employment (adjusted OR 4.0, 95%CI 2.5-6.3) and educational attainment (adjusted OR 1.9, 95%CI 1.2-2.8 for trade or certificate; adjusted OR 4.0, 95%CI 1.6-9.5 for degree qualification). CONCLUSIONS: Variation in driver licensing rates suggests different yet pervasive barriers to access. There is a strong association between driver licensing, education and employment. IMPLICATIONS: Licensing inequality has far-reaching impacts on the broader health and wellbeing of Aboriginal and Torres Strait Islander people, reinforcing the need for appropriate and accessible pathways to achieving and maintaining driver licensing. PMID- 27481275 TI - Biomacromolecular 3D-QSAR to Decipher Molecular Herbicide Resistance in Acetohydroxyacid Synthases. PMID- 27481276 TI - CORAL: Monte Carlo Method as a Tool for the Prediction of the Bioconcentration Factor of Industrial Pollutants. AB - The CORAL software (http://www.insilico.eu/coral/) has been evaluated for application in QSAR modeling of the bioconcentration factor in fish (logBCF). The data used include 237 organic substances (industrial pollutants). Six random splits of the data into sub-training (30-50 %), calibration (20-30 %), test (13 30 %), and validation sets (7-25 %) have been carried out. The following numbers display the average statistical characteristics of the models for the external validation set: correlation coefficient r(2) =0.880+/-0.017 and standard error of estimation s=0.559+/-0.131. The best models were obtained with a combined representation of the molecular structure by SMILES together with hydrogen suppressed graph. PMID- 27481277 TI - Evaluation of Adamantane Derivatives as Inhibitors of Dengue Virus mRNA Cap Methyltransferase by Docking and Molecular Dynamics Simulations. AB - Binding of the Dengue virus S-adenosyl-L-methionine (AdoMet)-dependent mRNA cap methyltransferase (NS5MTaseDV ) with adamantane derivatives was explored using molecular modeling methods and (nucleoside-2'O)-methyltransferase bioassay. The studied compounds include urea derivatives of adamantane and the antiviral drugs amantadine and rimantadine. The urea derivatives of adamantanes had previously been identified as inhibitors of NS5MTaseDV . The docking simulations using GOLD, Glide, and Dock give consistent binding modes and binding affinities of adamantanes in the AdoMet-binding site of NS5MTaseDV and, in particular, yield similar positions for the previously found inhibitors. Combined, they perfectly correspond to the bioassay measurements of nucleoside-2'O-methyltransferase activity of NS5TaseDV , which confirmed inhibitory properties of the active urea adamantane but did not show inhibitory activity for amantadine and rimantadine. We also employed microscopic molecular dynamics (MD) simulations and a linear interaction energy (LIE) method to verify the docking results. The MD/LIE binding free energies of selected protein-inhibitor complexes agree overall with the binding affinities from docking and demonstrate that amantadine and rimantadine only weakly bind at the explored site. The MD simulations also demonstrated the flexible character of a protein loop that is located between the beta2 and beta3 strands and is part of the AdoMet-binding pocket of NS5MTaseDV . PMID- 27481278 TI - Graph-Based Consensus Clustering for Combining Multiple Clusterings of Chemical Structures. AB - Consensus clustering methods have been successfully used for combining multiple classifiers in many areas such as machine learning, applied statistics, pattern recognition and bioinformatics. In this paper, consensus clustering is used for combining the clusterings of chemical structures to enhance the ability of separating biologically active molecules from inactive ones in each cluster. Two graph-based consensus clustering methods were examined. The Quality Partition Index method (QPI) was used to evaluate the clusterings and the results were compared to the Ward's clustering method. Two homogeneous and heterogeneous subsets DS1-DS2 of MDL Drug Data Report database (MDDR) were used for experiments and represented by two 2D fingerprints. The results, obtained by a combination of multiple runs of an individual clustering and a single run of multiple individual clusterings, showed that graph-based consensus clustering methods can improve the effectiveness of chemical structures clusterings. PMID- 27481279 TI - Cyclic Systems Distribution Along Similarity Measures: Insights for an Application to Activity Landscape Modeling. AB - The emerging concept of the activity landscape has been widely applied for structure?activity relationships (SAR) characterization. Since chemical space representation plays a crucial role in activity landscape modeling, an adequate selection of similarity measures is desirable. Herein a set of 658 cyclooxygenase inhibitors were structurally analyzed using 12 molecular similarity representations and two levels of chemotype classification. Then, three uncorrelated similarity measures and mean similarity (obtained with data fusion) were combined with chemotype information using the herein proposed chemotype?similarity graphs. Chemotype-similarity graphs showed the cumulative distribution of molecular pairs with the same and different chemotype along similarity values; leading to establish an interpretable, quantitative and activity independent threshold in similarity measures based on chemotype distributions. This approach gave additional information to similarity measures and can be considered as an interpretable criterion to define high and low similar compounds. The results were applied to model the activity landscape using Structure?Activity Similarity (SAS)-like maps. Some examples of pairs in each region of the SAS-like maps were analyzed which showed valuable SAR information for cyclooxygenase inhibitors. PMID- 27481280 TI - Structure-Activity Relationship Analysis of the Thermal Stabilities of Nitroaromatic Compounds Following Different Decomposition Mechanisms. AB - The decomposition behavior of energetic materials is very important for the safety problems concerning their production, transportation, use and storage, because molecular decomposition is intimately connected to their explosive properties. Nitroaromatic compounds, particularly nitrobenzene derivatives, are often considered as prototypical energetic molecules, and some of them are commonly used as high explosives. Quantitative structure-activity relationship (QSAR) represents a potential tool for predicting the thermal stability properties of energetic materials. But it is reported that constructing general reliable models to predict their stability and their potential explosive properties is a very difficult task. In this work, we make our efforts to investigate the relationship between the molecular structures and corresponding thermal stabilities of 77 nitrobenzene derivatives with various substituent functional groups (in ortho, meta and/or para positions). The proposed best MLR model, developed by the new software QSARINS, based on Genetic Algorithm for variable selection and with various validation tools, is robust, stable and predictive with R(2) of 0.86, QLOO (2) of 0.79 and CCC of 0.90. The results indicated that, though difficult, it is possible to build predictive, externally validated QSAR models to estimate the thermal stability of nitroaromatic compounds. PMID- 27481281 TI - Molecular Dynamics Investigation on the Inhibition of MDM2-p53 Interaction by Polyphenols. AB - Inhibition of the MDM2-p53 interaction has become a new therapeutic strategy to activate wild type p53 in tumors. Quercetin and taxifolin bind to p53 binding hydrophobic groove of MDM2, and alter the conformation of groove as evidenced by 65 ns molecular dynamics simulation. Quercetin showed hydrogen bonding with Gly 16, Ser 17, Phe 55 and Val 93 along with pi-pi interaction with His96 and pi sigma with Phe 55. Taxifolin also showed similar interactions except pi-sigma interaction with Phe 55. Further, we found that binding of ligands lead to the dissociation of MDM2-p53 complex. These ligands form stable hydrophobic interactions with MDM2 which led to complete disruption of MDM2-p53 hydrophobic interactions and dissociation of p53 from the complex. It was found that the pi pi stacking between Tyr 51 of MDM2 and ligands is the critical event in MDM2-p53 dissociation. PMID- 27481282 TI - A Strategy Combining Differential Low-Throughput Screening and Virtual Screening (DLS-VS) Accelerating the Discovery of new Modulators for the Orphan GPR34 Receptor. AB - The DLS-VS strategy was developed as an integrated method for identifying chemical modulators for orphan GPCRs. It combines differential low-throughput screening (DLS) and virtual screening (VS). The two cascaded techniques offer complementary advantages and allow the experimental testing of a minimal number of compounds. First, DLS identifies modulators specific for the considered receptor among a set of receptors, through the screening of a small library with diverse chemical compounds. Then, an active molecular model of the receptor is built by homology to a validated template, and it is progressively refined by rotamers modification for key side-chains, by VS of the already screened library, and by iterative selection of the model generating the best enrichment. The refined active model is finally used for the VS of a large chemical library and the selection of a small set of compounds for experimental testing. Applied to the orphan receptor GPR34, the DLS-VS strategy combined the experimental screening of 20 000 compounds and the virtual screening of 1 250 000 compounds. It identified one agonist and eight inverse agonists, showing a high chemical diversity. We describe the method. The strategy can be applied to other GPCRs. PMID- 27481283 TI - An Enzyme-based 1:2 Demultiplexer Interfaced with an Electrochemical Actuator. AB - An enzyme-based 1:2 demultiplexer is designed in a flow system composed of three cells where each one is modified with a different enzyme: hexokinase, glucose dehydrogenase and glucose-6-phosphate dehydrogenase. The Input signal activating the biocatalytic cascade is represented by glucose, while the Address signal represented by ATP is responsible for directing the Input signal to one of the output channels, depending on the logic value of the Address. The biomolecular 1:2 demultiplexer is extended to include two electrochemical actuators releasing entrapped DNA molecules in the active output channel. The modular design of the system allows for easy exchange and extension of the functional elements. The present demultiplexer can be easily integrated in various biomolecular logic systems, including different logic gates based on the enzyme- or DNA-based reactions, as well as containing different chemical actuators, for example, with a biomolecular release function. PMID- 27481284 TI - Sequential epitopes of Dermatophagoides farinae allergens identified using peptide microarray-based immunoassay. AB - House dust mites produce over 30 proteins proposed to induce immunoglobulin E (IgE) antibody production in patients. Continued identification of IgE-binding epitopes of these allergens is critical to advancing diagnosis and treatment of allergic disease. To identify possible sequential IgE-binding epitopes of the major- and mid-potency allergens from the house dust mite Dermatophagoides farinae by peptide microarray-based immunoassay, nucleotide sequences of D. farinae allergens (Der f) 1, 2, 4, 5, and 7 were used to generate overlapping peptides covering the full protein sequences minus signal peptides. Short peptides were printed onto microarray chips. Because asthma occurs as a symptom of mite allergy more commonly among children than adults, the peptide chips were exposed to sera pooled from six serum-positive pediatric patients with D. farinae hypersensitivity and six serum-negative control children for screening sequential IgE-binding epitopes by IgE immunolabeling. Higher-than-average immunolabel signal intensity was observed for 21 short peptides in the serum-positive group (P < 0.01). Due to sequence overlap, these 21 signals represented four fragments of Der f 1 (amino acid positions 46-53, 71-78, 99-110, 179-186), three fragments of Der f 2 (15-22, 80-89, 106-113), six fragments of Der f 4 (69-82, 107-116, 225 232, 261-268, 355-365, 483-496), one fragment of Der f 5 (102-109), and three fragments of Der f 7 (32-39, 52-64, 100-107). These findings not only demonstrate the utility of a peptide microarray immunoassay in identifying epitopes for these allergens, but also provide a foundation for future exploration of specific immunotherapies. (c) 2016 IUBMB Life, 68(10):792-798, 2016. PMID- 27481285 TI - Spatial and successional dynamics of microbial biofilm communities in a grassland stream ecosystem. AB - Biofilms represent a metabolically active and structurally complex component of freshwater ecosystems. Ephemeral prairie streams are hydrologically harsh and prone to frequent perturbation. Elucidating both functional and structural community changes over time within prairie streams provides a general understanding of microbial responses to environmental disturbance. We examined microbial succession of biofilm communities at three sites in a third-order stream at Konza Prairie over a 2- to 64-day period. Microbial abundance (bacterial abundance, chlorophyll a concentrations) increased and never plateaued during the experiment. Net primary productivity (net balance of oxygen consumption and production) of the developing biofilms did not differ statistically from zero until 64 days suggesting a balance of the use of autochthonous and allochthonous energy sources until late succession. Bacterial communities (MiSeq analyses of the V4 region of 16S rRNA) established quickly. Bacterial richness, diversity and evenness were high after 2 days and increased over time. Several dominant bacterial phyla (Beta-, Alphaproteobacteria, Bacteroidetes, Gemmatimonadetes, Acidobacteria, Chloroflexi) and genera (Luteolibacter, Flavobacterium, Gemmatimonas, Hydrogenophaga) differed in relative abundance over space and time. Bacterial community composition differed across both space and successional time. Pairwise comparisons of phylogenetic turnover in bacterial community composition indicated that early-stage succession (<=16 days) was driven by stochastic processes, whereas later stages were driven by deterministic selection regardless of site. Our data suggest that microbial biofilms predictably develop both functionally and structurally indicating distinct successional trajectories of bacterial communities in this ecosystem. PMID- 27481286 TI - Three successful deliveries involving a woman with congenital afibrinogenaemia - conventional fibrinogen concentrate infusion vs. 'as required' fibrinogen concentrate infusion based on changes in fibrinogen clearance. PMID- 27481287 TI - Motoneuron responsiveness to corticospinal tract stimulation during the silent period induced by transcranial magnetic stimulation. AB - Based on H-reflex data, spinal mechanisms are proposed to be responsible for the first 50-80 ms of the transcranial magnetic stimulation (TMS)-induced silent period. As several methodological issues can compromise H-reflex validity as a measure of motoneuron excitability, this study used transmastoid stimulation to elicit cervicomedullary motor evoked potentials (CMEPs) during the silent period. Eleven subjects made 1-3 visits which involved 32 or 44 brief (~3 s) isometric elbow flexor contractions at 25 % of maximal torque. During each contraction, transmastoid stimulation was delivered in isolation to elicit an unconditioned CMEP and at interstimulus intervals (ISIs) ranging from 50 to 150 ms after TMS to elicit a conditioned CMEP. Stimulus intensities for TMS and transmastoid stimulation were set to elicit a silent period of ~200 ms and an unconditioned CMEP of 15, 50, or 85 % of the maximal compound muscle action potential (M max), respectively. At all ISIs and intensities of transmastoid stimulation, the conditioned CMEP was significantly smaller than the unconditioned CMEP (p < 0.001). However, suppression of the conditioned CMEP was significantly less at 85 % compared to 15 or 50 % M max (p = 0.001). Contrary to published H-reflex data, the conditioned CMEP did not recover within 50-80 ms, remaining significantly suppressed at the longest ISI tested (150 ms). These data suggest the spinal portion of the TMS-evoked silent period is considerably longer than reported previously. Transmastoid stimulation, unlike peripheral nerve stimulation, does not impact proprioceptive inflow to motoneurons. Hence, relative to the H-reflex, the CMEP will be subjected to greater afferent-mediated disfacilitation and inhibition due to the TMS-induced muscle twitch. PMID- 27481288 TI - The characteristics and functions of a miniature inverted-repeat transposable element TaMITE81 in the 5' UTR of TaCHS7BL from Triticum aestivum. AB - Miniature inverted-repeat transposable elements (MITEs) are truncated derivatives of autonomous DNA transposons, and are dispersed abundantly in eukaryotic and prokaryotic genomes. In this article, a MITE, TaMITE81, was isolated from the 5' untranslated region (UTR) of TaCHS7BL, chalcone synthase (CHS) catalyzing the first committed step of anthocyanin biosynthesis, in the wheat cultivar 'Opata' with white grain. TaMITE81 was only 81 nucleotides, including a terminal inverted repeat with 39 nucleotides and was flanked by two nucleotides, "TA", target site duplications that were typical features of stowaway-like MITEs. Compared with the wheat cultivar 'Gy115' with purple grain, which is without the insertion, the expression of TaCHS7BL was lower in several organs of 'Opata'. The insertion of TaMITE81 into the 5' UTR of the GUS gene also reduced the transient expression of GUS on the coleoptiles of 'Opata', which means the insertion of TaMITE81 was the reason for the low expression of TaCHS7BL in 'Opata'. But the genotype of TaCHS7BL was not linked to phenotype of grain color in the RILs derived from a cross 'Gy115' and 'Opata'. The TaMITE81 density of the hexaploid variety of T. aestivum was more than 10 times that of diploid relatives, which implies that polyploidization caused the amplification of TaMITE81 homologous sequences. Further research should be conducted on decoding the relationship between TaCHS7BL and other traits relative to anthocyanin biosynthesis in wheat, and discovering the mechanism of TaMITE81 transposon action. PMID- 27481289 TI - Surface guidance of stem cell behavior: Chemically tailored co-presentation of integrin-binding peptides stimulates osteogenic differentiation in vitro and bone formation in vivo. AB - Surface modification stands out as a versatile technique to create instructive biomaterials that are able to actively direct stem cell fate. Chemical functionalization of titanium has been used in this work to stimulate the differentiation of human mesenchymal stem cells (hMSCs) into the osteoblastic lineage, by covalently anchoring a synthetic double-branched molecule (PTF) to the metal that allows a finely controlled presentation of peptidic motifs. In detail, the effect of the RGD adhesive peptide and its synergy motif PHSRN is studied, comparing a random distribution of the two peptides with the chemically tailored disposition within the custom made synthetic platform, which mimics the interspacing between the motifs observed in fibronectin. Contact angle measurement and XPS analysis are used to prove the efficiency of functionalization. We demonstrate that, by rationally designing ligands, stem cell response can be efficiently guided towards the osteogenic phenotype: In vitro, PTF-functionalized surfaces support hMSCs adhesion, with higher cell area and formation of focal contacts, expression of the integrin receptor alpha5beta1 and the osteogenic marker Runx2, and deposition a highly mineralized matrix, reaching values of mineralization comparable to fibronectin. Our strategy is also demonstrated to be efficient in promoting new bone growth in vivo in a rat calvarial defect. These results highlight the efficacy of chemical control over the presentation of bioactive peptides; such systems may be used to engineer bioactive surfaces with improved osseointegrative properties, or can be easily tuned to generate multi-functional coatings requiring a tailored disposition of the peptidic motifs. STATEMENT OF SIGNIFICANCE: Organic coatings have been proposed as a solution to foster osseointegration of orthopedic implants. Among them, extracellular matrix-derived peptide motifs are an interesting biomimetic strategy to harness cell-surface interactions. Nonetheless, the combination of multiple peptide motifs in a controlled manner is essential to achieve receptor specificity and fully exploit the potentiality of synthetic peptides. Herein, we covalently graft to titanium a double branched molecule to guide stem cell fate in vitro and generate an osseoinductive titanium surface in vivo. Such synthetic ligand allows for the simultaneous presentation of two bioactive motifs, thus is ideal to test the effect of synergic sequences, such as RGD and PHSRN, and is a clear example of the versatility and feasibility of rationally designed biomolecules. PMID- 27481290 TI - Biomimetic hydrogel with tunable mechanical properties for vitreous substitutes. AB - The vitreous humor of the eye is a biological hydrogel principally composed of collagen fibers interspersed with hyaluronic acid. Certain pathological conditions necessitate its removal and replacement. Current substitutes, like silicone oils and perfluorocarbons, are not biomimetic and have known complications. In this study, we have developed an in situ forming two-component biomimetic hydrogel with tunable mechanical and osmotic properties. The components are gellan, an analogue of collagen, and poly(methacrylamide-co methacrylate), an analogue of hyaluronic acid; both endowed with thiol side groups. We used response surface methodology to consider seventeen possible hydrogels to determine how each component affects the optical, mechanical, sol gel transition temperature and swelling properties. The optical and physical properties of the hydrogels were similar to vitreous. The shear storage moduli ranged from 3 to 358Pa at 1Hz and sol-gel transition temperatures from 35.5 to 43 degrees C. The hydrogel had the ability to remain swollen without degradation for four weeks in vitro. Three hydrogels were tested for biocompatibility on primary porcine retinal pigment epithelial cells, human retinal pigment epithelial cells, and fibroblast (3T3/NIH) cells, by electric cell-substrate impedance sensing system. The two-component hydrogels allowed for the tuning and optimizing of mechanical, swelling, and transition temperature to obtain three biocompatible hydrogels with properties similar to the vitreous. Future studies include testing of the optimized hydrogels in animal models for use as a long-term substitute, whose preliminary results are mentioned. STATEMENT OF SIGNIFICANCE: Although hydrogels are researched as long-term vitreous substitute, none have advanced sufficiently to reach clinical application. Our work focuses on the development of a novel two component in situ forming hydrogel that bio-mimic the natural vitreous. Our thiol-containing copolymers can be injected as an aqueous solution into the vitreous cavity wherein, at physiological temperature, the rigid component will instantaneously form a physical gel imbedding the random coil copolymer. Upon subsequent oxidation, the two components will form disulfide cross-links and a stable reversible hydrogel capable of providing osmotic pressure to reattach the retina. It may be left in the eye permanently or easily removed by injection of a simple reducing agent to cleave the disulfide bonds, rather than surgery. This contribution is significant because it is expected to provide patients with a much better quality of life by improving surgical outcomes, creating much less post-operative burden, and reducing the need for secondary surgeries. PMID- 27481291 TI - Role of scaffold mean pore size in meniscus regeneration. AB - Recently, meniscus tissue engineering offers a promising management for meniscus regeneration. Although rarely reported, the microarchitectures of scaffolds can deeply influence the behaviors of endogenous or exogenous stem/progenitor cells and subsequent tissue formation in meniscus tissue engineering. Herein, a series of three-dimensional (3D) poly(epsilon-caprolactone) (PCL) scaffolds with three distinct mean pore sizes (i.e., 215, 320, and 515MUm) were fabricated via fused deposition modeling. The scaffold with the mean pore size of 215MUm significantly improved both the proliferation and extracellular matrix (ECM) production/deposition of mesenchymal stem cells compared to all other groups in vitro. Moreover, scaffolds with mean pore size of 215MUm exhibited the greatest tensile and compressive moduli in all the acellular and cellular studies. In addition, the relatively better results of fibrocartilaginous tissue formation and chondroprotection were observed in the 215MUm scaffold group after substituting the rabbit medial meniscectomy for 12weeks. Overall, the mean pore size of 3D-printed PCL scaffold could affect cell behavior, ECM production, biomechanics, and repair effect significantly. The PCL scaffold with mean pore size of 215MUm presented superior results both in vitro and in vivo, which could be an alternative for meniscus tissue engineering. STATEMENT OF SIGNIFICANCE: Meniscus tissue engineering provides a promising strategy for meniscus regeneration. In this regard, the microarchitectures (e.g., mean pore size) of scaffolds remarkably impact the behaviors of cells and subsequent tissue formation, which has been rarely reported. Herein, three three-dimensional poly(epsilon-caprolactone) scaffolds with different mean pore sizes (i.e., 215, 320, and 515MUm) were fabricated via fused deposition modeling. The results suggested that the mean pore size significantly affected the behaviors of endogenous or exogenous stem/progenitor cells and subsequent tissue formation. This study furthers our understanding of the cell-scaffold interaction in meniscus tissue engineering, which provides unique insight into the design of meniscus scaffolds for future clinical application. PMID- 27481292 TI - A solo fluorogenic probe for the real-time sensing of SO3(2-) and SO4(2-)/HSO4(-) in aqueous medium and live cells by distinct turn-on emission signals. AB - A judiciously designed fluorogenic probe (L) rendered rapid and differential turn on responses by exhibiting strong blue fluorescence (lambdaem = 442 nm) for SO3(2 ) and greenish-yellow fluorescence (lambdaem = 511 nm) for SO4(2-)/HSO4(-) in 100% aqueous medium and live cells. PMID- 27481293 TI - Changes in sarcomere lengths of the human vastus lateralis muscle with knee flexion measured using in vivo microendoscopy. AB - Sarcomeres are the basic contractile units of muscle, and their lengths influence muscle force-generating capacity. Despite their importance, in vivo sarcomere lengths remain unknown for many human muscles. Second harmonic generation (SHG) microendoscopy is a minimally invasive technique for imaging sarcomeres in vivo and measuring their lengths. In this study, we used SHG microendoscopy to visualize sarcomeres of the human vastus lateralis, a large knee extensor muscle important for mobility, to examine how sarcomere lengths change with knee flexion and thus affect the muscle's force-generating capacity. We acquired in vivo sarcomere images of several muscle fibers of the resting vastus lateralis in six healthy individuals. Mean sarcomere lengths increased (p=0.031) from 2.84+/ 0.16MUm at 50 degrees of knee flexion to 3.17+/-0.13MUm at 110 degrees of knee flexion. The standard deviation of sarcomere lengths among different fibers within a muscle was 0.21+/-0.09MUm. Our results suggest that the sarcomeres of the resting vastus lateralis at 50 degrees of knee flexion are near optimal length. At a knee flexion angle of 110 degrees the resting sarcomeres of vastus lateralis are longer than optimal length. These results show a smaller sarcomere length change and greater conservation of force-generating capacity with knee flexion than estimated in previous studies. PMID- 27481294 TI - A Search for the Optimum Selenium Source to Obtain Mushroom-Derived Chemopreventive Preparations. AB - The objective of this research was to test whether selenium-yeast (Se-yeast) is a better source of selenium than sodium selenite for accumulation in mycelia and immunoactive cell wall polysaccharides. Culture media were enriched in selenium to a concentration of 20 ug/mL. Selenium was added to the medium either in the form of sodium selenite or in form of Se-yeast (Sel-Plex; Alltech Inc., Lexington, KY). The total selenium concentrations in the mycelium biomass and in the isolated crude polysaccharides were determined using atomic absorption spectroscopy. We found that selenium accumulated more efficiently in cultures enriched with Se-yeast. A higher concentration of selenium was also found in the crude polysaccharide fractions isolated from the mycelium grown in Se-yeast enriched media. With the use of the needle trap gas chromatography-mass spectrometry method, we found that there are significant differences in the composition of the volatile aroma and flavor compounds secreted by the mycelia cultivated in different media. PMID- 27481295 TI - Antibacterial and Antifungal Activities of Lectin Extracted from Fruiting Bodies of the Korean Cauliflower Medicinal Mushroom, Sparassis latifolia (Agaricomycetes). AB - In this article we describe the isolation and characterization of a novel lectin from fruiting bodies of the mushroom Sparassis latifolia. The antibacterial activity of the purified lectin against Escherichia coli and resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa as well as the antifungal activity against Candida and Fusarium species were determined. Circular dichroism spectroscopy and the tryptophan blue shift assay indicated that the lectin interacts with microbial surfaces. This suggests the potential of the lectin isolated from S. latifolia, a valuable source of bioactive constituents, as a therapeutic in pharmaceutical agent. PMID- 27481296 TI - Effects of Black Hoof Medicinal Mushroom, Phellinus linteus (Agaricomycetes), Polysaccharide Extract in Streptozotocin-Induced Diabetic Rats. AB - In this article we report the healing effects of a Phellinus linteus fruiting body hot water extract (PLE) in streptozotocin (STZ)-induced diabetic rats. PLE was given before and after STZ. The preprotective, protective, and postprotective effects of PLE on STZ-induced oxidative stress were studied using biochemical (caspase 3 activity, cytosolic-to-lysosomal ratio of cathepsin B and L, DNA fragmentation levels), ordinary histological and immuno-histochemical investigation parameters. Following oral administration of PLE after STZ application, the serum glucose concentration significantly decreased up to 41.13% compared with the control group (P < 0.05). The hypoglycemic potential of the PLE was further supported by an increase of insulin secretion in the islets of Langerhans. In addition, the number of cells in Langerhans islets increased by 45.89% when PLE was given after STZ application. On the other hand, the use of PLE before oxidative stress could not prevent the onset of diabetes. This is, to our knowledge, the first study of the effect of application time of orally administered Ph. Linteus hot water extract on STZ-induced diabetes. PMID- 27481297 TI - beta-(1->3)-Glucan of the Southern Bracket Mushroom, Ganoderma australe (Agaricomycetes), Stimulates Phagocytosis and Interleukin-6 Production in Mouse Peritoneal Macrophages. AB - Ganoderma australe was studied to determine the composition of the cell wall, and polysaccharide fraction SK5 was obtained after freeze-thawing an aqueous 5% potassium hydroxide extraction. The monosaccharide composition of the SK5 fraction revealed by gas chromatography-mass spectrometry showed 81.3% glucose, and analyses by 13C nuclear magnetic resonance spectroscopy confirmed a beta glucan with glycosidic links of the (1->3)-beta type and most likely 4-O substituted. In addition, the biological effect of the beta-glucan from G. australe was evaluated via in vitro cell cultures of peritoneal macrophages isolated from Swiss mice. Biological assays were assessed for toxicity and cell activation, interleukin-6 cytokine concentrations, and the ability to stimulate phagocytic activity. There was an increase in interleukin-6 by approximately 111% with 1.0 ug/mL of polysaccharide, and phagocyte activity was increased in all concentrations examined, obtaining 52.3% with 0.25 ug/mL polysaccharide. The results indicate that a beta-(1->3)-glucan isolated from G. australe can be classified as a biological response modifier. PMID- 27481298 TI - Study of Antimicrobial and Cytotoxic Potential of the Oyster Mushroom Pleurotus ostreatus cv. Florida (Agaricomycetes). AB - This work was undertaken to evaluate in vitro antimicrobial and cytotoxic potential of Pleurotus ostreatus cv. Florida. Mushroom basidiocarps were extracted in water:ethanol (1:1, v/v), and the resulting extract was subjected to antimicrobial studies against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella oxytoca, Bacillus subtilis, and Candida albicans. Cytotoxic potential on viable human leukocytes was studied. In vitro results showed excellent antimicrobial and cytotoxic potentials of the mushroom extract. Thus, functional properties of P. ostreatus cv. Florida could be used in the search for novel therapeutics. PMID- 27481299 TI - Comparison of Major Bioactive Compounds of the Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycetes), Fruiting Bodies Cultured on Wheat Substrate and Pupae. AB - In this study, the main bioactive compounds of the fruit bodies of Cordyceps militaris-such as adenosine, cordycepin, polysaccharides, mannitol, superoxide dismutase (SOD), and carotenoids-were cultivated on wheat and pupae, as well as sclerotium (the pupae portion) and sclerotium with fruiting bodies. The amounts of adenosine and polysaccharide in all the tested samples (except for the polysaccharides of sclerotium) are higher than the quality standards (adenosine >=0.055% and polysaccharide >=2.5%) determined by the Ministry of Health of the People's Republic of China. As the most important bioactive compound in C. militaris, cordycepin is the highest in the fruiting bodies on pupae than in other samples, whereas it is the lowest in the sclerotium. The amounts of cordycepin, carotenoids, and SOD were higher in the fruiting bodies on pupae than that in the fruiting bodies on wheat, whereas the amounts of adenosine, polysaccharides, and mannitol were higher in the fruiting bodies on wheat than in the fruiting bodies on pupae. There was no significant difference in the amounts of cordycepin, carotenoids, and SOD in the sclerotium with fruiting bodies and the fruiting bodies on wheat. The adenosine, polysaccharide, and mannitol contents in the sclerotium with fruiting bodies were significantly lower than those of the fruiting bodies on wheat. Overall, the results of this evaluation could not distinguish which is better: the fruiting bodies on pupae or those on wheat; each has its own merits. The fruiting bodies of C. militaris cultivated on both wheat and pupae are important candidates for medicinal and tonic use for the welfare of humankind. PMID- 27481300 TI - Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycetes): A Potential Bioresource for Commercialization in Sikkim Himalaya, India. AB - Ophiocordyceps sinensis has a long history of use in Tibetan traditional medicine and traditional Chinese medicine as a powerful tonic and aphrodisiac. The species is inextricably linked to the trade of medicinal and aromatic plants in East Asia. Its demand has increased substantially in the international market, and its collection and trade have significantly improved the socioeconomic status of the people in some regions. Nonetheless, in Sikkim this resource is still untapped formally, but it is traded illegally. Formal legalization and the community's involvement will ensure the conservation and sustainability of the species, as well as proper management of harvesting areas and monitoring of pressure on Yartsa Gunbu to exploit it. PMID- 27481301 TI - Diversity of Polypore Bracket Mushrooms, Polyporales (Agaricomycetes), Recorded in Armenia and Their Medicinal Properties. AB - The list of polypore bracket mushrooms (Polyporales) recorded in Armenia is presented. The order Polyporales in Armenia is currently represented by 87 species (4 varieties) belonging to 47 genera. Information regarding the study of the medicinal properties (e.g., antifungal, antibacterial, mitogenic, regenerative, antioxidant, proteolytic) of genetically identified mycelial collections of several polypore species-mainly from the genera Daedalea, Fomes, Fomitopsis, Ganoderma, Laetiporus, Piptoporus, Polyporus, and Trametes-is reported, as well. PMID- 27481302 TI - In Vitro Studies of Secondary Metabolite-Related Responses in Some Species of Genus Grifola (Agaricomycetes) from Argentina. AB - Grifola gargal Singer and Grifola sordulenta (Mont.) Singer mushrooms are related to Grifola frondosa (Dicks.) Gray, which is well known for its medicinal properties. In vitro studies were performed to find a useful guide for optimizing the environmental parameters through biotransformation of lignocellulosic materials and basidiome development, also considering secondary metabolism related responses (SMRRs) associated with these processes and the variability among species and strains; this optimization is necessary to make the mushroom's industrial cultivation profitable. Morphological features of mycelial cultures revealed that intraspecific variability was of taxonomic relevance. A low ligninolytic capacity in studied Grifola species was observed when compared with 2 control species: G. frondosa and Ganoderma lucidum. Experiments with nutrient media containing different carbohydrate sources indicated that G. gargal mycelia grew better in xylulose and G. sordulenta, in xylulose or cellulose; in addition, the latter species presented cellobiose dehydrogenase activity. An additional study of SMRRs under different light conditions (aroma, pigmentation, and morphogenic manifestations) showed that white light was better than blue, green, or red-filtered light at inducing advanced SMRRs. The results of SMRR stimulation are proposed as useful guidance for optimizing the environmental parameters for bioprocesses aimed at metabolite production. PMID- 27481303 TI - Gas Chromatography-Mass Spectrometry Analysis of Constituent Oil from Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), from Nigeria. AB - Gas chromatography-mass spectrometry analysis of constituent oil from dried Ganoderma lucidum was carried out. Fresh G. lucidum obtained from its natural environment was thoroughly washed with distilled water and air-dried for 2 weeks and the component oils were extracted and analyzed. Four predominant components identified were pentadecanoic acid, 14-methyl-ester (retention time [RT] = 19.752 minutes; percentage total = 25.489), 9,12-octadecadienoic acid (Z,Z)- (RT = 21.629 minutes and 21.663 minutes; percentage total = 25.054), n-hexadecanoic acid (RT = 20.153 minutes; percentage total = 24.275), and 9-octadecenoic acid (Z)-, methyl ester (RT = 21.297 minutes; percentage total = 13.027). The two minor oils identified were 9,12-octadecadienoic acid, methyl ester, (E,E)- and octadecanoic acid, methyl ester (RT = 21.246 minutes and 21.503 minutes; percentage total = 7.057 and 5.097, respectively). PMID- 27481304 TI - Endoscopic Pancreas Fluid Collection: Methods and Relevance for Clinical Care and Translational Science. AB - Pancreatic secretions have an important role in the regulation of a normal nutritional state but can be altered owing to a variety of pathophysiological mechanisms in the context of exocrine pancreatic disease. The development of an endoscopic technique for collection of pancreatic fluid, termed endoscopic pancreatic function testing, has led to improved understanding of these alterations and is particularly helpful to characterize chronic pancreatitis. In addition, investigators have found endoscopically collected pancreatic fluid to be a valuable biofluid for the purposes of translational science. Techniques such as proteomic, cytokine, genetic mutation, DNA methylation, and microRNA analyses, among others, can be utilized to gain a better understanding of the molecular characteristics of chronic pancreatitis and other pancreatic diseases. Endoscopic collection of pancreatic fluid is safe and relatively straightforward, permitting opportunities for longitudinal analysis of these translational markers throughout the course of disease. This manuscript summarizes our current knowledge of pancreatic fluid, with an emphasis on proper techniques for sample collection and handling, its clinical utility, and preliminary observations in translational science. PMID- 27481305 TI - A Rapid Bedside Screen to Predict Unplanned Hospitalization and Death in Outpatients With Cirrhosis: A Prospective Evaluation of the Clinical Frailty Scale. AB - OBJECTIVES: Screening tools to determine which outpatients with cirrhosis are at highest risk for unplanned hospitalization are lacking. Frailty is a novel prognostic factor but conventional screening for frailty is time consuming. We evaluated the ability of a 1 min bedside screen (Clinical Frailty Scale (CFS)) to predict unplanned hospitalization or death in outpatients with cirrhosis and compared the CFS with two conventional frailty measures (Fried Frailty Criteria (FFC) and Short Physical Performance Battery (SPPB)). METHODS: We prospectively enrolled consecutive outpatients from three tertiary care liver clinics. Frailty was defined by CFS >4. The primary outcome was the composite of unplanned hospitalization or death within 6 months of study entry. RESULTS: A total of 300 outpatients were enrolled (mean age 57 years, 35% female, 81% white, 66% hepatitis C or alcohol-related liver disease, mean Model for End-Stage Liver Disease (MELD) score 12, 28% with ascites). Overall, 54 (18%) outpatients were frail and 91 (30%) patients had an unplanned hospitalization or death within 6 months. CFS >4 was independently associated with increased rates of unplanned hospitalization or death (57% frail vs. 24% not frail, adjusted odds ratio 3.6; 95% confidence interval (CI): 1.7-7.5; P=0.0008) and there was a dose response (adjusted odds ratio 1.9 per 1-unit increase in CFS, 95% CI: 1.4-2.6; P<0.0001). Models including MELD, ascites, and CFS >4 had a greater discrimination (c statistic=0.84) than models using FFC or SPPB. CONCLUSIONS: Frailty is strongly and independently associated with an increased risk of unplanned hospitalization or death in outpatients with cirrhosis. The CFS is a rapid screen that could be easily adopted in liver clinics to identify those at highest risk of adverse events. PMID- 27481306 TI - Financial Incentives for Promoting Colorectal Cancer Screening: A Randomized, Comparative Effectiveness Trial. AB - OBJECTIVES: Offering financial incentives to promote or "nudge" participation in cancer screening programs, particularly among vulnerable populations who traditionally have lower rates of screening, has been suggested as a strategy to enhance screening uptake. However, effectiveness of such practices has not been established. Our aim was to determine whether offering small financial incentives would increase colorectal cancer (CRC) screening completion in a low-income, uninsured population. METHODS: We conducted a randomized, comparative effectiveness trial among primary care patients, aged 50-64 years, not up-to-date with CRC screening served by a large, safety net health system in Fort Worth, Texas. Patients were randomly assigned to mailed fecal immunochemical test (FIT) outreach (n=6,565), outreach plus a $5 incentive (n=1,000), or outreach plus a $10 incentive (n=1,000). Outreach included reminder phone calls and navigation to promote diagnostic colonoscopy completion for patients with abnormal FIT. Primary outcome was FIT completion within 1 year, assessed using an intent-to-screen analysis. RESULTS: FIT completion was 36.9% with vs. 36.2% without any financial incentive (P=0.60) and was also not statistically different for the $10 incentive (34.6%, P=0.32 vs. no incentive) or $5 incentive (39.2%, P=0.07 vs. no incentive) groups. Results did not differ substantially when stratified by age, sex, race/ethnicity, or neighborhood poverty rate. Median time to FIT return also did not differ across groups. CONCLUSIONS: Financial incentives, in the amount of $5 or $10 offered in exchange for responding to mailed invitation to complete FIT, do not impact CRC screening completion. PMID- 27481307 TI - A Genetic Variation in the Neonatal Fc-Receptor Affects Anti-TNF Drug Concentrations in Inflammatory Bowel Disease. AB - OBJECTIVES: Ample evidence exists that Anti-tumor necrosis factor (TNF) concentrations during induction determine short and long-term outcome in inflammatory bowel disease (IBD). We investigated if a variable number of tandem repeats (VNTR) polymorphism in the neonatal Fc-receptor (FcRn), responsible for extending half-life of IgG, influences anti-TNF concentrations in patients with IBD. METHODS: Retrospective single-center study, including a cohort of 395 infliximab (IFX) naive IBD patients treated with IFX 5 mg/kg on weeks 0, 2, and 6 and a second cohort of 139 adalimumab naive patients, treated with adalimumab 160 80-40 mg on weeks 0, 2, and 4. Area under the serum anti-TNF concentration-time curve (AUC), from week 2 and 6 for IFX and week 2 and 4 for adalimumab, was used to identify factors influencing these drug concentrations. RESULTS: The VNTR2/VNTR3 genotype was associated with a 14% lower IFX AUC compared with patients homozygous for VNTR3/VNTR3 (P=0.03), although this effect became apparent only when immunogenicity (26% lower concentrations, P=9 * 10-5) was not present. Prior anti-TNF use predicted a 27% lower IFX AUC (P=0.002). Similarly, VNTR2/VNTR3 patients had a 24% predicted lower adalimumab AUC than VNTR3/VNTR3 patients (P=0.005). The combined presence of VNTR2/VNTR3 genotype, male gender, and prior IFX use predicted a 41% lower adalimumab AUC concentration (P=0.04). CONCLUSIONS: The VNTR2/3 genotype in the FcRn gene is associated with lower IFX but also lower adalimumab drug exposure during induction in patients with IBD. Previously identified pharmacokinetic modifying factors were confirmed. Identifying risk factors in patients is important as higher induction doses may be needed to ensure optimal disease outcome. PMID- 27481308 TI - Cancer in Elderly Onset Inflammatory Bowel Disease: A Population-Based Study. AB - OBJECTIVES: Cancer may be a complication of inflammatory bowel disease (IBD) or its treatment. In elderly onset IBD patients the risk of malignancy is of particular concern. We studied this risk in a population-based cohort of elderly onset IBD patients. METHODS: In a French population-based cohort, we identified 844 patients aged >60 years at IBD diagnosis from 1988 to 2006, including 370 Crohn's disease (CD) and 474 ulcerative colitis (UC). We compared incidence of cancer among IBD patients with that observed in the French Network of population based Cancer Registries (FRANCIM). Confidence interval (CI) was estimated assuming a Poisson-specific law for rare events. Results were expressed using the standardized incidence ratios (SIRs) and their CI 95%. RESULTS: Median age at IBD diagnosis was 70 (65-76) years in CD and 69 (64-74) in UC. Median follow-up was 6 (2-11) years for both diseases with a number of person-years of 5,598. Among the 844 elderly onset IBD cases, 98 (11.6%; 42 CD and 56 UC) developed a cancer after IBD diagnosis (67 men and 31 women) corresponding to an overall SIR of 0.97 (0.80 1.18). These cancers occurred at a median age of 77 years (71-80) and 75 years (71-81) in patients with CD and UC, respectively. Median time between IBD diagnosis and cancers was 78 months (40-121). There was no significant increased risk of colorectal cancer in IBD (SIR=1.03 (0.62-1.70), CD (SIR=1.20 (0.57-2.52) nor in UC (SIR=0.91 (0.45-1.82) without significant protective role of 5 aminosalicylic acid (hazard ratio (HR)=0.7 (0.2-2.6)). No significant risk for other intestinal cancers was found, especially for small bowel carcinoma. An increased risk of malignant lymphoproliferative disorders was found in all IBD and in CD: SIR=2.49 (1.25-4.99) and SIR=3.09 (1.16-8.23), respectively. An increased risk of myeloproliferative disorders was found in all IBD (SIR=2.18 (1.09-4.35)). Thiopurines exposure, using a time-dependant Cox model, was not found as associated with an increased risk to develop cancer, HR=0.90 (0.48 1.68). CONCLUSIONS: There is no increased risk for developing intestinal cancer among patients with elderly onset IBD in this population-based cohort. There are increased risks of developing lymphoproliferative and myeloproliferative disorders in all IBD. Thiopurines exposure was not found as associated with an increased risk to lymphoproliferative disorders. These data reinforce the difference between elderly onset IBD as compared with patients with younger age at IBD onset. PMID- 27481309 TI - A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn's Disease. AB - OBJECTIVES: To assess the safety and efficacy of brodalumab, a human anti interleukin-17 receptor monoclonal antibody, in patients with moderate-to-severe Crohn's disease (CD). METHODS: Phase 2, randomized, double-blind, placebo controlled, dose-ranging study in patients with moderate-to-severe CD and evidence of active inflammation. Patients were randomized 1:1:1:1 to receive brodalumab (210, 350, or 700 mg at baseline and week 4) or placebo. The primary end point was proportion of patients achieving Crohn's disease activity index (CDAI) remission (<=150) at week 6. Secondary end points included proportion of patients with CDAI response (reduction from baseline of >=100) at week 6 and change from baseline in CDAI at week 6. RESULTS: The study was terminated early based on an imbalance in worsening CD in active treatment groups. At the time of termination, 130 patients had been randomized. At week 6, remission rates were 3% (210 mg), 15% (350 mg), 9% (700 mg), and 3% (placebo) and CDAI response occurred in 16% (210 mg), 27% (350 mg), 15% (700 mg), and 13% (placebo) of patients. Mean change in CDAI at week 6 was -8.7 (95.3) (210 mg), -35.4 (105.6) (350 mg), -0.6 (105.9) (700 mg), and -28.2 (86.0) (placebo). Besides worsening of CD, overall incidences of adverse events were similar across treatment groups. CONCLUSIONS: Treatment with brodalumab resulted in a disproportionate number of cases of worsening CD in patients with active CD and no evidence of meaningful efficacy. These analyses did not suggest additional safety risks of brodalumab beyond worsening of CD symptoms in patients with active CD. PMID- 27481310 TI - Enhancing Diagnostic Performance of Symptom-Based Criteria for Irritable Bowel Syndrome by Additional History and Limited Diagnostic Evaluation. AB - OBJECTIVES: Symptom-based criteria to diagnose irritable bowel syndrome (IBS) positively perform only modestly. Our aim was to assess whether including other items from the clinical history and limited diagnostic evaluation improves their performance. METHODS: We collected complete symptom, colonoscopy, and histology data from 318 consecutive, unselected adult patients with lower gastrointestinal (GI) symptoms in secondary care. All participants underwent colonoscopy, with relevant organic findings recorded. The reference standard used to define the presence of true IBS was patient-reported lower abdominal pain or discomfort associated with a change in bowel habit, in the absence of organic GI disease. Sensitivity, specificity, and positive and negative likelihood ratios (LRs), with 95% confidence intervals, were calculated for Rome III criteria, as well as for modifications, incorporating nocturnal stools, results of simple blood tests (hemoglobin and C-reactive protein (CRP)), measures of somatization, and/or affective disorders (hospital anxiety or depression scale (HADS) score). RESULTS: The sensitivity and specificity of the Rome III criteria for identifying IBS was 69.6%, and 82.0%, respectively, with positive and negative LRs of 3.87 and 0.37, respectively. Clinically useful enhancements in positive LRs were provided by combining Rome III criteria with: (a) high level of somatization (7.27); (b) normal hemoglobin and CRP with HADS score of >=8 (5.04); (c) normal hemoglobin and CRP with a high level of somatization (7.56); or (d) no nocturnal passage of stool with a high level of somatization (17.3). Specificity was >=95% with each of these modifications. CONCLUSIONS: Incorporating nocturnal stools, somatization, and affective disorders from the clinical history, and hemoglobin and CRP measurements, enhances the positive LR and specificity of symptom-based Rome III criteria for IBS. PMID- 27481311 TI - Impact of National Institutes of Health Gastrointestinal PROMIS Measures in Clinical Practice: Results of a Multicenter Controlled Trial. AB - OBJECTIVES: The National Institutes of Health (NIH) created the Patient Reported Outcomes Measurement Information System (PROMIS) to allow efficient, online measurement of patient-reported outcomes (PROs), but it remains untested whether PROMIS improves outcomes. Here, we aimed to compare the impact of gastrointestinal (GI) PROMIS measures vs. usual care on patient outcomes. METHODS: We performed a pragmatic clinical trial with an off-on study design alternating weekly between intervention (GI PROMIS) and control arms at one Veterans Affairs and three university-affiliated specialty clinics. Adults with GI symptoms were eligible. Intervention patients completed GI PROMIS symptom questionnaires on an e-portal 1 week before their visit; PROs were available for review by patients and their providers before and during the clinic visit. Usual care patients were managed according to customary practices. Our primary outcome was patient satisfaction as determined by the Consumer Assessment of Healthcare Providers and Systems questionnaire. Secondary outcomes included provider interpersonal skills (Doctors' Interpersonal Skills Questionnaire (DISQ)) and shared decision-making (9-item Shared Decision Making Questionnaire (SDM-Q-9)). RESULTS: There were 217 and 154 patients in the GI PROMIS and control arms, respectively. Patient satisfaction was similar between groups (P>0.05). Intervention patients had similar assessments of their providers' interpersonal skills (DISQ 89.4+/-11.7 vs. 89.8+/-16.0, P=0.79) and shared decision-making (SDM Q-9 79.3+/-12.4 vs. 79.0+/-22.0, P=0.85) vs. CONTROLS: CONCLUSIONS: This is the first controlled trial examining the impact of NIH PROMIS in clinical practice. One-time use of GI PROMIS did not improve patient satisfaction or assessment of provider interpersonal skills and shared decision-making. Future studies examining how to optimize PROs in clinical practice are encouraged before widespread adoption. PMID- 27481314 TI - Second malignancy risk among pediatric, adolescent, and young adult survivors of fusion-positive and fusion-negative sarcomas: Results from the SEER database, 1992 through 2012. AB - BACKGROUND: The current study builds on the hypothesis that cancer-predisposing germline mutations are less common among patients with fusion-positive (F+) sarcomas compared to those with fusion-negative (F-) sarcomas, resulting in a lower risk of developing second malignant neoplasms (SMNs) in those with F + sarcomas. METHODS: Standardized incidence ratios (SIRs) for developing SMNs were evaluated in 4822 survivors of F + and 3963 survivors of F- sarcomas that were diagnosed between 1992 and 2012 in pediatric, adolescent, and young adult patients (aged birth-39 years) and reported in the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards models (adjusted hazard ratio [aHR]) and competing risk methods (subhazard ratio [sHR]) were used to evaluate SMN risk in those with F- versus F + sarcomas while controlling for demographic and clinical variables. RESULTS: SMN risk was found to be nearly 2 fold greater among survivors of F + sarcomas (SIR, 1.86; 95% confidence interval [95% CI], 1.48-2.30) and nearly 3-fold greater among survivors of F- sarcomas (SIR, 2.89; 95% CI, 2.30-3.59) compared with the reference population. Although SMN types were noted to be similar between the fusion groups, the rate of any SMN was noted to be greater among survivors of F- sarcomas (aHR, 1.38 [95% CI, 1.01 1.89] and sHR, 1.27 [95% CI, 0.94-1.73]) when compared with survivors of F + sarcomas. The difference was most notable for solid tumor SMNs after index sarcomas were diagnosed between 2002 and 2012, for which rates of SMN were >2 fold greater among survivors of F- sarcomas (aHR, 2.31 [95% CI, 1.20-4.48] and sHR, 2.24 [95% CI, 1.13-4.43]). CONCLUSIONS: The findings of the current study highlight the increased SMN risk experienced by survivors of sarcoma and demonstrate higher SMN rates in survivors of F- sarcomas compared to those with a history of F + sarcomas. Cancer 2016;122:3492-3500. (c) 2016 American Cancer Society. PMID- 27481312 TI - Esophageal Sensorimotor Function and Psychological Factors Each Contribute to Symptom Severity in Globus Patients. AB - OBJECTIVES: Altered upper esophageal sphincter (UES) and esophageal body (EB) sensorimotor function and psychosocial factors may both be involved in symptom generation in globus, but their common impact is not yet assessed. The aim of the study is (1) to compare UES and EB sensitivity and compliance of globus patients with healthy controls (HC); (2) to study the association of globus symptom severity (GSS) with UES and EB sensitivity and compliance, UES motor function and psychosocial factors. METHODS: In 58 globus patients, GSS, somatization, and anxiety disorders were determined using validated questionnaires. In 26 HC and 42/58 patients, UES and EB sensitivity and compliance were assessed twice using barostat measurements. UES function of 27 globus patients was evaluated using high-resolution manometry. Bivariate correlations and a general linear model tested the association of these factors with GSS. RESULTS: UES and EB compliance did not differ between globus patients and HC. Upon repeated distension, UES habituation was seen in both groups, whereas EB sensitization (23.3+/-1.3 vs. 19.5+/-1.5 mm Hg, P<0.0001) only occurred in globus patients, (P=0.038). UES compliance (rho=0.37, P=0.04), change in EB compliance upon repeated distension (rho=0.45, P=0.007), somatization (rho=0.43, P=0.003), panic disorder (t=3.04, P=0.004), and post-traumatic stress severity (rho=0.40, P=0.005) were associated with GSS. UES compliance and somatization were independently associated with GSS. A trend (P=0.061) was found for the association of GSS with change in EB compliance. CONCLUSIONS: UES compliance, change in EB compliance, and somatization explain 40% of the variance in GSS. This indicates that globus is a complex disorder of the brain-gut axis rather than a "psychosomatic" disorder or a peripheral esophageal disorder. PMID- 27481313 TI - Erythropoietin treatment in murine multiple myeloma: immune gain and bone loss. AB - Multiple myeloma (MM) is a plasma cell malignancy, characterized by osteolytic lesions and monoclonal immunoglobulins. The anemia, accompanying the disease is often treated with recombinant human EPO. Diverse non-erythropoietic effects of EPO have led us to question its combined action on the immune system and bone in the 5T33MM mouse model. EPO administration to MM mice attenuated disease progression as demonstrated by a decrease in serum MM IgG2b, splenic CD138 expressing cells, IL-6 and RORgammatau transcripts in bone marrow (BM). IFN-gamma transcript levels and macrophages (F4/80(+)CD11b(+)) in the BM both increased ~1.5 fold in the EPO-treated MM mice. In-vitro, EPO stimulated phagocytosis of 5T33MM cells (+30%) by BM-derived macrophages. In contrast, high-resolution microCT analysis of distal femurs revealed EPO-associated bone loss in both healthy and 5T33MM mice. EPO significantly increased expression of the osteoclastogenic nuclear factor-kappa B ligand (RANKL) in healthy mice, but not in MM mice, likely due to antagonizing effects on MM progression. Thus, in MM, EPO may act as a double-edged-sword stimulating immune response, while accelerating bone resorption, possibly via direct action on BM macrophages. This study supports a prudent approach of treating anemia in MM patients, aiming to maintain EPO-associated anti-MM effects, while considering bone damage. PMID- 27481315 TI - Effectiveness and safety of imipenem/clavulanate and linezolid to treat multidrug and extensively drug-resistant tuberculosis at a referral hospital in Brazil. AB - Evidence on effectiveness, safety, and tolerability of imipenem/clavulanate (IC) and linezolid containing regimens to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) is scarce. The aim of this observational study is to evaluate the therapeutic contribution of IC and linezolid to manage MDR/XDR-TB cases at the reference centre of Sao Paulo state, Brazil. Twelve patients (9 males, 1 HIV positive in antiretroviral treatment, 4 MDR, 8 XDR) were treated with IC, 11 of them within linezolid-containing regimens. They all were previously treated with treatment failure, for a median (IQR, interquartile range) of 4.5 (2-6.5) times, having a severe resistance pattern (median number of resistances: 7 (5-8)) and being sputum smear and culture positive. IC and linezolid were prescribed at the dose of 1000mg/day and 600mg/day, respectively. The overall exposure was (median (IQR)) 419 (375.5-658) days for IC and 678 (392-720) days for linezolid. All of them converted their sputum (time to sputum conversion; 60 (37.5-90) days) and culture (75 (60-135) days), and 7 were cured while 5 are still on treatment with a gradually improving clinical picture. While no adverse events were reported for IC, 2 minor side effects, only, were attributed to linezolid (17%); in both cases the drug was re started without further problems. Our study suggests that IC and linezolid containing regimens can be used safely and with satisfactory outcomes in reference centres to treat MDR/XDR-TB patients. PMID- 27481316 TI - Acoustic effects of the reconstructed lateral epitympanic wall in a temporal bone and clinical study. AB - OBJECTIVE: Acoustic evaluation of reconstruction of the lateral epitympanic wall with bone or cartilage in a temporal bone study, and evaluation of audiometric data of patients who underwent cholesteatoma surgery with reconstruction of the lateral epitympanic wall with horseshoe-shaped cartilage. STUDY DESIGN: Temporal bone study and retrospective chart review. METHODS: Preparation of temporal bones included reconstruction of the epitympanic wall with fixated and loose cartilage and bone. The volume velocities of the stapes footplate were measured from the inner-ear side of the footplate by laser scanning doppler vibrometry following sound stimulation in the outer ear canal. Additionally, the audiometric data of 13 consecutive patients who underwent epitympanic cholesteatoma surgery, with an intact ossicular chain and reconstruction of the scutum with a horseshoe-shaped cartilage in contact with the malleus' neck, were evaluated retrospectively. RESULTS: The experimental results showed similar volume velocities at the stapes footplate for the fixated and unfixated cartilage as well as for the unfixated bone. However, the fixated bone yielded significantly reduced volume velocities. Clinical data confirmed that the cartilaginous horseshoe- technique allowed for a stable reconstruction of the scutum with satisfying audiometric outcome. CONCLUSION: In case of cholesteatoma surgery and the need for the reconstruction of the scutum, no adverse effects on hearing outcome are to be expected by using the malleus' neck as an anchoring point for cartilaginous scutum reconstruction. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1427-1434, 2017. PMID- 27481318 TI - Symptoms of palliative patients and their providers: depression, pain, nausea, and declines in quality of life. PMID- 27481317 TI - Protein Inhibitor of NOS1 Plays a Central Role in the Regulation of NOS1 Activity in Human Dilated Hearts. AB - An essential factor for the production of nitric oxide by nitric oxide synthase 1 (NOS1), major modulator of cardiac function, is the cofactor tetrahydrobiopterin (BH4). BH4 is regulated by GTP cyclohydrolase 1, the rate-limiting enzyme in BH4 biosynthesis which catalyses the formation of dihydroneopterin 3'triphosfate from GTP, producing BH4 after two further steps catalyzed by 6 pyruvoyltetrahydropterin synthase and sepiapterin reductase. However, there are other essential factors involved in the regulation of NOS1 activity, such as protein inhibitor of NOS1 (PIN), calmodulin, heat shock protein 90, and NOS interacting protein. All these molecules have never been analysed in human non ischemic dilated hearts (DCM). In this study we demonstrated that the upregulation of cardiac NOS1 is not accompanied by increased NOS1 activity in DCM, partly due to the elevated PIN levels and not because of alterations in biopterin biosynthesis. Notably, the PIN concentration was significantly associated with impaired ventricular function, highlighting the importance of this NOS1 activity inhibitor in Ca(2+) homeostasis. These results take a central role in the current list of targets for future studies focused on the complex cardiac dysfunction processes through more efficient harnessing of NOS1 signalling. PMID- 27481319 TI - CanSupport: a model for home-based palliative care delivery in India. AB - BACKGROUND: According to the 2014 WHO Global Atlas of Palliative Care, there is insufficient access to palliative care services worldwide, with the majority of unmet need in low- and middle-income countries. In India, there are major disparities in access to palliative care, with the majority of services being offered by non-governmental organizations (NGOs) scattered throughout the country. The barriers to expanding palliative care services in India are common to many lower- and middle-income countries-a lack of financial resources, a paucity of trained staff, and a focus on curative rather than comfort care. In this paper, we describe a model of palliative care being used by CanSupport, a non-governmental organization based in Delhi that was formed in 1996. They offer home-based services provided by multidisciplinary teams consisting of a physician, nurse, and social worker who are trained in palliative care. METHODS: Data on patient demographics, services provided, and outcomes were collected retrospectively for patients treated by CanSupport for the year 2009-2010. Sources include CanSupport's population data and direct discussions with CanSupport staff. RESULTS: During the year 2009-2010, CanSupport served 746 patients, with an average of 10 home visits per patient. Only 29% of patients were referred from hospitals or physicians, with the rest being self-referred or referred from CanSupport's help line. Pain scales were administered on each visit and 31% of patients received morphine. Of the 514 patient deaths, 76% occurred at home and a majority of families received bereavement counseling for up to 6 months. CONCLUSIONS: CanSupport has shown that a home-based care model can be successful in India and is desired by patients at the end of life or with chronic illness. Their model of care saves the patients the cost of a hospital visit while still providing evaluation by staff with training in palliative care. In addition, the multidisciplinary nature of the teams allows for symptom management and emotional counseling for both the patients and their families. CanSupport has developed a way to provide reliable, cost-effective palliative care to patients that can serve as a model for building palliative care capacity in low- and middle-income countries. PMID- 27481320 TI - The power of integration: radiotherapy and global palliative care. AB - Radiotherapy (RT) is a powerful tool for the palliation of the symptoms of advanced cancer, although access to it is limited or absent in many low- and middle-income countries (LMICs). There are multiple factors contributing to this, including assumptions about the economic feasibility of RT in LMICs, the logical challenges of building capacity to deliver it in those regions, and the lack of political support to drive change of this kind. It is encouraging that the problem of RT access has begun to be included in the global discourse on cancer control and that palliative care and RT have been incorporated into national cancer control plans in some LMICs. Further, RT twinning programs involving high- and low-resource settings have been established to improve knowledge transfer and exchange. However, without large-scale action, the consequences of limited access to RT in LMICs will become dire. The number of new cancer cases around the world is expected to double by 2030, with twice as many deaths occurring in LMICs as in high-income countries (HICs). A sustained and coordinated effort involving research, education, and advocacy is required to engage global institutions, universities, health care providers, policymakers, and private industry in the urgent need to build RT capacity and delivery in LMICs. PMID- 27481322 TI - Discordant expectations about prognosis in critically ill patients. PMID- 27481321 TI - Community-based participatory research: understanding a promising approach to addressing knowledge gaps in palliative care. AB - Concern over the need for effective and accessible healthcare for individuals with advanced chronic illness has drawn attention to the significant gaps in our knowledge of palliative medicine. To advance our understanding of this field, community-based participatory research (CBPR) is proposed as a tool for future research initiatives. This paper offers a rationale for how CBPR may be employed to address specific gaps in palliative care research. Several examples where this approach has been used previously are described, and potential obstacles to implementing this research method are delineated. Despite challenges to incorporating CBPR to palliative care research, this approach holds substantial potential to advance our current understanding of the field and promote sensitivity for future programs, practices and policies. PMID- 27481323 TI - An exploratory study into the health beliefs and behaviours of British Indians with type II diabetes. AB - : Aim To explore the influence of health beliefs and behaviours on diabetes management in British Indians, as successful management of diabetes is dependent on underlying cultural beliefs and behaviours. BACKGROUND: British South Asians are six times more likely to suffer from type II diabetes than those in the general population. Yet, little research has been carried out into beliefs about diabetes among the British Indian population. METHOD: The study used semi structured interviews, a structured vignette and a pile-sorting exercise. In all, 10 British Indians were interviewed at a General Practice in North West London. Findings Those interviewed were informed about their diabetes but had difficulties in adapting their diet. Themes identified included causal beliefs of diabetes, use of alternative therapies, moderation of food, adaption of exercise regimes and sources of information. All were aware of avoiding certain foods yet some still continued to consume these items. Participants expressed the need for culturally sensitive forums to help manage their diabetes. PMID- 27481324 TI - Machine learning approaches in medical image analysis: From detection to diagnosis. AB - Machine learning approaches are increasingly successful in image-based diagnosis, disease prognosis, and risk assessment. This paper highlights new research directions and discusses three main challenges related to machine learning in medical imaging: coping with variation in imaging protocols, learning from weak labels, and interpretation and evaluation of results. PMID- 27481327 TI - Mechanochemical Strecker Reaction: Access to alpha-Aminonitriles and Tetrahydroisoquinolines under Ball-Milling Conditions. AB - A mechanochemical version of the Strecker reaction for the synthesis of alpha aminonitriles was developed. The milling of aldehydes, amines, and potassium cyanide in the presence of SiO2 gave the corresponding alpha-aminonitriles in good to high yields. The high efficiency of the mechanochemical Strecker-type multicomponent reaction allowed the one-pot synthesis of tetrahydroisoquinolines after a subsequent internal N-alkylation reaction. PMID- 27481325 TI - Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching. AB - Antibody class switching is a feature of the adaptive immune system which enables diversification of the effector properties of antibodies. Even though class switching is essential for mounting a protective response to pathogens, the in vivo patterns and lineage characteristics of antibody class switching have remained uncharacterized in living humans. Here we comprehensively measured the landscape of antibody class switching in human adult twins using antibody repertoire sequencing. The map identifies how antibodies of every class are created and delineates a two-tiered hierarchy of class switch pathways. Using somatic hypermutations as a molecular clock, we discovered that closely related B cells often switch to the same class, but lose coherence as somatic mutations accumulate. Such correlations between closely related cells exist when purified B cells class switch in vitro, suggesting that class switch recombination is directed toward specific isotypes by a cell-autonomous imprinted state. PMID- 27481328 TI - A rethink of fusion surgery for lumbar spinal stenosis. AB - Lumbar spinal stenosis is one of the most common spinal disorders in elderly patients, how to choose decompression alone or decompression plus fusion is still controversial. It was reported that the rate of decompression alone for lumbar stenosis was decreased, whereas the rate of decompression plus fusion was increased recently. Two recent multicenter RCTs papers published in the same issue of N Engl J Med compare the outcomes of decompression alone or decompression plus fusion for lumbar spinal stenosis currently. We combined the results from these two studies using the Stata software, we found that the decompression plus fusion had a significantly more blood loss and longer operative time. And no significant difference was found in the parameters of length of hospital stay, SF-36 Physical Component Summary, Oswestry Disability Index, Visual analogue scales of back pain and leg pain between decompression alone group and decompression plus fusion group. Therefore, based on the current evidence, we advocate a rethink on the decompression plus fusion trend chosen by surgeons, the indications of fusion should be restricted to the lumbar stenosis patients accompanied with spinal instability or deformity. PMID- 27481326 TI - A mitochondrial DNA hypomorph of cytochrome oxidase specifically impairs male fertility in Drosophila melanogaster. AB - Due to their strict maternal inheritance in most animals and plants, mitochondrial genomes are predicted to accumulate mutations that are beneficial or neutral in females but harmful in males. Although a few male-harming mtDNA mutations have been identified, consistent with this 'Mother's Curse', their effect on females has been largely unexplored. Here, we identify COII(G177S), a mtDNA hypomorph of cytochrome oxidase II, which specifically impairs male fertility due to defects in sperm development and function without impairing other male or female functions. COII(G177S) represents one of the clearest examples of a 'male-harming' mtDNA mutation in animals and suggest that the hypomorphic mtDNA mutations like COII(G177S) might specifically impair male gametogenesis. Intriguingly, some D. melanogaster nuclear genetic backgrounds can fully rescue COII(G177S) -associated sterility, consistent with previously proposed models that nuclear genomes can regulate the phenotypic manifestation of mtDNA mutations. PMID- 27481329 TI - Molecular dynamics simulations and modelling of the residue interaction networks in the BRAF kinase complexes with small molecule inhibitors: probing the allosteric effects of ligand-induced kinase dimerization and paradoxical activation. AB - Protein kinases are central to proper functioning of cellular networks and are an integral part of many signal transduction pathways. The family of protein kinases represents by far the largest and most important class of therapeutic targets in oncology. Dimerization-induced activation has emerged as a common mechanism of allosteric regulation in BRAF kinases, which play an important role in growth factor signalling and human diseases. Recent studies have revealed that most of the BRAF inhibitors can induce dimerization and paradoxically stimulate enzyme transactivation by conferring an active conformation in the second monomer of the kinase dimer. The emerging connections between inhibitor binding and BRAF kinase domain dimerization have suggested a molecular basis of the activation mechanism in which BRAF inhibitors may allosterically modulate the stability of the dimerization interface and affect the organization of residue interaction networks in BRAF kinase dimers. In this work, we integrated structural bioinformatics analysis, molecular dynamics and binding free energy simulations with the protein structure network analysis of the BRAF crystal structures to determine dynamic signatures of BRAF conformations in complexes with different types of inhibitors and probe the mechanisms of the inhibitor-induced dimerization and paradoxical activation. The results of this study highlight previously unexplored relationships between types of BRAF inhibitors, inhibitor induced changes in the residue interaction networks and allosteric modulation of the kinase activity. This study suggests a mechanism by which BRAF inhibitors could promote or interfere with the paradoxical activation of BRAF kinases, which may be useful in informing discovery efforts to minimize the unanticipated adverse biological consequences of these therapeutic agents. PMID- 27481331 TI - Postoperative Complications and Short-Term Outcome Following Single-Session Bilateral Corrective Surgery for Medial Patellar Luxation in Dogs Weighing <15 kg: 50 Cases (2009-2014). AB - OBJECTIVE: To assess complication rates and short-term outcome in small dogs with bilateral medial patellar luxation (MPL) undergoing single-session bilateral corrective surgery. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs weighing <15 kg with congenital bilateral MPL that underwent single-session bilateral corrective surgery (n = 50). METHODS: Surgical procedures for MPL correction included trochlear wedge recession (TWR), crest transposition, lateral imbrication, and medial fascial release. Complication rates were correlated with number of surgical procedures, weight, whether or not a bandage was applied postoperatively, and surgeon experience (ACVS Diplomate vs resident). Results were compared with the most recent study evaluating single-session bilateral corrective surgery for MPL. RESULTS: Overall complication rate was 22% (11 of 50 dogs). Implant failure occurred in 2 dogs (3 stifles) requiring revision. Grade 1 patella reluxation was the most common minor complication at 10% (5/50). Overall complication and reluxation rates were similar to previous studies. There were no intraoperative complications after performing TWR in small dogs. CONCLUSION: Single-session bilateral corrective surgery for MPL is well tolerated in small dogs with complication rates historically similar to dogs undergoing unilateral or staged bilateral surgery. With individual case assessment, single-session surgery could be offered to owners, allowing one anesthetic episode and potentially lowering the chance for morbidity. Further studies, ideally prospective studies, are needed to assess long-term outcome following single session bilateral corrective surgery for MPL. PMID- 27481330 TI - Nutrient Channels Aid the Growth of Articular Surface-Sized Engineered Cartilage Constructs. AB - Symptomatic osteoarthritic lesions span large regions of joint surfaces and the ability to engineer cartilage constructs at clinically relevant sizes would be highly desirable. We previously demonstrated that nutrient transport limitations can be mitigated by the introduction of channels in 10 mm diameter cartilage constructs. In this study, we scaled up our previous system to cast and cultivate 40 mm diameter constructs (2.3 mm overall thickness); 4 mm diameter and channeled 10 mm diameter constructs were studied for comparison. Furthermore, to assess whether prior results using primary bovine cells are applicable for passaged cells-a more clinically realistic scenario-we cast constructs of each size with primary or twice-passaged cells. Constructs were assessed mechanically for equilibrium compressive Young's modulus (EY), dynamic modulus at 0.01 Hz (G*), and friction coefficient (MU); they were also assessed biochemically, histologically, and immunohistochemically for glycosaminoglycan (GAG) and collagen contents. By maintaining open channels, we successfully cultured robust constructs the size of entire human articular cartilage layers (growing to ~52 mm in diameter, 4 mm thick, mass of 8 g by day 56), representing a 100-fold increase in scale over our 4 mm diameter constructs, without compromising their functional properties. Large constructs reached EY of up to 623 kPa and GAG contents up to 8.9%/ww (% of wet weight), both within native cartilage ranges, had G* >2 MPa, and up to 3.5%/ww collagen. Constructs also exhibited some of the lowest MU reported for engineered cartilage (0.06-0.11). Passaged cells produced tissue of lower quality, but still exhibited native EY and GAG content, similar to their smaller controls. The constructs produced in this study are, to our knowledge, the largest engineered cartilage constructs to date which possess native EY and GAG, and are a testament to the effectiveness of nutrient channels in overcoming transport limitations in cartilage tissue engineering. PMID- 27481332 TI - Mitochondria-targeting ratiometric fluorescent probe for gamma glutamyltranspeptidase and its application to colon cancer. AB - A mitochondria-targeting ratiometric probe was designed for gamma glutamyltranspeptidase (gammaGT). Mechanistic study by HPLC and an inhibitor assay showed that the probe underwent gammaGT-mediated amide-to-amine transformation and induced a ratiometric fluorescence response in cellular mitochondria. Further application was successful for the detection of cancerous colons in mice. PMID- 27481333 TI - Fumarate-loaded electrospun nanofibers with anti-inflammatory activity for fast recovery of mild skin burns. AB - In the biomedical sector the availability of engineered scaffolds and dressings that control and reduce inflammatory states is highly desired, particularly for the management of burn wounds. In this work, we demonstrate for the first time, to the best of our knowledge, that electrospun fibrous dressings of poly(octyl cyanoacrylate) (POCA) combined with polypropylene fumarate (PPF) possess anti inflammatory activity and promote the fast and effective healing of mild skin burns in an animal model. The fibers produced had an average diameter of (0.8 +/ 0.1) um and they were able to provide a conformal coverage of the injured tissue. The application of the fibrous mats on the burned tissue effectively reduced around 80% of the levels of pro-inflammatory cytokines in the first 48 h in comparison with un-treated animals, and enhanced skin epithelialization. From histological analysis, the skin thickness of the animals treated with POCA : PPF dressings appeared similar to that of one of the naive animals: (13.7 +/- 1.4) um and (14.3 +/- 2.5) um for naive and treated animals, respectively. The density of dermal cells was comparable as well: (1100 +/- 112) cells mm(-2) and (1358 +/- 255) cells mm(-2) for naive and treated mice, respectively. The results demonstrate the suitability of the electrospun dressings in accelerating and effectively promoting the burn healing process. PMID- 27481334 TI - Desbuquois dysplasia type II in a patient with a homozygous mutation in XYLT1 and new unusual findings. PMID- 27481335 TI - Robinsoniella peoriensis, originally isolated from swine manure, and early periprosthetic hip infection: Case report and review of the literature. AB - We report on the first case of a periprosthetic joint infection with the anaerobic spore-forming Gram-positive rod Robinsoniella peoriensis as the causative agent. The bacterium was first isolated from a swine manure storage pit and has so far rarely been associated with human infections. PMID- 27481336 TI - Hypothermia in Uremic Dogs and Cats. AB - BACKGROUND: The prevalence of uremic hypothermia (UH) and the effects of improving uremia on body temperature have not been determined in veterinary patients. OBJECTIVES: To determine the prevalence of UH and correlations between uremia and body temperature in patients undergoing intermittent hemodialysis (IHD). ANIMALS: Uremic dogs (n = 122) and cats (n = 79) treated by IHD at the Bobst Hospital of the Animal Medical Center from 1997 to 2013. METHODS: Retrospective review of medical records. RESULTS: The prevalence of hypothermia was 38% in azotemic cats and 20.5% in azotemic dogs. Statistically significant temperature differences were observed between uremic and nonuremic dogs (nonuremic: mean, 100.8 degrees F; range, 91.2-109.5 degrees F; uremic: mean, 99.9 degrees F; range, 95.6-103.8 degrees F; P < .0001) and cats (nonuremic: mean, 100.6 degrees F; range, 94.0-103.8 degrees F; uremic: mean, 99.3 degrees F; range, 92.3-103.4 degrees F; P < .0001). In dog dialysis patients, significant models included (1) timing (pre-dialysis versus post-dialysis) with weight class (small [P < .0001], medium [P = .016], and large breed [P = .033] dogs), (2) timing with serum creatinine concentration (P = .021), and (3) timing with BUN concentration (P < .0001). In cat dialysis patients, there was a significant interaction between timing and weight as a categorical variable (<5 kg and >=5 kg). CONCLUSIONS AND CLINICAL IMPORTANCE: Uremic hypothermia appears to be a clinical phenomenon that occurs in cats and dogs. Uremic patients are hypothermic compared to ill nonuremic patients and body temperatures increase when uremia is corrected with IHD in dogs and in cats >5 kg. In cats, UH seems to be a more prevalent phenomenon driven by uremia. Uremic hypothermia does occur in dogs, but body weight is a more important predictor of body temperature. PMID- 27481337 TI - Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers from TRACK-HD. AB - We present a novel, general class of disease progression models for Huntington's disease (HD), a neurodegenerative disease caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion on the huntingtin gene. Models are fit to a selection of structural imaging markers from the TRACK 36-month database. The models are of mixed effects type and should be useful in predicting any continuous marker of HD state as a function of age and CAG length (the genetic factor that drives HD pathology). The effects of age and CAG length are modeled using flexible regression splines. Variability not accounted for by age, CAG length, or covariates is modeled using terms that represent measurement error, population variability (random slopes/intercepts), and variability due to the dynamics of the disease process (random walk terms). A Kalman filter is used to estimate variances of the random walk terms. PMID- 27481338 TI - Pediatric lead poisoning from folk prescription for treating epilepsy. AB - BACKGROUND: A case of lead poisoning resulting from the ingestion of a folk remedy for treating epilepsy is reported. RESULTS: The initial blood lead concentration of this 6-y-old boy was 63.6MUg/dl upon admission. He presented with abdominal pain, constipation, and irritability. The patient's liver function tests were significantly increased. Through chelation therapy, the blood lead concentration dropped markedly and clinical symptoms greatly improved. His blood and urine samples were collected for the kinetic analysis of lead elimination. CONCLUSIONS: Folk prescriptions for epilepsy should be considered as potential sources of lead intoxication. Lead poisoning should be taken into consideration for unknown causes of abdominal pain. PMID- 27481340 TI - Polysaccharide based bionanocomposites, properties and applications: A review. AB - Bio-nanocomposites, composed of biopolymers and inorganic solids, show dimensions in the nanometer range (1-100nm) which can be widely used in variety of areas owing to multidimensional properties like biocompatibility, antimicrobial activity and biodegradability. Considering these versatile properties of the bio nanocomposites this review sheds a light on the synthesis, modification, characterization and applications of bio-nanocomposites based on different polysaccharides functionalized by different nanofillers such as MMT, Ag, SiO2, TiO2, and ZnO. Most of them have been used in regenerative medicine, drug delivery, tissue engineering, electronics and food packaging. The modification of clays with biopolymers results an attractive alternative in the development of environmentally friendly materials for pollutants removal. All the technical scientific issues have been addressed highlighting the recent advancement. PMID- 27481339 TI - Fibroblast Growth Factor-2 facilitates the growth and chemo-resistance of leukemia cells in the bone marrow by modulating osteoblast functions. AB - Stromal cells and osteoblasts play major roles in forming and modulating the bone marrow (BM) hematopoietic microenvironment. We have reported that FGF2 compromises stromal cell support of normal hematopoiesis. Here, we examined the effects of FGF2 on the leukemia microenvironment. In vitro, FGF2 significantly decreased the number of stromal-dependent and stromal-independent G0-leukemia cells in the stromal layers. Accordingly, CML cells placed on FGF2-treated stromal layers were more sensitive to imatinib. Conversely, FGF2 increased the proliferation of osteoblasts via FGFR1 IIIc, but its effects on osteoblast support of leukemia cell growth were limited. We next treated a human leukemia mouse model with Ara-C with/without systemic FGF2 administration. BM sections from FGF2-treated mice had thickened bone trabeculae and increased numbers of leukemia cells compared to controls. Leukemia cell density was increased, especially in the endosteal region in FGF2/Ara-C -treated mice compared to mice treated with Ara-C only. Interestingly, FGF2 did not promote leukemia cell survival in Ara-C treated spleen. Microarray analysis showed that FGF2 did not alter expression of many genes linked to hematopoiesis in osteoblasts, but modulated regulatory networks involved in angiogenesis and osteoblastic differentiation. These observations suggest that FGF2 promotes leukemia cell growth in the BM by modulating osteoblast functions. PMID- 27481341 TI - Development of surface curcumin nanoparticles modified with biological macromolecules for anti-tumor effects. AB - The rationale of this study was to improve the stability, cellular uptake, and evaluate the cytotoxicity of surface modified curcumin nanoparticles (CUR NP). CUR NP were surface modified with proteins (transferrin [Tf] and gelatin [GT]) by adsorption to improve their stability and targeting property. CUR NP were evaluated for stability, in vitro drug release, cellular uptake and cell cytotoxicity. The particle sizes of CUR NP were 153.2+/-56.4nm (CUR NP), 145.0+/ 26.8nm (Tf-CUR NP), and 167.7+/-42.7nm (GT-CUR NP). The stabilities of Tf-CUR NP and GT-CUR NP were higher than that of CUR NP. Tf-CUR NP and GT-CUR NP showed faster drug release than those shown by CUR NP and CUR (pure) in pH 7.4 PBS and cell media (RPMI) for 36h. The cellular uptake and cytotoxicity of Tf- and GT modified CUR NP were higher than those of CUR NP in MCF-7 and A549 cells. In conclusion, Tf-CUR NP and GT-CUR NP exhibited improved stability, enhanced cellular uptake, and stronger cytotoxicity. PMID- 27481342 TI - Analgesic and anti-inflammatory actions on bradykinin route of a polysulfated fraction from alga Ulva lactuca. AB - We investigated structural features of polysaccharides from Ulva lactuca and their effects on the classical models of nociception and inflammation. Crude extract was obtained by enzymatic digestion and isolated by ion exchange chromatography on DEAE-cellulose. The fraction with higher yield was used in the tests (SP-Ul). Swiss mice received SP-Ul (1, 3 or 9mg/kg; i.v.), 30min prior to injection of 0.8%-acetic acid or 1%-formalin or prior to a thermal stimulus. At same doses, SP-Ul was tested on Wistar rats on paw edema elicited by different irritants (carrageenan, dextran, bradykinin, histamine or serotonin). The results of infrared characterization indicated the presence of hydroxyl groups, sulfate, uronic acid and glycosidic linkages in all SP fractions spectrums. SP-Ul decreased significantly the antinociception in response to acetic acid or formalin (second phase), but not in the hot-plate test, suggesting that its analgesia occurs through a peripheral mechanism. SP-Ul did not reduce carrageenan induced paw edema as supported by both histological and myeloperoxidase activity assessments. However, SP-Ul (1mg/kg; s.c.) reduced dextran-elicited edema, showing vascular anti-inflammatory effect, with bradykinin as major target because it did not reduce histamine- and serotonin-induced paw edemas. Therefore, SP-Ul acts on bradykinin pathway in its antinociceptive and anti-inflammatory responses. PMID- 27481343 TI - Pb(II) adsorption by a novel activated carbon - alginate composite material. A kinetic and equilibrium study. AB - The adsorption capacity of an activated carbon - calcium alginate composite material (ACAA-Ca) has been tested with the aim of developing a new and more efficient adsorbent material to remove Pb(II) ion from aqueous solution. The study was carried out at pH=5, in NaCl medium and in the ionic strength range 0.1 0.75molL-1. Differential Pulse Anodic Stripping Voltammetry (DP-ASV) technique was used to check the amount of Pb(II) ion removed during kinetic and equilibrium experiments. Different kinetic (pseudo first order, pseudo second order and Vermuelen) and equilibrium (Langmuir and Freundlich) models were used to fit experimental data, and were statistically compared. Calcium alginate (AA-Ca) improves the adsorption capacity (qm) of active carbon (AC) in the ACAA-Ca adsorbent material (e.g., qm=15.7 and 10.5mgg-1 at I=0.25molL-1, for ACAA-Ca and AC, respectively). SEM-EDX and thermogravimetric (TGA) measurements were carried out in order to characterize the composite material. The results of the speciation study on the Pb(II) solution and of the characterization of the ACAA Ca and of the pristine AA-Ca and AC were evaluated in order to explain the specific contribution of AC and AA-Ca to the adsorption of the metal ion. PMID- 27481344 TI - Preparation and characterization of pH-sensitive camptothecin-cis-aconityl grafted chitosan oligosaccharide nanomicelles. AB - Camptothecin (CPT) was introduced to water-soluble chitosan oligosaccharide (CHO) using cis-aconityl (CA), as a pH-sensitive linker, to develop a new hydrophobic structure, i.e. CPTCACHO. The triple conjugates were synthesized in three ratios (5%, 7.5%, and 10%) and characterized by Fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (1HNMR). Thermo gravimetric analysis and critical micelle concentration (CMC) assessments were performed. Prepared nano micelles were analyzed for particle size, polydispersity index (PDI), drug release and in vitro cytotoxicity. CPTCACHO 7.5% micelles as optimum micelles had a mean diameter of 50nm (observed by transmission electron microscopy), a zeta potential of +45.9mV, and a CMC of about 9.97*10-5g/L. The release results showed that CPTCACHO 7.5% has the burst release at acidic pH, and cytotoxicity study indicated that IC50 of CPTCACHO 7.5% for MCF-7 cell line was 0.8MUg/mL. These properties altogether make CPTCACHO micelles, as a pH sensitive cargo with inherent cytotoxicity, a potential candidate for hydrophobic anticancer drugs. PMID- 27481345 TI - Konjac glucomannan, a promising polysaccharide of Amorphophallus konjac K. Koch in health care. AB - In recent year, konjac glucomannan (KGM) has attracted more attention due to its non-harmful and non-toxic properties, good biocompatibility, biodegradability and hydrophilic ability. Moreover, KGM and their derivatives have several importances in the multidirectional research areas such as nutritional, biotechnological and fine chemical fields. In the previous article, we have reviewed the nutritional aspects of KGM covering the various aspects of functional foods, food additives and their derivatives. This review aims at highlighting the diverse biomedical research conducted on KGM in the past ten years, covering therapies for anti obesity, regulation in lipid metabolism, laxative effect, anti-diabetic, anti inflammatory, prebiotic to wound dressing applications. Moreover, this review deals with global health aspects of KGM and the disparate health related factors associated with diseases and their control measures. PMID- 27481346 TI - Trade-Offs between Silicon and Phenolic Defenses may Explain Enhanced Performance of Root Herbivores on Phenolic-Rich Plants. AB - Phenolic compounds play a role in plant defense against herbivores. For some herbivorous insects, particularly root herbivores, host plants with high phenolic concentrations promote insect performance and tissue consumption. This positive relationship between some insects and phenolics, however, could reflect a negative correlation with other plant defenses acting against insects. Silicon is an important element for plant growth and defense, particularly in grasses, as many grass species take up large amounts of silicon. Negative impact of a high silicon diet on insect herbivore performance has been reported aboveground, but is unreported for belowground herbivores. It has been hypothesized that some silicon accumulating plants exhibit a trade-off between carbon-based defense compounds, such as phenolics, and silicon-based defenses. Here, we investigated the impact of silicon concentrations and total phenolic concentrations in sugarcane roots on the performance of the root-feeding greyback canegrub (Dermolepida albohirtum). Canegrub performance was positively correlated with root phenolics, but negatively correlated with root silicon. We found a negative relationship in the roots between total phenolics and silicon concentrations. This suggests the positive impact of phenolic compounds on some insects may be the effect of lower concentrations of silicon compounds in plant tissue. This is the first demonstration of plant silicon negatively affecting a belowground herbivore. PMID- 27481347 TI - Pheromone-Based Pest Management in China: Past, Present, and Future Prospects. AB - Semiochemical-based pest management technology has been widely used to monitor and control insect pests in agricultural, forestry, and public health sectors in the western world. It became a popular tool in the early 1970s with tremendous efforts in developing environment-friendly control technologies for the integrated pest management. However, in China, similar research lagged 15 to 20 years and was not initiated until the late 1980s. In this review, we present the early history of pheromone research that has led to the current practical applications in China, particularly in the development of pheromone-based pest management products. We also provide information regarding the current status of pheromone-based product manufacturing, marketing, and regulatory issues related to local semiochemical industries, which may be useful to other international companies interested in pursuing business in China. In addition, we share some research topics that represent new directions of the present pheromone research to explore novel tools for advancing semiochemical-based pest management in China. PMID- 27481349 TI - Quality of Life and Medico-Legal Implications Following Iatrogenic Bile Duct Injuries. AB - In this review we aimed to evaluate quality of life after bile duct injury and the consequent medico-legal implications. A comprehensive English language literature search was performed on MEDLINE, Embase, Science Citation Index and GoogleTM Scholar databases for articles published between January 2000 and April 2016. The last date of search was 11 April 2016. Key search words included bile duct injury, iatrogenic, cholecystectomy, prevention, risks, outcomes, quality of life, litigation and were used in combination with the Boolean operators AND, OR and NOT. Long-term survival after bile duct injury is significantly impaired (all cause long-term mortality approximately 21 %) along with the quality of life (especially psychological/mental state remains affected). Bile duct injury is associated with high rates of litigation. Monetary compensation varied from L2500 to L216,000 in the UK, ?9826-?55,301 in the Netherlands and $628,138-$2,891,421 in the USA. Bile duct injuries have profound implications for patients, medical personnel and healthcare providers as they cause significant morbidity and mortality, high rates of litigation and raised healthcare expenditure. PMID- 27481350 TI - Anastomotic Recurrence After Curative Resection for Colorectal Cancer. AB - BACKGROUND: A precise understanding of anastomotic recurrence (AR) permits efficient surveillance and treatment strategies. This study aimed to evaluate the clinicopathologic characteristics of patients with AR undergoing curative resection for colorectal cancer (CRC), compare colonic with rectal tumors and investigate the risk factors related to AR. METHODS: A single-institution, retrospective cohort of 9024 patients who underwent curative surgery for CRC between 2000 and 2010 was enrolled. Patients were classified into AR group (n = 53) or non-AR group (n = 8971) and were also characterized by tumor location. RESULTS: The AR group was independently associated with old age (p = 0.046), advanced N stage (p = 0.003), the rectum (p = 0.001), a large tumor (p = 0.001) and mucinous differentiation (MU) (p = 0.026). In colon cancers, the AR group (n = 20) was independently associated with MU (p = 0.022) and lymphovascular invasion (LVI) (p = 0.001). In rectal cancers, the AR group (n = 33) was independently associated with N2 stage (p = 0.007) and a large tumor (p < 0.001). AR is a burden to patients and physicians because these tumors have a poor prognosis and more advanced pathologic stages than the primary tumors. However, N0 stage and curative resection of an AR tumor (p = 0.001 and p < 0.001, respectively) were found to be independently associated with improved survival in a Cox regression model. CONCLUSION: AR is independently associated with the rectum. In colon cancers, MU and LVI are independent risk factors for AR. In rectal cancers, a large tumor and N2 stage are independent risk factors for AR. Although AR shows a poor prognosis, early detection and curative resection may lead to an improved survival. PMID- 27481351 TI - Comparative and evolutionary analysis of alpha-amylase gene across monocots and dicots. AB - alpha-amylase is an important enzyme involved in starch degradation to provide energy to the germinating seedling. The present study was conducted to reveal structural and functional evolution of this gene among higher plants. Discounting polyploidy, most plant species showed only a single copy of the gene making multiple isoforms in different tissues and developmental stages. Genomic length of the gene ranged from 1472 bp in wheat to 2369 bp in soybean, and the size variation was mainly due to differences in the number and size of introns. In spite of this variation, the intron phase distribution and insertion sites were mostly conserved. The predicted protein size ranged from 414 amino acid (aa) in soybean to 449aa in Brachypodium. Overall, the protein sequence similarity among orthologs ranged from 56.4 to 97.4 %. Key motifs and domains along with their relative distances were conserved among plants although several species, genera, and class specific motifs were identified. The glycosyl hydrolase superfamily domain length varied from 342aa in soybean to 384aa in maize and sorghum while length of the C-terminal beta-sheet domain was highly conserved with 61aa in all monocots and Arabidopsis but was 59aa in soybean and Medicago. Compared to rice, 3D structure of the proteins showed 89.8 to 91.3 % similarity among the monocots and 72.7 to 75.8 % among the dicots. Sequence and relative location of the five key aa required for the ligand binding were highly conserved in all species except rice. PMID- 27481353 TI - Bradyarrhythmia induced by amiodarone-sofosbuvir co-administration. PMID- 27481352 TI - Immunogenicity and functional characterization of Leishmania-derived hepatitis C virus envelope glycoprotein complex. AB - Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are the main inducers of a cross-neutralizing antibody response which plays an important role in the early phase of viral infection. Correctly folded and immunologically active E1E2 complex can be expressed in mammalian cells, though the production process might still prove restrictive, even if the immunological response of a vaccine candidate is positive. Here, we report a characterization and immunogenicity study of a full-length (fE1E2) and soluble version of the E1E2 complex (tE1E2) from genotype 1a, successfully expressed in the cells of Leishmania tarentolae. In a functional study, we confirmed the binding of both Leishmania-derived E1E2 complexes to the CD-81 receptor and the presence of the major epitopes participating in a neutralizing antibody response. Both complexes were proved to be highly immunogenic in mice and elicited neutralizing antibody response. Moreover, cross-reactivity of the mouse sera was detected for all tested HCV genotypes with the highest signal intensity observed for genotypes 1a, 1b, 5 and 6. Since the development of a prophylactic vaccine against HCV is still needed to control the global infection, our Leishmania-derived E1E2 glycoproteins could be considered a potential cost-effective vaccine candidate. PMID- 27481354 TI - Characterization of new Salmonella serovars by whole-genome sequencing and traditional typing techniques. AB - Serotyping forms the basis of all national and international surveillance networks for Salmonella. Public health microbiology is currently being transformed by high-throughput DNA sequencing, which opens the door to serovar determination using this powerful technique. Twenty-nine Salmonella isolates referred to the Public Health England between 1994 and 2004 for serovar identification were selected for this study, and they all presented with novel antigenic formulae. Results from a combination of traditional phenotypic and molecular assays were compared. Twenty-two isolates (76 %) were subsequently independently confirmed as new types; of these, 18 (82 %) were grouped as Salmonellaenterica subspecies I, and four (18 %) were S. enterica subspecies II. In general, it is shown that there is concordance between the DNA sequence type and traditional phenotypic serotype, but it would be necessary to analyse a larger data set to confirm this. Traditional multilocus sequence typing (MLST) by Sanger sequencing also correlates to insilico whole-genome sequencing MLST. This permits the continuation of traditional serovar nomenclature alongside sequence type methods and enhances the ability to infer true phylogenetic relationships between isolates. PMID- 27481355 TI - [Clinical results following conservative and surgical treatment of osteoporotic distal radius fractures in the elderly : Overview of best available evidence]. AB - Fractures of the distal radius in elderly patients increasingly contribute to the workload in emergency departments worldwide. There is still no consensus about the best treatment option, e. g. closed reduction and cast stabilization, percutaneous pinning, external fixation or open reduction and internal fixation with volar locking plates (ORIF). In addition, the influence of pharmacological antiosteoporotic treatment (e. g. bisphosphonates) is unclear. In this overview five comparative studies were analyzed, which had been identified in a previous systematic review. The evaluation included 3 cohort studies and 2 randomized trials enrolling a total of 515 patients. A clinical or statistical advantage of ORIF over conservative treatment with respect to DASH scores 12 months after the index fracture event could not be demonstrated with a mean difference of 0.25 (95 % confidence interval CI -0.57-1.07). According to current best scientific evidence from preclinical and clinical investigations, antiosteoporotic medication does not have an unfavorable influence on fracture healing and should be continued due to its proven effectiveness in reducing subsequent osteoporotic fractures. Following distal radius fractures in elderly patients with clinical risk factors, an osteoporosis screening should be routine practice and a specific therapy should be initiated if the fracture risk is increased. PMID- 27481356 TI - Distinct Differentiation Programs Triggered by IL-6 and LPS in Teleost IgM(+) B Cells in The Absence of Germinal Centers. AB - Although originally identified as a B cell differentiation factor, it is now known that mammalian interleukin-6 (IL-6) only regulates B cells committed to plasma cells in response to T-dependent (TD) antigens within germinal centers (GCs). Even though adaptive immunity is present in teleost fish, these species lack lymph nodes and GCs. Thus, the aim of the present study was to establish the role of trout IL-6 on B cells, comparing its effects to those induced by bacterial lipopolysaccharide (LPS). We demonstrate that the effects of teleost IL 6 on naive spleen B cells include proliferation, activation of NF-kappaB, increased IgM secretion, up-regulation of Blimp1 transcription and decreased MHC II surface expression that point to trout IL-6 as a differentiation factor for IgM antibody-secreting cells (ASCs). However, LPS induced the secretion of IgM without up-regulating Blimp1, driving the cells towards an intermediate activation state in which antigen presenting mechanisms are elicited together with antibody secretion and expression of pro-inflammatory genes. Our results reveal that, in trout, IL-6 is a differentiation factor for B cells, stimulating IgM responses in the absence of follicular structures, and suggest that it was after follicular structures appeared that this cytokine evolved to modulate TD responses within the GC. PMID- 27481359 TI - MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound. AB - PURPOSE: A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500 Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain. PROCEDURES: Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5 [(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [18F]DCFPyL or YC-27, which competes for GCPII/PSMA binding. RESULTS: Dynamic PET imaging using [18F]DCFPyL demonstrated that target uptake reached a plateau by ~1 h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of ~4:1 at 45 min to ~7:1 by 80 min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24 h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS. CONCLUSIONS: MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS. PMID- 27481358 TI - Comparative Evaluation of Three TSPO PET Radiotracers in a LPS-Induced Model of Mild Neuroinflammation in Rats. AB - PURPOSE: Over the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in many neurodegenerative diseases, including Alzheimer's disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [18F]GE-180 and [18F]DPA-714 with (R)-[11C]PK11195 in a rodent model of subtle focal inflammation. PROCEDURES: Adult male Wistar rats were stereotactically injected with 1 MUg lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[11C]PK11195 and [18F]GE-180 (n = 6) or [18F]DPA-714 (n = 6). Ten animals were scanned with either [18F]GE-180 (n = 5) or [18F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BPND. Autoradiography and immunohistochemistry were performed to confirm in vivo results. RESULTS: At 40-60 min post-injection, [18F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R) [11C]PK11195 (3.41 +/- 1.09 vs. 2.43 +/- 0.39, p = 0.03); [18]DPA-714 did not (2.80 +/- 0.69 vs. 2.26 +/- 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BPND) in the core of the LPS injection site with [18F]GE-180 but not with [18F]DPA-714 vs. (R) [11C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BPND. CONCLUSIONS: Second generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [18F]GE-180 shows a higher core/contralateral ratio and BPND when compared to (R)-[11C]PK11195, while [18F]DPA-714 did not. PMID- 27481360 TI - Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women. AB - Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries. PMID- 27481362 TI - Effects of management in gestational diabetes mellitus with normal prepregnancy body mass index on pregnancy outcomes and placental ultrastructures: a prospective cohort study. AB - A great quantity of gestational diabetes mellitus with normal prepregnancy body mass index have emerged with the new criteria of gestational diabetes mellitus in China based on the International Diabetes in Pregnancy Consensus group criteria, and understanding placental changes and how they affect outcomes are necessary in order to develop effective management approach. The aim of this study was to prospectively explore the effect of active management starting from the late second trimester in gestational diabetes mellitus women with normal prepregnancy body mass index on pregnancy outcomes and placental ultrastructures, and to provide scientific evidences for optimizing the management of gestational diabetes mellitus in China. Gestational diabetes mellitus women with normal prepregnancy body mass index in the same period of this prospective cohort study were divided into intervention group (n = 51) and control group (n = 55). The intervention group was managed rigorously, while the control group received conventional prenatal cares. The glucose profile, gestational weight gain and pregnancy outcomes were followed up and placental ultrastructures were observed and recorded by transmission electron microscopy. The blood glucose level and gestational weight gain in intervention group were significantly better controlled than those in control group (P < 0.01). The incidences of fetal distress, cesarean section and large for gestational age were significantly lower in intervention group than in control group (P < 0.05). There was a significant reduction in the incidence of abnormal placental ultrastructure in the intervention group (P < 0.01). After adjustment for confounding factors, the undesirable glycemic control and conventional management were related to abnormal placental ultrastructure (P < 0.05). Meanwhile, the undesirable glycemic control, abnormal placental ultrastructure and conventional management made sense in the incidence of fetal distress (P < 0.05), and the target glycemic control, recommend weight gain and active management were associated with reductions in the prevalence of cesarean delivery and large for gestational age (P < 0.05). The active management of gestational diabetes mellitus women with normal prepregnancy body mass index can improve pregnancy outcomes and placental ultrastructures, and the abnormal placental ultrastructure might be closely associated with the undesirable glycemic control and adverse pregnancy outcomes. PMID- 27481361 TI - Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients. AB - Hypothyroidism is characterized by hypometabolism, and may be seen as a part of secondary failure due to pituitary insufficiency or tertiary due to hypothalamic disease. Secondary and tertiary failures are also referred to as central hypothyroidism. Whereas overt primary hypothyroidism has a well-known affection on the heart and cardiovascular system, and may result in cardiac failure, cardiovascular affection is less well recognized in central hypothyroidism. Studies on central hypothyroidism and cardiovascular outcome are few and given the rarity of the diseases often small. Further, there are several limitations given vast difficulties in diagnosing the condition correctly biochemically, and difficulties monitoring the treatment because normal thyroid-pituitary feedback interrelationships are disrupted. The present review summarizes available studies of central adult hypothyroidism and its possible influence on the cardiovascular system, describe differences from primary thyroid failure and seek evidence for performing guidelines for clinical management of this particular thyroid and hypothalamo-pituitary disorder. PMID- 27481363 TI - Patient-derived xenograft in zebrafish embryos: a new platform for translational research in neuroendocrine tumors. AB - Preclinical research on neuroendocrine tumors usually involves immortalized cell lines and few animal models. In the present study we described an in vivo model based on patient-derived xenografts of neuroendocrine tumor cells in zebrafish (Danio rerio) embryos, allowing a rapid analysis of the angiogenic and invasive potential. Patient-derived neuroendocrine tumor cells were transplanted in 48 hours post-fertilization Tg(fli1a:EGFP) y1 zebrafish embryos that express enhanced green fluorescent protein in the entire vasculature. Neuroendocrine tumor cells, stained with CM-Dil, were injected into the subperidermal (perivitelline) space, close to the developing subintestinal venous plexus. A proper control group, represented by zebrafish injected with only D-PBS, was included in this study. Angiogenic and invasive potentials of each patient derived xenograft were evaluated by both epifluorescence and confocal microscopes. Six out of eight neuroendocrine tumor samples were successfully transplanted in zebrafish embryos. Although the implanted tumor mass had a limited size (about 100 cells for embryos), patient-derived xenografts showed pro angiogenic (5 cases) and invasive (6 cases) behaviors within 48 hours post injection. Patient-derived xenograft in zebrafish embryos appears to be a reliable in vivo preclinical model for neuroendocrine tumors, tumors with often limited cell availability. The rapidity of this procedure makes our model a promising platform to perform preclinical drug screening and opens a new scenario for personalized treatment in patients with neuroendocrine tumors. PMID- 27481364 TI - Symptom-dependent cut-offs of urine metanephrines improve diagnostic accuracy for detecting pheochromocytomas in two separate cohorts, compared to symptom independent cut-offs. AB - The development of advanced imaging techniques has increased the detection of subclinical pheochromocytomas. Because of the substantial proportions of subclinical pheochromocytomas, measurement of urine metanephrine concentrations is crucial due to detect or exclude pheochromocytoma. Although urine metanephrines are elevated in symptomatic subjects, diagnostic cut-offs according to the presence of adrenergic symptoms have not been studied. Pheochromocytomas patients who underwent adrenalectomy at Samsung Medical Center and a control group were compared to determine cut-off concentrations of urine metanephrines. An independent population was analyzed for urine metanephrines with different kits to validate the improvement in diagnostic accuracy using adjusted cut-offs. Symptom-dependent cut-offs of urine metanephrines were higher for symptomatic patients (307 MUg/day in males, 235 MUg/day in females for urine metanephrine, and 1,045 MUg/day in males and 457 MUg/day in females for urine normetanephrine) than for asymptomatic patients (206 MUg/day in males, 199 MUg/day in females for urine metanephrine, and 489 MUg/day in males and 442 MUg/day in females for urine normetanephrine). Symptom-dependent cut-offs of urine metanephrines improved a specificity from 92.7 % to 96.3 % and a high sensitivity of 97.8 % was maintained. Using the Symptom-dependent cut-offs raised diagnostic accuracy by 5.5 % (p <0.001). Similar trend was also observed in an independent population using different hormone kits. Using symptom-dependent cut-offs of urine metanephrines in symptomatic patients for pheochromocytomas resulted in a significant improvement in diagnostic accuracy in two separate cohorts. PMID- 27481365 TI - Ultrasound measurement of median nerve cross-sectional area at the inlet and outlet of carpal tunnel after carpal tunnel release compared to electrodiagnostic findings. AB - INTRODUCTION: Ultrasound measurement of the cross-sectional area (CSA) of the median nerve can give information about regeneration of the nerve after carpal tunnel release (CTR), but the changes at selected follow-up points up to 1 year compared to electrodiagnostic findings are not known. We postoperatively measured the CSA of the median nerve with ultrasound and compared the measurements with electrophysiological findings over 12 months after open CTR. MATERIALS AND METHODS: In 21 hands that underwent open CTR, the CSA of the median nerve was measured at the inlet (proximal CSA) and outlet (distal CSA) of the carpal tunnel at 3- 6- and 12-month follow-up. The respective ratios [(CSA postoperatively/CSA preoperatively) * 100] were calculated and correlated with distal motor latency (DML) and sensory nerve conduction velocity (SCV). RESULTS: The proximal CSA ratio was 88.9, 84.5, and 78.4 % at 3-, 6-, and 12-month follow-up, respectively. Each value was significantly lower than that before surgery. The distal CSA ratio was 104.3, 99.1, and 91.8 % at 3-, 6-, and 12-month follow-up, respectively. The values were not significantly different compared to preoperative values. CONCLUSIONS: The proximal CSA of the median nerve decreased continuously over the time after CTR while the distal CSA increased up to 3 months before it decreased continuously, too. PMID- 27481366 TI - Is the prognosis the same for periprosthetic joint infections due to Staphylococcus aureus versus coagulase-negative staphylococci? A retrospective study of 101 patients with 2-year minimum follow-up. AB - BACKGROUND: Staphylococcus aureus (SA) and Coagulase-negative staphylococci (CoNS) are often responsible for infections of total hip arthroplasty (THA) and total knee arthroplasty (TKA). One of the main differences between these two microorganisms is their virulence, with SA presumed to be more virulent; however, few studies have specifically investigated the impact of this virulence. This inspired us to carry out a retrospective study to evaluate whether the healing rate differed between SA and CoNS infections. HYPOTHESIS: We hypothesised that the healing rate is lower for SA prosthetic joint infections. MATERIALS AND METHODS: This was a retrospective study of 101 consecutive Staphylococcus infection cases that occurred between 2007 and 2011. There were 56 men and 45 women with an average age of 69 years (range 23-95). The infection was associated with TKA in 38 cases and THA in 63 cases. Thirty-two percent of patients had one or more comorbidities with infectious potential. In our cohort, there were 32 SA infections (31.7 %) and 69 CoNS infections (68.3 %) with 58 of the infections being methicillin-resistant (15 SA and 43 CoNS); there were 27 polymicrobial infections (26.7 %). RESULTS: With a minimum 24-month follow-up after the end of antibiotic treatment, the healing rate was 70.3 % overall (71 patients). The healing rate was 75 % in the SA group (24 patients) versus 68.1 % (47 patients) in the CoNS group (P = 0.42). CONCLUSION: Our hypothesis was not confirmed: the healing rate of SA prosthetic joint infections was not lower than that of CoNS infections. LEVEL OF EVIDENCE: III, retrospective case-control study. PMID- 27481367 TI - Measurement of regional trabecular bone attenuation of the knee following anterior cruciate ligament rupture. AB - INTRODUCTION: The purpose of this study was to determine regional trabecular bone attenuation changes of the knee using computed tomography after anterior cruciate ligament rupture. MATERIALS AND METHODS: Thirty one patients'-computed tomography images of the injured knees were used to measure trabecular bone attenuation in seven predetermined regions. RESULTS: Trabecular bone attenuation at four of seven regions (anteromedial area of the proximal tibia, anterolateral area of the proximal tibia, posteromedial area of the proximal tibia, and posterocentral area of the proximal tibia) was negatively correlated with the duration after injury. Independent negative correlation between the duration after injury and the density in anteromedial area of the proximal tibia was detected. CONCLUSIONS: After anterior cruciate ligament injury, trabecular bone attenuation of the knee decreases by time in certain regions of proximal tibia. Anteromedial region is the most significantly effected of all, which it is the anterior cruciate ligament fixation area. PMID- 27481368 TI - Lung damage induced by hyperglycemia in diabetic rats: The role of signal transducer and activator of transcription 3 (STAT3). AB - Increased evidence has shown that diabetes can be a risk factor for pulmonary fibrosis. The objective of this study was to use streptozotocin-induced diabetic rats (STZ rats) to assess the possible signals associated with lung damage in diabetic disorders. The expression levels of signal transducer and activator of transcription 3 (STAT3) and connective tissue growth factor (CTGF) in lung tissues were measured through Western blot analysis and real-time PCR. Additionally, the potential mechanisms were confirmed in cultured rat lung cell line (L2) incubated in high-glucose (HG) medium to mimic the in vivo changes. The pathological changes in the lung tissues of STZ rats were characterized using the bleomycin-treated tissues as reference. Moreover, the higher expression levels of STAT3 and CTGF in the lung tissues of STZ rats were reversed by treating the hyperglycemia. CTGF expression increased following the higher expression of STAT3 in the cultured L2 cells exposed to HG, and this change was reversed by siRNA treatment specific for STAT3. Stattic, at a dose sufficient to inhibit STAT3, reduced the CTGF levels in the lungs of STZ rats. In conclusion, STAT3 enhanced CTGF expression in a type-1 diabetes model associated with lung damage. Thus, STAT3 inhibitors may be developed to improve diabetes-induced lung damage in the future. PMID- 27481369 TI - Revalidation - half-time score. PMID- 27481370 TI - The state of public health services in England - why hospital physicians should be worried. PMID- 27481371 TI - Changes to postgraduate medical education in the 21st century. AB - Medicine is a constantly evolving profession, especially with the advent of rapid advances in the scientific base that underpins this vocation. In order to ensure that training in medicine is contemporary with the continuous evolution of the profession, there has been a multitude of changes to postgraduate medical education, particularly in the UK. This article aims to provide an overview of relevant key changes to postgraduate medical education in the UK during the 21st century, including changes to the structure, governance and commissioning of medical education, effects of European Working Time Directive on training, recent recommendations in the Future Hospital Commission report and Shape of training report, and recent requirements for accreditation of medical education trainers. Many of these recommendations will require complex discussions often at organisational levels, hopefully with some realistic and pragmatic solutions for implementation. PMID- 27481372 TI - Options for taking time out of specialty training. AB - Trainees in higher specialty training programmes may have the option to take time out of their training programme to enhance or broaden their skills and perhaps develop a subspecialty interest. Traditionally, out of programme experience has been mostly taken by clinical academic trainees in order to undertake a higher research degree. However, there are a growing number of other ways to usefully spend time out of programme. This article is intended to highlight the range of opportunities and explain the modern processes for obtaining permissions to enable trainees to make good choices for themselves. PMID- 27481373 TI - 'The time it takes...' How doctors spend their time admitting a patient during the acute medical take. AB - Patient safety depends on adequate staffing but the number of doctors required for safe staffing for medical emergencies is not known. We measured the duration of the admission process for patients seen by medical teams in emergency departments (EDs) and acute medical units. History taking and examination by a core medical trainee took 22 minutes for a patient referred from the ED and 21 minutes for a patient referred from primary care. A complete admission clerking with prescription and ordering of investigations ranged from a mean of 15 minutes for a consultant in acute medicine to a mean of 55 minutes for a foundation year 1 trainee. The duration of post-take ward rounds also showed significant variability.Our data can be used to model staffing patterns if combined with information about admission numbers and local set up. PMID- 27481374 TI - Designing services for frequent attenders to the emergency department: a characterisation of this population to inform service design. AB - Frequent attendance to the emergency department (ED) is a growing public health concern. Designing services for frequent attenders poses challenges, given the heterogeneous nature of this group. This was a two-part observational study identifying frequent attenders from ED records. The first stage studied trends and developed personas with emphasis on differentiating moderate frequent attenders (attending between 5 and 20 times per year) and extreme frequent attenders (attending more than 20 times). Stage 2 included a case note review of 100 consecutive frequent attenders. Results showed an increase in frequent attendance from 2.59% to 4.12% over 8 years. Moderate frequent attenders accounted for 97%. Of the 100 frequent attenders studied, 45% had medically unexplained symptoms (MUS), associated with younger age (p<0.001) but not with gender (p>0.05). In conclusion, the ED is a useful hub for identifying frequent attenders with MUS, particularly among moderate frequent attenders; service design for this group should consider a 'whole-systems approach' with integration between primary and secondary care, including specialist liaison psychiatry services where appropriate. PMID- 27481375 TI - Optimising prescription and titration of oxygen for adult inpatients using novel silicone wristbands: results of a pilot project at three centres. AB - Oxygen is the most commonly used drug in the acute hospital setting. Oxygen can be lifesaving but there is increasing evidence that it can cause harm if it is not given correctly. Prescription of oxygen, according to target saturations, has been advocated since 2008 but compliance remains at low levels. This paper describes a novel approach to improve oxygen prescription and titration in three acute hospital trusts using a colour-coded silicone wristband. The project ran for 3 months and covered more than 2,000 emergency admissions to hospital. Data was collected for oxygen prescription and titration rates for 270 patients during the project period. The wristbands showed an improvement in prescription and titration of oxygen in two out of three sites. The results support a wider controlled study of colour-coded wristbands to improve oxygen safety in secondary care. PMID- 27481376 TI - Assessment for benign paroxysmal positional vertigo in medical patients admitted with falls in a district general hospital. AB - Having benign paroxysmal positional vertigo (BPPV) puts patients at a significantly higher risk of falling. It is poorly recognised and diagnosis is frequently delayed. BPPV has been studied in outpatient settings, but there have been no studies looking at the prevalence in patients admitted with falls. This study aims to establish how common BPPV is in these patients.For a 4-month period, patients admitted on an unselected medical take were screened for an admission precipitated by a fall. Patients who consented were assessed for BPPV using the Dix-Hallpike manoeuvre. Patients who tested positive were treated using the Epley manoeuvre. The assessments were carried out by specialist physiotherapists who were experienced at assessing and diagnosing patients with peripheral vestibular disorders. Out of the 111 patients initially identified, 37 (33%) were considered to be appropriate and consented to be part of the study. Of these, 20 patients (54%) had a positive Dix-Hallpike manoeuvre.Of the patients included in the study, over half tested positive for BPPV. This merits further study. Potentially, there is a proportion of patients admitted with falls who have an easily treatable contributing factor that is not being identified with standard practice. PMID- 27481377 TI - Selection of medical students on the basis of non-academic skills: is it worth the trouble? AB - In this article, we discuss the practical usefulness of selecting future medical students on the basis of increasingly popular non-academic tests (eg multiple mini-interviews, situational judgment tests) in addition to academic tests. Non academic tests assess skills such as ethical decision making, communication and collaboration skills, or traits such as conscientiousness. Although other studies showed that performance on non-academic tests could have a positive relationship with future professional performance, we argue that this relationship should be interpreted in the context of the base rate (the proportion of suitable candidates in the applicant pool) and the selection ratio (the proportion of selected applicants from the applicant pool). We provide some numerical examples in the context of medical student selection. Finally, we suggest that optimising training in non-academic skills may be a more successful alternative than selecting students on the basis of these skills. PMID- 27481378 TI - The thinking doctor: clinical decision making in contemporary medicine. AB - Diagnostic errors are responsible for a significant number of adverse events. Logical reasoning and good decision-making skills are key factors in reducing such errors, but little emphasis has traditionally been placed on how these thought processes occur, and how errors could be minimised. In this article, we explore key cognitive ideas that underpin clinical decision making and suggest that by employing some simple strategies, physicians might be better able to understand how they make decisions and how the process might be optimised. PMID- 27481379 TI - Genomics education for medical professionals - the current UK landscape. AB - Genomics education in the UK is at an early stage of development, and its pace of evolution has lagged behind that of the genomics research upon which it is based. As a result, knowledge of genomics and its applications remains limited among non specialist clinicians. In this review article, we describe the complex landscape for genomics education within the UK, and highlight the large number and variety of organisations that can influence, direct and provide genomics training to medical professionals. Postgraduate genomics education is being shaped by the work of the Health Education England (HEE) Genomics Education Programme, working in conjunction with the Joint Committee on Genomics in Medicine. The success of their work will be greatly enhanced by the full cooperation and engagement of the many groups, societies and organisations involved with medical education and training (such as the royal colleges). Without this cooperation, there is a risk of poor coordination and unnecessary duplication of work. Leadership from an organisation such as the HEE Genomics Education Programme will have a key role in guiding the formulation and delivery of genomics education policy by various stakeholders among the different disciplines in medicine. PMID- 27481380 TI - Drugs for hypercholesterolaemia - from statins to pro-protein convertase subtilisin kexin 9 (PCSK9) inhibition. AB - Cardiovascular disease (CVD) remains one of the commonest sources of morbidity and mortality in the world. Lipids and especially low density lipoprotein cholesterol (LDL-C) contribute to the risk of CVD events. Statins are the primary therapy for hypercholesterolaemia and recent evidence supports the use of ezetimibe as a second-line agent. Pro-protein convertase subtilisin kexin 9 (PCSK9) is a regulator of LDL receptor expression. Activating mutations in PCSK9 give rise to a form of familial hypercholesterolaemia, while inactivating mutations lead to lower LDL-C levels and fewer CVD events. Therapies to inhibit PCSK9 are in development and two antibody-based therapies - alirocumab and evolocumab - have recently been licensed. This article reviews the actions of PCSK9, the novel therapeutics targeted on this molecule and how they are likely to be used in clinical practice until large scale CVD outcome studies with PCSK9 inhibitors are published. PMID- 27481381 TI - An uncommon cause of deep venous thrombosis. AB - We present the case of a 23-year-old Turkish man who developed extensive deep venous thrombosis as a first presentation of Behcet's disease. We describe the work-up of his condition and discuss the potential for Behcet's disease to cause deep venous thrombosis as a presenting finding. PMID- 27481382 TI - Recent advances in the pathogenesis and treatment of osteoporosis. AB - Over recent decades, the perception of osteoporosis has changed from that of an inevitable consequence of ageing, to that of a well characterised and treatable chronic non-communicable disease, with major impacts on individuals, healthcare systems and societies. Characterisation of its pathophysiology from the hierarchical structure of bone and the role of its cell population, development of effective strategies for the identification of those most appropriate for treatment, and an increasing armamentarium of efficacious pharmacological therapies, have underpinned this evolution. Despite this marked progress, individuals who experience a fragility fracture remain under-treated in many areas of the world, and there is substantial need for investment both in secondary and primary prevention globally. In this brief article, we give an overview of the pathogenesis of osteoporosis, and summarise current and future approaches to its assessment and -treatment. PMID- 27481383 TI - New concepts in the pathogenesis and presentation of Parkinson's disease. AB - Parkinson's disease (PD) was first described by James Parkinson in 1817. He noted the complex nature of this condition and that non-motor symptoms (NMS) underpinned the classic motor symptoms of PD. The concept of what PD is has therefore undergone substantial changes and it is now recognised that PD is a combined motor and non-motor syndrome and NMS are present during the prodromal phase of PD, starting up to 20 years before the first clinical motor signs emerge. PD may originate from pathology in the gut, olfactory bulb and lower brainstem rather than in the substantia nigra. Complex phenotypes of PD may exist where clinical NMS overshadow motor features. Therapy needs to be adjusted based on motor and non-motor loads, ideally using validated tools. Recently, a multimodal biomarker battery in PD has emerged and might play an important role in the future. PMID- 27481384 TI - Imaging in Parkinson's disease. AB - The clinical presentation of Parkinson's disease (PD) is heterogeneous and overlaps with other conditions, including the parkinsonian variant of multiple system atrophy (MSA-P), progressive supranuclear palsy (PSP) and essential tremor. Imaging of the brain in patients with parkinsonism has the ability to increase the accuracy of differential diagnosis. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) allow brain imaging of structural, functional and molecular changes in vivo in patients with PD. Structural MRI is useful to differentiate PD from secondary and atypical forms of parkinsonism. 123I-ioflupane (DaTSCAN(TM)) SPECT is a valid tool in the differential diagnosis between PD and non degenerative tremors, while cardiac 123I-metaiodobenzylguanidine SPECT and 18F fluorodeoxyglucose PET are valid in the differential diagnosis between PD and atypical parkinsonism (MSA-P, PSP). However, despite significant evidence for the utility of neuroimaging in assessing parkinsonian patients, none of the neuroimaging techniques are specifically recommended for routine use in clinical practice. Hopefully, future larger trials will help to demonstrate additional evidence for the clinical utility of neuroimaging and will include an analysis of the financial benefits for the NHS in the longer term management of the patients. PMID- 27481385 TI - Parkinson's disease in the older patient. AB - Parkinson's disease (PD) is the second most commonly encountered neurodegenerative condition in clinical practice and probably offers a significantly greater variety of challenges than the management of Alzheimer's disease. As with most neurodegenerative diseases, age represents the leading risk factor for the development of PD. Current estimates would suggest that PD affects 1-2% of people over the age of 65 years and each decade sees an increasing number of cases. In addition, it is well recognised that most industrialised nations have an increasing proportion of individuals living longer. For example, recent data from Australia indicates that the prevalence of PD is anticipated to rise by 80% over the next 20 years and as such, we must all strive towards improving our clinical management of this common condition. In this article, we will attempt to highlight the issues that should be actively sought out and, where possible, addressed. We hope that an improved level of understanding will lead to better outcomes in older patients with PD. PMID- 27481386 TI - Restless legs syndrome. AB - Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common movement disorder characterised by an uncontrollable urge to move because of uncomfortable, sometimes painful sensations in the legs with a diurnal variation and a release with movement. The pathophysiology is only partially known and a genetic component together with dopaminergic and brain iron dysregulation plays an important role. Secondary causes for RLS need to be excluded. Treatment depends on the severity and frequency of RLS symptoms, comprises non-pharmacological (eg lifestyle changes) and pharmacological interventions (eg dopaminergic medication, alpha-2-delta calcium channel ligands, opioids) and relieves symptoms only. Augmentation is the main complication of long-term dopaminergic treatment of RLS. This article will provide a clinically useful overview of RLS with provision of diagnostic criteria, differential diagnoses, possible investigations and different treatment strategies with their associated complications. PMID- 27481387 TI - What is new in tics, dystonia and chorea? AB - Movement disorders comprise hyperkinetic involuntary movements (eg tremor, myoclonus, tics, dystonia and chorea) and hypokinetic (parkinsonism) disorders. Tics are cardinal features of primary tic disorders encompassing Tourette syndrome (TS), but are also found in some neurodegenerative conditions and may be induced by psychoactive substances. The first line treatment for tics is pharmacological (mainly dopamine receptor blockers or alpha-2 adrenergic agonists) and behavioural. Dystonia and chorea syndromes are considerably heterogeneous in aetiology, and age at onset, body distribution of the movement disorder, accompanying neurological motor and non-motor features, and systemic manifestations are all important to reach a correct aetiological diagnosis. While symptomatic pharmacological treatment remains the mainstay of treatment for choreas, deep brain stimulation surgery has a well-defined place in the management of medically refractory dystonia. PMID- 27481389 TI - Lesson of the month 1: Diabetic ketoacidosis in established renal failure. AB - Diabetic ketoacidosis (DKA) is a common medical emergency. The pathophysiology of DKA in patients with advanced chronic kidney disease differs significantly from patients with preserved renal function. We describe a patient with pre-dialysis renal failure who presented with DKA. This case highlights the importance of tailoring the established management guidelines appropriately. PMID- 27481390 TI - Lesson of the month 2: Against all odds. AB - When a patient who suffers from a serious underlying disease with an ever-present potential for recurrence or progression deteriorates, other alternative diagnoses (even treatable ones) are frequently not considered. However, these patients are often immunosuppressed, which makes them susceptible to reactivation of latent viral or tuberculosis infections. Three brief cases are presented to stress the importance of looking for unsuspected, treatable herpes virus infections in these settings and the relevant cognitive aspects of misdiagnosis are discussed. PMID- 27481391 TI - Image of the month: Radiological findings in bronchiectasis. PMID- 27481392 TI - Strong cider sold in scotland appears to be almost exclusively for dependent drinkers. PMID- 27481393 TI - Vitamin D - what is normal according to latest research and how should we deal with it? PMID- 27481394 TI - Viral arthritis. PMID- 27481395 TI - Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non ketotic hyperglycinemia in humans. AB - Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child who presented with NKH, but harbored no pathogenic variants in any of the three genes linked to this condition. Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A>G (p.Ser407Gly) that segregates with the disease within the family. This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function. In murine model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia. This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans. PMID- 27481398 TI - Spatial clustering of tuning in mouse primary visual cortex. AB - The primary visual cortex of higher mammals is organized into two-dimensional maps, where the preference of cells for stimulus parameters is arranged regularly on the cortical surface. In contrast, the preference of neurons in the rodent appears to be arranged randomly, in what is termed a salt-and-pepper map. Here we revisited the spatial organization of receptive fields in mouse primary visual cortex by measuring the tuning of pyramidal neurons in the joint orientation and spatial frequency domain. We found that the similarity of tuning decreases as a function of cortical distance, revealing a weak but statistically significant spatial clustering. Clustering was also observed across different cortical depths, consistent with a columnar organization. Thus, the mouse visual cortex is not strictly a salt-and-pepper map. At least on a local scale, it resembles a degraded version of the organization seen in higher mammals, hinting at a possible common origin. PMID- 27481396 TI - Evidence for Non-neutral Evolution in a Sodium Channel Gene in African Weakly Electric Fish (Campylomormyrus, Mormyridae). AB - Voltage-gated sodium channels, Nav1, play a crucial role in the generation and propagation of action potentials and substantially contribute to the shape of their rising phase. The electric organ discharge (EOD) of African weakly electric fish (Mormyroidea) is the sum of action potentials fired from all electrocytes of the electric organ at the same time and hence voltage-gated sodium channels are one factor-together with the electrocyte's morphology and innervation pattern that determines the properties of these EODs. Due to the fish-specific genome duplication, teleost fish possess eight copies of sodium channel genes (SCN), which encode for Nav1 channels. In mormyroids, SCN4aa is solely expressed in the electrocytes of the adult electric organ. In this study, we compared entire SCN4aa sequences of six species of the genus Campylomormyrus and identified nonsynonymous substitutions among them. SCN4aa in Campylomormyrus exhibits a much higher evolutionary rate compared to its paralog SCN4ab, whose expression is not restricted to the electric organ. We also found evidence for strong positive selection on the SCN4aa gene within Mormyridae and along the lineage ancestral to the Mormyridae. We have identified sites at which all nonelectric teleosts are monomorphic in their amino acid, but mormyrids have different amino acids. Our findings confirm the crucial role of SCN4aa in EOD evolution among mormyrid weakly electric fish. The inferred positive selection within Mormyridae makes this gene a prime candidate for further investigation of the divergent evolution of pulse-type EODs among closely related species. PMID- 27481399 TI - Psychometric field testing of the HemoLatin-QoL questionnaire. AB - PURPOSE: The present work aims to describe the psychometric field testing of the Latin American Hemophilia-Specific Quality of Life Assessment Measure for Adults (the HemoLatin-QoL questionnaire) in 306 adults (age range 16-80) with haemophilia living in seven Latin American countries (i.e. Argentina, Brasil, Chile, Nicaragua, Panama, Uruguay and Venezuela). METHODS: The HemoLatin-QoL questionnaire is a patient-reported outcomes instrument that evaluates relevant health-related quality-of-life domains for haemophilia, selected by an exploratory qualitative study with patients, and taking into account healthcare specialists in haemophilia also. Psychometric examination involved the assessment of the data quality, scaling assumptions, reliability (internal consistency and test-retest) and evidences for validity (dimensionality, convergent and external related clinical criterion). RESULTS: A 27-item version with a six-factor structure (e.g. physical functioning, pain, emotional functioning, social functioning, mental health, environment conditions) was psychometrically tested using exploratory factor analysis. The instrument and its subscales fulfilled the construct (dimensionality, convergent and criterion-related) validity hypotheses. The criteria for adequate internal consistency and test-retest reliability of the HemoLatin-QoL instrument were also met. CONCLUSION: The HemoLatin-QoL showed acceptable psychometric properties with respect to responses from haemophilia patients. The questionnaire is now available for adult assessment and is ready for use in research in Latin America. PMID- 27481397 TI - Recent and Long-Term Selection Across Synonymous Sites in Drosophila ananassae. AB - In Drosophila, many studies have examined the short- or long-term evolution occurring across synonymous sites. Few, however, have examined both the recent and long-term evolution to gain a complete view of this selection. Here we have analyzed Drosophila ananassae DNA polymorphism and divergence data using several different methods, and have identified evidence of positive selection favoring preferred codons in both recent and long-term evolutionary time scale. Further in D. ananassae, the strength of selection for preferred codons was stronger on the X chromosome compared to the autosomes. We show that this stronger selection is not due to higher gene expression of X-linked genes. Analysis of the selectively neutral introns indicated that the X chromosome also had a preference for GC over AT nucleotides, potentially from GC-biased gene conversions (gcBGCs) that can also affect the base composition of synonymous sites. Thus selection for preferred codons and gcBGC both seem to be partially responsible for shaping the D. ananassae synonymous site evolution. PMID- 27481400 TI - Brincidofovir treatment of acyclovir-resistant disseminated varicella zoster virus infection in an immunocompromised host. AB - Brincidofovir (BCV) is a broad-spectrum antiviral agent active in vitro against double-stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and poxviruses. We report successful BCV use in management of disseminated acyclovir- and cidofovir-resistant varicella zoster virus in an immunocompromised hematopoietic stem cell transplant patient with chronic graft versus-host disease who was intolerant to foscarnet. PMID- 27481401 TI - Retention behavior of isomeric polycyclic aromatic sulfur heterocycles in reversed-phase liquid chromatography. AB - Retention indices for 70 polycyclic aromatic sulfur heterocycles (PASHs) were determined using reversed-phase liquid chromatography (LC) on a monomeric and a polymeric C18 stationary phase. Molecular shape parameters [length, breadth, thickness (T), and length-to-breadth ratio (L/B)] were calculated for all the compounds studied. Correlations between the retention on the polymeric C18 phase and PASH geometry (L/B and T) were investigated for six specific PASH isomer groups with molecular mass (MM) 184Da, 234Da, 258Da, 284Da, 334Da, and 384Da. Similar to previous studies for polycyclic aromatic hydrocarbons (PAHs), PASH elution order on the polymeric C18 phase was generally found to follow increasing L/B values. Correlation coefficients for retention vs L/B ranged from r=0.45 (MM 184Da) to r=0.89 (MM 284Da). In the case of smaller PASHs (MM<=258Da), the location of the sulfur atom in the bay-region of the structure resulted in later than expected elution of these isomers based on L/B. In the case of the larger PASHs (MM>=284Da), nonplanarity had a significant influence on earlier than predicted elution based on L/B values. PMID- 27481402 TI - Analysis of psychoactive substances in water by information dependent acquisition on a hybrid quadrupole time-of-flight mass spectrometer. AB - Emerging drugs of abuse, belonging to many different chemical classes, are attracting users with promises of "legal" highs and easy access via internet. Prevalence of their consumption and abuse through wastewater-based epidemiology can only be realized if a suitable analytical screening procedure exists to detect and quantify them in water. Solid-phase extraction and ultra-high performance liquid chromatography quadrupole time-of-flight-mass spectrometry (UHPLC-QqTOF-MS/MS) was applied for rapid suspect screening as well as for the quantitative determination of 42 illicit drugs and metabolites in water. Using this platform, we were able to identify amphetamines, tryptamines, piperazines, pyrrolidinophenones, arylcyclohexylamines, cocainics, opioids and cannabinoids. Additionally, paracetamol, carbamazepine, ibersartan, valsartan, sulfamethoxazole, terbumeton, diuron, etc. (including degradation products as 3 hydroxy carbamazepine or deethylterbuthylazine) were detected. This method encompasses easy sample preparation and rapid identification of psychoactive drugs against a database that cover more than 2000 compounds that ionized in positive mode, and possibility to identify metabolites and degradation products as well as unknown compounds. The method for river water, influent and effluents samples was fully validated for the target psychoactive substances including assessment of matrix effects (-88-67.8%), recovery (42-115%), precision (<19%) and limits of quantification (1-100ngL(-1)). Method efficiency was thoroughly investigated for a wide range of waste and surface waters. Robust and repeatable functioning of this platform in the screening, identification and quantification of traditional and new psychoactive drugs biomarkers and other water contaminants is demonstrated. PMID- 27481403 TI - Modelling the time at which overcrowding and feed interruption emerge on the swine premises under movement restrictions during a classical swine fever outbreak. AB - A stochastic risk model was developed to estimate the time elapsed before overcrowding (TOC) or feed interruption (TFI) emerged on the swine premises under movement restrictions during a classical swine fever (CSF) outbreak in Indiana, USA. Nursery (19 to 65 days of age) and grow-to-finish (40 to 165 days of age) pork production operations were modelled separately. Overcrowding was defined as the total weight of pigs on premises exceeding 100% to 115% of the maximum capacity of the premises, which was computed as the total weight of the pigs at harvest/transition age. Algorithms were developed to estimate age-specific weight of the pigs on premises and to compare the daily total weight of the pigs with the threshold weight defining overcrowding to flag the time when the total weight exceeded the threshold (i.e. when overcrowding occurred). To estimate TFI, an algorithm was constructed to model a swine producer's decision to discontinue feed supply by incorporating the assumptions that a longer estimated epidemic duration, a longer time interval between the age of pigs at the onset of the outbreak and the harvest/transition age, or a longer progression of an ongoing outbreak would increase the probability of a producer's decision to discontinue the feed supply. Adverse animal welfare conditions were modelled to emerge shortly after an interruption of feed supply. Simulations were run with 100 000 iterations each for a 365-day period. Overcrowding occurred in all simulated iterations, and feed interruption occurred in 30% of the iterations. The median (5th and 95th percentiles) TOC was 24 days (10, 43) in nursery operations and 78 days (26, 134) in grow-to-finish operations. Most feed interruptions, if they emerged, occurred within 15 days of an outbreak. The median (5th and 95th percentiles) time at which either overcrowding or feed interruption emerged was 19 days (4, 42) in nursery and 57 days (4, 130) in grow-to-finish operations. The study findings suggest that overcrowding and feed interruption could emerge early during a CSF outbreak among swine premises under movement restrictions. The outputs derived from the risk model could be used to estimate and evaluate associated mitigation strategies for alleviating adverse animal welfare conditions resulting from movement restrictions. PMID- 27481404 TI - Aortic Pseudoaneurysm Causing Massive Upper GI Bleeding. PMID- 27481405 TI - Colonic Endometriosis Presenting With Rectal Bleeding. PMID- 27481406 TI - Acute Gastric Ischemia After Chemoembolization in a Patient with Hepatocellular Carcinoma. PMID- 27481407 TI - Spontaneous Pseudocystocolonic Fistula: An Unusual Complication of Acute Pancreatitis. PMID- 27481408 TI - Bouveret's Syndrome: Acute Gastric Outlet Obstruction from Gallstones. PMID- 27481409 TI - Cyst-Within-Cyst Found on EUS-Guided Cystoscopy of a Pancreatic Mucinous Cystic Neoplasia. PMID- 27481410 TI - Transesophageal Endoscopic Mediastinal Tumorectomy: The First Report in a Human. PMID- 27481415 TI - Response to To et al. PMID- 27481417 TI - It Is the Anemic and Elderly Patients Who Benefit Most from a "Second Pass" Examination of the Right Colon. PMID- 27481416 TI - The Importance of Smoking Cessation in Improving Disease Course in Crohn's Disease. PMID- 27481418 TI - Response to Triantafyllou et al. PMID- 27481419 TI - About the Diagnosis and Management of Functional Heartburn: Heartburn and Oesophageal Motility Disorders. PMID- 27481420 TI - Response to Scaringi et al. PMID- 27481421 TI - The Relationship Between Gastric and Esophageal Cancers in Italy. PMID- 27481422 TI - Response to Crocetti et al. PMID- 27481423 TI - Sustained Acid Suppression by Potassium-Competitive Acid Blocker (P-CAB) May Be An Attractive Treatment Candidate for Patients with Eosinophilic Esophagitis. PMID- 27481424 TI - Response to Ishimura et al. PMID- 27481425 TI - Bulb Biopsy in Adult Celiac Disease: Pros Outweigh the Cons? PMID- 27481426 TI - Response to Kurien et al. PMID- 27481427 TI - Reply to Dai et al. PMID- 27481428 TI - Association Between Affective-Cognitive Symptoms of Depression and Exacerbation of Crohn's Disease. PMID- 27481429 TI - Complete Response of Hepatocellular Carcinoma in a Patient With End-stage Liver Disease treated With Nivolumab: Whishful thinking or Possible? PMID- 27481430 TI - Capnography for Moderate Sedation During Routine EGD and Colonoscopy. PMID- 27481431 TI - Massive Gastrointestinal Bleeding Due to Isolated Jejunal Varices in a Patient With Extrahepatic Portal Hypertension: A Case Report. PMID- 27481432 TI - HLA Associations Distinguish Collagenous From Lymphocytic Colitis. PMID- 27481433 TI - A Rare Left Gastric Artery Pseudoaneurysm Presenting as a Pancreatic Mass. PMID- 27481435 TI - Erratum: CT and EUS Images of Primary Pancreatic Ewing's Sarcoma. PMID- 27481436 TI - Corrigendum: Aortic Occlusion in a Patient With Gastrointestinal Symptoms. PMID- 27481437 TI - Erratum: Admission Hematocrit and Rise in Blood Urea Nitrogen at 24 h Outperform other Laboratory Markers in Predicting Persistent Organ Failure and Pancreatic Necrosis in Acute Pancreatitis: A Post Hoc Analysis of Three Large Prospective Databases. PMID- 27481438 TI - A systematic forest survey showing an association of Saccharomyces paradoxus with oak leaf litter. AB - Although we understand the genetics of the laboratory model yeast Saccharomyces cerevisiae very well, we know little about the natural ecology and environment that shaped its genome. Most isolates of Saccharomyces paradoxus, the wild relative of S. cerevisiae, come from oak trees, but it is not known whether this is because oak is their primary habitat. We surveyed leaf litter in a forest in Northern Germany and found a strong correlation between isolation success of wild Saccharomyces and the proximity of the nearest oak. We compared the four most common tree genera and found Saccharomyces most frequently in oak litter. Interestingly, we show that Saccharomyces is much more abundant in oak leaf litter than on oak bark, suggesting that it grows in litter or soil rather than on the surfaces of oaks themselves. The distribution and abundance of Saccharomyces over the course of a year shows that oak leaf litter provides a stable habitat for the yeast, although there was significant tree-to-tree variation. Taken together, our results suggest that leaf litter rather than tree surfaces provide the better habitat for wild Saccharomyces, with oak being the preferred tree genus. 99.5% of all strains (633/636) isolated were S. paradoxus. PMID- 27481439 TI - Palladium-Catalyzed N-Arylation of Iminodibenzyls and Iminostilbenes with Aryl- and Heteroaryl Halides. AB - Compounds containing the iminodibenzyl and iminostilbene ring systems are prevalent in medicinal targets and functional materials. Herein, we report palladium-catalyzed conditions for the N-arylation of these ring systems. This protocol could be applied to a variety of (hetero)aryl chloride and bromide substrates, including ones, which are sterically hindered or those containing a variety of functional groups. Use of the fourth-generation palladacycle precatalyst gave good to excellent yields by using low palladium-catalyst loadings (0.1 to 1 mol %). PMID- 27481440 TI - X-ray fluorescence microscopic measurement of elemental distribution in the mouse retina with age. AB - The biologically important metals such as zinc, copper and iron play key roles in retinal function, yet no study has mapped the spatio-temporal distribution of retinal biometals in healthy or diseased retina. We investigated a natural mouse model of retinal degeneration, the Cln6nclf mouse. As dysfunctional metabolism of biometals is observed in the brains of these animals and deregulated metal homeostasis has been linked to retinal degeneration, we focused on mapping the elemental distribution in the healthy and Cln6nclf mouse retina with age. Retinal and RPE elemental homeostasis was mapped in Cln6nclf and C57BL6/J mice from 1 to 8 months of age using X-ray Fluorescence Microscopy at the Australian Synchrotron. In the healthy retina, we detected a progressive loss of phosphorus in the outer nuclear layer and significant reduction in iron in the inner segments of the photoreceptors. Further investigation revealed a unique elemental signature for each retinal layer, with high areal concentrations of iron and sulfur in the photoreceptor segments and calcium, phosphorus, zinc and potassium enrichment predominantly in the nuclear layers. The analysis of retinae from Cln6nclf mice did not show significant temporal changes in elemental distributions compared to age matched controls, despite significant photoreceptor cell loss. Our data therefore demonstrates that retinal layers have unique elemental composition. Elemental distribution is, with few exceptions, stably maintained over time in healthy and Cln6nclf mouse retina, suggesting conservation of elemental distribution is critical for basic retinal function with age and is not modulated by processes underlying retinal degeneration. PMID- 27481441 TI - Accurate adsorption energies for small molecules on oxide surfaces: CH4 /MgO(001) and C2 H6 /MgO(001). AB - A hybrid method is applied that combines second order Moller-Plesset perturbation theory (MP2) for cluster models with density functional theory for periodic (slab) models to obtain structures and energies for methane and ethane molecules adsorbed on the MgO(001) surface. Single point calculations are performed to estimate the effect of increasing the cluster size on the MP2 energies and to evaluate the difference between coupled cluster (CCSD(T)) and MP2 energies. The final estimates of the adsorption energies are 12.9 +/- 1.3 and 18.9 +/- 1.8 kJ/mol for CH4 and C2 H6 , respectively. (c) 2016 Wiley Periodicals, Inc. PMID- 27481442 TI - Detection of people at risk of diabetes in community pharmacies of Pontevedra (Spain) (DEDIPO). AB - OBJECTIVE: The aim of this study was to detect people at risk of suffering diabetes or changes in carbohydrate metabolism and to refer them for possible diagnosis to health care centres. The number of diagnoses and costs for the pharmacy were recorded. METHODS: A cross-sectional, observational study was conducted in community pharmacies in Pontevedra in September-October of 2014. The Findrisc questionnaire was completed by pharmacy users over 18 years old. If Findrisc score was >= 15, capillary blood glucose was measured, and the participant was referred to a physician if the value was >=110mg/dL. The main variables included score in the Findrisc questionnaire, number of diabetes diagnosed, and cost of the service. Differences between the groups were calculated using a Chi-squared test, a Student's t test, and/or a Wilcoxon test. RESULTS: This study was conducted in 180 pharmacies on a sample of 4,222 users, including 992 (23.5%) with a high or very high risk of diabetes (F>=15). In the 1,060 basal capillary blood glucose tests performed, mean glucose level was 110.2 (SD=20.4)mg/dL (56-254). The Galician Health Service sent information about 83 of the 384 (9.1%) subjects referred to a physician: 28 (33.7%) of them were diagnosed with diabetes (3.1% of the sample), and 26 (31.3%) were diagnosed with prediabetes (2.8% of the sample). Cost per diagnosed subject was ? 184.22 per subject with diabetes and ? 96.86 per subject with prediabetes. CONCLUSIONS: The proportion of subjects with new diagnosis of diabetes (3.1%) shows the high efficiency of a screening program for hidden diabetics implemented at community pharmacies as the one presented here. PMID- 27481443 TI - The diabetic paradox: Bone mineral density and fracture in type 2 diabetes. AB - Type 2 diabetes mellitus prevalence and morbidity are increasing. Osteoporotic fractures are among the 'non-classical' complications of diabetes and been overlooked for a long time, maybe because of their complex diagnostic and therapeutic approach. The usual tools for preventing fragility fractures (such as the fracture risk assessment tool and bone densitometry) underestimate risk of fractures in type2 diabetic patients. New techniques, such as trabecular bone score or bone turnover markers, could be useful, but greater scientific evidence is required to recommend their use in clinical practice. The special characteristics of their pathophysiology result in decreased bone remodeling with normal or even increased bone mineral density, but with low quality. These changes lead to the occurrence of osteoporotic fractures without evidence of densitometric changes, which could be called 'the diabetic paradox'. PMID- 27481444 TI - Cognitive and adaptive advantages of growth hormone treatment in children with Prader-Willi syndrome. AB - BACKGROUND: People with Prader-Willi syndrome (PWS) typically have mild to moderate intellectual deficits, compulsivity, hyperphagia, obesity, and growth hormone deficiencies. Growth hormone treatment (GHT) in PWS has well-established salutatory effects on linear growth and body composition, yet cognitive benefits of GHT, seen in other patient groups, have not been well studied in PWS. METHODS: Study 1 included 96 children and youth with PWS aged 4-21 years who naturalistically varied in their exposures to GHT. Controlling for socioeconomic status, analyses compared cognitive and adaptive behavior test scores across age matched treatment naive versus growth hormone treated children. Study II assessed if age of treatment initiation or treatment duration was associated with subsequent cognition or adaptive behavior in 127, 4- to 21-year olds with PWS. Study III longitudinally examined cognitive and adaptive behavior in 168 participants who were either consistently on versus off GHT for up to 4-5 years. RESULTS: Compared to the treatment naive group, children receiving GHT had significantly higher Verbal and Composite IQs, and adaptive communication and daily living skills. Children who began treatment before 12 months of age had higher Nonverbal and Composite IQs than children who began treatment between 1 and 5 years of age. Longitudinally, the groups differed in their intercepts, but not slopes, with each group showing stable IQ and adaptive behavior scores over time. CONCLUSIONS: Cognitive and adaptive advantages should be considered an ancillary benefit and additional justification for GHT in people with PWS. Future efforts need to target apparent socioeconomic inequities in accessing GHT in the PWS population. PMID- 27481445 TI - Decellularized Human Kidney Cortex Hydrogels Enhance Kidney Microvascular Endothelial Cell Maturation and Quiescence. AB - The kidney peritubular microvasculature is highly susceptible to injury from drugs and toxins, often resulting in acute kidney injury and progressive chronic kidney disease. Little is known about the process of injury and regeneration of human kidney microvasculature, resulting from the lack of appropriate kidney microvascular models that can incorporate the proper cells, extracellular matrices (ECMs), and architectures needed to understand the response and contribution of individual vascular components in these processes. In this study, we present methods to recreate the human kidney ECM (kECM) microenvironment by fabricating kECM hydrogels derived from decellularized human kidney cortex. The majority of native matrix proteins, such as collagen-IV, laminin, and heparan sulfate proteoglycan, and their isoforms were preserved in similar proportions as found in normal kidneys. Human kidney peritubular microvascular endothelial cells (HKMECs) became more quiescent when cultured on this kECM gel compared with culture on collagen-I-assessed using phenotypic, genotypic, and functional assays; whereas human umbilical vein endothelial cells became stimulated on kECM gels. We demonstrate for the first time that human kidney cortex can form a hydrogel suitable for use in flow-directed microphysiological systems. Our findings strongly suggest that selecting the proper ECM is a critical consideration in the development of vascularized organs on a chip and carries important implications for tissue engineering of all vascularized organs. PMID- 27481447 TI - Practice Patterns and Preferences Among Hematopoietic Cell Transplantation Clinicians. AB - Hematopoietic cell transplantation can cure many high-risk diseases but is associated with complexity, cost, and risk. Several areas in transplantation practice were identified in the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium (BMT CTN SOSS) as high priorities for further study. We developed a survey for hematopoietic cell transplantation clinicians to identify current practices in BMT CTN SOSS priority areas and to understand, more generally, the variation in approach to transplantation and estimation of transplantation benefit in current medical practice. Of 1439 transplantation clinicians surveyed, 305 responded (20% response rate). Clinicians were well represented by age, experience, geography, and size of practice. We found that several techniques identified in the BMT CTN SOSS, such as maintenance therapy for acute myeloid leukemia or myelodysplastic syndromes after allogeneic transplantation, were already being utilized in practice on and off study, with higher rates of use in higher-volume centers. There was significant variation among clinicians in use of transplantation technologies and approaches to common transplantation scenarios. Appraisals of risks and benefits of transplantation appeared to converge upon similar estimates despite the presentation of different hypothetical scenarios. These results suggest overall equipoise in several BMT CTN SOSS high-priority areas and support the need for better data to inform clinical practice. PMID- 27481448 TI - Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. AB - The Practice Guidelines Committee of the American Society of Blood or Marrow Transplantation (ASBMT) sought to develop an evidence-based review about personalizing busulfan-based conditioning. The Committee sought to grade the relevant published studies (June 1, 2008 through March 31, 2016) according to criteria set forth by the Steering Committee for Evidence Based Reviews from ASBMT. Unfortunately, the published literature was too heterogeneous and lacked adequately powered and sufficiently controlled studies for this to be feasible. Despite this observation, the continued interest in this topic led the Practice Guidelines Committee to develop a list of most frequently asked questions (FAQs) regarding personalized busulfan dosing. This "Considerations" document is a list of these FAQs and their responses, addressing topics of practical relevance to hematopoietic cell transplantation clinicians. PMID- 27481449 TI - In vitro bioactivity studies of ceramic structures isolated from marine sponges. AB - In this work, we focused on the potential of bioceramics from different marine sponges-namely Petrosia ficiformis, Agelas oroides and Chondrosia reniformis-for novel biomedical/industrial applications. The bioceramics from these sponges were obtained after calcination at 750 degrees C for 6 h in a furnace. The morphological characteristics were evaluated by scanning electron microscopy (SEM). The in vitro bioactivity of the bioceramics was evaluated in simulated body fluid (SBF) after 14 and 21 d. Observation of the bioceramics by SEM after immersion in SBF solution, coupled with spectroscopic elemental analysis (EDS), showed that the surface morphology was consistent with a calcium-phosphate (Ca/P) coating, similar to hydroxyapatite crystals (HA). Evaluation of the characteristic peaks of Ca/P crystals by Fourier transform infrared spectroscopy and x-ray diffraction further confirmed the existence of HA. Cytotoxicity studies were carried out with the different ceramics and these were compared with a commercially available Bioglass((r)). In vitro tests demonstrated that marine bioceramics from these sponges are non-cytotoxic and have the potential to be used as substitutes for synthetic Bioglass((r)). PMID- 27481446 TI - Molecular cloning of the tomato Hairless gene implicates actin dynamics in trichome-mediated defense and mechanical properties of stem tissue. AB - Trichomes are epidermal structures that provide a first line of defense against arthropod herbivores. The recessive hairless (hl) mutation in tomato (Solanum lycopersicum L.) causes severe distortion of trichomes on all aerial tissues, impairs the accumulation of sesquiterpene and polyphenolic compounds in glandular trichomes, and compromises resistance to the specialist herbivore Manduca sexta Here, we demonstrate that the tomato Hl gene encodes a subunit (SRA1) of the highly conserved WAVE regulatory complex that controls nucleation of actin filaments in a wide range of eukaryotic cells. The tomato SRA1 gene spans a 42-kb region containing both Solyc11g013280 and Solyc11g013290 The hl mutation corresponds to a complex 3-kb deletion that removes the last exon of the gene. Expression of a wild-type SRA1 cDNA in the hl mutant background restored normal trichome development, accumulation of glandular trichome-derived metabolites, and resistance to insect herbivory. These findings establish a role for SRA1 in the development of tomato trichomes and also implicate the actin-cytoskeleton network in cytosolic control of specialized metabolism for plant defense. We also show that the brittleness of hl mutant stems is associated with altered mechanical and cell morphological properties of stem tissue, and demonstrate that this defect is directly linked to the mutation in SRA1. PMID- 27481451 TI - Understanding Uncontrolled Hypertension. PMID- 27481452 TI - Coupling aquaculture with forest plantations for food, energy, and water resiliency. AB - Freshwater aquaculture and forest bioenergy markets are expanding globally in areas concurrently experiencing human population growth, urbanization and water shortages. Coupling these agroecosystems can improve food, energy, and water resiliency by enhancing ecosystem services through fertilization, water-reuse, carbon storage, and bioenergy via biomass production. This study evaluated how a model aquaculture-managed forest plantation could (1) provision fish and woody biomass; (2) regulate carbon, groundwater infiltration, and groundwater quality; and (3) support nutrient cycling over a two-year period. A 0.5-hectare hardwood bioenergy plantation was established with 12 Populus spp. genotypes adjacent to a 0.6-hectare freshwater aquaculture operation (hybrid striped bass, Morone chrysops*M. saxatilis); pond waters were land-applied on the plantation for two years. The aquaculture operation produced ~3.5Mg of fish and trees yielded 5.9Mgha(-1)yr(-1) of oven-dry biomass, sequestered 2.9Mg carbon (C) ha(-1)yr(-1) and stored 0.028Mg nitrogen (N) ha(-1)yr(-1). Biomass productivity, carbon storage, and nitrogen storage differed significantly among the evaluated Populus genotypes. Land application of pond water increased groundwater infiltration by 60% relative to the previous year. The integrated system regulated chlorophyll a, total organic carbon, and nitrogen in groundwater at concentrations below regulatory limits. This study demonstrated that coupled agroecosystems could deliver productive yields of food and bioenergy as well as support water re-use while meeting water quality regulations. More research is needed to evaluated long-term sustainability and economic viability of this coupled system and other land management practices that seek to improve food, energy, and water resiliency. PMID- 27481453 TI - Sea level rise impacts on rice production: The Ebro Delta as an example. AB - Climate change and sea level rise (SLR) are global impacts threatening the sustainability of coastal territories and valuable ecosystems such as deltas. The Ebro Delta is representative of the vulnerability of coastal areas to SLR. Rice cultivation is the main economic activity in the region. Rice fields occupy most of the delta (ca. 65%) and are vulnerable to accelerated SLR and consequent increase in soil salinity, the most important physical factor affecting rice production. We developed a model to predict the impacts of SLR on soil salinity and rice production under different scenarios predicted by the Fifth Assessment Report of the Intergovernmental Panel on Climate Change by coupling data from Geographic Information Systems with Generalized Linear Models. Soil salinity data were measured in agricultural parcels and rice production from surveys among farmers. The correlation between observed and soil salinity predicted values was high and significant (Pearson's r=0.72, P<0.0001), thus supporting the predictive ability of the model. Soil salinity was directly related to distances to the river, to the delta inner border, and to the river old mouth, while clay presence, winter river flow and surface elevation were inversely related to it. Surface elevation was the most important variable in explaining soil salinity. Rice production was negatively influenced by soil salinity, thus the models predict a decrease from higher elevation zones close to the river to the shoreline. The model predicts a maximum reduction in normalized rice production index from 61.2% in 2010 to 33.8% by 2100 in the worst considered scenario (SLR=1.8m), with a decrease of profit up to 300 ? per hectare. The model can be applied to other deltaic areas worldwide, and help rice farmers and stakeholders to identify the most vulnerable areas to SLR impacts. PMID- 27481450 TI - FGFR-associated craniosynostosis syndromes and gastrointestinal defects. AB - Craniosynostosis is a relatively common birth defect characterized by the premature fusion of one or more cranial sutures. Examples of craniosynostosis syndromes include Crouzon (CS), Pfeiffer (PS), and Apert (AS) syndrome, with clinical characteristics such as midface hypoplasia, hypertelorism, and in some cases, limb defects. Mutations in Fibroblast Growth Factor Receptor-2 comprise the majority of known mutations in syndromic forms of craniosynostosis. A number of clinical reports of FGFR-associated craniosynostosis patients and mouse mutants have been linked to gastrointestinal tract (GIT) disorders, leading to the hypothesis of a direct link between FGFR-associated craniosynostosis syndromes and GIT malformations. We conducted an investigation to determine GIT symptoms in a sample of FGFR-associated craniosynostosis syndrome patients and a mouse model of CS containing a mutation (W290R) in Fgfr2. We found that, compared to the general population, the incidence of intestinal/bowel malrotation (IM) was present at a higher level in our sample population of patients with FGFR associated craniosynostosis syndromes. We also showed that the mouse model of CS had an increased incidence of cecal displacement, suggestive of IM. These findings suggest a direct relationship between FGFR-related craniosynostosis syndromes and GIT malformations. Our study may shed further light on the potential widespread impact FGFR mutations on different developmental systems. Based on reports of GIT malformations in children with craniosynostosis syndromes and substantiation with our animal model, GIT malformations should be considered in any child with an FGFR2-associated craniosynostosis syndrome. (c) 2016 Wiley Periodicals, Inc. PMID- 27481454 TI - The identification of carbamazepine biodegrading phylotypes and phylotypes sensitive to carbamazepine exposure in two soil microbial communities. AB - Carbamazepine (CBZ), an antiepileptic drug, has been introduced into agricultural soils via irrigation with treated wastewater and biosolids application. Such contamination is problematic because CBZ is persistent and the risks to ecosystems or human health are unknown. The current study examined CBZ biodegradation in two agricultural soils (soil 1 and 2) and the effects on the soil microbial communities during CBZ exposure. The experimental design involved three CBZ concentrations (50, 500, 5000ng/g), under aerobic as well as anaerobic conditions. CBZ concentrations were determined using solid phase extraction and LC MS/MS. The effect of CBZ on the soil microbial community was investigated using high throughput sequencing and a computational approach to predict functional composition of the metagenomes (phylogenetic investigation of communities by reconstruction of unobserved states, PICRUSt). The most significant CBZ biodegradation occurred in soil 1 under aerobic conditions. In contrast, CBZ biodegradation was limited under anaerobic conditions in soil 1 and under both conditions in soil 2. For soil 1, several phylotypes were enriched following CBZ degradation compared to the controls, including unclassified Sphingomonadaceae, Xanthomonadaceae and Rhodobacteraceae, as well as Sphingomonas, Aquicella and Microvirga. These phylotypes are considered putative CBZ degraders as they appear to be benefiting from CBZ biodegradation. PICRUSt revealed that soil 1 contained a greater abundance of xenobiotic degrading genes compared to soil 2, and thus, this analysis method offers a potential valuable approach for predicting CBZ attenuation in soils. PICRUSt analysis also implicated Sphingomonadaceae and Xanthomonadaceae in drug metabolism. Interestingly, numerous phylotypes decreased in abundance following CBZ exposure and these varied with soil type, concentration, duration of exposure, and the availability of oxygen. For three phylotypes (Flavobacterium, 3 genus incertae sedis and unclassified Bacteroidetes), the relative abundance was reduced in both soils, indicating a notable sensitivity to CBZ for these microorganisms. PMID- 27481455 TI - In field conditions, commercial pigment grade TiO2 was not harmful to terrestrial isopods but reduced leaf litter fragmentation. AB - We investigated the effects of a commercial pigment grade rutile TiO2 on the terrestrial isopod Porcellio scaber in three locations that differed in terms of abiotic and biotic conditions: the laboratory, open air, and the closed barn. Mortality and isopod energy reserves (digestive gland total proteins, lipids and carbohydrates) were not affected following 14days exposure to up to 1000mg TiO2 per kg dry leaves (mg/kg) under any experimental scenario. However, in the field tests, isopods consumption of TiO2-coated leaves was reduced compared to that of uncoated leaves and the decrease was not dose-dependent. The highest reduction was in the closed barn (45-56%) rather than in the open-air (38-40%). In laboratory-based food choice tests, isopods neither preferred nor avoided leaves coated with TiO2, suggesting that rather than sensing the TiO2 on the leaves directly, the isopods under open-air and barn exposure responded to altered attractiveness and/or palatability of the TiO2 amended leaves. We propose that this could be due to altered microbial population on the leaves, a hypothesis that requires further investigation. Although short-term exposure to atmospheric deposition of up to 1000mg/kg commercial TiO2 is unlikely to pose an immediate threat to isopod mortality and energy balance, reduced leaf feeding may have implications for the decomposition of plant material. PMID- 27481456 TI - Effects of cisplatin and letrozole on surgically induced endometriosis and comparison of the two medications in a rat model. AB - This study was to investigate the effects of cisplatin (CDDP) and letrozole on surgically induced endometriosis and comparison of the two drugs in a rat model. Endometriosis was surgically induced by autologous transplantation of endometrial pieces. Thirty model rats were divided into three groups, randomly. Group 1 (n=10) served as control and received no medication. Group 2 (n=10) received 0.2mg/kg/day of oral letrozole. Group 3 (n=10) received 35mg/m(2) CDDP via peritoneal perfusion every four days. All the rats were treated for 24days. The growth and histologic score of the implants were evaluated. The proliferation- and angiogenesis-associated proteins were assessed using immunohistochemistry and western blotting. The serum sex hormones were assayed using ELISA. After the medication, the growth and histologic score of the implants were significantly lower in the 2 and 3 groups than in the control group. The protein expressions of vascular endothelial growth factor (VEGF), aromatase P450 (P450arom), transforming growth factor-beta (TGF-beta), and matrix metalloproteinase (MMP)-2, were significantly lower in groups 2 and 3 than in the control group. Further, the P450arom level was lower in the letrozole group than in the CDDP group. The TGF-beta and MMP-2 levels were lower in the CDDP group than in the letrozole group. Serum T level was significantly higher in the letrozole group, and serum E2 level was lower in the letrozole group. In conclusion, cisplatin and letrozole caused similar regression of the implants in the endometriosis model rats. But their effects on the proliferation- and angiogenesis-associated protein expressions and the serum sex hormone levels were different. Cisplatin and letrozole might cause the effects in the endometriotic foci through different mechanism. PMID- 27481458 TI - Reversible corticospinal tract hyperintensities in neurologic Lyme disease. PMID- 27481459 TI - Complete lingual palsy from bilateral Dejerine syndrome (bilateral medial medullary stroke). PMID- 27481460 TI - Real-time effects of centrotemporal spikes on cognition in rolandic epilepsy: An EEG-fMRI study. PMID- 27481457 TI - The role of discrimination in alcohol-related problems in samples of heavy drinking HIV-negative and positive men who have sex with men (MSM). AB - BACKGROUND: Heavy drinking is a major public health concern among men who have sex with men (MSM), as it is in many other populations. However, the consequences of heavy drinking among MSM may be particularly severe, especially for sexual risk behavior, due to the relatively high prevalence of HIV. Minority stress models suggest that, among members of marginalized groups, discrimination may be associated with heavier alcohol use as these individuals increasingly drink to cope with such experiences. Past studies have provided some support for this association. However, they have not explored the role other drinking motives play, how these relationships might differ across MSM who are HIV-positive versus HIV-negative, or how this relationship extends to alcohol-related problems. METHODS: In this study, we used path modeling to explore associations between perceived discrimination experiences, drinking motives, alcohol use, and alcohol related problems in samples of heavy drinking MSM with and without HIV. RESULTS: In both HIV-negative and positive MSM, perceived discrimination was significantly positively associated with alcohol problems. Drinking to cope appears to play an important role in this relationship in both samples. Reporting more discrimination experiences was associated with drinking more frequently for sexual reasons among both groups. While the total effect of drinking to facilitate sex was positively associated with alcohol-related problems, sex motives did not mediate associations between discrimination and either drinking outcome. CONCLUSION: These results suggest that interventions addressing discrimination and specific drinking motivations may be useful in helping reduce alcohol use of heavy drinking MSM. PMID- 27481461 TI - Real-time effects of centrotemporal spikes on cognition in rolandic epilepsy: An EEG-fMRI study. PMID- 27481462 TI - Residency Training: Work engagement during neurology training. AB - OBJECTIVE: Work engagement, defined as a positive, fulfilling, work-related state of mind that is characterized by vigor, dedication, and absorption, can ameliorate patient care and reduce medical errors. The purpose of this cross sectional study was to investigate work engagement among neurology residents in the region of Attica, Greece. METHODS: In total, 113 residents participated in this study. Demographic and work-related characteristics, as well as emotional exhaustion and personality traits (neuroticism), were examined via an anonymous questionnaire. Work engagement was measured by the Utrecht Work Engagement Scale. RESULTS: The study sample had a mean age of 34.6 +/- 3.6 years, ranging from 26 to 45 years. Sixty-two (54.9%) participants were women and 45 (39.8%) were married. After adjusting for sex, emotional exhaustion, and neuroticism, the main factors associated with work engagement were autonomy and chances for professional development. CONCLUSIONS: Providing more chances for trainees' professional development as well as allowing for and supporting greater job autonomy may improve work engagement during neurology training. PMID- 27481463 TI - Clinical Reasoning: An unusual case of blurry vision in a young woman after ovarian induction. PMID- 27481464 TI - Teaching NeuroImages: Mills syndrome: Metabolic and structural neuroimaging aids to the diagnostic. PMID- 27481465 TI - Teaching Video NeuroImages: The hopping lid twitch in myasthenia gravis. PMID- 27481466 TI - Broadly Neutralizing Activity of Zika Virus-Immune Sera Identifies a Single Viral Serotype. AB - Recent epidemics of Zika virus (ZIKV) have been associated with congenital malformation during pregnancy and Guillain-Barre syndrome. There are two ZIKV lineages (African and Asian) that share >95% amino acid identity. Little is known regarding the ability of neutralizing antibodies elicited against one lineage to protect against the other. We investigated the breadth of the neutralizing antibody response following ZIKV infection by measuring the sensitivity of six ZIKV strains to neutralization by ZIKV-confirmed convalescent human serum or plasma samples. Contemporary Asian and early African ZIKV strains were similarly sensitive to neutralization regardless of the cellular source of virus. Furthermore, mouse immune serum generated after infection with African or Asian ZIKV strains was capable of neutralizing homologous and heterologous ZIKV strains equivalently. Because our study only defines a single ZIKV serotype, vaccine candidates eliciting robust neutralizing antibody responses should inhibit infection of both ZIKV lineages, including strains circulating in the Americas. PMID- 27481467 TI - Ultrasound-enhanced enzymatic hydrolysis of poly(ethylene terephthalate). AB - The application of ultrasound was found to enhance enzymatic hydrolysis of poly(ethylene terephthalate) (PET). After a short activation phase up to 6.6times increase in the amount of released products was found. PET powder with lower crystallinity of 8% was hydrolyzed faster when compared to PET with 28% crystallinity. Ultrasound activation was found to be around three times more effective on powders vs. films most likely due to a larger surface area accessible to the enzyme. PMID- 27481468 TI - Nickel oxide nanoparticle-based method for simultaneous harvesting and disruption of microalgal cells. AB - Microalgae biodiesel is considered one of the most promising renewable fuels. However, the high cost of the downstream process is a major barrier to large scale microalgal lipid production. In this study, a novel approach based on nickel oxide nanoparticles (NiO NPs) was developed and its effectiveness for simultaneous harvesting and cell disruption in microalgal lipid production was determined. NiO NPs exhibited a microalgal harvesting efficiency of 98.75% in 1min at pH 7. Moreover, after treating with NiO NPs for 96h, the lipid extraction efficiency of microalgae (with 80% water content) reached 91.08% and was 208.37% compared to that without NiO treatment. This approach is simple and does not necessitate drying; furthermore, no equipment with high energy consumption was required. PMID- 27481469 TI - Effect of pyrolysis temperature on the chemical oxidation stability of bamboo biochar. AB - Biochar produced by biomass pyrolysis has the advantage of carbon sequestration. However, some of the carbon atoms in biochar are not very stable. In this study, the effect of pyrolysis temperature on the chemical oxidation stability of bamboo biochar was investigated using the atomic ratios of H/C and O/C, Fourier transform infrared spectroscopy, and potassium dichromate (K2Cr2O7) oxidation spectrophotometric method. The results show that the carbon yield and ratios of H/C and O/C decreased from 71.72%, 0.71, and 0.32 to 38.48%, 0.22, and 0.06, respectively, as the temperature was increased from 300 degrees C to 700 degrees C. Moreover, the main oxygen-containing functional groups gradually decreased, while the degree of aromatization increased accordingly. The biochar showed a better stability at a higher pyrolysis temperature. The proportion of carbon loss, i.e., the amount of oxidized carbon with respect to the total carbon of the biochar, decreased from 16.52% to 6.69% with increasing temperature. PMID- 27481470 TI - Differences in developmental competence and gene expression profiles between buffalo (Bubalus bubalis) preimplantation embryos cultured in three different embryo culture media. AB - The objective of this study was to compare effects of in vitro culture systems on embryonic development and expression patterns of developmentally important genes in preimplantation buffalo embryos. After IVM/IVF presumptive zygotes were cultured in one of three systems: undefined TCM-199, mCR2aa medium supplemented with 10 % FBS and defined PVA-myo-inositol-phosphate-EGF medium. No (P > 0.05) differences at 2-cell, 4-cell and 8-cell to 16- cell stages were observed among the three cultured media used, however, increased (P < 0.05) blastocyst yield, cell number and hatching rate were found in defined medium compared to undefined media. The expression patterns of genes implicated in embryo metabolism (GLUT-1), anti-apoptosis (BCL-2), imprinting (IGF-2R), DNA methylation (DNMT-3A) and maternal recognition of pregnancy (IFNT) were increased (P < 0.05) in hatched blastocysts derived from defined medium compared to undefined media. In conclusion, serum-free, defined medium improved developmental competence of in vitro cultured buffalo embryos. Whether these differences in morphological development and gene expression have long-term effects on buffalo calves born after embryo transfer remains unknown. However, it is possible that early adaptations of the preimplantation embryo to its environment persist during fetal and post-natal development. PMID- 27481471 TI - Sex, Race, and Socioeconomic Disparities in Patients With Aortic Stenosis (from a Nationwide Inpatient Sample). AB - Aortic stenosis (AS) is the third most prevalent cardiovascular disease following hypertension and coronary artery disease. The primary objective of this cross sectional study is to examine gender, racial, and socioeconomic disparities in AS related health care utilization in patients aged >=50 years using data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. AS was identified among inpatient discharges with International Classification of Diseases, Ninth Revision, Clinical Modification, code 424.1. Using stratum specific weighted totals, means, proportions, and regression models, we examined time trends and disparities for inhospital AS prevalence according to gender, race, and income over the 2002 to 2012 period, predictors of AS (gender, race, income, age, health insurance, co-morbidities, and hospital-level characteristics), and AS's role as a predictor of inhospital death, length of stay, and total charges. Inhospital AS prevalence increased from 2.10% in 2002 to 2.37% in 2012, with similar trends observed within gender, race, and income strata. Women were less likely to have AS compared with men (adjusted odds ratio [ORadj] 0.84; 95% confidence interval [CI] 0.83 to 0.86). Blacks (ORadj 0.68; 95% CI 0.66 to 0.71), Hispanics (ORadj 0.79; 95% CI 0.76 to 0.84), and Asians/Pacific Islanders (ORadj 0.68; 95% CI 0.64 to 0.74) were less likely than whites to have AS diagnosis that was directly associated with income. AS was inversely related to inhospital death but positively linked to total charges overall and longer hospital stays among men, whites, and middle-income patients. However, shorter stays with AS were observed among blacks. In conclusion, among older inpatients, AS prevalence was ~2% and was higher among males, whites, and higher income groups. Although inhospital death was lower and total charges were higher in AS, length of stay's association with AS varied by gender, race, and income. PMID- 27481472 TI - [Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension]. PMID- 27481474 TI - Calcium Phosphates and Angiogenesis: Implications and Advances for Bone Regeneration. AB - Calcium phosphates (CaPs) are among the most utilized synthetic biomaterials for bone regeneration, largely owing to their established osteoconductive and osteoinductive properties. While angiogenesis is a crucial prerequisite to bone formation, research and applications for CaPs have not appreciated its crucial role. This review discusses how CaPs influence angiogenesis, and highlights promising strategies that address this topic. The objective is to draw attention to the gap in the literature and to highlight the importance of angiogenesis in CaP research, development, and use. PMID- 27481475 TI - Using the Framework for 21st-Century School Nursing Practice in Daily Practice. AB - NASN recently developed a Framework for 21st-Century School Nursing Practice (Framework) to guide school nursing activities. The principles and components of the Framework can be used as a guide in achieving high-quality school nurse practice. The purpose of this article is to share how school nurses can use the Framework in their daily practice, invite nurses to identify one new way the Framework can be used in your practice this school year, and implement and evaluate the change. PMID- 27481476 TI - Hearing Loss Detection in Schools and Early Child Care Settings: An Overview of School-Age Hearing Screening Practices. AB - The school nurse is the key figure in successful school screening programs. A student with unidentified and unmet health care needs is unlikely to perform at their full potential, both academically and socially. The purpose of the article is to serve as a resource, providing guidance, strategies, and a discussion of available equipment to assist with successful screening programs. PMID- 27481473 TI - Quality control of nonstop membrane proteins at the ER membrane and in the cytosol. AB - Since messenger RNAs without a stop codon (nonstop mRNAs) for organelle-targeted proteins and their translation products (nonstop proteins) generate clogged translocon channels as well as stalled ribosomes, cells have mechanisms to degrade nonstop mRNAs and nonstop proteins and to clear the translocons (e.g. the Sec61 complex) by release of nonstop proteins into the organellar lumen. Here we followed the fate of nonstop endoplasmic reticulum (ER) membrane proteins with different membrane topologies in yeast to evaluate the importance of the Ltn1 dependent cytosolic degradation and the Dom34-dependent release of the nonstop membrane proteins. Ltn1-dependent degradation differed for membrane proteins with different topologies and its failure did not affect ER protein import or cell growth. On the other hand, failure in the Dom34-dependent release of the nascent polypeptide from the ribosome led to the block of the Sec61 channel and resultant inhibition of other protein import into the ER caused cell growth defects. Therefore, the nascent chain release from the translation apparatus is more instrumental in clearance of the clogged ER translocon channel and thus maintenance of normal cellular functions. PMID- 27481477 TI - Digital Forms of Dating Violence: What School Nurses Need to Know. AB - A substantial amount of U.S. teenagers experience physical or sexual abuse within their romantic relationship. With recent technological advances, teenage dating violence can also be perpetrated digitally by harassing or controlling a romantic partner through the Internet or mobile phone. School nurses are naturally positioned to act as first responders for victims of an abusive romantic relationship. As online and offline forms of dating violence are often intertwined, it is imperative that school nurses are able to identify different types of digital dating violence as this could signal the presence of offline forms of dating abuse. Therefore, being able to interpret potential warning signs could help school nurses to play an active role in prevention and intervention of different types of dating violence. In this article, we provide an overview of the recent research on the context and consequences of cyber dating abuse and outline several suggestions for prevention and intervention. PMID- 27481478 TI - Building Student and Family-Centered Care Coordination Through Ongoing Delivery System Design. AB - In 2016 the National Association of School Nurses released an updated framework for school nurse practice. One highlight of the new framework is 21st century care coordination. That is, moving beyond basic case management to a systems level approach for delivery of school health services. The framework broadly applies the term care coordination to include direct care and communication across systems. School nurses are often engaged in efforts to create school health care homes that serve as an axis of coordination for students and families between primary care offices and the schools. Effective care coordination requires that the school nurses not only know the principles of traditional case management but also understand complex systems that drive effective care coordination. The outcome of a system-level approach is enhanced access to services in an integrated health care delivery system that includes the school nurse as an integral member of the school's health care team. This article presents a comprehensive, system-level model of care coordination for school nurse leadership and practice. PMID- 27481479 TI - A Strategy to Promote Successful Transition to School Nursing. AB - The purpose of this article is to share the findings of implementing a standardized, blended approach to school nurse orientation. This includes using classroom training, mentor/supervisory support, and skills labs to assure specific competencies that are needed for new nurses to successfully transition into this independent setting. This includes a description of the specialized skills and knowledge that are needed to successfully transition into this nursing specialty. School nurses are caring for more complex students. For example, students who were once homebound requiring tube feedings, ventilator, and tracheostomy care are now attending schools. They are responsible for triaging students with diverse needs which requires critical thinking skills. They case manage students with chronic diseases including: diabetes, asthma, life threatening food allergies and seizures. Lastly, school nurses manage students with risky behaviors related to drug usage, bullying and unprotected sex resulting in pregnancy. PMID- 27481480 TI - Using Schools of Nursing to Help Fill the Gap. AB - The shortage of school nurses, school nurses covering multiple buildings, and the expanded role of the school nurse has called for innovative ideas to meet the growing health care needs of youth. Partnering with local schools of nursing may be a welcomed strategy. This brief article will share the benefits of hosting student nurses as well as identify ways to begin these partnerships. PMID- 27481481 TI - 21st-Century Diabetes: Technology Leads the Way. AB - Advances in technology continue to improve quality of life for people with diabetes and enhance their ability to perform diabetes self-management activities. Both insulin pumps and continuous glucose monitors (CGMs) are increasingly more popular among students with diabetes. This article will provide school nurses an overview of how insulin pumps and CGMs operate and the implications of their use in the school setting. PMID- 27481482 TI - Identification and characterization of the toll-like receptor 8 gene in the Chinese raccoon dog (Nyctereutes procyonoides). AB - TLR8 is an important sensor of single-stranded RNA (ssRNA) from the viral genome and plays an essential role in innate antiviral responses via the recognition of conserved viral molecular patterns. In this report, TLR8 in the Chinese raccoon dog was characterized and analyzed for the first time. The full-length sequence of raccoon dog TLR8 (RdTLR8) cDNA was cloned by rapid amplification of cDNA ends (RACE) and is 3191bp with a 3117-bp open reading frame (ORF) encoding 1038 amino acids. The putative protein exhibits typical features of the TLR families, with 19 leucine-rich repeats (LRRs) in the extracellular domain and a cytoplasmic TIR domain. Comparative analyses of the RdTLR8 amino acid sequence indicated a 73.6 99.4% sequence identity with dog, horse, pig, sheep, cattle, human and mouse TLR8. Phylogenetic analysis grouped 71 mammalian TLR proteins into five sub families, wherein RdTLR8 was clustered into a monophyletic TLR8 clade in the TLR9 family, which was completely coincident with the evolutionary relationship among mammals. Quantitative real-time PCR analysis revealed extensive expression of RdTLR8 in tissues from healthy Chinese raccoon dogs with the highest expression in the peripheral blood mononuclear cells (PBMCs) and the lowest expression in the skeletal muscle. HEK293 cells cotransfected with a RdTLR8 expression plasmid and an NF-kappaB-luciferase reporter plasmid significantly responded to the agonist 3M-002, indicating a functional TLR8 homolog. In addition, raccoon dog PBMCs exposed to the canine distemper virus (CDV) wild strain CDV-PS and the TLR8 agonist 3M-002 showed significant upregulation of RdTLR8 mRNA and proinflammatory cytokines TNF-alpha and IFN-alpha, suggesting that RdTLR8 might play an important role in the immune response to viral infections in the Chinese raccoon dog. PMID- 27481483 TI - Lysine-specific histone demethylase 1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch. AB - Lysine-specific histone demethylase 1 (LSD1) regulates histone methylation and influences the epigenetic state of cells during the generation of induced pluripotent stem cells (iPSCs). Here we reported that LSD1 inhibition via shRNA or specific inhibitor, tranylcypromine, promoted reprogramming at early stage via two mechanisms. At early stage of reprogramming, LSD1 inhibition increased the retrovirus-mediated exogenous expression of Oct4, Klf4, and Sox2 by blocking related H3K4 demethylation. Since LSD1 inhibition still promoted reprogramming even when iPSCs were induced with small-molecule compounds in a virus-free system, additional mechanisms should be involved. When RNA-seq was used for analysis, it was found that LSD1 inhibition reversed some gene expression changes induced by OKS, which subsequently promoted reprogramming. For example, by partially rescuing the decreased expression of Hif1alpha, LSD1 inhibition reversed the up-regulation of genes in oxidative phosphorylation pathway and the down-regulation of genes in glycolysis pathway. Such effects facilitated the metabolic switch from oxidative phosphorylation to glycolysis and subsequently promoted iPSCs induction. In addition, LSD1 inhibition also promoted the conversion from pre-iPSCs to iPSCs by facilitating the similar metabolic switch. Therefore, LSD1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch. PMID- 27481484 TI - Impact of mandibular invasion on prognosis in oral squamous cell carcinoma four centimeters or less in size. AB - OBJECTIVES/HYPOTHESIS: Previous studies have reported variable results for the impact of bone invasion on survival in oral cancer. It is unclear whether bone invasion in small (<=4 cm) squamous cell carcinomas (SCC) of the oral cavity is an independent adverse prognosticator. Our objective was to investigate impact on survival of bone invasion in SCC of floor of mouth (FOM), lower alveolus (LA), and retromolar trigone (RMT) <=4 cm in size. STUDY DESIGN: Retrospective study of 96 patients with SCC of the FOM, LA, and RMT undergoing primary surgical treatment. METHODS: Original pathology reports and slides were reviewed by three pathologists. Level of bone invasion was categorized as cortical or medullary. Main outcome measures were local control (LC) and overall survival (OS). RESULTS: Bone invasion was present in 31 cases (32%). On review of pathology slides, all cases of bone invasion demonstrated medullary involvement. Median follow-up was 36 months for all patients, and 53 months for patients not dying from cancer. Among tumors <=4 cm, bone invasion was associated with significantly worse LC (P =.04) and OS (P =.0005). Medullary invasion (hazard ratio: 2.2, 95% confidence interval: 1.1-4.4, P =.03), postoperative radiotherapy (hazard ratio: 0.3, 95% confidence interval: 0.1-0.5, P <.001), and positive pathologic nodal status (hazard ratio: 4.1, 95% confidence interval: 1.9-8.6, P <.001) were independent predictors of worse OS among the entire cohort. CONCLUSIONS: Mandibular medullary bone invasion is a poor prognosticator in oral cancers, irrespective of small size of primary tumor. Such cases should be considered for postoperative radiotherapy. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:849-854, 2017. PMID- 27481485 TI - Copper-catalyzed oxyamination of electron-deficient alkenes with N-acyloxyamines. AB - A Cu(i)-catalyzed direct intermolecular oxyamination of electron deficient alkenes is disclosed. This process is characterized by difunctionalization of a variety of alpha,beta-unsaturated ketones with easily available N-acyloxyamine reagents as both amine and oxygen donors, which delivers ester derivatives of beta-amino alcohols in good yields as well as with high regioselectivity. Control studies suggested the involvement of alkyl radical species on the way of product formation. PMID- 27481486 TI - Face off against ROS: Tcof1/Treacle safeguards neuroepithelial cells and progenitor neural crest cells from oxidative stress during craniofacial development. AB - One-third of all congenital birth defects affect the head and face, and most craniofacial anomalies are considered to arise through defects in the development of cranial neural crest cells. Cranial neural crest cells give rise to the majority of craniofacial bones, cartilages and connective tissues. Therefore, understanding the events that control normal cranial neural crest and subsequent craniofacial development is important for elucidating the pathogenetic mechanisms of craniofacial anomalies and for the exploring potential therapeutic avenues for their prevention. Treacher Collins syndrome (TCS) is a congenital disorder characterized by severe craniofacial anomalies. An animal model of TCS, generated through mutation of Tcof1, the mouse (Mus musculus) homologue of the gene primarily mutated in association with TCS in humans, has recently revealed significant insights into the pathogenesis of TCS. Apoptotic elimination of neuroepithelial cells including neural crest cells is the primary cause of craniofacial defects in Tcof1 mutant embryos. However, our understanding of the mechanisms that induce tissue-specific apoptosis remains incomplete. In this review, we describe recent advances in our understanding of the pathogenesis TCS. Furthermore, we discuss the role of Tcof1 in normal embryonic development, the correlation between genetic and environmental factors on the severity of craniofacial abnormalities, and the prospect for prenatal prevention of craniofacial anomalies. PMID- 27481487 TI - Intermittent At-Home Suctioning of Esophageal Content for Prevention of Recurrent Aspiration Pneumonia in 4 Dogs with Megaesophagus. AB - BACKGROUND: Megaesophagus carries a poor to guarded prognosis due to death from aspiration pneumonia. Options for medical management of regurgitation are limited to strategic oral or gastrostomy tube feeding. OBJECTIVES: To describe the use and efficacy of intermittent esophageal suctioning to prevent regurgitation and associated episodes of aspiration pneumonia in dogs with megaesophagus. ANIMALS: Four dogs with acquired idiopathic megaesophagus and recurrent aspiration pneumonia. METHODS: Retrospective review of medical records of dogs with megaesophagus in which intermittent suctioning of esophageal content was employed for management of recurrent aspiration pneumonia. RESULTS: Intermittent suctioning of the esophagus was initiated in 4 dogs after failure of strict gastrostomy tube feeding failed to prevent regurgitation and repeated episodes of aspiration pneumonia. Suctioning was accomplished by esophagostomy tube in 3 dogs and per os in 1 dog. After initiation of esophageal suctioning, dogs survived for a median of 13.5 additional months (range, 10-30 months) during which time 2 dogs had no additional episodes of aspiration pneumonia and 2 dogs had infrequent episodes of pneumonia, but aspiration was suspected to be a contributing factor in their death. Complications included clogging of the esophagostomy tube, esophagostomy site infections, and esophagitis. CONCLUSIONS AND CLINICAL IMPORTANCE: Use of intermittent esophageal suctioning in dogs with megaesophagus that continue to regurgitate despite gastrostomy tube feedings can reduce or abolish clinical episodes of aspiration pneumonia. PMID- 27481488 TI - Nephroprotective Effect of Bauhinia tomentosa Linn against Cisplatin-Induced Renal Damage. AB - Cisplatin (CP) is an important chemotherapeutic drug used for the treatment of a wide variety of solid tumors. However, clinical use of CP has been limited due to its adverse effect of nephrotoxicity. In the present study, we evaluate the nephroprotective effect of Bauhinia tomentosa against CP-induced renal damage in rats. Administration of methonolic extract of B. tomentosa (250 mg/kg b.w.) results in a significant increase in antioxidant enzymes including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Furthermore, treatment with B. tomentosa increased body weight and relative organ weight when compared with that of the CP-induced control group. Moreover, treatment with B. tomentosa extract significantly decreased lipid peroxidation(LPO), serum urea, and creatinine when compared with the CP-induced control group. Thus, the present study highlights the potential role of B. tomentosa and its use as a new protective strategy against CP-induced nephrotoxicity. PMID- 27481489 TI - Heavy Metal-Induced Systemic Dysfunction Attenuated by Tannic Acid. AB - Lead toxicity is a major public health concern. This study was designed to investigate the effects of oral administration of tannic acid (TA) on lead acetate (LA)-induced oxidative stress in rat liver and kidney. Rats were treated with 50 mg/kg body weight of TA against LA-induced oxidative stress 3 times/week for 2 weeks. At a rate of 50 mg/kg of body weight, LA was given intraperitoneally 3 times/week for 2 weeks. Results show significantly elevated levels of oxidative stress markers observed in LA-treated rats, whereas significant depletion in the activity of nonenzymatic and enzymatic antioxidants as well as histological changes were observed in LA-treated rat liver and kidney. TA treatment significantly attenuated the altered levels of oxidative stress biomarkers for nonenzymatic and enzymatic antioxidants. We demonstrated that TA exhibits potent antioxidant and protected against oxidative damage in rat liver and kidney induced by LA treatment. These findings were further supported by histopathological findings in liver and kidney showing that TA protected tissue from the deleterious effects of LA treatment. These outcomes suggest that the consumption of TA may confer a protective effect against lead intoxication through its antioxidative effect. PMID- 27481490 TI - The Prognostic Significance of FoxP3+ T Cells and CD8+ T Cells in Colorectal Carcinomas. AB - Recent studies report that tumor microenvironment effects prognosis of colorectal cancers. We analyzed the densities of FoxP3+ cells and CD8+ cells, the ratio of FoxP3+/CD8+ cells and the relationship between these parameters, clinicopathological features, and prognosis. A total of 186 colorectal adenocarcinoma were evaluated in terms of clinicopathological features. Immunohistochemically, densities of intratumoral (IT; IT-FoxP3) and nontumoral (NT; NT-FoxP3) FoxP3+ cells and IT-CD8 and NT-CD8 CD8+ cells were calculated. The ratio of Foxp3/CD8 was recorded. IT-FoxP3 and the ratio of IT-FoxP3/IT-CD8 were higher than NT-FoxP3 and the ratio of NT-FoxP3/NT-CD8, respectively. In multivariate analysis, high FoxP3+ cell density is the most important predictive marker after clinical stage and surgical margin positivity in disease-free survival and the most important predictive marker after clinical stage in overall survival (OS). Short OS time was correlated with clinical stage, decrease in IT FoxP3, increasing age, number of metastatic lymph nodes, surgical margin positivity, satellite tumor nodule, medullary carcinoma, and the number of pericolorectal lymph nodes. The ratio of FoxP3/CD8 increased noticeably in the IT area, but no relationship was found with survival. The relationships of the cells with one another in the tumor microenvironment seem to have many secrets. Studies in large series supported by molecular techniques can illuminate those secrets to some extent. PMID- 27481491 TI - Protective Effect of Troxerutin on Nickel-Induced Testicular Toxicity in Wistar Rats. AB - Nickel (Ni)-induced oxidative damage is a serious problem that leads to reproductive system failure through testicular damage. The present investigation was carried out to determine the effect of troxerutin (Txn) on testicular toxicity induced by Ni in experimental rat testes. The oral administration of Txn (100 mg/kg body weight [bw]) showed a significant (p < 0.01) increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), reduced glutathione, ascorbate, total sulphydryl groups, and testis-organ weight. Subsequently, the administration of Txn also significantly reduced the accumulation of Ni, lipid peroxidation products, and protein carbonyl levels in Txn-treated animals. Testicular protection in the experimental animals by Txn is further substantiated by a remarkable reduction of Ni, which was revealed through testicular tissue histopathology. These studies suggest that Txn could prevent oxidative damage and testicular toxicity induced by Ni in experimental animals. PMID- 27481492 TI - Dietary Nanosized Lactobacillus plantarum Enhances the Anticancer Effect of Kimchi on Azoxymethane and Dextran Sulfate Sodium-Induced Colon Cancer in C57BL/6J Mice. AB - This study was undertaken to evaluate enhancement of the chemopreventive properties of kimchi by dietary nanosized Lactobacillus (Lab.)plantarum (nLp) in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated colorectal cancer C57BL/6J mouse model. nLp is a dead, shrunken, processed form of Lab. Plantarum isolated from kimchi that is 0.5-1.0 um in size. The results obtained showed that animals fed kimchi with nLp (K-nLp) had longer colons and lower colon weights/length ratios and developed fewer tumors than mice fed kimchi alone (K). In addition, K-nLp administration reduced levels of proinflammatory cytokine serum levels and mediated the mRNA and protein expressions of inflammatory, apoptotic, and cell-cycle markers to suppress inflammation and induce tumor-cell apoptosis and cell-cycle arrest. Moreover, it elevated natural killer-cell cytotoxicity. The study suggests adding nLp to kimchi could improve the suppressive effect of kimchi on AOM/DSS-induced colorectal cancer. These findings indicate nLp has potential use as a functional chemopreventive ingredient in the food industry. PMID- 27481493 TI - Naringenin Alleviates Cadmium-Induced Toxicity through the Abrogation of Oxidative Stress in Swiss Albino Mice. AB - The present study evaluates the protective potential of the flavonoid naringenin (NRG) against experimentally induced cadmium (Cd) toxicity in Swiss albino mice. NRG (4 and 8 mg/kg) was orally administered to mice 30 min before oral administration of CdCl2 (12 mg/kg) for 11 consecutive days. On the 12th day, we evaluated body and organ weights, hematological profiles, serum biochemical profiles, and hepatic and renal tissue antioxidative parameters including lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase. Cotreatment with NRG markedly and significantly normalized body and organ weights, hematological profiles, and serum biochemical profiles and significantly modulated all of the hepatic and renal tissue biochemical parameters in Cd-intoxicated mice. The present findings show that NRG possesses a remarkable alleviative effect against Cd-induced toxicity in albino mice, mediated by abrogation of Cd-induced oxidative stress by multiple mechanisms. PMID- 27481494 TI - Reversal of Lead-Induced Acute Toxicity by Lipoic Acid with Nutritional Supplements in Male Wistar Rats. AB - Lead (Pb) is a pleiotropic toxicant. The potential role of oxidative stress injury that is associated with Pb poisoning suggests that antioxidants may enhance the efficacy of treatment designed to mitigate Pb-induced toxicity. The aim of this study is to investigate the comparative ameliorative potential of lipoic acid (LA) alone or in combination with calcium (Ca) and zinc (Zn). Pb acetate (50 mg/kg, intraperitoneally) was administered for 3 d. After 24 h of the last toxicant dose, LA (100 mg/kg, orally [po]) alone or in conjuction with Ca (50 mg/kg, po) and Zn (10 mg/kg, po) was administered for 3 d. Significant alterations in the concentration of urea, uric acid, triglycerides, cholesterol, aspartate amino transferase, alanine amino transferase, lipid peroxidation, and reduced glutathione as well as alterations in enzyme activity of delta aminolevulinic acid (ALA) dehydratase were observed following acute Pb exposure. These findings were also supported by elevated mean DNA damage and Pb body burden in blood and soft tissues compared to controls (p <= 0.05). Three d posttreatment with LA along with Zn and Ca could significantly restore the biochemical parameters and Pb body burden to near-normal status through antioxidant activity or by preventing bioaccumulation of Pb within the blood and tissues of experimental rats. PMID- 27481495 TI - Activating Photodynamic Therapy in vitro with Cerenkov Radiation Generated from Yttrium-90. AB - The translation of photodynamic therapy (PDT) to the clinical setting has primarily been limited to easily accessible and/or superficial diseases, for which traditional light delivery can be performed noninvasively. Cerenkov radiation, as generated from medically relevant radionuclides, has been suggested as a means to deliver light to deeper tissues noninvasively to overcome this depth limitation. This article investigates the utility of Cerenkov radiation, as generated from the radionuclide yttrium-90, for activating the PDT process using clinically approved aminolevulinic acid at 1.0 mm and also the more efficient porphyrin-based photosensitizer mesotetraphenylporphine with two sulfonate groups on adjacent phenyl rings (TPPS2a) at 1.2 um. Experiments were conducted with monolayer cultured glioma and breast tumor cell lines. Although aminolevulinic acid proved to be ineffective for generating a therapeutic effect at all but the highest activity levels, TPPS2a produced at least a 20% therapeutic effect at activities ranging from 6 to 60 uCi/well for the C6 glioma cell line. Importantly, these results demonstrate for the first time, to our knowledge, that Cerenkov radiation generated from a radionuclide can be used to activate PDT using clinically relevant photosensitizers. These results therefore provide evidence that it may be possible to generate a phototherapeutic effect in vivo using Cerenkov radiation and clinically relevant photosensitizers. PMID- 27481496 TI - Day-Case Treatment of Peripheral Arterial Disease: Results from a Multi-Center European Study. AB - PURPOSE: The purpose of the study was to investigate safety and feasibility of day-case endovascular procedures for the management of peripheral arterial disease. MATERIALS AND METHODS: This was a multi-center, retrospective study including all patients treated over a 30-month period with endovascular angioplasty or stenting for intermittent claudication (IC) or critical limb ischemia (CLI) on a day-case basis, in Interventional Radiology (IR) departments of three European tertiary hospitals. Exclusion criteria were not related to the type of lesion and included unavailability of an adult able to take care of patient overnight; high bleeding risk and ASA score >=4. Primary efficacy outcome was the rate of procedures performed on an outpatient basis requiring no further hospitalization and primary safety outcome was freedom from 30-day major complications' rate. RESULTS: The study included 652 patients (male 75 %; mean age 68 +/- 10 years; range: 27-93), 24.6 % treated for CLI. In 53.3 % of the cases a 6Fr sheath was used. Technical success was 97.1 %. Haemostasis was obtained by manual compression in 52.4 % of the accesses. The primary efficacy outcome occurred in 95.4 % (622/652 patients) and primary safety outcome in 98.6 % (643/652 patients). Major complications included five (0.7 %) retroperitoneal hematomas requiring transfusion; one (0.1 %) common femoral artery pseudoaneurysm successfully treated with US-guided thrombin injection, two cases of intra procedural distal embolization treated with catheter-directed local thrombolysis and one on-table cardiac arrest necessitating >24 h recovery. No major complication was noted after same-day discharge. CONCLUSIONS: Day-case endovascular procedures for the treatment of IC or CLI can be safely and efficiently performed in experienced IR departments of large tertiary hospitals. PMID- 27481497 TI - Simultaneous determination of four fluorescent whitening agents (including trans and cis isomers) in facial mask by dispersive solid-phase extraction combined with ultra high performance liquid chromatography and diode array detection. AB - A novel ultra high performance liquid chromatography with diode array detection method, based on the dispersive solid-phase extraction by using polymer weak anion exchange as the sorbent, was established for the simultaneous determination of fluorescent whitening agents 85, 28, 351, and 71 in facial mask. The amounts of polymer weak anion exchange, adsorption time, and volume of elution solvent in the dispersive solid-phase extraction technology were optimized, and the developed method was validated in terms of the method limit of detection, method limit of quantitation, linear range, recovery, accuracy, and precision. Results indicated that the standard curves were linear over the selected concentration ranges of 0.05-100 mg/L for four target analytes, with determination coefficients greater than 0.999. The method limits of quantitation of the target analytes were in the range of 0.6-2.8 mg/kg. Recoveries were calculated at the concentrations of 1.0-30 mg/kg spiked in negative samples and the values were between 89.3 and 102% with an RSD of 2.5-5.1% for intraday precision and 3.8-5.0% for interday precision. The method was successfully applied to analyze 20 facial mask samples and fluorescent whitening agent 85 was detected in one sample with the concentration of 4.7 mg/kg. PMID- 27481499 TI - A Bayesian approach to sequential meta-analysis. AB - As evidence accumulates within a meta-analysis, it is desirable to determine when the results could be considered conclusive to guide systematic review updates and future trial designs. Adapting sequential testing methodology from clinical trials for application to pooled meta-analytic effect size estimates appears well suited for this objective. In this paper, we describe a Bayesian sequential meta analysis method, in which an informative heterogeneity prior is employed and stopping rule criteria are applied directly to the posterior distribution for the treatment effect parameter. Using simulation studies, we examine how well this approach performs under different parameter combinations by monitoring the proportion of sequential meta-analyses that reach incorrect conclusions (to yield error rates), the number of studies required to reach conclusion, and the resulting parameter estimates. By adjusting the stopping rule thresholds, the overall error rates can be controlled within the target levels and are no higher than those of alternative frequentist and semi-Bayes methods for the majority of the simulation scenarios. To illustrate the potential application of this method, we consider two contrasting meta-analyses using data from the Cochrane Library and compare the results of employing different sequential methods while examining the effect of the heterogeneity prior in the proposed Bayesian approach. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27481498 TI - Brain tumors in eloquent areas: A European multicenter survey of intraoperative mapping techniques, intraoperative seizures occurrence, and antiepileptic drug prophylaxis. AB - Intraoperative mapping and monitoring techniques for eloquent area tumors are routinely used world wide. Very few data are available regarding mapping and monitoring methods and preferences, intraoperative seizures occurrence and perioperative antiepileptic drug management. A questionnaire was sent to 20 European centers with experience in intraoperative mapping or neurophysiological monitoring for the treatment of eloquent area tumors. Fifteen centers returned the completed questionnaires. Data was available on 2098 patients. 863 patients (41.1%) were operated on through awake surgery and intraoperative mapping, while 1235 patients (58.8%) received asleep surgery and intraoperative electrophysiological monitoring or mapping. There was great heterogeneity between centers with some totally AW oriented (up to 100%) and other almost totally ASL oriented (up to 92%) (31% SD). For awake surgery, 79.9% centers preferred an asleep-awake-asleep anesthesia protocol. Only 53.3% of the centers used ECoG or transcutaneous EEG. The incidence of intraoperative seizures varied significantly between centers, ranging from 2.5% to 54% (p < 0.001). It there appears to be a statistically significant link between the mastery of mapping technique and the risk of intraoperative seizures. Moreover, history of preoperative seizures can significantly increase the risk of intraoperative seizures (p < 0.001). Intraoperative seizures occurrence was similar in patients with or without perioperative drugs (12% vs. 12%, p = 0.2). This is the first European survey to assess intraoperative functional mapping and monitoring protocols and the management of peri- and intraoperative seizures. This data can help identify specific aspects that need to be investigated in prospective and controlled studies. PMID- 27481500 TI - Validation of a Fluorescence Sensor Microtiterplate for Biogenic Amines in Meat and Cheese. AB - An optical sensor microtiterplate for quantitative analysis of the total content of biogenic amines (TAC) in meat and cheese was developed and validated for the first time. In the plate, a chameleon dye (Py-1) is embedded in a polymeric cocktail which is deposited on the bottom of the wells in a common microtiterplate. On reaction with biogenic amines (BAs), the fluorescence of Py-1 at 620 nm rapidly delivers a precise TAC. After 10 min incubation at 25 degrees C the determination of the TAC in various (real) samples is possible in high throughput with a standard microplate reader. The optimized fluorescence method was validated for linearity, sensitivity, accuracy, precision (intraday and inter day repeatability) and recovery using histamine (HIS) as a representative BA. The sensor microtiterplate was successfully applied to quantitatively analyze the TAC in 10 real samples of cheese and meat obtained from various Egyptian markets. The TAC of these real samples obtained by the sensor microtiterplate was validated against the contents of BAs obtained by GC-MS at various times of storage. The data of the sensor microtiterplate agreed well with those of GC-MS. This demonstrates that the sensor microtiterplate is a reliable screening tool for the degradation status of food samples. PMID- 27481501 TI - Quercetin-Iron Complex: Synthesis, Characterization, Antioxidant, DNA Binding, DNA Cleavage, and Antibacterial Activity Studies. AB - Quercetin-iron (II) complex was synthesized and characterized by elemental analysis, ultraviolet-visible spectrophotometry, fourier transform infrared spectroscopy, mass spectrometry, proton nuclear magnetic resonance spectroscopy, thermogravimetry and differential scanning calorimetry, scanning electron micrography and molar conductivity. The low molar conductivity value investigates the non-electrolyte nature of the complex. The elemental analysis and other physical and spectroscopic methods reveal the 1:2 stoichiometric ratio (metal:ligand) of the complex. Antioxidant study of the quercetin and its metal complex against 2, 2-di-phenyl-1-picryl hydrazyl radical showed that the complex has much more radical scavenging activity than free quercetin. The interaction of quercetin-iron (II) complex with DNA was determined using ultraviolet visible spectra, fluorescence spectra and agarose gel electrophoresis. The results showed that quercetin-iron (II) complex can intercalate moderately with DNA, quench a strong intercalator ethidium bromide and compete for the intercalative binding sites. The complex showed significant cleavage of pBR 322 DNA from supercoiled form to nicked circular form and these cleavage effects were dose-dependent. Moreover, the mechanism of DNA cleavage indicated that it was an oxidative cleavage pathway. These results revealed the potential nuclease activity of complex to cleave DNA. In addition, antibacterial activity of complex on E.coli and S. aureus was also investigated. The results showed that complex has higher antibacterial activity than ligand. PMID- 27481502 TI - A New Sensitive and Selective Off-On Fluorescent Zn2+ Chemosensor Based on 3,3',5,5'-Tetraphenylsubstituted Dipyrromethene. AB - 3,3',5,5'-Tetraphenyl-2,2'-dipyrromethene was described as a highly sensitive and selective Off-on fluorescent colorimetric chemosensor for Zn2+ based on the chelation-enhanced fluorescence (CHEF) effect. The reaction of dipyrromethene ligand with Zn2+ induces the formation of the [ZnL2] complex, which exhibits the increasing fluorescence in 120 fold compared with ligand in the propanol 1/cyclohexane (1:30) binary mixture. The Zn2+ detection limit was 1.4 * 10-7 M. The UV-Vis and fluorescence spectroscopic studies demonstrated that the dipyrromethene sensor was highly selective toward Zn2+ cations over other metal ions (Na+, Mg2+, Co2+, Ni2+, Fe3+, Cu2+, Mn2+, Cd2+ and Pb2+), excluding Hg2+. PMID- 27481503 TI - Copper-catalyzed difluoromethylation of propargylamide-substituted indoles: synthesis of mono- and bis-difluoromethylated indoloazepinone derivatives. AB - A novel copper-catalyzed difluoromethylation of 2- or 3-propargylamide substituted indoles with ICF2CO2Et via a radical cascade cyclization process is described. A wide substrate scope is compatible with the reaction conditions to synthesize mono- and bis-difluoromethylated indoloazepinone derivatives, which contain a seven-membered ring. PMID- 27481504 TI - [Not Available]. PMID- 27481505 TI - [Not Available]. PMID- 27481506 TI - Phenotypic detection of AmpC beta-lactamases, extended-spectrum beta-lactamases and metallo-beta-lactamases in Enterobacteriaceae using a resazurin microtitre assay with inhibitor-based methods. AB - Dissemination of antibiotic resistance in Enterobacteriaceae mediated by AmpC beta-lactamase, extended-spectrum beta-lactamase (ESBL) and metallo-beta lactamase (MBL) is clinically significant. A simple and relatively quick method for the detection of these resistance phenotypes would greatly improve chemotherapeutic recommendation. This technology would provide valuable input in our surveillance of resistance on a global stage, particularly if the methodology could be applicable to resource-poor settings. A resazurin microtitre plate (RMP) assay incorporating cloxacillin, clavulanic acid and EDTA for the rapid phenotypic identification of AmpC, ESBL and MBL and the co-existence of beta lactamases has been developed. A total of 47 molecularly characterized Enterobacteriaceae clinical isolates producing AmpCs, ESBLs, co-producers of ESBL and AmpC, MBLs and co-producers of ESBL and MBL were phenotypically examined using the RMP assay. The ceftazidime- and cefotaxime-based RMP assays successfully detected all 16 AmpC, 14 ESBL and 9 MBL producers, 6 ESBL-AmpC co producers and 2 ESBL-MBL co-producers without false-positive results. The ceftazidime-based assay was more reliable in detecting AmpC alone, while the cefotaxime-based assay performed better in identifying co-producers of ESBL and AmpC. There was no difference in the detection of ESBL and MBL producers. The findings of the present study suggest that use of the RMP assay with particular beta-lactamase inhibitors explicitly detects three different beta-lactamases, as well as co-existence of beta-lactamases, within 6 h of initial isolation of the pathogen. This assay is applicable to carry out in any laboratory, is cost effective and is easy to interpret. It could be implemented in screening patients and controlling infection and for surveillance purposes. PMID- 27481507 TI - Imbalance between proliferation and apoptosis-related impaired GPR30 expression is involved in preeclampsia. AB - The proliferation and apoptosis of cells in the placenta play a critical role in preeclampsia (PE) in which estrogen has been implicated via estrogen receptors (ERs). A novel ER, G-protein-coupled receptor 30 (GPR30), has recently been shown to be involved in PE. We investigated the basic levels of proliferation and apoptosis in normal placentae and placentae with PE and compared GPR30 expression levels between the two groups. We demonstrated that low GPR30 expression levels, more apoptosis, and less proliferation were associated with PE. Moreover, our in vitro study showed that both the selective GPR30 agonist G1 and the general ER agonist 17-beta-estradiol were able to protect the placenta from hypoxia reoxygenation injuries, resulting in decreased apoptosis and increased proliferation. Furthermore, this protective effect was abolished by the addition of the selective GPR30 inhibitor G15. These results provide evidence that (1) GPR30 is involved in regulating cell proliferation and apoptosis; (2) pharmacologic upregulation of GPR30 is beneficial for PE management; (3) GPR30 may therefore be an interventional target for pregnancies complicated by PE. PMID- 27481508 TI - The antidepressant effect of musk in an animal model of depression: a histopathological study. AB - Depression is a significant public health concern all over the world, especially in modern communities. This study aims to assess the efficacy of musk in alleviating the behavioral, biochemical and histopathological changes induced by chronic unpredictable mild stress (CUMS) in an animal model of depression and to explore the underlying mechanism of this effect. Male Swiss albino mice were divided into four groups (n = 10): control, CUMS, CUMS+fluoxetine and CUMS+musk. At the end of the experiment, behavioral tests were administered and serum corticosterone and testosterone levels were assessed. Surface markers, proteins and gene expressions of brain-derived neurotropic factor (BDNF) and glucocorticoid receptors (GRs) in the hippocampus were assessed. The immunoexpression of glial fibrillary acidic protein, Ki67 and caspase-3 was also assessed. Data were analyzed using the Statistical Package for the Social Sciences and a P value of less than 0.05 was considered significant. Musk alleviated the behavioral changes caused by CUMS and reduced elevated corticosterone levels. It reduced CUMS-induced neuronal atrophy in the CA3 and dentate gyrus of the hippocampus and restored astrocytes. Musk reduced the neuro- and glial apoptosis observed in stressed mice in a manner comparable to that of fluoxetine. Musk induced these effects through up-regulating both BDNF and GR gene and protein expressions. Musk has an antidepressant-like effect in an animal model of depression, so it is advisable to assess its efficacy in people continually exposed to stressors. PMID- 27481509 TI - Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis. AB - Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCRbright) or low levels (NCRdull) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a specific NK cells transcriptomic signature in patients with AML. However, in vitro NK cells expansion erased this signature and up-regulated expression of central molecules of NK functions, such as NCR, NKG2D and also ETS-1, regardless of their origin, i.e., AML-NK vs HD-NK. ETS-1 transcription factor was shown to bind to a specific and common region in the NCRs promoters, thus appearing as a good candidate to explain the coordinated regulation of three NCRs. Such results are encouraging regarding in vitro AML-NK cytotoxicity restoration and provide a new conceptual support for innovative cellular therapy based on in vitro NK cells expansion before their reinfusion in AML patients. PMID- 27481510 TI - DMP1-CDG (CDG1e) with Significant Gastrointestinal Manifestations; Phenotype and Genotype Expansion. AB - The literature describes eight cases of mutations in the DPM1 gene generating DMP1-CDG, causing similar phenotype of early onset seizures, microcephaly and developmental delay. Investigations of these patients revealed associated abnormal findings on brain imaging, elevated CK, abnormal clotting factors and mildly deranged serum transaminases. We describe the ninth case of DMP1-CDG, whose clinical presentation includes severe gastrointestinal involvement, i.e. food protein induced enterocolitis syndrome (FPIES). Gastrointestinal manifestations (GIT) of the congenital glycosylation disorders have included deranged liver function, hepatomegaly, liver fibrosis, steatosis and protein losing enteropathy. This is the first report of a congenital glycosylation disorder being associated with FPIES. PMID- 27481511 TI - Intracellular ice formation in mouse zygotes and early morulae vs. cooling rate and temperature-experimental vs. theory. AB - In this study, mature female mice of the ICR strain were induced to superovultate, mated, and collected at either zygote or early morula stages. Embryos suspended in 1 M ethylene glycol in PBS containing 10 mg/L Snomax for 15 min, then transferred in sample holder to Linkam cryostage, cooled to and seeded at 7 degrees C, and then observed and photographed while being cooled to -70 degrees C at 0.5-20 degrees C/min. Intracellular ice formation (IIF) was observed as abrupt ''flashing''. Two types of flashing or IIF were observed in this study. Extracellular freezing occurred at a mean of -7.7 degrees C. In morulae, about 25% turned dark within +/-1 degrees C of extracellular ice formation (EIF). These we refer to as "high temperature'' flashers. In zygotes, there were no high temperature flashers. All the zygotes flashed at temperatures well below the temperature for EIF. Presumably high temperature flashers were a consequence of membrane damage prior to EIF or damage from EIF. We shall not discuss them further. In the majority of cases, IIF occurred well below -7.7 degrees C; these we call ''low temperature'' flashers. None flashed with cooling rate (CR) of 0.5 degrees C/min in either zygotes or morulae. Nearly all flashed with CR of 4 degrees C/min or higher, but the distribution of temperatures is much broader with morulae than with zygotes. Also, the mean flashing temperature is much higher with morulae (-20.9 degrees C) than with zygotes (-40.3 degrees C). We computed the kinetics of water loss with respect to CR and temperature in both mouse zygotes and in morulae based on published estimates of Lp and it is Ea. The resulting dehydration curves combined with knowledge of the embryo nucleation temperature permits an estimate of the likelihood of IIF as a function of CR and subzero temperature. The agreement between these computed probabilities and the observed values are good. PMID- 27481512 TI - CA27.29 as a tumour marker for risk evaluation and therapy monitoring in primary breast cancer patients. AB - Several trials showed that tumour markers are associated with an impaired prognosis for breast cancer. Whether earlier treatment can improve the course of the disease remains controversial. The SUCCESS Trial compares FEC (500/100/500) docetaxel (100) vs. FEC (500/100/500)-docetaxel/gemcitabine (75/2000) as well as 2 vs. 5 years of zoledronate in high-risk primary breast cancer patients. In 2669 patients, CA27.29 was measured before and after chemotherapy with the ST AIA-PACK CA27.29 reagent for the AIA-600II automated enzyme immunoassay (Tosoh Bioscience, Belgium). Values above 31 U/ml were considered positive. Of the patients, 7.6 % (n = 202, mean 19, range 3-410) and 19.1 % (n = 511, mean 21, range 3-331) had elevated marker levels before and after chemotherapy, respectively. Of the patients, 4.9 and 78 % showed elevated and low CA27.29, respectively, at both time points. After treatment, 35 % of the pre-therapy positive patients were negative, and 15 % of the initially negative patients became positive. The correlation between both time points was significant (p < 0.0001). No correlations among nodal status, grading, hormonal status, HER2 status and CA27.29 levels were found. However, tumour size (p = 0.02), older age (p < 0.001) and post-menopausal status (p = 0.006) were significantly associated with higher CA27.29 levels. Before treatment, the prevalence of elevated CA27.29 was equally distributed between both treatment arms, whereas after chemotherapy, 13.7 % of the patients in the FEC-doc arm showed an increased level vs. 25.4 % of the patients in the FEC-doc/gemcitabine arm (p < 0.0001). However, we could not show a significant association between the G-CSF application (yes vs. no) and CA27.29 status before/after chemotherapy (p = 0.75). These results indicate a close relationship between CA27.29 levels and tumour mass. Increased values after the completion of chemotherapy might be attributed to treatment effects and should be considered with caution. PMID- 27481513 TI - Neuropilin-1 (NRP-1)/GIPC1 pathway mediates glioma progression. AB - Glioma occurs due to multi-gene abnormalities. Neuropilin-1 (NRP-1), as a transmembrane protein, involves in glioma proliferation, invasion, and migration, as well as tumor angiogenesis. The cytoplasmic protein, GAIP/RGS19-interacting protein (GIPC1), could regulate the clathrin-vesicles trafficking and recycling. Here, we show that NRP-1 co-localizes and co-immunoprecipitates with GIPC1, and the C-terminal SEA-COOH motif of NRP-1 interacts specially with the named from three proteins: PSD-95 (a 95 kDa protein involved in signaling at the post synaptic density), DLG (the Drosophila melanogaster Discs Large protein) and ZO-1 (the zonula occludens 1 protein involved in maintenance of epithelial polarity) (PDZ) domain of GIPC1 in glioma cells. Knockdown of GIPC1 by small interfering RNA (siRNA) significantly reduces the proliferation and invasion of glioma cells in vitro and increases its apoptosis. Furthermore, si-GIPC1 prevents the action of adaptor proteins adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) and p130Cas and inhibits the downstream kirsten rat sarcoma viral oncogene homolog (KRAS)-ERK signaling pathway. This study demonstrated that NRP-1/GIPC1 pathway plays a vital role in glioma progression, and it is a potential important target for multi-gene combined therapeutics. PMID- 27481514 TI - Oral pathogens change proliferation properties of oral tumor cells by affecting gene expression of human defensins. AB - The impact of oral pathogens onto the generation and variability of oral tumors has only recently been investigated. To get further insights, oral cancer cells were treated with pathogens and additionally, as a result of this bacterial cellular infection, with human defensins, which are as anti-microbial peptide members of the innate immune system. After cell stimulation, proliferation behavior, expression analysis of oncogenic relevant defensin genes, and effects on EGFR signaling were investigated. The expression of oncogenic relevant anti microbial peptides was analyzed with real-time PCR and immunohistochemistry. Cell culture experiments were performed to examine cellular impacts caused by stimulation, i.e., altered gene expression, proliferation rate, and EGF receptor dependent signaling. Incubation of oral tumor cells with an oral pathogen (Porphyromonas gingivalis) and human alpha-defensins led to an increase in cell proliferation. In contrast, another oral bacterium used, Aggregatibacter actinomycetemcomitans, enhanced cell death. The bacteria and anti-microbial peptides exhibited diverse effects on the transcript levels of oncogenic relevant defensin genes and epidermal growth factor receptor signaling. These two oral pathogens exhibited opposite primary effects on the proliferation behavior of oral tumor cells. Nevertheless, both microbe species led to similar secondary impacts on the proliferation rate by modifying expression levels of oncogenic relevant alpha-defensin genes. In this respect, oral pathogens exerted multiplying effects on tumor cell proliferation. Additionally, human defensins were shown to differently influence epidermal growth factor receptor signaling, supporting the hypothesis that these anti-microbial peptides serve as ligands of EGFR, thus modifying the proliferation behavior of oral tumor cells. PMID- 27481515 TI - PKC iota promotes cellular proliferation by accelerated G1/S transition via interaction with CDK7 in esophageal squamous cell carcinoma. AB - Protein kinase C iota (PKCiota) has been shown to play an important role in tumorigenesis of many cancers. It was reported that frequent amplification and overexpression of PKCi were correlated with resistance to anoikis in primary esophageal squamous cell carcinomas (ESCC). In this study, we clarified a novel role of PKCiota on the cell cycle progression and proliferation in ESCC. Western blot and immunohistochemistry (IHC) analysis showed that the expression of PKCiota was higher in ESCC tumor tissues and cell lines. Meanwhile, IHC stain revealed that PKCiota was positively correlated with clinical pathologic variables such as tumor size, tumor grade, and tumor invasion, as well as ki67. Immunoprecipitation and immunofluorescence assay revealed that PKCiota/CDK7 has the physical interaction and were co-located in the cell nucleus. And this direct interaction could increase the phosphorylation level of CDK7. In vitro studies such as starvation and refeeding assay along with PKCiota-shRNA transfection assay demonstrated that PKCiota expression promoted proliferation of ESCC cells. And knocking PKCi down by silencing RNA (siRNA) significantly caused cell cycle arrest at G0/G1 phase, decreased rate of colony formation, and alleviated cellular apoptosis. This research provide new insights into PKCi signaling to more deeply understand its cancer-promoting function in ESCC. PMID- 27481516 TI - Mucin-1 correlates with survival, smoking status, and growth patterns in lung adenocarcinoma. AB - Mucin-1 (MUC1) affects cancer progression in lung adenocarcinoma, and its aberrant expression pattern has been correlated with poor tumor differentiation and impaired prognosis. In this study, the immunohistochemical expression of MUC1 and Mucin-4 (MUC4) was analyzed in a series of 106 surgically operated stage I-IV pulmonary adenocarcinomas. MUC1 immunohistochemistry was evaluated according to the Nagai classification, and the immunohistochemical profile of the tumors was correlated with detailed clinical and histological data. The effect of cigarette smoke on MUC1 expression in lung cancer cell lines was examined using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunoelectron microscopy (IEM). In contrast to the normal apical localization of MUC1, a basolateral and cytoplasmic (depolarized) MUC1 expression pattern was frequently encountered in the high-grade subtypes, i.e., solid predominant adenocarcinoma and the cribriform variant of acinar predominant adenocarcinoma (p < 0.001), and was rarely observed in tumors containing a non-predominant lepidic component (p < 0.001). Furthermore, the altered staining pattern of MUC1 correlated with stage (p = 0.002), reduced overall survival (p = 0.031), and was associated with smoking (p < 0.001). When H1650 adenocarcinoma cells were exposed to cigarette smoke and analyzed by RT-qPCR and IEM, the levels of the MUC1 transcript and protein were elevated (p = 0.042). In conclusion, MUC1 participates in the pathogenesis of lung adenocarcinoma and associates with smoking both in vitro and in vivo. In lung adenocarcinoma, depolarized MUC1 protein expression correlated with histological growth patterns, stage, and patient outcome. PMID- 27481519 TI - SVM Based Descriptor Selection and Classification of Neurodegenerative Disease Drugs for Pharmacological Modeling. AB - Systems pharmacological modeling of drug mode of action for the next generation of multitarget drugs may open new routes for drug design and discovery. Computational methods are widely used in this context amongst which support vector machines (SVM) have proven successful in addressing the challenge of classifying drugs with similar features. We have applied a variety of such SVM based approaches, namely SVM-based recursive feature elimination (SVM-RFE). We use the approach to predict the pharmacological properties of drugs widely used against complex neurodegenerative disorders (NDD) and to build an in-silico computational model for the binary classification of NDD drugs from other drugs. Application of an SVM-RFE model to a set of drugs successfully classified NDD drugs from non-NDD drugs and resulted in overall accuracy of ~80 % with 10 fold cross validation using 40 top ranked molecular descriptors selected out of total 314 descriptors. Moreover, SVM-RFE method outperformed linear discriminant analysis (LDA) based feature selection and classification. The model reduced the multidimensional descriptors space of drugs dramatically and predicted NDD drugs with high accuracy, while avoiding over fitting. Based on these results, NDD specific focused libraries of drug-like compounds can be designed and existing NDD-specific drugs can be characterized by a well-characterized set of molecular descriptors. PMID- 27481518 TI - Unexpected frequency of genomic alterations in histologically normal colonic tissue from colon cancer patients. AB - As shown by genomic studies, colorectal cancer (CRC) is a highly heterogeneous disease, where copy number alterations (CNAs) may greatly vary among different patients. To explore whether CNAs may be present also in histologically normal tissues from patients affected by CRC, we performed CGH + SNP Microarray on 15 paired tumoral and normal samples. Here, we report for the first time the occurrence of CNAs as a common feature of the histologically normal tissue from CRC patients, particularly CNAs affecting different oncogenes and tumor suppressor genes, including some not previously reported in CRC and others known as being involved in tumor progression. Moreover, from the comparison of normal vs paired tumoral tissue, we were able to identify three groups: samples with an increased number of CNAs in tumoral vs normal tissue, samples with a similar number of CNAs in both tissues, and samples with a decrease of CNAs in tumoral vs normal tissue, which may be likely due to a selection of the cell population within the tumor. In conclusion, our approach allowed us to uncover for the first time an unexpected frequency of genetic alteration in normal tissue, suggesting that tumorigenic genetic lesions are already present in histologically normal colonic tissue and that the use in array comparative genomic hybridization (CGH) studies of normal samples as reference for the paired tumors can lead to misrepresented genomic data, which may be incomplete or limited, especially if used for the research of target molecules for personalized therapy and for the possible correlation with clinical outcome. PMID- 27481520 TI - Binding Mechanism of Inhibitors to CDK5/p25 Complex: Free Energy Calculation and Ranking Aggregation Analysis. AB - Cyclin-dependent kinase-5 (CDK5) plays an indispensable role in the central nervous system. Competitive inhibition of the ATP-binding pocket of CDK5 is involved in fighting with neurodegenerative diseases, diabetes, tumors, inflammations etc. To better design ATP-binding competitive inhibitors, the binding mechanism of three important inhibitors of kinases, (R)-roscovitine (RRC), aloisine-A (ALH) and indirubin-3'-oxime (IXM), together with their receptor CDK5, were studied by molecular dynamics simulations. The H-bond analysis demonstrated that a strong bond was formed between the C?O or ?NH? groups in the backbone of Cys83 and the ?N? or ?NH? groups on the nitrogen containing ring of inhibitors. These hydrogen bonds significantly increase the binding and inhibitory efficiency. The free energy analysis show that the order of predicted binding affinities of these three inhibitors toward CDK5/p25 is IXM>ALH>RRC, which is consistent with the experimental data. Besides the hydrogen bond formation, the van der Waals interactions between residues Ile10, Val18, and Leu133 of CDK5 and inhibitors were discovered to constitute another substantial component of their binding mode. Worth mentioning is that the conformational turnover of the inhibitor RRC was observed during the course of molecular dynamics simulations. We believe that this is the reason why RRC has the lower H bond occupancy and binding affinity than the other two inhibitors. Furthermore, during the analysis of the per-residue decomposition, the ranking aggregation method was firstly employed to rank the contribution of different residues. The results demonstrated that the top five residues in the active pocket of CDK5 were Cys83, Leu133, Ile10, Phe82, and Glu81, which is in good agreement with the results of H-bond analysis and binding free energy analysis. These findings should provide insights into the inhibition mechanism of the CDK5/p25 complex and be useful for the rational design of novel ATP-binding competitive inhibitors in the near future. PMID- 27481517 TI - Rab11a sustains GSK3beta/Wnt/beta-catenin signaling to enhance cancer progression in pancreatic cancer. AB - The Rab family GTPases regulate many major biological processes during tumor progression such as cell proliferation, cytoskeleton organization, cell movement, and invasion. The present study aims to examine the clinical significance, biological roles, and molecular mechanism of Rab11a in pancreatic cancer progression. We examined expression pattern of Rab11a in 96 cases of pancreatic cancer specimens using immunohistochemistry and found Rab11a overexpression correlated with tumor-node-metastasis (TNM) stage (p = 0.0111). We depleted Rab11a in Bxpc3 cells using small interfering RNA (siRNA) and overexpressed Rab11a in Capan2 cells. Knockdown of Rab11a inhibited cell growth, invasion, and cell cycle progression while its overexpression facilitated cell growth, invasion, and cell cycle progression. In addition, Rab11a overexpression increased gemcitabine resistance and inhibited gemcitabine-induced apoptosis in Capan2 cells while its depletion reduced drug resistance. We investigated the role of Rab11a in the regulation of Wnt/beta-catenin signaling and we demonstrated that Rab11a overexpression upregulated GSK3beta phosphorylation and nuclear beta-catenin accumulation. Rab11a depletion inhibited while its overexpression enhanced beta-catenin/T-cell factor (TCF) transcriptional activity with corresponding change of Wnt target genes including cyclin D1, cyclin E, MMP7, and c-myc. Wnt inhibitor (FH535) partly attenuated the effects of Rab11a on cell proliferation and Wnt target genes. In conclusion, the present study demonstrated that Rab11a promotes aggressiveness of pancreatic cancer through GSK3beta/Wnt/beta-catenin signaling pathway. PMID- 27481521 TI - Transductive Support Vector Machines: Promising Approach to Model Small and Unbalanced Datasets. AB - Semi-supervised methods dealing with a combination of labeled and unlabeled data become more and more popular in machine-learning area, but not still used in chemoinformatics. Here, we demonstrate that Transductive Support Vector Machines (TSVM) - a semi-supervised large-margin classification method - can be particularly useful to build the models on small and unbalanced datasets which often represent a difficult problem in QSAR. Both TSVM and ordinary SVM have been applied to build classification models on 10 DUD datasets. The "transductive effect" (the difference in predictive performance between transductive and ordinary support vector machines) was investigated as a function of: (a) active/inactive ratio, (b) descriptor weighting, and (c) the training and test sets size and composition. PMID- 27481522 TI - Computational Investigation of SENP:SUMO Protein-Protein Interaction for Structure Based Drug Design. AB - SUMO specific proteases (SENPs) are cysteine proteases that carry out the proteolytic processing of SUMO from its pro form as well as its deconjugation from substrate proteins. SENPs have been implicated in various cancers including prostate cancer, thyroid cancer and colon cancer. Therefore, the inhibition of SENPs is an attractive strategy for the treatment of cancer. However, the current SENP inhibitor development strategies target catalytic site and involve the usage of reactive functionalities to facilitate the covalent binding with a catalytic cysteine, which makes them less desirable for therapeutic purposes. Based on the available structural knowledge about the interaction of SENPs with various SUMO paralogues, an alternative approach for inhibiting SENPs could be via targeting SENP:SUMO protein-protein interaction. Here we have investigated the protein protein interaction between SENP and SUMO as a target for structure based drug design using pocket prediction, ligand binding hotspot mapping, molecular dynamics simulation and in silico alanine mutagenesis. Finally, we have provided recommendations for the structure based design of SENP:SUMO protein-protein interaction inhibitors. Our study indicates that the SENP inhibitors targeting SENP:SUMO protein-protein interaction is a viable alternative strategy to existing inhibitors targeting the enzymatic site. PMID- 27481523 TI - QSAR and Predictors of Eye and Skin Effects. AB - In this study, the ensemble of features and training samples was examined with a collection of support vector machines. The effects of data sampling methods, ratio of positive to negative compounds, and types of base models combiner to produce ensemble models were explored. The ensemble method was applied to produce four separate in silico models to classify the labels for eye/skin corrosion (H314), skin irritation (H315), serious eye damage (H318), and eye irritation (H319), which are defined in the "Globally Harmonized System of Classification and Labelling of Chemicals". To the best of our knowledge, the training set used in this work is one of the largest (made of publicly available data) with acceptable prediction performances. These models were distributed via PaDEL DDPredictor (http://padel.nus.edu.sg/software/padelddpredictor) that can be downloaded freely for public use. PMID- 27481524 TI - Rendering Molecular Sketches for Publication Quality Output. AB - The creation of 2D molecular structure diagrams that make full use of the capabilities of modern display systems, using only input data expressed in file formats used for cheminformatics, is a complex task that requires a number of additional algorithms. Assuming that atom positions have been well chosen, the rendering engine is required to micromanage the precise positioning of atom labels, bonds and atom adjuncts, in such a way that the final output is correct, consistent with convention, and as pleasing to the eye as a diagram produced by a graphic designer. The techniques must be equally applicable when creating output for low-resolution screens and high resolution printed output, and make use of contemporary graphics file formats in such a way that the largest possible number of software platforms are able to display the output at any resolution without degradation or inconsistency. The main issues involved in meeting these criteria are discussed, and algorithms for satisfying them are presented. PMID- 27481525 TI - Determination of the Potential of Drug Candidates to Cause Severe Skin Disorders Using Computational Modeling. AB - Efficient and accurate prediction for drugs' potential to cause rare and severe adverse drug reactions (ADRs) is needed to facilitate the evaluation of risk benefit ratio of drug candidates during drug development. Severe skin disorders like the Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are life-threatening dermatological conditions, are such ADRs that have not received sufficient attention so far. In this study, a total of 1127 marketed drugs were screened for their potential to cause SJS/TEN, of which 255 were found to cause SJS/TEN and 239 were unlikely to cause SJS/TEN. One-class classification method was used to develop multiple prediction models. An applicability domain was determined to define the applicability of the model. Ensemble method was used to develop ensemble models to improve prediction ability. The final ensemble model achieved a sensitivity and specificity of 81 % and 67.4 %, respectively, when estimated using the external 5-fold cross validation method, and a sensitivity of 66.7 % when assessed using an external positive set. The results suggest the methods used in this study are potentially useful for facilitating the prediction of rare and severe ADRs. PMID- 27481526 TI - Corrigendum: Are Mechanistic and Statistical QSAR Approaches Really Different? MLR Studies on 158 Cycloalkyl-Pyranones. PMID- 27481527 TI - Rare compound heterozygosity involving dominant and recessive mutations of GJB2 gene in an assortative mating hearing impaired Indian family. AB - Connexin 26 (Cx-26), a gap junction protein coded by GJB2 gene, plays a very important role in recycling of potassium ions, one of the vital steps in the mechanotransduction process of hearing. Mutations in the GJB2 gene have been associated with both autosomal recessive as well as dominant nonsyndromic hearing loss. As Cx-26 is linked with skin homeostasis, mutations in this gene are sometimes associated with syndromic forms of hearing loss showing skin anomalies. We report here a non consanguineous assortatively mating hearing impaired family with one of the hearing impaired partners, their hearing impaired sibling and hearing impaired offspring showing compound heterozygosity in the GJB2 gene, involving a dominant mutation p.R184Q and two recessive mutations p.Q124X and c.IVS 1+1G>A in a unique triallelic combination. To the best of our knowledge, this is the first report from India on p.R184Q mutation in the GJB2 gene associated with rare compound heterozygosity showing nonsyndromic presentation. PMID- 27481529 TI - Visible-light induced oxidant-free oxidative cross-coupling for constructing allylic sulfones from olefins and sulfinic acids. AB - An oxidant-free dehydrogenative sulfonylation of alpha-methyl-styrene derivatives was developed for the construction of allylic sulfones by using eosin Y as a photosensitizer in conjunction with a cobaloxime catalyst. The process features a low-cost metal catalyst and atom economy, which provides an appealing strategy for future synthetic chemistry. PMID- 27481528 TI - A comparison of surgical outcomes and complications between hemostatic devices for thyroid surgery: a network meta-analysis. AB - This meta-analysis compared harmonic scalpel and LigaSure(r) systems with the conventional clamp-and-tie technique in thyroidectomy. Medline, Cochrane, EMBASE, and Google Scholar databases were searched until December 30, 2015. Randomized controlled studies (RCTs) or two-arm prospective studies were included. The primary outcome was operation time. The data were evaluated both by pair-wise meta-analyses and network meta-analysis within a Bayesian framework using Markov chain Monte Carlo methods. Compared with the conventional hemostasis, there was a significant reduction in operation time with harmonic scalpel (HS) and LigaSure (LS) (difference in means = -24.27 min, 95 % CI -28.11 to -20.44 min, P < 0.001; and difference in means = -13.08 min, 95 % CI -16.88 to -9.27 min, P < 0.001, respectively). For total thyroidectomy and hemi-thyroidectomy, subgroup pair-wise meta-analyses found a reduction of 26.31 and 21.90 min in operation time for harmonic scalpel, and a reduction of 12.77 and 17.48 min for LigaSure, respectively. Among studies with mixed total and hemi-thyroidectomy, no significant difference in operation time was seen between harmonic scalpel and the conventional hemostasis (P = 0.313). Network meta-analysis also found harmonic scalpel and LigaSure to have less operation time than the conventional hemostasis, and that harmonic scalpel was associated with a significant 9.78 min reduction in operation time than LigaSure which was not seen in pair-wise comparison. Harmonic scalpel had significantly less risk of definitive recurrent laryngeal nerve palsy, intra-operation blood loss, and post-operation bleeding than the conventional hemostasis. LigaSure was associated with significantly less intra-operative blood loss than the conventional hemostasis (P = 0.023). There was no significant difference among three different procedures in rates of transient recurrent laryngeal nerve palsy. This study found that harmonic scalpel and LigaSure decreased operation time compared with the conventional hemostasis and that harmonic scalpels was associated with the lowest operation time. PMID- 27481530 TI - Short Communication: Low False Recent Rate of Limiting Antigen-Avidity Assay Combined with HIV-1 RNA Data in Botswana. AB - Cross-sectional estimation of HIV incidence could misclassify some established or chronic HIV infections as recent. Usually long-term nonprogressors, elite and viremic controllers, and individuals on ART contribute to misclassification. Local data on the false recent rate (FRR) could minimize misclassification during estimation of HIV incidence. To improve monitoring of HIV incidence, we estimated local FRR in Botswana. A total of 1,036 specimens from individuals infected for at least 1.5-2 years were sampled between 2004 and 2009 and tested using the limiting antigen (LAg)-avidity assay using a cutoff of 1.5 normalized optical density units. The FRR was 0.97% (10/1,036; 95% confidence interval [CI] 0.46 1.77). Four samples had HIV-1 RNA >1,000 cps/ml, giving an adjusted FRR of 0.39% (4/1,036; 95% CI 0.11-0.99). A combination of LAg and HIV-1 RNA load data resulted in FRR below 1% in the Botswana population. PMID- 27481533 TI - Rotational autotransplantation of mandibular alveolar ridge. PMID- 27481531 TI - Phage Therapy in the Era of Synthetic Biology. AB - For more than a century, bacteriophage (or phage) research has enabled some of the most important discoveries in biological sciences and has equipped scientists with many of the molecular biology tools that have advanced our understanding of replication, maintenance, and expression of genetic material. Phages have also been recognized and exploited as natural antimicrobial agents and nanovectors for gene therapy, but their potential as therapeutics has not been fully exploited in Western medicine because of challenges such as narrow host range, bacterial resistance, and unique pharmacokinetics. However, increasing concern related to the emergence of bacteria resistant to multiple antibiotics has heightened interest in phage therapy and the development of strategies to overcome hurdles associated with bacteriophage therapeutics. Recent progress in sequencing technologies, DNA manipulation, and synthetic biology allowed scientists to refactor the entire bacterial genome of Mycoplasma mycoides, thereby creating the first synthetic cell. These new strategies for engineering genomes may have the potential to accelerate the construction of designer phage genomes with superior therapeutic potential. Here, we discuss the use of phage as therapeutics, as well as how synthetic biology can create bacteriophage with desirable attributes. PMID- 27481534 TI - Iohexol oral rinse to differentiate the palatoglossal surfaces in computed tomography of patients with obstructive sleep apnoea. PMID- 27481536 TI - Corrigendum to "Moderate to vigorous physical activity is associated with greater patellar cartilage volume over 2 years following anterior cruciate ligament reconstruction" [Osteoarthritis Cartilage 24 (2016) S195-S196]. PMID- 27481535 TI - Specific detection of interferon regulatory factor 5 (IRF5): A case of antibody inequality. AB - Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors. IRF5 was first identified and characterized as a transcriptional regulator of type I interferon expression after virus infection. In addition to its critical role(s) in the regulation and development of host immunity, subsequent studies revealed important roles for IRF5 in autoimmunity, cancer, obesity, pain, cardiovascular disease, and metabolism. Based on these important disease-related findings, a large number of commercial antibodies have become available to study the expression and function of IRF5. Here we validate a number of these antibodies for the detection of IRF5 by immunoblot, flow cytometry, and immunofluorescence or immunohistochemistry using well-established positive and negative controls. Somewhat surprising, the majority of commercial antibodies tested were unable to specifically recognize human or mouse IRF5. We present data on antibodies that do specifically recognize human or mouse IRF5 in a particular application. These findings reiterate the importance of proper controls and molecular weight standards for the analysis of protein expression. Given that dysregulated IRF5 expression has been implicated in the pathogenesis of numerous diseases, including autoimmune and cancer, results indicate that caution should be used in the evaluation and interpretation of IRF5 expression analysis. PMID- 27481532 TI - Yeast and Fungal Prions. AB - Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to lethal, with specific effects dependent on the prion protein and the specific prion variant ("prion strain"). The prion amyloids of Sup35p, Ure2p, and Rnq1p are in-register, parallel, folded beta-sheets, an architecture that naturally suggests a mechanism by which a protein can template its conformation, just as DNA or RNA templates its sequence. Prion propagation is critically affected by an array of chaperone systems, most notably the Hsp104/Hsp70/Hsp40 combination, which is responsible for generating new prion seeds from old filaments. The Btn2/Cur1 antiprion system cures most [URE3] prions that develop, and the Ssb antiprion system blocks [PSI+] generation. PMID- 27481538 TI - A likely inverse-Compton emission from the Type IIb SN 2013df. AB - The inverse-Compton X-ray emission model for supernovae has been well established to explain the X-ray properties of many supernovae for over 30 years. However, no observational case has yet been found to connect the X-rays with the optical lights as they should be. Here, we report the discovery of a hard X-ray source that is associated with a Type II-b supernova. Simultaneous emission enhancements have been found in both the X-ray and optical light curves twenty days after the supernova explosion. While the enhanced X-rays are likely dominated by inverse Compton scatterings of the supernova's lights from the Type II-b secondary peak, we propose a scenario of a high-speed supernova ejecta colliding with a low density pre-supernova stellar wind that produces an optically thin and high temperature electron gas for the Comptonization. The inferred stellar wind mass loss rate is consistent with that of the supernova progenitor candidate as a yellow supergiant detected by the Hubble Space Telescope, providing an independent proof for the progenitor. This is also new evidence of the inverse Compton emission during the early phase of a supernova. PMID- 27481537 TI - Single Particle and PET-based Platform for Identifying Optimal Plasmonic Nano Heaters for Photothermal Cancer Therapy. AB - Plasmonic nanoparticle-based photothermal cancer therapy is a promising new tool to inflict localized and irreversible damage to tumor tissue by hyperthermia, without harming surrounding healthy tissue. We developed a single particle and positron emission tomography (PET)-based platform to quantitatively correlate the heat generation of plasmonic nanoparticles with their potential as cancer killing agents. In vitro, the heat generation and absorption cross-section of single irradiated nanoparticles were quantified using a temperature sensitive lipid based assay and compared to their theoretically predicted photo-absorption. In vivo, the heat generation of irradiated nanoparticles was evaluated in human tumor xenografts in mice using 2-deoxy-2-[F-18]fluoro-D-glucose ((18)F-FDG) PET imaging. To validate the use of this platform, we quantified the photothermal efficiency of near infrared resonant silica-gold nanoshells (AuNSs) and benchmarked this against the heating of colloidal spherical, solid gold nanoparticles (AuNPs). As expected, both in vitro and in vivo the heat generation of the resonant AuNSs performed superior compared to the non-resonant AuNPs. Furthermore, the results showed that PET imaging could be reliably used to monitor early treatment response of photothermal treatment. This multidisciplinary approach provides a much needed platform to benchmark the emerging plethora of novel plasmonic nanoparticles for their potential for photothermal cancer therapy. PMID- 27481539 TI - The relationships between symptoms and quality of life over the course of cognitive-behavioral therapy for panic disorder in Japan. AB - INTRODUCTION: This study examined the relationships between changes in symptoms and changes in quality of life (QOL) during cognitive-behavioral therapy (CBT) for panic disorder (PD). METHODS: We treated 198 PD patients with group CBT in Japan. Using multiple regression analysis, we examined the associations between changes in QOL and changes in PD symptoms or comorbid psychological symptoms during CBT. RESULTS: Changes in anticipatory anxiety, agoraphobic fear/avoidance, and somatization were significant predictors of changes in some aspects of QOL. DISCUSSION: It might be useful to decrease somatization, anticipatory anxiety, and agoraphobic fear to improve QOL in CBT for PD. PMID- 27481541 TI - Hydrophobicity-Driven Self-Assembly of an Eighteen-Membered Honeycomb Lattice with Almost Classical Spins. AB - The design and synthesis of model compounds that do not exist naturally is one of the important targets in modern coordination chemistry. Herein, an eighteen membered honeycomb structure with equal numbers of MnII (s=5/2) and GdIII (s=7/2) metal centers has been prepared, for the first time, by using a hydrophobic force directed self-assembling process. Due to the weakly coupled GdIII pairs, the magnetic properties are mainly determined by eight-membered chains in the experimentally considered temperature range. These [Mn4 Gd4 ] "finite-size" chains, albeit with large Hilbert space, can be fully resolved by the high temperature series expansion and the powerful finite-temperature Lanczos method, which reveal that the exchange-couplings between the metal centers are antiferromagnetic and consistent with the magnetization measurement. Interestingly, from the surface-engineering point of view, the [Mn4 Gd4 ] chains are "precisely" assembled into a 2D honeycomb pattern, which is potentially desirable in the design of weakly coupled qubits. PMID- 27481540 TI - Non-equilibrium 8pi Josephson effect in atomic Kitaev wires. AB - The identification of fractionalized excitations, such as Majorana quasi particles, would be a striking signal of the realization of exotic quantum states of matter. While the paramount demonstration of such excitations would be a probe of their non-Abelian statistics via controlled braiding operations, alternative proposals exist that may be easier to access experimentally. Here we identify a signature of Majorana quasi-particles, qualitatively different from the behaviour of a conventional superconductor, which can be detected in cold atom systems using alkaline-earth-like atoms. The system studied is a Kitaev wire interrupted by an extra site, which gives rise to super-exchange coupling between two Majorana-bound states. We show that this system hosts a tunable, non-equilibrium Josephson effect with a characteristic 8pi periodicity of the Josephson current. The visibility of the 8pi periodicity of the Josephson current is then studied including the effects of dephasing and particle losses. PMID- 27481542 TI - Vascular Procr+ stem cells: Finding new branches while looking for the roots. AB - Generation and growth of the blood vasculature network is a highly synchronized process, requiring coordinated efforts of endothelial cells and pericytes to maintain blood vessel integrity and regeneration. In a recent paper published in Cell Research, Yu et al. identified and characterized bipotent Procr-expressing vascular endothelial stem cells, which give rise to both endothelial cells and pericytes. PMID- 27481543 TI - Highlighting early career scientists. PMID- 27481544 TI - Exposure to parental separation in childhood and later parenting quality as an adult: evidence from a 30-year longitudinal study. AB - BACKGROUND: Previous research has documented that exposure to parental separation/divorce during childhood can be associated with long-term consequences into adulthood. This study sought to extend this literature by examining associations between childhood exposure to parental separation/divorce and later parenting behavior as an adult in a New Zealand birth cohort. METHODS: Data were drawn from the Christchurch Health and Development Study (CHDS), a longitudinal study of a birth cohort of 1,265 children born in 1977 in Christchurch, New Zealand. Information about exposure to parental separation and divorce was gathered annually from birth to 15 years. At the 30-year follow-up, all cohort members who had become parents (biological or nonbiological) were assessed on several parenting dimensions (sensitivity, warmth, overreactivity, inconsistency, quality of child management, and physical punishment). RESULTS: The analyses showed that exposure to more frequent parental separation in childhood and adolescence was associated with lower levels of parental sensitivity and warmth, greater overreactivity, and an increased use of physical punishment as a parent, after controlling for a wide range of family socioeconomic and psychosocial factors, and individual child characteristics. CONCLUSIONS: The findings suggest that as exposure to parental separation increases, so does the likelihood of experiencing multiple developmental challenges in childhood and adolescence. As an adult, these life-course experiences can have small but significant associations with the quality of parenting behavior. PMID- 27481546 TI - Predictors of nonresponse to fluid restriction in hyponatraemia due to the syndrome of inappropriate antidiuresis. AB - BACKGROUND: Fluid restriction (FR), the first-line treatment for hyponatraemia due to the syndrome of inappropriate antidiuresis (SIAD), often does not lead to successful correction of hyponatraemia. Therefore, predictive markers of treatment response are desirable. We evaluated routinely measured serum (s) and urine (u) parameters, s-copeptin and s-mid-regional pro-atrial natriuretic peptide (s-MR-proANP), as possible predictors of FR response. METHODS: In this prospective observational study, we included patients with profound hyponatraemia (s-sodium <125 mmol L-1 ) due to SIAD. Patients were classified as FR responders (increase in s-sodium concentration of >3 mmol L-1 within 24 h) or nonresponders (increase of <=3 mmol L-1 within 24 h). Initial laboratory parameters were compared between groups with logistic regression analysis. RESULTS: Of 106 SIAD patients analysed, 82 underwent treatment with FR; 48 (59%) patients showed a successful response to FR and 34 (41%) were considered nonresponders. High levels of u-sodium and u-osmolality were significantly associated with nonresponse to FR [odds ratio (OR) 15.0, 95% confidence interval (CI) 2.4-95.8, P = 0.004 and OR 34.8, 95% CI 1.2-1038.8, P = 0.041, respectively). The association of u-sodium and nonresponse remained significant also after adjustment for diuretic use. Lower levels of s-MR-proANP were associated with nonresponse (OR 0.03, 95% CI 0.003-0.3, P = 0.004), whereas s-copeptin was not significantly associated with response to FR. CONCLUSION: Easily measured laboratory parameters, especially u sodium, correlate with therapeutic response and identify patients most likely to fail to respond to FR. Measurement of these parameters may facilitate early treatment choice in patients with SIAD. PMID- 27481545 TI - Delayed match-to-sample in working memory: A BrainMap meta-analysis. AB - Working memory (WM), or the ability to temporarily store and manipulate information, is one of the most widely studied constructs in cognitive psychology. Since its inception, it has become one of the leading explanations for how humans are able to operate on a cognitive level. The current study probed the neural networks underlying one of the most commonly used tasks, delayed match to-sample (DMTS), to study WM. An activation likelihood estimation (ALE) analysis of 42 functional neuroimaging studies (626 participants) was conducted to demonstrate neural network engagement during DMTS. Results demonstrated strong convergence in brain regions commonly associated with the working memory construct (i.e., dorsolateral prefrontal cortex, fusiform gyrus, and posterior parietal cortex). However, neural activation in two regions frequently attributed to WM were absent from this meta-analysis: the anterior cingulate and the rostral prefrontal cortex, suggesting that these regions may be more sensitive to task or stimuli characteristics. In a post-hoc analysis, we deconstructed the DMTS meta analysis to examine nonverbal versus verbal stimuli, and found notable neurofunctional differences such that DMTS using nonverbal stimuli consistently engaged the right middle frontal gyrus (BA 6/46) and precuneus (BA 7) more so than verbal stimuli based DMTS. These results provide a foundation for future models of functional connectivity that may elucidate subtle differences in working memory attributable to pathological processes. PMID- 27481547 TI - Impact of amino acid and CP restriction from 20 to 140 kg BW on performance and dynamics in empty body protein and lipid deposition of entire male, castrated and female pigs. AB - Breeding leaner pigs during the last decades may have changed pig's empty body (EB) composition, a key trait for elaborating feeding recommendations. This research aimed to provide new experimental data on changes in the chemical composition of the EB of pigs from 20 to 140 kg BW. In addition, the impact of a reduction in the dietary CP associated with lower lysine, methionine+cystine, threonine and tryptophan levels was determined. In total, 48 males, castrates and females weighing 20 kg BW were allocated either to a control grower-finisher diet formulated according to current Swiss feeding recommendations, or a low CP grower finisher diet (80% of control). Feed intake was monitored and pigs were weighed weekly. The chemical composition of EB (blood, hairs and hoofs, offals, bile, carcass) was determined at 20, 40, 60, 80, 100, 120 and 140 kg BW on four pigs per gender and diet (eight pigs per gender at 20 kg). The five fractions were weighed and samples were analysed for dry matter, protein, fat and energy. Nutrient deposition rates and N efficiency were calculated by using the 20 kg BW category as reference. Analysis revealed an accurate feed optimisation for the aforementioned essential amino acids (EAA), whereas digestible isoleucine content in the low CP diet was at 70% of the control diet. Despite similar feed intake, daily gain and feed efficiency were impaired (P<0.01) from 20 to 100 kg BW in the low CP compared with the control pigs. In the same growth period, castrates had the greatest feed intake but, together with females, displayed the lowest (P<0.01) feed efficiency. Protein deposition was reduced (P<0.01) by up to 31% with low CP diet and was lower (P<0.01) in castrates and females than males at 100 kg BW. The greatest fat deposition rates were found with low CP diet and castrates. N efficiency improved (P<0.05) by 10% with the low CP diet from 100 to 140 kg. The males displayed the greatest (P<0.05) N efficiency. These findings suggest that the CP content of finisher II diets could be reduced to 102, 102 and 104 g/kg for females, castrates and males, respectively, without a negative impact on protein deposition or growth. It remains unclear whether the negative effects found in the BW range from 20 to 100 kg on the EB deposition were due to the 20% reduction of the dietary CP and the five limiting EAA or to other EAA via an unbalanced EAA profile. PMID- 27481549 TI - Effect of physicochemical properties of a cement based on silicocarnotite/calcium silicate on in vitro cell adhesion and in vivo cement degradation. AB - A silicon calcium phosphate cement (Si-CPC) was developed to produce a composite of calcium phosphate and calcium silicate. The silicon cements prepared with low silicon (Si) content were composed of crystalline phases of brushite and silicocarnotite. However, the cements prepared with high Si content were mainly composed of amorphous phases of silicocarnotite, hydroxyapatite and calcium silicate. The cement porosity was about 40% with a shift of the average pore diameter to the nanometric range with increasing Si content. Interestingly, this new cement system provides a matrix with a high specific surface area of up to 29 m(2) g(-1). The cytocompatibility of the new Si-doped cements was tested with a human osteoblast-like cell line (MG-63) showing an enhancement of cell proliferation (up to threefold) when compared with unsubstituted material. Cements with a high silica content also improved the cell attachment. The in vivo results indicated that Si-CPCs induce the formation of new bone tissue, and modify cement resorption. We conclude that this cement provides an optimal environment to enhance osteoblast growth and proliferation that could be of interest in bone engineering. PMID- 27481548 TI - Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment. AB - The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that "very early" iCCA (single tumors <=2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with "very early" iCCA and those with "advanced" disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the "very early" iCCA group and 33/48 (69%) the "advanced" group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the "advanced" group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. CONCLUSION: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178-1188). PMID- 27481550 TI - Amphiphilic block copolymers as flexible membrane materials generating structural and functional mimics of green bacterial antenna complexes. AB - We describe the ability of a short-chain amphiphilic block copolymer to self assemble to form an artificial supramolecular light-harvesting system. Specifically, we demonstrate that the 2.5 kDa, poly(ethylene oxide)-block poly(butadiene) (PEO-b-PBD), exhibits sufficient morphological flexibility as a membrane material and enables generation of mimics of three-dimensional chlorosomes as well as supported membrane bilayers containing energy acceptors. This overall architecture replicates green bacterial light-harvesting function whereby these assemblies exhibit long-range order and three-dimensional morphology similar to native chlorosomes and are capable of energy transfer internally and to external acceptors, located in a supporting biomimetic polymer membrane. Unlike native green bacterial systems that use multiple lipids as a matrix to generate the appropriate environment for chlorosome assembly and function, the described system matrix is comprised entirely of a single polymer amphiphile. This work demonstrates the potential of short-chain amphiphilic block copolymers in generating self-assembled, bio-mimetic membrane architectures, and in doing so, generates scalable, spatial-energetic landscapes for photonic applications. Finally, the results presented provide evidence of minimal requirements to induce chlorosome-like organization and function. PMID- 27481551 TI - Non-invasive monitoring of reproductive and stress hormones in the endangered red panda (Ailurus fulgens fulgens). AB - The red panda (Ailurus fulgens fulgens) is classified as endangered due to its declining population, habitat fragmentation and poaching. Efforts are being made to breed them in captivity as part of nationwide conservation breeding program. This study aimed to standardize Enzyme immunoassays (EIAs) to monitor reproductive (Progesterone metabolite, Testosterone) and stress hormone (Cortisol) in red panda. For this purpose, we collected 1471 faecal samples from four females and one male over a period of one year from Padmaja Naidu Himalayan Zoological Park, Darjeeling, India. HPLC confirmed the presence of immunoreactive 5alpha-pregnan-3alpha-ol-20-one, testosterone and cortisol metabolites in faecal samples. Using 5alpha-pregnan-3alpha-ol-20-one EIA, we were able to monitor reproduction and detect pregnancy in one of the females, which successfully conceived and delivered during the study period. We were also able to monitor testosterone and cortisol in faecal samples of the red panda. Faecal testosterone levels were found in higher concentration in breeding season than in non-breeding season. Faecal cortisol concentrations showed a negative relationship with ambient temperature and peaked during winter months in all animals. Standardization of EIAs and faecal hormone monitoring would facilitate red panda conservation breeding programs in India and elsewhere. PMID- 27481552 TI - Protein modification in the post-mating spermatophore of the signal crayfish Pacifastacus leniusculus: insight into the tyrosine phosphorylation in a non motile spermatozoon. AB - After mating, spermatophores of signal crayfish are stored on the body of the female for a period before fertilization. This study compared the post-mating protein profile and pattern of protein tyrosine phosphorylation of the signal crayfish spermatophore to that of the freshly ejaculated spermatophore and found substantial differences. Two major bands of tyrosine-phosphorylated proteins of molecular weights 10 and 50kDa were observed in the freshly ejaculated spermatophore of the signal crayfish. While the tyrosine-phosphorylated protein band with molecular weight 10kDa was formed by protein(s) of similar pH, the band with molecular weight of 50kDa consisted of proteins of varying pH. In the post mating spermatophore, the band with molecular weight of 50kDa was not detected, and an increase in the level of protein tyrosine phosphorylation was observed in the 10kDa band. The microtubular radial arms of the spermatozoon showed a positive reaction to an anti-tyrosine antibody conjugated with gold particles in both the freshly ejaculated and post-mating spermatophores. In conclusion, the male gamete of the signal crayfish undergoes molecular modification during post mating storage on the body of the female including changes in the level of protein expression and protein tyrosine phosphorylation. Structural similarity of the radial arms in the crayfish immotile spermatozoon with flagellum, which is the main site of protein tyrosine phosphorylation in the mammalian motile spermatozoa, raises questions regarding evolution and function of such organelles across the animal kingdom that must be addressed in the future studies. PMID- 27481553 TI - Shaping emotion regulation: attunement, symptomatology, and stress recovery within mother-infant dyads. AB - The foundations of emotion regulation are organized, in part, through repeated interactions with one's caregiver in infancy. Less is known about how stress physiology covaries between a mother and her infant within these interactions, leaving a gap in our understanding of how the biological basis of emotion regulation develops. This study investigated physiological attunement between mothers and their 5-month-old infants, as well as the influence of maternal depression and anxiety, during stress recovery. During the reengagement phase of the Still Face Paradigm, mother-infant dyads exhibited negative attunement, as measured by inverse covariation of respiratory sinus arrhythmia (RSA). Increases in maternal RSA corresponded to decreases in infant RSA, underscoring dyadic adjustment during recovery. Moreover, infant regulation differed as a function of maternal anxiety, with more anxious mothers having infants with higher RSA during reengagement. Implications for the consolidation of regulatory capabilities within the context of the early caregiving relationship are discussed. PMID- 27481554 TI - NF-kappaB Signaling Pathway Inhibitors as Anticancer Drug Candidates. AB - Cancer incidence represents an important public health problem worldwide. Nuclear factor kappa B (NF- kappaB) transcription factor plays a pivotal role in the regulation of genes that control various responses in eukaryotic cells, including proliferation and survival, cytoskeletal remodeling, cellular adhesion and apoptosis. Extensive studies have demonstrated the contribution of NF-kappaB transcription in the promotion and progression of several hematological malignancies and solid tumors, in which NF-kappaB constitutive activation and/or overexpression are common clinical features. Moreover, triggering the NF-kappaB pathway is already considered one of the important mechanisms of resistance development to chemotherapy and radiotherapy, indicating that the inhibition of this signaling cascade is a promising approach to enhancing efficacy and preventing acquired resistance in cancer treatment. In this review, research efforts dedicated to the identification of novel NF-kappaB signaling pathway inhibitors as promising anticancer drug candidates are described. PMID- 27481555 TI - Deriving gradient measures of child speech from crowdsourced ratings. AB - Recent research has demonstrated that perceptual ratings aggregated across multiple non-expert listeners can reveal gradient degrees of contrast between sounds that listeners might transcribe identically. Aggregated ratings have been found to correlate strongly with acoustic gold standard measures both when individual raters use a continuous rating scale such as visual analog scaling (Munson et al., 2012) and when individual raters provide binary ratings (McAllister Byun, Halpin, & Szeredi, 2015). In light of evidence that inexperienced listeners use continuous scales less consistently than experienced listeners, this study investigated the relative merits of binary versus continuous rating scales when aggregating responses over large numbers of naive listeners recruited through online crowdsourcing. Stimuli were words produced by children in treatment for misarticulation of North American English /r/. Each listener rated the same 40 tokens two times: once using Visual Analog Scaling (VAS) and once using a binary rating scale. The gradient rhoticity of each item was then estimated using (a) VAS click location, averaged across raters; (b) the proportion of raters who assigned the "correct /r/" label to each item in the binary rating task (p^). First, we validate these two measures of rhoticity against each other and against an acoustic gold standard. Second, we explore the range of variability in individual response patterns that underlie these group level data. Third, we integrate statistical, theoretical, and practical considerations to offer guidelines for determining which measure to use in a given situation. PMID- 27481556 TI - A clinical update on the significance of the gut microbiota in systemic autoimmunity. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease where a loss of tolerance to nuclear antigens leads to inflammation in multiple organ systems. The cause of SLE remains ill defined, although it is known that a complex interplay between genes and environment is necessary for disease development. In recent years, case studies have reported that the incidence of SLE in the USA, for example, has increased by approximately 3 fold. Although the reason for this is likely to be multifactorial, it has been hypothesized that the increasing incidence of autoimmune disease is due to considerable shifts in the bacterial communities resident the gut, collectively known as the gut microbiota, following a change in diet and the widespread introduction of antibiotics. Furthermore, a growing body of evidence suggests that the gut microbiota plays a role in the development of a range of autoimmune diseases including inflammatory bowel disease, multiple sclerosis, type one diabetes and rheumatoid arthritis. In this review, we summarize how advances in DNA-based sequencing technologies have been critical in providing baseline information concerning the gut microbiota in health and how variation amongst individuals in controlled by multiples factors including age, genetics, environment and the diet. We also discuss the importance of the gut microbiota in the development of a healthy immune system and how changes in particular bacterial phyla have been associated with immune abnormalities in animal models of autoimmune disease. Finally, in order to place the data in a clinical context, we highlight recent findings showing that abnormalities in the gut microbiota can be detected in patients with SLE, which provides the rationale for greater investigation into whether microbiota-targeted therapies could be used for the treatment/prevention of disease. PMID- 27481557 TI - Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus. AB - Long noncoding RNAs (lncRNAs) have recently been identified to be tightly linked to diverse human diseases. However, our knowledge of Systemic Lupus Erythematosus (SLE)-related lncRNAs remains limited. In the present study we investigated the contribution of the lncRNA NEAT1 to the pathogenesis of SLE. Here, we found NEAT1 expression was abnormally increased in SLE patients and predominantly expressed in human monocytes. Additionally, NEAT1 expression was induced by LPS via p38 activation. Silencing NEAT1 significantly reduced the expression of a group of chemokines and cytokines, including IL-6, CXCL10, etc., which were induced by LPS continuously and in late stages. Furthermore, it was identified the involvement of NEAT1 in TLR4-mediated inflammatory process was through affecting the activation of the late MAPK signaling pathway. Importantly, there was a positive correlation between NEAT1 and clinical disease activity in SLE patients. In conclusion, the increased NEAT1 expression may be a potential contributor to the elevated production of a number of cytokines and chemokines in SLE patients. Our findings suggest lncRNA contributes to the pathogenesis of lupus and provides potentially novel target for therapeutic intervention. PMID- 27481558 TI - Synthesis and biological evaluation of matrine derivatives as anti-hepatocellular cancer agents. AB - We delineate herein the synthesis and anti-cancer effects of 15 matrine derivatives. The in vitro growth inhibitory assays showed that most of the prepared compounds exhibited improved anti-proliferative activities towards cancer cells with IC50 17-109 times lower than that of matrine. Compounds CH6 showed the most potent anti-proliferative activities in the four tested cancer cell lines. Moreover, compound CH6 could induce G1 cell cycle arrest and inhibit cell migration in human hepatocellular cancer cell lines Bel-7402 and HepG2 through up-regulation of P21, P27 and E-cadherin and down-regulation of N cadherin. PMID- 27481559 TI - Reactivity of the glutathione species towards the reduction of ormaplatin (or tetraplatin). AB - The reduction of ormaplatin (tetraplatin), a prototype for Pt(IV) anticancer prodrugs, by glutathione (GSH) was kinetically characterized over a wide pH range at 25.0 degrees C and 1.0M ionic strength. The reduction follows overall second order kinetics, giving rise to the oxidized glutathione as the oxidation product, which was identified by high-resolution mass spectrometry. The reaction mechanism put forward involves parallel attacks by all the GSH species on the Pt(IV) prodrug as rate-determining steps. All rate constants for the rate-determining steps have been derived for the first time, enabling the construction of the reactivity of GSH species versus their pH distribution diagram. The diagram clearly displays that only one out of the five GSH species is the mainly responsible for the reduction of ormaplatin at the physiological pH of 7.4. PMID- 27481560 TI - Rat intestinal sucrase inhibited by minor constituents from the leaves and twigs of Archidendron clypearia (Jack.) Nielsen. AB - In the search for plants, containing compounds with alpha-glucosidase inhibitory activity, we found that a methanolic extract from the leaves and twigs of Archidendron clypearia (Jack.) Nielsen significantly inhibited rat intestinal sucrase in vitro. A phytochemical investigation of the aqueous layer of an A. clypearia extract led to the isolation of 14 compounds (1-14). Their structures were established through extensive 1D and 2D NMR, CD data, and MS analysis. The methanolic extract, as well as the water layer at a concentration of 3.0mg/mL, showed potent sucrase inhibitory activity, with 67.78+/-2.53% and 95.33+/-2.15% inhibition, respectively. In addition, compounds 6, 7, and 10 (1.0mM) showed potent sucrase inhibition (88.36+/-1.15%, 81.57+/-1.07%, and 66.32+/-4.73% inhibition, respectively), which was comparable to that of the positive control, acarbose, which exhibited 89.54+/-0.91% inhibition. Other compounds showed moderate or weak inhibitory activity at the same concentration. The sucrase inhibitory activity of the extracts and purified compounds may provide a novel opportunity to develop a new class of antidiabetic agents. PMID- 27481562 TI - Ab initio potential energy surface and vibration-rotation energy levels of silicon dicarbide, SiC2. AB - The accurate ground-state potential energy surface of silicon dicarbide, SiC2 , has been determined from ab initio calculations using the coupled-cluster approach. Results obtained with the conventional and explicitly correlated coupled-cluster methods were compared. The core-electron correlation, higher order valence-electron correlation, and scalar relativistic effects were taken into account. The potential energy barrier to the linear SiCC configuration was predicted to be 1782 cm(-1) . The vibration-rotation energy levels of the SiC2 , (29) SiC2 , (30) SiC2 , and SiC(13) C isotopologues were calculated using a variational method. The experimental vibration-rotation energy levels of the main isotopologue were reproduced to high accuracy. In particular, the experimental energy levels of the highly anharmonic vibrational nu3 mode of SiC2 were reproduced to within 6.7 cm(-1) , up to as high as the v3 = 16 state. PMID- 27481561 TI - Design, synthesis and biological evaluation of photoaffinity probes of antiangiogenic homoisoflavonoids. AB - A naturally occurring homoisoflavonoid, cremastranone (1) inhibited angiogenesis in vitro and in vivo. We developed an analogue SH-11037 (2) which is more potent than cremastranone in human retinal microvascular endothelial cells (HRECs) and blocks neovascularization in animal models. Despite their efficacy, the mechanism of these compounds is not yet fully known. In the course of building on a strong foundation of SAR and creating a novel chemical tool for target identification of homoisoflavonoid-binding proteins, various types of photoaffinity probes were designed and synthesized in which benzophenone and biotin were attached to homoisoflavanonoids using PEG linkers on either the C-3' or C-7 position. Notably, the photoaffinity probes linking on the phenol group of the C-3' position retain excellent activity of inhibiting retinal endothelial cell proliferation with up to 72nM of GI50. PMID- 27481564 TI - Effects of dietary manganese supplementation on nutrient digestibility and production performance in male sika deer (Cervus Nippon). AB - This study aimed to investigate the effects of manganese (Mn) supplementation on nutrient digestibility and antler growth in male sika deer. Twenty 3-year-old male sika deer were divided into four groups (Control, T40, T80 and T120). The control diet contained 22.2 mg Mn/kg. The treatment diets were supplemented with 40, 80 and 120 mg of Mn/kg (provided as Mn methionine). The results showed that the digestibility of dry matter and crude protein in the T80 group was greater than other groups. Higher digestibility of neutral detergent fiber and acid detergent fiber was observed in the T80 group than in the control group. Plasma Mn concentrations in the T80 and T120 groups were higher (P < 0.01) than control and T40 group (P < 0.01). The concentration of Mn in feces was increased with increasing Mn amount. Average daily gain of fresh antler and dry antler of T80 was greater than other groups, especially the control group (P < 0.05). In conclusion, the suitable level of Mn supplementation was found to be 80 mg/kg (total Mn content 103.4 mg/kg dry matter), which significantly increased antler daily gain and feed digestibility in 3-year-old sika deer. PMID- 27481563 TI - Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development. AB - Gene abnormalities in RBFOX1, encoding an mRNA-splicing factor, have been shown to cause autism spectrum disorder and other neurodevelopmental disorders. Since pathophysiological significance of the dominant nuclear isoform in neurons, RBFOX1-isoform1 (iso1), remains to be elucidated, we performed comprehensive analyses of Rbfox1-iso1 during mouse corticogenesis. Knockdown of Rbfox1-iso1 by in utero electroporation caused abnormal neuronal positioning during corticogenesis, which was attributed to impaired migration. The defects were found to occur during radial migration and terminal translocation, perhaps due to impaired nucleokinesis. Axon extension and dendritic arborization were also suppressed in vivo in Rbfox1-iso1-deficient cortical neurons. In addition, electrophysiology experiments revealed significant defects in the membrane and synaptic properties of the deficient neurons. Aberrant morphology was further confirmed by in vitro analyses; Rbfox1-iso1-konckdown in hippocampal neurons resulted in the reduction of primary axon length, total length of dendrites, spine density and mature spine number. Taken together, this study shows that Rbfox1-iso1 plays an important role in neuronal migration and synapse network formation during corticogenesis. Defects in these critical processes may induce structural and functional defects in cortical neurons, and consequently contribute to the pathophysiology of neurodevelopmental disorders with RBFOX1 abnormalities. PMID- 27481565 TI - Typical facial gestalt in X-linked Kabuki syndrome. PMID- 27481566 TI - Description of Antihypertensive Medication Use in a Pediatric Practice: Single and Multiple Antihypertensive Medication Therapy. AB - Prescription of multiple antihypertensive medications for the treatment of essential hypertension (HTN) has been well described in adults but not in children and adolescents. The authors describe the frequency with which children with essential HTN are prescribed a single vs two or more concomitantly administered antihypertensive medications. They also describe demographic features and comorbidities associated with the prescription of a single vs multiple antihypertensive medications. Multiple antihypertensive medication use in the management of pediatric HTN, as in the management of adult HTN, is not uncommon. In this single-center, retrospective study of 113 children with essential HTN, 28% of children were concomitantly prescribed two or more antihypertensive medications for poorly controlled blood pressure following prescription of a single medication. Demographic and comorbid conditions associated with the prescription of more than one antihypertensive medication include advanced hypertensive stage, race, and a family history of HTN. PMID- 27481567 TI - Supercritical fluid chromatography with tandem mass spectrometry combined with postcolumn compensation and one-step acetone protein precipitation to evaluate the bioavailability of probucol solid dispersion tablet. AB - Solid dispersion technology was used to improve the bioavailability of probucol due to its low hydrophilicity and high lipophilicity. In this study, a highly rapid and sensitive supercritical fluid chromatography with tandem mass spectrometry method was optimized and validated for the determination of probucol in beagle dog plasma with diazepam as an internal standard. The analyte and internal standard were extracted by acetone and then separated on a polar 2 ethylpyridine phase column (100 mm * 3 mm, 1.7 MUm) at a flow rate of 1.0 mL/min using CO2 (>=99.99%) and methanol (95:5, v/v) as the mobile phase. The mass transition ion-pair was m/z 515.6->236.2 and 285.2->193.1 for probucol and internal standard, respectively. Excellent linearity was observed over the concentration range of 5-5000 ng/mL (r2 >= 0.9999) with a lower limit of quantification of 5 ng/mL. The intra- and inter-day accuracy and precision for all quality control samples were within +/-15%. The proposed method was accurate, rapid and reproducible, which was successfully applied to a bioavailabilty evaluation of probucol solid dispersion tablets. PMID- 27481568 TI - Early supported discharge following mild stroke: a qualitative study of patients' and their partners' experiences of rehabilitation at home. AB - BACKGROUND: Early supported discharge (ESD) allows mild-to-moderate stroke patients to return home as soon as possible and continue rehabilitation at their own pace in familiar surroundings. Thus, the main responsibility for continued rehabilitation is in the hands of patients and their partners, who must collaborate to adjust to poststroke everyday life. However, couples' joint experiences of stroke, early discharge and rehabilitation at home remain minimally investigated. AIM: To investigate how mild stroke patients' and their partners' experience and manage everyday life in a context of ESD. METHODS: We conducted qualitative interviews with a purposive sample of 22 ESD patients and 18 partners. Interviews were conducted 3-6 weeks after stroke, and we used thematic analysis to analyse the data. FINDINGS: The analysis identified three themes. First, 'Home as a healing place' involved the couples' experiences of a well-informed discharge from hospital. They trusted the health professionals' assessment that the patient was ready to go home. They described home as a comforting and calm place, where recovery could meaningfully take place. The second theme, 'Flow of everyday life', comprised the experiences of adapting to and continuing everyday life. Most of the interviewees had relatively minor physical and cognitive impairments, and the patients and their partners were hopeful for a full recovery in the foreseeable future. Finally, 'Professional safety net' involved the much appreciated stroke team. Although most of the participants only had one visit from the team, knowing that they were an accessible resource was very important to the couples. CONCLUSION: ESD was experienced as a meaningful and adequate rehabilitation service that allowed patients and partners to collaboratively reinvent and rebuild their flow of everyday life by jointly adjusting routines, activities and their relationship. PMID- 27481569 TI - Development of an Advanced Primary Human In Vitro Model of the Small Intestine. AB - Intestinal in vitro models are valuable tools in drug discovery and infection research. Despite several advantages, the standard cell line-based Transwell((r)) models based for example on colonic epithelial Caco-2 cells, lack the cellular complexity and transport activity associated with native small intestinal tissue. An additional experimental set-back arises from the most commonly used synthetic membranes, on which the cells are routinely cultured. These can lead to an additional barrier activity during in vitro testing. To overcome these limitations, we developed an alternative primary human small intestinal tissue model. This novel approach combines previously established gut organoid technology with a natural extracellular matrix (ECM) based on porcine small intestinal scaffold (SIS). Intestinal crypts from healthy human small intestine were expanded as gut organoids and seeded as single cells on SIS in a standardized Transwell-like setting. After only 7 days on the ECM scaffold, the primary cells formed an epithelial barrier while a subpopulation differentiated into intestinal specific cell types such as mucus-producing goblet cells or hormone-secreting enteroendocrine cells. Furthermore, we tested the influence of subepithelial fibroblasts and dynamic culture conditions on epithelial barrier function. The barrier integrity was stabilized by coculture in the presence of gut-derived fibroblasts. Compared to static or dynamic culture on an orbital shaker, dynamic culture in a defined perfusion bioreactor had an additional significant impact on epithelial cell differentiation, indicated by high prismatic cell morphology and upregulation of CYP3A4 enzyme and Mdr1 transporter activity. In summary, more physiological tissue models as presented in our study might be useful tools in preclinical research and development. PMID- 27481570 TI - Mapping current research trends on anterior cruciate ligament injury risk against the existing evidence: In vivo biomechanical risk factors - Response to Letter to the Editor. PMID- 27481571 TI - Non-coplanar trajectories to improve organ at risk sparing in volumetric modulated arc therapy for primary brain tumors. AB - BACKGROUND AND PURPOSE: To evaluate non-coplanar volumetric modulated arc radiotherapy (VMAT) trajectories for organ at risk (OAR) sparing in primary brain tumor radiotherapy. MATERIALS AND METHODS: Fifteen patients were planned using coplanar VMAT and compared against non-coplanar VMAT plans for three trajectory optimization techniques. A geometric heuristic technique (GH) combined beam scoring and Dijkstra's algorithm to minimize the importance-weighted sum of OAR volumes irradiated. Fluence optimization was used to perform a local search around coplanar and GH trajectories, producing fluence-based local search (FBLS) and FBLS+GH trajectories respectively. RESULTS: GH, FBLS, and FBLS+GH trajectories reduced doses to the contralateral globe, optic nerve, hippocampus, temporal lobe, and cochlea. However, FBLS increased dose to the ipsilateral lens, optic nerve and globe. Compared to GH, FBLS+GH increased dose to the ipsilateral temporal lobe and hippocampus, contralateral optics, and the brainstem and body. GH and FBLS+GH trajectories reduced bilateral hippocampi normal tissue complication probability (p=0.028 and p=0.043, respectively). All techniques reduced PTV conformity; GH and FBLS+GH trajectories reduced homogeneity but less so for FBLS+GH. CONCLUSIONS: The geometric heuristic technique best spared OARs and reduced normal tissue complication probability, however incorporating fluence information into non-coplanar trajectory optimization maintained PTV homogeneity. PMID- 27481572 TI - The Effect of Fasting Duration on Baseline Blood Glucose Concentration, Blood Insulin Concentration, Glucose/Insulin Ratio, Oral Sugar Test, and Insulin Response Test Results in Horses. AB - OBJECTIVES: Published descriptions of the oral sugar test (OST) and insulin response test (IRT) have been inconsistent when specifying the protocol for fasting horses before testing. The purpose of our study was to examine the effect of fasting duration on blood glucose concentration, blood insulin concentration, glucose/insulin ratio, OST, and IRT results in horses. ANIMALS: Ten healthy adult horses. PROCEDURES: Both OST and IRT were performed on horses without fasting and after fasting for 3, 6, and 12 hours. Thus, 8 tests were performed per horse in a randomized order. Blood collected at the initial time point of the OST was analysed for both blood glucose and serum insulin concentrations so that baseline concentrations and the glucose/insulin ratio could be determined. Unless fasted, horses had free-choice access to grass hay. RESULTS: There was no effect of fasting and fasting duration on blood glucose concentration, serum insulin concentration, glucose/insulin ratio, or the OST. Response to insulin in the IRT was decreased in fasted horses. The effect increased with fasting duration, with the least response to insulin administration after a 12-hour fast. CONCLUSIONS AND CLINICAL RELEVANCE: These data indicate that insulin sensitivity is not a fixed trait in horses. Fasting a horse is not recommended for a glucose/insulin ratio or IRT, and fasting a horse for 3 hours is recommended for the OST. PMID- 27481574 TI - Pilot study of once-a-day prophylaxis for youth and young adults with severe haemophilia A. AB - INTRODUCTION: Standard prophylaxis has been shown to be an effective treatment for severe haemophilia A. According to pharmacokinetic principles, daily factor infusions of smaller doses can maintain similar trough factor VIII (FVIII) levels, and perhaps the same protection as standard prophylaxis. AIM: This multicentre study examined the feasibility of daily prophylaxis for youth and young adults with severe haemophilia A in Montreal and Toronto. METHODS: Bleeding rates, joint status, quality of life and physical activity were monitored for 14 patients during this study. At baseline, subjects continued their regular treatment regimen and switched to daily prophylaxis after 4 months; nine had begun daily prophylaxis before enrolment. Additional visits occurred at 8 and 12 months which included a physical examination, inhibitor testing, HJHS and FISH assessments, the CHO-KLAT/Haemo-QoL-A and PDPAR. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication ver.II and perceived difficulty questions at the end of study. RESULTS AND CONCLUSIONS: There were no significant changes in quality of life except for concerns with the demanding daily infusion schedule. The number of bleeds did not statistically differ from the initial 4 months of the study to the last 8 months. Monthly bleeding rates from the year prior to the study and during the intervention phase were not statistically different. It was also found that daily prophylaxis used 24% less FVIII compared to standard prophylaxis. Taking all of this into account, we have found that providing daily prophylaxis is feasible and that it is feasible to prospectively study daily prophylaxis in youth and young adults. PMID- 27481575 TI - Image-guided biopsy in primary lung cancer: Why, when and how. AB - Initial histopathological analysis of a pulmonary lesion is mandatory whenever a lung cancer is suspected in order to determine the optimal diagnostic strategy. Adequate material must be obtained for a definite histological diagnosis (preferable to a cytological one) and in some cases (mainly in adenocarcinoma) molecular analysis. The two main methods to obtain adequate biopsy samples are flexible bronchoscopy and computed tomography (CT)-guided lung biopsy. Flexible bronchoscopy is a valuable method for proximal tumors. On the other hand, CT guided lung biopsy is more accurate for peripheral tumors. CT-guided lung biopsy is a reliable procedure that conveys a 90% sensitivity for the diagnosis of lung cancer. When performed in a secured environment after contraindications evaluation, its severe complications rate is low, mainly consisting of pneumothorax requiring chest tube placement and hemoptysis. PMID- 27481576 TI - CT findings of cecal volvulus following laparoscopic appendectomy. PMID- 27481573 TI - Identification of disease-specific motifs in the antibody specificity repertoire via next-generation sequencing. AB - Disease-specific antibodies can serve as highly effective biomarkers but have been identified for only a relatively small number of autoimmune diseases. A method was developed to identify disease-specific binding motifs through integration of bacterial display peptide library screening, next-generation sequencing (NGS) and computational analysis. Antibody specificity repertoires were determined by identifying bound peptide library members for each specimen using cell sorting and performing NGS. A computational algorithm, termed Identifying Motifs Using Next- generation sequencing Experiments (IMUNE), was developed and applied to discover disease- and healthy control-specific motifs. IMUNE performs comprehensive pattern searches, identifies patterns statistically enriched in the disease or control groups and clusters the patterns to generate motifs. Using celiac disease sera as a discovery set, IMUNE identified a consensus motif (QPEQPF[PS]E) with high diagnostic sensitivity and specificity in a validation sera set, in addition to novel motifs. Peptide display and sequencing (Display-Seq) coupled with IMUNE analysis may thus be useful to characterize antibody repertoires and identify disease-specific antibody epitopes and biomarkers. PMID- 27481577 TI - Outcomes of transjugular intrahepatic portosystemic shunt creation for flow enabled dissolution of spleno-mesenterico-portal venous thrombosis. AB - PURPOSE: To evaluate the outcomes of transjugular intrahepatic portosystemic shunt (TIPS) for flow-enabled clearance of portal (PVT), splenic (SVT) and/or superior mesenteric (MVT) vein thrombosis. PATIENTS AND METHODS: In this single center study, 12 patients underwent TIPS using Viatorr covered stent-grafts (W.L. Gore & Associates, Flagstaff, AZ, USA) from 2008-2014 for PVT as a primary (n=8) or secondary (n=4) indication. TIPS were not accompanied by pharmacomechanical clot disruption; rather, shunts served to increase portal blood flow to allow flow-mediated physiologic clot dissolution. Pre- and post-TIPS cross-sectional imaging were used to assess clot location, size, and clearance, defined by resolution (vessel patency with no clot), reduction (decrease in clot size), stability (no change in clot size), or extension (increase in clot size). RESULTS: The cohort included 5 men and 7 women (median age 63 years, range 45-73 years, median MELD score 15) with 30 non-occlusive and asymptomatic thrombi spanning main or intrahepatic PVT (n=15/30, 50%), SVT (n=6/30, 20%), and MVT (n=9/30, 30%). TIPS were generally created with 10mm covered stent-grafts; mean final portosystemic pressure gradient was 8mmHg. At mean 190 days post-TIPS, 58% (n=7/12) had clot resolution, 33% (n=4/12) had clot reduction, and 8% (n=1/12) had stable clot; there were no cases of clot extension. Resolution rate was 67% for PVT (10/15), SVT (4/6), and MVT (6/9). Two of 12 (17%) patients underwent successful liver transplant post-TIPS. CONCLUSION: TIPS prompts dissolution of or decrease in PVT, SVT, and MVT in cirrhotic patients. This may be a useful approach notwithstanding omission of pharmacomechanical methods. PMID- 27481578 TI - Spatiotemporal dynamics of urban green spaces and human-wildlife conflicts in Tokyo. AB - Although urban green spaces are increasingly important both for humans and wildlife, an increase in urban green spaces may also increase human-wildlife conflicts in urban areas. However, few studies have examined the relationship between the size of green spaces and the level of conflicts with wildlife in multiple taxa, including invertebrates and vertebrates. To better understand current pest statistics and predict changes that will occur as the area of green spaces increases, we analysed a dataset compiling the number of pest consultations in 53 metropolitan districts in Tokyo over a 20-year period and its relationships with the area of green space. Stinging insects (e.g., wasps) made up over 50% of pest consultations, followed (in order) by rats and other nuisance animals (e.g., snakes). The number of consultations per unit population did not correlate, or was even negatively correlated, with the proportions of green spaces (mainly forest) for many indoor pests, but did positively correlate for some outdoor pests, such as wasps and snakes. Therefore, wasps and snakes can increase when urban green spaces increase. Because even minor nuisances are relevant for urban lifestyles, considerations of ways to minimise conflicts with wildlife are critical for urban green space management. PMID- 27481579 TI - Efficacy of adjuvant chemotherapy in early stage uterine leiomyosarcoma: A systematic review and meta-analysis. AB - OBJECTIVE: We sought to review the current evidence in order to test the efficacy of adjuvant chemotherapy in improving disease-free survival in patients affected by early stage uterine leiomyosarcoma. METHODS: On July 2016, literature was searched in order to identify trials comparing different postoperative adjuvant strategies for patients diagnosed with early stage uterine leiomyosarcoma. RESULTS: Our analysis included 360 patients: 145 (40%), 53 (15%), and 155 (43%) had chemotherapy (with or without radiotherapy), radiotherapy, and observation, respectively. Seven (2%) patients who had radiotherapy with or without chemotherapy were excluded from further analysis in order to reduce risk of biases. Administration of chemotherapy (with or without radiotherapy) did not improve outcomes in comparison to observation (OR: 0.79 (95%CI: 0.48, 1.29)), or radiotherapy (OR: 0.90 (95%CI: 0.42, 1.94)). Loco-regional recurrence rate was similar comparing patients undergoing chemotherapy (with or without radiotherapy) with having observation alone (OR: 0.84 (95%CI: 0.44, 1.60)). Similarly, pooled results suggested that chemotherapy administration did not affect distant recurrence rate in comparison to no chemotherapy (OR: 0.80 (95%CI: 0.50, 1.28)), and observation alone (OR: 0.99 (95%CI: 0.60, 1.64)). However, patients undergoing chemotherapy (with or without radiotherapy) experienced a trend towards lower risk of developing distant recurrences (OR: 0.49 (95%CI: 0.24, 1.03)) and a higher risk of developing loco-regional recurrences (OR: 3.45 (95%CI: 1.02, 11.73)) than patients undergoing radiotherapy. CONCLUSIONS: In early stage uterine leiomyosarcoma, the role of adjuvant chemotherapy remains unclear. Owing to the high recurrence rate, even in the early stage of disease, further innovative therapeutic strategies have to be tested. PMID- 27481580 TI - Sry and SoxE genes: How they participate in mammalian sex determination and gonadal development? AB - In mammals, sex determination defines the differentiation of the bipotential genital ridge into either testes or ovaries. Sry, the mammalian Y-chromosomal testis-determining gene, is a master regulator of male sex determination. It acts to switch the undifferentiated genital ridge towards testis development, triggering the adoption of a male fate. Sry initiates a cascade of gene networks through the direct regulation of Sox9 expression and promotes supporting cell differentiation, Leydig cell specification, vasculature formation and testis cord development. In the absence of Sry, alternative genetic cascades, including female sex-determining genes RSPO1, Wnt4/beta-catenin and Foxl2, are involved in the formation of female genitalia and the maintenance of female ovarian development. The mutual antagonisms between male and female sex-determining pathways are crucial in not just the initiation but also the maintenance of the somatic sex of the gonad throughout the organism's lifetime. Any imbalances in above sex-determining genes can cause disorders of sex development in humans and mice. In this review, we provide a detailed summary of the expression profiles, biochemical properties and developmental functions of Sry and SoxE genes in embryonic testis development and adult gonadal development. We also briefly summarize the dedicate balances between male and female sex-determining genes in mammalian sex development, with particular highlights on the molecular actions of Sry and Sox9 transcription factors. PMID- 27481581 TI - Quantitative modelling of epithelial morphogenesis: integrating cell mechanics and molecular dynamics. AB - Epithelial tissues form and repair in complex processes influenced by molecular and physical factors. Recent years have witnessed the development of new microscopy modalities that push the limits of spatial resolution, and enable long term monitoring of developing animals. Increasingly, methods from the physical sciences are used to investigate the role of mechanical forces in living organisms. The application of these new technologies to developmental biology has led to ever-expanding volumes of data that must be interpreted and integrated. For these reasons, computer models are being applied to investigate tissue morphogenesis. Here, we discuss the use of vertex models to study the morphogenesis of epithelial tissues. We motivate the use of computational models and consider their advantages and limitations. We provide an introduction to the theoretical foundation of vertex models and describe how they can integrate mechanical and biochemical dynamics. Finally, we review recent advances in the application of vertex models to investigate dorsal closure, a morphogenetic process in the Drosophila embryo with parallels to both embryonic development and wound repair in vertebrate organisms. PMID- 27481583 TI - Novel association between the nonsynonymous A803G polymorphism of the N acetyltransferase 2 gene and impaired glucose homeostasis in obese children and adolescents. AB - BACKGROUND: The N-acetyltransferase 2 ( NAT2 ) A803G polymorphism has been associated with decreased insulin sensitivity in a large adult population with the A allele associated with insulin-resistance-related traits. OBJECTIVE: Evaluate the association of this polymorphism with anthropometric and metabolic parameters in obese children and adolescents. SUBJECTS: A total of 748 obese children and adolescents were enrolled. METHODS: Anthropometric and laboratory data were collected. During oral glucose tolerance test, the presence of a possible exaggerated plasma glucose excursion at 1 h (1HPG) or impaired glucose tolerance (IGT) was considered. Homeostasis model assessment, oral disposition index (oDI) and insulinogenic index (IDI) were calculated. Patients were genotyped for the NAT2 A803G polymorphism. RESULTS: The prevalence of both IGT and elevated-1HPG was higher in children carrying the A803 allele (P = .02 and P = .03). Moreover, this allele was associated with both oDI and IGI reduction (P = .01). No differences among the NAT2 A803G genotypes for the other parameters were shown. Children homozygous for the A allele presented an odds ratio (OR), to show IGT of 4.9 (P = .01). Children both homozygous and heterozygous for the A allele had higher risk to show elevated-1HPG (OR of 2.7, P = .005; and OR = 2.3, P = .005) compared with patients homozygous for the NAT2 803G allele. CONCLUSIONS: NAT2 A803 allele seems to play a role in worsening the destiny of obese children carrying it, predisposing them to elevated-1HPG and IGT and then to a possible future type 2 diabetes mellitus throughout an impairment of pancreatic beta cellular insulin secretion as suggested by oDI and IGI reduction. PMID- 27481582 TI - Polymer microfiber meshes facilitate cardiac differentiation of c-kit(+) human cardiac stem cells. AB - Electrospun microfiber meshes have been shown to support the proliferation and differentiation of many types of stem cells, but the phenotypic fate of c-kit(+) human cardiac stem cells (hCSCs) have not been explored. To this end, we utilized thin (~5um) elastomeric meshes consisting of aligned 1.7um diameter poly (ester urethane urea) microfibers as substrates to examine their effect on hCSC viability, morphology, proliferation, and differentiation relative to cells cultured on tissue culture polystyrene (TCPS). The results showed that cells on microfiber meshes displayed an elongated morphology aligned in the direction of fiber orientation, lower proliferation rates, but increased expressions of genes and proteins majorly associated with cardiomyocyte phenotype. The early (NK2 homeobox 5, Nkx2.5) and late (cardiac troponin I, cTnI) cardiomyocyte genes were significantly increased on meshes (Nkx=2.5 56.2+/-13.0, cTnl=2.9+/-0.56,) over TCPS (Nkx2.5=4.2+/-0.9, cTnl=1.6+/-0.5, n=9, p<0.05 for both groups) after differentiation. In contrast, expressions of smooth muscle markers, Gata6 and myosin heavy chain (SM-MHC), were decreased on meshes. Immunocytochemical analysis with cardiac antibody exhibited the similar pattern of above cardiac differentiation. We conclude that aligned microfiber meshes are suitable for guiding cardiac differentiation of hCSCs and may facilitate stem cell-based therapies for treatment of cardiac diseases. PMID- 27481584 TI - Pernicious anemia and colorectal cancer risk - A nested case-control study. AB - BACKGROUND: Hypergastrinemia was shown to stimulate colonic epithelial cell proliferation. AIMS: To evaluate the association between pernicious anemia (PA), a disease with hypergastrinemia, and colorectal cancer (CRC) risk. METHODS: We conducted a nested case-control study within a large database from the UK. Cases were defined as all individuals in the cohort with at least one medical code for CRC. Controls were selected based on incidence-density sampling. For each case, up to four eligible controls were matched on age at diagnosis, sex, practice site, and both duration and calendar time of follow-up. Exposure of interest was diagnosis of PA prior to CRC diagnosis date. The primary analysis was a multivariable conditional logistic regression. RESULTS: Our study included 22,098 CRC cases and 85,969 matched controls. We identified 154 (0.70%) cases and 563 (0.65%) controls with past history of PA. The adjusted OR for the association between PA and CRC risk was 1.02 (95% CI 0.85-1.22). There was no difference in the results after stratification according to sex. In a sensitivity analysis only among individuals without chronic use of proton pump inhibitors (PPIs) the adjusted OR was 1.14 (95% CI 0.90-1.45). There was no association between duration of PA and CRC risk. CONCLUSION: PA is not associated with higher CRC risk. PMID- 27481585 TI - Acceptance, yield and feasibility of attaching HCV birth cohort screening to colorectal cancer screening in Spain. AB - INTRODUCTION: The US Centers for Disease Control recommends hepatitis C virus (HCV) screening for baby boomers. Spain presents a similar distribution of infected patients. We performed a cross sectional prospective study to evaluate the prevalence of undiagnosed HCV infection in subjects born between 1949 and 1974. METHODS: All out-patients within the age range, both symptomatic and screening procedures, undergoing colonoscopy between December 2014 and June 2015 were offered a HCV antibody blood test and a survey including risk factors for HCV infection and attitude toward HCV screening. Patients with chronic HCV or with a previous negative HCV antibody test were excluded. RESULTS: A total of 570 subjects, 50% screening procedures, were analyzed. The median age was 55.7, 94.6% were born in Spain and 54.6% were women. Antibodies against HCV were found in 1.6% (95% CI: 0.8-3%) and HCV-RNA in 0.4% (0.1-1.3%). We found no statistically significant differences regarding HCV prevalence, risk factors or socioeconomic characteristics between subjects undergoing colorectal cancer screening and symptomatic subjects. CONCLUSION: Symptomatic and screening subjects undergoing colonoscopy support HCV screening and present a similar HCV risk profile. Results suggest linking colorectal and HCV screening would yield good results. PMID- 27481586 TI - Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis. AB - BACKGROUND: Cytokine-induced killer cells have been used as an adjuvant treatment for hepatocellular carcinoma with curative treatment. However, the outcomes remain controversial. AIM: We conducted this meta-analysis to assess the safety and efficacy of cytokine-induced killer cells. METHODS: Randomized controlled trials on cytokine-induced killer cells for hepatocellular carcinoma after curative treatments were identified by electronic searches. A meta-analysis was carried out to examine disease-free survival, overall survival rate and adverse effect. RESULTS: Six randomized controlled trials with 844 patients (85.9% with hepatitis B or C) were included. Our meta-analysis showed that cytokine-induced killer cells can not only improve the 1-year (RR=1.23, P<0.001), 2-year (RR=1.37, P<0.001) and 3-year (RR=1.35, P=0.004) disease-free survival, but also improve the 1-year (RR=1.08, P=0.001), 2-year (RR=1.14, P<0.001) and 3-year (RR=1.15, P=0.02) overall survival. However, it failed to affect the 4-year and 5-year disease-free survival and overall survival (P>0.05). At the same time, cytokine induced killer cells treatment was proved to be a safe strategy with the comparable adverse events comparing to the control group (P=0.39). CONCLUSIONS: This review provides the best available evidence that adjuvant cytokine-induced killer cells treatment can be safely used to improve the early disease-free survival and survival of hepatitis B or C related hepatocellular carcinoma. PMID- 27481587 TI - Nationwide prevalence and drug treatment practices of inflammatory bowel diseases in Hungary: A population-based study based on the National Health Insurance Fund database. AB - BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases associated with a substantial healthcare utilization. AIM: Our aim was to estimate the national prevalence of inflammatory bowel disease (IBD), CD and UC and to describe current drug treatment practices in CD and UC. METHODS: Patients and drug dispensing events were identified according to international classification codes for UC and CD in in-patient care, non-primary out-patient care and drug prescription databases (2011-2013) of the National Health Insurance Fund. RESULTS: A total of 55,039 individuals (men: 44.6%) with physician-diagnosed IBD were alive in Hungary in 2013, corresponding to a prevalence of 0.55% (95% CI, 0.55-0.56). The prevalence of CD 0.20% (95% CI, 0.19 0.20), and UC was 0.34% (95% CI, 0.33-0.34). The prevalence both in men and women was the highest in the 20-39 year-olds in CD. Current use of immunosuppressives and biological therapy was highest in the pediatric CD population (44% and 15%) followed by adult CD (33% and 9%), while their use was lowest in elderly patients. Interestingly, current use of 5-ASA (5-aminosalicylates) was high in both UC and CD irrespective of the age group. CONCLUSIONS: The Hungarian IBD prevalence based on nationwide database of the National Health Insurance Fund was high. We identified significant differences in the drug prescription practices according to age-groups. PMID- 27481588 TI - Total and cancer mortality in a cohort of ulcerative colitis and Crohn's disease patients: The Florence inflammatory bowel disease study, 1978-2010. AB - BACKGROUND: There is no consensus on the leading causes of death among inflammatory bowel diseases (IBD) patients. AIM: We present the results of an extended follow-up of the population-based Florence IBD cohort, including 689 ulcerative colitis and 231 Crohn's disease patients. METHODS: The causes of death of cohort members were determined through linkage with the local mortality registry. We calculated standardized mortality ratios (SMR) and 95% confidence intervals (95%CI) by applying gender-, age- and calendar time-death rates to person-years at risk. RESULTS: Ulcerative colitis patients had overall mortality comparable to the general population (SMR 0.99, 95%CI 0.85-1.14), though being at increased risk of dying from Hodgkin's disease (SMR 11.74, 95%CI 2.94-46.94), rectal cancer (SMR 3.69, 95%CI 1.66-8.22) and Alzheimer's disease (2.40, 95%CI 1.00-5.76). Crohn's disease patients had an increased overall mortality (SMR 1.79, 95%CI 1.39-2.27) and were at higher risk of dying from cancer (SMR 2.57, 95%CI 1.28-5.13) and non-cancer diseases of the respiratory system (SMR 2.51, 95%CI 1.05-6.04), brain cancer (SMR 6.26, 95%CI 1.57-25.02) and non-cancer diseases of the genitourinary system (SMR 4.38, 95%CI 1.10-17.52). CONCLUSIONS: IBD patients should be offered counselling on risk reduction strategies, as much of their mortality excess is potentially avoidable. PMID- 27481589 TI - Computational Resources for MHC Ligand Identification. AB - Advances in the high-throughput determination of functional modulators of major histocompatibility complex (MHC) and improved computational predictions of MHC ligands have rendered the rational design of immunomodulatory peptides feasible. Proteome-derived peptides and 'reverse vaccinology' by computational means will play a driving role in future vaccine design. Here we review the molecular mechanisms of the MHC mediated immune response, present the computational approaches that have emerged in this area of biotechnology, and provide an overview of publicly available computational resources for predicting and designing new peptidic MHC ligands. PMID- 27481590 TI - A Crowd-Based Process and Tool for HTS Hit Triage. PMID- 27481591 TI - Comparative Analysis of Cluster Validity Indices in Identifying Some Possible Genes Mediating Certain Cancers. AB - In this article, we compare the performance of 19 cluster validity indices, in identifying some possible genes mediating certain cancers, based on gene expression data. For the purpose of this comparison, we have developed a method. The proposed method involves cluster generation, selection of the best k-value or c-values, cluster identification, identifying the altered gene cluster, scoring an altered gene cluster and determining the best k-value or c-value exploring through biological repositories. The effectiveness of the method has been demonstrated on three gene expression data sets dealing with human lung cancer, colon cancer, and leukemia. Here, we have used three clustering algorithms, i.e., k-means, PAM and fuzzy c-means. We have used biochemical pathways related to these cancers and p-value statistics for validating the study. PMID- 27481592 TI - Structural Key Bit Occurrence Frequencies and Dependencies in PubChem and Their Effect on Similarity Searches. AB - Little published literature exists on the 881 bit structural keys used by PubChem for categorizing and comparing the compounds present in its database. We characterized these structural keys by examining their frequencies of occurrence within the PubChem compound database. In addition, bit dependencies, defined as the universal presence of a bit given the presence of another, were determined. We show that the vast majority of bits are rarely set and that substantial numbers of dependencies exist. A comparison of similarity searches with five United States Food and Drug Administration approved drugs as reference compounds using the full structural keys versus a variant in which all dependent bits were removed was performed using the Tanimoto coefficient. These bit dependencies not only affect similarity scores, but also alter the compounds returned in similarity searching. Judicious selection of bits is needed to maintain sufficient ability to differentiate related compounds. PMID- 27481593 TI - Predicting pKa Values in Aqueous Solution for the Guanidine Functional Group from Gas Phase Ab Initio Bond Lengths. AB - Here we applied a novel method1a to predict pKa values of the guanidine functional group, which is a notoriously difficult. This method, which was developed in our lab, uses only one ab initio bond length obtained at a low level of theory. The method is shown to work for drug molecules, delivers prediction errors of less than 0.5 log units, successfully treats tautomerisation in close relation with experiment, and demonstrates strong correlations with only a few data points. The high structural content of the ab initio bond length makes a given data set essentially divide itself into high correlation subsets. One then observes that molecules within a subset possess a common substructure. Each high correlation subset exists in its own region of chemical space. The high correlation subset method is explored with respect to this position in chemical space, in particular tautomerisation. The proposed method is able to distinguish between different tautomeric forms and the preferred tautomeric form emerges naturally, in agreement with experiment. PMID- 27481594 TI - Molecular Modeling and Active Site Binding Mode Characterization of Aspartate beta-Semialdehyde Dehydrogenase Family. AB - The enzyme aspartate beta-semialdehyde dehydrogenase (ASADH) plays a vital role in biosynthesis of essential amino acids and several important metabolites in microbes and some higher plants. So this key enzyme can be targeted selectively in these microbes to exhibit anti-bacterial and fungicidal effects. In this work, molecular modeling and comparative active site binding mode studies were performed for understanding the mode of action, in silico insight into the 3D structure, enzyme-substrate interactions with natural substrate in this homologous enzyme family. During comparative sequence analysis, high diversity was found in the sequences of different ASADHs and exhibited the same key binding interactions with the substrate. Both, the functional carboxylic and the phosphate group of the substrate are engaged in a bidentate interaction with the guanidinium N atom of two key arginyl active site residues of ASADHs. These structural and active site binding mode characterization studies can further be used for designing the more potent and selective substrate analogues inhibitors against ASADH family. PMID- 27481595 TI - Multiple e-Pharmacophore Modeling Combined with High-Throughput Virtual Screening and Docking to Identify Potential Inhibitors of beta-Secretase(BACE1). AB - beta-Secretase (BACE1) is an aspartate protease involved in the production of amyloid-beta a major peptide responsible for the pathogenesis of Alzheimer's disease. Given its role in the formation of amyloids leading to Alzheimer's disease, it has been a major therapeutic target for intervention and has been a challenge in the past and the progress has been very slow. More than hundred crystal structures with inhibitors are available in the protein data bank. Many strategies for drug design have been employed in the design of numerous diverse ligands for this target and many have failed due to undesirable drug properties primarily the inability to cross the blood-brain barrier. In the present work we attempted to consider multiple crystal structures with bound inhibitors showing affinity in the range of 2-210 nM efficacy and optimize the pharmacophoric requirement based on the energy involved in binding termed as e-pharmacophore mapping. A high throughput screening combined with molecular docking, ADMET predictions, logP values and in vitro assay led to the identification of 7 potential compounds showing inhibition at 10uM which could be further developed as novel inhibitors for beta-secretase. PMID- 27481596 TI - Corrigendum to "Clinical Effectiveness of Tolvaptan in Patients With Acute Heart Failure and Renal Dysfunction" Journal of Cardiac Failure, Vol. 22, No. 6, June 2016, pp. 423-432. PMID- 27481597 TI - Real time PCR assay for detection of all known lineages of West Nile virus. AB - West Nile virus (WNV) is one of the most widespread arbovirus and a large variety of WNV strains and lineages have been described. The molecular methods for the diagnosis of WNV target mainly lineages 1 and 2, which have caused outbreaks in humans, equines and birds. But the last few years new and putative WNV lineages of unknown pathogenicity have been described. Here we describe a new sensitive and specific real-time PCR assay for the detection and quantification of all the WNV lineages described until now. Primers and probe were designed in the 3' untranslated region (3'-UTR) of the WNV genome and were designed to match all sequenced WNV strains perfectly. The sensitivity of the assay ranged from 1,5 to 15 copies per reaction depending on the WNV lineage tested. The method was validated for WNV diagnosis using different viral strains, human samples (cerebrospinal fluid, biopsies, serum and plasma) and mosquito pools. The assay did not amplify any other phylogenetically or symptomatically related viruses. All of the above make it a very suitable tool for the diagnosis of WNV and for surveillance studies. PMID- 27481598 TI - Influence of Prior Cervical Surgery on Surgical Outcome of Endoscopic Posterior Cervical Foraminotomy for Osseous Foraminal Stenosis. AB - BACKGROUND: Posterior cervical foraminotomy is a valuable option as a treatment for cervical radiculopathy caused by osseous foraminal stenosis. Here the authors present their technique and results in a series of patients with and without previous surgery. METHODS: Forty-five patients suffering from cervical osseous foraminal stenosis were operated on via a microendoscopic posterior approach with the EasyGO system. All procedures were video recorded and afterwards retrospectively analyzed. The primary evaluation criterion was prior surgery or no prior surgery. Additionally, postoperative outcome according to Odom's criteria and Neck Disability Index (NDI), reoperation rate, and complications was considered. RESULTS: The 45 patients of this study showed an overall clinical success rate of 84%. There was no emergency stopping of any endoscopic procedure. Twenty patients (44.4%) had no and 25 patients (55.6%) had previous cervical surgery. In patients without previous surgery, the clinical success rate was 95.2%; NDI was 12%; and 100% of patients reported reduction of their preoperative arm pain and motor recovery. In patients with previous surgery, the clinical success rate was 75%. NDI was 24%. Most patients (91.7%) reported reduction of their preoperative arm pain, and 66.7% reported recovery of motor strength. CONCLUSION: This retrospective analysis shows that microendoscopic posterior cervical foraminotomy is a successful option in the treatment of osseous cervical foraminal stenosis. Nevertheless, clinical success in patients with previous surgery is much lower compared with patients without previous surgery. Thus, a more thorough clinical workup is recommended to identify the patients who are not going to benefit before subsequent surgical procedures. PMID- 27481599 TI - Association Between Vitamin D Deficiency and Outcomes Following Spinal Fusion Surgery: A Systematic Review. AB - BACKGROUND: Vitamin D deficiency is a relatively common occurrence in patients presenting for spinal surgery; however, whether this abnormality has any effect on spinal fusion outcomes remains unclear. We performed a systematic review of the available literature relevant to the association between vitamin D deficiency and spinal fusion outcomes. METHODS: We conducted a systematic and critical review of recent literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following databases were searched: MEDLINE/PubMed, Google Scholar, Cochrane, Web of Science, and Scopus. Key search terms were "vitamin D," "spinal surgery outcomes," "spinal fusion," and "pseudarthrosis." Papers included in the review were original research articles in peer-reviewed journals. The articles were thoroughly examined and compared on the basis of study design, outcomes, and results. RESULTS: A total of 5 studies were included in the qualitative analysis. In these studies, patients presenting with vitamin D deficiency achieved lower fusion rates and suffered higher rates of recurrent-persistent low back pain compared with patients with normal vitamin D levels. Studies examining the effect of postoperative vitamin D supplementation in deficient patients reported significant improvements in low back pain intensity, patient-reported outcomes scores, and fusion rates compared with baseline as well as with control groups. CONCLUSIONS: The literature suggests that patients presenting for spinal fusion may benefit from correction of vitamin D deficiency to maximize the chance of a successful arthrodesis and to achieve optimal surgical outcomes. Future prospective studies are needed to determine whether routine preoperative treatment of this metabolic derangement is warranted. PMID- 27481600 TI - Minimally Invasive Surgical Management of Thoracic Ossification of the Ligamentum Flavum Associated with X-linked Hypophosphatemia. AB - BACKGROUND: X-linked hypophosphatemia (XLH) is the most common inherited form of renal phosphate wasting and inherited rickets. Patients have hyperplasia of fibrochondrocytes in tendons and ligaments, causing the structures to thicken and calcify. Thickening of the lamina, hypertrophy of facet joints, and calcification of spinal ligaments are sequelae of this condition and can result in central or foraminal stenosis that compresses nerve roots or the spinal cord. We present a case of XLH with calcification of the ligamentum flavum in which the patient was operated on using minimally invasive posterior decompression. CASE DESCRIPTION: A 49-year-old man with a history of XLH presented to our emergency department with symptomatic myelopathy from multilevel thoracic stenosis. Radiographically, the calcified ligamentum flavum appeared to be the cause of the stenosis at various levels. The patient underwent a posterior decompression at the levels of compression, T4-T5, T8-T9, T9-T10, and T11-T12, via a minimally invasive spine surgery approach. Intraoperatively, the ligamentum flavum appeared to be both calcified and the source of spinal compression. Postoperatively, the patient experienced neurologic and radiographic improvement. CONCLUSION: Patients with a history of XLH and multilevel symptomatic spine stenosis can be treated successfully and safely with a minimally invasive posterior decompression. PMID- 27481601 TI - Combined Endoscopic Transoral and Endonasal Approach to the Jugular Foramen: A Multiportal Expanded Access to the Clivus. AB - BACKGROUND: The expanded endoscopic endonasal ("far medial") approach to the inferior clivus provides a unique surgical corridor to the ventral surface of the pontomedullary and cervicomedullary junctions. However, exposing neoplasms involving the jugular foramen (JF) through this approach requires extensive nasopharyngeal resection and lateral dissection beyond the boundaries of the endonasal corridor, limiting the extent of resection and restricting to use of this approach to expert surgeons. Here we describe a multiportal endoscopic transoral and endonasal approach to maximize surgical access to the JF and clivus. METHODS: A multiportal endoscopic transoral and endoscopic approach to the JF and lower clivus was simulated in 8 specimens. A transoral corridor was created through a soft palate incision. The JF and parapharyngeal space were dissected through the transoral trajectory under endoscopic endonasal view. The length of the corridor of the transnasal and transoral trajectories was measured. RESULTS: The JF was exposed intracranially and extracranially. The exposure extended superiorly to the sphenoid floor, inferiorly to the anterior atlanto occipital space, and laterally to the internal acoustic meatus and parapharyngeal space. The cisternal parts of the cranial nerves VII-XII and C1 nerve bundles were accessible. Exposure of the JF contents and parapharyngeal space was possible using straight scopes, without Eustachian tube resection. The working corridor to the JF was significantly shorter through the mouth than through the nose (P < 0.0001). CONCLUSIONS: This approach provides access to the JF from a ventromedial trajectory, enabling panoramic views, and outlines an expanded surgical exposure (superolateral intradural and inferolateral extracranial). It may provide optimal access for resection of dumbbell-shaped lesions of the JF. PMID- 27481602 TI - Pd-PEPPSI-IHept(Cl) : A General-Purpose, Highly Reactive Catalyst for the Selective Coupling of Secondary Alkyl Organozincs. AB - Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3 chloropyridyl)palladium(II) (Pd-PEPPSI-IHept(Cl) ), a new, very bulky yet flexible Pd-N-heterocyclic carbene (NHC) complex has been evaluated in the cross coupling of secondary alkylzinc reactants with a wide variety of oxidative addition partners in high yields and excellent selectivity. The desired, direct reductive elimination branched products were obtained with no sign of migratory insertion across electron-rich and electron-poor aromatics and all forms of heteroaromatics (five and six membered). Impressively, there is no impact of substituents at the site of reductive elimination (i.e., ortho or even di-ortho), which has not yet been demonstrated by another catalyst system to date. PMID- 27481603 TI - Changes in nail keratin observed by Raman spectroscopy after Nd:YAG laser treatment. AB - Lasers and photodynamic therapy have been considered a convergence treatment for onychomycosis, which is a fungal infection on the nail bed and nail plate. Laser therapies have shown satisfactory results without significant complications for onychomycosis; however, the mechanism of clearing remains unknown. In this work, we investigated changes in the chemical structure of nail keratin induced by Nd:YAG laser using Raman spectroscopy. Toe nails with onychomycosis were treated with 1064 nm Nd:YAG laser. After laser treatment, the disulfide band (490-590 cm 1 ) of nail keratin was rarely observed or was reduced in intensity. The amide I band (1500-1700 cm-1 ) also showed changes induced by the laser. The alpha helical (1652 cm-1 ) structures dominated the beta-sheet (1673 cm-1 ) in nontreated nail, but the opposite phenomenon was observed after laser treatment. PMID- 27481604 TI - Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity. PMID- 27481606 TI - Errata. PMID- 27481605 TI - SNMMI Procedure Standard/EANM Practice Guideline for Amyloid PET Imaging of the Brain 1.0. PMID- 27481618 TI - Uptake of childhood influenza vaccine from 2012-2013 to 2014-2015 in the UK and the implications for high-risk children: a retrospective observational cohort study. AB - OBJECTIVES: To evaluate changes in influenza vaccination rates in healthy and at risk children following the implementation of the UK's childhood influenza immunisation programme. DESIGN: Observational cohort study before and after initiation of the UK's childhood influenza immunisation programme over three influenza seasons (2012-2013, 2013-2014 and 2014-2015) using data from the Clinical Practice Research Datalink (CPRD). SETTING: More than 500 primary care practices in the UK. POPULATION: All individuals aged 2-17 years on 1 September, with at least 12 months of medical history documented in CPRD were retained in the analysis. INTERVENTION: Starting in 2013-2014, all children aged 2 and 3 years were offered influenza vaccination through general practice, and primary school-aged children were offered influenza vaccination in selected counties in England (described as pilot regions). The vaccination programme was extended to all children aged 4 years in England in 2014-2015. MAIN OUTCOME MEASURE: Cumulative vaccination rate from 1 September to 28 February of the next calendar year as assessed by a time-to-event statistical model (vaccination uptake). Age group, sex, region and type of high-risk medical condition were assessed as predictors. RESULTS: Vaccination uptake increased considerably from 2012-2013 to 2013-2014 in targeted children aged 2-3 years, both in children with a high-risk medical condition (from 40.7% to 61.1%) and those without (from 1.0% to 43.0%). Vaccination rates increased also, though less markedly, in older children. In 2014-2015, vaccination rates remained higher than 40% in healthy children aged 2 3 years, although they decreased slightly from 2013-2014 (from 43.0% to 41.8%). Vaccination rates in older healthy children continued to increase, driven primarily by an increase in children aged 4 years to 31.3% in 2014-2015. CONCLUSIONS: The introduction of a universal childhood vaccination policy in the UK increased vaccination rates for targeted children, including those with high risk conditions. PMID- 27481619 TI - Provision of care for chronic kidney disease by non-nephrologists in a developing nation: a national survey. AB - OBJECTIVES: The prevalence of chronic kidney disease (CKD) in developing countries has increased dramatically. This study aimed to explore the practice patterns of non-dialysis-dependent CKD care in an affluent developing country. SETTINGS: Primary and specialised healthcare facilities of public and private sectors in the United Arab Emirates. PARTICIPANTS: 159 non-nephrologist physicians practising in the United Arab Emirates. INTERVENTIONS: A 28-item online self-administered questionnaire based on CKD clinical practice guidelines. PRIMARY AND SECONDARY OUTCOME MEASURES: The physicians' approach to identifying and managing patients with CKD. RESULTS: The survey was completed by 159 non nephrologists, of whom 135 reported having treated patients with CKD. Almost all the respondents screen patients with hypertension and diabetes for CKD, but one third of them do not screen patients with cardiovascular disease and elderly patients for CKD. The use of accurate CKD screening tests (estimated glomerular filtration rate and albumin/creatinine ratio) was suboptimal (77% and 59% of physicians used the procedures, respectively). One-third of the physicians do not offer treatment with inhibitors of the renin-angiotensin system to patients with CKD, and only 66% offer antilipid treatment. In general, the primary healthcare physicians are more familiar than secondary healthcare physicians with the diagnosis and management of patients with CKD. CONCLUSIONS: We identified substantial physician-declared deficiencies in the practice of identifying and managing early CKD. Integration of quality CKD care within the healthcare system is required to face the increasing burden of CKD in the United Arab Emirates and possibly in other developing nations. PMID- 27481620 TI - Are schools and alcohol a good mix? A qualitative study of school principals' experiences of adults' alcohol use in Australian secondary schools. AB - OBJECTIVE: Parents, schools and the broader community influence children's socialisation to alcohol. In Australia, the UK and the USA, there have been media reports of adults consuming alcohol at family-focused school events such as fairs and graduations. The aim of this qualitative study was to describe school principals' experiences of adults' use of alcohol at school events, when children are present. DESIGN/SETTING/PARTICIPANTS: A qualitative study was undertaken. Publicly available lists were used to invite 60 principals from government and Catholic secondary schools in Victoria, Australia. In-depth interviews were conducted and analysed thematically and reported using the Consolidated Criteria for Reporting Qualitative Research guidelines. RESULTS: 14 principals (5 female, 9 male) participated. Most (10) of the participating principals reported adults' use of alcohol at events when students were present. Regarding these events, most principals reported concerns regarding potential harms and responsibility for decision-making about alcohol availability in schools. Some (4) principals believed alcohol should not be present at such events and this was their practice. Half of the participating schools had recently made changes to reduce the availability or management of alcohol at school functions. CONCLUSIONS: The findings confirm the common use of alcohol by adults at school events, the challenges this poses for school principals and suggests consideration needs to be given to identifying strategies for supporting schools and school principals in decision-making regarding the conduct of such events. PMID- 27481621 TI - Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial. AB - OBJECTIVE: To assess the incremental cost and cost-effectiveness of a restrictive versus a liberal red blood cell transfusion threshold after cardiac surgery. DESIGN: A within-trial cost-effectiveness analysis with a 3-month time horizon, based on a multicentre superiority randomised controlled trial from the perspective of the National Health Service (NHS) and personal social services in the UK. SETTING: 17 specialist cardiac surgery centres in UK NHS hospitals. PARTICIPANTS: 2003 patients aged >16 years undergoing non-emergency cardiac surgery with a postoperative haemoglobin of <9 g/dL. INTERVENTIONS: Restrictive (transfuse if haemoglobin <7.5 g/dL) or liberal (transfuse if haemoglobin <9 g/dL) threshold during hospitalisation after surgery. MAIN OUTCOME MEASURES: Health-related quality of life measured using the EQ-5D-3L to calculate quality adjusted life years (QALYs). RESULTS: The total costs from surgery up to 3 months were L17 945 and L18 127 in the restrictive and liberal groups (mean difference is -L182, 95% CI -L1108 to L744). The cost difference was largely attributable to the difference in the cost of red blood cells. Mean QALYs to 3 months were 0.18 in both groups (restrictive minus liberal difference is 0.0004, 95% CI -0.0037 to 0.0045). The point estimate for the base-case cost-effectiveness analysis suggested that the restrictive group was slightly more effective and slightly less costly than the liberal group and, therefore, cost-effective. However, there is great uncertainty around these results partly due to the negligible differences in QALYs gained. CONCLUSIONS: We conclude that there is no clear difference in the cost-effectiveness of restrictive and liberal thresholds for red blood cell transfusion after cardiac surgery. TRIAL REGISTRATION NUMBER: ISRCTN70923932; Results. PMID- 27481623 TI - Direct access to potential research participants for a cohort study using a confidentiality waiver included in UK National Health Service legal statutes. AB - OBJECTIVES: To describe our experience of using a confidentiality waiver (Section 251) in the National Health Service (NHS) Act to identify and recruit potential research participants to a cohort study and consider its use in a wider research context. DESIGN: Methodological discussion. SETTING: NHS Trusts in England. METHODS: We established a research recruitment process with quality health (QH), administrators of the National Cancer Patient Experience Survey, after an amendment to a Section 251 approval (reference number ECC-8-05d-2011). NHS Trusts agreeing to implement the process were requested to send the details of 16-24 year-olds, identified by a relevant ICD-10 code indicating a cancer diagnosis within a specified time period to QH. QH sent study information and a consent-to be-contacted form which allowed QH to send details to BRIGHTLIGHT, for BRIGHTLIGHT to contact the treating team confirming eligibility and for an interviewer from Ipsos MORI to contact them. Written consent was to be obtained at interview. RESULTS: The method was implemented in 98 trusts; 75 supplied patient details. QH sent information to 441 young people, of whom 64 (15%) responded. Of these, 23 had already consented to participate. Adverse events were reported by 6 (1%) invitees: 4 were distressed because they did not have cancer, their details being submitted to QH due to incorrect hospital coding, and 1 young person was distressed about their diagnosis and requested no further contact and 1 young person found out they had cancer from the invitation. CONCLUSIONS: Application of Section 251 of the NHS Act (2006) to directly approach participants can facilitate recruitment to research projects where routinely collected NHS data are available to select eligible patients. The benefits of this method are that it requires fewer resources to recruit across multiple sites, and is quicker. Further information on the impact on bias and adverse event profile are required. PMID- 27481622 TI - Early PREdiction of Severe Sepsis (ExPRES-Sepsis) study: protocol for an observational derivation study to discover potential leucocyte cell surface biomarkers. AB - INTRODUCTION: Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life threatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course. METHODS AND ANALYSIS: We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis. ETHICS AND DISSEMINATION: The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C REC. On conclusion of this study, the results will be disseminated via peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02188992; Pre-results. PMID- 27481625 TI - High-order species interactions shape ecosystem diversity. AB - Classical theory shows that large communities are destabilized by random interactions among species pairs, creating an upper bound on ecosystem diversity. However, species interactions often occur in high-order combinations, whereby the interaction between two species is modulated by one or more other species. Here, by simulating the dynamics of communities with random interactions, we find that the classical relationship between diversity and stability is inverted for high order interactions. More specifically, while a community becomes more sensitive to pairwise interactions as its number of species increases, its sensitivity to three-way interactions remains unchanged, and its sensitivity to four-way interactions actually decreases. Therefore, while pairwise interactions lead to sensitivity to the addition of species, four-way interactions lead to sensitivity to species removal, and their combination creates both a lower and an upper bound on the number of species. These findings highlight the importance of high-order species interactions in determining the diversity of natural ecosystems. PMID- 27481626 TI - Energetics and Electronic Structure of h-BN Nanoflakes. AB - We studied the energetics and electronic structure of hexagonal boron nitride (h BN) nanoribbons with hydrogenated and clean edges with respect to the detailed edge shapes using density functional theory. Our calculations showed that the stability of h-BN edges strongly depends on the edge termination. In the case of hydrogenated edges, the formation energy is constant for all edge angles ranging from armchair to zigzag, indicating that h-BN may exhibit rich variation in their edge atomic arrangements under static conditions. The hydrogenated h-BN nanoribbons are insulators with an energy gap of 4 eV irrespective of edge shape, in which the lowest branch of the conduction band exhibits nearly free electron states nature distributed in the vacuum region outside the ribbons. In contrast, the formation energy of h-BN nanoribbons with clean edges monotonically increases as the edge angle is changed from armchair to zigzag. Our analysis reveals that the increase of density of states at the Fermi level arising from dangling bond states leads to this monotonic increase of edge formation energy in h-BN nanoribbons with clean edges. PMID- 27481624 TI - Patient and carer experience of hospital-based rehabilitation from intensive care to hospital discharge: mixed methods process evaluation of the RECOVER randomised clinical trial. AB - OBJECTIVES: To explore and compare patient/carer experiences of rehabilitation in the intervention and usual care arms of the RECOVER trial (ISRCTN09412438); a randomised controlled trial of a complex intervention of post-intensive care unit (ICU) acute hospital-based rehabilitation following critical illness. DESIGN: Mixed methods process evaluation including comparison of patients' and carers' experience of usual care versus the complex intervention. We integrated and compared quantitative data from a patient experience questionnaire (PEQ) with qualitative data from focus groups with patients and carers. SETTING: Two university-affiliated hospitals in Scotland. PARTICIPANTS: 240 patients discharged from ICU who required >=48 hours of mechanical ventilation were randomised into the trial (120 per trial arm). Exclusion criteria comprised: primary neurologic diagnosis, palliative care, current/planned home ventilation and age <18 years. 182 patients completed the PEQ at 3 months postrandomisation. 22 participants (14 patients and 8 carers) took part in focus groups (2 per trial group) at >3 months postrandomisation. INTERVENTIONS: A complex intervention of post-ICU acute hospital rehabilitation, comprising enhanced physiotherapy, nutritional care and information provision, case-managed by dedicated rehabilitation assistants (RAs) working within existing ward-based clinical teams, delivered between ICU discharge and hospital discharge. Comparator was usual care. OUTCOME MEASURES: A novel PEQ capturing patient-reported aspects of quality care. RESULTS: The PEQ revealed statistically significant between-group differences across 4 key intervention components: physiotherapy (p=0.039), nutritional care (p=0.038), case management (p=0.045) and information provision (p<0.001), suggesting greater patient satisfaction in the intervention group. Focus group data strongly supported and helped explain these findings. Specifically, case management by dedicated RAs facilitated greater access to physiotherapy, nutritional care and information that cut across disciplinary boundaries and staffing constraints. Patients highly valued its individualisation according to their needs, abilities and preferences. CONCLUSIONS: Case management by dedicated RAs improves patients' experiences of post-ICU hospital-based rehabilitation and increases perceived quality of care. TRIAL REGISTRATION NUMBER: ISRCTN09412438. PMID- 27481627 TI - The potential role of Piezo2 in the mediation of visceral sensation. AB - Piezo2 is an important mechano-gated ion channel that is involved in light touch sensitivity and inflammatory allodynia. However, current research has focused on the function of Piezo2 in somatic sensation but not in visceral sensation. The present study aimed to investigate the role of Piezo2 in visceral sensation of mechanically innocuous and noxious stimuli under physiological and hyperalgesic conditions using rats as a model organism. Neonatal enema with acetic acid induced visceral hypersensitivity. Intrathecal administration of Piezo2-short hairpin RNA (shRNA) reduced Piezo2 expression in lumbosacral dorsal root ganglia (DRG) at both the mRNA and protein levels. Piezo2 knock-down in DRG attenuated visceral sensation to innocuous stimuli in control rats and to both innocuous and noxious stimuli in rats with neonatal irritation. Compared with control rats, Piezo2 was not up-regulated in irritated rats at the mRNA or protein levels in thoracolumbar or lumbosacral DRGs, while TRPV1 was up-regulated in lumbosacral DRGs. These data suggest a potential role of Piezo2 in the mediation of visceral sensation. PMID- 27481628 TI - Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis. AB - BACKGROUND: The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment. METHODS: RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta analysis. RESULTS: Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC >=10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events. CONCLUSIONS: The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients. PMID- 27481629 TI - Imaging of congenital Zika virus infection: the route to identification of prognostic factors. AB - Zika virus (ZIKV) has recently emerged as a novel teratogenic agent associated with severe neurological complications. The risk associated with maternal infection remains to be exactly defined but appears to be significant. Like other TORCH agents (toxoplasmosis, other agents, rubella, cytomegalovirus and herpes simplex), it is unlikely that all affected fetuses will be symptomatic at birth. It is therefore urgent to better define the spectrum of anomalies observed in infected fetuses to provide adequate parental counseling. In this review, we provide a comprehensive analysis of major cases described to date and highlight specific prenatal and postnatal radiological findings of congenital ZIKV infection. A total of 19 reports were included in our analysis. ZIKV seemed to harbor a specific tropism for the central nervous system, and anomalies were mostly limited to the brain. Major radiological findings were ventriculomegaly, diffuse calcifications and signs of abnormal gyration as well as cortical development. In addition, a significant number of fetuses suffered from intra uterine growth restriction. Based on these findings, we provide recommendations for adequate radiological monitoring of at-risk pregnancies. (c) 2016 John Wiley & Sons, Ltd. PMID- 27481630 TI - Carbon Capture and Storage: introductory lecture. AB - Carbon Capture and Storage (CCS) is the only available technology that allows us to significantly reduce our CO2 emissions while keeping up with the ever increasing global energy demand. Research in CCS focuses on reducing the costs of carbon capture and increasing our knowledge of geological storage to ensure the safe and permanent storage of CO2. This brief review will discuss progress in different capture and storage technologies. PMID- 27481631 TI - The experiences of working carers of older people regarding access to a web-based family care support network offered by a municipality. AB - Policy makers in Sweden and other European Member States pay increasing attention as to how best support working carers; carers juggling providing unpaid family care for older family members while performing paid work. Exploring perceived benefits and challenges with web-based information and communication technologies as a means of supporting working carers' in their caregiving role, this paper draws on findings from a qualitative study. The study aimed to describe working carers' experiences of having access to the web-based family care support network 'A good place' (AGP) provided by the municipality to support those caring for an older family member. Content analysis of interviews with nine working carers revealed three themes: A support hub, connections to peers, personnel and knowledge; Experiencing ICT support as relevant in changing life circumstances; and Upholding one's personal firewall. Findings indicate that the web-based family care support network AGP is an accessible, complementary means of support. Utilising support while balancing caregiving, work obligations and responsibilities was made easier with access to AGP; enabling working carers to access information, psychosocial support and learning opportunities. In particular, it provided channels for carers to share experiences with others, to be informed, and to gain insights into medical and care issues. This reinforced working carers' sense of competence, helping them meet caregiving demands and see positive aspects in their situation. Carers' low levels of digital skills and anxieties about using computer-based support were barriers to utilising web-based support and could lead to deprioritising of this support. However, to help carers overcome these barriers and to better match web-based support to working carers' preferences and situations, web-based support must be introduced in a timely manner and must more accurately meet each working carer's unique caregiving needs. PMID- 27481632 TI - Psychological variables underlying political orientations in an old and a new democracy: A comparative study between Sweden and Latvia. AB - This study examines in detail the psychological variables underlying ideological political orientation, and structure and contents of this orientation, in Sweden and Latvia. Individual political orientation is conceptualized on two dimensions: acceptance vs. rejection of social change and acceptance vs. rejection of inequality. Swedish (N = 320) and Latvian (N = 264) participants completed measures of political orientation, Social Dominance Orientation (SDO), Right Wing Authoritarianism (RWA), self vs. other orientation, tolerance for ambiguity, humanism and normativism, core political values, system justification, as well as moral foundations questionnaire and portrait values questionnaire. The results showed that the relation among the measured variables was similar in both samples. Swedish participants showed stronger endorsement of egalitarian attitudes and social values, whereas we found more self-enhancing and socially conservative values and attitudes among the Latvian participants. PMID- 27481633 TI - Nitrogen Removal and N2O Accumulation during Hydrogenotrophic Denitrification: Influence of Environmental Factors and Microbial Community Characteristics. AB - Hydrogenotrophic denitrification is regarded as an efficient alternative technology of removing nitrogen from nitrate-polluted water that has insufficient organics material. However, the biochemical process underlying this method has not been completely characterized, particularly with regard to the generation and reduction of nitrous oxide (N2O). In this study, the effects of key environmental factors on hydrogenotrophic denitrification and N2O accumulation were investigated in a series of batch tests. The results show that nitrogen removal was efficient with a specific denitrification rate of 0.66 kg N/(kg MLSS.d), and almost no N2O accumulation was observed when the dissolved hydrogen (DH) concentration was approximately 0.40 mg/L, the temperature was 30 degrees C, and the pH was 7.0. The reduction of nitrate was significantly affected by the pH, temperature, inorganic carbon (IC) content, and DH concentration. A considerable accumulation of N2O was only observed when the pH decreased to 6.0 and the temperature decreased to 15 degrees C, where little N2O accumulated under various IC and DH concentrations. To determine the microbial community structure, the hydrogenotrophic denitrifying enrichment culture was analyzed by Illumina high-throughput sequencing, and the dominant species were found to belong to the genera Paracoccus (26.1%), Azoarcus (24.8%), Acetoanaerobium (11.4%), Labrenzia (7.4%), and Dysgonomonas (6.0%). PMID- 27481635 TI - Relevance and challenges of computational fluid dynamics in the biomedical sciences. PMID- 27481634 TI - The ability of anterior thalamic signals to predict seizures in temporal lobe epilepsy in kainate-treated rats. AB - OBJECTIVE: To analyze the local field potential (LFP) of the anterior nucleus of the thalamus (ANT) of epileptic rats using the Generic Osorio-Frei algorithm (GOFA), and to determine the ability of the ANT LFP to predict clinical seizures in temporal lobe epilepsy. METHODS: GOFA is an advanced real-time technique used to detect and predict seizures. In this article, GOFA was utilized to process the electrical signals of ANT and the motor cortex recorded in 12 rat models of temporal lobe epilepsy (TLE) induced via the injection of kainic acid into the unilateral hippocampus. The electroencephalography (EEG) data included (1) 161 clinical seizures (each contained a 10-min segment) involving the ANT and cortical regions and (2) one hundred three 10-min segments of randomly selected interictal (no seizure) data. RESULTS: Minimal false-positives (0.51 +/- 0.36/h) and no false-negatives were detected based on the ANT LFP data processed using GOFA. In ANT LFP, the delay from electrographic onset (EO) to automated onset (AO) was 1.24 +/- 0.47 s, and the delay from AO to clinical onset (CO) was 7.73 +/- 3.23 s. The AO time occurred significantly earlier in the ANT than in the cortex (p = 0.001). In 75.2% of the clinical onsets predicted by ANT LFP, it was 1.37 +/- 0.82 s ahead of the prediction of cortical potentials (CPs), and the remainder were 0.84 +/- 0.31 s slower than the prediction of CPs. SIGNIFICANCE: ANT LFP appears to be an optimal option for the prediction of seizures in temporal lobe epilepsy. It was possible to upgrade the responsive neurostimulation system to emit electrical stimulation in response to the prediction of epileptic seizures based on the changes in the ANT LFP. PMID- 27481636 TI - In silico analysis highlights the copy number variation mechanism responsible for the historically reported VWF exon 42 deletion. PMID- 27481637 TI - Topographical anatomy of cricothyroid membrane and its relation with invasive airway access. AB - Cricothyroidotomy is a surgical procedure involving penetration through the skin and cricothyroid membrane to maintain airway patency during life-threatening emergency conditions. Complications such as bleeding and laryngeal stenosis can result from it. Our aim in this study was to identify the anatomical structures located on the membrane and to ascertain whether there is a safe area on the membrane for this procedure. Thirty larynx specimens fixed with 10% formaldehyde in the Department of Anatomy were dissected. The cricothyroid artery, the cricothyroid vein, the common artery and vein formed by the cricothyroid vessels, the pyramidal lobe of the thyroid gland and lymph nodes were observed on the membrane. The cricothyroid membrane was divided into four quadrants and the most common locations of these anatomical structures on the membrane were recorded. The cricothyroid artery and vein were located on the upper half of the membrane, the common vein was found in the midline, coursing to the thyroid gland, and the lobus pyramidalis and lymph nodes were located on the left side of the midline. Overall, the anatomical structures were mostly located on the upper half and lower left quadrant of the cricothyroid membrane. Thus, the lower right quadrant seems safer for invasive procedures such as needle cricothyroidotomy or other cannulation techniques. Needle puncture or cannulation through the lower right quadrant of the cricothyroid membrane will injure fewer anatomical structures so there should be fewer complications due to degradation of the vascular supply to this region. Clin. Anat. 29:949-954, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27481638 TI - Second-generation probes for biosynthetic intermediate capture: towards a comprehensive profiling of polyketide assembly. AB - Malonyl carba(dethia) N-decanoyl cysteamine methyl esters and novel acetoxymethyl esters were utilised as second-generation probes for polyketide intermediate capture. The use of these tools in vivo led to the characterisation of an almost complete set of biosynthetic intermediates from a modular assembly line, providing a first kinetic overview of intermediate processing leading to complex natural product formation. PMID- 27481639 TI - Effect of ovsynch versus prostaglandin F2alpha protocol on estrus response, ovulation rate, timing of ovulation and pregnancy per artificial insemination in Sahiwal cows. AB - Sahiwal cow is Bos indicus which is an important dairy breed of tropical and sub tropical region. Research on reproduction is rare in this breed. The objectives of the present study were to determine the effect of Ovsynch (OVS) versus prostaglandin F2alpha (PG) protocol on estrus response and its intensity, ovulation rate, timing of ovulation and pregnancy per artificial insemination (AI) in Sahiwal cows. Experimental cows (n = 80) were of mixed parity, lactating, suckled, >=120 days postpartum with body condition score 3.08 +/- 0.34 and 375 475 kg of body weight which were randomly assigned to receive either OVS (n = 46) or PG (n =34) protocol. Cows were inseminated twice at 12 and 24 h after second gonadotropin releasing hormone in the OVS group, and 72 and 84 h after administration of prostaglandin F2alpha in PG group, respectively. The results revealed that estrus response did not differ (P > 0.05) and was 87% in OVS and 78% in PG cows. Ovulation rate did not differ (P > 0.05) and was 50% in both, OVS and PG cows. The pregnancy per AI did not differ (P > 0.05) and was 43% in OVS compared to 31% in PG cows. It is concluded that estrus response, ovulation rate and pregnancy per AI of OVS protocol is the same as PG in Sahiwal cows. PMID- 27481640 TI - A hypervariable genomic island identified in clinical and environmental Mycobacterium avium subsp. hominissuis isolates from Germany. AB - Mycobacterium avium subsp. hominissuis (MAH) is an opportunistic human pathogen widespread in the environment. Genomic islands (GI)s represent a part of the accessory genome of bacteria and influence virulence, drug-resistance or fitness and trigger bacterial evolution. We previously identified a novel GI in four MAH genomes. Here, we further explored this GI in a larger collection of MAH isolates from Germany (n=41), including 20 clinical and 21 environmental isolates. Based on comparative whole genome analysis, we detected this GI in 39/41 (95.1%) isolates. Although all these GIs integrated in the same insertion hotspot, there is high variability in the genetic structure of this GI: eight different types of GI have been identified, designated A-H (sized 6.2-73.3kb). These GIs were arranged as single GI (23/41, 56.1%), combination of two different GIs (14/41, 34.1%) or combination of three different GIs (2/41, 4.9%) in the insertion hotspot. Moreover, two GI types shared more than 80% sequence identity with sequences of M. canettii, responsible for Tuberculosis. A total of 253 different genes were identified in all GIs, among which the previously documented virulence related genes mmpL10 and mce. The diversity of the GI and the sequence similarity with other mycobacteria suggests cross-species transfer, involving also highly pathogenic species. Shuffling of potential virulence genes such as mmpL10 via this GI may create new pathogens that can cause future outbreaks. PMID- 27481641 TI - A nano-microstructured artificial-hair-cell-type sensor based on topologically graded 3D carbon nanotube bundles. AB - A design for a unique artificial-hair-cell-type sensor (AHCTS) based entirely on 3D-structured, vertically aligned carbon nanotube (CNT) bundles is introduced. Standard microfabrication techniques were used for the straightforward micro-nano integration of vertically aligned carbon nanotube arrays composed of low-layer multi-walled CNTs (two to six layers). The mechanical properties of the carbon nanotube bundles were intensively characterized with regard to various substrates and CNT morphology, e.g. bundle height. The CNT bundles display excellent flexibility and mechanical stability for lateral bending, showing high tear resistance. The integrated 3D CNT sensor can detect three-dimensional forces using the deflection or compression of a central CNT bundle which changes the contact resistance to the shorter neighboring bundles. The complete sensor system can be fabricated using a single chemical vapor deposition (CVD) process step. Moreover, sophisticated external contacts to the surroundings are not necessary for signal detection. No additional sensors or external bias for signal detection are required. This simplifies the miniaturization and the integration of these nanostructures for future microsystem set-ups. The new nanostructured sensor system exhibits an average sensitivity of 2100 ppm in the linear regime with the relative resistance change per micron (ppm MUm(-1)) of the individual CNT bundle tip deflection. Furthermore, experiments have shown highly sensitive piezoresistive behavior with an electrical resistance decrease of up to ~11% at 50 MUm mechanical deflection. The detection sensitivity is as low as 1 MUm of deflection, and thus highly comparable with the tactile hair sensors of insects, having typical thresholds on the order of 30-50 MUm. The AHCTS can easily be adapted and applied as a flow, tactile or acceleration sensor as well as a vibration sensor. Potential applications of the latter might come up in artificial cochlear systems. In particular, the stable mechanical bending of the sensor up to 90 degrees opens up unique application opportunities. PMID- 27481642 TI - Development of an Injectable Calcium Phosphate/Hyaluronic Acid Microparticles System for Platelet Lysate Sustained Delivery Aiming Bone Regeneration. AB - Despite the biocompatibility and osteoinductive properties of calcium phosphate (CaP) cements their low biodegradability hampers full bone regeneration. Herein the incorporation of CaP cement with hyaluronic acid (HAc) microparticles loaded with platelet lysate (PL) to improve the degradability and biological performance of the cements is proposed. Cement formulations incorporating increasing weight ratios of either empty HAc microparticles or microparticles loaded with PL (10 and 20 wt%) are developed as well as cements directly incorporating PL. The direct incorporation of PL improves the mechanical properties of the plain cement, reaching values similar to native bone. Morphological analysis shows homogeneous particle distribution and high interconnectivity between the HAc microparticles. The cements incorporating PL (with or without the HAc microparticles) present a sustained release of PL proteins for up to 8 d. The sustained release of PL modulates the expression of osteogenic markers in seeded human adipose tissue derived stem cells, thus suggesting the stimulatory role of this hybrid system toward osteogenic commitment and bone regeneration applications. PMID- 27481644 TI - Inferior adaptation of bay sediments in a eutrophic shallow lake to winter season for organic matter decomposition. AB - Sediments in lake bays receive the greatest external pollutants mainly including terrestrial plants and river macrophyte detritus. This work investigated response and adaptation of bay sediments to organic matter (OM) decomposition under cold and hot seasons. After three month and incubated at 5 degrees C, it was found that the total organic carbon (TOC) removal efficiencies ranged from 15.4 to 13.1% in bay sediments to 22.6-25.7% in pelagic zone. These results determined that poorer OM decomposition occurred in the bay zone during the winter months compared to pelagic zone in a eutrophic shallow lake. High-throughput sequencing and network interactions revealed that the reactions were mainly due to the changing microbial community structure and species interaction at selected areas during different seasons. The bay zone communities are poorly adapted to utilizing the more recalcitrant carbon pool than the pelagic communities. Also, even though more taxa reside in bay communities, less co-occurrences interaction between taxa occurs, which mean that less inter taxa competition for the same resource. In consideration of our study, the potential harm, such as the terrestrialization process speeding up and water quality worsening will be happened, we need to exploit ways to enhance litter biodegradation in the bay zone in winter. PMID- 27481643 TI - Contamination and isotopic composition of Pb and Sr in offshore surface sediments from Jiulong River, Southeast China. AB - Concentrations and isotopic compositions of Pb and Sr in the surface sediment samples from Jiulong River, Southeast China, were determined to trace the sources of Pb and Sr. The average concentrations of Pb and Sr were 110.9 mg/kg and 69.2 mg/kg, approximately 3.2 and 2.0 times of the local soil background values, respectively. Average 62.9% of total Pb and 36.8% of total Sr in the investigated surface sediment samples were extracted by 0.5 mol/L HNO3. Pb and Sr presented slight contamination, and Pb showed low ecological risk for most of surface sediment samples in Jiulong River according to geo-accumulation index (Igeo) and potential ecological risk index (RI). The results of Pb isotopic compositions in sediment samples and potential sources showed that the Pb accumulated in the surface sediments of Jiulong River was mainly from parent material, coal combustion and Fujian Pb-Zn deposit, with the contribution rates of 34.4%, 34.0%, and 31.6%, respectively. The results of Pb isotopic compositions in 0.5 mol/L HNO3-extraction suggested that dilute HNO3-extraction was more sensitive in identifying anthropogenic Pb sources than total digestion. The results of Sr isotopic compositions showed that Sr accumulated in the surface sediments of Jiulong River estuary mainly derived from external source and natural source (parent material) with the contribution rates of 48.1% and 51.9%, respectively. PMID- 27481646 TI - Quantum-mechanical parameters for the risk assessment of multi-walled carbon nanotubes: A study using adsorption of probe compounds and its application to biomolecules. AB - This work forwards new insights into the risk-assessment of multi-walled carbon nanotubes (MWCNTs) while analysing the role of quantum-mechanical interactions between the electrons in the adsorption of probe compounds and biomolecules by MWCNTs. For this, the quantitative models are developed using quantum-chemical descriptors and their electron-correlation contribution. The major quantum chemical factors contributing to the adsorption are found to be mean polarizability, electron-correlation energy, and electron-correlation contribution to the absolute electronegativity and LUMO energy. The proposed models, based on only three quantum-chemical factors, are found to be even more robust and predictive than the previously known five or four factors based linear free-energy and solvation-energy relationships. The proposed models are employed to predict the adsorption of biomolecules including steroid hormones and DNA bases. The steroid hormones are predicted to be strongly adsorbed by the MWCNTs, with the order: hydrocortisone > aldosterone > progesterone > ethinyl-oestradiol > testosterone > oestradiol, whereas the DNA bases are found to be relatively less adsorbed but follow the order as: guanine > adenine > thymine > cytosine > uracil. Besides these, the developed electron-correlation based models predict several insecticides, pesticides, herbicides, fungicides, plasticizers and antimicrobial agents in cosmetics, to be strongly adsorbed by the carbon nanotubes. The present study proposes that the instantaneous inter-electronic interactions may be quite significant in various physico-chemical processes involving MWCNTs, and can be used as a reliable predictor for their risk assessment. PMID- 27481645 TI - Long-term impact of sewage sludge application on soil microbial biomass: An evaluation using meta-analysis. AB - The Long-Term Sludge Experiments (LTSE) began in 1994 as part of continuing research into the effects of sludge-borne heavy metals on soil fertility. The long-term effects of Zn, Cu, and Cd on soil microbial biomass carbon (Cmic) were monitored for 8 years (1997-2005) in sludge amended soils at nine UK field sites. To assess the statutory limits set by the UK Sludge (Use in Agriculture) Regulations the experimental data has been reviewed using the statistical methods of meta-analysis. Previous LTSE studies have focused predominantly on statistical significance rather than effect size, whereas meta-analysis focuses on the magnitude and direction of an effect, i.e. the practical significance, rather than its statistical significance. The results presented here show that significant decreases in Cmic have occurred in soils where the total concentrations of Zn and Cu fall below the current UK statutory limits. For soils receiving sewage sludge predominantly contaminated with Zn, decreases of approximately 7-11% were observed at concentrations below the UK statutory limit. The effect of Zn appeared to increase over time, with increasingly greater decreases in Cmic observed over a period of 8 years. This may be due to an interactive effect between Zn and confounding Cu contamination which has augmented the bioavailability of these metals over time. Similar decreases (7 12%) in Cmic were observed in soils receiving sewage sludge predominantly contaminated with Cu; however, Cmic appeared to show signs of recovery after a period of 6 years. Application of sewage sludge predominantly contaminated with Cd appeared to have no effect on Cmic at concentrations below the current UK statutory limit. PMID- 27481647 TI - Nickel nanoparticles-chitosan composite coated cellulose filter paper: An efficient and easily recoverable dip-catalyst for pollutants degradation. AB - In this report, we used cellulose filter paper (FP) as high surface area catalyst supporting green substrate for the synthesis of nickel (Ni) nanoparticles in thin chitosan (CS) coating layer and their easy separation was demonstrated for next use. In this work, FP was coated with a 1 wt% CS solution onto cellulose FP to prepare CS-FP as an economical and environment friendly host material. CS-FP was put into 0.2 M NiCl2 aqueous solution for the adsorption of Ni2+ ions by CS coating layer. The Ni2+ adsorbed CS-FP was treated with 0.1 M NaBH4 aqueous solution to convert the ions into nanoparticles. Thus, we achieved Ni nanoparticles-CS composite through water based in-situ preparation process. Successful Ni nanoparticles formations was assessed by FESEM and EDX analyses. FTIR used to track the interactions between nanoparticles and host material. Furthermore, we demonstrated that the nanocomposite displays an excellent catalytic activity and reusability in three reduction reactions of toxic compounds i.e. conversion of 4-nitrophenol to 4-aminophenol, 2-nitrophenol to 2 aminophenol, and methyl orange dye reduction by NaBH4. Such a fabrication process of Ni/CS-FP may be applicable for the immobilization of other metal nanoparticles onto FP for various applications in catalysis, sensing, and environmental sciences. PMID- 27481648 TI - Dental and Temporomandibular Joint Pathology of the Polar Bear (Ursus maritimus). AB - Museum specimens (maxillae and/or mandibles) from 317 polar bears (Ursus maritimus) were examined macroscopically according to predefined criteria and 249 specimens were included in this study. The specimens were acquired between 1906 and 2011. There were 126 specimens (50.6%) from male animals, 93 (37.3%) from female animals and 30 (12.1%) from animals of unknown sex. The ages of the animals ranged from neonate to adult, with 125 adults (50.2%) and 124 young adults (49.8%) included and neonates/juveniles excluded from the study. The number of teeth available for examination was 7,638 (73.5%); 12.3% of teeth were absent artefactually, 0.8% were deemed absent due to acquired tooth loss and 13.4% were absent congenitally. With respect to tooth morphology, 20 teeth (0.26% of available teeth) in 18 specimens (7.2% of available specimens) were small vestigial structures with crowns that were flush with the level of surrounding alveolar bone. One supernumerary tooth and one tooth with enamel hypoplasia were encountered. Persistent deciduous teeth and teeth with an aberrant number of roots were not found. Relatively few teeth (3.7%) displayed attrition/abrasion, 90% of which were the maxillary and mandibular incisor teeth, in 41 polar bears (16.5%). Nearly twice as many adult specimens exhibited attrition/abrasion as those from young adults; significantly more males were affected than females. Dental fractures were noted in 52 polar bears, affecting 20.9% of specimens and 1.3% of the total number of teeth present. More adult polar bears had dental fractures than young adults. There were 21 specimens (8.4%) that displayed overt periapical disease, affecting a total of 24 dental alveoli (0.23%). Some degree of periodontitis was seen in 199 specimens (79.9%); however, only 12.6% of dental alveoli had bony changes indicative of periodontitis. Lesions consistent with temporomandibular joint osteoarthritis (TMJ-OA) were found in 23 specimens (9.2%). TMJ-OA was significantly more common in adults than in young adults and in males than in females. Although the clinical significance of dental and TMJ pathology in the polar bear remains elusive, the occurrence and severity of these lesions may play an important role in the morbidity and mortality of this species. PMID- 27481650 TI - Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): Recommendation from the working group for creation of sarcopenia assessment criteria. AB - Sarcopenia is defined by muscle loss and muscle dysfunction. Sarcopenia is classified into primary and secondary types, based on the cause. Primary sarcopenia is mainly aging-related sarcopenia, whereas secondary sarcopenia is the reduced muscle mass and strength that accompanies an underlying disease. Given the essential role of the liver in metabolism, secondary sarcopenia due to nutritional disorders or other factors can frequently occur in liver disease. In 2015, the Japan Society of Hepatology (JSH) decided to establish its own assessment criteria for sarcopenia in liver disease because the number of liver disease patients with sarcopenia is expected to increase and there is cumulative evidence to indicate sarcopenic patients have poor clinical outcomes. A working group to create assessment criteria for sarcopenia has thus been established by the JSH. In this article, we summarize the current knowledge with regard to sarcopenia and present the assessment criteria for sarcopenia in liver disease proposed by the JSH (1st edition). To the best of our knowledge, this is globally the first proposed assessment criteria for sarcopenia specializing in liver disease. PMID- 27481649 TI - Ethnic Variation in the Association of Hypertension With Type 2 Diabetes. AB - Lifestyle changes occurring with urbanization increase the prevalence of both type 2 diabetes mellitus (T2DM) and hypertension (HTN). Yemenites who have immigrated to Israel have demonstrated a dramatic increase in T2DM but the prevalence of HTN in diabetic Yemenites is unclear. In a cross-sectional study, the authors evaluated the prevalence of HTN and lifestyle patterns in Israelis with T2DM of Yemenite (Y-DM) and non-Yemenite (NY-DM) origin. Y-DM (n=63) and NY DM (n=120) had similar age (63+/-7 vs 64+/-7 years, P=.5), diabetes duration, diet adherence, and exercise patterns. Y-DM had a lower prevalence of HTN (63%) than NY-DM (83%) (P<.01). Furthermore, Yemenite origin was independently associated with lower prevalence of HTN (odds ratio, 0.3; 95% confidence interval, 0.12-0.71). Blood pressure was well controlled with fewer antihypertensive medications in Y-DM than NY-DM (P<.01). Even though lifestyle patterns were similar in the two groups, Y-DM had a lower prevalence of HTN compared with NY-DM and required fewer antihypertensive medications. PMID- 27481651 TI - The genomic landscape of breast cancer and its interaction with host immunity. AB - Molecular profiling of thousands of primary breast cancers has uncovered remarkable genomic diversity between breast cancer subtypes, and even within subtypes. Only a few driver genes are recurrently altered at high frequency highlighting great challenges for precision medicine. Considerable evidence also confirms the role of host immunosurveillance in influencing response to therapy and prognosis in HER2+ and triple negative breast cancer. The role of immunosurveillance in ER + disease remains unclear. Advances in both these fields have lead to intensified interest in the interaction between genomic landscapes and host anti-tumour immune responses in breast cancer. In this review, we discuss the potential genomic determinants of host anti-tumour immunity - mutational load, driver alterations, mutational processes and neoantigens - and their relationship with immunity in breast cancer. Significant differences exist in both the genomic and immune characteristics amongst breast cancer subtypes. While ER + disease appears to be less immunogenic than HER2+ and triple negative breast cancer, it displays the greatest degree of heterogeneity. Mutational and neoantigen load appears to incompletely explains immune responses in breast cancer. Driver alterations do not appear to increase immunogenicity. Instead, they could contribute to immune-evasion or an immunosuppressive microenvironment, and therefore represent potential therapeutic targets. Finally, we also discuss the tailoring of immunotherapeutic strategies by genomic alterations, with possible multimodal combination approaches to maximise clinical benefits. PMID- 27481652 TI - Plasmon resonance energy transfer and plexcitonic solar cell. AB - Plasmon-mediated energy transfer is highly desirable in photo-electronic nanodevices, but the direct injection efficiency of "hot electrons" in plasmonic photo-detectors and plasmon-sensitized solar cells (plasmon-SSCs) is poor. On another front, Fano resonance induced by strong plasmon-exciton coupling provides an efficient channel of coherent energy transfer from metallic plasmons to molecular excitons, and organic dye molecules have a much better injection efficiency in exciton-SSCs than "hot electrons". Here, we investigate enhanced light-harvesting of chlorophyll-a molecules strongly coupled to Au nanostructured films via Fano resonance. The enhanced local field and plasmon resonance energy transfer are experimentally revealed by monitoring the ultrafast dynamical processes of the plexcitons and the photocurrent flows of the assembled plexciton SSCs. By tuning the Fano factor and anti-resonance wavelengths, we find that the local field is largely enhanced and the efficiency of plexciton-SSCs consisting of ultrathin TiO2 films is significantly improved. Most strikingly, the output power of the plexciton-SSCs is much larger than the sum of those of the individual plasmon- and exciton-SSCs. Our observations provide a practical approach to monitor energy and electron transfer in plasmon-exciton hybrids at a strong coupling regime and also offer a new strategy to design photovoltaic nanodevices. PMID- 27481654 TI - Remembering Edward J. Lammer, MD. PMID- 27481653 TI - Characterization of intravitreally delivered capsid mutant AAV2-Cre vector to induce tissue-specific mutations in murine retinal ganglion cells. AB - Targeted expression of Cre recombinase in murine retinal ganglion cells (RGCs) by viral vector is an effective strategy for creating tissue-specific gene knockouts for investigation of genetic contribution to RGC degeneration associated with optic neuropathies. Here we characterize dosage, efficacy and toxicity for sufficient intravitreal delivery of a capsid mutant Adeno-associated virus 2 (AAV2) vector encoding Cre recombinase. Wild type and Rosa26 (R26) LacZ mice were intravitreally injected with capsid mutant AAV2 viral vectors. Murine eyes were harvested at intervals ranging from 2 weeks to 15 weeks post-injection and were assayed for viral transduction, transgene expression and RGC survival. 10(9) vector genomes (vg) were sufficient for effective in vivo targeting of murine ganglion cell layer (GCL) retinal neurons. Transgene expression was observed as early as 2 weeks post-injection of viral vectors and persisted to 11 weeks. Early expression of Cre had no significant effect on RGC survival, while significant RGC loss was detected beginning 5 weeks post-injection. Early expression of viral Cre recombinase was robust, well-tolerated and predominantly found in GCL neurons suggesting this strategy can be effective in short-term RGC-specific mutation studies in experimental glaucoma models such as optic nerve crush and transection experiments. RGC degeneration with Cre expression for more than 4 weeks suggests that Cre toxicity is a limiting factor for targeted mutation strategies in RGCs. PMID- 27481656 TI - Nanofibrous polymeric beads from aramid fibers for efficient bilirubin removal. AB - Polymer based hemoperfusion has been developed as an effective therapy to remove the extra bilirubin from patients. However, the currently applied materials suffer from either low removal efficiency or poor blood compatibility. In this study, we report the development of a new class of nanofibrous absorbent that exhibited high bilirubin removal efficiency and good blood compatibility. The Kevlar nanofiber was prepared by dissolving micron-sized Kevlar fiber in proper solvent, and the beads were prepared by dropping Kevlar nanofiber solutions into ethanol. Owing to the nanofiborous structure of the Kevlar nanofiber, the beads displayed porous structures and large specific areas, which would facilitate the adsorption of toxins. In the adsorption test, it was noticed that the beads possessed an adsorption capacity higher than 40 mg g(-1) towards bilirubin. In plasma mimetic solutions, the beads still showed high bilirubin removal efficiency. Furthermore, after incorporating with carbon nanotubes, the beads were found to have increased adsorption capacity for human degradation waste. Moreover, the beads showed excellent blood compatibility in terms of a low hemolysis ratio, prolonged clotting times, suppressed coagulant activation, limited platelet activation, and inhibited blood related inflammatory activation. Additionally, the beads showed good compatibility with endothelial cells. In general, the Kevlar nanofiber beads, which integrated with high adsorption capacity, good blood compatibility and low cytotoxicity, may have great potential for hemoperfusion and some other applications in biomedical fields. PMID- 27481657 TI - Bone infections caused by Gemella haemolysans. PMID- 27481658 TI - GNPAT p.D519G variant and iron metabolism during oral iron tolerance test. PMID- 27481659 TI - Observed vulnerability of Filchner-Ronne Ice Shelf to wind-driven inflow of warm deep water. AB - The average rate of melting at the base of the large Filchner-Ronne Ice Shelf in the southern Weddell Sea is currently low, but projected to increase dramatically within the next century. In a model study, melt rates increase as changing ice conditions cause a redirection of a coastal current, bringing warm water of open ocean origin through the Filchner Depression and into the Filchner Ice Shelf cavity. Here we present observations from near Filchner Ice Shelf and from the Filchner Depression, which show that pulses of warm water already arrive as far south as the ice front. This southward heat transport follows the eastern flank of the Filchner Depression and is found to be directly linked to the strength of a wind-driven coastal current. Our observations emphasize the potential sensitivity of Filchner-Ronne Ice Shelf melt rates to changes in wind forcing. PMID- 27481661 TI - Towards coherent combining of X-band high power microwaves: phase-locked long pulse radiations by a relativistic triaxial klystron amplifier. AB - The radio-frequency breakdown due to ultrahigh electric field strength essentially limits power handling capability of an individual high power microwave (HPM) generator, and this issue becomes more challenging for high frequency bands. Coherent power combining therefore provides an alternative approach to achieve an equivalent peak power of the order of ~100 GW, which consequently provides opportunities to explore microwave related physics at extremes. The triaxial klystron amplifier (TKA) is a promising candidate for coherent power combing in high frequency bands owing to its intrinsic merit of high power capacity, nevertheless phase-locked long pulse radiation from TKA has not yet been obtained experimentally as the coaxial structure of TKA can easily lead to self-excitation of parasitic modes. In this paper, we present investigations into an X-band TKA capable of producing 1.1 GW HPMs with pulse duration of about 103 ns at the frequency of 9.375 GHz in experiment. Furthermore, the shot-to-shot fluctuation standard deviation of the phase shifts between the input and output microwaves is demonstrated to be less than 10 degrees . The reported achievements open up prospects for accomplishing coherent power combining of X-band HPMs in the near future, and might also excite new development interests concerning high frequency TKAs. PMID- 27481660 TI - Hepatocyte Isolation After Laparoscopic Liver Resection. AB - Liver tissue obtained from partial hepatectomy is a common source for isolation of primary human hepatocytes. Until now, liver resections were most commonly performed by conventional open surgery. Although the laparoscopic approach is currently emerging in liver surgery, data on the outcome of hepatocyte isolation from laparoscopically resected liver tissue are not available. A total of 22 hepatocyte isolations were performed using the two-step collagenase perfusion technique from October 2015 to March 2016. Liver tissue was obtained from n = 15 open liver resections (OLRs) and n = 7 laparoscopic liver resections (LLRs). Isolation parameters (cell yield, viability, and Percoll survival) were assessed and hepatocyte function (plating efficiency, urea, albumin, and aspartate aminotransferase) was measured over a culture period of 6 days (OLR: n = 13; LLR: n = 3). Total cell yield (OLR: 36.81 +/- 6.77 * 10(6) cells/g vs. LLR 16.84 +/- 10.66 * 10(6) cells/g, p = 0.0318) as well as viable yield (OLR 31.70 +/- 6.05 * 10(6) cells/g vs. LLR 14.70 +/- 9.89 * 10(6) cells/g, p = 0.0260) was significantly higher in the OLR group. Subgroup analysis revealed that the worse outcome of isolation of laparoscopically resected liver tissue was associated with right-lateral LLRs, whereas hepatocyte isolation from left-lateral LLRs was as effective as from open surgery. Hepatocyte function did not differ between hepatocytes from openly resected versus left-lateral laparoscopically resected liver tissue. We here present the first data on hepatocyte isolation from laparoscopic liver surgery. Although the overall outcome is worse compared with open surgery, our data suggest that liver tissue from laparoscopic resection of the left lobe is an excellent source for primary human hepatocytes. PMID- 27481662 TI - Sensitizing DNA Towards Low-Energy Electrons with 2-Fluoroadenine. AB - 2-Fluoroadenine ((2F) A) is a therapeutic agent, which is suggested for application in cancer radiotherapy. The molecular mechanism of DNA radiation damage can be ascribed to a significant extent to the action of low-energy (<20 eV) electrons (LEEs), which damage DNA by dissociative electron attachment. LEE induced reactions in (2F) A are characterized both isolated in the gas phase and in the condensed phase when it is incorporated into DNA. Information about negative ion resonances and anion-mediated fragmentation reactions is combined with an absolute quantification of DNA strand breaks in (2F) A-containing oligonucleotides upon irradiation with LEEs. The incorporation of (2F) A into DNA results in an enhanced strand breakage. The strand-break cross sections are clearly energy dependent, whereas the strand-break enhancements by (2F) A at 5.5, 10, and 15 eV are very similar. Thus, (2F) A can be considered an effective radiosensitizer operative at a wide range of electron energies. PMID- 27481663 TI - Activity Landscapes, Information Theory, and Structure - Activity Relationships. AB - Activity landscapes provide a comprehensive description of structure-activity relationships (SARs). An information theoretic assessment of their features, namely, activity cliffs, similarity cliffs, smooth-SAR, and featureless regions, is presented based on the probability of occurrence of these features. It is shown that activity cliffs provide highly informative SARs compared to smooth-SAR regions, although the latter are the basis for most QSAR studies. This follows since small structural changes in the former are coupled with relatively large changes in activity, thus pinpointing specific structural features associated with the changes in activity. In contrast, Smooth-SAR regions are typically associated with relatively small changes in both structure and activity. Surprisingly, similarity cliffs, which occur when both compounds in a compound pair have approximately equal activities but significantly different structures, are the most prevalent feature of activity landscapes. Hence, from an information theoretic point of view, they are the least informative landscape feature. Nevertheless, similarity cliffs do provide SAR information on potentially new active compound classes, and in that sense they are quite useful in drug discovery programs since they provide alternative possibilities should ADMET or other issues arise during the discovery and earlier preclinical development phases of drug research. PMID- 27481664 TI - Analysis of PPAR-alpha/gamma Activity by Combining 2-D QSAR and Molecular Simulation. AB - In the present study 2D-QSAR analysis was combined with information on crystallographic data and molecular modeling, in order to investigate dual PPAR alpha/gamma activity for a data set of 71 compounds, compiled from literature. Using Multivariate Data Analysis, satisfactory PLS models were generated for each receptor subtype separately. The models were based on simple and easily interpretable drug-like and constitutional descriptors, while the inclusion of MOLCONN-Z descriptors in the initial pool of variables had no considerable impact in model predictivity. By simultaneous analysis of both types of activity, a consensus PLS model for dual PPAR-alpha/gamma activity could be derived, displaying the molecular features, which may lead to a balanced activity. All models were validated by permutation tests, by dividing the data set into training and test sets, as well as by external validation using a blind test set. Detailed inspection of PPAR-alpha and PPAR-gamma crystal structures and molecular simulation supported the differentiation of most important descriptors in the separate PLS models, e.g. the higher impact of lipophilicity and bulk descriptors in PPAR-alpha and PPAR-gamma activity respectively, as well as the effect of specific structural descriptors. Molecular simulation provided also explanation for the behavior of certain outliers in the PLS models. PMID- 27481665 TI - Computational Insights into the Mechanism of Inhibition of OASS-A by a Small Molecule Inhibitor. AB - O-Acetylserine sulfhydrylase (isoform A, OASS-A) is a PLP-dependent enzyme involved in the last step of cysteine biosynthesis in many pathogens. Many microorganisms use cysteine as the main building block for sulfur-containing antioxidants, and cysteine depletion in several pathogens resulted in a reduced antibiotic resistance, thus leading to the identification of OASS as novel suitable molecular targets to overcome antimicrobial resistances. The precise molecular mechanism of OASS-A inhibition by small peptides or by small molecule inhibitors is still unclear. To shed more lights on the structural basis underlying the inhibition mechanism for OASS, we engaged ourselves in studying the dynamic properties of this enzyme. In this paper, we describe a computational study involving unbiased MD simulations of OASS-A from Haemophilus influenzae (HiOASS) in its inhibitor free, PLP-bound form, and in complex with a pentapeptide inhibitor and with UPAR40, a small molecule which we have recently reported as a potent OASS-A inhibitors. We proposed that UPAR40 inhibits HiOASS-A through the stabilization of a closed conformation. Moreover, preliminary docking studies and sequence analysis allow us to speculate about the non-specificity of UPAR40 toward a particular OASS enzyme species or isoforms. PMID- 27481666 TI - The Use of Rule-Based and QSPR Approaches in ADME Profiling: A Case Study on Caco 2 Permeability. AB - During the early ADME profiling the development of simple, interpretable and reliable in silico tools is very important. In this study, rule-based and QSPR approaches were investigated using a large Caco-2 permeability database. Three permeability classes were determined: high (H), moderate (M) and low (L). The main physicochemical properties related with permeability were ranked as follows: Polar Surface Area (PSA)>Lipophilicity (logP/logD)>Molecular Weight (MW)>number of Hydrogen Bond donors and acceptors>Ionization State>number of Rotatable Bonds>number of Rings. The best rule, based on the combination of PSA-MW-logD (3PRule), was able to identify the H, M and L classes with accuracy of 72.2, 72.9 and 70.6 %, respectively. Subsequently, a consensus system based on three voting binary classification trees was constructed. It accurately predicted 78.4/76.1/79.1 % of H/M/L compounds on training and 78.6/71.1/77.6 % on test set. Finally, the 3PRule and multiclassifier were validated with 23 drugs in a Caco-2 assay. The rule is very useful to improve assay design and prioritize the high absorption candidates. Meanwhile the QSPR model exhibits appropriate classification performance. Due to the simplicity, easy interpretation and accuracy, the 3PRule and consensus model developed here can be used in early ADME profiling. PMID- 27481667 TI - Ambit-Tautomer: An Open Source Tool for Tautomer Generation. AB - We present a new open source tool for automatic generation of all tautomeric forms of a given organic compound. Ambit-Tautomer is a part of the open source software package Ambit2. It implements three tautomer generation algorithms: combinatorial method, improved combinatorial method and incremental depth-first search algorithm. All algorithms utilize a set of fully customizable rules for tautomeric transformations. The predefined knowledge base covers 1-3, 1-5 and 1-7 proton tautomeric shifts. Some typical supported tautomerism rules are keto-enol, imin-amin, nitroso-oxime, azo-hydrazone, thioketo-thioenol, thionitroso thiooxime, amidine-imidine, diazoamino-diazoamino, thioamide-iminothiol and nitrosamine-diazohydroxide. Ambit-Tautomer uses a simple energy based system for tautomer ranking implemented by a set of empirically derived rules. A fine grained output control is achieved by a set of post-generation filters. We performed an exhaustive comparison of the Ambit-Tautomer Incremental algorithm against several other software packages which offer tautomer generation: ChemAxon Marvin, Molecular Networks MN.TAUTOMER, ACDLabs, CACTVS and the CDK implementation of the algorithm, based on the mobile H atoms listed in the InChI. According to the presented test results, Ambit-Tautomer's performance is either comparable to or better than the competing algorithms. Ambit-Tautomer module is available for download as a Java library, a command line application, a demo web page or OpenTox API compatible Web service. PMID- 27481668 TI - The Acid/Base Profile of the Human Metabolome and Natural Products. AB - Human small molecule metabolites (the human metabolome) are a set of compounds that interact with at least one macromolecule in the biosphere. This study investigates the acid/base profile of the human metabolome, natural products and drugs, together with an analysis of their physicochemical properties. Ionisation constants (pKa values) are estimated for each compound and the identity of the ionisable functional groups in each set is determined. The acid/base and physicochemical property profile of the lipid component of the metabolome differed considerably to the other datasets. In contrast, the acid/base properties of non-lipid metabolites were found to be similar to both drugs and natural products. While the non-lipid metabolites have lower average ClogP values and more hydrogen bond donors than the other datasets, the distribution of physicochemical property values overlapped considerably with the drug dataset. Considering also that the non-lipid metabolites are of biochemical interest, their characteristics have great potential to influence the selection of screening compounds for drug discovery. PMID- 27481669 TI - A Large-Scale Empirical Evaluation of Cross-Validation and External Test Set Validation in (Q)SAR. AB - (Q)SAR model validation is essential to ensure the quality of inferred models and to indicate future model predictivity on unseen compounds. Proper validation is also one of the requirements of regulatory authorities in order to accept the (Q)SAR model, and to approve its use in real world scenarios as alternative testing method. However, at the same time, the question of how to validate a (Q)SAR model, in particular whether to employ variants of cross-validation or external test set validation, is still under discussion. In this paper, we empirically compare a k-fold cross-validation with external test set validation. To this end we introduce a workflow allowing to realistically simulate the common problem setting of building predictive models for relatively small datasets. The workflow allows to apply the built and validated models on large amounts of unseen data, and to compare the performance of the different validation approaches. The experimental results indicate that cross-validation produces higher performant (Q)SAR models than external test set validation, reduces the variance of the results, while at the same time underestimates the performance on unseen compounds. The experimental results reported in this paper suggest that, contrary to current conception in the community, cross-validation may play a significant role in evaluating the predictivity of (Q)SAR models. PMID- 27481670 TI - Assessing the Stabilization of P-Glycoprotein's Nucleotide-Binding Domains by the Linker, Using Molecular Dynamics. AB - This paper focuses on the importance of the intermediate linker sequence for the stabilization of the cytoplasmic portion of murine P-glycoprotein, an ABC transporter involved in Multidrug Resistance (MDR) in cancer. Three putative protein-protein interaction areas were predicted to exist, two of them next to the C-terminal nucleotide-binding domain (NBD2) and the third one next to the inner leaflet interface of the lipid bilayer. These contact spots were confirmed by detailed contact maps from structures obtained before and after a 100 ns molecular dynamics production run, allowing a more thorough characterization of the type and number of residues involved in protein-protein contacts. It was found that these contact surfaces are located next to several highly conserved motifs of ABC transporters, serving as anchor points and assisting the linker's 'damper' function. PMID- 27481671 TI - Key Structural Features of Azanaphthoquinone Annelated Pyrrole Derivative as Anticancer Agents Based on the Rational Drug Design Approaches. AB - Azanaphthoquinone annelated pyrrole derivatives have been developed and synthesized with a continuous attempt to develop novel DNA intercalating agents as anti-cancer compounds with lower organ toxicity. With the remarkable antiproliferative activity of synthesized azanaphthoquinone annelated pyrrole derivatives, a structurally novel scaffold of these compounds is appropriated for further development of novel anti-cancer agents. Therefore, in the present study, 3D QSAR study (CoMSIA) was applied on 28 azanaphthoquinone annelated pyrrole derivatives to evaluate the structural requirement of these compounds. The resulting CoMSIA model is satisfied with r(2) of 0.99 and q(2) of 0.65. The interpretation of CoMSIA contours reveals the significant importance of steric, electrostatic, hydrophobic and hydrogen acceptor descriptors on the activities of azanaphthoquinone annelated pyrrole derivatives. Remarkably, the structural requirement of six substituent positions on the azanaphthoquinone annelated pyrrole scaffold was elucidated here. This result is the useful concept for design of new and more active azanaphthoquinone annelated pyrrole derivatives. Moreover, MD simulations using AMBER program were performed to model the binding of azanaphthoquinone annelated pyrrole derivatives in the intercalation site of the DNA duplex. Based on MD simulations, the information in terms of ligand-DNA interaction, complex structure and binding free energy was provided in this work. Therefore, the integrated results are informative for further modification of azanaphthoquinone annelated pyrrole scaffold leading to gain novel azanaphthoquinone annelated pyrrole derivatives possessing better antiproliferative activity. PMID- 27481672 TI - Timely follow-up of a GATA2 deficiency patient allows successful treatment. PMID- 27481673 TI - [Temporo-mandibular ankylosis]. AB - Ankylosis of the temporomandibular joint is defined as a permanent constriction of the jaws with less than 30mm mouth opening measured between the incisors, occurring because of bony, fibrous or fibro-osseous fusion. Resulting complications such as speech, chewing, swallowing impediment and deficient oral hygiene may occur. The overall incidence is decreasing but remains significant in some developing countries. The most frequent etiology in developed countries is the post-traumatic ankylosis occurring after condylar fracture. Other causes may be found: infection (decreasing since the advent of antibiotics), inflammation (rheumatoid arthritis and ankylosing spondylitis mainly) and congenital diseases (very rare). Management relies on surgery: resection of the ankylosis block in combination with bilateral coronoidectomy... The block resection may be offset by the interposition temporal fascia flap, a costochondral graft or a TMJ prosthesis according to the loss of height and to the impact on dental occlusion. Postoperative rehabilitation is essential and has to be started early, to be intense and prolonged. Poor rehabilitation is the main cause of ankylosis recurrence. PMID- 27481674 TI - [Temporo-mandibular joints and orthognathic surgery]. AB - Temporo-Mandibular Joints (TMJ) and orthognathic surgery are closely linked. In the past, some authors have even described (with mixed results) the correction of some dysmorphosis through direct procedures on the TMJs. Nowadays, performing orthognathic surgery involves the TMJ in three different occasions: (1) TMJ disorders potentially responsible for dento-maxillary dysmorphosis, (2) effects of orthognathic surgery on TMJs, and (3) condylar positioning methods in orthognathic surgery. These three chapters are developed in order to focus on the close relationships between TMJ and orthognathic surgery. Some perspectives close this article. PMID- 27481675 TI - Active release of pneumolysin prepores and pores by mammalian cells undergoing a Streptococcus pneumoniae attack. AB - BACKGROUND: Streptococcus pneumoniae is a potent human pathogen. Its pore-forming exotoxin pneumolysin is instrumental for breaching the host's epithelial barrier and for the incapacitation of the immune system. METHODS AND RESULTS: Using a combination of life imaging and cryo-electron microscopy we show that pneumolysin, released by cultured bacteria, is capable of permeabilizing the plasmalemma of host cells. However, such permeabilization does not lead to cell lysis since pneumolysin is actively removed by the host cells. The process of pore elimination starts with the formation of pore-bearing plasmalemmal nanotubes and proceeds by the shedding of pores that are embedded in the membrane of released microvesicles. Pneumolysin prepores are likewise removed. The protein composition of the toxin-induced microvesicles, assessed by mass spectrometry, is suggestive of a Ca(2+)-triggered mechanism encompassing the proteins of the annexin family and members of the endosomal sorting complex required for transport (ESCRT) complex. CONCLUSIONS: S. pneumoniae releases sufficient amounts of pneumolysin to perforate the plasmalemma of host cells, however, the immediate cell lysis, which is frequently reported as a result of treatment with purified and artificially concentrated toxin, appears to be an unlikely event in vivo since the toxin pores are efficiently eliminated by microvesicle shedding. Therefore the dysregulation of cellular homeostasis occurring as a result of transient pore formation/elimination should be held responsible for the damaging toxin action. GENERAL SIGNIFICANCE: We have achieved a comprehensive view of a general plasma membrane repair mechanism after injury by a major bacterial toxin. PMID- 27481676 TI - CRISPR interference as a titratable, trans-acting regulatory tool for metabolic engineering in the cyanobacterium Synechococcus sp. strain PCC 7002. AB - Trans-acting regulators provide novel opportunities to study essential genes and regulate metabolic pathways. We have adapted the clustered regularly interspersed palindromic repeats (CRISPR) system from Streptococcus pyogenes to repress genes in trans in the cyanobacterium Synechococcus sp. strain PCC 7002 (hereafter PCC 7002). With this approach, termed CRISPR interference (CRISPRi), transcription of a specific target sequence is repressed by a catalytically inactive Cas9 protein recruited to the target DNA by base-pair interactions with a single guide RNA that is complementary to the target sequence. We adapted this system for PCC 7002 and achieved conditional and titratable repression of a heterologous reporter gene, yellow fluorescent protein. Next, we demonstrated the utility of finely tuning native gene expression by downregulating the abundance of phycobillisomes. In addition, we created a conditional auxotroph by repressing synthesis of the carboxysome, an essential component of the carbon concentrating mechanism cyanobacteria use to fix atmospheric CO2. Lastly, we demonstrated a novel strategy for increasing central carbon flux by conditionally downregulating a key node in nitrogen assimilation. The resulting cells produced 2-fold more lactate than a baseline engineered cell line, representing the highest photosynthetically generated productivity to date. This work is the first example of titratable repression in cyanobacteria using CRISPRi, enabling dynamic regulation of essential processes and manipulation of flux through central carbon metabolism. This tool facilitates the study of essential genes of unknown function and enables groundbreaking metabolic engineering capability, by providing a straightforward approach to redirect metabolism and carbon flux in the production of high-value chemicals. PMID- 27481678 TI - Azygos vein aneurysm resection concomitant with heart valve repair via right thoracotomy. AB - Azygos vein aneurysm is very rare and is usually found incidentally because of its clinical silence. We report a case of recurrent pleural effusion caused by an azygos vein aneurysm in a patient with moderate mitral valve regurgitation (MR) and tricuspid valve regurgitation (TR). Since valve disease is considered a significant precipitating factor for both dyspnoea and pleural effusion, we decided to study the aetiologies of these conditions concomitantly. Azygos vein aneurysm resection in combination with tricuspid and mitral valve repair using cardiopulmonary bypass was performed successfully through a right anterior thoracotomy. The postoperative course was uneventful, and the patient reported improved exercise capacity. PMID- 27481677 TI - A Semantic Corpus Comparison Analysis of Couple-Focused Interventions for Problematic Alcohol Use. AB - : Incorporating spouses into interventions for problematic alcohol use is associated with increased efficacy; yet, little is known about the therapeutic processes that may explain these effects. In a study of partner language use during couple-focused alcohol interventions, we utilized a linguistic corpus comparison tool, Wmatrix, to identify semantic themes that differentiated couples with successful and unsuccessful treatment outcomes and may therefore also reflect potential change processes. Thirty-three couples participated in a randomized control trial of Family Systems Therapy (FST) or Cognitive Behavioural Therapy (CBT). Linguistic comparisons of partners' speech during the therapy sessions suggested that drinks and alcohol was a significant differentiating semantic theme. Specifically, patients and spouses in FST with successful outcomes used more language related to drinks and alcohol than patients and spouses in FST with unsuccessful outcomes. Post-hoc analyses of context suggested that, in FST, successful spouses spoke less about the patient's drinking and more about alcohol in general (without reference to an individual) than unsuccessful spouses. Conversely, spouses in CBT with successful outcomes used less language related to drinks and alcohol than spouses in CBT with unsuccessful outcomes. In CBT, successful spouses spoke more about the patient's and couple's drinking and less about the spouse's and other people's drinking than unsuccessful spouses. Results emphasize the role of spouse behaviour-in this case indexed via language use-in alcohol treatment outcomes. Findings also suggest potentially distinct therapeutic processes in FST and CBT and highlight the utility of linguistic corpus comparison methods in couple-focused intervention research. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Incorporating spouses into interventions for problematic alcohol use is associated with increased efficacy; yet, little is known about the specific therapeutic processes that may explain these effects. Findings from this study suggest that semantic themes such as drinks and alcohol in partner speech during therapy sessions differentiate successful and unsuccessful treatment outcomes among couples participating in two couple-focused interventions for problematic alcohol use. In addition, the context in which partners used alcohol-related language differed by intervention type and treatment outcome, which suggests potential therapeutic processes that are unique to the two interventions (Family Systems versus Cognitive Behavioural Therapy). PMID- 27481679 TI - Cardiac index assessment by the pressure recording analytical method in infants after paediatric cardiac surgery: a pilot retrospective study. AB - OBJECTIVES: Our aim was to verify whether the cardiac index (CI) estimated by the pressure recoding analytical method (PRAM) was associated with clinical metabolic indexes of tissue perfusion and mechanical ventilation duration in paediatric patients undergoing cardiac surgery on cardiopulmonary bypass (CPB) for congenital heart disease and whether it could therefore be considered a clinically reliable monitoring method. METHODS: A retrospective study was conducted in a paediatric cardiac intensive care unit (PCICU), applying PRAM, a minimally invasive advanced haemodynamic monitoring system (MostCare(r), Vygon, Vytech), for the first 24 postoperative hours. Haemodynamic and clinical average values were analysed as time-weighted average values at four postoperative time points (during the first 2 h from PCICU admission, from the 3rd to the 6th, from the 7th to the 12th and from the 13th to the 24th postoperative hours) and correlated with respective variables recorded and averaged at the same time points. RESULTS: Forty consecutive patients were enrolled. Median (interquartile range) age, CPB time and Aristotle score were 85 (47-200) days, 157 (112-185) minutes and 8.9 (7.5-10), respectively. CI values at the four time points were 2.89 (2.67-3.19), 2.94 (2.60-3.17), 2.84 (2.64-3.26) and 2.93 (2.58-3.46) l/min/m2, respectively. CI values correlated with lactate levels (r: -0.2; P = 0.01), systolic pressure (r: 0.34, P = 0.0001), heart rate (r: -0.4; P = 0.0001), vasoactive inotropic score (r: -0.3; P = 0.0001) and diuretic dose (r: -0.2; P = 0.01). In patients with low cardiac output syndrome (diagnosed according to clinical metabolic indexes), CI values estimated by PRAM were significantly lower than those of patients without signs of low cardiac output syndrome (P = 0.0001): 3.0 vs 2.8 (95% CI of difference -0.05 to 0.67), 3.1 vs 2.7 (95% CI of difference 0.13-0.85), 3.2 vs 2.7 (95% CI of difference 0.11-0.83) and 3.2 vs 2.7 (95% CI of difference 0.08-0.81) l/min/m2, respectively. Patients with a CI equal to or above 3 l/min/m2, compared with others, showed a significantly lower increase in creatinine levels from PCICU arrival to postoperative day 1: 0.07 (-0.1 to 0.2) vs 0.21 (0.05-0.3) mg/dl (P = 0.0016). Prediction of mechanical ventilation duration was independently associated only with CI (b: -3.4; r: -0.39; P = 0.04) in a multivariable model after adjustment for Aristotle score, vasoactive inotrope score, cross-clamp time, creatinine levels at PCICU admission and patient's age. CONCLUSIONS: CI estimated by PRAM after paediatric cardiac surgery was reliably associated with clinical indicators of tissue perfusion, with vasoactive and diuretic drug requirements, and predicted longer mechanical ventilation duration. PMID- 27481680 TI - Early outcomes of lung transplantation for bronchiolitis obliterans syndrome after allogeneic haematopoietic stem cell transplantation: a single-centre experience. AB - OBJECTIVES: Bronchiolitis obliterans syndrome (BOS) is a serious late complication following allogeneic haematopoietic stem cell transplantation (allo HSCT) and is associated with chronic graft-versus-host disease. However, the outcome of medical treatment for BOS, mainly immunosuppressive therapy, is disappointing. This study evaluated the early outcomes of lung transplantation (LTx) as a treatment option for severe BOS. METHODS: Between January 2010 and December 2014, we retrospectively reviewed the medical records and postoperative outcomes of 9 patients who underwent LTx for BOS after allo-HSCT at a single institution. RESULTS: The median age of patients at the time of LTx was 21 years, and the median interval from the diagnosis of BOS to LTx was 17.1 months. At the time of LTx, 5 patients were receiving oxygen therapy via nasal prongs, whereas the remaining 4 were receiving mechanical ventilation supports, 2 of whom requiring extracorporeal lung support. All patients underwent bilateral lung transplantation. During a median follow-up of 17 months after LTx, 2 patients died: one of intra-cranial haemorrhage and pneumonia during hospitalization and another patient of pneumonia and septic shock after discharge. Although the follow-up was short, the remaining 7 patients are currently healthy and active except one who developed BOS 45.3 months after LTx; he is on the waiting list for retransplantation. One patient experienced acute rejection that resolved after steroid pulse therapy. There was no relapse of the haematological disease after LTx. CONCLUSIONS: LTx could be a reasonable therapeutic option in selected patients with refractory BOS not responsive to conventional therapy. PMID- 27481681 TI - Pectus excavatum in mummies from ancient Egypt. AB - Pectus excavatum is one of the common congenital anomalies, yet there seems to be a suspicious absence of any cases or descriptions of this deformity from antiquity. This could represent a real change in disease prevalence but is more likely just due to an inadequate reporting in medico-historical literature. The current study reviews reports of computed tomography (CT) scans of 217 ancient Egyptian mummies, revealing 3 presumed cases of this deformity. Therefore, pectus excavatum was in fact present already in ancient times, with prevalence roughly similar to the modern one. PMID- 27481682 TI - Aberrant origin of left subclavian artery from the pulmonary artery and right aortic arch in an aortopulmonary window. AB - Aortopulmonary window (APW) is a rare congenital anomaly that occurs in 0.2-0.6% of congenital heart diseases. APW often coexists with other cardiac malformations. However, APW together with aberrant origin of the left subclavian artery (LSA) from the main pulmonary artery is rarely seen. Here, we report an infant with right aortic arch in APW, who was found to have aberrant origin of the LSA from the main pulmonary artery. We confirmed its origin in the anatomical settings and modified a repair technique according to his individual situation, which brought successful results to the patient. PMID- 27481683 TI - Left ventricular assist device implantation in patients after left ventricular reconstruction. AB - Left ventricular assist device (LVAD) implantation can be challenging in patients with a prior surgical ventricular restoration (SVR). In this case series of heart failure patients with a history of SVR, we describe the surgical technique and outcome of a customized approach for inflow cannula orientation. Seven patients with a history of SVR with end-stage chronic heart failure were accepted for long term LVAD support. In all patients, the Dacron patch was removed through left ventriculotomy and a Hegar 22 dilator was inserted at the estimated optimal position of the LVAD inflow cannula. The left ventricle was reconstructed around the dilator from the left ventricular (LV) apex to the base. Finally, the LVAD sewing ring was sutured onto the remaining apical defect and a HeartWare(r) LVAD was implanted. LVAD implantation was successful in all 7 patients. Transoesophageal echocardiography ensured an adequate LVAD position and inflow and outflow cannula Doppler flow recordings. The mean intensive care unit stay was 5.8 +/- 2.6 days, and the hospital stay after surgery was 32 +/- 16 days. All patients follow regular visits (follow-up 20 +/- 16 months) at the outpatient clinic without any remarkable event. Using the technique described, LVAD implantation in patients after SVR is feasible and safe. PMID- 27481684 TI - Atrio-oesophageal fistula: dismal outcome of a rare complication with no common solution. AB - Atrio-oesophageal fistula caused by diffusion of ablative energy through the left atrial wall to the oesophagus is a lethal complication. A high level of suspicion, rapid diagnosis and early correction are of crucial importance. In this review, we highlight the key points that will aid in the thought processes and provide guidance in the prevention, early diagnosis and management to reduce complications and improve outcome when atrio-oesophageal fistula is suspected. PMID- 27481686 TI - In reply to commentary on "Does the piezoelectric surgical technique produce fewer postoperative sequelae after lower third molar surgery than conventional rotary instruments? A systematic review and meta-analysis". PMID- 27481685 TI - Applicability of cardiogoniometry as a non-invasive screening tool for the detection of graft vasculopathy in heart transplant recipients. AB - Currently available diagnostic modalities for the detection of graft vasculopathy following orthotopic heart transplantation are subject to various restrictions. We hypothesized that cardiogoniometry, a novel non-invasive diagnostic tool for the detection of atherosclerotic coronary vessel disease, is applicable in the graft vasculopathy setting. Cardiogoniometric results were obtained during routine follow-up in 49 consecutive, unselected heart transplant recipients and then retrospectively correlated blindly by an independent reader to recent angiographic findings. Sensitivity of cardiogoniometry was 100%, specificity 62.3%, positive predictive value 68.75%, negative predictive value 100%, negative likelihood ratio 0 and positive likelihood ratio 2.888. Cardiogoniometry is potentially applicable as an easy-to-perform, non-invasive screening tool predominantly for the exclusion but also for the detection of graft vasculopathy in heart transplant recipients. PMID- 27481687 TI - Nasal radix augmentation in rhinoplasty: suggestion of an algorithm. AB - The purpose of this study was to evaluate four standard techniques for radix augmentation during primary rhinoplasty: Skoog, crushed septal cartilage, temporalis fascia, and crushed cartilage wrapped in temporalis fascia. The main criterion for a patient to be included in this study was the need for radix augmentation, which was determined through preoperative evaluations. All patients requiring total dorsal augmentation were excluded from the study. This study included 63 rhinoplasty patients who underwent radix augmentation. The Skoog technique was applied in 15 patients, crushed septal cartilage in 16, temporalis fascia in 17, and crushed cartilage wrapped in temporalis fascia in 15. In those undergoing the Skoog technique, sharp edges of graft were palpable in three patients and were even visible in one patient. In the crushed cartilage group, seven patients showed irregularities during the postoperative follow-up. The results of this study indicate that all four autologous grafts represent acceptable graft material for radix augmentation. The algorithm suggests using the easier techniques first and that secondary donor sites should be considered only when the ideal result is not achieved. PMID- 27481688 TI - Accuracy of three-dimensional facial soft tissue simulation in post-traumatic zygoma reconstruction. AB - The aim of this study was to evaluate the accuracy of novel software-CMF-preCADS for the prediction of soft tissue changes following repositioning surgery for zygomatic fractures. Twenty patients who had sustained an isolated zygomatic fracture accompanied by facial deformity and who were treated with repositioning surgery participated in this study. Cone beam computed tomography (CBCT) scans and three-dimensional (3D) stereophotographs were acquired preoperatively and postoperatively. The 3D skeletal model from the preoperative CBCT data was matched with the postoperative one, and the fractured zygomatic fragments were segmented and aligned to the postoperative position for prediction. Then, the predicted model was matched with the postoperative 3D stereophotograph for quantification of the simulation error. The mean absolute error in the zygomatic soft tissue region between the predicted model and the real one was 1.42+/-1.56mm for all cases. The accuracy of the prediction (mean absolute error <=2mm) was 87%. In the subjective assessment it was found that the majority of evaluators considered the predicted model and the postoperative model to be 'very similar'. CMF-preCADS software can provide a realistic, accurate prediction of the facial soft tissue appearance after repositioning surgery for zygomatic fractures. The reliability of this software for other types of repositioning surgery for maxillofacial fractures should be validated in the future. PMID- 27481689 TI - Critical incidents in a French department of paediatric anaesthesia. AB - BACKGROUND: Several studies have highlighted the importance of critical incident (CI) reporting in order to enhance patient safety. We have implemented an anonymous procedure for CI reporting in our department of paediatric anaesthesia. This study aims at analysing those CIs so as to improve patient care and risk management. MATERIAL AND METHODS: CIs were reported by the anaesthetic team using the World Health Organization classification and analysed using the ORION methodology. CIs were classified according to type, surgery and complications. Risk factors and consequences for patients and for the institution were analysed. Risk factors with high degree of harm for the patient were identified using a univariate analysis and odds ratios (OR). RESULTS: Over an 18-month period, 114 CIs were reported for 103 patients (median age: 7.0 years [95% CI: 3.6-9.8]). We found that 29.9% of reported CIs had consequences for the patients and 76.3% were considered preventable. The two main types of CI were "respiratory" (28.8%) and "drug-related" (22.8%) incidents. The main risk factor was 'human error' (42.3%). Several consequences for the patient and the hospital were identified. An ASA score>=3 (OR: 2.52; [95% CI: 1.10-5.78]) was an independent risk factor for a high degree of patient harm. CONCLUSION: Improving quality of care must be a priority for paediatric anaesthesiologists as most of the CIs observed are preventable and have consequences for the patient and the institution. PMID- 27481690 TI - Triage in military settings. AB - Triage, a medical term derived from the French word "trier", is the practical process of sorting casualties to rationally allocate limited resources. In combat settings with limited medical resources and long transportation times, triage is challenging since the objectives are to avoid overcrowding medical treatment facilities while saving a maximum of soldiers and to get as many of them back into action as possible. The new face of modern warfare, asymmetric and non conventional, has led to the integrative evolution of triage into the theatre of operations. This article defines different triage scores and algorithms currently implemented in military settings. The discrepancies associated with these military triage systems are highlighted. The assessment of combat casualty severity requires several scores and each nation adopts different systems for triage on the battlefield with the same aim of quickly identifying those combat casualties requiring lifesaving and damage control resuscitation procedures. Other areas of interest for triage in military settings are discussed, including predicting the need for massive transfusion, haemodynamic parameters and ultrasound exploration. PMID- 27481691 TI - Ready-to-use pre-filled syringes of atropine for anaesthesia care in French hospitals - a budget impact analysis. AB - BACKGROUND: Patient safety is improved by the use of labelled, ready-to-use, pre filled syringes (PFS) when compared to conventional methods of syringe preparation (CMP) of the same product from an ampoule. However, the PFS presentation costs more than the CMP presentation. OBJECTIVE: To estimate the budget impact for French hospitals of switching from atropine in ampoules to atropine PFS for anaesthesia care. METHODS: A model was constructed to simulate the financial consequences of the use of atropine PFS in operating theatres, taking into account wastage and medication errors. The model tested different scenarios and a sensitivity analysis was performed. RESULTS: In a reference scenario, the systematic use of atropine PFS rather than atropine CMP yielded a net one-year budget saving of ?5,255,304. Medication errors outweighed other cost factors relating to the use of atropine CMP (?9,425,448). Avoidance of wastage in the case of atropine CMP (prepared and unused) was a major source of savings (?1,167,323). Significant savings were made by means of other scenarios examined. The sensitivity analysis suggests that the results obtained are robust and stable for a range of parameter estimates and assumptions. STUDY LIMITATIONS: The financial model was based on data obtained from the literature and expert opinions. CONCLUSION: The budget impact analysis shows that even though atropine PFS is more expensive than atropine CMP, its use would lead to significant cost savings. Savings would mainly be due to fewer medication errors and their associated consequences and the absence of wastage when atropine syringes are prepared in advance. PMID- 27481692 TI - Upper airway modifications in head extension during development. AB - BACKGROUND: One of the requirements of laryngoscopy is to determine which head position will result in optimal visualization. Our hypothesis was that parameters derived from magnetic resonance imaging (MRI) can help quantify the effect of age on airway modifications due to head extension during development. METHOD: In children undergoing planned MRI, additional sequences on the upper airways were performed: one in a near-neutral position, the other with the head extended at 35 degrees . The axis of the face, the pharynx, the larynx, the trachea, and the line of glottic visualization were determined. The following angles were calculated: the Visu-Lar angle, formed by the line of glottic visualization and the laryngeal axis, and the Phar-Lar angle, formed by the pharyngeal and laryngeal axes. RESULTS: One hundred and fifty-five patients (1 to 222 months of age [25-145] months) were included and 54% were under general anaesthesia. Age had no effect on the variation in the Visu-Lar angle, which diminished as a function of head extension, nor on the variation in the Phar-Lar angle, which was minimal in the neutral position. During extension, anatomical axes rotated similarly, and the visualization axis rotated the most, followed by the pharyngeal and laryngeal axes. These results were not correlated with general anaesthesia. CONCLUSION: Regardless of age, head extension diminished the Visu Lar angle, and increased the Phar-Lar angle. This study supports that, as in adults, head extension is probably the key factor for good visualization conditions during laryngoscopy on children, but clinical data is needed to confirm this result. PMID- 27481694 TI - A positive association between active lifestyle and hemispheric lateralization for motor control and learning in older adults. AB - Physical activity (PA) is well known to have general health benefits for older adults, but it is unclear whether it can also positively affect brain function involved in motor control and learning. We have previously shown that interlimb transfer of visuomotor adaptation occurs asymmetrically in young adults, while that occurs symmetrically in older adults, which suggests that the lateralized function of each hemisphere during motor tasks is diminished with aging. Here, we investigated the association between the level of PA and hemispheric motor lateralization by comparing the pattern of interlimb transfer following visuomotor adaptation between physically active and inactive older adults. Subjects were divided into two groups based on their PA level (active, inactive). They were further divided into two groups, such that a half of the subjects in each group adapted to a 30 degrees rotation during targeted reaching movements with the left arm first, then with the right arm; and the other half with the right arm first, then with the left arm. Results indicated asymmetrical transfer (from left to right only) in the active subjects, whereas symmetrical transfer (from left to right, and vice versa) was observed in the inactive subjects. These findings suggest that older adults who maintain active lifestyle have a central nervous system that is more intact in terms of its lateralized motor function as compared with those who are inactive. PMID- 27481693 TI - Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801 induced cognitive dysfunction. AB - Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), which is a second receptor for prostaglandin (PG) D2, is involved in inflammatory responses in peripheral tissue; however, its role in cognitive function remains unclear. Here, we demonstrate that CRTH2 is involved in cognitive function using a well-established animal model of cognitive dysfunction induced by MK-801, an N-methyl-d-aspartate receptor antagonist. Genetic deletion and pharmacological inhibition of CRTH2 suppressed MK-801-induced cognitive dysfunction. Pharmacological inhibition of cyclooxygenase-1, a rate-limiting enzyme in PG synthesis, also suppressed MK-801-induced cognitive dysfunction. Moreover, an MK-801-induced increase in c-Fos expression in the paraventricular nucleus (PVN) was abolished in the CRTH2-deficient mice. Together, these results suggest that PGD2-CRTH2 signaling is involved in both MK-801-induced cognitive dysfunction and neuronal activity regulation in the PVN. Furthermore, genetic association studies suggest that CRTH2 is weakly associated with cognitive function in humans. Our study provides evidence that PGD2-CRTH2 signaling is involved in cognitive function and may represent a potential therapeutic target for cognitive dysfunction in patients with psychiatric disorders. PMID- 27481695 TI - Aging, motor function, and sensitivity to calcium channel blockers: An investigation using chronic methylmercury exposure. AB - Methylmercury (MeHg) neurotoxicity is thought to be mediated, in part, by dysregulation of calcium (Ca(2+)) homeostasis, a mechanism that may also slowly and progressively degrade neuronal function during normal aging. Longitudinal studies of MeHg exposure provide a powerful approach to studying neural and behavioral mechanisms by which both MeHg toxicity and aging affect motor function. Wheel-running and rotarod performance were assessed in two age groups of BALB/c mice chronically exposed to 0 or 1.2mg/kg/day MeHg and 0 or 20mg/kg/day nimodipine, a 1,4-dihyrdopyridine L-type calcium channel blocker (CCB), for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and retired breeders on PND 296. A log-survivor bout analysis partitioned wheel running into bouts that identified motor (within-bout rates) and motivational (bout-initiation rates) influences. Retired breeders ran farther, because of a higher bout-initiation rates, but performed more poorly on the rotarod than younger adults, a difference unaffected by nimodipine. MeHg produced relatively age-independent deficits in wheel-running and rotarod performance, whereas nimodipine afforded greater protection to adult mice than to retired breeders. Rotarod performance and within-bout response rate were more sensitive to and more reliable predictors of MeHg toxicity than bout-initiation rate, which was least affected by MeHg exposure. Thus the motivation to run was unimpaired as the ability to do so declined. While chronic MeHg exposure produced functionally similar behavior deficits between age groups, the age-dependent neuroprotection by nimodipine supports the notion that underlying neurobiological systems mediated by Ca(2+) signaling, are differentially affected in older adults. PMID- 27481696 TI - Comparing the ratio of mean red blood cell transfusion episode rate of 1 unit versus 2 units in hematopoietic stem cell transplant patients. AB - BACKGROUND: Two units of red blood cells (RBCs) were typically transfused with each transfusion among hematopoietic stem cell transplant (HSCT) patients. Concerns regarding this practice are increased morbidity, mortality, hospital acquired infections, length of stay (LOS), and transfusion-related complications. This study compared outcomes of transfusing 1 unit of RBCs per transfusion episode to 2 units of RBCs per episode among HSCT patients. STUDY DESIGN AND METHODS: A retrospective record review was used to evaluate a practice change of transfusing 1 RBC unit per episode among autologous and allogeneic HSCT patients. Primary endpoints included: 1) mean number of RBC transfusion episodes during the hospital stay, 2) mean number of RBC units transfused adjusted by LOS, and 3) mean LOS. RESULTS: Among autologous patients, the ratio of mean rate of transfusion episodes for transfusing 1 unit versus 2 units per transfusion was 1.24, with a one-tailed 95% upper limit of 1.42. With a noninferiority upper bound of 1.50, using 1 unit per transfusion episode was noninferior to 2 units per transfusion episode (p = 0.011). Among allogeneic HSCT patients, the ratio of mean transfusion episode rate was 1.26 with a one-tailed 95% upper limit of 1.52, which was slightly above the 1.50 noninferiority bound (p = 0.061). CONCLUSION: A single-unit transfusion policy was not inferior to the 2-unit policy for autologous HSCT patients and trended toward noninferiority for allogeneic transplant patients. The mean volume of blood per LOS was lower for the 1-unit practice for both groups. The gains from the practice change may outweigh the risks of not changing. PMID- 27481697 TI - Social Cognition, Child Neglect, and Child Injury Risk: The Contribution of Maternal Social Information Processing to Maladaptive Injury Prevention Beliefs Within a High-Risk Sample. AB - Objective: Inadequate supervision has been linked to children's injuries. Parental injury prevention beliefs may play a role in supervision, yet little theory has examined the origins of such beliefs. This study examined whether mothers who perpetrated child neglect, who as a group provide inadequate supervision, have more maladaptive beliefs. Then, it tested a social information processing (SIP) model for explaining these beliefs. Methods: SIP and injury prevention beliefs were assessed in disadvantaged mothers of preschoolers (N = 145), half with child neglect histories. Results: The neglect group exhibited significantly more maladaptive injury prevention beliefs than comparisons. As predicted, SIP was linked to beliefs that may increase injury risk, even after accounting for relevant sociodemographic variables. Conclusions: Findings support the link of beliefs to injury risk and suggest that specific cognitive problems may underlie these beliefs. Future work should further validate this model, which may inform enhancements to prevention efforts. PMID- 27481698 TI - Generation of rats from vitrified oocytes with surrounding cumulus cells via in vitro fertilization with cryopreserved sperm. AB - The objective of this study was to evaluate fertility and full-term development of rat vitrified oocytes after in vitro fertilization (IVF) with cryopreserved sperm. Oocytes with or without surrounding cumulus cells were vitrified with 30% ethylene glycol + 0.5 mol/L sucrose + 20% fetal calf serum by using the Cryotop method. The warmed oocytes were co-cultured with sperm. Although the denuded/vitrified oocytes were not fertilized, some of the oocytes vitrified with cumulus cells were fertilized (32.7%) after IVF with fresh sperm. When IVF was performed with cryopreserved sperm, vitrified or fresh oocytes with cumulus cells were fertilized (62.9% or 41.1%, respectively). In addition, to confirm the full term development of the vitrified oocytes with surrounding cumulus cells after IVF with cryopreserved sperm, 108 vitrified oocytes with two pronuclei (2PN) were transferred into eight pseudopregnant females, and eight pups were obtained from three recipients. The present work demonstrates that vitrified rat oocytes surrounded by cumulus cells can be fertilized in vitro with cryopreserved sperm, and that 2PN embryos derived from cryopreserved gametes can develop to term. To our knowledge, this is the first report of successful generation of rat offspring derived from vitrified oocytes that were fertilized in vitro with cryopreserved sperm. PMID- 27481699 TI - Assessing student clinical learning experiences. AB - BACKGROUND: This article describes the use of an activity worksheet and questionnaire to investigate the learning experience of students on clinical placement. The worksheet measures the amount of time students spend in different learning activities, and the questionnaire explores student satisfaction and preferred learning activities. An activity worksheet and questionnaire ... investigate[d] the learning experiences of students on clinical placement METHODS: The activity worksheet and questionnaire were used in a cohort pilot study of physiotherapy students on clinical placement. RESULTS: The activity worksheet provides details of the amount of time students engage in a range of clinical and non-clinical tasks while on placement, such as time spent treating patients, working individually, working with their peers and engaging in reflective practice. In combination with the questionnaire results, it allows clinicians to gain an understanding of the clinical learning environment experienced by their students. DISCUSSION: The data collected using these tools provide a description of the students' activities while undertaking the clinical placement. This information may guide the refinement of the clinical experience, and offers an opportunity to individualise learning activities to match students' needs and preferences. PMID- 27481700 TI - A novel prophage lysin Ply5218 with extended lytic activity and stability against Streptococcus suis infection. AB - Streptococcus suis (S. suis) is an emerging zoonotic agent that exhibits high level resistance to classic antibiotics and a heavy burden in the swine industry. Therefore alternative antibacterial agents need to be developed. A novel endolysin derived from the S. suis temperate phage phi5218, termed Ply5218, was identified. The minimum inhibitory concentration (MIC) of Ply5218 was 2.5 MUg ml( 1) against S. suis strain HA9801, an activity many times greater than the lysins reported previously (MIC of LY7917 and Ply30 against HA9801 were 80 and 64 MUg ml(-1), respectively). Ply5218 at 10 MUg ml(-1) in vitro exerted broad antibacterial activities against S. suis strains with OD600 ratios decreased from 1 to <0.2 within 1 h. Moreover, Ply5218 showed favorable thermal stability. It was stable at 50 degrees C >30 min, 4 degrees C >30 days, -80 degrees C >7 months, and >60% of the enzyme activity remained after 5 min pre-incubation at 70 degrees C. In vivo, a 0.2 mg dose of Ply5218 protected 90% (9/10) of mice after infection with S. suis HA9801. Finally, Ply5218 maintained high antibacterial activity in some bio-matrices, such as culture media and milk. The data indicate that Ply5218 has all the characteristics to be an effective therapeutic agent against multiple S. suis infections. PMID- 27481701 TI - Simultaneous detection of somatic and F-specific coliphages in different settings by Escherichia coli strain CB390. AB - Bacteriophages are increasingly being used as water quality indicators. Two groups of phages infecting Escherichia coli, somatic and F-specific coliphages, are being considered as indicators of fecal and viral contamination for several types of water around the world. However, some uncertainties remain regarding which coliphages to assess. Recently, E. coli strain CB390 has been reported to be suitable for simultaneous detection of both groups, which seems to be more informative than determining only one of the groups. Here, a significant number of samples from different settings, mostly those where F-specific phages have been reported to outnumber somatic coliphages, are analyzed for somatic coliphages, F-specific RNA phages by standardized methods and coliphages detected by host strain CB390. The results presented here confirm that the numbers of phages counted using CB390 are equivalent to the sum of the somatic and F specific coliphages counted independently in all settings. Hence the usefulness of this strain for simultaneous detection of somatic and F-specific coliphages is confirmed. Also, sets of data on the presence of coliphages in reclaimed and groundwater are reported. PMID- 27481702 TI - Membrane localization and topology of the DnpA protein control fluoroquinolone tolerance in Pseudomonas aeruginosa. AB - DnpA, a putative de-N-acetylase of the PIG-L superfamily, is required for antibiotic tolerance in Pseudomonas aeruginosa Exactly how dnpA (gene locus PA5002) directs the formation of antibiotic-tolerant persister cells is currently unknown. Previous research provided evidence for a role in surface-associated process(es), possibly in lipopolysaccharide biosynthesis. In silico sequence analysis of DnpA predicts a single transmembrane domain and Nin/Cout orientation of DnpA. In contrast, we here show that DnpA is an integral inner membrane protein containing two transmembrane domains, with the major C-terminal part located at the cytoplasmic face. Correct insertion into the inner membrane is necessary for DnpA to promote fluoroquinolone tolerance. The membrane localization of DnpA further supports its role in cell envelope-associated process(es). In addition to shedding light on the biological role of DnpA, this study highlights the risks of overreliance on the predictive value of bioinformatics tools and the importance of rigorous experimental validation of in silico predictions. PMID- 27481703 TI - Effects of MreB paralogs on poly-gamma-glutamic acid synthesis and cell morphology in Bacillus amyloliquefaciens. AB - Actin-like MreB paralogs play important roles in cell shape maintenance, cell wall synthesis and the regulation of the D,L-endopeptidases, CwlO and LytE. The gram-positive bacteria, Bacillus amyloliquefaciens LL3, is a poly-gamma-glutamic acid (gamma-PGA) producing strain that contains three MreB paralogs: MreB, Mbl and MreBH. In B. amyloliquefaciens, CwlO and LytE can degrade gamma-PGA. In this study, we aimed to test the hypothesis that modulating transcript levels of MreB paralogs would alter the synthesis and degradation of gamma-PGA. The results showed that overexpression or inhibition of MreB, Mbl or MreBH had distinct effects on cell morphology and the molecular weight of the gamma-PGA products. In fermentation medium, cells of mreB inhibition mutant were 50.2% longer than LL3, and the gamma-PGA titer increased by 55.7%. However, changing the expression level of mbl showed only slight effects on the morphology, gamma-PGA molecular weight and titer. In the mreBH inhibition mutant, gamma-PGA production and its molecular weight increased by 56.7% and 19.4%, respectively. These results confirmed our hypothesis that suppressing the expression of MreB paralogs might reduce gamma-PGA degradation, and that improving the cell size could strengthen gamma-PGA synthesis. This is the first report of enhanced gamma-PGA production via suppression of actin-like MreB paralogs. PMID- 27481704 TI - ydjN encodes an S-sulfocysteine transporter required by Escherichia coli for growth on S-sulfocysteine as a sulfur source. AB - Sulfur is an essential element for growth and many physiological functions. As sulfur sources for Escherichia coli and related bacteria, specific transporters import various sulfur-containing compounds from the environment. In this study, we identified and characterized an alternative function of the cystine transporter YdjN in E. coli as a transporter of S-sulfocysteine, a sulfur containing intermediate in the assimilatory cysteine biosynthesis that is used as a sulfur source for the growth of E. coli We also demonstrated that the transport of S-sulfocysteine via YdjN depends on the transcriptional regulator CysB, a master regulator that controls most of the genes involved in sulfur assimilation and cysteine metabolism. We found that the use of S-sulfocysteine as a sulfur source depends on glutathione because mutations in glutathione biosynthetic genes abolish growth when S-sulfocysteine is used as a sole sulfur source, thereby supporting the previous findings that the conversion of S-sulfocysteine to cysteine is catalyzed by glutaredoxins. To the best of our knowledge, this is the first report of a functional S-sulfocysteine transporter across organisms, which strongly supports the hypothesis that S-sulfocysteine is not only a metabolic intermediate but also a physiologically significant substance in specific natural environments. PMID- 27481705 TI - Inhibition by fructose 1,6-bisphosphate of transaldolase from Escherichia coli. AB - The effect of fructose 1,6-bisphosphate (Fru 1,6-P2) on the regulatory enzymes of pentose phosphate pathway of Escherichia coli was examined. Fru 1,6-P2 inhibited E. coli transaldolase (EC 2.2.1.2) competitively against fructose 6-phosphate and uncompetitively against erythrose 4-phosphate, whereas Fru 1,6-P2 did not affect glucose 6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44). Kinetic results can be explained by assuming that transaldolase has two kinds of binding sites for Fru 1,6-P2: a competitive binding site for fructose 6-phosphate and a second binding site on the enzyme erythrose 4-phosphate complex. Fru 1,6-P2 increased resulting from the stimulation of glycolysis, can inhibit transaldolase and further participates in the elevation of the concentration of ribose 5-phosphate that can be preferentially utilized for anabolic reaction in exponential phase of E. coli. PMID- 27481706 TI - Untreated, Uncontrolled, and Apparent Resistant Hypertension: Results of the German Health Examination Survey 2008-2011. AB - The prevalence and associated factors of untreated, uncontrolled, and apparent resistant hypertension (RH) in Germany are unknown. Based on European Society of Hypertension criteria, apparent RH was defined as blood pressure (BP) >=140/90 mm Hg (>=140/85 mm Hg in diabetics) under treatment with three different classes of antihypertensive agents including a diuretic. Data from the German Health Examination Survey (2008-2011; n=7115, age 18-79 years) including standardized BP measurements and Anatomical Therapeutic Chemical-coded taken medications were analyzed. Among patients aware of their hypertensive status (n=2205), 37.9% were uncontrolled and, among those, 33.4% were untreated. Being aware and having untreated and uncontrolled BP was associated with male sex, young age, not having cardiovascular disease, not performing BP self-measurement, not being obese, and not smoking. Apparent RH occurred in 6.8% of treated aware hypertensive patients and was positively associated with having diabetes. The proportion of uncontrolled BP is still high. Not having "obvious risk factors" has become a risk itself for having untreated and uncontrolled hypertension. PMID- 27481707 TI - Dissecting major signaling pathways in prostate cancer development and progression: Mechanisms and novel therapeutic targets. AB - Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy and leading cause of cancer mortality in men. At the initial stages, prostate cancer is dependent upon androgens for their growth and hence effectively combated by androgen deprivation therapy (ADT). However, most patients eventually recur with an androgen deprivation-resistant phenotype, referred to as castration resistant prostate cancer (CRPC), a more aggressive form for which there is no effective therapy presently available. The current review is an attempt to cover and establish an understanding of some major signaling pathways implicated in prostate cancer development and castration-resistance, besides addressing therapeutic strategies that targets the key signaling mechanisms. PMID- 27481708 TI - Second Messengers. AB - Second messengers are small molecules and ions that relay signals received by cell-surface receptors to effector proteins. They include a wide variety of chemical species and have diverse properties that allow them to signal within membranes (e.g., hydrophobic molecules such as lipids and lipid derivatives), within the cytosol (e.g., polar molecules such as nucleotides and ions), or between the two (e.g., gases and free radicals). Second messengers are typically present at low concentrations in resting cells and can be rapidly produced or released when cells are stimulated. The levels of second messengers are exquisitely controlled temporally and spatially, and, during signaling, enzymatic reactions or opening of ion channels ensure that they are highly amplified. These messengers then diffuse rapidly from the source and bind to target proteins to alter their properties (activity, localization, stability, etc.) to propagate signaling. PMID- 27481710 TI - The maturation of computational work and its place within the scope of JGP. PMID- 27481711 TI - Specific contributions of the four voltage-sensing domains in L-type calcium channels to gating and modulation. PMID- 27481709 TI - Signaling Receptors for TGF-beta Family Members. AB - Transforming growth factor beta (TGF-beta) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-beta receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3'-kinase, and Rho GTPases. PMID- 27481712 TI - Insights into the structure and function of HV1 from a meta-analysis of mutation studies. AB - The voltage-gated proton channel (HV1) is a widely distributed, proton-specific ion channel with unique properties. Since 2006, when genes for HV1 were identified, a vast array of mutations have been generated and characterized. Accessing this potentially useful resource is hindered, however, by the sheer number of mutations and interspecies differences in amino acid numbering. This review organizes all existing information in a logical manner to allow swift identification of studies that have characterized any particular mutation. Although much can be gained from this meta-analysis, important questions about the inner workings of HV1 await future revelation. PMID- 27481715 TI - ABSTRACTS OF PAPERS AT THE SEVENTIETH ANNUAL MEETING OF THE SOCIETY OF GENERAL PHYSIOLOGISTS: Genetic and Animal Models for Ion Channel Function in Physiology and Disease. PMID- 27481713 TI - The alpha2delta-1 subunit remodels CaV1.2 voltage sensors and allows Ca2+ influx at physiological membrane potentials. AB - Excitation-evoked calcium influx across cellular membranes is strictly controlled by voltage-gated calcium channels (CaV), which possess four distinct voltage sensing domains (VSDs) that direct the opening of a central pore. The energetic interactions between the VSDs and the pore are critical for tuning the channel's voltage dependence. The accessory alpha2delta-1 subunit is known to facilitate CaV1.2 voltage-dependent activation, but the underlying mechanism is unknown. In this study, using voltage clamp fluorometry, we track the activation of the four individual VSDs in a human L-type CaV1.2 channel consisting of alpha1C and beta3 subunits. We find that, without alpha2delta-1, the channel complex displays a right-shifted voltage dependence such that currents mainly develop at nonphysiological membrane potentials because of very weak VSD-pore interactions. The presence of alpha2delta-1 facilitates channel activation by increasing the voltage sensitivity (i.e., the effective charge) of VSDs I-III. Moreover, the alpha2delta-1 subunit also makes VSDs I-III more efficient at opening the channel by increasing the coupling energy between VSDs II and III and the pore, thus allowing Ca influx within the range of physiological membrane potentials. PMID- 27481717 TI - Errors in data interpretation and terminology must not deter us from meticulous, high quality colorectal cancer surgery. PMID- 27481714 TI - Coupling of TRPV6 and TMEM16A in epithelial principal cells of the rat epididymis. AB - The epididymis establishes a congenial environment for sperm maturation and protection. Its fluid is acidic, and the calcium concentration is low and declines along the length of the epididymal tubule. However, our knowledge of ionic currents and mechanisms of calcium homeostasis in rat epididymal epithelial cells remains enigmatic. In this study, to better understand calcium regulation in the epididymis, we use the patch-clamp method to record from single rat cauda epididymal principal cells. We detect a constitutively active Ca(2+) current with characteristics that match the epithelial calcium channel TRPV6. Electrophysiological and pharmacological data also reveal a constitutively active calcium-activated chloride conductance (CaCC). Removal of extracellular calcium attenuates not only the TRPV6-like conductance, but also the CaCC. Lanthanide block is time dependent such that the TRPV6-like component is inhibited first, followed by the CaCC. The putative CaCC blocker niflumic acid partially inhibits whole-cell currents, whereas La(3+) almost abolishes whole-cell currents in principal cells. Membrane potential measurements reveal an interplay between La(3+)-sensitive ion channels and those that are sensitive to the specific TMEM16A inhibitor tannic acid. In vivo perfusion of the cauda epididymal tubule shows a substantial rate of Ca(2+) reabsorption from the luminal side, which is dose-dependently suppressed by ruthenium red, a putative blocker of epithelial Ca(2+) channels and CaCC. Finally, we discover messenger RNA for both TRPV6 and TMEM16A in the rat epididymis and show that their proteins colocalize in the apical membrane of principal cells. Collectively, these data provide evidence for a coupling mechanism between TRPV6 and TMEM16A in principal cells that may play an important role in the regulation of calcium homeostasis in the epididymis. PMID- 27481718 TI - Commentary on 'Comparison of a low Hartmann's procedure with low colorectal anastomosis with and without defunctioning ileostomy after radiotherapy for rectal cancer: results from a national registry'. PMID- 27481719 TI - Life after PROSPER. What do people do for external rectal prolapse? AB - AIM: A questionnaire completed by members of the ACPGBI in 1997 was a precursor to the PROSPER trial. It showed a significant variation in favoured practice for the surgical treatment of external rectal prolapse. We repeated the same questionnaire to assess how practice has changed since the completion of the trial and its publication. METHOD: An online survey was circulated to all members of the ACPGBI with identical questions to those used in the original in 1997. RESULTS: Similar numbers of recipients responded (122/791 [15.4%] in 2014;153/600 [25.5%] in 1997). The median number of operations per surgeon per year was unchanged (6 [0-30] vs 6 [0-25]). The percentage of surgeons who favoured an abdominal approach in fit patients in 1997 rose significantly from 63.5% to 81.7% in 2014 (P < 0.01). Delorme's remains the most popular perineal procedure (78.5% vs 93.3%), but the Altemeier procedure increased from 14.9% to 39.3%. Ventral rectopexy was the preferred abdominal approach in 2014 (48.6% vs 5.9% [P < 0.01]), with 96.3% of these being performed laparoscopically. The number of surgeons carrying out posterior rectopexy decreased from 92.6% to 45.9% (P < 0.01). Only 9.9% of surgeons still undertook resection rectopexy compared with 39.7% in 1997 (P < 0.01). The numbers of surgeons favouring a perineal approach decreased (18.3% vs 36.5%) although the use of a perineal procedure in elderly or unfit patients was unchanged (38.5% vs 37.9%). CONCLUSION: The surgical management of external rectal prolapse had changed. More surgeons favoured a laparoscopic abdominal approach in 2014 than in 1997 and the use of perineal approaches had decreased. Of these Delorme's operation remained the most popular but the incidence of the use of Altmeier's procedure had increased. PMID- 27481723 TI - [Risk of venous thromboembolism in cancer patients: Reality, actuality and perspectives]. AB - Cancer is a leading cause of venous thromboembolism (VTE) and vice versa. Pulmonary embolism is the second cause of death in cancer patients. Tumor progression is associated with coagulation activation. The pathogenesis of thrombosis during cancer is particularly complex stemming from multiple connections of this disease with both systems of inflammation and hemostasis. The risk of VTE depends on cancer type and the stage of the disease, the anticancer treatments and the time since cancer diagnosis as well as on the presence of patient-related risk factors (i.e. age, obesity, previous history of VTE, underlying diseases...). The presence of other precipitating factors and the duration of the exposure to them are also key elements in the assessment of such a thrombotic risk. It is therefore important to identify all the VTE risk factors to identify patients at high vascular risk and to determine the period during which this risk is significantly increased. The integration of biomarkers of hypercoagulability in proposed risk assessment models for VTE will improve their capacity to identify patients eligible for pharmacological thromboprophylaxis. In this review, we report the current status of knowledge on the connection between cancer and hypercoagulability, the numerous risk factors for VTE must be identified in cancer patients and the best methodology to build a more accurate assessment of this vascular risk in such a complex medical context. PMID- 27481724 TI - Development and face validity of a cerebral visual impairment motor questionnaire for children with cerebral palsy. AB - AIM: The objectives of this study were (i) to develop two cerebral visual impairment motor questionnaires (CVI-MQ's) for children with cerebral palsy (CP): one for children with Gross Motor Function Classification System (GMFCS) levels I, II and III and one for children with GMFCS levels IV and V; (ii) to describe their face validity and usability; and (iii) to determine their sensitivity and specificity. BACKGROUNDS: The initial versions of the two CVI-MQ's were developed based on literature. Subsequently, the Delphi method was used in two groups of experts, one familiar with CVI and one not familiar with CVI, in order to gain consensus about face validity and usability. The sensitivity and specificity of the CVI-MQ's were subsequently assessed in 82 children with CP with (n = 39) and without CVI (n = 43). With the receiver operating curve the cut-off scores were determined to detect possible presence or absence of CVI in children with CP. RESULTS: Both questionnaires showed very good face validity (percentage agreement above 96%) and good usability (percentage agreement 95%) for practical use. The CVI-MQ version for GMFCS levels I, II and III had a sensitivity of 1.00 and specificity of 0.96, with a cut-off score of 12 points or higher, and the version for GMFCS levels IV and V had a sensitivity of 0.97 and a specificity of 0.98, with a cut-off score of eight points or higher. CONCLUSION: The CVI-MQ is able to identify at-risk children with CP for the probability of having CVI. PMID- 27481725 TI - Misclassification of Self-Directed Violence. AB - BACKGROUND: Inconsistent nomenclature and classification of suicidal behaviour have plagued the field of suicidology for a long time. Recently, the United States Centers for Disease Control (CDC) advocated for the usage of a specific classification system. Aim of the current study was to determine the extent of misdiagnosed acts of self-directed violence-controlling for the level of expertise in psychology/psychotherapy. Additionally, the effect of gender and diagnosis on misclassifications was assessed. METHOD: A total of 426 participants (laypersons, psychology students, psychotherapists-in-training, licensed psychotherapists) were presented with an array of case vignettes describing different acts of self-directed violence (e.g., non-suicidal self-directed violence, suicide attempt, suicide ideation) and were asked to make a classification. Gender and given diagnosis were varied systematically in two vignettes. RESULTS: Overall 51.6% of the cases were misclassified (according to the Self-Directed Violence Classification System). The level of expertise was almost unrelated to classification correctness. Yet, psychotherapists were more confident about their judgments. Female gender of the character described in the vignette and an ascribed diagnosis of Borderline Personality Disorder were associated with higher misclassification rates. LIMITATIONS: The validity of case vignettes is discussible. CONCLUSIONS: The results highlight the importance of more methodological and diagnostic training of psychologists regarding suicidal issues. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Misclassification of non-suicidal and suicidal events is common. Expertise is only weakly associated with classification correctness. Misclassification of suicide attempts occurs more often in women. Misclassification of suicide attempts occurs more often in Borderline Personality Disorder. The use of standardized diagnostic tools in relation to self-directed violence is highly recommended. PMID- 27481727 TI - Signaling events in pathogen-induced macrophage foam cell formation. AB - Macrophage foam cell formation is a key event in atherosclerosis. Several triggers induce low-density lipoprotein (LDL) uptake by macrophages to create foam cells, including infections with Porphyromonas gingivalis and Chlamydia pneumoniae, two pathogens that have been linked to atherosclerosis. While gene regulation during foam cell formation has been examined, comparative investigations to identify shared and specific pathogen-elicited molecular events relevant to foam cell formation are not well documented. We infected mouse bone marrow-derived macrophages with P. gingivalis or C. pneumoniae in the presence of LDL to induce foam cell formation, and examined gene expression using an atherosclerosis pathway targeted plate array. We found over 30 genes were significantly induced in response to both pathogens, including PPAR family members that are broadly important in atherosclerosis and matrix remodeling genes that may play a role in plaque development and stability. Six genes mainly involved in lipid transport were significantly downregulated. The response overall was remarkably similar and few genes were regulated in a pathogen specific manner. Despite very divergent lifestyles, P. gingivalis and C. pneumoniae activate similar gene expression profiles during foam cell formation that may ultimately serve as targets for modulating infection-elicited foam cell burden, and progression of atherosclerosis. PMID- 27481728 TI - Clinical outcomes of cardiac arrest patients according to opioid use history. AB - PURPOSE: Opioid analgesics are potent respiratory depressants. The purpose of this study was to describe the effects of opioids administered within 24hours before cardiac arrest on clinical outcomes. MATERIALS AND METHODS: We retrospectively collected the cardiac arrest data of noncancer patients who were admitted to the general ward of Asan Medical Center from January 2008 to August 2012. We investigated the proportion of these patients who received opioids within 24hours of a cardiac arrest event, as well as the cardiac arrest characteristics, survival rates, and opioid administration patterns. RESULTS: Of the 193 patients identified, 58 (30%) had been administered opioids within the previous 24hours (the opioid group), whereas the remaining 135 (70%) had not been administered opioids (the nonopioid group). The survival rate did not differ significantly between these 2 groups. In the opioid group, as-needed opioid administration was associated with a lower 24-hour survival rate than regular opioid administration (9 [33.3%] of 27 patients vs 20 [64.5%] of 31 patients; P=.030). In multivariate logistic regression analysis, as-needed opioid administration was negatively associated with 24-hour survival. CONCLUSIONS: Opioid administration within 24hours before cardiac arrest per se was not associated with adverse outcomes. However, administration of opioid analgesics on an as-needed basis was associated with poorer survival outcomes than regular dosing. Greater attention should be paid to patients who receive as-needed opioid administration in the general ward. PMID- 27481729 TI - Developing triggers for the surgical intensive care unit for palliative care integration. AB - PURPOSE: Despite the growing acceptance of palliative care as a component of high quality care for patients with serious illness, it remains underutilized in the surgical critical care setting. This article provides insight into a model for palliative care integration into the surgical intensive care unit (SICU), using triggers. METHODS: We performed a prospective cohort study after the implementation of a new set of palliative care triggers in the SICU of an 1170 bed tertiary medical center over the course of 9 months. We aimed to determine the ability of these triggers to identify patients who would benefit from palliative care consultation. RESULTS: There were 517 SICU admissions during the period of interest. Of this cohort, patients who had not yet been discharged at the time of analysis were excluded (n=25), and the remaining underwent analysis (n=492). Factors significantly associated with hospital death or hospice discharge were repeat SICU admission, metastatic/advanced cancer, SICU physician referral, and the matching of 2 or more secondary criteria. CONCLUSIONS: A series of triggers can help identify patients who may benefit from palliative care consultation. This approach can be used in intensive care settings to facilitate palliative care integration. PMID- 27481730 TI - How is life support withdrawn in intensive care units: A narrative review. AB - PURPOSE: Decisions to withdraw life-sustaining therapy (WDLS) are relatively common in intensive care units across Canada. As part of preliminary work to develop guidelines for WDLS, we performed a narrative review of the literature to identify published studies of WDLS. MATERIALS AND METHODS: A search of MEDLINE and EMBASE databases was performed. The results were reviewed and only articles relevant to WDLS were included. Any references within these articles deemed to be relevant were subsequently included. RESULTS: The initial search identified 3687 articles. A total of 100 articles of interest were identified from the initial search and a review of their references. The articles were primarily composed of observational data and expert opinion. The information from the literature was organized into 6 themes: preparation for WDLS, monitoring parameters, pharmacologic symptom management, withdrawing life-sustaining therapies, withdrawal of mechanical ventilation, and bereavement. CONCLUSIONS: This review describes current practices and opinions about WDLS, and also demonstrates the significant practice variation that currently exists. We believe that the development of guidelines to help increase transparency and standardize the process will be an important step to ensuring high quality care during WDLS. PMID- 27481726 TI - New translational perspectives for blood-based biomarkers of PTSD: From glucocorticoid to immune mediators of stress susceptibility. AB - Although biological systems have evolved to promote stress-resilience, there is variation in stress-responses. Understanding the biological basis of such individual differences has implications for understanding Posttraumatic Stress Disorder (PTSD) etiology, which is a maladaptive response to trauma occurring only in a subset of vulnerable individuals. PTSD involves failure to reinstate physiological homeostasis after traumatic events and is due to either intrinsic or trauma-related alterations in physiological systems across the body. Master homeostatic regulators that circulate and operate throughout the organism, such as stress hormones (e.g., glucocorticoids) and immune mediators (e.g., cytokines), are at the crossroads of peripheral and central susceptibility pathways and represent promising functional biomarkers of stress-response and target for novel therapeutics. PMID- 27481731 TI - Clinical significance of ventilator-associated event. AB - PURPOSE: A novel surveillance algorithm of ventilator-associated event (VAE) was introduced to overcome the subjectivity of conventional ventilator-associated pneumonia. We investigated the risk factors and prognostic values of VAE. METHODS: We conducted a retrospective study of 869 patients treated with mechanical ventilation for greater than or equal to 2 calendar days from January 2013 to June 2014. We compared the episodes of mechanical ventilation with or without VAE and analyzed risk factors and clinical outcomes of VAE. RESULTS: Among 1031 episodes of mechanical ventilation, 92 episodes were complicated with VAE. VAE occurred more frequently when the initial causes of mechanical ventilation were trauma (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.1 6.3) and pulmonary edema (OR, 2.4; 95% CI, 1.2-4.7). VAE was significantly associated with prolonged mechanical ventilation (5 vs 12 days; P<.001), reduced rate of successful extubation (50.1% vs 17.5%; P<.001), and increased 30-day mortality (35.6% vs 74.2%; P<.001). VAE was a significant risk factor of 30-day mortality on multivariate regression analysis (OR, 3.6; 95% CI, 2.0-6.6; P<.001). CONCLUSIONS: Patients treated with mechanical ventilation due to pulmonary edema or trauma had increased risk of VAE, with its development indicative of adverse clinical outcomes. PMID- 27481732 TI - Organ donation education initiatives: A report of the Donor Management Task Force. AB - PURPOSE: It is essential that hospitals and health professionals establish systems to facilitate patients' organ donation wishes. Donation education has been neither standardized nor systematic, and resources related to donation processes have not been widely accessible. This report describes 2 free, publicly available educational resources about the organ donation process created to advance the mission of basic education and improve donation processes within hospitals and health care systems. MATERIALS AND METHODS: Members of the Donor Management Task Force of the Organ Donation and Transplantation Alliance (the Alliance) and the Health Resources and Services Administration of the US Department of Health and Human Services convened annually in person and by teleconferencing during the year to develop 2 educational vehicles on organ donation. RESULTS: Two educational products were developed: the Organ Donation Toolbox, an online repository of documents and resources covering all aspects of the donation process, and the Educational Training Video that reviews the basic foundations of a successful hospital donation system. CONCLUSIONS: There is a need for more research and education about the process of organ donation as it relates to the medical and psychosocial care of patients and families before the end of life. The educational products described can help fill this critical need. PMID- 27481734 TI - Electrical impedance tomography in adult patients undergoing mechanical ventilation: A systematic review. AB - PURPOSE: The purpose of the study is to systematically review and summarize current literature concerning the validation and application of electrical impedance tomography (EIT) in mechanically ventilated adult patients. MATERIALS AND METHODS: An electronic search of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and the Web of Science was performed up to June 2014. Studies investigating the use of EIT in an adult human patient population treated with mechanical ventilation (MV) were included. Data extracted included study objectives, EIT details, interventions, MV protocol, validation and comparators, population characteristics, and key findings. RESULTS: Of the 67 included studies, 35 had the primary objective of validating EIT measures including regional ventilation distribution, lung volume, regional respiratory mechanics, and nonventilatory parameters. Thirty-two studies had the primary objective of applying EIT to monitor the response to therapeutic MV interventions including change in ventilation mode, patient repositioning, endotracheal suctioning, recruitment maneuvers, and change in positive end-expiratory pressure. CONCLUSIONS: In adult patients, EIT has been successfully validated for assessing ventilation distribution, measuring changes in lung volume, studying regional respiratory mechanics, and investigating nonventilatory parameters. Electrical impedance tomography has also been demonstrated to be useful in monitoring regional respiratory system changes during MV interventions, although existing literature lacks clinical outcome evidence. PMID- 27481733 TI - Opioid overdose leading to intensive care unit admission: Epidemiology and outcomes. AB - PURPOSE: There is a scarcity of studies assessing the patient population admitted to the intensive care unit (ICU) with opioid overdose. We sought to characterize the epidemiologic features and outcomes of this patient population. MATERIALS AND METHODS: This is a retrospective cohort study of adult patients admitted to the ICU at University of Louisville Hospital for opioid overdose. We reviewed each patient's hospital record for demographic data, comorbidities, opioid used, coingestions, and outcomes. RESULTS: We included 178 adult patients, of which 107 (60%) were females. The median age was 41 years (interquartile range [IQR], 23). Oxycodone and hydrocodone were the 2 most commonly abused opioids. Benzodiazepines were the most common drug coingested, followed by amphetamines. Tobacco smoking, chronic pain, and alcoholism were the most frequent comorbidities identified. Mental disorders were also common. Most patients required invasive mechanical ventilation (84.8%). Median ICU length of stay was 3 days. Eighteen patients (10.1%) died in the hospital, whereas 6 patients (3.4%) were discharged to a nursing home. Patients who had any coingestion were significantly more likely to undergo invasive mechanical ventilation (91% vs 77%; P=.014) and had longer ICU length of stay (3 [IQR, 2] vs 2 [IQR, 1.8] days; P=.024). CONCLUSION: Opioid overdose is a common cause of ICU admission and affects a relatively young population. Most have respiratory failure requiring mechanical ventilation. It is associated with a relatively high inhospital mortality. Coingestions appear to have an impact on outcomes. PMID- 27481735 TI - Can early initiation of continuous renal replacement therapy improve patient survival with septic acute kidney injury when enrolled in early goal-directed therapy? AB - PURPOSE: The purpose of our study was to investigate the timing of continuous renal replacement therapy (CRRT) application, based on the interval between the start of early goal-directed therapy (EGDT) and CRRT initiation, to ascertain whether the timing was an independent predictor of mortality in patients with septic acute kidney injury (AKI). MATERIALS AND METHODS: An observational retrospective cohort study was conducted of 60 patients (>18 years old) who had been admitted to the emergency department and received resuscitation according to the standard EGDT algorithm for severe sepsis and septic shock, and who were treated with CRRT due to septic AKI, between June 2008 and February 2013 at a tertiary hospital in Seoul, Korea. The patients were divided into 2 groups based on the median interval between the start of EGDT and the commencement of CRRT. The main outcome was 28-day all-cause mortality, and a multivariate Cox analysis for mortality was used to evaluate the independent impact of the early CRRT treatment. RESULTS: The mean patient age was 66.3 years, and 52 (86.7%) were male. The most common comorbid disease was diabetes mellitus (35.0%) followed by malignancy (26.7%). The median interval between the start of EGDT and commencement of CRRT was 26.4 hours. During the study period, 28-day mortality was 43.3% (26 of 60 patients). The 28-day all-cause mortality rate was significantly higher in the late CRRT group than in the early CRRT group (56.7 vs 30.0%, P= .037). Furthermore, the higher mortality risk in the late group remained significant even after adjusting for diabetes mellitus, liver failure, and Acute Physiology and Chronic Health Evaluation II scores (hazard ratio, 2.461; 95% confidence interval, 1.044-5.800; P= .026). CONCLUSION: Early initiation of CRRT may be of benefit. Given the complex nature of this intervention and the ongoing controversy regarding early vs late initiation of therapy in acute and chronic situations, it is vital to develop accurate clinical trials to find definitive answers. PMID- 27481736 TI - Causes of moral distress in the intensive care unit: A qualitative study. AB - PURPOSE: The purpose of the study is to examine the causes of moral distress in diverse members of the intensive care unit (ICU) team in both community and tertiary ICUs. MATERIALS AND METHODS: We used focus groups and coding of transcripts into themes and subthemes in 2 tertiary care ICUs and 1 community ICU. RESULTS: Based on input from 19 staff nurses (3 focus groups), 4 clinical nurse leaders (1 focus group), 13 physicians (3 focus groups), and 20 other health professionals (3 focus groups), the most commonly reported causes of moral distress were concerns about the care provided by other health care workers, the amount of care provided (especially too much care at end of life), poor communication, inconsistent care plans, and issues around end of life decision making. CONCLUSIONS: Causes of moral distress vary among ICU professional groups, but all are amenable to improvement. PMID- 27481737 TI - The association between prior statin use and long-term outcomes after critical care admission. AB - BACKGROUND: Statins may have immunomodulatory effects that benefit critically ill patients. Therefore, we retrospectively examined the association between survival and the prescription of statins prior to admission to an intensive care unit (ICU), or high dependency unit (HDU), as a result of major elective surgery or as an emergency with a presumed diagnosis of sepsis. METHODS: We retrospectively studied critical care patients (ICU or HDU) from a tertiary referral UK teaching hospital. Nottingham University Hospitals have more than 2200 beds, of which 39 are critical care beds. Over a 5-year period (2000-2005), 414 patients were identified with a presumed diagnosis of sepsis, and 672 patients were identified who had planned ICU/HDU admissions following elective major surgery. Patients prescribed statins prior to hospital admission were compared with those who were not. Demographics, medical history, drug history, and Acute Physiology and Chronic Health Evaluation II scores were examined. Univariate and multivariate analyses were applied using the primary end point of survival at 5 years after admission. RESULTS: Patients prescribed statins prior to critical care admission were, on average, older and had higher initial Acute Physiology and Chronic Health Evaluation II scores and more preexisting comorbidities. Statins were almost invariably stopped following admission to critical care. Statin use was not associated with significantly altered survival during hospital admission, or at 5 years, for either patients with sepsis (9% vs 15%, P=.121; 73% vs 84%, P=.503, respectively) or postoperative patients (55% vs 58%, P=.762; 57% vs 63%, P=.390). CONCLUSIONS: Prior statin use was not associated with improved outcomes in patients admitted to critical care after elective surgical cases or with a presumed diagnosis of sepsis. PMID- 27481738 TI - Clinical and economic burden of bloodstream infections in critical care patients with central venous catheters. AB - PURPOSE: Bloodstream infections (BSIs) complicate the management of intensive care unit (ICU) patients. We assessed the clinical and economic impact of BSI among patients of a managed care provider group who had a central venous catheter (CVC) placed in the ICU. METHODS: We considered hospitalizations occurring between January 1, 2011, and September 30, 2014, that involved an ICU stay during which a CVC was placed. Comparisons were made between episodes where the patient did vs did not develop BSI after CVC insertion. Length of stay, costs of index hospitalization, and total costs over the 180 days after discharge were compared using linear mixed models. Inhospital mortality and 30-day readmission rates were compared using negative binomial regression models. RESULTS: Development of BSI was associated with longer hospital stay (+7 days), more than 3-fold increase in risk of inhospital death, and an additional $129 000 in costs for the index hospitalization. No statistically significant differences in 30-day readmission rates or costs of care over the 180-day period after discharge from the index admission were observed. CONCLUSION: Bloodstream infections after CVC placement in ICU patients are associated with significant increases in costs of care and risk of death during the index hospitalization but no differences in readmissions or costs after discharge. PMID- 27481739 TI - How safe is gelatin? A systematic review and meta-analysis of gelatin-containing plasma expanders vs crystalloids and albumin. AB - Gelatin is a widely used synthetic colloid resuscitation fluid. We undertook a systematic review and meta-analysis of adverse effects in randomized and nonrandomized studies comparing gelatin with crystalloid or albumin for treatment of hypovolemia. Multiple databases were searched systematically without language restrictions until August 2015. We assessed risk of bias of individual studies and certainty in evidence assessment by the Grading of Recommendations Assessment, Development, and Evaluation approach. Sixty studies were eligible, including 30 randomized controlled trials, 8 nonrandomized studies, and 22 animal studies. After gelatin administration, the risk ratios were 1.15 (95% confidence interval, 0.96-1.38) for mortality, 1.10 (0.86-1.41) for requiring allogeneic blood transfusion, 1.35 (0.58-3.14) for acute kidney injury, and 3.01 (1.27-7.14) for anaphylaxis. Well-performed nonrandomized trials found increased rates of hospital mortality and acute kidney injury or renal replacement therapy in the gelatin intervention periods. Between 17% and 31% of administered gelatin was taken up extravascularly. The mean crystalloid-to-colloid ratio was 1.4. Gelatin solutions increase the risk of anaphylaxis and may be harmful by increasing mortality, renal failure, and bleeding possibly due to extravascular uptake and coagulation impairment. Until well-designed randomized controlled trials show that gelatin is safe, we caution against the use of gelatins because cheaper and safer fluid alternatives are available. PMID- 27481740 TI - Acid-base disturbances in acute poisoning and their association with survival. AB - PURPOSE: The purpose was to investigate the association between acid-base disturbances and mortality in acute poisoning. MATERIALS AND METHODS: We performed a retrospective cross-sectional exploratory study on all acutely poisoned patients older than 12 years who had been admitted to the main tertiary toxicology hospital in Tehran between March and August 2010. RESULTS: Of a total of 1167 patients (median age=25 years, 50.9% male), 98 died (74.5% male). Psychotropic medications were the most common cause of poisoning (36.5%), whereas narcotics and psychodysleptics were the most common cause of death (23.5%). Mixed respiratory alkalosis and metabolic acidosis with normal pH were the most common acid-base status (333, 28.5%). However, patients with primary metabolic acidosis and respiratory compensation had significantly higher mortality (31 cases, 18.8%). Logistic regression analysis identified age (odds ratio [OR], 1.051; 95% confidence interval [CI], 1.031-1.070; P<.001), intensive care unit admission (OR, 12.405; 95% CI, 7.178-21.440; P<.001), consciousness level (OR, 1.752; 95% CI, 1.301-2.359; P<.001), hospitalization period (OR, 1.1361; 95% CI, 1.079 1.195; P<.001), severe metabolic acidosis (OR, 6.016; 95% CI, 1.647-21.968; P=.007), and primary respiratory alkalosis (OR, 5.579; 95% CI, 1.353-23.001; P=.017) as death predictors during hospitalization (P<.001). CONCLUSION: On arrival acid-base status predicts survival and can be used in prognostication of the poisoned patients. PMID- 27481741 TI - Actuating critical care therapeutics. AB - Viewing the intensive care unit (ICU) as a control system with inputs (patients) and outputs (outcomes), we focus on actuation (therapies) of the system and how to enhance our understanding of status of patients and their trajectory in the ICU. To incorporate the results of these analytics meaningfully, we feel that a reassessment of predictive scoring systems and of ways to optimally characterize and display the patient's "state space" to clinicians is important. Advances in sensing (diagnostics) and computation have not yet led to significantly better actuation, and so we focus on ways that data can be used to improve actuation in the ICU, in particular by following therapeutic burden along with disease severity. This article is meant to encourage discussion about how the critical care community can best deal with the data they see each day, and prepare for recommendations that will inevitably arise from application of major federal and state initiatives in big data analytics and precision medicine. PMID- 27481742 TI - Acetate-buffered crystalloid fluids: Current knowledge, a systematic review. AB - INTRODUCTION: The concept of fluid resuscitation with balanced solutions containing acetate is relatively new. The knowledge about acetate mostly originates from nephrological research, as acetate was primarily used as a dialysis buffer where much higher doses of acetate are infused. The aim of this review is to give an overview of the advantages and disadvantages of an acetate buffered crystalloid fluid when compared with other crystalloid infusates. METHODS: We report trials with the primary object of comparing an acetate buffered infusion solute to another crystalloid infusate. A systematic literature search of MEDLINE and the Cochrane Controlled Clinical trials register was conducted to identify suitable studies. RESULTS: The search strategy used produced 1205 potential titles. After eliminating doubles, 312 titles and abstracts were screened, and 31 references were retrieved for full-text analysis. A total of 27 scientific studies were included in the study. CONCLUSION: Acetate buffered crystalloid solutes do have a favorable influence on microcirculation. To what extent the acetate-buffered crystalloids influence kidney function is controversially discussed and not yet clear. Metabolic alkalosis did not occur in a single study in humans after an acetate-buffered infusate; potassium levels stayed stable in all studies. Cardiac output and contractility seem to be positively influenced; nonetheless, data on maintenance of a target blood pressure remain inconclusive. Whether acetate-buffered crystalloid fluids lead to lower rates of acute kidney injury and increased survival when compared with normal saline is yet unclear and may depend on the amount of fluid administered. PMID- 27481743 TI - Changes in peripheral perfusion relate to visceral organ perfusion in early septic shock: A pilot study. AB - PURPOSE: To correlate clinical indicators of peripheral perfusion with visceral organ vascular tone in 30 septic shock patients. MATERIALS AND METHODS: In a prospective pilot study, capillary refill time, the Mottling score, and peripheral temperature were determined within 24, 48, and 72 hours after intensive care unit admission. Simultaneously, pulsatility indices in the liver, spleen, kidneys, and intestines were measured by Doppler ultrasonography. Correlation analyses were calculated, applying an adjusted significance level (P< .0125) to correct for multiple testing. RESULTS: Significant relationships were observed between the pulsatility index of selected organs and the capillary refill time (intestines: r= 0.325, P= .007), and the Mottling score (kidneys: r= 0.396, P= .006), but not peripheral temperature (all r< 0.14, P> .05). An association over time was observed for the capillary refill time and pulsatility index of the liver (P= .04) and intestines (P= .03) as well as for the Mottling score and the kidneys' pulsatility index (P= .03), but not for peripheral temperature and any visceral organs' pulsatility index. CONCLUSIONS: Capillary refill time and skin mottling may be correlated with the pulsatility index, a sonographic surrogate of vascular tone, of visceral organs in early septic shock. PMID- 27481744 TI - High-protein hypocaloric vs normocaloric enteral nutrition in critically ill patients: A randomized clinical trial. AB - PURPOSE: Appropriate caloric intake in critically ill patients receiving enteral nutrition is controversial. This study evaluates the impact of different caloric regimens on severity of organ failure measured with Sequential Organ Failure Assessment (SOFA). MATERIALS AND METHODS: We conducted a randomized prospective controlled trial. Study population included adult intensive care unit (ICU) patients expected to require enteral nutrition for more than 96 hours. Goals in the intervention group were hypocaloric (15 kcal/kg per day) enteral nutrition compared to normocaloric (25 kcal/kg per day) enteral nutrition, both with hyperproteic intake (1.7 g of protein/kg per day). Primary end point was change in SOFA score (DeltaSOFA) from baseline at 48 hours. Secondary end points were DeltaSOFA at 96 hours, insulin requirements, hyperglycemia or hypoglycemic episodes, length of ICU stay, days on ventilator, and 28-day mortality. RESULTS: After screening 443 patients, 120 patients were analyzed. There were no differences between groups in baseline characteristics. We did not find a statistically significant difference in DeltaSOFA at 48 hours. Patients in the hypocaloric group showed lower average daily insulin requirements and percentage of patients requiring any insulin. CONCLUSIONS: Hyperproteic, hypocaloric nutrition did not show different outcomes compared to normocaloric nutrition, except lower insulin requirements. Hypocaloric nutrition could provide a more physiologic approach with lower need for care and metabolic impact. PMID- 27481745 TI - IgG2 as an independent risk factor for mortality in patients with community acquired pneumonia. AB - BACKGROUND: Mortality in patients with community-acquired pneumonia (CAP) remains high despite improvements in treatment. OBJECTIVE: To determine immunoglobulin levels in patients with CAP and impact on disease severity and mortality. METHODOLOGY: Observational study. Hospitalized patients with CAP were followed up for 30 days. Levels of immunoglobulin G (IgG) and subclasses, immunoglobulin A (IgA) and immunoglobulin M (IgM) were measured in serum within 24 hours of CAP diagnosis. RESULTS: Three hundred sixty-two patients with CAP were enrolled -172 ward-treated and 190 intensive care unit-treated. Intensive care unit-treated patients had significantly lower values of IgG1, IgG2, IgG3 subclasses, and IgA than ward-treated patients. Thirty-eight patients died before 30 days. Levels of IgG2 were significantly lower in non-survivors than survivors (P=.004) and IgG2 <301 mg/dL was associated with poorer survival according to both the bivariate (hazard ratio 4.47; P<.001) and multivariate (HR 3.48; P=.003) analyses. CONCLUSIONS: Patients with CAP with IgG2 levels <301 mg/dL had a poorer prognosis and a higher risk of death. Our study suggests the usefulness of IgG2 to predict CAP evolution and to provide support measures or additional treatment. PMID- 27481746 TI - Postoperative acute kidney injury in high-risk patients undergoing major abdominal surgery. AB - PURPOSE: Acute kidney injury (AKI) is a frequent complication in high-risk patients undergoing major surgery and is associated with longer hospital stay, increased risk for nosocomial infection and significantly higher costs. MATERIALS AND METHODS: A prospective observational study exploring the incidence of AKI (AKIN classification at any stage) in high-risk patients within 48 hours after major abdominal surgery was conducted. Patients' preoperative characteristics, intraoperative management, and outcome were evaluated for associations with AKI using a logistic regression model. RESULTS: Data from 258 patients were analyzed. Thirty-one patients (12%) developed AKI, reaching the AKIN stage 1. No patient reached an AKIN stage higher than 1. AKI patients were older (75.2 vs 70.2 years; P = 0.0113) and had a higher body mass index (26.5 vs 25.1 kg/m(2)). In addition, AKI patients had a significantly longer ICU length of stay (3.4 vs 2.4 days; P= .0017). Creatinine levels of AKI patients increased significantly compared to the preoperative levels at 24 (P= .0486), 48 (P= .0011) and 72 hours (P= .0055), while after 72 hours it showed a downwards trend. At ICU discharge, 28 out of 31 patients (90.3%) recovered preoperative levels. Multivariate analysis identified age (OR 1.088; P= .002) and BMI (OR 1.124; P= .022) as risk factors for AKI development. Moreover, AKI development was an independent risk factor for ICU stays longer than 48 hours (OR 2.561; P= .019). CONCLUSIONS: Mild AKI is a not rare complication in high-risk patients undergoing major abdominal surgery. Although in almost the totality of cases, the indicators of renal function recovered to preoperative levels, post-operative AKI represents a primary risk factor for a prolonged ICU stay. PMID- 27481747 TI - Defining the characteristics and expectations of fluid bolus therapy: A worldwide perspective. AB - PURPOSE: The purpose of the study is to understand what clinicians believe defines fluid bolus therapy (FBT) and the expected response to such intervention. METHODS: We asked intensive care specialists in 30 countries to participate in an electronic questionnaire of their practice, definition, and expectations of FBT. RESULTS: We obtained 3138 responses. Despite much variation, more than 80% of respondents felt that more than 250 mL of either colloid or crystalloid fluid given over less than 30 minutes defined FBT, with crystalloids most acceptable. The most acceptable crystalloid and colloid for use as FBT were 0.9% saline and 4% albumin solution, respectively. Most respondents believed that one or more of the following physiological changes indicates a response to FBT: a mean arterial pressure increase greater than 10 mm Hg, a heart rate decrease greater than 10 beats per minute, an increase in urinary output by more than 10 mL/h, an increase in central venous oxygen saturation greater than 4%, or a lactate decrease greater than 1 mmol/L. CONCLUSIONS: Despite wide variability between individuals and countries, clear majority views emerged to describe practice, define FBT, and identify a response to it. Further investigation is now required to describe actual FBT practice and to identify the magnitude and duration of the physiological response to FBT and its relationship to patient-centered outcomes. PMID- 27481748 TI - Comparison of ultrasound guided brachiocephalic and internal jugular vein cannulation in critically ill children. AB - PURPOSE: To determine whether ultrasound (US)-guided longitudinal in-plane supraclavicular cannulation of the brachiocephalic vein (BCV) improves cannulation success rates compared to transverse out-of-plane internal jugular vein (IJV) cannulation in urgent insertion of temporary central venous catheters (CVC) in critically ill children. MATERIALS AND METHODS: Prospective open pilot (non-randomized) comparative study carried out in a pediatric intensive care unit (PICU) of a university-affiliated hospital. Newborns and children aged 0 to 14 years admitted to the PICU in whom an urgent CVC was clinically indicated and was inserted in the IJV or BCV by US guidance were eligible. First-attempt success rate, overall success rate, number of puncture attempts, and cannulation time were compared between IJV and BCV techniques. RESULTS: Forty-six procedures (24 IJV and 22 BCV) in 38 patients were included. Full-sample median (range) age and weight were 13 (0.6-160) months and 9.5 (0.94-50) kg. No significant differences between IJV and BCV groups were observed for sex, age, weight, admission diagnosis, intra-procedural mechanical ventilation and sedation protocol. First attempt success rate was higher in the BCV than the IJV group (73 vs 37.5%, P= .017). Overall success rate was slightly higher in the BCV group (95 vs 83%, P = nonsignificant). Median (range) number of cannulation attempts [1 (1-3) vs 2 (1 4)] and cannulation time [66 (25-300) vs 170 (40-500) seconds] were significantly lower in the BCV group (P< .05). Patient's weight was inversely related to the number of cannulation attempts (Pearson coefficient -0.537, P= .007) and cannulation time (Pearson coefficient -0.495, P= .014) in the IJV but not in the BCV group. No major complications were observed. CONCLUSIONS: Ultrasound-guided supraclavicular in-plane BCV cannulation improved first attempt CVC cannulation success rates and reduced puncture attempts and cannulation time compared to US guided out-of-plane IJV in critically ill children. A large randomized clinical trial is warranted to confirm our results. PMID- 27481749 TI - Comparison of high-flow nasal oxygen therapy with conventional oxygen therapy and noninvasive ventilation in adult patients with acute hypoxemic respiratory failure: A meta-analysis and systematic review. AB - PURPOSE: The role of high-flow nasal oxygen (HFNO) therapy in adult patients with acute hypoxemic respiratory failure is controversial. METHODS: This meta-analysis of prospective randomized controlled trials (RCTs) has been designed to compare HFNO with noninvasive ventilation (NIV) and conventional oxygen therapy in such patients. RESULTS: Initial database searching revealed 336 RCTs, of which 7 were included in this meta-analysis. Five RCTs compared HFNO with standard oxygen therapy, one compared HFNO with NIV, and one compared all three. HFNO did not decrease the requirement of higher respiratory support compared with control group. HFNO was associated with improved respiratory rate and dyspnea score, and better comfort in 3 RCTs, whereas other studies did not find any difference. CONCLUSION: High-flow nasal oxygen does not offer any benefit over NIV or conventional oxygen therapy in terms of requirement of higher respiratory support. PMID- 27481750 TI - Ketamine for analgosedation in critically ill patients. AB - PURPOSE: The purpose of this narrative review is to provide practical and useful guidance for clinicians considering the use of intravenous ketamine for its analgosedative properties in adult, critically ill patients. METHODS: MEDLINE was searched from inception until January 2016. Articles related to the pharmacological properties of ketamine were retrieved. Information pertaining to pharmacology, pharmacokinetics, dosing regimens, adverse effects, and outcomes was obtained from relevant studies. RESULTS: Although the primary mechanism for ketamine's pharmacological effects is N-methyl-d-aspartate blockade, there are several potential mechanisms of action. It has a very large volume of distribution due to its lipophilicity, which can lead to drug accumulation with sustained infusions. Ketamine has several advantages compared with conventional sedatives such as preserving pharyngeal and laryngeal protective reflexes, lowering airway resistance, increasing lung compliance, and being less likely to produce respiratory depression. It causes sympathetic stimulation, which is also unlike other sedatives and analgesics. There are psychotomimetic effects, which are a concern in terms of delirium. Dosing and monitoring recommendations are provided. CONCLUSIONS: Ketamine has a unique pharmacological profile compared with more traditional agents such as opioids, which makes it an appealing alternative agent for analgosedation in the intensive care unit setting. PMID- 27481751 TI - Palliative care in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is the only major worldwide cause of mortality that is currently increasing in prevalence. Furthermore, COPD is incurable, and the only therapy that has been shown to increase survival is oxygen therapy in selected patients. Compared to patients with cancer, patients with COPD experience similar levels of pain, breathlessness, fatigue, depression, and anxiety and have a worse quality of life but have comparatively little access to palliative care. When these patients do receive palliative care, they tend to be referred later than patients with cancer. Many disease, patient-, and provider related factors contribute to this phenomenon, including COPD's unpredictable course, misperceptions of palliative care among patients and physicians, and lack of advance care planning discussions outside of crisis situations. A new paradigm for palliative care would introduce palliative treatments alongside, rather than at the exclusion of disease-modifying interventions. This integrated approach would circumvent the issue of difficult prognostication in COPD, as any patient would receive individualized palliative interventions from the time of diagnosis. These points will be covered in this review, which discusses the challenges in providing palliative care to COPD patients, the strategies to mitigate the challenges, management of common symptoms, and the evidence for integrated palliative care models as well as some suggestions for future development. PMID- 27481752 TI - Effects of propofol on vasopressor use in patients with sepsis and severe sepsis: A pilot study. AB - PURPOSE: Propofol is one of the most commonly used sedatives in the intensive care unit (ICU) despite its undesirable hypotensive effects. The purpose of this study was to determine the effects of continuous intravenous (CIV) propofol on vasopressor requirements in mechanically ventilated patients with sepsis. MATERIALS AND METHODS: A multicenter, retrospective, propensity-matched pilot study was conducted comparing patients with sepsis or severe sepsis who received CIV propofol for sedation to those who did not. The primary outcome was incidence of vasopressor support. Secondary outcomes included change in mean arterial pressure, mortality, and length of stay. RESULTS: A total of 279 patients (149 CIV propofol, 130 non-CIV propofol) were evaluated, with 174 patients matched 1:1 based on propensity score. There was no difference in vasopressor support requirements (49.4% vs 54%; P= .65) or in those experiencing a greater than 20% decrease in mean arterial pressure from baseline (58.6% vs 63.2%; P= .53) in the CIV propofol and non-CIV propofol groups. Furthermore, there were no differences in any secondary outcomes including hospital mortality (32.2% vs 33.3%; P= .87). CONCLUSIONS: Continuous intravenous propofol for sedation did not increase vasopressor requirements in this septic population. Furthermore, CIV propofol was not associated with significant differences in the use of multiple vasopressors, change in mean arterial pressure, length of stay, or mortality. PMID- 27481753 TI - Fluid management in sepsis: The potential beneficial effects of albumin. AB - Fluid administration is a key intervention in hemodynamic resuscitation. Timely expansion (or restoration) of plasma volume may prevent tissue hypoxia and help to preserve organ function. In septic shock in particular, delaying fluid resuscitation may be associated with mitochondrial dysfunction and may promote inflammation. Ideally, infused fluids should remain in the plasma for a prolonged period. Colloids remain in the intravascular space for longer periods than do crystalloids, although their hemodynamic effect is affected by the usual metabolism of colloid substances; leakage through the endothelium in conditions with increased permeability, such as sepsis; and/or external losses, such as with hemorrhage and burns. Albumin has pleiotropic physiological activities including antioxidant effects and positive effects on vessel wall integrity. Its administration facilitates achievement of a negative fluid balance in hypoalbuminemia and in conditions associated with edema. Fluid resuscitation with human albumin is less likely to cause nephrotoxicity than with artificial colloids, and albumin infusion has the potential to preserve renal function in critically ill patients. These properties may be of clinical relevance in circulatory shock, capillary leak, liver cirrhosis, and de-escalation after volume resuscitation. Sepsis is a candidate condition in which human albumin infusion to preserve renal function should be substantiated. PMID- 27481754 TI - Routine delirium monitoring is independently associated with a reduction of hospital mortality in critically ill surgical patients: A prospective, observational cohort study. AB - PURPOSE: Although delirium monitoring is recommended in international guidelines, there is lacking evidence for improved outcome due to it. We hypothesized that adherence to routine delirium monitoring would improve clinical outcome in adult critically ill patients. MATERIAL AND METHODS: We present the results of a prospective, noninterventional, observational cohort study that was conducted on 2 intensive care units (ICUs) of a tertiary care medical center between July and October 2007 (International Standard Registered Clinical Trial Record identifier: 76100795). We assessed delirium-monitoring and outcome parameters on a daily basis. Besides multivariate logistic and robust linear regression to analyze the relationship between delirium monitoring and outcome, we used the doubly robust augmented inverse probability weighting method for observational data to estimate effect sizes. RESULTS: Of 355 screened patients, we included 185 surgical ICU patients into our final analysis, of which 87 were mechanically ventilated. We found an independent association between delirium-monitoring adherence and in hospital mortality for ventilated patients (odds ratio, 0.973; P= .041). Estimating the effect size, delirium monitoring indicated a reduction of 22% of in-hospital mortality if conducted 50% or more of ICU days per patient. The average ICU length of stay of 46 days was estimated to be reduced by 19 days (P= .031) if patients were sufficiently monitored. CONCLUSION: Our data suggest an improved outcome for mechanically ventilated patients being screened for delirium in clinical routine. PMID- 27481755 TI - Heart-type fatty acid-binding protein and myocardial creatine kinase enable rapid risk stratification in normotensive patients with pulmonary embolism. AB - BACKGROUND: Risk assessments of hemodynamically stable patients with pulmonary embolisms (PE) remain challenging. In this context heart-type fatty acid-binding protein (H-FABP), creatine kinase isoenzyme MB (CK-MB), and troponin I (TnI) may hold prognostic utility for patients with pulmonary embolism. METHODS: We included 161 consecutive normotensive (systolic blood pressure above 90 mm Hg) patients with confirmed PE to study the combined utility of echocardiographic signs of right ventricular dysfunction and several biomarkers (TnI, CK-MB, H FABP). The primary endpoint was defined as death within 30 days after admission to the hospital. RESULTS: Elevated biomarkers were measured in 26 patients (16.1%) for HFABP, in 66 (41%) for TnI and in 41 (25.5%) for CK-MB. Echocardiography revealed right ventricular dysfunction (RVD) in 99 (61.5%) patients. Overall, 16 patients (9.9%) died within the study period. In the H-FABP positive group 15 (57.7%) patients died compared to 13 (19.7%) patients in the TnI positive group and 15 (37.5%) patients in the CK-MB positive group (H-FABP positive vs TnI positive patients, P< .001; H-FABP positive vs CK-MB positive patients P= .13; CK-MB positive vs TnI positive patients P= .07). All elevated biomarkers correlated with the primary endpoint with H-FABP being strongly, CK-MB intermediately and TnI weakly associated with short term death (H-FABP r= 0.701, P< .001; CK-MB r= 0.486, P< .001; TnI r= 0.272, P= .001). In multivariate logistic regression analysis, a positive H-FABP test (OR 27.1, 95% CI 2.1-352.3, P= .001), elevated CK-MB levels (OR 5.3, 95% CI 1.3-23.3, P= .002) and a low systolic blood pressure on admission (OR 0.8, 95% CI 0.8-0.9, P< .001) emerged as independent predictors of 30-day mortality. CONCLUSIONS: Both H-FABP and CK-MB are associated with short term mortality in normotensive PE patients and could be advantageous for risk stratification in this intermediate risk group. PMID- 27481756 TI - Caregiver strain following critical care discharge: An exploratory evaluation. AB - OBJECTIVE: The objective of this exploratory evaluation was to understand the impact of critical care survivorship on caregivers. DESIGN: Family members who attended a quality improvement initiative within our critical care unit were asked to complete 4 questionnaires. SETTING: The setting for this study was a 20 bedded mixed critical care unit in a large teaching hospital in Scotland. Data were collected as a part of an evaluation of a quality improvement initiative. PARTICIPANTS: Thirty-six carers completed the questionnaire set. MEASUREMENTS AND MAIN RESULTS: A total of 53% of caregivers suffered significant strain. Poor quality of life in the patient was significantly associated with higher caregiver strain (P= .006). Anxiety was present in 69% of caregivers. Depression was present in 56% of caregivers, with a significant association between carer strain and depression (P< .001). Those caregivers who were defined as being strained also had significantly higher Insomnia Severity Index scores than those without carers strain (P= .007). CONCLUSION: This evaluation has demonstrated that there is a significant burden for caregivers of critical care survivors. Furthermore, they reported high levels of posttraumatic stress disorder, anxiety, depression, and insomnia. Future work on rehabilitation from critical care should focus on the inclusion of caregivers. PMID- 27481757 TI - Investigation of hemophagocytic lymphohistiocytosis in severe sepsis patients. AB - PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by uncontrolled inflammation and has common clinical and laboratory features with sepsis. The aim of this study was to investigate patients treated with severe sepsis who had bicytopenia for the presence of HLH. MATERIALS AND METHODS: Patients with severe sepsis who were non-responsive to treatment and developed at least bicytopenia were included. Peripheral blood samples were collected and stored for later evaluation for natural killer (NK) activity and soluble interleukin-2 receptor levels. Diagnostic criteria of HLH were retrospectively analyzed. RESULTS: Seventy-five of 382 patients (20%) were followed as severe sepsis and septic shock. Among them, 40 patients had bicytopenia. Twenty-six of 40 patients were excluded due to the presence of active solid or hematological malignancies. Three patients died before fulfillment of HLH criteria and one patient denied to give consent. All of the remaining 10 patients had at least five of the eight criteria according to criteria of the Histiocyte Society. Only one of 10 patients was diagnosed as HLH and received treatment during intensive care unit stay. None of the 10 patients survived. CONCLUSIONS: This study emphasizes to consider the possibility of HLH and the need of rapid assessment of patients with severe sepsis who had bicytopenia and were resistant to treatment in intensive care. PMID- 27481758 TI - Incidence and characterization of acute kidney injury after acetaminophen overdose. AB - PURPOSE: Acute kidney injury (AKI) occurs in 2-10% of patients with acetaminophen (APAP) overdose. Elevation in creatinine (SCr) typically occurs 2 to 5 days after ingestion, with a mean peak on day 7, and normalization over a month. However, it remains unclear whether renal impairment occurs without hepatotoxicity. We hypothesized that APAP-associated acute renal failure occurs in patients with and without severe liver dysfunction after APAP overdose. MATERIALS AND METHODS: We retrospectively evaluated all patients admitted to the Medical Intensive Care Unit at a tertiary hospital and received acetylcysteine between June 2009 and December 2014. Of the 303 patients meeting these criteria, 139 of these patients received acetylcysteine for APAP overdose. Of these patients, 138 had Model for End-Stage Liver Disease (MELD) Scores on Day 1 of admission. Using a modified MELD (m-MELD) score, only containing total bilirubin and international normalized ratio not the SCr, the median m-MELD score was calculated. Patients with m-MELD scores below the median were compared to those with scores above the median (low m-MELD score <2.9 or high m-MELD score >2.9). RESULTS: Baseline demographics were similar in the two groups with the exception of more hypertension in the low m MELD group (24 vs 7%; P= .02). Time to admission was shorter in the low m-MELD group (7.9 +/- 9.3 vs. 25.7 +/- 29.2 hours; P= .001). The mean admission APAP level was 96.9 (+/-119) MUg/mL in the low compared to 52.3 (+/-85.3) MUg/mL in the high m-MELD group (P= .012). Day one SCr (1.2 +/- 0.9 vs 2.7 +/- 2.2 mg/dL; P< .0001) and change from baseline to highest SCr (0.2 +/- 0.3 vs. 2.7 +/- 3.3 mg/dL; P< .0001) were both lower in the low m-MELD group compared to the high m MELD group. In addition, renal failure resolved upon discharge in all 2 patients (3%) with AKI in the low m-MELD group as compared to only 19 patients (44%) in the high m-MELD group. CONCLUSIONS: Mean day one SCr, maximum change in SCr, and lack of renal failure resolution were higher in patients with higher m-MELD scores. However, patients with low m-MELD scores presented much earlier than patients with high m-MELD scores and 26% developed AKI. PMID- 27481759 TI - Music therapy, a review of the potential therapeutic benefits for the critically ill. AB - Intensive care units are a stressful milieu for patients, particularly when under mechanical ventilation which they refer to as inhumane and anxiety producing. Anxiety can impose harmful effects on the course of recovery and overall well being of the patient. Resulting adverse effects may prolong weaning and recovery time. Music listening, widely used for stress release in all areas of medicine, tends to be a reliable and efficacious treatment for those critically ill patients. It can abate the stress response, decrease anxiety during mechanical ventilation, and induce an overall relaxation response without the use of medication. This relaxation response can lower cardiac workload and oxygen consumption resulting in more effective ventilation. Music may also improve sleep quality and reduce patient's pain with a subsequent decrease in sedative exposure leading to an accelerated ventilator weaning process and a speedier recovery. PMID- 27481760 TI - Predicting success of high-flow nasal cannula in pneumonia patients with hypoxemic respiratory failure: The utility of the ROX index. AB - PURPOSE: The purpose of the study is to describe early predictors and to develop a prediction tool that accurately identifies the need for mechanical ventilation (MV) in pneumonia patients with hypoxemic acute respiratory failure (ARF) treated with high-flow nasal cannula (HFNC). MATERIALS AND METHODS: This is a 4-year prospective observational 2-center cohort study including patients with severe pneumonia treated with HFNC. High-flow nasal cannula failure was defined as need for MV. ROX index was defined as the ratio of pulse oximetry/fraction of inspired oxygen to respiratory rate. RESULTS: One hundred fifty-seven patients were included, of whom 44 (28.0%) eventually required MV (HFNC failure). After 12 hours of HFNC treatment, the ROX index demonstrated the best prediction accuracy (area under the receiver operating characteristic curve 0.74 [95% confidence interval, 0.64-0.84]; P<.002). The best cutoff point for the ROX index was estimated to be 4.88. In the Cox proportional hazards model, a ROX index greater than or equal to 4.88 measured after 12 hours of HFNC was significantly associated with a lower risk for MV (hazard ratio, 0.273 [95% confidence interval, 0.121-0.618]; P=.002), even after adjusting for potential confounding. CONCLUSIONS: In patients with ARF and pneumonia, the ROX index can identify patients at low risk for HFNC failure in whom therapy can be continued after 12 hours. PMID- 27481761 TI - A clinical prediction tool for hospital mortality in critically ill elderly patients. AB - BACKGROUND: Very elderly (80 years of age and above) critically ill patients admitted to medical intensive care units (ICUs) have a high incidence of mortality, prolonged hospital length of stay, and living in a dependent state should they survive. OBJECTIVE: The objective was to develop a clinical prediction tool for hospital mortality to improve future end-of-life decision making for very elderly patients who are admitted to Canadian ICUs. DESIGN: This was a prospective, multicenter cohort study. SETTING: Data from 1033 very elderly medical patients admitted to 22 Canadian academic and nonacademic ICUs were analyzed. INTERVENTIONS: A univariate analysis of selected predictors to ascertain prognostic power was performed, followed by multivariable logistic regression to derive the final prediction tool. MAIN RESULTS: We included 1033 elderly patients in the analyses. Mean age was 84.6+/-3.5 years, 55% were male, mean Acute Physiology and Chronic Health Evaluation II score was 23.1+/-7.9, Sequential Organ Failure Assessment score was 5.3+/-3.4, median ICU length of stay was 4.1 (interquartile range, 6.2) days, median hospital length of stay was 16.2 (interquartile range, 25.0) days, and ICU mortality and all-cause hospital mortality were 27% and 41%, respectively. Important predictors of hospital mortality at the time of ICU admission include age (85-90 years of age had an odds ratio of hospital mortality of 1.63 [1.04-2.56]; >90 years of age had an odds ratio of hospital mortality of 2.64 [1.27-5.48]), serum creatinine (120-300 had an odds ratio of hospital mortality of 1.57 [1.01-2.44]; >300 had an odds ratio of hospital mortality of 5.29 [2.43-11.51]), Glasgow Coma Scale (13-14 had an odds ratio of hospital mortality of 2.09 [1.09-3.98]; 8-12 had an odds ratio of hospital mortality of 2.31 [1.34-3.97]; 4-7 had an odds ratio of hospital mortality of 5.75 [3.02-10.95]; 3 had an odds ratio of hospital mortality of 8.97 [3.70-21.74]), and serum pH (<7.15 had an odds ratio of hospital mortality of 2.44 [1.07-5.60]). CONCLUSION: We identified high-risk characteristics for hospital mortality in the elderly population and developed a Risk Scale that may be used to inform discussions regarding goals of care in the future. Further study is warranted to validate the Risk Scale in other settings and evaluate its impact on clinical decision making. PMID- 27481763 TI - Functional Properties and Morphological Characters of Soluble Dietary Fibers in Different Edible Parts of Angelica Keiskei. AB - This study comparatively investigated the functional properties, chemical compositions, and morphological characters of soluble dietary fibers (SDFs) from the root, stem, and leaf of Angelica keiskei. The SDFs showed relevant functional properties, with the root SDF (RSDF) exhibiting the highest water-holding capacity (22.6 g/g), oil-holding capacity (6.29 mL/g), swelling capacity (36.6 mL/g), emulsion stability, and fat adsorption (5.66 g/g). Stem SDF (SSDF) gave the highest foam stability, toxic ions adsorption (Pb: 1.12 mg/g; As: 3.22 mg/g), and bile acid salts adsorption (sodium cholate: 85.6 mg/g; sodium glycocholate: 93.1 mg/g; sodium taurocholate: 125.7 mg/g). RSDF and SSDF presented similar monosaccharide compositions, thermal property, chemical bonds and groups, and irregular, rough, and porous surfaces. It can be concluded that the obtained SDFs, especially for RSDF and SSDF, can be used in the food industry as fiber rich functional ingredients. PMID- 27481764 TI - The vulnerable immature cerebellum. PMID- 27481762 TI - Social participation of teenagers and young adults with developmental co ordination disorder and strategies that could help them: results from a scoping review. AB - BACKGROUND: The impact of developmental co-ordination disorder (DCD) on teenagers' and young adults' participation is not well documented. This article aims to synthesize the current knowledge on social participation, which is the performance of an individual in realizing his or her daily activities and social roles within its life environment. Strategies and interventions to support youths (15-25 years old) with DCD were also synthesized. METHODS: A scoping review interrogating three databases and using 'snowballing techniques' was performed to identify both scientific and grey literature published between 2004 and 2014. Over 1000 documents were screened and 57 were read in full; 28 met inclusion criteria. A charting form based on 12 life habits described in the disability creation process and developed by two reviewers was used to extract data and report the results. RESULTS: All life habits were reported to be affected for teenagers and young adults with DCD, with education and interpersonal relationships being the most frequently discussed. During adolescence and adulthood, new tasks and subsequent difficulties emerge, such as driving. Mental health difficulties emerged as a key theme. Few strategies and interventions were described to support social participation of youths with DCD. CONCLUSION: Many life habits are challenging for youths with DCD, but few evidence-based strategies and interventions have been designed to help them to increase their social participation. PMID- 27481765 TI - New QSAR Models for Human Cytochromes P450, 1A2, 2D6 and 3A4 Implicated in the Metabolism of Drugs. Relevance of Dataset on Model Development. PMID- 27481766 TI - Rough Set Theory as an Interpretable Method for Predicting the Inhibition of Cytochrome P450 1A2 and 2D6. AB - Early prediction of ADME properties such as the cytochrome P450 (CYP) mediated drug-drug interactions is an important challenge in the drug discovery area. In this study, we propose to couple an original data mining approach based on Rough Set Theory (RST) to a structural description of molecules. The latter was achieved by using two types of structural keys: (1) the MACCS keys and (2) a set of five in-house fingerprints based on properties of the electron density distributions of chemical groups. The compounds considered are involved in the inhibition of CYP1A2 and CYP2D6. RST allowed the extraction of rules further used as classifiers to predict the inhibitory profile of an independent set of molecules. The results reached prediction accuracies of 90.6 and 88.2 % for CYP1A2 and CYP2D6, respectively. In addition, these classifiers were analyzed to determine which structural fragments were most used for building the rules, revealing relationships between the occurrence of particular molecular fragments and CYP inhibition. The results assessed RST as a suitable tool to build strongly predictive models and infer structure-activity rules associated with potency. PMID- 27481767 TI - Information Theory and Voting Based Consensus Clustering for Combining Multiple Clusterings of Chemical Structures. AB - Many consensus clustering methods have been applied in different areas such as pattern recognition, machine learning, information theory and bioinformatics. However, few methods have been used for chemical compounds clustering. In this paper, an information theory and voting based algorithm (Adaptive Cumulative Voting-based Aggregation Algorithm A-CVAA) was examined for combining multiple clusterings of chemical structures. The effectiveness of clusterings was evaluated based on the ability of the clustering method to separate active from inactive molecules in each cluster, and the results were compared with Ward's method. The chemical dataset MDL Drug Data Report (MDDR) and the Maximum Unbiased Validation (MUV) dataset were used. Experiments suggest that the adaptive cumulative voting-based consensus method can improve the effectiveness of combining multiple clusterings of chemical structures. PMID- 27481768 TI - A Novel Strategy of Structural Similarity Based Consensus Modeling. AB - A novel strategy of "structural similarity based consensus modeling" (SSCM) based on "model distance and guided model selection" (MD-QGMS) submodel set was proposed. The SSCM strategy is built upon a hypothesis, that is, similar compounds are most probably predicted more accurately by a same submodel among a model population, which can be concluded from the fact that models employing a different set of descriptors can predict compounds with specific structures more accurately. It is proved that the proposed SSCM strategy can remarkably improve the external prediction ability of QSAR models by employing two different datasets. In future, the proposed SSCM strategy may provide a new direction to develop more accurate predictive models. PMID- 27481769 TI - Modelling Structure Activity Landscapes with Cliffs: a Kernel Regression-Based Approach. AB - Quantitative Structure-Activity Relationship (QSAR) models are increasingly used in hazard and risk assessment. Even when models with linear relationships between activity and a small number of descriptors are built and validated regarding predictivity and statistical assumptions, similar structures can exhibit large differences in activity known as similarity paradoxes or activity cliffs. In order to reduce the impact that similarity paradoxes can have on predictions we have devised a statistical method based on Nadaraya-Watson kernel regression. According to our method, activity cliffs filter out contributions of neighbouring chemicals especially along the cliff axis. Our method decreases density-based certainty in particular for chemicals with strong prediction errors and the implementation of Structure-Activity Landscape Index (SALI) curves shows that our method improves the prediction of activity cliff ranks. We also provide useful indications on the density-based applicability domain and the reliability of individual predictions. PMID- 27481770 TI - Pharmacophore Alignment Search Tool (PhAST): Significance Assessment of Chemical Similarity. AB - Previously, we proposed a ligand-based virtual screening technique (PhAST) based on global alignment of linearized interaction patterns. Here, we applied techniques developed for similarity assessment in local sequence alignments to our method resulting in p-values for chemical similarity. We compared two sampling strategies, a simple sampling strategy and a Markov Chain Monte Carlo (MCMC) method, and investigated the similarity of sampled distributions to Gaussian, Gumbel, modified Gumbel, and Gamma distributions. The Gumbel distribution with a Gaussian correction term was identified as the most similar to the observed empirical distributions. These techniques were applied in retrospective screenings on a drug-like dataset. Obtained p-values were adjusted to the size of the screening library with four different methods. Evaluation of E value thresholds corroborated the Bonferroni correction as a preferred means to identify significant chemical similarity with PhAST. An online version of PhAST with significance estimation is available at http://modlab-cadd.ethz.ch/. PMID- 27481771 TI - Exploring the Molecular Basis of Qo bc1 Complex Inhibitors Activity to Find Novel Antimalarials Hits. AB - Cytochrome bc1 complex is a crucial element in the mitochondrial respiratory chain, being indispensable for the survival of several species of Plasmodia that cause malaria and, therefore, it is a promising target for antimalarial drug development. We report a molecular docking study building on the most recently obtained X-ray structure of the Saccharomyces cerevisiae bc1 complex (PDB code: 3CX5) using several reported inhibitors with experimentally determined IC50 values against the Plasmodium falciparum bc1 complex. We produced a molecular docking model that correlated the calculated binding free energy with the experimental inhibitory activity of each compound. This Qo model was used to search the drug-like database included in the MOE package for novel potential bc1 complex inhibitors. Twenty three compounds were chosen to be tested for their antimalarial activity and four of these compounds demonstrated activity against the chloroquine-resistant W2 strain of P. falciparum. The most active compounds were also active against the atovaquone-resistant P. falciparum FCR3 strain and S. cerevisiae. Our study suggests the validity of the yeast bc1 complex structure as a model for the discovery of new antimalarial hits. PMID- 27481774 TI - A DNA-Based Assessment of the Phylogenetic Position of a Morphologically Distinct, Anchialine-Lake-Restricted Seahorse. AB - Isolated populations provide special opportunities to study local adaptation and incipient speciation. In some cases, however, morphological evolution can obscure the taxonomic status of recently founded populations. Here, we use molecular markers to show that an anchialine-lake-restricted population of seahorses, originally identified as Hippocampus reidi, appears on the basis of DNA data to be Hippocampus erectus We collected seahorses from Sweetings Pond, on Eleuthera Island, Bahamas, during the summer of 2014. We measured morphological traits and sequenced 2 genes, cytochrome b and ribosomal protein S7, from 19 seahorses in our sample. On the basis of morphology, Sweetings Pond seahorses could not be assigned definitively to either of the 2 species of seahorse, H. reidi and H. erectus, that occur in marine waters surrounding the Bahamas. However, our DNA based phylogenetic analysis showed that the Sweetings Pond fish were firmly nested within the H. erectus clade with a Bayesian posterior probability greater than 0.99. Thus, Sweetings Pond seahorses most recently shared a common ancestor with H. erectus populations from the Western Atlantic. Interestingly, the seahorses from Sweetings Pond differ morphologically from other marine populations of H. erectus in having a more even torso to tail length ratio. The substantial habitat differences between Sweetings Pond and the surrounding coastal habitat make Sweetings Pond seahorses particularly interesting from the perspectives of conservation, local adaptation, and incipient speciation. PMID- 27481772 TI - alpha-Synuclein: Experimental Pathology. AB - alpha-Synuclein, which is present as a small, soluble, cytosolic protein in healthy subjects, is converted to amyloid-like fibrils in diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Bulk synthesis of purified alpha-synuclein has made it more convenient to study the nature of the normal protein and the mechanism of its conversion to an abnormal form in vitro and in vivo. Synthetic alpha-synuclein fibrils and pathological alpha-synuclein from diseased brains can act as triggers to convert normal alpha-synuclein to an abnormal form via prion-like mechanisms. In this article, we describe the experimental pathologies of alpha-synuclein both in vitro and in vivo in human and animal models. Prion-like spreading of abnormal alpha-synuclein from cell to cell can account for the progression of these alpha synucleinopathies. PMID- 27481775 TI - Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. AB - The mineralocorticoid aldosterone is an important regulator of blood pressure, volume, and electrolyte balance. However, excess aldosterone can be deleterious as a driver of vascular remodeling and tissue fibrosis associated with cardiometabolic diseases. Aldosterone synthase (AS) inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists for blocking the pathologic effects of excess aldosterone. Discovery of selective ASIs has been challenging because of the high sequence identity (93%) AS shares with cortisol synthase (CS), and the low identity of rodent AS compared with human (63%). Using cynomolgus (cyno) monkey-based models, we identified BI 689648 [6-(5-methoxymethyl-pyridin-3-yl) 3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide], a novel, highly selective ASI that exhibits an in vitro IC50 of 2 nM against AS and 300 nm against CS (150-fold selectivity) compared with the recently described ASIs FAD286 [4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile] (3 nM AS; 90 nM CS; 40-fold) and LCI699 (4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5 yl]-3-fluorobenzonitrile) (10 nM AS; 80 nM CS; 8-fold). After oral administration in cyno monkeys, BI 689648 (5 mg/kg) exhibits a peak plasma concentration of ~500 nM. For in vivo profiling we used an adrenocorticotropin-challenge model in which BI 689648 was >20-fold more selective compared with FAD286 and LCI699. Because both FAD286 and LCI699 failed to provide adequate selectivity for CS when tested in patients, the desire for more selective molecules to test the ASI hypothesis remains high. Therefore, highly selective aldosterone synthase inhibitors such as BI 689648 represent an important step forward toward developing ASIs with greater potential for clinical success in cardiometabolic diseases. PMID- 27481776 TI - Oscillations-free PID control of anesthetic drug delivery in neuromuscular blockade. AB - BACKGROUND AND OBJECTIVES: The PID-control of drug delivery or the neuromuscular blockade (NMB) in closed-loop anesthesia is considered. The NMB system dynamics portrayed by a Wiener model can exhibit sustained nonlinear oscillations under realistic PID gains and for physiologically feasible values of the model parameters. Such oscillations, also repeatedly observed in clinical trials, lead to under- and over-dosing of the administered drug and undermine patient safety. This paper proposes a tuning policy for the proportional PID gain that via bifurcation analysis ensures oscillations-free performance of the control loop. Online estimates of the Wiener model parameters are needed for the controller implementation and monitoring of the closed-loop proximity to oscillation. METHODS: The nonlinear dynamics of the PID-controlled NMB system are studied by bifurcation analysis. A database of patient models estimated under PID-controlled neuromuscular blockade during general anesthesia is utilized, along with the corresponding clinical measurements. The performance of three recursive algorithms is compared in the application at hand: an extended Kalman filter, a conventional particle filter (PF), and a PF making use of an orthonormal basis to estimate the probability density function from the particle set. RESULTS: It is shown that with a time-varying proportional PID gain, the type of equilibria of the closed-loop system remains the same as in the case of constant controller gains. The recovery time and frequency of oscillations are also evaluated in simulation over the database of patient models. Nonlinear identification techniques based on model linearization yield biased parameter estimates and thus introduce superfluous uncertainty. The bias and variance of the estimated models are related to the computational complexity of the identification algorithms, highlighting the superiority of the PFs in this safety-critical application. CONCLUSIONS: The study demonstrates feasibility of the proposed oscillation-free control strategy combining bifurcation theory based design and online parameter estimation by PF. PMID- 27481773 TI - Bacterial Protein Synthesis as a Target for Antibiotic Inhibition. AB - Protein synthesis occurs on macromolecular machines, called ribosomes. Bacterial ribosomes and the translational machinery represent one of the major targets for antibiotics in the cell. Therefore, structural and biochemical investigations into ribosome-targeting antibiotics provide not only insight into the mechanism of action and resistance of antibiotics, but also insight into the fundamental process of protein synthesis. This review summarizes the recent advances in our understanding of protein synthesis, particularly with respect to X-ray and cryoelectron microscopy (cryo-EM) structures of ribosome complexes, and highlights the different steps of translation that are targeted by the diverse array of known antibiotics. Such findings will be important for the ongoing development of novel and improved antimicrobial agents to combat the rapid emergence of multidrug resistant pathogenic bacteria. PMID- 27481777 TI - Identification of nuclear genes affecting 2-Deoxyglucose resistance in Schizosaccharomyces pombe. AB - 2-Deoxyglucose (2-DG) is a toxic glucose analog. To identify genes involved in 2 DG toxicity in Schizosaccharomyces pombe, we screened a wild-type overexpression library for genes which render cells 2-DG resistant. A gene we termed odr1, encoding an uncharacterized hydrolase, led to strong resistance and altered invertase expression when overexpressed. We speculate that Odr1 neutralizes the toxic form of 2-DG, similar to the Saccharomyces cerevisiae Dog1 and Dog2 phosphatases which dephosphorylate 2-DG-6-phosphate synthesized by hexokinase. In a complementary approach, we screened a haploid deletion library to identify 2-DG resistant mutants. This screen identified the genes snf5, ypa1, pas1 and pho7 In liquid medium, deletions of these genes conferred 2-DG resistance preferentially under glucose-repressed conditions. The deletion mutants expressed invertase activity more constitutively than the control strain, indicating defects in the control of glucose repression. No S. cerevisiae orthologs of the pho7 gene is known, and no 2-DG resistance has been reported for any of the deletion mutants of the other genes identified here. Moreover, 2-DG leads to derepressed invertase activity in S. pombe, while in S. cerevisiae it becomes repressed. Taken together, these findings suggest that mechanisms involved in 2-DG resistance differ between budding and fission yeasts. PMID- 27481778 TI - From writing to reading the encyclopedia of life. AB - Prologue 'As the study of natural science advances, the language of scientific description may be greatly simplified and abridged. This has already been done by Linneaus and may be carried still further by other invention. The descriptions of natural orders and genera may be reduced to short definitions, and employment of signs, somewhat in the manner of algebra, instead of long descriptions. It is more easy to conceive this, than it is to conceive with what facility, and in how short a time, a knowledge of all the objects of natural history may ultimately be acquired; and that which is now considered learning and science, and confined to a few specially devoted to it, may at length be universally possessed in every civilized country and in every rank of life'. J. C. Louden 1829. Magazine of natural history, vol. 1: This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481780 TI - Dissecting host-associated communities with DNA barcodes. AB - DNA barcoding and metabarcoding methods have been invaluable in the study of interactions between host organisms and their symbiotic communities. Barcodes can help identify individual symbionts that are difficult to distinguish using morphological characters, and provide a way to classify undescribed species. Entire symbiont communities can be characterized rapidly using barcoding and especially metabarcoding methods, which is often crucial for isolating ecological signal from the substantial variation among individual hosts. Furthermore, barcodes allow the evolutionary histories of symbionts and their hosts to be assessed simultaneously and in reference to one another. Here, we describe three projects illustrating the utility of barcodes for studying symbiotic interactions: first, we consider communities of arthropods found in the ant occupied domatia of the East African ant-plant Vachellia (Acacia) drepanolobium; second, we examine communities of arthropod and protozoan inquilines in three species of Nepenthes pitcher plant in South East Asia; third, we investigate communities of gut bacteria of South American ants in the genus Cephalotes Advances in sequencing and computation, and greater database connectivity, will continue to expand the utility of barcoding methods for the study of species interactions, especially if barcoding can be approached flexibly by making use of alternative genetic loci, metagenomes and whole-genome data.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481779 TI - Insect symbionts in food webs. AB - Recent research has shown that the bacterial endosymbionts of insects are abundant and diverse, and that they have numerous different effects on their hosts' biology. Here we explore how insect endosymbionts might affect the structure and dynamics of insect communities. Using the obligate and facultative symbionts of aphids as an example, we find that there are multiple ways that symbiont presence might affect food web structure. Many symbionts are now known to help their hosts escape or resist natural enemy attack, and others can allow their hosts to withstand abiotic stress or affect host plant use. In addition to the direct effect of symbionts on aphid phenotypes there may be indirect effects mediated through trophic and non-trophic community interactions. We believe that by using data from barcoding studies to identify bacterial symbionts, this extra, microbial dimension to insect food webs can be better elucidated.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481781 TI - Imagining Sisyphus happy: DNA barcoding and the unnamed majority. AB - The vast majority of life on the Earth is physically small, and is classifiable as micro- or meiobiota. These organisms are numerically dominant and it is likely that they are also abundantly speciose. By contrast, the vast majority of taxonomic effort has been expended on 'charismatic megabionts': larger organisms where a wealth of morphology has facilitated Linnaean species definition. The hugely successful Linnaean project is unlikely to be extensible to the totality of approximately 10 million species in a reasonable time frame and thus alternative toolkits and methodologies need to be developed. One such toolkit is DNA barcoding, particularly in its metabarcoding or metagenetics mode, where organisms are identified purely by the presence of a diagnostic DNA sequence in samples that are not processed for morphological identification. Building on secure Linnaean foundations, classification of unknown (and unseen) organisms to molecular operational taxonomic units (MOTUs) and deployment of these MOTUs in biodiversity science promises a rewarding resolution to the Sisyphean task of naming all the world's species.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481782 TI - A new way to contemplate Darwin's tangled bank: how DNA barcodes are reconnecting biodiversity science and biomonitoring. AB - Encompassing the breadth of biodiversity in biomonitoring programmes has been frustrated by an inability to simultaneously identify large numbers of species accurately and in a timely fashion. Biomonitoring infers the state of an ecosystem from samples collected and identified using the best available taxonomic knowledge. The advent of DNA barcoding has now given way to the extraction of bulk DNA from mixed samples of organisms in environmental samples through the development of high-throughput sequencing (HTS). This DNA metabarcoding approach allows an unprecedented view of the true breadth and depth of biodiversity, but its adoption poses two important challenges. First, bioinformatics techniques must simultaneously perform complex analyses of large datasets and translate the results of these analyses to a range of users. Second, the insights gained from HTS need to be amalgamated with concepts such as Linnaean taxonomy and indicator species, which are less comprehensive but more intuitive. It is clear that we are moving beyond proof-of-concept studies to address the challenge of implementation of this new approach for environmental monitoring and regulation. Interpreting Darwin's 'tangled bank' through a DNA lens is now a reality, but the question remains: how can this information be generated and used reliably, and how does it relate to accepted norms in ecosystem study?This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481783 TI - Censusing marine eukaryotic diversity in the twenty-first century. AB - The ocean constitutes one of the vastest and richest biomes on our planet. Most recent estimations, all based on indirect approaches, suggest that there are millions of marine eukaryotic species. Moreover, a large majority of these are small (less than 1 mm), cryptic and still unknown to science. However, this knowledge gap, caused by the lack of diagnostic morphological features in small organisms and the limited sampling of the global ocean, is currently being filled, thanks to new DNA-based approaches. The molecular technique of PCR amplification of homologous gene regions combined with high-throughput sequencing, routinely used to census unculturable prokaryotes, is now also being used to characterize whole communities of marine eukaryotes. Here, we review how this methodological advancement has helped to better quantify the magnitude and patterns of marine eukaryotic diversity, with an emphasis on taxonomic groups previously largely overlooked. We then discuss obstacles remaining to achieve a global understanding of marine eukaryotic diversity. In particular, we argue that 18S variable regions do not provide sufficient taxonomic resolution to census marine life, and suggest combining broad eukaryotic surveys targeting the 18S rRNA region with more taxon-focused analyses of hypervariable regions to improve our understanding of the diversity of species, the functional units of marine ecosystems.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481784 TI - Barcoding the largest animals on Earth: ongoing challenges and molecular solutions in the taxonomic identification of ancient cetaceans. AB - Over the last few centuries, many cetacean species have witnessed dramatic global declines due to industrial overharvesting and other anthropogenic influences, and thus are key targets for conservation. Whale bones recovered from archaeological and palaeontological contexts can provide essential baseline information on the past geographical distribution and abundance of species required for developing informed conservation policies. Here we review the challenges with identifying whale bones through traditional anatomical methods, as well as the opportunities provided by new molecular analyses. Through a case study focused on the North Sea, we demonstrate how the utility of this (pre)historic data is currently limited by a lack of accurate taxonomic information for the majority of ancient cetacean remains. We then discuss current opportunities presented by molecular identification methods such as DNA barcoding and collagen peptide mass fingerprinting (zooarchaeology by mass spectrometry), and highlight the importance of molecular identifications in assessing ancient species' distributions through a case study focused on the Mediterranean. We conclude by considering high-throughput molecular approaches such as hybridization capture followed by next-generation sequencing as cost-effective approaches for enhancing the ecological informativeness of these ancient sample sets.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481785 TI - Counting animal species with DNA barcodes: Canadian insects. AB - Recent estimates suggest that the global insect fauna includes fewer than six million species, but this projection is very uncertain because taxonomic work has been limited on some highly diverse groups. Validation of current estimates minimally requires the investigation of all lineages that are diverse enough to have a substantial impact on the final species count. This study represents a first step in this direction; it employs DNA barcoding to evaluate patterns of species richness in 27 orders of Canadian insects. The analysis of over one million specimens revealed species counts congruent with earlier results for most orders. However, Diptera and Hymenoptera were unexpectedly diverse, representing two-thirds of the 46 937 barcode index numbers (=species) detected. Correspondence checks between known species and barcoded taxa showed that sampling was incomplete, a result confirmed by extrapolations from the barcode results which suggest the occurrence of at least 94 000 species of insects in Canada, a near doubling from the prior estimate of 54 000 species. One dipteran family, the Cecidomyiidae, was extraordinarily diverse with an estimated 16 000 species, a 10-fold increase from its predicted diversity. If Canada possesses about 1% of the global fauna, as it does for known taxa, the results of this study suggest the presence of 10 million insect species with about 1.8 million of these taxa in the Cecidomyiidae. If so, the global species count for this fly family may exceed the combined total for all 142 beetle families. If extended to more geographical regions and to all hyperdiverse groups, DNA barcoding can rapidly resolve the current uncertainty surrounding a species count for the animal kingdom. A newly detailed understanding of species diversity may illuminate processes important in speciation, as suggested by the discovery that the most diverse insect lineages in Canada employ an unusual mode of reproduction, haplodiploidy.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481786 TI - DNA barcoding and taxonomy: dark taxa and dark texts. AB - Both classical taxonomy and DNA barcoding are engaged in the task of digitizing the living world. Much of the taxonomic literature remains undigitized. The rise of open access publishing this century and the freeing of older literature from the shackles of copyright have greatly increased the online availability of taxonomic descriptions, but much of the literature of the mid- to late-twentieth century remains offline ('dark texts'). DNA barcoding is generating a wealth of computable data that in many ways are much easier to work with than classical taxonomic descriptions, but many of the sequences are not identified to species level. These 'dark taxa' hamper the classical method of integrating biodiversity data, using shared taxonomic names. Voucher specimens are a potential common currency of both the taxonomic literature and sequence databases, and could be used to help link names, literature and sequences. An obstacle to this approach is the lack of stable, resolvable specimen identifiers. The paper concludes with an appeal for a global 'digital dashboard' to assess the extent to which biodiversity data are available online.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481787 TI - Multilocus inference of species trees and DNA barcoding. AB - The unprecedented amount of data resulting from next-generation sequencing has opened a new era in phylogenetic estimation. Although large datasets should, in theory, increase phylogenetic resolution, massive, multilocus datasets have uncovered a great deal of phylogenetic incongruence among different genomic regions, due both to stochastic error and to the action of different evolutionary process such as incomplete lineage sorting, gene duplication and loss and horizontal gene transfer. This incongruence violates one of the fundamental assumptions of the DNA barcoding approach, which assumes that gene history and species history are identical. In this review, we explain some of the most important challenges we will have to face to reconstruct the history of species, and the advantages and disadvantages of different strategies for the phylogenetic analysis of multilocus data. In particular, we describe the evolutionary events that can generate species tree-gene tree discordance, compare the most popular methods for species tree reconstruction, highlight the challenges we need to face when using them and discuss their potential utility in barcoding. Current barcoding methods sacrifice a great amount of statistical power by only considering one locus, and a transition to multilocus barcodes would not only improve current barcoding methods, but also facilitate an eventual transition to species-tree-based barcoding strategies, which could better accommodate scenarios where the barcode gap is too small or inexistent.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481788 TI - Scaling up discovery of hidden diversity in fungi: impacts of barcoding approaches. AB - The fungal kingdom is a hyperdiverse group of multicellular eukaryotes with profound impacts on human society and ecosystem function. The challenge of documenting and describing fungal diversity is exacerbated by their typically cryptic nature, their ability to produce seemingly unrelated morphologies from a single individual and their similarity in appearance to distantly related taxa. This multiplicity of hurdles resulted in the early adoption of DNA-based comparisons to study fungal diversity, including linking curated DNA sequence data to expertly identified voucher specimens. DNA-barcoding approaches in fungi were first applied in specimen-based studies for identification and discovery of taxonomic diversity, but are now widely deployed for community characterization based on sequencing of environmental samples. Collectively, fungal barcoding approaches have yielded important advances across biological scales and research applications, from taxonomic, ecological, industrial and health perspectives. A major outstanding issue is the growing problem of 'sequences without names' that are somewhat uncoupled from the traditional framework of fungal classification based on morphology and preserved specimens. This review summarizes some of the most significant impacts of fungal barcoding, its limitations, and progress towards the challenge of effective utilization of the exponentially growing volume of data gathered from high-throughput sequencing technologies.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481789 TI - Biodiversity analysis in the digital era. AB - This paper explores what the virtual biodiversity e-infrastructure will look like as it takes advantage of advances in 'Big Data' biodiversity informatics and e research infrastructure, which allow integration of various taxon-level data types (genome, morphology, distribution and species interactions) within a phylogenetic and environmental framework. By overcoming the data scaling problem in ecology, this integrative framework will provide richer information and fast learning to enable a deeper understanding of biodiversity evolution and dynamics in a rapidly changing world. The Atlas of Living Australia is used as one example of the advantages of progressing towards this future. Living in this future will require the adoption of new ways of integrating scientific knowledge into societal decision making.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481790 TI - Telling plant species apart with DNA: from barcodes to genomes. AB - Land plants underpin a multitude of ecosystem functions, support human livelihoods and represent a critically important component of terrestrial biodiversity-yet many tens of thousands of species await discovery, and plant identification remains a substantial challenge, especially where material is juvenile, fragmented or processed. In this opinion article, we tackle two main topics. Firstly, we provide a short summary of the strengths and limitations of plant DNA barcoding for addressing these issues. Secondly, we discuss options for enhancing current plant barcodes, focusing on increasing discriminatory power via either gene capture of nuclear markers or genome skimming. The former has the advantage of establishing a defined set of target loci maximizing efficiency of sequencing effort, data storage and analysis. The challenge is developing a probe set for large numbers of nuclear markers that works over sufficient phylogenetic breadth. Genome skimming has the advantage of using existing protocols and being backward compatible with existing barcodes; and the depth of sequence coverage can be increased as sequencing costs fall. Its non-targeted nature does, however, present a major informatics challenge for upscaling to large sample sets.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481791 TI - Advancing taxonomy and bioinventories with DNA barcodes. AB - We use three examples-field and ecology-based inventories in Costa Rica and Papua New Guinea and a museum and taxonomic-based inventory of the moth family Geometridae-to demonstrate the use of DNA barcoding (a short sequence of the mitochondrial COI gene) in biodiversity inventories, from facilitating workflows of identification of freshly collected specimens from the field, to describing the overall diversity of megadiverse taxa from museum collections, and most importantly linking the fresh specimens, the general museum collections and historic type specimens. The process also flushes out unexpected sibling species hiding under long-applied scientific names, thereby clarifying and parsing previously mixed collateral data. The Barcode of Life Database has matured to an essential interactive platform for the multi-authored and multi-process collaboration. The BIN system of creating and tracking DNA sequence-based clusters as proxies for species has become a powerful way around some parts of the 'taxonomic impediment', especially in entomology, by providing fast but testable and tractable species hypotheses, tools for visualizing the distribution of those in time and space and an interim naming system for communication.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481792 TI - DNA barcoding in diverse educational settings: five case studies. AB - Despite 250 years of modern taxonomy, there remains a large biodiversity knowledge gap. Most species remain unknown to science. DNA barcoding can help address this gap and has been used in a variety of educational contexts to incorporate original research into school curricula and informal education programmes. A growing body of evidence suggests that actively conducting research increases student engagement and retention in science. We describe case studies in five different educational settings in Canada and the USA: a programme for primary and secondary school students (ages 5-18), a year-long professional development programme for secondary school teachers, projects embedding this research into courses in a post-secondary 2-year institution and a degree granting university, and a citizen science project. We argue that these projects are successful because the scientific content is authentic and compelling, DNA barcoding is conceptually and technically straightforward, the workflow is adaptable to a variety of situations, and online tools exist that allow participants to contribute high-quality data to the international research effort. Evidence of success includes the broad adoption of these programmes and assessment results demonstrating that participants are gaining both knowledge and confidence. There are exciting opportunities for coordination among educational projects in the future.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481794 TI - Correction to 'Running out of time: the decline of channel activity and nucleotide activation in adenosine triphosphate-sensitive K-channels'. PMID- 27481796 TI - Medical News Headlines: Don't Believe Everything You Read. PMID- 27481793 TI - The Trichoptera barcode initiative: a strategy for generating a species-level Tree of Life. AB - DNA barcoding was intended as a means to provide species-level identifications through associating DNA sequences from unknown specimens to those from curated reference specimens. Although barcodes were not designed for phylogenetics, they can be beneficial to the completion of the Tree of Life. The barcode database for Trichoptera is relatively comprehensive, with data from every family, approximately two-thirds of the genera, and one-third of the described species. Most Trichoptera, as with most of life's species, have never been subjected to any formal phylogenetic analysis. Here, we present a phylogeny with over 16 000 unique haplotypes as a working hypothesis that can be updated as our estimates improve. We suggest a strategy of implementing constrained tree searches, which allow larger datasets to dictate the backbone phylogeny, while the barcode data fill out the tips of the tree. We also discuss how this phylogeny could be used to focus taxonomic attention on ambiguous species boundaries and hidden biodiversity. We suggest that systematists continue to differentiate between 'Barcode Index Numbers' (BINs) and 'species' that have been formally described. Each has utility, but they are not synonyms. We highlight examples of integrative taxonomy, using both barcodes and morphology for species description.This article is part of the themed issue 'From DNA barcodes to biomes'. PMID- 27481798 TI - Letters to the Editor. PMID- 27481799 TI - Progressive Care Nurses Improving Patient Safety by Limiting Interruptions During Medication Administration. AB - BACKGROUND: Because of the high frequency of interruptions during medication administration, the effectiveness of strategies to limit interruptions during medication administration has been evaluated in numerous quality improvement initiatives in an effort to reduce medication administration errors. OBJECTIVES: To evaluate the effectiveness of evidence-based strategies to limit interruptions during scheduled, peak medication administration times in 3 progressive cardiac care units (PCCUs). A secondary aim of the project was to evaluate the impact of limiting interruptions on medication errors. METHODS: The percentages of interruptions and medication errors before and after implementation of evidence based strategies to limit interruptions were measured by using direct observations of nurses on 2 PCCUs. Nurses in a third PCCU served as a comparison group. RESULTS: Interruptions (P < .001) and medication errors (P = .02) decreased significantly in 1 PCCU after implementation of evidence-based strategies to limit interruptions. Avoidable interruptions decreased 83% in PCCU1 and 53% in PCCU2 after implementation of the evidence-based strategies. CONCLUSIONS: Implementation of evidence-based strategies to limit interruptions in PCCUs decreases avoidable interruptions and promotes patient safety. PMID- 27481800 TI - Preparing Drugs for Infusion Via Syringe Pump: A Key Step to Ensure Homogeneous Concentration. AB - OBJECTIVE: Preparation of drug solutions used with electronic syringe infusion pumps plays a crucial role in the delivery of an accurate drug concentration. Is there a correlation between drug concentrations during syringe pump infusion and preparation protocols? METHOD: Norepinephrine, insulin, and sufentanil were prepared in 3 different ways: (1) the drug was taken from the vial, then the solvent was added followed by an air bubble, and mixing was performed by turning the syringe top-to-bottom in a 180 degrees shaking movement 5 consecutive times; (2) the drug was taken from the vial, then the solvent was added and not mixed; and (3) the solvent was taken from a stock solution, then the drug was added and not mixed. Concentrations of drugs were determined at different times during administration by reverse-phase high-performance liquid chromatography with ultraviolet detection. All analyses were performed in triplicate and were based on measurement of peak areas. RESULTS: With no shaking of the syringe, the concentration of the injected drugs varies widely. In any case, mixing of the syringe contents by turning the syringe in a top-to-bottom 180 degrees shaking movement 5 times with an air bubble would ensure administration of the drug at a constant concentration. CONCLUSIONS: Without mixing, the concentrations of all drug solutions varied widely when administered via an electronic syringe infusion pump. Mixing syringe contents should be made part of the compulsory curriculum for administering medications at all levels of medical education. (Critical Care Nurse. 2016;36[4]:36-45). PMID- 27481801 TI - Treating Central Catheter-Associated Bacteremia Due to Methicillin-Resistant Staphylococcus aureus: Beyond Vancomycin. AB - Methicillin-resistant Staphylococcus aureus is a frequent cause of hospital associated infections, including central catheter-associated bacteremia. Vancomycin has been the drug of choice for treating this type of bacteremia for decades in patients who have no contraindications to the antibiotic. However, resistance to vancomycin is an emerging problem. Newer antibiotics approved by the Food and Drug Administration have activity against methicillin-resistant S aureus Some of the antibiotics also have activity against strains of S aureus that are intermediately susceptible or resistant to vancomycin. This article uses a case study to highlight the clinical signs of vancomycin failure and describes the indications for and appropriate use of alternative antimicrobials such as ceftaroline, daptomycin, linezolid, tigecycline, and telavancin. (Critical Care Nurse 2016;36[4]:46-57). PMID- 27481802 TI - Progressive Care of Obese Patients. AB - Obese patients have complex needs that complicate their care during hospitalization. These patients often have comorbid conditions, including hypertension, heart failure, obstructive sleep apnea, pressure ulcers, and difficulty with mobility. Obese patients may be well served in the progressive care setting because they may require more intensive nursing care than can be delivered in a general care unit. Progressive care nurses have core competencies that enable them to safely and effectively care for obese patients. A plan of care with interdisciplinary collaboration illustrates the integrative care for obese progressive care patients. (Critical Care Nurse 2016; 36[4]:58-63). PMID- 27481803 TI - Conventional and Unconventional Lifesaving Therapies in an Adolescent With Amlodipine Ingestion. AB - Amlodipine, a dihydropyridine calcium channel blocker, is commonly prescribed for the treatment of hypertension. Ingestion of an overdose leads to severe hypotension; if the hypotension is not treated, death may be imminent. Conventional and unconventional interventions were used to treat an adolescent who ingested a life-threatening dose of amlodipine. Severe hypotension resistant to conventional treatment with intralipids and hyperinsulinemia-euglycemia therapy led to the use of plasmapheresis and a pneumatic antishock garment as lifesaving measures. Plasmapheresis has been described in only one other case of severe amlodipine overdose, and the use of a pneumatic antishock garment has never been described in the management of a calcium channel blocker overdose. Because short-term use of a pneumatic antishock garment has associated risks, the critical care nurse's anticipation of side effects and promotion of safe use of the garment were instrumental in the patient's care and outcome. (Critical Care Nurse 2016; 36[4]:64-69). PMID- 27481804 TI - Ingestion of Laundry Detergent Packets in Children. AB - Ingestion of laundry detergent packets is an important threat to young children. Because of their developmental stage, toddlers are prone to place these small, colorful packets in their mouths. The packets can easily burst, sending a large volume of viscous, alkaline liquid throughout the oropharynx. Ingestion causes major toxic effects, including depression of the central nervous system, metabolic acidosis, respiratory distress, and dysphagia. Critical care nurses should anticipate these clinical effects and facilitate prompt intervention. Increased understanding of the risks and clinical effects of ingestion of laundry detergent packets will better prepare critical care nurses to provide care for these children. (Critical Care Nurse 2016; 36[4]:70-75). PMID- 27481805 TI - Life Can Get in the Way Sometimes. PMID- 27481806 TI - Nurse-Administered Sedation. PMID- 27481807 TI - Short-Course Versus Prolonged-Course Antibiotic Therapy for Hospital-Acquired Pneumonia in Critically Ill Adults. PMID- 27481809 TI - I Am a Critical Care Nurse. PMID- 27481810 TI - Challenges Caring for Adults With Congenital Heart Disease in Pediatric Settings: How Nurses Can Aid in the Transition. AB - As surgery for complex congenital heart disease is becoming more advanced, an increasing number of patients are surviving into adulthood, yet many of these adult patients remain in the pediatric hospital system. Caring for adult patients is often a challenge for pediatric nurses, because the nurses have less experience and comfort with adult care, medications, comorbid conditions, and rehabilitation techniques. As these patients age, the increased risk of complications and comorbid conditions from their heart disease may complicate their care further. Although these patients are admitted on a pediatric unit, nurses can aid in promoting their independence and help prepare them to transition into the adult medical system. Nurses, the comprehensive medical teams, and patients' families can all effectively influence the process of preparing these patients for transition to adult care. PMID- 27481811 TI - Pulmonary Artery/Central Venous Pressure Monitoring in Adults. PMID- 27481812 TI - Prevention of Catheter-Associated Urinary Tract Infections in Adults. PMID- 27481813 TI - Effect of milrinone on the developmental competence of growing lamb oocytes identified with brilliant cresyl blue. AB - Juvenile in vitro embryo transfer is a novel technique that can be used to increase the rate of genetic gain in a population and presents an alternative to embryo technologies on the basis of adult animals. However, oocytes from prepubertal animals have a lower viability than those obtained from adult ewe oocyte donors. In this research, we aimed to determine the optimum concentration and time of treatment of oocytes from prepubertal lambs with brilliant cresyl blue (BCB) stain and milrinone during IVM. This would improve the developmental rate of lamb oocytes and embryos after IVF. First, lamb cumulus-oocyte complexes were cultured under different concentrations (13 or 26 MUM) of BCB staining. Treated lamb oocytes were then divided into BCB- (colorless cytoplasm) and BCB+ (colored cytoplasm) groups on the basis of their glucose-6-phosphate dehydrogenase activity. The blastocyst efficiency rate of BCB+ oocytes treated with 13 MUM BCB (37.03%) was significantly higher than that of BCB+ oocytes treated with 26 MUM BCB (23.25%) and that of nontreated BCB control oocytes (15.37%), as well as that of BCB- oocytes (6.28%). Both control oocytes and BCB+ oocytes exhibited significantly higher cleavage rates (60.15% and 73.44%, respectively) than that of BCB- oocytes (36.19%). Moreover, the diameter and glutathione content of BCB+ oocytes were found to be significantly greater than those of BCB- oocytes (163.37 vs. 159.25 MUm and 6.39 vs. 0.26 pM, respectively). After culturing BCB- oocytes in different concentrations of milrinone (0, 50, 75, and 100 MUM) for 3, 6, or 9 hours, results reported that supplementation of IVM medium with 75 MUM milrinone for 6 hours yielded a significantly higher proportion of blastocysts than the other treatments. These results show that the staining of lamb cumulus-oocyte complexes with 13 MUM BCB before IVM may be used to select developmentally competent lamb oocytes. Furthermore, they suggest that milrinone can be used to promote lamb developmental competence of lamb embryos produced during IVF. PMID- 27481814 TI - Use of magnetic resonance imaging to assess ovarian maturation in live Rhinogobio ventralis (Sauvage & Dabry de Thiersant, 1874). AB - The aim of this study is to evaluate the application of magnetic resonance imaging (MRI) to assess ovarian maturation in live female Rhinogobio ventralis (Sauvage & Dabry de Thiersant, 1874). The fish were randomly collected from the Jiangjin area of the Yangtze River between January and April 2014. Magnetic resonance imaging was performed using a 3.0 T clinical MRI scanner with a brain coil and two pulse sequences (IDEAL and 3D CUBE) were employed. Magnetic resonance and histologic images at different stages of ovarian maturation (I-IV) were acquired. An empirical equation (y = -0.1 + 1.56 * x) was derived by traditional method to describe the relationship between the gonadosomatic index (y) and the percentage volume of the ovary (x). A significant correlation (R(2) = 0.977, P < 0.01, N = 53) was found between measurements of the percentage volume of the ovary by MRI and traditional methods. The research findings suggested that MRI was a reliable, rapid, and noninvasive method to assess stages of ovarian maturity in female R. ventralis. PMID- 27481815 TI - Interaction of bovine viral diarrhea virus with bovine cumulus-oocyte complex during IVM: Detection in permissive cells. AB - Structural changes in the zona pellucida (ZP) of bovine oocytes seem to modulate their interaction with various viral agents, facilitating the viral infection in in vitro production systems. To evaluate the susceptibility of bovine oocytes to noncytopathogenic bovine viral diarrhea virus (ncp-BVDV), cumulus-oocyte complexes were exposed to 10(7) tissue culture-infective doses (TCID50)/mL of an ncp-BVDV strain during IVM (in vitro maturation). After that, cumulus cells and the ZP were removed by hyaluronidase and pronase treatment, respectively, and the percentages of oocytes with polar body were analyzed as a sign of nuclear maturation. After passage through cell culture, the virus was isolated from granulosa cells, ZP-free mature oocytes, and ZP-intact mature oocytes. These results were confirmed by reverse transcription-polymerase chain reaction. After consecutive washes, the virus remained associated with ZP-free oocytes, maintaining its replication and infectivity in permissive cells. Based on these findings, it is concluded that the classical viral isolation procedure has a predictive value to detect BVDV associated with ZP-free oocytes and that it was novelty demonstrated that both washing and trypsin treatment of oocytes were ineffective to remove BVDV infection. PMID- 27481816 TI - Why are there no C4 forests? AB - C4 photosynthesis is absent from the arborescent life form, with the exception of seven Hawaiian Euphorbia species and a few desert shrubs that become arborescent with age. As a consequence, wherever C3 trees can establish, their height advantage enables them to outcompete low stature C4 vegetation. Had C4 photosynthesis been able to evolve in an arborescent life form, forest cover (by C4 trees) could have been much more extensive than today, with significant consequences for the biosphere. Here, we address why there are so few C4 trees. Physiological explanations associated with low light performance of C4 photosynthesis are not supported, because C4 shade-tolerant species exhibit similar performance as shade-tolerant C3 species in terms of quantum yield, steady-state photosynthetic and use of sunflecks. Hence, hypothetical C4 trees could occur in the regeneration niche of forests. Constraints associated with the evolutionary history of the C4 lineages are more plausible. Most C4 species are grasses and sedges, which lack meristems needed for arborescence, while most C4 eudicots are highly specialized for harsh (arid, saline, hot) or disturbed habitats where arborescence may be maladapted. Most C4 eudicot clades are also young, and have not had sufficient time to radiate beyond the extreme environments where C4 evolution is favored. In the case of the Hawaiian Euphorbia species, they belong to one of the oldest and most diverse C4 lineages, which primed this group to evolve arborescence in a low-competition environment that appeared on the remote Hawaiian Islands. PMID- 27481817 TI - Abnormal interactions of verbal- and spatial-memory networks in young people at familial high-risk for schizophrenia. AB - BACKGROUND: Working memory impairment (especially in verbal and spatial domains) is the core neurocognitive impairment in schizophrenia and the familial high-risk (FHR) population. Inconsistent results have been reported in clinical and neuroimaging studies examining the verbal- and spatial-memory deficits in the FHR subjects, due to sample differences and lack of understanding on interactions of the brain regions for processing verbal- and spatial-working memory. METHODS: Functional MRI data acquired during a verbal- vs. spatial-memory task were included from 51 young adults [26 FHR and 25 controls]. Group comparisons were conducted in brain activation patterns responding to 1) verbal-memory condition (A), 2) spatial-memory condition (B), 3) verbal higher than spatial (A-B), 4) spatial higher than verbal (B-A), 5) conjunction of brain regions that were activated during both A and B (A?B). Group difference of the laterality index (LI) in inferior frontal lobe for condition A was also assessed. RESULTS: Compared to controls, the FHR group exhibited significantly decreased brain activity in left inferior frontal during A, and significantly stronger involvement of ACC, PCC, paracentral gyrus for the contrast of A-B. The LI showed a trend of reduced left-higher-than-right pattern for verbal-memory processing in the HR group. CONCLUSIONS: Our findings suggest that in the entire functional brain network for working-memory processing, verbal information processing associated brain pathways are significantly altered in people at familial high risk for developing schizophrenia. Future studies will need to examine whether these alterations may indicate vulnerability for predicting the onset of Schizophrenia. PMID- 27481818 TI - Neutrophil extracellular traps in dermatology: Caught in the NET. AB - Neutrophil, or polymorphonuclear granulocytes (PMN) constitute the most abundant type of leucocytes in peripheral human blood. One of the major advances in the last decade was the discovery of neutrophil extracellular trap (NET) formation: a process by which neutrophils externalize web-like chromatin strands decorated with antimicrobial peptides. These structures were soon implicated in immune defense and auto-immunity alike and now link neutrophils to the pathogenesis of a variety of diseases of dermatological relevance. Currently, NET formation is mainly subdivided into suicidal and vital NETosis. Controversy exists regarding the capacity of NETs to kill pathogens, and little is known about the way NETs are formed in vivo. Here, we discuss the current terminology, methods for NET quantification, pathways leading to NET formation, and the role of NETs in systemic and cutaneous immune defense and auto-immunity, with a focus on psoriasis and systemic lupus erythematosus. PMID- 27481819 TI - Circumventing Biology. PMID- 27481820 TI - The Effect of the Mulligan Knee Taping Technique on Patellofemoral Pain and Lower Limb Biomechanics: Letter to the Editor. PMID- 27481821 TI - The Effect of the Mulligan Knee Taping Technique on Patellofemoral Pain and Lower Limb Biomechanics: Response. PMID- 27481822 TI - Arthroscopic Stabilization of Chronic Acromioclavicular Joint Dislocations: Letter to the Editor. PMID- 27481823 TI - Arthroscopic Stabilization of Chronic Acromioclavicular Joint Dislocations: Response. PMID- 27481825 TI - Adversity; Sometimes a Gift. PMID- 27481824 TI - Corrigendum. AB - Kida Y, Morihara T, Kotoura Y, Hojo T, Tachiiri H, Sukenari T, Iwata Y, Furukawa R, Oda R, Arai Y, Fujiwara H, Kubo T. Prevalence and clinical characteristics of osteochondritis dissecans of the humeral capitellum among adolescent baseball players. Am J Sports Med. 2014;42(8):1963-1971. (Original DOI: 10.1177/0363546514536843). PMID- 27481829 TI - Risk Scores After Acute Coronary Syndrome. AB - Acute coronary syndrome (ACS) is associated with both short- and long-term unfavorable prognosis. Therefore, medical societies developed risk scores for predicting mortality and assessing decision-making regarding early aggressive treatment in patients presenting an ACS. The Thrombolysis In Myocardial Infarction and the Global Registry of Acute Coronary Events risk scores are the most extensively investigated scores for ACS. Clinical judgment is also important. Significant differences in aggressive treatment of ACS still exist with respect to gender, age, and ethnicity. The reasons for these discrepancies need to be further elucidated in future studies. Therefore, generalizability of stratifications and risk scores in certain populations should be performed with caution. PMID- 27481827 TI - Testing the Validity of Taxonic Schizotypy Using Genetic and Environmental Risk Variables. AB - Background: Meehl regarded schizotypy as a categorial liability for schizophrenia that is the product of genes, environment, and gene-environment interactions. We sought to test whether schizophrenia-related genotypes and environmental risk factors predict membership in classes defined by taxometric analyses of positive (cognitive-perceptual), negative (interpersonal), and disorganized schizotypy. Methods: Participants (n = 500) completed the Schizotypal Personality Questionnaire (SPQ) and provided information on the following risk factors: cannabis use, pregnancy and obstetric complications, social adjustment, and family history of psychosis. Saliva samples were obtained so that the frequency of single-nucleotide polymorphism (SNP) alleles associated with risk for developing schizophrenia could be determined. Genotyped SNPs were rs1625579 (MIR137), rs7004633 (MMP16), rs7914558 (CNNM2), and rs12966547 (CCDC68). Sets of SPQ items were subject to multiple coherent cut kinetic (CCK) analyses, including mean-above-minus-below-a-cut, maximum covariance, maximum eigenvalue, and latent modes analyses. Results: CCK analyses indicated latent taxonicity of schizotypy across the 3 item sets. The cognitive-perceptual class had a base rate of 25%, and membership was predicted by the rs7004633 SNP (odds ratio = 2.33, 95% confidence interval = 1.15-4.72 in adjusted analyses). Poor social adjustment predicted memberships in the interpersonal (16%) and disorganized (21%) classes. Classes were found not to be mutually exclusive. Conclusions: Schizotypy is taxonic and schizotypy class membership is predicted by genetic and environmental factors that predict schizophrenia. The findings hold the promise that a more complete understanding of schizotypy as a schizophrenia liability state will come from investigation of other genes and environmental factors associated with schizophrenia. PMID- 27481826 TI - Structural Network Disorganization in Subjects at Clinical High Risk for Psychosis. AB - Previous network studies in chronic schizophrenia patients revealed impaired structural organization of the brain's rich-club members, a set of highly interconnected hub regions that play an important integrative role for global brain communication. Moreover, impaired rich-club connectivity has also been found in unaffected siblings of schizophrenia patients, suggesting that abnormal rich-club connectivity is related to familiar, possibly reflecting genetic, vulnerability for schizophrenia. However, no study has yet investigated whether structural rich-club organization is also impaired in individuals with a clinical risk syndrome for psychosis. Diffusion tensor imaging and probabilistic tractography was used to construct structural whole-brain networks in 24 healthy controls and 24 subjects with an at-risk mental state (ARMS). Graph theory was applied to quantify the structural rich-club organization and global network properties. ARMS subjects revealed a significantly altered structural rich-club organization compared with the control group. The disruption of rich-club organization was associated with the severity of negative psychotic symptoms and led to an elevated level of modularity in ARMS subjects. This study shows that abnormal structural rich-club organization is already evident in clinical high risk subjects for psychosis and further demonstrates the impact of rich-club disorganization on global network communication. Together with previous evidence in chronic schizophrenia patients and unaffected siblings, our findings suggest that abnormal structural rich-club organization may reflect an endophenotypic marker of psychosis. PMID- 27481828 TI - The Brassicaceae species Heliophila coronopifolia produces root border-like cells that protect the root tip and secrete defensin peptides. AB - Background and Aims: Root border cells and border-like cells (BLCs), the latter originally described in Arabidopsis thaliana , have been described as cells released at the root tips of the species in which they occur. BLCs are thought to provide protection to root meristems similar to classical root border cells. In addition, four defensin peptides (Hc-AFP1-4) have previously been characterized from Heliophila coronopifolia , a South African semi-desert flower, and found to be strongly antifungal. This provided an opportunity to evaluate if the BLCs of H. coronopifolia indeed produce these defensins, which would provide evidence towards a defence role for BLCs. Methods: Fluorescence microscopy, using live cell-imaging technology, was used to characterize the BLCs of H. coronopifolia . Quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence microscopy was used to characterize these defensin peptides. Key Results: BLCs originated at the root apical meristem and formed a protective sheath at the tip and along the sides as the root elongated in solid medium. BLCs have a cellulose-enriched cell wall, intact nuclei and are embedded in a layer of pectin-rich mucilage. Pectinase treatments led to the dissolution of the sheath and dissociation of the root BLCs. Hc-AFP1-4 genes were all expressed in root tissues, but Hc-AFP3 transcripts were the most abundant in these tissues as measured by qRT-PCR. A polyclonal antibody that was cross-reactive with all four defensins, and probably recognizing a general plant defensin epitope, was used in fluorescence microscopy analysis to examine the presence of the peptides in the root tip and BLCs. Data confirmed the peptides present in the root tip tissues, the mucilage sheath and the BLCs. Conclusions: This study provides a link between defensin peptides and BLCs, both embedded in a protective pectin mucilage sheath, during normal plant growth and development. The presence of the Hc-AFP3 defensin peptides in the BLCs suggests a role for these cells in root protection. PMID- 27481830 TI - Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-specific immunoassays. AB - OBJECTIVE: This multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCAs). METHODS: Sera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays. RESULTS: The area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945). CONCLUSIONS: Our comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision. PMID- 27481832 TI - Polio eradication: no time for complacency. PMID- 27481831 TI - Possibilities for preventive treatment in rheumatoid arthritis? Lessons from experimental animal models of arthritis: a systematic literature review and meta analysis. AB - OBJECTIVE: Current research in rheumatoid arthritis focuses on preclinical disease phases as it is hypothesised that early preclinical treatment might prevent progression to full-blown disease. Since performance of studies in prearthritis phases in humans is challenging, animal models offer an opportunity to evaluate preventive treatments. We performed a systematic literature review and summarised treatment effects during different stages of arthritis development in animal models. METHODS: Eight medical literature databases were systematically searched. Studies were selected if they reported effects of synthetic or biological disease-modifying antirheumatic drugs in animal models of arthritis (collagen-induced arthritis and adjuvant-induced arthritis) on arthritis severity, as measured with arthritis severity scores, paw swelling or paw volume. Quality was assessed using an 11-item checklist. Study characteristics were extracted and effect sizes obtained in high-quality studies were summarised in meta-analyses. Studies were categorised into three groups: prophylactic (prior to generation of autoantibody response), prearthritis (after induction of autoantibody response) and therapeutic intervention (after arthritis development). RESULTS: Out of 1415 screened articles, 22 studies (including n=712 animals) were eligible of good quality and included in meta-analyses. Prophylactic (16 experiments, n=312 animals) and prearthritis treatment (9 experiments, n=156 animals) both were associated with a reduction of arthritis severity (p<0.001 and p=0.005, respectively). Stratified analyses for different antirheumatic drugs initiated in the prearthritis phase suggested higher efficacy of methotrexate than of anti-tumour necrosis factor. CONCLUSIONS: Data of experimental studies in animal models of arthritis suggest that prophylactic and prearthritis treatment strategies are effective and hint at differences in efficacy between antirheumatic drugs. PMID- 27481833 TI - Tailoring mass drug administration to context: implementation research is critical in achieving equitable progress in the control and elimination of helminth neglected tropical diseases in sub-Saharan Africa. AB - The concept of a technological quick fix or 'magic-bullet' for control and elimination of Neglected Tropical Diseases (NTDs) is flawed. NTDs are embedded within complex biological and social systems that are shaped by ecological and political contexts. This commentary emphasises the need for implementation research to address implementation gaps in the control of NTDs. With a specific focus on sub-Saharan Africa and helminth diseases amenable to preventive chemotherapy through mass drug administration, we explore the important role of context, programme partnerships and community in achieving equitable and effective NTD control. PMID- 27481834 TI - Antimalarial mass drug administration: ethical considerations. AB - Falciparum malaria is a major cause of death and illness in tropical countries, particularly in childhood. In endemic countries, a significant proportion of the community is infected with malaria asymptomatically. One promising way to eliminate malaria is to give the entire population malaria treatment. This is called mass drug administration (MDA) and it raises a number of ethical issues, as possible long-term benefits are uncertain. The effectiveness of MDA is critically dependent on level of participation, so the promised benefits to the community can be annulled by non-participation of a small number of individuals. These potential benefits range a wide spectrum, from the permanent elimination of malaria (success) to a transient reduction in the prevalence of infection and the incidence of illness (failure). The drawbacks of MDA are: inconvenience, potential toxicity, loss of confidence in the elimination campaign, possible drug resistance (though highly unlikely), and the potential for a rebound of malaria illness (if immunity is lost and malaria is reintroduced later). Other ethical issues are related to balancing individual and public health interests, and potentially limiting individual autonomy by making MDA compulsory. PMID- 27481835 TI - Ethics of emergent information and communication technology applications in humanitarian medical assistance. AB - New applications of information and communication technology (ICT) are shaping the way we understand and provide humanitarian medical assistance in situations of disaster, disease outbreak or conflict. Each new crisis appears to be accompanied by advancements in humanitarian technology, leading to significant improvements in the humanitarian aid sector. However, ICTs raise ethical questions that warrant attention. Focusing on the context of humanitarian medical assistance, we review key domains of ICT innovation. We then discuss ethical challenges and uncertainties associated with the development and application of new ICTs in humanitarian medical assistance, including avoiding harm, ensuring privacy and security, responding to inequalities, demonstrating respect, protecting relationships, and addressing expectations. In doing so, we emphasize the centrality of ethics in humanitarian ICT design, application and evaluation. PMID- 27481836 TI - Molecular Structure of Aggregated Amyloid-beta: Insights from Solid-State Nuclear Magnetic Resonance. AB - Amyloid-beta (Abeta) peptides aggregate to form polymorphic amyloid fibrils and a variety of intermediate assemblies, including oligomers and protofibrils, both in vitro and in human brain tissue. Since the beginning of the 21st century, considerable progress has been made to characterize the molecular structures of Abeta aggregates. Full molecular structural models based primarily on data from measurements using solid-state nuclear magnetic resonance (ssNMR) have been developed for several in vitro Abeta fibrils and one metastable protofibril. Partial structural characterization of other aggregation intermediates has been achieved. One full structural model for fibrils derived from brain tissue has also been reported. Future work is likely to focus on additional structures from brain tissue and on further clarification of nonfibrillar Abeta aggregates. PMID- 27481837 TI - Spatial Heterogeneity in the Tumor Microenvironment. AB - Recent developments in studies of tumor heterogeneity have provoked new thoughts on cancer management. There is a desperate need to understand influence of the tumor microenvironment on cancer development and evolution. Applying principles and quantitative methods from ecology can suggest novel solutions to fulfil this need. We discuss spatial heterogeneity as a fundamental biological feature of the microenvironment, which has been largely ignored. Histological samples can provide spatial context of diverse cell types coexisting within the microenvironment. Advanced computer-vision techniques have been developed for spatial mapping of cells in histological samples. This has enabled the applications of experimental and analytical tools from ecology to cancer research, generating system-level knowledge of microenvironmental spatial heterogeneity. We focus on studies of immune infiltrate and tumor resource distribution, and highlight statistical approaches for addressing the emerging challenges based on these new approaches. PMID- 27481838 TI - Implementation of a Simplistic Bivalirudin-Warfarin Transition Protocol Is Associated With Improved Achievement of INR Values Within the Therapeutic Range. AB - BACKGROUND: Transition from bivalirudin to long-term warfarin therapy is often difficult to execute due to bivalirudin prolongation of the international normalized ratio (INR), and literature to help guide this transition is extremely limited. OBJECTIVE: To assess the transition from bivalirudin to warfarin after implementation of an institution-wide transition protocol. METHODS: In this retrospective quasiexperimental study, adult patients receiving bivalirudin directly followed by warfarin for nonprocedural systemic anticoagulation were evaluated to determine the frequency of successful transition to warfarin. Participants were compared before (preprotocol) and after (postprotocol) the implementation of the transition protocol. RESULTS: A total of 39 patients met inclusion criteria and were included in the analysis (preprotocol = 19; postprotocol = 20). The percentage of patients achieving a successful transition was significantly higher in the postprotocol group compared with the preprotocol group (80.0% vs 42.1%, P = 0.015). Bleeding events were similar between the 2 groups (23.1% vs 16.7%, P = 0.689). Withholding of warfarin doses or the use of anticoagulant reversal agents or blood transfusions for supratherapeutic INR levels, surgical procedures, or drop in hemoglobin was numerically lower in the postprotocol group compared with the preprotocol group (16.7% vs 46.2%, P = 0.202). CONCLUSION: Implementation of a simplistic bivalirudin-warfarin transition protocol significantly increased the frequency of therapeutic INR results on bivalirudin discontinuation. Additionally, patients treated according to this protocol were less likely to have warfarin doses withheld or require reversal agents. Larger studies testing this transition strategy are warranted. PMID- 27481839 TI - Comment. PMID- 27481840 TI - Reply. PMID- 27481841 TI - Association of a Biomarker of Glucose Peaks, 1,5-Anhydroglucitol, With Subclinical Cardiovascular Disease. AB - OBJECTIVE: 1,5-Anhydroglucitol (1,5-AG) is a biomarker of glucose peaks and has been associated with clinical cardiovascular disease. However, the association between 1,5-AG and subclinical cardiovascular disease is unknown. We investigated the association of 1,5-AG with subclinical myocardial damage (assessed by high sensitivity cardiac troponin T [hs-cTnT]) and atherosclerosis (assessed by carotid intima-media thickness [CIMT] and carotid plaque). RESEARCH DESIGN AND METHODS: We measured 1,5-AG, hs-cTnT, CIMT, and carotid plaque among 10,072 people without diabetes and 681 with diabetes who attended the second examination of the Atherosclerosis Risk in Communities (ARIC) Study (baseline, 1990-1992). We used Poisson regression to characterize the associations between 1,5-AG and prevalent elevated hs-cTnT, thick CIMT, or carotid plaque. Among 9,145 people with a second hs-cTnT measurement 6 years later, we used multinomial logistic regression to assess associations with incident elevation in hs-cTnT. RESULTS: We found that in people with diabetes, lower 1,5-AG (<6 MUg/mL) was cross sectionally associated with elevated hs-cTnT (prevalence ratio 2.06, 95% CI 1.23 3.46) compared with higher 1,5-AG (>=10 MUg/mL). Associations in people without diabetes and with thick CIMT or the presence of carotid plaque were less robust. Low 1,5-AG was prospectively associated with the 6-year incident elevation in hs cTnT (relative risk 2.90, 95% CI 1.23-6.85) in people with diabetes. All associations were strongly attenuated with further adjustment for HbA1c. CONCLUSIONS: In people with diabetes, 1,5-AG was associated with subclinical cardiovascular disease, particularly chronic subclinical myocardial damage. Nonetheless, whether observed associations are truly independent of average glycemia is unclear. PMID- 27481842 TI - The role of acroblast formation during Drosophila spermatogenesis. AB - Protein recycling is important for maintaining homeostasis of the Golgi and its cisternae. The Vps54 (Scat) protein, a subunit of the GARP tethering complex, is a central factor in retrograde transport to the trans-Golgi. We found the scat(1) mutant to be male sterile in Drosophila with individualization problems occurring during spermatogenesis. Another typically observed phenotype was the abnormal nuclear structure in elongated mutant cysts. When examining the structure and function of the Golgi, a failure in acrosome formation and endosome-Golgi vesicular transport were found in the scat(1) mutant. This acrosome formation defect was due to a fault in the trans-Golgi side of the acroblast ribbon. When testing a mutation in a second retrograde transport protein, Fws, a subunit of the conserved oligomeric Golgi (COG) tethering complex, the acroblast structure, was again disrupted. fws(P) caused a similar, albeit milder, acrosome and sperm individualization phenotype as the scat(1) mutant. In the case of fws(P) the cis side of the acroblast ribbon was dispersed, in-line with the intra-Golgi retrograde function of COG. Our results highlight the importance of an intact acroblast for acrosome formation, nuclear elongation and therefore sperm maturation. Moreover, these results suggest the importance of retrograde tethering complexes in the formation of a functional Golgi ribbon. PMID- 27481843 TI - Innate Invariant NKT Cell Recognition of HIV-1-Infected Dendritic Cells Is an Early Detection Mechanism Targeted by Viral Immune Evasion. AB - Invariant NKT (iNKT) cells are innate-like T cells that respond rapidly with a broad range of effector functions upon recognition of glycolipid Ags presented by CD1d. HIV-1 carries Nef- and Vpu-dependent mechanisms to interfere with CD1d surface expression, indirectly suggesting a role for iNKT cells in control of HIV 1 infection. In this study, we investigated whether iNKT cells can participate in the innate cell-mediated immune response to HIV-1. Infection of dendritic cells (DCs) with Nef- and Vpu-deficient HIV-1 induced upregulation of CD1d in a TLR7 dependent manner. Infection of DCs caused modulation of enzymes in the sphingolipid pathway and enhanced expression of the endogenous glucosylceramide Ag. Importantly, iNKT cells responded specifically to rare DCs productively infected with Nef- and Vpu-defective HIV-1. Transmitted founder viral isolates differed in their CD1d downregulation capacity, suggesting that diverse strains may be differentially successful in inhibiting this pathway. Furthermore, both iNKT cells and DCs expressing CD1d and HIV receptors resided in the female genital mucosa, a site where HIV-1 transmission occurs. Taken together, these findings suggest that innate iNKT cell sensing of HIV-1 infection in DCs is an early immune detection mechanism, which is independent of priming and adaptive recognition of viral Ag, and is actively targeted by Nef- and Vpu-dependent viral immune evasion mechanisms. PMID- 27481844 TI - Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells. AB - Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR-restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. However, the precise mechanisms of hTERT's uptake, processing, and presentation on MHC-II molecules to stimulate CD4 T cells are poorly understood. In this work, by using well characterized UCP-specific CD4 T cell clones, we showed that hTERT processing and presentation on MHC-II involve both classical endolysosomal and nonclassical cytosolic pathways. Furthermore, to our knowledge, we demonstrated for the first time that hTERT's internalization by dendritic cells requires its interaction with surface heparan sulfate proteoglycans. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells. PMID- 27481846 TI - First Membrane Proximal External Region-Specific Anti-HIV1 Broadly Neutralizing Monoclonal IgA1 Presenting Short CDRH3 and Low Somatic Mutations. AB - Mucosal HIV-1-specific IgA have been described as being able to neutralize HIV-1 and to block viral transcytosis. In serum and saliva, the anti-HIV IgA response is predominantly raised against the envelope of HIV-1. In this work, we describe the in vivo generation of gp41-specific IgA1 in humanized alpha1KI mice to produce chimeric IgA1. Mice were immunized with a conformational immunogenic gp41 transfected cell line. Among 2300 clones screened by immunofluorescence microscopy, six different gp41-specific IgA with strong recognition of gp41 were identified. Two of them have strong neutralizing activity against primary HIV-1 tier 1, 2, and 3 strains and present a low rate of somatic mutations and autoreactivity, unlike what was described for classical gp41-specific IgG. Epitopes were identified and located in the hepted repeat 2/membrane proximal external region. These Abs could be of interest in prophylactic treatment to block HIV-1 penetration in mucosa or in chronically infected patients in combination with antiretroviral therapy to reduce viral load and reservoir. PMID- 27481845 TI - Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells. AB - Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4(+) cells did not change, and CCR6(+) cells decreased. CXCR3(+), but not CXCR3(-), GC Tfh cells produced IFN-gamma (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4(+)IFN-gamma(+) T cells within the hyperplastic follicles during chronic SIV infection. CXCR3(+) GC Tfh cells also expressed higher levels of ICOS, CCR5, and alpha4beta7 and contained more copies of SIV DNA compared with CXCR3(-) GC Tfh cells. However, CXCR3(+) and CXCR3(-) GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs. PMID- 27481848 TI - Transduction of Functionally Contrasting Signals by Two Mycobacterial PPE Proteins Downstream of TLR2 Receptors. AB - As pathogen-associated molecular pattern sensors, the TLRs can detect diverse ligands to elicit either proinflammatory or anti-inflammatory responses, but the mechanism that dictates such contrasting immune responses is not well understood. In this work, we demonstrate that proline-proline-glutamic acid (PPE)17 protein of Mycobacterium tuberculosis induces TLR1/2 heterodimerization to elicit proinflammatory-type response, whereas PPE18-induced homodimerization of TLR2 triggers anti-inflammatory type responses. Ligation of TLR1/2 caused an increased recruitment of IL-1R-associated kinase (IRAK)1, MyD88, and protein kinase C (PKC)epsilon to the downstream TLR-signaling complex that translocated PKCepsilon into the nucleus in an IRAK1-dependent manner. PKCepsilon-mediated phosphorylation allowed the nuclear IRAK3 to be exported to the cytoplasm, leading to increased activation of ERK1/2, stabilization of MAPK phosphatase 1 (MKP-1), and induction of TNF-alpha with concomitant downregulation of p38MAPK. Silencing of TLR1 inhibited PPE17-triggered cytoplasmic export of IRAK3 as well as TNF-alpha induction, suggesting an important role of TLR1/2 heterodimer in regulating proinflammatory responses via the IRAK3-signaling pathway. In contrast, PPE18-mediated homodimerization of TLR2 caused poorer cytoplasmic export of nuclear IRAK3 and MKP-1 stabilization, resulting in increased p38MAPK activation. Our study hints to a novel mechanism that implicates PKCepsilon-IRAK3 MKP-1 signaling in the regulation of MAPK activity and inflammatory cascades downstream of TLR2 in tuberculosis. PMID- 27481847 TI - beta8 Integrin Expression and Activation of TGF-beta by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage. AB - Activation of TGF-beta by dendritic cells (DCs) expressing alphavbeta8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal Ags. We have recently shown that alphavbeta8 integrin is preferentially expressed by CD103(+) DCs and confers their ability to activate TGF-beta and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that beta8 expression is controlled by a combination of factors that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-beta itself, along with retinoic acid and TLR signaling, drives expression of alphavbeta8 in DCs. However, these signals only result in high levels of beta8 expression in cells of the cDC1 lineage, CD8alpha(+), or CD103(+)CD11b(-) DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory alphavbeta8-expressing DCs specialized for activation of TGF-beta to facilitate Treg generation. PMID- 27481849 TI - Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity. AB - The affinity of a TCR binding to peptide:MHC profoundly impacts the phenotype and function of effector and memory cell differentiation. Little is known about the effect of low-affinity priming on memory cell generation and function, which is particularly important in heterologous immunity, when microbe-specific T cells cross-react with allogeneic Ag and mediate graft rejection. We found that low affinity-primed memory CD8(+) T cells produced high levels of TNF ex vivo in response to heterologous rechallenge compared with high-affinity-primed memory T cells. Low-affinity secondary effectors significantly upregulated TNFR2 on the cell surface and contained a higher frequency of TNFR2(hi) proliferating cells. Low-affinity-primed secondary effectors concurrently downregulated TNF production. Importantly, blockade of TNFR2 attenuated graft rejection in low- but not high-affinity-primed animals. These data establish a functional connection between TNF signaling and TCR-priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation. PMID- 27481850 TI - Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency. AB - Although common variable immunodeficiency (CVID) has long been considered as a group of primary Ab deficiencies, growing experimental data now suggest a global disruption of the entire adaptive immune response in a segment of patients. Oligoclonality of the TCR repertoire was previously demonstrated; however, the manner in which it relates to other B cell and T cell findings reported in CVID remains unclear. Using a combination approach of high-throughput TCRbeta sequencing and multiparametric flow cytometry, we compared the TCR repertoire diversity between various subgroups of CVID patients according to their B cell immunophenotypes. Our data suggest that the reduction in repertoire diversity is predominantly restricted to those patients with severely reduced class-switched memory B cells and an elevated level of CD21(lo) B cells (Freiburg 1a), and may be driven by a reduced number of naive T cells unmasking underlying memory clonality. Moreover, our data indicate that this loss in repertoire diversity progresses with advancing age far exceeding the expected physiological rate. Radiological evidence supports the loss in thymic volume, correlating with the decrease in repertoire diversity. Evidence now suggests that primary thymic failure along with other well-described B cell abnormalities play an important role in the pathophysiology in Freiburg group 1a patients. Clinically, our findings emphasize the integration of combined B and T cell testing to identify those patients at the greatest risk for infection. Future work should focus on investigating the link between thymic failure and the severe reduction in class switched memory B cells, while gathering longitudinal laboratory data to examine the progressive nature of the disease. PMID- 27481852 TI - Invitation for Nominations for 2017. PMID- 27481851 TI - Changes in Gene Expression during G-CSF-Induced Emergency Granulopoiesis in Humans. AB - Emergency granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation induced by severe infection. Several studies point to a critical role for G-CSF as the main mediator of emergency granulopoiesis. However, the consequences of G-CSF stimulation on the transcriptome of neutrophils and their precursors have not yet been investigated in humans. In this work, we examine the changes in mRNA expression induced by administration of G-CSF in vivo, as a model of emergency granulopoiesis in humans. Blood samples were collected from healthy individuals after 5 d of G-CSF administration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry, and RNA was subjected to microarray analysis. mRNA levels were compared with previously published expression levels in corresponding populations of neutrophil precursors isolated from bone marrow of untreated, healthy individuals. One thousand one hundred and ten mRNAs were differentially expressed >2-fold throughout terminal granulopoiesis. Major changes were seen in pathways involved in apoptosis, cytokine signaling, and TLR pathways. In addition, G-CSF treatment reduced the levels of four of five measured granule proteins in mature neutrophils, including the proantibacterial protein hCAP-18, which was completely deficient in neutrophils from G-CSF-treated donors. These results indicate that multiple biological processes are altered to satisfy the increased demand for neutrophils during G-CSF-induced emergency granulopoiesis in humans. PMID- 27481855 TI - Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of Propofol: Dosing Recommendation for Anesthesia Induction. AB - The prevalence of obesity has markedly increased worldwide. Obese patients pose significant challenges to anesthesiologists with regard to accurate dosing of anesthetics due to potentially altered pharmacokinetics (PK). Here we determined the PK and pharmacodynamics (PD) of propofol for anesthesia induction in morbidly obese (MO) subjects (body mass index >35 kg/m(2)) at two dosing regimens: dosing based on total body weight and lean body weight (LBW), respectively. The propofol pharmacokinetic profile was well fitted with a two-compartment model. Both elimination clearance (223%-243% of controls, who had a body mass index <25 kg/m(2); P < 0.01) and peripheral compartment volume (156%-180% of controls; P < 0.01) were significantly increased in MO subjects, resulting in an equal or decreased propofol level in plasma (total body weight-based dosing). Furthermore, propofol PD (measured by the bispectral index) was adequately described by a PK/PD model that linked an effect compartment to the two-compartment PK model through a sigmoidal Emax model. All PD parameters except EC50 values (the half maximal effect concentration) were similar (P > 0.05) between MO subjects and controls. Morbid obesity led to a significant decrease (37.9%-38.6%; P < 0.01) in EC50 values, which suggests increased brain sensitivity to propofol in the MO population. Moreover, dose reduction (i.e., dosing based on LBW) generated identical anesthetic effects in MO subjects compared with controls. In conclusion, morbid obesity significantly altered both PK and PD of propofol. LBW was a better weight-based dosing scalar for anesthesia induction with propofol in MO subjects. PMID- 27481854 TI - High Viremia and Wasting Before Antiretroviral Therapy Are Associated With Pneumonia in Early-Treated HIV-Infected Kenyan Infants. AB - Background: Human immunodeficiency virus (HIV)-infected children are particularly susceptible to acute respiratory infections (ARIs). We determined incidence and cofactors for ARIs in HIV-infected infants receiving antiretroviral therapy (ART). Methods: Human immunodeficiency virus-infected infants initiated ART at <=12 months of age and were observed monthly for 2 years in Nairobi. Acute respiratory infection rates and cofactors were determined using Andersen-Gill models, allowing for multiple events per infant. Results: Among 111 HIV-infected infants, median age at ART initiation was 4.5 months. Pre-ART median CD4% was 19%, and 29% had wasting. During 24-months follow-up while on ART, upper respiratory infection (URI) and pneumonia rates were 122.6 and 34.7 per 100 person-years (py), respectively. Infants with higher pre-ART viral load (VL) (plasma HIV ribonucleic acid [RNA] >=7 log10 copies/mL) had 4.12-fold increased risk of pneumonia (95% confidence interval [CI], 2.17-7.80), and infants with wasting (weight-for-height z-score < -2) had 2.87-fold increased risk (95% CI, 1.56-5.28). Infants with both high pre-ART VL and wasting had a higher pneumonia rate (166.8 per 100 py) than those with only 1 of these risk factors (44.4 per 100 py) or neither (17.0 per 100 py). Infants with exposure to wood fuel had significantly higher risk of URI (hazard ratio [HR] = 1.82; 95% CI, 1.44-2.28) and pneumonia (HR = 3.31; 95% CI, 1.76-6.21). Conclusions: In early ART-treated HIV-infected infants, higher HIV RNA and wasting before ART were independent risk factors for pneumonia. Wood fuel use was associated with URI and pneumonia. Additional data on air pollution and respiratory outcomes in HIV-infected children may help optimize interventions to improve their lung health. PMID- 27481856 TI - An Optimized Method for Protein Extraction from OCT-Embedded Human Kidney Tissue for Protein Quantification by LC-MS/MS Proteomics. AB - The existing biobanks of remnant tissue from clinically indicated kidney biopsies are attractive potential reservoirs for quantification of clinically relevant human tissue proteins by quantitative proteomics. However, a significant caveat of this strategy is that the tissues are often preserved in optimal cutting temperature (OCT) medium. Although OCT is an effective method of preserving the morphologic and immunohistological characteristics of tissues for later study, it significantly impacts efforts to quantify protein expression by liquid chromatography-tandem mass spectrometry methods. We report here a simple, reproducible, and cost-effective procedure to extract proteins from OCT-embedded tissue samples. Briefly, the excess frozen OCT medium was scraped before thawing from the tissue specimens stored at -80 degrees C for ~3 months. The tissue samples were homogenized and diethyl ether/methanol extraction was performed to remove the remaining OCT medium. The recovered protein was denatured, reduced, and alkylated. The second step of protein extraction and desalting was performed by chloroform/methanol/water extraction of denatured proteins. The resultant protein pellet was trypsin-digested and the marker proteins of various kidney cellular compartments were quantified by targeted selective reaction monitoring proteomics. Upon comparison of peptide signals from OCT-embedded tissue and flash frozen tissue from the same donors, both individual protein quantities, and their interindividual variabilities, were similar. Therefore, the approach reported here can be applied to clinical reservoirs of OCT-preserved kidney tissue to be used for quantitative proteomics studies of clinically relevant proteins expressed in different parts of the kidney (including drug transporters and metabolizing enzymes). PMID- 27481857 TI - Diagnosis of acute rhinosinusitis in primary care: a systematic review of test accuracy. AB - BACKGROUND: Acute rhinosinusitis (ARS) is a common primary care infection, but there have been no recent, comprehensive diagnostic meta-analyses. AIM: To determine the accuracy of laboratory and imaging studies for the diagnosis of ARS. DESIGN AND SETTING: Systematic review of diagnostic tests in outpatient, primary care, and specialty settings. METHOD: The authors included studies of patients presenting with or referred for suspected ARS, and used bivariate meta analysis to calculate summary estimates of test accuracy and the area under the receiver operating characteristic (ROC) curve. The authors also plotted summary ROC curves to explore heterogeneity, cutoffs, and the impact of different reference standards. RESULTS: Using antral puncture as the reference standard, A mode ultrasound (positive likelihood ratio [LR+] 1.71, negative likelihood ratio [LR-] 0.41), B mode ultrasound (LR+ 1.64, LR- 0.69), and radiography (LR+ 2.01, LR- 0.28) had only modest accuracy. Accuracy was higher using imaging as the reference standard for both ultrasound (LR+12.4, LR- 0.35) and radiography (LR+ 9.4, LR- 0.27), although this likely overestimates accuracy. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) both had clear threshold effects, and modest overall accuracy. The LR+ for ESR >30 and >40 were 4.08 and 7.40, respectively. A dipstick of nasal secretions for leucocyte esterase was highly accurate (LR+ 18.4, LR- 0.17) but has not been validated. CONCLUSION: In general, tests were of limited value in the diagnosis of ARS. Normal radiography helps rule out sinusitis when negative, whereas CRP and ESR help rule in sinusitis when positive, although, given their limited accuracy as individual tests, they cannot be routinely recommended. Prospective studies integrating signs and symptoms with point-of-care CRP, dipstick, and/ or handheld B-mode ultrasound are needed. PMID- 27481858 TI - Behaviour change techniques in home-based cardiac rehabilitation: a systematic review. AB - BACKGROUND: Cardiac rehabilitation (CR) programmes offering secondary prevention for cardiovascular disease (CVD) advise healthy lifestyle behaviours, with the behaviour change techniques (BCTs) of goals and planning, feedback and monitoring, and social support recommended. More information is needed about BCT use in home-based CR to support these programmes in practice. AIM: To identify and describe the use of BCTs in home-based CR programmes. DESIGN AND SETTING: Randomised controlled trials of home-based CR between 2005 and 2015 were identified by searching MEDLINE((r)), Embase, PsycINFO, Web of Science, and Cochrane Database. METHOD: Reviewers independently screened titles and abstracts for eligibility. Relevant data, including BCTs, were extracted from included studies. A meta-analysis studied risk factor change in home-based and comparator programmes. RESULTS: From 2448 studies identified, 11 of good methodological quality (10 on post-myocardial infarction, one on heart failure, 1907 patients) were included. These reported the use of 20 different BCTs. Social support (unspecified) was used in all studies and goal setting (behaviour) in 10. Of the 11 studies, 10 reported effectiveness in reducing CVD risk factors, but one study showed no improvement compared to usual care. This study differed from effective programmes in that it didn't include BCTs that had instructions on how to perform the behaviour and monitoring, or a credible source. CONCLUSION: Social support and goal setting were frequently used BCTs in home-based CR programmes, with the BCTs related to monitoring, instruction on how to perform the behaviour, and credible source being included in effective programmes. Further robust trials are needed to determine the relative value of different BCTs within CR programmes. PMID- 27481860 TI - Job stress and needlestick injuries: which targets for organizational interventions? AB - BACKGROUND: Needlestick injuries (NSIs) represent a major concern for the safety of health care workers involved in clinical care. The percentage of health workers reporting these injuries varies between 9 and 38% and the occurrence of NSI is most frequent among employees having close clinical contact with patients or patient specimens. These injuries appear to occur most frequently where organizational factors contribute to the risk. AIMS: To investigate the interactions between organizational level interventions focused on work-related stress (WRS) and the occurrence of NSIs among nurses employed in hospital departments, and to determine the impact of such interventions on the safety budget. METHODS: Comparison of NSI occurrence among nurses employed in hospital health care departments in two 3-year periods, before and after interventions aimed at minimizing WRS. The economic cost of NSIs occurrence was calculated. RESULTS: The study group consisted of 765 nurses. The cumulative 3-year incidence of NSIs after the implementation of management stress interventions was significantly lower than the cumulative 3-year incidence observed before implementation (OR 0.60; 95% CI 0.43-0.83). A cost saving from managing fewer NSIs than during the first study period was found. CONCLUSIONS: This study found a reduction in NSI occurrence and associated costs following an intervention to bring about proactive, integrated and comprehensive management of stress in the workplace. PMID- 27481859 TI - Health information exchange for patients with intellectual disabilities: a general practice perspective. AB - BACKGROUND: Inadequate health information exchange (HIE) between patients with intellectual disabilities (ID), their carers, and GPs may lead to ineffective treatment and poor treatment compliance. Factors influencing HIE are largely unexplored in previous research. AIM: To provide insight into the perceived HIE facilitators of GPs and general practice assistants, and the barriers in GP consultations for patients with ID. DESIGN AND SETTING: An interview-based study with GPs (n = 19) and general practice assistants (n = 11) in the Netherlands. METHOD: Semi-structured interviews were conducted on topics relating to stages during and around GP consultation. Transcripts were coded and analysed using framework analysis. RESULTS: The main themes were impaired medical history taking and clinical decision making, and fragile patient follow-up. Factors negatively influencing HIE related to patient communication skills and professional carers' actions in preparing the consultation and in collecting, recording, and sharing information. HIE barriers resulted in risk of delay in diagnosis and treatment, misdiagnosis, unnecessary tests, and ineffective treatment regimens. HIE facilitators were described in terms of GP adjustments in communication, planning of consultations, and efforts to compensate for fragile follow-up situations. CONCLUSION: Inadequate HIE should be seen as a chain of events leading to less effective consultations, substandard treatment, and insufficient patient follow up. The results indicate a mismatch between GPs' expectations about professional carers' competencies, responsibilities, and roles in HIE and the setting in which professional carers operate. Further research should focus on how daily GP practice can be attuned to the practicalities of HIE with patients with ID and their professional carers. PMID- 27481861 TI - Job insecurity, financial difficulties and mental health in Europe. AB - BACKGROUND: The recession has increased job insecurity in the European Union (EU) which may result in higher levels of psychological distress, burnout and anxiety. AIMS: To investigate the association of job insecurity and financial difficulties with mental health in 27 member states of the EU and to explore the moderating effect of having financial difficulties on the relationship between job insecurity and mental health. METHODS: The sample consisted of employed people from 27 European countries where the Eurobarometer survey (73.2 wave, 2010) was administered by the European Commission. Mental well-being and psychological distress were measured using the Vitality and Mental Health Index (MHI-5) subscales from the Short-Form 36-item health survey (SF-36v2). Linear regression including an interaction term was used to test the underlying factors in this study. RESULTS: Among the 12594 respondents, experiencing job insecurity was associated with lower Vitality [beta = -3.82, 95% confidence interval (CI) -5.29 to -2.36] and MHI-5 (beta = -3.48, 95% CI -4.91 to -2.04). Similarly, having financial difficulties was significantly correlated with lower Vitality (beta = 8.65, 95% CI -12.07 to -5.24) and MHI-5 (beta = -11.51, 95% CI -15.08 to -7.94). However, having financial difficulties did not moderate the relationship between job insecurity and both mental health scales. CONCLUSIONS: This study highlights the negative effect of job insecurity and financial difficulties on mental health in the EU. Support to employees facing job security issues should be a priority regardless of the financial circumstances. PMID- 27481862 TI - Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children. AB - BACKGROUND: Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure. METHODS: We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease. RESULTS: Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%-12%) for each additional year of age and by 2% (95% CI, 1%-3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether lumefantrine. CONCLUSIONS: Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity. PMID- 27481864 TI - Correction to "Variability in Expression of CYP3A5 in Human Fetal Liver". PMID- 27481863 TI - Deployment of a Reverse Transcription Loop-Mediated Isothermal Amplification Test for Ebola Virus Surveillance in Remote Areas in Guinea. AB - To strengthen the laboratory diagnostic capacity for Ebola virus disease (EVD) in the remote areas of Guinea, we deployed a mobile field laboratory and implemented reverse transcription loop-mediated isothermal amplification (RT-LAMP) for postmortem testing. We tested 896 oral swab specimens and 21 serum samples, using both RT-LAMP and reverse transcription-polymerase chain reaction (RT-PCR). Neither test yielded a positive result, and the results from RT-LAMP and RT-PCR were consistent. More than 95% of the samples were tested within 2 days of sample collection. These results highlight the usefulness of the RT-LAMP assay as an EVD diagnostic testing method in the field or remote areas. PMID- 27481865 TI - Correction to "A Recombinant Humanized Anti-Cocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Rats". PMID- 27481867 TI - Limitations of the review and meta-analysis of fish and PUFA intake and mild-to severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. PMID- 27481868 TI - Reply to M Koch and MK Jensen. PMID- 27481869 TI - Beneficial effects of alcohol and East Asian ethnicity. PMID- 27481872 TI - Does aircraft noise exposure increase the risk of hypertension in the population living near airports in France? AB - OBJECTIVES: The largest study until now around 6 major European airports, the HYENA (HYpertension and Exposure to Noise near Airports) study, reported an excess risk of hypertension related to long-term aircraft noise exposure. The DEBATS (Discussion on the health effects of aircraft noise) study investigated the relationship between this exposure and the risk of hypertension in men and in women near French airports. METHODS: Blood pressure of 1244 participants older than 18 years of age was measured. Information about health, socioeconomic and lifestyle factors was collected by means of a face-to-face questionnaire performed at home by an interviewer. Aircraft noise exposure was assessed for each participant's home address using noise maps. They were calculated with the Integrated Noise Model with a 1 dB(A)-resolution. The major potential confounders being risk factors for hypertension were included in the logistic regression models: age, occupational activity, body mass index, physical activity and alcohol consumption. RESULTS: After adjustment for the main potential confounders, an exposure-response relationship was evidenced between the risk of hypertension and aircraft noise exposure at night for men only. A 10-dB(A) increase in Lnight was associated with an OR of 1.34 (95% CI 1.00 to 1.97). CONCLUSIONS: These findings contribute to the overall evidence suggesting that aircraft noise exposure at night-time may increase the risk of hypertension in men. Hypertension is a well-known and established risk factor for cardiovascular disease. The association reported in the present study between aircraft noise and hypertension implies that aircraft noise might be a risk factor also for cardiovascular disease. PMID- 27481874 TI - Severe Aortic Valve Stenosis. AB - Aortic valve stenosis (AVS) is the most common valve disease in adults. Severe forms are associated with acquired von Willebrand syndrome (aVWS) with loss of the largest von Willebrand factor (VWF) multimers. Diagnostic gold standard is the VWF multimer analysis. Valve replacement rapidly restores the VWF structure. Uncertainty exists if this effect is permanent and how functional VWF assays perform compared with multimer analysis. We studied 21 consecutive patients with severe AVS before and 6 to 18 months after valve surgery and compared them with 14 controls without valve disease referred for coronary angiography. The VWF multimers, VWF antigen (VWF:Ag), VWF collagen binding capacity (VWF:CB), VWF:CB/VWF:Ag ratio, in vitro bleeding time (PFA-100), factor VIII coagulation activity (FVIII:C), and VWF ristocetin cofactor activity (VWF:RCo) were determined. In all patients with AVS, the large VWF multimers were strongly reduced (56 +/- 13% of normal plasma); all controls had normal multimers. The PFA 100 collagen/ADP closure times (coll/ADP CT) were prolonged in patients with AVS compared with the controls (175 +/- 56 seconds vs 86 +/- 14 seconds, P < .001). The VWF:CB/VWF:Ag ratio was pathological in 20 of the 21 patients but normal in controls. After surgery, the multimers normalized in all patients and coll/ADP CT shortened (pre 184 +/- 65 seconds vs post 102 +/- 22 seconds; P < .001). The VWF:CB/VWF:Ag ratio strongly improved ( P < .001) and normalized in 14 of 17 patients. In conclusion, all consecutive patients with severe AVS had an aVWS. The combination of coll/ADP CT and VWF:CB/VWF:Ag ratio detected the aVWS in all patients. More than 6 months after valve replacement, the VWF multimers were still normalized in all patients indicating a permanent cure of the aVWS. PMID- 27481873 TI - Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial. AB - BACKGROUND: Respiratory viral infections (RVIs) are frequent complications of hematopoietic stem cell transplant (HSCT). Surgical masks are a simple and inexpensive intervention that may reduce nosocomial spread. METHODS: In this prospective single-center study, we instituted a universal surgical mask policy requiring all individuals with direct contact with HSCT patients to wear a surgical mask, regardless of symptoms or season. The primary endpoint was the incidence of RVIs in the mask period (2010-2014) compared with the premask period (2003-2009). RESULTS: RVIs decreased from 10.3% (95/920 patients) in the premask period to 4.4% (40/911) in the mask period (P < .001). Significant decreases occurred after both allogeneic (64/378 [16.9%] to 24/289 [8.3%], P = .001) and autologous (31/542 [5.7%] to 16/622 [2.6%], P = .007) transplants. After adjusting for multiple covariates including season and year in a segmented longitudinal analysis, the decrease in RVIs remained significant, with risk of RVI of 0.4 in patients in the mask group compared with the premask group (0.19 0.85, P = .02). In contrast, no decrease was observed during this same period in an adjacent hematologic malignancy unit, which followed the same infection control practices except for the mask policy. The majority of this decrease was in parainfluenza virus 3 (PIV3) (8.3% to 2.2%, P < .001). CONCLUSIONS: Requiring all individuals with direct patient contact to wear a surgical mask is associated with a reduction in RVIs, particularly PIV3, during the most vulnerable period following HSCT. PMID- 27481875 TI - Is Rivaroxaban Associated With Shorter Hospital Stays and Reduced Costs Versus Parenteral Bridging to Warfarin Among Patients With Pulmonary Embolism? AB - OBJECTIVE: We sought to compare the length of stay (LOS) and total costs for patients with pulmonary embolism (PE) treated with either rivaroxaban or parenterally bridged warfarin. METHODS: This retrospective claims analysis was performed in the Premier Database from November 2012 to March 2015. Adult patients were included if they had a hospital encounter for PE (an International Classification of Diseases, Ninth Revision code = 415.1*) in the primary position, a claim for >=1 diagnostic test for PE on day 0 to 2, and initiated rivaroxaban or parenteral anticoagulation/warfarin. Rivaroxaban users (allowing <=2 days of prior parenteral therapy) were 1:1 propensity score matched to patients receiving parenterally bridged warfarin. Length of stay, total costs, and readmission for venous thromboembolism (VTE) or major bleeding during the same or subsequent 2 months following the index event were compared between cohorts. Analysis restricted to patients with low-risk PE was also performed. RESULTS: Characteristics of the matched PE cohorts (n = 3466 per treatment) were well balanced. Rivaroxaban use was associated with a 1.36-day shorter LOS and $2304 reduction in total costs compared to parenterally bridged warfarin ( P < .001 for both). Rates of readmission for VTE were similar between cohorts (1.7% vs 1.6%; P = .64). No difference was observed between treatments for readmission for major bleeding (0.2% vs 0.2%; P > .99). In analyses restricted to low-risk patients (n = 1551 per treatment), rivaroxaban was associated with a 1.01-day and a $1855 reduction in LOS and costs, respectively ( P < .001 for both). Rates of readmission were again similar between treatments ( P > .56 for all). CONCLUSION: Rivaroxaban significantly reduced hospital LOS and costs compared to parenterally bridged warfarin, without increasing the risk of readmission. PMID- 27481876 TI - Endothelin-1 Gene Polymorphism and Its Level Predict the Risk of Venous Thromboembolism in Male Indian Population. AB - OBJECTIVES: Genes related to endothelial function are responsible for the regulation of vascular functions. AIM: The aim of this study is to investigate whether endothelial gene-associated polymorphism and their plasma levels can be used to predict the risk for venous thromboembolism (VTE). METHODS: We studied 133 patients with VTE and 164 healthy controls. Endothelin (EDN) G8002A, EDN T1370G, EDN 3A/4A, eNOSG894T, angiotensin-converting enzyme I/D, vascular endothelial growth factor C936T, and endothelial cell protein C receptor A6936G polymorphism was genotyped by restriction fragment length polymorphism. Plasma levels of endothelin 1 (EDN1), endothelial nitric oxide synthase, and angiotensin converting enzyme were measured by enzyme-linked immunoassay kit. RESULTS: The genotype and allele frequency between control and patients with VTE were significantly altered only for EDN T1370G polymorphism. The plasma EDN1 concentration was relatively higher in patients with VTE ( P = .0017) compared to healthy controls and showed an association with the EDN1 gene polymorphism in male Indian population. Logistic regression model analysis for EDN T1370G indicated a significant association between EDN G allele and occurrence of VTE. CONCLUSION: The EDN1 gene polymorphism may play a significant role in predicting individual's susceptibility toward VTE and its clinical progression. PMID- 27481877 TI - Catheter-Directed Treatment of Pulmonary Embolism: A Systematic Review and Meta Analysis of Modern Literature. AB - We summarize the evidence for the safety and efficacy of catheter-directed thrombolysis (CDT) with and without ultrasound-assisted therapy for treating submassive and massive pulmonary embolism (PE) in a systematic review. The primary efficacy outcome was mortality. Outcomes were pooled across studies with the random-effects model. Twenty-four studies enrolled 700 patients in total; 653 received mechanical thromboembolectomy treatments for PE (mortality rate, 9% [95% confidence interval (CI), 6%-13%], P = .12; rate of minor complications, 6% [95% CI, 2%-13%]). In the ultrasound-accelerated thrombolysis (USAT) studies, the mortality rate was 4% (95% CI, 1%-11%) and in the non-USAT studies, it was 9% (95% CI, 6%-13%). Secondary safety outcomes were all bleeding events, which occurred in 12% (95% CI, 7%-20%) of the USAT studies and in 10% (95% CI, 5%-20%) of the non-USAT studies. Current clinical evidence does not prove USAT is superior over CDT methods. PMID- 27481878 TI - Patient Perspectives on Biosimilars: A Survey by the European Federation of Crohn's and Ulcerative Colitis Associations. AB - BACKGROUND AND AIM: The aim of this survey was to find out the patients' perspectives concerning biosimilars. METHODS: An online survey consisting of 14 questions was made available between November 2014 and October 2015. Only respondents who had heard of biosimilars were asked to respond the final twelve questions. RESULTS: A total of 1181 patients responded. Of these, 38% had heard of biosimilars. The respondents worried about biosimilars' safety profile [47.0%], efficacy [40.3%], and molecular basis [35.0%]. Only 25.2% of the respondents had no concerns about biosimilars. Just over half [55.9%] of the respondents thought that the lower cost of the biosimilars should not come before their safety and efficacy. Only 12.5% of respondents felt that extrapolation made sense. The survey showed that 39.9% felt that patients should be systematically informed, and 26.7% felt that patient associations should be informed and able to give their opinions. It also revealed that 20.9% of the respondents would be against the idea of interchangeability if the patient was not aware; 65.7% of the respondents would want to know whether they were receiving the reference drug or the biosimilar, and have all necessary information in writing before the drug was administered. Only 31.0% of the respondents would be fully confident about biosimilars, even if they were prescribed and explained by the treating physician. CONCLUSIONS: Most patients were not familiar with biosimilars, and those who were had doubts and concerns about the biosimilars' safety and efficacy. The patients wished to be informed and involved in decision-making concerning biosimilars. PMID- 27481879 TI - Pharmacokinetics and Exposure-response Relationship of Golimumab in Patients with Moderately-to-severely Active Ulcerative Colitis: Results from Phase 2/3 PURSUIT Induction and Maintenance Studies. PMID- 27481881 TI - Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine. AB - OBJECTIVES: A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS: A randomized, single dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2*300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. RESULTS: Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. CONCLUSION: Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals. PMID- 27481882 TI - Temporal Relationship Between Cognitive and Physical Performance in Middle-Aged to Oldest Old People. AB - Background: Cognitive and physical impairment frequently co-occur in older people. The aim of this study was to assess the temporal order of these age related changes in cognitive and physical performance and to assess whether a relationship was different across specific cognitive and physical domains and age groups. Methods: Cognitive domains included global, executive, and memory function; physical domains included gait speed and handgrip strength. These domains were assessed in two population-based longitudinal cohorts covering the age ranges of 55-64, 65-74, 75-85, and 85-90 years with a follow-up of 5-12 years. Cross-lagged panel models were applied to assess the temporal relationships between the different cognitive and physical domains adjusting for age, sex, education, comorbidity, depressive symptoms, and physical activity. Results: Over all age groups, poorer executive function was associated with a steeper decline in gait speed (p < .05). From the age of 85 years, this relationship was found across all cognitive and physical domains (p < .02). From the age of 65 years, slower gait speed and/or weaker handgrip strength were associated with steeper declines in global cognitive function (p < .02), with statistically significant results across all cognitive domains in the age group of 75-85 years (p < .04). Conclusions: The temporal relationship between cognitive and physical performance differs across domains and age, suggesting a specific rather than a general relationship. This emphasizes the importance of repeated measurements on different domains and encourages future research to the development of domain- and age-specific interventions. PMID- 27481880 TI - Hemodynamics and Vascular Hypertrophy in African Americans and Caucasians With High Blood Pressure. AB - BACKGROUND: Hypertension in African Americans is characterized by greater systemic vascular resistance (SVR) compared with Caucasian Americans, but the responsible mechanisms are not known. The present study sought to determine if peripheral vascular hypertrophy is a potential mechanism contributing to elevated SVR in African Americans with high blood pressure (BP). METHODS: In a biracial sample of 80 men and women between the ages of 25 and 45 years, with clinic BP in the range 130/85-160/99mm Hg, we assessed cardiac output and SVR, in addition to BP. Minimum forearm vascular resistance (MFVR), a marker of vascular hypertrophy, also was assessed. RESULTS: SVR was elevated in African Americans compared with Caucasians (P < 0.001). Regression models indicated that age, body mass index, 24 hour diastolic BP, and ethnicity were significant predictors of SVR. There was also a significant interaction between ethnicity and MFVR in explaining SVR in the study sample. In particular, there was a significant positive association between MFVR and SVR among African Americans (P = 0.002), whereas the association was inverse and not statistically significant among Caucasians (P = 0.601). CONCLUSION: Hypertrophy of the systemic microvasculature may contribute to the elevated SVR that is characteristic of the early stages of hypertension in African American compared with Caucasians. PMID- 27481883 TI - Associations of Blood Cadmium Levels With Depression and Lower Handgrip Strength in a Community-Dwelling Elderly Population: A Repeated-Measures Panel Study. AB - BACKGROUND: Although biologically plausible, few studies have linked cadmium exposure to depression or muscle strength. Herein, we hypothesized that blood cadmium concentrations are associated with depression and lower handgrip strength in a community-dwelling elderly population. METHODS: Data from 983 elderly participants who completed up to 3 surveys between 2012 and 2015 were analyzed. At every survey, we assessed depressive status using the Korean version of the Geriatric Depression Scale-Short Form (SGDS-K) and measured handgrip strength and blood cadmium levels (mean, 1.24 MUg/L). We evaluated the associations of cadmium with depression using generalized linear mixed models, and handgrip strength using linear mixed models. All models were adjusted for sociodemographic factors, lifestyle factors including active and passive smoking, weight, height, and comorbidity status. RESULTS: Interquartile-range increase (0.645 MUg/L) in blood cadmium levels was associated with depression defined as SGDS-K score >=8 (odds ratio = 1.27, 95% confidence interval: 1.06, 1.52) and lower handgrip strength (right hand: beta = -0.40, 95% confidence interval: -0.75, -0.09; left hand: beta = -0.36, 95% confidence interval: -0.69, -0.04). The association between cadmium levels and handgrip strength was robust after further adjustment for depressive status, although it attenuated in size by 14.7%-18.0%. CONCLUSIONS: After adjusting for potential confounders, blood cadmium concentrations were associated with depression and lower handgrip strength in an elderly population. The participants' depressive status partially mediated the association between cadmium levels and handgrip strength. PMID- 27481884 TI - Topical administration of hyaluronic acid in children with recurrent or chronic middle ear inflammations. AB - Hyaluronic acid (HA) treatment has been successfully performed in patients with recurrent upper airway infections or rhinitis. The aim of this study was to assess the efficacy and safety of the topical nasal administration of an HA-based compound by investigating its effects in children with recurrent or chronic middle ear inflammations and chronic adenoiditis. A prospective, single-blind, 1:1 randomised controlled study was performed to compare otoscopy, tympanometry and pure-tone audiometry in children which received the daily topical administration of normal 0.9% sodium chloride saline solution (control group) or 9 mg of sodium hyaluronate in 3 mL of a 0.9% sodium saline solution. The final analysis was based on 116 children (49.1% boys; mean age, 62.9 +/- 17.9 months): 58 in the control group and 58 in the study group. At the end of follow-up, the prevalence of patients with impaired otoscopy was significantly lower in the study group (P value = 0.024) compared to baseline but not in the control group. In comparison with baseline, the prevalence of patients with impaired tympanometry at the end of the follow-up period was significantly lower in the study group (P value = 0.047) but not in the control group. The reduction in the prevalence of patients with conductive hearing loss (CHL) (P value = 0.008) and those with moderate CHL (P value = 0.048) was significant in the study group, but not in the control group. The mean auditory threshold had also significantly improved by the end of treatment in the study group (P value = 0.004) but not in the control group. Our findings confirm the safety of intermittent treatment with a topical nasal sodium hyaluronate solution and are the first to document its beneficial effect on clinical and audiological outcomes in children with recurrent or chronic middle ear inflammations associated with chronic adenoiditis. PMID- 27481885 TI - Living Gerontology: Providing Long-Distance, Long-term Care. AB - My own living and working through normative family transitions of parent care (as both a professional gerontologist and an intergenerational family member) facilitated five important kinds of growth: (a) providing parent care with optimal integrity; (b) understanding, elaborating, and teaching life-cycle theory with increasing depth; (c) using this theory to enrich practice approaches to long-term care; (d) identifying valuable new research directions; and (e) creating a multidimensional professional life that furthers theoretical development and identifies practice principles that promote individual, familial, and societal experiences of a "good old age." This reflective essay addresses these different kinds of growth, as they emerged from and contribute to the ever developing gerontological domains of theory and practice. PMID- 27481886 TI - Highlights from the Current Issue: August 2016. PMID- 27481887 TI - Animal Model of Chronic Perforation Is Best for Eardrum Regeneration Using Biological Materials. PMID- 27481888 TI - Response to "Animal Model of Chronic Perforation Is Best for Eardrum Regeneration Using Biological Materials". PMID- 27481889 TI - Experimental Evidence for Branch-to-Bird Transfer as a Mechanism for Avian Dispersal of the Hemlock Woolly Adelgid (Hemiptera: Adelgidae). AB - Birds have long been hypothesized as primary dispersal agents of the hemlock woolly adelgid (Adelges tsugae Annand). Although A. tsugae eggs and mobile first instars (crawlers) have been collected from wild birds, key mechanistic elements necessary for avian dispersal have never been examined. To evaluate the mechanisms of bird-mediated A. tsugae dispersal, we conducted both stationary (i.e., where crawlers must actively disperse) and disturbance (i.e., where crawlers may transfer from substrates due to mechanical abrasion) dispersal trials. For stationary trials, we tested the role of perching duration, ovisac density, and seasonal timing on the rate of crawler transfer to immobile preserved bird mounts at a single site in Connecticut. For disturbance trials, we explored if transfer rates were different when branches were actively brushed against birds. Both stationary and disturbance trials resulted in successful transfers of A. tsugae to bird mounts, with disturbance trials having significantly higher rates of transfers. Crawler counts from stationary trials increased significantly with local ovisac density. Additionally, we found a nonlinear relationship between crawler transfer and experimental week, with crawler transfer highest at the beginning of sampling in May, coinciding with avian spring migration in Connecticut and the emergence of progrediens crawlers, and spiking again near 14 June, when sistens generation crawlers began to emerge. While many aspects of potential avian dispersal of A. tsugae remain unknown, these results suggest that crawler transfer to birds may occur most often when peak crawler emergence coincides with the northward migration of many small passerine bird species. PMID- 27481890 TI - Inflammatory markers are associated with cardiac autonomic dysfunction in recent onset type 2 diabetes. AB - OBJECTIVE: Cardiovascular autonomic neuropathy is a common but underestimated diabetes-related disorder. Associations between cardiovascular autonomic dysfunction and subclinical inflammation, both risk factors of diabetic comorbidities and mortality, have been proposed in non-diabetic populations, while data for type 1 and type 2 diabetes are conflicting. Our aim was to investigate associations between inflammation-related biomarkers and cardiac autonomic dysfunction in patients with diabetes. METHODS: We characterised the associations between seven biomarkers of subclinical inflammation and cardiac autonomic dysfunction based on heart rate variability and cardiovascular autonomic reflex tests (CARTs) in 161 individuals with type 1 and 352 individuals with type 2 diabetes (time since diagnosis of diabetes <1 year). Analyses were adjusted for age, sex, anthropometric, metabolic and lifestyle factors, medication and cardiovascular comorbidities. RESULTS: In individuals with type 2 diabetes, higher serum interleukin (IL)-18 was associated with lower vagal activity (p<=0.015 for association with CARTs), whereas higher levels of total and high-molecular-weight adiponectin showed associations with very low frequency power, an indicator of reduced sympathetic activity (p<=0.014). Higher levels of soluble intercellular adhesion molecule-1 were associated with indicators of both lower vagal (p=0.025) and sympathetic (p=0.008) tone, soluble E-selectin with one indicator of lower vagal activity (p=0.047). Serum C-reactive protein and IL-6 were also related to cardiac autonomic dysfunction, but these associations were explained by confounding factors. No consistent associations were found in individuals with type 1 diabetes. CONCLUSIONS: Biomarkers of inflammation were differentially associated with diminished cardiac autonomic dysfunction in recent onset type 2 diabetes. PMID- 27481891 TI - The Disgust Box: a novel approach to illustrate water contamination with feces. AB - Inadequate drinking water, sanitation, and hand hygiene are responsible for approximately 800,000 deaths per year in low- and middle-income countries. We evaluated the benefits of a behavior change communication method to motivate water treatment practices in urban low income communities in Dhaka, Bangladesh. To motivate people to chlorinate their water we used a device called the 'Disgust Box'. This box provides a vivid demonstration of how piped water is contaminated with feces. Most of the respondents were able to recall the Disgust Box demonstration at both 4-month and 1-year follow-up qualitative assessments. At 4 months, the majority of participants stated that they still felt disgusted by the demonstration and mentioned it as a motivator for water chlorination. However, after one year, despite being able to recall the demonstration, disgust was no longer mentioned as a motivator to chlorinate water. The Disgust Box has the potential to be an effective communication method and is more likely to work if it is part of an intervention that includes repeated presentations and a more attractive water treatment option. PMID- 27481892 TI - Atypical Ductal Hyperplasia Bordering on Ductal Carcinoma In Situ. AB - BACKGROUND: The clinical implications of the diagnosis of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are very different. Yet there are "borderline" breast lesions that have characteristics of both ADH and DCIS. We examined interobserver diagnostic variability for such lesions and correlated pathologic features of the lesions with clinical outcomes. METHODS: We identified all cases of borderline ADH/DCIS lesions treated at our center from 1997 to 2010. Five specialized breast pathologists blinded to clinical outcomes independently reviewed all available slides from each case and were instructed to classify each as benign, ADH, or DCIS. A majority diagnosis (MajDx) was defined as a diagnosis agreed upon by >=3 pathologists. RESULTS: A total of 105 women with borderline ADH/DCIS and slides available for review were identified. The MajDx was ADH in 84 (80%), and DCIS in 18 (17%). There were split diagnoses in 3 (3%). MajDx of DCIS correlated significantly with lesion size and nuclear grade. There was diagnostic agreement by all 5 pathologists in 30% of cases, 4 pathologists in 42%, and 3 pathologists in 25%. At a median follow-up of 37 months, 4 (3.8%) patients developed subsequent ipsilateral breast carcinoma (2 invasive, 2 DCIS); all 4 cases had MajDx of ADH. CONCLUSIONS: Borderline ADH/DCIS represents an entity for which reproducible categorization as ADH or DCIS cannot be achieved. Furthermore, histologic features of borderline lesions resulting in MajDx of ADH vs. DCIS are not prognostic for risk of subsequent breast carcinoma. PMID- 27481894 TI - Ultrastructural Immunolocalization of Arabinogalactan Protein, Pectin and Hemicellulose Epitopes Through Anther Development in Brassica napus. AB - In this work, we performed an extensive and detailed analysis of the changes in cell wall composition during Brassica napus anther development. We used immunogold labeling to study the spatial and temporal patterns of the composition and distribution of different arabinogalactan protein (AGP), pectin, xyloglucan and xylan epitopes in high-pressure-frozen/freeze-substituted anthers, quantifying and comparing their relative levels in the different anther tissues and developmental stages. We used the following monoclonal antibodies: JIM13, JIM8, JIM14 and JIM16 for AGPs, LM5, LM6, JIM7, JIM5 and LM7 for pectins, CCRC M1, CCRC-M89 and LM15 for xyloglucan, and LM11 for xylan. Each cell wall epitope showed a characteristic temporal and spatial labeling pattern. Microspore, pollen and tapetal cells showed similar patterns for each epitope, whereas the outermost anther layers (epidermis, endothecium and middle layers) presented remarkably different patterns. Our results suggested that AGPs, pectins, xyloglucan and xylan have specific roles during anther development. The AGP epitopes studied appeared to belong to AGPs specifically involved in microspore differentiation, and contributed first by the tapetum and then, upon tapetal dismantling, by the endothecium and middle layers. In contrast, the changes in pectin and hemicellulose epitopes suggested a specific role in anther dehiscence, facilitating anther wall weakening and rupture. The distribution of the different cell wall constituents is regulated in a tissue- and stage-specific manner, which seems directly related to the role of each tissue at each stage. PMID- 27481893 TI - Cell Wall Composition and Candidate Biosynthesis Gene Expression During Rice Development. AB - Cell walls of grasses, including cereal crops and biofuel grasses, comprise the majority of plant biomass and intimately influence plant growth, development and physiology. However, the functions of many cell wall synthesis genes, and the relationships among and the functions of cell wall components remain obscure. To better understand the patterns of cell wall accumulation and identify genes that act in grass cell wall biosynthesis, we characterized 30 samples from aerial organs of rice (Oryza sativa cv. Kitaake) at 10 developmental time points, 3-100 d post-germination. Within these samples, we measured 15 cell wall chemical components, enzymatic digestibility and 18 cell wall polysaccharide epitopes/ligands. We also used quantitative reverse transcription-PCR to measure expression of 50 glycosyltransferases, 15 acyltransferases and eight phenylpropanoid genes, many of which had previously been identified as being highly expressed in rice. Most cell wall components vary significantly during development, and correlations among them support current understanding of cell walls. We identified 92 significant correlations between cell wall components and gene expression and establish nine strong hypotheses for genes that synthesize xylans, mixed linkage glucan and pectin components. This work provides an extensive analysis of cell wall composition throughout rice development, identifies genes likely to synthesize grass cell walls, and provides a framework for development of genetically improved grasses for use in lignocellulosic biofuel production and agriculture. PMID- 27481895 TI - CHLORORESPIRATORY REDUCTION 9 is a Novel Factor Required for Formation of Subcomplex A of the Chloroplast NADH Dehydrogenase-Like Complex. AB - In vascular plants, the chloroplast NADH dehydrogenase-like (NDH) complex, a homolog of respiratory NADH:quinone oxidoreductase (Complex I), mediates plastoquinone reduction using ferredoxin as an electron donor in cyclic electron transport around PSI in the thylakoid membrane. In angiosperms, chloroplast NDH is composed of five subcomplexes and forms a supercomplex with PSI. The modular assembly of stroma-protruded subcomplex A, which corresponds to the Q module of Complex I, was recently reported. However, the factors involved in the specific assembly steps have not been completely identified. Here, we isolated an Arabidopsis mutant, chlororespiratory reduction 9 (crr9), defective in NDH activity. The CRR9 gene encodes a novel stromal protein without any known functional domains or motifs. CRR9 is highly conserved in cyanobacteria and land plants but not in green algae, which do not have chloroplast NDH. Blue native PAGE and immunoblot analyses of thylakoid proteins indicated that formation of subcomplex A was impaired in crr9 CRR9 was specifically required for the accumulation of NdhK, a subcomplex A subunit, in NDH assembly intermediates in the stroma. Furthermore, two-dimensional clear native/SDS-PAGE analysis of the stroma fraction indicated that incorporation of NdhM into NDH assembly intermediate complex 400 was impaired in crr9 These results suggest that CRR9 is a novel factor required for the formation of NDH subcomplex A. PMID- 27481896 TI - Nitrate Protects Cucumber Plants Against Fusarium oxysporum by Regulating Citrate Exudation. AB - Fusarium wilt causes severe yield losses in cash crops. Nitrogen plays a critical role in the management of plant disease; however, the regulating mechanism is poorly understood. Using biochemical, physiological, bioinformatic and transcriptome approaches, we analyzed how nitrogen forms regulate the interactions between cucumber plants and Fusarium oxysporum f. sp. cucumerinum (FOC). Nitrate significantly suppressed Fusarium wilt compared with ammonium in both pot and hydroponic experiments. Fewer FOC colonized the roots and stems under nitrate compared with ammonium supply. Cucumber grown with nitrate accumulated less fusaric acid (FA) after FOC infection and exhibited increased tolerance to chemical FA by decreasing FA absorption and transportation in shoots. A lower citrate concentration was observed in nitrate-grown cucumbers, which was associated with lower MATE (multidrug and toxin compound extrusion) family gene and citrate synthase (CS) gene expression, as well as lower CS activity. Citrate enhanced FOC spore germination and infection, and increased disease incidence and the FOC population in ammonium-treated plants. Our study provides evidence that nitrate protects cucumber plants against F. oxysporum by decreasing root citrate exudation and FOC infection. Citrate exudation is essential for regulating disease development of Fusarium wilt in cucumber plants. PMID- 27481898 TI - Health State Utilities and Disease Duration in Systemic Sclerosis: Is There an Association? AB - OBJECTIVE: Health state utility values (HSUV) are used as weightings to calculate quality-adjusted life years in economic evaluations. Evidence suggests that patients' perceptions of a new diagnosis for a chronic disease, while initially poor, may improve over time. The objective of this study was to examine the association between disease duration and direct HSUV scores in patients with systemic sclerosis (SSc). METHODS: Our study included patients with SSc from a US SSc center. An interviewer administered direct HSUV techniques including the visual analog scale (VAS), time tradeoff (TTO), and standard gamble (SG). We calculated the Short Form 6D HSUV from the Medical Outcomes Study Short Form-36. Additional clinical and demographic variables were collected. RESULTS: The mean age of the SSc sample (n = 223) was 51 years (SD 16) with the majority being women (84%). Median disease duration was 5 years (interquartile range 1.5-9). Mean (SD) HSUV scores were 0.67 (0.19) for the VAS, 0.76 (0.28) for the TTO, 0.84 (0.22) for the SG, and 0.65 (0.13) for the SF-6D. In patients with early disease (defined as <= 2 yrs, n = 78), the mean HSUV values were 0.64 (VAS), 0.70 (TTO), 0.80 (SG), and 0.63 (SF-6D) versus for those with a longer disease duration: 0.69, 0.79, 0.87, and 0.67, respectively. In multivariate analysis, the SG measure showed a significant and positive association with disease duration measured as a continuous variable and using a threshold of 2 years (p = 0.047 and p = 0.023, respectively). CONCLUSION: Greater disease duration showed a positive association with a direct measure (SG) of utility elicitation after a period of 2 years. PMID- 27481899 TI - Usefulness of IgA Anti-alpha-fodrin Antibodies in Combination with Rheumatoid Factor and/or Antinuclear Antibodies as Substitute Immunological Criterion in Sjogren Syndrome with Negative Anti-SSA/SSB Antibodies. AB - OBJECTIVE: We aimed to evaluate the usefulness of anti-alpha-fodrin antibodies (AFA) in combination with rheumatoid factor (RF) and/or antinuclear antibodies (ANA) as an alternative immunological criterion for Sjogren syndrome (SS) among patients with negative anti-Ro/La serology. METHODS: The study included 350 patients (100 with rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, and 50 with primary SS) randomly selected and assessed for SS. All patients were tested for ANA, RF, anti-SSA/SSB, and AFA antibodies. SS diagnosis was made on a clinical basis by 2 rheumatologists based on the 6-item screening questionnaire, Schirmer-I test, nonstimulated whole salivary flow rate, fluorescein staining test, autoantibodies, lip biopsy, and medical chart review. Non-SS was defined as lack of clinical diagnosis and not fulfilling the American European Consensus Group classification criteria and the American College of Rheumatology (ACR) criteria. The ACR criteria were applied substituting the immunological criteria as follows: (1) RF plus ANA > 1:320, (2) RF plus AFA, (3) ANA > 1:320 plus AFA, (4) RF alone, and (5) 2 positive tests out of RF, ANA > 1:320, or AFA. We estimated the sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio positivity with 95% CI for each criterion. RESULTS: There were 236 patients (67%) who tested negative for anti-SSA/SSB antibodies, of whom 65 (27.5%) were clinically diagnosed as SS, and 149 (63%) with non-SS. RF + AFA and ANA + AFA performed similarly to RF + ANA > 1:320. The model 2 out of 3 of RF, ANA, or AFA improved the sensitivity from 56.9% to 70.7%, although the specificity decreased. CONCLUSION: The combination AFA + RF, AFA + ANA > 1:320, or at least 2 out of 3, performed well as a proxy immunological test for patients with SS and negative Ro/La serology. PMID- 27481900 TI - Effectiveness of Tumor Necrosis Factor Inhibitors in Combination with Various csDMARD in the Treatment of Rheumatoid Arthritis: Data from the DREAM Registry. AB - OBJECTIVE: To analyze and compare the effectiveness and drug survival in patients with rheumatoid arthritis, as measured by 28-joint Disease Activity Score (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI), of tumor necrosis factor inhibitor (TNFi) monotherapy, TNFi + leflunomide (LEF), TNFi + sulfasalazine (SSZ), TNFi + other conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and TNFi + methotrexate (MTX) therapy, in daily practice. METHODS: Data were collected from the DREAM registry. Patients beginning their first TNFi treatment were included in the study: TNFi monotherapy (n = 320), TNFi + SSZ (n = 103), TNFi + LEF (n = 80), TNFi + other csDMARD (n = 99), TNFi + MTX alone (n = 919), TNFi + MTX + other csDMARD (n = 412). Treatment effectiveness was analyzed using DAS28 and HAQ-DI with linear mixed models and the TNFi drug survival was analyzed using Kaplan-Meier curves and Cox regression. All analyses have been corrected for confounders. RESULTS: The patients who received TNFi + MTX had significantly better DAS28 and HAQ-DI values over time (both p < 0.001) and longer TNFi drug survival than TNFi monotherapy (p < 0.001). TNFi + SSZ and TNFi + other csDMARD had significantly better DAS28 values over time (p = 0.001) and longer drug survival (p = 0.001) versus TNFi monotherapy. TNFi + LEF was not significantly better compared to monotherapy. Adding other csDMARD to the TNFi + MTX combination provided no added value. CONCLUSION: Preferably, TNFi should be prescribed together with MTX. If this is not possible, we advise the use of other csDMARD. PMID- 27481902 TI - Ethnic Differences in Autoantibody Diversity and Hierarchy: More Clues from a US Cohort of Patients with Systemic Sclerosis. AB - OBJECTIVE: To determine the autoantibody repertoire and clinical associations in a multiethnic cohort of American patients with systemic sclerosis (SSc). METHODS: There were 1000 patients with SSc (196 Hispanic, 228 African American, 555 white, and 21 other) who were screened for antinuclear antibodies (ANA), including anticentromere antibodies (ACA) by indirect immunofluorescence assay, antitopoisomerase-1 (topo-1/Scl-70) by immunodiffusion, and anti-RNA polymerase III (RNAP III) by ELISA. Sera from 160 patients with mainly nucleolar and/or speckled ANA pattern, but negative for ACA, Scl-70, and RNAP III, were further characterized by immunoprecipitation for SSc-specific antibodies. RESULTS: The prevalence of antibodies against RNAP III, Th/To, and PM/Scl did not differ significantly among the ethnic groups. The frequency of anti-Scl-70 was lowest in whites (18.0%) compared with 24.0% and 26.8% in Hispanics and African Americans (p = 0.01), respectively. Compared with African American patients, Hispanic and white subjects had a higher frequency of ACA (p < 0.0001) and lower frequency of U3-RNP (p < 0.0001). U3-RNP antibodies were uniquely higher in African American patients, independent of clinical subset, while Th/To autoantibodies were associated with limited cutaneous SSc in white subjects. Overall, Hispanic and African American patients had an earlier age of onset and a predominance of diffuse cutaneous SSc compared with their white counterparts. CONCLUSION: SSc specific antibodies may predict disease subset; however, the hierarchy of their prevalence differs across ethnic groups. This study provides the most extensive analysis to date on the relevance of autoantibodies in the diagnosis and clinical manifestations of SSc in Hispanic American patients. PMID- 27481901 TI - Alarmin S100A9 Induces Proinflammatory and Catabolic Effects Predominantly in the M1 Macrophages of Human Osteoarthritic Synovium. AB - OBJECTIVE: The alarmins S100A8 and S100A9 have been shown to regulate synovial activation, cartilage damage, and osteophyte formation in osteoarthritis (OA). Here we investigated the effect of S100A9 on the production of proinflammatory cytokines and matrix metalloprotease (MMP) in OA synovium, granulocyte macrophage colony-stimulating factor (GM-CSF)-differentiated/macrophage colony-stimulating factor (M-CSF)-differentiated macrophages, and OA fibroblasts. METHODS: We determined which cell types in the synovium produced S100A8 and S100A9. Further, the production of proinflammatory cytokines and MMP, and the activation of canonical Wnt signaling, was determined in human OA synovium, OA fibroblasts, and monocyte-derived macrophages following stimulation with S100A9. RESULTS: We observed that S100A8 and S100A9 were mainly produced by GM-CSF-differentiated macrophages present in the synovium, and to a lesser extent by M-CSF differentiated macrophages, but not by fibroblasts. S100A9 stimulation of OA synovial tissue increased the production of the proinflammatory cytokines interleukin (IL) 1beta, IL-6, IL-8, and tumor necrosis factor-alpha. Additionally, various MMP were upregulated after S100A9 stimulation. Experiments to determine which cell type was responsible for these effects revealed that mainly stimulation of GM-CSF-differentiated macrophages and to a lesser extent M CSF-differentiated macrophages with S100A9 increased the expression of these proinflammatory cytokines and MMP. In contrast, stimulation of fibroblasts with S100A9 did not affect their expression. Finally, stimulation of GM-CSF differentiated, but not M-CSF-differentiated macrophages with S100A9 activated canonical Wnt signaling, whereas incubation of OA synovium with the S100A9 inhibitor paquinimod reduced the activation of canonical Wnt signaling. CONCLUSION: Predominantly mediated by M1-like macrophages, the alarmin S100A9 stimulates the production of proinflammatory and catabolic mediators and activates canonical Wnt signaling in OA synovium. PMID- 27481903 TI - Association Between Dietary Intake of Antioxidants and Prevalence of Femoral Head Cartilage Defects and Bone Marrow Lesions in Community-based Adults. AB - OBJECTIVE: Although there is evidence for a beneficial effect of dietary antioxidants on knee joint health, the data are sparse for the hip. Our aim was to examine the relationship between dietary antioxidants and early hip structural abnormalities in community-based adults. METHODS: The study included 214 participants without diagnosed hip osteoarthritis (OA) who underwent hip magnetic resonance imaging in 2009-2010. The prevalence of femoral head cartilage defects and bone marrow lesions (BML) was assessed. Intakes of antioxidant vitamins and their food sources were estimated from a food frequency questionnaire during 1990 1994. RESULTS: Higher intakes of Vitamin E (OR 0.63, 95% CI 0.41-0.96), lutein/zeaxanthin (OR 0.58, 95% CI 0.34-0.99), and lycopene (OR 0.64, 95% CI 0.44 0.95) were associated with a reduced prevalence of femoral head cartilage defects. Higher intakes of alpha-carotene (OR 0.42, 95% CI 0.19-0.94), beta carotene (OR 0.31, 95% CI 0.13-0.78), and lutein/zeaxanthin (OR 0.42, 95% CI 0.18 0.98) were associated with a reduced prevalence of femoral head BML. Higher vegetable consumption was associated with a reduced prevalence of femoral head cartilage defects (OR 0.65, 95% CI 0.46-0.91) and BML (OR 0.60, 95% CI 0.37 0.97). CONCLUSION: Higher carotenoids intake and vegetable consumption were associated with reduced risk of hip cartilage defects and BML, and higher Vitamin E intake was associated with reduced risk of hip cartilage defects. These findings suggest a beneficial effect of dietary antioxidants on hip joint health. Although our findings need to be confirmed in other longitudinal studies, they suggest that the modification of dietary antioxidant intake may be a strategy for the prevention of hip OA. PMID- 27481904 TI - Active Rheumatoid Arthritis in Central Africa: A Comparative Study Between Sudan and Sweden. AB - OBJECTIVE: To compare clinical characteristics and treatment between simultaneously investigated Sudanese and Swedish outpatients with rheumatoid arthritis (RA). METHODS: Outpatients with RA from Sudan (n = 281) and Sweden (n = 542) diagnosed according to the 1987 American College of Rheumatology criteria were recruited between December 2008 and September 2010 and compared concerning clinical presentation, treatment, and laboratory findings, including immunoglobulin M with rheumatoid factor (IgM-RF). RESULTS: Sudanese patients had lower inclusion age (median 49 vs 68 yrs), disease duration (48 vs 107 mos), and disease onset age (43 vs 56 yrs) as compared with Swedish patients (p < 0.0001 for all). When stratified concerning the age of inclusion, Swedish patients between 41-50 years had, however, a significantly lower age of onset, with a similar trend for all age groups above 30 years. The female preponderance was higher among Sudanese patients (89.3% vs 72.5%, p < 0.0001), and smoking was nonexistent among Sudanese female patients (p < 0.0001). Erythrocyte sedimentation rate levels and number of tender joints were significantly higher among Sudanese patients. The proportion of IgM-RF positivity was lower among Sudanese patients with RA (52.4% vs 75.5%, p < 0.0001). Higher proportions of Sudanese patients with RA were treated with methotrexate (MTX) and disease modifying antirheumatic drug combinations, but none of them used biologics. Sudanese patients used lower doses of MTX and sulfasalazine (p < 0.0001) and higher doses of prednisolone (p < 0.0001) than Swedish patients. CONCLUSION: Sudanese patients with RA have significantly higher disease activity and are often IgM-RF-seronegative. Together with reports from Uganda and Cameroon, our data indicate a cluster of highly active and often seronegative RA in central Africa. PMID- 27481905 TI - Ability of a Urine Assay of Type II Collagen Cleavage by Collagenases to Detect Early Onset and Progression of Articular Cartilage Degeneration: Results from a Population-based Cohort Study. AB - OBJECTIVE: To evaluate the association of a sandwich assay for cartilage collagenase-mediated degradation, the C2C human urine sandwich assay (IB-C2C HUSA), with early and late knee cartilage pathology and with progression of cartilage damage. METHODS: A population-based cohort with knee pain, age 40-79 years, was evaluated at baseline (n = 253) and after mean 3.3 years (n = 161). We evaluated the IB-C2C-HUSA and a related competitive inhibition assay (C2C). The C2C assay was applied to serum (sC2C) and urine (uC2C). Based on knee radiographs and magnetic resonance imaging (MRI), 3 subgroups [no cartilage pathology, preradiographic cartilage pathology, and radiographic osteoarthritis (ROA)] were evaluated cross-sectionally for association with biomarker levels. Longitudinally, we evaluated whether baseline assays predict subsequent progression of cartilage degeneration, defined by MRI cartilage loss. RESULTS: Cross-sectionally, statistically significant differences were seen in the 3 subgroups for IB-C2C-HUSA (p < 0.001), with the highest levels seen in ROA, and for sC2C (p = 0.023), while no differences were seen for uC2C (p = 0.501). Baseline IB-C2C-HUSA levels were higher in progressors vs nonprogressors (p = 0.003). In logistic regression analysis, only baseline IB-C2C-HUSA was associated with an increased risk of progression of cartilage damage (OR 1.78, 95% CI 1.03 3.09). CONCLUSION: The IB-C2C-HUSA degradation assay detects the generation of a pathology-related cartilage collagen peptide(s) that increase(s) with onset of degeneration of knee articular cartilage. The baseline values are associated with progression of cartilage degeneration over 3 subsequent years. This assay may have value in clinical OA trials. Further, it points to collagenase activity as a therapeutic target for controlling degeneration of articular cartilage. PMID- 27481906 TI - The Responsiveness of the Modified Childhood Health Assessment Questionnaire. AB - OBJECTIVE: To determine the ability of the revised version of the Childhood Health Assessment Questionnaire (CHAQ), the VASCHAQ, to detect clinical change over time in pediatric patients with juvenile idiopathic arthritis (JIA). We studied the relative responsiveness of the VASCHAQ as compared to the original CHAQ-30 and revised CHAQ-38, as well as the parent-patient, physician-patient, and physician-parent concordance. METHODS: The CHAQ-38 and VASCHAQ were administered to 30 parents and patients (if older than 8 years) with any subtype of JIA before and after the start of a new treatment. The standardized response means (SRM) were calculated for the VASCHAQ, the original CHAQ-30, and the CHAQ 38. Comparisons of SRM were made using the relative SRM. Parent-patient, physician-patient, and physician-parent concordances were assessed by calculating a series of intraclass correlation coefficients. RESULTS: Twenty-seven parents and 21 patients completed questionnaires at both visits. All questionnaires demonstrated large responsiveness; however, the VASCHAQ was found to be about 25% more responsive than both the original CHAQ-30 and CHAQ-38. CONCLUSION: The VASCHAQ was moderately more responsive than the CHAQ-30 and CHAQ-38 in both parent and patient groups and should be considered for use in studies evaluating change in function over time. PMID- 27481907 TI - Elevated Serum Krebs von den Lungen-6 in Early Disease Predicts Subsequent Deterioration of Pulmonary Function in Patients with Systemic Sclerosis and Interstitial Lung Disease. AB - OBJECTIVE: To identify predictors of poor prognosis in patients with systemic sclerosis (SSc) associated with interstitial lung disease (ILD). METHODS: Fifty patients with early-stage SSc-ILD who had never received disease-modifying drugs and were either observed for >= 10 years or died from ILD-related causes were enrolled. The baseline variables of patients who developed endstage lung disease (ESLD) were compared with those of patients who remained ESLD-free, and the Cox proportional hazard model was used to identify initial factors that correlated with ESLD development. RESULTS: Sixteen patients (32%) developed ESLD during 173.5 +/- 64.7 months of followup. Elevated serum Krebs von den Lungen-6 (KL-6) at initial assessment was highly correlated with ESLD development (p = 0.0002). Receiver-operating characteristic curve analysis revealed that a KL-6 value of 1273 U/ml effectively discriminated patients who developed ESLD from those who did not. Patients with KL-6 > 1273 U/ml were less likely to remain ESLD-free compared with those with lower KL-6 levels (p < 0.0001). Multivariate analysis showed that KL-6 > 1273 U/ml was the most reliable predictor of ESLD development (OR 51.2, 95% CI 7.6-343, p < 0.0001). Finally, the initial KL-6 level correlated with the forced vital capacity (FVC) decline rate (r = 0.58, p < 0.0001). CONCLUSION: The natural course of SSc-ILD is highly variable. Baseline serum KL-6 is a biomarker potentially useful for predicting FVC decline. PMID- 27481909 TI - The Use of Neck Support Pillows and Postural Exercises in the Management of Chronic Neck Pain. AB - OBJECTIVE: Chronic neck pain is a common problem with a profound effect on quality of life. Identifying evidence-based management strategies is fundamental in improving patient outcomes. This study is a reanalysis of the data from Helewa, et al to further characterize the effects of postural exercises and neck support pillows on neck pain. METHODS: A full factorial model was used. All interactions were analyzed adjusting for the Northwick Park Neck Pain Questionnaire (NPQ) at baseline. RESULTS: Postural exercises significantly decreased NPQ scores at >= 3 weeks, and the use of a neck support pillow significantly decreased NPQ scores at >= 12 weeks. CONCLUSION: These interventions could be beneficial in reducing neck pain symptoms. PMID- 27481908 TI - Gaps in Addressing Cardiovascular Risk in Rheumatoid Arthritis: Assessing Performance Using Cardiovascular Quality Indicators. AB - OBJECTIVE: Cardiovascular disease (CVD) is a major comorbidity for patients with rheumatoid arthritis (RA). This study sought to determine the performance of 11 recently developed CVD quality indicators (QI) for RA in clinical practice. METHODS: Medical charts for patients with RA (early disease or biologic-treated) followed at 1 center were retrospectively reviewed. A systematic assessment of adherence to 11 QI over a 2-year period was completed. Performance on the QI was reported as a percentage pass rate. RESULTS: There were 170 charts reviewed (107 early disease and 63 biologic-treated). The most frequent CVD risk factors present at diagnosis (early disease) and biologic start (biologic-treated) included hypertension (26%), obesity (25%), smoking (21%), and dyslipidemia (15%). Performance on the CVD QI was highly variable. Areas of low performance (< 10% pass rates) included documentation of a formal CVD risk assessment, communication to the primary care physician (PCP) that patients with RA were at increased risk of CVD, body mass index documentation and counseling if overweight, communication to a PCP about an elevated blood pressure, and discussion of risks and benefits of antiinflammatories in patients at CVD risk. Rates of diabetes screening and lipid screening were 67% and 69%, respectively. The area of highest performance was observed for documentation of intent to taper corticosteroids (98%-100% for yrs 1 and 2, respectively). CONCLUSION: Gaps in CVD risk management were found and highlight the need for quality improvements. Key targets for improvement include coordination of CVD care between rheumatology and primary care, and communication of increased CVD risk in RA. PMID- 27481910 TI - The Social Reach: 8-Month-Olds Reach for Unobtainable Objects in the Presence of Another Person. AB - Linguistic communication builds on prelinguistic communicative gestures, but the ontogenetic origins and complexities of these prelinguistic gestures are not well known. The current study tested whether 8-month-olds, who do not yet point communicatively, use instrumental actions for communicative purposes. In two experiments, infants reached for objects when another person was present and when no one else was present; the distance to the objects was varied. When alone, the infants reached for objects within their action boundaries and refrained from reaching for objects out of their action boundaries; thus, they knew about their individual action efficiency. However, when a parent (Experiment 1) or a less familiar person (Experiment 2) sat next to them, the infants selectively increased their reaching for out-of-reach objects. The findings reveal that before they communicate explicitly through pointing gestures, infants use instrumental actions with the apparent expectation that a partner will adopt and complete their goals. PMID- 27481911 TI - Childhood Adversity, Self-Esteem, and Diurnal Cortisol Profiles Across the Life Span. AB - Childhood adversity is associated with poor health outcomes in adulthood; the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a crucial biological intermediary of these long-term effects. Here, we tested whether childhood adversity was associated with diurnal cortisol parameters and whether this link was partially explained by self-esteem. In both adults and youths, childhood adversity was associated with lower levels of cortisol at awakening, and this association was partially driven by low self-esteem. Further, we found a significant indirect pathway through which greater adversity during childhood was linked to a flatter cortisol slope via self-esteem. Finally, youths who had a caregiver with high self-esteem experienced a steeper decline in cortisol throughout the day compared with youths whose caregiver reported low self-esteem. We conclude that self-esteem is a plausible psychological mechanism through which childhood adversity may get embedded in the activity of the HPA axis across the life span. PMID- 27481912 TI - Aneurysmal subarachnoid hemorrhage and severe, catheter-induced vasospasm associated with excessive consumption of a caffeinated energy drink. AB - Excessive consumption of over-the-counter stimulants is associated with coronary vasospasm, thrombotic complications, and sudden cardiac death. Their effects on cerebrovascular physiology are not yet described in the neurointerventional literature. Patients are increasingly exposed to high levels of these vasoactive substances in the form of caffeinated energy drinks and specialty coffees. We report a case of aneurysmal subarachnoid hemorrhage (SAH) and severe, catheter induced vasospasm during attempted endovascular repair of a ruptured anterior communicating artery (AComA) aneurysm in the setting of excessive energy drink consumption. We review the literature and alert clinicians to this potentially serious complication. PMID- 27481913 TI - Spontaneous obliteration of spontaneous vertebral arteriovenous fistula associated with fibromuscular dysplasia after partial surgery: A case report. AB - We describe a patient with spontaneous obliteration of spontaneous vertebral arteriovenous fistula (VAVF) associated with fibromuscular dysplasia (FMD) after partial surgery. A 52-year-old hypertensive female woke up one morning with left shoulder pain and weakness of the left upper extremity. A few days later, she developed left-sided audible bruit. She was treated for left frozen shoulder and supportive treatment for audible bruit for four years. She was referred from her general physician to a neurosurgeon because of left arm weakness. Physical examination showed signs of cervical radiculomyelopathy. Magnetic resonance imaging (MRI) showed an extradural mass on the left side of the cervical spinal canal from level C2 to C6. Provisional diagnosis was epidural vascular tumour. Laminectomy and partial removal of the mass was performed at level C5 to C6. Pathological report revealed suspected vascular malformation. Postoperative MRI showed thrombosed epidural vascular structure. Angiography showed dysplastic changes of both vertebral arteries representing FMD with VAVF of the left vertebral artery at level C1-C2. Two years after surgery, follow-up MRI demonstrated complete spontaneous resolution of the large thrombosed epidural vein. Disappearance of her audible bruit immediately after surgery and gradual improvement of her cervical radiculomyelopathy were observed after two years of clinical follow-up. From the literature, we found another 11 patients with 12 VAVFs who had spontaneous obliteration or cure of their fistulas. In the present case, spontaneous obliteration of the fistula seems to correlate with surgery inducing closure of the epidural venous exit leading to thrombosis of the enlarged epidural draining vein. PMID- 27481914 TI - Extracranial vertebral artery rupture likely secondary to "cupping therapy" superimposed on spontaneous dissection. AB - The extracranial vertebral artery (VA) is vulnerable to dissection and the V3 segment is the most common location for dissection. Dissection accounts for about 2% of all ischemic strokes and can occur after trauma or chiropractic neck maneuvers. We report an extremely rare case of spontaneous extracranial VA dissection presenting with posterior neck hematoma aggravated after cupping therapy, a treatment in traditional Oriental medicine. We treated the patient successfully by endovascular treatment without any complication. PMID- 27481916 TI - Child Maltreatment 2015 Best Article Award. PMID- 27481918 TI - Psychometric Properties of the Weiss Functional Impairment Rating Scale: Evidence for Utility in Research, Assessment, and Treatment of ADHD in Emerging Adults. AB - OBJECTIVE: The current study examines psychometric properties of the Weiss Functional Impairment Rating Scale (WFIRS), a measure of adult ADHD-related impairment. It is a self-report questionnaire that provides a metric of overall life impairment and domain-specific dysfunction. METHOD: Using data from a large (N = 2,093), multi-institution sample of college students and including a subsample of collateral informants (n = 262), a series of analyses were conducted. RESULTS: The WFIRS demonstrated robust internal reliability, cross informant agreement on par or superior to other measures of ADHD symptomatology and impairment, and concurrent validity. The WFIRS was not shown to be uniquely associated with ADHD, as internalizing symptoms also associated with the total and domain scores. CONCLUSION: The use of the WFIRS in identifying ADHD-related impairment in emerging adults appears to be psychometrically supported, and will prove useful to clinicians and researchers. PMID- 27481915 TI - Developmental Outcomes of Foster Children: A Meta-Analytic Comparison With Children From the General Population and Children at Risk Who Remained at Home. AB - Foster care is often preferred to other placement options for children in the child welfare system. However, it is not clear how the developmental outcomes of foster children relate to children in other living arrangements. In this study, a series of meta-analyses are performed to compare the cognitive, adaptive, and behavioral functioning of children placed in foster care (n = 2,305) with children at risk who remained with their biological parents (n = 4,335) and children from the general population (n = 4,971). A systematic literature search in PsycINFO, Medline, ERIC, and ProQuest identified 31 studies suitable for inclusion (N = 11,611). Results showed that foster children had generally lower levels of functioning than children from the general population. No clear differences were found between foster children and children at risk who remained at home, but both groups experienced developmental problems. Improving the quality of foster care and future research to identify which children are best served by either foster care or in-home services are recommended. PMID- 27481919 TI - Prevention is better than cure: the new ESC Guidelines. PMID- 27481920 TI - CardioPulse Articles. PMID- 27481921 TI - Asenapine for the Treatment of Psychotic Disorders. AB - OBJECTIVE: A systematic review was conducted to examine the efficacy, tolerability, and acceptability of asenapine compared with other antipsychotics in the treatment of psychotic disorders. METHODS: Four databases, 8 trial registries, and conference presentations were searched for randomized clinical trials of asenapine versus any comparator for the treatment of any psychotic illness. Primary outcome measures were changes in the Positive and Negative Syndrome Scale (PANSS) total score and the incidence of withdrawal due to adverse effects. RESULTS: Eight randomized clinical trials, encompassing 3765 patients, that compared asenapine with placebo ( n = 5) and olanzapine ( n = 3) were included. No differences were found between asenapine and olanzapine in terms of changes to PANSS total or PANSS negative subscale scores. Patients taking asenapine were more likely to experience worsening schizophrenia and/or psychosis than were those taking olanzapine. No differences were found between asenapine and olanzapine in rates of discontinuation due to adverse drug reactions or lack of efficacy, but those taking asenapine had higher rates of withdrawal for any reason than those taking olanzapine. Asenapine caused less clinically significant weight gain or increases in triglycerides than olanzapine and was more likely to cause extrapyramidal symptoms than olanzapine. In comparison to placebo, either no difference or superiority was demonstrated in favour of asenapine on all efficacy measures. CONCLUSION: The current evidence is limited, as asenapine has been compared only with placebo or olanzapine. In the randomized clinical trials analysed, asenapine was similar or superior to placebo and similar or inferior to olanzapine on most efficacy outcomes. While asenapine demonstrated fewer adverse metabolic outcomes than olanzapine, rates of extrapyramidal symptom-related adverse effects were higher. PMID- 27481922 TI - Polymorphisms in Inflammatory Mediator Genes and Risk of Preeclampsia in Taiyuan, China. AB - Excessive maternal inflammatory response is involved in the pathogenesis of preeclampsia. Few epidemiologic studies have investigated the associations between genetic variations in the inflammatory mediator genes and preeclampsia risk, and these studies have reached inconsistent results. We examined 31 single nucleotide polymorphisms in IL-1A, IL-1B, IL-1R1, IL-2RA, IL-5RA, IL-6, IL-6R, TNFSF11, TNFRSF11A, IL-28RA, IRAK4, and KIT genes and the risk of preeclampsia and its clinical subtypes in a nested case-control study including 203 preeclampsia cases and 233 controls. We found that IL-1R1, IL-5RA, IL-6R, and TNFSF11 were associated with the risk of preeclampsia. Although the significant associations observed for preeclampsia overall were mainly seen for late-onset preeclampsia and severe preeclampsia, IL-6R (rs2229238) and TNFSF11 (rs9525643) polymorphisms were associated with the risk of early-onset preeclampsia. TNFSF11 (rs2200287 and rs2148072) polymorphisms were associated with risk of mild preeclampsia. Our study provided the first evidence that genetic variations in inflammatory mediator genes IL-1R1, IL-6R, TNFSF11, and IL-5RA were associated with preeclampsia risk, and the risk varied by preeclampsia subtypes. PMID- 27481923 TI - Potential Role of Prenatal Inflammation in the Impairment of Lung Development Following Mechanical Ventilation of Preterm Lambs. AB - BACKGROUND: Our objective was to determine the effects of severe fetal inflammation, associated with an increase in the number and activation state of fetal polymorphonuclear leukocytes (PMNLs), on postnatal lung development in mechanically ventilated preterm lambs. METHODS: Four groups of preterm fetal sheep (0.85 term) were surgically prepared: (1) a granulocyte-colony stimulating factor (GCSF) group received intravenous GCSF to increase fetal PMNL count, (2) a lipopolysaccharide (LPS) group received intra-amniotic LPS to activate the fetal PMNLs, (3) a GCSF + LPS group received both GCSF and LPS, and (4) a control group received saline. After 10-day mechanical ventilation following preterm delivery, the lungs were examined histologically and analyzed morphometrically. RESULTS: Compared to the control group, the GCSF + LPS group exhibited necrotizing funisitis, lower surface density of alveolar walls, lower numerical density of alveoli, greater alveolar radius, and lower volume density of secondary septal crests (all P < .05). There was no evidence of tissue destruction, or elastin fragmentation or thick deposits of elastin, in the alveolar walls in any of the 4 groups. CONCLUSION: The mechanical ventilation following severe prenatal inflammation did not lead to overt lung injury or degradation of elastin but resulted in arrested alveolarization in the lungs of preterm lambs. PMID- 27481924 TI - How Does Tobacco Smoke Affect Fetal Growth Potential in the First Trimester of Pregnancy as Measured by Volume Parameters of the Fetus, Trophoblast, and Gestational Sac? AB - We aimed to assess if tobacco smoke, as measured by the serum concentration of cotinine and blood concentration of cadmium, influences the fetal, sac, and trophoblast volume in the first trimester of pregnancy. We enrolled women in weeks 11 to 14 of pregnancy: 35 smokers, 24 passive smokers, and 98 nonsmoking healthy women. We found that the fetus volume was similar in all groups (18.70 +/ 6.29, 17.11 +/- 5.4, 18.97 +/- 7.55 cm3). The trophoblast was significantly smallest in smokers (50.27 +/- 19.56, 56.71 +/- 23.50, 61.95 +/- 22.94 cm3). The trophoblast volume was correlated with cotinine and cadmium concentration ( r = 0.54, r = -0.44). In passive smokers, gestational sac and trophoblast volume grew systematically and were correlated with the mean parental height. In smokers, only the gestational sac grew systematically and was correlated with the mean parental height. The fetus volume was independent of mean parental height and intensity of exposure to tobacco smoke. Volumetric changes of the fetus, trophoblast, and sac may be observed in the first trimester; however, their consequences require further research. PMID- 27481925 TI - Comparative Subcellular Localization Analysis of Magnetosome Proteins Reveals a Unique Localization Behavior of Mms6 Protein onto Magnetite Crystals. AB - The magnetosome is an organelle specialized for inorganic magnetite crystal synthesis in magnetotactic bacteria. The complex mechanism of magnetosome formation is regulated by magnetosome proteins in a stepwise manner. Protein localization is a key step for magnetosome development; however, a global study of magnetosome protein localization remains to be conducted. Here, we comparatively analyzed the subcellular localization of a series of green fluorescent protein (GFP)-tagged magnetosome proteins. The protein localizations were categorized into 5 groups (short-length linear, middle-length linear, long length linear, cell membrane, and intracellular dispersing), which were related to the protein functions. Mms6, which regulates magnetite crystal growth, localized along magnetosome chain structures under magnetite-forming (microaerobic) conditions but was dispersed in the cell under nonforming (aerobic) conditions. Correlative fluorescence and electron microscopy analyses revealed that Mms6 preferentially localized to magnetosomes enclosing magnetite crystals. We suggest that a highly organized spatial regulation mechanism controls magnetosome protein localization during magnetosome formation in magnetotactic bacteria. IMPORTANCE: Magnetotactic bacteria synthesize magnetite (Fe3O4) nanocrystals in a prokaryotic organelle called the magnetosome. This organelle is formed using various magnetosome proteins in multiple steps, including vesicle formation, magnetosome alignment, and magnetite crystal formation, to provide compartmentalized nanospaces for the regulation of iron concentrations and redox conditions, enabling the synthesis of a morphologically controlled magnetite crystal. Thus, to rationalize the complex organelle development, the localization of magnetosome proteins is considered to be highly regulated; however, the mechanisms remain largely unknown. Here, we performed comparative localization analysis of magnetosome proteins that revealed the presence of a spatial regulation mechanism within the linear structure of magnetosomes. This discovery provides evidence of a highly regulated protein localization mechanism for this bacterial organelle development. PMID- 27481926 TI - Identification and Characterization of a Putative Manganese Export Protein in Vibrio cholerae. AB - Manganese plays an important role in the cellular physiology and metabolism of bacterial species, including the human pathogen Vibrio cholerae The intracellular level of manganese ions is controlled through coordinated regulation of the import and export of this element. We have identified a putative manganese exporter (VC0022), named mneA (manganese exporter A), which is highly conserved among Vibrio spp. An mneA mutant exhibited sensitivity to manganese but not to other cations. Under high-manganese conditions, the mneA mutant showed an almost 50-fold increase in intracellular manganese levels and reduced intracellular iron relative to those of its wild-type parent, suggesting that the mutant's manganese sensitivity is due to the accumulation of toxic levels of manganese and reduced iron. Expression of mneA suppressed the manganese-sensitive phenotype of an Escherichia coli strain carrying a mutation in the nonhomologous manganese export gene, mntP, further supporting a manganese export function for V. cholerae MneA. The level of mneA mRNA was induced approximately 2.5-fold after addition of manganese to the medium, indicating regulation of this gene by manganese. This study offers the first insights into understanding manganese homeostasis in this important pathogen. IMPORTANCE: Bacterial cells control intracellular metal concentrations by coordinating acquisition in metal-limited environments with export in metal-excess environments. We identified a putative manganese export protein, MneA, in Vibrio cholerae An mneA mutant was sensitive to manganese, and this effect was specific to manganese. The mneA mutant accumulated high levels of intracellular manganese with a concomitant decrease in intracellular iron levels when grown in manganese-supplemented medium. Expression of mneA in trans suppressed the manganese sensitivity of an E. coli mntP mutant. This study is the first to investigate manganese export in V. cholerae. PMID- 27481927 TI - Unexpected Diversity of Escherichia coli Sialate O-Acetyl Esterase NanS. AB - The sialic acids (N-acylneuraminates) are a group of nine-carbon keto-sugars existing mainly as terminal residues on animal glycoprotein and glycolipid carbohydrate chains. Bacterial commensals and pathogens exploit host sialic acids for nutrition, adhesion, or antirecognition, where N-acetyl- or N glycolylneuraminic acids are the two predominant chemical forms of sialic acids. Each form may be modified by acetyl esters at carbon position 4, 7, 8, or 9 and by a variety of less-common modifications. Modified sialic acids produce challenges for colonizing bacteria, because the chemical alterations to N acetylneuraminic acid (Neu5Ac) confer increased resistance to sialidase and aldolase activities essential for the catabolism of host sialic acids. Bacteria with O-acetyl sialate esterase(s) utilize acetylated sialic acids for growth, thereby gaining a presumed metabolic advantage over competitors lacking this activity. Here, we demonstrate the esterase activity of Escherichia coli NanS after purifying it as a C-terminal HaloTag fusion. Using a similar approach, we show that E. coli strain O157:H7 Stx prophage or prophage remnants invariably include paralogs of nanS often located downstream of the Shiga-like toxin genes. These paralogs may include sequences encoding N- or C-terminal domains of unknown function where the NanS domains can act as sialate O-acetyl esterases, as shown by complementation of an E. coli strain K-12 nanS mutant and the unimpaired growth of an E. coli O157 nanS mutant on O-acetylated sialic acid. We further demonstrate that nanS homologs in Streptococcus spp. also encode active esterase, demonstrating an unexpected diversity of bacterial sialate O-acetyl esterase. IMPORTANCE: The sialic acids are a family of over 40 naturally occurring 9-carbon keto-sugars that function in a variety of host-bacterium interactions. These sugars occur primarily as terminal carbohydrate residues on host glycoproteins and glycolipids. Available evidence indicates that diverse bacterial species use host sialic acids for adhesion or as sources of carbon and nitrogen. Our results show that the catabolism of the diacetylated form of host sialic acid requires a specialized esterase, NanS. Our results further show that nanS homologs exist in bacteria other than Escherichia coli, as well as part of toxigenic E. coli prophage. The unexpected diversity of these enzymes suggests new avenues for investigating host-bacterium interactions. Therefore, these original results extend our previous studies of nanS to include mucosal pathogens, prophage, and prophage remnants. This expansion of the nanS superfamily suggests important, although as-yet-unknown, functions in host-microbe interactions. PMID- 27481931 TI - Are Changes in Self-Rated Health Associated With Memory Decline in Older Adults? AB - OBJECTIVE: The association between patterns of change in self-rated health (SRH) and memory trajectories in older adults was examined using a systematic approach. METHOD: Data from the Health and Retirement Study ( n = 6,016) and the English Longitudinal Study of Ageing ( n = 734) were analyzed. Individuals were grouped into five categories according to their pattern of change in SRH over 8 years: stable excellent/very good/good, stable fair/poor, improvement, decline, and fluctuating pattern without a trend. Memory was measured using immediate and delayed recall tests. Kruskal-Wallis, chi-squares tests, and linear mixed models were used to examine the association. RESULTS: Different rates of decline in memory can be identified in the different patterns of change in SRH. Those who had a stable excellent/very good/good pattern had the slowest rate of decline. DISCUSSION: Our findings suggest that SRH status and patterns of change could be used as a marker of cognitive decline in prevention screening programs. PMID- 27481930 TI - Interaction of Erp Protein of Mycobacterium tuberculosis with Rv2212 Enhances Intracellular Survival of Mycobacterium smegmatis. AB - The Mycobacterium tuberculosis exported repetitive protein (RvErp) is a crucial virulence-associated factor as determined by its role in the survival and multiplication of mycobacteria in cultured macrophages and in vivo Although attempts have been made to understand the function of Erp protein, its exact role in Mycobacterium pathogenesis is still elusive. One way to determine this is by searching for novel interactions of RvErp. Using a yeast two-hybrid assay, an adenylyl cyclase (AC), Rv2212, was found to interact with RvErp. The interaction between RvErp and Rv2212 is direct and occurs at the endogenous level. The Erp protein of Mycobacterium smegmatis (MSMEG_6405, or MsErp) interacts neither with Rv2212 nor with Ms_4279, the M. smegmatis homologue of Rv2212. Deletion mutants of Rv2212 revealed its adenylyl cyclase domain to be responsible for the interaction. RvErp enhances Rv2212-mediated cyclic AMP (cAMP) production. Also, the biological significance of the interaction between RvErp and Rv2212 was demonstrated by the enhanced survival of M. smegmatis within THP-1 macrophages. Taken together, these studies address a novel mechanism by which Erp executes its function. IMPORTANCE: RvErp is one of the important virulence factors of M. tuberculosis This study describes a novel function of RvErp protein of M. tuberculosis by identifying Rv2212 as its interacting protein. Rv2212 is an adenylyl cyclase (AC) and produces cAMP, one of the prime second messengers that regulate the intracellular survival of mycobacteria. Therefore, the significance of investigating novel interactions of RvErp is paramount in unraveling the mechanisms governing the intracellular survival of mycobacteria. PMID- 27481928 TI - Large Sequence Diversity within the Biosynthesis Locus and Common Biochemical Features of Campylobacter coli Lipooligosaccharides. AB - Despite the importance of lipooligosaccharides (LOSs) in the pathogenicity of campylobacteriosis, little is known about the genetic and phenotypic diversity of LOS in Campylobacter coli In this study, we investigated the distribution of LOS locus classes among a large collection of unrelated C. coli isolates sampled from several different host species. Furthermore, we paired C. coli genomic information and LOS chemical composition for the first time to investigate possible associations between LOS locus class sequence diversity and biochemical heterogeneity. After identifying three new LOS locus classes, only 85% of the 144 isolates tested were assigned to a class, suggesting higher genetic diversity than previously thought. This genetic diversity is at the basis of a completely unexplored LOS structural heterogeneity. Mass spectrometry analysis of the LOSs of nine isolates, representing four different LOS classes, identified two features distinguishing C. coli LOS from that of Campylobacter jejuni 2-Amino-2 deoxy-d-glucose (GlcN)-GlcN disaccharides were present in the lipid A backbone, in contrast to the beta-1'-6-linked 3-diamino-2,3-dideoxy-d-glucopyranose (GlcN3N)-GlcN backbone observed in C. jejuni Moreover, despite the fact that many of the genes putatively involved in 3-acylamino-3,6-dideoxy-d-glucose (Quip3NAcyl) were apparently absent from the genomes of various isolates, this rare sugar was found in the outer core of all C. coli isolates. Therefore, regardless of the high genetic diversity of the LOS biosynthesis locus in C. coli, we identified species-specific phenotypic features of C. coli LOS that might explain differences between C. jejuni and C. coli in terms of population dynamics and host adaptation. IMPORTANCE: Despite the importance of C. coli to human health and its controversial role as a causative agent of Guillain-Barre syndrome, little is known about the genetic and phenotypic diversity of C. coli LOSs. Therefore, we paired C. coli genomic information and LOS chemical composition for the first time to address this paucity of information. We identified two species-specific phenotypic features of C. coli LOS, which might contribute to elucidating the reasons behind the differences between C. jejuni and C. coli in terms of population dynamics and host adaptation. PMID- 27481929 TI - Effects of tcpB Mutations on Biogenesis and Function of the Toxin-Coregulated Pilus, the Type IVb Pilus of Vibrio cholerae. AB - Vibrio cholerae is the etiological agent of the acute intestinal disorder cholera. The toxin-coregulated pilus (TCP), a type IVb pilus, is an essential virulence factor of V. cholerae Recent work has shown that TcpB is a large minor pilin encoded within the tcp operon. TcpB contributes to efficient pilus formation and is essential for all TCP functions. Here, we have initiated a detailed targeted mutagenesis approach to further characterize this salient TCP component. We have identified (thus far) 20 residues of TcpB which affect either the steady-state level of TcpB or alter one or more TCP functions. This study provides a solid framework for further understanding of the complex role of TcpB and will be of use upon determination of the crystal structure of TcpB or related minor pilin orthologs of type IVb pilus systems. IMPORTANCE: Type IV pili, such as the toxin-coregulated pilus (TCP) in V. cholerae, are bacterial appendages that often act as essential virulence factors. Minor pilins, like TcpB, of these pili systems often play integral roles in pilus assembly and function. In this study, we have generated mutations in tcpB to determine residues of importance for TCP stability and function. Combined with a predicted tertiary structure, characterization of these mutants allows us to better understand critical residues in TcpB and the role they may play in the mechanisms underlying minor pilin functions. PMID- 27481932 TI - Health in the Neighborhood and Household Contexts Among Older Chinese Americans. AB - OBJECTIVE: This study examined the associations of neighborhood characteristics and living arrangements with physical and mental health among older Chinese Americans. METHOD: A sample of 3,159 community-dwelling Chinese older adults in the Greater Chicago area provided reports of health, socio-demographic characteristics, living arrangements, social cohesion, and neighborhood disorder. We used multinomial logistic, Poisson, and negative binominal regression analyses. RESULTS: Neighborhood disorder was consistently associated with negative health indicators, including poor self-reported health, more chronic conditions, depressive symptoms, and anxiety symptoms. Findings about the relationships between social cohesion and health indicators were mixed. Social cohesion was more salient to mental health for those living with spouse, children, and/or grandchildren relative to those living with spouse only. DISCUSSION: Policies and interventions are needed to improve the physical and social environments of neighborhoods and to promote healthy aging among Chinese older adults and in the general population as well. PMID- 27481933 TI - Recurrent Swelling of the Lower Extremity in an Adolescent Female. PMID- 27481934 TI - A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo dG. AB - 8-oxo-7,8-dihydroxy-2'-deoxyguanosine (8-oxo-dG) has high mutagenic potential as it is prone to mispair with deoxyadenine (dA). In order to maintain genomic integrity, post-replicative 8-oxo-dG:dA mispairs are removed through DNA polymerase lambda (Pol lambda)-dependent MUTYH-initiated base excision repair (BER). Here, we describe seven novel crystal structures and kinetic data that fully characterize 8-oxo-dG bypass by Pol lambda. We demonstrate that Pol lambda has a flexible active site that can tolerate 8-oxo-dG in either the anti- or syn conformation. Importantly, we show that discrimination against the pro-mutagenic syn-conformation occurs at the extension step and identify the residue responsible for this selectivity. This residue acts as a kinetic switch, shunting repair toward long-patch BER upon correct dCMP incorporation, thus enhancing repair efficiency. Moreover, this switch also provides a potential mechanism to increase repair fidelity of MUTYH-initiated BER. PMID- 27481938 TI - Editorial: The mysteries of the spleen. PMID- 27481935 TI - The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. AB - We explore mechanisms that enable cancer cells to tolerate PI3K or Akt inhibitors. Prolonged treatment of breast cancer cells with PI3K or Akt inhibitors leads to increased expression and activation of a kinase termed SGK3 that is related to Akt. Under these conditions, SGK3 is controlled by hVps34 that generates PtdIns(3)P, which binds to the PX domain of SGK3 promoting phosphorylation and activation by its upstream PDK1 activator. Furthermore, under conditions of prolonged PI3K/Akt pathway inhibition, SGK3 substitutes for Akt by phosphorylating TSC2 to activate mTORC1. We characterise 14h, a compound that inhibits both SGK3 activity and activation in vivo, and show that a combination of Akt and SGK inhibitors induced marked regression of BT-474 breast cancer cell derived tumours in a xenograft model. Finally, we present the kinome-wide analysis of mRNA expression dynamics induced by PI3K/Akt inhibition. Our findings highlight the importance of the hVps34-SGK3 pathway and suggest it represents a mechanism to counteract inhibition of PI3K/Akt signalling. The data support the potential of targeting both Akt and SGK as a cancer therapeutic. PMID- 27481937 TI - A systematic review of high quality randomized controlled trials investigating motor skill programmes for children with developmental coordination disorder. AB - OBJECTIVE: To identify effective motor training interventions for children with developmental coordination disorder from research graded as high quality (using objective criteria) for the purpose of informing evidence-based clinical practice. DATA SOURCES: We followed the guidance for conducting systematic reviews issued by the Centre for Reviews and Dissemination. Six OvidSP electronic databases (AMED, All EBM reviews (including Cochrane), Embase, Ovid MEDLINE, PsychARTICLES Full Text, PsycINFO) were searched systematically. We aimed to retain only randomized control trials and systematic reviews of randomized control trials, defined as the highest level of evidence by the Oxford Centre for Evidence-Based Medicine. We searched reference lists of retained articles to identify further appropriate articles. REVIEW METHODS: Two reviewers critically appraised and categorized articles by effect size (including confidence intervals), inclusion of power calculations and quality using the Physiotherapy Evidence Database (PEDro) scale. Only studies scoring seven or more on the PEDro scale (classed by the PEDro as high reliability) were retained. RESULTS: No systematic reviews met our criteria for inclusion from 846 articles yielded by the systematic search. Nine randomized control trials investigating 15 interventions to improve motor skills met our inclusion criteria for 'high quality'. Nevertheless, not all included studies were adequately powered for determining an effect. CONCLUSION: Large effect sizes associated with 95 % confidence intervals suggest that 'Neuromotor Task Training', 'Task-oriented Motor Training' and 'Motor Imagery + Task Practice Training' are the most effective reported interventions for improving motor skills in children with developmental coordination disorder. PMID- 27481936 TI - Glymphatic clearance controls state-dependent changes in brain lactate concentration. AB - Brain lactate concentration is higher during wakefulness than in sleep. However, it is unknown why arousal is linked to an increase in brain lactate and why lactate declines within minutes of sleep. Here, we show that the glymphatic system is responsible for state-dependent changes in brain lactate concentration. Suppression of glymphatic function via acetazolamide treatment, cisterna magna puncture, aquaporin 4 deletion, or changes in body position reduced the decline in brain lactate normally observed when awake mice transition into sleep or anesthesia. Concurrently, the same manipulations diminished accumulation of lactate in cervical, but not in inguinal lymph nodes when mice were anesthetized. Thus, our study suggests that brain lactate is an excellent biomarker of the sleep-wake cycle and increases further during sleep deprivation, because brain lactate is inversely correlated with glymphatic-lymphatic clearance. This analysis provides fundamental new insight into brain energy metabolism by demonstrating that glucose that is not fully oxidized can be exported as lactate via glymphatic-lymphatic fluid transport. PMID- 27481939 TI - The relationship between non-HDL cholesterol and macrophage phenotypes in human adipose tissue. AB - Data from experimental animal models and in vitro studies suggest that both hyperlipoproteinemia and obesity predispose to development of proinflammatory pathways of macrophages within adipose tissue. The aim of this study was to analyze whether non-HDL cholesterol concentration in healthy living kidney donors (LKDs) is related to the number and phenotype of proinflammatory macrophages in visceral and subcutaneous adipose tissue. Adipose tissue samples were collected by cleansing the kidney grafts of LKDs obtained peroperatively. The stromal vascular fractions of these tissues were analyzed by flow cytometry. Proinflammatory macrophages were defined as CD14+ cells coexpressing CD16+ and high-expression CD36 as well (CD14+CD16+CD36+++), while CD16 negativity and CD163 positivity identified alternatively stimulated, anti-inflammatory macrophages. Non-HDL cholesterol concentration positively correlated to proinflammatory macrophages within visceral adipose tissue, with increased strength with more precise phenotype determination. On the contrary, the proportion of alternatively stimulated macrophages correlated negatively with non-HDL cholesterol. The present study suggests a relationship of non-HDL cholesterol concentration to the number and phenotype proportion of macrophages in visceral adipose tissue of healthy humans. PMID- 27481940 TI - Blunting Autoantigen-induced FOXO3a Protein Phosphorylation and Degradation Is a Novel Pathway of Glucocorticoids for the Treatment of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting multiple organs. Glucocorticoids (GCs), the potent anti-inflammatory drugs, remain as a cornerstone in the treatment for SLE; nevertheless, their clinical efficacy is compromised by the side effects of long term treatment and resistance. To improve the therapeutic efficacy of GCs in SLE, it is important to further decipher the molecular mechanisms of how GCs exert their anti inflammatory effects. In this investigation, FOXO3a was identified as a molecule that was down-regulated in the course of SLE. Of interest, GC treatment was found to rescue FOXO3a expression both in SLE mice and in SLE patients. Gain- and loss of-function studies demonstrated that FOXO3a played a crucial role in GC treatment of SLE via inhibiting inflammatory responses. Further studies showed that the up-regulation of FOXO3a by GCs relied on the suppression of pI3K/AKT mediated FOXO3a phosphorylation and the arrest of FOXO3a in the nucleus. Finally, our data revealed that FOXO3a was critical for GC-mediated inhibition of NF kappaB activity, which might involve its interaction with NF-kappaB p65 protein. Collectively, these data indicated that FOXO3a played an important role in GC treatment of SLE by suppressing pro-inflammatory response, and targeting FOXO3a might provide a novel therapeutic strategy against SLE. PMID- 27481942 TI - S-Palmitoylation of a Novel Site in the beta2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary. AB - We report here that a population of human beta2-adrenergic receptors (beta2AR), a canonical G protein-coupled receptor, traffics along a previously undescribed intracellular itinerary via the Golgi complex that is associated with the sequential S-palmitoylation and depalmitoylation of a previously undescribed site of modification, Cys-265 within the third intracellular loop. Basal S palmitoylation of Cys-265 is negligible, but agonist-induced beta2AR activation results in enhanced S-palmitoylation, which requires phosphorylation by the cAMP dependent protein kinase of Ser-261/Ser-262. Agonist-induced turnover of palmitate occurs predominantly on Cys-265. Cys-265 S-palmitoylation is mediated by the Golgi-resident palmitoyl transferases zDHHC9/14/18 and is followed by depalmitoylation by the plasma membrane-localized acyl-protein thioesterase APT1. Inhibition of depalmitoylation reveals that S-palmitoylation of Cys-265 may stabilize the receptor at the plasma membrane. In addition, beta2AR S palmitoylated at Cys-265 are selectively preserved under a sustained adrenergic stimulation, which results in the down-regulation and degradation of betaAR. Cys 265 is not conserved in beta1AR, and S-palmitoylation of Cys-265 may thus be associated with functional differences between beta2AR and beta1AR, including relative resistance of beta2AR to down-regulation in multiple pathophysiologies. Trafficking via the Golgi complex may underlie new roles in G protein-coupled receptor biology. PMID- 27481941 TI - Functional Rescue of a Misfolded Drosophila melanogaster Dopamine Transporter Mutant Associated with a Sleepless Phenotype by Pharmacological Chaperones. AB - Folding-defective mutants of the human dopamine transporter (DAT) cause a syndrome of infantile dystonia/parkinsonism. Here, we provide a proof-of principle that the folding deficit is amenable to correction in vivo by two means, the cognate DAT ligand noribogaine and the HSP70 inhibitor, pifithrin-MU. We examined the Drosophila melanogaster (d) mutant dDAT-G108Q, which leads to a sleepless phenotype in flies harboring this mutation. Molecular dynamics simulations suggested an unstable structure of dDAT-G108Q consistent with a folding defect. This conjecture was verified; heterologously expressed dDAT-G108Q and the human (h) equivalent hDAT-G140Q were retained in the endoplasmic reticulum in a complex with endogenous folding sensors (calnexin and HSP70-1A). Incubation of the cells with noribogaine (a DAT ligand selective for the inward facing state) and/or pifithrin-MU (an HSP70 inhibitor) restored folding of, and hence dopamine transport by, dDAT-G108Q and hDAT-G140Q. The mutated versions of DAT were confined to the cell bodies of the dopaminergic neurons in the fly brain and failed to reach the axonal compartments. Axonal delivery was restored, and sleep time was increased to normal length (from 300 to 1000 min/day) if the dDAT G108Q-expressing flies were treated with noribogaine and/or pifithrin-MU. Rescuing misfolded versions of DAT by pharmacochaperoning is of therapeutic interest; it may provide opportunities to remedy disorders arising from folding defective mutants of human DAT and of other related SLC6 transporters. PMID- 27481943 TI - Novel Biochemical and Structural Insights into the Interaction of Myristoylated Cargo with Unc119 Protein and Their Release by Arl2/3. AB - Primary cilia are highly specialized small antenna-like cellular protrusions that extend from the cell surface of many eukaryotic cell types. The protein content inside cilia and cytoplasm is very different, but details of the sorting process are not understood for most ciliary proteins. Recently, we have shown that prenylated proteins are sorted according to their affinity to the carrier protein PDE6delta and the ability of Arl3 but not Arl2 to release high affinity cargo inside the cilia (Fansa, E. K., Kosling, S. K., Zent, E., Wittinghofer, A., and Ismail, S. (2016) Nat. Commun. 7, 11366). Here we address the question whether a similar principle governs the transport of myristoylated cargo by the carrier proteins Unc119a and Unc119b. We thus analyzed the binding strength of N-terminal myristoylated cargo peptides (GNAT1, NPHP3, Cystin1, RP2, and Src) to Unc119a and Unc119b proteins. The affinity between myristoylated cargo and carrier protein, Unc119, varies between subnanomolar and micromolar. Peptides derived from ciliary localizing proteins (GNAT1, NPHP3, and Cystin1) bind with high affinity to Unc119 proteins, whereas a peptide derived from a non-ciliary localizing protein (Src) has low affinity. The peptide with intermediate affinity (RP2) is localized at the ciliary transition zone as a gate keeper. We show that the low affinity peptides are released by both Arl2.GppNHp and Arl3.GppNHp, whereas the high affinity peptides are exclusively released by only Arl3.GppNHp. Determination of the x-ray structure of myristoylated NPHP3 peptide in complex with Unc119a reveals the molecular details of high affinity binding and suggests the importance of the residues at the +2 and +3 positions relative to the myristoylated glycine for high and low affinities. The mutational analysis of swapping the residues at the +2 and +3 positions between high and low affinity peptides results in reversing their affinities for Unc119a and leads to a partial mislocalization of a low affinity mutant of NPHP3. PMID- 27481944 TI - Lateral Mobility and Nanoscale Spatial Arrangement of Chemokine-activated alpha4beta1 Integrins on T Cells. AB - Chemokine stimulation of integrin alpha4beta1-dependent T lymphocyte adhesion is a key step during lymphocyte trafficking. A central question regarding alpha4beta1 function is how its lateral mobility and organization influence its affinity and avidity following cell stimulation with chemokines and/or ligands. Using single particle tracking and superresolution imaging approaches, we explored the lateral mobility and spatial arrangement of individual alpha4beta1integrins on T cells exposed to different activating stimuli. We show that CXCL12 stimulation leads to rapid and transient alpha4beta1activation, measured by induction of the activation epitope recognized by the HUTS-21 anti beta1antibody and by increased talin-beta1 association. CXCL12-dependent alpha4beta1 activation directly correlated with restricted lateral diffusion and integrin immobilization. Moreover, co-stimulation by CXCL12 together with soluble VCAM-1 potentiated integrin immobilization with a 5-fold increase in immobile integrins compared with unstimulated conditions. Our data indicate that docking by talin of the chemokine-activated alpha4beta1 to the actin cytoskeleton favors integrin immobilization, which likely facilitates ligand interaction and increased adhesiveness. Superresolution imaging showed that the nanoscale organization of high-affinity alpha4beta1 remains unaffected following chemokine and/or ligand addition. Instead, newly activated alpha4beta1 integrins organize on the cell membrane as independent units without joining pre-established integrin sites to contribute to cluster formation. Altogether, our results provide a rationale to understand how the spatiotemporal organization of activated alpha4beta1 integrins regulates T lymphocyte adhesion. PMID- 27481946 TI - PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs). AB - Downstream of receptor tyrosine kinase and G protein-coupled receptor (GPCR) stimulation, the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchange factor (PREX) family of guanine nucleotide exchange factors (GEFs) activates Rho GTPases, leading to important roles for PREX proteins in numerous cellular processes and diseases, including cancer. PREX1 and PREX2 GEF activity is activated by the second messengers PIP3 and Gbetagamma, and further regulation of PREX GEF activity occurs by phosphorylation. Stimulation of receptor tyrosine kinases by neuregulin and insulin-like growth factor 1 (IGF1) leads to the phosphorylation of PREX1; however, the kinases that phosphorylate PREX1 downstream of these ligands are not known. We recently reported that the p21 activated kinases (PAKs), which are activated by GTP-bound Ras-related C3 botulinum toxin substrate 1 (Rac1), mediate the phosphorylation of PREX2 after insulin receptor activation. Here we show that certain phosphorylation events on PREX1 after insulin, neuregulin, and IGF1 treatment are PAK-dependent and lead to a reduction in PREX1 binding to PIP3 Like PREX2, PAK-mediated phosphorylation also negatively regulates PREX1 GEF activity. Furthermore, the onset of PREX1 phosphorylation was delayed compared with the phosphorylation of AKT, supporting a model of negative feedback downstream of PREX1 activation. We also found that the phosphorylation of PREX1 after isoproterenol and prostaglandin E2-mediated GPCR activation is partially PAK-dependent and likely also involves protein kinase A, which is known to reduce PREX1 function. Our data point to multiple mechanisms of PREX1 negative regulation by PAKs within receptor tyrosine kinase and GPCR-stimulated signaling pathways that have important roles in diseases such as diabetes and cancer. PMID- 27481947 TI - Executive Summary: Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. AB - It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. PMID- 27481948 TI - How Public-Private Collaborations Are Driving Solutions to the Antibacterial Drug Development Crisis. PMID- 27481945 TI - Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins: A SYSTEMATIC APPROACH TOWARD SELECTIVE INACTIVATION OF RHO FAMILY PROTEINS. AB - RHO GTPase-activating proteins (RHOGAPs) are one of the major classes of regulators of the RHO-related protein family that are crucial in many cellular processes, motility, contractility, growth, differentiation, and development. Using database searches, we extracted 66 distinct human RHOGAPs, from which 57 have a common catalytic domain capable of terminating RHO protein signaling by stimulating the slow intrinsic GTP hydrolysis (GTPase) reaction. The specificity of the majority of the members of RHOGAP family is largely uncharacterized. Here, we comprehensively investigated the sequence-structure-function relationship between RHOGAPs and RHO proteins by combining our in vitro data with in silico data. The activity of 14 representatives of the RHOGAP family toward 12 RHO family proteins was determined in real time. We identified and structurally verified hot spots in the interface between RHOGAPs and RHO proteins as critical determinants for binding and catalysis. We have found that the RHOGAP domain itself is nonselective and in some cases rather inefficient under cell-free conditions. Thus, we propose that other domains of RHOGAPs confer substrate specificity and fine-tune their catalytic efficiency in cells. PMID- 27481949 TI - Facilitating Antibacterial Drug Development in a Time of Great Need. AB - The continued development of new antibacterial drugs is critical to meet patient and public health needs. In this editorial, authors from the US Food and Drug Administration and European Medicines Agency reflect on the role of public private partnerships and the development of clinical trials networks as agents to guide and perform quality studies of antibacterial drugs. PMID- 27481951 TI - Advancing New Antibacterial Drug Development for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia. AB - The Clinical Trials Transformation Initiative (CTTI), a public-private partnership comprised of representatives from academia, the pharmaceutical industry, and the federal government including the US Food and Drug Administration, formed a group working toward a common goal of intensified research to facilitate the development of new antibacterial drug therapies for treatment of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). The summary of the CTTI HABP/VABP project in this supplement of Clinical Infectious Diseases is a first step in this direction. PMID- 27481950 TI - Improving Conduct and Feasibility of Clinical Trials to Evaluate Antibacterial Drugs to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team. AB - BACKGROUND: The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. RESULTS: CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. CONCLUSIONS: Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development. PMID- 27481952 TI - Streamlining Safety Data Collection in Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Trials: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team. AB - BACKGROUND: Resistant bacteria are one of the leading causes of hospital acquired/ventilator-associated bacterial pneumonia (HABP/VABP). HABP/VABP trials are complex and difficult to conduct due to the large number of medical procedures, adverse events, and concomitant medications involved. Differences in the legislative frameworks between different regions of the world may also lead to excessive data collection. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development (ABDD) by streamlining clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with current data collection processes. Experts defined "data collection" as the act of capturing and reporting certain data on the case report form as opposed to recording of data as part of routine clinical care. The ABDD Project Team developed strategies for streamlining safety data collection in HABP/VABP trials using a Quality by Design approach. RESULTS: Current safety data collection processes in HABP/VABP trials often include extraneous information. More targeted strategies for safety data collection in HABP/VABP trials will rely on optimal protocol design and prespecification of which safety data are essential to satisfy regulatory reporting requirements. CONCLUSIONS: A consensus and a cultural change in clinical trial design and conduct, which involve recognition of the need for more efficient data collection, are urgently needed to advance ABDD and to improve HABP/VABP trials in particular. PMID- 27481953 TI - The SAATELLITE and EVADE Clinical Studies Within the COMBACTE Consortium: A Public-Private Collaborative Effort in Designing and Performing Clinical Trials for Novel Antibacterial Drugs to Prevent Nosocomial Pneumonia. AB - The Innovative Medicines Initiative-funded COMBACTE consortium fosters academic industry partnership in pioneering studies to combat serious bacterial infections. We describe how this partnership is advancing the development of 2 monoclonal antibodies, MEDI4893 and MEDI3902, for the prevention of nosocomial pneumonia. PMID- 27481954 TI - Patient-Reported Outcome Assessments as Endpoints in Studies in Infectious Diseases. AB - The goal of administering medical interventions is to help patients live longer or live better. In keeping with this goal, there has been increasing interest in taking the "voice" of the patient into account during the development process, specifically in the evaluation of treatment benefits of medical interventions, and use of patient-centered outcome data to justify reimbursement. Patient reported outcomes (PROs) are outcome assessments (OAs) used to define endpoints that can provide direct evidence of treatment benefit on how patients feel or function. When PROs are appropriately developed, they can increase the efficiency and clinical relevance of clinical trials. Several PROs have been developed for OA in specific infectious diseases indications, and more are under development. PROs also hold promise for use in evaluating adherence, adverse effects, satisfaction with care, and routine clinical practice. PMID- 27481955 TI - Efficient Delivery of Investigational Antibacterial Agents via Sustainable Clinical Trial Networks. AB - The economics of antibiotics can be improved by infectious diseases-specific clinical trial networks. While developers would still need to implement an independent phase 1 program as well as studies focused on highly resistant pathogens, standardized procedures in a network focused on usual drug resistance phenotype isolates would permit sharing of controls and would predictably generate high-quality pivotal data for product registration while creating cost and time savings in the range of 30%-40%. This would reduce economic barriers to antibiotic development and contribute to public health. PMID- 27481957 TI - Uncharted Waters. PMID- 27481958 TI - Continuity of care: still important in modern-day general practice. PMID- 27481959 TI - National audit of diabetes: why it matters to general practice. PMID- 27481960 TI - Understanding the needs of carers of people with psychosis in primary care. PMID- 27481956 TI - Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. AB - RATIONALE: Culture-expanded cells originating from cardiac tissue that express the cell surface receptor cKit are undergoing clinical testing as a cell source for heart failure and congenital heart disease. Although accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit(+) cells (CSCs), the underlying mechanism for this synergistic effect remains incompletely understood. OBJECTIVE: To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and stem cell factor/cKit pathways. METHODS AND RESULTS: Using genetic lineage-tracing approaches, we show that in the postnatal murine heart, cKit(+) cells proliferate, migrate, and form cardiomyocytes, but not endothelial cells. CSCs exhibit marked chemotactic and proliferative responses when cocultured with MSCs but not with cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 (an SDF1/CXCR4 antagonist) inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (P<0.0001). Furthermore, MSCs enhanced CSC proliferation via the stem cell factor/cKit and SDF1/CXCR4 pathways (P<0.0001). CONCLUSIONS: Together these findings show that MSCs exhibit profound, yet differential, effects on CSC migration, proliferation, and differentiation and suggest a mechanism underlying the improved cardiac regeneration associated with combination therapy using CSCs and MSCs. These findings have important therapeutic implications for cell-based therapy strategies that use mixtures of CSCs and MSCs. PMID- 27481961 TI - Mindlines: making sense of evidence in practice. PMID- 27481962 TI - Innovations in primary care to promote general practice as a career to medical students. PMID- 27481963 TI - Encouraging medical students to pursue general practice. PMID- 27481964 TI - Preventing radicalisation and terrorism: is there a GP response? PMID- 27481965 TI - Migrant health. PMID- 27481966 TI - Risk stratification for free. PMID- 27481967 TI - Interpretation of electrocardiograms in primary care. PMID- 27481968 TI - Correction. PMID- 27481969 TI - Reflections on medically unexplained symptoms in older people. PMID- 27481970 TI - Is general practice in the wrong PLACE? PMID- 27481971 TI - Health promotion at the heart of our communities: good for patients; good for doctors. PMID- 27481972 TI - Writing liver function test guidelines: how hard can it be? PMID- 27481973 TI - Diabetes: the danger of exercise. PMID- 27481974 TI - Grass is greener? General practice in England and Australia. PMID- 27481976 TI - Reducing general practice workload. PMID- 27481975 TI - Cognitive load theory and teaching in primary care. PMID- 27481977 TI - Yonder: Communication with hospitals, telemonitoring, chronic pain, and 'sexting'. PMID- 27481978 TI - Art: Tate Modern - The Switch House. PMID- 27481979 TI - BJGP Library: The Grapes of Wrath: Californian Displacement. PMID- 27481980 TI - Book: Love, Fear and Health: How Our Attachments to Others Shape Health and Health Care: It's Not You it's Me. PMID- 27481981 TI - Being replaced by a robot. PMID- 27481982 TI - Chronic fatigue syndrome: is the biopsychosocial model responsible for patient dissatisfaction and harm? PMID- 27481983 TI - Should GPs avoid making ethical judgements? PMID- 27481984 TI - Rationalising data use for general practice: a missed opportunity? PMID- 27481985 TI - Problems with erupting wisdom teeth: signs, symptoms, and management. PMID- 27481986 TI - Differentiating milk allergy (IgE and non-IgE mediated) from lactose intolerance: understanding the underlying mechanisms and presentations. PMID- 27481987 TI - The Problem with Gout Is That It's Still Such a Problem. PMID- 27481988 TI - A Comparison of CAROC and FRAX in Patients with Fragility Fracture. PMID- 27481989 TI - Giant Cell Arteritis: Visual Loss Is Our Major Concern. PMID- 27481990 TI - Pachydermodactyly: A Benign Cutaneous Condition that May Be Misdiagnosed as a Joint Disorder. PMID- 27481991 TI - Vitamin D Deficiency May Explain the Possible Link Between Gout and Erectile Dysfunction. PMID- 27481992 TI - Dr. Schlesinger replies. PMID- 27481993 TI - Bath Ankylosing Spondylitis Functional Index Shows Promising Reliability and Validity in the Assessment of Activity Limitations in Axial Spondyloarthritis. PMID- 27481994 TI - The Systemic Juvenile Idiopathic Arthritis Cohort of the Childhood Arthritis and Rheumatology Research Alliance Registry: 2010-2013. PMID- 27481997 TI - ERRATUM. PMID- 27481996 TI - ERRATUM. PMID- 27481995 TI - OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression. AB - OLA1, an Obg-family GTPase, has been implicated in eukaryotic initiation factor 2 (eIF2)-mediated translational control, but its physiological functions remain obscure. Here we report that mouse embryos lacking OLA1 have stunted growth, delayed development leading to immature organs-especially lungs-at birth, and frequent perinatal lethality. Proliferation of primary Ola1(-/-) mouse embryonic fibroblasts (MEFs) is impaired due to defective cell cycle progression, associated with reduced cyclins D1 and E1, attenuated Rb phosphorylation, and increased p21(Cip1/Waf1) Accumulation of p21 in Ola1(-/-) MEFs is due to enhanced mRNA translation and can be prevented by either reconstitution of OLA1 expression or treatment with an eIF2alpha dephosphorylation inhibitor, suggesting that OLA1 regulates p21 through a translational mechanism involving eIF2. With immunohistochemistry, overexpression of p21 protein was detected in Ola1-null embryos with reduced cell proliferation. Moreover, we have generated p21(-/-) Ola1(-/-) mice and found that knockout of p21 can partially rescue the growth retardation defect of Ola1(-/-) embryos but fails to rescue them from developmental delay and the lethality. These data demonstrate, for the first time, that OLA1 is required for normal progression of mammalian development. OLA1 plays an important role in promoting cell proliferation at least in part through suppression of p21 and organogenesis via factors yet to be discovered. PMID- 27481998 TI - Achieving the Full "PROMISE" of Imaging Outcomes Research. PMID- 27481999 TI - Connecting the Dots: From Big Data to Healthy Heart. PMID- 27482001 TI - The Challenge to Implement Systems of Care for ST-Segment-Elevation Myocardial Infarction. PMID- 27482000 TI - Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator. AB - BACKGROUND: Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sought to increase the proportion of patients treated within guideline goals by organizing coordinated regional reperfusion plans. METHODS: We established leadership teams, coordinated protocols, and provided regular feedback for 484 hospitals and 1253 emergency medical services (EMS) agencies in 16 regions across the United States. RESULTS: Between July 2012 and December 2013, 23 809 patients presented with acute STEMI (direct to percutaneous coronary intervention hospital: 11 765 EMS transported and 6502 self-transported; 5542 transferred). EMS-transported patients differed from self-transported patients in symptom onset to first medical contact time (median, 47 versus 114 minutes), incidence of cardiac arrest (10% versus 3%), shock on admission (11% versus 3%), and in hospital mortality (8% versus 3%; P<0.001 for all comparisons). There was a significant increase in the proportion of patients meeting guideline goals of first medical contact-to-device time, including those directly presenting via EMS (50% to 55%; P<0.001) and transferred patients (44%-48%; P=0.002). Despite regional variability, the greatest gains occurred among patients in the 5 most improved regions, increasing from 45% to 57% (direct EMS; P<0.001) and 38% to 50% (transfers; P<0.001). CONCLUSIONS: This Mission: Lifeline STEMI Systems Accelerator demonstration project represents the largest national effort to organize regional STEMI care. By focusing on first medical contact-to-device time, coordinated treatment protocols, and regional data collection and reporting, we were able to increase significantly the proportion of patients treated within guideline goals. PMID- 27482004 TI - Treatment of Higher-Risk Patients With an Indication for Revascularization: Evolution Within the Field of Contemporary Percutaneous Coronary Intervention. AB - Patients with severe coronary artery disease with a clinical indication for revascularization but who are at high procedural risk because of patient comorbidities, complexity of coronary anatomy, and/or poor hemodynamics represent an understudied and potentially underserved patient population. Through advances in percutaneous interventional techniques and technologies and improvements in patient selection, current percutaneous coronary intervention may allow appropriate patients to benefit safely from revascularization procedures that might not have been offered in the past. The burgeoning interest in these procedures in some respects reflects an evolutionary step within the field of percutaneous coronary intervention. However, because of the clinical complexity of many of these patients and procedures, it is critical to develop dedicated specialists within interventional cardiology who are trained with the cognitive and technical skills to select these patients appropriately and to perform these procedures safely. Preprocedural issues such as multidisciplinary risk and treatment assessments are highly relevant to the successful treatment of these patients, and knowledge gaps and future directions to improve outcomes in this emerging area are discussed. Ultimately, an evolution of contemporary interventional cardiology is necessary to treat the increasingly higher-risk patients with whom we are confronted. PMID- 27482002 TI - Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial. AB - BACKGROUND: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown. METHODS: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size. RESULTS: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (-5.8%, P=0.017), and noninfarct myocardial fibrosis (-5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy. CONCLUSIONS: Treatment of patients with acute myocardial infarction with high dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729430. PMID- 27482003 TI - Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia. AB - BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. RESULTS: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. CONCLUSIONS: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage. PMID- 27482006 TI - Letter by Hess et al Regarding Article, "How to Manage Occult Atrial Fibrillation Detected on Long-Term Monitoring". PMID- 27482007 TI - Response by Lip to Letter Regarding Article, "How to Manage Occult Atrial Fibrillation Detected on Long-Term Monitoring". PMID- 27482005 TI - Ultrafast Magnetic Resonance Imaging for Iron Quantification in Thalassemia Participants in the Developing World: The TIC-TOC Study (Thailand and UK International Collaboration in Thalassaemia Optimising Ultrafast CMR). PMID- 27482010 TI - Negative pressure wound therapy and orthopaedic trauma: where are we now? PMID- 27482009 TI - The literature evolves: one step at a time. PMID- 27482008 TI - Consistent Reduction in Periprocedural Myocardial Infarction With Cangrelor as Assessed by Multiple Definitions: Findings From CHAMPION PHOENIX (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). AB - BACKGROUND: Cangrelor is an intravenous P2Y12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention not pretreated with a P2Y12 inhibitor. METHODS: A total of 11 145 patients were randomized to cangrelor or clopidogrel in the CHAMPION PHOENIX trial (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). We explored the effects of cangrelor on myocardial infarction (MI) using different definitions and performed sensitivity analyses on the primary end point of the trial. RESULTS: A total of 462 patients (4.2%) undergoing percutaneous coronary intervention had an MI as defined by the second universal definition. The majority of these MIs (n=433, 93.7%) were type 4a. Treatment with cangrelor reduced the incidence of MI at 48 hours (3.8% versus 4.7%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.67-0.97; P=0.02). When the Society of Coronary Angiography and Intervention definition of periprocedural MI was applied to potential ischemic events, there were fewer total MIs (n=134); however, the effects of cangrelor on MI remained significant (OR, 0.65; 95% CI, 0.46-0.92; P=0.01). Similar effects were seen in the evaluation of the effects of cangrelor on MIs with peak creatinine kinase-MB >=10 times the upper limit of normal (OR, 0.64; 95% CI, 0.45-0.91) and those with peak creatinine kinase-MB >=10 times the upper limit of normal, ischemic symptoms, or ECG changes (OR, 0.63; 95% CI, 0.48-0.84). MIs defined by any of these definitions were associated with increased risk of death at 30 days. Treatment with cangrelor reduced the composite end point of death, MI (Society of Coronary Angiography and Intervention definition), ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis (1.4% versus 2.1%; OR, 0.69; 95% CI, 0.51-0.92). CONCLUSIONS: MI in patients undergoing percutaneous coronary intervention, regardless of definition, remains associated with increased risk of death in the current era. Cangrelor compared with clopidogrel significantly reduces MI regardless of the definition. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT01156571. PMID- 27482011 TI - Antibiotic prophylaxis in orthopaedic surgery: difficult decisions in an era of evolving antibiotic resistance. AB - Prophylactic antibiotics can decrease the risk of wound infection and have been routinely employed in orthopaedic surgery for decades. Despite their widespread use, questions still surround the selection of antibiotics for prophylaxis, timing and duration of administration. The health economic costs associated with wound infections are significant, and the judicious but appropriate use of antibiotics can reduce this risk. This review examines the evidence behind commonly debated topics in antibiotic prophylaxis and highlights the uses and advantages of some commonly used antibiotics. Cite this article: Bone Joint J 2016;98-B:1014-19. PMID- 27482012 TI - The anatomy of the anterior cruciate ligament and its relevance to the technique of reconstruction. AB - Anterior cruciate ligament (ACL) reconstruction is commonly performed and has been for many years. Despite this, the technical details related to ACL anatomy, such as tunnel placement, are still a topic for debate. In this paper, we introduce the flat ribbon concept of the anatomy of the ACL, and its relevance to clinical practice. Cite this article: Bone Joint J 2016;98-B:1020-6. PMID- 27482013 TI - Intra-articular steroid injection for osteoarthritis of the hip prior to total hip arthroplasty : is it safe? a systematic review. AB - AIMS: Using a systematic review, we investigated whether there is an increased risk of post-operative infection in patients who have received an intra-articular corticosteroid injection to the hip for osteoarthritis prior to total hip arthroplasty (THA). METHODS: Studies dealing with an intra-articular corticosteroid injection to the hip and infection following subsequent THA were identified from databases for the period between 1990 to 2013. Retrieved articles were independently assessed for their methodological quality. RESULTS: A total of nine studies met the inclusion criteria. Two recommended against a steroid injection prior to THA and seven found no risk with an injection. No prospective controlled trials were identified. Most studies were retrospective. Lack of information about the methodology was a consistent flaw. CONCLUSIONS: The literature in this area is scarce and the evidence is weak. Most studies were retrospective, and confounding factors were poorly defined or not addressed. There is thus currently insufficient evidence to conclude that an intra-articular corticosteroid injection administered prior to THA increases the rate of infection. High quality, multicentre randomised trials are needed to address this issue. Cite this article: Bone Joint J 2016;98-B:1027-35. PMID- 27482014 TI - Greater inadvertent muscle damage in direct anterior approach when compared with the direct superior approach for total hip arthroplasty. AB - AIMS: We wished to quantify the extent of soft-tissue damage sustained during minimally invasive total hip arthroplasty through the direct anterior (DA) and direct superior (DS) approaches. MATERIALS AND METHODS: In eight cadavers, the DA approach was performed on one side, and the DS approach on the other, a single brand of uncemented hip prosthesis was implanted by two surgeons, considered expert in their surgical approaches. Subsequent reflection of the gluteus maximus allowed the extent of muscle and tendon damage to be measured and the percentage damage to each anatomical structure to be calculated. RESULTS: The DA approach caused substantially greater damage to the gluteus minimus muscle and tendon when compared with the DS approach (t-test, p = 0.049 and 0.003, respectively). The tensor fascia lata and rectus femoris muscles were damaged only in the DA approach. There was no difference in the amount of damage to the gluteus medius muscle and tendon, piriformis tendon, obturator internus tendon, obturator externus tendon or quadratus femoris muscle between approaches. The posterior soft-tissue releases of the DA approach damaged the gluteus minimus muscle and tendon, piriformis tendon and obturator internus tendon. CONCLUSION: The DS approach caused less soft-tissue damage than the DA approach. However the clinical relevance is unknown. Further clinical outcome studies, radiographic evaluation of component position, gait analyses and serum biomarker levels are necessary to evaluate and corroborate the safety and efficacy of the DS approach. Cite this article: Bone Joint J 2016;98-B1036-42. PMID- 27482016 TI - An 11- to 15-year clinical outcome study of the Advance Medial Pivot total knee arthroplasty: pivot knee arthroplasty. AB - AIMS: The Advance Medial-Pivot total knee arthroplasty (TKA) was designed to reflect contemporary data regarding the kinematics of the knee. We wished to examine the long-term results obtained with this prosthesis by extending a previous evaluation. PATIENTS AND METHODS: We retrospectively evaluated prospectively collected data from 225 consecutive patients (41 men and 184 women; mean age at surgery 71 years, 52 to 84) who underwent 284 TKAs with a mean follow up of 13.4 years (11 to 15). Implant failure, complication rate, clinical (both subjective and objective) and radiological outcome were assessed. Pre- and post operative clinical and radiographic data were available at regular intervals for all patients. A total of ten patients (4.4%; ten TKAs) were lost to follow-up. RESULTS: Survival analysis at 15 years showed a cumulative success rate of 97.3% (95% confidence interval (CI) 96.7 to 97.9) for revision for any reason, of 96.4% (95% CI 95.2 to 97.6) for all operations, and 98.8% (95% CI 98.2 to 99.4) for aseptic loosening as an end point. Three TKAs (1.06%) were revised due to aseptic loosening, two (0.7%) due to infection, one (0.35%) due to instability and one (0.35%) due to a traumatic dislocation. All patients showed a statistically significant improvement on the Knee Society Score (p = 0.001), Western Ontario and McMaster University Osteoarthritis Index (p = 0.001), Short Form-12 (p = 0.01), and Oxford Knee Score (p = 0.01). A total of 207 patients (92%) were able to perform age appropriate activities with a mean flexion of the knee of 117 degrees (85 degrees to 135 degrees ) at final follow-up. CONCLUSION: This study demonstrates satisfactory functional and radiographic long-term results for this implant. Cite this article: Bone Joint J 2016;98-B:1050-5. PMID- 27482015 TI - Component alignment and clinical outcome following total knee arthroplasty: a randomised controlled trial comparing an intramedullary alignment system with patient-specific instrumentation. AB - AIMS: We conducted a randomised controlled trial to assess the accuracy of positioning and alignment of the components in total knee arthroplasty (TKA), comparing those undertaken using standard intramedullary cutting jigs and those with patient-specific instruments (PSI). PATIENTS AND METHODS: There were 64 TKAs in the standard group and 69 in the PSI group. The post-operative hip-knee-ankle (HKA) angle and positioning was investigated using CT scans. Deviation of > 3 degrees from the planned position was regarded as an outlier. The operating time, Oxford Knee Scores (OKS) and Short Form-12 (SF-12) scores were recorded. RESULTS: There were 14 HKA-angle outliers (22%) in the standard group and nine (13%) in the PSI group (p = 0.251). The mean HKA-angle was 0.5 degrees varus in the standard group and 0.2 degrees varus in the PSI group (p = 0.492). The accuracy of alignment in the coronal and axial planes and the proportion of outliers was not different in the two groups. The femoral component was more flexed (p = 0.035) and there were significantly more tibial slope outliers (29% versus 13%) in the PSI group (p = 0.032). Operating time and the median three month OKS were similar (p = 0.218 and p = 0.472, respectively). Physical and mental SF-12 scores were not significantly different at three months (p = 0.418 and p = 0.267, respectively) or at one year post-operatively (p = 0.114 and p = 0.569). The median one-year Oxford knee score was two points higher in the PSI group (p = 0.049). CONCLUSION: Compared with standard intramedullary jigs, the use of PSI did not significantly reduce the number of outliers or the mean operating time, nor did it clinically improve the accuracy of alignment or the median Oxford Knee Scores. Our data do not support the routine use of PSI when undertaking TKA. Cite this article: Bone Joint J 2016;98-B:1043-9. PMID- 27482017 TI - Systematic review of aspirin for thromboprophylaxis in modern elective total hip and knee arthroplasty. AB - AIMS: There is uncertainty regarding the optimal means of thromboprophylaxis following total hip and knee arthroplasty (THA, TKA). This systematic review presents the evidence for acetylsalicylic acid (aspirin) as a thromboprophylactic agent in THA and TKA and compares it with other chemoprophylactic agents. MATERIALS AND METHODS: A search of literature published between 2004 and 2014 was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 13 studies were eligible for inclusion. RESULTS: Evidence from one good quality randomised controlled trial (RCT) showed no difference in rates of venous thrombo-embolism (VTE) in patients given aspirin or low molecular weight heparin (LMWH) following TKA. There was insufficient evidence from trials with moderate to severe risk of bias being present to suggest aspirin is more or less effective than LMWH, warfarin or dabigatran for the prevention of VTE in TKA or THA. Compared with aspirin, rates of asymptomatic deep vein thrombosis (DVT) in TKA may be reduced with rivaroxaban but insufficient evidence exists to demonstrate an effect on incidence of symptomatic DVT. Compared with aspirin there is evidence of more wound complications following THA and TKA with dabigatran and in TKA with rivaroxaban. Some studies highlighted concerns over bleeding complications and efficacy of aspirin. CONCLUSION: The results suggest aspirin may be considered a suitable alternative to other thromboprophylactic agents following THA and TKA. Further investigation is required to fully evaluate the safety and efficacy of aspirin. Cite this article: Bone Joint J 2016;98-B:1056-61. PMID- 27482018 TI - Articulating polymethylmethacrylate (PMMA) spacers may have an immunomodulating effect on synovial tissue. AB - AIMS: Tissue responses to debris formed by abrasion of polymethylmethacrylate (PMMA) spacers at two-stage revision arthroplasty for prosthetic joint infection are not well described. We hypothesised that PMMA debris induces immunomodulation in periprosthetic tissues. PATIENTS AND METHODS: Samples of tissue were taken during 35 two-stage revision arthroplasties (nine total hip and 26 total knee arthroplasties) in patients whose mean age was 67 years (44 to 85). Fourier transform infrared microscopy was used to confirm the presence of PMMA particles. Histomorphometry was performed using Sudan Red and Haematoxylin-Eosin staining. CD-68, CD-20, CD-11(c), CD-3 and IL-17 antibodies were used to immunophenotype the inflammatory cells. All slides were scored semi-quantitatively using the modified Willert scoring system. RESULTS: The mean CD-68 scores did not show any significant change during the six weeks between the stages. Perivascular and diffuse scores showed significant difference in CD-3, CD-20, CD-11(c) and IL-17. At the time of re-implantation, a shift in the pattern of the expression of dendritic cells towards a perivascular arrangement and towards the periphery of PMMA particles was observed. Positive microbiological cultures were found at the time of re-implantation in three patients. Five further revisions were required for other reasons. CONCLUSION: Our results represent a biological reaction of the synovial tissues to spacers with a less diffuse expression of dendritic cells and an increased expression of perivascular lymphocytes. The use of spacers in two stage revision for infection probably induces an immunomodulation of synovial tissues. Cite this article: Bone Joint J 2016;98-B:1062-8. PMID- 27482019 TI - Are radiographic measurements of the displacement of a distal radial fracture reliable and reproducible? AB - AIMS: The degree of displacement of a fracture of the distal radius is an important factor which can be assessed using simple radiographic measurements. Our aim was to investigate the reliability and reproducibility of these measurements and to determine if they should be used clinically. PATIENTS AND METHODS: A 10% sample was randomly generated from 3670 consecutive adult patients who had presented to University Hospitals of Leicester NHS Trust between 2007 and 2010 with a fracture of the distal radius. Radiographs of the 367 patients were assessed by two independent reviewers. Four measurements of displacement of the fracture were recorded and the inter-observer correlation assessed using the intra-class correlation coefficient. RESULTS: Inter-observer correlation was high (> 0.8) for three of the four measurements. Repeat measurements of a further randomly generated 10% sample (37) were made four weeks later to assess intra observer agreement, which was again high (> 0.8) for the same three parameters (radial height, radial inclination and dorsal/palmar tilt). Correlation was poor for articular step and gap. CONCLUSION: Radiographic assessment of radial angle, radial inclination and dorsal/palmar tilt is a reliable method of determining the degree of displacement of a fracture of the distal radius. Cite this article: Bone Joint J 2016;98-B:1069-73. PMID- 27482020 TI - Results of non-operative treatment of fractures of the glenoid fossa. AB - AIMS: Our aim was to investigate the outcomes of patients with a displaced fracture of the glenoid fossa who are treated conservatively. There is little information in the literature about the treatment of these rare injuries non operatively. PATIENTS AND METHODS: We reviewed 24 patients with a mean age of 52 years (19 to 81) at a mean of 5.6 years (11 months to 18 years) after the injury. RESULTS: At final follow-up, the mean Constant and Murley score was 79 points (18 to 98); the mean Western Ontario Shoulder Instability Index score (WOSI) was 77% (12 to 100) and the mean Rowe score was 93 points (50 to 100). Fractures with little intra-articular displacement (<= 3 mm) had an uneventful outcome. Those with intra-articular displacement of <= 3 mm had a significant better mean Constant and Murley score than those with displacement of >= 5 mm and/or a fracture gap of >= 5 mm. Poor clinical results such as nonunion and post traumatic osteoarthritis were associated with displaced or angulated glenoid fragments and significant intra-articular displacement. CONCLUSION: Glenoid fossa fractures with displacement of >= 5 mm should be treated surgically if the patient's condition allows. Displacement and angulation can lead to nonunion and a poor outcome if the degree of displacement results in a persistent fracture gap in the glenoid fossa or if the angulation of fragments leads to malunion. Cite this article: Bone Joint J 2016;98-B:1074-9. PMID- 27482021 TI - Patient-specific glenoid guides provide accuracy and reproducibility in total shoulder arthroplasty. AB - AIMS: Patient-specific glenoid guides (PSGs) claim an improvement in accuracy and reproducibility of the positioning of components in total shoulder arthroplasty (TSA). The results have not yet been confirmed in a prospective clinical trial. Our aim was to assess whether the use of PSGs in patients with osteoarthritis of the shoulder would allow accurate and reliable implantation of the glenoid component. PATIENTS AND METHODS: A total of 17 patients (three men and 14 women) with a mean age of 71 years (53 to 81) awaiting TSA were enrolled in the study. Pre- and post-operative version and inclination of the glenoid were measured on CT scans, using 3D planning automatic software. During surgery, a congruent 3D printed PSG was applied onto the glenoid surface, thus determining the entry point and orientation of the central guide wire used for reaming the glenoid and the introduction of the component. Manual segmentation was performed on post operative CT scans to compare the planned and the actual position of the entry point (mm) and orientation of the component ( degrees ). RESULTS: The mean error in the accuracy of the entry point was -0.1 mm (standard deviation (sd) 1.4) in the horizontal plane, and 0.8 mm (sd 1.3) in the vertical plane. The mean error in the orientation of the glenoid component was 3.4 degrees (sd 5.1 degrees ) for version and 1.8 degrees (sd 5.3 degrees ) for inclination. CONCLUSION: Pre operative planning with automatic software and the use of PSGs provides accurate and reproducible positioning and orientation of the glenoid component in anatomical TSA. Cite this article: Bone Joint J 2016;98-B:1080-5. PMID- 27482022 TI - Short-term clinical results of revision elbow arthroplasty using the Latitude total elbow arthroplasty. AB - AIMS: Revision total elbow arthroplasty (TEA) is often challenging. The aim of this study was to report on the clinical and radiological results of revision arthroplasty of the elbow with the Latitude TEA. PATIENTS AND METHODS: Between 2006 and 2010 we used the Latitude TEA for revision in 18 consecutive elbows (17 patients); mean age 53 years (28 to 80); 14 women. A Kudo TEA was revised in 15 elbows and a Souter-Strathclyde TEA in three. Stability, range of movement (ROM), visual analogue score (VAS) for pain and functional scores, Elbow Functional Assessment Scale (EFAS), the Functional Rating Index of Broberg and Morrey (FRIBM) and the Modified Andrews' Elbow Scoring System (MAESS) were assessed pre operatively and at each post-operative follow-up visit (six, 12 months and biennially thereafter). Radiographs were analysed for loosening, fractures and dislocation. The mean follow-up was 59 months (26 to 89). RESULTS: The ROM of the elbow did not improve significantly. The mean EFAS and MAESS scores improved significantly six months post-operatively (18.6 points, standard deviation (sd) 7.7; p = 0.03 and 28.8 points, sd 8.6; p = 0.006, respectively) and continued to improve slightly or reached a plateau. The mean pain scores at rest (Z = -3.2, p = 0.001) and during activity (Z = -3.2, p = 0.001), and stability (Z = -3.0, p = 0.003) improved significantly six months post-operatively. Thereafter scores continued to improve slightly or a plateau was reached. There were no signs of loosening. CONCLUSION: Revision surgery using the Latitude TEA results in improvement of functionality, reduced pain and better stability of the elbow. Improvement of ROM of the elbow should not be expected. Cite this article: Bone Joint J 2016;98-B:1086-92. PMID- 27482023 TI - The prevalence and impact of sarcopenia on degenerative lumbar spinal stenosis. AB - AIMS: The purpose of this study was to investigate the prevalence of sarcopenia and to examine its impact on patients with degenerative lumbar spinal stenosis (DLSS). PATIENTS AND METHODS: This case-control study included two groups: one group consisting of patients with DLSS and a second group of control subjects without low back or neck pain and related leg pain. Five control cases were randomly selected and matched by age and gender (n = 77 cases and n = 385 controls) for each DLSS case. Appendicular muscle mass, hand-grip strength, sit to-stand test, timed up and go (TUG) test, and clinical outcomes, including the Oswestry Disability Index (ODI) scores and the EuroQol EQ-5D were compared between the two groups. RESULTS: The prevalence of sarcopenia, as defined by hand grip strength, was significantly higher in the DLSS group (24%) when compared with the age- and gender-matched control group (12%) (p = 0.004). In the DLSS group, the sarcopenia subgroup demonstrated inferior results for the TUG test and ODI scores when compared with the non-sarcopenia subgroup (p = 0.006 and p = 0.039, respectively) after adjusting for age and gender. CONCLUSION: This study demonstrated a higher prevalence of sarcopenia in patients with DLSS and highlighted its negative effect on clinical outcomes. Cite this article: Bone Joint J 2016;98-B:1093-8. PMID- 27482025 TI - Type C tibial pilon fractures: short- and long-term outcome following operative intervention. AB - AIMS: The aim of this study was to report the outcome following primary fixation or a staged protocol for type C fractures of the tibial plafond. PATIENTS AND METHODS: We studied all patients who sustained a complex intra-articular fracture (AO type C) of the distal tibia over an 11-year period. The primary short-term outcome was infection. The primary long-term outcome was the Foot and Ankle Outcome Score (FAOS). RESULTS: There were 102 type C pilon fractures in 99 patients, whose mean age was 42 years (16 to 86) and 77 were male. Primary open reduction internal fixation (ORIF) was performed in 73 patients (71.6%), whilst 20 (19.6%) underwent primary external fixation with delayed ORIF. There were 18 wound infections (17.6%). A total of nine (8.8%) were deep and nine were superficial. Infection was associated with comorbidities (p = 0.008), open fractures (p = 0.008) and primary external fixation with delayed ORIF (p = 0.023). At a mean of six years (0.3 to 13; n = 53) after the injury, the mean FAOS was 76.2 (0 to 100) and 72% of patients were satisfied. CONCLUSION: This is currently the largest series reporting the outcome following fixation of complex AO type C tibial pilon fractures. Despite the severity of these injuries, we have demonstrated that a satisfactory outcome can be achieved in the appropriate patients using primary ORIF. Cite this article: Bone Joint J 2016;98-B:1106-11. PMID- 27482024 TI - Cement augmentation versus extended dorsal instrumentation in the treatment of osteoporotic vertebral fractures: a biomechanical comparison. AB - AIMS: Loosening of pedicle screws is a major complication of posterior spinal stabilisation, especially in the osteoporotic spine. Our aim was to evaluate the effect of cement augmentation compared with extended dorsal instrumentation on the stability of posterior spinal fixation. MATERIALS AND METHODS: A total of 12 osteoporotic human cadaveric spines (T11-L3) were randomised by bone mineral density into two groups and instrumented with pedicle screws: group I (SHORT) separated T12 or L2 and group II (EXTENDED) specimen consisting of T11/12 to L2/3. Screws were augmented with cement unilaterally in each vertebra. Fatigue testing was performed using a cranial-caudal sinusoidal, cyclic (1.0 Hz) load with stepwise increasing peak force. RESULTS: Augmentation showed no significant increase in the mean cycles to failure and fatigue force (SHORT p = 0.067; EXTENDED p = 0.239). Extending the instrumentation resulted in a significantly increased number of cycles to failure and a significantly higher fatigue force compared with the SHORT instrumentation (EXTENDED non-augmented + 76%, p < 0.001; EXTENDED augmented + 87%, p < 0.001). CONCLUSION: The stabilising effect of cement augmentation of pedicle screws might not be as beneficial as expected from biomechanical pull-out tests. Lengthening the dorsal instrumentation results in a much higher increase of stability during fatigue testing in the osteoporotic spine compared with cement augmentation. Cite this article: Bone Joint J 2016;98 B:1099-1105. PMID- 27482026 TI - Risk of acute renal failure and mortality after surgery for a fracture of the hip: a population-based cohort study. AB - AIMS: We examined risk of developing acute renal failure and the associated mortality among patients aged > 65 years undergoing surgery for a fracture of the hip. PATIENTS AND METHODS: We used medical databases to identify patients who underwent surgical treatment for a fracture of the hip in Northern Denmark between 2005 and 2011. Acute renal failure was classified as stage 1, 2 and 3 according to the Kidney Disease Improving Global Outcome criteria. We computed the risk of developing acute renal failure within five days after surgery with death as a competing risk, and the short-term (six to 30 days post-operatively) and long-term mortality (31 days to 365 days post-operatively). We calculated adjusted hazard ratios (HRs) for death with 95% confidence intervals (CIs). RESULTS: Among 13 529 patients who sustained a fracture of the hip, 1717 (12.7%) developed acute renal failure post-operatively, including 1218 (9.0%) with stage 1, 364 (2.7%) with stage 2, and 135 (1.0%) with stage 3 renal failure. The short term mortality was 15.9% and 5.6% for patients with and without acute renal failure, respectively (HR 2.8, 95% CI 2.4 to 3.2). The long-term mortality was 25.0% and 18.3% for those with and without acute renal failure, respectively (HR 1.3, 95% CI 1.2 to 1.5). The mortality was higher in patients with an increased severity of renal failure. CONCLUSION: Acute renal failure is a common complication of surgery in elderly patients who sustain a fracture of the hip, and is associated with increased mortality up to one year after surgery despite adjustment for coexisting comorbidity and medication before surgery. Cite this article: Bone Joint J 2016;98-B:1112-18. PMID- 27482027 TI - Management of rib fractures in traumatic flail chest: a meta-analysis of randomised controlled trials. AB - AIMS: Flail chest from a blunt injury to the thorax is associated with significant morbidity and mortality. Its management globally is predominantly non operative; however, there are an increasing number of centres which undertake surgical stabilisation. The aim of this meta-analysis was to compare the efficacy of this approach with that of non-operative management. PATIENTS AND METHODS: A systematic search of the literature was carried out to identify randomised controlled trials (RCTs) which compared the clinical outcome of patients with a traumatic flail chest treated by surgical stabilisation of any kind with that of non-operative management. RESULTS: Of 1273 papers identified, three RCTs reported the results of 123 patients with a flail chest. Surgical stabilisation was associated with a two thirds reduction in the incidence of pneumonia when compared with non-operative management (risk ratio 0.36, 95% confidence interval (CI) 0.15 to 0.85, p = 0.02). The duration of mechanical ventilation (mean difference -6.30 days, 95% CI -12.16 to -0.43, p = 0.04) and length of stay in an intensive care unit (mean difference -6.46 days, 95% CI 9.73 to -3.19, p = 0.0001) were significantly shorter in the operative group, as was the overall length of stay in hospital (mean difference -11.39, 95% CI -12.39 to -10.38, p < 0.0001). CONCLUSION: Surgical stabilisation for a traumatic flail chest is associated with significant clinical benefits in this meta-analysis of three relatively small RCTs. Cite this article: Bone Joint J 2016;98-B:1119-25. PMID- 27482028 TI - Antibiotic-loaded bone void filler accelerates healing in a femoral condylar rat model. AB - AIMS: Demineralised bone matrix (DBM) is rarely used for the local delivery of prophylactic antibiotics. Our aim, in this study, was to show that a graft with a bioactive glass and DBM combination, which is currently available for clinical use, can be loaded with tobramycin and release levels of antibiotic greater than the minimum inhibitory concentration for Staphylococcus aureus without interfering with the bone healing properties of the graft, thus protecting the graft and surrounding tissues from infection. MATERIALS AND METHODS: Antibiotic was loaded into a graft and subsequently evaluated for drug elution kinetics and the inhibition of bacterial growth. A rat femoral condylar plug model was used to determine the effect of the graft, loaded with antibiotic, on bone healing. RESULTS: We found that tobramycin loaded into a graft composed of bioglass and DBM eluted antibiotic above the minimum inhibitory concentration for three days in vitro. It was also found that the antibiotic loaded into the graft produced no adverse effects on the bone healing properties of the DBM at a lower level of antibiotic. CONCLUSION: This antibiotic-loaded bone void filler may represent a promising option for the delivery of local antibiotics in orthopaedic surgery. Cite this article: Bone Joint J 2016;98-B:1126-31. PMID- 27482029 TI - Compartment syndrome causes systemic inflammation in a rat. AB - AIMS: Compartment syndrome results from increased intra-compartmental pressure (ICP) causing local tissue ischaemia and cell death, but the systemic effects are not well described. We hypothesised that compartment syndrome would have a profound effect not only on the affected limb, but also on remote organs. METHODS: Using a rat model of compartment syndrome, its systemic effects on the viability of hepatocytes and on inflammation and circulation were directly visualised using intravital video microscopy. RESULTS: We found that hepatocellular injury was significantly higher in the compartment syndrome group (192 PI-labelled cells/10(-1) mm(3), standard error of the mean (sem) 51) compared with controls (30 PI-labelled cells/10(-1) mm(3), sem 12, p < 0.01). The number of adherent venular white blood cells was significantly higher for the compartment syndrome group (5 leukocytes/30s/10 000 MUm(2), sem 1) than controls (0.2 leukocytes/30 s/10 000 MUm(2), sem 0.2, p < 0.01). Volumetric blood flow was not significantly different between the two groups, although there was an increase in the heterogeneity of perfusion. CONCLUSIONS: Compartment syndrome can be accompanied by severe systemic inflammation and end organ damage. This study provides evidence of the relationship between compartment syndrome in a limb and systemic inflammation and dysfunction in a remote organ. Cite this article: Bone Joint J 2016; 98-B:1132-7. PMID- 27482030 TI - Ewing's sarcoma: only patients with 100% of necrosis after chemotherapy should be classified as having a good response. AB - AIMS: The purpose of this study was to review a large cohort of patients and further assess the correlation between the histological response to chemotherapy in patients with Ewing's sarcoma with the overall (OS) and event-free survival (EFS). PATIENTS AND METHODS: All patients treated for Ewing's sarcoma between 1980 and 2012 were reviewed. Of these, 293 patients without metastases at the time of diagnosis and treated with chemotherapy and surgery were included. Patients were grouped according to the percentage of necrosis after chemotherapy: Group I: 0% to 50%, Group II: 51% to 99% and Group III: 100%. RESULTS: The mean age at diagnosis was 16 years (1 to 62) and the mean follow-up was 9.1 years (six months to 32.6 years). The OS and EFS for the series were 75% and 65% at five years. There were significant differences in survival between the groups of necrosis: 0% to 50% (OS: 49% and EFS: 45% at five years, respectively) compared with 51% to 99% (OS: 72% and EFS: 59% at five years, respectively) and 100% (OS: 94% and EFS: 81% at five years, respectively) (p < 0.001). There were no significant differences in survival between patients treated between 1980 and 1989 compared with those treated between 1990 and 1999, and those treated between 2000 and 2012 (p = 0.55). CONCLUSION: Only patients with 100% necrosis after chemotherapy should be classified as having a good response to chemotherapy because they have significantly better rates of survival compared with those with any viable tumour in the surgical specimen. Cite this article: Bone Joint J 2016;98-B:1138-44. PMID- 27482032 TI - Errata. AB - K KURSUMOVIC, C P CHARALAMBOUS: Graft salvage following infected anterior cruciate ligament reconstruction. Bone Joint J 2016;98-B:608-615. PMID- 27482031 TI - The comparative, long-term effect of the Salter osteotomy and Pemberton acetabuloplasty on pelvic height, scoliosis and functional outcome. AB - AIMS: This study compared the long-term results following Salter osteotomy and Pemberton acetabuloplasty in children with developmental dysplasia of the hip (DDH). We assessed if there was a greater increase in pelvic height following the Salter osteotomy, and if this had a continued effect on pelvic tilt, lumbar curvature or functional outcomes. PATIENTS AND METHODS: We reviewed 42 children at more than ten years post-operatively following a unilateral Salter osteotomy or Pemberton acetabuloplasty. We measured the increase in pelvic height and the iliac crest tilt and sacral tilt at the most recent review and at an earlier review point in the first decade of follow-up. We measured the lumbar Cobb angle and the Short Form-36 (SF-36) and Harris hip scores were collected at the most recent review. RESULTS: During the first decade of follow-up, there was a greater increase in pelvic height in the children who had a Salter osteotomy (Salter, 10.1%; Pemberton, 4.3%, p < 0.001). The difference in the increase in pelvic height was insignificant at the most recent review (Salter, 4.4%; Pemberton, 3.1%, p = 0.249). There was no significant difference between the two groups for the lumbar Cobb angle, (Salter, 3.1 degrees ; Pemberton, 3.3 degrees , p = 0.906). A coronal lumbar curve was seen in 41 children (97%), 30 of these had a compensatory curve. Sacral tilt was the radiographic parameter for pelvic imbalance that correlated most with the lumbar Cobb angle (Pearson correlation co efficient 0.59). The Harris hip score and SF-36 were good and showed no differences between the two groups. CONCLUSION: In the long-term, we found no difference in the functional results or pelvic imbalance between Salter osteotomy and Pemberton acetabuloplasty in the management of children with DDH. Cite this article: Bone Joint J 2016;98-B:1145-50. PMID- 27482034 TI - Schizophrenia genetics moves into the light. AB - Two recent reports convincingly demonstrate that the risk of schizophrenia is influenced by common variation of C4, which codes for complement component 4, and by rare, disruptive mutations of SETD1A, which codes for a histone methylase. These important results open the way for major advances in our understanding of the fundamental biological processes leading to disease. PMID- 27482033 TI - Circulating Tumor DNA as an Early Indicator of Response to T-cell Transfer Immunotherapy in Metastatic Melanoma. AB - PURPOSE: Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma. Responding patients generally do not have significant changes in noncutaneous RECIST targets before 30 to 60 days following TIL infusion, and complete responses are often not confirmed for 1 to 2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of circulating tumor DNA (ctDNA) in separating responding from nonresponding patients. EXPERIMENTAL DESIGN: We studied BRAF V600E ctDNA levels by a sensitive allele-specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the NCI and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes. RESULTS: A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1 to 2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception. CONCLUSIONS: We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in metastatic melanoma can be used to rapidly identify responding from nonresponding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy. Clin Cancer Res; 22(22); 5480-6. (c)2016 AACR. PMID- 27482035 TI - Paternalism v. autonomy - are we barking up the wrong tree? AB - We explore whether we can reduce paternalism by increasing patient autonomy. We argue that autonomy should not have any automatic priority over other ethical values. Thus, balancing autonomy v. other ethical pillars and finding the optimal balance between the patient's wishes and those of other relevant stakeholders such as the patient's family has to be dynamic over time. PMID- 27482036 TI - Hospitalisation and compulsion: the research agenda. AB - Keown et al's paper highlights the complex nature of social determinants of hospital admission and compulsory care. We review here how research into compulsion in mental health has progressed beyond epidemiological studies of rates of admission. There is now a wider recognition of the range of compulsory and coercive processes used and how they are experienced by patients. The results of recent studies have confirmed the importance of confronting the complexity that Keown et al have presented. They have also produced unexpected and intriguing findings that set the direction for future research. PMID- 27482038 TI - Risk of dementia and death in community-dwelling older men with bipolar disorder. AB - BACKGROUND: Bipolar disorder has been associated with cognitive decline, but confirmatory evidence from a community-derived sample of older people is lacking. AIMS: To investigate the 13-year risk of dementia and death in older adults with bipolar disorder. METHOD: Cohort study of 37 768 men aged 65-85 years. Dementia (primary) and death (secondary), as recorded by electronic record linkage, were the outcomes of interest. RESULTS: Bipolar disorder was associated with increased adjusted hazard ratio (HR) of dementia (HR = 2.30, 95% CI 1.80-2.94). The risk of dementia was greatest among those with <5 years of history of bipolar disorder or who had had illness onset after 70 years of age. Bipolar disorder was also associated with increased mortality (HR = 1.51, 95% CI 1.28-1.77). Competing risk regression showed that bipolar disorder was associated with increased hazard of death by suicide, accidents, pneumonia or influenza, and diseases of the liver and digestive system. CONCLUSIONS: Bipolar disorder in later life is associated with increased risk of dementia and premature death. PMID- 27482041 TI - Biological v. psychotherapeutic: Friston and psychodynamic therapy. PMID- 27482042 TI - Evidence, not ideology, should guide the use of psychotherapy. PMID- 27482043 TI - Authors' reply. PMID- 27482044 TI - Ten books. PMID- 27482048 TI - Frederic Bard: The sweet side of traffic. PMID- 27482049 TI - Midbody remnant licenses primary cilia formation in epithelial cells. AB - Tethered midbody remnants dancing across apical microvilli, encountering the centrosome, and beckoning forth a cilium-who would have guessed this is how polarized epithelial cells coordinate the end of mitosis and the beginning of ciliogenesis? New evidence from Bernabe-Rubio et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201601020) supports this emerging model. PMID- 27482050 TI - Coming or going? Un-BLOC-ing delivery and recycling pathways during melanosome maturation. AB - Melanosome biogenesis requires successive waves of cargo delivery from endosomes to immature melanosomes, coupled with recycling of the trafficking machinery. Dennis et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201605090) report differential roles for BLOC-1 and BLOC-3 complexes in delivery and recycling of melanosomal biogenetic components, supplying directionality to melanosome maturation. PMID- 27482053 TI - Should exercise therapy for chronic musculoskeletal conditions focus on the anti inflammatory effects of exercise? PMID- 27482052 TI - Assembly and activation of dynein-dynactin by the cargo adaptor protein Hook3. AB - Metazoan cytoplasmic dynein moves processively along microtubules with the aid of dynactin and an adaptor protein that joins dynein and dynactin into a stable ternary complex. Here, we examined how Hook3, a cargo adaptor involved in Golgi and endosome transport, forms a motile dynein-dynactin complex. We show that the conserved Hook domain interacts directly with the dynein light intermediate chain 1 (LIC1). By solving the crystal structure of the Hook domain and using structure based mutagenesis, we identify two conserved surface residues that are each critical for LIC1 binding. Hook proteins with mutations in these residues fail to form a stable dynein-dynactin complex, revealing a crucial role for LIC1 in this interaction. We also identify a region of Hook3 specifically required for an allosteric activation of processive motility. Our work reveals the structural details of Hook3's interaction with dynein and offers insight into how cargo adaptors form processive dynein-dynactin motor complexes. PMID- 27482055 TI - Rewinding Frankenstein and the body-machine: organ transplantation in the dystopian young adult fiction series Unwind. AB - While the separation of body and mind (and the entailing metaphor of the body as a machine) has been a cornerstone of Western medicine for a long time, reactions to organ transplantation among others challenge this clear-cut dichotomy. The limits of the machine-body have been negotiated in science fiction, most canonically in Mary Shelley's Frankenstein (1818). Since then, Frankenstein's monster itself has become a motif that permeates both medical and fictional discourses. Neal Shusterman's contemporary dystology for young adults, Unwind, draws on traditional concepts of the machine-body and the Frankenstein myth. This article follows one of the young protagonists in the series, who is entirely constructed from donated tissue, and analyses how Shusterman explores the complicated relationship between body and mind and between self and other as the teenager matures into an adult. It will be shown that, by framing the story of a transplanted individual along the lines of a coming-of-age narrative, Shusterman inter-relates the acceptance of a donor organ with the transitional space of adolescence and positions the quest for embodied selfhood at the centre of both developments. By highlighting the interconnections between medical discourse and a literary tradition, the potential contribution of the series to the treatment and understanding of post-transplant patients will be addressed. PMID- 27482054 TI - Making physical activity evidence accessible: are these infographics the answer? PMID- 27482051 TI - BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers. AB - Endomembrane organelle maturation requires cargo delivery via fusion with membrane transport intermediates and recycling of fusion factors to their sites of origin. Melanosomes and other lysosome-related organelles obtain cargoes from early endosomes, but the fusion machinery involved and its recycling pathway are unknown. Here, we show that the v-SNARE VAMP7 mediates fusion of melanosomes with tubular transport carriers that also carry the cargo protein TYRP1 and that require BLOC-1 for their formation. Using live-cell imaging, we identify a pathway for VAMP7 recycling from melanosomes that employs distinct tubular carriers. The recycling carriers also harbor the VAMP7-binding scaffold protein VARP and the tissue-restricted Rab GTPase RAB38. Recycling carrier formation is dependent on the RAB38 exchange factor BLOC-3. Our data suggest that VAMP7 mediates fusion of BLOC-1-dependent transport carriers with melanosomes, illuminate SNARE recycling from melanosomes as a critical BLOC-3-dependent step, and likely explain the distinct hypopigmentation phenotypes associated with BLOC 1 and BLOC-3 deficiency in Hermansky-Pudlak syndrome variants. PMID- 27482056 TI - A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipid- and glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat diet-induced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4 Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD. PMID- 27482058 TI - Improving Safe Sleep Practices for Hospitalized Infants. AB - BACKGROUND AND OBJECTIVES: Adherence to the American Academy of Pediatrics safe sleep practice (SSP) recommendations among hospitalized infants is unknown, but is assumed to be low. This quality improvement study aimed to increase adherence to SSPs for infants admitted to a children's hospital general care unit between October 2013 and December 2014. METHODS: After development of a hospital policy and redesign of room setup processes, a multidisciplinary team developed intervention strategies based on root cause analysis and implemented changes using iterative Plan-Do-Study-Act cycles. Nurse knowledge was assessed before and after education. SSPs were measured continuously with room audits during sleeping episodes. Statistical process control and run charts identified improvements and sustainability in hospital SSPs. Caregiver home practices after discharge were assessed via structured questionnaires before and after intervention. RESULTS: Nursing knowledge of SSPs increased significantly for each item (P <= .001) except avoidance of bed sharing. Audits were completed for 316 sleep episodes. Simultaneous adherence to all SSP recommendations improved significantly from 0% to 26.9% after intervention. Significant improvements were noted in individual practices, including maintaining a flat, empty crib, with an appropriately bundled infant. The largest gains were noted in the proportion of empty cribs (from 3.4% to 60.3% after intervention, P < .001). Improvements in caregiver home practices after discharge were not statistically significant. CONCLUSIONS: Sustained improvements in hospital SSPs were achieved through this quality improvement initiative, with opportunity for continued improvement. Nurse knowledge increased during the intervention. It is uncertain whether these findings translate to changes in caregiver home practices after discharge. PMID- 27482057 TI - Parallel reverse genetic screening in mutant human cells using transcriptomics. AB - Reverse genetic screens have driven gene annotation and target discovery in model organisms. However, many disease-relevant genotypes and phenotypes cannot be studied in lower organisms. It is therefore essential to overcome technical hurdles associated with large-scale reverse genetics in human cells. Here, we establish a reverse genetic approach based on highly robust and sensitive multiplexed RNA sequencing of mutant human cells. We conduct 10 parallel screens using a collection of engineered haploid isogenic cell lines with knockouts covering tyrosine kinases and identify known and unexpected effects on signaling pathways. Our study provides proof of concept for a scalable approach to link genotype to phenotype in human cells, which has broad applications. In particular, it clears the way for systematic phenotyping of still poorly characterized human genes and for systematic study of uncharacterized genomic features associated with human disease. PMID- 27482059 TI - Comorbidity and Childhood Epilepsy: A Nationwide Registry Study. AB - BACKGROUND AND OBJECTIVE: Children with epilepsy are at increased risk of other disorders and difficulties, preceding, cooccurring with, or after the diagnosis of epilepsy. Risk estimates vary, few studies are population-based, and few provide comprehensive assessments of comorbidities. We used nationwide registry data to describe frequencies of medical, neurologic, developmental, and psychiatric conditions occurring before and after children are diagnosed with childhood epilepsy. METHODS: Data were obtained from the Norwegian Patient Registry, which is an administrative database recording International Classification of Diseases, 10th Revision diagnoses from all government-funded specialist health services in Norway (outpatient consultations and hospitalizations). We included data from the years 2008 through 2013 for all children born in Norway between 1996 and 2013 (0-17 years of age at the end of follow-up). Children with epilepsy were compared with the general child population, adjusting for sex and age. We also compared children with complicated epilepsies (ie, epilepsies with additional neurologic and/or developmental disorders) to children with uncomplicated epilepsies. RESULTS: The study population included 1 125 161 children. There were 6635 (0.6%) children with epilepsy. Nearly 80% of children with epilepsy had >=1 comorbid disorder. All types of disorders were more frequent in children with epilepsy, with additional medical disorders recorded in 55%, neurologic disorders in 41%, and developmental/psychiatric disorders in 43%. Children with complicated epilepsies had the highest overall levels of comorbidity, but the risk of medical and psychiatric comorbidities was also substantial among children with uncomplicated epilepsies. CONCLUSIONS: The overall frequency of comorbid disease is high in children with epilepsy, including children with presumably uncomplicated epilepsies. PMID- 27482060 TI - Trampoline Park and Home Trampoline Injuries. AB - BACKGROUND AND OBJECTIVE: Trampoline parks, indoor recreational facilities with wall-to-wall trampolines, are increasing in number and popularity. The objective was to identify trends in emergency department visits for trampoline park injuries (TPIs) and compare TPI characteristics with home trampoline injuries (HTIs). METHODS: Data on trampoline injuries from the National Electronic Injury Surveillance System from 2010 to 2014 were analyzed. Sample weights were applied to estimate yearly national injury trends; unweighted cases were used for comparison of injury patterns. RESULTS: Estimated US emergency department visits for TPI increased significantly, from 581 in 2010 to 6932 in 2014 (P = .045), whereas HTIs did not increase (P = .13). Patients with TPI (n = 330) were older than patients with HTI (n = 7933) (mean 13.3 vs 9.5 years, respectively, P < .001) and predominantly male. Sprains and fractures were the most common injuries at trampoline parks and homes. Compared with HTIs, TPIs were less likely to involve head injury (odds ratio [OR] 0.64; 95% confidence interval [CI], 0.46 0.89), more likely to involve lower extremity injury (OR 2.39; 95% CI, 1.91 2.98), more likely to be a dislocation (OR 2.12; 95% CI, 1.10-4.09), and more likely to warrant admission (OR 1.76; 95% CI, 1.19-2.61). TPIs necessitating hospital admission included open fractures and spinal cord injuries. TPI mechanisms included falls, contact with other jumpers, and flips. CONCLUSIONS: TPI patterns differed significantly from HTIs. TPIs are an emerging concern; additional investigation and strategies are needed to prevent injury at trampoline parks. PMID- 27482061 TI - Update on Diarrhea. PMID- 27482062 TI - Eating Disorders. PMID- 27482064 TI - Case 1: Growth Failure and Abnormal Radiographs in a 3-year-old Girl. PMID- 27482063 TI - Inflammatory Bowel Disease. PMID- 27482065 TI - Case 2: Recurrent Urinary Tract Infections in a 7-year-old Girl. PMID- 27482066 TI - Case 3: Anal Mass in a 4-month-old Girl. PMID- 27482067 TI - Fad Dieting and Weight Loss in Children. PMID- 27482068 TI - Visual Diagnosis: Emesis in A Young, Healthy Child: Benign or Beware? PMID- 27482070 TI - 5-HT2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo. AB - Pulmonary fibrosis is characterized by excessive accumulation of connective tissue, along with activated extracellular matrix (ECM)-producing cells, myofibroblasts. The pathological mechanisms are not well known, however serotonin (5-HT) and 5-HT class 2 (5-HT2) receptors have been associated with fibrosis. The aim of the present study was to investigate the role of 5-HT2B receptors in fibrosis, using small molecular 5-HT2B receptor antagonists EXT5 and EXT9, with slightly different receptor affinity. Myofibroblast differentiation [production of alpha-smooth muscle actin (alpha-SMA)] and ECM synthesis were quantified in vitro, and the effects of the receptor antagonists were evaluated. Pulmonary fibrosis was also modeled in mice by subcutaneous bleomycin administrations (under light isoflurane anesthesia), and the effects of receptor antagonists on tissue density, collagen-producing cells, myofibroblasts and decorin expression were investigated. In addition, cytokine expression was analyzed in serum. Lung fibroblasts displayed an increased alpha-SMA (P < 0.05) and total proteoglycan production (P < 0.01) when cultured with TGF-beta1 together with 5-HT, which were significantly reduced with both receptor antagonists. Following treatment with EXT5 or EXT9, tissue density, expression of decorin, number of collagen-producing cells, and myofibroblasts were significantly decreased in vivo compared to bleomycin-treated mice. Receptor antagonization also significantly reduced systemic levels of TNF-alpha and IL-1beta, indicating a role in systemic inflammation. In conclusion, 5-HT2B receptor antagonists have potential to prevent myofibroblast differentiation, in vitro and in vivo, with subsequent effect on matrix deposition. The attenuating effects of 5-HT2B receptor antagonists on fibrotic tissue remodeling suggest these receptors as novel targets for the treatment of pulmonary fibrosis. PMID- 27482071 TI - Aspirate from human stented saphenous vein grafts induces epicardial coronary vasoconstriction and impairs perfusion and left ventricular function in rat bioassay hearts with pharmacologically induced endothelial dysfunction. AB - Stent implantation into aortocoronary saphenous vein grafts (SVG) releases particulate debris and soluble vasoactive mediators, for example, serotonin. We now analyzed effects of the soluble mediators released into the coronary arterial blood during stent implantation on vasomotion of isolated rat epicardial coronary artery segments and on coronary flow and left ventricular developed pressure in isolated perfused rat hearts. Coronary blood was retrieved during percutaneous SVG intervention using a distal occlusion/aspiration protection device in nine symptomatic patients with stable angina pectoris and a flow-limiting SVG stenosis. The blood was separated into particulate debris and plasma. Responses to coronary plasma were determined in isolated rat epicardial coronary arteries and in isolated, constant pressure-perfused rat hearts (+/-nitric oxide synthase [NOS] inhibition and +/-serotonin receptor blockade, respectively). Coronary aspirate plasma taken after stent implantation induced a stronger vasoconstriction of rat epicardial coronary arteries (52 +/- 8% of maximal potassium chloride induced vasoconstriction [% KClmax = 100%]) than plasma taken before stent implantation (12 +/- 8% of KClmax); NOS inhibition augmented this vasoconstrictor response (to 110 +/- 15% and 24 +/- 9% of KClmax). Coronary aspirate plasma taken after stent implantation reduced in isolated perfused rat hearts only under NOS inhibition coronary flow by 17 +/- 3% and left ventricular developed pressure by 25 +/- 4%. Blockade of serotonin receptors abrogated these effects. Coronary aspirate plasma taken after stent implantation induces vasoconstriction in isolated rat epicardial coronary arteries and reduces coronary flow and left ventricular developed pressure in isolated perfused rat hearts with pharmacologically induced endothelial dysfunction. PMID- 27482072 TI - Immobilization rapidly induces muscle insulin resistance together with the activation of MAPKs (JNK and p38) and impairment of AS160 phosphorylation. AB - Acute short-duration physical inactivity induces the development of insulin resistance for glucose uptake in skeletal muscle. We examined the possibility that inactivity rapidly induces muscle insulin resistance via the excessive activation of proinflammatory/stress pathways including those of IKK/IkappaB/NF kappaB, JNK, and p38 MAPK We also examined the other possibility that inactivity induced rapid development of insulin resistance is associated with reduced phosphorylation of AS160, the most distal insulin-signaling protein that have been linked to the regulation of glucose uptake. Male Wistar rats were subjected to unilateral hindlimb immobilization for 6 h. At the end of the immobilization, the soleus muscles from both immobilized and contralateral non-immobilized hindlimbs were dissected out. Immobilization decreased insulin-stimulated 2 deoxyglucose uptake in rat soleus muscle within 6 h. This rapid development of insulin resistance was accompanied by elevated phosphorylation of both JNK and p38 (commonly used indicator of JNK and p38 pathway activity, respectively). In addition, the abundance of SPT2, a rate-limiting enzyme regulating ceramide biosynthesis, was increased in immobilized muscle. Immobilization did not alter the abundance of IkappaBalpha (commonly used indicator of IKK/IkappaB/NF-kappaB pathway activity). The basal phosphorylation of AS160 at Thr642 and Ser588 was decreased together with the development of insulin resistance. These results suggest the possibility that inactivity-induced rapid development of insulin resistance in immobilized muscle is related to enhanced activation of JNK and/or p38. Elevated ceramide biosynthesis pathway may contribute to this activation. Our results also indicate that decreased basal phosphorylation of AS160 may be involved in inactivity-induced insulin resistance. PMID- 27482074 TI - Feedforward consequences of isometric contractions: effort and ventilation. AB - The onset of voluntary muscle contractions causes rapid increases in ventilation and is accompanied by a sensation of effort. Both the ventilatory response and perception of effort are proportional to contraction intensity, but these behaviors have been generalized from contractions of a single muscle group. Our aim was to determine how these relationships are affected by simultaneous contractions of multiple muscle groups. We examined the ventilatory response and perceived effort of contraction during separate and simultaneous isometric contractions of the contralateral elbow flexors and of an ipsilateral elbow flexor and knee extensor. Subjects made 10-sec contractions at 25, 50, and 100% of maximum during normocapnia and hypercapnia. For simultaneous contractions, both muscle groups were activated at the same intensities. Ventilation was measured continuously and subjects rated the effort required to produce each contraction. As expected, ventilation and perceived effort increased proportionally with contraction intensity during individual contractions. However, during simultaneous contractions, neither ventilation nor effort reflected the combined muscle output. Rather, the ventilatory response was similar to when contractions were performed separately, and effort ratings showed a small but significant increase for simultaneous contractions. Hypercapnia at rest doubled baseline ventilation, but did not affect the difference in perceived effort between separate and simultaneous contractions. The ventilatory response and the sense of effort at the onset of muscle activity are not related to the total output of the motor pathways, or the working muscles, but arise from cortical regions upstream from the motor cortex. PMID- 27482073 TI - Beneficial effects of combined resveratrol and metformin therapy in treating diet induced insulin resistance. AB - The polyphenol compound resveratrol (RSV) has attracted attention due to its reputed beneficial effects on insulin sensitivity. Our lab has previously identified protective effects of RSV against the development of type 2 diabetes in rats. These effects occurred in a manner similar to thiazolidinedione's (TZDs), a class of insulin sensitizing drugs. TZDs are commonly prescribed in combination with metformin (MET) and thus we sought to examine the combined effects of RSV and MET in treating insulin resistance. Male C57BL6 mice were fed a low- (LFD; 10% Kcal from fat) or high-fat diet (HFD; 60% Kcal from fat) for 9 weeks to induce glucose and insulin intolerance. HFD mice were then assigned to control (HFD), MET (231.28 +/- 12.24 mg/kg/day), RSV (93.68 +/- 3.51 mg/kg/day), or combined (COM; MET 232.01 +/- 17.12 mg/kg/day and RSV 92.77 +/- 6.92 mg/kg/day) treatment groups. Changes in glucose and insulin tolerance and tissue specific insulin signaling were measured 4 weeks post-treatment. RSV or MET alone did not have beneficial effects on glucose tolerance, although MET significantly improved insulin tolerance compared to HFD Glucose and insulin tolerance were significantly improved in COM compared to HFD and this was mirrored by enhanced insulin-stimulated AKT phosphorylation in triceps muscle and inguinal subcutaneous adipose tissue in COM compared to HFD mice. Improvements with COM treatment were not explained by differences in body weight, adiposity, or markers of adipose tissue inflammation. In summary, this study provides evidence of beneficial effects of combined RSV and MET therapy in treating impairments in glucose homeostasis. PMID- 27482075 TI - Astaxanthin intake attenuates muscle atrophy caused by immobilization in rats. AB - Astaxanthin is a carotenoid pigment and has been shown to be an effective inhibitor of oxidative damage. We tested the hypothesis that astaxanthin intake would attenuate immobilization-induced muscle atrophy in rats. Male Wistar rats (14-week old) were fed for 24 days with either astaxanthin or placebo diet. After 14 days of each experimental diet intake, the hindlimb muscles of one leg were immobilized in plantar flexion position using a plaster cast. Following 10 days of immobilization, both the atrophic and the contralateral plantaris muscles were removed and analyzed to determine the level of muscle atrophy along with measurement of the protein levels of CuZn-superoxide dismutase (CuZn-SOD) and selected proteases. Compared with placebo diet animals, the degree of muscle atrophy in response to immobilization was significantly reduced in astaxanthin diet animals. Further, astaxanthin supplementation significantly prevented the immobilization-induced increase in the expression of CuZn-SOD, cathepsin L, calpain, and ubiquitin in the atrophied muscle. These results support the postulate that dietary astaxanthin intake attenuates the rate of disuse muscle atrophy by inhibiting oxidative stress and proteolysis via three major proteolytic pathways. PMID- 27482076 TI - The Quest for Understanding Phenotypic Variation via Integrated Approaches in the Field Environment. PMID- 27482077 TI - Glucosinolates from Host Plants Influence Growth of the Parasitic Plant Cuscuta gronovii and Its Susceptibility to Aphid Feeding. AB - Parasitic plants acquire diverse secondary metabolites from their hosts, including defense compounds that target insect herbivores. However, the ecological implications of this phenomenon, including the potential enhancement of parasite defenses, remain largely unexplored. We studied the translocation of glucosinolates from the brassicaceous host plant Arabidopsis (Arabidopsis thaliana) into parasitic dodder vines (Convolvulaceae; Cuscuta gronovii) and its effects on the parasite itself and on dodder-aphid interactions. Aliphatic and indole glucosinolates reached concentrations in parasite tissues higher than those observed in corresponding host tissues. Dodder growth was enhanced on cyp79B2 cyp79B3 hosts (without indole glucosinolates) but inhibited on atr1D hosts (with elevated indole glucosinolates) relative to wild-type hosts, which responded to parasitism with localized elevation of indole and aliphatic glucosinolates. These findings implicate indole glucosinolates in defense against parasitic plants. Rates of settling and survival on dodder vines by pea aphids (Acyrthosiphon pisum) were reduced significantly when dodder parasitized glucosinolate-producing hosts (wild type and atr1D) compared with glucosinolate free hosts (cyp79B2 cyp79B3 myb28 myb29). However, settling and survival of green peach aphids (Myzus persicae) were not affected. M. persicae population growth was actually reduced on dodder parasitizing glucosinolate-free hosts compared with wild-type or atr1D hosts, even though stems of the former contain less glucosinolates and more amino acids. Strikingly, this effect was reversed when the aphids fed directly upon Arabidopsis, which indicates an interactive effect of parasite and host genotype on M. persicae that stems from host effects on dodder. Thus, our findings indicate that glucosinolates may have both direct and indirect effects on dodder-feeding herbivores. PMID- 27482080 TI - Walter Kohn (1923-2016). PMID- 27482079 TI - S-Adenosylmethionine Synthetase 3 Is Important for Pollen Tube Growth. AB - S-Adenosylmethionine is widely used in a variety of biological reactions and participates in the methionine (Met) metabolic pathway. In Arabidopsis (Arabidopsis thaliana), one of the four S-adenosylmethionine synthetase genes, METHIONINE ADENOSYLTRANSFERASE3 (MAT3), is highly expressed in pollen. Here, we show that mat3 mutants have impaired pollen tube growth and reduced seed set. Metabolomics analyses confirmed that mat3 pollen and pollen tubes overaccumulate Met and that mat3 pollen has several metabolite profiles, such as those of polyamine biosynthesis, which are different from those of the wild type. Additionally, we show that disruption of Met metabolism in mat3 pollen affected transfer RNA and histone methylation levels. Thus, our results suggest a connection between metabolism and epigenetics. PMID- 27482078 TI - A Tale of Two Sugars: Trehalose 6-Phosphate and Sucrose. AB - Trehalose 6-phosphate (Tre6P), the intermediate of trehalose biosynthesis, is an essential signal metabolite in plants, linking growth and development to carbon status. The Suc-Tre6P nexus model postulates that Tre6P is both a signal and negative feedback regulator of Suc levels, forming part of a mechanism to maintain Suc levels within an optimal range and functionally comparable to the insulin-glucagon system for regulating blood Glc levels in animals. The target range and sensitivity of the Tre6P-Suc feedback control circuit can be adjusted according to the cell type, developmental stage, and environmental conditions. In source leaves, Tre6P modulates Suc levels by affecting Suc synthesis, whereas in sink organs it regulates Suc consumption. In illuminated leaves, Tre6P influences the partitioning of photoassimilates between Suc, organic acids, and amino acids via posttranslational regulation of phosphoenolpyruvate carboxylase and nitrate reductase. At night, Tre6P regulates the remobilization of leaf starch reserves to Suc, potentially linking starch turnover in source leaves to carbon demand from developing sink organs. Use of Suc for growth in developing tissues is strongly influenced by the antagonistic activities of two protein kinases: SUC NON-FERMENTING-1-RELATED KINASE1 (SnRK1) and TARGET OF RAPAMYCIN (TOR). The relationship between Tre6P and SnRK1 in developing tissues is complex and not yet fully resolved, involving both direct and indirect mechanisms, and positive and negative effects. No direct connection between Tre6P and TOR has yet been described. The roles of Tre6P in abiotic stress tolerance and stomatal regulation are also discussed. PMID- 27482081 TI - The threat (or not) of insecticide resistance for malaria control. PMID- 27482082 TI - Contrasting climate change impact on river flows from high-altitude catchments in the Himalayan and Andes Mountains. AB - Mountain ranges are the world's natural water towers and provide water resources for millions of people. However, their hydrological balance and possible future changes in river flow remain poorly understood because of high meteorological variability, physical inaccessibility, and the complex interplay between climate, cryosphere, and hydrological processes. Here, we use a state-of-the art glacio hydrological model informed by data from high-altitude observations and the latest climate change scenarios to quantify the climate change impact on water resources of two contrasting catchments vulnerable to changes in the cryosphere. The two study catchments are located in the Central Andes of Chile and in the Nepalese Himalaya in close vicinity of densely populated areas. Although both sites reveal a strong decrease in glacier area, they show a remarkably different hydrological response to projected climate change. In the Juncal catchment in Chile, runoff is likely to sharply decrease in the future and the runoff seasonality is sensitive to projected climatic changes. In the Langtang catchment in Nepal, future water availability is on the rise for decades to come with limited shifts between seasons. Owing to the high spatiotemporal resolution of the simulations and process complexity included in the modeling, the response times and the mechanisms underlying the variations in glacier area and river flow can be well constrained. The projections indicate that climate change adaptation in Central Chile should focus on dealing with a reduction in water availability, whereas in Nepal preparedness for flood extremes should be the policy priority. PMID- 27482083 TI - Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein alpha-synuclein. AB - The aggregation of alpha-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well. PMID- 27482084 TI - High-frequency oscillations in human and monkey neocortex during the wake-sleep cycle. AB - Beta (beta)- and gamma (gamma)-oscillations are present in different cortical areas and are thought to be inhibition-driven, but it is not known if these properties also apply to gamma-oscillations in humans. Here, we analyze such oscillations in high-density microelectrode array recordings in human and monkey during the wake-sleep cycle. In these recordings, units were classified as excitatory and inhibitory cells. We find that gamma-oscillations in human and beta-oscillations in monkey are characterized by a strong implication of inhibitory neurons, both in terms of their firing rate and their phasic firing with the oscillation cycle. The beta- and gamma-waves systematically propagate across the array, with similar velocities, during both wake and sleep. However, only in slow-wave sleep (SWS) beta- and gamma-oscillations are associated with highly coherent and functional interactions across several millimeters of the neocortex. This interaction is specifically pronounced between inhibitory cells. These results suggest that inhibitory cells are dominantly involved in the genesis of beta- and gamma-oscillations, as well as in the organization of their large-scale coherence in the awake and sleeping brain. The highest oscillation coherence found during SWS suggests that fast oscillations implement a highly coherent reactivation of wake patterns that may support memory consolidation during SWS. PMID- 27482085 TI - Timing and causes of mid-Holocene mammoth extinction on St. Paul Island, Alaska. AB - Relict woolly mammoth (Mammuthus primigenius) populations survived on several small Beringian islands for thousands of years after mainland populations went extinct. Here we present multiproxy paleoenvironmental records to investigate the timing, causes, and consequences of mammoth disappearance from St. Paul Island, Alaska. Five independent indicators of extinction show that mammoths survived on St. Paul until 5,600 +/- 100 y ago. Vegetation composition remained stable during the extinction window, and there is no evidence of human presence on the island before 1787 CE, suggesting that these factors were not extinction drivers. Instead, the extinction coincided with declining freshwater resources and drier climates between 7,850 and 5,600 y ago, as inferred from sedimentary magnetic susceptibility, oxygen isotopes, and diatom and cladoceran assemblages in a sediment core from a freshwater lake on the island, and stable nitrogen isotopes from mammoth remains. Contrary to other extinction models for the St. Paul mammoth population, this evidence indicates that this mammoth population died out because of the synergistic effects of shrinking island area and freshwater scarcity caused by rising sea levels and regional climate change. Degradation of water quality by intensified mammoth activity around the lake likely exacerbated the situation. The St. Paul mammoth demise is now one of the best-dated prehistoric extinctions, highlighting freshwater limitation as an overlooked extinction driver and underscoring the vulnerability of small island populations to environmental change, even in the absence of human influence. PMID- 27482086 TI - Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. AB - Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected "leaky" gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations. PMID- 27482087 TI - Distinct oxytocin effects on belief updating in response to desirable and undesirable feedback. AB - Humans update their beliefs upon feedback and, accordingly, modify their behaviors to adapt to the complex, changing social environment. However, people tend to incorporate desirable (better than expected) feedback into their beliefs but to discount undesirable (worse than expected) feedback. Such optimistic updating has evolved as an advantageous mechanism for social adaptation. Here, we examine the role of oxytocin (OT)-an evolutionary ancient neuropeptide pivotal for social adaptation-in belief updating upon desirable and undesirable feedback in three studies (n = 320). Using a double-blind, placebo-controlled between subjects design, we show that intranasally administered OT (IN-OT) augments optimistic belief updating by facilitating updates of desirable feedback but impairing updates of undesirable feedback. The IN-OT-induced impairment in belief updating upon undesirable feedback is more salient in individuals with high, rather than with low, depression or anxiety traits. IN-OT selectively enhances learning rate (the strength of association between estimation error and subsequent update) of desirable feedback. IN-OT also increases participants' confidence in their estimates after receiving desirable but not undesirable feedback, and the OT effect on confidence updating upon desirable feedback mediates the effect of IN-OT on optimistic belief updating. Our findings reveal distinct functional roles of OT in updating the first-order estimation and second order confidence judgment in response to desirable and undesirable feedback, suggesting a molecular substrate for optimistic belief updating. PMID- 27482089 TI - Water-soluble cavitands promote hydrolyses of long-chain diesters. AB - Water-soluble, deep cavitands serve as chaperones of long-chain diesters for their selective hydrolysis in aqueous solution. The cavitands bind the diesters in rapidly exchanging, folded J-shape conformations that bury the hydrocarbon chain and expose each ester group in turn to the aqueous medium. The acid hydrolyses in the presence of the cavitand result in enhanced yields of monoacid monoester products. Product distributions indicate a two- to fourfold relative decrease in the hydrolysis rate constant of the second ester caused by the confined space in the cavitand. The rate constant for the first acid hydrolysis step is enhanced approximately 10-fold in the presence of the cavitand, compared with control reactions of the molecules in bulk solution. Hydrolysis under basic conditions (saponification) with the cavitand gave >90% yields of the corresponding monoesters. Under basic conditions the cavitand complex of the monoanion precipitates from solution and prevents further reaction. PMID- 27482088 TI - Early gut colonizers shape parasite susceptibility and microbiota composition in honey bee workers. AB - Microbial symbionts living within animal guts are largely composed of resident bacterial species, forming communities that often provide benefits to the host. Gut microbiomes of adult honey bees (Apis mellifera) include core residents such as the betaproteobacterium Snodgrassella alvi, alongside transient parasites such as the protozoan Lotmaria passim To test how these species affect microbiome composition and host physiology, we administered S alvi and/or L passim inocula to newly emerged worker bees from four genetic backgrounds (GH) and reared them in normal (within hives) or stressed (protein-deficient, asocial) conditions. Microbiota acquired by normal bees were abundant but quantitatively differed across treatments, indicating treatment-associated dysbiosis. Pretreatment with S. alvi made normal bees more susceptible to L. passim and altered developmental and detoxification gene expression. Stressed bees were more susceptible to L. passim and were depauperate in core microbiota, yet supplementation with S. alvi did not alter this susceptibility. Microbiomes were generally more variable by GH in stressed bees, which also showed opposing and comparatively reduced modulation of gene expression responses to treatments compared with normal bees. These data provide experimental support for a link between altered gut microbiota and increased parasite and pathogen prevalence, as observed from honey bee colony collapse disorder. PMID- 27482091 TI - Slow motion increases perceived intent. AB - To determine the appropriate punishment for a harmful action, people must often make inferences about the transgressor's intent. In courtrooms and popular media, such inferences increasingly rely on video evidence, which is often played in "slow motion." Four experiments (n = 1,610) involving real surveillance footage from a murder or broadcast replays of violent contact in professional football demonstrate that viewing an action in slow motion, compared with regular speed, can cause viewers to perceive an action as more intentional. This slow motion intentionality bias occurred, in part, because slow motion video caused participants to feel like the actor had more time to act, even when they knew how much clock time had actually elapsed. Four additional experiments (n = 2,737) reveal that allowing viewers to see both regular speed and slow motion replay mitigates the bias, but does not eliminate it. We conclude that an empirical understanding of the effect of slow motion on mental state attribution should inform the life-or-death decisions that are currently based on tacit assumptions about the objectivity of human perception. PMID- 27482090 TI - Dynamic periplasmic chaperone reservoir facilitates biogenesis of outer membrane proteins. AB - Outer membrane protein (OMP) biogenesis is critical to bacterial physiology because the cellular envelope is vital to bacterial pathogenesis and antibiotic resistance. The process of OMP biogenesis has been studied in vivo, and each of its components has been studied in isolation in vitro. This work integrates parameters and observations from both in vivo and in vitro experiments into a holistic computational model termed "Outer Membrane Protein Biogenesis Model" (OMPBioM). We use OMPBioM to assess OMP biogenesis mathematically in a global manner. Using deterministic and stochastic methods, we are able to simulate OMP biogenesis under varying genetic conditions, each of which successfully replicates experimental observations. We observe that OMPs have a prolonged lifetime in the periplasm where an unfolded OMP makes, on average, hundreds of short-lived interactions with chaperones before folding into its native state. We find that some periplasmic chaperones function primarily as quality-control factors; this function complements the folding catalysis function of other chaperones. Additionally, the effective rate for the beta-barrel assembly machinery complex necessary for physiological folding was found to be higher than has currently been observed in vitro. Overall, we find a finely tuned balance between thermodynamic and kinetic parameters maximizes OMP folding flux and minimizes aggregation and unnecessary degradation. In sum, OMPBioM provides a global view of OMP biogenesis that yields unique insights into this essential pathway. PMID- 27482093 TI - Correction for Garcia-Ruiz et al., Changes in genetic selection differentials and generation intervals in US Holstein dairy cattle as a result of genomic selection. PMID- 27482092 TI - Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC. AB - Establishment and maintenance of gene expression states is central to development and differentiation. Transcriptional and epigenetic mechanisms interconnect in poorly understood ways to determine these states. We explore these mechanisms through dissection of the regulation of Arabidopsis thaliana FLOWERING LOCUS C (FLC). FLC can be present in a transcriptionally active state marked by H3K36me3 or a silent state marked by H3K27me3. Here, we investigate the trans factors modifying these opposing histone states and find a physical coupling in vivo between the H3K36 methyltransferase, SDG8, and the H3K27me3 demethylase, ELF6. Previous modeling has predicted this coupling would exist as it facilitates bistability of opposing histone states. We also find association of SDG8 with the transcription machinery, namely RNA polymerase II and the PAF1 complex. Delivery of the active histone modifications is therefore likely to be through transcription at the locus. SDG8 and ELF6 were found to influence the localization of each other on FLC chromatin, showing the functional importance of the interaction. In addition, both influenced accumulation of the associated H3K27me3 and H3K36me3 histone modifications at FLC We propose the physical coupling of activation and derepression activities coordinates transcriptional activity and prevents ectopic silencing. PMID- 27482094 TI - Rapid adaptation of harmful cyanobacteria to rising CO2. AB - Rising atmospheric CO2 concentrations are likely to affect many ecosystems worldwide. However, to what extent elevated CO2 will induce evolutionary changes in photosynthetic organisms is still a major open question. Here, we show rapid microevolutionary adaptation of a harmful cyanobacterium to changes in inorganic carbon (Ci) availability. We studied the cyanobacterium Microcystis, a notorious genus that can develop toxic cyanobacterial blooms in many eutrophic lakes and reservoirs worldwide. Microcystis displays genetic variation in the Ci uptake systems BicA and SbtA, where BicA has a low affinity for bicarbonate but high flux rate, and SbtA has a high affinity but low flux rate. Our laboratory competition experiments show that bicA + sbtA genotypes were favored by natural selection at low CO2 levels, but were partially replaced by the bicA genotype at elevated CO2 Similarly, in a eutrophic lake, bicA + sbtA strains were dominant when Ci concentrations were depleted during a dense cyanobacterial bloom, but were replaced by strains with only the high-flux bicA gene when Ci concentrations increased later in the season. Hence, our results provide both laboratory and field evidence that increasing carbon concentrations induce rapid adaptive changes in the genotype composition of harmful cyanobacterial blooms. PMID- 27482095 TI - Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition. AB - Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants. PMID- 27482096 TI - Indonesian fire activity and smoke pollution in 2015 show persistent nonlinear sensitivity to El Nino-induced drought. AB - The 2015 fire season and related smoke pollution in Indonesia was more severe than the major 2006 episode, making it the most severe season observed by the NASA Earth Observing System satellites that go back to the early 2000s, namely active fire detections from the Terra and Aqua Moderate Resolution Imaging Spectroradiometers (MODIS), MODIS aerosol optical depth, Terra Measurement of Pollution in the Troposphere (MOPITT) carbon monoxide (CO), Aqua Atmospheric Infrared Sounder (AIRS) CO, Aura Ozone Monitoring Instrument (OMI) aerosol index, and Aura Microwave Limb Sounder (MLS) CO. The MLS CO in the upper troposphere showed a plume of pollution stretching from East Africa to the western Pacific Ocean that persisted for 2 mo. Longer-term records of airport visibility in Sumatra and Kalimantan show that 2015 ranked after 1997 and alongside 1991 and 1994 as among the worst episodes on record. Analysis of yearly dry season rainfall from the Tropical Rainfall Measurement Mission (TRMM) and rain gauges shows that, due to the continued use of fire to clear and prepare land on degraded peat, the Indonesian fire environment continues to have nonlinear sensitivity to dry conditions during prolonged periods with less than 4 mm/d of precipitation, and this sensitivity appears to have increased over Kalimantan. Without significant reforms in land use and the adoption of early warning triggers tied to precipitation forecasts, these intense fire episodes will reoccur during future droughts, usually associated with El Nino events. PMID- 27482098 TI - Trading experience modulates anterior insula to reduce the endowment effect. AB - People often demand a greater price when selling goods that they own than they would pay to purchase the same goods-a well-known economic bias called the endowment effect. The endowment effect has been found to be muted among experienced traders, but little is known about how trading experience reduces the endowment effect. We show that when selling, experienced traders exhibit lower right anterior insula activity, but no differences in nucleus accumbens or orbitofrontal activation, compared with inexperienced traders. Furthermore, insula activation mediates the effect of experience on the endowment effect. Similar results are obtained for inexperienced traders who are incentivized to gain trading experience. This finding indicates that frequent trading likely mitigates the endowment effect indirectly by modifying negative affective responses in the context of selling. PMID- 27482099 TI - Learning to soar in turbulent environments. AB - Birds and gliders exploit warm, rising atmospheric currents (thermals) to reach heights comparable to low-lying clouds with a reduced expenditure of energy. This strategy of flight (thermal soaring) is frequently used by migratory birds. Soaring provides a remarkable instance of complex decision making in biology and requires a long-term strategy to effectively use the ascending thermals. Furthermore, the problem is technologically relevant to extend the flying range of autonomous gliders. Thermal soaring is commonly observed in the atmospheric convective boundary layer on warm, sunny days. The formation of thermals unavoidably generates strong turbulent fluctuations, which constitute an essential element of soaring. Here, we approach soaring flight as a problem of learning to navigate complex, highly fluctuating turbulent environments. We simulate the atmospheric boundary layer by numerical models of turbulent convective flow and combine them with model-free, experience-based, reinforcement learning algorithms to train the gliders. For the learned policies in the regimes of moderate and strong turbulence levels, the glider adopts an increasingly conservative policy as turbulence levels increase, quantifying the degree of risk affordable in turbulent environments. Reinforcement learning uncovers those sensorimotor cues that permit effective control over soaring in turbulent environments. PMID- 27482097 TI - Major neurotransmitter systems in dorsal hippocampus and basolateral amygdala control social recognition memory. AB - Social recognition memory (SRM) is crucial for reproduction, forming social groups, and species survival. Despite its importance, SRM is still relatively little studied. Here we examine the participation of the CA1 region of the dorsal hippocampus (CA1) and the basolateral amygdala (BLA) and that of dopaminergic, noradrenergic, and histaminergic systems in both structures in the consolidation of SRM. Male Wistar rats received intra-CA1 or intra-BLA infusions of different drugs immediately after the sample phase of a social discrimination task and 24-h later were subjected to a 5-min retention test. Animals treated with the protein synthesis inhibitor, anisomycin, into either the CA1 or BLA were unable to recognize the previously exposed juvenile (familiar) during the retention test. When infused into the CA1, the beta-adrenoreceptor agonist, isoproterenol, the D1/D5 dopaminergic receptor antagonist, SCH23390, and the H2 histaminergic receptor antagonist, ranitidine, also hindered the recognition of the familiar juvenile 24-h later. The latter drug effects were more intense in the CA1 than in the BLA. When infused into the BLA, the beta-adrenoreceptor antagonist, timolol, the D1/D5 dopamine receptor agonist, SKF38393, and the H2 histaminergic receptor agonist, ranitidine, also hindered recognition of the familiar juvenile 24-h later. In all cases, the impairment to recognize the familiar juvenile was abolished by the coinfusion of agonist plus antagonist. Clearly, both the CA1 and BLA, probably in that order, play major roles in the consolidation of SRM, but these roles are different in each structure vis-a-vis the involvement of the beta noradrenergic, D1/D5-dopaminergic, and H2-histaminergic receptors therein. PMID- 27482101 TI - Constraint, natural selection, and the evolution of human body form. AB - Variation in body form among human groups is structured by a blend of natural selection driven by local climatic conditions and random genetic drift. However, attempts to test ecogeographic hypotheses have not distinguished between adaptive traits (i.e., those that evolved as a result of selection) and those that evolved as a correlated response to selection on other traits (i.e., nonadaptive traits), complicating our understanding of the relationship between climate and morphological distinctions among populations. Here, we use evolutionary quantitative methods to test if traits previously identified as supporting ecogeographic hypotheses were actually adaptive by estimating the force of selection on individual traits needed to drive among-group differentiation. Our results show that not all associations between trait means and latitude were caused by selection acting directly on each individual trait. Although radial and tibial length and biiliac and femoral head breadth show signs of responses to directional selection matching ecogeographic hypotheses, the femur was subject to little or no directional selection despite having shorter values by latitude. Additionally, in contradiction to ecogeographic hypotheses, the humerus was under directional selection for longer values by latitude. Responses to directional selection in the tibia and radius induced a nonadaptive correlated response in the humerus that overwhelmed its own trait-specific response to selection. This result emphasizes that mean differences between groups are not good indicators of which traits are adaptations in the absence of information about covariation among characteristics. PMID- 27482102 TI - Correction for Keum et al., Phosphoinositide 5- and 3-phosphatase activities of a voltage-sensing phosphatase in living cells show identical voltage dependence. PMID- 27482100 TI - Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. AB - Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4(+) T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naive CD4(+) T cells. Ligation of SLAMF3 receptors on SLE CD4(+) T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2. PMID- 27482103 TI - Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. AB - Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (alpha syn) aggregates in affected oligodendrocytes. Several studies point to alpha-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of alpha-syn in vitro and in neuronal cell models of alpha-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate alpha-syn pathology and to mediate neuroprotection in proteolipid protein alpha-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of alpha-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated alpha-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX 765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting alpha-syn accumulation. PMID- 27482105 TI - Classification of topological phonons in linear mechanical metamaterials. AB - Topological phononic crystals, alike their electronic counterparts, are characterized by a bulk-edge correspondence where the interior of a material dictates the existence of stable surface or boundary modes. In the mechanical setup, such surface modes can be used for various applications such as wave guiding, vibration isolation, or the design of static properties such as stable floppy modes where parts of a system move freely. Here, we provide a classification scheme of topological phonons based on local symmetries. We import and adapt the classification of noninteracting electron systems and embed it into the mechanical setup. Moreover, we provide an extensive set of examples that illustrate our scheme and can be used to generate models in unexplored symmetry classes. Our work unifies the vast recent literature on topological phonons and paves the way to future applications of topological surface modes in mechanical metamaterials. PMID- 27482104 TI - O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis. AB - High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Conversely, in HPV-18-transformed HeLa cervical carcinoma cells, inhibition of O-GlcNAc with a low concentration of a chemical inhibitor impaired the transformed phenotypes in vitro. We showed that E6 elevated c-MYC via increased protein stability attributable to O-GlcNAcylation on Thr58. Reduction of HPV-mediated cell viability by a high concentration of O GlcNAc inhibitor was partially rescued by elevated c-MYC. Finally, knockdown of OGT or O-GlcNAc inhibition in HeLa cells or in TC-1 cells, a mouse cell line transformed by HPV16 E6/E7 and activated K-RAS, reduced c-MYC and suppressed tumorigenesis and metastasis. Thus, we have uncovered a mechanism for HPV oncoprotein-mediated transformation. These findings may eventually aid in the development of effective therapeutics for HPV-associated malignancies by targeting aberrant O-GlcNAc. PMID- 27482106 TI - Extensive phosphorylation of AMPA receptors in neurons. AB - Regulation of AMPA receptor (AMPAR) function is a fundamental mechanism controlling synaptic strength during long-term potentiation/depression and homeostatic scaling. AMPAR function and membrane trafficking is controlled by protein-protein interactions, as well as by posttranslational modifications. Phosphorylation of the GluA1 AMPAR subunit at S845 and S831 play especially important roles during synaptic plasticity. Recent controversy has emerged regarding the extent to which GluA1 phosphorylation may contribute to synaptic plasticity. Here we used a variety of methods to measure the population of phosphorylated GluA1-containing AMPARs in cultured primary neurons and mouse forebrain. Phosphorylated GluA1 represents large fractions from 12% to 50% of the total population under basal and stimulated conditions in vitro and in vivo. Furthermore, a large fraction of synapses are positive for phospho-GluA1 containing AMPARs. Our results support the large body of research indicating a prominent role of GluA1 phosphorylation in synaptic plasticity. PMID- 27482108 TI - Emerging single-phase state in small manganite nanodisks. AB - In complex oxides systems such as manganites, electronic phase separation (EPS), a consequence of strong electronic correlations, dictates the exotic electrical and magnetic properties of these materials. A fundamental yet unresolved issue is how EPS responds to spatial confinement; will EPS just scale with size of an object, or will the one of the phases be pinned? Understanding this behavior is critical for future oxides electronics and spintronics because scaling down of the system is unavoidable for these applications. In this work, we use La0.325Pr0.3Ca0.375MnO3 (LPCMO) single crystalline disks to study the effect of spatial confinement on EPS. The EPS state featuring coexistence of ferromagnetic metallic and charge order insulating phases appears to be the low-temperature ground state in bulk, thin films, and large disks, a previously unidentified ground state (i.e., a single ferromagnetic phase state emerges in smaller disks). The critical size is between 500 nm and 800 nm, which is similar to the characteristic length scale of EPS in the LPCMO system. The ability to create a pure ferromagnetic phase in manganite nanodisks is highly desirable for spintronic applications. PMID- 27482107 TI - Axitinib blocks Wnt/beta-catenin signaling and directs asymmetric cell division in cancer. AB - Oncogenic mutations of the Wnt (wingless)/beta-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/beta-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/beta-catenin signaling in cancer cells, zebrafish, and Apc(min/+) mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear beta-catenin degradation independent of the GSK3beta (glycogen synthase kinase3beta)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain containing helicase) as the direct target of axitinib in blocking Wnt/beta catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of beta-catenin. Our findings suggest a previously unreported mechanism of nuclear beta-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear beta-catenin activation. PMID- 27482110 TI - On the solution of the Helmholtz equation on regions with corners. AB - In this paper we solve several boundary value problems for the Helmholtz equation on polygonal domains. We observe that when the problems are formulated as the boundary integral equations of potential theory, the solutions are representable by series of appropriately chosen Bessel functions. In addition to being analytically perspicuous, the resulting expressions lend themselves to the construction of accurate and efficient numerical algorithms. The results are illustrated by a number of numerical examples. PMID- 27482111 TI - Tropical anvil clouds and climate sensitivity. PMID- 27482109 TI - Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation. AB - Pyrin, encoded by the MEFV gene, is best known for its gain-of-function mutations causing familial Mediterranean fever (FMF), an autoinflammatory disease. Pyrin forms a caspase-1-activating inflammasome in response to inactivating modifications of Rho GTPases by various bacterial toxins or effectors. Pyrin mediated innate immunity is unique in that it senses bacterial virulence rather than microbial molecules, but its mechanism of activation is unknown. Here we show that Pyrin was phosphorylated in bone marrow-derived macrophages and dendritic cells. We identified Ser-205 and Ser-241 in mouse Pyrin whose phosphorylation resulted in inhibitory binding by cellular 14-3-3 proteins. The two serines underwent dephosphorylation upon toxin stimulation or bacterial infection, triggering 14-3-3 dissociation, which correlated with Pyrin inflammasome activation. We developed antibodies specific for phosphorylated Ser 205 and Ser-241, which confirmed the stimuli-induced dephosphorylation of endogenous Pyrin. Mutational analyses indicated that both phosphorylation and signal-induced dephosphorylation of Ser-205/241 are important for Pyrin activation. Moreover, microtubule drugs, including colchicine, commonly used to treat FMF, effectively blocked activation of the Pyrin inflammasome. These drugs did not affect Pyrin dephosphorylation and 14-3-3 dissociation but inhibited Pyrin-mediated apoptosis-associated Speck-like protein containing CARD (ASC) aggregation. Our study reveals that site-specific (de)phosphorylation and microtubule dynamics critically control Pyrin inflammasome activation, illustrating a fine and complex mechanism in cytosolic immunity. PMID- 27482112 TI - Monoubiquitination in proteasomal degradation. PMID- 27482113 TI - Cryo-EM of viruses and vaccine design. PMID- 27482116 TI - Correction to Supporting Information for Wang et al., Unveiling the biosynthetic puzzle of destruxins in Metarhizium species. PMID- 27482114 TI - CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation. AB - Inflammation is characterized by the recruitment of leukocytes from the bloodstream. The rapid arrival of neutrophils is followed by a wave of inflammatory lymphocyte antigen 6 complex (Ly6C)-positive monocytes. In contrast Ly6C(low) monocytes survey the endothelium in the steady state, but their role in inflammation is still unclear. Here, using confocal intravital microscopy, we show that upon Toll-like receptor 7/8 (TLR7/8)-mediated inflammation of mesenteric veins, platelet activation drives the rapid mobilization of Ly6C(low) monocytes to the luminal side of the endothelium. After repeatedly interacting with platelets, Ly6C(low) monocytes commit to a meticulous patrolling of the endothelial wall and orchestrate the subsequent arrival and extravasation of neutrophils through the production of proinflammatory cytokines and chemokines. At a molecular level, we show that cysteine-rich protein 61 (CYR61)/CYR61 connective tissue growth factor nephroblastoma overexpressed 1 (CCN1) protein is released by activated platelets and enables the recruitment of Ly6C(low) monocytes upon vascular inflammation. In addition endothelium-bound CCN1 sustains the adequate patrolling of Ly6C(low) monocytes both in the steady state and under inflammatory conditions. Blocking CCN1 or platelets with specific antibodies impaired the early arrival of Ly6C(low) monocytes and abolished the recruitment of neutrophils. These results refine the leukocyte recruitment cascade model by introducing endothelium-bound CCN1 as an inflammation mediator and by demonstrating a role for platelets and patrolling Ly6C(low) monocytes in acute vascular inflammation. PMID- 27482115 TI - Transition path theory analysis of c-Src kinase activation. AB - Nonreceptor tyrosine kinases of the Src family are large multidomain allosteric proteins that are crucial to cellular signaling pathways. In a previous study, we generated a Markov state model (MSM) to simulate the activation of c-Src catalytic domain, used as a prototypical tyrosine kinase. The long-time kinetics of transition predicted by the MSM was in agreement with experimental observations. In the present study, we apply the framework of transition path theory (TPT) to the previously constructed MSM to characterize the main features of the activation pathway. The analysis indicates that the activating transition, in which the activation loop first opens up followed by an inward rotation of the alphaC-helix, takes place via a dense set of intermediate microstates distributed within a fairly broad "transition tube" in a multidimensional conformational subspace connecting the two end-point conformations. Multiple microstates with negligible equilibrium probabilities carry a large transition flux associated with the activating transition, which explains why extensive conformational sampling is necessary to accurately determine the kinetics of activation. Our results suggest that the combination of MSM with TPT provides an effective framework to represent conformational transitions in complex biomolecular systems. PMID- 27482117 TI - Partial squeeze film levitation modulates fingertip friction. AB - When touched, a glass plate excited with ultrasonic transverse waves feels notably more slippery than it does at rest. To study this phenomenon, we use frustrated total internal reflection to image the asperities of the skin that are in intimate contact with a glass plate. We observed that the load at the interface is shared between the elastic compression of the asperities of the skin and a squeeze film of air. Stroboscopic investigation reveals that the time evolution of the interfacial gap is partially out of phase with the plate vibration. Taken together, these results suggest that the skin bounces against the vibrating plate but that the bounces are cushioned by a squeeze film of air that does not have time to escape the interfacial separation. This behavior results in dynamic levitation, in which the average number of asperities in intimate contact is reduced, thereby reducing friction. This improved understanding of the physics of friction reduction provides key guidelines for designing interfaces that can dynamically modulate friction with soft materials and biological tissues, such as human fingertips. PMID- 27482118 TI - Charge-induced nematicity in FeSe. AB - The spontaneous appearance of nematicity, a state of matter that breaks rotation but not translation symmetry, is one of the most intriguing properties of the iron-based superconductors (Fe SC), and has relevance for the cuprates as well. Establishing the critical electronic modes behind nematicity remains a challenge, however, because their associated susceptibilities are not easily accessible by conventional probes. Here, using FeSe as a model system, and symmetry-resolved electronic Raman scattering as a probe, we unravel the presence of critical charge nematic fluctuations near the structural/nematic transition temperature, [Formula: see text] 90 K. The diverging behavior of the associated nematic susceptibility foretells the presence of a Pomeranchuk instability of the Fermi surface with d-wave symmetry. The excellent scaling between the observed nematic susceptibility and elastic modulus data demonstrates that the structural distortion is driven by this d-wave Pomeranchuk transition. Our results make a strong case for charge-induced nematicity in FeSe. PMID- 27482121 TI - The Central Role of Bayes' Theorem for Joint Estimation of Causal Effects and Propensity Scores. AB - Although propensity scores have been central to the estimation of causal effects for over 30 years, only recently has the statistical literature begun to consider in detail methods for Bayesian estimation of propensity scores and causal effects. Underlying this recent body of literature on Bayesian propensity score estimation is an implicit discordance between the goal of the propensity score and the use of Bayes theorem. The propensity score condenses multivariate covariate information into a scalar to allow estimation of causal effects without specifying a model for how each covariate relates to the outcome. Avoiding specification of a detailed model for the outcome response surface is valuable for robust estimation of causal effects, but this strategy is at odds with the use of Bayes theorem, which presupposes a full probability model for the observed data that adheres to the likelihood principle. The goal of this paper is to explicate this fundamental feature of Bayesian estimation of causal effects with propensity scores in order to provide context for the existing literature and for future work on this important topic. PMID- 27482122 TI - On the nucleation and initial film growth of rod-like organic molecules. AB - In this article, some fundamental topics related to the initial steps of organic film growth are reviewed. General conclusions will be drawn based on experimental results obtained for the film formation of oligophenylene and pentacene molecules on gold and mica substrates. Thin films were prepared via physical vapor deposition under ultrahigh-vacuum conditions and characterized in-situ mainly by thermal desorption spectroscopy, and ex-situ by X-ray diffraction and atomic force microscopy. In this short review article the following topics will be discussed: What are the necessary conditions to form island-like films which are either composed of flat-lying or of standing molecules? Does a wetting layer exist below and in between the islands? What is the reason behind the occasionally observed bimodal island size distribution? Can one describe the nucleation process with the diffusion-limited aggregation model? Do the impinging molecules directly adsorb on the surface or rather via a hot-precursor state? Finally, it will be described how the critical island size can be determined by an independent measurement of the deposition rate dependence of the island density and the capture-zone distribution via a universal relationship. PMID- 27482120 TI - Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen. AB - TGF-beta activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-kappaB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPase-activating protein (GAP) enzymes, and is exclusive to membrane-localized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection. PMID- 27482119 TI - Cross-linguistic patterns in the acquisition of quantifiers. AB - Learners of most languages are faced with the task of acquiring words to talk about number and quantity. Much is known about the order of acquisition of number words as well as the cognitive and perceptual systems and cultural practices that shape it. Substantially less is known about the acquisition of quantifiers. Here, we consider the extent to which systems and practices that support number word acquisition can be applied to quantifier acquisition and conclude that the two domains are largely distinct in this respect. Consequently, we hypothesize that the acquisition of quantifiers is constrained by a set of factors related to each quantifier's specific meaning. We investigate competence with the expressions for "all," "none," "some," "some...not," and "most" in 31 languages, representing 11 language types, by testing 768 5-y-old children and 536 adults. We found a cross linguistically similar order of acquisition of quantifiers, explicable in terms of four factors relating to their meaning and use. In addition, exploratory analyses reveal that language- and learner-specific factors, such as negative concord and gender, are significant predictors of variation. PMID- 27482123 TI - Improved Synthesis of MDL 73811 - a Potent AdoMetDC Inhibitor and Anti Trypanosomal Compound. AB - An improved synthesis of MDL 73811 - a potent AdoMetDC (S-adenosylmethionine decarboxylease) inhibitor and anti-trypanosomal compound with in vivo activity has been completed in four steps from commercially available 2',3'-O isopropylideneadenosine. Utilization of Mitsunobu chemistry was crucial for the reliable and scalable introduction of the 5'-methylamine moiety, which was problematic using traditional activation/displacement chemistry as previously reported. All reactions in this synthesis were run on gram-scale resulting in a five-fold increase in yield over the original synthesis. PMID- 27482124 TI - Educational Attainment and Mortality in the United States: Effects of Degrees, Years of Schooling, and Certification. AB - Researchers have extensively documented a strong and consistent education gradient for mortality, with more highly educated individuals living longer than those with less education. This study contributes to our understanding of the education-mortality relationship by determining the effects of years of education and degree attainment on mortality, and by including nondegree certification, an important but understudied dimension of educational attainment. We use data from the mortality-linked restricted-use files of the Panel Study of Income Dynamics (PSID) sample (N=9,821) and Cox proportional hazards models to estimate mortality risk among U.S. adults. Results indicate that more advanced degrees and additional years of education are associated with reduced mortality risk in separate models, but when included simultaneously, only degrees remain influential. Among individuals who have earned a high school diploma only, additional years of schooling (beyond 12) and vocational school certification (or similar accreditation) are both independently associated with reduced risks of death. Degrees appear to be most important for increasing longevity; the findings also suggest that any educational experience can be beneficial. Future research in health and mortality should consider including educational measures beyond a single variable for educational attainment. PMID- 27482125 TI - Scale Effects on Spatially Embedded Contact Networks. AB - Spatial phenomena are subject to scale effects, but there are rarely studies addressing such effects on spatially embedded contact networks. There are two types of structure in these networks, network structure and spatial structure. The network structure has been actively studied. The spatial structure of these networks has received attention only in recent years. Certainly little is known whether the two structures respond to each other. This study examines the scale effects, in terms of spatial extent, on the network structure and the spatial structure of spatially embedded contact networks. Two issues are explored, how the two types of structures change in response to scale changes, and the range of the scale effects. Two sets of areal units, regular grids with 24 different levels of spatial extent and census units of three levels of spatial extent, are used to divide one observed and two reference random networks into multiple scales. Six metrics are used to represent the two structures. Results show different scale effects. In terms of the network structure, the properties of the observed network are sensitive to scale changes at fine scales. In comparison, the clustered spatial structure of the network is scale independent. The behaviors of the network structure are affected by the spatial structure. This information helps identify vulnerable households and communities to health risks and helps deploy intervention strategies to spatially targeted areas. PMID- 27482127 TI - Usefulness of Total PSA Value in Prostate Diseases Diagnosis. AB - INTRODUCTION: Analysis of total value of prostate specific antigen (PSAT), with the unavoidable digital rectal examination (DRE) is the basis of prostate cancer detection. AIM: The aim of this study was to determine the specificity and sensitivity of the total value of PSAT in the diagnosis of prostate cancer. The aim was also to determine the significance of PSAT in diagnosis of benign prostate hyperplasia, precancerous conditions and inflammatory and atrophic changes of the prostate. MATERIAL AND METHODS: Data were collected from the "Register of PH biopsy" of Clinic of Urology, CCU Sarajevo. RESULTS: Analysis of correlation between the diagnosis and the PSAT value shows statistically significant negative correlation (r =-0,186; p = 0.006) in the sense that the value of the PSAT is highest in cancer patients, and the lowest in patients with benign prostatic hyperplasia. PSAT increases with age (r = 0.152; p = 0.025). For prostate cancer optimal sensitivity and specificity for PSAT value occurs at cut off value of> 8.6 ng /mL. Values lower than 2 ng/mL and higher than 10 ng/mL are most specific, and PPV increases with increasing value of PSAT. PSAT at values of <2 ng/mL and > 10 ng/mL are at high levels of specificity, and value > 10 ng / mL is also of high sensitivity in the detection of prostate cancer, and in this moment these values represent the optimal mode for the subsequent treatment. CONCLUSION: PSAT has a relative significance in the detection of prostate cancer, and should not be used as a guideline without DRE. PMID- 27482126 TI - A matter of scale: apparent niche differentiation of diploid and tetraploid plants may depend on extent and grain of analysis. AB - AIM: Emerging polyploids may depend on environmental niche shifts for successful establishment. Using the alpine plant Ranunculus kuepferi as a model system, we explore the niche shift hypothesis at different spatial resolutions and in contrasting parts of the species range. LOCATION: European Alps. METHODS: We sampled 12 individuals from each of 102 populations of R. kuepferi across the Alps, determined their ploidy levels, derived coarse-grain (100 * 100 m) environmental descriptors for all sampling sites by downscaling WorldClim maps, and calculated fine-scale environmental descriptors (2 * 2 m) from indicator values of the vegetation accompanying the sampled individuals. Both coarse and fine-scale variables were further computed for 8239 vegetation plots from across the Alps. Subsequently, we compared niche optima and breadths of diploid and tetraploid cytotypes by combining principal components analysis and kernel smoothing procedures. Comparisons were done separately for coarse and fine-grain data sets and for sympatric, allopatric and the total set of populations. RESULTS: All comparisons indicate that the niches of the two cytotypes differ in optima and/or breadths, but results vary in important details. The whole-range analysis suggests differentiation along the temperature gradient to be most important. However, sympatric comparisons indicate that this climatic shift was not a direct response to competition with diploid ancestors. Moreover, fine grained analyses demonstrate niche contraction of tetraploids, especially in the sympatric range, that goes undetected with coarse-grained data. MAIN CONCLUSIONS: Although the niche optima of the two cytotypes differ, separation along ecological gradients was probably less decisive for polyploid establishment than a shift towards facultative apomixis, a particularly effective strategy to avoid minority cytotype exclusion. In addition, our results suggest that coarse-grained analyses overestimate niche breadths of widely distributed taxa. Niche comparison analyses should hence be conducted at environmental data resolutions appropriate for the organism and question under study. PMID- 27482128 TI - Imaging Characteristics and Prevalence of Pancreatic Carcinoma in Kosovo During 2011-2015 - Diagnostic Method as Choice. AB - INTRODUCTION: Pancreatic cancer is the 10(th)most common malignancy and the 4(th)largest cancer killer in adults. AIM: The purpose of this paper is to evaluate the number of cases presented with pancreatic carcinoma during the years 2011-2015, our experience of the imaging characteristics of pancreatic carcinoma. We evaluated prevalence of the pancreatic cancers, distant metastases and other local infiltration signs among the total cases of the pancreatic cancers diagnosed in the University Clinical Center of Kosovo, with the aim to compare these research findings to similar studies made in the developed countries. This is a retrospective research study done during the period of 2011-2015. MATERIALS AND METHODOLOGY: This retrospective research study includes 362 patients recently diagnosed with pancreatic cancer, examined in the period of 2011-2015 at the University Clinical Center of Kosovo. The imaging diagnostics are performed with MSCT Sensation 64 Siemens, MSCT Emotion 6 Siemens, and 1.5T MRI Symphony Siemens, biopsy guide with MSCT Sensation 64 Siemens in the Radiologic Clinic of UCCK; while the histopathology diagnostics has been performed in Clinic of Pathology at UCCK and prevalence is taken from the number of cases Reported at the Institute of Oncology Institute of Statistics and NIPH (National Institute of Public Health of Kosovo). RESULTS: Out of a total of the 362 patients diagnosed with pancreas cancer, results is female 39.5% (n=143) and male 61.5% (n=219), report M: F (1: 1.6), 286 cases resulted in head and neck 79 % (n=286), 76 cases resulted in body and tail cancers (21%), distant metastases in first imaging modality were found in(n=155) patients 43 %, local infiltration was found in patients: gastric infiltration 15 % (n=54), duodenal and papilla infiltration 26% (n=94), local infiltration spleen 16% (n=57), local infiltration mesentery 43 % (n= 155), dilated biliary tree 34 % (n=123), regional lymph node infiltration 83 % (n= 300). Out of a total of the 362 patients diagnosed with pancreas cancer, 346 cases resulted > 2 cm and 16 cases resulted < 2 cm and with component cystic was 41.2 % (n = 149), solid with component cystic - necrotic 33% (n= 119), solid 25.7% (n= 93). The prevalence is 19.9: 100,000 inhabitants. CONCLUSIONS: Prevalence of carcinoma of the pancreas for 5 years in Kosovo has proved to be prevalence is 19.9: 100,000 inhabitants. Seventy-four percent (74 %, n= 268) of all cancers are found in Stage III and IV. From an imaging point of view, these cancers were presented in an advanced stage, mainly due to their late clinical symptoms and limited access to imaging methods in our country. PMID- 27482129 TI - A New Measurement Equivalence Technique Based on Latent Class Regression as Compared with Multiple Indicators Multiple Causes. AB - BACKGROUND: Measurement equivalence is an essential prerequisite for making valid comparisons in mental health questionnaires across groups. In most methods used for assessing measurement equivalence, which is known as Differential Item Functioning (DIF), latent variables are assumed to be continuous. OBJECTIVE: To compare a new method called Latent Class Regression (LCR) designed for discrete latent variable with the multiple indicators multiple cause (MIMIC) as a continuous latent variable technique to assess the measurement equivalence of the 12-item General Health Questionnaire (GHQ-12), which is a cross deferent subgroup of Iranian nurses. METHODS: A cross-sectional survey was conducted in 2014 among 771 nurses working in the hospitals of Fars and Bushehr provinces of southern Iran. To identify the Minor Psychiatric Disorders (MPD), the nurses completed self-report GHQ-12 questionnaires and sociodemographic questions. Two uniform-DIF detection methods, LCR and MIMIC, were applied for comparability when the GHQ-12 score was assumed to be discrete and continuous, respectively. RESULTS: The result of fitting LCR with 2 classes indicated that 27.4% of the nurses had MPD. Gender was identified as an influential factor of the level of MPD.LCR and MIMIC agree with detection of DIF and DIF-free items by gender, age, education and marital status in 83.3, 100.0, 91.7 and 83.3% cases, respectively. CONCLUSIONS: The results indicated that the GHQ-12 is to a great degree, an invariant measure for the assessment of MPD among nurses. High convergence between the two methods suggests using the LCR approach in cases of discrete latent variable, e.g. GHQ-12 and adequate sample size. PMID- 27482130 TI - Echocardiographic Assessment of Ischaemic Mitral Regurgitation, Mechanism, Severity, Impact on Treatment Strategy and Long Term Outcome. AB - INTRODUCTION: The commonest mitral regurgitation etiologies are degenerative (60%), rheumatic post-inflammatory, 12%) and functional (25%). Due to the large number of patients with acute MI, the incidence of ischaemic MR is also high. Ischaemic mitral regurgitation is a complex multifactorial disease that involves left ventricular geometry, the mitral annulus, and the valvular/subvalvular apparatus. Ischaemic mitral regurgitation is an important consequence of LV remodeling after myocardial infarction. RESEARCH OBJECTIVES: The objective of this study is to determine the role of echocardiography in detecting and assessment of mitral regurgitation mechanism, severity, impact on treatment strategy and long term outcome in patients with myocardial infarction during the follow up period of 5 years. Also one of objectives to determine if the absence or presence of ischaemic MR is associated with increased morbidity and mortality in patients with myocardial infarction. PATIENTS AND METHODS: The study covered 138 adult patients. All patients were subjected to echocardiography evaluation after acute myocardial infarction during the period of follow up for 5 years. The patients were examined on an ultrasound machine Philips iE 33 xMatrix, Philips HD 11 XE, and GE Vivid 7 equipped with all cardiologic probes for adults and multi plan TEE probes. We evaluated mechanisms and severity of mitral regurgitation which includes the regurgitant volume (RV), effective regurgitant orifice area (EROA), the regurgitant fraction (RF), Jet/LA area, also we measured the of vena contracta width (VC width cm) for assessment of IMR severity, papillary muscles anatomy and displacement, LV systolic function +/- dilation, LV regional wall motion abnormality WMA, LV WMI, Left ventricle LV remodeling, impact on treatment strategy and long term mortality. RESULTS: We analyzed and follow up 138 patients with previous (>16 days) Q-wave myocardial infarction by ECG who underwent TTE and TEE echocardiography for detection and assessment of ischaemic mitral regurgitation (IMR) with baseline age (62 +/- 9), ejection fraction (EF 41+/ 12%), the regurgitant volume (RV) were 42+/-21 mL/beat, and effective regurgitant orifice area (EROA) 20+/-16 mm(2), the regurgitant fraction (RF) were 48+/-10%, Jet/LA area 47+/-12%. Also we measured the of vena contracta width (VC width cm) 0,4+/-0,6 for assessment of IMR severity. During 5 years follow up, total mortality for patients with moderate/severe IMR-grade II-IV (54.2+/-1.8%) were higher than for those with mild IMR-grade I (30.4+/-2.9%) (P<0.05), the total mortality for patients with EROA >=20 mm(2)(54+/-1.9%) were higher than for those with EROA <20 mm(2)(27.2+/-2.7%) (P<0.05), and the total mortality for patients with RVol >=30 mL (56.8+/-1.7%) were higher than for those with RVol<30ml (29.4+/ 2.9%) (P<0.05). After assessment of IMR and during follow up period 64 patients (46%) underwent CABG alone or combined CABG with mitral valve repair or replacement. In this study, the procedure of concomitant down-sized ring annuloplasty at the time if CABG surgery has a failure rate around 24% in terms of high late recurrence rate of IMR during the follow period especially after 18 42 months. CONCLUSION: The presence of ischaemic MR is associated with increased morbidity and mortality. Chronic IMR, an independent predictor of mortality with a reported survival of 40-60% at 5 years. Ischaemic mitral regurgitation has important prognosis implications in patients with coronary heart disease. Recognizing the mechanism of valve incompetence is an essential point for the surgical planning and for a good result of the mitral repair. It is important that echocardiographers understand the complex nature of the condition. Despite remarkable progress in reparative surgery, further investigation is still necessary to find the best approach to treat ischaemic mitral regurgitation. PMID- 27482132 TI - Semantic-Web Architecture for Electronic Discharge Summary Based on OWL 2.0 Standard. AB - INTRODUCTION: Patients' electronic medical record contains all information related to treatment processes during hospitalization. One of the most important documents in this record is the record summary. In this document, summary of the whole treatment process is presented which is used for subsequent treatments and other issues pertaining to the treatment. Using suitable architecture for this document, apart from the aforementioned points we can use it in other fields such as data mining or decision making based on the cases. MATERIAL AND METHODS: In this study, at first, a model for patient's medical record summary has been suggested using semantic web-based architecture. Then, based on service-oriented architecture and using Java programming language, a software solution was designed and run in a way to generate medical record summary with this structure and at the end, new uses of this structure was explained. RESULTS: in this study a structure for medical record summaries along with corrective points within semantic web has been offered and a software running within Java along with special ontologies are provided. DISCUSSION AND CONCLUSION: After discussing the project with the experts of medical/health data management and medical informatics as well as clinical experts, it became clear that suggested design for medical record summary apart from covering many issues currently faced in the medical records has also many advantages including its uses in research projects, decision making based on the cases etc. PMID- 27482131 TI - One Year Follow-Up After Veriflex Phakic Intraocular Lenses Implantation for Correction of Myopia. AB - OBJECTIVES: The aim of this study was to evaluate visual and refractive outcomes after Veriflex phakic intraocular lenses (pIOL) implantation in moderately myopic eyes as well as postoperative complications. METHODS: This prospective clinical study included 40 eyes of 26 patients which underwent implantation of Veriflex for correction of myopia from -6.00 to -14.50 diopters (D) in the Eye Clinic Svjetlost Sarajevo, from January 2011 to January 2014. Uncorrected distance visual acuity (UDVA), manifest residual spherical equivalent (MRSE), intraocular pressure (IOP), endothelial cell (EC) density were evaluated at one, three, six and 12 months. Other complications in postoperative period were evaluated. For statistical analysis SPSS for Windows and Microsoft Excel were used. RESULTS: Out of 26 patients 14 had binocular and 12 monocular procedure, with mean age of 29.8+/-6.5 years. After 12 months mean UDVA was 0.73+/-0.20. Mean MRSE was 0.39+/-0.31D and 90% of eyes had MRSE within +/-1D. EC loss was 7.18+/-4.33%. There was no significant change of IOP by the end of 12 months follow up period. The only intraoperative complication was hyphema and occurred in one eye. Few postoperative complications were: subclinical inflammation in three eyes (7,5%), pigment dispersion in four eyes (10%), ovalisation of papilla in 2 eyes (5%) and decentration of pIOL in 2 eyes (5%). CONCLUSION: Implantation of iris-claw phakic lenses Veriflex for treating moderately high myopia is a procedure with good visual and refractive results and few postoperative complications. PMID- 27482134 TI - Mobile Phone Based System Opportunities to Home-based Managing of Chemotherapy Side Effects. AB - OBJECTIVE: Applying mobile base systems in cancer care especially in chemotherapy management have remarkable growing in recent decades. Because chemotherapy side effects have significant influences on patient's lives, therefore it is necessary to take ways to control them. This research has studied some experiences of using mobile phone based systems to home-based monitor of chemotherapy side effects in cancer. METHODS: In this literature review study, search was conducted with keywords like cancer, chemotherapy, mobile phone, information technology, side effects and self managing, in Science Direct, Google Scholar and Pub Med databases since 2005. RESULTS: Today, because of the growing trend of the cancer, we need methods and innovations such as information technology to manage and control it. Mobile phone based systems are the solutions that help to provide quick access to monitor chemotherapy side effects for cancer patients at home. Investigated studies demonstrate that using of mobile phones in chemotherapy management have positive results and led to patients and clinicians satisfactions. CONCLUSION: This study shows that the mobile phone system for home based monitoring chemotherapy side effects works well. In result, knowledge of cancer self-management and the rate of patient's effective participation in care process improved. PMID- 27482133 TI - Conceptual Framework for Developing a Diabetes Information Network. AB - OBJECTIVE: To provide a conceptual framework for managing diabetic patient care, and creating an information network for clinical research. BACKGROUND: A wide range of information technology (IT) based interventions such as distance learning, diabetes registries, personal or electronic health record systems, clinical information systems, and clinical decision support systems have so far been used in supporting diabetic care. Previous studies demonstrated that IT could improve diabetes care at its different aspects. There is however no comprehensive conceptual framework that defines how different IT applications can support diverse aspects of this care. Therefore, a conceptual framework that combines different IT solutions into a wide information network for improving care processes and for research purposes is widely lacking. In this study we describe the theoretical underpin of a big project aiming at building a wide diabetic information network namely DIANET. RESEARCH DESIGN AND METHODS: A literature review and a survey of national programs and existing regulations for diabetes management was conducted in order to define different aspects of diabetic care that should be supported by IT solutions. Both qualitative and quantitative research methods were used in this study. In addition to the results of a previous systematic literature review, two brainstorming and three expert panel sessions were conducted to identify requirements of a comprehensive information technology solution. Based on these inputs, the requirements for creating a diabetes information network were identified and used to create a questionnaire based on 9-point Likert scale. The questionnaire was finalized after removing some items based on calculated content validity ratio and content validity index coefficients. Cronbach's alpha reliability coefficient was also calculated (alphaTotal= 0.98, P<0.05, CI=0.95). The final questionnaire was containing 45 items. It was sent to 13 clinicians at two diabetes clinics of endocrine and metabolism research institute in order to assess the necessity level of the requirements for diabetes information network conceptual framework. The questionnaires were returned by 10 clinicians. Each requirement item was labeled as essential, semi-essential, or non-essential based on the mean of its scores. RESULTS: All requirement items were identified as essential or semi essential. Thus, all of them were used to build the conceptual framework. The requirements were allocated into 11 groups each one representing a module in the conceptual framework. Each module was described separately. CONCLUSION: We proposed a conceptual framework for supporting diabetes care and research. Integrating different and heterogeneous clinical information systems of healthcare facilities and creating a comprehensive diabetics data warehouse for research purposes, would be possible by using the DIANET framework. PMID- 27482135 TI - Investigation of the Impact of Extracting and Exchanging Health Information by Using Internet and Social Networks. AB - INTRODUCTION: Social networks (1) have been embedded in our daily life for a long time. They constitute a powerful tool used nowadays for both searching and exchanging information on different issues by using Internet searching engines (Google, Bing, etc.) and Social Networks (Facebook, Twitter etc.). In this paper, are presented the results of a research based on the frequency and the type of the usage of the Internet and the Social Networks by the general public and the health professionals. OBJECTIVES: The objectives of the research were focused on the investigation of the frequency of seeking and meticulously searching for health information in the social media by both individuals and health practitioners. The exchanging of information is a procedure that involves the issues of reliability and quality of information. METHODS: In this research, by using advanced statistical techniques an effort is made to investigate the participant's profile in using social networks for searching and exchanging information on health issues. RESULTS: Based on the answers 93 % of the people, use the Internet to find information on health-subjects. Considering principal component analysis, the most important health subjects were nutrition (0.719 %), respiratory issues (0.79 %), cardiological issues (0.777%), psychological issues (0.667%) and total (73.8%). CONCLUSIONS: The research results, based on different statistical techniques revealed that the 61.2% of the males and 56.4% of the females intended to use the social networks for searching medical information. Based on the principal components analysis, the most important sources that the participants mentioned, were the use of the Internet and social networks for exchanging information on health issues. These sources proved to be of paramount importance to the participants of the study. The same holds for nursing, medical and administrative staff in hospitals. PMID- 27482136 TI - Documentation of Medical Records in Hospitals of Mazandaran University of Medical Sciences in 2014: a Quantitative Study. AB - INTRODUCTION: Documentation of patient care in medical record formats is always emphasized. These documents are used as a means to go on treating the patients, staff in their own defense, assessment, care, any legal proceedings and medical science education. Therefore, in this study, each of the data elements available in patients' records are important and filling them indicates the importance put by the documenting teams, so it has been dealt with the documentation the patient records in the hospitals of Mazandaran province. METHOD: This cross-sectional study aimed to review medical records in 16 hospitals of Mazandaran University of Medical Sciences (MazUMS). In order to collection data, a check list was prepared based on the data elements including four forms of the admission, summary, patients' medical history and progress note. The data recording was defined as "Yes" with the value of 1, lack of recording was defined as "No" with the value of 2, and "Not applied" with the value of 0 for the cases in which the mentioned variable medical records are not applied. RESULTS: The overall evaluation of the documentation was considered as 95-100% equal to "good", 75-94% equal to "average" and below -75% equal to "poor". Using the stratified random sample volume formula, 381 cases were reviewed. The data were analyzed by the SPSS version 19 and descriptive statistics. RESULTS: The results showed that %62 of registration and all the four forms were in the "poor" category. There was no big difference in average registration among the hospitals. Among the educational groups Gynecology and Infectious were equal and had the highest average of documentation of %68. In the data categories, the highest documentation average belonged to the verification, %91. CONCLUSION: According to the overall assessment in which the rate of documentation was in the category "week", we should make much more efforts to reach better conditions. Even if a data element is recognized meaningless, unnecessary and repetitive by the in charge of documentation, it should not be neglected and skipped. In order to solve the problems of these types, it is suggested to discuss the medical records forms and elements that seem unnecessary in the related committees. PMID- 27482137 TI - Recommendations for Using Barcode in Hospital Process. AB - BACKGROUND: Lack of attention to the proper barcode using leads to lack of use or misuse in the hospitals. The present research aimed to investigate the requirements and barrier for using barcode technology and presenting suggestions to use it. METHODS: The research is observational-descriptive. The data was collected using the designed checklist which its validity was assessed. This check list consists of two parts: "Requirements" and "barrier" of using the barcodes. Research community included 10 teaching hospitals and a class of 65 participants included people in the hospitals. The collected data was analyzed using descriptive statistics. RESULTS: Required changes of workflow processes in the hospital and compliance them with the hospital policy are such requirements that had been infringed in the 90 % of hospitals. Prioritization of some hospital processes for barcoding, system integration with Hospital Information system (HIS), training of staff and budgeting are requirements for the successful implementation which had been infringed in the 80% of hospitals. Dissatisfaction with the quality of barcode labels and lacks of adequate scanners both whit the rate of 100 %, and the lack of understanding of the necessary requirements for implementation of barcodes as 80% were the most important barrier. CONCLUSION: Integrate bar code system with clinical workflow should be considered. Lack of knowledge and understanding toward the infrastructure, inadequate staff training and technologic problems are considered as the greatest barriers. PMID- 27482138 TI - Application of Agree II Instrument for Appraisal of Postpartum Hemorrhage Clinical Practice Guidelines in Bosnia and Herzegovina. AB - INTRODUCTION: Federal Minister of Health and Minister of Health and Social Welfare of the Republika Srpska as a Governmental health authorities in Federation of Bosnia and Herzegovina (FBiH) and the Republika Srpska nominated/appointed health professionals as their representatives to a multidisciplinary Guidelines Adaptation Group (GAG). This group started with its work in September 2015. The main purpose of the guidelines development exercise is to develop guidelines with worldwide recognized methodology for clinical guidelines development and adaptation. At the end of this consultancy, GAG would have develop a clinical practice guideline on Postpartum hemorrhage (PPH) through the adaptation method, starting from published international clinical guidelines and adapting it according to the country specific requirements. METHODOLOGY: During the process of identifying the best guideline for adaptation, the GAG had to pass several steps. One of the crucial steps was to identify the questions related to clinical practice and health policy for which answers are needed to be addressed by the guideline. These questions included relevant issues regarding the topic area such as diagnosis, prognosis, intervention, service delivery, and training. After that, six guidelines have been researched by the six members of the GAG to see if they answered the identified questions. Evaluating the methodological quality of the selected clinical guidelines was a second essential step before deciding which ones could best fit the needs and interests. AGREE II instrument has been chosen as methods for evaluating clinical guideline quality and appropriateness. Four appraisers conducted the assessment of each of the selected guidelines for PPH. All appraisers passed the training for the AGREE II instrument before conducting appraisals, as recommended by the AGREE collaboration. Each of the four guidelines was rated independently with the AGREE II tool by each appraiser. RESULTS: The highest score was obtained by the WHO recommendations for postpartum hemorrhage guidelines and each of four assessors recommended it to be adapted and further implemented. DISCUSSION: In spite of several serous attempts and two Agencies for quality improvement in BiH the whole process of guideline adaptation is still in the beginning and therefore the establishment of a strong connection with similar institutions and organizations from our region and the rest of the world is very important. Cooperation and collaboration across institutions and countries and key stakeholders have potential to significantly improve the validity and quality of the adapted guidelines and to positively influence implementation. PMID- 27482139 TI - Radiological Findings of Michel Aplasia. AB - INTRODUCTION: Congenital abnormalities of the inner ear is the most common cause of neurosensory hearing loss. Michel inner ear deformity is a rare developmental anomaly refers to the total aplasia of the inner ear. It is caused by developmental arrest of otic placode early during the third week of gestational age. CASE REPORT: We have discussed here that three year old girl diagnosed Michel aplasia with temporal bone computed tomography (CT) and temporal magnetic resonance imaging (MRI) findings. PMID- 27482140 TI - Ectopic Origin of Coronary Arteries Diagnozed by Coronary Angiography. AB - INTRODUCTION: Anomalous origin of coronary arteries from opposite sinus of Valsalva is rare finding. The incidence of anomalous origination of the left coronary artery from right sinus is 0.15% and the right coronary artery from the left sinus is 0.92%. The ectopic origin of left coronary artery or right coronary artery from opposite sinus depending on pathways and considering atherosclerotic changes are manifested with different clinical significance. CASE REPORT: We report two cases, the first case the coronary angiography showed the left coronary artery arising from the right coronary sinus, presenting with proximally and distally stenosed left anterior descending artery (LAD), associated with medial and distal stenosed right coronary artery (RCA). The second case the coronary angiography revealed the right coronary artery arising from the left coronary sinus, associated with tortuous medial and distal segments of left anterior descending artery (LAD), without atherosclerotic changes. The first case successfully underwent treatment procedures based on guidelines for revascularization. CONCLUSION: The coronary angiography of patients with coronary ischemia determines atherosclerotic disease with possibility of the presence of coronary artery anomalies that in cases with ectopic origin from opposite sinus continues to exist as a challenge during treatment in interventional cardiology. PMID- 27482141 TI - The Most Influential Scientists in the Development of Medical informatics (12): Joshua Lederberg. PMID- 27482142 TI - Love and Service in Adolescent Addiction Recovery. AB - This article is one of the first to examine the relationships among a specific combination of "spiritual virtues" (helping others and the experience of divine love) and outcomes related to criminal involvement, sobriety, and character development among adolescents. One-hundred ninety five adolescents with substance dependency court-referred to residential treatment were assessed at intake, discharge, and 6 months post-treatment. Higher service to others predicted reduced recidivism, reduced relapse, and greater character development. Experiencing divine love enhanced the effect of service on recidivism. Greater attention to spiritual virtues might improve treatment for youth involved with alcohol, drugs, and certain forms of crime. PMID- 27482143 TI - Stereoselective Synthesis of Trisubstituted Vinyl Bromides by Addition of Alkynes to Oxocarbenium Ions. AB - We have developed an efficient method for the synthesis of (E)-trisubstituted vinyl bromides via a Friedel-Crafts-type addition of alkynes to oxocarbenium ions formed in situ from acetals. The success of this reaction relies on identification of MgBr2.OEt2 as both a Lewis acid promoter and bromide source. This reaction employs simple, inexpensive starting materials and proceeds under mild conditions to allow the preparation of a range of vinyl bromide products in high yields and E:Z selectivities. Furthermore, the vinyl bromide products also contain an allylic ether functional group. Both the vinyl bromide and allylic ether are effective handles for the elaboration of these useful synthetic intermediates. PMID- 27482145 TI - Medicine and Charity in Eighteenth-century Northumberland: The Early Years of the Bamburgh Castle Dispensary and Surgery, c. 1772-1802. AB - In 1772 in Bamburgh Castle, Northumberland, a charitable institution was established by Dr John Sharp to offer medical provision to the poor of the parish, which was remote from the Newcastle and Edinburgh Infirmaries. Unlike urban institutions, which have dominated hospital historiography, the Bamburgh dispensary was small, occupying only a few rooms in the castle, and situated in a remote, coastal location. And yet, at its height, the Bamburgh dispensary treated thousands of patients per year, often exceeding dispensaries in large towns, and was equipped with the latest medical technologies. Unlike the majority of infirmaries and dispensaries it was not funded by subscription, nor run by governors, but was entirely funded by the Lord Crewe Trust, and administered by Dr Sharp. While Bamburgh is certainly an anomaly, it raises new questions about voluntary institutional medical provision for rural populations, and forms of medical philanthropy. PMID- 27482144 TI - ToF-SIMS imaging of molecular-level alteration mechanisms in Le Bonheur de vivre by Henri Matisse. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has recently been shown to be a valuable tool for cultural heritage studies, especially when used in conjunction with established analytical techniques in the field. The ability of ToF-SIMS to simultaneously image inorganic and organic species within a paint cross section at micrometer-level spatial resolution makes it a uniquely qualified analytical technique to aid in further understanding the processes of pigment and binder alteration, as well as pigment-binder interactions. In this study, ToF-SIMS was used to detect and image both molecular and elemental species related to CdS pigment and binding medium alteration on the painting Le Bonheur de vivre (1905-1906, The Barnes Foundation) by Henri Matisse. Three categories of inorganic and organic components were found throughout Le Bonheur de vivre and co localized in cross-sectional samples using high spatial resolution ToF-SIMS analysis: (1) species relating to the preparation and photo-induced oxidation of CdS yellow pigments (2) varying amounts of long-chain fatty acids present in both the paint and primary ground layer and (3) specific amino acid fragments, possibly relating to the painting's complex restoration history. ToF-SIMS's ability to discern both organic and inorganic species via cross-sectional imaging was used to compare samples collected from Le Bonheur de vivre to artificially aged reference paints in an effort to gather mechanistic information relating to alteration processes that have been previously explored using MUXANES, SR-MUXRF, SEM-EDX, and SR-FTIR. The relatively high sensitivity offered by ToF-SIMS imaging coupled to the high spatial resolution allowed for the positive identification of degradation products (such as cadmium oxalate) in specific paint regions that have before been unobserved. The imaging of organic materials has provided an insight into the extent of destruction of the original binding medium, as well as identifying unexpected organic materials in specific paint layers. PMID- 27482146 TI - Immigration, Statecraft and Public Health: The 1920 Aliens Order, Medical Examinations and the Limitations of the State in England. AB - This article considers the medical measures of the 1920 Aliens Order barring aliens from Britain. Building on existing local and port public health inspection, the requirement for aliens to be medically inspected before landing significantly expanded the duties of these state agencies and necessitated the creation of a new level of physical infrastructure and administrative machinery. This article closely examines the workings and limitations of alien medical inspection in two of England's major ports-Liverpool and London-and sheds light on the everyday working of the Act. In doing so it reflects on the ambitions, actions and limitations of the state and so extends research by historians of the nineteenth and early twentieth century on the disputed histories of public health and the complexities of statecraft. Overall it suggests the importance of developing nuanced understandings of the gaps and failures arising from the translation of legislation into practice. PMID- 27482147 TI - Transnational Nationalism and Idealistic Science: The Alcohol Question between the Wars. AB - This article studies the interwar international conferences on the alcohol problem. How did they view the alcohol problem and its causes; what were the consequences for the individual and the society as a whole; and which solutions merited discussion? The first post-war conferences enjoyed an optimistic and internationalistic atmosphere, added to by American prohibition, which had given the temperance movement plenty to be hopeful about. But when the 1920s turned to the 1930s, the conferences were transformed into arenas for national solutions and into outright propaganda pieces. The responses to the alcohol problem debated in the interwar conferences built on a combination of scientifically masked ideological conviction and ideologically inspired passion for science. The apparently neutral ethics of such thinking was manifested in various radical measures to combat alcohol abuse. PMID- 27482148 TI - Low Other-Regard and Adolescent Addiction. AB - Although 12-step literature posits inconsiderate behaviors to characterize alcoholics and addicts, there is little data to support this association among adolescent populations. Using a matched-pair study design with 579 youth aged 14 18 (52% female, 30% minority), a significant, dose-response relationship was found between greater alcohol and drug use severity and increased likelihood of driving under the influence, having unprotected sex with and without a history of sexually transmitted incidence, and low volunteerism among boys. Findings suggest that alcohol and drug use severity is associated with poor awareness of the impact of behaviors on others. PMID- 27482149 TI - Increased water use efficiency does not prevent growth decline of Pinus canariensis in a semi-arid treeline ecotone in Tenerife, Canary Islands (Spain). AB - KEY MESSAGE: Intrinsic water-use efficiency of Pinus canariensis (Sweet ex Spreng.) growing at a semi-arid treeline has increased during the past 37 years. Tree-ring width by contrast has declined, likely caused by reduced stomatal conductance due to increasing aridity. CONTEXT: Rising atmospheric CO2 concentration (Ca ) has been related to tree growth enhancement accompanied by increasing intrinsic water-use-efficiency (iWUE). Nevertheless, the extent of rising Ca on long-term changes in iWUE and growth has remained poorly understood to date in Mediterranean treeline ecosystems. AIMS: This study aimed to examine radial growth and physiological responses of P. canariensis in relation to rising Ca and increasing aridity at treeline in Tenerife, Canary Islands, Spain. METHODS: We evaluated temporal changes in secondary growth (tree-ring width; TRW) and tree ring stable C isotope signature for assessing iWUE from 1975 through 2011. RESULTS: Precipitation was the main factor controlling secondary growth. Over the last 36 years P. canariensis showed a decline in TRW at enhanced iWUE, likely caused by reduced stomatal conductance due to increasing aridity. CONCLUSION: Our results indicate that increasing aridity has overridden the potential CO2 fertilization on tree growth of P. canariensis at its upper distribution limit. PMID- 27482150 TI - [Developing Perceived Competence Scale (PCS) for Adolescents]. AB - In this study, Perceived Competence Scale was developed to measure high school students' perceived competence. Scale development process was verified on three different samples. Participants of the research are some high school students in 2011-2012 academic terms from Ankara. Participants' numbers are incorporated in exploratory factor analysis, confirmatory factor analysis and test-retest reliability respectively, as follows: 372, 668 and 75. Internal consistency coefficients (Cronbach's and stratified alpha) are calculated separately for each group. For data analysis Factor 8.02 and LISREL 8.70 package programs were used. According to results of the analyses, internal consistency coefficients (alpha) are .90 - .93 for academic competence, .82 - .86 for social competence in the samples that exploratory and confirmatory factor analysis performed. For the whole scale internal consistency coefficient (stratified alpha) is calculated as .91. As a result of test-retest reliability, adjusted correlation coefficients (r) are .94 for social competence and .90 for academic competence. In addition, to fit indexes and regression weights obtained from factor analysis, findings related convergent and discriminant validity, indicating that competence can be addressed in two dimensions which are academic (16 items) and social (14 items). PMID- 27482151 TI - A preliminary investigation of the relationship between early maladaptive schemas and compulsive sexual behaviors in a substance-dependent population. AB - Past research has consistently demonstrated high co-occurrence between substance use disorders (SUDs) and compulsive sexual behaviors (CSBs). Numerous studies have also indicated that maladaptive core beliefs and early maladaptive schemas (EMS) are prevalent among individuals with SUDs and CSBs. However, research has yet to examine the relationship between EMS and CSBs among substance-dependent populations. Thus, the purpose of the current study was to examine this relationship in a sample of 198 men and 62 women in residential treatment for SUDs. Findings demonstrated that the five EMS domains were positively associated with CSBs. Results further demonstrated that patients meeting the cutoff score for CSBs scored significantly higher than patients not meeting the cutoff score for CSBs on the EMS domains of disconnection/rejection, impaired autonomy, and impaired limit. These findings suggest that there is an important and significant relationship between EMS and CSBs among adults in substance use treatment. Results from the current study indicate that EMS may provide a potentially important focus for treatment, particularly among individuals with co-morbid CSBs and SUDs. Given the preliminary nature of this study, continued research is needed to replicate and extend the findings from the current study. PMID- 27482152 TI - Cultural ecosystem services of mountain regions: Modelling the aesthetic value. AB - Mountain regions meet an increasing demand for pleasant landscapes, offering many cultural ecosystem services to both their residents and tourists. As a result of global change, land managers and policy makers are faced with changes to this landscape and need efficient evaluation techniques to assess cultural ecosystem services. This study provides a spatially explicit modelling approach to estimating aesthetic landscape values by relating spatial landscape patterns to human perceptions via a photo-based survey. The respondents attributed higher aesthetic values to the Alpine landscape in respect to areas with settlements, infrastructure or intensive agricultural use. The aesthetic value of two study areas in the Central Alps (Stubai Valley, Austria and Vinschgau, Italy) was modelled for 10,215 viewpoints along hiking trails according to current land cover and a scenario considering the spontaneous reforestation of abandoned land. Viewpoints with high aesthetic values were mainly located at high altitude, allowing long vistas, and included views of lakes or glaciers, and the lowest values were for viewpoints close to streets and in narrow valleys with little view. The aesthetic values of the reforestation scenario decreased mainly at higher altitudes, but the whole area was affected, reducing aesthetic value by almost 10% in Stubai Valley and 15% in Vinschgau. Our proposed modelling approach allows the estimation of aesthetic values in spatial and qualitative terms for most viewpoints in the European Alps. The resulting maps can be used as information and the basis for discussion by stakeholders, to support the decision making process and landscape planning. This paper also discusses the role of mountain farming in preserving an attractive landscape and related cultural values. PMID- 27482153 TI - Validation and clinical implementation of commercial secondary check software with heterogeneity corrections. AB - AIM: To validate and implement PTW diamond secondary check software (SCS) in a routine clinical use. BACKGROUND: The secondary independent monitor unit or dose calculation verifications have led to a significant increase in the workflow associated with QA treatments. Modelling, validation and commissioning are necessary steps thereby making it a useful tool for QA. MATERIALS AND METHODS: PTW Diamond SCS is capable of calculating VMAT fields, based on modified Clarkson integration, accounting for multi-leaf collimators (MLC) transmission and measured collimator scatter factors. Validation for heterogeneity corrections is made using circular phantom with inserts of various density materials. 150 VMAT plans were compared using (i) plans calculated in homogeneous cylindrical phantom and (ii) VMAT plans calculated with heterogeneity corrections using electron density values for each organ. RESULTS: Diamond SCS calculated dose for homogeneous cylindrical phantom resulted in average deviation of (0.1 +/- 2.14%) with Eclipse TPS calculated dose and (-2.0 +/- 1.66%) with absolute measured dose. PTW's OCTAVIUS-4D phantom with 729 ion chamber detector array measurements agreed well with Eclipse TPS calculated dose showing an average deviation of ( 1.69 +/- 1.56%). Diamond SCS dose calculations were performed with heterogeneity corrections for 124 VMAT plans with isocentre at a region above -350 HU. The overall MU variations between Diamond SCS and TPS Acuros-XB algorithms were within +/-5%. CONCLUSION: Hence, the Diamond SCS can be used as an additional tool along with phantom measurements for patient specific quality assurance of VMAT plans with heterogeneity corrections having isocentre at a region above -350 HU. PMID- 27482154 TI - EPIDEMIOLOGY OF MUSCULOSKELETAL DISORDERS IN PRIMARY SCHOOL CHILDREN IN BOSNIA AND HERZEGOVINA. AB - INTRODUCTION: Musculoskeletal disorders represent a significant problem of modern society which are more pronounced in young people and school children. Etiology of these disorders is found in inadequate ergonomic conditions, too heavy school bag, school furniture inadequate to age, poor posture, sedentary lifestyle, reduction of physical activity and lack of exercise. MATERIAL AND METHODS: This cross-sectional study included 1315 pupils aged 8- 12 years. As a method was used "cluster sample" in the selection of subjects. The survey was conducted by questionnaire containing information on the demographic and individual characteristics of participants (age, gender, class), the manner and style of life and the performance of school tasks, followed by standardized Nordic questionnaire. The following parameters were measured: body height and weight for each student, and the weight of full and empty school bag that students that day brought to class. RESULTS: The incidence of musculoskeletal pain regardless of localization was 48%. There is a statistically significant correlation between acute pain in the right shoulder and total weight of school bags, duration of caring the bag in school and time of wearing bag from school to home but not with the manner in which school bag was carried. Acute pain in the right shoulder and acute neck pain were significantly associated with the duration of sitting in school or in front of a computer at home. Acute pain in the shoulder negatively correlated with BMI percentile value of the respondents. Acute pain in the neck is also significantly associated with the weight of a full school bags, as well as time spent sitting at home doing homework. Acute back pain is statistically significantly correlated with the weight of school bags and duration of sitting periods in school. CONCLUSION: The prevalence of musculoskeletal pain, particularly chronic pain in school children aged 8-12 years is high. Weight of school bags, manner in which the bag is carried to and from school, duration of carrying bags, time spent sitting in the school and in front of the computer, duration of sitting and posture during homework, body mass index are ergonomic reasons for the development of musculoskeletal pain. PMID- 27482155 TI - PATIENTS' SATISFACTION WITH HEALTH SERVICES AT THE NATIONAL INSTITUTE OF PUBLIC HEALTH OF KOSOVA. AB - AIM: Purpose of the research is to assess patient satisfaction with the quality of health services provided in National Institute of Public Health of Kosova. METHODS: Study was observational and cross-sectional. Interviews were conducted with 625 clients of IPH. Inclusion criteria for enrollment in the study were patients above 18 years old, with verbally informed consent. RESULTS: In our study, access to IPH, efficacy, patient-provider interpersonal communication, and explanations regarding procedures, readiness to answer to patients need and physical settings and appearance are valued satisfactorily whereas cleanliness was rated with minimal grades. Evaluated 12 quality components, were scored with average mark 3.6. CONCLUSIONS: SWOT analysis, and fishbone diagram should be used on regular bases and a new position for a manager for administrative issues, is opened, complaints box and list of rights and responsibilities of patients were dislocated in a more visible place, and internal staff turnover, is introduced. PMID- 27482156 TI - SOCIO-DEMOGRAPHIC AND LIFESTYLE CORRELATES OF SELF-PERCEIVED HEALTH STATUS IN A POPULATION-BASED SAMPLE OF ALBANIAN ADULT MEN AND WOMEN. AB - AIM: Self-perceived health is considered a suitable health indicator, based on a single item asking individuals to rate their health. It has been recommended as a reliable factor to assess the population health. Several socio-demographic and lifestyle determinants of self-perceived health status have been documented in different population. The aim of our study was to assess the socio-demographic and lifestyle correlates of self-perceived health status in a population-based sample of Albanian adult men and women. METHODS: Data from 12,554 individuals aged >=35 years collected by the Albania Living Standard Measurement Survey (LSMS) 2012, which is a national population-based cross-sectional study, were analyzed. The study participants rated their health in five categories: very good, good, average, poor and very poor, which in the analyses were dichotomized into "not poor" and "poor health". Other variables included demographic characteristics, economic level, employment status, smoking and alcohol intake. Binary logistic regression was used to assess the association of self-perceived health with demographic and lifestyle factors. RESULTS: Upon multivariate adjustment for all covariates in a backward stepwise elimination procedure, strong and significant "predictors" of poor self-perceived health status were older age (OR=3.0, 95%CI=2.4-3.7), unemployment (OR=5.6, 95%CI=4.0-7.8), male gender (OR=1.2, 95%CI=1.0-1.5), low education (OR=2.0, OR=1.3-3.0), current smoking (OR=1.7, 95%CI=1.2-2.4) and alcohol abstinence (OR=1.4, 95%CI=1.1-1.7). CONCLUSIONS: Our findings indicate that the low socioeconomic groups in Albania have a significantly lower self-perceived health status. Furthermore, smoking was a significant "determinant" of poor self-perceived health in this study population, which is compatible with previous reports from other countries. PMID- 27482157 TI - FEMALE SEXUAL DYSFUNCTION (FSD) IN WOMEN HEALTH CARE WORKERS. AB - PURPOSE: The main aim of this study is to investigate the occurrence and severity of FSD in women working in tertiary hospitals. MATERIAL AND METHODS: The study sample was drawn from health care women between the ages of 20 and 65 years, working in two hospitals in Greece. This descriptive study used a structured Greek questionnaire and sexual function screener and quality of life sectors were consisted of rated scale questions. Eighty eight questionnaires were returned properly completed. The statistical analysis used the SPSS statistical program. RESULTS: Female sexual dysfunction is a highly prevalent health issue whose exact incidence is not well defined. Factors that can contribute to female sexual dysfunction may be psychogenic, physical, mixed or unknown. Each of these factors consists of individual components that influence the sexual response; however their precise impact in FSD development and progression is unknown. Moreover, the role of circadian rhythm disorders (especially that of shift work sleep disorder) to the development and progression of FSD has been poorly investigated. CONCLUSION: Working environment and patterns of work schedules may play a role in FSD however it has been difficult to specify in what extent they contribute to FSD development. PMID- 27482158 TI - URINARY PROBLEMS AMONGST GYNECOLOGICAL CONSULTATIONS. ASSOCIATION BETWEEN PROLAPSE, GYNECOLOGICAL SURGERY AND DIABETES. AB - BACKGROUND: Urinary incontinence is the inability of a woman to maintain bladder control. Symptoms range from urgency, frequency, nocturia to urge incontinence (1). It limits functional and social activities and leads to depression and social withdrawal. (2). This observational study aimed to describe the common urinary problems amongst gynecological consultations. It also describes the relationship of urinary incontinence with history of diabetes, previous gynecological surgery and prolapse. METHODS: The study was conducted as a descriptive cross sectional study from Jan-May 2015 at Qassim University Clinic, Buraidah. Women with urinary problem and those without urinary problems were compared for risk factors including diabetes, prolapse and previous gynecological surgery. The Statistical Package for the Social Sciences 22 (SPSS 22) was used to conduct proportion z-tests to determine the association of prolapse, gynecological surgeries and diabetes with urinary incontinence. To test the hypothesis, differences between two groups on the aforementioned factors were examined. The groups included participants that reported having urinary problems (n = 111) and those who do not have urinary problems (n = 100). RESULTS: The most frequent complaints of participants with urinary problems were urgency (n = 66, 59.46%), Stress incontinence (SI) (n = 65, 58.56%) and frequency (n = 62, 55.86%). For participants with a urinary problem, 89.19% have not had a gynecological surgery (n = 99) and the remaining 10.81% of participants had a gynecological surgery (n = 12). For participants without a urinary problem, 97.0% have not had a gynecological surgery (n = 97) and the remaining 3.0% had a gynecological surgery (n = 3). For participants with a urinary problem, 72.97% did not have diabetes (n = 81) and the remaining 27.03% of participants did have diabetes (n = 30). For participants without a urinary problem, 92.0% did not have diabetes (n = 92) and the remaining 8.0% did report having diabetes (n = 8). For participants with a urinary problem, 91.89% had not experienced a prolapse (n = 102) and the remaining 8.11% of participants had experienced a prolapse (n = 9). For participants without a urinary problem, 98.0% have not experienced a prolapse (n = 98) and the remaining two participants had experienced a prolapse. CONCLUSION: Gynecological conditions such as prolapse of the uterus, surgery involving the pelvic floor as well as medical conditions such as diabetes mellitus are some of the key risk factors for urinary incontinence. Therefore control of these risk factors can avoid development of urinary incontinence. Bladder retraining, Kegel exercises, drinking of less fluids are some of the preventive measures to avoid development of this embarrassing condition. PMID- 27482159 TI - ASSESSMENT OF RISK FACTORS FOR DIABETES MELLITUS TYPE 2. AB - INTRODUCTION: Diabetes is a group of metabolic diseases characterized by hyperglycemia, and represents a disease of the modern age, disease of the 21st century. Prevention of this disease is listed as imperative. Aim of this article was to evaluate questionnaires on the assessment of risk factors for Diabetes Mellitus type 2. MATERIAL AND METHODS: A total of 540 questionnaires handed out randomly to citizens of Canton Sarajevo of all ages, sexes and educational levels (in January 2016) were analyzed. RESULTS: Analyzed questionnaires showed relatively low risk of getting diabetes in the next ten years in the majority of the population. These results are rather encouraging but may in some way be in confrontation with the statistics which show a rapid outburst of diabetes. CONCLUSION: The life-style is the main reason for such a thing to happen, and looking at these questionnaires, we might get the feeling that we really do live in a, conditionally speaking, physically active society. That, from our everyday experience is not entirely true. It would be wise to continue doing research on this topic on the territory of Bosnia and Herzegovina. PMID- 27482160 TI - THE EFFECT OF THE INTERNET ADDICTION ON THE INFORMATION-SEEKING BEHAVIOR OF THE POSTGRADUATE STUDENTS. AB - INTRODUCTION: Internet addiction is a typical use of the internet that causes the psychological, social, educational, or occupational problems for the people. Students need the internet more than other people due to their educational or research needs. The rate and type of the internet use may affect their information-seeking behavior too. This study aims to investigate the effect of the internet addiction on the information-seeking behavior of the postgraduate students. METHODS: This applied study that uses the correlation method. The research population composed of 1149 postgraduate students of Isfahan University of Medical Sciences, of which 284 were selected using the stratified random sampling as the sample. Yang's internet addiction questionnaire and the researcher-developed questionnaire of the information-seeking behavior were used as the data collection instruments. Instrument validity was confirmed by the specialists of librarianship and medical sciences and its reliability was confirmed using the Cronbach's alpha coefficient (0.86). Research data were analyzed using the descriptive statistics (mean and standard deviation) and inferential statistics (independent-t tests, Pearson correlation coefficient, and variance analysis). RESULTS: Based on the findings, there was no sign of internet addiction among the 86.6% of the students. However, 13% of the students were exposed to the internet addiction and only 0.4% of internet addiction was observed among the students. There was no significant difference between the information-seeking behavior of the male and female respondents. There was no sign of the internet addiction in any dimension of the information-seeking behavior of the students. CONCLUSION: This study showed that there is no relationship between the information-seeking behavior of the students and the age and the rate of the internet use. Promoting the network infrastructures and increasing the internet speed as well as facilitating the use of electronic resources should be prioritized by the officials. PMID- 27482162 TI - THE SOURCE OF INFECTION AND THE MOST FREQUENT CAUSES OF REACTIVE ARTHRITIS IN KOSOVO. AB - INTRODUCTION: Reactive arthritis is an autoimmune condition which emerges as a counteraction towards an infection which has a focus elsewhere in the body. The purpose of this study is isolation of causative agents of reactive arthritis and ascertains the source of infection. The study has been carried out in the Rheumatology Clinic in Prishtina and specialized ambulance O.S. "Vendenisi-AL" in Besiana, whereas isolation of causative agents has been carried out in the National Institute for Public Health (NIPH). The study has prospective, comparative and analytical feature. RESULTS: Out of 100 patients, 66% were males and 34% females. Among males we have noticed domination of post-urethritis and post-streptococcic reactive arthritis, whereas among females dominates reactive arthritis of enteral etiology. The study concludes that: urogenital tract was the source of infection with 66% of cases, nasopharyngeal tract with 19% of cases, and enteral tract with 15% of cases respectively. Predominantly presents bacteria are E. Coli with 21%, Staphylococcus aureus with 20%, Streptococcus B. hem. gr. A with 16% of cases respectively and other species. CONCLUSION: frequency of arthritis with urogenital etiology was 2:1 in favor of males, with nasopharyngeal etiology 3:1 in favor of males, whereas in arthritis with enteral etiology we have noticed a slight dominance in favor of females. PMID- 27482161 TI - APPRAISAL OF ACCESS TO DENTAL SERVICES IN SOUTH EAST OF IRAN USING FIVE AS MODEL. AB - BACKGROUND: Access to dental services not only refers to utilization but also to the extent by which the utilization is judged according to professional norms. This study aimed to study the access to dental services using the Five As model. METHODS: This cross sectional study was conducted in southeast of Iran. A sample of 400 subjects participated in the study according to a multistage sampling method. A questionnaire was used for data collection. Data were analyzed using independent T test, ANOVA and multivariate linear regression models by means of SPSS V.20 software. FINDINGS: Affordability, availability, accessibility, accommodation and acceptability mean scores were 58.2+/-12.2, 53.9+/-12.9, 59.4+/ 15.7, 60.2+/-8.6, 70+/-11.5 and 60.3+/-7.4 respectively. According to multivariate linear regression models, there was significant associations between affordability and age, education level, having basic insurance and family income. Moreover, total accessibility was significantly correlated with education and monthly family income. CONCLUSION: This study showed that access to dental services was at the moderate level among the studied population. It also revealed that age, basic insurance coverage, family income and level of education, are determinants of this accessibility. PMID- 27482163 TI - THE RELATIONSHIP BETWEEN ORGANIZATIONAL JUSTICE AND TURNOVER INTENTION OF HOSPITAL NURSES IN IRAN. AB - BACKGROUND: Despite advances in science and technology, human resources are of the major capital for organizations. Workforce retention is required to improve organizational efficiencies. OBJECTIVE: Therefore, in this study, the relationship between organizational justice (as one of the most influential factors) and turnover intention was investigated. METHODS: This descriptive analytic study was done in the Comprehensive Jame Women's Hospital of Tehran in 2015. The statistical sample consisted of 135 nursing staff members. The data were collected using a questionnaire of Beugre's organizational justice and analyzed by the use of Spearman's and Anova statistical tests. RESULTS: Averages of organizational justice was obtained to be 68.85 +/- 7.67 . Among different sorts of organizational justice, the highest average score of 75.24 +/- 16.68 was achieved relevant to interactional justice. A significant relationship was observed between organizational justice (r = -0.36), interactional justice (r = 0.38), and procedural justice (r = -0.36) and turnover intention, but no relation was found between turnover intention and systemic and distributive justice. Furthermore, there was no relationship between demographic variables, organizational justice, and turnover intention. CONCLUSION: Considering the prominent role of organizational justice in the personnel's intention to stay or leave and due to the high costs of recruiting and training new staff, managers should pay especial attention to justice and provide their employees' satisfaction and stability in their organizations by creating a positive mindset in them. PMID- 27482164 TI - FACTORS ASSOCIATED WITH HEALTH-RELATED QUALITY OF LIFE AMONG UNIVERSITY STUDENTS IN TURKEY. AB - INTRODUCTION: Purpose of this descriptive study is to determine the mental health problems and quality of life levels of college students and examine the relationship between them. METHODS: The sample of the study consisted of 429 students continuing their education in Health School at Afyon Kocatepe University. Data were collected by using information form, Brief Symptom Inventory (BSI), SF 36 Quality of Life Scale questionnaires. In the analysis of obtained data, descriptive statistics, t-test, ANOVA and correlation analyses were used. FINDINGS: Mental symptoms which the students got the highest scores from the subscales of BSI were respectively, depression (1.31+/-0.75), hostility (1.22+/-0.67) and anxiety (1.00+/-0.65). Discomfort severity index which is the overall score of the scale was found 1.07+/-0.61. Relation between state of mind and quality of life was found statistically significant (F: 70.894; p<0.000). When quality of life summary scores examined, it was found out that physical health summary score (48.92+/-7.93) and mental health summary score (43.44+/ 9.52) points were low. CONCLUSIONS: Consequently, according to averages of scores, it can be said that frequency of the mental symptoms of students are high but their quality of life is low. It was found that when students' quality of life decreased, their mental symptoms increased. PMID- 27482165 TI - ASSOCIATION BETWEEN DISABILITY AND QUALITY OF LIFE IN MULTIPLE SCLEROSIS PATIENTS IN AHVAZ, IRAN. AB - INTRODUCTION: Multiple Sclerosis (MS) is a neurodegenerative and chronic disease of central nervous system which affected the middle aged people. The disabling nature of this disease can limit the daily activities, restrict the society roles, unemployment and finally lead to decline the quality of life (QoL) in MS patients. So, the main purpose of this study was to determine association between disability and quality of life among MS patients in Ahvaz, Iran. MATERIALS AND METHODS: One hundred and one MS patients who living in Khouzestan participated in the cross-sectional study. Two questionnaires include the MSQoL-54 and World Health Organization disability assessment schedule 2.0 (WHODAS2.0) were used in order to measure the QoL and disability severity. Descriptive statistics as well as Pearson correlation coefficient and simple linear regression were used to analysis the data. RESULTS: The respondent rate was 100 percent. The disability showed a large and negative association with QoL (p<0.001) but QoL was not significantly associated with EDSS score. Social participation and cognition subscales recognized as QoL predictors according to simple regression results. CONCLUSION: The cognition and participation, disability subscales, were the most important predicators for QoL. Therefore, increasing employment opportunities, changing society's attitude and using the psychotherapy programs might improve the MS patient's QoL. PMID- 27482167 TI - WORK ETHICS, ORGANIZATIONAL ALIENATION AND JUSTICE AMONG HEALTH INFORMATION TECHNOLOGY MANAGERS. AB - INTRODUCTION: Failure to comply with work ethics by employees working in Health Information Technology (HIT) Departments and their negative attitudes about organizational justice may have an adverse impact on patient satisfaction, quality of care, collecting health statistics, reimbursement, and management and planning at all levels of health care; it can also lead to unbearable damages to the health information system in the country. As so far there has been no research on HIT managers to assess the moral and ethical aspects of works and their relationship with organizational alienation and justice, this study aimed to evaluate the relationship between work ethics and organizational justice and alienation among the HIT managers. METHODS: This study was performed in affiliated hospitals of Semnan University of medical sciences in Semnan, Iran, in 2015. In this study, a census method was used. The data collection tool was a researcher made questionnaire. RESULTS: There was a negative and significant relationship between work ethic and organizational alienation (B= - 0.217, P<0.001), and there was also a positive and significant relationship between work ethic and organizational justice (B= 0.580, P<0.001). There were negative and significant relationships among between education level and work ethic (B= - 0.215, P=0.034) and organizational justice (B=- 0.147, P=0.047). CONCLUSION: The results of this study showed that the managers' attitude toward justice and equality in the organization can affect their organizational commitment and loyalty and thus have a significant impact on the work ethics in the work environment. On the other hand, with increasing the education level of the managers, they will have higher expectation of the justice in the organization, and they feel that the justice is not observed in the organization. PMID- 27482166 TI - EFFECT OF THERAPEUTIC TOUCH ON PAIN RELATED PARAMETERS IN PATIENTS WITH CANCER: A RANDOMIZED CLINICAL TRIAL. AB - INTRODUCTION: In patients with cancer, pain may influence their life style, and feeling of satisfaction and comfort, leading to fatigue, and cause impairment of their quality of life, personal relationships, sleep and daily activities. The aim of this study was to evaluate the effect of therapeutic touch (TT) on pain related parameters of in patients with cancer. METHODS: In a randomized clinical trial a total of 90 male patients referring to Specialized Oncology Hospital in Mashhad, were conveniently selected and randomly divided into three intervention, placebo, and control groups. The intervention consisted of TT in 7 sessions for a 4-week period. The data were collected using a demographic questionnaire along with the Brief Pain Inventory, which were then analyzed and compared using Kruskal-Wallis and Mann-Whitney tests. RESULTS: By comparing scores parameters of pain scales (general activity, mood, walking ability, relations with other people and sleep) in the three groups, there was no significant difference at the beginning of the first session. However, a significant difference was observed at the end of TT sessions between the three groups (p= 0.001). Furthermore, the groups were compared two-by-two by using Mann-Whitney test and Bonferroni correction, and the result indicated significant differences between the two intervention and placebo groups as well as between the two intervention and control groups. CONCLUSION: The results of the study showed that TT had a positive impact on the positive management of pain related parameters in cancer patients. Therefore, TT is suggested to be used by healthcare providers as a complementary method for managing pain and its parameters. PMID- 27482168 TI - THE TRANSLATION, VALIDATION AND CULTURAL ADAPTATION OF FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY - SPIRITUAL WELL-BEING 12 (FACIT-SP12) SCALE IN GREEK LANGUAGE. AB - BACKGROUND: According to World Health Organization (WHO), spirituality is an important domain of quality of life especially in terminal, life threatens chronic diseases. For many people spirituality and religion are not just very important dimensions of their existence, but also a source of support that contributes to wellbeing and coping with everyday difficulties of life. AIM: Aim of the study was the translation of the Facit Spiritual Well Being Scale (Facit Sp12) in Greek language and the validation of the scale for the Greek population. MATERIAL AND METHODS: The Facit-Sp12 questionnaire is an anonymous self administered questionnaire that contains twelve, four point Likert scale, closed questions (0=Not at all, 1=A little bit, 2=Some-what, 3=Quite a bit, 4=Very Much). The questionnaire was translated into Greek language and then back translated in the English in order to be checked for any inconsistencies. The sample of the study was 183 chronic kidney disease patients, undergoing hemodialysis. Exploratory factor analysis, with principal components analysis with Varimax rotation was performed for checking the construct validity of the questionnaire. The test-retest reliability and the internal consistency were also examined. Statistical analysis performed by the use of SPSS 21.0. Statistical significance level was set at p=0.05. RESULTS: The final Greek version of the questionnaire includes all of the twelve questions. The mean age of the participants was 61.81+/-13.9. Three factors were exported from the statistical analysis. The Cronbach-alpha coefficient was 0.77 for the total questionnaire and for each subscale was 0.70 for "meaning", 0.73 for "peace" and 0.87 for "faith". Between the three subscales "meaning" had the highest score (mean 12.49, SD=2.865). CONCLUSIONS: The Facit Spiritual Wellbeing Scale-Facit-Sp12, is a valuable and reliable questionnaire of three dimensions that can be used for assessing spirituality and spiritual wellbeing in Greek population. PMID- 27482169 TI - THE ROLE OF CYSTEINE PROTEASE IN ALZHEIMER DISEASE. AB - INTRODUCTION: Cysteine protease are biological catalysts which play a pivotal role in numerous biological reactions in organism. Much of the literature is inscribed to their biochemical significance, distribution and mechanism of action. Many diseases, e.g. Alzheimer's disease, develop due to enzyme balance disruption. Understanding of cysteine protease's disbalance is therefor a key to unravel the new possibilities of treatment. Cysteine protease are one of the most important enzymes for protein disruption during programmed cell death. Whether protein disruption is part of cell deaths is not enough clear in any cases. Thereafter, any tissue disruption, including proteolysis, generate more or less inflammation appearance. REVIEW: This review briefly summarizes the current knowledge about pathological mechanism's that results in AD, with significant reference to the role of cysteine protease in it. Based on the summary, new pharmacological approach and development of novel potent drugs with selective toxicity targeting cysteine protease will be a major challenge in years to come. PMID- 27482170 TI - RETRACTED PAPERS FROM THE JOURNAL "MATERIA SOCIO-MEDICA". AB - [This retracts the article on p. 228 in vol. 26, PMID: 25395881.]. PMID- 27482172 TI - Digestive Disease Week. PMID- 27482171 TI - Comparing Multi-Informant Assessment Measures of Parental Monitoring and Their Links with Adolescent Delinquent Behavior. AB - OBJECTIVE: Parents' poor monitoring of adolescents' whereabouts and activities is commonly linked to adolescents' increased engagement in delinquent behaviors. Yet, different domains of parental monitoring (parental monitoring behaviors vs. parental knowledge) and reports from multiple informants (parent vs. adolescent) may vary in their links to delinquent behavior. DESIGN: Seventy-four parental caregivers and 74 adolescents completed survey measures of parental monitoring and knowledge, and adolescents completed self-report surveys of delinquent behavior. RESULTS: We observed low-to-moderate magnitudes of correspondence between parent- and adolescent-reports of parental monitoring behaviors and parental knowledge. Adolescent self-reported delinquent behavior related to parent and adolescent reports of parental monitoring behaviors and parental knowledge, with adolescents who self-reported engagement in delinquent behaviors evidencing lower levels of parental knowledge and higher levels of poor monitoring compared to adolescents who did not self-report engagement in delinquent behaviors. Adolescent self-reported engagement in delinquent behaviors evidenced stronger links to parental monitoring when based on adolescent reports of monitoring (relative to parent reports), whereas stronger links held between adolescent self-reported delinquent behavior and parental knowledge when based on parent reports of knowledge (relative to adolescent reports). CONCLUSIONS: Links between monitoring and adolescents' delinquent behavior vary by the kind of monitoring measure completed as well as the informant completing the measure. These findings inform measurement selection in research and clinical assessments of parental monitoring and adolescent delinquent behavior. PMID- 27482173 TI - Antiviral Therapy in Elderly Patients With Hepatitis C Virus Infection. AB - The emergence of direct-acting antiviral (DAA) agents has revolutionized the treatment schema for hepatitis C virus (HCV) infection. From cure rates to tolerability, DAA agents have shown outstanding profiles compared with the prior therapy of pegylated interferon with ribavirin. However, the efficacy and safety profiles of DAA therapy in older patients, particularly the elderly, have been unclear, and patients in the 1945 to 1965 birth cohort constitute the largest proportion of the HCV population in the United States. Treating elderly patients with pegylated interferon and ribavirin has been challenging due to the frequent presence of multiple comorbidities in the elderly and high discontinuation rates caused by adverse events. Now, as more DAA agents have become widely studied and approved, subgroup analyses for the elderly population are being elucidated. Analysis of the current literature shows that these agents have been effective, well tolerated, and safe in the elderly population. This article highlights the efficacy and safety differences in interferon-based therapy and interferon-free regimens for elderly patients with HCV infection. PMID- 27482176 TI - Roadblocks to Accessing Direct-Acting Antiviral Agents for Treatment of Hepatitis C Virus Infection. PMID- 27482174 TI - Chromoendoscopy and Dysplasia Surveillance in Inflammatory Bowel Disease: Past, Present, and Future. AB - The evidence supporting the practice of dysplasia surveillance in inflammatory bowel disease (IBD) has remained sparse, and optimal detection strategies are still lacking. These issues, added to the declining incidence of dysplasia in IBD, have led to much debate over the diagnosis and management of dysplasia. White-light endoscopy with targeted and random biopsies remains the technique of choice for most practicing gastroenterologists. However, during the past decade, a surge of literature has questioned the efficacy of this strategy. Simultaneously, chromoendoscopy has emerged as an alternative, and perhaps superior, technique that has been included in some society guidelines. Nevertheless, many issues remain unclear, such as the best way to implement chromoendoscopy into everyday practice, whether there are any outcome benefits that can be attributed to the use of chromoendoscopy, and, perhaps most importantly, how to manage dysplasia uncovered by this and other advanced techniques. In this article, we discuss the various techniques currently available for dysplasia surveillance in IBD, with a focus on chromoendoscopy. Additionally, we highlight the overarching issues of setting appropriate endpoints and individualizing the care of patients with long-standing colitis. PMID- 27482177 TI - New Targets for Small Molecules in Inflammatory Bowel Disease. PMID- 27482178 TI - Nonmedical Treatment of Gastroesophageal Reflux Disease. PMID- 27482175 TI - Management of Biliary Strictures After Liver Transplantation. AB - Strictures of the bile duct are a well-recognized complication of liver transplant and account for more than 50% of all biliary complications after deceased donor liver transplant and living donor liver transplant. Biliary strictures that develop after transplant are classified as anastomotic strictures or nonanastomotic strictures, depending on their location in the bile duct. The incidence, etiology, natural history, and response to therapy of the 2 types vary greatly, so their distinction is clinically important. The imaging modality of choice for the diagnosis of biliary strictures is magnetic resonance cholangiopancreatography because of its high rate of diagnostic accuracy and limited risk of complications. Biliary strictures that develop after liver transplant may be managed with endoscopic retrograde cholangiography (ERC), percutaneous transhepatic cholangiography (PTC), or surgical revision, including retransplant. The initial treatment of choice for these strictures is ERC with progressive balloon dilation and the placement of increasing numbers of plastic stents. PTC and surgery are generally reserved for failures of endoscopic therapy or for anatomic variants that are not suitable for ERC. In this article, we discuss the classification of biliary strictures, their diagnosis, and the therapeutic strategies that can be used to manage these common complications of liver transplant. PMID- 27482179 TI - Inflammatory Bowel Disease in Women. PMID- 27482180 TI - Gastro-Hep News. PMID- 27482181 TI - Sex-Specific Issues in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) affects approximately 1 in 500 people living in the United States and generally occurs with equal frequency in men and women. However, despite equal sex distribution of the disease, men and women face unique challenges that can significantly impact quality of life. As more is discovered regarding the pathogenesis, clinical manifestations, and treatment of IBD, physiologic and psychological differences between men and women with IBD have become increasingly apparent. It is important to understand these differences, as they have the potential to affect patient care and outcomes. This article will review sex-specific issues in IBD, such as impaired body image and sexuality, increased risk of cervical cancer, altered menstrual cycles, reduced fertility, and low bone mineral density. PMID- 27482182 TI - Autoimmune Pancreatitis: A Multiorgan Disease Presenting a Conundrum for Clinicians in the West. AB - Autoimmune pancreatitis (AIP), a clinical entity originally described in East Asia and more recently recognized in the United States and Europe, poses a diagnostic conundrum for clinicians in the West due to immunoglobulin G4 seronegativity. Although expert panels classify this disease into 2 types, it remains difficult to stratify the disease given that both types share most clinical, biochemical, and imaging characteristics. The classic presentation of AIP can mimic that of pancreatic carcinoma, which increases the urgency of evaluation, diagnosis, and treatment. In this article, we elucidate the differences between the 2 types of AIP, highlight the shortcomings of the current classification system, and propose a more inclusive view of the disorder. PMID- 27482184 TI - Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease. PMID- 27482185 TI - Screening for Barrett Esophagus With a Nonendoscopic Sponge Capsule. PMID- 27482183 TI - Advances in Capsule Endoscopy. AB - Wireless video capsule endoscopy (VCE) is a minimally invasive technology that has revolutionized the approach to small intestinal disease investigation and management. Designed primarily to provide diagnostic imaging of the small intestine, VCE is used predominantly for obscure gastrointestinal bleeding and suspected Crohn's disease; however, numerous other indications have been established, including the assessment of celiac disease, investigation of small bowel tumors, and surveillance of hereditary polyposis syndromes. Since the introduction of small bowel VCE in 2000, more than 1600 articles have been published describing the evolution of this technology. The main adverse outcome is capsule retention, which can potentially be avoided by careful patient selection or by using a patency capsule. Despite the numerous advances in the past 15 years, limitations such as incomplete VCE studies, missed lesions, and time-consuming reporting remain. The inability to control capsule movement for the application of targeted therapy or the acquisition of tissue for histologic analysis remains among the greatest challenges in the further development of capsule technology. This article outlines the recent technological and clinical advances in VCE and the future directions of research in this field. PMID- 27482186 TI - The Relationship Between the Gut Microbiota and Liver Disease. PMID- 27482187 TI - Novel Peppermint Oil Formulation for Dietary Management of Irritable Bowel Syndrome. PMID- 27482188 TI - Pancreatic Pseudocyst Drainage Using Lumen-Apposing Metal Stents. PMID- 27482189 TI - Early Gastric Cancer Just above a Heterotopic Pancreas. AB - We report the first case of early gastric cancer just above a heterotopic pancreas for which the differential diagnosis was carcinoma arising from heterotopic pancreas. Routine upper gastrointestinal endoscopy in an 83-year-old man with sigmoid colon cancer revealed a gastric cancer in the lesser curvature of the antrum. Endoscopic ultrasonography (EUS) for evaluating the depth of tumor invasion revealed a hypoechoic mass in the submucosal layer. The depth of tumor invasion was diagnosed as muscularis propria. Distal gastrectomy and sigmoidectomy were performed. Histologically, the resected specimen of the stomach unexpectedly revealed a heterotopic pancreas just below the gastric cancer. They were not linked, and the heterotopic pancreas had no dysplasia. The gastric cancer had slightly invaded the submucosa. The hypoechoic mass on EUS was not the invasive tumor but the heterotopic pancreas. The preoperative staging of the gastric cancer on EUS was confounded by the presence of the heterotopic pancreas just below the gastric cancer. PMID- 27482190 TI - Efficacy of Prothrombin Complex Concentrate Treatment in Patients with Liver Coagulopathy Who Underwent Various Invasive Hepatobiliary and Gastrointestinal Procedures. AB - BACKGROUND: Prothrombin complex concentrates (PCCs) containing prothrombin, factors VII, IX, and X, as well as the inhibitors protein C and S have been used as an emergent reversal for oral anticoagulation therapy. The use of PCCs in hepatobiliary disorder patients or patients with liver coagulopathy who need to undergo invasive procedures has not been well studied. OBJECTIVE: To evaluate the efficacy of PCC treatment in order to control or prevent bleeding complications in patients with liver coagulopathy who undergo various invasive procedures. METHODS: This was a prospective, open-label, non-randomized, before-and-after study in patients with hepatobiliary disorders who underwent invasive procedures accompanied by liver impairment and received PCC injection (Cofact((r)), Sanquin, The Netherlands). Patients with coagulopathy from various causes were recruited consecutively. Data collected were the episodes of bleeding, liver function test and the international normalized ratio (INR) before and after PCC therapy. The primary endpoint was INR change after treatment, while secondary endpoints included bleeding control and bleeding event after treatment. RESULTS: Thirty patients (17 men, 13 women) were enrolled. Patients' mean age was 57.0 + 15.5 years. Liver cirrhosis was found in 14 patients (46.7%). The procedures consisted of liver biopsy, liver abscess aspiration, abdominal paracentesis, therapeutic upper gastrointestinal endoscopy, abdominal surgery, endoscopic retrograde cholangiopancreatography and percutaneous transhepatic biliary drainage. After treatment, 25 patients (83.3%) showed a decreased median INR (from 1.6 to 1.3) (p < 0.001, Wilcoxon's signed-rank test). Five patients failed to show INR reduction. No new bleeding event related to the invasive procedures was observed. CONCLUSION: PCC treatment is effective to control and prevent bleeding complications in patients with liver coagulopathy who undergo invasive procedures. PMID- 27482192 TI - Crystal-Associated Colitis with Ulceration Leading to Hematochezia and Abdominal Pain. AB - Lower GI bleeding is a common cause for hospitalization in adults. Medication associated mucosal injury is an important clinical entity that can result in significant morbidity and mortality. We present the case of a 45-year-old woman with a 3-month history of intermittent abdominal cramping and rectal bleeding. Her medical history was extensive and included end-stage renal disease and a remote history of endometrial carcinoma that was treated with radiation. Initial workup was concerning for ischemic and radiation colitis, however, histology was most consistent with acute inflammation and ulceration associated with crystal fragments. Sevelamer and cholestyramine are commonly used ion-exchange resins that have been associated with mucosal damage. Both medications were discontinued and her symptoms resolved. Our case highlights an underrecognized but important cause of hematochezia. PMID- 27482191 TI - Early, Isolated Duodenal Mucosa-Associated Lymphoid Tissue Lymphoma Presenting without Symptoms or Grossly Apparent Endoscopic Lesions and Diagnosed by Random Duodenal Biopsies. AB - Clinical data regarding mucosa-associated lymphoid tissue lymphoma (MALToma) solely involving the duodenum are sparse because of the relative rarity of the disease. A comprehensive literature review revealed only 17 cases reported until 2004, and only a moderate number of cases have been reported since. MALToma can be asymptomatic in its very early stages but frequently produces localized or nonspecific symptoms, including early satiety, abdominal pain, vomiting, and involuntary weight loss in later stages. While gastric MALToma is strongly associated with gastric Helicobactor pylori infection, duodenal MALToma is often unassociated with H. pylori infection. A 74-year-old female presented with only dysphagia (without symptoms referable to a duodenal lesion), without systemic 'B' symptoms, and with no evident duodenal lesions at esophagogastroduodenoscopy; however, she was diagnosed with duodenal MALToma by pathologic examination of random duodenal biopsies performed to exclude celiac disease. An important clinical feature of this case is that duodenal MALToma was diagnosed by pathologic analysis of duodenal biopsies despite (1) no endoscopically apparent duodenal lesions; (2) duodenal involvement without gastric involvement; (3) lack of symptoms attributable to duodenal MALToma, and (4) absence of evident H. pylori infection. This work shows that early duodenal MALToma can be difficult to diagnose because of absent symptoms, absence of gastric involvement, absence of endoscopic abnormalities, and absence of H. pylori infection; it may require random duodenal biopsies for diagnosis. PMID- 27482193 TI - Ascending Colon Cancer Associated with Dermatomyositis Which Was Cured after Colon Resection. AB - A 76-year-old woman with muscle ache, weakness of the extremities, and skin rash was diagnosed with dermatomyositis (DM). Upon the diagnosis of DM, a systemic survey of malignancy revealed an advanced carcinoma of the ascending colon. The patient underwent right hemicolectomy approximately 2 months after the onset of DM. The symptoms and signs of DM disappeared after the surgery without additional therapy. DM is an idiopathic systemic inflammatory disease characterized by muscle ache, muscle weakness, and skin rash. In some cases, DM develops as paraneoplastic syndrome, and it is assumed that 30% of DM patients have cancer. Symptoms and signs of DM can be attenuated by treatment of the malignancy, and they reappear if the malignancy recurs. It is essential to perform a systemic survey of malignancy in DM patients, and treatment of the malignancy has to precede treatment of DM. PMID- 27482195 TI - Confocal Cornea Microscopy Detects Involvement of Corneal Nerve Fibers in a Patient with Light-Chain Amyloid Neuropathy Caused by Multiple Myeloma: A Case Report. AB - Changes in the subbasal corneal plexus detected by confocal cornea microscopy (CCM) have been described for various types of neuropathy. An involvement of these nerves within light-chain (AL) amyloid neuropathy (a rare cause of polyneuropathy) has never been shown. Here, we report on a case of a patient suffering from neuropathy caused by AL amyloidosis and underlying multiple myeloma. Small-fiber damage was detected by CCM. PMID- 27482194 TI - Radio-nanomaterials for biomedical applications: state of the art. AB - The incorporation of radioactive isotope(s) into conventional nanomaterials can bring extra properties which are not possessed by original materials. The resulting radioactive nanomaterials (radio-nanomaterials), with added physical/chemical properties, can be used as important tools for different biomedical applications. In this review, our goal is to provide an up-to-date overview on these applications using radio-nanomaterials. The first section illustrates the utilization of radionanomaterials for understanding of in vivo kinetics of their parent nano-materials. In the second section, we focus on two primary applications of radio-nanomaterials: imaging and therapeutic delivery. With various methods being used to form radio-nanomaterials, they can be used for positron emission tomography (PET), single-photon emission computed tomography (SPECT), and multimodal imaging. Therapeutic isotopes-loading radio-nanomaterials can possess selective killing efficacy of diseased cells (e.g. tumor cells) and can provide promises for certain isotopes which are not able to be used in a conventional manner. The successful and versatile biomedical applications of radio-nanomaterials warrants further investigations of those materials and their optimizations can pave the way to future imaging guidable, personalized treatments in patients. PMID- 27482196 TI - Intravenous Thrombolysis after Reversal of Dabigatran by Idarucizumab: A Case Report. AB - We describe a 75-year-old female patient with nonvalvular atrial fibrillation who presented with acute ischemic stroke during treatment with dabigatran 2 * 110 mg per day. After informed consent, we reversed the anticoagulant effects of dabigatran using idarucizumab and applied an intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (off-label use). An intracerebral hemorrhage was excluded after systemic thrombolysis. Despite the IVT, the patient's clinical condition deteriorated and she developed an ischemic lesion in the right pons, the right thalamus and right cerebellum. To date, the literature lacks data concerning the thrombolytic treatment of acute ischemic stroke in patients after specific reversal of the non-vitamin K oral anticoagulant dabigatran using idarucizumab. Given the rapid and sustainable efficacy of idarucizumab, the reversal of dabigatran followed by thrombolysis seems to be safe, but further studies and register data are still needed to confirm our preliminary observation, especially to provide additional data concerning the risk-benefit evaluation. PMID- 27482197 TI - Endogenous bioelectric fields: a putative regulator of wound repair and regeneration in the central nervous system. AB - Studies on a variety of highly regenerative tissues, including the central nervous system (CNS) in non-mammalian vertebrates, have consistently demonstrated that tissue damage induces the formation of an ionic current at the site of injury. These injury currents generate electric fields (EF) that are 100-fold increased in intensity over that measured for uninjured tissue. In vitro and in vivo experiments have convincingly demonstrated that these electric fields (by their orientation, intensity and duration) can drive the migration, proliferation and differentiation of a host of cell types. These cellular behaviors are all necessary to facilitate regeneration as blocking these EFs at the site of injury inhibits tissue repair while enhancing their intensity promotes repair. Consequently, injury-induced currents, and the EFs they produce, represent a potent and crucial signal to drive tissue regeneration and repair. In this review, we will discuss how injury currents are generated, how cells detect these currents and what cellular responses they can induce. Additionally, we will describe the growing evidence suggesting that EFs play a key role in regulating the cellular response to injury and may be a therapeutic target for inducing regeneration in the mammalian CNS. PMID- 27482199 TI - The intricacies of neurotrophic factor therapy for retinal ganglion cell rescue in glaucoma: a case for gene therapy. AB - Regeneration of damaged retinal ganglion cells (RGC) and their axons is an important aspect of reversing vision loss in glaucoma patients. While current therapies can effectively lower intraocular pressure, they do not provide extrinsic support to RGCs to actively aid in their protection and regeneration. The unmet need could be addressed by neurotrophic factor gene therapy, where plasmid DNA, encoding neurotrophic factors, is delivered to retinal cells to maintain sufficient levels of neurotrophins in the retina. In this review, we aim to describe the intricacies in the design of the therapy including: the choice of neurotrophic factor, the site and route of administration and target cell populations for gene delivery. Furthermore, we also discuss the challenges currently being faced in RGC-related therapy development with special considerations to the existence of multiple RGC subtypes and the lack of efficient and representative in vitro models for rapid and reliable screening in the drug development process. PMID- 27482200 TI - Discovery of nigral dopaminergic neurogenesis in adult mice. AB - Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra. As a result, intensive efforts have focused upon mechanisms that facilitate the death of mature dopaminergic neurons. Unfortunately, these efforts have been unsuccessful in providing an effective treatment to address neurodegeneration in this disease. Therefore, alternative theories of pathogenesis are being explored. Adult neurogenesis of dopaminergic neurons is an attractive concept that would provide a possible mechanism of neurodegeneration as well as offer an endogenous means to replenish affected neurons. To determine whether dopaminergic neurons experience neurogenesis in adult mice we developed a novel cell lineage tracing model that permitted detection of neurogenesis without many of the issues associated with popular techniques. Remarkably, we discovered that dopaminergic neurons are replenished in adult mice by Nestin+/Sox2- progenitor cells. What's more, the rate of neurogenesis is similar to the rate of dopaminergic neuron loss reported using a chronic, systemic inflammatory response mouse model. This observation may indicate that neuron loss in Parkinson's disease results from inhibition of neurogenesis. PMID- 27482198 TI - Neuroprotection and antioxidants. AB - Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial processes, such as protein agregation, reactions of free radicals, insufficient blood supply, glutamate excitotoxicity, and oxidative stress. The result of these processes can be apoptotic or necrotic cell death and it can lead to an irreversible damage. Therefore, neuroprotection and prevention of the neurodegeneration are highly important topics to study. There are several approaches to prevent the ischemic damage. Use of many modern therapeutical methods and the incorporation of several substances into the diet of patients is possible to stimulate the endogenous protective mechanisms and improve the life quality. PMID- 27482201 TI - Methylprednisolone for acute spinal cord injury: an increasingly philosophical debate. AB - Following publication of NASCIS II, methylprednisolone sodium succinate (MPSS) was hailed as a breakthrough for patients with acute spinal cord injury (SCI). MPSS use for SCI has since become very controversial and it is our opinion that additional evidence is unlikely to break the stalemate amongst clinicians. Patient opinion has the potential to break this stalemate and we review our recent findings which reported that spinal cord injured patients informed of the risks and benefits of MPSS reported a preference for MPSS administration. We discuss the implications of the current MPSS debate on translational research and seek to address some misconceptions which have evolved. As science has failed to resolve the MPSS debate we argue that the debate is an increasingly philosophical one. We question whether SCI might be viewed as a serious condition like cancer where serious side effects of therapeutics are tolerated even when benefits may be small. We also draw attention to the similarity between the side effects of MPSS and isotretinoin which is prescribed for the cosmetic disorder acne vulgaris. Ultimately we question how patient autonomy should be weighed in the context of current SCI guidelines and MPSS's status as a historical standard of care. PMID- 27482203 TI - Role of myelin auto-antigens in pain: a female connection. PMID- 27482202 TI - Oligodendrocyte ablation as a tool to study demyelinating diseases. AB - Multiple sclerosis (MS) is an autoimmune mediated neurodegenerative disease characterized by demyelination and oligodendrocyte (OL) loss in the central nervous system and accompanied by local inflammation and infiltration of peripheral immune cells. Although many risk factors and symptoms have been identified in MS, the pathology is complicated and the cause remains unknown. It is also unclear whether OL apoptosis precedes the inflammation or whether the local inflammation is the cause of OL death and demyelination. This review briefly discusses several models that have been developed to specifically ablate oligodendrocytes in an effort to separate the effects of demyelination from inflammation. PMID- 27482204 TI - Bursting the unfolded protein response accelerates axonal regeneration. PMID- 27482205 TI - Graphene platform for neural regenerative medicine. PMID- 27482206 TI - Neuroprotective role of galectin-1 in central nervous system pathophysiology. PMID- 27482207 TI - N-acetyl proline-glycine-proline: implications for neurological disorders. PMID- 27482208 TI - A shape shifting organelle: unusual mitochondrial phenotype determined with three dimensional electron microscopy reconstruction. PMID- 27482209 TI - Role of granulocyte macrophage colony stimulating factor in regeneration of the central nervous system. PMID- 27482210 TI - Neuroprotective properties of extracellular vesicles derived from mesenchymal stem cells. PMID- 27482211 TI - The role of postsynaptic density proteins in neural degeneration and regeneration. PMID- 27482212 TI - Modification of ubiquitin C-terminal hydrolase L1 by reactive lipid species: role in neural regeneration and diseases of aging. PMID- 27482213 TI - Targeting BPOZ-2 in Lewy body disease. PMID- 27482214 TI - ARBs improve stroke outcome through an AT2-dependent, BDNF-induced proangiogenic and prorecovery response. PMID- 27482215 TI - The implication of neurovascular unit signaling in controlling the subtle balance between injury and repair following ischemic stroke. PMID- 27482216 TI - Natural product based novel small molecules with promising neurotrophic, neurogenic and anti-neuroinflammatory actions can be developed as stroke therapeutics. PMID- 27482217 TI - Retinal ganglion cell neuroprotection induced by activation of alpha7 nicotinic acetylcholine receptors. PMID- 27482218 TI - Time dependent differences in gray matter volume post mild traumatic brain injury. PMID- 27482219 TI - Decorin treatment for reversing trabecular meshwork fibrosis in open-angle glaucoma. PMID- 27482220 TI - Time- and cell-type specific changes in iron, ferritin, and transferrin in the gerbil hippocampal CA1 region after transient forebrain ischemia. AB - In the present study, we used immunohistochemistry and western blot analysis to examine changes in the levels and cellular localization of iron, heavy chain ferritin (ferritin-H), and transferrin in the gerbil hippocampal CA1 region from 30 minutes to 7 days following transient forebrain ischemia. Relative to sham controls, iron reactivity increased significantly in the stratum pyramidale and stratum oriens at 12 hours following ischemic insult, transiently decreased at 1 2 days and then increased once again within the CA1 region at 4-7 days after ischemia. One day after ischemia, ferritin-H immunoreactivity increased significantly in the stratum pyramidale and decreased at 2 days. At 4-7 days after ischemia, ferritin-H immunoreactivity in the glial components in the CA1 region was significantly increased. Transferrin immunoreactivity was increased significantly in the stratum pyramidale at 12 hours, peaked at 1 day, and then decreased significantly at 2 days after ischemia. Seven days after ischemia, Transferrin immunoreactivity in the glial cells of the stratum oriens and radiatum was significantly increased. Western blot analyses supported these results, demonstrating that compared to sham controls, ferritin H and transferrin protein levels in hippocampal homogenates significantly increased at 1 day after ischemia, peaked at 4 days and then decreased. These results suggest that iron overload-induced oxidative stress is most prominent at 12 hours after ischemia in the stratum pyramidale, suggesting that this time window may be the optimal period for therapeutic intervention to protect neurons from ischemia-induced death. PMID- 27482222 TI - Developmental process of the arcuate fasciculus from infancy to adolescence: a diffusion tensor imaging study. AB - We investigated the radiologic developmental process of the arcuate fasciculus (AF) using subcomponent diffusion tensor imaging (DTI) analysis in typically developing volunteers. DTI data were acquired from 96 consecutive typically developing children, aged 0-14 years. AF subcomponents, including the posterior, anterior, and direct AF tracts were analyzed. Success rates of analysis (AR) and fractional anisotropy (FA) values of each subcomponent tract were measured and compared. AR of all subcomponent tracts, except the posterior, showed a significant increase with aging (P < 0.05). Subcomponent tracts had a specific developmental sequence: First, the posterior AF tract, second, the anterior AF tract, and last, the direct AF tract in identical hemispheres. FA values of all subcomponent tracts, except right direct AF tract, showed correlation with subject's age (P < 0.05). Increased AR and FA values were observed in female subjects in young age (0-2 years) group compared with males (P < 0.05). The direct AF tract showed leftward hemispheric asymmetry and this tendency showed greater consolidation in older age (3-14 years) groups (P < 0.05). These findings demonstrated the radiologic developmental patterns of the AF from infancy to adolescence using subcomponent DTI analysis. The AF showed a specific developmental sequence, sex difference in younger age, and hemispheric asymmetry in older age. PMID- 27482221 TI - Neuroprotective effects of bloodletting at Jing points combined with mild induced hypothermia in acute severe traumatic brain injury. AB - Bloodletting at Jing points has been used to treat coma in traditional Chinese medicine. Mild induced hypothermia has also been shown to have neuroprotective effects. However, the therapeutic effects of bloodletting at Jing points and mild induced hypothermia alone are limited. Therefore, we investigated whether combined treatment might have clinical effectiveness for the treatment of acute severe traumatic brain injury. Using a rat model of traumatic brain injury, combined treatment substantially alleviated cerebral edema and blood-brain barrier dysfunction. Furthermore, neurological function was ameliorated, and cellular necrosis and the inflammatory response were lessened. These findings suggest that the combined effects of bloodletting at Jing points (20 MUL, twice a day, for 2 days) and mild induced hypothermia (6 hours) are better than their individual effects alone. Their combined application may have marked neuroprotective effects in the clinical treatment of acute severe traumatic brain injury. PMID- 27482223 TI - Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up regulating caveolin-1 expression. AB - Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser(404)(p-tau (S(404))), and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S(404)) levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury. PMID- 27482224 TI - Mechanisms responsible for the effect of median nerve electrical stimulation on traumatic brain injury-induced coma: orexin-A-mediated N-methyl-D-aspartate receptor subunit NR1 upregulation. AB - Electrical stimulation of the median nerve is a noninvasive technique that facilitates awakening from coma. In rats with traumatic brain injury-induced coma, median nerve stimulation markedly enhances prefrontal cortex expression of orexin-A and its receptor, orexin receptor 1. To further understand the mechanism underlying wakefulness mediated by electrical stimulation of the median nerve, we evaluated its effects on the expression of the N-methyl-D-aspartate receptor subunit NR1 in the prefrontal cortex in rat models of traumatic brain injury induced coma, using immunohistochemistry and western blot assays. In rats with traumatic brain injury, NR1 expression increased with time after injury. Rats that underwent electrical stimulation of the median nerve (30 Hz, 0.5 ms, 1.0 mA for 15 minutes) showed elevated NR1 expression and greater recovery of consciousness than those without stimulation. These effects were reduced by intracerebroventricular injection of the orexin receptor 1 antagonist SB334867. Our results indicate that electrical stimulation of the median nerve promotes recovery from traumatic brain injury-induced coma by increasing prefrontal cortex NR1 expression via an orexin-A-mediated pathway. PMID- 27482225 TI - Large-conductance Ca(2+)-activated K(+) channel involvement in suppression of cerebral ischemia/reperfusion injury after electroacupuncture at Shuigou (GV26) acupoint in rats. AB - Excess activation and expression of large-conductance Ca(2+)-activated K(+) channels (BKCa channels) may be an important mechanism for delayed neuronal death after cerebral ischemia/reperfusion injury. Electroacupuncture can regulate BKCa channels after cerebral ischemia/reperfusion injury, but the precise mechanism remains unclear. In this study, we established a rat model of cerebral ischemia/reperfusion injury. Model rats received electroacupuncture of 1 mA and 2 Hz at Shuigou (GV26) for 10 minutes, once every 12 hours for a total of six times in 72 hours. We found that in cerebral ischemia/reperfusion injury rats, ischemic changes in the cerebral cortex were mitigated after electroacupuncture. Moreover, BKCa channel protein and mRNA expression were reduced in the cerebral cortex and neurological function noticeably improved. These changes did not occur after electroacupuncture at a non-acupoint (5 mm lateral to the left side of Shuigou). Thus, our findings indicate that electroacupuncture at Shuigou improves neurological function in rats following cerebral ischemia/reperfusion injury, and may be associated with down-regulation of BKCa channel protein and mRNA expression. Additionally, our results suggest that the Shuigou acupoint has functional specificity. PMID- 27482226 TI - Establishment of a rat model of chronic thoracolumbar cord compression with a flat plastic screw. AB - Previous studies of animal models of chronic mechanical compression of the spinal cord have mainly focused on cervical and thoracic lesions, but few studies have investigated thoracolumbar injury. The specific pathophysiological mechanism of chronic thoracolumbar cord injury has not yet been elucidated. The purpose of this study was to improve animal models of chronic thoracolumbar cord compression using the progressive screw. A custom-designed flat plastic screw was implanted in the spinal cord between thoracic vertebrae 12 and lumbar 1 of rats. The screw was tightened one complete turn (0.5 mm) every 7 days for 4 weeks to create different levels of chronic spinal cord compression. Following insertion of the screw, there was a significant decline in motor function of the hind limbs, and severe stenosis of micro-computed tomography parameters in the spinal cord. Cortical somatosensory evoked potential amplitudes were reduced remarkably, and latencies were prolonged at 30 minutes after surgery. The loss of motor neurons in the gray matter was marked. Demyelination and cavitation were observed in the white matter. An appropriate rat model of chronic thoracolumbar cord compression was successfully created using the progressive screw compression method, which simulated spinal cord compression injury. PMID- 27482227 TI - Central neuromechanisms underlying control of intragastric pressure through acupuncture at Zusanli (ST36) in rats: the upper cervical cord is the key link between the ascending and descending pathways. AB - Sensory inputs stimulated by Zusanli (ST36) acupuncture in the abdomen are known to converge in the upper cervical cord. However, it is unclear whether these inputs are subsequently conveyed to the hypothalamic paraventricular nucleus and what kind of afferent fibers are involved. We focused on the upper cervical cord, where afferent inputs converge, and detected c-fos expression in oxytocinergic neurons. We found that Zusanli acupuncture therapy effectively elevated intragastric pressure, but inhibited expression of c-fos in oxytocinergic neurons of the paraventricular nucleus in upper cervical cord injured rats. These Zusanli acupuncture effects remained even after complete dorsal cord transection. However, after complete transection of the spinal cord or dorsolateral funiculus, the effects were significantly attenuated and even disappeared. These findings suggest that the paraventricular nucleus is responsible for pooling and integrating signals from the Zusanli acupuncture and sensory information from the intragastric pressure variation, thereby contributing to the regulation of intragastric pressure. The upper cervical cord serves as the key link between ascending and descending pathways, which conveys afferent inputs to the paraventricular nucleus through the dorsolateral funiculus. PMID- 27482229 TI - ROCK inhibition enhances neurite outgrowth in neural stem cells by upregulating YAP expression in vitro. AB - Spontaneous axonal regeneration of neurons does not occur after spinal cord injury because of inhibition by myelin and other inhibitory factors. Studies have demonstrated that blocking the Rho/Rho-kinase (ROCK) pathway can promote neurite outgrowth in spinal cord injury models. In the present study, we investigated neurite outgrowth and neuronal differentiation in neural stem cells from the mouse subventricular zone after inhibition of ROCK in vitro. Inhibition of ROCK with Y-27632 increased neurite length, enhanced neuronal differentiation, and upregulated the expression of two major signaling pathway effectors, phospho-Akt and phospho-mitogen-activated protein kinase, and the Hippo pathway effector YAP. These results suggest that inhibition of ROCK mediates neurite outgrowth in neural stem cells by activating the Hippo signaling pathway. PMID- 27482228 TI - Atorvastatin activates autophagy and promotes neurological function recovery after spinal cord injury. AB - Atorvastatin, a lipid-lowering medication, provides neuroprotective effects, although the precise mechanisms of action remain unclear. Our previous studies confirmed activated autophagy following spinal cord injury, which was conducive to recovery of neurological functions. We hypothesized that atorvastatin could also activate autophagy after spinal cord injury, and subsequently improve recovery of neurological functions. A rat model of spinal cord injury was established based on the Allen method. Atorvastatin (5 mg/kg) was intraperitoneally injected at 1 and 2 days after spinal cord injury. At 7 days post-injury, western blot assay, reverse transcription-polymerase chain reaction, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining results showed increased Beclin-1 and light chain 3B gene and protein expressions in the spinal cord injury + atorvastatin group. Additionally, caspase 9 and caspase-3 expression was decreased, and the number of TUNEL-positive cells was reduced. Compared with the spinal cord injury + saline group, Basso, Beattie, and Bresnahan locomotor rating scale scores significantly increased in the spinal cord injury + atorvastatin group at 14-42 days post-injury. These findings suggest that atorvastatin activated autophagy after spinal cord injury, inhibited apoptosis, and promoted recovery of neurological function. PMID- 27482230 TI - Indirubin-3'-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation. AB - Indirubin-3'-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer's disease. Here, we found that indirubin-3'-monoxime improved the morphology and increased the survival rate of SH-SY5Y cells exposed to amyloid-beta 25-35 (Abeta25-35), and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3'-monoxime inhibited phosphorylation of glycogen synthase kinase-3beta (GSK-3beta). Our results suggest that indirubin 3'-monoxime reduced Abeta25-35-induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3beta-mediated mechanism. Indirubin-3'-monoxime is a promising drug candidate for Alzheimer's disease. PMID- 27482231 TI - Transplantation of human adipose tissue-derived stem cells for repair of injured spiral ganglion neurons in deaf guinea pigs. AB - Excessive noise, ototoxic drugs, infections, autoimmune diseases, and aging can cause loss of spiral ganglion neurons, leading to permanent sensorineural hearing loss in mammals. Stem cells have been confirmed to be able to differentiate into spiral ganglion neurons. Little has been reported on adipose tissue-derived stem cells (ADSCs) for repair of injured spiral ganglion neurons. In this study, we hypothesized that transplantation of neural induced-human ADSCs (NI-hADSCs) can repair the injured spiral ganglion neurons in guinea pigs with neomycin-induced sensorineural hearing loss. NI-hADSCs were induced with culture medium containing basic fibroblast growth factor and forskolin and then injected to the injured cochleae. Guinea pigs that received injection of Hanks' balanced salt solution into the cochleae were used as controls. Hematoxylin-eosin staining showed that at 8 weeks after cell transplantation, the number of surviving spiral ganglion neurons in the cell transplantation group was significantly increased than that in the control group. Also at 8 weeks after cell transplantation, immunohistochemical staining showed that a greater number of NI-hADSCs in the spiral ganglions were detected in the cell transplantation group than in the control group, and these NI-hADSCs expressed neuronal markers neurofilament protein and microtubule-associated protein 2. Within 8 weeks after cell transplantation, the guinea pigs in the cell transplantation group had a gradually decreased auditory brainstem response threshold, while those in the control group had almost no response to 80 dB of clicks or pure tone burst. These findings suggest that a large amount of NI-hADSCs migrated to the spiral ganglions, survived for a period of time, repaired the injured spiral ganglion cells, and thereby contributed to the recovery of sensorineural hearing loss in guinea pigs. PMID- 27482232 TI - miR-148b-3p promotes migration of Schwann cells by targeting cullin-associated and neddylation-dissociated 1. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that negatively adjust gene expression in multifarious biological processes. However, the regulatory effects of miRNAs on Schwann cells remain poorly understood. Previous microarray analysis results have shown that miRNA expression is altered following sciatic nerve transaction, thereby affecting proliferation and migration of Schwann cells. This study investigated whether miR-148b-3p could regulate migration of Schwann cells by directly targeting cullin-associated and neddylation-dissociated 1 (Cand1). Up regulated expression of miR-148b-3p promoted Schwann cell migration, whereas silencing of miR-148b-3p inhibited Schwann cell migration in vitro. Further experiments confirmed that Cand1 was a direct target of miR-148b-3p, and Cand1 knockdown reversed suppression of the miR-148b-3p inhibitor on Schwann cell migration. These results suggested that miR-148b-3p promoted migration of Schwann cells by directly targeting Cand1 in vitro. PMID- 27482233 TI - Synergetic effects of ciliary neurotrophic factor and olfactory ensheathing cells on optic nerve reparation (complete translation). AB - At present, there is no effective treatment for the repair of the optic nerve after injury, or improvement of its microenvironment for regeneration. Intravitreally injected ciliary neurotrophic factor (CNTF) and olfactory ensheathing cells (OECs) promote the long-distance regrowth of severed optic nerve fibers after intracranial injury. Here, we examined the efficacy of these techniques alone and in combination, in a rat model of optic nerve injury. We injected condensed OEC suspension at the site of injury, or CNTF into the vitreous body, or both simultaneously. Retrograde tracing techniques showed that 4 weeks postoperatively, the number of surviving retinal ganglion cells and their axonal density in the optic nerve were greater in rats subjected to OEC injection only than in those receiving CNTF injection only. Furthermore, combined OEC + CNTF injection achieved better results than either monotherapy. These findings confirm that OECs are better than CNTF at protecting injured neurons in the eye, but that combined OEC and CNTF therapy is notably more effective than either treatment alone. PMID- 27482234 TI - Optic radiation injury in a patient with intraventricular hemorrhage: a diffusion tensor tractography study. PMID- 27482236 TI - Changes in pre-hospital management of vascular risk factors among patients admitted due to recurrent stroke in Poland from 1995 to 2013. AB - INTRODUCTION: The aim of this study was to investigate long-term trends in secondary stroke prevention through management of vascular risk factors directly before hospital admission for recurrent stroke. MATERIAL AND METHODS: This is a retrospective registry-based analysis of consecutive recurrent acute stroke patients from a highly urbanized area (Warsaw, Poland) admitted to a single stroke center between 1995 and 2013 with previous ischemic stroke. We compared between four consecutive time periods: 1995-1999, 2000-2004, 2005-2009 and 2010 2013. RESULTS: During the study period, 894 patients with recurrent strokes were admitted (18% of all strokes), including 867 with previous ischemic stroke (our study group). Among those patients, the proportion of recurrent ischemic strokes (88.1% to 93.9%) (p = 0.319) and males (44% to 49.7%) (p = 0.5) remained stable. However, there was a rising trend in patients' age (median age of 73, 74, 76 and 77 years, respectively). There was also an increase in the use of antihypertensives (from 70.2% to 83.8%) (p = 0.013), vitamin K antagonists (from 4.8% to 15.6%) (p = 0.012) and statins (from 32.5% to 59.4%) (p < 0.001). Nonetheless, 21% of patients did not receive any antithrombotic prophylaxis. Tobacco smoking pattern remained unchanged. CONCLUSIONS: Our data indicate a clear overall improvement of secondary stroke prevention. However, persistent use of antithrombotic drugs and tobacco smoking after the first ischemic stroke is constantly suboptimal. PMID- 27482237 TI - Internet-Based Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder in Korea. AB - OBJECTIVE: Cognitive behavioral therapy (CBT) is regarded as one of the most effective intervention for obsessive-compulsive disorder (OCD). However, many patients remain untreated or inadequately treated due to time or geographical constraints. The purpose of this study was to develop an internet-based CBT (ICBT) for OCD, and to examine its efficacy in the Korean clinical setting. METHODS: The ICBT program ('COT') was developed from the same OCD manual in the standard CBT intervention. Twenty-seven participants of the total 42 patients completed all training sessions of the ICBT and the remainder (n=15) were classified as non-completers. Self-report measures of OCD, depression, anxiety, and work/social functioning, in addition to a neurocognitive test battery, were administered by face-to-face before and after treatment. RESULTS: The participants showed significant improvements in OCD and depressive symptoms, and in work/social functioning after ICBT completion. The presence of combined medication had no significant impact on treatment effect. The non-completers displayed more severe depressive and anxiety symptoms, and ICBT responders were younger and performed better in the Wisconsin Card Sorting Test. CONCLUSION: ICBT was found to be as effective for patients with moderate OC symptoms and little treatment experience. Considering the high accessibility and convenience of ICBT, it could be a helpful first treatment step for OCD patients when face-to-face treatment is unavailable. In the future a randomized controlled study will be necessary for verification and generalization of these results. PMID- 27482238 TI - Effects of Early Childhood Peer Relationships on Adolescent Mental Health: A 6- to 8-Year Follow-Up Study in South Korea. AB - OBJECTIVE: Peer relationships are one of the important factors in children's development. The present study examines the relationship between the effects of early peer relationships and adolescent psychological adjustment. METHODS: The first survey took place from 1998 to 2000, and a follow-up assessment obtained data in 2006, as the original participants reached 13-15 years of age. The first assessment used the Korean version of the Child Behavior Checklist (K-CBCL) and simple questions about peer relationships to evaluate the participants. The follow-up assessment administered the Korean Youth Self Report (K-YSR). RESULTS: Children's peer relationships have longitudinal effects on mental health and adjustment. Children who had qualitative peer-relation problems were more likely to exhibit internalizing problems as adolescents. CONCLUSION: Children who have poor peer relationships might become more vulnerable to emotional problems and social adjustment as adolescents. PMID- 27482235 TI - Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment optimization strategies. AB - Animal and clinical studies have confirmed the therapeutic effect of bone marrow mesenchymal stem cells on cerebral ischemia, but their mechanisms of action remain poorly understood. Here, we summarize the transplantation approaches, directional migration, differentiation, replacement, neural circuit reconstruction, angiogenesis, neurotrophic factor secretion, apoptosis, immunomodulation, multiple mechanisms of action, and optimization strategies for bone marrow mesenchymal stem cells in the treatment of ischemic stroke. We also explore the safety of bone marrow mesenchymal stem cell transplantation and conclude that bone marrow mesenchymal stem cell transplantation is an important direction for future treatment of cerebral ischemia. Determining the optimal timing and dose for the transplantation are important directions for future research. PMID- 27482239 TI - Differences between Impulsive and Non-Impulsive Suicide Attempts among Individuals Treated in Emergency Rooms of South Korea. AB - OBJECTIVE: A considerable proportion of suicide attempts are the result of sudden desires. Understanding such impulsive suicide attempts is necessary for effective interventions. We evaluated the impulsivity of suicide attempters treated in emergency rooms. The aim of the study was to identify the characteristics of impulsive suicide attempts by comparing these individuals to those who attempted to commit suicide in a non-impulsive manner. METHODS: This study analyzed suicide attempters who visited the emergency departments of seven selected university hospitals. A total of 269 medical records in which impulsivity of suicide attempt were confirmed were subject to be analyzed. The impulsivity of the suicide attempt was examined using a summative score of items 6 and 15 on the Suicide Intent Scale. RESULTS: A total of 48.0% of the participants were impelled by sudden inclinations to attempt suicide. Impulsive attempters were younger, unmarried and less physical illness than non-impulsive attempters, whereas no significant differences were found on psychiatric history and previous suicide history. Impulsive suicide attempters had suicide ideations that were not as severe (chi(2)=55.33, p<0.001) or intense (t=-8.38, p<0.001) as their counterparts'. Furthermore, medical results of impulsive suicide attempts were better than non-impulsive suicide attempts (t=-3.77, p<0.001). CONCLUSION: The results suggested that a considerable proportion of suicide attempts were the result of sudden inclinations. Impulsive attempts were made in relatively earlier stages of suicide ideation; consequently, they have less intent than non impulsive attempts. PMID- 27482240 TI - Linking an Anxiety-Related Personality Trait to Cardiac Autonomic Regulation in Well-Defined Healthy Adults: Harm Avoidance and Resting Heart Rate Variability. AB - OBJECTIVE: Anxiety trait, anxiety and depression states have all been reported to increase risks for cardiovascular disease (CVD), possibly through altering cardiac autonomic regulation. Our aim was to investigate whether the relationship between harm avoidance (HA, an anxiety-related personality trait) and cardiac autonomic regulation is independent of anxiety and depression states in healthy adults. METHODS: We recruited 535 physically and mentally healthy volunteers. Participants completed the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI) and Tri-dimensional Personality Questionnaire. Participants were divided into high or low HA groups as discriminated by the quartile value. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV). We obtained the time and frequency-domain indices of HRV including variance (total HRV), the low-frequency power (LF; 0.05-0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15-0.40 Hz), which reflects cardiac parasympathetic activity, as well as the LF/HF ratio. RESULTS: The BDI and HA scores showed associations with HRV parameters. After adjustment for the BDI scores and other control variables, HA is still associated with reduced variance, LF and HF power. Compared with the participants with low HA, those with high HA displayed significant reductions in variance, LF and HF power and a significant increase in their LF/HF ratio. CONCLUSION: This study highlights the independent role of HA in contributing to decreased autonomic cardiac regulation in healthy adults and provides a potential underlying mechanism for anxiety trait to confer increased risk for CVD. PMID- 27482241 TI - Application of Short Screening Tools for Post-Traumatic Stress Disorder in the Korean Elderly Population. AB - OBJECTIVE: Post-traumatic stress disorder (PTSD) is often missed or incorrectly diagnosed in primary care settings. Although brief screening instruments may be useful in detecting PTSD, an adequate validation study has not been conducted with older adults. This study aimed to evaluate the reliability and validity of the Korean version of the primary care PTSD screen (PC-PTSD) and single-item PTSD screener (SIPS) in elderly veterans. METHODS: The PC-PTSD and SIPS assessments were translated into Korean, with a back-translation to the original language to verify accuracy. Vietnamese war veterans [separated into a PTSD group (n=41) and a non-PTSD group (n=99)] participated in several psychometric assessments, including the Korean versions of the PC-PTSD (PC-PTSD-K), SIPS (SIPS-K), a structured clinical interview from the Diagnostic and Statistical Manual of Mental Disorders-IV(SCID), and PTSD checklist(PCL). RESULTS: The PC-PTSD-K showed high internal consistency (Cronbach alpha=0.76), and the test-retest reliability of the PC-PTSD-K and SIPS-K were also high (r=0.97 and r=0.91, respectively). A total score of 3 from the PC-PTSD-K yielded the highest diagnostic efficiency, with sensitivity and specificity values of 0.90 and 0.86, respectively. The 'bothered a lot' response level from the SIPS-K showed the highest diagnostic efficiency, with sensitivity and specificity values of 0.85 and 0.89, respectively. CONCLUSION: Our findings suggest that both PC-PTSD-K and SIPS-K have good psychometric properties with high validity and reliability for detecting PTSD symptoms in elderly Korean veterans. However, further research will be necessary to increase our understanding of PTSD characteristics in diverse groups with different types of trauma. PMID- 27482242 TI - Association between Medication Adherence and Duration of Outpatient Treatment in Patients with Schizophrenia. AB - OBJECTIVE: Medication adherence is important in the treatment of schizophrenia, and critical periods during treatment may be associated with relapse. However, the relationship between adherence and duration of outpatient treatment (DOT) remains unclear. The authors aimed to clarify the relationship between adherence and DOT at a psychiatric hospital in Japan. METHODS: For outpatients with schizophrenia who regularly visit Shin-Abuyama hospital, the authors conducted a single questionnaire survey (five questions covering gender, age, DOT, medication shortages, and residual medication) over one month period. Participants were divided into two groups whether DOT were from more than one year to within five years or not. Mantel-Haenszel analysis and logistic regression analysis were performed on the data regarding the medication adherence. RESULTS: Effective answers were received for 328 patients. The residual medication rate was significantly higher among those receiving outpatient treatment from more than one year to within five years than five years than those receiving outpatient treatment for more than five years or less than one year (p=0.016). CONCLUSION: This survey suggests that there are critical periods during which patients are most prone to poor adherence. Because poor adherence increases the risk of relapse, specific measures must be taken to improve adherence during these periods. PMID- 27482243 TI - Decreased Prolidase Activity in Patients with Posttraumatic Stress Disorder. AB - OBJECTIVE: Many neurochemical systems have been implicated in the development of Posttraumatic Stress Disorder (PTSD). The prolidase enzyme is a cytosolic exopeptidase that detaches proline or hydroxyproline from the carboxyl terminal position of dipeptides. Prolidase has important biological effects, and to date, its role in the etiology of PTSD has not been studied. In the present study, we aimed to evaluate prolidase activity in patients with PTSD. METHODS: The study group consisted of patients who were diagnosed with PTSD after the earthquake that occurred in the province of Van in Turkey in 2011 (n=25); the first control group consisted of patients who experienced the earthquake but did not show PTSD symptoms (n=26) and the second control group consisted of patients who have never been exposed to a traumatic event (n=25). Prolidase activities in the patients and the control groups were determined by the ELISA method using commercial kits. RESULTS: Prolidase activity in the patient group was significantly lower when compared to the control groups. Prolidase activity was also significantly lower in the traumatized healthy subjects compared to the other healthy group (p<0.01). CONCLUSION: The findings of the present study suggest that the decrease in prolidase activity may have neuroprotective effects in patients with PTSD. PMID- 27482244 TI - Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases. AB - OBJECTIVE: ObjectiveaaWe evaluated the distribution of alpha-2A adrenergic receptor (ADRA2A) and catechol-o-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) among ADHD subtypes and other homogeneous patient populations including treatment-resistant cases and patients with high symptom severity. METHODS: Methodsaa121 ADHD patients aged 6-18 years were included in the study. Diagnosis and subtypes designation were confirmed using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and symptoms were evaluated using the Conners' Parent (CPRS) and Teacher Rating Scales (CTRS). The response to methylphenidate was assessed objectively using the Clinical Global Impression-Severity Scale (CGI-S) and Global Assessment of Functioning Scale (GAS) as well as the Continuous Performance (CPT) and Trail Making tests (TMT-A, B). Patients were genotyped for ADRA2A (rs1800544) and COMT (rs4680) SNPs by PCR/RFLP and compared to a gender-matched control group. RESULTS: Although there was no association of COMT (rs4680) SNP with symptoms or diagnosis, the ADRA2A polymorphism, low socioeconomic status (SES), and comorbid psychiatric diagnosis were all associated with poor response to methylphenidate in logistic regression analysis. CONCLUSION: Clinicians may consider adjuvant strategies when these negative factors are present to increase the success of tailored ADHD treatments in the future. PMID- 27482245 TI - Predictive Validity of Some Common Animal Models of Bipolar Disorder Using Lithium and Lamotrigine Therapy: An Attempt towards a Battery-Based Approach for the Evaluation of Mood Stabilizers. AB - OBJECTIVE: To determine the predictive validity of some of the commonly employed models of mania and depression using standard drugs i.e. lithium (70 mg/kg) and lamotrigine (5 mg/kg) in male Wistar rats. METHODS: The depression facet of bipolar disorder was evaluated using forced swim test, tail suspension test, and chronic mild stress test. The models used to evaluate the mania facet of bipolar disorder were isolation-induced aggression test, saccharine preference test, and morphine-sensitized hyperlocomotion test. RESULTS: The immobility time was significantly (p<0.05) reduced by lamotrigine in the tail suspension test and the forced swim test, while lithium caused significant (p<0.05) reduction only in the tail suspension test. Rats exposed to chronic mild stress showed the maximal increment of 1% sucrose consumption at the 3rd week of treatment in both the lithium (p<0.001) and lamotrigine (p<0.01) groups. In the isolation-induced aggression test, the aggressive behaviour of rats was significantly reduced by both lithium [approach (p<0.001), attack (p<0.01), and bite (p<0.01)] and lamotrigine [approach (p<0.001), and attack (p<0.05)]. Neither of the drugs were effective in the saccharine preference test. Only lithium was able to significantly (p<0.05) reduce the crossing parameter in morphine-sensitized rats. CONCLUSION: Our study identifies the chronic mild stress test and isolation induced aggression test of having the highest predictive validity in the depression and mania facets of bipolar disorder, respectively, and should be a part of a battery of tests used to evaluate novel mood stabilizers. PMID- 27482246 TI - Times to Discontinue Antidepressants Over 6 Months in Patients with Major Depressive Disorder. AB - OBJECTIVE: The aim of the present study was to investigate differences in discontinuation time among antidepressants and total antidepressant discontinuation rate of patients with depression over a 6 month period in a naturalistic treatment setting. METHODS: We reviewed the medical records of 900 patients with major depressive disorder who were initially prescribed only one kind of antidepressant. The prescribed antidepressants and the reasons for discontinuation were surveyed at baseline and every 4 weeks during the 24 week study. We investigated the discontinuation rate and the mean time to discontinuation among six antidepressants groups. RESULTS: Mean and median overall discontinuation times were 13.8 and 12 weeks, respectively. Sertraline and escitalopram had longer discontinuation times than that of fluoxetine, and patients who used sertraline discontinued use significantly later than those taking mirtazapine. No differences in discontinuation rate were observed after 24 weeks among these antidepressants. About 73% of patients discontinued antidepressant treatment after 24 weeks. CONCLUSION: Sertraline and escitalopram tended to have longer mean times to discontinuation, although no difference in discontinuation rate was detected between antidepressants after 24 weeks. About three-quarters of patients discontinued antidepressant maintenance therapy after 24 weeks. PMID- 27482247 TI - Effectiveness of Duloxetine Monotherapy Compared to Combination Therapy with Other Antidepressants in Patients with Major Depressive Disorder: A Short-Term, Retrospective Study. AB - OBJECTIVE: The purpose of this study was to compare duloxetine monotherapy to combination therapy with other antidepressants in patients with major depressive disorder in a clinical, real world setting. METHODS: An eight-week, retrospective, multi-center study of outpatients with major depressive disorder was undertaken. After screening 415 patients, enrolled in this study from July 2009 to June 2014 were 82 patients from among three centers who had been taking duloxetine with or without other antidepressant and not administered with atypical antipsychotics. We compared the mean changes of the Clinical Global Impression-Severity Scale (CGI-S) as a primary measure and the discontinuation rate as a secondary measure between the duloxetine monotherapy group (n=36, 43.9%) and the combination therapy with other antidepressants group (n=46, 56.1%) at baseline, one, two, four and eight weeks. RESULTS: There were no significant differences across the demographic characteristics between two groups. There was, however, a statistically greater improvement on the CGI-S at weeks 2, 4 and 8 in the combination group compared with the monotherapy group. There were no significant differences in discontinuation rate and adverse events between two groups. No serious adverse events were reported in both groups during the study period. CONCLUSION: This result suggests that the duloxetine combination therapy with other antidepressants could improve effectiveness and have comparable tolerability with the monotherapy in the treatment of outpatients with major depressive disorders in a naturalistic setting. Adequately powered, well controlled clinical trials are strongly warranted to confirm our findings due to methodological shortcomings. PMID- 27482248 TI - Association of CACNA1C Variants with Bipolar Disorder in the Korean Population. AB - OBJECTIVE: Previous studies have suggested an association between CACNA1C and susceptibility of bipolar disorder. In this study, we examined the association of CACNA1C variants with bipolar disorder in the Korean population. METHODS: We selected 2 CACNA1C single nucleotide polymorphisms (SNPs), namely, rs723672 and rs1051375, based on their functions and minor allele frequencies described in previous studies. Genotypes of these 2 SNPs were analyzed by extracting DNA from blood samples collected from 287 patients with bipolar disorder and 340 healthy controls. RESULTS: Genotype frequencies of both rs723672 and rs1051375 SNPs were significantly different in patients and controls (p=0.0462 and 1.732E-14, respectively). Dominant, recessive, and allele models showed significant differences between patients and controls with respect to the rs1051375 SNP (p=1.72E-11, 4.17E-10, 4.95E-16, respectively). CONCLUSION: Our results suggested that CACNA1C SNPs rs723672 and rs1051375 were associated with bipolar disorder in the Korean population. In addition, our results highlighted the importance of CACNA1C in determining susceptibility to bipolar disorder. PMID- 27482249 TI - Blonanserin Augmentation of Atypical Antipsychotics in Patients with Schizophrenia-Who Benefits from Blonanserin Augmentation?: An Open-Label, Prospective, Multicenter Study. AB - OBJECTIVE: The purpose of this study was to investigate the efficacy and tolerability of atypical antipsychotics (AAPs) with augmentation by blonanserin in schizophrenic patients. METHODS: aA total of 100 patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP were recruited in this 12-week, open-label, non-comparative, multicenter study. Blonanserin was added to their existing AAP regimen, which was maintained during the study period. Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at weeks 2, 4, 8, and 12. Predictors for PANSS response (>=20% reduction) were investigated. RESULTS: The PANSS total score was significantly decreased at 12 weeks of blonanserin augmentation (-21.0+/-18.1, F=105.849, p<0.001). Moreover, 51.0% of participants experienced a response at week 12. Premature discontinuation of blonanserin occurred in 17 patients (17.0%); 4 of these patients dropped out due to adverse events. The patients who benefited the most from blonanserin were those with severe symptoms despite a treatment with a higher dose of AAP. CONCLUSION: Blonanserin augmentation could be an effective strategy for patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP. PMID- 27482250 TI - Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. AB - Major depressive disorder is often resistant to antidepressant treatment. Repetitive transcranial magnetic stimulation (rTMS) has been used in treatment resistant depression (TRD). Known adverse events of rTMS include transient headache, local pain, syncope, seizure induction, and hypomania induction. This report outlines a patient with TRD who unexpectedly improved following a seizure during the course of rTMS, which has never been reported. PMID- 27482251 TI - Women and Ischemic Heart Disease: Recognition, Diagnosis and Management. AB - Cardiovascular disease is one of the most frequent causes of death in both males and females throughout the world. However, women exhibit a greater symptom burden, more functional disability, and a higher prevalence of nonobstructive coronary artery disease (CAD) compared to men when evaluated for signs and symptoms of myocardial ischemia. This paradoxical sex difference appears to be linked to a sex-specific pathophysiology of myocardial ischemia including coronary microvascular dysfunction, a component of the 'Yentl Syndrome'. Accordingly, the term ischemic heart disease (IHD) is more appropriate for a discussion specific to women rather than CAD or coronary heart disease. Following the National Heart, Lung, and Blood Institute Heart Truth/American Heart Association, Women's Ischemia Syndrome Evaluation and guideline campaigns, the cardiovascular mortality in women has been decreased, although significant gender gaps in clinical outcomes still exist. Women less likely undergo testing, yet guidelines indicate that symptomatic women at intermediate to high IHD risk should have further test (e.g. exercise treadmill test or stress imaging) for myocardial ischemia and prognosis. Further, women have suboptimal use of evidence based guideline therapies compared with men with and without obstructive CAD. Anti-anginal and anti-atherosclerotic strategies are effective for symptom and ischemia management in women with evidence of ischemia and nonobstructive CAD, although more female-specific study is needed. IHD guidelines are not "cardiac catheterization" based but related to evidence of "myocardial ischemia and angina". A simplified approach to IHD management with ABCs (aspirin, angiotensin converting enzyme inhibitors/angiotensin-renin blockers, beta blockers, cholesterol management and statin) should be used and can help to increases adherence to guidelines. PMID- 27482252 TI - Revisit of Functional Tricuspid Regurgitation; Current Trends in the Diagnosis and Management. AB - Current knowledge of functional tricuspid regurgitation (FTR) as a progressive entity, worsening the prognosis of patients irrespective of its aetiology, has led to renewed interest in the pathophysiology and assessment of FTR. For the proper management of FTR, not only its severity, but also the mechanisms, the mode of leaflet coaptation, the degree of tricuspid annulus enlargement and leaflet tenting, and the haemodynamic consequences for right atrial and right ventricular morphology and function have to be taken into account. A better assessment of the anatomy and function of tricuspid apparatus and tricuspid regurgitation severity should help with the appropriate selection of patients who will benefit from either surgical tricuspid valve repair/replacement or a percutaneous procedure, especially among patients who are to undergo or have undergone primary left-sided valvular surgery. In this article, we review the anatomy, pathophysiology and the use of imaging techniques to assess patients with FTR, as well as the various treatment options for FTR, including emerging transcatheter procedures. The limitations affecting the current approach to FTR patients and the unmet clinical needs for their management have also been discussed. PMID- 27482254 TI - Pre-Treatment with Statins for Coronary Intervention: Pleiotropy of Statins or Effect of LDL-cholesterol Reduction? PMID- 27482253 TI - Systemic Hemodynamic Atherothrombotic Syndrome and Resonance Hypothesis of Blood Pressure Variability: Triggering Cardiovascular Events. AB - Blood pressure (BP) exhibits different variabilities and surges with different time phases, from the shortest beat-by-beat to longest yearly changes. We hypothesized that the synergistic resonance of these BP variabilites generates an extraordinarily large dynamic surge in BP and triggers cardiovascular events (the resonance hypothesis). The power of pulses is transmitted to the peripheral sites without attenuation by the large arteries, in individuals with stiffened arteries. Thus, the effect of a BP surge on cardiovascular risk would be especially exaggerated in high-risk patients with vascular disease. Based on this concept, our group recently proposed a new theory of systemic hemodynamic atherothromboltic syndrome (SHATS), a vicious cycle of hemodynamic stress and vascular disease that advances organ damage and triggers cardiovascular disease. Clinical phenotypes of SHATS are large-artery atherothombotic diseases such as stroke, coronary artery disease, and aortic and pheripheral artery disease; small artery diseases, and microcirculation-related disease such as vascular cognitive dysfunction, heart failure, and chronic kidney disease. The careful consideration of BP variability and vascular diseases such as SHATS, and the early detection and management of SHATS, will achieve more effective individualized cardiovascular protection. In the near future, information and communication technology-based 'anticipation medicine' predicted by the changes of individual BP values could be a promising approach to achieving zero cardiovascular events. PMID- 27482255 TI - Does Pre-Treatment with High Dose Atorvastatin Prevent Microvascular Dysfunction after Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome? AB - BACKGROUND AND OBJECTIVES: There is controversy surrounding whether or not high dose statin administration before percutaneous coronary intervention (PCI) decreases peri-procedural microvascular injury. We performed a prospective randomized study to investigate the mechanisms and effects of pre-treatment high dose atorvastatin on myocardial damage in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing PCI. SUBJECTS AND METHODS: Seventy seven patients with NSTE-ACS were randomly assigned to either the high dose group (atorvastatin 80 mg loading 12 to 24 h before PCI with a further 40 mg loading 2 h before PCI, n=39) or low dose group (atorvastatin 10 mg administration 12 to 24 h before PCI, n=38). Index of microcirculatory resistance (IMR) was measured after stent implantation. Creatine kinase-myocardial band (CK-MB) and high sensitivity C-reactive protein (CRP) levels were measured before and after PCI. RESULTS: The baseline characteristics were not different between the two patient groups. Compared to the low dose group, the high dose group had lower post PCI IMR (14.1+/-5.0 vs. 19.2+/-9.3 U, p=0.003). Post PCI CK-MB was also lower in the high dose group (median: 1.40 ng/mL (interquartile range [IQR: 0.75 to 3.45] vs. 4.00 [IQR: 1.70 to 7.37], p=0.002) as was the post-PCI CRP level (0.09 mg/dL [IQR: 0.04 to 0.16] vs. 0.22 [IQR: 0.08 to 0.60], p=0.001). CONCLUSION: Pre treatment with high dose atorvastatin reduces peri-PCI microvascular dysfunction verified by post-PCI IMR and exerts an immediate anti-inflammatory effect in patients with NSTE-ACS. PMID- 27482256 TI - Effect of n-3 Polyunsaturated Fatty Acids on Regression of Coronary Atherosclerosis in Statin Treated Patients Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND AND OBJECTIVES: Statins remain the mainstay of secondary coronary artery disease (CAD) prevention, but n-3 polyunsaturated fatty acids (omega-3 PUFA) display biological effects that may also reduce the risk of atherosclerosis and CAD. However, data on the possible antiatherosclerotic benefits of adding omega-3 PUFA to statin therapy are limited. This study aimed to investigate the potential additive effects of omega-3 PUFA on regression of atherosclerosis in CAD patients receiving statin therapy and stent implantation. SUBJECTS AND METHODS: Seventy-four CAD patients undergoing percutaneous coronary intervention (PCI) with stent implantation were enrolled, prescribed statins, and randomly assigned to two groups: n-3 group (omega-3 PUFA 3 g/day, n=38) or placebo group (placebo, n=36). All patients completed the study follow-up consisting of an intravascular ultrasound at baseline and at 12 months. RESULTS: There was no difference in the baseline characteristics and distribution of other medications. No significant differences were observed in primary endpoints, including changes in atheroma volume index (-12.65% vs. -8.51%, p=0.768) and percent atheroma volume (-4.36% vs. -9.98%, p=0.526), and in secondary endpoints including a change in neointimal volume index (7.84 vs. 4.94 mm(3)/mm, p=0.087). CONCLUSION: omega-3 PUFA had no definite additional effect on the regression of coronary atherosclerosis when added to statin in CAD patients undergoing PCI. PMID- 27482257 TI - Long-Term Clinical Outcomes of Transient and Persistent No Reflow Phenomena following Percutaneous Coronary Intervention in Patients with Acute Myocardial Infarction. AB - BACKGROUND AND OBJECTIVES: There is limited information on the transient or persistent no reflow phenomenon in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). SUBJECTS AND METHODS: The study analyzed 4329 patients with AMI from a Korean multicenter registry who underwent PCI using coronary stents (2668 ST-elevation and 1661 non-ST-elevation myocardial infarction [MI] patients): 4071 patients without any no reflow, 213 with transient no reflow (no reflow with final thrombolysis in myocardial infarction [TIMI] flow grade 3), and 45 with persistent no reflow (no reflow with final TIMI flow grade<=2). The primary endpoint was all-cause mortality during 3 year follow-up. We also analyzed the incidence of cardiac mortality, non-fatal MI, re-hospitalization due to heart failure, target vessel revascularization, and stent thrombosis. RESULTS: The persistent no reflow group was associated with higher all-cause mortality (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.08-3.65, p=0.028) and cardiac mortality (HR 3.28, 95% CI 1.54-6.95, p=0.002) compared with the normal reflow group. Transient no reflow increased all-cause mortality only when compared with normal reflow group (HR 1.58, 95% CI 1.11-2.24, p=0.010). When comparing transient and persistent no reflow, persistent no reflow was associated with increased all-cause mortality (46.7 vs. 24.4%, log rank p=0.033). CONCLUSION: The persistent no reflow phenomenon was associated with a poor in-hospital outcome and increased long-term mortality mainly driven by increased cardiac mortality compared to the transient no reflow phenomenon or normal reflow. PMID- 27482258 TI - Multimodality Intravascular Imaging Assessment of Plaque Erosion versus Plaque Rupture in Patients with Acute Coronary Syndrome. AB - BACKGROUND AND OBJECTIVES: We assessed plaque erosion of culprit lesions in patients with acute coronary syndrome in real world practice. SUBJECTS AND METHODS: Culprit lesion plaque rupture or plaque erosion was diagnosed with optical coherence tomography (OCT). Intravascular ultrasound (IVUS) was used to determine arterial remodeling. Positive remodeling was defined as a remodeling index (lesion/reference EEM [external elastic membrane area) >1.05. RESULTS: A total of 90 patients who had plaque rupture showing fibrous-cap discontinuity and ruptured cavity were enrolled. 36 patients showed definite OCT-plaque erosion, while 7 patients had probable OCT-plaque erosion. Overall, 26% (11/43) of definite/probable plaque erosion had non-ST elevation myocardial infarction (NSTEMI) while 35% (15/43) had ST elevation myocardial infarction (STEMI). Conversely, 14.5% (13/90) of plaque rupture had NSTEMI while 71% (64/90) had STEMI (p<0.0001). Among plaque erosion, white thrombus was seen in 55.8% (24/43) of patients and red thrombus in 27.9% (12/43) of patients. Compared to plaque erosion, plaque rupture more often showed positive remodeling (p=0.003) with a larger necrotic core area examined by virtual histology (VH)-IVUS, while negative remodeling was prominent in plaque erosion. Overall, 65% 28/43 of plaque erosions were located in the proximal 30 mm of a culprit vessel-similar to plaque ruptures (72%, 65/90, p=0.29). CONCLUSION: Although most of plaque erosions show nearly normal coronary angiogram, modest plaque burden with negative remodeling and an uncommon fibroatheroma might be the nature of plaque erosion. Multimodality intravascular imaging with OCT and VH-IVUS showed fundamentally different pathoanatomic substrates underlying plaque rupture and erosion. PMID- 27482259 TI - Thirty-Year Trends in Mortality from Cerebrovascular Diseases in Korea. AB - BACKGROUND AND OBJECTIVES: Cerebrovascular disease is a leading cause of mortality and morbidity in Korea. Understanding of cerebrovascular disease mortality trends is important to reduce the health burden from cerebrovascular diseases. We examined the changing pattern of mortality related to cerebrovascular disease in Korea over 30 years from 1983 to 2012. SUBJECTS AND METHODS: Numbers of deaths from cerebrovascular disease, hemorrhagic stroke, and cerebral infarction were obtained from the national Cause of Death Statistics. Crude and age-adjusted mortality rates were calculated for men and women for each year. Penalized B-spline methods, which reduce bias and variability in curve fitting, were used to identify the trends of 30-year mortality and identify the year of highest mortality. RESULTS: During the 30 years, cerebrovascular disease mortality has markedly declined. The age-adjusted cerebrovascular disease mortality rate has decreased by 78% in men and by 68% in women. In the case of hemorrhagic stroke, crude mortality peaked in 2001 but age-adjusted mortality peaked in 1994. Between 1994 and 2012, age-adjusted mortality from hemorrhagic stroke has decreased by 68% in men and 59% in women. In the case of cerebral infarction, crude and age-adjusted mortality rates steeply increased until 2004 and 2003, respectively, and both rates decreased rapidly thereafter. CONCLUSION: Cerebrovascular disease mortality rate has significantly decreased over the last 30 years in Korea, but remains a health burden. The prevalence of major cardiovascular risk factors are still highly prevalent in Korea. PMID- 27482260 TI - Incidence and Risk Factors for Atrial Fibrillation in Korea: the National Health Insurance Service Database (2002-2010). AB - BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) is a common arrhythmia that is known as an important independent risk factor for stroke. However, limited information is available on AF in Korea. This study evaluated the incidence of AF, its associated co-morbidities and risk factors for AF in Korea. SUBJECTS AND METHODS: The National Health Insurance Service database between 2002 and 2010 was used in the study. Individuals<30 years old and those diagnosed with AF between 2002 and 2004 were excluded. Hazard ratios (HRs) according to co-morbidities and risk factors for AF were determined using a Cox proportional hazard model. Population attributable fractions (PAFs) of AF risk factors were determined. RESULTS: During a 6-year follow-up period, 3517 (1.7%) developed AF. The incidence rates in men and women aged 30-39 years were 0.82 and 0.55 per 1000 person-years, respectively; the incidence rates further increased with age to 13.09 and 11.54 per 1000 person-years in men and women aged>=80 years, respectively. The risk factors for incident AF were age, sex, body mass index (BMI), hypertension, ischemic heart disease (IHD) and heart failure. After adjusting for variables related to AF, the risk of AF was significantly associated with hypertension (HR 1.667), IHD (HR 1.639), heart failure (HR 1.521), and the PAFs for age, sex, BMI, hypertension, IHD, heart failure and diabetes mellitus were 30.6%, 10.1%, 3.4%, 16.6%, 8.2%, 5.3% and 0.8%, respectively. CONCLUSION: Incidence of AF increased with age and was higher in men than in women. A larger proportion of AF events was attributable to hypertension than to other co-morbidities. PMID- 27482261 TI - The Relationship between P & QT Dispersions and Presence & Severity of Stable Coronary Artery Disease. AB - BACKGROUND AND OBJECTIVES: The study aimed to evaluate the correlation between electrocardiographic (ECG) parameters and presence and extent of coronary artery disease (CAD) to indicate the usefulness of these parameters as predictors of severity in patients with stable CAD. SUBJECTS AND METHODS: Two hundred fifty patients, without a history of any cardiovascular event were included in the study. The ECG parameters were measured manually by a cardiologist before coronary angiography. The patients were allocated into five groups: those with normal coronary arteries (Group 1), non-critical coronary lesions (Group 2), one, two and three vessel disease (Group 3, Group 4 and Group 5, respectively. RESULTS: Group 1 had the lowest P wave dispersion (PWD) and P wave (Pmax), QT interval (QTmax), QT dispersion (QTd), corrected QT dispersion (QTcd) and QT dispersion ratio (QTdR), while the patients in group 5 had the highest values of these parameters. Gensini score and QTmax, QTd, QTcmax, QTcd, QTdR, Pmax, and PWD were positively correlated. QTdR was the best ECG parameter to differentiate group 1 and 2 from groups with significant stenosis (groups 3, 4, and 5) (area under curve [AUC] 0.846). QTdR was the best ECG parameter to detect coronary arterial narrowing lesser than 50% and greater than 50%, respectively (AUC 0.858). CONCLUSION: Presence and severity of CAD can be determined by using ECG in patients with stable CAD and normal left ventricular function. PMID- 27482262 TI - Atrial Electromechanical Coupling in Patients with Lichen Planus. AB - BACKGROUND AND OBJECTIVES: A chronic inflammatory disease, lichen planus may cause disturbance of atrial electromechanical coupling and increase the risk of atrial fibrillation. The aim of this study was to evaluate atrial electromechanical delay with both electrocardiography (ECG) and echocardiography in patients with lichen planus (LP). SUBJECTS AND METHODS: Seventy-two LP patients (43 males [59.7%], mean age: 44.0+/-16.7 years) were enrolled in this cross-sectional case-control study. The control group was selected in a 1:1 ratio from 70 patients in an age and sex matched manner. P wave dispersion was measured by ECG to show atrial electromechanical delay. All of the patients underwent transthoracic echocardiography for measuring inter- and intra-atrial electromechanical delays. RESULTS: The baseline characteristics of the patients and the control group were similar except for the presence of LP. P-wave dispersion measured by ECG was significantly higher in patients with LP (p<0.001). Patients with LP had significantly prolonged intra- and interatrial electromechanical delays when compared to the control group (p<0.001). In addition, all of these variables were significantly correlated with high sensitive C-reactive protein (hsCRP) levels. CONCLUSION: Atrial electromechanical coupling, which is significantly correlated with increased hsCRP levels, is impaired in patients with LP. PMID- 27482263 TI - Prehypertension and Left Ventricular Diastolic Dysfunction in Middle-Aged Koreans. AB - BACKGROUND AND OBJECTIVES: Left ventricular diastolic dysfunction is known to be a marker of myocardial damage, in particular myocardial fibrosis resulting from hypertension (HT). However, few studies have shown an association between the grade of diastolic dysfunction and blood pressure classification. We investigated the association between diastolic dysfunction and prehypertension (preHT) in apparently healthy adults who underwent routine health examinations. SUBJECTS AND METHODS: The study sample included 4261 Koreans, 45 to 64 years of age with no previous history of HT, diabetes mellitus, malignancy, proven coronary artery disease, or valvular heart disease based on echocardiography, who underwent routine health examinations including echocardiography. The subjects were classified into three groups based on resting blood pressure: prehypertensive, hypertensive, and normotensive. RESULTS: The prevalence of preHT in our study was 42.1%. After adjusting for age, gender, smoking status, alcohol consumption, fasting blood sugar, serum lipid profile, and body mass index, left ventricular diastolic dysfunction grades 1 and 2 were significantly more frequent in subjects with preHT (odds ratio [OR] 1.66 [95% confidence interval {CI} 1.40-1.96] and 1.37 [95% CI 0.95-1.97], respectively). When analyzed according to gender, the increased OR was especially notable in males. CONCLUSION: Left ventricular diastolic dysfunction appears to be significantly associated with preHT in Korean middle-aged males. PMID- 27482264 TI - Non-Responders to Intravenous Immunoglobulin and Coronary Artery Dilatation in Kawasaki Disease: Predictive Parameters in Korean Children. AB - BACKGROUND AND OBJECTIVES: In Kawasaki disease (KD), high dose intravenous immunoglobulin (IVIG) significantly lowers the coronary complications. However, some patients either do not respond to initial therapy or develop coronary complications. We aimed to identify the predictive factors for unresponsiveness to initial IVIG therapy and coronary artery dilatation (CAD; defined by Z score>=2.5) in the acute phase and convalescent phase. SUBJECTS AND METHODS: A retrospective review was conducted of 703 patients with KD, admitted to Gachon University Gil Medical Center between January 2005 and June 2013. The patients were divided into two groups-IVIG responders vs. non-responders-based on the IVIG treatments, and presence of fever after treatment. Further, these groups were divided into two subgroups based on their CAD. RESULTS: Among the 703 patients with KD, the rate of non-responders to initial IVIG was 16.8%. Serum total bilirubin, platelet count, and neutrophil proportion were independent predictive parameters of unresponsiveness (p<0.05). CAD was found in 234 patients (33.3%) in the acute phase, and in 32 patients (4.6%) in the convalescent phase. Male gender, fever duration, serum C-reactive protein, and white blood cell count were related to CAD (p<0.05). CAD was detected more frequently in non-responders than in the responders (47.5% vs. 31.5%, p=0.001). Kobayashi, Egami, and Sano scoring systems applied to our study population reflected low sensitivities (28.0-33.9%). CONCLUSION: Several independent parameters were related to unresponsiveness to the initial IVIG or CAD. These parameters might be helpful in establishing more focused and careful monitoring of high-risk KD patients in Korea. PMID- 27482265 TI - Clinical Characteristics of Kawasaki Disease in Infants Younger than Six Months: A Single-Center Study. AB - BACKGROUND AND OBJECTIVES: Kawasaki disease (KD) is the leading cause of acquired heart disease, which predominantly occurs in children under the age of 5 years. However, there are fewer cases of KD in infants younger than 6 months, which makes it difficult to diagnose. We investigated the clinical manifestations of KD in this age group and compared them with those in the older age group. SUBJECTS AND METHODS: We retrospectively reviewed the medical records of 239 patients with KD admitted to the Hallym Sacred Heart Hospital from January 2013 to June 2015. The data were categorized into 2 groups by age: Group A (<=6 months, n=26) and Group B (>6 months, n=213). RESULTS: Group A had a longer hospitalization period than Group B (6.69 vs. 5.19 days, p=0.002). Group A had fewer clinical manifestations upon admission, due to which there was a higher incidence of incomplete KD (1.88 vs. 3.54 of the diagnostic criteria, p<0.05; and 19.2% vs. 4.2% incomplete KD incidence, p=0.002). The rate of cardiac complications was higher in Group A (30.8% vs. 11.7%, p=0.011). CONCLUSION: The rate of cardiac complications of the patients younger than 6 months was significantly higher than that of the older patients. Therefore, infants younger than 6 months with unexplained fever for more than 5 days should be suspected as having KD, even if the principal clinical features are not fully presented. Echocardiography must be appropriately used for diagnosis of KD in suspected patients. PMID- 27482266 TI - Single Stage Repair for Aortic Coarctation associated with Intracardiac Defects Using Extra-Anatomic Bypass Graft in Adults. AB - BACKGROUND AND OBJECTIVES: Coarctation of the aorta in adulthood is generally associated with other cardiovascular disorders requiring surgical management. An extra anatomic bypass grafting from the ascending to descending aorta by posterior pericardial approach via median sternotomy could be a reasonable single stage surgical strategy for these patients. SUBJECTS AND METHODS: Seven male patients aged between 14-41 years underwent an extra anatomic bypass grafting for coarctation repair concomitantly with the surgical management of the associated cardiovascular disorders via median sternotomy. Preoperative mean systolic arterial blood pressure was 161.8+/-24.5 mmHg, although the patients were under treatment of different combinations of antihypertensive agents. Additional surgical procedures were: aortic valve replacement (n=4), ventricular septal defect (VSD) closure (n=2), ascending aortic replacement (n=3) and Bentall procedure (n=1). None of our patients have been previously diagnosed or operated on for coarctation. Data were evaluated during their hospital stay and in post operative follow-up. RESULTS: The post-operative course was uneventful in all but one patient was re-operated on due to bleeding. There was neither mortality nor significant morbidity during the in-hospital period and all patients were discharged within 5-9 (mean: 6.3+/-1.5) days. The mean follow up period was 71.83+/-23 months (range: 23-95 months). Unfortunately one of our patients could not be contacted for a follow up period because of invalid personal data. CONCLUSION: Coarctation of the aorta in adulthood associated with other cardiovascular disorders can be operated on simultaneously via an extra anatomic bypass grafting technique with low morbidity and mortality. PMID- 27482267 TI - Influence of Thromboxane A2 on the Regulation of Adenosine Triphosphate-Sensitive Potassium Channels in Mouse Ventricular Myocytes. AB - BACKGROUND AND OBJECTIVES: Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels play an important role in myocardial protection. We examined the effects of thromboxane A2 on the regulation of KATP channel activity in single ventricular myocytes. SUBJECTS AND METHODS: Single ventricular myocytes were isolated from the hearts of adult Institute of Cancer Research (ICR) mice by enzymatic digestion. Single channel activity was recorded by excised inside-out and cell-attached patch clamp configurations at -60 mV holding potential during the perfusion of an ATP-free K-5 solution. RESULTS: In the excised inside-out patches, the thromboxane A2 analog, U46619, decreased the KATP channel activity in a dose-dependent manner; however, the thromboxane A2 receptor antagonist, SQ29548, did not significantly attenuate the inhibitory effect of U46619. In the cell-attached patches, U46619 inhibited dinitrophenol (DNP)-induced KATP channel activity in a dose-dependent manner, and SQ29548 attenuated the inhibitory effects of U46619 on DNP-induced KATP channel activity. CONCLUSION: Thromboxane A2 may inhibit KATP channel activity, and may have a harmful effect on ischemic myocardium. PMID- 27482268 TI - Remnant Pacemaker Lead Tips after Lead Extractions in Pacemaker Infections. AB - Complete hardware removal is recommended in the case of patients with cardiovascular implantable electronic device (CIED) infections. However, the complete extraction of chronically implanted leads is not always achieved. The outcomes and optimal management of CIED infections with retained material after lead extractions have not been elucidated. In this case report, we present five patients with CIED infections with remnant lead tips even after lead extractions. Two patients had localized pocket infections, and were managed with antibiotics for a period of more than two weeks. The other three patients had infective endocarditis, and were managed with antibiotics for a period of more than four weeks. In one patient, the lead tip migrated to the right pulmonary artery, but did not produce any symptoms or complications. Only one of five patients experienced a resurgence of an infection. PMID- 27482269 TI - Spontaneous Transition of Double Tachycardias with Atrial Fusion in a Patient with Wolff-Parkinson-White Syndrome. AB - Among patients with Wolff-Parkinson-White syndrome, atrioventricular reciprocating tachycardia (AVRT) and atrioventricular nodal reentrant tachycardia (AVNRT) can coexist in a single patient. Direct transition of both tachycardias is rare; however, it can occur after premature atrial or ventricular activity if the cycle lengths of the two tachycardias are similar. Furthermore, persistent atrial activation by an accessory pathway (AP) located outside of the AV node during ongoing AVNRT is also rare. This article describes a case of uncommon atrial activation by an AP during AVNRT and gradual transition of the two supraventricular tachycardias without any preceding atrial or ventricular activity in a patient with preexcitation syndrome. PMID- 27482270 TI - Conservative Management of Left Atrial Intramural Hematoma after Catheter Ablation. AB - Left atrial intramural hematoma is a very rare complication of radiofrequency ablation procedures. A patient with tachyarrhythmia underwent radiofrequency catheter ablation. Echocardiography performed the following morning showed a large mass in the left atrium, suggestive of intramural hematoma formation. The patient was in a stable condition; therefore, it was decided that follow-up should be conservative and her anticoagulation therapy was continued. The size of the hematoma decreased significantly over the following 50 days. This case highlights a rare complication of a complex catheter ablation procedure in the left atrium that was managed via a noninvasive approach, with which all interventionists should be familiar. PMID- 27482271 TI - Endovascular Repair Using Suture-Mediated Closure Devices and Balloon Tamponade following Inadvertent Subclavian Artery Catheterization with Large-Caliber Hemodialysis Catheter. AB - Accidental subclavian artery cannulation is an uncommon but potentially serious complication of central venous catheterization. Removal of a catheter inadvertently placed in the subclavian artery can lead to substantial bleeding, as achieving hemostasis in this area through manual compression presents considerable difficulty. Additionally, surgical treatment might be unsuitable for high-risk patients due to comorbidities. Here, we report a case of an inadvertently-inserted 11.5-French hemodialysis catheter in the subclavian artery during internal jugular venous catheterization. We performed percutaneous closure of the subclavian artery using three 6-French Perclose Proglide(r) devices with a balloon tamponade in the proximal part of the subclavian artery. Closure was completed without embolic neurological complications. PMID- 27482272 TI - 3D Printing Model before and after Transcatheter Aortic Valve Implantation for a Better Understanding of the Anatomy of Aortic Root. PMID- 27482273 TI - Erratum: Right Cardiac Catheterization Using the Antecubital Fossa Vein in Korean Patients. AB - [This corrects the article on p. 207 in vol. 46, PMID: 27014351.]. PMID- 27482274 TI - Erratum: Obesity and Hypertension in Association with Diastolic Dysfunction Could Reduce Exercise Capacity. AB - [This corrects the article on p. 394 in vol. 46, PMID: 27275176.]. PMID- 27482275 TI - Editorial. PMID- 27482276 TI - Detecting failed elements on phased array ultrasound transducers using the Edinburgh Pipe Phantom. AB - AIMS: Imaging faults with ultrasound transducers are common. Failed elements on linear and curvilinear array transducers can usually be detected with a simple image uniformity or 'paperclip' test. However, this method is less effective for phased array transducers, commonly used in cardiac imaging. The aim of this study was to assess whether the presence of failed elements could be detected through measurement of the resolution integral (R) using the Edinburgh Pipe Phantom. METHODS: A 128-element paediatric phased array transducer was studied. Failed elements were simulated using layered polyvinyl chloride (PVC) tape as an attenuator and measurements of resolution integral were carried out for several widths of attenuator. RESULTS: All widths of attenuator greater than 0.5 mm resulted in a significant reduction in resolution integral and low contrast penetration measurements compared to baseline (p < 0.05). CONCLUSIONS: Measurements of resolution integral and low contrast penetration both have the potential to be used as straightforward and inexpensive tests to detect failed elements on phased array transducers. Particularly encouraging is the result for low contrast penetration as this is a quick and simple measurement to make and can be performed with many different test objects, thus enabling 'in-the-field' checks. PMID- 27482277 TI - Extracranial internal carotid artery stenosis in children with sickle cell disease - Which transducer, what measurement? AB - BACKGROUND: Transcranial Doppler ultrasound is used to screen and assess the intracranial arteries of children with sickle cell disease. Recent findings suggest that extracranial internal carotid artery (eICA) stenosis is also a contributing factor to silent cerebral infarction. Stenosis has been measured using phased array transducers with no beam/flow angle correction and linear arrays with angle correction. METHODS: A total of 124 children undergoing TCD assessment were investigated for eICA velocities. Manual measurements of peak systolic velocity and TCD mean velocity were made with phased and linear array transducers. RESULTS: Peak systolic velocities ranged from 60 to 534 cm/s (median 126 cm/s) using the linear array and 53 to 394 cm/s (median 115 cm/s) using the phased array transducers. TCD mean ranged from 39 to 419 cm/s (median 81 cm/s) using the linear array and 34 to 295 cm/s (median 72 cm/s) using the phased array transducers. CONCLUSIONS: There are advantages and disadvantages of each method, but stenoses were readily identified as focal velocity increases. We suggest thresholds for each transducer and recommend that imaging of the eICA forms part of screening for this group of children. PMID- 27482278 TI - The clinical use of contrast-enhanced ultrasound in the kidney. AB - Traditional B-Mode and Doppler sonography have been the stalwart of renal tract imaging for many years, and indeed, are in daily use in most centres as the modality of choice for the initial assessment of renal pathology. However, traditional ultrasound scanning can be limited in its ability to accurately characterise renal pathology, and can be inaccurate at determining benign from malignant lesions. Contrast-enhanced ultrasound conveys many benefits, being safe (especially in patients with renal dysfunction), does not require the use of ionising radiation, is quick and relatively cheap and can help to establish whether a focal renal lesion is sinister. Furthermore, it is our experience that contrast-enhanced ultrasound is not a difficult technique to master for the experienced ultrasound practitioner. In this article, we discuss the technique, interpretation and value of contrast-enhanced ultrasound in renal imaging, and describe how we use it in our practice. PMID- 27482279 TI - Contrast-enhanced ultrasound in the evaluation of parotid gland lesions: an update of the literature. AB - High-resolution ultrasound is the first line examination for parotid gland diffuse disease and focal lesions, normally using grey-scale and colour-Doppler ultrasound. Unfortunately, grey-scale and colour-Doppler ultrasound features of benign and malignant salivary gland lesions may overlap, particularly with benign tumors, where pleomorphic adenomas are often indistinguishable from malignant lesions. With atypical lesions, contrast-enhanced magnetic resonance imaging is usually the second level imaging modality requested. The introduction of ultrasound contrast agents has opened further possible perspectives to improve the interpretation of parotid diseases, particularly the differentiation between benign and malignant lesions. We present a review of the current literature on contrast-enhanced ultrasound for the assessment of parotid gland lesions, considering all characteristics of the technique, evidence of usefulness, future perspectives and limitations. PMID- 27482280 TI - Imaging the hip joint in osteoarthritis: A place for ultrasound? AB - Osteoarthritis has traditionally been imaged with conventional radiographs; this has been regarded as the reference technique in osteoarthritis for a long time. However, in recent years, innovative imaging techniques such as ultrasonography have been used to obtain a better understanding of this disease. This is mainly due to tremendous technical advances and progressive developments of ultrasound equipment occurring over the past decade. Ultrasonography has been demonstrated to be a valuable imaging technique in the diagnosis and management of osteoarthritis of the hip joint. Application of this imaging methodology for osteoarthritis has improved the understanding of the disease process and may aid in the assessment of the efficacy of future therapies. The execution of ultrasound-guided procedures with safety and reliability has a relevant significance in patient management of osteoarthritis of the hip joint. This paper reviews the use of ultrasound as an imaging technique for the evaluation and treatment of osteoarthritis hip joint. PMID- 27482281 TI - Difficulties in prenatal diagnosis of tumour in the fetal sacrococcygeal area. AB - Prenatal ultrasound at the 20th week of gestation revealed a 3-cm tumour in the sacrococcygeal area. Initially, a sacrococcygeal teratoma was suspected on the basis of fetal ultrasonography, which revealed normal heart anatomy and an increasing tumour mass. The diagnosis was then changed to fetus in fetu or teratoma. Prenatal magnetic resonance imaging at the 34th week of pregnancy confirmed the ultrasound diagnosis. No other anomalies were found. Elective caesarean section was performed at term. The care team included a paediatric surgeon, obstetricians, neonatologists, midwives, and an anesthesiologist. A female newborn was delivered in good condition. The tumour was resected in the operating room and mature teratoma was established by histopathological evaluation. Surprisingly, agenesis of the right forearm was revealed which had not been detected prenatally, despite many examinations (both in our hospital and earlier at a primary care obstetrician office). PMID- 27482283 TI - Neighborhood Physical Disorder in New York City. AB - Neighborhood physical disorder, or the deterioration of urban environments, is associated with negative mental and physical health outcomes. Eleven trained raters used CANVAS, a web-based system for conducting reliable virtual street audits, to collect data on nine indicators of physical disorder using Google Street View imagery of 532 block faces in New York City, New York, USA. We combined the block face indicator data into a disorder scale using item response theory; indicators ranged in severity from presence of litter, a weak indicator of disorder, to abandoned cars, a strong indicator. Using this scale, we estimated disorder at the center point of each sampled block. We then used ordinary kriging to interpolate estimates of disorder levels throughout the city. The resulting map condenses a complex estimation process into an interpretable visualization of the spatial distribution of physical disorder in New York City. PMID- 27482284 TI - Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma. AB - OBJECTIVES: Despite the aggressive standard of care for patients with glioblastoma multiforme, survival rates typically do not exceed 2 years. Therefore, current research is focusing on discovering new therapeutics or rediscovering older medications that may increase the overall survival of patients with glioblastoma. Curcumin, a component of the Indian natural spice, turmeric, also known for its antioxidant and anti-inflammatory properties, has been found to be an effective inhibitor of proliferation and inducer of apoptosis in many cancers. The goal of this study was to investigate the expanded utility of curcumin as an antiglioma agent. METHODS: Using the PubMed MeSH database, we conducted a systematic review of the literature to include pertinent studies on the growth inhibitory effects of curcumin on glioblastoma cell lines based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 19 in vitro and five in vivo studies were analyzed. All of the studies indicated that curcumin decreased glioblastoma cell viability through various pathways (i.e. decrease in prosurvival proteins such as nuclear factor kappaB, activator protein 1, and phosphoinositide 3 kinase, and upregulation of apoptotic pathways like p21, p53, and executor caspase 3). Curcumin treatment also increased animal survival compared with control groups. CONCLUSIONS: Curcumin inhibits proliferation and induces apoptosis in certain subpopulations of glioblastoma tumors, and its ability to target multiple signaling pathways involved in cell death makes it an attractive therapeutic agent. As such, it should be considered as a potent anticancer treatment. Further experiments are warranted to elucidate the use of a bioavailable form of curcumin in clinical trials. PMID- 27482285 TI - Differences between invasive lobular and invasive ductal carcinoma of the breast: results and therapeutic implications. AB - Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC): ILC differs from invasive ductal carcinoma (IDC) in its clinicopathological characteristics and responsiveness to systemic therapy. From the clinical standpoint, data suggest that ILC derives a distinct benefit from systemic therapy compared to IDC. In addition, comprehensive molecular analyses have been reported for ILCs, confirming that these tumors have specific genomic profiles compared to IDC. Despite these differences, clinical trials and practical clinical guidelines tend to treat BC as a single entity. Here we discuss these clinical and molecular data and their therapeutic implications. PMID- 27482286 TI - CYP17 inhibitors in prostate cancer: latest evidence and clinical potential. AB - Since androgen signaling plays a pivotal role in the proliferation and metastasis of prostate cancer, androgen deprivation therapy (ADT) or castration therapy is considered the backbone of treatment for newly diagnosed metastatic prostate cancer. However, almost all men experience disease progression on ADT to a state known as metastatic castration-resistant prostate cancer (mCRPC), which continues to be driven by intratumoral androgen synthesis or androgen receptor signaling. Hence, the extragonadal ablation of androgen synthesis from pregnane precursors holds much promise. An inhibitor of cytochrome P450 17alpha-hydroxy/17,20-lyase (CYP17) enzymes, abiraterone acetate, has already been approved for men with mCRPC. Newer CYP17 inhibitors continue to be developed which are either more selective or have concomitant inhibitory actions on AR signaling. These include VT-464, orteronel, and galeterone. Herein, we focus on the molecular mechanism of action, efficacy, latest evidence, and clinical potential of CYP17 inhibitors in prostate cancer. PMID- 27482289 TI - Anti-androgen therapy in triple-negative breast cancer. PMID- 27482288 TI - From palliative therapy to prolongation of survival: (223)RaCl2 in the treatment of bone metastases. AB - Patients with hormone-refractory prostate cancer often have multiple bone metastases. The resulting bone pain is associated with reduced life quality, increased cost of therapy and impairment of overall survival. Trials with bone targeting beta-emitters have mostly showed an effect on alleviation of bone pain along with prolongation in survival, documented in only a limited number of patients. A randomized phase III trial (ALSYMPCA) using the alpha-emitter (223)RaCl2 (Xofigo(r)) showed for the first time, a longer overall survival of 3.6 months in treated patients as a sign of an antitumor effect. The time to first skeletal-related events was also significantly longer in the therapy group compared with placebo. Because of the short range of alpha-emitter, the bone marrow toxicity of radium therapy is low, and so this radionuclide could also be a candidate for combination with chemotherapy. The elimination of (223)RaCl2 is mainly through the gastrointestinal tract and side effects are mainly in this area. The procedure is similar to treatment with other bone-seeking agents and consists of six administrations of 50 kBq/kg bodyweight Xofigo(r), repeated every 4 weeks. At present Xofigo(r) is only approved for hormone-refractory prostate cancer. PMID- 27482290 TI - Pricing of innovative drugs: correlation between incremental cost and survival gain in four countries. PMID- 27482291 TI - Interpretation of survival data: which graphical analysis is appropriate? PMID- 27482287 TI - Current targeted therapies in the treatment of advanced colorectal cancer: a review. AB - Treatment strategies for metastatic colorectal cancer (mCRC) patients have undergone dramatic changes in the past decade and despite improved patient outcomes, there still exist areas for continued development. The introduction of targeted agents has provided clinicians with additional treatment options in mCRC, however, results have been mixed at best. These novel therapies were designed to interfere with specific molecules involved in the cellular carcinogenesis pathway and ultimately deliver a more focused treatment. Currently, their use in mCRC has been limited primarily as an adjunct to conventional chemotherapy regimens. This review explores the relevant cell signaling networks in colorectal cancer, provides focus on the current targeted agent armamentarium approved for use in mCRC and explores the usefulness of predictive mCRC biomarkers. PMID- 27482292 TI - A Label-free Sirtuin 1 Assay based on Droplet-Electrospray Ionization Mass Spectrometry. AB - Sirtuin 1(SIRT1) is a NAD+-dependent deacetylase which has been implicated in age related diseases such as cancer, Alzheimer's disease, type 2 diabetes, and vascular diseases. SIRT1 modulators are of interest for their potential therapeutic use and potential as chemical probes to study the role of SIRT1. Fluorescence-based assays used to identify SIRT1 activators have been shown to have artifacts related to the fluorophore substrates used in the assays. Such problems highlight the potential utility of a label-free high throughput screening (HTS) strategy. In this work, we describe a label-free SIRT1 assay suitable for HTS based on segmented flow-electrospray ionization-mass spectrometry (ESI-MS). In the assay, 0.5 MUM SIRT1 was incubated with 20 MUM acetylated 21-amino acid peptide, which acts as substrate for the protein. A stable-isotope labeled product peptide was added to the assay mixture as an internal standard after reaction quenching. The resulting samples are formatted into 100 nL droplets segmented by perfluorodecalin and then infused at 0.8 samples/s into an ESI-MS. To enable direct ESI-MS analysis, 11 MUM SIRT1 was dialyzed into a 200 MUM ammonium formate (pH 8.0) buffer prior to use in the assay. This buffer was demonstrated to minimally affect enzyme kinetics and yet be compatible with ESI-MS. The assay conditions were optimized through enzyme kinetic study, and tested by screening an 80-compound library. The assay Z-factor was 0.7. Four inhibitors and no activators were detected from the library. PMID- 27482293 TI - Analysis of trace amounts of adulterants found in powders/supplements utilizing Raman spectroscopy coupled to direct analyte-probed nanoextraction-nanospray ionization-mass spectrometry. AB - In the United States, all food products have to be regulated to inform the consumers of the ingredients contained within. Some ingredients are not included on the label and yet are still found in the products. Presented is a Raman imaging technique for rapid, nondestructive, and spatially relevant localization of adulterants in powders. Raman spectroscopy followed by direct analyte-probed nanoextraction coupled to nanospray ionization-mass spectrometry allows rapid determination of the presence of each adulterant, leading to positive identifications such as melamine. The location and identification of these trace particles can then be extracted using a nanomanipulator. The nanomanipulation technique uses a solvent filled capillary tip which can be positioned on the particle of interest. Direct mass spectrometric analysis via nanospray of the particulate of interest eliminates time consuming chromatographic techniques prior to mass spectrometry analysis. This coupled technique combines rapid Raman spectroscopy techniques with direct mass spectrometry to confirm the presence of an adulterant. This technique was applied to an FDA supplied test sample, in which sibutramine, phenolphthalein, and melamine were confirmed to be present. PMID- 27482294 TI - Curcumin and tetrahydrocurcumin both prevent osteoarthritis symptoms and decrease the expressions of pro-inflammatory cytokines in estrogen-deficient rats. AB - BACKGROUND: Menopausal symptoms are associated with inflammation. Curcumin is a well-known anti-inflammatory bioactive compound from turmeric whereas tetrahydrocurcumin (THC) is a major metabolite of curcumin that may have different efficacies. However, they have not been studied for anti-menopausal symptoms and anti-osteoarthritis effects. We compared the efficacies of curcumin and THC for preventing postmenopausal and osteoarthritis symptoms in ovariectomized (OVX) obese rats with monoiodoacetate (MIA) injections into the right knee to generate a similar pathology as osteoarthritis. METHODS: OVX rats were provided a 45 % fat diet containing either (1) 0.4 % curcumin (curcumin), (2) 0.4 % THC, (3) 30 MUg/kg body weight 17beta-estradiol + 0.4 % dextrin (positive control), (4) 0.4 % dextrin (placebo; control), or (5) 0.4 % dextrin with no MIA injection (normal control) for 4 weeks. At the beginning of the fifth week, OVX rats were given articular injections of MIA or normal-control saline into the right knee and the assigned diets were provided for an additional 3 weeks. RESULTS: Curcumin and THC had similar efficacies for skin tail temperature in OVX rats whereas THC, but not curcumin, prevented glucose intolerance, which might be involved in exacerbating osteoarthritis. Both protected against osteoarthritis symptoms and pain-related behaviors better than 17beta-estradiol treatment in estrogen-deficient rats. Curcumin and THC prevented the deterioration of articular cartilage compared to control. They also maintained lean body mass and lowered fat mass as much as 17beta-estradiol treatment. The improvement in osteoarthritis symptoms was associated with decreased gene expressions of matrix metalloproteinase (MMP)3 and MMP13 and tumor necrosis factor-alpha, interleukin (IL)1beta, and IL6 in the articular cartilage. CONCLUSIONS: THC and curcumin are effective for treating postmenopausal and osteoarthritis symptoms in OVX rats with MIA-induced osteoarthritis-like symptoms and may have potential as interventions for menopausal and osteoarthritic symptoms in humans. PMID- 27482295 TI - Effects of a healthy Nordic diet on gene expression changes in peripheral blood mononuclear cells in response to an oral glucose tolerance test in subjects with metabolic syndrome: a SYSDIET sub-study. AB - BACKGROUND: Diet has a great impact on the risk of developing features of metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVD). We evaluated whether a long-term healthy Nordic diet (ND) can modify the expression of inflammation and lipid metabolism-related genes in peripheral blood mononuclear cells (PBMCs) during a 2-h oral glucose tolerance test (OGTT) in individuals with MetS. METHODS: A Nordic multicenter randomized dietary study included subjects (n = 213) with MetS, randomized to a ND group or a control diet (CD) group applying an isocaloric study protocol. In this sub study, we included subjects (n = 89) from three Nordic centers: Kuopio (n = 26), Lund (n = 30), and Oulu (n = 33) with a maximum weight change of +/-4 kg, high sensitivity C-reactive protein concentration <=10 mg L(-1), and baseline body mass index <39 kg m(-2). PBMCs were isolated, and the mRNA gene expression analysis was measured by quantitative real-time polymerase chain reaction (qPCR). We analyzed the mRNA expression changes of 44 genes before and after a 2hOGTT at the beginning and the end of the intervention. RESULTS: The healthy ND significantly down-regulated the expression of toll-like receptor 4 (TLR4), interleukin 18 (IL18), and thrombospondin receptor (CD36) mRNA transcripts and significantly up-regulated the expression of peroxisome proliferator-activated receptor delta (PPARD) mRNA transcript after the 2hOGTT compared to the CD. CONCLUSIONS: A healthy ND is able to modify the gene expression in PBMCs after a 2hOGTT. However, more studies are needed to clarify the biological and clinical relevance of these findings. PMID- 27482296 TI - Methyl group donors abrogate adaptive responses to dietary restriction in C. elegans. AB - BACKGROUND: Almost all animals adapt to dietary restriction through alternative life history traits that affect their growth, reproduction, and survival. Economized management of fat stores is a prevalent type of such adaptations. Because one-carbon metabolism is a critical gauge of food availability, in this study, we used Caenorhabditis elegans to test whether the methyl group donor choline regulates adaptive responses to dietary restriction. We used a modest dietary restriction regimen that prolonged the fecund period without reducing the lifetime production of progeny, which is the best measure of fitness. RESULTS: We found that dietary supplementation with choline abrogate the dietary restriction induced prolongation of the reproductive period as well as the accumulation and delayed depletion of large lipid droplets and whole-fat stores and increased the survival rate in the cold. By contrast, the life span-prolonging effect of dietary restriction is not affected by choline. Moreover, we found that dietary restriction led to the enlargement of lipid droplets within embryos and enhancement of the cold tolerance of the progeny of dietarily restricted mothers. Both of these transgenerational responses to maternal dietary restriction were abrogated by exposing the parental generation to choline. CONCLUSIONS: In conclusion, supplementation with the methyl group donor choline abrogates distinct responses to dietary restriction related to reproduction, utilization of fat stored in large lipid droplets, cold tolerance, and thrifty phenotypes in C. elegans. PMID- 27482297 TI - Transcriptomic profile adaptations following exposure of equine satellite cells to nutriactive phytochemical gamma-oryzanol. AB - BACKGROUND: Adult skeletal muscle myogenesis depends on the activation of satellite cells that have the potential to differentiate into new fibers. Gamma oryzanol (GO), a commercially available nutriactive phytochemical, has gained global interest on account of its muscle-building and regenerating effects. Here, we investigated GO for its potential influence on myogenesis, using equine satellite cell culture model, since the horse is a unique animal, bred and exercised for competitive sport. To our knowledge, this is the first report where the global gene expression in cultured equine satellite cells has been described. METHODS: Equine satellite cells were isolated from semitendinosus muscle and cultured until the second day of differentiation. Differentiating cells were incubated with GO for the next 24 h. Subsequently, total RNA from GO-treated and control cells was isolated, amplified, labeled, and hybridized to two-color Horse Gene Expression Microarray slides. Quantitative PCR was used for the validation of microarray data. RESULTS: Our results revealed 58 genes with changed expression in GO-treated vs. control cells. Analysis of expression changes suggests that various processes are reinforced by GO in differentiating equine satellite cells, including inhibition of myoblast differentiation, increased proliferation and differentiation, stress response, and increased myogenic lineage commitment. CONCLUSIONS: The present study may confirm putative muscle enhancing abilities of GO; however, the collective role of GO in skeletal myogenesis remains equivocal. The diversity of these changes is likely due to heterogenous growth rate of cells in primary culture. Genes identified in our study, modulated by the presence of GO, may become potential targets of future research investigating impact of this supplement in skeletal muscle on proteomic and biochemical level. PMID- 27482298 TI - Expression of cardiac insulin signalling genes and proteins in rats fed a high sucrose diet: effect of bilberry anthocyanin extract. AB - SCOPE: Insulin resistance is associated with impaired cardiac function, but the underlying molecular abnormalities are largely unexplained. Bilberry anthocyanin (BAcn) may be protective, as it appears to potentiate insulin action. METHODS: Rats were randomly allocated to control, sucrose-fed (SF) or sucrose-fed + BAcn diets (SF-A) for 15 weeks. Cardiac insulin signalling genes and proteins were quantified using reverse transcription quantitative real-time polymerase chain reaction and western blots. RESULTS: Glucose tolerance was not different with treatment. SF showed lower (p < 0.05) ferric reducing antioxidant power, which increased with BAcn. SF resulted in significantly decreased (p < 0.05) expression of 10 genes: acetyl-coenzyme A carboxylase alpha; V-Akt murine thymoma viral oncogene homolog 1; Bcl2-like 1; cytosine-cytosine-adenosine-adenosine thymidine/enhancer binding protein; FK506 binding protein 12-rapamycin associated; glycerol-3-phosphate dehydrogenase 1 (soluble); solute carrier family 2 (facilitated glucose transporter), member 1, 4; hexokinase 2; and thyroglobulin. SF-A prevented these changes. Compared to SF-A, SF up-regulated (p < 0.05) complement factor D and phosphoinositide-3-kinase, regulatory subunit1 (alpha); sterol regulatory element binding transcription factor 1 was down regulated (p < 0.05). SF increased (p < 0.05) cardiac phospholamban and decreased phosphorylated troponin I, which were not attenuated by BAcn. Compared to control or SF, SF-A resulted in significantly lower (p < 0.05) 5'-AMP-activated protein kinase. CONCLUSIONS: SF lowered antioxidant capacity and changed the expression of insulin signalling genes, which were modulated by BAcn. PMID- 27482299 TI - Effect of a diet enriched with omega-6 and omega-3 fatty acids on the pig liver transcriptome. AB - The optimal ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) is important for keeping the homeostasis of biological processes and metabolism, yet the underlying biological mechanism is poorly understood. The objective of this study was to identify changes in the pig liver transcriptome induced by a diet enriched with omega-6 and omega-3 fatty acids and to characterize the biological mechanisms related to PUFA metabolism. Polish Landrace pigs (n = 12) were fed diet enriched with linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) or standard diet as a control. The fatty acid profiling was assayed in order to verify how feeding influenced the fatty acid content in the liver, and subsequently next-generation sequencing (NGS) was used to identify differentially expressed genes (DEG) between transcriptomes between dietary groups. The biological mechanisms and pathway interaction networks were identified using DAVID and Cytoscape tools. Fatty acid profile analysis indicated a higher contribution of PUFAs in the liver for LA- and ALA-enriched diet group, particularly for the omega-3 fatty acid family, but not omega-6. Next-generation sequencing identified 3565 DEG, 1484 of which were induced and 2081 were suppressed by PUFA supplementation. A low ratio of omega-6/omega-3 fatty acids resulted in the modulation of fatty acid metabolism pathways and over representation of genes involved in energy metabolism, signal transduction, and immune response pathways. In conclusion, a diet enriched with omega-6 and omega-3 fatty acids altered the transcriptomic profile of the pig liver and would influence animal health status. PMID- 27482300 TI - Oral environment and cancer. AB - Cancer is now the leading cause of death in Japan. A rapid increase in cancer mortality is expected as Japan is facing a super-aged society. Many causes of cancer are known to be closely linked to life style factors, such as smoking, drinking, and diet. The oral environment is known to be involved in the pathogenesis and development of various diseases such as bronchitis, pneumonia, diabetes, heart disease, and dementia. Because the oral cavity acts as the bodily entrance for air and food, it is constantly exposed to foreign substances, including bacteria and viruses. A large number of bacteria are endemic to the oral cavity, and indigenous oral flora act to prevent the settlement of foreign bacteria. The oral environment is influenced by local factors, including dental plaque, tartar, teeth alignment, occlusion, an incompatible prosthesis, and bad lifestyle habits, and systemic factors, including smoking, consumption of alcohol, irregular lifestyle and eating habits, obesity, stress, hormones, and heredity. It has recently been revealed that the oral environment is associated with cancer. In particular, commensal bacteria in the oral cavity are involved in the development of cancer. Moreover, Candida, human papilloma virus and Epstein Barr virus as well as commensal bacteria have been reported to be associated with the pathogenesis of cancer. In this review, we introduce recent findings of the correlation between the oral environment and cancer. PMID- 27482301 TI - Collaborative studies in toxicogenomics in rodent liver in JEMS.MMS; a useful application of principal component analysis on toxicogenomics. AB - Toxicogenomics is a rapidly developing discipline focused on the elucidation of the molecular and cellular effects of chemicals on biological systems. As a collaborative study group of Toxicogenomics/JEMS.MMS, we conducted studies on hepatocarcinogens in rodent liver in which 100 candidate marker genes were selected to discriminate genotoxic hepatocarcinogens from non-genotoxic hepatocarcinogens. Differential gene expression induced by 13 chemicals were examined using DNA microarray and quantitative real-time PCR (qPCR), including eight genotoxic hepatocarcinogens [o-aminoazotoluene, chrysene, dibenzo[a,l]pyrene, diethylnitrosamine (DEN), 7,12-dimethylbenz[a]anthracene, dimethylnitrosamine, dipropylnitrosamine and ethylnitrosourea (ENU)], four non genotoxic hepatocarcinogens [carbon tetrachloride, di(2-ethylhexyl)phthalate (DEHP), phenobarbital and trichloroethylene] and a non-genotoxic non hepatocarcinogen [ethanol]. Using qPCR, 30 key genes were extracted from mouse livers at 4 h and 28 days following dose-dependent gene expression alteration induced by DEN and ENU: the most significant changes in gene expression were observed at 4 h. Next, we selected key point times at 4 and 48 h from changes in time-dependent gene expression during the acute phase following administration of chrysene by qPCR. We successfully showed discrimination of eight genotoxic hepatocarcinogens [2-acetylaminofluorene, 2,4-diaminotoluene, diisopropanolnitrosamine, 4-dimethylaminoazobenzene, 4-(methylnitsosamino)-1-(3 pyridyl)-1-butanone, N-nitrosomorpholine, quinoline and urethane] from four non genotoxic hepatocarcinogens [1,4-dichlorobenzene, dichlorodiphenyltrichloroethane, DEHP and furan] using qPCR and principal component analysis. Additionally, we successfully identified two rat genotoxic hepatocarcinogens [DEN and 2,6-dinitrotoluene] from a nongenotoxic hepatocarcinogen [DEHP] and a non-genotoxic non-hepatocarcinogen [phenacetin] at 4 and 48 h. The subsequent gene pathway analysis by Ingenuity Pathway Analysis extracted the DNA damage response, resulting from the signal transduction of a p53-class mediator leading to the induction of apoptosis. The present review of these studies suggests that application of principal component analysis on the gene expression profile in rodent liver during the acute phase is useful to predict genotoxic hepatocarcinogens in comparison to non-genotoxic hepatocarcinogens and/or non-carcinogenic hepatotoxins. PMID- 27482302 TI - The Role of the Supplemental Nutrition Assistance Program in the Relationship between Food Insecurity and Probability of Maternal Depression. AB - Food insecurity is a substantial stressor for many households. Though an association between food insecurity and depression has been well established, most studies have been cross-sectional. Although many receive benefits from the Supplemental Nutrition Assistance Program (SNAP), its role in reducing distress associated with food insecurity is unclear. Using data from 1,225 women who participated in the Fragile Families and Child Wellbeing Study, this study investigated 1) whether change in food security status predicts change in depression severity over a two-year period, 2) whether participating in SNAP predicts depression, and 3) whether the relationship between food insecurity and depression varies based on receipt of SNAP. Food insecurity was linked to probability of depression over time. Additionally, for those who became food insecure over the two-year period, losing SNAP benefits was associated with increased probability of depression, while gaining benefits was associated with reduced probability of depression. This suggests that the SNAP program offsets emotional hardship for those who have recently become food insecure. Further research is needed to evaluate the most efficient and efficacious means to reduce food insecurity and improve emotional wellbeing among vulnerable families. PMID- 27482303 TI - Role of the Deposition Precursor Molecules in Defining Oxidation State of Deposited Copper in Surface Reduction Reactions on H-Terminated Si(111) Surface. AB - Surface-limited deposition reactions leading to the formation of copper nanoparticles on H-terminated Si(111) surface can serve as a model for understanding the role of structure of the deposition precursor molecules in determining the oxidation state of the metal deposited. This study compares three different precursor molecules: Cu(acac)2 (Cu(II) acetylacetonate), Cu(hfac)2, and Cu(hfac)VTMS (Cu(I)-(hexafluoroacetylacetonato)-vinyltrimethylsilane) as copper deposition sources in a process with a controlled oxidation state of copper. X ray photoelectron spectroscopy suggests that single-electron reduction governs the deposition of Cu(I) from the first two precursor molecules and that the last of the precursors studied yields predominantly metallic copper. Time-of-fight secondary ion mass spectrometry (ToF-SIMS) and infrared spectroscopy are utilized to interrogate surface species produced. Atomic force microscopy is used to quantify the deposition process and to follow the size distribution of the deposited copper containing nanoparticles. A plausible explanation supported by density functional theory calculations is offered on the basis of the difference in the reaction pathways for Cu(I) and Cu(II) precursors. PMID- 27482305 TI - Time for something different: the Korean Journal of Anesthesiology commences EPUB ahead of print. PMID- 27482304 TI - The Decline in Hydrocodone/Acetaminophen Prescriptions in Emergency Departments in the Veterans Health Administration Between 2009 to 2015. AB - INTRODUCTION: The purpose of the study was to measure national prescribing patterns for hydrocodone/acetaminophen among veterans seeking emergency medical care, and to see if patterns have changed since this medication became a Schedule II controlled substance. METHODS: We conducted a retrospective cohort study of emergency department (ED) visits within the Veterans Health Administration (VA) between January 2009 and June 2015. We looked at demographics, comorbidities, utilization measures, diagnoses, and prescriptions. RESULTS: During the study period, 1,709,545 individuals participated in 6,270,742 ED visits and received 471,221 prescriptions for hydrocodone/acetaminophen (7.5% of all visits). The most common diagnosis associated with a prescription was back pain. Prescriptions peaked at 80,776 in 2011 (8.7% of visits), and declined to 35,031 (5.6%) during the first half of 2015 (r=-0.99, p<0.001). The percentage of hydrocodone/acetaminophen prescriptions limited to 12 pills increased from 22% (13,949) in 2009 to 31% (11,026) in the first half of 2015. A prescription was more likely written for patients with a pain score>=7 (OR 3.199, CI [3.192 3.205]), a musculoskeletal (OR 1.622, CI [1.615-1.630]) or soft tissue (OR 1.656, CI [1.649-1.664]) diagnosis, and those below the first quartile for total ED visits (OR 1.282, CI [1.271-1.293]) and total outpatient ICD 9 codes (OR 1.843, CI [1.833-1.853]). CONCLUSION: Hydrocodone/acetaminophen is the most frequently prescribed ED medication in the VA. The rate of prescribing has decreased since 2011, with the rate of decline remaining unchanged after it was classified as a Schedule II controlled substance. The proportion of prescriptions falling within designated guidelines has increased but is not at goal. PMID- 27482306 TI - How to get away from the cold: body temperature during surgery. PMID- 27482307 TI - Monitored anesthesia care in and outside the operating room. AB - Monitored anesthesia care (MAC) is an anesthesia technique combining local anesthesia with parenteral drugs for sedation and analgesia. The use of MAC is increasing for a variety of diagnostic and therapeutic procedures in and outside of the operating room due to the rapid postoperative recovery with the use of relatively small amounts of sedatives and analgesics compared to general anesthesia. The purposes of MAC are providing patients with safe sedation, comfort, pain control and satisfaction. Preoperative evaluation for patients with MAC is similar to those of general or regional anesthesia in that patients should be comprehensively assessed. Additionally, patient cooperation with comprehension of the procedure is an essential component during MAC. In addition to local anesthesia by operators or anesthesiologists, systemic sedatives and analgesics are administered to provide patients with comfort during procedures performed with MAC. The discretion and judgment of an experienced anesthesiologist are required for the safety and efficacy profiles because the airway of the patients is not secured. The infusion of sedatives and analgesics should be individualized during MAC. Many procedures in and outside of the operating room, including eye surgery, otolaryngologic surgery, cardiovascular procedures, pain procedures, and endoscopy are performed with MAC to increase patient and operator satisfaction. PMID- 27482308 TI - Considerations when calculating the sample size for an inequality test. AB - Click here for Korean Translation. Calculating the sample size is a vital step during the planning of a study in order to ensure the desired power for detecting clinically meaningful differences. However, estimating the sample size is not always straightforward. A number of key components should be considered to calculate a suitable sample size. In this paper, general considerations for conducting sample size calculations for inequality tests are summarized. PMID- 27482309 TI - Surgical site infection after colorectal surgery according to the main anesthetic agent: a retrospective comparison between volatile anesthetics and propofol. AB - BACKGROUND: Anesthetic agents used for general anesthesia are emerging possible influential factors for surgical site infection (SSI). In this retrospective study, we evaluated the incidence of SSI after colorectal surgery according to the main anesthetic agents: volatile anesthetics vs. propofol. METHODS: A total 1,934 adult patients, who underwent elective colorectal surgery under general anesthesia between January 2011 and December 2013, were surveyed to evaluate the incidence of SSI: 1,519 using volatile anesthetics and 415 using propofol for main anesthetic agents. Patient, surgery, and anesthesia-related factors were investigated from all patients. Propensity-score matching was performed to reduce the risk of confounding and produced 390 patients in each group. RESULTS: Within the propensity-score matched groups, the incidence of SSI was higher in the volatile group compared with the propofol group (10 [2.6%] vs. 2 [0.5%], OR = 5.0 [95% CI = 1.1-2.8]). C-reactive protein was higher in the volatile group than in the propofol group (8.4 +/- 5.6 vs. 7.1 +/- 5.3 mg/dl, P = 0.001), and postoperative white blood cells count was higher in the volatile group than in the propofol group (9.2 +/- 3.2 * 10(3)/ul vs. 8.6 +/- 3.4 * 10(3)/ul, P = 0.041). CONCLUSIONS: The results of this study suggest that intravenous anesthesia may have beneficial effects for reducing SSI in colorectal surgery compared to volatile anesthesia. PMID- 27482310 TI - Synergism between rocuronium and cisatracurium: comparison of the Minto and Greco interaction models. AB - BACKGROUND: This study was conducted to investigate the pharmacodynamic interaction between rocuronium and cisatracurium using the response surface model, which is not subject to the limitations of traditional isobolographic analysis. METHODS: One hundred and twenty patients were randomly allocated to receive one of the fifteen predefined combinations of rocuronium and cisatracurium. To study single drugs, cisatracurium 0.2, 0.15, or 0.1 mg/kg or rocuronium 0.8, 0.6 or 0.4 mg/kg doses were administered alone. To study the pharmacodynamic interaction, drugs were applied in three types of combination ratio, i.e., half dose of each drug alone, 75% of each single dose of rocuronium and 25% of each single dose of cisatracurium, and vice versa. Train-of-four (TOF) ratio and T1% (first twitch of the TOF presented as percentage compared to the initial T1) were used as pharmacodynamic endpoints, and the Greco and Minto models were used as surface interaction models. RESULTS: The interaction term alpha of the Greco model for TOF ratio and T1% measurements showed synergism with values of 0.977 and 1.12, respectively. Application of the Minto model resulted in U50 (theta) values (normalized unit of concentration that produces 50% of the maximal effect in the 0 < theta < 1 region) less than 1 for both TOF ratio and T1% measurements, indicating that rocuronium and cisatracurium exhibit synergism. CONCLUSIONS: Response surface modeling of the interaction between rocuronium and cisatracurium, based on considerations of their effects on muscle relaxation as measured by TOF ratio and T1%, indicated that the two drugs show considerable synergism. PMID- 27482311 TI - Effect of hydroxyethyl starch on blood glucose levels. AB - BACKGROUND: Hydroxyethyl starch (HES), a commonly used resuscitation fluid, has the property to induce hyperglycemia as it contains large ethyl starch, which can be metabolized to produce glucose. We evaluated the effect of 6% HES-130 on the blood glucose levels in non-diabetic patients undergoing surgery under spinal anesthesia. METHODS: Patients scheduled to undergo elective lower limb surgery were enrolled. Fifty-eight patients were divided into two groups according to the type of the main intravascular fluid used before spinal anesthesia (Group LR: lactated Ringer's solution, n = 30 vs. Group HES: 6% hydroxyethyl starch 130/0.4, n = 28). Blood glucose levels were measured at the following time points: 0 (baseline), 20 min (T1), 1 h (T2), 2 h (T3), 4 h (T4), and 6 h (T6). RESULTS: Mean blood glucose levels at T5 in the LR group and T4, T5 in the HES group, increased significantly compared to baseline. There were no significant changes in the serial differences of mean blood glucose levels from baseline between the two groups. CONCLUSIONS: Administration of 6% HES-130 increased blood glucose levels within the physiologic limits, but the degree of glucose increase was not greater than that caused by administration of lactated Ringer's solution. In conclusion, we did not find evidence that 6% HES-130 induces hyperglycemia in non diabetic patients. PMID- 27482312 TI - A comparison of the temperature difference according to the placement of a nasopharyngeal temperature probe. AB - BACKGROUND: The purpose of this study was to compare temperatures measured at three different sites where a nasopharyngeal temperature probe is commonly placed. METHODS: Eighty elective abdominal surgical patients were enrolled. After anesthesia induction, four temperature probes were placed at the nasal cavity, upper portion of the nasopharynx, oropharynx, and the esophagus. The placement of the nasopharyngeal temperature probes was evaluated using a flexible nasendoscope, and the depth from the nares was measured. The four temperatures were simultaneously recorded at 10-minute intervals for 60 minutes. RESULTS: The average depths of the probes that were placed in the nasal cavity, upper nasopharynx, and the oropharynx were respectively 5.7 +/- 0.9 cm, 9.9 +/- 0.7 cm, and 13.6 +/- 1.7 cm from the nares. In the baseline temperatures, the temperature differences were significantly greater in the nasal cavity 0.32 (95% CI; 0.27 0.37)C than in the nasopharynx 0.02 (0.01-0.04)C, and oropharynx 0.02 (-0.01 to 0.05)C compared with the esophagus (P < 0.001). These differences were maintained for 60 minutes. Twenty patients showed a 0.5C or greater temperature difference between the nasal cavity and the esophagus, but no patient showed such a difference at the nasopharynx and oropharynx. CONCLUSIONS: During general anesthesia, the temperatures measured at the upper nasopharynx and the oropharynx, but not the nasal cavity, reflected the core temperature. Therefore, the authors recommend that a probe should be placed at the nasopharynx (~ 10 cm) or oropharynx (~ 14 cm) with mucosal attachment for accurate core temperature measurement. PMID- 27482313 TI - Preoperative interscalene brachial plexus block aids in perioperative temperature management during arthroscopic shoulder surgery. AB - BACKGROUND: Hypothermia is common during arthroscopic shoulder surgery under general anesthesia, and anesthetic-impaired thermoregulation is thought to be the major cause of hypothermia. This prospective, randomized, double-blind study was designed to compare perioperative temperature during arthroscopic shoulder surgery with interscalene brachial plexus block (IBPB) followed by general anesthesia vs. general anesthesia alone. METHODS: Patients scheduled for arthroscopic shoulder surgery were randomly allocated to receive IBPB followed by general anesthesia (group GB, n = 20) or general anesthesia alone (group GO, n = 20), and intraoperative and postoperative body temperatures were measured. RESULTS: The initial body temperatures were 36.5 +/- 0.3C vs. 36.4 +/- 0.4C in group GB vs. GO, respectively (P = 0.215). The body temperature at 120 minutes after induction of anesthesia was significantly higher in group GB than in group GO (35.8 +/- 0.3C vs. 34.9 +/- 0.3C; P < 0.001). The body temperatures at 60 minutes after admission to the post-anesthesia care unit were 35.8 +/- 0.3C vs. 35.2 +/- 0.2C in group GB vs. GO, respectively (P < 0.001). The concentrations of desflurane at 0, 15, and 120 minutes after induction of anesthesia were 6.0 vs. 6.0% (P = 0.330), 5.0 +/- 0.8% vs. 5.8 +/- 0.4% (P = 0.001), and 3.4 +/- 0.4% vs. 7.1 +/- 0.9% (P < 0.001) in group GB vs. GO, respectively. CONCLUSIONS: The present study demonstrated that preoperative IBPB could reduce both the intraoperative concentration of desflurane and the reduction in body temperature during and after arthroscopic shoulder surgery. PMID- 27482316 TI - Arytenoid cartilage dislocation after reversed total shoulder replacement surgery in the beach chair position: a case report. AB - Arytenoid cartilage dislocation is not a common complication, but its delayed diagnosis reduces the therapeutic effect of treatment. A male patient underwent reversed total shoulder replacement surgery in the beach chair position under general anesthesia. The patient experienced postoperative hoarseness, and it was revealed that he had right arytenoid dislocation. Voice restoration was accomplished with closed reduction. We discussed changes in patient position during the operation and how they may contribute to the arytenoid dislocation. Flexion and a slight rotation of the neck during the operation can lead to an increase in intracuff pressure of the endotracheal tube. It is necessary to check neck position and monitor intracuff pressure in patients undergoing operations in the beach chair position. Also, the anesthesiologist should suspect arytenoid dislocation in the case of persistent hoarseness after surgery in the beach chair position. PMID- 27482314 TI - An ultrasound-guided fascia iliaca catheter technique does not impair ambulatory ability within a clinical pathway for total hip arthroplasty. AB - BACKGROUND: Both neuraxial and peripheral regional analgesic techniques offer postoperative analgesia for total hip arthroplasty (THA) patients. While no single technique is preferred, quadriceps muscle weakness from peripheral nerve blocks may impede rehabilitation. We designed this study to compare postoperative ambulation outcome in THA patients who were treated with a new ultrasound-guided fascia iliaca catheter (FIC) technique or intrathecal morphine (ITM). METHODS: We reviewed the electronic health records of a sequential series of primary unilateral THA patients who were part of a standardized clinical pathway; apart from differences in regional analgesic technique, all other aspects of the pathway were the same. Our primary outcome was total ambulation distance (meters) combined for postoperative days 1 and 2. Secondary outcomes included daily opioid consumption (morphine milligram equivalents) and analgesic-related side effects. We examined the association between the primary outcome and analgesic technique by performing crude and adjusted ordinary least-squares linear regression. A P value < 0.05 was considered statistically-significant. RESULTS: The study analyzed the records of 179 patients (fascia iliaca, n = 106; intrathecal, n = 73). The primary outcome (total ambulation distance) did not differ between the groups (P = 0.08). Body mass index (BMI) was the only factor (beta = -1.7 [95% CI -0.5 to -2.9], P < 0.01) associated with ambulation distance. Opioid consumption did not differ, while increased pruritus was seen in the intrathecal group (P < 0.01). CONCLUSIONS: BMI affects postoperative ambulation outcome after hip arthroplasty, whereas the type of regional analgesic technique used does not. An ultrasound-guided FIC technique offers similar analgesia with fewer side effects when compared with ITM. PMID- 27482315 TI - Preoperative ultrasonographic findings of internal jugular veins and carotid arteries in kidney transplant recipients. AB - BACKGROUND: Hemodialysis via the internal jugular vein (IJV) has been widely used for patients with end stage renal disease (ESRD) patients, as they have a higher risk of arterial diseases. We investigated the ultrasonographic findings of the IJV and carotid artery (CA) in recipients of kidney transplantation (KT) and identified factors influencing IJV/CA abnormalities. METHODS: We enrolled 120 adult KT recipients. Patients in group A (n = 57) had a history of IJV hemodialysis, while those in group B (n = 63) were not yet on dialysis or undergoing dialysis methods not involving the IJV. The day before surgery, we evaluated the state of the IJV and CA using ultrasonography. We followed patients with IJV stenosis for six months after KT. RESULTS: Ultrasonography revealed that four patients (7%) in group A had IJV abnormalities, while no patients in group B had abnormalities (P = 0.118). Of the four patients with abnormalities, one with 57.4% stenosis normalized during follow- up. However, another patient with 90.1% stenosis progressed to occlusion, while the two patients with total occlusion remained the same. Twenty patients in group A (n = 11) and B (n = 9) had several CA abnormalities (P = 0.462). Upon multivariate analysis with stepwise selection, height and age were significantly correlated with IJV stenosis (P = 0.043, odds ratio = 0.9) and CA abnormality (P = 0.012, odds ratio = 1.1), respectively. CONCLUSIONS: IJV abnormalities (especially with a history of IJV hemodialysis) and CA abnormalities may be present in ESRD patients. Therefore, we recommend ultrasonographic evaluation before catheterization. PMID- 27482317 TI - Difficult endotracheal intubation secondary to tracheal deviation and stenosis in a patient with severe kyphoscoliosis: a case report. AB - We report on a case of difficult endotracheal intubation in a patient with marked tracheal deviation at an angle of 90 degrees combined with stenosis due to kyphoscoliosis with vertebral body fusion. After induction of general anesthesia, a proper laryngeal view was easily obtained using a videolaryngoscope. But a tracheal tube could not be advanced more than 3 cm beyond the vocal cords due to resistance, despite various attempts, including the use of small size tubes, full rotation of the tube tip, and fiberoptic bronchoscopy. Ultimately, the airway was successfully secured by placing a tube tip above the area of resistance and by additionally packing saline-soaked gauzes around the tracheal inlet to minimize gas leakage and to fasten the tube in the trachea. PMID- 27482318 TI - A two-stage approach to induction and intubation of two infants with Pierre Robin Sequence using a LMA ClassicTM and Air-Q(r): two cases report. AB - The laryngeal mask airway (LMA) ClassicTM and Air-Q(r) are supralaryngeal devices used for airway management in routine and difficult pediatric airways. We describe a novel two-stage technique of insertion of the LMA ClassicTM awake prior to induction of anesthesia, to assure oxygenation and ventilation, and after induction removal and placement of the Air-Q(r) for intubation using the flexible fiberoptic bronchoscope. The LMA Classic'sTM pliable design and relatively small size allow it to be easily placed in awake infants. In contrast, the Air-Q(r) is an excellent device for intubation because of its larger internal diameter and removable 9 mm adapter. Our goal was to reduce unpredictability and potentially increase the safety of induction of anesthesia and intubation in infants with Pierre Robin sequence. By using these devices in a two-stage approach we created a technique for consistent oxygenation, ventilation, and intubation in these infants. PMID- 27482319 TI - Tageted bipolar radiofrequency decompression with vertebroplasty for intractable radicular pain due to spinal metastasis: a case report. AB - Metastatic spinal tumors are usually quite difficult to treat. In patients with metastatic spinal tumors, conventional radiotherapy fails to relieve pain in 20 30% of cases and open surgery often causes considerable trauma and complications, which delays treatment of the primary disease. Percutaneous vertebroplasty (PVP) is considered to be useful in achieving rapid pain control and preventing further vertebral collapse due to spinal metastasis. However, symptoms of intraspinal neural compression can be contraindications to PVP. To overcome this problem, we performed PVP following targeted bipolar radiofrequency decompression, and examined the effect of the combined treatment in relieving severe radicular pain related to spinal cord compression caused by malignant metastatic tumors. PMID- 27482320 TI - Transesophageal echocardiographic guidance for percutaneous closure of aortic pseudoaneurysm using a type II Amplatzer vascular plug: a case report. AB - Aortic pseudoaneurysm after cardiac surgery is a rare entity, but it is potentially fatal due to its clinical course along with higher morbidity and mortality rates. Instead of open surgical repair, percutaneous procedures have been introduced as other options for managing an aortic pseudoaneurysm. In this case report, we describe transesophageal echocardiography guidance for successful percutaneous closure of an aortic pseudoaneurysm located in the left ventricular outflow tract by using a type II Amplatzer vascular plug in a patient in whom open surgical repair was not recommended. PMID- 27482321 TI - Spinal anesthesia for cesarean section in a patient with systemic sclerosis associated interstitial lung disease: a case report. AB - Systemic sclerosis or scleroderma is a rare autoimmune disorder characterized by excessive fibrosis and, vasculopathy, with multiorgan involvement. Anesthetic considerations in patients with systemic sclerosis must take into account the degree of organ dysfunction as well as airway management. Regional anesthesia is a preferable alternative to general anesthesia despite the reports of prolonged sensory block. Spinal anesthesia in patients with systemic sclerosis has been reported for only one patients undergoing cesarean section. Concurrent systemic sclerosis and pregnancy raise many obstetric and anesthetic considerations. We describe the case of a pregnant patient with systemic sclerosis who had a history of dyspnea and interstitial lung disease. The cesarean section was performed uneventfully under spinal anesthesia. PMID- 27482322 TI - Central hyperventilation syndrome due to massive pneumocephalus after endoscopic third ventriculostomy: a case report. AB - Pneumocephalus is common after brain surgeries, but usually is not substantial enough to cause serious complications. We recently encountered a case of post operative tachypnea after an endoscopic 3rd ventriculostomy. At first, we thought that the hyperventilation was the result of residual paralysis after emergence from anesthesia, but during further evaluation we found a massive pneumocephalus. In such unusual post-operative situations, physicians should consider surgery related complications as the possible cause as well, along with the anesthetic factors. PMID- 27482323 TI - Suspected anaphylactic reaction associated with sugammadex: a case report. AB - We describe a case of a 35-year-old male patient who was scheduled for laparoscopic cholecystectomy and developed a life-threatening anaphylactic reaction 2 min after the administration of sugammadex. He manifested erythematous wheals on the entire body, dyspnea, hypotension, and tachycardia. These symptoms disappeared after the administration of epinephrine. The patient recovered and was discharged at postoperative day 5 without any complications. After 7 weeks, we performed a skin prick test, and there was a weakly positive reaction for sugammadex. This case is suspected anaphylaxis associated with sugammadex, and we need to be aware that the use of sugammadex is associated with a serious risk of anaphylaxis. PMID- 27482324 TI - The Infiniti Plus ultrasound needle guidance system improves needle visualization during the placement of spinal anesthesia. PMID- 27482325 TI - Epstein-Barr Virus Infection and Opisthorchiasis: A Story of Cholangiocarcinoma in the Highly Endemic Area. PMID- 27482327 TI - Developing a WebGIS for Geo-Visualization of Cancer. AB - BACKGROUND: Considering the hygiene facilities and sharing the data of diseases, considerable attempts to promote the public awareness have been made by various media; however, most of the provided information is based on numerical and verbal statistics, and may not provide suitable understanding for people in regard with the situation of diseases. OBJECTIVES: The main aim of this study is to design an interactive WebGIS system in which people could simply produce and observe their favorite maps of different cancers and environmental parameters. They can use this tools to produce their personalized maps and explore various aspects of the cancer. MATERIALS AND METHODS: A system has been developed by using WebGIS for convenience of ordinary users without any knowledge about geospatial information system (GIS) to observe the situation of the diseases and environmental conditions in terms of static and user-produced interactive maps. It has also provided the possibility of spatial comparison of the arbitrary parameters in the framework of bar and pie diagrams. This system has been designed and launched on cancer database of Iran where information of meteorological stations has been embedded as environmental parameters. RESULTS: The innovative idea in this study has received less attention in previous works including possibility of producing web-based Choropleth map so that users could easily select the parameters and algorithms for classification and interactive coloring in the system to produce their personalized maps. CONCLUSIONS: Development of WebGIS tools and increased cooperation of people in terms of inserting the spatial labels on the map to report a disease or using their views about reasons of occurring a specific cancer in a specific region may cause turning the process of mono-direction flow of information to users to a bi-directional flow of information. As a result, cancer specialists could use the knowledge of local people and residents of different regions of the country to better analyze the situation of various kinds of cancers. PMID- 27482326 TI - Does Histologic Subtype Influence the Post-Operative Outcome in Spinal Meningioma? AB - BACKGROUND: Postoperative outcome of spinal meningiomas is an important issue in surgery decision-making. There are limited and conflicting data in the literature about the prognostic factors influencing recovery, especially about the histopathologic subtypes. OBJECTIVES: This study was carried out to evaluate the effect of some of these factors on postoperative outcome. PATIENTS AND METHODS: This study was performed on 39 patients operated for spinal meningioma between October 1998 and January 2012; their histopathologic subtype was determined according to WHO criteria. The follow up period ranged between 8 - 120 months. The influence of histopathologic subtype, grade, age, sex, surgical approach, local adhesion and anatomical location was assessed according to Frankel classification of neurologic deficit. RESULTS: From a total number of 39 spinal meningiomas, 34 cases were WHO grade I, from which 15 cases were psammomatous, 7 cases were meningothelial, 9 cases were transitional and 3 cases were fibroblastic. Five cases were grade II, 3 of which had clear cell appearance and the remaining 2 had chordoid appearance. The mean age was 51.6 (22 to 76) years; 25 cases were female and 14 cases were male. This study revealed that grade II meningioma cases had poor prognosis in all 5 cases and psammomatous subtype had poor postoperative outcome in 40% of cases while the other subtypes had good outcome in all cases (P = 0.026). Cervical location of the tumor was also related with poor outcome in 37.5% of the cases, while 22.5% had poor outcome in other locations (P = 0.029). Age below and above 45 years and sex had no significant influence on the outcome. CONCLUSIONS: Spinal meningiomas of psammomatous type and grade II spinal meningiomas are associated with less favorable postoperative neurologic outcome. Cervical location has also a negative correlation with a good outcome. PMID- 27482328 TI - Nanocarriers Usage for Drug Delivery in Cancer Therapy. AB - Conventional therapeutic agents have displayed significant shortcomings. For this reason, important achievements have effectively made in biotechnology for delivering the therapeutic agents to the site of action, and diminish side effects. Polymeric carriers, micelles, dendrimers, liposomes, solid lipid carriers, gold carriers, viral carriers, nanotubes and magnetic carriers incorporating cytotoxic therapeutics have developed. To improve biological distribution of therapeutic drugs, some modified carriers have designed in optimal size and modified surface area. Delivery of carriers to target cells could be done by passive and active targeting. PMID- 27482329 TI - Circulating Levels of M30 and M65 Molecules in Transitional Cell Carcinoma of the Bladder and Their Relation to Tumor Progression. AB - BACKGROUND: Various markers are suggested for diagnosis and monitoring of transitional cell carcinoma of the bladder (TCC), including cytokeratins (CKs). OBJECTIVES: In the present study, the circulating CK18 (M65) and its caspase cleaved form, ccCK18 (M30), have been investigated in a group of patients with TCC. PATIENTS AND METHODS: Serum samples were obtained from 60 patients before surgical resection, among which the samples of 26 patients after resection were also included. We measured the levels of soluble M30 and M65 molecules by enzyme linked immunosorbent assay. The relation between these markers and patients' clinical characteristics was evaluated. RESULTS: M30 and M65 in total patient sera were 148 +/- 16 U/L and 318 +/- 34 U/L, respectively. A correlation existed between pre-operative M30 and M65 levels (P < 0.0001, Spearman r = 0.51). M65, but not M30, showed a significant relation to tumor stage and grade. The M65 quantity in patients with T3/T4 tumor stages (350 +/- 42 U/L) was higher than that of patients with T1/T2 stages (293 +/- 45U/L; P < 0.038). Patients with tumor grades III/IV also showed higher levels of M65 compared to patients with tumor grades I/II (P < 0.04). The M30:M65 ratio in all patients was 0.54 +/- 0.04. There was a lower M30:M65 ratio in patients with T3/T4 stage tumors and those with tumor grades III/IV (P < 0.02). The M30 (133 +/- 19 U/L) and M65 levels (240 +/- 21 U/L) after surgery did not significantly differ compared to their pre-operative values. However, a correlation between the pre- and post operative M30:M65 ratio in patients >= 70 years was seen (P = 0.009). CONCLUSIONS: These data suggested a relationship of both M65 and the M30:M65 ratio to tumor progression which might imply their importance in TCC monitoring. PMID- 27482330 TI - The Effect of Complete Decongestive Therapy on Edema Volume Reduction and Pain in Women With Post Breast Surgery Lymph Edema. AB - BACKGROUND: Upper extremity lymph edema is the most common side effect of breast cancer treatment that may produce significant physical and psychological morbidity. Pain is the frequent symptom of lymph edema that causes impairment of activities in daily life. OBJECTIVES: The aim of this study was assessment of the effect of complex decongestive therapy (CDT) on upper extremity lymph edema and pain in women with post breast surgery lymph edema. PATIENTS AND METHODS: In this quasi- experimental research with before- after design, 36 women with moderate lymph edema after breast surgery participated in the program. Edema volume was measured by water displacement method; pain values were evaluated by visual analog scale (VAS). Data were recorded before intervention and 2 and 4 weeks after it. CDT included the first phase (intensive phase) and the second phase (maintenance phase). Each phase lasted 2 weeks. After use of Shapiro Wilk test for normality, analysis of variances with GEE and repeated measurements were used to analyze the data. RESULTS: After one month doing CDT program, significant decrease of edema was noticed (P < 0.0001), also pain decreased during 2 and 4 weeks after intervention (P < 0.0001). CONCLUSIONS: This study indicated that CDT program is effective in reducing lymph edema volume and pain in women with moderate post breast surgery lymph edema. It seems that raising patients' awareness and training healthcare professionals regarding lymph edema preventive strategies have an important role in earlier and better combating this complication. PMID- 27482332 TI - Abnormal Presentation of Choriocarcinoma and Literature Review. AB - INTRODUCTION: Gestational trophoblastic neoplasms have highly been malignant potential, which usually occurred in child-bearing age women. Unusual feature of this malignancy would be rare, it was important to take in mind the possibility of GTN in different manifestation. Based on the above mentioned, the aim of this presentation would be the management and outcome of a case series of choriocarcinoma patients with abnormal manifestation. CASE PRESENTATION: We have presented four patients, first who initially manifestation with signs of septic shock, the second case with severe gastrointestinal hemorrhage, the third case with postpartum infection and the forth case was a postmenopausal bleeding patient. CONCLUSIONS: In case of metastatic choriocarcinoma with precise history, accurate diagnosis and appropriate treatment have led us to curable results. PMID- 27482331 TI - Postmenopausal Breast Cancer Risk in Relation to Antibodies Specific to Benzo[a]Pyrene, Estradiol and Progesterone. AB - BACKGROUND: Antibodies might protect against low doses of environmental carcinogens by decreasing systemic uptake, activation of metabolic pathways, and redistribution of carcinogens within the organism. The features of antibody formation in relation to environmental carcinogens and sex steroids under natural conditions should be determined to identify breast cancer risk, then to develop cancer immune prevention strategies. OBJECTIVES: The purpose of this study was to investigate antibodies specifications to benzo(a)pyrene, estradiol and progesterone in postmenopausal women with invasive breast cancer. PATIENTS AND METHODS: A semi-quantitative non-competitive immunoassay of IgG antibodies to benzo(a)pyrene (IgG-Bp), estradiol (IgG-Es), and progesterone (IgG-Pg) has conducted. The assay has performed on 322 serum samples from patients with breast cancer and 179 serum samples from healthy postmenopausal women by using low molecular-weight Bp, Es, and Pg conjugated with bovine serum albumin. ROC analysis has also conducted to determine the odds ratio (OR). RESULTS: Combination of the high levels of IgG-Bp and IgG-Es without IpG-Pg was more frequent in breast cancer patients than that in healthy women, and the OR has increased to 3.8. Combination of the high levels of IgG-Pg with high levels of both IgG-Bp and IgG-Es were significantly more frequent in breast cancer patients (36.9%) than that in healthy women (5.6%), and the OR increased to 11.7. These differences have peculiarly expressed in breast cancer patients with hormone status ER+/PR- (OR = 26.7). The minimum OR (0.4) has obtained at low levels of the three antibodies. CONCLUSIONS: Immunoassay of antibodies against environmental carcinogens and sex steroid hormones could use to detect breast cancer risk. Induction of antibodies against Bp for cancer immunoprevention could lead to antibody formation against steroid hormones, thereby increasing breast cancer risk. PMID- 27482333 TI - Cytotoxic Effects of the Ethanol Bane Skin Extract in Human Prostate Cancer Pc3 Cells. AB - BACKGROUND: It is extensively supposed that vegetarian diet could affect cancer progress and increase the influence of formal chemotherapy. OBJECTIVES: The present study was designed to determine the effect of the ethanol Bane skin extract against chemo resistant prostate cancer PC3 cells. MATERIALS AND METHODS: PC3 and L929 cells were cultivated and then incubated in the ethanol Bane skin extract with various concentrations of 0.78, 1.5, 3.13, 6.25, 12.5 mg/mL in 3 times 24, 48, 72 hours. Cytotoxic effect of the ethanol Bane skin extract on PC3 and L929 cells was examined by MTT assay after 24, 48, and 72 hours. Morphology of PC3 cells was evaluated by Gimsa staining. RESULTS: The ethanol Bane skin extract inhibited proliferation and caused cell death with IC50 values of 2.8 mg/mL on PC3 cells and the IC50 was 6.1 mg/mL on l929 cells. Morphological changes and apoptotic bodies were observed in PC3 cells faced with the ethanol Bane skin extract by staining with Gimsa. CONCLUSIONS: The ethanol Bane skin extract could repress the growth of PC3 cell line. This inhibitory effect of the Bane extract depended on the dose and the time on PC3. The result of this study shows that the ethanol Bane skin extract includes photochemical and inhibitory function against proliferation and inducer of apoptosis in human prostate cancer PC3 cells and also has less cytotoxic effect on l929 than PC3 cells. The ethanol Bane skin extract might be a good candidate for the new herbal anticancer drug. PMID- 27482334 TI - Association Between Socioeconomic Status and Participation in Colonoscopy Screening Program in First Degree Relatives of Colorectal Cancer Patients. AB - BACKGROUND: Approximately 15% to 25% of colorectal cancer (CRC) cases have positive family history for disease. Colonoscopy screening test is the best way for prevention and early diagnosis. Studies have found that first degree relatives (FDRs) with low socioeconomic status are less likely to participate in colonoscopy screening program. OBJECTIVES: The aim of this study is to determine the association between socioeconomic status and participation in colonoscopy screening program in FDRs. PATIENTS AND METHODS: This descriptive cross sectional, study has been conducted on 200 FDRs who were consulted for undergoing colonoscopy screening program between 2007 and 2013 in research institute for gastroenterology and liver disease of Shahid Beheshti University of Medical Sciences, Tehran, Iran. They were interviewed via phone by a valid questionnaire about socioeconomic status. For data analysis, chi-square, exact fisher and multiple logistic regression were executed by SPSS 19. RESULTS: The results indicated 58.5% participants underwent colonoscopy screening test at least once to the time of the interview. There was not an association between participation in colonoscopy screening program and socioeconomic status to the time of the interview in binomial analysis. But statistical significance between intention to participate and educational and income level were found. We found, in logistic regression analysis, that high educational level (Diploma and University degree in this survey) was a predictor to participate in colonoscopy screening program in FDRs. CONCLUSIONS: According to this survey low socioeconomic status is an important factor to hinder participation of FDRs in colonoscopy screening program. Therefore, planned interventions for elevation knowledge and attitude in FDRs with low educational level are necessary. Also, reducing colonoscopy test costs should be a major priority for policy makers. PMID- 27482336 TI - Cancer Screening, Effective or Harmful? PMID- 27482335 TI - The Islamic Perspective of Spiritual Intervention Effectiveness on Bio Psychological Health Displayed by Gene Expression in Breast Cancer Patients. AB - BACKGROUND: During the last two decades, there have been spiritual/religious interventions in cancer patients to prevent or treat a range of physical problems, including managing chronic pain, coping with the disease, boosting hope and mental health. Although societies are of different faiths and belief systems, what they all share is spirituality. OBJECTIVES: Upon this we put forward the hypothesis of changes in gene receptor expressions as a result of spiritual intervention for the first time in the world. MATERIALS AND METHODS: In this study, the spiritual intervention was conducted on 57 volunteer females with early breast cancer involvement. Blood samples were collected prior to and after the spiritual intervention to analyze the changes in dopamine gene receptor expressions as the main site of effect. In order to administer the spiritual intervention backed by Quran, Islam and international standards, issues, with emphasis on peace, human growth and perfection, accepting God as an eternal source of power and kindness to build trust and reduce stress, were selected. They included prayer, patience, reliance, self-sacrifice and forgiveness, altruism and kindness, remission and repentance, thankfulness, zikr (mantra), meditation, and death concept. RESULTS: Obtained results from peripheral blood mononuclear cell samples analyzed by real time-PCR showed significant reduction in dopamine gene receptor (DRD1-5) expressions in comparison with those of pre test scores and the control group. CONCLUSIONS: Spiritual intervention based on Islamic principals can bring back mental health, increase hope and quality of life and eventually change dopamine gene receptor expressions resulting in reduction of cell proliferation, thus better prevention and management in breast cancer patients compared to other forms of treatment. PMID- 27482337 TI - Identification of Mycobacterium tuberculosis adherence-mediating components: a review of key methods to confirm adhesin function. AB - Anti-adhesion therapy represents a potentially promising avenue for the treatment and prevention of tuberculosis in a post-antibiotic era. Adhesins are surface exposed microbial structures or molecules that enable pathogenic organisms to adhere to host surfaces, a fundamental step towards host infection. Although several Mycobacterium tuberculosis adhesins have been identified, it is predicted that numerous additional adherence-mediating components contribute to the virulence and success of this pathogen. Significant further research to discern and characterize novel M. tuberculosis adhesins is, therefore, required to gain a holistic account of M. tuberculosis adhesion to the host. This would enable the identification of potential drug and vaccine targets for attenuating M. tuberculosis adherence and infectivity. Several methods have been successfully applied to the study and identification of M. tuberculosis adhesins. In this manuscript, we review these methods, which include adherence assays that utilize wild-type and gene knockout mutant strains, epitope masking and competitive inhibition analyses, extracellular matrix protein binding assays, microsphere adhesion assays, M. tuberculosis auto-aggregation assays, and in silico analyses. PMID- 27482338 TI - Protective effect of curcumin in fructose-induced metabolic syndrome and in streptozotocin-induced diabetes in rats. AB - OBJECTIVE: The aim of this study was to investigate the effect of pre-treatment with curcumin on metabolic changes induced by two different pathophysiological mechanisms in rats (fructose diet and streptozotocin (STZ)-induced diabetes mellitus). MATERIALS AND METHODS: Five groups with 10 rats per group were investigated: control group (healthy rats), fructose diet groups without any pre treatment (FD), fructose diet groups with curcumin pre-treatment (FDC), STZ induced diabetes mellitus without any pre-treatment (SID) and STZ-induced diabetes mellitus with curcumin pre-treatment (SIDC). Systolic blood pressure, and several metabolic and oxidative stress parameters were assessed. RESULTS: Systolic blood pressure significantly increased in all groups compared with control group (P<0.001), with significantly lower values on groups with curcumin pre-treatment compared with the group without any pre-treatment and same inducement (FDS vs. FD P<0.0001, SIDC vs. SID P<0.0001). High-density lipoprotein (HDL)-cholesterol was significantly lower in all groups compared with control group (P<0.05) while triglycerides (P<0.05), aspartate aminotransferase (AST, P<0.0001) and alanine aminotransferase (ALT, P<0.0001) were significantly higher. Within the group with same induction, curcumin pre-treatment significantly improved metabolic (total cholesterol, glycaemia, triglycerides, AST, ALT; P<0.05) and oxidative stress parameters (total oxidative status (NOx), Thiol, and malondialdehyde (MDA), P<0.02) compared to untreated groups. CONCLUSION: The pre treatment with curcumin in our experimental models significantly improved metabolic (total cholesterol, triglycerides, AST and ALT) as well as oxidative stress parameters (MDA, NOx, and Thiol) in both fructose diet and in STZ-induced diabetes in rats. These properties of curcumin may serve to improve the metabolic and oxidative stress conditions in patients with these pathological features. PMID- 27482339 TI - Swimming exercise attenuates psychological dependence and voluntary methamphetamine consumption in methamphetamine withdrawn rats. AB - OBJECTIVES: This study evaluated the effect of swimming exercise during spontaneous methamphetamine (METH) withdrawal on the anxiety, depression, obsessive-compulsive disorder (OCD) and voluntary METH consumption in METH dependent rats. MATERIALS AND METHODS: Male Wistar rats were repeatedly administered with bi-daily doses of METH (2 mg/kg, subcutaneous) over a period of 14 days. Exercised rats were submitted to swimming sessions (45 min/day, five days per week, for 14 days) during spontaneous METH-withdrawal. Then, all animals were tested for the assessment of anxiety by using the elevated plus-maze (EPM), the grooming behaviors (OCD), and depression using forced swimming test (FST) and voluntary METH consumption using a two-bottle choice (TBC) paradigm for the assessment of craving. RESULTS: The results showed that the swimmer METH withdrawn rats exhibited an increase in EPM open arm time and entries and a reduction of immobility and grooming behaviors compared with the sedentary METH groups. Also, voluntary METH consumption was less in the swimmer METH-withdrawn rats than the sedentary METH groups throughout 5-8 days. CONCLUSION: This study showed that regular swimming exercise reduced voluntary METH consumption in animal models of craving by reducing anxiety, OCD, and depression in the METH withdrawn rats. Thus, physical training may be ameliorating some of the withdrawal behavioral consequences of METH. PMID- 27482340 TI - Transcriptional regulation of E-cadherin and oncoprotein E7 by valproic acid in HPV positive cell lines. AB - OBJECTIVES: Valproic acid (VPA) has proven to be as one of the most promising useful drug with anticancer properties. In this study, we investigate the VPA effects on E-cadherin expression in HeLa, TC1, MKN45, and HCT116 cell lines. This study assesses the effects of VPA on human papillomavirus E7 expression in HPV positive cell lines. MATERIALS AND METHODS: Cell lines were treated by 2 mmol/l VPA and expression of E-cadherin and E7 was analyzed by quantitative real-time PCR. Student's t test and ANOVA were used to determine changes in expression levels. RESULTS: The results revealed that mean of E-cadherin expression is increased by VPA 1.8 times in HCT116 and MKN45 cell lines, also the mean of E cadherin mRNA levels is up-regulated 2.9 times in HeLa and TC1 cell lines. So, E cadherin augmentation induced by VPA in HeLa and TC-1, HPV positive cell lines, is higher than HPV negative cell lines MKN45 and HCT116. The mean of HPV E7 expression is decreased by VPA, 4.6 times in in HeLa and TC-1 cell lines. CONCLUSION: This study demonstrates that re-expression of E-cadherin by VPA in HPV positive cell lines is more than HPV negative cell lines. Whereas, HPV E7 reduces the expression of E-cadherin, reduction of HPV E7 expression by VPA is related to more augmentation of E-cadherin in HPV positive cell lines. So, this study demonstrates that VPA has more anticancer properties in HPV positive cell lines, and could potentially be a promising candidate for cervical cancer treatment. PMID- 27482341 TI - Effect of magnesium sulfate on hyperthermia and pentylen-tetrazol-induced seizure in developing rats. AB - OBJECTIVES: Febrile seizures (FS) are the most common type of convulsive events among children. Its prevalence has been estimated to be 2-5% in children between 3 months and 5 years old. Also, blood and CSF magnesium levels have been demonstrated to be reduced in children with FS. This study investigates the effect of MgSo4 pretreatment on the behaviors caused by hyperthermia (HT) and effect of these two on pentylen-tetrazol (PTZ)-induced seizure later in life. MATERIALS AND METHODS: Thirty two Wistar rats were assigned to 2 groups: saline hyperthermia-pentylentetrazol (SHP) and magnesium-hyperthermia-pentylentetrazol (MHP). In both groups, HT was induced at the age of 18-19 days old. Before the HT, MHP group received MgSo4 and SHP group received normal saline intraperitoneally (IP). Behaviors of the rats were recorded during the HT. Then, in half of each group (n=8) at the age of 25-26 days old and in other half at the age of 78-79 days, seizure was induced by PTZ. RESULTS: The HT successfully caused convulsive behaviors in the rats and pretreatment with MgSo4 before HT attenuated HT-induced convulsive behaviors. PTZ-induced seizures a week later was more severe than those of 2 months later. CONCLUSION: It can be concluded that pretreatment with MgSO4 inhibits HT-induced seizure and, in a long run, this intervention reduced PTZ-induced seizure later in life. PMID- 27482342 TI - Effect of antihypertensive agents - captopril and nifedipine - on the functional properties of rat heart mitochondria. AB - OBJECTIVES: Investigation of acute effect on cellular bioenergetics provides the opportunity to characterize the possible adverse effects of drugs more comprehensively. This study aimed to investigate the changes in biochemical and biophysical properties of heart mitochondria induced by captopril and nifedipine antihypertensive treatment. MATERIALS AND METHODS: Male, 12-week-old Wistar rats in two experimental models (in vivo and in vitro) were used. In four groups, the effects of escalating doses of captopril, nifedipine and combination of captopril + nifedipine added to the incubation medium (in vitro) or administered per os to rat (in vivo) on mitochondrial ATP synthase activity and membrane fluidity were monitored. RESULTS: In the in vitro model we observed a significant inhibitory effect of treatment on the ATP synthase activity (P<0.05) with nonsignificant differences in membrane fluidity. Decrease in the value of maximum reaction rate Vmax (P<0.05) without any change in the value of Michaelis-Menten constant Km, indicative of a noncompetitive inhibition, was presented. At the in vivo level, we did not demonstrate any significant changes in the ATP synthase activity and the membrane fluidity in rats receiving captopril, nifedipine, and combined therapy. CONCLUSION: In vitro kinetics study revealed that antihypertensive drugs (captopril and nifedipine) directly interact with mitochondrial ATP synthase. In vivo experiment did not prove any acute effect on myocardial bioenergetics and suggest that drugs do not enter cardiomyocyte and have no direct effect on mitochondria. PMID- 27482343 TI - Effect of ischemic preconditioning on the expression of c-myb in the CA1 region of the gerbil hippocampus after ischemia/reperfusion injury. AB - OBJECTIVES: In the present study, we investigated the effect of ischemic preconditioning (IPC) on c-myb immunoreactivity as well as neuronal damage/death after a subsequent lethal transient ischemia in gerbils. MATERIALS AND METHODS: IPC was subjected to a 2 min sublethal ischemia and a lethal transient ischemia was given 5 min transient ischemia. The animals in all of the groups were given recovery times of 1 day, 2 days and 5 days and we examined change in c-myb immunoreactivity as well as neuronal damage/death in the hippocampus induced by a lethal transient ischemia. RESULTS: A lethal transient ischemia induced a significant loss of cells in the stratum pyramidale (SP) of the hippocampal CA1 region at 5 days post-ischemia, and this insult showed that c-myb immunoreactivity in cells of the SP of the CA1 region was significantly decreased at 2 days post-ischemia and disappeared at 5 days post-ischemia. However, IPC effectively prevented the neuronal loss in the SP and showed that c-myb immunoreactivity was constitutively maintained in the SP after a lethal transient ischemia. CONCLUSION: Our results show that a lethal transient ischemia significantly decreased c-myb immunoreactivity in the SP of the CA1 region and that IPC well preserved c-myb immunoreactivity in the SP of the CA1 region. We suggest that the maintenance of c-myb might be related with IPC-mediated neuroprotection after a lethal ischemic insult. PMID- 27482344 TI - Time-dependent changes of autophagy and apoptosis in lipopolysaccharide-induced rat acute lung injury. AB - OBJECTIVES: Abnormal lung cell death including autophagy and apoptosis is the central feature in acute lung injury (ALI). To identify the cellular mechanisms and the chronology by which different types of lung cell death are activated during lipopolysaccharide (LPS)-induced ALI, we decided to evaluate autophagy (by LC3-II and autophagosome) and apoptosis (by caspase-3) at different time points after LPS treatment in a rat model of LPS-induced ALI. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into two groups: control group and LPS group. ALI was induced by LPS intraperitoneal injection (3 mg/kg). The lung tissues were collected to measure lung injury score by histopathological evaluation, the protein expression of LC3-II and caspase-3 by Western blot, and microstructural changes by electron microscopy analysis. RESULTS: During ALI, lung cell death exhibited modifications in the death process at different stages of ALI. At early stages (1 hr and 2 hr) of ALI, the mode of lung cell death started with autophagy in LPS group and reached a peak at 2 hr. As ALI process progressed, apoptosis was gradually increased in the lung tissues and reached its maximal level at later stages (6 hr), while autophagy was time-dependently decreased. CONCLUSION: These findings suggest that activated autophagy and apoptosis might play distinct roles at different stages of LPS-induced ALI. This information may enhance the understanding of lung pathophysiology at the cellular level during ALI and pulmonary infection, and thus help optimize the timing of innovating therapeutic approaches in future experiments with this model. PMID- 27482345 TI - Study of chondrogenic potential of stem cells in co-culture with chondrons. AB - OBJECTIVES: Three-dimensional biomimetic scaffolds have widespread applications in biomedical tissue engineering due to similarity of their nanofibrous architecture to native extracellular matrix. Co-culture system has stimulatory effect on chondrogenesis of adult mesenchymal stem cells. This work presents a co culture strategy using human articular chondrons and adipose-derived stem cells (ASCs) from infrapatellar fat pad (IPFP) for cartilage tissue production. MATERIALS AND METHODS: Isolated stem cells were characterized by flowcytometry. Electrospun and polycaprolactone (PCL) scaffolds (900 nm fiber diameter) was obtained from Bon Yakhteh (Tehran-Iran) and human infrapatellar fat pad-derived stem cells (IPFP-ASCs) were seeded on them. IPFP-ASCs on scaffolds were co cultured with articular chondrons using transwell. After 21 day, chondrogenic differentiation of stem cell was evaluated by determining the genes expression of collagen2, aggrecan and Indian hedgehog using real-time RT-PCR. RESULTS: Genes expression of collagen2, aggrecan by IPFP-ASCs did not alter significantly in comparison with control group. Howevers, expression of Indian hedgehog decreased significantly compared to control group (P< 0.05). CONCLUSION: These findings indicate that chondrons obtained from osteoarthritic articular cartilage did not stimulate chondrogenic differentiation of IPFP-ASCs in co-culture. PMID- 27482346 TI - Protective effect of pentoxifylline on male Wistar rat testicular germ cell apoptosis induced by 3,4-methylenedioxymeth amphetamine. AB - OBJECTIVES: 3, 4-methylenedioxymethamphetamine (MDMA) one of the methamphetamine derivatives that affect the reproductive system, has not been well understood. Many young people are consumers of drugs such as MDMA that can affect their reproductive capability. Apoptosis is the main mechanism for male infertility. Pentoxifylline (PTX) increases cAMP intracellularly and reduces tumor necrosis factor-alpha. This study aimed to investigate the protective effect of PTX administration in MDMA-induced apoptosis in testes of male Wistar rats. MATERIALS AND METHODS: Thirty male Wistar rats weighing 250-300 g were randomly divided into five groups: control group (without any intervention), group receiving 7.5 mg/kg MDMA three times every two hours for one day, first experimental group receiving 100 mg/kg PTX just at the time of third injection of MDMA, second experimental group receiving 100 mg/kg PTX a week before MDMA administration, and the vehicle group, which received MDMA+saline. Two weeks later, testes were removed and prepared for H&E staining, TUNEL and Western blot techniques. RESULTS: There was a significant decrease of the score in the MDMA group compared with the control group. In first and second experimental groups, the quality of seminiferous epithelium was improved compared with the MDMA group. The number of TUNEL-positive cells/tubule increased in MDMA and vehicle groups, which is decreased by administration of PTX before MDMA. Expression of active caspase-3 significantly increased in MDMA group, which is significantly decreased by administration of PTX before MDMA. CONCLUSION: PTX can significantly reduce the severity of lesions in the testes following administration of MDMA. PMID- 27482347 TI - Histomorphometric evaluation of treatment of rat azoosper-mic seminiferous tubules by allotransplantation of bone marrow-derived mesenchymal stem cells. AB - OBJECTIVES: Bone marrow-derived mesenchymal stem cells (BM-MSCs) potentials make them appropriate for cell therapy including ability of differentiation and release of anti-inflammatory cytokines and growth factors secreta. For treatment of azoospermia to induce proliferation and differentiation of germ cells, MSCs transplantation has been introduced. The aim of the present experimental case control study was to histomorphometric evaluation of the germinal cells in seminiferous tubules of azoospermic rats before and after BM-MSCs allotransplantation. MATERIALS AND METHODS: In the present study, BM-MSCs were isolated from six male rats and confirmed. Their testes also served as intact negative controls. The recipient rats (n=6) were received two doses of 10 mg/kg of busulfan with 21 days interval to induce azoospermia. After cessation of spermatogenesis, the rats were allotransplanted with the BM-MSCs into efferent duct of right testes. Thirty-five days later, the right cell-treated testes were compared to left azoospermic ones. RESULTS: Histomorphometric analyses showed that the seminiferous tubules treated with BM-MSCs had normal morphology in comparison with azoospermic testes, which were without germinal layer. In most BM MSCs-treated seminiferous tubules, spermatogenesis was observed. CONCLUSION: The allotransplanted BM-MSCs could induce spermatogenesis in seminiferous tubules of azoospermic rats. PMID- 27482348 TI - Evaluation of antioxidant and anti-melanogenic activities of different extracts from aerial parts of Nepeta binaludensis Jamzad in murine melanoma B16F10 cells. AB - OBJECTIVES: Nepeta binaludensis Jamzad (Lamiaceae) has been used in folk medicine of Iran to cure various diseases. The plant is an endemic species to the country that has recently been identified in Razavi Khorasan province. To evaluate the antioxidant and anti-melanogenesis of N. binaludensis, in this study the inhibitory activity of different extracts of N. binaludensis in murine melanoma B16F10 cells is investigated. MATERIALS AND METHODS: The effects of petroleum ether, dichloromethane, ethyl acetate, and methanol extracts isolated from the plant on melanogenesis in B16 melanoma cells were investigated. To assess the inhibitory effects of this plant on melanogenesis, various assays were used including cytotoxicity, inhibition of mushroom tyrosinase and cellular tyrosinase, determination of melanin content, the effect of extracts on reactive oxygen species and western blot analysis of proteins involved in melanogenesis process. RESULTS: The content of melanin and the activity of tyrosinase were significantly reduced with different extracts of N. binaludensis in cells. Reactive oxygen species was also significantly decreased following the treatment of cell with the mentioned extracts, while a resazurin assay showed no cytotoxicity. Furthermore, we have found that the plant decreased the amount of tyrosinase and microphthalmia-associated transcription factor proteins, which verify the role of suppression of microphthalmia-associated transcription factor protein in melanogenesis inhibition. CONCLUSION: Taken together the data indicate that N. binaludensis has inhibitory activity on melanin synthesis with no cytotoxic effects in B16 melanoma cells. Therefore, it merits future investigations to apply as whitening agent in hyperpigmentation. PMID- 27482349 TI - Colchicine protects rat skeletal muscle from ischemia/reperfusion injury by suppressing oxidative stress and inflammation. AB - OBJECTIVES: Neutrophils play an important role in ischemia/reperfusion (IR) induced skeletal muscle injury. Microtubules are required for neutrophil activation in response to various stimuli. This study aimed to investigate the effects of colchicine, a microtubule-disrupting agent, on skeletal muscle IR injury in a rat hindlimb ischemia model. MATERIALS AND METHODS: Twenty-one Sprague-Dawley rats were randomly allocated into three groups IR group, colchicine treated-IR (CO) group and sham operation (SM) group. Rats of both the IR and CO groups were subjected to 3 hr of ischemia by clamping the right femoral artery followed by 2 hr of reperfusion. Colchicine (1 mg/kg) was administrated intraperitoneally prior to hindlimb ischemia in the CO group. After 2 hr of reperfusion, we measured superoxide dismutase (SOD) and myeloperoxidase (MPO) activities, and malondialdehyde (MDA), tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels in the muscle samples. Plasma creatinine kinase (CK) and lactate dehydrogenase (LDH) levels were measured. We also evaluated the histological damage score and wet/dry weight (W/D) ratio. RESULTS: The histological damage score, W/D ratio, MPO activity, MDA, TNF-alpha and IL-1beta levels in muscle tissues were significantly increased, SOD activity was decreased, and plasma CK and LDH levels were remarkably elevated in both the IR and CO groups compared to the SM group (P<0.05). Colchicine treatment significantly reduced muscle damage and edema, oxidative stress and levels of the inflammatory parameters in the CO group compared to the IR group (P<0.05). CONCLUSION: Colchicine attenuates IR-induced skeletal muscle injury in rats. PMID- 27482350 TI - Effect of interaction between acute administration of morphine and cannabinoid compounds on spontaneous excitatory and inhibitory postsynaptic currents of magnocellular neurons of supraoptic nucleus. AB - OBJECTIVES: Opioids and cannabinoids are two important compounds that have been shown to influence the activity of magnocellular neurons (MCNs) of supraoptic nucleus (SON). The interaction between opioidergic and cannabinoidergic systems in various structures of the brain and spinal cord is now well established, but not in the MCNs of SON. MATERIALS AND METHODS: In this study, whole cell patch clamp recording of neurons in rat brain slice was used to investigate the effect of acute morphine and cannabinoid administration on spontaneous inhibitory and excitatory spostsynaptic currents (sIPSCs and sEPSCs) in MCNs. RESULTS: Bath application of morphine produced an increase in sEPSCs frequency and a decrease in sIPSCs frequency. In contrast, bath application of URB597 (fatty acid amide hydrolase (FAAH) inhibitor) produced a decrease in sEPSCs frequency but an increase in sIPSCs frequency. WIN55212-2 (cannabinoid receptor agonist) decreased both sIPSCs and sEPSCs frequencies of MCNs. Co-application of morphine and URB597 attenuated the effect of morphine on MCNs. CONCLUSION: Taken together, these data indicated that at the cellular level, pharmacological augmentation of endocannabinoids could attenuate morphine effects on MCNs. PMID- 27482351 TI - The protective effect of infliximab against carbon tetrachloride-induced acute lung injury. AB - OBJECTIVES: Carbon tetrachloride (CCl4) causes pulmonary toxicity. Infliximab (Ib) is a potent inhibitor of tumor necrosis factor-alpha (TNF-alpha). We aimed to investigate whether Ib has a protective effect on CCl4 induced lung injury. MATERIALS AND METHODS: Rats were divided into control, CCl4, and CCl4+Ib groups. A single dose of 2 ml/kg CCI4 was administered to CCI4 group and a single dose of 7 mg/kg Ib was given to CCl4+Ib group 24 hr before applying CCI4. RESULTS: TNF alpha, malondialdehyde (MDA), nitric oxide (NO) and caspase-3 levels of the CCl4 group were markedly higher than both the control and CCl4+Ib groups. The CCI4+Ib group had lower histopathological injury than the CCl4 group. CONCLUSION: Ib as a strong TNF-alpha blocker decreases the production of proinflammatory cytokines, MDA, and oxidative stress leading to a protective effect against CCl4 induced lung tissue injury. PMID- 27482352 TI - Anti-spermatogenic activities of Taraxacum officinale whole plant and leaves aqueous extracts. AB - Taraxacum officinale has been used in Jordan folk medicine to treat male infertility. A recent study has proved a contradictory effect of the whole plant aqueous extract. The aim of the current study was to determine if the leaves of T. officinale have similar anti-fertility activities, and whether this effect is mediated through the regulation of spermatogonial stem cells (SSCs). Fifty adult male rats were divided into five groups. Two groups were gavaged with 1/10 of LD50 of T. officinale whole plant (1.06 g kg(-1) body weight) or leaves (2.30 g kg(-1) body weight) aqueous extract; while two groups were gavaged with 1/20 of LD50 of T. officinale whole plant (2.13 g kg(-1)) or leaves (4.60 g kg(-1)) extract. The control group received distilled water. Oral administration of T. officinale (whole plant and leaves aqueous extract) caused a significant decrease in testis and seminal vesicle weight, a reduction in serum testosterone concentration, impaired sperm parameters, and a decrease in pregnancy parameters. Testicular histology of treated rats showed structural changes such as hypoplasia of germ cells, reduction in the thickness of germinal epithelium, arrest of spermatogenesis at spermatid stage (late maturation arrest) and reduction in the number of Leydig cells. Gene expression levels of two SSCs markers (GFRalpha1 and CSF1) responsible for self-renewal were relatively counter-balanced. In conclusion, T. officinale whole plant and leaves aqueous extracts changed the gene expression of two SSCs markers leading to the imbalance between spermatogonia self-renewal and differentiation causing late maturation arrest. PMID- 27482353 TI - Protective effect of leptin on induced apoptosis with trichostatin A on buffalo oocytes. AB - Leptin, the 16-kDa product of the obese (ob) gene, primarily secreted from adipose tissue, has been implicated to play an important role in the regulation of food intake and energy expenditure. This study investigated protective effect of leptin on trichostatin A-induced apoptotic on in vitro maturation ratio of buffalo oocytes. Ovaries were collected from abattoir and were transported immediately to the laboratory by a thermos flask containing sterile normal saline with antibiotics. Oocytes were aspirated from 2 to 8 mm visible follicles. Oocytes were placed in a culture plate and then incubated at 38.5 C with 5% CO2 in air for 24 hr. The maturation of oocytes was evaluated under a stereomicroscope. The FITC-Annexin V and propidium iodide staining method was used to detect oocyte apoptosis. In leptin treated groups with 0, 10, 50 and 100 ng mL(-1) and groups that apoptosis was induced, the percentage of oocytes maturation was 77.03, 86.12, 85.08, and 79.89% and 59.96, 56.93 and 51.98, respectively, while the percentage of apoptosis was 8.83, 7.90, 8.58, and 9.39%, and 10.37, 11.57 and 12.03, respectively. Our findings showed that addition of 10 and 50 ng mL(-1) leptin to IVM medium of buffalo oocytes could increase oocyte nuclear maturation, and could decrease oocyte apoptosis when trichostatin A added for inducing apoptosis. PMID- 27482355 TI - Histomorphogenesis of cranial nerves in Huso huso larvae. AB - In this study the cranial nerves development of H. huso are explained from 1 to 54-days-old (1, 3, 6, 15, 21 and 54 days). Despite all the researches on fish brain, there are no study on nerves evolution on H. huso during their larvae life. For this research 40 samples of larvae H. huso were obtained (from each age, about six samples were selected). The specimens were maintained in fiberglass tank, then histological samples were taken from tissues and stained with hematoxylin and eosin for general histological studies using light microscope. According to the results, on 1 and 3-days-old, no nerve was observed. The terminal nerve and their dendrites were observed around the nasal cavity and the axons projected to different areas in forebrain especially around olfactory bulb diffusely, on 6-day-old fish. Also, olfactory, optic, oculomotor, trochlear, trigeminal, lateral line and vagus nerves were detected on 6-day-old fish, however two parts of lateral line nerve were separated on 54-day-old. Three nerves, profundus, facial and octaval were observed on 54-day-old, however, up to this age, epiphysial nerve was not observed. PMID- 27482354 TI - Effects of diets supplemented by fish oil on sex ratio of pups in bitch. AB - The present study was conducted to evaluate the effect of fish oil supplementation prior to mating on secondary sex ratio of pups (the proportion of males at birth) in bitches. Sixty five bitches (German Shepherd, n = 35; Husky, n = 30) were enrolled in the study. Bitches (140-150 days post-estrus) were given 2% per dry matter intake palm oil and fish oil in the control (n = 33) and treatment (n = 32) groups, respectively. To induce estrus, bitches were received equine chorionic gonadotropin (eCG) administration (50 IU kg(-1)) 30 days after nutritional supplementation followed by human chorionic gonadotropin (hCG) administration (500 IU per dog) seven days later. Bitches were introduced to dogs of the same breed after hCG administration. The weight of bitches was increased over time (p < 0.05), but their weight change was not different between two groups (p > 0.05). The mating rate, pregnancy rate and litter size were not influenced by treatment and breed. Secondary sex ratio was higher in the treatment (105/164; 64.00%) than in the control (68/147; 46.30%) group (p < 0.05; adjusted odds ratio = 2.068). Moreover, secondary sex ratio was higher in Husky bitches (88/141; 62.40%) compared to German Shepherd (85/170; 50.00%; p < 0.05; adjusted odds ratio = 1.661). In conclusion, the present study showed that inclusion of fish oil in the diet of bitches prior to mating could increase the proportion of male pups at birth. In addition, it appears that there might be variation among dog breeds with regard to the sex ratio of offspring. PMID- 27482356 TI - Anatomical, radiographical and computed tomographic study of the limbs skeleton of the Euphrates soft shell turtle (Rafetus euphraticus). AB - Euphrates turtle is the only soft shell turtle of Iran, and unfortunately is in danger of extinction due to multiple reasons. Imaging techniques, in addition to their importance in diagnosis of injuries to animals, have been used as non invasive methods to provide normal anatomic views. A few studies have been conducted to understand body structure of the Euphrates turtle. Since there is only general information about the anatomy of turtle limbs, the normal skeleton of the Euphrates limbs was studied. For this purpose four adult Euphrates turtles were used. Digital radiographic examination was performed by computed radiographic (CR) in dorsoventral (DV) and lateral (L) positions. Spiral CT scanning was done and 3D images of the bones were reconstructed for anatomical evaluation. For skeletal preparation, the skeleton was cleaned by a combination of boiling and mealworm methods and limbs' bones were examined anatomically. In the present study, simultaneous anatomic, radiographic and CT studies of bones in individual turtles made us possible to describe bones anatomically and provided comparable and complementary conditions to represent the abilities of the radiography and CT for better understanding of the anatomy. Arrangement and the number of carpal and tarsal bones are used in turtles' classification. Among the studied species, Euphrates turtle carpal and tarsal bones show the most similarities to the Apolone spinifera. PMID- 27482357 TI - Protective effect of vitamin E on cypermethrin-induced follicular atresia in rat ovary: Evidence for energy dependent mechanism. AB - It has been shown that chronic exposure to cypermethrin (CPM), a pyrethroid pesticide, results in follicular atresia via pathologically affecting angiogenesis, disrupting endocrine potential and enhancing oxidative stress. This study was aimed to uncover the CPM-exposed energy dependent follicular cells apoptosis and to estimate protective effect of vitamin E (VitE) as a potent antioxidant. Thirty six Wistar rats were divided into six groups (n = 6 rats for each group) including; control-sham, CPM-received (CPM, 75 mg kg(-1), intraperitoneally), and CPM and VitE-treated (VitE, 150 mg kg(-1), orally) for 14 and 24 days. The protein biosynthesis of glucose transporter-1 (GLUT-1) and caspase-3 in follicles were estimated by using immuno-histochemical staining at preantral and antral stages. Moreover, the periodic acid Schiff (PAS) staining was performed in order to evaluate the intracytoplasmic carbohydrate ratio in follicular cells and oocyte. Percentages of follicles with GLUT-1, Caspase-3 and PAS-positive cells were compared between groups. Immunohistochemical analyses showed that, VitE significantly up-regulated the GLUT-1 expression and improved the intracytoplasmic carbohydrate supplementation especially at preantral follicles. The cross sections from the CPM-exposed ovaries represented remarkable elevation in percentage of atretic preantral and antral follicles with caspase-3 biosynthesis, which was remarkably (p < 0.05) diminished in VitE co-treated groups. In conclusion, our data showed that VitE by up-regulating of the GLUT-1 biosynthesis improved glucose uptake at follicular cells and oocyte levels that in turn inhibited pro-apoptotic protein caspase-3 biosynthesis. PMID- 27482358 TI - Protective effect of quercetin on skeletal and neural tube teratogenicity induced by cyclophosphamide in rat fetuses. AB - Cyclophosphamide (CP) is a drug commonly used to treat neoplastic disease and some autoimmune diseases. It is also a well-known and well-studied teratogen causing a variety of birth defects in fetuses of pregnant women treated with the drug. There are many reports that show the adverse effects of CP can be decreased by use of antioxidant drugs. It appears that, quercetin has antioxidant effect. The aim of this study was prevention or decrease of teratogenicity of CP in fetuses of rats by quercetin. This study was performed on 35 pregnant rats divided into six groups. Control group was received normal saline (5 mL kg(-1), intraperitoneally) and 2-6 groups received a single dose of CP (15 mg kg(-1)), a single dose of quercetin (75 or 200 mg kg(-1)), CP plus quercetin (75 or 200 mg kg(-1)) intraperitoneally at 9(th) day of gestation, respectively. Fetuses were collected at 20(th) day of gestation and after determination of weight and crown rump length were stained by alizarin red - alcian blue method and skeletal system were examined by stereomicroscope. The results showed that the cleft palate, exencephaly, spina bifida and omphalocele incidence were 55.56%, 27.77%, 33.34% and 11.11%, in fetuses of rat that received only CP, respectively. However, it decreased to 16.00%, 16.00%, 16.00% and 8.00% by quercetin (75 mg kg(-1)) and so to 12.90%, 12.90%, 6.45% and 3.28% by quercetin (200 mg kg(-1)), respectively. On the basis of results, quercetin significantly can decrease teratogenicity induced by CP. PMID- 27482359 TI - Effect of Echinophora platyloba DC. essential oil and lycopene on the stability of pasteurized cream obtained from cow milk. AB - The present study was carried out to enhance shelf life of pasteurized cream using Echinophora platyloba essential oil (EEO) and lycopene. For this purpose, two concentrations of EEO (0.10% and 0.50%) and lycopene (20 and 50 ppm) alone and together as combinations were added in pasteurized creams and analyzed for microbial characteristics, sensorial properties and lipid stability during storage at 4 C and 25 C for 14 days. Results of microbial and chemical analyses of experimental pasteurized creams showed that pasteurized creams treated with combinations of the EEO and lycopene in their higher concentrations had the best microbial and chemical properties and the most stability than control during storage (p < 0.05). Results of sensorial evaluation demonstrated that all treatments had favorable overall acceptability, even though, the best sensorial properties were observed in creams with combinations of EEO and lycopene in their lower concentrations. Therefore, based on the results of the present study, application of EEO and lycopene as natural preservatives is especially recommend in high fat dairy products such as butter and cream. PMID- 27482360 TI - The role of fibroblast growth factor receptor 2 (FGFR2) in differentiation of bovine spermatogonial stem cells (SCC). AB - The receptors 1 and 2 of fibroblast growth factor (FGFR1 and FGFR2, respectively) have been observed in all types of testicular cells. Culture on extracellular matrix (ECM) has been observed to lead to initiation of differentiation in spermatogonial stem cells (SSCs). The present study was carried out to investigate whether FGFR1 and FGFR2 play a role in SSCs differentiation. Following isolation, bovine testicular cells were cultured on ECM-coated or uncoated (control) plates for 12 days. The gene expression of THY1, cKIT, FGFR1 and FGFR2 was evaluated using quantitative real-time polymerase chain reaction (PCR). Results related to the gene expression of markers of with undifferentiated (THY1) and differentiated (cKIT) spermatogonia implicated stimulation of self renewal and differentiation in cells cultured on ECM-coated and uncoated plates, respectively (p < 0.05). Concomitantly, the expression of FGFR2 increased during culture in the ECM group (p < 0.05), whereas it did not change in the control group (p > 0.05). As a result, the gene expression of FGFR2 was greater in the ECM than control group (p < 0.05). Nevertheless, FGFR1 expression did not change during culture in the control and ECM groups (p > 0.05). In conclusion, the present study revealed the potential role of FGFR2 in differentiation of SSCs during culture on ECM. PMID- 27482361 TI - Prevalence and molecular characterization of staphylococci isolated from sheep with subclinical mastitis in West-Azerbaijan province, Iran. AB - This study was conducted to investigate the prevalence of subclinical mastitis caused by Staphylococcus spp. in ewes in West-Azerbaijan province of Iran. Molecular characterization of isolated Staphylococcus spp. from diseased ewes were performed using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) and DNA sequencing of glyceraldehyde-3 phosphate dehydrogenase (gap) gene. Also, antibiotic resistance of staphylococcal isolates against different antibiotics was investigated. A total number of 900 milk samples from 450 native ewes in their mid-lactation period were examined by the California mastitis test (CMT). The CMT positive samples were cultured and bacteria were isolated from 86 (9.50%) glands and 74 (16.40%) ewes. The prevalence of subclinical mastitis in the examined ewes was 16.40%. Microbiological analysis of milk samples revealed that 27 out of 74 sheep with subclinical mastitis were infected with Staphylococcus spp. Amplification of gap gene of 27 Staphylococcus isolates generated a single amplicon of 933 bp in size confirming that isolates were belonged to Staphylococcus genus. Digestion of PCR products by AluI endonuclease generated different RFLP patterns for each species. Nucleotide sequencing of gap gene followed by phylogenetic analysis showed that the most dominant Staphylococcus species were S. epidermidis, S. xylosus and S. chromogenes. Staphylococcal isolates showed the highest resistance to penicillin and ampicillin. In conclusion, Staphylococcus species, except for the southern parts of the province, play an important role in the development of subclinical mastitis in sheep in West-Azerbaijan province of Iran. Also, chloramphenicol, ciprofloxacin and neomycin are the most effective antibiotics for treatment of this disease. PMID- 27482362 TI - Molecular study on infection rates of Anaplasma ovis and Anaplasma marginale in sheep and cattle in West-Azerbaijan province, Iran. AB - This study was carried out to determine the presence and frequency of Anaplasma ovis and Anaplasma marginale in sheep and dairy cattle in West-Azerbaijan province, Iran. A total number of 200 blood samples were randomly collected via the jugular vein from apparently healthy cattle (100) and sheep (100). The extracted DNA from blood cells was screened using genus-specific (Anaplasma spp.) nested-polymerase chain reaction (PCR) based on 16S rRNA gene primer sets. Species-specific PCR was set up using major surface protein 4 (MSP4) gene primer set. None of cattle blood samples were positive for Anaplasma spp. by the first nested PCR. Five samples among the 100 sheep blood samples were both positive in the first nested PCR and A. ovis -specific PCR, based on MSP4 gene. In total, 5.00% of animals were A. ovis positive. This study identified a low prevalence of A. ovis in the blood of apparently healthy sheep in West Azerbaijan province. PMID- 27482363 TI - Androgen receptor blockade using flutamide skewed sex ratio of litters in mice. AB - Maternal testosterone has been indicated to affect sex ratio of offspring. The present study was conducted to elucidate the role of androgen receptor in this regard by blockade of androgen receptor using flutamide in female mice. Mice were randomly assigned to two experimental groups. Mice in the control (n = 20) and treatment (n = 20) groups received 8 IU equine chorionic gonadotropin (eCG) followed by human chorionic gonadotropin (hCG) injection (8 IU) 47 hr later. In addition, mice in the control and treatment groups received four injections of ethanol-saline vehicle and flutamide solution (2.50 mg), respectively, started from 1 hr before eCG injection until hCG injection at 12-hr intervals. Conception rate was not different between the treatment (18/20: 90.00%) and control (19/20: 95.00%) groups (p > 0.05). Litter size was higher in the treatment (8.22 +/- 0.26) than control (7.21 +/- 0.28) group (p < 0.05). Male sex ratio was lower in the flutamide-treated mice (67/148: 45.30%) as compared with the untreated ones (80/137: 58.40%; odds ratio = 1.69; p < 0.05). In conclusion, the results showed that androgen receptor blockade could skew sex ratio of offspring toward females implying that the effect of testosterone on sex ratio might be through binding to androgen receptor. In addition, the blockade of androgen receptor using flutamide appeared to enhance litter size. PMID- 27482364 TI - Case report of chondroma in a grass carp (Ctenopharyngodon idella). AB - The grass carp (Ctenopharyngodon idella) is a herbivorous, freshwater fish species of the family Cyprinidae, and the only species of the genus Ctenopharyngodon. Neoplasms in fishes are generally less aggressive than neoplasms in mammals and are most commonly discrete, focal and benign neoplasms. A 3-year-old grass carp with a big mass on the vertebrae was referred to the clinic. According to the owner's statements, the fish had no signs of lethargy, ataxia and abnormal behaviors. The size of the mass was 7 * 6 * 6 cm. It cut hardly with audible sounds. The consistency of the mass was as hard as a cartilage. Microscopic examination revealed numerous irregular crests of hyaline cartilage beneath the skin. According to histopathologic characteristics, chondroma on the vertebrae of grass carp was diagnosed. PMID- 27482365 TI - A case of asymmetrical monocephalus dipygus (tetrapus dibrachius) in a male Holstein calf in Iran. AB - Dipygus is a teratological fetus with a double pelvis, genitals, and extremities. Congenital duplications in cattle are rare. Caudal duplication is more common in sheep and pigs while cranial duplications seem to be predominant in cattle. Asymmetric or parasitic conjoined twins consisting of an incomplete twin (parasite) attached to the body of a fully-developed twin (autosite). This report deals with a male Holstein calf with two extra limbs, in the pelvic region which were directed ventrally between the two normal hind limbs. The extra limbs were completely developed in one side and in other side just a bony mass were observed. So classification has been made as asymmetrical attached twins. The genital system was not affected and just one extra kidney-like structure was found. To the authors' best knowledge, this is the first report of asymmetrical monocephalus dipygus (tetrapus dibrachius) in a male Holstein calf in Iran. PMID- 27482366 TI - UbFluor: A Mechanism-Based Probe for HECT E3 Ligases. AB - Homologous to E6AP Carboxyl Terminus E3 ubiquitin ligases (HECT, ~28 known) are genetically implicated in cancer, neurological, hypertensive, and autoimmune disorders, and are potential drug targets to treat these diseases. The major bottleneck in the field of HECT E3s is a lack of simple assays to quantify the enzymatic activity of these enzymes in the presence of small molecules. Typical assays require E1, E2, HECT E3, ubiquitin (Ub), ATP and additional reagents to detect the resulting free poly-ubiquitin chains. To address this need, we developed UbFluor, a fluorescent thioester conjugate between the C-terminus of Ub and fluorescein-thiol (Fluor-SH). UbFluor is a mechanism-based probe that undergoes a direct transthiolation reaction with the catalytic cysteine of the model HECT E3 ligase Rsp5, producing the catalytically active Rsp5~Ub (~ indicates thioester) accompanied by release of Fluor-SH. The kinetics of this two component reaction can be easily monitored with real-time fluorescence polarization (FP) assays. Importantly, UbFluor eliminates the need to use SDS PAGE, ATP, E1, E2 enzymes, and extra poly-ubiquitin chain detection reagents. Although the developed system lacks ATP, E1 and E2 enzymes, we show that UbFluor can recapitulate the native ubiquitination reaction by detecting and quantifying defects in transthiolation and isopeptide ligation of Rsp5 HECT E3 alanine mutants. Based on our findings, we show that UbFluor can be utilized to conduct high-throughput screens (HTS) of small molecules against HECT ligases. PMID- 27482367 TI - How Can People Be so Good at Intercepting Accelerating Objects if They Are so Poor at Visually Judging Acceleration? AB - People are known to be very poor at visually judging acceleration. Yet, they are extremely proficient at intercepting balls that fall under gravitational acceleration. How is this possible? We previously found that people make systematic errors when trying to tap on targets that move with different constant accelerations or decelerations on interleaved trials. Here, we show that providing contextual information that indicates how the target will decelerate on the next trial does not reduce such errors. Such errors do rapidly diminish if the same deceleration is present on successive trials. After observing several targets move with a particular acceleration or deceleration without attempting to tap on them, participants tapped as if they had never experienced the acceleration or deceleration. Thus, people presumably deal with acceleration when catching or hitting a ball by compensating for the errors that they made on preceding attempts. PMID- 27482368 TI - The Nature and Timing of Tele-Pseudoscopic Experiences. AB - Interchanging the left and right eye views of a scene (pseudoscopic viewing) has been reported to produce vivid stereoscopic effects under certain conditions. In two separate field studies, we examined the experiences of 124 observers (76 in Study 1 and 48 in Study 2) while pseudoscopically viewing a distant natural outdoor scene. We found large individual differences in both the nature and the timing of their pseudoscopic experiences. While some observers failed to notice anything unusual about the pseudoscopic scene, most experienced multiple pseudoscopic phenomena, including apparent scene depth reversals, apparent object shape reversals, apparent size and flatness changes, apparent reversals of border ownership, and even complex illusory foreground surfaces. When multiple effects were experienced, patterns of co-occurrence suggested possible causal relationships between apparent scene depth reversals and several other pseudoscopic phenomena. The latency for experiencing pseudoscopic phenomena was found to correlate significantly with observer visual acuity, but not stereoacuity, in both studies. PMID- 27482370 TI - Investigating what felt shapes look like. AB - A recent empirical study claims to show that the answer to Molyneux's question is negative, but, as John Schwenkler points out, its findings are inconclusive: Subjects tested in this study probably lacked the visual acuity required for a fair assessment of the question. Schwenkler is undeterred. He argues that the study could be improved by lowering the visual demands placed on subjects, a suggestion later endorsed and developed by Kevin Connolly. I suggest that Connolly and Schwenkler both underestimate the difficulties involved in rectifying the study they seek to fix. The problem is that the experimental paradigm under consideration fails to account for the role that rational inference plays in newly sighted subjects' ability or inability to recognize spatial properties across modalities. Since answering Molyneux's question requires establishing whether spatial properties can be recognized, across modalities, by newly sighted subjects without recourse to rational inference, this is a problem. Indeed, it is a problem that may be worsened by Schwenkler and Connolly's suggestions regarding the lowering of visual demands on subjects in cross-modal matching tasks. PMID- 27482369 TI - Face Perception and Test Reliabilities in Congenital Prosopagnosia in Seven Tests. AB - Congenital prosopagnosia, the innate impairment in recognizing faces, is a very heterogeneous disorder with different phenotypical manifestations. To investigate the nature of prosopagnosia in more detail, we tested 16 prosopagnosics and 21 controls with an extended test battery addressing various aspects of face recognition. Our results show that prosopagnosics exhibited significant impairments in several face recognition tasks: impaired holistic processing (they were tested amongst others with the Cambridge Face Memory Test (CFMT)) as well as reduced processing of configural information of faces. This test battery also revealed some new findings. While controls recognized moving faces better than static faces, prosopagnosics did not exhibit this effect. Furthermore, prosopagnosics had significantly impaired gender recognition-which is shown on a groupwise level for the first time in our study. There was no difference between groups in the automatic extraction of face identity information or in object recognition as tested with the Cambridge Car Memory Test. In addition, a methodological analysis of the tests revealed reduced reliability for holistic face processing tests in prosopagnosics. To our knowledge, this is the first study to show that prosopagnosics showed a significantly reduced reliability coefficient (Cronbach's alpha) in the CFMT compared to the controls. We suggest that compensatory strategies employed by the prosopagnosics might be the cause for the vast variety of response patterns revealed by the reduced test reliability. This finding raises the question whether classical face tests measure the same perceptual processes in controls and prosopagnosics. PMID- 27482371 TI - Turning water into rock: The inverted waves effect. AB - Humans perceive shape in two-dimensional shaded images, and turning such an image upside down can result in inversion of the relief of this image. Previous research indicates that this inversion is caused by assumptions related to overhead illumination, global convexity and viewpoint above the surface. In our article, we describe the inverted waves effect, in which turning an image of waves upside down changes its relief and also its perceived material properties. PMID- 27482372 TI - Convexity Bias and Perspective Cues in the Reverse-Perspective Illusion. AB - The present experiment was designed to examine the roles of painted linear perspective cues, and the convexity bias that are known to influence human observers' perception of three-dimensional (3D) objects and scenes. Reverse perspective stimuli were used to elicit a depth-inversion illusion, in which far points on the stimulus appear to be closer than near points and vice versa, with a 2 (Type of stimulus) * 2 (Fixation mark position) design. To study perspective, two types of stimuli were used: a version with painted linear perspective cues and a version with blank (unpainted) surfaces. To examine the role of convexity, two locations were used for the fixation mark: either in a locally convex or a locally concave part of each stimulus (painted and unpainted versions). Results indicated that the reverse-perspective illusion was stronger when the stimulus contained strong perspective cues and when observers fixated a locally concave region within the scene. PMID- 27482373 TI - The Bouba-Kiki Phenomenon Tested via Schematic Drawings of Facial Expressions: Further Validation of the Internal Simulation Hypothesis. AB - Sound-shape associations involving consistent matching of nonsense words such as 'bouba' and 'kiki' with curved and angular shapes, respectively, have been replicated in several studies. The purpose of the current study was to examine the robustness of previously noted sound-shape associations when shape variations (angular and curvy) are embedded in schematic expressions of emotions (sad and happy). Results revealed consistent matching tendencies based on sound-emotion expression mapping irrespective of the particular shape of the expressions. We suggest that internally simulating the facial expressions/oral gestures may have played a significant role in driving the matching preferences. PMID- 27482374 TI - In silico evo-devo: reconstructing stages in the evolution of animal segmentation. AB - BACKGROUND: The evolution of animal segmentation is a major research focus within the field of evolutionary-developmental biology. Most studied segmented animals generate their segments in a repetitive, anterior-to-posterior fashion coordinated with the extension of the body axis from a posterior growth zone. In the current study we ask which selection pressures and ordering of evolutionary events may have contributed to the evolution of this specific segmentation mode. RESULTS: To answer this question we extend a previous in silico simulation model of the evolution of segmentation by allowing the tissue growth pattern to freely evolve. We then determine the likelihood of evolving oscillatory sequential segmentation combined with posterior growth under various conditions, such as the presence or absence of a posterior morphogen gradient or selection for determinate growth. We find that posterior growth with sequential segmentation is the predominant outcome of our simulations only if a posterior morphogen gradient is assumed to have already evolved and selection for determinate growth occurs secondarily. Otherwise, an alternative segmentation mechanism dominates, in which divisions occur in large bursts through the entire tissue and all segments are created simultaneously. CONCLUSIONS: Our study suggests that the ancestry of a posterior signalling centre has played an important role in the evolution of sequential segmentation. In addition, it suggests that determinate growth evolved secondarily, after the evolution of posterior growth. More generally, we demonstrate the potential of evo-devo simulation models that allow us to vary conditions as well as the onset of selection pressures to infer a likely order of evolutionary innovations. PMID- 27482376 TI - Whose pain is it anyway? Comparability of pain reports from children and their parents. AB - BACKGROUND: There is a high demand for robust research into understanding the scope and consequences of musculoskeletal pain in children. An important part of this involves clarifying issues surrounding its measurement, not least differences in reporting from the children themselves and their parents. Therefore this study will assess the degree of agreement between parents' report of their child's pain and the child's own assessment. METHODS: Data were collected in 2013 and 2014 as part of a larger cohort study investigating the health of Danish school children. Two study samples included 354 and 334 child parent pairs who were independently asked whether the child had experienced musculoskeletal pain in the previous week. Children were between the ages of 10 and 14 years old. Parents provided answers via text message and children were questioned in person or via questionnaire at their school. RESULTS: Percentage agreement between parent and child assessment was around 50 % in Sample 1 and 68 % in Sample 2. The poor agreement was due to children reporting pain when their parent did not, the reverse very rarely occurred. Pain of greater intensity or longer duration resulted in better agreement between the child and parent. Child age and gender did not influence the likelihood of agreement. CONCLUSION: Children often experience pain that is not reported by their parents resulting in poor concordance between pain reports from the two sources. While it is not possible to say which is more valid we can conclude they are not interchangeable. PMID- 27482377 TI - Children and adolescents presenting to chiropractors in Norway: National Health Insurance data and a detailed survey. AB - BACKGROUND: The idea of chiropractors treating children is controversial, yet many parents seek chiropractic care for their children. The reasons for this are not well documented. Part one of this study aimed to document the profile of all paediatric patients consulting Norwegian chiropractors in 2013 using National Health Insurance data (NHI) with regards to age, gender and primary complaints. Part two aimed to provide a more detailed description of these patients in the form of a descriptive, paper-based survey. METHODS: Part one involved Norwegian NHI data from 2013. Part two consisted of a year-long, paper-based survey. Chiropractors registered with the Norwegian chiropractic association (NKF) were invited to participate via email. Participating chiropractors were assigned one random month to collect data. All paediatric patients (or their parents) during that were asked to complete questionnaires containing information on presenting complaint, consequences of this complaint, age, and mode of referral. RESULTS: In general, there was good concordance between part one and two of the study in terms of age, gender and presenting complaint. The youngest children constituted the largest paediatric group in Norwegian chiropractic practice. Musculoskeletal problems were the most common reason for children visiting a chiropractor in all of the age categories, according to NHI data. Part two of the study found that one-third of young school children and adolescents reported pain lasting longer than 1-year. Eleven percent of children found that their complaint had severely affected their mood and 22 % felt their activities were very limited by their condition. Referrals from healthcare professionals were uncommon. The survey's results were based on 161 completed questionnaires, received from 15 % of the Norwegian chiropractors. CONCLUSIONS: Musculoskeletal problems constituted the most common presenting complaint for children and adolescents presenting to Norwegian chiropractors. A sizable proportion of children seemed to be adversely affected by their complaints in terms of low mood and limitations of daily activities. Chronic presentations were not uncommon. The small sample size of the survey demands that the results be interpreted with caution. PMID- 27482375 TI - Dendritic and mast cell involvement in the inflammatory response to primary malignant bone tumours. AB - BACKGROUND: A chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs) and lymphocytes; dendritic cells (DCs) and mast cells (MCs) have also been identified but whether these and other inflammatory cells are seen commonly in specific types of bone sarcoma is uncertain. METHODS: In this study we determined the nature of the inflammatory cell infiltrate in 56 primary bone sarcomas. Immunohistochemistry using monoclonal antibodies was employed to assess semiquantitatively CD45+ leukocyte infiltration and the extent of the DC, MC, TAM and T and B lymphocyte infiltrate. RESULTS: The extent of the inflammatory infiltrate in individual sarcomas was very variable. A moderate or heavy leukocyte infiltrate was more commonly seen in conventional high-grade osteosarcoma, undifferentiated pleomorphic sarcoma and giant cell tumour of bone (GCTB) than in Ewing sarcoma, chordoma and chondrosarcoma. CD14+/CD68+ TAMs and CD3+ T lymphocytes were the major components of the inflammatory cell response but (DC-SIGN/CD11c+) DCs were also commonly noted when there was a significant TAM and T lymphocyte infiltrate. MCs were identified mainly at the periphery of sarcomas, including the osteolytic tumour-bone interface. DISCUSSION: Our findings indicate that, although variable, some malignant bone tumours (e.g. osteosarcoma, GCTB) are more commonly associated with a pronounced inflammatory cell infiltrate than others (e.g. chondrosarcoma. Ewing sarcoma); the infiltrate is composed mainly of TAMs but includes a significant DC, T lymphocyte and MC infiltrate. CONCLUSION: Tumours that contain a heavy inflammatory cell response, which includes DCs, TAMs and T lymphocytes, may be more amenable to immunomodulatory therapy. MCs are present mainly at the tumour edge and are likely to contribute to osteolysis and tumour invasion. PMID- 27482378 TI - A cadaveric study of surgical landmarks for retrograde parotidectomy. AB - PURPOSE: Retrograde parotidectomy is employed in situations where tumors or scar tissue obscure the facial nerve trunk, making anterograde parotidectomy hazardous. Hence, the reliability of anatomical landmarks in retrograde parotidectomy is of equal practical importance. METHODS: Distances from soft tissue and osseous landmarks to the corresponding peripheral branches of the facial nerve were measured in 41 half-head specimens. The distances were from: i) the zygomatic arch (Z) to the buccal branch (B); ii) the retromandibular vein (RMV) to the marginal mandibular branch (MM); and iii) the angle of the mandible (A) to MM. These distances were compared in left vs, right sides, male vs. female groups, occlusal vs. nonocclusal sides. RESULTS: No statistically significant differences were found in any of the three distances between all groups compared, amongst which, the mean distances from A to MM were the shortest and least variable (Male = 8.9 +/- 3.0 mm vs. Female = 6.8 +/- 3.5 mm; Left = 7.3 +/- 2.8 mm vs. Right = 8.8 +/- 3.9 mm; Occlusal = 8.6 +/- 3.5 mm vs. Nonocclusal = 7.8 +/ 3.4 mm). CONCLUSION: The findings indicate that all three landmarks are useful for surgeons to locate the facial nerve branches during retrograde parotidectomy. Since all three landmarks were consistent indicators for the corresponding facial nerve branches, the surgeon has more than one option should one landmark be obscured by tumors. The optimal landmark is the distance from A to MM because it is shortest and most reliable, followed by RMV to MM, and Z to B. PMID- 27482379 TI - The LifeLines Cohort Study: a resource providing new opportunities for environmental epidemiology. AB - BACKGROUND: Lifelines is a prospective population-based cohort study investigating the biological, behavioral and environmental determinants of healthy ageing among 167,729 participants from the North East region of the Netherlands. The collection and geocoding of (history of) home and work addresses allows linkage of individual-level health data to detailed exposure data. We describe the reasons for choosing particular assessments of environmental exposures in LifeLines and consider the implications for future investigations. METHODS: Exposure to ambient air pollution and road traffic noise was estimated using harmonized models. Data on noise annoyance, perceived exposure to electromagnetic fields, perceived living environment, and neighborhood characteristics were collected with questionnaires. A comprehensive medical assessment and questionnaires were completed in order to assess determinants of health and well-being. Blood and urine samples were collected from all participants and genome wide association data are available for a subsample of 15,638 participants. RESULTS: Mean age was 45 years (standard deviation (SD) 13 years), and 59 % were female. Median levels of NO2 and PM10 were 15.7 (interquartile range (IQR) 4.9) MUg/m(3) and 24.0 (IQR 0.6) MUg/m(3) respectively. Median levels of daytime road traffic noise were 54.0 (IQR 4.2) dB(A). CONCLUSIONS: The combination of harmonized environmental exposures and extensive assessment of health outcomes in LifeLines offers great opportunities for environmental epidemiology. LifeLines aims to be a resource for the international scientific community. PMID- 27482381 TI - Bioactive Natural Protein-Hydroxyapatite Nanocarriers for Optimizing Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Improving the controlled release of bioactive growth factors to regulate cell behavior and tissue regeneration remains a need in tissue engineering and regenerative medicine. Inorganic and polymeric nanoparticles have been extensively fabricated as bioactive biomaterials with enhanced biocompatibility and effective carriers of therapeutic agents, however, challenges remain such as the achievement of high loading capacity and sustained release, and the bioactivity preservation of growth factors. Here, a multilayered, silk coated hydroxyapatite (HA) nanocarrier with drug loading-release capacity superior to pure silk or HA nanoparticles was developed. Bone morphogenetic protein-2 (BMP-2) was bound to the silk coatings with a high binding efficiency of 99.6%, significantly higher than that in silk or the HA nanoparticles alone. The release of BMP-2 was sustained in vitro over a period of 21 days without burst release. Compared with BMP-2 loaded silk or HA particles, bone mesenchymal stem cells (BMSCs) showed improved proliferation and osteogenesis when cultured with the BMP 2 loaded composite nanocarriers. Therefore, these silk-HA composite nanoparticles present a useful approach to designing bioactive nanocarrier systems with enhanced functions for bone tissue regeneration needs. PMID- 27482382 TI - Uncovering periodic patterns of space use in animal tracking data with periodograms, including a new algorithm for the Lomb-Scargle periodogram and improved randomization tests. AB - BACKGROUND: Periodicity in activity level (rest/activity cycles) is ubiquitous in nature, but whether and how these periodicities translate into periodic patterns of space use by animals is much less documented. Here we introduce an analytical protocol based on the Lomb-Scargle periodogram (LSP) to facilitate exploration of animal tracking datasets for periodic patterns. The LSP accommodates missing observations and variation in the sampling intervals of the location time series. RESULTS: We describe a new, fast algorithm to compute the LSP. The gain in speed compared to other R implementations of the LSP makes it tractable to analyze long datasets (>10(6) records). We also give a detailed primer on periodicity analysis, focusing on the specificities of movement data. In particular, we warn against the risk of flawed inference when the sampling schedule creates artefactual periodicities and we introduce a new statistical test of periodicity that accommodates temporally autocorrelated background noise. Applying our LSP based analytical protocol to tracking data from three species revealed that an ungulate exhibited periodicity in its movement speed but not in its locations, that a central place-foraging seabird tracked moon phase, and that the movements of a range-resident canid included a daily patrolling component that was initially masked by the stochasticity of the movements. CONCLUSION: The new, fast algorithm tailored for movement data analysis and now available in the R-package ctmm makes the LSP a convenient exploratory tool to detect periodic patterns in animal movement data. PMID- 27482380 TI - Perimenstrual asthma: from pathophysiology to treatment strategies. AB - The prevalence of asthma is about 9,7 % in women and 5,5 % in men. Asthma can deteriorate during the perimenstrual period, a phenomenon known as perimenstrual asthma (PMA), which represents a unique, highly symptomatic asthma phenotype. It is distinguished from traditional allergic asthma by aspirin sensitivity, less atopy, and lower lung capacity. PMA incidence is reported to vary between 19 and 40 % of asthmatic women. The presence of PMA has been related to increases in asthma-related emergency department visits, hospitalizations and emergency treatment including intubations. It is hypothesized that hormonal status may influence asthma in women, focusing on the role of sex hormones, and specifically on the impact of estrogens' fluctuations at ovulation and before periods. This paper will focus on the pathophysiology of hormone triggered cycle related inflammatory/allergic events and their relation with asthma. We reviewed the scientific literature on Pubmed database for studies on PMA. Key word were PMA, mastcells, estrogens, inflammation, oral contraception, hormonal replacement therapy (HRT), and hormone free interval (HFI). Special attention will be devoted to the possibility of reducing the perimenstrual worsening of asthma and associated symptoms by reducing estrogens fluctuations, with appropriate hormonal contraception and reduced HFI. This novel therapeutical approach will be finally discussed. PMID- 27482383 TI - The impact of posttraumatic stress disorder on the symptomatology of borderline personality disorder. AB - BACKGROUND: Previous findings on the impact of co-occurring posttraumatic stress disorder (PTSD) in patients with borderline personality disorder (BPD) have revealed inconsistencies, which may have been related to small sample sizes or differences in the presence of childhood sexual abuse (CSA). In this study, the potentially aggravating impact of PTSD and the role of CSA were examined in a large cohort of BPD patients. METHODS: BPD patients with current PTSD (n = 142) were compared to BPD patients without PTSD (n = 225) regarding different BPD features such as non-suicidal self-injury. Further, we examined the potentially confounding role of CSA. RESULTS: BPD patients with PTSD showed elevated affect dysregulation, intrusions, dissociation, history of suicide attempts and self mutilation compared to those with only BPD. The effects of PTSD on BPD patients regarding dissociation and the history of suicide attempts were at least partially related to CSA. CONCLUSIONS: The additional diagnosis of PTSD in BPD patients can aggravate some, but not all BPD features. With respect to dissociation and suicide attempts, at least some of the impact seems to relate to CSA. PMID- 27482384 TI - Diabetes mellitus: an important risk factor for reactivation of tuberculosis. AB - Diabetes mellitus was identified as a risk factor for developing tuberculosis (TB) infection, and relapse after therapy. The risk of acquiring TB is described as comparable to that of HIV population. The fact that diabetics are 3* times more prone to develop pulmonary TB than nondiabetics cannot be overlooked. With DM recognized as global epidemic, and TB affecting one-third of the world population, physicians must remain vigilant. We present a 45-year-old woman born in Dominican Republic (DR), with 10-year history of T2DM treated with metformin, arrived to our Urgency Room complaining of dry cough for the past 3months. Interview unveiled unintentional 15lbs weight loss, night sweats, occasional unquantified fever, and general malaise but denied bloody sputum. She traveled to DR 2years before, with no known ill exposure. Physical examination showed a thin body habitus, otherwise well appearing woman with stable vital signs, presenting solely right middle lung field ronchi. LDH, ESR, hsCRP and Hg A1C were elevated. Imaging revealed a right middle lobe cavitation. Sputum for AFB disclosed active pulmonary TB. Our case portrays that the consideration of TB as differential diagnosis in diabetics should be exercised with the same strength, as it is undertaken during the evaluation of HIV patients with lung cavitation. Inability to recognize TB will endanger the patient, hospital dwellers and staff, and perpetuate this global public health menace. LEARNING POINTS: Diabetes mellitus should be considered an important risk factor for the reactivation of pulmonary tuberculosis.High clinical suspicious should be taken into consideration as radiological findings for pulmonary tuberculosis in patients with diabetes mellitus may be atypical, involving middle and lower lobes.Inability to recognize pulmonary tuberculosis will endanger the patient, hospital dwellers and staff, and perpetuate this global public health menace. PMID- 27482385 TI - Palpation thyroiditis following subtotal parathyroidectomy for hyperparathyroidism. AB - Thyrotoxicosis is an under-recognised but clinically important complication of parathyroidectomy. We report a case of a 37-year-old man with tertiary hyperparathyroidism who initially developed unexplained anxiety, diaphoresis, tachycardia, tremor and hyperreflexia one day after subtotal parathyroidectomy. Thyroid biochemistry revealed suppressed thyroid stimulating hormone and elevated serum free T4 and free T3 levels. Technetium-99m scintigraphy scan confirmed diffusely decreased radiotracer uptake consistent with thyroiditis. The patient was diagnosed with thyrotoxicosis resulting from palpation thyroiditis. Administration of oral beta-adrenergic antagonists alleviated his symptoms and there was biochemical evidence of resolution fourteen days later. This case illustrates the need to counsel patients about thyroiditis as one of the potential risks of parathyroid surgery. It also emphasises the need for biochemical surveillance in patients with unexplained symptoms in the post operative period and may help to minimise further invasive investigations for diagnostic clarification. LEARNING POINTS: Thyroiditis as a complication of parathyroidectomy surgery is uncommon but represents an under-recognised phenomenon.It is thought to occur due to mechanical damage of thyroid follicles by vigorous palpation.Palpation of the thyroid gland may impair the physical integrity of the follicular basement membrane, with consequent development of an inflammatory response.The majority of patients are asymptomatic, however clinically significant thyrotoxicosis occurs in a minority.Patients should be advised of thyroiditis/thyrotoxicosis as a potential complication of the procedure.Testing of thyroid function should be performed if clinically indicated, particularly if adrenergic symptoms occur post-operatively with no other cause identified. PMID- 27482386 TI - Deep vein thrombosis, an unreported first manifestation of polyglandular autoimmune syndrome type III. AB - A 71-year-old woman with severe right lower leg pain, edema and erythema was presented to the Emergency Department and was found to have an extensive deep vein thrombosis (DVT) confirmed by ultrasound. She underwent an extensive evaluation due to her prior history of malignancy and new hypercoagulable state, but no evidence of recurrent disease was detected. Further investigation revealed pernicious anemia (PA), confirmed by the presence of a macrocytic anemia (MCV=115.8fL/red cell, Hgb=9.0g/dL), decreased serum B12 levels (56pg/mL), with resultant increased methylmalonic acid (5303nmol/L) and hyperhomocysteinemia (131MUmol/L), the presumed etiology of the DVT. The patient also suffered from autoimmune thyroid disease (AITD), and both antithyroglobulin and anti-intrinsic factor antibodies were detected. She responded briskly to anticoagulation with heparin and coumadin and treatment of PA with intramuscular vitamin B12 injections. Our case suggests that a DVT secondary to hyperhomocystenemia may represent the first sign of polyglandular autoimmune syndrome III-B (PAS III-B), defined as the coexistent autoimmune conditions AITD and PA. It is important to recognize this clinical entity, as patients may not only require acute treatment with vitamin B12 supplementation and prolonged anticoagulation, as in this patient, but may also harbor other autoimmune diseases. LEARNING POINTS: A DVT can be the first physical manifestation of a polyglandular autoimmune syndrome.Hyperhomocysteinemia secondary to pernicious anemia should be considered as an etiology of an unprovoked DVT in a euthyroid patient with autoimmune thyroid disease.Patients with DVT secondary to hyperhomocysteinemia should undergo screening for the presence of co-existent autoimmune diseases in addition to treatment with B12 supplementation and anticoagulation to prevent recurrent thromboembolism. PMID- 27482387 TI - 'Peptoniphilus vaginalis' sp. nov., a new species isolated from human female genital tract. AB - We relate here the main characteristics of 'Peptoniphilus vaginalis', strain KHD2 (= CSUR P0125 = DSM 101742), a new member of the Peptoniphilus genus, cultivated from a vaginal sample of a woman with bacterial vaginosis. PMID- 27482388 TI - 'Phocea massiliensis' a new bacterial species isolated from the human gut. AB - We present here the main characteristics of 'Phocea massiliensis' strain Marseille-P2769(T) (CSUR P2769), which is a new genus isolated from the stool of a 45-year-old patient. PMID- 27482389 TI - HIV cure research: a formidable challenge. AB - The ultimate goal of HIV cure research is to allow HIV-infected individuals to be free of disease in the absence of antiretroviral therapy. We discuss current directions and future opportunities aimed at achieving sustained virological remission, and possibly eradication. A multidisciplinary approach to HIV cure research will be important, and ethical, social and behavioural research should be conducted in parallel with basic and clinical research. PMID- 27482390 TI - Towards the elimination and eradication of hepatitis B. AB - Despite the introduction of vaccination, chronic hepatitis B remains a major cause of liver-related morbidity and mortality including cirrhosis, decompensated cirrhosis and hepatocellular carcinoma. Maintenance antiviral therapy is required for most people, as low rates of cure occur. The stated aim of therapy presently is HBV DNA suppression; effective suppression of viral replication is associated with significant reductions in morbidity from end-stage liver failure and to an extent, hepatocellular carcinoma. Unfortunately, major barriers to cure, such as a reservoir of episomal covalently closed circular DNA (cccDNA) (the HBV minichromosome), and a dysfunctional immune response, pose challenges. These barriers will need to be overcome to ensure higher rates of cure than can be achieved presently. Quantitative and diagnostic testing for HBV DNA is not generally available, hampering effective monitoring and treatment in low-income countries. The majority of patients in resource-constrained countries are not identified before the onset of cirrhosis. Without coordinated action, and transfer of new diagnostic technologies and treatments to low-income countries, recent therapeutic advances will have little effect on the global burden of disease. A shift to curative treatment for the majority would be a major advance in the elimination of hepatitis B. New and improved molecular therapeutics and immunological strategies for the treatment of chronic hepatitis are emerging, however. A number of promising lines of development are in progress. A curative regimen may require a combination of viral suppression via nucleoside analogue therapy to prevent cccDNA amplification and viral propagation, safe selective cccDNA inhibitors to deplete, silence or degrade cccDNA, agents to block the entry of HBV into the hepatocyte plus compounds to prevent capsid assembly and cccDNA interactions. Targeted immune activation could restore the exhausted immune cell repertoire. PMID- 27482391 TI - HIV-1 resistance to dolutegravir: update and new insights. AB - Integrase strand transfer inhibitors (INSTIs) are the latest class of potent anti HIV drugs. Currently, three INSTIs have been approved by the US Food and Drug Administration: raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). Resistance mutations to RAL and EVG emerge rapidly, and significant cross resistance between these compounds has been documented. In addition, limited cross-resistance has been observed among DTG, a newer INSTI, and RAL and EVG even though clinical resistance to DTG, or mutations associated with DTG resistance in treatment-naive patients, has not yet been observed. This review summarises progress in studies on understanding resistance to DTG, mechanisms of possible resistance to DTG, and reasons for the absence of DTG-associated resistance mutations when the drug has been used in first-line therapy. PMID- 27482392 TI - Animal models in HIV cure research. AB - Current HIV antiretroviral therapy (ART) successfully inhibits viral replication in the majority of HIV-infected individuals. However, ART is not curative and lifelong adherence is required. Despite the undisputed benefit of ART, long-lived latently infected cells that carry HIV-integrated DNA remain. Hence, upon ART interruption, HIV-infected subjects experience viral rebound. Interestingly, similar disease course occurs in the well-characterised animal model of SIV infected non-human primates. Using these animal models to investigate the mechanisms involved in the generation of latently infected cells, define the phenotypic and anatomical nature of persistent viral reservoirs, and test novel interventions for viral eradication, is critical for strengthening our understanding of HIV persistence and developing novel therapeutics aimed at curing HIV. In this review, we discuss the current animal models used in AIDS cure research, with a particular focus on non-human primates, and outline the experimental strategies explored in the quest for virus eradication. PMID- 27482394 TI - Recruitment and ethical considerations in HIV cure trials requiring treatment interruption. AB - INTRODUCTION: Relative to antiretroviral treatment (ART), early HIV cure-related trials (HCRTs) carry limited therapeutic benefits and unknown risks. In HCRTs requiring treatment interruption (TI) the health risks and burdens may create a barrier to study enrolment and increase the possibility for unintentional ethical violations in recruitment. METHODS: An online survey was administered to over 2,000 HIV-positive ART users in the US. Using multivariable ordinal regression we assessed effects of research participation attitudes, health and demographic traits on willingness to participate in treatment interruption studies (WtP-TI). RESULTS: WtP-TI was greatest among those who were highly motivated to participate in research studies for the benefit of science, society and, to a lesser extent, personal benefit. Personal benefit was less of an influence on WtP-TI among persons with higher viral loads or a history of multiple ART regimens. WtP-TI was greater among respondents who were more likely to consider personal health in making decisions about trial participation. WtP-TI had no association with perceptions of the importance of compensation to research participation. After accounting for attitudes, health status and demographic traits were generally not significantly related to WtP-TI. Notable exceptions included viral suppression status and race/ethnicity. CONCLUSION: Recruitment strategies in TI studies can benefit from a focus on the long-term scientific and social benefits of study participation. Strategies targeted to particular demographic groups may have little impact on accrual, and in some cases will need to be accompanied by strategies to improve the quality of researcher-community relationships. Findings also suggest that informing communities about the health impacts of trial participation may positively impact participation decisions. However, more research is needed to interpret the impact of health messaging on recruitment and therapeutic expectations. Future work should explore the implications of altruism based expectations on the strategic and ethical appropriateness of TI study recruitment efforts. PMID- 27482393 TI - Hepatitis E virus in developed countries: one of the most successful zoonotic viral diseases in human history? AB - Until recently, hepatitis E was thought to be largely confined to hyperendemic areas in Asia, Africa and Mexico. Over the last 10 years it has become clear that this is not the case, as it is surprisingly common in developed countries. In these settings, it is caused by HEV genotypes 3 and 4, and is a porcine zoonosis. It causes a range of human illness including acute and chronic hepatitis, and a spectrum of neurological injury. HEV RNA has been found in donated blood from an increasing number of countries, and in some locations with a very high incidence. The clinical phenotype and burden of disease in humans is still emerging. In contrast to previous 'received wisdom', zoonotically transmitted HEV may be one of the most successful zoonotic viral infections in human history. How did we, as a scientific community, get this so badly wrong? This review considers this question from a largely clinical perspective, explores the places HEV has been 'hiding' and the emerging clinical phenotype in humans. PMID- 27482395 TI - Community participation in HIV cure research: perspectives from Thailand. AB - Thailand aims to end its AIDS epidemic by 2030, and key strategies to effect this include an increase in HIV testing coverage to 90% for key populations (i.e. men who have sex with men, sex workers, people who inject drugs and partners of people living with HIV) and antiretroviral treatment (ART) initiation for all, regardless of CD4 cell count. In order to recruit more key populations into HIV testing, offer immediate ART and retain both HIV-negative people for regular HIV testing and HIV-positive people for continued ART service, effective communication to the community about the clear benefits of early HIV diagnosis and early ART, including the possibility for HIV cure, has become more important than ever. We discuss the need for more innovative ways of communicating. PMID- 27482396 TI - HCV cure for everyone or which challenges remain? AB - Following the approval of the first HCV direct-acting antiviral (DAA) in 2011, an unforeseen revolution in the treatment of chronic hepatitis C has taken place. In 2015 several all-oral DAA regimens, combining agents from different families (NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors) are now commercially available. In clinical trials, these regimens result in an increase in sustained virological response (SVR) rates to above 90-95% and reduce the duration of treatment to 12 weeks or less. As these new all-oral therapies are easy to take, with some already available as simple fixed-dose combinations, and are associated with minimal adverse events, increasing numbers of HCV patients appear treatable with these modern regimens. Nevertheless, the questions remain on how far the spectacular treatment trial results can be reproduced in clinical practice and whether more challenging patient populations, including previous non-responders and patients with advanced cirrhosis, will continue to exist even in the era of all-oral DAA therapy. PMID- 27482397 TI - Low incidence of HIV infection in an anonymous HIV counselling and testing clinic cohort in Bangkok, Thailand despite high HIV prevalence and self-report of high risk behaviour. AB - BACKGROUND: HIV counselling and testing (HCT) clinics have the potential to be entry points for recruiting populations at high risk for HIV infection for HIV prevention and treatment studies. Cohort data from key populations are crucial for HIV study site selection. METHOD: This cohort study recruited clients at an HCT clinic in Bangkok, Thailand. HIV prevalence was assessed along with demographics, perception of risk and behavioural risk factors. Participants who were HIV negative at baseline were followed up every 4 months for up to 1 year to measure HIV incidence and changes in risk behaviour. RESULTS: A total of 992 subjects enrolled; median age was 30 years, 27% were men who have sex with men (MSM) and 8% were commercial sex workers (CSW). Baseline HIV prevalence was 10%. Factors positively associated with HIV infection were age >30 years, lower educational status and being MSM. Factors negatively associated with HIV infection were self-perception of minimal or moderate risk. Overall dropout rate was 49%, with 24% not returning after enrolment. HIV incidence was lower than expected at 0.50 per 100 person-years overall and 1.95 per 100 person-years for MSM. CONCLUSIONS: This HCT population had a high baseline HIV prevalence but a low incidence rate on follow-up. Overall retention in the cohort was poor and may have resulted from suboptimal reminders and characteristics of high-risk clients who use anonymous HIV testing services. MSM had higher HIV incidence and better retention than other high-risk groups. PMID- 27482398 TI - Cervical and anal HPV infection: cytological and histological abnormalities in HIV-infected women in Thailand. AB - BACKGROUND: Women infected with human immunodeficiency virus (HIV) have higher rates of persistent infection with high-risk human papillomavirus (hr-HPV) and cervical and anal dysplasia. We describe the epidemiology of hr-HPV, and cervical and anal intra-epithelial abnormalities in HIV-infected women in Thailand. METHODS: HIV-infected women aged 18-49 years, either HAART-naive or -experienced, were enrolled in Bangkok, Thailand. A demographic and sexual-risk behaviour questionnaire was administered and a pelvic examination with colposcopy was performed on every woman. Cervical and anal samples were tested for cytology and HPV genotyping. RESULTS: A total of 256 women were enrolled with a median [interquartile range (IQR)] age of 35 (32-40) years. Ninety (35.2%) had detectable cervical hr-HPV. Being post-menopausal was associated with increased risk for cervical hr-HPV, while years since HIV diagnosis and plasma HIV RNA <40 copies/mL were significantly associated with decreased risk in multivariable regression analyses. Abnormal cervical cytology was detected in 6.3%. Cervical biopsies that were taken from 99 women (39.3%) owing to abnormalities seen during colposcopy showed cervical intra-epithelial neoplasia (CIN) in 22.6%. The sensitivity of cervical cytology to detect CIN2+ was 10.0%. Among 102 women enrolled in the anal substudy, 18.8% had anal HPV infection and 11.1% had anal hr HPV. Two women had abnormal anal cytology. CONCLUSION: We found cervical and anal hr-HPV in 35.2% and 11.1% of Thai HIV-infected women, respectively. Moreover, the observed poor agreement between cervical cytology and histology results could indicate current cervical cancer screening programs for HIV-infected women might not be optimal for the detection of pre-neoplastic lesions. PMID- 27482399 TI - Analysis of minimum target prices for production of entecavir to treat hepatitis B in high- and low-income countries. AB - BACKGROUND: In 2013, an estimated 686,000 people died from hepatitis B virus (HBV) infection worldwide. Mass treatment programmes for hepatitis B will require very low drug costs. International treatment guidelines recommend first-line monotherapy with either entecavir or tenofovir disoproxil fumarate (TDF). While the basic patent on TDF expires in 2017/8, entecavir is already generic in several countries, including the US. The chemical structure of entecavir is related to abacavir, which costs <$200 per person-year in low-income countries. METHODS: The clinical efficacy, chemical structures, daily doses, routes of chemical synthesis, costs of raw materials and patent expiry dates were analysed for entecavir and TDF. Costs of sustainable, generic production were calculated for entecavir, and compared with published originator and generic prices in high- and low-income countries. RESULTS: With a daily dose of 0.5 mg, one year's supply of entecavir treatment requires <0.2 g of active pharmaceutical ingredient (API) per person, estimated to cost $4/year, based on quotations of API production from generic suppliers. With an additional $20 per year for formulation/packaging and a 50% profit margin, entecavir was estimated to cost a minimum of $36/person year, substantially lower than current originator and generic prices. Entecavir is no longer under patent protection in the USA, China, Brazil and South Africa, with European expiry in 2017. Given differences in daily dosing, production volumes for entecavir would be 600 times lower than TDF (300 mg once daily) for treating the same numbers of patients. CONCLUSIONS: Mass treatment for hepatitis B with generic entecavir could be achieved at very low cost in all countries, provided that important projections can be met in terms of pricing for the API and finished dosage form. PMID- 27482401 TI - Conference on Retroviruses and Opportunistic Infections 2015: 23-26 February 2015, Seattle, Washington, USA. PMID- 27482400 TI - Innovative strategies using communications technologies to engage gay men and other men who have sex with men into early HIV testing and treatment in Thailand. AB - OBJECTIVES: One-in-three men who have sex with men (MSM) surveyed between 2007 and 2010 in Bangkok were HIV infected; 54% of new infections in Thailand are expected to be among MSM. Although MSM are the top internet-accessing population in Thailand, it has not been optimally used to scale up early HIV testing and counselling (HTC) and linkage to treatment. Thailand needs innovative technology based strategies to help address the exploding epidemic of HIV among gay men and other MSM. METHODS: Adam's Love, an innovative web-based communications strategy, was launched in 2011 by the Thai Red Cross AIDS Research Centre. It includes a dedicated website, integrated social media and web message boards for online counselling, recruitment and appointment making, a club membership programme offering non-financial incentives for HTC, targeted marketing and promotions, and collaboration with MSM-friendly clinics and private hospitals to improve accessibility of HTC services. RESULTS: Between September 2011 and January 2015, the website engaged 1.69 million viewers, and gained more than 8 million page views. An estimated 11,120 gay men and other MSM received online counselling; 8,288 MSM were referred to HTC services; 1,223 to STI testing services; and 1,112 MSM living with HIV were advised regarding HIV treatment. In total, 1,181 MSM recruited online were enrolled in the club membership programme, and 15.5% were diagnosed with HIV. CONCLUSIONS: The Adam's Love programme has successfully demonstrated the potential for utilising 'online-to-offline' recruitment models in Thailand, and has attracted national and regional recognition as a trusted resource on HIV and referral to testing and care. PMID- 27482402 TI - Highlights from HIV Research for Prevention (R4P): 28-31 October 2014, Cape Town, South Africa. PMID- 27482403 TI - We all need to know about HIV cure research: a case report. AB - A cure for HIV is not near, yet publicity surrounding the possibility of cure is high. We present the case of an individual with acute HIV who delayed antiretroviral therapy due to misinformed expectations of availability of cure treatments. Researchers and the media need to be mindful of prematurely raising hope of a cure. PMID- 27482404 TI - Children are not small adults. PMID- 27482406 TI - Immunological and pharmacological strategies to reactivate HIV-1 from latently infected cells: a possibility for HIV-1 paediatric patients? AB - The limitations to establishing a viral reservoir facilitated by early cART in children could play a critical role in achieving natural control of viral replication upon discontinuation of cART, which could be defined as 'functional cure'. Viral reservoirs could provide a persistent source of recrudescent viraemia after withdrawal of cART, despite temporary remission of HIV-1 infection, as observed in the 'Mississippi baby'. Intensification of cART has been proposed as a strategy to control residual replication and to diminish the reservoirs. The effects of cART intensification with maraviroc persisted after discontinuation of the drug in HIV-1-infected adults. However, in HIV-1-infected children, the emergence of CXCR4-using variants occurs very early, and the use of CCR5 antagonists in these children as intensification therapy may not be the best alternative. New treatments to eradicate HIV-1 are focused on the activation of viral production from latently infected cells to purge and clear HIV-1 reservoirs. This strategy involves the use of a wide range of small molecules called latency-reversing agents (LRAs). Histone deacetylase inhibitors (HDACi) such as givinostat, belinostat and panobinostat, and class I-selective HDACis that include oxamflatin, NCH-51 and romidepsin, are the most advanced in clinical testing for HIV-1 LRAs. Panobinostat and romidepsin show an efficient reactivation profile in J89GFP cells, a lymphocyte HIV-1 latently infected cell line considered a relevant model to study post-integration HIV-1 latency and reactivation. Clinical trials with panobinostat and romidepsin have been performed in children with other pathologies and it could be reasonable to design a clinical trial using these drugs in combination with cART in HIV-1-infected children. PMID- 27482405 TI - Host factors and early treatments to restrict paediatric HIV infection and early disease progression. AB - A body of evidence indicates that a threshold level of the virus is required to establish systemic and persistent HIV infection in the host and that this level depends on virus-host interactions. Mother-to-child transmission (MTCT) of HIV is the main source of paediatric HIV infection and occurs when the host's immune system is still developing. Thus, innate resistance and immunity, rather than adaptive immune response, may be the main drivers in restricting the establishment of HIV reservoirs and the long-lived persistence of HIV infection in infants. Genetic variations in HIV co-receptors and their ligands, as well as in Toll-like receptors and defensins, key elements of innate immunity, have been demonstrated to influence the risk of perinatal HIV infection and disease progression in HIV-infected infants. Early treatments with combined antiretroviral therapy (cART) restrict paediatric infection by reducing the level of the transmitted/infecting virus to below the threshold required for the onset of immune response to the virus and also significantly reduce HIV reservoirs. However, despite long periods with no signs and symptoms of HIV infection, all early cART-treated children who later discontinued cART had a rebound of HIV, except for one case in whom a period of viral remission occurred. Which parameters predict viral remission or viral rebound after cART discontinuation? Could early cART prevent rather than just reduce the establishment of viral reservoirs? And, if so, how? Answers to these questions are also important in order to optimise the use of early cART in infants at high risk of HIV infection. PMID- 27482408 TI - Oral PrEP for HIV prevention. It works. AB - There is an ongoing need for effective methods for prevention of HIV infection. A wide range of tools is needed, in varying social and economic contexts, and against different modes of transmission. Recent advances have concentrated on biomedical approaches to prevention, including the use of antiretroviral therapy (ART) prior to possible exposure to HIV: pre-exposure prophylaxis (PrEP). PMID- 27482409 TI - HIV-1 co-receptor tropism and disease progression in children and young adults with perinatally acquired HIV-1 infection. The HICCUP Study. AB - OBJECTIVES: Retrospective analysis of evolution of HIV tropism and association with disease progression in perinatal HIV-1 infection (PaHIV). METHODOLOGY: Eligible patients with PaHIV were grouped as slow, rapid or long-term non progressors (LTNP). The V3 region of gp120 was sequenced from stored plasma samples and tropism determined by geno2pheno algorithm (FPR 5.75%). Logistic regression with generalised estimating equations assessed factors associated with R5 virus. Time to tropism change was assessed using standard survival methods. RESULTS: At baseline (n=48) median age was 12 years (IQR 9.3-14.8), 52% were female, 79% were Black African, 96% were non-B subtypes and 81% (39/48) had R5 using virus. Median follow-up was 7.7 years (308.6 person-years), with a median of five (range 1-14) samples per subject (total 252). Analysing all samples, R5 virus was associated with higher current CD4 cell count (median 520 cells/mm(3) R5 vs 202 for X4, P=0.0005), LTNP (35% vs 11%, P=0.05), non-Black ethnicity (74% vs 89%, P=0.05) and female gender (55% vs 28%, P=0.005). Twelve of 38 (31%) with R5 virus at baseline switched to X4/dual-using virus, with an estimated 5-year risk of switch of 24.4% (95% CI 9.7-39.2%) predicted by lower current CD4 cell count (unadjusted HR 0.62/50 cells higher, 95% CI 0.47-0.81, P=0.0006). Eleven of 19 (58%) with X4/dual-using virus subsequently had R5 virus at one or more time points. CONCLUSION: Maraviroc was a treatment option for 81% at 12 years, falling to 56% at 18 years, with lower CD4 cell count predictive of co-receptor switching. Paediatric studies of CCR5 antagonists should be expedited to ensure they are an early treatment option before tropism switching occurs. PMID- 27482407 TI - Adverse bone health among children and adolescents growing up with HIV. AB - Adverse bone health is one of the important non-communicable conditions during the course of life-long HIV treatment. Adolescence is the critical period of bone mineral acquisition for attaining adult peak bone mass. With traditional and HIV related risk factors, adolescents growing with HIV have a greater chance of having impaired bone mineral density (BMD). Prevalence of low BMD has been reported in 16-32% of HIV-infected adolescents from middle-income countries. The deep interaction between the immune and skeletal systems, called the immunoskeletal interface, is proposed as one of the underlying mechanisms of adverse bone health in HIV-infected individuals. Dual-energy X-ray absorptiometry (DXA) is a standard tool to assess BMD among HIV-infected adolescents. Non invasive imaging techniques such as quantitative computed tomography (QCT) and quantitative magnetic resonance imaging (QMRI) provide more information on true volumetric density and bone microarchitecture. To date, there are no paediatric recommendations on the treatment and prevention of adverse bone health. Having a healthy lifestyle, routine weight-bearing exercises and adequate dietary intake are the standard approaches to optimise bone health. There are several ongoing randomised clinical trials using pharmacological treatment options, for example vitamin D, calcium and alendronate to improve bone health among this population. PMID- 27482411 TI - Plasma pharmacokinetics of once-daily abacavir- and lamivudine-containing regimens and week 96 efficacy in HIV-infected Thai children. AB - BACKGROUND: Abacavir and lamivudine are approved for once-daily use in HIV infected adults. Limited pharmacokinetic (PK) data for abacavir and lamivudine in children are available. METHODS: A crossover study to compare PK of once- versus twice-daily abacavir and lamivudine was conducted in virologically suppressed HIV infected Thai children aged <18years, with bodyweight of at least 14 kg, HIV RNA <50 copies/mL and HLA-B*5701 negative. Abacavir and lamivudine daily doses by bodyweight were 300 and 150 mg for 14-<20 kg, 450 and 300 mg for 20-<25 kg, and 600 and 300 mg for >=25 kg, respectively. Originator abacavir and lamivudine scored tablets were administered. Intensive PK sampling was performed after 14 days of each dose. PK parameters were determined using non-compartmental analysis. RESULTS: Thirty children (57% male) were enrolled, 10 per weight band. Median (IQR) age was 8.8 (6.6-11.3) years and bodyweight was 21.9 (19.2-30.6) kg. The geometric means (GM) AUC0-24 of once- and twice-daily abacavir were 14.43 and 10.65 mg.h/L, respectively. The geometric mean ratio (GMR) of AUC0-24 for once- versus twice-daily abacavir dosing was 1.36 [90% confidence interval (CI) 1.11 1.66]. The GM AUC0-24 of once- and twice-daily lamivudine were 17.70 and 18.11 mg.h/L, respectively. The GMR of AUC0-24 for once- versus twice-daily lamivudine dosing was 0.98 (90% CI 0.84-1.14). At 96 weeks, 90% had HIV RNA <50 copies/mL and there were no serious adverse events. CONCLUSION: Abacavir exposure was greater with once-daily dosing, while lamivudine once- and twice-daily exposures were bioequivalent. Once-daily abacavir and lamivudine using weight-band dosing is a treatment option for children. PMID- 27482410 TI - HCV treatment in children and young adults with HIV/HCV co-infection in Europe. AB - OBJECTIVES: To describe use of treatment for chronic hepatitis C virus (HCV) infection in HIV/HCV co-infected children and young people living in Europe and to evaluate treatment outcomes. METHODS: HCV treatment data on children and young people aged <25 years with HIV/HCV co-infection were collected in a cohort collaboration of 11 European paediatric HIV cohorts. Factors associated with receipt of HCV treatment and with sustained virological response 24 weeks after treatment completion (SVR24) were explored. RESULTS: Of 229 HIV/HCV co-infected patients, 22% had a history of AIDS and of 55 who were treated for HCV, 47 (85%) were receiving combined antiretroviral therapy. The overall HCV treatment rate was 24% (n=55) but it varied substantially between countries, with the highest rate being in Russia at 61% (30/49). Other factors associated with treatment receipt were older age [adjusted odds ratio (AOR) 5.24, 95% confidence interval (CI) 1.9-14.4, for 18-24-year-olds vs 11-17-year-olds, P=0.001] and advanced fibrosis (AOR 5.5, 95% CI 1.3-23.7; for >=9.6 vs <=7.2 kPa, P=0.02). Of 50 patients with known treatment outcomes, 50% attained SVR24. Of these, 16 (80%) had genotype (GT) 2,3 and 8 (29%) had GT 1,4 (P<0.001). After adjusting for genotype (GT 1,4 vs GT 2,3), females (P=0.003), patients with non-vertical HCV acquisition (P=0.002) and those with shorter duration of HCV (P=0.009) were more likely to have successful treatment outcomes. CONCLUSION: Only half of the HIV/HCV co-infected youth achieved an HCV cure. HCV treatment success appears to be lower in the context of HIV co-infection than in HCV mono-infection, underscoring the urgent need to speed up approvals of new direct-acting antiviral combinations in children. PMID- 27482412 TI - Treating hepatitis C virus in children: time for a new paradigm. AB - Hepatitis C virus infection is a leading cause of liver-related morbidity and mortality. In the paediatric population, HCV infection is underdiagnosed and undertreated in the absence of robust screening policies worldwide, and a lack of tolerable, effective treatment. The recent advances in HCV drug development allow for optimism, a change in outcomes for the millions of children infected with this virus and a unique opportunity for strategies aiming at HCV eradication. The rapid development of the new compounds has been followed by a welcome shift in the regulatory processes; however, strategies aiming at improving diagnosis, selecting the best combinations and addressing mother-to-child transmission issues are required for the new therapeutic agents to be introduced safely and effectively in the paediatric population and to contribute to the goal of virus eradication. PMID- 27482413 TI - Ebola in children: a personal perspective. AB - This article documents reflections of a paediatrician working with the medical non-governmental organisation, Medecins Sans Frontieres, in two Ebola Management Centres in Sierra Leone, in December 2014 and January 2015. PMID- 27482414 TI - Viruses and exacerbations of chronic obstructive pulmonary disease: unmet clinical need. AB - Chronic obstructive pulmonary disease (COPD) is a non-communicable long-term condition characterised by accelerated lung-function decline and intermittent episodes of respiratory illness called exacerbations. We discuss the current understanding of the role of viruses in these elements of COPD. The burden of acute viral illness in COPD is great and largely unrecognised. Because naturally occurring exacerbations are inherently difficult to study, only recently have we understood underlying pathophysiological mechanisms and the true prevalence of viral exacerbations. Data are also emerging to support a potential role for chronic viral infection in the progression of stable COPD. As knowledge in these two areas develops, it is clear that the role of viruses in COPD represents a significant unmet clinical need. PMID- 27482416 TI - Highlights from the Children's HIV Association Conference: 22 May 2015, Leicester. PMID- 27482417 TI - Highlights from the Keystone Symposium on HIV Persistence 2015: 26-30 April 2015, Boston, Massachusetts, USA. PMID- 27482418 TI - 50th International Liver Congress: update on viral hepatitis: 22-26 April 2015, Vienna, Austria. PMID- 27482419 TI - Control of HIV viraemia is not enough in perinatal HIV. PMID- 27482415 TI - Second European Round Table on the Future Management of HIV: 10-11 October 2014, Barcelona, Spain. AB - The Second European Round Table on the Future Management of HIV took place in Barcelona, 10-11 October 2014 and focused on the HIV-1 reservoir, strategies for HIV cure and primary HIV infection (PHI). Important issues in the HIV-1 reservoir research field are the validity of reservoir measurement techniques and the potential of new drugs to target latently infected cells. Current HIV-1 cure concepts are based on theoretical assumptions of biologically plausible mechanisms, supported by several clinical observations. Three main potential strategies are under investigation in order to achieve a sterilising cure or maintain HIV-1 remission: latency reversal resulting in antigen expression and viral cytolysis or immune targeted cell-death; immunological control of the reservoir; or replacement of the complete autologous haematopoietic and lymphoid stem-cell repertoire by transplantation. An interesting opportunity for restricting the size of the reservoir entails the early initiation of antiretroviral treatment (ART) during PHI. In terms of the reservoir, early treatment limits its size, alters its composition, and restricts the genetic variability of integrated proviral HIV-1 DNA. The challenges ahead involve the identification of patients undergoing seroconversion to HIV-1 and the prompt initiation of treatment. How the seemingly beneficial impact of early treatment will make cure more feasible, and whether the positive effects of the cure efforts outweigh the potentially negative impact of life-long ART, are important aspects of future collaborative research prospects. PMID- 27482420 TI - Efforts to eliminate the latent reservoir in resting CD4+ T cells: strategies for curing HIV-1 infection. AB - Since the introduction of the first antiretroviral drug, zidovudine, in 1987, over 25 different antiretroviral agents from six different drug classes have been approved for the treatment of HIV-1 infection. Today, combination antiretroviral therapy (ART) is extremely effective in suppressing HIV-1 replication, providing durable control of the virus in adherent patients. However, despite the effectiveness of ART in blocking viral replication, HIV-1 infection cannot be cured by ART alone because HIV-1 establishes a state of latent infection in a small pool of resting, memory CD4+ T cells. Some new developments in the search for a cure are discussed. PMID- 27482421 TI - Novel immunological strategies for HIV-1 eradication. AB - Despite the significant advances in antiretroviral therapy (ART), HIV-1 is able to persist in cellular reservoirs. Preclinical studies suggest that the latent reservoir is established within days of virus exposure, even before virus can be detected in peripheral blood. Latently infected cells remain undetectable by the immune system and can persist for years without losing their ability to produce infectious virus when ART is discontinued. Novel concepts for viral eradication strategies combine pharmacological induction of latently infected cells to produce virus together with immune-enhancing interventions to enable the host to clear these cells. In this review, we describe the early establishment of HIV-1 latency and discuss current strategies to disrupt latency and potentially enable clearance of these persistently infected cells. PMID- 27482422 TI - HIV-infected cells are frequently clonally expanded after prolonged antiretroviral therapy: implications for HIV persistence. AB - HIV infection is controlled but not eradicated by combination antiretroviral therapy (cART), and persistence during therapy represents a substantial barrier to strategies to eradicate infection. The nature of persistence is uncertain, and a number of mechanisms have been proposed to explain HIV persistence in vivo, including low-level HIV replication, sanctuary sites for HIV-infected cells, and latent HIV residing within long-lived cells. Analysis of residual viraemia and of cell-associated HIV revealed evidence of multiple copies of identical HIV sequences suggesting infected cells can undergo cellular expansion. Recently, analysis of integration sites in HIV-infected cells derived from peripheral blood lymphocytes of patients undergoing long-term cART revealed direct evidence that HIV-infected cells undergo clonal expansion. These studies demonstrated that clonally expanded populations are common in HIV-infected individuals, persist for prolonged periods and increase in frequency during prolonged therapy. Several analyses reported that site of integration may affect persistence, clonal expansion, or both. As such, expanded populations may represent an important source of infectious HIV during cART. Many HIV integrants are defective for replication, however, and additional research is essential to determine to what degree clonally expanded populations represent a reservoir of replication competent HIV. PMID- 27482423 TI - Higher risks of mother-to-child HIV transmission in countries with lower HIV prevalence: UNAIDS 2013 results for 32 countries with generalised epidemics. AB - OBJECTIVES: Diagnosis and treatment of HIV-infected mothers significantly lower rates of mother-to-child transmission (MTCT) of HIV. Early infant diagnosis (EID) is required to monitor success of prevention of MTCT (pMTCT) programmes. Our aim was to compare rates of MTCT, EID and pMTCT in countries with generalised epidemics. METHODS: The UNAIDSinfo database includes country-level information on epidemic size, prevalence of HIV infection, EID rates and pMTCT coverage. The AIDS Spectrum model was used to estimate the number of children infected with HIV in 2013, for 32 countries with generalised epidemics. Least squares linear regression, weighted by epidemic size and controlling for GDP/capita, was used to correlate national adult HIV prevalence with estimated MTCT rates. RESULTS: There were 32 countries with generalised epidemics included in the analysis (31 in Africa). Higher-prevalence countries (>=5%) had significantly lower rates of MTCT (P<0.01) than lower-prevalence countries (<5%). For 20 lower-prevalence countries (total 7.4 million HIV-infected people), there were 105,300 childhood (0-14 years) infections in 2013. In 12 higher-prevalence countries (total 17.1 million HIV-infected people), there were an estimated 107,500 childhood infections in 2013. Regression analysis suggests that if all countries achieved the same MTCT rate as Botswana (2.0%), childhood HIV infections could be cut by 88% (from 105,300 to 12,300 per year) in lower-prevalence countries, and by 82% (from 107,500 to 19,700 per year) in higher-prevalence countries. CONCLUSIONS: In this analysis of 32 countries with generalised HIV epidemics, 49.5% (105,500/213,000) of childhood HIV infections in 2013 were in lower-prevalence countries. Targeting of prevention of MTCT in lower-prevalence countries needs to be prioritised, despite challenges, to reduce the number of children infected. PMID- 27482424 TI - The hepatitis C treatment revolution: how to avoid Asia missing out. AB - The Asia-Pacific region bears a high burden of hepatitis C virus (HCV) infections and the largest number of global deaths. Populations most at risk of infection and disease progression include people who inject drugs and those living with HIV. HCV treatment options have rapidly expanded in the past few years through the development of direct-acting antiviral (DAA) medicines, which can cure HCV in over 95% of cases, but are prohibitively expensive. While price is the major barrier to treatment access, voluntary licensing has resulted in limited availability of one DAA (sofosbuvir) through generic manufacturers in India. Regulatory barriers, such as the need for domestic clinical trials, cause further delays in local medicines approvals and access. Intensive advocacy by civil society in combination with mobilisation of global resources for HIV treatment were critical to achieving price reductions in HIV medicines in the early 2000s. While the current global economic situation is less conducive to substantial funding support for HCV treatment, community advocates are building awareness of the growing opportunities for HCV cure. Key immediate steps include the inclusion of DAAs in domestic essential medicines lists, as the World Health Organization has already done for globally, and fast-tracking domestic drug approvals to facilitate government-level price negotiations with originator and generic pharmaceutical companies. Urgent action by a broad range of stakeholders is needed to facilitate access to HCV treatment in order to ensure that the millions of people living with hepatitis C in the Asia-Pacific will not miss out on these life-saving treatments. PMID- 27482425 TI - IAS Towards an HIV Cure Symposium: people focused, science driven: 18-19 July 2015, Vancouver, Canada. AB - The International AIDS Society (IAS) convened the Towards an HIV Cure Symposium on 18-19 July 2015 in Vancouver, Canada, bringing together researchers and community to discuss the most recent advances in our understanding of HIV latency, reservoirs and a summary of the current clinical approaches towards an HIV cure. The symposium objectives were to: (1) gather researchers and stakeholders to present, review, and discuss the latest research towards an HIV cure; (2) promote cross-disciplinary global interactions between basic, clinical and social scientists; and (3) provide a platform for sharing information among scientists, clinicians, funders, media and civil society. The symposium examined basic molecular science and animal model data, and emerging and ongoing clinical trial results to prioritise strategies and determine the viral and immune responses that could lead to HIV remission without antiretroviral therapy. This report summarises some of the major findings discussed during the symposium. PMID- 27482426 TI - International Congress on Targeting Ebola: 28-29 May 2015, Pasteur Institute, Paris. PMID- 27482427 TI - Barriers and best practices of transitioning perinatally HIV-infected adolescents to adult care in Asia-Pacific. PMID- 27482428 TI - HIV-1 prophylactic vaccines: state of the art. AB - The quest for an effective HIV-1 vaccine began early in the course of the HIV pandemic. Over time, the paradigm has evolved from B cell- towards T cell-based vaccines. Results from initial Phase II/III trials have been disappointing; however, while modest, the unexpected results of the Phase II/III RV144 trial in Thailand have re-energised the field. Indeed a clear correlation was demonstrated in this trial between protection and immunological biomarkers, namely non neutralising antibodies against the V1V2 region. Recent data obtained from cohorts of recently HIV-1-infected individuals have enabled exploration of the role of neutralising antibodies and their potential use in HIV-1 prevention. Results from non-human primate models using a cytomegalovirus vector have also shown the potential for a prophylactic HIV vaccine to induce effective T cell responses. Finally, the development of new vaccine vectors and trial strategies has also allowed progress in the field. Therefore, HIV-1 vaccine research remains a dynamic field that has also been stimulated by the recent positive results of pre-exposure prophylaxis strategies with antiretrovirals. PMID- 27482429 TI - Alemtuzumab-induced elimination of HIV-1-infected immune cells. AB - BACKGROUND: Currently, there is no drug known that is able to eradicate either HIV or HIV-infected host cells. The effectiveness of all available treatments is based on the prevention of viral replication. We investigated whether the monoclonal, CD52 receptor-targeting antibody, alemtuzumab, which is currently approved for the treatment of multiple sclerosis, is able to eliminate HIV infected immune cells. METHOD: In blood samples from healthy donors and from HIV 1-infected subjects who were either treatment-naive or resistant to HAART, we studied whether the CD52 expression on T cells and their subsets (CD3, CD4, CD8), B cells (CD19), dendritic cells (CD123) and monocytes (CD11c) is retained in HIV 1 infection and whether alemtuzumab is able to eradicate infected cells, using four-colour flow cytometry. RESULTS: We found that CD52 expression on immune cells is retained in HIV-1 infection regardless of CD4 cell count, viral load and treatment status, and is amenable to alemtuzumab-induced depletion. CONCLUSIONS: For the first time it could be shown in vitro that HIV-1-infected immune cells can be eliminated by using the monoclonal antibody alemtuzumab. PMID- 27482430 TI - Hepatitis B virus genotypes A and D in Uganda. AB - BACKGROUND: The prevalence of hepatitis B virus (HBV) infection in Uganda is 10%. Hepatitis B virus genotypes impact on treatment response, rate of spontaneous recovery and progression of chronic HBV infection and hepatocellular carcinoma. There is little information on the HBV genotypic distribution in Uganda. OBJECTIVES: To determine HBV genotypes in Uganda. METHODS: The MBN clinical laboratory performs HBV viral load and genotype testing in Uganda. It receives hepatitis B surface antigen (HBsAg)-positive samples from all over the country for additional HBV testing. Samples are stored for 6 months before being discarded. Our study used delinked stored samples. PCR-positive samples had DNA extracted and used as template for HBV genome amplification by nested PCR. Reverse hybridisation was performed and genotypes were determined by the line probe assay method (INNO-LiPA). RESULTS: One hundred stored HBsAg-positive plasma samples with detectable viral loads were analysed. Of these, 93 samples showed PCR amplification products and gave genotype-specific probe lines on the INNO LiPA assay. Of the patients, where gender was recorded, 60.9% were female, and the overall median age (IQR) was 25 (2-60) years. There was a predominance of HBV genotype D (47 patients; 50.5%), followed by genotype A, (16 patients; 17.2%). One patient (1.1%) had genotype E. In 28% of the samples mixed infections were detected with genotypes A/E (9.7%) and A/D (6.5%) being most common. Genotypes B, C, E and H only occurred as part of mixed infections. CONCLUSION: Hepatitis B genotypes D and A were predominant in our study population. PMID- 27482432 TI - Rapid reductions in prices for generic sofosbuvir and daclatasvir to treat hepatitis C. AB - OBJECTIVES: Novel treatments for hepatitis C demonstrate high cure rates, but current high prices can be a barrier to rapid global treatment scale-up. Generic competition can rapidly lower drug prices. Using data on exports of raw materials in 2015, we calculated currently feasible generic prices of sofosbuvir and daclatasvir. METHODS: Data on per-kilogram prices of sofosbuvir and daclatasvir active pharmaceutical ingredients (API) exported from India were extracted from an online database. To the cost of the amount of API needed for a 12-week treatment course, we added cost estimates for formulation (40%), packaging (US$0.35/month), and a mark-up (50%). RESULTS: Between 1 January and 15 October 2015, over 5 tons of sofosbuvir were exported, with prices decreasing by US$702/kg/month, and observed prices of US$2501/kg in early September. Over the same period, 84 kg of daclatasvir were exported, with prices decreasing by US$1664/kg/month to US$1897/kg. Using the price estimation algorithm, we estimated the price of a generic sofosbuvir-daclatasvir combination regimen at US$200 per patient for a 12-week treatment course. CONCLUSION: The costs of generic production of sofosbuvir and daclatasvir are rapidly decreasing. Sofosbuvir-daclatasvir combination treatment could be produced for US$200 per patient per 12-week course. PMID- 27482431 TI - A qualitative assessment of barriers and facilitators to antiretroviral adherence in Thai patients. AB - OBJECTIVES: Excellent adherence to combination antiretroviral therapy can suppress HIV replication and produce life expectancies nearing those of individuals without HIV infection. This qualitative study sought to identify the barriers and facilitators to good antiretroviral medication adherence in Thai patients living with HIV. METHODS: Semi-structured interviews were conducted with a convenience sample (n=21) of patients attending routine clinic visits at Srinagarind Hospital in Khon Kaen, or HIV-NAT, the Thai Red Cross AIDS Research Centre in Bangkok. RESULTS: Median informant age was 43 years (range 27-60 years) and 43% were female. We identified key facilitators and barriers to adherence among HIV-infected Thai patients along three major themes (patient-related, health system-related and medication-related). Stigma was a primary concern for most informants, operating throughout Thai society to induce feelings of shame for Thai people living with HIV. Determination to stay healthy and incorporate taking cART into their daily routine were key components of good adherence. Supportive and trusting relationships, particularly with the clinic team, empowered patients to maintain good medication adherence. CONCLUSIONS: Changing public perceptions about HIV, and training of HIV clinic staff on the importance of trusting and supportive provider-patient relationships in promoting good health outcomes, will help Thailand achieve its aim of having zero new HIV infections, zero discrimination and zero AIDS-related deaths by 2030. PMID- 27482433 TI - Treatment outcomes of first-line antiretroviral therapy in HIV-1-positive patients in Serbia. AB - INTRODUCTION: Access to combination antiretroviral treatment (cART) and toxicity profiles of antiretroviral medications have significantly improved during the last three decades. In order to optimise treatment outcomes, achieve favourable virological suppression and immunological status, balanced with potential adverse effects of cART, it is considered beneficial to maintain first-line antiretroviral treatment for as long as possible. However, the Republic of Serbia, as a resource-limited setting, often experiences interruptions to drug supplies. Data are very limited in Serbia concerning the initial antiretroviral regimens prescribed and the reasons for treatment changes. AIMS: The aim of this study was to determine the most frequently prescribed antiretroviral drugs within first-line cART regimens in drug-naive patients in Serbia and the reasons for switching drugs. METHODS: All HIV-infected individuals who started cART at the HIV/AIDS Center of Infectious and Tropical Diseases, Clinical Centre of Serbia, from 1 January 2004 until 1 July 2014 were included. A cohort of 339 patients were retrospectively analysed to review their initial treatment regimens. All analyses were performed using the SPSS statistical package version 11.0. Descriptive measurements and Kaplan-Meier survival curves were used. RESULTS: The most frequently prescribed nucleoside reverse transcriptase inhibitor (NRTI) backbones in the cART regiment were fixed combinations of abacavir and lamivudine (n=181, 53.3%) and of zidovudine and lamivudine (n=103, 30.5%). Efavirenz was the most commonly prescribed 'third' drug (n=254, 75%). Where given, reasons for switching initial cART were shortage of antiretroviral drugs (e.g. out of stock, n=53, 37.6%), toxicity (n=49, 34.3%), physician choice (n=21, 14.6%), resistance (n=15, 10.6%), and patient choice (n=4, 2.9%). Mean duration of first-line cART was 20+/-17 months. CONCLUSION: The most frequently prescribed initial cART regimen in Serbia is not the preferred first choice, but an alternative option according to the international antiretroviral treatment guidelines. Duration of first-line cART is short and a switch to second-line cART is often made due to a shortage of antiretroviral medications and the more severe side effects resulting from the use of older drugs. PMID- 27482434 TI - Factors associated with HIV RNA viral loads in ART-naive patients: implications for treatment as prevention in concentrated epidemics. AB - BACKGROUND: Limited data are available on factors associated with HIV-RNA viral load (VL) among antiretroviral treatment (ART)-naive key populations in concentrated epidemics. METHODS: We conducted a cross-sectional survey of 1211 adult ART-naive patients at 19 HIV clinics in Ho Chi Minh City (HCMC), Vietnam. Data collection included a standardised questionnaire, routine laboratory testing, hepatitis serology and HIV VL. Correlation between CD4 cell count and VL was assessed across all participants. In 904 participants not meeting Vietnam criteria for ART (CD4 cell count >350 cells/mm(3), WHO clinical stage 1 or 2 and not pregnant), multivariate analyses were conducted to assess factors associated with HIV VL. RESULTS: Pre-ART patients had a median age of 31 years and 54% were male. Median CD4 cell count was 533 cells/mm(3). Median HIV VL was 17,378 copies/mL; 60% had VL greater than 10,000 copies/mL and 16% had VL above 100,000 copies/mL. Although declining CD4 cell count was correlated with rising VL across all CD4 cell counts, correlation of VL with CD4 cell counts between 351 and 500 cell/mm(3) was not significant. On multivariate linear regression, higher HIV VL was independently associated with male sex, men who have sex with men (MSM), CD4 cell count 351-500, HIV diagnosis within the previous 6 months, and hepatitis B (HBV). Lower HIV VL was independently associated with hepatitis C (HCV). CONCLUSIONS: The majority of HIV patients who were not eligible for ART in HCMC in 2014 had HIV VL greater than 10,000 copies/mL. These data support expanded eligibility of ART to all HIV patients with the goal of treatment as prevention. This study is also among the first to demonstrate that MSM had a higher VL than women and heterosexual men and highlights the need for improved outreach and linkages to HIV care for this high-risk group. PMID- 27482435 TI - Vertical transmission of hepatitis C: towards universal antenatal screening in the era of new direct acting antivirals (DAAs)? Short review and analysis of the situation in Switzerland. AB - At present, routine antenatal hepatitis C virus (HCV) screening is not recommended in pregnant women who do not have known risk factors for infection. The main reason for this attitude has been the lack of effective treatment options to avoid mother-to-child transmission (MTCT) during pregnancy or delivery. Hitherto available treatment regimens based on interferon (IFN) and ribavirin (RBV) were associated with sometimes long-lasting and severe side effects and thus their indication had to be carefully evaluated. In addition, ribavirin has teratogenic and embryocidal effects and is absolutely contraindicated during pregnancy. The situation has substantially changed with the advent of the newly available treatment regimens based on very effective and well-tolerated direct-acting antiviral agents (DAAs). The aim of this viewpoint is to briefly analyse, using the example of Switzerland, how recent developments in HCV therapy might impact prevention of HCV vertical transmission. PMID- 27482436 TI - Viral markers for HIV cure trials: are we getting any closer? PMID- 27482437 TI - Highlights from the Seventh International Workshop on HIV Persistence during Therapy, 8-11 December 2015, Miami, Florida, USA. AB - Over 4 days, more than 270 scientists involved in HIV persistence research convened to share their data and discuss future avenues to control HIV without continuous antiretroviral therapy. This 7(th) International Workshop on HIV Persistence followed the format of the preceding conferences but more time was given for discussing abstracts submitted by the participants and selected by the Steering and Scientific Committees. The topic of the workshop is HIV persistence: consequently, issues of HIV reservoirs and HIV cure are also addressed. In this article we report as closely as possible what was discussed. However, owing to length constraints, not everything is reported here but all the Workshop abstracts can be found online (www.viruseradication.com). PMID- 27482439 TI - The X awakens: multifactorial ramifications of sex-specific differences in HIV-1 infection. AB - Sex-specific differences have been described for a variety of infectious and autoimmune diseases. In HIV-1 infection women present with significantly lower viral loads during early infection, but during chronic infection women progress faster to AIDS for the same amount of viral replication. Recent studies have shown that sex differences during HIV-1 infection might also include the size of the latent viral reservoir, which represents a major obstacle towards a cure for HIV-1. Here we review different immunological and virological aspects that can be influenced by sex hormones and sex-specific genetic factors and their contribution to viral replication, as well as the creation and maintenance of the HIV-1 reservoir. PMID- 27482438 TI - What's new for antiretroviral treatment in women with HIV. AB - Currently, women represent 52% of persons infected with HIV worldwide and 23% of those in the United States. Combination antiretroviral therapy (cART) has resulted in remarkable reductions in HIV-associated morbidity and mortality, and has dramatically improved life expectancy. Treatment guidelines do not differ for HIV-infected men and non-pregnant women. However, clinical trials of antiretroviral agents have limited female enrolment, and results from these predominantly male studies are extrapolated to the female population. Furthermore, many of these studies do not report gender subgroup analyses, and those that do are underpowered to detect differences between men and women, limiting the ability to assess if results are equally applicable to both sexes. Women may have differential responses to and adverse events from cART. A limited number of female-only clinical trials have demonstrated that female recruitment and retention in these studies is feasible. Therefore, urgent attention is required to improve the body of knowledge regarding clinical efficacy, safety and tolerability of cART in women. In particular, women living with HIV are faced with various sexual and reproductive health concerns that may influence choice of cART. These include potential interactions with hormonal contraception, safety in pregnancy, and the impact of the transition through menopause and development of age-related comorbidities. Finally, the ongoing advances in biomedical HIV prevention, particularly pre-exposure prophylaxis (PrEP), provide an enormous opportunity to enhance HIV prevention in high-risk women, in efforts to further reduce global burden of the pandemic. PMID- 27482440 TI - Contraceptive challenges in adolescents living with or at risk of HIV. AB - Many adolescents living with or without HIV are sexually active and in need of continuous free access to a variety of contraceptive methods. Dual contraception, condom use together with reversible effective contraception (hormonal contraception [HC] or intrauterine device), seems to be the most effective option for female adolescents for protection from unintended pregnancy and sexually transmitted infections. When counselling on specific contraceptive choice, healthcare providers should be aware about possible interactions of some types of HC with the immune system, with possible changes in infectivity, as well as about drug interactions between mainly efavirenz and some types of progestins. Adding HC to HIV-positive status and antiretroviral therapy could have additive effects on metabolism. At the same time, the possible disadvantages of using HC in women living with HIV should be balanced against the advantages of very reliable methods of preventing unintended pregnancies. To reach and deliver a contraceptive service to more young women, it has proven effective to organise adolescent-friendly clinics and/or integrate them with HIV services. Diverse approaches, including community-based contraceptive service provision and the use of modern technologies, can complement the effort of providing contraceptive services to this target group of female adolescents living with HIV or at risk of HIV. PMID- 27482442 TI - Factors associated with HIV viral load suppression on antiretroviral therapy in Vietnam. AB - BACKGROUND: Limited data are available on HIV viral suppression rates among men and women on antiretroviral therapy (ART) and factors associated with HIV RNA viral load (VL) suppression in Vietnam. METHODS: We conducted a cross-sectional survey of 1255 adult patients on ART for at least 1 year across four provinces in Vietnam. Data collection included a standardised questionnaire, routine laboratory testing, and an HIV VL assay. Bivariate and logistic multivariate analyses were conducted to assess viral suppression rates and factors associated with unsuppressed HIV VL. RESULTS: The median age was 34.5 years and the median time on ART was 46 months. Gender was 66% male (n=828) and 34% female (n=427). HIV viral suppression below 1000 copies/mL was 93%. Viral suppression among woman was not significantly different than among men (93.7% vs 92.9%; P=0.59). On multivariate analysis, unsuppressed HIV VL was independently associated with lower CD4 cell count, social isolation, high stigma, not receiving a single tablet daily regimen, multiple late appointments in past year, and immunological failure. CONCLUSION: On-treatment viral load suppression rates in Vietnam are high and already exceed the UNAIDS 90% target for viral suppression on ART. Gender does not impact viral suppression rates of patients on ART in Vietnam. Access to routine viral load testing should be improved, adherence monitoring and counselling streamlined, and ART regimens simplified to maintain viral suppression rates, as more people start ART. Psychological and social factors are also associated with unsuppressed HIV VL, necessitating treatment support interventions to address social isolation and stigma among people living with HIV in Vietnam. PMID- 27482441 TI - Transgender populations and HIV: unique risks, challenges and opportunities. AB - Due to unique social, behavioural, structural and biological issues, transgender (TG) populations, especially TG women, are at high risk for HIV acquisition. This increased risk is multifactorial, due to differing psychosocial risk factors, poorer access to TG-specific healthcare, a higher likelihood of using exogenous hormones or fillers without direct medical supervision, interactions between hormonal therapy and antiretroviral therapy, and direct effects of hormonal therapy on HIV acquisition and immune control. Further research is needed to elucidate these mechanisms of risk and to help design interventions to reduce HIV risk among transgender populations. PMID- 27482444 TI - History of the prevention of mother-to-child transmission of HIV in Thailand. AB - Strategies for the prevention of mother-to-child transmission (PMTCT) of HIV have undergone considerable evolution based on scientific evidence, both at global and local levels. Because of the rapid expansion of the HIV epidemic among the heterosexual population, and the relatively advanced mother and child health infrastructure, Thailand has been the site of international study for more efficacious and cost-effective PMTCT regimens since mid-1990. The example of the Thai Red Cross Society in providing standard PMTCT care through public donations under the patronage of Her Royal Highness Princess Soamsawali is an example that non-governmental organisations in other countries can follow to accelerate access to standard PMTCT care. However, there are still many challenges before vertical transmission of HIV is completely eradicated. PMID- 27482443 TI - Response to hepatitis B vaccination among HIV-infected adults in Vietnam. AB - OBJECTIVES: We sought to determine the rate of response to hepatitis B (HBV) vaccination among HIV-infected adults in Vietnam. METHODS: We retrospectively abstracted data from a cohort of HIV-infected adults who had received HBV vaccine at an HIV clinic in Hanoi. We examined demographic, clinical and laboratory factors for associations with development of a protective antibody (Ab) response following vaccination (defined as 'responders' with anti-HBs >10 IU/L). RESULTS: Out of 302 HIV-infected patients who completed the vaccine series and follow-up serology testing, 189 (62.6%) had a positive protective Ab response. Female patients had a higher response rate compared to male patients (71.4% vs 56.8%, P=0.01). Among responders, mean CD4 T cell count was 309 cells/MUL as compared to 204 cells/MUL in non-responders (P<0.0001). On multivariable analysis, CD4 T cell count prior to vaccination was the only factor independently associated with a positive Ab response. Compared to patients with a count less than 100 cells/MUL, those with a CD4 T cell count between 100 and 200 cells/MUL were 20% more likely to be responders (relative risk [RR] 1.20, 95% confidence interval [CI] 0.77 1.87), those with a CD4 T cell count between 200 and 300 cells/MUL were 61% more likely to be responders (RR 1.61, 95% CI 1.05-2.45), and those with a CD4 T cell count greater than 300 cells/MUL were 89% more likely to be responders (RR 1.89, 95% CI 1.26-2.83). CONCLUSIONS: We found that the CD4 T cell count at the time of vaccination to be the sole predictor of response to HBV vaccination among HIV infected Vietnamese adults. Our findings highlight the importance of vaccinating HIV-infected adults prior to advanced immunosuppression. PMID- 27482445 TI - Ethical, strategic and meaningful involvement of women living with HIV starts at the beginning. AB - End-user involvement in HIV guidelines development is often little, late or absent. Other disciplines have long advocated 'handing over the stick' (i.e. power and control), as both ethical and strategic. Women HIV activists have called this respectful engagement with, and learning from, communities 'MIWA' (meaningful involvement of women living with HIV and AIDS). PMID- 27482446 TI - Human breast milk: is it the best milk to prevent HIV transmission? AB - A significant proportion of mother-to-child transmission (MTCT) of HIV still occurs during breastfeeding in settings where replacement feeding is unsafe and impractical. However, very few babies born to HIV-infected women and breastfed during the first 6 months of life become infected postnatally. The fact that the majority of babies who are breastfed by HIV-infected mothers remain uninfected even after several months of breastfeeding constitutes one of the major enigmas of HIV transmission via breast milk. PMID- 27482447 TI - The menopause transition in women living with HIV: current evidence and future avenues of research. AB - As the life expectancy of people living with HIV improves as a result of antiretroviral therapy, increasing numbers of women living with HIV (WLHIV) are now reaching menopausal age. The menopause transition in WLHIV remains a relatively overlooked area in clinical HIV research. Whilst there is some evidence to suggest that WLHIV experience menopause at an earlier age and that they have more menopausal symptoms, there is no clear consensus in the literature around an impact of HIV infection on either timing or symptomatology of the menopause. Data are also conflicting on whether HIV-related factors such as HIV viral load and CD4 cell count have an impact on the menopause. Furthermore, menopausal symptoms in WLHIV are known to go under-recognised by both healthcare providers and women themselves. There is likely to be a burden of unmet health needs among WLHIV transitioning through the menopause, with significant gaps in the evidence base for their care. With this in mind, we have developed the PRIME study (Positive Transitions Through the Menopause). This mixed-methods observational study will explore, for the first time in the UK, the impact of the menopause on the health and wellbeing of 1500 ethnically diverse WLHIV. In establishing a cohort of women in their midlife and following them up longitudinally, we hope to develop a nuanced understanding of the gendered aspects of ageing and HIV, informing the provision of appropriate services for WLHIV to ensure that they are supported in maintaining optimal health and wellbeing as they get older. PMID- 27482448 TI - Is there gender bias in HIV cure research? A case study of female representation at the 2015 HIV Persistence Workshop. PMID- 27482449 TI - The evolving role of interferons in viral eradication strategies. AB - Interferons (IFNs) are a family of pleiotropic cytokines that are released when viral infection is sensed by pattern recognition receptors. They induce an antiviral state in target cells through influencing the expression of hundreds of genes termed IFN-stimulated genes (ISGs), which interfere with the replication of viruses in wide-ranging ways, and they have stimulatory effects on antiviral cell mediated immunity. Although the role of therapeutic IFNs in the management of infectious diseases has predominantly been restricted to the treatment of chronic hepatotropic viruses, IFNs have effects on the replication of diverse families of viruses in cell culture models, and the potential to harness our endogenous defence system through therapeutic modulation of IFN pathways remains a tantalising prospect for both the broad-spectrum and tailored treatment of viral infections. Additionally, the study of the IFN system has become crucial to our understanding of host/pathogen molecular interactions, which provides plentiful targets for small molecule inhibitors of infection. Although the emergence of directly acting antivirals (DAAs) has resulted in the displacement of pegylated IFNalpha (pegIFNalpha) for the treatment of HCV, recent findings have suggested potential roles for IFNs and IFN-related therapies in HIV and HBV eradication strategies, opening up a new avenue of research for this important family of cytokines. PMID- 27482450 TI - Highlights from the Conference on Retroviruses and Opportunistic Infections 2016: 22-25 February 2016, Boston, Massachusetts, USA. PMID- 27482451 TI - Why CMV is a candidate for elimination and then eradication. AB - Cytomegalovirus (CMV) is well-known for the end organ diseases (EODs) it causes following viraemic dissemination in immunocompromised hosts. These are termed the direct effects of CMV, where a diagnosis can be made in an individual patient. In addition, CMV is associated with indirect effects where populations can be seen to be disadvantaged compared to those without CMV. These indirect effects have been described in solid organ transplants, bone marrow transplants, advanced HIV, people admitted to intensive care units, the elderly and the general population. We summarise the evidence that associates CMV with its direct effects following congenital infection, solid organ transplantation, bone marrow transplantation and advanced HIV as well as its indirect effects in all patient populations. We propose that the greatest worldwide burden of CMV comes from its indirect effects. Control of this infection at the population level is being sought through the development of vaccines to control EODs where cost effectiveness is expected. We propose that the financial case for universal immunisation will be enhanced even further by the potential benefits vaccines may produce against the indirect effects of CMV. PMID- 27482453 TI - Human cytomegalovirus and transplantation: drug development and regulatory issues. AB - Cytomegalovirus (CMV) infection is highly prevalent worldwide and can cause serious disease among immunocompromised individuals, including persons with HIV and transplant recipients on immunosuppressive therapies. It can also result in congenital cytomegalovirus when women are infected during pregnancy. Treatment and prevention of CMV in solid organ and haematopoietic stem cell transplant recipients is accomplished in one of three ways: (1) prophylactic therapy to prevent CMV viraemia; (2) pre-emptive therapy for those with low levels of replicating virus; and (3) treatment for established disease. Despite the high prevalence of CMV, there are few available approved drug therapies, and those that are available are hampered by toxicity and less-than-optimal efficacy. New therapies are being developed and tested; however, inconsistency in standardisation of virus levels and questions about potential endpoints in clinical trials present regulatory hurdles that must be addressed. This review covers the current state of CMV therapy, drugs currently under investigation, and clinical trial issues and questions that are in need of resolution. PMID- 27482452 TI - Human cytomegalovirus (CMV) in Africa: a neglected but important pathogen. AB - In Africa, human cytomegalovirus (CMV) is an important pathogen in a diverse range of patient groups. Congenital CMV infection is common, and most children undergo primary infection during the first year of life. Preliminary studies suggest that these early primary CMV infections could have population-wide effects on growth and development. In most studies of adults, CMV seroprevalence is close to 100%, but some studies have found that significant minorities of adults are seronegative. CMV is a common cause of pneumonia and meningitis in hospitalised immunosuppressed patient groups, and CMV DNAemia may be an important marker of rapid progression and poor outcomes of HIV infection, despite roll-out of antiretroviral therapy (ART). Diagnosis and treatment of CMV-related disease is broadly neglected in Africa, and no randomised clinical trials of anti-CMV drugs have been conducted to date. Autopsy is rarely performed in Africa, but identifies CMV as a frequent pathogen when it is carried out. Here we review the available literature on CMV in Africa, primarily in adult patients, and discuss this in the context of contemporary understanding of CMV as a human pathogen. PMID- 27482454 TI - HIV pre-exposure prophylaxis for women. AB - Women and girls comprise nearly half of HIV-infected individuals globally and 20% of new infections in the United States, indicating an urgent need to optimise HIV prevention options in this population. HIV pre-exposure prophylaxis (PrEP) - where antiretrovirals are administered to HIV-non-infected individuals at risk of HIV acquisition - is a promising, female-controlled HIV prevention strategy but has so far been underutilised in women. Clinical trial data demonstrate efficacy of daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for reduction of HIV acquisition among women when used consistently. Limited HIV risk perception and suboptimal PrEP awareness among women and healthcare personnel are among the challenges with PrEP delivery for women. Future research into the development of new drugs and delivery systems, and integrating PrEP delivery with reproductive healthcare services, provide opportunities to optimise this prevention strategy for women. PMID- 27482455 TI - The growing HIV epidemic in Central Europe: a neglected issue? AB - The number of new cases of HIV infection has been decreasing in some parts of the world (e.g. sub-Saharan Africa) with the highest burden of disease in recent years. However, other regions are showing a different trend, such as Eastern Europe, the Middle East, North Africa and Central Asia. This trend seems also to apply to the Central European region. This article analyses HIV data for Central Europe derived from annual surveillance reports of the European Centre for Disease Prevention and Control (ECDC) and gives an overview of the recent status of the epidemic in this specific region. We show that, although still at a low level, the HIV epidemic in Central Europe continues to grow and requires more resources and interventions to curtail the ongoing epidemic. PMID- 27482456 TI - Diagnostic utility of droplet digital PCR for HIV reservoir quantification. AB - Quantitative real-time PCR (qPCR) is implemented in many molecular laboratories worldwide for the quantification of viral nucleic acids. However, over the last two decades, there has been renewed interest in the concept of digital PCR (dPCR) as this platform offers direct quantification without the need for standard curves, a simplified workflow and the possibility to extend the current detection limit. These benefits are of great interest in terms of the quantification of low viral levels in HIV reservoir research because changes in the dynamics of residual HIV reservoirs will be important to monitor HIV cure efforts. Here, we have implemented a systematic literature screening and text mining approach to map the use of droplet dPCR (ddPCR) in the context of HIV quantification. In addition, several technical aspects of ddPCR were compared with qPCR: accuracy, sensitivity, precision and reproducibility, to determine its diagnostic utility. We have observed that ddPCR was used in different body compartments in multiple HIV-1 and HIV-2 assays, with the majority of reported assays focusing on HIV-1 DNA-based applications (i.e. total HIV DNA). Furthermore, ddPCR showed a higher accuracy, precision and reproducibility, but similar sensitivity when compared to qPCR due to reported false positive droplets in the negative template controls with a need for standardised data analysis (i.e. threshold determination). In the context of a low level of detection and HIV reservoir diagnostics, ddPCR can offer a valid alternative to qPCR-based assays but before this platform can be clinically accredited, some remaining issues need to be resolved. PMID- 27482458 TI - The use of HIV-1 integration site analysis information in clinical studies aiming at HIV cure. AB - The mechanisms for the establishment and the persistence of the latent HIV-1 reservoir remain to be completely defined. HIV-1 infection is characterised by the integration of the reverse transcribed proviral DNA into the host's genome. This integrated proviral DNA can remain replication silent, but a small part of it is fully competent to restart viral replication when treatment is interrupted. Hence, this replication-competent provirus is the cause of viral rebound and is called the viral reservoir. The exact site of proviral integration within the host's cellular chromosome may affect the transcriptional activity of HIV. Thanks to recent technological advances, HIV-1 integration site analysis has been used to assess HIV-1 reservoirs in HIV-infected individuals. Analysis of HIV-1 integration sites in infected individuals undergoing suppressive ART led to identification of expanded clonal cell populations, indicating that clonal proliferation of the proviral reservoir may contribute to the long-term persistence of viral reservoirs. Here we describe the findings of several clinical studies, where a comprehensive HIV-1 integration site analysis was performed. PMID- 27482457 TI - 'I can coexist with HIV': a qualitative study of perceptions of HIV cure among people living with HIV in Guangzhou, China. AB - Little is known about perceptions of HIV cure among people living with HIV (PLHIV), despite them being crucial stakeholders in ongoing HIV cure research. A qualitative research study was conducted in Guangzhou, China, to explore the perceptions of HIV cure among PLHIV in relation to their views on HIV treatment, stigma and social identity. We conducted in-depth interviews with 22 PLHIV from September 2014 to June 2015. Our qualitative data revealed three major themes: (1) Representations of HIV cure: PLHIV generally thought HIV cure was distant from them; (2) Possibility of HIV cure: ideas about the possibility of HIV cure ranged from optimism to scepticism and pessimism; and (3) Life without HIV cure: some participants had adjusted well to the chronic condition of HIV and ART adherence. Although some PLHIV looked forward to HIV being cured, most of the PLHIV in our study had little interest in it. On the contrary, many felt it is more important and realistic to have access to better ART medication and more education for the general public to decrease HIV stigma today rather than develop a cure for tomorrow. PMID- 27482459 TI - The difficulties of 'living while girl'. AB - In this Viewpoint, Judith Bruce answers questions from Journal of Virus Eradication Editor, Sabine Kinloch-de Loes, on the importance of fulfilling the basic human rights of adolescent girls and their relationship with viral epidemics such as HIV. Judith Bruce is a graduate of Harvard University and a Senior Associate and Policy Analyst at the Population Council, New York, USA, whose work is aimed at building the health, social and cognitive assets of girls in the poorest communities in the developing world. PMID- 27482460 TI - Immune checkpoints and the HIV-1 reservoir: proceed with caution. PMID- 27482461 TI - Highlights from the 2016 International Symposium on HIV & Emerging Infectious Diseases (ISHEID): 25-27 May, Marseille, France. AB - For three days in May 2016, the International Symposium on HIV & Emerging Infectious Diseases gathered participants from all over the world around the theme 'Fighting deadly viruses'. HIV infection remained the main topic of the meeting but hepatitis, Ebola and Zika viruses as well as other emergent pathogens were also extensively covered. In this article we have tried to summarise what was presented during the plenary lectures, the two keynote lectures, and some of the work accepted for oral presentation. However, all abstracts can be found on the Journal of Virus Eradication website ( viruseradication.com/abstract.php). PMID- 27482462 TI - Accelerating degradation rate of pure iron by zinc ion implantation. AB - Pure iron has been considered as a promising candidate for biodegradable implant applications. However, a faster degradation rate of pure iron is needed to meet the clinical requirement. In this work, metal vapor vacuum arc technology was adopted to implant zinc ions into the surface of pure iron. Results showed that the implantation depth of zinc ions was about 60 nm. The degradation rate of pure iron was found to be accelerated after zinc ion implantation. The cytotoxicity tests revealed that the implanted zinc ions brought a slight increase on cytotoxicity of the tested cells. In terms of hemocompatibility, the hemolysis of zinc ion implanted pure iron was lower than 2%. However, zinc ions might induce more adhered and activated platelets on the surface of pure iron. Overall, zinc ion implantation can be a feasible way to accelerate the degradation rate of pure iron for biodegradable applications. PMID- 27482463 TI - Hydrogen peroxide detection with high specificity in living cells and inflamed tissues. AB - Hydrogen peroxide (H2O2) detection in biological systems is of significant importance, which act as critical second messenger in fundamental biological processes. Here, we report on a chemoselective fluorescent naphthylimide peroxide probe (NPP) for the H2O2 detection in vitro and in vivo. NPP is a phenylboronic acid-caged chromophore that selectively responds to H2O2 through a self-immolate mechanism. NPP exhibited high sensitivity and selectivity to H2O2 with distinctive fluorescence change due to the excellent two-photon excitation property, which permits the facile detection of inflammation produced H2O2 and offers chance to monitor the inflammatory stages in diseased cells. PMID- 27482465 TI - Preparation and characterization of a degradable magnesium phosphate bone cement. AB - A kind of degradable magnesium phosphate bone cement (MPBC) was fabricated by using the mixed powders of magnesium oxide (MgO), potassium dihydrogen phosphate (KH2PO4) and calcium dihydrogen phosphate (Ca(H2PO4)2.H2O). As MgKPO4, the main product of MgO and KH2PO4 was alkaline, the Ca(H2PO4)2.H2O was added to neutralize the alkali of the system. And the effects of Ca(H2PO4)2.H2O on the performance of MPBC were discussed. The results showed that the adding of Ca(H2PO4)2.H2O extended the setting time, which was about 6 min to 18 min. The compressive strength increased first and then decreased, and maximum value reached 31.2 MPa after setting for 24 h without any additional pressure. The MPBC was degradable in Tris-HCl solution, and the extracts of the cytotoxicity assay showed that the MPBC had good biocompatibility, indicating that the MPBC had good biodegradable and biocompatible properties. PMID- 27482464 TI - Reduction of polyethylenimine-coated iron oxide nanoparticles induced autophagy and cytotoxicity by lactosylation. AB - Superparamagnetic iron oxide (SPIO) nanoparticles are excellent magnetic resonance contrast agents and surface engineering can expand their applications. When covered with amphiphilic alkyl-polyethyleneimine (PEI), the modified SPIO nanoparticles can be used as MRI visible gene/drug delivery carriers and cell tracking probes. However, the positively charged amines of PEI can also cause cytotoxicity and restricts their further applications. In this study, we used lactose to modify amphiphilic low molecular weight polyethylenimine (C12-PEI2K) at different lactosylation degree. It was found that the N-alkyl-PEI-lactobionic acid wrapped SPIO nanocomposites show better cell viability without compromising their labelling efficacy as well as MR imaging capability in RAW 264.7 cells, comparing to the unsubstituted ones. Besides, we found the PEI induced cell autophagy can be reduced via lactose modification, indicating the increased cell viability might rely on down-regulating autophagy. Thus, our findings provide a new approach to overcome the toxicity of PEI wrapped SPIO nanocomposites by lactose modification. PMID- 27482466 TI - Electrospun silk fibroin/poly (L-lactide-epsilon-caplacton) graft with platelet rich growth factor for inducing smooth muscle cell growth and infiltration. AB - The construction of a smooth muscle layer for blood vessel through electrospinning method plays a key role in vascular tissue engineering. However, smooth muscle cells (SMCs) penetration into the electrospun graft to form a smooth muscle layer is limited due to the dense packing of fibers and lack of inducing factors. In this paper, silk fibroin/poly (L-lactide-epsilon-caplacton) (SF/PLLA-CL) vascular graft loaded with platelet-rich growth factor (PRGF) was fabricated by electrospinning. The in vitro results showed that SMCs cultured in the graft grew fast, and the incorporation of PRGF could induce deeper SMCs infiltrating compared to the SF/PLLA-CL graft alone. Mechanical properties measurement showed that PRGF-incorporated graft had proper tensile stress, suture retention strength, burst pressure and compliance which could match the demand of native blood vessel. The success in the fabrication of PRGF-incorporated SF/PLLA CL graft to induce fast SMCs growth and their strong penetration into graft has important application for tissue-engineered blood vessels. PMID- 27482468 TI - Integrative genomics analyses unveil downstream biological effectors of disease specific polymorphisms buried in intergenic regions. AB - Functionally altered biological mechanisms arising from disease-associated polymorphisms, remain difficult to characterize when those variants are intergenic, or, fall between genes. We sought to identify shared downstream mechanisms by which inter- and intragenic single nucleotide polymorphisms (SNPs) contribute to a specific physiopathology. Using computational modeling of 2 million pairs of disease-associated SNPs drawn from genome wide association studies (GWAS), integrated with expression Quantitative Trait Loci (eQTL) and Gene Ontology functional annotations, we predicted 3,870 inter-intra and inter intra SNP pairs with convergent biological mechanisms (FDR<0.05). These prioritized SNP pairs with overlapping mRNA targets or similar functional annotations were more likely to be associated with the same disease than unrelated pathologies (OR>12). We additionally confirmed synergistic and antagonistic genetic interactions for a subset of prioritized SNP pairs in independent studies of Alzheimer's disease (entropy p=0.046), bladder cancer (entropy p=0.039), and rheumatoid arthritis (PheWAS case-control p<10-4). Using ENCODE datasets, we further statistically validated that the biological mechanisms shared within prioritized SNP pairs are frequently governed by matching transcription factor binding sites and long-range chromatin interactions. These results provide a "roadmap" of disease mechanisms emerging from GWAS and further identify candidate therapeutic targets among downstream effectors of intergenic SNPs. PMID- 27482469 TI - Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression. AB - Hormonal-receptor positive (HRP) breast cancer patients with positive metastatic axillary lymph nodes are characterized by poor prognosis and increased mortality rate. The mechanisms by which cancer cells invade lymph nodes have not yet been fully explored. Several studies have shown that expression of IL-6 and the proteolytic enzyme cathepsin B (CTSB) was associated with breast cancer poor prognosis. In the present study, the effect of different concentrations of recombinant human IL-6 on the invasiveness capacity of HRP breast cancer cell line MCF-7 was tested using an in vitro invasion chamber assay. The impact of IL 6 on expression and activity of CTSB was also investigated. IL-6 treatment promoted the invasiveness potential of MCF-7 cells in a dose-dependent manner. Furthermore, MCF-7 cells displayed elevated CTSB expression and activity associated with loss of E-cadherin and upregulation of vimentin protein levels upon IL-6 stimulation. To validate these results in vivo, the level of expression of IL-6 and CTSB in the carcinoma tissues of HRP-breast cancer patients with positive and negative axillary metastatic lymph nodes (pLNs and nLNs) was assessed. Western blot and immunohistochemical staining data showed that expression of IL-6 and CTSB was higher in carcinoma tissues in HRP-breast cancer with pLNs than those with nLNs patients. ELISA results showed carcinoma tissues of HRP-breast cancer with pLNs exhibited significantly elevated IL-6 protein levels by approximately 2.8-fold compared with those with nLNs patients (P < 0.05). Interestingly, a significantly positive correlation between IL-6 and CTSB expression was detected in clinical samples of HRP-breast cancer patients with pLNs (r = 0.78, P < 0.01). Collectively, this study suggests that IL-6-induced CTSB may play a role in lymph node metastasis, and that may possess future therapeutic implications for HRP-breast cancer patients with pLNs. Further studies are necessary to fully identify IL-6/CTSB axis in different molecular subtypes of breast cancer. PMID- 27482467 TI - High shear stress induces atherosclerotic vulnerable plaque formation through angiogenesis. AB - Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes. Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts. Shear stress (SS) influences the formation and development of atherosclerosis. The current review focuses on the vulnerable plaques observed in the high shear stress (HSS) regions, which localizes at the proximal region of the plaque intruding into the lumen. The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation. These results greatly challenge the established belief that low shear stress is important for expansive remodelling, which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions. PMID- 27482470 TI - Teen Dating Violence Prevention: Cluster-Randomized Trial of Teen Choices, an Online, Stage-Based Program for Healthy, Nonviolent Relationships. AB - OBJECTIVE: Teen dating violence is a serious public health problem. A cluster randomized trial was conducted to assess the efficacy of Teen Choices, a 3 session online program that delivers assessments and individualized guidance matched to dating history, dating violence experiences, and stage of readiness for using healthy relationship skills. For high risk victims of dating violence, the program addresses readiness to keep oneself safe in relationships. METHOD: Twenty high schools were randomly assigned to the Teen Choices condition (n=2,000) or a Comparison condition (n=1,901). Emotional and physical dating violence victimization and perpetration were assessed at 6 and 12 months in the subset of participants (total n=2,605) who reported a past-year history of dating violence at baseline, and/or who dated during the study. RESULTS: The Teen Choices program was associated with significantly reduced odds of all four types of dating violence (adjusted ORs ranging from .45 to .63 at 12 months follow-up). For three of the four violence outcomes, participants with a past-year history of that type of violence benefited significantly more from the intervention than students without a past-year history. CONCLUSIONS: The Teen Choices program provides an effective and practicable strategy for intervention for teen dating violence prevention. PMID- 27482471 TI - Multimodal Imaging of the White Dot Syndromes and Related Diseases. AB - The white dot syndromes encompass a group of rare posterior uveitis conditions that are characterized by outer retinal and/or choroidal hypopigmented lesions that are thought to be inflammatory in nature. The size, shape, and location of lesions in the fundus aid in differentiating these conditions. Multimodal imaging, including modalities such as fundus autofluorescence, optical coherence tomography, fluorescein angiography, and indocyanine green angiography, among others, has become integral in diagnosing and monitoring many of the white dot syndromes. Furthermore, multimodal imaging modalities have provided insights into the pathogenesis and exact sites within the retina and choroid affected by white dot syndromes. PMID- 27482473 TI - A New MI-Based Visualization Aided Validation Index for Mining Big Longitudinal Web Trial Data. AB - Web-delivered clinical trials generate big complex data. To help untangle the heterogeneity of treatment effects, unsupervised learning methods have been widely applied. However, identifying valid patterns is a priority but challenging issue for these methods. This paper, built upon our previous research on multiple imputation (MI)-based fuzzy clustering and validation, proposes a new MI-based Visualization-aided validation index (MIVOOS) to determine the optimal number of clusters for big incomplete longitudinal Web-trial data with inflated zeros. Different from a recently developed fuzzy clustering validation index, MIVOOS uses a more suitable overlap and separation measures for Web-trial data but does not depend on the choice of fuzzifiers as the widely used Xie and Beni (XB) index. Through optimizing the view angles of 3-D projections using Sammon mapping, the optimal 2-D projection-guided MIVOOS is obtained to better visualize and verify the patterns in conjunction with trajectory patterns. Compared with XB and VOS, our newly proposed MIVOOS shows its robustness in validating big Web trial data under different missing data mechanisms using real and simulated Web trial data. PMID- 27482472 TI - Osteoporosis Imaging in the Geriatric Patient. AB - Given the expected rapid growth of the geriatric world population (=individuals aged >65 years) to 1.3 billion by 2050, age-related diseases such as osteoporosis and its sequelae, osteoporotic fractures, are on the rise. Areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) is the current gold standard to diagnose osteoporosis, to assess osteoporotic fracture risk, and to monitor treatment-induced BMD changes. However, most fragility fractures occur in patients with normal or osteopenic aBMD, indicating that factors beyond BMD impact bone strength. Recent developments in DXA technology such as TBS, VFA, and hip geometry analysis are now available to assess some of these non-BMD parameters from the DXA image. This review will discuss the use of DXA and DXA assisted technologies and their respective advantages and disadvantages. Special attention is given to if and how each method is indicated in the geriatric population, and the latest ISCD 2015 guidelines have been incorporated. PMID- 27482474 TI - Management of Senile Ptosis with Levator Muscle Resection Using the Putterman Clamp. AB - Putterman clamp, a muscle clamp, is commonly used in conjunctival mullerectomies. We report 3 cases of senile ptosis repaired with levator muscle resection using the Putterman clamp. The redundant levator aponeurosis was removed with electrocautery after clamping with the Putterman clamp. The levator muscle was refixed to the tarsus with three 4-0 Vicryl stitches after adjusting the height of the eyelid fissure. No intraoperative difficulties were encountered. Ecchymosis and edema were limited in the immediate postoperative period. No complications were noted during the follow-up. The benefits of using the Putterman clamp in levator muscle resection are illustrated in these cases. PMID- 27482475 TI - Predictive Factors for Drainage Volume after Expander-based Breast Reconstruction. AB - BACKGROUND: Closed suction drains are widely used in breast reconstruction, and the drains are removed based on a volume criterion. However, to the best of our knowledge, there has been no study analyzing predictive factors for drainage volume after breast reconstruction. METHODS: Data of daily drainage in cases with expander-based breast reconstruction between February 2013 and March 2015 (131 patients and 134 expanders) were retrospectively analyzed. Patient factors and operative factors were examined for their influences on total drainage using univariate and multivariate analyses. RESULTS: The total drainage was 557.3 +/- 359.7 mL. A strong correlation was observed between total drainage and duration of drains (correlation coefficient, 0.908). Operative factors, such as mastectomy type, expander type, operative time, and blood loss, did not affect the total drainage. Patients with axillary lymph node dissection showed a higher total volume of drainage (P < 0.001). The weight of the resected specimen, body weight, and breast volume calculated preoperatively showed a strong correlation with total drainage (correlation coefficients, 0.454, 0.388, and 0.345, respectively). In multiple regression analysis with preoperative data, age (P = 0.008), body weight (P = 0.018), and scheduled axillary dissection (P < 0.001) were significant predictive factors for total drainage. Among postoperative data, age (P = 0.003), axillary dissection (P = 0.032), and weight of resected specimen (P = 0.013) were significant predictors. CONCLUSIONS: Based on preoperative and/or postoperative information, plastic surgeons can predict the total drainage and duration of drains after expander-based breast reconstruction. Age, breast mass, and axillary lymph node dissection are important factors for this prediction. PMID- 27482476 TI - Thoracic Outlet Syndrome: Past and Present-88 Surgeries in 30 Years at Chang Gung. AB - BACKGROUND: Thoracic outlet syndrome (TOS) is a highly controversial clinical entity. There is much debate on its terminology, existence, diagnosis, and treatment. The purpose of this study was to describe our opinions about these controversial topics of TOS and the treatment of TOS over the past 30 years. METHODS: From 1985 to 2014, a total of 80 patients underwent decompressive surgery for TOS. Eight patients requested a second surgery on the contralateral limb. They all had at least 1-year follow-up. Preoperative evaluation included provocative tests, plain X-ray, magnetic resonance angiography/computed tomography angiography, and electromyography. Surgical intervention for each patient involved a supraclavicular approach and near-total resection of the anterior scalene muscle and the first rib and of any cervical rib if it was present. Rib resection was performed with the use of Kerrison bone punch forceps. The operative time was typically 2 hours. RESULTS: Major postoperative complications were rare. Nearly all patients (98%) experienced significant symptom relief, with improvement in soreness and tightness of the shoulder, neck, and arm immediately on the first postoperative day or within a few weeks thereafter. There were no cases with symptoms recurring. CONCLUSIONS: It is evident that decompressive surgery through a supraclavicular approach for TOS not only is an effective and safe procedure but also provides a diagnosis of the cause of TOS. For a patient who meets the criteria for surgical indication, decompressive surgery usually results in resolution of symptoms and no recurrence. PMID- 27482477 TI - Large Ganglion Cyst with Unusual Location on the Back-A Case Report. AB - A ganglion cyst is a soft tissue tumor-like lesion filled with colloid material commonly located on the hand and wrist. We report a case of a large ganglion cyst with an unusual location on the back. The patient presented with a mass growing over 2 months measuring 11.2 * 4.7 * 7.2 cm on magnetic resonance imaging. Ultrasound and puncture was attempted twice without achieving drainage. After surgical removal, histologic examination diagnosed the tumor as a ganglion cyst. We conclude that when evaluating a subcutaneous soft tissue mass, regardless of localization, a ganglion cyst may be a differential diagnosis. PMID- 27482478 TI - Repair of Fingertip Defect Using an Anterograde Pedicle Flap Based on the Dorsal Perforator. AB - BACKGROUND: The purposes of this article are to introduce and assess the results of a long-term follow-up of using anterograde pedicle flap based on the dorsal branches of proper digital neurovascular bundles from the dorsum of the middle phalanx for the fingertip defect. METHODS: Between February 2011 and December 2012, 31 patients underwent reconstruction of fingertip defects using a homodigital flap based on the dorsal perforator in the middle phalanx. The defect size ranged from 1.3 cm * 1.5 cm to 2.4 cm * 3.0 cm. During surgery, the flap was designed on the dorsal middle phalangeal region. The pedicle was a neurovascular bundle consisting of an artery, vein, and sensory nerve; the rotation of pedicle was <90 degrees. RESULTS: The clinical results were satisfactory after 3 to 9 months of follow-up. The flaps were considered cosmetically acceptable by both patients and doctors. The sensory recovery was excellent, 2-point discrimination was 4.96 +/- 1.47 mm, and the recovery of range of motion of the interphalangeal joints was very good. CONCLUSIONS: The anterograde island flap based on the dorsal branches of proper digital neurovascular bundles is an ideal aesthetic reconstruction method for fingertip defect. A 90-degree rotated island pedicle flap was very versatile, easy to design, and had good survival. This technique is simple with less damage to the donor site, without sacrificing the branch of the digital artery and nerve. The reliable source of blood supply and satisfactory recovery of sensation can be achieved without affecting the interphalangeal joint activity. PMID- 27482479 TI - Bioengineered Self-assembled Skin as an Alternative to Skin Grafts. AB - For patients with extensive burns or donor site scarring, the limited availability of autologous and the inevitable rejection of allogeneic skin drive the need for new alternatives. Existing engineered biologic and synthetic skin analogs serve as temporary coverage until sufficient autologous skin is available. Here we report successful engraftment of a self-assembled bilayered skin construct derived from autologous skin punch biopsies in a porcine model. Dermal fibroblasts were stimulated to produce an extracellular matrix and were then seeded with epidermal progenitor cells to generate an epidermis. Autologous constructs were grafted onto partial- and full-thickness wounds. By gross examination and histology, skin construct vascularization and healing were comparable to autologous skin grafts and were superior to an autologous bilayered living cellular construct fabricated with fibroblasts cast in bovine collagen. This is the first demonstration of spontaneous vascularization and permanent engraftment of a self-assembled bilayered bioengineered skin that could supplement existing methods of reconstruction. PMID- 27482480 TI - Salvaging the Infected Breast Tissue Expander: A Standardized Multidisciplinary Approach. AB - BACKGROUND: Infections of breast tissue expander (TE) are complex, often requiring TE removal and hospitalization, which can delay further adjuvant therapy and add to the overall costs of breast reconstruction. Therefore, to reduce the rate of TE removal, hospitalization, and costs, we created a standardized same-day multidisciplinary outpatient quality improvement protocol for diagnosing and treating patients with early signs of TE infection. METHODS: We prospectively evaluated 26 consecutive patients who developed a surgical site infection between February 2013 and April 2014. On the same day, patients were seen in the Plastic Surgery and Infectious Diseases clinics, underwent breast ultrasonography with or without periprosthetic fluid aspiration, and were prescribed a standardized empiric oral or intravenous antimicrobial regimen active against biofilm-embedded microorganisms. All patients were managed as per our established treatment algorithm and were followed up for a minimum of 1 year. RESULTS: TEs were salvaged in 19 of 26 patients (73%). Compared with TE-salvaged patients, TE-explanted patients had a shorter median time to infection (20 vs 40 days; P = 0.09), a significantly higher median temperature at initial presentation [99.8 degrees F; interquartile range (IQR) = 2.1 vs 98.3 degrees F; IQR = 0.4 degrees F; P = 0.01], and a significantly longer median antimicrobial treatment duration (28 days; IQR = 27 vs 21 days; IQR = 14 days; P = 0.05). The TE salvage rates of patients whose specimen cultures yielded no microbial growth, Staphylococcus species, and Pseudomonas were 92%, 75%, and 0%, respectively. Patients who had developed a deep-seated pocket infection were significantly more likely than those with superficial cellulitis to undergo TE explantation (P = 0.021). CONCLUSIONS: Our same-day multidisciplinary diagnostic and treatment algorithm not only yielded a TE salvage rate higher than those previously reported but also decreased the rate of hospitalization, decreased overall costs, and identified several clinical scenarios in which TE explantation was likely. PMID- 27482481 TI - Caprini Scores, Risk Stratification, and Rivaroxaban in Plastic Surgery: Time to Reconsider Our Strategy. AB - Limited data are available regarding the pathophysiology of venous thromboembolism in plastic surgery patients. In an effort to identify patients at greater risk, some investigators promote individual risk assessment using Caprini scores. However, these scores do not correlate with relative risk values. Affected patients cannot be reliably predicted (97% false positive rate). Caprini scores make many body contouring patients candidates for chemoprophylaxis, an intervention that introduces risks related to anticoagulation. Caprini has financial conflicts with several companies that manufacture products such as enoxaparin, commonly used for chemoprophylaxis. Rivaroxaban, taken orally, has been used by some plastic surgeons as an alternative to enoxaparin injections. However, this medication is not United States Food and Drug Administration approved for venous thromboembolism prophylaxis in plastic surgery patients, and a reversal agent is unavailable. This article challenges the prevailing wisdom regarding individual risk stratification and chemoprophylaxis. Alternative methods to reduce risk for all patients include safer anesthesia methods and Doppler ultrasound surveillance. Clinical findings alone are unreliable in diagnosing deep venous thromboses. Only by using a reliable diagnostic tool such as Doppler ultrasound are we able to learn more about the natural history of this problem in our patients. Such knowledge is likely to better inform our treatment recommendations. PMID- 27482483 TI - Surgical Delay Facilitates Pedicled Nipple-sparing Mastectomy and Reconstruction in the Ptotic Patient. AB - Significant ptosis is a relative contraindication for nipple-sparing mastectomy and reconstruction. Repositioning of the nipple on the reconstructed breast is best accomplished using a pedicled approach that is risky in the immediate setting. We utilized a surgical delay before reconstruction that allowed for repositioning of the nipple-areola complex on an inferior pedicle. This also allows for resizing of the nipple-areola complex, reliable complete coverage of the prosthesis with viable tissue, and creation of an ideal skin envelope in patients with skin excess. Here, we present the first description of a surgical delay to facilitate pedicled nipple-sparing mastectomy and reconstruction. PMID- 27482482 TI - Gynecomastia Management: An Evolution and Refinement in Technique at UT Southwestern Medical Center. AB - Gynecomastia is a benign proliferation of male breast glandular tissue. Gynecomastia can affect men at any stage of life. Traditional treatment options involved excisional surgeries with periareolar or T-shaped scars, which can leave more visible scars on the chest. The technique presented represents a technique used by the senior author, which relies on ultrasonic liposuction and pull through technique to remove breast tissue. A retrospective chart review was performed, including all patients who were treated, from 2000 to 2013 by the senior author, for gynecomastia. A deidentified database was created to record patient characteristics, including age, height, weight, ptosis, stage of gynecomastia, and gynecomastia classification. Surgical approaches, complications, and revisions were also recorded. Our experience includes 75 patients with all grades of gynecomastia from 2000 to 2013. These cases span the evolution of our technique to include direct pull-through excision with ultrasound-assisted liposuction. The distribution of the grades I, II, III, and IV ptosis was 30.6%, 36 %, 22.6%, and 10.6% respectively. There were no complications in this series. Only one patient with grade III ptosis required revision surgery. This technique provides a safe and aesthetically pleasing way to treat gynecomastia with a low need for revision. PMID- 27482484 TI - An Unusual Case Presentation of the May-Thurner Syndrome. AB - A 56-year-old woman underwent abdominoplasty with no immediate complications. She had no known bleeding history nor any relevant past surgical history. Adequate preventive measures for venous thromboembolism were performed, including sequential compression devices, good hydration, and early ambulation. At 17 days post operation, the patient presented to the emergency room complaining of left leg swelling and sharp, shooting pain radiating down her left leg. Workup in the Emergency Room revealed significant venous thrombosis involving complete occlusion of the major veins of the left leg. There were no indications of cardiopulmonary compromise. Angiography revealed an anatomical variant consistent with May-Thurner Syndrome (MTS). This variant first described in 1957 may present in up to one-quarter of patients, more commonly in young women. This case appears to the first reported of MTS occurring in association with a postoperative complication of abdominoplasty. Diagnosis and management considerations are discussed. PMID- 27482485 TI - An Inexpensive Bismuth-Petrolatum Dressing for Treatment of Burns. AB - BACKGROUND: Xeroform remains the current standard for treating superficial partial-thickness burns but can be prohibitively expensive in developing countries with prevalent burn injuries. This study (1) describes the production of an alternative low-cost dressing and (2) compares the alternative dressing and Xeroform using the metrics of cost-effectiveness, antimicrobial activity, and biocompatibility in vitro, and wound healing in vivo. METHODS: To produce the alternative dressing, 3% bismuth tribromophenate powder was combined with petroleum jelly by hand and applied to Kerlix gauze. To assess cost effectiveness, the unit costs of Xeroform and components of the alternative dressing were compared. To assess antimicrobial properties, the dressings were placed on agar plated with Escherichia coli and the Kirby-Bauer assay performed. To assess biocompatibility, the dressings were incubated with human dermal fibroblasts and cells stained with methylene blue. To assess in vivo wound healing, dressings were applied to excisional wounds on rats and the rate of re epithelialization calculated. RESULTS: The alternative dressing costs 34% of the least expensive brand of Xeroform. Antimicrobial assays showed that both dressings had similar bacteriostatic effects. Biocompatibility assays showed that there was no statistical difference (P < 0.05) in the cytotoxicity of Xeroform, alternative dressing, and Kerlix gauze. Finally, the in vivo healing model showed no statistical difference (P < 0.05) in mean re-epithelialization time between Xeroform (13.0 +/- 1.6 days) and alternative dressing (13.5 +/- 1.0 days). CONCLUSIONS: Xeroform is biocompatible, reduces infection, and enhances healing of burn wounds by preventing desiccation and mechanical trauma. Handmade petrolatum gauze may be a low-cost replacement for Xeroform. Future studies will focus on clinical trials in burn units. PMID- 27482486 TI - Disparate British Breast Reconstruction Utilization: Is Universal Coverage Sufficient to Ensure Expanded Care? AB - Our intent is to improve the understanding of the ability of healthcare providers to deliver high-quality care as we approach an era of universal coverage. We adopted 2 unique vantage points in this article: (1) the mandated coverage for immediate breast reconstruction (IBR) surgery as a microcosmic surrogate for universal coverage overall and (2) we then scrutinized the respective IBR utilization rates in a contemporaneous system of 2 healthcare delivery models in the United Kingdom, that is, the public National Health Service trust versus private-sector hospitals. A literature review was performed for IBR rates across public trust and private-sector hospitals in the United Kingdom. The IBR rate among public trust hospitals was 17% compared with 43% in the private sector. In the trust hospital setting, the enactment of 2 government mandates, intended to increase the access to cancer care, seemed to fall short in maximizing the ability of surgical practitioners to deliver quality care to patients. Among women who did not receive IBR, 65% felt that they had received the sufficient amount of information to appropriately inform their decision. In addition, only 46% of this same cohort reported a consultation with a reconstructive surgeon preoperatively. Private-sector hospitals delivered better IBR care because of the likely presence of infrastructure and financial incentives for physicians. These results serve as a call for a better alignment between policy initiatives designed to expand care access and the perogatives of physicians to ensure an optimized delivery of the expanded care such policy mandates. PMID- 27482487 TI - Bifurcated Superficial Temporal Artery Island Flap for the Reconstruction of a Periorbital Burn: An Innovation. AB - BACKGROUND: Facial burns represent between one-fourth and one-third of all burns. The long-term sequelae of periorbital burns include significant ectropion and lagophthalmos as a result of secondary burn contractures in the lower and upper eyelids, in addition to complete or incomplete alopecia of the eyebrows. METHODS: A retrospective study of 14 reconstructive procedures for 12 postburn faces was conducted with all procedures performed since 2010 at the Department of Plastic Surgery, Al-Hussein University Hospital, and at the Craniofacial Unit, Nasser Institute Hospital. Four patients experienced chemical burns, and 8 patients experienced thermal burns. All patients underwent periorbital reconstruction using a bifurcated superficial temporal artery island flap to reconstruct the eyebrows, correct the lagophthalmos, and release the ectropion in both the upper and the lower eyelids. Two patients underwent bilateral periorbital flap reconstruction. The mean age of patients was 29 years, and the study was conducted on 8 males and 4 females. Patient satisfaction was assessed using a questionnaire completed by all patients postoperatively. RESULTS: The complete release of both the upper and the lower eyelids was achieved in all cases, together with ideal replacement of brow hair; no complications were noted, apart from one case in which a loss of hair density in the new eyebrow was observed, combined with the partial loss of the flap in the lower eyelid. Patient satisfaction results were collected and assembled in a table. CONCLUSION: A bifurcated superficial temporal artery island flap is an innovative flap for reconstructing both burned eyebrows and eyelids. PMID- 27482488 TI - Ear Reconstruction: Tridimensionality and Deception. PMID- 27482489 TI - Construction of a Flap That Can Move Functionally in Surgical Facial Repair. PMID- 27482492 TI - A Novel Technology for Vaginal Reconstruction Using Porcine Small Intestinal Submucosa. PMID- 27482490 TI - Bone Marrow-Derived Mesenchymal Stem Cells Enhance Bacterial Clearance and Preserve Bioprosthetic Integrity in a Model of Mesh Infection. AB - BACKGROUND: The reported incidence of mesh infection in contaminated operative fields is as high as 30% regardless of the material used. Recently, mesenchymal stem cells (MSCs) have been shown to possess favorable immunomodulatory properties and improve tissue incorporation when seeded onto bioprosthetics. The aim of this study was to evaluate whether seeding noncrosslinked bovine pericardium (Veritas Collagen Matrix) with allogeneic bone marrow-derived MSCs improves infection resistance in vivo after inoculation with Escherichia coli (E. coli). METHODS: Rat bone marrow-derived MSCs at passage 3 were seeded onto bovine pericardium and cultured for 7 days before implantation. Additional rats (n = 24) were implanted subcutaneously with MSC-seeded or unseeded mesh and inoculated with 7 * 10(5) colony-forming units of E. coli or saline before wound closure (group 1, unseeded mesh/saline; group 2, unseeded mesh/E. coli; group 3, MSC seeded mesh/E. coli; 8 rats per group). Meshes were explanted at 4 weeks and underwent microbiologic and histologic analyses. RESULTS: MSC-seeded meshes inoculated with E. coli demonstrated superior bacterial clearance and preservation of mesh integrity compared with E. coli-inoculated unseeded meshes (87.5% versus 0% clearance; p = 0.001). Complete mesh degradation concurrent with abscess formation was observed in 100% of rats in the unseeded/E. coli group, which is in contrast to 12.5% of rats in the MSC-seeded/E. coli group. Histologic evaluation determined that remodeling characteristics of E. coli-inoculated MSC seeded meshes were similar to those of uninfected meshes 4 weeks after implantation. CONCLUSIONS: Augmenting a bioprosthetic material with stem cells seems to markedly enhance resistance to bacterial infection in vivo and preserve mesh integrity. PMID- 27482491 TI - Varied Definitions of Nasolabial Angle: Searching for Consensus Among Rhinoplasty Surgeons and an Algorithm for Selecting the Ideal Method. AB - BACKGROUND: The nasolabial angle (NLA) is an important aesthetic metric for nasal assessment and correction. Although the literature offers many definitions, none has garnered universal acceptance. METHODS: To gauge the consensus level among practitioners, surveys were administered to a convenience sample of rhinoplasty surgeons soliciting practice characteristics, self-assessment of rhinoplasty experience and expertise, and preferred NLA definition. Choices of NLA definition included the angle between: (A) columella and line intersecting subnasale and labrale superius; (B) columella and line tangent to philtrum; (C) nostril long axis and Frankfort perpendicular; and (D) nostril long axis and vertical facial plane. RESULTS: Of the 82 total respondents, mean age was 50 years (range, 30 80years), and mean professional experience was 17 years (range, 0-67 years). Nineteen described themselves as novice rhinoplasty surgeons, 27 as intermediates, and 36 as experts. Mean number of lifetime rhinoplasties performed was 966 (range, 0-10,000). Twenty respondents (24%) agreed with definition A, 27 (33%) with B, 16 (20%) with C, and 13 (16%) with D. Six chose "other," offering their own explanations of NLA. Self-identified novices were more likely to prefer definition D than were experts (P = 0.009). CONCLUSIONS: No majority consensus was reached regarding the definition of NLA. Each method has its benefits and drawbacks, and establishing a single one may be unnecessary and even counterproductive in some cases. Having options available means that surgeons can tailor to each encounter, as long as they adopt a systematic methodology. We submit an algorithm to facilitate this effort. PMID- 27482493 TI - Can Acne Affect Prognosis of Breast Augmentation? PMID- 27482494 TI - An Examination of 123 Reconstructions of Facial Bone Patients with Titanium Implants: Does Titanium Benefit the Human Body? PMID- 27482495 TI - Oncologic Imaging in Patients Undergoing Breast Reduction. AB - Supplemental Digital Content is available in the text. PMID- 27482496 TI - Transconjunctival Approach for Zygomatic Fracture: A Single Surgeon's Experience of More Than 20 Years. AB - BACKGROUND: To let experts evaluate a single surgeon's experience with a combined transconjunctival and intraoral upper vestibular approach in the repair of zygomatic fractures encountered in 46 East Asian patients whom he treated over the past 20 years. METHODS: Patients were identified from a database, and a retrospective case note review was conducted. A total of 67 conjunctival and secondary incisions were made on 46 patients for repair of zygomatic fractures. All operative procedures were performed using a combination of transconjunctival and intraoral upper vestibular approaches to repair zygomatic fractures. RESULTS: The infraorbital rim and/or lateral buttress and/or lateral orbit was stabilized with titanium miniplates in 28 patients and absorbable miniplates in 11 patients. Seven patients required only reduction technique with no need of plates. Four cases needed additional canthotomy besides a conjunctival approach. No ectropion or entropion developed in any of the patients. Complications included eyelid laceration during surgery (n = 1), herniation of the conjunctiva (n = 1), temporary pyogenic granuloma of the conjunctiva after surgery (n = 1), and temporary entropion in a secondary incision (n = 1). CONCLUSIONS: A combined transconjunctival and intraoral upper vestibular approach in repairing zygomatic fractures is simple, easy, and effective, leaving no conspicuous facial scars. It is vitally important, however, that the surgeon masters the technique of transconjunctival approach well before he has good results in East Asian patients. PMID- 27482497 TI - The Fluorescent Intensity from the Transgenic Thy1-Yellow Fluorescent Protein 16 Mouse Correlates with the Amount of Regenerated Axons. PMID- 27482498 TI - Systematic Review of Quality of Patient Information on Liposuction in the Internet. AB - BACKGROUND: A large number of patients who are interested in esthetic surgery actively search the Internet, which represents nowadays the first source of information. However, the quality of information available in the Internet on liposuction is currently unknown. The aim of this study was to assess the quality of patient information on liposuction available in the Internet. METHODS: The quantitative and qualitative assessment of Web sites was based on a modified Ensuring Quality Information for Patients tool (36 items). Five hundred Web sites were identified by the most popular web search engines. RESULTS: Two hundred forty-five Web sites were assessed after duplicates and irrelevant sources were excluded. Only 72 (29%) Web sites addressed >16 items, and scores tended to be higher for professional societies, portals, patient groups, health departments, and academic centers than for Web sites developed by physicians, respectively. The Ensuring Quality Information for Patients score achieved by Web sites ranged between 8 and 29 of total 36 points, with a median value of 16 points (interquartile range, 14-18). The top 10 Web sites with the highest scores were identified. CONCLUSIONS: The quality of patient information on liposuction available in the Internet is poor, and existing Web sites show substantial shortcomings. There is an urgent need for improvement in offering superior quality information on liposuction for patients intending to undergo this procedure. PMID- 27482499 TI - Surgical Delay of the Nipple-Areolar Complex in High-risk Nipple-sparing Mastectomy Reconstruction. AB - As nipple-sparing mastectomy gains increasing popularity, minimizing the risk of nipple necrosis continues to be of critical importance to patients and surgeons. Patients with large or ptotic breasts, scars from previous cosmetic and/or oncologic breast surgery, or previous irradiation have often been denied nipple sparing mastectomy (NSM) because of increased risk of nipple necrosis. A variety of interventions have been suggested to minimize the ischemic insult to the nipple-areolar complex (NAC). This article presents our experience in 26 high risk patients with surgical delay of the NAC. PMID- 27482501 TI - L-positioned Perforator Propeller Flap for Partial Breast Reconstruction with Axillary Dead Space. AB - Partial breast reconstruction using perforator flaps harvested from the lateral chest wall has become a well-established surgical technique recently. In the case of a partial mastectomy with an axillary lymph node dissection, there are 2 main defects; one is a partial breast defect and the other is an axillary dead space. To reconstruct the 2 separate defects with local flaps, basically 2 different flaps are needed, and usually, it is rather difficult to harvest 2 different local flaps in the adjacent area. To resolve this problem, we introduce the L positioned perforator propeller flap (PPF). We used an L-positioned PPF on 2 female patients, aged 46 and 47 years old, who were suffering from breast cancer in the upper outer quadrant. The concept of this flap design is as follows: the partial breast defect is reconstructed with the longer lobe of the L-positioned PPF and the axillary defect is filled with the smaller lobe of the L-positioned PPF at the same time. The reconstruction time was 2 hours and 0 minutes and 1 hour and 46 minutes in each case. The patients were successfully provided with aesthetically acceptable breast reconstruction without postoperative complications. Moreover, both patients had consecutive postoperative radiotherapy on the reconstructed area without complications. With this flap design, it is possible for patients to have safe and aesthetic reconstruction with only 1 local flap and fewer invasive procedures. PMID- 27482500 TI - Is Sterile Better Than Aseptic? Comparing the Microbiology of Acellular Dermal Matrices. AB - INTRODUCTION: Postoperative infections are a major complication associated with tissue-expander-based breast reconstruction. The use of acellular dermal matrix (ADM) in this surgery has been identified as a potential reservoir of infection, prompting the development of sterile ADM. Although aseptic and sterile ADMs have been investigated, no study has focused on the occurrence and clinical outcome of bacterial colonization before implantation. METHODS: Samples of aseptic AlloDerm, sterile Ready-To-Use AlloDerm, and AlloMax were taken before implantation. These samples were incubated in Tryptic soy broth overnight before being streaked on Trypticase soy agar, MacConkey agar, and 5% blood agar plates for culture and incubated for 48 hours. Culture results were cross-referenced with patient outcomes for 1 year postoperatively. RESULTS: A total of 92 samples of ADM were collected from 63 patients. There were 15 cases of postoperative surgical site infection (16.3%). Only 1 sample of ADM (AlloMax) showed growth of Escherichia coli, which was likely a result of contamination. That patient did not develop any infectious sequelae. Patient outcomes showed no difference in the incidence of seroma or infection between sterile and aseptic ADMs. CONCLUSIONS: This study evaluates the microbiology of acellular dermal matrices before use in breast reconstruction. No difference was found in the preoperative bacterial load of either aseptic or sterile ADM. No significant difference was noted in infection or seroma formation. Given these results, we believe aseptic processing used on ADMs is equivalent to sterile processing in our patient cohort in terms of clinical infection and seroma occurrence postoperatively. PMID- 27482502 TI - Histology and Long-term Stability of Diced Cartilage Graft for Revision Rhinoplasty in a Cleft Patient. AB - Diced cartilage graft wrapped in Surgicel or fascia has been widely reported in the literature. Pure diced cartilage graft without the use of a "sleeve," on the contrary, is not as commonly reported. This could be due to concerns of graft dispersion, palpability, or visibility. In this case report, histologic findings of a pure diced cartilage graft placed 41/2 years ago are reported. In addition, advantages and disadvantages of this technique are discussed in detail. Two pieces of the diced cartilage graft placed 41/2 years prior were excised and sent for histologic analysis during a revision procedure. The microscopic examination reveals several small blocks of mature hyaline cartilage embedded in dense fibrous connective tissue with widely scattered small vascular channels. The cartilage is vital with scattered chondrocytes within their lacunae. Histology of the diced cartilage graft demonstrated viability and stability of the graft 41/2 years after insertion. This case report also suggests that pure diced cartilage graft can provide reliable volume augmentation of nasal dorsum in cleft rhinoplasty. PMID- 27482503 TI - A Predictable Approach for Osteotomy in Rhinoplasty: A New Concept of Open External Osteotomy. AB - Nasal osteotomies are a cornerstone step for closing an open roof deformity after dorsal hump surgery. Notwithstanding, the optimal method of nasal osteotomy remains controversial, as evidenced by the variety of approaches with no consensus between authors. Moreover, the election of the technique responds to surgeon's preference. We proposed a new way to perform both medial and lateral osteotomies under direct vision. Direct vision of nasal osteotomies provides more predictable control and precision than blind procedures, making this procedure more reliable and easier for both novel and experienced surgeons. Other advantages include conservation of nasal muscle, angular vasculature, and periosteum, which allow less postoperative ecchymosis and edema and less risk of synechia and lacrimal sac injury. PMID- 27482504 TI - Video Capture of Perforator Flap Harvesting Procedure with a Full High-definition Wearable Camera. AB - Recent advances in wearable recording technology have enabled high-quality video recording of several surgical procedures from the surgeon's perspective. However, the available wearable cameras are not optimal for recording the harvesting of perforator flaps because they are too heavy and cannot be attached to the surgical loupe. The Ecous is a small high-resolution camera that was specially developed for recording loupe magnification surgery. This study investigated the use of the Ecous for recording perforator flap harvesting procedures. The Ecous SC MiCron is a high-resolution camera that can be mounted directly on the surgical loupe. The camera is light (30 g) and measures only 28 * 32 * 60 mm. We recorded 23 perforator flap harvesting procedures with the Ecous connected to a laptop through a USB cable. The elevated flaps included 9 deep inferior epigastric artery perforator flaps, 7 thoracodorsal artery perforator flaps, 4 anterolateral thigh flaps, and 3 superficial inferior epigastric artery flaps. All procedures were recorded with no equipment failure. The Ecous recorded the technical details of the perforator dissection at a high-resolution level. The surgeon did not feel any extra stress or interference when wearing the Ecous. The Ecous is an ideal camera for recording perforator flap harvesting procedures. It fits onto the surgical loupe perfectly without creating additional stress on the surgeon. High-quality video from the surgeon's perspective makes accurate documentation of the procedures possible, thereby enhancing surgical education and allowing critical self-reflection. PMID- 27482505 TI - Chimeric Superficial Circumflex Iliac Perforator Flap Including External Oblique Fascia: A Refinement of Conventional Harvesting. AB - The superficial circumflex iliac perforator (SCIP) flap is one of the most suitable flaps to cover distal extremity defects due to its lack of bulkiness and donor site concealment. However, it is less popular than other perforator flaps due to its anatomical variations, short pedicle length, and small caliber vessels. We describe a novel design for the SCIP flap, consisting of a chimeric flap with a piece of the external oblique muscle fascia. The purpose of this design is to cover and protect the vascular anastomosis in distal lower limb defects where recipient vessels are superficial and skin coverage is poor. In addition, lengthening the pedicle with this design makes the flap more versatile. The addition of a cuff of fascia in harvesting of the SCIP flap lengthens the pedicle, allowing easier insetting of the skin paddle and providing complete protection and coverage of the vessels. This procedure allows greater versatility in inset of the skin paddle and is particularly suitable in cases where recipient vessels are superficial or when skin coverage is poor. PMID- 27482507 TI - Opening Skinner's Box: an Introduction. AB - Behavior analysts have redefined the subject matter of psychology, redesigned the experiments used to study that subject matter, renamed almost every part of the world pertaining to that subject matter, and created specialized organizations and journals. It is not surprising, then, that only a happy few ever hear what behavior analysts say. One problem is that we need to publish outside of the box, so to speak. Preaching to the choir ensures that the products of our scientific behavior affect only a few people, limits the variety of reinforcers we are likely to encounter, and limits the likelihood that the products of our scientific behavior will reinforce the behavior of others. Publishing in a wider variety of outlets can lead to greater visibility for behavior-analytic research and practice, increase the impact of our published work, and build clout for scholars in colleges and universities. PMID- 27482506 TI - Solely Penile Skin for Neovaginal Construction in Sex Reassignment Surgery. AB - BACKGROUND: Gender reassignment surgery due to transsexualism (International Classification of Diseases, Tenth Revision: F64.0) is a procedure becoming increasingly common worldwide as a result of a significant increase in diagnostic incidence. Several methods have been described for this complex surgery, but no internationally agreed upon gold standard exists, in particular with regard to which methods allow for creating a sufficient neovaginal depth. METHODS: We use a 2-stage technique using solely penile skin for creating a neovaginal cavity and present the long-term outcome in terms of measured neovaginal depth. Eighty patients were included. Patients' neovaginal depth was measured in a standardized fashion 6 months or more after initial surgery. Results were compared with published data on female anatomy. RESULTS: The average neovaginal depth achieved was 10.2 cm. Having had a postoperative complication and noncompliance to neovaginal dilatation were both negatively correlated with neovaginal depth, whereas higher body mass index was not. Most patients received a neovaginal depth sufficient for penetrative intercourse and within the range for biological women. CONCLUSIONS: Using solely penile skin for the vaginal lining is a satisfactory surgical method to achieve adequate vaginal depth, provided that the postoperative dilatation regimen is followed. This holds true regardless of age or body mass index. PMID- 27482509 TI - Handheld solar light use, durability, and retention among women and girls in internally displaced persons camps in Haiti - 2013-2014. AB - During conflict and disasters, women and girls are at increased risk of gender based violence. International humanitarian guidelines call for the distribution of individual lighting to meet women and girls' basic needs and to reduce risk of violence; however, little evidence exists to support these guidelines. This paper presents an evaluation of handheld solar light use, retention, and durability among women and girls living in two internally displaced persons camps in Port-au Prince, Haiti. Data was gathered prospectively via five household surveys from August 2013 to April 2014; a total of 754 females participated in the study. Women reported going outside at night more frequently at the end of the study than at the beginning. The handheld solar lights were the most common source of lighting at endline, whereas candle and gas lamp use declined significantly over time. Results from a Life-Table survival analysis estimated that households had an 83% probability of still owning a functioning light after seven months. Given the frequent use, acceptable durability, and retention of the lights, donors and humanitarian organizations should consider supporting light distribution to women and girls in internally displaced persons camps to help meet their basic needs. PMID- 27482508 TI - Convergence of Highly Resolved and Rapid Screening Platforms with Dynamically Engineered, Cell Phenotype-Prescriptive Biomaterials. AB - Biophysical and biochemical cues from the cellular microenvironment initiate intracellular signaling through cellular membrane receptors and trigger specific cell developmental programs. Extracellular substrates and matrix scaffolds engineered to mimic cell's native physiological environment must incorporate the multifactorial parameters (composition, micro and nanoscale organization and topography) of the extracellular matrix as well as the dynamic nature of the matrix. The design of such engineered biomaterials is challenged by the inherent complexity and dynamic nature of the cell-extracellular matrix reciprocity, while the validation of robust microenvironments requires a deeper, higher content phenotypic resolution of cell-matrix interactions alongside a rapid screening capability. To this end, high-throughput platforms are integral to facilitating the screening and optimization of complex engineered microenvironments for directing desired cell developmental pathway. This review highlights the recent advances in biomaterial platforms that present dynamic cues and enable high throughput screening of cell's response to a combination of micro-environmental factors. We also address some newer techniques involving high content image informatics to elucidate emergent cellular behaviors with a focus on stem cell regenerative endpoints. PMID- 27482510 TI - An important cause of non-resolving pneumonia. AB - We describe the case of a young patient with a history of non-resolving pneumonia. She was diagnosed with a limited form of Granulomatosis with Polyangiitis (GPA), by percutaneous core needle lung biopsy. In this report, we discuss the definition and clinical implications of limited GPA, treatment options, and highlight the importance of considering vasculitis in the differential diagnosis of non-resolving pneumonia. PMID- 27482511 TI - Modulation of LINE-1 Retrotransposition by a Human SAMHD1 Polymorphism. AB - The HIV-1 restriction factor SAMHD1 has the ability to negatively modulate retrotransposition of the long interspersed element 1(LINE-1). By exploring the ability of human SAMHD1 polymorphisms to inhibit LINE-1, we found that the single nucleotide polymorphism S33A present in the Korean population lose the ability to inhibit LINE-1 retrotransposition. Because SAMHD1 residue S33 is phosphorylated in human cycling and non-cycling cells, we demonstrated that SAMHD1 requires to be either phosphorylated on position 33 or to contain a bulky residue in order to inhibit LINE-1 retrotransposition. Therefore this unique mutation uncouples functions in this important restriction factor. PMID- 27482513 TI - Managing sticky situations - anti-biofilm agents. PMID- 27482512 TI - Health promotion practices as perceived by primary healthcare professionals at the Ministry of National Guard Health Affairs, Saudi Arabia. AB - INTRODUCTION: In recent years, several research studies have investigated health promotion practices in Saudi healthcare organizations, yet no published literature exists on health promotion practices of primary healthcare professionals working for the Ministry of National Guard Health Affairs (MNG-HA). METHODS: A cross-sectional study was conducted in a convenience sample of 206 primary healthcare professionals at the MNG-HA. A self-reporting questionnaire was used to investigate the attitudes, awareness, satisfaction, and methods regarding health promotion practices of primary healthcare professionals. RESULTS: Of the 206 primary healthcare professionals surveyed, 58.1% reported awareness of health promotion programs conducted in the hospitals and 64.6% reported that the health promotion system in the hospitals needs to be improved. Language barriers and cultural beliefs were viewed as obstacles to carrying out effective health promotion by 65% and 64.6% of primary healthcare professionals, respectively. The majority (79.9%) of the primary healthcare professionals perceived themselves as having the necessary skills to promote health and 80.6% believed that printed educational materials are the most prevalent method of health promotion/education, whereas 55.8% reported that counseling was the most preferred method of health promotion. CONCLUSION: The awareness level of health promotion policies, strategies, and programs conducted in the hospitals was not found to be satisfactory. Therefore, widespread training programs are recommended to improve the health promotion system in the hospitals. These programs include facilitating behavioral change, introducing health promotion policies and strategies in hospitals, mandatory workshops, and systematic reminders. PMID- 27482514 TI - Low bone mineral density and associated risk factors in HIV-infected patients. AB - BACKGROUND: Aging of persons with human immunodeficiency virus (HIV) resulted in high rates of osteopenia and osteoporosis. Multiple cohort studies have reported an increased prevalence of bone demineralization among HIV-infected individuals. The aim of this study was to evaluate bone mineral density (BMD) and risk factors for osteopenia/osteoporosis among HIV-positive patients attending the National Institute for Infectious Diseases "Prof.Dr. Matei Bals", Bucharest, Romania. METHODS: We performed a cross-sectional study that enrolled 60 patients with HIV. The association between BMD and lifestyle habits (smoking), body mass index (BMI), nadir cluster of differentiation 4 (CD4) cell count, current CD4 cell count, HIV viral load and history of combination antiretroviral therapy (cART) were investigated. The BMD was measured at the lumbar spine, hips and total body using dual-energy X-ray absorptiometry (DEXA). RESULTS: In the present study, DEXA evaluation showed an overall prevalence of osteoporosis of 16.66% (ten patients) and a prevalence of osteopenia of 48.33% (29 patients). In men, low BMI and cigarette smoking showed significant association with the diagnosis of lumbar spine demineralization (p=0.034 and p=0.041, respectively). Duration of exposure to cART classes in relation to BMD was also evaluated. The use of non-nucleoside reverse-transcriptase inhibitors (NNRTIs) was associated with low lumbar spine BMD in all patients (p=0.015). Reduced BMD was significantly associated with protease inhibitors (PIs)-containing treatment (p=0.043) in women. CONCLUSION: At lumbar spine DEXA, male gender was statistically associated with reduced BMD. At the left hip Ward's area, decreased BMD T scores were significantly associated with aging. The reduced BMD was higher in patients receiving PI- or NNRTI containing regimens. PMID- 27482515 TI - Diagnostic value of sputum adenosine deaminase (ADA) level in pulmonary tuberculosis. AB - INTRODUCTION: Tuberculosis is still a considerable health problem in many countries. Rapid diagnosis of this disease is important, and adenosine deaminase (ADA) has been used as a diagnostic test. The aim of this study was to assess the diagnostic value of ADA in the sputum of patients with pulmonary tuberculosis. METHODS: The current study included 40 patients with pulmonary tuberculosis (culture positive, smear +/-) and 42 patients with non tuberculosis pulmonary diseases (culture negative). ADA was measured on all of the samples. RESULTS: The median value of ADA in non-tuberculosis patients was 2.94 (4.2) U/L and 4.01 (6.54) U/L in tuberculosis patients, but this difference was not statistically significant (p=0.100). The cut-off point of 3.1 U/L had a sensitivity of 61% and a specificity of 53%, the cut-off point of 2.81 U/L had a sensitivity of 64% and a specificity of 50% and the cut-off point of 2.78 U/L had a sensitivity of 65% and a specificity of 48%. The positive predictive values for cut-off points of 3.1, 2.81 and 2.78 U/L were 55.7%, 57.44% and 69.23%, respectively. The negative predictive values for the abovementioned cut-off points were 56.75%, 57.14% and 55.88%, respectively. CONCLUSION: Our results showed that sputum ADA test is neither specific nor sensitive. Because of its low sensitivity and specificity, determination of sputum ADA for the diagnosis of pulmonary tuberculosis is not recommended. PMID- 27482516 TI - Nearing elimination of meningitis A from the African "meningitis belt" using meningococcal A conjugate vaccine. PMID- 27482517 TI - Emerging options for the treatment of melanoma - focus on ipilimumab. AB - Ipilimumab is a fully human immunoglobulin subclass G1 anticytotoxic-T-lymphocyte antigen-4 monoclonal antibody. It has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for use in advanced melanoma following clear evidence of survival benefit in randomized Phase III studies. It is also under investigation as a treatment for other solid tumors such as renal cell, lung, and prostate cancers. The purported mechanism of antitumor activity of ipilimumab is through T-cell activation, and the side effect profile reflects this. Immune-related adverse events (irAEs) affect 60% of treated patients and 15% are defined as severe. Fortunately, most irAEs are reversible with early diagnosis and correct management. FDA approval of ipilimumab is dependent on the careful execution of a risk evaluation and mitigation strategy, with the aim of increasing awareness amongst patients and clinicians of the immunological risks of treatment, and providing algorithms for management of irAEs as they develop. Ipilimumab is one of the first immunotherapies to become widely available in the setting of solid tumors, and ongoing research aims to elucidate optimal dosing, optimal scheduling, and expanded access to ipilimumab as an adjuvant or maintenance therapy where appropriate. The identification of clinical correlates or biomarkers to identify those likely to benefit from this high-cost therapy is a top priority. PMID- 27482519 TI - Validity and Reliability of a Self-administered Food Frequency Questionnaire to Assess Vitamin K Intake in Korean Adults. AB - This study was conducted to validate a food frequency questionnaire (FFQ) to assess vitamin K intake in clinical and research settings based on data from the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V). We collected a subset of data on informative food items using the 24-hour recall method from adults aged 19 to 64 years from KNHANES V. The cumulative percent contribution and cumulative multiple regression coefficients for vitamin K intake from each food were computed. Twenty-five foods items were selected for the FFQ to assess vitamin K intake. The FFQ was validated against intakes derived from a 5-day food record (5DR) (n = 48). To assess the reliability of the FFQ, participants completed the self-administered FFQ (FFQ1) and a second FFQ (FFQ2) after a 6-month period (n = 54). Data were analyzed using Pearson's correlation coefficients, the cross-classification method, and Bland-Altman plots. Mean intakes were similar for vitamin K between the FFQ and dietary records, with significant correlations observed (r = 0.652), and cross-classification analyses demonstrated no major misclassification of participants into intake quartiles. Bland-Altman plots showed no serious systematic bias between the administrations of the two dietary assessment methods over the range of mean intakes. FFQ reliability was high, with a Pearson's correlation coefficient of 0.560. This pilot study shows promising validation and reliability evidence for the use of this FFQ, which is focused on vitamin K intake in adults, as an efficient screening tool in clinical and research settings. PMID- 27482518 TI - Nutritional Factors Affecting Mental Health. AB - Dietary intake and nutritional status of individuals are important factors affecting mental health and the development of psychiatric disorders. Majority of scientific evidence relating to mental health focuses on depression, cognitive function, and dementia, and limited evidence is available about other psychiatric disorders including schizophrenia. As life span of human being is increasing, the more the prevalence of mental disorders is, the more attention rises. Lists of suggested nutritional components that may be beneficial for mental health are omega-3 fatty acids, phospholipids, cholesterol, niacin, folate, vitamin B6, and vitamin B12. Saturated fat and simple sugar are considered detrimental to cognitive function. Evidence on the effect of cholesterol is conflicting; however, in general, blood cholesterol levels are negatively associated with the risk of depression. Collectively, the aims of this review are to introduce known nutritional factors for mental health, and to discuss recent issues of the nutritional impact on cognitive function and healthy brain aging. PMID- 27482520 TI - Differences of Socio-psychology, Eating Behavior, Diet Quality and Quality of Life in South Korean Women according to Their Weight Status. AB - We aimed at assessing psychological variables and eating behaviors on quality of diet and life in South Korean women according to their weight status. Socio psychology, eating behavior, quality of diet and quality of life data were assessed in 114 women (mean age: 34.5 +/- 8.09 years). NEO Personality Inventory (NEO-PI-RS) and coping styles questionnaire were used to assess socio-psychology variables, and eating behavior was assessed using the Eating Attitudes Test-26 (EAT-26), Dutch Eating Behavior Questionnaire (DEBQ), and General Food Craving Questionnaire Test (G-FCQ-T). Quality of diet was analyzed by Diet Quality Index international (DQI-I), and obesity-related quality of life was evaluated using the Korean Obesity-related Quality of life Scale (KOQOL). Significant differences were in the psychological variables and eating behaviors in the obese group than the normal and overweight groups (p < 0.05). The overall score of DQI-I was significantly lower in the obese group than that of their counterparts (p < 0.05). BMI was positively correlated with neuroticism, emotional eating, and obesity-related quality of life, and negatively correlated with diet quality. Neuroticism was positively correlated with emotional eating and food craving. Emotional eating was positively correlated with obesity-related quality of life. In conclusion, women with a higher BMI had significantly more problematic eating behaviors, poor diet quality and quality of life. PMID- 27482521 TI - Application of Iron Oxide as a pH-dependent Indicator for Improving the Nutritional Quality. AB - Acid food indicators can be used as pH indicators for evaluating the quality and freshness of fermented products during the full course of distribution. Iron oxide particles are hardly suspended in water, but partially or completely agglomerated. The agglomeration degree of the iron oxide particles depends on the pH. The pH-dependent particle agglomeration or dispersion can be useful for monitoring the acidity of food. The zeta potential of iron oxide showed a decreasing trend as the pH increased from 2 to 8, while the point of zero charge (PZC) was observed around at pH 6.0-7.0. These results suggested that the size of the iron oxide particles was affected by the change in pH levels. As a result, the particle sizes of iron oxide were smaller at lower pH than at neutral pH. In addition, agglomeration of the iron oxide particles increased as the pH increased from 2 to 7. In the time-dependent aggregation test, the average particle size was 730.4 nm and 1,340.3 nm at pH 2 and 7, respectively. These properties of iron oxide particles can be used to develop an ideal acid indicator for food pH and to monitor food quality, besides a colorant or nutrient for nutrition enhancement and sensory promotion in food industry. PMID- 27482522 TI - The Association between Coffee Consumption and Bone Status in Young Adult Males according to Calcium Intake Level. AB - The purpose of this study was to investigate the association between coffee consumption and bone status (bone mineral density and bone metabolism-related markers) according to calcium intake level in Korean young adult males. Healthy and nonsmoking males (19-26 years, n = 330) participated in this study. Anthropometric measurements, dietary habits, and nutrient intakes were surveyed. Bone status of the calcaneus was measured by using quantitative ultrasound (QUS). Bone metabolism-related markers including serum total alkaline phosphatase activity (TALP), N-mid osteocalcin (OC), and type 1 collagen C-terminal telopeptide (1CTP) were analyzed. The subjects were divided into two groups based on daily calcium intake level: a calcium-sufficient group (calcium intake >= 75% RI, n = 171) and a calcium-deficient group (calcium intake < 75% RI, n = 159). Each group was then further divided into three subgroups based on daily average coffee consumption: no-coffee, less than one serving of coffee per day, and one or more servings of coffee per day. There were no significant differences in height, body weight, body mass index, energy intake, or calcium intake among the three coffee consumption subgroups. QUS parameters and serum 1CTP, TALP, and OC were not significantly different among either the two calcium-intake groups or the three coffee consumption subgroups. Our results may show that current coffee consumption level in Korean young men is not significantly associated with their bone status and metabolism according to the calcium intake level. PMID- 27482523 TI - Serum Phospholipid Docosahexaenoic Acid Is Inversely Associated with Arterial Stiffness in Metabolically Healthy Men. AB - We hypothesized that lower proportion of serum phospholipid docosahexaenoic acid (DHA) is inversely associated with increased cardiovascular risk and vascular function in metabolically healthy men. To elucidate it, we first compared serum phospholipid free fatty acid (FA) compositions and cardiovascular risk parameters between healthy men (n = 499) and male patients with coronary artery disease (CAD, n = 111) (30-69 years) without metabolic syndrome, and then further analyzed the association of serum phospholipid DHA composition with arterial stiffness expressed by brachial-ankle pulse wave velocity (ba-PWV) in metabolically healthy men. Basic parameters, lipid profiles, fasting glycemic status, adiponectin, high sensitivity C-reactive protein (hs-CRP) and LDL particle size, and serum phospholipid FA compositions were significantly different between the two subject groups. Serum phospholipid DHA was highly correlated with most of long-chain FAs. Metabolically healthy men were subdivided into tertile groups according to serum phospholipid DHA proportion: lower (< 2.061%), middle (2.061%-3.235%) and higher (> 3.235%). Fasting glucose, insulin resistance, hs-CRP and ba-PWVs were significantly higher and adiponectin and LDL particle size were significantly lower in the lower-DHA group than the higher-DHA group after adjusted for confounding factors. In metabolically healthy men, multiple stepwise regression analysis revealed that serum phospholipid DHA mainly contributed to arterial stiffness (beta'-coefficients = -0.127, p = 0.006) together with age, systolic blood pressure, triglyceride (r = 0.548, p = 0.023). Lower proportion of serum phospholipid DHA was associated with increased cardiovascular risk and arterial stiffness in metabolically healthy men. It suggests that maintaining higher proportion of serum phospholipid DHA may be beneficial for reducing cardiovascular risk including arterial stiffness in metabolically healthy men. PMID- 27482524 TI - Association of Serum Apolipoprotein B with the Increased Risk of Diabetes in Korean Men. AB - This study aimed to investigate the association of Apolipoprotein B (ApoB) with the risk of diabetes in Koreans. Korean men (n = 790, 40-79 years) who had been never diagnosed for diabetes before participating were enrolled. Subjects were categorized into normal fasting glucose (NFG, n = 519), impaired fasting glucose (IFG, n = 188) and newly-onset diabetes (n = 83) according to fasting glucose levels. Age was not significantly different among the subgroups. Mean values of BMI, waist circumference, Blood pressure(BP), triglyceride, non-HDL cholesterol were significantly higher in IFG or newly-onset diabetic subjects compared to NFG subjects. The levels of glucose, insulin, free fatty acid, insulin resistance and ApoB were highest in diabetic patients and lowest in NFG subjects. According to ApoB level, subjects were divided into two groups (high-ApoB group: >= 87.0 mg/dL vs. low-ApoB group: < 87.0 mg/dL). The risk of diabetes was higher in the high ApoB group than the low-ApoB group [OR0: 2.392, (95% CI: 1.470-3.893), P0 < 0.001]. This association was maintained after adjusted for age and BMI [OR1: 2.228, (95% CI: 1.362-3.646), P1 = 0.001] and further adjustment for blood pressure, triglyceride, HDL-cholesterol, LDL-cholesterol, non-HDL-cholesterol, ApoA1 and adiponectin [OR2: 1.984, (95% CI: 1.001-4.064), P2 = 0.049]. The association was much greater in subjects with metabolic syndrome (MetS) [OR1: 2.805 (95% CI: 1.137-5.737), P1 = 0.005] than in those without [OR1: 1.917 (95% CI: 0.989-3.718), P1 = 0.054]. After 3-month, further investigation was randomly performed in subjects with NFG or IFG who agreed to reinvestigation. Multiple stepwise regression analysis revealed that net change of ApoB levels was a main contributor to the net change of glucose levels (standardized b-coefficient: 0.315, p = 0.002). In conclusion, ApoB levels are closely associated with the increased risk of diabetes in Korean men. PMID- 27482525 TI - Preoperative Oral Carbohydrate Loading in Pancreaticoduodenectomy. AB - Overnight fasting before elective surgery has been the routine to reduce the risk of pulmonary aspiration. Recently, several international guidelines for preoperative fasting recommend to intake carbohydrate-containing fluids up to 2 to 3 hours before the induction of anesthesia to improve postoperative recovery. Based on the recommendations, we developed a "preoperative carbohydrate diet" provided for the preoperative patients. The purpose of this case report is to share our experience of applying preoperative carbohydrate loading prior to surgery. PMID- 27482526 TI - Return to Sport After Operative Management of Osteochondritis Dissecans of the Capitellum: A Systematic Review and Meta-analysis. AB - BACKGROUND: Capitellar osteochondritis dissecans (OCD) is commonly managed surgically in symptomatic adolesent throwers and gymnasts. Little is known about the impact that surgical technique has on return to sport. PURPOSE: To evaluate the clinical outcomes and return-to-sport rates after operative management of OCD lesions in adolescent athletes. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: The PubMed, CINAHL, EMBASE, SPORTDiscus (EBSCO), and Cochrane Central Register of Controlled Trials databases were queried for studies evaluating outcomes and return to sport after surgical management of OCD of the capitellum. Two independent reviewers conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies reporting patient outcomes with return-to-sport data and minimum 6-month follow-up were included in the review. RESULTS: After review, 24 studies reporting outcomes in 492 patients (mean age +/- SD, 14.3 +/- 0.9 years) were analyzed. The overall return-to-sport rate was 86% at a mean 5.6 months. Return to the highest preoperative level of sport was most common after osteochondral autograft procedures (94%) compared with debridement and marrow stimulation procedures (71%) or OCD fixation surgery (64%). Elbow range of motion improved by 15.9 degrees after surgery. The Timmerman-Andrews subjective and objective scores significantly improved after surgery. Complications were low (<5%), with 2 cases of donor site morbidity after osteoarticular autograft transfer (OAT) autograft harvest. The most common indications for reoperation were repeat debridement/loose body removal. CONCLUSION: A high rate of return to sport was observed after operative management of capitellar OCD. Patients were more likely to return to their highest level of preoperative sport after OAT autograft compared with debridement or fixation. Significant improvements in elbow range of motion and patient outcomes are seen with low complication rates after OCD surgery. PMID- 27482527 TI - Biomechanical Comparison of Single- and Double-Leg Jump Landings in the Sagittal and Frontal Plane. AB - BACKGROUND: Double-leg forward or drop-jump landing activities are typically used to screen for high-risk movement strategies and to determine the success of neuromuscular injury prevention programs. However, research suggests that these tasks that occur primarily in the sagittal plane may not adequately represent the lower extremity biomechanics that occur during unilateral foot contact or non sagittal plane movements that are characteristic of many multidirectional sports. PURPOSE: To examine the extent to which lower extremity biomechanics measured during a jump landing on a double leg (DL) after a sagittal plane (SAG) movement is representative of biomechanics measured during single-leg (SL) or frontal plane (FRONT) jump landing tasks. STUDY DESIGN: Controlled laboratory study. METHODS: Lower extremity biomechanics were measured in 15 recreationally active females (mean age [+/-SD], 19.4 +/- 2.1 years; mean height, 163.3 +/- 5.9 cm; mean weight, 61.1 +/- 7.1 kg) while performing SAGDL, SAGSL, FRONTDL, and FRONTSL jump landing tasks. Repeated-measures analyses of variance examined differences in lower extremity biomechanics between the 4 tasks, and linear regressions examined the extent to which an individual's biomechanics during SAGDL were representative of their biomechanics during SAGSL, FRONTDL, and FRONTSL. RESULTS: Lower extremity kinematics and kinetics differed by condition, with the SAGDL task generally eliciting greater hip and knee flexion angles and lower hip and knee forces than the other tasks (P < .05). Although biomechanics during the SAGDL task were strongly associated with those during the FRONTDL task (R (2), 0.41-0.82), weaker associations were observed between SAGDL and single-leg tasks for hip kinematics (R (2), 0.03-0.25) and kinetics (R (2), 0.05-0.20) and knee abduction moments (R (2), 0.06-0.18) (P < .05). CONCLUSION: Standard double-leg sagittal plane jump landing tasks used to screen for ACL injury risk and the effectiveness of ACL injury prevention programs may not adequately represent the lower extremity biomechanics that occur during single-leg activities. CLINICAL RELEVANCE: These results support further investigation of single-leg multidirectional landings to identify high-risk movement strategies in female athletes playing multidirectional sports. PMID- 27482528 TI - Analysis of the Tibial Epiphysis in the Skeletally Immature Knee Using Magnetic Resonance Imaging: An Update of Anatomic Parameters Pertinent to Physeal-Sparing Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Physeal-sparing anterior cruciate ligament (ACL) reconstruction is being performed increasingly in skeletally immature knees. PURPOSE: To determine normal values for the maximum oblique length and "safe" physeal-sparing length and their corresponding angular trajectories across the tibial epiphysis on reconstructed magnetic resonance images (MRIs) in children and adolescents. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: An electronic search for pediatric knee MR examinations from April 2003 to April 2013 was performed at our institution. A 3-dimensional system viewer was used to measure the maximum oblique length, physeal-sparing length, and their corresponding angular trajectories on reconstructed MRIs. Knees were stratified by age into 2 groups: group 1 consisted of boys <13 years and girls <12 years and group 2 consisted of older boys (13-14 years) and girls (12-14 years). Each cohort was further stratified by sex. Group 1 consisted of 36 knees (mean age, 10.9 years) and group 2 consisted of 59 knees (mean age, 13.6 years). RESULTS: Significant differences existed for the maximum oblique length and its angular trajectory for the younger versus older cohort (22.2 +/- 2.7 vs 23.8 +/- 2.7 mm, P = .007; 42.0 degrees +/- 4.0 degrees vs 39.4 degrees +/- 4.2 degrees , P = .003) and for the physeal-sparing length and its angular trajectory (19.4 +/- 2.8 vs 21.3 +/- 2.9 mm, P = .001; 30.1 degrees +/- 4.1 degrees vs 28.2 degrees +/- 4.5 degrees , P = .042). In group 2, females had shorter maximal oblique length and physeal sparing length than boys (22.7 +/- 2.3 vs 25.0 +/- 2.7 mm, P < .001; 20.3 +/- 2.6 vs 22.4 +/- 2.9 mm, P = .004). CONCLUSION: The maximum oblique length across the tibial epiphysis is shorter than previously believed, measuring approximately 22 mm and approximately 24 mm for high- and intermediate-risk knees, respectively. However, "safe" physeal-sparing lengths were only approximately 19 mm and 21 mm for the younger and older cohorts, respectively. The angles corresponding to the maximum and safe lengths are more acute than commonly thought, measuring approximately 40 degrees and 30 degrees , respectively. All prepubescent knees and intermediate-risk females should receive careful attention before ACL reconstruction due to the relative smaller size of their tibial epiphyses. CLINICAL RELEVANCE: Physeal-sparing ACL reconstruction is gaining acceptance as a surgical option for complete ACL tear in skeletally immature knees. Iatrogenic growth disturbance after violation of an open growth remains a real concern for surgeons tasked with providing operative management for the unstable pediatric knee. Inadvertent iatrogenic growth plate injury to the tibial physis has been shown to occur more commonly than surgeons would intend during physeal-sparing ACL reconstruction. PMID- 27482529 TI - Vitamin D Deficiency Among Professional Basketball Players. AB - BACKGROUND: Vitamin D plays an important role in several systems of the human body. Various studies have linked vitamin D deficiency to stress and insufficiency fractures, muscle recovery and function, and athletic performance. The prevalence of vitamin D deficiency in the elite athletic population has not been extensively studied, and very few reports exist among professional athletes. HYPOTHESIS: There is a high prevalence of vitamin D deficiency or insufficiency among players attending the National Basketball Association (NBA) Combine. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: This is a retrospective review of data previously collected as part of the routine medical evaluation of players in the NBA Combines from 2009 through 2013. Player parameters evaluated were height, weight, body mass index (BMI), and vitamin D level. Statistical analysis using t tests and analysis of variance was used to detect any correlation between the player parameters and vitamin D level. Vitamin D levels were categorized as deficient (<20 ng/mL), insufficient (20-32 ng/mL), and sufficient (>32 ng/mL). RESULTS: After institutional review board approval was submitted to the NBA, the NBA released deidentified data on 279 players who participated in the combines from 2009 through 2013. There were 90 players (32.3%) who were deficient, 131 players (47.0%) who were insufficient, and 58 players (20.8%) who were sufficient. A total of 221 players (79.3%) were either vitamin D deficient or insufficient. Among all players included, the average vitamin D level was 25.6 +/- 10.2 ng/mL. Among the players who were deficient, insufficient, and sufficient, the average vitamin D levels were 16.1 +/- 2.1 ng/mL, 25.0 +/- 3.4 ng/mL, and 41.6 +/- 8.6 ng/mL, respectively. Player height and weight were significantly increased in vitamin D-sufficient players compared with players who were not sufficient (P = .0008 and .009, respectively). Player age and BMI did not significantly differ depending on vitamin D status (P = .15 and .77, respectively). CONCLUSION: There is a high prevalence of vitamin D deficiency or insufficiency among participants in the NBA Combines. As a result, there should be a high suspicion for this metabolic abnormality among elite basketball players. CLINICAL RELEVANCE: Vitamin D level has been linked to bone health, muscle recovery and function, and athletic performance. Because of the high prevalence of vitamin D deficiency in the NBA Combines, clinicians should maintain a high suspicion for vitamin D abnormalities among elite basketball players. PMID- 27482530 TI - Patellar Articular Overlap on MRI Is a Simple Alternative to Conventional Measurements of Patellar Height. AB - BACKGROUND: Patella alta describes an abnormally high-riding patella in relationship to the femur and has been shown to correlate with patellofemoral pain, instability, chondromalacia, and arthrosis. Conventional measurements of patella alta involve multiple measurements and are often not defined on cross sectional imaging as related to radiographs. HYPOTHESIS: Patellar articular overlap on sagittal magnetic resonance imaging (MRI) will correlate well with conventional measurements of patella alta as measured by a standardized technique defined by our group. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: MRIs of 239 knees were reviewed by 3 attending surgeons with practices focusing on patellofemoral disease, as well as 2 sports medicine fellows and 1 musculoskeletal radiologist. Measurements included articular overlap, percentage of articular coverage, Caton-Deschamps index, Blackburne-Peel index, and modified Insall-Salvati index. RESULTS: Interrater reliability was high for Caton-Deschamps, Blackburne-Peel, and modified Insall-Salvati indices (intraclass correlation coefficient [ICC], 0.877, 0.828, and 0.787, respectively). Articular overlap and percentage articular coverage correlated well with each other (ICC, 0.961; P < .001) and with the Caton-Deschamps (overlap r = -0.271, P < .001; coverage r = -0.131, P = .037) and Blackburne-Peel (overlap r = 0.343, P < .001; coverage r = -0.238, P < .001) indices. Articular overlap and percentage coverage failed to correlate with the modified Insall-Salvati index (overlap r = -0.117, P = .091; coverage r = 0.007, P = .918). CONCLUSION: Patellar articular overlap and percentage of patellar articular coverage show promise as a simpler alternative to conventional, ratio-based measurements of patellar height. Future studies are needed to evaluate the range of normal and the relationship to our traditionally used measurements. PMID- 27482532 TI - Sample preparation for proteomic analysis using a GeLC-MS/MS strategy. AB - In-gel digestion coupled with mass spectrometric analysis (GeLC-MS/MS) is a cornerstone for protein identification and characterization. Here I review this versatile approach which combines classical and modern biochemistry strategies and allows for targeted and proteome-wide analyses. Starting with any protein sample, reduced and alkylated proteins are precipitated prior to fractionation by SDS-PAGE. Proteins are in-gel digested and the resulting peptides are extracted and desalted for downstream LC-MS/MS analysis. GeLC-MS/MS leverages the advantages of both traditional SDS-PAGE visualization and protein fractionation with the robust protein and post-translational modification identification and quantitation capabilities of state-of-the-art mass spectrometry-based technology. As such, this strategy allows for the visible assessment of protein amount and quality, prior to analysis via virtually any mass spectrometry platform. Moreover, gel extracted peptides may be derived from any sample type-e.g., from cell culture, tissue, body fluid, or recombinantly-expressed protein-and are fully compatible with isobaric tagging. GeLC-MS/MS is an invaluable technique for proteomic analyses. PMID- 27482531 TI - Statistical Methods in Integrative Genomics. AB - Statistical methods in integrative genomics aim to answer important biology questions by jointly analyzing multiple types of genomic data (vertical integration) or aggregating the same type of data across multiple studies (horizontal integration). In this article, we introduce different types of genomic data and data resources, and then review statistical methods of integrative genomics, with emphasis on the motivation and rationale of these methods. We conclude with some summary points and future research directions. PMID- 27482533 TI - Cognitive motor deficits in cannabis users. AB - Cannabis use affects cortico-striatal networks that are essential for producing movement. In this review, we summarize the literature on motor system dysfunction in cannabis users and provide a rationale for why motor learning should be considered an important area in cannabis research. A majority of studies have addressed cognitive impairments in cannabis users and some have focused on driving performance, motor impulsivity, and motor inhibition. Our review of the literature has found that cannabis use is associated with motor performance impairments; however, there is a gap in the literature regarding impairments in motor learning. The involvement of the cortico-striatal network in both cannabis addiction and movement also suggests potential avenues for treatment and rehabilitation via the motor system. PMID- 27482534 TI - An Alzheimer's Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults. AB - Variants at 21 genetic loci have been associated with an increased risk for Alzheimer's disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = -0.40; p = 0.003; WRS: r = -0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = -0.35; p = 0.009; WRS: r = -0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness. PMID- 27482535 TI - Dorsal Medial Habenula Regulation of Mood-Related Behaviors and Primary Reinforcement by Tachykinin-Expressing Habenula Neurons. AB - Animal models have been developed to investigate aspects of stress, anxiety, and depression, but our understanding of the circuitry underlying these models remains incomplete. Prior studies of the habenula, a poorly understood nucleus in the dorsal diencephalon, suggest that projections to the medial habenula (MHb) regulate fear and anxiety responses, whereas the lateral habenula (LHb) is involved in the expression of learned helplessness, a model of depression. Tissue specific deletion of the transcription factor Pou4f1 in the dorsal MHb (dMHb) results in a developmental lesion of this subnucleus. These dMHb-ablated mice show deficits in voluntary exercise, a possible correlate of depression. Here we explore the role of the dMHb in mood-related behaviors and intrinsic reinforcement. Lesions of the dMHb do not elicit changes in contextual conditioned fear. However, dMHb-lesioned mice exhibit shorter immobility time in the tail suspension test, another model of depression. dMHb-lesioned mice also display increased vulnerability to the induction of learned helplessness. However, this effect is not due specifically to the dMHb lesion, but appears to result from Pou4f1 haploinsufficiency elsewhere in the nervous system. Pou4f1 haploinsufficiency does not produce the other phenotypes associated with dMHb lesions. Using optogenetic intracranial self-stimulation, intrinsic reinforcement by the dMHb can be mapped to a specific population of neurokinin-expressing habenula neurons. Together, our data show that the dMHb is involved in the regulation of multiple mood-related behaviors, but also support the idea that these behaviors do not reflect a single functional pathway. PMID- 27482537 TI - Statistical Rigor and the Perils of Chance. PMID- 27482536 TI - The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus. AB - Because a rank-ordered recruitment of motor units occurs during isometric contraction of jaw-closing muscles, jaw-closing motoneurons (MNs) may be recruited in a manner dependent on their soma sizes or input resistances (IRs). In the dorsolateral part of the trigeminal motor nucleus (dl-TMN) in rats, MNs abundantly express TWIK (two-pore domain weak inwardly rectifying K channel) related acid-sensitive-K(+) channel (TASK)-1 and TASK3 channels, which determine the IR and resting membrane potential. Here we examined how TASK channels are involved in IR-dependent activation/recruitment of MNs in the rat dl-TMN by using multiple methods. The real-time PCR study revealed that single large MNs (>35 MUm) expressed TASK1 and TASK3 mRNAs more abundantly compared with single small MNs (15-20 MUm). The immunohistochemistry revealed that TASK1 and TASK3 channels were complementarily distributed in somata and dendrites of MNs, respectively. The density of TASK1 channels seemed to increase with a decrease in soma diameter while there were inverse relationships between the soma size of MNs and IR, resting membrane potential, or spike threshold. Dual whole-cell recordings obtained from smaller and larger MNs revealed that the recruitment of MNs depends on their IRs in response to repetitive stimulation of the presumed Ia afferents. 8-Bromoguanosine-cGMP decreased IRs in small MNs, while it hardly changed those in large MNs, and subsequently decreased the difference in spike-onset latency between the smaller and larger MNs, causing a synchronous activation of MNs. These results suggest that TASK channels play critical roles in rank-ordered recruitment of MNs in the dl-TMN. PMID- 27482538 TI - Claisen thermally rearranged (CTR) polymers. AB - Thermally rearranged (TR) polymers, which are considered the next-generation of membrane materials because of their excellent transport properties and high thermal and chemical stability, are proven to have significant drawbacks because of the high temperature required for the rearrangement and low degree of conversion during this process. We demonstrate that using a [3,3]-sigmatropic rearrangement, the temperature required for the rearrangement of a solid glassy polymer was reduced by 200 degrees C. Conversions of functionalized polyimide to polybenzoxazole of more than 97% were achieved. These highly mechanically stable polymers were almost five times more permeable and had more than two times higher degrees of conversion than the reference polymer treated under the same conditions. Properties of these second-generation TR polymers provide the possibility of preparing efficient polymer membranes in a form of, for example, thin-film composite membranes for various gas and liquid membrane separation applications. PMID- 27482539 TI - Large discrete jumps observed in the transition between Chern states in a ferromagnetic topological insulator. AB - A striking prediction in topological insulators is the appearance of the quantized Hall resistance when the surface states are magnetized. The surface Dirac states become gapped everywhere on the surface, but chiral edge states remain on the edges. In an applied current, the edge states produce a quantized Hall resistance that equals the Chern number C = +/-1 (in natural units), even in zero magnetic field. This quantum anomalous Hall effect was observed by Chang et al. With reversal of the magnetic field, the system is trapped in a metastable state because of magnetic anisotropy. We investigate how the system escapes the metastable state at low temperatures (10 to 200 mK). When the dissipation (measured by the longitudinal resistance) is ultralow, we find that the system escapes by making a few very rapid transitions, as detected by large jumps in the Hall and longitudinal resistances. Using the field at which the initial jump occurs to estimate the escape rate, we find that raising the temperature strongly suppresses the rate. From a detailed map of the resistance versus gate voltage and temperature, we show that dissipation strongly affects the escape rate. We compare the observations with dissipative quantum tunneling predictions. In the ultralow dissipation regime, two temperature scales (T 1 ~ 70 mK and T 2 ~ 145 mK) exist, between which jumps can be observed. The jumps display a spatial correlation that extends over a large fraction of the sample. PMID- 27482542 TI - Self-optimized superconductivity attainable by interlayer phase separation at cuprate interfaces. AB - Stabilizing superconductivity at high temperatures and elucidating its mechanism have long been major challenges of materials research in condensed matter physics. Meanwhile, recent progress in nanostructuring offers unprecedented possibilities for designing novel functionalities. Above all, thin films of cuprate and iron-based high-temperature superconductors exhibit remarkably better superconducting characteristics (for example, higher critical temperatures) than in the bulk, but the underlying mechanism is still not understood. Solving microscopic models suitable for cuprates, we demonstrate that, at an interface between a Mott insulator and an overdoped nonsuperconducting metal, the superconducting amplitude is always pinned at the optimum achieved in the bulk, independently of the carrier concentration in the metal. This is in contrast to the dome-like dependence in bulk superconductors but consistent with the astonishing independence of the critical temperature from the carrier density x observed at the interfaces of La2CuO4 and La2-x Sr x CuO4. Furthermore, we identify a self-organization mechanism as responsible for the pinning at the optimum amplitude: An emergent electronic structure induced by interlayer phase separation eludes bulk phase separation and inhomogeneities that would kill superconductivity in the bulk. Thus, interfaces provide an ideal tool to enhance and stabilize superconductivity. This interfacial example opens up further ways of shaping superconductivity by suppressing competing instabilities, with direct perspectives for designing devices. PMID- 27482541 TI - HU multimerization shift controls nucleoid compaction. AB - Molecular mechanisms controlling functional bacterial chromosome (nucleoid) compaction and organization are surprisingly enigmatic but partly depend on conserved, histone-like proteins HUalphaalpha and HUalphabeta and their interactions that span the nanoscale and mesoscale from protein-DNA complexes to the bacterial chromosome and nucleoid structure. We determined the crystal structures of these chromosome-associated proteins in complex with native duplex DNA. Distinct DNA binding modes of HUalphaalpha and HUalphabeta elucidate fundamental features of bacterial chromosome packing that regulate gene transcription. By combining crystal structures with solution x-ray scattering results, we determined architectures of HU-DNA nucleoproteins in solution under near-physiological conditions. These macromolecular conformations and interactions result in contraction at the cellular level based on in vivo imaging of native unlabeled nucleoid by soft x-ray tomography upon HUbeta and ectopic HUalpha38 expression. Structural characterization of charge-altered HUalphaalpha DNA complexes reveals an HU molecular switch that is suitable for condensing nucleoid and reprogramming noninvasive Escherichia coli into an invasive form. Collective findings suggest that shifts between networking and cooperative and noncooperative DNA-dependent HU multimerization control DNA compaction and supercoiling independently of cellular topoisomerase activity. By integrating x ray crystal structures, x-ray scattering, mutational tests, and x-ray imaging that span from protein-DNA complexes to the bacterial chromosome and nucleoid structure, we show that defined dynamic HU interaction networks can promote nucleoid reorganization and transcriptional regulation as efficient general microbial mechanisms to help synchronize genetic responses to cell cycle, changing environments, and pathogenesis. PMID- 27482543 TI - Recognition of influenza H3N2 variant virus by human neutralizing antibodies. AB - Since 2011, over 300 human cases of infection, especially in exposed children, with the influenza A H3N2 variant (H3N2v) virus that circulates in swine in the US have been reported. The structural and genetic basis for the lack of protection against H3N2v induced by vaccines containing seasonal H3N2 antigens is poorly understood. We isolated 17 human monoclonal antibodies (mAbs) that neutralized H3N2v virus from subjects experimentally immunized with an H3N2v candidate vaccine. Six mAbs exhibited very potent neutralizing activity (IC50 < 200 ng/ml) against the H3N2v virus but not against current human H3N2 circulating strains. Fine epitope mapping and structural characterization of antigen-antibody complexes revealed that H3N2v specificity was attributable to amino acid polymorphisms in the 150-loop and the 190-helix antigenic sites on the hemagglutinin protein. H3N2v-specific antibodies also neutralized human H3N2 influenza strains naturally circulating between 1995 and 2005. These results reveal a high level of antigenic relatedness between the swine H3N2v virus and previously circulating human strains, consistent with the fact that early human H3 seasonal strains entered the porcine population in the 1990s and reentered the human population, where they had not been circulating, as H3N2v about a decade later. The data also explain the increased susceptibility to H3N2v viruses in young children, who lack prior exposure to human seasonal strains from the 1990s. PMID- 27482544 TI - Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition. AB - High-grade serous ovarian carcinoma (HGS-OvCa) harbors p53 mutations and can originate from the epithelial cell compartment of the fallopian tube fimbriae. From this site, neoplastic cells detach, survive in the peritoneal cavity, and form cellular clusters that intercalate into the mesothelium to form ovarian and peritoneal masses. To examine the contribution of mutant p53 to phenotypic alterations associated with HGS-OvCA, we developed live-cell microscopy assays that recapitulate these early events in cultured fallopian tube nonciliated epithelial (FNE) cells. Expression of stabilizing mutant variants of p53, but not depletion of endogenous wild-type p53, in FNE cells promoted survival and cell cell aggregation under conditions of cell detachment, leading to the formation of cell clusters with mesothelium-intercalation capacity. Mutant p53R175H-induced phenotypes were dependent on fibronectin production, alpha5beta1 fibronectin receptor engagement, and TWIST1 expression. These results indicate that FNE cells expressing stabilizing p53 mutants acquire anchorage independence and subsequent mesothelial intercalation capacity through a mechanism involving mesenchymal transition and matrix production. These findings provide important new insights into activities of mutant p53 in the cells of origin of HGS-OvCa. PMID- 27482540 TI - Epigenetics and aging. AB - Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence. The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring. Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms. These new findings provide better understanding of the mechanisms involved in aging. Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age associated diseases, including cancer. PMID- 27482545 TI - Efficacy of lumacaftor-ivacaftor for the treatment of cystic fibrosis patients homozygous for the F508del-CFTR mutation. AB - Cystic fibrosis (CF) results from mutations in the CF transmembrane conductance regulator (CFTR) gene, which codes for the CFTR channel protein. The most common mutation in CF is F508del, which produces a misfolded protein with diminished channel activity. The development of small-molecule CFTR-modulator compounds offers an exciting and novel approach for pharmacological treatment of CF. The corrector lumacaftor helps rescue F508del-CFTR to the cell surface, and potentiator ivacaftor increases F508del-CFTR channel activity. The combination of lumacaftor-ivacaftor (Vertex Pharmaceuticals Incorporated) represents the first FDA-approved therapy for CF patients with two copies of the F508del mutation. Although this combination therapy is the first treatment to directly target the F508del-CFTR mutation, patients taking this drug displayed only modest improvements in lung function. This article summarizes recent data from clinical trials and research discoveries relating to the lumacaftor-ivacaftor treatment, and considers options for identifying future therapies that will be most efficacious for all CF patients. PMID- 27482546 TI - Myristoylated p110alpha Causes Embryonic Death Due to Developmental and Vascular Defects. AB - The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating the PIK3CA gene, encoding the p110alpha catalytic subunit of PI3K, is validated by frequent gain of function mutations in a range of human cancers. We generated a mouse model with an inducible constitutively active form of PI3K. In this model Cre recombinase activates expression of a myristoylated form of p110alpha (myr p110alpha). The myristoylated version of p110alpha brings the protein to the cytoplasmic side of the cell membrane, which mimics the normal activation mechanism for the p110alpha catalytic subunit and activates the PI3K enzyme. Constitutively activated PI3K signaling induced by myr-p110alpha in all cells of the developing mouse caused lethality during embryonic development. Transgenic Cre;myr-p110alpha heterozygous embryos displayed morphological malformation and poor vascular development with extremely dilated blood vessels and hemorrhage in the embryo and the extraembryonic yolk sac. Previous studies demonstrated that loss of p110alpha during embryonic development causes angiogenic disruption and here we show that constitutive activation of p110alpha by gain of function mutation during development also disrupts vasculogenesis/angiogenesis in what appears to be a similar manner. These finding demonstrate the importance of tight regulation of PI3K signaling during embryonic vasculogenesis/angiogenesis.. PMID- 27482547 TI - Electroporation by subnanosecond pulses. AB - Electropermeabilization of cell membranes by micro- and nanosecond-duration stimuli has been studied extensively, whereas effects of picosecond electric pulses (psEP) remain essentially unexplored. We utilized whole-cell patch clamp and Di-8-ANEPPS voltage-sensitive dye measurements to characterize plasma membrane effects of 500 ps stimuli in rat hippocampal neurons (RHN), NG108, and CHO cells. Even a single 500-ps pulse at 190 kV/cm increased membrane conductance and depolarized cells. These effects were augmented by applying brief psEP bursts (5-125 pulses), whereas the rate of pulse delivery (8Hz - 1 kHz) played little role. psEP-treated cells displayed large inward current at negative membrane potentials but modest or no conductance changes at positive potentials. A 1-kHz burst of 25 pulses increased the whole-cell conductance in the range (-100) - ( 60) mV to 22-26 nS in RHN and NG108 cells (from 3 and 0.7 nS, respectively), but only to 5 nS in CHO (from 0.3 nS). The conductance increase was reversible within about 2 min. Such pattern of cell permeabilization, with characteristic inward rectification and slow recovery, was similar to earlier reported effects of 60- and 600-ns pulses, pointing to the similarity of structural membrane rearrangements in spite of a different membrane charging mechanism. PMID- 27482549 TI - How to (properly) determine the beyond-use date and stability of a compounded formulation for pets. PMID- 27482550 TI - Attention and attractiveness. PMID- 27482548 TI - Microtubule-Mediated Misregulation of Junctophilin-2 Underlies T-Tubule Disruptions and Calcium Mishandling in mdx Mice. AB - Cardiac myocytes from the mdx mouse, the mouse model of Duchenne muscular dystrophy, exhibit t-tubule disarray and increased calcium sparks, but a unifying molecular mechanism has not been elucidated. Recently, improper trafficking of junctophilin-2 on an altered microtubule network caused t-tubule derangements and calcium mishandling in a pressure-overload heart failure model. Mdx cardiac myocytes have microtubule abnormalities, but how this may affect junctophilin-2, t-tubules, and calcium handling has not been established. Here, we investigated the hypothesis that an inverse relationship between microtubules and junctophilin 2 underlies t-tubule disruptions and calcium mishandling in mdx cardiac myocytes. Confocal microscopy revealed t-tubule disorganization in mdx cardiac myocytes. Quantitative Western blot analysis demonstrated junctophilin-2 was decreased by 75% and showed an inverse hyperbolic relationship with alpha- and beta-tubulin, the individual components of microtubules, in mdx hearts. Colchicine-induced microtubule depolymerization normalized junctophilin-2 protein levels and localization, corrected t-tubule architecture, and reduced calcium sparks. In summary, these results suggest microtubule-mediated misregulation of junctophilin 2 causes t-tubule derangements and altered calcium handling in mdx cardiac myocytes. PMID- 27482551 TI - THE ICEPICK OPERATION. PMID- 27482552 TI - Comment on "Multiple repressive mechanisms in the hippocampus during memory formation". AB - Cho et al. (Reports, 2 October 2015, p. 82) report that gene repression after contextual fear conditioning regulates hippocampal memory formation. We observe low levels of expression for many of the top candidate genes in the hippocampus and robust expression in the choroid plexus, as well as repression at 4 hours after contextual fear conditioning, suggesting the inclusion of choroid plexus messenger RNAs in Cho et al. hippocampal samples. PMID- 27482553 TI - Response to Comment on "Multiple repressive mechanisms in the hippocampus during memory formation". AB - Mathew et al. propose that many candidate genes identified in our study may reflect the events in the choroid plexus (ChP) potentially included in hippocampal samples. We reanalyze our data and find that the ChP inclusion is unlikely to affect our major conclusions regarding the basal suppression of translational machinery or the early translational repression (at 5 to 10 minutes). As Mathew et al. examined for a subset of genes at 4 hours, we agree that the late suppression may partly reflect the events in the ChP. Although the precise contribution of anatomical sources remains to be clarified, our behavioral analyses indicate that the late-phase suppression of these genes may contribute to memory formation. PMID- 27482554 TI - Zika Virus Infection and the Flint, Michigan, Water Crisis: A Study in Surprising Commonalities. PMID- 27482555 TI - Inspiring council change. PMID- 27482556 TI - The Saskatchewan Movement Disorders Program: Commitment Pays Off. PMID- 27482557 TI - Treatment of Refractory Status Epilepticus: Better Evidence is Needed. PMID- 27482558 TI - Diagnosis of Inclusion. PMID- 27482559 TI - A Year of Change and Further Changes Ahead. PMID- 27482560 TI - Obituary: Cesare Dal Palu MD 20-01-1923-18-01-2016. PMID- 27482561 TI - Illuminating Awareness: Implications of fMRI Research in Disorders of Consciousness. PMID- 27482562 TI - Zika Virus. PMID- 27482563 TI - Introduction: special issue on age effects in child language acquisition. PMID- 27482564 TI - Reply. PMID- 27482565 TI - Preprints in biology. PMID- 27482566 TI - Analyzing outliers: influential or nuisance? PMID- 27482567 TI - SYNTHETIC BIOLOGY. Customizing cell-cell communication. PMID- 27482568 TI - STRUCTURAL BIOLOGY. Breaking the diffraction barrier. PMID- 27482569 TI - GENOMICS. Cas9 and the importance of asymmetry. PMID- 27482570 TI - SENSORS AND PROBES. Yes to genetically encoded NO* sensors. PMID- 27482571 TI - SYSTEMS BIOLOGY. Protein isoforms: more than meets the eye. PMID- 27482572 TI - STEM CELLS. Reprogrammed cells leave their past lives behind. PMID- 27482573 TI - Pyrethroid Pesticide Metabolite in Urine and Microelements in Hair of Children Affected by Autism Spectrum Disorders: A Preliminary Investigation. AB - The number of children affected by Autism Spectrum Disorders (ASD) is dramatically increasing as well as the studies aimed at understanding the risk factors associated with the development of ASD. Since the etiology of ASD is partly genetic and partly environmental, factors (i.e., heavy metals, pesticides) as well as lifestyle seem to have a key role in the development of the disease. ASD and Control (CTR) children, aged 5-12 years, were compared. Gas chromatography coupled with trap mass detector was used to measure the level of 3 PBA, the main pyrethroid metabolite in urine in a group of ASD patients, while optical emission spectrometry analysis was employed to estimate the level of metals and microelements in hair in a different group of ASD children. The presence of 3-PBA in urine seems to be independent of age in ASD children, while a positive correlation between 3-PBA and age was observed in the control group of the same age range. Urine concentration of 3-BPA in ASD children had higher values than in the control group, which were marginally significant (p = 0.054). Mg results were significantly decreased in ASD with respect to controls, while V, S, Zn, and Ca/Mg were marginally increased, without reaching statistical significance. Results of Principal Component (PC) analysis of metals and microelements in hair were not associated with either age or health status. In conclusion, 3-PBA in urine and Mg in hair were changed in ASD children relative to control ones. PMID- 27482574 TI - Economies through Application of Nonmedical Primary-Preventative Health: Lessons from the Healthy Country Healthy People Experience of Australia's Aboriginal People. AB - The World Health Organization reports noncommunicable disease as a global pandemic. While national and international health research/policy bodies, such as the World Health Organization and the Australian Institute of Health and Welfare, emphasize the importance of preventative health, there is a continuing distortion in the allocation of resources to curative health as a result of government failure. Government failure is, in part, the result of a political response to individual preference for certainty in receiving treatment for specific health conditions, rather than the uncertainty of population-based preventative intervention. This has led to a failure to engage with those primary causative factors affecting chronic disease, namely the psychosocial stressors, in which the socioeconomic determinants are an important component. Such causal factors are open to manipulation through government policies and joint government government, government-private cooperation through application of nonmedical primary-preventative health policies. The health benefits of Aboriginal people in traditional land management, or caring-for-country, in remote to very remote Australia, is used to exemplify the social benefits of nonmedical primary preventative health intervention. Such practices form part of the "healthy country, health people" concept that is traditionally relied upon by Indigenous peoples. Possible health and wider private good and public good social benefits are shown to occur across multiple disciplines and jurisdictions with the possibility of substantial economies. General principles in the application of nonmedical primary-preventative health activities are developed through consideration of the experience of Afboriginal people participation in traditional caring-for-country. PMID- 27482575 TI - Response. PMID- 27482576 TI - Response. PMID- 27482577 TI - Response. PMID- 27482578 TI - Metastatic epithelioid angiosarcoma with bone marrow involvement. PMID- 27482579 TI - Response. PMID- 27482580 TI - Response. PMID- 27482581 TI - Response. PMID- 27482582 TI - Response. PMID- 27482583 TI - Response. PMID- 27482584 TI - Response. PMID- 27482585 TI - Response. PMID- 27482586 TI - Response. PMID- 27482587 TI - Response. PMID- 27482588 TI - Response. PMID- 27482589 TI - Preface. PMID- 27482590 TI - Transgender: why should we care? PMID- 27482591 TI - Suzanne Corkin. PMID- 27482592 TI - Overview and Summary: Healthcare and Quality: Perspectives from Nursing. PMID- 27482593 TI - Overview and Summary: APRN Roles: Opportunities and Challenges for Practice and Education. PMID- 27482594 TI - Overview and Summary: Healthy Nurses: Perspectives on Caring for Ourselves. PMID- 27482597 TI - Classical Characterization Techniques to Reveal the Structural Model of Nanocomposites with Bimetallic Monolayers of Porphyrins. AB - Nanocomposites with bimetallic monolayers of porphyrins were prepared. The well ordered metalloporphyrin monolayers covalently linked to the gold surface produce an important increase of the B band (~400 nm) shifted 20 nm relative to that of the related high-spin iron(III) complexes in solution. The position of the B band in the bimetallic architectures is highly dependent on the relative amount of the two porphyrins, showing the most significant shift for the SiO2/APTES/AuNp/Fe TPyP&M-TPyP (1:1) (30 nm, M = Ni(II) or Cu(II)). Resonance Raman based on the oxidation state marker bands (1553, 1354, and 390 cm(-1)) indicates that Fe-TPyP attached on gold nanoparticles adopts a low-spin Fe(II) conformation, which changes to Fe(II) intermediate spin or a low-spin Fe(III) in the presence of Cu TPyP or Ni-TPyP. Surface-enhanced Raman scattering studies confirmed the hypothesis. MALDI-TOF analysis of the composites on gold nanoparticles was very useful in the detection of oxygenated forms of the metal complexes. PMID- 27482595 TI - Prolonged Ocular Retention of Mucoadhesive Nanoparticle Eye Drop Formulation Enables Treatment of Eye Diseases Using Significantly Reduced Dosage. AB - Eye diseases, such as dry eye syndrome, are commonly treated with eye drop formulations. However, eye drop formulations require frequent dosing with high drug concentrations due to poor ocular surface retention, which leads to poor patient compliance and high risks of side effects. We developed a mucoadhesive nanoparticle eye drop delivery platform to prolong the ocular retention of topical drugs, thus enabling treatment of eye diseases using reduced dosage. Using fluorescent imaging on rabbit eyes, we showed ocular retention of the fluorescent dye delivered through these nanoparticles beyond 24 h while free dyes were mostly cleared from the ocular surface within 3 h after administration. Utilizing the prolonged retention of the nanoparticles, we demonstrated effective treatment of experimentally induced dry eye in mice by delivering cyclosporin A (CsA) bound to this delivery system. The once a week dosing of 0.005 to 0.01% CsA in NP eye drop formulation demonstrated both the elimination of the inflammation signs and the recovery of ocular surface goblet cells after a month. Thrice daily administration of RESTASIS on mice only showed elimination without recovering the ocular surface goblet cells. The mucoadhesive nanoparticle eye drop platform demonstrated prolonged ocular surface retention and effective treatment of dry eye conditions with up to 50- to 100-fold reduction in overall dosage of CsA compared to RESTASIS, which may significantly reduce side effects and, by extending the interdosing interval, improve patient compliance. PMID- 27482598 TI - Effects of the Grafting of Lanthanum Complexes on a Silica Surface on the Reactivity: Influence on Ethylene, Propylene, and 1,3-Butadiene Homopolymerization. AB - In this contribution, we report full details of the ethylene, 1,3-butadiene, and propylene homopolymerization processes mediated by alkylated bis(trimethyl)silylamide lanthanide-grafted complexes using a density functional theory (DFT) study of the initiation and first propagation steps. These systems allows us (i) to examine the role of the grafting mode on the kinetics and thermodynamics of the three processes considered, (ii) to confirm the catalytic behavior of these grafted complexes in ethylene polymerization, (iii) to rationalize the experimental preference for 1,4-cis polymerization of 1,3 butadiene, and (iv) to provide unprecedented information on the catalytic activity of the lanthanide-grafted complex as a propylene hompolymerization catalyst. PMID- 27482599 TI - Local Phase Separation of Co-solvents Enhances Pretreatment of Biomass for Bioenergy Applications. AB - Pretreatment facilitates more complete deconstruction of plant biomass to enable more economic production of lignocellulosic biofuels and byproducts. Various co solvent pretreatments have demonstrated advantages relative to aqueous-only methods by enhancing lignin removal to allow unfettered access to cellulose. However, there is a limited mechanistic understanding of the interactions between the co-solvents and cellulose that impedes further improvement of such pretreatment methods. Recently, tetrahydrofuran (THF) has been identified as a highly effective co-solvent for the pretreatment and fractionation of biomass. To elucidate the mechanism of the THF-water interactions with cellulose, we pair simulation and experimental data demonstrating that enhanced solubilization of cellulose can be achieved by the THF-water co-solvent system at equivolume mixtures and moderate temperatures (<=445 K). The simulations show that THF and water spontaneously phase separate on the local surface of a cellulose fiber, owing to hydrogen bonding of water molecules with the hydrophilic cellulose faces and stacking of THF molecules on the hydrophobic faces. Furthermore, a single fully solvated cellulose chain is shown to be preferentially bound by water molecules in the THF-water mixture. In light of these findings, co-solvent reactions were performed on microcrystalline cellulose and maple wood to show that THF significantly enhanced cellulose deconstruction and lignocellulose solubilization at simulation conditions, enabling a highly versatile and efficient biomass pretreatment and fractionation method. PMID- 27482600 TI - Do gender and birth height of infant affect calorie of human milk? An association study between human milk macronutrient and various birth factors. AB - OBJECTIVE: The purpose of this study is to analyze the macronutrient of human milk (HM) and to find out the various maternal-infantile factors that can affect HM composition. METHODS: 478 HM samples were collected from healthy and exclusively breast-feeding mothers who delivered healthy term neonates within 3 months. Macronutrient of the samples was analyzed and the birth data were collected. RESULTS: In multivariate logistic regression analysis, various maternal-infantile factors were found to be associated with HM composition changes; higher fat: cesarean section (OR = 2.47, p < 0.001) and birth height (OR = 0.84, p = 0.004); higher protein: postpartum age (OR = 0.89, p < 0.001); higher carbohydrate: vaginal delivery (OR = 0.50, p = 0.005) and female infant (OR = 0.56, p = 0.012); higher calorie: postpartum age (OR = 0.95, p = 0.003), female infant (OR = 0.33, p = 0.017), and birth height (OR = 0.74, p < 0.001). Female infant (OR = 0.36, p = 0.029), birth height (OR = 0.73, p = 0.001), and postpartum age (OR = 0.95, p = 0.005) were found as independent risk factors for higher HM calorie. CONCLUSION: Various maternal-infantile factors were found to affect HM composition. Interestingly, delivery mode, gender of infant, and birth height were associated with changes in HM macronutrient as well as postpartum age. PMID- 27482601 TI - Evaporation of Particle-Stabilized Emulsion Sunscreen Films. AB - We recently showed (Binks et al., ACS Appl. Mater. Interfaces, 2016, DOI: 10.1021/acsami.6b02696) how evaporation of sunscreen films consisting of solutions of molecular UV filters leads to loss of UV light absorption and derived sun protection factor (SPF). In the present work, we investigate evaporation-induced effects for sunscreen films consisting of particle-stabilized emulsions containing a dissolved UV filter. The emulsions contained either droplets of propylene glycol (PG) in squalane (SQ), droplets of SQ in PG or droplets of decane in PG. In these different emulsion types, the SQ is involatile and shows no evaporation, the PG is volatile and evaporates relatively slowly, whereas the decane is relatively very volatile and evaporates quickly. We have measured the film mass and area, optical micrographs of the film structure, and the UV absorbance spectra during evaporation. For emulsion films containing the involatile SQ, evaporation of the PG causes collapse of the emulsion structure with some loss of specular UV absorbance due to light scattering. However, for these emulsions with droplets much larger than the wavelength of light, the light is scattered only at small forward angles so does not contribute to the diffuse absorbance and the film SPF. The UV filter remains soluble throughout the evaporation and thus the UV absorption by the filter and the SPF remain approximately constant. Both PG-in-SQ and SQ-in-PG films behave similarly and do not show area shrinkage by dewetting. In contrast, the decane-in-PG film shows rapid evaporative loss of the decane, followed by slower loss of the PG resulting in precipitation of the UV filter and film area shrinkage by dewetting which cause the UV absorbance and derived SPF to decrease. Measured UV spectra during evaporation are in reasonable agreement with spectra calculated using models discussed here. PMID- 27482602 TI - The F0F1 ATP Synthase Complex Localizes to Membrane Rafts in Gonadotrope Cells. AB - Fertility in mammals requires appropriate communication within the hypothalamic pituitary-gonadal axis and the GnRH receptor (GnRHR) is a central conduit for this communication. The GnRHR resides in discrete membrane rafts and raft occupancy is required for signaling by GnRH. The present studies use immunoprecipitation and mass spectrometry to define peptides present within the raft associated with the GnRHR and flotillin-1, a key raft marker. These studies revealed peptides from the F0F1 ATP synthase complex. The catalytic subunits of the F1 domain were validated by immunoprecipitation, flow cytometry, and cell surface biotinylation studies demonstrating that this complex was present at the plasma membrane associated with the GnRHR. The F1 catalytic domain faces the extracellular space and catalyzes ATP synthesis when presented with ADP in normal mouse pituitary explants and a gonadotrope cell line. Steady-state extracellular ATP accumulation was blunted by coadministration of inhibitory factor 1, limiting inorganic phosphate in the media, and by chronic stimulation of the GnRHR. Steady state extracellular ATP accumulation was enhanced by pharmacological inhibition of ecto-nucleoside triphosphate diphosphohydrolases. Kisspeptin administration induced coincident GnRH and ATP release from the median eminence into the hypophyseal-portal vasculature in ovariectomized sheep. Elevated levels of extracellular ATP augmented GnRH-induced secretion of LH from pituitary cells in primary culture, which was blocked in media containing low inorganic phosphate supporting the importance of extracellular ATP levels to gonadotrope cell function. These studies indicate that gonadotropes have intrinsic ability to metabolize ATP in the extracellular space and extracellular ATP may serve as a modulator of GnRH-induced LH secretion. PMID- 27482604 TI - Equipment-Free Deposition of Graphene-Based Molybdenum Oxide Nanohybrid Langmuir Blodgett Films for Flexible Electrochromic Panel Application. AB - The potential electrochromic application of graphene-based nanohybrids is hampered by the challenges in interfacing the electrochromic nanoparticles with graphene at atomic scale and in fabricating their thin film on the substrate through a scalable method. In an effort to overcome these challenges, we demonstrate a highly dispersible graphene-based molybdenum oxide nanohybrid (mRGO MoO3-x) for flexible electrochromic application. With only a squeeze pipet, mRGO MoO3-x could be deposited with a high coverage on various substrates through a scalable equipment-free Langmuir-Blodgett film deposition method. By taking advantage of high transmittance benefited from its remarkable thinness, the mRGO MoO3-x Langmuir-Blodgett film shows a superior reversible electrochromic property with high coloration efficiency on both hard and flexible substrates. PMID- 27482605 TI - Understanding the Catalytic Mechanism of Xanthosine Methyltransferase in Caffeine Biosynthesis from QM/MM Molecular Dynamics and Free Energy Simulations. AB - S-Adenosyl-l-methionine (SAM) dependent xanthosine methyltransferase (XMT) is the key enzyme that catalyzes the first methyl transfer in the caffeine biosynthesis pathway to produce the intermediate 7-methylxanthosine (7mXR). Although XMT has been a subject of extensive discussions, the catalytic mechanism and nature of the substrate involved in the catalysis are still unclear. In this paper, quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy (potential of mean force or PMF) simulations are undertaken to determine the catalytic mechanism of the XMT-catalyzed reaction. Both xanthosine and its monoanionic form with N3 deprotonated are used as the substrates for the methylation. It is found that while the methyl group can be transferred to the monoanionic form of xanthosine with a reasonable free energy barrier (about 17 kcal/mol), that is not the case for the neutral xanthosine. The results suggest that the substrate for the first methylation step in the caffeine biosynthesis pathway is likely to be the monoanionic form of xanthosine rather than the neutral form as widely adopted. This conclusion is supported by the pKa value on N3 of xanthosine both measured in aqueous phase and calculated in the enzymatic environment. The structural and dynamics information from both the X-ray structure and MD simulations is also consistent with the monoanionic xanthosine scenario. The implications of this conclusion for caffeine biosynthesis are discussed. PMID- 27482603 TI - Metabolism and the Control of Cell Fate Decisions and Stem Cell Renewal. AB - Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical. PMID- 27482607 TI - Charge Injection at the Heterointerface in Perovskite CH3NH3PbI3 Solar Cells Studied by Simultaneous Microscopic Photoluminescence and Photocurrent Imaging Spectroscopy. AB - Charge carrier dynamics in perovskite CH3NH3PbI3 solar cells were studied by means of microscopic photoluminescence (PL) and photocurrent (PC) imaging spectroscopy. The PL intensity, PL lifetime, and PC intensity varied spatially on the order of several tens of micrometers. Simultaneous PL and PC image measurements revealed a positive correlation between the PL intensity and PL lifetime, and a negative correlation between PL and PC intensities. These correlations were due to the competition between photocarrier injection from the CH3NH3PbI3 layer into the charge transport layer and photocarrier recombination within the CH3NH3PbI3 layer. Furthermore, we found that the decrease in the carrier injection efficiency under prolonged light illumination leads to a reduction in PC, resulting in light-induced degradation of solar cell devices. Our findings provide important insights for understanding carrier injection at the interface and light-induced degradation in perovskite solar cells. PMID- 27482606 TI - Pd-on-Au Supra-nanostructures Decorated Graphene Oxide: An Advanced Electrocatalyst for Fuel Cell Application. AB - We report a very easy and effective approach for synthesizing unique palladium-on gold supra-nanostructure (Au@Pd-SprNS)-decorated graphene oxide (GO) nanosheets. The SprNSs comprising Au nanorods as core and a unique close-packed assembly of tiny anisotropic Pd nanoparticles (NPs) as shell were homogeneously distributed on the GO surface via electrostatic self-assembly. Compared with the traditional one-pot method for synthesis of metal NPs on GO sheets, the size and shape of core-shell Au@Pd SprNSs can be finely controlled and uniformly distributed on the GO carrier. Interestingly, this Au@Pd-SprNSs/GO nanocomposite displayed high electrocatalytic activities toward the oxidation of methanol, ethanol, and formic acid, which can be attributed to the abundance of intrinsic active sites including high density of atomic steps, ledges and kinks, Au-Pd heterojunctions and cooperative action of the two metals of the SprNSs. Additionally, uniform dispersion of the SprNSs over the GO nanosheets prevent agglomeration between the SprNSs, which is of great significance to enhance the long-term stability of catalyst. This work will introduce a highly efficient Pd-based nanoelectrocatalyst to be used in fuel cell application. PMID- 27482608 TI - EFFECTS OF LONG-TERM ALENDRONATE TREATMENT ON A LARGE SAMPLE OF PEDIATRIC PATIENTS WITH OSTEOGENESIS IMPERFECTA. AB - OBJECTIVE: Osteogenesis imperfecta (OI) is a group of inherited diseases characterized by reduced bone mass, recurrent bone fractures, and progressive bone deformities. Here, we evaluate the efficacy and safety of long-term treatment with alendronate in a large sample of Chinese children and adolescents with OI. METHODS: In this prospective study, a total of 91 children and adolescents with OI were included. The patients received 3 years' treatment with 70 mg alendronate weekly and 500 mg calcium daily. During the treatment, fracture incidence, bone mineral density (BMD), and serum levels of the bone turnover biomarkers (alkaline phosphatase [ALP] and cross-linked C-telopeptide of type I collagen [beta-CTX]) were evaluated. Linear growth speed and parameters of safety were also measured. RESULTS: After 3 years of treatment, the mean annual fracture incidence decreased from 1.2 +/- 0.8 to 0.2 +/- 0.3 (P<.01). BMD at the lumbar spine and femoral neck significantly increased by 74.6% and 39.5%, with their BMD Z-score increasing from -3.0 to 0.1 and from -4.2 to -1.3, respectively (both P<.01 vs. baseline). In addition, serum ALP and beta-CTX levels decreased by 35.6% and 44.3%, respectively (both P<.05 vs. baseline). Height significantly increased, but without an obvious increase in its Z-score. Patient tolerance of alendronate was good. CONCLUSION: Three years' treatment with alendronate was demonstrated for the first time to significantly reduce fracture incidence, increase lumbar spine and femoral neck BMD, and decrease bone turnover biomarkers in Chinese children and adolescents with OI. ABBREVIATIONS: ALP = alkaline phosphatase beta-CTX = cross-linked C-telopeptide of type I collagen BMD = bone mineral density BP = bisphosphonate DXA = dual-energy X-ray absorptiometry 25OHD = 25-hydroxyvitamin D OI = osteogenesis imperfecta PTH = parathyroid hormone. PMID- 27482609 TI - ITALIAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS STATEMENT-REPLACEMENT THERAPY FOR PRIMARY HYPOTHYROIDISM: A BRIEF GUIDE FOR CLINICAL PRACTICE. AB - OBJECTIVE: Hypothyroidism requires life-long thyroid hormone replacement therapy in most patients. Oral levothyroxine (LT4) is an established safe and effective treatment for hypothyroidism, but some issues remain unsettled. METHODS: The Italian Association of Clinical Endocrinologists appointed a panel of experts to provide an updated statement for appropriate use of thyroid hormone formulations for hypothyroidism replacement therapy. The American Association of Clinical Endocrinologists' protocol for standardized production of clinical practice guidelines was followed. RESULTS: LT4 is the first choice in replacement therapy. Thyroid-stimulating hormone (TSH) should be maintained between 1.0 and 3.0 mIU/L in young subjects and at the upper normal limit in elderly or fragile patients. Achievement of biochemical targets, patient well-being, and adherence to treatment should be addressed. In patients with unstable serum TSH, a search for interfering factors and patient compliance is warranted. Liquid or gel formulations may be considered in subjects with hampered LT4 absorption or who do not allow sufficient time before or after meals and LT4 replacement. Replacement therapy with LT4 and L-triiodothyronine (LT3) combination is generally not recommended. A trial may be considered in patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism only after co-existent nonthyroid problems have been excluded or optimally managed. LT3 should be administered in small (LT4:LT3 ratio, 10:1 to 20:1) divided daily doses. Combined therapy should be avoided in elderly patients or those with cardiac risk factors and in pregnancy. CONCLUSION: LT4 therapy should be aimed at resolution of symptoms of hypothyroidism, normalization of serum TSH, and improvement of quality of life. In selected cases, the use of liquid LT4 formulations or combined LT4/LT3 treatment may be considered to improve adherence to treatment or patient well-being. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists FT3 = free triiodothyronine FT4 = free thyroxine LT3 = levotriiodothyronine LT4 = levothyroxine MeSH = medicine medical subject headings QoL = quality of life TSH = thyroid-stimulating hormone. PMID- 27482610 TI - EFFECTS OF LIRAGLUTIDE 3.0 MG ON WEIGHT AND RISK FACTORS IN HISPANIC VERSUS NON HIPANIC POPULATIONS: SUBGROUP ANALYSIS FROM SCALE RANDOMIZED TRIALS. AB - OBJECTIVE: Scarce data exist on pharmacotherapy for obesity in Hispanic individuals. This post hoc analysis of pooled data from 4 phase 3a trials compared the efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to a reduced-calorie diet and physical activity, in Hispanic versus non-Hispanic subgroups. METHODS: We conducted the double-blind randomized, placebo-controlled trials in adults with a minimum body mass index (BMI) of 27 kg/m2 with at least 1 comorbidity, or a minimum BMI of 30 kg/m2, at clinical research sites worldwide. In this analysis, we investigated possible differences in treatment effects between 534 Hispanics (10.4% of the population) and 4,597 non-Hispanics (89.6%) through statistical tests of interaction between subgroups and treatment. Variables examined included mean and categorical weight change, cardiovascular risk markers, and safety data. RESULTS: Both subgroups achieved clinically significant mean weight loss at end-of-treatment with liraglutide 3.0 mg versus placebo: Hispanics 7.0% versus 1.5%, treatment difference -5.1% (95% CI, -6.2 to 4.0); non-Hispanics 7.5% versus 2.3%, -5.2% (95% CI, -5.5 to -4.8). More individuals in both subgroups lost >=5%, >10%, and >15% of their baseline weight with liraglutide 3.0 mg than with placebo. Efficacy endpoints generally did not vary with ethnicity (P>.05). Adverse events were comparable between ethnic subgroups, with more gastrointestinal disorders reported with liraglutide 3.0 mg than placebo. CONCLUSION: Efficacy and safety were largely similar between Hispanic and non-Hispanic subgroups. Results support that liraglutide 3.0 mg, used with a reduced-calorie diet and physical activity, can facilitate weight loss in Hispanic individuals. ABBREVIATIONS: A1c = glycated hemoglobin BMI = body mass index CI = confidence interval FPG = fasting plasma glucose GLP-1 = glucagon like peptide-1 hsCRP = high-sensitivity C-reactive protein SCALE = Satiety and Clinical Adiposity - Liraglutide Evidence in individuals with and without diabetes T2DM = type 2 diabetes mellitus. PMID- 27482611 TI - PRE-ABLATION THYROGLOBULIN AND THYROGLOBULIN TO THYROID-STIMULATING HORMONE RATIO MAY BE ASSOCIATED WITH PULMONARY METASTASES IN CHILDREN WITH DIFFERENTIATED THYROID CANCER. AB - OBJECTIVE: Pediatric differentiated thyroid cancer (DTC) frequently presents with extensive disease. We studied the value of pre-ablation thyroglobulin (Tg) and Tg normalized to thyroid-stimulating hormone (TSH) levels in predicting distant metastases in pediatric patients with DTC. METHODS: This is a retrospective cohort study of patients <21 years old who underwent thyroidectomy followed by 131I ablation for DTC at 3 university hospitals over 20 years. Tg levels and the Tg/TSH ratio following surgery but prior to 131I ablation were assessed. The presence of distant metastatic disease was determined from the postablation whole body scan. RESULTS: We studied 44 patients with a mean age of 15.2 years (range 7 to 21 years) and mean tumor size of 2.8 cm. Eight patients had distant metastases and had a higher mean pre-ablation Tg value compared to patients without distant metastases (1,037 MUg/L versus 93.5 MUg/L, P<.01). The pre-ablation Tg/TSH ratio was also associated with the presence of distant metastases: 12.5 +/- 18.8 MUg/mU in patients with distant metastases versus 0.7 +/- 1.8 MUg/mU in patients without (P<.01). A nomogram to predict distant metastases yielded areas under the receiver operating characteristic curve of 0.85 for Tg and 0.83 for Tg/TSH ratio. CONCLUSION: After initial thyroidectomy, elevated preablation Tg and Tg/TSH ratio are associated with distant metastatic disease in pediatric DTC. This may inform the decision to ablate with 131I, as well as the dosage. ABBREVIATIONS: ATA = American Thyroid Association CI = confidence interval DTC = differentiated thyroid cancer OR = odds ratio ROC = receiver operating characteristic Tg = thyroglobulin. PMID- 27482612 TI - THE ASSOCIATION OF THYROID HORMONES AND TSH WITH THE METABOLIC SYNDROME IN EUTHYROID TAIWANESE INDIVIDUALS. AB - OBJECTIVE: There are conflicting studies in euthyroid males and females regarding associations between thyroidrelated hormones and parameters of the metabolic syndrome (MetS). We investigated the association between serum thyroid hormones and thyroid-stimulating hormone (TSH) concentrations and MetS in euthyroid men and women. METHODS: Taiwanese subjects aged 20 to 65 years who had undergone a voluntary health examination at a preventive examination agency in Taipei were enrolled in this cross-sectional study. The definition of MetS was suggested by the Bureau of Health Promotion, Department of Health, Taiwan. Euthyroidism was defined as TSH and free thyroxine (FT4) levels within the normal reference ranges while not taking any thyroid medication. We conducted multiple logistic regression to identify the ability of serum triiodothyronine (T3), FT4, and TSH concentrations to identify the relative risk for the presence of MetS and components of the MetS in euthyroid Taiwanese individuals. RESULTS: A total of 8,207 Taiwanese subjects (mean age: men, 45.3 +/- 9.9 years; women, 43.5 +/- 9.3 years) were enrolled in this study. A total of 1,672 subjects (20.4%) were defined as having MetS; these subjects had significantly higher (P<.0001) mean age (48.4 +/- 9.1 years vs. 43.6 +/- 10.7 years), prevalence of men (78.7% vs. 53.4%), and smoking (16.8% vs. 11.6%) than those without MetS. The median TSH, FT4, and T3 levels in all subjects were 1.70 mIU/L, 1.41 ng/dL, and 1.20 ng/mL, respectively. Higher T3 and lower FT4 values rather than TSH increased the odds ratio for MetS in men and women after adjusting for smoking and age, particularly for the association of T3 and MetS in women (uppermost quartile versus lowermost quartile: odds ratio, 2.4; 95% confidence interval, 1.6 to 3.5; P for trend <.0001). CONCLUSION: In euthyroid Taiwanese men and women, relatively high serum T3 concentrations was most strongly associated with the presence of the MetS; relatively low serum T4 was less strongly related, and serum TSH levels were not associated with the MetS. It is not known if the relationship of serum T3 and T4 to the MetS is causal. ABBREVIATIONS: BMI = body mass index FT4 = free thyroxine MetS = metabolic syndrome OR = odds ratio T3 = triiodothyronine TSH = thyroid stimulating hormone WC = waist circumference. PMID- 27482613 TI - PERFORMANCE OF A1C VERSUS OGTT FOR THE DIAGNOSIS OF PREDIABETES IN A COMMUNITY BASED SCREENING. AB - OBJECTIVE: Reliable identification of individuals at risk for developing diabetes is critical to instituting preventative strategies. Studies suggest that the accuracy of using hemoglobin A1c as a sole diagnostic criterion for diabetes may be variable across different ethnic groups. We postulate that there will be lack of concordance between A1c and the oral glucose tolerance test (OGTT) for diagnosing prediabetes across Hispanic and non-Hispanic white (NHW) populations. METHODS: A total of 218 asymptomatic adults at risk for type 2 diabetes (T2D) were assessed with A1c and OGTT for the diagnosis of prediabetes. Glucose homeostasis status was assigned as no diabetes (A1c <5.7% [39 mmol/mol]), prediabetes (A1c 5.7 to 6.4% [46 mmol/mol]), and T2D (A1c >6.4% [46 mmol/mol]). Inclusion criteria were age >18 years and at least one of the following: a family history of diabetes, a history of gestational diabetes, Hispanic ethnicity, non Caucasian race, or obesity. Subjects received a fasting 75-g OGTT and A1c on the same day. Bowker's test of symmetry was employed to determine agreement between the tests. RESULTS: Data from 99 Hispanic patients and 79 NHW patients were analyzed. There was no concordance between A1c and OGTT for Hispanic (P = .002) or NHW individuals (P = .003) with prediabetes. CONCLUSION: A1c is discordant with OGTT among Hispanic and NHW subjects for the diagnosis of prediabetes. Sole use of A1c to designate glycemic status will result in a greater prevalence of prediabetes among Hispanic and NHW New Mexicans. ABBREVIATIONS: A1c = hemoglobin A1c BMI = body mass index CDC = Centers for Disease Control CI = confidence interval FPG = fasting plasma glucose NHW = non-Hispanic white OGTT = oral glucose tolerance test T2D = type 2 diabetes WHO = World Health Organization. PMID- 27482614 TI - SERUM LEVELS OF CARCINOEMBRYONIC ANTIGEN IN PATIENTS WITH TYPE 2 DIABETES. AB - OBJECTIVE: To investigate whether serum carcinoembryonic antigen (CEA) levels are associated with type 2 diabetes mellitus (T2DM) and glycated hemoglobin (HbA1c). METHODS: A comparative, cross-sectional, observational study was conducted at Jordan University Hospital, Amman, Jordan, on 282 adult subjects from March 2012 to June 2015. Subjects were classified into 2 groups: T2DM subjects (n = 168) and a healthy comparison group (n = 114). Subjects with any condition known to be associated with elevated CEA levels were excluded. HbA1c and serum CEA levels were measured, and body mass index (BMI) was determined. RESULTS: Subjects with T2DM had significantly higher mean serum CEA than controls (2.4 +/- 1.5 vs. 1.5 +/- 1.2 ng/mL, P<.0001). Sex did not correlate with CEA levels, while age (Spearman's rho [rho] = 0.18, P = .002) and HbA1c (rho = 0.56, P<.0001) did; however, age no longer correlated after correcting for diabetic status. HbA1c was the only variable shown to correlate with CEA in a stepwise linear regression (r = 0 .37, P<.001). CONCLUSION: We observed a statistically significant association between elevated CEA and T2DM, despite average CEA values for both groups being within the reference range. In addition, serum CEA levels correlated positively with HbA1c values. ABBREVIATIONS: ADA = American Diabetes Association BMI = body mass index CA 19-9 = carbohydrate antigen 19-9 CEA = carcinoembryonic antigen CRP = C-reactive protein DM = diabetes mellitus HbA1c = glycated hemoglobin JUH = Jordan University Hospital T2DM = type 2 diabetes mellitus rho = Spearman's correlation coefficient. PMID- 27482615 TI - THE CLINICAL CHARACTERISTICS AND EFFICACY OF BISPHOSPHONATES IN AUDLT PATIENTS WITH OSTEOGENESIS IMPERGECTA. AB - OBJECTIVE: Osteogenesis imperfecta (OI) is characterized by low bone mass and recurrent fractures. Adults with OI are often treated with oral or intravenous bisphosphonates (BPs). We investigated the clinical phenotypes of adult OI patients and prospectively compared the efficacy of oral alendronate (ALN) with intravenous zoledronic acid (ZOL) in OI patients. METHODS: This 24-month, observational, randomized clinical study included 60 adult patients with OI. We compared the differences in bone mineral density (BMD) and bone turnover biomarkers between OI adults and healthy subjects. Thereafter, OI patients were randomized at a 2:1 ratio to receive either weekly oral ALN 70 mg or once-yearly infusion of ZOL 5 mg. The efficacy outcomes were changes in BMD, bone turnover biomarkers, and fracture incidence. RESULTS: Adult OI patients had significantly lower BMD and significantly higher cross-linked C-telopeptide of type I collagen (beta-CTX) levels than age-/sex-/BMI-matched healthy subjects. A total of 52 patients completed the 24-month clinical study. BMD at lumbar spine, femoral neck, and total hip were equivalently elevated in the ALN (10.5, 13.2, and 14.7%, respectively) and ZOL (11.3, 13.7, and 11.7%, respectively; all P>.05) groups. Serum alkaline phosphatase decreased by 30.3% in the ALN group and 37.3% in the ZOL group (P = .12), and beta-CTX decreased by 58.0% in the ALN group and 63.6% in the ZOL group (P = .48). Compared to the prior fracture rates, clinical fracture incidences were decreased in the ALN and ZOL groups (both P<.05). CONCLUSION: Adults with OI present significantly lower bone mass and higher bone resorption biomarkers than healthy populations. Oral ALN and intravenous ZOL are equally effective at increasing BMD and inhibiting bone turnover in adults with OI. The treatment may reduce fractures in this study, but further efforts are still needed to demonstrate the anti-fracture efficacy of BPs. ABBREVIATIONS: 25OHD = 25-hydroxyvitamin D ALN = alendronate ALP = alkaline phosphatase BMD = bone mineral density BMI = body mass index BP = bisphosphonate beta-CTX = cross linked C-telopeptide of type I collagen FN = femoral neck LS = lumbar spine OI = osteogenesis imperfecta RCT = randomized controlled trial TH = total hip ZOL = zoledronic acid. PMID- 27482618 TI - Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5 (trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against gamma Thrombin. AB - Here, we describe the development of a series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3. Of these, 9j (PAR4 IC50 = 445 nM, PAR1 response IC50 > 30 MUM) and 10h (PAR4 IC50 = 179 nM, PAR1 response IC50 > 30 MUM) maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against gamma-thrombin. PMID- 27482620 TI - Global and Regional Evaluation of Energy for Water. AB - Despite significant effort to quantify the interdependence of the water and energy sectors, global requirements of energy for water (E4W) are still poorly understood, which may result in biases in projections and consequently in water and energy management and policy. This study estimates water-related energy consumption by water source, sector, and process for 14 global regions from 1973 to 2012. Globally, E4W amounted to 10.2 EJ of primary energy consumption in 2010, accounting for 1.7%-2.7% of total global primary energy consumption, of which 58% pertains to fresh surface water, 30% to fresh groundwater, and 12% to nonfresh water, assuming median energy intensity levels. The sectoral E4W allocation includes municipal (45%), industrial (30%), and agricultural (25%), and main process-level contributions are from source/conveyance (39%), water purification (27%), water distribution (12%), and wastewater treatment (18%). While the United States was the largest E4W consumer from the 1970s until the 2000s, the largest consumers at present are the Middle East, India, and China, driven by rapid growth in desalination, groundwater-based irrigation, and industrial and municipal water use, respectively. The improved understanding of global E4W will enable enhanced consistency of both water and energy representations in integrated assessment models. PMID- 27482619 TI - The effects of backward walking training on balance and mobility in an individual with chronic incomplete spinal cord injury: A case report. AB - BACKGROUND/PURPOSE: Individuals with incomplete spinal cord injuries (ISCIs) commonly face persistent gait impairments. Backward walking training may be a useful rehabilitation approach, providing novel gait and balance challenges. However, little is known about the effects of this approach for individuals with ISCIs. The purpose of this case report was to describe the effects of backward walking training on strength, balance, and upright mobility in an individual with chronic ISCI. METHODS: A 28-year-old female, 11-years post ISCI (C4, AIS D) completed 18-sessions of backward walking training on a treadmill with partial body-weight support and overground. Training emphasized stepping practice, speed, and kinematics. Outcome measures included: Lower Extremity Motor Score, Berg Balance Scale (BBS), Sensory Organization Test (SOT), 10-Meter Walk Test (10MWT), 3-meter backward walking test, Timed Up and Go (TUG), and Activities-Specific Balance Confidence (ABC) Scale. RESULTS: Strength did not change. Improved balance was evident based on BBS (20 to 37/56) and SOT scores (27 to 40/100). Upright mobility improved based on TUG times (57 to 32.7 s), increased 10MWT speed (0.23 to 0.31 m/s), and backward gait speed (0.07 to 0.12 m/s). Additionally, self-reported balance confidence (ABC Scale) increased from 36.9% to 49.6%. CONCLUSIONS: The results suggest that backward walking may be a beneficial rehabilitation approach; examination of the clinical efficacy is warranted. PMID- 27482621 TI - Angle-resolved heat capacity of heavy fermion superconductors. AB - Owing to a strong Coulomb repulsion, heavy electron superconductors mostly have anisotropic gap functions which have nodes for certain directions in the momentum space. Since the nodal structure is closely related to the pairing mechanism, its experimental determination is of primary importance. This article discusses the experimental methods of the gap determination by bulk heat capacity measurements in a rotating magnetic field. The basic idea is based on the fact that the quasiparticle density of states in the vortex state of nodal superconductors is field and direction dependent. We present our recent experimental results of the field-orientation dependence of the heat capacity in heavy fermion superconductors CeTIn5 (T = Co, Ir), UPt3, CeCu2Si2, and UBe13 and discuss their gap structures. PMID- 27482622 TI - Leptospira interrogans in Rodents from Cape Verde. AB - Leptospirosis is an important worldwide zoonotic disease that can infect both animals and humans. In most cases, leptospirosis is a nonspecific self-limiting illness, but some patients can develop a severe form with a high mortality. This study was carried out in Santiago Island, Cape Verde, in 2012-2013. A total of 62 wild rodents (Rattus rattus and Mus domesticus) were analyzed. The lipL32 gene, present only in pathogenic Leptospira spp., was amplified by PCR, and 16 samples were positive (25.8%). In both rodent species, Leptospira interrogans was identified. The results show the presence of pathogenic Leptospira in the three localities analyzed in Santiago. The presence of L. interrogans demonstrates a serious health risk for the population, since this species has been associated with the most severe form of leptospirosis, the Weil's disease in humans, a severe infection with jaundice, renal failure, and hemorrhage. PMID- 27482623 TI - Electron Energy Loss Spectroscopy Investigation into Symmetry in Gold Trimer and Tetramer Plasmonic Nanoparticle Structures. AB - We present a combined scanning transmission electron microscopy-electron energy loss spectroscopy (STEM-EELS) investigation into the mode symmetries of plasmonic nanoparticle trimer and tetramer structures. We obtain nanometer-resolved energy loss spectra for both trimer and tetramer structures and compare these to boundary element method simulations. We show that EELS, in conjunction with eigenmode simulations, offers a complete characterization of the individual superstructures, and we trace the evolution of both optically dark and bright modes and identify multipolar mode contributions. We then apply this technique to tetramer structures that exhibit an expanded range of mode symmetries for two dimensional and three-dimensional self-assembled geometries. These findings provide a comprehensive experimental account of the available photonic states in self-assembled nanoparticle clusters. PMID- 27482624 TI - Evaluation of the Spatiotemporal Dynamics of Oxytetracycline and Its Control Effect Against Citrus Huanglongbing via Trunk Injection. AB - Citrus huanglongbing (HLB) or greening is a devastating bacterial disease that has destroyed millions of trees and is associated with phloem-residing 'Candidatus Liberibacter asiaticus' (Las) in Florida. In this study, we evaluated the spatiotemporal dynamics of oxytetracycline in planta and its control effect against HLB via trunk injection. Las-infected 'Hamlin' sweet orange trees on 'Swingle' citrumelo rootstock at the early stage of decline were treated with oxytetracycline hydrochloride (OTC) using trunk injection with varying number of injection ports. Spatiotemporal distribution of OTC and dynamics of Las populations were monitored by high-performance liquid chromatography method and qPCR assay, respectively. Uniform distribution of OTC throughout tree canopies and root system was achieved 2 days postinjection. High levels of OTC (>850 ug/kg) were maintained in leaf and root for at least 1 month and moderate OTC (>500 ug/kg) persisted for more than 9 months. Reduction of Las populations in root system and leaves of OTC-treated trees were over 95% and 99% (i.e., 1.76 and 2.19 log reduction) between 2 and 28 days postinjection. Conditions of trees receiving OTC treatment were improved, fruit yield was increased, and juice acidity was lowered than water-injected control even though their differences were not statistically significant during the test period. Our study demonstrated that trunk injection of OTC could be used as an effective measure for integrated management of citrus HLB. PMID- 27482625 TI - Microbiome Networks: A Systems Framework for Identifying Candidate Microbial Assemblages for Disease Management. AB - Network models of soil and plant microbiomes provide new opportunities for enhancing disease management, but also challenges for interpretation. We present a framework for interpreting microbiome networks, illustrating how observed network structures can be used to generate testable hypotheses about candidate microbes affecting plant health. The framework includes four types of network analyses. "General network analysis" identifies candidate taxa for maintaining an existing microbial community. "Host-focused analysis" includes a node representing a plant response such as yield, identifying taxa with direct or indirect associations with that node. "Pathogen-focused analysis" identifies taxa with direct or indirect associations with taxa known a priori as pathogens. "Disease-focused analysis" identifies taxa associated with disease. Positive direct or indirect associations with desirable outcomes, or negative associations with undesirable outcomes, indicate candidate taxa. Network analysis provides characterization not only of taxa with direct associations with important outcomes such as disease suppression, biofertilization, or expression of plant host resistance, but also taxa with indirect associations via their association with other key taxa. We illustrate the interpretation of network structure with analyses of microbiomes in the oak phyllosphere, and in wheat rhizosphere and bulk soil associated with the presence or absence of infection by Rhizoctonia solani. PMID- 27482626 TI - Disease Management in the Genomics Era-Summaries of Focus Issue Papers. AB - The genomics revolution has contributed enormously to research and disease management applications in plant pathology. This development has rapidly increased our understanding of the molecular mechanisms underpinning pathogenesis and resistance, contributed novel markers for rapid pathogen detection and diagnosis, and offered further insights into the genetics of pathogen populations on a larger scale. The availability of whole genome resources coupled with next generation sequencing (NGS) technologies has helped fuel genomics-based approaches to improve disease resistance in crops. NGS technologies have accelerated the pace at which whole plant and pathogen genomes have become available, and made possible the metagenomic analysis of plant-associated microbial communities. Furthermore, NGS technologies can now be applied routinely and cost effectively to rapidly generate plant and/or pathogen genome or transcriptome marker sequences associated with virulence phenotypes in the pathogen or resistance phenotypes in the plant, potentially leading to improvements in plant disease management. In some systems, investments in plant and pathogen genomics have led to immediate, tangible benefits. This focus issue covers some of the systems. The articles in this focus issue range from overall perspective articles to research articles describing specific genomics applications for detection and control of diseases caused by nematode, viral, bacterial, fungal, and oomycete pathogens. The following are representative short summaries of the articles that appear in this Focus Issue . PMID- 27482627 TI - Spatiotemporal Patterns in the Airborne Dispersal of Spinach Downy Mildew. AB - Downy mildew is the most devastating disease threatening sustainable spinach production, particularly in the organic sector. The disease is caused by the biotrophic oomycete pathogen Peronospora effusa, and the disease results in yellow lesions that render the crop unmarketable. In this study, the levels of DNA from airborne spores of P. effusa were assessed near a field of susceptible plants in Salinas, CA during the winter months of 2013-14 and 2014/15 using rotating-arm impaction spore-trap samplers that were assessed with a species specific quantitative polymerase chain reaction (qPCR) assay. Low levels of P. effusa DNA were detectable from December through February in both winters but increased during January in both years, in correlation with observed disease incidence; sharp peaks in P. effusa DNA detection were associated with the onset of disease incidence. The incidence of downy mildew in the susceptible field displayed logistic-like dynamics but with considerable interseason variation. Analysis of the area under the disease progress curves suggested that the 2013-14 epidemic was significantly more severe than the 2014-15 epidemic. Spatial analyses indicated that disease incidence was dependent within an average range of 5.6 m, approximately equivalent to the width of three planted beds in a typical production field. The spatial distribution of spores captured during an active epidemic most closely fit a power-law distribution but could also be fit with an exponential distribution. These studies revealed two important results in the epidemiology of spinach downy mildew in California. First, they demonstrated the potential of impaction spore-trap samplers linked with a qPCR assay for indicating periods of high disease risk, as well as the detection of long distance dispersal of P. effusa spores. Second, at the scale of individual crops, a high degree of spatial aggregation in disease incidence was revealed. PMID- 27482628 TI - Colonization and Intrusive Invasion of Potato Psyllid by 'Candidatus Liberibacter solanacearum'. AB - Previous studies have shown that the fastidious bacterial plant pathogen 'Candidatus Liberibacter solanacearum' (CLso) is transmitted circulatively and propagatively by the potato psyllid (PoP) Bactericera cockerelli. In this study, the temporal and spatial interrelationships between CLso PoP were investigated by scanning electron microscopy of the digestive system of PoP immature and adult instars and salivary glands of adults post CLso ingestion. CLso biofilms were not detectable on the outer midgut surface of the first and second instars; however, for third to fifth instars and teneral and mature adults, biofilms were observed in increasing numbers in each successive developmental stage. In adult PoP midguts, CLso cells were observed between the basal lamina and basal epithelial cell membranes; in basal laminar perforations, on the outer basal laminar surface, and in the ventricular lumen, epithelial cytosol, and filter chamber periventricular space. CLso were also abundantly visible in the salivary gland pericellular spaces and in the epidermal cell cytosol of the head. Collectively, these results point to an intrusive, systemic invasion of PoP by CLso that employs an endo/exocytosis-like mechanism, in the context of a propagative, circulative mode of transmission. PMID- 27482629 TI - Conducting Interface in Oxide Homojunction: Understanding of Superior Properties in Black TiO2. AB - Black TiO2 nanoparticles with a crystalline core and amorphous-shell structure exhibit superior optoelectronic properties in comparison with pristine TiO2. The fundamental mechanisms underlying these enhancements, however, remain unclear, largely due to the inherent complexities and limitations of powder materials. Here, we fabricate TiO2 homojunction films consisting of an oxygen-deficient amorphous layer on top of a highly crystalline layer, to simulate the structural/functional configuration of black TiO2 nanoparticles. Metallic conduction is achieved at the crystalline-amorphous homointerface via electronic interface reconstruction, which we show to be the main reason for the enhanced electron transport of black TiO2. This work not only achieves an unprecedented understanding of black TiO2 but also provides a new perspective for investigating carrier generation and transport behavior at oxide interfaces, which are of tremendous fundamental and technological interest. PMID- 27482630 TI - The cystine/glutamate antiporter system xc- drives breast tumor cell glutamate release and cancer-induced bone pain. AB - Bone is one of the leading sites of metastasis for frequently diagnosed malignancies, including those arising in the breast, prostate and lung. Although these cancers develop unnoticed and are painless in their primary sites, bone metastases result in debilitating pain. Deeper investigation of this pain may reveal etiology and lead to early cancer detection. Cancer-induced bone pain (CIBP) is inadequately managed with current standard-of-care analgesics and dramatically diminishes patient quality of life. While CIBP etiology is multifaceted, elevated levels of glutamate, an excitatory neurotransmitter, in the bone-tumor microenvironment may drive maladaptive nociceptive signaling. Here, we establish a relationship between the reactive nitrogen species peroxynitrite, tumor-derived glutamate, and CIBP. In vitro and in a syngeneic in vivo model of breast CIBP, murine mammary adenocarcinoma cells significantly elevated glutamate via the cystine/glutamate antiporter system xc. The well-known system xc inhibitor sulfasalazine significantly reduced levels of glutamate and attenuated CIBP-associated flinching and guarding behaviors. Peroxynitrite, a highly reactive species produced in tumors, significantly increased system xc functional expression and tumor cell glutamate release. Scavenging peroxynitrite with the iron and mangano-based porphyrins, FeTMPyP and SRI10, significantly diminished tumor cell system xc functional expression, reduced femur glutamate levels and mitigated CIBP. In sum, we demonstrate how breast cancer bone metastases upregulate a cystine/glutamate co-transporter to elevate extracellular glutamate. Pharmacological manipulation of peroxynitrite or system xc attenuates CIBP, supporting a role for tumor-derived glutamate in CIBP and validating the targeting of system xc as a novel therapeutic strategy for the management of metastatic bone pain. PMID- 27482632 TI - Zwitterionic Phosphorylcholine-TPE Conjugate for pH-Responsive Drug Delivery and AIE Active Imaging. AB - Polymeric micelles have emerged as a promising nanoplatform for cancer theranostics. Herein, we developed doxorubicin (DOX) encapsulated pH-responsive polymeric micelles for combined aggregation induced emission (AIE) imaging and chemotherapy. The novel zwitterionic copolymer poly(2 methacryloyloxyethylphosphorylcholine-co-2-(4-formylphenoxy)ethyl methacrylate) (poly(MPC-co-FPEMA)) was synthesized via RAFT polymerization and further converted to PMPC-hyd-TPE after conjugation of tetraphenylethene (TPE, a typical AIE chromophore) via acid-cleavable hydrazone bonds. The AIE activatable copolymer PMPC-hyd-TPE could self-assemble into spherical PC-hyd-TPE micelles, and DOX could be loaded through hydrophobic interactions. The zwitterionic micelles exhibited excellent physiological stability and low protein adsorption due to the stealthy phosphorylcholine (PC) shell. In addition, the cleavage of hydrophobic TPE molecules under acidic conditions could induce swelling of micelles, which was verified by size changes with time at pH 5.0. The in vitro DOX release profile also exhibited accelerated release rate with pH value decreasing from 7.4 to 5.0. Fluorescent microscopy and flow cytometry studies further demonstrated fast internalization and accumulation of drug loaded PC-hyd TPE-DOX micelles in HepG2 cells, resulting in considerable time/dose-dependent cytotoxicity. Meanwhile, high-quality AIE imaging of PC-hyd-TPE micelles was confirmed in HepG2 cells. Notably, ex vivo imaging study exhibited efficient accumulation and drug release of PC-hyd-TPE-DOX micelles in the tumor tissue. Consequently, the multifunctional micelles with combined nonfouling surface, AIE active imaging, and pH-responsive drug delivery showed great potential as novel nanoplatforms for a new generation of cancer theranostics. PMID- 27482631 TI - The mitogen and stress-activated protein kinase 1 regulates the rapid epigenetic tagging of dorsal horn neurons and nocifensive behaviour. AB - Phosphorylation of histone H3 at serine 10 (p-H3S10) is a marker of active gene transcription. Using cognitive models of neural plasticity, p-H3S10 was shown to be downstream of extracellular signal-regulated kinase (ERK) signalling in the hippocampus. In this study, we show that nociceptive signalling after peripheral formalin injection increased p-H3S10 expression in the ipsilateral dorsal horn. This increase was maximal 30 minutes after formalin injection and occurred mainly within p-ERK-positive neurons. Spinal p-H3S10-enhanced expression was also observed in neurokinin 1 receptor (NK1R), c-Fos, and Zif268 positive neurons and was inhibited by ablation of serotonergic descending controls. The mitogen and stress-activated protein kinase 1 (MSK1) is downstream of ERK and can induce p H3S10. We found that, after formalin injection, most phospho-MSK1 (p-MSK1) positive cells (87% +/- 3%) expressed p-ERK and the majority of p-H3S10-positive cells (85% +/- 5%) expressed p-MSK1. Inhibition of ERK activity with the MEK inhibitor SL327 reduced formalin-induced p-ERK, p-MSK1, and p-H3S10, demonstrating that spinal p-MSK1 and p-H3S10 were at least partly downstream of ERK signalling. Crucially, pharmacological blockade of spinal MSK1 activity with the novel MSK1 inhibitor SB727651A inhibited formalin-induced spinal p-H3S10 and nocifensive behaviour. These findings are the first to establish the involvement of p-H3S10 and its main kinase, MSK1, in ERK regulation of nociception. Given the general importance of ERK signalling in pain processing, our results suggest that p-H3S10 could play a role in the response to injury. PMID- 27482634 TI - A case of CIC-rearranged undifferentiated round-cell sarcoma with exclusive spindled morphology and diffuse CD99 positivity: a potential pitfall. PMID- 27482633 TI - Arbovirus and insect-specific virus discovery in Kenya by novel six genera multiplex high-resolution melting analysis. AB - A broad diversity of arthropod-borne viruses (arboviruses) of global health concern are endemic to East Africa, yet most surveillance efforts are limited to just a few key viral pathogens. Additionally, estimates of arbovirus diversity in the tropics are likely to be underestimated as their discovery has lagged significantly over past decades due to limitations in fast and sensitive arbovirus identification methods. Here, we developed a nearly pan-arbovirus detection assay that uses high-resolution melting (HRM) analysis of RT-PCR products from highly multiplexed assays to differentiate broad diversities of arboviruses. We differentiated 15 viral culture controls and seven additional synthetic viral DNA sequence controls, within Flavivirus, Alphavirus, Nairovirus, Phlebovirus, Orthobunyavirus and Thogotovirus genera. Among Bunyamwera, sindbis, dengue and Thogoto virus serial dilutions, detection by multiplex RT-PCR-HRM was comparable to the gold standard Vero cell plaque assays. We applied our low-cost method for enhanced broad-range pathogen surveillance from mosquito samples collected in Kenya and identified diverse insect-specific viruses, including a new clade in anopheline mosquitoes, and Wesselsbron virus, an arbovirus that can cause viral haemorrhagic fever in humans and has not previously been isolated in Kenya, in Culex spp. and Anopheles coustani mosquitoes. Our findings demonstrate how multiplex RT-PCR-HRM can identify novel viral diversities and potential disease threats that may not be included in pathogen detection panels of routine surveillance efforts. This approach can be adapted to other pathogens to enhance disease surveillance and pathogen discovery efforts, as well as the study of pathogen diversity and viral evolutionary ecology. PMID- 27482636 TI - UV photodetectors based on 3D periodic Au-decorated nanocone ZnO films. AB - Thermal nanoimprinting technology was employed to fabricate 3D periodic nanocone ZnO films with different height/pitch values for photodetectors to optimize their light capturing property. The photocurrents of patterned film photodetectors increase with the height/pitch values. The patterned ZnO-Au hybrid film further boosts the ultraviolet (UV) response. Due to the co-contribution of the light trapping of 3D periodic structures and the driving force of the Schottky barrier in the Au/ZnO interface, the patterned ZnO-Au hybrid films with height/pitch of 40 nm/866 nm exhibit the best UV photoresponse (I on/I off = 779.927), which is 3.8 times higher than its film counterpart (I on/I off = 164.1). PMID- 27482635 TI - Airway Remodeling and Hyperreactivity in a Model of Bronchopulmonary Dysplasia and Their Modulation by IL-1 Receptor Antagonist. AB - Bronchopulmonary dysplasia (BPD) is a chronic disease of extreme prematurity that has serious long-term consequences including increased asthma risk. We earlier identified IL-1 receptor antagonist (IL-1Ra) as a potent inhibitor of murine BPD induced by combining perinatal inflammation (intraperitoneal LPS to pregnant dams) and exposure of pups to hyperoxia (fraction of inspired oxygen = 0.65). In this study, we determined whether airway remodeling and hyperresponsiveness similar to asthma are evident in this model, and whether IL-1Ra is protective. During 28-day exposure to air or hyperoxia, pups received vehicle or 10 mg/kg IL 1Ra by daily subcutaneous injection. Lungs were then prepared for histology and morphometry of alveoli and airways, or for real-time PCR, or inflated with agarose to prepare precision-cut lung slices to visualize ex vivo intrapulmonary airway contraction and relaxation by phase-contrast microscopy. In pups reared under normoxic conditions, IL-1Ra treatment did not affect alveolar or airway structure or airway responses. Pups reared in hyperoxia developed a severe BPD like lung disease, with fewer, larger alveoli, increased subepithelial collagen, and increased expression of alpha-smooth muscle actin and cyclin D1. After hyperoxia, methacholine elicited contraction with similar potency but with an increased maximum reduction in lumen area (air, 44%; hyperoxia, 89%), whereas dilator responses to salbutamol were maintained. IL-1Ra treatment prevented hyperoxia-induced alveolar disruption and airway fibrosis but, surprisingly, not the increase in methacholine-induced airway contraction. The current study is the first to demonstrate ex vivo airway hyperreactivity caused by systemic maternal inflammation and postnatal hyperoxia, and it reveals further preclinical mechanistic insights into IL-1Ra as a treatment targeting key pathophysiological features of BPD. PMID- 27482637 TI - Lanthanide Organic Framework Luminescent Thermometers. AB - Metal-organic frameworks (MOFs) are excellent platforms for engineering luminescence properties as their building blocks, metal ions, linkers, and guest ions or molecules, are all potential sources of light emission. Temperature is one of the most important physical properties affecting the dynamics and viability of natural and engineered systems. Because the luminescence of certain lanthanide-bearing MOFs changes considerably with temperature, in the last few years, these materials have been explored as optical thermometers, especially in temperature sensing based on the intensity ratios of two separate electronic transitions. This review discusses the main concepts and ideas assisting the design of such ratiometric thermometers, and identifies the main challenges presented to this nascent field: develop nanothermometers for bio-applications and nanomedicine; understand the energy transfer mechanisms determining the thermal sensitivity; achieve effective primary thermometers; realize multifunctional nanothermometers; integrate Ln3+ -based thermometers in commercial products. PMID- 27482638 TI - Determinants of Quality of Family Planning Counseling among Private Health Facilities in Lagos. AB - We use a unique dataset that includes an objective measure of the quality of family planning counseling from 927 private health facilities in Lagos State, Nigeria, to determine which variables at the facility and provider levels are most closely correlated with the quality of family planning counseling. Our data on quality come from mystery client surveys in which the clients posed as women seeking family planning counseling. We find that quality is strongly associated with the cadre of provider, with doctors delivering substantially higher-quality counselling than nurses. Doctors not only outperform nurses overall, but also perform better on each category of quality and spend nearly three minutes longer on average counseling the mystery client. Location, fees charged for the service, and facility type are also strongly correlated with quality. The degree to which a facility specializes in family planning and facility size are only weakly predictive of quality. PMID- 27482641 TI - MYOPIC CHOROIDAL NEOVASCULARIZATION: Diagnosis and Treatment. AB - PURPOSE: To review and summarize the latest developments in the diagnosis and management of myopic choroidal neovascularization (mCNV). METHODS: A review of the literature was performed, focusing on tests and investigations for diagnosing mCNV, as well as the key treatment options available for mCNV. RESULTS: Standard essential tests and investigations for diagnosing mCNV include spectral-domain optical coherence tomography for screening, fluorescein angiography for confirmation, and indocyanine green angiography and fundus autofluorescence for providing supplementary information. The current first line treatment of mCNV is the use of anti-vascular endothelial growth factor therapy. CONCLUSION: Various investigations can assist the differentiation of mCNV from other coexisting retinal pathologies associated with myopia or choroidal neovascularization resulting from other causes. Prompt use of anti-vascular endothelial growth factor therapy has good efficacy and safety in the treatment of mCNV. PMID- 27482639 TI - Prognosis of patients with syncope seen in the emergency room department: an evaluation of four different risk scores recommended by the European Society of Cardiology guidelines. AB - AIM: To apply, analyze, and evaluate the four syncope risk scores recommended by the 2009 European guidelines and the different parameters that they use to predict death, syncope recurrence, and hospital readmission in the population seen in the emergency room department (ERD) for syncope. METHODS AND RESULTS: A total of 323 patients aged older than 14 years [mean age 59 (32-75) years] and seen in ERD for syncope over a 2-month period were included in the study; 50.7% were women. Patients were evaluated using the four risk scores and were followed up for at least 2 years. In all, 275 patients (85.2%) were discharged directly from ERD after evaluation. During 28+/-5 months of follow-up, 8% died, 18.3% presented a further syncopal episode, and 18.6% were readmitted to hospital. Only two of the four risk scores were useful in risk discrimination, but no statistically significant differences were detected between predicted risk and observed risk. Multivariate analysis indicated relationships between age and death, a history of cardiovascular disease and syncope recurrence, and between presyncopal palpitations and hospital readmission. CONCLUSION: Although a large number of events occur after syncope, the risk scores recommended by guidelines overestimate risk, but there were no statistically significant differences between observed and predicted risk. PMID- 27482642 TI - SUPRACHOROIDAL BUCKLING FOR THE MANAGEMENT OF RHEGMATOGENOUS RETINAL DETACHMENTS SECONDARY TO PERIPHERAL RETINAL BREAKS. AB - PURPOSE: To evaluate functional and anatomical outcomes of eyes undergoing suprachoroidal buckling for the management of peripheral retinal breaks in rhegmatogenous retinal detachment. METHODS: Retrospective cohort study of 41 eyes of 41 patients undergoing suprachoroidal buckling for the management of rhegmatogenous retinal detachment secondary to single or multiple retinal breaks. Suprachoroidal indentation was achieved through the introduction of filler material using a 23-gauge (23-G) olive-tipped, suprachoroidal cannula. This allowed for the creation of a suprachoroidal dome and chorio-retinal apposition. Healon5 (Abbott Medical Optics) was used as filler material in all eyes. Combined 25-G vitrectomy was performed in 5 eyes. Cryopexy and laserpexy were used in 37 and 4 eyes, respectively. RESULTS: Mean visual acuity gain was the primary outcome measure. Final retinal reattachment rate, single-surgery reattachment rate, and complications were secondary outcome measures. Mean best-corrected distance visual acuity improved from 20/1,100 to 20/42. Single surgery reattachment rate was 92.7% (38/41 eyes). Final retinal reattachment was achieved in all 41 eyes (100%). There was no statistically significant difference in visual acuity gain or anatomical reattachment in terms of retinal break quadrant or extent. No major complications were observed. Two localized suprachoroidal hemorrhages occurred at the entry site for the cannula. These resolved without further intervention. CONCLUSION: Suprachoroidal buckling using a specially designed cannula is a safe and effective procedure for the management of rhegmatogenous retinal detachment secondary to peripheral retinal breaks. PMID- 27482643 TI - Prognostic value of SUVmax measured by pretreatment 18F-FDG PET/CT in patients with primary gastric lymphoma. AB - PURPOSE: The aim of this retrospective study was to determine whether glucose metabolism assessed by fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) provides prognostic information independent of established prognostic factors in patients with gastric lymphoma. PATIENTS AND METHODS: We reviewed the medical records of 86 patients retrospectively (men, 42; women, 44; mean age 58+/-13 years) with pathologically proven gastric lymphoma (34 mucosa associated lymphoid tissue and 52 aggressive non-Hodgkin's lymphoma). They underwent F-FDG PET/CT as part of a pretreatment work-up from February 2004 to July 2012. For the analysis, patients were classified by age, sex, Musshoff stage, serum lactate dehydrogenase, International Prognostic Index score, extragastric spread, and visual intensity [visual assessment and maximum standardized uptake value (SUVmax), respectively]. The relationship between F-FDG uptake and survival was analyzed using the Kaplan-Meier method with a log-rank test and Cox's proportional-hazard regression method. RESULTS: The median survival of all 86 study participants was 1117 days and the median SUV measured by PET/CT was 6.1 (range, 1.9-32.7). Patients with an SUVmax less than or equal to 5.2 survived significantly longer than patients with an SUVmax more than 5.2 (median, 1163 vs. 1004 days; P=0.003). Survival was also found to be significantly related to age (P=0.0005), histological type (P=0.004), extragastric spread (P=0.0004), International Prognostic Index score (P<0.0001), serum lactate dehydrogenase (P=0.02), stage (P<0.0001), and visual intensity (P=0.041). A multivariate analysis showed that patients with a higher SUVmax [P=0.021; 95% confidence interval (CI), 1.52-8.14; hazard ratio (HR)=6.29], older age (P=0.001; 95% CI, 4.64-219.96; HR=18.8), more aggressive histologic type (P=0.006; 95% CI, 2.20-70.63; HR=12.76), and higher stage (P=0.0006; 95% CI, 5.81 206.43; HR=17.48) showed worse survival. CONCLUSION: A higher SUVmax on pretreatment F-FDG PET/CT can predict poorer survival in patients with gastric lymphoma. PMID- 27482644 TI - Solubility of the Sodium and Ammonium Salts of Oxalic Acid in Water with Ammonium Sulfate. AB - The solubility of the sodium and ammonium salts of oxalic acid in water with ammonium sulfate present has been studied using differential scanning calorimetry, X-ray crystallography, and infrared spectroscopy. The crystals that form from aqueous mixtures of ammonium sulfate/sodium hydrogen oxalate were determined to be sodium hydrogen oxalate monohydrate under low ammonium sulfate conditions and ammonium hydrogen oxalate hemihydrate under high ammonium sulfate conditions. Crystals from aqueous mixtures of ammonium sulfate/sodium oxalate were determined to be ammonium oxalate monohydrate under moderate to high ammonium sulfate concentrations and sodium oxalate under low ammonium sulfate concentrations. It was also found that ammonium sulfate enhances the solubility of the sodium oxalate salts (salting in effect) and decreases the solubility of the ammonium oxalate salts (salting out effect). In addition, a partial phase diagram for the ammonium hydrogen oxalate/water system was determined. PMID- 27482645 TI - Liver protects metastatic prostate cancer from induced death by activating E cadherin signaling. AB - : Liver is one of the most common sites of cancer metastasis. Once disseminated, the prognosis is poor as these tumors often display generalized chemoresistance, particularly for carcinomas that derive not from the aerodigestive tract. When these cancers seed the liver, the aggressive cells usually undergo a mesenchymal to epithelial reverting transition that both aids colonization and renders the tumor cells chemoresistant. In vitro studies demonstrate that hepatocytes drive this phenotypic shift. However, the in vivo evidence and the molecular signals that protect these cells from induced death are yet to be defined. Herein, we report that membrane surface E-cadherin-expressing prostate cancer cells were resistant to cell death by chemotherapeutic drugs but E-cadherin null cells or those expressing E-cadherin only in the cytoplasm were sensitive to death signals and chemotherapies both in vitro and in vivo. While cell-cell E-cadherin ligandation reduced mitogenesis, this chemoprotection was proliferation independent as killing of both 5-ethynyl-2'-deoxyuridine-positive (or Ki67+ ) and 5-ethynyl-2'-deoxyuridine-negative (Ki67- ) cells was inversely related to membrane-bound E-cadherin. Inhibiting the canonical survival kinases extracellular signal-regulated protein kinases, protein kinase B, and Janus kinase, which are activated by chemotherapeutics in epithelial cell-transitioned prostate cancer, abrogated the chemoresistance both in cell culture and in animal models of metastatic cancer. For disseminated tumors, protein kinase B disruption in itself had no effect on tumor survival but was synergistic with chemotherapy, leading to increased killing. CONCLUSION: Liver microenvironment-driven phenotypic switching of carcinoma cells and subsequent survival signaling results in activation of canonical survival pathways that protect the disseminated prostate cancer liver micrometastases in a proliferation-independent manner, and these pathways can be targeted as an adjuvant treatment to improve the efficacy of traditional chemotherapeutics (Hepatology 2016;64:1725-1742). PMID- 27482646 TI - Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study. AB - BACKGROUND: The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical. METHODS: Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ?20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ?20%). RESULTS: A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003). CONCLUSIONS: Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation. PMID- 27482647 TI - Evaluating the risk of ovarian cancer before surgery using the ADNEX model: a multicentre external validation study. AB - BACKGROUND: The International Ovarian Tumour Analysis (IOTA) group have developed the ADNEX (The Assessment of Different NEoplasias in the adneXa) model to predict the risk that an ovarian mass is benign, borderline, stage I, stages II-IV or metastatic. We aimed to externally validate the ADNEX model in the hands of examiners with varied training and experience. METHODS: This was a multicentre cross-sectional cohort study for diagnostic accuracy. Patients were recruited from three cancer centres in Europe. Patients who underwent transvaginal ultrasonography and had a histological diagnosis of surgically removed tissue were included. The diagnostic performance of the ADNEX model with and without the use of CA125 as a predictor was calculated. RESULTS: Data from 610 women were analysed. The overall prevalence of malignancy was 30%. The area under the receiver operator curve (AUC) for the ADNEX diagnostic performance to differentiate between benign and malignant masses was 0.937 (95% CI: 0.915-0.954) when CA125 was included, and 0.925 (95% CI: 0.902-0.943) when CA125 was excluded. The calibration plots suggest good correspondence between the total predicted risk of malignancy and the observed proportion of malignancies. The model showed good discrimination between the different subtypes. CONCLUSIONS: The performance of the ADNEX model retains its performance on external validation in the hands of ultrasound examiners with varied training and experience. PMID- 27482649 TI - Reply. PMID- 27482648 TI - De novo post-diagnosis statin use, breast cancer-specific and overall mortality in women with stage I-III breast cancer. AB - BACKGROUND: Prior evidence suggests a role for statins in the management of cancer. However, the benefit of statin use in the adjuvant setting remains uncertain. This study investigates associations between statin use initiated after a breast cancer diagnosis and mortality. METHODS: Women with stage I-III breast cancer were identified from the National Cancer Registry of Ireland (N=4243). Post-diagnostic statin initiators were identified from pharmacy claims data (N=837). Multivariate models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between de novo statin use and mortality. RESULTS: The median duration of statin use was 6.7 years. No association was found between post-diagnostic statin use and breast cancer specific (HR 0.88, 95% CI 0.66, 1.17) or all-cause mortality (HR 1.00, 95% CI 0.82, 1.21). CONCLUSIONS: The results from our study suggest that initiating statin use after a diagnosis of stage I-III breast cancer is not associated with a reduction in breast cancer-specific mortality. PMID- 27482650 TI - Molecular phenotyping of maternally mediated parallel adaptive divergence within Rana arvalis and Rana temporaria. AB - When similar selection acts on the same traits in multiple species or populations, parallel evolution can result in similar phenotypic changes, yet the underlying molecular architecture of parallel phenotypic divergence can be variable. Maternal effects can influence evolution at ecological timescales and facilitate local adaptation, but their contribution to parallel adaptive divergence is unclear. In this study, we (i) tested for variation in embryonic acid tolerance in a common garden experiment and (ii) used molecular phenotyping of egg coats to investigate the molecular basis of maternally mediated parallel adaptive divergence in two amphibian species (Rana arvalis and Rana temporaria). Our results on three R. arvalis and two R. temporaria populations show that adaptive divergence in embryonic acid tolerance is mediated via maternally derived egg coats in both species. We find extensive polymorphism in egg jelly coat glycoproteins within both species and that acid-tolerant clutches have more negatively charged egg jelly - indicating that the glycosylation status of the jelly coat proteins is under divergent selection in acidified environments, likely due to its impact on jelly water balance. Overall, these data provide evidence for parallel mechanisms of adaptive divergence in two species. Our study highlights the importance of studying intraspecific molecular variation in egg coats and, specifically, their glycoproteins, to increase understanding of underlying forces maintaining variation in jelly coats. PMID- 27482651 TI - Validation of Interstitial Fractional Volume Quantification by Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Porcine Skeletal Muscles. AB - OBJECTIVES: The aim of our study was to assess the accuracy of fractional interstitial volume determination in low perfused and low vascularized tissue by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: The fractional interstitial volume (ve) was determined in the medial thigh muscle of 12 female pigs by using a 3-dimensional gradient echo sequence with k-space sharing and administering gadolinium-based contrast agent (gadoterate meglumine). Analysis was performed using 3 pharmacokinetic models: the simple Tofts model (TM), the extended TM (ETM), and the 2-compartment exchange model (2CXM). We investigated the effect of varying acquisition durations (ADs) on the model parameter estimates of the 3 models and compared the ve values with the results of histological examinations of muscle sections of the medial thigh muscle. RESULTS: Histological measurements yielded a median value (25%-75% quartile) of 4.8% (3.7%-6.2%) for ve. The interstitial fractional volume determined by DCE-MRI was comparable to the histological results but varied strongly with AD for the TM and ETM. For the TM and the ETM, the results were virtually the same. Choosing arterial hematocrit to Hcta = 0.4, the lowest median ve value determined by DCE-MRI was 5.2% (3.3%-6.1%) for the ETM at a 6-minute AD. The maximum ve value determined with the ETM at a 15-minute AD was 7.7% (4.5% 9.0%). The variation with AD of median ve values obtained with the 2CXM was much smaller: 6.2% (3.1%-9.2%) for the 6-minute AD and 6.3% (4.3%-9.8%) for the 15 minute AD. The best fit for the 2CXM was found at the 10-minute AD with ve values of 6.6% (3.7%-8.2%). No significant correlation between the histological and any DCE-MRI modeling results was found. Considering the expected accuracy of histological measurements, the medians of the MR modeling results were in good agreement with the histological prediction. A parameter determination uncertainty was identified with the use of the TMs. This is due to underfitting and has a major effect even on the analysis of tissues with low vascularization and low perfusion, where the estimated ve values depend on the AD. For the TM and ETM, the results best matched the histological measurements for an AD of 6 minutes. CONCLUSIONS: Owing to more fitting parameters, the 2CXM yielded better fits and the median interstitium-to-plasma rate constant kep was less depending on the AD; however, the uncertainty expressed by the 25% to 75% quartile range was found to be larger. An AD of 10 minutes was needed for the 2CXM to achieve accuracy comparable to those of the TMs with shorter ADs. PMID- 27482652 TI - Brincidofovir clearance of acyclovir-resistant herpes simplex virus-1 and adenovirus infection after stem cell transplantation. AB - Infections with adenovirus (AdV) and herpesviruses can result in considerable morbidity and mortality in pediatric hematopoietic stem cell transplant (SCT) recipients. Herpes simplex virus (HSV) reactivations are usually prevented by acyclovir (ACV) prophylaxis, whereas cidofovir (CDV) has been used off indication to manage AdV infections. We report a child with myelodysplastic syndrome undergoing multiple SCT, who experienced HSV-1 disease including severe mucositis and herpetic whitlow, as well as high viral load AdV DNAemia. Both ACV and CDV were ineffective; however, viral loads were decreased with brincidofovir, resulting in viral clearance. A subsequent Epstein-Barr virus disease with relevant meningoencephalitis responded to rituximab. PMID- 27482654 TI - Metal-Ion-Induced Switch of Liquid-Crystalline Orientation of Metallomacrocycles. AB - A new series of shape-persistent imine-bridged macrocycles were synthesized based on dynamic covalent chemistry. The macrocycles had an alternating sequence of dibenzothiophene and N,N'-bis(salicylidene)-ethylenediamine (salen) tethering branched alkyl chains. The macrocycles and tetranuclear metallomacrocycles bearing long and branched alkyl chains exhibited thermotropic columnar liquid crystalline phases over a wide temperature range and the metallomacrocycles greatly depended on the characteristics of the coordinated metal ions. The metal free macrocycle showed a liquid-crystalline phase with a lamellar structure and poor birefringence. In sharp contrast, the macrocyclic Ni complex showed a columnar oblique liquid-crystalline phase, whereas the Pd and Cu complexes showed columnar liquid-crystalline phases with a lamellar structure. The macroscopic organization and thermal properties of the corresponding liquid-crystalline metallomacrocycles were significantly dependent on the subtle structural differences among the planar macrocycles, which were revealed by single-crystal X ray crystallographic analysis of the macrocycles with shorter alkyl chains. PMID- 27482653 TI - Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio. AB - Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics. PMID- 27482655 TI - Glyceride-Mimetic Prodrugs Incorporating Self-Immolative Spacers Promote Lymphatic Transport, Avoid First-Pass Metabolism, and Enhance Oral Bioavailability. AB - First-pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first-pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first-pass drug, glyceride-mimetic prodrugs incorporating self immolative (SI) spacers, resulted in remarkable increases (up to 90-fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first-pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue. PMID- 27482656 TI - Upconverting nanoparticles for the near infrared photoactivation of transition metal complexes: new opportunities and challenges in medicinal inorganic photochemistry. AB - The article highlights the emergent use of upconverting nanoparticles as tools for the near infrared photoactivation of transition metal complexes, identifying opportunities and challenges of this approach in the context of medicinal inorganic chemistry. PMID- 27482658 TI - TRIENNIAL REPRODUCTION SYMPOSIUM: Beef heifer development and lifetime productivity in rangeland-based production systems. AB - Nutritional and environmental factors have been shown to cause epigenetic changes that influence characteristics of the offspring throughout life. In livestock, small differences in nutrition during gestation may alter lifetime production efficiency of offspring. Therefore, the potential for fetal programing should be considered when determining supplemental feeding strategies during gestation. For example, female offspring born to cows grazing dormant winter pasture supplemented with 1.1 kg/d of alfalfa hay during the last third of gestation were 10 kg heavier and had greater BCS at 5 yr of age than those from dams supplemented with 1.8 kg/d of alfalfa hay. These differences were beneficial for maintaining reproductive performance in offspring managed with fewer harvested feed inputs. Evaluation of female offspring from cows wintered on either low quality or high-quality pasture for 30 to 45 d during the fifth to sixth month of gestation indicated a trend for longer duration of productivity in daughters from cows wintered on improved pasture. In recent studies comparing offspring from cows with or without protein supplementation while grazing dormant winter range during late gestation, heifers from protein-supplemented dams had greater BW at weaning. This BW increase persisted throughout pregnancy and to subsequent calving, and pregnancy rates were greater in heifers from protein-supplemented dams. Heifers from protein-supplemented dams had lower G:F compared with heifers from unsupplemented dams. Therefore, in utero exposure to nutritionally limited environments (nonsupplemented dams) may promote greater feed efficiency in the heifer offspring later in life. Nutrition during postweaning development may also affect lifetime productivity. Heifers developed on low-quality native range with RUP supplementation had greater retention beyond 3 yr of age than cohorts developed in a feedlot with higher quality feed and greater ADG. Collectively, these examples show nutritional management strategies used during gestation and development may influence lifetime productivity. PMID- 27482657 TI - TRIENNIAL REPRODUCTION SYMPOSIUM: Developmental programming of fertility. AB - The 2015 Triennial Reproduction Symposium focused on developmental programming of fertility. The topics covered during the morning session included the role of the placenta in programming of fetal growth and development, effects of feeding system and level of feeding during pregnancy on the annual production cycle and lifetime productivity of heifer offspring, effects of litter size and level of socialization postnatally on reproductive performance of pigs, effects of postnatal dietary intake on maturation of the hypothalamic-pituitary-gonadal axis and onset of puberty in heifers, effects of housing systems on growth performance and reproductive efficiency of gilts, and effects of energy balance on sexual differentiation in rodent models. The morning session concluded with presentation of the American Society of Animal Science L. E. Casida Award for Excellence in Graduate Education to Dr. Michael Smith from the University of Missouri, Columbia, who shared his philosophy of graduate education. The afternoon session included talks on the role of epigenetic modifications in developmental programming and transgenerational inheritance of reproductive dysfunction, effects of endocrine disrupting compounds on fetal development and long-term physiology of the individual, and potential consequences of real-life exposure to environmental contaminants on reproductive health. The symposium concluded with a summary talk and the posing of 2 questions to the audience. From an evolutionary standpoint, programming and epigenetic events must be adaptive; when do they become maladaptive? If there are so many environmental factors that induce developmental programming, are we doomed, and if not, what is or are the solution or solutions? PMID- 27482659 TI - TRIENNIAL REPRODUCTION SYMPOSIUM: American Society of Animal Science L. E. Casida Award for Excellence in Graduate Education: Thoughts on mentoring graduate students in reproductive biology. AB - Programs in animal science are particularly well suited for graduate education because students can receive comprehensive training in the laboratory as well as with the whole animal. Furthermore, graduate students in animal science have the opportunity to understand how their research relates to a real world problem. Graduate students need to take ownership of their education by identifying training goals, choosing a mentor who will help them achieve their goals, and becoming engaged in research as soon as possible. In my own graduate program, I emphasize concepts more than techniques and I believe that graduate course work should focus on the basic areas of science that underlie reproductive biology (e.g., endocrinology, biochemistry, physiology, immunology, and statistics). Based on the increase in technology available for scientific investigation and the diversity of expertise required to address important research problems, graduate students need to learn the importance of establishing productive collaborations and begin building a scientific network. Preparation for graduate school frequently begins early with a curiosity and passion for understanding how biology works. Undergraduate courses can facilitate scientific thinking by providing opportunities in lectures and laboratories for students to transition from passive learners to thinking of themselves as animal scientists. There is a profound difference between individuals who view themselves as practitioners of a discipline and those who are simply trying to complete a course requirement. Teachers of undergraduate courses should incorporate experiential learning exercises into their lectures and laboratories to provide undergraduate students the opportunity to function as animal scientists and to embrace their scientific education. Graduate training has been the most enjoyable aspect of my career and it has been a joy to witness the achievements of students following completion of their degree! PMID- 27482660 TI - TRIENNIAL REPRODUCTION SYMPOSIUM: Environmental programming of reproduction during fetal life: Effects of intrauterine position and the endocrine disrupting chemical bisphenol A. AB - During critical periods in fetal life, there is an increased vulnerability to perturbations in endocrine function due to environmental factors. Small shifts in concentrations of hormones that regulate the differentiation of organs, such as estradiol and testosterone, can have permanent effects on morphology, enzymatic activity, and hormone receptors in tissues as well as neurobehavioral effects. These changes can lead to effects throughout life, including impacting the risk for various diseases (referred to as the Developmental Origins of Adult Health and Disease hypothesis). The intrauterine position phenomenon concerns the consequence for fetuses of randomly implanting next to embryos of the same or opposite sex. An intrauterine position next to males vs. females results in small differences in serum testosterone and estradiol during fetal life that are associated with marked effects on life history (such as lifetime fecundity) in both males and females born in litters (mice, rats, gerbils, rabbits, and swine) as well as human twins. Research with mice subsequently demonstrated that a very small experimental change in fetal serum estradiol levels altered organogenesis and caused permanent changes in organ function. Taken together, these findings led to the hypothesis that environmental chemicals that mimic or antagonize hormone action (e.g., endocrine disrupting chemicals) could also be causing harm at very low exposures (the "low dose" hypothesis) within the range of exposure of humans, domesticated animals, and wildlife. There is now extensive evidence from experimental laboratory animals, sheep, and humans that fetal exposure to very low (presumably safe) doses of the endocrine disrupting chemical bisphenol A (BPA), which exhibits estrogenic activity, can cause permanent changes that can increase the risk of a wide array of diseases. The reasons that federal regulatory agencies are ignoring the massive literature showing adverse effects of BPA and other endocrine disrupting chemicals are discussed. PMID- 27482661 TI - Characterization and functional analyses of a novel chicken CD8alpha variant X1 (CD8alpha1). AB - We provide the first description of cloning and of structural and functional analysis of a novel variant in the chicken cluster of differentiation 8 alpha (CD8a) family, termed the CD8alpha X1 (CD8alpha1) gene. Multiple alignments of CD8alpha1 with known CD8alpha and CD8beta sequences of other species revealed relatively low conservation of AA residues involved in the specific and unique structural domains among CD8alpha genes. For example, cysteine residues that are involved in disulfide bonding to form the V domain are conserved. In contrast, the O-linked glycosylation sites (XPXX motif) are not found in the chicken CD8alpha1 sequence, and the A beta strand and complementarity-determining region 1 and 2 sequences are poorly conserved between chicken CD8alpha1 and avian CD8alpha. Furthermore, the alignment showed that the transmembrane regions show relatively high sequence similarity, whereas the cytoplasmic regions show relatively low similarity, indicating poor conservation. Moreover, the motif (CXCP) that is thought to be responsible for binding the p56 lymphocyte cell kinase subunit (p56) is missing in the CD8alpha1 sequence. The chicken CD8alpha1 genomic structure is similar to that of chicken CD8alpha, but their protein structures differ. Phylogenetic analysis showed that chicken CD8alpha1 grouped with known avian CD8alpha sequences but was somewhat distantly related to the CD8alpha molecules of other species. Moreover, we analyzed the signal transduction and cytokine response to CD8alpha1 treatment to determine the specific biological functions of chicken CD8alpha1 in immune cells. The results showed that chicken CD8alpha1 is a key regulator of the expression of genes that are associated and cooperate with transcription factors in the major histocompatibility complex class I and II promoter regions and activates Janus kinase (JAK) 1/2, signal transducer and activator of transcription (STAT), and suppressor of cytokine signaling (SOCS) 1 signaling-related genes. Immune cells that express functional CD8alpha1 induce proinflammatory cytokines as well as innate immune responses. Therefore, our data indicate that CD8alpha1 may have immunoregulatory activity by regulating the expression of proinflammatory or anti inflammatory cytokines via its effect on immune cells. PMID- 27482662 TI - Accuracy of genomic breeding values for meat tenderness in Polled Nellore cattle. AB - Zebu () cattle, mostly of the Nellore breed, comprise more than 80% of the beef cattle in Brazil, given their tolerance of the tropical climate and high resistance to ectoparasites. Despite their advantages for production in tropical environments, zebu cattle tend to produce tougher meat than Bos taurus breeds. Traditional genetic selection to improve meat tenderness is constrained by the difficulty and cost of phenotypic evaluation for meat quality. Therefore, genomic selection may be the best strategy to improve meat quality traits. This study was performed to compare the accuracies of different Bayesian regression models in predicting molecular breeding values for meat tenderness in Polled Nellore cattle. The data set was composed of Warner-Bratzler shear force (WBSF) of longissimus muscle from 205, 141, and 81 animals slaughtered in 2005, 2010, and 2012, respectively, which were selected and mated so as to create extreme segregation for WBSF. The animals were genotyped with either the Illumina BovineHD (HD; 777,000 from 90 samples) chip or the GeneSeek Genomic Profiler (GGP Indicus HD; 77,000 from 337 samples). The quality controls of SNP were Hard Weinberg Proportion -value >= 0.1%, minor allele frequency > 1%, and call rate > 90%. The FImpute program was used for imputation from the GGP Indicus HD chip to the HD chip. The effect of each SNP was estimated using ridge regression, least absolute shrinkage and selection operator (LASSO), Bayes A, Bayes B, and Bayes Cpi methods. Different numbers of SNP were used, with 1, 2, 3, 4, 5, 7, 10, 20, 40, 60, 80, or 100% of the markers preselected based on their significance test ( value from genomewide association studies [GWAS]) or randomly sampled. The prediction accuracy was assessed by the correlation between genomic breeding value and the observed WBSF phenotype, using a leave-one-out cross-validation methodology. The prediction accuracies using all markers were all very similar for all models, ranging from 0.22 (Bayes Cpi) to 0.25 (Bayes B). When preselecting SNP based on GWAS results, the highest correlation (0.27) between WBSF and the genomic breeding value was achieved using the Bayesian LASSO model with 15,030 (3%) markers. Although this study used relatively few animals, the design of the segregating population ensured wide genetic variability for meat tenderness, which was important to achieve acceptable accuracy of genomic prediction. Although all models showed similar levels of prediction accuracy, some small advantages were observed with the Bayes B approach when higher numbers of markers were preselected based on their -values resulting from a GWAS analysis. PMID- 27482663 TI - Direct and maternal genetic effects on growth, reproduction, and ultrasound traits in zebu Brahman cattle in Colombia. AB - Covariance components and genetic parameters were estimated for birth weight (BiW); adjusted weights at 4, 7, 12, and 18 mo; and ADG between 0 and 4 mo, between 4 and 7 mo, between 7 and 12 mo, and between 12 and 18 mo. Additionally, reproductive traits, calving interval, and age at first calving were analyzed, together with traits measured by ultrasound: loin eye area, deep fat mean, back fat, and rump fat. Analyses were performed using an animal model, considering the fixed effects of the farm ( = 37), year and month of birth, sex, calving number (1 to 7), season (dry and rainy seasons), region (North Coast, Andean Region, and Oriental Savannas), and conception (natural mating or AI), whereas the age of the cows at calving was considered a polynomial covariate with linear and quadratic effects. Three different models were used to find the one with the best fit for each trait: a single-trait model with an additive direct genetic effect, a single trait model with additive direct and maternal genetic effects, and finally, a multitrait model with an additive direct genetic effect. For the growth traits, the heritability was between 0.24 and 0.47, with the lowest value for weight at 7 mo and the greatest value for BiW, and the maternal heritability was found to be between 0.15 and 0.21 but did not decrease later on. The correlation between direct and maternal effects was high and negative (-0.59 to -0.76). With ultrasound traits, a model with only direct effects was used. The heritability was between 0.13 and 0.28 for back fat and loin eye area, respectively. The heritabilities for deep fat mean and rump fat were similar, being 0.19 and 0.21, respectively. The reproductive traits showed high residual variance. In particular, the heritability of calving interval was low (0.06). The results showed that the growth traits have an important genetic component, which is a favorable indicator for obtaining improvement progress in the zebu Brahman breed for beef production in tropical regions of Colombia. The maternal effects influenced the weight performance from 4 to 18 mo and should be taken into account in genetic analyses. In general, the direct heritability of medium magnitude estimated for growth and traits measured by ultrasound suggests that individual selection for these traits will be effective. PMID- 27482664 TI - Genetic parameters estimated at receiving for circulating cortisol, immunoglobulin G, interleukin 8, and incidence of bovine respiratory disease in feedlot beef steers. AB - Bovine respiratory disease complex (i.e., shipping fever and bacterial bronchopneumonia) is a multifaceted respiratory illness influenced by numerous environmental factors and microorganisms. Bovine respiratory disease (BRD) is just one component of BRD complex. Because BRD is moderately heritable, it may be possible to reduce the incidence of BRD through genetic selection. The objectives of this study were to determine the heritability and associative genetic relationships among immune system traits (i.e., cortisol, total IgG, IgG isotypes, and IL-8) in cattle monitored for BRD incidence. At an average of 83 d after weaning (219 d age and mean = 221.7 kg [SD 4.34]), crossbred steer calves ( = 2,869) were received at a commercial feedlot in southeastern Colorado over a 2 yr period. At receiving, jugular blood samples were collected at 212 (yr 1) and 226 d (yr 2) of age for immune trait analyses. The BRD phenotype was defined as a binomial variable (0 = no and 1 = yes) and compared with immune system traits measured at receiving (prior to illness onset). An animal identified as BRD positive exhibited >= 2 clinical signs (i.e., eye or nasal discharge, cough, lethargy, rapid breathing, acute interstitial pneumonia, or acute upper respiratory syndrome and/or a rectal temperature > 39.7 degrees C). Heritability and genetic correlation estimates for categorical variable BRD, cortisol, IgG, IgG1, IgG2, and IL-8 were estimated from a sire model using ASREML. Heritability estimates were low to moderate for BRD (0.17 +/- 0.08), cortisol (0.13 +/- 0.05), IgG (0.15 +/- 0.05), IgG1 (0.11 +/- 0.05), IgG2 (0.24 +/- 0.06), and IL-8 (0.30 +/- 0.06). A moderate negative genetic correlation was determined between BRD and cortisol ( = -0.19 +/- 0.32). Moderate positive correlations were found between BRD with IgG (0.42 +/- 0.28), IgG1 (0.36 +/- 0.32), and IL-8 ( = 0.26 +/- 0.26). Variation in the BRD phenotype and immune system traits suggested herd health improvement may be achieved through genetic selection. PMID- 27482665 TI - Linkage disequilibrium, persistence of phase, and effective population size in Spanish local beef cattle breeds assessed through a high-density single nucleotide polymorphism chip. AB - Linkage disequilibrium (LD) and persistence of phase are fundamental approaches for exploring the genetic basis of economically important traits in cattle, including the identification of QTL for genomic selection and the estimation of effective population size () to determine the size of the training populations. In this study, we have used the Illumina BovineHD chip in 168 trios of 7 Spanish beef cattle breeds to obtain an overview of the magnitude of LD and the persistence of LD phase through the physical distance between markers. Also, we estimated the time of divergence based on the persistence of the LD phase and calculated past from LD estimates using different alternatives to define the recombination rate. Estimates of average (as a measure of LD) for adjacent markers were close to 0.52 in the 7 breeds and decreased with the distance between markers, although in long distances, some LD still remained (0.07 and 0.05 for markers 200 kb and 1 Mb apart, respectively). A panel with a lower boundary of 38,000 SNP would be necessary to launch a successful within-breed genomic selection program. Persistence of phase, measured as the pairwise correlations between estimates of in 2 breeds at short distances (10 kb), was in the 0.89 to 0.94 range and decreased from 0.33 to 0.52 to a range of 0.01 to 0.08 when marker distance increased from 200 kb to 1 Mb, respectively. The magnitude of the persistence of phase between the Spanish beef breeds was similar to those found in dairy breeds. For across-breed genomic selection, the size of the SNP panels must be in the range of 50,000 to 83,000 SNP. Estimates of past showed values ranging from 26 to 31 for 1 generation ago in all breeds. The divergence among breeds occurred between 129 and 207 generations ago. The results of this study are relevant for the future implementation of within- and across-breed genomic selection programs in the Spanish beef cattle populations. Our results suggest that a reduced subset of the SNP panel would be enough to achieve an adequate precision of the genomic predictions. PMID- 27482666 TI - Leukemia inhibitory factor as a mediator of lipopolysaccharide effects on appetite and selected hormones and metabolites. AB - Leukemia inhibitory factor (LIF) has been suggested to function as a potent inhibitor of feed intake in rodents. In sheep, intravenous injection of lipopolysaccharide (LPS) resulted in an increase in gene expression for LIF in the arcuate nucleus ( < 0.01). In the same experiment, agouti related protein (AgRP) expression was elevated ( < 0.05) but there were no effects on proopiomelanocortin expression. Another group of sheep were provided intracerebroventricular (ICV) injections of LIF at 250, 500, 1,000, and 2,500 ng per sheep. Cumulative feed intake was inhibited by the 1,000- and 2,500-ng doses at 8 and 10 h after ICV injection ( < 0.03). All doses of LIF elevated temperature above 40 degrees C, indicating a fever. When AgRP was intracerebroventricularly injected before LIF, there was no effect of LIF to reduce feed intake, suggesting the LIF inhibition of feed intake is consistent with the concept that the effect is mediated by the melanocortin-4 receptor. In an experiment to determine whether endocrine and metabolic effects of LIF were similar to reported effects of LPS, sheep were intracerebroventricularly injected with 2,500 ng LIF, and blood samples were collected at 10-min intervals for 6 h for assay of LH, samples from the first 3 h were assayed for GH, and samples at 30-min intervals were assayed for glucose and free fatty acids. The effect of treatment and treatment * time interaction was significant, indicating elevated plasma free fatty acids ( < 0.03 and < 0.001, respectively) and glucose ( < 0.01 and < 0.0001, respectively). There was also a treatment * time interaction on circulating concentrations of LH such that LIF caused LH to decrease ( < 0.0001). Additionally, there was a tendency for LIF treatment to increase circulating concentrations of GH (P = 0.0874). The effects of LIF on feed intake and other parameters was similar to the effects of LPS and leads to a hypothesis that LIF expression in response to LPS may be a component of the mechanism for feed intake inhibition and perhaps for changes in selected hormone and metabolites in disease models. PMID- 27482667 TI - The metabolic, stress axis, and hematology response of zilpaterol hydrochloride supplemented beef heifers when exposed to a dual corticotropin-releasing hormone and vasopressin challenge. AB - The objective of this study was to determine the metabolic, stress, and hematology response of beef heifers supplemented with zilpaterol hydrochloride (ZH) when exposed to an endocrine stress challenge. Heifers ( = 20; 556 +/- 7 kg BW) were randomized into 2 treatment groups: 1) control (CON), no ZH supplementation, and 2) zilpaterol (ZIL), supplemented with ZH at 8.33 mg/kg (DM basis). The ZIL group was supplemented ZH for 20 d, with a 3-d withdrawal period. On d 24, heifers received an intravenous bolus of corticotropin-releasing hormone (CRH; 0.3 ug/kg BW) and arginine vasopressin (VP; 1.0 ug/kg BW) to activate the stress axis. Blood samples were collected at 30-min intervals for serum and 60 min intervals for plasma and whole blood, from -2 to 8 h relative to the challenge at 0 h (1000 h). Samples were analyzed for glucose, insulin, NEFA, blood urea nitrogen (BUN), cortisol, epinephrine, norepinephrine, and complete blood cell counts. Following the challenge, cattle were harvested over a 3-d period. Liver, LM, and biceps femoris (BF) samples were collected and analyzed for glucose, lactate, and glycolytic potential (GP). There was a treatment ( <= 0.001) effect for vaginal temperature (VT), with ZIL having a 0.1 degrees C decrease in VT when compared with CON. A treatment * time effect ( = 0.002) was observed for NEFA. A treatment effect was observed for BUN; ZIL had decreased BUN concentrations compared with CON ( < 0.001) prior to the challenge; however, no treatment * time effect was observed. There was also a treatment effect for cortisol ( <= 0.01) and epinephrine ( = 0.003); ZIL had decreased cortisol and epinephrine during the CRH/VP challenge when compared with CON. There was a time effect for total white blood cells, lymphocytes, and monocytes; each variable increased ( <= 0.01) 2 h postchallenge. Additionally, neutrophil counts decreased ( <= 0.01) in response to CRH/VP challenge in both treatment groups. Glucose concentrations within the LM were greater ( = 0.03) in CON when compared with ZIL. Lactate concentrations and GP within the BF were greater in CON ( = 0.05) when compared with ZIL. These data suggest there are some variations observed between treatments in terms of response to the CRH/VP challenge; however, in the environmental conditions of this trial, none of the variations observed suggest that the supplementation of ZH detrimentally alters the ability of cattle to effectively respond to stressful stimuli. PMID- 27482668 TI - The effect of GnRH vaccination on performance, carcass, and meat quality and hormonal regulation in boars, barrows, and gilts. AB - The aim of this study was to assess the effect of GnRH vaccination in boars (BO), barrows (BA), and gilts (GI) slaughtered at an average BW of 133 kg. Forty BO, 40 BA, and 40 GI were housed individually, fed ad libitum, and divided into 2 groups of 20 pigs per sex, a control group (CON) and a GnRH vaccinated group (IC). The IC group received 2 injections of GnRH vaccine (Improvac) at 70 and 105 kg. In BA, GnRH vaccination had minor effects on performance. Observed effects in BO and GI are therefore probably not caused by the GnRH vaccination itself but by the subsequent withdrawal of gonadal hormones. In BO, the increased feed intake after GnRH vaccination ( < 0.001), accompanied by a fall in estradiol and testosterone levels, led to faster growth ( = 0.014), increased back fat thickness ( = 0.021), and a tendency for a decreased meat percentage ( = 0.052). GnRH vaccination of BO decreased the boar taint-related sensory attribute scores similar to the levels of BA and GI ( < 0.001). In GI, the increased feed intake after GnRH vaccination ( < 0.001), accompanied by low progesterone levels, led to faster growth ( < 0.001), increased back fat thickness ( = 0.018), decreased meat percentage ( = 0.032), and a decreased shear force ( = 0.002) without significant differences in the sensory profile. PMID- 27482669 TI - In vivo determination of subcutaneous and abdominal adipose tissue depots in German Holstein dairy cattle. AB - Ultrasonography was used as a noninvasive method for quantitative estimation of the subcutaneous and abdominal adipose tissue depots in dairy cattle. The prediction model was created and validated with a total of 29 German Holstein cows; 6 were in early lactation (<=100 d in milk [DIM]) and 16 were in advanced lactation (101 to 292 DIM). Seven cows were nonpregnant and nonlactating and had been off milk for 350 to 450 d. Transcutaneous assessment of the thickness of subcutaneous and retroperitoneal adipose tissue was done at 16 sites on the body surface of all cows. After completion of the ultrasonographic measurements, the cows were slaughtered and the adipose depots were separately weighed. A stepwise multivariate regression analysis of the ultrasonographic variables was performed to estimate the slaughter weights of the different fat depots. Slaughter weights of the fat depots ranged from 5.0 to 43.0 kg for subcutaneous adipose tissue (SCAT), from 13.7 to 98.8 kg for abdominal adipose tissue (AAT), from 3.4 to 30.3 kg for retroperitoneal adipose tissue (RPAT), from 5.2 to 39.6 kg for omental adipose tissue (OMAT), and from 4.0 to 35.8 kg for mesenteric adipose tissue (MAT). The relationship between calculated amount of fat and slaughter weight of fat had coefficients of determination () and root mean square errors (kg) of 0.88 and 3.4, respectively, for SCAT; 0.94 and 6.1, respectively, for AAT; 0.94 and 1.7, respectively, for RPAT; 0.83 and 3.2, respectively, for OMAT; and 0.95 and 1.6, respectively, for MAT. The accuracy of ultrasonographic measurement of the different fat depots appears sufficient for the quantitative assessment of internal and subcutaneous fat stores in cows. This method is noninvasive and therefore allows safe and repeated monitoring of the amount of stored fat in different adipose tissue depots of German Holsteins cows. PMID- 27482670 TI - Effect of heat stress on the serum concentrations of free amino acids and some of their metabolites in growing pigs. AB - Exposure to heat stress (HS) may affect the intestinal epithelia of pigs, resulting in impaired digestive and absorptive capacity. The serum concentration (SC) of free AA in pigs can be used as indicators of their availability. This study was conducted with 12 crossbred (Landrace * Hampshire * Duroc) pigs (29.0 +/- 2.8 kg initial BW) distributed into 2 groups to analyze the SC of free AA and some AA metabolites in pigs exposed to HS conditions. The treatments were pigs housed under natural HS conditions in a room with no ambient temperature control (23.6 to 37.6 degrees C, HS) and pigs housed at thermoneutral conditions (24 +/- 2 degrees C), feed restricted to a level similar to that of their HS counterparts. All pigs received a wheat-soybean meal diet. Blood samples were collected at both the absorptive (2.5 h after a meal) and postabsorptive (10.0 h after a meal) phase. At the absorptive phase, the SC of free Arg, Leu, Lys, Phe, Thr, and Trp were lower ( < 0.05) and the SC of His, Val, Ala, Pro, Ser, and Tyr tended to be lower ( < 0.10) in HS pigs. At the postabsorptive phase, the SC of free Arg, His, Met, Asn, Gln, and Tyr were higher ( < 0.05) but the SC of Ala was lower ( < 0.01) and the SC of Pro tended to be lower ( < 0.10) in HS pigs. The absorptive SC of carnosine, ornithine (Orn), and Tau were lower ( < 0.05) and of citrulline (Cit), cystathionine, and urea tended to be lower ( < 0.10) in HS pigs. The postabsorptive SC of 3-methyl-His, homo-Cys, OH-Lys, and OH-Pro increased ( = 0.05) and of Cit tended to increase ( = 0.10) but that of carnosine and sarcosine ( < 0.05) decreased in HS pigs. The results of this study show a marked and differential effect of HS on the SC of AA. These data indicate that HS negatively affects the digestive and absorptive capacity of pigs and that the metabolism of some AA is modified in pigs to counteract the negative effects of the HS. PMID- 27482671 TI - Defining the physical properties of corn grown under drought-stressed conditions and the associated energy and nutrient content for swine. AB - Historically high temperatures and low rainfall during the 2012 growing season resulted in drought-stressed conditions in much of the U.S. corn belt. The objective of this experiment was to investigate the impact of these conditions on the composition and energy content in corn and determine if relationships exist among corn quality measurements, chemical composition, and digestibility of energy. Twenty-eight samples of corn from the 2012 drought-stressed crop (DS), plus 2 representative corn samples from the 2011 crop (CNTRL), were collected in Iowa and Illinois using yield as an initial screen for drought impact. Yields ranged from 2.5 to 14.8 t/ha. Each sample was graded by an official of the U.S. grain inspection agency and analyzed for 1,000 kernel weight, kernel density, ether extract, starch, GE, NDF, and CP content. Diets were formulated using each of the 30 corn samples and were fed at 2.6 times the estimated maintenance energy requirement according to the . Sixty individually housed barrows (PIC 359 * C29; 34.2 +/- 0.2 kg initial BW) were randomly allotted in an incomplete crossover design to 30 diets across 4 periods. Diet and fecal samples were analyzed to determine DE values. Both ME and NE values were then calculated from DE values using methods developed by and , respectively. Mean DE, ME, and NE values between the CNTRL and DS were not different (3.72 vs. 3.68 Mcal/kg, respectively, 3.66 vs. 3.62 Mcal/kg, respectively, and 2.92 vs. 2.87 Mcal/kg, respectively; > 0.10). Comparing CNTRL with DS, there were no differences ( > 0.10) in ether extract (4.07 vs. 3.96%), CP (8.56 vs. 9.18%), or starch (70.5 vs. 69.5%). However, ADF and NDF were higher in the DS (2.23 and 8.19%, respectively) when compared with CNTRL (1.89 and 6.92%, respectively; < 0.001 and = 0.015, respectively). Small but significant correlations were observed between DE and NDF ( = -0.51, = 0.008), kernel density ( = 0.51, = 0.007), and percent damaged kernels ( = 0.41, = 0.031). No statistically significant correlations were observed between DE and starch or ADF content or between DE and test weight. We can conclude that corn grown in drought-stressed conditions has energy content similar to corn grown under more favorable conditions and, therefore, can be successfully used in swine diets. Furthermore, NDF proved to be superior to fat, starch, and ADF content in explaining the variation in corn energy content. PMID- 27482672 TI - Influence of dietary fat source and feeding duration on finishing pig growth performance, carcass composition, and fat quality. AB - A total of 160 finishing pigs (PIC 327 * 1050; initially 45.6 kg) were used in an 84-d experiment to evaluate the effects of dietary fat source and feeding duration on growth performance, carcass characteristics, and carcass fat quality. There were 2 pigs per pen with 8 pens per treatment. The 10 dietary treatments were a corn-soybean meal control diet with no added fat and a 3 * 3 factorial with main effects of fat source (4% tallow, 4% soybean oil, or a blend of 2% tallow and 2% soybean oil) and feeding duration (d 0 to 42, 42 to 84, or 0 to 84). The control corn-soybean meal diet was fed in place of added fat diets when needed for duration treatment purposes. On d 0, 1 pig was identified in each pen and fat biopsy samples of the back, belly, and jowl were collected on d 0, 41, and 81 for fatty acid analysis. At the conclusion of the study, all pigs were harvested, carcass characteristics were determined, and back, belly, and jowl fat samples were collected for analysis. Overall (d 0 to 84), there were no differences among pigs fed the different fat sources for growth and carcass characteristics; however, pigs fed diets with added fat for the entire study had improved ( = 0.036) G:F compared with pigs fed the control diet without added fat. Pigs fed supplemental fat throughout the entire study also had improved ( < 0.05) ADG and G:F as well as heavier d-84 BW ( = 0.006) compared with pigs fed additional fat during only 1 period. Adding fat for the entire study increased ( = 0.032) backfat and tended to reduce ( = 0.079) the fat free lean index compared with pigs fed the control diet without added fat. Added fat also increased ( < 0.05) the iodine value (IV) when compared with pigs fed the control diet. Increasing the feeding duration of soybean oil lowered MUFA and increased PUFA concentrations for all fat depots, whereas these values remained relatively unchanged by the addition of tallow (duration * fat source interactions, < 0.05). Our study failed to show any feeding period * fat source interactions ( < 0.05) in fatty acid composition or IV for jowl fat, whereas this interaction occurred for belly fat and backfat, which would indicate a longer turnover rate for jowl fat. In conclusion, feeding additional fat improved ADG and G:F; however, feeding soybean oil for an increased duration, either alone or in combination with tallow, negatively affected the fatty acid composition and IV of different fat depots. PMID- 27482673 TI - Dietary selenium and prolonged exercise alter gene expression and activity of antioxidant enzymes in equine skeletal muscle. AB - Untrained Thoroughbred horses (6 mares and 6 geldings; 11 yr [SE 1] and 565 kg [SE 11]) were used to evaluate antioxidant gene expression and enzyme activity in blood and skeletal muscle in response to prolonged exercise after receiving 2 levels of dietary selenium for 36 d: 0.1 (CON; = 6) or 0.3 mg/kg DM (SEL; = 6). Horses were individually fed 1.6% BW coastal bermudagrass hay, 0.4% BW whole oats, and a mineral/vitamin premix containing no Se. Sodium selenite was added to achieve either 0.1 or 0.3 mg Se/kg DM in the total diet. On d 35, horses underwent 2 h of submaximal exercise in a free-stall exerciser. Blood samples were obtained before (d 0) and after 34 d of Se supplementation and on d 35 to 36 immediately after exercise and at 6 and 24 h after exercise. Biopsies of the middle gluteal muscle were obtained on d 0, before exercise on d 34, and at 6 and 24 h after exercise. Supplementation with Se above the NRC requirement (SEL) increased serum Se ( = 0.011) and muscle thioredoxin reductase (TrxR) activity ( = 0.051) but had no effect on glutathione peroxidase (GPx) activity in plasma, red blood cell (RBC) lysate, or muscle in horses at rest. Serum creatine kinase activity increased ( < 0.0001) in response to prolonged exercise but was not affected by dietary treatment. Serum lipid hydroperoxides were affected by treatment ( = 0.052) and were higher ( = 0.012) in horses receiving CON than SEL immediately following exercise. Muscle expression of was unchanged at 6 h but increased ( = 0.005) 2.8-fold 24 h after exercise, whereas muscle TrxR activity remained unchanged. Glutathione peroxidase activity increased in plasma (P < 0.0001) and decreased in RBC lysate ( = 0.010) after prolonged exercise. A Se treatment * time interaction was observed for RBC GPx activity (P = 0.048). Muscle and expression and GPx activity did not change during the 24-h period after exercise. Level of dietary Se had no overall effect on expression of , , , , , , or in muscle following exercise. The impact of prolonged exercise on the activities of antioxidant enzymes varied. Furthermore, changes in enzyme activity did not necessarily align with enzyme gene expression following exercise. A higher level of Se intake elevated Se status of untrained horses, increased GPx activity, and lessened lipid peroxidation following exercise, suggesting that Se may be beneficial for mitigating oxidative muscle damage and aiding in postexercise recovery. PMID- 27482674 TI - Tannin is a key factor in the determination and prediction of energy content in sorghum grains fed to growing pigs. AB - This study was conducted to determine and compare the DE and ME content as well as the apparent total tract digestibility (ATTD) of GE in 28 samples of sorghum grain fed to growing pigs and to generate prediction equations for DE, ME, and the ATTD of GE based on chemical analysis. The 28 samples included 8 low-tannin sorghum cultivars (LTS; tannin <= 0.16%), 10 medium-tannin sorghum cultivars (MTS: 0.67% <= tannin <= 0.98%), and 10 high-tannin sorghum cultivars (HTS; 1.11% <= tannin <= 1.51%) obtained from 9 provinces in China and 3 samples of LTS cultivars were obtained internationally. The 28 diets were formulated to contain 96.9% of 1 of the 28 sorghum grains and 3.1% of vitamins and minerals. Eighty four barrows (36.5 +/- 3.4 kg initial BW) were used in a randomized complete block design conducted during 2 consecutive periods ( = 6 per treatment) with the pigs fed different diets during the 2 periods. For each period, pigs were placed in metabolic crates for a 5-d total collection of feces and urine following 7 d of adaptation to the diets. Among the 28 samples, GE, CP, and ADF content (DM basis) ranged from 4,363 to 4,496 kcal/kg, 8.26 to 13.41%, and 3.26 to 5.78%, respectively. The average tannin content was 0.08, 0.84, and 1.29% in the LTS, MTS, and HTS samples, respectively. The DE and ME content (DM basis) ranged from 3,861 to 3,989 and from 3,784 to 3,905 kcal/kg, respectively, in LTS; from 3,646 to 3,740 and from 3,588 to 3,669 kcal/kg, respectively, in MTS; and from 3,481 to 3,617 and from 3,418 to 3,538 kcal/kg, respectively, in HTS. The mean DE, ME, DE/GE, ME/GE, and ATTD of GE in MTS were less than those in LTS ( < 0.05) and greater than those in HTS ( < 0.05). The correlation coefficients between DE, ME, or the ATTD of GE and tannin content were all -0.96 ( < 0.01). The best-fit equations for DE and ME (kcal/kg DM) for the complete set of 28 sorghum grains were 6,974 - (236 * % tannin) - (43.27 * % ADF) + (24.96 * % CP) - (0.71 * % GE) for DE and 3,973 - (262 * % tannin) - (27.24 * % ADF) for ME. Our results strongly indicate that the DE and ME content of sorghum grains are related to their chemical composition, especially their tannin content. The DE and ME content could decrease by more than 200 kcal/kg when the tannin content is increased by 1% in the sorghum grain. Overall, tannin is a key predictor for the DE and ME content as well as the ATTD of GE in sorghum grains, and the potent antinutritive properties from tannin should not be ignored when sorghum is used as an energy source for pigs. PMID- 27482675 TI - Comparison of growth performance and excreta composition in broiler chickens when ranked according to various feed efficiency metrics. AB - Several feed efficiency (FE) metrics are currently used in livestock production to select for improved FE. Whether or not different FE metrics similarly estimate physiological characteristics in chickens of diverging FE has not been reported so far. This study aimed to assess potential differences in feed intake (FI), performance, and nutrient excretion in broiler chickens of diverging FE when ranked according to their residual FI (RFI), residual BW gain (RBG), RFI and BW gain (RIG), and G:F between d 7 and 35 of life. The FI was determined daily and BW was recorded once a week. The ranking of chickens into good, medium, and poor FE groups was completed separately for each FE metric. Freshly dropped excreta were collected for pH and DM measurements on d 30 to 32 of life and total excreta for determination of nutrient excretion was collected on d 34 to 36 of life. Relationships among FE metrics were evaluated using regression analysis showing that RFI, RIG, and G:F were more related to each other than to RBG. The FE values greatly varied among chickens for all FE metrics and chickens did not always cluster within the same FE group when using RFI, RIG, RBG, and G:F as the FE metrics because of the calculation approaches. Due to sex-related differences in performance, data of male and female chickens were analyzed separately. The RFI and RIG metrics showed a linear increase ( < 0.01) in total FI from good to poor FE in male and female chickens, whereas G:F showed this effect ( <= 0.011) only when BW gain was standardized to 1,500 g. The RBG did not clearly select chickens of enhanced total BW gain and only tended ( < 0.1) to select for greater BW gain from good to poor FE in female chickens. Excreta pH linearly decreased by 0.7 log units and DM content increased in males from good to poor FE when using RFI and RIG, respectively ( < 0.01). In both sexes, RFI ( < 0.05) and RIG metrics ( <= 0.06) showed a linear increase in daily nitrogen excretion from good to poor FE. In conclusion, results demonstrate that selection of the metric used to determine the FE of chickens modified the results obtained for comparison of production parameters and nutrient excretion among FE groups. Thereby, the RFI, RIG, and G:F metrics were beneficial in selecting the most feed efficient chickens to reduce feed costs, whereas the use of RFI and RIG may be better to select chickens with improved nitrogen retention and thus reduced excretion of an environmental pollutant. PMID- 27482676 TI - Lipid digestibility and energy content of distillers' corn oil in swine and poultry. AB - Two experiments were conducted to determine the DE and ME and apparent total tract digestibility of ether extract of 3 distillers' corn oil (DCO; 4.9, 12.8, or 13.9% free fatty acids [FFA]) samplescompared with a sample of refined corn oil (CO; 0.04% FFA) and an industrially hydrolyzed high-FFA DCO (93.8% FFA) in young pigs and growing broilers. In Exp. 1, 54 barrows (initial age = 28 d) were fed a common diet for 7 d and then fed their allotted dietary treatment (either 100% basal diet or 1 of 5 test diets consisting of 90% basal diet plus 10% test lipid) for the next 7 d in group pens (9 pigs/pen). For the next 10 d, pigs were moved to individual metabolism crates for continued diet and crate adaptation and to a twice-daily feeding regimen. Pigs remained on their respective diets for a 4 d total fecal and urine collection period. For Exp. 2, 567 male broilers were obtained from a commercial hatchery (1 d of age) and reared in grower battery cages that contained 9 chicks per cage. Broilers were fed a common corn-soybean meal starter diet from placement until the beginning of the trial (19 d of age). Birds were then randomly assigned to 1 of 6 dietary treatments (94% basal diet plus 6% dextrose or 94% basal diet plus 6% test lipid substituted for dextrose) on d 19 and were allowed an 8-d dietary acclimation period followed by a 48-h energy balance assay. In Exp. 1, the DCO sample with 12.8% FFA contained the lowest ( < 0.05) DE (8,036 kcal/kg) content compared with the 0.04% refined CO sample and the 4.9 or 93.8% FFA DCO samples (8,814, 8,828, and 8,921 kcal/kg, respectively), with the DCO source containing 13.9% FFA having intermediate DE (8,465 kcal/kg) content. The ME content of these lipid sources also differed among treatments ( < 0.01), following trends similar to their DE values, with no differences noted for ME as a percentage of DE ( > 0.35) content among the lipids evaluated. In Exp. 2, lipids containing 0.04, 4.9, 12.8, and 13.9% FFA had similar nitrogen corrected apparent ME (AME) values (8,072, 7,936, 8,036, and 7,694 respectively), except for the industrially hydrolyzed DCO sample containing 93.8% FFA, which contained 6,276 kcal/kg ( < 0.01). Using published prediction equations, the predicted DE of these lipids for swine was 3.5% greater than the values determined in Exp. 1 for all lipid sources, except for the DCO sample containing 93.8% FFA, which the predicted DE was underestimated. Likewise, the predicted AME of these lipids for broilers was 7.4% greater than the determined AMEn (Exp. 2) for all lipid sources. PMID- 27482677 TI - Effects of live yeast dietary supplementation on nutrient digestibility and fecal microflora in beagle dogs. AB - The effects of live yeast (strain CNCM I-4407; Actisaf Sc 47; Phileo Lesaffre Animal Care, Marcq-en-Baroeul, France) administration on nutrient digestibility and fecal microflora in dogs were investigated. The study included 24 young beagle dogs. They were allocated in control and live yeast (LY) groups (6 males and 6 females in each). During the Adaptation (d 1 to 28) and Trial (d 29 to 70) periods, the dogs received a standard dry pelleted diet. In the Trial period, the LY dogs were given capsuled Actisaf Sc 47 at 1 g/kg live weight with at 2.9 * 10 cfu/g. The control dogs received empty capsules. Live weight and feed consumption were recorded. Blood samples for complete blood count (CBC) and serum biochemistry (urea, creatinine, alkaline phosphatase, and alanine aminotransferase) and fecal samples for pH, microbiology, DM, lactic acid, and ammonia and digestibility evaluation were collected during the Trial period from each dog. The LY dogs had a higher ( < 0.05) weight gain during the Trial period than the control ones. Feed consumption was not adversely affected by LY. The CBC values and urea, creatinine, alkaline phosphatase, and alanine aminotransferase were not adversely affected by LY. Live yeast did not significantly influence pH of fresh feces. Fecal lactic acid and ammonia concentrations were not affected. The LY dogs showed lower ( < 0.05) Escherichia coli and fecal enterococci counts in feces than the control ones. Lactic acid bacteria, Clostridium perfringens, and total coliforms did not show any significant differences between the treatments. The LY dogs showed a higher ( < 0.05) apparent digestibility of NDF. Digestibilities of DM, ash, crude fiber, CP, and fat were not influenced. PMID- 27482678 TI - Effect of corn inclusion on soybean hull-based diet digestibility and growth performance in continuous culture fermenters and beef cattle. AB - Two experiments were conducted using soybean hull (SH) diets with increasing corn proportions to determine increasing corn inclusion effects on fermentation characteristics, diet digestibility, and feedlot performance. The hypothesis was that fiber digestibility would quadratically respond to starch proportion in the diet with a break point where starch inclusion improved fiber digestion and feedlot performance. Proportionately, the diets contained 100:0 (SH100), 90:10 (SH90), 80:20 (SH80), 60:40 (SH60), or 20:80 SH:corn (SH20). In Exp. 1, diets were randomly distributed over 24 continuous culture fermenters and fed for 7 d. In Exp. 2, forty steers (347 +/- 29 kg BW) and 50 heifers (374 +/- 24 kg BW) were blocked by gender, stratified by BW, and distributed across diets. Cattle were fed for 70 d with titanium dioxide included in the diet for the final 14 d and fecal samples collected to measure digestibility. Individual DMI was measured using GrowSafe Feed Intake system. Data were analyzed using the MIXED procedure of SAS with diet evaluated as the fixed effect. In Exp. 1, NDF digestibility (NDFd) linearly decreased ( = 0.04) and ADF digestibility (ADFd) tended to linearly decrease ( = 0.09) as corn increased. Dry matter digestibility (DMd) was cubic ( = 0.01) and OM digestibility (OMd) was quadratic ( = 0.03), and among the 4 SH-based diets, DMd and OMd were greatest for SH90. Acetate:propionate ratio and pH were quadratic ( < 0.01) and greatest for SH80. In Exp. 2, ADG and G:F linearly increased ( < 0.01) as corn inclusion increased. Among the 4 SH-based diets, ADG was numerically greatest for SH80. There was no DMI difference ( >= 0.4) due to diet. As corn inclusion increased, DMd tended to linearly increase (P = 0.06), as did OMd ( = 0.05). Both NDFd and ADFd were quadratic ( = 0.04) and greatest for SH80. Overall, feedlot performance increased and fiber digestibility decreased as corn inclusion increased. However, based on continuous culture digestibility and VFA values as well as feedlot digestibility and performance, optimal corn inclusion for growth and diet utilization in the 4 SH-based diets fell between SH80 and SH90, or 0.4 and 0.2% BW corn supplementation. In this study, providing 0.4% BW corn supplementation in fiber-based diets (SH80) provided greater improvement in performance compared with 0.2% BW corn supplementation (SH90). PMID- 27482679 TI - Influence of growing phase feed efficiency classification on finishing phase growth performance and carcass characteristics of beef steers fed different diet types. AB - A 5-yr study was conducted using 985 crossbred steers (464 kg [SD 32]) fed in 6 separate, replicated groups to determine the influence of growing phase (GP) feed efficiency (FE) classification and diet type on finishing phase (FP) FE of steers. During the GP at the University of Missouri, steers were fed either a whole shell corn-based diet (G-Corn; 528 steers) or a roughage-based diet (G Rough; 457 steers) using GrowSafe feed bunks to measure DMI for 69 to 89 d. At the end of the GP, steers were ranked by residual feed intake (RFI) within diet, shipped to Iowa State University, and blocked into FP pens (5 to 6 steers/pen) by GP diet and RFI rank (upper, middle, or lower one-third). Steers were transitioned to either FP cracked corn- or byproduct-based diets and fed until 1.27 cm backfat was reached. After completion of the sixth group, average GP G:F within GP diet was calculated for each FP pen (168 total pens) using GP initial BW as a covariate (G-Corn: 0.207 [SD 0.038]; G-Rough: 0.185 [SD 0.036]). Pens were classified as highly feed efficient (HFE; >0.5 SD from the G:F mean; 58 pens), mid feed efficient (MFE; +/-0.5 SD from the G:F mean; 60 pens), or lowly feed efficient (LFE; <0.5 SD from the G:F mean; 50 pens). Data were analyzed using PROC MIXED of SAS. Experimental unit was FP pen and the model included the fixed effects of GP diet, FE classification, FP diet, and the interactions. Group (1 to 6) was included as a fixed effect. There were no 3-way interactions ( >= 0.2) for any measured traits. Finishing phase G:F was not affected by any interactions ( >= 0.5) but was greater ( <= 0.03) for HFE versus MFE and LFE and greater ( = 0.02) for MFE versus LFE. Growing phase diet * FE classification effects were detected ( <= 0.01) for FP final BW (FBW), ADG, and DMI. Among G Rough steers, HFE and MFE had greater ( <= 0.04) FBW and ADG than LFE, but among G-Corn steers, LFE had heavier ( = 0.03) FBW than HFE whereas ADG was unaffected ( >= 0.2) by FE classification. Dry matter intake was unaffected ( >= 0.3) by FE classification among G-Rough steers, but among G-Corn steers, LFE had greater ( <= 0.003) DMI than MFE and HFE. Overall, differences in FP G:F between FE classifications were driven by different factors depending on diet; ADG differed among roughage-grown steers and DMI differed among corn-grown steers. Ultimately, steers classified as HFE during the GP still had superior FE during the FP. PMID- 27482680 TI - The effects of zilpaterol hydrochloride and shade on blood metabolites of finishing beef steers. AB - The effects of feeding zilpaterol hydrochloride (ZH) and shade were evaluated on blood metabolites in finishing beef steers ( = 480). Cattle were fed 0 or 8.33 mg/kg of diet DM ZH for 21 d with a 3- or 4-d withdrawal before harvest and were housed in open or shaded pens. Blood samples were collected the day before ZH was fed and on the day the cattle were shipped to the commercial abattoir. Lactate concentration was not different between cattle fed ZH in open or shaded pens ( = 0.12). Nonetheless, a tendency for a diet * time interaction was detected for lactate concentration ( = 0.09), in which it was greater in cattle fed the control diet in open pens before being fed ZH. Cortisol concentration was less before and after ZH was fed ( = 0.01). Glucose was greater for cattle fed the control diet than cattle fed ZH for 21 d ( = 0.03). Cattle fed in open vs. shaded pens did not differ in glucose concentration ( = 0.12), whereas glucose concentrations were greater before ZH was fed than after ( = 0.02). In contrast, plasma urea nitrogen (PUN) concentration was not different in response to diet ( = 0.24), housing type ( = 0.65), or before vs. after being fed ZH ( = 0.60). Lactate concentrations were not different across diet or shade treatments before ZH was fed, whereas after ZH, lactate concentrations were greater in control cattle than cattle fed ZH. Additionally, cortisol was less after feeding ZH. Glucose was greater before than after feeding ZH. PMID- 27482681 TI - Relationship between antioxidant capacity, oxidative stress, and feed efficiency in beef steers. AB - Feed efficiency (FE) can vary between individuals but sources of variation are not well characterized. Oxidative stress is among the biological mechanisms believed to contribute to variation. The objective of this study was to evaluate the relationship between FE, antioxidant activity, and oxidative stress in feedlot steers representing phenotypic extremes for FE. Crossbred beef steers ( = 181) fed 70-d growing phase (GP) whole-shell corn-based (G-Corn) or rye baleage and soybean hull-based (G-Rough) diets in GrowSafe bunks at the University of Missouri were shipped to Iowa State University where the 12 most feed efficient (HFE) and 12 least feed efficient (LFE) steers from each diet (n = 48; 467 kg [SD 51]) were selected for evaluation. Steers received diets similar to GP diets, and 3 d after arrival, blood was sampled to evaluate antioxidant activity and oxidative stress markers for the GP following transit. Steers were transitioned to finishing phase (FP) cracked corn-based (F-Corn) or dried distillers' grains and soybean hull-based (F-Byp) diets, and on FP d 97, blood samples for the FP were collected. Data for the GP were analyzed as a 2 * 2 factorial, and data for the FP were analyzed as a 2 * 2 * 2 factorial using PROC MIXED of SAS. No GP diet * FP diet, FP diet * FE group, or 3-way interactions were noted ( >= 0.11) for FP measures. Steers fed the G-Rough diet had greater ( = 0.04) GP plasma protein carbonyl concentrations. During the GP, HFE steers had greater ( <= 0.04) protein carbonyl and ratio of oxidized:reduced blood lysate glutathione concentrations than LFE steers. There were GP diet * FE group interactions ( <= 0.03) during the GP and FP. During the GP, total blood lysate superoxide dismutase (SOD) activity was greater ( <= 0.03) in G-Rough/LFE steers than in G-Rough/HFE and G-Corn/LFE steers; G-Corn/HFE steers were intermediate. The G-Rough/LFE steers had greater ( < 0.04) glutathione peroxidase (GPX) activity than other groups and greater ( = 0.03) plasma malondialdehyde concentrations than G-Corn/LFE steers. During the FP, the G-Rough/LFE steers had greater ( <= 0.04) GPX activity than G-Rough/HFE and G-Corn/LFE steers; G-Corn/HFE steers were intermediate. The F-Byp diet had greater ( < 0.01) protein carbonyl than the F-Corn diet, and no other FP diet effects were noted ( >= 0.3) for any FP measures. The GP diet and FE groups had stronger relationships with antioxidant activity and oxidative stress markers measured for the GP than for the FP. Overall, antioxidant activity may play a role in FE as LFE steers, driven largely by G-Rough/LFE steers, had greater SOD activity and GPX activity than HFE steers, potentially using a greater proportion of energy otherwise available for tissue accretion. PMID- 27482682 TI - Evaluation of the efficacy of Grofactor, a beta-adrenergic agonist based on zilpaterol hydrochloride, using feedlot finishing bulls. AB - Beta-adrenergic agonists (beta-AA) have been shown to positively impact finishing performance and some carcass traits of feedlot cattle. Our objective was to evaluate the efficacy of a beta-AA on the basis of zilpaterol hydrochloride (Grofactor, Laboratorios Virbac Mexico, Guadalajara, Mexico) on growth and DMI, carcass characteristics, and meat quality of finishing bulls. Forty-five bulls (75% 25% ) initially weighing 448.7 +/- 2.58 kg were blocked by BW and randomly assigned to 1 of 3 diets, using pens of 3 animals, in a randomized complete block design: 1) daily feeding without beta-AA in the basal diet (Control), 2) daily feeding with 0.15 mg/kg BW of Grofactor added to the basal diet (ZHG), or 3) daily feeding with 0.15 mg/kg BW of Zilmax (MSD Salud Animal Mexico, Mexico City, Mexico) added to the basal diet (ZHZ). The duration of the feeding period was 30 d with a subsequent 4-d withdrawal period. Compared with Control bulls, the group fed ZHG had a 12% better ( < 0.025) G:F ratio, and their final BW ( 0.094) and ADG ( 0.084) tended to be enhanced. Feedlot performance of ZHG and ZHZ bulls was similar, although the DMI was ~4% lower ( 0.05) in ZHG bulls vs. the ZHZ and Control groups. The HCW ( 0.001) and dressing percentage ( 0.015) were higher by 20 kg and 3%, respectively, in ZHG bulls vs. Control bulls. The KPH fat was lower ( 0.007) in bulls fed ZHG than in nonsupplemented bulls, but other carcass characteristics were not different in the ZHG and ZHZ bulls, and noncarcass components were not affected by ZHG or ZHZ supplementation. At 48 h postmortem, ZHG bulls had lower ( 0.007) water holding capacity and trended toward ( 0.06) increased chroma and reduced pH ( 0.09) compared to Control bulls. However, compared to ZHZ bulls, ZHG bulls had higher ( 0.02) chroma and a trend ( 0.08) toward increased hue angle. At 14 d postmortem, meat quality variables did not differ between the 3 groups of bulls. Supplementation of ZH Grofactor improved feedlot performance and some carcass characteristics of finishing bulls without affecting meat quality. The effects of Grofactor on feedlot performance, carcass traits, and meat quality were similar to those of Zilmax. PMID- 27482683 TI - Effect of abomasal butyrate infusion on net nutrient flux across the portal drained viscera and liver of growing lambs. AB - The purpose of this experiment was to determine if supplying butyrate to the postruminal gastrointestinal tract of growing lambs alters blood flow and nutrient flux across the portal-drained viscera (PDV) and hepatic tissues. Polled Dorset wether lambs ( = 10; initial BW = 55 +/- 3.3 kg) had catheters surgically implanted into the portal vein, a branch of the hepatic vein, a mesenteric vein, and the abdominal aorta. A cannula was placed in the abomasum to deliver the treatment. Lambs were fed a pelleted ration once daily consisting of 69.7% dehydrated alfalfa, 30.0% ground corn, and 0.3% salt at 1.3 * NE requirement. The experimental design was a crossover balanced in time, so that each lamb received both treatments. Treatments consisted of either a pulse dose infusion of butyrate (buffered solution) to supply butyrate (10 mg/kg BW) or a buffered saline solution (1 mL/kg BW) once daily at the time of feeding. On d 14 of the treatment period, nutrient fluxes were measured using para-aminohippuric acid as a blood flow marker. Blood samples were collected from the aorta, portal vein, and hepatic vein every hour for 9 h beginning at 30 min prior to treatment/feeding. There was a tendency for a treatment * time interaction ( = 0.05) for portal vein blood flow, indicating that blood flow began to decrease earlier postprandial in lambs receiving butyrate. The butyrate treatment tended to increase the uptake of O ( = 0.07) and increased the uptake of glucose ( = 0.002), glutamate ( = 0.04), and glutamine ( = 0.02) by the PDV. There was a treatment * time interaction ( < 0.01) for flux of acetate, propionate, butyrate, isobutyrate, and valerate across the PDV. The interaction was mainly due to an earlier postprandial peak and associated decrease in the flux rate of the VFA. The alteration in timing of the postprandial peak of VFA flux was also observed in hepatic fluxes of VFA. It appears that supplying butyrate to the postruminal tissues through an abomasal cannula increases glucose, glutamate, and glutamine metabolism by the PDV. PMID- 27482684 TI - Intake, digestibility, nitrogen balance, performance, and carcass yield of lambs fed licuri cake. AB - This study aimed to determine the impact of the inclusion of licuri cake in the diets of crossbred Santa Ines lambs, based on intake, digestibility, N balance, urea N, and performance. We used 44 male lambs that were vaccinated and wormed, with an average age of 6 mo and an average BW of 21.2 kg +/- 2.7 kg. The lambs were fed a mixture of Tifton-85 hay (40%) and a concentrated mixture (60%) composed of ground corn, soybean meal, and mineral premix. For the treatments, licuri cake was added at levels of 0, 8, 16, and 24% of DM, with the licuri cake replacing soybean meal and ground corn. We used 11 lambs per treatment in a randomized design. The lambs were confined for 70 d, and the digestibility trial occurred between Day 40 and Day 55. The increased level of licuri cake inclusion promoted a linear reduction in DM intake ( = 0.00) with a 39% reduction between treatments with the 0 and 24% cakes. On the other hand, ether extract () consumption showed an initial quadratic increase ( = 0.00). The total weight gain and ADG showed a linear decrease ( = 0.00) with the addition of licuri cake. The inclusion of licuri cake linearly enhanced ( = 0.02) the digestibility of CP and EE, whereas the digestibility of other nutrients in lambs remained unchanged ( > 0.05). The licuri cake increase led to a linear decrease ( < 0.05) in the N intake, fecal N, and retained N in lambs. Urinary N was not changed. The slaughter carcass weight, HCW, cold carcass weight, hot carcass yield, and cold carcass yield showed linear decreases ( < 0.05) with the addition of licuri cake. Carcass morphometric measurements were influenced by experimental diets, showing linear decreases ( < 0.05) with the addition of licuri cake to diets. The fat thickness, conformation, external length, internal length, leg length, rump width, and chest circumference showed linear decreases ( < 0.05) with the inclusion of licuri cake in diets. The inclusion of licuri cake decreased DMI and digestibility, reflecting the lower ADG. Although feed efficiency was not affected, the lambs weighed less at slaughter and the licuri cake had a negative impact on carcass yield. Therefore, the use of the studied levels of licuri cake in diets for finishing lambs cannot be recommended. PMID- 27482685 TI - Feeding slowly fermentable grains has the potential to ameliorate heat stress in grain-fed wethers. AB - During heat stress (HS), livestock reduce metabolic heat production by lowering activity and feed intake. Because this has obvious consequences for productivity, the aim of these experiments was to investigate nutritional methods for reducing digestive metabolic heat production, thereby allowing livestock more opportunity to dissipate excess heat. In the first experiment, the fermentation rates of corn and wheat grains were compared in an in vitro gas production system containing buffered rumen fluid. This experiment showed that corn had a slower (-15%; < 0.001) rate of gas production than wheat and no differences in total amount of gas production after 24 h of incubation. In the second experiment, we hypothesized that the lower rate of fermentation of corn would reduce metabolic heat load in wethers and, in turn, improve tolerance to HS. Twenty-two Merino * Poll Dorset wethers were housed in 2 climate-controlled rooms and were fed either corn grain plus forage (CD; 39% starch) or wheat grain plus forage (WD; 37% starch) during 3 experimental periods: period 1 (P1), which consisted of 7 d of thermoneutral conditions (18 to 21 degrees C and 40 to 50% relative humidity [RH]) and restricted feed intake (1.3 times maintenance); period 2 (P2), which consisted of 7 d of HS (28 to 38 degrees C and 30 to 50% RH) and restricted feed intake; and period 3 (P3), which consisted of 7 d of HS as in P2 with unrestricted feed intake (1.5 times maintenance) in a randomized control experiment. Water was offered ad libitum. The level of HS was quantified by increases in rectal temperature (RT), respiration rate (RR), and left and right flank skin temperature (LFT and RFT, respectively) and blood acid-base balance. Rectal temperature, RR, LFT, and RFT were elevated ( < 0.001) during HS, especially when wethers had unrestricted feed intake (P3). Wethers fed CD had lower RR, RT, LFT, and RFT ( < 0.001) than wethers fed WD, and this benefit was greatest during HS (P2 and P3). The reduction in RR with CD resulted in less CO exhalation (greater partial pressure of CO2) and greater HCO3 ( < 0.05) than with WD, indicating reduced efforts to dissipate heat by evaporative heat loss via panting. The greatest heat from fermentation was apparent in WD wethers, which had elevated LFT compared with RFT ( < 0.001). Crucially, this large difference was not observed with the CD wethers, indicating that the slow rate of fermentation of CD was expressed as low heat released during feed fermentation in the rumen. These data demonstrated that feeding CD may be a useful management strategy to reduce the impact of high environmental heat loads in sheep. PMID- 27482686 TI - Carcass traits and meat quality of crossbred Boer goats fed peanut cake as a substitute for soybean meal. AB - This study aimed to determine the impact of replacing soybean meal with peanut cake in the diets of crossbred Boer goats as determined by carcass characteristics and quality and by the fatty acid profile of meat. Forty vaccinated and dewormed crossbred Boer goats were used. Goats had an average age of 5 mo and an average BW of 15.6 +/- 2.7 kg. Goats were fed Tifton-85 hay and a concentrate consisting of corn bran, soybean meal, and mineral premix. Peanut cake was substituted for soybean meal at levels of 0.0, 33.33, 66.67, and 100%. Biometric and carcass morphometric measurements of crossbred Boer goats were not affected by replacing soybean meal with peanut cake in the diet. There was no influence of the replacement of soybean meal with peanut cake on weight at slaughter ( = 0.28), HCW ( = 0.26), cold carcass weight ( = 0.23), noncarcass components of weight ( = 0.71), or muscularity index values ( = 0.11). However, regression equations indicated that there would be a reduction of 18 and 11% for loin eye area and muscle:bone ratio, respectively, between the treatment without peanut cake and the treatment with total soybean meal replacement. The weights and yields of the commercial cuts were not affected ( > 0.05) by replacing soybean meal with peanut cake in the diet. Replacing soybean meal with peanut cake did not affect the pH ( = 0.79), color index ( > 0.05), and chemical composition ( > 0.05) of the meat (). However, a quadratic trend for the ash content was observed with peanut cake inclusion in the diet ( = 0.09). Peanut cake inclusion in the diet did not affect the concentrations of the sum of SFA ( = 0.29), the sum of unsaturated fatty acids (UFA; = 0.29), or the sum of PUFA ( = 0.97) or the SFA:UFA ratio ( = 0.23) in goat meat. However, there was a linear decrease ( = 0.01) in the sum of odd-chain fatty acids in the meat with increasing peanut cake in the diet. Soybean meal replacement with peanut cake did not affect the n-6:n-3 ratio ( = 0.13) or the medium-chain fatty acid ( = 0.76), long-chain fatty acid ( = 0.74), or atherogenicity index values ( = 0.60) in the meat. The sensory attributes of the longissimus lumborum did not differ with the inclusion of peanut cake in the diet as a replacement for soybean meal. These results suggest that based on carcass and meat characteristics, peanut cake can completely substitute soybean meal in the diet of crossbred Boer goats. PMID- 27482687 TI - Effects of yeast combined with chromium propionate on growth performance and carcass quality of finishing steers. AB - A combination of yeast and chromium propionate (Y+Cr) was added to the diets of crossbred finishing steers ( = 504; 402 kg +/- 5.76 initial BW) to evaluate impact on feedlot performance and carcass traits. We hypothesized supplementation of Y+Cr would increase growth of feedlot steers. Steers with initial plasma glucose concentrations <=6.0 m were stratified by initial BW and randomly allocated, within strata, to receive 0 (control) or 3.3 g/d Y+Cr. Steers were further divided into heavy and light weight blocks with 6 pens/diet within each weight block. Cattle were housed in dirt-surfaced pens with 21 steers/pen and had ad libitum access to feed. Body weights were measured at 21-d intervals. Blood samples were collected on d 49 and 94 from a subset of steers (5/pen) for analyses of plasma glucose and lactate concentrations. At the end of the finishing phase, animals were weighed and transported 450 km to an abattoir in Holcomb, KS. Severity of liver abscesses and HCW were collected the day of harvest, and after 36 h of refrigeration, USDA yield and quality grades, LM area, and 12th rib subcutaneous fat thickness were determined. There were no treatment * time * weight block interactions ( > 0.05) and no treatment * block interaction for ADG, DMI, or final BW ( >= 0.06), but a treatment * block interaction ( = 0.03) was observed for G:F, in which control, light cattle had poorer efficiency compared with other groups. Treatment * weight group interactions were observed for overall yield grade and carcasses that graded yield grade 1 ( <= 0.04). Light steers supplemented with Y+Cr had decreased overall yield grade and increased percentage of carcasses grading yield grade 1 compared with their control counterparts, with no differences observed for heavy steers. Regardless of weight group, a greater percentage of carcasses from steers supplemented with Y+Cr graded yield grade 2 ( = 0.03) and fewer carcasses from steers supplemented Y+Cr graded yield grade 3 ( < 0.01) than control steers. No interactions or effects of treatment were detected for other carcass measurements ( >= 0.07). There were no treatment * weight group interactions or effects of treatment for plasma glucose or lactate concentrations on d 49 or 94 ( > 0.10). Overall, yeast in combination with chromium propionate may improve feed efficiency and decrease yield grade of light cattle but had no effect on remaining carcass traits and blood constituents. PMID- 27482688 TI - Wheat bran reduces concentrations of digestible, metabolizable, and net energy in diets fed to pigs, but energy values in wheat bran determined by the difference procedure are not different from values estimated from a linear regression procedure. AB - An experiment was conducted to determine effects on DE, ME, and NE for growing pigs of adding 15 or 30% wheat bran to a corn-soybean meal diet and to compare values for DE, ME, and NE calculated using the difference procedure with values obtained using linear regression. Eighteen barrows (54.4 +/- 4.3 kg initial BW) were individually housed in metabolism crates. The experiment had 3 diets and 6 replicate pigs per diet. The control diet contained corn, soybean meal, and no wheat bran. Two additional diets were formulated by mixing 15 or 30% wheat bran with 85 or 70% of the control diet, respectively. The experimental period lasted 15 d. During the initial 7 d, pigs were adapted to their experimental diets and housed in metabolism crates and fed 573 kcal ME/kg BW per day. On d 8, metabolism crates with the pigs were moved into open-circuit respiration chambers for measurement of O consumption and CO and CH production. The feeding level was the same as in the adaptation period, and feces and urine were collected during this period. On d 13 and 14, pigs were fed 225 kcal ME/kg BW per day, and pigs were then fasted for 24 h to obtain fasting heat production. Results of the experiment indicated that the apparent total tract digestibility of DM, GE, crude fiber, ADF, and NDF linearly decreased ( <= 0.05) as wheat bran inclusion increased in the diets. The daily O consumption and CO and CH production by pigs fed increasing concentrations of wheat bran linearly decreased ( <= 0.05), resulting in a linear decrease ( <= 0.05) in heat production. The DE (3,454, 3,257, and 3,161 kcal/kg for diets containing 0, 15, and 30% wheat bran, respectively for diets containing 0, 15, and 30% wheat bran, respectively), ME (3,400, 3,209, and 3,091 kcal/kg for diets containing 0, 15, and 30% wheat bran, respectively), and NE (1,808, 1,575, and 1,458 kcal/kg for diets containing 0, 15, and 30% wheat bran, respectively) of diets decreased (linear, <= 0.05) as wheat bran inclusion increased. The DE, ME, and NE of wheat bran determined using the difference procedure were 2,168, 2,117, and 896 kcal/kg, respectively, and these values were within the 95% confidence interval of the DE (2,285 kcal/kg), ME (2,217 kcal/kg), and NE (961 kcal/kg) estimated by linear regression. In conclusion, increasing the inclusion of wheat bran in a corn-soybean meal based diet reduced energy and nutrient digestibility and heat production as well as DE, ME, and NE of diets, but values for DE, ME, and NE for wheat bran determined using the difference procedure were not different from values determined using linear regression. PMID- 27482689 TI - Reducing sow confinement during farrowing and in early lactation increases piglet mortality. AB - The aim of this study was to investigate the effect of sow confinement and nonconfinement during parturition and early lactation on the performance of sows and piglets prior to weaning. Sows and their litters were housed in either a conventional farrowing crate (control; 1.7 * 2.4 m) or a swing-sided pen (2.8 * 2.15 m). Sows housed in the swing-sided pen had the crate open (open) or closed (closed) during farrowing and opened on d 3 (LAC3) or 7 (LAC7) of lactation. Data are means +/- SEM. The numbers of total and live-born piglets were not different between treatments and averaged 13.1 +/- 0.4 and 12.3 +/- 0.2 piglets/litter, respectively. Sows housed in a farrowing crate had a greater ( = 0.03) number of stillborn piglets compared with open sows from pens (1.1 +/- 0.2 vs. 0.6 +/- 0.1 piglets/litter, respectively). Live-born piglet mortality before litter equalization on d 1 was greater ( < 0.01) for open sows compared with closed and control sows (1.6 +/- 0.2 vs. 0.9 +/- 0.2 vs. 1.1 +/- 0.1 piglets/litter, respectively) and was largely explained by an increase in the incidence of piglets overlain ( < 0.01) in the open compared to closed and control sows (1.3 +/- 0.1 vs. 0.5 +/- 0.1 vs. 0.8 +/- 0.1 piglets/litter, respectively). Overlay mortality between d 3 and 7 of lactation was greater ( = 0.03) in LAC3 sows compared to LAC7 and control sows (0.4 +/- 0.1 vs. 0.2 +/- 0.1 vs. 0.2 +/- 0.1 piglets/litter, respectively). Treatment did not affect either the incidence or cause of piglet mortality after d 7 of lactation ( > 0.05). Total live-born piglet mortality from birth until weaning for the control, closedLAC7, closedLAC3, openLAC7, and openLAC3 was 1.86 +/- 0.19, 1.95 +/- 0.23, 2.10 +/- 0.39, 2.45 +/- 0.27, and 3.74 +/- 0.48, piglets/litter, respectively. Total live born piglet mortality from birth until weaning was greater in the openLAC3 and openLAC7 treatments compared to control ( < 0.01), and openLAC3 was also greater than openLAC7, closedLAC3, and closedLAC7 ( < 0.01). The current data indicated that reducing sow confinement during parturition decreased stillborn number but increased live-born piglet mortality compared to a farrowing crate, and removing confinement on d 3 of lactation further increased total piglet mortality compared to removing sow confinement on d 7 of lactation in sows that farrowed open. Sows that were confined during farrowing and until d 3 or 7 of lactation in a swing sided pen had a similar piglet mortality compared to those in a farrowing crate. PMID- 27482690 TI - Decreasing the frequency and rate of wet brewers grains supplementation did not impact growth but reduced humoral immune response of preconditioning beef heifers. AB - This study evaluated growth and measurements of innate and humoral immunity of preconditioning beef heifers supplemented with wet brewers grains (WBG) at 2 supplementation rates and frequencies. At 14 d after weaning (d 0), Angus heifers ( = 36; 213 +/- 2 kg BW and 254 +/- 7 d of age) were stratified by BW and age and randomly assigned to 1 of 12 drylot pens (3 heifers/pen). Treatments were randomly assigned to pens, in a 2 * 2 factorial design, and consisted of heifers provided ground tall fescue hay ad libitum (55% TDN and 12% CP of DM) and supplemented with WBG (75% TDN and 36% CP of DM) either daily (7X) or 3 times weekly (3X; Monday, Wednesday, and Friday) at 0.5 or 1.0% of BW (DM basis) for 42 d. Heifers were vaccinated against infectious bovine rhinotracheitis (IBR), bovine viral diarrhea virus (BVDV), Mannheimia haemolytica, and Clostridium on d 14 and 28. Individual BW was measured before feeding on d 0 and 42 following 12 h of feed and water withdrawal. Blood samples were collected via jugular venipuncture 4 h after WBG supplementation on d 14, 15, 16, 17, 21, 28, 29, 30, 31, 35, and 42. Heifers fed WBG 3X had less hay DMI (2.6 +/- 0.16 vs. 3.2 +/- 0.16 kg/d; < 0.0001) but greater total DMI (5.6 +/- 0.16 vs. 3.8 +/- 0.16 kg/d; < 0.0001) than 7X heifers on days that all heifers received WBG supplementation. However, overall hay and total DMI was not affected ( >= 0.40) by supplementation frequency. Therefore, ADG, BW, and G:F from d 0 to 42 did not differ among treatments ( >= 0.29). Plasma concentrations of haptoglobin on d 15 and cortisol on d 14 were greater for 3X heifers vs. 7X heifers ( <= 0.04). Heifers fed WBG at 0.5% of BW tended to have greater plasma cortisol concentrations on d 15, 17, and 35 ( <= 0.09) than heifers fed at 1.0% of BW. Serum BVDV-1a titers were greater ( = 0.04) for 7X heifers vs. 3X heifers on d 42 (4.2 +/- 0.28 vs. 3.3 +/- 0.28 log), whereas serum titers against BVDV-2 and IBR were greater for heifers fed WBG at 1.0% of BW vs. heifers fed WBG at 0.5% of BW (7.6 vs. 6.7 and 3.3 vs. 2.8 +/- 0.19 log, respectively). In summary, decreasing WBG supplementation frequency (7 vs. 3 times weekly) or rate (1.0 vs. 0.5% of BW) for recently weaned beef heifers did not affect growth but decreased vaccine-induced antibody production against pathogens associated with bovine respiratory disease during a 42-d preconditioning period. PMID- 27482691 TI - Feeding behavior of growing-finishing pigs reared under precision feeding strategies. AB - The feeding behavior of growing-finishing pigs reared under precision feeding strategies was studied in 35 barrows and 35 females (average initial BW of 30.4 +/- 2.2 kg) over 84 d. Five different feeding programs were evaluated, namely a conventional 3-phase program in which pigs were fed with a constant blend of diet A (high nutrient density) and diet B (low nutrient density) and 4 daily phase feeding programs in which pigs were fed daily with a blend meeting 110, 100, 90, or 80% of the individual Lys requirements. Electronic feeder systems automatically recorded the visits to the feeder, the time of the meals, and the amount of feed consumed per meal. The trial lasted 84 d and the database contained 59,701 feeder visits. The recorded database was used to calculate the number of meals per day, feeding time per meal (min), intervals between meals (min), feed intake per meal (g), and feed consumption rate (feed intake divided by feeding time per meal, expressed in g/min) of each animal. The feeding pattern was predominantly diurnal (73% of the feeder visits). Number of meals, duration of meals, time between meals, feed consumed per meal, and feed consumption rate were not affected by the feeding programs. The females ingested 19% less feed per meal and had a 6% lower feed consumption rate in comparison with the barrows ( < 0.05). Pig feeding behavior was not correlated with diet composition. However, feed efficiency was negatively correlated with amount of feed consumed per meal ( = -0.38, < 0.05) and feed consumption rate ( = -0.44, < 0.05). Feed consumption rate was also negatively correlated with protein efficiency ( = -0.44, < 0.05). Multivariate analysis indicated that feed consumption rate and number of meals per day are the variables related most closely to pig production performance results. Current results indicate that using precision feeding as an approach to reduce Lys intake does not interfere with the feeding behavior of growing finishing pigs. PMID- 27482692 TI - Effects of timing of anabolic implant insertion on growth and immunity of recently weaned beef steers. AB - We evaluated the effects of timing of estrogenic implant insertion, relative to weaning, on growth performance and measurements of innate and humoral immunity of beef calves. On d -14, Angus * Simmental crossbred steers ( = 48; BW = 217 +/- 5 kg; age = 191 +/- 3 d) were stratified by BW, age, and cow parity and randomly assigned to receive no implant (NOIP) or 36 mg of zeranol on d -14, 0, or 14, relative to weaning (IP-14, IP0, and IP+14, respectively; 12 steers/treatment). From d -14 to 0, cow-calf pairs remained on a single, tall-fescue pasture with no access to concentrate supplementation. Steers were weaned on d 0, stratified by treatment and BW, and then allocated into 1 of 16 drylot pens to receive daily free-choice access to a corn silage-based diet during the preconditioning phase (d 0 to 56). Steers were vaccinated against infectious bovine rhinotracheitis (IBRV), bovine viral diarrhea virus (BVDV), and on d -27 and 0. From d 56 to 252 (postpreconditioning phase), steers remained in their respective feedlot pens and were provided free-choice access to corn silage-based growing (d 56 to 167) and finishing total mixed rations (d 168 to 252). Body weight on d 0 did not differ among treatments ( >= 0.29) but was greater for IP-14 and IP0 than NOIP and IP+14 steers on d 14, 42, and 56 ( <= 0.05). Treatment effects were not detected for G:F and DMI from d 0 to 56 ( >= 0.34), but ADG from d -14 to 56 was greater for IP-14 compared to NOIP ( <= 0.05) and intermediate for IP0 and IP+14 steers. Plasma IGF-1 concentrations were greater for IP-14 than NOIP ( <= 0.05) and intermediate for IP0 and IP+14 steers on d -7, 0, 14, and 21. Plasma concentrations of cortisol and haptoglobin and serum titers against BVDV types 1a and 2 did not differ among treatments from d 0 to 56 ( >= 0.37). However, serum IBRV titers were greater for IP+14 than NOIP, IP-14, and IP0 steers ( <= 0.02). On d 252, BW was greater for IP-14 and IP0 than NOIP steers ( <= 0.05) and intermediate for IP+14 steers, but ADG and G:F from d 57 to 252 and carcass characteristics at slaughter did not differ among treatments ( >= 0.16). Thus, the 36-mg zeranol implant did not elicit an inflammatory response or affect the overall vaccine response of steers (except for IBRV titers). However, growth of steers during a 56-d preconditioning period was enhanced by administering 36-mg zeranol implant 14 d before weaning, without affecting subsequent postpreconditioning growth and carcass characteristics at slaughter. PMID- 27482694 TI - The influence of taste in willingness-to-pay valuations of sirloin steaks from postextraction algal residue-fed cattle. AB - Consumer preferences and willingness-to-pay (WTP) for beef sirloin steaks with differing production, physical, and credence attributes related to the use of postextraction algal residue (PEAR), a novel feed ingredient, were estimated. Ninety-six consumers participated in a sensory tasting panel before completing a choice set survey; 127 consumers completed only the choice set survey without sampling products. Steaks from grain- and PEAR-fed steers had similar Warner Bratzler shear force (WBSF) scores (1.89 kg and 2.01 kg, respectively; = 0.77) and had lower WBSF scores than steaks from grass-fed steers (3.37 kg; < 0.05). Eicosapentaenoic acid (20:5) was not different among steaks from grain- and PEAR fed steers ( = 0.39) but was greater compared with steaks from grass-fed cattle ( <= 0.03). Panelists in the sensory portion of the study evaluated beef samples for like/dislike of overall sample, overall flavor, beefy flavor, and juiciness. Panelist rating of overall like, overall flavor like, and beefy flavor like were not different between the PEAR- and grain-fed treatments ( > 0.26). Panelists rated the juiciness like/dislike of steaks from PEAR-fed cattle the highest ( < 0.01) among the 3 samples. Sensory tasting of the products was observed to alter the preferences of consumers. Consumers who completed only the survey negatively perceived beef from PEAR-fed cattle compared with beef from grain-fed cattle, with a WTP discount of -US$1.17/kg. However, with sensory tasting, the WTP for beef from PEAR-fed cattle was not discounted relative to beef from grain-fed cattle ( = 0.21). The nontasting consumers had much higher stated WTP values for credence attributes. Factors that influence the eating experience (tenderness and quality grade) dominated as the most important attributes on WTP among the tasting group. The use of no hormones and no antibiotics in production had a premium of $2.34/kg among the nontasting group, but with tasting, the premium was $1.19/kg. If PEAR-fed beef came to market, there would be no need to differentiate it from grain-fed beef unless retailers wanted to market it as a differentiated product. If it were marketed as a differentiated product, retailers would need to hold promotional tastings to change consumer's preconceived notions about the product. PMID- 27482693 TI - Effects of genotype, wilting, and additives on the nutritive value and fermentation of bermudagrass silage. AB - Bermudagrass is the main warm-season grass species used for livestock production in the southeastern United States; however, when it is ensiled, the silage fermentation parameters are often less than desirable. The objective of this study was to investigate the effects of management practices on the nutritive value and fermentation characteristics of bermudagrass silage. In Exp. 1, treatments were the factorial combinations of 2 bermudagrass genotypes, 'Jiggs' () and 'Tifton 85' ( sp.), 4 additives, and 2 DM concentrations at ensiling. The additives were 1) untreated control (deionized water), 2) Ecosyl, 3) B500, or 4) sugarcane molasses. The 2 DM concentrations at ensiling were low DM (22% DM) or high DM (53% DM). Treatments were replicated 3 times in a completely randomized design. Silage treated with molasses had a lesser ( < 0.05) pH and greater ( < 0.01) lactate concentrations than the control, Ecosyl, and B500 in silage with low DM concentrations and greater ( < 0.01) in vitro true digestibility (IVTD) and lesser ( < 0.01) ADF concentrations than the other treatments at either DM concentration. Silage treated with B500 had the greatest ( < 0.01) aerobic stability, whereas that treated with molasses had the least aerobic stability. However, all treatments presented long aerobic stability (>=150 h). Jiggs had lesser ( < 0.01) ADF and NDF and NDF digestibility (NDFD) concentrations than Tifton 85 and Tifton 85 had greater ( < 0.01) IVTD than Jiggs in the silage with a high DM concentration. In Exp. 2, Jiggs silage treated with either molasses (20 g molasses [DM]/kg forage [as-fed basis]) or nothing (control, untreated silage) was fed to 16 beef heifers ( sp.) in individual drylot pens in a completely randomized design with 8 replicates for voluntary DMI, in vivo apparent DM digestibility, and NDFD evaluations. There were no differences ( = 0.36) among treatments in NDFD; however, there was a trend ( < 0.08) for greater in vivo apparent DM digestibility and DMI in heifers fed the molasses-treated silage. Microbial inoculants had decreased effects on Jiggs and Tifton 85 bermudagrass silage ensiled at a low DM concentration; however, adding molasses was an effective management practice to improve its nutritive value and fermentation characteristics. PMID- 27482695 TI - Effect of immunological castration management strategy on lipid oxidation and sensory characteristics of bacon stored under simulated food service conditions. AB - The objectives of this study were to determine the effect of 1) immunological castration (Improvest, a gonadotropin releasing factor analog-diphtheria toxoid conjugate) management strategy (age at slaughter and time of slaughter after second dose) and 2) sex on lipid oxidation and sensory characteristics of bacon stored under simulated food service conditions. For Objective 1, immunological castration management strategies included 24-wk-old immunologically castrated (IC) barrows 4, 6, 8, or 10 wk after the second Improvest dose (ASD); 26-wk-old IC barrows 6 wk ASD; and 28-wk-old IC barrows 8 wk ASD ( = 63). Objective 2 ( = 97) included IC barrows, physically castrated (PC) barrows, and gilts slaughtered at 24, 26, and 28 wks of age. Bellies from 2 slaughter dates were manufactured into bacon under commercial conditions. Bacon slices were laid out on parchment paper, packaged in oxygen-permeable poly-vinyl-lined boxes, and frozen (-33 degrees C) for 1, 4, 8, or 12 wk to simulate food service conditions. At the end of each storage period, bacon was evaluated for lipid oxidation, moisture and lipid content, and sensory characteristics. Data from both objectives were analyzed using the MIXED procedure in SAS with belly as the experimental unit. For both objectives, as storage time increased, lipid oxidation of bacon increased ( < 0.01), regardless of management strategy or sex. Also, there was no sex or management strategy * week of frozen storage interaction for any traits evaluated ( >= 0.25). For Objective 1, lipid content of bacon from IC barrows increased as time of slaughter ASD increased ( < 0.05), regardless of age at slaughter. Additionally, there were no differences in sensory attributes of bacon across management strategies. For the evaluation of sex effects in Objective 2, lipid oxidation was greater ( < 0.05) in IC barrows compared with PC barrows but was not different than gilts ( > 0.05). After 12 wk of frozen storage, lipid oxidation values for IC barrows, PC barrows, and gilts were still below 0.5 mg malondialdehyde/kg of meat, the threshold at which trained panelists may deem a food to be rancid. In conclusion, bacon shelf life characteristics were not altered by the immunological castration management strategy and bacon from IC barrows was similar to bacon from gilts. Therefore, bacon from IC barrows would result in shelf life and sensory quality similar to PC barrows and gilts. PMID- 27482696 TI - Poor maternal nutrition during gestation alters the expression of genes involved in muscle development and metabolism in lambs. AB - Poor maternal nutrition during gestation can result in reduced muscle mass and increased adiposity of the muscle tissue in the offspring. This can have long lasting consequences on offspring health and productivity. However, the mechanisms by which poor maternal nutrition affects postnatal muscle development are poorly understood. We hypothesized that poor maternal nutrition during gestation would alter expression of key pathways and genes involved in growth, development, and maintenance of the muscle of lambs. For this study, beginning at d 31 +/- 1.3 of gestation, ewes were fed 100 (control), 60 (restricted), or 140% (overfed) of the NRC requirements. Within 24 h of birth, lambs were necropsied and semitendinosus muscle tissue was collected for gene expression analysis. Using RNA sequencing (RNA-seq) across dietary treatment groups, 35 and 10 differentially expressed genes were identified using the and reference annotations, respectively. Maternal overfeeding caused changes in the expression of genes involved in regulating muscle protein synthesis and growth as well as metabolism. Alternately, maternal nutrient restriction affected genes that are involved in muscle cell proliferation and signal transduction. That is, despite a similar phenotype, the genes identified differed between offspring born to restricted- or overfed, ewes indicating that the mechanism for the phenotypic changes in muscle are due to different mechanisms. PMID- 27482697 TI - Erratum. PMID- 27482698 TI - Chemical Constituents and Insecticidal Activities of Ajania fruticulosa Essential Oil. AB - The insecticidal activity and chemical constituents of the essential oil from Ajania fruticulosa were investigated. Twelve constituents representing 91.0% of the essential oil were identified, and the main constituents were 1,8-cineole (41.40%), (+)-camphor (32.10%), and myrtenol (8.15%). The essential oil exhibited contact toxicity against Tribolium castaneum and Liposcelis bostrychophila adults with LD50 values of 105.67 MUg/adult and 89.85 MUg/cm(2) , respectively. The essential oil also showed fumigant toxicity against two species of insect with LC50 values of 11.52 and 0.65 mg/l, respectively. 1,8-Cineole exhibited excellent fumigant toxicity (LC50 = 5.47 mg/l) against T. castaneum. (+)-Camphor showed obvious fumigant toxicity (LC50 = 0.43 mg/l) against L. bostrychophila. Myrtenol showed contact toxicity (LD50 = 29.40 MUg/cm(2) ) and fumigant toxicity (LC50 = 0.50 mg/l) against L. bostrychophila. 1,8-Cineole and (+)-camphor showed strong insecticidal activity to some important insects, and they are main constituents of A. fruticulosa essential oil. The two compounds may be related to insecticidal activity of A. fruticulosa essential oil against T. castaneum and L. bostrychophila. PMID- 27482700 TI - [The Future of Fecal Microbiota Transplantation Method In Neuropsychiatric Disorders]. AB - Letter to the editor. PMID- 27482701 TI - [The Importance of Camera Records In The Forensic Psychiatric Expert Practices]. AB - Letter to the editor. PMID- 27482699 TI - Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors. AB - OBJECTIVE: Vascular dysfunction represents a disease-initiating event in systemic sclerosis (SSc; scleroderma). Results of recent studies suggest that epigenetic dysregulation impairs normal angiogenesis and can result in abnormal patterns of blood vessel growth. Histone deacetylases (HDACs) control endothelial cell (EC) proliferation and regulate EC migration. Specifically, HDAC-5 appears to be antiangiogenic. This study was undertaken to test whether HDAC-5 contributes to impaired angiogenesis in SSc by repressing proangiogenic factors in ECs. METHODS: Dermal ECs were isolated from patients with diffuse cutaneous SSc and healthy controls. Angiogenesis was assessed using an in vitro Matrigel tube formation assay. An assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed to assess and localize the genome-wide effects of HDAC5 knockdown on chromatin accessibility. RESULTS: The expression of HDAC5 was significantly increased in ECs from patients with SSc compared to healthy control ECs. Silencing of HDAC5 in SSc ECs restored normal angiogenesis. HDAC5 knockdown followed by ATAC-seq assay in SSc ECs identified key HDAC5-regulated genes involved in angiogenesis and fibrosis, such as CYR61, PVRL2, and FSTL1. Simultaneous knockdown of HDAC5 in conjunction with either CYR61, PVRL2, or FSTL1 inhibited angiogenesis in SSc ECs. Conversely, overexpression of these genes individually led to an increase in tube formation as assessed by Matrigel assay, suggesting that these genes play functional roles in the impairment of angiogenesis in SSc. CONCLUSION: Several novel HDAC5-regulated target genes associated with impaired angiogenesis were identified in SSc ECs by ATAC-seq. The results of this study provide a potential link between epigenetic regulation and impaired angiogenesis in SSc, and identify a novel mechanism for the dysregulated angiogenesis that characterizes this disease. PMID- 27482702 TI - [Bipolarity In Differential Diagnosis of Childhood-Onset Psychiatric Symptoms]. AB - Letter to the editor. PMID- 27482703 TI - IFAR AUGUST EDITORIAL. PMID- 27482704 TI - Improved Metabolic Models for E. coli and Mycoplasma genitalium from GlobalFit, an Algorithm That Simultaneously Matches Growth and Non-Growth Data Sets. AB - Constraint-based metabolic modeling methods such as Flux Balance Analysis (FBA) are routinely used to predict the effects of genetic changes and to design strains with desired metabolic properties. The major bottleneck in modeling genome-scale metabolic systems is the establishment and manual curation of reliable stoichiometric models. Initial reconstructions are typically refined through comparisons to experimental growth data from gene knockouts or nutrient environments. Existing methods iteratively correct one erroneous model prediction at a time, resulting in accumulating network changes that are often not globally optimal. We present GlobalFit, a bi-level optimization method that finds a globally optimal network, by identifying the minimal set of network changes needed to correctly predict all experimentally observed growth and non-growth cases simultaneously. When applied to the genome-scale metabolic model of Mycoplasma genitalium, GlobalFit decreases unexplained gene knockout phenotypes by 79%, increasing accuracy from 87.3% (according to the current state-of-the art) to 97.3%. While currently available computers do not allow a global optimization of the much larger metabolic network of E. coli, the main strengths of GlobalFit are already played out when considering only one growth and one non growth case simultaneously. Application of a corresponding strategy halves the number of unexplained cases for the already highly curated E. coli model, increasing accuracy from 90.8% to 95.4%. PMID- 27482707 TI - A New Fuzzy-Evidential Controller for Stabilization of the Planar Inverted Pendulum System. AB - In order to realize the stability control of the planar inverted pendulum system, which is a typical multi-variable and strong coupling system, a new fuzzy evidential controller based on fuzzy inference and evidential reasoning is proposed. Firstly, for each axis, a fuzzy nine-point controller for the rod and a fuzzy nine-point controller for the cart are designed. Then, in order to coordinate these two controllers of each axis, a fuzzy-evidential coordinator is proposed. In this new fuzzy-evidential controller, the empirical knowledge for stabilization of the planar inverted pendulum system is expressed by fuzzy rules, while the coordinator of different control variables in each axis is built incorporated with the dynamic basic probability assignment (BPA) in the frame of fuzzy inference. The fuzzy-evidential coordinator makes the output of the control variable smoother, and the control effect of the new controller is better compared with some other work. The experiment in MATLAB shows the effectiveness and merit of the proposed method. PMID- 27482705 TI - Significantly Reduced Genoprevalence of Vaccine-Type HPV-16/18 Infections among Vaccinated Compared to Non-Vaccinated Young Women 5.5 Years after a Bivalent HPV 16/18 Vaccine (Cervarix(r)) Pilot Project in Uganda. AB - The objective of this study was to determine the prevalence and some predictors for vaccine and non-vaccine types of HPV infections among bivalent HPV vaccinated and non-vaccinated young women in Uganda. This was a comparative cross sectional study 5.5 years after a bivalent HPV 16/18 vaccination (Cervarix(r), GlaxoSmithKline, Belgium) pilot project in western Uganda. Cervical swabs were collected between July 2014-August 2014 and analyzed with a HPV genotyping test, CLART(r) HPV2 assay (Genomica, Madrid Spain) which is based on PCR followed by microarray for determination of genotype. Blood samples were also tested for HIV and syphilis infections as well as CD4 and CD8 lymphocyte levels. The age range of the participants was 15-24 years and mean age was 18.6(SD 1.4). Vaccine-type HPV-16/18 strains were significantly less prevalent among vaccinated women compared to non-vaccinated women (0.5% vs 5.6%, p 0.006, OR 95% CI 0.08(0.01 0.64). At type-specific level, significant difference was observed for HPV16 only. Other STIs (HIV/syphilis) were important risk factors for HPV infections including both vaccine types and non-vaccine types. In addition, for non-vaccine HPV types, living in an urban area, having a low BMI, low CD4 count and having had a high number of life time sexual partners were also significant risk factors. Our data concurs with the existing literature from other parts of the world regarding the effectiveness of bivalent HPV-16/18 vaccine in reducing the prevalence of HPV infections particularly vaccine HPV- 16/18 strains among vaccinated women. This study reinforces the recommendation to vaccinate young girls before sexual debut and integrate other STI particularly HIV and syphilis interventions into HPV vaccination packages. PMID- 27482706 TI - Facility-Based Delivery during the Ebola Virus Disease Epidemic in Rural Liberia: Analysis from a Cross-Sectional, Population-Based Household Survey. AB - BACKGROUND: The Ebola virus disease (EVD) epidemic has threatened access to basic health services through facility closures, resource diversion, and decreased demand due to community fear and distrust. While modeling studies have attempted to estimate the impact of these disruptions, no studies have yet utilized population-based survey data. METHODS AND FINDINGS: We conducted a two-stage, cluster-sample household survey in Rivercess County, Liberia, in March-April 2015, which included a maternal and reproductive health module. We constructed a retrospective cohort of births beginning 4 y before the first day of survey administration (beginning March 24, 2011). We then fit logistic regression models to estimate associations between our primary outcome, facility-based delivery (FBD), and time period, defined as the pre-EVD period (March 24, 2011-June 14, 2014) or EVD period (June 15, 2014-April 13, 2015). We fit both univariable and multivariable models, adjusted for known predictors of facility delivery, accounting for clustering using linearized standard errors. To strengthen causal inference, we also conducted stratified analyses to assess changes in FBD by whether respondents believed that health facility attendance was an EVD risk factor. A total of 1,298 women from 941 households completed the survey. Median age at the time of survey was 29 y, and over 80% had a primary education or less. There were 686 births reported in the pre-EVD period and 212 in the EVD period. The unadjusted odds ratio of facility-based delivery in the EVD period was 0.66 (95% confidence interval [CI] 0.48-0.90, p-value = 0.010). Adjustment for potential confounders did not change the observed association, either in the principal model (adjusted odds ratio [AOR] = 0.70, 95%CI 0.50-0.98, p = 0.037) or a fully adjusted model (AOR = 0.69, 95%CI 0.50-0.97, p = 0.033). The association was robust in sensitivity analyses. The reduction in FBD during the EVD period was observed among those reporting a belief that health facilities are or may be a source of Ebola transmission (AOR = 0.59, 95%CI 0.36-0.97, p = 0.038), but not those without such a belief (AOR = 0.90, 95%CI 0.59-1.37, p = 0.612). Limitations include the possibility of FBD secular trends coincident with the EVD period, recall errors, and social desirability bias. CONCLUSIONS: We detected a 30% decreased odds of FBD after the start of EVD in a rural Liberian county with relatively few cases. Because health facilities never closed in Rivercess County, this estimate may under-approximate the effect seen in the most heavily affected areas. These are the first population-based survey data to show collateral disruptions to facility-based delivery caused by the West African EVD epidemic, and they reinforce the need to consider the full spectrum of implications caused by public health emergencies. PMID- 27482708 TI - In Vivo Mouse Intervertebral Disc Degeneration Model Based on a New Histological Classification. AB - Although human intervertebral disc degeneration can lead to several spinal diseases, its pathogenesis remains unclear. This study aimed to create a new histological classification applicable to an in vivo mouse intervertebral disc degeneration model induced by needle puncture. One hundred six mice were operated and the L4/5 intervertebral disc was punctured with a 35- or 33-gauge needle. Micro-computed tomography scanning was performed, and the punctured region was confirmed. Evaluation was performed by using magnetic resonance imaging and histology by employing our classification scoring system. Our histological classification scores correlated well with the findings of magnetic resonance imaging and could detect degenerative progression, irrespective of the punctured region. However, the magnetic resonance imaging analysis revealed that there was no significant degenerative intervertebral disc change between the ventrally punctured and non-punctured control groups. To induce significant degeneration in the lumbar intervertebral discs, the central or dorsal region should be punctured instead of the ventral region. PMID- 27482709 TI - Cost-Effectiveness Analysis of Different Genetic Testing Strategies for Lynch Syndrome in Taiwan. AB - Patients with Lynch syndrome (LS) have a significantly increased risk of developing colorectal cancer (CRC) and other cancers. Genetic screening for LS among patients with newly diagnosed CRC aims to identify mutations in the disease causing genes (i.e., the DNA mismatch repair genes) in the patients, to offer genetic testing for relatives of the patients with the mutations, and then to provide early prevention for the relatives with the mutations. Several genetic tests are available for LS, such as DNA sequencing for MMR genes and tumor testing using microsatellite instability and immunohistochemical analyses. Cost effectiveness analyses of different genetic testing strategies for LS have been performed in several studies from different countries such as the US and Germany. However, a cost-effectiveness analysis for the testing has not yet been performed in Taiwan. In this study, we evaluated the cost-effectiveness of four genetic testing strategies for LS described in previous studies, while population specific parameters, such as the mutation rates of the DNA mismatch repair genes and treatment costs for CRC in Taiwan, were used. The incremental cost effectiveness ratios based on discounted life years gained due to genetic screening were calculated for the strategies relative to no screening and to the previous strategy. Using the World Health Organization standard, which was defined based on Taiwan's Gross Domestic Product per capita, the strategy based on immunohistochemistry as a genetic test followed by BRAF mutation testing was considered to be highly cost-effective relative to no screening. Our probabilistic sensitivity analysis results also suggest that the strategy has a probability of 0.939 of being cost-effective relative to no screening based on the commonly used threshold of $50,000 to determine cost-effectiveness. To the best of our knowledge, this is the first cost-effectiveness analysis for evaluating different genetic testing strategies for LS in Taiwan. The results will be informative for the government when considering offering screening for LS in patients newly diagnosed with CRC. PMID- 27482710 TI - Reported Outcome Measures in Degenerative Cervical Myelopathy: A Systematic Review. AB - OBJECTIVE: Degenerative cervical myelopathy [DCM] is a disabling and increasingly prevalent group of diseases. Heterogeneous reporting of trial outcomes limits effective inter-study comparison and optimisation of treatment. This is recognised in many fields of healthcare research. The present study aims to assess the heterogeneity of outcome reporting in DCM as the premise for the development of a standardised reporting set. METHODS: A systematic review of MEDLINE and EMBASE databases, registered with PROSPERO (CRD42015025497) was conducted in accordance with PRISMA guidelines. Full text articles in English, with >50 patients (prospective) or >200 patients (retrospective), reporting outcomes of DCM were eligible. RESULTS: 108 studies, assessing 23,876 patients, conducted world-wide, were identified. Reported outcome themes included function (reported by 97, 90% of studies), complications (reported by 56, 52% of studies), quality of life (reported by 31, 29% of studies), pain (reported by 29, 27% of studies) and imaging (reported by 59, 55% of studies). Only 7 (6%) studies considered all of domains in a single publication. All domains showed variability in reporting. CONCLUSIONS: Significant heterogeneity exists in the reporting of outcomes in DCM. The development of a consensus minimum dataset will facilitate future research synthesis. PMID- 27482711 TI - Influence of Season and Feedlot Location on Prevalence and Virulence Factors of Seven Serogroups of Escherichia coli in Feces of Western-Canadian Slaughter Cattle. AB - Pooled feces collected over two years from 1749 transport trailers hauling western-Canadian slaughter cattle were analysed by PCR for detection of Escherichia coli serogroups O26, O45, O103, O111, O121, O145, and O157. Sequential immunomagnetic separation was then used to collect bacterial isolates (n = 1035) from feces positive for target serogroups. Isolated bacteria were tested by PCR to confirm serogroup and the presence of eae, ehxA, stx1, and stx2 virulence genes. Based on PCR screening, serogroup prevalence in feces ranged from 7.0% (O145) to 94.4% (O103) with at least 3 serogroups present in 79.5% of samples. Origin of cattle affected serogroup PCR prevalence and O157 was most prevalent in feces from south-west Alberta (P < 0.001). All serogroups demonstrated seasonal variations in PCR prevalence, with O26, O45, O103, O121, and O157 least prevalent (P < 0.001) in cooler winter months, while uncommon serogroups O111 and O145 increased in prevalence during winter (P < 0.001). However, isolates collected during winter were predominantly from serogroups O103 and O45. No seasonal variation was noted in proportion of isolates which were Shiga toxin containing E. coli (STEC; P = 0.18) or positive for Shiga toxin and eae (enterohemorrhagic E. coli; EHEC; P = 0.29). Isolates of serogroups O111, O145, and O157 were more frequently EHEC than were others, although 37.6-54.3% of isolates from other serogroups were also EHEC. Shiga-toxin genes present also varied by geographic origin of cattle (P < 0.05) in all serogroups except O157. As cattle within feedlots are sourced from multiple regions, locational differences in serogroup prevalence and virulence genes imply existence of selection pressures for E. coli and their virulence in western-Canadian cattle. Factors which reduce carriage or expression of virulence genes, particularly in non-O157 serogroups, should be investigated. PMID- 27482712 TI - Unveiling the Mechanism of Arginine Transport through AdiC with Molecular Dynamics Simulations: The Guiding Role of Aromatic Residues. AB - Commensal and pathogenic enteric bacteria have developed several systems to adapt to proton leakage into the cytoplasm resulting from extreme acidic conditions. One such system involves arginine uptake followed by export of the decarboxylated product agmatine, carried out by the arginine/agmatine antiporter (AdiC), which thus works as a virtual proton pump. Here, using classical and targeted molecular dynamics, we investigated at the atomic level the mechanism of arginine transport through AdiC of E. coli. Overall, our MD simulation data clearly demonstrate that global rearrangements of several transmembrane segments are necessary but not sufficient for achieving transitions between structural states along the arginine translocation pathway. In particular, local structural changes, namely rotameric conversions of two aromatic residues, are needed to regulate access to both the outward- and inward-facing states. Our simulations have also enabled identification of a few residues, overwhelmingly aromatic, which are essential to guiding arginine in the course of its translocation. Most of them belong to gating elements whose coordinated motions contribute to the alternating access mechanism. Their conservation in all known E. coli acid resistance antiporters suggests that the transport mechanisms of these systems share common features. Last but not least, knowledge of the functional properties of AdiC can advance our understanding of the members of the amino acid-carbocation-polyamine superfamily, notably in eukaryotic cells. PMID- 27482713 TI - FLIM FRET Visualization of Cdc42 Activation by Netrin-1 in Embryonic Spinal Commissural Neuron Growth Cones. AB - Netrin-1 is an essential extracellular chemoattractant that signals through its receptor DCC to guide commissural axon extension in the embryonic spinal cord. DCC directs the organization of F-actin in growth cones by activating an intracellular protein complex that includes the Rho GTPase Cdc42, a critical regulator of cell polarity and directional migration. To address the spatial distribution of signaling events downstream of netrin-1, we expressed the FRET biosensor Raichu-Cdc42 in cultured embryonic rat spinal commissural neurons. Using FLIM-FRET imaging we detected rapid activation of Cdc42 in neuronal growth cones following application of netrin-1. Investigating the signaling mechanisms that control Cdc42 activation by netrin-1, we demonstrate that netrin-1 rapidly enriches DCC at the leading edge of commissural neuron growth cones and that netrin-1 induced activation of Cdc42 in the growth cone is blocked by inhibiting src family kinase signaling. These findings reveal the activation of Cdc42 in embryonic spinal commissural axon growth cones and support the conclusion that src family kinase activation downstream of DCC is required for Cdc42 activation by netrin-1. PMID- 27482714 TI - The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum Mediated NLRC4 Inflammasome Activation. AB - Rickettsial agents are sensed by pattern recognition receptors but lack pathogen associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1beta and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum. PMID- 27482715 TI - Diagnostic Performance of Breast Magnetic Resonance Imaging in Non-Calcified Equivocal Breast Findings: Results from a Systematic Review and Meta-Analysis. AB - OBJECTIVES: To evaluate the performance of MRI for diagnosis of breast cancer in non-calcified equivocal breast findings. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of peer-reviewed studies in PubMed from 01/01/1986 until 06/15/2015. Eligible were studies applying dynamic contrast enhanced breast MRI as an adjunct to conventional imaging (mammography, ultrasound) to clarify equivocal findings without microcalcifications. Reference standard for MRI findings had to be established by histopathological sampling or imaging follow-up of at least 12 months. Number of true or false positives and negatives and other characteristics were extracted, and possible bias was determined using the QUADAS-2 applet. Statistical analyses included data pooling and heterogeneity testing. RESULTS: Fourteen out of 514 studies comprising 2,316 lesions met our inclusion criteria. Pooled diagnostic parameters were: sensitivity (99%, 95%-CI: 93-100%), specificity (89%, 95%-CI: 85-92%), PPV (56%, 95%-CI: 42-70%) and NPV (100%, 95%-CI: 99-100%). These estimates displayed significant heterogeneity (P<0.001). CONCLUSIONS: Breast MRI demonstrates an excellent diagnostic performance in case of non-calcified equivocal breast findings detected in conventional imaging. However, considering the substantial heterogeneity with regard to prevalence of malignancy, problem solving criteria need to be better defined. PMID- 27482717 TI - Spin-Blocking Effect in CO and H2 Binding Reactions to Molybdenocene and Tungstenocene: A Theoretical Study on the Reaction Mechanism via the Minimum Energy Intersystem Crossing Point. AB - Potential energy profiles and electronic structural interpretation of the CO and H2 binding reactions to molybdenocene and tungstenocene complexes [MCp2] (M = Mo and W, Cp = cycropentadienyl) were studied using density functional theory calculations and ab initio multiconfigurational electronic structure calculations. Experimentally observed slow H2 binding was reasonably explained in terms of the spin-blocking effect. Electronic structural analysis at the minimum energy intersystem crossing point (MEISCP) revealed that the singly occupied molecular orbital's pi-bonding/sigma-antibonding character in the M-CO/H2 moiety determines the energy levels of the MEISCP. Analysis of the reaction coordinate showed that the singlet-triplet gap significantly depends on the Cp-M-Cp angle. Therefore, not only the metal-ligand distance but also the Cp-M-Cp angle is an important reaction coordinate to reach the MEISCP, the transition state of H2 binding. The role of spin-orbit coupling is also discussed. PMID- 27482716 TI - Interstitial Release of Cisplatin from Triggerable Liposomes Enhances Efficacy against Triple Negative Breast Cancer Solid Tumor Analogues. AB - Liposomal cisplatin, a promising triple negative breast cancer treatment modality, has been shown to decrease toxicities associated with cisplatin's free agent form. However, the heterogeneous intratumoral distributions of the liposomes themselves, combined with limited release of cisplatin from them contribute to limited penetration of cisplatin within tumors reducing efficacy. This study uses pH-responsive liposomes designed to release cisplatin within the acidic tumor interstitium (7.0 > pH >= 6.0) with a dual aim (1) to improve the penetration of the free drug within tumors on the assumption of greater diffusivities based on the free drug's much smaller size than its carrier's size and (2) to increase the availability of the free agent near cancer cells deep into the tumor. On cell monolayers treated with pH-releasing liposomal cisplatin, acidification of the extracellular solution resulted in decreased LD50 values, which were significantly lower than the LD50 values for non-pH-releasing liposomal cisplatin. In multicellular spheroids with acidic interstitia, pH releasing liposomal cisplatin significantly decreased spheroid volumes relative to non-pH-releasing liposomal cisplatin. Improved efficacy was correlated with increased spheroid penetration of a fluorescent cisplatin surrogate. These findings demonstrate that interstitial release of cisplatin by pH-responsive liposomes may improve the intratumoral distributions of the free drug enhancing efficacy. PMID- 27482718 TI - Controlling Electronic Transitions in Fullerene van der Waals Aggregates via Supramolecular Assembly. AB - Morphologies crucially determine the optoelectronic properties of organic semiconductors. Therefore, hierarchical and supramolecular approaches have been developed for targeted design of supramolecular ensembles of organic semiconducting molecules and performance improvement of, e.g., organic solar cells (OSCs), organic light emitting diodes (OLEDs), and organic field-effect transistors (OFETs). We demonstrate how the photonic properties of fullerenes change with the formation of van der Waals aggregates. We identified supramolecular structures with broadly tunable absorption in the visible spectral range and demonstrated how to form aggregates with targeted visible (vis) absorption. To control supramolecular structure formation, we functionalized the C60-backbone with polar (bis-polyethylene glycol malonate-MPEG) tails, thus yielding an amphiphilic fullerene derivative that self-assembles at interfaces. Aggregates of systematically tuned size were obtained from concentrating MPEGC60 in stearic acid matrices, while different supramolecular geometries were provoked via different thin film preparation methods, namely spin-casting and Langmuir Blodgett (LB) deposition from an air-water interface. We demonstrated that differences in molecular orientation in LB films (C2v type point group aggregates) and spin-casting (stochastic aggregates) lead to huge changes in electronic absorption spectra due to symmetry and orientation reasons. These differences in the supramolecular structures, causing the different photonic properties of spin-cast and LB films, could be identified by means of quantum chemical calculations. Employing supramolecular assembly, we propounded that molecular symmetry in fullerene aggregates is extremely important in controlling vis absorption to harvest photons efficiently, when mixed with a donor molecule, thus improving active layer design and performance of OSCs. PMID- 27482719 TI - Virus-Enabled Optimization and Delivery of the Genetic Machinery for Efficient Unnatural Amino Acid Mutagenesis in Mammalian Cells and Tissues. AB - Unnatural amino acid (UAA) mutagenesis of recombinant proteins in live mammalian cells requires coexpression of the mutant target, as well as an engineered tRNA/aminoacyl-tRNA synthetase pair. The ability to readily determine the optimal relative expression levels of these three genetic components for efficient expression of the UAA-modified target is highly desirable, but remains challenging to accomplish. Here we report a facile strategy to achieve this by taking advantage of the efficient gene-delivery by a baculovirus vector, which enables systematic variation of the expression level of each genetic component in a population-wide manner. Insights gained from this study led to the design of an optimal expression system, which can be delivered into mammalian cells by a single baculovirus vector to provide significantly improved UAA incorporation efficiency at a low virus load. Furthermore, this optimized baculovirus vector was shown to enable efficient UAA mutagenesis of proteins expressed in mouse brain tissue. PMID- 27482720 TI - Nonequivalent Substitution and Charge-Induced Emitter-Migration Design of Tuning Spectral and Duration Properties of NaCa2GeO4F:Mn(2+) Persistent Luminescent Phosphor. AB - We combine nonequivalent substitution and charge-induced emitter-migration approaches and design an efficient method to optionally tune the spectral and duration properties of NaCa2GeO4F:Mn(2+) phosphor. A series of representative codopants have been investigated in detail and classified into two categories: RA (RA = Li(+), Al(3+), N(3-), Ga(3+), B(3+)) and RB (RB = Mg(2+), F(-), Bi(3+), Zn(2+), Cd(2+), Sc(3+), Tm(3+)). Results reveal that the nonequivalent substitution of RA codopants would induce foreign negative defects and stabilize Mn(2+) emitters at octahedral Na/Ca sites for red emission. In constrast, the RB codopants would generate foreign positive defects and make Mn(2+) emitters migrate to tetrahedral Ge(4+) sites for green-yellow emission. At the same time, the RA codopants are in favor of the generation of intrinsic positive traps with shallow trap depth and thus efficiently improve the duration properties of phosphors. On the basis of the experimental results, a possible nonequivalent substitution and charge-induced emitter-migration model has been proposed, and we can optionally tune the spectral (568 <-> 627 nm) and the duration (minutes to more than 6 h) properties according to this model. PMID- 27482721 TI - Piezoresistive Sensor with High Elasticity Based on 3D Hybrid Network of Sponge@CNTs@Ag NPs. AB - Pressure sensors with high elasticity are in great demand for the realization of intelligent sensing, but there is a need to develope a simple, inexpensive, and scalable method for the manufacture of the sensors. Here, we reported an efficient, simple, facile, and repeatable "dipping and coating" process to manufacture a piezoresistive sensor with high elasticity, based on homogeneous 3D hybrid network of carbon nanotubes@silver nanoparticles (CNTs@Ag NPs) anchored on a skeleton sponge. Highly elastic, sensitive, and wearable sensors are obtained using the porous structure of sponge and the synergy effect of CNTs/Ag NPs. Our sensor was also tested for over 2000 compression-release cycles, exhibiting excellent elasticity and cycling stability. Sensors with high performance and a simple fabrication process are promising devices for commercial production in various electronic devices, for example, sport performance monitoring and man machine interfaces. PMID- 27482724 TI - Catalytic Graphitization of Coal-Based Carbon Materials with Light Rare Earth Elements. AB - The catalytic graphitization mechanism of coal-based carbon materials with light rare earth elements was investigated using X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, selected-area electron diffraction, and high-resolution transmission electron microscopy. The interface between light rare earth elements and carbon materials was carefully observed, and two routes of rare earth elements catalyzing the carbon materials were found: dissolution-precipitation and carbide formation-decomposition. These two simultaneous processes certainly accelerate the catalytic graphitization of carbon materials, and light rare earth elements exert significant influence on the microstructure and thermal conductivity of graphite. Moreover, by virtue of praseodymium (Pr), it was found that a highly crystallographic orientation of graphite was induced and formed, which was reasonably attributed to the similar arrangements of the planes perpendicular to (001) in both graphite and Pr crystals. The interface between Pr and carbon was found to be an important factor for the orientation of graphite structure. PMID- 27482722 TI - Unprecedently Large-Scale Kinase Inhibitor Set Enabling the Accurate Prediction of Compound-Kinase Activities: A Way toward Selective Promiscuity by Design? AB - Drug discovery programs frequently target members of the human kinome and try to identify small molecule protein kinase inhibitors, primarily for cancer treatment, additional indications being increasingly investigated. One of the challenges is controlling the inhibitors degree of selectivity, assessed by in vitro profiling against panels of protein kinases. We manually extracted, compiled, and standardized such profiles published in the literature: we collected 356 908 data points corresponding to 482 protein kinases, 2106 inhibitors, and 661 patents. We then analyzed this data set in terms of kinome coverage, results reproducibility, popularity, and degree of selectivity of both kinases and inhibitors. We used the data set to create robust proteochemometric models capable of predicting kinase activity (the ligand-target space was modeled with an externally validated RMSE of 0.41 +/- 0.02 log units and R02 0.74 +/- 0.03), in order to account for missing or unreliable measurements. The influence on the prediction quality of parameters such as number of measurements, Murcko scaffold frequency or inhibitor type was assessed. Interpretation of the models enabled to highlight inhibitors and kinases properties correlated with higher affinities, and an analysis in the context of kinases crystal structures was performed. Overall, the models quality allows the accurate prediction of kinase inhibitor activities and their structural interpretation, thus paving the way for the rational design of compounds with a targeted selectivity profile. PMID- 27482725 TI - Large Format Surface-Enhanced Raman Spectroscopy Substrate Optimized for Enhancement and Uniformity. AB - Gratings have been widely investigated both theoretically and experimentally as surface-enhanced Raman spectroscopy (SERS) substrates, exhibiting, under appropriate circumstances, increased far-field extinctions and near-field intensities over those of an appropriately equivalent number of isolated particles. When the grating order transitions from evanescent to radiative, narrow resonance peaks are observed in the extinction spectrum whose properties can be manipulated by controlling the grating's geometric parameters. Here we report the application of the architectural principles of grating fabrication using a square two-dimensional array of gold-coated nanostructures that achieves SERS enhancements of 10(7) uniformly over areas of square centimeters. The high performance grating substrates were fabricated using commonly available foundry based techniques that have been chosen for their applicability to large-scale wafer processing. Additionally, we restricted ourselves to a parametric regime that optimizes SERS performance in a repeatable and reproducible manner. PMID- 27482723 TI - Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain. AB - Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with <1% blood brain barrier penetration for testing in a rat neuropathy induced by unilateral sciatic nerve entrapment (SNE). The SNE-induced mechanical allodynia was reversibly suppressed, partially or completely, after intraperitoneal or oral administration of several indenes. At doses that relieve neuropathy symptoms, the indenes completely lacked, while the brain-permeant CB1R agonist HU-210 (1) exhibited strong CNS side effects, in catalepsy, hypothermia, and motor incoordination assays. Pharmacokinetic findings of ~0.001 cerebrospinal fluid:plasma ratio further supported limited CNS penetration. Pretreatment with selective CB1R or CB2R blockers suggested mainly CB1R contribution to an indene's antiallodynic effects. Therefore, this class of CB1R agonists holds promise as a viable treatment for neuropathic pain. PMID- 27482726 TI - Gold-Catalyzed Domino Synthesis of Functionalized Benzofurans and Tetracyclic Isochromans via Formal Carboalkoxylation. AB - A domino synthesis of benzofurans with the modification of side chains from alpha alkoxyalkyl o-alkynylaryl ethers (n = 0) and electron-rich arenes has been developed. In the present domino reaction, which would proceed via the alpha alkoxyalkylation of arenes with an intermediate in the migratory cycloisomerization of o-alkynylaryl ethers followed by the nucleophilic addition of benzofurans to benzyl ethers, a cationic Au(III) catalyst activates the C-C pi bond and the C-O sigma bond. The present method could be extended to Au(I) catalyzed domino synthesis of tetracyclic isochromans from alpha-alkoxyalkyl (o alkynylaryl)methyl ethers (n = 1) and aryl methoxymethyl ethers. PMID- 27482727 TI - Perpendicular Iliac Screw Placement for Reinforcement of Spinopelvic Stabilization. AB - Iliac fixation is indicated to provide spinopelvic stabilization in select cases of long segment thoracolumbar spine fusion, spinal osteotomy/realignment, trauma, and instability caused by tumor or infection. Traditional iliac fixation with iliac screws or S2 alar/iliac (S2AI) screws may provide inadequate fixation in select clinical scenarios, such as severely compromised bone quality or spinopelvic dissociation. The purpose of this article is to describe the perpendicular iliac screw technique with ipsilateral iliac crest screw plus S2AI fixation. The technique may be applied for select individuals in cases of 3 column osteotomy in the lower lumbar spine, spinopelvic dissociation (caused by trauma, neoplasm, or Charcot arthropathy), and failure of previous iliac fixation and when anatomic constraints limit standard iliac screw or S2AI screw placement. [Orthopedics. 2016; 39(6):e1209-e1212.]. PMID- 27482728 TI - Minimally Invasive Transforaminal Lumbar Interbody Fusion in the Outpatient Setting. AB - Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has been shown to have long-term clinical outcomes similar to those with open TLIF and decreased perioperative morbidity. This study assessed whether this procedure can be safely performed in outpatient settings. Ninety-six consecutive patients undergoing 1- or 2-level MIS-TLIFs were retrospectively reviewed. They were divided into inpatient and outpatient cohorts (36%). All had a minimum of 2 years of follow-up. Patient demographics, comorbidities, complications, and readmissions were examined. Early postoperative complications were stratified into wound related, infection, neurologic, implant related, and vascular injuries. Patients in the outpatient cohort were significantly younger, had lower American Society of Anesthesiologists physical status scores, and had lower Charlson Comorbidity Index scores than patients in the inpatient cohort. There were no statistically significant differences in overall postoperative complication rates, readmission rates, or final Oswestry Disability Index or visual analog scale scores between the 2 cohorts. The clinical outcomes of the outpatient TLIF procedure were similar to those of the inpatient procedure and it had an acceptable complication rate. [Orthopedics. 2016; 39(6):e1218-e1222.]. PMID- 27482729 TI - Severe Brachial Plexus Injuries in American Football. AB - This article reports a series of severe permanent brachial plexus injuries in American football players. The authors describe the mechanisms of injury and outcomes from a more contemporary treatment approach in the form of nerve transfer tailored to the specific injuries sustained. Three cases of nerve transfer for brachial plexus injury in American football players are discussed in detail. Two of these patients regained functional use of the extremity, but 1 patient with a particularly severe injury did not regain significant function. Brachial plexus injuries are found along a spectrum of brachial plexus stretch or contusion that includes the injuries known as "stingers." Early identification of these severe brachial plexus injuries allows for optimal outcomes with timely treatment. Diagnosis of the place of a given injury along this spectrum is difficult and requires a combination of imaging studies, nerve conduction studies, and close monitoring of physical examination findings over time. Although certain patients may be at higher risk for stingers, there is no evidence to suggest that this correlates with a higher risk of severe brachial plexus injury. Unfortunately, no equipment or strengthening program has been shown to provide a protective effect against these severe injuries. Patients with more severe injuries likely have less likelihood of functional recovery. In these patients, nerve transfer for brachial plexus injury offers the best possibility of meaningful recovery without significant morbidity. [ Orthopedics. 2016; 39(6):e1188-e1192.]. PMID- 27482730 TI - Current Concepts and the Role of Surgery in the Treatment of Jumper's Knee. AB - Jumper's knee is a common cause of anterior knee pain among athletes and active populations. Numerous treatments have been described with variable results. To better delineate this, the authors reviewed all articles from 2000 to 2014 pertaining to the treatment of patellar tendinopathy, focusing namely on treatment of recalcitrant cases. Open and arthroscopic techniques were found to achieve similar satisfactory results in 81% (range, 45%-100%) and 91% (range, 86% 96%) of patients, respectively. Average time to return to play was 5.6 months and 5 months, respectively. A recently described technique, percutaneous ultrasonic tenotomy, potentially represents an attractive alternative option for definitive intervention. [Orthopedics. 2016; 39(6):e1028-e1035.]. PMID- 27482731 TI - Cheating the Acetabular Component Horizontally in Total Hip Arthroplasty. AB - To avoid inadvertent vertical positioning of the acetabular component during total hip arthroplasty (THA), the authors routinely "cheat" component abduction an additional 10 degrees horizontal (goal=30 degrees ). This likely increases the incidence of components placed into abduction of less than 30 degrees , the clinical consequences of which are not well studied. The purpose of this study was to determine the clinical and radiographic outcomes in patients undergoing THA with acetabular components positioned in less than 30 degrees of abduction as compared with those with components positioned between 30 degrees and 50 degrees . A retrospective review was performed of consecutive patients undergoing primary THA with horizontally cheated acetabular component position performed by a single surgeon. Patients were grouped into cohorts with either component abduction less than 30 degrees or between 30 degrees and 50 degrees . Demographic data, operative data, and complications were recorded. Harris Hip Scores (HHS) and radiographic analysis were obtained from preoperative and most recent clinic visits. Between September 2004 and September 2010, 320 consecutive THA procedures were performed. A total of 149 hips had component abduction less than 30 degrees (mean, 25.8 degrees ; range, 15.7 degrees -29.4 degrees ). No components had greater than 50 degrees of abduction. At an average 37-month follow-up, no significant difference in HHS was found between the 2 cohorts (P=.137). The horizontal cohort had no dislocations, component loosening, or osteolysis. By cheating the acetabular component more horizontal, an excessively vertical position was avoided. Component abduction less than 30 degrees yielded equivalent clinical outcomes to component abduction between 30 degrees and 50 degrees . [Orthopedics. 2016; 39(6):e1092-e1096.]. PMID- 27482732 TI - Calculating the Position of the Joint Line of the Knee Using Anatomical Landmarks. AB - Restoration of the joint line of the knee during primary and revision total knee arthroplasty is a step that directly influences patient outcomes. In revision total knee arthroplasty, necessary bony landmarks may be missing or obscured, so there remains a lack of consensus on how to accurately identify and restore the joint line of the knee. In this study, 50 magnetic resonance images of normal knees were analyzed to determine a quantitative relationship between the joint line of the knee and 6 bony landmarks: medial and lateral femoral epicondyles, medial and lateral femoral metaphyseal flares, tibial tubercle, and proximal tibio-fibular joint. Wide variability was found in the absolute distance from each landmark to the joint line of the knee, including significant differences between the sexes. Normalization of the absolute distances to femoral or tibial diameters revealed reliable spatial relationships to the joint line of the knee. The joint line was found to be equidistant from the lateral femoral epicondyle and the proximal tibio-fibular joint, representing a reproducible point of reference for joint line restoration. The authors propose a simple 3-step algorithm that can be used with magnetic resonance imaging, computed tomography, or radiography to reliably determine the anatomical location of the joint line of the knee relative to the surrounding bony anatomy. [Orthopedics. 2016; 39(6):381 386.]. PMID- 27482733 TI - Giant Intraosseous Cyst in an Osteoarthritic Knee. AB - This article describes osteoarthritis of the knee and a giant intraosseous cyst of the medial femoral condyle in an 83-year-old man that was treated successfully with total knee arthroplasty and autologous bone grafts. The patient presented to the authors' hospital with a 2-year history of right knee pain. A plain radiograph of the right knee revealed grade 3 medial compartment osteoarthritis with an oval area of radiolucency in the medial femoral condyle. The area of radiolucency seen on the radiograph was larger than that on the radiograph obtained 2 years earlier, with no progression of osteoarthritis. Computed tomography showed a well-defined giant intraosseous cyst adjacent to the medial femoral cortex measuring 3.5*3.5*1.6 cm. A medial femoral cortical defect and a small bone break on the articular surface of the medial femoral condyle, both of which allowed communication between the cyst and the joint, were also detected, along with gases in the cyst. Total knee arthroplasty with bone grafts was performed. Resection of the distal femur revealed that the fatty synovia intruded into the cyst through the medial cortical defect. Two years after the surgery, the grafted bone was well incorporated, without loosening of the prosthesis. Two theories, the synovial intrusion theory and the bone contusion theory, have been proposed for the etiology of cyst formation in an osteoarthritic knee. The current case strongly supports the synovial intrusion theory as the mechanism underlying the development of an intraosseous giant cyst in the osteoarthritic knee. [Orthopedics. 2016; 39(6):e1193-e1196.]. PMID- 27482734 TI - Mechanical Robustness of Graphene on Flexible Transparent Substrates. AB - This study reports on a facile and widely applicable method of transferring chemical vapor deposited (CVD) graphene uniformly onto optically transparent and mechanically flexible substrates using commercially available, low-cost ultraviolet adhesive (UVA) and hot-press lamination (HPL). We report on the adhesion potential between the graphene and the substrate, and we compare these findings with those of the more commonly used cast polymer handler transfer processes. Graphene transferred with the two proposed methods showed lower surface energy and displayed a higher degree of adhesion (UVA: 4.40 +/- 1.09 N/m, HPL: 0.60 +/- 0.26 N/m) compared to equivalent CVD-graphene transferred using conventional poly(methyl methacrylate) (PMMA: 0.44 +/- 0.06 N/m). The mechanical robustness of the transferred graphene was investigated by measuring the differential resistance as a function of bend angle and repeated bend-relax cycles across a range of bend radii. At a bend angle of 100 degrees and a 2.5 mm bend radius, for both transfer techniques, the normalized resistance of graphene transferred on polyethylene terephthalate (PET) was around 80 times less than that of indium-tin oxide on PET. After 10(4) bend cycles, the resistance of the transferred graphene on PET using UVA and HPL was found to be, on average, around 25.5 and 8.1% higher than that of PMMA-transferred graphene, indicating that UVA- and HPL-transferred graphene are more strongly adhered compared to PMMA transferred graphene. The robustness, in terms of maintained electrical performance upon mechanical fatigue, of the transferred graphene was around 60 times improved over ITO/PET upon many thousands of repeated bending stress cycles. On the basis of present production methods, the development of the next generation of highly conformal, diverse form factor electronics, exploiting the emerging family of two-dimensional materials, necessitates the development of simple, low-cost, and mechanically robust transfer processes; the developed UVA and HPL approaches show significant potential and allow for large-area compatible, near-room temperature transfer of graphene onto a diverse range of polymeric supports. PMID- 27482735 TI - Cisplatin-Protein Interactions: Unexpected Drug Binding to N-Terminal Amine and Lysine Side Chains. AB - Literature studies carried out by mass spectrometry and X-ray crystallography have demonstrated that cisplatin is able to bind proteins mainly close to Met, His, and free Cys side chains. To identify possible alternative modes of cisplatin binding to proteins at the molecular level, here we have solved the high-resolution X-ray structure of the adduct formed in the reaction between the drug and the model protein thaumatin, which does not contain any His and free Cys residues and possesses just one buried Met. Our data reveal unexpected cisplatin binding sites on the protein surface that could have general significance: cisplatin fragments -[Pt(NH3)2Cl](+), -[Pt(NH3)Cl2], and -[Pt(NH3)2(OH2)](2+) bind to a protein N-terminus and close to Lys and Glu side chains. PMID- 27482736 TI - Keldysh field theory for driven open quantum systems. AB - Recent experimental developments in diverse areas-ranging from cold atomic gases to light-driven semiconductors to microcavity arrays-move systems into the focus which are located on the interface of quantum optics, many-body physics and statistical mechanics. They share in common that coherent and driven-dissipative quantum dynamics occur on an equal footing, creating genuine non-equilibrium scenarios without immediate counterpart in equilibrium condensed matter physics. This concerns both their non-thermal stationary states and their many-body time evolution. It is a challenge to theory to identify novel instances of universal emergent macroscopic phenomena, which are tied unambiguously and in an observable way to the microscopic drive conditions. In this review, we discuss some recent results in this direction. Moreover, we provide a systematic introduction to the open system Keldysh functional integral approach, which is the proper technical tool to accomplish a merger of quantum optics and many-body physics, and leverages the power of modern quantum field theory to driven open quantum systems. PMID- 27482737 TI - ZnSe hollow nanospheres in mechanically stable near-IR antireflection coatings for ZnSe substrates. AB - Though possessing low absorption throughout a wide infrared (IR) spectral regime, owing to a high refractive index, zinc selenide substrates are generally covered by antireflection coatings (ARCs) for practical optical uses. However, achieving a high transmission of ZnSe substrates in the near-IR (NIR) region is still challenging. Herein, for the first time, colloidal ZnSe hollow nanospheres (HNSs) smaller than 100 nm were prepared and adopted to assemble ARCs for ZnSe substrates. The voiding kinetics of the HNSs was found to agree well with the nanoscale Kirkendall effect, and the self-diffusion of the Zn ion in the core was faster than its diffusion through the ZnSe shell. With single-index ARCs, the transmission of ZnSe substrates was remarkably enhanced in the NIR region, with up to an 18% increase at 840 nm. Besides, the ZnSe HNS-based ARCs showed superior mechanical stability even under violent ultrasonication in organic solutions. We expect that ZnSe HNSs will make it possible to construct graded-index ARCs to realize omnidirectional and broadband antireflection in IR, through further tuning of HNSs' void fraction. PMID- 27482739 TI - (Per)chlorate in Biology on Earth and Beyond. AB - Respiration of perchlorate and chlorate [collectively, (per)chlorate] was only recognized in the last 20 years, yet substantial advances have been made in our understanding of the underlying metabolisms. Although it was once considered solely anthropogenic, pervasive natural sources, both terrestrial and extraterrestrial, indicate an ancient (per)chlorate presence across our solar system. These discoveries stimulated interest in (per)chlorate microbiology, and the application of advanced approaches highlights exciting new facets. Forward and reverse genetics revealed new information regarding underlying molecular biology and associated regulatory mechanisms. Structural and functional analysis characterized core enzymes and identified novel reaction sequences. Comparative genomics elucidated evolutionary aspects, and stress analysis identified novel response mechanisms to reactive chlorine species. Finally, systems biology identified unique metabolic versatility and novel mechanisms of (per)chlorate respiration, including symbiosis and a hybrid enzymatic-abiotic metabolism. While many published studies focus on (per)chlorate and their basic metabolism, this review highlights seminal advances made over the last decade and identifies new directions and potential novel applications. PMID- 27482738 TI - Genomics of Natural Populations of Staphylococcus aureus. AB - Staphylococcus aureus is a major human pathogen and an important cause of livestock infections. The first S. aureus genomes to be published, 15 years ago, provided the first view of genome structure and gene content. Since then, thousands of genomes from a wide array of strains from different sources have been sequenced. Comparison of these sequences has resulted in broad insights into population structure, bacterial evolution, clone emergence and expansion, and the molecular basis of niche adaptation. Furthermore, this information is now being applied clinically in outbreak investigations to inform infection control measures and to determine appropriate treatment regimens. In this review, we summarize some of the broad insights into S. aureus biology gained from the analysis of genomes and discuss future directions and opportunities in this dynamic field of research. PMID- 27482740 TI - Lessons from Digestive-Tract Symbioses Between Bacteria and Invertebrates. AB - In most animals, digestive tracts harbor the greatest number of bacteria in the animal that contribute to its health: by aiding in the digestion of nutrients, provisioning essential nutrients and protecting against colonization by pathogens. Invertebrates have been used to enhance our understanding of metabolic processes and microbe-host interactions owing to experimental advantages. This review describes how advances in DNA sequencing technologies have dramatically altered how researchers investigate microbe-host interactions, including 16S rRNA gene surveys, metagenome experiments, and metatranscriptome studies. Advantages and challenges of each of these approaches are described herein. Hypotheses generated through omics studies can be directly tested using site-directed mutagenesis, and findings from transposon studies and site-directed experiments are presented. Finally, unique structural aspects of invertebrate digestive tracts that contribute to symbiont specificity are presented. The combination of omics approaches with genetics and microscopy allows researchers to move beyond correlations to identify conserved mechanisms of microbe-host interactions. PMID- 27482741 TI - Insights into the Coral Microbiome: Underpinning the Health and Resilience of Reef Ecosystems. AB - Corals are fundamental ecosystem engineers, creating large, intricate reefs that support diverse and abundant marine life. At the core of a healthy coral animal is a dynamic relationship with microorganisms, including a mutually beneficial symbiosis with photosynthetic dinoflagellates (Symbiodinium spp.) and enduring partnerships with an array of bacterial, archaeal, fungal, protistan, and viral associates, collectively termed the coral holobiont. The combined genomes of this coral holobiont form a coral hologenome, and genomic interactions within the hologenome ultimately define the coral phenotype. Here we integrate contemporary scientific knowledge regarding the ecological, host-specific, and environmental forces shaping the diversity, specificity, and distribution of microbial symbionts within the coral holobiont, explore physiological pathways that contribute to holobiont fitness, and describe potential mechanisms for holobiont homeostasis. Understanding the role of the microbiome in coral resilience, acclimation, and environmental adaptation is a new frontier in reef science that will require large-scale collaborative research efforts. PMID- 27482742 TI - Biological Diversity and Molecular Plasticity of FIC Domain Proteins. AB - The ubiquitous proteins with FIC (filamentation induced by cyclic AMP) domains use a conserved enzymatic machinery to modulate the activity of various target proteins by posttranslational modification, typically AMPylation. Following intensive study of the general properties of FIC domain catalysis, diverse molecular activities and biological functions of these remarkably versatile proteins are now being revealed. Here, we review the biological diversity of FIC domain proteins and summarize the underlying structure-function relationships. The original and most abundant genuine bacterial FIC domain proteins are toxins that use diverse molecular activities to interfere with bacterial physiology in various, yet ill-defined, biological contexts. Host-targeted virulence factors have evolved repeatedly out of this pool by exaptation of the enzymatic FIC domain machinery for the manipulation of host cell signaling in favor of bacterial pathogens. The single human FIC domain protein HypE (FICD) has a specific function in the regulation of protein stress responses. PMID- 27482743 TI - The Modern Synthesis in the Light of Microbial Genomics. AB - We review the theoretical implications of findings in genomics for evolutionary biology since the Modern Synthesis. We examine the ways in which microbial genomics has influenced our understanding of the last universal common ancestor, the tree of life, species, lineages, and evolutionary transitions. We conclude by advocating a piecemeal toolkit approach to evolutionary biology, in lieu of any grand unified theory updated to include microbial genomics. PMID- 27482744 TI - Staphylococcus aureus RNAIII and Its Regulon Link Quorum Sensing, Stress Responses, Metabolic Adaptation, and Regulation of Virulence Gene Expression. AB - Staphylococcus aureus RNAIII is one of the main intracellular effectors of the quorum-sensing system. It is a multifunctional RNA that encodes a small peptide, and its noncoding parts act as antisense RNAs to regulate the translation and/or the stability of mRNAs encoding transcriptional regulators, major virulence factors, and cell wall metabolism enzymes. In this review, we explain how regulatory proteins and RNAIII are embedded in complex regulatory circuits to express virulence factors in a dynamic and timely manner in response to stress and environmental and metabolic changes. PMID- 27482745 TI - Care in the Final Month of Life among Adolescent and Young Adult Cancer Patients in Kaiser Permanente Southern California. AB - BACKGROUND: Little is known about the care that adolescent and young adult (AYA) patients with cancer receive at the end of life (EOL). OBJECTIVE: To examine care in the last month of life among AYA patients with cancer. DESIGN: Medical record review of the last 30 days of life. SETTING/SUBJECTS: One hundred eleven AYA patients aged 15-39 years at death with either stage I-III cancer and evidence of cancer recurrence or stage IV cancer at diagnosis. Patients received care in Kaiser Permanente Southern California, an integrated healthcare delivery system, and died from 2007 to 2010. MEASUREMENTS: Use of intensive measures, including chemotherapy in the last 14 days of life and emergency room visits, hospitalizations, and intensive care unit admissions in the last 30 days; documented care preferences; symptom prevalence and treatment; advance care planning; hospice use; and location of death. RESULTS: One hundred seven patients (96%) had documented care preferences in the last month of life. At first documentation, 72% of patients wished for life-prolonging care, 20% wished for care focused on comfort, and 8% were undecided. Forty-seven percent of patients had documented changes in preferences in the last month, with 40% wishing for life-prolonging care when preferences were last noted before death, 56% preferring comfort, and 4% undecided. Seventy-eight percent of patients received at least one form of intensive EOL care, including 75% of those who preferred comfort measures at last documentation. CONCLUSIONS: Many AYA patients enter the last month of life wishing for life-prolonging care. While most ultimately wish for comfort, intensive care is prevalent even among such patients. PMID- 27482746 TI - Effects of Tribulus terrestris saponins on exercise performance in overtraining rats and the underlying mechanisms. AB - The objective of this study was to determine the effects of Tribulus terrestris L. (TT) saponins on exercise performance and the underlying mechanisms. A rat overtraining model was established and animals were treated with TT extracts (120 mg/kg body mass) 30 min before each training session. Serum levels of testosterone and corticosterone and levels of androgen receptor (AR) and insulin growth factor-1 receptor (IGF-1R) in the liver, gastrocnemius, and soleus were determined by ELISA and Western blot. Treatment of rats with TT saponins significantly improved the performance of the overtraining rats, reflected by the extension of time to exhaustion, with a concomitant increase in body mass, relative mass, and protein levels of gastrocnemius. Overtraining alone induced a significant decrease in the serum level of testosterone. In contrast, treatment with TT saponins dramatically increased the serum level of testosterone in overtraining rats to about 150% of control and 216% of overtraining groups, respectively. In addition, TT saponins resulted in a further significant increase in AR in gastrocnemius and significantly suppressed the overtraining-induced increase in IGF-1R in the liver. These results indicated that TT saponins increased performance, body mass, and gastrocnemius mass of rats undergoing overtraining, which might be attributed to the changes in androgen-AR axis and IGF-1R signaling. PMID- 27482748 TI - A New Cost Function for Evolution of S-Boxes. AB - Substitution Boxes (S-Boxes) play an important role in many modern-day cryptographic algorithms, more commonly known as ciphers. Without carefully chosen S-Boxes, such ciphers would be easier to break. Therefore, it is not surprising that the design of suitable S-Boxes attracts a lot of attention in the cryptography community. The evolutionary computation (EC) community also had several attempts using evolutionary paradigms to evolve S-Boxes with good cryptographic properties. This article focuses on a fitness function one should use when evolving highly nonlinear S-Boxes. After an extensive experimental analysis of the current state-of-the-art fitness functions, we present a new one that offers higher speed and better results when compared with the aforementioned fitness functions. PMID- 27482747 TI - Can experience modulate handler responses to boxes designed to decrease musculoskeletal load? AB - Biomechanical load during the handling of commercial (cardboard box with and without cut out) and non-commercial boxes (cardboard box with a retreat on the bottom edges), on experienced compared to inexperienced subjects was evaluated. Thirty-seven inexperienced and 21 experienced workers handled all boxes at shoulder and ground levels. Biomechanical load on upper limb was investigated through posture and electromyography (EMG) recordings. Comfort and effort were assessed immediately after each handling. In general, experienced workers had low range of motion. On the other hand, EMG was similar between both groups, except when non-commercial boxes were handled in non-favourable heights. Comfort was higher when a non-commercial box was handled versus a commercial one, regardless of the group. Both groups had a lower biomechanical load when handling the non commercial boxes compared to the commercial ones. However, experienced workers did not have the same advantage as inexperienced subjects when handling those new boxes. Practitioner Summary: Box designs favouring intuitive hand coupling and more efficient postures have potential to reduce the risk of upper-limb musculoskeletal disorders in inexperienced subjects. However, ergonomist has to deal with workers on different levels of experience. Results of this study can support the development of effective recommendations for the working context. PMID- 27482749 TI - Evolutionary Algorithms for Boolean Functions in Diverse Domains of Cryptography. AB - The role of Boolean functions is prominent in several areas including cryptography, sequences, and coding theory. Therefore, various methods for the construction of Boolean functions with desired properties are of direct interest. New motivations on the role of Boolean functions in cryptography with attendant new properties have emerged over the years. There are still many combinations of design criteria left unexplored and in this matter evolutionary computation can play a distinct role. This article concentrates on two scenarios for the use of Boolean functions in cryptography. The first uses Boolean functions as the source of the nonlinearity in filter and combiner generators. Although relatively well explored using evolutionary algorithms, it still presents an interesting goal in terms of the practical sizes of Boolean functions. The second scenario appeared rather recently where the objective is to find Boolean functions that have various orders of the correlation immunity and minimal Hamming weight. In both these scenarios we see that evolutionary algorithms are able to find high-quality solutions where genetic programming performs the best. PMID- 27482752 TI - Detection and Molecular Characterization of Escherichia coli Strains Producers of Extended-Spectrum and CMY-2 Type Beta-Lactamases, Isolated from Turtles in Mexico. AB - Multidrug-resistant bacteria are a growing problem in different environments and hosts, but scarce information exists about their prevalence in reptiles. The aim of this study was to analyze the resistance mechanisms, molecular typing, and plasmid content of cefotaxime-resistant (CTX(R)) Escherichia coli isolates recovered from cloacal samples of 71 turtles sheltered in a herpetarium in Mexico. CTX(R)-E. coli were recovered in 11 of 71 samples (15.5%), and one isolate/sample was characterized. Extended-spectrum beta-lactamase (ESBL) producing E. coli isolates were detected in four samples (5.6%): two strains carried the blaCTX-M-2 gene (phylogroup D and ST2732) and two contained the blaCTX-M-15 gene (phylogroup B1 and lineages ST58 and ST156). The blaCMY-2 gene was detected by PCR in E. coli isolates of eight samples (9.8%) (one of them also carried blaCTX-M-2); these isolates were distributed into phylogroups A (n = 1), B1 (n = 6), and D (n = 1) and typed as ST155, ST156, ST2329, and ST2732. Plasmid mediated quinolone resistance (PMQR) genes were detected in five isolates [aac(6')Ib-cr, qnrA, qnrB19, and oqxB]. From three to five replicon plasmids were detected among the strains, being IncFIB, IncI1, IncFrep, and IncK the most prevalent. ESBL or pAmpC genes were transferred by conjugation in four strains, and the blaCTX-M-15 and blaCMY-2 genes were localized in IncFIB or IncI1 plasmids by Southern blot hybridization assays. Class 1 and/or class 2 integrons were detected in eight strains with six different structures of gene cassette arrays. Nine pulsed-field gel electrophoresis patterns were found among the 11 studied strains. To our knowledge, this is the first detection of ESBL, CMY-2, PMQR, and mobile determinants of antimicrobial resistance in E. coli of turtle origin, highlighting the potential dissemination of multidrug-resistant bacteria from these animals to other environments and hosts, including humans. PMID- 27482750 TI - Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men. AB - CONTEXT: T deprivation increases risk of insulin resistance in men, but whether this risk is independent of changes in body composition is unknown. Further, the metabolic roles of T and its metabolite estradiol have not been clearly defined in men. OBJECTIVE: This study sought to establish the effects of selective sex steroid withdrawal on insulin sensitivity in healthy men. DESIGN, SETTING, AND PARTICIPANTS: This was a double-blinded, placebo-controlled, randomized trial at an academic medical center of 56 healthy men, 19-55 years of age. INTERVENTIONS: Subjects received the GnRH antagonist acyline plus one of the following: placebo gel (Castrate), 1.25 g testosterone gel (Low T/E), 5 g testosterone gel (Normal T/E), or 5 g testosterone gel with letrozole (Normal T/Low E) daily for 4 weeks. Body composition and glucose tolerance were assessed at baseline and end of treatment. MAIN OUTCOME MEASURE: Insulin sensitivity was quantified by the Matsuda index. RESULTS: Predicted circulating sex steroid concentrations were achieved in all treatment groups. The time-by-group interaction for Matsuda index did not achieve significance in overall repeated measures ANOVA (baseline vs week 4; P = .16). A significant time-by-group interaction was observed for fat mass (P = .003), with changes in fat mass attributable predominantly to estrogen exposure in linear regression analysis (P = .016). A time-by-group interaction also was observed for lean mass (P = .03) and influenced by androgen exposure (P = .003). CONCLUSIONS: Short-term sex steroid withdrawal in healthy men causes adverse changes in body composition. These findings support the role of estradiol as a determinant of adiposity in men. PMID- 27482753 TI - [Atomoxetine Treatment For Encopresis In A Child With Attention Deficit Hyperactivity Disorder]. AB - Letter to the editor. PMID- 27482754 TI - Binary System for MicroRNA-Targeted Imaging in Single Cells and Photothermal Cancer Therapy. AB - Abnormal expression of microRNAs (miRNAs) is often associated with tumorigenesis, metastasis, and progression. Among them, miRNA-21 is found to be overexpressed in most of the cancer cells. Here, a binary system is designed for miRNA-21 targeted imaging and photothermal treatment in single cells. The binary system is composed by a pair of probes (probe-1 and probe-2), which are encapsulated in liposomes for cell delivery. Both of the two probes adopt gold nanoparticles (AuNPs) as the core material, and the AuNPs are functionalized with Cy5-marked molecular beacon (MB-1/MB-2 for probe-1/probe-2, respectively). The loop part of MBs are designed to be complementary with miRNA-21. Therefore, after the binary system enters into the cytoplasm, MBs can be opened upon miRNA-21 triggered hybridization, which turns "on" the fluorescence of Cy5 for the localization of miRNA-21. At the same time, a cross-linking between the probes occurs since the far ends of MB-1 and MB 2 are designed to be complementary with each other. The miRNA-induced aggregation shifts the absorption of AuNPs to near-infrared, which can be observed under dark field microscopy (DFM) and used for the following photothermal therapy. Under near-infrared (NIR) irradiation, MCF-7 breast cancer cells are successfully killed. The proposed system can be further applied in tumor-bearing mice and shows significant therapeutic effect. This work provides a new tool for intracellular miRNA analysis and targeted treatment against cancer. PMID- 27482755 TI - Cold Flow as Versatile Approach for Stable and Highly Luminescent Quantum Dot Salt Composites. AB - Since the beginning of the 1980s, colloidally synthesized quantum dots (QDs) have been in the focus of interest due to their possible implementation for color conversion, luminescent light concentrators, and lasing. For all these applications, the QDs benefit from being embedded into a host matrix to ensure stability and usability. Many different host materials used for this purpose still have their individual shortcomings. Here, we present a universal, fast, and flexible approach for the direct incorporation of a wide range of QDs into inorganic ionic crystals using cold flow. The QD solution is mixed with a finely milled salt, followed by the removal of the solvent under vacuum. Under high pressure (GPa), the salt powder loaded with QDs transforms into transparent pellets. This effect is well-known for many inorganic salts (e.g., KCl, KBr, KI, NaCl, CsI, AgCl) from, e.g., sample preparation for IR spectroscopy. With this approach, we are able to obtain strongly luminescent QD-salt composites, have precise control over the loading, and provide a chemically robust matrix ensuring long-term stability of the embedded QDs. Furthermore, we show the photo-, chemical, and thermal stability of the composite materials and their use as color conversion layers for a white light-emitting diode (w-LED). The method presented can potentially be used for all kinds of nanoparticles synthesized in organic as well as in aqueous media. PMID- 27482756 TI - Multifunctional and High Affinity Polymer Ligand that Provides Bio-Orthogonal Coating of Quantum Dots. AB - We detail the design of hydrophilic metal-coordinating ligands and their use for the effective coating of luminescent quantum dots (QDs). The ligand design exploits the specific, reagent-free nucleophilic addition reaction of amine modified molecules toward maleic anhydride to introduce several lipoic acid metal anchors, hydrophilic zwitterion moieties, and specific reactive groups along a poly(isobutylene-alt-maleic anhydride) (PIMA) chain. Tunable reactive groups tested in this study include azide, biotin, carboxyl, and amine. Cap exchange with these multilipoic acid ligands via a photochemical ligation strategy yields homogeneous QD dispersions that are colloidally stable over several biologically relevant conditions and for extended periods of time. The zwitterionic coating yields compact nanoparticle size and imparts nonsticky surface properties onto the QDs, preventing protein absorption. The introduction of a controllable number of reactive groups allows conjugation of the QDs to biomolecules via bio orthogonal coupling chemistries including (1) attachment of the neurotransmitter dopamine to QDs via amine-isothiocyanate reaction to produce a platform capable of probing interactions with cysteine in proteins, based on charge transfer interactions; (2) self-assembly of biotinylated QDs with streptavidin-dye; and (3) ligation of azide-functionalized QDs to cyclooctyne-modified transferrin via copper-free click chemistry, used for intracellular delivery. This ligand design strategy can be used to prepare an array of metal-coordinating ligands adapted for coating other inorganic nanoparticles, including magnetic and plasmonic nanomaterials. PMID- 27482757 TI - Extensive Parallelism between Crystal Parameters and Magnetic Phase Transitions of Unusually Ferromagnetic Praseodymium Manganite Nanoparticles. AB - The alterations in physical property across different space groups of the same material are sometimes conveniently reflected by the crystal structure as a function of temperature. However, mirroring the physical property and crystal parameters over a wide range of temperatures within the same space group is quite unusual. Remarkably, Rietveld analyses of the X-ray diffraction patterns of PrMn0.9O3 (ABO3) nanoparticles (NPs) with a constant Pnma space group from 300 to 10 K could successfully predict the four magnetic phases, viz. paramagnetic, antiferromagnetic (AFM), ferromagnetic (FM), and spin-glass-like ordering. The increase in Mn-O-Mn bond angles and tolerance factor leads to FM ordering below ~100 K in usually AFM PrMn0.9O3 NPs. The concurrent decrease of lattice cell volume and Mn-O-Mn bond angles near the AFM to FM transition temperature (Tc) suggests that the AFM character increases just above Tc due to atomic deformations and reduced Mn-Mn separation. The predictions from crystal structure refinement were successfully verified from the cooling path of the temperature dependent field-cooled magnetization measurements. A mechanism involving incoherent spin reversal due to competition between the neighboring spins undergoing antiparallel to parallel spin rotations was suggested. The structure property parallelism was cross-checked with the A-site vacant Pr0.9MnO3.2 NPs. PMID- 27482759 TI - Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. AB - The stability of protein-protein interfaces can be essential for protein function. For ionotropic glutamate receptors, a family of ligand-gated ion channels vital for normal function of the central nervous system, such an interface exists between the extracellular ligand binding domains (LBDs). In the full-length protein, the LBDs are arranged as a dimer of dimers. Agonist binding to the LBDs opens the ion channel, and briefly after activation the receptor desensitizes. Several residues at the LBD dimer interface are known to modulate desensitization, and conformational changes around these residues are believed to be involved in the state transition. The general hypothesis is that the interface is disrupted upon desensitization, and structural evidence suggests that the disruption might be substantial. However, when cross-linking the central part of this interface, functional data suggest that the receptor can still undergo desensitization, contradicting the hypothesis of major interface disruption. Here, we illustrate how opening the dimer interface using steered molecular dynamics (SMD) simulations, and analyzing the work values required, provides a quantitative measure for interface stability. For one subtype of glutamate receptors, which is regulated by ion binding to the dimer interface, we show that opening the interface without ions bound requires less work than with ions present, suggesting that ion binding indeed stabilizes the interface. Likewise, for interface mutants with longer-lived active states, the interface is more stable, while the work required to open the interface is reduced for less active mutants. Moreover, a cross-linked mutant can still undergo initial interface opening motions similar to the native receptor and at similar energetic cost. Thus, our results support that interface opening is involved in desensitization. Furthermore, they provide reconciliation of apparently opposing data and demonstrate that SMD simulations can give relevant biological insight into longer time scale processes without the need for expensive calculations. PMID- 27482760 TI - Semifluorinated Alkylphosphonic Acids Form High-Quality Self-Assembled Monolayers on Ag-Coated Yttrium Barium Copper Oxide Tapes and Enable Filamentization of the Tapes by Microcontact Printing. AB - A custom-designed semifluorinated phosphonic acid, (9,9,10,10,11,11,12,12,13,13,14,14,15,15,16,16,16 heptadecafluorohexadecyl)phosphonic acid (F8H8PA), and a normal hexadecylphosphonic acid (H16PA) were synthesized and used to generate self assembled monolayers (SAMs) on commercially available yttrium barium copper oxide (YBCO) tapes. In this study, we wished to evaluate the effectiveness of these monolayer films as coatings for selectively etching YBCO. Initial films formed by solution deposition and manual stamping using a non-patterned polydimethylsiloxane stamp allowed for a comparison of the film-formation characteristics. The resulting monolayers were characterized by X-ray photoelectron spectroscopy (XPS), contact angle goniometry, and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). To prepare line-patterned (filamentized) YBCO tapes, standard microcontact printing (MU-CP) procedures were used. The stamped patterns on the YBCO tapes were characterized by scanning electron microscopy (SEM) before and after etching to confirm the effectiveness of the patterning process on the YBCO surface and energy-dispersive X-ray spectroscopy (EDX) to obtain the atomic composition of the exposed interface. PMID- 27482761 TI - Flexible Nanoporous WO3-x Nonvolatile Memory Device. AB - Flexible resistive random access memory (RRAM) devices have attracted great interest for future nonvolatile memories. However, making active layer films at high temperature can be a hindrance to RRAM device fabrication on flexible substrates. Here, we introduced a flexible nanoporous (NP) WO3-x RRAM device using anodic treatment in a room-temperature process. The flexible NP WO3-x RRAM device showed bipolar switching characteristics and a high ION/IOFF ratio of ~10(5). The device also showed stable retention time over 5 * 10(5) s, outstanding cell-to-cell uniformity, and bending endurance over 10(3) cycles when measured in both the flat and the maximum bending conditions. PMID- 27482758 TI - Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas. AB - Metabolism of the essential amino acid L-tryptophan (TRP) is implicated in a number of neurological conditions including depression, neurodegenerative diseases, and cancer. The TRP catabolite kynurenine (KYN) has recently emerged as an important neuroactive factor in brain tumor pathogenesis, with additional studies implicating KYN in other types of cancer. Often highlighted as a modulator of the immune response and a contributor to immune escape for malignant tumors, it is well-known that KYN has effects on the production of the coenzyme nicotinamide adenine dinucleotide (NAD(+)), which can have a direct impact on DNA repair, replication, cell division, redox signaling, and mitochondrial function. Additional effects of KYN signaling are imparted through its role as an endogenous agonist for the aryl hydrocarbon receptor (AhR), and it is largely through activation of the AhR that KYN appears to mediate malignant progression in gliomas. We have recently reported on the ability of KYN signaling to modulate expression of human DNA polymerase kappa (hpol kappa), a translesion enzyme involved in bypass of bulky DNA lesions and activation of the replication stress response. Given the impact of KYN on NAD(+) production, AhR signaling, and translesion DNA synthesis, it follows that dysregulation of KYN signaling in cancer may promote malignancy through alterations in the level of endogenous DNA damage and replication stress. In this perspective, we discuss the connections between KYN signaling, DNA damage tolerance, and genomic instability, as they relate to cancer. PMID- 27482762 TI - Spectroscopic and Computational Study of Acetic Acid and Its Cyclic Dimer in the Near-Infrared Region. AB - Anharmonic vibrational analysis of near-infrared (NIR) spectra of acetic acid was carried out by anharmonic quantum chemical calculation in a wide concentration range of its CCl4 solution. By predicting vibrational spectra of acetic acid for the first time over a wide NIR region, it was possible to elucidate the influence of the formation of acetic acid cyclic dimer on its NIR spectrum. Quantum chemical simulations were based on coupled cluster and density functional theory quantum methods. Additionally, Moller-Plesset perturbation theory was employed for the additional calculation of hydrogen bonding stabilization energies. An anharmonic vibrational analysis was performed with the use of generalized second order vibrational perturbation theory (GVPT2). A hybrid approach was assumed, in which monomeric species was treated by CCSD(T)/aug-cc-pVDZ (harmonic approximation) and B3LYP/SNSD (anharmonic approximation) methods. For the cyclic dimer, B3LYP and B2PLYP single and double hybrid functionals, paired with an SNSD basis set, were employed. DFT calculations were augmented with additional empirical dispersion correction. It was found that quantum chemically calculated vibrational modes in the NIR region are in a good agreement with experimental data. The results of anharmonic vibrational analysis were supported by a harmonic shift analysis, for elucidating the very strong anharmonic coupling observed between stretching modes of hydrogen bonded bridge in the cyclic dimer. However, the calculated wavenumbers for combination modes of double hydrogen bonded bridge in the cyclic dimer, which are very sensitive to the formation of hydrogen bonding, were found to be underestimated by quantum chemical methods. Therefore, by band fitting, the wavenumbers and shape parameters for these bands were found, and the modeled spectra were adjusted accordingly. A high accuracy of simulated spectra was achieved, and a detailed analysis of the experimental NIR spectra of acetic acid was possible, with successful identification of numerous experimental bands, including those which originate from concentration effects. It was also found that the main spectral features observed in the NIR spectra of carboxylic acid upon the formation of hydrogen bond should be accounted for combination modes of the stretching and bending vibrations of double hydrogen-bonded bridge in the cyclic dimers of acetic acid. PMID- 27482763 TI - Incidence of Primary Mitochondrial Disease in Children Younger Than 2 Years Presenting With Acute Liver Failure. AB - BACKGROUND: Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an important cause of acute liver failure (ALF) in infancy. Early and accurate diagnosis is important because liver transplantation (LT) is often contraindicated. It is unclear which methods are the best to diagnose MLD in the setting of ALF. OBJECTIVE: The aim of the study was to determine the incidence of MLD in children younger than 2 years with ALF and the utility of routine investigations to detect MLD. METHODS: Thirty-nine consecutive infants with ALF were admitted to a single unit from 2009 to 2011. All were extensively investigated using an established protocol. Genes implicated in mitochondrial DNA depletion syndrome were sequenced in all cases and tissue mtDNA copy number measured where available. RESULTS: Five infants (17%) had genetically proven MLD: DGUOK (n = 2), POLG (n = 2), and MPV17 (1). Four of these died, whereas 1 recovered. Two had normal muscle mtDNA copy number and 3 had normal muscle respiratory chain enzymes. An additional 8 children had low hepatic mtDNA copy number but pathogenic mutations were not detected. One of these developed fatal multisystemic disease after LT, whereas 5 who survived remain well without evidence of multisystemic disease up to 6 years later. Magnetic resonance spectroscopy did not distinguish between those with and without MLD. CONCLUSIONS: Low liver mtDNA copy number may be a secondary phenomenon in ALF.Screening for mtDNA maintenance gene mutations may be the most efficient way to confirm MLD in ALF in the first 2 years of life. PMID- 27482764 TI - Duodenal Disaccharidase Activities During and After Weaning off Parenteral Nutrition in Pediatric Intestinal Failure. AB - OBJECTIVES: Data on factors affecting absorptive function in children with intestinal failure (IF) are sparse. We evaluated duodenal disaccharidase activities and inflammation in relation to parenteral nutrition (PN) and intestinal resection in pediatric onset IF. METHODS: Disaccharidase (maltase, sucrase, and lactase) activities and histologic inflammation were evaluated from duodenal biopsies in 58 patients during PN (n = 23) or full enteral nutrition (n = 40) and in 43 matched controls. The first and the last postresection biopsies were analyzed separately after 4.3 (1.2-9.7) years and 6.5 (2.3-12.4) years, respectively. RESULTS: During PN, maltase and sucrase activities were 1.6-fold lower and mucosal inflammation more frequent (22% vs 3%) when compared to matched controls (P < 0.05 for both). In patients on full enteral nutrition, activities of maltase and sucrase were significantly higher than that in patients receiving PN and comparable to those of matched controls. Postresection time correlated positively (r = 0.448 and r = 0.369) and percentage length of the remaining small intestine inversely (r = -0.337 and r = -0.407) with maltase and sucrase activity in patients on full enteral nutrition (P < 0.05 for all), whereas proportional length of remaining colon correlated positively with maltase and lactase activity (r = 0.424-0.544, P < 0.05) in patients receiving PN. CONCLUSIONS: In children with IF, PN dependency associated with decreased duodenal maltase and sucrase activities and mucosal inflammation, which may disturb intestinal absorptive function. Localization and extent of intestinal resection and post-resection time correlated with duodenal disaccharidase activities. PMID- 27482766 TI - Prevalence, Clinical Profile, and Outcome of Ascitic Fluid Infection in Children With Liver Disease. AB - OBJECTIVES: Pediatric literature on spontaneous bacterial peritonitis (SBP) is limited. We evaluated the prevalence, subtypes, clinical profile, and effect on outcome of ascitic fluid infection (AFI) in children with liver disease. METHODS: Children with liver disease-related ascites and subjected to paracentesis were classified as no-AFI and AFI (SBP, culture-negative neutrocytic ascites [CNNA], and monomicrobial non-neutrocytic bacterascites). Clinical and laboratory parameters, in-hospital mortality, and outcome in follow-up were noted. RESULTS: Two hundred sixty-two children (163 boys; age 84 [1-240] months, chronic liver disease [CLD, n = 173], non-CLD [n = 89]) were enrolled. A total of 28.6% (n = 75) had SBP/CNNA, more common in CLD than non-CLD (55/173 [31.7%] vs 20/89 [22.4%]; P = 0.1). A total of 50.6% SBP/CNNA cases were symptomatic for AFI. Gram negative bacilli were isolated from 70% SBP cases. Twenty-five percent (18/72) CLD children with AFI had a poor hospital outcome, with INR, Child-Pugh score and gastrointestinal bleeding predicting outcome on multivariate analysis. Patients with CLD with SBP had higher in-hospital mortality (10/20 vs 5/35; P = 0.01) than those with CNNA, but similar Child-Pugh score (12[7-15] vs 11[7-14]; P = 0.1), recurrence of AFI (3/9 vs 6/24; P = 0.6) and mortality in follow-up (22.2% vs 25%; P = 0.1). Patients with CLD with SBP/CNNA had higher mortality over 1 year follow-up than no-AFI (24.2% [8/33] vs 12.2% [7/57]; P = 0.1) but the difference was not significant. CONCLUSIONS: A total of 28.6% children with liver disease related ascites have SBP/CNNA; 50% are symptomatic. Patients with CLD with SBP/CNNA have a mortality of 24% over 1year follow-up. CLD with SBP is similar to CNNA except for higher in-hospital mortality. PMID- 27482767 TI - Cognitive Abilities of Children With Neurological and Liver Forms of Wilson Disease. AB - Cognitive impairment in adult patients experiencing Wilson disease is now more clearly described, even in liver forms of the disease. Although this condition can appear during childhood, the cognitive abilities of children have not yet been reported in a substantial case series. This retrospective study included 21 children with Wilson disease who had undergone general cognitive assessment. The results argue in favor of a poor working memory capacity in the liver form of the disease, and more extensive cognitive impairments in its neurological form. Extensive neuropsychological investigations on all children experiencing Wilson disease are thus required. PMID- 27482768 TI - Comparison of Patients' and Doctors' Reports on Health-related Quality of Life in Celiac Disease. AB - OBJECTIVE: To investigate whether implementation of a celiac disease (CD) specific health-related quality of life (HRQOL) questionnaire would add value to CD follow-up visits; we compared patients' self-reported CD-specific HRQOL with the physician's report provided during a regular CD follow-up visit in children and young adults. METHODS: A cross-sectional study in the control group of a study on self-management in CD (CoelKids). Eligible patients had CD for >=1 year and were 25 years or younger. They completed a CD-specific HRQOL questionnaire (CDDUX) after their regular follow-up visit. Their physicians were unaware of the present study's objectives or self-reported HRQOL. PRIMARY OUTCOME: agreement between physician-reported and self-reported HRQOL. SECONDARY OUTCOMES: patient variables predicting a discrepancy between reports, or a lower HRQOL. RESULTS: Physician-reported HRQOL was available in 70 of 78 enrolled patients. The self reported and physician-reported HRQOL were concordant in 30 of 70 (K = 0.093), 6 of them had a poor self-reported HRQOL. Reports were discrepant in 40 of 70; all 40 self-reported a poor HRQOL. Discrepancies occurred more frequently in patients with a disease duration <9 years (32/40 with discrepant reports were diagnosed <9 years ago vs 17/30 with no discrepancy, P<0.001) and in females (35/40 with discrepant reports were girls versus 16 of 30 with no discrepancy, P = 0.001). Both factors were predictors of a poorer HRQOL. CONCLUSIONS: During regular CD follow-up visits, physicians did not report a poor HRQOL in 40 of 46 children and young adults with a poor self-reported HRQOL. This is consistent with previous studies examining other chronic diseases and supports the implementation of self reported CD-specific HRQOL measurements in CD follow-up visits. PMID- 27482769 TI - Regio- and Stereoselective Oxysulfonylation of Allenes. AB - A highly regio- and stereoselective oxysulfonylation of allenes was developed that provided direct access to 2-sulfonyl allylic alcohols in good yields. By means of dioxygen activation, selective difunctionlization of allenes could be successfully achieved under mild metal-free conditions. Preliminary mechanistic investigation disclosed that this transformation probably goes through a radical process. PMID- 27482770 TI - Crystallization of LiAlSiO4 Glass in Hydrothermal Environments at Gigapascal Pressures-Dense Hydrous Aluminosilicates. AB - High-pressure hydrothermal environments can drastically reduce the kinetic constraints of phase transitions and afford high-pressure modifications of oxides at comparatively low temperatures. Under certain circumstances such environments allow access to kinetically favored phases, including hydrous ones with water incorporated as hydroxyl. We studied the crystallization of glass in the presence of a large excess of water in the pressure range of 0.25-10 GPa and at temperatures from 200 to 600 degrees C. The p and T quenched samples were analyzed by powder X-ray diffraction, scanning electron microscopy, and IR spectroscopy. At pressures of 0.25-2 GPa metastable zeolite Li-ABW and stable alpha-eucryptite are obtained at low and high temperatures, respectively, with crystal structures based on tetrahedrally coordinated Al and Si atoms. At 5 GPa a new, hydrous phase of LiAlSiO4, LiAlSiO3(OH)2 = LiAlSiO4.H2O, is produced. Its crystal structure was characterized from single-crystal X-ray diffraction data (space group P21/c, a = 9.547(3) A, b = 14.461(5) A, c = 5.062(2) A, beta = 104.36(1) degrees ). The monoclinic structure resembles that of alpha-spodumene (LiAlSi2O6) and constitutes alternating layers of chains of corner-condensed SiO4 tetrahedra and chains of edge-sharing AlO6 octahedra. OH groups are part of the octahedral Al coordination and extend into channels provided within the SiO4 tetrahedron chain layers. At 10 GPa another hydrous phase of LiAlSiO4 with presently unknown structure is produced. The formation of hydrous forms of LiAlSiO4 shows the potential of hydrothermal environments at gigapascal pressures for creating truly new materials. In this particular case it indicates the possibility of generally accessing pyroxene-type aluminosilicates with crystallographic amounts of hydroxyl incorporated. This could also have implications to geosciences by representing a mechanism of water storage and transport in the depths of the Earth. PMID- 27482771 TI - Novel Molten Oxide Membrane for Ultrahigh Purity Oxygen Separation from Air. AB - We present a novel solid/liquid Co3O4-36 wt % Bi2O3 composite that can be used as molten oxide membrane, MOM ( Belousov, V. V. Electrical and Mass Transport Processes in Molten Oxide Membranes. Ionics 22 , 2016 , 451 - 469 ), for ultrahigh purity oxygen separation from air. This membrane material consists of Co3O4 solid grains and intergranular liquid channels (mainly molten Bi2O3). The solid grains conduct electrons, and the intergranular liquid channels predominantly conduct oxygen ions. The liquid channels also provide the membrane material gas tightness and ductility. This last property allows us to deal successfully with the problem of thermal incompatibility. Oxygen and nitrogen permeation fluxes, oxygen ion transport number, and conductivity of the composite were measured by the gas flow, volumetric measurements of the faradaic efficiency, and four-probe dc techniques, accordingly. The membrane material showed the highest oxygen selectivity jO2/jN2 > 10(5) and sufficient oxygen permeability 2.5 * 10(-8) mol cm(-1) s(-1) at 850 degrees C. In the range of membrane thicknesses 1.5-3.3 mm, the oxygen permeation rate was controlled by chemical diffusion. The ease of the MOM fabrication, combined with superior oxygen selectivity and competitive oxygen permeability, shows the promise of the membrane material for ultrahigh purity oxygen separation from air. PMID- 27482772 TI - A Brief Period of Hypothermia Induced by Total Liquid Ventilation Decreases End Organ Damage and Multiorgan Failure Induced by Aortic Cross-Clamping. AB - BACKGROUND: In animal models, whole-body cooling reduces end-organ injury after cardiac arrest and other hypoperfusion states. The benefits of cooling in humans, however, are uncertain, possibly because detrimental effects of prolonged cooling may offset any potential benefit. Total liquid ventilation (TLV) provides both ultrafast cooling and rewarming. In previous reports, ultrafast cooling with TLV potently reduced neurological injury after experimental cardiac arrest in animals. We hypothesized that a brief period of rapid cooling and rewarming via TLV could also mitigate multiorgan failure (MOF) after ischemia-reperfusion induced by aortic cross-clamping. METHODS: Anesthetized rabbits were submitted to 30 minutes of supraceliac aortic cross-clamping followed by 300 minutes of reperfusion. They were allocated either to a normothermic procedure with conventional ventilation (control group) or to hypothermic TLV (33 degrees C) before, during, and after cross-clamping (pre-clamp, per-clamp, and post-clamp groups, respectively). In all TLV groups, hypothermia was maintained for 75 minutes and switched to a rewarming mode before resumption to conventional mechanical ventilation. End points included cardiovascular, renal, liver, and inflammatory parameters measured 300 minutes after reperfusion. RESULTS: In the normothermic (control) group, ischemia-reperfusion injury produced evidence of MOF including severe vasoplegia, low cardiac output, acute kidney injury, and liver failure. In the TLV group, we observed gradual improvements in cardiac output in post-clamp, per-clamp, and pre-clamp groups versus control (53 +/- 8, 64 +/- 12, and 90 +/- 24 vs 36 +/- 23 mL/min/kg after 300 minutes of reperfusion, respectively). Liver biomarker levels were also lower in pre-clamp and per-clamp groups versus control. However, acute kidney injury was prevented in pre-clamp, and to a limited extent in per-clamp groups, but not in the post-clamp group. For instance, creatinine clearance was 4.8 +/- 3.1 and 0.5 +/- 0.6 mL/kg/min at the end of the follow-up in pre-clamp versus control animals (P = .0004). Histological examinations of the heart, kidney, liver, and jejunum in TLV and control groups also demonstrated reduced injury with TLV. CONCLUSIONS: A brief period of ultrafast cooling with TLV followed by rapid rewarming attenuated biochemical and histological markers of MOF after aortic cross-clamping. Cardiovascular and liver dysfunctions were limited by a brief period of hypothermic TLV, even when started after reperfusion. Conversely, acute kidney injury was limited only when hypothermia was started before reperfusion. Further work is needed to determine the clinical significance of our results and to identify the optimal duration and timing of TLV-induced hypothermia for end-organ protection in hypoperfusion states. PMID- 27482773 TI - Clinical Performance and Safety of Closed-Loop Systems: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - Automated systems can improve the stability of controlled variables and reduce the workload in clinical practice without increasing the risks to patients. We conducted this review and meta-analysis to assess the clinical performance of closed-loop systems compared with manual control. Our primary outcome was the accuracy of closed-loop systems in comparison with manual control to maintain a given variable in a desired target range. The occurrence of overshoot and undershoot episodes was the secondary outcome. We retrieved randomized controlled trials on accuracy and safety of closed-loop systems versus manual control. Our primary outcome was the percentage of time during which the system was able to maintain a given variable (eg, bispectral index or oxygen saturation) in a desired range or the proportion of the target measurements that was within the required range. Our secondary outcome was the percentage of time or the number of episodes that the controlled variable was above or below the target range. The standardized mean difference and 95% confidence interval (CI) were calculated for continuous outcomes, whereas the odds ratio and 95% CI were estimated for dichotomous outcomes. Thirty-six trials were included. Compared with manual control, automated systems allowed better maintenance of the controlled variable in the anesthesia drug delivery setting (95% CI, 11.7%-23.1%; percentage of time, P < 0.0001, number of studies: n = 15), in patients with diabetes mellitus (95% CI, 11.5%-30.9%; percentage of time, P = 0.001, n = 8), and in patients mechanically ventilated (95% CI, 1.5%-23.1%; percentage of time, P = 0.03, n = 8). Heterogeneity among the studies was high (>75%). We observed a significant reduction of episodes of overshooting and undershooting when closed-loop systems were used. The use of automated systems can result in better control of a given target within a selected range. There was a decrease of overshooting or undershooting of a given target with closed-loop systems. PMID- 27482774 TI - Athletic Head Trauma. PMID- 27482775 TI - Biomechanical Perspectives on Concussion in Sport. AB - Concussions can occur in any sport. Often, clinical and biomechanical research efforts are disconnected. This review paper analyzes current concussion issues in sports from a biomechanical perspective and is geared toward Sports Med professionals. Overarching themes of this review include the biomechanics of the brain during head impact, role of protective equipment, potential population based differences in concussion tolerance, potential intervention strategies to reduce the incidence of injury, and common biomechanical misconceptions. PMID- 27482777 TI - Neuropsychological Testing in Mild Traumatic Brain Injury: What to Do When Baseline Testing Is Not Available. AB - Barth and colleagues' seminal study using baseline neuropsychological testing as a model for sports concussion management serves as the template for many collegiate sports medicine programs. However, there remains a significant need for an evidence-based strategy in cases where no baseline testing has been conducted. In this article, we further articulate such a model based on work with athletes at our Division I university. The foundation of the model involves base rates of impairment in a typical neurocognitive sports concussion battery, with decision rules that differ slightly for males and females. There is flexibility in the model such that its application can start during an acute period postconcussion when athletes are still potentially symptomatic, as well as after athletes self-report being symptom free. We use our population of collegiate athletes and the tests we administer as a framework to provide concrete values to the proposed algorithm based on specific tests, but the logic of our evidence based model could easily be applied to other sports concussion populations and neurocognitive test batteries. Our proposed neuropsychological concussion management guidelines are evidence based, but also allow for accommodating trends in the literature which suggest that increasingly individualistic clinical concussion management approaches are most prudent. PMID- 27482778 TI - Mild Traumatic Brain Injury and Post-concussion Syndrome: Treatment and Related Sequela for Persistent Symptomatic Disease. AB - Sport-related concussion typically resolves within a few weeks of the injury; however, persistent symptoms have been reported to occur in 10% to 15% of concussions. These ongoing symptoms can cause significant disability and be frustrating for the patient and family. In addition, factors other than brain injury can cause complications for these patients, such as adjustment disorder or exacerbation of preexisting conditions such as depression or migraine. Individuals with prolonged symptoms of concussion may be classified as having post-concussion syndrome. A careful and thoughtful evaluation is important, as the clinician must determine whether these prolonged symptoms reflect brain injury pathophysiology versus another process. Although there have been numerous studies on the acute management of concussion, much less is available on the treatment of persistent disease. This review will provide an evaluation approach for the patient with prolonged concussion symptoms and review recent literature on treatment strategies. PMID- 27482776 TI - Potential Blood-based Biomarkers for Concussion. AB - Mounting research in the field of sports concussion biomarkers has led to a greater understanding of the effects of brain injury from sports. A recent systematic review of clinical studies examining biomarkers of brain injury following sports-related concussion established that almost all studies have been published either in or after the year 2000. In an effort to prevent chronic traumatic encephalopathy and long-term consequences of concussion, early diagnostic and prognostic tools are becoming increasingly important; particularly in sports and in military personnel, where concussions are common occurrences. Early and tailored management of athletes following a concussion with biomarkers could provide them with the best opportunity to avoid further injury. Should blood-based biomarkers for concussion be validated and become widely available, they could have many roles. For instance, a point-of-care test could be used on the field by trained sport medicine professionals to help detect a concussion. In the clinic or hospital setting, it could be used by clinicians to determine the severity of concussion and be used to screen players for neuroimaging (computed tomography and/or magnetic resonance imaging) and further neuropsychological testing. Furthermore, biomarkers could have a role in monitoring progression of injury and recovery and in managing patients at high risk of repeated injury by being incorporated into guidelines for return to duty, work, or sports activities. There may even be a role for biomarkers as surrogate measures of efficacy in the assessment of new treatments and therapies for concussion. PMID- 27482779 TI - Concussion Management in the Collegiate Athlete. AB - Concussions have always been common in sports, but the awareness and associated diagnosis of the condition have been trending upward, gaining significant attention through medical literature, news media, and entertainment. Concussion management in the collegiate athlete is of specific concern, as over 460,000 young adults compete in collegiate athletics annually. The NCAA and other groups have strived to provide consensus guidelines, but many student-athletes still are not being managed as recommended. The return to play process should begin only after a student-athlete is symptom free and has returned to his or her baseline functioning. Return to play should follow a progressive, stepwise approach, using uniform steps that have been established through association recommendations. Returning to academics, or return to learn, often proves to be more challenging, as this process requires a multidisciplinary approach involving academic and administrative representatives in addition to the medical team. As further scientific evidence comes out, is it imperative that professionals providing concussion care remain up-to-date on this ever-evolving topic. PMID- 27482780 TI - Treatment Perspectives Based on Our Current Understanding of Concussion. AB - Sports-related concussion also referred to in the literature as mild traumatic brain injury remains a popular area of study for physicians, neurologists, neuropsychologists, neuroimaging, athletic trainers, and researchers across the other areas of brain sciences. Treatment for concussion is an emerging area of focus with investigators seeking to improve outcomes and protect patients from the deleterious short-term and long-term consequences which have been extensively studied and identified. Broadly, current treatment strategies for athletes recovering from concussion have remained largely unchanged since early 2000s. Knowledge of the complex pathophysiology surrounding injury should improve or advance our ability to identify processes which may serve as targets for therapeutic intervention. Clinicians working with athletes recovering from sports related concussion should have an advanced understanding of the injury cascade and also be aware of the current efforts within the research to treat concussion. In addition, how clinicians use the word "treatment" should be carefully defined and promoted so the patient is aware of the level of intervention and what stage of recovery or healing is being affected by a specific intervention. The purpose of this review is to bring together efforts across disciplines of brain science into 1 platform where clinicians can assimilate this information before making best practices decisions regarding the treatment of patients and athletes under their care. PMID- 27482781 TI - Evolution of Sports-related Headgear. AB - The major focus of this review is to establish concussion in sport as a silent epidemic in our society that is not an accident. Brain injury has a definitive pattern and distinct nonrandom predictable characteristic. The development of successful head protection requires a scientific database approach to the mechanics of headgear. It is the responsibility of the health care clinician to help with the maintenance of protective standards for headgear and support rule changes to decrease the morbidity and mortality of athletes. PMID- 27482782 TI - Structural Neuroimaging Findings in Mild Traumatic Brain Injury. AB - Common neuroimaging findings in mild traumatic brain injury (mTBI), including sport-related concussion (SRC), are reviewed based on computed tomography and magnetic resonance imaging (MRI). Common abnormalities radiologically identified on the day of injury, typically a computed tomographic scan, are in the form of contusions, small subarachnoid or intraparenchymal hemorrhages as well as subdural and epidural collections, edema, and skull fractures. Common follow-up neuroimaging findings with MRI include white matter hyperintensities, hypointense signal abnormalities that reflect prior hemorrhage, focal encephalomalacia, presence of atrophy and/or dilated Virchow-Robins perivascular space. The MRI findings from a large pediatric mTBI study show low frequency of positive MRI findings at 6 months postinjury. The review concludes with an examination of some of the advanced MRI-based image analysis methods that can be performed in the patient who has sustained an mTBI. PMID- 27482784 TI - Prevalence of hepatic steatosis in apparently healthy medical students: a transient elastography study on the basis of a controlled attenuation parameter. AB - OBJECTIVE: Despite the increasing burden of nonalcoholic fatty liver disease (NAFLD) in modern societies, the optimal screening method to detect hepatic steatosis in the general population remains to be established. Controlled attenuation parameter (CAP) measured with transient elastography (TE) has recently emerged as a reliable imaging tool for the screening and diagnosis of NAFLD. Here, we sought to investigate the prevalence of TE-defined hepatic steatosis in a sample of apparently healthy medical students. We also assessed the relationships between CAP and traditional NAFLD risk factors. MATERIALS AND METHODS: A total of 112 Turkish medical students (48 women and 64 men, mean age 20.5+/-1.1 years) underwent TE. On the basis of previous studies, a cut-off value of 238 dB/m for CAP was used for the diagnosis of hepatic steatosis. RESULTS: On the basis of the selected cut-off for CAP, we identified 26 students (23.2%) with TE-defined NAFLD. Univariate correlation analyses showed that CAP values were significantly associated with BMI (r=0.40, P<0.001), waist circumference (r=0.39, P<0.001), and hip circumference (r=0.34, P<0.001). In multivariable analysis, only BMI retained its independent association with CAP (beta=0.36, t=3.4, P<0.001). CONCLUSION: NAFLD is highly prevalent even in apparently healthy young individuals. CAP assessment with TE may be useful for an early, noninvasive identification of hepatic steatosis. PMID- 27482785 TI - Cytomegalovirus disease in inflammatory bowel disease: epidemiology and disease characteristics in a large single-centre experience. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) show an increased risk of developing cytomegalovirus (CMV) disease because of immunosuppressive medication and malnutrition. Here, we aimed to investigate the prevalence and clinical characteristics of CMV disease in our cohort of IBD patients. PATIENTS AND METHODS: We carried out a retrospective analysis of 1023 IBD patients treated at our IBD clinic at the University Hospital Zurich between 2007 and 2014. CMV disease was defined as a positive immunohistochemistry for CMV and 14 patients were identified. RESULTS: The prevalence of CMV disease in our IBD cohort was 1.37%. Twelve patients had ulcerative colitis and two had Crohn's disease with colonic involvement. All patients who developed CMV disease received immunosuppressive medication or, as in one case, had HIV infection. The most used immunosuppressive medications were steroids and azathioprine. The most common therapeutic strategy was the consecutive use of ganciclovir and valganciclovir. Ten patients recovered and two were treatment refractory; among these, one required colectomy and two had a relapse. CONCLUSION: CMV disease may influence the clinical course of IBD. There is probably an association between CMV disease and IBD-specific medication. Risk factors, epidemiology and therapeutic strategy need to be further investigated. PMID- 27482783 TI - Stability, Survival, and Tolerability of an Auditory Osseointegrated Implant for Bone Conduction Hearing: Long-Term Follow-Up of a Randomized Controlled Trial. AB - OBJECTIVE: To compare implant stability, survival, and soft tissue reactions for a novel (test) and previous generation (control) percutaneous auditory osseointegrated implant for bone conduction hearing at long-term follow-up of 5 years. STUDY DESIGN: Single follow-up visit of a previously completed multicenter, randomized, controlled trial. PATIENTS: Fifty-seven of the 77 participants of a completed randomized controlled trial on a new auditory osseointegrated implant underwent a single follow-up visit 5 years after implantation, which comprised implant stability measurements and collection of Holgers scores. Additionally, implant survival was recorded for all 77 patients from the original trial. RESULTS: The test implant showed significantly higher implant stability quotient (ISQ) values compared with the control implant throughout the 5-year follow-up. Mean area under the curve of ISQ high from baseline to 5 years was 71.6 (standard deviation [SD] +/-2.0) and 66.7 (SD +/ 3.4) for the test and control implant, respectively (p < 0.0001). For both implants, the mean ISQ value recorded at 5 years was higher compared with implantation (test group +2.03 [SD +/-2.55, within group p < 0.0001] and control group +2.25 [SD +/-4.95, within group p = 0.12]). No difference was noticed in increase from baseline between groups (p = 0.64). Furthermore, evaluation of soft tissue reactions continued to show superiority of the test implant. At the 5-year follow-up visit, one patient (2.5%) presented with a Holgers grade 2 in the test group, compared with four patients (23.5%) in the control group (p = 0.048); no patient presented with more severe soft tissue reactions. Excluding explantations, the survival rate was 95.8% for the test group and 95.0% for the control group. The corresponding rates including explantations were 93.9 and 90.0%. CONCLUSION: The test implant showed superiority in terms of higher mean ISQ values and less adverse soft tissue reactions, both at the single 5-year follow-up visit and during the complete follow-up. In addition, both implants showed an equally high implant survival. PMID- 27482786 TI - Short article: Etiologic profile and endoscopic findings in immunocompromised children and adolescents with gastrointestinal bleeding. AB - BACKGROUND: Gastrointestinal bleeding (GIB) is one of the potential causes of increased morbidity and mortality in immunocompromised patients, but data on characteristics of GIB in immunocompromised children are sparse. OBJECTIVES: This study aimed to identify the etiology, endoscopic, and histologic findings of GIB in immunocompromised children. DESIGN: This was a retrospective descriptive study. PATIENTS: We identified 33 patients (aged<20 years) and 45 GIB episodes related to GIB between January 2007 and April 2015 from a tertiary care and teaching hospital. RESULTS: The mean age at endoscopy was 10.7+/-4.6 years. Most common indications for endoscopy were melena in upper GIB and hematochezia in lower GIB. The median delay of duration between GIB presentation to endoscopy was 3 days. All except one child had at least one endoscopic abnormality. The most common cause of upper GIB was cytomegalovirus (CMV)-related gastrointestinal disease (35%), followed by esophageal varices (26%), and the most common cause of lower GIB was CMV-related gastrointestinal disease (55%). Fourteen percent of patients died during upper GIB episodes and 15% died during lower GIB episodes. CONCLUSION: Among immunocompromised individuals aged younger than 20 years presenting with GIB, CMV-related gastrointestinal disease is the most prevalent in our study population. However, the etiology of immunocompromised state needs to be taken into consideration when evaluating these children presenting with GIB. PMID- 27482787 TI - American Clinical Neurophysiology Society Guideline 4: Recording Clinical EEG on Digital Media. AB - Digital EEG recording systems are now widely available and relatively inexpensive. They offer multiple advantages over previous analog/paper systems, such as higher fidelity recording, signal postprocessing, automated detection, and efficient data storage. This document provides guidance for the creation of digital EEG recordings including (1) documentation of patient information, (2) notation of information during the recording, (3) digital signal acquisition parameters during the recording, (4) storage of digital information, and (5) display of digital EEG signals. PMID- 27482788 TI - American Clinical Neurophysiology Society Guideline 1: Minimum Technical Requirements for Performing Clinical Electroencephalography. PMID- 27482789 TI - American Clinical Neurophysiology Society Guideline 6: Minimum Technical Standards for EEG Recording in Suspected Cerebral Death. AB - This revision to the EEG Guidelines is an update incorporating current EEG technology and practice. The role of the EEG in making the determination of brain death is discussed as are suggested technical criteria for making the diagnosis of electrocerebral inactivity. PMID- 27482790 TI - American Clinical Neurophysiology Society Guideline 7: Guidelines for EEG Reporting. AB - This EEG Guideline incorporates the practice of structuring a report of results obtained during routine adult electroencephalography. It is intended to reflect one of the current practices in reporting an EEG and serves as a revision of the previous guideline entitled "Writing an EEG Report." The goal of this guideline is not only to convey clinically relevant information, but also to improve interrater reliability for clinical and research use by standardizing the format of EEG reports. With this in mind, there is expanded documentation of the patient history to include more relevant clinical information that can affect the EEG recording and interpretation. Recommendations for the technical conditions of the recording are also enhanced to include post hoc review parameters and type of EEG recording. Sleep feature documentation is also expanded upon. More descriptive terms are included for background features and interictal discharges that are concordant with efforts to standardize terminology. In the clinical correlation section, examples of common clinical scenarios are now provided that encourages uniformity in reporting. Including digital samples of abnormal waveforms is now readily available with current EEG recording systems and may be beneficial in augmenting reports when controversial waveforms or important features are encountered. PMID- 27482791 TI - American Clinical Neurophysiology Society Guideline 5: Minimum Technical Standards for Pediatric Electroencephalography. AB - This revision to the EEG Guidelines is an update incorporating the current electroencephalography technology and practice. It was previously published as Guideline 2. Similar to the prior guideline, it delineates the aspects of Guideline 1 that should be modified for neonates and young children. Recording conditions for photic stimulation and hyperventilation are revised to enhance the provocation of epileptiform discharges. Revisions recognize the difficulties involved in performing an EEG under sedation in young children. Recommended neonatal EEG montages are displayed for the reduced set of electrodes only since the montages in Guideline 3 should be used for a 21-electrode 10-20 system array. Neonatal documentation is updated to use current American Academy of Pediatrics term "postmenstrual age" rather than "conceptional age." Finally, because therapeutic hypothermia alters the prognostic value of neonatal EEG, the necessity of documenting the patient's temperature at the time of recording is emphasized. PMID- 27482793 TI - Terminologia Padronizada de Eletroencefalograma em Pacientes Criticos da Sociedade Americana de Neurofisiologia Clinica (ACNS-American Clinical Neurophysiology Society): Versao 2012-Traducao e Adaptacao Para a Lingua Portuguesa. PMID- 27482792 TI - American Clinical Neurophysiology Society: EEG Guidelines Introduction. AB - This revision to the EEG Guidelines is an update incorporating current EEG technology and practice. "Standards of practice in clinical electroencephalography" (previously Guideline 4) has been removed. It is currently undergoing revision through collaboration among multiple medical societies and will become part of "Qualifications and Responsibilities of Personnel Performing and Interpreting Clinical Neurophysiology Procedures." The remaining guidelines are reordered and renumbered. PMID- 27482794 TI - American Clinical Neurophysiology Society Guideline 2: Guidelines for Standard Electrode Position Nomenclature. AB - This revision to the EEG Guidelines is an update incorporating current electroencephalography technology and practice and was previously published as Guideline 5. While the 10-10 system of electrode position nomenclature has been accepted internationally for almost two decades, it has not been used universally. The reasons for this and clinical scenarios when the 10-10 system provides additional localizing information are discussed in this revision. In addition, situations in which AF1/2, AF5/6, PO1/2 and PO5/6 electrode positions may be utilized for EEG recording are discussed. PMID- 27482795 TI - American Clinical Neurophysiology Society Guideline 3: A Proposal for Standard Montages to Be Used in Clinical EEG. AB - This revision to the EEG Guidelines is an update incorporating current electroencephalography technology and practice and was previously published as Guideline 6. A discussion of methodology for the appropriate selection of reference electrodes is added. In addition, montages are added to assist with localization of abnormal activity in mesial frontal and anterior temporal regions. PMID- 27482796 TI - Observational Management of CIN 2 in Young Women: A Prospective Multicenter Trial. AB - OBJECTIVES: We present the rationale and methods for PRINCess-a multicenter prospective trial-which aims to determine outcome and predictors of regression in a large cohort of women younger than 25 years with cervical intraepithelial neoplasia grade 2 (CIN 2) undergoing observational management. MATERIALS AND METHODS: Six hundred women younger than 25 years with newly diagnosed biopsy proven CIN 2 are being recruited to observational management (i.e., repeat colposcopy, cytology, and cervical biopsy every 6 months for 2 years). Five hundred fifty-two women from throughout New Zealand and 1 site in Australia have been recruited so far. Measures include histology, cytology, human papillomavirus genotyping, and immunohistochemical staining. Women who develop CIN 3 will be treated with large loop excision of the transformation zone. The primary outcomes are rates of clinical regression of CIN 2 (i.e., 2 consecutive colposcopy follow ups showing CIN 1 or normal), loss to follow-up, and progression to invasion. CONCLUSIONS: The optimal treatment for young women with a diagnosis of CIN 2 is controversial. Although many undergo surgical treatment, observational management is increasingly recommended. However, there is little evidence from large clinical trials of the safety and practicality of observational management of young women with CIN 2. When completed, we will have adequate evidence by which to counsel women regarding their likely outcomes and to offer advice on clinical follow-up protocols. PMID- 27482797 TI - Analysis of Human Papillomavirus Infection in 16,320 Patients From a Gynecology Clinic in Central South China. AB - OBJECTIVE: This study aimed to investigate the relationship between persistent human papillomavirus (HPV) infection and cervical lesion. METHODS: Clinical data of 16,320 patients who visited our clinic between January 2009 and December 2013 were collected. Retrospective analysis was performed to analyze the overall HPV infection and compare the infection rates of different subtypes among different age groups, to reveal the relationship between persistent HPV infection and cervical cytology. RESULTS: The overall prevalence of HPV was 26.54%. The most common genotypes were HPV 52, HPV 16, HPV 58, CP8304, and HPV 53. The highest overall high-risk HPV prevalence was found in women older than 60 years, and the lowest prevalence was found in women between the ages of 30 and 39 years. There was no significant difference in low-risk HPV prevalence among different age groups (p = .693). The HPV clearance rate after 1 year among those with initial positive test was 87.65%. The constituent ratios of high- or low-risk HPV subtypes were not significantly different (p = .545) between nonpersistent positive and persistent-positive (PP) groups. Conversely, the constituent ratios of singe- or multi-type HPV infection were significantly different (p < .05) between these 2 groups. The most common subtypes in PP group were HPV 16, 52, 58, CP8304, and 33. The occurrence rates of atypical squamous cells of undetermined significance, high-grade squamous intraepithelial lesion, and squamous cell carcinoma in the PP group significantly increased (p < .05). CONCLUSIONS: Persistent HPV infections are mainly caused by multiple types of HPV and high risk HPV. Our region should particularly pay attention to the prevention and treatment of HPV 16, 52, and 58. PMID- 27482798 TI - Change Suboptimal Tactics and Promote a National Mandatory Human Papillomavirus Vaccination Program. PMID- 27482799 TI - Spatial analysis and identification of high risk plague regions in Pakistan based on associated rodent species distribution. AB - Plague, caused by Yersinia pestitis, is an infectious bacterial disease that has a high fatality rate if untreated. Rodents are plague reservoirs and play an important role in disease spread. Plague cases have been reported extensively since the second pandemic from the 14th century in countries sharing borders with Pakistan, such as China and India, as well as nearby countries including Russia and central Asia. Despite being centrally located in a plague-infested geographical zone, there has been no plague incidence reported from Pakistan. This study aims to pinpoint some of the potentially important aspects of the disease, which have to be considered when assessing potential risk associated with a plague outbreak in Pakistan. In this context, the occurrence and distribution of plague-associated rodent reservoirs in different regions of Pakistan in relation to those found in the neighboring countries were mapped. In addition, the climatic factors that may also influence disease spread by affecting the growth of the bacteria are also discussed. The combined epidemiological and ecological surveillance studies suggest a prevalence of several potential rodent carriers in certain districts with the possibility of a plague outbreak in Pakistan. PMID- 27482800 TI - Knowledge, attitudes, and practices about tuberculosis and choice of communication channels in Thailand. AB - INTRODUCTION: The aim of this study was to assess tuberculosis (TB) knowledge, attitudes, and practices in both the general population and risk groups in Thailand. METHODOLOGY: In a cross-sectional survey, a general population (n = 3,074) and family members of a TB patient (n = 559) were randomly selected, using stratified multistage sampling, and interviewed. RESULTS: The average TB knowledge score was 5.7 (maximum = 10) in the Thai and 5.1 in the migrant and ethnic minorities general populations, 6.3 in Thais with a family member with TB, and 5.4 in migrants and ethnic minorities with a family member with TB. In multivariate linear regression among the Thai general population, higher education, higher income, and knowing a person from the community with TB were all significantly associated with level of TB knowledge. Across the different study populations, 18.6% indicated that they had undergone a TB screening test. Multivariate logistic regression found that older age, lower education, being a migrant or belonging to an ethnic minority group, residing in an area supported by the Global Fund, better TB knowledge, having a family member with TB, and knowing other people in the community with TB was associated having been screened for TB. CONCLUSION: This study revealed deficiencies in the public health knowledge about TB, particularly among migrants and ethnic minorities in Thailand. Sociodemographic factors should be considered when designing communication strategies and TB prevention and control interventions. PMID- 27482801 TI - Platelet aggregation promoted by biofilms of oral bacteria and the effect of mouth rinses in vitro. AB - INTRODUCTION: The purpose of this study was to observe platelet aggregation promoted by biofilms of Streptococcus sanguinis and Porphyromonas gingivalis and to evaluate the effect of two different mouth rinses on this process. METHODOLOGY: In the first experiment, the same amount of S. sanguinis, P. gingivalis, and the S. sanguinis + P. gingivalis mixed solution was added to an equivalent amount of platelet-rich plasma (PRP). Aggregation was measured using a recording platelet aggregometer. In the second experiment, S. sanguinis, P. gingivalis, S sanguinis + P. gingivalis mixed solutions were pretreated with either Listerine antiseptic mouth rinse or Xipayi mouth rinse for 3 minutes, 6 minutes, and 10 minutes, respectively. The same amount of solution was added to the PRP, and the inhibition of aggregation was measured. RESULTS: In the first experiment, S. sanguinis and P. gingivalis were able to induce platelet aggregation. The aggregation rate of S. sanguinis + P. gingivalis was significantly lower than that of either S. sanguinis or P. gingivalis. In the second experiment, when S. sanguinis, P. gingivalis, and the S. sanguinis + P. gingivalis mixed solutions were pretreated with Listerine antiseptic mouth rinse for 3 minutes and Xipayi mouth rinse for 10 minutes, there was no significant platelet aggregation. CONCLUSIONS: Platelets could adhere to S. sanguinis or P. gingivalis, but when S. sanguinis was mixed with P. gingivalis, the aggregation rate was reduced significantly. Treatment with Listerine antiseptic mouth rinse or Xipayi mouth rinse inhibited the ability of the bacteria to induce platelet aggregation. PMID- 27482802 TI - Genotypic and virulence characteristics of Listeria monocytogenes recovered from food items in Lebanon. AB - INTRODUCTION: Listeria monocytogenes is the agent of listeriosis, a life threatening foodborne disease for immunocompromised patients and pregnant women. This bacterium is not routinely screened for in Lebanon and there is lack of data about the prevalent strains and their potential pathogenicity. To that purpose, this study was undertaken to characterize L. monocytogenes from various food products, by assessing the in vitro biofilm forming ability, detecting their virulence potential, and characterizing them at the strain level. METHODOLOGY: Fifty-nine isolates were obtained from the Lebanese Agriculture Research Institute (LARI). They were collected in 2012-2013 from local and imported food products in the Lebanese market. Biofilm formation was measured using the Microtiter Plate Assay. PCR amplification was performed for three main virulence genes; hly, actA, and inlB. Pulsed field gel electrophoresis (PFGE) and BIONUMERICS analysis were carried out. RESULTS: Lebanese isolates from cheese and raw meat showed higher biofilm formation than imported and Lebanese seafood isolates. A total of 100% of the isolates were PCR positive for hly and actA genes and 98.3% for inlB gene. PFGE analysis demonstrated the prevalence of 13 different subtypes with 100% similarity. Detected subtypes were grouped into 6 clusters of 90% genomic similarity. Clustered subtypes were particular to the country of origin. CONCLUSION: This study highlights the presence of L. monocytogenes in the Lebanese food market with high pathogenic potential and stresses the importance of enhanced surveillance and the implementation of strict regulations on local and imported food. Future investigations may be conducted on a larger food selection. PMID- 27482803 TI - Carbapenemases and extended-spectrum beta-lactamases producing Enterobacteriaceae isolated from Tunisian and Libyan hospitals. AB - INTRODUCTION: The aim of the study was to investigate the prevalence of extended spectrum beta-lactamase (ESBL) and carbapenemase production among clinical isolates of Enterobacteriaceae recovered from Tunisian and Libyan hospitals. METHODOLOGY: Bacterial isolates were recovered from patients in intensive care units and identified by biochemical tests and MALDI-TOF. Antibiotic susceptibility testing was performed by disk diffusion and the E-test method. ESBL and carbapenemase activities were detected using standard microbiological tests. Antibiotic resistance-encoding genes were screened by PCR and sequencing. Clonal relationships between Klebsiella pneumoniae strains were carried out using multi-locus sequence typing (MLST). RESULTS: A total of 87 isolates were characterized, with 51 and 36, respectively, identified as E. coli and K. pneumoniae. Overall the resistance prevalence was high for aminoglycosides (> 60%), fluoroquinolones (> 80%), and extended-spectrum cephalosporins (> 94%), and was low for imipenem (11.4%). Among this collection, 58 strains (66.6%) were ESBL producers and 10 K. pneumoniae strains (11.4%) were carbapenemase producers. The antibiotic resistance-encoding genes detected were blaCTX-M-15 (51.7%), blaTEM-1 (35.6%), several variants of blaSHV (21.8%), and blaOXA-48 (11.4%). The MLST typing of K. pneumoniae isolates revealed the presence of multiple clones and three novel sequence types. Also, close relationships between the OXA-48 producing strains from Tunisia and Libya were demonstrated. CONCLUSIONS: This study is the first paper describing the emergence of carbapenemase- and ESBL producing Enterobacteriaceae, sensitive to colistin, isolated in Tunisia and Libya. Active surveillance and testing for susceptibility to colistin should be implementing because resistance to colistin, mainly in Klebsiella, has been recently reported worldwide. PMID- 27482804 TI - Characteristics of ciprofloxacin-resistant Enterobacteriaceae isolates recovered from wastewater of an Algerian hospital. AB - INTRODUCTION: Hospital effluents are a source of environmental pollution by drugs, antibiotic-resistant bacteria, and resistance genes. Quinolones, particularly ciprofloxacin, are commonly detected in these effluents, contributing to the emergence of antimicrobial resistance. The objective of this study was to characterize ciprofloxacin-resistant Enterobacteriaceae in hospital effluents. METHODOLOGY: Isolates were selected on Tergitol-7 agar supplemented with ciprofloxacin and genotyped by ERIC-PCR. Antibiotic susceptibility testing was done using the disk diffusion method, and minimum inhibitory concentrations were determined using the agar dilution method. Resistance genes, integrons, phylogenetic groups, and sequence types were identified by PCR and sequencing. RESULTS: A total of 17 ciprofloxacin-resistant isolates were characterized: Escherichia coli, Escherichia vulneris, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter freundii, and Citrobacter koseri/farmeri. Isolates presented concomitant resistance to nalidixic acid, ciprofloxacin, ofloxacin, and pefloxacin. A diversity in mutation patterns in gyrA and parC genes and new amino acid substitutions in GyrA subunit were observed. Quinolone plasmidic resistance genes qnrB1, qnrB2, qnrB5/19, qnrS1, and aac(6')-Ib-cr were detected. Resistance to other antibiotic classes was observed. Class 1 integrons and resistance genes blaCTX-M-15, blaOXA-1, sul1, sul2, sul3, tetA, tetB, aadA1/2, aadA5, aph(3')-Ia, aac(3)II, dfrA1, dfrA5, dfrA7, and dfrA12 were detected. Bacterial tolerance to cadmium, zinc, and mercury was observed with the presence of the merA gene. E. coli isolates belonged to phylogenetic groups A, B1, and D and to sequence types ST405, ST443, ST101, ST10, and ST347. CONCLUSIONS: This study highlighted bacterial multidrug resistance linked to ciprofloxacin and, consequently, the risk of bacterial exposure to this antibiotic. PMID- 27482806 TI - Viral etiology in adult influenza-like illness/acute respiratory infection and predictivity of C-reactive protein. AB - INTRODUCTION: Influenza-like illness (ILI) and acute respiratory infection (ARI) are common presentations during winter and indiscriminate antibiotic use contributes significantly to the emerging post-antibiotic era. METHODOLOGY: Otherwise healthy 152 patients, presenting to outpatient clinics with ILI/ARI, were included. Patients had history & physical, CRP, hemogram and nasopharyngeal swabs for rhinovirus A/B, influenza A/B, adenovirus A/B/C/D/E, coronavirus 229E/NL63 and OC43, parainfluenza virus 1/2/3, respiratory syncytial virusA/B, metapneumovirus and Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila and Bordetella pertussis by PCR and for ABHS culture. RESULTS: Median (IR) age was 26.5 (16.5). Time to presentation was shorter in men (p = 0.027). Patients with rhinovirus had lower rates (20%) of myalgia (p = 0.043). Patients with influenza virus had higher rates (97%) of elevated CRP (p = 0.016). Logistic regression revealed that patients with ILI/ARI and CRP >= 5 mg/L were 60 times more likely to have influenza virus infection than other viral agents (OR = 60.0, 95% CI = 2.65 to 1,358.2, p = 0.010). Rhinovirus predominated in December (54%), March (36%), and April (33%). Influenza virus predominated in January (51%). Fever was most common with adenovirus (p = 0.198). All GABHS cultures were negative. Atypical organisms and Bordetella pertussis were negative in all but one patient. CONCLUSIONS: Influenza virus is the most likely pathogen in ILI/ARI when CRP >= 5 mg/L. This might be explained by tissue destruction. Myalgia is rare with rhinovirus probably due to absence of viremia. Negative bacteria by PCR and culture suggest unnecessary antibiotic use in ILI/ARI. PMID- 27482805 TI - Mumps antibody in the Thai population 17 years after the universal measles mumps rubella vaccination program. AB - INTRODUCTION: mumps vaccination implementation in the form of MMR - measles, mumps, and rubella) in Thailand for first-grade school students since 1997 and for infants 9-12 months of age since 2010 resulted in a dramatic decline in the incidence of and deaths from mumps. However, there has been a resurgence of mumps outbreaks in Thailand, even in vaccinated populations. METHODOLOGY: We aimed to determine the current seroprevalence of IgG antibodies to mumps in those 0-60 years of age from four different geographic areas of Thailand, and compare the results with our previous serosurvey in 2004. RESULTS: Seropositivity rates in children 0-7 years of age increased significantly from 45.8% in 2004 to 72.3% in 2014 after the launch of the MMR vaccine for infants. In the 8-14-year age group who had received one dose of mumps vaccination, the seropositivity rate was 66.7%. In the 15-19-year age group the seropositivity rate was the lowest, at 52.5%. DISCUSSION: Our findings correspond well with the vaccination schedules, as the highest seropositivity rate was found in children between 0 and 7 years of age. For those older than 7, there was a decline in seropositivity rate despite good vaccine coverage and reached its lowest in the 15-19-year age group. This suggested that certain population groups might be incompletely vaccinated, or the humoral immunity provided by vaccination gradually declined over time. CONCLUSIONS: We recommend a booster dose of MMR vaccine for Thai adolescents in order to prevent future mumps outbreaks. PMID- 27482807 TI - Are healthcare workers ready for Ebola? An assessment of their knowledge and attitude in a referral hospital in South India. AB - INTRODUCTION: The World Health Organization (WHO) declared the Ebola virus disease (EVD) epidemic to be a public health emergency of international concern. Healthcare workers (HCWs) are at the highest risk of infection, as they may come into contact with patients' blood or fluids. This study was conducted to assess knowledge and attitudes of HCWs towards EVD in India. METHODOLOGY: A descriptive, cross-sectional study was conducted in a multispecialty public sector referral hospital of Telangana, India. Knowledge and attitude of HCWs were evaluated using a pre-validated questionnaire. A sample of 278 participants was selected to participate in this study. The Chi-squared test was used to assess the relationship between attitudes and demographic characteristics. Logistic regression was used examine the association between knowledge and study variables. RESULTS: Of 257 participants who responded (92.4% response rate), 157 (61.1%) were females. The majority of the respondents were physicians (n = 117, 45.5%). Radio and television were the major sources of information about EVD reported by participants (89%). Overall knowledge of HCWs was poor (mean knowledge score: 6.57 +/- 2.57). Knowledge of physicians and experienced workers (>= 10 years) was significantly higher than their respective groups. The overall attitude of the participants was positive (mean attitude score: 1.62 +/- 0.57). Significant positive correlations between knowledge and attitude were observed. CONCLUSIONS: The findings indicate that participants lack basic understanding of EVD. We recommend future studies be conducted across India to identify and subsequently bridge the knowledge gaps among HCWs. PMID- 27482808 TI - A multi-center clinical study comparing Sansure Magb and CAP/CTM HBV tests in the quantitative detection of HBV DNA. AB - INTRODUCTION: As the most reliable means of diagnosing hepatitis (HBV) infection and predicting the prognosis of HBV-related chronic liver disease, the COBAS AmpliPrep/COBAS TaqMan real-time polymerase chain reaction (PCR) (CAP/CTM) assay provides a highly sensitive and accurate method for quantifying HBV DNA. However, the high cost of the COBAS reagents is prohibitive in many developing countries. Thus, we compared the Sansure magnetic bead (Magb) assay, a novel technology developed by a Chinese company, with the CAP/CTM assay. METHODOLOGY: The reproducibility and sensitivity of the Sansure Magb assay were first validated using HBV DNA reference samples. Next, the quantitative results for the two assays using 635 blood samples collected from chronic hepatitis B patients and 10 healthy controls were compared. RESULTS: The Sansure Magb assay showed high reproducibility and was at least as sensitive and specific as the CAP/CTM assay. Among the patient samples, 407 tested positive by both methods, with 386 (94.84%) showing quantitative differences of less than 1 log unit and 21 (5.16%) showing quantitative differences of between 1 and 2 log units. The results from the assays were closely correlated. Bland-Altman plot analysis showed that only 6.6% of the data points fell outside the 95% limits of agreement, which suggests that the differences between methods are clinically acceptable. CONCLUSIONS: This study demonstrates that the Sansure Magb assay is highly sensitive and reproducible. Based on its reduced cost, the Sansure Magb assay may be more applicable than the CAP/CTM assay for HBV diagnosis in developing countries such as China. PMID- 27482809 TI - Antiretroviral therapy does not affect response to chronic hepatitis C therapy in HIV-coinfected patients. AB - INTRODUCTION: Many patients coinfected with the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are using highly active antiretroviral therapy (HAART) and HCV therapy with peginterferon (PEG-IFN) and ribavirina (RBV) because the use of direct-acting antivirals is not a reality in some countries. To know the impact of such medications in the sustained virological response (SVR) during HCV treatment is of great importance. METHODOLOGY: This was a retrospective cohort study of 215 coinfected HIV/HCV patients. The patients were treated with PEG-IFN and RBV between 2007 and 2013 and analyzed by intention to treat. Treatment-experienced patients to HCV and carriers of hepatitis B were excluded. Demographic data (gender, age), mode of infection, HCV genotype, HCV viral load, hepatic fibrosis, HIV status, and type of PEG were evaluated. One hundred eighty eight (87.4%) patients were using HAART. RESULTS: SVR was achieved in 55 (29.3%) patients using HAART and in 9 (33.3%) patients not using HAART (p = 0.86). There was no difference in SVR between different HAART medications and regimens using two reverse transcriptase inhibitor nucleosides (NRTIs) or the use of protease inhibitors and non-NRTIs (27.1% versus 31.5%; p = 0.61). The predictive factors for obtaining SVR were low HCV viral load, non-1 genotype, and the use of peginterferon-alpha2a. CONCLUSIONS: The use of HAART does not influence the SVR of HCV under PEG-IFN and RBV therapy in HIV/HCV coinfected patients. PMID- 27482810 TI - Clinical characteristics of imported malaria: An 11-year experience in a Serbian referral center. AB - INTRODUCTION: Due to intercontinental traffic, population migration trends, natural disasters, and climate change, imported malaria remains important to consider in a febrile returning traveler. This study aims to raise awareness about malaria and help European clinicians maintain a working knowledge of this disease by reviewing the most important clinical characteristics in a non-endemic setting. METHODOLOGY: Using medical records, a retrospective study was performed on clinical and laboratory data in order to analyze 103 malaria cases managed at the Clinic for Infectious and Tropical Diseases in Belgrade, from 2000 to 2010. Descriptive statistics, Chi-squared test, Spearman's rank correlation, and analysis of variance were used. RESULTS: Patients were predominantly male (89.3%) with a mean age of 46.66 +/- 12.45 years, and most (98.06%) returned from Africa without having taken chemoprophylaxis (72.88%). Fever, arthralgia, myalgia, headache, vomiting, dark urine, and cough were common at presentation. Hepatosplenomegaly, jaundice, neurological and pulmonary findings, and thrombocytopenia were dominant findings on physical and laboratory examinations. Most (73.48%) were infected with P. falciparum. Few patients (17.55%) who were hyperparasitemic had significantly higher values of bilirubin and more frequent neurological complications. All patients were treated with artemisinin-based drug combinations regardless of Plasmodium species. Three (2.9%) patients succumbed to P. falciparum malaria. CONCLUSION: We suggest a high index of suspicion of malaria be maintained when evaluating febrile patients returning from endemic regions, especially if thrombocytopenia and hemolysis are present. Hyperparasitemia, high bilirubin levels, and neurological symptoms are associated with severe malaria. The importance of adequate malaria chemoprophylaxis cannot be overstated. PMID- 27482811 TI - Direct transfer of multilayer graphene grown on a rough metal surface using PDMS adhesion engineering. AB - The direct transfer of graphene using polydimethylsiloxane (PDMS) stamping has advantages such as a 'pick-and-place' capability and no chemical residue problems. However, it is not easy to apply direct PDMS stamping to graphene grown via chemical vapor deposition on rough, grainy metal surfaces due to poor contact between the PDMS and graphene. In this study, graphene consisting of a mixture of monolayers and multiple layers grown on a rough Ni surface was directly transferred without the use of an adhesive layer. Liquid PDMS was cured on graphene to effect a conformal contact with the graphene. A fast release of graphene from substrate was achieved by carrying out wet-etching-assisted mechanical peeling. We also carried out a thermal post-curing of PDMS to control the level of adhesion between PDMS and graphene and hence facilitate a damage free release of the graphene. Characterization of the transferred graphene by micro-Raman spectroscopy, SEM/EDS and optical microscopy showed neither cracks nor contamination from the transfer. This technique allows a fast and simple transfer of graphene, even for multilayer graphene grown on a rough surface. PMID- 27482814 TI - Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I. AB - Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1(Arg681*) and missense NF1(Gly848Arg) mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1(Gly848Arg) mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1(Arg681*) mutation are not viable. Mice with one Nf1(Arg681*) allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf1(4F/Arg681*); DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1. PMID- 27482812 TI - Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells. AB - Ageing is a process that inevitably affects most living organisms and involves the accumulation of macromolecular damage, genomic instability and loss of heterochromatin. Together, these alterations lead to a decline in stem cell function and to a reduced capability to regenerate tissue. In recent years, several genetic pathways and biochemical mechanisms that contribute to physiological ageing have been described, but further research is needed to better characterize this complex biological process. Because premature ageing (progeroid) syndromes, including progeria, mimic many of the characteristics of human ageing, research into these conditions has proven to be very useful not only to identify the underlying causal mechanisms and identify treatments for these pathologies, but also for the study of physiological ageing. In this Review, we summarize the main cellular and animal models used in progeria research, with an emphasis on patient-derived induced pluripotent stem cell models, and define a series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing. Finally, we describe the therapeutic strategies being investigated for the treatment of progeroid syndromes, and their main limitations. PMID- 27482813 TI - Telomeres in aging and disease: lessons from zebrafish. AB - Age is the highest risk factor for some of the most prevalent human diseases, including cancer. Telomere shortening is thought to play a central role in the aging process in humans. The link between telomeres and aging is highlighted by the fact that genetic diseases causing telomerase deficiency are associated with premature aging and increased risk of cancer. For the last two decades, this link has been mostly investigated using mice that have long telomeres. However, zebrafish has recently emerged as a powerful and complementary model system to study telomere biology. Zebrafish possess human-like short telomeres that progressively decline with age, reaching lengths in old age that are observed when telomerase is mutated. The extensive characterization of its well-conserved molecular and cellular physiology makes this vertebrate an excellent model to unravel the underlying relationship between telomere shortening, tissue regeneration, aging and disease. In this Review, we explore the advantages of using zebrafish in telomere research and discuss the primary discoveries made in this model that have contributed to expanding our knowledge of how telomere attrition contributes to cellular senescence, organ dysfunction and disease. PMID- 27482815 TI - A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease. AB - Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1 Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1 To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba(-/-) mice and the control littermate (gba(+/+)) by infecting differentiated primary cortical neurons in culture with an EF1alpha-SV40T lentivirus. Immortalized gba(-/-) neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP dependent calcium-influx response; these phenotypical characteristics were absent in gba(+/+) neurons. This null allele gba(-/-) mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies. PMID- 27482816 TI - Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9. AB - Cavitation is a key pathological feature of human tuberculosis (TB), and is a well-recognized risk factor for transmission of infection, relapse after treatment and the emergence of drug resistance. Despite intense interest in the mechanisms underlying cavitation and its negative impact on treatment outcomes, there has been limited study of this phenomenon, owing in large part to the limitations of existing animal models. Although cavitation does not occur in conventional mouse strains after infection with Mycobacterium tuberculosis, cavitary lung lesions have occasionally been observed in C3HeB/FeJ mice. However, to date, there has been no demonstration that cavitation can be produced consistently enough to support C3HeB/FeJ mice as a new and useful model of cavitary TB. We utilized serial computed tomography (CT) imaging to detect pulmonary cavitation in C3HeB/FeJ mice after aerosol infection with M. tuberculosis Post-mortem analyses were performed to characterize lung lesions and to localize matrix metalloproteinases (MMPs) previously implicated in cavitary TB in situ A total of 47-61% of infected mice developed cavities during primary disease or relapse after non-curative treatments. Key pathological features of human TB, including simultaneous presence of multiple pathologies, were noted in lung tissues. Optical imaging demonstrated increased MMP activity in TB lesions and MMP-9 was significantly expressed in cavitary lesions. Tissue MMP-9 activity could be abrogated by specific inhibitors. In situ, three-dimensional analyses of cavitary lesions demonstrated that 22.06% of CD11b+ signal colocalized with MMP 9. C3HeB/FeJ mice represent a reliable, economical and tractable model of cavitary TB, with key similarities to human TB. This model should provide an excellent tool to better understand the pathogenesis of cavitation and its effects on TB treatments. PMID- 27482817 TI - Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome. AB - Primary cilia extend from the plasma membrane of most vertebrate cells and mediate signaling pathways. Ciliary dysfunction underlies ciliopathies, which are genetic syndromes that manifest multiple clinical features, including renal cystic disease and obesity. THM1 (also termed TTC21B or IFT139) encodes a component of the intraflagellar transport-A complex and mutations in THM1 have been identified in 5% of individuals with ciliopathies. Consistent with this, deletion of murine Thm1 during late embryonic development results in cystic kidney disease. Here, we report that deletion of murine Thm1 during adulthood results in obesity, diabetes, hypertension and fatty liver disease, with gender differences in susceptibility to weight gain and metabolic dysfunction. Pair feeding of Thm1 conditional knock-out mice relative to control littermates prevented the obesity and related disorders, indicating that hyperphagia caused the obese phenotype. Thm1 ablation resulted in increased localization of adenylyl cyclase III in primary cilia that were shortened, with bulbous distal tips on neurons of the hypothalamic arcuate nucleus, an integrative center for signals that regulate feeding and activity. In pre-obese Thm1 conditional knock-out mice, expression of anorexogenic pro-opiomelanocortin (Pomc) was decreased by 50% in the arcuate nucleus, which likely caused the hyperphagia. Fasting of Thm1 conditional knock-out mice did not alter Pomc nor orexogenic agouti-related neuropeptide (Agrp) expression, suggesting impaired sensing of changes in peripheral signals. Together, these data indicate that the Thm1-mutant ciliary defect diminishes sensitivity to feeding signals, which alters appetite regulation and leads to hyperphagia, obesity and metabolic disease. PMID- 27482818 TI - Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARalpha activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARalpha, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARalpha activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARalpha activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARalpha activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4 PBA resulted from the induction of PPARalpha expression, as 4-PBA pre-treatment promoted upregulation of PPARalpha, and inhibition of PPARalpha by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARalpha activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARalpha inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARalpha activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARalpha could be a potential therapeutic strategy to ameliorate ALF. PMID- 27482820 TI - Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats. PMID- 27482819 TI - Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies. AB - Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAF(V600E) inhibitor, Vemurafenib, in adult zebrafish harboring BRAF(V600E) melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases. PMID- 27482821 TI - The Sinorhizobium fredii HH103 MucR1 Global Regulator Is Connected With the nod Regulon and Is Required for Efficient Symbiosis With Lotus burttii and Glycine max cv. Williams. AB - Sinorhizobium fredii HH103 is a rhizobial strain showing a broad host range of nodulation. In addition to the induction of bacterial nodulation genes, transition from a free-living to a symbiotic state requires complex genetic expression changes with the participation of global regulators. We have analyzed the role of the zinc-finger transcriptional regulator MucR1 from S. fredii HH103 under both free-living conditions and symbiosis with two HH103 host plants, Glycine max and Lotus burttii. Inactivation of HH103 mucR1 led to a severe decrease in exopolysaccharide (EPS) biosynthesis but enhanced production of external cyclic glucans (CG). This mutant also showed increased cell aggregation capacity as well as a drastic reduction in nitrogen-fixation capacity with G. max and L. burttii. However, in these two legumes, the number of nodules induced by the mucR1 mutant was significantly increased and decreased, respectively, with respect to the wild-type strain, indicating that MucR1 can differently affect nodulation depending on the host plant. RNA-Seq analysis carried out in the absence and the presence of flavonoids showed that MucR1 controls the expression of hundreds of genes (including some related to EPS production and CG transport), some of them being related to the nod regulon. PMID- 27482823 TI - Two Days. PMID- 27482822 TI - Pathogen Infection and MORC Proteins Affect Chromatin Accessibility of Transposable Elements and Expression of Their Proximal Genes in Arabidopsis. AB - To assess the role of MORC1 in epigenetics in relation to plant immunity, genome wide chromatin accessibility was compared between mock- or Pseudomonas syringae pv. tomato-inoculated wild type (WT) Arabidopsis, the morc1/2 double mutant, or both. Most changes in chromatin accessibility, scored by DNase I hypersensitive sites (DHSs), were located in the promoters of genes and transposable elements (TEs). Comparisons between morc1/2 and WT receiving the same treatment revealed differential DHSs (dDHSs) predominantly associated with heterochromatic TEs. By contrast, comparisons between mock- and P. syringae pv. tomato-inoculated plants from the same genotype showed dDHSs associated with biotic and abiotic stress related genes; a smaller but significant population was in TEs. Moreover, many defense genes, including PR-1, PR-2, and PR-5, were proximal to P. syringae pv. tomato-induced, TE-associated dDHSs. A random subset of these defense genes showed moderately delayed or reduced expression or both in P. syringae pv. tomato infected morc1/2 as compared with WT. MORC1 was physically bound to chromatin in a P. syringae pv. tomato infection-responsive manner at sites dispersed throughout the genome. Notably, silencing of TE-associated dDHSs proximal to these infection-induced, MORC1-interacting sites led to significant suppression of P. syringae pv. tomato-induced transcription of adjacent defense genes, including PR-1. These results provide evidence that MORC1 is associated with TEs and suggest that a subset of these TEs may help regulate their proximal defense genes. PMID- 27482824 TI - Differentiating Keratoconus and Corneal Warpage by Analyzing Focal Change Patterns in Corneal Topography, Pachymetry, and Epithelial Thickness Maps. AB - PURPOSE: To differentiate between keratoconus and contact lens-related corneal warpage by combining focal change patterns in anterior corneal topography, pachymetry, and epithelial thickness maps. METHODS: Pachymetry and epithelial thickness maps of normal, keratoconus, and warpage, and forme fruste keratoconus (FFK) eyes were obtained from a Fourier-domain optical coherence tomography (OCT). Epithelial pattern standard deviation (PSD) was calculated and combined with two novel indices, the Warpage Index and the Anterior Ectasia Index, to differentiate between normal, keratoconus, and warpage eyes. The values of the three parameters were compared between groups. RESULTS: The study included 22 normal, 31 keratoconic, 11 warpage, and 8 FFK eyes. The epithelial PSD was normal (< 0.041) for 100% normal eyes and abnormal (> 0.041) for 100% of keratoconic eyes, 81.8% of warpage eyes, and 87.5% of FFK eyes. The Anterior Ectasia Index of normal eyes (1.66 +/- 0.74) was significantly lower than that for the keratoconus eyes (17.5 +/- 7.17), the warpage eyes (2.98 +/- 1.69), and the FFK eyes (6.95 +/ 5.86). The Warpage Index was positive in all warpage eyes and negative for all keratoconic and FFK eyes except three wearing rigid gas-permeable contact lens. CONCLUSIONS: The epithelial PSD can distinguish normal from keratoconus or warpage, but does not distinguish between these two conditions. The Anterior Ectasia Index is abnormal in keratoconus but not warpage. The Warpage Index is positive for warpage and negative for keratoconus, except in cases where keratoconus and warpage coexist. Together, the three parameters are strong tripartite discriminators of normal, keratoconus, and warpage. PMID- 27482826 TI - Antibacterial activity of fractions from three Chumash medicinal plant extracts and in vitro inhibition of the enzyme enoyl reductase by the flavonoid jaceosidin. AB - We have investigated the in vitro antibacterial bioactivity of dichloromethane soluble fractions of Artemisia californica, Trichostema lanatum, Salvia apiana, Sambucus nigra ssp. cerulea and Quercus agrifolia Nee against a DeltatolC mutant strain of Escherichia coli. These plants are traditional medicinal plants of the Chumash American Indians of Southern California. Bioassay-guided fractionation led to the isolation of three flavonoid compounds from A. californica: jaceosidin (1), jaceidin (2), and chrysoplenol B (3). Compounds 1 and 2 exhibited antibacterial activity against E. coli DeltatolC in liquid cultures. The in vitro activity of 1 against the enoyl reductase enzyme (FabI) was measured using a spectrophotometric assay and found to completely inhibit FabI activity at a concentration of 100 MUM. However, comparison of minimum inhibitory concentration values for 1-3 against E. coli DeltatolC and an equivalent strain containing a plasmid constitutively expressing fabI did not reveal any selectivity for FabI in vivo. PMID- 27482825 TI - Comparison of Different Treatment Modalities for Type 1 Diabetes, Including Sensor-Augmented Insulin Regimens, in 52 Weeks of Follow-Up: A COMISAIR Study. AB - OBJECTIVE: To compare different treatment modalities for patients with type 1 diabetes (T1D) based on real-time continuous glucose monitoring (RT-CGM) or self monitoring of blood glucose (SMBG) combined with multiple daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: Sixty-five T1D patients were followed up for a year. Of these, 27 started RT-CGM as part of a sensor-augmented insulin regimen (SAIR); within this SAIR group, 15 subjects started sensor-augmented pump (SAP) therapy and the remaining 12 continued with MDIs (MDIs + RT-CGM). A second group of 20 patients initiated CSII without RT-CGM, while a third group of 18 subjects continued on MDIs and SMBG. The main endpoints were reduction of HbA1c, glycemic variability (GV), and incidence of hypoglycemia. RESULTS: After a year, the baseline mean HbA1c in the SAIR group (8.3%) decreased to 7.1% (P < 0.0001); both SAIR subgroups, SAP and MDIs + RT-CGM, showed comparable improvement. The CSII group also had reduced HbA1c (8.4% +/- 0.9% vs. 7.9% +/- 0.7%; P < 0.05). Both SAIRs were superior to MDIs (P = 0.002) and CSII (P = 0.0032). GV was also lowered, both in the SAIR (P < 0.0001) and CSII (P < 0.05) groups. Reduced incidence of hypoglycemia was observed only with SAIR (8% +/- 4% vs. 6% +/- 3%; P < 0.01). CONCLUSION: Both SAIRs, SAP and MDIs + RT-CGM, provided significant and comparable decrease of HbA1c with concurrent reduction of hypoglycemia. This improvement was greater than that seen with CSII. The combination of RT-CGM and MDIs can be a suitable alternative to SAP for some patients. PMID- 27482827 TI - Sex-Dimorphic Effects of Prenatal Treatment With Dexamethasone. AB - CONTEXT: Dexamethasone (DEX) is used to prevent virilization in female fetuses at risk of congenital adrenal hyperplasia (CAH). Given that treatment has to be started before the genotype is known, 7 out of 8 fetuses will be exposed to DEX without benefit. OBJECTIVE: To evaluate long-term cognitive effects of prenatal DEX therapy in healthy (non-CAH) DEX-treated children. DESIGN AND SETTING: Observational study with patient and control groups from a single research institute. PARTICIPANTS: Healthy (non-CAH) DEX-treated subjects (n = 34) and untreated population controls (n = 66) from Sweden, aged 7-17 years. INTERVENTION: DEX-treatment used in unborn children at risk of CAH, during first trimester of fetal life. MAIN OUTCOME MEASURES: Standardized neuropsychological tests and questionnaires were used. RESULTS: DEX treatment has widespread negative effects in girls. In Wechsler Intelligence Scales for Children-III scale subtests, we observed significant interactions between DEX and GENDER (coding, P = .044; block design, P = .013; vocabulary, P = .025) and a trend for the subtest digit span (P = .074). All interactions were driven by DEX effects in girls, but not boys, with DEX-treated females showing lower scores than female untreated controls (coding, P = .068, d = 0.66; block design, P = .021, d = 0.81; vocabulary, P = .014, d = 0.84; digit span, P = .001, d = 1.0). Likewise, DEX treated girls tend to have poorer visual spatial working memory performance than controls (span board test forward: P = .065, d = .80). We observed no effects on long-term memory, handedness, speed of processing, nor self-perceived or parentally reported scholastic performance. CONCLUSIONS: Early prenatal DEX exposure affects cognitive functions in healthy girls, ie, children who do not benefit from the treatment. It can therefore not be considered safe to use this therapy in the context of CAH. PMID- 27482828 TI - Methylene Blue Facilitates Memory Retention in Zebrafish in a Dose-Dependent Manner. AB - Methylene blue (MB) is an FDA-grandfathered drug with memory-enhancing effects at low doses, but opposite effects at high doses. We investigated the effects of four MB doses (0.1, 0.5, 5.0, or 10.0 MUM) on zebrafish memory retention in the T maze task. After training fish to swim into a certain arm of the T-maze, the fish were placed into a tank containing one of the four MB doses or a control tank containing blue food dye. Subsequently, fish were placed into the T-maze for memory retention testing. Results indicated that MB produced hormetic dose response effects on memory. Fish that received the 0.5 MUM dose performed significantly better at the T-maze than those that received higher doses. Fish who received 5.0 MUM did not exhibit a significant difference in performance from control fish, and the fish that received the 10.0 MUM dose performed significantly worse than lower doses. These findings support the utility of zebrafish in comparative research and their potential value for testing of MB and other neuropsychopharmacological treatments in animal models of memory disorders. PMID- 27482829 TI - Enterovirus Exposure Uniquely Discriminates Type 1 Diabetes Patients with a Homozygous from a Heterozygous Melanoma Differentiation-Associated Protein 5/Interferon Induced with Helicase C Domain 1 A946T Genotype. AB - In children at risk for type 1 diabetes, innate immune activity is detected before seroconversion. Enterovirus infections have been linked to diabetes development, and a polymorphism (A946T) in the innate immune sensor recognizing enterovirus RNA, interferon-induced with helicase C domain 1/melanoma differentiation-associated protein 5, predisposes to disease. We hypothesized that the strength of innate antienteroviral responses is affected in autoimmune type 1 diabetes patients and linked to the A946T polymorphism. We compared induction of interferon-stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in healthy individuals and diabetes patients upon stimulation with enterovirus, enterovirus-antibody complexes, or ligands mimicking infection in relation to the A946T polymorphism. Overall, PBMCs of diabetes patients and healthy donors showed comparable ISG induction upon stimulation. No differences were observed in DCs. Interestingly, the data imply that the magnitude of responses to enterovirus and enterovirus-antibody complexes in PBMCs is critically influenced by the A946T polymorphism and elevated in heterozygotes compared to TT homozygous individuals in autoimmune diabetes patients, but not healthy controls. These data imply an intrinsic difference in the responses to enterovirus and enterovirus-antibody complexes in diabetes patients carrying a TT risk genotype compared to heterozygotes that may influence control of enterovirus clearance. PMID- 27482830 TI - Intravenous Immunoglobulin as Potential Adjunct Therapy for Interstitial Lung Disease. AB - Intravenous Ig (IVIg) is a pooled plasma product consisting primarily of monomeric IgG. For the past several decades, the use of IVIg has expanded to include the treatment of various autoimmune and inflammatory disorders, including Kawasaki's disease, antineutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosis, and the inflammatory myopathies. IVIg is thought to exert its immunomodulatory effects through a variety of mechanisms: neutralization of pathogenic autoantibodies; alteration of immune cell effector function; suppression of cytokine and chemokine activity; and interference with complement activation. Interstitial lung disease (ILD) is a frequent complication of autoimmune disorders and connective tissue diseases, and the presence of ILD is associated with significant morbidity and mortality. Although there are currently no large studies to support the use of IVIg in the treatment of ILD, it is being used off-label with increasing frequency for refractory cases that have failed to respond to standard immunosuppression. Although associated with less systemic toxicity and global immunosuppression than traditional agents, IVIg is much more costly. Therefore, although the routine use of IVIg to treat ILD is not currently recommended, future studies to determine its role in pulmonary disease are warranted. PMID- 27482832 TI - Procedures for Analysis of Dried Plasma Using Microsampling Devices to Detect Sulfur Mustard-Albumin Adducts for Verification of Poisoning. AB - Incorporation of the chemical warfare agent sulfur mustard (SM) produces a covalent adduct with human serum albumin (HSA) representing an established plasma biomarker of poisoning. Bioanalytical verification requires both plasma generation from whole blood and shipping to specialized laboratories following strict guidelines for complex packaging. These needs often push the infrastructural boundary in crisis regions and war zones. Therefore, we herein originally introduce different reliable bioanalytical procedures using filter paper as well as novel volumetric microsampling tools (Mitra devices and Noviplex DUO cards) to generate dried plasma samples not liable to the shipping constraints. In addition, the Noviplex device enables in-transit separation of plasma from whole blood without the need of a centrifuge. Plasma-loaded and dried devices were subjected to pronase treatment yielding the alkylated dipeptide hydroxyethylthioethyl-CysPro (HETE-CP) derived from the HSA-SM adduct that was detected by microbore liquid chromatography-electrospray ionization tandem-mass spectrometry (MULC-ESI MS/MS). For all devices, samples exposed to SM yielded excellent linearity (0.025-50 MUM SM) and good precision (<=13%) and fulfilled forensic quality criteria for ion ratios of qualifying and quantifying product ions. Stability of the HSA-SM adduct in dried and liquid plasma is shown under conditions of three climatic zones (temperate climate, hot and dry climate, and hot and humid climate) for at least 9 days simulating the period of delayed sample shipping. Our results originally document that dried plasma is appropriate for storage and shipping at ambient temperature and that novel microsampling tools are of essential benefit when targeting the HSA-SM adduct for verification analysis. PMID- 27482833 TI - Low Friction Droplet Transportation on a Substrate with a Selective Leidenfrost Effect. AB - An energy saving Leidenfrost levitation method is introduced to transport microdroplets with virtually frictionless contact between the liquid and solid substrate. Through microengineering of the heating units, selective areas of the whole substrate can be electrothermally activated. A droplet can be levitated as a result of the Leidenfrost effect and further transported when the substrate is tilted slightly. Selective electroheating produces a uniform temperature distribution on the heating units within 1 s in response to a triggering voltage. Alongside these experimental observations, finite element simulations were conducted to understand the role of substrate thermal conductivity on the temperature profile of the selectively heated substrate. We also generated phase diagrams to verify the Leidenfrost regime for different substrate materials. Finally, we demonstrated the possibility of controlling low friction high speed droplet transportation (~65 mm/s) when the substrate is tilted (~7 degrees ) by structurally designing the substrate. This work establishes the basis for an entirely new approach to droplet microfluidics. PMID- 27482834 TI - Electronic Structure and Multicatalytic Features of Redox-Active Bis(arylimino)acenaphthene (BIAN)-Derived Ruthenium Complexes. AB - The article examines the newly designed and structurally characterized redox active BIAN-derived [Ru(trpy)(R-BIAN)Cl]ClO4 ([1a]ClO4-[1c]ClO4), [Ru(trpy)(R BIAN)(H2O)](ClO4)2 ([3a](ClO4)2-[3c](ClO4)2), and BIAO-derived [Ru(trpy)(BIAO)Cl]ClO4 ([2a]ClO4) (trpy = 2,2':6',2''-terpyridine, R-BIAN = bis(arylimino)acenaphthene (R = H (1a(+), 3a(2+)), 4-OMe (1b(+), 3b(2+)), 4-NO2 (1c(+), 3c(2+)), BIAO = [N-(phenyl)imino]acenapthenone). The experimental (X-ray, (1)H NMR, spectroelectrochemistry, EPR) and DFT/TD-DFT calculations of 1a(n) 1c(n) or 2a(n) collectively establish {Ru(II)-BIAN(0)} or {Ru(II)-BIAO(0)} configuration in the native state, metal-based oxidation to {Ru(III)-BIAN(0)} or {Ru(III)-BIAO(0)}, and successive electron uptake processes by the alpha-diimine fragment, followed by trpy and naphthalene pi-system of BIAN or BIAO, respectively. The impact of the electron-withdrawing NO2 function in the BIAN moiety in 1c(+) has been reflected in the five nearby reduction steps within the accessible potential limit of -2 V versus SCE, leading to a fully reduced BIAN(4 ) state in [1c](4-). The aqua derivatives ({Ru(II)-OH2}, 3a(2+)-3c(2+)) undergo simultaneous 2e(-)/2H(+) transfer to the corresponding {Ru(IV)?O} state and the catalytic current associated with the Ru(IV)/Ru(V) response probably implies its involvement in the electrocatalytic water oxidation. The aqua derivatives (3a(2+) 3c(2+)) are efficient and selective precatalysts in transforming a wide variety of alkenes to corresponding epoxides in the presence of PhI(OAc)2 as an oxidant in CH2Cl2 at 298 K as well as oxidation of primary, secondary, and heterocyclic alcohols with a large substrate scope with H2O2 as the stoichiometric oxidant in CH3CN at 343 K. The involvement of the {Ru(IV)?O} intermediate as the active catalyst in both the oxidation processes has been ascertained via a sequence of experimental evidence. PMID- 27482835 TI - Visible Light Mediated Photoredox Catalytic Arylation Reactions. AB - Introducing aryl- and heteroaryl moieties into molecular scaffolds are often key steps in the syntheses of natural products, drugs, or functional materials. A variety of cross-coupling methods have been well established, mainly using transition metal mediated reactions between prefunctionalized substrates and arenes or C-H arylations with functionalization in only one coupling partner. Although highly developed, one drawback of the established sp2-sp2 arylations is the required transition metal catalyst, often in combination with specific ligands and additives. Therefore, photoredox mediated arylation methods have been developed as alternative over the past decade. We begin our survey with visible light photo-Meerwein arylation reactions, which allow C-H arylation of heteroarenes, enones, alkenes, and alkynes with organic dyes, such as eosin Y, as the photocatalyst. A good number of examples from different groups illustrate the broad application of the reaction in synthetic transformations. While initially only photo-Meerwein arylation-elimination processes were reported, the reaction was later extended to photo-Meerwein arylation-addition reactions giving access to the photoinduced three component synthesis of amides and esters from alkenes, aryl diazonium salts, nitriles or formamides, respectively. Other substrates with redox-active leaving groups have been explored in photocatalyzed arylation reactions, such as diaryliodonium and triarylsulfonium salts, and arylsulfonyl chlorides. We discus some examples with their scope and limitations. The scope of arylation reagents for photoredox reactions was extended to aryl halides. The challenge here is the extremely negative reduction potential of aryl halides in the initial electron transfer step compared to, e.g., aryl diazonium or diaryliodonium salts. In order to reach reduction potentials over -2.0 V vs SCE two consecutive photoinduced electron transfer steps were used. The intermediary formed colored radical anion of the organic dye perylenediimide is excited by a second photon allowing the one electron reduction of acceptor substituted aryl chlorides. The radical anion of the aryl halide fragments under the loss of a halide ion and the aryl radical undergoes C-H arylation with biologically important pyrrole derivatives or adds to a double bond. Rhodamine 6G as an organic photocatalyst allows an even higher degree of control of the reaction. The dye is photoreduced in the presence of an amine donor under irradiation with green light (e.g., 530 nm), yielding its radical anion, which is a mild reducing reagent. The hypsochromic shift of the absorption of the rhodamine 6G radical anion toward blue region of the visible light spectrum allows its selective excitation using blue light (e.g., 455 nm). The excited radical anion is highly reducing and able to activate even bromoanisole for C-H arylation reactions, although only in moderate yield. Photoredox catalytic C-H arylation reactions are valuable alternatives to metal catalyzed reactions. They have an excellent functional group tolerance, could potentially avoid metal containing catalysts, and use visible light as a traceless reagent for the activation of arylating reagents. PMID- 27482836 TI - The Effect of Protein Electrostatic Interactions on Globular Protein-Polymer Block Copolymer Self-Assembly. AB - Mutation of a superfolder green fluorescent protein (GFP) was used to design GFP variants with formal net charges of 0, -8, and -21, providing a set of three proteins in which the total charge is varied to tune protein-protein interactions while controlling for the protein size and tertiary structure. After conjugating poly(N-isopropylacrylamide) (PNIPAM) to each of these three GFP variants, the concentrated solution phase behavior of these three block copolymers is studied using a combination of small-angle X-ray scattering (SAXS), depolarized light scattering (DPLS), and turbidimetry to characterize their morphologies. The electrostatic repulsion between supercharged GFP suppresses ordering, increasing the order-disorder transition concentration (CODT) and decreasing the quality of the ordered nanostructures as measured by the full width at half-maximum of the primary scattering peak. By contrast, the charge distribution of the neutrally charged GFP results in its largest dipole moment, calculated about the protein's center of mass, among the three GFP variants and a self-complementary Janus-like electrostatic surface potential that enhances nanostructure formation. The different electrostatic properties result in different protein-protein interactions that affect the high temperature morphologies, including the formation of macrophase separated or homogeneous micellar phases and the smaller hexagonal ordering window of the supercharged GFP. Small improvements in the quality of the ordered nanostructures of GFP(-21)-PNIPAM can be achieved through protein-divalent cation interactions. Therefore, varying protein charge and electrostatics is demonstrated as a method of tuning the magnitude and directionality of protein-protein interactions to control self-assembly. PMID- 27482837 TI - Guanylate cyclase stimulators for pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension is a condition of complex aetiology that culminates in right heart failure and early death. Soluble guanylate cyclase (sGC) stimulators are a promising class of agents that have recently gained approval for use. OBJECTIVES: To evaluate the efficacy of sGC stimulators in pulmonary hypertension. SEARCH METHODS: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and the reference lists of articles. Searches are current as of 12 February 2016. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) involving participants with pulmonary hypertension of all ages, severities and durations of treatment. DATA COLLECTION AND ANALYSIS: AW, MS and RW independently selected studies, assessed evidence quality and extracted data. This process was overseen by RT and SG. All included studies were sponsored by the drug manufacturer. MAIN RESULTS: Five trials involving 962 participants are included in this review. All trials were of relatively short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype.Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI -44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improved 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not available for pooling. Importantly, when participants receiving phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80).Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD -2.77 mmHg, 95% CI -4.96 to -0.58; participants = 744; studies = 5). There was no significant difference in serious adverse events on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD -3.50, 95% CI -5.54 to -1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1).It is important to consider the results for PAH in the context of a person who is not also receiving a phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only.Evidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis. AUTHORS' CONCLUSIONS: sGC stimulators improve pulmonary artery pressures in people with PAH (who are treatment naive or receiving a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieved without notable complication. However, sGC stimulators should not be taken by people also receiving phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no evidence supporting their use in pulmonary hypertension associated with left heart disease. There is no evidence supporting their use in children. These conclusions are based on data with limitations, including unavailable data from two of the trials. PMID- 27482838 TI - Sponge Phases and Nanoparticle Dispersions in Aqueous Mixtures of Mono- and Diglycerides. AB - The lipid liquid crystalline sponge phase (L3) has the advantages that it is a nanoscopically bicontinuous bilayer network able to accommodate large amounts of water and it is easy to manipulate due to its fluidity. This paper reports on the detailed characterization of L3 phases with water channels large enough to encapsulate bioactive macromolecules such as proteins. The aqueous phase behavior of a novel lipid mixture system, consisting of diglycerol monooleate (DGMO), and a mixture of mono-, di- and triglycerides (Capmul GMO-50) was studied. In addition, sponge-like nanoparticles (NPs) stabilized by Polysorbate 80 (P80) were prepared based on the DGMO/GMO-50 system, and their structure was correlated with the phase behavior of the corresponding bulk system. These NPs were characterized by dynamic light scattering (DLS), cryo-transmission electron microscopy (Cryo TEM) and small angle X-ray scattering (SAXS) to determine their size, shape, and inner structure as a function of the DGMO/GMO-50 ratio. In addition, the effect of P80 as stabilizer was investigated. We found that the NPs have aqueous pores with diameters up to 13 nm, similar to the ones in the bulk phase. PMID- 27482840 TI - Light induced catalytic intramolecular hydrofunctionalization of allylphenols mediated by porphyrin rhodium(iii) complexes. AB - Catalytic intramolecular hydrofunctionalization of allylphenols to heterocyclic compounds mediated by rhodium(iii) porphyrin complexes was described. The Wacker type intermediate beta-heterocyclic alkyl rhodium complex was independently synthesized and crystallized. PMID- 27482841 TI - Synthesis of Functionalized Azacalix[1]arene[3]pyridine Macrocycles from Cu(II) Mediated Direct Amination Reactions of Arene through High Valent Arylcopper(III) Intermediates. AB - Mediated by Cu(ClO4)2 in the presence of K3PO4 under mild conditions, azacalix[1]arene[3]pyridines underwent arene C-H bond amination with a number of sulfonamides, imides, and saccharin to afford the diverse C-N bond forming products. Based on different reactivity between arylcopper(II) and arylcopper(III) compounds toward nitrogen nucleophiles, the reaction proceeded most likely through arene C-H bond metalation via reactive arylcopper(III) intermediates and their binding to nitrogen anions which were derived from deprotonation of acidic N-H bonds of nitrogen nucleophiles of pKa (DMSO) < 17.5 followed by reductive elimination. The study not only provides a convenient and straightforward access to functionalized heteracalixaromatics that are not readily obtained by other means but also enriches our understanding of high valent organocopper chemistry. PMID- 27482842 TI - Compatibilization of All-Conjugated Polymer Blends for Organic Photovoltaics. AB - Compatibilization of an immiscible binary blend comprising a conjugated electron donor and a conjugated electron acceptor polymer with suitable electronic properties upon addition of a block copolymer (BCP) composed of the same building blocks is demonstrated. Efficient compatibilization during melt-annealing is feasible when the two polymers are immiscible in the melt, i.e. above the melting point of ~250 degrees C of the semicrystalline donor polymer P3HT. To generate immiscibility at these high temperatures, the acceptor polymer PCDTBT is equipped with fluorinated side chains leading to an increased Flory-Huggins interaction parameter. Compatibilization in bulk and thin films is demonstrated, showing that the photovoltaic performance of pristine microphase separated and nanostructured BCPs can also be obtained for compatibilized blend films containing low contents of 10-20 wt % BCP. Thermodynamically stable domain sizes range between several tens of microns for pure blends and ~10 nm for pure block copolymers. In addition to controlling domain size, the amount of block copolymer added dictates the ratio of edge-on and face-on P3HT crystals, with compatibilized films showing an increasing amount of face-on P3HT crystals with increasing amount of compatibilizer. This study demonstrates the prerequisites and benefits of compatibilizing all-conjugated semicrystalline polymer blends for organic photovoltaics. PMID- 27482839 TI - Cationic microRNA-delivering nanocarriers for efficient treatment of colon carcinoma in xenograft model. AB - Manipulation of tumor microRNAs (miRNAs) may offer novel avenues for treatment of cancer. However, development of safe, robust, non-viral delivery methods remains a main challenge to obtain the promise of gene therapy. The miR-145 is dysregulated in many cancers, including colon carcer, and further in vitro investigation established antiproliferative and proapoptotic roles of miR-145. Herein, we study a PLGA/PEI (poly (d, l-lactide-co-glycolide)/polyethylenimine) mediated miRNA vector delivery system; the validation of the method was carried out using a colon cancer xenograft model with miR-145 vector encoding for the expression of miR-145 (pDNA). First, high-molecular-weight PEI (25000 Da) was conjugated with cetyl to formulate reducible cetylated PEI (PEI-cet), and then PEI-cet was introduced to PLGA suspension. Next, PLGA/PEI-cet was crosslinked with hyaluronic acid (HA) to facilitate cellular uptake of miRNA plasmid vector via HA receptor-mediated endocytosis. After local administration of PLGA/PEI/HA complexes, intact miRNA plasmid vectors were delivered into HCT-116 colon cancer cells and xenograft tumor-bearing mice, and significant antitumor effects were achieved. The results show that the HA-based miR-145 nanocarrier could efficiently facilitate cellular uptake and significantly enhance miR-145 expression in HCT-116 cells. Consequently, the increased miR-145 induced G1 cell cycle arrest, reduced tumor proliferation and increased apoptosis, inhibited HCT 116 cell migration and suppressed c-MYC expressions, a regulatory target of miR 145. Of particular importance is the significant decrease in tumor growth in the mice model of colon cancer with the targeting miR-145 delivery system. The results in this work show that miR-145 has been effectively delivered to colon carcinomas through a PLGA/PEI/HA vehicle, indicating a promising miRNA replacement therapy strategy. PMID- 27482843 TI - Omics Studies of the Murine Intestinal Ecosystem Exposed to Subchronic and Mild Social Defeat Stress. AB - The microbiota-gut-brain axis plays an important role in the development of stress-induced mental disorders. We previously established the subchronic and mild social defeat stress (sCSDS) model, a murine experimental model of depression, and investigated the metabolomic profiles of plasma and liver. Here we used omics approaches to identify stress-induced changes in the gastrointestinal tract. Mice exposed to sCSDS for 10 days showed the following changes: (1) elevation of cholic acid and reduction of 5-aminovaleric acid among cecal metabolites; (2) downregulation of genes involved in the immune response in the terminal ileum; (3) a shift in the diversity of the microbiota in cecal contents and feces; and (4) fluctuations in the concentrations of cecal metabolites produced by gut microbiota reflected in plasma and hepatic metabolites. Operational taxonomic units within the family Lachnospiraceae showed an inverse correlation with certain metabolites. The social interaction score correlated with cecal metabolites, IgA, and cecal and fecal microbiota, suggesting that sCSDS suppressed the ileal immune response, altering the balance of microbiota, which together with host cells and host enzymes resulted in a pattern of accumulated metabolites in the intestinal ecosystem distinct from that of control mice. PMID- 27482844 TI - OH Radical Reaction Rate Coefficients, Infrared Spectrum, and Global Warming Potential of (CF3)2CFCH?CHF (HFO-1438ezy(E)). AB - Rate coefficients, k(T), for the OH radical + (E)-(CF3)2CFCH?CHF ((E)-1,3,4,4,4 pentafluoro-3-(trifluoromethyl)-1-butene, HFO-1438ezy(E)) gas-phase reaction were measured using pulsed laser photolysis-laser-induced fluorescence (PLP-LIF) between 214 and 380 K and 50 and 450 Torr (He or N2 bath gas) and with a relative rate method at 296 K between 100 and 400 Torr (synthetic air). Over the range of pressures included in this study, no pressure dependence in k(T) was observed. k(296 K) obtained using the two techniques agreed to within ~3% with (3.26 +/- 0.26) * 10(-13) cm(3) molecule(-1) s(-1) (2sigma absolute uncertainty) obtained using the PLP-LIF technique. k(T) displayed non-Arrhenius behavior that is reproduced by (7.34 +/- 0.30) * 10(-19)T(2) exp[(481 +/- 10)/T) cm(3) molecule( 1) s(-1). With respect to OH reactive loss, the atmospheric lifetime of HFO 1438ezy(E) is estimated to be ~36 days and HFO-1438ezy(E) is considered a very short-lived substance (VSLS) (the actual lifetime will depend on the time and location of the HFO-1438ezy(E) emission). On the basis of the HFO-1438ezy(E) infrared absorption spectrum measured in this work and its estimated lifetime, a radiative efficiency of 0.306 W m(-2) ppb(-1) (well-mixed gas) was calculated and its 100-year time-horizon global warming potential, GWP100, was estimated to be 8.6. CF3CFO, HC(O)F, and CF2O were identified using infrared spectroscopy as stable end products in the oxidation of HFO-1438ezy(E) in the presence of O2. Two additional fluorinated products were observed and theoretical calculations of the infrared spectra of likely degradation products are presented. The photochemical ozone creation potential of HFO-1438ezy(E) was estimated to be ~2.15. PMID- 27482845 TI - The Application of Positive Psychotherapy in Mental Health Care: A Systematic Review. AB - OBJECTIVE: Positive psychotherapy (PPT) stems from the positive psychology movement and is a multicomponent model promoting therapeutic change by developing engagement, pleasure, and meaning. There is some evidence it is effective for depression. PPT is recommended as a flexible model that can be applied to other patient groups alongside other treatments approaches. However, it remains unclear which of the many components are applied. The study aimed to identify how PPT is applied in mental health care. METHOD: We systematically searched online databases, including Medline, Embase, PsycINFO, British Nursing Index, Cumulative Index of Nursing and Applied Health, and Cochrane registers (CENTRAL), and completed complementary hand and citation searches. Narrative synthesis was used for analysis. RESULTS: A total of 12 papers (from 9 studies) widely applied some PPT components (e.g., blessings journal, character strengths) and scarcely applied others (e.g., satisficing plan or family strengths tree). However, papers poorly described the intervention and rationale for applying components. CONCLUSION: Given the lack of rationale for applying PPT, further research is needed to establish which components are acceptable and feasible for use in different patient groups and settings. PMID- 27482846 TI - The (in)complete organelle genome: exploring the use and nonuse of available technologies for characterizing mitochondrial and plastid chromosomes. AB - Not long ago, scientists paid dearly in time, money and skill for every nucleotide that they sequenced. Today, DNA sequencing technologies epitomize the slogan 'faster, easier, cheaper and more', and in many ways, sequencing an entire genome has become routine, even for the smallest laboratory groups. This is especially true for mitochondrial and plastid genomes. Given their relatively small sizes and high copy numbers per cell, organelle DNAs are currently among the most highly sequenced kind of chromosome. But accurately characterizing an organelle genome and the information it encodes can require much more than DNA sequencing and bioinformatics analyses. Organelle genomes can be surprisingly complex and can exhibit convoluted and unconventional modes of gene expression. Unravelling this complexity can demand a wide assortment of experiments, from pulsed-field gel electrophoresis to Southern and Northern blots to RNA analyses. Here, we show that it is exactly these types of 'complementary' analyses that are often lacking from contemporary organelle genome papers, particularly short 'genome announcement' articles. Consequently, crucial and interesting features of organelle chromosomes are going undescribed, which could ultimately lead to a poor understanding and even a misrepresentation of these genomes and the genes they express. High-throughput sequencing and bioinformatics have made it easy to sequence and assemble entire chromosomes, but they should not be used as a substitute for or at the expense of other types of genomic characterization methods. PMID- 27482847 TI - Ultrafast Relaxation Dynamics of Photoexcited Zinc-Porphyrin: Electronic Vibrational Coupling. AB - Cyclic tetrapyrroles are the active core of compounds with crucial roles in living systems, such as hemoglobin and chlorophyll, and in technology as photocatalysts and light absorbers for solar energy conversion. Zinc tetraphenylporphyrin (Zn-TPP) is a prototypical cyclic tetrapyrrole that has been intensely studied in past decades. Because of its importance for photochemical processes the optical properties are of particular interest, and, accordingly, numerous studies have focused on light absorption and excited-state dynamics of Zn-TPP. Relaxation after photoexcitation in the Soret band involves internal conversion that is preceded by an ultrafast process. This relaxation process has been observed by several groups. Hitherto, it has not been established if it involves a higher lying "dark" state or vibrational relaxation in the excited S2 state. Here we combine high time resolution electronic and vibrational spectroscopy to show that this process constitutes vibrational relaxation in the anharmonic S2 potential. PMID- 27482849 TI - Modulation by Amino Acids: Toward Superior Control in the Synthesis of Zirconium Metal-Organic Frameworks. AB - The synthesis of zirconium metal-organic frameworks (Zr MOFs) modulated by various amino acids, including l-proline, glycine, and l-phenylalanine, is shown to be a straightforward approach toward functional-group incorporation and particle-size control. High yields in Zr-MOF synthesis are achieved by employing 5 equivalents of the modulator at 120 degrees C. At lower temperatures, the method provides a series of Zr MOFs with increased particle size, including many suitable for single-crystal X-ray diffraction studies. Furthermore, amino acid modulators can be incorporated at defect sites in Zr MOFs with an amino acid/ligand ratio of up to 1:1, depending on the ligand structure and reaction conditions. The MOFs obtained through amino acid modulation exhibit an improved CO2 -capture capacity relative to nonfunctionalized materials. PMID- 27482848 TI - The impact of mechanical compression on cortical microtubules in Arabidopsis: a quantitative pipeline. AB - Exogenous mechanical perturbations on living tissues are commonly used to investigate whether cell effectors can respond to mechanical cues. However, in most of these experiments, the applied mechanical stress and/or the biological response are described only qualitatively. We developed a quantitative pipeline based on microindentation and image analysis to investigate the impact of a controlled and prolonged compression on microtubule behaviour in the Arabidopsis shoot apical meristem, using microtubule fluorescent marker lines. We found that a compressive stress, in the order of magnitude of turgor pressure, induced apparent microtubule bundling. Importantly, that response could be reversed several hours after the release of compression. Next, we tested the contribution of microtubule severing to compression-induced bundling: microtubule bundling seemed less pronounced in the katanin mutant, in which microtubule severing is dramatically reduced. Conversely, some microtubule bundles could still be observed 16 h after the release of compression in the spiral2 mutant, in which severing rate is instead increased. To quantify the impact of mechanical stress on anisotropy and orientation of microtubule arrays, we used the nematic tensor based FibrilTool ImageJ/Fiji plugin. To assess the degree of apparent bundling of the network, we developed several methods, some of which were borrowed from geostatistics. The final microtubule bundling response could notably be related to tissue growth velocity that was recorded by the indenter during compression. Because both input and output are quantified, this pipeline is an initial step towards correlating more precisely the cytoskeleton response to mechanical stress in living tissues. PMID- 27482850 TI - Giant lamellar bodies associated with adenocarcinoma of the lung. PMID- 27482851 TI - Ligand Design for Luminescent Lanthanide-Containing Metallopolymers. AB - The isolation of emissive materials with lanthanide ions is a topic of interest for imaging, display, and sensing applications, and it requires tuning of the electronics of the systems, such that, during the process of sensitization of the metal-centered luminescence, energy transfer from the sensitizer to the lanthanide ion is efficient and the resulting materials have the characteristics required for a given application. We discuss here our group's work in controlling the singlet- and triplet-state energies of sensitizing ligands through the choice of functional groups on the pyridine rings chelating to the lanthanide ions and show how we achieved progressively higher emission efficiencies. We describe targeted functionalization that led to highly emissive systems in solution and in the solid state and to new metallopolymers with norbornene or dicyclopentadiene based backbones and pyridinebis(oxazoline) pendants, which display red EuIII based, green TbIII-based, and, for the first time, blue TmIII-based emission. PMID- 27482852 TI - Asymmetric Construction of 2,3-Dihydroisoxazoles via an Organocatalytic Formal [3 + 2] Cycloaddition of Enynes with N-Hydroxylamines. AB - An organocatalytic asymmetric formal [3 + 2] cycloaddition of enynones with N hydroxylamines has been described. A newly designed multifunctional organocatalyst was found to be highly effective, and the method allowed the synthesis of a variety of 2,3-dihydroisoxazoles in good yields with excellent enantioselectivity. PMID- 27482853 TI - Reply. PMID- 27482855 TI - Design of a high-bandwidth tripod scanner for high speed atomic force microscopy. AB - Tip-scanning high-speed atomic force microscopes (HS-AFMs) have several advantages over their sample-scanning counterparts. Firstly, they can be used on samples of almost arbitrary size since the high imaging bandwidth of the system is immune to the added mass of the sample and its holder. Depending on their layouts, they also enable the use of several tip-scanning HS-AFMs in combination. However, the need for tracking the cantilever with the readout laser makes designing tip-scanning HS-AFMs difficult. This often results in a reduced resonance frequency of the HS-AFM scanner, or a complex and large set of precision flexures. Here, we present a compact, simple HS-AFM designed for integrating the self-sensing cantilever into the tip-scanning configuration, so that the difficulty of tracking small cantilever by laser beam is avoided. The position of cantilever is placed to the end of whole structure, hence making the optical viewing of the cantilever possible. As the core component of proposed system, a high bandwidth tripod scanner is designed, with a scan size of 5.8 um * 5.8 um and a vertical travel range of 5.9 um. The hysteresis of the piezoactuators in X- and Y-axes are linearized using input shaping technique. To reduce in-plane crosstalk and vibration-related dynamics, we implement both filters and compensators on a field programmable analog array. Based on these, images with 512 * 256 pixels are successfully obtained at scan rates up to 1024 lines/s, corresponding to a 4 mm/stip velocity. SCANNING 38:889-900, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27482854 TI - Validation of Standardized Questionnaires Evaluating Symptoms of Depression in Rheumatoid Arthritis Patients: Approaches to Screening for a Frequent Yet Underrated Challenge. AB - OBJECTIVE: To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Asberg Depression Rating Scale (MADRS), a standardized structured interview. METHODS: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 +/- 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard. RESULTS: According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (rho > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (rho < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (rho >= 0.70) was the BDI-II (rs = 0.77), which also achieved the best results for both sensitivity and specificity (>80%) when using the MADRS as the gold standard. CONCLUSION: The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity. PMID- 27482856 TI - Strain diversity and host specificity in a specialized gut symbiont of honeybees and bumblebees. AB - Host-restricted lineages of gut bacteria often include many closely related strains, but this fine-scale diversity is rarely investigated. The specialized gut symbiont Snodgrassella alvi has codiversified with honeybees (Apis mellifera) and bumblebees (Bombus) for millions of years. Snodgrassella alvi strains are nearly identical for 16S rRNA gene sequences but have distinct gene repertoires potentially affecting host biology and community interactions. We examined S. alvi strain diversity within and between hosts using deep sequencing both of a single-copy coding gene (minD) and of the V4 region of the 16S rRNA gene. We sampled workers from domestic and feral A. mellifera colonies and wild-caught Bombus representing 14 species. Conventional analyses of community profiles, based on the V4 region of the 16S rRNA gene, failed to expose most strain variation. In contrast, the minD analysis revealed extensive strain variation within and between host species and individuals. Snodgrassella alvi strain diversity is significantly higher in A. mellifera than in Bombus, supporting the hypothesis that colony founding by swarms of workers enables retention of more diversity than colony founding by a single queen. Most Bombus individuals (72%) are dominated by a single S. alvi strain, whereas most A. mellifera (86%) possess multiple strains. No S. alvi strains are shared between A. mellifera and Bombus, indicating some host specificity. Among Bombus-restricted strains, some are restricted to a single host species or subgenus, while others occur in multiple subgenera. Findings demonstrate that strains diversify both within and between host species and can be highly specific or relatively generalized in their host associations. PMID- 27482857 TI - Acidic Ultrafine Tungsten Oxide Molecular Wires for Cellulosic Biomass Conversion. AB - The application of nanocatalysis based on metal oxides for biomass conversion is of considerable interest in fundamental research and practical applications. New acidic transition-metal oxide molecular wires were synthesized for the conversion of cellulosic biomass. The ultrafine molecular wires were constructed by repeating (NH4 )2 [XW6 O21 ] (X=Te or Se) along the length, exhibiting diameters of only 1.2 nm. The nanowires dispersed in water and were observed using high angle annular dark-field scanning transmission electron microscopy. Acid sites were created by calcination without collapse of the molecular wire structure. The acidic molecular wire exhibited high activity and stability and promoted the hydrolysis of the glycosidic bond. Various biomasses including cellulose were able to be converted to hexoses as main products. PMID- 27482858 TI - 3-Bromo-2-Pyrone: An Alternative and Convenient Route to Functionalized Phosphinines. AB - The facile access to 3-bromo-2-pyrone allows the preparation of 6-bromo-2 trimethylsilyl-phosphinine by a [4+2] cycloaddition with Me3 Si-C=P for the first time. The regioselectivity of this reaction could be verified by means of single crystal X-ray diffraction of the corresponding W(0) complex. In the presence of ZnBr2 and dppp (1,3-bis(diphenylphosphino)propane) as a bidentate ligand, the bromo-phosphinine quantitatively undergoes a Negishi cross-coupling reaction with PhLi that selectively leads to 6-phenyl-2-trimethylsilyl-phosphinine. This heterocycle could again be characterized by means of X-ray diffraction as a W(0) complex. These results describe a new and convenient route to 2,6-disubstituted phosphinines that makes use of readily available starting materials. PMID- 27482859 TI - Structural Proof for the First Dianion of a Polychloride: Investigation of [Cl8 ](2.). AB - The polychloride salt [CCl(NMe2 )2 ](+) 2 [Cl8 ](2-) was synthesized and crystallized in the ionic liquid [BMP]OTf. The compound was fully characterized by Raman spectroscopy as well as X-ray single-crystal structure determination, and represents the first example of a polychloride dianion to be described. Detailed gas-phase and solid-state calculations concerning the nature of the bonding situation were also performed. PMID- 27482860 TI - Evaluation of the Allelopathic Potential of Leaf, Stem, and Root Extracts of Ocotea pulchella Nees et Mart. AB - Despite the increase in recent decades in herbicide research on the potential of native plants, current knowledge is considered to be low. Very few studies have been carried out on the chemical profile or the biological activity of the Brazilian savanna (Cerrado) species. In the study reported here, the allelopathic activity of AcOEt and MeOH extracts of leaves, stems, and roots from Ocotea pulchella Nees was evaluated. The extracts were assayed on etiolated wheat coleoptiles. The AcOEt leaf extract was the most active and this was tested on standard target species (STS). Lycopersicon esculentum and Lactuca sativa were the most sensitive species in this test. A total of eleven compounds have been isolated and characterized. Compounds 1, 2, 4, and 6 have not been identified previously from O. pulchella and ocoteol (9) is reported for the first time in the literature. Eight compounds were tested on wheat coleoptile growth, and spathulenol, benzyl salicylate, and benzyl benzoate showed the highest activities. These compounds showed inhibitory activity on L. esculentum. The values obtained correspond to the activity exhibited by the extract and these compounds may therefore be responsible for the allelopathic activity shown by O. pulchella. PMID- 27482861 TI - Analysis of cytokine gene polymorphisms in Mestizo and native populations from Mexico. AB - OBJECTIVES: To determine whether the well-known genetic structure of the Mexican population observed with other multiallelic markers can be detected by analyzing functional polymorphisms of cytokine and other inflammatory-response-related genes. METHODS: A total of 834 Mestizo individuals from five Mexican cities and 92 Lacandonians - an Amerindian group from southeastern Mexico - were genotyped for 14 polymorphisms in the CRP, IL10, IL6, TGFB1, TNFA, LTA, ICAM1 IFNG, and IL1RN genes. Allele and haplotype frequencies were used for genetic structure analysis using F-statistics pairwise distances and multidimensional scaling plot. Ancestry analysis was performed, as well. RESULTS: Significant interpopulational differences at the allele and haplotype frequency level were observed, mainly between Northern (Guadalajara, Monterrey, and Culiacan) and Southern (Tierra Blanca and Puebla) Mexican populations. Also, low but significant substructure was detected between some populations from these two broad regions. Interestingly, both Lacandonian populations were highly differentiated from each other and with respect to Mestizos. Consistent with previous data, Amerindian ancestry in the Southern Mexican groups was higher compared to Northern ones. CONCLUSIONS: The Mexican population exhibits regional differences in functional polymorphisms of inflammatory-response genes, as observed for other genetic markers. This information constitutes a reference for epidemiological studies that include these genetic markers to assess the susceptibility of the Mexican population to several immune-response-related diseases, such as diabetes, obesity, and renal disease, which have been shown to be common in the Mexican population but with prevalence differences within this country. PMID- 27482863 TI - Cardiovascular Disease Risk in Psoriatic Arthritis-Common Soil Due to Proinflammatory State and Autoimmune Activation: Comment on the Article by Polachek et al. PMID- 27482862 TI - Brief Report: Synovial Fluid White Blood Cell Count in Knee Osteoarthritis: Association With Structural Findings and Treatment Response. AB - OBJECTIVE: Osteoarthritis (OA) is a disease with a significant inflammatory component. The aim of this analysis was to determine the relationship between synovial fluid (SF) white blood cell (WBC) count and 2 parameters: disease severity and the reduction in knee pain after intraarticular (IA) steroid injection. METHODS: Subjects with painful knee OA were recruited for participation in an open-label study of IA steroid therapy. Information was obtained about knee pain using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, and a proportion of subjects underwent magnetic resonance imaging (MRI). Prior to injection with 80 mg methylprednisolone acetate, the index knee joint was aspirated and the fluid obtained was forwarded for assessment of SF WBC count. RESULTS: Information on SF WBC count was available for 55 subjects. An increase in WBC count category (<=100, 101-250, and 251-1,000 cells/mm3 ) was associated with an increase in synovial tissue volume (P = 0.028) and with other MRI-based measures of disease severity. Also, with each increase in SF WBC count category, there was a greater reduction in KOOS score after steroid injection (for WBC count of <=100 cells/mm3 [referent], mean +/- SD 12.5 +/- 15.2; for WBC count of 101-250 cells/mm3 , mean +/- SD 21.3 +/- 20.6 [beta coefficient 0.279, P = 0.049]; for WBC count of 251-1,000 cells/mm3 , mean +/- SD 29.3 +/- 15.2 [beta coefficient 0.320, P = 0.024]). CONCLUSION: Although all participants in the analysis had SF WBC counts within the "normal" range, total SF WBC count appears to be a biomarker for synovitis on MRI and may also predict response to antiinflammatory treatment. PMID- 27482864 TI - Effects of neonatal treatment with two phytoestrogens on male rat sexual behavior and partner preference. AB - The aim of this work was to compare the effect of neonatal treatment with the phytoestrogens coumestrol (COU) and genistein (GEN), administered in equimolecular doses, on the sexual behavior and partner preference of male rats. Four groups of male rats were injected daily from day 1 to 5 with 150 ug of GEN, an equivalent amount of COU, 1 ug of beta-estradiol 3-benzoato (EB), or olive oil (VEH) (control). A fifth group remained intact. In the GEN group, intromission and ejaculation latencies decreased, whereas ejaculatory frequency increased. Contrasting results were observed in COU males. EB males could not ejaculate and their mount and intromission latencies increased significantly. To determine sexual-partner preferences, a multiple partner preference arena was used and two types of tests were performed, the first one without allowing contact test (CT) with the stimulus animals, followed by a CT. COU and GEN groups did not show preference for any stimulus animal, whereas the EB males preferred the expert male. When CT with the stimulus animals was allowed, GEN-males preferred the receptive female, unlike the COU and EB groups. It is concluded that neonatal treatment with COU and GEN induced opposite effects, the effects of COU being more estrogenic. PMID- 27482865 TI - Can We Detect Chronic Pancreatitis With Low Serum Pancreatic Enzyme Levels? AB - OBJECTIVES: The aims of this study were to evaluate whether serum pancreatic enzyme levels could be used to aid screening for chronic pancreatitis (CP). METHODS: 170 healthy volunteers were screened and prospectively enrolled in the control group. 150 patients who were diagnosed with calcific CP were enrolled in the patient group by retrospective review. Serum amylase and lipase levels were compared between the 2 groups. RESULTS: The mean values +/- SD of the control group were compared with those of the patient group for serum amylase level (48.1 +/- 13.2 vs 34.8 +/- 17.2 U/L, P < 0.001) and serum lipase level (26.4 +/- 11.3 vs 16.3 +/- 11.2 U/L, P < 0.001). On the receiver operating characteristic curve analysis for amylase level, area under the curve was 0.740 (95% confidence interval), and sensitivity and specificity were 38.7% and 94.1%, respectively, with a cutoff value of 27.5 U/L. On the receiver operating characteristic curve analysis for lipase level, area under the curve was 0.748 (95% confidence interval), and sensitivity and specificity were 33.3% and 95.9%, respectively, with a cutoff value of 10.5 U/L. CONCLUSIONS: Our results suggest that low serum pancreatic enzyme levels can be used to aid in detection of CP. PMID- 27482866 TI - Molsidomine Attenuates Ventricular Electrical Remodeling and Arrhythmogenesis in Rats With Chronic beta-Adrenergic Receptor Activation Through the NO/cGMP/PKG Pathway. AB - This study investigated the effects and associated underlying mechanisms of molsidomine, a nitric oxide (NO) donor, on cardiac electrical remodeling and ventricular tachycardias (VTs) induced by chronic isoprenaline (ISO) stimulation in rats. The rats were randomly divided into groups that were treated with saline (control group), ISO (ISO group), ISO + molsidomine (ISO + M group), and ISO + molsidomine + the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one (ODQ, ISO + M + O group) for 14 days. An electrophysiological study was performed to assess cardiac repolarization, action potential duration restitution, and the induction of action potential duration alternans and VTs in vitro. The properties of the Ca transients, Ca handling-related proteins, and NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway were examined. Compared with the control group, chronic ISO stimulation prolonged the cardiac repolarization, decreased the Ca transient alternans and action potential duration alternans thresholds, and increased the maximum slope (Smax) of the action potential duration restitution curve and incidence of VTs in vitro. All these effects were attenuated by molsidomine treatment (P < 0.05). Moreover, molsidomine activated cGMP/PKG signaling and stabilized the expression of calcium handling-related proteins compared with the ISO group. However, the protective effects of molsidomine were partially inhibited by ODQ. Our results suggest that molsidomine stabilizes calcium handling and attenuates cardiac electrical remodeling and arrhythmogenesis in rats with chronic beta-adrenergic receptor activation. These effects are at least partially mediated by the activation of NO/cGMP/PKG pathway. PMID- 27482867 TI - Evidence of Delocalization in Charge-Transfer State Manifold for Donor:Acceptor Organic Photovoltaics. AB - How charge-transfer states (CTSs) assist charge separation of a Coulombically bound exciton in organic photovoltaics has been a hot topic. It is believed that the delocalization feature of a CTS plays a crucial role in the charge separation process. However, the delocalization of the "hot" and the "relaxed" CTSs is still under debate. Here, with a novel frequency dependent charge-modulated electroabsorption spectroscopy (CMEAS) technique, we elucidate clearly that both "hot" and "relaxed" CTSs are loosely bound and delocalized states. This is confirmed by comparing the CMEAS results of CTSs with those of localized polaron states. Our results reveal the role of CTS delocalization on charge separation and indicate that no substantial delocalization gradient exists in CTSs. PMID- 27482868 TI - Parallel beta-Sheet Structure of Alanine Tetrapeptide in the Solid State As Studied by Solid-State NMR Spectroscopy. AB - The structural analysis of alanine oligopeptides is important for understanding the crystalline region in silks from spiders and wild silkworms and also the mechanism of cellular toxicity of human diseases arising from expansion in polyalanine sequences. The atomic-level structures of alanine tripeptide and tetrapeptide with antiparallel beta-sheet structures (AP-Ala3 and AP-Ala4, respectively) together with alanine tripeptide with parallel beta-sheet structures (P-Ala3) have been determined, but alanine tetrapeptide with a parallel beta-sheet structure (P-Ala4) has not been reported yet. In this article, first, we established the preparation protocol of P-Ala4 from more stable AP-Ala4. Second, complete assignments of the (13)C, (15)N, and (1)H solid state NMR spectra were performed with (13)C- and (15)N-labeled Ala4 samples using several solid-state NMR techniques. Then, the structural constraints were obtained, for example, the amide proton peaks of P-Ala4 in the (1)H double quantum magic-angle spinning NMR spectrum were heavily overlapped and observed at about 7.4 ppm, which was a much higher field than that of 8.7-9.1 ppm observed for AP-Ala4, indicating that the intermolecular hydrogen-bond lengths across strands (N-H...O?C) were considerably longer for P-Ala4, that is, 2.21-2.34 A, than those reported for AP-Ala4, that is, 1.8-1.9 A. The structural model was proposed for P-Ala4 by NMR results and MD calculations. PMID- 27482869 TI - Voices: A Conversation with Allen J. Wilcox. AB - Allen James Wilcox was born on 30 September 1946 in Columbus, OH. He studied medicine at the University of Michigan, graduated in 1973, and after a rotating internship, he completed a master's degree in maternal and child health (1976) and a PhD in epidemiology (1979) at the University of North Carolina in Chapel Hill. After graduation, he went to work at the National Institute of Environmental Health Sciences (NIEHS, one of the US National Institutes of Health) in Durham, NC, where he has spent his career. He developed a research program in reproductive and perinatal epidemiology, a relatively unexplored area at the time. His studies include the early pregnancy study, which documented the extent of subclinical pregnancy loss in humans and established the fertile days of a woman's menstrual cycle. He served as the Chief of the Epidemiology Branch from 1991 to 2001, and as Editor-in-Chief of the journal EPIDEMIOLOGY from 2001 to 2014. His textbook, Fertility and Pregnancy-An Epidemiologic Perspective, was published by Oxford University Press in 2010. He was elected to the American Epidemiological Society in 1989, and served as its president in 2003. He also served as president of the Society of Pediatric and Perinatal Epidemiological Research (1996) and the president of the Society of Epidemiological Research (1998). He holds adjunct teaching appointments at the University of North Carolina, Harvard University, and the University of Bergen (Norway), which awarded him an honorary doctoral degree in 2008. PMID- 27482870 TI - Patient Safety and Workplace Bullying: An Integrative Review. AB - Workplace bullying is strongly associated with negative nursing outcomes, such as work dissatisfaction, turnover, and intent to leave; however, results of studies examining associations with specific patient safety outcomes are limited or nonspecific. This integrative review explores and synthesizes the published articles that address the impact of workplace nurse bullying on patient safety. PMID- 27482871 TI - Nurses' Perceptions of Quality Care. AB - Limited research has been conducted on how nurses define or perceive "quality nursing care." We conducted focus groups to identify nurses' perceptions of quality care at a Midwestern academic medical center. Transcripts of the focus group sessions were analyzed using thematic analysis techniques, and 11 themes emerged: Leadership, Staffing, Resources, Timeliness, Effective Communication/Collaboration, Professionalism, Relationship-Based Care, Environment/Culture, Simplicity, Outcomes, and Patient Experience. PMID- 27482872 TI - Exploring Safety Culture in Jordanian Hospitals: A Baseline Study. AB - Medical error is a serious issue in hospitals in Jordan. This study explored Jordanian nurses' perceptions of the culture of safety in their hospitals. The Hospital Survey of Patient Safety Culture translated into Arabic was administered to a convenience sample of 391 nurses from 7 hospitals in Jordan. The positive responses to the 12 dimensions of safety culture ranged from 20.0% to 74.6%. These are lower than the benchmarks of the Agency for Healthcare Research and Quality. Jordanian nurses perceive their hospitals as places that need more effort to improve the safety culture. PMID- 27482874 TI - Use of Daily Interruption of Sedation and Early Mobility in US Hospitals. AB - Although the Awakening and Breathing Coordination, Delirium assessment, and Early exercise/mobility (ABCDE) bundle may be effective, individual components of ABCDE may not be implemented as intended. We examined the use of daily interruption of sedation (DIS) and early mobility, looking for an association between these bundle elements. Despite the growing use of DIS and early mobility, the two do not seem to be adopted together, with serious implications for the effectiveness of the ABCDE bundle. PMID- 27482873 TI - The Baptist Health High-Risk Falls Assessment: One Assessment Fits All. AB - Assessing high risk for falling among psychiatric inpatients is particularly challenging in that assessments with strong sensitivity and specificity are not available. The purpose of this study was to determine the sensitivity, specificity, and diagnostic odds ratio of the Baptist Health High Risk Falls Assessment (BHHRFA), a medical-surgical fall risk assessment, in a psychiatric inpatient population. Data collected on 5910 psychiatric inpatients using the BHHRFA showed acceptable sensitivity, specificity, and diagnostic odds ratio (0.68/0.70/4.964). PMID- 27482875 TI - Validity of the Johns Hopkins Fall Risk Assessment Tool for Predicting Falls on Inpatient Medicine Services. AB - The Johns Hopkins Fall Risk Assessment Tool (JHFRAT) is widely used but few studies have examined its psychometric properties. We examined the predictive validity of the JHFRAT for 13 574 patient admissions to medicine units at a large academic medical center in 2014. There were 204 patient falls reported. While patients who fell had higher JHFRAT total scores, a majority of patients who fell were classified by the JHFRAT as moderate or low risk. PMID- 27482876 TI - Growth of ordered molecular layers of PTCDA on Pb/Si(111) surfaces: a scanning tunneling microscopy study. AB - The growth of well-ordered layers of PTCDA (3,4,9,10-perylene-tetracarboxylic dianhydride) molecules on Pb/Si(111) surfaces has been investigated by scanning tunneling microscopy (STM) under ultra-high vacuum conditions. These Pb/Si(111) substrates, which present several distinct phases with different reconstructions, have allowed the exploration of new passivation schemes for the growth of ordered organic layers on Si(111) surfaces. According to our STM measurements, the higher Pb coverage phases (namely the so-called hexagonal incommensurate and [Formula: see text] reconstructions) present rather inert surfaces that allow easy diffusion of PTCDA molecules at room temperature and the formation of a well ordered first molecular layer which displays a herringbone reconstruction. For multilayer PTCDA coverage on these Pb/Si(111) phases, the formation of three dimensional crystallites, with structure similar to that of the bulk PTCDA crystal, has been observed, indicating that a Stranski-Krastanov growth mode is dominant. On lower Pb coverage substrates (presenting the defective [Formula: see text] and mosaic [Formula: see text] reconstructions) no long range PTCDA order has been obtained. The systematic variation of the substrate reconstruction has allowed in the present work the relation of the surface reactivity of each reconstruction to the formation of ordered layers of PTCDA on Pb/Si(111) substrates. PMID- 27482877 TI - Is the use of antidepressants associated with patient-reported outcomes following total hip replacement surgery? AB - Background and purpose - Patients with anxiety and/or depression tend to report less pain reduction and less satisfaction with surgical treatment. We hypothesized that the use of antidepressants would be correlated to patient reported outcomes (PROs) 1 year after total hip replacement (THR), where increased dosage or discontinuation would be associated with worse outcomes. Patients and methods - THR cases with pre- and postoperative patient-reported outcome measures (PROMs) were selected from the Swedish Hip Arthroplasty Register (n = 9,092; women: n = 5,106). The PROMs were EQ-5D, visual analog scale (VAS) for pain, Charnley class, and VAS for satisfaction after surgery. These cases were merged with a national database of prescription purchases to determine the prevalence of antidepressant purchases. Regression analyses were performed where PROs were dependent variables and sex, age, Charnley class, preoperative pain, preoperative health-related quality of life (HRQoL), patient-reported anxiety/depression, and antidepressant use were independent variables. Results - Antidepressants were used by 10% of the cases (n = 943). Patients using antidepressants had poorer HRQoL and higher levels of pain before and after surgery and they experienced less satisfaction. Preoperative antidepressant use was independently associated with PROs 1 year after THR regardless of patient reported anxiety/depression. Interpretation - Antidepressant usage before surgery was associated with reduced PROs after THR. Cases at risk of poorer outcomes may be identified through review of the patient's medical record. Clinicians are encouraged to screen for antidepressant use preoperatively, because their use may be associated with PROs after THR. PMID- 27482878 TI - Segmentation of facial bone surfaces by patch growing from cone beam CT volumes. AB - OBJECTIVES: The motivation behind this work was to design an automatic algorithm capable of segmenting the exterior of the dental and facial bones including the mandible, teeth, maxilla and zygomatic bone with an open surface (a surface with a boundary) from CBCT images for the anatomy-based reconstruction of radiographs. Such an algorithm would provide speed, consistency and improved image quality for clinical workflows, for example, in planning of implants. METHODS: We used CBCT images from two studies: first to develop (n = 19) and then to test (n = 30) a segmentation pipeline. The pipeline operates by parameterizing the topology and shape of the target, searching for potential points on the facial bone-soft tissue edge, reconstructing a triangular mesh by growing patches on from the edge points with good contrast and regularizing the result with a surface polynomial. This process is repeated for convergence. RESULTS: The output of the algorithm was benchmarked against a hand-drawn reference and reached a 0.50 +/- 1.0-mm average and 1.1-mm root mean squares error in Euclidean distance from the reference to our automatically segmented surface. These results were achieved with images affected by inhomogeneity, noise and metal artefacts that are typical for dental CBCT. CONCLUSIONS: Previously, this level of accuracy and precision in dental CBCT has been reported in segmenting only the mandible, a much easier target. The segmentation results were consistent throughout the data set and the pipeline was found fast enough (<1-min average computation time) to be considered for clinical use. PMID- 27482879 TI - A Biosecurity Survey in Kenya, November 2014 to February 2015. AB - A biosecurity survey was performed to gather information on the biosecurity level and laboratory capacity in Kenya for the purpose of providing information outlining relevant components for biosecurity legislation, biosecurity implementation, and enforcement of biosecurity measures in Kenya. This survey is, to the authors' knowledge, the first to be published from an African country. A total of 86 facilities with laboratories covering relevant categories, such as training laboratories, human diagnostic laboratories, veterinary diagnostic laboratories, and research laboratories, were selected to participate in the survey. Each facility was visited by a survey team and staff were asked to answer 29 groups of questions from a questionnaire. The survey showed that Kenyan laboratory facilities contain biological agents of biosecurity concern. The restrictions for these agents were found to be limited for several of the facilities, in that many laboratory facilities and storage units were open for access by either students or staff who had no need of access to the laboratory. The survey showed a great deal of confusion in the terms biosecurity and biosafety and a generally limited biosecurity awareness among laboratory personnel. The survey showed that the security of biological agents of biosecurity concern in many facilities does not meet the international requirements. The authors recommend developing a legal framework in Kenya for effective controls, including national biosecurity regulations, guidelines, and procedures, thereby reducing the risk that a Kenyan laboratory would be the source of a future biological attack. PMID- 27482880 TI - Biocidal and Sporicidal Efficacy of Pathoster((r)) 0.35% and Pathoster((r)) 0.50% Against Bacterial Agents in Potential Bioterrorism Use. AB - The use of products that can neutralize or significantly reduce the microbial load and that are not harmful to human health and the environment represents a milestone in the fight against the spread of infectious diseases. Peracetic acid, besides being an excellent sterilizing and sporicidal agent, is harmless to humans and the environment when it is used in a common dosage. However, the high costs and loss of efficacy of the product very quickly after its reconstitution limit its use. We evaluated the efficacy and stability of 2 commercial products, based on stabilized peracetic acid (Pathoster((r)) 0.35% and Pathoster((r)) 0.50%) used against spores of Bacillus anthracis and spores of Bacillus cereus and vegetative forms of Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis, Brucella abortus, and Brucella melitensis. The efficacy tests were based on the direct contact of the products with a standard suspension of the bacteria. The stability of the products was defined as the period of time during which the biocidal and sporicidal properties remained unchanged. The limit of effectiveness was the period after which the product was unable to exert a complete sterilization after a contact of 5 minutes with at least 1 of the 8 bacteria used in this work. Both formulations showed good efficacy against the microorganisms used in the study, confirming the utility of peracetic acid as a sterilizing product. After the reconstitution, Pathoster((r)) 0.35% was stable until 16+/-1 days, while Pathoster((r)) 0.50% was stable until 24+/-1 days. The formulations used in this study showed good performance and a significant stability of peracetic acid. PMID- 27482881 TI - A Role for Science in Responding to Health Crises. AB - The Department of Homeland Security's (DHS) Science and Technology (S&T) Directorate plays a role in public health that extends beyond biodefense. These responsibilities were exercised as part of the 2014-16 Ebola outbreak, leading to productive and beneficial contributions to the international public health response and improved operations in the United States. However, we and others have identified numerous areas for improvement. Based on our successes and lessons learned, we propose a number of ways that DHS, the interagency, and academia can act now to ensure improved responses to future public health crises. These include pre-developing scientific capabilities to respond agnostically to threats, and disease-specific master question lists to organize and inform initial efforts. We are generating DHS-specific playbooks and tools for anticipating future needs and capturing requests from DHS components and our national and international partners, where efforts will also be used to refine and exercise communication and information-sharing practices. These experiences and improvement efforts have encouraged discussions on the role of science in developing government policy, specifically responding to public health crises. We propose specific considerations for both scientists and government decision makers to ensure that the best available science is incorporated into policy and operational decisions to facilitate highly effective responses to future health crises. PMID- 27482882 TI - Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis. AB - ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol accumulation and alters T cell homeostasis, which may contribute to progression of atherosclerosis. Here, we investigated how the selective loss of ABCG1 in T cells impacts atherosclerosis in LDL receptor-deficient (LDLR-deficient) mice, a model of the disease. In LDLR-deficient mice fed a high-cholesterol diet, T cell specific ABCG1 deficiency protected against atherosclerotic lesions. Furthermore, T cell-specific ABCG1 deficiency led to a 30% increase in Treg percentages in aorta and aorta-draining lymph nodes (LNs) of these mice compared with animals with only LDLR deficiency. When Abcg1 was selectively deleted in Tregs of LDLR deficient mice, we observed a 30% increase in Treg percentages in aorta and aorta draining LNs and reduced atherosclerosis. In the absence of ABCG1, intracellular cholesterol accumulation led to downregulation of the mTOR pathway, which increased the differentiation of naive CD4 T cells into Tregs. The increase in Tregs resulted in reduced T cell activation and increased IL-10 production by T cells. Last, we found that higher ABCG1 expression in Tregs was associated with a higher frequency of these cells in human blood samples. Our study indicates that ABCG1 regulates T cell differentiation into Tregs, highlighting a pathway by which cholesterol accumulation can influence T cell homeostasis in atherosclerosis. PMID- 27482883 TI - The impact of hypoxia on tumor-associated macrophages. AB - The role of tumor-associated macrophages (TAMs) in cancer is often correlated with poor prognosis, even though this statement should be interpreted with care, as the effects of macrophages primarily depend on their localization within the tumor. This versatile cell type orchestrates a broad spectrum of biological functions and exerts very complex and even opposing functions on cell death, immune stimulation or suppression, and angiogenesis, resulting in an overall pro- or antitumoral effect. We are only beginning to understand the environmental cues that contribute to transient retention of macrophages in a specific phenotype. It has become clear that hypoxia shapes and induces specific macrophage phenotypes that serve tumor malignancy, as hypoxia promotes immune evasion, angiogenesis, tumor cell survival, and metastatic dissemination. Additionally, TAMs in the hypoxic niches within the tumor are known to mediate resistance to several anticancer treatments and to promote cancer relapse. Thus, a careful characterization and understanding of this macrophage differentiation state is needed in order to efficiently tailor cancer therapy. PMID- 27482884 TI - Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin. AB - Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1 mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases. PMID- 27482885 TI - Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development. PMID- 27482886 TI - EGFR regulates macrophage activation and function in bacterial infection. AB - EGFR signaling regulates macrophage function, but its role in bacterial infection has not been investigated. Here, we assessed the role of macrophage EGFR signaling during infection with Helicobacter pylori, a bacterial pathogen that causes persistent inflammation and gastric cancer. EGFR was phosphorylated in murine and human macrophages during H. pylori infection. In human gastric tissues, elevated levels of phosphorylated EGFR were observed throughout the histologic cascade from gastritis to carcinoma. Deleting Egfr in myeloid cells attenuated gastritis and increased H. pylori burden in infected mice. EGFR deficiency also led to a global defect in macrophage activation that was associated with decreased cytokine, chemokine, and NO production. We observed similar alterations in macrophage activation and disease phenotype in the Citrobacter rodentium model of murine infectious colitis. Mechanistically, EGFR signaling activated NF-kappaB and MAPK1/3 pathways to induce cytokine production and macrophage activation. Although deletion of Egfr had no effect on DC function, EGFR-deficient macrophages displayed impaired Th1 and Th17 adaptive immune responses to H. pylori, which contributed to decreased chronic inflammation in infected mice. Together, these results indicate that EGFR signaling is central to macrophage function in response to enteric bacterial pathogens and is a potential therapeutic target for infection-induced inflammation and associated carcinogenesis. PMID- 27482887 TI - Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma. AB - Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands. PMID- 27482888 TI - Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. AB - BACKGROUND: T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS: T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS: SB-mediated genetic transposition and stimulation resulted in 2,200 to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30 month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS: CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach. TRIAL REGISTRATION: Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow up, NCT01492036. FUNDING: National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details. PMID- 27482889 TI - Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. AB - High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the progression of diabetic kidney disease (DKD), but their contribution to organ damage in DKD remains largely unknown. Here, we investigated the function of local and systemic TNF in podocyte injury. We cultured human podocytes with sera collected from DKD patients, who displayed elevated TNF levels, and focal segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of healthy patients. Exogenous TNF administration or local TNF expression was equally sufficient to cause free cholesterol-dependent apoptosis in podocytes by acting through a dual mechanism that required a reduction in ATP-binding cassette transporter A1-mediated (ABCA1-mediated) cholesterol efflux and reduced cholesterol esterification by sterol-O-acyltransferase 1 (SOAT1). TNF-induced albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and was partially prevented by cholesterol depletion with cyclodextrin. TNF stimulated free cholesterol-dependent apoptosis in podocytes was mediated by nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or cholesterol depletion was sufficient to reduce albuminuria in mice with podocyte specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol-dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels. PMID- 27482890 TI - Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease. AB - The telomerase RNA component (TERC) is a critical determinant of cellular self renewal. Poly(A)-specific ribonuclease (PARN) is required for posttranscriptional maturation of TERC. PARN mutations lead to incomplete 3' end processing and increased destruction of nascent TERC RNA transcripts, resulting in telomerase deficiency and telomere diseases. Here, we determined that overexpression of TERC increased telomere length in PARN-deficient cells and hypothesized that decreasing posttranscriptional 3' oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domain-containing 5 (PAPD5) increased TERC levels in PARN-mutant patient cells. PAPD5 inhibition was also associated with increases in TERC stability, telomerase activity, and telomere elongation. Our results demonstrate that manipulating posttranscriptional regulatory pathways may be a potential strategy to reverse the molecular hallmarks of telomere disease. PMID- 27482892 TI - On Risk Estimation versus Risk Stratification in Early Prostate Cancer. AB - In a Perspective article, Sigrid Carlsson and Michael Kattan discuss Gnanapragasam and colleagues' accompanying research study on refining risk stratification in early prostate cancer. PMID- 27482891 TI - Longitudinal Metagenomic Analysis of Hospital Air Identifies Clinically Relevant Microbes. AB - We describe the sampling of sixty-three uncultured hospital air samples collected over a six-month period and analysis using shotgun metagenomic sequencing. Our primary goals were to determine the longitudinal metagenomic variability of this environment, identify and characterize genomes of potential pathogens and determine whether they are atypical to the hospital airborne metagenome. Air samples were collected from eight locations which included patient wards, the main lobby and outside. The resulting DNA libraries produced 972 million sequences representing 51 gigabases. Hierarchical clustering of samples by the most abundant 50 microbial orders generated three major nodes which primarily clustered by type of location. Because the indoor locations were longitudinally consistent, episodic relative increases in microbial genomic signatures related to the opportunistic pathogens Aspergillus, Penicillium and Stenotrophomonas were identified as outliers at specific locations. Further analysis of microbial reads specific for Stenotrophomonas maltophilia indicated homology to a sequenced multi drug resistant clinical strain and we observed broad sequence coverage of resistance genes. We demonstrate that a shotgun metagenomic sequencing approach can be used to characterize the resistance determinants of pathogen genomes that are uncharacteristic for an otherwise consistent hospital air microbial metagenomic profile. PMID- 27482893 TI - Not all non-drinkers with HIV are equal: demographic and clinical comparisons among current non-drinkers with and without a history of prior alcohol use disorders. AB - Studies of persons living with HIV (PLWH) have compared current non-drinkers to at-risk drinkers without differentiating whether current non-drinkers had a prior alcohol use disorder (AUD). The purpose of this study was to compare current non drinkers with and without a prior AUD on demographic and clinical characteristics to understand the impact of combining them. We included data from six sites across the US from 1/2013 to 3/2015. Patients completed tablet-based clinical assessments at routine clinic appointments using the most recent assessment. Current non-drinkers were identified by AUDIT-C scores of 0. We identified a prior probable AUD by a prior AUD diagnosis in the electronic medical record (EMR) or a report of attendance at alcohol treatment in the clinical assessment. We used multivariate logistic regression to examine factors associated with prior AUD. Among 2235 PLWH who were current non-drinkers, 36% had a prior AUD with more patients with an AUD identified by the clinical assessment than the EMR. Higher proportions with a prior AUD were male, depressed, and reported current drug use compared to non-drinkers without a prior AUD. Former cocaine/crack (70% vs. 25%), methamphetamine/crystal (49% vs. 16%), and opioid/heroin use (35% vs. 7%) were more commonly reported by those with a prior AUD. In adjusted analyses, male sex, past methamphetamine/crystal use, past marijuana use, past opioid/heroin use, past and current cocaine/crack use, and cigarette use were associated with a prior AUD. In conclusion, this study found that among non-drinking PLWH in routine clinical care, 36% had a prior AUD. We found key differences between those with and without prior AUD in demographic and clinical characteristics, including drug use and depression. These results suggest that non-drinkers are heterogeneous and need further differentiation in studies and that prior alcohol misuse (including alcohol treatment) should be included in behavioural health assessments as part of clinical care. PMID- 27482895 TI - Nomogram Incorporating CD44v6 and Clinicopathological Factors to Predict Lymph Node Metastasis for Early Gastric Cancer. AB - BACKGROUND: Treatment strategy for early gastric cancer depends on the probability of lymph node metastasis. The aim of this study is to develop a nomogram predicting lymph node metastasis in early gastric cancer using clinicopathological factors and biomarkers. METHODS: A literature review was performed to identify biomarkers related to lymph node metastasis in gastric cancer. Seven markers were selected and immunohistochemistry was performed in 336 early gastric cancer tissues. Based on the multivariable analysis, a prediction model including clinicopatholgical factors and biomarkers was developed, and benefit of adding biomarkers was evaluated using the area under the receiver operating curve and net reclassification improvement. Functional study in gastric cancer cell line was performed to evaluate mechanism of biomarker. RESULTS: Of the seven biomarkers studied, alpha1 catenin and CD44v6 were significantly associated with lymph node metastasis. A conventional prediction model, including tumor size, histological type, lymphatic blood vessel invasion, and depth of invasion, was developed. Then, a new prediction model including both clinicopathological factors and CD44v6 was developed. Net reclassification improvement analysis revealed a significant improvement of predictive performance by the addition of CD44v6, and a similar result was shown in the internal validation using bootstrapping. Prediction nomograms were then constructed based on these models. In the functional study, CD44v6 was revealed to affect cell proliferation, migration and invasion. CONCLUSIONS: Overexpression of CD44v6 was a significant predictor of lymph node metastasis in early gastric cancer. The prediction nomograms incorporating CD44v6 can be useful to determine treatment plans in patients with early gastric cancer. PMID- 27482894 TI - Integrity of Narrow Epithelial Tubes in the C. elegans Excretory System Requires a Transient Luminal Matrix. AB - Most epithelial cells secrete a glycoprotein-rich apical extracellular matrix that can have diverse but still poorly understood roles in development and physiology. Zona Pellucida (ZP) domain glycoproteins are common constituents of these matrices, and their loss in humans is associated with a number of diseases. Understanding of the functions, organization and regulation of apical matrices has been hampered by difficulties in imaging them both in vivo and ex vivo. We identified the PAN-Apple, mucin and ZP domain glycoprotein LET-653 as an early and transient apical matrix component that shapes developing epithelia in C. elegans. LET-653 has modest effects on shaping of the vulva and epidermis, but is essential to prevent lumen fragmentation in the very narrow, unicellular excretory duct tube. We were able to image the transient LET-653 matrix by both live confocal imaging and transmission electron microscopy. Structure/function and fluorescence recovery after photobleaching studies revealed that LET-653 exists in two separate luminal matrix pools, a loose fibrillar matrix in the central core of the lumen, to which it binds dynamically via its PAN domains, and an apical-membrane-associated matrix, to which it binds stably via its ZP domain. The PAN domains are both necessary and sufficient to confer a cyclic pattern of duct lumen localization that precedes each molt, while the ZP domain is required for lumen integrity. Ectopic expression of full-length LET-653, but not the PAN domains alone, could expand lumen diameter in the developing gut tube, where LET 653 is not normally expressed. Together, these data support a model in which the PAN domains regulate the ability of the LET-653 ZP domain to interact with other factors at the apical membrane, and this ZP domain interaction promotes expansion and maintenance of lumen diameter. These data identify a transient apical matrix component present prior to cuticle secretion in C. elegans, demonstrate critical roles for this matrix component in supporting lumen integrity within narrow bore tubes such as those found in the mammalian microvasculature, and reveal functional importance of the evolutionarily conserved ZP domain in this tube protecting activity. PMID- 27482897 TI - Rotavirus Strategies Against the Innate Antiviral System. AB - "Rotaviruses represent the most important etiological agents of acute, severe gastroenteritis in the young of many animal species, including humans." This statement, variations of which are a common beginning in articles about rotaviruses, reflects the fact that these viruses have evolved efficient strategies for evading the innate immune response of the host and for successfully replicating in the population. In this review, we summarize what is known about the defense mechanisms that host cells employ to prevent rotavirus invasion and the countermeasures that these viruses have successfully developed to surpass cellular defenses. Rotaviruses use at least two viral multifunctional proteins to directly interact with, and prevent the activation of, the interferon system, and they use at least one other protein to halt the protein synthesis machinery and prevent the expression of most of the transcriptional antiviral program of the cell. Characterization of the confrontation between rotaviruses and their host cells has allowed us to learn about the virus-host coevolution that prevents the damaging effects of the innate immune response. PMID- 27482896 TI - The Structural Biology of Hepatitis B Virus: Form and Function. AB - Hepatitis B virus is one of the smallest human pathogens, encoded by a 3,200-bp genome with only four open reading frames. Yet the virus shows a remarkable diversity in structural features, often with the same proteins adopting several conformations. In part, this is the parsimony of viruses, where a minimal number of proteins perform a wide variety of functions. However, a more important theme is that weak interactions between components as well as components with multiple conformations that have similar stabilities lead to a highly dynamic system. In hepatitis B virus, this is manifested as a virion where the envelope proteins have multiple structures, the envelope-capsid interaction is irregular, and the capsid is a dynamic compartment that actively participates in metabolism of the encapsidated genome and carries regulated signals for intracellular trafficking. PMID- 27482899 TI - Single-Cell Studies of Phage lambda: Hidden Treasures Under Occam's Rug. AB - Studies over more than half a century have resulted in what some consider a complete narrative for the life cycle of bacteriophage lambda. However, this narrative is only complete within the limited resolution offered by the traditional genetic and biochemical approaches that were used to create it. A recent series of studies performed at the single-cell and single-phage levels has revealed a wealth of previously unknown features. By pointing to many open questions, these new studies highlight the limitations of our current understanding of lambda, but they also initiate the process of forming a more detailed and quantitative narrative for the system. PMID- 27482898 TI - Nuclear Exodus: Herpesviruses Lead the Way. AB - Most DNA viruses replicate in the nucleus and exit it either by passing through the nuclear pores or by rupturing the nuclear envelope. Unusually, herpesviruses have evolved a complex mechanism of nuclear escape whereby nascent capsids bud at the inner nuclear membrane to form perinuclear virions that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytosol. Although this general scheme is accepted in the field, the players and their roles are still debated. Recent studies illuminated critical mechanistic features of this enigmatic process and uncovered surprising parallels with a novel cellular nuclear export process. This review summarizes our current understanding of nuclear egress in herpesviruses, examines the experimental evidence and models, and outlines outstanding questions with the goal of stimulating new research in this area. PMID- 27482901 TI - More than Meets the Eye: Hidden Structures in the Proteome. AB - A central dogma of molecular biology is that the sequence of a protein dictates its particular fold and the fold dictates its function. Indeed, the sequence -> structure -> function hypothesis has been a guiding principle by which scientists approach molecular biology. Every student knows that the genome encodes information for the progression from primary sequence to secondary, tertiary, and ultimately quaternary structure. Yet with a growing number of proteins, a fifth level has been identified: rearrangement of existing structures into distinct forms. Recent observations indicate that replication of Ebola virus depends on this fifth level. We believe other viruses with compact genomes and rapid evolution under selective pressure will be a rich source of examples of polypeptides that rearrange to gain added functions. In this review, we describe mechanisms by which viral, prokaryotic, and eukaryotic polypeptides have adopted alternate structures to control or gain function. PMID- 27482900 TI - The Discovery of Reverse Transcriptase. AB - In 1970 the independent and simultaneous discovery of reverse transcriptase in retroviruses (then RNA tumor viruses) by David Baltimore and Howard Temin revolutionized molecular biology and laid the foundations for retrovirology and cancer biology. In this historical review we describe the formulation of the controversial provirus hypothesis by Temin, which ultimately was proven by his discovery of reverse transcriptase in Rous sarcoma virus virions. Baltimore arrived at the same discovery through his studies on replication of RNA containing viruses, starting with poliovirus and then moving to vesicular stomatitis virus, where he discovered a virion RNA polymerase. Subsequent studies of reverse transcriptase led to the elucidation of the mechanism of retrovirus replication, the discovery of oncogenes, the advent of molecular cloning, the search for human cancer viruses, and the discovery and treatment of HIV/AIDS. PMID- 27482902 TI - Climate Change and the Arboviruses: Lessons from the Evolution of the Dengue and Yellow Fever Viruses. AB - The impact of anticipated changes in global climate on the arboviruses and the diseases they cause poses a significant challenge for public health. The past evolution of the dengue and yellow fever viruses provides clues about the influence of changes in climate on their future evolution. The evolution of both viruses has been influenced by virus interactions involving the mosquito species and the primate hosts involved in virus transmission, and by their domestic and sylvatic cycles. Information is needed on how viral genes in general influence phenotypic variance for important viral functions. Changes in global climate will alter the interactions of mosquito species with their primate hosts and with the viruses in domestic cycles, and greater attention should be paid to the sylvatic cycles. There is great danger for the evolution of novel viruses, such as new serotypes, that could compromise vaccination programs and jeopardize public health. It is essential to understand (a) both sylvatic and domestic cycles and (b) the role of virus genetic and environmental variances in shaping virus phenotypic variance to more fully assess the impact of global climate change. PMID- 27482903 TI - Time Trends in Prevalence of Chronic Diseases and Multimorbidity Not Only due to Aging: Data from General Practices and Health Surveys. AB - INTRODUCTION: Chronic diseases and multimorbidity are common and expected to rise over the coming years. The objective of this study is to examine the time trend in the prevalence of chronic diseases and multimorbidity over the period 2001 till 2011 in the Netherlands, and the extent to which this can be ascribed to the aging of the population. METHODS: Monitoring study, using two data sources: 1) medical records of patients listed in a nationally representative network of general practices over the period 2002-2011, and 2) national health interview surveys over the period 2001-2011. Regression models were used to study trends in the prevalence-rates over time, with and without standardization for age. RESULTS: An increase from 34.9% to 41.8% (p<0.01) in the prevalence of chronic diseases was observed in the general practice registration over the period 2004 2011 and from 41.0% to 46.6% (p<0.01) based on self-reported diseases over the period 2001-2011. Multimorbidity increased from 12.7% to 16.2% (p<0.01) and from 14.3% to 17.5% (p<0.01), respectively. Aging of the population explained part of these trends: about one-fifth based on general practice data, and one-third for chronic diseases and half of the trend for multimorbidity based on health surveys. CONCLUSIONS: The prevalence of chronic diseases and multimorbidity increased over the period 2001-2011. Aging of the population only explained part of the increase, implying that other factors such as health care and society related developments are responsible for a substantial part of this rise. PMID- 27482904 TI - Biomarkers for Diabetic Retinopathy - Could Endothelin 2 Be Part of the Answer? AB - PURPOSE: The endothelins are a family of three highly conserved and homologous vasoactive peptides that are expressed across all organ systems. Endothelin (Edn) dysregulation has been implicated in a number of pathophysiologies, including diabetes and diabetes-related complications. Here we examined Edn2 and endothelin receptor B (Endrb) expression in retinae of diabetic mouse models and measured serum Edn2 to assess its biomarker potential. MATERIALS AND METHODS: Edn2 and Ednrb mRNA and Edn2 protein expression were assessed in young (8wk) and mature (24wk) C57Bl/6 (wild type; wt), Kimba (model of retinal neovascularisation, RNV), Akita (Type 1 diabetes; T1D) and Akimba mice (T1D plus RNV) by qRT-PCR and immunohistochemistry. Edn2 protein concentration in serum was measured using ELISA. RESULTS: Fold-changes in Edn2 and Ednrb mRNA were seen only in young Kimba (Edn2: 5.3; Ednrb: 6.0) and young Akimba (Edn2: 7.9, Ednrb: 8.8) and in mature Kimba (Edn2:9.2, Ednrb:11.2) and mature Akimba (Edn2:14.0, Ednrb:17.5) mice. Co localisation of Edn2 with Muller-cell-specific glutamine synthetase demonstrated Muller cells and photoreceptors as the major cell types for Edn2 expression in all animal models. Edn2 serum concentrations in young Kimba, Akita and Akimba mice were not elevated compared to wt. However, in mature mice, Edn2 serum concentration was increased in Akimba (6.9pg/mg total serum protein) compared to wt, Kimba and Akita mice (3.9, 4.6, and 3.8pg/mg total serum protein, respectively; p<0.05). CONCLUSIONS: These results demonstrated that long-term hyperglycaemia in conjunction with VEGF-driven RNV increased Edn2 serum concentration suggesting Edn2 might be a candidate biomarker for vascular changes in diabetic retinopathy. PMID- 27482905 TI - GPU-Acceleration of Sequence Homology Searches with Database Subsequence Clustering. AB - Sequence homology searches are used in various fields and require large amounts of computation time, especially for metagenomic analysis, owing to the large number of queries and the database size. To accelerate computing analyses, graphics processing units (GPUs) are widely used as a low-cost, high-performance computing platform. Therefore, we mapped the time-consuming steps involved in GHOSTZ, which is a state-of-the-art homology search algorithm for protein sequences, onto a GPU and implemented it as GHOSTZ-GPU. In addition, we optimized memory access for GPU calculations and for communication between the CPU and GPU. As per results of the evaluation test involving metagenomic data, GHOSTZ-GPU with 12 CPU threads and 1 GPU was approximately 3.0- to 4.1-fold faster than GHOSTZ with 12 CPU threads. Moreover, GHOSTZ-GPU with 12 CPU threads and 3 GPUs was approximately 5.8- to 7.7-fold faster than GHOSTZ with 12 CPU threads. PMID- 27482908 TI - Correction: The Actin Filament-Binding Protein Coronin Regulates Motility in Plasmodium Sporozoites. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005710.]. PMID- 27482907 TI - Big Data Sensors of Organic Advocacy: The Case of Leonardo DiCaprio and Climate Change. AB - The strategies that experts have used to share information about social causes have historically been top-down, meaning the most influential messages are believed to come from planned events and campaigns. However, more people are independently engaging with social causes today than ever before, in part because online platforms allow them to instantaneously seek, create, and share information. In some cases this "organic advocacy" may rival or even eclipse top down strategies. Big data analytics make it possible to rapidly detect public engagement with social causes by analyzing the same platforms from which organic advocacy spreads. To demonstrate this claim we evaluated how Leonardo DiCaprio's 2016 Oscar acceptance speech citing climate change motivated global English language news (Bloomberg Terminal news archives), social media (Twitter postings) and information seeking (Google searches) about climate change. Despite an insignificant increase in traditional news coverage (54%; 95%CI: -144 to 247), tweets including the terms "climate change" or "global warming" reached record highs, increasing 636% (95%CI: 573-699) with more than 250,000 tweets the day DiCaprio spoke. In practical terms the "DiCaprio effect" surpassed the daily average effect of the 2015 Conference of the Parties (COP) and the Earth Day effect by a factor of 3.2 and 5.3, respectively. At the same time, Google searches for "climate change" or "global warming" increased 261% (95%CI, 186-335) and 210% (95%CI 149-272) the day DiCaprio spoke and remained higher for 4 more days, representing 104,190 and 216,490 searches. This increase was 3.8 and 4.3 times larger than the increases observed during COP's daily average or on Earth Day. Searches were closely linked to content from Dicaprio's speech (e.g., "hottest year"), as unmentioned content did not have search increases (e.g., "electric car"). Because these data are freely available in real time our analytical strategy provides substantial lead time for experts to detect and participate in organic advocacy while an issue is salient. Our study demonstrates new opportunities to detect and aid agents of change and advances our understanding of communication in the 21st century media landscape. PMID- 27482906 TI - Formation of Tankyrase Inhibitor-Induced Degradasomes Requires Proteasome Activity. AB - In canonical Wnt signaling, the protein levels of the key signaling mediator beta catenin are under tight regulation by the multimeric destruction complex that mediates proteasomal degradation of beta-catenin. In colorectal cancer, destruction complex activity is often compromised due to mutations in the multifunctional scaffolding protein Adenomatous Polyposis Coli (APC), leading to a stabilization of beta-catenin. Recently, tankyrase inhibitors (TNKSi), a novel class of small molecule inhibitors, were shown to re-establish a functional destruction complex in APC-mutant cancer cell lines by stabilizing AXIN1/2, whose protein levels are usually kept low via poly(ADP-ribosyl)ation by the tankyrase enzymes (TNKS1/2). Surprisingly, we found that for the formation of the morphological correlates of destruction complexes, called degradasomes, functional proteasomes are required. In addition we found that AXIN2 is strongly upregulated after 6 h of TNKS inhibition. The proteasome inhibitor MG132 counteracted TNKSi-induced degradasome formation and AXIN2 stabilization, and this was accompanied by reduced transcription of AXIN2. Mechanistically we could implicate the transcription factor FoxM1 in this process, which was recently shown to be a transcriptional activator of AXIN2. We observed a substantial reduction in TNKSi-induced stabilization of AXIN2 after siRNA-mediated depletion of FoxM1 and found that proteasome inhibition reduced the active (phosphorylated) fraction of FoxM1. This can explain the decreased protein levels of AXIN2 after MG132 treatment. Our findings have implications for the design of in vitro studies on the destruction complex and for clinical applications of TNKSi. PMID- 27482909 TI - Effects of Experienced Disgust on Morally-Relevant Judgments. AB - Although disgust has been implicated in moral judgments, the extent to which the influence of disgust on moral judgment is distinct from other negative affective states remains unclear. To address this gap in knowledge, participants in Study 1 were randomized to a disgust (hand submersion in imitation vomit), discomfort (hand submersion in ice water), or neutral (hand submersion in room temperature water) affect condition while moral judgments of offenses were simultaneously assessed. The results showed that participants in the discomfort condition made the most severe moral judgments, particularly for moderate offenses. To examine if disgust may have more of an effect on some moral violations than others, participants in Study 2 were randomized to similar affect inductions while judgments of purity and non-purity offenses were simultaneously assessed. The results showed that those who had their hand submerged in imitation vomit recommended harsher punishment for purity violations relative to moral violations unrelated to purity. The opposite was true for those who submerged their hands in ice water, whereas punishment ratings for purity and non-purity violations did not significantly differ for those who submerged their hands in room temperature water. The implications of these findings for further delineating the specific role of experienced disgust in moral decision-making are discussed. PMID- 27482910 TI - Trichoderma Biodiversity of Agricultural Fields in East China Reveals a Gradient Distribution of Species. AB - We surveyed the Trichoderma (Hypocreales, Ascomycota) biodiversity in agricultural fields in four major agricultural provinces of East China. Trichoderma strains were identified based on molecular approaches and morphological characteristics. In three sampled seasons (spring, summer and autumn), 2078 strains were isolated and identified to 17 known species: T. harzianum (429 isolates), T. asperellum (425), T. hamatum (397), T. virens (340), T. koningiopsis (248), T. brevicompactum (73), T. atroviride (73), T. fertile (26), T. longibrachiatum (22), T. pleuroticola (16), T. erinaceum (16), T. oblongisporum (2), T. polysporum (2), T. spirale (2), T. capillare (2), T. velutinum (2), and T. saturnisporum (1). T. harzianum, T. asperellum, T. hamatum, and T. virens were identified as the dominant species with dominance (Y) values of 0.057, 0.052, 0.048, and 0.039, respectively. The species amount, isolate numbers and the dominant species of Trichoderma varied between provinces. Zhejiang Province has shown the highest diversity, which was reflected in the highest species amount (14) and the highest Shannon-Wiener diversity index of Trichoderma haplotypes (1.46). We observed that relative frequencies of T. hamatum and T. koningiopsis under rice soil were higher than those under wheat and maize soil, indicating the preference of Trichoderma to different crops. Remarkable seasonal variation was shown, with summer exhibiting the highest biodiversity of the studied seasons. These results show that Trichoderma biodiversity in agricultural fields varies by region, crop, and season. Zhejiang Province (the southernmost province in the investigated area) had more T. hamatum than Shandong Province (the northernmost province), not only in isolate amounts but also in haplotype amounts. Furthermore, at haplotype level, only T. hamatum showed a gradient distribution from south to north in correspondence analysis among the four dominant species. The above results would contribute to the application of Trichoderma biocontrol strains. PMID- 27482911 TI - Differences in Interactions of Benzoic Acid and Benzoate with Interfaces. AB - The interaction of benzoic acid and benzoate with model membrane systems was characterized to understand the molecular interactions of the two forms of a simple aromatic acid with the components of the membrane. The microemulsion system based on bis(2-ethylhexyl)sulfosuccinate (AOT) allowed determination of the molecular positioning using 1D NMR and 2D NMR spectroscopic methods. Benzoic acid and benzoate were both found to penetrate the membrane/water interfaces; however, the benzoic acid was able to penetrate much deeper and thus is more readily able to traverse a membrane. The Langmuir monolayer model system, using dipalmitoylphosphatidylcholine, was used as a generic membrane lipid for a cell. Compression isotherms of monolayers demonstrated a pH dependent interaction with a lipid monolayer and confirming the pH dependent observations shown in the reverse micellar model system. These studies provide an explanation for the antimicrobial activity of benzoic acid while benzoate is inactive. Furthermore, these studies form the framework upon which we are investigating the mode of bacterial uptake of pyrazinoic acid, the active form of pyrazinamide, a front line drug used to combat tuberculosis. PMID- 27482917 TI - Vibrational Analysis of Lung Tumor Cell Lines: Implementation of an Invasiveness Scale Based on the Cell Infrared Signatures. AB - Assessing the tumor invasiveness is a paramount diagnostic step to improve the patients care. Infrared spectroscopy access the chemical composition of samples; and in combination with statistical multivariate processing, presents the capacity to highlight subtle molecular alterations associated with malignancy development. Our investigation demonstrated that infrared signatures of cell lines presenting various invasiveness phenotypes contain discriminant spectral features, which are useful informative signals to implement an objective invasiveness scale. This last development reflects the interest of vibrational approach as a candidate biophotonic label-free technique, usable in routine clinics, to characterize quantitatively tumor aggressiveness. In addition, the methodology can reveal the heterogeneity of cancer cells, opening the way to further researches in cancer science. PMID- 27482918 TI - The Paradox of Waiting for Heart Transplant: Between Control and Fate. AB - OBJECTIVES: Understanding a patient's perspective has received increased attention. Awaiting heart transplant remains a great challenge, not only for patients and their families but also for health professionals. This particular challenge has multiple aspects, the most important being the psychological one. Understanding candidates for heart transplant is vital for all caregivers. In this study, our aim was to present the individual's experience of awaiting heart transplant. MATERIALS AND METHODS: Structured interviews and the Pictorial Representation of Illness and Self Measure, Hospital Anxiety and Depression Scale, the Illness Cognition Questionnaire, and the Illness Perception Questionnaire-Revised measurements were performed in 2 male patients (60 and 61 years old) who were on heart transplant wait list. RESULTS: The patients expressed their concerns and perceived severe consequences of heart disease. They also demonstrated the importance of significant others and hope. The results suggest the existence of realistic cognitive pictures of the disease. The patients revealed high sense of control along with the awareness of being dependent on fate. The lack of severe anxiety and depressive symptoms along with high perceived benefits' scores suggest the existence of an adaptation process. CONCLUSIONS: Awaiting heart transplant appears to be a multidimensional phenomenon. The paradoxic configuration of a high sense of control along with the awareness of being dependent on fate was apparent. Significant others and hope seem to be of great importance. The Pictorial Representation of Illness and Self Measure allows a better understanding of a patient's perspective and allows the patient to share personal views. The individual approach provides opportunities that go far beyond routine clinical assessment. PMID- 27482919 TI - Liquid-Infused Poly(styrene-b-isobutylene-b-styrene) Microfiber Coating Prevents Bacterial Attachment and Thrombosis. AB - Infection and thrombosis associated with medical implants cause significant morbidity and mortality worldwide. As we know, current technologies to prevent infection and thrombosis may cause severe side effects. To overcome these complications without using antimicrobial and anticoagulant drugs, we attempt to prepare a liquid-infused poly(styrene-b-isobutylene-b-styrene) (SIBS) microfiber coating, which can be directly coated onto medical devices. Notably, the SIBS microfiber was fabricated through solution blow spinning. Compared to electrospinning, the solution blow spinning method is faster and less expensive, and it is easy to spray fibers onto different targets. The lubricating liquids then wick into and strongly adhere the microfiber coating. These slippery coatings can effectively suppress blood cell adhesion, reduce hemolysis, and inhibit blood coagulation in vitro. In addition, Pseudomonas aeruginosa (P. aeruginosa) on the lubricant infused coatings slides readily, and no visible residue is left after tilting. We furthermore confirm that the lubricants have no effects on bacterial growth. The slippery coatings are also not cytotoxic to L929 cells. This liquid-infused SIBS microfiber coating could reduce the infection and thrombosis of medical devices, thus benefiting human health. PMID- 27482920 TI - Zirconium(IV)-Benzene Phosphonate Coordination Polymers: Lanthanide and Actinide Extraction and Thermal Properties. AB - Coordination polymers with different P/(Zr + P) molar ratios were prepared by combining aqueous solutions of Zr(IV) and benzenephosphonate derivatives. 1,3,5 Benzenetrisphosphonic acid (BTP) as well as phosphonocarboxylate derivatives in which carboxylate substitutes one or two of the phosphonate groups were chosen as the building blocks. The precipitates obtained on combining the two solutions were not X-ray amorphous but rather were indicative of poorly ordered materials. Hydrothermal treatment did not alter the structure of the materials produced but did result in improved crystalline order. The use of HF as a mineralizing agent during hydrothermal synthesis resulted in the crystallization of at least three relatively crystalline phases whose structure could not be determined owing to the complexity of the diffraction patterns. Gauging from the similarity of the diffraction patterns of all the phases, the poorly ordered precipitates and crystalline materials appeared to have similar underlying structures. The BTP based zirconium phosphonates all showed a higher selectivity for lanthanides and thorium compared with cations such as Cs(+), Sr(2+), and Co(2+). Substitution of phosphonate groups by carboxylate groups did little to alter the pattern of selectivity implying that selectivity in the system was entirely determined by the -POH group with little influence from the -COOH groups. Samples with the highest phosphorus content showed the highest extraction efficiencies for lanthanide elements, especially the heavy lanthanides such as Dy(3+) and Ho(3+) with separation factors of around four with respect to La(3+). In highly acid solutions (4 M HNO3) there was a pronounced variation in extraction efficiency across the lanthanide series. In situ, nonambient diffraction was performed on ZrBTP-0.8 loaded with Th, Ce, and a complex mixture of lanthanides. In all cases the crystalline Zr2P2O7 pyrophosphate phase was formed at ~800 degrees C demonstrating the versatility of this structure. PMID- 27482921 TI - Subnano Pt Particles from a First-Principles Stochastic Surface Walking Global Search. AB - Subnano transition metal particles have wide applications in chemistry. For the complexity of their potential energy surface, it has long been a great challenge for both theory and experiment to determine the structure of subnano clusters and thus predict their physiochemical properties. Here we explore the structure configurations for 35 subnano PtN (N = 12-46) clusters using a first-principles Stochastic Surface Walking (SSW) global search. For each cluster, thousands of structure candidates are collected from a parallel SSW search. This leads to the finding of 20 new global minima in 35 clusters, which reflects the essence of a first-principles global search for revealing the structure of subnano transition metal clusters. PtN subnano clusters with N being 14, 18, 22, 27, 36, and 44 have higher stability than their neighboring size clusters and are characterized as magic number clusters. These PtN subnano clusters exhibit metallic characteristics with a diminishing HOMO-LUMO gap, much poorer binding energy (by 1-1.7 eV), and a much higher Fermi level (by 1-1.5 eV) than bulk metal, implying their high chemical activity. By analyzing their structures, we observe the presence of a rigid core and a soft shell for PtN clusters and find that the core shell 3-D architecture evolves as early as N > 22. For these core-shell clusters, a good core-shell lattice match is the key to achieve the high stability. PMID- 27482922 TI - National Survey of Prison Health Care: Selected Findings. AB - OBJECTIVES: This report presents selected findings on the provision of health care services in U.S. state prisons. Findings on admissions testing for infectious disease, cardiovascular risk factors, and mental health conditions, as well as the location of the provision of care and utilization of telemedicine are all included. PMID- 27482923 TI - Dynamic Interactions between a Silica Sphere and Deformable Interfaces in Organic Solvents Studied by Atomic Force Microscopy. AB - Recent studies have successfully measured surface forces using atomic force microscope (AFM) and modeled surface deformations using the Stokes-Reynolds-Young Laplace (SRYL) equations for particle-droplet, particle-bubble, droplet-droplet, and bubble-bubble systems in various solutions. The current work focuses on interactions between spherical silica particles and a viscoelastic interface of water droplets in crude oil. The self-assembly of surface active natural polyaromatic molecules (NPAMs) at the oil-water interface has previously been shown to change a viscous dominant oil-water interface to an elastic dominant interface upon aging, due to gradual formation of rigid interfacial networks. AFM was used to measure the interactions between a small silica sphere (D ~ 8 MUm) and a deformable water droplet (D ~ 70 MUm), which exhibits time-dependent interfacial viscoelasticity in NPAM solutions. Unlike the systems studied previously, the measured deformation shown as a repulsive force over the region of constant compliance could not be modeled adequately by the conventional SRYL equations which are applicable only to purely Laplacian interfaces. As the water droplet ages in NPAM solutions, a rigid "skin" forms at the oil-water interface, with the interface exhibiting increased elasticity. Over a short aging period (up to 15 min in NPAM-in-toluene solution), interfacial deformation is well predicted by the SRYL model. However, upon further exposure to the NPAM solution, droplet deformation is overpredicted by the model. Physical properties of this mechanical barrier as a function of interfacial aging were further investigated by measuring interfacial tension, dilatational rheology, and interfacial "crumpling" (non smooth, non-Laplacian interface) upon droplet volume reduction. By introducing a viscoelasticity parameter to account for interfacial stiffening and using experimentally determined elasticity, we are able to correct this discrepancy and predict droplet deformation under AFM cantilever compression. This parameter appears to be important for modeling non-Laplacian systems of significant viscoelastic contributions, such as biological cell membranes or polymer blends. PMID- 27482924 TI - Metal stressors consistently modulate bacterial conjugal plasmid uptake potential in a phylogenetically conserved manner. AB - The environmental stimulants and inhibitors of conjugal plasmid transfer in microbial communities are poorly understood. Specifically, it is not known whether exposure to stressors may cause a community to alter its plasmid uptake ability. We assessed whether metals (Cu, Cd, Ni, Zn) and one metalloid (As), at concentrations causing partial growth inhibition, modulate community permissiveness (that is, uptake ability) against a broad-host-range IncP-type plasmid (pKJK5). Cells were extracted from an agricultural soil as recipient community and a cultivation-minimal filter mating assay was conducted with an exogenous E. coli donor strain. The donor hosted a gfp-tagged pKJK5 derivative from which conjugation events could be microscopically quantified and transconjugants isolated and phylogenetically described at high resolution via FACS and 16S rRNA amplicon sequencing. Metal stress consistently decreased plasmid transfer frequencies to the community, while the transconjugal pool richness remained unaffected with OTUs belonging to 12 bacterial phyla. The taxonomic composition of the transconjugal pools was distinct from their respective recipient communities and clustered dependent on the stress type and dose. However, for certain OTUs, stress increased or decreased permissiveness by more than 1000-fold and this response was typically correlated across different metals and doses. The response to some stresses was, in addition, phylogenetically conserved. This is the first demonstration that community permissiveness is sensitive to metal(loid) stress in a manner that is both partially consistent across stressors and phylogenetically conserved. PMID- 27482925 TI - Modeling succession of key resource-harvesting traits of mixotrophic plankton. AB - Unicellular eukaryotes make up the base of the ocean food web and exist as a continuum in trophic strategy from pure heterotrophy (phagotrophic zooplankton) to pure photoautotrophy ('phytoplankton'), with a dominance of mixotrophic organisms combining both strategies. Here we formulate a trait-based model for mixotrophy with three key resource-harvesting traits: photosynthesis, phagotrophy and inorganic nutrient uptake, which predicts the trophic strategy of species throughout the seasonal cycle. Assuming that simple carbohydrates from photosynthesis fuel respiration, and feeding primarily provides building blocks for growth, the model reproduces the observed light-dependent ingestion rates and species-specific growth rates with and without prey from the laboratory. The combination of traits yielding the highest growth rate suggests high investments in photosynthesis, and inorganic nutrient uptake in the spring and increased phagotrophy during the summer, reflecting general seasonal succession patterns of temperate waters. Our trait-based model presents a simple and general approach for the inclusion of mixotrophy, succession and evolution in ecosystem models. PMID- 27482927 TI - Root microbiota dynamics of perennial Arabis alpina are dependent on soil residence time but independent of flowering time. AB - Recent field and laboratory experiments with perennial Boechera stricta and annual Arabidopsis thaliana suggest that the root microbiota influences flowering time. Here we examined in long-term time-course experiments the bacterial root microbiota of the arctic-alpine perennial Arabis alpina in natural and controlled environments by 16S rRNA gene profiling. We identified soil type and residence time of plants in soil as major determinants explaining up to 15% of root microbiota variation, whereas environmental conditions and host genotype explain maximally 11% of variation. When grown in the same soil, the root microbiota composition of perennial A. alpina is largely similar to those of its annual relatives A. thaliana and Cardamine hirsuta. Non-flowering wild-type A. alpina and flowering pep1 mutant plants assemble an essentially indistinguishable root microbiota, thereby uncoupling flowering time from plant residence time-dependent microbiota changes. This reveals the robustness of the root microbiota against the onset and perpetual flowering of A. alpina. Together with previous studies, this implies a model in which parts of the root microbiota modulate flowering time, whereas, after microbiota acquisition during vegetative growth, the established root-associated bacterial assemblage is structurally robust to perturbations caused by flowering and drastic changes in plant stature. PMID- 27482928 TI - Functional traits dominate the diversity-related selection of bacterial communities in the rhizosphere. AB - We studied the impact of community diversity on the selection of bacterial communities in the rhizosphere by comparing the composition and the functional traits of these communities in soil and rhizosphere. Differences in diversity were established by inoculating into sterilized soils diluted suspensions of the same soil. We used 16S ribosomal RNA amplicon sequencing to determine the taxonomical structure of the bacterial communities and a shotgun metagenomics approach to investigate the potential functional diversity of the communities. By comparing the bacterial communities in soil and rhizosphere, the selective power of the plant was observed both at the taxonomic and functional level, although the diversity indices of soil and rhizosphere samples showed a highly variable, irregular pattern. Lesser variation, that is, more homogenization, was found for both the taxonomic structure and the functional profile of the rhizosphere communities as compared to the communities of the bulk soil. Network analysis revealed stronger interactions among bacterial operational taxonomic units in the rhizosphere than in the soil. The enrichment processes in the rhizosphere selected microbes with particular functional genes related to transporters, the Embden-Meyerhof-Parnas pathway and hydrogen metabolism. This selection was not random across bacteria with these functional traits, but it was species specific. Overall, this suggests that functional traits are a key to the assembly of bacterial rhizosphere communities. PMID- 27482926 TI - Cold adaptation regulated by cryptic prophage excision in Shewanella oneidensis. AB - Among the environmental stresses experienced by bacteria, temperature shifts are one of the most important. In this study, we discovered a novel cold adaptation mechanism in Shewanella oneidensis that occurs at the DNA level and is regulated by cryptic prophage excision. Previous studies on bacterial cold tolerance mainly focus on the structural change of cell membrane and changes at the RNA and protein levels. Whether or not genomic change can also contribute to this process has not been explored. Here we employed a whole-genome deep-sequencing method to probe the changes at DNA level in a model psychrotrophic bacteria strain. We found that temperature downshift induced a 10 000-fold increase of the excision of a novel P4-like cryptic prophage. Importantly, although prophage excision only occurred in a relatively small population of bacteria, it was able to facilitate biofilm formation and promote the survival of the entire population. This prophage excision affected cell physiology by disrupting a critical gene encoding transfer-messenger RNA (tmRNA). In addition, we found that the histone-like nucleoid-structuring protein (H-NS) could silence prophage excision via binding to the promoter of the putative excisionase gene at warm temperatures. H-NS level was reduced at cold temperatures, leading to de-repression of prophage excision. Collectively, our results reveal that cryptic prophage excision acts as a regulatory switch to enable the survival of the host at low temperature by controlling the activity of tmRNA and biofilm formation. PMID- 27482929 TI - DeepShape: Deep-Learned Shape Descriptor for 3D Shape Retrieval. AB - Complex geometric variations of 3D models usually pose great challenges in 3D shape matching and retrieval. In this paper, we propose a novel 3D shape feature learning method to extract high-level shape features that are insensitive to geometric deformations of shapes. Our method uses a discriminative deep auto encoder to learn deformation-invariant shape features. First, a multiscale shape distribution is computed and used as input to the auto-encoder. We then impose the Fisher discrimination criterion on the neurons in the hidden layer to develop a deep discriminative auto-encoder. Finally, the outputs from the hidden layers of the discriminative auto-encoders at different scales are concatenated to form the shape descriptor. The proposed method is evaluated on four benchmark datasets that contain 3D models with large geometric variations: McGill, SHREC'10 ShapeGoogle, SHREC'14 Human and SHREC'14 Large Scale Comprehensive Retrieval Track Benchmark datasets. Experimental results on the benchmark datasets demonstrate the effectiveness of the proposed method for 3D shape retrieval. PMID- 27482930 TI - Mechanochemical synthesis of mesoporous tin oxide: a new generation nanosorbent for (68)Ge/(68)Ga generator technology. AB - The present article reports the synthesis and characterization of mesoporous tin oxide (MTO) nanoparticles by a solid-state mechanochemical route. The synthesized material was used as an advanced sorbent material for (68)Ge/(68)Ga radionuclide generator technology. Gallium-68 (t1/2 = 68 min) obtained from the (68)Ge/(68)Ga generator is an important diagnostic radioisotope which holds tremendous potential in the non-invasive monitoring of various diseases, including cancer, using positron emission tomography (PET). The crystallite size of the MTO nanoparticles was in the range of 6-12 nm with a large surface area of 265 +/- 16 m(2) g(-1), while the mean pore radius was found to be 2.1 +/- 0.6 nm. Determination of the zeta-potential of the MTO nanoparticles dispersed in solutions at different pH values aided in understanding the sorption and separation mechanisms, which were based on the surface charge developed on the nanosorbent. The sorption capacity observed under column-flow conditions was 85 +/- 5 mg Ge per g of nanosorbent. A clinical-scale (68)Ge/(68)Ga generator (740 MBq) was developed using this nanosorbent. Gallium-68 could be regularly eluted from this generator over a prolonged period of 1 year with >70% elution yield and met all the requirements for clinical use. The suitability of (68)Ga obtained from it was evaluated in preclinical settings by the preparation of a (68)Ga labeled peptide containing the arginine-glycine-aspartic acid (RGD) motif. To the best of our knowledge, this is the first report on the synthesis of MTO nanoparticles by a mechanochemical route which could be effectively utilized for the routine preparation of clinical-scale (68)Ge/(68)Ga generators. The promising results obtained in this study would facilitate greater implementation of mechanochemistry for the synthesis of nanosorbents for radionuclide generator technology since this method is simple, economical and convenient. PMID- 27482931 TI - Stereoselective Chirality Extension of syn,anti- and syn,syn-Oxazine and Stereochemical Analysis of Chiral 1,3-Oxazines: Stereoselective Total Syntheses of (+)-1-Deoxygalactonojirimycin and (-)-1-Deoxygulonojirimycin. AB - This paper describes the stereoselective total syntheses of (+)-1 deoxygalactonojirimycin and (-)-1-deoxygulonojirimycin via new chiral building blocks syn,anti,syn-oxazine 11a and syn,syn,anti-oxazine 13a. These were accomplished in four steps in 44.1 and 33.7% overall yields, respectively. These chirons were derived from the stereoselective addition of a nucleophile to the corresponding aldehydes of syn,anti-oxazine 10 and syn,syn-oxazine 12. Furthermore, this paper describes the stereochemical analysis of three types of chiral 1,3-oxazines; anti,syn-, syn,anti-, and syn,syn-oxazines using the NOESY technique. PMID- 27482932 TI - Directed Self-Assembly of Triblock Copolymer on Chemical Patterns for Sub-10-nm Nanofabrication via Solvent Annealing. AB - Directed self-assembly (DSA) of block copolymers (BCPs) is a leading strategy to pattern at sublithographic resolution in the technology roadmap for semiconductors and is the only known solution to fabricate nanoimprint templates for the production of bit pattern media. While great progress has been made to implement block copolymer lithography with features in the range of 10-20 nm, patterning solutions below 10 nm are still not mature. Many BCP systems self assemble at this length scale, but challenges remain in simultaneously tuning the interfacial energy atop the film to control the orientation of BCP domains, designing materials, templates, and processes for ultra-high-density DSA, and establishing a robust pattern transfer strategy. Among the various solutions to achieve domains that are perpendicular to the substrate, solvent annealing is advantageous because it is a versatile method that can be applied to a diversity of materials. Here we report a DSA process based on chemical contrast templates and solvent annealing to fabricate 8 nm features on a 16 nm pitch. To make this possible, a number of innovations were brought in concert with a common platform: (1) assembling the BCP in the phase-separated, solvated state, (2) identifying a larger process window for solvated triblock vs diblock BCPs as a function of solvent volume fraction, (3) employing templates for sub-10-nm BCP systems accessible by lithography, and (4) integrating a robust pattern transfer strategy by vapor infiltration of organometallic precursors for selective metal oxide synthesis to prepare an inorganic hard mask. PMID- 27482933 TI - Understanding Thermodynamic and Spectroscopic Properties of Tetragonal Mn12 Single-Molecule Magnets from Combined Density Functional Theory/Spin-Hamiltonian Calculations. AB - We apply broken-symmetry density functional theory to determine isotropic exchange-coupling constants and local zero-field splitting (ZFS) tensors for the tetragonal Mn12(t)BuAc single-molecule magnet. The obtained parametrization of the many-spin Hamiltonian (MSH), taking into account all 12 spin centers, is assessed by comparing theoretical predictions for thermodynamic and spectroscopic properties with available experimental data. The magnetic susceptibility (calculated by the finite-temperature Lanczos method) is well approximated, and the intermultiplet excitation spectrum from inelastic neutron scattering (INS) experiments is correctly reproduced. In these respects, the present parametrization of the 12-spin model represents a significant improvement over previous theoretical estimates of exchange-coupling constants in Mn12, and additionally offers a refined interpretation of INS spectra. Treating anisotropic interactions at the third order of perturbation theory, the MSH is mapped onto the giant-spin Hamiltonian describing the S = 10 ground multiplet. Although the agreement with high-field EPR experiments is not perfect, the results clearly point in the right direction and for the first time rationalize the angular dependence of the transverse-field spectra from a fully microscopic viewpoint. Importantly, transverse anisotropy of the effective S = 10 manifold is explicitly shown to arise largely from the ZFS-induced mixing of exchange multiplets. This effect is given a thorough analysis in the approximate D2d spin-permutational symmetry group of the exchange Hamiltonian. PMID- 27482934 TI - User-independent EBSD parameters to study the progress of recovery and recrystallization in Cu-Zn alloy during in situ heating. AB - Microstructural evolution of cold-rolled Cu-5%Zn alloy during in situ heating inside field-emission scanning electron microscope was utilized to obtain user independent parameters in order to trace the progress of static recovery and recrystallization. Electron back-scattered diffraction (EBSD)-based orientation imaging microscopy was used to obtain micrographs at various stages of in situ heating. It is shown that unlike the pre-existing methods, additional EBSD-based parameter can be used to trace the progress of recovery and recrystallization, which is not dependent on user input and hence less prone to error. True strain of 0.3 was imposed during cold rolling of alloy sample. Rolled sample was subjected to in situ heating from room temperature to 500 degrees C (~0.58 Tm) with soaking time of 10 min, at each of the intermediate temperatures viz. 100, 200, 300, 400 and 450 degrees C. After reaching 500 degrees C, the sample was kept at this temperature for a maximum duration of around 15 h. The sample showed clear signs of recovery for temperature up to 450 degrees C, and at 500 degrees C, recrystallization started to take place. Recrystallization kinetics was moderate, and full recrystallization was achieved in approximately 120 min. We found that EBSD parameter, namely, band contrast intensity can be used as an extra handle to map out the progress of recrystallization occurring in the sample. By contrast, mean angular deviation can be used to understand the evolution of recovery in samples. The parameters mentioned in the current study, unlike other pre-existing methods, can also be used for mapping local microstructural transformations due to recovery and recrystallization. We discuss the benefits and limitations in using these additional handles in understanding the changes taking place in the material during in situ heating. PMID- 27482936 TI - Controllable Orientation of Ester-Group-Induced Intermolecular Halogen Bonding in a 2D Self-Assembly. AB - Halogen bonding with high specificity and directionality in the geometry has proven to be an important type of noncovalent interaction to fabricate and control 2D molecular architectures on surfaces. Herein, we first report how the orientation of the ester substituent for thienophenanthrene derivatives (5,10 DBTD and 5,10-DITD) affects positive charge distribution of halogens by density functional theory, thus determining the formation of an intermolecular halogen bond and different self-assembled patterns by scanning tunneling microscopy. The system presented here mainly includes heterohalogen X...O?C and X...S halogen bonds, H...Br and H...O hydrogen bonds, and I...I interaction, where the directionality and strength of such weak bonds determine the molecular arrangement by varying the halogen substituent. This study provides a detailed understanding of the role of ester orientation, concentration, and solvent effects on the formation of halogen bonds and proves relevant for identification of multiple halogen bonding in supramolecular chemistry. PMID- 27482935 TI - Bidirectional cross talk between patient-derived melanoma and cancer-associated fibroblasts promotes invasion and proliferation. AB - Tumor-stroma interactions are critical for epithelial-derived tumors, and among the stromal cell types, cancer-associated fibroblasts (CAFs) exhibit multiple functions that fuel growth, dissemination, and drug resistance. However, these interactions remain insufficiently characterized in non-epithelial tumors such as malignant melanoma. We generated monocultures of melanoma cells and matching CAFs from patients' metastatic lesions, distinguished by oncogenic drivers and immunoblotting of characteristic markers. RNA sequencing of CAFs revealed a homogenous epigenetic program that strongly resembled the signatures from epithelial cancers, including enrichment for an epithelial-to-mesenchymal transition (EMT). Melanoma CAFs in monoculture displayed robust invasive behavior while patient-derived melanoma monocultures showed very little invasiveness. Instead, melanoma cells showed increased invasion when co-cultured with CAFs. In turn, CAFs showed increased proliferation when exposed to melanoma conditioned media (CM), mediated in part by melanoma-secreted transforming growth factor alpha that acted on CAFs via the epidermal growth factor receptor. This study provides evidence that bidirectional interactions between melanoma and CAFs regulate progression of metastatic melanoma. PMID- 27482937 TI - Health-related quality of life in rehabilitants with different cancer entities. AB - The focus of the study is the analysis of changes in health-related quality of life in various cancer entities during and after an inpatient rehabilitation programme. In a multicentre longitudinal study, a total of 211 cancer patients (breast cancer: N = 84; prostate cancer: N = 90; colon cancer: N = 37) were asked about their quality of life (EORTC QLQ-C30; HADS) at the beginning, the end and 3 months after the end of the rehabilitation programme. In different domains of quality of life significant and mostly clinically relevant improvements were found during rehabilitation. The breast and prostate cancer patients improved most in emotional functioning, colon cancer patients in global quality of life. With regard to the severity of symptoms, the fatigue burden improved in breast and colon cancer patients, nausea in the prostate cancer patients. However, they are increases 3 months after rehabilitation. Functional burdens improved 3 months after the end of rehabilitation in the physical domain for all cancer patients. For breast cancer patients, emotional functioning decreased significantly 3 months after rehabilitation. An inpatient oncological rehabilitation programme can lead to an improvement in quality of life. PMID- 27482938 TI - Ligand Displacement Reaction Paths in a Diiron Hydrogenase Active Site Model Complex. AB - The mechanism and energetics of CO, 1-hexene, and 1-hexyne substitution from the complexes (SBenz)2 [Fe2 (CO)6 ] (SBenz=SCH2 Ph) (1-CO), (SBenz)2 [Fe2 (CO)5 (eta(2) -1-hexene)] (1-(eta(2) -1-hexene)), and (SBenz)2 [Fe2 (CO)5 (eta(2) -1 hexyne)] (1-(eta(2) -1-hexyne)) were studied by using time-resolved infrared spectroscopy. Exchange of both CO and 1-hexyne by P(OEt)3 and pyridine, respectively, proceeds by a bimolecular mechanism. As similar activation enthalpies are obtained for both reactions, the rate-determining step in both cases is assumed to be the rotation of the Fe(CO)2 L (L=CO or 1-hexyne) unit to accommodate the incoming ligand. The kinetic profile for the displacement of 1 hexene is quite different than that for the alkyne and, in this case, both reaction channels, that is, dissociative (SN 1) and associative (SN 2), were found to be competitive. Because DFT calculations predict similar binding enthalpies of alkene and alkyne to the iron center, the results indicate that the bimolecular pathway in the case of the alkyne is lower in free energy than that of the alkene. In complexes of this type, subtle changes in the departing ligand characteristics and the nature of the mercapto bridge can influence the exchange mechanism, such that more than one reaction pathway is available for ligand substitution. The difference between this and the analogous study of (MU pdt)[Fe(CO)3 ]2 (pdt=S(CH2 )3 S) underscores the unique characteristics of a three-atom S-S linker in the active site of diiron hydrogenases. PMID- 27482939 TI - Antiepidermis autoantibodies induced by anti-PD-1 therapy in metastatic melanoma. AB - Skin rashes induced by anti-PD-1s are often reported; however, their immunological profiles are currently unknown. We report the case of an atypical eruption induced by pembrolizumab, associated with the occurrence of antiepidermis autoantibodies. As the onset of lesions was concomitant with the favorable tumor response, we suggest that this hybrid rash belongs to a new category of paraneoplastic syndrome, reflecting the intense immunomodulation induced by pembrolizumab. With the increasing use of anti-PD-1s, this kind of report may become frequent. For a better understanding of immune-related adverse events, physicians should document the immunological characteristics of atypical skin toxicities. Moreover, the kinetics of induced autoantibodies could provide a proxy measure of anti-PD-1 activity after treatment disruption. PMID- 27482940 TI - Strongest Ferromagnetic Coupling in Designed Gadolinium(III)-Nitroxide Coordination Compounds. AB - Three novel gadolinium(III)-radical complexes [Gd(III)(hfac)3(H2O)(L)] [Gd-L; L = tert-butyl phenyl nitroxide (phNO) and its derivatives (tert-butyl 3-tolyl nitroxide and tert-butyl 4-tert-butylphenyl nitroxide)] were synthesized, and all compounds showed ferromagnetic coupling, obeying the empirical relation: out-of plane coordination of the Gd ion from the radical pi system favors ferromagnetic coupling. In particular, Gd-phNO has a considerably large torsion angle around Gd O-N-Csp(2) (69.8(9) degrees on average) and the largest ferromagnetic coupling parameter (2J/kB = +18.0(4) K) in Gd-nitroxide compounds ever known. The validity of our molecular design was assessed on the basis of the magneto-structure relation analysis with many literature data including various paramagnetic ligating groups. PMID- 27482942 TI - Reply. PMID- 27482941 TI - Rhodomyrtials A and B, Two Meroterpenoids with a Triketone-Sesquiterpene Triketone Skeleton from Rhodomyrtus tomentosa: Structural Elucidation and Biomimetic Synthesis. AB - Rhodomyrtials A and B (1 and 2), two unprecedented triketone-sesquiterpene triketone adducts, along with five biogenetically related intermediates, rhodomentone A (3) and tomentodiones A-D (4-7), were isolated from the leaves of Rhodomyrtus tomentosa. Their structures and absolute configurations were determined by a combination of NMR spectroscopy, chemical conversion, and X-ray diffraction analysis. Compounds 1 and 2 were biomimetically synthesized via 5 and 4, respectively, rather than 3, revealing their key ordering of biosynthetic events and confirming their structural assignments. Compound 7 exhibited potent metastatic inhibitory activity against DLD-1 cells by suppressing the activation of matrix metalloproteinase (MMP)-2 and MMP-9. PMID- 27482943 TI - The Pharmacogenomic Association of Fcgamma Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. AB - OBJECTIVE: The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcgamma receptors (FcgammaR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively. METHODS: Functional SNPs for FcgammaR (FcgammaRIIa 519G>A, FcgammaRIIb 695T>C, FcgammaRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests. RESULTS: No significant associations were identified between complete remission and any FcgammaR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcgammaRIIa and complete remission (P = 0.01). The 519AA genotype predicted complete remission (P = 0.006) and a shorter time to complete remission (P < 0.001). CONCLUSION: The finding that the homozygous FcgammaRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcgammaRIIa may be broadly involved in disease pathogenesis and response to therapy. PMID- 27482944 TI - Separation of high-purity syringol and acetosyringone from rice straw-derived bio oil by combining the basification-acidification process and column chromatography. AB - Numerous technologies have been used to reclaim valuable chemicals from bio-oil. In this study, a combination of the basification-acidification process and column chromatography was employed for the separation of high-purity syringol and acetosyringone from rice straw-derived bio-oil. The optimal conditions for the basification-acidification process and the possible precipitation mechanism of the basification were explored. The results showed the following as the optimal conditions for the basification process: mass ratio of calcium hydroxide (Ca(OH)2 ) to bio-oil, 2.0; reaction temperature, 70 degrees C; and reaction time, 30 min. The results also showed that 1.6 mol of hydrochloric acid (HCl) per gram of bio oil was optimal for the acidification. The precipitation was found to proceed via a possible mechanism involving the reaction of the phenolic compounds in the bio oil with Ca(OH)2 to produce a precipitate. After further separation by column chromatography, purities of 91.4 and 96.2% (from gas chromatography-mass spectrometry) were obtained for syringol and acetosyringone, respectively. Their recoveries for the whole process were 73.0 and 39.3%, respectively. PMID- 27482945 TI - Niche shifts and range expansions along cordilleras drove diversification in a high-elevation endemic plant genus in the tropical Andes. AB - The tropical Andes represent one of the world's biodiversity hot spots, but the evolutionary drivers generating their striking species diversity still remain poorly understood. In the treeless high-elevation Andean environments, Pleistocene glacial oscillations and niche differentiation are frequently hypothesized diversification mechanisms; however, sufficiently densely sampled population genetic data supporting this are still lacking. Here, we reconstruct the evolutionary history of Loricaria (Asteraceae), a plant genus endemic to the Andean treeless alpine zone, based on comprehensive population-level sampling of 289 individuals from 67 populations across the entire distribution ranges of its northern Andean species. Partly incongruent AFLP and plastid DNA markers reveal that the distinct genetic structure was shaped by a complex interplay of biogeography (spread along and across the cordilleras), history (Pleistocene glacial oscillations) and local ecological conditions. While plastid variation documents an early split or colonization of the northern Andes by at least two lineages, one of which further diversified, a major split in the AFLP data correlate with altitudinal ecological differentiation. This suggests that niche shifts may be important drivers of Andean diversification not only in forest alpine transitions, but also within the treeless alpine zone itself. The patterns of genetic differentiation at the intraspecific level reject the hypothesized separation in spatially isolated cordilleras and instead suggest extensive gene flow among populations from distinct mountain chains. Our study highlights that leveraging highly variable markers against extensive population-level sampling is a promising approach to address mechanisms of rapid species diversifications. PMID- 27482946 TI - High-precision (34) S/(32) S measurements in vertebrate bioapatites using purge and-trap elemental analyser/isotope ratio mass spectrometry technology. AB - RATIONALE: In ecological studies, the sulfur isotope compositions (delta(34) S values) of soft tissues (e.g. hair, skin, nail, muscle, collagen) allow the determination of both past and present-day living environments of organisms. However, technical limitations have so far prevented reliable sulfur isotope analyses of minerals having low sulfur content, such as bioapatite, which is the crystalline component of skeletal tissues. The development of 'purge-and-trap' technology in elemental analysers recently demonstrated new possibilities to solve some of those technical difficulties. METHODS: We have used a VarioPYROcube elemental analyser (EA) equipped with 'purge-and-trap' technology, interfaced in continuous flow mode to an Isoprime 100 isotope ratio mass spectrometer, to measure the sulfur isotope compositions of bioapatite samples. We first characterised a working calibrated material of chemical composition close to those of our samples, the low-S bearing phosphorite BCR32, against the two delta(34) SV-CDT reference-calibrated materials, NBS-127 and IAEA-SO-5. We have confirmed a delta(34) SV-CDT value of +18.40/00 (1sigma = 0.5; n = 18) in agreement with the previously published value. Using BCR32 as a compositional and isotopic reference material, we have then measured the delta(34) SV-CDT values of various bioapatite tissues (bone, dentine and enamel) from both modern and fossil vertebrates living in different environments (marine, freshwater and terrestrial). RESULTS: Our results demonstrate the capacity of this analytical setup to measure the delta(34) SV-CDT values of low-S bioapatite samples (0.14 to 1.19 wt%) with a good analytical precision (1sigma = 0.5; n = 14). Our results also show that the delta(34) SV-CDT values of modern and fossil vertebrate bioapatites allow discrimination between marine environments and freshwater or terrestrial ones. CONCLUSIONS: Sulfur isotope analysis of bioapatite has great potential to track the living environment of extinct vertebrates for which only fossilised bones or teeth have been preserved. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27482947 TI - Femtosecond Hydrogen Bond Dynamics of Bulk-like and Bound Water at Positively and Negatively Charged Lipid Interfaces Revealed by 2D HD-VSFG Spectroscopy. AB - Interfacial water in the vicinity of lipids plays an important role in many biological processes, such as drug delivery, ion transportation, and lipid fusion. Hence, molecular-level elucidation of the properties of water at lipid interfaces is of the utmost importance. We report the two-dimensional heterodyne detected vibrational sum frequency generation (2D HD-VSFG) study of the OH stretch of HOD at charged lipid interfaces, which shows that the hydrogen bond dynamics of interfacial water differ drastically, depending on the lipids. The data indicate that the spectral diffusion of the OH stretch at a positively charged lipid interface is dominated by the ultrafast (<~100 fs) component, followed by the minor sub-picosecond slow dynamics, while the dynamics at a negatively charged lipid interface exhibit sub-picosecond dynamics almost exclusively, implying that fast hydrogen bond fluctuation is prohibited. These results reveal that the ultrafast hydrogen bond dynamics at the positively charged lipid-water interface are attributable to the bulk-like property of interfacial water, whereas the slow dynamics at the negatively charged lipid interface are due to bound water, which is hydrogen-bonded to the hydrophilic head group. PMID- 27482949 TI - First-Generation Subporphyrinatoboron(III) Sensitizers Surpass the 10 % Power Conversion Efficiency Threshold. AB - Subporphyrinatoboron(III) (SubB) sensitizers were synthesized for use in dye sensitized solar cells (DSSCs). The prototype, which comprises a sterically demanding 3,5-di-tert-butylphenyl scaffold, a meso-ethynylphenyl spacer, and a cyanoacrylic acid anchoring group, achieved an open-circuit voltage VOC of 836 mV, short-circuit current density JSC of 15.3 mA cm(-2) , fill factor of 0.786, and a photon-to-current conversion efficiency of 10.1 %. Such astonishing figures suggest that a bright future lies ahead for SubB in the realm of DSSCs. PMID- 27482948 TI - 6-Azido-6-deoxy-l-idose as a Hetero-Bifunctional Spacer for the Synthesis of Azido-Containing Chemical Probes. AB - The design of 6-azido-6-deoxy-l-idose for use as a hetero-bifunctional spacer is reported. The hemiacetal at one terminus is an equivalent of an aldehyde and can react with nucleophiles, such as amino groups and electron-rich aromatics. The azido group at the other terminus bio-orthogonally undergoes a Huisgen [3+2] cycloaddition with an acetylene. The idose derivative exhibited a higher level of reactivity towards oxime formation than a corresponding glucose derivative. The (13) C NMR spectrum of the uniformly (13) C-labeled 6-azido-idose indicated that the acyclic forms of the sugar totaled 0.3 % of all the isomers, whereas those of glucose totaled 0.01 %. The larger population of the acyclic forms of the idose derivative would result in higher reactivity towards electrophilic addition in comparison with glucose derivatives. Finally, we prepared a C-idosyl epigallocatechin gallate (EGCG) that bears an azido group through C-glycosylation of EGCG with 6-azido-idose. This glycosyl form of the C-idosyl EGCG exhibited a cytotoxicity against U266 cells that was comparable to that of EGCG. These results suggested that the EGCG derivative could be used as an effective chemical probe for the elucidation of EGCG biological functions. PMID- 27482950 TI - Recent Advances of Using Hybrid Nanocarriers in Remotely Controlled Therapeutic Delivery. AB - The development of hybrid biomaterials has been attracting great attention in the design of materials for biomedicine. The nanosized level of inorganic and organic or even bioactive components can be combined into a single material by this approach, which has created entirely new advanced compositions with truly unique properties for drug delivery. The recent advances in using hybrid nanovehicles as remotely controlled therapeutic delivery carriers are summarized with respect to different nanostructures, including hybrid host-guest nanoconjugates, micelles, nanogels, core-shell nanoparticles, liposomes, mesoporous silica, and hollow nanoconstructions. In addition, the controlled release of guest molecules from these hybrid nanovehicles in response to various remote stimuli such as alternating magnetic field, near infrared, or ultrasound triggers is further summarized to introduce the different mechanisms of remotely triggered release behavior. Through proper chemical functionalization, the hybrid nanovehicle system can be further endowed with many new properties toward specific biomedical applications. PMID- 27482952 TI - Effect of Experimental Palatal Prosthesis on Voice Onset Time. AB - PURPOSE: Objective evaluation of a patient's speech is needed in prosthetic dentistry because the prostheses can affect the intelligibility of speech. Measurement of voice onset time is one evaluation method of consonant production used in phonetic science. The purpose of this study was to confirm the influence of a palatal prosthesis on consonant production by measuring voice onset time. MATERIALS AND METHODS: In this study, voice onset time was measured in 10 healthy women (mean age 26.5 years) under two conditions: with and without an experimental palatal prosthesis. In this study, voice onset time of /ta/ and /ka/ were used to determine the effect of wearing a palatal prosthesis; /pa/ was tested as a control, with the null hypothesis that voice onset time of /ta/ and /ka/ would not change when wearing a palatal prosthesis. RESULTS: Medial voice onset time of /pa/, /ta/, and /ka/ syllables without the palatal prosthesis was 22.5 ms, 19.5 ms, and 42.5 ms, whereas that with the palatal prosthesis was 22.5 ms, 23.5 ms, and 55.0 ms. Voice onset times for /ta/ and /ka/ were prolonged when wearing the experimental palatal prosthesis, whereas /pa/ showed no significant difference. CONCLUSION: Consonant production was affected by wearing a palatal prosthesis, and this change in sound was detected by measuring voice onset time. PMID- 27482953 TI - Editorial: Epigenetics in Systemic Sclerosis. PMID- 27482954 TI - Patterns and Consequences of Multimorbidity in the General Population: There is No Chronic Disease Management Without Rheumatic Disease Management. AB - OBJECTIVE: To identify empirical model-based patterns of multimorbidity from chronic noncommunicable diseases in the general population, with a focus on the contribution of rheumatic and musculoskeletal diseases (RMDs), and to quantify their association with adverse health outcomes. METHODS: Cross-sectional data from the Portuguese Fourth National Health Survey were analyzed (n = 23,754). Latent class analysis was used to identify patterns of coexistence of 11 chronic noncommunicable diseases (RMDs, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, stroke, depression, myocardial infarction, cancer, osteoporosis, asthma, and renal failure). Based on the Outcome Measures in Rheumatology, filter 2.0, health outcomes included life impact, pathophysiologic manifestations, and resource use. We assessed the association between patterns and adverse health outcomes, through sex-, age-, and body mass index-adjusted prevalence ratios with 95% confidence intervals, obtained using Poisson regression. RESULTS: Four patterns of chronic noncommunicable diseases co occurrence were identified and labeled as low disease probability, cardiometabolic conditions, respiratory conditions, and RMDs and depression. RMDs were highly prevalent in patients with chronic diseases (from 38.6% in cardiometabolic conditions to 66.7% in RMDs and depression). While negative self rated health, short-term disability, and chronic pain were more strongly associated with cardiometabolic conditions and respiratory conditions, all multimorbidity patterns were similarly associated with long-term disability, frequent health care utilization, and out-of-pocket health care expenses. CONCLUSION: Our study emphasizes RMDs as a major presence in multimorbidity in the general population. All multimorbidity patterns were associated with a wide set of adverse health outcomes. Management strategies for the patient with chronic cardiometabolic, respiratory, or depressive conditions should also target RMDs. PMID- 27482955 TI - Encephalitis With Antibodies to GluN2B During Administration of Clozapine. AB - Clozapine's immunomodulatory properties may contribute to its effect on schizophrenia as well as various adverse effects. However, a possible relationship between N-methyl-D-aspartate-type glutamate receptor antibodies, refractory schizophrenia, and clozapine has not been reported. We experienced a patient who developed refractory schizophrenia that mimicked an exacerbation of encephalitis with antibodies to N-methyl-D-aspartate-type glutamate receptor (GluN2B) after administration of clozapine for 26 days. We performed plasma exchange 5 times and subsequent steroid pulse therapy. The level of consciousness improved within a few weeks, but involuntary movement as well as psychotic symptoms remained. The production of anti-GluN2B antibodies may have contributed to the patient's resistance to the antipsychotic effects of clozapine in addition to mediating the encephalitis. When we administer clozapine to patients with refractory schizophrenia, we should be careful to differentiate between a diagnosis of refractory schizophrenia and encephalitis with antibodies to GluN2B. PMID- 27482956 TI - Dr. Sue McDiarmid, UCLA: Advancing Outcomes After Pediatric Liver and Vascular Composite Tissue Transplantation. PMID- 27482958 TI - Longitudinal Pharmacokinetics of Tacrolimus in Elderly Compared With Younger Recipients in the First 6 Months After Renal Transplantation. AB - BACKGROUND: Elderly (Eld) (>=60 years) recipients are receiving renal transplants more frequently. The pharmacokinetics (PK) studies of immunosuppressive drugs in healthy volunteers, rarely, include old patients. METHODS: We studied 208 12-hour tacrolimus (TAC) PK (0, 20, 40, 60, 90, 120, 180, 240, 360, 480, 600, 720 min) in 44 Eld (65 +/- 3 years) and compared the results with 31 younger controls (Ctrl) (35 +/- 6 years) recipients, taking oral TAC/mycophenolate sodium (MPS)/prednisone, at 4 different timepoints: PK1 (8 +/- 2 days; n = 72), PK2 (31 +/- 4 days; n = 61), PK3 (63 +/- 6 days; n = 44), and PK4 (185 +/- 10 days; n = 31). Tacrolimus PK was measured by ultraperformance liquid chromatography coupled to a mass spectrometer repetition and noncompartmental PKs were analyzed using Phoenix WinNonlin. RESULTS: Mean TAC dose was lower in the Eld group than in Ctrl ones throughout timepoints either by total daily dose or adjusted (Adj) per body weight. Mean TAC trough level (Cmin), used to adjust daily dose, was not different between the 2 groups in all timepoints. AdjCmax and AdjTAC-area under the curve at dosing interval were both higher in the Eld compared to the Ctrl group in PKs1, 3, and 4. Estimated total body clearance normalized by dose and weight was lower in the Eld group compared with the Ctrl in all PKs and statistically lower at PKs 1 and 3. Similar to younger recipients TAC trough level has also a high correlation (R = 0.76) with area under the curve at dosing interval. CONCLUSIONS: These data indicate that Eld recipients have a lower TAC clearance and therefore need a lower TAC dose than younger recipients. PMID- 27482960 TI - Evaluation of Flagging Criteria of United States Kidney Transplant Center Performance: How to Best Define Outliers? AB - BACKGROUND: Scientific Registry of Transplant Recipients report cards of US organ transplant center performance are publicly available and used for quality oversight. Low center performance (LP) evaluations are associated with changes in practice including reduced transplant rates and increased waitlist removals. In 2014, Scientific Registry of Transplant Recipients implemented new Bayesian methodology to evaluate performance which was not adopted by Center for Medicare and Medicaid Services (CMS). In May 2016, CMS altered their performance criteria, reducing the likelihood of LP evaluations. METHODS: Our aims were to evaluate incidence, survival rates, and volume of LP centers with Bayesian, historical (old-CMS) and new-CMS criteria using 6 consecutive program-specific reports (PSR), January 2013 to July 2015 among adult kidney transplant centers. RESULTS: Bayesian, old-CMS and new-CMS criteria identified 13.4%, 8.3%, and 6.1% LP PSRs, respectively. Over the 3-year period, 31.9% (Bayesian), 23.4% (old-CMS), and 19.8% (new-CMS) of centers had 1 or more LP evaluation. For small centers (<83 transplants/PSR), there were 4-fold additional LP evaluations (52 vs 13 PSRs) for 1-year mortality with Bayesian versus new-CMS criteria. For large centers (>183 transplants/PSR), there were 3-fold additional LP evaluations for 1-year mortality with Bayesian versus new-CMS criteria with median differences in observed and expected patient survival of -1.6% and -2.2%, respectively. CONCLUSIONS: A significant proportion of kidney transplant centers are identified as low performing with relatively small survival differences compared with expected. Bayesian criteria have significantly higher flagging rates and new-CMS criteria modestly reduce flagging. Critical appraisal of performance criteria is needed to assess whether quality oversight is meeting intended goals and whether further modifications could reduce risk aversion, more efficiently allocate resources, and increase transplant opportunities. PMID- 27482961 TI - Age-Dependent Risk of Graft Failure in Young Kidney Transplant Recipients. AB - BACKGROUND: The risk of graft failure in young kidney transplant recipients has been found to increase during adolescence and early adulthood. However, this question has not been addressed outside the United States so far. Our objective was to investigate whether the hazard of graft failure also increases during this age period in France irrespective of age at transplantation. METHODS: Data of all first kidney transplantation performed before 30 years of age between 1993 and 2012 were extracted from the French kidney transplant database. The hazard of graft failure was estimated at each current age using a 2-stage modelling approach that accounted for both age at transplantation and time since transplantation. Hazard ratios comparing the risk of graft failure during adolescence or early adulthood to other periods were estimated from time dependent Cox models. RESULTS: A total of 5983 renal transplant recipients were included. The risk of graft failure was found to increase around the age of 13 years until the age of 21 years, and decrease thereafter. Results from the Cox model indicated that the hazard of graft failure during the age period 13 to 23 years was almost twice as high as than during the age period 0 to 12 years, and 25% higher than after 23 years. CONCLUSIONS: Among first kidney transplant recipients younger than 30 years in France, those currently in adolescence or early adulthood have the highest risk of graft failure. PMID- 27482959 TI - Progress in Clinical Encapsulated Islet Xenotransplantation. AB - At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework. PMID- 27482962 TI - Diabetes Mellitus in Living Pancreas Donors: Use of Integrated National Registry and Pharmacy Claims Data to Characterize Donation-Related Health Outcomes. AB - BACKGROUND: Living donor pancreas transplant is a potential treatment for diabetic patients with end-organ complications. Although early surgical risks of donation have been reported, long-term medical outcomes in living pancreas donors are not known. METHODS: We integrated national Scientific Registry of Transplant Recipients data (1987-2015) with records from a nationwide pharmacy claims warehouse (2005-2015) to examine prescriptions for diabetes medications and supplies as a measure of postdonation diabetes mellitus. To compare outcomes in controls with baseline good health, we matched living pancreas donors to living kidney donors (1:3) by demographic traits and year of donation. RESULTS: Among 73 pancreas donors in the study period, 45 were identified in the pharmacy database: 62% women, 84% white, and 80% relatives of the recipient. Over a mean postdonation follow-up period of 16.3 years, 26.7% of pancreas donors filled prescriptions for diabetes treatments, compared with 5.9% of kidney donors (odds ratio, 4.13; 95% confidence interval, 1.91-8.93; P = 0.0003). Use of insulin (11.1% vs 0%) and oral agents (20.0% vs 5.9%; odds ratio, 4.50, 95% confidence interval, 2.09-9.68; P = 0.0001) was also higher in pancreas donors. CONCLUSIONS: Diabetes is more common after living pancreas donation than after living kidney donation, supporting clinical consequences from reduced endocrine reserve. PMID- 27482963 TI - Premortem Heparin Administration and Location of Withdrawal of Life-Sustaining Interventions in DCD: Lack of High-Quality Evidence Precludes Definitive Conclusions. PMID- 27482964 TI - Chronic Norovirus Infection as a Risk Factor for Secondary Lactose Maldigestion in Renal Transplant Recipients: A Prospective Parallel Cohort Pilot Study. AB - BACKGROUND: Chronic norovirus infection is an emerging challenge in the immunocompromised host, in whom it may be asymptomatic or present as chronic diarrhea. The mechanisms of diarrhea in chronic norovirus infection are not well understood, but in analogy to Gardia lamblia and rotavirus infections, secondary lactose maldigestion (LM) might be implicated. METHODS: Adult renal transplant recipients who had symptomatic chronic norovirus infection with diarrhea were asked to participate in this prospective parallel cohort study. Renal transplant recipients with otherwise unexplainable chronic diarrhea but absent infection served as control group. In both groups, a lactose hydrogen breath test and a lactose tolerance test were performed after exclusion of primary LM by a negative lactase gene test. RESULTS: Of approximately 800 patients in the cohort of renal transplant recipients at our institution, 15 subjects were included in the present study. Of these, 7 had chronic symptomatic norovirus infection with diarrhea (noro group), and 8 had diarrhea in the absence of norovirus (control group). Lactose hydrogen breath test and lactose tolerance test were positive in all 7 patients (100%) in the noro group, whereas only 1 (12.5%) of 8 patients in the control group had a positive test. Thus, secondary LM was highly prevalent in the noro compared with the control group with an odds ratio of 75.0 (95% confidence interval, 2.6-2153, P = 0.01). CONCLUSIONS: This is the first report showing a positive association of chronic norovirus infection and secondary LM. Further studies with larger patient numbers and longer follow-up are needed to test a causative relationship between both entities. PMID- 27482966 TI - Disaster Preparedness Among Michigan's Licensed Child Care Programs. AB - OBJECTIVE: This study aimed to assess if Michigan child care directors have created disaster management plans, and if local resources were used to develop and implement plans. METHODS: From December 2013 to March 2014, the Early Childhood Investment Corporation conducted a survey of licensed child care programs in Michigan. An online survey regarding disaster preparedness and training resources was distributed to the directors of a convenience sample of registered child care centers among the Early Childhood Investment Corporation's statewide network of 11 resource centers. RESULTS: A total of 210 child care programs responded. Most (91%) of respondents had a disaster plan, but 40% did not include accommodations for special needs children, 51% did not have a family/child identification or reunification plan, and 67% did not have car safety devices and a predetermined route for evacuation. Fewer than 9% made disaster plans available online. Few collaborated with local fire (22%), police (27%), or pediatric or emergency medicine organizations (11%). Online modules were the most desirable training format. CONCLUSIONS: In a state without mandated child care guidelines for disaster preparedness, a substantial proportion of child care programs were missing critical components of disaster planning. Future interventions must focus on increasing partnerships with local organizations and developing guidelines and training to include plans for special needs children, family/child identification and reunification, and evacuation/relocation. PMID- 27482967 TI - The Sonographic Appearance of Spinal Fluid at Clinically Selected Interspaces in Sitting Versus Lateral Positions. AB - OBJECTIVE: Our objective was to describe the sonographic appearance of fluid at clinically selected interspinous spaces and see if additional interspaces could be identified as suitable and safe targets for needle insertion. We also measured the reproducibility of fluid measurements and assessed for positional differences. METHODS: A prospective convenience sample of infants younger than 3 months was enrolled in the pediatric emergency department. Excluded were clinically unstable infants or those with spinal dysraphism. Infants were first held in standard lateral lumbar puncture position. Pediatric emergency medicine (PEM) physicians marked infants' backs at the level they would insert a needle using the landmark palpation technique. A PEM sonologist imaged and measured the spinal fluid in 2 orthogonal planes at this marked level in lateral then sitting positions. Fluid measurements were repeated by a second blinded PEM sonologist. RESULTS: Forty-six infants were enrolled. Ultrasound verified the presence of fluid at the marked level as determined by the landmark palpation technique in 98% of cases. Ultrasound identified additional suitable spaces 1 space higher (82%) and 2 spaces higher (41%). Intraclass correlation coefficient of all measurements was excellent (>0.85), with differences noted for sitting versus lateral position in mean area of fluid 0.34 mm versus 0.31 mm (difference, 0.03; 95% confidence interval [CI], 0.005-0.068), dorsal fluid pocket 0.23 mm versus 0.15 mm (difference, 0.08; 95% CI, 0.031-0.123), and nerve root-to-canal ratio 0.44 versus 0.51 (difference, 0.07; 95% CI, 0.004-0.117). CONCLUSIONS: Ultrasound can verify the presence of fluid at interspaces determined by the landmark palpation technique and identify additional suitable spaces at higher levels. There were statistically greater fluid measurements in sitting versus lateral positions. These novel fluid measurements were shown to be reliable. PMID- 27482968 TI - Highly Sensitive Plasmonic Optical Sensors Based on Gold Core-Satellite Nanostructures Immobilized on Glass Substrates. AB - Fabrication of discrete nanostructures consisting of noble metal nanoparticles immobilized on substrates is challenging because of structural complexity but important for chip-based plasmonic sensor technology. Here we report optical sensing capabilities of core-satellite nanostructures made of gold nanoparticles immobilized on glass substrate, which were fabricated by combining stepwise interconnection of gold nanoparticles through dithiol linkers and surface treatment using vacuum ultraviolet light. The nanostructures exhibit large changes in coupled plasmon resonance peak upon surrounding refractive index, with sensitibity of ca. 350 nm RIU(-1), thus providing highly sensitive optical sensors for determining the surrounding refractive index and detecting organic vapors. PMID- 27482965 TI - Has the Department of Veterans Affairs Found a Way to Avoid Racial Disparities in the Evaluation Process for Kidney Transplantation? AB - BACKGROUND: Minority groups are affected by significant disparities in kidney transplantation (KT) in Veterans Affairs (VA) and non-VA transplant centers. However, prior VA studies have been limited to retrospective, secondary database analyses that focused on multiple stages of the KT process simultaneously. Our goal was to determine whether disparities during the evaluation period for KT exist in the VA as has been found in non-VA settings. METHODS: We conducted a multicenter longitudinal cohort study of 602 patients undergoing initial evaluation for KT at 4 National VA KT Centers. Participants completed a telephone interview to determine whether, after controlling for medical factors, differences in time to acceptance for transplant were explained by patients' demographic, cultural, psychosocial, or transplant knowledge factors. RESULTS: There were no significant racial disparities in the time to acceptance for KT [Log-Rank chi = 1.04; P = 0.594]. Younger age (hazards ratio [HR], 0.98; 95% confidence interval [CI], 0.97-0.99), fewer comorbidities (HR, 0.89; 95% CI, 0.84 0.95), being married (HR, 0.81; 95% CI, 0.66-0.99), having private and public insurance (HR, 1.29; 95% CI, 1.03-1.51), and moderate or greater levels of depression (HR, 1.87; 95% CI, 1.03-3.29) predicted a shorter time to acceptance. The influence of preference for type of KT (deceased or living donor) and transplant center location on days to acceptance varied over time. CONCLUSIONS: Our results indicate that the VA National Transplant System did not exhibit the racial disparities in evaluation for KT as have been found in non-VA transplant centers. PMID- 27482969 TI - Reversible Splenial Lesion Related to Acute Lithium Intoxication in a Bipolar Patient: A Case Report. PMID- 27482970 TI - A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia. AB - The antidepressant mirtazapine is an alternative to classical hypnotics, and this study investigated the efficacy and safety of esmirtazapine (Org 50081, the maleic acid salt of S-mirtazapine) in patients given a diagnosis of primary insomnia after acute (2-day) treatment. Patients aged 18 to 65 years with primary insomnia were randomized to receive placebo or 1.5-, 3.0-, or 4.5-mg esmirtazapine in a balanced 4-way crossover study; 2 sleep laboratory nights with polysomnography were separated by 5-day, single-blind placebo washout periods. Polysomnography-determined total sleep time (primary end point) and patient reported total sleep time improved by at least 25 minutes with all 3 doses of esmirtazapine (P <= 0.001 vs placebo). Polysomnography-measured wake time after sleep onset (P <= 0.0001) and latency to persistent sleep also improved vs placebo (P <= 0.01, 3.0 and 4.5 mg). Patient-reported sleep quality improved with 3.0- and 4.5-mg esmirtazapine (P <= 0.01 and P <= 0.05, respectively, vs placebo). Morning alertness and contentment were not altered after esmirtazapine, and calmness increased with 4.5-mg esmirtazapine vs placebo. Evening questionnaires showed no difference in duration of daytime naps but reduced energy and ability to work/function after esmirtazapine treatment periods vs placebo (P < 0.05), although this effect was limited to the first night of each 2 night period. There were few adverse events, no serious adverse events, or clinically relevant treatment differences in vital signs, laboratory values, or electrocardiogram. Esmirtazapine doses of 1.5 to 4.5 mg/day significantly improved quantity and quality of sleep and were generally well tolerated, with no evidence of safety concerns or consistent pattern of residual effects. PMID- 27482971 TI - Comparison of Different TMAO Force Fields and Their Impact on the Folding Equilibrium of a Hydrophobic Polymer. AB - Trimethylamine N-oxide (TMAO) is a protective osmolyte able to preserve protein folded states in the presence of denaturants like urea and under extreme thermodynamic conditions of high pressure and temperature. The current understanding posits that TMAO exerts its stabilizing effect on proteins by preferential exclusion from the macromolecular hydration shell. Additionally, TMAO is also known to favor the folding of hydrophobic polymers. In this latter case, theoretical and experimental studies support a scenario in which TMAO directly interacts with the macromolecule. While atomistic simulations may potentially elucidate the precise TMAO-induced stabilization mechanism, the comparative accuracy of the different TMAO force field models available in the literature remains elusive. Herein, we compare four different TMAO models, study their structural hydration properties, and validate the models against experimental osmotic coefficients and air-water surface tension data over a broad range of TMAO concentrations. The models were furthermore applied to study the effect of TMAO on the folding equilibrium of a generic hydrophobic polymer in aqueous solution. Interestingly, we find that TMAO increasingly stabilizes the compact globular state of the polymer up to approximately 1 M TMAO, while in turn destabilizing it with further increase in TMAO concentration. Hence, TMAO acts as a stabilizing osmolyte or as a denaturant depending on the TMAO concentration of the solution. TMAO-induced stabilization up to 1 M is accompanied by positive preferential TMAO binding and with an increase in the chain configurational entropy, which is reduced at concentrations higher than 1 M. These results are qualitatively independent of the TMAO force field. PMID- 27482972 TI - The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease. AB - BACKGROUND: Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. METHODS: A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. RESULTS: One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%-9%), only one of whom had NRH. There was no clinically overt portal hypertension. CONCLUSIONS: The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation. PMID- 27482973 TI - Characteristics and Behavior of Elderly-onset Inflammatory Bowel Disease: A Multi center US Study. AB - BACKGROUND: Existing data conflict regarding differences in inflammatory bowel disease (IBD) characteristics between adult-onset and elderly-onset IBD. IBD extent and behavior are strong predictors of IBD-related surgery and complications. The aim of this study was to compare disease characteristics and behavior of adult- and elderly-onset IBD in a multi-center US study. METHODS: We performed a multi-center retrospective cohort study of patients with IBD. Chart review was performed to confirm IBD diagnoses and extract data regarding IBD characteristics, medications, surgery, cancer, and death. Patients were classified based on age at IBD diagnosis as adult onset (18-64 years) or elderly onset (>=65 years). RESULTS: A total of 1665 patients were confirmed to have IBD; 272 patients were >=65 years at IBD diagnosis. Whites were more likely than non whites to have elderly-onset IBD (adjusted odds ratio 2.26, 95% confidence interval 1.36-3.76). Patients with ulcerative colitis were more likely than CD patients to have elderly-onset IBD (aOR 1.50, 95% confidence interval 1.11-2.03). Compared with patients with adult-onset CD, patients with elderly-onset CD were more likely to have isolated colonic disease and nonstricturing, nonpenetrating phenotype, but less likely to have perianal complications or receive immunosuppressants. Rates of bowel resection, and both colonic and extra-colonic malignancies did not differ based on age of IBD onset. CONCLUSIONS: There are several significant differences in the disease characteristics between adult- and late-onset IBD; these differences may reflect differences in natural history of IBD and influence approaches to management among patients with elderly-onset IBD. PMID- 27482974 TI - Correlation Between Calprotectin and Modified Rutgeerts Score. AB - BACKGROUND: Endoscopic recurrence after surgery for Crohn's disease (CD) is high, and it has important prognostic value. Crohn's disease will recur in the majority of patients after surgery. Fecal calprotectin (FC) and lactoferrin (FL) have attracted interest in the postoperative setting for predicting relapse. We have evaluated the accuracy of FC and FL in diagnosing endoscopic recurrence (ER) using the modified Rutgeerts score (MRS) compared with the Rutgeerts score (RS). METHODS: A series of consecutive patients who underwent ileocolonic resection for Crohn's disease were evaluated. Biomarkers, clinical indexes, and fecal markers were recorded on the day of ileocolonoscopy. ER was defined as a MRS >= i2b or a RS >= i2. RESULTS: Ninety-nine patients were included in this prospective cohort. The median time between surgery and colonoscopy was 87.5 months (IQR, 31-137). FC and FL levels were higher in patients with ER than in those in remission (Median FC, 196.5 MUg/g [IQR, 96-634 MUg/g] versus 42.1 MUg/g [IQR 19-91.60 MUg/g; P < 0.001]; Median FL, 23.27 MUg/g [IQR 8.9-47.8 MUg/g] versus 2 MUg/g [IQR 0.9-7.26 MUg/g; P < 0.001]). Using the MRS, 34% of patients presented with ER compared with 76% if the RS was used. The RS performed worse than the MRS with a decrease in sensitivity (74% versus 48% for FC and 85% versus 55% for FL) and in NPV (91% versus 33% for FC, and 90% versus 37% for FL). Furthermore, the accuracy of the MRS was higher than that of the RS (75% versus 55%). CONCLUSIONS: Both FC and FL proved to correlate well with endoscopic findings in the evaluation of Crohn's disease after surgery. Both markers predicted recurrence with greater accuracy when the MRS was used. Fecal markers can be used to monitor disease recurrence after intestinal resection, with patients being selected to undergo further endoscopic evaluation. PMID- 27482975 TI - Antibody-Based Targeted Delivery of Interleukin-22 Promotes Rapid Clinical Recovery in Mice With DSS-Induced Colitis. AB - BACKGROUND: We have recently described the potential of the alternatively spliced extradomain A of fibronectin as a target for antibody-based pharmacodelivery applications in ulcerative colitis. Here, we report on the cloning and therapeutic properties of novel antibody-based fusion proteins, comprising the F8 antibody specific to extradomain A and murine interleukin (IL)-22, a globular cytokine belonging to the IL10 family. A protective function for IL22 in colitis has previously been described, as this cytokine induces antimicrobial, proliferative, and antiapoptotic pathways, preventing tissue damage and promoting epithelial repair. METHODS: Two fusion proteins comprising IL22, fused at the N- or at the C-terminus of the F8 antibody in diabody format, were expressed in mammalian cells. The ability of radiolabeled preparations of the 2 fusion proteins to localize at sites of disease was assessed by autoradiography in a murine model of dextran sodium sulfate-induced colitis and by quantitative biodistribution analysis in a syngeneic mouse teratocarcinoma model. Therapeutic activity was assessed in mice with dextran sodium sulfate-induced colitis, which received intravenous injections of antibody-cytokine fusion proteins. RESULTS: Both fusion proteins were able to selectively accumulate at the site of disease. The fusion protein with the cytokine moiety at the N-terminal extremity (IL22-F8) exhibited better results than the C-terminal fusion, both in terms of targeting selectivity and therapeutic efficacy. Mice treated with IL22-F8 showed a more rapid recovery from clinical symptoms compared with controls and improved macroscopic and microscopic morphology of the colon. CONCLUSIONS: IL22-F8 is a promising biopharmaceutical drug candidate for the treatment of ulcerative colitis. PMID- 27482976 TI - Rising Incidence of Inflammatory Bowel Disease in Canterbury, New Zealand. AB - BACKGROUND: A population-based study of inflammatory bowel disease (IBD) in the Canterbury province of New Zealand demonstrated an incidence of Crohn's disease (CD) of 16.5 per 100,000 population in 2004, along with a high rate of IBD overall. At the time, this was one of the highest rates of CD in the world. The current study aimed to ascertain the incidence of IBD in the same area 10 years later. METHODS: All patients diagnosed with IBD in 2014 within the Canterbury region were identified and characterized. Diagnosis and disease classification were ascertained using standard accepted criteria. Projected population data for age and gender were used to calculate incidence rates for IBD overall and for CD, ulcerative colitis (UC), and inflammatory bowel disease-unclassified (IBDU). RESULTS: During the 2014 years, 205 patients were diagnosed with IBD in Canterbury. This group comprised 134 patients with CD, 69 with UC, and 2 with IBDU. The age-standardized incidence of IBD, CD, UC, and IBDU was 39.5, 26.4, 12.6, and 0.17 per 100,000, respectively. Disease location of CD patients was evenly distributed (ileal 29%, colonic 35%, and ileocolonic 32%). Similarly, patients with UC had even distribution of proctitis, left-sided, and extensive disease. CONCLUSIONS: This study demonstrates a substantial increase in the incidence of IBD in this geographically well-defined area. Overall, incidence rates were 1.6-fold greater than when assessed 10 years earlier. The reasons contributing to these continued increases remain unclear. However, further increases in rates of IBD indicate growing health system demands in the future. PMID- 27482977 TI - Environmental Hygiene and Risk of Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. AB - BACKGROUND: According to the hygiene hypothesis, individuals raised in a sanitary environment have a higher risk of developing inflammatory bowel diseases (IBD). However, results have been inconsistent. We conducted this systematic review of factors related to environmental hygiene and risk of IBD, Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A systematic search was performed on MEDLINE between 1980 and 2015 to identify studies of the association between IBD and contact with pets and farm animals, number of siblings, bedroom sharing in childhood, and access to personal toilet and hot water. Random- or fixed-effect meta-analyses were performed, and analysis further stratified based on ethnicity of the included cohort. RESULTS: A total of 29 relevant studies were included. Having a pet (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.63-0.88) and contact with farm animals was inversely associated with risk of IBD (OR, 0.45; 95% CI, 0.31-0.60). However, the strength of association with farm animals was statistically stronger in non-white cohorts (OR, 0.27; 95% CI, 0.02-0.53) than in white cohorts (OR, 0.55; 95% CI, 0.45-0.65) (P = 0.028). Access to toilet (OR, 0.71; 95% CI, 0.56-0.85) and hot water (OR, 0.67; 95% CI, 0.44-0.89) was inversely associated with UC in non-white populations but not whites. Having more than 2 siblings was inversely associated with risk of CD. CONCLUSIONS: Several factors pertaining to reduced environmental hygiene are inversely associated with risk of IBD. However, underlying ethnicity influences susceptibility to the effect of these factors. PMID- 27482978 TI - Impact of Specialized Inpatient IBD Care on Outcomes of IBD Hospitalizations: A Cohort Study. AB - BACKGROUND: The management of inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) is increasingly complex. Specialized care has been associated with improved ambulatory IBD outcomes. AIMS: To examine if the implementation of specialized inpatient IBD care modified short-term and long-term clinical outcomes in IBD-related hospitalizations. METHODS: This retrospective cohort study included IBD patients hospitalized between July 2013 and April 2015 at a single tertiary referral center where a specialized inpatient IBD care model was implemented in July 2014. In-hospital medical and surgical outcomes as well as postdischarge outcomes at 30 and 90 days were analyzed along with measures of quality of in-hospital care. Effect of specialist IBD care was examined on multivariate analysis. RESULTS: A total of 408 IBD-related admissions were included. With implementation of specialized IBD inpatient care, we observed increased frequency of use of high-dose biologic therapy for induction (26% versus 9%, odds ratio 5.50, 95% confidence interval 1.30-23.17) and higher proportion of patients in remission at 90 days after discharge (multivariate odds ratio 1.60, 95% confidence interval 0.99-2.69). Although there was no difference in surgery by 90 days, among those who underwent surgery, early surgery defined as in-hospital or within 30 days of discharge, was more common in the study period (71%) compared with the control period (46%, multivariate odds ratio 2.73, 95% confidence interval 1.22-6.12). There was no difference in length of stay between the 2 years. CONCLUSIONS: Implementation of specialized inpatient IBD care beneficially impacted remission and facilitated early surgical treatment. PMID- 27482979 TI - Assessing Self-reported Medication Adherence in Inflammatory Bowel Disease: A Comparison of Tools. AB - BACKGROUND: Capturing (non)-adherence to medical prescriptions in patients with inflammatory bowel disease (IBD) is challenging. We aimed to compare 3 different tools to measure self-assessed medication adherence of patients with IBD. METHODS: Adult patients with Crohn's disease and ulcerative colitis were prospectively followed. IBD-specific medication use was collected by 3-monthly questionnaires. At 2.5 years of follow-up, medication adherence was assessed using 3 tools: (1) the 8-item Morisky Medication Adherence Scale (MMAS-8), (2) the single question how well patients take their daily medication using a Visual Analogue Scale (VAS), and (3) the Forget Medicine scale (FM), assessing how often patients forget their medication. Cross-sectional agreement among measures was visualized with scatterplots and quantified with Spearman's rank correlations. RESULTS: In total, 913 patients with IBD were analyzed, 697 of whom received IBD specific medication. High adherence on the MMAS-8 was consistent with high scores on the VAS and low scores on the FM. Disagreement between tools increased when patients were less adherent. A correlation of 0.44 was found between the MMAS-8 and VAS; -0.59 between the MMAS-8 and FM, and -0.55 between the VAS and FM (all P < 0.01). The VAS most optimally represented the quantitative variability of adherence, whereas the MMAS-8 and the FM might have resulted in overestimation or underestimation of adherence due to unequal differences in outcome possibilities. CONCLUSIONS: In patients with IBD, a VAS seems the most appropriate tool for quantifying medication adherence in clinical practice. The MMAS-8 may be used additionally to provide insight in specific reasons for non-adherence. PMID- 27482980 TI - Patient-reported Anxiety: A Possible Predictor of Pediatric Inflammatory Bowel Disease Health Care Use. AB - BACKGROUND: Anxiety is linked with adverse health-related outcomes and increased health-seeking behaviors among patients with chronic illness. Yet, this relationship has received little attention in pediatric inflammatory bowel disease. The aim of this study was to examine whether anxiety symptoms predicted youth at increased risk for repeated disease relapse and greater gastrointestinal health care use over the subsequent 12 months. METHODS: Eighty-six pediatric patients aged 11 to 18 years (M = 14.7, SD = 2.0), and their caregivers completed a validated anxiety questionnaire during a gastrointestinal specialty appointment (baseline). Medical records were reviewed for the subsequent year to record the number of disease relapses and gastrointestinal health care services and generate disease activity scores at baseline and 12 months. Analysis of variance was used to examine anxiety levels between those who experienced <=1 versus >=2 disease relapses. Poisson regressions were used to model the relationship between child- and caregiver-reported anxiety and health care use, controlling for disease activity. RESULTS: The sample was predominantly white (81%) and male (56%). Patients with higher anxiety at baseline (M = 19.6; SD = 13.7) had more frequent (>=2) disease relapses compared with those with lower anxiety at baseline (M = 12.6; SD = 10.3). Higher anxiety, irrespective of reporter, also predicted greater total gastrointestinal health care use (P < 0.01). This included hospital based interventions (P < 0.01), but not office encounters or outpatient endoscopic procedures. Findings remained significant after controlling for disease severity (P < 0.05). CONCLUSIONS: Assessment of anxiety may be one mechanism by which to identify those youth who are most vulnerable for disease exacerbation and costly interventions in the near future. PMID- 27482981 TI - Why Does Threshold Level Change in Transcranial Motor-evoked Potentials During Surgery for Supratentorial Lesions? AB - BACKGROUND: Rising threshold level during monitoring of motor-evoked potentials (MEP) using transcranial electrical stimulation (TES) has been described without damage to the motor pathway in the cranial surgery, suggesting the need for monitoring of affected and unaffected hemisphere. We aimed to determine the factors that lead to a change in threshold level and to establish reliable criteria for adjusting stimulation intensity during surgery for supratentorial lesions. MATERIALS AND METHODS: Between October 2014 and October 2015, TES-MEP were performed in 143 patients during surgery for unilateral supratentorial lesions in motor-eloquent brain areas. All procedures were performed under general anesthesia using a strict protocol to maintain stable blood pressure. MEP were evaluated bilaterally to assess the percentage increase in threshold level, which was considered significant if it exceeded 20% on the contralateral side beyond the percentage increase on the ipsilateral side. Patients who developed a postoperative motor deficit were excluded. Volume of subdural air was measured on postoperative magnetic resonance imaging. Logistic regression was performed to identify factors associated with the intraoperative recorded changes in threshold level. RESULTS: A total of 123 patients were included in the study. On the affected side, 82 patients (66.7%) showed an increase in threshold level, which ranged from 2% to 48% and 41 patients (33.3%) did not show any change. The difference to the unaffected side was under 20% in all patients. The recorded range of changes in the systolic and mean pressure did not exceed 20 mm Hg in any of the patients. Pneumocephalus was detected on postoperative magnetic resonance imaging scans in 87 patients (70.7%) and 81 of them (93.1%) had an intraoperative increase in threshold level on either sides. Pneumocephalus was the only factor associated with an increase in threshold level on the affected side (P<0.001), while each of pneumocephalus and length of the procedure correlated with a change in threshold level on the unaffected side (P<0.001 and 0.032, respectively). CONCLUSIONS: Pneumocephalus was the only factor associated with increase in threshold level during MEP monitoring without damaging motor pathway. Threshold level on the affected side can rise up to 48% without being predictive of postoperative paresis, as long as the difference between the increased threshold of the affected and unaffected side is within 20%. Changes in systolic or mean blood pressure within a range of 20 mm Hg do not seem to influence intraoperative MEP. PMID- 27482982 TI - Effective improvement in optical properties of colloidal CdTe@ZnS quantum dots synthesized from aqueous solution. AB - Efficient synthesis of high-quality quantum dots (QDs) with excellent optical properties by aqueous synthesis is still of great significance for extended optical applications. Herein we highlight the advantages in optical properties of colloidal CdTe@ZnS QDs prepared by a facile and highly effective aqueous synthesis method. These achievements were realized by delicate manipulation of the conditions involved in nucleation and the growth process. Transmission electron microscopy (TEM) images indicated the QDs were uniform size and well dispersible. The emission peaks of the as-prepared QDs could shift from 496 to 698 nm with narrow full width at half maximum (FWHM), and the corresponding fluorescent color changed from green to red. Moreover, the emission could even reach to the near-infrared (NIR) region (706-796 nm) by extending the reaction time. The highest photoluminescence (PL) quantum yield (QY) of the QDs could reach to 60%, and the average of FWHM was about 55 nm. To address the problem of wide size-distribution in PL QY decrease and FWHM broadening, the colloids of QDs prepared at long reaction time (above 3 h) were centrifuged (12 000 r min(-1)). In addition, the assessment of QD cytotoxicity indicated the CdTe@ZnS QDs were much less cytotoxic and showed good biocompatibility. Compared with organic synthesis, our aqueous synthesis of QDs could be carried out efficiently on a large scale and showed good batch-to-batch reproducibility. The as-prepared CdTe@ZnS QDs exhibited excellent optical properties and hold a good potential to be applied in optoelectronic and biological applications. PMID- 27482983 TI - Neural correlates of motor recovery after robot-assisted stroke rehabilitation: a case series study. AB - Robot-assisted bilateral arm therapy (RBAT) has shown promising results in stroke rehabilitation; however, connectivity mapping of the sensorimotor networks after RBAT remains unclear. We used fMRI before and after RBAT and a dose-matched control intervention (DMCI) to explore the connectivity changes in 6 subacute stroke patients. Sensorimotor functions improved in the RBAT and DMCI groups after treatment. Enhanced activation changes were observed in bilateral primary motor cortex (M1) and bilateral supplementary motor area (SMA) after RBAT. Dynamic causal model analysis revealed that interhemispheric connections were enhanced in RBAT patients. These preliminary findings suggest that intracortical and intercortical coupling might underlie poststroke RBAT. PMID- 27482985 TI - NADH oxidase, a new player in the field of Streptococcus suis infection. PMID- 27482984 TI - SPIROMICS Protocol for Multicenter Quantitative Computed Tomography to Phenotype the Lungs. AB - Multidetector row computed tomography (MDCT) is increasingly taking a central role in identifying subphenotypes within chronic obstructive pulmonary disease (COPD), asthma, and other lung-related disease populations, allowing for the quantification of the amount and distribution of altered parenchyma along with the characterization of airway and vascular anatomy. The embedding of quantitative CT (QCT) into a multicenter trial with a variety of scanner makes and models along with the variety of pressures within a clinical radiology setting has proven challenging, especially in the context of a longitudinal study. SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), sponsored by the National Institutes of Health, has established a QCT lung assessment system (QCT-LAS), which includes scanner-specific imaging protocols for lung assessment at total lung capacity and residual volume. Also included are monthly scanning of a standardized test object and web-based tools for subject registration, protocol assignment, and data transmission coupled with automated image interrogation to assure protocol adherence. The SPIROMICS QCT-LAS has been adopted and contributed to by a growing number of other multicenter studies in which imaging is embedded. The key components of the SPIROMICS QCT-LAS along with evidence of implementation success are described herein. While imaging technologies continue to evolve, the required components of a QCT-LAS provide the framework for future studies, and the QCT results emanating from SPIROMICS and the growing number of other studies using the SPIROMICS QCT-LAS will provide a shared resource of image-derived pulmonary metrics. PMID- 27482986 TI - Fetopathies associated with exposure to angiotensin converting enzyme inhibitor from Tropaeolum majus L. AB - The prevalence of the use of herbal medicines is on the rise across the world, especially amongst pregnant women. A fact that draws attention is that many species commonly used by pregnant women, including the Tropaeolum majus L. (Tropaeolaceae), also present inhibitory activity on the angiotensin-converting enzyme (ACE). Herein, we have investigated the effects of T. majus extract (HETM) on fetal development, evaluating its relationship with possible ACE inhibitory activity. Pregnant Wistar rats were treated with different HETM doses (3, 30 and 300 mg/kg/day) from gestational days 8-20. Rats were sacrificed on the day 20 of pregnancy and the following parameters were evaluated: clinical symptoms of maternal toxicity; maternal body weight; feed and water intake; maternal liver, kidney, and ovary weights, maternal ACE activity and aldosterone levels, live fetuses mean; dead fetuses percentage, fetus weight, and fetal malformation. All pregnant rats treated with high HETM doses showed significant reduction in plasma ACE activity accompanied by a decrease in serum aldosterone levels. Moreover, significant changes in fetal development were observed, including growth retardation and renal damage after 20 days of gestation. Thus, data presented demonstrate the significant effects of the use of HETM on fetal development during pregnancy. PMID- 27482987 TI - A Decade of AENJ. PMID- 27482988 TI - Treating Adult Asthma Exacerbations With a 2-Day Course of Dexamethasone in the Emergency Department: New Protocols to Improve Compliance. AB - The Research to Practice column is intended to improve the research critique skills of the advanced practice registered nurse and emergency nurse (RN) and to assist with the translation of research into practice. For each column, a topic and a research study are selected. The stage is set with a case presentation. The research article is then reviewed and critiqued, and the findings are discussed in relation to the case presented. In the current column, we examine the findings of from their article, titled "Two Days of Dexamethasone Versus 5 Days of Prednisone in the Treatment of Acute Asthma: A Randomized Controlled Trial." PMID- 27482989 TI - Dislocation of the Temporomandibular Joint and Relocation Procedures. AB - Temporomandibular joint (TMJ) dislocation requires prompt medical attention due to the crucial impact of airway, nutrition acquisition, and communication. Recognition of this injury by the practitioner, based on clinical presentation and history, is paramount for identification of accurate diagnosis and prompt treatment of TMJ dislocation. Relocation or reduction methods vary on the basis of the severity of the injury and whether it is an acute or chronic dislocation. PMID- 27482990 TI - N-Acetylcysteine Use in Non-Acetaminophen-Induced Acute Liver Failure. AB - This article will review the available evidence related to the management of non acetaminophen induced acute liver failure with N-acetylcysteine. Randomized controlled trials and a meta-analysis were included in this review. The efficacy of N-acetylcysteine in the treatment of acute liver failure from causes other than acetaminophen toxicity was evaluated. The efficacy of N-acetylcysteine in non-acetaminophen-induced acute liver failure is limited to specific patient populations. Patients classified as Coma Grade I or II are more likely to benefit from the use of this agent. The use of N-acetylcysteine is associated with improved transplant-free survival, not overall survival, in adults. N Acetylcysteine does not improve the overall survival of patients with non acetaminophen-induced acute liver failure but may be beneficial in those patients with Coma Grades I-II. Liver transplantation remains the only definitive therapy in advanced disease. PMID- 27482991 TI - Case Report: Postpartum Cough and Dyspnea. AB - Peripartum/postpartum cardiomyopathy (PPCM) is a rare condition associated with pregnancy in which there is left ventricular (LV) dysfunction resulting in symptoms of heart failure (). This occurs in previously healthy women and is seen in the last month of pregnancy or during the first 5 months postpartum (). Incidence ranges from 1 in 1,300 to 1 in 15,000 pregnancies in the United States (). A case study is presented of a patient with severe impairment of LV function seen in the emergency department (ED). The ED is a common location for initial presentation; therefore, the ED provider should be cognizant of key features of PPCM. The differential diagnosis and medical management of PPCM are discussed. Emergency department management should focus on 3 key elements: an increase in inotropy and a reduction in preload and afterload. Differences between postpartum and peripartum states are outlined. PMID- 27482992 TI - Shift in Emergency Department Provider Attitudes Toward Patients With Sickle Cell Disease. AB - Patients with sickle cell disease frequently seek care in the emergency department. They have reported experiencing negative attitudes from emergency providers. This study was undertaken to evaluate change in emergency provider attitudes toward patients with sickle cell disease over a 2.5-year time period when several educational efforts were ongoing. The General Perceptions about Sickle Cell Disease Patients Scale was used to measure emergency provider attitudes at 2 emergency departments at baseline, 6 months, and 30 months into the project. Analyses of covariance were used to test for effects of site, time, and provider type, as well as their interactions, on Negative attitudes, Uneasiness With Care, and Positive Attitudes subscale scores, after controlling for years of provider experience. The number of surveys returned at the 3 time points was 216, 182, and 113, respectively. The mean Negative Attitudes subscale scores decreased significantly over time, with significantly higher mean Negative Attitudes subscale scores reported by nurses than by physicians. The mean Uneasiness With Care subscale scores did not differ significantly over time, but the mean score was significantly higher for physicians than for nurses. The mean Positive Attitudes subscale scores significantly improved over time, with physicians tending to have a higher mean Positive Attitudes subscale scores than nurses. During the observation period, there was improvement in attitudes, with a decline in mean Negative Attitudes subscale scores and increase in mean Positive Attitudes subscale scores. Physicians reported better attitudes than nurses. PMID- 27482993 TI - The Sexual Assault Nurse Examiner's Interactions Within the Sexual Assault Response Team: A Systematic Review. AB - Many emergency department nurses care for the sexually assaulted victim, when sexual assault nurse examiner (SANE) programs are not available. Therefore, it is important for emergency department nurses to understand the roles of both the SANE and the sexual assault response team (SART). The purpose of this systematic review was to identify the current research on the integration of the SANE among the SART and evaluate the gaps in research of the SANE's role, attitude, behavior, and satisfaction within the collaborative SART. Studies published between 2004 and 2014 using key words were evaluated. A 3-stage search strategy revealed 582 articles. The articles were assessed and categorized according to Level of Evidence definitions. Twelve qualitative and mixed-methods studies were identified. Studies ranged from SART protocols or responses to situational factors to SANE relationships with other SART members. The review reflected the need for more research within the collaborative atmosphere of this multidisciplinary and interagency team that defines the SART, and the individual member's perceptions. Further studies are needed on the SANE's impact on patient outcome and the emergency department nurses role when a SANE or SART program is not available. PMID- 27482994 TI - Dental Procedures. AB - Dental problems are a common complaint in emergency departments in the United States. There are a wide variety of dental issues addressed in emergency department visits such as dental caries, loose teeth, dental trauma, gingival infections, and dry socket syndrome. Review of the most common dental blocks and dental procedures will allow the practitioner the opportunity to make the patient more comfortable and reduce the amount of analgesia the patient will need upon discharge. Familiarity with the dental equipment, tooth, and mouth anatomy will help prepare the practitioner for to perform these dental procedures. PMID- 27482995 TI - Can Team Triage Improve Patient Flow in the Emergency Department? A Systematic Review and Meta-Analysis. AB - This systematic review was performed as a feasibility study for revamping the triage service of an emergency department (ED) in a district hospital. In view of the overcrowding problem that plagues EDs worldwide, we reviewed evidence from randomized controlled trials (RCTs) to determine whether ED team triage improves patient flow in comparison with single-nurse triage. We measured improvement in patient flow in terms of the reduction in length of stay (LOS) or wait time (WT) for all ED patients. Adopting the Cochrane methodology, we searched and evaluated data sources for RCTs comparing patients assessed by an ED triage team, with patients receiving single-nurse triage at the same site. The data extracted were independently reviewed by 2 authors for inclusion and quality assessment. As for risk of bias across studies, there was an overall assessment of every outcome across the included studies according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for RCTs. In total, 2,164 studies were identified and 2,106 were excluded on the basis of title/abstract, leaving 58 articles for full assessment. Four trials (all cluster RCTs) involving 14,772 patients (165 clusters) met the inclusion criteria. On the basis of our analysis, there was no statistically significant or clinically relevant reduction of LOS and WT for all patients in these studies. One study reported death as an outcome: Relative risk was 0.34 (95% CI [0.01, 8.24]), which suggested that team triage might reduce mortality. Overall, although we have found no conclusive evidence from RCTs to support the use of team triage for improving patient flow in the ED, the results need not deter nursing managers intending to introduce team triage for improving the morale of the triage nurse. However, they may need to consider economic and organizational factors, such as resource reallocation and staff receptiveness, in implementing the new practice. PMID- 27482996 TI - Dislocation of the Temporomandibular Joint and Relocation Procedures. PMID- 27482997 TI - Oral Presentations 2016 AANS Annual Scientific Meeting Chicago, IL * April 30-May 4, 2016 Published online April 1, 2016; DOI: 10.3171/2016.4.JNS.AANS2016abstracts. PMID- 27482998 TI - Effectiveness of Antidepressant Medications for Symptoms of Irritability and Disruptive Behaviors in Children and Adolescents. AB - OBJECTIVES: Chronic irritability is a common presenting symptom in children and youth in both clinical settings (25%) and in the community (6%-8%). Treatment of irritability is relatively understudied. The purpose of this article is to synthesize evidence regarding the efficacy and safety of antidepressant medications for the treatment of irritability and related symptom dimensions in children and youth. METHODS: Systematic review of the literature was conducted to identify studies (including youth aged 6-18) that assessed the effectiveness of antidepressant medications for the treatment of irritability or related behavioral phenotypes, including aggression or symptoms of. Studies of youth with developmental disabilities or autism spectrum disorders were excluded. RESULTS: We identified 99 studies (three randomized trials) assessing the effect of antidepressants in improving irritability, aggression, or oppositional symptoms as secondary outcomes. Only two studies specifically measured the outcome of irritability. Eight of the 11 studies reported significant effects on aggression, oppositionality, or irritability with antidepressant exposure, although effect sizes in all, but two of these, studies were less than 0.25. These effects were significantly reduced, but remained significant in seven of these studies after controlling for changes in comorbid depression scores with treatment. The other three studies reported no change, an increase in frequency of self-harm or aggressive behaviors or benefit in only a subsample of youth who tolerated the antidepressants after 1 year of follow-up. CONCLUSION: Antidepressant medication exposure appears to have a small effect on irritability and related symptoms in youth. Heterogeneity in the study sample and absence of irritability being measured as a primary outcome across studies restrict the validity of the conclusions. Irritability is a debilitating outcome that needs specific attention in medication treatment studies. PMID- 27482999 TI - Unhealthy alcohol use in primary care patients who screen positive for drug use. AB - BACKGROUND: Unhealthy alcohol use (UAU) is common among people who use other drugs; however, little information is available about UAU among patients who screen positive for drugs in primary care, where the clinical priority might be assumed to be drug use. This study aimed at describing the occurrence of UAU and its association with substance use-related outcomes in such patients. METHODS: This cohort study is a secondary analysis of data from a randomized trial of brief intervention for primary care patients screening positive for drug use. UAU was assessed at baseline; the main independent variable was any heavy drinking day in the past month. Outcomes including drug use characteristics and substance use-related consequences were assessed at baseline and 6 months later. RESULTS: Of 589 primary care patients with drug use, 48% had at least 1 past-month heavy drinking day. The self-identified main drug was marijuana for 64%, cocaine for 18%, and an opioid for 16%. Any heavy drinking at baseline was negatively associated with number of days use of the main drug at 6 months (incidence rate ratio [IRR] = 0.75, 95% confidence interval [CI]: 0.62-0.91), but positively associated with the use of more than 1 drug (IRR = 1.73, 95% CI: 1.17-2.55) and unsafe sex (odds ratio [OR] = 1.90, 95% CI: 1.21-2.98). CONCLUSION: Unhealthy alcohol use is common among patients identified by screening in primary care as using other drugs. Unexpectedly, UAU was negatively associated with days of main drug use. But, as expected, it was positively associated with other drug use characteristics and substance use-related consequences. These findings suggest that attention should be given to alcohol use among primary care patients who use other drugs. PMID- 27483000 TI - Impact of ionic and nanoparticle speciation states of silver on light harnessing photosynthetic events in Spirodela polyrhiza. AB - Owing to wide range of applications, nanotechnology is growing expeditiously. Likely negative impact of nanoparticles (NPs), which are inevitably released into our surroundings, on living organisms is of growing concern. Findings presented here are outcome of investigations carried out to evaluate the impact of ionic and NP speciation states of silver on light harnessing photosynthetic events in Spirodela polyrhiza fronds. Fronds exposed to ionic speciation state showed significant decline in PS (photosystem) II efficiency (Fv/Fm; variable fluorescence/maximal fluorescence), while those exposed to silver nanoparticles (Ag-NPs) showed marginal decline. Accordingly, decline in amplitude of Chl a fluorescence transients was sharper in fronds treated with Ag+ than those treated with Ag-NPs. Of the various phases Chl a fluorescence transient, J-I phase [which reflects reduction of plastoquinone (PQ) pool] was most sensitive to both Ag+ and Ag-NPs. Phenomenological yield models, built using Biolyzer software, revealed that fronds exposed to Ag+ possessed significantly lower potential to trap and harness absorbed light energy for photochemical reactions than those exposed to Ag-NPs. Accordingly, dissipation of absorbed light energy as heat was significantly higher in fronds exposed to Ag+ than those exposed to Ag-NPs. These findings revealed that NP speciation state of silver is significantly less toxic to light harnessing photosynthetic machinery of S. polyrhiza, compared to ionic speciation state. PMID- 27483001 TI - Economic Evaluation of Companion Diagnostic Testing for EGFR Mutations and First Line Targeted Therapy in Advanced Non-Small Cell Lung Cancer Patients in South Korea. AB - BACKGROUND: As targeted therapy becomes increasingly important, diagnostic techniques for identifying targeted biomarkers have also become an emerging issue. The study aims to evaluate the cost-effectiveness of treating patients as guided by epidermal growth factor receptor (EGFR) mutation status compared with a no-testing strategy that is the current clinical practice in South Korea. METHODS: A cost-utility analysis was conducted to compare an EGFR mutation testing strategy with a no-testing strategy from the Korean healthcare payer's perspective. The study population consisted of patients with stage 3b and 4 lung adenocarcinoma. A decision tree model was employed to select the appropriate treatment regimen according to the results of EGFR mutation testing and a Markov model was constructed to simulate disease progression of advanced non-small cell lung cancer. The length of a Markov cycle was one month, and the time horizon was five years (60 cycles). RESULTS: In the base case analysis, the testing strategy was a dominant option. Quality-adjusted life-years gained (QALYs) were 0.556 and 0.635, and total costs were $23,952 USD and $23,334 USD in the no-testing and testing strategy respectively. The sensitivity analyses showed overall robust results. The incremental cost-effectiveness ratios (ICERs) increased when the number of patients to be treated with erlotinib increased, due to the high cost of erlotinib. CONCLUSION: Treating advanced adenocarcinoma based on EGFR mutation status has beneficial effects and saves the cost compared to no testing strategy in South Korea. However, the cost-effectiveness of EGFR mutation testing was heavily affected by the cost-effectiveness of the targeted therapy. PMID- 27483003 TI - Necrotizing Soft Tissue Infections: A Review. AB - BACKGROUND: Soft tissue infections are a common reason for general surgical consultation. Necrotizing soft tissue infections (NSTI) are a rapidly progressive form of this infection that account for significant morbidity and many deaths. METHODS: Review of relevant English-language publications. RESULTS: There are approximately 500-1,500 cases of NSTI annually in the United States, although accurate estimates of their frequency are difficult to obtain. These infections may be polymicrobial or monomicrobial, and substantial regional heterogeneity exists regarding anatomic location and the involved organisms. Source control with early surgical debridement and targeted anti-microbial therapy are the mainstays of treatment. CONCLUSION: Necrotizing soft tissue infections remain a common indication for general surgical consultation. Early diagnosis and prompt surgical treatment are essential for effective control. PMID- 27483002 TI - Blinding Trachoma: Systematic Review of Rates and Risk Factors for Progressive Disease. AB - BACKGROUND: Sight loss from trachoma is the end result of a scarring disease process starting in early childhood and characterised by repeated episodes of conjunctival inflammation (active trachoma). Subsequently, the conjunctiva becomes scarred, causing the eyelashes to turn inwards and scratch the cornea (trichiasis), damaging the corneal surface and leading to corneal opacification and visual impairment. It is thought that this process is initiated and driven by repeated infection with Chlamydia trachomatis. We review published longitudinal studies to re-examine the disease process, its progression rates and risk factors. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed for studies presenting incidence and progression data for the different stages of trachoma natural history. We only included studies reporting longitudinal data and identified 11 publications meeting this criterion. The studies were very heterogeneous in design, disease stage, duration, size and location, precluding meta-analysis. Severe conjunctival inflammation was consistently associated with incident and progressive scarring in five studies in which this was examined. One study reported an association between C. trachomatis infection and incident scarring. No studies have yet demonstrated an association between C. trachomatis infection and progressive scarring. Several studies conducted in regions with low prevalence active disease and C. trachomatis infection found evidence of on-going scarring progression. CONCLUSIONS/SIGNIFICANCE: Overall, there are few longitudinal studies that provide estimates of progression rates and risk factors, reflecting the challenges of conducting such studies. Our understanding of this disease process and the long-term impact of control measures is partial. Intense conjunctival inflammation was consistently associated with scarring, however, direct evidence demonstrating an association between C. trachomatis and progression is limited. This suggests that on-going chlamydial reinfection may not be mandatory for progression of established scarring, indicating that sight threatening trichiasis may continue to evolve in older people in formerly endemic populations, that will require service provision for years after active disease is controlled. PMID- 27483005 TI - Computational Simulation of the Activation Cycle of Galpha Subunit in the G Protein Cycle Using an Elastic Network Model. AB - Agonist-activated G protein-coupled receptors (GPCRs) interact with GDP-bound G protein heterotrimers (Galphabetagamma) promoting GDP/GTP exchange, which results in dissociation of Galpha from the receptor and Gbetagamma. The GTPase activity of Galpha hydrolyzes GTP to GDP, and the GDP-bound Galpha interacts with Gbetagamma, forming a GDP-bound G protein heterotrimer. The G protein cycle is allosterically modulated by conformational changes of the Galpha subunit. Although biochemical and biophysical methods have elucidated the structure and dynamics of Galpha, the precise conformational mechanisms underlying the G protein cycle are not fully understood yet. Simulation methods could help to provide additional details to gain further insight into G protein signal transduction mechanisms. In this study, using the available X-ray crystal structures of Galpha, we simulated the entire G protein cycle and described not only the steric features of the Galpha structure, but also conformational changes at each step. Each reference structure in the G protein cycle was modeled as an elastic network model and subjected to normal mode analysis. Our simulation data suggests that activated receptors trigger conformational changes of the Galpha subunit that are thermodynamically favorable for opening of the nucleotide binding pocket and GDP release. Furthermore, the effects of GTP binding and hydrolysis on mobility changes of the C and N termini and switch regions are elucidated. In summary, our simulation results enabled us to provide detailed descriptions of the structural and dynamic features of the G protein cycle. PMID- 27483004 TI - Mek1 Down Regulates Rad51 Activity during Yeast Meiosis by Phosphorylation of Hed1. AB - During meiosis, programmed double strand breaks (DSBs) are repaired preferentially between homologs to generate crossovers that promote proper chromosome segregation at Meiosis I. In many organisms, there are two strand exchange proteins, Rad51 and the meiosis-specific Dmc1, required for interhomolog (IH) bias. This bias requires the presence, but not the strand exchange activity of Rad51, while Dmc1 is responsible for the bulk of meiotic recombination. How these activities are regulated is less well established. In dmc1Delta mutants, Rad51 is actively inhibited, thereby resulting in prophase arrest due to unrepaired DSBs triggering the meiotic recombination checkpoint. This inhibition is dependent upon the meiosis-specific kinase Mek1 and occurs through two different mechanisms that prevent complex formation with the Rad51 accessory factor Rad54: (i) phosphorylation of Rad54 by Mek1 and (ii) binding of Rad51 by the meiosis-specific protein Hed1. An open question has been why inhibition of Mek1 affects Hed1 repression of Rad51. This work shows that Hed1 is a direct substrate of Mek1. Phosphorylation of Hed1 at threonine 40 helps suppress Rad51 activity in dmc1Delta mutants by promoting Hed1 protein stability. Rad51-mediated recombination occurring in the absence of Hed1 phosphorylation results in a significant increase in non-exchange chromosomes despite wild-type levels of crossovers, confirming previous results indicating a defect in crossover assurance. We propose that Rad51 function in meiosis is regulated in part by the coordinated phosphorylation of Rad54 and Hed1 by Mek1. PMID- 27483006 TI - De Novo Transcriptome Assembly and Annotation of the Leaves and Callus of Cyclocarya Paliurus (Bata1) Iljinskaja. AB - Cyclocarya Paliurus (Bata1) Iljinskaja contains various bioactive secondary metabolites especially in leaves, such as triterpenes, flavonoids, polysaccharides and alkaloids, and its leaves are widely used as an hyperglycemic tea in China. In the present paper, we sequenced the transcriptome of the leaves and callus of Cyclocarya Paliurus using Illumina Hiseq 4000 platform. After sequencing and de novo assembly, a total of 65,654 unigenes were generated with an N50 length of 1,244bp. Among them, 35,041 (53.37%) unigenes were annotated in NCBI Non-Redundant database, 19,453 (29.63%) unigenes were classified into Gene Ontology (GO) database, and 7,259 (11.06%) unigenes were assigned to Clusters of Orthologous Group (COG) categories. Furthermore, 11,697 (17.81%) unigenes were mapped onto 335 pathways in Kyoto Encyclopedia of Genes and Genomes (KEGG), among which 1,312 unigenes were identified to be involved in biosynthesis of secondary metabolites. In addition, a total of 11,247 putative simple sequence repeats (SSRs) were detected. This transcriptome dataset provides a comprehensive sequence resource for gene expression profiling, genetic diversity, evolution and further molecular genetics research on Cyclocarya Paliurus. PMID- 27483007 TI - Healthcare Resource Utilisation Associated with Herpes Zoster in a Prospective Cohort of Older Australian Adults. AB - BACKGROUND: Herpes zoster (HZ) is a common condition that increases in incidence with older age but vaccines are available to prevent the disease. However, there are limited data estimating the health system burden attributable to herpes zoster by age. METHODS: In this study, we quantified excess healthcare resource usage associated with HZ during the acute/sub-acute period of disease (21days before to 90 days after onset) in 5952 cases and an equal number of controls matched on age, sex, and prior healthcare resource usage. Estimates were adjusted for potential confounders in multivariable regression models. Using population based estimates of HZ incidence, we calculated the age-specific excess number of health service usage events attributable to HZ in the population. RESULTS: Per HZ case, there was an average of 0.06 (95% CI 0.04-0.08) excess hospitalisations, 1.61 (95% CI 1.51-1.69) excess general practitioner visits, 1.96 (95% CI 1.86 2.15) excess prescriptions filled and 0.11 (95% CI 0.09-0.13) excess emergency department visits. The average number of healthcare resource use events, and the estimated excess per 100,000 population increased with increasing age but were similar for men and women, except for higher rates of hospitalisation in men. The excess annual HZ associated burden of hospitalisations was highest in adults >=80 years (N = 2244, 95%CI 1719-2767); GP visits was highest in those 60-69 years (N = 50567, 95%CI 39958-61105), prescriptions and ED visits were highest in 70-79 years (N = 50524, 95%CI 40634-60471 and N = 2891, 95%CI 2319-3449 respectively). CONCLUSIONS: This study provides important data to establish the healthcare utilisation associated with HZ against which detailed cost-effectiveness analyses of HZ immunisation in older adults can be conducted. PMID- 27483009 TI - Construction and Nanoscale Detection of Interfacial Charge Transfer of Elegant Z Scheme WO3/Au/In2S3 Nanowire Arrays. AB - Elegant Z-scheme WO3/Au/In2S3 nanowire arrays were precisely constructed through a facile step-by-step route. Surface potential change on pristine or In2S3-Au coated WO3 single nanowire under dark and illumination detected through a Kelvin probe force microscopy (KPFM) technique indicates that the vectorial holes transfer of In2S3 -> Au -> WO3 should occur upon the excitation of both WO3 and In2S3. In such charge transfer processes, the embedded Au nanoparticles in the heterojunction systems act as a charge mediator for electrons in the conduction band of WO3 and holes in the valence band of In2S3. The strong charge carrier separation ability of this structure will finally enhance the oxidation ability of WO3 with high concertation of photogenerated holes and, further, leave the free electrons in the In2S3 with long surviving time. Therefore, the unique Z scheme WO3/Au/In2S3 heterostructure shows great visible-light activity toward photocatalytic reduction of CO2 in the presence of water vapor into renewable hydrocarbon fuel (methane: CH4). PMID- 27483010 TI - Combining Ruthenium(II) Complexes with Metal-Organic Frameworks to Realize Effective Two-Photon Absorption for Singlet Oxygen Generation. AB - Singlet oxygen ((1)O2), as a reactive oxygen species, has garnered serious attention in physical, chemical, and biological studies. In this paper, we designed and synthesized a new type of singlet-oxygen generation system by exchanging cationic ruthenium complexes (RCs) into anionic bio-MOF-1. The resulting bio-MOF-1&RCs can be used as effective photocatalysts for generation of singlet oxygen under both single-photon and two-photon excitation. Especially, the excellent two-photon absorption (TPA) behavior of bio-MOF-1&RCs aroused our interest greatly because their two-photon absorption band lies in the optical window of biological tissue. Here, we measured the ability of bio-MOF-1&RCs to generate (1)O2 by irradiation under both 490 and 800 nm wavelength light in DMF. 1,3-Diphenylisobenzofuran (DPBF) and 2',7'-dichlorofluorescein (DCFH) were used as typical (1)O2 traps to detect and evaluate the efficiency of generation of (1)O2 under single-photon and two-photon excitation, respectively. Results indicated that bio-MOF-1&[Ru(phen)3](2+) was able to effectively generate (1)O2 under both conditions. Our work creates a novel synergistic TPA system with the excellent photophysical properties of RCs and the unique microporous structure benefit of MOFs, which may open a new avenue for creation of a cancer treatment system with both photodynamic therapy and chemotherapy. PMID- 27483008 TI - Clinical Evaluation of the BD FACSPrestoTM Near-Patient CD4 Counter in Kenya. AB - BACKGROUND: The BD FACSPrestoTM Near-Patient CD4 Counter was developed to expand HIV/AIDS management in resource-limited settings. It measures absolute CD4 counts (AbsCD4), percent CD4 (%CD4), and hemoglobin (Hb) from a single drop of capillary or venous blood in approximately 23 minutes, with throughput of 10 samples per hour. We assessed the performance of the BD FACSPresto system, evaluating accuracy, stability, linearity, precision, and reference intervals using capillary and venous blood at KEMRI/CDC HIV-research laboratory, Kisumu, Kenya, and precision and linearity at BD Biosciences, California, USA. METHODS: For accuracy, venous samples were tested using the BD FACSCaliburTM instrument with BD TritestTM CD3/CD4/CD45 reagent, BD TrucountTM tubes, and BD MultisetTM software for AbsCD4 and %CD4, and the SysmexTM KX-21N for Hb. Stability studies evaluated duration of staining (18-120-minute incubation), and effects of venous blood storage <6-24 hours post-draw. A normal cohort was tested for reference intervals. Precision covered multiple days, operators, and instruments. Linearity required mixing two pools of samples, to obtain evenly spaced concentrations for AbsCD4, total lymphocytes, and Hb. RESULTS: AbsCD4 and %CD4 venous/capillary (N = 189/ N = 162) accuracy results gave Deming regression slopes within 0.97-1.03 and R2 >=0.96. For Hb, Deming regression results were R2 >=0.94 and slope >=0.94 for both venous and capillary samples. Stability varied within 10% 2 hours after staining and for venous blood stored less than 24 hours. Reference intervals results showed that gender-but not age-differences were statistically significant (p<0.05). Precision results had <3.5% coefficient of variation for AbsCD4, %CD4, and Hb, except for low AbsCD4 samples (<6.8%). Linearity was 42-4,897 cells/MUL for AbsCD4, 182-11,704 cells/MUL for total lymphocytes, and 2-24 g/dL for Hb. CONCLUSIONS: The BD FACSPresto system provides accurate, precise clinical results for capillary or venous blood samples and is suitable for near-patient CD4 testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT02396355. PMID- 27483012 TI - Origin of Surface-Driven Passive Liquid Flows. AB - Passive liquid flow occurs in nature in the transport of water up tall trees and is desired for high-heat flux removal in thermal management devices. Typically, liquid-vapor surface tension is used to generate passive flows (e.g., capillary and Marangoni flows). In this work, we perform a fundamental molecular study on passive liquid flow driven by the solid-liquid surface tension force. Such surface tension values are first estimated by placing a liquid film over the surface and simulating various surface temperatures, followed by which simulations are performed by differential heating of the liquid film over the surface. Very strong passive liquid flows are obtained that lead to steady-state, continuous, and high-heat flux removal close to the maximum theoretical limit, as predicted by the kinetic theory of evaporation. Nondimensional empirical relations are developed for surface tension gradient, flow velocity, and evaporation rate. PMID- 27483011 TI - Saccadic Eye Movement Abnormalities in Children with Epilepsy. AB - Childhood onset epilepsy is associated with disrupted developmental integration of sensorimotor and cognitive functions that contribute to persistent neurobehavioural comorbidities. The role of epilepsy and its treatment on the development of functional integration of motor and cognitive domains is unclear. Oculomotor tasks can probe neurophysiological and neurocognitive mechanisms vulnerable to developmental disruptions by epilepsy-related factors. The study involved 26 patients and 48 typically developing children aged 8-18 years old who performed a prosaccade and an antisaccade task. Analyses compared medicated chronic epilepsy patients and unmedicated controlled epilepsy patients to healthy control children on saccade latency, accuracy and dynamics, errors and correction rate, and express saccades. Patients with medicated chronic epilepsy had impaired and more variable processing speed, reduced accuracy, increased peak velocity and a greater number of inhibitory errors, younger unmedicated patients also showed deficits in error monitoring. Deficits were related to reported behavioural problems in patients. Epilepsy factors were significant predictors of oculomotor functions. An earlier age at onset predicted reduced latency of prosaccades and increased express saccades, and the typical relationship between express saccades and inhibitory errors was absent in chronic patients, indicating a persistent reduction in tonic cortical inhibition and aberrant cortical connectivity. In contrast, onset in later childhood predicted altered antisaccade dynamics indicating disrupted neurotransmission in frontoparietal and oculomotor networks with greater demand on inhibitory control. The observed saccadic abnormalities are consistent with a dysmaturation of subcortical-cortical functional connectivity and aberrant neurotransmission. Eye movements could be used to monitor the impact of epilepsy on neurocognitive development and help assess the risk for poor neurobehavioural outcomes. PMID- 27483013 TI - Identification and Characterization of Salvia miltiorrhizain miRNAs in Response to Replanting Disease. AB - Replanting disease is a major factor limiting the artificial cultivation of the traditional Chinese medicinal herb Salvia miltiorrhiza. At present, little information is available regarding the role of miRNAs in response to replanting disease. In this study, two small RNA libraries obtained from first-year (FPR) and second-year plant (SPR) roots were subjected to a high-throughput sequencing method. Bioinformatics analysis revealed that 110 known and 7 novel miRNAs were annotated in the roots of S. miltiorrhiza. Moreover, 39 known and 2 novel miRNAs were identified and validated for differential expression in FPR compared with SPR. Thirty-one of these miRNAs were further analyzed by qRT-PCR, which revealed that 5 miRNAs negatively regulated the expression levels of 7 target genes involved in root development or stress responses. This study not only provides novel insights into the miRNA content of S. miltiorrhiza in response to replanting disease but also demonstrates that 5 miRNAs may be involved in these responses. Interactions among the differentially expressed miRNAs with their targets may form an important component of the molecular basis of replanting disease in S. miltiorrhiza. PMID- 27483015 TI - Internal and Predictive Validity of the French Health of the Nation Outcome Scales: Need for Future Directions. AB - The Health of the Nation Outcome Scales (HoNOS) is a widely used measure of health and social functioning of people with mental illness. The goals of this study were to verify the internal validity of the one factor and several four factor scoring structures and to evaluate the predictive validity of HoNOS items with regards to duration of hospitalization, probability of readmission in the following year and time before readmission. 6175 hospital stays at the department of psychiatry of Lausanne University Hospital were screened and the first HoNOS of each patient was taken into account (N = 2722). Data were analyzed through Confirmatory Factor Analysis (CFA) and the predictive validity of HoNOS items was evaluated with two approaches: item level regressions and latent class analysis (LCA). CFA indicated that the suggested factor structures were not supported by the data. Predictive validity of the 12 items was weak but LCA revealed five distinct and meaningful profiles that were related to length of stay or readmission. HoNOS may be more adapted to the evaluation of patients case-mix rather than to the individual level and concepts such as predictive validity may be more appropriate than internal validity to guide its use. PMID- 27483016 TI - Correction: Osteopathology in Rhinocerotidae from 50 Million Years to the Present. AB - [This corrects the article DOI: 10.1371/journal.pone.0146221.]. PMID- 27483017 TI - Flexible Free-Standing III-Nitride Thin Films for Emitters and Displays. AB - The majority of a GaN light-emitting diode (LED) is released from its sapphire substrate through selective-area laser lift-off to form a freely suspended light emitter. By virtue of being suspended in air without supporting substrates, the ultrathin crystalline and crack-free film possesses flexibility and bendability. The free-standing LEDs benefit from significant relaxation of strain, evident from red-shifting of the E2(high) phonon frequencies as measured by Raman spectroscopy toward those of strain-free free-standing GaN substrates. The phonon frequencies remain invariant upon bending of the film; this indicates that the properties of the flexible device will not be dependent on the bending curvatures. The observation of pronounced spectral blue-shifts from the photoluminescence (PL) spectrum from the flexible regions further confirms the occurrence of strain relaxation in the quantum wells. Being free-standing and thus lacking a direct heat-sinking pathway, emissions from the different regions of the suspended film can be affected by thermal effects to different extents, which are investigated by long-wave infrared thermometry. Heat accumulation is determined to be most severe at the far end of the flexible stripe at higher currents, leading to reduced efficiencies and electroluminescence (EL) spectral red-shifts. Based on this architecture, a monolithic 3 * 4 dot-matrix microdisplay prototype is demonstrated, comprising three adjacent flexible stripe emitters with four individually addressable pixels on each stripe. This proof-of concept demonstration opens up new opportunities for GaN optoelectronics for a wide range of flexible display and visual applications. PMID- 27483018 TI - Activation of Aryl Halides by Nickel(I) Pincer Complexes: Reaction Pathways of Stoichiometric and Catalytic Dehalogenations. AB - Homolytic C-X bond cleavage of organohalides by the T-shaped nickel(I) complexes [LigNi(I)] 1 bearing the iso-PyrrMeBox ligand had been found previously to be the crucial activation step in the asymmetric hydrodehalogenation of geminal dihalides. Here, this mechanistic investigation is extended to aryl halides, which allowed a systematic study of the activation process by a combination of experimental data and density functional theory modeling. While the activation of both aryl chlorides and geminal dichlorides appears to proceed via an analogous transition state, the generation of a highly stabile nickel(II)aryl species in the reaction of the aryl chlorides for the former represents a major difference in the reactive behavior. This difference was found to have a crucial impact on the activity of these nickel pincer systems as catalysts in the dehalogenation of aryl chlorides compared to geminal dichlorides and highlights the importance of the regulatory pathways controlling the nickel(I) concentration throughout the catalysis. These results along with the identification and characterization of novel nickel(II)aryl species are presented. PMID- 27483019 TI - The ammonium sulfate inhibition of human angiogenin. AB - In this study, we investigate the inhibition of human angiogenin by ammonium sulfate. The inhibitory potency of ammonium sulfate for human angiogenin (IC50 = 123.5 +/- 14.9 mm) is comparable to that previously reported for RNase A (119.0 +/- 6.5 mm) and RNase 2 (95.7 +/- 9.3 mm). However, analysis of two X-ray crystal structures of human angiogenin in complex with sulfate anions (in acidic and basic pH environments, respectively) indicates an entirely distinct mechanism of inhibition. While ammonium sulfate inhibits the ribonucleolytic activity of RNase A and RNase 2 by binding to the active site of these enzymes, sulfate anions bind only to peripheral substrate anion-binding subsites of human angiogenin, and not to the active site. PMID- 27483020 TI - Higher 25-Hydroxyvitamin D Levels Are Associated With Lower Proteinuria in Kidney Transplant Recipients. AB - OBJECTIVES: Proteinuria is associated with decreased graft and patient survival after kidney transplantation. Increasing evidence shows that vitamin D has antiproteinuric and renoprotective effects. The aim of our study was to assess the influence of 25-hydroxyvitamin D levels on proteinuria after kidney transplantation. MATERIAL AND METHODS: Between May 1, 2012, and November 30, 2012, we tested 395 kidney transplant recipients for 25-hydroxyvitamin D levels during their regular visits to our transplant center together with routine blood sampling and proteinuria testing. Patients within 12 months of transplant, who had undergone parathyroidectomy, had unstable graft function, had concomitant intake of calcineurin inhibitors and mammalian target of rapamycin inhibitors were not included in the study. Subjects with advanced liver disease, or receiving vitamin D supplementation were also excluded. All laboratory, clinical, and therapeutic factors for proteinuria were taken into consideration. Statistical analyses included descriptive statistics and univariate and multivariate log-log regression with backward selection (SPSS version 22.0; SPSS Inc., Chicago, IL, USA), with significance at P < .05. Determination of total 25 hydroxyvitamin D levels was performed by a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Our study group included 230 patients (148 men, 82 women). Positive association was established between proteinuria and history of diabetes mellitus, rejection episode 12 months within testing for 25 hydroxyvitamin D levels, and use of mammalian target of rapamycin inhibitors (P < .05). Significant negative relations were detected for patient age, graft function, and 25-hydroxyvitamin D concentrations (P < .05). CONCLUSIONS: Our study established that better vitamin D status is associated with lower proteinuria. However, further research is needed to clarify the possible renoprotective properties of vitamin D. PMID- 27483021 TI - 3D Quasi-Static Ultrasound Elastography With Plane Wave In Vivo. AB - In biological tissue, an increase in elasticity is often a marker of abnormalities. Techniques such as quasi-static ultrasound elastography have been developed to assess the strain distribution in soft tissues in two dimensions using a quasi-static compression. However, as abnormalities can exhibit very heterogeneous shapes, a three dimensional approach would be necessary to accurately measure their volume and remove operator dependency. Acquisition of volumes at high rates is also critical to performing real-time imaging with a simple freehand compression. In this study, we developed for the first time a 3D quasi-static ultrasound elastography method with plane waves that estimates axial strain distribution in vivo in entire volumes at high volume rate. Acquisitions were performed with a 2D matrix array probe of 2.5 MHz frequency and 256 elements. Plane waves were emitted at a volume rate of 100 volumes/s during a continuous motorized and freehand compression. 3D B-mode volumes and 3D cumulative axial strain volumes were successfully estimated in inclusion phantoms and in ex vivo canine liver before and after a high intensity focused ultrasound ablation. We also demonstrated the in vivo feasibility of the method using freehand compression on the calf muscle of a human volunteer and were able to retrieve 3D axial strain volume at a high volume rate depicting the differences in stiffness of the two muscles which compose the calf muscle. 3D ultrasound quasi-static elastography with plane waves could become an important technique for the imaging of the elasticity in human bodies in three dimensions using simple freehand scanning. PMID- 27483022 TI - National Hospital Care Survey Demonstration Projects: Traumatic Brain Injury. AB - Purpose-This report demonstrates the analytical potential of the National Hospital Care Survey (NHCS) through a case study of inpatient discharges and ambulatory visits for traumatic brain injury (TBI) based on unweighted data from the 2013 NHCS of inpatient and emergency department (ED) encounters and the 2013 and 2014 NHCS for outpatient department (OPD) encounters. PMID- 27483023 TI - Reversible Adsorption Kinetics of Near Surface Dimer Colloids. AB - We investigate the effect of shape on reversible adsorption kinetics using colloidal polystyrene dimers near a solid glass surface as a model system. The interaction between colloid and wall is tuned using electrostatic, depletion, and gravity forces to produce a double-well potential. The dwell time in each of the potential wells is measured from long duration particle trajectories. The height of each monomer relative to the glass surface is measured to a resolution of <20 nm by in-line holographic microscopy. The measured transition probability distributions are used in kinetic equations to describe the flux of particles to and from the surface. The dimers are compared to independent isolated monomers to determine the effects of shape on adsorption equilibria and kinetics. To elucidate these differences, we consider both mass and surface coverage and two definitions of surface coverage. The results show that dimers with single coverage produce slower adsorption, lower surface coverage, and higher mass coverage in comparison to those of monomers, while dimers with double coverage adsorb faster and result in higher surface coverage. PMID- 27483024 TI - Poly(ester amine) Composed of Polyethylenimine and Pluronic Enhance Delivery of Antisense Oligonucleotides In Vitro and in Dystrophic mdx Mice. AB - A series of poly(esteramine)s (PEAs) constructed from low molecular weight polyethyleneimine (LPEI) and Pluronic were evaluated for the delivery of antisense oligonuclotides (AOs), 2'-O-methyl phosphorothioate RNA (2'-OMePS) and phosphorodiamidate morpholino oligomer (PMO) in cell culture and dystrophic mdx mice. Improved exon-skipping efficiency of both 2'-OMePS and PMO was observed in the C2C12E50 cell line with all PEA polymers compared with PEI 25k or LF-2k. The degree of efficiency was found in the order of PEA 01, PEA 04 > PEA 05 > others. The in vivo study in mdx mice demonstrated enhanced exon-skipping of 2'-OMePS with the order of PEA 06 > PEA 04, PEA 07 > PEA 03 > PEA 01 > others, and much higher than PEI 25k formulated 2'-OMePS. Exon-skipping efficiency of PMO in formulation with the PEAs were significantly enhanced in the order of PEA 02 > PEA 10 > PEA 01, PEA 03 > PEA 05, PEA 07, PEA 08 > others, with PEA 02 reaching fourfold of Endo-porter formulated PMO. PEAs improve PMO delivery more effectively than 2'-OMePS delivery in vivo, and the systemic delivery evaluation further highlight the efficiency of PEA for PMO delivery in all skeletal muscle. The results suggest that the flexibility of PEA polymers could be explored for delivery of different AO chemistries, especially for antisense therapy. PMID- 27483025 TI - Silencing Myostatin Using Cholesterol-conjugated siRNAs Induces Muscle Growth. AB - Short interfering RNAs (siRNAs) are a valuable tool for gene silencing with applications in both target validation and therapeutics. Many advances have recently been made to improve potency and specificity, and reduce toxicity and immunostimulation. However, siRNA delivery to a variety of tissues remains an obstacle for this technology. To date, siRNA delivery to muscle has only been achieved by local administration or by methods with limited potential use in the clinic. We report systemic delivery of a highly chemically modified cholesterol conjugated siRNA targeting muscle-specific gene myostatin (Mstn) to a full range of muscles in mice. Following a single intravenous injection, we observe 85-95% knockdown of Mstn mRNA in skeletal muscle and >65% reduction in circulating Mstn protein sustained for >21 days. This level of Mstn knockdown is also accompanied by a functional effect on skeletal muscle, with animals showing an increase in muscle mass, size, and strength. The cholesterol-conjugated siRNA platform described here could have major implications for treatment of a variety of muscle disorders, including muscular atrophic diseases, muscular dystrophy, and type II diabetes. PMID- 27483026 TI - Systematic Analysis of Long Noncoding RNAs in the Senescence-accelerated Mouse Prone 8 Brain Using RNA Sequencing. AB - Long noncoding RNAs (lncRNAs) may play an important role in Alzheimer's disease (AD) pathogenesis. However, despite considerable research in this area, the comprehensive and systematic understanding of lncRNAs in AD is still limited. The emergence of RNA sequencing provides a predictor and has incomparable advantage compared with other methods, including microarray. In this study, we identified lncRNAs in a 7-month-old mouse brain through deep RNA sequencing using the senescence-accelerated mouse prone 8 (SAMP8) and senescence-accelerated mouse resistant 1 (SAMR1) models. A total of 599,985,802 clean reads and 23,334 lncRNA transcripts were obtained. Then, we identified 97 significantly upregulated and 114 significantly downregulated lncRNA transcripts from all cases in SAMP8 mice relative to SAMR1 mice. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these significantly dysregulated lncRNAs were involved in regulating the development of AD from various angles, such as nerve growth factor term (GO: 1990089), mitogen-activated protein kinase signaling pathway, and AD pathway. Furthermore, the most probable AD-associated lncRNAs were predicted and listed in detail. Our study provided the systematic dissection of lncRNA profiling in SAMP8 mouse brain and accelerated the development of lncRNA biomarkers in AD. These attracting biomarkers could provide significant insights into AD therapy in the future. PMID- 27483027 TI - Arsenic Induced Phytate Exudation, and Promoted FeAsO4 Dissolution and Plant Growth in As-Hyperaccumulator Pteris vittata. AB - Arsenic hyperaccumulator Pteris vittata (PV) is efficient in taking up As and nutrients from As-contaminated soils. We evaluated the mechanisms used by PV to mobilize As and Fe by examining the impacts of As and root exudates on FeAsO4 solubilization, and As and Fe uptake in four plants: As-hyperaccumulators PV and Pteris multifida (PM), nonhyperaccumulator Pteris ensiformis (PE), and angiosperm plant tomato (Solanum lycopersicum). Phytate and oxalate were dominant in fern plants (>93%), which were 50-83, 15-42, and 0-32 mg kg(-1) phytate and 10-15, 7 26, and 4-12 mg kg(-1) oxalate for PV, PM, and PE respectively, with higher As inducing greater phytate exudation and no phytate being detected in tomato exudates. PV treated with phytate+FeAsO4 had higher As and Fe contents and larger biomass than phytate or FeAsO4 treatment, which were 340 vs 20 and 130 mg kg(-1) As in the fronds and 7900 vs 1600 and 4100 mg kg(-1) Fe in the roots. We hypothesized that As-induced phytate exudation helped PV to take up Fe and As from insoluble FeAsO4 and promoted PV growth. Our study suggests that phytate exudation may be special to fern plants, which may play an important role in enhancing As and nutrient uptake by plants, thereby increasing their efficiency in phytoremediation of As-contaminated soils. PMID- 27483028 TI - Non-covalent functionalization of WS2 monolayer with small fullerenes: tuning electronic properties and photoactivity. AB - Atomically thin two-dimensional transition metal dichalcogenides (TMDCs) heterostructures have recently attracted growing interest due to their massive potential in solar energy applications due to their band gap in the visible spectral range and extremely strong light-matter interactions. Herein, heterostructures composed of WS2 and MoS2 monolayers, as representative TMDCs, with small fullerenes (B12 and C20) are investigated to explore their applications in solar energy conversion using first principles calculations based on density functional theory (DFT). The WS2 (MoS2) monolayer and fullerene form a van der Waals (vdW) heterostructure. Compared to pure monolayers, the heterostructures have a smaller band gap, which favours enhancing visible light absorption. The amount of charge transfer at the interface induced by vdW interactions depends on the type of fullerene. Most importantly, a type-II staggered band alignment is formed between WS2 (MoS2) and fullerene with the latter possessing the higher electron affinity which results in the robust separation of photoexcited charge carriers between them. These results indicate that the electronic properties and photoactivity of TMDCs monolayers can be tuned by non-covalent coupling with small fullerenes, thus meeting the needs of various applications. PMID- 27483031 TI - Thermochemical Properties and Bond Dissociation Energies for Fluorinated Methanol, CH3-xFxOH, and Fluorinated Methyl Hydroperoxides, CH3-xFxOOH: Group Additivity. AB - Oxygenated fluorocarbons are routinely found in sampling of environmental soils and waters as a result of the widespread use of fluoro and chlorofluoro carbons as heat transfer fluids, inert materials, polymers, fire retardants and solvents; the influence of these chemicals on the environment is a growing concern. The thermochemical properties of these species are needed for understanding their stability and reactions in the environment and in thermal process. Structures and thermochemical properties on the mono- to trifluoromethanol, CH3-xFxOH, and fluoromethyl hydroperoxide, CH3-xFxOOH (1 <= x <= 3), are determined by CBS-QB3, CBS-APNO, and G4 calculations. Entropy, S degrees 298, and heat capacities, Cp(T)'s (300 <= T/K <= 1500) from vibration, translation, and external rotation contributions are calculated on the basis of the vibration frequencies and structures obtained from the B3LYP/6-31+G(d,p) density functional method. Potential barriers for the internal rotations are also calculated from this method and used to calculate hindered rotor contributions to S degrees 298 and Cp(T)'s using direct integration over energy levels of the internal rotational potentials. Standard enthalpies of formation, DeltafH degrees 298 (units in kcal mol(-1)) are CH2FOOH (-83.7), CHF2OOH (-138.1), CF3OOH (-193.6), CH2FOO(*) ( 44.9), CHF2OO(*) (-99.6), CF3OO(*) (-153.8), CH2FOH (-101.9), CHF2OH (-161.6), CF3OH (-218.1), CH2FO(*) (-49.1), CHF2O(*) (-97.8), CF3O(*) (-150.5), CH2F(*) ( 7.6), CHF2(*) (-58.8), and CF3(*) (-112.6). Bond dissociation energies for the R OOH, RO-OH, ROO-H, R-OO(*), RO-O(*), R-OH, RO-H, R-O(*), and R-H bonds are determined and compared with methyl hydroperoxide to observe the trends from added fluoro substitutions. Enthalpy of formation for the fluoro-hydrocarbon oxygen groups C/F/H2/O, C/F2/H/O, C/F3/O, are derived from the above fluorinated methanol and fluorinated hydroperoxide species for use in Benson's Group Additivity. It was determined that fluorinated peroxides require interaction terms O/CH2F/O, O/CHF2/O, and O/CF3/O, as opposed to the common (O/C/O) group in hydrocarbons, resulting from interactions of the peroxide oxygen with the fluorines. Hydrogen bond dissociation increment (HBI) groups are also developed. PMID- 27483029 TI - Interaction of Individual Structural Domains of hnRNP LL with the BCL2 Promoter i Motif DNA. AB - The recently discovered role of the BCL2 (B-cell lymphoma 2 gene) promoter i motif DNA in modulation of gene expression via interaction with the ribonucleoprotein hnRNP L-like (hnRNP LL) has prompted a more detailed study of the nature of this protein-DNA interaction. The RNA recognition motifs (RRMs) of hnRNP LL were expressed individually, and both RRM1 and RRM2 were found to bind efficiently to the BCL2 i-motif DNA, as well as being critical for transcriptional activation, whereas RRM3-4 bound only weakly to this DNA. Binding was followed by unfolding of the DNA as monitored by changes in the CD spectrum. Mutational analysis of the i-motif DNA revealed that binding involved primarily the lateral loops of the i-motif. The kinetics of binding of the DNA with RRM1 was explored by recording CD spectra at predetermined times following admixture of the protein and DNA. The change in molar ellipticity was readily apparent after 30 s and largely complete within 1 min. A more detailed view of protein-DNA interaction was obtained by introducing the fluorescence donor 6-CNTrp in RRM1 at position 137, and the acceptor 4-aminobenzo[g]quinazoline-2-one (Cf) in lieu of cytidine22 in the i-motif DNA. The course of binding of the two species was monitored by FRET, which reflected a steady increase in energy transfer over a period of several minutes. The FRET signal could be diminished by the further addition of (unlabeled) RRM2, no doubt reflecting competition for binding to the i-motif DNA. These experiments using the individual RRM domains from hnRNP LL confirm the role of this transcription factor in activation of BCL2 transcription via the i-motif in the promoter element. PMID- 27483032 TI - Rapid Voltammetric Measurements at Conducting Polymer Microelectrodes Using Ultralow-Capacitance Poly(3,4-ethylenedioxythiophene):Tosylate. AB - We use a vapor-phase synthesis to generate conducting polymer films with low apparent capacitance and high conductance enabling rapid electrochemical measurements. Specifically, oxidative chemical vapor deposition was used to create thin films of poly(3,4-ethylenedioxythiophene):tosylate ( PEDOT: tosylate). These films had a conductance of 17.1 +/- 1.7 S/cm. Furthermore, they had an apparent capacitance of 197 +/- 14 MUF/cm(2), which is an order of magnitude lower than current commercially available and previously reported PEDOT. Using a multistage photolithography process, these films were patterned into PEDOT: tosylate microelectrodes and were used to perform fast-scan cyclic voltammetry (FSCV) measurements. Using a scan rate of 100 V/s, we measured ferrocene carboxylic acid and dopamine by FSCV. In contrast to carbon-fiber microelectrodes, the reduction peak showed higher sensitivity when compared to the oxidation peak. The adsorption characteristics of dopamine at the polymer electrode were fit to a Langmuir isotherm. The low apparent capacitance and the microlithographic processes for electrode design make PEDOT: tosylate an attractive material for future applications as an implantable biosensor for FSCV measurements. Additionally, the integration of PEDOT: tosylate electrodes on plastic substrates enables new electrochemical measurements at this polymer using FSCV. PMID- 27483033 TI - Repetitive Dosing of Fumed Silica Leads to Profibrogenic Effects through Unique Structure-Activity Relationships and Biopersistence in the Lung. AB - Contrary to the notion that the use of fumed silica in consumer products can "generally (be) regarded as safe" (GRAS), the high surface reactivity of pyrogenic silica differs from other forms of synthetic amorphous silica (SAS), including the capacity to induce membrane damage and acute proinflammatory changes in the murine lung. In addition, the chain-like structure and reactive surface silanols also allow fumed silica to activate the NLRP3 inflammasome, leading to IL-1beta production. This pathway is known to be associated with subchronic inflammation and profibrogenic effects in the lung by alpha-quartz and carbon nanotubes. However, different from the latter materials, bolus dose instillation of 21 mg/kg fumed silica did not induce sustained IL-1beta production or subchronic pulmonary effects. In contrast, the NLRP3 inflammasome pathway was continuously activated by repetitive-dose administration of 3 * 7 mg/kg fumed silica, 1 week apart. We also found that while single-dose exposure failed to induce profibrotic effects in the lung, repetitive dosing can trigger increased collagen production, even at 3 * 3 mg/kg. The change between bolus and repetitive dosing was due to a change in lung clearance, with recurrent dosing leading to fumed silica biopersistence, sustained macrophage recruitment, and activation of the NLRP3 pathway. These subchronic proinflammatory effects disappeared when less surface-reactive titanium-doped fumed silica was used for recurrent administration. All considered, these data indicate that while fumed silica may be regarded as safe for some applications, we should reconsider the GRAS label during repetitive or chronic inhalation exposure conditions. PMID- 27483034 TI - Hyperpolarization of Frozen Hydrocarbon Gases by Dynamic Nuclear Polarization at 1.2 K. AB - We report a simple and general method for the hyperpolarization of condensed gases by dynamic nuclear polarization (DNP). The gases are adsorbed in the pores of structured mesoporous silica matrices known as HYPSOs (HYper Polarizing SOlids) that have paramagnetic polarizing agents covalently bound to the surface of the mesopores. DNP is performed at low temperatures and moderate magnetic fields (T = 1.2 K and B0 = 6.7 T). Frequency-modulated microwave irradiation is applied close to the electron spin resonance frequency (f = 188.3 GHz), and the electron spin polarization of the polarizing agents of HYPSO is transferred to the nuclear spins of the frozen gas. A proton polarization as high as P((1)H) = 70% can be obtained, which can be subsequently transferred to (13)C in natural abundance by cross-polarization, yielding up to P((13)C) = 27% for ethylene. PMID- 27483036 TI - Synthesis, Structure and Catalytic Activity of NHC-Ag(I) Carboxylate Complexes. AB - A general synthetic route was used to prepare 15 new N-heterocyclic carbene (NHC) Ag(I) complexes bearing anionic carboxylate ligands [Ag(NHC)(O2 CR)], including a homologous series of complexes of sterically flexible ITent ligands, which permit a systematic spectroscopic and theoretical study of the structural and electronic features of these compounds. The complexes displayed a significant ligand accelerated effect in the intramolecular cyclisation of propargylic amides to oxazolidines. The substrate scope is highly complementary to that previously achieved by NHC-Au and pyridyl-Ag(I) complexes. PMID- 27483035 TI - Genomic landscape of early ecological speciation initiated by selection on nuptial colour. AB - Ecological speciation is the evolution of reproductive isolation as a consequence of direct divergent natural selection or ecologically mediated divergent sexual selection. While the genomic signature of the former has been extensively studied in recent years, only few examples exist for genomic differentiation where environment-dependent sexual selection has played an important role. Here, we describe a very young (~90 years old) population of threespine sticklebacks exhibiting phenotypic and genomic differentiation between two habitats within the same pond. We show that differentiation among habitats is limited to male throat colour and nest type, traits known to be subject to sexual selection. Divergence in these traits mirrors divergence in much older benthic and limnetic stickleback species pairs from North American west coast lakes, which also occur in sympatry but are strongly reproductively isolated from each other. We demonstrate that in our population, differences in throat colour and breeding have been stable over a decade, but in contrast to North American benthic and limnetic stickleback species, these mating trait differences are not accompanied by divergence in morphology related to feeding, predator defence or swimming performance. Using genomewide SNP data, we find multiple genomic islands with moderate differentiation spread across several chromosomes, whereas the rest of the genome is undifferentiated. The islands contain potential candidate genes involved in visual perception of colour. Our results suggest that phenotypic and multichromosome genomic divergence of these morphs was driven by environment dependent sexual selection, demonstrating incipient speciation after only a few decades of divergence in sympatry. PMID- 27483037 TI - Nonsuicidal Self-Injury in Adolescents: Characterization of the Disorder and the Issue of Distress and Impairment. AB - Nonsuicidal self-injury disorder (NSSID) is a condition in need of further study to assess the validity of the potential diagnosis and its suggested criteria. This study examined the NSSID diagnosis and investigated the distress/impairment criterion by comparing community adolescents who met all criteria for NSSID (n = 186) to adolescents with five or more nonsuicidal self-injury (NSSI) episodes (n = 314), and to a group of adolescents who met all criteria but negated that their NSSI caused them any distress or impairment, thus failing to meet criterion E (n = 29). The NSSID group delimited from the >= 5 NSSI group by reporting significantly more frequent and severe self-injurious thoughts and behaviors, as well as having more experiences of negative life events and higher levels of trauma symptoms. There were also some differences between the NSSID group and adolescents without distress/impairment, which together contribute valuable information on the potential NSSID diagnosis, as well as the discussion of criterion E. PMID- 27483039 TI - Understanding women's experience of memory over the menopausal transition: subjective and objective memory in pre-, peri-, and postmenopausal women. AB - OBJECTIVE: Many women complain of forgetfulness during the menopausal transition. This study aimed to examine women's subjective perception of memory and their objective memory performance across the menopausal transition. METHODS: One hundred thirty women, aged 40 to 60 years were recruited from outpatient Menopause and Gynaecological clinics at the Royal Women's Hospital, Melbourne. Women were divided into menopausal stage groups according to the Stages of Reproductive Aging Workshop criteria based on menstrual patterns. All women completed self-report measures of depressive, anxiety, vasomotor, and sleep symptoms; attitude to menopause; and various aspects of memory, including memory contentment, frequency of forgetting, sense of control over memory, and use of memory strategies. Women also completed a comprehensive neuropsychological evaluation assessing memory and executive function. RESULTS: Comprehensive neuropsychological assessment showed no difference between premenopausal (n = 36), perimenopausal (n = 54), and postmenopausal (n = 40) groups in performance on memory and executive tasks. Perimenopausal women, however, reported significantly more frequent forgetting (eta = 0.09, P < 0.01) and less contentment with their memory (eta = 0.08, P < 0.01) than pre- and postmenopausal women. CONCLUSIONS: Although no impairment was observed in neuropsychological performance, when compared with pre- and postmenopausal women, perimenopausal women were more likely to be dissatisfied with their memory. During the menopausal transition women with a more negative attitude to menopause and more intense depressive, anxiety, vasomotor, and sleep symptoms are more vulnerable to feeling less content with their memory. PMID- 27483038 TI - Calcium plus vitamin D supplementation and height loss: findings from the Women's Health Initiative Calcium and Vitamin D clinical trial. AB - OBJECTIVE: The aim of this study was to determine the associations between calcium + vitamin D supplementation (vs placebo) and height loss in 36,282 participants of the Women's Health Initiative Calcium and Vitamin D trial. METHODS: Post hoc analysis of data from a double-blind randomized controlled trial of 1,000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily (CaD) or placebo in postmenopausal women at 40 US clinical centers. Height was measured annually (mean follow-up 5.9 y) with a stadiometer. RESULTS: Average height loss was 1.28 mm/y among participants assigned to CaD versus 1.26 mm/y for women assigned to placebo (P = 0.35). Effect modification of the CaD intervention was not observed by age, race/ethnicity, or baseline intake of calcium or vitamin D. Randomization to the CaD group did not reduce the risk of clinical height loss (loss of >=1.5 inches [3.8 cm]: hazard ratio (95% CI) = 1.00 (0.81, 1.23). A strong association (P < 0.001) was observed between age group and height loss. When we censored follow-up data in participants who became nonadherent to study pills, the results were similar to those of our primary analysis. CONCLUSIONS: Compared with placebo, the CaD supplement used in this trial did not prevent height loss in healthy postmenopausal women. PMID- 27483040 TI - Associations between dietary patterns and psychological factors: a cross sectional study among Chinese postmenopausal women. AB - OBJECTIVE: The aim of this study is to explore the association of dietary patterns with depression, perceived stress, and self-esteem among postmenopausal Chinese women. METHODS: A cross-sectional study was conducted among 906 participants who attended the screening visits for two soy trials. Dietary data were collected using a validated food frequency questionnaire containing 85 food items. Principal component factor analysis was used to derive dietary patterns based on 11 food groups. Psychological factors were assessed by the Center for Epidemiologic Studies Depression Scale, Perceived Stress Scale, and Rosenberg Self-esteem Scale. RESULTS: We identified three dietary patterns as follows: processed foods (refined grains, preserved foods, fat meat, fried foods, and sweets), whole plant foods (whole grains, vegetables, and fruits), and animal foods (fish, lean meat, and milk products). Multivariable linear regression analyses indicated that whole plant food intake was negatively associated with depression score (P = 0.030). Processed food intake was positively associated with perceived stress (P = 0.025) and depression (P = 0.073), and negatively associated with scores of self-esteem (P = 0.046). The highest tertile of processed foods score was associated with 79.3% increased risk of depression (P for trend = 0.006), whereas the highest tertile of whole plant food score was associated with 26% reduction of depression (P for trend = 0.023) relative to the lowest tertile. CONCLUSIONS: Dietary patterns featuring a low intake of processed foods and/or a high intake of whole plant foods were associated with a reduced risk of depression and perceived stress. PMID- 27483041 TI - A Mesoionic Carbene as Neutral Ligand for Phosphorescent Cationic Ir(III) Complexes. AB - Two phosphorescent Ir(III) complexes bearing a mesoionic carbene ligand based on 1,2,3-triazolylidene are obtained for the first time. A silver-iridium transmetalation of the in situ-generated mesoionic carbene affords the cationic dichloro complex [Ir(trizpy)2Cl2](+) (3, trizpy = 1-benzyl-3-methyl-4-(pyridin-2 yl)-1H-1,2,3-triazolylidene) that reacts with a bis-tetrazolate (b-trz) dianionic ligand to give [Ir(trizpy)2(b-trz)](+) (5). The new compounds are fully characterized by NMR spectroscopy and mass spectrometry, and the X-ray structure of 3 is determined. The electrochemical behavior is somewhat different compared to most standard cationic iridium complexes. The first oxidation process is shifted to substantially higher potential in both 3 and 5, due to peculiar and different ligand-induced effects in the two cases, which stabilize the highest occupied molecular orbital; reduction processes are centered on the mesoionic carbene ligands. Both compounds exhibit a mostly ligand-centered luminescence band in the blue-green spectral region, substantially stronger in the case of 5 versus 3, both in CH3CN solution and in poly(methyl methacrylate) matrix at room temperature. Optimized geometries, orbital energies, spin densities, and electronic transitions are determined via density functional theory calculations, which support a full rationalization of the electrochemical and photophysical behavior. This work paves the way for the development of Ir-based emitters with neutral mesoionic carbene ligands and anionic ancillary ligands, a new concept in the area of cationic Ir(III) complexes. PMID- 27483043 TI - Organocatalytic Enantioselective Cross-Dehydrogenative Coupling of N-Carbamoyl Cyclic Amines with Aldehydes. AB - The existing catalytic enantioselective cross-dehydrogenative coupling of cyclic amines predominantly focused on reactive N-aryl tetrahydroisoquinolines, which typically suffered from limited substrate generality and synthetic utility, and required the use of metal catalyst. Herein, a metal-free catalytic enantioselective cross-dehydrogenative coupling of N-carbamoyl cyclic amines and aldehydes has been reported for the first time. Employing an easily installed and functionalized acyl protecting group rather than the widely adopted aryl moiety endows the enantioselective process with better substrate generality and broader synthetic utility. PMID- 27483042 TI - Advanced oxidation protein products induce apoptosis of human chondrocyte through reactive oxygen species-mediated mitochondrial dysfunction and endoplasmic reticulum stress pathways. AB - Advanced oxidation production products (AOPPs) have been confirmed to accumulate in patients with rheumatoid arthritis (RA). Previous study demonstrated that AOPPs could accelerate cartilage destruction in rabbit arthritis model. However, the effect of AOPP stimulation on apoptosis of human chondrocyte and the underlying mechanisms remains unclear. This study demonstrated that exposure of chondrocyte to AOPPs resulted in cell apoptosis. AOPP stimulation triggered reactive oxygen species (ROS) production, which induced mitochondrial dysfunction and endoplasmic reticulum stress (ER stress) resulted in caspase activation. Furthermore, an antioxidant, N-acetylcysteine, markedly blocked these signals. Our study demonstrated that AOPPs induce apoptosis via ROS-related mitochondria- and ER-dependent signals in human chondrocyte. Targeting AOPP-triggered ROS generation might be as a promising option for patients with RA. PMID- 27483044 TI - Use of a 2-tier histologic grading system for canine cutaneous mast cell tumors on cytology specimens. AB - BACKGROUND: Mast cell tumors (MCT) represent the most common malignant skin tumor in the dog. Diagnosis of an MCT can be achieved through cytologic examination of a fine-needle aspirate. However, the grade of the tumor is an important prognostic marker and currently requires histologic assessment. Recently a 2-tier histologic grading system based on nuclear features including number of mitoses, multinucleated cells, bizarre nuclei, and karyomegaly was proposed. OBJECTIVES: The aim of this study was to assess if the cytomorphologic criteria proposed in the 2-tier histologic grading system are applicable to cytology specimens. METHODS: A total of 141 MCT specimens reported as grade I, II, or III according to the Patnaik system with both histologic specimens and fine-needle aspirates available were histologically and cytologically reevaluated in a retrospective study. RESULTS: According to the 2-tier grading system, 38 cases were diagnosed histologically as high-grade and 103 as low-grade MCT. Cytologic grading resulted in 36 high-grade and 105 low-grade tumors. Agreement between histologic and cytologic grading based on the 2-tier grading system was achieved in 133 cases (sensitivity 86.8%, specificity 97.1%, kappa value 0.853), but 5 high-grade tumors on histology were classified as low-grade on cytology. CONCLUSION: Cytologic grading of MCT in the dog is helpful for initial assessment. However, the reliability of cytology using the 2-tier grading system is considered inadequate at this point. Prospective studies including clinical outcome should be pursued to further determine diagnostic accuracy of cytologic mast cell grading. PMID- 27483045 TI - High-Resolution Magnetic Resonance Imaging of Scalp Arteries for the Diagnosis of Giant Cell Arteritis: Results of a Prospective Cohort Study. AB - OBJECTIVE: To examine the concordance between high-resolution magnetic resonance imaging (MRI) of the scalp arteries and temporal artery biopsy for the diagnosis of giant cell arteritis (GCA). METHODS: We conducted a prospective cohort study of patients with suspected GCA. Participants underwent high-field 3T MRI of the scalp arteries followed by temporal artery biopsy. Arterial wall thickness and enhancement on multiplanar postcontrast T1-weighted spin-echo images were graded according to a published severity scale (range 0-3). MRI findings were compared with temporal artery biopsy results and the American College of Rheumatology (ACR) criteria for GCA. RESULTS: One hundred seventy-one patients were included in the study. Temporal artery biopsy findings were positive in 31 patients (18.1%), and MRI findings were abnormal in 60 patients (35.1%). ACR criteria were met in 137 patients (80.1%). With temporal artery biopsy as the reference test, MRI had a sensitivity of 93.6% (95% confidence interval [95% CI] 78.6-99.2) and a specificity of 77.9% (95% CI 70.1-84.4). The corresponding negative predictive value of MRI was 98.2% (95% CI 93.6-99.8) and positive predictive value was 48.3% (95% CI 35.2-61.6). CONCLUSION: In patients with suspected GCA, normal findings on scalp artery MRI are very strongly associated with negative temporal artery biopsy findings. This suggests that MRI could be used as the initial diagnostic procedure in GCA, with temporal artery biopsy being reserved for patients with abnormal MRI findings. PMID- 27483046 TI - Impact of 60-GHz millimeter waves on stress and pain-related protein expression in differentiating neuron-like cells. AB - Millimeter waves (MMW) will be increasingly used for future wireless telecommunications. Previous studies on skin keratinocytes showed that MMW could impact the mRNA expression of Transient Receptor Potential cation channel subfamily Vanilloid, member 2 (TRPV2). Here, we investigated the effect of MMW exposure on this marker, as well as on other membrane receptors such as Transient Receptor Potential cation channel subfamily Vanilloid, member 1 (TRPV1) and purinergic receptor P2X, ligand-gated ion channel, 3 (P2 * 3). We exposed the Neuroscreen-1 cell line (a PC12 subclone), in order to evaluate if acute MMW exposures could impact expression of these membrane receptors at the protein level. Proteotoxic stress-related chaperone protein Heat Shock Protein 70 (HSP70) expression level was also assessed. We used an original high-content screening approach, based on fluorescence microscopy, to allow cell-by-cell analysis and to detect any cell sub-population responding to exposure. Immunocytochemistry was done after 24 h MMW exposure of cells at 60.4 GHz, with an incident power density of 10 mW/cm(2) . Our results showed no impact of MMW exposure on protein expressions of HSP70, TRPV1, TRPV2, and P2 * 3. Moreover, no specific cell sub populations were found to express one of the studied markers at a different level, compared to the rest of the cell populations. However, a slight insignificant increase in HSP70 expression and an increase in protein expression variability within cell population were observed in exposed cells, but controls showed that this was related to thermal effect. Bioelectromagnetics. 37:444-454, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27483047 TI - Population genomic evidence for multiple Pliocene refugia in a montane-restricted harvestman (Arachnida, Opiliones, Sclerobunus robustus) from the southwestern United States. AB - The integration of ecological niche modelling into phylogeographic analyses has allowed for the identification and testing of potential refugia under a hypothesis-based framework, where the expected patterns of higher genetic diversity in refugial populations and evidence of range expansion of nonrefugial populations are corroborated with empirical data. In this study, we focus on a montane-restricted cryophilic harvestman, Sclerobunus robustus, distributed throughout the heterogeneous Southern Rocky Mountains and Intermontane Plateau of southwestern North America. We identified hypothetical refugia using ecological niche models (ENMs) across three time periods, corroborated these refugia with population genetic methods using double-digest RAD-seq data and conducted population-level phylogenetic and divergence dating analyses. ENMs identify two large temporally persistent regions in the mid-latitude highlands. Genetic patterns support these two hypothesized refugia with higher genetic diversity within refugial populations and evidence for range expansion in populations found outside hypothesized refugia. Phylogenetic analyses identify five to six genetically divergent, geographically cohesive clades of S. robustus. Divergence dating analyses suggest that these separate refugia date to the Pliocene and that divergence between clades pre-dates the late Pleistocene glacial cycles, while diversification within clades was likely driven by these cycles. Population genetic analyses reveal effects of both isolation by distance (IBD) and isolation by environment (IBE), with IBD more important in the continuous mountainous portion of the distribution, while IBE was stronger in the populations inhabiting the isolated sky islands of the south. Using model-based coalescent approaches, we find support for postdivergence migration between clades from separate refugia. PMID- 27483048 TI - Female Sex Hormones Influence the Febrile Response Induced by Lipopolysaccharide, Cytokines and Prostaglandins but not by Interleukin-1beta in Rats. AB - There are differences in the immune response, and particularly fever, between males and females. In the present study, we investigated how the febrile responses induced by lipopolysaccharide (LPS) and different endogenous pyrogens were affected by female gonadal hormones. The febrile response to i.p. injection of LPS (50 MUg/kg) was 40% lower in female rats compared to male or ovariectomised (OVX) female rats. Accordingly, oestrogen replacement in OVX animals reduced LPS-induced fever. Treatment with the prostaglandin synthesis inhibitor indomethacin (2 mg/kg, i.p. 30 min before) reduced the febrile response induced by LPS in both OVX (88%) and sham-operated (71%) rats. In line with the enhanced fever in OVX rats, there was increased expression of cyclooxygenase-2 (COX-2) in the hypothalamus and elevated levels of prostaglandin E2 (PGE2 ). In addition, OVX rats were hyper-responsive to PGE2 injected i.c.v. By contrast to the enhanced fever in response to LPS and PGE2 , the febrile response induced by i.c.v. injection of interleukin (IL)-1beta was unaffected by ovariectomy, whereas the responses induced by tumour necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-1alpha were completely abrogated. These results suggest that the mediators involved in the febrile response in females are similar to males, although the reduction of female hormones may decrease the responsiveness of some mediators such as TNF-alpha and MIP-1alpha. Compensatory mechanisms may be activated in females after ovariectomy such as an augmented synthesis of COX-2 and PGE2 . PMID- 27483049 TI - Esters, Including Triglycerides, and Hydrogen as Feedstocks for the Ruthenium Catalyzed Direct N-Alkylation of Amines. AB - Triglycerides are used for the direct N-alkylation of amines with molecular hydrogen for the first time. A broad range of interesting and industrially relevant secondary and tertiary amines are obtained in the presence of an in situ formed Ru/Triphos complex. Notably, plant oil can be efficiently applied in this single-step process. Moreover, a variety of other methyl esters can be used as N alkylation agents in the presence of hydrogen for the synthesis of more advanced building blocks. PMID- 27483050 TI - Enhanced Photocatalytic Performance of ZnO Nanorods Coupled by Two-Dimensional alpha-MoO3 Nanoflakes under UV and Visible Light Irradiation. AB - We exploit the utilization of two-dimensional (2D) molybdenum oxide nanoflakes as a co-catalyst for ZnO nanorods (NRs) to enhance their photocatalytic performance. The 2D nanoflakes of orthorhombic alpha-MoO3 were synthesized through a sonication-aided exfoliation technique. The 2D MoO3 nanoflakes can be further converted to substoichiometric quasi-metallic MoO3-x by using UV irradiation. Subsequently, 1D-2D MoO3 /ZnO NR and MoO3-x /ZnO NR composite photocatalysts have been successfully synthesized. The photocatalytic performances of the novel nanosystems in the decomposition of methylene blue are studied by using UV- and visible-illumination setup. The incorporated 2D nanoflakes show a positive influence on the photocatalytic activity of the ZnO. The obtained rate constant values follow the order of pristine ZnO NR